diff --git a/README.md b/README.md index cc53d57..a71c22f 100644 --- a/README.md +++ b/README.md @@ -1,236 +1,174 @@ ---- -geometry: margin=2.5cm ---- -# Transformer Natural Language Processing (NLP) | Functional Genomics +# Functional Genomics NLP ## Overview -Data and python code to train transformer based models for natural language processing, in particular named entity recognition (NER) and entity linking (EL) for functional genomics papers. +Data and python code to train transformer based models for named entity recognition and entity linking for functional genomics papers. `main.py` and other tools should have help pages, supply `-h` as a command line option to see these (e.g. `python foo.py -h`) -## Usage +## General Usage -To use the code to retrain models on updated datasets, follow the guidance in quick usage. -Other sections have details about specific operations. -Don't forget to check the help pages for main.py and any of the programs in the tools folder. +### Scripts -### Important Notes +The shell scripts provided give shortcut commands to using the codebase as well as examples of usage, they should be executed from the top level folder. +They assume you have a properly configured virtual environment at ~/user_venv, if you dont, run `create_venv.sh`. +`retrain_new_data.sh` and its child scripts `regen_fgen_data.sh`, `analyse_fgen_data.sh`, `current_best_l.sh`, provide an example pipeline of data processing, analysis, and model training. +`analyse_fgen_data.sh` requires pandoc to be installed. +Scripts ending in `_l`, e.g. `current_best_l.sh`, will redirect stdout and stderr to `outputs/log.txt` unbuffered for ease of background execution and monitering. +Once trained, data about the models and their training are typically stored in `outputs/outputs_db.json`. -Commands given assume you are using python 3, if you have python 2 and 3 installed run all python programs using 'python3' not 'python'. -Scripts use 'python3' for compatability. -Shell scripts assume you have a properly configured virtual environment at ~/user_venv. -If you dont, run **sh create_venv.sh**. +### Data Preparation -### Quick usage +There are various programs in the tools folder that allow you to create and manipulate json databases for the model. +See their help pages for more specific information. -* To re-run the best models on new available V2 data (and also analyse it) run **sh retrain_new_data.sh**. -It may take a while for models to train, use ctrl+z to suspend the process and then use command 'bg' to let the models train in the background. -* Note - converting the rough analysis markdown files to pdfs is done with pandoc so without it this step will fail -* The shell script will log model training to **outputs/log.txt** unbuffered so you can check this file periodically to see progress. -* Once trained, data about the models and their training are stored in **outputs/outputs_db.json**. -* Make a copy of the templates **link_full_analysis.json** and **tagging_full_analysis.json** that are found in the **configs/templates** folder. -* Take the names of the models found in **outputs/outputs_db.json** and put them in list keyed by "MODELS". -* Put the linking ones in the link copy and the tagging ones in the tag copy. -Optionally, change the save folders / output paths in the configs to avoid overwritting. -* Run the config files with **python3 main.py config_path1 config_path2**. -The config paths should point to the configs you made when you copied the templates. -* Use your markdown viewer / image viewer of choice to review the graphs and files generated. -Default folder for these is **model_analysis**. +### Data Format -### Preparing Data +Example data for the models to be trained on is given in `json_data/v2_marked_and_linked.json` and similar files. +It consists of a dictionary keyed by abstract names. +The values in the dictionary are lists of all word datums in that abstract. +Words are defined as a contiguous block of non-whitespace characters. +Each word datum has at least the following fields: -There are various programs in the tools folder that allow you to create and manipulate json databases for the model. -Tools can be used manually, however 2 shell scripts are given to automate this for the functional genomics task. -**regen_fgen_data.sh** will create a number of json databases from the given folders in raw_data, including test and train databases for the NER task. -**analyse_fgen_data.sh** will run rough_analyser on these databases and then create pdfs detailing statistics of the data. -For manual use, run 'python tools/some_program.py -h' for more information on that particular program. +* `WORD`: The characters of that word. +* `TOKENS`: The tokens resulting from that word from the given tokenizer, each to be fed into the transformer based model. +* `SENTENCE`: Which (0-indexed) sentence in the abstract this word occours in. +* `POS`: Which (0-indexed) character in the abstract this word starts at. + +It then additionally has fields for each tag category. +These fields contain lists of tag data for tags belonging to that category. +Each tag datum has at least the following fields: + +* `id`: The id of the tag this datum belongs to, as tags can spread across many contiguous words +* `link_ids`: A list of link id's. +Tag datums which share link ids are considered to be linked. +* `schema`: Beggining/Inner/End/Singular (BIES) schema indicator. +This indicates where this word sits in the tagged span of words with this tag. +Models can be trained using simpler schemas, such as BIO, which can be easily derived from this. + +Addtionally each tag datum then has another key-value entry where the key is the tag sub-category (often the same as the tag category), and the value is the label of the tag. ### Running Models Models are run using main.py. -To run a model create a config file (see below) and then pass the path to this file as an argument to main.py. E.g. 'python main.py my_config'. -You can also give it multiple configs and folders of configs, see main.py -h for more information. -Various shell scripts are given that will run files in the respective folders in configs/. +To run a model create a config file (see below) and then pass this files path as an argument to main.py. E.g. `python3 main.py my_config.json`. +You can also give it multiple configs and folders of configs, see `main.py`'s help page for more information, or scripts for example usage. -### Analysing runs +### Analysing Training Run Metrics -See quick usage, more will be added here later. +This has not been automated yet, an example workflow is given instead: +* Make a copy of the templates `link_full_analysis.json` and `tagging_full_analysis.json` that are found in the `configs/templates` folder. +* Take the names of the models found in `outputs/outputs_db.json` and put them in list keyed by `MODELS`. +* Put the linking ones in the link copy and the tagging ones in the tag copy. +Optionally, change the save folders / output paths in the configs to avoid overwritting. +* Run the config files with `python3 main.py config_path1 config_path2`. +The config paths should point to the configs made when copying the templates. +* Open markdown/image viewer of choice to review the graphs and files generated. +Default folder for these is `model_analysis`. -### Trouble shooting -* If you get errors relating to packages, make sure you are in a properly configured virtual environment or if runnning things manually that you have the correct packages installed -* The data agreement tool still has hardcoded tag categories (currently setup for v2) so make sure to alter them (or generalise like the other programs) if the tag scheme changes +### Troubleshooting + +* For errors relating to packages, make sure virtual environment is properly configured or correct packages are installed. +* The data agreement tool still has hardcoded tag categories (currently setup for v2) so make sure to alter them (or generalise like the other programs) for different tag schemes. ## Other information ### Head names -For tagging, head names must be the name of a field that is also given in the tag categories file given in the configuration file. +For tagging, head names must be the name of a field that is also given in the tag categories file. +This file is used in the `MODEL` -> `TAG_CATEGORY_DEFINITIONS` field, and the `-c` option of `tools/rough_analyser.py`. +For examples see `tag_categories.json` and `tag_categories_v2.json`. For linking there are several possible head names, each with different effects. -See src/dataloading.py for the code. -Apologies if this is confusing, only the first two given (link_only and link_same_tag_only) are probably relevant and useful. -The rest are for interest only. -link_only will use and try and predict links as they are given by the MAE software. +See `src/dataloading.py` for the code. +`link_only` is the most relevant and useful, others are mainly provided for interest. + +* `link_only` will use and try and predict links as they are given by the MAE software. Essentially it tries to predict if 2 tokens have the same link id. -link_same_tag_only will try and predict if 2 tokens are part of the same tag. +* `link_same_tag_only` will try and predict if 2 tokens are part of the same tag. This is only useful when a schema (e.g. BIO) is not being used. -link_all will do both of the above and will not distinguish between the two types of linking. -link_same_tag_and_link will combine the first 2 like link_all but will instead have 2 different labels for the two different types of link. -This is directly equivalent to a transformer with link_only and link_same_tag_only heads, though it combines things when reporting f1 scores which may not be very helpful. -link_same_tag_and_link_split is a special kind of linker that instead of learning on all possible links for all tagged items (like the other linkers), it only considers links between same_tags of the same actual tag value. -This is smarter than the normal same_tag_only but the lack of negative training data probably makes it worse. -It is possible to train things using link_same_tag_only but at deploy time only consider things of the same tag value but this has not been implemented yet on the deploy side of things. +* `link_same_tag_and_link` will do both `link_only` and `link_same_tag_only`, with 2 different labels for the two different types of link. +This is directly equivalent to a transformer with link_only and link_same_tag_only heads, though it combines metrics such as f1 scores. +* `link_all` will do both `link_only` and `link_same_tag_only`, and will not distinguish between the two types of linking at all. +* `link_same_tag_and_link_split` is a special kind of linker that instead of learning on all possible links for all tagged items (like the other linkers), it only considers links between tags of the same actual tag value. +This is smarter than the normal `link_same_tag_only` but lack of negative training data can lead to worse performance. +It should be possible to train things using `link_same_tag_only` but at deploy time use this, but this has not been implemented yet on the deploy side of things. -### Multi GPU / not using cuda:0 +### GPU Notes -By default the method which returns the cuda device (found in src/misc) will return cuda:0. -This is then saved on the model and in the heads as obj.cuda_device. +By default the method which returns the cuda device (found in `src/misc`) will return `cuda:0`. +This is then saved on the model and in the heads as `obj.cuda_device`. When creating new tensors in the code you can use this to make sure they are put on the right device. -Theoretically you should be able to modify the method ins src/misc to return cuda:1 to put everything on the second gpu. -However there seems to be an issue with the transformer from hugging face being initialised on cuda:0. -If you can find a way to initialise the transformer onto the same device as the model itself, running on any gpu is possible. -This should then be a config argument to alter which gpu the model runs on. - -DataParallel is pytorch method often used to train models over multiple gpus. -This hasn't been used since it's not possible with batch size 1. -Whilst larger batch sizes would work with it, model run time seems to be the only factor affecting performance when batch size and number of epochs are concerned. -In essence, the ratio of epochs to batch size is all that matters so using DataParallel to allow for bigger batch size is pointless. - -There are some untested models (see configs/more_vram_needed) that are too large for the 12GB GPUs on the server. -These are the 'large' transformer models. -If access to more VRAM was obtained then it would be a high priority to test these models as they may give improvements. -Just make sure the configs in that folder are up to date in terms of what is best for all there other parameters. - - -## To Do - -### High Priority - -* Analysis of latest models on v2 data -* Crf head - * Find a way to speed up - * Find a way to balance losses - * Pushing / pulling the logits should work, logic for it is done however it needs to be coded in a way that will preserve tensor gradients and also be efficient - * Train on bs1 for 36 epochs -* Improve code documentation and information in README - * Configs -* Variance for k-folding - * In analysis based on special config parameter - * Or generate after training with tool to calc for existing db entries - -### Medium Priotity - -* Make data_agreement tool use a tag categories definition file rather than hardcoding -* Combined accuracy of joint prediction - * Predict tags with one model and then links with other - * How to measure this joint accuracy? -* fgen deploy - * Multi model deploy method that can decide on tags and then link them (using 2 models) - * Some sort of continuous tag detection that groups output for those words (could be done via explicit methods or using link predictions) - * Add link prediction to deploy method -* Fully support multi-input to transformer heads - * Test multi input heads -* Linking improvements - * [CLS] Token link predictions - * Entity start and entity end markers for BIO entities for linking - * Need ability to have many inputs for transformer input so each tag pair can be tested -* Per label prf1a - * Support for this in analyse - -### Low Priotity - -* Training and testing of different architectures - * Different dropout - * Different nonlin head setups - * Head keyword argument that specifies full non-linear classifier architecture -* No category head & cp2l for more epochs as result is inconclusive -* Code clean / refactoring - * Move dataloading and misc stuff into either classes, util or combined file - * Copious type annotations - * abc abstract classing? - * Public / privating in model.py - * Type conditions in construction of main things (i.e. tell linter what's a head or model) -* Use end of text when over 512 tokens -* Write data format explanations -* Rough analysis of sentence lengths -* Ability to specify set colours in analysis config -* Multi-model framework extension -* Add tag links to data agreement -* Model checkpointing -* Unit testing +Theoretically you should be able to modify the method in `src/misc` to return `cuda:1` to put everything on the second gpu. +However there seems to be an issue with the transformer from hugging face being always initialised on `cuda:0`. +Modification of the code to initialise the transformer onto the same device as the model itself would allow running on any gpu. +Support for a config argument to alter which gpu the model runs on should then be added. ## Config File -Note this section is currently unfinished. Refer to existing configs for examples. -Be careful of older configs which may be setup differently, when in doubt trust the newer one. +Be careful of older configs which may be setup differently, when in doubt trust newer ones. +The ones in `configs/current_best` are most up to date. ### Notes: -If a key is not marked as (ar) or (o) then it only needs to be present if it is in the refs of another value in the parent dict - -refs -> required extra fields - -ar -> always required - -o -> Optional +If a key is not marked as always required (AR) or optional (Opt) then it only needs to be present if it is in the required extra fields (REFs) of another value in the parent dict. ### Config options: -* MODE (ar) - * train, refs: MODEL, DATA, TRAINING - * test, refs: MODEL, DATA, TESTING - * deploy, refs: MODEL, DATA, DEPLOY - * analyse, refs: HISTORY_DATA, ANALYSIS +* MODE (AR) + * train REFs: MODEL, DATA, TRAINING + * test REFs: MODEL, DATA, TESTING + * deploy REFs: MODEL, DATA, DEPLOY + * analyse REFs: HISTORY_DATA, ANALYSIS * MODEL - * TYPE (ar) - * pretrained, refs: TRANSFORMER_MODEL, HEADS, MAX_TOKEN_LENGTH, TAG_CATEGORY_DEFINITIONS - * existing, refs: PATH + * TYPE (AR) + * pretrained REFs: TRANSFORMER_MODEL, HEADS, MAX_TOKEN_LENGTH, TAG_CATEGORY_DEFINITIONS + * existing REFs: PATH * TRANSFORMER_MODEL: Transformer to use, called via AutoModel - * TRANSFORMER_KWARGS (o): Dict containing kwargs for the automodel call + * TRANSFORMER_KWARGS (Opt): Dict containing kwargs for the automodel call * HEADS: Dict containing data on heads for the model, keys are the head names and values are dicts of args for that head, keys for those dicts are given below. Head names may need to be matched to things in TAG_CATEGORY_DEFINITIONS or in dataloading. - * htype (ar): The head class to use e.g. single_label, multi_label or link - * num_labels (ar): Number of labels head will need to predict for - * schema (o): Schema to use, E.g. 'BIO' - * TOKENIZER_MODEL (o): Tokenizer to use, called via AutoTokenizer, defaults to TRANSFORMER_MODEL - * TOKENIZER_KWARGS (o): Dict containing kwargs for the autotokenizer call - * TAG_LIST_DEFINITIONS (o): Path to a file contained definitions of tag lists for the heads, helps when data does not contain them all + * htype (AR): The head class to use e.g. single_label, multi_label or link + * num_labels (AR): Number of labels head will need to predict for + * schema (Opt): Schema to use, E.g. 'BIO' + * TOKENIZER_MODEL (Opt): Tokenizer to use, called via AutoTokenizer, defaults to TRANSFORMER_MODEL + * TOKENIZER_KWARGS (Opt): Dict containing kwargs for the autotokenizer call + * TAG_LIST_DEFINITIONS (Opt): Path to a file contained definitions of tag lists for the heads, helps when data does not contain them all * TAG_CATEGORY_DEFINITIONS: Path to file containing data on tag categories to be used by dataloading to know what to look for. These files are also used by the maexml_to_json_data tool * MAX_TOKEN_LENGTH: Max token length of any input, usually 512 for big input tasks * PATH: Path to transformer file (.pkl), file extension is not needed * DATA (TEST_DATA) - * PATH (ar): Path to file with data on it - * FILETYPE (ar): Currently only json_fgeom is supported - * BATCH_SIZE (ar): Batch size for model inputs - * BALANCE_CLASSES (ar): 0 means no balancing of losses, 1 means full balancing (i.e. if a label in single_label or positive value in multi_label occours half as often compared to the average / negative value then scale losses for this label by 2), in between values mix between these + * PATH (AR): Path to file with data on it + * FILETYPE (AR): Currently only json_fgeom is supported + * BATCH_SIZE (AR): Batch size for model inputs + * BALANCE_CLASSES (AR): 0 means no balancing of losses, 1 means full balancing (i.e. if a label in single_label or positive value in multi_label occours half as often compared to the average / negative value then scale losses for this label by 2), in between values mix between these * TRAINING - * TRAINED_NAME (ar): Name to give trained model when saving it - * OPTIMIZER_CLASS (ar): Class for the optimiser, currently only AdamW supported - * OPTIMIZER_KWARGS (ar): Dict of kwargs for optimiser call, putting lr and eps is recommended - * EPOCHS (ar): Number of epochs to run for - * FULL_FINETUNING (o): Default True, whether to tune the transformer as well as the classifier - * MAX_GRAD_NORM (o): For clipping gradients norms, default is 1 - * VERBOSE (o): Verbosity level, 0-3, default is 1 + * TRAINED_NAME (AR): Name to give trained model when saving it + * OPTIMIZER_CLASS (AR): Class for the optimiser, currently only AdamW supported + * OPTIMIZER_KWARGS (AR): Dict of kwargs for optimiser call, putting lr and eps is recommended + * EPOCHS (AR): Number of epochs to run for + * FULL_FINETUNING (Opt): Default True, whether to tune the transformer as well as the classifier + * MAX_GRAD_NORM (Opt): For clipping gradients norms, default is 1 + * VERBOSE (Opt): Verbosity level, 0-3, default is 1 * 0: Don't print any training info * 1: Print epoch numbers * 2: Print epoch loss / accuracy and time left * 3: Print batch numbers and when calculating accuracy - * K_FOLDS (o): If present will use this number of folds in k-fold cross validation, validation scores are averaged across all folds and train losses are given from the final train across the whole dataset + * K_FOLDS (Opt): If present will use this number of folds in k-fold cross validation, validation scores are averaged across all folds and train losses are given from the final train across the whole dataset * TESTING: Currently no args but its presence is required for testing or post train testing diff --git a/abstract_analysis/pubmed_10k_abstracts.json b/abstract_analysis/pubmed_10k_abstracts.json index 9cc4a93..5ebd741 100644 --- a/abstract_analysis/pubmed_10k_abstracts.json +++ b/abstract_analysis/pubmed_10k_abstracts.json @@ -53,13 +53,9 @@ "33432172": "Breast cancer remains a global challenge, causing over 600,000 deaths in 2018 (ref. 1). To achieve earlier cancer detection, health organizations worldwide recommend screening mammography, which is estimated to decrease breast cancer mortality by 20-40% (refs. 2,3). Despite the clear value of screening mammography, significant false positive and false negative rates along with non-uniformities in expert reader availability leave opportunities for improving quality and access4,5. To address these limitations, there has been much recent interest in applying deep learning to mammography6-18, and these efforts have highlighted two key difficulties: obtaining large amounts of annotated training data and ensuring generalization across populations, acquisition equipment and modalities. Here we present an annotation-efficient deep learning approach that (1) achieves state-of-the-art performance in mammogram classification, (2) successfully extends to digital breast tomosynthesis (DBT; '3D mammography'), (3) detects cancers in clinically negative prior mammograms of patients with cancer, (4) generalizes well to a population with low screening rates and (5) outperforms five out of five full-time breast-imaging specialists with an average increase in sensitivity of 14%. By creating new 'maximum suspicion projection' (MSP) images from DBT data, our progressively trained, multiple-instance learning approach effectively trains on DBT exams using only breast-level labels while maintaining localization-based interpretability. Altogether, our results demonstrate promise towards software that can improve the accuracy of and access to screening mammography worldwide.", "33442014": "Underserved populations experience higher levels of pain. These disparities persist even after controlling for the objective severity of diseases like osteoarthritis, as graded by human physicians using medical images, raising the possibility that underserved patients' pain stems from factors external to the knee, such as stress. Here we use a deep learning approach to measure the severity of osteoarthritis, by using knee X-rays to predict patients' experienced pain. We show that this approach dramatically reduces unexplained racial disparities in pain. Relative to standard measures of severity graded by radiologists, which accounted for only 9% (95% confidence interval (CI), 3-16%) of racial disparities in pain, algorithmic predictions accounted for 43% of disparities, or 4.7× more (95% CI, 3.2-11.8×), with similar results for lower-income and less-educated patients. This suggests that much of underserved patients' pain stems from factors within the knee not reflected in standard radiographic measures of severity. We show that the algorithm's ability to reduce unexplained disparities is rooted in the racial and socioeconomic diversity of the training set. Because algorithmic severity measures better capture underserved patients' pain, and severity measures influence treatment decisions, algorithmic predictions could potentially redress disparities in access to treatments like arthroplasty.", "33122860": "Traditional screening for COVID-19 typically includes survey questions about symptoms and travel history, as well as temperature measurements. Here, we explore whether personal sensor data collected over time may help identify subtle changes indicating an infection, such as in patients with COVID-19. We have developed a smartphone app that collects smartwatch and activity tracker data, as well as self-reported symptoms and diagnostic testing results, from individuals in the United States, and have assessed whether symptom and sensor data can differentiate COVID-19 positive versus negative cases in symptomatic individuals. We enrolled 30,529 participants between 25 March and 7 June 2020, of whom 3,811 reported symptoms. Of these symptomatic individuals, 54 reported testing positive and 279 negative for COVID-19. We found that a combination of symptom and sensor data resulted in an area under the curve (AUC) of 0.80 (interquartile range (IQR): 0.73-0.86) for discriminating between symptomatic individuals who were positive or negative for COVID-19, a performance that is significantly better (P < 0.01) than a model1 that considers symptoms alone (AUC = 0.71; IQR: 0.63-0.79). Such continuous, passively captured data may be complementary to virus testing, which is generally a one-off or infrequent sampling assay.", - "33247288": "A Correction to this paper has been published: https://doi.org/10.1038/s41591-020-01181-w.", "33542537": "Diverging from tested vaccination regimens without scientific evidence could undermine public confidence in vaccines against COVID-19 and the success of a global vaccination strategy to curtail the pandemic.", "33664492": "Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors1. Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively coexpressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies2,3. Resistance to enzalutamide was associated with cancer cell-intrinsic epithelial-mesenchymal transition and transforming growth factor-β signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6 and NR1D2 (refs. 4-6). Additionally, a subset of patients had high expression of dysfunction markers on cytotoxic CD8+ T cells undergoing clonal expansion following enzalutamide treatment. Collectively, the transcriptional characterization of cancer and immune cells from human metastatic castration-resistant prostate cancer provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition.", - "33247287": "A Correction to this paper has been published: https://doi.org/10.1038/s41591-020-0919-z.", - "33247290": "A Correction to this paper has been published: https://doi.org/10.1038/s41591-020-01176-7.", "33859435": "Apart from well-defined factors in neuronal cells1, only a few reports consider that the variability of sporadic amyotrophic lateral sclerosis (ALS) progression can depend on less-defined contributions from glia2,3 and blood vessels4. In this study we use an expression-weighted cell-type enrichment method to infer cell activity in spinal cord samples from patients with sporadic ALS and mouse models of this disease. Here we report that patients with sporadic ALS present cell activity patterns consistent with two mouse models in which enrichments of vascular cell genes preceded microglial response. Notably, during the presymptomatic stage, perivascular fibroblast cells showed the strongest gene enrichments, and their marker proteins SPP1 and COL6A1 accumulated in enlarged perivascular spaces in patients with sporadic ALS. Moreover, in plasma of 574 patients with ALS from four independent cohorts, increased levels of SPP1 at disease diagnosis repeatedly predicted shorter survival with stronger effect than the established risk factors of bulbar onset or neurofilament levels in cerebrospinal fluid. We propose that the activity of the recently discovered perivascular fibroblast can predict survival of patients with ALS and provide a new conceptual framework to re-evaluate definitions of ALS etiology.", - "33247289": "A Correction to this paper has been published: https://doi.org/10.1038/s41591-020-01186-5.", "34031608": "The surge in COVID-19 cases in India and Brazil highlights the need to improve vaccine manufacturing capacity and investment in public health at the local level.", "34580492": "With the end of the COVID-19 pandemic nowhere in sight, a return to safe, in-person schooling must be prioritized now to avoid lifelong setbacks", "33958794": "Immune-checkpoint blockade (ICB) combined with neoadjuvant chemotherapy improves pathological complete response in breast cancer. To understand why only a subset of tumors respond to ICB, patients with hormone receptor-positive or triple-negative breast cancer were treated with anti-PD1 before surgery. Paired pre- versus on-treatment biopsies from treatment-naive patients receiving anti-PD1 (n = 29) or patients receiving neoadjuvant chemotherapy before anti-PD1 (n = 11) were subjected to single-cell transcriptome, T cell receptor and proteome profiling. One-third of tumors contained PD1-expressing T cells, which clonally expanded upon anti-PD1 treatment, irrespective of tumor subtype. Expansion mainly involved CD8+ T cells with pronounced expression of cytotoxic-activity (PRF1, GZMB), immune-cell homing (CXCL13) and exhaustion markers (HAVCR2, LAG3), and CD4+ T cells characterized by expression of T-helper-1 (IFNG) and follicular-helper (BCL6, CXCR5) markers. In pre-treatment biopsies, the relative frequency of immunoregulatory dendritic cells (PD-L1+), specific macrophage phenotypes (CCR2+ or MMP9+) and cancer cells exhibiting major histocompatibility complex class I/II expression correlated positively with T cell expansion. Conversely, undifferentiated pre-effector/memory T cells (TCF7+, GZMK+) or inhibitory macrophages (CX3CR1+, C3+) were inversely correlated with T cell expansion. Collectively, our data identify various immunophenotypes and associated gene sets that are positively or negatively correlated with T cell expansion following anti-PD1 treatment. We shed light on the heterogeneity in treatment response to anti-PD1 in breast cancer.", diff --git a/abstract_analysis/pubmed_10k_abstracts.txt b/abstract_analysis/pubmed_10k_abstracts.txt index 25b49e3..29694ce 100644 --- a/abstract_analysis/pubmed_10k_abstracts.txt +++ b/abstract_analysis/pubmed_10k_abstracts.txt @@ -160,27 +160,15 @@ Underserved populations experience higher levels of pain. These disparities pers 33122860 Traditional screening for COVID-19 typically includes survey questions about symptoms and travel history, as well as temperature measurements. Here, we explore whether personal sensor data collected over time may help identify subtle changes indicating an infection, such as in patients with COVID-19. We have developed a smartphone app that collects smartwatch and activity tracker data, as well as self-reported symptoms and diagnostic testing results, from individuals in the United States, and have assessed whether symptom and sensor data can differentiate COVID-19 positive versus negative cases in symptomatic individuals. We enrolled 30,529 participants between 25 March and 7 June 2020, of whom 3,811 reported symptoms. Of these symptomatic individuals, 54 reported testing positive and 279 negative for COVID-19. We found that a combination of symptom and sensor data resulted in an area under the curve (AUC) of 0.80 (interquartile range (IQR): 0.73-0.86) for discriminating between symptomatic individuals who were positive or negative for COVID-19, a performance that is significantly better (P < 0.01) than a model1 that considers symptoms alone (AUC = 0.71; IQR: 0.63-0.79). Such continuous, passively captured data may be complementary to virus testing, which is generally a one-off or infrequent sampling assay. -33247288 -A Correction to this paper has been published: https://doi.org/10.1038/s41591-020-01181-w. - 33542537 Diverging from tested vaccination regimens without scientific evidence could undermine public confidence in vaccines against COVID-19 and the success of a global vaccination strategy to curtail the pandemic. 33664492 Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors1. Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively coexpressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies2,3. Resistance to enzalutamide was associated with cancer cell-intrinsic epithelial-mesenchymal transition and transforming growth factor-β signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6 and NR1D2 (refs. 4-6). Additionally, a subset of patients had high expression of dysfunction markers on cytotoxic CD8+ T cells undergoing clonal expansion following enzalutamide treatment. Collectively, the transcriptional characterization of cancer and immune cells from human metastatic castration-resistant prostate cancer provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition. -33247287 -A Correction to this paper has been published: https://doi.org/10.1038/s41591-020-0919-z. - -33247290 -A Correction to this paper has been published: https://doi.org/10.1038/s41591-020-01176-7. - 33859435 Apart from well-defined factors in neuronal cells1, only a few reports consider that the variability of sporadic amyotrophic lateral sclerosis (ALS) progression can depend on less-defined contributions from glia2,3 and blood vessels4. In this study we use an expression-weighted cell-type enrichment method to infer cell activity in spinal cord samples from patients with sporadic ALS and mouse models of this disease. Here we report that patients with sporadic ALS present cell activity patterns consistent with two mouse models in which enrichments of vascular cell genes preceded microglial response. Notably, during the presymptomatic stage, perivascular fibroblast cells showed the strongest gene enrichments, and their marker proteins SPP1 and COL6A1 accumulated in enlarged perivascular spaces in patients with sporadic ALS. Moreover, in plasma of 574 patients with ALS from four independent cohorts, increased levels of SPP1 at disease diagnosis repeatedly predicted shorter survival with stronger effect than the established risk factors of bulbar onset or neurofilament levels in cerebrospinal fluid. We propose that the activity of the recently discovered perivascular fibroblast can predict survival of patients with ALS and provide a new conceptual framework to re-evaluate definitions of ALS etiology. -33247289 -A Correction to this paper has been published: https://doi.org/10.1038/s41591-020-01186-5. - 34031608 The surge in COVID-19 cases in India and Brazil highlights the need to improve vaccine manufacturing capacity and investment in public health at the local level. diff --git a/abstract_analysis/pubmed_tag_link.json b/abstract_analysis/pubmed_tag_link.json new file mode 100644 index 0000000..271d502 --- /dev/null +++ b/abstract_analysis/pubmed_tag_link.json @@ -0,0 +1,277420 @@ +[ + { + "PMID": "33335323", + "TEXT": "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19), has caused a global pandemic, and safe, effective vaccines are urgently needed1. Strong, Th1-skewed T cell responses can drive protective humoral and cell-mediated immune responses2 and might reduce the potential for disease enhancement3. Cytotoxic T cells clear virus-infected host cells and contribute to control of infection4. Studies of patients infected with SARS-CoV-2 have suggested a protective role for both humoral and cell-mediated immune responses in recovery from COVID-19 (refs. 5,6). ChAdOx1 nCoV-19 (AZD1222) is a candidate SARS-CoV-2 vaccine comprising a replication-deficient simian adenovirus expressing full-length SARS-CoV-2 spike protein. We recently reported preliminary safety and immunogenicity data from a phase 1/2 trial of the ChAdOx1 nCoV-19 vaccine (NCT04400838)7 given as either a one- or two-dose regimen. The vaccine was tolerated, with induction of neutralizing antibodies and antigen-specific T cells against the SARS-CoV-2 spike protein. Here we describe, in detail, exploratory analyses of the immune responses in adults, aged 18-55 years, up to 8 weeks after vaccination with a single dose of ChAdOx1 nCoV-19 in this trial, demonstrating an induction of a Th1-biased response characterized by interferon-γ and tumor necrosis factor-α cytokine secretion by CD4+ T cells and antibody production predominantly of IgG1 and IgG3 subclasses. CD8+ T cells, of monofunctional, polyfunctional and cytotoxic phenotypes, were also induced. Taken together, these results suggest a favorable immune profile induced by ChAdOx1 nCoV-19 vaccine, supporting the progression of this vaccine candidate to ongoing phase 2/3 trials to assess vaccine efficacy.", + "TAG_DATA": [ + "160, adults, {'context': 'B-patient'}", + "162, 18-55 {'context': 'I-patient'}", + "197, CD4+ {'context': 'B-cells'}", + "198, T {'context': 'I-cells'}", + "199, cells {'context': 'I-cells'}", + "209, CD8+ {'context': 'B-cells'}", + "210, T {'context': 'I-cells'}", + "211, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "160, adults, ['l0', 'l1', 'l2', 'l3', 'l4']", + "162, 18-55 ['l0', 'l5', 'l6', 'l7', 'l8']", + "163, years, ['l1', 'l5', 'l9', 'l10', 'l11']", + "197, CD4+ ['l2', 'l6', 'l9', 'l12', 'l13']", + "198, T ['l3', 'l7', 'l10', 'l12', 'l14']", + "199, cells ['l4', 'l8', 'l11', 'l13', 'l14']", + "209, CD8+ ['l15', 'l16']", + "210, T ['l15', 'l17']", + "211, cells, ['l16', 'l17']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33398162", + "TEXT": "Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8+ T cells from systemic circulation. Within the liver, activated antigen-specific Fas+CD8+ T cells undergo apoptosis following their interaction with FasL+CD11b+F4/80+ monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8+ T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity.", + "TAG_DATA": [ + "60, mouse {'context': 'B-organism'}", + "61, models, {'context': 'I-organism'}", + "77, liver, {'context': 'B-tissue/organ'}", + "81, T {'context': 'I-cells'}", + "82, cells {'context': 'I-cells'}", + "83, undergo {'effect': 'B-positive'}", + "84, apoptosis {'phenotype': 'B-apoptosis'}", + "104, patients {'context': 'B-patient'}", + "107, metastases {'phenotype': 'I-metastasis'}", + "110, peripheral {'context': 'B-cells'}", + "111, T {'context': 'I-cells'}", + "112, cell {'context': 'I-cells'}", + "116, tumoral {'context': 'B-cells'}", + "117, T {'context': 'I-cells'}", + "118, cell {'context': 'I-cells'}", + "129, hepatic {'context': 'B-cells'}", + "130, macrophages, {'context': 'I-cells'}", + "132, hepatic {'context': 'B-cells'}", + "133, T {'context': 'I-cells'}", + "134, cell {'context': 'I-cells'}", + "141, T {'context': 'B-cells'}", + "142, cells. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "60, mouse ['l0', 'l1', 'l2']", + "61, models, ['l0', 'l3', 'l4']", + "77, liver, ['l1', 'l3', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "81, T ['l5', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "82, cells ['l2', 'l4', 'l6', 'l11', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "83, undergo ['l7', 'l12', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "84, apoptosis ['l8', 'l13', 'l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "104, patients ['l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "106, liver ['l34', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "107, metastases ['l35', 'l46', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "110, peripheral ['l14', 'l36', 'l47', 'l57', 'l66', 'l67', 'l68', 'l69', 'l70']", + "111, T ['l15', 'l21', 'l26', 'l30', 'l37', 'l48', 'l58', 'l66', 'l71', 'l72', 'l73', 'l74']", + "112, cell ['l9', 'l16', 'l22', 'l27', 'l31', 'l38', 'l49', 'l59', 'l67', 'l71', 'l75', 'l76', 'l77']", + "116, tumoral ['l39', 'l50', 'l60', 'l68', 'l72', 'l75', 'l78', 'l79']", + "117, T ['l17', 'l23', 'l28', 'l32', 'l40', 'l51', 'l61', 'l69', 'l73', 'l76', 'l78', 'l80']", + "118, cell ['l10', 'l18', 'l24', 'l29', 'l33', 'l41', 'l52', 'l62', 'l70', 'l74', 'l77', 'l79', 'l80']", + "123, preclinical ['l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "124, models, ['l42', 'l53', 'l63', 'l81', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "129, hepatic ['l43', 'l54', 'l64', 'l82', 'l89', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "130, macrophages, ['l44', 'l55', 'l65', 'l83', 'l90', 'l96', 'l102', 'l103', 'l104', 'l105', 'l106']", + "132, hepatic ['l84', 'l91', 'l97', 'l102', 'l107', 'l108', 'l109', 'l110']", + "133, T ['l85', 'l92', 'l98', 'l103', 'l107', 'l111', 'l112', 'l113']", + "134, cell ['l45', 'l56', 'l86', 'l93', 'l99', 'l104', 'l108', 'l111', 'l114', 'l115']", + "141, T ['l87', 'l94', 'l100', 'l105', 'l109', 'l112', 'l114', 'l116']", + "142, cells. ['l88', 'l95', 'l101', 'l106', 'l110', 'l113', 'l115', 'l116']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "liver," + ] + }, + "effect": { + "val": "positive", + "words": [ + "undergo" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "liver," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "undergo" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "undergo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + }, + "context": { + "val": "cells", + "words": [ + "peripheral", + "T", + "cell", + "tumoral", + "hepatic", + "macrophages," + ] + } + } + ] + }, + { + "PMID": "33398160", + "TEXT": "White fat stores excess energy, whereas brown and beige fat are thermogenic and dissipate energy as heat. Thermogenic adipose tissues markedly improve glucose and lipid homeostasis in mouse models, although the extent to which brown adipose tissue (BAT) influences metabolic and cardiovascular disease in humans is unclear1,2. Here we retrospectively categorized 134,529 18F-fluorodeoxyglucose positron emission tomography-computed tomography scans from 52,487 patients, by presence or absence of BAT, and used propensity score matching to assemble a study cohort. Scans in the study population were initially conducted for indications related to cancer diagnosis, treatment or surveillance, without previous stimulation. We report that individuals with BAT had lower prevalences of cardiometabolic diseases, and the presence of BAT was independently correlated with lower odds of type 2 diabetes, dyslipidemia, coronary artery disease, cerebrovascular disease, congestive heart failure and hypertension. These findings were supported by improved blood glucose, triglyceride and high-density lipoprotein values. The beneficial effects of BAT were more pronounced in individuals with overweight or obesity, indicating that BAT might play a role in mitigating the deleterious effects of obesity. Taken together, our findings highlight a potential role for BAT in promoting cardiometabolic health.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33398161", + "TEXT": "Intratumoral heterogeneity (ITH) is a fundamental property of cancer; however, the origins of ITH remain poorly understood. We performed single-cell transcriptome profiling of peritoneal carcinomatosis (PC) from 15 patients with gastric adenocarcinoma (GAC), constructed a map of 45,048 PC cells, profiled the transcriptome states of tumor cell populations, incisively explored ITH of malignant PC cells and identified significant correlates with patient survival. The links between tumor cell lineage/state compositions and ITH were illustrated at transcriptomic, genotypic, molecular and phenotypic levels. We uncovered the diversity in tumor cell lineage/state compositions in PC specimens and defined it as a key contributor to ITH. Single-cell analysis of ITH classified PC specimens into two subtypes that were prognostically independent of clinical variables, and a 12-gene prognostic signature was derived and validated in multiple large-scale GAC cohorts. The prognostic signature appears fundamental to GAC carcinogenesis and progression and could be practical for patient stratification.", + "TAG_DATA": [ + "52, malignant {'context': 'B-transformed cells'}", + "53, PC {'context': 'I-transformed cells'}", + "54, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "52, malignant ['l0', 'l1']", + "53, PC ['l0', 'l2']", + "54, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33462444", + "TEXT": "The role of the androgen receptor (AR) in estrogen receptor (ER)-α-positive breast cancer is controversial, constraining implementation of AR-directed therapies. Using a diverse, clinically relevant panel of cell-line and patient-derived models, we demonstrate that AR activation, not suppression, exerts potent antitumor activity in multiple disease contexts, including resistance to standard-of-care ER and CDK4/6 inhibitors. Notably, AR agonists combined with standard-of-care agents enhanced therapeutic responses. Mechanistically, agonist activation of AR altered the genomic distribution of ER and essential co-activators (p300, SRC-3), resulting in repression of ER-regulated cell cycle genes and upregulation of AR target genes, including known tumor suppressors. A gene signature of AR activity positively predicted disease survival in multiple clinical ER-positive breast cancer cohorts. These findings provide unambiguous evidence that AR has a tumor suppressor role in ER-positive breast cancer and support AR agonism as the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity.", + "TAG_DATA": [ + "52, CDK4/6 {'perturbing_action': 'B-pharmacological inhibition'}", + "53, inhibitors. {'perturbing_action': 'I-pharmacological inhibition'}", + "55, AR {'perturbing_action': 'B-pharmacological augmentation'}", + "56, agonists {'perturbing_action': 'I-pharmacological augmentation'}", + "65, agonist {'perturbing_action': 'B-pharmacological augmentation'}", + "66, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "67, of {'perturbing_action': 'I-pharmacological augmentation'}", + "68, AR {'perturbing_action': 'I-pharmacological augmentation'}" + ], + "LINK_DATA": [ + "52, CDK4/6 ['l0']", + "53, inhibitors. ['l0']", + "55, AR ['l1', 'l2', 'l3', 'l4', 'l5']", + "56, agonists ['l1', 'l6', 'l7', 'l8', 'l9']", + "65, agonist ['l2', 'l6', 'l10', 'l11', 'l12']", + "66, activation ['l3', 'l7', 'l10', 'l13', 'l14']", + "67, of ['l4', 'l8', 'l11', 'l13', 'l15']", + "68, AR ['l5', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32929268", + "TEXT": "A key unsolved question in the current coronavirus disease 2019 (COVID-19) pandemic is the duration of acquired immunity. Insights from infections with the four seasonal human coronaviruses might reveal common characteristics applicable to all human coronaviruses. We monitored healthy individuals for more than 35 years and determined that reinfection with the same seasonal coronavirus occurred frequently at 12 months after infection.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33479501", + "TEXT": "Personal neoantigen vaccines have been envisioned as an effective approach to induce, amplify and diversify antitumor T cell responses. To define the long-term effects of such a vaccine, we evaluated the clinical outcome and circulating immune responses of eight patients with surgically resected stage IIIB/C or IVM1a/b melanoma, at a median of almost 4 years after treatment with NeoVax, a long-peptide vaccine targeting up to 20 personal neoantigens per patient ( NCT01970358 ). All patients were alive and six were without evidence of active disease. We observed long-term persistence of neoantigen-specific T cell responses following vaccination, with ex vivo detection of neoantigen-specific T cells exhibiting a memory phenotype. We also found diversification of neoantigen-specific T cell clones over time, with emergence of multiple T cell receptor clonotypes exhibiting distinct functional avidities. Furthermore, we detected evidence of tumor infiltration by neoantigen-specific T cell clones after vaccination and epitope spreading, suggesting on-target vaccine-induced tumor cell killing. Personal neoantigen peptide vaccines thus induce T cell responses that persist over years and broaden the spectrum of tumor-specific cytotoxicity in patients with melanoma.", + "TAG_DATA": [ + "39, patients {'context': 'B-patient'}", + "41, surgically {'context': 'B-neoplasm'}", + "42, resected {'context': 'I-neoplasm'}", + "43, stage {'context': 'I-neoplasm'}", + "44, IIIB/C {'context': 'I-neoplasm'}", + "45, or {'context': 'I-neoplasm'}", + "46, IVM1a/b {'context': 'I-neoplasm'}", + "47, melanoma, {'context': 'I-neoplasm'}", + "102, T {'context': 'B-cells'}", + "103, cells {'context': 'I-cells'}", + "139, neoantigen-specific {'context': 'B-cells'}", + "140, T {'context': 'I-cells'}", + "141, cell {'context': 'I-cells'}", + "142, clones {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "39, patients ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "41, surgically ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "42, resected ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "43, stage ['l2', 'l8', 'l13', 'l20', 'l21', 'l22', 'l23']", + "44, IIIB/C ['l3', 'l9', 'l14', 'l20', 'l24', 'l25', 'l26']", + "45, or ['l4', 'l10', 'l15', 'l21', 'l24', 'l27', 'l28']", + "46, IVM1a/b ['l5', 'l11', 'l16', 'l22', 'l25', 'l27', 'l29', 'l30', 'l31']", + "47, melanoma, ['l6', 'l12', 'l17', 'l23', 'l26', 'l28', 'l29']", + "102, T ['l18', 'l30', 'l32']", + "103, cells ['l19', 'l31', 'l32']", + "139, neoantigen-specific ['l33', 'l34', 'l35']", + "140, T ['l33', 'l36', 'l37']", + "141, cell ['l34', 'l36', 'l38']", + "142, clones ['l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33020644", + "TEXT": "Autologous chimeric antigen receptor (CAR) T cell therapies targeting CD19 have high efficacy in large B cell lymphomas (LBCLs), but long-term remissions are observed in less than half of patients, and treatment-associated adverse events, such as immune effector cell-associated neurotoxicity syndrome (ICANS), are a clinical challenge. We performed single-cell RNA sequencing with capture-based cell identification on autologous axicabtagene ciloleucel (axi-cel) anti-CD19 CAR T cell infusion products to identify transcriptomic features associated with efficacy and toxicity in 24 patients with LBCL. Patients who achieved a complete response by positron emission tomography/computed tomography at their 3-month follow-up had three-fold higher frequencies of CD8 T cells expressing memory signatures than patients with partial response or progressive disease. Molecular response measured by cell-free DNA sequencing at day 7 after infusion was significantly associated with clinical response (P = 0.008), and a signature of CD8 T cell exhaustion was associated (q = 2.8 × 10-149) with a poor molecular response. Furthermore, a rare cell population with monocyte-like transcriptional features was associated (P = 0.0002) with high-grade ICANS. Our results suggest that heterogeneity in the cellular and molecular features of CAR T cell infusion products contributes to variation in efficacy and toxicity after axi-cel therapy in LBCL, and that day 7 molecular response might serve as an early predictor of CAR T cell efficacy.", + "TAG_DATA": [ + "77, patients {'context': 'B-patient'}", + "78, with {'context': 'I-patient'}", + "79, LBCL. {'context': 'I-patient'}", + "80, Patients {'context': 'B-patient'}", + "100, CD8 {'context': 'B-cells'}", + "101, T {'context': 'I-cells'}", + "102, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "77, patients ['l0', 'l1', 'l2']", + "78, with ['l0', 'l3', 'l4']", + "79, LBCL. ['l1', 'l3', 'l5']", + "80, Patients ['l2', 'l4', 'l5', 'l6', 'l7']", + "100, CD8 ['l8', 'l9']", + "101, T ['l6', 'l8', 'l10']", + "102, cells ['l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33432175", + "TEXT": "The gut microbiome is shaped by diet and influences host metabolism; however, these links are complex and can be unique to each individual. We performed deep metagenomic sequencing of 1,203 gut microbiomes from 1,098 individuals enrolled in the Personalised Responses to Dietary Composition Trial (PREDICT 1) study, whose detailed long-term diet information, as well as hundreds of fasting and same-meal postprandial cardiometabolic blood marker measurements were available. We found many significant associations between microbes and specific nutrients, foods, food groups and general dietary indices, which were driven especially by the presence and diversity of healthy and plant-based foods. Microbial biomarkers of obesity were reproducible across external publicly available cohorts and in agreement with circulating blood metabolites that are indicators of cardiovascular disease risk. While some microbes, such as Prevotella copri and Blastocystis spp., were indicators of favorable postprandial glucose metabolism, overall microbiome composition was predictive for a large panel of cardiometabolic blood markers including fasting and postprandial glycemic, lipemic and inflammatory indices. The panel of intestinal species associated with healthy dietary habits overlapped with those associated with favorable cardiometabolic and postprandial markers, indicating that our large-scale resource can potentially stratify the gut microbiome into generalizable health levels in individuals without clinically manifest disease.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33335322", + "TEXT": "More than 190 vaccines are currently in development to prevent infection by the novel severe acute respiratory syndrome coronavirus 2. Animal studies suggest that while neutralizing antibodies against the viral spike protein may correlate with protection, additional antibody functions may also be important in preventing infection. Previously, we reported early immunogenicity and safety outcomes of a viral vector coronavirus vaccine, ChAdOx1 nCoV-19 (AZD1222), in a single-blinded phase 1/2 randomized controlled trial of healthy adults aged 18-55 years ( NCT04324606 ). Now we describe safety and exploratory humoral and cellular immunogenicity of the vaccine, from subgroups of volunteers in that trial, who were subsequently allocated to receive a homologous full-dose (SD/SD D56; n = 20) or half-dose (SD/LD D56; n = 32) ChAdOx1 booster vaccine 56 d following prime vaccination. Previously reported immunogenicity data from the open-label 28-d interval prime-boost group (SD/SD D28; n = 10) are also presented to facilitate comparison. Additionally, we describe volunteers boosted with the comparator vaccine (MenACWY; n = 10). In this interim report, we demonstrate that a booster dose of ChAdOx1 nCoV-19 is safe and better tolerated than priming doses. Using a systems serology approach we also demonstrate that anti-spike neutralizing antibody titers, as well as Fc-mediated functional antibody responses, including antibody-dependent neutrophil/monocyte phagocytosis, complement activation and natural killer cell activation, are substantially enhanced by a booster dose of vaccine. A booster dose of vaccine induced stronger antibody responses than a dose-sparing half-dose boost, although the magnitude of T cell responses did not increase with either boost dose. These data support the two-dose vaccine regime that is now being evaluated in phase 3 clinical trials.", + "TAG_DATA": [ + "72, healthy {'context': 'B-cells'}", + "73, adults {'context': 'I-organism'}", + "75, 18-55 {'context': 'I-patient'}", + "203, natural {'context': 'B-cells'}", + "204, killer {'context': 'B-cells'}", + "205, cell {'context': 'I-cells'}", + "234, T {'context': 'B-cells'}", + "235, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "72, healthy ['l0', 'l1', 'l2', 'l3']", + "73, adults ['l0', 'l4', 'l5', 'l6']", + "74, aged ['l1', 'l4', 'l7', 'l8']", + "75, 18-55 ['l2', 'l5', 'l7', 'l9']", + "76, years ['l3', 'l6', 'l8', 'l9']", + "203, natural ['l10', 'l11']", + "204, killer ['l10', 'l12']", + "205, cell ['l11', 'l12']", + "234, T ['l13']", + "235, cell ['l13']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33479499", + "TEXT": "The carbohydrate-insulin model of obesity posits that high-carbohydrate diets lead to excess insulin secretion, thereby promoting fat accumulation and increasing energy intake. Thus, low-carbohydrate diets are predicted to reduce ad libitum energy intake as compared to low-fat, high-carbohydrate diets. To test this hypothesis, 20 adults aged 29.9 ± 1.4 (mean ± s.e.m.) years with body mass index of 27.8 ± 1.3 kg m-2 were admitted as inpatients to the National Institutes of Health Clinical Center and randomized to consume ad libitum either a minimally processed, plant-based, low-fat diet (10.3% fat, 75.2% carbohydrate) with high glycemic load (85 g 1,000 kcal-1) or a minimally processed, animal-based, ketogenic, low-carbohydrate diet (75.8% fat, 10.0% carbohydrate) with low glycemic load (6 g 1,000 kcal-1) for 2 weeks followed immediately by the alternate diet for 2 weeks. One participant withdrew due to hypoglycemia during the low-carbohydrate diet. The primary outcomes compared mean daily ad libitum energy intake between each 2-week diet period as well as between the final week of each diet. We found that the low-fat diet led to 689 ± 73 kcal d-1 less energy intake than the low-carbohydrate diet over 2 weeks (P < 0.0001) and 544 ± 68 kcal d-1 less over the final week (P < 0.0001). Therefore, the predictions of the carbohydrate-insulin model were inconsistent with our observations. This study was registered on ClinicalTrials.gov as NCT03878108 .", + "TAG_DATA": [ + "44, adults {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33020647", + "TEXT": "Chimeric antigen receptor (CAR) T cells targeting CD19 are a breakthrough treatment for relapsed, refractory B cell malignancies1-5. Despite impressive outcomes, relapse with CD19- disease remains a challenge. We address this limitation through a first-in-human trial of bispecific anti-CD20, anti-CD19 (LV20.19) CAR T cells for relapsed, refractory B cell malignancies. Adult patients with B cell non-Hodgkin lymphoma or chronic lymphocytic leukemia were treated on a phase 1 dose escalation and expansion trial (NCT03019055) to evaluate the safety of 4-1BB-CD3ζ LV20.19 CAR T cells and the feasibility of on-site manufacturing using the CliniMACS Prodigy system. CAR T cell doses ranged from 2.5 × 105-2.5 × 106 cells per kg. Cell manufacturing was set at 14 d with the goal of infusing non-cryopreserved LV20.19 CAR T cells. The target dose of LV20.19 CAR T cells was met in all CAR-naive patients, and 22 patients received LV20.19 CAR T cells on protocol. In the absence of dose-limiting toxicity, a dose of 2.5 × 106 cells per kg was chosen for expansion. Grade 3-4 cytokine release syndrome occurred in one (5%) patient, and grade 3-4 neurotoxicity occurred in three (14%) patients. Eighteen (82%) patients achieved an overall response at day 28, 14 (64%) had a complete response, and 4 (18%) had a partial response. The overall response rate to the dose of 2.5 × 106 cells per kg with non-cryopreserved infusion (n = 12) was 100% (complete response, 92%; partial response, 8%). Notably, loss of the CD19 antigen was not seen in patients who relapsed or experienced treatment failure. In conclusion, on-site manufacturing and infusion of non-cryopreserved LV20.19 CAR T cells were feasible and therapeutically safe, showing low toxicity and high efficacy. Bispecific CARs may improve clinical responses by mitigating", + "TAG_DATA": [ + "50, Adult {'context': 'B-patient'}", + "51, patients {'context': 'I-patient'}", + "52, with {'context': 'I-neoplasm'}", + "53, B {'context': 'B-neoplasm'}", + "54, cell {'context': 'I-neoplasm'}", + "55, non-Hodgkin {'context': 'I-neoplasm'}", + "56, lymphoma {'context': 'I-neoplasm'}", + "58, chronic {'context': 'B-neoplasm'}", + "59, lymphocytic {'context': 'I-neoplasm'}", + "60, leukemia {'context': 'I-neoplasm'}", + "237, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "50, Adult ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "51, patients ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "52, with ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "53, B ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "54, cell ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "55, non-Hodgkin ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "56, lymphoma ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "58, chronic ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "59, lymphocytic ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "60, leukemia ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33432170", + "TEXT": "Most of what we know about adaptive immunity has come from inbred mouse studies, using methods that are often difficult or impossible to confirm in humans. In addition, vaccine responses in mice are often poorly predictive of responses to those same vaccines in humans. Here we use human tonsils, readily available lymphoid organs, to develop a functional organotypic system that recapitulates key germinal center features in vitro, including the production of antigen-specific antibodies, somatic hypermutation and affinity maturation, plasmablast differentiation and class-switch recombination. We use this system to define the essential cellular components necessary to produce an influenza vaccine response. We also show that it can be used to evaluate humoral immune responses to two priming antigens, rabies vaccine and an adenovirus-based severe acute respiratory syndrome coronavirus 2 vaccine, and to assess the effects of different adjuvants. This system should prove useful for studying critical mechanisms underlying adaptive immunity in much greater depth than previously possible and to rapidly test vaccine candidates and adjuvants in an entirely human system.", + "TAG_DATA": [ + "47, human {'context': 'B-tissue/organ'}", + "48, tonsils, {'context': 'I-tissue/organ'}", + "65, in {'context': 'B-in vitro'}", + "66, vitro, {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "47, human ['l0', 'l1', 'l2']", + "48, tonsils, ['l0', 'l3', 'l4']", + "65, in ['l1', 'l3', 'l5']", + "66, vitro, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32989314", + "TEXT": "22q11.2 deletion syndrome (22q11DS) is a highly penetrant and common genetic cause of neuropsychiatric disease. Here we generated induced pluripotent stem cells from 15 individuals with 22q11DS and 15 control individuals and differentiated them into three-dimensional (3D) cerebral cortical organoids. Transcriptional profiling across 100 days showed high reliability of differentiation and revealed changes in neuronal excitability-related genes. Using electrophysiology and live imaging, we identified defects in spontaneous neuronal activity and calcium signaling in both organoid- and 2D-derived cortical neurons. The calcium deficit was related to resting membrane potential changes that led to abnormal inactivation of voltage-gated calcium channels. Heterozygous loss of DGCR8 recapitulated the excitability and calcium phenotypes and its overexpression rescued these defects. Moreover, the 22q11DS calcium abnormality could also be restored by application of antipsychotics. Taken together, our study illustrates how stem cell derived models can be used to uncover and rescue cellular phenotypes associated with genetic forms of neuropsychiatric disease.", + "TAG_DATA": [ + "18, induced {'context': 'B-cells'}", + "19, pluripotent {'context': 'I-cells'}", + "20, stem {'context': 'I-cells'}", + "21, cells {'context': 'I-cells'}", + "74, organoid- {'context': 'B-organoid'}", + "76, 2D-derived {'context': 'B-cells'}", + "77, cortical {'context': 'I-cells'}", + "78, neurons. {'context': 'I-cells'}", + "98, Heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "99, loss {'perturbing_action': 'I-gene loss-of-function'}", + "100, of {'perturbing_action': 'I-gene loss-of-function'}", + "101, DGCR8 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "18, induced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "19, pluripotent ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "20, stem ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "21, cells ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "74, organoid- ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "76, 2D-derived ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "77, cortical ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "78, neurons. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "98, Heterozygous ['l28', 'l29', 'l30']", + "99, loss ['l28', 'l31', 'l32']", + "100, of ['l29', 'l31', 'l33']", + "101, DGCR8 ['l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33106665", + "TEXT": "Acute myeloid leukemia (AML) is the most common diagnosed leukemia. In older adults, AML confers an adverse outcome1,2. AML originates from a dominant mutation, then acquires collaborative transformative mutations leading to myeloid transformation and clinical/biological heterogeneity. Currently, AML treatment is initiated rapidly, precluding the ability to consider the mutational profile of a patient's leukemia for treatment decisions. Untreated patients with AML ≥ 60 years were prospectively enrolled on the ongoing Beat AML trial (ClinicalTrials.gov NCT03013998 ), which aims to provide cytogenetic and mutational data within 7 days (d) from sample receipt and before treatment selection, followed by treatment assignment to a sub-study based on the dominant clone. A total of 487 patients with suspected AML were enrolled; 395 were eligible. Median age was 72 years (range 60-92 years; 38% ≥75 years); 374 patients (94.7%) had genetic and cytogenetic analysis completed within 7 d and were centrally assigned to a Beat AML sub-study; 224 (56.7%) were enrolled on a Beat AML sub-study. The remaining 171 patients elected standard of care (SOC) (103), investigational therapy (28) or palliative care (40); 9 died before treatment assignment. Demographic, laboratory and molecular characteristics were not significantly different between patients on the Beat AML sub-studies and those receiving SOC (induction with cytarabine + daunorubicin (7 + 3 or equivalent) or hypomethylation agent). Thirty-day mortality was less frequent and overall survival was significantly longer for patients enrolled on the Beat AML sub-studies versus those who elected SOC. A precision medicine therapy strategy in AML is feasible within 7 d, allowing patients and physicians to rapidly incorporate genomic data into treatment decisions without increasing early death or adversely impacting overall survival.", + "TAG_DATA": [ + "58, patients {'context': 'I-patient'}", + "59, with {'context': 'I-patient'}", + "60, AML ≥ 60 {'context': 'I-patient'}", + "61, years {'context': 'I-patient'}", + "108, patients {'context': 'B-patient'}", + "110, suspected {'context': 'I-patient'}", + "111, AML {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "58, patients ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "59, with ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "60, AML ≥ 60 ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "61, years ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "108, patients ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "110, suspected ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "111, AML ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33020649", + "TEXT": "Comprehensive genomic profiling enables genomic biomarker detection in advanced solid tumors. Here, to evaluate the utility of circulating tumor DNA (ctDNA) genotyping, we compare trial enrollment using ctDNA sequencing in 1,687 patients with advanced gastrointestinal (GI) cancer in SCRUM-Japan GOZILA (no. UMIN000016343), an observational ctDNA-based screening study, to enrollment using tumor tissue sequencing in the same centers and network (GI-SCREEN, 5,621 patients). ctDNA genotyping significantly shortened the screening duration (11 versus 33 days, P < 0.0001) and improved the trial enrollment rate (9.5 versus 4.1%, P < 0.0001) without compromising treatment efficacy compared to tissue genotyping. We also describe the clonal architecture of ctDNA profiles in ~2,000 patients with advanced GI cancer, which reinforces the relevance of many targetable oncogenic drivers and highlights multiple new drivers as candidates for clinical development. ctDNA genotyping has the potential to accelerate innovation in precision medicine and its delivery to individual patients.", + "TAG_DATA": [ + "32, advanced {'context': 'B-neoplasm'}", + "33, gastrointestinal {'context': 'I-neoplasm'}", + "34, (GI) {'context': 'I-neoplasm'}", + "35, cancer {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "32, advanced ['l0', 'l1', 'l2']", + "33, gastrointestinal ['l0', 'l3', 'l4']", + "34, (GI) ['l1', 'l3', 'l5']", + "35, cancer ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33184509", + "TEXT": "Emerging data indicate that SARS-CoV-2-specific CD8+ T cells targeting different viral proteins are detectable in up to 70% of convalescent individuals1-5. However, very little information is currently available about the abundance, phenotype, functional capacity and fate of pre-existing and induced SARS-CoV-2-specific CD8+ T cell responses during the natural course of SARS-CoV-2 infection. Here, we define a set of optimal and dominant SARS-CoV-2-specific CD8+ T cell epitopes. We also perform a high-resolution ex vivo analysis of pre-existing and induced SARS-CoV-2-specific CD8+ T cells, applying peptide-loaded major histocompatibility complex class I (pMHCI) tetramer technology. We observe rapid induction, prolonged contraction and emergence of heterogeneous and functionally competent cross-reactive and induced memory CD8+ T cell responses in cross-sectionally analyzed individuals with mild disease following SARS-CoV-2 infection and three individuals longitudinally assessed for their T cells pre- and post-SARS-CoV-2 infection. SARS-CoV-2-specific memory CD8+ T cells exhibited functional characteristics comparable to influenza-specific CD8+ T cells and were detectable in SARS-CoV-2 convalescent individuals who were seronegative for anti-SARS-CoV-2 antibodies targeting spike (S) and nucleoprotein (N). These results define cross-reactive and induced SARS-CoV-2-specific CD8+ T cell responses as potentially important determinants of immune protection in mild SARS-CoV-2 infection.", + "TAG_DATA": [ + "79, CD8+ {'context': 'B-cells'}", + "80, T {'context': 'I-cells'}", + "81, cells, {'context': 'I-cells'}", + "108, memory {'context': 'B-cells'}", + "109, CD8+ {'context': 'I-cells'}", + "110, T {'context': 'I-cells'}", + "111, cell {'context': 'I-cells'}", + "116, individuals {'context': 'B-patient'}", + "137, memory {'context': 'B-cells'}", + "138, CD8+ {'context': 'I-cells'}", + "139, T {'context': 'I-cells'}", + "140, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "79, CD8+ ['l0', 'l1', 'l2', 'l3']", + "80, T ['l0', 'l4', 'l5']", + "81, cells, ['l1', 'l4', 'l6']", + "108, memory ['l7', 'l8', 'l9', 'l10']", + "109, CD8+ ['l7', 'l11', 'l12', 'l13']", + "110, T ['l8', 'l11', 'l14', 'l15']", + "111, cell ['l2', 'l9', 'l12', 'l14', 'l16']", + "116, individuals ['l3', 'l5', 'l6', 'l10', 'l13', 'l15', 'l16']", + "137, memory ['l17', 'l18', 'l19']", + "138, CD8+ ['l17', 'l20', 'l21']", + "139, T ['l18', 'l20', 'l22']", + "140, cells ['l19', 'l21', 'l22']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33020650", + "TEXT": "The Zero Childhood Cancer Program is a precision medicine program to benefit children with poor-outcome, rare, relapsed or refractory cancer. Using tumor and germline whole genome sequencing (WGS) and RNA sequencing (RNAseq) across 252 tumors from high-risk pediatric patients with cancer, we identified 968 reportable molecular aberrations (39.9% in WGS and RNAseq, 35.1% in WGS only and 25.0% in RNAseq only). Of these patients, 93.7% had at least one germline or somatic aberration, 71.4% had therapeutic targets and 5.2% had a change in diagnosis. WGS identified pathogenic cancer-predisposing variants in 16.2% of patients. In 76 central nervous system tumors, methylome analysis confirmed diagnosis in 71.1% of patients and contributed to a change of diagnosis in two patients (2.6%). To date, 43 patients have received a recommended therapy, 38 of whom could be evaluated, with 31% showing objective evidence of clinical benefit. Comprehensive molecular profiling resolved the molecular basis of virtually all high-risk cancers, leading to clinical benefit in some patients.", + "TAG_DATA": [ + "95, central {'context': 'B-neoplasm'}", + "96, nervous {'context': 'I-neoplasm'}", + "97, system {'context': 'I-neoplasm'}", + "98, tumors, {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "95, central ['l0', 'l1', 'l2']", + "96, nervous ['l0', 'l3', 'l4']", + "97, system ['l1', 'l3', 'l5']", + "98, tumors, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33169017", + "TEXT": "We developed a metagenomic next-generation sequencing (mNGS) test using cell-free DNA from body fluids to identify pathogens. The performance of mNGS testing of 182 body fluids from 160 patients with acute illness was evaluated using two sequencing platforms in comparison to microbiological testing using culture, 16S bacterial PCR and/or 28S-internal transcribed ribosomal gene spacer (28S-ITS) fungal PCR. Test sensitivity and specificity of detection were 79 and 91% for bacteria and 91 and 89% for fungi, respectively, by Illumina sequencing; and 75 and 81% for bacteria and 91 and 100% for fungi, respectively, by nanopore sequencing. In a case series of 12 patients with culture/PCR-negative body fluids but for whom an infectious diagnosis was ultimately established, seven (58%) were mNGS positive. Real-time computational analysis enabled pathogen identification by nanopore sequencing in a median 50-min sequencing and 6-h sample-to-answer time. Rapid mNGS testing is a promising tool for diagnosis of unknown infections from body fluids.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33398163", + "TEXT": "The state of intermediate hyperglycemia is indicative of elevated risk of developing type 2 diabetes1. However, the current definition of prediabetes neither reflects subphenotypes of pathophysiology of type 2 diabetes nor is predictive of future metabolic trajectories. We used partitioning on variables derived from oral glucose tolerance tests, MRI-measured body fat distribution, liver fat content and genetic risk in a cohort of extensively phenotyped individuals who are at increased risk for type 2 diabetes2,3 to identify six distinct clusters of subphenotypes. Three of the identified subphenotypes have increased glycemia (clusters 3, 5 and 6), but only individuals in clusters 5 and 3 have imminent diabetes risks. By contrast, those in cluster 6 have moderate risk of type 2 diabetes, but an increased risk of kidney disease and all-cause mortality. Findings were replicated in an independent cohort using simple anthropomorphic and glycemic constructs4. This proof-of-concept study demonstrates that pathophysiological heterogeneity exists before diagnosis of type 2 diabetes and highlights a group of individuals who have an increased risk of complications without rapid progression to overt type 2 diabetes.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33106666", + "TEXT": "Acute liver failure (ALF) is a fulminant complication of multiple etiologies, characterized by rapid hepatic destruction, multi-organ failure and mortality. ALF treatment is mainly limited to supportive care and liver transplantation. Here we utilize the acetaminophen (APAP) and thioacetamide (TAA) ALF models in characterizing 56,527 single-cell transcriptomes to define the mouse ALF cellular atlas. We demonstrate that unique, previously uncharacterized stellate cell, endothelial cell, Kupffer cell, monocyte and neutrophil subsets, and their intricate intercellular crosstalk, drive ALF. We unravel a common MYC-dependent transcriptional program orchestrating stellate, endothelial and Kupffer cell activation during ALF, which is regulated by the gut microbiome through Toll-like receptor (TLR) signaling. Pharmacological inhibition of MYC, upstream TLR signaling checkpoints or microbiome depletion suppress this cell-specific, MYC-dependent program, thereby attenuating ALF. In humans, we demonstrate upregulated hepatic MYC expression in ALF transplant recipients compared to healthy donors. Collectively we demonstrate that detailed cellular/genetic decoding may enable pathway-specific ALF therapeutic intervention.", + "TAG_DATA": [ + "104, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "105, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "106, of {'perturbing_action': 'I-pharmacological inhibition'}", + "107, MYC, {'perturbing_action': 'I-pharmacological inhibition'}", + "124, humans, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "104, Pharmacological ['l0', 'l1', 'l2', 'l3']", + "105, inhibition ['l0', 'l4', 'l5']", + "106, of ['l1', 'l4', 'l6']", + "107, MYC, ['l2', 'l5', 'l6']", + "124, humans, ['l3']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological" + ] + }, + "context": { + "val": "organism", + "words": [ + "humans," + ] + } + } + ] + }, + { + "PMID": "32895572", + "TEXT": "Recent studies show that aneuploidy and driver gene mutations precede cancer diagnosis by many years1-4. We assess whether these genomic signals can be used for early detection and pre-emptive cancer treatment using the neoplastic precursor lesion Barrett's esophagus as an exemplar5. Shallow whole-genome sequencing of 777 biopsies, sampled from 88 patients in Barrett's esophagus surveillance over a period of up to 15 years, shows that genomic signals can distinguish progressive from stable disease even 10 years before histopathological transformation. These findings are validated on two independent cohorts of 76 and 248 patients. These methods are low-cost and applicable to standard clinical biopsy samples. Compared with current management guidelines based on histopathology and clinical presentation, genomic classification enables earlier treatment for high-risk patients as well as reduction of unnecessary treatment and monitoring for patients who are unlikely to develop cancer.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33077954", + "TEXT": "Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33077955", + "TEXT": "An open question in aggressive cancers such as melanoma is how malignant cells can shift the immune system to pro-tumorigenic functions. Here we identify midkine (MDK) as a melanoma-secreted driver of an inflamed, but immune evasive, microenvironment that defines poor patient prognosis and resistance to immune checkpoint blockade. Mechanistically, MDK was found to control the transcriptome of melanoma cells, allowing for coordinated activation of nuclear factor-κB and downregulation of interferon-associated pathways. The resulting MDK-modulated secretome educated macrophages towards tolerant phenotypes that promoted CD8+ T cell dysfunction. In contrast, genetic targeting of MDK sensitized melanoma cells to anti-PD-1/anti-PD-L1 treatment. Emphasizing the translational relevance of these findings, the expression profile of MDK-depleted tumors was enriched in key indicators of a good response to immune checkpoint blockers in independent patient cohorts. Together, these data reveal that MDK acts as an internal modulator of autocrine and paracrine signals that maintain immune suppression in aggressive melanomas.", + "TAG_DATA": [ + "76, macrophages {'context': 'B-cells'}", + "82, CD8+ {'context': 'B-cells'}", + "83, T {'context': 'I-cells'}", + "84, cell {'context': 'I-cells'}", + "88, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "89, targeting {'perturbing_action': 'I-gene loss-of-function'}", + "90, of {'perturbing_action': 'I-gene loss-of-function'}", + "91, MDK {'perturbing_action': 'I-rnai/knockdown'}", + "93, melanoma {'context': 'B-transformed cells'}", + "94, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "76, macrophages ['l0', 'l1', 'l2']", + "82, CD8+ ['l0', 'l3', 'l4']", + "83, T ['l1', 'l3', 'l5']", + "84, cell ['l2', 'l4', 'l5']", + "88, genetic ['l6', 'l7', 'l8', 'l9', 'l10']", + "89, targeting ['l6', 'l11', 'l12', 'l13', 'l14']", + "90, of ['l7', 'l11', 'l15', 'l16', 'l17']", + "91, MDK ['l8', 'l12', 'l15', 'l18', 'l19']", + "93, melanoma ['l9', 'l13', 'l16', 'l18', 'l20']", + "94, cells ['l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "targeting", + "of" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "MDK" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cells" + ] + } + } + ] + }, + { + "PMID": "33046868", + "TEXT": "Vα24-invariant natural killer T (NKT) cells have shown potent anti-tumor properties in murine tumor models and have been linked to favorable outcomes in patients with cancer. However, low numbers of these cells in humans have hindered their clinical applications. Here we report interim results from all three patients enrolled on dose level 1 in a phase 1 dose-escalation trial of autologous NKT cells engineered to co-express a GD2-specific chimeric antigen receptor (CAR) with interleukin-15 in children with relapsed or resistant neuroblastoma (NCT03294954). Primary and secondary objectives were to assess safety and anti-tumor responses, respectively, with immune response evaluation as an additional objective. We ex vivo expanded highly pure NKT cells (mean ± s.d., 94.7 ± 3.8%) and treated patients with 3 × 106 CAR-NKT cells per square meter of body surface area after lymphodepleting conditioning with cyclophosphamide/fludarabine (Cy/Flu). Cy/Flu conditioning was the probable cause for grade 3-4 hematologic adverse events, as they occurred before CAR-NKT cell infusion, and no dose-limiting toxicities were observed. CAR-NKT cells expanded in vivo, localized to tumors and, in one patient, induced an objective response with regression of bone metastatic lesions. These initial results suggest that CAR-NKT cells can be expanded to clinical scale and safely applied to treat patients with cancer.", + "TAG_DATA": [ + "60, autologous {'context': 'B-cells'}", + "61, NKT {'context': 'I-cells'}", + "62, cells {'context': 'I-cells'}", + "75, children {'context': 'B-patient'}", + "77, relapsed {'context': 'B-neoplasm'}", + "78, or {'context': 'I-neoplasm'}", + "79, resistant {'context': 'I-neoplasm'}", + "80, neuroblastoma {'context': 'I-neoplasm'}", + "108, NKT {'context': 'I-cells'}", + "109, cells {'context': 'I-cells'}", + "118, patients {'context': 'B-patient'}", + "123, CAR-NKT {'context': 'B-cells'}", + "124, cells {'context': 'I-cells'}", + "163, CAR-NKT {'context': 'B-cells'}", + "164, cells {'context': 'I-cells'}", + "166, in {'context': 'B-in vivo'}", + "167, vivo, {'context': 'I-in vivo'}", + "170, tumors {'context': 'B-neoplasm'}", + "180, regression {'phenotype': 'B-tumour regression'}", + "182, bone {'phenotype': 'B-metastasis'}", + "183, metastatic {'phenotype': 'I-metastasis'}", + "184, lesions. {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "60, autologous ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "61, NKT ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "62, cells ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "75, children ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "77, relapsed ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "78, or ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37']", + "79, resistant ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l39', 'l40']", + "80, neuroblastoma ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l38', 'l41', 'l42']", + "108, NKT ['l7', 'l15', 'l22', 'l28', 'l33', 'l39', 'l41', 'l43', 'l44', 'l45', 'l46']", + "109, cells ['l8', 'l16', 'l23', 'l29', 'l34', 'l37', 'l40', 'l42', 'l43', 'l47']", + "118, patients ['l44', 'l48', 'l49']", + "123, CAR-NKT ['l45', 'l48', 'l50']", + "124, cells ['l46', 'l47', 'l49', 'l50']", + "163, CAR-NKT ['l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "164, cells ['l51', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "166, in ['l52', 'l59', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "167, vivo, ['l53', 'l60', 'l66', 'l72', 'l73', 'l74', 'l75', 'l76']", + "170, tumors ['l54', 'l61', 'l67', 'l72']", + "180, regression ['l55', 'l62', 'l68', 'l73', 'l77', 'l78', 'l79']", + "182, bone ['l56', 'l63', 'l69', 'l74', 'l77', 'l80', 'l81']", + "183, metastatic ['l57', 'l64', 'l70', 'l75', 'l78', 'l80', 'l82']", + "184, lesions. ['l58', 'l65', 'l71', 'l76', 'l79', 'l81', 'l82']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CAR-NKT", + "cells" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CAR-NKT", + "cells" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "bone", + "metastatic", + "lesions." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "bone", + "metastatic", + "lesions." + ] + } + } + ] + }, + { + "PMID": "33046870", + "TEXT": "Preoperative immunotherapy with anti-PD1 plus anti-CTLA4 antibodies has shown remarkable pathological responses in melanoma1 and colorectal cancer2. In NABUCCO (ClinicalTrials.gov: NCT03387761 ), a single-arm feasibility trial, 24 patients with stage III urothelial cancer (UC) received two doses of ipilimumab and two doses of nivolumab, followed by resection. The primary endpoint was feasibility to resect within 12 weeks from treatment start. All patients were evaluable for the study endpoints and underwent resection, 23 (96%) within 12 weeks. Grade 3-4 immune-related adverse events occurred in 55% of patients and in 41% of patients when excluding clinically insignificant laboratory abnormalities. Eleven patients (46%) had a pathological complete response (pCR), meeting the secondary efficacy endpoint. Fourteen patients (58%) had no remaining invasive disease (pCR or pTisN0/pTaN0). In contrast to studies with anti-PD1/PD-L1 monotherapy, complete response to ipilimumab plus nivolumab was independent of baseline CD8+ presence or T-effector signatures. Induction of tertiary lymphoid structures upon treatment was observed in responding patients. Our data indicate that combined CTLA-4 plus PD-1 blockade might provide an effective preoperative treatment strategy in locoregionally advanced UC, irrespective of pre-existing CD8+ T cell activity.", + "TAG_DATA": [ + "27, patients {'context': 'B-patient'}", + "29, stage {'context': 'B-neoplasm'}", + "30, III {'context': 'I-neoplasm'}", + "31, urothelial {'context': 'I-neoplasm'}", + "32, cancer {'context': 'I-neoplasm'}", + "33, (UC) {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "27, patients ['l0', 'l1', 'l2', 'l3', 'l4']", + "29, stage ['l0', 'l5', 'l6', 'l7', 'l8']", + "30, III ['l1', 'l5', 'l9', 'l10', 'l11']", + "31, urothelial ['l2', 'l6', 'l9', 'l12', 'l13']", + "32, cancer ['l3', 'l7', 'l10', 'l12', 'l14']", + "33, (UC) ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33020648", + "TEXT": "Immune and targeted therapies achieve long-term survival in metastatic melanoma; however, new treatment strategies are needed to improve patients' outcomes1,2. We report on the efficacy, safety and biomarker analysis from the single-arm safety run-in (part 1; n = 9) and biomarker (part 2; n = 27) cohorts of the randomized, placebo-controlled, phase 3 COMBI-i trial (NCT02967692) of the anti-PD-1 antibody spartalizumab, in combination with the BRAF inhibitor dabrafenib and MEK inhibitor trametinib. Patients (n = 36) had previously untreated BRAF V600-mutant unresectable or metastatic melanoma. In part 1, the recommended phase 3 regimen was identified based on the incidence of dose-limiting toxicities (DLTs; primary endpoint): 400 mg of spartalizumab every 4 weeks plus 150 mg of dabrafenib twice daily plus 2 mg of trametinib once daily. Part 2 characterized changes in PD-L1 levels and CD8+ cells following treatment (primary endpoint), and analyzed additional biomarkers. Assessments of efficacy and safety were key secondary endpoints (median follow-up, 24.3 months). Spartalizumab plus dabrafenib and trametinib led to an objective response rate (ORR) of 78%, including 44% complete responses (CRs). Grade ≥3 treatment-related adverse events (TRAEs) were experienced by 72% of patients. All patients had temporary dose modifications, and 17% permanently discontinued all three study drugs due to TRAEs. Early progression-free survival (PFS) events were associated with low tumor mutational burden/T cell-inflamed gene expression signature (GES) or high immunosuppressive tumor microenvironment (TME) GES levels at baseline; an immunosuppressive TME may also preclude CR. Overall, the efficacy, safety and on-treatment biomarker modulations associated with spartalizumab plus dabrafenib and trametinib are promising, and biomarkers that may predict long-term benefit were identified.", + "TAG_DATA": [ + "74, unresectable {'context': 'B-neoplasm'}", + "75, or {'context': 'I-neoplasm'}", + "76, metastatic {'context': 'I-neoplasm'}", + "77, melanoma. {'context': 'I-neoplasm'}", + "120, CD8+ {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "74, unresectable ['l0', 'l1', 'l2']", + "75, or ['l0', 'l3', 'l4']", + "76, metastatic ['l1', 'l3', 'l5']", + "77, melanoma. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32778827", + "TEXT": "PD-1 blockade is highly effective in classical Hodgkin lymphomas (cHLs), which exhibit frequent copy-number gains of CD274 (PD-L1) and PDC1LG2 (PD-L2) on chromosome 9p24.1. However, in this largely MHC-class-I-negative tumor, the mechanism of action of anti-PD-1 therapy remains undefined. We utilized the complementary approaches of T cell receptor (TCR) sequencing and cytometry by time-of-flight analysis to obtain a peripheral immune signature of responsiveness to PD-1 blockade in 56 patients treated in the CheckMate 205 phase II clinical trial (NCT02181738). Anti-PD-1 therapy was most effective in patients with a diverse baseline TCR repertoire and an associated expansion of singleton clones during treatment. CD4+, but not CD8+, TCR diversity significantly increased during therapy, most strikingly in patients who had achieved complete responses. Additionally, patients who responded to therapy had an increased abundance of activated natural killer cells and a newly identified CD3-CD68+CD4+GrB+ subset. These studies highlight the roles of recently expanded, clonally diverse CD4+ T cells and innate effectors in the efficacy of PD-1 blockade in cHL.", + "TAG_DATA": [ + "85, patients {'context': 'B-patient'}", + "132, natural {'context': 'B-cells'}", + "133, killer {'context': 'I-cells'}", + "134, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "132, natural ['l0', 'l1']", + "133, killer ['l0', 'l2']", + "134, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33020651", + "TEXT": "The coronavirus disease 2019 (COVID-19) pandemic is straining public health systems worldwide, and major non-pharmaceutical interventions have been implemented to slow its spread1-4. During the initial phase of the outbreak, dissemination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was primarily determined by human mobility from Wuhan, China5,6. Yet empirical evidence on the effect of key geographic factors on local epidemic transmission is lacking7. In this study, we analyzed highly resolved spatial variables in cities, together with case count data, to investigate the role of climate, urbanization and variation in interventions. We show that the degree to which cases of COVID-19 are compressed into a short period of time (peakedness of the epidemic) is strongly shaped by population aggregation and heterogeneity, such that epidemics in crowded cities are more spread over time, and crowded cities have larger total attack rates than less populated cities. Observed differences in the peakedness of epidemics are consistent with a meta-population model of COVID-19 that explicitly accounts for spatial hierarchies. We paired our estimates with globally comprehensive data on human mobility and predict that crowded cities worldwide could experience more prolonged epidemics.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33106664", + "TEXT": "The dry season is a major challenge for Plasmodium falciparum parasites in many malaria endemic regions, where water availability limits mosquito vectors to only part of the year. How P. falciparum bridges two transmission seasons months apart, without being cleared by the human host or compromising host survival, is poorly understood. Here we show that low levels of P. falciparum parasites persist in the blood of asymptomatic Malian individuals during the 5- to 6-month dry season, rarely causing symptoms and minimally affecting the host immune response. Parasites isolated during the dry season are transcriptionally distinct from those of individuals with febrile malaria in the transmission season, coinciding with longer circulation within each replicative cycle of parasitized erythrocytes without adhering to the vascular endothelium. Low parasite levels during the dry season are not due to impaired replication but rather to increased splenic clearance of longer-circulating infected erythrocytes, which likely maintain parasitemias below clinical and immunological radar. We propose that P. falciparum virulence in areas of seasonal malaria transmission is regulated so that the parasite decreases its endothelial binding capacity, allowing increased splenic clearance and enabling several months of subclinical parasite persistence.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33462450", + "TEXT": "The impact of single-agent antibodies against programmed death-ligand 1 (PD-L1) as maintenance therapy is unknown in patients with metastatic breast cancer. The SAFIR02-BREAST IMMUNO substudy included patients with human epidermal growth factor receptor type 2 (Her2)-negative metastatic breast cancer whose disease did not progress after six to eight cycles of chemotherapy. Patients (n = 199) were randomized to either durvalumab (10 mg kg-1 every 2 weeks) or maintenance chemotherapy. In the overall population, durvalumab did not improve progression-free survival (adjusted hazard ratio (HR): 1.40, 95% confidence interval (CI): 1.00-1.96; P = 0.047) or overall survival (OS; adjusted HR: 0.84, 95% CI: 0.54-1.29; P = 0.423). In an exploratory subgroup analysis, durvalumab improved OS in patients with triple-negative breast cancer (TNBC; n = 82; HR: 0.54, 95% CI: 0.30-0.97, P = 0.0377). Exploratory analysis showed that the HR of death was 0.37 (95% CI: 0.12-1.13) for patients with PD-L1+ TNBC (n = 32) and 0.49 (95% CI: 0.18-1.34) for those with PD-L1- TNBC (n = 29). In patients with TNBC, exploratory analyses showed that the HR for durvalumab efficacy (OS) was 0.18 (95% CI: 0.05-0.71; log-rank test, P = 0.0059) in patients with CD274 gain/amplification (n = 23) and 1.12 (95% CI: 0.42-2.99; log-rank test, P = 0.8139) in patients with CD274 normal/loss (n = 32). Tumor infiltration by lymphocytes (CD8, FoxP3 and CD103 expressions) and homologous recombination deficiency did not predict sensitivity to durvalumab in exploratory analyses.", + "TAG_DATA": [ + "37, breast {'context': 'I-neoplasm'}", + "107, patients {'context': 'B-patient'}", + "109, triple-negative {'context': 'B-neoplasm'}", + "110, breast {'context': 'I-neoplasm'}", + "111, cancer {'context': 'I-neoplasm'}", + "112, (TNBC; {'context': 'I-neoplasm'}", + "134, patients {'context': 'B-patient'}", + "151, patients {'context': 'B-patient'}", + "153, TNBC, {'context': 'I-patient'}", + "173, patients {'context': 'B-patient'}", + "187, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "36, metastatic ['l0', 'l1']", + "37, breast ['l0', 'l2']", + "38, cancer ['l1', 'l2']", + "107, patients ['l3', 'l4', 'l5', 'l6', 'l7']", + "109, triple-negative ['l3', 'l8', 'l9', 'l10', 'l11']", + "110, breast ['l4', 'l8', 'l12', 'l13', 'l14']", + "111, cancer ['l5', 'l9', 'l12', 'l15', 'l16']", + "112, (TNBC; ['l6', 'l10', 'l13', 'l15', 'l17']", + "134, patients ['l7', 'l11', 'l14', 'l16', 'l17']", + "151, patients ['l18', 'l19']", + "153, TNBC, ['l18', 'l20']", + "173, patients ['l19', 'l20', 'l21']", + "187, patients ['l21']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33188278", + "TEXT": "Ribonucleoprotein (RNP) granules are biomolecular condensates-liquid-liquid phase-separated droplets that organize and manage messenger RNA metabolism, cell signaling, biopolymer assembly, biochemical reactions and stress granule responses to cellular adversity. Dysregulated RNP granules drive neuromuscular degenerative disease but have not previously been linked to heart failure. By exploring the molecular basis of congenital dilated cardiomyopathy (DCM) in genome-edited pigs homozygous for an RBM20 allele encoding the pathogenic R636S variant of human RNA-binding motif protein-20 (RBM20), we discovered that RNP granules accumulated abnormally in the sarcoplasm, and we confirmed this finding in myocardium and reprogrammed cardiomyocytes from patients with DCM carrying the R636S allele. Dysregulated sarcoplasmic RBM20 RNP granules displayed liquid-like material properties, docked at precisely spaced intervals along cytoskeletal elements, promoted phase partitioning of cardiac biomolecules and fused with stress granules. Our results link dysregulated RNP granules to myocardial cellular pathobiology and heart failure in gene-edited pigs and patients with DCM caused by RBM20 mutation.", + "TAG_DATA": [ + "56, pigs {'context': 'B-organism'}", + "57, homozygous {'perturbing_action': 'B-other'}", + "58, for {'perturbing_action': 'I-other'}", + "59, an {'perturbing_action': 'I-other'}", + "60, RBM20 {'perturbing_action': 'I-other'}", + "61, allele {'perturbing_action': 'I-other'}", + "62, encoding {'perturbing_action': 'I-other'}", + "63, the {'perturbing_action': 'I-other'}", + "64, pathogenic {'perturbing_action': 'I-other'}", + "65, R636S {'perturbing_action': 'I-other'}", + "66, variant {'perturbing_action': 'I-other'}", + "67, of {'perturbing_action': 'I-other'}", + "68, human {'perturbing_action': 'I-other'}", + "69, RNA-binding {'perturbing_action': 'I-other'}", + "70, motif {'perturbing_action': 'I-other'}", + "71, protein-20 {'perturbing_action': 'I-other'}", + "72, (RBM20), {'perturbing_action': 'I-other'}", + "89, myocardium {'context': 'B-tissue/organ'}", + "92, cardiomyocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "56, pigs ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "57, homozygous ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "58, for ['l1', 'l8', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "59, an ['l2', 'l9', 'l24', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "60, RBM20 ['l3', 'l10', 'l25', 'l39', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "61, allele ['l4', 'l11', 'l26', 'l40', 'l53', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "62, encoding ['l5', 'l12', 'l27', 'l41', 'l54', 'l66', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "63, the ['l6', 'l13', 'l28', 'l42', 'l55', 'l67', 'l78', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "64, pathogenic ['l14', 'l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "65, R636S ['l15', 'l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l100', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "66, variant ['l16', 'l31', 'l45', 'l58', 'l70', 'l81', 'l91', 'l101', 'l110', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "67, of ['l17', 'l32', 'l46', 'l59', 'l71', 'l82', 'l92', 'l102', 'l111', 'l119', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "68, human ['l18', 'l33', 'l47', 'l60', 'l72', 'l83', 'l93', 'l103', 'l112', 'l120', 'l127', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139']", + "69, RNA-binding ['l19', 'l34', 'l48', 'l61', 'l73', 'l84', 'l94', 'l104', 'l113', 'l121', 'l128', 'l134', 'l140', 'l141', 'l142', 'l143', 'l144']", + "70, motif ['l20', 'l35', 'l49', 'l62', 'l74', 'l85', 'l95', 'l105', 'l114', 'l122', 'l129', 'l135', 'l140', 'l145', 'l146', 'l147', 'l148']", + "71, protein-20 ['l21', 'l36', 'l50', 'l63', 'l75', 'l86', 'l96', 'l106', 'l115', 'l123', 'l130', 'l136', 'l141', 'l145', 'l149', 'l150', 'l151']", + "72, (RBM20), ['l22', 'l37', 'l51', 'l64', 'l76', 'l87', 'l97', 'l107', 'l116', 'l124', 'l131', 'l137', 'l142', 'l146', 'l149', 'l152', 'l153']", + "89, myocardium ['l7', 'l23', 'l38', 'l52', 'l65', 'l77', 'l88', 'l98', 'l108', 'l117', 'l125', 'l132', 'l138', 'l143', 'l147', 'l150', 'l152']", + "92, cardiomyocytes ['l99', 'l109', 'l118', 'l126', 'l133', 'l139', 'l144', 'l148', 'l151', 'l153']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "pigs" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "homozygous", + "for", + "an", + "RBM20", + "allele", + "encoding", + "the" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "homozygous", + "for", + "an", + "RBM20", + "allele", + "encoding", + "the", + "pathogenic", + "R636S", + "variant", + "of", + "human", + "RNA-binding", + "motif", + "protein-20", + "(RBM20)," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "myocardium" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "the", + "pathogenic", + "R636S", + "variant", + "of", + "human", + "RNA-binding", + "motif", + "protein-20", + "(RBM20)," + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes" + ] + } + } + ] + }, + { + "PMID": "32812012", + "TEXT": "Recent reports highlight a new clinical syndrome in children related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1-multisystem inflammatory syndrome in children (MIS-C)-which comprises multiorgan dysfunction and systemic inflammation2-13. We performed peripheral leukocyte phenotyping in 25 children with MIS-C, in the acute (n = 23; worst illness within 72 h of admission), resolution (n = 14; clinical improvement) and convalescent (n = 10; first outpatient visit) phases of the illness and used samples from seven age-matched healthy controls for comparisons. Among the MIS-C cohort, 17 (68%) children were SARS-CoV-2 seropositive, suggesting previous SARS-CoV-2 infections14,15, and these children had more severe disease. In the acute phase of MIS-C, we observed high levels of interleukin-1β (IL-1β), IL-6, IL-8, IL-10, IL-17, interferon-γ and differential T and B cell subset lymphopenia. High CD64 expression on neutrophils and monocytes, and high HLA-DR expression on γδ and CD4+CCR7+ T cells in the acute phase, suggested that these immune cell populations were activated. Antigen-presenting cells had low HLA-DR and CD86 expression, potentially indicative of impaired antigen presentation. These features normalized over the resolution and convalescence phases. Overall, MIS-C presents as an immunopathogenic illness1 and appears distinct from Kawasaki disease.", + "TAG_DATA": [ + "149, Antigen-presenting {'context': 'B-cells'}", + "150, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "149, Antigen-presenting ['l0']", + "150, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33462448", + "TEXT": "Animal studies implicate meningeal lymphatic dysfunction in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (PD). However, there is no direct evidence in humans to support this role1-5. In this study, we used dynamic contrast-enhanced magnetic resonance imaging to assess meningeal lymphatic flow in cognitively normal controls and patients with idiopathic PD (iPD) or atypical Parkinsonian (AP) disorders. We found that patients with iPD exhibited significantly reduced flow through the meningeal lymphatic vessels (mLVs) along the superior sagittal sinus and sigmoid sinus, as well as a notable delay in deep cervical lymph node perfusion, compared to patients with AP. There was no significant difference in the size (cross-sectional area) of mLVs in patients with iPD or AP versus controls. In mice injected with α-synuclein (α-syn) preformed fibrils, we showed that the emergence of α-syn pathology was followed by delayed meningeal lymphatic drainage, loss of tight junctions among meningeal lymphatic endothelial cells and increased inflammation of the meninges. Finally, blocking flow through the mLVs in mice treated with α-syn preformed fibrils increased α-syn pathology and exacerbated motor and memory deficits. These results suggest that meningeal lymphatic drainage dysfunction aggravates α-syn pathology and contributes to the progression of PD.", + "TAG_DATA": [ + "124, mice {'context': 'B-organism'}", + "168, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32934372", + "TEXT": "Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a new human disease with few effective treatments1. Convalescent plasma, donated by persons who have recovered from COVID-19, is the acellular component of blood that contains antibodies, including those that specifically recognize SARS-CoV-2. These antibodies, when transfused into patients infected with SARS-CoV-2, are thought to exert an antiviral effect, suppressing virus replication before patients have mounted their own humoral immune responses2,3. Virus-specific antibodies from recovered persons are often the first available therapy for an emerging infectious disease, a stopgap treatment while new antivirals and vaccines are being developed1,2. This retrospective, propensity score-matched case-control study assessed the effectiveness of convalescent plasma therapy in 39 patients with severe or life-threatening COVID-19 at The Mount Sinai Hospital in New York City. Oxygen requirements on day 14 after transfusion worsened in 17.9% of plasma recipients versus 28.2% of propensity score-matched controls who were hospitalized with COVID-19 (adjusted odds ratio (OR), 0.86; 95% confidence interval (CI), 0.75-0.98; chi-square test P value = 0.025). Survival also improved in plasma recipients (adjusted hazard ratio (HR), 0.34; 95% CI, 0.13-0.89; chi-square test P = 0.027). Convalescent plasma is potentially effective against COVID-19, but adequately powered, randomized controlled trials are needed.", + "TAG_DATA": [], + "LINK_DATA": [ + "126, Sinai ['l0', 'l1', 'l2', 'l3', 'l4']", + "127, Hospital ['l0', 'l5', 'l6', 'l7', 'l8']", + "128, in ['l1', 'l5', 'l9', 'l10', 'l11']", + "129, New ['l2', 'l6', 'l9', 'l12', 'l13']", + "130, York ['l3', 'l7', 'l10', 'l12', 'l14']", + "131, City. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33139948", + "TEXT": "Growing up on a farm is associated with an asthma-protective effect, but the mechanisms underlying this effect are largely unknown. In the Protection against Allergy: Study in Rural Environments (PASTURE) birth cohort, we modeled maturation using 16S rRNA sequence data of the human gut microbiome in infants from 2 to 12 months of age. The estimated microbiome age (EMA) in 12-month-old infants was associated with previous farm exposure (β = 0.27 (0.12-0.43), P = 0.001, n = 618) and reduced risk of asthma at school age (odds ratio (OR) = 0.72 (0.56-0.93), P = 0.011). EMA mediated the protective farm effect by 19%. In a nested case-control sample (n = 138), we found inverse associations of asthma with the measured level of fecal butyrate (OR = 0.28 (0.09-0.91), P = 0.034), bacterial taxa that predict butyrate production (OR = 0.38 (0.17-0.84), P = 0.017) and the relative abundance of the gene encoding butyryl-coenzyme A (CoA):acetate-CoA-transferase, a major enzyme in butyrate metabolism (OR = 0.43 (0.19-0.97), P = 0.042). The gut microbiome may contribute to asthma protection through metabolites, supporting the concept of a gut-lung axis in humans.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33046869", + "TEXT": "Immune checkpoint therapy is being tested in the neoadjuvant setting for patients with localized urothelial carcinoma1,2, with one study reporting data in cisplatin-ineligible patients who received anti-PD-L1 monotherapy2. The study reported that patients with bulky tumors, a known high-risk feature defined as greater than clinical T2 disease, had fewer responses, with pathological complete response rate of 17%2. Here we report on the first pilot combination neoadjuvant trial ( NCT02812420 ) with anti-PD-L1 (durvalumab) plus anti-CTLA-4 (tremelimumab) in cisplatin-ineligible patients, with all tumors identified as having high-risk features (n = 28). High-risk features were defined by bulky tumors, variant histology, lymphovascular invasion, hydronephrosis and/or high-grade upper tract disease3-5. The primary endpoint was safety and we observed 6 of 28 patients (21%) with grade ≥3 immune-related adverse events, consisting of asymptomatic laboratory abnormalities (n = 4), hepatitis and colitis (n = 2). We also observed pathological complete response of 37.5% and downstaging to pT1 or less in 58% of patients who completed surgery (n = 24). In summary, we provide initial safety, efficacy and biomarker data with neoadjuvant combination anti-PD-L1 plus anti-CTLA-4, which warrants further development for patients with localized urothelial carcinoma, especially cisplatin-ineligible patients with high-risk features who do not currently have an established standard-of-care neoadjuvant treatment.", + "TAG_DATA": [ + "81, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "143, downstaging ['l0']", + "145, pT1 ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33097835", + "TEXT": "We use COVID-19 case and mortality data from 1 February 2020 to 21 September 2020 and a deterministic SEIR (susceptible, exposed, infectious and recovered) compartmental framework to model possible trajectories of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and the effects of non-pharmaceutical interventions in the United States at the state level from 22 September 2020 through 28 February 2021. Using this SEIR model, and projections of critical driving covariates (pneumonia seasonality, mobility, testing rates and mask use per capita), we assessed scenarios of social distancing mandates and levels of mask use. Projections of current non-pharmaceutical intervention strategies by state-with social distancing mandates reinstated when a threshold of 8 deaths per million population is exceeded (reference scenario)-suggest that, cumulatively, 511,373 (469,578-578,347) lives could be lost to COVID-19 across the United States by 28 February 2021. We find that achieving universal mask use (95% mask use in public) could be sufficient to ameliorate the worst effects of epidemic resurgences in many states. Universal mask use could save an additional 129,574 (85,284-170,867) lives from September 22, 2020 through the end of February 2021, or an additional 95,814 (60,731-133,077) lives assuming a lesser adoption of mask wearing (85%), when compared to the reference scenario.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33462446", + "TEXT": "Deep brain stimulation is a promising treatment for severe depression, but lack of efficacy in randomized trials raises questions regarding anatomical targeting. We implanted multi-site intracranial electrodes in a severely depressed patient and systematically assessed the acute response to focal electrical neuromodulation. We found an elaborate repertoire of distinctive emotional responses that were rapid in onset, reproducible, and context and state dependent. Results provide proof of concept for personalized, circuit-specific medicine in psychiatry.", + "TAG_DATA": [ + "29, severely {'context': 'B-patient'}", + "30, depressed {'context': 'I-patient'}", + "31, patient {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "29, severely ['l0', 'l1']", + "30, depressed ['l0', 'l2']", + "31, patient ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32895569", + "TEXT": "Intestinal failure, following extensive anatomical or functional loss of small intestine, has debilitating long-term consequences for children1. The priority of patient care is to increase the length of functional intestine, particularly the jejunum, to promote nutritional independence2. Here we construct autologous jejunal mucosal grafts using biomaterials from pediatric patients and show that patient-derived organoids can be expanded efficiently in vitro. In parallel, we generate decellularized human intestinal matrix with intact nanotopography, which forms biological scaffolds. Proteomic and Raman spectroscopy analyses reveal highly analogous biochemical profiles of human small intestine and colon scaffolds, indicating that they can be used interchangeably as platforms for intestinal engineering. Indeed, seeding of jejunal organoids onto either type of scaffold reliably reconstructs grafts that exhibit several aspects of physiological jejunal function and that survive to form luminal structures after transplantation into the kidney capsule or subcutaneous pockets of mice for up to 2 weeks. Our findings provide proof-of-concept data for engineering patient-specific jejunal grafts for children with intestinal failure, ultimately aiding in the restoration of nutritional autonomy.", + "TAG_DATA": [ + "58, in {'context': 'B-in vitro'}", + "59, vitro. {'context': 'I-in vitro'}", + "107, jejunal {'context': 'B-organoid'}", + "108, organoids {'context': 'I-organoid'}", + "136, kidney {'context': 'B-tissue/organ'}", + "137, capsule {'context': 'I-tissue/organ'}", + "142, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "58, in ['l0']", + "59, vitro. ['l0']", + "107, jejunal ['l1', 'l2', 'l3', 'l4']", + "108, organoids ['l1', 'l5', 'l6', 'l7']", + "136, kidney ['l2', 'l5', 'l8', 'l9']", + "137, capsule ['l3', 'l6', 'l8', 'l10']", + "142, mice ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32908282", + "TEXT": "Despite the increasing adoption of insulin pumps and continuous glucose monitoring devices, most people with type 1 diabetes do not achieve their glycemic goals1. This could be related to a lack of expertise or inadequate time for clinicians to analyze complex sensor-augmented pump data. We tested whether frequent insulin dose adjustments guided by an automated artificial intelligence-based decision support system (AI-DSS) is as effective and safe as those guided by physicians in controlling glucose levels. ADVICE4U was a six-month, multicenter, multinational, parallel, randomized controlled, non-inferiority trial in 108 participants with type 1 diabetes, aged 10-21 years and using insulin pump therapy (ClinicalTrials.gov no. NCT03003806). Participants were randomized 1:1 to receive remote insulin dose adjustment every three weeks guided by either an AI-DSS, (AI-DSS arm, n = 54) or by physicians (physician arm, n = 54). The results for the primary efficacy measure-the percentage of time spent within the target glucose range (70-180 mg dl-1 (3.9-10.0 mmol l-1))-in the AI-DSS arm were statistically non-inferior to those in the physician arm (50.2 ± 11.1% versus 51.6 ± 11.3%, respectively, P < 1 × 10-7). The percentage of readings below 54 mg dl-1 (<3.0 mmol l-1) within the AI-DSS arm was statistically non-inferior to that in the physician arm (1.3 ± 1.4% versus 1.0 ± 0.9%, respectively, P < 0.0001). Three severe adverse events related to diabetes (two severe hypoglycemia, one diabetic ketoacidosis) were reported in the physician arm and none in the AI-DSS arm. In conclusion, use of an automated decision support tool for optimizing insulin pump settings was non-inferior to intensive insulin titration provided by physicians from specialized academic diabetes centers.", + "TAG_DATA": [ + "88, participants {'context': 'B-patient'}", + "91, 1 {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "88, participants ['l0', 'l1', 'l2']", + "90, type ['l0', 'l3', 'l4']", + "91, 1 ['l1', 'l3', 'l5']", + "92, diabetes, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33169016", + "TEXT": "The 22q11.2 deletion syndrome (22q11DS) is associated with a 20-25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. Polygenic scores were not only associated with schizophrenia and baseline intelligence quotient (IQ), respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with sub-threshold psychosis. Furthermore, in comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of individuals with 22q11DS had schizophrenia, and 63% versus 24% of individuals had intellectual disability. Collectively, these data show a shared genetic basis for schizophrenia and schizophrenia-related phenotypes and also highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33398159", + "TEXT": "Sustained pain is a major characteristic of clinical pain disorders, but it is difficult to assess in isolation from co-occurring cognitive and emotional features in patients. In this study, we developed a functional magnetic resonance imaging signature based on whole-brain functional connectivity that tracks experimentally induced tonic pain intensity and tested its sensitivity, specificity and generalizability to clinical pain across six studies (total n = 334). The signature displayed high sensitivity and specificity to tonic pain across three independent studies of orofacial tonic pain and aversive taste. It also predicted clinical pain severity and classified patients versus controls in two independent studies of clinical low back pain. Tonic and clinical pain showed similar network-level representations, particularly in somatomotor, frontoparietal and dorsal attention networks. These patterns were distinct from representations of experimental phasic pain. This study identified a brain biomarker for sustained pain with high potential for clinical translation.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33462447", + "TEXT": "Nearly one billion people worldwide suffer from obsessive-compulsive behaviors1,2, yet our mechanistic understanding of these behaviors is incomplete, and effective therapeutics are unavailable. An emerging perspective characterizes obsessive-compulsive behaviors as maladaptive habit learning3,4, which may be associated with abnormal beta-gamma neurophysiology of the orbitofrontal-striatal circuitry during reward processing5,6. We target the orbitofrontal cortex with alternating current, personalized to the intrinsic beta-gamma frequency of the reward network, and show rapid, reversible, frequency-specific modulation of reward- but not punishment-guided choice behavior and learning, driven by increased exploration in the setting of an actor-critic architecture. Next, we demonstrate that chronic application of the procedure over 5 days robustly attenuates obsessive-compulsive behavior in a non-clinical population for 3 months, with the largest benefits for individuals with more severe symptoms. Finally, we show that convergent mechanisms underlie modulation of reward learning and reduction of obsessive-compulsive symptoms. The results contribute to neurophysiological theories of reward, learning and obsessive-compulsive behavior, suggest a unifying functional role of rhythms in the beta-gamma range, and set the groundwork for the development of personalized circuit-based therapeutics for related disorders.", + "TAG_DATA": [ + "51, orbitofrontal {'context': 'B-tissue/organ'}", + "52, cortex {'context': 'I-tissue/organ'}", + "109, non-clinical {'context': 'B-patient'}", + "110, population {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "51, orbitofrontal ['l0']", + "52, cortex ['l0']", + "109, non-clinical ['l1']", + "110, population ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33442015", + "TEXT": "Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1fl/fl;Postn-Cre mice with cabozantinib, an inhibitor of multiple tyrosine kinases, caused a reduction in PN size and number and differential modulation of kinases in cell lineages that drive PN growth. Based on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a phase II, open-label, nonrandomized Simon two-stage study to assess the safety, efficacy and biologic activity of cabozantinib in patients ≥16 years of age with NF1 and progressive or symptomatic, inoperable PN ( NCT02101736 ). The trial met its primary outcome, defined as ≥25% of patients achieving a partial response (PR, defined as ≥20% reduction in target lesion volume as assessed by magnetic resonance imaging (MRI)) after 12 cycles of therapy. Secondary outcomes included adverse events (AEs), patient-reported outcomes (PROs) assessing pain and quality of life (QOL), pharmacokinetics (PK) and the levels of circulating endothelial cells and cytokines. Eight of 19 evaluable (42%) trial participants achieved a PR. The median change in tumor volume was 15.2% (range, +2.2% to -36.9%), and no patients had disease progression while on treatment. Nine patients required dose reduction or discontinuation of therapy due to AEs; common AEs included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia. A total of 11 grade 3 AEs occurred in eight patients. Patients with PR had a significant reduction in tumor pain intensity and pain interference in daily life but no change in global QOL scores. These data indicate that cabozantinib is active in NF1-associated PN, resulting in tumor volume reduction and pain improvement.", + "TAG_DATA": [ + "21, Nf1fl/fl;Postn-Cre {'perturbing_action': 'B-gene loss-of-function'}", + "22, mice {'context': 'B-organism'}", + "80, patients {'context': 'B-patient'}", + "106, patients {'context': 'B-patient'}", + "173, tumor {'context': 'B-neoplasm'}", + "186, progression {'phenotype': 'I-tumour progression'}", + "232, tumor {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "21, Nf1fl/fl;Postn-Cre ['l0', 'l1', 'l2']", + "22, mice ['l0', 'l3', 'l4']", + "80, patients ['l1', 'l3', 'l5']", + "106, patients ['l2', 'l4', 'l5']", + "173, tumor ['l6']", + "186, progression ['l6']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nf1fl/fl;Postn-Cre" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nf1fl/fl;Postn-Cre" + ] + }, + "context": { + "val": "patient", + "words": [ + "patients" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "progression" + ] + } + } + ] + }, + { + "PMID": "33077958", + "TEXT": "The risk of tuberculosis (TB) is variable among individuals with latent Mycobacterium tuberculosis infection (LTBI), but validated estimates of personalized risk are lacking. In pooled data from 18 systematically identified cohort studies from 20 countries, including 80,468 individuals tested for LTBI, 5-year cumulative incident TB risk among people with untreated LTBI was 15.6% (95% confidence interval (CI), 8.0-29.2%) among child contacts, 4.8% (95% CI, 3.0-7.7%) among adult contacts, 5.0% (95% CI, 1.6-14.5%) among migrants and 4.8% (95% CI, 1.5-14.3%) among immunocompromised groups. We confirmed highly variable estimates within risk groups, necessitating an individualized approach to risk stratification. Therefore, we developed a personalized risk predictor for incident TB (PERISKOPE-TB) that combines a quantitative measure of T cell sensitization and clinical covariates. Internal-external cross-validation of the model demonstrated a random effects meta-analysis C-statistic of 0.88 (95% CI, 0.82-0.93) for incident TB. In decision curve analysis, the model demonstrated clinical utility for targeting preventative treatment, compared to treating all, or no, people with LTBI. We challenge the current crude approach to TB risk estimation among people with LTBI in favor of our evidence-based and patient-centered method, in settings aiming for pre-elimination worldwide.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32943787", + "TEXT": "Superspreading events (SSEs) have characterized previous epidemics of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) infections1-6. For SARS-CoV-2, the degree to which SSEs are involved in transmission remains unclear, but there is growing evidence that SSEs might be a typical feature of COVID-197,8. Using contact tracing data from 1,038 SARS-CoV-2 cases confirmed between 23 January and 28 April 2020 in Hong Kong, we identified and characterized all local clusters of infection. We identified 4-7 SSEs across 51 clusters (n = 309 cases) and estimated that 19% (95% confidence interval, 15-24%) of cases seeded 80% of all local transmission. Transmission in social settings was associated with more secondary cases than households when controlling for age (P = 0.002). Decreasing the delay between symptom onset and case confirmation did not result in fewer secondary cases (P = 0.98), although the odds that an individual being quarantined as a contact interrupted transmission was 14.4 (95% CI, 1.9-107.2). Public health authorities should focus on rapidly tracing and quarantining contacts, along with implementing restrictions targeting social settings to reduce the risk of SSEs and suppress SARS-CoV-2 transmission.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33257893", + "TEXT": "The effectiveness of control measures to contain coronavirus disease 2019 (COVID-19) in Wanzhou, China was assessed. Epidemiological data were analyzed for 183 confirmed COVID-19 cases and their close contacts from five generations of transmission of severe acute respiratory syndrome coronavirus 2 throughout the entire COVID-19 outbreak in Wanzhou. Approximately 67.2% and 32.8% of cases were symptomatic and asymptomatic, respectively. Asymptomatic and presymptomatic transmission accounted for 75.9% of the total recorded transmission. The reproductive number was 1.64 (95% confidence interval: 1.16-2.40) for G1-to-G2 transmission, decreasing to 0.31-0.39 in later generations, concomitant with implementation of rigorous control measures. Substantially higher infection risk was associated with contact within 5 d after the infectors had been infected, frequent contact and ≥8 h of contact duration. The spread of COVID-19 was effectively controlled in Wanzhou by breaking the transmission chain through social distancing, extensive contact tracing, mass testing and strict quarantine of close contacts.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33020646", + "TEXT": "Preclinical modeling suggests that intermittent BRAF inhibitor therapy may delay acquired resistance when blocking oncogenic BRAFV600 in melanoma1,2. We conducted S1320, a randomized, open-label, phase 2 clinical trial (NCT02196181) evaluating whether intermittent dosing of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib improves progression-free survival in patients with metastatic and unresectable BRAFV600 melanoma. Patients were enrolled at 68 academic and community sites nationally. All patients received continuous dabrafenib and trametinib during an 8-week lead-in period, after which patients with non-progressing tumors were randomized to either continuous or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. The trial has completed accrual and 206 patients with similar baseline characteristics were randomized 1:1 to the two study arms (105 to continuous dosing, 101 to intermittent dosing). Continuous dosing yielded a statistically significant improvement in post-randomization progression-free survival compared with intermittent dosing (median 9.0 months versus 5.5 months, P = 0.064, pre-specified two-sided α = 0.2). Therefore, contrary to the initial hypothesis, intermittent dosing did not improve progression-free survival in patients. There were no differences in the secondary outcomes, including overall survival and the overall incidence of treatment-associated toxicity, between the two groups.", + "TAG_DATA": [ + "47, patients {'context': 'B-patient'}", + "49, metastatic {'context': 'B-neoplasm'}", + "50, and {'context': 'I-neoplasm'}", + "51, unresectable {'context': 'I-neoplasm'}", + "52, BRAFV600 {'context': 'I-neoplasm'}", + "53, melanoma. {'context': 'I-neoplasm'}", + "78, patients {'context': 'B-patient'}", + "80, non-progressing {'context': 'B-neoplasm'}", + "81, tumors {'context': 'I-neoplasm'}", + "105, patients {'context': 'B-patient'}", + "165, patients. {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "47, patients ['l0', 'l1', 'l2', 'l3', 'l4']", + "49, metastatic ['l0', 'l5', 'l6', 'l7', 'l8']", + "50, and ['l1', 'l5', 'l9', 'l10', 'l11']", + "51, unresectable ['l2', 'l6', 'l9', 'l12', 'l13', 'l14', 'l15']", + "52, BRAFV600 ['l3', 'l7', 'l10', 'l12', 'l16', 'l17', 'l18']", + "53, melanoma. ['l4', 'l8', 'l11', 'l13', 'l16']", + "78, patients ['l14', 'l17', 'l19', 'l20']", + "80, non-progressing ['l19', 'l21']", + "81, tumors ['l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33288923", + "TEXT": "Seasonal influenza viruses constantly change through antigenic drift and the emergence of pandemic influenza viruses through antigenic shift is unpredictable. Conventional influenza virus vaccines induce strain-specific neutralizing antibodies against the variable immunodominant globular head domain of the viral hemagglutinin protein. This necessitates frequent re-formulation of vaccines and handicaps pandemic preparedness. In this completed, observer-blind, randomized, placebo-controlled phase I trial (NCT03300050), safety and immunogenicity of chimeric hemagglutinin-based vaccines were tested in healthy, 18-39-year-old US adults. The study aimed to test the safety and ability of the vaccines to elicit broadly cross-reactive antibodies against the hemagglutinin stalk domain. Participants were enrolled into five groups to receive vaccinations with live-attenuated followed by AS03-adjuvanted inactivated vaccine (n = 20), live-attenuated followed by inactivated vaccine (n = 15), twice AS03-adjuvanted inactivated vaccine (n = 16) or placebo (n = 5, intranasal followed by intramuscular; n = 10, twice intramuscular) 3 months apart. Vaccination was found to be safe and induced a broad, strong, durable and functional immune response targeting the conserved, immunosubdominant stalk of the hemagglutinin. The results suggest that chimeric hemagglutinins have the potential to be developed as universal vaccines that protect broadly against influenza viruses.", + "TAG_DATA": [ + "71, 18-39-year-old {'context': 'I-organism'}", + "72, US {'context': 'I-organism'}", + "73, adults. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "71, 18-39-year-old ['l0', 'l1']", + "72, US ['l0', 'l2']", + "73, adults. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33432171", + "TEXT": "The clinical impact of rare loss-of-function variants has yet to be determined for most genes. Integration of DNA sequencing data with electronic health records (EHRs) could enhance our understanding of the contribution of rare genetic variation to human disease1. By leveraging 10,900 whole-exome sequences linked to EHR data in the Penn Medicine Biobank, we addressed the association of the cumulative effects of rare predicted loss-of-function variants for each individual gene on human disease on an exome-wide scale, as assessed using a set of diverse EHR phenotypes. After discovering 97 genes with exome-by-phenome-wide significant phenotype associations (P < 10-6), we replicated 26 of these in the Penn Medicine Biobank, as well as in three other medical biobanks and the population-based UK Biobank. Of these 26 genes, five had associations that have been previously reported and represented positive controls, whereas 21 had phenotype associations not previously reported, among which were genes implicated in glaucoma, aortic ectasia, diabetes mellitus, muscular dystrophy and hearing loss. These findings show the value of aggregating rare predicted loss-of-function variants into 'gene burdens' for identifying new gene-disease associations using EHR phenotypes in a medical biobank. We suggest that application of this approach to even larger numbers of individuals will provide the statistical power required to uncover unexplored relationships between rare genetic variation and disease phenotypes.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33432172", + "TEXT": "Breast cancer remains a global challenge, causing over 600,000 deaths in 2018 (ref. 1). To achieve earlier cancer detection, health organizations worldwide recommend screening mammography, which is estimated to decrease breast cancer mortality by 20-40% (refs. 2,3). Despite the clear value of screening mammography, significant false positive and false negative rates along with non-uniformities in expert reader availability leave opportunities for improving quality and access4,5. To address these limitations, there has been much recent interest in applying deep learning to mammography6-18, and these efforts have highlighted two key difficulties: obtaining large amounts of annotated training data and ensuring generalization across populations, acquisition equipment and modalities. Here we present an annotation-efficient deep learning approach that (1) achieves state-of-the-art performance in mammogram classification, (2) successfully extends to digital breast tomosynthesis (DBT; '3D mammography'), (3) detects cancers in clinically negative prior mammograms of patients with cancer, (4) generalizes well to a population with low screening rates and (5) outperforms five out of five full-time breast-imaging specialists with an average increase in sensitivity of 14%. By creating new 'maximum suspicion projection' (MSP) images from DBT data, our progressively trained, multiple-instance learning approach effectively trains on DBT exams using only breast-level labels while maintaining localization-based interpretability. Altogether, our results demonstrate promise towards software that can improve the accuracy of and access to screening mammography worldwide.", + "TAG_DATA": [ + "140, patients {'context': 'B-patient'}", + "141, with {'context': 'I-patient'}", + "142, cancer, {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "140, patients ['l0', 'l1']", + "141, with ['l0', 'l2']", + "142, cancer, ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33442014", + "TEXT": "Underserved populations experience higher levels of pain. These disparities persist even after controlling for the objective severity of diseases like osteoarthritis, as graded by human physicians using medical images, raising the possibility that underserved patients' pain stems from factors external to the knee, such as stress. Here we use a deep learning approach to measure the severity of osteoarthritis, by using knee X-rays to predict patients' experienced pain. We show that this approach dramatically reduces unexplained racial disparities in pain. Relative to standard measures of severity graded by radiologists, which accounted for only 9% (95% confidence interval (CI), 3-16%) of racial disparities in pain, algorithmic predictions accounted for 43% of disparities, or 4.7× more (95% CI, 3.2-11.8×), with similar results for lower-income and less-educated patients. This suggests that much of underserved patients' pain stems from factors within the knee not reflected in standard radiographic measures of severity. We show that the algorithm's ability to reduce unexplained disparities is rooted in the racial and socioeconomic diversity of the training set. Because algorithmic severity measures better capture underserved patients' pain, and severity measures influence treatment decisions, algorithmic predictions could potentially redress disparities in access to treatments like arthroplasty.", + "TAG_DATA": [ + "121, lower-income {'context': 'B-cells'}", + "122, and {'context': 'I-cells'}", + "123, less-educated {'context': 'I-cells'}", + "124, patients. {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "121, lower-income ['l0', 'l1', 'l2']", + "122, and ['l0', 'l3', 'l4']", + "123, less-educated ['l1', 'l3', 'l5']", + "124, patients. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33122860", + "TEXT": "Traditional screening for COVID-19 typically includes survey questions about symptoms and travel history, as well as temperature measurements. Here, we explore whether personal sensor data collected over time may help identify subtle changes indicating an infection, such as in patients with COVID-19. We have developed a smartphone app that collects smartwatch and activity tracker data, as well as self-reported symptoms and diagnostic testing results, from individuals in the United States, and have assessed whether symptom and sensor data can differentiate COVID-19 positive versus negative cases in symptomatic individuals. We enrolled 30,529 participants between 25 March and 7 June 2020, of whom 3,811 reported symptoms. Of these symptomatic individuals, 54 reported testing positive and 279 negative for COVID-19. We found that a combination of symptom and sensor data resulted in an area under the curve (AUC) of 0.80 (interquartile range (IQR): 0.73-0.86) for discriminating between symptomatic individuals who were positive or negative for COVID-19, a performance that is significantly better (P < 0.01) than a model1 that considers symptoms alone (AUC = 0.71; IQR: 0.63-0.79). Such continuous, passively captured data may be complementary to virus testing, which is generally a one-off or infrequent sampling assay.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33542537", + "TEXT": "Diverging from tested vaccination regimens without scientific evidence could undermine public confidence in vaccines against COVID-19 and the success of a global vaccination strategy to curtail the pandemic.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33664492", + "TEXT": "Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors1. Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively coexpressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies2,3. Resistance to enzalutamide was associated with cancer cell-intrinsic epithelial-mesenchymal transition and transforming growth factor-β signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6 and NR1D2 (refs. 4-6). Additionally, a subset of patients had high expression of dysfunction markers on cytotoxic CD8+ T cells undergoing clonal expansion following enzalutamide treatment. Collectively, the transcriptional characterization of cancer and immune cells from human metastatic castration-resistant prostate cancer provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition.", + "TAG_DATA": [ + "56, adenocarcinoma {'context': 'B-transformed cells'}", + "57, cells {'context': 'I-transformed cells'}", + "89, Small {'context': 'B-transformed cells'}", + "90, cell {'context': 'I-transformed cells'}", + "91, carcinoma {'context': 'I-transformed cells'}", + "92, cells {'context': 'I-transformed cells'}", + "124, CD8+ {'context': 'I-cells'}", + "125, T {'context': 'I-cells'}", + "126, cells {'context': 'I-cells'}", + "128, clonal {'phenotype': 'B-colony formation'}", + "129, expansion {'phenotype': 'I-colony formation'}" + ], + "LINK_DATA": [ + "56, adenocarcinoma ['l0']", + "57, cells ['l0']", + "89, Small ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "90, cell ['l1', 'l7', 'l8', 'l9', 'l10']", + "91, carcinoma ['l2', 'l7', 'l11', 'l12', 'l13']", + "92, cells ['l3', 'l8', 'l11']", + "124, CD8+ ['l4', 'l14', 'l15', 'l16', 'l17']", + "125, T ['l5', 'l9', 'l12', 'l14', 'l18', 'l19', 'l20']", + "126, cells ['l6', 'l10', 'l13', 'l15', 'l18', 'l21', 'l22']", + "128, clonal ['l16', 'l19', 'l21', 'l23']", + "129, expansion ['l17', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD8+", + "T", + "cells" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonal", + "expansion" + ] + } + } + ] + }, + { + "PMID": "33859435", + "TEXT": "Apart from well-defined factors in neuronal cells1, only a few reports consider that the variability of sporadic amyotrophic lateral sclerosis (ALS) progression can depend on less-defined contributions from glia2,3 and blood vessels4. In this study we use an expression-weighted cell-type enrichment method to infer cell activity in spinal cord samples from patients with sporadic ALS and mouse models of this disease. Here we report that patients with sporadic ALS present cell activity patterns consistent with two mouse models in which enrichments of vascular cell genes preceded microglial response. Notably, during the presymptomatic stage, perivascular fibroblast cells showed the strongest gene enrichments, and their marker proteins SPP1 and COL6A1 accumulated in enlarged perivascular spaces in patients with sporadic ALS. Moreover, in plasma of 574 patients with ALS from four independent cohorts, increased levels of SPP1 at disease diagnosis repeatedly predicted shorter survival with stronger effect than the established risk factors of bulbar onset or neurofilament levels in cerebrospinal fluid. We propose that the activity of the recently discovered perivascular fibroblast can predict survival of patients with ALS and provide a new conceptual framework to re-evaluate definitions of ALS etiology.", + "TAG_DATA": [ + "76, mouse {'context': 'B-organism'}", + "77, models {'context': 'I-organism'}", + "93, perivascular {'context': 'B-cells'}", + "94, fibroblast {'context': 'I-cells'}", + "95, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "76, mouse ['l0', 'l1', 'l2']", + "77, models ['l0', 'l3']", + "93, perivascular ['l4', 'l5']", + "94, fibroblast ['l1', 'l4', 'l6']", + "95, cells ['l2', 'l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "34031608", + "TEXT": "The surge in COVID-19 cases in India and Brazil highlights the need to improve vaccine manufacturing capacity and investment in public health at the local level.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "34580492", + "TEXT": "With the end of the COVID-19 pandemic nowhere in sight, a return to safe, in-person schooling must be prioritized now to avoid lifelong setbacks", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33958794", + "TEXT": "Immune-checkpoint blockade (ICB) combined with neoadjuvant chemotherapy improves pathological complete response in breast cancer. To understand why only a subset of tumors respond to ICB, patients with hormone receptor-positive or triple-negative breast cancer were treated with anti-PD1 before surgery. Paired pre- versus on-treatment biopsies from treatment-naive patients receiving anti-PD1 (n = 29) or patients receiving neoadjuvant chemotherapy before anti-PD1 (n = 11) were subjected to single-cell transcriptome, T cell receptor and proteome profiling. One-third of tumors contained PD1-expressing T cells, which clonally expanded upon anti-PD1 treatment, irrespective of tumor subtype. Expansion mainly involved CD8+ T cells with pronounced expression of cytotoxic-activity (PRF1, GZMB), immune-cell homing (CXCL13) and exhaustion markers (HAVCR2, LAG3), and CD4+ T cells characterized by expression of T-helper-1 (IFNG) and follicular-helper (BCL6, CXCR5) markers. In pre-treatment biopsies, the relative frequency of immunoregulatory dendritic cells (PD-L1+), specific macrophage phenotypes (CCR2+ or MMP9+) and cancer cells exhibiting major histocompatibility complex class I/II expression correlated positively with T cell expansion. Conversely, undifferentiated pre-effector/memory T cells (TCF7+, GZMK+) or inhibitory macrophages (CX3CR1+, C3+) were inversely correlated with T cell expansion. Collectively, our data identify various immunophenotypes and associated gene sets that are positively or negatively correlated with T cell expansion following anti-PD1 treatment. We shed light on the heterogeneity in treatment response to anti-PD1 in breast cancer.", + "TAG_DATA": [ + "46, patients {'context': 'I-patient'}", + "51, patients {'context': 'B-patient'}", + "71, tumors {'context': 'B-neoplasm'}", + "89, CD8+ {'context': 'B-cells'}", + "90, T {'context': 'I-cells'}", + "91, cells {'context': 'I-cells'}", + "108, CD4+ {'context': 'B-cells'}", + "109, T {'context': 'I-cells'}", + "140, cancer {'context': 'B-transformed cells'}", + "141, cells {'context': 'I-transformed cells'}", + "152, T {'context': 'B-cells'}", + "153, cell {'context': 'B-cells'}", + "156, undifferentiated {'context': 'B-cells'}", + "157, pre-effector/memory {'context': 'I-cells'}", + "158, T {'context': 'I-cells'}", + "159, cells {'context': 'I-cells'}", + "163, inhibitory {'context': 'B-cells'}", + "164, macrophages {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "46, patients ['l0']", + "51, patients ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "71, tumors ['l0', 'l1']", + "89, CD8+ ['l2', 'l8', 'l9', 'l10', 'l11', 'l12']", + "90, T ['l3', 'l8', 'l13', 'l14', 'l15', 'l16']", + "91, cells ['l4', 'l9', 'l13', 'l17', 'l18', 'l19']", + "108, CD4+ ['l5', 'l10', 'l14', 'l17', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "109, T ['l6', 'l11', 'l15', 'l18', 'l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "110, cells ['l7', 'l12', 'l16', 'l19', 'l21', 'l26']", + "140, cancer ['l22', 'l27', 'l31', 'l32', 'l33']", + "141, cells ['l23', 'l28', 'l31', 'l34', 'l35']", + "152, T ['l24', 'l29', 'l32', 'l34', 'l36']", + "153, cell ['l25', 'l30', 'l33', 'l35', 'l36']", + "156, undifferentiated ['l37', 'l38', 'l39', 'l40', 'l41']", + "157, pre-effector/memory ['l37', 'l42', 'l43', 'l44', 'l45']", + "158, T ['l38', 'l42', 'l46', 'l47', 'l48']", + "159, cells ['l39', 'l43', 'l46', 'l49', 'l50']", + "163, inhibitory ['l40', 'l44', 'l47', 'l49', 'l51']", + "164, macrophages ['l41', 'l45', 'l48', 'l50', 'l51']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33479500", + "TEXT": "Substantial global effort has been devoted to curtailing the tobacco epidemic over the past two decades, especially after the adoption of the Framework Convention on Tobacco Control1 by the World Health Organization in 2003. In 2015, in recognition of the burden resulting from tobacco use, strengthened tobacco control was included as a global development target in the 2030 Agenda for Sustainable Development2. Here we show that comprehensive tobacco control policies-including smoking bans, health warnings, advertising bans and tobacco taxes-are effective in reducing smoking prevalence; amplified positive effects are seen when these policies are implemented simultaneously within a given country. We find that if all 155 countries included in our counterfactual analysis had adopted smoking bans, health warnings and advertising bans at the strictest level and raised cigarette prices to at least 7.73 international dollars in 2009, there would have been about 100 million fewer smokers in the world in 2017. These findings highlight the urgent need for countries to move toward an accelerated implementation of a set of strong tobacco control practices, thus curbing the burden of smoking-attributable diseases and deaths.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33558725", + "TEXT": "Genetically engineered T cell therapy can induce remarkable tumor responses in hematologic malignancies. However, it is not known if this type of therapy can be applied effectively to epithelial cancers, which account for 80-90% of human malignancies. We have conducted a first-in-human, phase 1 clinical trial of T cells engineered with a T cell receptor targeting HPV-16 E7 for the treatment of metastatic human papilloma virus-associated epithelial cancers (NCT02858310). The primary endpoint was maximum tolerated dose. Cell dose was not limited by toxicity with a maximum dose of 1 × 1011 engineered T cells administered. Tumor responses following treatment were evaluated using RECIST (Response Evaluation Criteria in Solid Tumors) guidelines. Robust tumor regression was observed with objective clinical responses in 6 of 12 patients, including 4 of 8 patients with anti-PD-1 refractory disease. Responses included extensive regression of bulky tumors and complete regression of most tumors in some patients. Genomic studies, which included intra-patient tumors with dichotomous treatment responses, revealed resistance mechanisms from defects in critical components of the antigen presentation and interferon response pathways. These findings demonstrate that engineered T cells can mediate regression of common carcinomas, and they reveal immune editing as a constraint on the curative potential of cellular therapy and possibly other immunotherapies in advanced epithelial cancer.", + "TAG_DATA": [ + "62, metastatic {'context': 'B-neoplasm'}", + "63, human {'context': 'I-neoplasm'}", + "64, papilloma {'context': 'I-neoplasm'}", + "65, virus-associated {'context': 'I-neoplasm'}", + "66, epithelial {'context': 'I-neoplasm'}", + "67, cancers {'context': 'I-neoplasm'}", + "109, tumor {'phenotype': 'B-tumour regression'}", + "110, regression {'phenotype': 'I-tumour regression'}", + "143, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "62, metastatic ['l0', 'l1', 'l2', 'l3', 'l4']", + "63, human ['l0', 'l5', 'l6', 'l7', 'l8', 'l9']", + "64, papilloma ['l1', 'l5', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "65, virus-associated ['l2', 'l6', 'l10', 'l16', 'l17', 'l18', 'l19']", + "66, epithelial ['l3', 'l7', 'l11', 'l16', 'l20']", + "67, cancers ['l4', 'l8', 'l12', 'l17', 'l20']", + "108, Robust ['l9', 'l13', 'l18', 'l21', 'l22']", + "109, tumor ['l14', 'l19', 'l21', 'l23']", + "110, regression ['l15', 'l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "papilloma", + "virus-associated" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + } + } + ] + }, + { + "PMID": "33820995", + "TEXT": "Bronchiectasis, a progressive chronic airway disease, is characterized by microbial colonization and infection. We present an approach to the multi-biome that integrates bacterial, viral and fungal communities in bronchiectasis through weighted similarity network fusion ( https://integrative-microbiomics.ntu.edu.sg ). Patients at greatest risk of exacerbation have less complex microbial co-occurrence networks, reduced diversity and a higher degree of antagonistic interactions in their airway microbiome. Furthermore, longitudinal interactome dynamics reveals microbial antagonism during exacerbation, which resolves following treatment in an otherwise stable multi-biome. Assessment of the Pseudomonas interactome shows that interaction networks, rather than abundance alone, are associated with exacerbation risk, and that incorporation of microbial interaction data improves clinical prediction models. Shotgun metagenomic sequencing of an independent cohort validated the multi-biome interactions detected in targeted analysis and confirmed the association with exacerbation. Integrative microbiomics captures microbial interactions to determine exacerbation risk, which cannot be appreciated by the study of a single microbial group. Antibiotic strategies probably target the interaction networks rather than individual microbes, providing a fresh approach to the understanding of respiratory infection.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33495604", + "TEXT": "Synovial sarcoma (SyS) is an aggressive neoplasm driven by the SS18-SSX fusion, and is characterized by low T cell infiltration. Here, we studied the cancer-immune interplay in SyS using an integrative approach that combines single-cell RNA sequencing (scRNA-seq), spatial profiling and genetic and pharmacological perturbations. scRNA-seq of 16,872 cells from 12 human SyS tumors uncovered a malignant subpopulation that marks immune-deprived niches in situ and is predictive of poor clinical outcomes in two independent cohorts. Functional analyses revealed that this malignant cell state is controlled by the SS18-SSX fusion, is repressed by cytokines secreted by macrophages and T cells, and can be synergistically targeted with a combination of HDAC and CDK4/CDK6 inhibitors. This drug combination enhanced malignant-cell immunogenicity in SyS models, leading to induced T cell reactivity and T cell-mediated killing. Our study provides a blueprint for investigating heterogeneity in fusion-driven malignancies and demonstrates an interplay between immune evasion and oncogenic processes that can be co-targeted in SyS and potentially in other malignancies.", + "TAG_DATA": [ + "48, cells {'context': 'I-cells'}", + "51, human {'context': 'B-neoplasm'}", + "52, SyS {'context': 'I-neoplasm'}", + "53, tumors {'context': 'I-neoplasm'}", + "110, CDK4/CDK6 {'perturbing_action': 'B-pharmacological inhibition'}", + "111, inhibitors. {'perturbing_action': 'I-pharmacological inhibition'}", + "116, malignant-cell {'context': 'B-cells'}", + "119, SyS {'context': 'B-neoplasm'}", + "120, models, {'context': 'I-neoplasm'}", + "124, T {'context': 'B-cells'}", + "125, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "48, cells ['l0', 'l1', 'l2']", + "51, human ['l0', 'l3', 'l4']", + "52, SyS ['l1', 'l3', 'l5']", + "53, tumors ['l2', 'l4', 'l5']", + "110, CDK4/CDK6 ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "111, inhibitors. ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "116, malignant-cell ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "119, SyS ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "120, models, ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "124, T ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "125, cell ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK4/CDK6", + "inhibitors." + ] + }, + "context": { + "val": "cells", + "words": [ + "malignant-cell", + "T", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK4/CDK6", + "inhibitors." + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "SyS", + "models," + ] + } + } + ] + }, + { + "PMID": "33311702", + "TEXT": "Reducing COVID-19 burden for populations will require equitable and effective risk-based allocations of scarce preventive resources, including vaccinations1. To aid in this effort, we developed a general population risk calculator for COVID-19 mortality based on various sociodemographic factors and pre-existing conditions for the US population, combining information from the UK-based OpenSAFELY study with mortality rates by age and ethnicity across US states. We tailored the tool to produce absolute risk estimates in future time frames by incorporating information on pandemic dynamics at the community level. We applied the model to data on risk factor distribution from a variety of sources to project risk for the general adult population across 477 US cities and for the Medicare population aged 65 years and older across 3,113 US counties, respectively. Validation analyses using 54,444 deaths from 7 June to 1 October 2020 show that the model is well calibrated for the US population. Projections show that the model can identify relatively small fractions of the population (for example 4.3%) that might experience a disproportionately large number of deaths (for example 48.7%), but there is wide variation in risk across communities. We provide a web-based risk calculator and interactive maps for viewing community-level risks.", + "TAG_DATA": [ + "105, general {'context': 'B-cells'}", + "106, adult {'context': 'I-organism'}", + "107, population {'context': 'I-organism'}", + "115, Medicare {'context': 'B-cells'}", + "116, population {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "105, general ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "106, adult ['l0', 'l6', 'l7']", + "107, population ['l1', 'l6', 'l8']", + "111, cities ['l2', 'l7', 'l8']", + "115, Medicare ['l9', 'l10', 'l11', 'l12']", + "116, population ['l9', 'l13', 'l14', 'l15']", + "117, aged ['l3', 'l10', 'l13', 'l16', 'l17']", + "118, 65 ['l4', 'l11', 'l14', 'l16', 'l18']", + "119, years ['l5', 'l12', 'l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33958797", + "TEXT": "Langerhans cell histiocytosis (LCH) is a potentially fatal condition characterized by granulomatous lesions with characteristic clonal mononuclear phagocytes (MNPs) harboring activating somatic mutations in mitogen-activated protein kinase (MAPK) pathway genes, most notably BRAFV600E. We recently discovered that the BRAFV600E mutation can also affect multipotent hematopoietic progenitor cells (HPCs) in multisystem LCH disease. How the BRAFV600E mutation in HPCs leads to LCH is not known. Here we show that enforced expression of the BRAFV600E mutation in early mouse and human multipotent HPCs induced a senescence program that led to HPC growth arrest, apoptosis resistance and a senescence-associated secretory phenotype (SASP). SASP, in turn, promoted HPC skewing toward the MNP lineage, leading to the accumulation of senescent MNPs in tissue and the formation of LCH lesions. Accordingly, elimination of senescent cells using INK-ATTAC transgenic mice, as well as pharmacologic blockade of SASP, improved LCH disease in mice. These results identify senescent cells as a new target for the treatment of LCH.", + "TAG_DATA": [ + "68, enforced {'perturbing_action': 'B-other'}", + "69, expression {'perturbing_action': 'I-other'}", + "70, of {'perturbing_action': 'I-other'}", + "71, the {'perturbing_action': 'I-other'}", + "72, BRAFV600E {'perturbing_action': 'I-other'}", + "73, mutation {'perturbing_action': 'I-other'}", + "75, early {'context': 'B-cells'}", + "76, mouse {'context': 'I-cells'}", + "77, and {'context': 'I-cells'}", + "78, human {'context': 'I-cells'}", + "79, multipotent {'context': 'I-cells'}", + "80, HPCs {'context': 'I-cells'}", + "81, induced {'effect': 'B-positive'}", + "83, senescence {'phenotype': 'B-senescence'}", + "84, program {'phenotype': 'I-senescence'}", + "86, led {'effect': 'B-positive'}", + "87, to {'effect': 'I-positive'}", + "88, HPC {'context': 'B-cells'}", + "89, growth {'phenotype': 'I-cell growth'}", + "90, arrest, {'effect': 'B-negative'}", + "91, apoptosis {'phenotype': 'B-apoptosis'}", + "92, resistance {'effect': 'B-negative'}", + "130, INK-ATTAC {'perturbing_action': 'B-gene gain-of-function'}", + "131, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "132, mice, {'context': 'B-organism'}", + "136, pharmacologic {'perturbing_action': 'B-pharmacological inhibition'}", + "137, blockade {'perturbing_action': 'I-pharmacological inhibition'}", + "138, of {'perturbing_action': 'I-pharmacological inhibition'}", + "139, SASP, {'perturbing_action': 'I-pharmacological inhibition'}", + "144, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "68, enforced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "69, expression ['l0', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "70, of ['l1', 'l21', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "71, the ['l2', 'l22', 'l41', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "72, BRAFV600E ['l3', 'l23', 'l42', 'l60', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "73, mutation ['l4', 'l24', 'l43', 'l61', 'l78', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "75, early ['l5', 'l25', 'l44', 'l62', 'l79', 'l95', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "76, mouse ['l6', 'l26', 'l45', 'l63', 'l80', 'l96', 'l111', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "77, and ['l7', 'l27', 'l46', 'l64', 'l81', 'l97', 'l112', 'l126', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "78, human ['l8', 'l28', 'l47', 'l65', 'l82', 'l98', 'l113', 'l127', 'l137', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "79, multipotent ['l9', 'l29', 'l48', 'l66', 'l83', 'l99', 'l114', 'l128', 'l138', 'l149', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168']", + "80, HPCs ['l10', 'l30', 'l49', 'l67', 'l84', 'l100', 'l115', 'l129', 'l139', 'l150', 'l158', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "81, induced ['l11', 'l31', 'l50', 'l68', 'l85', 'l101', 'l116', 'l130', 'l140', 'l151', 'l159', 'l169', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "83, senescence ['l12', 'l32', 'l51', 'l69', 'l86', 'l102', 'l117', 'l141', 'l160', 'l170', 'l179', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195']", + "84, program ['l13', 'l33', 'l52', 'l70', 'l87', 'l103', 'l118', 'l142', 'l161', 'l171', 'l180', 'l188', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202']", + "86, led ['l14', 'l34', 'l53', 'l71', 'l88', 'l104', 'l119', 'l131', 'l143', 'l152', 'l162', 'l172', 'l181', 'l189', 'l196', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208']", + "87, to ['l15', 'l35', 'l54', 'l72', 'l89', 'l105', 'l120', 'l132', 'l144', 'l153', 'l163', 'l173', 'l182', 'l190', 'l197', 'l203', 'l209', 'l210', 'l211', 'l212', 'l213']", + "88, HPC ['l16', 'l36', 'l55', 'l73', 'l90', 'l106', 'l121', 'l133', 'l145', 'l154', 'l164', 'l174', 'l183', 'l191', 'l198', 'l204', 'l209', 'l214', 'l215', 'l216', 'l217']", + "89, growth ['l17', 'l37', 'l56', 'l74', 'l91', 'l107', 'l122', 'l134', 'l146', 'l155', 'l165', 'l175', 'l184', 'l192', 'l199', 'l205', 'l210', 'l214', 'l218', 'l219', 'l220']", + "90, arrest, ['l18', 'l38', 'l57', 'l75', 'l92', 'l108', 'l123', 'l135', 'l147', 'l156', 'l166', 'l176', 'l185', 'l193', 'l200', 'l206', 'l211', 'l215', 'l218', 'l221', 'l222']", + "91, apoptosis ['l19', 'l39', 'l58', 'l76', 'l93', 'l109', 'l124', 'l167', 'l177', 'l186', 'l194', 'l201', 'l207', 'l212', 'l216', 'l219', 'l221', 'l223']", + "92, resistance ['l20', 'l40', 'l59', 'l77', 'l94', 'l110', 'l125', 'l136', 'l148', 'l157', 'l168', 'l178', 'l187', 'l195', 'l202', 'l208', 'l213', 'l217', 'l220', 'l222', 'l223']", + "130, INK-ATTAC ['l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230']", + "131, transgenic ['l224', 'l231', 'l232', 'l233', 'l234']", + "132, mice, ['l225', 'l231', 'l235']", + "136, pharmacologic ['l226', 'l236', 'l237', 'l238', 'l239']", + "137, blockade ['l227', 'l236', 'l240', 'l241', 'l242']", + "138, of ['l228', 'l232', 'l237', 'l240', 'l243', 'l244']", + "139, SASP, ['l229', 'l233', 'l238', 'l241', 'l243', 'l245']", + "144, mice. ['l230', 'l234', 'l235', 'l239', 'l242', 'l244', 'l245']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "enforced", + "expression", + "of", + "the", + "BRAFV600E", + "mutation" + ] + }, + "context": { + "val": "cells", + "words": [ + "early", + "mouse", + "and", + "human", + "multipotent", + "HPCs", + "HPC" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "enforced", + "expression", + "of", + "the", + "BRAFV600E", + "mutation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "led", + "to" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "enforced", + "expression", + "of", + "the", + "BRAFV600E", + "mutation" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence", + "program" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "enforced", + "expression", + "of", + "the", + "BRAFV600E", + "mutation" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "enforced", + "expression", + "of", + "the", + "BRAFV600E", + "mutation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest,", + "resistance" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "enforced", + "expression", + "of", + "the", + "BRAFV600E", + "mutation" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "early", + "mouse", + "and", + "human", + "multipotent", + "HPCs", + "HPC" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "led", + "to" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "early", + "and", + "multipotent", + "HPCs", + "HPC" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence", + "program" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "early", + "mouse", + "and", + "human", + "multipotent", + "HPCs", + "HPC" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "early", + "mouse", + "and", + "human", + "multipotent", + "HPCs", + "HPC" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest,", + "resistance" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "early", + "multipotent", + "HPCs", + "HPC" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "led", + "to" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence", + "program" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "led", + "to" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "led", + "to" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "senescence", + "words": [ + "senescence", + "program" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest,", + "resistance" + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest,", + "resistance" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "arrest,", + "resistance" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "INK-ATTAC", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "blockade", + "of", + "SASP," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "33707773", + "TEXT": "Hutchinson-Gilford progeria syndrome (HGPS) is a rare accelerated aging disorder characterized by premature death from myocardial infarction or stroke. It is caused by de novo single-nucleotide mutations in the LMNA gene that activate a cryptic splice donor site, resulting in the production of a toxic form of lamin A, which is termed progerin. Here we present a potential genetic therapeutic strategy that utilizes antisense peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) to block pathogenic splicing of mutant transcripts. Of several candidates, PPMO SRP-2001 provided the most significant decrease in progerin transcripts in patient fibroblasts. Intravenous delivery of SRP-2001 to a transgenic mouse model of HGPS produced significant reduction of progerin transcripts in the aorta, a particularly critical target tissue in HGPS. Long-term continuous treatment with SRP-2001 yielded a 61.6% increase in lifespan and rescue of vascular smooth muscle cell loss in large arteries. These results provide a rationale for proceeding to human trials.", + "TAG_DATA": [ + "90, patient {'context': 'B-cells'}", + "91, fibroblasts. {'context': 'I-cells'}", + "98, transgenic {'context': 'B-organism'}", + "99, mouse {'context': 'I-organism'}", + "100, model {'context': 'I-organism'}", + "101, of {'context': 'I-organism'}", + "102, HGPS {'context': 'I-organism'}", + "111, aorta, {'context': 'B-tissue/organ'}", + "131, rescue {'effect': 'B-rescues'}", + "133, vascular {'context': 'B-cells'}", + "134, smooth {'context': 'I-cells'}", + "135, muscle {'context': 'I-cells'}", + "136, cell {'context': 'I-cells'}", + "139, large {'context': 'B-tissue/organ'}", + "140, arteries. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "90, patient ['l0']", + "91, fibroblasts. ['l0']", + "98, transgenic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "99, mouse ['l1', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "100, model ['l2', 'l11', 'l17', 'l18', 'l19', 'l20', 'l21']", + "101, of ['l3', 'l12', 'l17', 'l22', 'l23', 'l24', 'l25']", + "102, HGPS ['l4', 'l13', 'l18', 'l22', 'l26']", + "111, aorta, ['l5', 'l14', 'l19', 'l23', 'l26']", + "131, rescue ['l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "133, vascular ['l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "134, smooth ['l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "135, muscle ['l6', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "136, cell ['l7', 'l15', 'l20', 'l24', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "137, loss ['l8', 'l16', 'l21', 'l25', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "139, large ['l9', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "140, arteries. ['l10', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "rescues", + "words": [ + "rescue" + ] + }, + "context": { + "val": "cells", + "words": [ + "vascular", + "smooth", + "muscle", + "cell" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescue" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "large", + "arteries." + ] + } + } + ] + }, + { + "PMID": "33057181", + "TEXT": "The Coronavirus Disease 2019 (COVID-19) pandemic has changed many social, economic, environmental and healthcare determinants of health. We applied an ensemble of 16 Bayesian models to vital statistics data to estimate the all-cause mortality effect of the pandemic for 21 industrialized countries. From mid-February through May 2020, 206,000 (95% credible interval, 178,100-231,000) more people died in these countries than would have had the pandemic not occurred. The number of excess deaths, excess deaths per 100,000 people and relative increase in deaths were similar between men and women in most countries. England and Wales and Spain experienced the largest effect: ~100 excess deaths per 100,000 people, equivalent to a 37% (30-44%) relative increase in England and Wales and 38% (31-45%) in Spain. Bulgaria, New Zealand, Slovakia, Australia, Czechia, Hungary, Poland, Norway, Denmark and Finland experienced mortality changes that ranged from possible small declines to increases of 5% or less in either sex. The heterogeneous mortality effects of the COVID-19 pandemic reflect differences in how well countries have managed the pandemic and the resilience and preparedness of the health and social care system.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33737750", + "TEXT": "Errors in medication self-administration (MSA) lead to poor treatment adherence, increased hospitalizations and higher healthcare costs. These errors are particularly common when medication delivery involves devices such as inhalers or insulin pens. We present a contactless and unobtrusive artificial intelligence (AI) framework that can detect and monitor MSA errors by analyzing the wireless signals in the patient's home, without the need for physical contact. The system was developed by observing self-administration conducted by volunteers and evaluated by comparing its prediction with human annotations. Findings from this study demonstrate that our approach can automatically detect when patients use their inhalers (area under the curve (AUC) = 0.992) or insulin pens (AUC = 0.967), and assess whether patients follow the appropriate steps for using these devices (AUC = 0.952). The work shows the potential of leveraging AI-based solutions to improve medication safety with minimal overhead for patients and health professionals.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33603241", + "TEXT": "Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune microenvironment in operable NSCLC remain unclear. We report the results of the phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC, using major pathologic response (MPR) as the primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and 50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab resulted in higher pathologic complete response rates (10% versus 38%), less viable tumor (median 50% versus 9%), and greater frequencies of effector, tissue-resident memory and effector memory T cells. Increased abundance of gut Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances pathologic responses, tumor immune infiltrates and immunologic memory, and merits further investigation in operable NSCLC.", + "TAG_DATA": [ + "51, patients {'context': 'B-patient'}", + "52, with {'context': 'I-patient'}", + "53, operable {'context': 'I-neoplasm'}", + "54, NSCLC, {'context': 'I-neoplasm'}", + "144, less {'effect': 'B-negative'}", + "156, tissue-resident {'context': 'I-cells'}", + "157, memory {'context': 'I-cells'}", + "158, and {'context': 'I-cells'}", + "159, effector {'context': 'B-cells'}", + "160, memory {'context': 'I-cells'}", + "161, T {'context': 'I-cells'}", + "162, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "51, patients ['l0', 'l1', 'l2']", + "52, with ['l0', 'l3', 'l4']", + "53, operable ['l1', 'l3', 'l5']", + "54, NSCLC, ['l2', 'l4', 'l5']", + "144, less ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "145, viable ['l6', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "146, tumor ['l7', 'l16', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "155, effector, ['l8', 'l17', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "156, tissue-resident ['l9', 'l18', 'l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "157, memory ['l10', 'l19', 'l27', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "158, and ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "159, effector ['l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57']", + "160, memory ['l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l58', 'l59']", + "161, T ['l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58', 'l60']", + "162, cells. ['l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "less" + ] + }, + "context": { + "val": "cells", + "words": [ + "tissue-resident", + "memory", + "and", + "effector", + "T", + "cells." + ] + } + } + ] + }, + { + "PMID": "33692530", + "TEXT": "Reports of long-lasting coronavirus disease 2019 (COVID-19) symptoms, the so-called 'long COVID', are rising but little is known about prevalence, risk factors or whether it is possible to predict a protracted course early in the disease. We analyzed data from 4,182 incident cases of COVID-19 in which individuals self-reported their symptoms prospectively in the COVID Symptom Study app1. A total of 558 (13.3%) participants reported symptoms lasting ≥28 days, 189 (4.5%) for ≥8 weeks and 95 (2.3%) for ≥12 weeks. Long COVID was characterized by symptoms of fatigue, headache, dyspnea and anosmia and was more likely with increasing age and body mass index and female sex. Experiencing more than five symptoms during the first week of illness was associated with long COVID (odds ratio = 3.53 (2.76-4.50)). A simple model to distinguish between short COVID and long COVID at 7 days (total sample size, n = 2,149) showed an area under the curve of the receiver operating characteristic curve of 76%, with replication in an independent sample of 2,472 individuals who were positive for severe acute respiratory syndrome coronavirus 2. This model could be used to identify individuals at risk of long COVID for trials of prevention or treatment and to plan education and rehabilitation services.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33767405", + "TEXT": "Despite signs of infection-including taste loss, dry mouth and mucosal lesions such as ulcerations, enanthema and macules-the involvement of the oral cavity in coronavirus disease 2019 (COVID-19) is poorly understood. To address this, we generated and analyzed two single-cell RNA sequencing datasets of the human minor salivary glands and gingiva (9 samples, 13,824 cells), identifying 50 cell clusters. Using integrated cell normalization and annotation, we classified 34 unique cell subpopulations between glands and gingiva. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral entry factors such as ACE2 and TMPRSS members were broadly enriched in epithelial cells of the glands and oral mucosae. Using orthogonal RNA and protein expression assessments, we confirmed SARS-CoV-2 infection in the glands and mucosae. Saliva from SARS-CoV-2-infected individuals harbored epithelial cells exhibiting ACE2 and TMPRSS expression and sustained SARS-CoV-2 infection. Acellular and cellular salivary fractions from asymptomatic individuals were found to transmit SARS-CoV-2 ex vivo. Matched nasopharyngeal and saliva samples displayed distinct viral shedding dynamics, and salivary viral burden correlated with COVID-19 symptoms, including taste loss. Upon recovery, this asymptomatic cohort exhibited sustained salivary IgG antibodies against SARS-CoV-2. Collectively, these data show that the oral cavity is an important site for SARS-CoV-2 infection and implicate saliva as a potential route of SARS-CoV-2 transmission.", + "TAG_DATA": [ + "123, epithelial {'context': 'B-cells'}", + "124, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "123, epithelial ['l0']", + "124, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "34017133", + "TEXT": "Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are prevalent liver conditions that underlie the development of life-threatening cirrhosis, liver failure and liver cancer. Chronic necro-inflammation is a critical factor in development of NASH, yet the cellular and molecular mechanisms of immune dysregulation in this disease are poorly understood. Here, using single-cell transcriptomic analysis, we comprehensively profiled the immune composition of the mouse liver during NASH. We identified a significant pathology-associated increase in hepatic conventional dendritic cells (cDCs) and further defined their source as NASH-induced boost in cycling of cDC progenitors in the bone marrow. Analysis of blood and liver from patients on the NAFLD/NASH spectrum showed that type 1 cDCs (cDC1) were more abundant and activated in disease. Sequencing of physically interacting cDC-T cell pairs from liver-draining lymph nodes revealed that cDCs in NASH promote inflammatory T cell reprogramming, previously associated with NASH worsening. Finally, depletion of cDC1 in XCR1DTA mice or using anti-XCL1-blocking antibody attenuated liver pathology in NASH mouse models. Overall, our study provides a comprehensive characterization of cDC biology in NASH and identifies XCR1+ cDC1 as an important driver of liver pathology.", + "TAG_DATA": [ + "147, depletion {'perturbing_action': 'B-gene loss-of-function'}", + "148, of {'perturbing_action': 'I-gene loss-of-function'}", + "149, cDC1 {'perturbing_action': 'I-gene loss-of-function'}", + "152, mice {'context': 'B-organism'}", + "158, liver {'context': 'B-tissue/organ'}", + "162, mouse {'context': 'B-organism'}", + "163, models. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "147, depletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "148, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "149, cDC1 ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "152, mice ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "158, liver ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "162, mouse ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "163, models. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "cDC1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "cDC1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "33531710", + "TEXT": "A surprising feature of the SARS-CoV-2 pandemic to date is the low burdens reported in sub-Saharan Africa (SSA) countries relative to other global regions. Potential explanations (for example, warmer environments1, younger populations2-4) have yet to be framed within a comprehensive analysis. We synthesized factors hypothesized to drive the pace and burden of this pandemic in SSA during the period from 25 February to 20 December 2020, encompassing demographic, comorbidity, climatic, healthcare capacity, intervention efforts and human mobility dimensions. Large diversity in the probable drivers indicates a need for caution in interpreting analyses that aggregate data across low- and middle-income settings. Our simulation shows that climatic variation between SSA population centers has little effect on early outbreak trajectories; however, heterogeneity in connectivity, although rarely considered, is likely an important contributor to variance in the pace of viral spread across SSA. Our synthesis points to the potential benefits of context-specific adaptation of surveillance systems during the ongoing pandemic. In particular, characterizing patterns of severity over age will be a priority in settings with high comorbidity burdens and poor access to care. Understanding the spatial extent of outbreaks warrants emphasis in settings where low connectivity could drive prolonged, asynchronous outbreaks resulting in extended stress to health systems.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33633408", + "TEXT": "To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 × 10-8), hospitalization (OR = 0.61, P = 8 × 10-8) and susceptibility (OR = 0.78, P = 8 × 10-6). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case-control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33879890", + "TEXT": "Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16+C1QA/B/C+) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34+ hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8+ T cells and an increased ratio of CD8+ effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy.", + "TAG_DATA": [ + "88, CD34+ {'context': 'B-cells'}", + "89, hematopoietic {'context': 'I-cells'}", + "90, stem/progenitor {'context': 'I-cells'}", + "91, cells {'context': 'I-cells'}", + "99, megakaryocyte-committed {'context': 'B-cells'}", + "100, progenitors {'context': 'I-cells'}", + "103, platelet {'context': 'B-cells'}", + "107, CD8+ {'context': 'B-cells'}", + "108, T {'context': 'I-cells'}", + "109, cells {'context': 'I-cells'}", + "115, CD8+ {'context': 'B-cells'}", + "116, effector {'context': 'I-cells'}", + "117, T {'context': 'I-cells'}", + "118, cells {'context': 'I-cells'}", + "120, effector {'context': 'B-cells'}", + "121, memory {'context': 'I-cells'}", + "122, T {'context': 'I-cells'}", + "123, cells {'context': 'I-cells'}", + "129, follicular {'context': 'I-cells'}", + "130, helper {'context': 'I-cells'}", + "131, T {'context': 'I-cells'}", + "132, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "88, CD34+ ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "89, hematopoietic ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "90, stem/progenitor ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "91, cells ['l2', 'l15', 'l27', 'l38', 'l39', 'l40']", + "99, megakaryocyte-committed ['l3', 'l16', 'l28', 'l38', 'l41', 'l42', 'l43', 'l44', 'l45']", + "100, progenitors ['l4', 'l17', 'l29', 'l39', 'l41', 'l46', 'l47']", + "103, platelet ['l5', 'l18', 'l30', 'l40', 'l42', 'l46', 'l48']", + "107, CD8+ ['l6', 'l19', 'l31', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "108, T ['l7', 'l20', 'l32', 'l43', 'l49', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "109, cells ['l8', 'l21', 'l33', 'l44', 'l47', 'l48', 'l50', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "115, CD8+ ['l51', 'l61', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "116, effector ['l52', 'l62', 'l70', 'l77', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "117, T ['l9', 'l22', 'l53', 'l63', 'l71', 'l78', 'l87', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "118, cells ['l10', 'l23', 'l34', 'l54', 'l64', 'l72', 'l79', 'l88', 'l95', 'l102', 'l103', 'l104', 'l105', 'l106']", + "120, effector ['l55', 'l65', 'l73', 'l80', 'l89', 'l96', 'l102', 'l107', 'l108', 'l109', 'l110', 'l111']", + "121, memory ['l11', 'l24', 'l35', 'l56', 'l66', 'l74', 'l81', 'l90', 'l97', 'l103', 'l107', 'l112', 'l113', 'l114', 'l115']", + "122, T ['l12', 'l25', 'l36', 'l57', 'l67', 'l75', 'l82', 'l91', 'l98', 'l104', 'l108', 'l112', 'l116', 'l117']", + "123, cells ['l13', 'l26', 'l37', 'l45', 'l58', 'l68', 'l76', 'l83', 'l92', 'l99', 'l105', 'l109', 'l113', 'l116']", + "129, follicular ['l118', 'l119', 'l120']", + "130, helper ['l84', 'l118', 'l121', 'l122']", + "131, T ['l85', 'l93', 'l100', 'l110', 'l114', 'l119', 'l121', 'l123']", + "132, cells ['l59', 'l86', 'l94', 'l101', 'l106', 'l111', 'l115', 'l117', 'l120', 'l122', 'l123']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "34031607", + "TEXT": "Vital signs, including heart rate and body temperature, are useful in detecting or monitoring medical conditions, but are typically measured in the clinic and require follow-up laboratory testing for more definitive diagnoses. Here we examined whether vital signs as measured by consumer wearable devices (that is, continuously monitored heart rate, body temperature, electrodermal activity and movement) can predict clinical laboratory test results using machine learning models, including random forest and Lasso models. Our results demonstrate that vital sign data collected from wearables give a more consistent and precise depiction of resting heart rate than do measurements taken in the clinic. Vital sign data collected from wearables can also predict several clinical laboratory measurements with lower prediction error than predictions made using clinically obtained vital sign measurements. The length of time over which vital signs are monitored and the proximity of the monitoring period to the date of prediction play a critical role in the performance of the machine learning models. These results demonstrate the value of commercial wearable devices for continuous and longitudinal assessment of physiological measurements that today can be measured only with clinical laboratory tests.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33619371", + "TEXT": "Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID1. To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334 ), a genetic variant that confers specific protection against malaria2, as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%.", + "TAG_DATA": [ + "71, children {'context': 'B-organism'}", + "82, individuals {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "71, children ['l0']", + "82, individuals ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33707775", + "TEXT": "Multimorbidity, the simultaneous presence of multiple chronic conditions, is an increasing global health problem and research into its determinants is of high priority. We used baseline untargeted plasma metabolomics profiling covering >1,000 metabolites as a comprehensive readout of human physiology to characterize pathways associated with and across 27 incident noncommunicable diseases (NCDs) assessed using electronic health record hospitalization and cancer registry data from over 11,000 participants (219,415 person years). We identified 420 metabolites shared between at least 2 NCDs, representing 65.5% of all 640 significant metabolite-disease associations. We integrated baseline data on over 50 diverse clinical risk factors and characteristics to identify actionable shared pathways represented by those metabolites. Our study highlights liver and kidney function, lipid and glucose metabolism, low-grade inflammation, surrogates of gut microbial diversity and specific health-related behaviors as antecedents of common NCD multimorbidity with potential for early prevention. We integrated results into an open-access webserver ( https://omicscience.org/apps/mwasdisease/ ) to facilitate future research and meta-analyses.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33707772", + "TEXT": "Hutchinson-Gilford progeria syndrome (HGPS) is a rare, invariably fatal childhood premature aging disorder caused by a pre-messenger RNA (mRNA) splicing defect in the LMNA gene. We used combined in vitro screening and in vivo validation to systematically explore the effects of target sequence, backbone chemistry and mechanism of action to identify optimized antisense oligonucleotides (ASOs) for therapeutic use in HGPS. In a library of 198 ASOs, the most potent ASOs targeted the LMNA exon 12 junction and acted via non-RNase H-mediated mechanisms. Treatment with an optimized lead candidate resulted in extension of lifespan in a mouse model of HGPS. Progerin mRNA levels were robustly reduced in vivo, but the extent of progerin protein reduction differed between tissues, suggesting a long half-life and tissue-specific turnover of progerin in vivo. These results identify a novel therapeutic agent for HGPS and provide insight into the HGPS disease mechanism.", + "TAG_DATA": [ + "95, mouse {'context': 'B-organism'}", + "96, model {'context': 'I-organism'}", + "97, of {'context': 'I-organism'}", + "98, HGPS. {'context': 'I-organism'}", + "105, in {'context': 'B-in vivo'}", + "106, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "95, mouse ['l0', 'l1', 'l2']", + "96, model ['l0', 'l3', 'l4']", + "97, of ['l1', 'l3', 'l5']", + "98, HGPS. ['l2', 'l4', 'l5']", + "105, in ['l6']", + "106, vivo, ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33875890", + "TEXT": "Studies on the real-life effect of the BNT162b2 vaccine for Coronavirus Disease 2019 (COVID-19) prevention are urgently needed. In this study, we conducted a retrospective analysis of data from the Israeli Ministry of Health collected between 28 August 2020 and 24 February 2021. We studied the temporal dynamics of the number of new COVID-19 cases and hospitalizations after the vaccination campaign, which was initiated on 20 December 2020. To distinguish the possible effects of the vaccination on cases and hospitalizations from other factors, including a third lockdown implemented on 8 January 2021, we performed several comparisons: (1) individuals aged 60 years and older prioritized to receive the vaccine first versus younger age groups; (2) the January lockdown versus the September lockdown; and (3) early-vaccinated versus late-vaccinated cities. A larger and earlier decrease in COVID-19 cases and hospitalization was observed in individuals older than 60 years, followed by younger age groups, by the order of vaccination prioritization. This pattern was not observed in the previous lockdown and was more pronounced in early-vaccinated cities. Our analysis demonstrates the real-life effect of a national vaccination campaign on the pandemic dynamics.", + "TAG_DATA": [ + "97, individuals {'context': 'B-patient'}", + "140, individuals {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "140, individuals ['l0', 'l1', 'l2', 'l3']", + "141, older ['l0', 'l4', 'l5', 'l6']", + "142, than ['l1', 'l4', 'l7', 'l8']", + "143, 60 ['l2', 'l5', 'l7', 'l9']", + "144, years, ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33837377", + "TEXT": "Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 × 10-6; IFNAR2, P = 9.8 × 10-11 and IL-10RB, P = 2.3 × 10-14) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.", + "TAG_DATA": [ + "70, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33664494", + "TEXT": "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global COVID-19 pandemic. Rapidly spreading SARS-CoV-2 variants may jeopardize newly introduced antibody and vaccine countermeasures. Here, using monoclonal antibodies (mAbs), animal immune sera, human convalescent sera and human sera from recipients of the BNT162b2 mRNA vaccine, we report the impact on antibody neutralization of a panel of authentic SARS-CoV-2 variants including a B.1.1.7 isolate, chimeric strains with South African or Brazilian spike genes and isogenic recombinant viral variants. Many highly neutralizing mAbs engaging the receptor-binding domain or N-terminal domain and most convalescent sera and mRNA vaccine-induced immune sera showed reduced inhibitory activity against viruses containing an E484K spike mutation. As antibodies binding to spike receptor-binding domain and N-terminal domain demonstrate diminished neutralization potency in vitro against some emerging variants, updated mAb cocktails targeting highly conserved regions, enhancement of mAb potency or adjustments to the spike sequences of vaccines may be needed to prevent loss of protection in vivo.", + "TAG_DATA": [ + "123, in {'context': 'B-in vitro'}", + "124, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "123, in ['l0']", + "124, vitro ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33589825", + "TEXT": "The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to spread relentlessly, associated with a high frequency of respiratory failure and mortality. Children experience largely asymptomatic disease, with rare reports of multisystem inflammatory syndrome in children (MIS-C). Identifying immune mechanisms that result in these disparate clinical phenotypes in children could provide critical insights into coronavirus disease 2019 (COVID-19) pathogenesis. Using systems serology, in this study we observed in 25 children with acute mild COVID-19 a functional phagocyte and complement-activating IgG response to SARS-CoV-2, similar to the acute responses generated in adults with mild disease. Conversely, IgA and neutrophil responses were significantly expanded in adults with severe disease. Moreover, weeks after the resolution of SARS-CoV-2 infection, children who develop MIS-C maintained highly inflammatory monocyte-activating SARS-CoV-2 IgG antibodies, distinguishable from acute disease in children but with antibody levels similar to those in convalescent adults. Collectively, these data provide unique insights into the potential mechanisms of IgG and IgA that might underlie differential disease severity as well as unexpected complications in children infected with SARS-CoV-2.", + "TAG_DATA": [ + "70, children {'context': 'B-patient'}", + "104, adults {'context': 'B-organism'}", + "116, children {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33927414", + "TEXT": "Alzheimer's disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These 'subtypes' were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of 'typical AD' and a revisiting of tau pathological staging.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33531709", + "TEXT": "The first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in South Africa was identified on 5 March 2020, and by 26 March the country was in full lockdown (Oxford stringency index of 90)1. Despite the early response, by November 2020, over 785,000 people in South Africa were infected, which accounted for approximately 50% of all known African infections2. In this study, we analyzed 1,365 near whole genomes and report the identification of 16 new lineages of SARS-CoV-2 isolated between 6 March and 26 August 2020. Most of these lineages have unique mutations that have not been identified elsewhere. We also show that three lineages (B.1.1.54, B.1.1.56 and C.1) spread widely in South Africa during the first wave, comprising ~42% of all infections in the country at the time. The newly identified C lineage of SARS-CoV-2, C.1, which has 16 nucleotide mutations as compared with the original Wuhan sequence, including one amino acid change on the spike protein, D614G (ref. 3), was the most geographically widespread lineage in South Africa by the end of August 2020. An early South African-specific lineage, B.1.106, which was identified in April 2020 (ref. 4), became extinct after nosocomial outbreaks were controlled in KwaZulu-Natal Province. Our findings show that genomic surveillance can be implemented on a large scale in Africa to identify new lineages and inform measures to control the spread of SARS-CoV-2. Such genomic surveillance presented in this study has been shown to be crucial in the identification of the 501Y.V2 variant in South Africa in December 2020 (ref. 5).", + "TAG_DATA": [ + "199, Province. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "198, KwaZulu-Natal ['l0']", + "199, Province. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33619369", + "TEXT": "Multiple myeloma (MM) is a neoplastic plasma-cell disorder characterized by clonal proliferation of malignant plasma cells. Despite extensive research, disease heterogeneity within and between treatment-resistant patients is poorly characterized. In the present study, we conduct a prospective, multicenter, single-arm clinical trial (NCT04065789), combined with longitudinal single-cell RNA-sequencing (scRNA-seq) to study the molecular dynamics of MM resistance mechanisms. Newly diagnosed MM patients (41), who either failed to respond or experienced early relapse after a bortezomib-containing induction regimen, were enrolled to evaluate the safety and efficacy of a daratumumab, carfilzomib, lenalidomide and dexamethasone combination. The primary clinical endpoint was safety and tolerability. Secondary endpoints included overall response rate, progression-free survival and overall survival. Treatment was safe and well tolerated; deep and durable responses were achieved. In prespecified exploratory analyses, comparison of 41 primary refractory and early relapsed patients, with 11 healthy subjects and 15 newly diagnosed MM patients, revealed new MM molecular pathways of resistance, including hypoxia tolerance, protein folding and mitochondria respiration, which generalized to larger clinical cohorts (CoMMpass). We found peptidylprolyl isomerase A (PPIA), a central enzyme in the protein-folding response pathway, as a potential new target for resistant MM. CRISPR-Cas9 deletion of PPIA or inhibition of PPIA with a small molecule inhibitor (ciclosporin) significantly sensitizes MM tumor cells to proteasome inhibitors. Together, our study defines a roadmap for integrating scRNA-seq in clinical trials, identifies a signature of highly resistant MM patients and discovers PPIA as a potent therapeutic target for these tumors.", + "TAG_DATA": [ + "57, Newly {'context': 'B-transformed cells'}", + "58, diagnosed {'context': 'B-transformed cells'}", + "59, MM {'context': 'I-transformed cells'}", + "60, patients {'context': 'I-transformed cells'}", + "61, (41), {'context': 'I-transformed cells'}", + "190, CRISPR-Cas9 {'perturbing_action': 'B-gene loss-of-function'}", + "191, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "192, of {'perturbing_action': 'I-gene loss-of-function'}", + "193, PPIA {'perturbing_action': 'I-gene loss-of-function'}", + "195, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "196, of {'perturbing_action': 'I-pharmacological inhibition'}", + "197, PPIA {'perturbing_action': 'I-pharmacological inhibition'}", + "198, with {'perturbing_action': 'I-pharmacological inhibition'}", + "199, a {'perturbing_action': 'I-pharmacological inhibition'}", + "200, small {'perturbing_action': 'I-pharmacological inhibition'}", + "201, molecule {'perturbing_action': 'I-pharmacological inhibition'}", + "202, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "203, (ciclosporin) {'perturbing_action': 'I-pharmacological inhibition'}", + "206, MM {'context': 'B-transformed cells'}", + "207, tumor {'context': 'I-transformed cells'}", + "208, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "57, Newly ['l0', 'l1', 'l2', 'l3']", + "58, diagnosed ['l0', 'l4', 'l5', 'l6']", + "59, MM ['l1', 'l4', 'l7', 'l8']", + "60, patients ['l2', 'l5', 'l7', 'l9']", + "61, (41), ['l3', 'l6', 'l8', 'l9']", + "190, CRISPR-Cas9 ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "191, deletion ['l10', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "192, of ['l11', 'l25', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "193, PPIA ['l12', 'l26', 'l39', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "195, inhibition ['l13', 'l27', 'l40', 'l52', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "196, of ['l14', 'l28', 'l41', 'l53', 'l64', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "197, PPIA ['l15', 'l29', 'l42', 'l54', 'l65', 'l75', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "198, with ['l16', 'l30', 'l43', 'l55', 'l66', 'l76', 'l85', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "199, a ['l17', 'l31', 'l44', 'l56', 'l67', 'l77', 'l86', 'l94', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "200, small ['l18', 'l32', 'l45', 'l57', 'l68', 'l78', 'l87', 'l95', 'l102', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "201, molecule ['l19', 'l33', 'l46', 'l58', 'l69', 'l79', 'l88', 'l96', 'l103', 'l109', 'l115', 'l116', 'l117', 'l118', 'l119']", + "202, inhibitor ['l20', 'l34', 'l47', 'l59', 'l70', 'l80', 'l89', 'l97', 'l104', 'l110', 'l115', 'l120', 'l121', 'l122', 'l123']", + "203, (ciclosporin) ['l21', 'l35', 'l48', 'l60', 'l71', 'l81', 'l90', 'l98', 'l105', 'l111', 'l116', 'l120', 'l124', 'l125', 'l126']", + "206, MM ['l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l99', 'l106', 'l112', 'l117', 'l121', 'l124', 'l127', 'l128']", + "207, tumor ['l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l100', 'l107', 'l113', 'l118', 'l122', 'l125', 'l127', 'l129']", + "208, cells ['l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l108', 'l114', 'l119', 'l123', 'l126', 'l128', 'l129']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CRISPR-Cas9", + "deletion", + "of", + "PPIA" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MM", + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "PPIA", + "with", + "a", + "small", + "molecule", + "inhibitor", + "(ciclosporin)" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MM", + "tumor", + "cells" + ] + } + } + ] + }, + { + "PMID": "33526928", + "TEXT": "An increasing amount of publications are recognizing that a person’s risk of diabetes and diabetes outcomes are influenced largely by social determinants of health. This renewed understanding of disease should influence health provision and diabetes research, but will it?", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33972795", + "TEXT": "Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001, d = 0.91) and to significantly decrease the SDS total score (P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was -24.4 (s.d. 11.6) in the MDMA group and -13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33723455", + "TEXT": "Despite advances in technologies for cardiac repair after myocardial infarction (MI), new integrated therapeutic approaches still need to be developed. In this study, we designed a perfusable, multifunctional epicardial device (PerMed) consisting of a biodegradable elastic patch (BEP), permeable hierarchical microchannel networks (PHMs) and a system to enable delivery of therapeutic agents from a subcutaneously implanted pump. After its implantation into the epicardium, the BEP is designed to provide mechanical cues for ventricular remodeling, and the PHMs are designed to facilitate angiogenesis and allow for infiltration of reparative cells. In a rat model of MI, implantation of the PerMed improved ventricular function. When connected to a pump, the PerMed enabled targeted, sustained and stable release of platelet-derived growth factor-BB, amplifying the efficacy of cardiac repair as compared to the device without a pump. We also demonstrated the feasibility of minimally invasive surgical PerMed implantation in pigs, demonstrating its promise for clinical translation to treat heart disease.", + "TAG_DATA": [ + "91, rat {'context': 'B-organism'}", + "92, model {'context': 'I-organism'}", + "93, of {'context': 'I-organism'}", + "94, MI, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "91, rat ['l0', 'l1', 'l2']", + "92, model ['l0', 'l3', 'l4']", + "93, of ['l1', 'l3', 'l5']", + "94, MI, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33558721", + "TEXT": "Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN ( NCT02437279 ) and phase 2 OpACIN-neo ( NCT02977052 ) studies1,2. While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P < 0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-γ score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-γ score/high TMB; patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-γ score. Our findings provide a strong rationale for a randomized phase 3 study comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant therapy with antibodies against the programmed cell death protein-1 (anti-PD-1) in macroscopic stage III melanoma.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33772244", + "TEXT": "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.7 and B.1.351 variants were first identified in the United Kingdom and South Africa, respectively, and have since spread to many countries. These variants harboring diverse mutations in the gene encoding the spike protein raise important concerns about their immune evasion potential. Here, we isolated infectious B.1.1.7 and B.1.351 strains from acutely infected individuals. We examined sensitivity of the two variants to SARS-CoV-2 antibodies present in sera and nasal swabs from individuals infected with previously circulating strains or who were recently vaccinated, in comparison with a D614G reference virus. We utilized a new rapid neutralization assay, based on reporter cells that become positive for GFP after overnight infection. Sera from 58 convalescent individuals collected up to 9 months after symptoms, similarly neutralized B.1.1.7 and D614G. In contrast, after 9 months, convalescent sera had a mean sixfold reduction in neutralizing titers, and 40% of the samples lacked any activity against B.1.351. Sera from 19 individuals vaccinated twice with Pfizer Cominarty, longitudinally tested up to 6 weeks after vaccination, were similarly potent against B.1.1.7 but less efficacious against B.1.351, when compared to D614G. Neutralizing titers increased after the second vaccine dose, but remained 14-fold lower against B.1.351. In contrast, sera from convalescent or vaccinated individuals similarly bound the three spike proteins in a flow cytometry-based serological assay. Neutralizing antibodies were rarely detected in nasal swabs from vaccinees. Thus, faster-spreading SARS-CoV-2 variants acquired a partial resistance to neutralizing antibodies generated by natural infection or vaccination, which was most frequently detected in individuals with low antibody levels. Our results indicate that B1.351, but not B.1.1.7, may increase the risk of infection in immunized individuals.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33782619", + "TEXT": "Beyond their substantial protection of individual vaccinees, coronavirus disease 2019 (COVID-19) vaccines might reduce viral load in breakthrough infection and thereby further suppress onward transmission. In this analysis of a real-world dataset of positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test results after inoculation with the BNT162b2 messenger RNA vaccine, we found that the viral load was substantially reduced for infections occurring 12-37 d after the first dose of vaccine. These reduced viral loads hint at a potentially lower infectiousness, further contributing to vaccine effect on virus spread.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33888901", + "TEXT": "Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor that frequently accumulates in clear cell renal cell carcinoma (ccRCC), resulting in constitutive activation of genes involved in carcinogenesis. Belzutifan (MK-6482, previously known as PT2977) is a potent, selective small molecule inhibitor of HIF-2α. Maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of belzutifan were evaluated in this first-in-human phase 1 study (NCT02974738). Patients had advanced solid tumors (dose-escalation cohort) or previously treated advanced ccRCC (dose-expansion cohort). Belzutifan was administered orally using a 3 + 3 dose-escalation design, followed by expansion at the recommended phase 2 dose (RP2D) in patients with ccRCC. In the dose-escalation cohort (n = 43), no dose-limiting toxicities occurred at doses up to 160 mg once daily, and the maximum tolerated dose was not reached; the RP2D was 120 mg once daily. Plasma erythropoietin reductions were observed at all doses; erythropoietin concentrations correlated with plasma concentrations of belzutifan. In patients with ccRCC who received 120 mg once daily (n = 55), the confirmed objective response rate was 25% (all partial responses), and the median progression-free survival was 14.5 months. The most common grade ≥3 adverse events were anemia (27%) and hypoxia (16%). Belzutifan was well tolerated and demonstrated preliminary anti-tumor activity in heavily pre-treated patients, suggesting that HIF-2α inhibition might offer an effective treatment for ccRCC.", + "TAG_DATA": [ + "61, Patients {'context': 'B-patient'}", + "63, advanced {'context': 'B-neoplasm'}", + "64, solid {'context': 'I-neoplasm'}", + "65, tumors {'context': 'I-neoplasm'}", + "71, advanced {'context': 'B-neoplasm'}", + "72, ccRCC {'context': 'I-neoplasm'}", + "95, patients {'context': 'B-patient'}", + "96, with {'context': 'I-patient'}", + "97, ccRCC. {'context': 'B-neoplasm'}", + "145, patients {'context': 'B-patient'}", + "146, with {'context': 'I-patient'}", + "147, ccRCC {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "61, Patients ['l0', 'l1', 'l2', 'l3', 'l4']", + "63, advanced ['l0', 'l5', 'l6', 'l7', 'l8']", + "64, solid ['l1', 'l5', 'l9', 'l10', 'l11']", + "65, tumors ['l2', 'l6', 'l9', 'l12']", + "71, advanced ['l3', 'l7', 'l10', 'l12', 'l13', 'l14', 'l15', 'l16']", + "72, ccRCC ['l4', 'l8', 'l11', 'l13', 'l17', 'l18', 'l19']", + "95, patients ['l14', 'l17', 'l20', 'l21']", + "96, with ['l15', 'l18', 'l20', 'l22']", + "97, ccRCC. ['l16', 'l19', 'l21', 'l22']", + "145, patients ['l23', 'l24']", + "146, with ['l23', 'l25']", + "147, ccRCC ['l24', 'l25']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "34083812", + "TEXT": "Machine learning (ML) holds great promise for impacting healthcare delivery; however, to date most methods are tested in 'simulated' environments that cannot recapitulate factors influencing real-world clinical practice. We prospectively deployed and evaluated a random forest algorithm for therapeutic curative-intent radiation therapy (RT) treatment planning for prostate cancer in a blinded, head-to-head study with full integration into the clinical workflow. ML- and human-generated RT treatment plans were directly compared in a retrospective simulation with retesting (n = 50) and a prospective clinical deployment (n = 50) phase. Consistently throughout the study phases, treating physicians assessed ML- and human-generated RT treatment plans in a blinded manner following a priori defined standardized criteria and peer review processes, with the selected RT plan in the prospective phase delivered for patient treatment. Overall, 89% of ML-generated RT plans were considered clinically acceptable and 72% were selected over human-generated RT plans in head-to-head comparisons. RT planning using ML reduced the median time required for the entire RT planning process by 60.1% (118 to 47 h). While ML RT plan acceptability remained stable between the simulation and deployment phases (92 versus 86%), the number of ML RT plans selected for treatment was significantly reduced (83 versus 61%, respectively). These findings highlight that retrospective or simulated evaluation of ML methods, even under expert blinded review, may not be representative of algorithm acceptance in a real-world clinical setting when patient care is at stake.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "34345050", + "TEXT": "COVID-19 has shown that international collaborations and global data sharing are essential for health research, but legal obstacles are preventing data sharing for non–pandemic-related research among public researchers across the world, with potentially damaging effects for citizens and patients.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "34045736", + "TEXT": "Mutations in the melanocortin 4 receptor gene (MC4R) are associated with obesity but little is known about the prevalence and impact of such mutations throughout human growth and development. We examined the MC4R coding sequence in 5,724 participants from the Avon Longitudinal Study of Parents and Children, functionally characterized all nonsynonymous MC4R variants and examined their association with anthropometric phenotypes from childhood to early adulthood. The frequency of heterozygous loss-of-function (LoF) mutations in MC4R was ~1 in 337 (0.30%), considerably higher than previous estimates. At age 18 years, mean differences in body weight, body mass index and fat mass between carriers and noncarriers of LoF mutations were 17.76 kg (95% CI 9.41, 26.10), 4.84 kg m-2 (95% CI 2.19, 7.49) and 14.78 kg (95% CI 8.56, 20.99), respectively. MC4R LoF mutations may be more common than previously reported and carriers of such variants may enter adult life with a substantial burden of excess adiposity.", + "TAG_DATA": [ + "105, mutations {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33603240", + "TEXT": "The genus Orthonairovirus, which is part of the family Nairoviridae, includes the important tick-transmitted pathogens Crimean-Congo hemorrhagic fever virus and Nairobi sheep disease virus, as well as many other poorly characterized viruses found in ticks, birds and mammals1,2. In this study, we identified a new orthonairovirus, Songling virus (SGLV), from patients who reported being bitten by ticks in Heilongjiang Province in northeastern China. SGLV shared similar genomic and morphological features with orthonairoviruses and phylogenetically formed a unique clade in Tamdy orthonairovirus of the Nairoviridae family. The isolated SGLV induced cytopathic effects in human hepatoma cells in vitro. SGLV infection was confirmed in 42 hospitalized patients analyzed between 2017 and 2018, with the main clinical manifestations being headache, fever, depression, fatigue and dizziness. More than two-thirds (69%) of patients generated virus-specific antibody responses in the acute phase. Taken together, these results suggest that this newly discovered orthonairovirus is associated with human febrile illness in China.", + "TAG_DATA": [ + "92, human {'context': 'B-transformed cells'}", + "93, hepatoma {'context': 'I-transformed cells'}", + "94, cells {'context': 'I-transformed cells'}", + "95, in {'context': 'B-in vitro'}", + "96, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "92, human ['l0', 'l1', 'l2', 'l3']", + "93, hepatoma ['l0', 'l4', 'l5', 'l6']", + "94, cells ['l1', 'l4', 'l7', 'l8']", + "95, in ['l2', 'l5', 'l7', 'l9']", + "96, vitro. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "34099924", + "TEXT": "Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 × 10-7), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10-28), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10-15), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10-9) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10-4). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.", + "TAG_DATA": [ + "71, cancer {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "70, hematological ['l0']", + "71, cancer ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33558724", + "TEXT": "We engineered three severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses containing key spike mutations from the newly emerged United Kingdom (UK) and South African (SA) variants: N501Y from UK and SA; 69/70-deletion + N501Y + D614G from UK; and E484K + N501Y + D614G from SA. Neutralization geometric mean titers (GMTs) of 20 BTN162b2 vaccine-elicited human sera against the three mutant viruses were 0.81- to 1.46-fold of the GMTs against parental virus, indicating small effects of these mutations on neutralization by sera elicited by two BNT162b2 doses.", + "TAG_DATA": [ + "50, human {'context': 'B-patient'}", + "51, sera {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "50, human ['l0']", + "51, sera ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "34083811", + "TEXT": "Around 5% of the population is affected by a rare genetic disease, yet most endure years of uncertainty before receiving a genetic test. A common feature of genetic diseases is the presence of multiple rare phenotypes that often span organ systems. Here, we use diagnostic billing information from longitudinal clinical data in the electronic health records (EHRs) of 2,286 patients who received a chromosomal microarray test, and 9,144 matched controls, to build a model to predict who should receive a genetic test. The model achieved high prediction accuracies in a held-out test sample (area under the receiver operating characteristic curve (AUROC), 0.97; area under the precision-recall curve (AUPRC), 0.92), in an independent hospital system (AUROC, 0.95; AUPRC, 0.62), and in an independent set of 172,265 patients in which cases were broadly defined as having an interaction with a genetics provider (AUROC, 0.9; AUPRC, 0.63). Patients carrying a putative pathogenic copy number variant were also accurately identified by the model. Compared with current approaches for genetic test determination, our model could identify more patients for testing while also increasing the proportion of those tested who have a genetic disease. We demonstrate that phenotypic patterns representative of a wide range of genetic diseases can be captured from EHRs to systematize decision-making for genetic testing, with the potential to speed up diagnosis, improve care and reduce costs.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33864052", + "TEXT": "Despite progress in clinical care for patients with coronavirus disease 2019 (COVID-19)1, population-wide interventions are still crucial to manage the pandemic, which has been aggravated by the emergence of new, highly transmissible variants. In this study, we combined the SIDARTHE model2, which predicts the spread of SARS-CoV-2 infections, with a new data-based model that projects new cases onto casualties and healthcare system costs. Based on the Italian case study, we outline several scenarios: mass vaccination campaigns with different paces, different transmission rates due to new variants and different enforced countermeasures, including the alternation of opening and closure phases. Our results demonstrate that non-pharmaceutical interventions (NPIs) have a higher effect on the epidemic evolution than vaccination alone, advocating for the need to keep NPIs in place during the first phase of the vaccination campaign. Our model predicts that, from April 2021 to January 2022, in a scenario with no vaccine rollout and weak NPIs ([Formula: see text] = 1.27), as many as 298,000 deaths associated with COVID-19 could occur. However, fast vaccination rollouts could reduce mortality to as few as 51,000 deaths. Implementation of restrictive NPIs ([Formula: see text] = 0.9) could reduce COVID-19 deaths to 30,000 without vaccinating the population and to 18,000 with a fast rollout of vaccines. We also show that, if intermittent open-close strategies are adopted, implementing a closing phase first could reduce deaths (from 47,000 to 27,000 with slow vaccine rollout) and healthcare system costs, without substantive aggravation of socioeconomic losses.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33888899", + "TEXT": "While CD19-directed chimeric antigen receptor (CAR) T cells can induce remission in patients with B cell acute lymphoblastic leukemia (ALL), a large subset relapse with CD19- disease. Like CD19, CD22 is broadly expressed by B-lineage cells and thus serves as an alternative immunotherapy target in ALL. Here we present the composite outcomes of two pilot clinical trials ( NCT02588456 and NCT02650414 ) of T cells bearing a 4-1BB-based, CD22-targeting CAR in patients with relapsed or refractory ALL. The primary end point of these studies was to assess safety, and the secondary end point was antileukemic efficacy. We observed unexpectedly low response rates, prompting us to perform detailed interrogation of the responsible CAR biology. We found that shortening of the amino acid linker connecting the variable heavy and light chains of the CAR antigen-binding domain drove receptor homodimerization and antigen-independent signaling. In contrast to CD28-based CARs, autonomously signaling 4-1BB-based CARs demonstrated enhanced immune synapse formation, activation of pro-inflammatory genes and superior effector function. We validated this association between autonomous signaling and enhanced function in several CAR constructs and, on the basis of these observations, designed a new short-linker CD22 single-chain variable fragment for clinical evaluation. Our findings both suggest that tonic 4-1BB-based signaling is beneficial to CAR function and demonstrate the utility of bedside-to-bench-to-bedside translation in the design and implementation of CAR T cell therapies.", + "TAG_DATA": [ + "63, T {'context': 'B-cells'}", + "64, cells {'context': 'B-cells'}", + "71, patients {'context': 'B-patient'}", + "76, ALL. {'context': 'I-neoplasm'}", + "116, shortening {'perturbing_action': 'B-other'}", + "117, of {'perturbing_action': 'I-other'}", + "118, the {'perturbing_action': 'I-other'}", + "119, amino {'perturbing_action': 'I-other'}", + "120, acid {'perturbing_action': 'I-other'}", + "121, linker {'perturbing_action': 'I-other'}", + "122, connecting {'perturbing_action': 'I-other'}", + "123, the {'perturbing_action': 'I-other'}", + "124, variable {'perturbing_action': 'I-other'}", + "125, heavy {'perturbing_action': 'I-other'}", + "126, and {'perturbing_action': 'I-other'}", + "127, light {'perturbing_action': 'I-other'}", + "128, chains {'perturbing_action': 'I-other'}", + "129, of {'perturbing_action': 'I-other'}", + "130, the {'perturbing_action': 'I-other'}", + "131, CAR {'perturbing_action': 'I-other'}", + "132, antigen-binding {'perturbing_action': 'I-other'}", + "133, domain {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "63, T ['l0', 'l1', 'l2']", + "64, cells ['l0', 'l3', 'l4']", + "71, patients ['l1', 'l3', 'l5']", + "76, ALL. ['l2', 'l4', 'l5']", + "116, shortening ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "117, of ['l6', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "118, the ['l7', 'l23', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "119, amino ['l8', 'l24', 'l39', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "120, acid ['l9', 'l25', 'l40', 'l54', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "121, linker ['l10', 'l26', 'l41', 'l55', 'l68', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "122, connecting ['l11', 'l27', 'l42', 'l56', 'l69', 'l81', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "123, the ['l12', 'l28', 'l43', 'l57', 'l70', 'l82', 'l93', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "124, variable ['l13', 'l29', 'l44', 'l58', 'l71', 'l83', 'l94', 'l104', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "125, heavy ['l14', 'l30', 'l45', 'l59', 'l72', 'l84', 'l95', 'l105', 'l114', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "126, and ['l15', 'l31', 'l46', 'l60', 'l73', 'l85', 'l96', 'l106', 'l115', 'l123', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "127, light ['l16', 'l32', 'l47', 'l61', 'l74', 'l86', 'l97', 'l107', 'l116', 'l124', 'l131', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "128, chains ['l17', 'l33', 'l48', 'l62', 'l75', 'l87', 'l98', 'l108', 'l117', 'l125', 'l132', 'l138', 'l144', 'l145', 'l146', 'l147', 'l148']", + "129, of ['l18', 'l34', 'l49', 'l63', 'l76', 'l88', 'l99', 'l109', 'l118', 'l126', 'l133', 'l139', 'l144', 'l149', 'l150', 'l151', 'l152']", + "130, the ['l19', 'l35', 'l50', 'l64', 'l77', 'l89', 'l100', 'l110', 'l119', 'l127', 'l134', 'l140', 'l145', 'l149', 'l153', 'l154', 'l155']", + "131, CAR ['l20', 'l36', 'l51', 'l65', 'l78', 'l90', 'l101', 'l111', 'l120', 'l128', 'l135', 'l141', 'l146', 'l150', 'l153', 'l156', 'l157']", + "132, antigen-binding ['l21', 'l37', 'l52', 'l66', 'l79', 'l91', 'l102', 'l112', 'l121', 'l129', 'l136', 'l142', 'l147', 'l151', 'l154', 'l156', 'l158']", + "133, domain ['l22', 'l38', 'l53', 'l67', 'l80', 'l92', 'l103', 'l113', 'l122', 'l130', 'l137', 'l143', 'l148', 'l152', 'l155', 'l157', 'l158']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33737751", + "TEXT": "β-Thalassemia pathology is due not only to loss of β-globin (HBB), but also to erythrotoxic accumulation and aggregation of the β-globin-binding partner, α-globin (HBA1/2). Here we describe a Cas9/AAV6-mediated genome editing strategy that can replace the entire HBA1 gene with a full-length HBB transgene in β-thalassemia-derived hematopoietic stem and progenitor cells (HSPCs), which is sufficient to normalize β-globin:α-globin messenger RNA and protein ratios and restore functional adult hemoglobin tetramers in patient-derived red blood cells. Edited HSPCs were capable of long-term and bilineage hematopoietic reconstitution in mice, establishing proof of concept for replacement of HBA1 with HBB as a novel therapeutic strategy for curing β-thalassemia.", + "TAG_DATA": [ + "45, β-thalassemia-derived {'context': 'B-cells'}", + "46, hematopoietic {'context': 'I-cells'}", + "47, stem {'context': 'I-cells'}", + "48, and {'context': 'I-cells'}", + "49, progenitor {'context': 'I-cells'}", + "50, cells {'context': 'I-cells'}", + "51, (HSPCs), {'context': 'I-cells'}", + "70, patient-derived {'context': 'B-cells'}", + "71, red {'context': 'I-cells'}", + "72, blood {'context': 'I-cells'}", + "73, cells. {'context': 'I-cells'}", + "75, HSPCs {'context': 'B-cells'}", + "85, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "45, β-thalassemia-derived ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "46, hematopoietic ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "47, stem ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "48, and ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "49, progenitor ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "50, cells ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "51, (HSPCs), ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "70, patient-derived ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "71, red ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "72, blood ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "73, cells. ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "75, HSPCs ['l55']", + "85, mice, ['l55']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33574608", + "TEXT": "To address how the microbiome might modify the interaction between diet and cardiometabolic health, we analyzed longitudinal microbiome data from 307 male participants in the Health Professionals Follow-Up Study, together with long-term dietary information and measurements of biomarkers of glucose homeostasis, lipid metabolism and inflammation from blood samples. Here, we demonstrate that a healthy Mediterranean-style dietary pattern is associated with specific functional and taxonomic components of the gut microbiome, and that its protective associations with cardiometabolic health vary depending on microbial composition. In particular, the protective association between adherence to the Mediterranean diet and cardiometabolic disease risk was significantly stronger among participants with decreased abundance of Prevotella copri. Our findings advance the concept of precision nutrition and have the potential to inform more effective and precise dietary approaches for the prevention of cardiometabolic disease mediated through alterations in the gut microbiome.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "34127852", + "TEXT": "Agonism of the glucagon-like peptide-1 receptor (GLP-1R) results in glycemic lowering and body weight loss and is a therapeutic strategy to treat type 2 diabetes (T2D) and obesity. We developed danuglipron (PF-06882961), an oral small-molecule GLP-1R agonist and found it had comparable efficacy to injectable peptidic GLP-1R agonists in a humanized mouse model. We then completed a placebo-controlled, randomized, double-blind, multiple ascending-dose phase 1 study ( NCT03538743 ), in which we enrolled 98 patients with T2D on background metformin and randomized them to receive multiple ascending doses of danuglipron or placebo for 28 d, across eight cohorts. The primary outcomes were assessment of adverse events (AEs), safety laboratory tests, vital signs and 12-lead electrocardiograms. Most AEs were mild, with nausea, dyspepsia and vomiting most commonly reported. There were no clinically meaningful AEs in laboratory values across groups. Heart rate generally increased with danuglipron treatment at day 28, but no heart-rate AEs were reported. Systolic blood pressure was slightly decreased and changes in diastolic blood pressure were similar with danuglipron treatment at day 28, compared with placebo. There were no clinically meaningful electrocardiogram findings. In this study in T2D, danuglipron was generally well tolerated, with a safety profile consistent with the mechanism of action of GLP-1R agonism.", + "TAG_DATA": [ + "50, humanized {'context': 'B-organism'}", + "51, mouse {'context': 'I-organism'}", + "52, model. {'context': 'I-organism'}", + "73, patients {'context': 'B-patient'}", + "75, T2D {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "50, humanized ['l0', 'l1', 'l2', 'l3']", + "51, mouse ['l0', 'l4', 'l5', 'l6']", + "52, model. ['l1', 'l4', 'l7', 'l8']", + "73, patients ['l2', 'l5', 'l7', 'l9']", + "75, T2D ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33649496", + "TEXT": "Degeneration of dopamine (DA) neurons in the midbrain underlies the pathogenesis of Parkinson's disease (PD). Supplement of DA via L-DOPA alleviates motor symptoms but does not prevent the progressive loss of DA neurons. A large body of experimental studies, including those in nonhuman primates, demonstrates that transplantation of fetal mesencephalic tissues improves motor symptoms in animals, which culminated in open-label and double-blinded clinical trials of fetal tissue transplantation for PD1. Unfortunately, the outcomes are mixed, primarily due to the undefined and unstandardized donor tissues1,2. Generation of induced pluripotent stem cells enables standardized and autologous transplantation therapy for PD. However, its efficacy, especially in primates, remains unclear. Here we show that over a 2-year period without immunosuppression, PD monkeys receiving autologous, but not allogenic, transplantation exhibited recovery from motor and depressive signs. These behavioral improvements were accompanied by robust grafts with extensive DA neuron axon growth as well as strong DA activity in positron emission tomography (PET). Mathematical modeling reveals correlations between the number of surviving DA neurons with PET signal intensity and behavior recovery regardless autologous or allogeneic transplant, suggesting a predictive power of PET and motor behaviors for surviving DA neuron number.", + "TAG_DATA": [ + "116, PD {'context': 'B-organism'}", + "117, monkeys {'context': 'I-organism'}", + "141, DA {'context': 'B-cells'}", + "142, neuron {'context': 'I-cells'}", + "143, axon {'phenotype': 'B-autophagy'}", + "144, growth {'phenotype': 'I-cell growth'}" + ], + "LINK_DATA": [ + "116, PD ['l0', 'l1', 'l2', 'l3', 'l4']", + "117, monkeys ['l0', 'l5', 'l6', 'l7', 'l8']", + "141, DA ['l1', 'l5', 'l9', 'l10', 'l11']", + "142, neuron ['l2', 'l6', 'l9', 'l12', 'l13']", + "143, axon ['l3', 'l7', 'l10', 'l12', 'l14']", + "144, growth ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "PD", + "monkeys" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "axon" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "PD", + "monkeys" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "DA", + "neuron" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "axon" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "DA", + "neuron" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + } + ] + }, + { + "PMID": "33795869", + "TEXT": "Leber congenital amaurosis due to CEP290 ciliopathy is being explored by treatment with the antisense oligonucleotide (AON) sepofarsen. One patient who was part of a larger cohort (ClinicalTrials.gov NCT03140969 ) was studied for 15 months after a single intravitreal sepofarsen injection. Concordant measures of visual function and retinal structure reached a substantial efficacy peak near 3 months after injection. At 15 months, there was sustained efficacy, even though there was evidence of reduction from peak response. Efficacy kinetics can be explained by the balance of AON-driven new CEP290 protein synthesis and a slow natural rate of CEP290 protein degradation in human foveal cone photoreceptors.", + "TAG_DATA": [], + "LINK_DATA": [ + "101, foveal ['l0']", + "102, cone ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33619368", + "TEXT": "B cell maturation antigen (BCMA) is a target for various immunotherapies and a biomarker for tumor load in multiple myeloma (MM). We report a case of irreversible BCMA loss in a patient with MM who was enrolled in the KarMMa trial ( NCT03361748 ) and progressed after anti-BCMA CAR T cell therapy. We identified selection of a clone with homozygous deletion of TNFRSF17 (BCMA) as the underlying mechanism of immune escape. Furthermore, we found heterozygous TNFRSF17 loss or monosomy 16 in 37 out of 168 patients with MM, including 28 out of 33 patients with hyperhaploid MM who had not been previously treated with BCMA-targeting therapies, suggesting that heterozygous TNFRSF17 deletion at baseline could theoretically be a risk factor for BCMA loss after immunotherapy.", + "TAG_DATA": [ + "31, patient {'context': 'B-patient'}", + "32, with {'context': 'I-patient'}", + "33, MM {'context': 'I-neoplasm'}", + "87, MM, {'context': 'B-neoplasm'}", + "93, patients {'context': 'B-patient'}", + "96, MM {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "31, patient ['l0', 'l1']", + "32, with ['l0', 'l2']", + "33, MM ['l1', 'l2']", + "93, patients ['l3']", + "96, MM ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "34007070", + "TEXT": "Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are being deployed, but the global need greatly exceeds the supply, and different formulations might be required for specific populations. Here we report Day 42 interim safety and immunogenicity data from an observer-blinded, dose escalation, randomized controlled study of a virus-like particle vaccine candidate produced in plants that displays the SARS-CoV-2 spike glycoprotein (CoVLP: NCT04450004 ). The co-primary outcomes were the short-term tolerability/safety and immunogenicity of CoVLP formulations assessed by neutralizing antibody (NAb) and cellular responses. Secondary outcomes in this ongoing study include safety and immunogenicity assessments up to 12 months after vaccination. Adults (18-55 years, n = 180) were randomized at two sites in Quebec, Canada, to receive two intramuscular doses of CoVLP (3.75 μg, 7.5 μg, and 15 μg) 21 d apart, alone or adjuvanted with AS03 or CpG1018. All formulations were well tolerated, and adverse events after vaccination were generally mild to moderate, transient and highest in the adjuvanted groups. There was no CoVLP dose effect on serum NAbs, but titers increased significantly with both adjuvants. After the second dose, NAbs in the CoVLP + AS03 groups were more than tenfold higher than titers in Coronavirus 2019 convalescent sera. Both spike protein-specific interferon-γ and interleukin-4 cellular responses were also induced. This pre-specified interim analysis supports further evaluation of the CoVLP vaccine candidate.", + "TAG_DATA": [ + "102, Adults {'context': 'B-organism'}", + "103, (18-55 {'context': 'I-organism'}", + "104, years, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "102, Adults ['l0', 'l1', 'l2']", + "103, (18-55 ['l0', 'l3', 'l4']", + "104, years, ['l1', 'l3', 'l5']", + "113, Canada, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33990806", + "TEXT": "Congenital heart disease (CHD) is the most common birth defect. Fetal screening ultrasound provides five views of the heart that together can detect 90% of complex CHD, but in practice, sensitivity is as low as 30%. Here, using 107,823 images from 1,326 retrospective echocardiograms and screening ultrasounds from 18- to 24-week fetuses, we trained an ensemble of neural networks to identify recommended cardiac views and distinguish between normal hearts and complex CHD. We also used segmentation models to calculate standard fetal cardiothoracic measurements. In an internal test set of 4,108 fetal surveys (0.9% CHD, >4.4 million images), the model achieved an area under the curve (AUC) of 0.99, 95% sensitivity (95% confidence interval (CI), 84-99%), 96% specificity (95% CI, 95-97%) and 100% negative predictive value in distinguishing normal from abnormal hearts. Model sensitivity was comparable to that of clinicians and remained robust on outside-hospital and lower-quality images. The model's decisions were based on clinically relevant features. Cardiac measurements correlated with reported measures for normal and abnormal hearts. Applied to guideline-recommended imaging, ensemble learning models could significantly improve detection of fetal CHD, a critical and global diagnostic challenge.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33941921", + "TEXT": "Durvalumab is a programmed death-ligand 1 (PD-L1) inhibitor with clinical activity in advanced urothelial cancer (AUC)1. AUC is characterized by several recurrent targetable genomic alterations2-5. This study ( NCT02546661 , BISCAY) combined durvalumab with relevant targeted therapies in biomarker-selected chemotherapy-refractory AUC populations including: (1) fibroblast growth factor receptor (FGFR) inhibitors in tumors with FGFR DNA alterations (FGFRm); (2) pharmacological inhibitor of the enzyme poly-ADP ribose polymerase (PARP) in tumors with and without DNA homologous recombination repair deficiency (HRRm); and (3) TORC1/2 inhibitors in tumors with DNA alteration to the mTOR/PI3K pathway3-5.This trial adopted a new, biomarker-driven, multiarm adaptive design. Safety, efficacy and relevant biomarkers were evaluated. Overall, 391 patients were screened of whom 135 were allocated to one of six study arms. Response rates (RRs) ranged 9-36% across the study arms, which did not meet efficacy criteria for further development. Overall survival (OS) and progression-free survival (PFS) were similar in the combination arms and durvalumab monotherapy arm. Biomarker analysis showed a correlation between circulating plasma-based DNA (ctDNA) and tissue for FGFRm. Sequential circulating tumor DNA analysis showed that changes to FGFRm correlated with clinical outcome. Our data support the clinical activity of FGFR inhibition and durvalumab monotherapy but do not show increased activity for any of the combinations. These findings question the targeted/immune therapy approach in AUC.", + "TAG_DATA": [ + "40, AUC {'context': 'B-neoplasm'}", + "51, tumors {'context': 'B-neoplasm'}", + "68, tumors {'context': 'B-neoplasm'}", + "80, TORC1/2 {'perturbing_action': 'B-pharmacological inhibition'}", + "81, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "83, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "40, AUC ['l0', 'l1']", + "51, tumors ['l0', 'l2']", + "68, tumors ['l1', 'l2']", + "80, TORC1/2 ['l3', 'l4']", + "81, inhibitors ['l3', 'l5']", + "83, tumors ['l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "TORC1/2", + "inhibitors" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + } + ] + }, + { + "PMID": "33927413", + "TEXT": "The goal of this study was to determine whether a phosphodiesterase-4D (PDE4D) allosteric inhibitor (BPN14770) would improve cognitive function and behavioral outcomes in patients with fragile X syndrome (FXS). This phase 2 trial was a 24-week randomized, placebo-controlled, two-way crossover study in 30 adult male patients (age 18-41 years) with FXS. Participants received oral doses of BPN14770 25 mg twice daily or placebo. Primary outcomes were prespecified as safety and tolerability with secondary efficacy outcomes of cognitive performance, caregiver rating scales and physician rating scales (ClinicalTrials.gov identifier: NCT03569631 ). The study met the primary outcome measure since BPN14770 was well tolerated with no meaningful differences between the active and placebo treatment arms. The study also met key secondary efficacy measures of cognition and daily function. Cognitive benefit was demonstrated using the National Institutes of Health Toolbox Cognition Battery assessments of Oral Reading Recognition (least squares mean difference +2.81, P = 0.0157), Picture Vocabulary (+5.81, P = 0.0342) and Cognition Crystallized Composite score (+5.31, P = 0.0018). Benefit as assessed by visual analog caregiver rating scales was judged to be clinically meaningful for language (+14.04, P = 0.0051) and daily functioning (+14.53, P = 0.0017). Results from this study using direct, computer-based assessment of cognitive performance by adult males with FXS indicate significant cognitive improvement in domains related to language with corresponding improvement in caregiver scales rating language and daily functioning.", + "TAG_DATA": [ + "43, adult {'context': 'B-patient'}", + "44, male {'context': 'I-patient'}", + "45, patients {'context': 'I-patient'}", + "46, (age {'context': 'I-patient'}", + "47, 18-41 {'context': 'I-organism'}", + "48, years) {'context': 'I-organism'}", + "49, with {'context': 'I-patient'}", + "50, FXS. {'context': 'I-patient'}", + "195, adult {'context': 'B-organism'}", + "196, males {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "43, adult ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "44, male ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "45, patients ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "46, (age ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "47, 18-41 ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "48, years) ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "49, with ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "50, FXS. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "195, adult ['l28']", + "196, males ['l28']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "34031605", + "TEXT": "A combination of plasma phospho-tau (P-tau) and other accessible biomarkers might provide accurate prediction about the risk of developing Alzheimer's disease (AD) dementia. We examined this in participants with subjective cognitive decline and mild cognitive impairment from the BioFINDER (n = 340) and Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 543) studies. Plasma P-tau, plasma Aβ42/Aβ40, plasma neurofilament light, APOE genotype, brief cognitive tests and an AD-specific magnetic resonance imaging measure were examined using progression to AD as outcome. Within 4 years, plasma P-tau217 predicted AD accurately (area under the curve (AUC) = 0.83) in BioFINDER. Combining plasma P-tau217, memory, executive function and APOE produced higher accuracy (AUC = 0.91, P < 0.001). In ADNI, this model had similar AUC (0.90) using plasma P-tau181 instead of P-tau217. The model was implemented online for prediction of the individual probability of progressing to AD. Within 2 and 6 years, similar models had AUCs of 0.90-0.91 in both cohorts. Using cerebrospinal fluid P-tau, Aβ42/Aβ40 and neurofilament light instead of plasma biomarkers did not improve the accuracy significantly. The clinical predictions by memory clinic physicians had significantly lower accuracy (4-year AUC = 0.71). In summary, plasma P-tau, in combination with brief cognitive tests and APOE genotyping, might greatly improve the diagnostic prediction of AD and facilitate recruitment for AD trials.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33859411", + "TEXT": "Deep learning methods have been shown to achieve excellent performance on diagnostic tasks, but how to optimally combine them with expert knowledge and existing clinical decision pathways is still an open challenge. This question is particularly important for the early detection of cancer, where high-volume workflows may benefit from (semi-)automated analysis. Here we present a deep learning framework to analyze samples of the Cytosponge-TFF3 test, a minimally invasive alternative to endoscopy, for detecting Barrett's esophagus, which is the main precursor of esophageal adenocarcinoma. We trained and independently validated the framework on data from two clinical trials, analyzing a combined total of 4,662 pathology slides from 2,331 patients. Our approach exploits decision patterns of gastrointestinal pathologists to define eight triage classes of varying priority for manual expert review. By substituting manual review with automated review in low-priority classes, we can reduce pathologist workload by 57% while matching the diagnostic performance of experienced pathologists.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33558722", + "TEXT": "The association among pathological response, recurrence-free survival (RFS) and overall survival (OS) with neoadjuvant therapy in melanoma remains unclear. In this study, we pooled data from six clinical trials of anti-PD-1-based immunotherapy or BRAF/MEK targeted therapy. In total, 192 patients were included; 141 received immunotherapy (104, combination of ipilimumab and nivolumab; 37, anti-PD-1 monotherapy), and 51 received targeted therapy. A pathological complete response (pCR) occurred in 40% of patients: 47% with targeted therapy and 33% with immunotherapy (43% combination and 20% monotherapy). pCR correlated with improved RFS (pCR 2-year 89% versus no pCR 50%, P < 0.001) and OS (pCR 2-year OS 95% versus no pCR 83%, P = 0.027). In patients with pCR, near pCR or partial pathological response with immunotherapy, very few relapses were seen (2-year RFS 96%), and, at this writing, no patient has died from melanoma, whereas, even with pCR from targeted therapy, the 2-year RFS was only 79%, and OS was only 91%. Pathological response should be an early surrogate endpoint for clinical trials and a new benchmark for development and approval in melanoma.", + "TAG_DATA": [ + "107, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33846610", + "TEXT": "On 1 August 2018, the Democratic Republic of the Congo (DRC) declared its tenth Ebola virus disease (EVD) outbreak. To aid the epidemiologic response, the Institut National de Recherche Biomédicale (INRB) implemented an end-to-end genomic surveillance system, including sequencing, bioinformatic analysis and dissemination of genomic epidemiologic results to frontline public health workers. We report 744 new genomes sampled between 27 July 2018 and 27 April 2020 generated by this surveillance effort. Together with previously available sequence data (n = 48 genomes), these data represent almost 24% of all laboratory-confirmed Ebola virus (EBOV) infections in DRC in the period analyzed. We inferred spatiotemporal transmission dynamics from the genomic data as new sequences were generated, and disseminated the results to support epidemiologic response efforts. Here we provide an overview of how this genomic surveillance system functioned, present a full phylodynamic analysis of 792 Ebola genomes from the Nord Kivu outbreak and discuss how the genomic surveillance data informed response efforts and public health decision making.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "34099923", + "TEXT": "People with human immunodeficiency virus (HIV) have higher rates of certain comorbidities, particularly cardiovascular disease and cancer, than people without HIV1-5. In view of observations that somatic mutations associated with age-related clonal hematopoiesis (CH) are linked to similar comorbidities in the general population6-10, we hypothesized that CH may be more prevalent in people with HIV. To address this issue, we established a prospective cohort study, the ARCHIVE study (NCT04641013), in which 220 HIV-positive and 226 HIV-negative participants aged 55 years or older were recruited in Australia. Demographic characteristics, clinical data and peripheral blood were collected to assess the presence of CH mutations and to identify potential risk factors for and clinical sequelae of CH. In total, 135 CH mutations were identified in 100 (22.4%) of 446 participants. CH was more prevalent in HIV-positive participants than in HIV-negative participants (28.2% versus 16.8%, P = 0.004), overall and across all age groups; the adjusted odds ratio for having CH in those with HIV was 2.16 (95% confidence interval 1.34-3.48, P = 0.002). The most common genes mutated overall were DNMT3A (47.4%), TET2 (20.0%) and ASXL1 (13.3%). CH and HIV infection were independently associated with increases in blood parameters and biomarkers associated with inflammation. These data suggest a selective advantage for the emergence of CH in the context of chronic infection and inflammation related to HIV infection.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33737749", + "TEXT": "Many observational studies and some randomized trials demonstrate how fetal growth can be influenced by environmental insults (for example, maternal infections)1 and preventive interventions (for example, multiple-micronutrient supplementation)2 that can have a long-lasting effect on health, growth, neurodevelopment and even educational attainment and income in adulthood3. In a cohort of pregnant women (n = 3,598), followed-up between 2012 and 2019 at six sites worldwide4, we studied the associations between ultrasound-derived fetal cranial growth trajectories, measured longitudinally from <14 weeks' gestation, against international standards5,6, and growth and neurodevelopment up to 2 years of age7,8. We identified five trajectories associated with specific neurodevelopmental, behavioral, visual and growth outcomes, independent of fetal abdominal growth, postnatal morbidity and anthropometric measures at birth and age 2. The trajectories, which changed within a 20-25-week gestational age window, were associated with brain development at 2 years of age according to a mirror (positive/negative) pattern, mostly focused on maturation of cognitive, language and visual skills. Further research should explore the potential for preventive interventions in pregnancy to improve infant neurodevelopmental outcomes before the critical window of opportunity that precedes the divergence of growth at 20-25 weeks' gestation.", + "TAG_DATA": [ + "50, pregnant {'context': 'B-patient'}", + "51, women {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "50, pregnant ['l0', 'l1']", + "51, women ['l0', 'l2']", + "52, (n = 3,598), ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33958795", + "TEXT": "We have conducted a pragmatic clinical trial aimed to assess whether an electrocardiogram (ECG)-based, artificial intelligence (AI)-powered clinical decision support tool enables early diagnosis of low ejection fraction (EF), a condition that is underdiagnosed but treatable. In this trial ( NCT04000087 ), 120 primary care teams from 45 clinics or hospitals were cluster-randomized to either the intervention arm (access to AI results; 181 clinicians) or the control arm (usual care; 177 clinicians). ECGs were obtained as part of routine care from a total of 22,641 adults (N = 11,573 intervention; N = 11,068 control) without prior heart failure. The primary outcome was a new diagnosis of low EF (≤50%) within 90 days of the ECG. The trial met the prespecified primary endpoint, demonstrating that the intervention increased the diagnosis of low EF in the overall cohort (1.6% in the control arm versus 2.1% in the intervention arm, odds ratio (OR) 1.32 (1.01-1.61), P = 0.007) and among those who were identified as having a high likelihood of low EF (that is, positive AI-ECG, 6% of the overall cohort) (14.5% in the control arm versus 19.5% in the intervention arm, OR 1.43 (1.08-1.91), P = 0.01). In the overall cohort, echocardiogram utilization was similar between the two arms (18.2% control versus 19.2% intervention, P = 0.17); for patients with positive AI-ECGs, more echocardiograms were obtained in the intervention compared to the control arm (38.1% control versus 49.6% intervention, P < 0.001). These results indicate that use of an AI algorithm based on ECGs can enable the early diagnosis of low EF in patients in the setting of routine primary care.", + "TAG_DATA": [ + "43, primary {'context': 'B-cells'}", + "44, care {'context': 'I-cells'}", + "45, teams {'context': 'I-cells'}", + "46, from {'context': 'I-cells'}", + "47, 45 {'context': 'I-cells'}", + "48, clinics {'context': 'I-cells'}", + "50, hospitals {'context': 'I-cells'}", + "85, adults {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "43, primary ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "44, care ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "45, teams ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "46, from ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "47, 45 ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "48, clinics ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "50, hospitals ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "85, adults ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33958799", + "TEXT": "Cystic fibrosis (CF) is a lethal autosomal recessive disorder that afflicts more than 70,000 people. People with CF experience multi-organ dysfunction resulting from aberrant electrolyte transport across polarized epithelia due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF-related lung disease is by far the most important determinant of morbidity and mortality. Here we report results from a multi-institute consortium in which single-cell transcriptomics were applied to define disease-related changes by comparing the proximal airway of CF donors (n = 19) undergoing transplantation for end-stage lung disease with that of previously healthy lung donors (n = 19). Disease-dependent differences observed include an overabundance of epithelial cells transitioning to specialized ciliated and secretory cell subsets coupled with an unexpected decrease in cycling basal cells. Our study yields a molecular atlas of the proximal airway epithelium that will provide insights for the development of new targeted therapies for CF airway disease.", + "TAG_DATA": [ + "77, airway {'context': 'I-tissue/organ'}", + "103, epithelial {'context': 'B-cells'}", + "104, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "103, epithelial ['l0']", + "104, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33888900", + "TEXT": "An effective vaccine is needed to end the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Here, we assess the preliminary safety, tolerability and immunogenicity data from an ongoing single-center (in Jiangsu province, China), parallel-group, double-blind phase 1 trial of the vaccine candidate BNT162b1 in 144 healthy SARS-CoV-2-naive Chinese participants. These participants are randomized 1:1:1 to receive prime and boost vaccinations of 10 µg or 30 µg BNT162b1 or placebo, given 21 d apart, with equal allocation of younger (aged 18-55 years) and older adults (aged 65-85 years) to each treatment group (ChiCTR2000034825). BNT162b1 encodes the SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD) and is one of several messenger RNA-based vaccine candidates under clinical investigation. Local reactions and systemic events were generally dose dependent, transient and mild to moderate. Fever was the only grade 3 adverse event. BNT162b1 induced robust interferon-γ T cell responses to a peptide pool including the RBD in both younger and older Chinese adults, and geometric mean neutralizing titers reached 2.1-fold (for younger participants) and 1.3-fold (for the older participants) that of a panel of COVID-19 convalescent human sera obtained at least 14 d after positive SARS-CoV-2 polymerase chain reaction test. In summary, BNT162b1 has an acceptable safety profile and produces high levels of humoral and T cell responses in an Asian population.", + "TAG_DATA": [ + "48, Chinese {'context': 'B-cells'}", + "49, participants. {'context': 'I-organism'}", + "75, younger {'context': 'B-cells'}", + "76, (aged {'context': 'I-cells'}", + "79, older {'context': 'I-cells'}", + "80, adults {'context': 'I-cells'}", + "146, younger {'context': 'B-organism'}", + "147, and {'context': 'I-organism'}", + "148, older {'context': 'I-organism'}", + "149, Chinese {'context': 'I-organism'}", + "150, adults, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "48, Chinese ['l0']", + "49, participants. ['l0']", + "75, younger ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "76, (aged ['l1', 'l8', 'l9', 'l10', 'l11', 'l12']", + "77, 18-55 years) ['l2', 'l8', 'l13', 'l14', 'l15', 'l16', 'l17']", + "78, and ['l3', 'l9', 'l13', 'l18', 'l19', 'l20', 'l21', 'l22']", + "79, older ['l4', 'l10', 'l14', 'l18', 'l23', 'l24', 'l25']", + "80, adults ['l5', 'l11', 'l15', 'l19', 'l23', 'l26', 'l27']", + "81, (aged ['l6', 'l12', 'l16', 'l20', 'l24', 'l26', 'l28']", + "146, younger ['l29', 'l30', 'l31', 'l32']", + "147, and ['l29', 'l33', 'l34', 'l35']", + "148, older ['l21', 'l30', 'l33', 'l36', 'l37']", + "149, Chinese ['l31', 'l34', 'l36', 'l38']", + "150, adults, ['l7', 'l17', 'l22', 'l25', 'l27', 'l28', 'l32', 'l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "33619370", + "TEXT": "Staphylococcus aureus colonizes patients with atopic dermatitis (AD) and exacerbates disease by promoting inflammation. The present study investigated the safety and mechanisms of action of Staphylococcus hominis A9 (ShA9), a bacterium isolated from healthy human skin, as a topical therapy for AD. ShA9 killed S. aureus on the skin of mice and inhibited expression of a toxin from S. aureus (psmα) that promotes inflammation. A first-in-human, phase 1, double-blinded, randomized 1-week trial of topical ShA9 or vehicle on the forearm skin of 54 adults with S. aureus-positive AD (NCT03151148) met its primary endpoint of safety, and participants receiving ShA9 had fewer adverse events associated with AD. Eczema severity was not significantly different when evaluated in all participants treated with ShA9 but a significant decrease in S. aureus and increased ShA9 DNA were seen and met secondary endpoints. Some S. aureus strains on participants were not directly killed by ShA9, but expression of mRNA for psmα was inhibited in all strains. Improvement in local eczema severity was suggested by post-hoc analysis of participants with S. aureus directly killed by ShA9. These observations demonstrate the safety and potential benefits of bacteriotherapy for AD.", + "TAG_DATA": [ + "50, mice {'context': 'B-organism'}", + "79, forearm {'context': 'B-tissue/organ'}", + "80, skin {'context': 'I-tissue/organ'}", + "83, adults {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "79, forearm ['l0', 'l1']", + "80, skin ['l0', 'l2']", + "83, adults ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32989313", + "TEXT": "Access to healthcare is a requirement for human well-being that is constrained, in part, by the allocation of healthcare resources relative to the geographically dispersed human population1-3. Quantifying access to care globally is challenging due to the absence of a comprehensive database of healthcare facilities. We harness major data collection efforts underway by OpenStreetMap, Google Maps and academic researchers to compile the most complete collection of facility locations to date. Leveraging the geographically variable strengths of our facility datasets, we use an established methodology4 to characterize travel time to healthcare facilities in unprecedented detail. We produce maps of travel time with and without access to motorized transport, thus characterizing travel time to healthcare for populations distributed across the wealth spectrum. We find that just 8.9% of the global population (646 million people) cannot reach healthcare within one hour if they have access to motorized transport, and that 43.3% (3.16 billion people) cannot reach a healthcare facility by foot within one hour. Our maps highlight an additional vulnerability faced by poorer individuals in remote areas and can help to estimate whether individuals will seek healthcare when it is needed, as well as providing an evidence base for efficiently distributing limited healthcare and transportation resources to underserved populations both now and in the future.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32895571", + "TEXT": "We report on molecular analyses of baseline tumor samples from the phase 3 JAVELIN Renal 101 trial (n = 886; NCT02684006 ), which demonstrated significantly prolonged progression-free survival (PFS) with first-line avelumab + axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We found that neither expression of the commonly assessed biomarker programmed cell death ligand 1 (PD-L1) nor tumor mutational burden differentiated PFS in either study arm. Similarly, the presence of FcɣR single nucleotide polymorphisms was unimpactful. We identified important biological features associated with differential PFS between the treatment arms, including new immunomodulatory and angiogenesis gene expression signatures (GESs), previously undescribed mutational profiles and their corresponding GESs, and several HLA types. These findings provide insight into the determinants of response to combined PD-1/PD-L1 and angiogenic pathway inhibition and may aid in the development of strategies for improved patient care in aRCC.", + "TAG_DATA": [ + "33, advanced {'context': 'B-neoplasm'}", + "34, renal {'context': 'I-neoplasm'}", + "35, cell {'context': 'I-neoplasm'}", + "36, carcinoma {'context': 'I-neoplasm'}", + "37, (aRCC). {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "33, advanced ['l0', 'l1', 'l2', 'l3']", + "34, renal ['l0', 'l4', 'l5', 'l6']", + "35, cell ['l1', 'l4', 'l7', 'l8']", + "36, carcinoma ['l2', 'l5', 'l7', 'l9']", + "37, (aRCC). ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32895570", + "TEXT": "Drug-induced liver injury (DILI) is a leading cause of termination in drug development programs and removal of drugs from the market; this is partially due to the inability to identify patients who are at risk1. In this study, we developed a polygenic risk score (PRS) for DILI by aggregating effects of numerous genome-wide loci identified from previous large-scale genome-wide association studies2. The PRS predicted the susceptibility to DILI in patients treated with fasiglifam, amoxicillin-clavulanate or flucloxacillin and in primary hepatocytes and stem cell-derived organoids from multiple donors treated with over ten different drugs. Pathway analysis highlighted processes previously implicated in DILI, including unfolded protein responses and oxidative stress. In silico screening identified compounds that elicit transcriptomic signatures present in hepatocytes from individuals with elevated PRS, supporting mechanistic links and suggesting a novel screen for safety of new drug candidates. This genetic-, cellular-, organoid- and human-scale evidence underscored the polygenic architecture underlying DILI vulnerability at the level of hepatocytes, thus facilitating future mechanistic studies. Moreover, the proposed 'polygenicity-in-a-dish' strategy might potentially inform designs of safer, more efficient and robust clinical trials.", + "TAG_DATA": [ + "69, patients {'context': 'B-patient'}", + "78, primary {'context': 'B-cells'}", + "79, hepatocytes {'context': 'I-cells'}", + "81, stem {'context': 'B-organoid'}", + "82, cell-derived {'context': 'I-organoid'}", + "83, organoids {'context': 'I-organoid'}", + "119, hepatocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "69, patients ['l0']", + "78, primary ['l1', 'l2', 'l3', 'l4']", + "79, hepatocytes ['l0', 'l1', 'l5', 'l6', 'l7']", + "81, stem ['l2', 'l5', 'l8', 'l9']", + "82, cell-derived ['l3', 'l6', 'l8', 'l10']", + "83, organoids ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32807933", + "TEXT": "Osteoarthritis (OA) is a degenerative disease resulting in irreversible, progressive destruction of articular cartilage1. The etiology of OA is complex and involves a variety of factors, including genetic predisposition, acute injury and chronic inflammation2-4. Here we investigate the ability of resident skeletal stem-cell (SSC) populations to regenerate cartilage in relation to age, a possible contributor to the development of osteoarthritis5-7. We demonstrate that aging is associated with progressive loss of SSCs and diminished chondrogenesis in the joints of both mice and humans. However, a local expansion of SSCs could still be triggered in the chondral surface of adult limb joints in mice by stimulating a regenerative response using microfracture (MF) surgery. Although MF-activated SSCs tended to form fibrous tissues, localized co-delivery of BMP2 and soluble VEGFR1 (sVEGFR1), a VEGF receptor antagonist, in a hydrogel skewed differentiation of MF-activated SSCs toward articular cartilage. These data indicate that following MF, a resident stem-cell population can be induced to generate cartilage for treatment of localized chondral disease in OA.", + "TAG_DATA": [ + "94, chondral {'context': 'B-tissue/organ'}", + "95, surface {'context': 'I-tissue/organ'}", + "97, adult {'context': 'B-tissue/organ'}", + "98, limb {'context': 'I-tissue/organ'}", + "99, joints {'context': 'I-tissue/organ'}", + "101, mice {'context': 'B-organism'}", + "113, SSCs {'context': 'B-cells'}", + "134, skewed {'effect': 'B-positive'}", + "135, differentiation {'phenotype': 'B-differentiation'}", + "138, SSCs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "94, chondral ['l0', 'l1', 'l2', 'l3', 'l4']", + "95, surface ['l0', 'l5', 'l6', 'l7', 'l8']", + "97, adult ['l1', 'l5', 'l9', 'l10', 'l11']", + "98, limb ['l2', 'l6', 'l9', 'l12', 'l13']", + "99, joints ['l3', 'l7', 'l10', 'l12', 'l14']", + "101, mice ['l4', 'l8', 'l11', 'l13', 'l14']", + "134, skewed ['l15', 'l16']", + "135, differentiation ['l15', 'l17']", + "138, SSCs ['l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "skewed" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "skewed" + ] + }, + "context": { + "val": "cells", + "words": [ + "SSCs" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "SSCs" + ] + } + } + ] + }, + { + "PMID": "32770169", + "TEXT": "Case isolation and contact tracing can contribute to the control of COVID-19 outbreaks1,2. However, it remains unclear how real-world social networks could influence the effectiveness and efficiency of such approaches. To address this issue, we simulated control strategies for SARS-CoV-2 transmission in a real-world social network generated from high-resolution GPS data that were gathered in the course of a citizen-science experiment3,4. We found that tracing the contacts of contacts reduced the size of simulated outbreaks more than tracing of only contacts, but this strategy also resulted in almost half of the local population being quarantined at a single point in time. Testing and releasing non-infectious individuals from quarantine led to increases in outbreak size, suggesting that contact tracing and quarantine might be most effective as a 'local lockdown' strategy when contact rates are high. Finally, we estimated that combining physical distancing with contact tracing could enable epidemic control while reducing the number of quarantined individuals. Our findings suggest that targeted tracing and quarantine strategies would be most efficient when combined with other control measures such as physical distancing.", + "TAG_DATA": [ + "91, local {'context': 'B-tissue/organ'}", + "92, population {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "91, local ['l0']", + "92, population ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32747829", + "TEXT": "Tumor protein p53 (TP53) is the most frequently mutated gene in cancer1,2. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease3,4, rapid transformation to acute myeloid leukemia (AML)5, resistance to conventional therapies6-8 and dismal outcomes9. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations10. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R)11. Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response.", + "TAG_DATA": [ + "142, transformation {'phenotype': 'B-transformation'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32719487", + "TEXT": "We asked whether pharmacological stimulation of endogenous neural precursor cells (NPCs) may promote cognitive recovery and brain repair, focusing on the drug metformin, in parallel rodent and human studies of radiation injury. In the rodent cranial radiation model, we found that metformin enhanced the recovery of NPCs in the dentate gyrus, with sex-dependent effects on neurogenesis and cognition. A pilot double-blind, placebo-controlled crossover trial was conducted (ClinicalTrials.gov, NCT02040376) in survivors of pediatric brain tumors who had been treated with cranial radiation. Safety, feasibility, cognitive tests and MRI measures of white matter and the hippocampus were evaluated as endpoints. Twenty-four participants consented and were randomly assigned to complete 12-week cycles of metformin (A) and placebo (B) in either an AB or BA sequence with a 10-week washout period at crossover. Blood draws were conducted to monitor safety. Feasibility was assessed as recruitment rate, medication adherence and procedural adherence. Linear mixed modeling was used to examine cognitive and MRI outcomes as a function of cycle, sequence and treatment. We found no clinically relevant safety concerns and no serious adverse events associated with metformin. Sequence effects were observed for all cognitive outcomes in our linear mixed models. For the subset of participants with complete data in cycle 1, metformin was associated with better performance than placebo on tests of declarative and working memory. We present evidence that a clinical trial examining the effects of metformin on cognition and brain structure is feasible in long-term survivors of pediatric brain tumors and that metformin is safe to use and tolerable in this population. This pilot trial was not intended to test the efficacy of metformin for cognitive recovery and brain growth, but the preliminary results are encouraging and warrant further investigation in a large multicenter phase 3 trial.", + "TAG_DATA": [ + "34, rodent {'context': 'B-organism'}", + "35, cranial {'context': 'I-organism'}", + "36, radiation {'context': 'I-organism'}", + "37, model, {'context': 'I-organism'}", + "46, NPCs {'context': 'B-cells'}", + "49, dentate {'context': 'B-tissue/organ'}", + "50, gyrus, {'context': 'I-tissue/organ'}", + "69, survivors {'context': 'B-patient'}", + "70, of {'context': 'I-neoplasm'}", + "71, pediatric {'context': 'I-neoplasm'}", + "72, brain {'context': 'I-neoplasm'}", + "73, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "34, rodent ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "35, cranial ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "36, radiation ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "37, model, ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "46, NPCs ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "49, dentate ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "50, gyrus, ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "69, survivors ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "70, of ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "71, pediatric ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "72, brain ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "73, tumors ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32661401", + "TEXT": "Patients awaiting lung transplantation face high wait-list mortality, as injury precludes the use of most donor lungs. Although ex vivo lung perfusion (EVLP) is able to recover marginal quality donor lungs, extension of normothermic support beyond 6 h has been challenging. Here we demonstrate that acutely injured human lungs declined for transplantation, including a lung that failed to recover on EVLP, can be recovered by cross-circulation of whole blood between explanted human lungs and a Yorkshire swine. This xenogeneic platform provided explanted human lungs a supportive, physiologic milieu and systemic regulation that resulted in functional and histological recovery after 24 h of normothermic support. Our findings suggest that cross-circulation can serve as a complementary approach to clinical EVLP to recover injured donor lungs that could not otherwise be utilized for transplantation, as well as a translational research platform for immunomodulation and advanced organ bioengineering.", + "TAG_DATA": [ + "46, human {'context': 'B-tissue/organ'}", + "47, lungs {'context': 'I-tissue/organ'}", + "53, lung {'context': 'B-tissue/organ'}", + "70, human {'context': 'B-tissue/organ'}", + "71, lungs {'context': 'I-tissue/organ'}", + "74, Yorkshire {'context': 'B-organism'}", + "75, swine. {'context': 'I-organism'}", + "81, human {'context': 'B-tissue/organ'}", + "82, lungs {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "46, human ['l0', 'l1', 'l2', 'l3']", + "47, lungs ['l0', 'l4', 'l5']", + "53, lung ['l1', 'l6', 'l7', 'l8', 'l9', 'l10']", + "70, human ['l2', 'l4', 'l6', 'l11', 'l12', 'l13', 'l14', 'l15']", + "71, lungs ['l3', 'l5', 'l7', 'l11', 'l16', 'l17', 'l18', 'l19']", + "74, Yorkshire ['l8', 'l12', 'l16', 'l20', 'l21', 'l22']", + "75, swine. ['l9', 'l13', 'l17', 'l20', 'l23', 'l24']", + "81, human ['l14', 'l18', 'l21', 'l23', 'l25']", + "82, lungs ['l10', 'l15', 'l19', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32661390", + "TEXT": "Disruption of systemic homeostasis by either chronic or acute stressors, such as obesity1 or surgery2, alters cancer pathogenesis. Patients with cancer, particularly those with breast cancer, can be at increased risk of cardiovascular disease due to treatment toxicity and changes in lifestyle behaviors3-5. While elevated risk and incidence of cardiovascular events in breast cancer is well established, whether such events impact cancer pathogenesis is not known. Here we show that myocardial infarction (MI) accelerates breast cancer outgrowth and cancer-specific mortality in mice and humans. In mouse models of breast cancer, MI epigenetically reprogrammed Ly6Chi monocytes in the bone marrow reservoir to an immunosuppressive phenotype that was maintained at the transcriptional level in monocytes in both the circulation and tumor. In parallel, MI increased circulating Ly6Chi monocyte levels and recruitment to tumors and depletion of these cells abrogated MI-induced tumor growth. Furthermore, patients with early-stage breast cancer who experienced cardiovascular events after cancer diagnosis had increased risk of recurrence and cancer-specific death. These preclinical and clinical results demonstrate that MI induces alterations in systemic homeostasis, triggering cross-disease communication that accelerates breast cancer.", + "TAG_DATA": [ + "74, breast {'context': 'B-neoplasm'}", + "75, cancer {'context': 'I-neoplasm'}", + "81, mice {'context': 'B-organism'}", + "85, mouse {'context': 'B-neoplasm'}", + "86, models {'context': 'I-neoplasm'}", + "87, of {'context': 'I-neoplasm'}", + "88, breast {'context': 'I-neoplasm'}", + "89, cancer, {'context': 'I-neoplasm'}", + "118, tumor. {'context': 'B-neoplasm'}", + "135, cells {'context': 'B-cells'}", + "136, abrogated {'effect': 'B-negative'}", + "137, MI-induced {'effect': 'B-positive'}", + "138, tumor {'phenotype': 'B-tumour growth'}", + "139, growth. {'phenotype': 'I-tumour growth'}", + "141, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "74, breast ['l0', 'l1', 'l2']", + "75, cancer ['l0', 'l3', 'l4']", + "81, mice ['l1', 'l3', 'l5', 'l6']", + "85, mouse ['l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "86, models ['l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "87, of ['l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "88, breast ['l5', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "89, cancer, ['l2', 'l4', 'l6', 'l10', 'l15', 'l19', 'l22', 'l25']", + "98, marrow ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']", + "118, tumor. ['l12', 'l17', 'l21', 'l24', 'l26']", + "135, cells ['l27', 'l28', 'l29', 'l30']", + "136, abrogated ['l27', 'l31', 'l32', 'l33']", + "137, MI-induced ['l28', 'l31', 'l34', 'l35']", + "138, tumor ['l29', 'l32', 'l34', 'l36']", + "139, growth. ['l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abrogated" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "MI-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogated" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "MI-induced" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + } + ] + }, + { + "PMID": "32601336", + "TEXT": "The conserved region of influenza hemagglutinin (HA) stalk (or stem) has gained attention as a potent target for universal influenza vaccines1-5. Although the HA stalk region is relatively well conserved, the evolutionarily dynamic nature of influenza viruses6 raises concerns about the possible emergence of viruses carrying stalk escape mutation(s) under sufficient immune pressure. Here we show that immune pressure on the HA stalk can lead to expansion of escape mutant viruses in study participants challenged with a 2009 H1N1 pandemic influenza virus inoculum containing an A388V polymorphism in the HA stalk (45% wild type and 55% mutant). High level of stalk antibody titers was associated with the selection of the mutant virus both in humans and in vitro. Although the mutant virus showed slightly decreased replication in mice, it was not observed in cell culture, ferrets or human challenge participants. The A388V mutation conferred resistance to some of the potent HA stalk broadly neutralizing monoclonal antibodies (bNAbs). Co-culture of wild-type and mutant viruses in the presence of either a bNAb or human serum resulted in rapid expansion of the mutant. These data shed light on a potential obstacle for the success of HA-stalk-targeting universal influenza vaccines-viral escape from vaccine-induced stalk immunity.", + "TAG_DATA": [ + "116, in {'context': 'B-in vitro'}", + "117, vitro. {'context': 'I-in vitro'}", + "127, mice, {'context': 'B-organism'}", + "133, cell {'context': 'B-cells'}", + "134, culture, {'context': 'I-cells'}", + "135, ferrets {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "116, in ['l0']", + "117, vitro. ['l0']", + "127, mice, ['l1', 'l2', 'l3']", + "133, cell ['l1', 'l4', 'l5']", + "134, culture, ['l2', 'l4', 'l6']", + "135, ferrets ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32555424", + "TEXT": "The clinical features and immune responses of asymptomatic individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have not been well described. We studied 37 asymptomatic individuals in the Wanzhou District who were diagnosed with RT-PCR-confirmed SARS-CoV-2 infections but without any relevant clinical symptoms in the preceding 14 d and during hospitalization. Asymptomatic individuals were admitted to the government-designated Wanzhou People's Hospital for centralized isolation in accordance with policy1. The median duration of viral shedding in the asymptomatic group was 19 d (interquartile range (IQR), 15-26 d). The asymptomatic group had a significantly longer duration of viral shedding than the symptomatic group (log-rank P = 0.028). The virus-specific IgG levels in the asymptomatic group (median S/CO, 3.4; IQR, 1.6-10.7) were significantly lower (P = 0.005) relative to the symptomatic group (median S/CO, 20.5; IQR, 5.8-38.2) in the acute phase. Of asymptomatic individuals, 93.3% (28/30) and 81.1% (30/37) had reduction in IgG and neutralizing antibody levels, respectively, during the early convalescent phase, as compared to 96.8% (30/31) and 62.2% (23/37) of symptomatic patients. Forty percent of asymptomatic individuals became seronegative and 12.9% of the symptomatic group became negative for IgG in the early convalescent phase. In addition, asymptomatic individuals exhibited lower levels of 18 pro- and anti-inflammatory cytokines. These data suggest that asymptomatic individuals had a weaker immune response to SARS-CoV-2 infection. The reduction in IgG and neutralizing antibody levels in the early convalescent phase might have implications for immunity strategy and serological surveys.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32514171", + "TEXT": "Although disinfection is key to infection control, the colonization patterns and resistomes of hospital-environment microbes remain underexplored. We report the first extensive genomic characterization of microbiomes, pathogens and antibiotic resistance cassettes in a tertiary-care hospital, from repeated sampling (up to 1.5 years apart) of 179 sites associated with 45 beds. Deep shotgun metagenomics unveiled distinct ecological niches of microbes and antibiotic resistance genes characterized by biofilm-forming and human-microbiome-influenced environments with corresponding patterns of spatiotemporal divergence. Quasi-metagenomics with nanopore sequencing provided thousands of high-contiguity genomes, phage and plasmid sequences (>60% novel), enabling characterization of resistome and mobilome diversity and dynamic architectures in hospital environments. Phylogenetics identified multidrug-resistant strains as being widely distributed and stably colonizing across sites. Comparisons with clinical isolates indicated that such microbes can persist in hospitals for extended periods (>8 years), to opportunistically infect patients. These findings highlight the importance of characterizing antibiotic resistance reservoirs in hospitals and establish the feasibility of systematic surveys to target resources for preventing infections.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32514169", + "TEXT": "In Alzheimer's disease, amyloid deposits along the brain vasculature lead to a condition known as cerebral amyloid angiopathy (CAA), which impairs blood-brain barrier (BBB) function and accelerates cognitive degeneration. Apolipoprotein (APOE4) is the strongest risk factor for CAA, yet the mechanisms underlying this genetic susceptibility are unknown. Here we developed an induced pluripotent stem cell-based three-dimensional model that recapitulates anatomical and physiological properties of the human BBB in vitro. Similarly to CAA, our in vitro BBB displayed significantly more amyloid accumulation in APOE4 compared to APOE3. Combinatorial experiments revealed that dysregulation of calcineurin-nuclear factor of activated T cells (NFAT) signaling and APOE in pericyte-like mural cells induces APOE4-associated CAA pathology. In the human brain, APOE and NFAT are selectively dysregulated in pericytes of APOE4 carriers, and inhibition of calcineurin-NFAT signaling reduces APOE4-associated CAA pathology in vitro and in vivo. Our study reveals the role of pericytes in APOE4-mediated CAA and highlights calcineurin-NFAT signaling as a therapeutic target in CAA and Alzheimer's disease.", + "TAG_DATA": [ + "53, stem {'context': 'I-cells'}", + "54, cell-based {'context': 'I-cells'}", + "67, in {'context': 'B-in vitro'}", + "68, vitro. {'context': 'I-in vitro'}", + "73, in {'context': 'B-in vitro'}", + "74, vitro {'context': 'I-in vitro'}", + "103, pericyte-like {'context': 'B-cells'}", + "104, mural {'context': 'I-cells'}", + "105, cells {'context': 'I-cells'}", + "112, human {'context': 'B-tissue/organ'}", + "113, brain, {'context': 'I-tissue/organ'}", + "134, in {'context': 'B-in vitro'}", + "135, vitro {'context': 'I-in vitro'}", + "137, in {'context': 'B-in vivo'}", + "138, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "51, induced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "52, pluripotent ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "53, stem ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "54, cell-based ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "67, in ['l3', 'l9', 'l14', 'l18', 'l22']", + "68, vitro. ['l4', 'l10', 'l15', 'l19', 'l22']", + "73, in ['l5', 'l11', 'l16', 'l20', 'l23']", + "74, vitro ['l6', 'l12', 'l17', 'l21', 'l23']", + "103, pericyte-like ['l24', 'l25', 'l26', 'l27']", + "104, mural ['l24', 'l28', 'l29', 'l30']", + "105, cells ['l25', 'l28', 'l31', 'l32']", + "112, human ['l26', 'l29', 'l31', 'l33', 'l34']", + "113, brain, ['l27', 'l30', 'l32', 'l33', 'l35']", + "134, in ['l34', 'l35', 'l36', 'l37', 'l38']", + "135, vitro ['l36', 'l39', 'l40']", + "137, in ['l37', 'l39', 'l41']", + "138, vivo. ['l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32483360", + "TEXT": "In many areas of oncology, we lack sensitive tools to track low-burden disease. Although cell-free DNA (cfDNA) shows promise in detecting cancer mutations, we found that the combination of low tumor fraction (TF) and limited number of DNA fragments restricts low-disease-burden monitoring through the prevailing deep targeted sequencing paradigm. We reasoned that breadth may supplant depth of sequencing to overcome the barrier of cfDNA abundance. Whole-genome sequencing (WGS) of cfDNA allowed ultra-sensitive detection, capitalizing on the cumulative signal of thousands of somatic mutations observed in solid malignancies, with TF detection sensitivity as low as 10-5. The WGS approach enabled dynamic tumor burden tracking and postoperative residual disease detection, associated with adverse outcome. Thus, we present an orthogonal framework for cfDNA cancer monitoring via genome-wide mutational integration, enabling ultra-sensitive detection, overcoming the limitation of cfDNA abundance and empowering treatment optimization in low-disease-burden oncology care.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32483359", + "TEXT": "An increasing fraction of patients with metastatic cancer develop leptomeningeal dissemination of disease (LMD), and survival is dismal1-3. We conducted a single-arm, phase 2 study of pembrolizumab in patients with solid tumor malignancies and LMD (NCT02886585). Patients received 200 mg of pembrolizumab intravenously every 3 weeks until definitive progression or unacceptable toxicity. The primary endpoint was rate of overall survival at 3 months (OS3). Secondary objectives included toxicity, response rate and time to intracranial or extracranial disease progression. A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 43%. Twenty patients-17 with breast cancer, two with lung cancer and one with ovarian cancer-were enrolled into the pre-specified evaluation group having received at least one dose of pembrolizumab. The median follow-up of surviving patients was 6.3 months (range, 2.2-12.5 months). The percentage of patients who experienced one (or more) grade 3 or higher adverse events at least possibly related to treatment was 40%, the most frequent being hyperglycemia (n = 6), nausea (n = 7) and vomiting (n = 7). The study met the primary endpoint, as 12 of 20 (OS3, 0.60; 90% confidence interval, 0.39-0.78) patients were alive at 3 months after enrollment. Pembrolizumab is safe and feasible and displays promising activity in patients with LMD. Further investigations are needed to identify which patients with LMD can benefit from pembrolizumab.", + "TAG_DATA": [ + "99, breast {'context': 'B-neoplasm'}", + "100, cancer, {'context': 'I-neoplasm'}", + "102, with {'context': 'B-neoplasm'}", + "103, lung {'context': 'B-neoplasm'}", + "104, cancer {'context': 'I-neoplasm'}", + "108, ovarian {'context': 'I-neoplasm'}", + "109, cancer-were {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "99, breast ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "100, cancer, ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "102, with ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "103, lung ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "104, cancer ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "108, ovarian ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "109, cancer-were ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32405062", + "TEXT": "Serum interleukin-8 (IL-8) levels and tumor neutrophil infiltration are associated with worse prognosis in advanced cancers. Here, using a large-scale retrospective analysis, we show that elevated baseline serum IL-8 levels are associated with poor outcome in patients (n = 1,344) with advanced cancers treated with nivolumab and/or ipilimumab, everolimus or docetaxel in phase 3 clinical trials, revealing the importance of assessing serum IL-8 levels in identifying unfavorable tumor immunobiology and as an independent biomarker in patients receiving immune-checkpoint inhibitors.", + "TAG_DATA": [ + "36, patients {'context': 'B-patient'}", + "39, advanced {'context': 'B-neoplasm'}", + "40, cancers {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "36, patients ['l0', 'l1']", + "39, advanced ['l0', 'l2']", + "40, cancers ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32382154", + "TEXT": "The COVID-19 pandemic has precipitated a global crisis, with more than 1,430,000 confirmed cases and more than 85,000 confirmed deaths globally as of 9 April 20201-4. Mitigation and suppression of new infections have emerged as the two predominant public health control strategies5. Both strategies focus on reducing new infections by limiting human-to-human interactions, which could be both socially and economically unsustainable in the long term. We have developed and analyzed an epidemiological intervention model that leverages serological tests6,7 to identify and deploy recovered individuals8 as focal points for sustaining safer interactions via interaction substitution, developing what we term 'shield immunity' at the population scale. The objective of a shield immunity strategy is to help to sustain the interactions necessary for the functioning of essential goods and services9 while reducing the probability of transmission. Our shield immunity approach could substantively reduce the length and reduce the overall burden of the current outbreak, and can work synergistically with social distancing. The present model highlights the value of serological testing as part of intervention strategies, in addition to its well-recognized roles in estimating prevalence10,11 and in the potential development of plasma-based therapies12-15.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32341580", + "TEXT": "Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.", + "TAG_DATA": [ + "97, primary, {'context': 'B-neoplasm'}", + "98, metastatic {'context': 'I-neoplasm'}", + "99, and {'context': 'I-neoplasm'}", + "100, recurrent {'context': 'I-neoplasm'}", + "101, group {'context': 'I-neoplasm'}", + "102, 3 {'context': 'I-neoplasm'}", + "103, medulloblastoma {'context': 'I-neoplasm'}", + "105, PFA {'context': 'B-xenograft'}", + "106, ependymoma {'context': 'I-xenograft'}", + "107, xenografts {'context': 'I-xenograft'}", + "109, mouse {'context': 'B-organism'}", + "110, models. {'context': 'I-organism'}", + "119, antigen {'context': 'I-cells'}", + "120, receptor {'context': 'I-cells'}", + "121, T {'context': 'I-cells'}", + "122, cells {'context': 'I-cells'}", + "141, mouse {'context': 'I-neoplasm'}", + "142, models {'context': 'I-neoplasm'}", + "143, of {'context': 'I-neoplasm'}", + "145, 3 {'context': 'I-neoplasm'}", + "146, medulloblastoma {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "97, primary, ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "98, metastatic ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "99, and ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "100, recurrent ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "101, group ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "102, 3 ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "103, medulloblastoma ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "105, PFA ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "106, ependymoma ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "107, xenografts ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "109, mouse ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "110, models. ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "119, antigen ['l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "120, receptor ['l66', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "121, T ['l67', 'l75', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "122, cells ['l68', 'l76', 'l83', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "141, mouse ['l69', 'l77', 'l84', 'l90', 'l96', 'l97', 'l98', 'l99', 'l100']", + "142, models ['l70', 'l78', 'l85', 'l91', 'l96', 'l101', 'l102', 'l103', 'l104']", + "143, of ['l71', 'l79', 'l86', 'l92', 'l97', 'l101', 'l105', 'l106', 'l107']", + "144, group ['l72', 'l80', 'l87', 'l93', 'l98', 'l102', 'l105', 'l108', 'l109']", + "145, 3 ['l73', 'l81', 'l88', 'l94', 'l99', 'l103', 'l106', 'l108', 'l110']", + "146, medulloblastoma ['l74', 'l82', 'l89', 'l95', 'l100', 'l104', 'l107', 'l109', 'l110']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32341579", + "TEXT": "Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months1,2. We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs. 3,4), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT5,6, B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3.BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies.", + "TAG_DATA": [ + "103, ATRT {'context': 'I-xenograft'}", + "104, xenografts {'context': 'I-xenograft'}", + "106, mice, {'context': 'B-organism'}", + "142, ATRT {'context': 'B-xenograft'}", + "143, xenografts, {'context': 'I-xenograft'}", + "160, brain {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "103, ATRT ['l0', 'l1']", + "104, xenografts ['l0', 'l2']", + "106, mice, ['l1', 'l2']", + "142, ATRT ['l3', 'l4']", + "143, xenografts, ['l3', 'l5']", + "160, brain ['l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32284612", + "TEXT": "Base editing by nucleotide deaminases linked to programmable DNA-binding proteins represents a promising approach to permanently remedy blood disorders, although its application in engrafting hematopoietic stem cells (HSCs) remains unexplored. In this study, we purified A3A (N57Q)-BE3 base editor for ribonucleoprotein (RNP) electroporation of human-peripheral-blood-mobilized CD34+ hematopoietic stem and progenitor cells (HSPCs). We observed frequent on-target cytosine base edits at the BCL11A erythroid enhancer at +58 with few indels. Fetal hemoglobin (HbF) induction in erythroid progeny after base editing or nuclease editing was similar. A single therapeutic base edit of the BCL11A enhancer prevented sickling and ameliorated globin chain imbalance in erythroid progeny from sickle cell disease and β-thalassemia patient-derived HSPCs, respectively. Moreover, efficient multiplex editing could be achieved with combined disruption of the BCL11A erythroid enhancer and correction of the HBB -28A>G promoter mutation. Finally, base edits could be produced in multilineage-repopulating self-renewing human HSCs with high frequency as assayed in primary and secondary recipient animals resulting in potent HbF induction in vivo. Together, these results demonstrate the potential of RNP base editing of human HSPCs as a feasible alternative to nuclease editing for HSC-targeted therapeutic genome modification.", + "TAG_DATA": [ + "108, β-thalassemia {'context': 'B-cells'}", + "109, patient-derived {'context': 'I-cells'}", + "110, HSPCs, {'context': 'I-cells'}", + "143, self-renewing {'context': 'I-cells'}", + "144, human {'context': 'I-cells'}", + "145, HSCs {'context': 'I-cells'}", + "152, primary {'context': 'B-cells'}", + "153, and {'context': 'I-cells'}", + "154, secondary {'context': 'I-cells'}", + "155, recipient {'context': 'I-cells'}", + "156, animals {'context': 'I-organism'}", + "162, in {'context': 'B-in vivo'}", + "163, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "101, erythroid ['l0', 'l1', 'l2', 'l3']", + "102, progeny ['l0', 'l4', 'l5', 'l6']", + "108, β-thalassemia ['l1', 'l4', 'l7', 'l8']", + "109, patient-derived ['l2', 'l5', 'l7', 'l9']", + "110, HSPCs, ['l3', 'l6', 'l8', 'l9']", + "143, self-renewing ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "144, human ['l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "145, HSCs ['l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "152, primary ['l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "153, and ['l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "154, secondary ['l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "155, recipient ['l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "156, animals ['l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "162, in ['l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "163, vivo. ['l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32284590", + "TEXT": "Our understanding of Alzheimer's disease (AD) pathophysiology remains incomplete. Here we used quantitative mass spectrometry and coexpression network analysis to conduct the largest proteomic study thus far on AD. A protein network module linked to sugar metabolism emerged as one of the modules most significantly associated with AD pathology and cognitive impairment. This module was enriched in AD genetic risk factors and in microglia and astrocyte protein markers associated with an anti-inflammatory state, suggesting that the biological functions it represents serve a protective role in AD. Proteins from this module were elevated in cerebrospinal fluid in early stages of the disease. In this study of >2,000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brains that may serve as therapeutic targets and fluid biomarkers for the disease.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32273609", + "TEXT": "Polygenic risk scores (PRSs) have shown promise in predicting susceptibility to common diseases1-3. We estimated their added value in clinical risk prediction of five common diseases, using large-scale biobank data (FinnGen; n = 135,300) and the FINRISK study with clinical risk factors to test genome-wide PRSs for coronary heart disease, type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer. We evaluated the lifetime risk at different PRS levels, and the impact on disease onset and on prediction together with clinical risk scores. Compared to having an average PRS, having a high PRS contributed 21% to 38% higher lifetime risk, and 4 to 9 years earlier disease onset. PRSs improved model discrimination over age and sex in type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer, and over clinical risk in type 2 diabetes, breast cancer and prostate cancer. In all diseases, PRSs improved reclassification over clinical thresholds, with the largest net reclassification improvements for early-onset coronary heart disease, atrial fibrillation and prostate cancer. This study provides evidence for the additional value of PRSs in clinical disease prediction. The practical applications of polygenic risk information for stratified screening or for guiding lifestyle and medical interventions in the clinical setting remain to be defined in further studies.", + "TAG_DATA": [ + "120, breast {'context': 'B-neoplasm'}", + "121, cancer {'context': 'I-neoplasm'}", + "123, prostate {'context': 'B-neoplasm'}", + "124, cancer, {'context': 'I-neoplasm'}", + "133, breast {'context': 'B-neoplasm'}", + "134, cancer {'context': 'I-neoplasm'}", + "136, prostate {'context': 'B-neoplasm'}", + "137, cancer. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "120, breast ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "121, cancer ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "123, prostate ['l1', 'l7', 'l12', 'l13', 'l14', 'l15', 'l16']", + "124, cancer, ['l2', 'l8', 'l12', 'l17', 'l18']", + "133, breast ['l3', 'l9', 'l13', 'l19', 'l20', 'l21']", + "134, cancer ['l4', 'l10', 'l14', 'l17', 'l19', 'l22', 'l23']", + "136, prostate ['l5', 'l15', 'l20', 'l22', 'l24']", + "137, cancer. ['l6', 'l11', 'l16', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32251406", + "TEXT": "Cellular immunity is critical for controlling intracellular pathogens, but individual cellular dynamics and cell-cell cooperativity in evolving human immune responses remain poorly understood. Single-cell RNA-sequencing (scRNA-seq) represents a powerful tool for dissecting complex multicellular behaviors in health and disease1,2 and nominating testable therapeutic targets3. Its application to longitudinal samples could afford an opportunity to uncover cellular factors associated with the evolution of disease progression without potentially confounding inter-individual variability4. Here, we present an experimental and computational methodology that uses scRNA-seq to characterize dynamic cellular programs and their molecular drivers, and apply it to HIV infection. By performing scRNA-seq on peripheral blood mononuclear cells from four untreated individuals before and longitudinally during acute infection5, we were powered within each to discover gene response modules that vary by time and cell subset. Beyond previously unappreciated individual- and cell-type-specific interferon-stimulated gene upregulation, we describe temporally aligned gene expression responses obscured in bulk analyses, including those involved in proinflammatory T cell differentiation, prolonged monocyte major histocompatibility complex II upregulation and persistent natural killer (NK) cell cytolytic killing. We further identify response features arising in the first weeks of infection, for example proliferating natural killer cells, which potentially may associate with future viral control. Overall, our approach provides a unified framework for characterizing multiple dynamic cellular responses and their coordination.", + "TAG_DATA": [ + "99, peripheral {'context': 'B-cells'}", + "100, blood {'context': 'I-cells'}", + "101, mononuclear {'context': 'I-cells'}", + "102, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "99, peripheral ['l0', 'l1', 'l2']", + "100, blood ['l0', 'l3', 'l4']", + "101, mononuclear ['l1', 'l3', 'l5']", + "102, cells ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32251405", + "TEXT": "While polygenic risk scores (PRSs) are poised to be translated into clinical practice through prediction of inborn health risks1, a strategy to utilize genetics to prioritize modifiable risk factors driving heath outcome is warranted2. To this end, we investigated the association of the genetic susceptibility to complex traits with human lifespan in collaboration with three worldwide biobanks (ntotal = 675,898; BioBank Japan (n = 179,066), UK Biobank (n = 361,194) and FinnGen (n = 135,638)). In contrast to observational studies, in which discerning the cause-and-effect can be difficult, PRSs could help to identify the driver biomarkers affecting human lifespan. A high systolic blood pressure PRS was trans-ethnically associated with a shorter lifespan (hazard ratio = 1.03[1.02-1.04], Pmeta = 3.9 × 10-13) and parental lifespan (hazard ratio = 1.06[1.06-1.07], P = 2.0 × 10-86). The obesity PRS showed distinct effects on lifespan in Japanese and European individuals (Pheterogeneity = 9.5 × 10-8 for BMI). The causal effect of blood pressure and obesity on lifespan was further supported by Mendelian randomization studies. Beyond genotype-phenotype associations, our trans-biobank study offers a new value of PRSs in prioritization of risk factors that could be potential targets of medical treatment to improve population health.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32251404", + "TEXT": "Mounting evidence suggests that function and connectivity of the striatum is disrupted in schizophrenia1-5. We have developed a new hypothesis-driven neuroimaging biomarker for schizophrenia identification, prognosis and subtyping based on functional striatal abnormalities (FSA). FSA scores provide a personalized index of striatal dysfunction, ranging from normal to highly pathological. Using inter-site cross-validation on functional magnetic resonance images acquired from seven independent scanners (n = 1,100), FSA distinguished individuals with schizophrenia from healthy controls with an accuracy exceeding 80% (sensitivity, 79.3%; specificity, 81.5%). In two longitudinal cohorts, inter-individual variation in baseline FSA scores was significantly associated with antipsychotic treatment response. FSA revealed a spectrum of severity in striatal dysfunction across neuropsychiatric disorders, where dysfunction was most severe in schizophrenia, milder in bipolar disorder, and indistinguishable from healthy individuals in depression, obsessive-compulsive disorder and attention-deficit hyperactivity disorder. Loci of striatal hyperactivity recapitulated the spatial distribution of dopaminergic function and the expression profiles of polygenic risk for schizophrenia. In conclusion, we have developed a new biomarker to index striatal dysfunction and established its utility in predicting antipsychotic treatment response, clinical stratification and elucidating striatal dysfunction in neuropsychiatric disorders.", + "TAG_DATA": [ + "65, individuals {'context': 'B-patient'}", + "67, schizophrenia {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "65, individuals ['l0']", + "67, schizophrenia ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32152583", + "TEXT": "Intensive-care clinicians are presented with large quantities of measurements from multiple monitoring systems. The limited ability of humans to process complex information hinders early recognition of patient deterioration, and high numbers of monitoring alarms lead to alarm fatigue. We used machine learning to develop an early-warning system that integrates measurements from multiple organ systems using a high-resolution database with 240 patient-years of data. It predicts 90% of circulatory-failure events in the test set, with 82% identified more than 2 h in advance, resulting in an area under the receiver operating characteristic curve of 0.94 and an area under the precision-recall curve of 0.63. On average, the system raises 0.05 alarms per patient and hour. The model was externally validated in an independent patient cohort. Our model provides early identification of patients at risk for circulatory failure with a much lower false-alarm rate than conventional threshold-based systems.", + "TAG_DATA": [ + "123, cohort. {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "122, patient ['l0']", + "123, cohort. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32152581", + "TEXT": "Drug delivery to the skin is highly constrained by the stratum corneum barrier layer1. Here, we developed star-shaped particles, termed STAR particles, to dramatically increase skin permeability. STAR particles are millimeter-scale particles made of aluminum oxide or stainless steel with micron-scale projections designed to create microscopic pores across the stratum corneum. After gentle topical application for 10 s to porcine skin ex vivo, delivery of dermatological drugs and macromolecules, including those that cannot be given topically, was increased by 1 to 2 orders of magnitude. In mice treated with topical 5-fluorouracil, use of STAR particles increased the efficacy of the drug in suppressing the growth of subcutaneous melanoma tumors and prolonging survival. Moreover, topical delivery of tetanus toxoid vaccine to mice using STAR particles generated immune responses that were at least as strong as delivery of the vaccine by intramuscular injection, albeit at a higher dose for topical than intramuscular vaccine administration. STAR particles were well tolerated and effective at creating micropores when applied to the skin of human participants. Use of STAR particles provides a simple, low-cost and well-tolerated method for increasing drug and vaccine delivery to the skin and could widen the range of compounds that can be topically administered.", + "TAG_DATA": [ + "58, porcine {'context': 'B-tissue/organ'}", + "59, skin {'context': 'I-tissue/organ'}", + "85, mice {'context': 'B-organism'}", + "105, subcutaneous {'context': 'B-neoplasm'}", + "106, melanoma {'context': 'I-neoplasm'}", + "107, tumors {'context': 'I-neoplasm'}", + "119, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "58, porcine ['l0', 'l1', 'l2']", + "59, skin ['l0']", + "85, mice ['l1', 'l3', 'l4', 'l5']", + "105, subcutaneous ['l3', 'l6', 'l7']", + "106, melanoma ['l4', 'l6', 'l8']", + "107, tumors ['l2', 'l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32123386", + "TEXT": "With the potential development of new disease-modifying Alzheimer's disease (AD) therapies, simple, widely available screening tests are needed to identify which individuals, who are experiencing symptoms of cognitive or behavioral decline, should be further evaluated for initiation of treatment. A blood-based test for AD would be a less invasive and less expensive screening tool than the currently approved cerebrospinal fluid or amyloid β positron emission tomography (PET) diagnostic tests. We examined whether plasma tau phosphorylated at residue 181 (pTau181) could differentiate between clinically diagnosed or autopsy-confirmed AD and frontotemporal lobar degeneration. Plasma pTau181 concentrations were increased by 3.5-fold in AD compared to controls and differentiated AD from both clinically diagnosed (receiver operating characteristic area under the curve of 0.894) and autopsy-confirmed frontotemporal lobar degeneration (area under the curve of 0.878). Plasma pTau181 identified individuals who were amyloid β-PET-positive regardless of clinical diagnosis and correlated with cortical tau protein deposition measured by 18F-flortaucipir PET. Plasma pTau181 may be useful to screen for tau pathology associated with AD.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32066978", + "TEXT": "Schistosomiasis treatment relies on the use of a single drug, praziquantel, which is insufficient to control transmission in highly endemic areas1. Novel medicines and vaccines are urgently needed2,3. An experimental human model for schistosomiasis could accelerate the development of these products. We performed a dose-escalating clinical safety trial in 17 volunteers with male Schistosoma mansoni cercariae, which do not produce eggs (clinicaltrials.gov NCT02755324), at the Leiden University Medical Center, the Netherlands. The primary endpoints were adverse events and infectivity. We found a dose-related increase in adverse events related to acute schistosomiasis syndrome, which occurred in 9 of 17 volunteers. Overall, 5 volunteers (all 3 of the high dose group and 2 of 11 of the medium dose group) reported severe adverse events. Worm-derived circulating anodic antigen, the biomarker of the primary infection endpoint, peaked in 82% of volunteers at 3-10 weeks following exposure. All volunteers showed IgM and IgG1 seroconversion and worm-specific cytokine production by CD4+ T cells. All volunteers were cured with praziquantel provided at 12 weeks after exposure. Infection with 20 Schistosoma mansoni cercariae led to severe adverse events in 18% of volunteers and high infection rates. This infection model paves the way for fast-track product development for treatment and prevention of schistosomiasis.", + "TAG_DATA": [ + "155, CD4+ {'context': 'B-cells'}", + "156, T {'context': 'I-cells'}", + "157, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "155, CD4+ ['l0', 'l1']", + "156, T ['l0', 'l2']", + "157, cells. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32066977", + "TEXT": "Adjuvants are central to the efficacy of subunit vaccines. Aluminum hydroxide (alum) is the most commonly used vaccine adjuvant, yet its adjuvanticity is often weak and mechanisms of triggering antibody responses remain poorly understood. We demonstrate that site-specific modification of immunogens with short peptides composed of repeating phosphoserine (pSer) residues enhances binding to alum and prolongs immunogen bioavailability. The pSer-modified immunogens formulated in alum elicited greatly increased germinal center, antibody, neutralizing antibody, memory and long-lived plasma cell responses compared to conventional alum-adsorbed immunogens. Mechanistically, pSer-immunogen:alum complexes form nanoparticles that traffic to lymph nodes and trigger B cell activation through multivalent and oriented antigen display. Direct uptake of antigen-decorated alum particles by B cells upregulated antigen processing and presentation pathways, further enhancing B cell activation. These data provide insights into mechanisms of action of alum and introduce a readily translatable approach to significantly improve humoral immunity to subunit vaccines using a clinical adjuvant.", + "TAG_DATA": [ + "75, plasma {'context': 'B-cells'}", + "76, cell {'context': 'I-cells'}", + "95, B {'context': 'B-cells'}", + "96, cell {'context': 'I-cells'}", + "111, B {'context': 'B-cells'}", + "112, cells {'context': 'I-cells'}", + "121, B {'context': 'B-cells'}", + "122, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "75, plasma ['l0', 'l1', 'l2']", + "76, cell ['l0']", + "95, B ['l1', 'l3']", + "96, cell ['l2', 'l3']", + "111, B ['l4', 'l5', 'l6']", + "112, cells ['l4', 'l7', 'l8']", + "121, B ['l5', 'l7', 'l9']", + "122, cell ['l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32066975", + "TEXT": "The involvement of host immunity in the gut microbiota-mediated colonization resistance to Clostridioides difficile infection (CDI) is incompletely understood. Here, we show that interleukin (IL)-22, induced by colonization of the gut microbiota, is crucial for the prevention of CDI in human microbiota-associated (HMA) mice. IL-22 signaling in HMA mice regulated host glycosylation, which enabled the growth of succinate-consuming bacteria Phascolarctobacterium spp. within the gut microbiome. Phascolarctobacterium reduced the availability of luminal succinate, a crucial metabolite for the growth of C. difficile, and therefore prevented the growth of C. difficile. IL-22-mediated host N-glycosylation is likely impaired in patients with ulcerative colitis (UC) and renders UC-HMA mice more susceptible to CDI. Transplantation of healthy human-derived microbiota or Phascolarctobacterium reduced luminal succinate levels and restored colonization resistance in UC-HMA mice. IL-22-mediated host glycosylation thus fosters the growth of commensal bacteria that compete with C. difficile for the nutritional niche.", + "TAG_DATA": [ + "47, HMA {'context': 'B-organism'}", + "48, mice {'context': 'I-organism'}", + "109, Transplantation {'perturbing_action': 'B-gene gain-of-function'}", + "112, human-derived {'context': 'I-cells'}", + "113, microbiota {'context': 'I-cells'}", + "125, UC-HMA {'context': 'B-organism'}", + "126, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "47, HMA ['l0']", + "48, mice ['l0']", + "109, Transplantation ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "110, of ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "111, healthy ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "112, human-derived ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "113, microbiota ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "125, UC-HMA ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "126, mice. ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transplantation" + ] + }, + "context": { + "val": "cells", + "words": [ + "human-derived", + "microbiota" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transplantation" + ] + }, + "context": { + "val": "organism", + "words": [ + "UC-HMA", + "mice." + ] + } + } + ] + }, + { + "PMID": "32042196", + "TEXT": "Immune checkpoint blockade (ICB) of PD-1 and CTLA-4 to treat metastatic melanoma (MM) has variable therapeutic benefit. To explore this in peripheral samples, we characterized CD8+ T cell gene expression across a cohort of patients with MM receiving anti-PD-1 alone (sICB) or in combination with anti-CTLA-4 (cICB). Whereas CD8+ transcriptional responses to sICB and cICB involve a shared gene set, the magnitude of cICB response is over fourfold greater, with preferential induction of mitosis- and interferon-related genes. Early samples from patients with durable clinical benefit demonstrated overexpression of T cell receptor-encoding genes. By mapping T cell receptor clonality, we find that responding patients have more large clones (those occupying >0.5% of repertoire) post-treatment than non-responding patients or controls, and this correlates with effector memory T cell percentage. Single-cell RNA-sequencing of eight post-treatment samples demonstrates that large clones overexpress genes implicated in cytotoxicity and characteristic of effector memory T cells, including CCL4, GNLY and NKG7. The 6-month clinical response to ICB in patients with MM is associated with the large CD8+ T cell clone count 21 d after treatment and agnostic to clonal specificity, suggesting that post-ICB peripheral CD8+ clonality can provide information regarding long-term treatment response and, potentially, facilitate treatment stratification.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32042194", + "TEXT": "Despite rare cancers accounting for 25% of adult tumors1, they are difficult to study due to the low disease incidence and geographically dispersed patient populations, which has resulted in significant unmet clinical needs for patients with rare cancers. We assessed whether a patient-partnered research approach using online engagement can overcome these challenges, focusing on angiosarcoma, a sarcoma with an annual incidence of 300 cases in the United States. Here we describe the development of the Angiosarcoma Project (ASCproject), an initiative enabling US and Canadian patients to remotely share their clinical information and biospecimens for research. The project generates and publicly releases clinically annotated genomic data on tumor and germline specimens on an ongoing basis. Over 18 months, 338 patients registered for the ASCproject, which comprises a large proportion of all patients with angiosarcoma. Whole-exome sequencing (WES) of 47 tumors revealed recurrently mutated genes that included KDR, TP53, and PIK3CA. PIK3CA-activating mutations were observed predominantly in primary breast angiosarcoma, which suggested a therapeutic rationale. Angiosarcoma of the head, neck, face and scalp (HNFS) was associated with a high tumor mutation burden (TMB) and a dominant ultraviolet damage mutational signature, which suggested that for the subset of patients with angiosarcoma of HNFS, ultraviolet damage may be a causative factor and that immune checkpoint inhibition may be beneficial. Medical record review revealed that two patients with HNFS angiosarcoma had received off-label therapeutic use of antibody to the programmed death-1 protein (anti-PD-1) and had experienced exceptional responses, which highlights immune checkpoint inhibition as a therapeutic avenue for HNFS angiosarcoma. This patient-partnered approach has catalyzed an opportunity to discover the etiology and potential therapies for patients with angiosarcoma. Collectively, this proof-of-concept study demonstrates that empowering patients to directly participate in research can overcome barriers in rare diseases and can enable discoveries.", + "TAG_DATA": [ + "223, HNFS {'context': 'B-neoplasm'}", + "224, angiosarcoma {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "223, HNFS ['l0']", + "224, angiosarcoma ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32042191", + "TEXT": "Developmental processes underlying normal tissue regeneration have been implicated in cancer, but the degree of their enactment during tumor progression and under the selective pressures of immune surveillance, remain unknown. Here we show that human primary lung adenocarcinomas are characterized by the emergence of regenerative cell types, typically seen in response to lung injury, and by striking infidelity among transcription factors specifying most alveolar and bronchial epithelial lineages. In contrast, metastases are enriched for key endoderm and lung-specifying transcription factors, SOX2 and SOX9, and recapitulate more primitive transcriptional programs spanning stem-like to regenerative pulmonary epithelial progenitor states. This developmental continuum mirrors the progressive stages of spontaneous outbreak from metastatic dormancy in a mouse model and exhibits SOX9-dependent resistance to natural killer cells. Loss of developmental stage-specific constraint in macrometastases triggered by natural killer cell depletion suggests a dynamic interplay between developmental plasticity and immune-mediated pruning during metastasis.", + "TAG_DATA": [ + "112, mouse {'context': 'B-organism'}", + "113, model {'context': 'I-organism'}", + "131, natural {'perturbing_action': 'B-gene loss-of-function'}", + "132, killer {'perturbing_action': 'B-gene loss-of-function'}", + "133, cell {'perturbing_action': 'I-gene loss-of-function'}", + "134, depletion {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "112, mouse ['l0']", + "113, model ['l0']", + "131, natural ['l1', 'l2', 'l3']", + "132, killer ['l1', 'l4', 'l5']", + "133, cell ['l2', 'l4', 'l6']", + "134, depletion ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31988461", + "TEXT": "Young-onset Parkinson's disease (YOPD), defined by onset at <50 years, accounts for approximately 10% of all Parkinson's disease cases and, while some cases are associated with known genetic mutations, most are not. Here induced pluripotent stem cells were generated from control individuals and from patients with YOPD with no known mutations. Following differentiation into cultures containing dopamine neurons, induced pluripotent stem cells from patients with YOPD showed increased accumulation of soluble α-synuclein protein and phosphorylated protein kinase Cα, as well as reduced abundance of lysosomal membrane proteins such as LAMP1. Testing activators of lysosomal function showed that specific phorbol esters, such as PEP005, reduced α-synuclein and phosphorylated protein kinase Cα levels while increasing LAMP1 abundance. Interestingly, the reduction in α-synuclein occurred through proteasomal degradation. PEP005 delivery to mouse striatum also decreased α-synuclein production in vivo. Induced pluripotent stem cell-derived dopaminergic cultures reveal a signature in patients with YOPD who have no known Parkinson's disease-related mutations, suggesting that there might be other genetic contributions to this disorder. This signature was normalized by specific phorbol esters, making them promising therapeutic candidates.", + "TAG_DATA": [ + "33, induced {'context': 'B-cells'}", + "34, pluripotent {'context': 'I-cells'}", + "35, stem {'context': 'I-cells'}", + "36, cells {'context': 'I-cells'}", + "56, dopamine {'context': 'B-cells'}", + "57, neurons, {'context': 'I-cells'}", + "58, induced {'context': 'B-cells'}", + "59, pluripotent {'context': 'I-cells'}", + "60, stem {'context': 'I-cells'}", + "61, cells {'context': 'I-cells'}", + "63, patients {'context': 'B-patient'}", + "127, mouse {'context': 'B-tissue/organ'}", + "128, striatum {'context': 'I-tissue/organ'}", + "133, in {'context': 'B-in vivo'}", + "134, vivo. {'context': 'I-in vivo'}", + "135, Induced {'context': 'B-cells'}", + "136, pluripotent {'context': 'I-cells'}", + "137, stem {'context': 'I-cells'}", + "138, cell-derived {'context': 'I-cells'}", + "139, dopaminergic {'context': 'I-cells'}", + "140, cultures {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "33, induced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "34, pluripotent ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "35, stem ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "36, cells ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "56, dopamine ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "57, neurons, ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "58, induced ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "59, pluripotent ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "60, stem ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "61, cells ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "63, patients ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "127, mouse ['l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "128, striatum ['l55', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "133, in ['l56', 'l61', 'l67', 'l68']", + "134, vivo. ['l57', 'l62', 'l67', 'l69', 'l70', 'l71']", + "135, Induced ['l72', 'l73', 'l74', 'l75', 'l76']", + "136, pluripotent ['l72', 'l77', 'l78', 'l79', 'l80']", + "137, stem ['l58', 'l63', 'l69', 'l73', 'l77', 'l81', 'l82', 'l83']", + "138, cell-derived ['l59', 'l64', 'l70', 'l74', 'l78', 'l81', 'l84', 'l85']", + "139, dopaminergic ['l65', 'l75', 'l79', 'l82', 'l84', 'l86']", + "140, cultures ['l60', 'l66', 'l68', 'l71', 'l76', 'l80', 'l83', 'l85', 'l86']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31959992", + "TEXT": "Anti-CD19 chimeric antigen receptor (CAR)-expressing T cells are an effective treatment for B-cell lymphoma, but often cause neurologic toxicity. We treated 20 patients with B-cell lymphoma on a phase I, first-in-human clinical trial of T cells expressing the new anti-CD19 CAR Hu19-CD828Z (NCT02659943). The primary objective was to assess safety and feasibility of Hu19-CD828Z T-cell therapy. Secondary objectives included assessments of blood levels of CAR T cells, anti-lymphoma activity, second infusions and immunogenicity. All objectives were met. Fifty-five percent of patients who received Hu19-CD828Z T cells obtained complete remission. Hu19-CD828Z T cells had clinical anti-lymphoma activity similar to that of T cells expressing FMC63-28Z, an anti-CD19 CAR tested previously by our group, which contains murine binding domains and is used in axicabtagene ciloleucel. However, severe neurologic toxicity occurred in only 5% of patients who received Hu19-CD828Z T cells, whereas 50% of patients who received FMC63-28Z T cells experienced this degree of toxicity (P = 0.0017). T cells expressing Hu19-CD828Z released lower levels of cytokines than T cells expressing FMC63-28Z. Lower levels of cytokines were detected in blood from patients who received Hu19-CD828Z T cells than in blood from those who received FMC63-28Z T cells, which could explain the lower level of neurologic toxicity associated with Hu19-CD828Z. Levels of cytokines released by CAR-expressing T cells particularly depended on the hinge and transmembrane domains included in the CAR design.", + "TAG_DATA": [ + "100, T {'context': 'B-cells'}", + "101, cells {'context': 'B-cells'}", + "146, cells {'context': 'I-cells'}", + "153, T {'context': 'B-cells'}", + "154, cells {'context': 'I-cells'}", + "163, T {'context': 'B-cells'}", + "164, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "100, T ['l0', 'l1', 'l2']", + "101, cells ['l0', 'l3', 'l4']", + "145, T ['l1', 'l3', 'l5']", + "146, cells ['l2', 'l4', 'l5']", + "153, T ['l6', 'l7', 'l8']", + "154, cells ['l6', 'l9', 'l10']", + "163, T ['l7', 'l9', 'l11']", + "164, cells ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31959991", + "TEXT": "Mucociliary clearance, the physiological process by which mammalian conducting airways expel pathogens and unwanted surface materials from the respiratory tract, depends on the coordinated function of multiple specialized cell types, including basal stem cells, mucus-secreting goblet cells, motile ciliated cells, cystic fibrosis transmembrane conductance regulator (CFTR)-rich ionocytes, and immune cells1,2. Bronchiectasis, a syndrome of pathological airway dilation associated with impaired mucociliary clearance, may occur sporadically or as a consequence of Mendelian inheritance, for example in cystic fibrosis, primary ciliary dyskinesia (PCD), and select immunodeficiencies3. Previous studies have identified mutations that affect ciliary structure and nucleation in PCD4, but the regulation of mucociliary transport remains incompletely understood, and therapeutic targets for its modulation are lacking. Here we identify a bronchiectasis syndrome caused by mutations that inactivate NIMA-related kinase 10 (NEK10), a protein kinase with previously unknown in vivo functions in mammals. Genetically modified primary human airway cultures establish NEK10 as a ciliated-cell-specific kinase whose activity regulates the motile ciliary proteome to promote ciliary length and mucociliary transport but which is dispensable for normal ciliary number, radial structure, and beat frequency. Together, these data identify a novel and likely targetable signaling axis that controls motile ciliary function in humans and has potential implications for other respiratory disorders that are characterized by impaired mucociliary clearance.", + "TAG_DATA": [ + "125, NIMA-related {'perturbing_action': 'I-other'}", + "126, kinase {'perturbing_action': 'I-other'}", + "127, 10 {'perturbing_action': 'I-other'}", + "128, (NEK10), {'perturbing_action': 'I-other'}", + "142, primary {'context': 'B-cells'}", + "143, human {'context': 'I-cells'}", + "144, airway {'context': 'I-cells'}", + "145, cultures {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "124, inactivate ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "125, NIMA-related ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "126, kinase ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "127, 10 ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "128, (NEK10), ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "142, primary ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "143, human ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "144, airway ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "145, cultures ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "NIMA-related", + "kinase", + "10", + "(NEK10)," + ] + }, + "context": { + "val": "cells", + "words": [ + "primary", + "human", + "airway", + "cultures" + ] + } + } + ] + }, + { + "PMID": "31932807", + "TEXT": "Gestational diabetes mellitus (GDM) poses increased risk of short- and long-term complications for mother and offspring1-4. GDM is typically diagnosed at 24-28 weeks of gestation, but earlier detection is desirable as this may prevent or considerably reduce the risk of adverse pregnancy outcomes5,6. Here we used a machine-learning approach to predict GDM on retrospective data of 588,622 pregnancies in Israel for which comprehensive electronic health records were available. Our models predict GDM with high accuracy even at pregnancy initiation (area under the receiver operating curve (auROC) = 0.85), substantially outperforming a baseline risk score (auROC = 0.68). We validated our results on both a future validation set and a geographical validation set from the most populated city in Israel, Jerusalem, thereby emulating real-world performance. Interrogating our model, we uncovered previously unreported risk factors, including results of previous pregnancy glucose challenge tests. Finally, we devised a simpler model based on just nine questions that a patient could answer, with only a modest reduction in accuracy (auROC = 0.80). Overall, our models may allow early-stage intervention in high-risk women, as well as a cost-effective screening approach that could avoid the need for glucose tolerance tests by identifying low-risk women. Future prospective studies and studies on additional populations are needed to assess the real-world clinical utility of the model.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31932804", + "TEXT": "Progress in high-throughput metabolic profiling provides unprecedented opportunities to obtain insights into the effects of drugs on human metabolism. The Biobanking BioMolecular Research Infrastructure of the Netherlands has constructed an atlas of drug-metabolite associations for 87 commonly prescribed drugs and 150 clinically relevant plasma-based metabolites assessed by proton nuclear magnetic resonance. The atlas includes a meta-analysis of ten cohorts (18,873 persons) and uncovers 1,071 drug-metabolite associations after evaluation of confounders including co-treatment. We show that the effect estimates of statins on metabolites from the cross-sectional study are comparable to those from intervention and genetic observational studies. Further data integration links proton pump inhibitors to circulating metabolites, liver function, hepatic steatosis and the gut microbiome. Our atlas provides a tool for targeted experimental pharmaceutical research and clinical trials to improve drug efficacy, safety and repurposing. We provide a web-based resource for visualization of the atlas (http://bbmri.researchlumc.nl/atlas/).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31932785", + "TEXT": "Thinking the e-mail was a system error, she almost didn’t learn that her genetic test result had been revised. With the advent of commercial genomic screening, who is ethically responsible for communicating variant reclassification?", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31907459", + "TEXT": "The intestinal microbiota is a complex community of bacteria, archaea, viruses, protists and fungi1,2. Although the composition of bacterial constituents has been linked to immune homeostasis and infectious susceptibility3-7, the role of non-bacterial constituents and cross-kingdom microbial interactions in these processes is poorly understood2,8. Fungi represent a major cause of infectious morbidity and mortality in immunocompromised individuals, although the relationship of intestinal fungi (that is, the mycobiota) with fungal bloodstream infections remains undefined9. We integrated an optimized bioinformatics pipeline with high-resolution mycobiota sequencing and comparative genomic analyses of fecal and blood specimens from recipients of allogeneic hematopoietic cell transplant. Patients with Candida bloodstream infection experienced a prior marked intestinal expansion of pathogenic Candida species; this expansion consisted of a complex dynamic between multiple species and subspecies with a stochastic translocation pattern into the bloodstream. The intestinal expansion of pathogenic Candida spp. was associated with a substantial loss in bacterial burden and diversity, particularly in the anaerobes. Thus, simultaneous analysis of intestinal fungi and bacteria identifies dysbiosis states across kingdoms that may promote fungal translocation and facilitate invasive disease. These findings support microbiota-driven approaches to identify patients at risk of fungal bloodstream infections for pre-emptive therapeutic intervention.", + "TAG_DATA": [], + "LINK_DATA": [ + "95, allogeneic ['l0', 'l1', 'l2']", + "96, hematopoietic ['l0', 'l3', 'l4']", + "97, cell ['l1', 'l3', 'l5']", + "98, transplant. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31873312", + "TEXT": "Gene silencing with virally delivered shRNA represents a promising approach for treatment of inherited neurodegenerative disorders. In the present study we develop a subpial technique, which we show in adult animals successfully delivers adeno-associated virus (AAV) throughout the cervical, thoracic and lumbar spinal cord, as well as brain motor centers. One-time injection at cervical and lumbar levels just before disease onset in mice expressing a familial amyotrophic lateral sclerosis (ALS)-causing mutant SOD1 produces long-term suppression of motoneuron disease, including near-complete preservation of spinal α-motoneurons and muscle innervation. Treatment after disease onset potently blocks progression of disease and further α-motoneuron degeneration. A single subpial AAV9 injection in adult pigs or non-human primates using a newly designed device produces homogeneous delivery throughout the cervical spinal cord white and gray matter and brain motor centers. Thus, spinal subpial delivery in adult animals is highly effective for AAV-mediated gene delivery throughout the spinal cord and supraspinal motor centers.", + "TAG_DATA": [ + "62, mice {'context': 'B-organism'}", + "63, expressing {'perturbing_action': 'B-other'}", + "64, a {'perturbing_action': 'I-other'}", + "65, familial {'perturbing_action': 'I-other'}", + "66, amyotrophic {'perturbing_action': 'I-other'}", + "67, lateral {'perturbing_action': 'I-other'}", + "68, sclerosis {'perturbing_action': 'I-other'}", + "69, (ALS)-causing {'perturbing_action': 'I-other'}", + "70, mutant {'perturbing_action': 'I-other'}", + "71, SOD1 {'perturbing_action': 'I-other'}", + "76, motoneuron {'context': 'B-cells'}", + "82, spinal {'context': 'B-cells'}", + "83, α-motoneurons {'context': 'I-cells'}", + "85, muscle {'context': 'B-tissue/organ'}", + "98, α-motoneuron {'context': 'B-cells'}", + "106, adult {'context': 'B-organism'}", + "107, pigs {'context': 'I-organism'}", + "109, non-human {'context': 'B-organism'}", + "110, primates {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "62, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "63, expressing ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "64, a ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "65, familial ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "66, amyotrophic ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "67, lateral ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "68, sclerosis ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "69, (ALS)-causing ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "70, mutant ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "71, SOD1 ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "76, motoneuron ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "82, spinal ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "83, α-motoneurons ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "85, muscle ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']", + "106, adult ['l91', 'l92', 'l93']", + "107, pigs ['l91', 'l94', 'l95']", + "109, non-human ['l92', 'l94', 'l96']", + "110, primates ['l93', 'l95', 'l96']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "a", + "familial", + "amyotrophic", + "lateral", + "sclerosis", + "(ALS)-causing", + "mutant", + "SOD1" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "a", + "familial", + "amyotrophic", + "lateral", + "sclerosis", + "(ALS)-causing", + "mutant", + "SOD1" + ] + }, + "context": { + "val": "cells", + "words": [ + "motoneuron", + "spinal", + "α-motoneurons" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "a", + "familial", + "amyotrophic", + "lateral", + "sclerosis", + "(ALS)-causing", + "mutant", + "SOD1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscle" + ] + } + } + ] + }, + { + "PMID": "31792455", + "TEXT": "Early disease diagnosis is key to the effective treatment of diseases. Histopathological analysis of human biopsies is the gold standard to diagnose tissue alterations. However, this approach has low resolution and overlooks 3D (three-dimensional) structural changes resulting from functional alterations. Here, we applied multiphoton imaging, 3D digital reconstructions and computational simulations to generate spatially resolved geometrical and functional models of human liver tissue at different stages of non-alcoholic fatty liver disease (NAFLD). We identified a set of morphometric cellular and tissue parameters correlated with disease progression, and discover profound topological defects in the 3D bile canalicular (BC) network. Personalized biliary fluid dynamic simulations predicted an increased pericentral biliary pressure and micro-cholestasis, consistent with elevated cholestatic biomarkers in patients' sera. Our spatially resolved models of human liver tissue can contribute to high-definition medicine by identifying quantitative multiparametric cellular and tissue signatures to define disease progression and provide new insights into NAFLD pathophysiology.", + "TAG_DATA": [ + "60, human {'context': 'B-tissue/organ'}", + "61, liver {'context': 'I-tissue/organ'}", + "62, tissue {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "60, human ['l0', 'l1']", + "61, liver ['l0', 'l2']", + "62, tissue ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31768065", + "TEXT": "Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis.", + "TAG_DATA": [ + "63, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "64, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "65, of {'perturbing_action': 'I-pharmacological inhibition'}", + "66, RET {'perturbing_action': 'I-pharmacological inhibition'}", + "67, (selpercatinib) {'perturbing_action': 'I-pharmacological inhibition'}", + "68, and {'perturbing_action': 'I-pharmacological inhibition'}", + "72, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "63, selective ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "64, inhibition ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "65, of ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "66, RET ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "67, (selpercatinib) ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "68, and ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "72, patients ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "inhibition", + "of", + "RET", + "(selpercatinib)", + "and" + ] + }, + "context": { + "val": "patient", + "words": [ + "patients" + ] + } + } + ] + }, + { + "PMID": "31768064", + "TEXT": "Multidrug resistant organisms are a serious threat to human health1,2. Fast, accurate antibiotic susceptibility testing (AST) is a critical need in addressing escalating antibiotic resistance, since delays in identifying multidrug resistant organisms increase mortality3,4 and use of broad-spectrum antibiotics, further selecting for resistant organisms. Yet current growth-based AST assays, such as broth microdilution5, require several days before informing key clinical decisions. Rapid AST would transform the care of patients with infection while ensuring that our antibiotic arsenal is deployed as efficiently as possible. Growth-based assays are fundamentally constrained in speed by doubling time of the pathogen, and genotypic assays are limited by the ever-growing diversity and complexity of bacterial antibiotic resistance mechanisms. Here we describe a rapid assay for combined genotypic and phenotypic AST through RNA detection, GoPhAST-R, that classifies strains with 94-99% accuracy by coupling machine learning analysis of early antibiotic-induced transcriptional changes with simultaneous detection of key genetic resistance determinants to increase accuracy of resistance detection, facilitate molecular epidemiology and enable early detection of emerging resistance mechanisms. This two-pronged approach provides phenotypic AST 24-36 h faster than standard workflows, with <4 h assay time on a pilot instrument for hybridization-based multiplexed RNA detection implemented directly from positive blood cultures.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31700190", + "TEXT": "Late-onset sepsis (LOS) is thought to result from systemic spread of commensal microbes from the intestines of premature infants. Clinical use of probiotics for LOS prophylaxis has varied owing to limited efficacy, reflecting an incomplete understanding of relationships between development of the intestinal microbiome, neonatal dysbiosis and LOS. Using a model of LOS, we found that components of the developing microbiome were both necessary and sufficient to prevent LOS. Maternal antibiotic exposure that eradicated or enriched transmission of Lactobacillus murinus exacerbated and prevented disease, respectively. Prophylactic administration of some, but not all Lactobacillus spp. was protective, as was administration of Escherichia coli. Intestinal oxygen level was a major driver of colonization dynamics, albeit via mechanisms distinct from those in adults. These results establish a link between neonatal dysbiosis and LOS, and provide a basis for rational selection of probiotics that modulate primary succession of the microbiome to prevent disease.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31700189", + "TEXT": "Probiotics are routinely administered to hospitalized patients for many potential indications1 but have been associated with adverse effects that may outweigh their potential benefits2-7. It is particularly alarming that probiotic strains can cause bacteremia8,9, yet direct evidence for an ancestral link between blood isolates and administered probiotics is lacking. Here we report a markedly higher risk of Lactobacillus bacteremia for intensive care unit (ICU) patients treated with probiotics compared to those not treated, and provide genomics data that support the idea of direct clonal transmission of probiotics to the bloodstream. Whole-genome-based phylogeny showed that Lactobacilli isolated from treated patients' blood were phylogenetically inseparable from Lactobacilli isolated from the associated probiotic product. Indeed, the minute genetic diversity among the blood isolates mostly mirrored pre-existing genetic heterogeneity found in the probiotic product. Some blood isolates also contained de novo mutations, including a non-synonymous SNP conferring antibiotic resistance in one patient. Our findings support that probiotic strains can directly cause bacteremia and adaptively evolve within ICU patients.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31700181", + "TEXT": "Functional diversity of the highly polymorphic human leukocyte antigen class I (HLA-I) genes underlies successful immunologic control of both infectious disease and cancer. The divergent allele advantage hypothesis dictates that an HLA-I genotype with two alleles with sequences that are more divergent enables presentation of more diverse immunopeptidomes1-3. However, the effect of sequence divergence between HLA-I alleles-a quantifiable measure of HLA-I evolution-on the efficacy of immune checkpoint inhibitor (ICI) treatment for cancer remains unknown. In the present study the germline HLA-I evolutionary divergence (HED) of patients with cancer treated with ICIs was determined by quantifying the physiochemical sequence divergence between HLA-I alleles of each patient's genotype. HED was a strong determinant of survival after treatment with ICIs. Even among patients fully heterozygous at HLA-I, patients with an HED in the upper quartile respond better to ICIs than patients with a low HED. Furthermore, HED strongly impacts the diversity of tumor, viral and self-immunopeptidomes and intratumoral T cell receptor clonality. Similar to tumor mutation burden, HED is a fundamental metric of diversity at the major histocompatibility complex-peptide complex, which dictates ICI efficacy. The data link divergent HLA allele advantage to immunotherapy efficacy and unveil how ICI response relies on the evolved efficiency of HLA-mediated immunity.", + "TAG_DATA": [ + "85, patients {'context': 'B-patient'}", + "86, with {'context': 'I-patient'}", + "87, cancer {'context': 'I-neoplasm'}", + "119, patients {'context': 'B-patient'}", + "124, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "85, patients ['l0', 'l1']", + "86, with ['l0', 'l2']", + "87, cancer ['l1', 'l2']", + "119, patients ['l3']", + "124, patients ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31700171", + "TEXT": "The G-protein-coupled receptor accessory protein MRAP2 is implicated in energy control in rodents, notably via the melanocortin-4 receptor1. Although some MRAP2 mutations have been described in people with obesity1-3, their functional consequences on adiposity remain elusive. Using large-scale sequencing of MRAP2 in 9,418 people, we identified 23 rare heterozygous variants associated with increased obesity risk in both adults and children. Functional assessment of each variant shows that loss-of-function MRAP2 variants are pathogenic for monogenic hyperphagic obesity, hyperglycemia and hypertension. This contrasts with other monogenic forms of obesity characterized by excessive hunger, including melanocortin-4 receptor deficiency, that present with low blood pressure and normal glucose tolerance4. The pleiotropic metabolic effect of loss-of-function mutations in MRAP2 might be due to the failure of different MRAP2-regulated G-protein-coupled receptors in various tissues including pancreatic islets.", + "TAG_DATA": [ + "67, loss-of-function {'perturbing_action': 'B-gene loss-of-function'}", + "68, MRAP2 {'perturbing_action': 'I-gene loss-of-function'}", + "69, variants {'perturbing_action': 'I-gene loss-of-function'}", + "110, loss-of-function {'perturbing_action': 'B-gene loss-of-function'}", + "111, mutations {'perturbing_action': 'I-gene loss-of-function'}", + "112, in {'perturbing_action': 'I-gene loss-of-function'}", + "113, MRAP2 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "67, loss-of-function ['l0', 'l1']", + "68, MRAP2 ['l0', 'l2']", + "69, variants ['l1', 'l2']", + "110, loss-of-function ['l3', 'l4', 'l5']", + "111, mutations ['l3', 'l6', 'l7']", + "112, in ['l4', 'l6', 'l8']", + "113, MRAP2 ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31700167", + "TEXT": "Ziad Obermeyer is an acting associate professor at the University of California, Berkeley, and an emergency physician. His teaching and research focus on how algorithms can aid in human decision-making in health care. Previously, he taught at Harvard Medical School, where he received the Early Independence Award, the most prestigious award for early-career scientists given by the US National Institutes of Health.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31686034", + "TEXT": "We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease.", + "TAG_DATA": [ + "43, APOE3 {'perturbing_action': 'I-other'}", + "44, Christchurch {'perturbing_action': 'I-other'}", + "45, (R136S) {'perturbing_action': 'I-other'}", + "46, mutation, {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "43, APOE3 ['l0', 'l1', 'l2']", + "44, Christchurch ['l0', 'l3', 'l4']", + "45, (R136S) ['l1', 'l3', 'l5']", + "46, mutation, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31636454", + "TEXT": "Dysregulation of the mammalian target of rapamycin (mTOR) signaling, which is mediated by two structurally and functionally distinct complexes, mTORC1 and mTORC2, has been implicated in several neurological disorders1-3. Individuals carrying loss-of-function mutations in the phosphatase and tensin homolog (PTEN) gene, a negative regulator of mTOR signaling, are prone to developing macrocephaly, autism spectrum disorder (ASD), seizures and intellectual disability2,4,5. It is generally believed that the neurological symptoms associated with loss of PTEN and other mTORopathies (for example, mutations in the tuberous sclerosis genes TSC1 or TSC2) are due to hyperactivation of mTORC1-mediated protein synthesis1,2,4,6,7. Using molecular genetics, we unexpectedly found that genetic deletion of mTORC2 (but not mTORC1) activity prolonged lifespan, suppressed seizures, rescued ASD-like behaviors and long-term memory, and normalized metabolic changes in the brain of mice lacking Pten. In a more therapeutically oriented approach, we found that administration of an antisense oligonucleotide (ASO) targeting mTORC2's defining component Rictor specifically inhibits mTORC2 activity and reverses the behavioral and neurophysiological abnormalities in adolescent Pten-deficient mice. Collectively, our findings indicate that mTORC2 is the major driver underlying the neuropathophysiology associated with Pten-deficiency, and its therapeutic reduction could represent a promising and broadly effective translational therapy for neurological disorders where mTOR signaling is dysregulated.", + "TAG_DATA": [ + "102, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "103, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "104, of {'perturbing_action': 'I-gene loss-of-function'}", + "105, mTORC2 {'perturbing_action': 'I-gene loss-of-function'}", + "106, (but {'perturbing_action': 'I-gene loss-of-function'}", + "109, activity {'perturbing_action': 'I-gene loss-of-function'}", + "126, brain {'context': 'B-tissue/organ'}", + "128, mice {'context': 'B-organism'}", + "129, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "130, Pten. {'perturbing_action': 'I-gene loss-of-function'}", + "164, Pten-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "165, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "102, genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "103, deletion ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "104, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "105, mTORC2 ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "106, (but ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "109, activity ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "126, brain ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "128, mice ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "129, lacking ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "130, Pten. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "164, Pten-deficient ['l45']", + "165, mice. ['l45']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "mTORC2", + "(but", + "activity", + "lacking", + "Pten." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "mTORC2", + "(but", + "activity", + "lacking", + "Pten.", + "Pten-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "31591601", + "TEXT": "Insulin and other injectable biologic drugs have transformed the treatment of patients suffering from diabetes1,2, yet patients and healthcare providers often prefer to use and prescribe less effective orally dosed medications3-5. Compared with subcutaneously administered drugs, oral formulations create less patient discomfort4, show greater chemical stability at high temperatures6, and do not generate biohazardous needle waste7. An oral dosage form for biologic medications is ideal; however, macromolecule drugs are not readily absorbed into the bloodstream through the gastrointestinal tract8. We developed an ingestible capsule, termed the luminal unfolding microneedle injector, which allows for the oral delivery of biologic drugs by rapidly propelling dissolvable drug-loaded microneedles into intestinal tissue using a set of unfolding arms. During ex vivo human and in vivo swine studies, the device consistently delivered the microneedles to the tissue without causing complete thickness perforations. Using insulin as a model drug, we showed that, when actuated, the luminal unfolding microneedle injector provided a faster pharmacokinetic uptake profile and a systemic uptake >10% of that of a subcutaneous injection over a 4-h sampling period. With the ability to load a multitude of microneedle formulations, the device can serve as a platform to orally deliver therapeutic doses of macromolecule drugs.", + "TAG_DATA": [ + "119, in {'context': 'B-in vivo'}", + "120, vivo {'context': 'I-in vivo'}", + "121, swine {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "119, in ['l0', 'l1']", + "120, vivo ['l0', 'l2']", + "121, swine ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31591596", + "TEXT": "The essential product of the Duchenne muscular dystrophy (DMD) gene is dystrophin1, a rod-like protein2 that protects striated myocytes from contraction-induced injury3,4. Dystrophin-related protein (or utrophin) retains most of the structural and protein binding elements of dystrophin5. Importantly, normal thymic expression in DMD patients6 should protect utrophin by central immunologic tolerance. We designed a codon-optimized, synthetic transgene encoding a miniaturized utrophin (µUtro), deliverable by adeno-associated virus (AAV) vectors. Here, we show that µUtro is a highly functional, non-immunogenic substitute for dystrophin, preventing the most deleterious histological and physiological aspects of muscular dystrophy in small and large animal models. Following systemic administration of an AAV-µUtro to neonatal dystrophin-deficient mdx mice, histological and biochemical markers of myonecrosis and regeneration are completely suppressed throughout growth to adult weight. In the dystrophin-deficient golden retriever model, µUtro non-toxically prevented myonecrosis, even in the most powerful muscles. In a stringent test of immunogenicity, focal expression of µUtro in the deletional-null German shorthaired pointer model produced no evidence of cell-mediated immunity, in contrast to the robust T cell response against similarly constructed µDystrophin (µDystro). These findings support a model in which utrophin-derived therapies might be used to treat clinical dystrophin deficiency, with a favorable immunologic profile and preserved function in the face of extreme miniaturization.", + "TAG_DATA": [ + "106, dystrophin-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "107, mdx {'context': 'I-organism'}", + "108, mice, {'context': 'I-organism'}", + "127, dystrophin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "128, golden {'context': 'B-organism'}", + "129, retriever {'context': 'I-organism'}", + "130, model, {'context': 'I-organism'}", + "133, prevented {'effect': 'B-negative'}", + "134, myonecrosis, {'phenotype': 'B-necrosis'}", + "140, muscles. {'context': 'B-tissue/organ'}", + "147, focal {'perturbing_action': 'B-gene gain-of-function'}", + "148, expression {'perturbing_action': 'I-gene gain-of-function'}", + "149, of {'perturbing_action': 'I-gene gain-of-function'}", + "150, µUtro {'perturbing_action': 'I-gene gain-of-function'}", + "153, deletional-null {'perturbing_action': 'B-gene loss-of-function'}", + "154, German {'context': 'B-organism'}", + "155, shorthaired {'context': 'I-organism'}", + "156, pointer {'context': 'I-organism'}", + "157, model {'context': 'I-organism'}", + "169, T {'context': 'B-cells'}", + "170, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "106, dystrophin-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "107, mdx ['l0', 'l7', 'l8', 'l9', 'l10']", + "108, mice, ['l1', 'l7']", + "127, dystrophin-deficient ['l2', 'l8', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "128, golden ['l3', 'l9', 'l11', 'l17', 'l18', 'l19', 'l20', 'l21']", + "129, retriever ['l4', 'l12', 'l17', 'l22', 'l23', 'l24', 'l25']", + "130, model, ['l5', 'l10', 'l13', 'l18', 'l22', 'l26', 'l27', 'l28']", + "133, prevented ['l14', 'l19', 'l23', 'l26', 'l29', 'l30']", + "134, myonecrosis, ['l15', 'l20', 'l24', 'l27', 'l29', 'l31']", + "140, muscles. ['l6', 'l16', 'l21', 'l25', 'l28', 'l30', 'l31']", + "147, focal ['l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "148, expression ['l32', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "149, of ['l33', 'l42', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "150, µUtro ['l34', 'l43', 'l51', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "153, deletional-null ['l35', 'l44', 'l52', 'l59', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "154, German ['l36', 'l45', 'l53', 'l60', 'l66', 'l72', 'l73', 'l74', 'l75', 'l76']", + "155, shorthaired ['l37', 'l46', 'l54', 'l61', 'l67', 'l72', 'l77', 'l78', 'l79', 'l80']", + "156, pointer ['l38', 'l47', 'l55', 'l62', 'l68', 'l73', 'l77', 'l81', 'l82', 'l83']", + "157, model ['l39', 'l48', 'l56', 'l63', 'l69', 'l74', 'l78', 'l81', 'l84', 'l85']", + "169, T ['l40', 'l49', 'l57', 'l64', 'l70', 'l75', 'l79', 'l82', 'l84', 'l86']", + "170, cell ['l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l83', 'l85', 'l86']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient", + "deletional-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mdx", + "mice,", + "golden", + "retriever", + "model,", + "German", + "shorthaired", + "pointer", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscles." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "myonecrosis," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "golden", + "retriever", + "model," + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "golden", + "retriever", + "model," + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "myonecrosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "myonecrosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscles." + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "myonecrosis," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscles." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "focal", + "expression", + "of", + "µUtro" + ] + }, + "context": { + "val": "organism", + "words": [ + "German", + "shorthaired", + "pointer", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "focal", + "expression", + "of", + "µUtro" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletional-null" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + } + ] + }, + { + "PMID": "31591588", + "TEXT": "Oncogenesis is driven by germline, environmental and stochastic factors. It is unknown how these interact to produce the molecular phenotypes of tumors. We therefore quantified the influence of germline polymorphisms on the somatic epigenome of 589 localized prostate tumors. Predisposition risk loci influence a tumor's epigenome, uncovering a mechanism for cancer susceptibility. We identified and validated 1,178 loci associated with altered methylation in tumoral but not nonmalignant tissue. These tumor methylation quantitative trait loci influence chromatin structure, as well as RNA and protein abundance. One prominent tumor methylation quantitative trait locus is associated with AKT1 expression and is predictive of relapse after definitive local therapy in both discovery and validation cohorts. These data reveal intricate crosstalk between the germ line and the epigenome of primary tumors, which may help identify germline biomarkers of aggressive disease to aid patient triage and optimize the use of more invasive or expensive diagnostic assays.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31570822", + "TEXT": "Whole-genome sequencing (WGS) brings comprehensive insights to cancer genome interpretation. To explore the clinical value of WGS, we sequenced 254 triple-negative breast cancers (TNBCs) for which associated treatment and outcome data were collected between 2010 and 2015 via the population-based Sweden Cancerome Analysis Network-Breast (SCAN-B) project (ClinicalTrials.gov ID:NCT02306096). Applying the HRDetect mutational-signature-based algorithm to classify tumors, 59% were predicted to have homologous-recombination-repair deficiency (HRDetect-high): 67% explained by germline/somatic mutations of BRCA1/BRCA2, BRCA1 promoter hypermethylation, RAD51C hypermethylation or biallelic loss of PALB2. A novel mechanism of BRCA1 abrogation was discovered via germline SINE-VNTR-Alu retrotransposition. HRDetect provided independent prognostic information, with HRDetect-high patients having better outcome on adjuvant chemotherapy for invasive disease-free survival (hazard ratio (HR) = 0.42; 95% confidence interval (CI) = 0.2-0.87) and distant relapse-free interval (HR = 0.31, CI = 0.13-0.76) compared to HRDetect-low, regardless of whether a genetic/epigenetic cause was identified. HRDetect-intermediate, some possessing potentially targetable biological abnormalities, had the poorest outcomes. HRDetect-low cancers also had inadequate outcomes: ~4.7% were mismatch-repair-deficient (another targetable defect, not typically sought) and they were enriched for (but not restricted to) PIK3CA/AKT1 pathway abnormalities. New treatment options need to be considered for now-discernible HRDetect-intermediate and HRDetect-low categories. This population-based study advocates for WGS of TNBC to better inform trial stratification and improve clinical decision-making.", + "TAG_DATA": [ + "20, triple-negative {'context': 'B-neoplasm'}", + "21, breast {'context': 'I-neoplasm'}", + "22, cancers {'context': 'I-neoplasm'}", + "23, (TNBCs) {'context': 'I-neoplasm'}", + "147, cancers {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "20, triple-negative ['l0', 'l1', 'l2']", + "21, breast ['l0', 'l3', 'l4']", + "22, cancers ['l1', 'l3', 'l5']", + "23, (TNBCs) ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31501614", + "TEXT": "Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ+ T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3 expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3 in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3 deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3 upregulation can subvert therapy-induced anticancer immunosurveillance.", + "TAG_DATA": [ + "35, mice {'context': 'B-organism'}", + "44, transplantable {'context': 'B-neoplasm'}", + "45, tumors. {'context': 'I-neoplasm'}", + "66, dendritic {'context': 'B-cells'}", + "67, cell {'context': 'I-cells'}", + "68, (DC) {'context': 'I-cells'}", + "96, murine {'context': 'B-organism'}", + "97, models, {'context': 'I-organism'}", + "102, enforced {'perturbing_action': 'B-gene gain-of-function'}", + "103, expression {'perturbing_action': 'I-gene gain-of-function'}", + "104, of {'perturbing_action': 'I-gene gain-of-function'}", + "105, Tsc22d3 {'perturbing_action': 'I-gene gain-of-function'}", + "107, DC {'context': 'B-cells'}", + "115, tumors. {'context': 'B-neoplasm'}", + "123, DC-specific {'perturbing_action': 'B-gene loss-of-function'}", + "124, Tsc22d3 {'perturbing_action': 'I-gene loss-of-function'}", + "125, deletion {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "35, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "42, neoplasias ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "44, transplantable ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "45, tumors. ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "66, dendritic ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "67, cell ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "68, (DC) ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "96, murine ['l21', 'l22', 'l23']", + "97, models, ['l21', 'l24']", + "102, enforced ['l25', 'l26', 'l27', 'l28', 'l29']", + "103, expression ['l25', 'l30', 'l31', 'l32', 'l33']", + "104, of ['l26', 'l30', 'l34', 'l35', 'l36']", + "105, Tsc22d3 ['l27', 'l31', 'l34', 'l37', 'l38']", + "107, DC ['l22', 'l28', 'l32', 'l35', 'l37', 'l39']", + "115, tumors. ['l23', 'l24', 'l29', 'l33', 'l36', 'l38', 'l39']", + "123, DC-specific ['l40', 'l41']", + "124, Tsc22d3 ['l40', 'l42']", + "125, deletion ['l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "enforced", + "expression", + "of", + "Tsc22d3" + ] + }, + "context": { + "val": "cells", + "words": [ + "DC" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "enforced", + "expression", + "of", + "Tsc22d3" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors." + ] + } + } + ] + }, + { + "PMID": "31501613", + "TEXT": "The worldwide obesity epidemic1 makes it important to understand how lipid turnover (the capacity to store and remove lipids) regulates adipose tissue mass. Cross-sectional studies have shown that excess body fat is associated with decreased adipose lipid removal rates2,3. Whether lipid turnover is constant over the life span or changes during long-term weight increase or loss is unknown. We determined the turnover of fat cell lipids in adults followed for up to 16 years, by measuring the incorporation of nuclear bomb test-derived 14C in adipose tissue triglycerides. Lipid removal rate decreases during aging, with a failure to reciprocally adjust the rate of lipid uptake resulting in weight gain. Substantial weight loss is not driven by changes in lipid removal but by the rate of lipid uptake in adipose tissue. Furthermore, individuals with a low baseline lipid removal rate are more likely to remain weight-stable after weight loss. Therefore, lipid turnover adaptation might be important for maintaining pronounced weight loss. Together these findings identify adipose lipid turnover as an important factor for the long-term development of overweight/obesity and weight loss maintenance in humans.", + "TAG_DATA": [ + "67, adults {'context': 'B-patient'}", + "127, adipose {'context': 'B-cells'}", + "128, tissue. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "127, adipose ['l0']", + "128, tissue. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31501610", + "TEXT": "Natalizumab (NZM), a humanized monoclonal IgG4 antibody to α4 integrins, is used to treat patients with relapsing-remitting multiple sclerosis (MS)1,2, but in about 6% of the cases persistent neutralizing anti-drug antibodies (ADAs) are induced leading to therapy discontinuation3,4. To understand the basis of the ADA response and the mechanism of ADA-mediated neutralization, we performed an in-depth analysis of the B and T cell responses in two patients. By characterizing a large panel of NZM-specific monoclonal antibodies, we found that, in both patients, the response was polyclonal and targeted different epitopes of the NZM idiotype. The neutralizing activity was acquired through somatic mutations and correlated with a slow dissociation rate, a finding that was supported by structural data. Interestingly, in both patients, the analysis of the CD4+ T cell response, combined with mass spectrometry-based peptidomics, revealed a single immunodominant T cell epitope spanning the FR2-CDR2 region of the NZM light chain. Moreover, a CDR2-modified version of NZM was not recognized by T cells, while retaining binding to α4 integrins. Collectively, our integrated analysis identifies the basis of T-B collaboration that leads to ADA-mediated therapeutic resistance and delineates an approach to design novel deimmunized antibodies for autoimmune disease and cancer treatment.", + "TAG_DATA": [ + "125, CD4+ {'context': 'B-cells'}", + "126, T {'context': 'I-cells'}", + "127, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "125, CD4+ ['l0', 'l1']", + "126, T ['l0', 'l2']", + "127, cell ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31501609", + "TEXT": "During cancer therapy, tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique resistance mechanisms in an individual patient1-3. Previous case reports and small case series have suggested that liquid biopsy (specifically, cell-free DNA (cfDNA)) may better capture the heterogeneity of acquired resistance4-8. However, the effectiveness of cfDNA versus standard single-lesion tumor biopsies has not been directly compared in larger-scale prospective cohorts of patients following progression on targeted therapy. Here, in a prospective cohort of 42 patients with molecularly defined gastrointestinal cancers and acquired resistance to targeted therapy, direct comparison of postprogression cfDNA versus tumor biopsy revealed that cfDNA more frequently identified clinically relevant resistance alterations and multiple resistance mechanisms, detecting resistance alterations not found in the matched tumor biopsy in 78% of cases. Whole-exome sequencing of serial cfDNA, tumor biopsies and rapid autopsy specimens elucidated substantial geographic and evolutionary differences across lesions. Our data suggest that acquired resistance is frequently characterized by profound tumor heterogeneity, and that the emergence of multiple resistance alterations in an individual patient may represent the 'rule' rather than the 'exception'. These findings have profound therapeutic implications and highlight the potential advantages of cfDNA over tissue biopsy in the setting of acquired resistance.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31501601", + "TEXT": "People living with HIV (PLWH) have expressed concern about the life-long burden and stigma associated with taking pills daily and can experience medication fatigue that might lead to suboptimal treatment adherence and the emergence of drug-resistant viral variants, thereby limiting future treatment options1-3. As such, there is strong interest in long-acting antiretroviral (ARV) agents that can be administered less frequently4. Herein, we report GS-CA1, a new archetypal small-molecule HIV capsid inhibitor with exceptional potency against HIV-2 and all major HIV-1 types, including viral variants resistant to the ARVs currently in clinical use. Mechanism-of-action studies indicate that GS-CA1 binds directly to the HIV-1 capsid and interferes with capsid-mediated nuclear import of viral DNA, HIV particle production and ordered capsid assembly. GS-CA1 selects in vitro for unfit GS-CA1-resistant capsid variants that remain fully susceptible to other classes of ARVs. Its high metabolic stability and low solubility enabled sustained drug release in mice following a single subcutaneous dosing. GS-CA1 showed high antiviral efficacy as a long-acting injectable monotherapy in a humanized mouse model of HIV-1 infection, outperforming long-acting rilpivirine. Collectively, these results demonstrate the potential of ultrapotent capsid inhibitors as new long-acting agents for the treatment of HIV-1 infection.", + "TAG_DATA": [ + "121, in {'context': 'B-in vitro'}", + "122, vitro {'context': 'I-in vitro'}", + "149, mice {'context': 'B-organism'}", + "167, humanized {'context': 'B-organism'}", + "168, mouse {'context': 'I-organism'}", + "169, model {'context': 'I-organism'}", + "170, of {'context': 'I-organism'}", + "171, HIV-1 {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "121, in ['l0', 'l1']", + "122, vitro ['l0', 'l2']", + "149, mice ['l1', 'l2']", + "167, humanized ['l3', 'l4', 'l5', 'l6', 'l7']", + "168, mouse ['l3', 'l8', 'l9', 'l10', 'l11']", + "169, model ['l4', 'l8', 'l12', 'l13', 'l14']", + "170, of ['l5', 'l9', 'l12', 'l15', 'l16']", + "171, HIV-1 ['l6', 'l10', 'l13', 'l15', 'l17']", + "172, infection, ['l7', 'l11', 'l14', 'l16', 'l17']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31501599", + "TEXT": "Fanconi anemia (FA) is a DNA repair syndrome generated by mutations in any of the 22 FA genes discovered to date1,2. Mutations in FANCA account for more than 60% of FA cases worldwide3,4. Clinically, FA is associated with congenital abnormalities and cancer predisposition. However, bone marrow failure is the primary pathological feature of FA that becomes evident in 70-80% of patients with FA during the first decade of life5,6. In this clinical study (ClinicalTrials.gov, NCT03157804 ; European Clinical Trials Database, 2011-006100-12), we demonstrate that lentiviral-mediated hematopoietic gene therapy reproducibly confers engraftment and proliferation advantages of gene-corrected hematopoietic stem cells (HSCs) in non-conditioned patients with FA subtype A. Insertion-site analyses revealed the multipotent nature of corrected HSCs and showed that the repopulation advantage of these cells was not due to genotoxic integrations of the therapeutic provirus. Phenotypic correction of blood and bone marrow cells was shown by the acquired resistance of hematopoietic progenitors and T lymphocytes to DNA cross-linking agents. Additionally, an arrest of bone marrow failure progression was observed in patients with the highest levels of gene marking. The progressive engraftment of corrected HSCs in non-conditioned patients with FA supports that gene therapy should constitute an innovative low-toxicity therapeutic option for this life-threatening disorder.", + "TAG_DATA": [ + "92, proliferation {'phenotype': 'B-proliferation'}", + "93, advantages {'effect': 'B-positive'}", + "96, hematopoietic {'context': 'B-cells'}", + "97, stem {'context': 'I-cells'}", + "98, cells {'context': 'I-cells'}", + "99, (HSCs) {'context': 'I-cells'}", + "101, non-conditioned {'context': 'B-patient'}", + "102, patients {'context': 'I-patient'}", + "138, blood {'context': 'B-cells'}", + "139, and {'context': 'I-cells'}", + "140, bone {'context': 'I-cells'}", + "141, marrow {'context': 'I-cells'}", + "142, cells {'context': 'I-cells'}", + "150, hematopoietic {'context': 'B-cells'}", + "151, progenitors {'context': 'I-cells'}", + "153, T {'context': 'B-cells'}", + "154, lymphocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "92, proliferation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "93, advantages ['l0', 'l6', 'l7', 'l8']", + "96, hematopoietic ['l1', 'l9', 'l10', 'l11', 'l12', 'l13']", + "97, stem ['l2', 'l6', 'l9', 'l14', 'l15', 'l16', 'l17']", + "98, cells ['l3', 'l7', 'l10', 'l14', 'l18', 'l19', 'l20']", + "99, (HSCs) ['l4', 'l8', 'l11', 'l15', 'l18', 'l21', 'l22']", + "101, non-conditioned ['l12', 'l16', 'l19', 'l21', 'l23']", + "102, patients ['l5', 'l13', 'l17', 'l20', 'l22', 'l23']", + "138, blood ['l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "139, and ['l24', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "140, bone ['l25', 'l32', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "141, marrow ['l26', 'l33', 'l39', 'l45', 'l46', 'l47', 'l48', 'l49']", + "142, cells ['l27', 'l34', 'l40', 'l45', 'l50', 'l51', 'l52', 'l53']", + "150, hematopoietic ['l28', 'l35', 'l41', 'l46', 'l50', 'l54', 'l55', 'l56']", + "151, progenitors ['l29', 'l36', 'l42', 'l47', 'l51', 'l54', 'l57', 'l58']", + "153, T ['l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l57', 'l59']", + "154, lymphocytes ['l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58', 'l59']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "advantages" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cells", + "(HSCs)" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "patient", + "words": [ + "patients" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "advantages" + ] + }, + "context": { + "val": "cells", + "words": [ + "stem", + "cells", + "(HSCs)" + ] + } + } + ] + }, + { + "PMID": "31477906", + "TEXT": "Chimeric antigen receptor (CAR)-modified T cells targeting CD19 demonstrate unparalleled responses in relapsed/refractory acute lymphoblastic leukemia (ALL)1-5, but toxicity, including cytokine-release syndrome (CRS) and neurotoxicity, limits broader application. Moreover, 40-60% of patients relapse owing to poor CAR T cell persistence or emergence of CD19- clones. Some factors, including the choice of single-chain spacer6 and extracellular7 and costimulatory domains8, have a profound effect on CAR T cell function and persistence. However, little is known about the impact of CAR binding affinity. There is evidence of a ceiling above which increased immunoreceptor affinity may adversely affect T cell responses9-11. We generated a novel CD19 CAR (CAT) with a lower affinity than FMC63, the high-affinity binder used in many clinical studies1-4. CAT CAR T cells showed increased proliferation and cytotoxicity in vitro and had enhanced proliferative and in vivo antitumor activity compared with FMC63 CAR T cells. In a clinical study (CARPALL, NCT02443831 ), 12/14 patients with relapsed/refractory pediatric B cell acute lymphoblastic leukemia treated with CAT CAR T cells achieved molecular remission. Persistence was demonstrated in 11 of 14 patients at last follow-up, with enhanced CAR T cell expansion compared with published data. Toxicity was low, with no severe CRS. One-year overall and event-free survival were 63% and 46%, respectively.", + "TAG_DATA": [ + "120, T {'context': 'B-cells'}", + "121, cells {'context': 'I-cells'}", + "123, increased {'effect': 'B-positive'}", + "124, proliferation {'phenotype': 'B-proliferation'}", + "127, in {'context': 'B-in vitro'}", + "128, vitro {'context': 'I-in vitro'}", + "142, T {'context': 'I-cells'}", + "143, cells. {'context': 'I-cells'}", + "152, patients {'context': 'B-patient'}", + "154, relapsed/refractory {'context': 'B-neoplasm'}", + "155, pediatric {'context': 'I-neoplasm'}", + "156, B {'context': 'I-neoplasm'}", + "157, cell {'context': 'I-neoplasm'}", + "158, acute {'context': 'I-neoplasm'}", + "159, lymphoblastic {'context': 'I-neoplasm'}", + "160, leukemia {'context': 'I-neoplasm'}", + "165, T {'context': 'B-cells'}", + "166, cells {'context': 'I-cells'}", + "184, T {'context': 'B-cells'}", + "185, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "120, T ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "121, cells ['l0', 'l6', 'l7', 'l8', 'l9']", + "123, increased ['l1', 'l6', 'l10', 'l11', 'l12']", + "124, proliferation ['l2', 'l7', 'l10', 'l13', 'l14']", + "127, in ['l3', 'l8', 'l11', 'l13', 'l15']", + "128, vitro ['l4', 'l9', 'l12', 'l14', 'l15']", + "134, in ['l16', 'l17']", + "142, T ['l16', 'l18']", + "143, cells. ['l5', 'l17', 'l18']", + "152, patients ['l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "154, relapsed/refractory ['l19', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "155, pediatric ['l20', 'l28', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "156, B ['l21', 'l29', 'l36', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "157, cell ['l22', 'l30', 'l37', 'l43', 'l49', 'l50', 'l51', 'l52', 'l53']", + "158, acute ['l23', 'l31', 'l38', 'l44', 'l49', 'l54', 'l55', 'l56', 'l57']", + "159, lymphoblastic ['l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l58', 'l59', 'l60']", + "160, leukemia ['l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l58', 'l61', 'l62']", + "165, T ['l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l61', 'l63']", + "166, cells ['l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l62', 'l63']", + "184, T ['l64']", + "185, cell ['l64']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "31451782", + "TEXT": "The exact etiology of dementia is still unclear, but both genetic and lifestyle factors are thought to be key drivers of this complex disease. The recognition of familial patterns of dementia has led to the discovery of genetic factors that have a role in the pathogenesis of dementia, including the apolipoprotein E (APOE) genotype and a large and still-growing number of genetic variants1,2. Beyond genetic architecture, several modifiable risk factors have been implicated in the development of dementia3. Prevention trials of measures to halt or delay cognitive decline are increasingly recruiting older individuals who are genetically predisposed to dementia. However, it remains unclear whether targeted health and lifestyle interventions can attenuate or even offset increased genetic risk. Here, we leverage long-term data on both genetic and modifiable risk factors from 6,352 individuals aged 55 years and older in the population-based Rotterdam Study. In this study, we demonstrate that, in individuals at low and intermediate genetic risk, favorable modifiable-risk profiles are related to a lower risk of dementia compared to unfavorable profiles. In contrast, these protective associations were not found in those at high genetic risk.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31406350", + "TEXT": "TRK fusions are found in a variety of cancer types, lead to oncogenic addiction, and strongly predict tumor-agnostic efficacy of TRK inhibition1-8. With the recent approval of the first selective TRK inhibitor, larotrectinib, for patients with any TRK-fusion-positive adult or pediatric solid tumor, to identify mechanisms of treatment failure after initial response has become of immediate therapeutic relevance. So far, the only known resistance mechanism is the acquisition of on-target TRK kinase domain mutations, which interfere with drug binding and can potentially be addressable through second-generation TRK inhibitors9-11. Here, we report off-target resistance in patients treated with TRK inhibitors and in patient-derived models, mediated by genomic alterations that converge to activate the mitogen-activated protein kinase (MAPK) pathway. MAPK pathway-directed targeted therapy, administered alone or in combination with TRK inhibition, re-established disease control. Experimental modeling further suggests that upfront dual inhibition of TRK and MEK may delay time to progression in cancer types prone to the genomic acquisition of MAPK pathway-activating alterations. Collectively, these data suggest that a subset of patients will develop off-target mechanisms of resistance to TRK inhibition with potential implications for clinical management and future clinical trial design.", + "TAG_DATA": [ + "97, TRK {'perturbing_action': 'B-pharmacological inhibition'}", + "98, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "127, TRK {'perturbing_action': 'B-pharmacological inhibition'}", + "128, inhibition, {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "97, TRK ['l0']", + "98, inhibitors ['l0']", + "127, TRK ['l1']", + "128, inhibition, ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31384041", + "TEXT": "Here we present a miniaturized analog of a blinking human eye to reverse engineer the complexity of the interface between the ocular system and the external environment. Our model comprises human cells and provides unique capabilities to replicate multiscale structural organization, biological phenotypes and dynamically regulated environmental homeostasis of the human ocular surface. Using this biomimetic system, we discovered new biological effects of blink-induced mechanical forces. Furthermore, we developed a specialized in vitro model of evaporative dry-eye disease for high-content drug screening. This work advances our ability to emulate how human physiological systems interface with the external world, and may contribute to the future development of novel screening platforms for biopharmaceutical and environmental applications.", + "TAG_DATA": [ + "71, in {'context': 'B-in vitro'}", + "72, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "71, in ['l0']", + "72, vitro ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31332392", + "TEXT": "Polycystic ovary syndrome (PCOS) is characterized by androgen excess, ovulatory dysfunction and polycystic ovaries1, and is often accompanied by insulin resistance2. The mechanism of ovulatory dysfunction and insulin resistance in PCOS remains elusive, thus limiting the development of therapeutics. Improved metabolic health is associated with a relatively high microbiota gene content and increased microbial diversity3,4. This study aimed to investigate the impact of the gut microbiota and its metabolites on the regulation of PCOS-associated ovarian dysfunction and insulin resistance. Here, we report that Bacteroides vulgatus was markedly elevated in the gut microbiota of individuals with PCOS, accompanied by reduced glycodeoxycholic acid and tauroursodeoxycholic acid levels. Transplantation of fecal microbiota from women with PCOS or B. vulgatus-colonized recipient mice resulted in increased disruption of ovarian functions, insulin resistance, altered bile acid metabolism, reduced interleukin-22 secretion and infertility. Mechanistically, glycodeoxycholic acid induced intestinal group 3 innate lymphoid cell IL-22 secretion through GATA binding protein 3, and IL-22 in turn improved the PCOS phenotype. This finding is consistent with the reduced levels of IL-22 in individuals with PCOS. This study suggests that modifying the gut microbiota, altering bile acid metabolism and/or increasing IL-22 levels may be of value for the treatment of PCOS.", + "TAG_DATA": [ + "117, mice {'context': 'B-organism'}", + "140, intestinal {'context': 'B-cells'}", + "141, group {'context': 'I-cells'}", + "142, 3 {'context': 'I-cells'}", + "143, innate {'context': 'I-cells'}", + "144, lymphoid {'context': 'I-cells'}", + "145, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "117, mice ['l0', 'l1']", + "140, intestinal ['l2', 'l3', 'l4', 'l5', 'l6']", + "141, group ['l2', 'l7', 'l8', 'l9', 'l10']", + "142, 3 ['l3', 'l7', 'l11', 'l12', 'l13']", + "143, innate ['l4', 'l8', 'l11', 'l14', 'l15']", + "144, lymphoid ['l0', 'l5', 'l9', 'l12', 'l14', 'l16']", + "145, cell ['l1', 'l6', 'l10', 'l13', 'l15', 'l16']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31332390", + "TEXT": "Checkpoint inhibitors produce durable responses in numerous metastatic cancers, but immune-related adverse events (irAEs) complicate and limit their benefit. IrAEs can affect organ systems idiosyncratically; presentations range from mild and self-limited to fulminant and fatal. The molecular mechanisms underlying irAEs are poorly understood. Here, we report a fatal case of encephalitis arising during anti-programmed cell death receptor 1 therapy in a patient with metastatic melanoma. Histologic analyses revealed robust T cell infiltration and prominent programmed death ligand 1 expression. We identified 209 reported cases in global pharmacovigilance databases (across multiple cancer types) of encephalitis associated with checkpoint inhibitor regimens, with a 19% fatality rate. We performed further analyses from the index case and two additional cases to shed light on this recurrent and fulminant irAE. Spatial and multi-omic analyses pinpointed activated memory CD4+ T cells as highly enriched in the inflamed, affected region. We identified a highly oligoclonal T cell receptor repertoire, which we localized to activated memory cytotoxic (CD45RO+GZMB+Ki67+) CD4 cells. We also identified Epstein-Barr virus-specific T cell receptors and EBV+ lymphocytes in the affected region, which we speculate contributed to neural inflammation in the index case. Collectively, the three cases studied here identify CD4+ and CD8+ T cells as culprits of checkpoint inhibitor-associated immune encephalitis.", + "TAG_DATA": [ + "61, patient {'context': 'B-patient'}", + "63, metastatic {'context': 'B-neoplasm'}", + "64, melanoma. {'context': 'I-neoplasm'}", + "131, memory {'context': 'B-cells'}", + "132, CD4+ {'context': 'I-cells'}", + "133, T {'context': 'I-cells'}", + "134, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "61, patient ['l0', 'l1']", + "63, metastatic ['l0', 'l2']", + "64, melanoma. ['l1', 'l2']", + "131, memory ['l3', 'l4', 'l5']", + "132, CD4+ ['l3', 'l6', 'l7']", + "133, T ['l4', 'l6', 'l8']", + "134, cells ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31285632", + "TEXT": "Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality; however, the extent to which genetic factors increase risk for PAD is largely unknown. Using electronic health record data, we performed a genome-wide association study in the Million Veteran Program testing ~32 million DNA sequence variants with PAD (31,307 cases and 211,753 controls) across veterans of European, African and Hispanic ancestry. The results were replicated in an independent sample of 5,117 PAD cases and 389,291 controls from the UK Biobank. We identified 19 PAD loci, 18 of which have not been previously reported. Eleven of the 19 loci were associated with disease in three vascular beds (coronary, cerebral, peripheral), including LDLR, LPL and LPA, suggesting that therapeutic modulation of low-density lipoprotein cholesterol, the lipoprotein lipase pathway or circulating lipoprotein(a) may be efficacious for multiple atherosclerotic disease phenotypes. Conversely, four of the variants appeared to be specific for PAD, including F5 p.R506Q, highlighting the pathogenic role of thrombosis in the peripheral vascular bed and providing genetic support for Factor Xa inhibition as a therapeutic strategy for PAD. Our results highlight mechanistic similarities and differences among coronary, cerebral and peripheral atherosclerosis and provide therapeutic insights.", + "TAG_DATA": [ + "57, veterans {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31263281", + "TEXT": "The treatment of lymphatic anomaly, a rare devastating disease spectrum of mostly unknown etiologies, depends on the patient manifestations1. Identifying the causal genes will allow for developing affordable therapies in keeping with precision medicine implementation2. Here we identified a recurrent gain-of-function ARAF mutation (c.640T>C:p.S214P) in a 12-year-old boy with advanced anomalous lymphatic disease unresponsive to conventional sirolimus therapy and in another, unrelated, adult patient. The mutation led to loss of a conserved phosphorylation site. Cells transduced with ARAF-S214P showed elevated ERK1/2 activity, enhanced lymphangiogenic capacity, and disassembly of actin skeleton and VE-cadherin junctions, which were rescued using the MEK inhibitor trametinib. The functional relevance of the mutation was also validated by recreating a lymphatic phenotype in a zebrafish model, with rescue of the anomalous phenotype using a MEK inhibitor. Subsequent therapy of the lead proband with a MEK inhibitor led to dramatic clinical improvement, with remodeling of the patient's lymphatic system with resolution of the lymphatic edema, marked improvement in his pulmonary function tests, cessation of supplemental oxygen requirements and near normalization of daily activities. Our results provide a representative demonstration of how knowledge of genetic classification and mechanistic understanding guides biologically based medical treatments, which in our instance was life-saving.", + "TAG_DATA": [ + "74, Cells {'context': 'B-cells'}", + "75, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "76, with {'perturbing_action': 'I-gene gain-of-function'}", + "77, ARAF-S214P {'perturbing_action': 'I-gene gain-of-function'}", + "100, trametinib. {'perturbing_action': 'I-pharmacological inhibition'}", + "117, zebrafish {'context': 'B-organism'}", + "118, model, {'context': 'I-organism'}", + "127, MEK {'perturbing_action': 'B-pharmacological inhibition'}", + "128, inhibitor. {'perturbing_action': 'I-pharmacological inhibition'}", + "137, MEK {'perturbing_action': 'B-pharmacological inhibition'}", + "138, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "74, Cells ['l0', 'l1', 'l2', 'l3']", + "75, transduced ['l0', 'l4', 'l5', 'l6']", + "76, with ['l1', 'l4', 'l7', 'l8']", + "77, ARAF-S214P ['l2', 'l5', 'l7', 'l9']", + "100, trametinib. ['l3', 'l6', 'l8', 'l9', 'l10']", + "117, zebrafish ['l11', 'l12', 'l13']", + "118, model, ['l10', 'l11', 'l14', 'l15']", + "127, MEK ['l12', 'l14', 'l16']", + "128, inhibitor. ['l13', 'l15', 'l16']", + "137, MEK ['l17']", + "138, inhibitor ['l17']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "ARAF-S214P" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Cells" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "trametinib." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "trametinib.", + "MEK", + "inhibitor." + ] + }, + "context": { + "val": "organism", + "words": [ + "model,", + "zebrafish" + ] + } + } + ] + }, + { + "PMID": "31235964", + "TEXT": "The human gut microbiome is linked to many states of human health and disease1. The metabolic repertoire of the gut microbiome is vast, but the health implications of these bacterial pathways are poorly understood. In this study, we identify a link between members of the genus Veillonella and exercise performance. We observed an increase in Veillonella relative abundance in marathon runners postmarathon and isolated a strain of Veillonella atypica from stool samples. Inoculation of this strain into mice significantly increased exhaustive treadmill run time. Veillonella utilize lactate as their sole carbon source, which prompted us to perform a shotgun metagenomic analysis in a cohort of elite athletes, finding that every gene in a major pathway metabolizing lactate to propionate is at higher relative abundance postexercise. Using 13C3-labeled lactate in mice, we demonstrate that serum lactate crosses the epithelial barrier into the lumen of the gut. We also show that intrarectal instillation of propionate is sufficient to reproduce the increased treadmill run time performance observed with V. atypica gavage. Taken together, these studies reveal that V. atypica improves run time via its metabolic conversion of exercise-induced lactate into propionate, thereby identifying a natural, microbiome-encoded enzymatic process that enhances athletic performance.", + "TAG_DATA": [ + "77, mice {'context': 'B-organism'}", + "129, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31110349", + "TEXT": "With an estimated 160,000 deaths in 2018, lung cancer is the most common cause of cancer death in the United States1. Lung cancer screening using low-dose computed tomography has been shown to reduce mortality by 20-43% and is now included in US screening guidelines1-6. Existing challenges include inter-grader variability and high false-positive and false-negative rates7-10. We propose a deep learning algorithm that uses a patient's current and prior computed tomography volumes to predict the risk of lung cancer. Our model achieves a state-of-the-art performance (94.4% area under the curve) on 6,716 National Lung Cancer Screening Trial cases, and performs similarly on an independent clinical validation set of 1,139 cases. We conducted two reader studies. When prior computed tomography imaging was not available, our model outperformed all six radiologists with absolute reductions of 11% in false positives and 5% in false negatives. Where prior computed tomography imaging was available, the model performance was on-par with the same radiologists. This creates an opportunity to optimize the screening process via computer assistance and automation. While the vast majority of patients remain unscreened, we show the potential for deep learning models to increase the accuracy, consistency and adoption of lung cancer screening worldwide.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31068712", + "TEXT": "A 15-year-old patient with cystic fibrosis with a disseminated Mycobacterium abscessus infection was treated with a three-phage cocktail following bilateral lung transplantation. Effective lytic phage derivatives that efficiently kill the infectious M. abscessus strain were developed by genome engineering and forward genetics. Intravenous phage treatment was well tolerated and associated with objective clinical improvement, including sternal wound closure, improved liver function, and substantial resolution of infected skin nodules.", + "TAG_DATA": [ + "2, patient {'context': 'I-patient'}", + "59, liver {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "2, patient ['l0', 'l1', 'l2']", + "20, lung ['l0', 'l3', 'l4']", + "21, transplantation. ['l1', 'l3', 'l5']", + "59, liver ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31061540", + "TEXT": "Owing to recent medical and technological advances in neonatal care, infants born extremely premature have increased survival rates1,2. After birth, these infants are at high risk of hypoxic episodes because of lung immaturity, hypotension and lack of cerebral-flow regulation, and can develop a severe condition called encephalopathy of prematurity3. Over 80% of infants born before post-conception week 25 have moderate-to-severe long-term neurodevelopmental impairments4. The susceptible cell types in the cerebral cortex and the molecular mechanisms underlying associated gray-matter defects in premature infants remain unknown. Here we used human three-dimensional brain-region-specific organoids to study the effect of oxygen deprivation on corticogenesis. We identified specific defects in intermediate progenitors, a cortical cell type associated with the expansion of the human cerebral cortex, and showed that these are related to the unfolded protein response and changes. Moreover, we verified these findings in human primary cortical tissue and demonstrated that a small-molecule modulator of the unfolded protein response pathway can prevent the reduction in intermediate progenitors following hypoxia. We anticipate that this human cellular platform will be valuable for studying the environmental and genetic factors underlying injury in the developing human brain.", + "TAG_DATA": [ + "87, human {'context': 'B-organoid'}", + "88, three-dimensional {'context': 'I-organoid'}", + "89, brain-region-specific {'context': 'I-organoid'}", + "90, organoids {'context': 'I-organoid'}", + "139, human {'context': 'B-tissue/organ'}", + "140, primary {'context': 'I-tissue/organ'}", + "141, cortical {'context': 'I-tissue/organ'}", + "142, tissue {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "87, human ['l0', 'l1', 'l2']", + "88, three-dimensional ['l0', 'l3', 'l4']", + "89, brain-region-specific ['l1', 'l3', 'l5']", + "90, organoids ['l2', 'l4', 'l5']", + "139, human ['l6', 'l7', 'l8']", + "140, primary ['l6', 'l9', 'l10']", + "141, cortical ['l7', 'l9', 'l11']", + "142, tissue ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31011208", + "TEXT": "Anti-tumor immunity is driven by self versus non-self discrimination. Many immunotherapeutic approaches to cancer have taken advantage of tumor neoantigens derived from somatic mutations. Here, we demonstrate that gene fusions are a source of immunogenic neoantigens that can mediate responses to immunotherapy. We identified an exceptional responder with metastatic head and neck cancer who experienced a complete response to immune checkpoint inhibitor therapy, despite a low mutational load and minimal pre-treatment immune infiltration in the tumor. Using whole-genome sequencing and RNA sequencing, we identified a novel gene fusion and demonstrated that it produces a neoantigen that can specifically elicit a host cytotoxic T cell response. In a cohort of head and neck tumors with low mutation burden, minimal immune infiltration and prevalent gene fusions, we also identified gene fusion-derived neoantigens that generate cytotoxic T cell responses. Finally, analyzing additional datasets of fusion-positive cancers, including checkpoint-inhibitor-treated tumors, we found evidence of immune surveillance resulting in negative selective pressure against gene fusion-derived neoantigens. These findings highlight an important class of tumor-specific antigens and have implications for targeting gene fusion events in cancers that would otherwise be less poised for response to immunotherapy, including cancers with low mutational load and minimal immune infiltration.", + "TAG_DATA": [ + "48, metastatic {'context': 'B-neoplasm'}", + "49, head {'context': 'I-neoplasm'}", + "50, and {'context': 'I-neoplasm'}", + "51, neck {'context': 'I-neoplasm'}", + "52, cancer {'context': 'I-neoplasm'}", + "75, tumor. {'context': 'B-neoplasm'}", + "109, head {'context': 'B-neoplasm'}", + "110, and {'context': 'I-neoplasm'}", + "111, neck {'context': 'I-neoplasm'}", + "112, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "48, metastatic ['l0', 'l1', 'l2', 'l3', 'l4']", + "49, head ['l0', 'l5', 'l6', 'l7', 'l8']", + "50, and ['l1', 'l5', 'l9', 'l10', 'l11']", + "51, neck ['l2', 'l6', 'l9', 'l12', 'l13']", + "52, cancer ['l3', 'l7', 'l10', 'l12', 'l14']", + "75, tumor. ['l4', 'l8', 'l11', 'l13', 'l14']", + "109, head ['l15', 'l16', 'l17']", + "110, and ['l15', 'l18', 'l19']", + "111, neck ['l16', 'l18', 'l20']", + "112, tumors ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30911135", + "TEXT": "Re-expression of the paralogous γ-globin genes (HBG1/2) could be a universal strategy to ameliorate the severe β-globin disorders sickle cell disease (SCD) and β-thalassemia by induction of fetal hemoglobin (HbF, α2γ2)1. Previously, we and others have shown that core sequences at the BCL11A erythroid enhancer are required for repression of HbF in adult-stage erythroid cells but are dispensable in non-erythroid cells2-6. CRISPR-Cas9-mediated gene modification has demonstrated variable efficiency, specificity, and persistence in hematopoietic stem cells (HSCs). Here, we demonstrate that Cas9:sgRNA ribonucleoprotein (RNP)-mediated cleavage within a GATA1 binding site at the +58 BCL11A erythroid enhancer results in highly penetrant disruption of this motif, reduction of BCL11A expression, and induction of fetal γ-globin. We optimize conditions for selection-free on-target editing in patient-derived HSCs as a nearly complete reaction lacking detectable genotoxicity or deleterious impact on stem cell function. HSCs preferentially undergo non-homologous compared with microhomology-mediated end joining repair. Erythroid progeny of edited engrafting SCD HSCs express therapeutic levels of HbF and resist sickling, while those from patients with β-thalassemia show restored globin chain balance. Non-homologous end joining repair-based BCL11A enhancer editing approaching complete allelic disruption in HSCs is a practicable therapeutic strategy to produce durable HbF induction.", + "TAG_DATA": [ + "120, patient-derived {'context': 'B-cells'}", + "121, HSCs {'context': 'I-cells'}", + "134, stem {'context': 'B-cells'}", + "135, cell {'context': 'I-cells'}", + "137, HSCs {'context': 'B-cells'}", + "151, engrafting {'context': 'I-xenograft'}", + "152, SCD {'context': 'I-xenograft'}", + "153, HSCs {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "120, patient-derived ['l0', 'l1', 'l2']", + "121, HSCs ['l0', 'l3', 'l4']", + "134, stem ['l1', 'l3', 'l5', 'l6']", + "135, cell ['l2', 'l4', 'l5']", + "137, HSCs ['l6', 'l7']", + "151, engrafting ['l8', 'l9']", + "152, SCD ['l8', 'l10']", + "153, HSCs ['l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30911133", + "TEXT": "The hippocampus is one of the most affected areas in Alzheimer's disease (AD)1. Moreover, this structure hosts one of the most unique phenomena of the adult mammalian brain, namely, the addition of new neurons throughout life2. This process, called adult hippocampal neurogenesis (AHN), confers an unparalleled degree of plasticity to the entire hippocampal circuitry3,4. Nonetheless, direct evidence of AHN in humans has remained elusive. Thus, determining whether new neurons are continuously incorporated into the human dentate gyrus (DG) during physiological and pathological aging is a crucial question with outstanding therapeutic potential. By combining human brain samples obtained under tightly controlled conditions and state-of-the-art tissue processing methods, we identified thousands of immature neurons in the DG of neurologically healthy human subjects up to the ninth decade of life. These neurons exhibited variable degrees of maturation along differentiation stages of AHN. In sharp contrast, the number and maturation of these neurons progressively declined as AD advanced. These results demonstrate the persistence of AHN during both physiological and pathological aging in humans and provide evidence for impaired neurogenesis as a potentially relevant mechanism underlying memory deficits in AD that might be amenable to novel therapeutic strategies.", + "TAG_DATA": [ + "111, neurons {'context': 'I-cells'}", + "114, DG {'context': 'B-tissue/organ'}", + "128, neurons {'context': 'B-cells'}", + "148, neurons {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "111, neurons ['l0']", + "114, DG ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30903101", + "TEXT": "In the version of this article originally published, the key for Fig. 4c was incorrect. The symbols for 'Sham' and 'Den' were reversed. The error has been corrected in the PDF and HTML versions of the manuscript.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30858617", + "TEXT": "Stroke is the second leading cause of death worldwide and accounts for >2 million deaths annually in China1,2. Ischemic stroke (IS) and intracerebral hemorrhage (ICH) account for an equal number of deaths in China, despite a fourfold greater incidence of IS1,2. Stroke incidence and ICH proportion are higher in China than in Western populations3-5, despite having a lower mean low-density lipoprotein cholesterol (LDL-C) concentration. Observational studies reported weaker positive associations of LDL-C with IS than with coronary heart disease (CHD)6,7, but LDL-C-lowering trials demonstrated similar risk reductions for IS and CHD8-10. Mendelian randomization studies of LDL-C and IS have reported conflicting results11-13, and concerns about the excess risks of ICH associated with lowering LDL-C14,15 may have prevented the more widespread use of statins in China. We examined the associations of biochemically measured lipids with stroke in a nested case-control study in the China Kadoorie Biobank (CKB) and compared the risks for both stroke types associated with equivalent differences in LDL-C in Mendelian randomization analyses. The results demonstrated positive associations of LDL-C with IS and equally strong inverse associations with ICH, which were confirmed by genetic analyses and LDL-C-lowering trials. Lowering LDL-C is still likely to have net benefit for the prevention of overall stroke and cardiovascular disease in China.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30842678", + "TEXT": "Quantitative changes in leptin concentration lead to alterations in food intake and body weight, but the regulatory mechanisms that control leptin gene expression are poorly understood. Here we report that fat-specific and quantitative leptin expression is controlled by redundant cis elements and trans factors interacting with the proximal promoter together with a long noncoding RNA (lncOb). Diet-induced obese mice lacking lncOb show increased fat mass with reduced plasma leptin levels and lose weight after leptin treatment, whereas control mice do not. Consistent with this finding, large-scale genetic studies of humans reveal a significant association of single-nucleotide polymorphisms (SNPs) in the region of human lncOb with lower plasma leptin levels and obesity. These results show that reduced leptin gene expression can lead to a hypoleptinemic, leptin-responsive form of obesity and provide a framework for elucidating the pathogenic mechanism in the subset of obese patients with low endogenous leptin levels.", + "TAG_DATA": [ + "58, mice {'context': 'B-organism'}", + "59, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "60, lncOb {'perturbing_action': 'I-gene loss-of-function'}", + "78, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "58, mice ['l0', 'l1']", + "59, lacking ['l0', 'l2']", + "60, lncOb ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "lncOb" + ] + } + } + ] + }, + { + "PMID": "30833751", + "TEXT": "Cancer cells can evade immune surveillance through the expression of inhibitory ligands that bind their cognate receptors on immune effector cells. Expression of programmed death ligand 1 in tumor microenvironments is a major immune checkpoint for tumor-specific T cell responses as it binds to programmed cell death protein-1 on activated and dysfunctional T cells1. The activity of myeloid cells such as macrophages and neutrophils is likewise regulated by a balance between stimulatory and inhibitory signals. In particular, cell surface expression of the CD47 protein creates a 'don't eat me' signal on tumor cells by binding to SIRPα expressed on myeloid cells2-5. Using a haploid genetic screen, we here identify glutaminyl-peptide cyclotransferase-like protein (QPCTL) as a major component of the CD47-SIRPα checkpoint. Biochemical analysis demonstrates that QPCTL is critical for pyroglutamate formation on CD47 at the SIRPα binding site shortly after biosynthesis. Genetic and pharmacological interference with QPCTL activity enhances antibody-dependent cellular phagocytosis and cellular cytotoxicity of tumor cells. Furthermore, interference with QPCTL expression leads to a major increase in neutrophil-mediated killing of tumor cells in vivo. These data identify QPCTL as a novel target to interfere with the CD47 pathway and thereby augment antibody therapy of cancer.", + "TAG_DATA": [ + "147, activity {'perturbing_action': 'I-rnai/knockdown'}", + "148, enhances {'effect': 'B-positive'}", + "156, tumor {'context': 'B-transformed cells'}", + "157, cells. {'context': 'I-transformed cells'}", + "159, interference {'perturbing_action': 'B-rnai/knockdown'}", + "160, with {'perturbing_action': 'I-rnai/knockdown'}", + "161, QPCTL {'perturbing_action': 'I-rnai/knockdown'}", + "162, expression {'perturbing_action': 'I-rnai/knockdown'}", + "172, tumor {'context': 'B-transformed cells'}", + "173, cells {'context': 'I-transformed cells'}", + "174, in {'context': 'B-in vivo'}", + "175, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "146, QPCTL ['l0', 'l1', 'l2', 'l3']", + "147, activity ['l0', 'l4', 'l5', 'l6']", + "148, enhances ['l1', 'l4', 'l7', 'l8']", + "156, tumor ['l2', 'l5', 'l7', 'l9']", + "157, cells. ['l3', 'l6', 'l8', 'l9']", + "159, interference ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "160, with ['l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "161, QPCTL ['l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "162, expression ['l12', 'l18', 'l23', 'l28', 'l29', 'l30', 'l31']", + "172, tumor ['l13', 'l19', 'l24', 'l28', 'l32', 'l33', 'l34']", + "173, cells ['l14', 'l20', 'l25', 'l29', 'l32', 'l35', 'l36']", + "174, in ['l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l37']", + "175, vivo. ['l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "activity" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "activity", + "interference", + "with", + "QPCTL", + "expression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells.", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "interference", + "with", + "QPCTL", + "expression" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "30833748", + "TEXT": "Pancreatic ductal adenocarcinoma (PDA) was responsible for ~ 44,000 deaths in the United States in 2018 and is the epitome of a recalcitrant cancer driven by a pharmacologically intractable oncoprotein, KRAS1-4. Downstream of KRAS, the RAF→MEK→ERK signaling pathway plays a central role in pancreatic carcinogenesis5. However, paradoxically, inhibition of this pathway has provided no clinical benefit to patients with PDA6. Here we show that inhibition of KRAS→RAF→MEK→ERK signaling elicits autophagy, a process of cellular recycling that protects PDA cells from the cytotoxic effects of KRAS pathway inhibition. Mechanistically, inhibition of MEK1/2 leads to activation of the LKB1→AMPK→ULK1 signaling axis, a key regulator of autophagy. Furthermore, combined inhibition of MEK1/2 plus autophagy displays synergistic anti-proliferative effects against PDA cell lines in vitro and promotes regression of xenografted patient-derived PDA tumors in mice. The observed effect of combination trametinib plus chloroquine was not restricted to PDA as other tumors, including patient-derived xenografts (PDX) of NRAS-mutated melanoma and BRAF-mutated colorectal cancer displayed similar responses. Finally, treatment of a patient with PDA with the combination of trametinib plus hydroxychloroquine resulted in a partial, but nonetheless striking disease response. These data suggest that this combination therapy may represent a novel strategy to target RAS-driven cancers.", + "TAG_DATA": [ + "63, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "67, elicits {'effect': 'B-positive'}", + "68, autophagy, {'phenotype': 'B-autophagy'}", + "76, PDA {'context': 'B-transformed cells'}", + "77, cells {'context': 'I-transformed cells'}", + "87, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "88, of {'perturbing_action': 'I-pharmacological inhibition'}", + "89, MEK1/2 {'perturbing_action': 'I-pharmacological inhibition'}", + "105, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "106, of {'perturbing_action': 'I-pharmacological inhibition'}", + "107, MEK1/2 {'perturbing_action': 'I-pharmacological inhibition'}", + "115, PDA {'context': 'B-transformed cells'}", + "116, cell {'context': 'I-transformed cells'}", + "117, lines {'context': 'I-transformed cells'}", + "118, in {'context': 'B-in vitro'}", + "119, vitro {'context': 'I-in vitro'}", + "121, promotes {'effect': 'B-positive'}", + "122, regression {'phenotype': 'B-tumour regression'}", + "124, xenografted {'context': 'B-xenograft'}", + "125, patient-derived {'context': 'I-xenograft'}", + "126, PDA {'context': 'I-xenograft'}", + "127, tumors {'context': 'I-xenograft'}", + "129, mice. {'context': 'B-organism'}", + "145, tumors, {'context': 'B-neoplasm'}", + "147, patient-derived {'context': 'B-xenograft'}", + "148, xenografts {'context': 'I-xenograft'}", + "149, (PDX) {'context': 'I-xenograft'}", + "155, colorectal {'context': 'B-neoplasm'}", + "156, cancer {'context': 'I-neoplasm'}", + "164, patient {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "63, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "67, elicits ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "68, autophagy, ['l1', 'l15', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "76, PDA ['l2', 'l16', 'l24', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "77, cells ['l3', 'l17', 'l25', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "87, inhibition ['l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "88, of ['l46', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "89, MEK1/2 ['l47', 'l63', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "105, inhibition ['l48', 'l64', 'l79', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "106, of ['l49', 'l65', 'l80', 'l94', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "107, MEK1/2 ['l50', 'l66', 'l81', 'l95', 'l108', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "115, PDA ['l4', 'l18', 'l26', 'l34', 'l40', 'l51', 'l67', 'l82', 'l96', 'l109', 'l121', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "116, cell ['l5', 'l19', 'l27', 'l35', 'l41', 'l52', 'l68', 'l83', 'l97', 'l110', 'l122', 'l133', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "117, lines ['l6', 'l20', 'l28', 'l36', 'l42', 'l53', 'l69', 'l84', 'l98', 'l111', 'l123', 'l134', 'l144', 'l153', 'l154', 'l155', 'l156', 'l157']", + "118, in ['l7', 'l21', 'l29', 'l37', 'l43', 'l54', 'l70', 'l85', 'l99', 'l112', 'l124', 'l135', 'l145', 'l153', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "119, vitro ['l8', 'l22', 'l30', 'l38', 'l44', 'l55', 'l71', 'l86', 'l100', 'l113', 'l125', 'l136', 'l146', 'l154', 'l158', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "121, promotes ['l9', 'l23', 'l31', 'l39', 'l45', 'l56', 'l72', 'l87', 'l101', 'l114', 'l126', 'l137', 'l147', 'l155', 'l159', 'l166', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "122, regression ['l10', 'l57', 'l73', 'l88', 'l102', 'l115', 'l127', 'l138', 'l148', 'l160', 'l167', 'l173', 'l179', 'l180', 'l181', 'l182', 'l183']", + "124, xenografted ['l58', 'l74', 'l89', 'l103', 'l116', 'l128', 'l139', 'l161', 'l168', 'l174', 'l179', 'l184', 'l185', 'l186', 'l187']", + "125, patient-derived ['l11', 'l59', 'l75', 'l90', 'l104', 'l117', 'l129', 'l140', 'l149', 'l162', 'l169', 'l175', 'l180', 'l184', 'l188', 'l189', 'l190']", + "126, PDA ['l12', 'l60', 'l76', 'l91', 'l105', 'l118', 'l130', 'l141', 'l150', 'l156', 'l163', 'l170', 'l176', 'l181', 'l185', 'l188', 'l191', 'l192']", + "127, tumors ['l13', 'l32', 'l61', 'l77', 'l92', 'l106', 'l119', 'l131', 'l142', 'l151', 'l157', 'l164', 'l171', 'l177', 'l182', 'l186', 'l189', 'l191', 'l193']", + "129, mice. ['l14', 'l62', 'l78', 'l93', 'l107', 'l120', 'l132', 'l143', 'l152', 'l165', 'l172', 'l178', 'l183', 'l187', 'l190', 'l192', 'l193']", + "145, tumors, ['l194', 'l195', 'l196', 'l197', 'l198', 'l199']", + "147, patient-derived ['l194', 'l200', 'l201', 'l202', 'l203', 'l204']", + "148, xenografts ['l195', 'l200', 'l205', 'l206', 'l207', 'l208']", + "149, (PDX) ['l196', 'l201', 'l205', 'l209', 'l210', 'l211']", + "152, melanoma ['l197', 'l202', 'l206', 'l209', 'l212', 'l213']", + "155, colorectal ['l198', 'l203', 'l207', 'l210', 'l212', 'l214']", + "156, cancer ['l199', 'l204', 'l208', 'l211', 'l213', 'l214']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "MEK1/2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "elicits", + "promotes" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "MEK1/2" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "PDA", + "cells", + "cell", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "MEK1/2" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "MEK1/2" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "MEK1/2" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "patient-derived", + "PDA", + "tumors", + "xenografted" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "MEK1/2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "elicits", + "promotes" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "elicits", + "promotes" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "PDA", + "cells", + "cell", + "lines" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "elicits", + "promotes" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "PDA", + "cells", + "cell", + "lines" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + }, + "context": { + "val": "xenograft", + "words": [ + "tumors" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "PDA", + "cell" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenografted", + "patient-derived", + "PDA", + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenografted", + "patient-derived", + "PDA", + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "30742122", + "TEXT": "Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.", + "TAG_DATA": [ + "48, recurrent, {'context': 'B-neoplasm'}", + "49, surgically {'context': 'I-neoplasm'}", + "50, resectable {'context': 'I-neoplasm'}", + "51, glioblastoma. {'context': 'I-neoplasm'}", + "111, tumor, {'context': 'B-neoplasm'}", + "131, tumor {'context': 'B-neoplasm'}", + "133, enhanced {'effect': 'B-positive'}", + "134, clonal {'phenotype': 'B-colony formation'}", + "135, expansion {'phenotype': 'I-colony formation'}", + "137, T {'context': 'B-cells'}", + "138, cells, {'context': 'B-cells'}", + "143, peripheral {'context': 'B-cells'}", + "144, blood {'context': 'I-cells'}", + "145, T {'context': 'I-cells'}", + "146, cells {'context': 'I-cells'}", + "150, monocytic {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "48, recurrent, ['l0', 'l1', 'l2']", + "49, surgically ['l0', 'l3', 'l4']", + "50, resectable ['l1', 'l3', 'l5']", + "51, glioblastoma. ['l2', 'l4', 'l5']", + "131, tumor ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "133, enhanced ['l6', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "134, clonal ['l7', 'l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "135, expansion ['l8', 'l16', 'l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "137, T ['l9', 'l17', 'l24', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "138, cells, ['l10', 'l18', 'l25', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "143, peripheral ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l45', 'l46', 'l47', 'l48']", + "144, blood ['l12', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l49', 'l50']", + "145, T ['l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l49', 'l51']", + "146, cells ['l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "150, monocytic ['l48']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonal", + "expansion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonal", + "expansion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells,", + "peripheral", + "blood", + "cells" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "clonal", + "expansion" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells,", + "peripheral", + "blood", + "cells" + ] + } + } + ] + }, + { + "PMID": "30692700", + "TEXT": "In the version of this article originally published, there was an error in the legend for Extended Data Fig. 7. The legend for panel f was originally: \"f, FACS analysis of IL7R-, CD62L- and CD45RA- expression on TRAC-1928ζ and TRAC-1XX CAR T cells at day 63 post CAR infusion (representative for at least n = 3 mice per group in one independent experiment).\" The legend should have been: \"f, FACS analysis of IL7R+, CD62L+ and CD45RA+ expression on TRAC-1928ζ and TRAC-1XX CAR T cells at day 63 post CAR infusion (representative for at least n = 3 mice per group in one independent experiment).\" The error has been corrected in the HTML and PDF versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30692697", + "TEXT": "Current non-invasive prenatal screening is targeted toward the detection of chromosomal abnormalities in the fetus1,2. However, screening for many dominant monogenic disorders associated with de novo mutations is not available, despite their relatively high incidence3. Here we report on the development and validation of, and early clinical experience with, a new approach for non-invasive prenatal sequencing for a panel of causative genes for frequent dominant monogenic diseases. Cell-free DNA (cfDNA) extracted from maternal plasma was barcoded, enriched, and then analyzed by next-generation sequencing (NGS) for targeted regions. Low-level fetal variants were identified by a statistical analysis adjusted for NGS read count and fetal fraction. Pathogenic or likely pathogenic variants were confirmed by a secondary amplicon-based test on cfDNA. Clinical tests were performed on 422 pregnancies with or without abnormal ultrasound findings or family history. Follow-up studies on cases with available outcome results confirmed 20 true-positive, 127 true-negative, zero false-positive, and zero-false negative results. The initial clinical study demonstrated that this non-invasive test can provide valuable molecular information for the detection of a wide spectrum of dominant monogenic diseases, complementing current screening for aneuploidies or carrier screening for recessive disorders.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30643290", + "TEXT": "Major depressive disorder is a devastating psychiatric disease that afflicts up to 17% of the world's population. Postmortem brain analyses and imaging studies of patients with depression have implicated basal lateral amygdala (BLA) dysfunction in the pathophysiology of depression. However, the circuit and molecular mechanisms through which BLA neurons modulate depressive behavior are largely uncharacterized. Here, in mice, we identified that BLA cholecystokinin (CCK) glutamatergic neurons mediated negative reinforcement via D2 medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and that chronic social defeat selectively potentiated excitatory transmission of the CCKBLA-D2NAc circuit in susceptible mice via reduction of presynaptic cannabinoid type-1 receptor (CB1R). Knockdown of CB1R in the CCKBLA-D2NAc circuit elevated synaptic activity and promoted stress susceptibility. Notably, selective inhibition of the CCKBLA-D2NAc circuit or administration of synthetic cannabinoids in the NAc was sufficient to produce antidepressant-like effects. Overall, our studies reveal the circuit and molecular mechanisms of depression.", + "TAG_DATA": [ + "57, mice, {'context': 'B-organism'}", + "95, mice {'context': 'B-organism'}", + "104, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "105, of {'perturbing_action': 'I-rnai/knockdown'}", + "106, CB1R {'perturbing_action': 'I-rnai/knockdown'}", + "107, in {'perturbing_action': 'I-rnai/knockdown'}", + "108, the {'perturbing_action': 'I-rnai/knockdown'}", + "109, CCKBLA-D2NAc {'perturbing_action': 'I-rnai/knockdown'}", + "110, circuit {'perturbing_action': 'I-rnai/knockdown'}", + "119, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "120, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "121, of {'perturbing_action': 'I-pharmacological inhibition'}", + "122, the {'perturbing_action': 'I-pharmacological inhibition'}", + "123, CCKBLA-D2NAc {'perturbing_action': 'I-pharmacological inhibition'}", + "124, circuit {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "104, Knockdown ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "105, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "106, CB1R ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "107, in ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "108, the ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "109, CCKBLA-D2NAc ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "110, circuit ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "119, selective ['l21', 'l22', 'l23', 'l24', 'l25']", + "120, inhibition ['l21', 'l26', 'l27', 'l28', 'l29']", + "121, of ['l22', 'l26', 'l30', 'l31', 'l32']", + "122, the ['l23', 'l27', 'l30', 'l33', 'l34']", + "123, CCKBLA-D2NAc ['l24', 'l28', 'l31', 'l33', 'l35']", + "124, circuit ['l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30643289", + "TEXT": "There has been a striking generational increase in life-threatening food allergies in Westernized societies1,2. One hypothesis to explain this rising prevalence is that twenty-first century lifestyle practices, including misuse of antibiotics, dietary changes, and higher rates of Caesarean birth and formula feeding have altered intestinal bacterial communities; early-life alterations may be particularly detrimental3,4. To better understand how commensal bacteria regulate food allergy in humans, we colonized germ-free mice with feces from healthy or cow's milk allergic (CMA) infants5. We found that germ-free mice colonized with bacteria from healthy, but not CMA, infants were protected against anaphylactic responses to a cow's milk allergen. Differences in bacterial composition separated the healthy and CMA populations in both the human donors and the colonized mice. Healthy and CMA colonized mice also exhibited unique transcriptome signatures in the ileal epithelium. Correlation of ileal bacteria with genes upregulated in the ileum of healthy or CMA colonized mice identified a clostridial species, Anaerostipes caccae, that protected against an allergic response to food. Our findings demonstrate that intestinal bacteria are critical for regulating allergic responses to dietary antigens and suggest that interventions that modulate bacterial communities may be therapeutically relevant for food allergy.", + "TAG_DATA": [ + "66, germ-free {'context': 'B-organism'}", + "67, mice {'context': 'I-organism'}", + "81, germ-free {'context': 'B-organism'}", + "82, mice {'context': 'I-organism'}", + "120, mice. {'context': 'B-organism'}", + "125, mice {'context': 'B-organism'}", + "150, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "66, germ-free ['l0']", + "67, mice ['l0']", + "81, germ-free ['l1']", + "82, mice ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30643287", + "TEXT": "Primary tumors may create the premetastatic niche in secondary organs for subsequent metastasis. Humoral immunity contributes to the progression of certain cancers, but the roles of B cells and their derived antibodies in premetastatic niche formation are poorly defined. Using a mouse model of spontaneous lymph node metastasis of breast cancer, we show that primary tumors induced B cell accumulation in draining lymph nodes. These B cells selectively promoted lymph node metastasis by producing pathogenic IgG that targeted glycosylated membrane protein HSPA4, and activated the HSPA4-binding protein ITGB5 and the downstream Src/NF-κB pathway in tumor cells for CXCR4/SDF1α-axis-mediated metastasis. High serum anti-HSPA4 IgG was correlated with high tumor HSPA4 expression and poor prognosis of breast cancer subjects. Our findings identify a key role for tumor-educated B cells and their derived antibodies in lymph node premetastatic niche formation, providing potential targets for cancer intervention.", + "TAG_DATA": [ + "41, mouse {'context': 'B-organism'}", + "42, model {'context': 'I-organism'}", + "54, primary {'context': 'B-neoplasm'}", + "55, tumors {'context': 'I-neoplasm'}", + "57, B {'context': 'B-cells'}", + "58, cell {'context': 'I-cells'}", + "61, draining {'context': 'B-tissue/organ'}", + "62, lymph {'context': 'I-tissue/organ'}", + "63, nodes. {'context': 'I-tissue/organ'}", + "65, B {'context': 'B-cells'}", + "66, cells {'context': 'I-cells'}", + "68, promoted {'effect': 'B-positive'}", + "69, lymph {'phenotype': 'B-metastasis'}", + "70, node {'phenotype': 'I-metastasis'}", + "71, metastasis {'phenotype': 'I-metastasis'}", + "94, tumor {'context': 'B-transformed cells'}", + "95, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "41, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "42, model ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "54, primary ['l1', 'l6', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "55, tumors ['l2', 'l7', 'l11', 'l19', 'l20', 'l21', 'l22', 'l23']", + "57, B ['l3', 'l8', 'l12', 'l19', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "58, cell ['l4', 'l9', 'l13', 'l20', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "61, draining ['l14', 'l21', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "62, lymph ['l15', 'l22', 'l26', 'l31', 'l35', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "63, nodes. ['l5', 'l10', 'l16', 'l23', 'l27', 'l32', 'l36', 'l43', 'l50', 'l51']", + "65, B ['l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "66, cells ['l37', 'l44', 'l52', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "68, promoted ['l38', 'l45', 'l53', 'l59', 'l65', 'l66', 'l67', 'l68', 'l69']", + "69, lymph ['l39', 'l46', 'l54', 'l60', 'l65', 'l70', 'l71', 'l72', 'l73']", + "70, node ['l17', 'l28', 'l33', 'l40', 'l47', 'l50', 'l55', 'l61', 'l66', 'l70', 'l74', 'l75', 'l76']", + "71, metastasis ['l18', 'l29', 'l34', 'l41', 'l48', 'l51', 'l56', 'l62', 'l67', 'l71', 'l74', 'l77', 'l78']", + "94, tumor ['l57', 'l63', 'l68', 'l72', 'l75', 'l77', 'l79']", + "95, cells ['l42', 'l49', 'l58', 'l64', 'l69', 'l73', 'l76', 'l78', 'l79']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "primary" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "node", + "metastasis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "B", + "cell", + "cells" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "node", + "metastasis", + "lymph" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "draining", + "lymph" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "draining", + "lymph", + "nodes." + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "lymph", + "node", + "metastasis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "B", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "lymph", + "node", + "metastasis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "lymph", + "node", + "metastasis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + } + ] + }, + { + "PMID": "30617325", + "TEXT": "Defective brain hormonal signaling has been associated with Alzheimer's disease (AD), a disorder characterized by synapse and memory failure. Irisin is an exercise-induced myokine released on cleavage of the membrane-bound precursor protein fibronectin type III domain-containing protein 5 (FNDC5), also expressed in the hippocampus. Here we show that FNDC5/irisin levels are reduced in AD hippocampi and cerebrospinal fluid, and in experimental AD models. Knockdown of brain FNDC5/irisin impairs long-term potentiation and novel object recognition memory in mice. Conversely, boosting brain levels of FNDC5/irisin rescues synaptic plasticity and memory in AD mouse models. Peripheral overexpression of FNDC5/irisin rescues memory impairment, whereas blockade of either peripheral or brain FNDC5/irisin attenuates the neuroprotective actions of physical exercise on synaptic plasticity and memory in AD mice. By showing that FNDC5/irisin is an important mediator of the beneficial effects of exercise in AD models, our findings place FNDC5/irisin as a novel agent capable of opposing synapse failure and memory impairment in AD.", + "TAG_DATA": [ + "63, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "64, of {'perturbing_action': 'I-rnai/knockdown'}", + "65, brain {'perturbing_action': 'I-rnai/knockdown'}", + "66, FNDC5/irisin {'perturbing_action': 'I-rnai/knockdown'}", + "76, mice. {'context': 'B-organism'}", + "78, boosting {'perturbing_action': 'B-gene gain-of-function'}", + "79, brain {'perturbing_action': 'I-gene gain-of-function'}", + "80, levels {'perturbing_action': 'I-gene gain-of-function'}", + "81, of {'perturbing_action': 'I-gene gain-of-function'}", + "82, FNDC5/irisin {'perturbing_action': 'I-gene gain-of-function'}", + "89, AD {'context': 'B-organism'}", + "90, mouse {'context': 'I-organism'}", + "91, models. {'context': 'I-organism'}", + "92, Peripheral {'perturbing_action': 'B-gene gain-of-function'}", + "93, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "94, of {'perturbing_action': 'I-gene gain-of-function'}", + "95, FNDC5/irisin {'perturbing_action': 'I-gene gain-of-function'}", + "101, of {'perturbing_action': 'I-rnai/knockdown'}", + "104, or {'perturbing_action': 'I-rnai/knockdown'}", + "105, brain {'perturbing_action': 'I-rnai/knockdown'}", + "106, FNDC5/irisin {'perturbing_action': 'I-rnai/knockdown'}", + "120, AD {'context': 'B-organism'}", + "121, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "63, Knockdown ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "64, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "65, brain ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "66, FNDC5/irisin ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21', 'l22']", + "76, mice. ['l3', 'l9', 'l14', 'l18']", + "78, boosting ['l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "79, brain ['l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "80, levels ['l24', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "81, of ['l19', 'l25', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "82, FNDC5/irisin ['l26', 'l32', 'l37', 'l41', 'l45', 'l46', 'l47']", + "89, AD ['l4', 'l10', 'l15', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l48', 'l49']", + "90, mouse ['l5', 'l11', 'l16', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l50']", + "91, models. ['l6', 'l12', 'l17', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l50']", + "92, Peripheral ['l51', 'l52', 'l53', 'l54', 'l55']", + "93, overexpression ['l51', 'l56', 'l57', 'l58']", + "94, of ['l52', 'l56', 'l59', 'l60']", + "95, FNDC5/irisin ['l53', 'l57', 'l59']", + "101, of ['l61', 'l62', 'l63', 'l64', 'l65']", + "104, or ['l61', 'l66', 'l67', 'l68', 'l69']", + "105, brain ['l62', 'l66', 'l70', 'l71', 'l72']", + "106, FNDC5/irisin ['l63', 'l67', 'l70', 'l73', 'l74']", + "120, AD ['l54', 'l64', 'l68', 'l71', 'l73', 'l75']", + "121, mice. ['l55', 'l58', 'l60', 'l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "brain", + "FNDC5/irisin", + "or" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "AD", + "mouse", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "boosting", + "brain", + "levels", + "of", + "FNDC5/irisin", + "Peripheral", + "overexpression" + ] + }, + "context": { + "val": "organism", + "words": [ + "AD", + "mouse", + "models.", + "mice." + ] + } + } + ] + }, + { + "PMID": "30617323", + "TEXT": "Syndromic genetic conditions, in aggregate, affect 8% of the population1. Many syndromes have recognizable facial features2 that are highly informative to clinical geneticists3-5. Recent studies show that facial analysis technologies measured up to the capabilities of expert clinicians in syndrome identification6-9. However, these technologies identified only a few disease phenotypes, limiting their role in clinical settings, where hundreds of diagnoses must be considered. Here we present a facial image analysis framework, DeepGestalt, using computer vision and deep-learning algorithms, that quantifies similarities to hundreds of syndromes. DeepGestalt outperformed clinicians in three initial experiments, two with the goal of distinguishing subjects with a target syndrome from other syndromes, and one of separating different genetic subtypes in Noonan syndrome. On the final experiment reflecting a real clinical setting problem, DeepGestalt achieved 91% top-10 accuracy in identifying the correct syndrome on 502 different images. The model was trained on a dataset of over 17,000 images representing more than 200 syndromes, curated through a community-driven phenotyping platform. DeepGestalt potentially adds considerable value to phenotypic evaluations in clinical genetics, genetic testing, research and precision medicine.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30510257", + "TEXT": "Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.", + "TAG_DATA": [ + "81, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "82, of {'perturbing_action': 'I-gene gain-of-function'}", + "83, miR-203, {'perturbing_action': 'I-gene gain-of-function'}", + "102, induces {'effect': 'B-positive'}", + "104, cell {'phenotype': 'B-cell death'}", + "105, death, {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "81, overexpression ['l0', 'l1', 'l2', 'l3', 'l4']", + "82, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "83, miR-203, ['l1', 'l5', 'l9', 'l10', 'l11']", + "102, induces ['l2', 'l6', 'l9', 'l12', 'l13']", + "104, cell ['l3', 'l7', 'l10', 'l12', 'l14']", + "105, death, ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "miR-203," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "miR-203," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + } + ] + }, + { + "PMID": "30510256", + "TEXT": "The melanoma genome is dominated by ultraviolet radiation (UVR)-induced mutations. Their relevance in disease progression is unknown. Here we classify melanomas by mutation signatures and identify ten recurrently mutated UVR signature genes that predict patient survival. We validate these findings in primary human melanomas; in mice we show that this signature is imprinted by short-wavelength UVR and that four exposures to UVR are sufficient to accelerate melanomagenesis.", + "TAG_DATA": [ + "41, primary {'context': 'B-neoplasm'}", + "42, human {'context': 'I-neoplasm'}", + "43, melanomas; {'context': 'I-neoplasm'}", + "45, mice {'context': 'B-organism'}", + "65, accelerate {'effect': 'B-positive'}", + "66, melanomagenesis. {'phenotype': 'B-tumourigenesis'}" + ], + "LINK_DATA": [ + "41, primary ['l0', 'l1', 'l2']", + "42, human ['l0', 'l3', 'l4']", + "43, melanomas; ['l1', 'l3', 'l5']", + "45, mice ['l6', 'l7']", + "65, accelerate ['l2', 'l4', 'l5', 'l6', 'l8']", + "66, melanomagenesis. ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "primary", + "human", + "melanomas;" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerate" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerate" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "melanomagenesis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "accelerate" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "melanomagenesis." + ] + } + } + ] + }, + { + "PMID": "30510250", + "TEXT": "Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T cells at such tumor sites1. However, these efforts only have value if the intratumoral T cell receptor (TCR) repertoire of such cells is intrinsically tumor reactive, and this has not been established in an unbiased manner for most human cancers. To address this issue, we analyzed the intrinsic tumor reactivity of the intratumoral TCR repertoire of CD8+ T cells in ovarian and colorectal cancer-two tumor types for which T cell infiltrates form a positive prognostic marker2,3. Data obtained demonstrate that a capacity to recognize autologous tumor is limited to approximately 10% of intratumoral CD8+ T cells. Furthermore, in two of four patient samples tested, no tumor-reactive TCRs were identified, despite infiltration of their tumors by T cells. These data indicate that the intrinsic capacity of intratumoral T cells to recognize adjacent tumor tissue can be rare and variable, and suggest that clinical efforts to reactivate intratumoral T cells will benefit from approaches that simultaneously increase the quality of the intratumoral TCR repertoire.", + "TAG_DATA": [ + "86, ovarian {'context': 'B-neoplasm'}", + "87, and {'context': 'I-neoplasm'}", + "88, colorectal {'context': 'I-neoplasm'}", + "89, cancer-two {'context': 'I-neoplasm'}", + "139, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "86, ovarian ['l0', 'l1', 'l2']", + "87, and ['l0', 'l3', 'l4']", + "88, colorectal ['l1', 'l3', 'l5']", + "89, cancer-two ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30479380", + "TEXT": "In the version of this article originally published, an author was missing from the author list. Alexander J. Lazar should have been included between Jorge M. Blando and James P. Allison. The author has been added to the list, and the author contributions section has been updated to include Alexander J. Lazar's contribution to the study. The error has been corrected in the print, PDF and HTML versions of the manuscript.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30455436", + "TEXT": "Ibrutinib plus venetoclax is a highly effective combination in mantle cell lymphoma. However, strategies to enable the evaluation of therapeutic response are required. Our prospective analyses of patients within the AIM study revealed genomic profiles that clearly dichotomized responders and nonresponders. Mutations in ATM were present in most patients who achieved a complete response, while chromosome 9p21.1-p24.3 loss and/or mutations in components of the SWI-SNF chromatin-remodeling complex were present in all patients with primary resistance and two-thirds of patients with relapsed disease. Circulating tumor DNA analysis revealed that these alterations could be dynamically monitored, providing concurrent information on treatment response and tumor evolution. Functional modeling demonstrated that compromise of the SWI-SNF complex facilitated transcriptional upregulation of BCL2L1 (Bcl-xL) providing a selective advantage against ibrutinib plus venetoclax. Together these data highlight important insights into the molecular basis of therapeutic response and provide a model for real-time assessment of innovative targeted therapies.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30420754", + "TEXT": "We report the first case series of immune checkpoint inhibitors (ICI)-associated colitis successfully treated with fecal microbiota transplantation, with reconstitution of the gut microbiome and a relative increase in the proportion of regulatory T-cells within the colonic mucosa. These preliminary data provide evidence that modulation of the gut microbiome may abrogate ICI-associated colitis.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30420752", + "TEXT": "Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Leukemia stem cells (LSCs) drive the initiation and perpetuation of AML, are quantifiably associated with worse clinical outcomes, and often persist after conventional chemotherapy resulting in relapse1-5. In this report, we show that treatment of older patients with AML with the B cell lymphoma 2 (BCL-2) inhibitor venetoclax in combination with azacitidine results in deep and durable remissions and is superior to conventional treatments. We hypothesized that these promising clinical results were due to targeting LSCs. Analysis of LSCs from patients undergoing treatment with venetoclax + azacitidine showed disruption of the tricarboxylic acid (TCA) cycle manifested by decreased α-ketoglutarate and increased succinate levels, suggesting inhibition of electron transport chain complex II. In vitro modeling confirmed inhibition of complex II via reduced glutathionylation of succinate dehydrogenase. These metabolic perturbations suppress oxidative phosphorylation (OXPHOS), which efficiently and selectively targets LSCs. Our findings show for the first time that a therapeutic intervention can eradicate LSCs in patients with AML by disrupting the metabolic machinery driving energy metabolism, resulting in promising clinical activity in a patient population with historically poor outcomes.", + "TAG_DATA": [ + "47, older {'context': 'B-patient'}", + "48, patients {'context': 'I-patient'}", + "49, with {'context': 'I-patient'}", + "50, AML {'context': 'I-patient'}", + "53, B {'perturbing_action': 'B-pharmacological inhibition'}", + "56, 2 {'perturbing_action': 'I-pharmacological inhibition'}", + "57, (BCL-2) {'perturbing_action': 'I-pharmacological inhibition'}", + "58, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "90, LSCs {'context': 'B-transformed cells'}", + "92, patients {'context': 'B-patient'}", + "121, In {'context': 'B-in vitro'}", + "122, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "47, older ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "48, patients ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "49, with ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "50, AML ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "53, B ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "54, cell ['l4', 'l13', 'l21', 'l28', 'l34', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "55, lymphoma ['l5', 'l14', 'l22', 'l29', 'l35', 'l41', 'l47', 'l48', 'l49', 'l50', 'l51']", + "56, 2 ['l6', 'l15', 'l23', 'l30', 'l36', 'l42', 'l47', 'l52', 'l53', 'l54', 'l55']", + "57, (BCL-2) ['l7', 'l16', 'l24', 'l31', 'l37', 'l43', 'l48', 'l52', 'l56', 'l57', 'l58']", + "58, inhibitor ['l8', 'l17', 'l25', 'l32', 'l38', 'l44', 'l49', 'l53', 'l56', 'l59', 'l60']", + "90, LSCs ['l9', 'l18', 'l26', 'l33', 'l39', 'l45', 'l50', 'l54', 'l57', 'l59', 'l61']", + "92, patients ['l40', 'l46', 'l51', 'l55', 'l58', 'l60', 'l61']", + "121, In ['l62']", + "122, vitro ['l62']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "patient", + "words": [ + "older", + "patients", + "with", + "AML" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "B", + "2", + "(BCL-2)", + "inhibitor" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "B", + "2", + "(BCL-2)", + "inhibitor" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "LSCs" + ] + } + } + ] + }, + { + "PMID": "30397355", + "TEXT": "Tuberculosis kills more people than any other infectious disease. Three pivotal trials testing 4-month regimens failed to meet non-inferiority margins; however, approximately four-fifths of participants were cured. Through a pooled analysis of patient-level data with external validation, we identify populations eligible for 4-month treatment, define phenotypes that are hard to treat and evaluate the impact of adherence and dosing strategy on outcomes. In 3,405 participants included in analyses, baseline smear grade of 3+ relative to <2+, HIV seropositivity and adherence of ≤90% were significant risk factors for unfavorable outcome. Four-month regimens were non-inferior in participants with minimal disease defined by <2+ sputum smear grade or non-cavitary disease. A hard-to-treat phenotype, defined by high smear grades and cavitation, may require durations >6 months to cure all. Regimen duration can be selected in order to improve outcomes, providing a stratified medicine approach as an alternative to the 'one-size-fits-all' treatment currently used worldwide.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30397354", + "TEXT": "Here we performed a systematic search to identify breast-cancer-specific small noncoding RNAs, which we have collectively termed orphan noncoding RNAs (oncRNAs). We subsequently discovered that one of these oncRNAs, which originates from the 3' end of TERC, acts as a regulator of gene expression and is a robust promoter of breast cancer metastasis. This oncRNA, which we have named T3p, exerts its prometastatic effects by acting as an inhibitor of RISC complex activity and increasing the expression of the prometastatic genes NUPR1 and PANX2. Furthermore, we have shown that oncRNAs are present in cancer-cell-derived extracellular vesicles, raising the possibility that these circulating oncRNAs may also have a role in non-cell autonomous disease pathogenesis. Additionally, these circulating oncRNAs present a novel avenue for cancer fingerprinting using liquid biopsies.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30397353", + "TEXT": "Focal radiation therapy enhances systemic responses to anti-CTLA-4 antibodies in preclinical studies and in some patients with melanoma1-3, but its efficacy in inducing systemic responses (abscopal responses) against tumors unresponsive to CTLA-4 blockade remained uncertain. Radiation therapy promotes the activation of anti-tumor T cells, an effect dependent on type I interferon induction in the irradiated tumor4-6. The latter is essential for achieving abscopal responses in murine cancers6. The mechanisms underlying abscopal responses in patients treated with radiation therapy and CTLA-4 blockade remain unclear. Here we report that radiation therapy and CTLA-4 blockade induced systemic anti-tumor T cells in chemo-refractory metastatic non-small-cell lung cancer (NSCLC), where anti-CTLA-4 antibodies had failed to demonstrate significant efficacy alone or in combination with chemotherapy7,8. Objective responses were observed in 18% of enrolled patients, and 31% had disease control. Increased serum interferon-β after radiation and early dynamic changes of blood T cell clones were the strongest response predictors, confirming preclinical mechanistic data. Functional analysis in one responding patient showed the rapid in vivo expansion of CD8 T cells recognizing a neoantigen encoded in a gene upregulated by radiation, supporting the hypothesis that one explanation for the abscopal response is radiation-induced exposure of immunogenic mutations to the immune system.", + "TAG_DATA": [ + "99, metastatic {'context': 'B-neoplasm'}", + "100, non-small-cell {'context': 'I-neoplasm'}", + "101, lung {'context': 'I-neoplasm'}", + "102, cancer {'context': 'I-neoplasm'}", + "103, (NSCLC), {'context': 'I-neoplasm'}", + "165, in {'context': 'B-in vivo'}", + "166, vivo {'context': 'B-in vivo'}", + "169, CD8 {'context': 'B-cells'}", + "170, T {'context': 'I-cells'}", + "171, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "99, metastatic ['l0', 'l1', 'l2', 'l3']", + "100, non-small-cell ['l0', 'l4', 'l5', 'l6']", + "101, lung ['l1', 'l4', 'l7', 'l8']", + "102, cancer ['l2', 'l5', 'l7', 'l9']", + "103, (NSCLC), ['l3', 'l6', 'l8', 'l9']", + "165, in ['l10', 'l11', 'l12', 'l13']", + "166, vivo ['l10', 'l14', 'l15', 'l16']", + "169, CD8 ['l11', 'l14', 'l17', 'l18']", + "170, T ['l12', 'l15', 'l17', 'l19']", + "171, cells ['l13', 'l16', 'l18', 'l19']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30374200", + "TEXT": "Preventing the immune escape of tumor cells by blocking inhibitory checkpoints, such as the interaction between programmed death ligand-1 (PD-L1) and programmed death-1 (PD-1) receptor, is a powerful anticancer approach. However, many patients do not respond to checkpoint blockade. Tumor PD-L1 expression is a potential efficacy biomarker, but the complex mechanisms underlying its regulation are not completely understood. Here, we show that the eukaryotic translation initiation complex, eIF4F, which binds the 5' cap of mRNAs, regulates the surface expression of interferon-γ-induced PD-L1 on cancer cells by regulating translation of the mRNA encoding the signal transducer and activator of transcription 1 (STAT1) transcription factor. eIF4F complex formation correlates with response to immunotherapy in human melanoma. Pharmacological inhibition of eIF4A, the RNA helicase component of eIF4F, elicits powerful antitumor immune-mediated effects via PD-L1 downregulation. Thus, eIF4A inhibitors, in development as anticancer drugs, may also act as cancer immunotherapies.", + "TAG_DATA": [ + "83, cancer {'context': 'B-transformed cells'}", + "84, cells {'context': 'I-transformed cells'}", + "114, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "115, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "116, of {'perturbing_action': 'I-pharmacological inhibition'}", + "117, eIF4A, {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "83, cancer ['l0']", + "84, cells ['l0']", + "114, Pharmacological ['l1', 'l2', 'l3']", + "115, inhibition ['l1', 'l4', 'l5']", + "116, of ['l2', 'l4', 'l6']", + "117, eIF4A, ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30374199", + "TEXT": "Mutationally activated BRAFV600E influences the behavior of different types of cells in the brain and leads to promotion of seizures as well as brain tumors, indicating how both can be pharmacologically targeted in the clinic.", + "TAG_DATA": [ + "1, activated {'perturbing_action': 'I-other'}", + "2, BRAFV600E {'perturbing_action': 'I-other'}", + "10, cells {'context': 'B-cells'}", + "13, brain {'context': 'B-tissue/organ'}", + "17, promotion {'effect': 'B-positive'}", + "23, brain {'context': 'B-neoplasm'}", + "24, tumors, {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "1, activated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "2, BRAFV600E ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "10, cells ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "11, in ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "12, the ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "13, brain ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "17, promotion ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "23, brain ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "24, tumors, ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "activated", + "BRAFV600E" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "activated", + "BRAFV600E" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "activated", + "BRAFV600E" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotion" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "activated", + "BRAFV600E" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "brain", + "tumors," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotion" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "brain" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotion" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "brain", + "tumors," + ] + } + } + ] + }, + { + "PMID": "30374197", + "TEXT": "The discovery of the highly efficient site-specific nuclease system CRISPR-Cas9 from Streptococcus pyogenes has galvanized the field of gene therapy1,2. The immunogenicity of Cas9 nuclease has been demonstrated in mice3,4. Preexisting immunity against therapeutic gene vectors or their cargo can decrease the efficacy of a potentially curative treatment and may pose significant safety issues3-6. S. pyogenes is a common cause for infectious diseases in humans, but it remains unclear whether it induces a T cell memory against the Cas9 nuclease7,8. Here, we show the presence of a preexisting ubiquitous effector T cell response directed toward the most widely used Cas9 homolog from S. pyogenes (SpCas9) within healthy humans. We characterize SpCas9-reactive T cells within the CD4/CD8 compartments for multi-effector potency, cytotoxicity, and lineage determination. In-depth analysis of SpCas9-reactive T cells reveals a high frequency of SpCas9-reactive regulatory T cells that can mitigate SpCas9-reactive effector T cell proliferation and function in vitro. Our results shed light on T cell-mediated immunity toward CRISPR-associated nucleases and offer a possible solution to overcome the problem of preexisting immunity.", + "TAG_DATA": [ + "128, T {'context': 'I-cells'}", + "129, cells {'context': 'I-cells'}", + "136, regulatory {'context': 'B-cells'}", + "137, T {'context': 'I-cells'}", + "138, cells {'context': 'I-cells'}", + "141, mitigate {'effect': 'B-negative'}", + "143, effector {'context': 'B-cells'}", + "144, T {'context': 'I-cells'}", + "145, cell {'context': 'I-cells'}", + "146, proliferation {'phenotype': 'B-proliferation'}", + "149, in {'context': 'B-in vitro'}", + "150, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "128, T ['l0', 'l1', 'l2']", + "129, cells ['l0', 'l3', 'l4']", + "136, regulatory ['l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "137, T ['l1', 'l3', 'l5', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "138, cells ['l2', 'l4', 'l6', 'l14', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "141, mitigate ['l7', 'l15', 'l22', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "143, effector ['l8', 'l16', 'l23', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "144, T ['l9', 'l17', 'l24', 'l30', 'l35', 'l40', 'l41', 'l42', 'l43']", + "145, cell ['l10', 'l18', 'l25', 'l31', 'l36', 'l40', 'l44', 'l45', 'l46']", + "146, proliferation ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l47', 'l48']", + "149, in ['l12', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l49']", + "150, vitro. ['l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l49']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "regulatory", + "T", + "cells", + "effector", + "cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "mitigate" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "regulatory", + "T", + "cells", + "effector", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "mitigate" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "mitigate" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "30374196", + "TEXT": "Tau and amyloid beta (Aβ) proteins accumulate along neuronal circuits in Alzheimer's disease. Unraveling the genetic background for the regional vulnerability of these proteinopathies can help in understanding the mechanisms of pathology progression. To that end, we developed a novel graph theory approach and used it to investigate the intersection of longitudinal Aβ and tau positron emission tomography imaging of healthy adult individuals and the genetic transcriptome of the Allen Human Brain Atlas. We identified distinctive pathways for tau and Aβ accumulation, of which the tau pathways correlated with cognitive levels. We found that tau propagation and Aβ propagation patterns were associated with a common genetic profile related to lipid metabolism, in which APOE played a central role, whereas the tau-specific genetic profile was classified as 'axon related' and the Aβ profile as 'dendrite related'. This study reveals distinct genetic profiles that may confer vulnerability to tau and Aβ in vivo propagation in the human brain.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30361511", + "TEXT": "In the version of this article originally published, there was an error in Fig. 1. In the neoadjuvant phase column, the n values for arms A and B were both reported to be 20. The n values for arms A and B were actually 12 and 11, respectively. Also, the URL underlying the accession code in the data availability section was incorrect. The URL was originally https://www.ebi.ac.uk/ega/studies/EGAS00001002698. It should have been https://www.ebi.ac.uk/ega/studies/EGAS00001003178. The errors have been corrected in the print, HTML and PDF versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30353100", + "TEXT": "In the version of this article originally published, Dimitry G. Sayenko's affiliations were not correct. The following affiliation for this author was missing: Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, USA. This affiliation has been added for the author, and the rest of the affiliations have been renumbered accordingly. The error has been corrected in the HTML and PDF versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30297912", + "TEXT": "Acute intermittent porphyria (AIP) results from haploinsufficiency of porphobilinogen deaminase (PBGD), the third enzyme in the heme biosynthesis pathway. Patients with AIP have neurovisceral attacks associated with increased hepatic heme demand. Phenobarbital-challenged mice with AIP recapitulate the biochemical and clinical characteristics of patients with AIP, including hepatic overproduction of the potentially neurotoxic porphyrin precursors. Here we show that intravenous administration of human PBGD (hPBGD) mRNA (encoded by the gene HMBS) encapsulated in lipid nanoparticles induces dose-dependent protein expression in mouse hepatocytes, rapidly normalizing urine porphyrin precursor excretion in ongoing attacks. Furthermore, hPBGD mRNA protected against mitochondrial dysfunction, hypertension, pain and motor impairment. Repeat dosing in AIP mice showed sustained efficacy and therapeutic improvement without evidence of hepatotoxicity. Finally, multiple administrations to nonhuman primates confirmed safety and translatability. These data provide proof-of-concept for systemic hPBGD mRNA as a potential therapy for AIP.", + "TAG_DATA": [ + "32, mice {'context': 'B-organism'}", + "79, mouse {'context': 'B-cells'}", + "80, hepatocytes, {'context': 'I-cells'}", + "105, AIP {'context': 'B-organism'}", + "106, mice {'context': 'I-organism'}", + "121, nonhuman {'context': 'B-organism'}", + "122, primates {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "32, mice ['l0', 'l1']", + "79, mouse ['l0', 'l2']", + "80, hepatocytes, ['l1', 'l2']", + "105, AIP ['l3']", + "106, mice ['l3']", + "121, nonhuman ['l4']", + "122, primates ['l4']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30297904", + "TEXT": "CRISPR-Cas-based genome editing holds great promise for targeting genetic disorders, including inborn errors of hepatocyte metabolism. Precise correction of disease-causing mutations in adult tissues in vivo, however, is challenging. It requires repair of Cas9-induced double-stranded DNA (dsDNA) breaks by homology-directed mechanisms, which are highly inefficient in nondividing cells. Here we corrected the disease phenotype of adult phenylalanine hydroxylase (Pah)enu2 mice, a model for the human autosomal recessive liver disease phenylketonuria (PKU)1, using recently developed CRISPR-Cas-associated base editors2-4. These systems enable conversion of C∙G to T∙A base pairs and vice versa, independent of dsDNA break formation and homology-directed repair (HDR). We engineered and validated an intein-split base editor, which allows splitting of the fusion protein into two parts, thereby circumventing the limited cargo capacity of adeno-associated virus (AAV) vectors. Intravenous injection of AAV-base editor systems resulted in Pahenu2 gene correction rates that restored physiological blood phenylalanine (L-Phe) levels below 120 µmol/l [5]. We observed mRNA correction rates up to 63%, restoration of phenylalanine hydroxylase (PAH) enzyme activity, and reversion of the light fur phenotype in Pahenu2 mice. Our findings suggest that targeting genetic diseases in vivo using AAV-mediated delivery of base-editing agents is feasible, demonstrating potential for therapeutic application.", + "TAG_DATA": [ + "59, mice, {'context': 'B-organism'}", + "174, Pahenu2 {'perturbing_action': 'B-other'}", + "175, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "174, Pahenu2 ['l0']", + "175, mice. ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Pahenu2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "30297903", + "TEXT": "In utero gene editing has the potential to prenatally treat genetic diseases that result in significant morbidity and mortality before or shortly after birth. We assessed the viral vector-mediated delivery of CRISPR-Cas9 or base editor 3 in utero, seeking therapeutic modification of Pcsk9 or Hpd in wild-type mice or the murine model of hereditary tyrosinemia type 1, respectively. We observed long-term postnatal persistence of edited cells in both models, with reduction of plasma PCSK9 and cholesterol levels following in utero Pcsk9 targeting and rescue of the lethal phenotype of hereditary tyrosinemia type 1 following in utero Hpd targeting. The results of this proof-of-concept work demonstrate the possibility of efficiently performing gene editing before birth, pointing to a potential new therapeutic approach for selected congenital genetic disorders.", + "TAG_DATA": [ + "47, mice {'context': 'B-organism'}", + "50, murine {'context': 'B-organism'}", + "51, model {'context': 'I-organism'}", + "65, cells {'context': 'B-cells'}", + "80, Pcsk9 {'perturbing_action': 'I-other'}", + "81, targeting {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "47, mice ['l0', 'l1']", + "50, murine ['l0', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "51, model ['l1', 'l2', 'l8', 'l9', 'l10']", + "65, cells ['l3', 'l8', 'l11', 'l12', 'l13', 'l14']", + "78, in ['l4', 'l11', 'l15', 'l16', 'l17']", + "79, utero ['l5', 'l12', 'l15', 'l18', 'l19']", + "80, Pcsk9 ['l6', 'l9', 'l13', 'l16', 'l18', 'l20']", + "81, targeting ['l7', 'l10', 'l14', 'l17', 'l19', 'l20']", + "94, in ['l21', 'l22']", + "96, Hpd ['l21', 'l23']", + "97, targeting. ['l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "murine", + "model" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Pcsk9", + "targeting" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Pcsk9", + "targeting" + ] + } + } + ] + }, + { + "PMID": "30297899", + "TEXT": "Impaired immunity in patients with late-stage cancer is not limited to antitumor responses, as demonstrated by poor vaccination protection and high susceptibility to infection1-3. This has been largely attributed to chemotherapy-induced impairment of innate immunity, such as neutropenia2, whereas systemic effects of tumors on hematopoiesis and adoptive immunity remain incompletely understood. Here we observed anemia associated with severe deficiency of CD8+ T cell responses against pathogens in treatment-naive mice bearing large tumors. Specifically, we identify CD45+ erythroid progenitor cells (CD71+TER119+; EPCs) as robust immunosuppressors. CD45+ EPCs, induced by tumor growth-associated extramedullary hematopoiesis, accumulate in the spleen to become a major population, outnumbering regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). The CD45+ EPC transcriptome closely resembles that of MDSCs, and, like MDSCs, reactive oxygen species production is a major mechanism underlying CD45+ EPC-mediated immunosuppression. Similarly, an immunosuppressive CD45+ EPC population was detected in patients with cancer who have anemia. These findings identify a major population of immunosuppressive cells that likely contributes to the impaired T cell responses commonly observed in patients with advanced cancer.", + "TAG_DATA": [ + "60, CD8+ {'context': 'B-cells'}", + "61, T {'context': 'I-cells'}", + "62, cell {'context': 'I-cells'}", + "67, treatment-naive {'context': 'B-organism'}", + "68, mice {'context': 'I-organism'}", + "95, spleen {'context': 'B-tissue/organ'}", + "102, regulatory {'context': 'B-cells'}", + "103, T {'context': 'I-cells'}", + "104, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "60, CD8+ ['l0', 'l1', 'l2', 'l3']", + "61, T ['l0', 'l4', 'l5', 'l6']", + "62, cell ['l1', 'l4', 'l7', 'l8']", + "67, treatment-naive ['l2', 'l5', 'l7', 'l9']", + "68, mice ['l3', 'l6', 'l8', 'l9']", + "95, spleen ['l10', 'l11', 'l12']", + "102, regulatory ['l10', 'l13', 'l14']", + "103, T ['l11', 'l13', 'l15']", + "104, cells ['l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30275569", + "TEXT": "We identified genetic mutations in CD19 and loss of heterozygosity at the time of CD19- relapse to chimeric antigen receptor (CAR) therapy. The mutations are present in the vast majority of resistant tumor cells and are predicted to lead to a truncated protein with a nonfunctional or absent transmembrane domain and consequently to a loss of surface antigen. This irreversible loss of CD19 advocates for an alternative targeting or combination CAR approach.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30275566", + "TEXT": "Chronic kidney disease (CKD), a condition in which the kidneys are unable to clear waste products, affects 700 million people globally. Genome-wide association studies (GWASs) have identified sequence variants for CKD; however, the biological basis of these GWAS results remains poorly understood. To address this issue, we created an expression quantitative trait loci (eQTL) atlas for the glomerular and tubular compartments of the human kidney. Through integrating the CKD GWAS with eQTL, single-cell RNA sequencing and regulatory region maps, we identified novel genes for CKD. Putative causal genes were enriched for proximal tubule expression and endolysosomal function, where DAB2, an adaptor protein in the TGF-β pathway, formed a central node. Functional experiments confirmed that reducing Dab2 expression in renal tubules protected mice from CKD. In conclusion, compartment-specific eQTL analysis is an important avenue for the identification of novel genes and cellular pathways involved in CKD development and thus potential new opportunities for its treatment.", + "TAG_DATA": [ + "114, reducing {'perturbing_action': 'B-gene loss-of-function'}", + "115, Dab2 {'perturbing_action': 'I-rnai/knockdown'}", + "116, expression {'perturbing_action': 'I-rnai/knockdown'}", + "121, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "114, reducing ['l0', 'l1', 'l2']", + "115, Dab2 ['l0', 'l3', 'l4']", + "116, expression ['l1', 'l3', 'l5']", + "121, mice ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "reducing" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Dab2", + "expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "30250143", + "TEXT": "Mutations in the mitochondrial DNA (mtDNA) are responsible for several metabolic disorders, commonly involving muscle and the central nervous system1. Because of the critical role of mtDNA in oxidative phosphorylation, the majority of pathogenic mtDNA mutations are heteroplasmic, co-existing with wild-type molecules1. Using a mouse model with a heteroplasmic mtDNA mutation2, we tested whether mitochondrial-targeted TALENs (mitoTALENs)3,4 could reduce the mutant mtDNA load in muscle and heart. AAV9-mitoTALEN was administered via intramuscular, intravenous, and intraperitoneal injections. Muscle and heart were efficiently transduced and showed a robust reduction in mutant mtDNA, which was stable over time. The molecular defect, namely a decrease in transfer RNAAla levels, was restored by the treatment. These results showed that mitoTALENs, when expressed in affected tissues, could revert disease-related phenotypes in mice.", + "TAG_DATA": [ + "44, mouse {'context': 'B-organism'}", + "45, model {'context': 'I-organism'}", + "76, Muscle {'context': 'B-tissue/organ'}", + "78, heart {'context': 'B-tissue/organ'}", + "125, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "44, mouse ['l0']", + "45, model ['l0']", + "76, Muscle ['l1']", + "78, heart ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30250141", + "TEXT": "Brain-computer interface (BCI) neurotechnology has the potential to reduce disability associated with paralysis by translating neural activity into control of assistive devices1-9. Surveys of potential end-users have identified key BCI system features10-14, including high accuracy, minimal daily setup, rapid response times, and multifunctionality. These performance characteristics are primarily influenced by the BCI's neural decoding algorithm1,15, which is trained to associate neural activation patterns with intended user actions. Here, we introduce a new deep neural network16 decoding framework for BCI systems enabling discrete movements that addresses these four key performance characteristics. Using intracortical data from a participant with tetraplegia, we provide offline results demonstrating that our decoder is highly accurate, sustains this performance beyond a year without explicit daily retraining by combining it with an unsupervised updating procedure3,17-20, responds faster than competing methods8, and can increase functionality with minimal retraining by using a technique known as transfer learning21. We then show that our participant can use the decoder in real-time to reanimate his paralyzed forearm with functional electrical stimulation (FES), enabling accurate manipulation of three objects from the grasp and release test (GRT)22. These results demonstrate that deep neural network decoders can advance the clinical translation of BCI technology.", + "TAG_DATA": [ + "163, forearm {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30224756", + "TEXT": "Pediatric brain tumors are highly associated with epileptic seizures1. However, their epileptogenic mechanisms remain unclear. Here, we show that the oncogenic BRAF somatic mutation p.Val600Glu (V600E) in developing neurons underlies intrinsic epileptogenicity in ganglioglioma, one of the leading causes of intractable epilepsy2. To do so, we developed a mouse model harboring the BRAFV600E somatic mutation during early brain development to reflect the most frequent mutation, as well as the origin and timing thereof. Therein, the BRAFV600E mutation arising in progenitor cells during brain development led to the acquisition of intrinsic epileptogenic properties in neuronal lineage cells, whereas tumorigenic properties were attributed to high proliferation of glial lineage cells. RNA sequencing analysis of patient brain tissues with the mutation revealed that BRAFV600E-induced epileptogenesis is mediated by RE1-silencing transcription factor (REST), which is a regulator of ion channels and neurotransmitter receptors associated with epilepsy. Moreover, we found that seizures in mice were significantly alleviated by an FDA-approved BRAFV600E inhibitor, vemurafenib, as well as various genetic inhibitions of Rest. Accordingly, this study provides direct evidence of a BRAF somatic mutation contributing to the intrinsic epileptogenicity in pediatric brain tumors and suggests that BRAF and REST could be treatment targets for intractable epilepsy.", + "TAG_DATA": [ + "48, mouse {'context': 'B-organism'}", + "49, model {'context': 'I-organism'}", + "93, neuronal {'context': 'B-cells'}", + "94, lineage {'context': 'I-cells'}", + "95, cells, {'context': 'I-cells'}", + "97, tumorigenic {'phenotype': 'B-tumourigenesis'}", + "103, proliferation {'phenotype': 'B-proliferation'}", + "105, glial {'context': 'B-cells'}", + "106, lineage {'context': 'I-cells'}", + "107, cells. {'context': 'I-cells'}", + "148, mice {'context': 'B-organism'}", + "155, BRAFV600E {'perturbing_action': 'B-pharmacological inhibition'}", + "156, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "48, mouse ['l0', 'l1', 'l2', 'l3']", + "49, model ['l0', 'l4', 'l5', 'l6']", + "93, neuronal ['l1', 'l4', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "94, lineage ['l2', 'l5', 'l7', 'l13']", + "95, cells, ['l3', 'l6', 'l8', 'l13']", + "97, tumorigenic ['l9', 'l14', 'l15', 'l16', 'l17']", + "103, proliferation ['l10', 'l14', 'l18', 'l19', 'l20']", + "105, glial ['l15', 'l18', 'l21', 'l22']", + "106, lineage ['l11', 'l16', 'l19', 'l21', 'l23']", + "107, cells. ['l12', 'l17', 'l20', 'l22', 'l23']", + "148, mice ['l24', 'l25']", + "155, BRAFV600E ['l24', 'l26']", + "156, inhibitor, ['l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "neuronal", + "glial", + "lineage", + "cells." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenic" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neuronal", + "glial", + "lineage", + "cells." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BRAFV600E", + "inhibitor," + ] + } + } + ] + }, + { + "PMID": "30194411", + "TEXT": "Preconception cold-induced alterations of sperm DNA methylation result in offspring with altered brown adipose tissue and improved adaptation to overnutrition and hypothermia.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30150718", + "TEXT": "Glioblastoma is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the role of the epigenome in glioblastoma disease progression. Here, we present genome-scale maps of DNA methylation in matched primary and recurring glioblastoma tumors, using data from a highly annotated clinical cohort that was selected through a national patient registry. We demonstrate the feasibility of DNA methylation mapping in a large set of routinely collected FFPE samples, and we validate bisulfite sequencing as a multipurpose assay that allowed us to infer a range of different genetic, epigenetic, and transcriptional characteristics of the profiled tumor samples. On the basis of these data, we identified subtle differences between primary and recurring tumors, links between DNA methylation and the tumor microenvironment, and an association of epigenetic tumor heterogeneity with patient survival. In summary, this study establishes an open resource for dissecting DNA methylation heterogeneity in a genetically diverse and heterogeneous cancer, and it demonstrates the feasibility of integrating epigenomics, radiology, and digital pathology for a national cohort, thereby leveraging existing samples and data collected as part of routine clinical practice.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30111893", + "TEXT": "In the version of this article originally published, the y axis labels in Fig. 4b,d were incorrect. In Fig. 4b, the unit on the label was (ng mg-1). This should have been (ng/ml). In Fig. 4d, the y axis label was Serum Fst (ng ml-1). It should have been Serum insulin (ng/ml). The errors have been corrected in the HTML and PDF versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30104770", + "TEXT": "In the version of this article originally published, a grant was omitted from the Acknowledgements section. The following sentence should have been included: \"R.B.M. was supported by a Department of Veterans Affairs Merit Award (5I01BX003272).\" The error has been corrected in the HTML and PDF versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30104769", + "TEXT": "In the version of this article originally published, information regarding several funding sources was omitted from the Acknowledgements section. The following sentences should have been included: \"This work was supported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shots Program, the UT Lung SPORE 5 P50 CA07090, and the MD Anderson Cancer Center Support Grant P30CA01667. V.P is supported by R01CA155196-01A1 from the National Cancer Institute.\" Also, reference 18 was incorrect. The original reference was: Kim, E. S. et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov. 1, 44-53 (2011). It should have been: Papadimitrakopoulou, V. et al. The BATTLE-2 study: a biomarker-integrated targeted therapy study in previously treated patients with advanced non-small-cell lung cancer. J Clin. Oncol. 34, 3638-3647 (2016). The errors have been corrected in the HTML and PDF versions of this article.", + "TAG_DATA": [ + "121, advanced {'context': 'B-neoplasm'}", + "122, non-small-cell {'context': 'I-neoplasm'}", + "123, lung {'context': 'I-neoplasm'}", + "124, cancer. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "121, advanced ['l0', 'l1', 'l2']", + "122, non-small-cell ['l0', 'l3', 'l4']", + "123, lung ['l1', 'l3', 'l5']", + "124, cancer. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30087436", + "TEXT": "In the version of this article originally published, the bars in the mean temperature graph in Fig. 1a were incorrectly aligned. The left-most bar should have been aligned with the Apr label on the projected month of conception axis. The error has been corrected in the print, PDF and HTML versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30082870", + "TEXT": "Although programmed death-ligand 1-programmed death 1 (PD-L1-PD-1) inhibitors are broadly efficacious, improved outcomes have been observed in patients with high PD-L1 expression or high tumor mutational burden (TMB). PD-L1 testing is required for checkpoint inhibitor monotherapy in front-line non-small-cell lung cancer (NSCLC). However, obtaining adequate tumor tissue for molecular testing in patients with advanced disease can be challenging. Thus, an unmet medical need exists for diagnostic approaches that do not require tissue to identify patients who may benefit from immunotherapy. Here, we describe a novel, technically robust, blood-based assay to measure TMB in plasma (bTMB) that is distinct from tissue-based approaches. Using a retrospective analysis of two large randomized trials as test and validation studies, we show that bTMB reproducibly identifies patients who derive clinically significant improvements in progression-free survival from atezolizumab (an anti-PD-L1) in second-line and higher NSCLC. Collectively, our data show that high bTMB is a clinically actionable biomarker for atezolizumab in NSCLC.", + "TAG_DATA": [ + "135, second-line {'context': 'B-neoplasm'}", + "137, higher {'context': 'I-neoplasm'}", + "138, NSCLC. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "135, second-line ['l0', 'l1']", + "137, higher ['l0', 'l2']", + "138, NSCLC. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30082863", + "TEXT": "Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite that enhances both platelet responsiveness and in vivo thrombosis potential in animal models, and TMAO plasma levels predict incident atherothrombotic event risks in human clinical studies. TMAO is formed by gut microbe-dependent metabolism of trimethylamine (TMA) moiety-containing nutrients, which are abundant in a Western diet. Here, using a mechanism-based inhibitor approach targeting a major microbial TMA-generating enzyme pair, CutC and CutD (CutC/D), we developed inhibitors that are potent, time-dependent, and irreversible and that do not affect commensal viability. In animal models, a single oral dose of a CutC/D inhibitor significantly reduced plasma TMAO levels for up to 3 d and rescued diet-induced enhanced platelet responsiveness and thrombus formation, without observable toxicity or increased bleeding risk. The inhibitor selectively accumulated within intestinal microbes to millimolar levels, a concentration over 1-million-fold higher than needed for a therapeutic effect. These studies reveal that mechanism-based inhibition of gut microbial TMA and TMAO production reduces thrombosis potential, a critical adverse complication in heart disease. They also offer a generalizable approach for the selective nonlethal targeting of gut microbial enzymes linked to host disease limiting systemic exposure of the inhibitor in the host.", + "TAG_DATA": [ + "87, animal {'context': 'B-organism'}", + "88, models, {'context': 'I-organism'}", + "95, CutC/D {'perturbing_action': 'B-pharmacological inhibition'}", + "96, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "111, platelet {'context': 'B-cells'}", + "114, thrombus {'phenotype': 'B-tumourigenesis'}", + "115, formation, {'phenotype': 'I-tumourigenesis'}" + ], + "LINK_DATA": [ + "87, animal ['l0', 'l1', 'l2']", + "88, models, ['l0', 'l3', 'l4']", + "95, CutC/D ['l5', 'l6', 'l7', 'l8']", + "96, inhibitor ['l5', 'l9', 'l10', 'l11']", + "111, platelet ['l1', 'l3', 'l6', 'l9', 'l12', 'l13']", + "114, thrombus ['l7', 'l10', 'l12', 'l14']", + "115, formation, ['l2', 'l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "animal", + "models," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CutC/D", + "inhibitor" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelet" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CutC/D", + "inhibitor" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "thrombus", + "formation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "platelet" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "thrombus", + "formation," + ] + } + } + ] + }, + { + "PMID": "30038221", + "TEXT": "Cellular transformation is accompanied by extensive rewiring of many biological processes leading to augmented levels of distinct types of cellular stress, including proteotoxic stress. Cancer cells critically depend on stress-relief pathways for their survival. However, the mechanisms underlying the transcriptional initiation and maintenance of the oncogenic stress response remain elusive. Here, we show that the expression of heat shock transcription factor 1 (HSF1) and the downstream mediators of the heat shock response is transcriptionally upregulated in T cell acute lymphoblastic leukemia (T-ALL). Hsf1 ablation suppresses the growth of human T-ALL and eradicates leukemia in mouse models of T-ALL, while sparing normal hematopoiesis. HSF1 drives a compact transcriptional program and among the direct HSF1 targets, specific chaperones and co-chaperones mediate its critical role in T-ALL. Notably, we demonstrate that the central T-ALL oncogene NOTCH1 hijacks the cellular stress response machinery by inducing the expression of HSF1 and its downstream effectors. The NOTCH1 signaling status controls the levels of chaperone/co-chaperone complexes and predicts the response of T-ALL patient samples to HSP90 inhibition. Our data demonstrate an integral crosstalk between mediators of oncogene and non-oncogene addiction and reveal critical nodes of the heat shock response pathway that can be targeted therapeutically.", + "TAG_DATA": [ + "82, Hsf1 {'perturbing_action': 'B-gene loss-of-function'}", + "83, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "88, human {'context': 'B-neoplasm'}", + "89, T-ALL {'context': 'I-neoplasm'}", + "92, leukemia {'context': 'B-neoplasm'}", + "94, mouse {'context': 'B-organism'}", + "95, models {'context': 'I-neoplasm'}", + "96, of {'context': 'I-neoplasm'}", + "97, T-ALL, {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "82, Hsf1 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "83, ablation ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "88, human ['l1', 'l8', 'l15']", + "89, T-ALL ['l2', 'l9', 'l15']", + "92, leukemia ['l3', 'l10', 'l16', 'l17', 'l18', 'l19']", + "94, mouse ['l4', 'l11', 'l16', 'l20', 'l21', 'l22']", + "95, models ['l5', 'l12', 'l17', 'l20', 'l23', 'l24']", + "96, of ['l6', 'l13', 'l18', 'l21', 'l23', 'l25']", + "97, T-ALL, ['l7', 'l14', 'l19', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hsf1", + "ablation" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "T-ALL", + "leukemia", + "models", + "of", + "T-ALL," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hsf1", + "ablation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + } + ] + }, + { + "PMID": "30038218", + "TEXT": "Despite decades of research, our understanding of the processes controlling late-stage atherosclerotic plaque stability remains poor. A prevailing hypothesis is that reducing inflammation may improve advanced plaque stability, as recently tested in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial, in which post-myocardial infarction subjects were treated with an IL-1β antibody. Here, we performed intervention studies in which smooth muscle cell (SMC) lineage-tracing Apoe-/- mice with advanced atherosclerosis were treated with anti-IL-1β or IgG control antibodies. Surprisingly, we found that IL-1β antibody treatment between 18 and 26 weeks of Western diet feeding induced a marked reduction in SMC and collagen content, but increased macrophage numbers in the fibrous cap. Moreover, although IL-1β antibody treatment had no effect on lesion size, it completely inhibited beneficial outward remodeling. We also found that SMC-specific knockout of Il1r1 (encoding IL-1 receptor type 1) resulted in smaller lesions nearly devoid of SMCs and lacking a fibrous cap, whereas macrophage-selective loss of IL-1R1 had no effect on lesion size or composition. Taken together, these results show that IL-1β has multiple beneficial effects in late-stage murine atherosclerosis, including promotion of outward remodeling and formation and maintenance of an SMC- and collagen-rich fibrous cap.", + "TAG_DATA": [ + "58, smooth {'context': 'B-cells'}", + "59, muscle {'context': 'I-cells'}", + "60, cell {'context': 'I-cells'}", + "61, (SMC) {'context': 'I-cells'}", + "62, lineage-tracing {'perturbing_action': 'I-gene loss-of-function'}", + "63, Apoe-/- {'perturbing_action': 'I-gene loss-of-function'}", + "64, mice {'context': 'B-organism'}", + "96, SMC {'context': 'B-cells'}", + "102, macrophage {'context': 'B-cells'}", + "129, SMC-specific {'perturbing_action': 'B-gene loss-of-function'}", + "130, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "131, of {'perturbing_action': 'I-gene loss-of-function'}", + "132, Il1r1 {'perturbing_action': 'I-gene loss-of-function'}", + "133, (encoding {'perturbing_action': 'I-gene loss-of-function'}", + "134, IL-1 {'perturbing_action': 'I-gene loss-of-function'}", + "135, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "136, type {'perturbing_action': 'I-gene loss-of-function'}", + "137, 1) {'perturbing_action': 'I-gene loss-of-function'}", + "145, SMCs {'context': 'B-cells'}", + "152, macrophage-selective {'perturbing_action': 'B-gene loss-of-function'}", + "153, loss {'perturbing_action': 'I-gene loss-of-function'}", + "154, of {'perturbing_action': 'I-gene loss-of-function'}", + "155, IL-1R1 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "58, smooth ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "59, muscle ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "60, cell ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "61, (SMC) ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "62, lineage-tracing ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "63, Apoe-/- ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "64, mice ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "96, SMC ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33']", + "102, macrophage ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34']", + "129, SMC-specific ['l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "130, knockout ['l35', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "131, of ['l36', 'l44', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "132, Il1r1 ['l37', 'l45', 'l52', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "133, (encoding ['l38', 'l46', 'l53', 'l59', 'l65', 'l66', 'l67', 'l68', 'l69']", + "134, IL-1 ['l39', 'l47', 'l54', 'l60', 'l65', 'l70', 'l71', 'l72', 'l73']", + "135, receptor ['l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l74', 'l75', 'l76']", + "136, type ['l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l77', 'l78']", + "137, 1) ['l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l77', 'l79']", + "145, SMCs ['l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l76', 'l78', 'l79']", + "152, macrophage-selective ['l80', 'l81', 'l82']", + "153, loss ['l80', 'l83', 'l84']", + "154, of ['l81', 'l83', 'l85']", + "155, IL-1R1 ['l82', 'l84', 'l85']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "smooth", + "muscle", + "cell", + "(SMC)", + "SMC", + "macrophage", + "SMCs" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lineage-tracing", + "Apoe-/-", + "SMC-specific", + "knockout", + "of", + "Il1r1", + "(encoding", + "IL-1", + "receptor", + "type", + "1)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lineage-tracing", + "Apoe-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "29988125", + "TEXT": "Pancreatic beta cell loss is a key factor in the pathogenesis of type 1 diabetes (T1D), but therapies to halt this process are lacking. We previously reported that the approved antihypertensive calcium-channel blocker verapamil, by decreasing the expression of thioredoxin-interacting protein, promotes the survival of insulin-producing beta cells and reverses diabetes in mouse models1. To translate these findings into humans, we conducted a randomized double-blind placebo-controlled phase 2 clinical trial ( NCT02372253 ) to assess the efficacy and safety of oral verapamil added for 12 months to a standard insulin regimen in adult subjects with recent-onset T1D. Verapamil treatment, compared with placebo was well tolerated and associated with an improved mixed-meal-stimulated C-peptide area under the curve, a measure of endogenous beta cell function, at 3 and 12 months (prespecified primary endpoint), as well as with a lower increase in insulin requirements, fewer hypoglycemic events and on-target glycemic control (secondary endpoints). Thus, addition of once-daily oral verapamil may be a safe and effective novel approach to promote endogenous beta cell function and reduce insulin requirements and hypoglycemic episodes in adult individuals with recent-onset T1D.", + "TAG_DATA": [ + "45, insulin-producing {'context': 'B-cells'}", + "46, beta {'context': 'I-cells'}", + "47, cells {'context': 'I-cells'}", + "52, mouse {'context': 'B-organism'}", + "53, models1. {'context': 'I-organism'}", + "92, adult {'context': 'B-organism'}", + "93, subjects {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "45, insulin-producing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "46, beta ['l0', 'l6', 'l7', 'l8']", + "47, cells ['l1', 'l6', 'l9', 'l10']", + "52, mouse ['l2', 'l7', 'l9', 'l11']", + "53, models1. ['l3', 'l8', 'l10', 'l11']", + "92, adult ['l4', 'l12', 'l13']", + "93, subjects ['l5', 'l12', 'l14']", + "96, T1D. ['l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29967347", + "TEXT": "In the version of this article initially published, Figs. 5a,c and 6a were incorrect because of an error in a metadata spreadsheet that led to the healthy donor patient 2 (HD2) samples being used twice in the analysis of baseline samples and in the analysis at 12 weeks of anti-PD-1 therapy, while HD3 samples had not been used.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "29942093", + "TEXT": "Intratumoral stimulatory dendritic cells (SDCs) play an important role in stimulating cytotoxic T cells and driving immune responses against cancer. Understanding the mechanisms that regulate their abundance in the tumor microenvironment (TME) could unveil new therapeutic opportunities. We find that in human melanoma, SDC abundance is associated with intratumoral expression of the gene encoding the cytokine FLT3LG. FLT3LG is predominantly produced by lymphocytes, notably natural killer (NK) cells in mouse and human tumors. NK cells stably form conjugates with SDCs in the mouse TME, and genetic and cellular ablation of NK cells in mice demonstrates their importance in positively regulating SDC abundance in tumor through production of FLT3L. Although anti-PD-1 'checkpoint' immunotherapy for cancer largely targets T cells, we find that NK cell frequency correlates with protective SDCs in human cancers, with patient responsiveness to anti-PD-1 immunotherapy, and with increased overall survival. Our studies reveal that innate immune SDCs and NK cells cluster together as an excellent prognostic tool for T cell-directed immunotherapy and that these innate cells are necessary for enhanced T cell tumor responses, suggesting this axis as a target for new therapies.", + "TAG_DATA": [ + "73, NK {'context': 'B-cells'}", + "74, cells {'context': 'I-cells'}", + "90, NK {'context': 'B-cells'}", + "91, cells {'context': 'I-cells'}", + "93, mice {'context': 'B-organism'}", + "117, cells, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "73, NK ['l0', 'l1', 'l2', 'l3']", + "74, cells ['l0', 'l4', 'l5', 'l6']", + "90, NK ['l1', 'l4', 'l7', 'l8']", + "91, cells ['l2', 'l5', 'l7', 'l9']", + "93, mice ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29934534", + "TEXT": "In the version of this article originally published, some labels in Fig. 1f are incorrect. The \"β-actin\" labels on the second and fourth rows of blots should instead be \"β-tubulin\". The error has been corrected in the HTML and PDF versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "29892069", + "TEXT": "The brain microenvironment imposes a particularly intense selective pressure on metastasis-initiating cells, but successful metastases bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of this microenvironment that confine brain metastasis without infiltrating the lesion. Here, we describe that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by signal transducer and activator of transcription 3 (STAT3) in a subpopulation of reactive astrocytes surrounding metastatic lesions. These reactive astrocytes benefit metastatic cells by their modulatory effect on the innate and acquired immune system. In patients, active STAT3 in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. We also show that a safe and orally bioavailable treatment that inhibits STAT3 exhibits significant antitumor effects in patients with advanced systemic disease that included brain metastasis. Responses to this therapy were notable in the central nervous system, where several complete responses were achieved. Given that brain metastasis causes substantial morbidity and mortality, our results identify a novel treatment for increasing survival in patients with secondary brain tumors.", + "TAG_DATA": [ + "112, reactive {'context': 'B-cells'}", + "113, astrocytes {'context': 'I-cells'}", + "114, reduces {'effect': 'B-negative'}", + "116, brain {'phenotype': 'B-metastasis'}", + "117, metastasis {'phenotype': 'I-metastasis'}", + "120, primary {'context': 'B-neoplasm'}", + "121, tumor {'context': 'I-neoplasm'}", + "122, sources, {'context': 'I-neoplasm'}", + "147, patients {'context': 'B-patient'}", + "154, brain {'phenotype': 'B-metastasis'}", + "155, metastasis. {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "112, reactive ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "113, astrocytes ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "114, reduces ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "116, brain ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "117, metastasis ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "120, primary ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "121, tumor ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "122, sources, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "147, patients ['l28', 'l29']", + "154, brain ['l28', 'l30']", + "155, metastasis. ['l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "reactive", + "astrocytes" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "reactive", + "astrocytes" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "brain", + "metastasis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "brain", + "metastasis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "primary", + "tumor", + "sources," + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "brain", + "metastasis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "primary", + "tumor", + "sources," + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "brain", + "metastasis." + ] + } + } + ] + }, + { + "PMID": "29892064", + "TEXT": "Paradigm-shifting studies in the mouse have identified tissue macrophage heterogeneity as a critical determinant of immune responses. In contrast, surprisingly little is known regarding macrophage heterogeneity in humans. Macrophages within the mouse heart are partitioned into CCR2- and CCR2+ subsets with divergent origins, repopulation mechanisms, and functions. Here, we demonstrate that the human myocardium also contains distinct subsets of CCR2- and CCR2+ macrophages. Analysis of sex-mismatched heart transplant recipients revealed that CCR2- macrophages are a tissue-resident population exclusively replenished through local proliferation, whereas CCR2+ macrophages are maintained through monocyte recruitment and proliferation. Moreover, CCR2- and CCR2+ macrophages have distinct functional properties, analogous to reparative CCR2- and inflammatory CCR2+ macrophages in the mouse heart. Clinically, CCR2+ macrophage abundance is associated with left ventricular remodeling and systolic function in heart failure patients. Collectively, these observations provide initial evidence for the functional importance of macrophage heterogeneity in the human heart.", + "TAG_DATA": [ + "71, CCR2- {'context': 'B-cells'}", + "72, macrophages {'context': 'B-cells'}", + "84, macrophages {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "71, CCR2- ['l0', 'l1']", + "72, macrophages ['l0', 'l2']", + "84, macrophages ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29892061", + "TEXT": "Lung cancer is a devastating disease that remains a top cause of cancer mortality. Despite improvements with targeted and immunotherapies, the majority of patients with lung cancer lack effective therapies, underscoring the need for additional treatment approaches. Genomic studies have identified frequent alterations in components of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A. To understand the mechanisms of tumorigenesis driven by mutations in this complex, we developed a genetically engineered mouse model of lung adenocarcinoma by ablating Smarca4 in the lung epithelium. We demonstrate that Smarca4 acts as a bona fide tumor suppressor and cooperates with p53 loss and Kras activation. Gene expression analyses revealed the signature of enhanced oxidative phosphorylation (OXPHOS) in SMARCA4 mutant tumors. We further show that SMARCA4 mutant cells have enhanced oxygen consumption and increased respiratory capacity. Importantly, SMARCA4 mutant lung cancer cell lines and xenograft tumors have marked sensitivity to inhibition of OXPHOS by a novel small molecule, IACS-010759, that is under clinical development. Mechanistically, we show that SMARCA4-deficient cells have a blunted transcriptional response to energy stress creating a therapeutically exploitable synthetic lethal interaction. These findings provide the mechanistic basis for further development of OXPHOS inhibitors as therapeutics against SWI/SNF mutant tumors.", + "TAG_DATA": [ + "70, genetically {'context': 'B-organism'}", + "71, engineered {'context': 'I-organism'}", + "72, mouse {'context': 'I-organism'}", + "73, model {'context': 'I-organism'}", + "74, of {'context': 'I-neoplasm'}", + "75, lung {'context': 'I-neoplasm'}", + "76, adenocarcinoma {'context': 'I-neoplasm'}", + "78, ablating {'perturbing_action': 'B-gene loss-of-function'}", + "79, Smarca4 {'perturbing_action': 'I-gene loss-of-function'}", + "80, in {'perturbing_action': 'I-gene loss-of-function'}", + "81, the {'perturbing_action': 'I-gene loss-of-function'}", + "82, lung {'perturbing_action': 'I-gene loss-of-function', 'context': 'B-tissue/organ'}", + "83, epithelium. {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-tissue/organ'}", + "115, SMARCA4 {'perturbing_action': 'B-other'}", + "116, mutant {'perturbing_action': 'I-other'}", + "117, tumors. {'context': 'B-neoplasm'}", + "122, SMARCA4 {'perturbing_action': 'B-other'}", + "123, mutant {'perturbing_action': 'I-other'}", + "124, cells {'context': 'B-cells'}", + "134, SMARCA4 {'perturbing_action': 'B-other'}", + "135, mutant {'perturbing_action': 'I-other'}", + "136, lung {'context': 'B-transformed cells'}", + "137, cancer {'context': 'I-transformed cells'}", + "138, cell {'context': 'I-transformed cells'}", + "139, lines {'context': 'I-transformed cells'}", + "141, xenograft {'context': 'B-xenograft'}", + "142, tumors {'context': 'I-xenograft'}", + "165, SMARCA4-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "166, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "70, genetically ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "71, engineered ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "72, mouse ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "73, model ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "74, of ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "75, lung ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "76, adenocarcinoma ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "78, ablating ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "79, Smarca4 ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "80, in ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "81, the ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "82, lung ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "83, epithelium. ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "115, SMARCA4 ['l78', 'l79', 'l80', 'l81', 'l82']", + "116, mutant ['l78', 'l83', 'l84', 'l85', 'l86']", + "117, tumors. ['l79', 'l83', 'l87', 'l88']", + "122, SMARCA4 ['l80', 'l84', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "123, mutant ['l81', 'l85', 'l87', 'l89', 'l96']", + "124, cells ['l82', 'l86', 'l88', 'l90', 'l96']", + "134, SMARCA4 ['l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "135, mutant ['l91', 'l97', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "136, lung ['l92', 'l98', 'l104', 'l110', 'l111', 'l112', 'l113', 'l114']", + "137, cancer ['l93', 'l99', 'l105', 'l110', 'l115', 'l116', 'l117', 'l118']", + "138, cell ['l94', 'l100', 'l106', 'l111', 'l115', 'l119', 'l120', 'l121']", + "139, lines ['l95', 'l101', 'l107', 'l112', 'l116', 'l119', 'l122']", + "141, xenograft ['l102', 'l108', 'l113', 'l117', 'l120', 'l123']", + "142, tumors ['l103', 'l109', 'l114', 'l118', 'l121', 'l122', 'l123']", + "165, SMARCA4-deficient ['l124']", + "166, cells ['l124']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "genetically", + "engineered", + "mouse", + "model" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablating", + "Smarca4", + "in", + "the", + "lung", + "epithelium." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lung", + "epithelium.", + "ablating", + "Smarca4", + "in", + "the" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung", + "epithelium." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "of", + "lung", + "adenocarcinoma" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablating", + "Smarca4", + "in", + "the", + "lung", + "epithelium." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "SMARCA4", + "mutant" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "SMARCA4", + "mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "SMARCA4", + "mutant" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "lung", + "cancer", + "cell", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "SMARCA4", + "mutant" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SMARCA4-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "29808010", + "TEXT": "The role of KRAS, when activated through canonical mutations, has been well established in cancer1. Here we explore a secondary means of KRAS activation in cancer: focal high-level amplification of the KRAS gene in the absence of coding mutations. These amplifications occur most commonly in esophageal, gastric and ovarian adenocarcinomas2-4. KRAS-amplified gastric cancer models show marked overexpression of the KRAS protein and are insensitive to MAPK blockade owing to their capacity to adaptively respond by rapidly increasing KRAS-GTP levels. Here we demonstrate that inhibition of the guanine-exchange factors SOS1 and SOS2 or the protein tyrosine phosphatase SHP2 can attenuate this adaptive process and that targeting these factors, both genetically and pharmacologically, can enhance the sensitivity of KRAS-amplified models to MEK inhibition in both in vitro and in vivo settings. These data demonstrate the relevance of copy-number amplification as a mechanism of KRAS activation, and uncover the therapeutic potential for targeting of these tumors through combined SHP2 and MEK inhibition.", + "TAG_DATA": [ + "83, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "84, of {'perturbing_action': 'I-pharmacological inhibition'}", + "85, the {'perturbing_action': 'I-pharmacological inhibition'}", + "86, guanine-exchange {'perturbing_action': 'I-pharmacological inhibition'}", + "87, factors {'perturbing_action': 'I-pharmacological inhibition'}", + "88, SOS1 {'perturbing_action': 'I-pharmacological inhibition'}", + "89, and {'perturbing_action': 'I-pharmacological inhibition'}", + "90, SOS2 {'perturbing_action': 'I-pharmacological inhibition'}", + "91, or {'perturbing_action': 'I-pharmacological inhibition'}", + "92, the {'perturbing_action': 'I-pharmacological inhibition'}", + "93, protein {'perturbing_action': 'I-pharmacological inhibition'}", + "94, tyrosine {'perturbing_action': 'I-pharmacological inhibition'}", + "95, phosphatase {'perturbing_action': 'I-pharmacological inhibition'}", + "96, SHP2 {'perturbing_action': 'I-pharmacological inhibition'}", + "117, models {'context': 'B-neoplasm'}", + "119, MEK {'perturbing_action': 'B-pharmacological inhibition'}", + "120, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "123, in {'context': 'B-in vitro'}", + "124, vitro {'context': 'I-in vitro'}", + "126, in {'context': 'B-in vivo'}", + "127, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "83, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "84, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "85, the ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "86, guanine-exchange ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "87, factors ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "88, SOS1 ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "89, and ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "90, SOS2 ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "91, or ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "92, the ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "93, protein ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "94, tyrosine ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l88', 'l94', 'l95', 'l96', 'l97', 'l98']", + "95, phosphatase ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l89', 'l94', 'l99', 'l100', 'l101', 'l102']", + "96, SHP2 ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l90', 'l95', 'l99', 'l103', 'l104']", + "117, models ['l85', 'l91', 'l96', 'l100', 'l103', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "119, MEK ['l105', 'l111', 'l112', 'l113', 'l114', 'l115']", + "120, inhibition ['l106', 'l111', 'l116', 'l117', 'l118', 'l119']", + "123, in ['l86', 'l92', 'l97', 'l101', 'l107', 'l112', 'l116', 'l120', 'l121', 'l122']", + "124, vitro ['l87', 'l93', 'l98', 'l102', 'l104', 'l108', 'l113', 'l117', 'l120', 'l123', 'l124']", + "126, in ['l109', 'l114', 'l118', 'l121', 'l123', 'l125']", + "127, vivo ['l110', 'l115', 'l119', 'l122', 'l124', 'l125']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "the", + "protein", + "tyrosine", + "phosphatase", + "SHP2", + "MEK", + "inhibition" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "the", + "protein", + "tyrosine", + "phosphatase", + "SHP2", + "MEK", + "inhibition" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "MEK", + "inhibition" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "29808008", + "TEXT": "Defining the environmental context in which genes enhance disease susceptibility can provide insight into the pathogenesis of complex disorders. We report that the intra-uterine environment modulates the association of schizophrenia with genomic risk (in this study, genome-wide association study-derived polygenic risk scores (PRSs)). In independent samples from the United States, Italy, and Germany, the liability of schizophrenia explained by PRS is more than five times greater in the presence of early-life complications (ELCs) compared with their absence. Patients with ELC histories have significantly higher PRS than patients without ELC histories, which is confirmed in additional samples from Germany and Japan. The gene set composed of schizophrenia loci that interact with ELCs is highly expressed in placenta, is differentially expressed in placentae from complicated in comparison with normal pregnancies, and is differentially upregulated in placentae from male compared with female offspring. Pathway analyses reveal that genes driving the PRS-ELC interaction are involved in cellular stress response; genes that do not drive such interaction implicate orthogonal biological processes (for example, synaptic function). We conclude that a subset of the most significant genetic variants associated with schizophrenia converge on a developmental trajectory sensitive to events that affect the placental response to stress, which may offer insights into sex biases and primary prevention.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "29808006", + "TEXT": "RAS mutations are frequent in human cancer, especially in pancreatic, colorectal and non-small-cell lung cancers (NSCLCs)1-3. Inhibition of the RAS oncoproteins has proven difficult4, and attempts to target downstream effectors5-7 have been hampered by the activation of compensatory resistance mechanisms8. It is also well established that KRAS-mutant tumors are insensitive to inhibition of upstream growth factor receptor signaling. Thus, epidermal growth factor receptor antibody therapy is only effective in KRAS wild-type colon cancers9,10. Consistently, inhibition of SHP2 (also known as PTPN11), which links receptor tyrosine kinase signaling to the RAS-RAF-MEK-ERK pathway11,12, was shown to be ineffective in KRAS-mutant or BRAF-mutant cancer cell lines13. Our data also indicate that SHP2 inhibition in KRAS-mutant NSCLC cells under normal cell culture conditions has little effect. By contrast, SHP2 inhibition under growth factor-limiting conditions in vitro results in a senescence response. In vivo, inhibition of SHP2 in KRAS-mutant NSCLC also provokes a senescence response, which is exacerbated by MEK inhibition. Our data identify SHP2 inhibition as an unexpected vulnerability of KRAS-mutant NSCLC cells that remains undetected in cell culture and can be exploited therapeutically.", + "TAG_DATA": [ + "74, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "75, of {'perturbing_action': 'I-pharmacological inhibition'}", + "76, SHP2 {'perturbing_action': 'I-pharmacological inhibition'}", + "77, (also {'perturbing_action': 'I-pharmacological inhibition'}", + "97, KRAS-mutant {'perturbing_action': 'B-other'}", + "99, BRAF-mutant {'perturbing_action': 'B-other'}", + "100, cancer {'context': 'B-transformed cells'}", + "101, cell {'context': 'I-transformed cells'}", + "102, lines13. {'context': 'I-transformed cells'}", + "108, SHP2 {'perturbing_action': 'B-pharmacological inhibition'}", + "109, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "111, KRAS-mutant {'perturbing_action': 'B-other'}", + "112, NSCLC {'context': 'B-transformed cells'}", + "113, cells {'context': 'I-transformed cells'}", + "120, little {'effect': 'B-no effect'}", + "121, effect. {'effect': 'I-no effect'}", + "124, SHP2 {'perturbing_action': 'B-pharmacological inhibition'}", + "125, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "130, in {'context': 'B-in vitro'}", + "131, vitro {'context': 'I-in vitro'}", + "132, results {'effect': 'B-positive'}", + "133, in {'effect': 'I-positive'}", + "135, senescence {'phenotype': 'B-senescence'}", + "136, response. {'phenotype': 'I-senescence'}", + "137, In {'context': 'B-in vivo'}", + "138, vivo, {'context': 'I-in vivo'}", + "139, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "140, of {'perturbing_action': 'I-pharmacological inhibition'}", + "141, SHP2 {'perturbing_action': 'I-pharmacological inhibition'}", + "143, KRAS-mutant {'perturbing_action': 'B-other'}", + "144, NSCLC {'context': 'B-neoplasm'}", + "146, provokes {'effect': 'B-positive'}", + "148, senescence {'phenotype': 'B-senescence'}", + "149, response, {'phenotype': 'I-senescence'}", + "154, MEK {'perturbing_action': 'B-pharmacological inhibition'}", + "155, inhibition. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "74, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "75, of ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "76, SHP2 ['l1', 'l16', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "77, (also ['l2', 'l17', 'l32', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "97, KRAS-mutant ['l3', 'l18', 'l33', 'l46', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "99, BRAF-mutant ['l4', 'l19', 'l34', 'l47', 'l60', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "100, cancer ['l5', 'l20', 'l35', 'l48', 'l61', 'l66', 'l80', 'l81']", + "101, cell ['l6', 'l21', 'l36', 'l49', 'l62', 'l67', 'l80', 'l82']", + "102, lines13. ['l7', 'l22', 'l37', 'l50', 'l63', 'l68', 'l81', 'l82']", + "108, SHP2 ['l23', 'l51', 'l69', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "109, inhibition ['l8', 'l24', 'l38', 'l52', 'l70', 'l83', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "111, KRAS-mutant ['l9', 'l25', 'l39', 'l53', 'l71', 'l84', 'l97', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "112, NSCLC ['l10', 'l26', 'l40', 'l54', 'l64', 'l72', 'l85', 'l98', 'l110', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "113, cells ['l11', 'l27', 'l41', 'l55', 'l65', 'l73', 'l86', 'l99', 'l111', 'l121', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "120, little ['l12', 'l28', 'l42', 'l56', 'l74', 'l87', 'l100', 'l112', 'l122', 'l130', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "121, effect. ['l13', 'l29', 'l43', 'l57', 'l75', 'l88', 'l101', 'l113', 'l123', 'l131', 'l136', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "124, SHP2 ['l89', 'l102', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160']", + "125, inhibition ['l90', 'l103', 'l114', 'l137', 'l150', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "130, in ['l91', 'l104', 'l115', 'l124', 'l138', 'l144', 'l151', 'l161', 'l168', 'l169', 'l170', 'l171', 'l172']", + "131, vitro ['l92', 'l105', 'l116', 'l125', 'l139', 'l145', 'l152', 'l162', 'l168', 'l173', 'l174', 'l175', 'l176']", + "132, results ['l76', 'l93', 'l106', 'l117', 'l126', 'l132', 'l140', 'l146', 'l153', 'l163', 'l169', 'l173', 'l177', 'l178', 'l179']", + "133, in ['l14', 'l30', 'l44', 'l58', 'l77', 'l94', 'l107', 'l118', 'l127', 'l133', 'l141', 'l147', 'l154', 'l164', 'l170', 'l174', 'l177', 'l180', 'l181']", + "135, senescence ['l78', 'l95', 'l108', 'l119', 'l128', 'l134', 'l142', 'l148', 'l155', 'l165', 'l171', 'l175', 'l178', 'l180', 'l182']", + "136, response. ['l15', 'l31', 'l45', 'l59', 'l79', 'l96', 'l109', 'l120', 'l129', 'l135', 'l143', 'l149', 'l156', 'l166', 'l172', 'l176', 'l179', 'l181', 'l182']", + "137, In ['l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "138, vivo, ['l183', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203']", + "139, inhibition ['l184', 'l194', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212']", + "140, of ['l185', 'l195', 'l204', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220']", + "141, SHP2 ['l186', 'l196', 'l205', 'l213', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227']", + "143, KRAS-mutant ['l187', 'l197', 'l206', 'l214', 'l221', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233']", + "144, NSCLC ['l157', 'l188', 'l198', 'l207', 'l215', 'l222', 'l228', 'l234', 'l235', 'l236', 'l237', 'l238']", + "146, provokes ['l158', 'l189', 'l199', 'l208', 'l216', 'l223', 'l229', 'l234', 'l239', 'l240', 'l241', 'l242']", + "148, senescence ['l159', 'l190', 'l200', 'l209', 'l217', 'l224', 'l230', 'l235', 'l239', 'l243', 'l244', 'l245']", + "149, response, ['l160', 'l167', 'l191', 'l201', 'l210', 'l218', 'l225', 'l231', 'l236', 'l240', 'l243', 'l246']", + "154, MEK ['l192', 'l202', 'l211', 'l219', 'l226', 'l232', 'l237', 'l241', 'l244', 'l247']", + "155, inhibition. ['l193', 'l203', 'l212', 'l220', 'l227', 'l233', 'l238', 'l242', 'l245', 'l246', 'l247']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2", + "(also" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cell", + "lines13.", + "NSCLC", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2", + "(also" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "little", + "effect." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2", + "(also", + "MEK", + "inhibition." + ] + }, + "effect": { + "val": "positive", + "words": [ + "in", + "results", + "provokes" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2", + "(also", + "MEK", + "inhibition." + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "response.", + "senescence", + "response," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "KRAS-mutant", + "BRAF-mutant" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cell", + "lines13.", + "NSCLC", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BRAF-mutant", + "KRAS-mutant" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "little", + "effect." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BRAF-mutant", + "KRAS-mutant" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in", + "provokes" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BRAF-mutant", + "KRAS-mutant" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence", + "response.", + "response," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "SHP2", + "inhibition" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "KRAS-mutant" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "NSCLC", + "cells" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "little", + "effect." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "NSCLC", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "NSCLC", + "cells" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence", + "response." + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "little", + "effect." + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "little", + "effect." + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence", + "response." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "SHP2", + "inhibition", + "of", + "MEK", + "inhibition." + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "NSCLC" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence", + "response." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in", + "provokes" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence", + "response.", + "response," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2", + "MEK", + "inhibition." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "KRAS-mutant" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "effect": { + "val": "positive", + "words": [ + "provokes" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence", + "response," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "KRAS-mutant" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "NSCLC" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "NSCLC" + ] + }, + "effect": { + "val": "positive", + "words": [ + "provokes" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "NSCLC" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence", + "response," + ] + } + } + ] + }, + { + "PMID": "29785027", + "TEXT": "Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is caused by mutations in ATRX, which encodes a chromatin-remodeling protein. Genome-wide analyses in mouse and human cells indicate that ATRX tends to bind to G-rich sequences with a high potential to form G-quadruplexes. Here, we report that Atrx mutation induces aberrant upregulation of Xlr3b expression in the mouse brain, an outcome associated with neuronal pathogenesis displayed by ATR-X model mice. We show that ATRX normally binds to G-quadruplexes in CpG islands of the imprinted Xlr3b gene, regulating its expression by recruiting DNA methyltransferases. Xlr3b binds to dendritic mRNAs, and its overexpression inhibits dendritic transport of the mRNA encoding CaMKII-α, promoting synaptic dysfunction. Notably, treatment with 5-ALA, which is converted into G-quadruplex-binding metabolites, reduces RNA polymerase II recruitment and represses Xlr3b transcription in ATR-X model mice. 5-ALA treatment also rescues decreased synaptic plasticity and cognitive deficits seen in ATR-X model mice. Our findings suggest a potential therapeutic strategy to target G-quadruplexes and decrease cognitive impairment associated with ATR-X syndrome.", + "TAG_DATA": [ + "44, Atrx {'perturbing_action': 'B-other'}", + "45, mutation {'perturbing_action': 'I-other'}", + "54, mouse {'context': 'B-tissue/organ'}", + "55, brain, {'context': 'I-tissue/organ'}", + "129, ATR-X {'perturbing_action': 'B-other', 'context': 'B-organism'}", + "130, model {'context': 'I-organism'}", + "131, mice. {'context': 'B-organism'}", + "144, ATR-X {'perturbing_action': 'B-other'}", + "145, model {'context': 'I-organism'}", + "146, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "44, Atrx ['l0', 'l1', 'l2']", + "45, mutation ['l0', 'l3', 'l4']", + "54, mouse ['l1', 'l3', 'l5']", + "55, brain, ['l2', 'l4', 'l5']", + "129, ATR-X ['l6', 'l7']", + "130, model ['l6', 'l8']", + "131, mice. ['l7', 'l8']", + "144, ATR-X ['l9', 'l10']", + "145, model ['l9', 'l11']", + "146, mice. ['l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Atrx", + "mutation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "brain," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "ATR-X" + ] + }, + "context": { + "val": "organism", + "words": [ + "ATR-X", + "model", + "mice." + ] + } + } + ] + }, + { + "PMID": "29785025", + "TEXT": "Beige adipocytes have recently been shown to regulate energy dissipation when activated and help organisms defend against hypothermia and obesity. Prior reports indicate that beige-like adipocytes exist in adult humans and that they may present novel opportunities to curb the global epidemic in obesity and metabolic illnesses. In an effort to identify unique features of activated beige adipocytes, we found that expression of the cholinergic receptor nicotinic alpha 2 subunit (Chrna2) was induced in subcutaneous fat during the activation of these cells and that acetylcholine-producing immune cells within this tissue regulated this signaling pathway via paracrine mechanisms. CHRNA2 functioned selectively in uncoupling protein 1 (Ucp1)-positive beige adipocytes, increasing thermogenesis through a cAMP- and protein kinase A-dependent pathway. Furthermore, this signaling via CHRNA2 was conserved and present in human subcutaneous adipocytes. Inactivation of Chrna2 in mice compromised the cold-induced thermogenic response selectively in subcutaneous fat and exacerbated high-fat diet-induced obesity and associated metabolic disorders, indicating that even partial loss of beige fat regulation in vivo had detrimental consequences. Our results reveal a beige-selective immune-adipose interaction mediated through CHRNA2 and identify a novel function of nicotinic acetylcholine receptors in energy metabolism. These findings may lead to identification of therapeutic targets to counteract human obesity.", + "TAG_DATA": [ + "130, Inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "131, of {'perturbing_action': 'I-gene loss-of-function'}", + "132, Chrna2 {'perturbing_action': 'I-gene loss-of-function'}", + "134, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "130, Inactivation ['l0', 'l1', 'l2']", + "131, of ['l0', 'l3', 'l4']", + "132, Chrna2 ['l1', 'l3', 'l5']", + "134, mice ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Inactivation", + "of", + "Chrna2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "29713086", + "TEXT": "Germline mutations in BRCA1/2 predispose individuals to breast cancer (termed germline-mutated BRCA1/2 breast cancer, gBRCA-BC) by impairing homologous recombination (HR) and causing genomic instability. HR also repairs DNA lesions caused by platinum agents and PARP inhibitors. Triple-negative breast cancers (TNBCs) harbor subpopulations with BRCA1/2 mutations, hypothesized to be especially platinum-sensitive. Cancers in putative 'BRCAness' subgroups-tumors with BRCA1 methylation; low levels of BRCA1 mRNA (BRCA1 mRNA-low); or mutational signatures for HR deficiency and those with basal phenotypes-may also be sensitive to platinum. We assessed the efficacy of carboplatin and another mechanistically distinct therapy, docetaxel, in a phase 3 trial in subjects with unselected advanced TNBC. A prespecified protocol enabled biomarker-treatment interaction analyses in gBRCA-BC and BRCAness subgroups. The primary endpoint was objective response rate (ORR). In the unselected population (376 subjects; 188 carboplatin, 188 docetaxel), carboplatin was not more active than docetaxel (ORR, 31.4% versus 34.0%, respectively; P = 0.66). In contrast, in subjects with gBRCA-BC, carboplatin had double the ORR of docetaxel (68% versus 33%, respectively; biomarker, treatment interaction P = 0.01). Such benefit was not observed for subjects with BRCA1 methylation, BRCA1 mRNA-low tumors or a high score in a Myriad HRD assay. Significant interaction between treatment and the basal-like subtype was driven by high docetaxel response in the nonbasal subgroup. We conclude that patients with advanced TNBC benefit from characterization of BRCA1/2 mutations, but not BRCA1 methylation or Myriad HRD analyses, to inform choices on platinum-based chemotherapy. Additionally, gene expression analysis of basal-like cancers may also influence treatment selection.", + "TAG_DATA": [ + "98, subjects {'context': 'B-patient'}", + "101, advanced {'context': 'B-neoplasm'}", + "102, TNBC. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "98, subjects ['l0', 'l1']", + "101, advanced ['l0', 'l2']", + "102, TNBC. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29662203", + "TEXT": "Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs) with mutated histone H3 K27M (H3-K27M)1-5 are aggressive and universally fatal pediatric brain cancers 6 . Chimeric antigen receptor (CAR)-expressing T cells have mediated impressive clinical activity in B cell malignancies7-10, and recent results suggest benefit in central nervous system malignancies11-13. Here, we report that patient-derived H3-K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2. Anti-GD2 CAR T cells incorporating a 4-1BBz costimulatory domain 14 demonstrated robust antigen-dependent cytokine generation and killing of DMG cells in vitro. In five independent patient-derived H3-K27M+ DMG orthotopic xenograft models, systemic administration of GD2-targeted CAR T cells cleared engrafted tumors except for a small number of residual GD2lo glioma cells. To date, GD2-targeted CAR T cells have been well tolerated in clinical trials15-17. Although GD2-targeted CAR T cell administration was tolerated in the majority of mice bearing orthotopic xenografts, peritumoral neuroinflammation during the acute phase of antitumor activity resulted in hydrocephalus that was lethal in a fraction of animals. Given the precarious neuroanatomical location of midline gliomas, careful monitoring and aggressive neurointensive care management will be required for human translation. With a cautious multidisciplinary clinical approach, GD2-targeted CAR T cell therapy for H3-K27M+ diffuse gliomas of pons, thalamus and spinal cord could prove transformative for these lethal childhood cancers.", + "TAG_DATA": [ + "56, patient-derived {'perturbing_action': 'B-other'}", + "57, H3-K27M-mutant {'perturbing_action': 'I-other'}", + "58, glioma {'context': 'B-transformed cells'}", + "59, cell {'context': 'I-transformed cells'}", + "60, cultures {'context': 'I-transformed cells'}", + "87, DMG {'context': 'B-transformed cells'}", + "88, cells {'context': 'I-transformed cells'}", + "89, in {'context': 'B-in vitro'}", + "90, vitro. {'context': 'I-in vitro'}", + "94, patient-derived {'context': 'B-xenograft'}", + "95, H3-K27M+ {'context': 'I-xenograft'}", + "96, DMG {'context': 'I-xenograft'}", + "97, orthotopic {'context': 'I-xenograft'}", + "98, xenograft {'context': 'I-xenograft'}", + "99, models, {'context': 'I-xenograft'}", + "105, T {'context': 'I-cells'}", + "106, cells {'context': 'I-cells'}", + "108, engrafted {'context': 'B-xenograft'}", + "109, tumors {'context': 'I-xenograft'}", + "118, glioma {'context': 'B-transformed cells'}", + "119, cells. {'context': 'I-transformed cells'}", + "145, mice {'context': 'B-organism'}", + "147, orthotopic {'context': 'B-xenograft'}", + "148, xenografts, {'context': 'I-xenograft'}", + "168, animals. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, patient-derived ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "57, H3-K27M-mutant ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "58, glioma ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "59, cell ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "60, cultures ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "87, DMG ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "88, cells ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "89, in ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "90, vitro. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "94, patient-derived ['l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "95, H3-K27M+ ['l36', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "96, DMG ['l37', 'l47', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "97, orthotopic ['l38', 'l48', 'l57', 'l66', 'l67', 'l68', 'l69']", + "98, xenograft ['l39', 'l49', 'l58', 'l66', 'l70']", + "99, models, ['l40', 'l50', 'l59', 'l67', 'l70']", + "105, T ['l41', 'l51', 'l60', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "106, cells ['l42', 'l52', 'l61', 'l71', 'l79', 'l80', 'l81', 'l82']", + "108, engrafted ['l43', 'l53', 'l62', 'l72', 'l79', 'l83', 'l84', 'l85']", + "109, tumors ['l44', 'l54', 'l63', 'l68', 'l73', 'l80', 'l83', 'l86', 'l87']", + "118, glioma ['l45', 'l55', 'l64', 'l74', 'l81', 'l84', 'l86', 'l88', 'l89', 'l90', 'l91']", + "119, cells. ['l46', 'l56', 'l65', 'l69', 'l75', 'l82', 'l85', 'l87', 'l88']", + "145, mice ['l76', 'l89', 'l92', 'l93', 'l94']", + "147, orthotopic ['l77', 'l90', 'l92', 'l95', 'l96']", + "148, xenografts, ['l78', 'l91', 'l93', 'l95', 'l97']", + "168, animals. ['l94', 'l96', 'l97']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "patient-derived", + "H3-K27M-mutant" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "glioma", + "cell", + "cultures", + "DMG", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "patient-derived", + "H3-K27M-mutant" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "29662201", + "TEXT": "Proliferating cells, compared with quiescent cells, are more dependent on glucose for their growth. Although glucose transport in keratinocytes is mediated largely by the Glut1 facilitative transporter, we found that keratinocyte-specific ablation of Glut1 did not compromise mouse skin development and homeostasis. Ex vivo metabolic profiling revealed altered sphingolipid, hexose, amino acid, and nucleotide metabolism in Glut1-deficient keratinocytes, thus suggesting metabolic adaptation. However, cultured Glut1-deficient keratinocytes displayed metabolic and oxidative stress and impaired proliferation. Similarly, Glut1 deficiency impaired in vivo keratinocyte proliferation and migration within wounded or UV-damaged mouse skin. Notably, both genetic and pharmacological Glut1 inactivation decreased hyperplasia in mouse models of psoriasis-like disease. Topical application of a Glut1 inhibitor also decreased inflammation in these models. Glut1 inhibition decreased the expression of pathology-associated genes in human psoriatic skin organoids. Thus, Glut1 is selectively required for injury- and inflammation-associated keratinocyte proliferation, and its inhibition offers a novel treatment strategy for psoriasis.", + "TAG_DATA": [ + "30, keratinocyte-specific {'perturbing_action': 'B-gene loss-of-function'}", + "31, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "32, of {'perturbing_action': 'I-gene loss-of-function'}", + "33, Glut1 {'perturbing_action': 'I-gene loss-of-function'}", + "56, Glut1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "57, keratinocytes, {'context': 'B-cells'}", + "64, Glut1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "65, keratinocytes {'context': 'B-cells'}", + "72, impaired {'effect': 'B-negative'}", + "73, proliferation. {'phenotype': 'B-proliferation'}", + "75, Glut1 {'perturbing_action': 'B-gene loss-of-function'}", + "76, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "77, impaired {'effect': 'B-negative'}", + "78, in {'context': 'B-in vivo'}", + "79, vivo {'context': 'B-in vivo'}", + "80, keratinocyte {'context': 'B-cells'}", + "81, proliferation {'phenotype': 'B-proliferation'}", + "83, migration {'phenotype': 'B-migration'}", + "88, mouse {'context': 'B-tissue/organ'}", + "89, skin. {'context': 'I-tissue/organ'}", + "94, pharmacological {'perturbing_action': 'B-gene loss-of-function'}", + "95, Glut1 {'perturbing_action': 'I-gene loss-of-function'}", + "96, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "100, mouse {'context': 'B-organism'}", + "101, models {'context': 'I-organism'}", + "109, Glut1 {'perturbing_action': 'B-pharmacological inhibition'}", + "110, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "117, Glut1 {'perturbing_action': 'B-pharmacological inhibition'}", + "118, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "126, human {'context': 'B-organoid'}", + "127, psoriatic {'context': 'I-organoid'}", + "128, skin {'context': 'I-organoid'}", + "129, organoids. {'context': 'I-organoid'}" + ], + "LINK_DATA": [ + "30, keratinocyte-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "31, ablation ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "32, of ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "33, Glut1 ['l2', 'l14', 'l25', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "56, Glut1-deficient ['l3', 'l15', 'l26', 'l37', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "57, keratinocytes, ['l4', 'l16', 'l27', 'l38', 'l47', 'l53', 'l54', 'l55', 'l56', 'l57']", + "64, Glut1-deficient ['l5', 'l17', 'l28', 'l39', 'l48', 'l53', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "65, keratinocytes ['l6', 'l18', 'l29', 'l40', 'l49', 'l54', 'l58', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "72, impaired ['l7', 'l19', 'l30', 'l41', 'l50', 'l55', 'l59', 'l69', 'l77']", + "73, proliferation. ['l8', 'l20', 'l31', 'l42', 'l51', 'l56', 'l60', 'l70', 'l77']", + "75, Glut1 ['l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "76, deficiency ['l78', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "77, impaired ['l9', 'l21', 'l32', 'l43', 'l61', 'l71', 'l79', 'l87', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "78, in ['l62', 'l80', 'l88', 'l95', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "79, vivo ['l63', 'l72', 'l81', 'l89', 'l96', 'l102', 'l108', 'l109', 'l110', 'l111', 'l112']", + "80, keratinocyte ['l10', 'l22', 'l33', 'l44', 'l64', 'l73', 'l82', 'l90', 'l97', 'l103', 'l108', 'l113', 'l114', 'l115', 'l116']", + "81, proliferation ['l11', 'l23', 'l34', 'l45', 'l52', 'l57', 'l65', 'l74', 'l83', 'l91', 'l98', 'l104', 'l109', 'l113', 'l117']", + "83, migration ['l12', 'l24', 'l35', 'l46', 'l66', 'l75', 'l84', 'l92', 'l99', 'l105', 'l110', 'l114', 'l117', 'l118', 'l119']", + "88, mouse ['l67', 'l85', 'l93', 'l100', 'l106', 'l111', 'l115', 'l118', 'l120']", + "89, skin. ['l36', 'l68', 'l76', 'l86', 'l94', 'l101', 'l107', 'l112', 'l116', 'l119', 'l120']", + "94, pharmacological ['l121', 'l122', 'l123', 'l124']", + "95, Glut1 ['l121', 'l125', 'l126', 'l127']", + "96, inactivation ['l122', 'l125', 'l128', 'l129']", + "100, mouse ['l123', 'l126', 'l128', 'l130']", + "101, models ['l124', 'l127', 'l129', 'l130']", + "109, Glut1 ['l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "110, inhibitor ['l131', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "117, Glut1 ['l132', 'l138', 'l144', 'l145', 'l146', 'l147', 'l148']", + "118, inhibition ['l133', 'l139', 'l144', 'l149', 'l150', 'l151', 'l152']", + "126, human ['l134', 'l140', 'l145', 'l149', 'l153', 'l154', 'l155']", + "127, psoriatic ['l135', 'l141', 'l146', 'l150', 'l153', 'l156', 'l157']", + "128, skin ['l136', 'l142', 'l147', 'l151', 'l154', 'l156', 'l158']", + "129, organoids. ['l137', 'l143', 'l148', 'l152', 'l155', 'l157', 'l158']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "keratinocyte-specific", + "ablation", + "of", + "Glut1", + "Glut1-deficient", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "keratinocytes,", + "keratinocytes", + "keratinocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "keratinocyte-specific", + "ablation", + "of", + "Glut1", + "Glut1-deficient", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "keratinocyte-specific", + "ablation", + "of", + "Glut1", + "Glut1-deficient", + "deficiency" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation.", + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "keratinocyte-specific", + "ablation", + "of", + "Glut1", + "Glut1-deficient", + "deficiency" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "Glut1-deficient", + "Glut1", + "deficiency" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skin.", + "mouse" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "keratinocytes,", + "keratinocytes", + "keratinocyte" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "keratinocytes,", + "keratinocytes", + "keratinocyte" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation.", + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Glut1-deficient", + "Glut1", + "deficiency" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "keratinocytes", + "keratinocyte" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation.", + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "skin." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "skin." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pharmacological", + "Glut1", + "inactivation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Glut1", + "inhibitor", + "inhibition" + ] + }, + "context": { + "val": "organoid", + "words": [ + "human", + "psoriatic", + "skin", + "organoids." + ] + } + } + ] + }, + { + "PMID": "29578538", + "TEXT": "Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer diagnosed in more than 200,000 women each year and is recalcitrant to targeted therapies. Although TNBCs harbor multiple hyperactive receptor tyrosine kinases (RTKs), RTK inhibitors have been largely ineffective in TNBC patients thus far. We developed a broadly effective therapeutic strategy for TNBC that is based on combined inhibition of receptors that share the negative regulator PTPN12. Previously, we and others identified the tyrosine phosphatase PTPN12 as a tumor suppressor that is frequently inactivated in TNBC. PTPN12 restrains several RTKs, suggesting that PTPN12 deficiency leads to aberrant activation of multiple RTKs and a co-dependency on these receptors. This in turn leads to the therapeutic hypothesis that PTPN12-deficient TNBCs may be responsive to combined RTK inhibition. However, the repertoire of RTKs that are restrained by PTPN12 in human cells has not been systematically explored. By methodically identifying the suite of RTK substrates (MET, PDGFRβ, EGFR, and others) inhibited by PTPN12, we rationalized a combination RTK-inhibitor therapy that induced potent tumor regression across heterogeneous models of TNBC. Orthogonal approaches revealed that PTPN12 was recruited to and inhibited these receptors after ligand stimulation, thereby serving as a feedback mechanism to limit receptor signaling. Cancer-associated mutation of PTPN12 or reduced PTPN12 protein levels diminished this feedback mechanism, leading to aberrant activity of these receptors. Restoring PTPN12 protein levels restrained signaling from RTKs, including PDGFRβ and MET, and impaired TNBC survival. In contrast with single agents, combined inhibitors targeting the PDGFRβ and MET receptors induced the apoptosis in TNBC cells in vitro and in vivo. This therapeutic strategy resulted in tumor regressions in chemo-refractory patient-derived TNBC models. Notably, response correlated with PTPN12 deficiency, suggesting that impaired receptor feedback may establish a combined addiction to these proto-oncogenic receptors. Taken together, our data provide a rationale", + "TAG_DATA": [ + "93, PTPN12 {'perturbing_action': 'B-gene loss-of-function'}", + "167, induced {'effect': 'B-positive'}", + "169, tumor {'phenotype': 'B-tumour regression'}", + "170, regression {'phenotype': 'I-tumour regression'}", + "175, TNBC. {'context': 'B-neoplasm'}", + "201, Cancer-associated {'perturbing_action': 'B-other'}", + "202, mutation {'perturbing_action': 'I-other'}", + "203, of {'perturbing_action': 'I-other'}", + "204, PTPN12 {'perturbing_action': 'I-other'}", + "206, reduced {'perturbing_action': 'B-gene loss-of-function'}", + "221, Restoring {'perturbing_action': 'B-gene gain-of-function'}", + "222, PTPN12 {'perturbing_action': 'I-gene gain-of-function'}", + "223, protein {'perturbing_action': 'I-gene gain-of-function'}", + "224, levels {'perturbing_action': 'I-gene gain-of-function'}", + "235, TNBC {'context': 'B-neoplasm'}", + "250, induced {'effect': 'B-positive'}", + "252, apoptosis {'phenotype': 'B-apoptosis'}", + "254, TNBC {'context': 'B-transformed cells'}", + "255, cells {'context': 'I-transformed cells'}", + "256, in {'context': 'B-in vitro'}", + "257, vitro {'context': 'I-in vitro'}", + "259, in {'context': 'B-in vivo'}", + "260, vivo. {'context': 'I-in vivo'}", + "264, resulted {'effect': 'B-positive'}", + "266, tumor {'phenotype': 'B-tumour regression'}", + "267, regressions {'phenotype': 'I-tumour regression'}", + "270, patient-derived {'context': 'B-neoplasm'}", + "271, TNBC {'context': 'I-neoplasm'}", + "272, models. {'context': 'I-neoplasm'}", + "277, PTPN12 {'perturbing_action': 'B-gene loss-of-function'}", + "278, deficiency, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "93, PTPN12 ['l0']", + "167, induced ['l0', 'l1', 'l2', 'l3']", + "169, tumor ['l1', 'l4', 'l5']", + "170, regression ['l2', 'l4', 'l6']", + "175, TNBC. ['l3', 'l5', 'l6']", + "201, Cancer-associated ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "202, mutation ['l7', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "203, of ['l8', 'l24', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "204, PTPN12 ['l9', 'l25', 'l39', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "206, reduced ['l10', 'l26', 'l40', 'l53', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "208, protein ['l11', 'l27', 'l41', 'l54', 'l67', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "221, Restoring ['l68', 'l84', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "222, PTPN12 ['l12', 'l55', 'l69', 'l85', 'l97', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "223, protein ['l13', 'l28', 'l42', 'l56', 'l70', 'l86', 'l98', 'l117', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "224, levels ['l14', 'l29', 'l43', 'l57', 'l71', 'l87', 'l99', 'l118', 'l136', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "235, TNBC ['l15', 'l30', 'l44', 'l58', 'l72', 'l88', 'l100', 'l119', 'l137', 'l149', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "250, induced ['l16', 'l31', 'l45', 'l59', 'l73', 'l89', 'l101', 'l120', 'l138', 'l150', 'l158', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "252, apoptosis ['l17', 'l32', 'l46', 'l60', 'l74', 'l90', 'l102', 'l121', 'l139', 'l151', 'l159', 'l166', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "254, TNBC ['l18', 'l33', 'l47', 'l61', 'l75', 'l91', 'l103', 'l122', 'l140', 'l152', 'l160', 'l167', 'l173', 'l179', 'l180', 'l181', 'l182', 'l183']", + "255, cells ['l19', 'l34', 'l48', 'l62', 'l76', 'l92', 'l104', 'l123', 'l141', 'l153', 'l161', 'l168', 'l174', 'l179', 'l184', 'l185', 'l186', 'l187']", + "256, in ['l20', 'l35', 'l49', 'l63', 'l77', 'l93', 'l105', 'l124', 'l142', 'l154', 'l162', 'l169', 'l175', 'l180', 'l184', 'l188', 'l189', 'l190']", + "257, vitro ['l21', 'l36', 'l50', 'l64', 'l78', 'l94', 'l106', 'l125', 'l143', 'l155', 'l163', 'l170', 'l176', 'l181', 'l185', 'l188', 'l191', 'l192']", + "259, in ['l22', 'l37', 'l51', 'l65', 'l79', 'l95', 'l107', 'l126', 'l144', 'l156', 'l164', 'l171', 'l177', 'l182', 'l186', 'l189', 'l191', 'l193']", + "260, vivo. ['l23', 'l38', 'l52', 'l66', 'l80', 'l96', 'l108', 'l127', 'l145', 'l157', 'l165', 'l172', 'l178', 'l183', 'l187', 'l190', 'l192', 'l193']", + "264, resulted ['l81', 'l109', 'l128', 'l146', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200']", + "266, tumor ['l82', 'l110', 'l129', 'l147', 'l194', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206']", + "267, regressions ['l83', 'l111', 'l130', 'l148', 'l195', 'l201', 'l207', 'l208', 'l209', 'l210', 'l211']", + "270, patient-derived ['l112', 'l131', 'l196', 'l202', 'l207', 'l212', 'l213', 'l214', 'l215']", + "271, TNBC ['l113', 'l132', 'l197', 'l203', 'l208', 'l212', 'l216', 'l217', 'l218']", + "272, models. ['l114', 'l133', 'l198', 'l204', 'l209', 'l213', 'l216', 'l219', 'l220']", + "277, PTPN12 ['l115', 'l134', 'l199', 'l205', 'l210', 'l214', 'l217', 'l219', 'l221']", + "278, deficiency, ['l116', 'l135', 'l200', 'l206', 'l211', 'l215', 'l218', 'l220', 'l221']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PTPN12", + "reduced", + "deficiency," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "resulted" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "resulted" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression", + "regressions" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "resulted" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "TNBC.", + "TNBC", + "patient-derived", + "models." + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression", + "regressions" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "TNBC.", + "patient-derived", + "TNBC", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Cancer-associated", + "mutation", + "of", + "PTPN12" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "TNBC" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Cancer-associated", + "mutation", + "of", + "PTPN12" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Cancer-associated", + "mutation", + "of", + "PTPN12" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Cancer-associated", + "mutation", + "of", + "PTPN12" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Cancer-associated", + "mutation", + "of", + "PTPN12" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Cancer-associated", + "mutation", + "of", + "PTPN12" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "reduced", + "PTPN12", + "deficiency," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "TNBC", + "patient-derived", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "reduced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "reduced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "reduced" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "reduced", + "PTPN12", + "deficiency," + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regressions" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoring", + "PTPN12", + "protein", + "levels" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "TNBC", + "patient-derived", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoring", + "PTPN12", + "protein", + "levels" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "resulted" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoring", + "PTPN12", + "protein", + "levels" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoring", + "PTPN12", + "protein", + "levels" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoring", + "PTPN12", + "protein", + "levels" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoring", + "PTPN12", + "protein", + "levels" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoring", + "PTPN12", + "protein" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regressions" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "TNBC" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "29505033", + "TEXT": "Most anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung tumors initially respond to small-molecule ALK inhibitors, but drug resistance often develops. Of tumors that develop resistance to highly potent second-generation ALK inhibitors, approximately half harbor resistance mutations in ALK, while the other half have other mechanisms underlying resistance. Members of the latter group often have activation of at least one of several different tyrosine kinases driving resistance. Such tumors are not expected to respond to lorlatinib-a third-generation inhibitor targeting ALK that is able to overcome all clinically identified resistant mutations in ALK-and further therapeutic options are limited. Herein, we deployed a shRNA screen of 1,000 genes in multiple ALK-inhibitor-resistant patient-derived cells (PDCs) to discover those that confer sensitivity to ALK inhibition. This approach identified SHP2, a nonreceptor protein tyrosine phosphatase, as a common targetable resistance node in multiple PDCs. SHP2 provides a parallel survival input downstream of multiple tyrosine kinases that promote resistance to ALK inhibitors. Treatment with SHP099, the recently discovered small-molecule inhibitor of SHP2, in combination with the ALK tyrosine kinase inhibitor (TKI) ceritinib halted the growth of resistant PDCs through preventing compensatory RAS and ERK1 and ERK2 (ERK1/2) reactivation. These findings suggest that combined ALK and SHP2 inhibition may be a promising therapeutic strategy for resistant cancers driven by several different ALK-independent mechanisms underlying resistance.", + "TAG_DATA": [ + "108, cells {'context': 'I-cells'}", + "156, SHP099, {'perturbing_action': 'B-pharmacological inhibition'}", + "157, the {'perturbing_action': 'I-pharmacological inhibition'}", + "160, small-molecule {'perturbing_action': 'I-pharmacological inhibition'}", + "161, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "162, of {'perturbing_action': 'I-pharmacological inhibition'}", + "163, SHP2, {'perturbing_action': 'I-pharmacological inhibition'}", + "178, resistant {'context': 'B-transformed cells'}", + "179, PDCs {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "107, patient-derived ['l0']", + "108, cells ['l0']", + "156, SHP099, ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "157, the ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "160, small-molecule ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "161, inhibitor ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "162, of ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "163, SHP2, ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "178, resistant ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "179, PDCs ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "SHP099,", + "the", + "small-molecule", + "inhibitor", + "of", + "SHP2," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "resistant", + "PDCs" + ] + } + } + ] + }, + { + "PMID": "29480894", + "TEXT": "We grafted human spinal cord-derived neural progenitor cells (NPCs) into sites of cervical spinal cord injury in rhesus monkeys (Macaca mulatta). Under three-drug immunosuppression, grafts survived at least 9 months postinjury and expressed both neuronal and glial markers. Monkey axons regenerated into grafts and formed synapses. Hundreds of thousands of human axons extended out from grafts through monkey white matter and synapsed in distal gray matter. Grafts gradually matured over 9 months and improved forelimb function beginning several months after grafting. These findings in a 'preclinical trial' support translation of NPC graft therapy to humans with the objective of reconstituting both a neuronal and glial milieu in the site of spinal cord injury.", + "TAG_DATA": [ + "2, human {'context': 'B-cells'}", + "3, spinal {'context': 'I-cells'}", + "4, cord-derived {'context': 'I-cells'}", + "5, neural {'context': 'I-cells'}", + "6, progenitor {'context': 'I-cells'}", + "7, cells {'context': 'I-cells'}", + "8, (NPCs) {'context': 'I-cells'}", + "17, rhesus {'context': 'B-organism'}", + "18, monkeys {'context': 'I-organism'}", + "19, (Macaca {'context': 'I-organism'}", + "20, mulatta). {'context': 'I-organism'}", + "38, Monkey {'context': 'B-cells'}", + "39, axons {'context': 'I-cells'}", + "50, human {'context': 'B-cells'}", + "51, axons {'context': 'I-cells'}", + "74, forelimb {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "2, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "3, spinal ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "4, cord-derived ['l1', 'l16', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "5, neural ['l2', 'l17', 'l31', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "6, progenitor ['l3', 'l18', 'l32', 'l45', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "7, cells ['l4', 'l19', 'l33', 'l46', 'l58', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "8, (NPCs) ['l5', 'l20', 'l34', 'l47', 'l59', 'l70', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "17, rhesus ['l6', 'l21', 'l35', 'l48', 'l60', 'l71', 'l81', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "18, monkeys ['l7', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l97', 'l98', 'l99', 'l100']", + "19, (Macaca ['l8', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l97', 'l101', 'l102', 'l103', 'l104']", + "20, mulatta). ['l9', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l98', 'l101', 'l105', 'l106', 'l107']", + "38, Monkey ['l10', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l99', 'l102', 'l105', 'l108', 'l109', 'l110', 'l111']", + "39, axons ['l11', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l95', 'l100', 'l103', 'l106', 'l108', 'l112', 'l113']", + "50, human ['l12', 'l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l109', 'l114', 'l115', 'l116']", + "51, axons ['l13', 'l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l114', 'l117', 'l118', 'l119']", + "57, monkey ['l14', 'l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l110', 'l112', 'l115', 'l117', 'l120']", + "59, matter ['l15', 'l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l96', 'l104', 'l107', 'l111', 'l113', 'l116', 'l118', 'l120']", + "74, forelimb ['l119']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29400710", + "TEXT": "The adoptive transfer of T cells engineered with a chimeric antigen receptor (CAR) (hereafter referred to as CAR-T cells) specific for the B lymphocyte antigen CD19 has shown impressive clinical responses in patients with refractory B cell malignancies. However, the therapeutic effects of CAR-T cells that target other malignancies have not yet resulted in significant clinical benefit. Although inefficient tumor trafficking and various immunosuppressive mechanisms can impede CAR-T cell effector responses, the signals delivered by the current CAR constructs may still be insufficient to fully activate antitumor T cell functions. Optimal T cell activation and proliferation requires multiple signals, including T cell receptor (TCR) engagement (signal 1), co-stimulation (signal 2) and cytokine engagement (signal 3). However, CAR constructs currently being tested in the clinic contain a CD3z (TCR signaling) domain and co-stimulatory domain(s) but not a domain that transmits signal 3 (refs. 13, 14, 15, 16, 17, 18). Here we have developed a novel CAR construct capable of inducing cytokine signaling after antigen stimulation. This new-generation CD19 CAR encodes a truncated cytoplasmic domain from the interleukin (IL)-2 receptor β-chain (IL-2Rβ) and a STAT3-binding tyrosine-X-X-glutamine (YXXQ) motif, together with the TCR signaling (CD3z) and co-stimulatory (CD28) domains (hereafter referred to as 28-ΔIL2RB-z(YXXQ)). The 28-ΔIL2RB-z(YXXQ) CAR-T cells showed antigen-dependent activation of the JAK kinase and of the STAT3 and STAT5 transcription factors signaling pathways, which promoted their proliferation and prevented terminal differentiation in vitro. The 28-ΔIL2RB-z(YXXQ) CAR-T cells demonstrated superior in vivo persistence and antitumor effects in models of liquid and solid tumors as compared with CAR-T cells expressing a CD28 or 4-1BB co-stimulatory domain alone. Taken", + "TAG_DATA": [ + "204, cells {'context': 'I-cells'}", + "223, promoted {'effect': 'B-positive'}", + "225, proliferation {'phenotype': 'B-proliferation'}", + "227, prevented {'effect': 'B-negative'}", + "228, terminal {'phenotype': 'B-differentiation'}", + "229, differentiation {'phenotype': 'I-differentiation'}", + "230, in {'context': 'B-in vitro'}", + "231, vitro. {'context': 'I-in vitro'}", + "235, cells {'context': 'I-cells'}", + "238, in {'context': 'B-in vivo'}", + "239, vivo {'context': 'I-in vivo'}", + "245, models {'context': 'B-neoplasm'}", + "247, liquid {'context': 'B-neoplasm'}", + "248, and {'context': 'I-neoplasm'}", + "249, solid {'context': 'I-neoplasm'}", + "250, tumors {'context': 'I-neoplasm'}", + "254, CAR-T {'context': 'B-cells'}", + "255, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "204, cells ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "223, promoted ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "225, proliferation ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "227, prevented ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "228, terminal ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "229, differentiation ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "230, in ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "231, vitro. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "235, cells ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "238, in ['l28', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "239, vivo ['l29', 'l37', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "245, models ['l30', 'l38', 'l45', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "247, liquid ['l31', 'l39', 'l46', 'l52', 'l58', 'l59', 'l60', 'l61', 'l62']", + "248, and ['l32', 'l40', 'l47', 'l53', 'l58', 'l63', 'l64', 'l65', 'l66']", + "249, solid ['l33', 'l41', 'l48', 'l54', 'l59', 'l63', 'l67', 'l68', 'l69']", + "250, tumors ['l34', 'l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l70', 'l71']", + "254, CAR-T ['l35', 'l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l72']", + "255, cells ['l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l69', 'l71', 'l72']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "terminal", + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "terminal", + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "terminal", + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "terminal", + "differentiation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "29377004", + "TEXT": "Hematopoietic stem cells (HSCs) quiescently reside in bone marrow niches and have the capacity to self-renew or differentiate to form all of the blood cells throughout the lifespan of an animal. Allogeneic HSC transplantation is a life-saving treatment for malignant and nonmalignant disorders. HSCs isolated from umbilical cord blood (CB) are used for hematopoietic cell transplantation (HCT), but due to the limited numbers of HSCs in single units of umbilical CB, a number of methods have been proposed for ex vivo expansion of human HSCs. We show here that antagonism of peroxisome proliferator-activated receptor (PPAR)-γ promotes ex vivo expansion of phenotypically and functionally defined subsets of human CB HSCs and hematopoietic progenitor cells (HSPCs). PPAR-γ antagonism in CB HSPCs strongly downregulated expression of several differentiation-associated genes, as well as fructose-bisphosphatase 1 (FBP1; which encodes a negative regulator of glycolysis), and enhanced glycolysis without compromising mitochondrial metabolism. The expansion of CB HSPCs by PPAR-γ antagonism was completely suppressed by removal of glucose or inhibition of glycolysis. Moreover, knockdown of FBP1 expression promoted glycolysis and ex vivo expansion of long-term repopulating CB HSPCs, whereas overexpression of FBP1 suppressed the expansion of CB HSPCs that was induced by PPAR-γ antagonism. Our study suggests the possibility for a new and simple means for metabolic reprogramming of CB HSPCs to improve the efficacy of HCT.", + "TAG_DATA": [ + "89, antagonism {'perturbing_action': 'B-pharmacological inhibition'}", + "90, of {'perturbing_action': 'I-pharmacological inhibition'}", + "91, peroxisome {'perturbing_action': 'I-pharmacological inhibition'}", + "92, proliferator-activated {'perturbing_action': 'I-pharmacological inhibition'}", + "93, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "94, (PPAR)-γ {'perturbing_action': 'I-pharmacological inhibition'}", + "106, human {'context': 'B-cells'}", + "107, CB {'context': 'I-cells'}", + "108, HSCs {'context': 'I-cells'}", + "110, hematopoietic {'context': 'B-cells'}", + "111, progenitor {'context': 'I-cells'}", + "112, cells {'context': 'I-cells'}", + "113, (HSPCs). {'context': 'I-cells'}", + "114, PPAR-γ {'perturbing_action': 'B-pharmacological inhibition'}", + "115, antagonism {'perturbing_action': 'I-pharmacological inhibition'}", + "117, CB {'context': 'B-cells'}", + "118, HSPCs {'context': 'I-cells'}", + "149, CB {'context': 'B-cells'}", + "150, HSPCs {'context': 'I-cells'}", + "152, PPAR-γ {'perturbing_action': 'B-pharmacological inhibition'}", + "153, antagonism {'perturbing_action': 'I-pharmacological inhibition'}", + "166, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "167, of {'perturbing_action': 'I-rnai/knockdown'}", + "168, FBP1 {'perturbing_action': 'I-rnai/knockdown'}", + "169, expression {'perturbing_action': 'I-rnai/knockdown'}", + "177, long-term {'context': 'B-cells'}", + "178, repopulating {'context': 'I-cells'}", + "179, CB {'context': 'I-cells'}", + "180, HSPCs, {'context': 'I-cells'}", + "182, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "183, of {'perturbing_action': 'I-gene gain-of-function'}", + "184, FBP1 {'perturbing_action': 'I-gene gain-of-function'}", + "189, CB {'context': 'B-cells'}", + "190, HSPCs {'context': 'I-cells'}", + "195, PPAR-γ {'perturbing_action': 'B-pharmacological inhibition'}", + "196, antagonism. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "89, antagonism ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "90, of ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "91, peroxisome ['l1', 'l17', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "92, proliferator-activated ['l2', 'l18', 'l33', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "93, receptor ['l3', 'l19', 'l34', 'l48', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "94, (PPAR)-γ ['l4', 'l20', 'l35', 'l49', 'l62', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "106, human ['l5', 'l21', 'l36', 'l50', 'l63', 'l75', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "107, CB ['l6', 'l22', 'l37', 'l51', 'l64', 'l76', 'l87', 'l93', 'l94', 'l95', 'l96', 'l97']", + "108, HSCs ['l7', 'l23', 'l38', 'l52', 'l65', 'l77', 'l88', 'l93', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "110, hematopoietic ['l8', 'l24', 'l39', 'l53', 'l66', 'l78', 'l98', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "111, progenitor ['l9', 'l25', 'l40', 'l54', 'l67', 'l79', 'l99', 'l104', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "112, cells ['l10', 'l26', 'l41', 'l55', 'l68', 'l80', 'l89', 'l94', 'l100', 'l105', 'l114', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "113, (HSPCs). ['l11', 'l27', 'l42', 'l56', 'l69', 'l81', 'l90', 'l95', 'l101', 'l106', 'l115', 'l123', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "114, PPAR-γ ['l12', 'l28', 'l43', 'l57', 'l70', 'l82', 'l107', 'l116', 'l124', 'l130', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "115, antagonism ['l13', 'l29', 'l44', 'l58', 'l71', 'l83', 'l108', 'l117', 'l125', 'l131', 'l136', 'l143', 'l144', 'l145', 'l146', 'l147']", + "117, CB ['l14', 'l30', 'l45', 'l59', 'l72', 'l84', 'l91', 'l96', 'l102', 'l109', 'l118', 'l126', 'l132', 'l137', 'l143', 'l148', 'l149']", + "118, HSPCs ['l15', 'l31', 'l46', 'l60', 'l73', 'l85', 'l92', 'l97', 'l103', 'l110', 'l119', 'l127', 'l133', 'l138', 'l144', 'l148', 'l150']", + "149, CB ['l111', 'l120', 'l128', 'l134', 'l139', 'l145', 'l151', 'l152', 'l153']", + "150, HSPCs ['l16', 'l32', 'l47', 'l61', 'l74', 'l86', 'l112', 'l121', 'l129', 'l135', 'l140', 'l146', 'l149', 'l150', 'l151', 'l154', 'l155']", + "152, PPAR-γ ['l141', 'l152', 'l154', 'l156']", + "153, antagonism ['l113', 'l122', 'l142', 'l147', 'l153', 'l155', 'l156']", + "166, knockdown ['l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163']", + "167, of ['l157', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "168, FBP1 ['l158', 'l164', 'l170', 'l171', 'l172', 'l173', 'l174']", + "169, expression ['l159', 'l165', 'l170', 'l175', 'l176', 'l177', 'l178']", + "177, long-term ['l160', 'l166', 'l171', 'l175', 'l179', 'l180', 'l181']", + "178, repopulating ['l161', 'l167', 'l172', 'l176', 'l179', 'l182', 'l183']", + "179, CB ['l162', 'l168', 'l173', 'l177', 'l180', 'l182', 'l184']", + "180, HSPCs, ['l163', 'l169', 'l174', 'l178', 'l181', 'l183', 'l184']", + "182, overexpression ['l185', 'l186', 'l187', 'l188', 'l189', 'l190']", + "183, of ['l185', 'l191', 'l192', 'l193', 'l194', 'l195']", + "184, FBP1 ['l186', 'l191', 'l196', 'l197', 'l198', 'l199']", + "189, CB ['l187', 'l192', 'l196', 'l200', 'l201', 'l202']", + "190, HSPCs ['l188', 'l193', 'l197', 'l200', 'l203', 'l204']", + "195, PPAR-γ ['l189', 'l194', 'l198', 'l201', 'l203', 'l205']", + "196, antagonism. ['l190', 'l195', 'l199', 'l202', 'l204', 'l205']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antagonism", + "of", + "peroxisome", + "proliferator-activated", + "receptor", + "(PPAR)-γ", + "PPAR-γ", + "antagonism." + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "CB", + "HSCs", + "hematopoietic", + "progenitor", + "cells", + "(HSPCs).", + "HSPCs" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "FBP1", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "long-term", + "repopulating", + "CB", + "HSPCs," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "FBP1" + ] + }, + "context": { + "val": "cells", + "words": [ + "CB", + "HSPCs" + ] + } + } + ] + }, + { + "PMID": "29334376", + "TEXT": "Metastasis results from a complex set of traits acquired by tumor cells, distinct from those necessary for tumorigenesis. Here, we investigate the contribution of enhancer elements to the metastatic phenotype of osteosarcoma. Through epigenomic profiling, we identify substantial differences in enhancer activity between primary and metastatic human tumors and between near isogenic pairs of highly lung metastatic and nonmetastatic osteosarcoma cell lines. We term these regions metastatic variant enhancer loci (Met-VELs). Met-VELs drive coordinated waves of gene expression during metastatic colonization of the lung. Met-VELs cluster nonrandomly in the genome, indicating that activity of these enhancers and expression of their associated gene targets are positively selected. As evidence of this causal association, osteosarcoma lung metastasis is inhibited by global interruptions of Met-VEL-associated gene expression via pharmacologic BET inhibition, by knockdown of AP-1 transcription factors that occupy Met-VELs, and by knockdown or functional inhibition of individual genes activated by Met-VELs, such as that encoding coagulation factor III/tissue factor (F3). We further show that genetic deletion of a single Met-VEL at the F3 locus blocks metastatic cell outgrowth in the lung. These findings indicate that Met-VELs and the genes they regulate play a functional role in metastasis and may be suitable targets for antimetastatic therapies.", + "TAG_DATA": [ + "116, inhibited {'effect': 'B-negative'}", + "129, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "162, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "163, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "164, of {'perturbing_action': 'I-gene loss-of-function'}", + "165, a {'perturbing_action': 'I-gene loss-of-function'}", + "166, single {'perturbing_action': 'I-gene loss-of-function'}", + "167, Met-VEL {'perturbing_action': 'I-gene loss-of-function'}", + "168, at {'perturbing_action': 'I-gene loss-of-function'}", + "169, the {'perturbing_action': 'I-gene loss-of-function'}", + "170, F3 {'perturbing_action': 'I-gene loss-of-function'}", + "171, locus {'perturbing_action': 'I-gene loss-of-function'}", + "172, blocks {'effect': 'B-negative'}", + "173, metastatic {'phenotype': 'B-metastasis'}", + "174, cell {'phenotype': 'I-metastasis'}", + "175, outgrowth {'phenotype': 'I-metastasis'}", + "178, lung. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "116, inhibited ['l0']", + "129, knockdown ['l0']", + "162, genetic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "163, deletion ['l1', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "164, of ['l2', 'l15', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "165, a ['l3', 'l16', 'l28', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "166, single ['l4', 'l17', 'l29', 'l40', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "167, Met-VEL ['l5', 'l18', 'l30', 'l41', 'l51', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "168, at ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "169, the ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "170, F3 ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "171, locus ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l91', 'l92', 'l93', 'l94', 'l95']", + "172, blocks ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l96', 'l97', 'l98', 'l99']", + "173, metastatic ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l100', 'l101', 'l102']", + "174, cell ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l103', 'l104']", + "175, outgrowth ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l105']", + "178, lung. ['l14', 'l27', 'l39', 'l50', 'l60', 'l69', 'l77', 'l84', 'l90', 'l95', 'l99', 'l102', 'l104', 'l105']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "a", + "single", + "Met-VEL", + "at", + "the", + "F3", + "locus" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "a", + "single", + "Met-VEL", + "at", + "the", + "F3", + "locus" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "cell", + "outgrowth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "a", + "single", + "Met-VEL", + "at", + "the", + "F3", + "locus" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "cell", + "outgrowth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung." + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "cell", + "outgrowth" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung." + ] + } + } + ] + }, + { + "PMID": "29334371", + "TEXT": "Intratumor heterogeneity is a key factor contributing to therapeutic failure and, hence, cancer lethality. Heterogeneous tumors show partial therapy responses, allowing for the emergence of drug-resistant clones that often express high levels of the receptor tyrosine kinase AXL. In melanoma, AXL-high cells are resistant to MAPK pathway inhibitors, whereas AXL-low cells are sensitive to these inhibitors, rationalizing a differential therapeutic approach. We developed an antibody-drug conjugate, AXL-107-MMAE, comprising a human AXL antibody linked to the microtubule-disrupting agent monomethyl auristatin E. We found that AXL-107-MMAE, as a single agent, displayed potent in vivo anti-tumor activity in patient-derived xenografts, including melanoma, lung, pancreas and cervical cancer. By eliminating distinct populations in heterogeneous melanoma cell pools, AXL-107-MMAE and MAPK pathway inhibitors cooperatively inhibited tumor growth. Furthermore, by inducing AXL transcription, BRAF/MEK inhibitors potentiated the efficacy of AXL-107-MMAE. These findings provide proof of concept for the premise that rationalized combinatorial targeting of distinct populations in heterogeneous tumors may improve therapeutic effect, and merit clinical validation of AXL-107-MMAE in both treatment-naive and drug-resistant cancers in mono- or combination therapy.", + "TAG_DATA": [ + "90, in {'context': 'B-in vivo'}", + "91, vivo {'context': 'B-in vivo'}", + "95, patient-derived {'context': 'B-xenograft'}", + "96, xenografts, {'context': 'I-xenograft'}", + "98, melanoma, {'context': 'B-neoplasm'}", + "99, lung, {'context': 'B-neoplasm'}", + "100, pancreas {'context': 'I-neoplasm'}", + "102, cervical {'context': 'B-neoplasm'}", + "103, cancer. {'context': 'I-neoplasm'}", + "110, melanoma {'context': 'B-transformed cells'}", + "111, cell {'context': 'I-transformed cells'}", + "119, inhibited {'effect': 'B-negative'}", + "120, tumor {'phenotype': 'B-tumour growth'}", + "121, growth. {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "90, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "91, vivo ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "95, patient-derived ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "96, xenografts, ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "98, melanoma, ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "99, lung, ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "100, pancreas ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "102, cervical ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "103, cancer. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "110, melanoma ['l36', 'l37', 'l38', 'l39']", + "111, cell ['l36', 'l40', 'l41', 'l42']", + "119, inhibited ['l37', 'l40', 'l43', 'l44']", + "120, tumor ['l38', 'l41', 'l43', 'l45']", + "121, growth. ['l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cell" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + } + ] + }, + { + "PMID": "29309057", + "TEXT": "Rhabdomyolysis is a serious syndrome caused by skeletal muscle injury and the subsequent release of breakdown products from damaged muscle cells into systemic circulation. The muscle damage most often results from strenuous exercise, muscle hypoxia, medications, or drug abuse and can lead to life-threatening complications, such as acute kidney injury (AKI). Rhabdomyolysis and the AKI complication can also occur during crush syndrome, an emergency condition that commonly occurs in victims of natural disasters, such as earthquakes, and man-made disasters, such as wars and terrorism. Myoglobin released from damaged muscle is believed to trigger renal dysfunction in this form of AKI. Recently, macrophages were implicated in the disease pathogenesis of rhabdomyolysis-induced AKI, but the precise molecular mechanism remains unclear. In the present study, we show that macrophages released extracellular traps (ETs) comprising DNA fibers and granule proteins in a mouse model of rhabdomyolysis. Heme-activated platelets released from necrotic muscle cells during rhabdomyolysis enhanced the production of macrophage extracellular traps (METs) through increasing intracellular reactive oxygen species generation and histone citrullination. Here we report, for the first time to our knowledge, this unanticipated role for METs and platelets as a sensor of myoglobin-derived heme in rhabdomyolysis-induced AKI. This previously unknown mechanism might be targeted for treatment of the disease. Finally, we found a new therapeutic tool for prevention of AKI after rhabdomyolysis, which might rescue some sufferers of this pathology.", + "TAG_DATA": [ + "125, macrophages {'context': 'B-cells'}", + "138, mouse {'context': 'B-organism'}", + "139, model {'context': 'I-organism'}", + "146, necrotic {'context': 'B-cells'}", + "147, muscle {'context': 'I-cells'}", + "148, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "125, macrophages ['l0', 'l1']", + "138, mouse ['l0', 'l2']", + "139, model ['l1', 'l2']", + "146, necrotic ['l3', 'l4']", + "147, muscle ['l3', 'l5']", + "148, cells ['l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29227477", + "TEXT": "Activation of apoptosis signal-regulating kinase 1 (ASK1) in hepatocytes is a key process in the progression of nonalcoholic steatohepatitis (NASH) and a promising target for treatment of the condition. However, the mechanism underlying ASK1 activation is still unclear, and thus the endogenous regulators of this kinase remain open to be exploited as potential therapeutic targets. In screening for proteins that interact with ASK1 in the context of NASH, we identified the deubiquitinase tumor necrosis factor alpha-induced protein 3 (TNFAIP3) as a key endogenous suppressor of ASK1 activation, and we found that TNFAIP3 directly interacts with and deubiquitinates ASK1 in hepatocytes. Hepatocyte-specific ablation of Tnfaip3 exacerbated nonalcoholic fatty liver disease- and NASH-related phenotypes in mice, including glucose metabolism disorders, lipid accumulation and enhanced inflammation, in an ASK1-dependent manner. In contrast, transgenic or adeno-associated virus-mediated TNFAIP3 gene delivery in the liver in both mouse and nonhuman primate models of NASH substantially blocked the onset and progression of the disease. These results implicate TNFAIP3 as a functionally important endogenous suppressor of ASK1 hyperactivation in the pathogenesis of NASH and identify it as a potential new molecular target for NASH therapy.", + "TAG_DATA": [ + "100, Hepatocyte-specific {'perturbing_action': 'B-gene loss-of-function'}", + "101, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "102, of {'perturbing_action': 'I-gene loss-of-function'}", + "103, Tnfaip3 {'perturbing_action': 'I-gene loss-of-function'}", + "113, mice, {'context': 'B-organism'}", + "129, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "130, or {'perturbing_action': 'I-gene gain-of-function'}", + "131, adeno-associated {'perturbing_action': 'I-gene gain-of-function'}", + "132, virus-mediated {'perturbing_action': 'I-gene gain-of-function'}", + "133, TNFAIP3 {'perturbing_action': 'I-gene gain-of-function'}", + "134, gene {'perturbing_action': 'I-gene gain-of-function'}", + "135, delivery {'perturbing_action': 'I-gene gain-of-function'}", + "138, liver {'context': 'B-tissue/organ'}", + "141, mouse {'context': 'B-organism'}", + "143, nonhuman {'context': 'B-organism'}", + "144, primate {'context': 'I-organism'}", + "145, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "100, Hepatocyte-specific ['l0', 'l1', 'l2', 'l3']", + "101, ablation ['l0', 'l4', 'l5', 'l6']", + "102, of ['l1', 'l4', 'l7', 'l8']", + "103, Tnfaip3 ['l2', 'l5', 'l7', 'l9']", + "113, mice, ['l3', 'l6', 'l8', 'l9']", + "129, transgenic ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "130, or ['l10', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "131, adeno-associated ['l11', 'l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "132, virus-mediated ['l12', 'l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "133, TNFAIP3 ['l13', 'l23', 'l32', 'l40', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "134, gene ['l14', 'l24', 'l33', 'l41', 'l48', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "135, delivery ['l15', 'l25', 'l34', 'l42', 'l49', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "138, liver ['l16', 'l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "141, mouse ['l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l70', 'l71', 'l72']", + "143, nonhuman ['l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l70', 'l73', 'l74']", + "144, primate ['l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l73', 'l75']", + "145, models ['l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hepatocyte-specific", + "ablation", + "of", + "Tnfaip3" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "or", + "adeno-associated", + "virus-mediated", + "TNFAIP3", + "gene", + "delivery" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "or", + "adeno-associated", + "virus-mediated", + "TNFAIP3", + "gene", + "delivery" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "nonhuman", + "primate", + "models" + ] + } + } + ] + }, + { + "PMID": "29200205", + "TEXT": "Alzheimer's disease (AD) is characterized by extracellular amyloid-β (Aβ) plaques and intracellular tau inclusions. However, the exact mechanistic link between these two AD lesions remains enigmatic. Through injection of human AD-brain-derived pathological tau (AD-tau) into Aβ plaque-bearing mouse models that do not overexpress tau, we recapitulated the formation of three major types of AD-relevant tau pathologies: tau aggregates in dystrophic neurites surrounding Aβ plaques (NP tau), AD-like neurofibrillary tangles (NFTs) and neuropil threads (NTs). These distinct tau pathologies have different temporal onsets and functional consequences on neural activity and behavior. Notably, we found that Aβ plaques created a unique environment that facilitated the rapid amplification of proteopathic AD-tau seeds into large tau aggregates, initially appearing as NP tau, which was followed by the formation and spread of NFTs and NTs, likely through secondary seeding events. Our study provides insights into a new multistep mechanism underlying Aβ plaque-associated tau pathogenesis.", + "TAG_DATA": [ + "37, mouse {'context': 'B-organism'}", + "38, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "37, mouse ['l0']", + "38, models ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29106402", + "TEXT": "Sleep deprivation is a major source of morbidity with widespread health effects, including increased risk of hypertension, diabetes, obesity, heart attack, and stroke. Moreover, sleep deprivation brings about vehicle accidents and medical errors and is therefore an urgent topic of investigation. During sleep deprivation, homeostatic and circadian processes interact to build up sleep pressure, which results in slow behavioral performance (cognitive lapses) typically attributed to attentional thalamic and frontoparietal circuits, but the underlying mechanisms remain unclear. Recently, through study of electroencephalograms (EEGs) in humans and local field potentials (LFPs) in nonhuman primates and rodents it was found that, during sleep deprivation, regional 'sleep-like' slow and theta (slow/theta) waves co-occur with impaired behavioral performance during wakefulness. Here we used intracranial electrodes to record single-neuron activities and LFPs in human neurosurgical patients performing a face/nonface categorization psychomotor vigilance task (PVT) over multiple experimental sessions, including a session after full-night sleep deprivation. We find that, just before cognitive lapses, the selective spiking responses of individual neurons in the medial temporal lobe (MTL) are attenuated, delayed, and lengthened. These 'neuronal lapses' are evident on a trial-by-trial basis when comparing the slowest behavioral PVT reaction times to the fastest. Furthermore, during cognitive lapses, LFPs exhibit a relative local increase in slow/theta activity that is correlated with degraded single-neuron responses and with baseline theta activity. Our results show that cognitive lapses involve local state-dependent changes in neuronal activity already present in the MTL.", + "TAG_DATA": [ + "127, human {'context': 'B-patient'}", + "128, neurosurgical {'context': 'I-patient'}", + "129, patients {'context': 'I-patient'}", + "162, neurons {'context': 'B-cells'}", + "163, in {'context': 'I-cells'}", + "164, the {'context': 'I-cells'}", + "165, medial {'context': 'I-cells'}", + "166, temporal {'context': 'I-cells'}", + "167, lobe {'context': 'I-cells'}", + "168, (MTL) {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "127, human ['l0', 'l1', 'l2', 'l3']", + "128, neurosurgical ['l0', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "129, patients ['l1', 'l4']", + "162, neurons ['l5', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "163, in ['l6', 'l12', 'l18', 'l19', 'l20', 'l21', 'l22']", + "164, the ['l7', 'l13', 'l18', 'l23', 'l24', 'l25', 'l26']", + "165, medial ['l8', 'l14', 'l19', 'l23', 'l27', 'l28', 'l29']", + "166, temporal ['l9', 'l15', 'l20', 'l24', 'l27', 'l30', 'l31']", + "167, lobe ['l2', 'l10', 'l16', 'l21', 'l25', 'l28', 'l30', 'l32']", + "168, (MTL) ['l3', 'l11', 'l17', 'l22', 'l26', 'l29', 'l31', 'l32']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29035370", + "TEXT": "Natural killer (NK) cells play an essential role in antiviral immunity, but knowledge of their function in secondary lymphoid organs is incomplete. Lymph node follicles constitute a major viral reservoir during infections with HIV-1 and simian immunodeficiency virus of macaques (SIVmac). In contrast, during nonpathogenic infection with SIV from African green monkeys (SIVagm), follicles remain generally virus free. We show that NK cells in secondary lymphoid organs from chronically SIVagm-infected African green monkeys (AGMs) were frequently CXCR5+ and entered and persisted in lymph node follicles throughout the follow-up (240 d post-infection). These follicles were strongly positive for IL-15, which was primarily presented in its membrane-bound form by follicular dendritic cells. NK cell depletion through treatment with anti-IL-15 monoclonal antibody during chronic SIVagm infection resulted in high viral replication rates in follicles and the T cell zone and increased viral DNA in lymph nodes. Our data suggest that, in nonpathogenic SIV infection, NK cells migrate into follicles and play a major role in viral reservoir control in lymph nodes.", + "TAG_DATA": [ + "61, NK {'context': 'B-cells'}", + "62, cells {'context': 'I-cells'}", + "64, secondary {'context': 'B-tissue/organ'}", + "65, lymphoid {'context': 'I-tissue/organ'}", + "66, organs {'context': 'I-tissue/organ'}", + "70, African {'context': 'B-organism'}", + "71, green {'context': 'I-organism'}", + "72, monkeys {'context': 'I-organism'}", + "73, (AGMs) {'context': 'I-organism'}", + "110, NK {'context': 'B-cells'}", + "111, cell {'context': 'I-cells'}", + "133, T {'context': 'B-cells'}", + "134, cell {'context': 'I-cells'}", + "135, zone {'context': 'I-tissue/organ'}", + "141, lymph {'context': 'B-tissue/organ'}", + "142, nodes. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "61, NK ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "62, cells ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "64, secondary ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "65, lymphoid ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "66, organs ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "70, African ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "71, green ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "72, monkeys ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "73, (AGMs) ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "110, NK ['l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "111, cell ['l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "133, T ['l37', 'l42', 'l47', 'l48', 'l49', 'l50']", + "134, cell ['l38', 'l43', 'l47', 'l51', 'l52']", + "135, zone ['l39', 'l44', 'l48', 'l51', 'l53']", + "141, lymph ['l40', 'l45', 'l49', 'l54']", + "142, nodes. ['l41', 'l46', 'l50', 'l52', 'l53', 'l54']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29035368", + "TEXT": "Nonalcoholic fatty liver disease is becoming the most common chronic liver disease in Western countries, and limited therapeutic options are available. Here we uncovered a role for intestinal hypoxia-inducible factor (HIF) in hepatic steatosis. Human-intestine biopsies from individuals with or without obesity revealed that intestinal HIF-2α signaling was positively correlated with body-mass index and hepatic toxicity. The causality of this correlation was verified in mice with an intestine-specific disruption of Hif2a, in which high-fat-diet-induced hepatic steatosis and obesity were substantially lower as compared to control mice. PT2385, a HIF-2α-specific inhibitor, had preventive and therapeutic effects on metabolic disorders that were dependent on intestine HIF-2α. Intestine HIF-2α inhibition markedly reduced intestine and serum ceramide levels. Mechanistically, intestine HIF-2α regulates ceramide metabolism mainly from the salvage pathway, by positively regulating the expression of Neu3, the gene encoding neuraminidase 3. These results suggest that intestinal HIF-2α could be a viable target for hepatic steatosis therapy.", + "TAG_DATA": [ + "64, mice {'context': 'B-organism'}", + "67, intestine-specific {'perturbing_action': 'B-gene loss-of-function'}", + "68, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "69, of {'perturbing_action': 'I-gene loss-of-function'}", + "70, Hif2a, {'perturbing_action': 'I-gene loss-of-function'}", + "85, mice. {'context': 'B-organism'}", + "86, PT2385, {'perturbing_action': 'B-pharmacological inhibition'}", + "87, a {'perturbing_action': 'I-pharmacological inhibition'}", + "88, HIF-2α-specific {'perturbing_action': 'I-pharmacological inhibition'}", + "89, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "104, Intestine {'perturbing_action': 'B-pharmacological inhibition'}", + "105, HIF-2α {'perturbing_action': 'I-pharmacological inhibition'}", + "106, inhibition {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "64, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "67, intestine-specific ['l0', 'l5', 'l6', 'l7', 'l8']", + "68, disruption ['l1', 'l5', 'l9', 'l10', 'l11']", + "69, of ['l2', 'l6', 'l9', 'l12', 'l13']", + "70, Hif2a, ['l3', 'l7', 'l10', 'l12', 'l14']", + "85, mice. ['l4', 'l8', 'l11', 'l13', 'l14']", + "86, PT2385, ['l15', 'l16', 'l17']", + "87, a ['l15', 'l18', 'l19']", + "88, HIF-2α-specific ['l16', 'l18', 'l20', 'l21']", + "89, inhibitor, ['l17', 'l19', 'l20']", + "104, Intestine ['l22', 'l23']", + "105, HIF-2α ['l22', 'l24']", + "106, inhibition ['l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "intestine-specific", + "disruption", + "of", + "Hif2a," + ] + } + } + ] + }, + { + "PMID": "28967921", + "TEXT": "In the quest for a functional cure or the eradication of HIV infection, it is necessary to know the sizes of the reservoirs from which infection rebounds after treatment interruption. Thus, we quantified SIV and HIV tissue burdens in tissues of infected nonhuman primates and lymphoid tissue (LT) biopsies from infected humans. Before antiretroviral therapy (ART), LTs contained >98% of the SIV RNA+ and DNA+ cells. With ART, the numbers of virus (v) RNA+ cells substantially decreased but remained detectable, and their persistence was associated with relatively lower drug concentrations in LT than in peripheral blood. Prolonged ART also decreased the levels of SIV- and HIV-DNA+ cells, but the estimated size of the residual tissue burden of 108 vDNA+ cells potentially containing replication-competent proviruses, along with evidence of continuing virus production in LT despite ART, indicated two important sources for rebound following treatment interruption. The large sizes of these tissue reservoirs underscore challenges in developing 'HIV cure' strategies targeting multiple sources of virus production.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28967920", + "TEXT": "Treating KRAS-mutant lung adenocarcinoma (LUAD) remains a major challenge in cancer treatment given the difficulties associated with directly inhibiting the KRAS oncoprotein. One approach to addressing this challenge is to define mutations that frequently co-occur with those in KRAS, which themselves may lead to therapeutic vulnerabilities in tumors. Approximately 20% of KRAS-mutant LUAD tumors carry loss-of-function mutations in the KEAP1 gene encoding Kelch-like ECH-associated protein 1 (refs. 2, 3, 4), a negative regulator of nuclear factor erythroid 2-like 2 (NFE2L2; hereafter NRF2), which is the master transcriptional regulator of the endogenous antioxidant response. The high frequency of mutations in KEAP1 suggests an important role for the oxidative stress response in lung tumorigenesis. Using a CRISPR-Cas9-based approach in a mouse model of KRAS-driven LUAD, we examined the effects of Keap1 loss in lung cancer progression. We show that loss of Keap1 hyperactivates NRF2 and promotes KRAS-driven LUAD in mice. Through a combination of CRISPR-Cas9-based genetic screening and metabolomic analyses, we show that Keap1- or Nrf2-mutant cancers are dependent on increased glutaminolysis, and this property can be therapeutically exploited through the pharmacological inhibition of glutaminase. Finally, we provide a rationale for stratification of human patients with lung cancer harboring KRAS/KEAP1- or KRAS/NRF2-mutant lung tumors as likely to respond to glutaminase inhibition.", + "TAG_DATA": [ + "119, model {'context': 'I-organism'}", + "128, Keap1 {'perturbing_action': 'B-gene loss-of-function'}", + "129, loss {'perturbing_action': 'I-gene loss-of-function'}", + "131, lung {'context': 'B-neoplasm'}", + "137, loss {'perturbing_action': 'B-gene loss-of-function'}", + "138, of {'perturbing_action': 'I-gene loss-of-function'}", + "139, Keap1 {'perturbing_action': 'I-gene loss-of-function'}", + "143, promotes {'effect': 'B-positive'}", + "145, LUAD {'phenotype': 'B-necrosis'}", + "147, mice. {'context': 'B-organism'}", + "161, Keap1- {'perturbing_action': 'B-other'}", + "162, or {'perturbing_action': 'I-other'}", + "163, Nrf2-mutant {'perturbing_action': 'I-other'}", + "164, cancers {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "119, model ['l0', 'l1', 'l2']", + "128, Keap1 ['l0', 'l3', 'l4', 'l5', 'l6']", + "129, loss ['l1', 'l3', 'l7', 'l8', 'l9']", + "131, lung ['l2', 'l4', 'l7']", + "137, loss ['l10', 'l11', 'l12', 'l13', 'l14']", + "138, of ['l10', 'l15', 'l16', 'l17', 'l18']", + "139, Keap1 ['l11', 'l15', 'l19', 'l20', 'l21']", + "143, promotes ['l5', 'l8', 'l12', 'l16', 'l19', 'l22', 'l23']", + "145, LUAD ['l6', 'l9', 'l13', 'l17', 'l20', 'l22', 'l24']", + "147, mice. ['l14', 'l18', 'l21', 'l23', 'l24']", + "161, Keap1- ['l25', 'l26', 'l27']", + "162, or ['l25', 'l28', 'l29']", + "163, Nrf2-mutant ['l26', 'l28', 'l30']", + "164, cancers ['l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "model", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Keap1", + "loss", + "of" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Keap1", + "loss" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Keap1", + "loss", + "of" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Keap1", + "loss", + "of" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "LUAD" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "LUAD" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "LUAD" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Keap1-", + "or", + "Nrf2-mutant" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "cancers" + ] + } + } + ] + }, + { + "PMID": "28967919", + "TEXT": "Tumor recurrence remains the main reason for breast cancer-associated mortality, and there are unmet clinical demands for the discovery of new biomarkers and development of treatment solutions to benefit patients with breast cancer at high risk of recurrence. Here we report the identification of chromosomal copy-number amplification at 1q21.3 that is enriched in subpopulations of breast cancer cells bearing characteristics of tumor-initiating cells (TICs) and that strongly associates with breast cancer recurrence. Amplification is present in ∼10-30% of primary tumors but in more than 70% of recurrent tumors, regardless of breast cancer subtype. Detection of amplification in cell-free DNA (cfDNA) from blood is strongly associated with early relapse in patients with breast cancer and could also be used to track the emergence of tumor resistance to chemotherapy. We further show that 1q21.3-encoded S100 calcium-binding protein (S100A) family members, mainly S100A7, S100A8, and S100A9 (S100A7/8/9), and IL-1 receptor-associated kinase 1 (IRAK1) establish a reciprocal feedback loop driving tumorsphere growth. Notably, this functional circuitry can be disrupted by the small-molecule kinase inhibitor pacritinib, leading to preferential impairment of the growth of 1q21.3-amplified breast tumors. Our study uncovers the 1q21.3-directed S100A7/8/9-IRAK1 feedback loop as a crucial component of breast cancer recurrence, serving as both a trackable biomarker and an actionable therapeutic target for breast cancer.", + "TAG_DATA": [ + "180, breast {'context': 'B-neoplasm'}", + "181, tumors. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "180, breast ['l0']", + "181, tumors. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28920957", + "TEXT": "A deeper understanding of the metastatic process is required for the development of new therapies that improve patient survival. Metastatic tumor cell growth and survival in distant organs is facilitated by the formation of a pre-metastatic niche that is composed of hematopoietic cells, stromal cells and extracellular matrix (ECM). Perivascular cells, including vascular smooth muscle cells (vSMCs) and pericytes, are involved in new vessel formation and in promoting stem cell maintenance and proliferation. Given the well-described plasticity of perivascular cells, we hypothesized that perivascular cells similarly regulate tumor cell fate at metastatic sites. We used perivascular-cell-specific and pericyte-specific lineage-tracing models to trace the fate of perivascular cells in the pre-metastatic and metastatic microenvironments. We show that perivascular cells lose the expression of traditional vSMC and pericyte markers in response to tumor-secreted factors and exhibit increased proliferation, migration and ECM synthesis. Increased expression of the pluripotency gene Klf4 in these phenotypically switched perivascular cells promoted a less differentiated state, characterized by enhanced ECM production, that established a pro-metastatic fibronectin-rich environment. Genetic inactivation of Klf4 in perivascular cells decreased formation of a pre-metastatic niche and metastasis. Our data revealed a previously unidentified role for perivascular cells in pre-metastatic niche formation and uncovered novel strategies for limiting metastasis.", + "TAG_DATA": [ + "116, perivascular {'context': 'B-cells'}", + "117, cells {'context': 'I-cells'}", + "134, increased {'effect': 'B-positive'}", + "135, proliferation, {'phenotype': 'B-proliferation'}", + "136, migration {'phenotype': 'B-migration'}", + "140, Increased {'perturbing_action': 'B-gene gain-of-function'}", + "141, expression {'perturbing_action': 'I-gene gain-of-function'}", + "142, of {'perturbing_action': 'I-gene gain-of-function'}", + "143, the {'perturbing_action': 'I-gene gain-of-function'}", + "144, pluripotency {'perturbing_action': 'I-gene gain-of-function'}", + "145, gene {'perturbing_action': 'I-gene gain-of-function'}", + "146, Klf4 {'perturbing_action': 'I-gene gain-of-function'}", + "151, perivascular {'context': 'B-cells'}", + "152, cells {'context': 'I-cells'}", + "153, promoted {'effect': 'B-positive'}", + "157, state, {'phenotype': 'I-differentiation'}", + "169, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "170, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "171, of {'perturbing_action': 'I-gene loss-of-function'}", + "172, Klf4 {'perturbing_action': 'I-gene loss-of-function'}", + "174, perivascular {'context': 'B-cells'}", + "175, cells {'context': 'I-cells'}", + "176, decreased {'effect': 'B-negative'}", + "183, metastasis. {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "116, perivascular ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "117, cells ['l0', 'l8', 'l9', 'l10']", + "134, increased ['l1', 'l8', 'l11', 'l12']", + "135, proliferation, ['l2', 'l9', 'l11', 'l13']", + "136, migration ['l3', 'l10', 'l12', 'l13']", + "140, Increased ['l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "141, expression ['l14', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "142, of ['l15', 'l24', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "143, the ['l4', 'l16', 'l25', 'l33', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "144, pluripotency ['l17', 'l26', 'l34', 'l41', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "145, gene ['l5', 'l18', 'l27', 'l35', 'l42', 'l48', 'l54', 'l55', 'l56', 'l57', 'l58']", + "146, Klf4 ['l6', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l59', 'l60', 'l61', 'l62']", + "151, perivascular ['l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l63', 'l64', 'l65']", + "152, cells ['l7', 'l21', 'l30', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l66', 'l67']", + "153, promoted ['l22', 'l31', 'l39', 'l46', 'l52', 'l57', 'l61', 'l64', 'l66', 'l68']", + "157, state, ['l23', 'l32', 'l40', 'l47', 'l53', 'l58', 'l62', 'l65', 'l67', 'l68']", + "169, Genetic ['l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "170, inactivation ['l69', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "171, of ['l70', 'l76', 'l82', 'l83', 'l84', 'l85', 'l86']", + "172, Klf4 ['l71', 'l77', 'l82', 'l87', 'l88', 'l89', 'l90']", + "174, perivascular ['l72', 'l78', 'l83', 'l87', 'l91', 'l92', 'l93']", + "175, cells ['l73', 'l79', 'l84', 'l88', 'l91', 'l94', 'l95']", + "176, decreased ['l74', 'l80', 'l85', 'l89', 'l92', 'l94', 'l96']", + "183, metastasis. ['l75', 'l81', 'l86', 'l90', 'l93', 'l95', 'l96']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "perivascular", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "promoted" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "perivascular", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "perivascular", + "cells" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "perivascular", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "the", + "gene", + "Klf4", + "Increased", + "expression", + "of", + "pluripotency" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Increased", + "expression", + "of", + "the", + "pluripotency", + "gene", + "Klf4" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Increased", + "expression", + "of", + "the", + "pluripotency", + "gene", + "Klf4" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "state," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "perivascular", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "state," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "state," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "inactivation", + "of", + "Klf4" + ] + }, + "context": { + "val": "cells", + "words": [ + "perivascular", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "inactivation", + "of", + "Klf4" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "inactivation", + "of", + "Klf4" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "perivascular", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "perivascular", + "cells" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + } + ] + }, + { + "PMID": "28886003", + "TEXT": "The essential job of precision medicine is to match the right drugs to the right patients. In cancer, precision medicine has been nearly synonymous with genomics. However, sobering recent studies have generally shown that most patients with cancer who receive genomic testing do not benefit from a genomic precision medicine strategy. Although some call the entire project of precision cancer medicine into question, I suggest instead that the tools employed must be broadened. Instead of relying exclusively on big data measurements of initial conditions, we should also acquire highly actionable functional information by perturbing-for example, with cancer therapies-viable primary tumor cells from patients with cancer.", + "TAG_DATA": [ + "98, primary {'context': 'B-transformed cells'}", + "99, tumor {'context': 'I-transformed cells'}", + "100, cells {'context': 'I-transformed cells'}", + "102, patients {'context': 'B-patient'}", + "103, with {'context': 'I-patient'}", + "104, cancer. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "98, primary ['l0', 'l1', 'l2', 'l3', 'l4']", + "99, tumor ['l0', 'l5', 'l6', 'l7', 'l8']", + "100, cells ['l1', 'l5', 'l9', 'l10', 'l11']", + "102, patients ['l2', 'l6', 'l9', 'l12', 'l13']", + "103, with ['l3', 'l7', 'l10', 'l12', 'l14']", + "104, cancer. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28825715", + "TEXT": "Major depressive disorder (MDD) is a leading cause of disease burden worldwide. While the incidence, symptoms and treatment of MDD all point toward major sex differences, the molecular mechanisms underlying this sexual dimorphism remain largely unknown. Here, combining differential expression and gene coexpression network analyses, we provide a comprehensive characterization of male and female transcriptional profiles associated with MDD across six brain regions. We overlap our human profiles with those from a mouse model, chronic variable stress, and capitalize on converging pathways to define molecular and physiological mechanisms underlying the expression of stress susceptibility in males and females. Our results show a major rearrangement of transcriptional patterns in MDD, with limited overlap between males and females, an effect seen in both depressed humans and stressed mice. We identify key regulators of sex-specific gene networks underlying MDD and confirm their sex-specific impact as mediators of stress susceptibility. For example, downregulation of the female-specific hub gene Dusp6 in mouse prefrontal cortex mimicked stress susceptibility in females, but not males, by increasing ERK signaling and pyramidal neuron excitability. Such Dusp6 downregulation also recapitulated the transcriptional remodeling that occurs in prefrontal cortex of depressed females. Together our findings reveal marked sexual dimorphism at the transcriptional level in MDD and highlight the importance of studying sex-specific treatments for this disorder.", + "TAG_DATA": [ + "148, downregulation {'perturbing_action': 'B-rnai/knockdown'}", + "149, of {'perturbing_action': 'I-rnai/knockdown'}", + "150, the {'perturbing_action': 'I-rnai/knockdown'}", + "151, female-specific {'perturbing_action': 'I-rnai/knockdown'}", + "152, hub {'perturbing_action': 'I-rnai/knockdown'}", + "153, gene {'perturbing_action': 'I-rnai/knockdown'}", + "154, Dusp6 {'perturbing_action': 'I-rnai/knockdown'}", + "156, mouse {'context': 'B-tissue/organ'}", + "157, prefrontal {'context': 'I-tissue/organ'}", + "158, cortex {'context': 'I-tissue/organ'}", + "163, females, {'context': 'B-organism'}", + "172, pyramidal {'context': 'B-cells'}", + "173, neuron {'context': 'I-cells'}", + "186, prefrontal {'context': 'B-tissue/organ'}", + "187, cortex {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "148, downregulation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "149, of ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "150, the ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "151, female-specific ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "152, hub ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "153, gene ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "154, Dusp6 ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "156, mouse ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "157, prefrontal ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "158, cortex ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "163, females, ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "172, pyramidal ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "173, neuron ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "186, prefrontal ['l78']", + "187, cortex ['l78']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "downregulation", + "of", + "the", + "female-specific", + "hub", + "gene", + "Dusp6" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "prefrontal", + "cortex" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "downregulation", + "of", + "the", + "female-specific", + "hub", + "gene", + "Dusp6" + ] + }, + "context": { + "val": "organism", + "words": [ + "females," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "downregulation", + "of", + "the", + "female-specific", + "hub", + "gene", + "Dusp6" + ] + }, + "context": { + "val": "cells", + "words": [ + "pyramidal", + "neuron" + ] + } + } + ] + }, + { + "PMID": "28805822", + "TEXT": "Bromodomain and extraterminal domain (BET) protein inhibitors are emerging as promising anticancer therapies. The gene encoding the E3 ubiquitin ligase substrate-binding adaptor speckle-type POZ protein (SPOP) is the most frequently mutated in primary prostate cancer. Here we demonstrate that wild-type SPOP binds to and induces ubiquitination and proteasomal degradation of BET proteins (BRD2, BRD3 and BRD4) by recognizing a degron motif common among them. In contrast, prostate cancer-associated SPOP mutants show impaired binding to BET proteins, resulting in decreased proteasomal degradation and accumulation of these proteins in prostate cancer cell lines and patient specimens and causing resistance to BET inhibitors. Transcriptome and BRD4 cistrome analyses reveal enhanced expression of the GTPase RAC1 and cholesterol-biosynthesis-associated genes together with activation of AKT-mTORC1 signaling as a consequence of BRD4 stabilization. Our data show that resistance to BET inhibitors in SPOP-mutant prostate cancer can be overcome by combination with AKT inhibitors and further support the evaluation of SPOP mutations as biomarkers to guide BET-inhibitor-oriented therapy in patients with prostate cancer.", + "TAG_DATA": [ + "87, prostate {'context': 'B-transformed cells'}", + "88, cancer {'context': 'I-transformed cells'}", + "89, cell {'context': 'I-transformed cells'}", + "90, lines {'context': 'I-transformed cells'}", + "98, BET {'perturbing_action': 'B-pharmacological inhibition'}", + "99, inhibitors. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "87, prostate ['l0', 'l1', 'l2']", + "88, cancer ['l0', 'l3', 'l4']", + "89, cell ['l1', 'l3', 'l5']", + "90, lines ['l2', 'l4', 'l5']", + "98, BET ['l6']", + "99, inhibitors. ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28714990", + "TEXT": "The principles that govern the evolution of tumors exposed to targeted therapy are poorly understood. Here we modeled the selection and propagation of an amplification in the BRAF oncogene (BRAFamp) in patient-derived tumor xenografts (PDXs) that were treated with a direct inhibitor of the kinase ERK, either alone or in combination with other ERK signaling inhibitors. Single-cell sequencing and multiplex fluorescence in situ hybridization analyses mapped the emergence of extra-chromosomal amplification in parallel evolutionary trajectories that arose in the same tumor shortly after treatment. The evolutionary selection of BRAFamp was determined by the fitness threshold, the barrier that subclonal populations need to overcome to regain fitness in the presence of therapy. This differed for inhibitors of ERK signaling, suggesting that sequential monotherapy is ineffective and selects for a progressively higher BRAF copy number. Concurrent targeting of the RAF, MEK and ERK kinases, however, imposed a sufficiently high fitness threshold to prevent the propagation of subclones with high-level BRAFamp. When administered on an intermittent schedule, this treatment inhibited tumor growth in 11/11 PDXs of lung cancer or melanoma without apparent toxicity in mice. Thus, gene amplification can be acquired and expanded through parallel evolution, enabling tumors to adapt while maintaining their intratumoral heterogeneity. Treatments that impose the highest fitness threshold will likely prevent the evolution of resistance-causing alterations and, thus, merit testing in patients.", + "TAG_DATA": [ + "40, direct {'perturbing_action': 'B-pharmacological inhibition'}", + "41, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "42, of {'perturbing_action': 'I-pharmacological inhibition'}", + "43, the {'perturbing_action': 'I-pharmacological inhibition'}", + "44, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "45, ERK, {'perturbing_action': 'I-pharmacological inhibition'}", + "166, inhibited {'effect': 'B-negative'}", + "167, tumor {'phenotype': 'B-tumour growth'}", + "168, growth {'phenotype': 'I-tumour growth'}", + "173, lung {'context': 'B-neoplasm'}", + "174, cancer {'context': 'I-neoplasm'}", + "176, melanoma {'context': 'B-neoplasm'}", + "181, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "40, direct ['l0', 'l1', 'l2', 'l3', 'l4']", + "41, inhibitor ['l0', 'l5', 'l6', 'l7', 'l8']", + "42, of ['l1', 'l5', 'l9', 'l10', 'l11']", + "43, the ['l2', 'l6', 'l9', 'l12', 'l13']", + "44, kinase ['l3', 'l7', 'l10', 'l12', 'l14']", + "45, ERK, ['l4', 'l8', 'l11', 'l13', 'l14']", + "166, inhibited ['l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "167, tumor ['l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "168, growth ['l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "173, lung ['l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "174, cancer ['l18', 'l23', 'l27', 'l30', 'l33']", + "176, melanoma ['l19', 'l24', 'l28', 'l31', 'l33', 'l34']", + "181, mice. ['l20', 'l25', 'l29', 'l32', 'l34']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lung", + "cancer", + "melanoma" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lung", + "cancer", + "melanoma" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "28692064", + "TEXT": "Polo-like kinase 1 (PLK1), an essential regulator of cell division, is currently undergoing clinical evaluation as a target for cancer therapy. We report an unexpected function of Plk1 in sustaining cardiovascular homeostasis. Plk1 haploinsufficiency in mice did not induce obvious cell proliferation defects but did result in arterial structural alterations, which frequently led to aortic rupture and death. Specific ablation of Plk1 in vascular smooth muscle cells (VSMCs) led to reduced arterial elasticity, hypotension, and an impaired arterial response to angiotensin II in vivo. Mechanistically, we found that Plk1 regulated angiotensin II-dependent activation of RhoA and actomyosin dynamics in VSMCs in a mitosis-independent manner. This regulation depended on Plk1 kinase activity, and the administration of small-molecule Plk1 inhibitors to angiotensin II-treated mice led to reduced arterial fitness and an elevated risk of aneurysm and aortic rupture. We thus conclude that a partial reduction of Plk1 activity that does not block cell division can nevertheless impair aortic homeostasis. Our findings have potentially important implications for current approaches aimed at PLK1 inhibition for cancer therapy.", + "TAG_DATA": [ + "35, mice {'context': 'B-organism'}", + "38, induce {'effect': 'I-no effect'}", + "40, cell {'context': 'B-cells'}", + "41, proliferation {'phenotype': 'B-proliferation'}", + "42, defects {'effect': 'B-negative'}", + "58, Specific {'perturbing_action': 'B-gene loss-of-function'}", + "59, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "60, of {'perturbing_action': 'I-gene loss-of-function'}", + "61, Plk1 {'perturbing_action': 'I-gene loss-of-function'}", + "63, vascular {'context': 'B-cells'}", + "64, smooth {'context': 'I-cells'}", + "65, muscle {'context': 'I-cells'}", + "66, cells {'context': 'I-cells'}", + "67, (VSMCs) {'context': 'I-cells'}", + "82, in {'context': 'B-in vivo'}", + "83, vivo. {'context': 'I-in vivo'}", + "99, VSMCs {'context': 'B-cells'}", + "115, small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "116, Plk1 {'perturbing_action': 'I-pharmacological inhibition'}", + "117, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "121, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "35, mice ['l0', 'l1', 'l2', 'l3']", + "38, induce ['l0', 'l4', 'l5', 'l6']", + "40, cell ['l1', 'l4', 'l7', 'l8']", + "41, proliferation ['l2', 'l5', 'l7', 'l9']", + "42, defects ['l3', 'l6', 'l8', 'l9']", + "58, Specific ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "59, ablation ['l10', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "60, of ['l11', 'l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "61, Plk1 ['l12', 'l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "63, vascular ['l13', 'l23', 'l32', 'l40', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "64, smooth ['l14', 'l24', 'l33', 'l41', 'l48', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "65, muscle ['l15', 'l25', 'l34', 'l42', 'l49', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "66, cells ['l16', 'l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "67, (VSMCs) ['l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l70', 'l71', 'l72']", + "82, in ['l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l70', 'l73']", + "83, vivo. ['l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l73']", + "99, VSMCs ['l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72']", + "115, small-molecule ['l74', 'l75', 'l76']", + "116, Plk1 ['l74', 'l77', 'l78']", + "117, inhibitors ['l75', 'l77', 'l79']", + "121, mice ['l76', 'l78', 'l79']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defects" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defects" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defects" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Specific", + "ablation", + "of", + "Plk1" + ] + }, + "context": { + "val": "cells", + "words": [ + "vascular", + "smooth", + "muscle", + "cells", + "(VSMCs)", + "VSMCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Specific", + "ablation", + "of", + "Plk1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "Plk1", + "inhibitors" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "28692063", + "TEXT": "The choroid plexus epithelium (CPE) secretes higher volumes of fluid (cerebrospinal fluid, CSF) than any other epithelium and simultaneously functions as the blood-CSF barrier to gate immune cell entry into the central nervous system. Posthemorrhagic hydrocephalus (PHH), an expansion of the cerebral ventricles due to CSF accumulation following intraventricular hemorrhage (IVH), is a common disease usually treated by suboptimal CSF shunting techniques. PHH is classically attributed to primary impairments in CSF reabsorption, but little experimental evidence supports this concept. In contrast, the potential contribution of CSF secretion to PHH has received little attention. In a rat model of PHH, we demonstrate that IVH causes a Toll-like receptor 4 (TLR4)- and NF-κB-dependent inflammatory response in the CPE that is associated with a ∼3-fold increase in bumetanide-sensitive CSF secretion. IVH-induced hypersecretion of CSF is mediated by TLR4-dependent activation of the Ste20-type stress kinase SPAK, which binds, phosphorylates, and stimulates the NKCC1 co-transporter at the CPE apical membrane. Genetic depletion of TLR4 or SPAK normalizes hyperactive CSF secretion rates and reduces PHH symptoms, as does treatment with drugs that antagonize TLR4-NF-κB signaling or the SPAK-NKCC1 co-transporter complex. These data uncover a previously unrecognized contribution of CSF hypersecretion to the pathogenesis of PHH, demonstrate a new role for TLRs in regulation of the internal brain milieu, and identify a kinase-regulated mechanism of CSF secretion that could be targeted by repurposed US Food and Drug Administration (FDA)-approved drugs to treat hydrocephalus.", + "TAG_DATA": [ + "95, rat {'context': 'B-organism'}", + "96, model {'context': 'I-organism'}", + "155, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "156, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "157, of {'perturbing_action': 'I-gene loss-of-function'}", + "158, TLR4 {'perturbing_action': 'I-gene loss-of-function'}", + "159, or {'perturbing_action': 'I-gene loss-of-function'}", + "160, SPAK {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "95, rat ['l0']", + "96, model ['l0']", + "155, Genetic ['l1', 'l2', 'l3', 'l4', 'l5']", + "156, depletion ['l1', 'l6', 'l7', 'l8', 'l9']", + "157, of ['l2', 'l6', 'l10', 'l11', 'l12']", + "158, TLR4 ['l3', 'l7', 'l10', 'l13', 'l14']", + "159, or ['l4', 'l8', 'l11', 'l13', 'l15']", + "160, SPAK ['l5', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28671689", + "TEXT": "The treatment of common bile duct (CBD) disorders, such as biliary atresia or ischemic strictures, is restricted by the lack of biliary tissue from healthy donors suitable for surgical reconstruction. Here we report a new method for the isolation and propagation of human cholangiocytes from the extrahepatic biliary tree in the form of extrahepatic cholangiocyte organoids (ECOs) for regenerative medicine applications. The resulting ECOs closely resemble primary cholangiocytes in terms of their transcriptomic profile and functional properties. We explore the regenerative potential of these organoids in vivo and demonstrate that ECOs self-organize into bile duct-like tubes expressing biliary markers following transplantation under the kidney capsule of immunocompromised mice. In addition, when seeded on biodegradable scaffolds, ECOs form tissue-like structures retaining biliary characteristics. The resulting bioengineered tissue can reconstruct the gallbladder wall and repair the biliary epithelium following transplantation into a mouse model of injury. Furthermore, bioengineered artificial ducts can replace the native CBD, with no evidence of cholestasis or occlusion of the lumen. In conclusion, ECOs can successfully reconstruct the biliary tree, providing proof of principle for organ regeneration using human primary cholangiocytes expanded in vitro.", + "TAG_DATA": [ + "107, mice. {'context': 'I-organism'}", + "140, mouse {'context': 'B-organism'}", + "141, model {'context': 'I-organism'}", + "146, artificial {'context': 'I-organoid'}", + "147, ducts {'context': 'I-organoid'}", + "181, primary {'context': 'I-cells'}", + "182, cholangiocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "129, gallbladder ['l0', 'l1']", + "140, mouse ['l0', 'l2']", + "141, model ['l1', 'l2']", + "146, artificial ['l3', 'l4', 'l5']", + "147, ducts ['l3', 'l6', 'l7']", + "181, primary ['l4', 'l6', 'l8']", + "182, cholangiocytes ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28604701", + "TEXT": "The potential of bispecific T cell-engaging antibodies is hindered by manufacturing challenges and short serum half-life. We circumvented these limitations by treating mice with in vitro-transcribed pharmacologically optimized, nucleoside-modified mRNA encoding the antibody. We achieved sustained endogenous synthesis of the antibody, which eliminated advanced tumors as effectively as the corresponding purified bispecific antibody. Because manufacturing of pharmaceutical mRNA is fast, this approach could accelerate the clinical development of novel bispecific antibodies.", + "TAG_DATA": [ + "22, mice {'context': 'B-organism'}", + "44, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28504724", + "TEXT": "Recent advances in single-cell transcriptomics are ideally placed to unravel intratumoral heterogeneity and selective resistance of cancer stem cell (SC) subpopulations to molecularly targeted cancer therapies. However, current single-cell RNA-sequencing approaches lack the sensitivity required to reliably detect somatic mutations. We developed a method that combines high-sensitivity mutation detection with whole-transcriptome analysis of the same single cell. We applied this technique to analyze more than 2,000 SCs from patients with chronic myeloid leukemia (CML) throughout the disease course, revealing heterogeneity of CML-SCs, including the identification of a subgroup of CML-SCs with a distinct molecular signature that selectively persisted during prolonged therapy. Analysis of nonleukemic SCs from patients with CML also provided new insights into cell-extrinsic disruption of hematopoiesis in CML associated with clinical outcome. Furthermore, we used this single-cell approach to identify a blast-crisis-specific SC population, which was also present in a subclone of CML-SCs during the chronic phase in a patient who subsequently developed blast crisis. This approach, which might be broadly applied to any malignancy, illustrates how single-cell analysis can identify subpopulations of therapy-resistant SCs that are not apparent through cell-population analysis.", + "TAG_DATA": [ + "151, patient {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28481360", + "TEXT": "The balance between detrimental, pro-aging, often stochastic processes and counteracting homeostatic mechanisms largely determines the progression of aging. There is substantial evidence suggesting that the endocannabinoid system (ECS) is part of the latter system because it modulates the physiological processes underlying aging. The activity of the ECS declines during aging, as CB1 receptor expression and coupling to G proteins are reduced in the brain tissues of older animals and the levels of the major endocannabinoid 2-arachidonoylglycerol (2-AG) are lower. However, a direct link between endocannabinoid tone and aging symptoms has not been demonstrated. Here we show that a low dose of Δ9-tetrahydrocannabinol (THC) reversed the age-related decline in cognitive performance of mice aged 12 and 18 months. This behavioral effect was accompanied by enhanced expression of synaptic marker proteins and increased hippocampal spine density. THC treatment restored hippocampal gene transcription patterns such that the expression profiles of THC-treated mice aged 12 months closely resembled those of THC-free animals aged 2 months. The transcriptional effects of THC were critically dependent on glutamatergic CB1 receptors and histone acetylation, as their inhibition blocked the beneficial effects of THC. Thus, restoration of CB1 signaling in old individuals could be an effective strategy to treat age-related cognitive impairments.", + "TAG_DATA": [ + "111, mice {'context': 'B-organism'}", + "148, mice {'context': 'B-organism'}", + "157, animals {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "148, mice ['l0']", + "157, animals ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28459437", + "TEXT": "Respiratory viral infections represent the most common cause of allergic asthma exacerbations. Amplification of the type-2 immune response is strongly implicated in asthma exacerbation, but how virus infection boosts type-2 responses is poorly understood. We report a significant correlation between the release of host double-stranded DNA (dsDNA) following rhinovirus infection and the exacerbation of type-2 allergic inflammation in humans. In a mouse model of allergic airway hypersensitivity, we show that rhinovirus infection triggers dsDNA release associated with the formation of neutrophil extracellular traps (NETs), known as NETosis. We further demonstrate that inhibiting NETosis by blocking neutrophil elastase or by degrading NETs with DNase protects mice from type-2 immunopathology. Furthermore, the injection of mouse genomic DNA alone is sufficient to recapitulate many features of rhinovirus-induced type-2 immune responses and asthma pathology. Thus, NETosis and its associated extracellular dsDNA contribute to the pathogenesis and may represent potential therapeutic targets of rhinovirus-induced asthma exacerbations.", + "TAG_DATA": [ + "61, mouse {'context': 'B-organism'}", + "62, model {'context': 'I-organism'}", + "104, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "61, mouse ['l0']", + "62, model ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28436957", + "TEXT": "Diabetic nephropathy (DN) is a major cause of end-stage renal disease, and therapeutic options for preventing its progression are limited. To identify novel therapeutic strategies, we studied protective factors for DN using proteomics on glomeruli from individuals with extreme duration of diabetes (ł50 years) without DN and those with histologic signs of DN. Enzymes in the glycolytic, sorbitol, methylglyoxal and mitochondrial pathways were elevated in individuals without DN. In particular, pyruvate kinase M2 (PKM2) expression and activity were upregulated. Mechanistically, we showed that hyperglycemia and diabetes decreased PKM2 tetramer formation and activity by sulfenylation in mouse glomeruli and cultured podocytes. Pkm-knockdown immortalized mouse podocytes had higher levels of toxic glucose metabolites, mitochondrial dysfunction and apoptosis. Podocyte-specific Pkm2-knockout (KO) mice with diabetes developed worse albuminuria and glomerular pathology. Conversely, we found that pharmacological activation of PKM2 by a small-molecule PKM2 activator, TEPP-46, reversed hyperglycemia-induced elevation in toxic glucose metabolites and mitochondrial dysfunction, partially by increasing glycolytic flux and PGC-1α mRNA in cultured podocytes. In intervention studies using DBA2/J and Nos3 (eNos) KO mouse models of diabetes, TEPP-46 treatment reversed metabolic abnormalities, mitochondrial dysfunction and kidney pathology. Thus, PKM2 activation may protect against DN by increasing glucose metabolic flux, inhibiting the production of toxic glucose metabolites and inducing mitochondrial biogenesis to restore mitochondrial function.", + "TAG_DATA": [ + "95, mouse {'context': 'B-tissue/organ'}", + "96, glomeruli {'context': 'I-tissue/organ'}", + "98, cultured {'context': 'B-cells'}", + "99, podocytes. {'context': 'I-cells'}", + "100, Pkm-knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "101, immortalized {'context': 'B-cells'}", + "102, mouse {'context': 'I-cells'}", + "103, podocytes {'context': 'I-cells'}", + "114, apoptosis. {'phenotype': 'B-apoptosis'}", + "115, Podocyte-specific {'perturbing_action': 'B-gene loss-of-function'}", + "116, Pkm2-knockout {'perturbing_action': 'I-gene loss-of-function'}", + "117, (KO) {'perturbing_action': 'I-gene loss-of-function'}", + "118, mice {'context': 'B-organism'}", + "131, pharmacological {'perturbing_action': 'B-pharmacological augmentation'}", + "132, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "133, of {'perturbing_action': 'I-pharmacological augmentation'}", + "134, PKM2 {'perturbing_action': 'I-pharmacological augmentation'}", + "135, by {'perturbing_action': 'I-pharmacological augmentation'}", + "136, a {'perturbing_action': 'I-pharmacological augmentation'}", + "137, small-molecule {'perturbing_action': 'I-pharmacological augmentation'}", + "138, PKM2 {'perturbing_action': 'I-pharmacological augmentation'}", + "139, activator, {'perturbing_action': 'I-pharmacological augmentation'}", + "140, TEPP-46, {'perturbing_action': 'I-pharmacological augmentation'}", + "160, cultured {'context': 'B-cells'}", + "161, podocytes. {'context': 'I-cells'}", + "168, Nos3 {'perturbing_action': 'I-gene loss-of-function'}", + "169, (eNos) {'perturbing_action': 'I-gene loss-of-function'}", + "170, KO {'perturbing_action': 'I-gene loss-of-function'}", + "171, mouse {'context': 'B-organism'}", + "172, models {'context': 'I-organism'}", + "183, kidney {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "95, mouse ['l0', 'l1', 'l2', 'l3']", + "96, glomeruli ['l0', 'l4', 'l5', 'l6', 'l7']", + "98, cultured ['l1', 'l4', 'l8', 'l9', 'l10', 'l11']", + "99, podocytes. ['l2', 'l5', 'l8', 'l12', 'l13', 'l14']", + "100, Pkm-knockdown ['l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "101, immortalized ['l15', 'l21', 'l22', 'l23']", + "102, mouse ['l9', 'l12', 'l16', 'l21', 'l24', 'l25']", + "103, podocytes ['l6', 'l10', 'l13', 'l17', 'l22', 'l24', 'l26']", + "114, apoptosis. ['l3', 'l7', 'l11', 'l14', 'l18', 'l23', 'l25', 'l26']", + "115, Podocyte-specific ['l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "116, Pkm2-knockout ['l27', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "117, (KO) ['l19', 'l28', 'l41', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "118, mice ['l20', 'l29', 'l42', 'l55', 'l64', 'l65', 'l66']", + "131, pharmacological ['l43', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "132, activation ['l30', 'l44', 'l67', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "133, of ['l31', 'l45', 'l56', 'l68', 'l81', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "134, PKM2 ['l32', 'l46', 'l57', 'l69', 'l82', 'l91', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "135, by ['l33', 'l47', 'l58', 'l70', 'l83', 'l92', 'l100', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "136, a ['l34', 'l48', 'l59', 'l71', 'l84', 'l93', 'l101', 'l108', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "137, small-molecule ['l35', 'l49', 'l72', 'l85', 'l94', 'l102', 'l109', 'l115', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "138, PKM2 ['l36', 'l50', 'l73', 'l86', 'l95', 'l103', 'l110', 'l116', 'l122', 'l130', 'l131', 'l132', 'l133', 'l134']", + "139, activator, ['l37', 'l51', 'l60', 'l74', 'l87', 'l96', 'l104', 'l111', 'l117', 'l123', 'l130', 'l135', 'l136', 'l137', 'l138']", + "140, TEPP-46, ['l38', 'l52', 'l61', 'l64', 'l75', 'l88', 'l97', 'l105', 'l112', 'l118', 'l124', 'l131', 'l135', 'l139', 'l140']", + "160, cultured ['l39', 'l53', 'l62', 'l65', 'l76', 'l89', 'l98', 'l106', 'l113', 'l119', 'l125', 'l132', 'l136', 'l139', 'l141']", + "161, podocytes. ['l40', 'l54', 'l63', 'l66', 'l77', 'l90', 'l99', 'l107', 'l114', 'l120', 'l126', 'l133', 'l137', 'l140', 'l141']", + "166, DBA2/J ['l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "167, and ['l142', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "168, Nos3 ['l78', 'l127', 'l143', 'l149', 'l155', 'l156', 'l157', 'l158', 'l159']", + "169, (eNos) ['l79', 'l121', 'l128', 'l134', 'l138', 'l144', 'l150', 'l155', 'l160', 'l161', 'l162', 'l163']", + "170, KO ['l145', 'l151', 'l156', 'l160', 'l164', 'l165', 'l166']", + "171, mouse ['l146', 'l152', 'l157', 'l161', 'l164', 'l167', 'l168']", + "172, models ['l80', 'l129', 'l147', 'l153', 'l158', 'l162', 'l165', 'l167', 'l169']", + "183, kidney ['l148', 'l154', 'l159', 'l163', 'l166', 'l168', 'l169']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "glomeruli" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "podocytes.", + "immortalized", + "mouse", + "podocytes" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Pkm-knockdown" + ] + }, + "context": { + "val": "cells", + "words": [ + "immortalized", + "mouse", + "podocytes" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Pkm-knockdown" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Pkm-knockdown" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Podocyte-specific", + "Pkm2-knockout", + "(KO)", + "Nos3", + "(eNos)", + "KO" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "models" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Podocyte-specific", + "Pkm2-knockout", + "(KO)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "podocytes." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "models" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "TEPP-46,", + "pharmacological", + "small-molecule" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "pharmacological", + "activation", + "of", + "PKM2", + "by", + "a", + "small-molecule", + "activator,", + "TEPP-46," + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "podocytes." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nos3", + "(eNos)", + "KO" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidney" + ] + } + } + ] + }, + { + "PMID": "28414330", + "TEXT": "Despite years of fully suppressive antiretroviral therapy (ART), HIV persists in its hosts and is never eradicated. One major barrier to eradication is that the virus infects multiple cell types that may individually contribute to HIV persistence. Tissue macrophages are critical contributors to HIV pathogenesis; however, their specific role in HIV persistence during long-term suppressive ART has not been established. Using humanized myeloid-only mice (MoM), we demonstrate that HIV infection of tissue macrophages is rapidly suppressed by ART, as reflected by a rapid drop in plasma viral load and a dramatic decrease in the levels of cell-associated viral RNA and DNA. No viral rebound was observed in the plasma of 67% of the ART-treated animals at 7 weeks after ART interruption, and no replication-competent virus was rescued from the tissue macrophages obtained from these animals. In contrast, in a subset of animals (∼33%), a delayed viral rebound was observed that is consistent with the establishment of persistent infection in tissue macrophages. These observations represent the first direct evidence, to our knowledge, of HIV persistence in tissue macrophages in vivo.", + "TAG_DATA": [ + "61, humanized {'context': 'B-organism'}", + "62, myeloid-only {'context': 'I-organism'}", + "63, mice {'context': 'I-organism'}", + "64, (MoM), {'context': 'I-organism'}", + "71, tissue {'context': 'B-cells'}", + "72, macrophages {'context': 'I-cells'}", + "114, animals {'context': 'B-organism'}", + "129, tissue {'context': 'B-cells'}", + "130, macrophages {'context': 'I-cells'}", + "134, animals. {'context': 'B-organism'}", + "141, animals {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "61, humanized ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "62, myeloid-only ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "63, mice ['l1', 'l6', 'l11', 'l12', 'l13']", + "64, (MoM), ['l2', 'l7', 'l11', 'l14', 'l15']", + "71, tissue ['l3', 'l8', 'l12', 'l14', 'l16']", + "72, macrophages ['l4', 'l9', 'l13', 'l15', 'l16']", + "114, animals ['l5', 'l10']", + "129, tissue ['l17', 'l18']", + "130, macrophages ['l17', 'l19']", + "134, animals. ['l18', 'l19']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28414329", + "TEXT": "Adaptive thermogenesis is the process of heat generation in response to cold stimulation. It is under the control of the sympathetic nervous system, whose chief effector is the catecholamine norepinephrine (NE). NE enhances thermogenesis through β3-adrenergic receptors to activate brown adipose tissue and by 'browning' white adipose tissue. Recent studies have reported that alternative activation of macrophages in response to interleukin (IL)-4 stimulation induces the expression of tyrosine hydroxylase (TH), a key enzyme in the catecholamine synthesis pathway, and that this activation provides an alternative source of locally produced catecholamines during the thermogenic process. Here we report that the deletion of Th in hematopoietic cells of adult mice neither alters energy expenditure upon cold exposure nor reduces browning in inguinal adipose tissue. Bone marrow-derived macrophages did not release NE in response to stimulation with IL-4, and conditioned media from IL-4-stimulated macrophages failed to induce expression of thermogenic genes, such as uncoupling protein 1 (Ucp1), in adipocytes cultured with the conditioned media. Furthermore, chronic treatment with IL-4 failed to increase energy expenditure in wild-type, Ucp1-/- and interleukin-4 receptor-α double-negative (Il4ra-/-) mice. In agreement with these findings, adipose-tissue-resident macrophages did not express TH. Thus, we conclude that alternatively activated macrophages do not synthesize relevant amounts of catecholamines, and hence, are not likely to have a direct role in adipocyte metabolism or adaptive thermogenesis.", + "TAG_DATA": [ + "99, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "100, of {'perturbing_action': 'I-gene loss-of-function'}", + "101, Th {'perturbing_action': 'I-gene loss-of-function'}", + "103, hematopoietic {'context': 'B-cells'}", + "104, cells {'context': 'I-cells'}", + "106, adult {'context': 'B-organism'}", + "107, mice {'context': 'I-organism'}", + "119, inguinal {'context': 'B-tissue/organ'}", + "120, adipose {'context': 'I-tissue/organ'}", + "121, tissue. {'context': 'I-tissue/organ'}", + "122, Bone {'context': 'B-cells'}", + "123, marrow-derived {'context': 'I-cells'}", + "124, macrophages {'context': 'I-cells'}", + "140, macrophages {'context': 'B-cells'}", + "155, adipocytes {'context': 'B-cells'}", + "173, Ucp1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "175, interleukin-4 {'perturbing_action': 'B-gene loss-of-function'}", + "176, receptor-α {'perturbing_action': 'I-gene loss-of-function'}", + "177, double-negative {'perturbing_action': 'I-gene loss-of-function'}", + "178, (Il4ra-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "179, mice. {'context': 'B-organism'}", + "185, adipose-tissue-resident {'context': 'B-cells'}", + "186, macrophages {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "99, deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "100, of ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "101, Th ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "103, hematopoietic ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "104, cells ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "106, adult ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54']", + "107, mice ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l55', 'l56', 'l57']", + "119, inguinal ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l55', 'l58', 'l59', 'l60', 'l61', 'l62']", + "120, adipose ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l56', 'l58', 'l63', 'l64', 'l65', 'l66']", + "121, tissue. ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l57', 'l59', 'l63', 'l67']", + "122, Bone ['l9', 'l20', 'l30', 'l39', 'l47', 'l60', 'l64', 'l68', 'l69', 'l70', 'l71']", + "123, marrow-derived ['l10', 'l21', 'l31', 'l40', 'l48', 'l61', 'l65', 'l68', 'l72', 'l73', 'l74']", + "124, macrophages ['l11', 'l22', 'l32', 'l41', 'l49', 'l54', 'l62', 'l66', 'l67', 'l69', 'l72', 'l75', 'l76']", + "140, macrophages ['l70', 'l73', 'l75', 'l77']", + "155, adipocytes ['l71', 'l74', 'l76', 'l77']", + "173, Ucp1-/- ['l78', 'l79', 'l80', 'l81', 'l82']", + "175, interleukin-4 ['l78', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "176, receptor-α ['l79', 'l83', 'l89', 'l90', 'l91', 'l92', 'l93']", + "177, double-negative ['l80', 'l84', 'l89', 'l94', 'l95', 'l96', 'l97']", + "178, (Il4ra-/-) ['l81', 'l85', 'l90', 'l94', 'l98', 'l99', 'l100']", + "179, mice. ['l82', 'l86', 'l91', 'l95', 'l98']", + "185, adipose-tissue-resident ['l87', 'l92', 'l96', 'l99', 'l101']", + "186, macrophages ['l88', 'l93', 'l97', 'l100', 'l101']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Th", + "interleukin-4", + "receptor-α", + "double-negative", + "(Il4ra-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "cells", + "Bone", + "marrow-derived", + "macrophages", + "adipose-tissue-resident" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Th", + "Ucp1-/-", + "interleukin-4", + "receptor-α", + "double-negative", + "(Il4ra-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "adult", + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Th" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "inguinal", + "adipose", + "tissue." + ] + } + } + ] + }, + { + "PMID": "28394329", + "TEXT": "Chromosomal instability (CIN), a feature of most adult neoplasms from their early stages onward, is a driver of tumorigenesis. However, several malignancy subtypes, including some triple-negative breast cancers, display a paucity of genomic aberrations, thus suggesting that tumor development may occur in the absence of CIN. Here we show that the differentiation status of normal human mammary epithelial cells dictates cell behavior after an oncogenic event and predetermines the genetic routes toward malignancy. Whereas oncogene induction in differentiated cells induces massive DNA damage, mammary stem cells are resistant, owing to a preemptive program driven by the transcription factor ZEB1 and the methionine sulfoxide reductase MSRB3. The prevention of oncogene-induced DNA damage precludes induction of the oncosuppressive p53-dependent DNA-damage response, thereby increasing stem cells' intrinsic susceptibility to malignant transformation. In accord with this model, a subclass of breast neoplasms exhibit unique pathological features, including high ZEB1 expression, a low frequency of TP53 mutations and low CIN.", + "TAG_DATA": [ + "77, differentiated {'context': 'B-cells'}", + "78, cells {'context': 'I-cells'}", + "83, mammary {'context': 'B-cells'}", + "84, stem {'context': 'I-cells'}", + "85, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "77, differentiated ['l0']", + "78, cells ['l0']", + "83, mammary ['l1', 'l2']", + "84, stem ['l1', 'l3']", + "85, cells ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28346412", + "TEXT": "To date, anti-CTLA-4 (ipilimumab) or anti-PD-1 (nivolumab) monotherapy has not been demonstrated to be of substantial clinical benefit in patients with prostate cancer. To identify additional immune-inhibitory pathways in the prostate-tumor microenvironment, we evaluated untreated and ipilimumab-treated tumors from patients in a presurgical clinical trial. Levels of the PD-L1 and VISTA inhibitory molecules increased on independent subsets of macrophages in treated tumors. Our data suggest that VISTA represents another compensatory inhibitory pathway in prostate tumors after ipilimumab therapy.", + "TAG_DATA": [ + "37, tumors {'context': 'B-neoplasm'}", + "39, patients {'context': 'B-patient'}", + "58, macrophages {'context': 'B-cells'}", + "61, tumors. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "37, tumors ['l0', 'l1']", + "39, patients ['l0', 'l2']", + "58, macrophages ['l1', 'l2', 'l3']", + "61, tumors. ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28288110", + "TEXT": "Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', were associated with BRCA1/BRCA2 dysfunction. Herein we used a lasso logistic regression model to identify six distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2-deficient samples. HRDetect identifies BRCA1/BRCA2-deficient tumors with 98.7% sensitivity (area under the curve (AUC) = 0.98). Application of this model in a cohort of 560 individuals with breast cancer, of whom 22 were known to carry a germline BRCA1 or BRCA2 mutation, allowed us to identify an additional 22 tumors with somatic loss of BRCA1 or BRCA2 and 47 tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers and demonstrated its efficacy in alternative sequencing strategies. Integrating all of the classes of mutational signatures thus reveals a larger proportion of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%) than hitherto appreciated (∼1-5%) who could have selective therapeutic sensitivity to PARP inhibition.", + "TAG_DATA": [ + "100, tumors {'context': 'B-neoplasm'}", + "122, breast {'context': 'B-neoplasm'}", + "123, cancer, {'context': 'I-neoplasm'}", + "144, tumors {'context': 'B-neoplasm'}", + "154, tumors {'context': 'B-neoplasm'}", + "171, breast, {'context': 'B-neoplasm'}", + "172, ovarian {'context': 'I-neoplasm'}", + "173, and {'context': 'I-neoplasm'}", + "174, pancreatic {'context': 'I-neoplasm'}", + "175, cancers {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "122, breast ['l0', 'l1']", + "123, cancer, ['l0', 'l2']", + "144, tumors ['l1', 'l2']", + "154, tumors ['l3', 'l4', 'l5', 'l6', 'l7']", + "171, breast, ['l3', 'l8', 'l9', 'l10', 'l11']", + "172, ovarian ['l4', 'l8', 'l12', 'l13', 'l14']", + "173, and ['l5', 'l9', 'l12', 'l15', 'l16']", + "174, pancreatic ['l6', 'l10', 'l13', 'l15', 'l17']", + "175, cancers ['l7', 'l11', 'l14', 'l16', 'l17']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28263313", + "TEXT": "Efficient hematopoietic stem cell (HSC) homing is important for hematopoietic cell transplantation (HCT), especially when HSC numbers are limited, as in the use of cord blood (CB). In a screen of small-molecule compounds, we identified glucocorticoid (GC) hormone signaling as an activator of CXCR4 expression in human CB HSCs and hematopoietic progenitor cells (HPCs). Short-term GC pretreatment of human CB HSCs and HPCs promoted SDF-1-CXCR4-axis-mediated chemotaxis, homing, and long-term engraftment when these cells were transplanted into primary- and secondary-recipient NSG mice. Mechanistically, activated glucocorticoid receptor binds directly to a glucocorticoid response element in the CXCR4 promoter and recruits the SRC-1-p300 complex to promote H4K5 and H4K16 histone acetylation, facilitating transcription of CXCR4. These results suggest a new and readily available means to enhance the clinical efficacy of CB HCT.", + "TAG_DATA": [ + "58, human {'context': 'B-cells'}", + "59, CB {'context': 'I-cells'}", + "60, HSCs {'context': 'I-cells'}", + "62, HPCs {'context': 'B-cells'}", + "63, promoted {'effect': 'B-positive'}", + "72, cells {'context': 'B-cells'}", + "76, primary- {'context': 'B-organism'}", + "77, and {'context': 'I-cells'}", + "78, secondary-recipient {'context': 'I-organism'}", + "79, NSG {'context': 'I-organism'}", + "80, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "58, human ['l0', 'l1', 'l2', 'l3', 'l4']", + "59, CB ['l0', 'l5', 'l6', 'l7', 'l8']", + "60, HSCs ['l1', 'l5', 'l9', 'l10', 'l11']", + "62, HPCs ['l2', 'l6', 'l9', 'l12', 'l13']", + "63, promoted ['l3', 'l7', 'l10', 'l12']", + "72, cells ['l4', 'l8', 'l11', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "76, primary- ['l14', 'l19', 'l20', 'l21', 'l22']", + "77, and ['l15', 'l19', 'l23', 'l24', 'l25']", + "78, secondary-recipient ['l16', 'l20', 'l23', 'l26', 'l27']", + "79, NSG ['l17', 'l21', 'l24', 'l26', 'l28']", + "80, mice. ['l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "CB", + "HSCs", + "HPCs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + } + ] + }, + { + "PMID": "28218918", + "TEXT": "African Americans have a heightened risk of developing chronic and end-stage kidney disease, an association that is largely attributed to two common genetic variants, termed G1 and G2, in the APOL1 gene. Direct evidence demonstrating that these APOL1 risk alleles are pathogenic is still lacking because the APOL1 gene is present in only some primates and humans; thus it has been challenging to demonstrate experimental proof of causality of these risk alleles for renal disease. Here we generated mice with podocyte-specific inducible expression of the APOL1 reference allele (termed G0) or each of the risk-conferring alleles (G1 or G2). We show that mice with podocyte-specific expression of either APOL1 risk allele, but not of the G0 allele, develop functional (albuminuria and azotemia), structural (foot-process effacement and glomerulosclerosis) and molecular (gene-expression) changes that closely resemble human kidney disease. Disease development was cell-type specific and likely reversible, and the severity correlated with the level of expression of the risk allele. We further found that expression of the risk-variant APOL1 alleles interferes with endosomal trafficking and blocks autophagic flux, which ultimately leads to inflammatory-mediated podocyte death and glomerular scarring. In summary, this is the first demonstration that the expression of APOL1 risk alleles is causal for altered podocyte function and glomerular disease in vivo.", + "TAG_DATA": [ + "78, mice {'context': 'B-organism'}", + "80, podocyte-specific {'perturbing_action': 'B-gene gain-of-function'}", + "81, inducible {'perturbing_action': 'I-gene gain-of-function'}", + "82, expression {'perturbing_action': 'I-gene gain-of-function'}", + "83, of {'perturbing_action': 'I-gene gain-of-function'}", + "84, the {'perturbing_action': 'I-gene gain-of-function'}", + "85, APOL1 {'perturbing_action': 'I-gene gain-of-function'}", + "86, reference {'perturbing_action': 'I-gene gain-of-function'}", + "87, allele {'perturbing_action': 'I-gene gain-of-function'}", + "88, (termed {'perturbing_action': 'I-gene gain-of-function'}", + "89, G0) {'perturbing_action': 'I-gene gain-of-function'}", + "102, mice {'context': 'B-organism'}", + "104, podocyte-specific {'perturbing_action': 'B-gene gain-of-function'}", + "105, expression {'perturbing_action': 'I-gene gain-of-function'}", + "106, of {'perturbing_action': 'I-gene gain-of-function'}", + "107, either {'perturbing_action': 'I-gene gain-of-function'}", + "108, APOL1 {'perturbing_action': 'I-other'}", + "109, risk {'perturbing_action': 'I-gene gain-of-function'}", + "110, allele, {'perturbing_action': 'I-gene gain-of-function'}", + "173, blocks {'effect': 'B-negative'}", + "174, autophagic {'phenotype': 'B-autophagy'}", + "175, flux, {'phenotype': 'I-autophagy'}", + "181, podocyte {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "78, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "80, podocyte-specific ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "81, inducible ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "82, expression ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "83, of ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "84, the ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "85, APOL1 ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "86, reference ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "87, allele ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "88, (termed ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "89, G0) ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "102, mice ['l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "104, podocyte-specific ['l55', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "105, expression ['l56', 'l62', 'l68', 'l69', 'l70', 'l71', 'l72']", + "106, of ['l57', 'l63', 'l68', 'l73', 'l74', 'l75', 'l76']", + "107, either ['l58', 'l64', 'l69', 'l73', 'l77', 'l78', 'l79']", + "108, APOL1 ['l59', 'l65', 'l70', 'l74', 'l77', 'l80', 'l81']", + "109, risk ['l60', 'l66', 'l71', 'l75', 'l78', 'l80', 'l82']", + "110, allele, ['l61', 'l67', 'l72', 'l76', 'l79', 'l81', 'l82']", + "173, blocks ['l83', 'l84', 'l85']", + "174, autophagic ['l83', 'l86', 'l87']", + "175, flux, ['l84', 'l86', 'l88']", + "181, podocyte ['l85', 'l87', 'l88']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "podocyte-specific", + "inducible", + "expression", + "of", + "the", + "APOL1", + "reference", + "allele", + "(termed", + "G0)", + "either", + "risk", + "allele," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "APOL1" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagic", + "flux," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocyte" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagic", + "flux," + ] + }, + "context": { + "val": "cells", + "words": [ + "podocyte" + ] + } + } + ] + }, + { + "PMID": "28191885", + "TEXT": "Lung cancer is the leading cause of cancer deaths worldwide, with the majority of mortality resulting from metastatic spread. However, the molecular mechanism by which cancer cells acquire the ability to disseminate from primary tumors, seed distant organs, and grow into tissue-destructive metastases remains incompletely understood. We combined tumor barcoding in a mouse model of human lung adenocarcinoma with unbiased genomic approaches to identify a transcriptional program that confers metastatic ability and predicts patient survival. Small-scale in vivo screening identified several genes, including Cd109, that encode novel pro-metastatic factors. We uncovered signaling mediated by Janus kinases (Jaks) and the transcription factor Stat3 as a critical, pharmacologically targetable effector of CD109-driven lung cancer metastasis. In summary, by coupling the systematic genomic analysis of purified cancer cells in distinct malignant states from mouse models with extensive human validation, we uncovered several key regulators of metastatic ability, including an actionable pro-metastatic CD109-Jak-Stat3 axis.", + "TAG_DATA": [ + "52, mouse {'context': 'B-organism'}", + "53, model {'context': 'I-neoplasm'}", + "54, of {'context': 'I-neoplasm'}", + "55, human {'context': 'I-neoplasm'}", + "56, lung {'context': 'I-neoplasm'}", + "57, adenocarcinoma {'context': 'I-neoplasm'}", + "76, in {'context': 'B-in vivo'}", + "77, vivo {'context': 'B-in vivo'}", + "110, lung {'context': 'B-neoplasm'}", + "111, cancer {'context': 'I-neoplasm'}", + "112, metastasis. {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "52, mouse ['l0', 'l1', 'l2', 'l3', 'l4']", + "53, model ['l0', 'l5', 'l6', 'l7', 'l8']", + "54, of ['l1', 'l5', 'l9', 'l10', 'l11', 'l12']", + "55, human ['l2', 'l6', 'l9', 'l13', 'l14', 'l15']", + "56, lung ['l3', 'l7', 'l10', 'l13', 'l16', 'l17', 'l18']", + "57, adenocarcinoma ['l4', 'l8', 'l11', 'l14', 'l16', 'l19', 'l20']", + "76, in ['l17', 'l19', 'l21', 'l22', 'l23', 'l24']", + "77, vivo ['l12', 'l15', 'l18', 'l20', 'l21', 'l25']", + "110, lung ['l22', 'l26', 'l27']", + "111, cancer ['l23', 'l25', 'l26', 'l28']", + "112, metastasis. ['l24', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "lung", + "cancer" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + } + ] + }, + { + "PMID": "28112735", + "TEXT": "The prefrontal cortex (PFC) underlies higher cognitive processes that are modulated by nicotinic acetylcholine receptor (nAChR) activation by cholinergic inputs. PFC spontaneous default activity is altered in neuropsychiatric disorders, including schizophrenia-a disorder that can be accompanied by heavy smoking. Recently, genome-wide association studies (GWAS) identified single-nucleotide polymorphisms (SNPs) in the human CHRNA5 gene, encoding the α5 nAChR subunit, that increase the risks for both smoking and schizophrenia. Mice with altered nAChR gene function exhibit PFC-dependent behavioral deficits, but it is unknown how the corresponding human polymorphisms alter the cellular and circuit mechanisms underlying behavior. Here we show that mice expressing a human α5 SNP exhibit neurocognitive behavioral deficits in social interaction and sensorimotor gating tasks. Two-photon calcium imaging in awake mouse models showed that nicotine can differentially influence PFC pyramidal cell activity by nAChR modulation of layer II/III hierarchical inhibitory circuits. In α5-SNP-expressing and α5-knockout mice, lower activity of vasoactive intestinal polypeptide (VIP) interneurons resulted in an increased somatostatin (SOM) interneuron inhibitory drive over layer II/III pyramidal neurons. The decreased activity observed in α5-SNP-expressing mice resembles the hypofrontality observed in patients with psychiatric disorders, including schizophrenia and addiction. Chronic nicotine administration reversed this hypofrontality, suggesting that administration of nicotine may represent a therapeutic strategy for the treatment of schizophrenia, and a physiological basis for the tendency of patients with schizophrenia to self-medicate by smoking.", + "TAG_DATA": [ + "98, mice {'context': 'B-organism'}", + "99, expressing {'perturbing_action': 'B-other'}", + "100, a {'perturbing_action': 'I-other'}", + "101, human {'perturbing_action': 'I-other'}", + "102, α5 {'perturbing_action': 'I-other'}", + "103, SNP {'perturbing_action': 'I-other'}", + "119, awake {'context': 'B-organism'}", + "120, mouse {'context': 'I-organism'}", + "121, models {'context': 'I-organism'}", + "128, PFC {'context': 'B-cells'}", + "130, cell {'context': 'I-cells'}", + "142, α5-SNP-expressing {'perturbing_action': 'B-other'}", + "144, α5-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "145, mice, {'context': 'B-organism'}", + "164, layer {'context': 'B-cells'}", + "165, II/III {'context': 'I-cells'}", + "166, pyramidal {'context': 'I-cells'}", + "167, neurons. {'context': 'I-cells'}", + "174, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "98, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "99, expressing ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "100, a ['l1', 'l8', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "101, human ['l2', 'l9', 'l18', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "102, α5 ['l3', 'l10', 'l19', 'l27', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "103, SNP ['l4', 'l11', 'l20', 'l28', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "119, awake ['l12', 'l21', 'l29', 'l36', 'l41', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "120, mouse ['l5', 'l13', 'l22', 'l30', 'l37', 'l42', 'l46', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "121, models ['l6', 'l14', 'l23', 'l31', 'l38', 'l43', 'l47', 'l53', 'l59', 'l60', 'l61', 'l62']", + "128, PFC ['l15', 'l24', 'l32', 'l39', 'l44', 'l48', 'l54', 'l59', 'l63', 'l64', 'l65', 'l66']", + "130, cell ['l7', 'l16', 'l25', 'l33', 'l40', 'l45', 'l49', 'l55', 'l60', 'l63', 'l67', 'l68', 'l69']", + "142, α5-SNP-expressing ['l17', 'l26', 'l34', 'l50', 'l56', 'l61', 'l64', 'l67', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "144, α5-knockout ['l51', 'l57', 'l65', 'l68', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "145, mice, ['l52', 'l58', 'l62', 'l66', 'l69', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "164, layer ['l72', 'l77', 'l81', 'l85', 'l86', 'l87', 'l88']", + "165, II/III ['l73', 'l78', 'l82', 'l85', 'l89', 'l90', 'l91']", + "166, pyramidal ['l74', 'l79', 'l83', 'l86', 'l89', 'l92', 'l93']", + "167, neurons. ['l75', 'l80', 'l84', 'l87', 'l90', 'l92', 'l94']", + "174, mice ['l88', 'l91', 'l93', 'l94']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "awake", + "mouse", + "models", + "mice," + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "a", + "human", + "α5", + "SNP", + "α5-SNP-expressing" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "a", + "human", + "α5", + "SNP", + "α5-SNP-expressing" + ] + }, + "context": { + "val": "cells", + "words": [ + "PFC", + "cell", + "layer", + "II/III", + "pyramidal", + "neurons." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "awake", + "mouse", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "α5-knockout" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "PFC", + "cell", + "layer", + "II/III", + "pyramidal", + "neurons." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "α5-knockout" + ] + } + } + ] + }, + { + "PMID": "28067899", + "TEXT": "Heritable thoracic aortic aneurysms and dissections (TAAD), including Marfan syndrome (MFS), currently lack a cure, and causative mutations have been identified for only a fraction of affected families. Here we identify the metalloproteinase ADAMTS1 and inducible nitric oxide synthase (NOS2) as therapeutic targets in individuals with TAAD. We show that Adamts1 is a major mediator of vascular homeostasis, given that genetic haploinsufficiency of Adamts1 in mice causes TAAD similar to MFS. Aortic nitric oxide and Nos2 levels were higher in Adamts1-deficient mice and in a mouse model of MFS (hereafter referred to as MFS mice), and Nos2 inactivation protected both types of mice from aortic pathology. Pharmacological inhibition of Nos2 rapidly reversed aortic dilation and medial degeneration in young Adamts1-deficient mice and in young or old MFS mice. Patients with MFS showed elevated NOS2 and decreased ADAMTS1 protein levels in the aorta. These findings uncover a possible causative role for the ADAMTS1-NOS2 axis in human TAAD and warrant evaluation of NOS2 inhibitors for therapy.", + "TAG_DATA": [ + "80, Adamts1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "81, mice {'context': 'B-organism'}", + "85, mouse {'context': 'B-organism'}", + "86, model {'context': 'I-organism'}", + "96, Nos2 {'perturbing_action': 'B-gene loss-of-function'}", + "97, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "102, mice {'context': 'B-organism'}", + "106, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "107, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "108, of {'perturbing_action': 'I-pharmacological inhibition'}", + "109, Nos2 {'perturbing_action': 'I-pharmacological inhibition'}", + "119, Adamts1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "120, mice {'context': 'B-organism'}", + "123, young {'context': 'B-organism'}", + "124, or {'context': 'I-organism'}", + "125, old {'context': 'I-organism'}", + "127, mice. {'context': 'I-organism'}", + "141, aorta. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "63, Adamts1 ['l0', 'l1']", + "80, Adamts1-deficient ['l0', 'l2']", + "81, mice ['l1', 'l2']", + "85, mouse ['l3', 'l4', 'l5']", + "86, model ['l3', 'l6', 'l7']", + "87, of ['l4', 'l6', 'l8']", + "96, Nos2 ['l9', 'l10']", + "97, inactivation ['l9', 'l11']", + "102, mice ['l5', 'l7', 'l8', 'l10', 'l11']", + "106, Pharmacological ['l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "107, inhibition ['l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "108, of ['l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "109, Nos2 ['l14', 'l23', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "119, Adamts1-deficient ['l15', 'l24', 'l32', 'l39', 'l45', 'l46', 'l47', 'l48', 'l49']", + "120, mice ['l16', 'l25', 'l33', 'l40', 'l45', 'l50', 'l51', 'l52']", + "123, young ['l17', 'l26', 'l34', 'l41', 'l46', 'l50', 'l53', 'l54', 'l55']", + "124, or ['l18', 'l27', 'l35', 'l42', 'l47', 'l53', 'l56', 'l57']", + "125, old ['l19', 'l28', 'l36', 'l43', 'l48', 'l51', 'l54', 'l56', 'l58']", + "127, mice. ['l20', 'l29', 'l37', 'l44', 'l49', 'l52', 'l55', 'l57', 'l58']", + "141, aorta. ['l21', 'l30', 'l38']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Adamts1-deficient", + "Nos2", + "inactivation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "young", + "or", + "old", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "Nos2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "young", + "or", + "old", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "aorta." + ] + } + } + ] + }, + { + "PMID": "27991918", + "TEXT": "Type 2 diabetes and insulin resistance are associated with reduced glucose utilization in the muscle and poor exercise performance. Here we find that depletion of the epigenome modifier histone deacetylase 3 (HDAC3) specifically in skeletal muscle causes severe systemic insulin resistance in mice but markedly enhances endurance and resistance to muscle fatigue, despite reducing muscle force. This seemingly paradoxical phenotype is due to lower glucose utilization and greater lipid oxidation in HDAC3-depleted muscles, a fuel switch caused by the activation of anaplerotic reactions driven by AMP deaminase 3 (Ampd3) and catabolism of branched-chain amino acids. These findings highlight the pivotal role of amino acid catabolism in muscle fatigue and type 2 diabetes pathogenesis. Further, as genome occupancy of HDAC3 in skeletal muscle is controlled by the circadian clock, these results delineate an epigenomic regulatory mechanism through which the circadian clock governs skeletal muscle bioenergetics. These findings suggest that physical exercise at certain times of the day or pharmacological targeting of HDAC3 could potentially be harnessed to alter systemic fuel metabolism and exercise performance.", + "TAG_DATA": [ + "23, depletion {'perturbing_action': 'B-gene loss-of-function'}", + "24, of {'perturbing_action': 'I-gene loss-of-function'}", + "25, the {'perturbing_action': 'I-gene loss-of-function'}", + "26, epigenome {'perturbing_action': 'I-gene loss-of-function'}", + "27, modifier {'perturbing_action': 'I-gene loss-of-function'}", + "28, histone {'perturbing_action': 'I-gene loss-of-function'}", + "29, deacetylase {'perturbing_action': 'I-gene loss-of-function'}", + "30, 3 {'perturbing_action': 'I-gene loss-of-function'}", + "31, (HDAC3) {'perturbing_action': 'I-gene loss-of-function'}", + "32, specifically {'perturbing_action': 'I-gene loss-of-function'}", + "33, in {'perturbing_action': 'I-gene loss-of-function'}", + "34, skeletal {'perturbing_action': 'I-gene loss-of-function'}", + "35, muscle {'perturbing_action': 'I-gene loss-of-function'}", + "42, mice {'context': 'B-organism'}", + "72, muscles, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "23, depletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "24, of ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "25, the ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "26, epigenome ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "27, modifier ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "28, histone ['l4', 'l17', 'l29', 'l40', 'l50', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "29, deacetylase ['l5', 'l18', 'l30', 'l41', 'l51', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "30, 3 ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "31, (HDAC3) ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "32, specifically ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l90', 'l91', 'l92', 'l93', 'l94']", + "33, in ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l95', 'l96', 'l97', 'l98']", + "34, skeletal ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l99', 'l100', 'l101']", + "35, muscle ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l102', 'l103']", + "42, mice ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l104']", + "72, muscles, ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l104']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "the", + "epigenome", + "modifier", + "histone", + "deacetylase", + "3", + "(HDAC3)", + "specifically", + "in", + "skeletal", + "muscle" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "the", + "epigenome", + "modifier", + "histone", + "deacetylase", + "3", + "(HDAC3)", + "specifically", + "in", + "skeletal", + "muscle" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscles," + ] + } + } + ] + }, + { + "PMID": "27918564", + "TEXT": "Preterm birth (PTB) is a leading cause of neonatal death worldwide. Intrauterine and systemic infection and inflammation cause 30-40% of spontaneous preterm labor (PTL), which precedes PTB. Although antibody production is a major immune defense mechanism against infection, and B cell dysfunction has been implicated in pregnancy complications associated with PTL, the functions of B cells in pregnancy are not well known. We found that choriodecidua of women undergoing spontaneous PTL harbored functionally altered B cell populations. B cell-deficient mice were markedly more susceptible than wild-type (WT) mice to PTL after inflammation, but B cells conferred interleukin (IL)-10-independent protection against PTL. B cell deficiency in mice resulted in a lower uterine level of active progesterone-induced blocking factor 1 (PIBF1), and therapeutic administration of PIBF1 mitigated PTL and uterine inflammation in B cell-deficient mice. B cells are a significant producer of PIBF1 in human choriodecidua and mouse uterus in late gestation. PIBF1 expression by B cells is induced by the mucosal alarmin IL-33 (ref. 9). Human PTL was associated with diminished expression of the α-chain of IL-33 receptor on choriodecidual B cells and a lower level of active PIBF1 in late gestation choriodecidua. These results define a vital regulatory cascade involving IL-33, decidual B cells and PIBF1 in safeguarding term pregnancy and suggest new therapeutic approaches based on IL-33 and PIBF1 to prevent human PTL.", + "TAG_DATA": [ + "77, B {'perturbing_action': 'B-gene loss-of-function'}", + "78, cell-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "79, mice {'context': 'B-organism'}", + "87, mice {'context': 'B-organism'}", + "93, B {'context': 'B-cells'}", + "94, cells {'context': 'I-cells'}", + "101, B {'perturbing_action': 'B-gene loss-of-function'}", + "102, cell {'perturbing_action': 'I-gene loss-of-function'}", + "103, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "105, mice {'context': 'B-organism'}", + "130, B {'perturbing_action': 'B-gene loss-of-function'}", + "131, cell-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "132, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "77, B ['l0', 'l1', 'l2', 'l3', 'l4']", + "78, cell-deficient ['l0', 'l5', 'l6', 'l7', 'l8']", + "79, mice ['l1', 'l5', 'l9', 'l10', 'l11']", + "87, mice ['l2', 'l6', 'l9', 'l12', 'l13']", + "93, B ['l3', 'l7', 'l10', 'l12', 'l14']", + "94, cells ['l4', 'l8', 'l11', 'l13', 'l14']", + "101, B ['l15', 'l16', 'l17']", + "102, cell ['l15', 'l18', 'l19']", + "103, deficiency ['l16', 'l18', 'l20']", + "105, mice ['l17', 'l19', 'l20']", + "130, B ['l21', 'l22']", + "131, cell-deficient ['l21', 'l23']", + "132, mice. ['l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "B", + "cell-deficient", + "cell", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "B", + "cell-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "B", + "cells" + ] + } + } + ] + }, + { + "PMID": "27841875", + "TEXT": "Familial dysautonomia (FD) is a debilitating disorder that affects derivatives of the neural crest (NC). For unknown reasons, people with FD show marked differences in disease severity despite carrying an identical, homozygous point mutation in IKBKAP, encoding IκB kinase complex-associated protein. Here we present disease-related phenotypes in human pluripotent stem cells (PSCs) that capture FD severity. Cells from individuals with severe but not mild disease show impaired specification of NC derivatives, including autonomic and sensory neurons. In contrast, cells from individuals with severe and mild FD show defects in peripheral neuron survival, indicating that neurodegeneration is the main culprit for cases of mild FD. Although genetic repair of the FD-associated mutation reversed early developmental NC defects, sensory neuron specification was not restored, indicating that other factors may contribute to disease severity. Whole-exome sequencing identified candidate modifier genes for individuals with severe FD. Our study demonstrates that PSC-based modeling is sensitive in recapitulating disease severity, which presents an important step toward personalized medicine.", + "TAG_DATA": [ + "47, human {'context': 'B-cells'}", + "48, pluripotent {'context': 'I-cells'}", + "49, stem {'context': 'I-cells'}", + "50, cells {'context': 'I-cells'}", + "51, (PSCs) {'context': 'I-cells'}", + "56, Cells {'context': 'B-cells'}", + "78, cells {'context': 'B-cells'}", + "89, peripheral {'context': 'B-cells'}", + "90, neuron {'context': 'I-cells'}", + "116, sensory {'context': 'B-cells'}", + "117, neuron {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "47, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "48, pluripotent ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "49, stem ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "50, cells ['l2', 'l9', 'l15', 'l21', 'l22', 'l23']", + "51, (PSCs) ['l3', 'l10', 'l16', 'l21', 'l24', 'l25', 'l26', 'l27']", + "56, Cells ['l4', 'l11', 'l17', 'l22', 'l24', 'l28', 'l29']", + "78, cells ['l5', 'l12', 'l18', 'l25', 'l28', 'l30', 'l31']", + "89, peripheral ['l6', 'l13', 'l19', 'l26', 'l30', 'l32']", + "90, neuron ['l7', 'l14', 'l20', 'l23', 'l27', 'l29', 'l31', 'l32']", + "116, sensory ['l33']", + "117, neuron ['l33']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27841873", + "TEXT": "Although the majority of patients with acute myeloid leukemia (AML) initially respond to chemotherapy, many of them subsequently relapse, and the mechanistic basis for AML persistence following chemotherapy has not been determined. Recurrent somatic mutations in DNA methyltransferase 3A (DNMT3A), most frequently at arginine 882 (DNMT3AR882), have been observed in AML and in individuals with clonal hematopoiesis in the absence of leukemic transformation. Patients with DNMT3AR882 AML have an inferior outcome when treated with standard-dose daunorubicin-based induction chemotherapy, suggesting that DNMT3AR882 cells persist and drive relapse. We found that Dnmt3a mutations induced hematopoietic stem cell expansion, cooperated with mutations in the FMS-like tyrosine kinase 3 gene (Flt3ITD) and the nucleophosmin gene (Npm1c) to induce AML in vivo, and promoted resistance to anthracycline chemotherapy. In patients with AML, the presence of DNMT3AR882 mutations predicts minimal residual disease, underscoring their role in AML chemoresistance. DNMT3AR882 cells showed impaired nucleosome eviction and chromatin remodeling in response to anthracycline treatment, which resulted from attenuated recruitment of histone chaperone SPT-16 following anthracycline exposure. This defect led to an inability to sense and repair DNA torsional stress, which resulted in increased mutagenesis. Our findings identify a crucial role for DNMT3AR882 mutations in driving AML chemoresistance and highlight the importance of chromatin remodeling in response to cytotoxic chemotherapy.", + "TAG_DATA": [ + "89, Dnmt3a {'perturbing_action': 'B-other'}", + "90, mutations {'perturbing_action': 'I-other'}", + "92, hematopoietic {'context': 'B-cells'}", + "93, stem {'context': 'I-cells'}", + "94, cell {'context': 'I-cells'}", + "115, in {'context': 'B-in vivo'}", + "116, vivo, {'context': 'I-in vivo'}", + "142, DNMT3AR882 {'context': 'B-cells'}", + "143, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "89, Dnmt3a ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "90, mutations ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "92, hematopoietic ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "93, stem ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "94, cell ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "114, AML ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "115, in ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "116, vivo, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "142, DNMT3AR882 ['l28']", + "143, cells ['l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Dnmt3a", + "mutations" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Dnmt3a", + "mutations" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + } + ] + }, + { + "PMID": "27820605", + "TEXT": "Molecular understanding of serological immunity to influenza has been confounded by the complexity of the polyclonal antibody response in humans. Here we used high-resolution proteomics analysis of immunoglobulin (referred to as Ig-seq) coupled with high-throughput sequencing of transcripts encoding B cell receptors (BCR-seq) to quantitatively determine the antibody repertoire at the individual clonotype level in the sera of young adults before and after vaccination with trivalent seasonal influenza vaccine. The serum repertoire comprised between 40 and 147 clonotypes that were specific to each of the three monovalent components of the trivalent influenza vaccine, with boosted pre-existing clonotypes accounting for ∼60% of the response. An unexpectedly high fraction of serum antibodies recognized both the H1 and H3 monovalent vaccines. Recombinant versions of these H1 + H3 cross-reactive antibodies showed broad binding to hemagglutinins (HAs) from previously circulating virus strains; several of these antibodies, which were prevalent in the serum of multiple donors, recognized the same conserved epitope in the HA head domain. Although the HA-head-specific H1 + H3 antibodies did not show neutralization activity in vitro, they protected mice against infection with the H1N1 and H3N2 virus strains when administered before or after challenge. Collectively, our data reveal unanticipated insights regarding the serological response to influenza vaccination and raise questions about the added benefits of using a quadrivalent vaccine instead of a trivalent vaccine.", + "TAG_DATA": [ + "173, in {'context': 'B-in vitro'}", + "174, vitro, {'context': 'I-in vitro'}", + "177, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "173, in ['l0', 'l1']", + "174, vitro, ['l0', 'l2']", + "177, mice ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27798614", + "TEXT": "A major therapeutic goal for type 1 diabetes (T1D) is to induce autoantigen-specific tolerance of T cells. This could suppress autoimmunity in those at risk for the development of T1D, as well as in those with established disease who receive islet replacement or regeneration therapy. Because functional studies of human autoreactive T cell responses have been limited largely to peripheral blood-derived T cells, it is unclear how representative the peripheral T cell repertoire is of T cells infiltrating the islets. Our knowledge of the insulitic T cell repertoire is derived from histological and immunohistochemical analyses of insulitis, the identification of autoreactive CD8+ T cells in situ, in islets of human leukocyte antigen (HLA)-A2+ donors and isolation and identification of DQ8 and DQ2-DQ8 heterodimer-restricted, proinsulin-reactive CD4+ T cells grown from islets of a single donor with T1D. Here we present an analysis of 50 of a total of 236 CD4+ and CD8+ T cell lines grown from individual handpicked islets or clones directly sorted from handpicked, dispersed islets from nine donors with T1D. Seventeen of these T cell lines and clones reacted to a broad range of studied native islet antigens and to post-translationally modified peptides. These studies demonstrate the existence of a variety of islet-infiltrating, islet-autoantigen reactive T cells in individuals with T1D, and these data have implications for the design of successful immunotherapies.", + "TAG_DATA": [ + "148, CD4+ {'context': 'B-cells'}", + "149, and {'context': 'I-cells'}", + "150, CD8+ {'context': 'I-cells'}", + "151, T {'context': 'I-cells'}", + "152, cell {'context': 'I-cells'}", + "153, lines {'context': 'I-cells'}", + "158, islets {'context': 'I-cells'}", + "166, islets {'context': 'B-cells'}", + "175, T {'context': 'B-cells'}", + "176, cell {'context': 'I-cells'}", + "177, lines {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "148, CD4+ ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "149, and ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "150, CD8+ ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "151, T ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "152, cell ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "153, lines ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "158, islets ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "166, islets ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "175, T ['l28', 'l29']", + "176, cell ['l28', 'l30']", + "177, lines ['l29', 'l30']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27798613", + "TEXT": "Mycobacterium tuberculosis remains a leading cause of death worldwide, especially among individuals infected with HIV. Whereas phylogenetic analysis has revealed M. tuberculosis spread throughout history and in local outbreaks, much less is understood about its dissemination within the body. Here we report genomic analysis of 2,693 samples collected post mortem from lung and extrapulmonary biopsies of 44 subjects in KwaZulu-Natal, South Africa, who received minimal antitubercular treatment and most of whom were HIV seropositive. We found that purifying selection occurred within individual patients, without the need for patient-to-patient transmission. Despite negative selection, mycobacteria diversified within individuals to form sublineages that co-existed for years. These sublineages, as well as distinct strains from mixed infections, were differentially distributed throughout the lung, suggesting temporary barriers to pathogen migration. As a consequence, samples taken from the upper airway often captured only a fraction of the population diversity, challenging current methods of outbreak tracing and resistance diagnostics. Phylogenetic analysis indicated that dissemination from the lungs to extrapulmonary sites was as frequent as between lung sites, supporting the idea of similar migration routes within and between organs, at least in subjects with HIV. Genomic diversity therefore provides a record of pathogen diversification and repeated dissemination across the body.", + "TAG_DATA": [ + "60, South {'context': 'I-tissue/organ'}", + "61, Africa, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "59, KwaZulu-Natal, ['l0', 'l1']", + "60, South ['l0', 'l2']", + "61, Africa, ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27775706", + "TEXT": "Checkpoint blockade with antibodies specific for cytotoxic T lymphocyte-associated protein (CTLA)-4 or programmed cell death 1 (PDCD1; also known as PD-1) elicits durable tumor regression in metastatic cancer, but these dramatic responses are confined to a minority of patients. This suboptimal outcome is probably due in part to the complex network of immunosuppressive pathways present in advanced tumors, which are unlikely to be overcome by intervention at a single signaling checkpoint. Here we describe a combination immunotherapy that recruits a variety of innate and adaptive immune cells to eliminate large tumor burdens in syngeneic tumor models and a genetically engineered mouse model of melanoma; to our knowledge tumors of this size have not previously been curable by treatments relying on endogenous immunity. Maximal antitumor efficacy required four components: a tumor-antigen-targeting antibody, a recombinant interleukin-2 with an extended half-life, anti-PD-1 and a powerful T cell vaccine. Depletion experiments revealed that CD8+ T cells, cross-presenting dendritic cells and several other innate immune cell subsets were required for tumor regression. Effective treatment induced infiltration of immune cells and production of inflammatory cytokines in the tumor, enhanced antibody-mediated tumor antigen uptake and promoted antigen spreading. These results demonstrate the capacity of an elicited endogenous immune response to destroy large, established tumors and elucidate essential characteristics of combination immunotherapies that are capable of curing a majority of tumors in experimental settings typically viewed as intractable.", + "TAG_DATA": [ + "93, syngeneic {'context': 'B-neoplasm'}", + "94, tumor {'context': 'I-neoplasm'}", + "95, models {'context': 'I-neoplasm'}", + "98, genetically {'context': 'B-organism'}", + "99, engineered {'context': 'I-organism'}", + "100, mouse {'context': 'I-organism'}", + "101, model {'context': 'I-neoplasm'}", + "102, of {'context': 'I-neoplasm'}", + "103, melanoma; {'context': 'I-neoplasm'}", + "149, CD8+ {'context': 'B-cells'}", + "150, T {'context': 'I-cells'}", + "151, cells, {'context': 'I-cells'}", + "165, tumor {'phenotype': 'B-tumour regression'}", + "166, regression. {'phenotype': 'I-tumour regression'}", + "181, tumor, {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "93, syngeneic ['l0', 'l1', 'l2', 'l3']", + "94, tumor ['l0', 'l4']", + "95, models ['l1', 'l4']", + "98, genetically ['l5', 'l6', 'l7', 'l8', 'l9']", + "99, engineered ['l5', 'l10', 'l11', 'l12', 'l13']", + "100, mouse ['l6', 'l10', 'l14', 'l15', 'l16']", + "101, model ['l7', 'l11', 'l14', 'l17', 'l18']", + "102, of ['l2', 'l8', 'l12', 'l15', 'l17', 'l19']", + "103, melanoma; ['l3', 'l9', 'l13', 'l16', 'l18', 'l19']", + "149, CD8+ ['l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "150, T ['l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "151, cells, ['l21', 'l26', 'l31', 'l32', 'l33']", + "154, cells ['l22', 'l27', 'l31', 'l34', 'l35', 'l36']", + "165, tumor ['l23', 'l28', 'l32', 'l34', 'l37']", + "166, regression. ['l24', 'l29', 'l33', 'l35', 'l37']", + "181, tumor, ['l25', 'l30', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD8+", + "T", + "cells," + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression." + ] + } + } + ] + }, + { + "PMID": "27694933", + "TEXT": "Microsatellite instability (MSI), the spontaneous loss or gain of nucleotides from repetitive DNA tracts, is a diagnostic phenotype for gastrointestinal, endometrial, and colorectal tumors, yet the landscape of instability events across a wider variety of cancer types remains poorly understood. To explore MSI across malignancies, we examined 5,930 cancer exomes from 18 cancer types at more than 200,000 microsatellite loci and constructed a genomic classifier for MSI. We identified MSI-positive tumors in 14 of the 18 cancer types. We also identified loci that were more likely to be unstable in particular cancer types, resulting in specific instability signatures that involved cancer-associated genes, suggesting that instability patterns reflect selective pressures and can potentially identify novel cancer drivers. We also observed a correlation between survival outcomes and the overall burden of unstable microsatellites, suggesting that MSI may be a continuous, rather than discrete, phenotype that is informative across cancer types. These analyses offer insight into conserved and cancer-specific properties of MSI and reveal opportunities for improved methods of clinical MSI diagnosis and cancer gene discovery.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27694931", + "TEXT": "Infection with Zika virus has been associated with serious neurological complications and fetal abnormalities. However, the dynamics of viral infection, replication and shedding are poorly understood. Here we show that both rhesus and cynomolgus macaques are highly susceptible to infection by lineages of Zika virus that are closely related to, or are currently circulating in, the Americas. After subcutaneous viral inoculation, viral RNA was detected in blood plasma as early as 1 d after infection. Viral RNA was also detected in saliva, urine, cerebrospinal fluid (CSF) and semen, but transiently in vaginal secretions. Although viral RNA during primary infection was cleared from blood plasma and urine within 10 d, viral RNA was detectable in saliva and seminal fluids until the end of the study, 3 weeks after the resolution of viremia in the blood. The control of primary Zika virus infection in the blood was correlated with rapid innate and adaptive immune responses. We also identified Zika RNA in tissues, including the brain and male and female reproductive tissues, during early and late stages of infection. Re-infection of six animals 45 d after primary infection with a heterologous strain resulted in complete protection, which suggests that primary Zika virus infection elicits protective immunity. Early invasion of Zika virus into the nervous system of healthy animals and the extent and duration of shedding in saliva and semen underscore possible concern for additional neurologic complications and nonarthropod-mediated transmission in humans.", + "TAG_DATA": [ + "179, animals {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27668938", + "TEXT": "Clostridium difficile is the most commonly reported nosocomial pathogen in the United States and is an urgent public health concern worldwide. Over the past decade, incidence, severity and costs associated with C. difficile infection (CDI) have increased dramatically. CDI is most commonly initiated by antibiotic-mediated disruption of the gut microbiota; however, non-antibiotic-associated CDI cases are well documented and on the rise. This suggests that unexplored environmental, nutrient and host factors probably influence CDI. Here we show that excess dietary zinc (Zn) substantially alters the gut microbiota and, in turn, reduces the minimum amount of antibiotics needed to confer susceptibility to CDI. In mice colonized with C. difficile, excess dietary Zn severely exacerbated C. difficile-associated disease by increasing toxin activity and altering the host immune response. In addition, we show that the Zn-binding S100 protein calprotectin has antimicrobial effects against C. difficile and is an essential component of the innate immune response to CDI. Taken together, these data suggest that nutrient Zn levels have a key role in determining susceptibility to CDI and severity of disease, and that calprotectin-mediated metal limitation is an important factor in the host immune response to C. difficile.", + "TAG_DATA": [ + "102, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27668936", + "TEXT": "Broadly neutralizing antibodies (bnAbs) are a focal component of HIV-1 vaccine design, yet basic aspects of their induction remain poorly understood. Here we report on viral, host and disease factors that steer bnAb evolution using the results of a systematic survey in 4,484 HIV-1-infected individuals that identified 239 bnAb inducers. We show that three parameters that reflect the exposure to antigen-viral load, length of untreated infection and viral diversity-independently drive bnAb evolution. Notably, black participants showed significantly (P = 0.0086-0.038) higher rates of bnAb induction than white participants. Neutralization fingerprint analysis, which was used to delineate plasma specificity, identified strong virus subtype dependencies, with higher frequencies of CD4-binding-site bnAbs in infection with subtype B viruses (P = 0.02) and higher frequencies of V2-glycan-specific bnAbs in infection with non-subtype B viruses (P = 1 × 10-5). Thus, key host, disease and viral determinants, including subtype-specific envelope features that determine bnAb specificity, remain to be unraveled and harnessed for bnAb-based vaccine design.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27618651", + "TEXT": "We describe the development of fetal brain lesions after Zika virus (ZIKV) inoculation in a pregnant pigtail macaque. Periventricular lesions developed within 10 d and evolved asymmetrically in the occipital-parietal lobes. Fetal autopsy revealed ZIKV in the brain and significant cerebral white matter hypoplasia, periventricular white matter gliosis, and axonal and ependymal injury. Our observation of ZIKV-associated fetal brain lesions in a nonhuman primate provides a model for therapeutic evaluation.", + "TAG_DATA": [ + "15, pregnant {'context': 'B-organism'}", + "16, pigtail {'context': 'I-organism'}", + "17, macaque. {'context': 'I-organism'}", + "30, lobes. {'context': 'I-tissue/organ'}", + "37, brain {'context': 'B-tissue/organ'}", + "62, nonhuman {'context': 'B-organism'}", + "63, primate {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "15, pregnant ['l0', 'l1', 'l2', 'l3', 'l4']", + "16, pigtail ['l0', 'l5', 'l6', 'l7', 'l8']", + "17, macaque. ['l1', 'l5', 'l9', 'l10', 'l11']", + "29, occipital-parietal ['l2', 'l6', 'l9', 'l12', 'l13']", + "30, lobes. ['l3', 'l7', 'l10', 'l12', 'l14']", + "37, brain ['l4', 'l8', 'l11', 'l13', 'l14']", + "62, nonhuman ['l15']", + "63, primate ['l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27595324", + "TEXT": "The absence of a gold standard to determine when antibiotics induce a sterilizing cure has confounded the development of new approaches to treat pulmonary tuberculosis (PTB). We detected positron emission tomography and computerized tomography (PET-CT) imaging response patterns consistent with active disease, along with the presence of Mycobacterium tuberculosis (MTB) mRNA in sputum and bronchoalveolar lavage samples, in a substantial proportion of adult, HIV-negative patients with PTB after a standard 6-month treatment plus 1 year follow-up, including patients with a durable cure and others who later developed recurrent disease. The presence of MTB mRNA in the context of nonresolving and intensifying lesions on PET-CT images might indicate ongoing transcription, suggesting that even apparently curative treatment for PTB may not eradicate all of the MTB bacteria in most patients. This suggests an important complementary role for the immune response in maintaining a disease-free state. Sterilizing drugs or host-directed therapies, and better treatment response markers, are probably needed for the successful development of improved and shortened PTB-treatment strategies.", + "TAG_DATA": [ + "62, adult, {'context': 'B-patient'}", + "63, HIV-negative {'context': 'I-patient'}", + "64, patients {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "62, adult, ['l0', 'l1']", + "63, HIV-negative ['l0', 'l2']", + "64, patients ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27595322", + "TEXT": "The use of selective serotonin-reuptake inhibitors (SSRIs) has been associated with an increased risk of bone fracture, raising concerns about their increasingly broader usage. This deleterious effect is poorly understood, and thus strategies to avoid this side effect remain elusive. We show here that fluoxetine (Flx), one of the most-prescribed SSRIs, acts on bone remodeling through two distinct mechanisms. Peripherally, Flx has anti-resorptive properties, directly impairing osteoclast differentiation and function through a serotonin-reuptake-independent mechanism that is dependent on intracellular Ca2+ levels and the transcription factor Nfatc1. With time, however, Flx also triggers a brain-serotonin-dependent rise in sympathetic output that increases bone resorption sufficiently to counteract its local anti-resorptive effect, thus leading to a net effect of impaired bone formation and bone loss. Accordingly, neutralizing this second mode of action through co-treatment with the β-blocker propranolol, while leaving the peripheral effect intact, prevents Flx-induced bone loss in mice. Hence, this study identifies a dual mode of action of SSRIs on bone remodeling and suggests a therapeutic strategy to block the deleterious effect on bone homeostasis from their chronic use.", + "TAG_DATA": [ + "146, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27595321", + "TEXT": "Tuberculosis is classically divided into states of latent infection and active disease. Using combined positron emission and computed tomography in 35 asymptomatic, antiretroviral-therapy-naive, HIV-1-infected adults with latent tuberculosis, we identified ten individuals with pulmonary abnormalities suggestive of subclinical, active disease who were substantially more likely to progress to clinical disease. Our findings challenge the conventional two-state paradigm and may aid future identification of biomarkers that are predictive of progression.", + "TAG_DATA": [ + "24, adults {'context': 'I-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27571347", + "TEXT": "Orthopedic implants containing biodegradable magnesium have been used for fracture repair with considerable efficacy; however, the underlying mechanisms by which these implants improve fracture healing remain elusive. Here we show the formation of abundant new bone at peripheral cortical sites after intramedullary implantation of a pin containing ultrapure magnesium into the intact distal femur in rats. This response was accompanied by substantial increases of neuronal calcitonin gene-related polypeptide-α (CGRP) in both the peripheral cortex of the femur and the ipsilateral dorsal root ganglia (DRG). Surgical removal of the periosteum, capsaicin denervation of sensory nerves or knockdown in vivo of the CGRP-receptor-encoding genes Calcrl or Ramp1 substantially reversed the magnesium-induced osteogenesis that we observed in this model. Overexpression of these genes, however, enhanced magnesium-induced osteogenesis. We further found that an elevation of extracellular magnesium induces magnesium transporter 1 (MAGT1)-dependent and transient receptor potential cation channel, subfamily M, member 7 (TRPM7)-dependent magnesium entry, as well as an increase in intracellular adenosine triphosphate (ATP) and the accumulation of terminal synaptic vesicles in isolated rat DRG neurons. In isolated rat periosteum-derived stem cells, CGRP induces CALCRL- and RAMP1-dependent activation of cAMP-responsive element binding protein 1 (CREB1) and SP7 (also known as osterix), and thus enhances osteogenic differentiation of these stem cells. Furthermore, we have developed an innovative, magnesium-containing intramedullary nail that facilitates femur fracture repair in rats with ovariectomy-induced osteoporosis. Taken together, these findings reveal a previously undefined role of magnesium in promoting CGRP-mediated osteogenic differentiation, which suggests the therapeutic potential of this ion in orthopedics.", + "TAG_DATA": [ + "52, distal {'context': 'B-tissue/organ'}", + "53, femur {'context': 'I-tissue/organ'}", + "55, rats. {'context': 'B-organism'}", + "92, sensory {'context': 'B-cells'}", + "93, nerves {'context': 'I-cells'}", + "95, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "96, in {'context': 'B-in vivo'}", + "97, vivo {'context': 'I-in vivo'}", + "98, of {'perturbing_action': 'I-rnai/knockdown'}", + "99, the {'perturbing_action': 'I-rnai/knockdown'}", + "100, CGRP-receptor-encoding {'perturbing_action': 'I-rnai/knockdown'}", + "101, genes {'perturbing_action': 'I-rnai/knockdown'}", + "102, Calcrl {'perturbing_action': 'I-rnai/knockdown'}", + "103, or {'perturbing_action': 'I-rnai/knockdown'}", + "104, Ramp1 {'perturbing_action': 'I-rnai/knockdown'}", + "116, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "117, of {'perturbing_action': 'I-gene gain-of-function'}", + "118, these {'perturbing_action': 'I-gene gain-of-function'}", + "119, genes, {'perturbing_action': 'I-gene gain-of-function'}", + "170, rat {'context': 'B-cells'}", + "171, DRG {'context': 'I-cells'}", + "172, neurons. {'context': 'I-cells'}", + "175, rat {'context': 'B-cells'}", + "176, periosteum-derived {'context': 'I-cells'}", + "177, stem {'context': 'I-cells'}", + "178, cells, {'context': 'I-cells'}", + "200, enhances {'effect': 'B-positive'}", + "205, stem {'context': 'B-cells'}", + "206, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "52, distal ['l0', 'l1', 'l2', 'l3']", + "53, femur ['l0', 'l4']", + "55, rats. ['l1', 'l4']", + "92, sensory ['l2', 'l5', 'l6']", + "93, nerves ['l3', 'l5', 'l7']", + "95, knockdown ['l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "96, in ['l8', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "97, vivo ['l9', 'l20', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "98, of ['l10', 'l21', 'l31', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "99, the ['l11', 'l22', 'l32', 'l41', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "100, CGRP-receptor-encoding ['l12', 'l23', 'l33', 'l42', 'l51', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "101, genes ['l13', 'l24', 'l34', 'l43', 'l52', 'l60', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "102, Calcrl ['l14', 'l25', 'l35', 'l44', 'l53', 'l61', 'l68', 'l74', 'l75', 'l76', 'l77', 'l78']", + "103, or ['l15', 'l26', 'l36', 'l45', 'l54', 'l62', 'l69', 'l74', 'l79', 'l80', 'l81', 'l82']", + "104, Ramp1 ['l6', 'l7', 'l16', 'l27', 'l37', 'l46', 'l55', 'l63', 'l70', 'l75', 'l79', 'l83', 'l84', 'l85']", + "116, Overexpression ['l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "117, of ['l86', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "118, these ['l87', 'l99', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "119, genes, ['l47', 'l56', 'l64', 'l88', 'l100', 'l111', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "170, rat ['l17', 'l28', 'l38', 'l48', 'l57', 'l65', 'l71', 'l76', 'l80', 'l83', 'l89', 'l101', 'l112', 'l122', 'l132', 'l133']", + "171, DRG ['l18', 'l29', 'l39', 'l49', 'l58', 'l66', 'l72', 'l77', 'l81', 'l84', 'l90', 'l102', 'l113', 'l123', 'l132', 'l134']", + "172, neurons. ['l19', 'l30', 'l40', 'l50', 'l59', 'l67', 'l73', 'l78', 'l82', 'l85', 'l91', 'l103', 'l114', 'l124', 'l133', 'l134']", + "175, rat ['l92', 'l104', 'l115', 'l125', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "176, periosteum-derived ['l93', 'l105', 'l116', 'l126', 'l135', 'l141', 'l142', 'l143', 'l144', 'l145']", + "177, stem ['l94', 'l106', 'l117', 'l127', 'l136', 'l141', 'l146', 'l147', 'l148', 'l149']", + "178, cells, ['l95', 'l107', 'l118', 'l128', 'l137', 'l142', 'l146', 'l150', 'l151', 'l152']", + "200, enhances ['l96', 'l108', 'l119', 'l129', 'l138', 'l143', 'l147', 'l150', 'l153', 'l154']", + "205, stem ['l97', 'l109', 'l120', 'l130', 'l139', 'l144', 'l148', 'l151', 'l153', 'l155']", + "206, cells. ['l98', 'l110', 'l121', 'l131', 'l140', 'l145', 'l149', 'l152', 'l154', 'l155']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "sensory", + "nerves", + "rat", + "DRG", + "neurons." + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Ramp1", + "knockdown", + "of", + "the", + "CGRP-receptor-encoding", + "genes", + "Calcrl", + "or" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "the", + "CGRP-receptor-encoding", + "genes", + "Calcrl", + "or", + "Ramp1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "these", + "genes," + ] + }, + "context": { + "val": "cells", + "words": [ + "rat", + "DRG", + "neurons.", + "periosteum-derived", + "stem", + "cells,", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "these", + "genes," + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "rat", + "periosteum-derived", + "stem", + "cells,", + "cells." + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + } + } + ] + }, + { + "PMID": "27548575", + "TEXT": "Cerebral cavernous malformations (CCMs) are vascular malformations that affect the central nervous system and result in cerebral hemorrhage, seizure and stroke. CCMs arise from loss-of-function mutations in one of three genes: KRIT1 (also known as CCM1), CCM2 or PDCD10 (also known as CCM3). PDCD10 mutations in humans often result in a more severe form of the disease relative to mutations in the other two CCM genes, and PDCD10-knockout mice show severe defects, the mechanistic basis for which is unclear. We have recently reported that CCM3 regulates exocytosis mediated by the UNC13 family of exocytic regulatory proteins. Here, in investigating the role of endothelial cell exocytosis in CCM disease progression, we found that CCM3 suppresses UNC13B- and vesicle-associated membrane protein 3 (VAMP3)-dependent exocytosis of angiopoietin 2 (ANGPT2) in brain endothelial cells. CCM3 deficiency in endothelial cells augments the exocytosis and secretion of ANGPT2, which is associated with destabilized endothelial cell junctions, enlarged lumen formation and endothelial cell-pericyte dissociation. UNC13B deficiency, which blunts ANGPT2 secretion from endothelial cells, or treatment with an ANGPT2-neutralizing antibody normalizes the defects in the brain and retina caused by endothelial-cell-specific CCM3 deficiency, including the disruption of endothelial cell junctions, vessel dilation and pericyte dissociation. Thus, enhanced secretion of ANGPT2 in endothelial cells contributes to the progression of CCM disease, providing a new therapeutic approach for treating this devastating pathology.", + "TAG_DATA": [ + "127, brain {'context': 'B-cells'}", + "128, endothelial {'context': 'I-cells'}", + "129, cells. {'context': 'I-cells'}", + "130, CCM3 {'perturbing_action': 'B-gene loss-of-function'}", + "131, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "133, endothelial {'context': 'B-cells'}", + "134, cells {'context': 'I-cells'}", + "157, UNC13B {'perturbing_action': 'B-gene loss-of-function'}", + "158, deficiency, {'perturbing_action': 'I-gene loss-of-function'}", + "164, endothelial {'context': 'B-cells'}", + "165, cells, {'context': 'I-cells'}", + "177, brain {'context': 'B-tissue/organ'}", + "179, retina {'context': 'B-tissue/organ'}", + "182, endothelial-cell-specific {'perturbing_action': 'B-gene loss-of-function'}", + "183, CCM3 {'perturbing_action': 'I-gene loss-of-function'}", + "184, deficiency, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "127, brain ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "128, endothelial ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "129, cells. ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "130, CCM3 ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "131, deficiency ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "133, endothelial ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "134, cells ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "157, UNC13B ['l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "158, deficiency, ['l21', 'l27', 'l28', 'l29', 'l30']", + "164, endothelial ['l22', 'l27', 'l31', 'l32', 'l33']", + "165, cells, ['l23', 'l28', 'l31']", + "177, brain ['l24', 'l29', 'l32', 'l34', 'l35', 'l36', 'l37']", + "179, retina ['l25', 'l30', 'l33', 'l34', 'l38', 'l39', 'l40']", + "182, endothelial-cell-specific ['l35', 'l38', 'l41', 'l42']", + "183, CCM3 ['l36', 'l39', 'l41', 'l43']", + "184, deficiency, ['l26', 'l37', 'l40', 'l42', 'l43']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "brain", + "endothelial", + "cells.", + "cells", + "cells," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CCM3", + "deficiency", + "UNC13B", + "deficiency," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "UNC13B", + "deficiency,", + "endothelial-cell-specific", + "CCM3" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain", + "retina" + ] + } + } + ] + }, + { + "PMID": "27525523", + "TEXT": "The binding of autoantibodies (autoAbs) to interferon (IFN)-γ in people with mycobacterial diseases has become an emerging medical concern. Many patients display specific human leukocyte antigen (HLA) class II haplotypes, which suggests that a common T cell-dependent and B cell-dependent mechanism might underlie the production of specific anti-IFN-γ autoAbs. We show here that these autoAbs target a major epitope (amino acids 121-131, designated position (P)121-131) in a region crucial for IFN-γ receptor (IFN-γR) activation to impair IFN-γ-mediated activities. The amino acid sequence of this epitope is highly homologous to a stretch in the Noc2 protein of Aspergillus spp., which was cross-reactive with autoAbs from patients. Rats immunized with Aspergillus Noc2 developed antibodies that reacted with human IFN-γ. We generated an epitope-erased variant of IFN-γ (EE-IFN-γ), in which the major neutralizing epitope region was altered. The binding affinity of anti-IFN-γ autoAbs for EE-IFN-γ was reduced by about 40%, as compared to that for IFN-γ1-131. Moreover, EE-IFN-γ activated the IFN-γR downstream signaling pathway ex vivo, irrespectively of anti-IFN-γ autoAbs. In conclusion, we identified a common, crucial B cell epitope that bound to anti-IFN-γ autoAbs in patients, and we propose a molecular-mimicry model for autoAb development. In addition, treatment with EE-IFN-γ might be worth investigating in patients producing anti-IFN-γ autoAbs.", + "TAG_DATA": [ + "105, Rats {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27455511", + "TEXT": "Direct inhibitors of coagulation factor Xa (FXa) or thrombin are promising oral anticoagulants that are becoming widely adopted. The ability to reverse their anticoagulant effects is important when serious bleeding occurs or urgent medical procedures are needed. Here, using experimental mouse models of hemostasis, we show that a variant coagulation factor, FXa(I16L), rapidly restores hemostasis in the presence of the anticoagulant effects of these inhibitors. The ability of FXa(I16L) to reverse the anticoagulant effects of FXa inhibitor depends, at least in part, on the ability of the active site inhibitor to hinder antithrombin-dependent FXa inactivation, paradoxically allowing uninhibited FXa to persist in plasma. Because of its inherent catalytic activity, FXa(I16L) is more potent (by >50-fold) in the hemostasis models tested than a noncatalytic antidote that is currently in clinical development. FXa(I16L) also reduces the anticoagulant-associated bleeding in vivo that is induced by the thrombin inhibitor dabigatran. FXa(I16L) may be able to fill an important unmet clinical need for a rapid, pro-hemostatic agent to reverse the effects of several new anticoagulants.", + "TAG_DATA": [ + "136, in {'context': 'B-in vivo'}", + "137, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "136, in ['l0']", + "137, vivo ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27376579", + "TEXT": "Age-related changes in the niche have long been postulated to impair the function of somatic stem cells. Here we demonstrate that the aged stem cell niche in skeletal muscle contains substantially reduced levels of fibronectin (FN), leading to detrimental consequences for the function and maintenance of muscle stem cells (MuSCs). Deletion of the gene encoding FN from young regenerating muscles replicates the aging phenotype and leads to a loss of MuSC numbers. By using an extracellular matrix (ECM) library screen and pathway profiling, we characterize FN as a preferred adhesion substrate for MuSCs and demonstrate that integrin-mediated signaling through focal adhesion kinase and the p38 mitogen-activated protein kinase pathway is strongly de-regulated in MuSCs from aged mice because of insufficient attachment to the niche. Reconstitution of FN levels in the aged niche remobilizes stem cells and restores youth-like muscle regeneration. Taken together, we identify the loss of stem cell adhesion to FN in the niche ECM as a previously unknown aging mechanism.", + "TAG_DATA": [ + "50, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "51, of {'perturbing_action': 'I-gene loss-of-function'}", + "52, the {'perturbing_action': 'I-gene loss-of-function'}", + "53, gene {'perturbing_action': 'I-gene loss-of-function'}", + "54, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "55, FN {'perturbing_action': 'I-gene loss-of-function'}", + "57, young {'context': 'B-cells'}", + "58, regenerating {'context': 'I-cells'}", + "59, muscles {'context': 'I-cells'}", + "70, MuSC {'context': 'B-cells'}", + "115, aged {'context': 'B-organism'}", + "116, mice {'context': 'I-organism'}", + "130, aged {'context': 'B-tissue/organ'}", + "131, niche {'context': 'I-tissue/organ'}", + "133, stem {'context': 'B-cells'}", + "134, cells {'context': 'I-cells'}", + "138, muscle {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "50, Deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "51, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "52, the ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "53, gene ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "54, encoding ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "55, FN ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "57, young ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53']", + "58, regenerating ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l54', 'l55']", + "59, muscles ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l54', 'l56']", + "70, MuSC ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l55', 'l56']", + "115, aged ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l57']", + "116, mice ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l57']", + "130, aged ['l58', 'l59', 'l60', 'l61']", + "131, niche ['l58', 'l62', 'l63', 'l64']", + "133, stem ['l59', 'l62', 'l65', 'l66']", + "134, cells ['l60', 'l63', 'l65', 'l67']", + "138, muscle ['l61', 'l64', 'l66', 'l67']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "gene", + "encoding", + "FN" + ] + }, + "context": { + "val": "cells", + "words": [ + "young", + "regenerating", + "muscles", + "MuSC" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "gene", + "encoding", + "FN" + ] + }, + "context": { + "val": "organism", + "words": [ + "aged", + "mice" + ] + } + } + ] + }, + { + "PMID": "27376577", + "TEXT": "Positive expectations contribute to the clinical benefits of the placebo effect. Such positive expectations are mediated by the brain's reward system; however, it remains unknown whether and how reward system activation affects the body's physiology and, specifically, immunity. Here we show that activation of the ventral tegmental area (VTA), a key component of the reward system, strengthens immunological host defense. We used 'designer receptors exclusively activated by designer drugs' (DREADDs) to directly activate dopaminergic neurons in the mouse VTA and characterized the subsequent immune response after exposure to bacteria (Escherichia coli), using time-of-flight mass cytometry (CyTOF) and functional assays. We found an increase in innate and adaptive immune responses that were manifested by enhanced antibacterial activity of monocytes and macrophages, reduced in vivo bacterial load and a heightened T cell response in the mouse model of delayed-type hypersensitivity. By chemically ablating the sympathetic nervous system (SNS), we showed that the reward system's effects on immunity are, at least partly, mediated by the SNS. Thus, our findings establish a causal relationship between the activity of the VTA and the immune response to bacterial infection.", + "TAG_DATA": [ + "73, dopaminergic {'context': 'B-cells'}", + "74, neurons {'context': 'I-cells'}", + "75, in {'context': 'I-cells'}", + "76, the {'context': 'I-cells'}", + "77, mouse {'context': 'B-tissue/organ'}", + "78, VTA {'context': 'I-tissue/organ'}", + "117, monocytes {'context': 'B-cells'}", + "119, macrophages, {'context': 'B-cells'}", + "121, in {'context': 'B-in vivo'}", + "122, vivo {'context': 'I-in vivo'}", + "128, T {'context': 'B-cells'}", + "129, cell {'context': 'B-cells'}", + "133, mouse {'context': 'B-organism'}", + "134, model {'context': 'I-organism'}", + "139, chemically {'perturbing_action': 'B-gene loss-of-function'}", + "140, ablating {'perturbing_action': 'I-gene loss-of-function'}", + "141, the {'perturbing_action': 'I-gene loss-of-function'}", + "142, sympathetic {'perturbing_action': 'I-gene loss-of-function'}", + "143, nervous {'perturbing_action': 'I-gene loss-of-function'}", + "144, system {'perturbing_action': 'I-gene loss-of-function'}", + "145, (SNS), {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "73, dopaminergic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "74, neurons ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "75, in ['l1', 'l7', 'l13', 'l14', 'l15', 'l16']", + "76, the ['l2', 'l8', 'l13', 'l17', 'l18']", + "77, mouse ['l3', 'l9', 'l14', 'l17', 'l19']", + "78, VTA ['l4', 'l10', 'l15', 'l18', 'l19']", + "117, monocytes ['l5', 'l11', 'l16', 'l20', 'l21', 'l22']", + "119, macrophages, ['l6', 'l12', 'l20', 'l23', 'l24']", + "121, in ['l21', 'l23', 'l25', 'l26']", + "122, vivo ['l22', 'l24', 'l25']", + "128, T ['l27', 'l28', 'l29']", + "129, cell ['l26', 'l27', 'l30', 'l31']", + "133, mouse ['l28', 'l30', 'l32']", + "134, model ['l29', 'l31', 'l32']", + "139, chemically ['l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "140, ablating ['l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "141, the ['l34', 'l39', 'l44', 'l45', 'l46', 'l47']", + "142, sympathetic ['l35', 'l40', 'l44', 'l48', 'l49', 'l50']", + "143, nervous ['l36', 'l41', 'l45', 'l48', 'l51', 'l52']", + "144, system ['l37', 'l42', 'l46', 'l49', 'l51', 'l53']", + "145, (SNS), ['l38', 'l43', 'l47', 'l50', 'l52', 'l53']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27322744", + "TEXT": "Genetic heterogeneity contributes to clinical outcome and progression of most tumors, but little is known about allelic diversity for epigenetic compartments, and almost no data exist for acute myeloid leukemia (AML). We examined epigenetic heterogeneity as assessed by cytosine methylation within defined genomic loci with four CpGs (epialleles), somatic mutations, and transcriptomes of AML patient samples at serial time points. We observed that epigenetic allele burden is linked to inferior outcome and varies considerably during disease progression. Epigenetic and genetic allelic burden and patterning followed different patterns and kinetics during disease progression. We observed a subset of AMLs with high epiallele and low somatic mutation burden at diagnosis, a subset with high somatic mutation and lower epiallele burdens at diagnosis, and a subset with a mixed profile, suggesting distinct modes of tumor heterogeneity. Genes linked to promoter-associated epiallele shifts during tumor progression showed increased single-cell transcriptional variance and differential expression, suggesting functional impact on gene regulation. Thus, genetic and epigenetic heterogeneity can occur with distinct kinetics likely to affect the biological and clinical features of tumors.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27294874", + "TEXT": "Despite the high response rates of individuals with myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)) to treatment with lenalidomide (LEN) and the recent identification of cereblon (CRBN) as the molecular target of LEN, the cellular mechanism by which LEN eliminates MDS clones remains elusive. Here we performed an RNA interference screen to delineate gene regulatory networks that mediate LEN responsiveness in an MDS cell line, MDSL. We identified GPR68, which encodes a G-protein-coupled receptor that has been implicated in calcium metabolism, as the top candidate gene for modulating sensitivity to LEN. LEN induced GPR68 expression via IKAROS family zinc finger 1 (IKZF1), resulting in increased cytosolic calcium levels and activation of a calcium-dependent calpain, CAPN1, which were requisite steps for induction of apoptosis in MDS cells and in acute myeloid leukemia (AML) cells. In contrast, deletion of GPR68 or inhibition of calcium and calpain activation suppressed LEN-induced cytotoxicity. Moreover, expression of calpastatin (CAST), an endogenous CAPN1 inhibitor that is encoded by a gene (CAST) deleted in del(5q) MDS, correlated with LEN responsiveness in patients with del(5q) MDS. Depletion of CAST restored responsiveness of LEN-resistant non-del(5q) MDS cells and AML cells, providing an explanation for the superior responses of patients with del(5q) MDS to LEN treatment. Our study describes a cellular mechanism by which LEN, acting through CRBN and IKZF1, has cytotoxic effects in MDS and AML that depend on a calcium- and calpain-dependent pathway.", + "TAG_DATA": [ + "122, induction {'effect': 'B-positive'}", + "124, apoptosis {'phenotype': 'B-apoptosis'}", + "126, MDS {'context': 'B-transformed cells'}", + "127, cells {'context': 'I-transformed cells'}", + "130, acute {'context': 'B-transformed cells'}", + "131, myeloid {'context': 'I-transformed cells'}", + "132, leukemia {'context': 'I-transformed cells'}", + "133, (AML) {'context': 'I-transformed cells'}", + "134, cells. {'context': 'I-transformed cells'}", + "137, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "138, of {'perturbing_action': 'I-gene loss-of-function'}", + "139, GPR68 {'perturbing_action': 'I-gene loss-of-function'}", + "179, Depletion {'perturbing_action': 'B-gene loss-of-function'}", + "180, of {'perturbing_action': 'I-gene loss-of-function'}", + "181, CAST {'perturbing_action': 'I-gene loss-of-function'}", + "185, LEN-resistant {'context': 'B-transformed cells'}", + "186, non-del(5q) {'context': 'I-transformed cells'}", + "187, MDS {'context': 'I-transformed cells'}", + "188, cells {'context': 'I-transformed cells'}", + "190, AML {'context': 'B-transformed cells'}", + "191, cells, {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "122, induction ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "124, apoptosis ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "126, MDS ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "127, cells ['l2', 'l9', 'l15', 'l21', 'l22']", + "130, acute ['l3', 'l10', 'l16', 'l23', 'l24', 'l25', 'l26']", + "131, myeloid ['l4', 'l11', 'l17', 'l23', 'l27', 'l28', 'l29', 'l30', 'l31']", + "132, leukemia ['l5', 'l12', 'l18', 'l24', 'l27', 'l32', 'l33', 'l34']", + "133, (AML) ['l6', 'l13', 'l19', 'l21', 'l25', 'l28', 'l32', 'l35']", + "134, cells. ['l7', 'l14', 'l20', 'l22', 'l26', 'l29', 'l33', 'l35']", + "137, deletion ['l36', 'l37']", + "138, of ['l30', 'l34', 'l36', 'l38']", + "139, GPR68 ['l31', 'l37', 'l38']", + "179, Depletion ['l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "180, of ['l39', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "181, CAST ['l40', 'l47', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "185, LEN-resistant ['l41', 'l48', 'l54', 'l60', 'l61', 'l62', 'l63', 'l64']", + "186, non-del(5q) ['l42', 'l49', 'l55', 'l60', 'l65', 'l66', 'l67', 'l68']", + "187, MDS ['l43', 'l50', 'l56', 'l61', 'l65', 'l69', 'l70', 'l71']", + "188, cells ['l44', 'l51', 'l57', 'l62', 'l66', 'l69', 'l72', 'l73']", + "190, AML ['l45', 'l52', 'l58', 'l63', 'l67', 'l70', 'l72', 'l74']", + "191, cells, ['l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l73', 'l74']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MDS", + "cells", + "acute", + "myeloid", + "leukemia", + "(AML)", + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MDS", + "cells", + "acute", + "myeloid", + "leukemia", + "(AML)", + "cells." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "myeloid", + "leukemia", + "LEN-resistant", + "non-del(5q)", + "MDS", + "cells", + "AML", + "cells," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "GPR68", + "Depletion", + "CAST" + ] + } + } + ] + }, + { + "PMID": "27270588", + "TEXT": "Brain metastases represent the greatest clinical challenge in treating HER2-positive breast cancer. We report the development of orthotopic patient-derived xenografts (PDXs) of HER2-expressing breast cancer brain metastases (BCBM), and their use for the identification of targeted combination therapies. Combined inhibition of PI3K and mTOR resulted in durable tumor regressions in three of five PDXs, and therapeutic response was correlated with a reduction in the phosphorylation of 4EBP1, an mTORC1 effector. The two nonresponding PDXs showed hypermutated genomes with enrichment of mutations in DNA-repair genes, which suggests an association of genomic instability with therapeutic resistance. These findings suggest that a biomarker-driven clinical trial of PI3K inhibitor in combination with an mTOR inhibitor should be conducted for patients with HER2-positive BCBM.", + "TAG_DATA": [ + "38, Combined {'perturbing_action': 'B-pharmacological inhibition'}", + "39, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "40, of {'perturbing_action': 'I-pharmacological inhibition'}", + "41, PI3K {'perturbing_action': 'I-pharmacological inhibition'}", + "42, and {'perturbing_action': 'I-pharmacological inhibition'}", + "43, mTOR {'perturbing_action': 'I-pharmacological inhibition'}", + "44, resulted {'effect': 'B-positive'}", + "45, in {'effect': 'I-positive'}", + "47, tumor {'phenotype': 'B-tumour regression'}", + "48, regressions {'phenotype': 'I-tumour regression'}" + ], + "LINK_DATA": [ + "38, Combined ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "39, inhibition ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "40, of ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "41, PI3K ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "42, and ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "43, mTOR ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "44, resulted ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "45, in ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "46, durable ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "47, tumor ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "48, regressions ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Combined", + "inhibition", + "of", + "PI3K", + "and", + "mTOR" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Combined", + "inhibition", + "of", + "PI3K", + "and", + "mTOR" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regressions" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regressions" + ] + } + } + ] + }, + { + "PMID": "27270587", + "TEXT": "The discovery of genetic mechanisms for resistance to obesity and diabetes may illuminate new therapeutic strategies for the treatment of this global health challenge. We used the polygenic 'lean' mouse model, which has been selected for low adiposity over 60 generations, to identify mitochondrial thiosulfate sulfurtransferase (Tst; also known as rhodanese) as a candidate obesity-resistance gene with selectively increased expression in adipocytes. Elevated adipose Tst expression correlated with indices of metabolic health across diverse mouse strains. Transgenic overexpression of Tst in adipocytes protected mice from diet-induced obesity and insulin-resistant diabetes. Tst-deficient mice showed markedly exacerbated diabetes, whereas pharmacological activation of TST ameliorated diabetes in mice. Mechanistically, TST selectively augmented mitochondrial function combined with degradation of reactive oxygen species and sulfide. In humans, TST mRNA expression in adipose tissue correlated positively with insulin sensitivity in adipose tissue and negatively with fat mass. Thus, the genetic identification of Tst as a beneficial regulator of adipocyte mitochondrial function may have therapeutic significance for individuals with type 2 diabetes.", + "TAG_DATA": [ + "76, Transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "77, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "78, of {'perturbing_action': 'I-gene gain-of-function'}", + "79, Tst {'perturbing_action': 'I-gene gain-of-function'}", + "81, adipocytes {'context': 'B-cells'}", + "83, mice {'context': 'B-organism'}", + "90, Tst-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "91, mice {'context': 'B-organism'}", + "97, pharmacological {'perturbing_action': 'B-pharmacological augmentation'}", + "98, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "99, of {'perturbing_action': 'I-pharmacological augmentation'}", + "100, TST {'perturbing_action': 'I-pharmacological augmentation'}", + "104, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "76, Transgenic ['l0', 'l1', 'l2', 'l3', 'l4']", + "77, overexpression ['l0', 'l5', 'l6', 'l7', 'l8']", + "78, of ['l1', 'l5', 'l9', 'l10', 'l11']", + "79, Tst ['l2', 'l6', 'l9', 'l12', 'l13']", + "81, adipocytes ['l3', 'l7', 'l10', 'l12', 'l14']", + "83, mice ['l4', 'l8', 'l11', 'l13', 'l14']", + "90, Tst-deficient ['l15']", + "91, mice ['l15']", + "97, pharmacological ['l16', 'l17', 'l18', 'l19']", + "98, activation ['l16', 'l20', 'l21', 'l22']", + "99, of ['l17', 'l20', 'l23', 'l24']", + "100, TST ['l18', 'l21', 'l23', 'l25']", + "104, mice. ['l19', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgenic", + "overexpression", + "of", + "Tst" + ] + }, + "context": { + "val": "cells", + "words": [ + "adipocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgenic", + "overexpression", + "of", + "Tst" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tst-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "pharmacological", + "activation", + "of", + "TST" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "27239760", + "TEXT": "The mechanisms responsible for the persistence of HIV-1 after many years of suppressive antiretroviral therapy (ART) have been only partially elucidated. Most of the studies investigating HIV-1 persistence have been performed with blood, although it is well known that germinal centers (GCs) within lymph nodes (LNs) serve as primary sites for HIV-1 replication. We sought to identify the memory CD4 T cell populations in blood and LNs that are responsible for the production of replication-competent and infectious HIV-1, as well as for active and persistent virus transcription in ART-treated (for 1.5-14.0 years), aviremic (<50 HIV RNA copies/ml) HIV-infected individuals. We demonstrate that LN CD4 T cells that express programmed cell death 1 (PDCD1; also known as PD-1), which are composed of about 65% T follicular helper cells as defined by the expression of the cell surface receptors CXCR5 and PD-1, are the major source of replication-competent HIV-1 and of infectious virus, as compared to any other (CXCR5(-)PD-1(-) and CXCR5(+)PD-1(-)) blood or LN memory CD4 T cell populations. LN PD-1(+) cells accounted for 46% and 96% of the total pools of memory CD4 T cells containing inducible replication-competent or infectious virus, respectively. Notably, higher levels of cell-associated HIV-1 RNA were present in LN PD-1(+) cells after long-term (up to 12 years) ART than in other memory CD4 T cell subpopulations. These results indicate that LN PD-1(+) cells are the major CD4 T cell compartment in the blood and LNs for the production of replication-competent and infectious HIV-1, and for active and persistent virus transcription in long-term-ART-treated aviremic individuals. Thus, these cells may represent a major obstacle to finding a functional cure for HIV-1 infection.", + "TAG_DATA": [ + "167, LN {'context': 'B-cells'}", + "168, PD-1(+) {'context': 'I-cells'}", + "169, cells {'context': 'I-cells'}", + "180, memory {'context': 'B-cells'}", + "181, CD4 {'context': 'I-cells'}", + "182, T {'context': 'I-cells'}", + "183, cells {'context': 'I-cells'}", + "201, LN {'context': 'B-cells'}", + "202, PD-1(+) {'context': 'I-cells'}", + "203, cells {'context': 'I-cells'}", + "214, memory {'context': 'B-cells'}", + "215, CD4 {'context': 'I-cells'}", + "216, T {'context': 'I-cells'}", + "217, cell {'context': 'I-cells'}", + "218, subpopulations. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "167, LN ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "168, PD-1(+) ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "169, cells ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "180, memory ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "181, CD4 ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "182, T ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "183, cells ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "201, LN ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "202, PD-1(+) ['l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "203, cells ['l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "214, memory ['l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "215, CD4 ['l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "216, T ['l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "217, cell ['l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "218, subpopulations. ['l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27183217", + "TEXT": "Human leukocyte antigen class I (HLA)-restricted CD8(+) T lymphocyte (CTL) responses are crucial to HIV-1 control. Although HIV can evade these responses, the longer-term impact of viral escape mutants remains unclear, as these variants can also reduce intrinsic viral fitness. To address this, we here developed a metric to determine the degree of HIV adaptation to an HLA profile. We demonstrate that transmission of viruses that are pre-adapted to the HLA molecules expressed in the recipient is associated with impaired immunogenicity, elevated viral load and accelerated CD4(+) T cell decline. Furthermore, the extent of pre-adaptation among circulating viruses explains much of the variation in outcomes attributed to the expression of certain HLA alleles. Thus, viral pre-adaptation exploits 'holes' in the immune response. Accounting for these holes may be key for vaccine strategies seeking to elicit functional responses from viral variants, and to HIV cure strategies that require broad CTL responses to achieve successful eradication of HIV reservoirs.", + "TAG_DATA": [ + "86, CD4(+) {'context': 'B-cells'}", + "87, T {'context': 'I-cells'}", + "88, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "86, CD4(+) ['l0', 'l1']", + "87, T ['l0', 'l2']", + "88, cell ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27158906", + "TEXT": "Astrocytes have important roles in the central nervous system (CNS) during health and disease. Through genome-wide analyses we detected a transcriptional response to type I interferons (IFN-Is) in astrocytes during experimental CNS autoimmunity and also in CNS lesions from patients with multiple sclerosis (MS). IFN-I signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis (EAE) disease scores via the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) and the suppressor of cytokine signaling 2 (SOCS2). The anti-inflammatory effects of nasally administered interferon (IFN)-β are partly mediated by AHR. Dietary tryptophan is metabolized by the gut microbiota into AHR agonists that have an effect on astrocytes to limit CNS inflammation. EAE scores were increased following ampicillin treatment during the recovery phase, and CNS inflammation was reduced in antibiotic-treated mice by supplementation with the tryptophan metabolites indole, indoxyl-3-sulfate, indole-3-propionic acid and indole-3-aldehyde, or the bacterial enzyme tryptophanase. In individuals with MS, the circulating levels of AHR agonists were decreased. These findings suggest that IFN-Is produced in the CNS function in combination with metabolites derived from dietary tryptophan by the gut flora to activate AHR signaling in astrocytes and suppress CNS inflammation.", + "TAG_DATA": [ + "126, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27158905", + "TEXT": "Genome-wide association studies (GWASs) have reported many single nucleotide polymorphisms (SNPs) associated with psychiatric disorders, but knowledge is lacking regarding molecular mechanisms. Here we show that risk alleles spanning multiple genes across the 10q24.32 schizophrenia-related locus are associated in the human brain selectively with an increase in the expression of both BLOC-1 related complex subunit 7 (BORCS7) and a previously uncharacterized, human-specific arsenite methyltransferase (AS3MT) isoform (AS3MT(d2d3)), which lacks arsenite methyltransferase activity and is more abundant in individuals with schizophrenia than in controls. Conditional-expression analysis suggests that BORCS7 and AS3MT(d2d3) signals are largely independent. GWAS risk SNPs across this region are linked with a variable number tandem repeat (VNTR) polymorphism in the first exon of AS3MT that is associated with the expression of AS3MT(d2d3) in samples from both Caucasians and African Americans. The VNTR genotype predicts promoter activity in luciferase assays, as well as DNA methylation within the AS3MT gene. Both AS3MT(d2d3) and BORCS7 are expressed in adult human neurons and astrocytes, and they are upregulated during human stem cell differentiation toward neuronal fates. Our results provide a molecular explanation for the prominent 10q24.32 locus association, including a novel and evolutionarily recent protein that is involved in early brain development and confers risk for psychiatric illness.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27111282", + "TEXT": "Extensive cross-linking introduced during routine tissue fixation of clinical pathology specimens severely hampers chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) analysis from archived tissue samples. This limits the ability to study the epigenomes of valuable, clinically annotated tissue resources. Here we describe fixed-tissue chromatin immunoprecipitation sequencing (FiT-seq), a method that enables reliable extraction of soluble chromatin from formalin-fixed paraffin-embedded (FFPE) tissue samples for accurate detection of histone marks. We demonstrate that FiT-seq data from FFPE specimens are concordant with ChIP-seq data from fresh-frozen samples of the same tumors. By using multiple histone marks, we generate chromatin-state maps and identify cis-regulatory elements in clinical samples from various tumor types that can readily allow us to distinguish between cancers by the tissue of origin. Tumor-specific enhancers and superenhancers that are elucidated by FiT-seq analysis correlate with known oncogenic drivers in different tissues and can assist in the understanding of how chromatin states affect gene regulation.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27089513", + "TEXT": "Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality, yet antistromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor-β (TGF-β) signaling have high epithelial STAT3 activity and develop stiff, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several KRAS-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby STAT3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial STAT3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated STAT3 were associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors and highlight STAT3 and mechanics as key drivers of this phenotype.", + "TAG_DATA": [ + "52, mouse {'context': 'B-organism'}", + "53, models, {'context': 'I-organism'}", + "84, epithelial {'perturbing_action': 'B-gene loss-of-function'}", + "85, STAT3 {'perturbing_action': 'I-gene loss-of-function'}", + "86, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "87, attenuated {'effect': 'B-negative'}", + "88, tumor {'phenotype': 'B-tumour progression'}", + "89, progression {'phenotype': 'I-tumour progression'}" + ], + "LINK_DATA": [ + "52, mouse ['l0']", + "53, models, ['l0']", + "84, epithelial ['l1', 'l2', 'l3', 'l4', 'l5']", + "85, STAT3 ['l1', 'l6', 'l7', 'l8', 'l9']", + "86, ablation ['l2', 'l6', 'l10', 'l11', 'l12']", + "87, attenuated ['l3', 'l7', 'l10', 'l13', 'l14']", + "88, tumor ['l4', 'l8', 'l11', 'l13', 'l15']", + "89, progression ['l5', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "epithelial", + "STAT3", + "ablation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "epithelial", + "STAT3", + "ablation" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + } + ] + }, + { + "PMID": "27064449", + "TEXT": "Tumor necrosis factor (TNF) superfamily member 11 (TNFSF11, also known as RANKL) regulates multiple physiological or pathological functions, including osteoclast differentiation and osteoporosis. TNFRSF11A (also called RANK) is considered to be the sole receptor for RANKL. Herein we report that leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) is another receptor for RANKL. LGR4 competes with RANK to bind RANKL and suppresses canonical RANK signaling during osteoclast differentiation. RANKL binding to LGR4 activates the Gαq and GSK3-β signaling pathway, an action that suppresses the expression and activity of nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 (NFATC1) during osteoclastogenesis. Both whole-body (Lgr4(-/-)) and monocyte conditional knockout mice of Lgr4 (Lgr4 CKO) exhibit osteoclast hyperactivation (including elevation of osteoclast number, surface area, and size) and increased bone erosion. The soluble LGR4 extracellular domain (ECD) binds RANKL and inhibits osteoclast differentiation in vivo. Moreover, LGR4-ECD therapeutically abrogated RANKL-induced bone loss in three mouse models of osteoporosis. Therefore, LGR4 acts as a second RANKL receptor that negatively regulates osteoclast differentiation and bone resorption.", + "TAG_DATA": [ + "103, (Lgr4(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "105, monocyte {'perturbing_action': 'B-gene loss-of-function'}", + "106, conditional {'perturbing_action': 'I-gene loss-of-function'}", + "107, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "108, mice {'context': 'B-organism'}", + "109, of {'perturbing_action': 'I-gene loss-of-function'}", + "110, Lgr4 {'perturbing_action': 'I-gene loss-of-function'}", + "111, (Lgr4 {'perturbing_action': 'I-gene loss-of-function'}", + "112, CKO) {'perturbing_action': 'I-gene loss-of-function'}", + "138, inhibits {'effect': 'B-negative'}", + "140, differentiation {'phenotype': 'B-differentiation'}", + "141, in {'context': 'B-in vivo'}", + "142, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "103, (Lgr4(-/-)) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "105, monocyte ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "106, conditional ['l1', 'l8', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "107, knockout ['l2', 'l9', 'l16', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "108, mice ['l3', 'l10', 'l17', 'l23', 'l29', 'l30', 'l31', 'l32']", + "109, of ['l4', 'l11', 'l18', 'l24', 'l29', 'l33', 'l34', 'l35', 'l36']", + "110, Lgr4 ['l5', 'l12', 'l19', 'l25', 'l30', 'l33', 'l37', 'l38', 'l39', 'l40']", + "111, (Lgr4 ['l6', 'l13', 'l20', 'l26', 'l31', 'l34', 'l37', 'l41', 'l42']", + "112, CKO) ['l7', 'l14', 'l21', 'l27', 'l32', 'l35', 'l38', 'l41']", + "138, inhibits ['l43', 'l44', 'l45']", + "140, differentiation ['l15', 'l22', 'l28', 'l36', 'l39', 'l42', 'l43', 'l46', 'l47']", + "141, in ['l44', 'l46', 'l48']", + "142, vivo. ['l40', 'l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "(Lgr4(-/-))", + "monocyte", + "conditional", + "knockout", + "of", + "Lgr4", + "(Lgr4", + "CKO)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "monocyte", + "conditional", + "knockout", + "of", + "Lgr4", + "(Lgr4" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lgr4" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "27064447", + "TEXT": "Small RNAs can be engineered to target and eliminate expression of disease-causing genes or infectious viruses, resulting in the preclinical and clinical development of RNA interference (RNAi) therapeutics using these small RNAs. To ensure the success of RNAi therapeutics, small hairpin RNAs (shRNAs) must co-opt sufficient quantities of the endogenous microRNA machinery to elicit efficient gene knockdown without impeding normal cellular function. We previously observed liver toxicity-including hepatocyte turnover, loss of gene repression and lethality-in mice receiving high doses of a recombinant adeno-associated virus (rAAV) vector expressing shRNAs (rAAV-shRNAs); however the mechanism by which toxicity ensues has not been elucidated. Using rAAV-shRNAs we have now determined that hepatotoxicity arises when exogenous shRNAs exceed 12% of the total amount of liver microRNAs. After this threshold was surpassed, shRNAs specifically reduced the initially synthesized 22-nucleotide isoform of microRNA (miR)-122-5p without substantially affecting other microRNAs, resulting in functional de-repression of miR-122 target mRNAs. Delivery of a rAAV-shRNA vector expressing mature miR-122-5p could circumvent toxicity, despite the exogenous shRNA accounting for 70% of microRNAs. Toxicity was also not observed in Mir122-knockout mice regardless of the level or sequence of the shRNA. Our study establishes limits to the microRNA machinery that is available for therapeutic siRNAs and suggests new paradigms for the role of miR-122 in liver homeostasis in mice.", + "TAG_DATA": [ + "75, mice {'context': 'B-organism'}", + "176, Mir122-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "177, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "176, Mir122-knockout ['l0']", + "177, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mir122-knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "27019328", + "TEXT": "The corticospinal tract (CST) is the most important motor system in humans, yet robust regeneration of this projection after spinal cord injury (SCI) has not been accomplished. In murine models of SCI, we report robust corticospinal axon regeneration, functional synapse formation and improved skilled forelimb function after grafting multipotent neural progenitor cells into sites of SCI. Corticospinal regeneration requires grafts to be driven toward caudalized (spinal cord), rather than rostralized, fates. Fully mature caudalized neural grafts also support corticospinal regeneration. Moreover, corticospinal axons can emerge from neural grafts and regenerate beyond the lesion, a process that is potentially related to the attenuation of the glial scar. Rat corticospinal axons also regenerate into human donor grafts of caudal spinal cord identity. Collectively, these findings indicate that spinal cord 'replacement' with homologous neural stem cells enables robust regeneration of the corticospinal projection within and beyond spinal cord lesion sites, achieving a major unmet goal of SCI research and offering new possibilities for clinical translation.", + "TAG_DATA": [ + "28, murine {'context': 'B-organism'}", + "29, models {'context': 'I-organism'}", + "43, skilled {'context': 'B-tissue/organ'}", + "44, forelimb {'context': 'I-tissue/organ'}", + "48, multipotent {'context': 'B-cells'}", + "49, neural {'context': 'I-cells'}", + "50, progenitor {'context': 'I-cells'}", + "51, cells {'context': 'I-cells'}", + "106, Rat {'context': 'B-cells'}", + "107, corticospinal {'context': 'I-cells'}", + "108, axons {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "28, murine ['l0']", + "29, models ['l0']", + "43, skilled ['l1', 'l2']", + "44, forelimb ['l1', 'l3', 'l4', 'l5', 'l6']", + "48, multipotent ['l3', 'l7', 'l8', 'l9']", + "49, neural ['l4', 'l7', 'l10', 'l11']", + "50, progenitor ['l5', 'l8', 'l10', 'l12']", + "51, cells ['l2', 'l6', 'l9', 'l11', 'l12']", + "106, Rat ['l13', 'l14']", + "107, corticospinal ['l13', 'l15']", + "108, axons ['l14', 'l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27019327", + "TEXT": "Commensal gut bacteria impact the host immune system and can influence disease processes in several organs, including the brain. However, it remains unclear whether the microbiota has an impact on the outcome of acute brain injury. Here we show that antibiotic-induced alterations in the intestinal flora reduce ischemic brain injury in mice, an effect transmissible by fecal transplants. Intestinal dysbiosis alters immune homeostasis in the small intestine, leading to an increase in regulatory T cells and a reduction in interleukin (IL)-17-positive γδ T cells through altered dendritic cell activity. Dysbiosis suppresses trafficking of effector T cells from the gut to the leptomeninges after stroke. Additionally, IL-10 and IL-17 are required for the neuroprotection afforded by intestinal dysbiosis. The findings reveal a previously unrecognized gut-brain axis and an impact of the intestinal flora and meningeal IL-17(+) γδ T cells on ischemic injury.", + "TAG_DATA": [ + "51, mice, {'context': 'B-organism'}", + "65, small {'context': 'B-tissue/organ'}", + "66, intestine, {'context': 'I-tissue/organ'}", + "86, dendritic {'context': 'B-cells'}", + "87, cell {'context': 'I-cells'}", + "93, effector {'context': 'B-cells'}", + "94, T {'context': 'I-cells'}", + "95, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "51, mice, ['l0', 'l1', 'l2', 'l3']", + "65, small ['l0', 'l4', 'l5', 'l6']", + "66, intestine, ['l1', 'l4', 'l7', 'l8']", + "86, dendritic ['l2', 'l5', 'l7', 'l9']", + "87, cell ['l3', 'l6', 'l8', 'l9']", + "93, effector ['l10', 'l11']", + "94, T ['l10', 'l12']", + "95, cells ['l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26974310", + "TEXT": "Phosphatase and tensin homolog (PTEN) is a negative regulator of the phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) signaling pathway and a potent tumor suppressor in many types of cancer. To test a tumor suppressive role for PTEN in pre-B acute lymphoblastic leukemia (ALL), we induced Cre-mediated deletion of Pten in mouse models of pre-B ALL. In contrast to its role as a tumor suppressor in other cancers, loss of one or both alleles of Pten caused rapid cell death of pre-B ALL cells and was sufficient to clear transplant recipient mice of leukemia. Small-molecule inhibition of PTEN in human pre-B ALL cells resulted in hyperactivation of AKT, activation of the p53 tumor suppressor cell cycle checkpoint and cell death. Loss of PTEN function in pre-B ALL cells was functionally equivalent to acute activation of autoreactive pre-B cell receptor signaling, which engaged a deletional checkpoint for the removal of autoreactive B cells. We propose that targeted inhibition of PTEN and hyperactivation of AKT triggers a checkpoint for the elimination of autoreactive B cells and represents a new strategy to overcome drug resistance in human ALL.", + "TAG_DATA": [ + "46, induced {'perturbing_action': 'B-gene loss-of-function'}", + "47, Cre-mediated {'perturbing_action': 'B-gene loss-of-function'}", + "48, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "49, of {'perturbing_action': 'I-gene loss-of-function'}", + "50, Pten {'perturbing_action': 'I-gene loss-of-function'}", + "52, mouse {'context': 'B-neoplasm'}", + "53, models {'context': 'I-neoplasm'}", + "54, of {'context': 'I-neoplasm'}", + "55, pre-B {'context': 'I-neoplasm'}", + "56, ALL. {'context': 'I-neoplasm'}", + "69, loss {'perturbing_action': 'B-gene loss-of-function'}", + "70, of {'perturbing_action': 'I-gene loss-of-function'}", + "71, one {'perturbing_action': 'I-gene loss-of-function'}", + "72, or {'perturbing_action': 'I-gene loss-of-function'}", + "73, both {'perturbing_action': 'I-gene loss-of-function'}", + "74, alleles {'perturbing_action': 'I-gene loss-of-function'}", + "75, of {'perturbing_action': 'I-gene loss-of-function'}", + "76, Pten {'perturbing_action': 'I-gene loss-of-function'}", + "77, caused {'effect': 'B-positive'}", + "79, cell {'phenotype': 'B-cell death'}", + "80, death {'phenotype': 'I-cell death'}", + "82, pre-B {'context': 'B-transformed cells'}", + "83, ALL {'context': 'I-transformed cells'}", + "84, cells {'context': 'I-transformed cells'}", + "92, mice {'context': 'B-organism'}", + "94, leukemia. {'context': 'B-neoplasm'}", + "95, Small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "96, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "97, of {'perturbing_action': 'I-pharmacological inhibition'}", + "98, PTEN {'perturbing_action': 'I-pharmacological inhibition'}", + "100, human {'context': 'B-transformed cells'}", + "101, pre-B {'context': 'I-transformed cells'}", + "102, ALL {'context': 'I-transformed cells'}", + "103, cells {'context': 'I-transformed cells'}", + "104, resulted {'effect': 'B-positive'}", + "105, in {'effect': 'I-positive'}", + "119, cell {'phenotype': 'B-cell death'}", + "120, death. {'phenotype': 'I-cell death'}", + "121, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "122, of {'perturbing_action': 'I-gene loss-of-function'}", + "123, PTEN {'perturbing_action': 'I-gene loss-of-function'}", + "124, function {'perturbing_action': 'I-gene loss-of-function'}", + "126, pre-B {'context': 'B-transformed cells'}", + "127, ALL {'context': 'I-transformed cells'}", + "128, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "46, induced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "47, Cre-mediated ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "48, deletion ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "49, of ['l2', 'l16', 'l29', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "50, Pten ['l3', 'l17', 'l30', 'l43', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "52, mouse ['l4', 'l18', 'l31', 'l44', 'l56', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "53, models ['l5', 'l19', 'l32', 'l45', 'l57', 'l67', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "54, of ['l6', 'l20', 'l33', 'l46', 'l58', 'l68', 'l77', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "55, pre-B ['l7', 'l21', 'l34', 'l47', 'l59', 'l69', 'l78', 'l86', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "56, ALL. ['l8', 'l22', 'l35', 'l48', 'l60', 'l70', 'l79', 'l87', 'l94', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "69, loss ['l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "70, of ['l107', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "71, one ['l108', 'l122', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "72, or ['l109', 'l123', 'l141', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "73, both ['l110', 'l124', 'l142', 'l158', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "74, alleles ['l111', 'l125', 'l143', 'l159', 'l174', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198']", + "75, of ['l112', 'l126', 'l144', 'l160', 'l175', 'l189', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207']", + "76, Pten ['l36', 'l49', 'l113', 'l127', 'l145', 'l161', 'l176', 'l190', 'l199', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215']", + "77, caused ['l9', 'l23', 'l37', 'l50', 'l61', 'l71', 'l80', 'l88', 'l95', 'l101', 'l114', 'l128', 'l146', 'l162', 'l177', 'l191', 'l200', 'l208', 'l216', 'l217', 'l218', 'l219', 'l220']", + "79, cell ['l10', 'l24', 'l38', 'l51', 'l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l115', 'l129', 'l147', 'l163', 'l178', 'l192', 'l201', 'l209', 'l216', 'l221', 'l222', 'l223', 'l224']", + "80, death ['l11', 'l25', 'l39', 'l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l116', 'l130', 'l148', 'l164', 'l179', 'l193', 'l202', 'l210', 'l217', 'l221', 'l225', 'l226', 'l227']", + "82, pre-B ['l12', 'l26', 'l40', 'l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l117', 'l131', 'l149', 'l165', 'l180', 'l194', 'l203', 'l211', 'l218', 'l222', 'l225', 'l228', 'l229']", + "83, ALL ['l13', 'l27', 'l41', 'l54', 'l65', 'l75', 'l84', 'l92', 'l99', 'l105', 'l118', 'l132', 'l150', 'l166', 'l181', 'l195', 'l204', 'l212', 'l219', 'l223', 'l226', 'l228', 'l230']", + "84, cells ['l14', 'l28', 'l42', 'l55', 'l66', 'l76', 'l85', 'l93', 'l100', 'l106', 'l119', 'l133', 'l151', 'l167', 'l182', 'l196', 'l205', 'l213', 'l220', 'l224', 'l227', 'l229', 'l230']", + "92, mice ['l120', 'l134', 'l152', 'l168', 'l183', 'l197', 'l206', 'l214', 'l231']", + "94, leukemia. ['l121', 'l135', 'l153', 'l169', 'l184', 'l198', 'l207', 'l215', 'l231']", + "95, Small-molecule ['l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244']", + "96, inhibition ['l232', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254']", + "97, of ['l233', 'l245', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263']", + "98, PTEN ['l234', 'l246', 'l255', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271']", + "100, human ['l235', 'l247', 'l256', 'l264', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278']", + "101, pre-B ['l236', 'l248', 'l257', 'l265', 'l272', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284']", + "102, ALL ['l136', 'l154', 'l170', 'l185', 'l237', 'l249', 'l258', 'l266', 'l273', 'l279', 'l285', 'l286', 'l287', 'l288', 'l289']", + "103, cells ['l137', 'l155', 'l171', 'l186', 'l238', 'l250', 'l259', 'l267', 'l274', 'l280', 'l285', 'l290', 'l291', 'l292', 'l293']", + "104, resulted ['l138', 'l239', 'l251', 'l260', 'l268', 'l275', 'l281', 'l286', 'l290', 'l294', 'l295', 'l296']", + "105, in ['l139', 'l156', 'l172', 'l187', 'l240', 'l252', 'l261', 'l269', 'l276', 'l282', 'l287', 'l291', 'l294', 'l297', 'l298']", + "119, cell ['l241', 'l253', 'l262', 'l270', 'l277', 'l283', 'l288', 'l292', 'l295', 'l297', 'l299']", + "120, death. ['l140', 'l157', 'l173', 'l188', 'l242', 'l254', 'l263', 'l271', 'l278', 'l284', 'l289', 'l293', 'l296', 'l298', 'l299']", + "121, Loss ['l300', 'l301', 'l302', 'l303', 'l304', 'l305']", + "122, of ['l300', 'l306', 'l307', 'l308', 'l309', 'l310']", + "123, PTEN ['l301', 'l306', 'l311', 'l312', 'l313', 'l314']", + "124, function ['l302', 'l307', 'l311', 'l315', 'l316', 'l317']", + "126, pre-B ['l303', 'l308', 'l312', 'l315', 'l318', 'l319']", + "127, ALL ['l243', 'l304', 'l309', 'l313', 'l316', 'l318', 'l320']", + "128, cells ['l244', 'l305', 'l310', 'l314', 'l317', 'l319', 'l320']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "induced", + "Cre-mediated", + "deletion", + "of", + "Pten", + "loss", + "one", + "or", + "both", + "alleles" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "models", + "of", + "pre-B", + "ALL.", + "leukemia." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "induced", + "Cre-mediated", + "deletion", + "of", + "Pten", + "loss", + "one", + "or", + "both", + "alleles" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused", + "resulted", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "induced", + "Cre-mediated", + "deletion", + "of", + "Pten", + "loss", + "one", + "or", + "both", + "alleles" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "induced", + "Cre-mediated", + "deletion", + "of", + "Pten", + "loss", + "one", + "or", + "both", + "alleles", + "Loss", + "PTEN", + "function" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "pre-B", + "ALL", + "cells" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "models", + "of", + "pre-B", + "ALL." + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "models", + "of", + "pre-B", + "ALL." + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "one", + "or", + "both", + "alleles", + "Pten" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused", + "resulted", + "in" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused", + "resulted", + "in" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "pre-B", + "ALL", + "cells", + "human" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death", + "death." + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "pre-B", + "ALL", + "cells", + "human" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Small-molecule", + "inhibition", + "of", + "PTEN" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "pre-B", + "ALL", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Small-molecule", + "inhibition", + "of", + "PTEN" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Small-molecule", + "inhibition", + "of", + "PTEN" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "26928464", + "TEXT": "Astrocytes isolated from individuals with amyotrophic lateral sclerosis (ALS) are toxic to motor neurons (MNs) and play a non-cell autonomous role in disease pathogenesis. The mechanisms underlying the susceptibility of MNs to cell death remain unclear. Here we report that astrocytes derived from either mice bearing mutations in genes associated with ALS or human subjects with ALS reduce the expression of major histocompatibility complex class I (MHCI) molecules on MNs; reduced MHCI expression makes these MNs susceptible to astrocyte-induced cell death. Increasing MHCI expression on MNs increases survival and motor performance in a mouse model of ALS and protects MNs against astrocyte toxicity. Overexpression of a single MHCI molecule, HLA-F, protects human MNs from ALS astrocyte-mediated toxicity, whereas knockdown of its receptor, the killer cell immunoglobulin-like receptor KIR3DL2, on human astrocytes results in enhanced MN death. Thus, our data indicate that, in ALS, loss of MHCI expression on MNs renders them more vulnerable to astrocyte-mediated toxicity.", + "TAG_DATA": [ + "40, astrocytes {'context': 'B-cells'}", + "44, mice {'context': 'B-organism'}", + "46, mutations {'perturbing_action': 'B-other'}", + "75, MNs {'context': 'B-cells'}", + "79, cell {'phenotype': 'B-cell death'}", + "80, death. {'phenotype': 'I-cell death'}", + "81, Increasing {'perturbing_action': 'B-gene gain-of-function'}", + "82, MHCI {'perturbing_action': 'I-gene gain-of-function'}", + "83, expression {'perturbing_action': 'I-gene gain-of-function'}", + "85, MNs {'context': 'B-cells'}", + "93, mouse {'context': 'B-organism'}", + "94, model {'context': 'I-organism'}", + "95, of {'context': 'I-organism'}", + "96, ALS {'context': 'I-organism'}", + "99, MNs {'context': 'B-cells'}", + "103, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "104, of {'perturbing_action': 'I-gene gain-of-function'}", + "105, a {'perturbing_action': 'I-gene gain-of-function'}", + "106, single {'perturbing_action': 'I-gene gain-of-function'}", + "107, MHCI {'perturbing_action': 'I-gene gain-of-function'}", + "108, molecule, {'perturbing_action': 'I-gene gain-of-function'}", + "109, HLA-F, {'perturbing_action': 'I-gene gain-of-function'}", + "111, human {'context': 'B-cells'}", + "112, MNs {'context': 'I-cells'}", + "118, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "119, of {'perturbing_action': 'I-rnai/knockdown'}", + "120, its {'perturbing_action': 'I-rnai/knockdown'}", + "121, receptor, {'perturbing_action': 'I-rnai/knockdown'}", + "122, the {'perturbing_action': 'I-rnai/knockdown'}", + "123, killer {'perturbing_action': 'I-rnai/knockdown'}", + "124, cell {'perturbing_action': 'I-rnai/knockdown'}", + "125, immunoglobulin-like {'perturbing_action': 'I-rnai/knockdown'}", + "126, receptor {'perturbing_action': 'I-rnai/knockdown'}", + "127, KIR3DL2, {'perturbing_action': 'I-rnai/knockdown'}", + "129, human {'context': 'B-cells'}", + "130, astrocytes {'context': 'I-cells'}", + "134, MN {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "40, astrocytes ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "44, mice ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "46, mutations ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "75, MNs ['l2', 'l12', 'l21', 'l33', 'l34', 'l35', 'l36', 'l37']", + "79, cell ['l3', 'l13', 'l22', 'l33', 'l38', 'l39', 'l40', 'l41']", + "80, death. ['l4', 'l14', 'l23', 'l34', 'l38', 'l42', 'l43']", + "81, Increasing ['l24', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "82, MHCI ['l25', 'l44', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "83, expression ['l5', 'l15', 'l26', 'l45', 'l52', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "85, MNs ['l6', 'l16', 'l27', 'l35', 'l39', 'l42', 'l46', 'l53', 'l59', 'l65', 'l66', 'l67', 'l68', 'l69']", + "93, mouse ['l7', 'l17', 'l28', 'l47', 'l54', 'l60', 'l65', 'l70', 'l71', 'l72', 'l73']", + "94, model ['l8', 'l18', 'l29', 'l48', 'l55', 'l61', 'l66', 'l70', 'l74', 'l75', 'l76']", + "95, of ['l9', 'l19', 'l30', 'l36', 'l40', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l77', 'l78']", + "96, ALS ['l10', 'l20', 'l31', 'l37', 'l41', 'l43', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l77', 'l79']", + "99, MNs ['l32', 'l51', 'l58', 'l64', 'l69', 'l73', 'l76', 'l78', 'l79']", + "103, Overexpression ['l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "104, of ['l80', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "105, a ['l81', 'l97', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127']", + "106, single ['l82', 'l98', 'l113', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141']", + "107, MHCI ['l83', 'l99', 'l114', 'l128', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "108, molecule, ['l84', 'l100', 'l115', 'l129', 'l142', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "109, HLA-F, ['l85', 'l101', 'l116', 'l130', 'l143', 'l155', 'l166', 'l167', 'l168', 'l169', 'l170']", + "111, human ['l86', 'l102', 'l117', 'l131', 'l144', 'l156', 'l166', 'l171']", + "112, MNs ['l87', 'l103', 'l118', 'l132', 'l145', 'l157', 'l167', 'l171']", + "118, knockdown ['l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183']", + "119, of ['l172', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "120, its ['l173', 'l184', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "121, receptor, ['l174', 'l185', 'l195', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213']", + "122, the ['l88', 'l104', 'l119', 'l133', 'l146', 'l158', 'l175', 'l186', 'l196', 'l205', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221']", + "123, killer ['l89', 'l105', 'l120', 'l134', 'l147', 'l159', 'l176', 'l187', 'l197', 'l206', 'l214', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228']", + "124, cell ['l90', 'l106', 'l121', 'l135', 'l148', 'l160', 'l177', 'l188', 'l198', 'l207', 'l215', 'l222', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234']", + "125, immunoglobulin-like ['l91', 'l107', 'l122', 'l136', 'l149', 'l161', 'l178', 'l189', 'l199', 'l208', 'l216', 'l223', 'l229', 'l235', 'l236', 'l237', 'l238', 'l239']", + "126, receptor ['l92', 'l108', 'l123', 'l137', 'l150', 'l162', 'l168', 'l179', 'l190', 'l200', 'l209', 'l217', 'l224', 'l230', 'l235', 'l240', 'l241', 'l242', 'l243']", + "127, KIR3DL2, ['l93', 'l109', 'l124', 'l138', 'l151', 'l163', 'l169', 'l180', 'l191', 'l201', 'l210', 'l218', 'l225', 'l231', 'l236', 'l240', 'l244', 'l245', 'l246']", + "129, human ['l94', 'l110', 'l125', 'l139', 'l152', 'l181', 'l192', 'l202', 'l211', 'l219', 'l226', 'l232', 'l237', 'l241', 'l244', 'l247', 'l248']", + "130, astrocytes ['l95', 'l111', 'l126', 'l140', 'l153', 'l164', 'l182', 'l193', 'l203', 'l212', 'l220', 'l227', 'l233', 'l238', 'l242', 'l245', 'l247', 'l249']", + "134, MN ['l96', 'l112', 'l127', 'l141', 'l154', 'l165', 'l170', 'l183', 'l194', 'l204', 'l213', 'l221', 'l228', 'l234', 'l239', 'l243', 'l246', 'l248', 'l249']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "astrocytes", + "MNs" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutations" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "astrocytes", + "MNs" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "astrocytes", + "MNs", + "human", + "MN" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "Increasing", + "MHCI", + "Overexpression", + "of", + "a", + "single", + "molecule,", + "HLA-F," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "model", + "of", + "ALS" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutations" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "of", + "ALS" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "model", + "of", + "ALS" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "Increasing", + "MHCI" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutations" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "its", + "receptor,", + "the", + "killer", + "cell", + "immunoglobulin-like", + "receptor", + "KIR3DL2," + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "astrocytes", + "MN" + ] + } + } + ] + }, + { + "PMID": "26878233", + "TEXT": "RAR-related orphan receptor-γt (ROR-γt) directs differentiation of proinflammatory T helper 17 (TH17) cells and is a potential therapeutic target in chronic autoimmune and inflammatory diseases. However, ROR-γt-dependent group 3 innate lymphoid cells ILC3s provide essential immunity and tissue protection in the intestine, suggesting that targeting ROR-γt could also result in impaired host defense after infection or enhanced tissue damage. Here, we demonstrate that transient chemical inhibition of ROR-γt in mice selectively reduces cytokine production from TH17 but not ILCs in the context of intestinal infection with Citrobacter rodentium, resulting in preserved innate immunity. Temporal deletion of Rorc (encoding ROR-γt) in mature ILCs also did not impair cytokine response in the steady state or during infection. Finally, pharmacologic inhibition of ROR-γt provided therapeutic benefit in mouse models of intestinal inflammation and reduced the frequency of TH17 cells but not ILCs isolated from primary intestinal samples of individuals with inflammatory bowel disease (IBD). Collectively, these results reveal differential requirements for ROR-γt in the maintenance of TH17 cell and ILC3 responses and suggest that transient inhibition of ROR-γt is a safe and effective therapeutic approach during intestinal inflammation.", + "TAG_DATA": [ + "63, transient {'perturbing_action': 'B-pharmacological inhibition'}", + "64, chemical {'perturbing_action': 'I-pharmacological inhibition'}", + "65, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "66, of {'perturbing_action': 'I-pharmacological inhibition'}", + "67, ROR-γt {'perturbing_action': 'I-pharmacological inhibition'}", + "69, mice {'context': 'B-organism'}", + "93, Temporal {'perturbing_action': 'B-gene loss-of-function'}", + "94, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "95, of {'perturbing_action': 'I-gene loss-of-function'}", + "96, Rorc {'perturbing_action': 'I-gene loss-of-function'}", + "97, (encoding {'perturbing_action': 'I-gene loss-of-function'}", + "98, ROR-γt) {'perturbing_action': 'I-gene loss-of-function'}", + "100, mature {'context': 'B-cells'}", + "101, ILCs {'context': 'I-cells'}", + "116, pharmacologic {'perturbing_action': 'B-pharmacological inhibition'}", + "117, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "118, of {'perturbing_action': 'I-pharmacological inhibition'}", + "119, ROR-γt {'perturbing_action': 'I-pharmacological inhibition'}", + "124, mouse {'context': 'B-organism'}", + "134, TH17 {'context': 'B-cells'}", + "135, cells {'context': 'I-cells'}", + "138, ILCs {'context': 'B-cells'}", + "141, primary {'context': 'B-cells'}", + "142, intestinal {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "63, transient ['l0', 'l1', 'l2', 'l3', 'l4']", + "64, chemical ['l0', 'l5', 'l6', 'l7', 'l8']", + "65, inhibition ['l1', 'l5', 'l9', 'l10', 'l11']", + "66, of ['l2', 'l6', 'l9', 'l12', 'l13']", + "67, ROR-γt ['l3', 'l7', 'l10', 'l12', 'l14']", + "69, mice ['l4', 'l8', 'l11', 'l13', 'l14']", + "93, Temporal ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "94, deletion ['l15', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "95, of ['l16', 'l25', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "96, Rorc ['l17', 'l26', 'l34', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "97, (encoding ['l18', 'l27', 'l35', 'l42', 'l48', 'l49', 'l50', 'l51', 'l52']", + "98, ROR-γt) ['l19', 'l28', 'l36', 'l43', 'l48', 'l53', 'l54', 'l55']", + "100, mature ['l20', 'l29', 'l37', 'l44', 'l49', 'l53', 'l56']", + "101, ILCs ['l21', 'l30', 'l38', 'l45', 'l50', 'l54', 'l56']", + "116, pharmacologic ['l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "117, inhibition ['l57', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "118, of ['l58', 'l68', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "119, ROR-γt ['l59', 'l69', 'l78', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "124, mouse ['l22', 'l31', 'l39', 'l46', 'l51', 'l60', 'l70', 'l79', 'l87', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "125, models ['l23', 'l32', 'l40', 'l47', 'l52', 'l55', 'l61', 'l71', 'l80', 'l88', 'l95', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "134, TH17 ['l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l108', 'l109', 'l110', 'l111', 'l112']", + "135, cells ['l24', 'l33', 'l41', 'l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l108', 'l113', 'l114', 'l115', 'l116']", + "138, ILCs ['l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l109', 'l113', 'l117', 'l118', 'l119']", + "141, primary ['l65', 'l75', 'l84', 'l92', 'l99', 'l105', 'l110', 'l114', 'l117', 'l120', 'l121']", + "142, intestinal ['l66', 'l76', 'l85', 'l93', 'l100', 'l106', 'l111', 'l115', 'l118', 'l120', 'l122']", + "143, samples ['l67', 'l77', 'l86', 'l94', 'l101', 'l107', 'l112', 'l116', 'l119', 'l121', 'l122']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "transient", + "chemical", + "inhibition", + "of", + "ROR-γt", + "pharmacologic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Temporal", + "deletion", + "of", + "Rorc", + "(encoding", + "ROR-γt)" + ] + }, + "context": { + "val": "cells", + "words": [ + "mature", + "ILCs", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Temporal", + "deletion", + "of", + "Rorc", + "(encoding" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "ROR-γt" + ] + }, + "context": { + "val": "cells", + "words": [ + "TH17", + "cells", + "ILCs", + "primary", + "intestinal" + ] + } + } + ] + }, + { + "PMID": "26855149", + "TEXT": "Patients with advanced Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant lung adenocarcinoma are currently treated with standard chemotherapy because of a lack of efficacious targeted therapies. We reasoned that the identification of mediators of Kras signaling in early mouse lung hyperplasias might bypass the difficulties that are imposed by intratumor heterogeneity in advanced tumors, and that it might unveil relevant therapeutic targets. Transcriptional profiling of Kras(G12V)-driven mouse hyperplasias revealed intertumor diversity with a subset that exhibited an aggressive transcriptional profile analogous to that of advanced human adenocarcinomas. The top-scoring gene in this profile encodes the tyrosine kinase receptor DDR1. The genetic and pharmacological inhibition of DDR1 blocked tumor initiation and tumor progression, respectively. The concomitant inhibition of both DDR1 and Notch signaling induced the regression of KRAS;TP53-mutant patient-derived lung xenografts (PDX) with a therapeutic efficacy that was at least comparable to that of standard chemotherapy. Our data indicate that the combined inhibition of DDR1 and Notch signaling could be an effective targeted therapy for patients with KRAS-mutant lung adenocarcinoma.", + "TAG_DATA": [ + "65, Kras(G12V)-driven {'perturbing_action': 'B-other'}", + "102, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "103, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "104, of {'perturbing_action': 'I-pharmacological inhibition'}", + "105, DDR1 {'perturbing_action': 'I-pharmacological inhibition'}", + "106, blocked {'effect': 'B-negative'}", + "107, tumor {'phenotype': 'B-tumour initiation'}", + "108, initiation {'phenotype': 'I-tumour initiation'}", + "110, tumor {'phenotype': 'B-tumour progression'}", + "111, progression, {'phenotype': 'I-tumour progression'}", + "122, induced {'effect': 'B-positive'}", + "124, regression {'phenotype': 'B-tumour regression'}", + "126, KRAS;TP53-mutant {'perturbing_action': 'B-other'}", + "127, patient-derived {'context': 'B-xenograft'}", + "128, lung {'context': 'I-xenograft'}", + "129, xenografts {'context': 'I-xenograft'}", + "130, (PDX) {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "102, pharmacological ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "103, inhibition ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "104, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "105, DDR1 ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "106, blocked ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "107, tumor ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "108, initiation ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "110, tumor ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "111, progression, ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "122, induced ['l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "124, regression ['l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "126, KRAS;TP53-mutant ['l37', 'l42', 'l47', 'l48', 'l49', 'l50']", + "127, patient-derived ['l38', 'l43', 'l47', 'l51', 'l52', 'l53']", + "128, lung ['l39', 'l44', 'l48', 'l51', 'l54', 'l55']", + "129, xenografts ['l40', 'l45', 'l49', 'l52', 'l54', 'l56']", + "130, (PDX) ['l41', 'l46', 'l50', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "DDR1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "DDR1" + ] + }, + "phenotype": { + "val": "tumour initiation", + "words": [ + "tumor", + "initiation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "DDR1" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "tumour initiation", + "words": [ + "tumor", + "initiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "KRAS;TP53-mutant" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "patient-derived", + "lung", + "xenografts", + "(PDX)" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "KRAS;TP53-mutant" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "patient-derived", + "lung", + "xenografts", + "(PDX)" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "KRAS;TP53-mutant" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "patient-derived", + "lung", + "xenografts", + "(PDX)" + ] + } + } + ] + }, + { + "PMID": "26828196", + "TEXT": "Exposure of newborns to the maternal vaginal microbiota is interrupted with cesarean birthing. Babies delivered by cesarean section (C-section) acquire a microbiota that differs from that of vaginally delivered infants, and C-section delivery has been associated with increased risk for immune and metabolic disorders. Here we conducted a pilot study in which infants delivered by C-section were exposed to maternal vaginal fluids at birth. Similarly to vaginally delivered babies, the gut, oral and skin bacterial communities of these newborns during the first 30 d of life was enriched in vaginal bacteria--which were underrepresented in unexposed C-section-delivered infants--and the microbiome similarity to those of vaginally delivered infants was greater in oral and skin samples than in anal samples. Although the long-term health consequences of restoring the microbiota of C-section-delivered infants remain unclear, our results demonstrate that vaginal microbes can be partially restored at birth in C-section-delivered babies.", + "TAG_DATA": [ + "52, infants {'context': 'B-organism'}", + "78, newborns {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "52, infants ['l0']", + "78, newborns ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26828195", + "TEXT": "Although mechanisms of acquired resistance of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. Here we observe that acquired resistance caused by the EGFR(T790M) gatekeeper mutation can occur either by selection of pre-existing EGFR(T790M)-positive clones or via genetic evolution of initially EGFR(T790M)-negative drug-tolerant cells. The path to resistance impacts the biology of the resistant clone, as those that evolved from drug-tolerant cells had a diminished apoptotic response to third-generation EGFR inhibitors that target EGFR(T790M); treatment with navitoclax, an inhibitor of the anti-apoptotic factors BCL-xL and BCL-2 restored sensitivity. We corroborated these findings using cultures derived directly from EGFR inhibitor-resistant patient tumors. These findings provide evidence that clinically relevant drug-resistant cancer cells can both pre-exist and evolve from drug-tolerant cells, and they point to therapeutic opportunities to prevent or overcome resistance in the clinic.", + "TAG_DATA": [ + "81, diminished {'effect': 'B-negative'}", + "82, apoptotic {'phenotype': 'B-apoptosis'}", + "83, response {'phenotype': 'I-apoptosis'}", + "85, third-generation {'perturbing_action': 'B-pharmacological inhibition'}", + "86, EGFR {'perturbing_action': 'B-pharmacological inhibition'}", + "87, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "89, target {'perturbing_action': 'I-pharmacological inhibition'}", + "110, cultures {'context': 'B-cells'}", + "116, patient {'context': 'I-neoplasm'}", + "117, tumors. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "81, diminished ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "82, apoptotic ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "83, response ['l1', 'l6', 'l11', 'l12', 'l13']", + "85, third-generation ['l2', 'l7', 'l11', 'l14', 'l15', 'l16']", + "86, EGFR ['l3', 'l8', 'l12', 'l14', 'l17', 'l18']", + "87, inhibitors ['l4', 'l9', 'l13', 'l15', 'l17', 'l19']", + "89, target ['l5', 'l10', 'l16', 'l18', 'l19']", + "110, cultures ['l20', 'l21']", + "116, patient ['l20', 'l22']", + "117, tumors. ['l21', 'l22']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "diminished" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "response" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "diminished" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "third-generation", + "EGFR", + "inhibitors", + "target" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "response" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "third-generation", + "EGFR", + "inhibitors", + "target" + ] + } + } + ] + }, + { + "PMID": "26779814", + "TEXT": "Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin-dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladapted hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis.", + "TAG_DATA": [ + "44, mice, {'context': 'B-organism'}", + "128, PCECs, {'context': 'B-cells'}", + "137, perivascular {'context': 'B-cells'}", + "138, fibroblasts {'context': 'I-cells'}", + "145, CXCR7 {'perturbing_action': 'B-pharmacological augmentation'}", + "146, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "148, PCEC-targeted {'perturbing_action': 'B-rnai/knockdown'}", + "149, Jag1 {'perturbing_action': 'I-rnai/knockdown'}", + "150, shRNA {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "128, PCECs, ['l0', 'l1']", + "137, perivascular ['l0', 'l2']", + "138, fibroblasts ['l1', 'l2']", + "145, CXCR7 ['l3', 'l4', 'l5', 'l6']", + "146, agonist ['l3', 'l7', 'l8', 'l9']", + "148, PCEC-targeted ['l4', 'l7', 'l10', 'l11']", + "149, Jag1 ['l5', 'l8', 'l10', 'l12']", + "150, shRNA ['l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26779812", + "TEXT": "Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials. One PARP inhibitor, olaparib (Lynparza, AstraZeneca), was recently approved by the FDA to treat ovarian cancer with mutations in BRCA genes. BRCA1 and BRCA2 have essential roles in repairing DNA double-strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition. Here we show that the receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907 (PARP1 pTyr907 or pY907). PARP1 pY907 increases PARP1 enzymatic activity and reduces binding to a PARP inhibitor, thereby rendering cancer cells resistant to PARP inhibition. The combination of c-Met and PARP1 inhibitors synergized to suppress the growth of breast cancer cells in vitro and xenograft tumor models, and we observed similar synergistic effects in a lung cancer xenograft tumor model. These results suggest that the abundance of PARP1 pY907 may predict tumor resistance to PARP inhibitors, and that treatment with a combination of c-Met and PARP inhibitors may benefit patients whose tumors show high c-Met expression and who do not respond to PARP inhibition alone.", + "TAG_DATA": [ + "97, cancer {'context': 'B-transformed cells'}", + "98, cells {'context': 'I-transformed cells'}", + "106, c-Met {'perturbing_action': 'B-pharmacological inhibition'}", + "107, and {'perturbing_action': 'I-pharmacological inhibition'}", + "108, PARP1 {'perturbing_action': 'I-pharmacological inhibition'}", + "109, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "116, breast {'context': 'B-transformed cells'}", + "117, cancer {'context': 'I-transformed cells'}", + "118, cells {'context': 'I-transformed cells'}", + "119, in {'context': 'B-in vitro'}", + "120, vitro {'context': 'I-in vitro'}", + "122, xenograft {'context': 'B-xenograft'}", + "123, tumor {'context': 'I-xenograft'}", + "124, models, {'context': 'I-xenograft'}", + "133, lung {'context': 'B-xenograft'}", + "134, cancer {'context': 'I-xenograft'}", + "135, xenograft {'context': 'I-xenograft'}", + "136, tumor {'context': 'I-xenograft'}", + "137, model. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "97, cancer ['l0', 'l1', 'l2', 'l3']", + "98, cells ['l0', 'l4', 'l5']", + "106, c-Met ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "107, and ['l6', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "108, PARP1 ['l7', 'l17', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "109, inhibitors ['l8', 'l18', 'l27', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "116, breast ['l1', 'l9', 'l19', 'l28', 'l36', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "117, cancer ['l2', 'l4', 'l10', 'l20', 'l29', 'l37', 'l44', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "118, cells ['l3', 'l5', 'l11', 'l21', 'l30', 'l38', 'l45', 'l51', 'l57', 'l58', 'l59', 'l60']", + "119, in ['l12', 'l22', 'l31', 'l39', 'l46', 'l52', 'l57', 'l61', 'l62', 'l63', 'l64']", + "120, vitro ['l13', 'l23', 'l32', 'l40', 'l47', 'l53', 'l58', 'l61', 'l65', 'l66', 'l67']", + "122, xenograft ['l14', 'l24', 'l33', 'l41', 'l48', 'l54', 'l62', 'l65', 'l68', 'l69']", + "123, tumor ['l15', 'l25', 'l34', 'l42', 'l49', 'l55', 'l59', 'l63', 'l66', 'l68', 'l70']", + "124, models, ['l16', 'l26', 'l35', 'l43', 'l50', 'l56', 'l60', 'l64', 'l67', 'l69', 'l70']", + "133, lung ['l71', 'l72', 'l73', 'l74']", + "134, cancer ['l71', 'l75', 'l76', 'l77']", + "135, xenograft ['l72', 'l75', 'l78', 'l79']", + "136, tumor ['l73', 'l76', 'l78', 'l80']", + "137, model. ['l74', 'l77', 'l79', 'l80']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "c-Met", + "and", + "PARP1", + "inhibitors" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "breast", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "c-Met", + "and", + "PARP1", + "inhibitors" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "c-Met", + "and", + "PARP1", + "inhibitors" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "tumor", + "models," + ] + } + } + ] + }, + { + "PMID": "26735405", + "TEXT": "Sentinel macrophages in the lymph node provide a first line of defense against invading viruses. A new study visualizes inflammasome activation in virally infected nodal macrophages in mice and shows that this activation augments both innate and adaptive immunity.", + "TAG_DATA": [ + "24, nodal {'context': 'B-cells'}", + "25, macrophages {'context': 'I-cells'}", + "27, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "24, nodal ['l0', 'l1']", + "25, macrophages ['l0', 'l2']", + "27, mice ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26726878", + "TEXT": "Acute kidney injury (AKI) is associated with prolonged hospitalization and high mortality, and it predisposes individuals to chronic kidney disease. To date, no effective AKI treatments have been established. Here we show that the apoptosis inhibitor of macrophage (AIM) protein on intraluminal debris interacts with kidney injury molecule (KIM)-1 and promotes recovery from AKI. During AKI, the concentration of AIM increases in the urine, and AIM accumulates on necrotic cell debris within the kidney proximal tubules. The AIM present in this cellular debris binds to KIM-1, which is expressed on injured tubular epithelial cells, and enhances the phagocytic removal of the debris by the epithelial cells, thus contributing to kidney tissue repair. When subjected to ischemia-reperfusion (IR)-induced AKI, AIM-deficient mice exhibited abrogated debris clearance and persistent renal inflammation, resulting in higher mortality than wild-type (WT) mice due to progressive renal dysfunction. Treatment of mice with IR-induced AKI using recombinant AIM resulted in the removal of the debris, thereby ameliorating renal pathology. We observed this effect in both AIM-deficient and WT mice, but not in KIM-1-deficient mice. Our findings provide a basis for the development of potentially novel therapies for AKI.", + "TAG_DATA": [ + "118, AIM-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "119, mice {'context': 'B-organism'}", + "135, mice {'context': 'B-organism'}", + "143, mice {'context': 'B-organism'}", + "167, AIM-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "170, mice, {'context': 'B-organism'}", + "174, KIM-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "175, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "118, AIM-deficient ['l0', 'l1']", + "119, mice ['l0', 'l2']", + "135, mice ['l1', 'l2']", + "167, AIM-deficient ['l3', 'l4', 'l5']", + "170, mice, ['l3', 'l6', 'l7']", + "174, KIM-1-deficient ['l4', 'l6', 'l8']", + "175, mice. ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "AIM-deficient", + "KIM-1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice,", + "mice." + ] + } + } + ] + }, + { + "PMID": "26726877", + "TEXT": "Regulated necrosis (necroptosis) and apoptosis are crucially involved in severe cardiac pathological conditions, including myocardial infarction, ischemia-reperfusion injury and heart failure. Whereas apoptotic signaling is well defined, the mechanisms that underlie cardiomyocyte necroptosis remain elusive. Here we show that receptor-interacting protein 3 (RIP3) triggers myocardial necroptosis, in addition to apoptosis and inflammation, through activation of Ca(2+)-calmodulin-dependent protein kinase (CaMKII) rather than through the well-established RIP3 partners RIP1 and MLKL. In mice, RIP3 deficiency or CaMKII inhibition ameliorates myocardial necroptosis and heart failure induced by ischemia-reperfusion or by doxorubicin treatment. RIP3-induced activation of CaMKII, via phosphorylation or oxidation or both, triggers opening of the mitochondrial permeability transition pore and myocardial necroptosis. These findings identify CaMKII as a new RIP3 substrate and delineate a RIP3-CaMKII-mPTP myocardial necroptosis pathway, a promising target for the treatment of ischemia- and oxidative stress-induced myocardial damage and heart failure.", + "TAG_DATA": [ + "43, triggers {'effect': 'B-positive'}", + "45, necroptosis, {'phenotype': 'B-necroptosis'}", + "70, mice, {'context': 'B-organism'}", + "71, RIP3 {'perturbing_action': 'B-gene loss-of-function'}", + "72, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "74, CaMKII {'perturbing_action': 'B-pharmacological inhibition'}", + "75, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "76, ameliorates {'effect': 'B-negative'}", + "78, necroptosis {'phenotype': 'B-necroptosis'}", + "99, triggers {'effect': 'B-positive'}", + "109, necroptosis. {'phenotype': 'B-necroptosis'}" + ], + "LINK_DATA": [ + "43, triggers ['l0']", + "45, necroptosis, ['l0']", + "70, mice, ['l1', 'l2', 'l3', 'l4']", + "71, RIP3 ['l1', 'l5', 'l6', 'l7']", + "72, deficiency ['l2', 'l5', 'l8', 'l9']", + "74, CaMKII ['l10', 'l11', 'l12', 'l13', 'l14']", + "75, inhibition ['l10', 'l15', 'l16', 'l17', 'l18']", + "76, ameliorates ['l3', 'l6', 'l8', 'l11', 'l15', 'l19']", + "78, necroptosis ['l4', 'l7', 'l9', 'l12', 'l16', 'l19']", + "99, triggers ['l13', 'l17', 'l20']", + "109, necroptosis. ['l14', 'l18', 'l20']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "phenotype": { + "val": "necroptosis", + "words": [ + "necroptosis,", + "necroptosis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "RIP3", + "deficiency" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "negative", + "words": [ + "ameliorates" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "necroptosis", + "words": [ + "necroptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "RIP3", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "ameliorates" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "RIP3", + "deficiency" + ] + }, + "phenotype": { + "val": "necroptosis", + "words": [ + "necroptosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CaMKII", + "inhibition" + ] + }, + "effect": { + "val": "negative", + "words": [ + "ameliorates" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CaMKII", + "inhibition" + ] + }, + "phenotype": { + "val": "necroptosis", + "words": [ + "necroptosis", + "necroptosis." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CaMKII", + "inhibition" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "ameliorates" + ] + }, + "phenotype": { + "val": "necroptosis", + "words": [ + "necroptosis" + ] + } + } + ] + }, + { + "PMID": "26692332", + "TEXT": "The inflammasome is activated in response to a variety of pathogens and has an important role in shaping adaptive immunity, yet the spatiotemporal orchestration of inflammasome activation in vivo and the mechanisms by which it promotes an effective immune response are not fully understood. Using an in vivo reporter to visualize inflammasome assembly, we establish the distribution, kinetics and propagation of the inflammasome response to a local viral infection. We show that modified vaccinia Ankara virus induces inflammasome activation in subcapsular sinus (SCS) macrophages, which is immediately followed by cell death and release of extracellular ASC specks. This transient inflammasome signaling in the lymph node generates a robust influx of inflammatory cells and mobilizes T cells from the circulation to increase the magnitude of T cell responses. We propose that after infection, SCS macrophages deliver a burst response of inflammasome activity and cell death that translates into the broadening of T cell responses, identifying an important aspect of inflammasome-driven vaccination strategies.", + "TAG_DATA": [ + "80, subcapsular {'context': 'B-cells'}", + "81, sinus {'context': 'I-cells'}", + "82, (SCS) {'context': 'I-cells'}", + "83, macrophages, {'context': 'I-cells'}", + "89, cell {'phenotype': 'B-cell death'}", + "90, death {'phenotype': 'I-cell death'}", + "103, lymph {'context': 'B-tissue/organ'}", + "104, node {'context': 'I-tissue/organ'}", + "114, T {'context': 'B-cells'}", + "115, cells {'context': 'B-cells'}", + "124, T {'context': 'B-cells'}", + "125, cell {'context': 'B-cells'}", + "142, cell {'phenotype': 'B-cell death'}", + "143, death {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "80, subcapsular ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "81, sinus ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "82, (SCS) ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "83, macrophages, ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "89, cell ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "90, death ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "103, lymph ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27', 'l28', 'l29', 'l30', 'l31']", + "104, node ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27', 'l32', 'l33', 'l34', 'l35']", + "114, T ['l28', 'l32', 'l36', 'l37', 'l38']", + "115, cells ['l29', 'l33', 'l36', 'l39', 'l40']", + "124, T ['l30', 'l34', 'l37', 'l39', 'l41']", + "125, cell ['l31', 'l35', 'l38', 'l40', 'l41']", + "142, cell ['l42']", + "143, death ['l42']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "subcapsular", + "sinus", + "(SCS)", + "macrophages," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lymph", + "node" + ] + } + } + ] + }, + { + "PMID": "26657143", + "TEXT": "Senescent cells (SCs) accumulate with age and after genotoxic stress, such as total-body irradiation (TBI). Clearance of SCs in a progeroid mouse model using a transgenic approach delays several age-associated disorders, suggesting that SCs play a causative role in certain age-related pathologies. Thus, a 'senolytic' pharmacological agent that can selectively kill SCs holds promise for rejuvenating tissue stem cells and extending health span. To test this idea, we screened a collection of compounds and identified ABT263 (a specific inhibitor of the anti-apoptotic proteins BCL-2 and BCL-xL) as a potent senolytic drug. We show that ABT263 selectively kills SCs in culture in a cell type- and species-independent manner by inducing apoptosis. Oral administration of ABT263 to either sublethally irradiated or normally aged mice effectively depleted SCs, including senescent bone marrow hematopoietic stem cells (HSCs) and senescent muscle stem cells (MuSCs). Notably, this depletion mitigated TBI-induced premature aging of the hematopoietic system and rejuvenated the aged HSCs and MuSCs in normally aged mice. Our results demonstrate that selective clearance of SCs by a pharmacological agent is beneficial in part through its rejuvenation of aged tissue stem cells. Thus, senolytic drugs may represent a new class of radiation mitigators and anti-aging agents.", + "TAG_DATA": [ + "97, SCs {'context': 'B-cells'}", + "99, culture {'context': 'B-cells'}", + "108, inducing {'effect': 'B-positive'}", + "109, apoptosis. {'phenotype': 'B-apoptosis'}", + "120, aged {'context': 'I-organism'}", + "121, mice {'context': 'I-organism'}", + "124, SCs, {'context': 'B-cells'}", + "126, senescent {'context': 'B-cells'}", + "127, bone {'context': 'I-cells'}", + "128, marrow {'context': 'I-cells'}", + "129, hematopoietic {'context': 'I-cells'}", + "130, stem {'context': 'I-cells'}", + "131, cells {'context': 'I-cells'}", + "132, (HSCs) {'context': 'I-cells'}", + "134, senescent {'context': 'B-cells'}", + "135, muscle {'context': 'I-cells'}", + "136, stem {'context': 'I-cells'}", + "137, cells {'context': 'I-cells'}", + "138, (MuSCs). {'context': 'I-cells'}", + "148, hematopoietic {'context': 'B-tissue/organ'}", + "149, system {'context': 'I-tissue/organ'}", + "153, aged {'context': 'B-cells'}", + "154, HSCs {'context': 'I-cells'}", + "156, MuSCs {'context': 'B-cells'}", + "159, aged {'context': 'I-organism'}", + "160, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "97, SCs ['l0', 'l1', 'l2']", + "99, culture ['l0', 'l3', 'l4']", + "108, inducing ['l1', 'l3', 'l5']", + "109, apoptosis. ['l2', 'l4', 'l5']", + "120, aged ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "121, mice ['l6', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "124, SCs, ['l7', 'l20', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "126, senescent ['l8', 'l21', 'l33', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "127, bone ['l9', 'l22', 'l34', 'l45', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "128, marrow ['l10', 'l23', 'l35', 'l46', 'l56', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "129, hematopoietic ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "130, stem ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "131, cells ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "132, (HSCs) ['l14', 'l27', 'l39', 'l50', 'l60', 'l69', 'l77', 'l84', 'l90', 'l96', 'l97', 'l98', 'l99', 'l100']", + "134, senescent ['l15', 'l28', 'l40', 'l51', 'l61', 'l70', 'l78', 'l85', 'l91', 'l96', 'l101', 'l102', 'l103', 'l104', 'l105']", + "135, muscle ['l16', 'l29', 'l41', 'l52', 'l62', 'l71', 'l79', 'l86', 'l92', 'l97', 'l101', 'l106', 'l107', 'l108', 'l109', 'l110']", + "136, stem ['l17', 'l30', 'l42', 'l53', 'l63', 'l72', 'l80', 'l87', 'l93', 'l98', 'l102', 'l106', 'l111', 'l112', 'l113']", + "137, cells ['l18', 'l31', 'l43', 'l54', 'l64', 'l73', 'l81', 'l88', 'l94', 'l99', 'l103', 'l107', 'l111', 'l114', 'l115']", + "138, (MuSCs). ['l19', 'l32', 'l44', 'l55', 'l65', 'l74', 'l82', 'l89', 'l95', 'l100', 'l104', 'l108', 'l112', 'l114', 'l116']", + "148, hematopoietic ['l109', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "149, system ['l105', 'l110', 'l113', 'l115', 'l116', 'l117', 'l123', 'l124']", + "153, aged ['l118', 'l123', 'l125', 'l126', 'l127', 'l128']", + "154, HSCs ['l119', 'l124', 'l125', 'l129', 'l130', 'l131']", + "156, MuSCs ['l120', 'l126', 'l129', 'l132', 'l133']", + "159, aged ['l121', 'l127', 'l130', 'l132', 'l134']", + "160, mice. ['l122', 'l128', 'l131', 'l133', 'l134']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "SCs", + "culture" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "SCs", + "culture" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "26657141", + "TEXT": "It is unclear how the immune response in early life becomes appropriately stimulated to provide protection while also avoiding excessive activation as a result of diverse new antigens. T cells are integral to adaptive immunity; mouse studies indicate that tissue localization of T cell subsets is important for both protective immunity and immunoregulation. In humans, however, the early development and function of T cells in tissues remain unexplored. We present here an analysis of lymphoid and mucosal tissue T cells derived from pediatric organ donors in the first two years of life, as compared to adult organ donors, revealing early compartmentalization of T cell differentiation and regulation. Whereas adult tissues contain a predominance of memory T cells, in pediatric blood and tissues the main subset consists of naive recent thymic emigrants, with effector memory T cells (T(EM)) found only in the lungs and small intestine. Additionally, regulatory T (T(reg)) cells comprise a high proportion (30-40%) of CD4(+) T cells in pediatric tissues but are present at much lower frequencies (1-10%) in adult tissues. Pediatric tissue T(reg) cells suppress endogenous T cell activation, and early T cell functionality is confined to the mucosal sites that have the lowest T(reg):T(EM) cell ratios, which suggests control in situ of immune responses in early life.", + "TAG_DATA": [ + "173, Pediatric {'context': 'B-cells'}", + "174, tissue {'context': 'I-cells'}", + "175, T(reg) {'context': 'I-cells'}", + "176, cells {'context': 'I-cells'}", + "179, T {'context': 'B-cells'}", + "180, cell {'context': 'B-cells'}", + "184, T {'context': 'B-cells'}", + "185, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "173, Pediatric ['l0', 'l1', 'l2', 'l3', 'l4']", + "174, tissue ['l0', 'l5', 'l6', 'l7', 'l8']", + "175, T(reg) ['l1', 'l5', 'l9', 'l10', 'l11']", + "176, cells ['l2', 'l6', 'l9', 'l12', 'l13']", + "179, T ['l3', 'l7', 'l10', 'l12', 'l14']", + "180, cell ['l4', 'l8', 'l11', 'l13', 'l14']", + "184, T ['l15']", + "185, cell ['l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26618722", + "TEXT": "Mitochondrial dysfunction represents a critical step during the pathogenesis of Parkinson's disease (PD), and increasing evidence suggests abnormal mitochondrial dynamics and quality control as important underlying mechanisms. The VPS35 gene, which encodes a key component of the membrane protein-recycling retromer complex, is the third autosomal-dominant gene associated with PD. However, how VPS35 mutations lead to neurodegeneration remains unclear. Here we demonstrate that PD-associated VPS35 mutations caused mitochondrial fragmentation and cell death in cultured neurons in vitro, in mouse substantia nigra neurons in vivo and in human fibroblasts from an individual with PD who has the VPS35(D620N) mutation. VPS35-induced mitochondrial deficits and neuronal dysfunction could be prevented by inhibition of mitochondrial fission. VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation. Notably, oxidative stress increased the VPS35-DLP1 interaction, which we also found to be increased in the brains of sporadic PD cases. These results revealed a novel cellular mechanism for the involvement of VPS35 in mitochondrial fission, dysregulation of which is probably involved in the pathogenesis of familial, and possibly sporadic, PD.", + "TAG_DATA": [ + "62, PD-associated {'perturbing_action': 'B-other'}", + "63, VPS35 {'perturbing_action': 'I-other'}", + "64, mutations {'perturbing_action': 'I-other'}", + "65, caused {'effect': 'B-positive'}", + "69, cell {'phenotype': 'B-cell death'}", + "70, death {'phenotype': 'I-cell death'}", + "72, cultured {'context': 'B-cells'}", + "73, neurons {'context': 'I-cells'}", + "74, in {'context': 'B-in vitro'}", + "75, vitro, {'context': 'I-in vitro'}", + "77, mouse {'context': 'B-cells'}", + "78, substantia {'context': 'I-cells'}", + "79, nigra {'context': 'I-cells'}", + "80, neurons {'context': 'I-cells'}", + "81, in {'context': 'B-in vivo'}", + "82, vivo {'context': 'I-in vivo'}", + "85, human {'context': 'B-cells'}", + "86, fibroblasts {'context': 'I-cells'}", + "94, the {'perturbing_action': 'I-other'}", + "95, VPS35(D620N) {'perturbing_action': 'B-other'}", + "96, mutation. {'perturbing_action': 'I-other'}", + "111, VPS35 {'perturbing_action': 'B-other'}", + "112, mutants {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "62, PD-associated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "63, VPS35 ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "64, mutations ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "65, caused ['l2', 'l15', 'l27', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "69, cell ['l3', 'l16', 'l28', 'l38', 'l44', 'l45', 'l46', 'l47', 'l48']", + "70, death ['l4', 'l17', 'l29', 'l39', 'l44', 'l49', 'l50', 'l51', 'l52']", + "72, cultured ['l5', 'l18', 'l30', 'l40', 'l45', 'l49', 'l53', 'l54', 'l55']", + "73, neurons ['l6', 'l19', 'l31', 'l41', 'l46', 'l50', 'l53', 'l56', 'l57']", + "74, in ['l7', 'l20', 'l32', 'l42', 'l47', 'l51', 'l54', 'l56', 'l58']", + "75, vitro, ['l8', 'l21', 'l33', 'l43', 'l48', 'l52', 'l55', 'l57', 'l58']", + "77, mouse ['l9', 'l22', 'l34', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "78, substantia ['l59', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "79, nigra ['l10', 'l23', 'l60', 'l66', 'l72', 'l73', 'l74', 'l75', 'l76']", + "80, neurons ['l11', 'l24', 'l35', 'l61', 'l67', 'l72', 'l77', 'l78', 'l79', 'l80']", + "81, in ['l12', 'l25', 'l36', 'l62', 'l68', 'l73', 'l77', 'l81', 'l82', 'l83']", + "82, vivo ['l13', 'l26', 'l37', 'l63', 'l69', 'l74', 'l78', 'l81', 'l84', 'l85']", + "85, human ['l64', 'l70', 'l75', 'l79', 'l82', 'l84', 'l86', 'l87', 'l88', 'l89']", + "86, fibroblasts ['l65', 'l71', 'l76', 'l80', 'l83', 'l85', 'l86', 'l90', 'l91', 'l92']", + "94, the ['l87', 'l90', 'l93', 'l94']", + "95, VPS35(D620N) ['l88', 'l91', 'l93', 'l95']", + "96, mutation. ['l89', 'l92', 'l94', 'l95']", + "111, VPS35 ['l96']", + "112, mutants ['l96']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "PD-associated", + "VPS35", + "mutations" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "PD-associated", + "VPS35", + "mutations" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "PD-associated", + "VPS35", + "mutations", + "the", + "VPS35(D620N)", + "mutation." + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "neurons", + "mouse", + "nigra", + "human", + "fibroblasts" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "PD-associated", + "VPS35", + "mutations" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "PD-associated", + "VPS35", + "mutations" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "neurons" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "neurons" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + } + ] + }, + { + "PMID": "26523972", + "TEXT": "Membrane-associated RING-CH 8 (MARCH8) is one of 11 members of the recently discovered MARCH family of RING (really interesting new gene)-finger E3 ubiquitin ligases. MARCH8 downregulates several host transmembrane proteins, including major histocompatibility complex (MHC)-II, CD86, interleukin (IL)-1 receptor accessory protein, TNF-related apoptosis-inducing ligand (TRAIL) receptor 1 and the transferrin receptor. However, its physiological roles remain largely unknown. Here we identify MARCH8 as a novel antiviral factor. The ectopic expression of MARCH8 in virus-producing cells does not affect levels of lentivirus production, but it does markedly reduce viral infectivity. MARCH8 blocks the incorporation of HIV-1 envelope glycoprotein into virus particles by downregulating it from the cell surface, probably through their interaction, resulting in a substantial reduction in the efficiency of viral entry. The inhibitory effect of MARCH8 on vesicular stomatitis virus G-glycoprotein is even more remarkable, suggesting a broad-spectrum inhibition of enveloped viruses by MARCH8. Notably, the endogenous expression of MARCH8 is high in monocyte-derived macrophages and dendritic cells, and MARCH8 knockdown or knockout in macrophages significantly increases the infectivity of virions produced by these cells. Our findings thus indicate that MARCH8 is highly expressed in terminally differentiated myeloid cells, and that it is a potent antiviral protein that targets viral envelope glycoproteins and reduces their incorporation into virions.", + "TAG_DATA": [ + "68, ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "69, expression {'perturbing_action': 'I-gene gain-of-function'}", + "70, of {'perturbing_action': 'I-gene gain-of-function'}", + "71, MARCH8 {'perturbing_action': 'I-gene gain-of-function'}", + "73, virus-producing {'context': 'B-cells'}", + "74, cells {'context': 'I-cells'}", + "160, MARCH8 {'perturbing_action': 'B-rnai/knockdown'}", + "161, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "165, macrophages {'context': 'B-cells'}", + "175, cells. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "68, ectopic ['l0', 'l1', 'l2', 'l3', 'l4']", + "69, expression ['l0', 'l5', 'l6', 'l7', 'l8']", + "70, of ['l1', 'l5', 'l9', 'l10', 'l11']", + "71, MARCH8 ['l2', 'l6', 'l9', 'l12', 'l13']", + "73, virus-producing ['l3', 'l7', 'l10', 'l12', 'l14']", + "74, cells ['l4', 'l8', 'l11', 'l13', 'l14']", + "160, MARCH8 ['l15', 'l16', 'l17']", + "161, knockdown ['l15', 'l18', 'l19']", + "165, macrophages ['l16', 'l18', 'l20']", + "175, cells. ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "expression", + "of", + "MARCH8" + ] + }, + "context": { + "val": "cells", + "words": [ + "virus-producing", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "MARCH8", + "knockdown" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages", + "cells." + ] + } + } + ] + }, + { + "PMID": "26501192", + "TEXT": "Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet-fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders.", + "TAG_DATA": [ + "108, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "110, antisense {'perturbing_action': 'B-rnai/knockdown'}", + "111, targeting {'perturbing_action': 'I-rnai/knockdown'}", + "112, of {'perturbing_action': 'I-rnai/knockdown'}", + "113, miR-128-1 {'perturbing_action': 'I-rnai/knockdown'}", + "114, or {'perturbing_action': 'I-rnai/knockdown'}", + "115, miR-148a {'perturbing_action': 'I-rnai/knockdown'}", + "121, Apoe-null {'perturbing_action': 'B-gene loss-of-function'}", + "122, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "108, overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "110, antisense ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "111, targeting ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "112, of ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "113, miR-128-1 ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "114, or ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "115, miR-148a ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "121, Apoe-null ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "122, mice ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antisense", + "targeting", + "of", + "miR-128-1", + "or", + "miR-148a" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apoe-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "26413780", + "TEXT": "By convention, CD4+ T lymphocytes recognize foreign and self peptides derived from internalized antigens in combination with major histocompatibility complex class II molecules. Alternative pathways of epitope production have been identified, but their contributions to host defense have not been established. We show here in a mouse infection model that the CD4+ T cell response to influenza, critical for durable protection from the virus, is driven principally by unconventional processing of antigen synthesized within the infected antigen-presenting cell, not by classical processing of endocytosed virions or material from infected cells. Investigation of the cellular components involved, including the H2-M molecular chaperone, the proteasome and γ-interferon-inducible lysosomal thiol reductase revealed considerable heterogeneity in the generation of individual epitopes, an arrangement that ensures peptide diversity and broad CD4+ T cell engagement. These results could fundamentally revise strategies for rational vaccine design and may lead to key insights into the induction of autoimmune and anti-tumor responses.", + "TAG_DATA": [ + "46, mouse {'context': 'B-organism'}", + "51, CD4+ {'context': 'B-cells'}", + "52, T {'context': 'I-cells'}", + "53, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "46, mouse ['l0', 'l1', 'l2']", + "51, CD4+ ['l0', 'l3', 'l4']", + "52, T ['l1', 'l3', 'l5']", + "53, cell ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26390242", + "TEXT": "Tauopathies, including frontotemporal dementia (FTD) and Alzheimer's disease (AD), are neurodegenerative diseases in which tau fibrils accumulate. Recent evidence supports soluble tau species as the major toxic species. How soluble tau accumulates and causes neurodegeneration remains unclear. Here we identify tau acetylation at Lys174 (K174) as an early change in AD brains and a critical determinant in tau homeostasis and toxicity in mice. The acetyl-mimicking mutant K174Q slows tau turnover and induces cognitive deficits in vivo. Acetyltransferase p300-induced tau acetylation is inhibited by salsalate and salicylate, which enhance tau turnover and reduce tau levels. In the PS19 transgenic mouse model of FTD, administration of salsalate after disease onset inhibited p300 activity, lowered levels of total tau and tau acetylated at K174, rescued tau-induced memory deficits and prevented hippocampal atrophy. The tau-lowering and protective effects of salsalate were diminished in neurons expressing K174Q tau. Targeting tau acetylation could be a new therapeutic strategy against human tauopathies.", + "TAG_DATA": [ + "65, mutant {'perturbing_action': 'I-other'}", + "66, K174Q {'perturbing_action': 'I-other'}", + "74, in {'context': 'B-in vivo'}", + "75, vivo. {'context': 'I-in vivo'}", + "96, PS19 {'perturbing_action': 'B-other'}", + "97, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "98, mouse {'context': 'B-organism'}", + "99, model {'context': 'I-organism'}", + "100, of {'context': 'I-organism'}", + "101, FTD, {'context': 'I-organism'}", + "139, neurons {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "65, mutant ['l0', 'l1', 'l2']", + "66, K174Q ['l0', 'l3', 'l4']", + "74, in ['l1', 'l3', 'l5']", + "75, vivo. ['l2', 'l4', 'l5']", + "96, PS19 ['l6', 'l7', 'l8', 'l9', 'l10']", + "97, transgenic ['l6', 'l11', 'l12', 'l13', 'l14']", + "98, mouse ['l7', 'l11', 'l15', 'l16', 'l17']", + "99, model ['l8', 'l12', 'l15', 'l18', 'l19']", + "100, of ['l9', 'l13', 'l16', 'l18', 'l20']", + "101, FTD, ['l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "K174Q" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "PS19" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "FTD," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "FTD," + ] + } + } + ] + }, + { + "PMID": "26390241", + "TEXT": "Improved treatment for major depressive disorder (MDD) remains elusive because of the limited understanding of its underlying biological mechanisms. It is likely that stress-induced maladaptive transcriptional regulation in limbic neural circuits contributes to the development of MDD, possibly through epigenetic factors that regulate chromatin structure. We establish that persistent upregulation of the ACF (ATP-utilizing chromatin assembly and remodeling factor) ATP-dependent chromatin-remodeling complex, occurring in the nucleus accumbens of stress-susceptible mice and depressed humans, is necessary for stress-induced depressive-like behaviors. We found that altered ACF binding after chronic stress was correlated with altered nucleosome positioning, particularly around the transcription start sites of affected genes. These alterations in ACF binding and nucleosome positioning were associated with repressed expression of genes implicated in susceptibility to stress. Together, our findings identify the ACF chromatin-remodeling complex as a critical component in the development of susceptibility to depression and in regulating stress-related behaviors.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "26322579", + "TEXT": "Macrophage phagocytosis of tumor cells mediated by CD47-specific blocking antibodies has been proposed to be the major effector mechanism in xenograft models. Here, using syngeneic immunocompetent mouse tumor models, we reveal that the therapeutic effects of CD47 blockade depend on dendritic cell but not macrophage cross-priming of T cell responses. The therapeutic effects of anti-CD47 antibody therapy were abrogated in T cell-deficient mice. In addition, the antitumor effects of CD47 blockade required expression of the cytosolic DNA sensor STING, but neither MyD88 nor TRIF, in CD11c+ cells, suggesting that cytosolic sensing of DNA from tumor cells is enhanced by anti-CD47 treatment, further bridging the innate and adaptive responses. Notably, the timing of administration of standard chemotherapy markedly impacted the induction of antitumor T cell responses by CD47 blockade. Together, our findings indicate that CD47 blockade drives T cell-mediated elimination of immunogenic tumors.", + "TAG_DATA": [ + "24, syngeneic {'context': 'B-neoplasm'}", + "25, immunocompetent {'context': 'I-neoplasm'}", + "26, mouse {'context': 'I-neoplasm'}", + "27, tumor {'context': 'I-neoplasm'}", + "28, models, {'context': 'I-neoplasm'}", + "60, T {'perturbing_action': 'B-gene loss-of-function'}", + "61, cell-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "62, mice. {'context': 'B-organism'}", + "85, CD11c+ {'context': 'B-cells'}", + "86, cells, {'context': 'I-cells'}", + "122, T {'context': 'B-cells'}", + "123, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "24, syngeneic ['l0', 'l1', 'l2', 'l3']", + "25, immunocompetent ['l0', 'l4', 'l5', 'l6']", + "26, mouse ['l1', 'l4', 'l7', 'l8']", + "27, tumor ['l2', 'l5', 'l7', 'l9']", + "28, models, ['l3', 'l6', 'l8', 'l9']", + "60, T ['l10', 'l11', 'l12', 'l13']", + "61, cell-deficient ['l10', 'l14', 'l15', 'l16']", + "62, mice. ['l11', 'l14', 'l17', 'l18']", + "85, CD11c+ ['l12', 'l15', 'l17', 'l19']", + "86, cells, ['l13', 'l16', 'l18', 'l19']", + "122, T ['l20']", + "123, cell ['l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "T", + "cell-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "T", + "cell-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD11c+", + "cells," + ] + } + } + ] + }, + { + "PMID": "26236991", + "TEXT": "Kidney fibrosis is marked by an epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells (TECs). Here we find that, during renal fibrosis, TECs acquire a partial EMT program during which they remain associated with their basement membrane and express markers of both epithelial and mesenchymal cells. The functional consequence of the EMT program during fibrotic injury is an arrest in the G2 phase of the cell cycle and lower expression of several solute and solvent transporters in TECs. We also found that transgenic expression of either Twist1 (encoding twist family bHLH transcription factor 1, known as Twist) or Snai1 (encoding snail family zinc finger 1, known as Snail) expression is sufficient to promote prolonged TGF-β1-induced G2 arrest of TECs, limiting the cells' potential for repair and regeneration. In mouse models of experimentally induced renal fibrosis, conditional deletion of Twist1 or Snai1 in proximal TECs resulted in inhibition of the EMT program and the maintenance of TEC integrity, while also restoring cell proliferation, dedifferentiation-associated repair and regeneration of the kidney parenchyma and attenuating interstitial fibrosis. Thus, inhibition of the EMT program in TECs during chronic renal injury represents a potential anti-fibrosis therapy.", + "TAG_DATA": [ + "81, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "82, expression {'perturbing_action': 'I-gene gain-of-function'}", + "83, of {'perturbing_action': 'I-gene gain-of-function'}", + "84, either {'perturbing_action': 'I-gene gain-of-function'}", + "85, Twist1 {'perturbing_action': 'I-gene gain-of-function'}", + "86, (encoding {'perturbing_action': 'I-gene gain-of-function'}", + "87, twist {'perturbing_action': 'I-gene gain-of-function'}", + "88, family {'perturbing_action': 'I-gene gain-of-function'}", + "89, bHLH {'perturbing_action': 'I-gene gain-of-function'}", + "90, transcription {'perturbing_action': 'I-gene gain-of-function'}", + "91, factor {'perturbing_action': 'I-gene gain-of-function'}", + "92, 1, {'perturbing_action': 'I-gene gain-of-function'}", + "93, known {'perturbing_action': 'I-gene gain-of-function'}", + "94, as {'perturbing_action': 'I-gene gain-of-function'}", + "95, Twist) {'perturbing_action': 'I-gene gain-of-function'}", + "96, or {'perturbing_action': 'I-gene gain-of-function'}", + "97, Snai1 {'perturbing_action': 'I-gene gain-of-function'}", + "107, expression {'perturbing_action': 'I-gene gain-of-function'}", + "111, promote {'effect': 'B-positive'}", + "114, G2 {'phenotype': 'B-cell cycle arrest'}", + "115, arrest {'phenotype': 'I-cell cycle arrest'}", + "117, TECs, {'context': 'B-cells'}", + "127, mouse {'context': 'B-organism'}", + "128, models {'context': 'I-organism'}", + "134, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "135, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "136, of {'perturbing_action': 'I-gene loss-of-function'}", + "137, Twist1 {'perturbing_action': 'I-gene loss-of-function'}", + "138, or {'perturbing_action': 'I-gene loss-of-function'}", + "139, Snai1 {'perturbing_action': 'I-gene loss-of-function'}", + "141, proximal {'context': 'B-cells'}", + "142, TECs {'context': 'I-cells'}", + "145, inhibition {'effect': 'B-negative'}", + "148, EMT {'phenotype': 'B-epithelial-mesenchymal transition'}", + "149, program {'phenotype': 'I-epithelial-mesenchymal transition'}", + "154, TEC {'context': 'B-cells'}", + "158, restoring {'effect': 'B-rescues'}", + "159, cell {'context': 'B-cells'}", + "160, proliferation, {'phenotype': 'B-proliferation'}", + "167, kidney {'context': 'B-tissue/organ'}", + "168, parenchyma {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "81, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "82, expression ['l0', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "83, of ['l1', 'l22', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "84, either ['l2', 'l23', 'l43', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "85, Twist1 ['l3', 'l24', 'l44', 'l62', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "86, (encoding ['l4', 'l25', 'l45', 'l63', 'l80', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "87, twist ['l5', 'l26', 'l46', 'l64', 'l81', 'l97', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "88, family ['l6', 'l27', 'l47', 'l65', 'l82', 'l98', 'l114', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "89, bHLH ['l7', 'l28', 'l48', 'l66', 'l83', 'l99', 'l115', 'l131', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163']", + "90, transcription ['l8', 'l29', 'l49', 'l67', 'l84', 'l100', 'l116', 'l132', 'l148', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "91, factor ['l9', 'l30', 'l50', 'l68', 'l85', 'l101', 'l117', 'l133', 'l149', 'l164', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191']", + "92, 1, ['l10', 'l31', 'l51', 'l69', 'l86', 'l102', 'l118', 'l134', 'l150', 'l165', 'l179', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203']", + "93, known ['l11', 'l32', 'l52', 'l70', 'l87', 'l103', 'l119', 'l135', 'l151', 'l166', 'l180', 'l192', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214']", + "94, as ['l12', 'l33', 'l53', 'l71', 'l88', 'l104', 'l120', 'l136', 'l152', 'l167', 'l181', 'l193', 'l204', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224']", + "95, Twist) ['l13', 'l34', 'l54', 'l72', 'l89', 'l105', 'l121', 'l137', 'l153', 'l168', 'l182', 'l194', 'l205', 'l215', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233']", + "96, or ['l14', 'l35', 'l55', 'l73', 'l90', 'l106', 'l122', 'l138', 'l154', 'l169', 'l183', 'l195', 'l206', 'l216', 'l225', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240']", + "97, Snai1 ['l15', 'l36', 'l56', 'l74', 'l91', 'l107', 'l123', 'l139', 'l155', 'l170', 'l184', 'l196', 'l207', 'l217', 'l226', 'l234', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249']", + "107, expression ['l16', 'l37', 'l57', 'l75', 'l92', 'l108', 'l124', 'l140', 'l156', 'l171', 'l185', 'l197', 'l208', 'l218', 'l227', 'l235', 'l241', 'l250', 'l251', 'l252', 'l253', 'l254']", + "111, promote ['l17', 'l38', 'l58', 'l76', 'l93', 'l109', 'l125', 'l141', 'l157', 'l172', 'l186', 'l198', 'l209', 'l219', 'l228', 'l236', 'l242', 'l250', 'l255', 'l256', 'l257']", + "114, G2 ['l18', 'l39', 'l59', 'l77', 'l94', 'l110', 'l126', 'l142', 'l158', 'l173', 'l187', 'l199', 'l210', 'l220', 'l229', 'l237', 'l243', 'l251', 'l255', 'l258', 'l259']", + "115, arrest ['l19', 'l40', 'l60', 'l78', 'l95', 'l111', 'l127', 'l143', 'l159', 'l174', 'l188', 'l200', 'l211', 'l221', 'l230', 'l238', 'l244', 'l252', 'l256', 'l258', 'l260']", + "117, TECs, ['l20', 'l41', 'l61', 'l79', 'l96', 'l112', 'l128', 'l144', 'l160', 'l175', 'l189', 'l201', 'l212', 'l222', 'l231', 'l239', 'l245', 'l253', 'l257', 'l259', 'l260']", + "127, mouse ['l129', 'l145', 'l161', 'l176', 'l190', 'l202', 'l213', 'l223', 'l232', 'l246', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272']", + "128, models ['l21', 'l42', 'l113', 'l130', 'l146', 'l162', 'l177', 'l191', 'l203', 'l214', 'l224', 'l233', 'l240', 'l247', 'l254', 'l261', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282']", + "134, conditional ['l283', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298']", + "135, deletion ['l283', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304', 'l305', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311', 'l312', 'l313']", + "136, of ['l284', 'l299', 'l314', 'l315', 'l316', 'l317', 'l318', 'l319', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327']", + "137, Twist1 ['l285', 'l300', 'l314', 'l328', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340']", + "138, or ['l286', 'l301', 'l315', 'l328', 'l341', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348', 'l349', 'l350', 'l351', 'l352']", + "139, Snai1 ['l287', 'l302', 'l316', 'l329', 'l341', 'l353', 'l354', 'l355', 'l356', 'l357', 'l358', 'l359', 'l360', 'l361', 'l362', 'l363']", + "141, proximal ['l262', 'l288', 'l303', 'l317', 'l330', 'l342', 'l353', 'l364', 'l365', 'l366', 'l367', 'l368', 'l369', 'l370', 'l371', 'l372', 'l373']", + "142, TECs ['l263', 'l273', 'l289', 'l304', 'l318', 'l331', 'l343', 'l354', 'l364', 'l374', 'l375', 'l376', 'l377', 'l378', 'l379', 'l380', 'l381', 'l382']", + "145, inhibition ['l264', 'l274', 'l290', 'l305', 'l319', 'l332', 'l344', 'l355', 'l365', 'l374', 'l383', 'l384', 'l385', 'l386', 'l387', 'l388', 'l389', 'l390']", + "148, EMT ['l248', 'l265', 'l275', 'l291', 'l306', 'l320', 'l333', 'l345', 'l356', 'l366', 'l375', 'l383', 'l391', 'l392', 'l393', 'l394', 'l395', 'l396', 'l397']", + "149, program ['l147', 'l163', 'l178', 'l249', 'l266', 'l276', 'l292', 'l307', 'l321', 'l334', 'l346', 'l357', 'l367', 'l376', 'l384', 'l391', 'l398', 'l399', 'l400', 'l401', 'l402', 'l403']", + "154, TEC ['l267', 'l277', 'l293', 'l308', 'l322', 'l335', 'l347', 'l358', 'l368', 'l377', 'l385', 'l392', 'l398', 'l404', 'l405', 'l406', 'l407', 'l408']", + "158, restoring ['l268', 'l278', 'l294', 'l309', 'l323', 'l336', 'l348', 'l359', 'l369', 'l378', 'l386', 'l393', 'l399', 'l404', 'l409', 'l410', 'l411', 'l412']", + "159, cell ['l269', 'l279', 'l295', 'l310', 'l324', 'l337', 'l349', 'l360', 'l370', 'l379', 'l387', 'l394', 'l400', 'l405', 'l409', 'l413', 'l414', 'l415']", + "160, proliferation, ['l270', 'l280', 'l296', 'l311', 'l325', 'l338', 'l350', 'l361', 'l371', 'l380', 'l388', 'l395', 'l401', 'l406', 'l410', 'l413', 'l416', 'l417']", + "167, kidney ['l271', 'l281', 'l297', 'l312', 'l326', 'l339', 'l351', 'l362', 'l372', 'l381', 'l389', 'l396', 'l402', 'l407', 'l411', 'l414', 'l416', 'l418']", + "168, parenchyma ['l272', 'l282', 'l298', 'l313', 'l327', 'l340', 'l352', 'l363', 'l373', 'l382', 'l390', 'l397', 'l403', 'l408', 'l412', 'l415', 'l417', 'l418']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "of", + "either", + "Twist1", + "(encoding", + "twist", + "family", + "bHLH", + "transcription", + "factor", + "1,", + "known", + "as", + "Twist)", + "or", + "Snai1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promote" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "of", + "either", + "Twist1", + "(encoding", + "twist", + "family", + "bHLH", + "transcription", + "factor", + "1,", + "known", + "as", + "Twist)", + "or", + "Snai1" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G2", + "arrest" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "of", + "either", + "Twist1", + "(encoding", + "twist", + "family", + "bHLH", + "transcription", + "factor", + "1,", + "known", + "as", + "Twist)", + "or", + "Snai1" + ] + }, + "context": { + "val": "cells", + "words": [ + "TECs," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "(encoding", + "twist", + "family", + "bHLH", + "transcription", + "factor", + "1,", + "known", + "as", + "Twist)", + "or", + "Snai1" + ] + }, + "context": { + "val": "organism", + "words": [ + "models", + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "family", + "bHLH", + "transcription", + "Snai1" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "program", + "EMT" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G2", + "arrest" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote" + ] + }, + "context": { + "val": "cells", + "words": [ + "TECs," + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G2", + "arrest" + ] + }, + "context": { + "val": "cells", + "words": [ + "TECs," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EMT", + "program" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restoring" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "deletion", + "of", + "Twist1", + "or", + "Snai1" + ] + }, + "context": { + "val": "cells", + "words": [ + "proximal", + "TECs", + "TEC", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "deletion", + "of", + "Twist1", + "or", + "Snai1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "deletion", + "of", + "Twist1", + "or", + "Snai1" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EMT", + "program" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "deletion", + "of", + "Twist1", + "or", + "Snai1" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restoring" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "deletion", + "of", + "Twist1", + "or", + "Snai1" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "deletion", + "of", + "Twist1", + "or", + "Snai1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidney", + "parenchyma" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "proximal", + "TECs", + "TEC", + "cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "proximal", + "TECs", + "TEC", + "cell" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EMT", + "program" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "proximal", + "TECs", + "TEC", + "cell" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restoring" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "proximal", + "TECs", + "TEC", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EMT", + "program" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidney", + "parenchyma" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EMT", + "program" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restoring" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EMT", + "program" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidney", + "parenchyma" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restoring" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restoring" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidney", + "parenchyma" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidney", + "parenchyma" + ] + } + } + ] + }, + { + "PMID": "26214836", + "TEXT": "We carried out metagenomic shotgun sequencing and a metagenome-wide association study (MGWAS) of fecal, dental and salivary samples from a cohort of individuals with rheumatoid arthritis (RA) and healthy controls. Concordance was observed between the gut and oral microbiomes, suggesting overlap in the abundance and function of species at different body sites. Dysbiosis was detected in the gut and oral microbiomes of RA patients, but it was partially resolved after RA treatment. Alterations in the gut, dental or saliva microbiome distinguished individuals with RA from healthy controls, were correlated with clinical measures and could be used to stratify individuals on the basis of their response to therapy. In particular, Haemophilus spp. were depleted in individuals with RA at all three sites and negatively correlated with levels of serum autoantibodies, whereas Lactobacillus salivarius was over-represented in individuals with RA at all three sites and was present in increased amounts in cases of very active RA. Functionally, the redox environment, transport and metabolism of iron, sulfur, zinc and arginine were altered in the microbiota of individuals with RA. Molecular mimicry of human antigens related to RA was also detectable. Our results establish specific alterations in the gut and oral microbiomes in individuals with RA and suggest potential ways of using microbiome composition for prognosis and diagnosis.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "26151327", + "TEXT": "Inflammatory disease research is burgeoning. Large data sets are being generated to characterize the human immune response, while detailed mechanistic studies are defining the role of specific cell types and sensors in inflammatory disease. Future efforts are needed to integrate these approaches and guide precision medicine.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "26099047", + "TEXT": "Amyloid-β (Aβ) plaques and α-synuclein (α-syn)-rich Lewy bodies are the major neuropathological hallmarks of Alzheimer's disease (AD) and Parkinson's disease, respectively. An overlap of pathologies is found in most individuals with dementia with Lewy bodies (DLB) and in more than 50% of AD cases. Their brains display substantial α-syn accumulation not only in Lewy bodies, but also in dystrophic neurites decorating Aβ plaques. Several studies report binding and coaggregation of Aβ and α-syn, yet the precise role of α-syn in amyloid plaque formation remains elusive. Here we performed intracerebral injections of α-syn-containing preparations into amyloid precursor protein (APP) transgenic mice (expressing APP695(KM670/671NL) and PSEN1(L166P) under the control of the neuron-specific Thy-1 promoter; referred to here as 'APPPS1'). Unexpectedly, α-syn failed to cross-seed Aβ plaques in vivo, but rather it inhibited plaque formation in APPPS1 mice coexpressing SNCA(A30P) (referred to here as 'APPPS1 × [A30P]aSYN' double-transgenic mice). This was accompanied by increased Aβ levels in cerebrospinal fluid despite unchanged overall Aβ levels. Notably, the seeding activity of Aβ-containing brain homogenates was considerably reduced by α-syn, and Aβ deposition was suppressed in grafted tissue from [A30P]aSYN transgenic mice. Thus, we conclude that an interaction between Aβ and α-syn leads to inhibition of Aβ deposition and to reduced plaque formation.", + "TAG_DATA": [ + "94, amyloid {'perturbing_action': 'B-gene gain-of-function'}", + "96, protein {'perturbing_action': 'I-gene gain-of-function'}", + "97, (APP) {'perturbing_action': 'I-gene gain-of-function'}", + "98, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "99, mice {'context': 'B-organism'}", + "101, APP695(KM670/671NL) {'perturbing_action': 'I-gene gain-of-function'}", + "102, and {'perturbing_action': 'I-gene gain-of-function'}", + "103, PSEN1(L166P) {'perturbing_action': 'I-gene gain-of-function'}", + "104, under {'perturbing_action': 'I-gene gain-of-function'}", + "106, control {'perturbing_action': 'I-gene gain-of-function'}", + "107, of {'perturbing_action': 'I-gene gain-of-function'}", + "108, the {'perturbing_action': 'I-gene gain-of-function'}", + "109, neuron-specific {'perturbing_action': 'I-gene gain-of-function'}", + "110, Thy-1 {'perturbing_action': 'I-gene gain-of-function'}", + "111, promoter; {'perturbing_action': 'I-gene gain-of-function'}", + "124, in {'context': 'B-in vivo'}", + "125, vivo, {'context': 'I-in vivo'}", + "133, APPPS1 {'perturbing_action': 'B-other'}", + "134, mice {'context': 'I-organism'}", + "135, coexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "136, SNCA(A30P) {'perturbing_action': 'I-gene gain-of-function'}", + "183, [A30P]aSYN {'perturbing_action': 'B-gene gain-of-function'}", + "184, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "185, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "94, amyloid ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "96, protein ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "97, (APP) ['l1', 'l17', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "98, transgenic ['l2', 'l18', 'l33', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "99, mice ['l3', 'l19', 'l34', 'l48', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "101, APP695(KM670/671NL) ['l4', 'l20', 'l35', 'l49', 'l62', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "102, and ['l5', 'l21', 'l36', 'l50', 'l63', 'l75', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "103, PSEN1(L166P) ['l6', 'l22', 'l37', 'l51', 'l64', 'l76', 'l89', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "104, under ['l7', 'l23', 'l38', 'l52', 'l65', 'l77', 'l90', 'l101', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "105, the ['l8', 'l24', 'l39', 'l53', 'l66', 'l78', 'l91', 'l102', 'l113', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "106, control ['l9', 'l25', 'l40', 'l54', 'l67', 'l79', 'l92', 'l103', 'l114', 'l124', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "107, of ['l10', 'l26', 'l41', 'l55', 'l68', 'l80', 'l93', 'l104', 'l115', 'l125', 'l135', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "108, the ['l11', 'l27', 'l42', 'l56', 'l69', 'l81', 'l94', 'l105', 'l116', 'l126', 'l136', 'l145', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162']", + "109, neuron-specific ['l12', 'l28', 'l43', 'l57', 'l70', 'l82', 'l95', 'l106', 'l117', 'l127', 'l137', 'l146', 'l155', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170']", + "110, Thy-1 ['l13', 'l29', 'l44', 'l58', 'l71', 'l83', 'l96', 'l107', 'l118', 'l128', 'l138', 'l147', 'l156', 'l163', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177']", + "111, promoter; ['l14', 'l30', 'l45', 'l59', 'l72', 'l84', 'l97', 'l108', 'l119', 'l129', 'l139', 'l148', 'l157', 'l164', 'l171', 'l178', 'l179', 'l180', 'l181', 'l182']", + "124, in ['l15', 'l31', 'l46', 'l60', 'l73', 'l85', 'l98', 'l109', 'l120', 'l130', 'l140', 'l149', 'l158', 'l165', 'l172', 'l178', 'l183']", + "125, vivo, ['l16', 'l32', 'l47', 'l61', 'l74', 'l86', 'l99', 'l110', 'l121', 'l131', 'l141', 'l150', 'l159', 'l166', 'l173', 'l179', 'l183']", + "133, APPPS1 ['l87', 'l100', 'l111', 'l122', 'l132', 'l142', 'l151', 'l160', 'l167', 'l174', 'l180', 'l184', 'l185', 'l186']", + "134, mice ['l88', 'l112', 'l123', 'l133', 'l143', 'l152', 'l161', 'l168', 'l175', 'l181', 'l184', 'l187', 'l188']", + "135, coexpressing ['l153', 'l169', 'l176', 'l185', 'l187', 'l189']", + "136, SNCA(A30P) ['l134', 'l144', 'l154', 'l162', 'l170', 'l177', 'l182', 'l186', 'l188', 'l189']", + "180, grafted ['l190', 'l191', 'l192', 'l193']", + "181, tissue ['l190', 'l194', 'l195', 'l196']", + "183, [A30P]aSYN ['l191', 'l194', 'l197', 'l198']", + "184, transgenic ['l192', 'l195', 'l197', 'l199']", + "185, mice. ['l193', 'l196', 'l198', 'l199']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "amyloid", + "protein", + "(APP)", + "transgenic", + "APP695(KM670/671NL)", + "and", + "PSEN1(L166P)", + "under", + "control", + "of", + "the", + "neuron-specific", + "Thy-1", + "promoter;", + "coexpressing", + "SNCA(A30P)", + "[A30P]aSYN" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "amyloid", + "protein", + "(APP)", + "transgenic", + "APP695(KM670/671NL)", + "and", + "PSEN1(L166P)", + "under", + "control", + "of", + "the", + "neuron-specific", + "Thy-1", + "promoter;" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "APPPS1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "26053624", + "TEXT": "Depending on the inflammatory milieu, injury can result either in a tissue's complete regeneration or in its degeneration and fibrosis, the latter of which could potentially lead to permanent organ failure. Yet how inflammatory cells regulate matrix-producing cells involved in the reparative process is unknown. Here we show that in acutely damaged skeletal muscle, sequential interactions between multipotent mesenchymal progenitors and infiltrating inflammatory cells determine the outcome of the reparative process. We found that infiltrating inflammatory macrophages, through their expression of tumor necrosis factor (TNF), directly induce apoptosis of fibro/adipogenic progenitors (FAPs). In states of chronic damage, however, such as those in mdx mice, macrophages express high levels of transforming growth factor β1 (TGF-β1), which prevents the apoptosis of FAPs and induces their differentiation into matrix-producing cells. Treatment with nilotinib, a kinase inhibitor with proposed anti-fibrotic activity, can block the effect of TGF-β1 and reduce muscle fibrosis in mdx mice. Our findings reveal an unexpected anti-fibrotic role of TNF and suggest that disruption of the precisely timed progression from a TNF-rich to a TGF-β-rich environment favors fibrotic degeneration of the muscle during chronic injury.", + "TAG_DATA": [ + "86, induce {'effect': 'B-positive'}", + "87, apoptosis {'phenotype': 'B-apoptosis'}", + "104, macrophages {'context': 'B-cells'}", + "115, prevents {'effect': 'B-negative'}", + "117, apoptosis {'phenotype': 'B-apoptosis'}", + "119, FAPs {'context': 'B-cells'}", + "121, induces {'effect': 'B-positive'}", + "123, differentiation {'phenotype': 'B-differentiation'}", + "145, muscle {'context': 'B-tissue/organ'}", + "148, mdx {'context': 'B-organism'}", + "149, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "86, induce ['l0']", + "87, apoptosis ['l0']", + "104, macrophages ['l1', 'l2', 'l3', 'l4', 'l5']", + "115, prevents ['l1', 'l6', 'l7', 'l8', 'l9']", + "117, apoptosis ['l2', 'l6', 'l10', 'l11', 'l12']", + "119, FAPs ['l3', 'l7', 'l10', 'l13', 'l14']", + "121, induces ['l4', 'l8', 'l11', 'l13', 'l15']", + "123, differentiation ['l5', 'l9', 'l12', 'l14', 'l15']", + "145, muscle ['l16', 'l17']", + "148, mdx ['l16', 'l18']", + "149, mice. ['l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induce", + "induces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "macrophages", + "FAPs" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "macrophages", + "FAPs" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "macrophages", + "FAPs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "macrophages", + "FAPs" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "26030179", + "TEXT": "Colorectal cancers (CRCs) evolve by a reiterative process of genetic diversification and clonal evolution. The molecular profile of CRC is routinely assessed in surgical or bioptic samples. Genotyping of CRC tissue has inherent limitations; a tissue sample represents a single snapshot in time, and it is subjected to spatial selection bias owing to tumor heterogeneity. Repeated tissue samples are difficult to obtain and cannot be used for dynamic monitoring of disease progression and response to therapy. We exploited circulating tumor DNA (ctDNA) to genotype colorectal tumors and track clonal evolution during treatment with the epidermal growth factor receptor (EGFR)-specific antibodies cetuximab or panitumumab. We identified alterations in ctDNA of patients with primary or acquired resistance to EGFR blockade in the following genes: KRAS, NRAS, MET, ERBB2, FLT3, EGFR and MAP2K1. Mutated KRAS clones, which emerge in blood during EGFR blockade, decline upon withdrawal of EGFR-specific antibodies, indicating that clonal evolution continues beyond clinical progression. Pharmacogenomic analysis of CRC cells that had acquired resistance to cetuximab reveals that upon antibody withdrawal KRAS clones decay, whereas the population regains drug sensitivity. ctDNA profiles of individuals who benefit from multiple challenges with anti-EGFR antibodies exhibit pulsatile levels of mutant KRAS. These results indicate that the CRC genome adapts dynamically to intermittent drug schedules and provide a molecular explanation for the efficacy of rechallenge therapies based on EGFR blockade.", + "TAG_DATA": [ + "157, CRC {'context': 'B-transformed cells'}", + "158, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "157, CRC ['l0']", + "158, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26005854", + "TEXT": "B cell malignancies frequently colonize the bone marrow. The mechanisms responsible for this preferential homing are incompletely understood. Here we studied multiple myeloma (MM) as a model of a terminally differentiated B cell malignancy that selectively colonizes the bone marrow. We found that extracellular CyPA (eCyPA), secreted by bone marrow endothelial cells (BMECs), promoted the colonization and proliferation of MM cells in an in vivo scaffold system via binding to its receptor, CD147, on MM cells. The expression and secretion of eCyPA by BMECs was enhanced by BCL9, a Wnt-β-catenin transcriptional coactivator that is selectively expressed by these cells. eCyPA levels were higher in bone marrow serum than in peripheral blood in individuals with MM, and eCyPA-CD147 blockade suppressed MM colonization and tumor growth in the in vivo scaffold system. eCyPA also promoted the migration of chronic lymphocytic leukemia and lymphoplasmacytic lymphoma cells, two other B cell malignancies that colonize the bone marrow and express CD147. These findings suggest that eCyPA-CD147 signaling promotes the bone marrow homing of B cell malignancies and offer a compelling rationale for exploring this axis as a therapeutic target for these malignancies.", + "TAG_DATA": [ + "53, promoted {'effect': 'B-positive'}", + "57, proliferation {'phenotype': 'B-proliferation'}", + "59, MM {'context': 'B-transformed cells'}", + "60, cells {'context': 'I-transformed cells'}", + "63, in {'context': 'B-in vivo'}", + "64, vivo {'context': 'I-in vivo'}", + "65, scaffold {'context': 'I-in vivo'}", + "66, system {'context': 'I-tissue/organ'}", + "74, MM {'context': 'B-transformed cells'}", + "75, cells. {'context': 'I-transformed cells'}", + "118, suppressed {'effect': 'B-negative'}", + "119, MM {'context': 'B-cells'}", + "122, tumor {'phenotype': 'B-tumour growth'}", + "123, growth {'phenotype': 'I-tumour growth'}", + "126, in {'context': 'B-in vivo'}", + "127, vivo {'context': 'I-in vivo'}", + "132, promoted {'effect': 'B-positive'}", + "134, migration {'phenotype': 'B-migration'}", + "136, chronic {'context': 'B-neoplasm'}", + "137, lymphocytic {'context': 'I-neoplasm'}", + "138, leukemia {'context': 'I-neoplasm'}", + "139, and {'context': 'I-transformed cells'}", + "140, lymphoplasmacytic {'context': 'B-transformed cells'}", + "141, lymphoma {'context': 'I-transformed cells'}", + "142, cells, {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "53, promoted ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "57, proliferation ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "59, MM ['l1', 'l7', 'l12', 'l13', 'l14', 'l15', 'l16']", + "60, cells ['l2', 'l8', 'l12', 'l17', 'l18', 'l19']", + "63, in ['l3', 'l9', 'l13', 'l17', 'l20', 'l21', 'l22', 'l23', 'l24']", + "64, vivo ['l4', 'l10', 'l14', 'l18', 'l20', 'l25', 'l26', 'l27', 'l28']", + "65, scaffold ['l5', 'l15', 'l21', 'l25', 'l29', 'l30', 'l31']", + "66, system ['l6', 'l11', 'l16', 'l19', 'l22', 'l26', 'l29', 'l32', 'l33']", + "74, MM ['l23', 'l27', 'l30', 'l32', 'l34']", + "75, cells. ['l24', 'l28', 'l31', 'l33', 'l34']", + "118, suppressed ['l35', 'l36', 'l37', 'l38', 'l39']", + "119, MM ['l35', 'l40', 'l41', 'l42']", + "122, tumor ['l36', 'l40', 'l43', 'l44', 'l45']", + "123, growth ['l37', 'l41', 'l43']", + "126, in ['l38', 'l44', 'l46']", + "127, vivo ['l39', 'l42', 'l45', 'l46']", + "132, promoted ['l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "134, migration ['l47', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "136, chronic ['l48', 'l55', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "137, lymphocytic ['l49', 'l56', 'l62', 'l68', 'l69', 'l70', 'l71', 'l72']", + "138, leukemia ['l50', 'l57', 'l63', 'l68', 'l73', 'l74', 'l75', 'l76']", + "139, and ['l51', 'l58', 'l64', 'l69', 'l73', 'l77', 'l78', 'l79']", + "140, lymphoplasmacytic ['l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l80', 'l81']", + "141, lymphoma ['l53', 'l60', 'l66', 'l71', 'l75', 'l78', 'l80', 'l82']", + "142, cells, ['l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l81', 'l82']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MM", + "cells", + "and", + "lymphoplasmacytic", + "lymphoma", + "cells," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "scaffold" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "system" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MM", + "cells" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "system" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "cells", + "words": [ + "MM" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "MM" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "chronic", + "lymphocytic", + "leukemia" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "chronic", + "lymphocytic", + "leukemia" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "and", + "lymphoplasmacytic", + "lymphoma", + "cells," + ] + } + } + ] + }, + { + "PMID": "25985365", + "TEXT": "Pancreatic beta cell death is a hallmark of type 1 (T1D) and type 2 (T2D) diabetes, but the molecular mechanisms underlying this aspect of diabetic pathology are poorly understood. Here we report that expression of the microRNA (miR)-200 family is strongly induced in islets of diabetic mice and that beta cell-specific overexpression of miR-200 in mice is sufficient to induce beta cell apoptosis and lethal T2D. Conversely, mir-200 ablation in mice reduces beta cell apoptosis and ameliorates T2D. We show that miR-200 negatively regulates a conserved anti-apoptotic and stress-resistance network that includes the essential beta cell chaperone Dnajc3 (also known as p58IPK) and the caspase inhibitor Xiap. We also observed that mir-200 dosage positively controls activation of the tumor suppressor Trp53 and thereby creates a pro-apoptotic gene-expression signature found in islets of diabetic mice. Consequently, miR-200-induced T2D is suppressed by interfering with the signaling of Trp53 and Bax, a proapoptotic member of the B cell lymphoma 2 protein family. Our results reveal a crucial role for the miR-200 family in beta cell survival and the pathophysiology of diabetes.", + "TAG_DATA": [ + "45, diabetic {'context': 'B-organism'}", + "46, mice {'context': 'I-organism'}", + "49, beta {'perturbing_action': 'B-gene gain-of-function'}", + "50, cell-specific {'perturbing_action': 'I-gene gain-of-function'}", + "51, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "52, of {'perturbing_action': 'I-gene gain-of-function'}", + "53, miR-200 {'perturbing_action': 'I-gene gain-of-function'}", + "55, mice {'context': 'B-organism'}", + "59, induce {'effect': 'B-positive'}", + "60, beta {'context': 'B-cells'}", + "61, cell {'context': 'I-cells'}", + "62, apoptosis {'phenotype': 'B-apoptosis'}", + "67, mir-200 {'perturbing_action': 'B-gene loss-of-function'}", + "68, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "70, mice {'context': 'B-organism'}", + "71, reduces {'effect': 'B-negative'}", + "72, beta {'context': 'B-cells'}", + "73, cell {'context': 'I-cells'}", + "74, apoptosis {'phenotype': 'B-apoptosis'}", + "133, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "45, diabetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "46, mice ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "49, beta ['l1', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "50, cell-specific ['l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "51, overexpression ['l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "52, of ['l14', 'l23', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "53, miR-200 ['l15', 'l24', 'l32', 'l40', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "55, mice ['l2', 'l7', 'l16', 'l25', 'l33', 'l41', 'l49', 'l56', 'l57', 'l58', 'l59']", + "59, induce ['l3', 'l8', 'l17', 'l26', 'l34', 'l42', 'l50', 'l56', 'l60', 'l61', 'l62']", + "60, beta ['l4', 'l9', 'l18', 'l27', 'l35', 'l43', 'l51', 'l57', 'l60', 'l63', 'l64']", + "61, cell ['l5', 'l10', 'l19', 'l28', 'l36', 'l44', 'l52', 'l58', 'l61', 'l63', 'l65']", + "62, apoptosis ['l6', 'l11', 'l20', 'l29', 'l37', 'l45', 'l53', 'l59', 'l62', 'l64', 'l65']", + "67, mir-200 ['l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "68, ablation ['l66', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "70, mice ['l67', 'l73', 'l79', 'l80', 'l81', 'l82']", + "71, reduces ['l38', 'l46', 'l54', 'l68', 'l74', 'l79', 'l83', 'l84', 'l85']", + "72, beta ['l47', 'l69', 'l75', 'l80', 'l83', 'l86', 'l87']", + "73, cell ['l21', 'l30', 'l39', 'l48', 'l55', 'l70', 'l76', 'l81', 'l84', 'l86', 'l88']", + "74, apoptosis ['l71', 'l77', 'l82', 'l85', 'l87', 'l88']", + "133, mice. ['l72', 'l78']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "diabetic", + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "beta", + "cell-specific", + "overexpression", + "of", + "miR-200" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "diabetic", + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "diabetic", + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "beta", + "cell-specific", + "overexpression", + "of", + "miR-200" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "beta", + "cell-specific", + "overexpression", + "of", + "miR-200" + ] + }, + "context": { + "val": "cells", + "words": [ + "beta", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "beta", + "cell-specific", + "overexpression", + "of", + "miR-200" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "miR-200" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "beta", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "beta", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "mir-200", + "ablation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "mir-200", + "ablation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "mir-200", + "ablation" + ] + }, + "context": { + "val": "cells", + "words": [ + "beta", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "mir-200", + "ablation" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "context": { + "val": "cells", + "words": [ + "beta", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "25962121", + "TEXT": "Dysregulation of the actin cytoskeleton in podocytes represents a common pathway in the pathogenesis of proteinuria across a spectrum of chronic kidney diseases (CKD). The GTPase dynamin has been implicated in the maintenance of cellular architecture in podocytes through its direct interaction with actin. Furthermore, the propensity of dynamin to oligomerize into higher-order structures in an actin-dependent manner and to cross-link actin microfilaments into higher-order structures has been correlated with increased actin polymerization and global organization of the actin cytoskeleton in the cell. We found that use of the small molecule Bis-T-23, which promotes actin-dependent dynamin oligomerization and thus increased actin polymerization in injured podocytes, was sufficient to improve renal health in diverse models of both transient kidney disease and CKD. In particular, administration of Bis-T-23 in these renal disease models restored the normal ultrastructure of podocyte foot processes, lowered proteinuria, lowered collagen IV deposits in the mesangial matrix, diminished mesangial matrix expansion and extended lifespan. These results further establish that alterations in the actin cytoskeleton of kidney podocytes is a common hallmark of CKD, while also underscoring the substantial regenerative potential of injured glomeruli and identifying the oligomerization cycle of dynamin as an attractive potential therapeutic target to treat CKD.", + "TAG_DATA": [ + "104, podocytes, {'context': 'B-cells'}", + "136, podocyte {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25939062", + "TEXT": "Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood cancer. We performed a chemical screen in patient-derived DIPG cultures along with RNA-seq analyses and integrated computational modeling to identify potentially effective therapeutic strategies. The multi-histone deacetylase inhibitor panobinostat demonstrated therapeutic efficacy both in vitro and in DIPG orthotopic xenograft models. Combination testing of panobinostat and the histone demethylase inhibitor GSK-J4 revealed that the two had synergistic effects. Together, these data suggest a promising therapeutic strategy for DIPG.", + "TAG_DATA": [ + "42, in {'context': 'B-in vitro'}", + "43, vitro {'context': 'I-in vitro'}", + "46, DIPG {'context': 'B-xenograft'}", + "47, orthotopic {'context': 'I-xenograft'}", + "48, xenograft {'context': 'I-xenograft'}", + "49, models. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "42, in ['l0', 'l1', 'l2', 'l3']", + "43, vitro ['l0', 'l4', 'l5']", + "46, DIPG ['l6', 'l7', 'l8']", + "47, orthotopic ['l1', 'l6', 'l9', 'l10']", + "48, xenograft ['l2', 'l4', 'l7', 'l9', 'l11']", + "49, models. ['l3', 'l5', 'l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25894828", + "TEXT": "Gastric cancer, a leading cause of cancer-related deaths, is a heterogeneous disease. We aim to establish clinically relevant molecular subtypes that would encompass this heterogeneity and provide useful clinical information. We use gene expression data to describe four molecular subtypes linked to distinct patterns of molecular alterations, disease progression and prognosis. The mesenchymal-like type includes diffuse-subtype tumors with the worst prognosis, the tendency to occur at an earlier age and the highest recurrence frequency (63%) of the four subtypes. Microsatellite-unstable tumors are hyper-mutated intestinal-subtype tumors occurring in the antrum; these have the best overall prognosis and the lowest frequency of recurrence (22%) of the four subtypes. The tumor protein 53 (TP53)-active and TP53-inactive types include patients with intermediate prognosis and recurrence rates (with respect to the other two subtypes), with the TP53-active group showing better prognosis. We describe key molecular alterations in each of the four subtypes using targeted sequencing and genome-wide copy number microarrays. We validate these subtypes in independent cohorts in order to provide a consistent and unified framework for further clinical and preclinical translational research.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25894827", + "TEXT": "During an inflammatory response, lymphocyte recruitment into tissue must be tightly controlled because dysregulated trafficking contributes to the pathogenesis of chronic disease. Here we show that during inflammation and in response to adiponectin, B cells tonically inhibit T cell trafficking by secreting a peptide (PEPITEM) proteolytically derived from 14.3.3 zeta delta (14.3.3.ζδ) protein. PEPITEM binds cadherin-15 on endothelial cells, promoting synthesis and release of sphingosine-1 phosphate, which inhibits trafficking of T cells without affecting recruitment of other leukocytes. Expression of adiponectin receptors on B cells and adiponectin-induced PEPITEM secretion wanes with age, implying immune senescence of the pathway. Additionally, these changes are evident in individuals with type 1 diabetes or rheumatoid arthritis, and circulating PEPITEM in patient serum is reduced compared to that of healthy age-matched donors. In both diseases, tonic inhibition of T cell trafficking across inflamed endothelium is lost. Control of patient T cell trafficking is re-established by treatment with exogenous PEPITEM. Moreover, in animal models of peritonitis, hepatic ischemia-reperfusion injury, Salmonella infection, uveitis and Sjögren's syndrome, PEPITEM reduced T cell recruitment into inflamed tissues.", + "TAG_DATA": [ + "37, T {'context': 'B-cells'}", + "133, T {'context': 'B-cells'}", + "134, cell {'context': 'B-cells'}", + "138, endothelium {'context': 'I-tissue/organ'}", + "143, patient {'context': 'B-patient'}", + "144, T {'context': 'B-cells'}", + "145, cell {'context': 'B-cells'}", + "156, animal {'context': 'B-organism'}", + "157, models {'context': 'I-organism'}", + "171, T {'context': 'B-cells'}", + "172, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "133, T ['l0', 'l1', 'l2']", + "134, cell ['l0', 'l3', 'l4']", + "138, endothelium ['l1', 'l3', 'l5']", + "143, patient ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "144, T ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "145, cell ['l7', 'l12', 'l17', 'l18', 'l19']", + "156, animal ['l8', 'l13', 'l20', 'l21', 'l22']", + "157, models ['l9', 'l14', 'l17', 'l20', 'l23', 'l24']", + "171, T ['l10', 'l15', 'l18', 'l21', 'l23', 'l25']", + "172, cell ['l2', 'l4', 'l5', 'l11', 'l16', 'l19', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25849133", + "TEXT": "Metformin is a first-line therapeutic option for the treatment of type 2 diabetes, even though its underlying mechanisms of action are relatively unclear. Metformin lowers blood glucose levels by inhibiting hepatic glucose production (HGP), an effect originally postulated to be due to a hepatic AMP-activated protein kinase (AMPK)-dependent mechanism. However, studies have questioned the contribution of hepatic AMPK to the effects of metformin on lowering hyperglycemia, and a gut-brain-liver axis that mediates intestinal nutrient- and hormone-induced lowering of HGP has been identified. Thus, it is possible that metformin affects HGP through this inter-organ crosstalk. Here we show that intraduodenal infusion of metformin for 50 min activated duodenal mucosal Ampk and lowered HGP in a rat 3 d high fat diet (HFD)-induced model of insulin resistance. Inhibition of duodenal Ampk negated the HGP-lowering effect of intraduodenal metformin, and both duodenal glucagon-like peptide-1 receptor (Glp-1r)-protein kinase A (Pka) signaling and a neuronal-mediated gut-brain-liver pathway were required for metformin to lower HGP. Preabsorptive metformin also lowered HGP in rat models of 28 d HFD-induced obesity and insulin resistance and nicotinamide (NA)-streptozotocin (STZ)-HFD-induced type 2 diabetes. In an unclamped setting, inhibition of duodenal Ampk reduced the glucose-lowering effects of a bolus metformin treatment in rat models of diabetes. These findings show that, in rat models of both obesity and diabetes, metformin activates a previously unappreciated duodenal Ampk-dependent pathway to lower HGP and plasma glucose levels.", + "TAG_DATA": [ + "114, rat {'context': 'B-organism'}", + "125, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "126, of {'perturbing_action': 'I-pharmacological inhibition'}", + "127, duodenal {'perturbing_action': 'I-pharmacological inhibition'}", + "128, Ampk {'perturbing_action': 'I-pharmacological inhibition'}", + "165, rat {'context': 'B-organism'}", + "166, models {'context': 'I-organism'}", + "186, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "187, of {'perturbing_action': 'I-pharmacological inhibition'}", + "188, duodenal {'perturbing_action': 'I-pharmacological inhibition'}", + "189, Ampk {'perturbing_action': 'I-pharmacological inhibition'}", + "200, rat {'context': 'B-organism'}", + "201, models {'context': 'I-organism'}", + "202, of {'context': 'I-organism'}", + "203, diabetes. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "125, Inhibition ['l0', 'l1', 'l2', 'l3', 'l4']", + "126, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "127, duodenal ['l1', 'l5', 'l9', 'l10', 'l11']", + "128, Ampk ['l2', 'l6', 'l9', 'l12']", + "165, rat ['l3', 'l7', 'l10', 'l13']", + "166, models ['l4', 'l8', 'l11', 'l12', 'l13']", + "186, inhibition ['l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "187, of ['l14', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "188, duodenal ['l15', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "189, Ampk ['l16', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "200, rat ['l17', 'l23', 'l28', 'l32', 'l36', 'l37', 'l38']", + "201, models ['l18', 'l24', 'l29', 'l33', 'l36', 'l39', 'l40']", + "202, of ['l19', 'l25', 'l30', 'l34', 'l37', 'l39', 'l41']", + "203, diabetes. ['l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "duodenal", + "Ampk", + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "rat", + "models", + "of", + "diabetes." + ] + } + } + ] + }, + { + "PMID": "25751817", + "TEXT": "Cardiac healing after myocardial ischemia depends on the recruitment and local expansion of myeloid cells, particularly macrophages. Here we identify Reg3β as an essential regulator of macrophage trafficking to the damaged heart. Using mass spectrometry-based secretome analysis, we found that dedifferentiating cardiomyocytes release Reg3β in response to the cytokine OSM, which signals through Jak1 and Stat3. Loss of Reg3β led to a large decrease in the number of macrophages in the ischemic heart, accompanied by increased ventricular dilatation and insufficient removal of neutrophils. This defect in neutrophil removal in turn caused enhanced matrix degradation, delayed collagen deposition and increased susceptibility to cardiac rupture. Our data indicate that OSM, acting through distinct intracellular pathways, regulates both cardiomyocyte dedifferentiation and cardiomyocyte-dependent regulation of macrophage trafficking. Release of OSM from infiltrating neutrophils and macrophages initiates a positive feedback loop in which OSM-induced production of Reg3β in cardiomyocytes attracts additional OSM-secreting macrophages. The activity of the feedback loop controls the degree of macrophage accumulation in the heart, which is instrumental in myocardial healing.", + "TAG_DATA": [ + "41, cardiomyocytes {'context': 'I-cells'}", + "56, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "57, of {'perturbing_action': 'I-gene loss-of-function'}", + "58, Reg3β {'perturbing_action': 'I-gene loss-of-function'}", + "68, macrophages {'context': 'B-cells'}", + "72, heart, {'context': 'B-tissue/organ'}", + "143, cardiomyocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "41, cardiomyocytes ['l0', 'l1', 'l2', 'l3', 'l4']", + "56, Loss ['l0', 'l5', 'l6', 'l7', 'l8']", + "57, of ['l1', 'l5', 'l9', 'l10', 'l11']", + "58, Reg3β ['l2', 'l6', 'l9', 'l12', 'l13']", + "68, macrophages ['l3', 'l7', 'l10', 'l12', 'l14']", + "72, heart, ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cardiomyocytes", + "macrophages" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Loss", + "of", + "Reg3β" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Loss", + "of", + "Reg3β" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "heart," + ] + } + } + ] + }, + { + "PMID": "25706873", + "TEXT": "Metabolic reprogramming occurs in response to the cellular environment to mediate differentiation, but the fundamental mechanisms linking metabolic processes to differentiation programs remain to be elucidated. During osteoclast differentiation, a shift toward more oxidative metabolic processes occurs. In this study we identified the de novo DNA methyltransferase 3a (Dnmt3a) as a transcription factor that couples these metabolic changes to osteoclast differentiation. We also found that receptor activator of nuclear factor-κB ligand (RANKL), an essential cytokine for osteoclastogenesis, induces this metabolic shift towards oxidative metabolism, which is accompanied by an increase in S-adenosylmethionine (SAM) production. We found that SAM-mediated DNA methylation by Dnmt3a regulates osteoclastogenesis via epigenetic repression of anti-osteoclastogenic genes. The importance of Dnmt3a in bone homeostasis was underscored by the observations that Dnmt3a-deficient osteoclast precursor cells do not differentiate efficiently into osteoclasts and that mice with an osteoclast-specific deficiency in Dnmt3a have elevated bone mass due to a smaller number of osteoclasts. Furthermore, inhibition of DNA methylation by theaflavin-3,3'-digallate abrogated bone loss in models of osteoporosis. Thus, this study reveals the role of epigenetic processes in the regulation of cellular metabolism and differentiation, which may provide the molecular basis for a new therapeutic strategy for a variety of bone disorders.", + "TAG_DATA": [ + "123, Dnmt3a-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "124, osteoclast {'context': 'B-cells'}", + "125, precursor {'context': 'I-cells'}", + "126, cells {'context': 'I-cells'}", + "127, do {'effect': 'B-negative'}", + "128, not {'effect': 'I-no effect'}", + "129, differentiate {'phenotype': 'B-differentiation'}", + "135, mice {'context': 'B-organism'}", + "138, osteoclast-specific {'perturbing_action': 'B-gene loss-of-function'}", + "139, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "140, in {'perturbing_action': 'I-gene loss-of-function'}", + "141, Dnmt3a {'perturbing_action': 'I-gene loss-of-function'}", + "152, osteoclasts. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "123, Dnmt3a-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "124, osteoclast ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "125, precursor ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "126, cells ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "127, do ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "128, not ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "129, differentiate ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "135, mice ['l21', 'l22', 'l23', 'l24', 'l25']", + "138, osteoclast-specific ['l21', 'l26', 'l27', 'l28', 'l29']", + "139, deficiency ['l22', 'l26', 'l30', 'l31', 'l32']", + "140, in ['l23', 'l27', 'l30', 'l33', 'l34']", + "141, Dnmt3a ['l24', 'l28', 'l31', 'l33', 'l35']", + "152, osteoclasts. ['l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dnmt3a-deficient", + "osteoclast-specific", + "deficiency", + "in", + "Dnmt3a" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast", + "precursor", + "cells", + "osteoclasts." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dnmt3a-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "do" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dnmt3a-deficient" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dnmt3a-deficient" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoclast", + "precursor", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "do" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoclast", + "precursor", + "cells" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoclast", + "precursor", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "do" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "osteoclast-specific", + "deficiency", + "in", + "Dnmt3a" + ] + } + } + ] + }, + { + "PMID": "25686105", + "TEXT": "The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1β (IL-1β) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease.", + "TAG_DATA": [ + "52, MCC950, {'perturbing_action': 'B-pharmacological inhibition'}", + "58, of {'perturbing_action': 'I-pharmacological inhibition'}", + "89, in {'context': 'B-in vivo'}", + "90, vivo {'context': 'I-in vivo'}", + "114, mouse {'context': 'B-organism'}", + "115, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "52, MCC950, ['l0']", + "58, of ['l0']", + "89, in ['l1']", + "90, vivo ['l1']", + "114, mouse ['l2']", + "115, model ['l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25581518", + "TEXT": "Paracrine-acting proteins are emerging as a central mechanism by which bone marrow cell-based therapies improve tissue repair and heart function after myocardial infarction (MI). We carried out a bioinformatic secretome analysis in bone marrow cells from patients with acute MI to identify novel secreted proteins with therapeutic potential. Functional screens revealed a secreted protein encoded by an open reading frame on chromosome 19 (C19orf10) that promotes cardiac myocyte survival and angiogenesis. We show that bone marrow-derived monocytes and macrophages produce this protein endogenously to protect and repair the heart after MI, and we named it myeloid-derived growth factor (MYDGF). Whereas Mydgf-deficient mice develop larger infarct scars and more severe contractile dysfunction compared to wild-type mice, treatment with recombinant Mydgf reduces scar size and contractile dysfunction after MI. This study is the first to assign a biological function to MYDGF, and it may serve as a prototypical example for the development of protein-based therapies for ischemic tissue repair.", + "TAG_DATA": [ + "100, Mydgf-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "101, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "100, Mydgf-deficient ['l0']", + "101, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mydgf-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "25501907", + "TEXT": "A key determinant of geriatric frailty is sarcopenia, the age-associated loss of skeletal muscle mass and strength. Although the etiology of sarcopenia is unknown, the correlation during aging between the loss of activity of satellite cells, which are endogenous muscle stem cells, and impaired muscle regenerative capacity has led to the hypothesis that the loss of satellite cell activity is also a cause of sarcopenia. We tested this hypothesis in male sedentary mice by experimentally depleting satellite cells in young adult animals to a degree sufficient to impair regeneration throughout the rest of their lives. A detailed analysis of multiple muscles harvested at various time points during aging in different cohorts of these mice showed that the muscles were of normal size, despite low regenerative capacity, but did have increased fibrosis. These results suggest that lifelong reduction of satellite cells neither accelerated nor exacerbated sarcopenia and that satellite cells did not contribute to the maintenance of muscle size or fiber type composition during aging, but that their loss may contribute to age-related muscle fibrosis.", + "TAG_DATA": [ + "70, male {'context': 'B-organism'}", + "71, sedentary {'context': 'I-organism'}", + "72, mice {'context': 'I-organism'}", + "76, satellite {'context': 'B-cells'}", + "77, cells {'context': 'I-cells'}", + "79, young {'context': 'B-organism'}", + "80, adult {'context': 'I-organism'}", + "81, animals {'context': 'I-organism'}", + "113, mice {'context': 'B-organism'}", + "117, muscles {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "70, male ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "71, sedentary ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "72, mice ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "76, satellite ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "77, cells ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "79, young ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "80, adult ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "81, animals ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "113, mice ['l28']", + "117, muscles ['l28']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25485910", + "TEXT": "Activating mutations in genes encoding G protein α (Gα) subunits occur in 4-5% of all human cancers, but oncogenic alterations in Gβ subunits have not been defined. Here we demonstrate that recurrent mutations in the Gβ proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling. Multiple mutations in GNB1 affect the protein interface that binds Gα subunits as well as downstream effectors and disrupt Gα interactions with the Gβγ dimer. Different mutations in Gβ proteins clustered partly on the basis of lineage; for example, all 11 GNB1 K57 mutations were in myeloid neoplasms, and seven of eight GNB1 I80 mutations were in B cell neoplasms. Expression of patient-derived GNB1 variants in Cdkn2a-deficient mouse bone marrow followed by transplantation resulted in either myeloid or B cell malignancies. In vivo treatment with the dual PI3K-mTOR inhibitor BEZ235 suppressed GNB1-induced signaling and markedly increased survival. In several human tumors, mutations in the gene encoding GNB1 co-occurred with oncogenic kinase alterations, including the BCR-ABL fusion protein, the V617F substitution in JAK2 and the V600K substitution in BRAF. Coexpression of patient-derived GNB1 variants with these mutant kinases resulted in inhibitor resistance in each context. Thus, GNB1 and GNB2 alterations confer transformed and resistance phenotypes across a range of human tumors and may be targetable with inhibitors of G protein signaling.", + "TAG_DATA": [ + "110, of {'perturbing_action': 'I-other'}", + "111, patient-derived {'perturbing_action': 'I-other'}", + "112, GNB1 {'perturbing_action': 'I-other'}", + "113, variants {'perturbing_action': 'I-other'}", + "115, Cdkn2a-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "116, mouse {'context': 'B-tissue/organ'}", + "117, bone {'context': 'I-tissue/organ'}", + "118, marrow {'context': 'I-tissue/organ'}", + "125, myeloid {'context': 'B-neoplasm'}", + "126, or {'context': 'I-neoplasm'}", + "127, B {'context': 'I-neoplasm'}", + "128, cell {'context': 'I-neoplasm'}", + "129, malignancies. {'context': 'I-neoplasm'}", + "130, In {'context': 'B-in vivo'}", + "131, vivo {'context': 'I-in vivo'}", + "135, dual {'perturbing_action': 'I-pharmacological inhibition'}", + "136, PI3K-mTOR {'perturbing_action': 'I-pharmacological inhibition'}", + "137, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "138, BEZ235 {'perturbing_action': 'I-pharmacological inhibition'}", + "148, human {'context': 'B-neoplasm'}", + "177, Coexpression {'perturbing_action': 'B-gene gain-of-function'}", + "178, of {'perturbing_action': 'I-other'}", + "179, patient-derived {'perturbing_action': 'I-other'}", + "180, GNB1 {'perturbing_action': 'I-other'}", + "181, variants {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "109, Expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "110, of ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "111, patient-derived ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "112, GNB1 ['l2', 'l16', 'l29', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "113, variants ['l3', 'l17', 'l30', 'l42', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "115, Cdkn2a-deficient ['l4', 'l18', 'l31', 'l43', 'l54', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "116, mouse ['l5', 'l19', 'l32', 'l44', 'l55', 'l65', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "117, bone ['l6', 'l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "118, marrow ['l7', 'l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l82', 'l88', 'l89', 'l90', 'l91', 'l92']", + "125, myeloid ['l8', 'l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l83', 'l88', 'l93', 'l94', 'l95', 'l96']", + "126, or ['l9', 'l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l84', 'l89', 'l93', 'l97', 'l98', 'l99']", + "127, B ['l10', 'l24', 'l37', 'l49', 'l60', 'l70', 'l79', 'l85', 'l90', 'l94', 'l97', 'l100', 'l101']", + "128, cell ['l11', 'l25', 'l38', 'l50', 'l61', 'l71', 'l80', 'l86', 'l91', 'l95', 'l98', 'l100', 'l102']", + "129, malignancies. ['l12', 'l26', 'l39', 'l51', 'l62', 'l72', 'l81', 'l87', 'l92', 'l96', 'l99', 'l101', 'l102']", + "130, In ['l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "131, vivo ['l103', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "135, dual ['l104', 'l110', 'l116', 'l117', 'l118', 'l119', 'l120']", + "136, PI3K-mTOR ['l105', 'l111', 'l116', 'l121', 'l122', 'l123', 'l124']", + "137, inhibitor ['l106', 'l112', 'l117', 'l121', 'l125', 'l126', 'l127']", + "138, BEZ235 ['l107', 'l113', 'l118', 'l122', 'l125', 'l128', 'l129']", + "148, human ['l13', 'l27', 'l40', 'l52', 'l63', 'l73', 'l108', 'l114', 'l119', 'l123', 'l126', 'l128', 'l130']", + "149, tumors, ['l14', 'l28', 'l41', 'l53', 'l64', 'l74', 'l109', 'l115', 'l120', 'l124', 'l127', 'l129', 'l130']", + "177, Coexpression ['l131', 'l132', 'l133', 'l134']", + "178, of ['l131', 'l135', 'l136', 'l137']", + "179, patient-derived ['l132', 'l135', 'l138', 'l139']", + "180, GNB1 ['l133', 'l136', 'l138', 'l140']", + "181, variants ['l134', 'l137', 'l139', 'l140']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "of", + "patient-derived", + "GNB1", + "variants" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "bone", + "marrow" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "of", + "patient-derived", + "GNB1", + "variants" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "myeloid", + "or", + "B", + "cell", + "malignancies.", + "human" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cdkn2a-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "bone", + "marrow" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cdkn2a-deficient" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "myeloid", + "or", + "B", + "cell", + "malignancies.", + "human" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "dual", + "PI3K-mTOR", + "inhibitor", + "BEZ235" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "dual", + "PI3K-mTOR", + "inhibitor", + "BEZ235" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human" + ] + } + } + ] + }, + { + "PMID": "25419708", + "TEXT": "α4β7 integrin-expressing CD4(+) T cells preferentially traffic to gut-associated lymphoid tissue (GALT) and have a key role in HIV and simian immunodeficiency virus (SIV) pathogenesis. We show here that the administration of an anti-α4β7 monoclonal antibody just prior to and during acute infection protects rhesus macaques from transmission following repeated low-dose intravaginal challenges with SIVmac251. In treated animals that became infected, the GALT was significantly protected from infection and CD4(+) T cell numbers were maintained in both the blood and the GALT. Thus, targeting α4β7 reduces mucosal transmission of SIV in macaques.", + "TAG_DATA": [ + "44, rhesus {'context': 'B-organism'}", + "45, macaques {'context': 'I-organism'}", + "57, animals {'context': 'B-organism'}", + "62, GALT {'context': 'B-tissue/organ'}", + "69, CD4(+) {'context': 'B-cells'}", + "70, T {'context': 'I-cells'}", + "71, cell {'context': 'I-cells'}", + "83, targeting {'perturbing_action': 'B-other'}", + "84, α4β7 {'perturbing_action': 'I-other'}", + "91, macaques. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "44, rhesus ['l0']", + "45, macaques ['l0']", + "57, animals ['l1', 'l2', 'l3', 'l4']", + "62, GALT ['l1', 'l5', 'l6', 'l7']", + "69, CD4(+) ['l2', 'l5', 'l8', 'l9']", + "70, T ['l3', 'l6', 'l8', 'l10']", + "71, cell ['l4', 'l7', 'l9', 'l10']", + "83, targeting ['l11', 'l12']", + "84, α4β7 ['l11', 'l13']", + "91, macaques. ['l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "targeting", + "α4β7" + ] + }, + "context": { + "val": "organism", + "words": [ + "macaques." + ] + } + } + ] + }, + { + "PMID": "25344739", + "TEXT": "Lymph node biopsy is employed in many cancer surgeries to identify metastatic disease and to determine cancer stage, yet morbidity and diagnostic delays associated with lymph node biopsy could be avoided if noninvasive imaging of nodal involvement were reliable. Molecular imaging has potential in this regard; however, variable delivery and nonspecific uptake of imaging tracers have made conventional approaches ineffective clinically. Here we present a method of correcting for nonspecific uptake with injection of a second untargeted tracer that allows for quantification of tumor burden in lymph nodes. We confirmed the approach in an athymic mouse model of metastatic human breast cancer by targeting epidermal growth factor receptor, a cell surface receptor overexpressed by many cancers. We observed a significant correlation between in vivo (dual-tracer) and ex vivo measures of tumor burden (r = 0.97, P < 0.01), with an ultimate sensitivity of approximately 200 cells (potentially more sensitive than conventional lymph node biopsy).", + "TAG_DATA": [ + "94, athymic {'context': 'B-organism'}", + "95, mouse {'context': 'I-organism'}", + "96, model {'context': 'I-neoplasm'}", + "97, of {'context': 'I-neoplasm'}", + "98, metastatic {'context': 'I-neoplasm'}", + "99, human {'context': 'I-neoplasm'}", + "100, breast {'context': 'I-neoplasm'}", + "101, cancer {'context': 'I-neoplasm'}", + "105, growth {'perturbing_action': 'I-rnai/knockdown'}", + "106, factor {'perturbing_action': 'I-rnai/knockdown'}", + "107, receptor, {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "94, athymic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "95, mouse ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "96, model ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "97, of ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "98, metastatic ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "99, human ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "100, breast ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "101, cancer ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "104, epidermal ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "105, growth ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "106, factor ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "107, receptor, ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "athymic", + "mouse" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "growth", + "factor", + "receptor," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "model", + "of", + "metastatic", + "human", + "breast", + "cancer" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "growth", + "factor", + "receptor," + ] + } + } + ] + }, + { + "PMID": "25326803", + "TEXT": "Differentiation of human pluripotent stem cells (hPSCs) into organ-specific subtypes offers an exciting avenue for the study of embryonic development and disease processes, for pharmacologic studies and as a potential resource for therapeutic transplant. To date, limited in vivo models exist for human intestine, all of which are dependent upon primary epithelial cultures or digested tissue from surgical biopsies that include mesenchymal cells transplanted on biodegradable scaffolds. Here, we generated human intestinal organoids (HIOs) produced in vitro from human embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) that can engraft in vivo. These HIOs form mature human intestinal epithelium with intestinal stem cells contributing to the crypt-villus architecture and a laminated human mesenchyme, both supported by mouse vasculature ingrowth. In vivo transplantation resulted in marked expansion and maturation of the epithelium and mesenchyme, as demonstrated by differentiated intestinal cell lineages (enterocytes, goblet cells, Paneth cells, tuft cells and enteroendocrine cells), presence of functional brush-border enzymes (lactase, sucrase-isomaltase and dipeptidyl peptidase 4) and visible subepithelial and smooth muscle layers when compared with HIOs in vitro. Transplanted intestinal tissues demonstrated digestive functions as shown by permeability and peptide uptake studies. Furthermore, transplanted HIO-derived tissue was responsive to systemic signals from the host mouse following ileocecal resection, suggesting a role for circulating factors in the intestinal adaptive response. This model of the human small intestine may pave the way for studies of intestinal physiology, disease and translational studies.", + "TAG_DATA": [ + "75, in {'context': 'B-in vitro'}", + "76, vitro {'context': 'I-in vitro'}", + "78, human {'context': 'B-cells'}", + "79, embryonic {'context': 'I-cells'}", + "80, stem {'context': 'I-cells'}", + "81, cells {'context': 'I-cells'}", + "82, (ESCs) {'context': 'I-cells'}", + "84, induced {'context': 'B-cells'}", + "85, pluripotent {'context': 'I-cells'}", + "86, stem {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}", + "92, in {'context': 'B-in vivo'}", + "93, vivo. {'context': 'I-in vivo'}", + "121, In {'context': 'B-in vivo'}", + "122, vivo {'context': 'I-in vivo'}", + "132, epithelium {'context': 'B-tissue/organ'}", + "134, mesenchyme, {'context': 'B-tissue/organ'}", + "140, cell {'context': 'I-cells'}", + "174, in {'context': 'B-in vitro'}", + "175, vitro. {'context': 'I-in vitro'}", + "177, intestinal {'context': 'B-tissue/organ'}", + "178, tissues {'context': 'I-tissue/organ'}", + "192, HIO-derived {'context': 'B-organoid'}", + "193, tissue {'context': 'I-tissue/organ'}", + "202, mouse {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "70, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "71, intestinal ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "75, in ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "76, vitro ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "78, human ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "79, embryonic ['l4', 'l11', 'l17', 'l22', 'l26', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "80, stem ['l5', 'l12', 'l18', 'l23', 'l27', 'l37', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "81, cells ['l6', 'l13', 'l19', 'l24', 'l28', 'l38', 'l48', 'l56', 'l57', 'l58', 'l59']", + "82, (ESCs) ['l7', 'l14', 'l20', 'l25', 'l29', 'l39', 'l49', 'l56', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "84, induced ['l30', 'l40', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "85, pluripotent ['l66', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "86, stem ['l31', 'l41', 'l50', 'l60', 'l67', 'l77', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "87, cells ['l32', 'l42', 'l51', 'l57', 'l61', 'l68', 'l78', 'l88', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "92, in ['l33', 'l43', 'l52', 'l58', 'l62', 'l69', 'l79', 'l89', 'l98', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "93, vivo. ['l34', 'l44', 'l53', 'l59', 'l63', 'l70', 'l80', 'l90', 'l99', 'l105', 'l111', 'l112', 'l113', 'l114']", + "121, In ['l81', 'l91', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "122, vivo ['l71', 'l82', 'l92', 'l115', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "132, epithelium ['l72', 'l83', 'l93', 'l100', 'l106', 'l111', 'l116', 'l123', 'l130', 'l131', 'l132', 'l133']", + "134, mesenchyme, ['l45', 'l73', 'l84', 'l94', 'l101', 'l107', 'l112', 'l117', 'l124', 'l130', 'l134', 'l135', 'l136']", + "139, intestinal ['l74', 'l85', 'l95', 'l102', 'l108', 'l118', 'l125', 'l131', 'l134', 'l137', 'l138']", + "140, cell ['l35', 'l46', 'l54', 'l64', 'l75', 'l86', 'l96', 'l103', 'l109', 'l113', 'l119', 'l126', 'l132', 'l135', 'l137', 'l139']", + "141, lineages ['l36', 'l47', 'l55', 'l65', 'l76', 'l87', 'l97', 'l104', 'l110', 'l114', 'l120', 'l127', 'l133', 'l136', 'l138', 'l139']", + "174, in ['l121', 'l128', 'l140']", + "175, vitro. ['l122', 'l129', 'l140']", + "177, intestinal ['l141', 'l142']", + "178, tissues ['l141']", + "192, HIO-derived ['l143', 'l144']", + "193, tissue ['l143', 'l145']", + "202, mouse ['l142', 'l144', 'l145']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25326800", + "TEXT": "Neurofibrillary tangles (NFTs), composed of truncated and hyperphosphorylated tau, are a common feature of numerous aging-related neurodegenerative diseases, including Alzheimer's disease (AD). However, the molecular mechanisms mediating tau truncation and aggregation during aging remain elusive. Here we show that asparagine endopeptidase (AEP), a lysosomal cysteine proteinase, is activated during aging and proteolytically degrades tau, abolishes its microtubule assembly function, induces tau aggregation and triggers neurodegeneration. AEP is upregulated and active during aging and is activated in human AD brain and tau P301S-transgenic mice with synaptic pathology and behavioral impairments, leading to tau truncation in NFTs. Tau P301S-transgenic mice with deletion of the gene encoding AEP show substantially reduced tau hyperphosphorylation, less synapse loss and rescue of impaired hippocampal synaptic function and cognitive deficits. Mice infected with adeno-associated virus encoding an uncleavable tau mutant showed attenuated pathological and behavioral defects compared to mice injected with adeno-associated virus encoding tau P301S. Together, these observations indicate that AEP acts as a crucial mediator of tau-related clinical and neuropathological changes. Inhibition of AEP may be therapeutically useful for treating tau-mediated neurodegenerative diseases.", + "TAG_DATA": [ + "80, tau {'perturbing_action': 'B-gene gain-of-function'}", + "81, P301S-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "82, mice {'context': 'B-organism'}", + "95, Tau {'perturbing_action': 'B-gene gain-of-function'}", + "96, P301S-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "97, mice {'context': 'B-organism'}", + "99, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "100, of {'perturbing_action': 'I-gene loss-of-function'}", + "101, the {'perturbing_action': 'I-gene loss-of-function'}", + "102, gene {'perturbing_action': 'I-gene loss-of-function'}", + "103, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "104, AEP {'perturbing_action': 'I-gene loss-of-function'}", + "123, Mice {'context': 'B-organism'}", + "141, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "80, tau ['l0', 'l1']", + "81, P301S-transgenic ['l0', 'l2']", + "82, mice ['l1', 'l2']", + "95, Tau ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "96, P301S-transgenic ['l3', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "97, mice ['l4', 'l11', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "99, deletion ['l5', 'l12', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "100, of ['l6', 'l13', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32']", + "101, the ['l7', 'l14', 'l20', 'l25', 'l29', 'l33', 'l34', 'l35']", + "102, gene ['l8', 'l15', 'l21', 'l26', 'l30', 'l33', 'l36', 'l37']", + "103, encoding ['l9', 'l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l38']", + "104, AEP ['l10', 'l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l38']", + "123, Mice ['l39']", + "141, mice ['l39']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "tau", + "P301S-transgenic", + "Tau" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "gene", + "encoding", + "AEP" + ] + } + } + ] + }, + { + "PMID": "25295935", + "TEXT": "Altered stem cell homeostasis underlies functional tissue decline during muscle aging and disease progression. Janus kinase–signal transducer and activator of transcription (JAK-STAT) signal transduction is a crucial regulator of muscle regeneration, and targeting this pathway in mice relieves aspects of debilitating muscle wasting.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25261994", + "TEXT": "Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months. PDAC has been linked with obesity and glucose intolerance, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from individuals with pancreatic cancer (cases) and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched-chain amino acids (BCAAs) are associated with a greater than twofold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years before diagnosis, when occult disease is probably present. We show that plasma BCAAs are also elevated in mice with early-stage pancreatic cancers driven by mutant Kras expression but not in mice with Kras-driven tumors in other tissues, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early-stage disease. Together, these findings suggest that increased whole-body protein breakdown is an early event in development of PDAC.", + "TAG_DATA": [ + "135, mice {'context': 'B-organism'}", + "137, early-stage {'context': 'B-neoplasm'}", + "138, pancreatic {'context': 'I-neoplasm'}", + "139, cancers {'context': 'I-neoplasm'}", + "142, mutant {'perturbing_action': 'B-other'}", + "143, Kras {'perturbing_action': 'I-other'}", + "144, expression {'perturbing_action': 'I-other'}", + "148, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "135, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "137, early-stage ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "138, pancreatic ['l1', 'l7', 'l12', 'l13', 'l14', 'l15']", + "139, cancers ['l2', 'l8', 'l12', 'l16', 'l17', 'l18']", + "142, mutant ['l3', 'l9', 'l13', 'l16', 'l19', 'l20', 'l21', 'l22']", + "143, Kras ['l4', 'l10', 'l14', 'l17', 'l19', 'l23', 'l24', 'l25']", + "144, expression ['l5', 'l11', 'l15', 'l18', 'l20', 'l23', 'l26', 'l27']", + "148, mice ['l21', 'l24', 'l26', 'l28']", + "151, tumors ['l6', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "Kras", + "expression" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "early-stage", + "pancreatic", + "cancers" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "Kras", + "expression" + ] + } + } + ] + }, + { + "PMID": "25216636", + "TEXT": "Astrocytes have complex roles in health and disease, thus it is important to study the pathways that regulate their function. Here we report that lactosylceramide (LacCer) synthesized by β-1,4-galactosyltransferase 6 (B4GALT6) is upregulated in the central nervous system (CNS) of mice during chronic experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). LacCer acts in an autocrine manner to control astrocyte transcriptional programs that promote neurodegeneration. In addition, LacCer in astrocytes controls the recruitment and activation of microglia and CNS-infiltrating monocytes in a non-cell autonomous manner by regulating production of the chemokine CCL2 and granulocyte-macrophage colony-stimulating factor (GM-CSF), respectively. We also detected high B4GALT6 gene expression and LacCer concentrations in CNS MS lesions. Inhibition of LacCer synthesis in mice suppressed local CNS innate immunity and neurodegeneration in EAE and interfered with the activation of human astrocytes in vitro. Thus, B4GALT6 regulates astrocyte activation and is a potential therapeutic target for MS and other neuroinflammatory disorders.", + "TAG_DATA": [ + "119, mice {'context': 'B-organism'}", + "135, human {'context': 'B-cells'}", + "136, astrocytes {'context': 'I-cells'}", + "137, in {'context': 'B-in vitro'}", + "138, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "119, mice ['l0', 'l1']", + "135, human ['l0', 'l2', 'l3', 'l4']", + "136, astrocytes ['l1', 'l2', 'l5', 'l6']", + "137, in ['l3', 'l5', 'l7']", + "138, vitro. ['l4', 'l6', 'l7']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25198046", + "TEXT": "Aging and a high-fat diet are predisposing factors for type 2 diabetes. A study in mice suggests that dietary fat and aging lead to atypical transforming growth factor-β1 signaling in the hypothalamus, which disturbs whole-body glucose regulation.", + "TAG_DATA": [ + "15, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "15, mice ['l0']", + "31, hypothalamus, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25198045", + "TEXT": "Disrupted differentiation of Schwann cells contributes to axonal loss in a rat model of Charcot-Marie-Tooth 1A neuropathy. Early neuregulin-1 treatment promotes Schwann cell differentiation, preserves axons and restores nerve function in this model.", + "TAG_DATA": [ + "20, promotes {'effect': 'B-positive'}", + "21, Schwann {'context': 'B-cells'}", + "22, cell {'context': 'I-cells'}", + "23, differentiation, {'phenotype': 'B-differentiation'}", + "25, axons {'context': 'B-cells'}", + "28, nerve {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "20, promotes ['l0', 'l1', 'l2', 'l3', 'l4']", + "21, Schwann ['l0', 'l5', 'l6', 'l7', 'l8']", + "22, cell ['l1', 'l5', 'l9', 'l10', 'l11']", + "23, differentiation, ['l2', 'l6', 'l9', 'l12', 'l13']", + "25, axons ['l3', 'l7', 'l10', 'l12', 'l14']", + "28, nerve ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "cells", + "words": [ + "Schwann", + "cell", + "axons" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "nerve" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Schwann", + "cell", + "axons" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "nerve" + ] + } + } + ] + }, + { + "PMID": "25194569", + "TEXT": "Diminished regenerative capacity of skeletal muscle occurs during adulthood. We identified a reduction in the intrinsic capacity of mouse adult satellite cells to contribute to muscle regeneration and repopulation of the niche. Gene expression analysis identified higher expression of JAK-STAT signaling targets in 3-week [corrected] 18-month-old mice [corrected]. Knockdown of Jak2 or Stat3 significantly stimulated symmetric satellite stem cell divisions on cultured myofibers. Genetic knockdown of Jak2 or Stat3 expression in prospectively isolated satellite cells markedly enhanced their ability to repopulate the satellite cell niche after transplantation into regenerating tibialis anterior muscle. Pharmacological inhibition of Jak2 and Stat3 activity similarly stimulated symmetric expansion of satellite cells in vitro and their engraftment in vivo. Intramuscular injection of these drugs resulted in a marked enhancement of muscle repair and force generation after cardiotoxin injury. Together these results reveal age-related intrinsic properties that functionally distinguish satellite cells and suggest a promising therapeutic avenue for the treatment of muscle-wasting diseases.", + "TAG_DATA": [ + "48, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "49, of {'perturbing_action': 'I-rnai/knockdown'}", + "50, Jak2 {'perturbing_action': 'I-rnai/knockdown'}", + "51, or {'perturbing_action': 'I-rnai/knockdown'}", + "52, Stat3 {'perturbing_action': 'I-rnai/knockdown'}", + "56, satellite {'context': 'B-cells'}", + "57, stem {'context': 'I-cells'}", + "58, cell {'context': 'I-cells'}", + "61, cultured {'context': 'B-cells'}", + "62, myofibers. {'context': 'I-cells'}", + "63, Genetic {'perturbing_action': 'B-rnai/knockdown'}", + "64, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "65, of {'perturbing_action': 'I-rnai/knockdown'}", + "66, Jak2 {'perturbing_action': 'I-rnai/knockdown'}", + "67, or {'perturbing_action': 'I-rnai/knockdown'}", + "68, Stat3 {'perturbing_action': 'I-rnai/knockdown'}", + "69, expression {'perturbing_action': 'I-rnai/knockdown'}", + "73, satellite {'context': 'B-cells'}", + "74, cells {'context': 'I-cells'}", + "88, regenerating {'context': 'B-tissue/organ'}", + "89, tibialis {'context': 'I-tissue/organ'}", + "90, anterior {'context': 'I-tissue/organ'}", + "91, muscle. {'context': 'I-tissue/organ'}", + "92, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "93, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "94, of {'perturbing_action': 'I-pharmacological inhibition'}", + "95, Jak2 {'perturbing_action': 'I-pharmacological inhibition'}", + "96, and {'perturbing_action': 'I-pharmacological inhibition'}", + "97, Stat3 {'perturbing_action': 'I-pharmacological inhibition'}", + "98, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "104, satellite {'context': 'B-cells'}", + "105, cells {'context': 'I-cells'}", + "106, in {'context': 'B-in vitro'}", + "107, vitro {'context': 'I-in vitro'}", + "111, in {'context': 'B-in vivo'}", + "112, vivo. {'context': 'I-in vivo'}", + "124, muscle {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "48, Knockdown ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "49, of ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "50, Jak2 ['l1', 'l15', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "51, or ['l2', 'l16', 'l31', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "52, Stat3 ['l3', 'l17', 'l32', 'l47', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "56, satellite ['l4', 'l18', 'l33', 'l48', 'l59', 'l70', 'l71', 'l72', 'l73']", + "57, stem ['l5', 'l19', 'l34', 'l49', 'l60', 'l70', 'l74', 'l75', 'l76']", + "58, cell ['l6', 'l20', 'l35', 'l50', 'l61', 'l71', 'l74', 'l77', 'l78']", + "61, cultured ['l7', 'l21', 'l36', 'l51', 'l62', 'l72', 'l75', 'l77', 'l79', 'l80', 'l81', 'l82']", + "62, myofibers. ['l8', 'l22', 'l37', 'l52', 'l63', 'l73', 'l76', 'l78', 'l79', 'l83', 'l84', 'l85', 'l86', 'l87']", + "63, Genetic ['l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "64, knockdown ['l88', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "65, of ['l89', 'l104', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "66, Jak2 ['l90', 'l105', 'l118', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "67, or ['l38', 'l91', 'l106', 'l119', 'l131', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "68, Stat3 ['l23', 'l39', 'l92', 'l107', 'l120', 'l132', 'l143', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "69, expression ['l24', 'l40', 'l93', 'l108', 'l121', 'l133', 'l144', 'l153', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "73, satellite ['l9', 'l25', 'l41', 'l53', 'l64', 'l83', 'l94', 'l109', 'l122', 'l134', 'l145', 'l154', 'l162', 'l170', 'l171', 'l172', 'l173', 'l174']", + "74, cells ['l10', 'l26', 'l42', 'l54', 'l65', 'l80', 'l84', 'l95', 'l110', 'l123', 'l135', 'l146', 'l155', 'l163', 'l170', 'l175', 'l176', 'l177', 'l178']", + "88, regenerating ['l11', 'l27', 'l43', 'l55', 'l66', 'l96', 'l111', 'l124', 'l136', 'l147', 'l156', 'l164', 'l171', 'l175', 'l179', 'l180', 'l181']", + "89, tibialis ['l12', 'l28', 'l44', 'l56', 'l67', 'l85', 'l97', 'l112', 'l125', 'l137', 'l148', 'l157', 'l165', 'l172', 'l176', 'l179', 'l182', 'l183']", + "90, anterior ['l13', 'l29', 'l45', 'l57', 'l68', 'l81', 'l86', 'l98', 'l113', 'l126', 'l138', 'l149', 'l158', 'l166', 'l173', 'l177', 'l180', 'l182', 'l184']", + "91, muscle. ['l14', 'l30', 'l46', 'l58', 'l69', 'l82', 'l87', 'l99', 'l114', 'l127', 'l139', 'l150', 'l159', 'l167', 'l174', 'l178', 'l181', 'l183', 'l184']", + "92, Pharmacological ['l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197']", + "93, inhibition ['l185', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208']", + "94, of ['l186', 'l198', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218']", + "95, Jak2 ['l187', 'l199', 'l209', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227']", + "96, and ['l188', 'l200', 'l210', 'l219', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235']", + "97, Stat3 ['l189', 'l201', 'l211', 'l220', 'l228', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242']", + "98, activity ['l190', 'l202', 'l212', 'l221', 'l229', 'l236', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248']", + "104, satellite ['l100', 'l115', 'l128', 'l140', 'l151', 'l160', 'l168', 'l191', 'l203', 'l213', 'l222', 'l230', 'l237', 'l243', 'l249', 'l250', 'l251', 'l252', 'l253']", + "105, cells ['l101', 'l116', 'l129', 'l141', 'l152', 'l161', 'l169', 'l192', 'l204', 'l214', 'l223', 'l231', 'l238', 'l244', 'l249', 'l254', 'l255']", + "106, in ['l102', 'l193', 'l205', 'l215', 'l224', 'l232', 'l239', 'l245', 'l250', 'l254', 'l256', 'l257', 'l258']", + "107, vitro ['l103', 'l117', 'l130', 'l142', 'l194', 'l206', 'l216', 'l225', 'l233', 'l240', 'l246', 'l251', 'l255', 'l256', 'l259', 'l260']", + "111, in ['l195', 'l207', 'l217', 'l226', 'l234', 'l241', 'l247', 'l252', 'l257', 'l259', 'l261']", + "112, vivo. ['l196', 'l208', 'l218', 'l227', 'l235', 'l242', 'l248', 'l253', 'l258', 'l260', 'l261']", + "124, muscle ['l197']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "Jak2", + "or", + "Stat3", + "Genetic", + "knockdown", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "satellite", + "stem", + "cell", + "cultured", + "myofibers.", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "Jak2", + "or", + "Stat3", + "Genetic", + "knockdown", + "expression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "regenerating", + "tibialis", + "anterior", + "muscle." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Genetic", + "knockdown", + "of", + "Jak2" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "Jak2", + "and", + "Stat3", + "activity" + ] + }, + "context": { + "val": "cells", + "words": [ + "satellite", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "Jak2", + "and", + "Stat3", + "activity" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "Jak2", + "and", + "Stat3", + "activity" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscle" + ] + } + } + ] + }, + { + "PMID": "25100521", + "TEXT": "Inflammatory diseases typically display circadian variation in symptom severity. A new study in mice shows how a pulmonary epithelial cell clock controls neutrophil recruitment to the lungs and provides insight into interactions between local and systemic circadian clocks.", + "TAG_DATA": [ + "13, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25086906", + "TEXT": "The brain, in particular the hypothalamus, plays a role in regulating glucose homeostasis; however, it remains unclear whether this organ is causally and etiologically involved in the development of diabetes. Here, we found that hypothalamic transforming growth factor-β (TGF-β) production is excessive under conditions of not only obesity but also aging, which are two general etiological factors of type 2 diabetes. Pharmacological and genetic approaches revealed that central TGF-β excess caused hyperglycemia and glucose intolerance independent of a change in body weight. Further, using cell-specific genetic analyses in vivo, we found that astrocytes and proopiomelanocortin neurons are responsible for the production and prodiabetic effect of central TGF-β, respectively. Mechanistically, TGF-β excess induced a hypothalamic RNA stress response, resulting in accelerated mRNA decay of IκBα, an inhibitor of proinflammatory nuclear factor-κB. These results reveal an atypical, mRNA metabolism-driven hypothalamic nuclear factor-κB activation, a mechanism that links obesity as well as aging to hypothalamic inflammation and ultimately to type 2 diabetes.", + "TAG_DATA": [ + "87, in {'context': 'B-in vivo'}", + "88, vivo, {'context': 'I-in vivo'}", + "92, astrocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "87, in ['l0', 'l1']", + "88, vivo, ['l0', 'l2']", + "92, astrocytes ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25064128", + "TEXT": "The circadian system is an important regulator of immune function. Human inflammatory lung diseases frequently show time-of-day variation in symptom severity and lung function, but the mechanisms and cell types underlying these effects remain unclear. We show that pulmonary antibacterial responses are modulated by a circadian clock within epithelial club (Clara) cells. These drive circadian neutrophil recruitment to the lung via the chemokine CXCL5. Genetic ablation of the clock gene Bmal1 (also called Arntl or MOP3) in bronchiolar cells disrupts rhythmic Cxcl5 expression, resulting in exaggerated inflammatory responses to lipopolysaccharide and an impaired host response to Streptococcus pneumoniae infection. Adrenalectomy blocks rhythmic inflammatory responses and the circadian regulation of CXCL5, suggesting a key role for the adrenal axis in driving CXCL5 expression and pulmonary neutrophil recruitment. Glucocorticoid receptor occupancy at the Cxcl5 locus shows circadian oscillations, but this is disrupted in mice with bronchiole-specific ablation of Bmal1, leading to enhanced CXCL5 expression despite normal corticosteroid secretion. The therapeutic effects of the synthetic glucocorticoid dexamethasone depend on intact clock function in the airway. We now define a regulatory mechanism that links the circadian clock and glucocorticoid hormones to control both time-of-day variation and the magnitude of pulmonary inflammation and responses to bacterial infection.", + "TAG_DATA": [ + "64, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "65, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "66, of {'perturbing_action': 'I-gene loss-of-function'}", + "67, the {'perturbing_action': 'I-gene loss-of-function'}", + "68, clock {'perturbing_action': 'I-gene loss-of-function'}", + "69, gene {'perturbing_action': 'I-gene loss-of-function'}", + "70, Bmal1 {'perturbing_action': 'I-gene loss-of-function'}", + "71, (also {'perturbing_action': 'I-gene loss-of-function'}", + "72, called {'perturbing_action': 'I-gene loss-of-function'}", + "73, Arntl {'perturbing_action': 'I-gene loss-of-function'}", + "75, MOP3) {'perturbing_action': 'I-gene loss-of-function'}", + "77, bronchiolar {'context': 'B-cells'}", + "78, cells {'context': 'I-cells'}", + "141, mice {'context': 'B-organism'}", + "143, bronchiole-specific {'perturbing_action': 'B-gene loss-of-function'}", + "144, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "145, of {'perturbing_action': 'I-gene loss-of-function'}", + "146, Bmal1, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "64, Genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "65, ablation ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "66, of ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "67, the ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "68, clock ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "69, gene ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "70, Bmal1 ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "71, (also ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "72, called ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "73, Arntl ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "75, MOP3) ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "77, bronchiolar ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "78, cells ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "141, mice ['l78', 'l79', 'l80', 'l81']", + "143, bronchiole-specific ['l78', 'l82', 'l83', 'l84']", + "144, ablation ['l79', 'l82', 'l85', 'l86']", + "145, of ['l80', 'l83', 'l85', 'l87']", + "146, Bmal1, ['l81', 'l84', 'l86', 'l87']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "ablation", + "of", + "the", + "clock", + "gene", + "Bmal1", + "(also", + "called", + "Arntl", + "MOP3)" + ] + }, + "context": { + "val": "cells", + "words": [ + "bronchiolar", + "cells" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "bronchiole-specific", + "ablation", + "of", + "Bmal1," + ] + } + } + ] + }, + { + "PMID": "24999940", + "TEXT": "Stress has long been thought to be a major contributing factor to cardiovascular disease, although little is known about the underlying cellular mechanisms. A new study illustrates that chronic stress promotes hematopoietic stem cell proliferation in bone marrow, leading to increased leukocyte production, circulation, and recruitment to the vasculature.", + "TAG_DATA": [ + "30, promotes {'effect': 'B-positive'}", + "31, hematopoietic {'context': 'B-cells'}", + "32, stem {'context': 'I-cells'}", + "33, cell {'context': 'I-cells'}", + "34, proliferation {'phenotype': 'B-proliferation'}", + "36, bone {'context': 'B-tissue/organ'}", + "37, marrow, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "30, promotes ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "31, hematopoietic ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "32, stem ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "33, cell ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "34, proliferation ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "36, bone ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "37, marrow, ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "bone", + "marrow," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "bone", + "marrow," + ] + } + } + ] + }, + { + "PMID": "24999934", + "TEXT": "The 83 institutes and research facilities of the Max Planck Society, established in 1948, include some of the world's leading scholars in the life sciences, including 17 Noble Prize winners, and publish 15,000 research papers annually. For the past 18 years, biologists have stood at the helm of the prestigious German organization. But last month, an electrochemist and materials scientist, Martin Stratmann, began a six-year term as president of the Munich-based society.Stratmann, who is 60, served as the director of the Max Planck Institute for Iron Research in Düsseldorf since 2000, where he helped develop self-healing coatings that can protect steels and other metals from rust. Stratmann spoke with David Levine about his vision for the Max Planck Society and about what the change of guard will mean for biomedical research. The conversation has been edited for clarity.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24997608", + "TEXT": "It is well known that the ω-3 fatty acids (ω-3-FAs; also known as n-3 fatty acids) can exert potent anti-inflammatory effects. Commonly consumed as fish products, dietary supplements and pharmaceuticals, ω-3-FAs have a number of health benefits ascribed to them, including reduced plasma triglyceride levels, amelioration of atherosclerosis and increased insulin sensitivity. We reported that Gpr120 is the functional receptor for these fatty acids and that ω-3-FAs produce robust anti-inflammatory, insulin-sensitizing effects, both in vivo and in vitro, in a Gpr120-dependent manner. Indeed, genetic variants that predispose to obesity and diabetes have been described in the gene encoding GPR120 in humans (FFAR4). However, the amount of fish oils that would have to be consumed to sustain chronic agonism of Gpr120 is too high to be practical, and, thus, a high-affinity small-molecule Gpr120 agonist would be of potential clinical benefit. Accordingly, Gpr120 is a widely studied drug discovery target within the pharmaceutical industry. Gpr40 is another lipid-sensing G protein-coupled receptor, and it has been difficult to identify compounds with a high degree of selectivity for Gpr120 over Gpr40 (ref. 11). Here we report that a selective high-affinity, orally available, small-molecule Gpr120 agonist (cpdA) exerts potent anti-inflammatory effects on macrophages in vitro and in obese mice in vivo. Gpr120 agonist treatment of high-fat diet-fed obese mice causes improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that Gpr120 agonists could become new insulin-sensitizing drugs for the treatment of type 2 diabetes and other human insulin-resistant states in the future.", + "TAG_DATA": [ + "197, macrophages {'context': 'B-cells'}", + "198, in {'context': 'B-in vitro'}", + "199, vitro {'context': 'I-in vitro'}", + "202, obese {'context': 'B-organism'}", + "203, mice {'context': 'I-organism'}", + "204, in {'context': 'B-in vivo'}", + "205, vivo. {'context': 'I-in vivo'}", + "206, Gpr120 {'perturbing_action': 'B-pharmacological augmentation'}", + "207, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "208, treatment {'perturbing_action': 'I-pharmacological augmentation'}", + "212, obese {'context': 'B-organism'}", + "213, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "197, macrophages ['l0', 'l1', 'l2', 'l3', 'l4']", + "198, in ['l0', 'l5', 'l6', 'l7']", + "199, vitro ['l1', 'l5', 'l8', 'l9', 'l10']", + "202, obese ['l2', 'l6', 'l8', 'l11', 'l12', 'l13']", + "203, mice ['l3', 'l7', 'l9', 'l11', 'l14', 'l15']", + "204, in ['l4', 'l10', 'l12', 'l14', 'l16']", + "205, vivo. ['l13', 'l15', 'l16']", + "206, Gpr120 ['l17', 'l18', 'l19', 'l20']", + "207, agonist ['l17', 'l21', 'l22', 'l23']", + "208, treatment ['l18', 'l21', 'l24', 'l25']", + "212, obese ['l19', 'l22', 'l24', 'l26']", + "213, mice ['l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Gpr120", + "agonist", + "treatment" + ] + }, + "context": { + "val": "organism", + "words": [ + "obese", + "mice" + ] + } + } + ] + }, + { + "PMID": "24973919", + "TEXT": "The realization of long-term human organ preservation will have groundbreaking effects on the current practice of transplantation. Herein we present a new technique based on subzero nonfreezing preservation and extracorporeal machine perfusion that allows transplantation of rat livers preserved for up to four days, thereby tripling the viable preservation duration.", + "TAG_DATA": [ + "36, rat {'context': 'B-tissue/organ'}", + "37, livers {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "36, rat ['l0']", + "37, livers ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24973918", + "TEXT": "In Alzheimer's disease (AD), memory impairment is the most prominent feature that afflicts patients and their families. Although reactive astrocytes have been observed around amyloid plaques since the disease was first described, their role in memory impairment has been poorly understood. Here, we show that reactive astrocytes aberrantly and abundantly produce the inhibitory gliotransmitter GABA by monoamine oxidase-B (Maob) and abnormally release GABA through the bestrophin 1 channel. In the dentate gyrus of mouse models of AD, the released GABA reduces spike probability of granule cells by acting on presynaptic GABA receptors. Suppressing GABA production or release from reactive astrocytes fully restores the impaired spike probability, synaptic plasticity, and learning and memory in the mice. In the postmortem brain of individuals with AD, astrocytic GABA and MAOB are significantly upregulated. We propose that selective inhibition of astrocytic GABA synthesis or release may serve as an effective therapeutic strategy for treating memory impairment in AD.", + "TAG_DATA": [ + "70, dentate {'context': 'B-tissue/organ'}", + "71, gyrus {'context': 'I-tissue/organ'}", + "73, mouse {'context': 'B-organism'}", + "74, models {'context': 'I-organism'}", + "84, granule {'context': 'B-cells'}", + "85, cells {'context': 'I-cells'}", + "114, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "70, dentate ['l0', 'l1', 'l2', 'l3', 'l4']", + "71, gyrus ['l0', 'l5', 'l6', 'l7', 'l8']", + "73, mouse ['l1', 'l5', 'l9', 'l10', 'l11']", + "74, models ['l2', 'l6', 'l9', 'l12', 'l13']", + "84, granule ['l3', 'l7', 'l10', 'l12', 'l14']", + "85, cells ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24929951", + "TEXT": "Leptin treatment reverses hyperglycemia in animal models of poorly controlled type 1 diabetes (T1D), spurring great interest in the possibility of treating patients with this hormone. The antidiabetic effect of leptin has been postulated to occur through suppression of glucagon production, suppression of glucagon responsiveness or both; however, there does not appear to be a direct effect of leptin on the pancreatic alpha cell. Thus, the mechanisms responsible for the antidiabetic effect of leptin remain poorly understood. We quantified liver-specific rates of hepatic gluconeogenesis and substrate oxidation in conjunction with rates of whole-body acetate, glycerol and fatty acid turnover in three rat models of poorly controlled diabetes, including a model of diabetic ketoacidosis. We show that the higher rates of hepatic gluconeogenesis in all these models could be attributed to hypoleptinemia-induced activity of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in higher rates of adipocyte lipolysis, hepatic conversion of glycerol to glucose through a substrate push mechanism and conversion of pyruvate to glucose through greater hepatic acetyl-CoA allosteric activation of pyruvate carboxylase flux. Notably, these effects could be dissociated from changes in plasma insulin and glucagon concentrations and hepatic gluconeogenic protein expression. All the altered systemic and hepatic metabolic fluxes could be mimicked by infusing rats with Intralipid or corticosterone and were corrected by leptin replacement. These data demonstrate a critical role for lipolysis and substrate delivery to the liver, secondary to hypoleptinemia and HPA axis activity, in promoting higher hepatic gluconeogenesis and hyperglycemia in poorly controlled diabetes.", + "TAG_DATA": [ + "203, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24880617", + "TEXT": "Small-cell lung cancer (SCLC), an aggressive neuroendocrine tumor with early dissemination and dismal prognosis, accounts for 15-20% of lung cancer cases and ∼200,000 deaths each year. Most cases are inoperable, and biopsies to investigate SCLC biology are rarely obtainable. Circulating tumor cells (CTCs), which are prevalent in SCLC, present a readily accessible 'liquid biopsy'. Here we show that CTCs from patients with either chemosensitive or chemorefractory SCLC are tumorigenic in immune-compromised mice, and the resultant CTC-derived explants (CDXs) mirror the donor patient's response to platinum and etoposide chemotherapy. Genomic analysis of isolated CTCs revealed considerable similarity to the corresponding CDX. Most marked differences were observed between CDXs from patients with different clinical outcomes. These data demonstrate that CTC molecular analysis via serial blood sampling could facilitate delivery of personalized medicine for SCLC. CDXs are readily passaged, and these unique mouse models provide tractable systems for therapy testing and understanding drug resistance mechanisms.", + "TAG_DATA": [ + "66, SCLC {'context': 'B-neoplasm'}", + "70, immune-compromised {'context': 'B-organism'}", + "71, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "66, SCLC ['l0', 'l1']", + "70, immune-compromised ['l0', 'l2']", + "71, mice, ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24880615", + "TEXT": "Chemoradiation-resistant cancers limit treatment efficacy and safety. We show here the cancer cell-specific, on-demand intracellular amplification of chemotherapy and chemoradiation therapy via gold nanoparticle- and laser pulse-induced mechanical intracellular impact. Cancer aggressiveness promotes the clustering of drug nanocarriers and gold nanoparticles in cancer cells. This cluster, upon exposure to a laser pulse, generates a plasmonic nanobubble, the mechanical explosion that destroys the host cancer cell or ejects the drug into its cytoplasm by disrupting the liposome and endosome. The same cluster locally amplifies external X-rays. Intracellular synergy of the mechanical impact of plasmonic nanobubble, ejected drug and amplified X-rays improves the efficacy of standard chemoradiation in resistant and aggressive head and neck cancer by 100-fold in vitro and 17-fold in vivo, reduces the effective entry doses of drugs and X-rays to 2-6% of their clinical doses and efficiently spares normal cells. The developed quadrapeutics technology combines four clinically validated components and transforms a standard macrotherapy into an intracellular on-demand theranostic microtreatment with radically amplified therapeutic efficacy and specificity.", + "TAG_DATA": [ + "42, cancer {'context': 'B-transformed cells'}", + "43, cells. {'context': 'I-transformed cells'}", + "106, resistant {'context': 'B-neoplasm'}", + "107, and {'context': 'I-neoplasm'}", + "108, aggressive {'context': 'I-neoplasm'}", + "109, head {'context': 'I-neoplasm'}", + "110, and {'context': 'I-neoplasm'}", + "111, neck {'context': 'I-neoplasm'}", + "112, cancer {'context': 'I-neoplasm'}", + "115, in {'context': 'B-in vitro'}", + "116, vitro {'context': 'I-in vitro'}", + "119, in {'context': 'B-in vivo'}", + "120, vivo, {'context': 'I-in vivo'}", + "140, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "42, cancer ['l0']", + "43, cells. ['l0']", + "106, resistant ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "107, and ['l1', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "108, aggressive ['l2', 'l11', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "109, head ['l3', 'l12', 'l20', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "110, and ['l4', 'l13', 'l21', 'l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "111, neck ['l5', 'l14', 'l22', 'l29', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "112, cancer ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l46', 'l47', 'l48', 'l49']", + "115, in ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l50', 'l51', 'l52']", + "116, vitro ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l53', 'l54']", + "119, in ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l55']", + "120, vivo, ['l10', 'l19', 'l27', 'l34', 'l40', 'l45', 'l49', 'l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24836576", + "TEXT": "Translating whole-exome sequencing (WES) for prospective clinical use may have an impact on the care of patients with cancer; however, multiple innovations are necessary for clinical implementation. These include rapid and robust WES of DNA derived from formalin-fixed, paraffin-embedded tumor tissue, analytical output similar to data from frozen samples and clinical interpretation of WES data for prospective use. Here, we describe a prospective clinical WES platform for archival formalin-fixed, paraffin-embedded tumor samples. The platform employs computational methods for effective clinical analysis and interpretation of WES data. When applied retrospectively to 511 exomes, the interpretative framework revealed a 'long tail' of somatic alterations in clinically important genes. Prospective application of this approach identified clinically relevant alterations in 15 out of 16 patients. In one patient, previously undetected findings guided clinical trial enrollment, leading to an objective clinical response. Overall, this methodology may inform the widespread implementation of precision cancer medicine.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24784231", + "TEXT": "Gout is characterized by an acute inflammatory reaction and the accumulation of neutrophils in response to monosodium urate (MSU) crystals. Inflammation resolves spontaneously within a few days, although MSU crystals can still be detected in the synovial fluid and affected tissues. Here we report that neutrophils recruited to sites of inflammation undergo oxidative burst and form neutrophil extracellular traps (NETs). Under high neutrophil densities, these NETs aggregate and degrade cytokines and chemokines via serine proteases. Tophi, the pathognomonic structures of chronic gout, share characteristics with aggregated NETs, and MSU crystals can induce NETosis and aggregation of NETs. In individuals with impaired NETosis, MSU crystals induce uncontrolled production of inflammatory mediators from neutrophils and persistent inflammation. Furthermore, in models of neutrophilic inflammation, NETosis-deficient mice develop exacerbated and chronic disease that can be reduced by adoptive transfer of aggregated NETs. These findings suggest that aggregated NETs promote the resolution of neutrophilic inflammation by degrading cytokines and chemokines and disrupting neutrophil recruitment and activation.", + "TAG_DATA": [ + "121, NETosis-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "122, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "121, NETosis-deficient ['l0']", + "122, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NETosis-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "24747747", + "TEXT": "Mitochondrial redox signals have a central role in neuronal physiology and disease. Here we describe a new optical approach to measure fast redox signals with single-organelle resolution in living mice that express genetically encoded redox biosensors in their neuronal mitochondria. Moreover, we demonstrate how parallel measurements with several biosensors can integrate these redox signals into a comprehensive characterization of mitochondrial function. This approach revealed that axonal mitochondria undergo spontaneous 'contractions' that are accompanied by reversible redox changes. These contractions are amplified by neuronal activity and acute or chronic neuronal insults. Multiparametric imaging reveals that contractions constitute respiratory chain-dependent episodes of depolarization coinciding with matrix alkalinization, followed by uncoupling. In contrast, permanent mitochondrial damage after spinal cord injury depends on calcium influx and mitochondrial permeability transition. Thus, our approach allows us to identify heterogeneity among physiological and pathological redox signals, correlate such signals to functional and structural organelle dynamics and dissect the underlying mechanisms.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24705334", + "TEXT": "Cardiac failure is the most common cause of mortality in Friedreich's ataxia (FRDA), a mitochondrial disease characterized by neurodegeneration, hypertrophic cardiomyopathy and diabetes. FRDA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in the biosynthesis of iron-sulfur (Fe-S) clusters. Impaired mitochondrial oxidative phosphorylation, bioenergetics imbalance, deficit of Fe-S cluster enzymes and mitochondrial iron overload occur in the myocardium of individuals with FRDA. No treatment exists as yet for FRDA cardiomyopathy. A conditional mouse model with complete frataxin deletion in cardiac and skeletal muscle (Mck-Cre-Fxn(L3/L-) mice) recapitulates most features of FRDA cardiomyopathy, albeit with a more rapid and severe course. Here we show that adeno-associated virus rh10 vector expressing human FXN injected intravenously in these mice fully prevented the onset of cardiac disease. Moreover, later administration of the frataxin-expressing vector, after the onset of heart failure, was able to completely reverse the cardiomyopathy of these mice at the functional, cellular and molecular levels within a few days. Our results demonstrate that cardiomyocytes with severe energy failure and ultrastructure disorganization can be rapidly rescued and remodeled by gene therapy and establish the preclinical proof of concept for the potential of gene therapy in treating FRDA cardiomyopathy.", + "TAG_DATA": [ + "76, conditional {'context': 'B-organism'}", + "77, mouse {'context': 'B-organism'}", + "78, model {'context': 'I-organism'}", + "80, complete {'perturbing_action': 'B-gene loss-of-function'}", + "81, frataxin {'perturbing_action': 'I-gene loss-of-function'}", + "82, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "83, in {'perturbing_action': 'I-gene loss-of-function'}", + "84, cardiac {'perturbing_action': 'I-gene loss-of-function', 'context': 'B-tissue/organ'}", + "85, and {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "86, skeletal {'context': 'I-cells'}", + "87, muscle {'context': 'I-tissue/organ'}", + "108, adeno-associated {'perturbing_action': 'B-gene gain-of-function'}", + "109, virus {'perturbing_action': 'I-gene gain-of-function'}", + "110, rh10 {'perturbing_action': 'I-gene gain-of-function'}", + "111, vector {'perturbing_action': 'I-gene gain-of-function'}", + "112, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "113, human {'perturbing_action': 'I-gene gain-of-function'}", + "114, FXN {'perturbing_action': 'I-gene gain-of-function'}", + "119, mice {'context': 'B-organism'}", + "149, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "76, conditional ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "77, mouse ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "78, model ['l1', 'l11', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "80, complete ['l2', 'l12', 'l20', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "81, frataxin ['l3', 'l13', 'l21', 'l31', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "82, deletion ['l4', 'l14', 'l22', 'l32', 'l47', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "83, in ['l5', 'l15', 'l23', 'l33', 'l48', 'l62', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "84, cardiac ['l6', 'l16', 'l24', 'l34', 'l49', 'l63', 'l76', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "85, and ['l7', 'l17', 'l25', 'l35', 'l50', 'l64', 'l77', 'l89', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "86, skeletal ['l8', 'l18', 'l26', 'l36', 'l51', 'l65', 'l78', 'l90', 'l101', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "87, muscle ['l9', 'l19', 'l27', 'l37', 'l52', 'l66', 'l79', 'l91', 'l102', 'l112', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "89, mice) ['l38', 'l53', 'l67', 'l80', 'l92', 'l103', 'l113', 'l122', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "108, adeno-associated ['l39', 'l54', 'l68', 'l81', 'l93', 'l104', 'l114', 'l123', 'l131', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145']", + "109, virus ['l40', 'l55', 'l69', 'l82', 'l94', 'l105', 'l115', 'l124', 'l132', 'l139', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151']", + "110, rh10 ['l41', 'l56', 'l70', 'l83', 'l95', 'l106', 'l116', 'l125', 'l133', 'l140', 'l146', 'l152', 'l153', 'l154', 'l155', 'l156']", + "111, vector ['l42', 'l57', 'l71', 'l84', 'l96', 'l107', 'l117', 'l126', 'l134', 'l141', 'l147', 'l152', 'l157', 'l158', 'l159', 'l160']", + "112, expressing ['l43', 'l58', 'l72', 'l85', 'l97', 'l108', 'l118', 'l127', 'l135', 'l142', 'l148', 'l153', 'l157', 'l161', 'l162', 'l163']", + "113, human ['l28', 'l44', 'l59', 'l73', 'l86', 'l98', 'l109', 'l119', 'l128', 'l136', 'l143', 'l149', 'l154', 'l158', 'l161', 'l164', 'l165']", + "114, FXN ['l10', 'l29', 'l45', 'l60', 'l74', 'l87', 'l99', 'l110', 'l120', 'l129', 'l137', 'l144', 'l150', 'l155', 'l159', 'l162', 'l164', 'l166']", + "119, mice ['l30', 'l46', 'l61', 'l75', 'l88', 'l100', 'l111', 'l121', 'l130', 'l138', 'l145', 'l151', 'l156', 'l160', 'l163', 'l165', 'l166']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "conditional", + "mouse", + "model", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "complete", + "frataxin", + "deletion", + "in", + "cardiac", + "and" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cardiac", + "complete", + "frataxin", + "deletion", + "in", + "and" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "cardiac", + "muscle" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "and", + "complete", + "frataxin", + "deletion", + "in", + "cardiac" + ] + }, + "context": { + "val": "cells", + "words": [ + "and", + "skeletal" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "conditional", + "model", + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "FXN", + "human", + "adeno-associated", + "virus", + "rh10", + "vector", + "expressing" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "cardiac", + "muscle" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adeno-associated", + "virus", + "rh10", + "vector", + "expressing", + "human", + "FXN" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "and", + "skeletal" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adeno-associated", + "virus", + "rh10", + "vector", + "expressing", + "human", + "FXN" + ] + } + } + ] + }, + { + "PMID": "24681597", + "TEXT": "Kindlin-1 is an integrin tail binding protein that controls integrin activation. Mutations in the FERMT-1 gene, which encodes for Kindlin-1, lead to Kindler syndrome in man, which is characterized by skin blistering, premature skin aging and skin cancer of unknown etiology. Here we show that loss of Kindlin-1 in mouse keratinocytes recapitulates Kindler syndrome and also produces enlarged and hyperactive stem cell compartments, which lead to hyperthickened epidermis, ectopic hair follicle development and increased skin tumor susceptibility. Mechanistically, Kindlin-1 controls keratinocyte adhesion through β1-class integrins and proliferation and differentiation of cutaneous epithelial stem cells by promoting α(v)β(6) integrin-mediated transforming growth factor-β (TGF-β) activation and inhibiting Wnt-β-catenin signaling through integrin-independent regulation of Wnt ligand expression. Our findings assign Kindlin-1 the previously unknown and essential task of controlling cutaneous epithelial stem cell homeostasis by balancing TGF-β-mediated growth-inhibitory signals and Wnt-β-catenin-mediated growth-promoting signals.", + "TAG_DATA": [ + "45, loss {'perturbing_action': 'B-gene loss-of-function'}", + "46, of {'perturbing_action': 'I-gene loss-of-function'}", + "47, Kindlin-1 {'perturbing_action': 'I-gene loss-of-function'}", + "49, mouse {'context': 'B-cells'}", + "50, keratinocytes {'context': 'I-cells'}", + "74, skin {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}", + "79, controls {'effect': 'B-regulates'}", + "86, proliferation {'phenotype': 'B-proliferation'}", + "88, differentiation {'phenotype': 'B-differentiation'}", + "90, cutaneous {'context': 'B-cells'}", + "91, epithelial {'context': 'I-cells'}", + "92, stem {'context': 'I-cells'}", + "93, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "46, of ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "47, Kindlin-1 ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "49, mouse ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "50, keratinocytes ['l3', 'l14', 'l24', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "74, skin ['l4', 'l15', 'l25', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "79, controls ['l5', 'l16', 'l26', 'l44', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "86, proliferation ['l6', 'l17', 'l27', 'l35', 'l40', 'l45', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "88, differentiation ['l7', 'l18', 'l28', 'l36', 'l41', 'l46', 'l52', 'l57', 'l62', 'l63', 'l64', 'l65']", + "90, cutaneous ['l8', 'l19', 'l29', 'l47', 'l53', 'l58', 'l62', 'l66', 'l67', 'l68']", + "91, epithelial ['l9', 'l20', 'l30', 'l48', 'l54', 'l59', 'l63', 'l66', 'l69', 'l70']", + "92, stem ['l10', 'l21', 'l31', 'l37', 'l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l71']", + "93, cells ['l11', 'l22', 'l32', 'l38', 'l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l71']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Kindlin-1" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "keratinocytes", + "cutaneous", + "epithelial", + "stem", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Kindlin-1" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "skin" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Kindlin-1" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "skin" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "skin" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "skin" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Kindlin-1" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "controls" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Kindlin-1" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Kindlin-1" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "keratinocytes", + "cutaneous", + "epithelial", + "stem", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "skin" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "keratinocytes", + "cutaneous", + "epithelial", + "stem", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "keratinocytes", + "cutaneous", + "epithelial", + "stem", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "skin" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "controls" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "skin" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "controls" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "skin" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "skin" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "controls" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "controls" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "controls" + ] + }, + "context": { + "val": "cells", + "words": [ + "cutaneous", + "epithelial", + "stem", + "cells" + ] + } + } + ] + }, + { + "PMID": "24608097", + "TEXT": "Alzheimer's disease causes a progressive dementia that currently affects over 35 million individuals worldwide and is expected to affect 115 million by 2050 (ref. 1). There are no cures or disease-modifying therapies, and this may be due to our inability to detect the disease before it has progressed to produce evident memory loss and functional decline. Biomarkers of preclinical disease will be critical to the development of disease-modifying or even preventative therapies. Unfortunately, current biomarkers for early disease, including cerebrospinal fluid tau and amyloid-β levels, structural and functional magnetic resonance imaging and the recent use of brain amyloid imaging or inflammaging, are limited because they are either invasive, time-consuming or expensive. Blood-based biomarkers may be a more attractive option, but none can currently detect preclinical Alzheimer's disease with the required sensitivity and specificity. Herein, we describe our lipidomic approach to detecting preclinical Alzheimer's disease in a group of cognitively normal older adults. We discovered and validated a set of ten lipids from peripheral blood that predicted phenoconversion to either amnestic mild cognitive impairment or Alzheimer's disease within a 2-3 year timeframe with over 90% accuracy. This biomarker panel, reflecting cell membrane integrity, may be sensitive to early neurodegeneration of preclinical Alzheimer's disease.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24603783", + "TEXT": "Many big-name pharmaceutical companies have made strides toward data transparency in recent years, but perhaps none is as open as Johnson & Johnson (J&J) is now. On 29 January, the New Jersey-based drug giant announced that it will make all of its clinical trial data available through an academic clearinghouse for scientific information known as the Yale University Open Data Access (YODA) project. Under the agreement-the most comprehensive industry-academic partnership of its kind-YODA will independently review and make decisions about requests to access de-identified, patient-level data from the clinical studies supporting all of J&J's approved drugs.It's a major step forward for YODA, which was born in 2011 out of an initial project with the global drug and device manufacturer Medtronic, which is headquartered in Minneapolis, to release data from studies of the company's Infuse product, which contains recombinant human bone morphogenetic protein-2, used to promote bone formation. At the helm of YODA is Harlan Krumholz, a physician-scientist who for almost two decades has led the Yale-New Haven Hospital Center for Outcomes Research and Evaluation, which aims to help compare the effectiveness of various healthcare interventions and, ultimately, improve clinical decision-making. Krumholz spoke with Roxanne Khamsi about how greater access to data is a boon for medicine.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24584119", + "TEXT": "Immunohistochemistry (IHC) is a tool for visualizing protein expression that is employed as part of the diagnostic workup for the majority of solid tissue malignancies. Existing IHC methods use antibodies tagged with fluorophores or enzyme reporters that generate colored pigments. Because these reporters exhibit spectral and spatial overlap when used simultaneously, multiplexed IHC is not routinely used in clinical settings. We have developed a method that uses secondary ion mass spectrometry to image antibodies tagged with isotopically pure elemental metal reporters. Multiplexed ion beam imaging (MIBI) is capable of analyzing up to 100 targets simultaneously over a five-log dynamic range. Here, we used MIBI to analyze formalin-fixed, paraffin-embedded human breast tumor tissue sections stained with ten labels simultaneously. The resulting data suggest that MIBI can provide new insights into disease pathogenesis that will be valuable for basic research, drug discovery and clinical diagnostics.", + "TAG_DATA": [ + "108, human {'context': 'I-neoplasm'}", + "109, breast {'context': 'I-neoplasm'}", + "110, tumor {'context': 'I-neoplasm'}", + "111, tissue {'context': 'I-neoplasm'}", + "112, sections {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "108, human ['l0', 'l1', 'l2', 'l3']", + "109, breast ['l0', 'l4', 'l5', 'l6']", + "110, tumor ['l1', 'l4', 'l7', 'l8']", + "111, tissue ['l2', 'l5', 'l7', 'l9']", + "112, sections ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24531377", + "TEXT": "The defective generation or function of regulatory T (Treg) cells in autoimmune disease contributes to chronic inflammation and tissue injury. We report the identification of FoxA1 as a transcription factor in T cells that, after ectopic expression, confers suppressive properties in a newly identified Treg cell population, herein called FoxA1(+) Treg cells. FoxA1 bound to the Pdl1 promoter, inducing programmed cell death ligand 1 (Pd-l1) expression, which was essential for the FoxA1(+) Treg cells to kill activated T cells. FoxA1(+) Treg cells develop primarily in the central nervous system in response to autoimmune inflammation, have a distinct transcriptional profile and are CD4(+)FoxA1(+)CD47(+)CD69(+)PD-L1(hi)FoxP3(-). Adoptive transfer of stable FoxA1(+) Treg cells inhibited experimental autoimmune encephalomyelitis in a FoxA1-and Pd-l1-dependent manner. The development of FoxA1(+) Treg cells is induced by interferon-β (IFN-β) and requires T cell-intrinsic IFN-α/β receptor (Ifnar) signaling, as the frequency of FoxA1(+) Treg cells was reduced in Ifnb(-/-) and Ifnar(-/-) mice. In individuals with relapsing-remitting multiple sclerosis, clinical response to treatment with IFN-β was associated with an increased frequency of suppressive FoxA1(+) Treg cells in the blood. These findings suggest that FoxA1 is a lineage-specification factor that is induced by IFN-β and supports the differentiation and suppressive function of FoxA1(+) Treg cells.", + "TAG_DATA": [ + "106, FoxA1(+) {'context': 'I-cells'}", + "107, Treg {'context': 'I-cells'}", + "108, cells {'context': 'I-cells'}", + "121, FoxA1(+) {'context': 'B-cells'}", + "122, Treg {'context': 'I-cells'}", + "141, FoxA1(+) {'context': 'B-cells'}", + "142, Treg {'context': 'I-cells'}", + "143, cells {'context': 'I-cells'}", + "147, Ifnb(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "149, Ifnar(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "150, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "106, FoxA1(+) ['l0', 'l1', 'l2', 'l3']", + "107, Treg ['l0', 'l4', 'l5', 'l6']", + "108, cells ['l1', 'l4', 'l7']", + "121, FoxA1(+) ['l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "122, Treg ['l2', 'l5', 'l8', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "123, cells ['l3', 'l6', 'l7', 'l9', 'l16', 'l22', 'l23']", + "141, FoxA1(+) ['l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28']", + "142, Treg ['l11', 'l18', 'l22', 'l24', 'l29', 'l30', 'l31', 'l32']", + "143, cells ['l12', 'l19', 'l23', 'l25', 'l29', 'l33', 'l34']", + "147, Ifnb(-/-) ['l13', 'l20', 'l26', 'l30', 'l33', 'l35', 'l36']", + "149, Ifnar(-/-) ['l14', 'l27', 'l31', 'l35', 'l37']", + "150, mice. ['l15', 'l21', 'l28', 'l32', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "FoxA1(+)", + "Treg", + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ifnb(-/-)", + "Ifnar(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ifnb(-/-)", + "Ifnar(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "24509526", + "TEXT": "The vast majority of new HIV infections result from relatively inefficient transmission of the virus across mucosal surfaces during sexual intercourse. A consequence of this inefficiency is that small numbers of transmitted founder viruses initiate most heterosexual infections. This natural bottleneck to transmission has stimulated efforts to develop interventions that are aimed at blocking this step of the infection process. Despite the promise of this strategy, clinical trials of preexposure prophylaxis have had limited degrees of success in humans, in part because of lack of adherence to the recommended preexposure treatment regimens. In contrast, a number of existing vaccines elicit systemic immunity that protects against mucosal infections, such as the vaccines for influenza and human papilloma virus. We recently demonstrated the ability of vectored immunoprophylaxis (VIP) to prevent intravenous transmission of HIV in humanized mice using broadly neutralizing antibodies. Here we demonstrate that VIP is capable of protecting humanized mice from intravenous as well as vaginal challenge with diverse HIV strains despite repeated exposures. Moreover, animals receiving VIP that expresses a modified VRC07 antibody were completely resistant to repetitive intravaginal challenge by a heterosexually transmitted founder HIV strain, suggesting that VIP may be effective in preventing vaginal transmission of HIV between humans.", + "TAG_DATA": [ + "133, humanized {'context': 'B-organism'}", + "134, mice {'context': 'I-organism'}", + "148, humanized {'context': 'B-organism'}", + "149, mice {'context': 'I-organism'}", + "165, animals {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "133, humanized ['l0']", + "134, mice ['l0']", + "148, humanized ['l1']", + "149, mice ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24487433", + "TEXT": "Technologies that enable the rapid detection and localization of bacterial infections in living animals could address an unmet need for infectious disease diagnostics. We describe a molecular imaging approach for the specific, noninvasive detection of S. aureus based on the activity of the S. aureus secreted nuclease, micrococcal nuclease (MN). Several short synthetic oligonucleotides, rendered resistant to mammalian serum nucleases by various chemical modifications and flanked with a fluorophore and quencher, were activated upon degradation by purified MN and in S. aureus culture supernatants. A probe consisting of a pair of deoxythymidines flanked by several 2'-O-methyl-modified nucleotides was activated in culture supernatants of S. aureus but not in culture supernatants of several other pathogenic bacteria. Systemic administration of this probe to mice bearing S. aureus muscle infections resulted in probe activation at the infection sites in an MN-dependent manner. This new bacterial imaging approach has potential clinical applicability for infections with S. aureus and several other medically important pathogens.", + "TAG_DATA": [ + "121, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24441828", + "TEXT": "Spontaneous Ca(2+) release from intracellular stores is important for various physiological and pathological processes. In cardiac muscle cells, spontaneous store overload-induced Ca(2+) release (SOICR) can result in Ca(2+) waves, a major cause of ventricular tachyarrhythmias (VTs) and sudden death. The molecular mechanism underlying SOICR has been a mystery for decades. Here we show that a point mutation, E4872A, in the helix bundle crossing region (the proposed gate) of the cardiac ryanodine receptor (RyR2) completely abolishes luminal, but not cytosolic, Ca(2+) activation of RyR2. The introduction of metal-binding histidines at this site converts RyR2 into a luminal Ni(2+)-gated channel. Mouse hearts harboring a heterozygous RyR2 mutation at this site (E4872Q) are resistant to SOICR and are completely protected against Ca(2+)-triggered VTs. These data show that the RyR2 gate directly senses luminal (store) Ca(2+), explaining the regulation of RyR2 by luminal Ca(2+), the initiation of Ca(2+) waves and Ca(2+)-triggered arrhythmias. This newly identified store-sensing gate structure is conserved in all RyR and inositol 1,4,5-trisphosphate receptor isoforms.", + "TAG_DATA": [ + "55, point {'perturbing_action': 'B-other'}", + "56, mutation, {'perturbing_action': 'I-other'}", + "57, E4872A, {'perturbing_action': 'I-other'}", + "58, in {'perturbing_action': 'I-other'}", + "59, the {'perturbing_action': 'I-other'}", + "60, helix {'perturbing_action': 'I-other'}", + "61, bundle {'perturbing_action': 'I-other'}", + "62, crossing {'perturbing_action': 'I-other'}", + "63, region {'perturbing_action': 'I-other'}", + "64, (the {'perturbing_action': 'I-other'}", + "66, gate) {'perturbing_action': 'I-other'}", + "67, of {'perturbing_action': 'I-other'}", + "68, the {'perturbing_action': 'I-other'}", + "69, cardiac {'perturbing_action': 'I-other'}", + "70, ryanodine {'perturbing_action': 'I-other'}", + "71, receptor {'perturbing_action': 'I-other'}", + "72, (RyR2) {'perturbing_action': 'I-other'}", + "98, Mouse {'context': 'B-tissue/organ'}", + "99, hearts {'context': 'I-tissue/organ'}", + "101, a {'perturbing_action': 'I-other'}", + "102, heterozygous {'perturbing_action': 'B-other'}", + "103, RyR2 {'perturbing_action': 'I-other'}", + "104, mutation {'perturbing_action': 'I-other'}", + "105, at {'perturbing_action': 'I-other'}", + "106, this {'perturbing_action': 'I-other'}", + "107, site {'perturbing_action': 'I-other'}", + "108, (E4872Q) {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "55, point ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "56, mutation, ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "57, E4872A, ['l1', 'l16', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "58, in ['l2', 'l17', 'l31', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "59, the ['l3', 'l18', 'l32', 'l45', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "60, helix ['l4', 'l19', 'l33', 'l46', 'l58', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "61, bundle ['l5', 'l20', 'l34', 'l47', 'l59', 'l70', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "62, crossing ['l6', 'l21', 'l35', 'l48', 'l60', 'l71', 'l81', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "63, region ['l7', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "64, (the ['l8', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l100', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "66, gate) ['l9', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l108', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "67, of ['l10', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l115', 'l121', 'l122', 'l123', 'l124', 'l125']", + "68, the ['l11', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l121', 'l126', 'l127', 'l128', 'l129']", + "69, cardiac ['l12', 'l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l126', 'l130', 'l131', 'l132']", + "70, ryanodine ['l13', 'l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l118', 'l123', 'l127', 'l130', 'l133', 'l134']", + "71, receptor ['l14', 'l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l113', 'l119', 'l124', 'l128', 'l131', 'l133', 'l135']", + "72, (RyR2) ['l15', 'l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l129', 'l132', 'l134', 'l135']", + "98, Mouse ['l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "99, hearts ['l136', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "101, a ['l137', 'l145', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159']", + "102, heterozygous ['l138', 'l146', 'l153', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "103, RyR2 ['l139', 'l147', 'l154', 'l160', 'l166', 'l167', 'l168', 'l169', 'l170']", + "104, mutation ['l140', 'l148', 'l155', 'l161', 'l166', 'l171', 'l172', 'l173', 'l174']", + "105, at ['l141', 'l149', 'l156', 'l162', 'l167', 'l171', 'l175', 'l176', 'l177']", + "106, this ['l142', 'l150', 'l157', 'l163', 'l168', 'l172', 'l175', 'l178', 'l179']", + "107, site ['l143', 'l151', 'l158', 'l164', 'l169', 'l173', 'l176', 'l178', 'l180']", + "108, (E4872Q) ['l144', 'l152', 'l159', 'l165', 'l170', 'l174', 'l177', 'l179', 'l180']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "Mouse", + "hearts" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "a", + "heterozygous", + "RyR2", + "mutation", + "at", + "this", + "site", + "(E4872Q)" + ] + } + } + ] + }, + { + "PMID": "24412923", + "TEXT": "Progressive inflammation in atherosclerotic plaques is associated with increasing risk of plaque rupture. Molecular imaging of activated macrophages with 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) has been proposed for identification of patients at higher risk for acute vascular events. Because mannose is an isomer of glucose that is taken up by macrophages through glucose transporters and because mannose receptors are expressed on a subset of the macrophage population in high-risk plaques, we applied (18)F-labeled mannose (2-deoxy-2-[(18)F]fluoro-D-mannose, [(18)F]FDM) for targeting of plaque inflammation. Here, we describe comparable uptake of [(18)F]FDM and [(18)F]FDG in atherosclerotic lesions in a rabbit model; [(18)F]FDM uptake was proportional to the plaque macrophage population. Our FDM competition studies in cultured cells with 2-deoxy-2-[(14)C]carbon-D-glucose ([(14)C]2DG) support at least 35% higher [(18)F]FDM uptake by macrophages in cell experiments. We also demonstrate that FDM restricts binding of anti-mannose receptor antibody to macrophages by approximately 35% and that mannose receptor targeting may provide an additional avenue for imaging of plaque inflammation.", + "TAG_DATA": [ + "92, rabbit {'context': 'B-organism'}", + "93, model; {'context': 'I-organism'}", + "108, cultured {'context': 'B-cells'}", + "109, cells {'context': 'I-cells'}", + "121, macrophages {'context': 'B-cells'}", + "123, cell {'context': 'B-cells'}", + "124, experiments. {'context': 'I-cells'}", + "137, macrophages {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "92, rabbit ['l0']", + "93, model; ['l0']", + "108, cultured ['l1', 'l2', 'l3', 'l4']", + "109, cells ['l1', 'l5', 'l6', 'l7']", + "121, macrophages ['l2', 'l5', 'l8', 'l9']", + "123, cell ['l3', 'l6', 'l8', 'l10']", + "124, experiments. ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24362933", + "TEXT": "Before they infect red blood cells and cause malaria, Plasmodium parasites undergo an obligate and clinically silent expansion phase in the liver that is supposedly undetected by the host. Here, we demonstrate the engagement of a type I interferon (IFN) response during Plasmodium replication in the liver. We identified Plasmodium RNA as a previously unrecognized pathogen-associated molecular pattern (PAMP) capable of activating a type I IFN response via the cytosolic pattern recognition receptor Mda5. This response, initiated by liver-resident cells through the adaptor molecule for cytosolic RNA sensors, Mavs, and the transcription factors Irf3 and Irf7, is propagated by hepatocytes in an interferon-α/β receptor-dependent manner. This signaling pathway is critical for immune cell-mediated host resistance to liver-stage Plasmodium infection, which we find can be primed with other PAMPs, including hepatitis C virus RNA. Together, our results show that the liver has sensor mechanisms for Plasmodium that mediate a functional antiparasite response driven by type I IFN.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24317119", + "TEXT": "In this study, we monitored glycolysis in mouse lymphoma and lung tumors by measuring the conversion of hyperpolarized [U-2H, U-13C]glucose to lactate using 13C magnetic resonance spectroscopy and spectroscopic imaging. We observed labeled lactate only in tumors and not in surrounding normal tissue or other tissues in the body and found that it was markedly decreased at 24 h after treatment with a chemotherapeutic drug. We also detected an increase in a resonance assigned to 6-phosphogluconate in the pentose phosphate pathway. This technique could provide a new way of detecting early evidence of tumor treatment response in the clinic and of monitoring tumor pentose phosphate pathway activity.", + "TAG_DATA": [ + "7, mouse {'context': 'B-neoplasm'}", + "8, lymphoma {'context': 'I-neoplasm'}", + "10, lung {'context': 'B-neoplasm'}", + "11, tumors {'context': 'I-neoplasm'}", + "36, tumors {'context': 'B-neoplasm'}", + "40, surrounding {'context': 'B-cells'}", + "41, normal {'context': 'I-tissue/organ'}", + "42, tissue {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "7, mouse ['l0', 'l1', 'l2']", + "8, lymphoma ['l0', 'l3', 'l4']", + "10, lung ['l1', 'l3', 'l5']", + "11, tumors ['l2', 'l4', 'l5']", + "36, tumors ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "40, surrounding ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "41, normal ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "42, tissue ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "45, tissues ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "46, in ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "48, body ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24270544", + "TEXT": "Podocytes are critical in the maintenance of a healthy glomerular filter; however, they have been difficult to study in the intact kidney because of technical limitations. Here we report the development of serial multiphoton microscopy (MPM) of the same glomeruli over several days to visualize the motility of podocytes and parietal epithelial cells (PECs) in vivo. In podocin-GFP mice, podocytes formed sporadic multicellular clusters after unilateral ureteral ligation and migrated into the parietal Bowman's capsule. The tracking of single cells in podocin-confetti mice featuring cell-specific expression of CFP, GFP, YFP or RFP revealed the simultaneous migration of multiple podocytes. In phosphoenolpyruvate carboxykinase (PEPCK)-GFP mice, serial MPM found PEC-to-podocyte migration and nanotubule connections. Our data support a highly dynamic rather than a static nature of the glomerular environment and cellular composition. Future application of this new approach should advance our understanding of the mechanisms of glomerular injury and regeneration.", + "TAG_DATA": [ + "54, in {'context': 'B-in vivo'}", + "55, vivo. {'context': 'I-in vivo'}", + "57, podocin-GFP {'perturbing_action': 'B-gene gain-of-function'}", + "58, mice, {'context': 'B-organism'}", + "59, podocytes {'context': 'B-cells'}", + "82, mice {'context': 'B-organism'}", + "95, migration {'phenotype': 'B-migration'}", + "98, podocytes. {'context': 'B-cells'}", + "100, phosphoenolpyruvate {'perturbing_action': 'B-gene gain-of-function'}", + "103, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "54, in ['l0', 'l1', 'l2', 'l3']", + "55, vivo. ['l0', 'l4', 'l5', 'l6']", + "57, podocin-GFP ['l1', 'l4', 'l7', 'l8']", + "58, mice, ['l2', 'l5', 'l7', 'l9']", + "59, podocytes ['l3', 'l6', 'l8', 'l9']", + "82, mice ['l10', 'l11']", + "95, migration ['l10', 'l12']", + "98, podocytes. ['l11', 'l12']", + "100, phosphoenolpyruvate ['l13']", + "103, mice, ['l13']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "podocin-GFP" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "podocin-GFP", + "phosphoenolpyruvate" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "podocin-GFP" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocytes" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocytes." + ] + } + } + ] + }, + { + "PMID": "24185693", + "TEXT": "Hypertension and chronic kidney disease (CKD) are complex traits representing major global health problems. Multiple genome-wide association studies have identified common variants in the promoter of the UMOD gene, which encodes uromodulin, the major protein secreted in normal urine, that cause independent susceptibility to CKD and hypertension. Despite compelling genetic evidence for the association between UMOD risk variants and disease susceptibility in the general population, the underlying biological mechanism is not understood. Here, we demonstrate that UMOD risk variants increased UMOD expression in vitro and in vivo. Uromodulin overexpression in transgenic mice led to salt-sensitive hypertension and to the presence of age-dependent renal lesions similar to those observed in elderly individuals homozygous for UMOD promoter risk variants. The link between uromodulin and hypertension is due to activation of the renal sodium cotransporter NKCC2. We demonstrated the relevance of this mechanism in humans by showing that pharmacological inhibition of NKCC2 was more effective in lowering blood pressure in hypertensive patients who are homozygous for UMOD promoter risk variants than in other hypertensive patients. Our findings link genetic susceptibility to hypertension and CKD to the level of uromodulin expression and uromodulin's effect on salt reabsorption in the kidney. These findings point to uromodulin as a therapeutic target for lowering blood pressure and preserving renal function.", + "TAG_DATA": [ + "82, in {'context': 'B-in vitro'}", + "83, vitro {'context': 'I-in vitro'}", + "85, in {'context': 'B-in vivo'}", + "86, vivo. {'context': 'I-in vivo'}", + "87, Uromodulin {'perturbing_action': 'B-gene gain-of-function'}", + "88, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "90, transgenic {'perturbing_action': 'B-gene gain-of-function', 'context': 'B-cells'}", + "91, mice {'context': 'I-organism'}", + "145, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "146, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "147, of {'perturbing_action': 'I-pharmacological inhibition'}", + "148, NKCC2 {'perturbing_action': 'I-pharmacological inhibition'}", + "157, hypertensive {'context': 'B-patient'}", + "158, patients {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "82, in ['l0', 'l1', 'l2']", + "83, vitro ['l0', 'l3', 'l4']", + "85, in ['l1', 'l3', 'l5']", + "86, vivo. ['l2', 'l4', 'l5']", + "87, Uromodulin ['l6', 'l7', 'l8']", + "88, overexpression ['l6', 'l9', 'l10']", + "90, transgenic ['l7', 'l9', 'l11']", + "91, mice ['l8', 'l10', 'l11']", + "145, pharmacological ['l12', 'l13', 'l14', 'l15', 'l16']", + "146, inhibition ['l12', 'l17', 'l18', 'l19', 'l20']", + "147, of ['l13', 'l17', 'l21', 'l22', 'l23']", + "148, NKCC2 ['l14', 'l18', 'l21', 'l24', 'l25']", + "157, hypertensive ['l15', 'l19', 'l22', 'l24', 'l26']", + "158, patients ['l16', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Uromodulin", + "overexpression", + "transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Uromodulin", + "overexpression", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "NKCC2" + ] + }, + "context": { + "val": "patient", + "words": [ + "hypertensive", + "patients" + ] + } + } + ] + }, + { + "PMID": "24162814", + "TEXT": "Globally, about 1% of pregnant women are persistently infected with the hepatitis C virus (HCV). Mother-to-child transmission of HCV occurs in 3-5% of pregnancies and accounts for most new childhood infections. HCV-specific CD8(+) cytotoxic T lymphocytes (CTLs) are vital in the clearance of acute HCV infections, but in the 60-80% of infections that persist, these cells become functionally exhausted or select for mutant viruses that escape T cell recognition. Increased HCV replication during pregnancy suggests that maternofetal immune tolerance mechanisms may further impair HCV-specific CTLs, limiting their selective pressure on persistent viruses. To assess this possibility, we characterized circulating viral quasispecies during and after consecutive pregnancies in two women. This revealed a loss of some escape mutations in HLA class I epitopes during pregnancy that was associated with emergence of more fit viruses. CTL selective pressure was reimposed after childbirth, at which point escape mutations in these epitopes again predominated in the quasispecies and viral load dropped sharply. Importantly, the viruses transmitted perinatally were those with enhanced fitness due to reversion of escape mutations. Our findings indicate that the immunoregulatory changes of pregnancy reduce CTL selective pressure on HCV class I epitopes, thereby facilitating vertical transmission of viruses with optimized replicative fitness.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24141423", + "TEXT": "Sirtuin 1 (Sirt1), a NAD(+)-regulated deacetylase with numerous known positive effects on cellular and whole-body metabolism, is expressed in the renal cortex and medulla. It is known to have protective effects against age-related disease, including diabetes. Here we investigated the protective role of Sirt1 in diabetic renal damage. We found that Sirt1 in proximal tubules (PTs) was downregulated before albuminuria occurred in streptozotocin-induced or obese (db/db) diabetic mice. PT-specific SIRT1 transgenic and Sirt1 knockout mice showed prevention and aggravation of the glomerular changes that occur in diabetes, respectively, and nondiabetic knockout mice exhibited albuminuria, suggesting that Sirt1 in PTs affects glomerular function. Downregulation of Sirt1 and upregulation of the tight junction protein Claudin-1 by SIRT1-mediated epigenetic regulation in podocytes contributed to albuminuria. We did not observe these phenomena in 5/6 nephrectomized mice. We also demonstrated retrograde interplay from PTs to glomeruli using nicotinamide mononucleotide (NMN) from conditioned medium, measurement of the autofluorescence of photoactivatable NMN and injection of fluorescence-labeled NMN. In human subjects with diabetes, the levels of SIRT1 and Claudin-1 were correlated with proteinuria levels. These results suggest that Sirt1 in PTs protects against albuminuria in diabetes by maintaining NMN concentrations around glomeruli, thus influencing podocyte function.", + "TAG_DATA": [ + "66, diabetic {'context': 'I-organism'}", + "67, mice. {'context': 'I-organism'}", + "68, PT-specific {'perturbing_action': 'B-gene gain-of-function'}", + "69, SIRT1 {'perturbing_action': 'I-gene gain-of-function'}", + "70, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "72, Sirt1 {'perturbing_action': 'B-gene loss-of-function'}", + "73, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "74, mice {'context': 'B-organism'}", + "91, mice {'context': 'B-organism'}", + "131, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "66, diabetic ['l0']", + "67, mice. ['l0']", + "68, PT-specific ['l1', 'l2', 'l3', 'l4', 'l5']", + "69, SIRT1 ['l1', 'l6', 'l7', 'l8', 'l9']", + "70, transgenic ['l2', 'l6', 'l10', 'l11', 'l12']", + "72, Sirt1 ['l3', 'l7', 'l10', 'l13', 'l14']", + "73, knockout ['l4', 'l8', 'l11', 'l13', 'l15']", + "74, mice ['l5', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PT-specific", + "SIRT1", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sirt1", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "24141421", + "TEXT": "Here we show that Mst1, a proapoptotic kinase, impairs protein quality control mechanisms in the heart through inhibition of autophagy. Stress-induced activation of Mst1 in cardiomyocytes promoted accumulation of p62 and aggresome formation, accompanied by the disappearance of autophagosomes. Mst1 phosphorylated the Thr108 residue in the BH3 domain of Beclin1, which enhanced the interaction between Beclin1 and Bcl-2 and/or Bcl-xL, stabilized the Beclin1 homodimer, inhibited the phosphatidylinositide 3-kinase activity of the Atg14L-Beclin1-Vps34 complex and suppressed autophagy. Furthermore, Mst1-induced sequestration of Bcl-2 and Bcl-xL by Beclin1 allows Bax to become active, thereby stimulating apoptosis. Mst1 promoted cardiac dysfunction in mice subjected to myocardial infarction by inhibiting autophagy, associated with increased levels of Thr108-phosphorylated Beclin1. Moreover, dilated cardiomyopathy in humans was associated with increased levels of Thr108-phosphorylated Beclin1 and signs of autophagic suppression. These results suggest that Mst1 coordinately regulates autophagy and apoptosis by phosphorylating Beclin1 and consequently modulating a three-way interaction among Bcl-2 proteins, Beclin1 and Bax.", + "TAG_DATA": [ + "25, cardiomyocytes {'context': 'B-cells'}", + "74, suppressed {'effect': 'B-negative'}", + "75, autophagy. {'phenotype': 'B-autophagy'}", + "91, stimulating {'effect': 'B-positive'}", + "92, apoptosis. {'phenotype': 'B-apoptosis'}", + "98, mice {'context': 'B-organism'}", + "104, inhibiting {'effect': 'B-negative'}", + "105, autophagy, {'phenotype': 'B-autophagy'}" + ], + "LINK_DATA": [ + "74, suppressed ['l0', 'l1', 'l2']", + "75, autophagy. ['l0', 'l3', 'l4']", + "91, stimulating ['l1', 'l3', 'l5']", + "92, apoptosis. ['l2', 'l4', 'l5']", + "98, mice ['l6', 'l7']", + "104, inhibiting ['l6', 'l8']", + "105, autophagy, ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "suppressed", + "inhibiting" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy.", + "autophagy," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy." + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulating" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulating" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibiting" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + } + } + ] + }, + { + "PMID": "24100980", + "TEXT": "A signaling cascade is activated in podocytes to induce survival and cope with stress during advanced glomerular disease, a new study shows. The findings may also explain why the immunosuppressor sirolimus, an inhibitor of this pathway, can cause proteinuria in a subset of patients with chronic kidney disease (pages 1288–1296).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24013746", + "TEXT": "Macrophages accumulate in atherosclerotic lesions during the inflammation that is part of atherosclerosis development and progression. A new study in mice indicates that the accumulation of macrophages in atherosclerotic plaques depends on local macrophage proliferation rather than the recruitment of circulating monocytes.", + "TAG_DATA": [ + "20, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24013745", + "TEXT": "Interleukin-17 (IL-17) released in the tumor microenvironment in response to drugs blocking vascular endothelial growth factor (VEGF) triggers stromal-derived inflammatory and VEGF-independent angiogenic programs that induce the drug refractoriness found in cancers resistant to anti-angiogenic therapy.", + "TAG_DATA": [ + "31, cancers {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24013739", + "TEXT": "In April 2012, an e-mail announcing the impending closure of the Global Health Council following the cancellation of its annual conference sent shockwaves through its community of 325 organizational members spanning 39 countries. For 40 years, the Alexandria, Virginia-based nonprofit had acted as an umbrella organization for stakeholders that include some of the world's most prominent medical institutions and drug companies. As the June 2012 closure of the GHC approached, several members stepped in to rescue the operation, including Jonathan Quick, a family physician and CEO of Management Sciences for Health, a Cambridge, Massachusetts-based outfit that works to strengthen health systems and infrastructure around the globe. In January, a new GHC board was elected, with Quick at the helm. In the ensuing months the board members have built the organization back up-albeit as a leaner and more targeted operation. This past summer, they launched a revamped website (www.globalhealth.org) and are looking ahead to convening GHC members at the UN General Assembly on 18 September in New York, where the discussion of Millennium Development Goals will take place. As Nature Medicine went to press, the relaunched GHC was in the midst of recruiting for its first staff position, executive director. Roxanne Khamsi spoke with Quick about the health of the organization.", + "TAG_DATA": [ + "154, GHC {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23995283", + "TEXT": "Aspergillus fumigatus is a saprophytic fungus that is ubiquitous in the environment and is commonly associated with allergic sensitization and severe asthma in humans. Although A. fumigatus is recognized by multiple microbial pattern-recognition receptors, we found that an A. fumigatus-derived glycosphingolipid, asperamide B, directly activates invariant natural killer T (iNKT) cells in vitro in a CD1d-restricted, MyD88-independent and dectin-1-independent fashion. Moreover, asperamide B, when loaded onto CD1d, directly stained, and was sufficient to activate, human and mouse iNKT cells. In vivo, asperamide B rapidly induced airway hyperreactivity, which is a cardinal feature of asthma, by activating pulmonary iNKT cells in an interleukin-33 (IL-33)-ST2-dependent fashion. Asperamide B is thus the first fungal glycolipid found to directly activate iNKT cells. These results extend the range of microorganisms that can be directly detected by iNKT cells to the kingdom of fungi and may explain how A. fumigatus can induce severe chronic respiratory diseases in humans.", + "TAG_DATA": [ + "45, invariant {'context': 'B-cells'}", + "46, natural {'context': 'I-cells'}", + "47, killer {'context': 'I-cells'}", + "48, T {'context': 'I-cells'}", + "49, (iNKT) {'context': 'I-cells'}", + "50, cells {'context': 'I-cells'}", + "51, in {'context': 'B-in vitro'}", + "52, vitro {'context': 'I-in vitro'}", + "74, human {'context': 'B-cells'}", + "75, and {'context': 'I-cells'}", + "76, mouse {'context': 'I-cells'}", + "77, iNKT {'context': 'I-cells'}", + "78, cells. {'context': 'I-cells'}", + "79, In {'context': 'B-in vivo'}", + "80, vivo, {'context': 'I-in vivo'}", + "96, pulmonary {'context': 'B-cells'}", + "97, iNKT {'context': 'I-cells'}", + "98, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, invariant ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "46, natural ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "47, killer ['l1', 'l7', 'l14', 'l15', 'l16', 'l17', 'l18']", + "48, T ['l2', 'l8', 'l14', 'l19', 'l20', 'l21', 'l22']", + "49, (iNKT) ['l3', 'l9', 'l15', 'l19', 'l23', 'l24', 'l25']", + "50, cells ['l4', 'l10', 'l16', 'l20', 'l23', 'l26', 'l27']", + "51, in ['l5', 'l11', 'l17', 'l21', 'l24', 'l26', 'l28']", + "52, vitro ['l6', 'l12', 'l18', 'l22', 'l25', 'l27', 'l28']", + "74, human ['l29', 'l30', 'l31', 'l32']", + "75, and ['l29', 'l33', 'l34', 'l35']", + "76, mouse ['l30', 'l33', 'l36', 'l37']", + "77, iNKT ['l31', 'l34', 'l36', 'l38']", + "78, cells. ['l13', 'l32', 'l35', 'l37', 'l38']", + "79, In ['l39', 'l40', 'l41', 'l42']", + "80, vivo, ['l39', 'l43', 'l44', 'l45']", + "96, pulmonary ['l40', 'l43', 'l46', 'l47']", + "97, iNKT ['l41', 'l44', 'l46', 'l48']", + "98, cells ['l42', 'l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23975026", + "TEXT": "Beta-cell dysfunction and impaired insulin production are hallmarks of diabetes, but despite the growing diabetes epidemic, the molecular mechanisms underlying this disease have remained unclear. We identified thioredoxin-interacting protein (TXNIP), a cellular redox regulator, as a crucial factor in beta-cell biology and show that beta-cell TXNIP is upregulated in diabetes, whereas TXNIP deficiency protects against diabetes by preventing beta-cell apoptosis. Here we show that TXNIP and diabetes induce beta-cell expression of a specific microRNA, miR-204, which in turn blocks insulin production by directly targeting and downregulating MAFA, a known insulin transcription factor. In particular, we first discovered the regulation of miR-204 by TXNIP by microarray analysis, followed by validation studies in INS-1 beta cells, islets of Txnip-deficient mice, diabetic mouse models and primary human islets. We then further found that TXNIP induces miR-204 by inhibiting the activity of signal transducer and activator of transcription 3 (STAT3), a transcription factor that is involved in miR-204 regulation. We also identified MAFA as a target that is downregulated by miR-204. Taken together, our results demonstrate that TXNIP controls microRNA expression and insulin production and that miR-204 is involved in beta-cell function. The newly identified TXNIP-miR-204-MAFA-insulin pathway may contribute to diabetes progression and provides new insight into TXNIP function and microRNA biology in health and disease.", + "TAG_DATA": [ + "111, INS-1 {'context': 'B-cells'}", + "112, beta {'context': 'I-cells'}", + "113, cells, {'context': 'I-cells'}", + "114, islets {'context': 'B-cells'}", + "116, Txnip-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "117, mice, {'context': 'B-organism'}", + "118, diabetic {'context': 'B-organism'}", + "119, mouse {'context': 'I-organism'}", + "120, models {'context': 'I-organism'}", + "122, primary {'context': 'B-cells'}", + "123, human {'context': 'I-cells'}", + "124, islets. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "111, INS-1 ['l0', 'l1', 'l2', 'l3', 'l4']", + "112, beta ['l0', 'l5', 'l6']", + "113, cells, ['l1', 'l5', 'l7']", + "114, islets ['l2', 'l6', 'l7', 'l8', 'l9', 'l10']", + "116, Txnip-deficient ['l3', 'l8', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "117, mice, ['l4', 'l9', 'l11', 'l17']", + "118, diabetic ['l18', 'l19', 'l20', 'l21', 'l22']", + "119, mouse ['l12', 'l18', 'l23', 'l24', 'l25', 'l26']", + "120, models ['l10', 'l13', 'l17', 'l19', 'l23', 'l27', 'l28', 'l29']", + "122, primary ['l14', 'l20', 'l24', 'l27', 'l30', 'l31']", + "123, human ['l15', 'l21', 'l25', 'l28', 'l30', 'l32']", + "124, islets. ['l16', 'l22', 'l26', 'l29', 'l31', 'l32']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "INS-1", + "islets", + "primary", + "human", + "islets." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Txnip-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Txnip-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mouse", + "models" + ] + } + } + ] + }, + { + "PMID": "23872715", + "TEXT": "Eosinophilic esophagitis (EoE) is a food allergy-associated inflammatory disease characterized by esophageal eosinophilia. Current management strategies for EoE are nonspecific, and thus there is a need to identify specific immunological pathways that could be targeted to treat this disease. EoE is associated with polymorphisms in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation, but how TSLP might contribute to EoE disease pathogenesis has been unclear. Here, we describe a new mouse model of EoE-like disease that developed independently of IgE, but was dependent on TSLP and basophils, as targeting TSLP or basophils during the sensitization phase limited disease. Notably, therapeutic TSLP neutralization or basophil depletion also ameliorated established EoE-like disease. In human subjects with EoE, we observed elevated TSLP expression and exaggerated basophil responses in esophageal biopsies, and a gain-of-function TSLP polymorphism was associated with increased basophil responses in patients with EoE. Together, these data suggest that the TSLP-basophil axis contributes to the pathogenesis of EoE and could be therapeutically targeted to treat this disease.", + "TAG_DATA": [ + "107, neutralization {'perturbing_action': 'I-rnai/knockdown'}", + "135, gain-of-function {'perturbing_action': 'B-gene gain-of-function'}", + "136, TSLP {'perturbing_action': 'I-gene gain-of-function'}", + "137, polymorphism {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "135, gain-of-function ['l0', 'l1']", + "136, TSLP ['l0', 'l2']", + "137, polymorphism ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23836211", + "TEXT": "Most research prizes in biomedicine, from the Nobels to the Laskers, are restricted to three recipients. But in an age of big science, when much larger teams are generally needed to make important research discoveries, all the people who provide seminal contributions deserve to be awarded.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23832090", + "TEXT": "Tumors have a greater reliance on anaerobic glycolysis for energy production than normal tissues. We developed a noninvasive method for imaging glucose uptake in vivo that is based on magnetic resonance imaging and allows the uptake of unlabeled glucose to be measured through the chemical exchange of protons between hydroxyl groups and water. This method differs from existing molecular imaging methods because it permits detection of the delivery and uptake of a metabolically active compound in physiological quantities. We show that our technique, named glucose chemical exchange saturation transfer (glucoCEST), is sensitive to tumor glucose accumulation in colorectal tumor models and can distinguish tumor types with differing metabolic characteristics and pathophysiologies. The results of this study suggest that glucoCEST has potential as a useful and cost-effective method for characterizing disease and assessing response to therapy in the clinic.", + "TAG_DATA": [ + "97, colorectal {'context': 'B-neoplasm'}", + "98, tumor {'context': 'I-neoplasm'}", + "99, models {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "97, colorectal ['l0', 'l1']", + "98, tumor ['l0', 'l2']", + "99, models ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23793099", + "TEXT": "Here we show that glioblastoma express high levels of branched-chain amino acid transaminase 1 (BCAT1), the enzyme that initiates the catabolism of branched-chain amino acids (BCAAs). Expression of BCAT1 was exclusive to tumors carrying wild-type isocitrate dehydrogenase 1 (IDH1) and IDH2 genes and was highly correlated with methylation patterns in the BCAT1 promoter region. BCAT1 expression was dependent on the concentration of α-ketoglutarate substrate in glioma cell lines and could be suppressed by ectopic overexpression of mutant IDH1 in immortalized human astrocytes, providing a link between IDH1 function and BCAT1 expression. Suppression of BCAT1 in glioma cell lines blocked the excretion of glutamate and led to reduced proliferation and invasiveness in vitro, as well as significant decreases in tumor growth in a glioblastoma xenograft model. These findings suggest a central role for BCAT1 in glioma pathogenesis, making BCAT1 and BCAA metabolism attractive targets for the development of targeted therapeutic approaches to treat patients with glioblastoma.", + "TAG_DATA": [ + "73, ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "74, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "75, of {'perturbing_action': 'I-gene gain-of-function'}", + "76, mutant {'perturbing_action': 'I-gene gain-of-function'}", + "77, IDH1 {'perturbing_action': 'I-gene gain-of-function'}", + "79, immortalized {'context': 'B-cells'}", + "80, human {'context': 'I-cells'}", + "81, astrocytes, {'context': 'I-cells'}", + "91, Suppression {'perturbing_action': 'B-pharmacological inhibition'}", + "92, of {'perturbing_action': 'I-pharmacological inhibition'}", + "93, BCAT1 {'perturbing_action': 'I-pharmacological inhibition'}", + "95, glioma {'context': 'B-transformed cells'}", + "96, cell {'context': 'I-transformed cells'}", + "97, lines {'context': 'I-transformed cells'}", + "106, reduced {'effect': 'B-negative'}", + "107, proliferation {'phenotype': 'B-proliferation'}", + "109, invasiveness {'phenotype': 'B-invasion'}", + "110, in {'context': 'B-in vitro'}", + "111, vitro, {'context': 'I-in vitro'}", + "116, decreases {'effect': 'B-negative'}", + "118, tumor {'phenotype': 'B-tumour growth'}", + "119, growth {'phenotype': 'I-tumour growth'}", + "122, glioblastoma {'context': 'B-xenograft'}", + "123, xenograft {'context': 'I-xenograft'}", + "124, model. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "73, ectopic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "74, overexpression ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "75, of ['l1', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "76, mutant ['l2', 'l13', 'l22', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "77, IDH1 ['l3', 'l14', 'l23', 'l32', 'l40', 'l41', 'l42']", + "79, immortalized ['l4', 'l15', 'l24', 'l33', 'l40', 'l43', 'l44']", + "80, human ['l5', 'l16', 'l25', 'l34', 'l41', 'l43', 'l45']", + "81, astrocytes, ['l6', 'l17', 'l26', 'l35', 'l42', 'l44', 'l45']", + "91, Suppression ['l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "92, of ['l46', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "93, BCAT1 ['l47', 'l62', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "95, glioma ['l48', 'l63', 'l77', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "96, cell ['l7', 'l18', 'l27', 'l36', 'l49', 'l64', 'l78', 'l91', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "97, lines ['l8', 'l19', 'l28', 'l37', 'l50', 'l65', 'l79', 'l92', 'l99', 'l105', 'l106', 'l107', 'l108', 'l109']", + "106, reduced ['l9', 'l20', 'l29', 'l38', 'l51', 'l66', 'l80', 'l93', 'l100', 'l105', 'l110', 'l111', 'l112', 'l113']", + "107, proliferation ['l10', 'l21', 'l30', 'l39', 'l52', 'l67', 'l81', 'l94', 'l101', 'l106', 'l110', 'l114', 'l115', 'l116']", + "109, invasiveness ['l11', 'l31', 'l53', 'l68', 'l82', 'l95', 'l102', 'l107', 'l111', 'l114', 'l117', 'l118']", + "110, in ['l54', 'l69', 'l83', 'l96', 'l103', 'l108', 'l112', 'l115', 'l117', 'l119']", + "111, vitro, ['l55', 'l70', 'l84', 'l97', 'l104', 'l109', 'l113', 'l116', 'l118', 'l119']", + "116, decreases ['l56', 'l71', 'l85', 'l98', 'l120', 'l121', 'l122', 'l123', 'l124']", + "118, tumor ['l57', 'l72', 'l86', 'l120', 'l125', 'l126', 'l127', 'l128']", + "119, growth ['l58', 'l73', 'l87', 'l121', 'l125', 'l129', 'l130', 'l131']", + "122, glioblastoma ['l59', 'l74', 'l88', 'l122', 'l126', 'l129', 'l132', 'l133']", + "123, xenograft ['l60', 'l75', 'l89', 'l123', 'l127', 'l130', 'l132', 'l134']", + "124, model. ['l61', 'l76', 'l90', 'l124', 'l128', 'l131', 'l133', 'l134']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "mutant", + "IDH1" + ] + }, + "context": { + "val": "cells", + "words": [ + "immortalized", + "human", + "astrocytes," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "mutant" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cell", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "mutant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "mutant" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "of" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Suppression", + "of", + "BCAT1" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "glioma", + "cell", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Suppression", + "of", + "BCAT1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced", + "decreases" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Suppression", + "of", + "BCAT1" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Suppression", + "of", + "BCAT1" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Suppression", + "of", + "BCAT1" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Suppression", + "of", + "BCAT1" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Suppression", + "of", + "BCAT1" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "glioblastoma", + "xenograft", + "model." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "glioma", + "cell", + "lines" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced", + "decreases" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "glioma", + "cell", + "lines" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "glioma", + "cell", + "lines" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreases" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreases" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "glioblastoma", + "xenograft", + "model." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "glioblastoma", + "xenograft", + "model." + ] + } + } + ] + }, + { + "PMID": "23770691", + "TEXT": "The clinical application of adeno-associated virus vectors (AAVs) is limited because of concerns about AAV integration-mediated tumorigenicity. We performed integration-site analysis after AAV1-LPL(S447X) intramuscular injection in five lipoprotein lipase-deficient subjects, revealing random nuclear integration and hotspots in mitochondria. We conclude that AAV integration is potentially safe and that vector breakage and integration may occur from each position of the vector genome. Future viral integration-site analyses should include the mitochondrial genome.", + "TAG_DATA": [ + "27, lipoprotein {'perturbing_action': 'B-gene loss-of-function'}", + "28, lipase-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "29, subjects, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "27, lipoprotein ['l0', 'l1']", + "28, lipase-deficient ['l0', 'l2']", + "29, subjects, ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lipoprotein", + "lipase-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "subjects," + ] + } + } + ] + }, + { + "PMID": "23744146", + "TEXT": "New insights into the actions of the hormone glucagon are provided by a recent study in rodents, which shows that glucagon can suppress hepatic glucose production by acting through the mediobasal hypothalamic region of the brain. This central regulatory mechanism is impaired in rats fed a high-fat diet, suggesting that hypothalamic glucagon resistance may be relevant to the hyperglycemia observed in obesity, diabetes or both (pages 766–772).", + "TAG_DATA": [ + "16, rodents, {'context': 'B-organism'}", + "43, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23733210", + "TEXT": "A new regulatory pathway established last year allows drugs with dramatic early clinical promise to be expedited to the market quicker than ever before. To date, most of these 'breakthrough' designations have gone to cancer agents, raising the prospect of faster access to the latest lifesaving therapies for the estimated 4,500 people newly diagnosed with cancer each day in the US. Elie Dolgin looks at what sets these breakthrough medicines apart.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23708291", + "TEXT": "The commensal flora can promote both immunity to pathogens and mucosal inflammation. How commensal-driven inflammation is regulated in the context of infection remains poorly understood. Here, we show that during acute mucosal infection of mice with Toxoplasma gondii, inflammatory monocytes acquire a tissue-specific regulatory phenotype associated with production of the lipid mediator prostaglandin E2 (PGE2). Notably, in response to commensals, inflammatory monocytes can directly inhibit neutrophil activation in a PGE2-dependent manner. Further, in the absence of inflammatory monocytes, mice develop severe neutrophil-mediated pathology in response to pathogen challenge that can be controlled by PGE2 analog treatment. Complementing these findings, inhibition of PGE2 led to enhanced neutrophil activation and host mortality after infection. These data demonstrate a previously unappreciated dual action of inflammatory monocytes in controlling pathogen expansion while limiting commensal-mediated damage to the gut. Collectively, our results place inflammatory monocyte-derived PGE2 at the center of a commensal-driven regulatory loop required to control host-commensal dialog during pathogen-induced inflammation.", + "TAG_DATA": [ + "34, mice {'context': 'B-organism'}", + "74, absence {'perturbing_action': 'B-gene loss-of-function'}", + "75, of {'perturbing_action': 'I-gene loss-of-function'}", + "76, inflammatory {'perturbing_action': 'I-gene loss-of-function'}", + "77, monocytes, {'perturbing_action': 'I-gene loss-of-function'}", + "78, mice {'context': 'B-organism'}", + "99, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "100, of {'perturbing_action': 'I-pharmacological inhibition'}", + "101, PGE2 {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "74, absence ['l0', 'l1', 'l2', 'l3']", + "75, of ['l0', 'l4', 'l5', 'l6']", + "76, inflammatory ['l1', 'l4', 'l7', 'l8']", + "77, monocytes, ['l2', 'l5', 'l7', 'l9']", + "78, mice ['l3', 'l6', 'l8', 'l9']", + "99, inhibition ['l10', 'l11']", + "100, of ['l10', 'l12']", + "101, PGE2 ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "inflammatory", + "monocytes," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23685843", + "TEXT": "To study T cell activation in vivo in real time, we introduced a newly developed fluorescence resonance energy transfer-based, genetically encoded calcium indicator into autoantigen-specific and non-autoantigen-specific CD4(+) T cells. Using two-photon microscopy, we explored the responses of retrovirally transduced calcium indicator-expressing T cells to antigen in the lymph nodes and the central nervous system. In lymph nodes, the administration of exogenous antigen caused an almost immediate arrest of T cells around antigen-presenting cells and an instant rise of cytosolic calcium. In contrast, encephalitogenic T cells entering the leptomeningeal space, one main portal into the central nervous system parenchyma during experimental autoimmune encephalomyelitis, showed elevated intracellular calcium concentrations while still meandering through the space. This approach enabled us to follow the migration and activation patterns of T cells in vivo during the course of the disease.", + "TAG_DATA": [ + "42, T {'context': 'B-cells'}", + "43, cells {'context': 'B-cells'}", + "56, lymph {'context': 'B-tissue/organ'}", + "57, nodes, {'context': 'I-tissue/organ'}", + "69, T {'context': 'B-cells'}", + "70, cells {'context': 'B-cells'}", + "72, antigen-presenting {'context': 'B-cells'}", + "73, cells {'context': 'I-cells'}", + "84, T {'context': 'I-cells'}", + "85, cells {'context': 'I-cells'}", + "126, T {'context': 'B-cells'}", + "127, cells {'context': 'B-cells'}", + "128, in {'context': 'B-in vivo'}", + "129, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "42, T ['l0', 'l1', 'l2']", + "43, cells ['l0', 'l3']", + "56, lymph ['l4', 'l5', 'l6', 'l7', 'l8']", + "57, nodes, ['l1', 'l3', 'l4', 'l9', 'l10', 'l11', 'l12']", + "69, T ['l5', 'l9', 'l13', 'l14', 'l15']", + "70, cells ['l2', 'l6', 'l10', 'l13', 'l16', 'l17']", + "72, antigen-presenting ['l7', 'l11', 'l14', 'l16', 'l18']", + "73, cells ['l8', 'l12', 'l15', 'l17', 'l18']", + "84, T ['l19']", + "85, cells ['l19']", + "126, T ['l20', 'l21', 'l22']", + "127, cells ['l20', 'l23', 'l24']", + "128, in ['l21', 'l23', 'l25']", + "129, vivo ['l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23644516", + "TEXT": "Substantial regressions of metastatic lesions have been observed in up to 70% of patients with melanoma who received adoptively transferred autologous tumor-infiltrating lymphocytes (TILs) in phase 2 clinical trials. In addition, 40% of patients treated in a recent trial experienced complete regressions of all measurable lesions for at least 5 years following TIL treatment. To evaluate the potential association between the ability of TILs to mediate durable regressions and their ability to recognize potent antigens that presumably include mutated gene products, we developed a new screening approach involving mining whole-exome sequence data to identify mutated proteins expressed in patient tumors. We then synthesized and evaluated candidate mutated T cell epitopes that were identified using a major histocompatibility complex-binding algorithm for recognition by TILs. Using this approach, we identified mutated antigens expressed on autologous tumor cells that were recognized by three bulk TIL lines from three individuals with melanoma that were associated with objective tumor regressions following adoptive transfer. This simplified approach for identifying mutated antigens recognized by T cells avoids the need to generate and laboriously screen cDNA libraries from tumors and may represent a generally applicable method for identifying mutated antigens expressed in a variety of tumor types.", + "TAG_DATA": [ + "132, autologous {'context': 'B-transformed cells'}", + "133, tumor {'context': 'I-transformed cells'}", + "134, cells {'context': 'I-transformed cells'}", + "140, bulk {'context': 'B-cells'}", + "141, TIL {'context': 'I-cells'}", + "142, lines {'context': 'I-cells'}", + "147, melanoma {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "132, autologous ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "133, tumor ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "134, cells ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "140, bulk ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "141, TIL ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "142, lines ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "147, melanoma ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23644515", + "TEXT": "Major depressive disorder (MDD) is a cause of disability that affects approximately 16% of the world's population; however, little is known regarding the underlying biology of this disorder. Animal studies, postmortem brain analyses and imaging studies of patients with depression have implicated glial dysfunction in MDD pathophysiology. However, the molecular mechanisms through which astrocytes modulate depressive behaviors are largely uncharacterized. Here, we identified ATP as a key factor involved in astrocytic modulation of depressive-like behavior in adult mice. We observed low ATP abundance in the brains of mice that were susceptible to chronic social defeat. Furthermore, we found that the administration of ATP induced a rapid antidepressant-like effect in these mice. Both a lack of inositol 1,4,5-trisphosphate receptor type 2 and transgenic blockage of vesicular gliotransmission induced deficiencies in astrocytic ATP release, causing depressive-like behaviors that could be rescued via the administration of ATP. Using transgenic mice that express a Gq G protein-coupled receptor only in astrocytes to enable selective activation of astrocytic Ca(2+) signaling, we found that stimulating endogenous ATP release from astrocytes induced antidepressant-like effects in mouse models of depression. Moreover, we found that P2X2 receptors in the medial prefrontal cortex mediated the antidepressant-like effects of ATP. These results highlight astrocytic ATP release as a biological mechanism of MDD.", + "TAG_DATA": [ + "87, mice {'context': 'B-organism'}", + "110, mice. {'context': 'B-organism'}", + "113, lack {'perturbing_action': 'B-gene loss-of-function'}", + "145, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "146, mice {'context': 'I-organism'}", + "148, express {'perturbing_action': 'I-gene gain-of-function'}", + "149, a {'perturbing_action': 'I-gene gain-of-function'}", + "150, Gq {'perturbing_action': 'I-gene gain-of-function'}", + "151, G {'perturbing_action': 'I-gene gain-of-function'}", + "152, protein-coupled {'perturbing_action': 'I-gene gain-of-function'}", + "153, receptor {'perturbing_action': 'I-gene gain-of-function'}", + "154, only {'perturbing_action': 'I-gene gain-of-function'}", + "156, astrocytes {'context': 'B-cells'}", + "173, astrocytes {'context': 'B-cells'}", + "178, mouse {'context': 'B-organism'}", + "179, models {'context': 'I-organism'}", + "180, of {'context': 'I-organism'}", + "181, depression. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "87, mice ['l0']", + "110, mice. ['l0']", + "145, transgenic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "146, mice ['l1', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "148, express ['l2', 'l15', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "149, a ['l3', 'l16', 'l28', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "150, Gq ['l4', 'l17', 'l29', 'l40', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "151, G ['l5', 'l18', 'l30', 'l41', 'l51', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "152, protein-coupled ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "153, receptor ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "154, only ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "156, astrocytes ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l91', 'l92', 'l93', 'l94', 'l95']", + "173, astrocytes ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l96', 'l97', 'l98', 'l99']", + "178, mouse ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l100', 'l101', 'l102']", + "179, models ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l103', 'l104']", + "180, of ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l105']", + "181, depression. ['l14', 'l27', 'l39', 'l50', 'l60', 'l69', 'l77', 'l84', 'l90', 'l95', 'l99', 'l102', 'l104', 'l105']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "express", + "a", + "Gq", + "G", + "protein-coupled", + "receptor", + "only" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "models", + "of", + "depression." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "express", + "a", + "Gq", + "G", + "protein-coupled", + "receptor", + "only" + ] + }, + "context": { + "val": "cells", + "words": [ + "astrocytes" + ] + } + } + ] + }, + { + "PMID": "23603815", + "TEXT": "The imbalance between energy intake and expenditure is the underlying cause of the current obesity and diabetes pandemics. Central to these pathologies is the fat depot: white adipose tissue (WAT) stores excess calories, and brown adipose tissue (BAT) consumes fuel for thermogenesis using tissue-specific uncoupling protein 1 (UCP1). BAT was once thought to have a functional role in rodents and human infants only, but it has been recently shown that in response to mild cold exposure, adult human BAT consumes more glucose per gram than any other tissue. In addition to this nonshivering thermogenesis, human BAT may also combat weight gain by becoming more active in the setting of increased whole-body energy intake. This phenomenon of BAT-mediated diet-induced thermogenesis has been observed in rodents and suggests that activation of human BAT could be used as a safe treatment for obesity and metabolic dysregulation. In this study, we isolated anatomically defined neck fat from adult human volunteers and compared its gene expression, differentiation capacity and basal oxygen consumption to different mouse adipose depots. Although the properties of human neck fat vary substantially between individuals, some human samples share many similarities with classical, also called constitutive, rodent BAT.", + "TAG_DATA": [ + "151, fat {'context': 'I-tissue/organ'}", + "153, adult {'context': 'B-organism'}", + "154, human {'context': 'I-organism'}", + "155, volunteers {'context': 'I-organism'}", + "169, mouse {'context': 'B-tissue/organ'}", + "170, adipose {'context': 'I-tissue/organ'}", + "171, depots. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "150, neck ['l0', 'l1', 'l2', 'l3', 'l4']", + "151, fat ['l0', 'l5', 'l6', 'l7']", + "153, adult ['l1', 'l5', 'l8', 'l9', 'l10', 'l11', 'l12']", + "154, human ['l2', 'l6', 'l8', 'l13', 'l14', 'l15', 'l16']", + "155, volunteers ['l3', 'l7', 'l9', 'l13', 'l17', 'l18', 'l19']", + "169, mouse ['l10', 'l14', 'l17', 'l20', 'l21']", + "170, adipose ['l11', 'l15', 'l18', 'l20', 'l22']", + "171, depots. ['l4', 'l12', 'l16', 'l19', 'l21', 'l22']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23603813", + "TEXT": "The previously observed supraclavicular depot of brown adipose tissue (BAT) in adult humans was commonly believed to be the equivalent of the interscapular thermogenic organ of small mammals. This view was recently disputed on the basis of the demonstration that this depot consists of beige (also called brite) brown adipocytes, a newly identified type of brown adipocyte that is distinct from the classical brown adipocytes that make up the interscapular thermogenic organs of other mammals. A combination of high-resolution imaging techniques and histological and biochemical analyses showed evidence for an anatomically distinguishable interscapular BAT (iBAT) depot in human infants that consists of classical brown adipocytes, a cell type that has so far not been shown to exist in humans. On the basis of these findings, we conclude that infants, similarly to rodents, have the bona fide iBAT thermogenic organ consisting of classical brown adipocytes that is essential for the survival of small mammals in a cold environment.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23584089", + "TEXT": "Colorectal cancer (CRC) is a major cause of cancer mortality. Whereas some patients respond well to therapy, others do not, and thus more precise, individualized treatment strategies are needed. To that end, we analyzed gene expression profiles from 1,290 CRC tumors using consensus-based unsupervised clustering. The resultant clusters were then associated with therapeutic response data to the epidermal growth factor receptor-targeted drug cetuximab in 80 patients. The results of these studies define six clinically relevant CRC subtypes. Each subtype shares similarities to distinct cell types within the normal colon crypt and shows differing degrees of 'stemness' and Wnt signaling. Subtype-specific gene signatures are proposed to identify these subtypes. Three subtypes have markedly better disease-free survival (DFS) after surgical resection, suggesting these patients might be spared from the adverse effects of chemotherapy when they have localized disease. One of these three subtypes, identified by filamin A expression, does not respond to cetuximab but may respond to cMET receptor tyrosine kinase inhibitors in the metastatic setting. Two other subtypes, with poor and intermediate DFS, associate with improved response to the chemotherapy regimen FOLFIRI in adjuvant or metastatic settings. Development of clinically deployable assays for these subtypes and of subtype-specific therapies may contribute to more effective management of this challenging disease.", + "TAG_DATA": [ + "39, CRC {'context': 'B-neoplasm'}", + "40, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "39, CRC ['l0']", + "40, tumors ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23584088", + "TEXT": "Platelets have a key role in atherogenesis and its complications. Both hypercholesterolemia and increased platelet production promote atherothrombosis; however, a potential link between altered cholesterol homeostasis and platelet production has not been explored. Here we show that transplantation of bone marrow deficient in ABCG4, a transporter of unknown function, into Ldlr(-/-) mice resulted in thrombocytosis, accelerated thrombosis and atherosclerosis. Although not detected in atherosclerotic lesions, Abcg4 was highly expressed in bone marrow megakaryocyte progenitors (MkPs). Abcg4(-/-) MkPs had defective cholesterol efflux to high-density lipoprotein (HDL), increased cell surface expression of the thrombopoietin (TPO) receptor (c-MPL) and enhanced proliferation. These consequences of ABCG4 deficiency seemed to reflect disruption of negative feedback regulation of c-MPL signaling by the E3 ligase c-CBL and the cholesterol-sensing LYN kinase. HDL infusion reduced platelet counts in Ldlr(-/-) mice and in a mouse model of myeloproliferative neoplasm in an ABCG4-dependent fashion. HDL infusions may offer a new approach to reducing atherothrombotic events associated with increased platelet production.", + "TAG_DATA": [ + "39, bone {'perturbing_action': 'I-gene loss-of-function', 'context': 'B-cells'}", + "40, marrow {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-tissue/organ'}", + "41, deficient {'perturbing_action': 'I-gene loss-of-function'}", + "42, in {'perturbing_action': 'I-gene loss-of-function'}", + "43, ABCG4, {'perturbing_action': 'I-gene loss-of-function'}", + "50, Ldlr(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "51, mice {'context': 'B-organism'}", + "55, accelerated {'effect': 'B-positive'}", + "75, Abcg4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "76, MkPs {'context': 'B-cells'}", + "96, enhanced {'effect': 'B-positive'}", + "97, proliferation. {'phenotype': 'B-proliferation'}", + "101, ABCG4 {'perturbing_action': 'B-gene loss-of-function'}", + "102, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "130, Ldlr(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "131, mice {'context': 'B-organism'}", + "135, mouse {'context': 'B-neoplasm'}", + "136, model {'context': 'I-neoplasm'}", + "137, of {'context': 'I-neoplasm'}", + "138, myeloproliferative {'context': 'I-neoplasm'}", + "139, neoplasm {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "39, bone ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "40, marrow ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "41, deficient ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "42, in ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "43, ABCG4, ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "50, Ldlr(-/-) ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "51, mice ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "55, accelerated ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "75, Abcg4(-/-) ['l28', 'l29', 'l30', 'l31']", + "76, MkPs ['l28', 'l32', 'l33', 'l34']", + "96, enhanced ['l29', 'l32', 'l35']", + "97, proliferation. ['l30', 'l33', 'l35', 'l36']", + "101, ABCG4 ['l37', 'l38']", + "102, deficiency ['l31', 'l34', 'l36', 'l37']", + "130, Ldlr(-/-) ['l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "131, mice ['l38', 'l39', 'l45', 'l46']", + "135, mouse ['l40', 'l47', 'l48', 'l49', 'l50']", + "136, model ['l41', 'l47', 'l51', 'l52', 'l53']", + "137, of ['l42', 'l45', 'l48', 'l51', 'l54', 'l55']", + "138, myeloproliferative ['l43', 'l49', 'l52', 'l54', 'l56']", + "139, neoplasm ['l44', 'l46', 'l50', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "bone", + "Abcg4(-/-)", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "bone", + "MkPs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "bone", + "marrow" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "marrow" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "bone", + "marrow", + "deficient", + "in", + "ABCG4,", + "Ldlr(-/-)", + "ABCG4" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "bone", + "marrow", + "deficient", + "in", + "ABCG4,", + "Ldlr(-/-)", + "Abcg4(-/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerated", + "enhanced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "bone", + "MkPs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerated", + "enhanced" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "marrow" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerated" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerated" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Abcg4(-/-)", + "deficiency" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "MkPs" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ldlr(-/-)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "myeloproliferative", + "neoplasm" + ] + } + } + ] + }, + { + "PMID": "23563706", + "TEXT": "A shift from oxidative to glycolytic metabolism has been associated with skeletal muscle insulin resistance in type 2 diabetes. However, whether this metabolic switch is deleterious or adaptive remains under debate, in part because of a limited understanding of the regulatory network that directs the metabolic and contractile specification of fast-twitch glycolytic muscle. Here we show that Baf60c (also called Smarcd3), a transcriptional cofactor enriched in fast-twitch muscle, promotes a switch from oxidative to glycolytic myofiber type through DEP domain-containing mTOR-interacting protein (Deptor)-mediated Akt activation. Muscle-specific transgenic expression of Baf60c activates a program of molecular, metabolic and contractile changes characteristic of glycolytic muscle. In addition, Baf60c is required for maintaining glycolytic capacity in adult skeletal muscle in vivo. Baf60c expression is significantly lower in skeletal muscle from obese mice compared to that from lean mice. Activation of the glycolytic muscle program by transgenic expression of Baf60c protects mice from diet-induced insulin resistance and glucose intolerance. Further mechanistic studies revealed that Deptor is induced by the Baf60c-Six4 transcriptional complex and mediates activation of Akt and glycolytic metabolism by Baf60c in a cell-autonomous manner. This work defines a fundamental mechanism underlying the specification of fast-twitch glycolytic muscle and illustrates that the oxidative-to-glycolytic metabolic shift in skeletal muscle is potentially adaptive and beneficial in the diabetic state.", + "TAG_DATA": [ + "85, Muscle-specific {'perturbing_action': 'B-gene gain-of-function'}", + "86, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "87, expression {'perturbing_action': 'I-gene gain-of-function'}", + "88, of {'perturbing_action': 'I-gene gain-of-function'}", + "89, Baf60c {'perturbing_action': 'I-gene gain-of-function'}", + "113, adult {'context': 'B-tissue/organ'}", + "114, skeletal {'context': 'I-tissue/organ'}", + "115, muscle {'context': 'I-tissue/organ'}", + "116, in {'context': 'B-in vivo'}", + "117, vivo. {'context': 'I-in vivo'}", + "142, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "143, expression {'perturbing_action': 'I-gene gain-of-function'}", + "144, of {'perturbing_action': 'I-gene gain-of-function'}", + "145, Baf60c {'perturbing_action': 'I-gene gain-of-function'}", + "147, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "85, Muscle-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "86, transgenic ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "87, expression ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "88, of ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "89, Baf60c ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "113, adult ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "114, skeletal ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "115, muscle ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "116, in ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "117, vivo. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "142, transgenic ['l45', 'l46', 'l47', 'l48']", + "143, expression ['l45', 'l49', 'l50', 'l51']", + "144, of ['l46', 'l49', 'l52', 'l53']", + "145, Baf60c ['l47', 'l50', 'l52', 'l54']", + "147, mice ['l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Muscle-specific", + "transgenic", + "expression", + "of", + "Baf60c" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "adult", + "skeletal", + "muscle" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Muscle-specific", + "transgenic", + "expression", + "of", + "Baf60c" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "of", + "Baf60c" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23542786", + "TEXT": "Peroxisome proliferator-activated receptors (PPARs) act as metabolic sensors and central regulators of fat and glucose homeostasis. Furthermore, PPARγ has been implicated as major catabolic regulator of bone mass in mice and humans. However, a potential involvement of other PPAR subtypes in the regulation of bone homeostasis has remained elusive. Here we report a previously unrecognized role of PPARβ/δ as a key regulator of bone turnover and the crosstalk between osteoblasts and osteoclasts. In contrast to activation of PPARγ, activation of PPARβ/δ amplified Wnt-dependent and β-catenin-dependent signaling and gene expression in osteoblasts, resulting in increased expression of osteoprotegerin (OPG) and attenuation of osteoblast-mediated osteoclastogenesis. Accordingly, PPARβ/δ-deficient mice had lower Wnt signaling activity, lower serum concentrations of OPG, higher numbers of osteoclasts and osteopenia. Pharmacological activation of PPARβ/δ in a mouse model of postmenopausal osteoporosis led to normalization of the altered ratio of tumor necrosis factor superfamily, member 11 (RANKL, also called TNFSF11) to OPG, a rebalancing of bone turnover and the restoration of normal bone density. Our findings identify PPARβ/δ as a promising target for an alternative approach in the treatment of osteoporosis and related diseases.", + "TAG_DATA": [ + "78, activation {'perturbing_action': 'B-pharmacological augmentation'}", + "79, of {'perturbing_action': 'I-pharmacological augmentation'}", + "80, PPARβ/δ {'perturbing_action': 'I-pharmacological augmentation'}", + "90, osteoblasts, {'context': 'B-cells'}", + "104, PPARβ/δ-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "105, mice {'context': 'B-organism'}", + "119, osteoclasts {'context': 'B-cells'}", + "122, Pharmacological {'perturbing_action': 'B-pharmacological augmentation'}", + "123, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "124, of {'perturbing_action': 'I-pharmacological augmentation'}", + "125, PPARβ/δ {'perturbing_action': 'I-pharmacological augmentation'}", + "128, mouse {'context': 'B-organism'}", + "129, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "78, activation ['l0', 'l1', 'l2', 'l3']", + "79, of ['l0', 'l4', 'l5', 'l6', 'l7']", + "80, PPARβ/δ ['l1', 'l4', 'l8', 'l9', 'l10']", + "90, osteoblasts, ['l2', 'l5', 'l8']", + "104, PPARβ/δ-deficient ['l11', 'l12']", + "105, mice ['l6', 'l9', 'l11', 'l13']", + "119, osteoclasts ['l3', 'l7', 'l10', 'l12', 'l13']", + "122, Pharmacological ['l14', 'l15', 'l16', 'l17', 'l18']", + "123, activation ['l14', 'l19', 'l20', 'l21', 'l22']", + "124, of ['l15', 'l19', 'l23', 'l24', 'l25']", + "125, PPARβ/δ ['l16', 'l20', 'l23', 'l26', 'l27']", + "128, mouse ['l17', 'l21', 'l24', 'l26', 'l28']", + "129, model ['l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "of", + "PPARβ/δ" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoblasts,", + "osteoclasts" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "of", + "PPARβ/δ", + "Pharmacological", + "activation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PPARβ/δ-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PPARβ/δ-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclasts" + ] + } + } + ] + }, + { + "PMID": "23475202", + "TEXT": "We report that K5.Smad7 mice, which express a Smad7 transgene under the control of a keratin 5 promoter, were resistant to radiation-induced oral mucositis, a painful oral ulceration. In addition to nuclear factor κB (NF-κB) activation, which is known to contribute to oral mucositis, we found activated transforming growth factor β (TGF-β) signaling in cells from this condition. Smad7 dampened both pathways to attenuate inflammation, growth inhibition and apoptosis. Additionally, Smad7 promoted oral epithelial migration to close the wound. Further analyses revealed that TGF-β signaling Smads and their co-repressor C-terminal binding protein 1 (CtBP1) transcriptionally repressed Rac1, and that Smad7 abrogated this repression. Knocking down Rac1 expression in mouse keratinocytes abrogated Smad7-induced migration. Topical application of Smad7 protein conjugated with a cell-permeable Tat tag to oral mucosa showed prophylactic and therapeutic effects on radiation-induced oral mucositis in mice. Thus, we have identified new molecular mechanisms involved in oral mucositis pathogenesis, and our data suggest an alternative therapeutic strategy to block multiple pathological processes in this condition.", + "TAG_DATA": [ + "3, K5.Smad7 {'perturbing_action': 'B-other'}", + "4, mice, {'context': 'B-organism'}", + "54, cells {'context': 'B-cells'}", + "68, apoptosis. {'phenotype': 'B-apoptosis'}", + "71, promoted {'effect': 'B-positive'}", + "103, Knocking {'perturbing_action': 'B-rnai/knockdown'}", + "104, down {'perturbing_action': 'I-rnai/knockdown'}", + "105, Rac1 {'perturbing_action': 'I-rnai/knockdown'}", + "106, expression {'perturbing_action': 'I-rnai/knockdown'}", + "108, mouse {'context': 'B-cells'}", + "109, keratinocytes {'context': 'I-cells'}", + "110, abrogated {'effect': 'B-negative'}", + "111, Smad7-induced {'effect': 'B-positive'}", + "112, migration. {'phenotype': 'B-migration'}", + "125, oral {'context': 'B-tissue/organ'}", + "126, mucosa {'context': 'I-tissue/organ'}", + "137, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "3, K5.Smad7 ['l0', 'l1', 'l2', 'l3']", + "4, mice, ['l0', 'l4', 'l5', 'l6']", + "54, cells ['l1', 'l4', 'l7']", + "68, apoptosis. ['l2', 'l5', 'l7']", + "71, promoted ['l3', 'l6']", + "103, Knocking ['l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "104, down ['l8', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "105, Rac1 ['l9', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "106, expression ['l10', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "108, mouse ['l11', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "109, keratinocytes ['l12', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "110, abrogated ['l13', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "111, Smad7-induced ['l14', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "112, migration. ['l15', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "125, oral ['l45', 'l46']", + "126, mucosa ['l16', 'l45', 'l47']", + "137, mice. ['l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "K5.Smad7" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "K5.Smad7" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "K5.Smad7" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "K5.Smad7" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knocking", + "down", + "Rac1", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "keratinocytes" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knocking", + "down", + "Rac1", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abrogated" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knocking", + "down", + "Rac1", + "expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "Smad7-induced" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knocking", + "down", + "Rac1", + "expression" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knocking" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mucosa" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "keratinocytes" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abrogated" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "keratinocytes" + ] + }, + "effect": { + "val": "positive", + "words": [ + "Smad7-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "keratinocytes" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogated" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Smad7-induced" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + } + ] + }, + { + "PMID": "23475201", + "TEXT": "The majority of HIV-infected individuals fail to produce protective antibodies and have diminished responses to new immunizations. We report here that even though there is an expansion of follicular helper T (TFH) cells in HIV-infected individuals, the cells are unable to provide adequate B cell help. We found a higher frequency of programmed cell death ligand 1 (PD-L1)(+) germinal center B cells from lymph nodes of HIV-infected individuals suggesting a potential role for PD-1-PD-L1 interaction in regulating TFH cell function. In fact, we show that engagement of PD-1 on TFH cells leads to a reduction in cell proliferation, activation, inducible T-cell co-stimulator (ICOS) expression and interleukin-21 (IL-21) cytokine secretion. Blocking PD-1 signaling enhances HIV-specific immunoglobulin production in vitro. We further show that at least part of this defect involves IL-21, as addition of this cytokine rescues antibody responses and plasma cell generation in vitro. Our results suggest that deregulation of TFH cell-mediated B cell help diminishes B cell responses during HIV infection and may be related to PD-1 triggering on TFH cells. These results demonstrate a role for TFH cell impairment in HIV pathogenesis and suggest that enhancing their function could have a major impact on the outcome and control of HIV infection, preventing future infections and improving immune responses to vaccinations.", + "TAG_DATA": [ + "89, TFH {'context': 'B-cells'}", + "90, cells {'context': 'I-cells'}", + "94, reduction {'effect': 'B-negative'}", + "96, cell {'context': 'B-cells'}", + "97, proliferation, {'phenotype': 'B-proliferation'}", + "116, in {'context': 'B-in vitro'}", + "117, vitro. {'context': 'I-in vitro'}", + "139, plasma {'context': 'B-cells'}", + "140, cell {'context': 'I-cells'}", + "142, in {'context': 'B-in vitro'}", + "143, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "89, TFH ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "90, cells ['l0', 'l6', 'l7', 'l8']", + "94, reduction ['l1', 'l6', 'l9', 'l10']", + "96, cell ['l2', 'l7', 'l9', 'l11']", + "97, proliferation, ['l3', 'l8', 'l10', 'l11']", + "116, in ['l4', 'l12']", + "117, vitro. ['l5', 'l12']", + "139, plasma ['l13', 'l14', 'l15']", + "140, cell ['l13', 'l16', 'l17']", + "142, in ['l14', 'l16', 'l18']", + "143, vitro. ['l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "TFH", + "cells", + "cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduction" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "TFH", + "cells", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduction" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + } + ] + }, + { + "PMID": "23455712", + "TEXT": "Although susceptibility of neurons in the brain to microbial infection is a major determinant of clinical outcome, little is known about the molecular factors governing this vulnerability. Here we show that two types of neurons from distinct brain regions showed differential permissivity to replication of several positive-stranded RNA viruses. Granule cell neurons of the cerebellum and cortical neurons from the cerebral cortex have unique innate immune programs that confer differential susceptibility to viral infection ex vivo and in vivo. By transducing cortical neurons with genes that were expressed more highly in granule cell neurons, we identified three interferon-stimulated genes (ISGs; Ifi27, Irg1 and Rsad2 (also known as Viperin)) that mediated the antiviral effects against different neurotropic viruses. Moreover, we found that the epigenetic state and microRNA (miRNA)-mediated regulation of ISGs correlates with enhanced antiviral response in granule cell neurons. Thus, neurons from evolutionarily distinct brain regions have unique innate immune signatures, which probably contribute to their relative permissiveness to infection.", + "TAG_DATA": [ + "49, Granule {'context': 'B-cells'}", + "50, cell {'context': 'I-cells'}", + "51, neurons {'context': 'I-cells'}", + "52, of {'context': 'I-cells'}", + "53, the {'context': 'I-cells'}", + "54, cerebellum {'context': 'I-cells'}", + "56, cortical {'context': 'B-cells'}", + "57, neurons {'context': 'I-cells'}", + "58, from {'context': 'I-cells'}", + "59, the {'context': 'I-cells'}", + "60, cerebral {'context': 'I-cells'}", + "61, cortex {'context': 'I-cells'}", + "81, cortical {'context': 'B-cells'}", + "82, neurons {'context': 'I-cells'}", + "136, granule {'context': 'B-cells'}", + "137, cell {'context': 'I-cells'}", + "138, neurons. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "49, Granule ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "50, cell ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "51, neurons ['l1', 'l11', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "52, of ['l2', 'l12', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "53, the ['l3', 'l13', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "54, cerebellum ['l4', 'l14', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "56, cortical ['l5', 'l15', 'l26', 'l35', 'l43', 'l50', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "57, neurons ['l6', 'l16', 'l27', 'l36', 'l44', 'l51', 'l56', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "58, from ['l7', 'l17', 'l28', 'l37', 'l45', 'l52', 'l57', 'l63', 'l69', 'l70', 'l71', 'l72', 'l73']", + "59, the ['l8', 'l18', 'l29', 'l38', 'l46', 'l53', 'l58', 'l64', 'l69', 'l74', 'l75', 'l76', 'l77']", + "60, cerebral ['l9', 'l19', 'l30', 'l39', 'l47', 'l54', 'l59', 'l65', 'l70', 'l74', 'l78', 'l79', 'l80']", + "61, cortex ['l10', 'l20', 'l31', 'l40', 'l48', 'l55', 'l60', 'l66', 'l71', 'l75', 'l78', 'l81', 'l82']", + "81, cortical ['l21', 'l61', 'l67', 'l72', 'l76', 'l79', 'l81', 'l83']", + "82, neurons ['l22', 'l32', 'l41', 'l49', 'l62', 'l68', 'l73', 'l77', 'l80', 'l82', 'l83']", + "136, granule ['l84', 'l85']", + "137, cell ['l84', 'l86']", + "138, neurons. ['l85', 'l86']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23396210", + "TEXT": "Hepatic insulin resistance is a driving force in the pathogenesis of type 2 diabetes mellitus (T2DM) and is tightly coupled with excessive storage of fat and the ensuing inflammation within the liver. There is compelling evidence that activation of the transcription factor nuclear factor-κB (NF-κB) and downstream inflammatory signaling pathways systemically and in the liver are key events in the etiology of hepatic insulin resistance and β-cell dysfunction, although the molecular mechanisms involved are incompletely understood. We here test the hypothesis that receptor activator of NF-κB ligand (RANKL), a prototypic activator of NF-κB, contributes to this process using both an epidemiological and experimental approach. In the prospective population-based Bruneck Study, a high serum concentration of soluble RANKL emerged as a significant (P<0.001) and independent risk predictor of T2DM manifestation. In close agreement, systemic or hepatic blockage of RANKL signaling in genetic and nutritional mouse models of T2DM resulted in a marked improvement of hepatic insulin sensitivity and amelioration or even normalization of plasma glucose concentrations and glucose tolerance. Overall, this study provides evidence for a role of RANKL signaling in the pathogenesis of T2DM. If so, translation to the clinic may be feasible given current pharmacological strategies to lower RANKL activity to treat osteoporosis.", + "TAG_DATA": [ + "143, mouse {'context': 'B-organism'}", + "144, models {'context': 'I-organism'}", + "145, of {'context': 'I-organism'}", + "146, T2DM {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "143, mouse ['l0', 'l1', 'l2']", + "144, models ['l0', 'l3', 'l4']", + "145, of ['l1', 'l3', 'l5']", + "146, T2DM ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23377280", + "TEXT": "The mechanisms that regulate hematopoietic stem cell (HSC) regeneration after myelosuppressive injury are not well understood. We identified epidermal growth factor (EGF) to be highly enriched in the bone marrow serum of mice bearing deletion of Bak and Bax in TIE2-expressing cells in Tie2Cre; Bak1(-/-); Bax(flox/-) mice. These mice showed radioprotection of the HSC pool and 100% survival after a lethal dose of total-body irradiation (TBI). Bone marrow HSCs from wild-type mice expressed functional EGF receptor (EGFR), and systemic administration of EGF promoted the recovery of the HSC pool in vivo and improved the survival of mice after TBI. Conversely, administration of erlotinib, an EGFR antagonist, decreased both HSC regeneration and the survival of mice after TBI. Mice with EGFR deficiency in VAV-expressing hematopoietic cells also had delayed recovery of bone marrow stem and progenitor cells after TBI. Mechanistically, EGF reduced radiation-induced apoptosis of HSCs and mediated this effect through repression of the proapoptotic protein PUMA. Our findings show that EGFR signaling regulates HSC regeneration after myelosuppressive injury.", + "TAG_DATA": [ + "32, mice {'context': 'B-organism'}", + "34, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "35, of {'perturbing_action': 'I-gene loss-of-function'}", + "36, Bak {'perturbing_action': 'I-gene loss-of-function'}", + "37, and {'perturbing_action': 'I-gene loss-of-function'}", + "38, Bax {'perturbing_action': 'I-gene loss-of-function'}", + "40, TIE2-expressing {'context': 'B-cells'}", + "41, cells {'context': 'I-cells'}", + "43, Tie2Cre; {'perturbing_action': 'B-gene loss-of-function'}", + "44, Bak1(-/-); {'perturbing_action': 'B-gene loss-of-function'}", + "45, Bax(flox/-) {'perturbing_action': 'B-gene loss-of-function'}", + "46, mice. {'context': 'B-organism'}", + "48, mice {'context': 'B-organism'}", + "71, mice {'context': 'B-organism'}", + "87, HSC {'context': 'B-cells'}", + "89, in {'context': 'B-in vivo'}", + "90, vivo {'context': 'I-in vivo'}", + "96, mice {'context': 'B-organism'}", + "105, antagonist, {'perturbing_action': 'I-pharmacological inhibition'}", + "108, HSC {'context': 'B-cells'}", + "114, mice {'context': 'B-organism'}", + "117, Mice {'context': 'B-organism'}", + "119, EGFR {'perturbing_action': 'B-gene loss-of-function'}", + "120, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "122, VAV-expressing {'context': 'B-cells'}", + "123, hematopoietic {'context': 'I-cells'}", + "124, cells {'context': 'I-cells'}", + "130, bone {'context': 'B-cells'}", + "131, marrow {'context': 'I-cells'}", + "132, stem {'context': 'I-cells'}", + "133, and {'context': 'I-cells'}", + "134, progenitor {'context': 'I-cells'}", + "135, cells {'context': 'I-cells'}", + "140, reduced {'effect': 'B-negative'}", + "141, radiation-induced {'effect': 'B-positive'}", + "142, apoptosis {'phenotype': 'B-apoptosis'}", + "144, HSCs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "32, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "34, deletion ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "35, of ['l1', 'l8', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "36, Bak ['l2', 'l9', 'l21', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "37, and ['l3', 'l10', 'l22', 'l33', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "38, Bax ['l4', 'l11', 'l23', 'l34', 'l44', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "40, TIE2-expressing ['l5', 'l12', 'l24', 'l35', 'l45', 'l54', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "41, cells ['l6', 'l13', 'l25', 'l36', 'l46', 'l55', 'l63', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "43, Tie2Cre; ['l14', 'l26', 'l37', 'l47', 'l56', 'l64', 'l74', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "44, Bak1(-/-); ['l65', 'l75', 'l84', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "45, Bax(flox/-) ['l66', 'l76', 'l85', 'l93', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "46, mice. ['l15', 'l27', 'l38', 'l48', 'l57', 'l67', 'l77', 'l86', 'l94', 'l103', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "48, mice ['l7', 'l16', 'l28', 'l39', 'l49', 'l58', 'l68', 'l78', 'l87', 'l95', 'l104', 'l112', 'l118', 'l119', 'l120', 'l121']", + "71, mice ['l17', 'l29', 'l40', 'l50', 'l59', 'l69', 'l79', 'l88', 'l96', 'l105', 'l113', 'l118', 'l122', 'l123', 'l124', 'l125']", + "87, HSC ['l18', 'l30', 'l41', 'l51', 'l60', 'l70', 'l80', 'l89', 'l97', 'l106', 'l114', 'l119', 'l122', 'l126', 'l127']", + "89, in ['l19', 'l31', 'l42', 'l52', 'l61', 'l71', 'l81', 'l90', 'l98', 'l107', 'l115', 'l120', 'l123', 'l126', 'l128']", + "90, vivo ['l20', 'l32', 'l43', 'l53', 'l62', 'l72', 'l82', 'l91', 'l99', 'l108', 'l116', 'l121', 'l124', 'l127', 'l128']", + "96, mice ['l73', 'l83', 'l92', 'l100', 'l109', 'l117', 'l125']", + "103, an ['l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "104, EGFR ['l129', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "105, antagonist, ['l130', 'l149', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185']", + "108, HSC ['l101', 'l110', 'l131', 'l150', 'l168', 'l186']", + "114, mice ['l102', 'l111', 'l132', 'l151', 'l169', 'l186']", + "117, Mice ['l133', 'l152', 'l170', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201']", + "119, EGFR ['l134', 'l153', 'l171', 'l187', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215']", + "120, deficiency ['l135', 'l154', 'l172', 'l188', 'l202', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228']", + "122, VAV-expressing ['l136', 'l155', 'l173', 'l189', 'l203', 'l216', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240']", + "123, hematopoietic ['l137', 'l156', 'l174', 'l190', 'l204', 'l217', 'l229', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251']", + "124, cells ['l138', 'l157', 'l175', 'l191', 'l205', 'l218', 'l230', 'l241', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261']", + "130, bone ['l139', 'l158', 'l176', 'l192', 'l206', 'l219', 'l231', 'l242', 'l252', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270']", + "131, marrow ['l140', 'l159', 'l177', 'l193', 'l207', 'l220', 'l232', 'l243', 'l253', 'l262', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278']", + "132, stem ['l141', 'l160', 'l178', 'l194', 'l208', 'l221', 'l233', 'l244', 'l254', 'l263', 'l271', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285']", + "133, and ['l142', 'l161', 'l179', 'l195', 'l209', 'l222', 'l234', 'l245', 'l255', 'l264', 'l272', 'l279', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291']", + "134, progenitor ['l143', 'l162', 'l180', 'l196', 'l210', 'l223', 'l235', 'l246', 'l256', 'l265', 'l273', 'l280', 'l286', 'l292', 'l293', 'l294', 'l295', 'l296']", + "135, cells ['l144', 'l163', 'l181', 'l197', 'l211', 'l224', 'l236', 'l247', 'l257', 'l266', 'l274', 'l281', 'l287', 'l292', 'l297', 'l298', 'l299']", + "140, reduced ['l145', 'l164', 'l182', 'l198', 'l212', 'l225', 'l237', 'l248', 'l258', 'l267', 'l275', 'l282', 'l288', 'l293', 'l297', 'l300', 'l301', 'l302']", + "141, radiation-induced ['l146', 'l165', 'l183', 'l199', 'l213', 'l226', 'l238', 'l249', 'l259', 'l268', 'l276', 'l283', 'l289', 'l294', 'l300', 'l303', 'l304']", + "142, apoptosis ['l147', 'l166', 'l184', 'l200', 'l214', 'l227', 'l239', 'l250', 'l260', 'l269', 'l277', 'l284', 'l290', 'l295', 'l298', 'l301', 'l303', 'l305']", + "144, HSCs ['l148', 'l167', 'l185', 'l201', 'l215', 'l228', 'l240', 'l251', 'l261', 'l270', 'l278', 'l285', 'l291', 'l296', 'l299', 'l302', 'l304', 'l305']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Bak", + "and", + "Bax", + "Tie2Cre;", + "Bak1(-/-);", + "Bax(flox/-)", + "EGFR", + "deficiency" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Bak", + "and", + "Bax", + "Tie2Cre;", + "Bak1(-/-);", + "Bax(flox/-)", + "EGFR", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "TIE2-expressing", + "cells", + "HSC", + "VAV-expressing", + "hematopoietic", + "bone", + "marrow", + "stem", + "and", + "progenitor", + "HSCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Bak", + "and", + "Bax", + "Tie2Cre;", + "Bak1(-/-);", + "Bax(flox/-)" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antagonist," + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC", + "VAV-expressing", + "hematopoietic", + "cells", + "bone", + "marrow", + "stem", + "and", + "progenitor", + "HSCs" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antagonist," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "Mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antagonist," + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antagonist," + ] + }, + "effect": { + "val": "positive", + "words": [ + "radiation-induced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antagonist," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "radiation-induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EGFR", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EGFR", + "deficiency" + ] + }, + "effect": { + "val": "positive", + "words": [ + "radiation-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EGFR", + "deficiency" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "VAV-expressing", + "hematopoietic", + "cells", + "bone", + "marrow", + "stem", + "and", + "progenitor", + "HSCs" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "VAV-expressing", + "hematopoietic", + "cells", + "bone", + "marrow", + "stem", + "and", + "progenitor", + "HSCs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "radiation-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "VAV-expressing", + "hematopoietic", + "cells", + "bone", + "marrow", + "stem", + "and", + "progenitor", + "HSCs" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "radiation-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "23314057", + "TEXT": "Left ventricular noncompaction (LVNC) causes prominent ventricular trabeculations and reduces cardiac systolic function. The clinical presentation of LVNC ranges from asymptomatic to heart failure. We show that germline mutations in human MIB1 (mindbomb homolog 1), which encodes an E3 ubiquitin ligase that promotes endocytosis of the NOTCH ligands DELTA and JAGGED, cause LVNC in autosomal-dominant pedigrees, with affected individuals showing reduced NOTCH1 activity and reduced expression of target genes. Functional studies in cells and zebrafish embryos and in silico modeling indicate that MIB1 functions as a dimer, which is disrupted by the human mutations. Targeted inactivation of Mib1 in mouse myocardium causes LVNC, a phenotype mimicked by inactivation of myocardial Jagged1 or endocardial Notch1. Myocardial Mib1 mutants show reduced ventricular Notch1 activity, expansion of compact myocardium to proliferative, immature trabeculae and abnormal expression of cardiac development and disease genes. These results implicate NOTCH signaling in LVNC and indicate that MIB1 mutations arrest chamber myocardium development, preventing trabecular maturation and compaction.", + "TAG_DATA": [ + "27, germline {'perturbing_action': 'B-other'}", + "28, mutations {'perturbing_action': 'I-other'}", + "29, in {'perturbing_action': 'I-other'}", + "30, human {'perturbing_action': 'I-other'}", + "31, MIB1 {'perturbing_action': 'I-other'}", + "32, (mindbomb {'perturbing_action': 'I-other'}", + "72, cells {'context': 'B-cells'}", + "74, zebrafish {'context': 'B-organism'}", + "75, embryos {'context': 'I-organism'}", + "94, Targeted {'perturbing_action': 'B-gene loss-of-function'}", + "95, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "96, of {'perturbing_action': 'I-gene loss-of-function'}", + "97, Mib1 {'perturbing_action': 'I-gene loss-of-function'}", + "99, mouse {'context': 'B-tissue/organ'}", + "100, myocardium {'context': 'I-tissue/organ'}", + "107, inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "108, of {'perturbing_action': 'I-gene loss-of-function'}", + "109, myocardial {'perturbing_action': 'I-gene loss-of-function'}", + "110, Jagged1 {'perturbing_action': 'I-gene loss-of-function'}", + "111, or {'perturbing_action': 'I-gene loss-of-function'}", + "112, endocardial {'perturbing_action': 'I-gene loss-of-function'}", + "113, Notch1. {'perturbing_action': 'I-gene loss-of-function'}", + "114, Myocardial {'perturbing_action': 'B-other'}", + "115, Mib1 {'perturbing_action': 'I-other'}", + "116, mutants {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "27, germline ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "28, mutations ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "29, in ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "30, human ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "31, MIB1 ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "32, (mindbomb ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "72, cells ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "74, zebrafish ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "75, embryos ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "94, Targeted ['l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "95, inactivation ['l36', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "96, of ['l37', 'l48', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "97, Mib1 ['l38', 'l49', 'l59', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "99, mouse ['l39', 'l50', 'l60', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "100, myocardium ['l40', 'l51', 'l61', 'l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "107, inactivation ['l41', 'l52', 'l62', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "108, of ['l42', 'l53', 'l63', 'l71', 'l78', 'l84', 'l90', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "109, myocardial ['l43', 'l54', 'l64', 'l72', 'l79', 'l85', 'l91', 'l97', 'l103', 'l104', 'l105', 'l106', 'l107']", + "110, Jagged1 ['l44', 'l55', 'l65', 'l73', 'l80', 'l86', 'l92', 'l98', 'l103', 'l108', 'l109', 'l110', 'l111']", + "111, or ['l45', 'l56', 'l66', 'l74', 'l81', 'l87', 'l93', 'l99', 'l104', 'l108', 'l112', 'l113', 'l114']", + "112, endocardial ['l46', 'l57', 'l67', 'l75', 'l82', 'l88', 'l94', 'l100', 'l105', 'l109', 'l112', 'l115', 'l116']", + "113, Notch1. ['l47', 'l58', 'l68', 'l76', 'l83', 'l89', 'l95', 'l101', 'l106', 'l110', 'l113', 'l115', 'l117']", + "114, Myocardial ['l118', 'l119', 'l120']", + "115, Mib1 ['l118', 'l121', 'l122']", + "116, mutants ['l119', 'l121', 'l123']", + "125, myocardium ['l96', 'l102', 'l107', 'l111', 'l114', 'l116', 'l117', 'l120', 'l122', 'l123']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "germline", + "mutations", + "in", + "human", + "MIB1", + "(mindbomb" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "germline", + "mutations", + "in", + "human", + "MIB1", + "(mindbomb" + ] + }, + "context": { + "val": "organism", + "words": [ + "zebrafish", + "embryos" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Targeted", + "inactivation", + "of", + "Mib1", + "myocardial", + "Jagged1", + "or", + "endocardial", + "Notch1." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "myocardium" + ] + } + } + ] + }, + { + "PMID": "23296015", + "TEXT": "Mesenchymal stem cells (MSCs) are the focus of intensive efforts worldwide directed not only at elucidating their nature and unique properties but also developing cell-based therapies for a diverse range of diseases. More than three decades have passed since the original formulation of the concept, revolutionary at the time, that multiple connective tissues could emanate from a common progenitor or stem cell retained in the postnatal bone marrow. Despite the many important advances made since that time, substantial ambiguities still plague the field regarding the nature, identity, function, mode of isolation and experimental handling of MSCs. These uncertainties have a major impact on their envisioned therapeutic use.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23295996", + "TEXT": "Stephen O'Brien joined the US National Cancer Institute as a post doc in 1971 and climbed the ranks to become head of the institute's Laboratory of Genomic Diversity, a position he held for 25 years. But, after four decades at the government agency, O'Brien was ready for something new. In December 2011, he stepped down and took up a three-year, $5 million 'megagrant' in Russia through a program started a year earlier by the Russian Ministry of Education and Science to attract big-name researchers to work at least part-time in that country. O'Brien used his money to help launch the Theodosius Dobzhansky Center for Genome Bioinformatics at Saint Petersburg State University. Although O'Brien is a cancer researcher, he has diverse scientific interests. He led the team that discovered the CCR5-Δ32 mutation that confers resistance to HIV, and he has helped document the remarkable genetic uniformity of African cheetahs. Recently, he and two California scientists started the Genome 10K project, which aims to sequence the genetic blueprints of 10,000 vertebrate species. On a trip back to the US, O'Brien spoke with Elie Dolgin about how comparative genomics and his new Russian center will help advance the search for new therapeutics.", + "TAG_DATA": [ + "146, African {'context': 'B-organism'}", + "147, cheetahs. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "146, African ['l0']", + "147, cheetahs. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23291630", + "TEXT": "Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.", + "TAG_DATA": [ + "106, ABT-199. {'perturbing_action': 'I-pharmacological inhibition'}", + "113, BCL-2-dependent {'context': 'B-neoplasm'}", + "114, tumors {'context': 'I-neoplasm'}", + "115, in {'context': 'B-in vivo'}", + "116, vivo {'context': 'I-in vivo'}", + "119, human {'context': 'B-cells'}", + "120, platelets. {'context': 'I-cells'}", + "128, patients {'context': 'B-patient'}", + "131, chronic {'context': 'I-neoplasm'}", + "132, lymphocytic {'context': 'I-neoplasm'}", + "133, leukemia {'context': 'I-neoplasm'}", + "134, resulted {'effect': 'B-positive'}", + "136, tumor {'phenotype': 'B-tumour regression'}", + "137, lysis {'phenotype': 'I-tumour regression'}" + ], + "LINK_DATA": [ + "106, ABT-199. ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "113, BCL-2-dependent ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "114, tumors ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "115, in ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "116, vivo ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "119, human ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "120, platelets. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "128, patients ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "130, refractory ['l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "131, chronic ['l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "132, lymphocytic ['l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "133, leukemia ['l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "134, resulted ['l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "136, tumor ['l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "137, lysis ['l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ABT-199." + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "BCL-2-dependent", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ABT-199." + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ABT-199." + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "platelets." + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulted" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "lysis" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "chronic", + "lymphocytic", + "leukemia" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulted" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "chronic", + "lymphocytic", + "leukemia" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "lysis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulted" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "lysis" + ] + } + } + ] + }, + { + "PMID": "23242472", + "TEXT": "In contrast with many capillary beds, the glomerulus readily supports leukocyte recruitment. However, little is known regarding the actions of leukocytes following their recruitment to glomeruli. We used multiphoton confocal microscopy to examine leukocyte behavior in the glomerular microvasculature. In normal glomeruli, neutrophils and monocytes were retained in capillaries for several minutes, remaining static or migrating intravascularly. Induction of glomerular inflammation resulted in an increase in the duration of retention of static and migratory leukocytes. In response to immune complex deposition, both static and migratory neutrophils generated oxidants in inflamed glomeruli via a Mac-1-dependent mechanism. Our results describe a new paradigm for glomerular inflammation, suggesting that the major effect of acute inflammation is to increase the duration of leukocyte retention in the glomerulus. Moreover, these findings describe a previously unknown form of multicellular intravascular patrolling that involves both monocytes and neutrophils, which may underlie the susceptibility of the glomerulus to inflammation.", + "TAG_DATA": [ + "41, glomeruli, {'context': 'B-tissue/organ'}", + "73, migratory {'phenotype': 'B-migration'}", + "74, leukocytes. {'context': 'B-cells'}", + "90, glomeruli {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "73, migratory ['l0']", + "74, leukocytes. ['l0']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "migration", + "words": [ + "migratory" + ] + }, + "context": { + "val": "cells", + "words": [ + "leukocytes." + ] + } + } + ] + }, + { + "PMID": "23202296", + "TEXT": "Chemotherapeutic agents are widely used for cancer treatment. In addition to their direct cytotoxic effects, these agents harness the host's immune system, which contributes to their antitumor activity. Here we show that two clinically used chemotherapeutic agents, gemcitabine (Gem) and 5-fluorouracil (5FU), activate the NOD-like receptor family, pyrin domain containing-3 protein (Nlrp3)-dependent caspase-1 activation complex (termed the inflammasome) in myeloid-derived suppressor cells (MDSCs), leading to production of interleukin-1β (IL-1β), which curtails anticancer immunity. Chemotherapy-triggered IL-1β secretion relied on lysosomal permeabilization and the release of cathepsin B, which bound to Nlrp3 and drove caspase-1 activation. MDSC-derived IL-1β induced secretion of IL-17 by CD4(+) T cells, which blunted the anticancer efficacy of the chemotherapy. Accordingly, Gem and 5FU exerted higher antitumor effects when tumors were established in Nlrp3(-/-) or Casp1(-/-) mice or wild-type mice treated with interleukin-1 receptor antagonist (IL-1Ra). Altogether, these results identify how activation of the Nlrp3 inflammasome in MDSCs by 5FU and Gem limits the antitumor efficacy of these chemotherapeutic agents.", + "TAG_DATA": [ + "101, CD4(+) {'context': 'B-cells'}", + "102, T {'context': 'I-cells'}", + "103, cells, {'context': 'I-cells'}", + "121, tumors {'context': 'B-neoplasm'}", + "125, Nlrp3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "126, or {'perturbing_action': 'I-gene loss-of-function'}", + "127, Casp1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "128, mice {'context': 'B-organism'}", + "131, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "101, CD4(+) ['l0', 'l1']", + "102, T ['l0', 'l2']", + "103, cells, ['l1', 'l2']", + "121, tumors ['l3', 'l4', 'l5', 'l6']", + "125, Nlrp3(-/-) ['l3', 'l7', 'l8', 'l9', 'l10']", + "126, or ['l4', 'l7', 'l11', 'l12']", + "127, Casp1(-/-) ['l5', 'l8', 'l11', 'l13', 'l14']", + "128, mice ['l6', 'l9', 'l12', 'l13']", + "131, mice ['l10', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nlrp3(-/-)", + "or", + "Casp1(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nlrp3(-/-)", + "or", + "Casp1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23202295", + "TEXT": "Despite growing interest and a recent surge in papers, the role of autophagy in glucose and lipid metabolism is unclear. We produced mice with skeletal muscle-specific deletion of Atg7 (encoding autophagy-related 7). Unexpectedly, these mice showed decreased fat mass and were protected from diet-induced obesity and insulin resistance; this phenotype was accompanied by increased fatty acid oxidation and browning of white adipose tissue (WAT) owing to induction of fibroblast growth factor 21 (Fgf21). Mitochondrial dysfunction induced by autophagy deficiency increased Fgf21 expression through induction of Atf4, a master regulator of the integrated stress response. Mitochondrial respiratory chain inhibitors also induced Fgf21 in an Atf4-dependent manner. We also observed induction of Fgf21, resistance to diet-induced obesity and amelioration of insulin resistance in mice with autophagy deficiency in the liver, another insulin target tissue. These findings suggest that autophagy deficiency and subsequent mitochondrial dysfunction promote Fgf21 expression, a hormone we consequently term a 'mitokine', and together these processes promote protection from diet-induced obesity and insulin resistance.", + "TAG_DATA": [ + "22, mice {'context': 'B-organism'}", + "24, skeletal {'perturbing_action': 'B-gene loss-of-function'}", + "25, muscle-specific {'perturbing_action': 'I-gene loss-of-function'}", + "26, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "27, of {'perturbing_action': 'I-gene loss-of-function'}", + "28, Atg7 {'perturbing_action': 'I-gene loss-of-function'}", + "29, (encoding {'perturbing_action': 'I-gene loss-of-function'}", + "30, autophagy-related {'perturbing_action': 'I-gene loss-of-function'}", + "31, 7). {'perturbing_action': 'I-gene loss-of-function'}", + "34, mice {'context': 'B-organism'}", + "121, mice {'context': 'B-organism'}", + "127, liver, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "22, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "24, skeletal ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "25, muscle-specific ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "26, deletion ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "27, of ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "28, Atg7 ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "29, (encoding ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "30, autophagy-related ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "31, 7). ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "34, mice ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "121, mice ['l45']", + "127, liver, ['l45']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "skeletal", + "muscle-specific", + "deletion", + "of", + "Atg7", + "(encoding", + "autophagy-related", + "7)." + ] + } + } + ] + }, + { + "PMID": "23202293", + "TEXT": "β-arrestins are associated with numerous aspects of G protein-coupled receptor (GPCR) signaling and regulation and accordingly influence diverse physiological and pathophysiological processes. Here we report that β-arrestin 2 expression is elevated in two independent cohorts of individuals with Alzheimer's disease. Overexpression of β-arrestin 2 leads to an increase in amyloid-β (Aβ) peptide generation, whereas genetic silencing of Arrb2 (encoding β-arrestin 2) reduces generation of Aβ in cell cultures and in Arrb2(-/-) mice. Moreover, in a transgenic mouse model of Alzheimer's disease, genetic deletion of Arrb2 leads to a reduction in the production of Aβ(40) and Aβ(42). Two GPCRs implicated previously in Alzheimer's disease (GPR3 and the β(2)-adrenergic receptor) mediate their effects on Aβ generation through interaction with β-arrestin 2. β-arrestin 2 physically associates with the Aph-1a subunit of the γ-secretase complex and redistributes the complex toward detergent-resistant membranes, increasing the catalytic activity of the complex. Collectively, these studies identify β-arrestin 2 as a new therapeutic target for reducing amyloid pathology and GPCR dysfunction in Alzheimer's disease.", + "TAG_DATA": [ + "40, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "41, of {'perturbing_action': 'I-gene gain-of-function'}", + "42, β-arrestin {'perturbing_action': 'I-gene gain-of-function'}", + "43, 2 {'perturbing_action': 'I-gene gain-of-function'}", + "54, genetic {'perturbing_action': 'B-rnai/knockdown'}", + "55, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "56, of {'perturbing_action': 'I-rnai/knockdown'}", + "57, Arrb2 {'perturbing_action': 'I-rnai/knockdown'}", + "58, (encoding {'perturbing_action': 'I-rnai/knockdown'}", + "59, β-arrestin {'perturbing_action': 'I-rnai/knockdown'}", + "60, 2) {'perturbing_action': 'I-rnai/knockdown'}", + "66, cell {'context': 'B-cells'}", + "67, cultures {'context': 'I-cells'}", + "70, Arrb2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "71, mice. {'context': 'B-organism'}", + "75, transgenic {'context': 'B-organism'}", + "76, mouse {'context': 'I-organism'}", + "77, model {'context': 'I-organism'}", + "78, of {'context': 'I-organism'}", + "79, Alzheimer's {'context': 'I-organism'}", + "80, disease, {'context': 'I-organism'}", + "81, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "82, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "83, of {'perturbing_action': 'I-gene loss-of-function'}", + "84, Arrb2 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "40, Overexpression ['l0', 'l1', 'l2', 'l3', 'l4']", + "41, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "42, β-arrestin ['l1', 'l5', 'l9', 'l10', 'l11']", + "43, 2 ['l2', 'l6', 'l9', 'l12', 'l13']", + "54, genetic ['l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "55, silencing ['l14', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "56, of ['l15', 'l29', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "57, Arrb2 ['l16', 'l30', 'l44', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "58, (encoding ['l17', 'l31', 'l45', 'l58', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "59, β-arrestin ['l18', 'l32', 'l46', 'l59', 'l71', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "60, 2) ['l19', 'l33', 'l47', 'l60', 'l72', 'l83', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "66, cell ['l3', 'l7', 'l10', 'l12', 'l20', 'l34', 'l48', 'l61', 'l73', 'l84', 'l94', 'l104']", + "67, cultures ['l4', 'l8', 'l11', 'l13', 'l21', 'l35', 'l49', 'l62', 'l74', 'l85', 'l95', 'l104']", + "70, Arrb2(-/-) ['l22', 'l36', 'l50', 'l63', 'l75', 'l86', 'l96', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "71, mice. ['l23', 'l37', 'l51', 'l64', 'l76', 'l87', 'l97', 'l105', 'l112', 'l113', 'l114', 'l115', 'l116']", + "75, transgenic ['l38', 'l52', 'l65', 'l77', 'l88', 'l98', 'l106', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "76, mouse ['l24', 'l39', 'l53', 'l66', 'l78', 'l89', 'l99', 'l107', 'l112', 'l117', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "77, model ['l25', 'l40', 'l54', 'l67', 'l79', 'l90', 'l100', 'l108', 'l113', 'l118', 'l126', 'l133', 'l134', 'l135', 'l136']", + "78, of ['l26', 'l41', 'l55', 'l68', 'l80', 'l91', 'l101', 'l109', 'l114', 'l119', 'l127', 'l133', 'l137', 'l138', 'l139']", + "79, Alzheimer's ['l27', 'l42', 'l56', 'l69', 'l81', 'l92', 'l102', 'l110', 'l115', 'l120', 'l128', 'l134', 'l137', 'l140', 'l141']", + "80, disease, ['l28', 'l43', 'l57', 'l70', 'l82', 'l93', 'l103', 'l111', 'l116', 'l121', 'l129', 'l135', 'l138', 'l140', 'l142']", + "81, genetic ['l122', 'l130', 'l143', 'l144', 'l145']", + "82, deletion ['l123', 'l143', 'l146', 'l147']", + "83, of ['l124', 'l131', 'l144', 'l146', 'l148']", + "84, Arrb2 ['l125', 'l132', 'l136', 'l139', 'l141', 'l142', 'l145', 'l147', 'l148']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "β-arrestin", + "2" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "cultures" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "genetic", + "silencing", + "of", + "Arrb2", + "(encoding", + "β-arrestin", + "2)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "cultures" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "genetic", + "silencing", + "of", + "Arrb2", + "(encoding", + "β-arrestin", + "2)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mouse", + "model", + "of", + "Alzheimer's", + "disease,", + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Arrb2(-/-)", + "genetic", + "deletion", + "of", + "Arrb2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "transgenic", + "mouse", + "model", + "of", + "Alzheimer's", + "disease," + ] + } + } + ] + }, + { + "PMID": "23178246", + "TEXT": "The role of the immune response to oncolytic Herpes simplex viral (oHSV) therapy for glioblastoma is controversial because it might enhance or inhibit efficacy. We found that within hours of oHSV infection of glioblastomas in mice, activated natural killer (NK) cells are recruited to the site of infection. This response substantially diminished the efficacy of glioblastoma virotherapy. oHSV-activated NK cells coordinated macrophage and microglia activation within tumors. In vitro, human NK cells preferentially lysed oHSV-infected human glioblastoma cell lines. This enhanced killing depended on the NK cell natural cytotoxicity receptors (NCRs) NKp30 and NKp46, whose ligands are upregulated in oHSV-infected glioblastoma cells. We found that HSV titers and oHSV efficacy are increased in Ncr1(-/-) mice and a Ncr1(-/-) NK cell adoptive transfer model of glioma, respectively. These results demonstrate that glioblastoma virotherapy is limited partially by an antiviral NK cell response involving specific NCRs, uncovering new potential targets to enhance cancer virotherapy.", + "TAG_DATA": [ + "58, NK {'context': 'B-cells'}", + "59, cells {'context': 'I-cells'}", + "67, In {'context': 'B-in vitro'}", + "68, vitro, {'context': 'I-in vitro'}", + "69, human {'context': 'B-cells'}", + "70, NK {'context': 'I-cells'}", + "71, cells {'context': 'I-cells'}", + "75, human {'context': 'B-transformed cells'}", + "76, glioblastoma {'context': 'I-transformed cells'}", + "77, cell {'context': 'I-transformed cells'}", + "78, lines. {'context': 'I-transformed cells'}", + "100, glioblastoma {'context': 'B-transformed cells'}", + "101, cells. {'context': 'I-transformed cells'}", + "113, Ncr1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "114, mice {'context': 'B-organism'}", + "117, Ncr1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "118, NK {'context': 'B-cells'}", + "119, cell {'context': 'I-cells'}", + "120, adoptive {'context': 'I-xenograft'}", + "121, transfer {'context': 'I-xenograft'}", + "122, model {'context': 'I-xenograft'}", + "123, of {'context': 'I-xenograft'}", + "124, glioma, {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "58, NK ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "59, cells ['l0', 'l8', 'l9']", + "67, In ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "68, vitro, ['l1', 'l10', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "69, human ['l11', 'l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "70, NK ['l2', 'l12', 'l21', 'l29', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "71, cells ['l3', 'l13', 'l22', 'l30', 'l37', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "75, human ['l4', 'l14', 'l23', 'l31', 'l38', 'l44', 'l50', 'l51', 'l52', 'l53', 'l54']", + "76, glioblastoma ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l55', 'l56', 'l57', 'l58']", + "77, cell ['l6', 'l8', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l59', 'l60', 'l61']", + "78, lines. ['l7', 'l9', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l62', 'l63']", + "100, glioblastoma ['l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l62', 'l64']", + "101, cells. ['l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l64']", + "113, Ncr1(-/-) ['l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "114, mice ['l65', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "117, Ncr1(-/-) ['l66', 'l74', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "118, NK ['l67', 'l75', 'l82', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "119, cell ['l68', 'l76', 'l83', 'l89', 'l95', 'l96', 'l97', 'l98', 'l99']", + "120, adoptive ['l69', 'l77', 'l84', 'l90', 'l95', 'l100', 'l101', 'l102', 'l103']", + "121, transfer ['l70', 'l78', 'l85', 'l91', 'l96', 'l100', 'l104', 'l105', 'l106']", + "122, model ['l71', 'l79', 'l86', 'l92', 'l97', 'l101', 'l104', 'l107', 'l108']", + "123, of ['l72', 'l80', 'l87', 'l93', 'l98', 'l102', 'l105', 'l107', 'l109']", + "124, glioma, ['l73', 'l81', 'l88', 'l94', 'l99', 'l103', 'l106', 'l108', 'l109']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ncr1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ncr1(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "NK", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ncr1(-/-)" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "adoptive", + "transfer", + "model", + "of" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ncr1(-/-)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "glioma," + ] + } + } + ] + }, + { + "PMID": "23160239", + "TEXT": "Enhancement of hematopoietic recovery after radiation, chemotherapy, or hematopoietic stem cell (HSC) transplantation is clinically relevant. Dipeptidylpeptidase (DPP4) cleaves a wide variety of substrates, including the chemokine stromal cell-derived factor-1 (SDF-1). In the course of experiments showing that inhibition of DPP4 enhances SDF-1-mediated progenitor cell survival, ex vivo cytokine expansion and replating frequency, we unexpectedly found that DPP4 has a more general role in regulating colony-stimulating factor (CSF) activity. DPP4 cleaved within the N-termini of the CSFs granulocyte-macrophage (GM)-CSF, G-CSF, interleukin-3 (IL-3) and erythropoietin and decreased their activity. Dpp4 knockout or DPP4 inhibition enhanced CSF activities both in vitro and in vivo. The reduced activity of DPP4-truncated versus full-length human GM-CSF was mechanistically linked to effects on receptor-binding affinity, induction of GM-CSF receptor oligomerization and signaling capacity. Hematopoiesis in mice after radiation or chemotherapy was enhanced in Dpp4(-/-) mice or mice receiving an orally active DPP4 inhibitor. DPP4 inhibition enhanced engraftment in mice without compromising HSC function, suggesting the potential clinical utility of this approach.", + "TAG_DATA": [ + "38, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "39, of {'perturbing_action': 'I-pharmacological inhibition'}", + "40, DPP4 {'perturbing_action': 'I-pharmacological inhibition'}", + "43, progenitor {'context': 'B-cells'}", + "44, cell {'context': 'I-cells'}", + "88, Dpp4 {'perturbing_action': 'B-gene loss-of-function'}", + "89, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "91, DPP4 {'perturbing_action': 'B-pharmacological inhibition'}", + "92, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "97, in {'context': 'B-in vitro'}", + "98, vitro {'context': 'I-in vitro'}", + "100, in {'context': 'B-in vivo'}", + "101, vivo. {'context': 'I-in vivo'}", + "129, mice {'context': 'B-organism'}", + "137, Dpp4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "138, mice {'context': 'B-organism'}", + "140, mice {'context': 'B-organism'}", + "143, orally {'perturbing_action': 'B-pharmacological inhibition'}", + "144, active {'perturbing_action': 'B-pharmacological inhibition'}", + "145, DPP4 {'perturbing_action': 'B-pharmacological inhibition'}", + "146, inhibitor. {'perturbing_action': 'I-pharmacological inhibition'}", + "147, DPP4 {'perturbing_action': 'B-pharmacological inhibition'}", + "148, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "152, mice {'context': 'B-organism'}", + "155, HSC {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "38, inhibition ['l0', 'l1', 'l2', 'l3']", + "39, of ['l0', 'l4', 'l5', 'l6']", + "40, DPP4 ['l1', 'l4', 'l7', 'l8']", + "43, progenitor ['l2', 'l5', 'l7', 'l9']", + "44, cell ['l3', 'l6', 'l8', 'l9']", + "88, Dpp4 ['l10', 'l11', 'l12', 'l13', 'l14']", + "89, knockout ['l10', 'l15', 'l16']", + "91, DPP4 ['l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "92, inhibition ['l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "97, in ['l12', 'l15', 'l18', 'l23', 'l28', 'l29', 'l30']", + "98, vitro ['l13', 'l16', 'l19', 'l24', 'l28', 'l31', 'l32']", + "100, in ['l20', 'l25', 'l29', 'l31', 'l33', 'l34']", + "101, vivo. ['l14', 'l21', 'l26', 'l30', 'l32', 'l33', 'l35']", + "129, mice ['l22', 'l27', 'l34', 'l35', 'l36']", + "137, Dpp4(-/-) ['l37', 'l38']", + "138, mice ['l36', 'l37']", + "140, mice ['l38']", + "143, orally ['l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "144, active ['l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "145, DPP4 ['l40', 'l46', 'l52', 'l53', 'l54', 'l55', 'l56']", + "146, inhibitor. ['l41', 'l47', 'l52', 'l57', 'l58', 'l59']", + "147, DPP4 ['l42', 'l48', 'l53', 'l60', 'l61', 'l62']", + "148, inhibition ['l43', 'l49', 'l54', 'l57', 'l60', 'l63', 'l64']", + "152, mice ['l44', 'l50', 'l55', 'l58', 'l61', 'l63', 'l65']", + "155, HSC ['l45', 'l51', 'l56', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "DPP4", + "orally", + "active", + "inhibitor." + ] + }, + "context": { + "val": "cells", + "words": [ + "progenitor", + "cell", + "HSC" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dpp4", + "knockout" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dpp4" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "DPP4", + "inhibition" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "DPP4", + "inhibition" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "DPP4", + "inhibition", + "orally", + "active", + "inhibitor." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dpp4(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23160238", + "TEXT": "In multiple sclerosis, an inflammatory disease of the central nervous system (CNS), axonal and neuronal loss are major causes for irreversible neurological disability. However, which molecules contribute to axonal and neuronal injury under inflammatory conditions remains largely unknown. Here we show that the transient receptor potential melastatin 4 (TRPM4) cation channel is crucial in this process. TRPM4 is expressed in mouse and human neuronal somata, but it is also expressed in axons in inflammatory CNS lesions in experimental autoimmune encephalomyelitis (EAE) in mice and in human multiple sclerosis tissue. Deficiency or pharmacological inhibition of TRPM4 using the antidiabetic drug glibenclamide resulted in reduced axonal and neuronal degeneration and attenuated clinical disease scores in EAE, but this occurred without altering EAE-relevant immune function. Furthermore, Trpm4(-/-) mouse neurons were protected against inflammatory effector mechanisms such as excitotoxic stress and energy deficiency in vitro. Electrophysiological recordings revealed TRPM4-dependent neuronal ion influx and oncotic cell swelling upon excitotoxic stimulation. Therefore, interference with TRPM4 could translate into a new neuroprotective treatment strategy.", + "TAG_DATA": [ + "91, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "92, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "93, of {'perturbing_action': 'I-pharmacological inhibition'}", + "94, TRPM4 {'perturbing_action': 'I-pharmacological inhibition'}", + "95, using {'perturbing_action': 'I-pharmacological inhibition'}", + "96, the {'perturbing_action': 'I-pharmacological inhibition'}", + "97, antidiabetic {'perturbing_action': 'I-pharmacological inhibition'}", + "98, drug {'perturbing_action': 'I-pharmacological inhibition'}", + "99, glibenclamide {'perturbing_action': 'I-pharmacological inhibition'}", + "123, Trpm4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "124, mouse {'context': 'B-cells'}", + "125, neurons {'context': 'I-cells'}", + "139, in {'context': 'B-in vitro'}", + "140, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "91, pharmacological ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "92, inhibition ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "93, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "94, TRPM4 ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "95, using ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "96, the ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "97, antidiabetic ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "98, drug ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "99, glibenclamide ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "123, Trpm4(-/-) ['l36', 'l37', 'l38', 'l39']", + "124, mouse ['l36', 'l40', 'l41', 'l42']", + "125, neurons ['l37', 'l40', 'l43', 'l44']", + "139, in ['l38', 'l41', 'l43', 'l45']", + "140, vitro. ['l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trpm4(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "neurons" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trpm4(-/-)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "23142820", + "TEXT": "We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate that has superior sex-independent efficacy over either of the individual hormones alone to correct obesity, hyperglycemia and dyslipidemia in mice. The therapeutic benefits are driven by pleiotropic dual hormone action to improve energy, glucose and lipid metabolism, as shown by loss-of-function models and genetic action profiling. Notably, the peptide-based targeting strategy also prevents hallmark side effects of estrogen in male and female mice, such as reproductive endocrine toxicity and oncogenicity. Collectively, selective activation of estrogen receptors in GLP-1-targeted tissues produces unprecedented efficacy to enhance the metabolic benefits of GLP-1 agonism. This example of targeting the metabolic syndrome represents the discovery of a new class of therapeutics that enables synergistic co-agonism through peptide-based selective delivery of small molecules. Although our observations with the GLP-1-estrogen conjugate justify translational studies for diabetes and obesity, the multitude of other possible combinations of peptides and small molecules may offer equal promise for other diseases.", + "TAG_DATA": [ + "57, mice. {'context': 'B-organism'}", + "97, male {'context': 'B-organism'}", + "98, and {'context': 'I-organism'}", + "99, female {'context': 'I-organism'}", + "100, mice, {'context': 'I-organism'}", + "107, oncogenicity. {'phenotype': 'B-tumourigenesis'}", + "110, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "111, of {'perturbing_action': 'I-pharmacological augmentation'}", + "112, estrogen {'perturbing_action': 'I-pharmacological augmentation'}", + "113, receptors {'perturbing_action': 'I-pharmacological augmentation'}" + ], + "LINK_DATA": [ + "97, male ['l0', 'l1', 'l2', 'l3']", + "98, and ['l0', 'l4', 'l5', 'l6']", + "99, female ['l1', 'l4', 'l7', 'l8']", + "100, mice, ['l2', 'l5', 'l7', 'l9']", + "107, oncogenicity. ['l3', 'l6', 'l8', 'l9']", + "110, activation ['l10', 'l11', 'l12']", + "111, of ['l10', 'l13', 'l14']", + "112, estrogen ['l11', 'l13', 'l15']", + "113, receptors ['l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "male", + "and", + "female", + "mice," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "oncogenicity." + ] + } + } + ] + }, + { + "PMID": "23135509", + "TEXT": "Two anatomical niches for hematopoietic stem cells (HSCs) have been reported in the bone marrow, but a distinct function for each of these niches has remained unclear. A new role in stem cell proliferation has now been identified for the adhesion molecule E-selectin expressed by bone marrow endothelial cells at the vascular niche (pages 1651-1657).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23135501", + "TEXT": "Thirty years ago, technology companies began nestling their facilities close to academia, and the idea of the university research park was born. Soon after, the concept took off in the field of medicine, and today it's not hard to find such innovation hubs that house biomedical startups drawing on the brainpower of professors and students alike. In late September, the Tucson, Arizona-based Association of University Research Parks--which includes about 170 research parks--announced that David Baker would serve as president of the organization's board of directors for the next year and help guide its strategic goals for the next five years. Baker, who is also the executive director of the University Technology Park at the Illinois Institute of Technology in Chicago, spoke with Roxanne Khamsi about how the organization hopes to branch out and transform these workplaces.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23023498", + "TEXT": "Hemophilia A is a bleeding disorder resulting from coagulation factor VIII (FVIII) deficiency. Exogenously provided FVIII effectively reduces bleeding complications in patients with severe hemophilia A. In approximately 30% of such patients, however, the 'foreignness' of the FVIII molecule causes them to develop inhibitory antibodies against FVIII (inhibitors), precluding FVIII treatment in this set of patients. Moreover, the poor pharmacokinetics of FVIII, attributed to low subcutaneous bioavailability and a short half-life of 0.5 d, necessitates frequent intravenous injections. To overcome these drawbacks, we generated a humanized bispecific antibody to factor IXa (FIXa) and factor X (FX), termed hBS23, that places these two factors into spatially appropriate positions and mimics the cofactor function of FVIII. hBS23 exerted coagulation activity in FVIII-deficient plasma, even in the presence of inhibitors, and showed in vivo hemostatic activity in a nonhuman primate model of acquired hemophilia A. Notably, hBS23 had high subcutaneous bioavailability and a 2-week half-life and would not be expected to elicit the development of FVIII-specific inhibitory antibodies, as its molecular structure, and hence antigenicity, differs from that of FVIII. A long-acting, subcutaneously injectable agent that is unaffected by the presence of inhibitors could markedly reduce the burden of care for the treatment of hemophilia A.", + "TAG_DATA": [ + "129, in {'context': 'B-in vivo'}", + "130, vivo {'context': 'I-in vivo'}", + "135, nonhuman {'context': 'B-organism'}", + "136, primate {'context': 'I-organism'}", + "137, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "129, in ['l0', 'l1', 'l2', 'l3', 'l4']", + "130, vivo ['l0', 'l5', 'l6', 'l7', 'l8']", + "135, nonhuman ['l1', 'l5', 'l9', 'l10', 'l11']", + "136, primate ['l2', 'l6', 'l9', 'l12', 'l13']", + "137, model ['l3', 'l7', 'l10', 'l12', 'l14']", + "141, A. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23001182", + "TEXT": "We found that hematopoietic cell-specific Lyn substrate 1 (HCLS1 or HS1) is highly expressed in human myeloid cells and that stimulation with granulocyte colony-stimulating factor (G-CSF) leads to HCLS1 phosphorylation. HCLS1 binds the transcription factor lymphoid-enhancer binding factor 1 (LEF-1), transporting LEF-1 into the nucleus upon G-CSF stimulation and inducing LEF-1 autoregulation. In patients with severe congenital neutropenia, inherited mutations in the gene encoding HCLS1-associated protein X-1 (HAX1) lead to profound defects in G-CSF-triggered phosphorylation of HCLS1 and subsequently to reduced autoregulation and expression of LEF-1. Consistent with these results, HCLS1-deficient mice are neutropenic. In bone marrow biopsies of the majority of tested patients with acute myeloid leukemia, HCLS1 protein expression is substantially elevated, associated with high levels of G-CSF synthesis and, in some individuals, a four-residue insertion in a proline-rich region of HCLS1 protein known to accelerate intracellular signaling. These data demonstrate the importance of HCLS1 in myelopoiesis in vitro and in vivo.", + "TAG_DATA": [ + "58, inherited {'perturbing_action': 'B-other'}", + "59, mutations {'perturbing_action': 'I-other'}", + "60, in {'perturbing_action': 'I-other'}", + "61, the {'perturbing_action': 'I-other'}", + "62, gene {'perturbing_action': 'I-other'}", + "63, encoding {'perturbing_action': 'I-other'}", + "64, HCLS1-associated {'perturbing_action': 'I-other'}", + "65, protein {'perturbing_action': 'I-other'}", + "66, X-1 {'perturbing_action': 'I-other'}", + "67, (HAX1) {'perturbing_action': 'I-other'}", + "90, HCLS1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "91, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "58, inherited ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "59, mutations ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "60, in ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "61, the ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "62, gene ['l3', 'l11', 'l18', 'l24', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "63, encoding ['l4', 'l12', 'l19', 'l25', 'l31', 'l37', 'l38', 'l39', 'l40', 'l41']", + "64, HCLS1-associated ['l5', 'l13', 'l20', 'l26', 'l32', 'l37', 'l42', 'l43', 'l44', 'l45']", + "65, protein ['l6', 'l14', 'l21', 'l27', 'l33', 'l38', 'l42', 'l46', 'l47', 'l48']", + "66, X-1 ['l7', 'l15', 'l22', 'l28', 'l34', 'l39', 'l43', 'l46', 'l49', 'l50']", + "67, (HAX1) ['l8', 'l16', 'l23', 'l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l51']", + "90, HCLS1-deficient ['l52']", + "91, mice ['l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l51', 'l52']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "the", + "gene", + "encoding", + "HCLS1-associated", + "protein", + "X-1", + "(HAX1)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "HCLS1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "22961108", + "TEXT": "Live attenuated simian immunodeficiency virus (SIV) vaccines (LAVs) remain the most efficacious of all vaccines in nonhuman primate models of HIV and AIDS, yet the basis of their robust protection remains poorly understood. Here we show that the degree of LAV-mediated protection against intravenous wild-type SIVmac239 challenge strongly correlates with the magnitude and function of SIV-specific, effector-differentiated T cells in the lymph node but not with the responses of such T cells in the blood or with other cellular, humoral and innate immune parameters. We found that maintenance of protective T cell responses is associated with persistent LAV replication in the lymph node, which occurs almost exclusively in follicular helper T cells. Thus, effective LAVs maintain lymphoid tissue-based, effector-differentiated, SIV-specific T cells that intercept and suppress early wild-type SIV amplification and, if present in sufficient frequencies, can completely control and perhaps clear infection, an observation that provides a rationale for the development of safe, persistent vectors that can elicit and maintain such responses.", + "TAG_DATA": [ + "101, lymph {'context': 'B-tissue/organ'}", + "102, node, {'context': 'I-tissue/organ'}", + "108, follicular {'context': 'B-cells'}", + "109, helper {'context': 'I-cells'}", + "110, T {'context': 'I-cells'}", + "111, cells. {'context': 'I-cells'}", + "121, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "101, lymph ['l0', 'l1', 'l2', 'l3', 'l4']", + "102, node, ['l0', 'l5', 'l6', 'l7', 'l8']", + "108, follicular ['l1', 'l5', 'l9', 'l10', 'l11']", + "109, helper ['l2', 'l6', 'l9', 'l12', 'l13']", + "110, T ['l3', 'l7', 'l10', 'l12', 'l14']", + "111, cells. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22922411", + "TEXT": "Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Disease onset and progression are variable, with survival ranging from months to decades. Factors underlying this variability may represent targets for therapeutic intervention. Here, we have screened a zebrafish model of ALS and identified Epha4, a receptor in the ephrin axonal repellent system, as a modifier of the disease phenotype in fish, rodents and humans. Genetic as well as pharmacological inhibition of Epha4 signaling rescues the mutant SOD1 phenotype in zebrafish and increases survival in mouse and rat models of ALS. Motor neurons that are most vulnerable to degeneration in ALS express higher levels of Epha4, and neuromuscular re-innervation by axotomized motor neurons is inhibited by the presence of Epha4. In humans with ALS, EPHA4 expression inversely correlates with disease onset and survival, and loss-of-function mutations in EPHA4 are associated with long survival. Furthermore, we found that knockdown of Epha4 also rescues the axonopathy induced by expression of mutant TAR DNA-binding protein 43 (TDP-43), another protein causing familial ALS, and the axonopathy induced by knockdown of survival of motor neuron 1, a model for spinomuscular atrophy. This suggests that Epha4 generically modulates the vulnerability of (motor) neurons to axonal degeneration and may represent a new target for therapeutic intervention.", + "TAG_DATA": [ + "71, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "72, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "73, of {'perturbing_action': 'I-pharmacological inhibition'}", + "74, Epha4 {'perturbing_action': 'I-pharmacological inhibition'}", + "75, signaling {'perturbing_action': 'I-pharmacological inhibition'}", + "82, zebrafish {'context': 'B-organism'}", + "87, mouse {'context': 'B-organism'}", + "88, and {'context': 'I-organism'}", + "89, rat {'context': 'I-organism'}", + "90, models {'context': 'I-organism'}", + "91, of {'context': 'I-organism'}", + "92, ALS. {'context': 'I-organism'}", + "93, Motor {'context': 'B-cells'}", + "94, neurons {'context': 'I-cells'}", + "113, motor {'context': 'I-cells'}", + "114, neurons {'context': 'I-cells'}", + "149, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "150, of {'perturbing_action': 'I-rnai/knockdown'}", + "151, Epha4 {'perturbing_action': 'I-rnai/knockdown'}", + "158, expression {'perturbing_action': 'B-other'}", + "160, mutant {'perturbing_action': 'B-other'}", + "161, TAR {'perturbing_action': 'I-other'}", + "162, DNA-binding {'perturbing_action': 'I-other'}", + "163, protein {'perturbing_action': 'I-other'}", + "164, 43 {'perturbing_action': 'I-other'}", + "165, (TDP-43), {'perturbing_action': 'I-other'}", + "176, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "177, of {'perturbing_action': 'I-rnai/knockdown'}", + "178, survival {'perturbing_action': 'I-rnai/knockdown'}", + "179, of {'perturbing_action': 'I-rnai/knockdown'}", + "180, motor {'perturbing_action': 'I-rnai/knockdown'}", + "181, neuron {'perturbing_action': 'I-rnai/knockdown', 'context': 'I-cells'}", + "182, 1, {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "71, pharmacological ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "72, inhibition ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "73, of ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "74, Epha4 ['l2', 'l16', 'l29', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "75, signaling ['l3', 'l17', 'l30', 'l42', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "82, zebrafish ['l4', 'l18', 'l31', 'l43', 'l54', 'l65', 'l66']", + "87, mouse ['l5', 'l19', 'l32', 'l44', 'l55', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "88, and ['l6', 'l20', 'l33', 'l45', 'l56', 'l67', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "89, rat ['l7', 'l21', 'l34', 'l46', 'l57', 'l68', 'l76', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "90, models ['l8', 'l22', 'l35', 'l47', 'l58', 'l69', 'l77', 'l84', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "91, of ['l9', 'l23', 'l36', 'l48', 'l59', 'l65', 'l70', 'l78', 'l85', 'l91', 'l97', 'l98', 'l99', 'l100', 'l101']", + "92, ALS. ['l10', 'l24', 'l37', 'l49', 'l60', 'l66', 'l71', 'l79', 'l86', 'l92', 'l97', 'l102', 'l103', 'l104', 'l105']", + "93, Motor ['l11', 'l25', 'l38', 'l50', 'l61', 'l72', 'l80', 'l87', 'l93', 'l98', 'l102', 'l106', 'l107', 'l108']", + "94, neurons ['l12', 'l26', 'l39', 'l51', 'l62', 'l73', 'l81', 'l88', 'l94', 'l99', 'l103', 'l106', 'l109', 'l110']", + "113, motor ['l13', 'l27', 'l40', 'l52', 'l63', 'l74', 'l82', 'l89', 'l95', 'l100', 'l104', 'l107', 'l109', 'l111']", + "114, neurons ['l14', 'l28', 'l41', 'l53', 'l64', 'l75', 'l83', 'l90', 'l96', 'l101', 'l105', 'l108', 'l110', 'l111']", + "149, knockdown ['l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127']", + "150, of ['l112', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "151, Epha4 ['l113', 'l128', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156']", + "158, expression ['l114', 'l129', 'l143', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162']", + "160, mutant ['l115', 'l130', 'l144', 'l157', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168']", + "161, TAR ['l116', 'l131', 'l145', 'l158', 'l163', 'l169', 'l170', 'l171', 'l172']", + "162, DNA-binding ['l117', 'l132', 'l146', 'l159', 'l164', 'l169', 'l173', 'l174', 'l175']", + "163, protein ['l118', 'l133', 'l147', 'l160', 'l165', 'l170', 'l173', 'l176', 'l177']", + "164, 43 ['l119', 'l134', 'l148', 'l161', 'l166', 'l171', 'l174', 'l176', 'l178']", + "165, (TDP-43), ['l120', 'l135', 'l149', 'l162', 'l167', 'l172', 'l175', 'l177', 'l178']", + "176, knockdown ['l121', 'l136', 'l150', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184']", + "177, of ['l122', 'l137', 'l151', 'l179', 'l185', 'l186', 'l187', 'l188', 'l189']", + "178, survival ['l123', 'l138', 'l152', 'l180', 'l185', 'l190', 'l191', 'l192', 'l193']", + "179, of ['l124', 'l139', 'l153', 'l181', 'l186', 'l190', 'l194', 'l195', 'l196']", + "180, motor ['l125', 'l140', 'l154', 'l182', 'l187', 'l191', 'l194', 'l197', 'l198']", + "181, neuron ['l126', 'l141', 'l155', 'l183', 'l188', 'l192', 'l195', 'l197', 'l199']", + "182, 1, ['l127', 'l142', 'l156', 'l168', 'l184', 'l189', 'l193', 'l196', 'l198', 'l199']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "Epha4", + "signaling" + ] + }, + "context": { + "val": "organism", + "words": [ + "zebrafish", + "mouse", + "and", + "rat", + "models", + "of", + "ALS." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "Epha4", + "signaling" + ] + }, + "context": { + "val": "cells", + "words": [ + "Motor", + "neurons", + "motor" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "Epha4", + "survival", + "motor", + "neuron" + ] + }, + "context": { + "val": "cells", + "words": [ + "neuron" + ] + } + } + ] + }, + { + "PMID": "22885997", + "TEXT": "Previous imaging and postmortem studies have reported a lower brain volume and a smaller size and density of neurons in the dorsolateral prefrontal cortex (dlPFC) of subjects with major depressive disorder (MDD). These findings suggest that synapse number and function are decreased in the dlPFC of patients with MDD. However, there has been no direct evidence reported for synapse loss in MDD, and the gene expression alterations underlying these effects have not been identified. Here we use microarray gene profiling and electron microscopic stereology to reveal lower expression of synaptic-function–related genes (CALM2, SYN1, RAB3A, RAB4B and TUBB4) in the dlPFC of subjects with MDD and a corresponding lower number of synapses. We also identify a transcriptional repressor, GATA1, expression of which is higher in MDD and that, when expressed in PFC neurons, is sufficient to decrease the expression of synapse-related genes, cause loss of dendritic spines and dendrites, and produce depressive behavior in rat models of depression.", + "TAG_DATA": [ + "153, rat {'context': 'B-organism'}", + "154, models {'context': 'I-organism'}", + "156, depression. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "153, rat ['l0', 'l1', 'l2']", + "154, models ['l0', 'l3', 'l4']", + "155, of ['l1', 'l3', 'l5']", + "156, depression. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22863787", + "TEXT": "Chronic low-grade adipose tissue and liver inflammation is a major cause of systemic insulin resistance and is a key component of the low degree of insulin sensitivity that exists in obesity and type 2 diabetes. Immune cells, such as macrophages, T cells, B cells, mast cells and eosinophils, have all been implicated as having a role in this process. Neutrophils are typically the first immune cells to respond to inflammation and can exacerbate the chronic inflammatory state by helping to recruit macrophages and by interacting with antigen-presenting cells. Neutrophils secrete several proteases, one of which is neutrophil elastase, which can promote inflammatory responses in several disease models. Here we show that treatment of hepatocytes with neutrophil elastase causes cellular insulin resistance and that deletion of neutrophil elastase in high-fat-diet–induced obese (DIO) mice leads to less tissue inflammation that is associated with lower adipose tissue neutrophil and macrophage content. These changes are accompanied by improved glucose tolerance and increased insulin sensitivity. Taken together, we show that neutrophils can be added to the extensive repertoire of immune cells that participate in inflammation-induced metabolic disease.", + "TAG_DATA": [ + "113, hepatocytes {'context': 'B-cells'}", + "123, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "124, of {'perturbing_action': 'I-gene loss-of-function'}", + "125, neutrophil {'perturbing_action': 'I-gene loss-of-function'}", + "126, elastase {'perturbing_action': 'I-gene loss-of-function'}", + "131, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "123, deletion ['l0', 'l1', 'l2', 'l3']", + "124, of ['l0', 'l4', 'l5', 'l6']", + "125, neutrophil ['l1', 'l4', 'l7', 'l8']", + "126, elastase ['l2', 'l5', 'l7', 'l9']", + "131, mice ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "neutrophil", + "elastase" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "22863786", + "TEXT": "Acquired resistance to anticancer treatments is a substantial barrier to reducing the morbidity and mortality that is attributable to malignant tumors. Components of tissue microenvironments are recognized to profoundly influence cellular phenotypes, including susceptibilities to toxic insults. Using a genome-wide analysis of transcriptional responses to genotoxic stress induced by cancer therapeutics, we identified a spectrum of secreted proteins derived from the tumor microenvironment that includes the Wnt family member wingless-type MMTV integration site family member 16B (WNT16B). We determined that WNT16B expression is regulated by nuclear factor of κ light polypeptide gene enhancer in B cells 1 (NF-κB) after DNA damage and subsequently signals in a paracrine manner to activate the canonical Wnt program in tumor cells. The expression of WNT16B in the prostate tumor microenvironment attenuated the effects of cytotoxic chemotherapy in vivo, promoting tumor cell survival and disease progression. These results delineate a mechanism by which genotoxic therapies given in a cyclical manner can enhance subsequent treatment resistance through cell nonautonomous effects that are contributed by the tumor microenvironment.", + "TAG_DATA": [ + "124, tumor {'context': 'I-tissue/organ'}", + "132, in {'context': 'B-in vivo'}", + "133, vivo, {'context': 'I-in vivo'}", + "134, promoting {'effect': 'B-positive'}", + "135, tumor {'context': 'B-transformed cells'}", + "136, cell {'context': 'I-transformed cells'}", + "137, survival {'phenotype': 'I-cell survival'}" + ], + "LINK_DATA": [ + "123, prostate ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "124, tumor ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "132, in ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "133, vivo, ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "134, promoting ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "135, tumor ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "136, cell ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "137, survival ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "tumor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "survival" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "survival" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "survival" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "survival" + ] + } + } + ] + }, + { + "PMID": "22797811", + "TEXT": "Both rectal and vaginal mucosal surfaces serve as transmission routes for pathogenic microorganisms. Vaccination through large intestinal mucosa, previously proven protective for both of these mucosal sites in animal studies, can be achieved successfully by direct intracolorectal (i.c.r.) administration, but this route is clinically impractical. Oral vaccine delivery seems preferable but runs the risk of the vaccine's destruction in the upper gastrointestinal tract. Therefore, we designed a large intestine-targeted oral delivery with pH-dependent microparticles containing vaccine nanoparticles, which induced colorectal immunity in mice comparably to colorectal vaccination and protected against rectal and vaginal viral challenge. Conversely, vaccine targeted to the small intestine induced only small intestinal immunity and provided no rectal or vaginal protection, demonstrating functional compartmentalization within the gut mucosal immune system. Therefore, using this oral vaccine delivery system to target the large intestine, but not the small intestine, may represent a feasible new strategy for immune protection of rectal and vaginal mucosa.", + "TAG_DATA": [ + "82, mice {'context': 'B-organism'}", + "100, small {'context': 'B-tissue/organ'}", + "101, intestine {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "100, small ['l0']", + "101, intestine ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22797809", + "TEXT": "The ataxia telangiectasia mutated (ATM) kinase, a master regulator of the DNA damage response (DDR), acts as a barrier to cellular senescence and tumorigenesis. Aside from DDR signaling, ATM also functions in oxidative defense. Here we show that Atm in mice is activated specifically in immature vessels in response to the accumulation of reactive oxygen species (ROS). Global or endothelial-specific Atm deficiency in mice blocked pathological neoangiogenesis in the retina. This block resulted from increased amounts of ROS and excessive activation of the mitogen activated kinase p38α rather than from defects in the canonical DDR pathway. Atm deficiency also lowered tumor angiogenesis and enhanced the antiangiogenic action of vascular endothelial growth factor (Vegf) blockade. These data suggest that pathological neoangiogenesis requires ATM-mediated oxidative defense and that agents that promote excessive ROS generation may have beneficial effects in the treatment of neovascular disease.", + "TAG_DATA": [ + "59, endothelial-specific {'perturbing_action': 'B-gene loss-of-function'}", + "60, Atm {'perturbing_action': 'I-gene loss-of-function'}", + "61, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "63, mice {'context': 'B-organism'}", + "69, retina. {'context': 'B-tissue/organ'}", + "96, Atm {'perturbing_action': 'B-gene loss-of-function'}", + "97, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "100, tumor {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "59, endothelial-specific ['l0', 'l1', 'l2', 'l3']", + "60, Atm ['l0', 'l4', 'l5', 'l6']", + "61, deficiency ['l1', 'l4', 'l7', 'l8']", + "63, mice ['l2', 'l5', 'l7', 'l9']", + "69, retina. ['l3', 'l6', 'l8', 'l9']", + "96, Atm ['l10', 'l11']", + "97, deficiency ['l10', 'l12']", + "100, tumor ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "endothelial-specific", + "Atm", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "endothelial-specific", + "Atm", + "deficiency" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "retina." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atm", + "deficiency" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + } + ] + }, + { + "PMID": "22797808", + "TEXT": "At present, clinicians routinely apply ultrasound endoscopy in a variety of interventional procedures that provide treatment solutions for diseased organs. Ultrasound endoscopy not only produces high-resolution images, but also is safe for clinical use and broadly applicable. However, for soft tissue imaging, its mechanical wave-based image contrast fundamentally limits its ability to provide physiologically specific functional information. By contrast, photoacoustic endoscopy possesses a unique combination of functional optical contrast and high spatial resolution at clinically relevant depths, ideal for imaging soft tissues. With these attributes, photoacoustic endoscopy can overcome the current limitations of ultrasound endoscopy. Moreover, the benefits of photoacoustic imaging do not come at the expense of existing ultrasound functions; photoacoustic endoscopy systems are inherently compatible with ultrasound imaging, thereby enabling multimodality imaging with complementary contrast. Here we present simultaneous photoacoustic and ultrasonic dual-mode endoscopy and show its ability to image internal organs in vivo, thus illustrating its potential clinical application.", + "TAG_DATA": [ + "144, in {'context': 'B-in vivo'}", + "145, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "144, in ['l0']", + "145, vivo, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22706385", + "TEXT": "In most adult humans, hepatitis B is a self-limiting disease leading to life-long protective immunity, which is the consequence of a robust adaptive immune response occurring weeks after hepatitis B virus (HBV) infection. Notably, HBV-specific T cells can be detected shortly after infection, but the mechanisms underlying this early immune priming and its consequences for subsequent control of viral replication are poorly understood. Using primary human and mouse hepatocytes and mouse models of transgenic and adenoviral HBV expression, we show that HBV-expressing hepatocytes produce endoplasmic reticulum (ER)-associated endogenous antigenic lipids including lysophospholipids that are generated by HBV-induced secretory phospholipases and that lead to activation of natural killer T (NKT) cells. The absence of NKT cells or CD1d or a defect in ER-associated transfer of lipids onto CD1d results in diminished HBV-specific T and B cell responses and delayed viral control in mice. NKT cells may therefore contribute to control of HBV infection through sensing of HBV-induced modified self-lipids.", + "TAG_DATA": [ + "64, primary {'context': 'B-cells'}", + "65, human {'context': 'I-cells'}", + "66, and {'context': 'I-cells'}", + "67, mouse {'context': 'I-cells'}", + "68, hepatocytes {'context': 'I-cells'}", + "70, mouse {'context': 'B-organism'}", + "71, models {'context': 'I-organism'}", + "72, of {'perturbing_action': 'I-gene gain-of-function'}", + "73, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "74, and {'perturbing_action': 'I-gene gain-of-function'}", + "75, adenoviral {'perturbing_action': 'I-gene gain-of-function'}", + "76, HBV {'perturbing_action': 'I-gene gain-of-function'}", + "77, expression, {'perturbing_action': 'I-gene gain-of-function'}", + "81, HBV-expressing {'context': 'B-cells'}", + "82, hepatocytes {'context': 'I-cells'}", + "105, natural {'context': 'B-cells'}", + "106, killer {'context': 'I-cells'}", + "107, T {'context': 'I-cells'}", + "108, (NKT) {'context': 'I-cells'}", + "109, cells. {'context': 'I-cells'}", + "113, NKT {'context': 'B-cells'}", + "114, cells {'context': 'I-cells'}", + "131, T {'context': 'B-cells'}", + "132, and {'context': 'I-cells'}", + "133, B {'context': 'I-cells'}", + "134, cell {'context': 'I-cells'}", + "141, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "64, primary ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "65, human ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "66, and ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "67, mouse ['l2', 'l10', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29']", + "68, hepatocytes ['l3', 'l11', 'l18', 'l25', 'l30', 'l31', 'l32', 'l33']", + "70, mouse ['l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "71, models ['l34', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "72, of ['l35', 'l48', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "73, transgenic ['l19', 'l36', 'l49', 'l61', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "74, and ['l37', 'l50', 'l62', 'l73', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "75, adenoviral ['l38', 'l51', 'l63', 'l74', 'l84', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "76, HBV ['l4', 'l12', 'l20', 'l26', 'l30', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "77, expression, ['l5', 'l13', 'l21', 'l27', 'l31', 'l40', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "81, HBV-expressing ['l6', 'l14', 'l22', 'l28', 'l32', 'l41', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "82, hepatocytes ['l7', 'l15', 'l23', 'l29', 'l33', 'l42', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l118', 'l124', 'l125', 'l126', 'l127', 'l128']", + "105, natural ['l43', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l113', 'l119', 'l124', 'l129', 'l130', 'l131', 'l132']", + "106, killer ['l44', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l129', 'l133', 'l134', 'l135']", + "107, T ['l45', 'l58', 'l70', 'l81', 'l91', 'l100', 'l108', 'l115', 'l121', 'l126', 'l130', 'l133', 'l136', 'l137']", + "108, (NKT) ['l46', 'l59', 'l71', 'l82', 'l92', 'l101', 'l109', 'l116', 'l122', 'l127', 'l131', 'l134', 'l136', 'l138']", + "109, cells. ['l8', 'l16', 'l24', 'l47', 'l60', 'l72', 'l83', 'l93', 'l102', 'l110', 'l117', 'l123', 'l128', 'l132', 'l135', 'l137', 'l138']", + "113, NKT ['l139', 'l140', 'l141', 'l142', 'l143']", + "114, cells ['l139', 'l144', 'l145', 'l146', 'l147']", + "131, T ['l140', 'l144', 'l148', 'l149', 'l150', 'l151']", + "132, and ['l141', 'l145', 'l148', 'l152', 'l153', 'l154']", + "133, B ['l142', 'l146', 'l149', 'l152', 'l155', 'l156']", + "134, cell ['l143', 'l147', 'l150', 'l153', 'l155', 'l157']", + "141, mice. ['l151', 'l154', 'l156', 'l157']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "primary", + "human", + "and", + "mouse", + "hepatocytes", + "HBV-expressing", + "natural", + "killer", + "T", + "(NKT)", + "cells." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "HBV", + "expression,", + "transgenic", + "of", + "and", + "adenoviral" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "transgenic", + "and", + "adenoviral", + "HBV", + "expression," + ] + } + } + ] + }, + { + "PMID": "22683780", + "TEXT": "Although the treatment of acute myeloid leukemia (AML) has improved substantially in the past three decades, more than half of all patients develop disease that is refractory to intensive chemotherapy. Functional genomics approaches offer a means to discover specific molecules mediating the aberrant growth and survival of cancer cells. Thus, using a loss-of-function RNA interference genomic screen, we identified the aberrant expression of hepatocyte growth factor (HGF) as a crucial element in AML pathogenesis. We found HGF expression leading to autocrine activation of its receptor tyrosine kinase, MET, in nearly half of the AML cell lines and clinical samples we studied. Genetic depletion of HGF or MET potently inhibited the growth and survival of HGF-expressing AML cells. However, leukemic cells treated with the specific MET kinase inhibitor crizotinib developed resistance resulting from compensatory upregulation of HGF expression, leading to the restoration of MET signaling. In cases of AML where MET is coactivated with other tyrosine kinases, such as fibroblast growth factor receptor 1 (FGFR1), concomitant inhibition of FGFR1 and MET blocked this compensatory HGF upregulation, resulting in sustained logarithmic cell killing both in vitro and in xenograft models in vivo. Our results show a widespread dependence of AML cells on autocrine activation of MET, as well as the key role of compensatory upregulation of HGF expression in maintaining leukemogenic signaling by this receptor. We anticipate that these findings will lead to the design of additional strategies to block adaptive cellular responses that drive compensatory ligand expression as an essential component of the targeted inhibition of oncogenic receptors in human cancers.", + "TAG_DATA": [ + "101, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "102, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "103, of {'perturbing_action': 'I-gene loss-of-function'}", + "104, HGF {'perturbing_action': 'I-gene loss-of-function'}", + "105, or {'perturbing_action': 'I-gene loss-of-function'}", + "106, MET {'perturbing_action': 'I-gene loss-of-function'}", + "114, HGF-expressing {'context': 'B-transformed cells'}", + "115, AML {'context': 'I-transformed cells'}", + "116, cells. {'context': 'I-transformed cells'}", + "118, leukemic {'context': 'B-transformed cells'}", + "119, cells {'context': 'I-transformed cells'}", + "165, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "166, of {'perturbing_action': 'I-pharmacological inhibition'}", + "167, FGFR1 {'perturbing_action': 'I-pharmacological inhibition'}", + "168, and {'perturbing_action': 'I-pharmacological inhibition'}", + "169, MET {'perturbing_action': 'I-pharmacological inhibition'}", + "179, cell {'phenotype': 'B-cell death'}", + "180, killing {'phenotype': 'I-cell death'}", + "182, in {'context': 'B-in vitro'}", + "183, vitro {'context': 'I-in vitro'}", + "186, xenograft {'context': 'B-xenograft'}", + "187, models {'context': 'I-xenograft'}", + "188, in {'context': 'B-in vivo'}", + "189, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "101, Genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "102, depletion ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "103, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "104, HGF ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28']", + "105, or ['l3', 'l11', 'l18', 'l24', 'l29', 'l30', 'l31', 'l32', 'l33']", + "106, MET ['l4', 'l12', 'l19', 'l25', 'l29', 'l34', 'l35', 'l36']", + "114, HGF-expressing ['l5', 'l13', 'l20', 'l26', 'l30', 'l34', 'l37', 'l38']", + "115, AML ['l6', 'l14', 'l21', 'l27', 'l31', 'l35', 'l37', 'l39']", + "116, cells. ['l7', 'l15', 'l22', 'l28', 'l32', 'l36', 'l38', 'l39']", + "118, leukemic ['l40', 'l41', 'l42', 'l43', 'l44']", + "119, cells ['l8', 'l16', 'l23', 'l33', 'l40', 'l45', 'l46']", + "165, inhibition ['l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "166, of ['l47', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "167, FGFR1 ['l48', 'l59', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "168, and ['l49', 'l60', 'l70', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "169, MET ['l50', 'l61', 'l71', 'l80', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "179, cell ['l41', 'l45', 'l51', 'l62', 'l72', 'l81', 'l89', 'l97', 'l98', 'l99']", + "180, killing ['l42', 'l46', 'l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l100', 'l101']", + "182, in ['l43', 'l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l100', 'l102']", + "183, vitro ['l44', 'l54', 'l65', 'l75', 'l84', 'l92', 'l99', 'l101', 'l102']", + "186, xenograft ['l55', 'l66', 'l76', 'l85', 'l93', 'l103', 'l104', 'l105']", + "187, models ['l56', 'l67', 'l77', 'l86', 'l94', 'l103', 'l106', 'l107']", + "188, in ['l57', 'l68', 'l78', 'l87', 'l95', 'l104', 'l106', 'l108']", + "189, vivo. ['l58', 'l69', 'l79', 'l88', 'l96', 'l105', 'l107', 'l108']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "depletion", + "of", + "HGF", + "or", + "MET" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HGF-expressing", + "AML", + "cells.", + "cells" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "leukemic", + "cells" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "killing" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "FGFR1", + "and", + "MET" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "killing" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "FGFR1", + "and", + "MET" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "FGFR1", + "and", + "MET" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "models" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "FGFR1", + "and", + "MET" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "killing" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "22683778", + "TEXT": "Neoadjuvant chemotherapy (NAC) induces a pathological complete response (pCR) in ~30% of patients with breast cancer. However, many patients have residual cancer after chemotherapy, which correlates with a higher risk of metastatic recurrence and poorer outcome than those who achieve a pCR. We hypothesized that molecular profiling of tumors after NAC would identify genes associated with drug resistance. Digital transcript counting was used to profile surgically resected breast cancers after NAC. Low concentrations of dual specificity protein phosphatase 4 (DUSP4), an ERK phosphatase, correlated with high post-NAC tumor cell proliferation and with basal-like breast cancer (BLBC) status. BLBC had higher DUSP4 promoter methylation and gene expression patterns of Ras-ERK pathway activation relative to other breast cancer subtypes. DUSP4 overexpression increased chemotherapy-induced apoptosis, whereas DUSP4 depletion dampened the response to chemotherapy. Reduced DUSP4 expression in primary tumors after NAC was associated with treatment-refractory high Ki-67 scores and shorter recurrence-free survival. Finally, inhibition of mitogen-activated protein kinase kinase (MEK) synergized with docetaxel treatment in BLBC xenografts. Thus, DUSP4 downregulation activates the Ras-ERK pathway in BLBC, resulting in an attenuated response to anti-cancer chemotherapy.", + "TAG_DATA": [ + "117, DUSP4 {'perturbing_action': 'B-gene gain-of-function'}", + "118, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "119, increased {'effect': 'B-positive'}", + "120, chemotherapy-induced {'effect': 'B-positive'}", + "121, apoptosis, {'phenotype': 'B-apoptosis'}", + "123, DUSP4 {'perturbing_action': 'B-gene loss-of-function'}", + "124, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "150, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "151, of {'perturbing_action': 'I-pharmacological inhibition'}", + "152, mitogen-activated {'perturbing_action': 'I-pharmacological inhibition'}", + "153, protein {'perturbing_action': 'I-pharmacological inhibition'}", + "154, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "155, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "156, (MEK) {'perturbing_action': 'I-pharmacological inhibition'}", + "162, BLBC {'context': 'B-xenograft'}", + "163, xenografts. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "117, DUSP4 ['l0', 'l1', 'l2', 'l3']", + "118, overexpression ['l0', 'l4', 'l5', 'l6']", + "119, increased ['l1', 'l4', 'l7', 'l8']", + "120, chemotherapy-induced ['l2', 'l5', 'l7', 'l9']", + "121, apoptosis, ['l3', 'l6', 'l8', 'l9']", + "123, DUSP4 ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "124, depletion ['l10']", + "150, inhibition ['l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "151, of ['l16', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "152, mitogen-activated ['l11', 'l17', 'l24', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "153, protein ['l12', 'l18', 'l25', 'l31', 'l37', 'l38', 'l39', 'l40', 'l41']", + "154, kinase ['l13', 'l19', 'l26', 'l32', 'l37', 'l42', 'l43', 'l44', 'l45']", + "155, kinase ['l14', 'l20', 'l27', 'l33', 'l38', 'l42', 'l46', 'l47', 'l48']", + "156, (MEK) ['l15', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l49', 'l50']", + "162, BLBC ['l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l51']", + "163, xenografts. ['l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l51']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "DUSP4", + "overexpression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "chemotherapy-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "DUSP4", + "overexpression" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased", + "chemotherapy-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "mitogen-activated", + "protein", + "kinase", + "(MEK)" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "BLBC", + "xenografts." + ] + } + } + ] + }, + { + "PMID": "22660636", + "TEXT": "Spinal and bulbar muscular atrophy (SBMA) is an inherited neurodegenerative disorder caused by the expansion of the polyglutamine (polyQ) tract of the androgen receptor (AR-polyQ). Characteristics of SBMA include proximal muscular atrophy, weakness, contraction fasciculation and bulbar involvement. MicroRNAs (miRNAs) are a diverse class of highly conserved small RNA molecules that function as crucial regulators of gene expression in animals and plants. Recent functional studies have shown the potent activity of specific miRNAs as disease modifiers both in vitro and in vivo. Thus, potential therapeutic approaches that target the miRNA processing pathway have recently attracted attention. Here we describe a novel therapeutic approach using the adeno-associated virus (AAV) vector–mediated delivery of a specific miRNA for SBMA. We found that miR-196a enhanced the decay of the AR mRNA by silencing CUGBP, Elav-like family member 2 (CELF2). CELF2 directly acted on AR mRNA and enhanced the stability of AR mRNA. Furthermore, we found that the early intervention of miR-196a delivered by an AAV vector ameliorated the SBMA phenotypes in a mouse model. Our results establish the proof of principle that disease-specific miRNA delivery could be useful in neurodegenerative diseases.", + "TAG_DATA": [ + "128, silencing {'perturbing_action': 'B-rnai/knockdown'}", + "129, CUGBP, {'perturbing_action': 'I-rnai/knockdown'}", + "130, Elav-like {'perturbing_action': 'I-rnai/knockdown'}", + "131, family {'perturbing_action': 'I-rnai/knockdown'}", + "132, member {'perturbing_action': 'I-rnai/knockdown'}", + "133, 2 {'perturbing_action': 'I-rnai/knockdown'}", + "134, (CELF2). {'perturbing_action': 'I-rnai/knockdown'}", + "168, mouse {'context': 'B-organism'}", + "169, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "128, silencing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "129, CUGBP, ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "130, Elav-like ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "131, family ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "132, member ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "133, 2 ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "134, (CELF2). ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "168, mouse ['l21']", + "169, model. ['l21']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22660634", + "TEXT": "Endometriosis is considered to be an estrogen-dependent inflammatory disease, but its etiology is unclear. Thus far, a mechanistic role for steroid receptor coactivators (SRCs) in the progression of endometriosis has not been elucidated. An SRC-1-null mouse model reveals that the mouse SRC-1 gene has an essential role in endometriosis progression. Notably, a previously unidentified 70-kDa SRC-1 proteolytic isoform is highly elevated both in the endometriotic tissue of mice with surgically induced endometriosis and in endometriotic stromal cells biopsied from patients with endometriosis compared to normal endometrium. Tnf⁻/⁻ and Mmp9⁻/⁻ mice with surgically induced endometriosis showed that activation of tumor necrosis factor a (TNF-α)-induced matrix metallopeptidase 9 (MMP9) activity mediates formation of the 70-kDa SRC-1 C-terminal isoform in endometriotic mouse tissue. In contrast to full-length SRC-1, the endometriotic 70-kDa SRC-1 C-terminal fragment prevents TNF-α-mediated apoptosis in human endometrial epithelial cells and causes the epithelial-mesenchymal transition and the invasion of human endometrial cells that are hallmarks of progressive endometriosis. Collectively, the newly identified TNF-α-MMP9-SRC-1 isoform functional axis promotes pathogenic progression of endometriosis.", + "TAG_DATA": [ + "34, SRC-1-null {'perturbing_action': 'B-gene loss-of-function'}", + "35, mouse {'context': 'B-organism'}", + "36, model {'context': 'I-organism'}", + "86, Tnf⁻/⁻ {'perturbing_action': 'B-gene loss-of-function'}", + "87, and {'perturbing_action': 'B-gene loss-of-function'}", + "88, Mmp9⁻/⁻ {'perturbing_action': 'B-gene loss-of-function'}", + "89, mice {'context': 'B-organism'}", + "131, prevents {'effect': 'B-negative'}", + "133, apoptosis {'phenotype': 'B-apoptosis'}", + "135, human {'context': 'B-cells'}", + "136, endometrial {'context': 'I-cells'}", + "137, epithelial {'context': 'I-cells'}", + "138, cells {'context': 'I-cells'}", + "140, causes {'effect': 'B-positive'}", + "142, epithelial-mesenchymal {'phenotype': 'B-epithelial-mesenchymal transition'}", + "143, transition {'phenotype': 'I-epithelial-mesenchymal transition'}", + "146, invasion {'phenotype': 'B-invasion'}", + "148, human {'context': 'B-cells'}", + "149, endometrial {'context': 'I-cells'}", + "150, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "34, SRC-1-null ['l0', 'l1']", + "35, mouse ['l0', 'l2']", + "36, model ['l1', 'l2']", + "86, Tnf⁻/⁻ ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "87, and ['l3', 'l9', 'l10', 'l11', 'l12', 'l13']", + "88, Mmp9⁻/⁻ ['l4', 'l9', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "89, mice ['l5', 'l10', 'l14', 'l22', 'l23']", + "131, prevents ['l15', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "133, apoptosis ['l16', 'l24', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "135, human ['l17', 'l25', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "136, endometrial ['l6', 'l11', 'l18', 'l26', 'l37', 'l45', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "137, epithelial ['l7', 'l12', 'l19', 'l22', 'l27', 'l38', 'l46', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "138, cells ['l8', 'l13', 'l20', 'l23', 'l28', 'l39', 'l47', 'l56', 'l63', 'l69', 'l70', 'l71']", + "140, causes ['l29', 'l40', 'l48', 'l57', 'l64', 'l69', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "142, epithelial-mesenchymal ['l30', 'l41', 'l49', 'l58', 'l65', 'l70', 'l72', 'l78', 'l79', 'l80', 'l81', 'l82']", + "143, transition ['l21', 'l31', 'l42', 'l50', 'l59', 'l66', 'l71', 'l73', 'l78', 'l83', 'l84', 'l85', 'l86']", + "146, invasion ['l32', 'l43', 'l51', 'l60', 'l67', 'l74', 'l79', 'l83', 'l87', 'l88', 'l89']", + "148, human ['l33', 'l52', 'l75', 'l80', 'l84', 'l87', 'l90', 'l91']", + "149, endometrial ['l34', 'l53', 'l61', 'l76', 'l81', 'l85', 'l88', 'l90', 'l92']", + "150, cells ['l35', 'l44', 'l54', 'l62', 'l68', 'l77', 'l82', 'l86', 'l89', 'l91', 'l92']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SRC-1-null", + "Tnf⁻/⁻", + "and", + "Mmp9⁻/⁻" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tnf⁻/⁻", + "and", + "Mmp9⁻/⁻" + ] + }, + "context": { + "val": "cells", + "words": [ + "endometrial", + "epithelial", + "cells", + "human" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mmp9⁻/⁻" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mmp9⁻/⁻" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mmp9⁻/⁻" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "transition" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "endometrial", + "epithelial", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "epithelial-mesenchymal", + "transition" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "endometrial", + "epithelial", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "causes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "endometrial", + "epithelial", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "causes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "endometrial", + "epithelial", + "cells" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "epithelial-mesenchymal", + "transition" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "endometrial", + "epithelial", + "cells" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "epithelial-mesenchymal", + "transition" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + } + ] + }, + { + "PMID": "22635006", + "TEXT": "Safe and effective vaccines are crucial for maintaining public health and reducing the global burden of infectious disease. Here we introduce a new vaccine platform that uses hydrogen peroxide (H(2)O(2)) to inactivate viruses for vaccine production. H(2)O(2) rapidly inactivates both RNA and DNA viruses with minimal damage to antigenic structure or immunogenicity and is a highly effective method when compared with conventional vaccine inactivation approaches such as formaldehyde or β-propiolactone. Mice immunized with H(2)O(2)-inactivated lymphocytic choriomeningitis virus (LCMV) generated cytolytic, multifunctional virus-specific CD8(+) T cells that conferred protection against chronic LCMV infection. Likewise, mice vaccinated with H(2)O(2)-inactivated vaccinia virus or H(2)O(2)-inactivated West Nile virus showed high virus-specific neutralizing antibody titers and were fully protected against lethal challenge. Together, these studies demonstrate that H(2)O(2)-based vaccines are highly immunogenic, provide protection against a range of viral pathogens in mice and represent a promising new approach to future vaccine development.", + "TAG_DATA": [ + "70, Mice {'context': 'B-organism'}", + "82, CD8(+) {'context': 'B-cells'}", + "83, T {'context': 'I-cells'}", + "84, cells {'context': 'I-cells'}", + "93, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "70, Mice ['l0', 'l1', 'l2']", + "82, CD8(+) ['l0', 'l3', 'l4']", + "83, T ['l1', 'l3', 'l5']", + "84, cells ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22610280", + "TEXT": "Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. However, the mechanism that activates infiltrating macrophages in the ischemic brain remains to be clarified. Here we demonstrate that peroxiredoxin (Prx) family proteins released extracellularly from necrotic brain cells induce expression of inflammatory cytokines including interleukin-23 in macrophages through activation of Toll-like receptor 2 (TLR2) and TLR4, thereby promoting neural cell death, even though intracellular Prxs have been shown to be neuroprotective. The extracellular release of Prxs in the ischemic core occurred 12 h after stroke onset, and neutralization of extracellular Prxs with antibodies suppressed inflammatory cytokine expression and infarct volume growth. In contrast, high mobility group box 1 (HMGB1), a well-known damage-associated molecular pattern molecule, was released before Prx and had a limited role in post-ischemic macrophage activation. We thus propose that extracellular Prxs are previously unknown danger signals in the ischemic brain and that its blocking agents are potent neuroprotective tools.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22610278", + "TEXT": "Entamoeba histolytica, a protozoan intestinal parasite, is the causative agent of human amebiasis. Amebiasis is the fourth leading cause of death and the third leading cause of morbidity due to protozoan infections worldwide(1), resulting in ~70,000 deaths annually. E. histolytica has been listed by the National Institutes of Health as a category B priority biodefense pathogen in the United States. Treatment relies on metronidazole(2), which has adverse effects(3), and potential resistance of E. histolytica to the drug is an increasing concern(4,5). To facilitate drug screening for this anaerobic protozoan, we developed and validated an automated, high-throughput screen (HTS). This screen identified auranofin, a US Food and Drug Administration (FDA)-approved drug used therapeutically for rheumatoid arthritis, as active against E. histolytica in culture. Auranofin was ten times more potent against E. histolytica than metronidazole. Transcriptional profiling and thioredoxin reductase assays suggested that auranofin targets the E. histolytica thioredoxin reductase, preventing the reduction of thioredoxin and enhancing sensitivity of trophozoites to reactive oxygen-mediated killing. In a mouse model of amebic colitis and a hamster model of amebic liver abscess, oral auranofin markedly decreased the number of parasites, the detrimental host inflammatory response and hepatic damage. This new use of auranofin represents a promising therapy for amebiasis, and the drug has been granted orphan-drug status from the FDA.", + "TAG_DATA": [ + "121, culture. {'context': 'B-in vitro'}", + "164, mouse {'context': 'B-organism'}", + "165, model {'context': 'I-organism'}", + "171, hamster {'context': 'B-organism'}", + "172, model {'context': 'I-organism'}", + "174, amebic {'context': 'I-tissue/organ'}", + "175, liver {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "118, E. ['l0']", + "121, culture. ['l0']", + "164, mouse ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "165, model ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "171, hamster ['l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "172, model ['l2', 'l7', 'l12', 'l18', 'l19', 'l20', 'l21', 'l22']", + "173, of ['l3', 'l8', 'l13', 'l18', 'l23', 'l24', 'l25', 'l26']", + "174, amebic ['l14', 'l19', 'l23', 'l27', 'l28', 'l29']", + "175, liver ['l4', 'l9', 'l15', 'l20', 'l24', 'l27', 'l30', 'l31']", + "176, abscess, ['l5', 'l10', 'l16', 'l21', 'l25', 'l28', 'l30', 'l32']", + "184, parasites, ['l6', 'l11', 'l17', 'l22', 'l26', 'l29', 'l31', 'l32']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22610277", + "TEXT": "The Wnt–β-catenin and PI3K-AKT-FOXO3a pathways have a central role in cancer. AKT phosporylates FOXO3a, relocating it from the cell nucleus to the cytoplasm, an effect that is reversed by PI3K and AKT inhibitors. Simultaneous hyperactivation of the Wnt–β-catenin pathway and inhibition of PI3K-AKT signaling promote nuclear accumulation of β-catenin and FOXO3a, respectively, promoting cell scattering and metastasis by regulating a defined set of target genes. Indeed, the anti-tumoral AKT inhibitor API-2 promotes nuclear FOXO3a accumulation and metastasis of cells with high nuclear β-catenin content. Nuclear β-catenin confers resistance to the FOXO3a-mediated apoptosis induced by PI3K and AKT inhibitors in patient-derived primary cultures and in corresponding xenograft tumors in mice. This resistance is reversed by XAV-939, an inhibitor of Wnt–β-catenin signaling. In the presence of high nuclear β-catenin content, activation of FOXO3a by PI3K or AKT inhibitors makes it behave as a metastasis inductor rather than a proapoptotic tumor suppressor. We show that it is possible to evaluate the β-catenin status of patients' carcinomas and the response of patient-derived cells to target-directed drugs that accumulate FOXO3a in the nucleus before deciding on a course of treatment. We propose that this evaluation could be essential to the provision of a safer and more effective personalized treatment.", + "TAG_DATA": [ + "71, promotes {'effect': 'B-positive'}", + "76, metastasis {'phenotype': 'B-metastasis'}", + "78, cells {'context': 'B-cells'}", + "87, resistance {'effect': 'B-negative'}", + "90, FOXO3a-mediated {'effect': 'B-regulates'}", + "91, apoptosis {'phenotype': 'B-apoptosis'}", + "92, induced {'effect': 'B-positive'}", + "94, PI3K {'perturbing_action': 'B-pharmacological inhibition'}", + "95, and {'perturbing_action': 'I-pharmacological inhibition'}", + "96, AKT {'perturbing_action': 'I-pharmacological inhibition'}", + "97, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "99, patient-derived {'context': 'B-cells'}", + "100, primary {'context': 'I-cells'}", + "101, cultures {'context': 'I-cells'}", + "105, xenograft {'context': 'B-xenograft'}", + "106, tumors {'context': 'I-xenograft'}", + "108, mice. {'context': 'B-organism'}", + "134, AKT {'perturbing_action': 'B-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "71, promotes ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "76, metastasis ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "78, cells ['l1', 'l6', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "87, resistance ['l2', 'l7', 'l14', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "90, FOXO3a-mediated ['l8', 'l15', 'l23', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "91, apoptosis ['l9', 'l16', 'l24', 'l36', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "92, induced ['l10', 'l17', 'l25', 'l37', 'l48', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "94, PI3K ['l26', 'l38', 'l49', 'l59', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "95, and ['l27', 'l39', 'l50', 'l60', 'l68', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "96, AKT ['l28', 'l40', 'l51', 'l61', 'l69', 'l77', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "97, inhibitors ['l18', 'l29', 'l41', 'l52', 'l62', 'l70', 'l78', 'l85', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "99, patient-derived ['l3', 'l11', 'l19', 'l30', 'l42', 'l53', 'l63', 'l71', 'l79', 'l86', 'l92', 'l98', 'l99', 'l100']", + "100, primary ['l4', 'l12', 'l20', 'l31', 'l43', 'l54', 'l64', 'l72', 'l80', 'l87', 'l93', 'l98', 'l101']", + "101, cultures ['l5', 'l13', 'l21', 'l32', 'l44', 'l55', 'l65', 'l73', 'l81', 'l88', 'l94', 'l99', 'l101']", + "105, xenograft ['l33', 'l45', 'l56', 'l74', 'l82', 'l89', 'l95', 'l102', 'l103']", + "106, tumors ['l22', 'l34', 'l46', 'l57', 'l66', 'l75', 'l83', 'l90', 'l96', 'l100', 'l102', 'l104']", + "108, mice. ['l35', 'l47', 'l58', 'l67', 'l76', 'l84', 'l91', 'l97', 'l103', 'l104']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promotes", + "induced" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes", + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "patient-derived", + "primary", + "cultures" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "patient-derived", + "primary", + "cultures" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "FOXO3a-mediated" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "patient-derived", + "primary", + "cultures" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "patient-derived", + "primary", + "cultures" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "FOXO3a-mediated" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "patient-derived", + "primary", + "cultures" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "patient-derived", + "primary", + "cultures" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "PI3K", + "and", + "AKT" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PI3K", + "and", + "AKT", + "inhibitors" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "tumors" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "FOXO3a-mediated" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "FOXO3a-mediated" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PI3K", + "and", + "AKT", + "inhibitors" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "FOXO3a-mediated" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "tumors" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "FOXO3a-mediated" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PI3K", + "and", + "AKT", + "inhibitors" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "tumors" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PI3K", + "and", + "AKT", + "inhibitors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PI3K", + "and", + "AKT", + "inhibitors" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PI3K", + "and", + "AKT", + "inhibitors" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "22561801", + "TEXT": "Recent advances in asthma research have altered views of how the disease is triggered and sustained. What remains to be seen is whether this knowledge can be integrated into the clinic to alter the natural course of disease.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22561686", + "TEXT": "Fatty liver disease is associated with obesity and type 2 diabetes, and hepatic lipid accumulation may contribute to insulin resistance. Histone deacetylase 3 (Hdac3) controls the circadian rhythm of hepatic lipogenesis. Here we show that, despite severe hepatosteatosis, mice with liver-specific depletion of Hdac3 have higher insulin sensitivity without any changes in insulin signaling or body weight compared to wild-type mice. Hdac3 depletion reroutes metabolic precursors towards lipid synthesis and storage within lipid droplets and away from hepatic glucose production. Perilipin 2, which coats lipid droplets, is markedly induced upon Hdac3 depletion and contributes to the development of both steatosis and improved tolerance to glucose. These findings suggest that the sequestration of hepatic lipids in perilipin 2–coated droplets ameliorates insulin resistance and establish Hdac3 as a pivotal epigenomic modifier that integrates signals from the circadian clock in the regulation of hepatic intermediary metabolism.", + "TAG_DATA": [ + "38, mice {'context': 'B-organism'}", + "40, liver-specific {'perturbing_action': 'B-gene loss-of-function'}", + "41, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "42, of {'perturbing_action': 'I-gene loss-of-function'}", + "43, Hdac3 {'perturbing_action': 'I-gene loss-of-function'}", + "60, mice. {'context': 'B-organism'}", + "61, Hdac3 {'perturbing_action': 'B-gene loss-of-function'}", + "62, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "90, Hdac3 {'perturbing_action': 'B-gene loss-of-function'}", + "91, depletion {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "40, liver-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "41, depletion ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "42, of ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "43, Hdac3 ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "60, mice. ['l3', 'l8', 'l12', 'l15']", + "61, Hdac3 ['l4', 'l9', 'l13', 'l16', 'l18', 'l19', 'l20']", + "62, depletion ['l5', 'l10', 'l14', 'l17', 'l18', 'l21', 'l22']", + "90, Hdac3 ['l19', 'l21', 'l23']", + "91, depletion ['l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "liver-specific", + "depletion", + "of", + "Hdac3" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "22522563", + "TEXT": "Few effective measures exist to combat the worldwide obesity epidemic(1), and the identification of potential therapeutic targets requires a deeper understanding of the mechanisms that control energy balance. Leptin, an adipocyte-derived hormone that signals the long-term status of bodily energy stores, acts through multiple types of leptin receptor long isoform (LepRb)-expressing neurons (called here LepRb neurons) in the brain to control feeding, energy expenditure and endocrine function(2-4). The modest contributions to energy balance that are attributable to leptin action in many LepRb populations(5-9) suggest that other previously unidentified hypothalamic LepRb neurons have key roles in energy balance. Here we examine the role of LepRb in neuronal nitric oxide synthase (NOS1)-expressing LebRb (LepRb(NOS1)) neurons that comprise approximately 20% of the total hypothalamic LepRb neurons. Nos1(cre)-mediated genetic ablation of LepRb (Lepr(Nos1KO)) in mice produces hyperphagic obesity, decreased energy expenditure and hyperglycemia approaching that seen in whole-body LepRb-null mice. In contrast, the endocrine functions in Lepr(Nos1KO) mice are only modestly affected by the genetic ablation of LepRb in these neurons. Thus, hypothalamic LepRb(NOS1) neurons are a key site of action of the leptin-mediated control of systemic energy balance.", + "TAG_DATA": [ + "123, Nos1(cre)-mediated {'perturbing_action': 'B-gene loss-of-function'}", + "124, genetic {'perturbing_action': 'I-gene loss-of-function'}", + "125, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "126, of {'perturbing_action': 'I-gene loss-of-function'}", + "127, LepRb {'perturbing_action': 'I-gene loss-of-function'}", + "128, (Lepr(Nos1KO)) {'perturbing_action': 'I-gene loss-of-function'}", + "130, mice {'context': 'B-organism'}", + "144, LepRb-null {'perturbing_action': 'B-gene loss-of-function'}", + "145, mice. {'context': 'B-organism'}", + "152, Lepr(Nos1KO) {'perturbing_action': 'B-gene loss-of-function'}", + "153, mice {'context': 'B-organism'}", + "160, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "161, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "162, of {'perturbing_action': 'I-gene loss-of-function'}", + "163, LepRb {'perturbing_action': 'I-gene loss-of-function'}", + "166, neurons. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "123, Nos1(cre)-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "124, genetic ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "125, ablation ['l1', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "126, of ['l2', 'l9', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "127, LepRb ['l3', 'l10', 'l15', 'l20', 'l25', 'l26', 'l27', 'l28']", + "128, (Lepr(Nos1KO)) ['l4', 'l11', 'l16', 'l21', 'l25', 'l29', 'l30']", + "130, mice ['l5', 'l12', 'l17', 'l22', 'l26', 'l29']", + "144, LepRb-null ['l6', 'l18', 'l23', 'l27', 'l31']", + "145, mice. ['l7', 'l13', 'l19', 'l24', 'l28', 'l30', 'l31']", + "152, Lepr(Nos1KO) ['l32', 'l33', 'l34', 'l35', 'l36']", + "153, mice ['l32', 'l37']", + "160, genetic ['l38', 'l39', 'l40', 'l41']", + "161, ablation ['l33', 'l38', 'l42', 'l43', 'l44']", + "162, of ['l34', 'l39', 'l42', 'l45', 'l46']", + "163, LepRb ['l35', 'l40', 'l43', 'l45', 'l47']", + "166, neurons. ['l36', 'l37', 'l41', 'l44', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nos1(cre)-mediated", + "genetic", + "ablation", + "of", + "LepRb", + "(Lepr(Nos1KO))", + "LepRb-null", + "Lepr(Nos1KO)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lepr(Nos1KO)", + "genetic", + "ablation", + "of", + "LepRb" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons." + ] + } + } + ] + }, + { + "PMID": "22504484", + "TEXT": "The difficulty in delineating brain tumor margins is a major obstacle in the path toward better outcomes for patients with brain tumors. Current imaging methods are often limited by inadequate sensitivity, specificity and spatial resolution. Here we show that a unique triple-modality magnetic resonance imaging-photoacoustic imaging-Raman imaging nanoparticle (termed here MPR nanoparticle) can accurately help delineate the margins of brain tumors in living mice both preoperatively and intraoperatively. The MPRs were detected by all three modalities with at least a picomolar sensitivity both in vitro and in living mice. Intravenous injection of MPRs into glioblastoma-bearing mice led to MPR accumulation and retention by the tumors, with no MPR accumulation in the surrounding healthy tissue, allowing for a noninvasive tumor delineation using all three modalities through the intact skull. Raman imaging allowed for guidance of intraoperative tumor resection, and a histological correlation validated that Raman imaging was accurately delineating the brain tumor margins. This new triple-modality-nanoparticle approach has promise for enabling more accurate brain tumor imaging and resection.", + "TAG_DATA": [ + "63, mice {'context': 'I-organism'}", + "83, in {'context': 'B-in vitro'}", + "84, vitro {'context': 'I-in vitro'}", + "87, living {'context': 'B-organism'}", + "88, mice. {'context': 'I-organism'}", + "94, glioblastoma-bearing {'context': 'B-organism'}", + "95, mice {'context': 'I-organism'}", + "104, tumors, {'context': 'B-neoplasm'}", + "113, tissue, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "83, in ['l0', 'l1', 'l2']", + "84, vitro ['l0', 'l3', 'l4']", + "87, living ['l1', 'l3', 'l5']", + "88, mice. ['l2', 'l4', 'l5']", + "94, glioblastoma-bearing ['l6', 'l7', 'l8']", + "95, mice ['l6', 'l9', 'l10']", + "104, tumors, ['l7', 'l9', 'l11']", + "113, tissue, ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22481405", + "TEXT": "Changes in gut microbial composition have been linked to inflammatory bowel disease, obesity and allergies in humans. A new study shows that pattern recognition of commensal bacteria by B cells reduces allergic inflammation in mice, adding to the mounting evidence for the ‘hygiene hypothesis’.", + "TAG_DATA": [ + "34, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22466704", + "TEXT": "Ataxia telangiectasia is a neurodegenerative disease caused by mutation of the Atm gene. Here we report that ataxia telangiectasia mutated (ATM) deficiency causes nuclear accumulation of histone deacetylase 4 (HDAC4) in neurons and promotes neurodegeneration. Nuclear HDAC4 binds to chromatin, as well as to myocyte enhancer factor 2A (MEF2A) and cAMP-responsive element binding protein (CREB), leading to histone deacetylation and altered neuronal gene expression. Blocking either HDAC4 activity or its nuclear accumulation blunts these neurodegenerative changes and rescues several behavioral abnormalities of ATM-deficient mice. Full rescue of the neurodegeneration, however, also requires the presence of HDAC4 in the cytoplasm, suggesting that the ataxia telangiectasia phenotype results both from a loss of cytoplasmic HDAC4 as well as its nuclear accumulation. To remain cytoplasmic, HDAC4 must be phosphorylated. The activity of the HDAC4 phosphatase, protein phosphatase 2A (PP2A), is downregulated by ATM-mediated phosphorylation. In ATM deficiency, enhanced PP2A activity leads to HDAC4 dephosphorylation and the nuclear accumulation of HDAC4. Our results define a crucial role of the cellular localization of HDAC4 in the events leading to ataxia telangiectasia neurodegeneration.", + "TAG_DATA": [ + "82, ATM-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "83, mice. {'context': 'B-organism'}", + "142, ATM {'perturbing_action': 'B-gene loss-of-function'}", + "143, deficiency, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "82, ATM-deficient ['l0']", + "83, mice. ['l0']", + "142, ATM ['l1']", + "143, deficiency, ['l1']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ATM-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "22466703", + "TEXT": "Alternative splicing has a major role in cardiac adaptive responses, as exemplified by the isoform switch of the sarcomeric protein titin, which adjusts ventricular filling. By positional cloning using a previously characterized rat strain with altered titin mRNA splicing, we identified a loss-of-function mutation in the gene encoding RNA binding motif protein 20 (Rbm20) as the underlying cause of pathological titin isoform expression. The phenotype of Rbm20-deficient rats resembled the pathology seen in individuals with dilated cardiomyopathy caused by RBM20 mutations. Deep sequencing of the human and rat cardiac transcriptome revealed an RBM20-dependent regulation of alternative splicing. In addition to titin (TTN), we identified a set of 30 genes with conserved splicing regulation between humans and rats. This network is enriched for genes that have previously been linked to cardiomyopathy, ion homeostasis and sarcomere biology. Our studies emphasize the key role of post-transcriptional regulation in cardiac function and provide mechanistic insights into the pathogenesis of human heart failure.", + "TAG_DATA": [ + "42, loss-of-function {'perturbing_action': 'B-gene loss-of-function'}", + "43, mutation {'perturbing_action': 'I-gene loss-of-function'}", + "44, in {'perturbing_action': 'I-gene loss-of-function'}", + "45, the {'perturbing_action': 'I-gene loss-of-function'}", + "46, gene {'perturbing_action': 'I-gene loss-of-function'}", + "47, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "48, RNA {'perturbing_action': 'I-gene loss-of-function'}", + "49, binding {'perturbing_action': 'I-gene loss-of-function'}", + "50, motif {'perturbing_action': 'I-gene loss-of-function'}", + "51, protein {'perturbing_action': 'I-gene loss-of-function'}", + "52, 20 {'perturbing_action': 'I-gene loss-of-function'}", + "53, (Rbm20) {'perturbing_action': 'I-gene loss-of-function'}", + "66, Rbm20-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "67, rats {'context': 'B-organism'}", + "79, RBM20 {'perturbing_action': 'B-other'}", + "80, mutations. {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "42, loss-of-function ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "43, mutation ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "44, in ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "45, the ['l2', 'l12', 'l21', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "46, gene ['l3', 'l13', 'l22', 'l32', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "47, encoding ['l4', 'l14', 'l23', 'l33', 'l44', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "48, RNA ['l5', 'l15', 'l24', 'l34', 'l45', 'l53', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "49, binding ['l6', 'l16', 'l25', 'l35', 'l46', 'l54', 'l63', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "50, motif ['l7', 'l17', 'l26', 'l36', 'l47', 'l55', 'l64', 'l72', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "51, protein ['l8', 'l18', 'l27', 'l37', 'l48', 'l56', 'l65', 'l73', 'l80', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "52, 20 ['l9', 'l19', 'l28', 'l38', 'l49', 'l57', 'l66', 'l74', 'l81', 'l87', 'l93', 'l94', 'l95', 'l96', 'l97']", + "53, (Rbm20) ['l10', 'l20', 'l29', 'l39', 'l50', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l98', 'l99', 'l100', 'l101']", + "66, Rbm20-deficient ['l40', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l102', 'l103', 'l104']", + "67, rats ['l30', 'l41', 'l51', 'l60', 'l69', 'l77', 'l84', 'l90', 'l95', 'l99', 'l102', 'l105', 'l106']", + "79, RBM20 ['l42', 'l61', 'l70', 'l78', 'l85', 'l91', 'l96', 'l100', 'l103', 'l105', 'l107']", + "80, mutations. ['l31', 'l43', 'l52', 'l62', 'l71', 'l79', 'l86', 'l92', 'l97', 'l101', 'l104', 'l106', 'l107']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "in", + "the", + "gene", + "encoding", + "RNA", + "binding", + "motif", + "protein", + "20", + "(Rbm20)", + "Rbm20-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rats" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "RBM20", + "mutations." + ] + } + } + ] + }, + { + "PMID": "22447074", + "TEXT": "Commensal bacteria that colonize mammalian barrier surfaces are reported to influence T helper type 2 (T(H)2) cytokine-dependent inflammation and susceptibility to allergic disease, although the mechanisms that underlie these observations are poorly understood. In this report, we find that deliberate alteration of commensal bacterial populations via oral antibiotic treatment resulted in elevated serum IgE concentrations, increased steady-state circulating basophil populations and exaggerated basophil-mediated T(H)2 cell responses and allergic inflammation. Elevated serum IgE levels correlated with increased circulating basophil populations in mice and subjects with hyperimmunoglobulinemia E syndrome. Furthermore, B cell-intrinsic expression of myeloid differentiation factor 88 (MyD88) was required to limit serum IgE concentrations and circulating basophil populations in mice. Commensal-derived signals were found to influence basophil development by limiting proliferation of bone marrow-resident precursor populations. Collectively, these results identify a previously unrecognized pathway through which commensal-derived signals influence basophil hematopoiesis and susceptibility to T(H)2 cytokine-dependent inflammation and allergic disease.", + "TAG_DATA": [ + "109, mice. {'context': 'B-organism'}", + "119, limiting {'effect': 'B-negative'}", + "120, proliferation {'phenotype': 'B-proliferation'}", + "122, bone {'context': 'B-cells'}", + "123, marrow-resident {'context': 'I-cells'}", + "124, precursor {'context': 'I-cells'}", + "125, populations. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "119, limiting ['l0', 'l1', 'l2', 'l3', 'l4']", + "120, proliferation ['l0', 'l5', 'l6', 'l7', 'l8']", + "122, bone ['l1', 'l5', 'l9', 'l10', 'l11']", + "123, marrow-resident ['l2', 'l6', 'l9', 'l12', 'l13']", + "124, precursor ['l3', 'l7', 'l10', 'l12', 'l14']", + "125, populations. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "limiting" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limiting" + ] + }, + "context": { + "val": "cells", + "words": [ + "bone", + "marrow-resident", + "precursor", + "populations." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "bone", + "marrow-resident", + "precursor", + "populations." + ] + } + } + ] + }, + { + "PMID": "22426422", + "TEXT": "Mutations in the Bdnf gene, which produces transcripts with either short or long 3' untranslated regions (3' UTRs), cause human obesity; however, the precise role of brain-derived neurotrophic factor (BDNF) in the regulation of energy balance is unknown. Here we show the relationship between Bdnf mRNA with a long 3' UTR (long 3' UTR Bdnf mRNA), leptin, neuronal activation and body weight. We found that long 3' UTR Bdnf mRNA was enriched in the dendrites of hypothalamic neurons and that insulin and leptin could stimulate its translation in dendrites. Furthermore, mice harboring a truncated long Bdnf 3' UTR developed severe hyperphagic obesity, which was completely reversed by viral expression of long 3' UTR Bdnf mRNA in the hypothalamus. In these mice, the ability of leptin to activate hypothalamic neurons and inhibit food intake was compromised despite normal activation of leptin receptors. These results reveal a novel mechanism linking leptin action to BDNF expression during hypothalamic-mediated regulation of body weight, while also implicating dendritic protein synthesis in this process.", + "TAG_DATA": [ + "90, mice {'context': 'B-organism'}", + "92, a {'perturbing_action': 'B-other'}", + "93, truncated {'perturbing_action': 'B-other'}", + "94, long {'perturbing_action': 'I-other'}", + "95, Bdnf {'perturbing_action': 'I-other'}", + "96, 3' {'perturbing_action': 'I-other'}", + "97, UTR {'perturbing_action': 'I-other'}", + "107, viral {'perturbing_action': 'B-gene gain-of-function'}", + "108, expression {'perturbing_action': 'I-gene gain-of-function'}", + "109, of {'perturbing_action': 'I-gene gain-of-function'}", + "110, long {'perturbing_action': 'I-gene gain-of-function'}", + "111, 3' {'perturbing_action': 'I-gene gain-of-function'}", + "112, UTR {'perturbing_action': 'I-gene gain-of-function'}", + "113, Bdnf {'perturbing_action': 'I-gene gain-of-function'}", + "114, mRNA {'perturbing_action': 'I-gene gain-of-function'}", + "115, in {'perturbing_action': 'I-gene gain-of-function'}", + "116, the {'perturbing_action': 'I-gene gain-of-function'}", + "117, hypothalamus. {'context': 'B-tissue/organ'}", + "120, mice, {'context': 'B-organism'}", + "127, hypothalamic {'context': 'B-cells'}", + "128, neurons {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "90, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "92, a ['l0', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "93, truncated ['l5', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "94, long ['l1', 'l6', 'l19', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "95, Bdnf ['l2', 'l7', 'l20', 'l32', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "96, 3' ['l3', 'l8', 'l21', 'l33', 'l42', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "97, UTR ['l4', 'l9', 'l22', 'l34', 'l43', 'l48', 'l56', 'l57', 'l58', 'l59']", + "107, viral ['l10', 'l23', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "108, expression ['l11', 'l24', 'l35', 'l49', 'l60', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "109, of ['l12', 'l25', 'l36', 'l50', 'l61', 'l71', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "110, long ['l62', 'l72', 'l80', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "111, 3' ['l63', 'l73', 'l81', 'l89', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "112, UTR ['l13', 'l26', 'l64', 'l74', 'l82', 'l90', 'l98', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "113, Bdnf ['l14', 'l27', 'l37', 'l51', 'l65', 'l75', 'l83', 'l91', 'l99', 'l106', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "114, mRNA ['l15', 'l28', 'l38', 'l44', 'l52', 'l56', 'l66', 'l76', 'l84', 'l92', 'l100', 'l107', 'l113', 'l119', 'l120', 'l121', 'l122']", + "115, in ['l16', 'l29', 'l39', 'l45', 'l53', 'l57', 'l67', 'l77', 'l85', 'l93', 'l101', 'l108', 'l114', 'l119', 'l123', 'l124']", + "116, the ['l17', 'l30', 'l40', 'l46', 'l54', 'l58', 'l68', 'l78', 'l86', 'l94', 'l102', 'l109', 'l115', 'l120', 'l123', 'l125']", + "117, hypothalamus. ['l18', 'l31', 'l41', 'l47', 'l55', 'l59', 'l69', 'l79', 'l87', 'l95', 'l103', 'l110', 'l116', 'l121', 'l124', 'l125']", + "120, mice, ['l126', 'l127']", + "127, hypothalamic ['l96', 'l104', 'l111', 'l117', 'l126', 'l128']", + "128, neurons ['l70', 'l88', 'l97', 'l105', 'l112', 'l118', 'l122', 'l127', 'l128']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "a", + "long", + "Bdnf", + "3'", + "UTR" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "a", + "truncated", + "long", + "Bdnf", + "3'", + "UTR" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hypothalamus." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "viral", + "expression", + "of", + "long", + "3'", + "UTR", + "Bdnf", + "mRNA", + "in", + "the" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hypothalamus." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "viral", + "of", + "long", + "3'", + "UTR", + "Bdnf", + "mRNA" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons", + "hypothalamic" + ] + } + } + ] + }, + { + "PMID": "22426420", + "TEXT": "During fasting, induction of hepatic gluconeogenesis is crucial to ensure proper energy homeostasis. Such induction is dysregulated in type 2 diabetes, resulting in the development of fasting hyperglycemia. Hormonal and nutrient regulation of metabolic adaptation during fasting is mediated predominantly by the transcriptional coactivator peroxisome proliferative activated receptor γ coactivator 1α (PGC-1α) in concert with various other transcriptional regulators. Although CITED2 (CBP- and p300-interacting transactivator with glutamic acid- and aspartic acid-rich COOH-terminal domain 2) interacts with many of these molecules, the role of this protein in the regulation of hepatic gluconeogenesis was previously unknown. Here we show that CITED2 is required for the regulation of hepatic gluconeogenesis through PGC-1α. The abundance of CITED2 was increased in the livers of mice by fasting and in cultured hepatocytes by glucagon-cAMP-protein kinase A (PKA) signaling, and the amount of CITED2 in liver was higher in mice with type 2 diabetes than in non-diabetic mice. CITED2 inhibited the acetylation of PGC-1α by blocking its interaction with the acetyltransferase general control of amino acid synthesis 5-like 2 (GCN5). The consequent downregulation of PGC-1α acetylation resulted in an increase in its transcriptional coactivation activity and an increased expression of gluconeogenic genes. The interaction of CITED2 with GCN5 was disrupted by insulin in a manner that was dependent on phosphoinositide 3-kinase (PI3K)-thymoma viral proto-oncogene (Akt) signaling. Our results show that CITED2 functions as a transducer of glucagon and insulin signaling in the regulation of PGC-1α activity that is associated with the transcriptional control of gluconeogenesis and that this function is mediated through the modulation of GCN5-dependent PGC-1α acetylation. We also found that loss of hepatic CITED2 function suppresses gluconeogenesis", + "TAG_DATA": [ + "117, livers {'context': 'B-tissue/organ'}", + "119, mice {'context': 'B-organism'}", + "124, cultured {'context': 'B-cells'}", + "125, hepatocytes {'context': 'I-cells'}", + "138, liver {'context': 'B-tissue/organ'}", + "142, mice {'context': 'B-organism'}", + "149, non-diabetic {'context': 'B-organism'}", + "150, mice. {'context': 'I-organism'}", + "265, loss {'perturbing_action': 'B-gene loss-of-function'}", + "266, of {'perturbing_action': 'I-gene loss-of-function'}", + "267, hepatic {'perturbing_action': 'I-gene loss-of-function'}", + "268, CITED2 {'perturbing_action': 'I-gene loss-of-function'}", + "269, function {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "117, livers ['l0', 'l1', 'l2']", + "119, mice ['l0', 'l3', 'l4']", + "124, cultured ['l1', 'l3', 'l5', 'l6', 'l7']", + "125, hepatocytes ['l2', 'l4', 'l5', 'l8', 'l9']", + "138, liver ['l6', 'l8', 'l10']", + "142, mice ['l7', 'l9', 'l10', 'l11', 'l12']", + "149, non-diabetic ['l11', 'l13']", + "150, mice. ['l12', 'l13']", + "265, loss ['l14', 'l15', 'l16', 'l17']", + "266, of ['l14', 'l18', 'l19', 'l20']", + "267, hepatic ['l15', 'l18', 'l21', 'l22']", + "268, CITED2 ['l16', 'l19', 'l21', 'l23']", + "269, function ['l17', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22426419", + "TEXT": "Inflammatory bowel diseases (IBDs) are chronic relapsing and remitting conditions associated with long-term gut dysfunction resulting from alterations to the enteric nervous system and a loss of enteric neurons. The mechanisms underlying inflammation-induced enteric neuron death are unknown. Here using in vivo models of experimental colitis we report that inflammation causes enteric neuron death by activating a neuronal signaling complex composed of P2X7 receptors (P2X7Rs), pannexin-1 (Panx1) channels, the Asc adaptor protein and caspases. Inhibition of P2X7R, Panx1, Asc or caspase activity prevented inflammation-induced neuron cell death. Preservation of enteric neurons by inhibiting Panx1 in vivo prevented the onset of inflammation-induced colonic motor dysfunction. Panx1 expression was reduced in Crohn's disease but not ulcerative colitis. We conclude that activation of neuronal Panx1 underlies neuron death and the subsequent development of abnormal gut motility in IBD. Targeting Panx1 represents a new neuroprotective strategy to ameliorate the progression of IBD-associated dysmotility.", + "TAG_DATA": [ + "51, enteric {'context': 'B-cells'}", + "52, neuron {'context': 'I-cells'}", + "74, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "75, of {'perturbing_action': 'I-pharmacological inhibition'}", + "76, P2X7R, {'perturbing_action': 'I-pharmacological inhibition'}", + "77, Panx1, {'perturbing_action': 'I-pharmacological inhibition'}", + "78, Asc {'perturbing_action': 'I-pharmacological inhibition'}", + "82, prevented {'effect': 'B-negative'}", + "83, inflammation-induced {'effect': 'B-positive'}", + "84, neuron {'context': 'B-cells'}", + "85, cell {'phenotype': 'B-cell death'}", + "86, death. {'phenotype': 'I-cell death'}", + "89, enteric {'context': 'B-cells'}", + "90, neurons {'context': 'I-cells'}", + "92, inhibiting {'perturbing_action': 'B-pharmacological inhibition'}", + "93, Panx1 {'perturbing_action': 'I-pharmacological inhibition'}", + "94, in {'context': 'B-in vivo'}", + "95, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "51, enteric ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "52, neuron ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "74, Inhibition ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "75, of ['l15', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "76, P2X7R, ['l16', 'l24', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "77, Panx1, ['l1', 'l8', 'l17', 'l25', 'l32', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "78, Asc ['l2', 'l9', 'l18', 'l26', 'l33', 'l39', 'l45', 'l46', 'l47', 'l48', 'l49']", + "82, prevented ['l3', 'l10', 'l19', 'l27', 'l34', 'l40', 'l45', 'l50', 'l51', 'l52', 'l53']", + "83, inflammation-induced ['l4', 'l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l50', 'l54', 'l55', 'l56']", + "84, neuron ['l5', 'l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l54', 'l57', 'l58']", + "85, cell ['l6', 'l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l57', 'l59']", + "86, death. ['l7', 'l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58', 'l59']", + "89, enteric ['l60', 'l61', 'l62', 'l63', 'l64']", + "90, neurons ['l60', 'l65', 'l66', 'l67', 'l68']", + "92, inhibiting ['l61', 'l65', 'l69', 'l70', 'l71']", + "93, Panx1 ['l62', 'l66', 'l69', 'l72', 'l73']", + "94, in ['l63', 'l67', 'l70', 'l72', 'l74']", + "95, vivo ['l64', 'l68', 'l71', 'l73', 'l74']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "enteric", + "neuron", + "neurons" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Panx1,", + "Asc", + "Inhibition", + "of", + "P2X7R,", + "inhibiting", + "Panx1" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "enteric", + "neuron" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "enteric", + "neuron" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inflammation-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "enteric", + "neuron" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "P2X7R,", + "Panx1,", + "Asc" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "P2X7R,", + "Panx1,", + "Asc" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inflammation-induced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "P2X7R,", + "Panx1,", + "Asc" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inflammation-induced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibiting", + "Panx1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "22366951", + "TEXT": "We report on a new straightforward magnetic cell-labeling approach that combines three US Food and Drug Administration (FDA)-approved drugs--ferumoxytol, heparin and protamine--in serum-free medium to form self-assembling nanocomplexes that effectively label cells for in vivo magnetic resonance imaging (MRI). We observed that the ferumoxytol-heparin-protamine (HPF) nanocomplexes were stable in serum-free cell culture medium. HPF nanocomplexes show a threefold increase in T2 relaxivity compared to ferumoxytol. Electron microscopy showed internalized HPF in endosomes, which we confirmed by Prussian blue staining of labeled cells. There was no long-term effect or toxicity on cellular physiology or function of HPF-labeled hematopoietic stem cells, bone marrow stromal cells, neural stem cells or T cells when compared to controls. In vivo MRI detected 1,000 HPF-labeled cells implanted in rat brains. This HPF labeling method should facilitate the monitoring by MRI of infused or implanted cells in clinical trials.", + "TAG_DATA": [ + "81, cells. {'context': 'B-cells'}", + "96, hematopoietic {'context': 'B-cells'}", + "97, stem {'context': 'I-cells'}", + "98, cells, {'context': 'I-cells'}", + "99, bone {'context': 'B-cells'}", + "100, marrow {'context': 'I-cells'}", + "101, stromal {'context': 'I-cells'}", + "102, cells, {'context': 'I-cells'}", + "103, neural {'context': 'B-cells'}", + "104, stem {'context': 'I-cells'}", + "105, cells {'context': 'I-cells'}", + "107, T {'context': 'B-cells'}", + "108, cells {'context': 'I-cells'}", + "113, In {'context': 'B-in vivo'}", + "114, vivo {'context': 'I-in vivo'}", + "122, rat {'context': 'B-tissue/organ'}", + "123, brains. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "81, cells. ['l0']", + "96, hematopoietic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "97, stem ['l0', 'l1', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "98, cells, ['l2', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "99, bone ['l3', 'l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "100, marrow ['l4', 'l14', 'l23', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "101, stromal ['l5', 'l15', 'l24', 'l32', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "102, cells, ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l52', 'l53', 'l54', 'l55', 'l56']", + "103, neural ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l57', 'l58', 'l59', 'l60']", + "104, stem ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l61', 'l62', 'l63']", + "105, cells ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l64', 'l65']", + "107, T ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l66']", + "108, cells ['l11', 'l21', 'l30', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l65', 'l66']", + "113, In ['l67', 'l68', 'l69']", + "114, vivo ['l67', 'l70', 'l71']", + "122, rat ['l68', 'l70', 'l72']", + "123, brains. ['l69', 'l71', 'l72']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22344294", + "TEXT": "Limited neural input results in muscle weakness in neuromuscular disease because of a reduction in the density of muscle innervation, the rate of neuromuscular junction activation or the efficiency of synaptic transmission. We developed a small-molecule fast-skeletal-troponin activator, CK-2017357, as a means to increase muscle strength by amplifying the response of muscle when neural input is otherwise diminished secondary to neuromuscular disease. Binding selectively to the fast-skeletal-troponin complex, CK-2017357 slows the rate of calcium release from troponin C and sensitizes muscle to calcium. As a consequence, the force-calcium relationship of muscle fibers shifts leftwards, as does the force-frequency relationship of a nerve-muscle pair, so that CK-2017357 increases the production of muscle force in situ at sub-maximal nerve stimulation rates. Notably, we show that sensitization of the fast-skeletal-troponin complex to calcium improves muscle force and grip strength immediately after administration of single doses of CK-2017357 in a model of the neuromuscular disease myasthenia gravis. Troponin activation may provide a new therapeutic approach to improve physical activity in diseases where neuromuscular function is compromised.", + "TAG_DATA": [ + "90, muscle {'context': 'B-cells'}", + "91, fibers {'context': 'I-cells'}", + "110, muscle {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "90, muscle ['l0', 'l1']", + "91, fibers ['l0', 'l2']", + "110, muscle ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22310680", + "TEXT": "Parkinson's disease affects more than five million people worldwide, yet no therapeutic has been identified that can slow or halt the progression of this debilitating disease. A new study in tau knockout mice suggests that tau deficiency causes impaired ferroportin-coupled iron export, by retention of the amyloid precursor protein, a neuronal ferroxidase partner, in the endoplasmic reticulum. This leads to parkinsonism through intracellular iron accumulation and degeneration of dopamine neurons (pages X-Y).", + "TAG_DATA": [ + "30, tau {'perturbing_action': 'B-gene loss-of-function'}", + "31, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "32, mice {'context': 'B-organism'}", + "35, tau {'perturbing_action': 'B-gene loss-of-function'}", + "36, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "68, dopamine {'context': 'B-cells'}", + "69, neurons {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "30, tau ['l0', 'l1', 'l2', 'l3']", + "31, knockout ['l0', 'l4', 'l5', 'l6', 'l7']", + "32, mice ['l1', 'l4', 'l8', 'l9', 'l10']", + "35, tau ['l2', 'l5', 'l8', 'l11', 'l12', 'l13']", + "36, deficiency ['l3', 'l6', 'l9', 'l11', 'l14', 'l15']", + "68, dopamine ['l12', 'l14', 'l16']", + "69, neurons ['l7', 'l10', 'l13', 'l15', 'l16']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "tau", + "knockout", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout", + "tau", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons", + "dopamine" + ] + } + } + ] + }, + { + "PMID": "22306733", + "TEXT": "Molecules associated with the transforming growth factor β (TGF-β) superfamily, such as bone morphogenic proteins (BMPs) and TGF-β, are key regulators of inflammation, apoptosis and cellular transitions. Here we show that the BMP receptor activin-like kinase 3 (Alk3) is elevated early in diseased kidneys after injury. We also found that its deletion in the tubular epithelium leads to enhanced TGF-β1-Smad family member 3 (Smad3) signaling, epithelial damage and fibrosis, suggesting a protective role for Alk3-mediated signaling in the kidney. A structure-function analysis of the BMP-Alk3-BMP receptor, type 2 (BMPR2) ligand-receptor complex, along with synthetic organic chemistry, led us to construct a library of small peptide agonists of BMP signaling that function through the Alk3 receptor. One such peptide agonist, THR-123, suppressed inflammation, apoptosis and the epithelial-to-mesenchymal transition program and reversed established fibrosis in five mouse models of acute and chronic renal injury. THR-123 acts specifically through Alk3 signaling, as mice with a targeted deletion for Alk3 in their tubular epithelium did not respond to therapy with THR-123. Combining THR-123 and the angiotensin-converting enzyme inhibitor captopril had an additive therapeutic benefit in controlling renal fibrosis. Our studies show that BMP signaling agonists constitute a new line of therapeutic agents with potential utility in the clinic to induce regeneration, repair and reverse established fibrosis.", + "TAG_DATA": [ + "55, epithelium {'context': 'I-tissue/organ'}", + "120, suppressed {'effect': 'B-negative'}", + "122, apoptosis {'phenotype': 'B-apoptosis'}", + "125, epithelial-to-mesenchymal {'phenotype': 'B-epithelial-mesenchymal transition'}", + "126, transition {'phenotype': 'I-epithelial-mesenchymal transition'}", + "127, program {'phenotype': 'I-epithelial-mesenchymal transition'}", + "134, mouse {'context': 'B-organism'}", + "135, models {'context': 'I-organism'}", + "149, mice {'context': 'B-organism'}", + "152, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "153, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "154, for {'perturbing_action': 'I-gene loss-of-function'}", + "155, Alk3 {'perturbing_action': 'I-gene loss-of-function'}", + "156, in {'perturbing_action': 'I-gene loss-of-function'}", + "157, their {'perturbing_action': 'I-gene loss-of-function'}", + "158, tubular {'perturbing_action': 'I-gene loss-of-function'}", + "159, epithelium {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "54, tubular ['l0', 'l1']", + "55, epithelium ['l0', 'l2']", + "120, suppressed ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "122, apoptosis ['l3', 'l9', 'l10', 'l11', 'l12', 'l13']", + "125, epithelial-to-mesenchymal ['l4', 'l9', 'l14', 'l15', 'l16', 'l17']", + "126, transition ['l5', 'l10', 'l14', 'l18', 'l19', 'l20']", + "127, program ['l1', 'l2', 'l6', 'l11', 'l15', 'l18', 'l21', 'l22']", + "134, mouse ['l7', 'l12', 'l16', 'l19', 'l21', 'l23']", + "135, models ['l8', 'l13', 'l17', 'l20', 'l22', 'l23']", + "149, mice ['l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "152, targeted ['l24', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "153, deletion ['l25', 'l32', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "154, for ['l26', 'l33', 'l39', 'l45', 'l46', 'l47', 'l48', 'l49']", + "155, Alk3 ['l27', 'l34', 'l40', 'l45', 'l50', 'l51', 'l52', 'l53']", + "156, in ['l28', 'l35', 'l41', 'l46', 'l50', 'l54', 'l55', 'l56']", + "157, their ['l29', 'l36', 'l42', 'l47', 'l51', 'l54', 'l57', 'l58']", + "158, tubular ['l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l57', 'l59']", + "159, epithelium ['l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58', 'l59']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "epithelium" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "program" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "epithelial-to-mesenchymal", + "transition", + "program" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "epithelial-to-mesenchymal", + "transition", + "program" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "deletion", + "for", + "Alk3", + "in", + "their", + "tubular", + "epithelium" + ] + } + } + ] + }, + { + "PMID": "22306732", + "TEXT": "Aging reduces the number of mesenchymal stem cells (MSCs) that can differentiate into osteoblasts in the bone marrow, which leads to impairment of osteogenesis. However, if MSCs could be directed toward osteogenic differentiation, they could be a viable therapeutic option for bone regeneration. We have developed a method to direct MSCs to the bone surface by attaching a synthetic high-affinity and specific peptidomimetic ligand (LLP2A) against integrin α4β1 on the MSC surface to a bisphosphonate (alendronate, Ale) that has a high affinity for bone. LLP2A-Ale induced MSC migration and osteogenic differentiation in vitro. A single intravenous injection of LLP2A-Ale increased trabecular bone formation and bone mass in both xenotransplantation studies and in immunocompetent mice. Additionally, LLP2A-Ale prevented trabecular bone loss after peak bone acquisition was achieved or as a result of estrogen deficiency. These results provide proof of principle that LLP2A-Ale can direct MSCs to the bone to form new bone and increase bone strength.", + "TAG_DATA": [ + "85, induced {'effect': 'B-positive'}", + "86, MSC {'context': 'B-cells'}", + "87, migration {'phenotype': 'B-migration'}", + "89, osteogenic {'phenotype': 'B-differentiation'}", + "90, differentiation {'phenotype': 'I-differentiation'}", + "91, in {'context': 'B-in vitro'}", + "92, vitro. {'context': 'I-in vitro'}", + "108, xenotransplantation {'context': 'B-xenograft'}", + "112, immunocompetent {'context': 'B-organism'}", + "113, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "85, induced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "86, MSC ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "87, migration ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "89, osteogenic ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "90, differentiation ['l3', 'l8', 'l12', 'l15', 'l18']", + "91, in ['l4', 'l9', 'l13', 'l16', 'l19']", + "92, vitro. ['l5', 'l10', 'l14', 'l17', 'l18', 'l19']", + "108, xenotransplantation ['l20', 'l21']", + "112, immunocompetent ['l20', 'l22']", + "113, mice. ['l21', 'l22']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "MSC" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "osteogenic", + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "MSC" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "MSC" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "osteogenic", + "differentiation" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "osteogenic", + "differentiation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "22286306", + "TEXT": "Metabolic skeletal disorders associated with impaired bone formation are a major clinical challenge. One approach to treat these defects is to silence bone-formation-inhibitory genes by small interference RNAs (siRNAs) in osteogenic-lineage cells that occupy the niche surrounding the bone-formation surfaces. We developed a targeting system involving dioleoyl trimethylammonium propane (DOTAP)-based cationic liposomes attached to six repetitive sequences of aspartate, serine, serine ((AspSerSer)(6)) for delivering siRNAs specifically to bone-formation surfaces. Using this system, we encapsulated an osteogenic siRNA that targets casein kinase-2 interacting protein-1 (encoded by Plekho1, also known as Plekho1). In vivo systemic delivery of Plekho1 siRNA in rats using our system resulted in the selective enrichment of the siRNAs in osteogenic cells and the subsequent depletion of Plekho1. A bioimaging analysis further showed that this approach markedly promoted bone formation, enhanced the bone micro-architecture and increased the bone mass in both healthy and osteoporotic rats. These results indicate (AspSerSer)(6)-liposome as a promising targeted delivery system for RNA interference-based bone anabolic therapy.", + "TAG_DATA": [ + "90, In {'context': 'B-in vivo'}", + "91, vivo {'context': 'I-in vivo'}", + "95, Plekho1 {'perturbing_action': 'B-rnai/knockdown'}", + "96, siRNA {'perturbing_action': 'I-rnai/knockdown'}", + "98, rats {'context': 'B-organism'}", + "111, osteogenic {'context': 'B-cells'}", + "112, cells {'context': 'I-cells'}", + "128, promoted {'effect': 'B-positive'}", + "129, bone {'phenotype': 'B-self-renewal'}", + "130, formation, {'phenotype': 'I-tumourigenesis'}", + "145, rats. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "90, In ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "91, vivo ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "95, Plekho1 ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "96, siRNA ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "98, rats ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "111, osteogenic ['l4', 'l9', 'l13', 'l16', 'l18', 'l20', 'l21']", + "112, cells ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "128, promoted ['l22', 'l23', 'l24']", + "129, bone ['l22', 'l25', 'l26']", + "130, formation, ['l21', 'l23', 'l25']", + "145, rats. ['l24', 'l26']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Plekho1", + "siRNA" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Plekho1", + "siRNA" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Plekho1", + "siRNA" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteogenic", + "cells" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteogenic" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "bone" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats." + ] + } + }, + { + "phenotype": { + "val": "self-renewal", + "words": [ + "bone" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats." + ] + } + } + ] + }, + { + "PMID": "22270724", + "TEXT": "Antibodies against epidermal growth factor receptor (EGFR)--cetuximab and panitumumab--are widely used to treat colorectal cancer. Unfortunately, patients eventually develop resistance to these agents. We describe an acquired EGFR ectodomain mutation (S492R) that prevents cetuximab binding and confers resistance to cetuximab. Cells with this mutation, however, retain binding to and are growth inhibited by panitumumab. Two of ten subjects studied here with disease progression after cetuximab treatment acquired this mutation. A subject with cetuximab resistance harboring the S492R mutation responded to treatment with panitumumab.", + "TAG_DATA": [ + "40, Cells {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22270721", + "TEXT": "Noise-induced hearing loss (NIHL) is a global health hazard with considerable pathophysiological and social consequences that has no effective treatment. In the heart, lung and other organs, cyclic guanosine monophosphate (cGMP) facilitates protective processes in response to traumatic events. We therefore analyzed NIHL in mice with a genetic deletion of the gene encoding cGMP-dependent protein kinase type I (Prkg1) and found a greater vulnerability to and markedly less recovery from NIHL in these mice as compared to mice without the deletion. Prkg1 was expressed in the sensory cells and neurons of the inner ear of wild-type mice, and its expression partly overlapped with the expression profile of cGMP-hydrolyzing phosphodiesterase 5 (Pde5). Treatment of rats and wild-type mice with the Pde5 inhibitor vardenafil almost completely prevented NIHL and caused a Prkg1-dependent upregulation of poly (ADP-ribose) in hair cells and the spiral ganglion, suggesting an endogenous protective cGMP-Prkg1 signaling pathway that culminates in the activation of poly (ADP-ribose) polymerase. These data suggest vardenafil or related drugs as possible candidates for the treatment of NIHL.", + "TAG_DATA": [ + "44, mice {'context': 'B-organism'}", + "47, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "48, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "49, of {'perturbing_action': 'I-gene loss-of-function'}", + "50, the {'perturbing_action': 'I-gene loss-of-function'}", + "51, gene {'perturbing_action': 'I-gene loss-of-function'}", + "52, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "53, cGMP-dependent {'perturbing_action': 'I-gene loss-of-function'}", + "54, protein {'perturbing_action': 'I-gene loss-of-function'}", + "55, kinase {'perturbing_action': 'I-gene loss-of-function'}", + "56, type {'perturbing_action': 'I-gene loss-of-function'}", + "57, I {'perturbing_action': 'I-gene loss-of-function'}", + "58, (Prkg1) {'perturbing_action': 'I-gene loss-of-function'}", + "73, mice {'context': 'B-organism'}", + "77, mice {'context': 'B-organism'}", + "113, rats {'context': 'B-organism'}", + "116, mice {'context': 'B-organism'}", + "119, Pde5 {'perturbing_action': 'B-pharmacological inhibition'}", + "120, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "121, vardenafil {'perturbing_action': 'I-pharmacological inhibition'}", + "135, hair {'context': 'B-cells'}", + "136, cells {'context': 'I-cells'}", + "139, spiral {'context': 'B-cells'}", + "140, ganglion, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "44, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "47, genetic ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "48, deletion ['l7', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "49, of ['l8', 'l20', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "50, the ['l9', 'l21', 'l32', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "51, gene ['l10', 'l22', 'l33', 'l43', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "52, encoding ['l11', 'l23', 'l34', 'l44', 'l53', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "53, cGMP-dependent ['l0', 'l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "54, protein ['l1', 'l13', 'l25', 'l36', 'l46', 'l55', 'l63', 'l70', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "55, kinase ['l2', 'l14', 'l26', 'l37', 'l47', 'l56', 'l64', 'l71', 'l77', 'l83', 'l84', 'l85', 'l86', 'l87']", + "56, type ['l3', 'l15', 'l27', 'l38', 'l48', 'l57', 'l65', 'l72', 'l78', 'l83', 'l88', 'l89', 'l90', 'l91']", + "57, I ['l4', 'l16', 'l28', 'l39', 'l49', 'l58', 'l66', 'l73', 'l79', 'l84', 'l88', 'l92', 'l93', 'l94']", + "58, (Prkg1) ['l5', 'l17', 'l29', 'l40', 'l50', 'l59', 'l67', 'l74', 'l80', 'l85', 'l89', 'l92', 'l95', 'l96']", + "73, mice ['l6', 'l18', 'l30', 'l41', 'l51', 'l60', 'l68', 'l75', 'l81', 'l86', 'l90', 'l93', 'l95']", + "77, mice ['l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l76', 'l82', 'l87', 'l91', 'l94', 'l96']", + "113, rats ['l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "116, mice ['l97', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "119, Pde5 ['l98', 'l105', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "120, inhibitor ['l99', 'l106', 'l112', 'l118', 'l119', 'l120', 'l121', 'l122']", + "121, vardenafil ['l100', 'l107', 'l113', 'l118', 'l123', 'l124', 'l125', 'l126']", + "135, hair ['l101', 'l108', 'l114', 'l119', 'l123', 'l127', 'l128', 'l129']", + "136, cells ['l102', 'l109', 'l115', 'l120', 'l124', 'l127', 'l130', 'l131']", + "139, spiral ['l103', 'l110', 'l116', 'l121', 'l125', 'l128', 'l130', 'l132']", + "140, ganglion, ['l104', 'l111', 'l117', 'l122', 'l126', 'l129', 'l131', 'l132']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cGMP-dependent", + "protein", + "kinase", + "type", + "I", + "(Prkg1)", + "genetic", + "deletion", + "of", + "the", + "gene", + "encoding" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rats", + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pde5", + "inhibitor", + "vardenafil" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pde5", + "inhibitor", + "vardenafil" + ] + }, + "context": { + "val": "cells", + "words": [ + "hair", + "cells", + "spiral", + "ganglion," + ] + } + } + ] + }, + { + "PMID": "22237151", + "TEXT": "T cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we report the presence of loss-of-function mutations and deletions of the EZH2 and SUZ12 genes, which encode crucial components of the Polycomb repressive complex 2 (PRC2), in 25% of T-ALLs. To further study the role of PRC2 in T-ALL, we used NOTCH1-dependent mouse models of the disease, as well as human T-ALL samples, and combined locus-specific and global analysis of NOTCH1-driven epigenetic changes. These studies demonstrated that activation of NOTCH1 specifically induces loss of the repressive mark Lys27 trimethylation of histone 3 (H3K27me3) by antagonizing the activity of PRC2. These studies suggest a tumor suppressor role for PRC2 in human leukemia and suggest a hitherto unrecognized dynamic interplay between oncogenic NOTCH1 and PRC2 function for the regulation of gene expression and cell transformation.", + "TAG_DATA": [ + "64, mouse {'context': 'B-organism'}", + "65, models {'context': 'I-organism'}", + "72, human {'context': 'B-transformed cells'}", + "73, T-ALL {'context': 'I-transformed cells'}", + "74, samples, {'context': 'I-transformed cells'}", + "89, activation {'perturbing_action': 'B-pharmacological augmentation'}", + "90, of {'perturbing_action': 'I-pharmacological augmentation'}", + "91, NOTCH1 {'perturbing_action': 'I-pharmacological augmentation'}" + ], + "LINK_DATA": [ + "64, mouse ['l0', 'l1']", + "65, models ['l0']", + "72, human ['l2', 'l3']", + "73, T-ALL ['l2', 'l4']", + "74, samples, ['l1', 'l3', 'l4']", + "89, activation ['l5', 'l6']", + "90, of ['l5', 'l7']", + "91, NOTCH1 ['l6', 'l7']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22179319", + "TEXT": "Huntington's disease is a fatal neurodegenerative disorder caused by an expanded polyglutamine repeat in huntingtin (HTT) protein. We previously showed that calorie restriction ameliorated Huntington's disease pathogenesis and slowed disease progression in mice that model Huntington's disease (Huntington's disease mice). We now report that overexpression of sirtuin 1 (Sirt1), a mediator of the beneficial metabolic effects of calorie restriction, protects neurons against mutant HTT toxicity, whereas reduction of Sirt1 exacerbates mutant HTT toxicity. Overexpression of Sirt1 improves motor function, reduces brain atrophy and attenuates mutant-HTT-mediated metabolic abnormalities in Huntington's disease mice. Further mechanistic studies suggested that Sirt1 prevents the mutant-HTT-induced decline in brain-derived neurotrophic factor (BDNF) concentrations and the signaling of its receptor, TrkB, and restores dopamine- and cAMP-regulated phosphoprotein, 32 kDa (DARPP32) concentrations in the striatum. Sirt1 deacetylase activity is required for Sirt1-mediated neuroprotection in Huntington's disease cell models. Notably, we show that mutant HTT interacts with Sirt1 and inhibits Sirt1 deacetylase activity, which results in hyperacetylation of Sirt1 substrates such as forkhead box O3A (Foxo3a), thereby inhibiting its pro-survival function. Overexpression of Sirt1 counteracts the mutant-HTT-induced deacetylase deficit, enhances the deacetylation of Foxo3a and facilitates cell survival. These findings show a neuroprotective role for Sirt1 in mammalian Huntington's disease models and open new avenues for the development of neuroprotective strategies in Huntington's disease.", + "TAG_DATA": [ + "44, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "45, of {'perturbing_action': 'I-gene gain-of-function'}", + "46, sirtuin {'perturbing_action': 'I-gene gain-of-function'}", + "47, 1 {'perturbing_action': 'I-gene gain-of-function'}", + "48, (Sirt1), {'perturbing_action': 'I-gene gain-of-function'}", + "60, neurons {'context': 'B-cells'}", + "66, reduction {'perturbing_action': 'B-gene loss-of-function'}", + "67, of {'perturbing_action': 'I-gene loss-of-function'}", + "68, Sirt1 {'perturbing_action': 'I-gene loss-of-function'}", + "73, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "74, of {'perturbing_action': 'I-gene gain-of-function'}", + "75, Sirt1 {'perturbing_action': 'I-gene gain-of-function'}", + "88, Huntington's {'context': 'B-organism'}", + "89, disease {'context': 'I-organism'}", + "90, mice. {'context': 'I-organism'}", + "126, striatum. {'context': 'B-tissue/organ'}", + "172, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "173, of {'perturbing_action': 'I-gene gain-of-function'}", + "174, Sirt1 {'perturbing_action': 'I-gene gain-of-function'}", + "186, facilitates {'effect': 'B-positive'}", + "187, cell {'phenotype': 'B-cell survival'}", + "188, survival. {'phenotype': 'I-cell survival'}" + ], + "LINK_DATA": [ + "44, overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "45, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "46, sirtuin ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "47, 1 ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "48, (Sirt1), ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "60, neurons ['l4', 'l14', 'l23', 'l31', 'l38']", + "66, reduction ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "67, of ['l6', 'l16', 'l25', 'l33', 'l40', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "68, Sirt1 ['l7', 'l17', 'l26', 'l34', 'l41', 'l46', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "73, Overexpression ['l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "74, of ['l62', 'l68', 'l69', 'l70', 'l71', 'l72']", + "75, Sirt1 ['l52', 'l57', 'l63', 'l68', 'l73', 'l74', 'l75', 'l76']", + "88, Huntington's ['l8', 'l18', 'l27', 'l35', 'l42', 'l47', 'l53', 'l58', 'l64', 'l69', 'l73', 'l77', 'l78', 'l79']", + "89, disease ['l9', 'l19', 'l28', 'l36', 'l43', 'l48', 'l54', 'l59', 'l65', 'l70', 'l74', 'l77', 'l80']", + "90, mice. ['l10', 'l20', 'l29', 'l37', 'l44', 'l49', 'l55', 'l60', 'l66', 'l71', 'l75', 'l78', 'l80']", + "126, striatum. ['l50', 'l56', 'l61', 'l67', 'l72', 'l76', 'l79']", + "172, Overexpression ['l81', 'l82', 'l83', 'l84', 'l85']", + "173, of ['l81', 'l86', 'l87', 'l88', 'l89']", + "174, Sirt1 ['l82', 'l86', 'l90', 'l91', 'l92']", + "186, facilitates ['l83', 'l87', 'l90', 'l93', 'l94']", + "187, cell ['l84', 'l88', 'l91', 'l93', 'l95']", + "188, survival. ['l85', 'l89', 'l92', 'l94', 'l95']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "sirtuin", + "1", + "(Sirt1)," + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "sirtuin", + "1", + "(Sirt1),", + "Overexpression", + "Sirt1" + ] + }, + "context": { + "val": "organism", + "words": [ + "Huntington's", + "disease", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "reduction", + "of", + "Sirt1" + ] + }, + "context": { + "val": "organism", + "words": [ + "Huntington's", + "disease", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "reduction", + "of", + "Sirt1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "striatum." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "Sirt1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "striatum." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "Sirt1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "facilitates" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "Sirt1" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "survival." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "facilitates" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "survival." + ] + } + } + ] + }, + { + "PMID": "22179316", + "TEXT": "Sirt1, a NAD-dependent protein deacetylase, has emerged as a key regulator of mammalian transcription in response to cellular metabolic status and stress. Here we show that Sirt1 has a neuroprotective role in models of Huntington's disease, an inherited neurodegenerative disorder caused by a glutamine repeat expansion in huntingtin protein (HTT). Brain-specific knockout of Sirt1 results in exacerbation of brain pathology in a mouse model of Huntington's disease, whereas overexpression of Sirt1 improves survival, neuropathology and the expression of brain-derived neurotrophic factor (BDNF) in Huntington's disease mice. We show that Sirt1 deacetylase activity directly targets neurons to mediate neuroprotection from mutant HTT. The neuroprotective effect of Sirt1 requires the presence of CREB-regulated transcription coactivator 1 (TORC1), a brain-specific modulator of CREB activity. We show that under normal conditions, Sirt1 deacetylates and activates TORC1 by promoting its dephosphorylation and its interaction with CREB. We identified BDNF as a key target of Sirt1 and TORC1 transcriptional activity in both normal and Huntington's disease neurons. Mutant HTT interferes with the TORC1-CREB interaction to repress BDNF transcription, and Sirt1 rescues this defect in vitro and in vivo. These studies suggest a key role for Sirt1 in transcriptional networks in both the normal and Huntington's disease brain and offer an opportunity for therapeutic development.", + "TAG_DATA": [ + "50, Brain-specific {'perturbing_action': 'B-gene loss-of-function'}", + "51, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "52, of {'perturbing_action': 'I-gene loss-of-function'}", + "53, Sirt1 {'perturbing_action': 'I-gene loss-of-function'}", + "62, mouse {'context': 'B-organism'}", + "63, model {'context': 'I-organism'}", + "64, of {'context': 'I-organism'}", + "65, Huntington's {'context': 'I-organism'}", + "66, disease, {'context': 'I-organism'}", + "68, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "69, of {'perturbing_action': 'I-gene gain-of-function'}", + "70, Sirt1 {'perturbing_action': 'I-gene gain-of-function'}", + "83, Huntington's {'context': 'B-organism'}", + "84, disease {'context': 'I-organism'}", + "85, mice. {'context': 'B-organism'}", + "160, neurons. {'context': 'B-cells'}", + "177, in {'context': 'B-in vitro'}", + "178, vitro {'context': 'I-in vitro'}", + "180, in {'context': 'B-in vivo'}", + "181, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "50, Brain-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "51, knockout ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "52, of ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "53, Sirt1 ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "62, mouse ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "63, model ['l4', 'l14', 'l23', 'l31', 'l38', 'l44', 'l45', 'l46', 'l47', 'l48']", + "64, of ['l5', 'l15', 'l24', 'l32', 'l39', 'l44', 'l49', 'l50', 'l51', 'l52']", + "65, Huntington's ['l6', 'l16', 'l25', 'l33', 'l40', 'l45', 'l49', 'l53', 'l54', 'l55']", + "66, disease, ['l7', 'l17', 'l26', 'l34', 'l41', 'l46', 'l50', 'l53', 'l56', 'l57']", + "68, overexpression ['l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "69, of ['l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "70, Sirt1 ['l59', 'l64', 'l69', 'l70', 'l71', 'l72']", + "83, Huntington's ['l8', 'l18', 'l27', 'l35', 'l60', 'l65', 'l69', 'l73', 'l74']", + "84, disease ['l9', 'l19', 'l28', 'l36', 'l42', 'l47', 'l51', 'l54', 'l56', 'l61', 'l66', 'l70', 'l73', 'l75']", + "85, mice. ['l10', 'l20', 'l29', 'l37', 'l43', 'l48', 'l52', 'l55', 'l57', 'l62', 'l67', 'l71', 'l74', 'l75']", + "160, neurons. ['l63', 'l68', 'l72']", + "177, in ['l76', 'l77', 'l78']", + "178, vitro ['l76', 'l79', 'l80']", + "180, in ['l77', 'l79', 'l81']", + "181, vivo. ['l78', 'l80', 'l81']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Brain-specific", + "knockout", + "of", + "Sirt1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "Huntington's", + "disease,", + "disease", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Sirt1" + ] + }, + "context": { + "val": "organism", + "words": [ + "Huntington's", + "disease", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Sirt1" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons." + ] + } + } + ] + }, + { + "PMID": "22157678", + "TEXT": "Exuberant fibroproliferation is a common complication after injury for reasons that are not well understood. One key component of wound repair that is often overlooked is mechanical force, which regulates cell-matrix interactions through intracellular focal adhesion components, including focal adhesion kinase (FAK). Here we report that FAK is activated after cutaneous injury and that this process is potentiated by mechanical loading. Fibroblast-specific FAK knockout mice have substantially less inflammation and fibrosis than control mice in a model of hypertrophic scar formation. We show that FAK acts through extracellular-related kinase (ERK) to mechanically trigger the secretion of monocyte chemoattractant protein-1 (MCP-1, also known as CCL2), a potent chemokine that is linked to human fibrotic disorders. Similarly, MCP-1 knockout mice form minimal scars, indicating that inflammatory chemokine pathways are a major mechanism by which FAK mechanotransduction induces fibrosis. Small-molecule inhibition of FAK blocks these effects in human cells and reduces scar formation in vivo through attenuated MCP-1 signaling and inflammatory cell recruitment. These findings collectively indicate that physical force regulates fibrosis through inflammatory FAK-ERK-MCP-1 pathways and that molecular strategies targeting FAK can effectively uncouple mechanical force from pathologic scar formation.", + "TAG_DATA": [ + "61, Fibroblast-specific {'perturbing_action': 'B-gene loss-of-function'}", + "62, FAK {'perturbing_action': 'I-gene loss-of-function'}", + "63, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "64, mice {'context': 'B-organism'}", + "73, mice {'context': 'B-organism'}", + "115, MCP-1 {'perturbing_action': 'B-gene loss-of-function'}", + "116, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "117, mice {'context': 'B-organism'}", + "136, Small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "137, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "138, of {'perturbing_action': 'I-pharmacological inhibition'}", + "139, FAK {'perturbing_action': 'I-pharmacological inhibition'}", + "144, human {'context': 'B-cells'}", + "145, cells {'context': 'I-cells'}", + "150, in {'context': 'B-in vivo'}", + "151, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "61, Fibroblast-specific ['l0', 'l1', 'l2', 'l3']", + "62, FAK ['l0', 'l4', 'l5', 'l6']", + "63, knockout ['l1', 'l4', 'l7', 'l8']", + "64, mice ['l2', 'l5', 'l7', 'l9']", + "73, mice ['l3', 'l6', 'l8', 'l9']", + "115, MCP-1 ['l10', 'l11', 'l12', 'l13']", + "116, knockout ['l10', 'l14', 'l15']", + "117, mice ['l11', 'l14', 'l16']", + "136, Small-molecule ['l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "137, inhibition ['l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "138, of ['l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "139, FAK ['l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "144, human ['l12', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40']", + "145, cells ['l13', 'l15', 'l16', 'l21', 'l27', 'l32', 'l36', 'l39']", + "150, in ['l22', 'l28', 'l33', 'l37', 'l41']", + "151, vivo ['l23', 'l29', 'l34', 'l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fibroblast-specific", + "FAK", + "knockout", + "MCP-1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MCP-1", + "knockout" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Small-molecule", + "inhibition", + "of", + "FAK" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Small-molecule", + "inhibition", + "of", + "FAK" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "22146454", + "TEXT": "IgA regulates intestinal homeostasis by maintaining appropriate communities of bacteria within the gut. A new study shows that intestinal bacteria regulate metabolism via IgA (pages 1585–1593).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22120177", + "TEXT": "Tissue homeostasis requires an effective, limited wound-healing response to injury. In chronic disease, failure to regenerate parenchymal tissue leads to the replacement of lost cellular mass with a fibrotic matrix. The mechanisms that dictate the balance of cell regeneration and fibrogenesis are not well understood. Here we report that fibrogenic hepatic stellate cells (HSCs) in the liver are negative regulators of hepatocyte regeneration. This negative regulatory function requires stimulation of the 5-hydroxytryptamine 2B receptor (5-HT(2B)) on HSCs by serotonin, which activates expression of transforming growth factor β1 (TGF-β1), a powerful suppressor of hepatocyte proliferation, through signaling by mitogen-activated protein kinase 1 (ERK) and the transcription factor JunD. Selective antagonism of 5-HT(2B) enhanced hepatocyte growth in models of acute and chronic liver injury. We also observed similar effects in mice lacking 5-HT(2B) or JunD or upon selective depletion of HSCs in wild-type mice. Antagonism of 5-HT(2B) attenuated fibrogenesis and improved liver function in disease models in which fibrosis was pre-established and progressive. Pharmacological targeting of 5-HT(2B) is clinically safe in humans and may be therapeutic in chronic liver disease.", + "TAG_DATA": [ + "107, Selective {'perturbing_action': 'B-pharmacological inhibition'}", + "108, antagonism {'perturbing_action': 'I-pharmacological inhibition'}", + "109, of {'perturbing_action': 'I-pharmacological inhibition'}", + "110, 5-HT(2B) {'perturbing_action': 'I-pharmacological inhibition'}", + "112, hepatocyte {'context': 'B-cells'}", + "128, mice {'context': 'B-organism'}", + "129, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "130, 5-HT(2B) {'perturbing_action': 'I-gene loss-of-function'}", + "131, or {'perturbing_action': 'I-gene loss-of-function'}", + "132, JunD {'perturbing_action': 'I-gene loss-of-function'}", + "138, HSCs {'context': 'B-cells'}", + "141, mice. {'context': 'B-organism'}", + "142, Antagonism {'perturbing_action': 'B-pharmacological inhibition'}", + "143, of {'perturbing_action': 'I-pharmacological inhibition'}", + "144, 5-HT(2B) {'perturbing_action': 'I-pharmacological inhibition'}", + "149, liver {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "107, Selective ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "108, antagonism ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "109, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "110, 5-HT(2B) ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "112, hepatocyte ['l3', 'l11', 'l18', 'l24']", + "128, mice ['l4', 'l12', 'l19', 'l25', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "129, lacking ['l5', 'l13', 'l20', 'l26', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "130, 5-HT(2B) ['l6', 'l14', 'l21', 'l27', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "131, or ['l7', 'l15', 'l22', 'l28', 'l32', 'l37', 'l41', 'l45', 'l46', 'l47']", + "132, JunD ['l8', 'l16', 'l23', 'l29', 'l33', 'l38', 'l42', 'l45', 'l48', 'l49']", + "138, HSCs ['l34', 'l39', 'l43', 'l46', 'l48', 'l50']", + "141, mice. ['l35', 'l40', 'l44', 'l47', 'l49', 'l50']", + "142, Antagonism ['l51', 'l52', 'l53']", + "143, of ['l51', 'l54', 'l55']", + "144, 5-HT(2B) ['l52', 'l54', 'l56']", + "149, liver ['l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Selective", + "antagonism", + "of", + "5-HT(2B)" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocyte" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Selective", + "antagonism", + "of", + "5-HT(2B)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "5-HT(2B)", + "or", + "JunD" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "5-HT(2B)", + "or", + "JunD" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSCs" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Antagonism", + "of", + "5-HT(2B)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "22101767", + "TEXT": "Stem cell-based regenerative medicine is a promising approach in tissue reconstruction. Here we show that proinflammatory T cells inhibit the ability of exogenously added bone marrow mesenchymal stem cells (BMMSCs) to mediate bone repair. This inhibition is due to interferon γ (IFN-γ)-induced downregulation of the runt-related transcription factor 2 (Runx-2) pathway and enhancement of tumor necrosis factor α (TNF-α) signaling in the stem cells. We also found that, through inhibition of nuclear factor κB (NF-κB), TNF-α converts the signaling of the IFN-γ-activated, nonapoptotic form of TNF receptor superfamily member 6 (Fas) in BMMSCs to a caspase 3- and caspase 8-associated proapoptotic cascade, resulting in the apoptosis of these cells. Conversely, reduction of IFN-γ and TNF-α concentrations by systemic infusion of Foxp3(+) regulatory T cells, or by local administration of aspirin, markedly improved BMMSC-based bone regeneration and calvarial defect repair in C57BL/6 mice. These data collectively show a previously unrecognized role of recipient T cells in BMMSC-based tissue engineering.", + "TAG_DATA": [ + "92, BMMSCs {'context': 'B-cells'}", + "102, resulting {'effect': 'B-positive'}", + "103, in {'effect': 'I-positive'}", + "105, apoptosis {'phenotype': 'B-apoptosis'}", + "108, cells. {'context': 'B-cells'}", + "120, Foxp3(+) {'context': 'B-cells'}", + "121, regulatory {'context': 'I-cells'}", + "122, T {'context': 'I-cells'}", + "123, cells, {'context': 'I-cells'}", + "136, calvarial {'context': 'B-neoplasm'}", + "140, C57BL/6 {'context': 'B-organism'}", + "141, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "92, BMMSCs ['l0', 'l1', 'l2', 'l3']", + "102, resulting ['l0', 'l4', 'l5', 'l6']", + "103, in ['l1', 'l4', 'l7', 'l8']", + "105, apoptosis ['l2', 'l5', 'l7', 'l9']", + "108, cells. ['l3', 'l6', 'l8', 'l9']", + "120, Foxp3(+) ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "121, regulatory ['l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "122, T ['l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "123, cells, ['l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "133, bone ['l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38']", + "136, calvarial ['l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l40', 'l41']", + "137, defect ['l15', 'l22', 'l28', 'l33', 'l37', 'l39', 'l42', 'l43']", + "140, C57BL/6 ['l16', 'l23', 'l29', 'l34', 'l40', 'l42', 'l44']", + "141, mice. ['l17', 'l24', 'l30', 'l35', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "BMMSCs", + "cells." + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "BMMSCs", + "cells." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "22101764", + "TEXT": "Amyotrophic lateral sclerosis (ALS) is characterized by upper and lower motor neuron dysfunction and loss, rapidly progressive muscle weakness, wasting and death. Many factors, including mitochondrial dysfunction, may contribute to ALS pathogenesis. Riluzole, which has shown only modest benefits in a measure of survival time without demonstrated effects on muscle strength or function, is the only approved treatment for ALS. We tested the putative mitochondrial modulator dexpramipexole (KNS-760704; (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine) in subjects with ALS in a two-part, double-blind safety and tolerability study, with a preliminary assessment of its effects on functional decline and mortality. In part 1, the effects of dexpramipexole (50, 150 or 300 mg d(-1)) versus placebo were assessed over 12 weeks. In part 2, after a 4-week, single-blind placebo washout, continuing subjects were re-randomized to dexpramipexole at 50 mg d(-1) or 300 mg d(-1) as double-blind active treatment for 24 weeks. Dexpramipexole was safe and well tolerated. Trends showing a dose-dependent attenuation of the slope of decline of the ALS Functional Rating Scale-Revised (ALSFRS-R) in part 1 and a statistically significant (P = 0.046) difference between groups in a joint rank test of change from baseline in ALSFRS-R and mortality in part 2 strongly support further testing of dexpramipexole in ALS.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22064409", + "TEXT": "Although erythropoietin (Epo) is commonly used as a therapy for anemia, recent studies have suggested that Epo therapy is associated with adverse outcomes. A new study shows that polymeric IgA1 positively regulates erythropoiesis through binding to transferrin receptor 1 (Tfr1), suggesting new therapeutic routes for anemia (pages 1456–1465).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22001906", + "TEXT": "Although the lung is a defining feature of air-breathing animals, the pathway controlling the formation of type I pneumocytes, the cells that mediate gas exchange, is poorly understood. In contrast, the glucocorticoid receptor and its cognate ligand have long been known to promote type II pneumocyte maturation; prenatal administration of glucocorticoids is commonly used to attenuate the severity of infant respiratory distress syndrome (RDS). Here we show that knock-in mutations of the nuclear co-repressor SMRT (silencing mediator of retinoid and thyroid hormone receptors) in C57BL/6 mice (SMRTmRID) produces a previously unidentified respiratory distress syndrome caused by prematurity of the type I pneumocyte. Though unresponsive to glucocorticoids, treatment with anti-thyroid hormone drugs (propylthiouracil or methimazole) completely rescues SMRT-induced RDS, suggesting an unrecognized and essential role for the thyroid hormone receptor (TR) in lung development. We show that TR and SMRT control type I pneumocyte differentiation through Klf2, which, in turn, seems to directly activate the type I pneumocyte gene program. Conversely, mice without lung Klf2 lack mature type I pneumocytes and die shortly after birth, closely recapitulating the SMRTmRID phenotype. These results identify TR as a second nuclear receptor involved in lung development, specifically type I pneumocyte differentiation, and suggest a possible new type of therapeutic option in the treatment of RDS that is unresponsive to glucocorticoids.", + "TAG_DATA": [ + "68, knock-in {'perturbing_action': 'B-rnai/knockdown'}", + "69, mutations {'perturbing_action': 'I-rnai/knockdown'}", + "70, of {'perturbing_action': 'I-rnai/knockdown'}", + "71, the {'perturbing_action': 'I-rnai/knockdown'}", + "72, nuclear {'perturbing_action': 'I-rnai/knockdown'}", + "73, co-repressor {'perturbing_action': 'I-rnai/knockdown'}", + "74, SMRT {'perturbing_action': 'I-rnai/knockdown'}", + "75, (silencing {'perturbing_action': 'I-rnai/knockdown'}", + "76, mediator {'perturbing_action': 'I-rnai/knockdown'}", + "77, of {'perturbing_action': 'I-rnai/knockdown'}", + "78, retinoid {'perturbing_action': 'I-rnai/knockdown'}", + "79, and {'perturbing_action': 'I-rnai/knockdown'}", + "80, thyroid {'perturbing_action': 'I-rnai/knockdown'}", + "81, hormone {'perturbing_action': 'I-rnai/knockdown'}", + "82, receptors) {'perturbing_action': 'I-rnai/knockdown'}", + "84, C57BL/6 {'context': 'B-organism'}", + "85, mice {'context': 'I-organism'}", + "160, mice {'context': 'B-organism'}", + "161, without {'perturbing_action': 'B-gene loss-of-function'}", + "162, lung {'perturbing_action': 'I-gene loss-of-function'}", + "163, Klf2 {'perturbing_action': 'I-gene loss-of-function'}", + "166, type {'context': 'B-cells'}", + "167, I {'context': 'B-cells'}", + "168, pneumocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "68, knock-in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "69, mutations ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "70, of ['l1', 'l16', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "71, the ['l2', 'l17', 'l31', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "72, nuclear ['l3', 'l18', 'l32', 'l45', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "73, co-repressor ['l4', 'l19', 'l33', 'l46', 'l58', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "74, SMRT ['l5', 'l20', 'l34', 'l47', 'l59', 'l70', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "75, (silencing ['l6', 'l21', 'l35', 'l48', 'l60', 'l71', 'l81', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "76, mediator ['l7', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "77, of ['l8', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l100', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "78, retinoid ['l9', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l108', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "79, and ['l10', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l115', 'l121', 'l122', 'l123', 'l124', 'l125']", + "80, thyroid ['l11', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l121', 'l126', 'l127', 'l128', 'l129']", + "81, hormone ['l12', 'l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l126', 'l130', 'l131', 'l132']", + "82, receptors) ['l13', 'l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l118', 'l123', 'l127', 'l130', 'l133', 'l134']", + "84, C57BL/6 ['l14', 'l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l113', 'l119', 'l124', 'l128', 'l131', 'l133', 'l135']", + "85, mice ['l15', 'l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l129', 'l132', 'l134', 'l135']", + "160, mice ['l136', 'l137', 'l138', 'l139', 'l140', 'l141']", + "161, without ['l136', 'l142', 'l143', 'l144', 'l145', 'l146']", + "162, lung ['l137', 'l142', 'l147', 'l148', 'l149', 'l150']", + "163, Klf2 ['l138', 'l143', 'l147', 'l151', 'l152', 'l153']", + "166, type ['l139', 'l144', 'l148', 'l151', 'l154', 'l155']", + "167, I ['l140', 'l145', 'l149', 'l152', 'l154', 'l156']", + "168, pneumocytes ['l141', 'l146', 'l150', 'l153', 'l155', 'l156']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knock-in", + "mutations", + "of", + "the", + "nuclear", + "co-repressor", + "SMRT", + "(silencing", + "mediator", + "retinoid", + "and", + "thyroid", + "hormone", + "receptors)" + ] + }, + "context": { + "val": "organism", + "words": [ + "C57BL/6", + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "without", + "lung", + "Klf2" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "without", + "lung", + "Klf2" + ] + }, + "context": { + "val": "cells", + "words": [ + "type", + "I", + "pneumocytes" + ] + } + } + ] + }, + { + "PMID": "21988993", + "TEXT": "A study in a mouse model of immune-mediated glomerular disease and in people with rapidly progressive glomerulonephritis shows activation of epidermal growth factor receptor (EFGR) signaling in podocytes by a molecule expressed in the kidney (pages 1242–1250). Blocking this axis may open new doors to treat inflammatory kidney conditions.", + "TAG_DATA": [ + "4, mouse {'context': 'B-organism'}", + "5, model {'context': 'I-organism'}", + "12, people {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "4, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "5, model ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "6, of ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "7, immune-mediated ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "8, glomerular ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "9, disease ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "12, people ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21983857", + "TEXT": "Small-cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer for which there is no effective treatment. Using a mouse model in which deletion of Rb1 and Trp53 in the lung epithelium of adult mice induces SCLC, we found that the Hedgehog signaling pathway is activated in SCLC cells independently of the lung microenvironment. Constitutive activation of the Hedgehog signaling molecule Smoothened (Smo) promoted the clonogenicity of human SCLC in vitro and the initiation and progression of mouse SCLC in vivo. Reciprocally, deletion of Smo in Rb1 and Trp53-mutant lung epithelial cells strongly suppressed SCLC initiation and progression in mice. Furthermore, pharmacological blockade of Hedgehog signaling inhibited the growth of mouse and human SCLC, most notably following chemotherapy. These findings show a crucial cell-intrinsic role for Hedgehog signaling in the development and maintenance of SCLC and identify Hedgehog pathway inhibition as a therapeutic strategy to slow the progression of disease and delay cancer recurrence in individuals with SCLC.", + "TAG_DATA": [ + "21, mouse {'context': 'B-organism'}", + "22, model {'context': 'I-organism'}", + "25, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "26, of {'perturbing_action': 'I-gene loss-of-function'}", + "27, Rb1 {'perturbing_action': 'I-gene loss-of-function'}", + "28, and {'perturbing_action': 'I-gene loss-of-function'}", + "29, Trp53 {'perturbing_action': 'I-gene loss-of-function'}", + "30, in {'perturbing_action': 'I-gene loss-of-function'}", + "31, the {'perturbing_action': 'I-gene loss-of-function'}", + "32, lung {'perturbing_action': 'I-gene loss-of-function'}", + "33, epithelium {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-tissue/organ'}", + "35, adult {'context': 'B-organism'}", + "36, mice {'context': 'I-organism'}", + "56, Constitutive {'perturbing_action': 'B-gene gain-of-function'}", + "57, activation {'perturbing_action': 'I-gene gain-of-function'}", + "58, of {'perturbing_action': 'I-gene gain-of-function'}", + "59, the {'perturbing_action': 'I-gene gain-of-function'}", + "60, Hedgehog {'perturbing_action': 'I-gene gain-of-function'}", + "61, signaling {'perturbing_action': 'I-gene gain-of-function'}", + "62, molecule {'perturbing_action': 'I-gene gain-of-function'}", + "63, Smoothened {'perturbing_action': 'I-gene gain-of-function'}", + "64, (Smo) {'perturbing_action': 'I-gene gain-of-function'}", + "65, promoted {'effect': 'B-positive'}", + "67, clonogenicity {'phenotype': 'B-colony formation'}", + "69, human {'context': 'B-neoplasm'}", + "70, SCLC {'context': 'I-neoplasm'}", + "71, in {'context': 'B-in vitro'}", + "72, vitro {'context': 'I-in vitro'}", + "79, mouse {'context': 'B-neoplasm'}", + "80, SCLC {'context': 'I-neoplasm'}", + "81, in {'context': 'B-in vivo'}", + "82, vivo. {'context': 'I-in vivo'}", + "84, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "85, of {'perturbing_action': 'I-gene loss-of-function'}", + "86, Smo {'perturbing_action': 'I-gene loss-of-function'}", + "88, Rb1 {'perturbing_action': 'I-gene loss-of-function'}", + "89, and {'perturbing_action': 'B-other'}", + "90, Trp53-mutant {'perturbing_action': 'B-other'}", + "91, lung {'context': 'B-cells'}", + "92, epithelial {'context': 'I-cells'}", + "93, cells {'context': 'I-cells'}", + "96, SCLC {'context': 'B-neoplasm'}", + "101, mice. {'context': 'B-organism'}", + "112, mouse {'context': 'B-neoplasm'}", + "113, and {'context': 'I-neoplasm'}", + "114, human {'context': 'I-neoplasm'}", + "115, SCLC, {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "21, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "22, model ['l0', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "25, deletion ['l1', 'l30', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "26, of ['l2', 'l31', 'l60', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "27, Rb1 ['l3', 'l32', 'l61', 'l89', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "28, and ['l4', 'l33', 'l62', 'l90', 'l117', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "29, Trp53 ['l5', 'l34', 'l63', 'l91', 'l118', 'l144', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "30, in ['l6', 'l35', 'l64', 'l92', 'l119', 'l145', 'l170', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218']", + "31, the ['l7', 'l36', 'l65', 'l93', 'l120', 'l146', 'l171', 'l195', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241']", + "32, lung ['l8', 'l37', 'l66', 'l94', 'l121', 'l147', 'l172', 'l196', 'l219', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263']", + "33, epithelium ['l9', 'l38', 'l67', 'l95', 'l122', 'l148', 'l173', 'l197', 'l220', 'l242', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284']", + "35, adult ['l10', 'l39', 'l68', 'l96', 'l123', 'l149', 'l174', 'l198', 'l221', 'l243', 'l264', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304']", + "36, mice ['l11', 'l40', 'l69', 'l97', 'l124', 'l150', 'l175', 'l199', 'l222', 'l244', 'l265', 'l285', 'l305', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315', 'l316', 'l317']", + "56, Constitutive ['l41', 'l70', 'l98', 'l125', 'l151', 'l176', 'l200', 'l223', 'l245', 'l266', 'l286', 'l318', 'l319', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327', 'l328', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340']", + "57, activation ['l12', 'l42', 'l71', 'l99', 'l126', 'l152', 'l177', 'l201', 'l224', 'l246', 'l267', 'l287', 'l318', 'l341', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348', 'l349', 'l350', 'l351', 'l352', 'l353', 'l354', 'l355', 'l356', 'l357', 'l358', 'l359', 'l360']", + "58, of ['l13', 'l43', 'l72', 'l100', 'l127', 'l153', 'l178', 'l202', 'l225', 'l247', 'l268', 'l288', 'l319', 'l341', 'l361', 'l362', 'l363', 'l364', 'l365', 'l366', 'l367', 'l368', 'l369', 'l370', 'l371', 'l372', 'l373', 'l374', 'l375', 'l376', 'l377', 'l378', 'l379']", + "59, the ['l14', 'l44', 'l73', 'l101', 'l128', 'l154', 'l179', 'l203', 'l226', 'l248', 'l269', 'l289', 'l320', 'l342', 'l361', 'l380', 'l381', 'l382', 'l383', 'l384', 'l385', 'l386', 'l387', 'l388', 'l389', 'l390', 'l391', 'l392', 'l393', 'l394', 'l395', 'l396', 'l397', 'l398']", + "60, Hedgehog ['l15', 'l45', 'l74', 'l102', 'l129', 'l155', 'l180', 'l204', 'l227', 'l249', 'l270', 'l290', 'l321', 'l343', 'l362', 'l380', 'l399', 'l400', 'l401', 'l402', 'l403', 'l404', 'l405', 'l406', 'l407', 'l408', 'l409', 'l410', 'l411', 'l412', 'l413', 'l414', 'l415']", + "61, signaling ['l16', 'l46', 'l75', 'l103', 'l130', 'l156', 'l181', 'l205', 'l228', 'l250', 'l271', 'l291', 'l322', 'l344', 'l363', 'l381', 'l399', 'l416', 'l417', 'l418', 'l419', 'l420', 'l421', 'l422', 'l423', 'l424', 'l425', 'l426', 'l427', 'l428', 'l429', 'l430', 'l431']", + "62, molecule ['l17', 'l47', 'l76', 'l104', 'l131', 'l157', 'l182', 'l206', 'l229', 'l251', 'l272', 'l292', 'l305', 'l323', 'l345', 'l364', 'l382', 'l400', 'l416', 'l432', 'l433', 'l434', 'l435', 'l436', 'l437', 'l438', 'l439', 'l440', 'l441', 'l442', 'l443', 'l444', 'l445', 'l446']", + "63, Smoothened ['l18', 'l48', 'l77', 'l105', 'l132', 'l158', 'l183', 'l207', 'l230', 'l252', 'l273', 'l293', 'l306', 'l324', 'l346', 'l365', 'l383', 'l401', 'l417', 'l432', 'l447', 'l448', 'l449', 'l450', 'l451', 'l452', 'l453', 'l454', 'l455', 'l456', 'l457', 'l458', 'l459', 'l460']", + "64, (Smo) ['l19', 'l49', 'l78', 'l106', 'l133', 'l159', 'l184', 'l208', 'l231', 'l253', 'l274', 'l294', 'l307', 'l325', 'l347', 'l366', 'l384', 'l402', 'l418', 'l433', 'l447', 'l461', 'l462', 'l463', 'l464', 'l465', 'l466', 'l467', 'l468', 'l469', 'l470', 'l471']", + "65, promoted ['l20', 'l50', 'l79', 'l107', 'l134', 'l160', 'l185', 'l209', 'l232', 'l254', 'l275', 'l295', 'l308', 'l326', 'l348', 'l367', 'l385', 'l403', 'l419', 'l434', 'l448', 'l461', 'l472', 'l473', 'l474', 'l475', 'l476']", + "67, clonogenicity ['l21', 'l51', 'l80', 'l108', 'l135', 'l161', 'l186', 'l210', 'l233', 'l255', 'l276', 'l296', 'l309', 'l327', 'l349', 'l368', 'l386', 'l404', 'l420', 'l435', 'l449', 'l462', 'l472', 'l477', 'l478', 'l479', 'l480']", + "69, human ['l22', 'l52', 'l81', 'l109', 'l136', 'l162', 'l187', 'l211', 'l234', 'l256', 'l277', 'l297', 'l310', 'l328', 'l350', 'l369', 'l387', 'l405', 'l421', 'l436', 'l450', 'l463', 'l473', 'l477', 'l481', 'l482', 'l483']", + "70, SCLC ['l23', 'l53', 'l82', 'l110', 'l137', 'l163', 'l188', 'l212', 'l235', 'l257', 'l278', 'l298', 'l311', 'l329', 'l351', 'l370', 'l388', 'l406', 'l422', 'l437', 'l451', 'l464', 'l474', 'l478', 'l481', 'l484', 'l485']", + "71, in ['l24', 'l54', 'l83', 'l111', 'l138', 'l164', 'l189', 'l213', 'l236', 'l258', 'l279', 'l299', 'l312', 'l330', 'l352', 'l371', 'l389', 'l407', 'l423', 'l438', 'l452', 'l465', 'l475', 'l479', 'l482', 'l484', 'l486']", + "72, vitro ['l25', 'l55', 'l84', 'l112', 'l139', 'l165', 'l190', 'l214', 'l237', 'l259', 'l280', 'l300', 'l313', 'l331', 'l353', 'l372', 'l390', 'l408', 'l424', 'l439', 'l453', 'l466', 'l476', 'l480', 'l483', 'l485', 'l486']", + "79, mouse ['l26', 'l56', 'l85', 'l113', 'l140', 'l166', 'l191', 'l215', 'l238', 'l260', 'l281', 'l301', 'l314', 'l332', 'l354', 'l373', 'l391', 'l409', 'l425', 'l440', 'l454', 'l467', 'l487', 'l488', 'l489']", + "80, SCLC ['l27', 'l57', 'l86', 'l114', 'l141', 'l167', 'l192', 'l216', 'l239', 'l261', 'l282', 'l302', 'l315', 'l333', 'l355', 'l374', 'l392', 'l410', 'l426', 'l441', 'l455', 'l468', 'l487', 'l490', 'l491']", + "81, in ['l28', 'l58', 'l87', 'l115', 'l142', 'l168', 'l193', 'l217', 'l240', 'l262', 'l283', 'l303', 'l316', 'l334', 'l356', 'l375', 'l393', 'l411', 'l427', 'l442', 'l456', 'l469', 'l488', 'l490', 'l492']", + "82, vivo. ['l29', 'l59', 'l88', 'l116', 'l143', 'l169', 'l194', 'l218', 'l241', 'l263', 'l284', 'l304', 'l317', 'l335', 'l357', 'l376', 'l394', 'l412', 'l428', 'l443', 'l457', 'l470', 'l489', 'l491', 'l492']", + "84, deletion ['l493', 'l494', 'l495', 'l496', 'l497', 'l498', 'l499', 'l500', 'l501', 'l502']", + "85, of ['l493', 'l503', 'l504', 'l505', 'l506', 'l507', 'l508', 'l509', 'l510', 'l511']", + "86, Smo ['l494', 'l503', 'l512', 'l513', 'l514', 'l515', 'l516', 'l517', 'l518', 'l519']", + "88, Rb1 ['l495', 'l504', 'l512', 'l520', 'l521', 'l522', 'l523', 'l524', 'l525', 'l526']", + "89, and ['l496', 'l505', 'l513', 'l520', 'l527', 'l528', 'l529', 'l530', 'l531', 'l532']", + "90, Trp53-mutant ['l497', 'l506', 'l514', 'l521', 'l527', 'l533', 'l534', 'l535', 'l536', 'l537']", + "91, lung ['l336', 'l498', 'l507', 'l515', 'l522', 'l528', 'l533', 'l538', 'l539', 'l540', 'l541']", + "92, epithelial ['l337', 'l395', 'l499', 'l508', 'l516', 'l523', 'l529', 'l534', 'l538', 'l542', 'l543', 'l544']", + "93, cells ['l338', 'l358', 'l377', 'l396', 'l413', 'l429', 'l444', 'l458', 'l471', 'l500', 'l509', 'l517', 'l524', 'l530', 'l535', 'l539', 'l542', 'l545', 'l546']", + "96, SCLC ['l339', 'l359', 'l378', 'l397', 'l414', 'l430', 'l445', 'l459', 'l501', 'l510', 'l518', 'l525', 'l531', 'l536', 'l540', 'l543', 'l545', 'l547']", + "101, mice. ['l340', 'l360', 'l379', 'l398', 'l415', 'l431', 'l446', 'l460', 'l502', 'l511', 'l519', 'l526', 'l532', 'l537', 'l541', 'l544', 'l546', 'l547']", + "112, mouse ['l548', 'l549', 'l550']", + "113, and ['l548', 'l551', 'l552']", + "114, human ['l549', 'l551', 'l553']", + "115, SCLC, ['l550', 'l552', 'l553']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "adult", + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Rb1", + "and", + "Trp53", + "in", + "the", + "lung", + "epithelium", + "Smo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "epithelium", + "deletion", + "of", + "Rb1", + "and", + "Trp53", + "in", + "the", + "lung" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "epithelium" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "adult", + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "activation", + "of", + "the", + "Hedgehog", + "signaling", + "molecule", + "Smoothened", + "(Smo)", + "Constitutive" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "adult", + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "adult", + "mice" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenicity" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Rb1", + "and", + "Trp53", + "in", + "the", + "lung", + "epithelium" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Rb1", + "and", + "Trp53", + "in", + "the", + "lung", + "epithelium" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenicity" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Rb1", + "and", + "Trp53", + "in", + "the", + "lung", + "epithelium", + "Smo" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "SCLC", + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Rb1", + "and", + "Trp53", + "in", + "the", + "lung", + "epithelium" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Rb1", + "and", + "Trp53", + "in", + "the", + "lung", + "epithelium" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "epithelium" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Constitutive", + "activation", + "of", + "the", + "Hedgehog", + "signaling", + "molecule", + "Smoothened", + "(Smo)" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "epithelium" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "epithelium" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenicity" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Constitutive", + "activation", + "of", + "the", + "Hedgehog", + "signaling", + "molecule", + "Smoothened", + "(Smo)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Constitutive", + "activation", + "of", + "the", + "Hedgehog", + "signaling", + "molecule", + "Smoothened", + "(Smo)" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenicity" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Constitutive", + "activation", + "of", + "the", + "Hedgehog", + "signaling", + "molecule", + "Smoothened", + "(Smo)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "SCLC", + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Constitutive", + "activation", + "of", + "the", + "Hedgehog", + "signaling", + "molecule", + "Smoothened", + "(Smo)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Constitutive", + "activation", + "of", + "the", + "Hedgehog", + "signaling", + "molecule", + "Smoothened", + "(Smo)" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Constitutive", + "activation", + "of", + "the", + "Hedgehog", + "signaling", + "molecule", + "Smoothened", + "(Smo)" + ] + }, + "context": { + "val": "cells", + "words": [ + "lung", + "epithelial", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenicity" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "SCLC" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenicity" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "SCLC" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenicity" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Smo", + "Rb1" + ] + }, + "context": { + "val": "cells", + "words": [ + "lung", + "epithelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "and", + "Trp53-mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "lung", + "epithelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "and", + "Trp53-mutant" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "SCLC" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "and", + "Trp53-mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "21946536", + "TEXT": "BRCA1, a well-known tumor suppressor with multiple interacting partners, is predicted to have diverse biological functions. However, so far its only well-established role is in the repair of damaged DNA and cell cycle regulation. In this regard, the etiopathological study of low-penetrant variants of BRCA1 provides an opportunity to uncover its other physiologically important functions. Using this rationale, we studied the R1699Q variant of BRCA1, a potentially moderate-risk variant, and found that it does not impair DNA damage repair but abrogates the repression of microRNA-155 (miR-155), a bona fide oncomir. Mechanistically, we found that BRCA1 epigenetically represses miR-155 expression via its association with HDAC2, which deacetylates histones H2A and H3 on the miR-155 promoter. We show that overexpression of miR-155 accelerates but the knockdown of miR-155 attenuates the growth of tumor cell lines in vivo. Our findings demonstrate a new mode of tumor suppression by BRCA1 and suggest that miR-155 is a potential therapeutic target for BRCA1-deficient tumors.", + "TAG_DATA": [ + "117, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "118, of {'perturbing_action': 'I-gene gain-of-function'}", + "119, miR-155 {'perturbing_action': 'I-gene gain-of-function'}", + "123, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "124, of {'perturbing_action': 'I-rnai/knockdown'}", + "125, miR-155 {'perturbing_action': 'I-rnai/knockdown'}", + "130, tumor {'context': 'B-transformed cells'}", + "131, cell {'context': 'I-transformed cells'}", + "132, lines {'context': 'I-transformed cells'}", + "133, in {'context': 'B-in vivo'}", + "134, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "117, overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "118, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "119, miR-155 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "123, knockdown ['l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "124, of ['l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "125, miR-155 ['l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "130, tumor ['l2', 'l8', 'l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "131, cell ['l3', 'l9', 'l14', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "132, lines ['l4', 'l10', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "133, in ['l5', 'l11', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "134, vivo. ['l6', 'l12', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "miR-155" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "miR-155" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "miR-155" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "miR-155" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "21909104", + "TEXT": "Epileptic seizures are a common and poorly understood comorbidity for individuals with primary brain tumors. To investigate peritumoral seizure etiology, we implanted human-derived glioma cells into severe combined immunodeficient mice. Within 14-18 d, glioma-bearing mice developed spontaneous and recurring abnormal electroencephalogram events consistent with progressive epileptic activity. Acute brain slices from these mice showed marked glutamate release from the tumor mediated by the system x(c)(-) cystine-glutamate transporter (encoded by Slc7a11). Biophysical and optical recordings showed glutamatergic epileptiform hyperexcitability that spread into adjacent brain tissue. We inhibited glutamate release from the tumor and the ensuing hyperexcitability by sulfasalazine (SAS), a US Food and Drug Administration-approved drug that blocks system x(c)(-). We found that acute administration of SAS at concentrations equivalent to those used to treat Crohn's disease in humans reduced epileptic event frequency in tumor-bearing mice compared with untreated controls. SAS should be considered as an adjuvant treatment to ameliorate peritumoral seizures associated with glioma in humans.", + "TAG_DATA": [ + "22, human-derived {'context': 'B-transformed cells'}", + "23, glioma {'context': 'I-transformed cells'}", + "24, cells {'context': 'I-transformed cells'}", + "26, severe {'context': 'B-organism'}", + "27, combined {'context': 'I-organism'}", + "28, immunodeficient {'context': 'I-organism'}", + "29, mice. {'context': 'I-organism'}", + "33, glioma-bearing {'context': 'B-organism'}", + "34, mice {'context': 'I-organism'}", + "52, mice {'context': 'B-organism'}", + "90, tumor {'context': 'B-neoplasm'}", + "133, tumor-bearing {'context': 'B-organism'}", + "134, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "22, human-derived ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "23, glioma ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "24, cells ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "26, severe ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "27, combined ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "28, immunodeficient ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "29, mice. ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40']", + "33, glioma-bearing ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l41', 'l42']", + "34, mice ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l41', 'l43']", + "52, mice ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l42', 'l43']", + "133, tumor-bearing ['l44']", + "134, mice ['l44']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21909103", + "TEXT": "Osteoclasts resorb the mineralized matrices formed by chondrocytes or osteoblasts. The cytokine receptor activator of nuclear factor-κB ligand (RANKL) is essential for osteoclast formation and thought to be supplied by osteoblasts or their precursors, thereby linking bone formation to resorption. However, RANKL is expressed by a variety of cell types, and it is unclear which of them are essential sources for osteoclast formation. Here we have used a mouse strain in which RANKL can be conditionally deleted and a series of Cre-deleter strains to demonstrate that hypertrophic chondrocytes and osteocytes, both of which are embedded in matrix, are essential sources of the RANKL that controls mineralized cartilage resorption and bone remodeling, respectively. Moreover, osteocyte RANKL is responsible for the bone loss associated with unloading. Contrary to the current paradigm, RANKL produced by osteoblasts or their progenitors does not contribute to adult bone remodeling. These results suggest that the rate-limiting step of matrix resorption is controlled by cells embedded within the matrix itself.", + "TAG_DATA": [ + "68, mouse {'context': 'B-organism'}", + "69, strain {'context': 'I-organism'}", + "72, RANKL {'perturbing_action': 'I-gene loss-of-function'}", + "73, can {'perturbing_action': 'I-gene loss-of-function'}", + "74, be {'perturbing_action': 'I-gene loss-of-function'}", + "75, conditionally {'perturbing_action': 'I-gene loss-of-function'}", + "76, deleted {'perturbing_action': 'I-gene loss-of-function'}", + "81, Cre-deleter {'perturbing_action': 'B-gene loss-of-function'}", + "86, hypertrophic {'context': 'B-cells'}", + "87, chondrocytes {'context': 'I-cells'}", + "89, osteocytes, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "68, mouse ['l0', 'l1']", + "69, strain ['l0', 'l2']", + "72, RANKL ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "73, can ['l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "74, be ['l4', 'l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "75, conditionally ['l5', 'l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "76, deleted ['l6', 'l12', 'l18', 'l23', 'l28', 'l29', 'l30']", + "81, Cre-deleter ['l13', 'l19', 'l24', 'l31', 'l32', 'l33']", + "86, hypertrophic ['l7', 'l14', 'l20', 'l25', 'l28', 'l31', 'l34', 'l35']", + "87, chondrocytes ['l8', 'l15', 'l21', 'l26', 'l29', 'l32', 'l34', 'l36']", + "89, osteocytes, ['l9', 'l16', 'l22', 'l27', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "strain" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "RANKL" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "RANKL", + "can", + "be", + "conditionally", + "deleted", + "Cre-deleter" + ] + }, + "context": { + "val": "cells", + "words": [ + "hypertrophic", + "chondrocytes", + "osteocytes," + ] + } + } + ] + }, + { + "PMID": "21892182", + "TEXT": "Here we show that p38 mitogen-activated protein kinase (p38 MAPK) phosphorylates the spliced form of X-box binding protein 1 (Xbp1s) on its Thr48 and Ser61 residues and greatly enhances its nuclear migration in mice, whereas mutation of either residue to alanine substantially reduces its nuclear translocation and activity. We also show that p38 MAPK activity is markedly reduced in the livers of obese mice compared with lean mice. Further, we show that activation of p38 MAPK by expression of constitutively active MAP kinase kinase 6 (MKK6Glu) greatly enhances nuclear translocation of Xbp1s, reduces endoplasmic reticulum stress and establishes euglycemia in severely obese and diabetic mice. Hence, our results define a crucial role for phosphorylation on Thr48 and Ser61 of Xbp1s in the maintenance of glucose homeostasis in obesity, and they suggest that p38 MAPK activation in the livers of obese mice could lead to a new therapeutic approach to the treatment of type 2 diabetes.", + "TAG_DATA": [ + "72, activation {'perturbing_action': 'B-pharmacological augmentation'}", + "73, of {'perturbing_action': 'I-pharmacological augmentation'}", + "74, p38 {'perturbing_action': 'I-pharmacological augmentation'}", + "75, MAPK {'perturbing_action': 'I-pharmacological augmentation'}", + "76, by {'perturbing_action': 'I-pharmacological augmentation'}", + "77, expression {'perturbing_action': 'B-gene gain-of-function'}", + "78, of {'perturbing_action': 'I-gene gain-of-function'}", + "79, constitutively {'perturbing_action': 'I-gene gain-of-function'}", + "80, active {'perturbing_action': 'I-gene gain-of-function'}", + "81, MAP {'perturbing_action': 'I-gene gain-of-function'}", + "82, kinase {'perturbing_action': 'I-gene gain-of-function'}", + "83, kinase {'perturbing_action': 'I-gene gain-of-function'}", + "84, 6 {'perturbing_action': 'I-gene gain-of-function'}", + "85, (MKK6Glu) {'perturbing_action': 'I-gene gain-of-function'}", + "101, obese {'context': 'B-organism'}", + "102, and {'context': 'I-organism'}", + "103, diabetic {'context': 'I-organism'}", + "104, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "38, residue ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "72, activation ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "73, of ['l1', 'l17', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "74, p38 ['l2', 'l18', 'l34', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "75, MAPK ['l3', 'l19', 'l35', 'l50', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "76, by ['l4', 'l20', 'l36', 'l51', 'l65', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "77, expression ['l5', 'l21', 'l37', 'l52', 'l66', 'l79', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "78, of ['l6', 'l22', 'l38', 'l53', 'l67', 'l80', 'l92', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "79, constitutively ['l7', 'l23', 'l39', 'l54', 'l68', 'l81', 'l93', 'l104', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "80, active ['l8', 'l24', 'l40', 'l55', 'l69', 'l82', 'l94', 'l105', 'l115', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "81, MAP ['l9', 'l25', 'l41', 'l56', 'l70', 'l83', 'l95', 'l106', 'l116', 'l125', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141']", + "82, kinase ['l10', 'l26', 'l42', 'l57', 'l71', 'l84', 'l96', 'l107', 'l117', 'l126', 'l134', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "83, kinase ['l11', 'l27', 'l43', 'l58', 'l72', 'l85', 'l97', 'l108', 'l118', 'l127', 'l135', 'l142', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "84, 6 ['l12', 'l28', 'l44', 'l59', 'l73', 'l86', 'l98', 'l109', 'l119', 'l128', 'l136', 'l143', 'l149', 'l155', 'l156', 'l157', 'l158', 'l159']", + "85, (MKK6Glu) ['l13', 'l29', 'l45', 'l60', 'l74', 'l87', 'l99', 'l110', 'l120', 'l129', 'l137', 'l144', 'l150', 'l155', 'l160', 'l161', 'l162', 'l163']", + "101, obese ['l14', 'l30', 'l46', 'l61', 'l75', 'l88', 'l100', 'l111', 'l121', 'l130', 'l138', 'l145', 'l151', 'l156', 'l160', 'l164', 'l165', 'l166']", + "102, and ['l15', 'l31', 'l47', 'l62', 'l76', 'l89', 'l101', 'l112', 'l122', 'l131', 'l139', 'l146', 'l152', 'l157', 'l161', 'l164', 'l167', 'l168']", + "103, diabetic ['l32', 'l48', 'l63', 'l77', 'l90', 'l102', 'l113', 'l123', 'l132', 'l140', 'l147', 'l153', 'l158', 'l162', 'l165', 'l167', 'l169']", + "104, mice. ['l16', 'l33', 'l49', 'l64', 'l78', 'l91', 'l103', 'l114', 'l124', 'l133', 'l141', 'l148', 'l154', 'l159', 'l163', 'l166', 'l168', 'l169']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "of", + "p38", + "MAPK", + "by" + ] + }, + "context": { + "val": "organism", + "words": [ + "obese", + "and", + "diabetic", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "constitutively", + "active", + "MAP", + "kinase", + "6", + "(MKK6Glu)" + ] + }, + "context": { + "val": "organism", + "words": [ + "obese", + "and", + "diabetic", + "mice." + ] + } + } + ] + }, + { + "PMID": "21873986", + "TEXT": "Vascular anastomosis is the cornerstone of vascular, cardiovascular and transplant surgery. Most anastomoses are performed with sutures, which are technically challenging and can lead to failure from intimal hyperplasia and foreign body reaction. Numerous alternatives to sutures have been proposed, but none has proven superior, particularly in small or atherosclerotic vessels. We have developed a new method of sutureless and atraumatic vascular anastomosis that uses US Food and Drug Administration (FDA)-approved thermoreversible tri-block polymers to temporarily maintain an open lumen for precise approximation with commercially available glues. We performed end-to-end anastomoses five times more rapidly than we performed hand-sewn controls, and vessels that were too small (<1.0 mm) to sew were successfully reconstructed with this sutureless approach. Imaging of reconstructed rat aorta confirmed equivalent patency, flow and burst strength, and histological analysis demonstrated decreased inflammation and fibrosis at up to 2 years after the procedure. This new technology has potential for improving efficiency and outcomes in the surgical treatment of cardiovascular disease.", + "TAG_DATA": [ + "101, vessels {'context': 'B-tissue/organ'}", + "120, rat {'context': 'B-tissue/organ'}", + "121, aorta {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "101, vessels ['l0', 'l1']", + "120, rat ['l0', 'l2']", + "121, aorta ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21857651", + "TEXT": "Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate genes involved in energy metabolism and inflammation. For biological activity, PPARs require cognate lipid ligands, heterodimerization with retinoic X receptors, and coactivation by PPAR-γ coactivator-1α or PPAR-γ coactivator-1β (PGC-1α or PGC-1β, encoded by Ppargc1a and Ppargc1b, respectively). Here we show that lipolysis of cellular triglycerides by adipose triglyceride lipase (patatin-like phospholipase domain containing protein 2, encoded by Pnpla2; hereafter referred to as Atgl) generates essential mediator(s) involved in the generation of lipid ligands for PPAR activation. Atgl deficiency in mice decreases mRNA levels of PPAR-α and PPAR-δ target genes. In the heart, this leads to decreased PGC-1α and PGC-1β expression and severely disrupted mitochondrial substrate oxidation and respiration; this is followed by excessive lipid accumulation, cardiac insufficiency and lethal cardiomyopathy. Reconstituting normal PPAR target gene expression by pharmacological treatment of Atgl-deficient mice with PPAR-α agonists completely reverses the mitochondrial defects, restores normal heart function and prevents premature death. These findings reveal a potential treatment for the excessive cardiac lipid accumulation and often-lethal cardiomyopathy in people with neutral lipid storage disease, a disease marked by reduced or absent ATGL activity.", + "TAG_DATA": [ + "86, Atgl {'perturbing_action': 'B-gene loss-of-function'}", + "87, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "89, mice {'context': 'B-organism'}", + "101, heart, {'context': 'B-tissue/organ'}", + "140, Atgl-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "141, mice {'context': 'B-organism'}", + "152, heart {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "86, Atgl ['l0', 'l1', 'l2']", + "87, deficiency ['l0', 'l3', 'l4']", + "89, mice ['l1', 'l3', 'l5']", + "101, heart, ['l2', 'l4', 'l5']", + "140, Atgl-deficient ['l6', 'l7']", + "141, mice ['l6', 'l8']", + "152, heart ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atgl", + "deficiency", + "Atgl-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atgl", + "deficiency", + "Atgl-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "heart,", + "heart" + ] + } + } + ] + }, + { + "PMID": "21804541", + "TEXT": "One of the great challenges in science and engineering today is to develop technologies to improve the health of people in the poorest regions of the world. Here we integrated new procedures for manufacturing, fluid handling and signal detection in microfluidics into a single, easy-to-use point-of-care (POC) assay that faithfully replicates all steps of ELISA, at a lower total material cost. We performed this 'mChip' assay in Rwanda on hundreds of locally collected human samples. The chip had excellent performance in the diagnosis of HIV using only 1 μl of unprocessed whole blood and an ability to simultaneously diagnose HIV and syphilis with sensitivities and specificities that rival those of reference benchtop assays. Unlike most current rapid tests, the mChip test does not require user interpretation of the signal. Overall, we demonstrate an integrated strategy for miniaturizing complex laboratory assays using microfluidics and nanoparticles to enable POC diagnostics and early detection of infectious diseases in remote settings.", + "TAG_DATA": [], + "LINK_DATA": [ + "73, human ['l0']", + "74, samples. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21804539", + "TEXT": "Focal segmental glomerulosclerosis (FSGS) is a cause of proteinuric kidney disease, compromising both native and transplanted kidneys. Treatment is limited because of a complex pathogenesis, including unknown serum factors. Here we report that serum soluble urokinase receptor (suPAR) is elevated in two-thirds of subjects with primary FSGS, but not in people with other glomerular diseases. We further find that a higher concentration of suPAR before transplantation underlies an increased risk for recurrence of FSGS after transplantation. Using three mouse models, we explore the effects of suPAR on kidney function and morphology. We show that circulating suPAR activates podocyte β(3) integrin in both native and grafted kidneys, causing foot process effacement, proteinuria and FSGS-like glomerulopathy. Our findings suggest that the renal disease only develops when suPAR sufficiently activates podocyte β(3) integrin. Thus, the disease can be abrogated by lowering serum suPAR concentrations through plasmapheresis, or by interfering with the suPAR-β(3) integrin interaction through antibodies and small molecules targeting either uPAR or β(3) integrin. Our study identifies serum suPAR as a circulating factor that may cause FSGS.", + "TAG_DATA": [ + "78, mouse {'context': 'B-organism'}", + "79, models, {'context': 'I-organism'}", + "104, grafted {'context': 'B-tissue/organ'}", + "105, kidneys, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "78, mouse ['l0']", + "79, models, ['l0']", + "104, grafted ['l1']", + "105, kidneys, ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21785430", + "TEXT": "Foxp3(+) regulatory T (T(reg)) cells suppress different types of immune responses to help maintain homeostasis in the body. How T(reg) cells regulate humoral immunity, including germinal center reactions, is unclear. Here we identify a subset of T(reg) cells expressing CXCR5 and Bcl-6 that localize to the germinal centers in mice and humans. The expression of CXCR5 on T(reg) cells depends on Bcl-6. These CXCR5(+)Bcl-6(+) T(reg) cells are absent in the thymus but can be generated de novo from CXCR5(-)Foxp3(+) natural T(reg) precursors. A lack of CXCR5(+) T(reg) cells leads to greater germinal center reactions including germinal center B cells, affinity maturation of antibodies and the differentiation of plasma cells. These results unveil a Bcl-6-CXCR5 axis in T(reg) cells that drives the development of follicular regulatory T (T(FR)) cells that function to inhibit the germinal center reactions.", + "TAG_DATA": [ + "85, CXCR5(+) {'context': 'B-cells'}", + "86, T(reg) {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}", + "105, differentiation {'phenotype': 'B-differentiation'}", + "107, plasma {'context': 'B-cells'}", + "108, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "85, CXCR5(+) ['l0', 'l1', 'l2', 'l3', 'l4']", + "86, T(reg) ['l0', 'l5', 'l6', 'l7', 'l8']", + "87, cells ['l1', 'l5', 'l9', 'l10', 'l11']", + "105, differentiation ['l2', 'l6', 'l9', 'l12', 'l13']", + "107, plasma ['l3', 'l7', 'l10', 'l12', 'l14']", + "108, cells. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CXCR5(+)", + "T(reg)", + "cells", + "plasma", + "cells." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "21706028", + "TEXT": "Naturally simian immunodeficiency virus (SIV)-infected sooty mangabeys do not progress to AIDS despite high-level virus replication. We previously showed that the fraction of CD4(+)CCR5(+) T cells is lower in sooty mangabeys compared to humans and macaques. Here we found that, after in vitro stimulation, sooty mangabey CD4(+) T cells fail to upregulate CCR5 and that this phenomenon is more pronounced in CD4(+) central memory T cells (T(CM) cells). CD4(+) T cell activation was similarly uncoupled from CCR5 expression in sooty mangabeys in vivo during acute SIV infection and the homeostatic proliferation that follows antibody-mediated CD4(+) T cell depletion. Sooty mangabey CD4(+) T(CM) cells that express low amounts of CCR5 showed reduced susceptibility to SIV infection both in vivo and in vitro when compared to CD4(+) T(CM) cells of rhesus macaques. These data suggest that low CCR5 expression on sooty mangabey CD4(+) T cells favors the preservation of CD4(+) T cell homeostasis and promotes an AIDS-free status by protecting CD4(+) T(CM) cells from direct virus infection.", + "TAG_DATA": [ + "41, in {'context': 'B-in vitro'}", + "42, vitro {'context': 'I-in vitro'}", + "44, sooty {'context': 'B-cells'}", + "45, mangabey {'context': 'I-cells'}", + "46, CD4(+) {'context': 'I-cells'}", + "47, T {'context': 'I-cells'}", + "48, cells {'context': 'I-cells'}", + "61, CD4(+) {'context': 'B-cells'}", + "62, central {'context': 'I-cells'}", + "63, memory {'context': 'I-cells'}", + "64, T {'context': 'I-cells'}", + "65, cells {'context': 'I-cells'}", + "67, cells). {'context': 'I-cells'}", + "68, CD4(+) {'context': 'B-cells'}", + "69, T {'context': 'I-cells'}", + "70, cell {'context': 'I-cells'}", + "79, sooty {'context': 'B-organism'}", + "80, mangabeys {'context': 'I-organism'}", + "81, in {'context': 'B-in vivo'}", + "82, vivo {'context': 'I-in vivo'}", + "90, proliferation {'phenotype': 'B-proliferation'}", + "98, Sooty {'context': 'B-cells'}", + "99, mangabey {'context': 'I-cells'}", + "100, CD4(+) {'context': 'I-cells'}", + "101, T(CM) {'context': 'I-cells'}", + "102, cells {'context': 'I-cells'}", + "116, in {'context': 'B-in vivo'}", + "117, vivo {'context': 'I-in vivo'}", + "119, in {'context': 'B-in vitro'}", + "120, vitro {'context': 'I-in vitro'}", + "124, CD4(+) {'context': 'B-cells'}", + "125, T(CM) {'context': 'I-cells'}", + "126, cells {'context': 'I-cells'}", + "128, rhesus {'context': 'B-organism'}", + "129, macaques. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "41, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "42, vitro ['l0', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "44, sooty ['l1', 'l19', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "45, mangabey ['l2', 'l20', 'l36', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "46, CD4(+) ['l3', 'l21', 'l37', 'l53', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "47, T ['l4', 'l22', 'l38', 'l54', 'l69', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "48, cells ['l5', 'l23', 'l39', 'l55', 'l70', 'l84', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "61, CD4(+) ['l6', 'l40', 'l56', 'l71', 'l85', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "62, central ['l7', 'l24', 'l41', 'l57', 'l72', 'l86', 'l98', 'l110', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "63, memory ['l8', 'l25', 'l42', 'l58', 'l73', 'l87', 'l99', 'l111', 'l123', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145']", + "64, T ['l9', 'l26', 'l43', 'l59', 'l74', 'l88', 'l100', 'l112', 'l124', 'l135', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "65, cells ['l10', 'l27', 'l44', 'l60', 'l75', 'l89', 'l101', 'l113', 'l125', 'l136', 'l146', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164']", + "67, cells). ['l11', 'l28', 'l45', 'l61', 'l76', 'l90', 'l102', 'l114', 'l126', 'l137', 'l147', 'l156', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "68, CD4(+) ['l12', 'l29', 'l46', 'l62', 'l77', 'l91', 'l103', 'l115', 'l127', 'l138', 'l148', 'l157', 'l165', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179']", + "69, T ['l13', 'l30', 'l47', 'l63', 'l78', 'l92', 'l104', 'l116', 'l128', 'l139', 'l149', 'l158', 'l166', 'l173', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185']", + "70, cell ['l14', 'l31', 'l48', 'l64', 'l79', 'l93', 'l105', 'l117', 'l129', 'l140', 'l150', 'l159', 'l167', 'l174', 'l180', 'l186', 'l187', 'l188', 'l189', 'l190']", + "79, sooty ['l15', 'l32', 'l49', 'l65', 'l80', 'l94', 'l106', 'l118', 'l130', 'l141', 'l151', 'l160', 'l168', 'l175', 'l181', 'l186', 'l191', 'l192', 'l193', 'l194']", + "80, mangabeys ['l16', 'l33', 'l50', 'l66', 'l81', 'l95', 'l107', 'l119', 'l131', 'l142', 'l152', 'l161', 'l169', 'l176', 'l182', 'l187', 'l191', 'l195', 'l196', 'l197']", + "81, in ['l17', 'l34', 'l51', 'l67', 'l82', 'l96', 'l108', 'l120', 'l132', 'l143', 'l153', 'l162', 'l170', 'l177', 'l183', 'l188', 'l192', 'l195', 'l198']", + "82, vivo ['l18', 'l35', 'l52', 'l68', 'l83', 'l97', 'l109', 'l121', 'l133', 'l144', 'l154', 'l163', 'l171', 'l178', 'l184', 'l189', 'l193', 'l196', 'l198']", + "90, proliferation ['l122', 'l134', 'l145', 'l155', 'l164', 'l172', 'l179', 'l185', 'l190', 'l194', 'l197']", + "98, Sooty ['l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209']", + "99, mangabey ['l199', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221']", + "100, CD4(+) ['l200', 'l210', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232']", + "101, T(CM) ['l201', 'l211', 'l222', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241']", + "102, cells ['l202', 'l212', 'l223', 'l233', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250']", + "116, in ['l203', 'l213', 'l224', 'l234', 'l242', 'l251', 'l252', 'l253']", + "117, vivo ['l204', 'l214', 'l225', 'l235', 'l243', 'l251', 'l254', 'l255']", + "119, in ['l205', 'l215', 'l226', 'l236', 'l244', 'l252', 'l254', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261']", + "120, vitro ['l206', 'l216', 'l227', 'l237', 'l245', 'l253', 'l255', 'l256', 'l262', 'l263', 'l264', 'l265', 'l266']", + "124, CD4(+) ['l217', 'l228', 'l246', 'l257', 'l262', 'l267', 'l268', 'l269', 'l270']", + "125, T(CM) ['l207', 'l218', 'l229', 'l238', 'l247', 'l258', 'l263', 'l267', 'l271', 'l272', 'l273']", + "126, cells ['l208', 'l219', 'l230', 'l239', 'l248', 'l259', 'l264', 'l268', 'l271', 'l274', 'l275']", + "128, rhesus ['l220', 'l231', 'l240', 'l249', 'l260', 'l265', 'l269', 'l272', 'l274', 'l276']", + "129, macaques. ['l209', 'l221', 'l232', 'l241', 'l250', 'l261', 'l266', 'l270', 'l273', 'l275', 'l276']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "central", + "memory", + "T", + "cells", + "cells).", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "sooty", + "mangabeys" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "21685897", + "TEXT": "Chuvash polycythemia is a rare congenital form of polycythemia caused by homozygous R200W and H191D mutations in the VHL (von Hippel-Lindau) gene, whose gene product is the principal negative regulator of hypoxia-inducible factor. However, the molecular mechanisms underlying some of the hallmark abnormalities of Chuvash polycythemia, such as hypersensitivity to erythropoietin, are unclear. Here we show that VHL directly binds suppressor of cytokine signaling 1 (SOCS1) to form a heterodimeric E3 ligase that targets phosphorylated JAK2 (pJAK2) for ubiquitin-mediated destruction. In contrast, Chuvash polycythemia-associated VHL mutants have altered affinity for SOCS1 and do not engage with and degrade pJAK2. Systemic administration of a highly selective JAK2 inhibitor, TG101209, reversed the disease phenotype in Vhl(R200W/R200W) knock-in mice, an experimental model that recapitulates human Chuvash polycythemia. These results show that VHL is a SOCS1-cooperative negative regulator of JAK2 and provide biochemical and preclinical support for JAK2-targeted therapy in individuals with Chuvash polycythemia.", + "TAG_DATA": [ + "103, highly {'perturbing_action': 'I-pharmacological inhibition'}", + "104, selective {'perturbing_action': 'I-pharmacological inhibition'}", + "105, JAK2 {'perturbing_action': 'I-pharmacological inhibition'}", + "106, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "107, TG101209, {'perturbing_action': 'I-pharmacological inhibition'}", + "113, Vhl(R200W/R200W) {'perturbing_action': 'B-other'}", + "114, knock-in {'perturbing_action': 'I-rnai/knockdown'}", + "115, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "103, highly ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "104, selective ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "105, JAK2 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "106, inhibitor, ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "107, TG101209, ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "113, Vhl(R200W/R200W) ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "114, knock-in ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "115, mice, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "highly", + "selective", + "JAK2", + "inhibitor,", + "TG101209," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Vhl(R200W/R200W)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knock-in" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "21602803", + "TEXT": "Glutamate acting on N-methyl-D-aspartate (NMDA) receptors induces neuronal injury following stroke, through activation of poly(ADP-ribose) polymerase-1 (PARP-1) and generation of the death molecule poly(ADP-ribose) (PAR) polymer. Here we identify Iduna, a previously undescribed NMDA receptor-induced survival protein that is neuroprotective against glutamate NMDA receptor-mediated excitotoxicity both in vitro and in vivo and against stroke through interfering with PAR polymer-induced cell death (parthanatos). Iduna's protective effects are independent and downstream of PARP-1 activity. Iduna is a PAR polymer-binding protein, and mutation at the PAR polymer binding site abolishes the PAR binding activity of Iduna and attenuates its protective actions. Iduna is protective in vivo against NMDA-induced excitotoxicity and middle cerebral artery occlusion-induced stroke in mice. To our knowledge, these results define Iduna as the first known endogenous inhibitor of parthanatos. Interfering with PAR polymer signaling could be a new therapeutic strategy for the treatment of neurologic disorders.", + "TAG_DATA": [ + "55, interfering {'effect': 'B-negative'}", + "56, with {'effect': 'B-negative'}", + "59, cell {'phenotype': 'B-cell death'}", + "60, death {'phenotype': 'I-cell death'}", + "101, in {'context': 'B-in vivo'}", + "102, vivo {'context': 'I-in vivo'}", + "113, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "55, interfering ['l0', 'l1', 'l2']", + "56, with ['l0', 'l3', 'l4']", + "59, cell ['l1', 'l3', 'l5']", + "60, death ['l2', 'l4', 'l5']", + "101, in ['l6', 'l7']", + "102, vivo ['l6', 'l8']", + "113, mice. ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "interfering", + "with" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + } + ] + }, + { + "PMID": "21602802", + "TEXT": "The human skeleton is affected by mutations in low-density lipoprotein receptor-related protein 5 (LRP5). To understand how LRP5 influences bone properties, we generated mice with osteocyte-specific expression of inducible Lrp5 mutations that cause high and low bone mass phenotypes in humans. We found that bone properties in these mice were comparable to bone properties in mice with inherited mutations. We also induced an Lrp5 mutation in cells that form the appendicular skeleton but not in cells that form the axial skeleton; we observed that bone properties were altered in the limb but not in the spine. These data indicate that Lrp5 signaling functions locally, and they suggest that increasing LRP5 signaling in mature bone cells may be a strategy for treating human disorders associated with low bone mass, such as osteoporosis.", + "TAG_DATA": [ + "23, mice {'context': 'B-organism'}", + "25, osteocyte-specific {'perturbing_action': 'B-gene gain-of-function'}", + "26, expression {'perturbing_action': 'I-other'}", + "27, of {'perturbing_action': 'I-other'}", + "28, inducible {'perturbing_action': 'I-other'}", + "29, Lrp5 {'perturbing_action': 'I-other'}", + "30, mutations {'perturbing_action': 'I-other'}", + "48, mice {'context': 'B-organism'}", + "55, mice {'context': 'B-organism'}", + "61, induced {'perturbing_action': 'B-other'}", + "63, Lrp5 {'perturbing_action': 'B-other'}", + "64, mutation {'perturbing_action': 'I-other'}", + "66, cells {'context': 'B-cells'}", + "67, that {'context': 'B-cells'}", + "75, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "23, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "25, osteocyte-specific ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "26, expression ['l1', 'l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "27, of ['l2', 'l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "28, inducible ['l3', 'l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "29, Lrp5 ['l4', 'l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "30, mutations ['l5', 'l10', 'l15', 'l19', 'l22', 'l24']", + "48, mice ['l11', 'l16', 'l20', 'l23', 'l25']", + "55, mice ['l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "61, induced ['l26', 'l32', 'l33', 'l34', 'l35', 'l36']", + "63, Lrp5 ['l27', 'l32', 'l37', 'l38', 'l39', 'l40']", + "64, mutation ['l28', 'l33', 'l37', 'l41', 'l42', 'l43']", + "66, cells ['l29', 'l34', 'l38', 'l41', 'l44', 'l45']", + "67, that ['l30', 'l35', 'l39', 'l42', 'l44', 'l46']", + "75, cells ['l31', 'l36', 'l40', 'l43', 'l45', 'l46']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "osteocyte-specific" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "inducible", + "Lrp5", + "mutations", + "induced", + "mutation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "induced", + "Lrp5", + "mutation" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "that" + ] + } + } + ] + }, + { + "PMID": "21572427", + "TEXT": "In regions of high rates of malaria transmission, mosquitoes repeatedly transmit liver-tropic Plasmodium sporozoites to individuals who already have blood-stage parasitemia. This manifests itself in semi-immune children (who have been exposed since birth to Plasmodium infection and as such show low levels of peripheral parasitemia but can still be infected) older than 5 years of age by concurrent carriage of different parasite genotypes at low asymptomatic parasitemias. Superinfection presents an increased risk of hyperparasitemia and death in less immune individuals but counterintuitively is not frequently observed in the young. Here we show in a mouse model that ongoing blood-stage infections, above a minimum threshold, impair the growth of subsequently inoculated sporozoites such that they become growth arrested in liver hepatocytes and fail to develop into blood-stage parasites. Inhibition of the liver-stage infection is mediated by the host iron regulatory hormone hepcidin, whose synthesis we found to be stimulated by blood-stage parasites in a density-dependent manner. We mathematically modeled this phenomenon and show how density-dependent protection against liver-stage malaria can shape the epidemiological patterns of age-related risk and the complexity of malaria infections seen in young children. The interaction between these two Plasmodium stages and host iron metabolism has relevance for the global efforts to reduce malaria transmission and for evaluation of iron supplementation programs in malaria-endemic regions.", + "TAG_DATA": [ + "94, mouse {'context': 'B-organism'}", + "95, model {'context': 'I-organism'}", + "118, liver {'context': 'B-cells'}", + "119, hepatocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "94, mouse ['l0']", + "95, model ['l0']", + "118, liver ['l1']", + "119, hepatocytes ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21540856", + "TEXT": "CD4(+)CD25(high)CD127(low/-) forkhead box p3 (Foxp3)(+) regulatory T cells (T(reg) cells) possess functional plasticity. Here we describe a higher frequency of T helper type 1 (T(H)1)-like, interferon-γ (IFN-γ)-secreting Foxp3(+) T cells in untreated subjects with relapsing remitting multiple sclerosis (RRMS) as compared to healthy control individuals. In subjects treated with IFN-β, the frequency of IFN-γ(+)Foxp3(+) T cells is similar to that in healthy control subjects. In vitro, human T(reg) cells from healthy subjects acquire a T(H)1-like phenotype when cultured in the presence of interleukin-12 (IL-12). T(H)1-like T(reg) cells show reduced suppressive activity in vitro, which can partially be reversed by IFN-γ-specific antibodies or by removal of IL-12.", + "TAG_DATA": [ + "64, In {'context': 'B-in vitro'}", + "65, vitro, {'context': 'I-in vitro'}", + "66, human {'context': 'B-cells'}", + "67, T(reg) {'context': 'I-cells'}", + "68, cells {'context': 'I-cells'}", + "84, T(H)1-like {'context': 'B-cells'}", + "85, T(reg) {'context': 'I-cells'}", + "86, cells {'context': 'I-cells'}", + "91, in {'context': 'B-in vitro'}", + "92, vitro, {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "64, In ['l0', 'l1', 'l2', 'l3']", + "65, vitro, ['l0', 'l4', 'l5', 'l6']", + "66, human ['l1', 'l4', 'l7', 'l8']", + "67, T(reg) ['l2', 'l5', 'l7', 'l9']", + "68, cells ['l3', 'l6', 'l8', 'l9']", + "84, T(H)1-like ['l10', 'l11', 'l12', 'l13']", + "85, T(reg) ['l10', 'l14', 'l15', 'l16']", + "86, cells ['l11', 'l14', 'l17', 'l18']", + "91, in ['l12', 'l15', 'l17', 'l19']", + "92, vitro, ['l13', 'l16', 'l18', 'l19']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21532595", + "TEXT": "The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear receptor that is activated by lipids to induce the expression of genes involved in lipid and glucose metabolism, thereby converting nutritional signals into metabolic consequences. PPAR-γ is the target of the thiazolidinedione (TZD) class of insulin-sensitizing drugs, which have been widely prescribed to treat type 2 diabetes mellitus. A common side effect of treatment with TZDs is weight gain. Here we report a previously unknown role for central nervous system (CNS) PPAR-γ in the regulation of energy balance. We found that both acute and chronic activation of CNS PPAR-γ, by either TZDs or hypothalamic overexpression of a fusion protein consisting of PPAR-γ and the viral transcriptional activator VP16 (VP16-PPAR-γ), led to positive energy balance in rats. Blocking the endogenous activation of CNS PPAR-γ with pharmacological antagonists or reducing its expression with shRNA led to negative energy balance, restored leptin sensitivity in high-fat-diet (HFD)-fed rats and blocked the hyperphagic response to oral TZD treatment. These findings have implications for the widespread clinical use of TZD drugs and for understanding the etiology of diet-induced obesity.", + "TAG_DATA": [ + "93, activation {'perturbing_action': 'I-gene gain-of-function'}", + "94, of {'perturbing_action': 'I-gene gain-of-function'}", + "95, CNS {'perturbing_action': 'I-gene gain-of-function'}", + "96, PPAR-γ, {'perturbing_action': 'I-gene gain-of-function'}", + "101, hypothalamic {'perturbing_action': 'B-gene gain-of-function'}", + "102, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "103, of {'perturbing_action': 'I-gene gain-of-function'}", + "104, a {'perturbing_action': 'I-gene gain-of-function'}", + "105, fusion {'perturbing_action': 'I-gene gain-of-function'}", + "106, protein {'perturbing_action': 'I-gene gain-of-function'}", + "107, consisting {'perturbing_action': 'I-gene gain-of-function'}", + "108, of {'perturbing_action': 'I-gene gain-of-function'}", + "109, PPAR-γ {'perturbing_action': 'I-gene gain-of-function'}", + "110, and {'perturbing_action': 'I-gene gain-of-function'}", + "111, the {'perturbing_action': 'I-gene gain-of-function'}", + "112, viral {'perturbing_action': 'I-gene gain-of-function'}", + "113, transcriptional {'perturbing_action': 'I-gene gain-of-function'}", + "114, activator {'perturbing_action': 'I-gene gain-of-function'}", + "115, VP16 {'perturbing_action': 'I-gene gain-of-function'}", + "116, (VP16-PPAR-γ), {'perturbing_action': 'I-gene gain-of-function'}", + "123, rats. {'context': 'B-organism'}", + "135, reducing {'perturbing_action': 'B-rnai/knockdown'}", + "136, its {'perturbing_action': 'I-rnai/knockdown'}", + "137, expression {'perturbing_action': 'I-rnai/knockdown'}", + "138, with {'perturbing_action': 'I-rnai/knockdown'}", + "139, shRNA {'perturbing_action': 'I-rnai/knockdown'}", + "151, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "93, activation ['l0', 'l1', 'l2', 'l3']", + "94, of ['l0', 'l4', 'l5', 'l6']", + "95, CNS ['l1', 'l4', 'l7', 'l8']", + "96, PPAR-γ, ['l2', 'l5', 'l7', 'l9']", + "101, hypothalamic ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "102, overexpression ['l10', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "103, of ['l11', 'l26', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "104, a ['l12', 'l27', 'l41', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "105, fusion ['l13', 'l28', 'l42', 'l55', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "106, protein ['l14', 'l29', 'l43', 'l56', 'l69', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "107, consisting ['l15', 'l30', 'l44', 'l57', 'l70', 'l82', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "108, of ['l16', 'l31', 'l45', 'l58', 'l71', 'l83', 'l94', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "109, PPAR-γ ['l17', 'l32', 'l46', 'l59', 'l72', 'l84', 'l95', 'l105', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "110, and ['l18', 'l33', 'l47', 'l60', 'l73', 'l85', 'l96', 'l106', 'l115', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "111, the ['l19', 'l34', 'l48', 'l61', 'l74', 'l86', 'l97', 'l107', 'l116', 'l124', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "112, viral ['l20', 'l35', 'l49', 'l62', 'l75', 'l87', 'l98', 'l108', 'l117', 'l125', 'l132', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "113, transcriptional ['l21', 'l36', 'l50', 'l63', 'l76', 'l88', 'l99', 'l109', 'l118', 'l126', 'l133', 'l139', 'l145', 'l146', 'l147', 'l148', 'l149']", + "114, activator ['l22', 'l37', 'l51', 'l64', 'l77', 'l89', 'l100', 'l110', 'l119', 'l127', 'l134', 'l140', 'l145', 'l150', 'l151', 'l152', 'l153']", + "115, VP16 ['l23', 'l38', 'l52', 'l65', 'l78', 'l90', 'l101', 'l111', 'l120', 'l128', 'l135', 'l141', 'l146', 'l150', 'l154', 'l155', 'l156']", + "116, (VP16-PPAR-γ), ['l24', 'l39', 'l53', 'l66', 'l79', 'l91', 'l102', 'l112', 'l121', 'l129', 'l136', 'l142', 'l147', 'l151', 'l154', 'l157', 'l158']", + "123, rats. ['l3', 'l6', 'l8', 'l9', 'l25', 'l40', 'l54', 'l67', 'l80', 'l92', 'l103', 'l113', 'l122', 'l130', 'l137', 'l143', 'l148', 'l152', 'l155', 'l157']", + "135, reducing ['l159', 'l160', 'l161', 'l162', 'l163']", + "136, its ['l159', 'l164', 'l165', 'l166', 'l167']", + "137, expression ['l160', 'l164', 'l168', 'l169', 'l170']", + "138, with ['l161', 'l165', 'l168', 'l171', 'l172']", + "139, shRNA ['l162', 'l166', 'l169', 'l171', 'l173']", + "151, rats ['l68', 'l81', 'l93', 'l104', 'l114', 'l123', 'l131', 'l138', 'l144', 'l149', 'l153', 'l156', 'l158', 'l163', 'l167', 'l170', 'l172', 'l173']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "activation", + "of", + "CNS", + "PPAR-γ,", + "hypothalamic", + "overexpression", + "a", + "fusion", + "protein", + "consisting", + "PPAR-γ", + "and", + "the", + "viral", + "transcriptional", + "activator", + "VP16", + "(VP16-PPAR-γ)," + ] + }, + "context": { + "val": "organism", + "words": [ + "rats.", + "rats" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "reducing", + "its", + "expression", + "with", + "shRNA" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + } + ] + }, + { + "PMID": "21516087", + "TEXT": "Hepatitis C virus (HCV) is a major cause of liver disease, but therapeutic options are limited and there are no prevention strategies. Viral entry is the first step of infection and requires the cooperative interaction of several host cell factors. Using a functional RNAi kinase screen, we identified epidermal growth factor receptor and ephrin receptor A2 as host cofactors for HCV entry. Blocking receptor kinase activity by approved inhibitors broadly impaired infection by all major HCV genotypes and viral escape variants in cell culture and in a human liver chimeric mouse model in vivo. The identified receptor tyrosine kinases (RTKs) mediate HCV entry by regulating CD81-claudin-1 co-receptor associations and viral glycoprotein-dependent membrane fusion. These results identify RTKs as previously unknown HCV entry cofactors and show that tyrosine kinase inhibitors have substantial antiviral activity. Inhibition of RTK function may constitute a new approach for prevention and treatment of HCV infection.", + "TAG_DATA": [ + "82, cell {'context': 'B-cells'}", + "83, culture {'context': 'I-in vitro'}", + "87, human {'context': 'B-organism'}", + "88, liver {'context': 'I-organism'}", + "89, chimeric {'context': 'I-organism'}", + "90, mouse {'context': 'I-organism'}", + "91, model {'context': 'I-organism'}", + "92, in {'context': 'B-in vivo'}", + "93, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "82, cell ['l0']", + "83, culture ['l0']", + "87, human ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "88, liver ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "89, chimeric ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "90, mouse ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "91, model ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "92, in ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "93, vivo. ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21483405", + "TEXT": "A recently recognized human rhinovirus species C (HRV-C) is associated with up to half of HRV infections in young children. Here we propagated two HRV-C isolates ex vivo in organ culture of nasal epithelial cells, sequenced a new C15 isolate and developed the first, to our knowledge, reverse genetics system for HRV-C. Using contact points for the known HRV receptors, intercellular adhesion molecule-1 (ICAM-1) and low-density lipoprotein receptor (LDLR), inter- and intraspecies footprint analyses predicted a unique cell attachment site for HRV-Cs. Antibodies directed to binding sites for HRV-A and -B failed to inhibit HRV-C attachment, consistent with the alternative receptor footprint. HRV-A and HRV-B infected HeLa and WisL cells but HRV-C did not. However, HRV-C RNA synthesized in vitro and transfected into both cell types resulted in cytopathic effect and recovery of functional virus, indicating that the viral attachment mechanism is a primary distinguishing feature of HRV-C.", + "TAG_DATA": [ + "29, organ {'context': 'B-in vitro'}", + "30, culture {'context': 'I-in vitro'}", + "32, nasal {'context': 'B-cells'}", + "33, epithelial {'context': 'I-cells'}", + "34, cells, {'context': 'I-cells'}", + "106, HeLa {'context': 'B-cells'}", + "107, and {'context': 'I-cells'}", + "108, WisL {'context': 'I-cells'}", + "109, cells {'context': 'I-cells'}", + "118, in {'context': 'B-in vitro'}", + "119, vitro {'context': 'I-in vitro'}", + "124, cell {'context': 'B-cells'}", + "125, types {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "29, organ ['l0', 'l1', 'l2', 'l3']", + "30, culture ['l0', 'l4', 'l5', 'l6']", + "32, nasal ['l1', 'l4', 'l7', 'l8']", + "33, epithelial ['l2', 'l5', 'l7', 'l9']", + "34, cells, ['l3', 'l6', 'l8', 'l9']", + "106, HeLa ['l10', 'l11', 'l12', 'l13']", + "107, and ['l10', 'l14', 'l15', 'l16']", + "108, WisL ['l11', 'l14', 'l17', 'l18']", + "109, cells ['l12', 'l15', 'l17']", + "118, in ['l19', 'l20', 'l21']", + "119, vitro ['l19', 'l22', 'l23']", + "124, cell ['l20', 'l22', 'l24']", + "125, types ['l13', 'l16', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21441918", + "TEXT": "Hypofunction of the N-methyl D-aspartate subtype of glutamate receptor (NMDAR) is hypothesized to be a mechanism underlying cognitive dysfunction in individuals with schizophrenia. For the schizophrenia-linked genes NRG1 and ERBB4, NMDAR hypofunction is thus considered a key detrimental consequence of the excessive NRG1-ErbB4 signaling found in people with schizophrenia. However, we show here that neuregulin 1β-ErbB4 (NRG1β-ErbB4) signaling does not cause general hypofunction of NMDARs. Rather, we find that, in the hippocampus and prefrontal cortex, NRG1β-ErbB4 signaling suppresses the enhancement of synaptic NMDAR currents by the nonreceptor tyrosine kinase Src. NRG1β-ErbB4 signaling prevented induction of long-term potentiation at hippocampal Schaffer collateral-CA1 synapses and suppressed Src-dependent enhancement of NMDAR responses during theta-burst stimulation. Moreover, NRG1β-ErbB4 signaling prevented theta burst-induced phosphorylation of GluN2B by inhibiting Src kinase activity. We propose that NRG1-ErbB4 signaling participates in cognitive dysfunction in schizophrenia by aberrantly suppressing Src-mediated enhancement of synaptic NMDAR function.", + "TAG_DATA": [ + "71, hippocampus {'context': 'B-tissue/organ'}", + "73, prefrontal {'context': 'I-tissue/organ'}", + "74, cortex, {'context': 'I-tissue/organ'}", + "98, hippocampal {'context': 'B-cells'}", + "99, Schaffer {'context': 'I-cells'}", + "100, collateral-CA1 {'context': 'I-cells'}", + "101, synapses {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "71, hippocampus ['l0', 'l1', 'l2', 'l3']", + "73, prefrontal ['l0', 'l4', 'l5', 'l6', 'l7']", + "74, cortex, ['l1', 'l4', 'l8']", + "98, hippocampal ['l2', 'l5', 'l9', 'l10', 'l11']", + "99, Schaffer ['l6', 'l9', 'l12', 'l13']", + "100, collateral-CA1 ['l10', 'l12', 'l14']", + "101, synapses ['l3', 'l7', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21441917", + "TEXT": "We simultaneously transduced cells with three lentiviral gene ontology (LeGO) vectors encoding red, green or blue fluorescent proteins. Individual cells were thereby marked by different combinations of inserted vectors, resulting in the generation of numerous mixed colors, a principle we named red-green-blue (RGB) marking. We show that lentiviral vector-mediated RGB marking remained stable after cell division, thus facilitating the analysis of clonal cell fates in vitro and in vivo. Particularly, we provide evidence that RGB marking allows assessment of clonality after regeneration of injured livers by transplanted primary hepatocytes. We also used RGB vectors to mark hematopoietic stem/progenitor cells that generated colored spleen colonies. Finally, based on limiting-dilution and serial transplantation assays with tumor cells, we found that clonal tumor cells retained their specific color-code over extensive periods of time. We conclude that RGB marking represents a useful tool for cell clonality studies in tissue regeneration and pathology.", + "TAG_DATA": [ + "3, cells {'context': 'B-cells'}", + "19, cells {'context': 'B-cells'}", + "54, cell {'phenotype': 'B-proliferation'}", + "55, division, {'phenotype': 'I-proliferation'}", + "65, vitro {'context': 'I-in vitro'}", + "67, in {'context': 'B-in vivo'}", + "68, vivo. {'context': 'I-in vivo'}", + "87, primary {'context': 'B-cells'}", + "88, hepatocytes. {'context': 'I-cells'}", + "96, hematopoietic {'context': 'B-cells'}", + "97, stem/progenitor {'context': 'I-cells'}", + "98, cells {'context': 'I-cells'}", + "102, spleen {'context': 'B-tissue/organ'}", + "103, colonies. {'phenotype': 'I-tumourigenesis'}", + "113, tumor {'context': 'B-transformed cells'}", + "114, cells, {'context': 'I-transformed cells'}", + "118, clonal {'context': 'B-transformed cells'}", + "119, tumor {'context': 'I-transformed cells'}", + "120, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "3, cells ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "19, cells ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "54, cell ['l1', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "55, division, ['l2', 'l11', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "65, vitro ['l3', 'l12', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32']", + "67, in ['l4', 'l13', 'l20', 'l25', 'l29', 'l33', 'l34', 'l35']", + "68, vivo. ['l5', 'l14', 'l21', 'l26', 'l30', 'l33', 'l36', 'l37']", + "87, primary ['l6', 'l15', 'l22', 'l27', 'l31', 'l34', 'l36', 'l38']", + "88, hepatocytes. ['l7', 'l16', 'l23', 'l28', 'l32', 'l35', 'l37', 'l38']", + "96, hematopoietic ['l39', 'l40', 'l41', 'l42']", + "97, stem/progenitor ['l8', 'l39', 'l43', 'l44', 'l45']", + "98, cells ['l9', 'l17', 'l40', 'l43', 'l46', 'l47']", + "102, spleen ['l41', 'l44', 'l46', 'l48']", + "103, colonies. ['l42', 'l45', 'l47', 'l48']", + "113, tumor ['l49', 'l50', 'l51', 'l52']", + "114, cells, ['l49', 'l53', 'l54', 'l55']", + "118, clonal ['l50', 'l53', 'l56', 'l57']", + "119, tumor ['l51', 'l54', 'l56', 'l58']", + "120, cells ['l52', 'l55', 'l57', 'l58']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells", + "primary", + "hepatocytes." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "vitro" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem/progenitor", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "colonies." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "spleen" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "colonies." + ] + } + } + ] + }, + { + "PMID": "21317886", + "TEXT": "To date, the only known role of the spliced form of X-box-binding protein-1 (XBP-1s) in metabolic processes has been its ability to act as a transcription factor that regulates the expression of genes that increase the endoplasmic reticulum (ER) folding capacity, thereby improving insulin sensitivity. Here we show that XBP-1s interacts with the Forkhead box O1 (FoxO1) transcription factor and directs it toward proteasome-mediated degradation. Given this new insight, we tested modest hepatic overexpression of XBP-1s in vivo in mouse models of insulin deficiency or insulin resistance and found it improved serum glucose concentrations, even without improving insulin signaling or ER folding capacity. The notion that XBP-1s can act independently of its role in the ER stress response is further supported by our finding that in the severely insulin resistant ob/ob mouse strain a DNA-binding-defective mutant of XBP-1s, which does not have the ability to increase ER folding capacity, is still capable of reducing serum glucose concentrations and increasing glucose tolerance. Our results thus provide the first evidence to our knowledge that XBP-1s, through its interaction with FoxO1, can bypass hepatic insulin resistance independent of its effects on ER folding capacity, suggesting a new therapeutic approach for the treatment of type 2 diabetes.", + "TAG_DATA": [ + "72, hepatic {'perturbing_action': 'B-gene gain-of-function'}", + "73, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "74, of {'perturbing_action': 'I-gene gain-of-function'}", + "75, XBP-1s {'perturbing_action': 'I-gene gain-of-function'}", + "76, in {'context': 'B-in vivo'}", + "77, vivo {'context': 'I-in vivo'}", + "79, mouse {'context': 'B-organism'}", + "80, models {'context': 'I-organism'}", + "130, ob/ob {'context': 'I-organism'}", + "131, mouse {'context': 'I-organism'}", + "132, strain {'context': 'I-organism'}", + "134, DNA-binding-defective {'perturbing_action': 'B-other'}", + "135, mutant {'perturbing_action': 'I-other'}", + "136, of {'perturbing_action': 'I-other'}", + "137, XBP-1s, {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "72, hepatic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "73, overexpression ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "74, of ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "75, XBP-1s ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "76, in ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "77, vivo ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "79, mouse ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "80, models ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "130, ob/ob ['l28', 'l29', 'l30', 'l31']", + "131, mouse ['l28', 'l32', 'l33', 'l34', 'l35']", + "132, strain ['l29', 'l32', 'l36', 'l37', 'l38']", + "134, DNA-binding-defective ['l39', 'l40', 'l41']", + "135, mutant ['l33', 'l36', 'l39', 'l42', 'l43']", + "136, of ['l30', 'l34', 'l37', 'l40', 'l42', 'l44']", + "137, XBP-1s, ['l31', 'l35', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hepatic", + "overexpression", + "of", + "XBP-1s" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hepatic", + "overexpression", + "of", + "XBP-1s" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "ob/ob", + "mouse", + "strain" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "of", + "XBP-1s,", + "mutant" + ] + } + } + ] + }, + { + "PMID": "21317885", + "TEXT": "The TP53 gene (encoding the p53 tumor suppressor) is rarely mutated, although frequently inactivated, in medulloblastoma and ependymoma. Recent work in mouse models showed that the loss of p53 accelerated the development of medulloblastoma. The mechanism underlying p53 inactivation in human brain tumors is not completely understood. We show that ubiquitination factor E4B (UBE4B), an E3 and E4 ubiquitin ligase, physically interacts with p53 and Hdm2 (also known as Mdm2 in mice). UBE4B promotes p53 polyubiquitination and degradation and inhibits p53-dependent transactivation and apoptosis. Notably, silencing UBE4B expression impairs xenotransplanted tumor growth in a p53-dependent manner and overexpression of UBE4B correlates with decreased expression of p53 in these tumors. We also show that UBE4B overexpression is often associated with amplification of its gene in human brain tumors. Our data indicate that amplification and overexpression of UBE4B represent previously undescribed molecular mechanisms of inactivation of p53 in brain tumors.", + "TAG_DATA": [ + "79, inhibits {'effect': 'B-negative'}", + "83, apoptosis. {'phenotype': 'B-apoptosis'}", + "85, silencing {'perturbing_action': 'B-rnai/knockdown'}", + "86, UBE4B {'perturbing_action': 'I-rnai/knockdown'}", + "87, expression {'perturbing_action': 'I-rnai/knockdown'}", + "88, impairs {'effect': 'B-negative'}", + "89, xenotransplanted {'context': 'B-xenograft'}", + "90, tumor {'phenotype': 'B-tumour growth'}", + "91, growth {'phenotype': 'I-tumour growth'}", + "108, tumors. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "79, inhibits ['l0']", + "83, apoptosis. ['l0']", + "85, silencing ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "86, UBE4B ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "87, expression ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "88, impairs ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "89, xenotransplanted ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "90, tumor ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "91, growth ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "UBE4B", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "UBE4B", + "expression" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenotransplanted" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "UBE4B", + "expression" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenotransplanted" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenotransplanted" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + } + ] + }, + { + "PMID": "21278748", + "TEXT": "The development of technologies for the in vitro amplification of abnormal conformations of prion protein (PrP(Sc)) has generated the potential for sensitive detection of prions. Here we developed a new PrP(Sc) amplification assay, called real-time quaking-induced conversion (RT-QUIC), which allows the detection of ≥1 fg of PrP(Sc) in diluted Creutzfeldt-Jakob disease (CJD) brain homogenate. Moreover, we assessed the technique first in a series of Japanese subjects and then in a blind study of 30 cerebrospinal fluid specimens from Australia, which achieved greater than 80% sensitivity and 100% specificity. These findings indicate the promising enhanced diagnostic capacity of RT-QUIC in the antemortem evaluation of suspected CJD.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21258336", + "TEXT": "Hyperglycemia is associated with greater hematoma expansion and poor clinical outcomes after intracerebral hemorrhage. We show that cerebral hematoma expansion triggered by intracerebral infusion of autologous blood is greater in diabetic rats and mice compared to nondiabetic controls and that this augmented expansion is ameliorated by plasma kallikrein (PK) inhibition or deficiency. Intracerebral injection of purified PK augmented hematoma expansion in both diabetic and acutely hyperglycemic rats, whereas injection of bradykinin, plasmin or tissue plasminogen activator did not elicit such a response. This response, which occurs rapidly, was prevented by co-injection of the glycoprotein VI agonist convulxin and was mimicked by glycoprotein VI inhibition or deficiency, implicating an effect of PK on inhibiting platelet aggregation. We show that PK inhibits collagen-induced platelet aggregation by binding collagen, a response enhanced by elevated glucose concentrations. The effect of hyperglycemia on hematoma expansion and PK-mediated inhibition of platelet aggregation could be mimicked by infusing mannitol. These findings suggest that hyperglycemia augments cerebral hematoma expansion by PK-mediated osmotic-sensitive inhibition of hemostasis.", + "TAG_DATA": [ + "66, rats, {'context': 'B-organism'}", + "93, glycoprotein {'perturbing_action': 'I-pharmacological augmentation'}", + "94, VI {'perturbing_action': 'I-pharmacological augmentation'}", + "95, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "101, glycoprotein {'perturbing_action': 'B-pharmacological inhibition'}", + "102, VI {'perturbing_action': 'I-pharmacological inhibition'}", + "103, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "119, inhibits {'effect': 'B-negative'}", + "121, platelet {'context': 'B-cells'}", + "122, aggregation {'phenotype': 'B-autophagy'}", + "144, platelet {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "93, glycoprotein ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "94, VI ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "95, agonist ['l1', 'l7', 'l14', 'l15', 'l16', 'l17', 'l18']", + "101, glycoprotein ['l8', 'l19', 'l20', 'l21', 'l22', 'l23']", + "102, VI ['l2', 'l9', 'l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "103, inhibition ['l3', 'l10', 'l15', 'l20', 'l24', 'l28', 'l29', 'l30']", + "119, inhibits ['l4', 'l11', 'l16', 'l21', 'l25', 'l28', 'l31', 'l32']", + "121, platelet ['l5', 'l12', 'l17', 'l22', 'l26', 'l29', 'l31', 'l33']", + "122, aggregation ['l6', 'l13', 'l18', 'l23', 'l27', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "glycoprotein", + "VI", + "agonist" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "glycoprotein", + "VI", + "agonist" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelet" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "glycoprotein", + "VI", + "agonist" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "aggregation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "glycoprotein", + "VI", + "inhibition" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "glycoprotein", + "VI", + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelet" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "glycoprotein", + "VI", + "inhibition" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "aggregation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelet" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "aggregation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "platelet" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "aggregation" + ] + } + } + ] + }, + { + "PMID": "21240264", + "TEXT": "Many proteins have been proposed to act as surrogate markers of organ damage, yet for many candidates the essential biomarker characteristics that link the protein to the injured organ have not yet been described. We generated an Ngal reporter mouse by inserting a double-fusion reporter gene encoding luciferase-2 and mCherry (Luc2-mC) into the Ngal (Lcn2) locus. The Ngal-Luc2-mC reporter accurately recapitulated the endogenous message and illuminated injuries in vivo in real time. In the kidney, Ngal-Luc2-mC imaging showed a sensitive, rapid, dose-dependent, reversible, and organ- and cell-specific relationship with tubular stress, which correlated with the level of urinary Ngal (uNgal). Unexpectedly, specific cells of the distal nephron were the source of uNgal. Cells isolated from Ngal-Luc2-mC mice also revealed both the onset and the resolution of the injury, and the actions of NF-κB inhibitors and antibiotics during infection. Thus, imaging of Ngal-Luc2-mC mice and cells identified injurious and reparative agents that affect kidney damage.", + "TAG_DATA": [ + "67, in {'context': 'B-in vivo'}", + "68, vivo {'context': 'I-in vivo'}", + "74, kidney, {'context': 'B-tissue/organ'}", + "102, cells {'context': 'B-cells'}", + "104, the {'context': 'I-cells'}", + "105, distal {'context': 'I-cells'}", + "106, nephron {'context': 'I-cells'}", + "112, Cells {'context': 'B-cells'}", + "115, Ngal-Luc2-mC {'perturbing_action': 'B-other'}", + "116, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "67, in ['l0', 'l1']", + "68, vivo ['l0', 'l2']", + "74, kidney, ['l1', 'l2']", + "102, cells ['l3', 'l4', 'l5']", + "104, the ['l3', 'l6', 'l7']", + "105, distal ['l4', 'l6', 'l8']", + "106, nephron ['l5', 'l7', 'l8']", + "112, Cells ['l9', 'l10']", + "115, Ngal-Luc2-mC ['l9', 'l11']", + "116, mice ['l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Cells" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Ngal-Luc2-mC" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Ngal-Luc2-mC" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "21186368", + "TEXT": "Myocardial infarction is a leading cause of mortality worldwide. Here we report that modulation of microRNA-499 (miR-499) levels affects apoptosis and the severity of myocardial infarction and cardiac dysfunction induced by ischemia-reperfusion. We found that both the α- and β-isoforms of the calcineurin catalytic subunit are direct targets of miR-499 and that miR-499 inhibits cardiomyocyte apoptosis through its suppression of calcineurin-mediated dephosphorylation of dynamin-related protein-1 (Drp1), thereby decreasing Drp1 accumulation in mitochondria and Drp1-mediated activation of the mitochondrial fission program. We also found that p53 transcriptionally downregulates miR-499 expression. Our data reveal a role for miR-499 in regulating the mitochondrial fission machinery and we suggest that modulation of miR-499 levels may provide a therapeutic approach for treating myocardial infarction.", + "TAG_DATA": [ + "53, inhibits {'effect': 'B-negative'}", + "54, cardiomyocyte {'context': 'B-cells'}", + "55, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "53, inhibits ['l0', 'l1']", + "54, cardiomyocyte ['l0', 'l2']", + "55, apoptosis ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocyte" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cardiomyocyte" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "21102457", + "TEXT": "Interleukin-6 (IL-6)-Janus kinase (JAK) signaling is viewed as crucial for persistent signal transducer and activator of transcription-3 (STAT3) activation in cancer. However, IL-6-induced STAT3 activation is normally transient. Here we identify a key mechanism for persistent STAT3 activation in tumor cells and the tumor microenvironment. We show that expression of sphingosine-1-phosphate receptor-1 (S1PR1), a G protein-coupled receptor for the lysophospholipid sphingosine-1-phosphate (S1P), is elevated in STAT3-positive tumors. STAT3 is a transcription factor for the S1pr1 gene. Reciprocally, enhanced S1pr1 expression activates STAT3 and upregulates Il6 gene expression, thereby accelerating tumor growth and metastasis in a STAT3-dependent manner. Silencing S1pr1 in tumor cells or immune cells inhibits tumor STAT3 activity, tumor growth and metastasis. S1P-S1PR1-induced STAT3 activation is persistent, in contrast to transient STAT3 activation by IL-6. S1PR1 activates STAT3 in part by upregulating JAK2 tyrosine kinase activity. We show that STAT3-induced S1PR1 expression, as well as the S1P-S1PR1 pathway reciprocal regulation of STAT3 activity, is a major positive feedback loop for persistent STAT3 activation in cancer cells and the tumor microenvironment and for malignant progression.", + "TAG_DATA": [ + "88, accelerating {'effect': 'B-positive'}", + "89, tumor {'phenotype': 'B-tumour growth'}", + "90, growth {'phenotype': 'I-tumour growth'}", + "92, metastasis {'phenotype': 'B-metastasis'}", + "97, Silencing {'perturbing_action': 'B-rnai/knockdown'}", + "98, S1pr1 {'perturbing_action': 'I-rnai/knockdown'}", + "100, tumor {'context': 'B-transformed cells'}", + "101, cells {'context': 'I-transformed cells'}", + "103, immune {'context': 'B-cells'}", + "104, cells {'context': 'I-cells'}", + "105, inhibits {'effect': 'B-negative'}", + "106, tumor {'context': 'B-neoplasm'}", + "109, tumor {'phenotype': 'B-tumour growth'}", + "110, growth {'phenotype': 'I-tumour growth'}", + "112, metastasis. {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "88, accelerating ['l0', 'l1', 'l2']", + "89, tumor ['l0', 'l3', 'l4']", + "90, growth ['l1', 'l3', 'l5']", + "92, metastasis ['l2', 'l4', 'l5']", + "97, Silencing ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "98, S1pr1 ['l6', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "100, tumor ['l7', 'l16', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "101, cells ['l8', 'l17', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "103, immune ['l9', 'l18', 'l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "104, cells ['l10', 'l19', 'l27', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "105, inhibits ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "106, tumor ['l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57']", + "109, tumor ['l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l58', 'l59']", + "110, growth ['l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58', 'l60']", + "112, metastasis. ['l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "accelerating" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "accelerating" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "S1pr1" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "S1pr1" + ] + }, + "context": { + "val": "cells", + "words": [ + "immune", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "S1pr1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "S1pr1" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "S1pr1" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "S1pr1" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "immune", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "immune", + "cells" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "immune", + "cells" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + } + ] + }, + { + "PMID": "21052073", + "TEXT": "Although substantial progress has been made in understanding the molecular and pathological bases of neurodegeneration, there have been few successes in the clinic and a number of fundamental questions remain unanswered. Is this skepticism misplaced, or do the words of Sir Isaac Newton hold true, that \"what we know is a drop, what we don't know is an ocean\"?", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21037588", + "TEXT": "Immunodominance is defined as restricted responsiveness of T cells to a few selected epitopes from complex antigens. Strategies currently used for elucidating CD4(+) T cell epitopes are inadequate. To understand the mechanism of epitope selection for helper T cells, we established a cell-free antigen processing system composed of defined proteins: human leukocyte antigen-DR1 (HLA-DR1), HLA-DM and cathepsins. Our reductionist system successfully identified the physiologically selected immunodominant epitopes of two model antigens: hemagglutinin-1 (HA1) from influenza virus (A/Texas/1/77) and type II collagen (CII). When applied for identification of new epitopes from a recombinant liver-stage antigen of malaria falciparum (LSA-NRC) or HA1 from H5N1 influenza virus ('avian flu'), the system selected single epitopes from each protein that were confirmed to be immunodominant by their capacity to activate CD4(+) T cells from H5N1-immunized HLA-DR1-transgenic mice and LSA-NRC-vaccinated HLA-DR1-positive human volunteers. Thus, we provide a new tool for the identification of physiologically relevant helper T cell epitopes from antigens.", + "TAG_DATA": [ + "125, CD4(+) {'context': 'B-cells'}", + "126, T {'context': 'I-cells'}", + "127, cells {'context': 'I-cells'}", + "130, HLA-DR1-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "131, mice {'context': 'B-organism'}", + "135, human {'context': 'B-organism'}", + "136, volunteers. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "125, CD4(+) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "126, T ['l0', 'l6', 'l7', 'l8', 'l9']", + "127, cells ['l1', 'l6', 'l10', 'l11']", + "130, HLA-DR1-transgenic ['l2', 'l7', 'l10', 'l12', 'l13', 'l14']", + "131, mice ['l3', 'l8', 'l11', 'l12', 'l15']", + "135, human ['l4', 'l13', 'l16']", + "136, volunteers. ['l5', 'l9', 'l14', 'l15', 'l16']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "HLA-DR1-transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "HLA-DR1-transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "human", + "volunteers." + ] + } + } + ] + }, + { + "PMID": "21037586", + "TEXT": "Autophagy is crucial in the turnover of cell components, and clearance of damaged organelles by the autophagic-lysosomal pathway is essential for tissue homeostasis. Defects of this degradative system have a role in various diseases, but little is known about autophagy in muscular dystrophies. We have previously found that muscular dystrophies linked to collagen VI deficiency show dysfunctional mitochondria and spontaneous apoptosis, leading to myofiber degeneration. Here we demonstrate that this persistence of abnormal organelles and apoptosis are caused by defective autophagy. Skeletal muscles of collagen VI-knockout (Col6a1(-/-)) mice had impaired autophagic flux, which matched the lower induction of beclin-1 and BCL-2/adenovirus E1B-interacting protein-3 (Bnip3) and the lack of autophagosomes after starvation. Forced activation of autophagy by genetic, dietary and pharmacological approaches restored myofiber survival and ameliorated the dystrophic phenotype of Col6a1(-/-) mice. Furthermore, muscle biopsies from subjects with Bethlem myopathy or Ullrich congenital muscular dystrophy had reduced protein amounts of beclin-1 and Bnip3. These findings indicate that defective activation of the autophagic machinery is pathogenic in some congenital muscular dystrophies.", + "TAG_DATA": [ + "81, Skeletal {'context': 'B-tissue/organ'}", + "82, muscles {'context': 'I-tissue/organ'}", + "84, collagen {'perturbing_action': 'B-gene loss-of-function'}", + "85, VI-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "86, (Col6a1(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "87, mice {'context': 'B-organism'}", + "89, impaired {'effect': 'B-negative'}", + "90, autophagic {'phenotype': 'B-autophagy'}", + "91, flux, {'phenotype': 'I-autophagy'}", + "111, Forced {'effect': 'B-positive'}", + "112, activation {'effect': 'B-positive'}", + "114, autophagy {'phenotype': 'B-autophagy'}", + "122, myofiber {'context': 'B-cells'}", + "130, Col6a1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "131, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "81, Skeletal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "82, muscles ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "84, collagen ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "85, VI-knockout ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "86, (Col6a1(-/-)) ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "87, mice ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "89, impaired ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "90, autophagic ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "91, flux, ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "111, Forced ['l36', 'l37', 'l38', 'l39', 'l40']", + "112, activation ['l36', 'l41', 'l42', 'l43', 'l44']", + "114, autophagy ['l37', 'l41', 'l45', 'l46', 'l47']", + "122, myofiber ['l38', 'l42', 'l45']", + "130, Col6a1(-/-) ['l39', 'l43', 'l46', 'l48']", + "131, mice. ['l40', 'l44', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "Skeletal", + "muscles" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "collagen", + "VI-knockout", + "(Col6a1(-/-))" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "Skeletal", + "muscles" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "Skeletal", + "muscles" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagic", + "flux," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "collagen", + "VI-knockout", + "(Col6a1(-/-))", + "Col6a1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "collagen", + "VI-knockout", + "(Col6a1(-/-))" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "collagen", + "VI-knockout", + "(Col6a1(-/-))", + "Col6a1(-/-)" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagic", + "flux,", + "autophagy" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagic", + "flux,", + "autophagy" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagic", + "flux," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Forced", + "activation" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Forced", + "activation" + ] + }, + "context": { + "val": "cells", + "words": [ + "myofiber" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Forced", + "activation" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Col6a1(-/-)" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Forced", + "activation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + }, + "context": { + "val": "cells", + "words": [ + "myofiber" + ] + } + } + ] + }, + { + "PMID": "20972434", + "TEXT": "Bitter taste receptors (TAS2Rs) on the tongue probably evolved to evoke signals for avoiding ingestion of plant toxins. We found expression of TAS2Rs on human airway smooth muscle (ASM) and considered these to be avoidance receptors for inhalants that, when activated, lead to ASM contraction and bronchospasm. TAS2R agonists such as saccharin, chloroquine and denatonium evoked increased intracellular calcium ([Ca²(+)](i)) in ASM in a Gβγ-, phospholipase Cβ (PLCβ)- and inositol trisphosphate (IP₃) receptor-dependent manner, which would be expected to evoke contraction. Paradoxically, bitter tastants caused relaxation of isolated ASM and dilation of airways that was threefold greater than that elicited by β-adrenergic receptor agonists. The relaxation induced by TAS2Rs is associated with a localized [Ca²(+)](i) response at the cell membrane, which opens large-conductance Ca²(+)-activated K(+) (BK(Ca)) channels, leading to ASM membrane hyperpolarization. Inhaled bitter tastants decreased airway obstruction in a mouse model of asthma. Given the need for efficacious bronchodilators for treating obstructive lung diseases, this pathway can be exploited for therapy with the thousands of known synthetic and naturally occurring bitter tastants.", + "TAG_DATA": [ + "47, TAS2R {'perturbing_action': 'B-pharmacological augmentation'}", + "48, agonists {'perturbing_action': 'I-pharmacological augmentation'}", + "61, ASM {'context': 'B-cells'}", + "88, ASM {'context': 'B-cells'}", + "92, airways {'context': 'B-tissue/organ'}", + "140, mouse {'context': 'B-organism'}", + "141, model {'context': 'I-organism'}", + "142, of {'context': 'I-organism'}", + "143, asthma. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "47, TAS2R ['l0', 'l1', 'l2']", + "48, agonists ['l0', 'l3', 'l4']", + "61, ASM ['l1', 'l3']", + "88, ASM ['l2', 'l4', 'l5']", + "92, airways ['l5']", + "140, mouse ['l6', 'l7', 'l8']", + "141, model ['l6', 'l9', 'l10']", + "142, of ['l7', 'l9', 'l11']", + "143, asthma. ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "TAS2R", + "agonists" + ] + }, + "context": { + "val": "cells", + "words": [ + "ASM" + ] + } + } + ] + }, + { + "PMID": "20948534", + "TEXT": "Despite substantial investment by the pharmaceutical industry over several decades, there has been little progress in developing new, efficacious and safe analgesics. As a result, many large pharmaceutical companies are leaving the area of pain medication. Nevertheless, the chances of success could increase if analgesic drug development strategy changed. To achieve such a paradigm shift we must understand why development of drugs for pain relief is so challenging.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20948532", + "TEXT": "Pain is a ubiquitous phenomenon, but the experience of pain varies considerably from person to person. Advances in understanding of the growing number of pathophysiologic mechanisms that underlie the generation of pain and the influence of the brain on the experience of pain led to the investigation of numerous compounds for treating pain. Improved knowledge of the subjective nature of pain, the variations in the measurement of pain, the mind-body placebo effect and the impact of differences in the conduct of a clinical trial on the outcome have changed approaches to design and implement studies. Careful consideration of how these concepts affect the choice of study population, the randomization and blinding process, the measurement and collection of data, and the analysis and interpretation of results should improve the quality of clinical trials for potential pain therapies.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20835248", + "TEXT": "We propose that a C-type lectin receptor, SIGNR-1 (also called Cd209b), helps to condition dendritic cells (DCs) in the gastrointestinal lamina propria (LPDCs) for the induction of oral tolerance in a model of food-induced anaphylaxis. Oral delivery of BSA bearing 51 molecules of mannoside (Man(51)-BSA) substantially reduced the BSA-induced anaphylactic response. Man(51)-BSA selectively targeted LPDCs that expressed SIGNR1 and induced the expression of interleukin-10 (IL-10), but not IL-6 or IL-12 p70. We found the same effects in IL-10-GFP knock-in (tiger) mice treated with Man(51)-BSA. The Man(51)-BSA-SIGNR1 axis in LPDCs, both in vitro and in vivo, promoted the generation of CD4(+) type 1 regulatory T (Tr1)-like cells that expressed IL-10 and interferon-γ (IFN-γ), in a SIGNR-1- and IL-10-dependent manner, but not of CD4(+)CD25(+)Foxp3(+) regulatory T cells. The Tr1-like cells could transfer tolerance. These results suggest that sugar-modified antigens might be used to induce oral tolerance by targeting SIGNR1 and LPDCs.", + "TAG_DATA": [ + "54, LPDCs {'context': 'B-cells'}", + "77, IL-10-GFP {'perturbing_action': 'B-rnai/knockdown'}", + "78, knock-in {'perturbing_action': 'I-rnai/knockdown'}", + "79, (tiger) {'perturbing_action': 'I-rnai/knockdown'}", + "80, mice {'context': 'B-organism'}", + "88, LPDCs, {'context': 'B-cells'}", + "90, in {'context': 'B-in vitro'}", + "91, vitro {'context': 'I-in vitro'}", + "93, in {'context': 'B-in vivo'}", + "94, vivo, {'context': 'I-in vivo'}", + "99, CD4(+) {'context': 'B-cells'}", + "100, type {'context': 'I-cells'}", + "101, 1 {'context': 'I-cells'}", + "102, regulatory {'context': 'I-cells'}", + "103, T {'context': 'I-cells'}", + "104, (Tr1)-like {'context': 'I-cells'}", + "105, cells {'context': 'I-cells'}", + "121, CD4(+)CD25(+)Foxp3(+) {'context': 'B-cells'}", + "122, regulatory {'context': 'I-cells'}", + "123, T {'context': 'I-cells'}", + "124, cells. {'context': 'I-cells'}", + "126, Tr1-like {'context': 'B-cells'}", + "127, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "77, IL-10-GFP ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "78, knock-in ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "79, (tiger) ['l1', 'l11', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "80, mice ['l2', 'l12', 'l23', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "88, LPDCs, ['l13', 'l24', 'l34', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "90, in ['l14', 'l25', 'l35', 'l44', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "91, vitro ['l3', 'l15', 'l26', 'l36', 'l45', 'l59', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "93, in ['l46', 'l60', 'l70', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "94, vivo, ['l47', 'l61', 'l71', 'l80', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "99, CD4(+) ['l4', 'l16', 'l27', 'l37', 'l48', 'l62', 'l72', 'l81', 'l92', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "100, type ['l5', 'l17', 'l28', 'l38', 'l49', 'l63', 'l73', 'l82', 'l93', 'l103', 'l109', 'l110', 'l111', 'l112', 'l113']", + "101, 1 ['l6', 'l18', 'l29', 'l39', 'l50', 'l64', 'l74', 'l83', 'l94', 'l104', 'l109', 'l114', 'l115', 'l116', 'l117']", + "102, regulatory ['l7', 'l19', 'l30', 'l40', 'l51', 'l65', 'l75', 'l84', 'l95', 'l105', 'l110', 'l114', 'l118', 'l119', 'l120']", + "103, T ['l8', 'l20', 'l31', 'l41', 'l52', 'l66', 'l76', 'l85', 'l96', 'l106', 'l111', 'l115', 'l118', 'l121', 'l122']", + "104, (Tr1)-like ['l9', 'l21', 'l32', 'l42', 'l53', 'l67', 'l77', 'l86', 'l97', 'l107', 'l112', 'l116', 'l119', 'l121', 'l123']", + "105, cells ['l10', 'l22', 'l33', 'l43', 'l54', 'l68', 'l78', 'l87', 'l98', 'l108', 'l113', 'l117', 'l120', 'l122', 'l123']", + "121, CD4(+)CD25(+)Foxp3(+) ['l55', 'l88', 'l99', 'l124', 'l125', 'l126', 'l127', 'l128']", + "122, regulatory ['l56', 'l89', 'l100', 'l124', 'l129', 'l130', 'l131', 'l132']", + "123, T ['l57', 'l69', 'l79', 'l90', 'l101', 'l125', 'l129', 'l133', 'l134', 'l135']", + "124, cells. ['l58', 'l91', 'l102', 'l126', 'l130', 'l133', 'l136']", + "126, Tr1-like ['l127', 'l131', 'l134', 'l137']", + "127, cells ['l128', 'l132', 'l135', 'l136', 'l137']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "IL-10-GFP", + "knock-in", + "(tiger)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "IL-10-GFP", + "knock-in", + "(tiger)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "vitro", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "IL-10-GFP", + "knock-in", + "(tiger)" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "type", + "1", + "regulatory", + "T", + "(Tr1)-like", + "cells", + "LPDCs," + ] + } + } + ] + }, + { + "PMID": "20802500", + "TEXT": "Neutrophils have key roles in modulating the immune response. We present a robust methodology for rapidly isolating neutrophils directly from whole blood with 'on-chip' processing for mRNA and protein isolation for genomics and proteomics. We validate this device with an ex vivo stimulation experiment and by comparison with standard bulk isolation methodologies. Last, we implement this tool as part of a near-patient blood processing system within a multi-center clinical study of the immune response to severe trauma and burn injury. The preliminary results from a small cohort of subjects in our study and healthy controls show a unique time-dependent gene expression pattern clearly demonstrating the ability of this tool to discriminate temporal transcriptional events of neutrophils within a clinical setting.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20802498", + "TEXT": "By comparing HIV-1 variants from people who became infected at the beginning of the epidemic and from people who have recently contracted the virus, we observed an enhanced resistance of the virus to antibody neutralization over time, accompanied by an increase in the length of the variable loops and in the number of potential N-linked glycosylation sites on the HIV-1 envelope gp120 subunit. The enhanced neutralization resistance of HIV-1 in contemporary seroconverters coincided with the poorer elicitation of neutralizing antibody responses, which may have implications for vaccine design.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20639890", + "TEXT": "Improved techniques to noninvasively image protein-protein interactions (PPIs) are essential. We molecularly engineered a positron emission tomography (PET)-based split reporter (herpes simplex virus type 1 thymidine kinase), cleaved between Thr265 and Ala266, and used this in a protein-fragment complementation assay (PCA) to quantify PPIs in mammalian cells and to microPET image them in living mice. An introduced point mutation (V119C) markedly enhanced thymidine kinase complementation in PCAs, on the basis of rapamycin modulation of FKBP12-rapamycin-binding domain (FRB) and FKBP12 (FK506 binding protein), the interaction of hypoxia-inducible factor-1alpha with the von Hippel-Lindau tumor suppressor, and in an estrogen receptor intramolecular protein folding assay. Applications of this unique split thymidine kinase are potentially far reaching, including, for example, considerably more accurate monitoring of immune and stem cell therapies, allowing for fully quantitative and tomographic PET localization of PPIs in preclinical small- and large-animal models of disease.", + "TAG_DATA": [ + "45, mammalian {'context': 'B-cells'}", + "46, cells {'context': 'I-cells'}", + "53, living {'context': 'B-organism'}", + "54, mice. {'context': 'I-organism'}", + "57, point {'perturbing_action': 'I-other'}", + "58, mutation {'perturbing_action': 'I-other'}", + "59, (V119C) {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "45, mammalian ['l0']", + "46, cells ['l0']", + "53, living ['l1']", + "54, mice. ['l1']", + "57, point ['l2', 'l3']", + "58, mutation ['l2', 'l4']", + "59, (V119C) ['l3', 'l4']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20616797", + "TEXT": "RNA-binding proteins of the Musashi (Msi) family are expressed in stem cell compartments and in aggressive tumors, but they have not yet been widely explored in the blood. Here we demonstrate that Msi2 is the predominant form expressed in hematopoietic stem cells (HSCs), and its knockdown leads to reduced engraftment and depletion of HSCs in vivo. Overexpression of human MSI2 in a mouse model increases HSC cell cycle progression and cooperates with the chronic myeloid leukemia-associated BCR-ABL1 oncoprotein to induce an aggressive leukemia. MSI2 is overexpressed in human myeloid leukemia cell lines, and its depletion leads to decreased proliferation and increased apoptosis. Expression levels in human myeloid leukemia directly correlate with decreased survival in patients with the disease, thereby defining MSI2 expression as a new prognostic marker and as a new target for therapy in acute myeloid leukemia (AML).", + "TAG_DATA": [ + "53, HSCs {'context': 'B-cells'}", + "54, in {'context': 'B-in vivo'}", + "55, vivo. {'context': 'I-in vivo'}", + "56, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "57, of {'perturbing_action': 'I-gene gain-of-function'}", + "58, human {'perturbing_action': 'I-gene gain-of-function'}", + "59, MSI2 {'perturbing_action': 'I-gene gain-of-function'}", + "62, mouse {'context': 'B-organism'}", + "63, model {'context': 'I-organism'}", + "65, HSC {'context': 'B-cells'}", + "82, leukemia. {'context': 'B-neoplasm'}", + "87, human {'context': 'B-transformed cells'}", + "88, myeloid {'context': 'I-transformed cells'}", + "89, leukemia {'context': 'I-transformed cells'}", + "90, cell {'context': 'I-transformed cells'}", + "91, lines, {'context': 'I-transformed cells'}", + "97, decreased {'effect': 'B-negative'}", + "98, proliferation {'phenotype': 'B-proliferation'}", + "100, increased {'effect': 'B-positive'}", + "101, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "53, HSCs ['l0', 'l1']", + "54, in ['l0', 'l2']", + "55, vivo. ['l1', 'l2']", + "56, Overexpression ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "57, of ['l3', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "58, human ['l4', 'l18', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "59, MSI2 ['l5', 'l19', 'l31', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "62, mouse ['l6', 'l20', 'l32', 'l41', 'l50', 'l51', 'l52', 'l53', 'l54']", + "63, model ['l7', 'l21', 'l33', 'l42', 'l50', 'l55', 'l56']", + "65, HSC ['l8', 'l22', 'l34', 'l43', 'l51', 'l55', 'l57']", + "82, leukemia. ['l9', 'l23', 'l35', 'l44', 'l52', 'l56', 'l57', 'l58', 'l59', 'l60']", + "87, human ['l10', 'l24', 'l36', 'l45', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "88, myeloid ['l11', 'l25', 'l37', 'l46', 'l61', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "89, leukemia ['l12', 'l26', 'l38', 'l47', 'l58', 'l62', 'l69', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "90, cell ['l13', 'l27', 'l39', 'l48', 'l53', 'l59', 'l63', 'l70', 'l76', 'l82', 'l83', 'l84', 'l85', 'l86']", + "91, lines, ['l14', 'l28', 'l40', 'l49', 'l54', 'l60', 'l64', 'l71', 'l77', 'l82', 'l87', 'l88', 'l89', 'l90']", + "97, decreased ['l15', 'l29', 'l65', 'l72', 'l78', 'l83', 'l87', 'l91', 'l92', 'l93']", + "98, proliferation ['l16', 'l66', 'l73', 'l79', 'l84', 'l88', 'l91', 'l94', 'l95']", + "100, increased ['l17', 'l30', 'l67', 'l74', 'l80', 'l85', 'l89', 'l92', 'l94', 'l96']", + "101, apoptosis. ['l68', 'l75', 'l81', 'l86', 'l90', 'l93', 'l95', 'l96']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "human", + "MSI2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "human", + "MSI2" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "human", + "MSI2" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "human", + "MSI2" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "myeloid", + "leukemia", + "cell", + "lines," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "myeloid", + "leukemia", + "cell", + "lines," + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "myeloid", + "leukemia", + "cell", + "lines," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "myeloid", + "leukemia", + "cell", + "lines," + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "myeloid", + "leukemia", + "cell", + "lines," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "20613748", + "TEXT": "Chromosomal translocations can promote cancers by eliciting the expression of fusion genes with oncogenic activity. The identification of translocations affecting RAF genes in prostate and gastric cancers and melanoma provides compelling evidence for the key role of RAF signaling in a subset of these cancers and suggests possible new avenues for personalized cancer therapy.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20581837", + "TEXT": "During pregnancy, the energy requirements of the fetus impose changes in maternal metabolism. Increasing insulin resistance in the mother maintains nutrient flow to the growing fetus, whereas prolactin and placental lactogen counterbalance this resistance and prevent maternal hyperglycemia by driving expansion of the maternal population of insulin-producing beta cells. However, the exact mechanisms by which the lactogenic hormones drive beta cell expansion remain uncertain. Here we show that serotonin acts downstream of lactogen signaling to stimulate beta cell proliferation. Expression of serotonin synthetic enzyme tryptophan hydroxylase-1 (Tph1) and serotonin production rose sharply in beta cells during pregnancy or after treatment with lactogens in vitro. Inhibition of serotonin synthesis by dietary tryptophan restriction or Tph inhibition blocked beta cell expansion and induced glucose intolerance in pregnant mice without affecting insulin sensitivity. Expression of the G alpha(q)-linked serotonin receptor 5-hydroxytryptamine receptor-2b (Htr2b) in maternal islets increased during pregnancy and normalized just before parturition, whereas expression of the G alpha(i)-linked receptor Htr1d increased at the end of pregnancy and postpartum. Blocking Htr2b signaling in pregnant mice also blocked beta cell expansion and caused glucose intolerance. These studies reveal an integrated signaling pathway linking beta cell mass to anticipated insulin need during pregnancy. Modulators of this pathway, including medications and diet, may affect the risk of gestational diabetes.", + "TAG_DATA": [ + "102, in {'context': 'B-in vitro'}", + "103, vitro. {'context': 'I-in vitro'}", + "113, Tph {'perturbing_action': 'B-pharmacological inhibition'}", + "114, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "116, beta {'context': 'B-cells'}", + "117, cell {'context': 'I-cells'}", + "124, pregnant {'context': 'B-organism'}", + "125, mice {'context': 'I-organism'}", + "141, maternal {'context': 'B-cells'}", + "142, islets {'context': 'I-cells'}", + "171, pregnant {'context': 'B-organism'}", + "172, mice {'context': 'I-organism'}", + "175, beta {'context': 'B-cells'}", + "176, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "102, in ['l0', 'l1']", + "103, vitro. ['l0', 'l2']", + "113, Tph ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "114, inhibition ['l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "116, beta ['l4', 'l10', 'l16', 'l17', 'l18']", + "117, cell ['l1', 'l2', 'l5', 'l11', 'l16', 'l19', 'l20']", + "124, pregnant ['l6', 'l12', 'l17', 'l19', 'l21', 'l22', 'l23']", + "125, mice ['l7', 'l13', 'l18', 'l20', 'l21']", + "141, maternal ['l8', 'l14', 'l22', 'l24']", + "142, islets ['l9', 'l15', 'l23', 'l24']", + "171, pregnant ['l25', 'l26', 'l27']", + "172, mice ['l25', 'l28', 'l29']", + "175, beta ['l26', 'l28', 'l30']", + "176, cell ['l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Tph", + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "beta", + "cell", + "maternal", + "islets" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Tph", + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "pregnant", + "mice" + ] + } + } + ] + }, + { + "PMID": "20543851", + "TEXT": "Orthotopic liver transplantation is the only available treatment for severe liver failure, but it is currently limited by organ shortage. One technical challenge that has thus far limited the development of a tissue-engineered liver graft is oxygen and nutrient transport. Here we demonstrate a novel approach to generate transplantable liver grafts using decellularized liver matrix. The decellularization process preserves the structural and functional characteristics of the native microvascular network, allowing efficient recellularization of the liver matrix with adult hepatocytes and subsequent perfusion for in vitro culture. The recellularized graft supports liver-specific function including albumin secretion, urea synthesis and cytochrome P450 expression at comparable levels to normal liver in vitro. The recellularized liver grafts can be transplanted into rats, supporting hepatocyte survival and function with minimal ischemic damage. These results provide a proof of principle for the generation of a transplantable liver graft as a potential treatment for liver disease.", + "TAG_DATA": [ + "77, adult {'context': 'B-cells'}", + "78, hepatocytes {'context': 'I-cells'}", + "83, in {'context': 'B-in vitro'}", + "84, vitro {'context': 'I-in vitro'}", + "85, culture. {'context': 'I-in vitro'}", + "88, graft {'context': 'B-tissue/organ'}", + "107, in {'context': 'B-in vitro'}", + "108, vitro. {'context': 'I-in vitro'}", + "111, liver {'context': 'B-tissue/organ'}", + "112, grafts {'context': 'I-xenograft'}", + "117, rats, {'context': 'B-organism'}", + "119, hepatocyte {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "77, adult ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "78, hepatocytes ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "83, in ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "84, vitro ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "85, culture. ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "88, graft ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "107, in ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "108, vitro. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "111, liver ['l28', 'l29', 'l30']", + "112, grafts ['l28', 'l31', 'l32']", + "117, rats, ['l29', 'l31', 'l33']", + "119, hepatocyte ['l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20526311", + "TEXT": "Cancer clinical trials in the US are at a major crossroads. Current government-sponsored research is some of the best in the world, but the field shares a worrying number of similarities with the American auto industry in its heyday. For clinical research to survive, the field must transform itself now to prevent a similar decline.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20526310", + "TEXT": "The notoriously drug-resistant bug MRSA has made headlines for years, but a whole other class of bacteria may prove even more troublesome. These microbes, Gram-negative bacteria, are increasingly a threat--and yet not a single late-stage drug in development specifically targets them. Christian Torres follows one man's quest to get the antibacterial pipeline flowing once again.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20526309", + "TEXT": "Each cell in the body possesses hundreds to thousands of mitochondria, known as 'powerhouses' for the energy they provide. But gene mutations can cause these important organelles to fail, often resulting in devastating disease. Erica Westly reports on the patient advocates--and politicians--pushing for new treatments for mitochondrial disease.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20495571", + "TEXT": "Here we present methods to longitudinally track islet allograft-infiltrating T cells in live mice by endoscopic confocal microscopy and to analyze circulating T cells by in vivo flow cytometry. We developed a new reporter mouse whose T cell subsets express distinct, 'color-coded' proteins enabling in vivo detection and identification of effector T cells (T(eff) cells) and discrimination between natural and induced regulatory T cells (nT(reg) and iT(reg) cells). Using these tools, we observed marked differences in the T cell response in recipients receiving tolerance-inducing therapy (CD154-specific monoclonal antibody plus rapamycin) compared to untreated controls. These results establish real-time cell tracking as a powerful means to probe the dynamic cellular interplay mediating immunologic rejection or transplant tolerance.", + "TAG_DATA": [ + "77, T {'context': 'B-cells'}", + "78, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "77, T ['l0', 'l1']", + "78, cell ['l0', 'l2']", + "81, recipients ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20473307", + "TEXT": "A key step in gene therapy is the efficient transfer of genes in a cell type- and tissue-specific manner. To better understand the mechanism of adeno-associated virus serotype 6 (AAV6) transduction, we used comparative gene analysis (CGA) combined with pathway visualization software to identify a positive correlation between AAV6 transduction and epidermal growth factor receptor (EGFR) expression. Subsequent experiments suggested that EGFR is necessary for vector internalization and probably functions as a co-receptor for AAV6.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20436485", + "TEXT": "Mammalian genomes contain many repetitive elements, including long terminal repeats (LTRs), which have long been suspected to have a role in tumorigenesis. Here we present evidence that aberrant LTR activation contributes to lineage-inappropriate gene expression in transformed human cells and that such gene expression is central for tumor cell survival. We show that B cell-derived Hodgkin's lymphoma cells depend on the activity of the non-B, myeloid-specific proto-oncogene colony-stimulating factor 1 receptor (CSF1R). In these cells, CSF1R transcription initiates at an aberrantly activated endogenous LTR of the MaLR family (THE1B). Derepression of the THE1 subfamily of MaLR LTRs is widespread in the genome of Hodgkin's lymphoma cells and is associated with impaired epigenetic control due to loss of expression of the corepressor CBFA2T3. Furthermore, we detect LTR-driven CSF1R transcripts in anaplastic large cell lymphoma, in which CSF1R is known to be expressed aberrantly. We conclude that LTR derepression is involved in the pathogenesis of human lymphomas, a finding that might have diagnostic, prognostic and therapeutic implications.", + "TAG_DATA": [ + "53, B {'context': 'B-transformed cells'}", + "54, cell-derived {'context': 'I-transformed cells'}", + "55, Hodgkin's {'context': 'I-transformed cells'}", + "56, lymphoma {'context': 'I-transformed cells'}", + "57, cells {'context': 'I-transformed cells'}", + "132, lymphoma, {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "53, B ['l0', 'l1', 'l2', 'l3']", + "54, cell-derived ['l0', 'l4', 'l5', 'l6']", + "55, Hodgkin's ['l1', 'l4', 'l7', 'l8']", + "56, lymphoma ['l2', 'l5', 'l7', 'l9']", + "57, cells ['l3', 'l6', 'l8', 'l9']", + "130, large ['l10', 'l11']", + "131, cell ['l10', 'l12']", + "132, lymphoma, ['l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20418887", + "TEXT": "Obsessive-compulsive disorder (OCD) is a common psychiatric disorder defined by the presence of obsessive thoughts and repetitive compulsive actions, and it often encompasses anxiety and depressive symptoms. Recently, the corticostriatal circuitry has been implicated in the pathogenesis of OCD. However, the etiology, pathophysiology and molecular basis of OCD remain unknown. Several studies indicate that the pathogenesis of OCD has a genetic component. Here we demonstrate that loss of a neuron-specific transmembrane protein, SLIT and NTRK-like protein-5 (Slitrk5), leads to OCD-like behaviors in mice, which manifests as excessive self-grooming and increased anxiety-like behaviors, and is alleviated by the selective serotonin reuptake inhibitor fluoxetine. Slitrk5(-/-) mice show selective overactivation of the orbitofrontal cortex, abnormalities in striatal anatomy and cell morphology and alterations in glutamate receptor composition, which contribute to deficient corticostriatal neurotransmission. Thus, our studies identify Slitrk5 as an essential molecule at corticostriatal synapses and provide a new mouse model of OCD-like behaviors.", + "TAG_DATA": [ + "66, loss {'perturbing_action': 'B-gene loss-of-function'}", + "67, of {'perturbing_action': 'I-gene loss-of-function'}", + "68, a {'perturbing_action': 'I-gene loss-of-function'}", + "69, neuron-specific {'perturbing_action': 'I-gene loss-of-function'}", + "70, transmembrane {'perturbing_action': 'I-gene loss-of-function'}", + "71, protein, {'perturbing_action': 'I-gene loss-of-function'}", + "72, SLIT {'perturbing_action': 'I-gene loss-of-function'}", + "73, and {'perturbing_action': 'I-gene loss-of-function'}", + "74, NTRK-like {'perturbing_action': 'I-gene loss-of-function'}", + "75, protein-5 {'perturbing_action': 'I-gene loss-of-function'}", + "76, (Slitrk5), {'perturbing_action': 'I-gene loss-of-function'}", + "82, mice, {'context': 'B-organism'}", + "102, Slitrk5(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "103, mice {'context': 'B-organism'}", + "109, orbitofrontal {'context': 'B-tissue/organ'}", + "110, cortex, {'context': 'I-tissue/organ'}", + "116, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "66, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "67, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "68, a ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "69, neuron-specific ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "70, transmembrane ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "71, protein, ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "72, SLIT ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "73, and ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "74, NTRK-like ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "75, protein-5 ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "76, (Slitrk5), ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "82, mice, ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "102, Slitrk5(-/-) ['l66', 'l67', 'l68', 'l69']", + "103, mice ['l66', 'l70', 'l71', 'l72']", + "109, orbitofrontal ['l67', 'l70', 'l73', 'l74']", + "110, cortex, ['l68', 'l71', 'l73', 'l75']", + "116, cell ['l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "a", + "neuron-specific", + "transmembrane", + "protein,", + "SLIT", + "and", + "NTRK-like", + "protein-5", + "(Slitrk5),", + "Slitrk5(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Slitrk5(-/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "orbitofrontal", + "cortex," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Slitrk5(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + } + ] + }, + { + "PMID": "20418885", + "TEXT": "Fibrogenesis is a pathological wound repair process that fails to cease, even when the initial insult has been removed. Fibroblasts are principal mediators of fibrosis, and fibroblasts from fibrotic tissues fail to return to their quiescent stage, including when cultured in vitro. In a search for underlying molecular mechanisms, we hypothesized that this perpetuation of fibrogenesis is caused by epigenetic modifications. We demonstrate here that hypermethylation of RASAL1, encoding an inhibitor of the Ras oncoprotein, is associated with the perpetuation of fibroblast activation and fibrogenesis in the kidney. RASAL1 hypermethylation is mediated by the methyltransferase Dnmt1 in renal fibrogenesis, and kidney fibrosis is ameliorated in Dnmt1(+/-) heterozygous mice. These studies demonstrate that epigenetic modifications may provide a molecular basis for perpetuated fibroblast activation and fibrogenesis in the kidney.", + "TAG_DATA": [ + "100, kidney {'context': 'B-tissue/organ'}", + "105, Dnmt1(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "106, heterozygous {'perturbing_action': 'I-gene loss-of-function'}", + "107, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "105, Dnmt1(+/-) ['l0', 'l1']", + "106, heterozygous ['l0', 'l2']", + "107, mice. ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dnmt1(+/-)", + "heterozygous" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "20376052", + "TEXT": "Atherosclerosis and related cardiovascular diseases represent one of the greatest threats to human health worldwide. Despite important progress in prevention and treatment, these conditions still account for one third of all deaths annually. Often presented together with obesity, insulin resistance and type 2 diabetes, these chronic diseases are strongly influenced by pathways that lie at the interface of chronic inflammation and nutrient metabolism. Here I discuss recent advances in the study of endoplasmic reticulum stress as one mechanism that links immune response with nutrient sensing in the pathogenesis of atherosclerosis and its complications.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20376036", + "TEXT": "Counterfeit drugs are a menacing and deadly problem worldwide. The proliferation of fake drugs is astounding, with over 100 countries reporting incidents of fake drugs, according to a 2008 report from the Pharmaceutical Security Institute. And incidents of drug counterfeiting show no evidence of declining: some industry insiders suggest that the number of counterfeit medicines on the market has increased as much as 25% each year over the past several years.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20364125", + "TEXT": "Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder characterized by vascular malformations. Many affected individuals develop recurrent nosebleeds, which can severely affect their quality of life and are clinically difficult to treat. We report here that treatment with thalidomide reduced the severity and frequency of nosebleeds (epistaxis) in the majority of a small group of subjects with HHT tested. The blood hemoglobin levels of the treated individuals rose as a result of reduced hemorrhage and enhanced blood vessel stabilization. In mice heterozygous for a null mutation in the Eng gene (encoding endoglin), an experimental model of HHT, thalidomide treatment stimulated mural cell coverage and thus rescued vessel wall defects. Thalidomide treatment increased platelet-derived growth factor-B (PDGF-B) expression in endothelial cells and stimulated mural cell activation. The effects of thalidomide treatment were partially reversed by pharmacological or genetic interference with PDGF signaling from endothelial cells to pericytes. Biopsies of nasal epithelium from individuals with HHT treated or not with thalidomide showed that similar mechanisms may explain the effects of thalidomide treatment in humans. Our findings demonstrate the ability of thalidomide to induce vessel maturation, which may be useful as a therapeutic strategy for the treatment of vascular malformations.", + "TAG_DATA": [ + "80, mice {'context': 'B-organism'}", + "81, heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "82, for {'perturbing_action': 'I-gene loss-of-function'}", + "83, a {'perturbing_action': 'I-gene loss-of-function'}", + "84, null {'perturbing_action': 'I-gene loss-of-function'}", + "85, mutation {'perturbing_action': 'I-gene loss-of-function'}", + "86, in {'perturbing_action': 'I-gene loss-of-function'}", + "87, the {'perturbing_action': 'I-gene loss-of-function'}", + "88, Eng {'perturbing_action': 'I-gene loss-of-function'}", + "89, gene {'perturbing_action': 'I-gene loss-of-function'}", + "90, (encoding {'perturbing_action': 'I-gene loss-of-function'}", + "91, endoglin), {'perturbing_action': 'I-gene loss-of-function'}", + "100, mural {'context': 'B-cells'}", + "101, cell {'context': 'I-cells'}", + "118, endothelial {'context': 'B-cells'}", + "119, cells {'context': 'I-cells'}", + "122, mural {'context': 'B-cells'}", + "123, cell {'context': 'I-cells'}", + "142, endothelial {'context': 'B-cells'}", + "143, cells {'context': 'I-cells'}", + "145, pericytes. {'context': 'B-cells'}", + "148, nasal {'context': 'B-tissue/organ'}", + "149, epithelium {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "80, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "81, heterozygous ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "82, for ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "83, a ['l2', 'l14', 'l25', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "84, null ['l3', 'l15', 'l26', 'l37', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "85, mutation ['l4', 'l16', 'l27', 'l38', 'l48', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "86, in ['l5', 'l17', 'l28', 'l39', 'l49', 'l58', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "87, the ['l6', 'l18', 'l29', 'l40', 'l50', 'l59', 'l67', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "88, Eng ['l7', 'l19', 'l30', 'l41', 'l51', 'l60', 'l68', 'l75', 'l82', 'l83', 'l84', 'l85', 'l86']", + "89, gene ['l8', 'l20', 'l31', 'l42', 'l52', 'l61', 'l69', 'l76', 'l82', 'l87', 'l88', 'l89', 'l90']", + "90, (encoding ['l9', 'l21', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l83', 'l87', 'l91', 'l92', 'l93', 'l94']", + "91, endoglin), ['l10', 'l22', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l88', 'l91', 'l95', 'l96']", + "100, mural ['l11', 'l23', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l89', 'l92', 'l95', 'l97']", + "101, cell ['l12', 'l24', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l90', 'l93', 'l96', 'l97']", + "118, endothelial ['l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "119, cells ['l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l94', 'l98', 'l104', 'l105', 'l106', 'l107']", + "122, mural ['l99', 'l104', 'l108', 'l109', 'l110', 'l111']", + "123, cell ['l100', 'l105', 'l108', 'l112', 'l113']", + "142, endothelial ['l101', 'l106', 'l109', 'l112', 'l114', 'l115', 'l116', 'l117']", + "143, cells ['l102', 'l107', 'l110', 'l113', 'l114', 'l118', 'l119', 'l120']", + "145, pericytes. ['l103', 'l111', 'l115', 'l118', 'l121', 'l122']", + "148, nasal ['l116', 'l119', 'l121', 'l123']", + "149, epithelium ['l117', 'l120', 'l122', 'l123']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "heterozygous", + "for", + "a", + "null", + "mutation", + "in", + "the", + "Eng", + "gene", + "(encoding", + "endoglin)," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "heterozygous", + "for", + "a", + "null", + "mutation", + "in", + "the", + "Eng", + "gene", + "(encoding", + "endoglin)," + ] + }, + "context": { + "val": "cells", + "words": [ + "mural", + "cell", + "cells" + ] + } + } + ] + }, + { + "PMID": "20348926", + "TEXT": "Despite the fact that X-box binding protein-1 (XBP-1) is one of the main regulators of the unfolded protein response (UPR), the modulators of XBP-1 are poorly understood. Here, we show that the regulatory subunits of phosphotidyl inositol 3-kinase (PI3K), p85alpha (encoded by Pik3r1) and p85beta (encoded by Pik3r2) form heterodimers that are disrupted by insulin treatment. This disruption of heterodimerization allows the resulting monomers of p85 to interact with, and increase the nuclear translocation of, the spliced form of XBP-1 (XBP-1s). The interaction between p85 and XBP-1s is lost in ob/ob mice, resulting in a severe defect in XBP-1s translocation to the nucleus and thus in the resolution of endoplasmic reticulum (ER) stress. These defects are ameliorated when p85alpha and p85beta are overexpressed in the liver of ob/ob mice. Our results define a previously unknown insulin receptor signaling pathway and provide new mechanistic insight into the development of ER stress during obesity.", + "TAG_DATA": [ + "90, ob/ob {'perturbing_action': 'B-gene loss-of-function', 'context': 'B-organism'}", + "91, mice, {'context': 'I-organism'}", + "118, p85alpha {'perturbing_action': 'B-gene gain-of-function'}", + "119, and {'perturbing_action': 'I-gene gain-of-function'}", + "120, p85beta {'perturbing_action': 'I-gene gain-of-function'}", + "121, are {'perturbing_action': 'I-gene gain-of-function'}", + "122, overexpressed {'perturbing_action': 'I-gene gain-of-function'}", + "125, liver {'context': 'B-tissue/organ'}", + "127, ob/ob {'context': 'B-organism'}", + "128, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "90, ob/ob ['l0']", + "91, mice, ['l0']", + "118, p85alpha ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "119, and ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "120, p85beta ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "121, are ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "122, overexpressed ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "125, liver ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "127, ob/ob ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "128, mice. ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ob/ob" + ] + }, + "context": { + "val": "organism", + "words": [ + "ob/ob" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "p85alpha", + "and", + "p85beta", + "are", + "overexpressed" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "p85alpha", + "and", + "p85beta", + "are", + "overexpressed" + ] + }, + "context": { + "val": "organism", + "words": [ + "ob/ob", + "mice." + ] + } + } + ] + }, + { + "PMID": "20348923", + "TEXT": "Class Ia phosphoinositide 3-kinase (PI3K), an essential mediator of the metabolic actions of insulin, is composed of a catalytic (p110alpha or p110beta) and regulatory (p85alphaalpha, p85betaalpha or p55alpha) subunit. Here we show that p85alphaalpha interacts with X-box-binding protein-1 (XBP-1), a transcriptional mediator of the unfolded protein response (UPR), in an endoplasmic reticulum (ER) stress-dependent manner. Cell lines with knockout or knockdown of p85alphaalpha show marked alterations in the UPR, including reduced ER stress-dependent accumulation of nuclear XBP-1, decreased induction of UPR target genes and increased rates of apoptosis. This is associated with a decreased activation of inositol-requiring protein-1alpha (IRE1alpha) and activating transcription factor-6alphaalpha (ATF6alpha). Mice with deletion of p85alpha in liver (L-Pik3r1(-/-)) show a similar attenuated UPR after tunicamycin administration, leading to an increased inflammatory response. Thus, p85alphaalpha forms a previously unrecognized link between the PI3K pathway, which is central to insulin action, and the regulation of the cellular response to ER stress, a state that when unresolved leads to insulin resistance.", + "TAG_DATA": [ + "55, Cell {'context': 'B-cells'}", + "56, lines {'context': 'I-cells'}", + "60, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "61, of {'perturbing_action': 'I-rnai/knockdown'}", + "62, p85alphaalpha {'perturbing_action': 'I-rnai/knockdown'}", + "84, increased {'effect': 'B-positive'}", + "85, rates {'effect': 'I-positive'}", + "87, apoptosis. {'phenotype': 'B-apoptosis'}", + "104, Mice {'context': 'B-organism'}", + "106, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "107, of {'perturbing_action': 'I-gene loss-of-function'}", + "108, p85alpha {'perturbing_action': 'I-gene loss-of-function'}", + "110, liver {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "55, Cell ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "56, lines ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "60, knockdown ['l11', 'l12', 'l13', 'l14', 'l15']", + "61, of ['l1', 'l6', 'l11', 'l16', 'l17', 'l18', 'l19']", + "62, p85alphaalpha ['l2', 'l7', 'l12', 'l16', 'l20', 'l21', 'l22']", + "84, increased ['l3', 'l8', 'l13', 'l17', 'l20', 'l23', 'l24']", + "85, rates ['l4', 'l9', 'l14', 'l18', 'l21', 'l23', 'l25']", + "87, apoptosis. ['l5', 'l10', 'l15', 'l19', 'l22', 'l24', 'l25']", + "104, Mice ['l26', 'l27', 'l28', 'l29']", + "106, deletion ['l26', 'l30', 'l31', 'l32']", + "107, of ['l27', 'l30', 'l33', 'l34']", + "108, p85alpha ['l28', 'l31', 'l33', 'l35']", + "110, liver ['l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Cell", + "lines" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "p85alphaalpha" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Cell", + "lines" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "rates" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Cell", + "lines" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "p85alphaalpha" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "rates" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "p85alphaalpha" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased", + "rates" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "p85alpha" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "p85alpha" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "20305662", + "TEXT": "Hematopoietic stem cell (HSC) self-renewal is regulated by both intrinsic and extrinsic signals. Although some of the pathways that regulate HSC self-renewal have been uncovered, it remains largely unknown whether these pathways can be triggered by deliverable growth factors to induce HSC growth or regeneration. Here we show that pleiotrophin, a neurite outgrowth factor with no known function in hematopoiesis, efficiently promotes HSC expansion in vitro and HSC regeneration in vivo. Treatment of mouse bone marrow HSCs with pleiotrophin caused a marked increase in long-term repopulating HSC numbers in culture, as measured in competitive repopulating assays. Treatment of human cord blood CD34(+)CDCD38(-)Lin(-) cells with pleiotrophin also substantially increased severe combined immunodeficient (SCID)-repopulating cell counts in culture, compared to input and cytokine-treated cultures. Systemic administration of pleiotrophin to irradiated mice caused a pronounced expansion of bone marrow stem and progenitor cells in vivo, indicating that pleiotrophin is a regenerative growth factor for HSCs. Mechanistically, pleiotrophin activated phosphoinositide 3-kinase (PI3K) signaling in HSCs; antagonism of PI3K or Notch signaling inhibited pleiotrophin-mediated expansion of HSCs in culture. We identify the secreted growth factor pleiotrophin as a new regulator of both HSC expansion and regeneration.", + "TAG_DATA": [ + "62, HSC {'context': 'B-cells'}", + "64, in {'context': 'B-in vitro'}", + "65, vitro {'context': 'I-in vitro'}", + "67, HSC {'context': 'B-cells'}", + "69, in {'context': 'B-in vivo'}", + "70, vivo. {'context': 'I-in vivo'}", + "73, mouse {'context': 'B-cells'}", + "74, bone {'context': 'I-cells'}", + "75, marrow {'context': 'I-cells'}", + "76, HSCs {'context': 'I-cells'}", + "86, HSC {'context': 'B-cells'}", + "89, culture, {'context': 'I-in vitro'}", + "98, human {'context': 'B-cells'}", + "99, cord {'context': 'I-cells'}", + "100, blood {'context': 'I-cells'}", + "101, CD34(+)CDCD38(-)Lin(-) {'context': 'I-cells'}", + "102, cells {'context': 'I-cells'}", + "115, culture, {'context': 'I-in vitro'}", + "121, cultures. {'context': 'B-cells'}", + "128, mice {'context': 'B-organism'}", + "134, bone {'context': 'B-cells'}", + "135, marrow {'context': 'I-cells'}", + "136, stem {'context': 'I-cells'}", + "137, and {'context': 'I-cells'}", + "138, progenitor {'context': 'I-cells'}", + "139, cells {'context': 'I-cells'}", + "140, in {'context': 'B-in vivo'}", + "141, vivo, {'context': 'I-in vivo'}", + "171, HSCs {'context': 'B-cells'}", + "172, in {'context': 'B-in vitro'}", + "173, culture. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "62, HSC ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "64, in ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "65, vitro ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "67, HSC ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "69, in ['l3', 'l10', 'l16', 'l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "70, vivo. ['l4', 'l11', 'l17', 'l22', 'l29', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "73, mouse ['l23', 'l30', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "74, bone ['l24', 'l31', 'l37', 'l42', 'l47', 'l48', 'l49', 'l50']", + "75, marrow ['l25', 'l32', 'l38', 'l43', 'l47', 'l51', 'l52', 'l53']", + "76, HSCs ['l5', 'l12', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l54', 'l55']", + "86, HSC ['l6', 'l13', 'l19', 'l27', 'l34', 'l40', 'l45', 'l49', 'l52', 'l54', 'l56']", + "89, culture, ['l7', 'l14', 'l20', 'l28', 'l35', 'l41', 'l46', 'l50', 'l53', 'l55', 'l56']", + "98, human ['l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "99, cord ['l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "100, blood ['l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "101, CD34(+)CDCD38(-)Lin(-) ['l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "102, cells ['l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "115, culture, ['l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "121, cultures. ['l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "128, mice ['l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "134, bone ['l78', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "135, marrow ['l79', 'l87', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "136, stem ['l80', 'l88', 'l95', 'l101', 'l102', 'l103', 'l104', 'l105']", + "137, and ['l81', 'l89', 'l96', 'l101', 'l106', 'l107', 'l108', 'l109']", + "138, progenitor ['l82', 'l90', 'l97', 'l102', 'l106', 'l110', 'l111', 'l112', 'l113']", + "139, cells ['l83', 'l91', 'l98', 'l103', 'l107', 'l110', 'l114', 'l115']", + "140, in ['l84', 'l92', 'l99', 'l104', 'l108', 'l111', 'l114', 'l116', 'l117', 'l118']", + "141, vivo, ['l85', 'l93', 'l100', 'l105', 'l109', 'l112', 'l115', 'l116', 'l119']", + "171, HSCs ['l117', 'l120', 'l121']", + "172, in ['l86', 'l94', 'l113', 'l118', 'l119', 'l120', 'l122']", + "173, culture. ['l121', 'l122']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20305660", + "TEXT": "Observational clinical and ex vivo studies have established a strong association between atrial fibrillation and inflammation. However, whether inflammation is the cause or the consequence of atrial fibrillation and which specific inflammatory mediators may increase the atria's susceptibility to fibrillation remain elusive. Here we provide experimental and clinical evidence for the mechanistic involvement of myeloperoxidase (MPO), a heme enzyme abundantly expressed by neutrophils, in the pathophysiology of atrial fibrillation. MPO-deficient mice pretreated with angiotensin II (AngII) to provoke leukocyte activation showed lower atrial tissue abundance of the MPO product 3-chlorotyrosine, reduced activity of matrix metalloproteinases and blunted atrial fibrosis as compared to wild-type mice. Upon right atrial electrophysiological stimulation, MPO-deficient mice were protected from atrial fibrillation, which was reversed when MPO was restored. Humans with atrial fibrillation had higher plasma concentrations of MPO and a larger MPO burden in right atrial tissue as compared to individuals devoid of atrial fibrillation. In the atria, MPO colocalized with markedly increased formation of 3-chlorotyrosine. Our data demonstrate that MPO is a crucial prerequisite for structural remodeling of the myocardium, leading to an increased vulnerability to atrial fibrillation.", + "TAG_DATA": [ + "69, MPO-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "70, mice {'context': 'B-organism'}", + "109, MPO-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "110, mice {'context': 'B-organism'}", + "152, atria, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "69, MPO-deficient ['l0']", + "70, mice ['l0']", + "109, MPO-deficient ['l1']", + "110, mice ['l1']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MPO-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "20190767", + "TEXT": "Control of blood vessel tone is central to vascular homeostasis. Here we show that metabolism of tryptophan to kynurenine by indoleamine 2,3-dioxygenase (Ido) expressed in endothelial cells contributes to arterial vessel relaxation and the control of blood pressure. Infection of mice with malarial parasites (Plasmodium berghei) or induction of endotoxemia in mice led to endothelial expression of Ido, decreased plasma tryptophan concentration, increased kynurenine concentration and hypotension. Pharmacological inhibition of Ido increased blood pressure in systemically inflamed mice but not in mice deficient in Ido or interferon-gamma, which is required for Ido induction. Both tryptophan and kynurenine dilated preconstricted porcine coronary arteries; the dilating effect of tryptophan required the presence of active Ido and an intact endothelium, whereas the effect of kynurenine was endothelium independent. The arterial relaxation induced by kynurenine was mediated by activation of the adenylate and soluble guanylate cyclase pathways. Kynurenine administration decreased blood pressure in a dose-dependent manner in spontaneously hypertensive rats. Our results identify tryptophan metabolism by Ido as a new pathway contributing to the regulation of vascular tone.", + "TAG_DATA": [ + "40, mice {'context': 'B-organism'}", + "51, mice {'context': 'B-organism'}", + "67, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "68, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "69, of {'perturbing_action': 'I-pharmacological inhibition'}", + "70, Ido {'perturbing_action': 'I-pharmacological inhibition'}", + "77, mice {'context': 'B-organism'}", + "81, mice {'context': 'B-organism'}", + "82, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "83, in {'perturbing_action': 'I-gene loss-of-function'}", + "84, Ido {'perturbing_action': 'I-gene loss-of-function'}", + "99, porcine {'context': 'B-tissue/organ'}", + "100, coronary {'context': 'I-tissue/organ'}", + "101, arteries; {'context': 'I-tissue/organ'}", + "153, spontaneously {'context': 'B-organism'}", + "155, rats. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "40, mice ['l0']", + "51, mice ['l0']", + "67, Pharmacological ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "68, inhibition ['l1', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "69, of ['l2', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "70, Ido ['l3', 'l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "77, mice ['l4', 'l14', 'l23', 'l31', 'l39']", + "81, mice ['l5', 'l15', 'l24', 'l32', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "82, deficient ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "83, in ['l7', 'l17', 'l26', 'l34', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "84, Ido ['l8', 'l18', 'l27', 'l35', 'l39', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57']", + "99, porcine ['l9', 'l19', 'l28', 'l36', 'l43', 'l48', 'l52', 'l55', 'l58', 'l59']", + "100, coronary ['l10', 'l20', 'l29', 'l37', 'l44', 'l49', 'l53', 'l56', 'l58', 'l60']", + "101, arteries; ['l11', 'l21', 'l30', 'l38', 'l45', 'l50', 'l54', 'l57', 'l59', 'l60']", + "153, spontaneously ['l61', 'l62']", + "154, hypertensive ['l61', 'l63']", + "155, rats. ['l62', 'l63']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "Ido" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "Ido" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "porcine", + "coronary", + "arteries;" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ido", + "deficient", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Ido" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "porcine", + "coronary", + "arteries;" + ] + } + } + ] + }, + { + "PMID": "20190766", + "TEXT": "Hyperexcitability of spinal reflexes and reduced synaptic inhibition are commonly associated with spasticity after spinal cord injury (SCI). In adults, the activation of gamma-aminobutyric acid(A) (GABAA) and glycine receptors inhibits neurons as a result of low intracellular chloride (Cl-) concentration, which is maintained by the potassium-chloride cotransporter KCC2 (encoded by Slc12a5). We show that KCC2 is downregulated after SCI in rats, particularly in motoneuron membranes, thereby depolarizing the Cl- equilibrium potential and reducing the strength of postsynaptic inhibition. Blocking KCC2 in intact rats reduces the rate-dependent depression (RDD) of the Hoffmann reflex, as is observed in spasticity. RDD is also decreased in KCC2-deficient mice and in intact rats after intrathecal brain-derived neurotrophic factor (BDNF) injection, which downregulates KCC2. The early decrease in KCC2 after SCI is prevented by sequestering BDNF at the time of SCI. Conversely, after SCI, BDNF upregulates KCC2 and restores RDD. Our results open new perspectives for the development of therapeutic strategies to alleviate spasticity.", + "TAG_DATA": [ + "78, Blocking {'perturbing_action': 'B-pharmacological inhibition'}", + "79, KCC2 {'perturbing_action': 'I-pharmacological inhibition'}", + "81, intact {'context': 'B-organism'}", + "82, rats {'context': 'I-organism'}", + "102, KCC2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "103, mice {'context': 'B-organism'}", + "106, intact {'context': 'B-organism'}", + "107, rats {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "78, Blocking ['l0', 'l1', 'l2', 'l3']", + "79, KCC2 ['l0', 'l4', 'l5']", + "81, intact ['l1', 'l4', 'l6']", + "82, rats ['l2', 'l5', 'l6']", + "102, KCC2-deficient ['l7', 'l8', 'l9']", + "103, mice ['l3', 'l7', 'l10', 'l11']", + "106, intact ['l8', 'l10', 'l12']", + "107, rats ['l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blocking", + "KCC2" + ] + }, + "context": { + "val": "organism", + "words": [ + "intact", + "rats", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "KCC2-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "intact", + "rats" + ] + } + } + ] + }, + { + "PMID": "20134472", + "TEXT": "Muscle diseases can take many forms, from the progressive muscle degeneration of dystrophies to the childhood cancer rhabdomyosarcoma. In 'Bench to Bedside', Joel R. Chamberlain and Jeffrey S. Chamberlain discuss studies using antisense oligonucleotides to treat Duchenne muscular dystrophy and myotonic dystrophy. In 'Bedside to Bench', Simone Hettmer and Amy J. Wagers examine the implications of clinical studies describing a type of rhabdomyosarcoma that resembles acute leukemia. The findings dovetail with other studies suggesting that some of these cancers might originate outside of muscle tissue and highlight the need for a better understanding of the cells that give rise to this condition.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20081861", + "TEXT": "Lung cancer is the leading cause of cancer death worldwide. Recent data suggest that tumor-associated inflammatory cells may modify lung tumor growth and invasiveness. To determine the role of neutrophil elastase (encoded by Elane) on tumor progression, we used the loxP-Stop-loxP K-ras(G12D) (LSL-K-ras) model of mouse lung adenocarcinoma to generate LSL-K-ras-Elane(-/-) mice. Tumor burden was markedly reduced in LSL-K-ras-Elane(-/-) mice at all time points after induction of mutant K-ras expression. Kaplan-Meier survival analysis showed that whereas all LSL-K-ras-Elane(+/+) mice died, none of the mice lacking neutrophil elastase died. Neutrophil elastase directly induced tumor cell proliferation in both human and mouse lung adenocarcinomas by gaining access to an endosomal compartment within tumor cells, where it degraded insulin receptor substrate-1 (IRS-1). Immunoprecipitation studies showed that, as neutrophil elastase degraded IRS-1, there was increased interaction between phosphatidylinositol 3-kinase (PI3K) and the potent mitogen platelet-derived growth factor receptor (PDGFR), thereby skewing the PI3K axis toward tumor cell proliferation. The inverse relationship identified between neutrophil elastase and IRS-1 in LSL-K-ras mice was also identified in human lung adenocarcinomas, thus translating these findings to human disease. This study identifies IRS-1 as a key regulator of PI3K within malignant cells. Additionally, to our knowledge, this is the first description of a secreted proteinase gaining access to the inside of a cell and altering intracellular signaling.", + "TAG_DATA": [ + "40, loxP-Stop-loxP {'perturbing_action': 'B-other'}", + "41, K-ras(G12D) {'perturbing_action': 'I-other'}", + "42, (LSL-K-ras) {'perturbing_action': 'I-other'}", + "43, model {'perturbing_action': 'I-other'}", + "44, of {'perturbing_action': 'I-other'}", + "45, mouse {'context': 'B-neoplasm'}", + "46, lung {'context': 'I-neoplasm'}", + "47, adenocarcinoma {'context': 'I-neoplasm'}", + "50, LSL-K-ras-Elane(-/-) {'perturbing_action': 'B-other'}", + "51, mice. {'context': 'B-organism'}", + "56, reduced {'effect': 'B-negative'}", + "58, LSL-K-ras-Elane(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "59, mice {'context': 'B-organism'}", + "65, induction {'perturbing_action': 'B-other'}", + "67, mutant {'perturbing_action': 'B-other'}", + "68, K-ras {'perturbing_action': 'I-other'}", + "69, expression. {'perturbing_action': 'I-other'}", + "77, LSL-K-ras-Elane(+/+) {'perturbing_action': 'B-other'}", + "78, mice {'context': 'B-organism'}", + "83, mice {'context': 'B-organism'}", + "91, induced {'effect': 'B-positive'}", + "92, tumor {'context': 'B-transformed cells'}", + "93, cell {'context': 'I-transformed cells'}", + "94, proliferation {'phenotype': 'B-proliferation'}", + "97, human {'context': 'B-neoplasm'}", + "98, and {'context': 'I-neoplasm'}", + "99, mouse {'context': 'I-neoplasm'}", + "100, lung {'context': 'I-neoplasm'}", + "101, adenocarcinomas {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "40, loxP-Stop-loxP ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "41, K-ras(G12D) ['l0', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "42, (LSL-K-ras) ['l1', 'l24', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "43, model ['l2', 'l25', 'l46', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "44, of ['l3', 'l26', 'l47', 'l61', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "45, mouse ['l4', 'l27', 'l48', 'l62', 'l73', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "46, lung ['l5', 'l28', 'l49', 'l63', 'l74', 'l84', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "47, adenocarcinoma ['l6', 'l29', 'l50', 'l64', 'l75', 'l85', 'l91', 'l97', 'l98', 'l99', 'l100', 'l101']", + "50, LSL-K-ras-Elane(-/-) ['l7', 'l30', 'l51', 'l65', 'l76', 'l86', 'l92', 'l97', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "51, mice. ['l8', 'l31', 'l52', 'l66', 'l77', 'l87', 'l93', 'l98', 'l102', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "52, Tumor ['l9', 'l32', 'l53', 'l67', 'l78', 'l88', 'l94', 'l99', 'l103', 'l111', 'l117', 'l118']", + "56, reduced ['l10', 'l33', 'l54', 'l68', 'l79', 'l89', 'l95', 'l100', 'l104', 'l112', 'l117', 'l119']", + "58, LSL-K-ras-Elane(-/-) ['l11', 'l34', 'l55', 'l69', 'l80', 'l105', 'l113', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "59, mice ['l12', 'l35', 'l56', 'l70', 'l81', 'l90', 'l96', 'l101', 'l106', 'l114', 'l118', 'l119', 'l120', 'l134', 'l135']", + "65, induction ['l13', 'l36', 'l57', 'l71', 'l82', 'l107', 'l115', 'l121', 'l134', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "67, mutant ['l14', 'l37', 'l58', 'l108', 'l122', 'l136', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "68, K-ras ['l15', 'l38', 'l59', 'l109', 'l123', 'l137', 'l144', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166']", + "69, expression. ['l16', 'l39', 'l60', 'l72', 'l83', 'l110', 'l116', 'l124', 'l135', 'l138', 'l145', 'l155', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "77, LSL-K-ras-Elane(+/+) ['l156', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184']", + "78, mice ['l157', 'l175', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "83, mice ['l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202']", + "91, induced ['l125', 'l146', 'l158', 'l176', 'l185', 'l194', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210']", + "92, tumor ['l126', 'l147', 'l159', 'l167', 'l177', 'l186', 'l195', 'l203', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217']", + "93, cell ['l17', 'l40', 'l127', 'l139', 'l148', 'l160', 'l168', 'l178', 'l187', 'l196', 'l204', 'l211', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223']", + "94, proliferation ['l18', 'l41', 'l128', 'l149', 'l161', 'l169', 'l179', 'l188', 'l197', 'l205', 'l212', 'l218', 'l224', 'l225', 'l226', 'l227', 'l228']", + "97, human ['l19', 'l42', 'l129', 'l140', 'l150', 'l162', 'l170', 'l180', 'l189', 'l198', 'l206', 'l213', 'l219', 'l224', 'l229', 'l230', 'l231', 'l232']", + "98, and ['l20', 'l43', 'l130', 'l141', 'l151', 'l163', 'l171', 'l181', 'l190', 'l199', 'l207', 'l214', 'l220', 'l225', 'l229', 'l233', 'l234', 'l235']", + "99, mouse ['l21', 'l131', 'l152', 'l164', 'l172', 'l182', 'l191', 'l200', 'l208', 'l215', 'l221', 'l226', 'l230', 'l233', 'l236', 'l237']", + "100, lung ['l22', 'l44', 'l132', 'l142', 'l153', 'l165', 'l173', 'l183', 'l192', 'l201', 'l209', 'l216', 'l222', 'l227', 'l231', 'l234', 'l236', 'l238']", + "101, adenocarcinomas ['l23', 'l45', 'l133', 'l143', 'l154', 'l166', 'l174', 'l184', 'l193', 'l202', 'l210', 'l217', 'l223', 'l228', 'l232', 'l235', 'l237', 'l238']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "loxP-Stop-loxP", + "K-ras(G12D)", + "(LSL-K-ras)", + "model", + "of", + "LSL-K-ras-Elane(-/-)", + "induction", + "mutant", + "K-ras", + "expression.", + "LSL-K-ras-Elane(+/+)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "lung", + "adenocarcinoma", + "human", + "and", + "adenocarcinomas" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "loxP-Stop-loxP", + "K-ras(G12D)", + "(LSL-K-ras)", + "model", + "of", + "LSL-K-ras-Elane(-/-)", + "induction", + "expression.", + "K-ras", + "LSL-K-ras-Elane(+/+)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "loxP-Stop-loxP", + "K-ras(G12D)", + "(LSL-K-ras)", + "model", + "of", + "LSL-K-ras-Elane(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "loxP-Stop-loxP", + "K-ras(G12D)", + "induction", + "mutant", + "K-ras", + "expression.", + "LSL-K-ras-Elane(+/+)" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cell", + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "loxP-Stop-loxP", + "K-ras(G12D)", + "mutant", + "K-ras", + "expression.", + "LSL-K-ras-Elane(+/+)" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "lung", + "adenocarcinoma" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "LSL-K-ras-Elane(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "LSL-K-ras-Elane(-/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "LSL-K-ras-Elane(-/-)" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "LSL-K-ras-Elane(-/-)" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "LSL-K-ras-Elane(-/-)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "and", + "mouse", + "lung", + "adenocarcinomas" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "K-ras", + "LSL-K-ras-Elane(+/+)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "and", + "mouse", + "lung", + "adenocarcinomas" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "and", + "mouse", + "lung", + "adenocarcinomas" + ] + } + } + ] + }, + { + "PMID": "20057417", + "TEXT": "A common retrovirus encases itself in an extracellular matrix, enabling its transfer between T4 cells. The discovery of this new mode of infectivity has the potential to lead to new ways to combat the virus, human T cell leukemia virus type 1 (HTLV-1), which is associated with cancers and inflammatory disorders (pages 83–89).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20057412", + "TEXT": "The epigenome consists of a system of chemical tags that attach to our DNA and its associated molecules, switching genes on and off. But the system is not without glitches-and scientists think that the misplacement of these tags can cause disease. This idea has led to new drugs that aim to correct gene activity (and obliterate disease) by altering the proteins around which DNA winds. Cassandra Willyard examines whether this approach will unlock the long-awaited promise of epigenetic therapy.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20023635", + "TEXT": "The B cell lymphoma-6 (Bcl-6) and Bcl-xL proteins are expressed in germinal center B cells and enable them to endure the proliferative and mutagenic environment of the germinal center. By introducing these genes into peripheral blood memory B cells and culturing these cells with two factors produced by follicular helper T cells, CD40 ligand (CD40L) and interleukin-21 (IL-21), we convert them to highly proliferating, cell surface B cell receptor (BCR)-positive, immunoglobulin-secreting B cells with features of germinal center B cells, including expression of activation-induced cytidine deaminase (AID). We generated cloned lines of B cells specific for respiratory syncytial virus and used these cells as a source of antibodies that effectively neutralized this virus in vivo. This method provides a new tool to study B cell biology and signal transduction through antigen-specific B cell receptors and for the rapid generation of high-affinity human monoclonal antibodies.", + "TAG_DATA": [ + "42, cells {'context': 'B-cells'}", + "71, B {'context': 'B-cells'}", + "72, cells {'context': 'I-cells'}", + "92, B {'context': 'B-cells'}", + "93, cells {'context': 'I-cells'}", + "102, cells {'context': 'B-cells'}", + "113, in {'context': 'B-in vivo'}", + "114, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "42, cells ['l0', 'l1']", + "71, B ['l0', 'l2']", + "72, cells ['l1', 'l2']", + "92, B ['l3', 'l4']", + "93, cells ['l3']", + "102, cells ['l4', 'l5', 'l6']", + "113, in ['l5', 'l7']", + "114, vivo. ['l6', 'l7']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19966810", + "TEXT": "The identification of the genes associated with chromosomal translocation breakpoints has fundamentally changed understanding of the molecular basis of hematological malignancies. By contrast, the study of chromosomal deletions has been hampered by the large number of genes deleted and the complexity of their analysis. We report the generation of a mouse model for human 5q- syndrome using large-scale chromosomal engineering. Haploinsufficiency of the Cd74-Nid67 interval (containing Rps14, encoding the ribosomal protein S14) caused macrocytic anemia, prominent erythroid dysplasia and monolobulated megakaryocytes in the bone marrow. These effects were associated with defective bone marrow progenitor development, the appearance of bone marrow cells expressing high amounts of the tumor suppressor p53 and increased bone marrow cell apoptosis. Notably, intercrossing with p53-deficient mice completely rescued the progenitor cell defect, restoring common myeloid progenitor and megakaryocytic-erythroid progenitor, granulocyte-monocyte progenitor and hematopoietic stem cell bone marrow populations. This mouse model suggests that a p53-dependent mechanism underlies the pathophysiology of the 5q- syndrome.", + "TAG_DATA": [ + "60, Haploinsufficiency {'perturbing_action': 'B-gene loss-of-function'}", + "61, of {'perturbing_action': 'I-gene loss-of-function'}", + "62, the {'perturbing_action': 'I-gene loss-of-function'}", + "63, Cd74-Nid67 {'perturbing_action': 'I-gene loss-of-function'}", + "64, interval {'perturbing_action': 'I-gene loss-of-function'}", + "65, (containing {'perturbing_action': 'I-gene loss-of-function'}", + "98, bone {'context': 'B-cells'}", + "99, marrow {'context': 'I-cells'}", + "100, cells {'context': 'I-cells'}", + "110, increased {'effect': 'B-positive'}", + "111, bone {'context': 'B-cells'}", + "112, marrow {'context': 'I-cells'}", + "113, cell {'context': 'I-cells'}", + "114, apoptosis. {'phenotype': 'B-apoptosis'}", + "118, p53-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "119, mice {'context': 'B-organism'}", + "123, progenitor {'context': 'B-cells'}", + "124, cell {'context': 'I-cells'}", + "127, common {'context': 'B-cells'}", + "128, myeloid {'context': 'I-cells'}", + "129, progenitor {'context': 'I-cells'}", + "130, and {'context': 'I-cells'}", + "131, megakaryocytic-erythroid {'context': 'I-cells'}", + "132, progenitor, {'context': 'I-cells'}", + "133, granulocyte-monocyte {'context': 'I-cells'}", + "134, progenitor {'context': 'I-cells'}", + "136, hematopoietic {'context': 'I-cells'}", + "137, stem {'context': 'I-cells'}", + "138, cell {'context': 'I-cells'}", + "139, bone {'context': 'I-cells'}", + "140, marrow {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "60, Haploinsufficiency ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "61, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "62, the ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "63, Cd74-Nid67 ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "64, interval ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "65, (containing ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "98, bone ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "99, marrow ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "100, cells ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "110, increased ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "111, bone ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "112, marrow ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "113, cell ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "114, apoptosis. ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']", + "118, p53-deficient ['l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "119, mice ['l91', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "123, progenitor ['l92', 'l107', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "124, cell ['l93', 'l108', 'l122', 'l131', 'l132', 'l133', 'l134', 'l135']", + "127, common ['l94', 'l109', 'l123', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "128, myeloid ['l95', 'l110', 'l124', 'l131', 'l136', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158']", + "129, progenitor ['l96', 'l111', 'l125', 'l132', 'l137', 'l148', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168']", + "130, and ['l97', 'l112', 'l126', 'l133', 'l138', 'l149', 'l159', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177']", + "131, megakaryocytic-erythroid ['l98', 'l113', 'l127', 'l134', 'l139', 'l150', 'l160', 'l169', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185']", + "132, progenitor, ['l99', 'l114', 'l128', 'l135', 'l140', 'l151', 'l161', 'l170', 'l178', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192']", + "133, granulocyte-monocyte ['l100', 'l115', 'l129', 'l141', 'l152', 'l162', 'l171', 'l179', 'l186', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198']", + "134, progenitor ['l101', 'l116', 'l130', 'l142', 'l153', 'l163', 'l172', 'l180', 'l187', 'l193', 'l199', 'l200', 'l201', 'l202', 'l203']", + "136, hematopoietic ['l102', 'l117', 'l143', 'l154', 'l164', 'l173', 'l181', 'l188', 'l194', 'l199', 'l204', 'l205', 'l206', 'l207']", + "137, stem ['l103', 'l118', 'l144', 'l155', 'l165', 'l174', 'l182', 'l189', 'l195', 'l200', 'l204', 'l208', 'l209', 'l210']", + "138, cell ['l104', 'l119', 'l145', 'l156', 'l166', 'l175', 'l183', 'l190', 'l196', 'l201', 'l205', 'l208', 'l211', 'l212']", + "139, bone ['l105', 'l120', 'l146', 'l157', 'l167', 'l176', 'l184', 'l191', 'l197', 'l202', 'l206', 'l209', 'l211', 'l213']", + "140, marrow ['l106', 'l121', 'l147', 'l158', 'l168', 'l177', 'l185', 'l192', 'l198', 'l203', 'l207', 'l210', 'l212', 'l213']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Haploinsufficiency", + "of", + "the", + "Cd74-Nid67", + "interval", + "(containing", + "p53-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "bone", + "marrow", + "cells", + "cell", + "progenitor", + "common", + "myeloid", + "and", + "megakaryocytic-erythroid", + "progenitor,", + "granulocyte-monocyte", + "hematopoietic", + "stem" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Haploinsufficiency", + "of", + "the", + "Cd74-Nid67", + "interval", + "(containing" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Haploinsufficiency", + "of", + "the", + "Cd74-Nid67", + "interval", + "(containing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "bone", + "marrow", + "cells", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "bone", + "marrow", + "cells", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "19966779", + "TEXT": "The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired gamma-aminobutyric acid (GABA)-ergic inhibition remains an attractive hypothesis. In contrast, we show here that extrasynaptic GABA(A) receptor-dependent 'tonic' inhibition is increased in thalamocortical neurons from diverse genetic and pharmacological models of absence seizures. Increased tonic inhibition is due to compromised GABA uptake by the GABA transporter GAT-1 in the genetic models tested, and GAT-1 is crucial in governing seizure genesis. Extrasynaptic GABA(A) receptors are a requirement for seizures in two of the best characterized models of absence epilepsy, and the selective activation of thalamic extrasynaptic GABA(A) receptors is sufficient to elicit both electrographic and behavioral correlates of seizures in normal rats. These results identify an apparently common cellular pathology in typical absence seizures that may have epileptogenic importance and highlight potential therapeutic targets for the treatment of absence epilepsy.", + "TAG_DATA": [ + "41, thalamocortical {'context': 'B-cells'}", + "42, neurons {'context': 'I-cells'}", + "119, rats. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "41, thalamocortical ['l0']", + "42, neurons ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19966777", + "TEXT": "The normal microflora of the skin includes staphylococcal species that will induce inflammation when present below the dermis but are tolerated on the epidermal surface without initiating inflammation. Here we reveal a previously unknown mechanism by which a product of staphylococci inhibits skin inflammation. This inhibition is mediated by staphylococcal lipoteichoic acid (LTA) and acts selectively on keratinocytes triggered through Toll-like receptor 3(TLR3). We show that TLR3 activation is required for normal inflammation after injury and that keratinocytes require TLR3 to respond to RNA from damaged cells with the release of inflammatory cytokines. Staphylococcal LTA inhibits both inflammatory cytokine release from keratinocytes and inflammation triggered by injury through a TLR2-dependent mechanism. To our knowledge, these findings show for the first time that the skin epithelium requires TLR3 for normal inflammation after wounding and that the microflora can modulate specific cutaneous inflammatory responses.", + "TAG_DATA": [ + "101, keratinocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19915594", + "TEXT": "Osteoarthritis is associated with the irreversible degeneration of articular cartilage. Notably, in this condition, articular cartilage chondrocytes undergo phenotypic and gene expression changes that are reminiscent of their end-stage differentiation in the growth plate during skeletal development. Hedgehog (Hh) signaling regulates normal chondrocyte growth and differentiation; however, the role of Hh signaling in chondrocytes in osteoarthritis is unknown. Here we examine human osteoarthritic samples and mice in which osteoarthritis was surgically induced and find that Hh signaling is activated in osteoarthritis. Using several genetically modified mice, we found that higher levels of Hh signaling in chondrocytes cause a more severe osteoarthritic phenotype. Furthermore, we show in mice and in human cartilage explants that pharmacological or genetic inhibition of Hh signaling reduces the severity of osteoarthritis and that runt-related transcription factor-2 (RUNX2) potentially mediates this process by regulating a disintegrin and metalloproteinase with thrombospondin type 1 motif-5 (ADAMTS5) expression. Together, these findings raise the possibility that Hh blockade can be used as a therapeutic approach to inhibit articular cartilage degeneration.", + "TAG_DATA": [ + "65, mice {'context': 'B-organism'}", + "85, mice, {'context': 'B-organism'}", + "95, chondrocytes {'context': 'B-cells'}", + "106, mice {'context': 'B-organism'}", + "109, human {'context': 'B-tissue/organ'}", + "110, cartilage {'context': 'I-tissue/organ'}", + "111, explants {'context': 'I-tissue/organ'}", + "115, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "116, inhibition {'perturbing_action': 'I-gene loss-of-function'}", + "117, of {'perturbing_action': 'I-gene loss-of-function'}", + "118, Hh {'perturbing_action': 'I-gene loss-of-function'}", + "119, signaling {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "65, mice ['l0']", + "85, mice, ['l0']", + "106, mice ['l1']", + "109, human ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "110, cartilage ['l2', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "111, explants ['l1', 'l3', 'l9', 'l15', 'l16', 'l17', 'l18', 'l19']", + "115, genetic ['l4', 'l10', 'l15', 'l20', 'l21', 'l22', 'l23']", + "116, inhibition ['l5', 'l11', 'l16', 'l20', 'l24', 'l25', 'l26']", + "117, of ['l6', 'l12', 'l17', 'l21', 'l24', 'l27', 'l28']", + "118, Hh ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l29']", + "119, signaling ['l8', 'l14', 'l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "human", + "cartilage", + "explants" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inhibition", + "of", + "Hh", + "signaling" + ] + } + } + ] + }, + { + "PMID": "19881492", + "TEXT": "Z-disks, the mechanical integration sites of heart and skeletal muscle cells, link anchorage of myofilaments to force reception and processing. The key molecules that enable the Z-disk to persistently withstand the extreme mechanical forces during muscle contraction have not yet been identified. Here we isolated nexilin (encoded by NEXN) as a novel Z-disk protein. Loss of nexilin in zebrafish led to perturbed Z-disk stability and heart failure. To evaluate the role of nexilin in human heart failure, we performed a genetic association study on individuals with dilated cardiomyopathy and found several mutations in NEXN associated with the disease. Nexilin mutation carriers showed the same cardiac Z-disk pathology as observed in nexilin-deficient zebrafish. Expression in zebrafish of nexilin proteins encoded by NEXN mutant alleles induced Z-disk damage and heart failure, demonstrating a dominant-negative effect and confirming the disease-causing nature of these mutations. Increasing mechanical strain aggravated Z-disk damage in nexilin-deficient skeletal muscle, implying a unique role of nexilin in protecting Z-disks from mechanical trauma.", + "TAG_DATA": [ + "54, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "55, of {'perturbing_action': 'I-gene loss-of-function'}", + "56, nexilin {'perturbing_action': 'I-gene loss-of-function'}", + "58, zebrafish {'context': 'B-organism'}", + "110, nexilin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "111, zebrafish. {'context': 'B-organism'}", + "112, Expression {'perturbing_action': 'B-other'}", + "114, zebrafish {'context': 'B-organism'}", + "115, of {'perturbing_action': 'I-other'}", + "116, nexilin {'perturbing_action': 'I-other'}", + "117, proteins {'perturbing_action': 'I-other'}", + "118, encoded {'perturbing_action': 'I-other'}", + "119, by {'perturbing_action': 'I-other'}", + "120, NEXN {'perturbing_action': 'I-other'}", + "121, mutant {'perturbing_action': 'I-other'}", + "122, alleles {'perturbing_action': 'I-other'}", + "148, nexilin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "149, skeletal {'context': 'B-tissue/organ'}", + "150, muscle, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "54, Loss ['l0', 'l1', 'l2']", + "55, of ['l0', 'l3', 'l4']", + "56, nexilin ['l1', 'l3', 'l5']", + "58, zebrafish ['l2', 'l4', 'l5']", + "110, nexilin-deficient ['l6']", + "111, zebrafish. ['l6']", + "112, Expression ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "114, zebrafish ['l7', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "115, of ['l8', 'l19', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "116, nexilin ['l9', 'l20', 'l30', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "117, proteins ['l10', 'l21', 'l31', 'l40', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "118, encoded ['l11', 'l22', 'l32', 'l41', 'l49', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "119, by ['l12', 'l23', 'l33', 'l42', 'l50', 'l57', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "120, NEXN ['l13', 'l24', 'l34', 'l43', 'l51', 'l58', 'l64', 'l70', 'l71', 'l72', 'l73', 'l74']", + "121, mutant ['l14', 'l25', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l75', 'l76', 'l77', 'l78']", + "122, alleles ['l15', 'l26', 'l36', 'l45', 'l53', 'l60', 'l66', 'l71', 'l75', 'l79', 'l80', 'l81']", + "148, nexilin-deficient ['l16', 'l27', 'l37', 'l46', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l82', 'l83']", + "149, skeletal ['l17', 'l28', 'l38', 'l47', 'l55', 'l62', 'l68', 'l73', 'l77', 'l80', 'l82', 'l84']", + "150, muscle, ['l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l69', 'l74', 'l78', 'l81', 'l83', 'l84']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Loss", + "of", + "nexilin", + "nexilin-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "zebrafish", + "zebrafish." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Expression", + "of", + "nexilin", + "proteins", + "encoded", + "by", + "NEXN", + "mutant", + "alleles" + ] + }, + "context": { + "val": "organism", + "words": [ + "zebrafish" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Expression", + "of", + "nexilin", + "proteins", + "encoded", + "by", + "NEXN", + "mutant", + "alleles" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skeletal", + "muscle," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nexilin-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skeletal", + "muscle," + ] + } + } + ] + }, + { + "PMID": "19855400", + "TEXT": "Notch receptor signaling is implicated in controlling smooth muscle cell proliferation and in maintaining smooth muscle cells in an undifferentiated state. Pulmonary arterial hypertension is characterized by excessive vascular resistance, smooth muscle cell proliferation in small pulmonary arteries, leading to elevation of pulmonary vascular resistance, right ventricular failure and death. Here we show that human pulmonary hypertension is characterized by overexpression of NOTCH3 in small pulmonary artery smooth muscle cells and that the severity of disease in humans and rodents correlates with the amount of NOTCH3 protein in the lung. We further show that mice with homozygous deletion of Notch3 do not develop pulmonary hypertension in response to hypoxic stimulation and that pulmonary hypertension can be successfully treated in mice by administration of N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a gamma-secretase inhibitor that blocks activation of Notch3 in smooth muscle cells. We show a mechanistic link from NOTCH3 receptor signaling through the Hairy and enhancer of Split-5 (HES-5) protein to smooth muscle cell proliferation and a shift to an undifferentiated smooth muscle cell phenotype. These results suggest that the NOTCH3-HES-5 signaling pathway is crucial for the development of pulmonary arterial hypertension and provide a target pathway for therapeutic intervention.", + "TAG_DATA": [ + "94, mice {'context': 'B-organism'}", + "96, homozygous {'perturbing_action': 'B-gene loss-of-function'}", + "97, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "98, of {'perturbing_action': 'I-gene loss-of-function'}", + "99, Notch3 {'perturbing_action': 'I-gene loss-of-function'}", + "119, mice {'context': 'B-organism'}", + "136, smooth {'context': 'B-cells'}", + "137, muscle {'context': 'B-cells'}", + "138, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "94, mice ['l0', 'l1', 'l2', 'l3']", + "96, homozygous ['l0', 'l4', 'l5', 'l6']", + "97, deletion ['l1', 'l4', 'l7', 'l8']", + "98, of ['l2', 'l5', 'l7', 'l9']", + "99, Notch3 ['l3', 'l6', 'l8', 'l9']", + "119, mice ['l10', 'l11', 'l12']", + "136, smooth ['l10', 'l13', 'l14']", + "137, muscle ['l11', 'l13', 'l15']", + "138, cells. ['l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "homozygous", + "deletion", + "of", + "Notch3" + ] + } + } + ] + }, + { + "PMID": "19838202", + "TEXT": "Macrophages rapidly engulf apoptotic cells to limit the release of noxious cellular contents and to restrict autoimmune responses against self antigens. Although factors participating in recognition and engulfment of apoptotic cells have been identified, the transcriptional basis for the sensing and the silent disposal of apoptotic cells is unknown. Here we show that peroxisome proliferator-activated receptor-delta (PPAR-delta) is induced when macrophages engulf apoptotic cells and functions as a transcriptional sensor of dying cells. Genetic deletion of PPAR-delta decreases expression of opsonins such as complement component-1qb (C1qb), resulting in impairment of apoptotic cell clearance and reduction in anti-inflammatory cytokine production. This increases autoantibody production and predisposes global and macrophage-specific Ppard(-/-) mice to autoimmune kidney disease, a phenotype resembling the human disease systemic lupus erythematosus. Thus, PPAR-delta has a pivotal role in orchestrating the timely disposal of apoptotic cells by macrophages, ensuring that tolerance to self is maintained.", + "TAG_DATA": [ + "73, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "74, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "75, of {'perturbing_action': 'I-gene loss-of-function'}", + "76, PPAR-delta {'perturbing_action': 'I-gene loss-of-function'}", + "91, cell {'phenotype': 'I-apoptosis'}", + "107, macrophage-specific {'perturbing_action': 'B-gene loss-of-function'}", + "108, Ppard(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "109, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, Genetic ['l0', 'l1', 'l2', 'l3']", + "74, deletion ['l0', 'l4', 'l5', 'l6']", + "75, of ['l1', 'l4', 'l7', 'l8']", + "76, PPAR-delta ['l2', 'l5', 'l7', 'l9']", + "91, cell ['l3', 'l6', 'l8', 'l9']", + "107, macrophage-specific ['l10', 'l11']", + "108, Ppard(-/-) ['l10', 'l12']", + "109, mice ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "deletion", + "of", + "PPAR-delta" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "macrophage-specific", + "Ppard(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "19812566", + "TEXT": "Imatinib (trade name Gleevec) preserves fertility in female mice treated with the common chemotherapeutic agent cisplatin. Imatinib seems to block an apoptotic pathway activated by cisplatin in ovarian germ cells (pages 1179– 1185). The findings could lead to new ways to protect germ cells from the damaging effects of cancer treatment.", + "TAG_DATA": [ + "7, female {'context': 'B-organism'}", + "8, mice {'context': 'I-organism'}", + "19, block {'effect': 'B-negative'}", + "21, apoptotic {'phenotype': 'B-apoptosis'}", + "22, pathway {'phenotype': 'I-apoptosis'}", + "23, activated {'effect': 'B-positive'}", + "27, ovarian {'context': 'B-transformed cells'}", + "28, germ {'context': 'I-transformed cells'}", + "29, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "7, female ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "8, mice ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "19, block ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "21, apoptotic ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "22, pathway ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "23, activated ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "27, ovarian ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "28, germ ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "29, cells ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "female", + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "block" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "female", + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "pathway" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "female", + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "activated" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "block" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "pathway" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "block" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "germ", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "pathway" + ] + }, + "effect": { + "val": "positive", + "words": [ + "activated" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "pathway" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "germ", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "activated" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "germ", + "cells" + ] + } + } + ] + }, + { + "PMID": "19767732", + "TEXT": "The therapeutic efficacy of anticancer chemotherapies may depend on dendritic cells (DCs), which present antigens from dying cancer cells to prime tumor-specific interferon-gamma (IFN-gamma)-producing T lymphocytes. Here we show that dying tumor cells release ATP, which then acts on P2X(7) purinergic receptors from DCs and triggers the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3)-dependent caspase-1 activation complex ('inflammasome'), allowing for the secretion of interleukin-1beta (IL-1beta). The priming of IFN-gamma-producing CD8+ T cells by dying tumor cells fails in the absence of a functional IL-1 receptor 1 and in Nlpr3-deficient (Nlrp3(-/-)) or caspase-1-deficient (Casp-1(-/-)) mice unless exogenous IL-1beta is provided. Accordingly, anticancer chemotherapy turned out to be inefficient against tumors established in purinergic receptor P2rx7(-/-) or Nlrp3(-/-) or Casp1(-/-) hosts. Anthracycline-treated individuals with breast cancer carrying a loss-of-function allele of P2RX7 developed metastatic disease more rapidly than individuals bearing the normal allele. These results indicate that the NLRP3 inflammasome links the innate and adaptive immune responses against dying tumor cells.", + "TAG_DATA": [ + "70, CD8+ {'context': 'B-cells'}", + "71, T {'context': 'I-cells'}", + "72, cells {'context': 'I-cells'}", + "75, tumor {'context': 'I-transformed cells'}", + "76, cells {'context': 'I-transformed cells'}", + "89, Nlpr3-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "90, (Nlrp3(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "92, caspase-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "93, (Casp-1(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "94, mice {'context': 'B-organism'}", + "109, tumors {'context': 'B-neoplasm'}", + "112, purinergic {'perturbing_action': 'B-gene loss-of-function'}", + "113, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "114, P2rx7(-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "116, Nlrp3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "117, or {'perturbing_action': 'I-gene loss-of-function'}", + "118, Casp1(-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "123, breast {'context': 'B-neoplasm'}", + "124, cancer {'context': 'I-neoplasm'}", + "126, a {'perturbing_action': 'B-gene loss-of-function'}", + "127, loss-of-function {'perturbing_action': 'B-gene loss-of-function'}", + "128, allele {'perturbing_action': 'I-gene loss-of-function'}", + "129, of {'perturbing_action': 'I-gene loss-of-function'}", + "130, P2RX7 {'perturbing_action': 'I-gene loss-of-function'}", + "131, developed {'effect': 'B-negative'}", + "132, metastatic {'phenotype': 'B-metastasis'}", + "133, disease {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "70, CD8+ ['l0', 'l1', 'l2', 'l3']", + "71, T ['l0', 'l4', 'l5', 'l6']", + "72, cells ['l1', 'l4', 'l7', 'l8']", + "75, tumor ['l2', 'l5', 'l7', 'l9']", + "76, cells ['l3', 'l6', 'l8', 'l9']", + "89, Nlpr3-deficient ['l10', 'l11', 'l12', 'l13', 'l14']", + "90, (Nlrp3(-/-)) ['l10', 'l15', 'l16', 'l17', 'l18']", + "92, caspase-1-deficient ['l11', 'l15', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "93, (Casp-1(-/-)) ['l12', 'l16', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "94, mice ['l13', 'l17', 'l20', 'l26', 'l32', 'l33', 'l34', 'l35']", + "109, tumors ['l14', 'l18', 'l21', 'l27', 'l32', 'l36', 'l37', 'l38']", + "112, purinergic ['l22', 'l28', 'l33', 'l36', 'l39', 'l40', 'l41', 'l42', 'l43']", + "113, receptor ['l23', 'l29', 'l34', 'l37', 'l39', 'l44', 'l45', 'l46', 'l47']", + "114, P2rx7(-/-) ['l24', 'l30', 'l35', 'l38', 'l40', 'l44', 'l48', 'l49', 'l50']", + "116, Nlrp3(-/-) ['l25', 'l31', 'l41', 'l45', 'l48', 'l51', 'l52', 'l53', 'l54']", + "117, or ['l42', 'l46', 'l49', 'l51', 'l55', 'l56', 'l57']", + "118, Casp1(-/-) ['l43', 'l47', 'l50', 'l52', 'l55', 'l58', 'l59']", + "123, breast ['l53', 'l56', 'l58', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "124, cancer ['l54', 'l57', 'l59', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "126, a ['l61', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "127, loss-of-function ['l62', 'l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "128, allele ['l63', 'l71', 'l78', 'l84', 'l90', 'l91', 'l92', 'l93', 'l94']", + "129, of ['l64', 'l72', 'l79', 'l85', 'l90', 'l95', 'l96', 'l97', 'l98']", + "130, P2RX7 ['l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l99', 'l100', 'l101']", + "131, developed ['l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l102', 'l103']", + "132, metastatic ['l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l104']", + "133, disease ['l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l104']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nlpr3-deficient", + "(Nlrp3(-/-))", + "caspase-1-deficient", + "(Casp-1(-/-))", + "purinergic", + "receptor", + "P2rx7(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nlpr3-deficient", + "(Nlrp3(-/-))", + "caspase-1-deficient", + "(Casp-1(-/-))", + "purinergic", + "receptor", + "P2rx7(-/-)", + "Nlrp3(-/-)", + "or", + "Casp1(-/-)", + "a", + "loss-of-function", + "allele", + "of", + "P2RX7" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "breast", + "cancer" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "breast", + "cancer" + ] + }, + "effect": { + "val": "negative", + "words": [ + "developed" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "breast", + "cancer" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "disease" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "a", + "loss-of-function", + "allele", + "of", + "P2RX7" + ] + }, + "effect": { + "val": "negative", + "words": [ + "developed" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "a", + "loss-of-function", + "allele", + "of", + "P2RX7" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "disease" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "developed" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "disease" + ] + } + } + ] + }, + { + "PMID": "19734908", + "TEXT": "Integrins regulate adhesion-dependent growth, survival and invasion of tumor cells. In particular, expression of integrin alpha(v)beta(3) is associated with progression of a variety of human tumors. Here we reveal a previously undescribed adhesion-independent role for integrin alpha(v)beta(3) in pancreatic cancer and other carcinomas. Specifically, alpha(v)beta(3) expressed in carcinoma cells enhanced anchorage-independent tumor growth in vitro and increased lymph node metastases in vivo. These effects required recruitment of c-Src to the beta(3) integrin cytoplasmic tail, leading to c-Src activation, Crk-associated substrate (CAS) phosphorylation and tumor cell survival that, unexpectedly, was independent of cell adhesion or focal adhesion kinase (FAK) activation. Pharmacological blockade of c-Src kinase activity or decreased expression of endogenous alpha(v)beta(3) integrin or c-Src not only inhibited anchorage-independent growth but also suppressed metastasis in vivo, yet these manipulations did not affect tumor cell migration or invasion. These data define an unexpected role for an integrin as a mediator of anchorage independence, suggesting that an alpha(v)beta(3)-c-Src signaling module may account for the aggressive behavior of integrin alpha(v)beta(3)-expressing tumors in humans.", + "TAG_DATA": [ + "49, enhanced {'effect': 'B-positive'}", + "51, tumor {'phenotype': 'B-tumour growth'}", + "52, growth {'phenotype': 'I-tumour growth'}", + "53, in {'context': 'B-in vitro'}", + "54, vitro {'context': 'I-in vitro'}", + "56, increased {'effect': 'B-positive'}", + "57, lymph {'phenotype': 'B-metastasis'}", + "58, node {'phenotype': 'I-metastasis'}", + "59, metastases {'phenotype': 'I-metastasis'}", + "60, in {'context': 'B-in vivo'}", + "61, vivo. {'context': 'I-in vivo'}", + "83, tumor {'context': 'B-transformed cells'}", + "84, cell {'phenotype': 'B-cell survival'}", + "85, survival {'phenotype': 'I-cell survival'}", + "99, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "100, blockade {'perturbing_action': 'I-pharmacological inhibition'}", + "101, of {'perturbing_action': 'I-pharmacological inhibition'}", + "102, c-Src {'perturbing_action': 'I-pharmacological inhibition'}", + "103, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "104, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "106, decreased {'perturbing_action': 'B-other'}", + "107, expression {'perturbing_action': 'I-rnai/knockdown'}", + "108, of {'perturbing_action': 'I-rnai/knockdown'}", + "109, endogenous {'perturbing_action': 'I-rnai/knockdown'}", + "110, alpha(v)beta(3) {'perturbing_action': 'I-rnai/knockdown'}", + "111, integrin {'perturbing_action': 'I-rnai/knockdown'}", + "112, or {'perturbing_action': 'I-rnai/knockdown'}", + "113, c-Src {'perturbing_action': 'I-rnai/knockdown'}", + "116, inhibited {'effect': 'B-negative'}", + "121, suppressed {'effect': 'B-negative'}", + "122, metastasis {'phenotype': 'B-metastasis'}", + "123, in {'context': 'B-in vivo'}", + "124, vivo, {'context': 'I-in vivo'}", + "128, did {'effect': 'B-no effect'}", + "129, not {'effect': 'I-no effect'}", + "130, affect {'effect': 'I-no effect'}", + "131, tumor {'context': 'B-transformed cells'}", + "132, cell {'context': 'I-transformed cells'}", + "133, migration {'phenotype': 'B-migration'}", + "135, invasion. {'phenotype': 'B-invasion'}" + ], + "LINK_DATA": [ + "49, enhanced ['l0', 'l1', 'l2', 'l3', 'l4']", + "51, tumor ['l0', 'l5', 'l6', 'l7']", + "52, growth ['l1', 'l5', 'l8', 'l9']", + "53, in ['l2', 'l6', 'l8', 'l10', 'l11']", + "54, vitro ['l3', 'l7', 'l9', 'l10', 'l12']", + "56, increased ['l4', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "57, lymph ['l13', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "58, node ['l14', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "59, metastases ['l15', 'l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "60, in ['l16', 'l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "61, vivo. ['l17', 'l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "83, tumor ['l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "84, cell ['l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "85, survival ['l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l48']", + "99, Pharmacological ['l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "100, blockade ['l49', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "101, of ['l50', 'l72', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "102, c-Src ['l51', 'l73', 'l90', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "103, kinase ['l52', 'l74', 'l91', 'l104', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "104, activity ['l53', 'l75', 'l92', 'l105', 'l115', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "106, decreased ['l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "107, expression ['l134', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170']", + "108, of ['l54', 'l76', 'l135', 'l153', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "109, endogenous ['l55', 'l136', 'l154', 'l171', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203']", + "110, alpha(v)beta(3) ['l56', 'l77', 'l93', 'l106', 'l116', 'l125', 'l137', 'l155', 'l172', 'l188', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218']", + "111, integrin ['l57', 'l78', 'l94', 'l107', 'l117', 'l126', 'l138', 'l156', 'l173', 'l189', 'l204', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232']", + "112, or ['l58', 'l79', 'l95', 'l108', 'l118', 'l127', 'l139', 'l157', 'l174', 'l190', 'l205', 'l219', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245']", + "113, c-Src ['l59', 'l80', 'l96', 'l109', 'l119', 'l128', 'l140', 'l158', 'l175', 'l191', 'l206', 'l220', 'l233', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257']", + "116, inhibited ['l60', 'l81', 'l97', 'l110', 'l120', 'l129', 'l141', 'l159', 'l176', 'l192', 'l207', 'l221', 'l234', 'l246', 'l258', 'l259', 'l260', 'l261']", + "121, suppressed ['l61', 'l82', 'l98', 'l111', 'l121', 'l130', 'l142', 'l160', 'l177', 'l193', 'l208', 'l222', 'l235', 'l247', 'l258', 'l262', 'l263', 'l264']", + "122, metastasis ['l62', 'l83', 'l99', 'l112', 'l122', 'l131', 'l143', 'l161', 'l178', 'l194', 'l209', 'l223', 'l236', 'l248', 'l259', 'l262', 'l265', 'l266']", + "123, in ['l63', 'l84', 'l100', 'l113', 'l123', 'l132', 'l144', 'l162', 'l179', 'l195', 'l210', 'l224', 'l237', 'l249', 'l260', 'l263', 'l265', 'l267']", + "124, vivo, ['l64', 'l85', 'l101', 'l114', 'l124', 'l133', 'l145', 'l163', 'l180', 'l196', 'l211', 'l225', 'l238', 'l250', 'l261', 'l264', 'l266', 'l267']", + "128, did ['l65', 'l86', 'l146', 'l164', 'l181', 'l197', 'l212', 'l226', 'l239', 'l251', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273']", + "129, not ['l66', 'l87', 'l147', 'l165', 'l182', 'l198', 'l213', 'l227', 'l240', 'l252', 'l268', 'l274', 'l275', 'l276', 'l277', 'l278']", + "130, affect ['l67', 'l88', 'l102', 'l148', 'l166', 'l183', 'l199', 'l214', 'l228', 'l241', 'l253', 'l269', 'l274', 'l279', 'l280', 'l281', 'l282']", + "131, tumor ['l68', 'l149', 'l167', 'l184', 'l200', 'l215', 'l229', 'l242', 'l254', 'l270', 'l275', 'l279', 'l283', 'l284', 'l285']", + "132, cell ['l69', 'l89', 'l103', 'l150', 'l168', 'l185', 'l201', 'l216', 'l230', 'l243', 'l255', 'l271', 'l276', 'l280', 'l283', 'l286', 'l287']", + "133, migration ['l70', 'l151', 'l169', 'l186', 'l202', 'l217', 'l231', 'l244', 'l256', 'l272', 'l277', 'l281', 'l284', 'l286', 'l288']", + "135, invasion. ['l71', 'l152', 'l170', 'l187', 'l203', 'l218', 'l232', 'l245', 'l257', 'l273', 'l278', 'l282', 'l285', 'l287', 'l288']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced", + "increased" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "lymph", + "node", + "metastases" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "survival" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "lymph", + "node", + "metastases", + "metastasis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo.", + "vivo," + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "lymph", + "node", + "metastases" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "survival" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "survival" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "c-Src", + "kinase", + "activity" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "c-Src", + "kinase", + "activity" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "c-Src", + "kinase", + "activity" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "affect" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "decreased" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "decreased" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "decreased" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "affect" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "decreased" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "endogenous", + "alpha(v)beta(3)", + "integrin", + "or", + "c-Src" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "endogenous", + "alpha(v)beta(3)", + "integrin", + "or", + "c-Src" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "endogenous", + "alpha(v)beta(3)", + "integrin", + "or", + "c-Src" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "endogenous", + "alpha(v)beta(3)", + "integrin", + "or", + "c-Src" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "affect" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "endogenous", + "alpha(v)beta(3)", + "integrin", + "or", + "c-Src" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "endogenous", + "alpha(v)beta(3)", + "integrin", + "or", + "c-Src" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "endogenous", + "alpha(v)beta(3)", + "integrin", + "or", + "c-Src" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "suppressed" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "suppressed" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "affect" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "affect" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "affect" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion." + ] + } + } + ] + }, + { + "PMID": "19718039", + "TEXT": "Cystic kidney disease represents a major cause of end-stage renal disease, yet the molecular mechanisms of pathogenesis remain largely unclear. Recent emphasis has been placed on a potential role for canonical Wnt signaling, but investigation of this pathway in adult renal homeostasis is lacking. Here we provide evidence of a previously unidentified canonical Wnt activity in adult mammalian kidney homeostasis, the loss of which leads to cystic kidney disease. Loss of the Jouberin (Jbn) protein in mouse leads to the cystic kidney disease nephronophthisis, owing to an unexpected decrease in endogenous Wnt activity. Jbn interacts with and facilitates beta-catenin nuclear accumulation, resulting in positive modulation of downstream transcription. Finally, we show that Jbn is required in vivo for a Wnt response to injury and renal tubule repair, the absence of which triggers cystogenesis.", + "TAG_DATA": [ + "69, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "70, of {'perturbing_action': 'I-gene loss-of-function'}", + "71, the {'perturbing_action': 'I-gene loss-of-function'}", + "72, Jouberin {'perturbing_action': 'I-gene loss-of-function'}", + "73, (Jbn) {'perturbing_action': 'I-gene loss-of-function'}", + "74, protein {'perturbing_action': 'I-gene loss-of-function'}", + "76, mouse {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "69, Loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "70, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "71, the ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "72, Jouberin ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "73, (Jbn) ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "74, protein ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "76, mouse ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Loss", + "of", + "the", + "Jouberin", + "(Jbn)", + "protein" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + } + ] + }, + { + "PMID": "19701206", + "TEXT": "Members of the NADPH oxidase (NOX) family of enzymes, which catalyze the reduction of O(2) to reactive oxygen species, have increased in number during eukaryotic evolution. Seven isoforms of the NOX gene family have been identified in mammals; however, specific roles of NOX enzymes in mammalian physiology and pathophysiology have not been fully elucidated. The best established physiological role of NOX enzymes is in host defense against pathogen invasion in diverse species, including plants. The prototypical member of this family, NOX-2 (gp91(phox)), is expressed in phagocytic cells and mediates microbicidal activities. Here we report a role for the NOX4 isoform in tissue repair functions of myofibroblasts and fibrogenesis. Transforming growth factor-beta1 (TGF-beta1) induces NOX-4 expression in lung mesenchymal cells via SMAD-3, a receptor-regulated protein that modulates gene transcription. NOX-4-dependent generation of hydrogen peroxide (H(2)O(2)) is required for TGF-beta1-induced myofibroblast differentiation, extracellular matrix (ECM) production and contractility. NOX-4 is upregulated in lungs of mice subjected to noninfectious injury and in cases of human idiopathic pulmonary fibrosis (IPF). Genetic or pharmacologic targeting of NOX-4 abrogates fibrogenesis in two murine models of lung injury. These studies support a function for NOX4 in tissue fibrogenesis and provide proof of concept for therapeutic targeting of NOX-4 in recalcitrant fibrotic disorders.", + "TAG_DATA": [ + "116, lung {'context': 'B-cells'}", + "117, mesenchymal {'context': 'I-cells'}", + "118, cells {'context': 'I-cells'}", + "138, myofibroblast {'context': 'B-cells'}", + "139, differentiation, {'phenotype': 'B-differentiation'}", + "152, mice {'context': 'B-organism'}", + "168, pharmacologic {'perturbing_action': 'B-pharmacological inhibition'}", + "169, targeting {'perturbing_action': 'I-pharmacological inhibition'}", + "170, of {'perturbing_action': 'I-pharmacological inhibition'}", + "171, NOX-4 {'perturbing_action': 'I-pharmacological inhibition'}", + "176, murine {'context': 'B-organism'}", + "177, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "116, lung ['l0', 'l1', 'l2', 'l3', 'l4']", + "117, mesenchymal ['l0', 'l5', 'l6', 'l7', 'l8', 'l9']", + "118, cells ['l1', 'l5', 'l10', 'l11', 'l12']", + "137, TGF-beta1-induced ['l6', 'l13', 'l14', 'l15']", + "138, myofibroblast ['l2', 'l7', 'l10', 'l13', 'l16', 'l17']", + "139, differentiation, ['l3', 'l8', 'l11', 'l14', 'l16', 'l18']", + "152, mice ['l4', 'l9', 'l12', 'l15', 'l17', 'l18']", + "168, pharmacologic ['l19', 'l20', 'l21', 'l22', 'l23']", + "169, targeting ['l19', 'l24', 'l25', 'l26', 'l27']", + "170, of ['l20', 'l24', 'l28', 'l29', 'l30']", + "171, NOX-4 ['l21', 'l25', 'l28', 'l31', 'l32']", + "176, murine ['l22', 'l26', 'l29', 'l31', 'l33']", + "177, models ['l23', 'l27', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "lung", + "mesenchymal", + "cells", + "myofibroblast" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "targeting", + "of", + "NOX-4" + ] + }, + "context": { + "val": "organism", + "words": [ + "murine", + "models" + ] + } + } + ] + }, + { + "PMID": "19684583", + "TEXT": "Antigen-specific human monoclonal antibodies (mAbs) are key candidates for therapeutic agents. However, the availability of a suitable screening system for antigen-specific antibody-secreting cells (ASCs) is limited in humans. Here we present a unique method for detecting individual ASCs using microwell array chips, which enables the analysis of live cells on a single-cell basis and offers a rapid, efficient and high-throughput (up to 234,000 individual cells) system for identifying and recovering objective ASCs. We applied the system to detect and retrieve ASCs for hepatitis B virus and influenza viruses from human peripheral blood lymphocytes and produced human mAbs with virus-neutralizing activities within a week. Furthermore, we show that the system is useful for detecting ASCs for multiple antigens as well as for selection of ASCs secreting high-affinity antibodies on a chip. Our method can open the way for the generation of therapeutic antibodies for individual patients.", + "TAG_DATA": [ + "89, human {'context': 'B-cells'}", + "90, peripheral {'context': 'I-cells'}", + "91, blood {'context': 'I-cells'}", + "92, lymphocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "89, human ['l0', 'l1', 'l2']", + "90, peripheral ['l0', 'l3', 'l4']", + "91, blood ['l1', 'l3', 'l5']", + "92, lymphocytes ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19668193", + "TEXT": "We have previously shown that a granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-15 (IL-15) 'fusokine' (GIFT15) exerts immune suppression via aberrant signaling through the IL-15 receptor on lymphomyeloid cells. We show here that ex vivo GIFT15 treatment of mouse splenocytes generates suppressive regulatory cells of B cell ontogeny (hereafter called GIFT15 B(reg) cells). Arising from CD19+ B cells, GIFT15 B(reg) cells express major histocompatibility complex class I (MHCI) and MHCII, surface IgM and IgD, and secrete IL-10, akin to previously described B10 and T2-MZP B(reg) cells, but lose expression of the transcription factor PAX5, coupled to upregulation of CD138 and reciprocal suppression of CD19. Mice with experimental autoimmune encephalomyelitis went into complete remission after intravenous infusion of GIFT15 B(reg) cells paralleled by suppressed neuroinflammation. The clinical effect was abolished when GIFT15 B(reg) cells were derived from mmicroMT (lacking B cells), MHCII-knockout, signal transducer and activator of transcription-6 (STAT-6)-knockout, IL-10-knockout or allogeneic splenocytes, consistent with a pivotal role for MHCII and IL-10 by sygeneic B cells for the observed therapeutic effect. We propose that autologous GIFT15 B(reg) cells may serve as a new treatment for autoimmune ailments.", + "TAG_DATA": [ + "37, mouse {'context': 'B-cells'}", + "38, splenocytes {'context': 'I-cells'}", + "103, Mice {'context': 'B-organism'}", + "117, B(reg) {'context': 'I-cells'}", + "118, cells {'context': 'I-cells'}", + "129, GIFT15 {'context': 'B-cells'}", + "130, B(reg) {'context': 'I-cells'}", + "131, cells {'context': 'I-cells'}", + "137, B {'context': 'B-cells'}", + "139, MHCII-knockout, {'perturbing_action': 'B-gene loss-of-function'}", + "146, (STAT-6)-knockout, {'perturbing_action': 'I-gene loss-of-function'}", + "147, IL-10-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "149, allogeneic {'context': 'B-cells'}", + "150, splenocytes, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "37, mouse ['l0']", + "38, splenocytes ['l0']", + "103, Mice ['l1', 'l2']", + "117, B(reg) ['l1', 'l3']", + "118, cells ['l2', 'l3']", + "129, GIFT15 ['l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "130, B(reg) ['l4', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "131, cells ['l5', 'l15', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "135, mmicroMT ['l6', 'l16', 'l24', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "136, (lacking ['l7', 'l17', 'l25', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "137, B ['l8', 'l18', 'l26', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "138, cells), ['l9', 'l19', 'l27', 'l35', 'l41', 'l46', 'l51', 'l52']", + "139, MHCII-knockout, ['l10', 'l20', 'l28', 'l36', 'l42', 'l47', 'l51', 'l53', 'l54', 'l55', 'l56']", + "146, (STAT-6)-knockout, ['l11', 'l21', 'l29', 'l37', 'l43', 'l48', 'l52', 'l53', 'l57', 'l58', 'l59']", + "147, IL-10-knockout ['l12', 'l22', 'l30', 'l38', 'l44', 'l49', 'l54', 'l57', 'l60', 'l61']", + "149, allogeneic ['l13', 'l31', 'l55', 'l58', 'l60', 'l62']", + "150, splenocytes, ['l14', 'l23', 'l32', 'l39', 'l45', 'l50', 'l56', 'l59', 'l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "GIFT15", + "B(reg)", + "cells", + "B", + "allogeneic", + "splenocytes," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MHCII-knockout,", + "(STAT-6)-knockout,", + "IL-10-knockout" + ] + } + } + ] + }, + { + "PMID": "19648927", + "TEXT": "We have identified a new human immunodeficiency virus in a Cameroonian woman. It is closely related to gorilla simian immunodeficiency virus (SIVgor) and shows no evidence of recombination with other HIV-1 lineages. This new virus seems to be the prototype of a new HIV-1 lineage that is distinct from HIV-1 groups M, N and O. We propose to designate it HIV-1 group P.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19561616", + "TEXT": "Previous proteomic and transcriptional analyses of multiple sclerosis lesions revealed modulation of the renin-angiotensin and the opposing kallikrein-kinin pathways. Here we identify kinin receptor B1 (Bdkrb1) as a specific modulator of immune cell entry into the central nervous system (CNS). We demonstrate that the Bdkrb1 agonist R838 (Sar-[D-Phe]des-Arg(9)-bradykinin) markedly decreases the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in SJL mice, whereas the Bdkrb1 antagonist R715 (Ac-Lys-[D-betaNal(7), Ile(8)]des-Arg(9)-bradykinin) resulted in earlier onset and greater severity of the disease. Bdkrb1-deficient (Bdkrb1(-/-)) C57BL/6 mice immunized with a myelin oligodendrocyte glycoprotein fragment, MOG(35-55), showed more severe disease with enhanced CNS-immune cell infiltration. The same held true for mixed bone marrow-chimeric mice reconstituted with Bdkrb1(-/-) T lymphocytes, which showed enhanced T helper type 17 (T(H)17) cell invasion into the CNS. Pharmacological modulation of Bdkrb1 revealed that in vitro migration of human T(H)17 lymphocytes across blood-brain barrier endothelium is regulated by this receptor. Taken together, these results suggest that the kallikrein-kinin system is involved in the regulation of CNS inflammation, limiting encephalitogenic T lymphocyte infiltration into the CNS, and provide evidence that Bdkrb1 could be a new target for the treatment of chronic inflammatory diseases such as multiple sclerosis.", + "TAG_DATA": [ + "44, Bdkrb1 {'perturbing_action': 'B-pharmacological augmentation'}", + "45, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "46, R838 {'perturbing_action': 'I-pharmacological augmentation'}", + "59, SJL {'context': 'B-organism'}", + "60, mice, {'context': 'I-organism'}", + "63, Bdkrb1 {'perturbing_action': 'B-pharmacological inhibition'}", + "64, antagonist {'perturbing_action': 'I-pharmacological inhibition'}", + "65, R715 {'perturbing_action': 'I-pharmacological augmentation'}", + "78, Bdkrb1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "79, (Bdkrb1(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "80, C57BL/6 {'context': 'B-organism'}", + "81, mice {'context': 'I-organism'}", + "104, mixed {'context': 'B-organism'}", + "105, bone {'context': 'I-organism'}", + "106, marrow-chimeric {'context': 'I-organism'}", + "107, mice {'context': 'I-organism'}", + "110, Bdkrb1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "111, T {'context': 'B-cells'}", + "112, lymphocytes, {'context': 'I-cells'}", + "116, T {'context': 'B-cells'}", + "117, helper {'context': 'I-cells'}", + "118, type {'context': 'I-cells'}", + "119, 17 {'context': 'I-cells'}", + "120, (T(H)17) {'context': 'I-cells'}", + "121, cell {'context': 'I-cells'}", + "132, in {'context': 'B-in vitro'}", + "133, vitro {'context': 'I-in vitro'}", + "136, human {'context': 'B-cells'}", + "137, T(H)17 {'context': 'I-cells'}", + "138, lymphocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "44, Bdkrb1 ['l0', 'l1', 'l2', 'l3']", + "45, agonist ['l0', 'l4', 'l5', 'l6']", + "46, R838 ['l1', 'l4', 'l7', 'l8']", + "59, SJL ['l2', 'l5', 'l7', 'l9']", + "60, mice, ['l3', 'l6', 'l8', 'l9']", + "63, Bdkrb1 ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "64, antagonist ['l10', 'l16', 'l17', 'l18', 'l19']", + "65, R715 ['l11', 'l16', 'l20', 'l21', 'l22']", + "78, Bdkrb1-deficient ['l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "79, (Bdkrb1(-/-)) ['l13', 'l17', 'l20', 'l23', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "80, C57BL/6 ['l14', 'l18', 'l21', 'l24', 'l39', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "81, mice ['l15', 'l19', 'l22', 'l25', 'l40', 'l54', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "104, mixed ['l26', 'l41', 'l55', 'l67', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "105, bone ['l27', 'l42', 'l56', 'l68', 'l79', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "106, marrow-chimeric ['l28', 'l43', 'l57', 'l69', 'l80', 'l91', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "107, mice ['l29', 'l44', 'l58', 'l70', 'l81', 'l92', 'l102', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "110, Bdkrb1(-/-) ['l30', 'l45', 'l82', 'l93', 'l103', 'l112', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "111, T ['l31', 'l46', 'l59', 'l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "112, lymphocytes, ['l32', 'l47', 'l60', 'l72', 'l84', 'l95', 'l105', 'l114', 'l122', 'l129', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141']", + "116, T ['l33', 'l48', 'l61', 'l73', 'l85', 'l96', 'l106', 'l115', 'l123', 'l130', 'l136', 'l142', 'l143', 'l144', 'l145', 'l146']", + "117, helper ['l34', 'l49', 'l62', 'l74', 'l86', 'l97', 'l107', 'l116', 'l124', 'l131', 'l137', 'l142', 'l147', 'l148', 'l149', 'l150']", + "118, type ['l35', 'l50', 'l63', 'l75', 'l87', 'l98', 'l108', 'l117', 'l125', 'l132', 'l138', 'l143', 'l147', 'l151', 'l152', 'l153']", + "119, 17 ['l36', 'l51', 'l64', 'l76', 'l88', 'l99', 'l109', 'l118', 'l126', 'l133', 'l139', 'l144', 'l148', 'l151', 'l154', 'l155']", + "120, (T(H)17) ['l37', 'l52', 'l65', 'l77', 'l89', 'l100', 'l110', 'l119', 'l127', 'l134', 'l140', 'l145', 'l149', 'l152', 'l154', 'l156']", + "121, cell ['l38', 'l53', 'l66', 'l78', 'l90', 'l101', 'l111', 'l120', 'l128', 'l135', 'l141', 'l146', 'l150', 'l153', 'l155', 'l156']", + "132, in ['l157', 'l158', 'l159', 'l160']", + "133, vitro ['l157', 'l161', 'l162', 'l163']", + "136, human ['l158', 'l161', 'l164', 'l165']", + "137, T(H)17 ['l159', 'l162', 'l164', 'l166']", + "138, lymphocytes ['l160', 'l163', 'l165', 'l166']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Bdkrb1", + "agonist", + "R838", + "R715" + ] + }, + "context": { + "val": "organism", + "words": [ + "SJL", + "mice,", + "C57BL/6", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Bdkrb1", + "antagonist" + ] + }, + "context": { + "val": "organism", + "words": [ + "C57BL/6", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bdkrb1-deficient", + "(Bdkrb1(-/-))", + "Bdkrb1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "C57BL/6", + "mice", + "mixed", + "bone", + "marrow-chimeric" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bdkrb1-deficient", + "(Bdkrb1(-/-))", + "Bdkrb1(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "lymphocytes,", + "helper", + "type", + "17", + "(T(H)17)", + "cell" + ] + } + } + ] + }, + { + "PMID": "19543283", + "TEXT": "HIV persists in a reservoir of latently infected CD4(+) T cells in individuals treated with highly active antiretroviral therapy (HAART). Here we identify central memory (T(CM)) and transitional memory (T(TM)) CD4(+) T cells as the major cellular reservoirs for HIV and find that viral persistence is ensured by two different mechanisms. HIV primarily persists in T(CM) cells in subjects showing reconstitution of the CD4(+) compartment upon HAART. This reservoir is maintained through T cell survival and low-level antigen-driven proliferation and is slowly depleted with time. In contrast, proviral DNA is preferentially detected in T(TM) cells from aviremic individuals with low CD4(+) counts and higher amounts of interleukin-7-mediated homeostatic proliferation, a mechanism that ensures the persistence of these cells. Our results suggest that viral eradication might be achieved through the combined use of strategic interventions targeting viral replication and, as in cancer, drugs that interfere with the self renewal and persistence of proliferating memory T cells.", + "TAG_DATA": [ + "55, T(CM) {'context': 'B-cells'}", + "56, cells {'context': 'I-cells'}", + "93, T(TM) {'context': 'B-cells'}", + "94, cells {'context': 'I-cells'}", + "117, cells. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "55, T(CM) ['l0']", + "56, cells ['l0']", + "93, T(TM) ['l1']", + "94, cells ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19491843", + "TEXT": "Nonobese diabetic (NOD) mice provide an excellent model of type 1 diabetes. The genetic contribution to this disease is complex, with more than 20 loci implicated in diabetes onset. One of the challenges for researchers using the NOD mouse model (and, indeed, other models of spontaneous autoimmune disease) has been the high density of sequence variation within candidate chromosomal segments. Furthermore, the scope for analyzing many putative disease loci via gene targeting has been hampered by the lack of NOD embryonic stem (ES) cells. We describe here the derivation of NOD ES cell lines capable of generating chimeric mice after stable genetic modification. These NOD ES cell lines also show efficient germline transmission, with offspring developing diabetes. The availability of these cells will not only enable the dissection of closely linked loci and the role they have in the onset of type 1 diabetes but also facilitate the generation of new transgenics.", + "TAG_DATA": [ + "90, NOD {'context': 'B-cells'}", + "91, ES {'context': 'I-cells'}", + "92, cell {'context': 'I-cells'}", + "93, lines {'context': 'I-cells'}", + "104, NOD {'context': 'B-cells'}", + "105, ES {'context': 'I-cells'}", + "106, cell {'context': 'I-cells'}", + "107, lines {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "90, NOD ['l0', 'l1', 'l2']", + "91, ES ['l0', 'l3', 'l4']", + "92, cell ['l1', 'l3', 'l5']", + "93, lines ['l2', 'l4', 'l5']", + "104, NOD ['l6', 'l7', 'l8']", + "105, ES ['l6', 'l9', 'l10']", + "106, cell ['l7', 'l9', 'l11']", + "107, lines ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19483694", + "TEXT": "We describe here the paradoxical development of spontaneous experimental autoimmune encephalomyelitis (EAE) in transgenic mice expressing a myelin oligodendrocyte glycoprotein (MOG)-specific T cell antigen receptor (TCR) in the absence of MOG. We report that in Mog-deficient mice (Mog-/-), the autoimmune response by transgenic T cells is redirected to a neuronal cytoskeletal self antigen, neurofilament-M (NF-M). Although components of radically different protein classes, the cross-reacting major histocompatibility complex I-Ab-restricted epitope sequences of MOG35-55 and NF-M18-30 share essential TCR contact positions. This pattern of cross-reaction is not specific to the transgenic TCR but is also commonly seen in MOG35-55-I-Ab-reactive T cells. We propose that in the C57BL/6 mouse, MOG and NF-M response components add up to overcome the general resistance of this strain to experimental induction of autoimmunity. Similar cumulative responses against more than one autoantigen may have a role in spontaneously developing human autoimmune diseases.", + "TAG_DATA": [ + "35, Mog-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "36, mice {'context': 'B-organism'}", + "44, cells {'context': 'I-cells'}", + "98, cells. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "35, Mog-deficient ['l0', 'l1']", + "36, mice ['l0', 'l2']", + "44, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mog-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mog-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "19448634", + "TEXT": "Distal myopathy with rimmed vacuoles (DMRV)-hereditary inclusion body myopathy (hIBM) is an adult-onset, moderately progressive autosomal recessive myopathy; eventually, affected individuals become wheelchair bound1. It is characterized clinically by skeletal muscle atrophy and weakness, and pathologically by rimmed vacuoles, which are actually accumulations of autophagic vacuoles2, 3, 4, scattered angular fibers and intracellular accumulation of amyloid and other proteins5. To date, no therapy is available for this debilitating myopathy, primarily because the disease pathomechanism has been enigmatic. It is known that the disease gene underlying DMRV-hIBM is GNE, encoding glucosamine (UDP-N-acetyl)-2-epimerase and N-acetylmannosamine kinase6, 7, 8--two essential enzymes in sialic acid biosynthesis9. It is still unclear, however, whether decreased sialic acid production causes muscle degeneration, as GNE has been proposed to have roles other than for sialic acid biosynthesis10, 11, 12. By showing that muscle atrophy and weakness are completely prevented in a mouse model of DMRV-hIBM after treatment with sialic acid metabolites orally, we provide evidence that hyposialylation is indeed one of the key factors in the pathomechanism of DMRV-hIBM. These results support the notion that DMRV-hIBM can potentially be treated simply by giving sialic acids, a strategy that could be applied in clinical trials in the near future.", + "TAG_DATA": [ + "143, mouse {'context': 'B-organism'}", + "144, model {'context': 'I-organism'}", + "145, of {'context': 'I-organism'}", + "146, DMRV-hIBM {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "143, mouse ['l0', 'l1', 'l2']", + "144, model ['l0', 'l3', 'l4']", + "145, of ['l1', 'l3', 'l5']", + "146, DMRV-hIBM ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19448633", + "TEXT": "The key to an effective HIV vaccine is development of an immunogen that elicits persisting antibodies with broad neutralizing activity against field strains of the virus. Unfortunately, very little progress has been made in finding or designing such immunogens. Using the simian immunodeficiency virus (SIV) model, we have taken a markedly different approach: delivery to muscle of an adeno-associated virus gene transfer vector expressing antibodies or antibody-like immunoadhesins having predetermined SIV specificity. With this approach, SIV-specific molecules are endogenously synthesized in myofibers and passively distributed to the circulatory system. Using such an approach in monkeys, we have now generated long-lasting neutralizing activity in serum and have observed complete protection against intravenous challenge with virulent SIV. In essence, this strategy bypasses the adaptive immune system and holds considerable promise as a unique approach to an effective HIV vaccine.", + "TAG_DATA": [ + "94, monkeys, {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19430489", + "TEXT": "Inflammation and oxidative stress are pathogenic mediators of many diseases, but molecules that could be therapeutic targets remain elusive. Inflammation and matrix degradation in the vasculature are crucial for abdominal aortic aneurysm (AAA) formation. Cyclophilin A (CypA, encoded by Ppia) is highly expressed in vascular smooth muscle cells (VSMCs), is secreted in response to reactive oxygen species (ROS) and promotes inflammation. Using the angiotensin II (AngII)-induced AAA model in Apoe-/- mice, we show that Apoe-/-Ppia-/- mice are completely protected from AngII-induced AAA formation, in contrast to Apoe-/-Ppia+/+ mice. Apoe-/-Ppia-/- mice show decreased inflammatory cytokine expression, elastic lamina degradation and aortic expansion. These features were not altered by reconstitution of bone marrow cells from Ppia+/+ mice. Mechanistic studies showed that VSMC-derived intracellular and extracellular CypA are required for ROS generation and matrix metalloproteinase-2 activation. These data define a previously undescribed role for CypA in AAA formation and suggest CypA as a new target for treating cardiovascular disease.", + "TAG_DATA": [ + "69, Apoe-/- {'perturbing_action': 'B-gene loss-of-function'}", + "70, mice, {'context': 'B-organism'}", + "74, Apoe-/-Ppia-/- {'perturbing_action': 'B-gene loss-of-function'}", + "75, mice {'context': 'B-organism'}", + "86, Apoe-/-Ppia+/+ {'perturbing_action': 'B-gene loss-of-function'}", + "87, mice. {'context': 'B-organism'}", + "88, Apoe-/-Ppia-/- {'perturbing_action': 'B-gene loss-of-function'}", + "89, mice {'context': 'B-organism'}", + "109, bone {'context': 'B-cells'}", + "110, marrow {'context': 'I-cells'}", + "111, cells {'context': 'I-cells'}", + "114, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "69, Apoe-/- ['l0']", + "70, mice, ['l0']", + "74, Apoe-/-Ppia-/- ['l1']", + "75, mice ['l1']", + "86, Apoe-/-Ppia+/+ ['l2']", + "87, mice. ['l2']", + "88, Apoe-/-Ppia-/- ['l3', 'l4', 'l5']", + "89, mice ['l3']", + "109, bone ['l6', 'l7', 'l8']", + "110, marrow ['l4', 'l6', 'l9', 'l10']", + "111, cells ['l5', 'l7', 'l9', 'l11']", + "114, mice. ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apoe-/-", + "Apoe-/-Ppia-/-", + "Apoe-/-Ppia+/+" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apoe-/-Ppia-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "marrow", + "cells" + ] + } + } + ] + }, + { + "PMID": "19424198", + "TEXT": "In 1970, the US government chartered the Institute of Medicine (IOM), a component of the National Academies, to serve as an independent counsel on issues concerning health policy. Today, the IOM has become a leading adviser on an array of topics from vaccine safety to the organizational structure of the National Institutes of Health (NIH). The institute has nearly 1,600 members who carry out studies, conduct workshops, hold public forums and publish influential reports. Harvey Fineberg, former provost of Harvard University, has served at the helm of the IOM as the institute's president since 2002. During his tenure at the institute, Fineberg has overseen a raft of studies on topics ranging from AIDS prevention to new medical technologies. He spoke to Prashant Nair about the role of the IOM in biomedical research in the US.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19412173", + "TEXT": "In salt-sensitive hypertension, the accumulation of Na(+) in tissue has been presumed to be accompanied by a commensurate retention of water to maintain the isotonicity of body fluids. We show here that a high-salt diet (HSD) in rats leads to interstitial hypertonic Na(+) accumulation in skin, resulting in increased density and hyperplasia of the lymphcapillary network. The mechanisms underlying these effects on lymphatics involve activation of tonicity-responsive enhancer binding protein (TonEBP) in mononuclear phagocyte system (MPS) cells infiltrating the interstitium of the skin. TonEBP binds the promoter of the gene encoding vascular endothelial growth factor-C (VEGF-C, encoded by Vegfc) and causes VEGF-C secretion by macrophages. MPS cell depletion or VEGF-C trapping by soluble VEGF receptor-3 blocks VEGF-C signaling, augments interstitial hypertonic volume retention, decreases endothelial nitric oxide synthase expression and elevates blood pressure in response to HSD. Our data show that TonEBP-VEGF-C signaling in MPS cells is a major determinant of extracellular volume and blood pressure homeostasis and identify VEGFC as an osmosensitive, hypertonicity-driven gene intimately involved in salt-induced hypertension.", + "TAG_DATA": [ + "37, rats {'context': 'B-organism'}", + "45, skin, {'context': 'B-tissue/organ'}", + "104, macrophages. {'context': 'B-cells'}", + "105, MPS {'context': 'B-cells'}", + "106, cell {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "107, depletion {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "37, rats ['l0', 'l1']", + "45, skin, ['l0']", + "104, macrophages. ['l1']", + "105, MPS ['l2', 'l3', 'l4']", + "106, cell ['l2', 'l5', 'l6']", + "107, depletion ['l3', 'l5', 'l7']", + "114, receptor-3 ['l4', 'l6', 'l7']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "MPS", + "cell" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cell", + "depletion" + ] + } + } + ] + }, + { + "PMID": "19398967", + "TEXT": "The in vitro analysis of intestinal epithelium has been hampered by a lack of suitable culture systems. Here we describe robust long-term methodology for small and large intestinal culture, incorporating an air-liquid interface and underlying stromal elements. These cultures showed prolonged intestinal epithelial expansion as sphere-like organoids with proliferation and multilineage differentiation. The Wnt growth factor family positively regulates proliferation of the intestinal epithelium in vivo. Accordingly, culture growth was inhibited by the Wnt antagonist Dickkopf-1 (Dkk1) and markedly stimulated by a fusion protein between the Wnt agonist R-spondin-1 and immunoglobulin Fc (RSpo1-Fc). Furthermore, treatment with the gamma-secretase inhibitor dibenzazepine and neurogenin-3 overexpression induced goblet cell and enteroendocrine cell differentiation, respectively, consistent with endogenous Notch signaling and lineage plasticity. Epithelial cells derived from both leucine-rich repeat-containing G protein-coupled receptor-5-positive (Lgr5(+)) and B lymphoma moloney murine leukemia virus insertion region homolog-1-positive (Bmi1(+)) lineages, representing putative intestinal stem cell (ISC) populations, were present in vitro and were expanded by treatment with RSpo1-Fc; this increased number of Lgr5(+) cells upon RSpo1-Fc treatment was subsequently confirmed in vivo. Our results indicate successful long-term intestinal culture within a microenvironment accurately recapitulating the Wnt- and Notch-dependent ISC niche.", + "TAG_DATA": [ + "64, in {'context': 'B-in vivo'}", + "65, vivo. {'context': 'I-in vivo'}", + "67, culture {'phenotype': 'B-cell growth'}", + "101, neurogenin-3 {'perturbing_action': 'B-gene gain-of-function'}", + "102, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "103, induced {'effect': 'B-positive'}", + "104, goblet {'context': 'B-cells'}", + "105, cell {'context': 'I-cells'}", + "107, enteroendocrine {'context': 'B-cells'}", + "108, cell {'context': 'I-cells'}", + "109, differentiation, {'phenotype': 'B-differentiation'}", + "119, Epithelial {'context': 'B-cells'}", + "120, cells {'context': 'I-cells'}", + "151, in {'context': 'B-in vitro'}", + "152, vitro {'context': 'I-in vitro'}", + "164, Lgr5(+) {'context': 'B-cells'}", + "165, cells {'context': 'I-cells'}", + "172, in {'context': 'B-in vivo'}", + "173, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "64, in ['l0']", + "65, vivo. ['l0']", + "101, neurogenin-3 ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "102, overexpression ['l1', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "103, induced ['l2', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26']", + "104, goblet ['l3', 'l13', 'l22', 'l27', 'l28', 'l29', 'l30', 'l31']", + "105, cell ['l4', 'l14', 'l23', 'l27', 'l32', 'l33', 'l34']", + "107, enteroendocrine ['l5', 'l15', 'l24', 'l28', 'l32', 'l35', 'l36', 'l37']", + "108, cell ['l6', 'l16', 'l25', 'l29', 'l33', 'l35', 'l38']", + "109, differentiation, ['l7', 'l17', 'l26', 'l30', 'l34', 'l36', 'l38']", + "119, Epithelial ['l8', 'l18', 'l39', 'l40', 'l41']", + "120, cells ['l9', 'l19', 'l31', 'l37', 'l39', 'l42', 'l43']", + "151, in ['l10', 'l20', 'l40', 'l42', 'l44']", + "152, vitro ['l11', 'l21', 'l41', 'l43', 'l44']", + "164, Lgr5(+) ['l45', 'l46', 'l47']", + "165, cells ['l45', 'l48', 'l49']", + "172, in ['l46', 'l48', 'l50']", + "173, vivo. ['l47', 'l49', 'l50']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "neurogenin-3", + "overexpression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "neurogenin-3", + "overexpression" + ] + }, + "context": { + "val": "cells", + "words": [ + "goblet", + "cell", + "enteroendocrine", + "Epithelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "neurogenin-3", + "overexpression" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "neurogenin-3", + "overexpression" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "goblet", + "cell", + "enteroendocrine" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "goblet", + "cell", + "enteroendocrine" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + } + ] + }, + { + "PMID": "19305413", + "TEXT": "Inhibitors of alpha(v)beta(3) and alpha(v)beta(5) integrin have entered clinical trials as antiangiogenic agents for cancer treatment but generally have been unsuccessful. Here we present in vivo evidence that low (nanomolar) concentrations of RGD-mimetic alpha(v)beta(3) and alpha(v)beta(5) inhibitors can paradoxically stimulate tumor growth and tumor angiogenesis. We show that low concentrations of these inhibitors promote VEGF-mediated angiogenesis by altering alpha(v)beta(3) integrin and vascular endothelial growth factor receptor-2 trafficking, thereby promoting endothelial cell migration to VEGF. The proangiogenic effects of low concentrations of RGD-mimetic integrin inhibitors could compromise their efficacy as anticancer agents and have major implications for the use of RGD-mimetic compounds in humans.", + "TAG_DATA": [ + "24, in {'context': 'B-in vivo'}", + "25, vivo {'context': 'I-in vivo'}", + "32, RGD-mimetic {'perturbing_action': 'B-pharmacological inhibition'}", + "33, alpha(v)beta(3) {'perturbing_action': 'I-pharmacological inhibition'}", + "34, and {'perturbing_action': 'I-pharmacological inhibition'}", + "35, alpha(v)beta(5) {'perturbing_action': 'I-pharmacological inhibition'}", + "36, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "39, stimulate {'effect': 'B-positive'}", + "40, tumor {'phenotype': 'B-tumour growth'}", + "41, growth {'phenotype': 'I-tumour growth'}", + "43, tumor {'context': 'B-neoplasm'}", + "68, promoting {'effect': 'B-positive'}", + "69, endothelial {'context': 'B-cells'}", + "70, cell {'context': 'I-cells'}", + "71, migration {'phenotype': 'B-migration'}" + ], + "LINK_DATA": [ + "24, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "25, vivo ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "32, RGD-mimetic ['l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "33, alpha(v)beta(3) ['l11', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "34, and ['l12', 'l23', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "35, alpha(v)beta(5) ['l13', 'l24', 'l34', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "36, inhibitors ['l1', 'l6', 'l14', 'l25', 'l35', 'l44', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "39, stimulate ['l2', 'l7', 'l15', 'l26', 'l36', 'l45', 'l53', 'l61', 'l62', 'l63']", + "40, tumor ['l3', 'l8', 'l16', 'l27', 'l37', 'l46', 'l54', 'l61', 'l64', 'l65']", + "41, growth ['l4', 'l9', 'l17', 'l28', 'l38', 'l47', 'l55', 'l62', 'l64', 'l66']", + "43, tumor ['l5', 'l10', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l65', 'l66']", + "68, promoting ['l19', 'l30', 'l40', 'l49', 'l57', 'l67', 'l68', 'l69']", + "69, endothelial ['l20', 'l31', 'l41', 'l50', 'l58', 'l67', 'l70', 'l71']", + "70, cell ['l21', 'l32', 'l42', 'l51', 'l59', 'l68', 'l70', 'l72']", + "71, migration ['l22', 'l33', 'l43', 'l52', 'l60', 'l69', 'l71', 'l72']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulate" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "RGD-mimetic", + "alpha(v)beta(3)", + "and", + "alpha(v)beta(5)", + "inhibitors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulate", + "promoting" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "RGD-mimetic", + "alpha(v)beta(3)", + "and", + "alpha(v)beta(5)", + "inhibitors" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "RGD-mimetic", + "alpha(v)beta(3)", + "and", + "alpha(v)beta(5)", + "inhibitors" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "RGD-mimetic", + "alpha(v)beta(3)", + "and", + "alpha(v)beta(5)", + "inhibitors" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "RGD-mimetic", + "alpha(v)beta(3)", + "and", + "alpha(v)beta(5)", + "inhibitors" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulate" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulate" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + } + ] + }, + { + "PMID": "19252502", + "TEXT": "Osteoclasts are acid-secreting polykaryons that have high energy demands and contain abundant mitochondria. How mitochondrial biogenesis is integrated with osteoclast differentiation is unknown. We found that the transcription of Ppargc1b, which encodes peroxisome proliferator-activated receptor-gamma coactivator 1beta (PGC-1beta), was induced during osteoclast differentiation by cAMP response element-binding protein (CREB) as a result of reactive oxygen species. Knockdown of Ppargc1b in vitro inhibited osteoclast differentiation and mitochondria biogenesis, whereas deletion of the Ppargc1b gene in mice resulted in increased bone mass due to impaired osteoclast function. We also observed defects in PGC-1beta-deficient osteoblasts. Owing to the heightened iron demand in osteoclast development, transferrin receptor 1 (TfR1) expression was induced post-transcriptionally via iron regulatory protein 2. TfR1-mediated iron uptake promoted osteoclast differentiation and bone-resorbing activity, associated with the induction of mitochondrial respiration, production of reactive oxygen species and accelerated Ppargc1b transcription. Iron chelation inhibited osteoclastic bone resorption and protected against bone loss following estrogen deficiency resulting from ovariectomy. These data establish mitochondrial biogenesis orchestrated by PGC-1beta, coupled with iron uptake through TfR1 and iron supply to mitochondrial respiratory proteins, as a fundamental pathway linked to osteoclast activation and bone metabolism.", + "TAG_DATA": [ + "56, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "57, of {'perturbing_action': 'I-rnai/knockdown'}", + "58, Ppargc1b {'perturbing_action': 'I-rnai/knockdown'}", + "59, in {'context': 'B-in vitro'}", + "60, vitro {'context': 'I-in vitro'}", + "61, inhibited {'effect': 'B-negative'}", + "62, osteoclast {'context': 'B-cells'}", + "63, differentiation {'phenotype': 'B-differentiation'}", + "68, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "69, of {'perturbing_action': 'I-gene loss-of-function'}", + "70, the {'perturbing_action': 'I-gene loss-of-function'}", + "71, Ppargc1b {'perturbing_action': 'I-gene loss-of-function'}", + "72, gene {'perturbing_action': 'I-gene loss-of-function'}", + "74, mice {'context': 'B-organism'}", + "90, PGC-1beta-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "91, osteoblasts. {'context': 'B-cells'}", + "117, promoted {'effect': 'B-positive'}", + "118, osteoclast {'context': 'B-cells'}", + "119, differentiation {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "56, Knockdown ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "57, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "58, Ppargc1b ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "59, in ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27']", + "60, vitro ['l3', 'l11', 'l18', 'l24', 'l28', 'l29', 'l30']", + "61, inhibited ['l4', 'l12', 'l19', 'l25', 'l28', 'l31', 'l32']", + "62, osteoclast ['l5', 'l13', 'l20', 'l26', 'l29', 'l31', 'l33']", + "63, differentiation ['l6', 'l14', 'l21', 'l27', 'l30', 'l32', 'l33']", + "68, deletion ['l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "69, of ['l34', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "70, the ['l35', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "71, Ppargc1b ['l36', 'l44', 'l51', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "72, gene ['l37', 'l45', 'l52', 'l58', 'l64', 'l65', 'l66', 'l67']", + "74, mice ['l7', 'l15', 'l22', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l69']", + "90, PGC-1beta-deficient ['l70', 'l71', 'l72', 'l73']", + "91, osteoblasts. ['l39', 'l47', 'l54', 'l60', 'l70', 'l74', 'l75', 'l76']", + "117, promoted ['l40', 'l48', 'l55', 'l61', 'l65', 'l68', 'l71', 'l74', 'l77', 'l78']", + "118, osteoclast ['l41', 'l49', 'l56', 'l62', 'l66', 'l72', 'l75', 'l77', 'l79']", + "119, differentiation ['l8', 'l16', 'l23', 'l42', 'l50', 'l57', 'l63', 'l67', 'l69', 'l73', 'l76', 'l78', 'l79']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "Ppargc1b" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "Ppargc1b" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "Ppargc1b" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "Ppargc1b" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "Ppargc1b" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoclast", + "osteoblasts." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "Ppargc1b", + "gene" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "Ppargc1b", + "gene", + "PGC-1beta-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoblasts.", + "osteoclast" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "Ppargc1b", + "gene", + "PGC-1beta-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "Ppargc1b", + "gene", + "PGC-1beta-deficient" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoblasts.", + "osteoclast" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "19198615", + "TEXT": "Profound neuronal dysfunction in the entorhinal cortex contributes to early loss of short-term memory in Alzheimer's disease. Here we show broad neuroprotective effects of entorhinal brain-derived neurotrophic factor (BDNF) administration in several animal models of Alzheimer's disease, with extension of therapeutic benefits into the degenerating hippocampus. In amyloid-transgenic mice, BDNF gene delivery, when administered after disease onset, reverses synapse loss, partially normalizes aberrant gene expression, improves cell signaling and restores learning and memory. These outcomes occur independently of effects on amyloid plaque load. In aged rats, BDNF infusion reverses cognitive decline, improves age-related perturbations in gene expression and restores cell signaling. In adult rats and primates, BDNF prevents lesion-induced death of entorhinal cortical neurons. In aged primates, BDNF reverses neuronal atrophy and ameliorates age-related cognitive impairment. Collectively, these findings indicate that BDNF exerts substantial protective effects on crucial neuronal circuitry involved in Alzheimer's disease, acting through amyloid-independent mechanisms. BDNF therapeutic delivery merits exploration as a potential therapy for Alzheimer's disease.", + "TAG_DATA": [ + "47, amyloid-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "48, mice, {'context': 'B-organism'}", + "50, gene {'perturbing_action': 'I-gene gain-of-function'}", + "51, delivery, {'perturbing_action': 'I-gene gain-of-function'}", + "84, aged {'context': 'B-organism'}", + "85, rats, {'context': 'I-organism'}", + "102, adult {'context': 'B-organism'}", + "103, rats {'context': 'I-organism'}", + "105, primates, {'context': 'I-organism'}", + "111, entorhinal {'context': 'B-cells'}", + "112, cortical {'context': 'I-cells'}", + "113, neurons. {'context': 'I-cells'}", + "115, aged {'context': 'B-organism'}", + "116, primates, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "47, amyloid-transgenic ['l0', 'l1', 'l2']", + "48, mice, ['l0', 'l3', 'l4']", + "50, gene ['l1', 'l3', 'l5']", + "51, delivery, ['l2', 'l4', 'l5']", + "84, aged ['l6', 'l7']", + "85, rats, ['l6']", + "102, adult ['l8', 'l9', 'l10', 'l11', 'l12']", + "103, rats ['l8', 'l13', 'l14', 'l15', 'l16']", + "105, primates, ['l9', 'l13', 'l17', 'l18', 'l19']", + "111, entorhinal ['l10', 'l14', 'l17', 'l20', 'l21']", + "112, cortical ['l11', 'l15', 'l18', 'l20', 'l22']", + "113, neurons. ['l7', 'l12', 'l16', 'l19', 'l21', 'l22']", + "115, aged ['l23']", + "116, primates, ['l23']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "amyloid-transgenic", + "gene", + "delivery," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "19151728", + "TEXT": "Cerebral cavernous malformation (CCM) is a common vascular dysplasia that affects both systemic and central nervous system blood vessels. Loss of function mutations in the CCM2 gene cause CCM. Here we show that targeted disruption of Ccm2 in mice results in failed lumen formation and early embryonic death through an endothelial cell autonomous mechanism. We show that CCM2 regulates endothelial cytoskeletal architecture, cell-to-cell interactions and lumen formation. Heterozygosity at Ccm2, a genotype equivalent to that in human CCM, results in impaired endothelial barrier function. On the basis of our biochemical studies indicating that loss of CCM2 results in activation of RHOA GTPase, we rescued the cellular phenotype and barrier function in heterozygous mice with simvastatin, a drug known to inhibit Rho GTPases. These data offer the prospect for pharmacological treatment of a human vascular dysplasia with a widely available and safe drug.", + "TAG_DATA": [ + "33, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "34, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "35, of {'perturbing_action': 'I-gene loss-of-function'}", + "36, Ccm2 {'perturbing_action': 'I-gene loss-of-function'}", + "38, mice {'context': 'B-organism'}", + "47, death {'phenotype': 'I-necrosis'}", + "67, Heterozygosity {'perturbing_action': 'B-other'}", + "68, at {'perturbing_action': 'I-other'}", + "69, Ccm2, {'perturbing_action': 'I-other'}", + "93, loss {'perturbing_action': 'B-gene loss-of-function'}", + "94, of {'perturbing_action': 'I-gene loss-of-function'}", + "95, CCM2 {'perturbing_action': 'I-gene loss-of-function'}", + "111, heterozygous {'perturbing_action': 'B-other'}", + "112, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "33, targeted ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "34, disruption ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "35, of ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "36, Ccm2 ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "38, mice ['l3', 'l8', 'l12', 'l15', 'l18']", + "46, embryonic ['l4', 'l9', 'l13', 'l16', 'l19']", + "47, death ['l5', 'l10', 'l14', 'l17', 'l18', 'l19']", + "67, Heterozygosity ['l20', 'l21']", + "68, at ['l20', 'l22']", + "69, Ccm2, ['l21', 'l22']", + "93, loss ['l23', 'l24']", + "94, of ['l23', 'l25']", + "95, CCM2 ['l24', 'l25']", + "111, heterozygous ['l26']", + "112, mice ['l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "disruption", + "of", + "Ccm2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "disruption", + "of", + "Ccm2" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "death" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "death" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "19151727", + "TEXT": "Cerebral cavernous malformations (CCMs) are human vascular malformations caused by mutations in three genes of unknown function: KRIT1, CCM2 and PDCD10. Here we show that the heart of glass (HEG1) receptor, which in zebrafish has been linked to ccm gene function, is selectively expressed in endothelial cells. Heg1(-/-) mice showed defective integrity of the heart, blood vessels and lymphatic vessels. Heg1(-/-); Ccm2(lacZ/+) and Ccm2(lacZ/lacZ) mice had more severe cardiovascular defects and died early in development owing to a failure of nascent endothelial cells to associate into patent vessels. This endothelial cell phenotype was shared by zebrafish embryos deficient in heg, krit1 or ccm2 and reproduced in CCM2-deficient human endothelial cells in vitro. Defects in the hearts of zebrafish lacking heg or ccm2, in the aortas of early mouse embryos lacking CCM2 and in the lymphatic vessels of neonatal mice lacking HEG1 were associated with abnormal endothelial cell junctions like those observed in human CCMs. Biochemical and cellular imaging analyses identified a cell-autonomous pathway in which the HEG1 receptor couples to KRIT1 at these cell junctions. This study identifies HEG1-CCM protein signaling as a crucial regulator of heart and vessel formation and integrity.", + "TAG_DATA": [ + "47, Heg1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "48, mice {'context': 'B-organism'}", + "60, Heg1(-/-); {'perturbing_action': 'B-gene loss-of-function'}", + "61, Ccm2(lacZ/+) {'perturbing_action': 'B-gene loss-of-function'}", + "62, and {'perturbing_action': 'I-gene loss-of-function'}", + "63, Ccm2(lacZ/lacZ) {'perturbing_action': 'B-gene loss-of-function'}", + "64, mice {'context': 'B-organism'}", + "81, endothelial {'context': 'B-cells'}", + "82, cells {'context': 'I-cells'}", + "95, zebrafish {'context': 'B-organism'}", + "96, embryos {'context': 'I-organism'}", + "97, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "98, in {'perturbing_action': 'I-gene loss-of-function'}", + "99, heg, {'perturbing_action': 'I-gene loss-of-function'}", + "100, krit1 {'perturbing_action': 'I-gene loss-of-function'}", + "101, or {'perturbing_action': 'I-gene loss-of-function'}", + "102, ccm2 {'perturbing_action': 'I-gene loss-of-function'}", + "106, CCM2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "107, human {'context': 'B-cells'}", + "108, endothelial {'context': 'I-cells'}", + "109, cells {'context': 'I-cells'}", + "110, in {'context': 'B-in vitro'}", + "111, vitro. {'context': 'I-in vitro'}", + "115, hearts {'context': 'B-tissue/organ'}", + "117, zebrafish {'context': 'B-organism'}", + "118, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "119, heg {'perturbing_action': 'I-gene loss-of-function'}", + "120, or {'perturbing_action': 'I-gene loss-of-function'}", + "121, ccm2, {'perturbing_action': 'I-gene loss-of-function'}", + "124, aortas {'context': 'B-tissue/organ'}", + "126, early {'context': 'B-organism'}", + "127, mouse {'context': 'I-organism'}", + "128, embryos {'context': 'I-organism'}", + "129, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "130, CCM2 {'perturbing_action': 'I-gene loss-of-function'}", + "134, lymphatic {'context': 'B-tissue/organ'}", + "135, vessels {'context': 'I-tissue/organ'}", + "137, neonatal {'context': 'B-organism'}", + "138, mice {'context': 'I-organism'}", + "139, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "140, HEG1 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "47, Heg1(-/-) ['l0']", + "48, mice ['l0']", + "60, Heg1(-/-); ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "61, Ccm2(lacZ/+) ['l1', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "62, and ['l2', 'l20', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "63, Ccm2(lacZ/lacZ) ['l3', 'l21', 'l38', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "64, mice ['l4', 'l22', 'l39', 'l55', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "81, endothelial ['l5', 'l23', 'l40', 'l56', 'l73', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "82, cells ['l6', 'l24', 'l41', 'l57', 'l74', 'l84', 'l90']", + "95, zebrafish ['l7', 'l25', 'l42', 'l58', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "96, embryos ['l8', 'l26', 'l43', 'l59', 'l75', 'l91', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "97, deficient ['l9', 'l27', 'l44', 'l60', 'l76', 'l92', 'l110', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "98, in ['l10', 'l28', 'l45', 'l61', 'l77', 'l93', 'l111', 'l124', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "99, heg, ['l11', 'l29', 'l46', 'l62', 'l78', 'l94', 'l112', 'l125', 'l141', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "100, krit1 ['l12', 'l30', 'l47', 'l63', 'l79', 'l85', 'l95', 'l113', 'l126', 'l142', 'l158', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184']", + "101, or ['l13', 'l31', 'l48', 'l64', 'l80', 'l86', 'l96', 'l114', 'l127', 'l143', 'l159', 'l173', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "102, ccm2 ['l14', 'l32', 'l49', 'l65', 'l81', 'l87', 'l97', 'l115', 'l128', 'l144', 'l160', 'l174', 'l185', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200']", + "106, CCM2-deficient ['l66', 'l98', 'l116', 'l129', 'l145', 'l161', 'l175', 'l186', 'l194', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212']", + "107, human ['l15', 'l33', 'l50', 'l67', 'l99', 'l117', 'l130', 'l146', 'l162', 'l176', 'l187', 'l195', 'l201', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220']", + "108, endothelial ['l16', 'l34', 'l51', 'l68', 'l82', 'l88', 'l100', 'l118', 'l131', 'l147', 'l163', 'l177', 'l188', 'l196', 'l202', 'l213', 'l221', 'l222', 'l223', 'l224', 'l225']", + "109, cells ['l17', 'l35', 'l52', 'l69', 'l83', 'l89', 'l90', 'l101', 'l119', 'l132', 'l148', 'l164', 'l178', 'l189', 'l197', 'l203', 'l214', 'l221', 'l226', 'l227']", + "110, in ['l18', 'l36', 'l53', 'l70', 'l102', 'l120', 'l133', 'l149', 'l165', 'l179', 'l190', 'l198', 'l204', 'l215', 'l222', 'l226', 'l228', 'l229']", + "111, vitro. ['l19', 'l37', 'l54', 'l71', 'l103', 'l121', 'l134', 'l150', 'l166', 'l180', 'l191', 'l199', 'l205', 'l216', 'l223', 'l227', 'l228', 'l230']", + "115, hearts ['l72', 'l104', 'l122', 'l135', 'l151', 'l167', 'l181', 'l192', 'l200', 'l206', 'l217', 'l224', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241']", + "117, zebrafish ['l152', 'l207', 'l231', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252']", + "118, lacking ['l105', 'l136', 'l153', 'l168', 'l182', 'l208', 'l218', 'l232', 'l242', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262']", + "119, heg ['l106', 'l137', 'l154', 'l169', 'l209', 'l233', 'l243', 'l253', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271']", + "120, or ['l107', 'l138', 'l155', 'l170', 'l183', 'l210', 'l219', 'l234', 'l244', 'l254', 'l263', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279']", + "121, ccm2, ['l108', 'l123', 'l139', 'l156', 'l171', 'l184', 'l193', 'l211', 'l220', 'l225', 'l235', 'l245', 'l255', 'l264', 'l272', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286']", + "124, aortas ['l109', 'l140', 'l157', 'l172', 'l212', 'l236', 'l246', 'l256', 'l265', 'l273', 'l280', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292']", + "126, early ['l237', 'l247', 'l257', 'l266', 'l274', 'l281', 'l287', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301']", + "127, mouse ['l238', 'l248', 'l258', 'l267', 'l275', 'l282', 'l288', 'l293', 'l302', 'l303', 'l304', 'l305', 'l306', 'l307', 'l308', 'l309']", + "128, embryos ['l239', 'l249', 'l259', 'l268', 'l276', 'l283', 'l289', 'l294', 'l302', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315', 'l316']", + "129, lacking ['l240', 'l250', 'l260', 'l269', 'l277', 'l284', 'l290', 'l295', 'l303', 'l310', 'l317', 'l318', 'l319', 'l320', 'l321', 'l322']", + "130, CCM2 ['l241', 'l251', 'l261', 'l270', 'l278', 'l285', 'l291', 'l296', 'l304', 'l311', 'l317', 'l323', 'l324', 'l325', 'l326', 'l327']", + "134, lymphatic ['l297', 'l305', 'l312', 'l318', 'l323', 'l328', 'l329', 'l330', 'l331', 'l332']", + "135, vessels ['l252', 'l262', 'l271', 'l279', 'l286', 'l292', 'l298', 'l306', 'l313', 'l319', 'l324', 'l328', 'l333', 'l334', 'l335', 'l336']", + "137, neonatal ['l329', 'l333', 'l337', 'l338', 'l339']", + "138, mice ['l299', 'l307', 'l314', 'l320', 'l325', 'l330', 'l334', 'l337', 'l340', 'l341']", + "139, lacking ['l300', 'l308', 'l315', 'l321', 'l326', 'l331', 'l335', 'l338', 'l340', 'l342']", + "140, HEG1 ['l301', 'l309', 'l316', 'l322', 'l327', 'l332', 'l336', 'l339', 'l341', 'l342']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Heg1(-/-)", + "Heg1(-/-);", + "Ccm2(lacZ/+)", + "and", + "Ccm2(lacZ/lacZ)", + "deficient", + "in", + "heg,", + "krit1", + "or", + "ccm2", + "CCM2-deficient", + "lacking", + "heg", + "ccm2,", + "CCM2", + "HEG1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "zebrafish", + "embryos", + "early", + "mouse", + "neonatal" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Heg1(-/-);", + "Ccm2(lacZ/+)", + "and", + "Ccm2(lacZ/lacZ)", + "krit1", + "or", + "ccm2", + "deficient", + "in", + "heg,", + "CCM2-deficient", + "lacking", + "ccm2," + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells", + "human" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Heg1(-/-);", + "Ccm2(lacZ/+)", + "and", + "Ccm2(lacZ/lacZ)", + "deficient", + "in", + "heg,", + "krit1", + "or", + "ccm2", + "CCM2-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ccm2(lacZ/lacZ)", + "deficient", + "in", + "heg,", + "krit1", + "or", + "ccm2", + "CCM2-deficient", + "lacking", + "heg", + "ccm2,", + "CCM2", + "HEG1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hearts", + "aortas", + "vessels", + "lymphatic" + ] + } + } + ] + }, + { + "PMID": "19122659", + "TEXT": "We report the development of a new method to induce glioblastoma multiforme in adult immunocompetent mice by injecting Cre-loxP-controlled lentiviral vectors expressing oncogenes. Cell type- or region-specific expression of activated forms of the oncoproteins Harvey-Ras and AKT in fewer than 60 glial fibrillary acidic protein-positive cells in the hippocampus, subventricular zone or cortex of mice heterozygous for the gene encoding the tumor suppressor Tp53 were tested. Mice developed glioblastoma multiforme when transduced either in the subventricular zone or the hippocampus. However, tumors were rarely detected when the mice were transduced in the cortex. Transplantation of brain tumor cells into naive recipient mouse brain resulted in the formation of glioblastoma multiforme-like tumors, which contained CD133(+) cells, formed tumorspheres and could differentiate into neurons and astrocytes. We suggest that the use of Cre-loxP-controlled lentiviral vectors is a novel way to generate a mouse glioblastoma multiforme model in a region- and cell type-specific manner in adult mice.", + "TAG_DATA": [ + "52, cortex {'context': 'B-tissue/organ'}", + "54, mice {'context': 'B-organism'}", + "55, heterozygous {'perturbing_action': 'B-other'}", + "56, for {'perturbing_action': 'I-other'}", + "57, the {'perturbing_action': 'I-other'}", + "58, gene {'perturbing_action': 'I-other'}", + "59, encoding {'perturbing_action': 'I-other'}", + "60, the {'perturbing_action': 'I-other'}", + "61, tumor {'perturbing_action': 'I-other'}", + "62, suppressor {'perturbing_action': 'I-other'}", + "63, Tp53 {'perturbing_action': 'I-other'}", + "66, Mice {'context': 'B-organism'}", + "71, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "76, zone {'context': 'I-tissue/organ'}", + "81, tumors {'phenotype': 'B-tumourigenesis'}", + "87, mice {'context': 'B-organism'}", + "92, cortex. {'context': 'B-tissue/organ'}", + "95, brain {'context': 'B-transformed cells'}", + "96, tumor {'context': 'I-transformed cells'}", + "97, cells {'context': 'I-transformed cells'}", + "100, recipient {'context': 'B-tissue/organ'}", + "101, mouse {'context': 'I-tissue/organ'}", + "102, brain {'context': 'I-tissue/organ'}", + "108, glioblastoma {'phenotype': 'B-tumourigenesis'}", + "109, multiforme-like {'phenotype': 'I-tumourigenesis'}", + "110, tumors, {'phenotype': 'B-tumourigenesis'}", + "116, tumorspheres {'phenotype': 'B-tumourigenesis'}", + "119, differentiate {'phenotype': 'B-differentiation'}", + "121, neurons {'context': 'B-cells', 'phenotype': 'B-differentiation'}", + "123, astrocytes. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "52, cortex ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "54, mice ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "55, heterozygous ['l1', 'l12', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "56, for ['l2', 'l13', 'l27', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "57, the ['l3', 'l14', 'l28', 'l42', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "58, gene ['l4', 'l15', 'l29', 'l43', 'l56', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "59, encoding ['l16', 'l30', 'l44', 'l57', 'l69', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "60, the ['l5', 'l17', 'l31', 'l45', 'l58', 'l70', 'l81', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "61, tumor ['l6', 'l18', 'l32', 'l46', 'l59', 'l71', 'l82', 'l92', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "62, suppressor ['l19', 'l33', 'l47', 'l60', 'l72', 'l83', 'l93', 'l102', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "63, Tp53 ['l7', 'l20', 'l34', 'l48', 'l61', 'l73', 'l84', 'l94', 'l103', 'l111', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "66, Mice ['l8', 'l21', 'l35', 'l49', 'l62', 'l74', 'l85', 'l95', 'l104', 'l112', 'l119', 'l126', 'l127', 'l128']", + "71, transduced ['l9', 'l22', 'l36', 'l50', 'l63', 'l75', 'l86', 'l96', 'l105', 'l113', 'l120', 'l126', 'l129', 'l130', 'l131', 'l132']", + "76, zone ['l10', 'l23', 'l37', 'l51', 'l64', 'l76', 'l87', 'l97', 'l106', 'l114', 'l121', 'l127', 'l129', 'l133']", + "79, hippocampus. ['l11', 'l24', 'l38', 'l52', 'l65', 'l77', 'l88', 'l98', 'l107', 'l115', 'l122', 'l128', 'l130', 'l133', 'l134', 'l135']", + "81, tumors ['l25', 'l39', 'l53', 'l66', 'l78', 'l89', 'l99', 'l108', 'l116', 'l123', 'l131', 'l134', 'l136', 'l137']", + "87, mice ['l40', 'l54', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l124', 'l136', 'l138']", + "92, cortex. ['l26', 'l41', 'l55', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l125', 'l132', 'l135', 'l137', 'l138']", + "95, brain ['l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150']", + "96, tumor ['l139', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160']", + "97, cells ['l140', 'l151', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "100, recipient ['l141', 'l152', 'l161', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176']", + "101, mouse ['l142', 'l153', 'l162', 'l168', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184']", + "102, brain ['l143', 'l154', 'l163', 'l169', 'l177', 'l185', 'l186', 'l187', 'l188']", + "108, glioblastoma ['l144', 'l155', 'l164', 'l170', 'l178', 'l185', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "109, multiforme-like ['l145', 'l156', 'l165', 'l171', 'l179', 'l186', 'l189', 'l195', 'l196', 'l197', 'l198', 'l199']", + "110, tumors, ['l146', 'l157', 'l166', 'l172', 'l180', 'l187', 'l190', 'l195', 'l200', 'l201', 'l202']", + "116, tumorspheres ['l147', 'l158', 'l167', 'l173', 'l181', 'l188', 'l191', 'l196', 'l200', 'l203', 'l204', 'l205']", + "119, differentiate ['l148', 'l174', 'l182', 'l192', 'l197', 'l203', 'l206', 'l207']", + "121, neurons ['l149', 'l159', 'l175', 'l183', 'l193', 'l198', 'l201', 'l204', 'l206', 'l208']", + "123, astrocytes. ['l150', 'l160', 'l176', 'l184', 'l194', 'l199', 'l202', 'l205', 'l207', 'l208']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "cortex", + "zone", + "cortex." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous", + "for", + "the", + "gene", + "tumor", + "Tp53", + "encoding", + "suppressor" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "cortex", + "zone", + "cortex." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "Mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous", + "for", + "the", + "gene", + "encoding", + "tumor", + "suppressor", + "Tp53" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "Mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous", + "for", + "the", + "gene", + "encoding", + "tumor", + "suppressor", + "Tp53" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors", + "glioblastoma", + "multiforme-like", + "tumors,", + "tumorspheres" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "cortex.", + "recipient", + "mouse", + "brain" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "brain", + "tumor", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "glioblastoma", + "multiforme-like", + "tumors,", + "tumorspheres" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "brain", + "tumor" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate", + "neurons" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neurons", + "astrocytes." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "neurons", + "differentiate" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "recipient", + "mouse" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate", + "neurons" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "glioblastoma", + "multiforme-like", + "tumors,", + "tumorspheres" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons", + "astrocytes." + ] + } + } + ] + }, + { + "PMID": "19122656", + "TEXT": "Several microRNAs (miRNAs), including liver-specific miR-122, have been implicated in the control of hepatitis C virus (HCV) RNA replication and its response to interferon (IFN) in human hepatoma cells. Our analysis of liver biopsies from subjects with chronic hepatitis C (CHC) undergoing IFN therapy revealed no correlation of miR-122 expression with viral load and markedly decreased pretreatment miR-122 levels in subjects who had no virological response during later IFN therapy; other investigated miRNAs showed only limited changes. These data have implications for the prospect of targeting miRNAs for CHC therapy.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19098907", + "TEXT": "Gamma-secretase inhibitors (GSIs) block the activation of the oncogenic protein Notch homolog-1 (NOTCH1) in T cell acute lymphoblastic leukemia (T-ALL). However, limited antileukemic cytotoxicity and severe gastrointestinal toxicity have restricted the clinical application of these targeted drugs. Here we show that combination therapy with GSIs plus glucocorticoids can improve the antileukemic effects of GSIs and reduce their gut toxicity in vivo. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid receptor autoupregulation and induced apoptotic cell death through induction of the gene encoding BCL-2-like apoptosis initiator-11 (BCL2L11). GSI treatment resulted in cell cycle arrest and accumulation of goblet cells in the gut mediated by upregulation of the gene encoding the transcription factor Krüppel-like factor-4 (Klf4), a negative regulator of the cell cycle required for goblet cell differentiation. In contrast, glucocorticoid treatment induced transcriptional upregulation of cyclin D2 (Ccnd2) and protected mice from developing the intestinal goblet cell metaplasia typically induced by inhibition of NOTCH signaling with GSIs. These results support a role for glucocorticoids plus GSIs in the treatment of glucocorticoid-resistant T-ALL.", + "TAG_DATA": [ + "66, glucocorticoid-resistant {'context': 'B-neoplasm'}", + "67, T-ALL {'context': 'I-neoplasm'}", + "73, induced {'effect': 'B-positive'}", + "74, apoptotic {'phenotype': 'B-apoptosis'}", + "75, cell {'phenotype': 'I-apoptosis'}", + "76, death {'phenotype': 'I-apoptosis'}", + "89, resulted {'effect': 'B-positive'}", + "90, in {'effect': 'I-positive'}", + "91, cell {'phenotype': 'B-cell cycle arrest'}", + "92, cycle {'phenotype': 'I-cell cycle arrest'}", + "93, arrest {'phenotype': 'I-cell cycle arrest'}", + "97, goblet {'context': 'B-cells'}", + "98, cells {'context': 'I-cells'}", + "101, gut {'context': 'B-tissue/organ'}", + "140, mice {'context': 'B-organism'}", + "145, goblet {'context': 'I-cells'}", + "146, cell {'context': 'I-cells'}", + "147, metaplasia {'phenotype': 'B-transformation'}" + ], + "LINK_DATA": [ + "66, glucocorticoid-resistant ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "67, T-ALL ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "73, induced ['l1', 'l12', 'l22', 'l23', 'l24', 'l25']", + "74, apoptotic ['l2', 'l13', 'l22', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "75, cell ['l3', 'l14', 'l23', 'l26', 'l35', 'l36']", + "76, death ['l4', 'l15', 'l24', 'l27', 'l35', 'l37']", + "89, resulted ['l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "90, in ['l5', 'l28', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "91, cell ['l6', 'l16', 'l29', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "92, cycle ['l7', 'l17', 'l30', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "93, arrest ['l8', 'l18', 'l31', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "97, goblet ['l9', 'l19', 'l32', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "98, cells ['l10', 'l20', 'l25', 'l33', 'l36', 'l37', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "101, gut ['l11', 'l21', 'l34', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "140, mice ['l66', 'l67', 'l68', 'l69']", + "144, intestinal ['l66', 'l70', 'l71', 'l72']", + "145, goblet ['l67', 'l70', 'l73', 'l74']", + "146, cell ['l68', 'l71', 'l73', 'l75']", + "147, metaplasia ['l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "glucocorticoid-resistant", + "T-ALL" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "in" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "glucocorticoid-resistant", + "T-ALL" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "glucocorticoid-resistant", + "T-ALL" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "in" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "resulted", + "in" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "goblet" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "goblet", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "gut" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "gut" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + }, + "context": { + "val": "cells", + "words": [ + "goblet", + "cells" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "gut" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "metaplasia" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "goblet", + "cell" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "metaplasia" + ] + } + } + ] + }, + { + "PMID": "19079257", + "TEXT": "Systemic lupus erythematosus (SLE) is an autoimmune disease mediated by autoantibodies and preferentially affecting women of childbearing age. Because the offspring of mothers with SLE show a high frequency of learning disorders, we hypothesized that maternally transferred autoantibodies that bind DNA and the N-methyl-D-aspartate receptor (NMDAR) could have a pathogenic role during fetal brain development. Here we describe a maternal SLE mouse model wherein pregnant dams harbored DNA-specific, NMDAR-specific autoantibodies throughout gestation. High titers of these autoantibodies in maternal circulation led to histological abnormalities in fetal brain and subsequent cognitive impairments in adult offspring. These data support a paradigm in which in utero exposure to neurotoxic autoantibodies causes abnormal brain development with long-term consequences. This paradigm may apply to multiple congenital neuropsychiatric disorders.", + "TAG_DATA": [ + "85, fetal {'context': 'B-tissue/organ'}", + "86, brain {'context': 'I-tissue/organ'}", + "92, adult {'context': 'B-organism'}", + "93, offspring. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "85, fetal ['l0']", + "86, brain ['l0']", + "92, adult ['l1']", + "93, offspring. ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19029987", + "TEXT": "Previous studies have demonstrated that normal mouse mammary tissue contains a rare subset of mammary stem cells. We now describe a method for detecting an analogous subpopulation in normal human mammary tissue. Dissociated cells are suspended with fibroblasts in collagen gels, which are then implanted under the kidney capsule of hormone-treated immunodeficient mice. After 2-8 weeks, the gels contain bilayered mammary epithelial structures, including luminal and myoepithelial cells, their in vitro clonogenic progenitors and cells that produce similar structures in secondary transplants. The regenerated clonogenic progenitors provide an objective indicator of input mammary stem cell activity and allow the frequency and phenotype of these human mammary stem cells to be determined by limiting-dilution analysis. This new assay procedure sets the stage for investigations of mechanisms regulating normal human mammary stem cells (and possibly stem cells in other tissues) and their relationship to human cancer stem cell populations.", + "TAG_DATA": [ + "33, cells {'context': 'B-cells'}", + "37, fibroblasts {'context': 'B-cells'}", + "69, in {'context': 'B-in vitro'}", + "70, vitro {'context': 'I-in vitro'}", + "104, human {'context': 'B-cells'}", + "105, mammary {'context': 'I-cells'}", + "106, stem {'context': 'I-cells'}", + "107, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "33, cells ['l0', 'l1']", + "37, fibroblasts ['l0', 'l2', 'l3']", + "69, in ['l2', 'l4']", + "70, vitro ['l1', 'l3', 'l4']", + "104, human ['l5', 'l6', 'l7']", + "105, mammary ['l5', 'l8', 'l9']", + "106, stem ['l6', 'l8', 'l10']", + "107, cells ['l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19029986", + "TEXT": "There is a pressing need for antiviral agents that are effective against multiple classes of viruses. Broad specificity might be achieved by targeting phospholipids that are widely expressed on infected host cells or viral envelopes. We reasoned that events occurring during virus replication (for example, cell activation or preapoptotic changes) would trigger the exposure of normally intracellular anionic phospholipids on the outer surface of virus-infected cells. A chimeric antibody, bavituximab, was used to identify and target the exposed anionic phospholipids. Infection of cells with Pichinde virus (a model for Lassa fever virus, a potential bioterrorism agent) led to the exposure of anionic phospholipids. Bavituximab treatment cured overt disease in guinea pigs lethally infected with Pichinde virus. Direct clearance of infectious virus from the blood and antibody-dependent cellular cytotoxicity of virus-infected cells seemed to be the major antiviral mechanisms. Combination therapy with bavituximab and ribavirin was more effective than either drug alone. Bavituximab also bound to cells infected with multiple other viruses and rescued mice with lethal mouse cytomegalovirus infections. Targeting exposed anionic phospholipids with bavituximab seems to be safe and effective. Our study demonstrates that anionic phospholipids on infected host cells and virions may provide a new target for the generation of antiviral agents.", + "TAG_DATA": [ + "82, cells {'context': 'B-cells'}", + "109, guinea {'context': 'B-organism'}", + "110, pigs {'context': 'I-organism'}", + "130, cells {'context': 'B-cells'}", + "155, cells {'context': 'B-cells'}", + "163, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "109, guinea ['l0', 'l1']", + "110, pigs ['l0', 'l2']", + "130, cells ['l1', 'l2']", + "155, cells ['l3']", + "163, mice ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18989280", + "TEXT": "Two big challenges of transplantation biology are controlling the reaction of the graft to the host after hematopoietic stem cell transplantation and preventing rejection of donor organs by the host. Raewyn Broady and Megan K. Levings discuss the first challenge, examining studies suggesting that statins might be helpful to control graft-versus-host disease. Kathryn Wood tackles the second challenge in the context of the 'Edmonton protocol', a procedure that can restore the ability to control blood glucose in people with type 1 diabetes--but only in the short term.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "18978797", + "TEXT": "Cytotoxic T lymphocytes (CTLs) directed to nonviral tumor-associated antigens do not survive long term and have limited antitumor activity in vivo, in part because such tumor cells typically lack the appropriate costimulatory molecules. We therefore engineered Epstein-Barr virus (EBV)-specific CTLs to express a chimeric antigen receptor directed to the diasialoganglioside GD2, a nonviral tumor-associated antigen expressed by human neuroblastoma cells. We reasoned that these genetically engineered lymphocytes would receive optimal costimulation after engagement of their native receptors, enhancing survival and antitumor activity mediated through their chimeric receptors. Here we show in individuals with neuroblastoma that EBV-specific CTLs expressing a chimeric GD2-specific receptor indeed survive longer than T cells activated by the CD3-specific antibody OKT3 and expressing the same chimeric receptor but lacking virus specificity. Infusion of these genetically modified cells seemed safe and was associated with tumor regression or necrosis in half of the subjects tested. Hence, virus-specific CTLs can be modified to function as tumor-directed effector cells.", + "TAG_DATA": [ + "91, individuals {'context': 'B-patient'}", + "92, with {'context': 'I-patient'}", + "93, neuroblastoma {'context': 'B-neoplasm'}", + "95, EBV-specific {'context': 'B-cells'}", + "96, CTLs {'context': 'I-cells'}", + "106, T {'context': 'B-cells'}", + "107, cells {'context': 'B-cells'}", + "129, cells {'context': 'B-cells'}", + "136, tumor {'phenotype': 'B-tumour regression'}", + "137, regression {'phenotype': 'I-tumour regression'}", + "139, necrosis {'phenotype': 'B-necrosis'}" + ], + "LINK_DATA": [ + "91, individuals ['l0', 'l1']", + "92, with ['l0', 'l2']", + "93, neuroblastoma ['l1', 'l2', 'l3']", + "95, EBV-specific ['l4', 'l5', 'l6']", + "96, CTLs ['l3', 'l4', 'l7', 'l8']", + "106, T ['l5', 'l7', 'l9']", + "107, cells ['l6', 'l8', 'l9']", + "129, cells ['l10', 'l11', 'l12', 'l13']", + "134, associated ['l10', 'l14', 'l15', 'l16']", + "136, tumor ['l11', 'l14', 'l17', 'l18']", + "137, regression ['l12', 'l15', 'l17', 'l19']", + "139, necrosis ['l13', 'l16', 'l18', 'l19']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + } + ] + }, + { + "PMID": "18953352", + "TEXT": "The cellular tropisms of eukaryotic viruses are shaped by their need for entry receptors and intracellular transcription factors. Here we show that viral tropisms can also be regulated by tissue-specific microRNAs (miRNAs). Target sequences complementary to muscle-specific miRNAs were inserted into the 3' untranslated region (UTR) of an oncolytic picornavirus that causes lethal myositis in tumor-bearing mice. The recombinant virus still propagated in subcutaneous tumors, causing total regression and sustained viremia, but could not replicate in cells expressing complementary miRNAs and therefore did not cause myositis. This altered tropism was not due to insertional attenuation, as a control virus containing a 3' UTR insert with a disrupted miRNA target sequence fully retained its lethal myotropism. Tissue-specific destabilization of viral genomes by miRNA target insertion provides a potentially versatile new mechanism for controlling the tropism of replicating viruses for therapy and may serve as a new modality for attenuating viruses for vaccine purposes.", + "TAG_DATA": [ + "55, tumor-bearing {'context': 'B-organism'}", + "56, mice. {'context': 'I-organism'}", + "63, subcutaneous {'context': 'B-neoplasm'}", + "64, tumors, {'context': 'I-tissue/organ'}", + "76, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "55, tumor-bearing ['l0', 'l1']", + "56, mice. ['l0']", + "63, subcutaneous ['l2']", + "64, tumors, ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18953351", + "TEXT": "Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder caused by mutations in the acidic compartment (which we define as the late endosome and the lysosome) protein, NPC1. The function of NPC1 is unknown, but when it is dysfunctional, sphingosine, glycosphingolipids, sphingomyelin and cholesterol accumulate. We have found that NPC1-mutant cells have a large reduction in the acidic compartment calcium store compared to wild-type cells. Chelating luminal endocytic calcium in normal cells with high-affinity Rhod-dextran induced an NPC disease cellular phenotype. In a drug-induced NPC disease cellular model, sphingosine storage in the acidic compartment led to calcium depletion in these organelles, which then resulted in cholesterol, sphingomyelin and glycosphingolipid storage in these compartments. Sphingosine storage is therefore an initiating factor in NPC1 disease pathogenesis that causes altered calcium homeostasis, leading to the secondary storage of sphingolipids and cholesterol. This unique calcium phenotype represents a new target for therapeutic intervention, as elevation of cytosolic calcium with curcumin normalized NPC1 disease cellular phenotypes and prolonged survival of the NPC1 mouse.", + "TAG_DATA": [ + "51, NPC1-mutant {'perturbing_action': 'B-other'}", + "52, cells {'context': 'B-cells'}", + "73, cells {'context': 'B-cells'}", + "168, NPC1 {'context': 'B-organism'}", + "169, mouse. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "51, NPC1-mutant ['l0', 'l1']", + "52, cells ['l0']", + "73, cells ['l1']", + "168, NPC1 ['l2']", + "169, mouse. ['l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "NPC1-mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "18953350", + "TEXT": "The major known genetic risk factors in multiple sclerosis reside in the major histocompatibility complex (MHC) region. Although there is strong evidence implicating MHC class II alleles and CD4(+) T cells in multiple sclerosis pathogenesis, possible contributions from MHC class I genes and CD8(+) T cells are controversial. We have generated humanized mice expressing the multiple sclerosis-associated MHC class I alleles HLA-A(*)0301 (encoding human leukocyte antigen-A3 (HLA-A3)) and HLA-A(*)0201 (encoding HLA-A2) and a myelin-specific autoreactive T cell receptor (TCR) derived from a CD8(+) T cell clone from an individual with multiple sclerosis to study mechanisms of disease susceptibility. We demonstrate roles for HLA-A3-restricted CD8(+) T cells in induction of multiple sclerosis-like disease and for CD4(+) T cells in its progression, and we also define a possible mechanism for HLA-A(*)0201-mediated protection. To our knowledge, these data provide the first direct evidence incriminating MHC class I genes and CD8(+) T cells in the pathogenesis of human multiple sclerosis and reveal a network of MHC interactions that shape the risk of multiple sclerosis.", + "TAG_DATA": [ + "51, humanized {'context': 'B-organism'}", + "52, mice {'context': 'I-organism'}", + "82, CD8(+) {'context': 'B-cells'}", + "83, T {'context': 'I-cells'}", + "84, cell {'context': 'I-cells'}", + "114, CD4(+) {'context': 'B-cells'}", + "115, T {'context': 'I-cells'}", + "116, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "51, humanized ['l0', 'l1', 'l2', 'l3']", + "52, mice ['l0', 'l4', 'l5', 'l6']", + "82, CD8(+) ['l1', 'l4', 'l7', 'l8']", + "83, T ['l2', 'l5', 'l7', 'l9']", + "84, cell ['l3', 'l6', 'l8', 'l9']", + "114, CD4(+) ['l10', 'l11']", + "115, T ['l10', 'l12']", + "116, cells ['l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18841137", + "TEXT": "Genetic inactivation of the mitochondrial self-destruction mechanism improves cognition in a mouse model of Alzheimer’s disease (pages 1097–1105).", + "TAG_DATA": [ + "1, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "2, of {'perturbing_action': 'I-gene loss-of-function'}", + "3, the {'perturbing_action': 'I-gene loss-of-function'}", + "4, mitochondrial {'perturbing_action': 'I-gene loss-of-function'}", + "5, self-destruction {'perturbing_action': 'I-gene loss-of-function'}", + "6, mechanism {'perturbing_action': 'I-gene loss-of-function'}", + "11, mouse {'context': 'B-organism'}", + "12, model {'context': 'I-organism'}", + "13, of {'context': 'I-organism'}", + "14, Alzheimer’s {'context': 'I-organism'}", + "15, disease {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "1, inactivation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "2, of ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "3, the ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "4, mitochondrial ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "5, self-destruction ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "6, mechanism ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "11, mouse ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "12, model ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "13, of ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "14, Alzheimer’s ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "15, disease ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "the", + "mitochondrial", + "self-destruction", + "mechanism" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "Alzheimer’s", + "disease" + ] + } + } + ] + }, + { + "PMID": "18836460", + "TEXT": "Because of their abundance, resistance to proteolysis, rapid aggregation and neurotoxicity, N-terminally truncated and, in particular, pyroglutamate (pE)-modified Abeta peptides have been suggested as being important in the initiation of pathological cascades resulting in the development of Alzheimer's disease. We found that the N-terminal pE-formation is catalyzed by glutaminyl cyclase in vivo. Glutaminyl cyclase expression was upregulated in the cortices of individuals with Alzheimer's disease and correlated with the appearance of pE-modified Abeta. Oral application of a glutaminyl cyclase inhibitor resulted in reduced Abeta(3(pE)-42) burden in two different transgenic mouse models of Alzheimer's disease and in a new Drosophila model. Treatment of mice was accompanied by reductions in Abeta(x-40/42), diminished plaque formation and gliosis and improved performance in context memory and spatial learning tests. These observations are consistent with the hypothesis that Abeta(3(pE)-42) acts as a seed for Abeta aggregation by self-aggregation and co-aggregation with Abeta(1-40/42). Therefore, Abeta(3(pE)-40/42) peptides seem to represent Abeta forms with exceptional potency for disturbing neuronal function. The reduction of brain pE-Abeta by inhibition of glutaminyl cyclase offers a new therapeutic option for the treatment of Alzheimer's disease and provides implications for other amyloidoses, such as familial Danish dementia.", + "TAG_DATA": [ + "77, glutaminyl {'perturbing_action': 'B-pharmacological inhibition'}", + "78, cyclase {'perturbing_action': 'I-pharmacological inhibition'}", + "79, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "88, transgenic {'context': 'B-organism'}", + "89, mouse {'context': 'I-organism'}", + "90, models {'context': 'I-organism'}", + "91, of {'context': 'I-organism'}", + "92, Alzheimer's {'context': 'I-organism'}", + "93, disease {'context': 'I-organism'}", + "98, Drosophila {'context': 'B-organism'}", + "99, model. {'context': 'I-organism'}", + "102, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "77, glutaminyl ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "78, cyclase ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "79, inhibitor ['l1', 'l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "88, transgenic ['l2', 'l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "89, mouse ['l3', 'l12', 'l18', 'l23', 'l28', 'l29', 'l30', 'l31']", + "90, models ['l4', 'l13', 'l19', 'l24', 'l28', 'l32', 'l33', 'l34']", + "91, of ['l5', 'l14', 'l20', 'l25', 'l29', 'l32', 'l35', 'l36']", + "92, Alzheimer's ['l6', 'l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l37']", + "93, disease ['l7', 'l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l37']", + "98, Drosophila ['l8', 'l38']", + "99, model. ['l9', 'l38']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "glutaminyl", + "cyclase", + "inhibitor" + ] + }, + "context": { + "val": "organism", + "words": [ + "transgenic", + "mouse", + "models", + "of", + "Alzheimer's", + "disease", + "Drosophila", + "model." + ] + } + } + ] + }, + { + "PMID": "18836459", + "TEXT": "Vascularization is essential for tissue development and in restoration of tissue integrity after an ischemic injury. In studies of vascularization, the focus has largely been placed on vascular endothelial growth factor (VEGF), yet other factors may also orchestrate this process. Here we show that succinate accumulates in the hypoxic retina of rodents and, via its cognate receptor G protein-coupled receptor-91 (GPR91), is a potent mediator of vessel growth in the settings of both normal retinal development and proliferative ischemic retinopathy. The effects of GPR91 are mediated by retinal ganglion neurons (RGCs), which, in response to increased succinate levels, regulate the production of numerous angiogenic factors including VEGF. Accordingly, succinate did not have proangiogenic effects in RGC-deficient rats. Our observations show a pathway of metabolite signaling where succinate, acting through GPR91, governs retinal angiogenesis and show the propensity of RGCs to act as sensors of ischemic stress. These findings provide a new therapeutic target for modulating revascularization.", + "TAG_DATA": [ + "115, RGC-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "116, rats. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "115, RGC-deficient ['l0']", + "116, rats. ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "RGC-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats." + ] + } + } + ] + }, + { + "PMID": "18776884", + "TEXT": "The complexity of factors that regulate bleeding and coagulation has long confounded researchers. Andrew Wei and Shaun Jackson help clear the air by examining clinical findings pointing to a mechanistic basis for a common bleeding disorder, immune thrombocytopenic purpura. Mark Kahn tackles two research studies that could lead to improved therapies for a coagulation syndrome that hits people with severe sepsis.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "18641660", + "TEXT": "Although prognostic gene expression signatures for survival in early-stage lung cancer have been proposed, for clinical application, it is critical to establish their performance across different subject populations and in different laboratories. Here we report a large, training-testing, multi-site, blinded validation study to characterize the performance of several prognostic models based on gene expression for 442 lung adenocarcinomas. The hypotheses proposed examined whether microarray measurements of gene expression either alone or combined with basic clinical covariates (stage, age, sex) could be used to predict overall survival in lung cancer subjects. Several models examined produced risk scores that substantially correlated with actual subject outcome. Most methods performed better with clinical data, supporting the combined use of clinical and molecular information when building prognostic models for early-stage lung cancer. This study also provides the largest available set of microarray data with extensive pathological and clinical annotation for lung adenocarcinomas.", + "TAG_DATA": [ + "56, lung {'context': 'B-neoplasm'}", + "57, adenocarcinomas. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "56, lung ['l0']", + "57, adenocarcinomas. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18587407", + "TEXT": "Despite the well-documented association between gallstones and the metabolic syndrome, the mechanistic links between these two disorders remain unknown. Here we show that mice solely with hepatic insulin resistance, created by liver-specific disruption of the insulin receptor (LIRKO mice) are markedly predisposed toward cholesterol gallstone formation due to at least two distinct mechanisms. Disinhibition of the forkhead transcription factor FoxO1, increases expression of the biliary cholesterol transporters Abcg5 and Abcg8, resulting in an increase in biliary cholesterol secretion. Hepatic insulin resistance also decreases expression of the bile acid synthetic enzymes, particularly Cyp7b1, and produces partial resistance to the farnesoid X receptor, leading to a lithogenic bile salt profile. As a result, after twelve weeks on a lithogenic diet, all of the LIRKO mice develop gallstones. Thus, hepatic insulin resistance provides a crucial link between the metabolic syndrome and increased cholesterol gallstone susceptibility.", + "TAG_DATA": [ + "31, liver-specific {'perturbing_action': 'B-gene loss-of-function'}", + "32, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "33, of {'perturbing_action': 'I-gene loss-of-function'}", + "34, the {'perturbing_action': 'I-gene loss-of-function'}", + "35, insulin {'perturbing_action': 'I-gene loss-of-function'}", + "36, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "38, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "53, Disinhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "54, of {'perturbing_action': 'I-pharmacological inhibition'}", + "55, the {'perturbing_action': 'I-pharmacological inhibition'}", + "56, forkhead {'perturbing_action': 'I-pharmacological inhibition'}", + "57, transcription {'perturbing_action': 'I-pharmacological inhibition'}", + "58, factor {'perturbing_action': 'I-pharmacological inhibition'}", + "59, FoxO1, {'perturbing_action': 'I-pharmacological inhibition'}", + "121, LIRKO {'perturbing_action': 'B-gene loss-of-function'}", + "122, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "31, liver-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "32, disruption ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "33, of ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "34, the ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "35, insulin ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "36, receptor ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "38, mice) ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "53, Disinhibition ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "54, of ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "55, the ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "56, forkhead ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "57, transcription ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "58, factor ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "59, FoxO1, ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']", + "121, LIRKO ['l91']", + "122, mice ['l91']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "LIRKO" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "18568033", + "TEXT": "Tuberous sclerosis is a single-gene disorder caused by heterozygous mutations in the TSC1 (9q34) or TSC2 (16p13.3) gene and is frequently associated with mental retardation, autism and epilepsy. Even individuals with tuberous sclerosis and a normal intelligence quotient (approximately 50%) are commonly affected with specific neuropsychological problems, including long-term and working memory deficits. Here we report that mice with a heterozygous, inactivating mutation in the Tsc2 gene (Tsc2(+/-) mice) show deficits in learning and memory. Cognitive deficits in Tsc2(+/-) mice emerged in the absence of neuropathology and seizures, demonstrating that other disease mechanisms are involved. We show that hyperactive hippocampal mammalian target of rapamycin (mTOR) signaling led to abnormal long-term potentiation in the CA1 region of the hippocampus and consequently to deficits in hippocampal-dependent learning. These deficits included impairments in two spatial learning tasks and in contextual discrimination. Notably, we show that a brief treatment with the mTOR inhibitor rapamycin in adult mice rescues not only the synaptic plasticity, but also the behavioral deficits in this animal model of tuberous sclerosis. The results presented here reveal a biological basis for some of the cognitive deficits associated with tuberous sclerosis, and they show that treatment with mTOR antagonists ameliorates cognitive dysfunction in a mouse model of this disorder.", + "TAG_DATA": [ + "57, mice {'context': 'B-organism'}", + "60, heterozygous, {'perturbing_action': 'B-other'}", + "61, inactivating {'perturbing_action': 'I-other'}", + "62, mutation {'perturbing_action': 'I-other'}", + "63, in {'perturbing_action': 'I-other'}", + "64, the {'perturbing_action': 'I-other'}", + "65, Tsc2 {'perturbing_action': 'I-other'}", + "66, gene {'perturbing_action': 'I-other'}", + "68, mice) {'context': 'B-organism'}", + "78, Tsc2(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "79, mice {'context': 'B-organism'}", + "114, region {'context': 'I-cells'}", + "115, of {'context': 'I-cells'}", + "147, mTOR {'perturbing_action': 'B-pharmacological inhibition'}", + "148, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "149, rapamycin {'perturbing_action': 'I-pharmacological inhibition'}", + "151, adult {'context': 'B-organism'}", + "152, mice {'context': 'I-organism'}", + "166, animal {'context': 'B-organism'}", + "167, model {'context': 'I-organism'}", + "203, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "57, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "60, heterozygous, ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "61, inactivating ['l1', 'l13', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "62, mutation ['l2', 'l14', 'l26', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "63, in ['l3', 'l15', 'l27', 'l38', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "64, the ['l4', 'l16', 'l28', 'l39', 'l49', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "65, Tsc2 ['l5', 'l17', 'l29', 'l40', 'l50', 'l59', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "66, gene ['l6', 'l18', 'l30', 'l41', 'l51', 'l60', 'l68', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "68, mice) ['l7', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l76', 'l83', 'l84', 'l85', 'l86']", + "78, Tsc2(+/-) ['l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l87', 'l88', 'l89', 'l90', 'l91']", + "79, mice ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l87', 'l92', 'l93', 'l94', 'l95']", + "114, region ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l83', 'l88', 'l92', 'l96', 'l97', 'l98']", + "115, of ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l84', 'l89', 'l93', 'l96', 'l99', 'l100']", + "116, the ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l85', 'l90', 'l94', 'l97', 'l99', 'l101']", + "117, hippocampus ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l86', 'l91', 'l95', 'l98', 'l100', 'l101']", + "147, mTOR ['l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "148, inhibitor ['l102', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "149, rapamycin ['l103', 'l111', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "151, adult ['l104', 'l112', 'l119', 'l126', 'l127', 'l128', 'l129', 'l130']", + "152, mice ['l105', 'l113', 'l120', 'l126', 'l131', 'l132', 'l133', 'l134']", + "166, animal ['l106', 'l114', 'l121', 'l127', 'l131', 'l135', 'l136', 'l137', 'l138']", + "167, model ['l107', 'l115', 'l122', 'l128', 'l132', 'l135', 'l139', 'l140', 'l141']", + "168, of ['l108', 'l116', 'l123', 'l129', 'l133', 'l136', 'l139', 'l142', 'l143']", + "169, tuberous ['l109', 'l117', 'l124', 'l130', 'l134', 'l137', 'l140', 'l142', 'l144']", + "203, model ['l110', 'l118', 'l125', 'l138', 'l141', 'l143', 'l144']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice)" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous,", + "inactivating", + "mutation", + "in", + "the", + "Tsc2", + "gene" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous,", + "inactivating", + "mutation", + "in", + "the", + "Tsc2", + "gene" + ] + }, + "context": { + "val": "cells", + "words": [ + "region", + "of" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tsc2(+/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tsc2(+/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "region", + "of" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibitor", + "rapamycin" + ] + }, + "context": { + "val": "organism", + "words": [ + "adult", + "mice", + "animal", + "model" + ] + } + } + ] + }, + { + "PMID": "18552856", + "TEXT": "Autosomal dominant polycystic kidney disease (ADPKD) is caused by heterozygous mutations in either PKD1 or PKD2, genes that encode polycystin-1 and polycystin-2, respectively. We show here that tumor necrosis factor-alpha (TNF-alpha), an inflammatory cytokine present in the cystic fluid of humans with ADPKD, disrupts the localization of polycystin-2 to the plasma membrane and primary cilia through a scaffold protein, FIP2, which is induced by TNF-alpha. Treatment of mouse embryonic kidney organ cultures with TNF-alpha resulted in formation of cysts, and this effect was exacerbated in the Pkd2(+/-) kidneys. TNF-alpha also stimulated cyst formation in vivo in Pkd2(+/-) mice. In contrast, treatment of Pkd2(+/-) mice with the TNF-alpha inhibitor etanercept prevented cyst formation. These data reveal a pathway connecting TNF-alpha signaling, polycystins and cystogenesis, the activation of which may reduce functional polycystin-2 below a critical threshold, precipitating the ADPKD cellular phenotype.", + "TAG_DATA": [ + "67, mouse {'context': 'B-cells'}", + "68, embryonic {'context': 'I-cells'}", + "69, kidney {'context': 'I-cells'}", + "70, organ {'context': 'I-cells'}", + "71, cultures {'context': 'I-cells'}", + "86, Pkd2(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "87, kidneys. {'context': 'B-tissue/organ'}", + "90, stimulated {'effect': 'B-positive'}", + "93, in {'context': 'B-in vivo'}", + "94, vivo {'context': 'I-in vivo'}", + "96, Pkd2(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "97, mice. {'context': 'B-organism'}", + "102, Pkd2(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "103, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "67, mouse ['l0', 'l1', 'l2', 'l3', 'l4']", + "68, embryonic ['l0', 'l5', 'l6', 'l7', 'l8', 'l9']", + "69, kidney ['l1', 'l5', 'l10', 'l11', 'l12']", + "70, organ ['l2', 'l6', 'l10', 'l13']", + "71, cultures ['l3', 'l7', 'l11', 'l13']", + "86, Pkd2(+/-) ['l8', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "87, kidneys. ['l4', 'l9', 'l12', 'l14', 'l20', 'l21', 'l22', 'l23']", + "90, stimulated ['l15', 'l20', 'l24', 'l25', 'l26', 'l27']", + "91, cyst ['l16', 'l21', 'l24', 'l28', 'l29', 'l30']", + "93, in ['l17', 'l22', 'l25', 'l28', 'l31', 'l32']", + "94, vivo ['l18', 'l23', 'l26', 'l29', 'l31', 'l33']", + "96, Pkd2(+/-) ['l34']", + "97, mice. ['l19', 'l27', 'l30', 'l32', 'l33', 'l34']", + "102, Pkd2(+/-) ['l35']", + "103, mice ['l35']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "embryonic" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pkd2(+/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pkd2(+/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidneys." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pkd2(+/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pkd2(+/-)" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pkd2(+/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "kidneys." + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "18542050", + "TEXT": "Reactive oxygen species (ROS) induce chemokines responsible for the recruitment of inflammatory cells to sites of injury or infection. Here we show that the plasma membrane Ca(2+)-permeable channel TRPM2 controls ROS-induced chemokine production in monocytes. In human U937 monocytes, hydrogen peroxide (H(2)O(2)) evokes Ca(2+) influx through TRPM2 to activate Ca(2+)-dependent tyrosine kinase Pyk2 and amplify Erk signaling via Ras GTPase. This elicits nuclear translocation of nuclear factor-kappaB essential for the production of the chemokine interleukin-8 (CXCL8). In monocytes from Trpm2-deficient mice, H(2)O(2)-induced Ca(2+) influx and production of the macrophage inflammatory protein-2 (CXCL2), the mouse CXCL8 functional homolog, were impaired. In the dextran sulfate sodium-induced colitis inflammation model, CXCL2 expression, neutrophil infiltration and ulceration were attenuated by Trpm2 disruption. Thus, TRPM2 Ca(2+) influx controls the ROS-induced signaling cascade responsible for chemokine production, which aggravates inflammation. We propose functional inhibition of TRPM2 channels as a new therapeutic strategy for treating inflammatory diseases.", + "TAG_DATA": [ + "36, human {'context': 'B-cells'}", + "37, U937 {'context': 'I-cells'}", + "38, monocytes, {'context': 'I-cells'}", + "77, monocytes {'context': 'B-cells'}", + "79, Trpm2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "80, mice, {'context': 'B-organism'}", + "116, Trpm2 {'perturbing_action': 'B-gene loss-of-function'}", + "117, disruption. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "36, human ['l0', 'l1', 'l2']", + "37, U937 ['l0', 'l3', 'l4']", + "38, monocytes, ['l1', 'l3', 'l5']", + "77, monocytes ['l2', 'l4', 'l5', 'l6', 'l7']", + "79, Trpm2-deficient ['l6', 'l8']", + "80, mice, ['l7', 'l8']", + "116, Trpm2 ['l9']", + "117, disruption. ['l9']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "monocytes" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trpm2-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trpm2-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "18535579", + "TEXT": "The adenovirus type 5 (Ad5)-based vaccine developed by Merck failed to either prevent HIV-1 infection or suppress viral load in subsequently infected subjects in the STEP human Phase 2b efficacy trial. Analogous vaccines had previously also failed in the simian immunodeficiency virus (SIV) challenge-rhesus macaque model. In contrast, vaccine protection studies that used challenge with a chimeric simian-human immunodeficiency virus (SHIV89.6P) in macaques did not predict the human trial results. Ad5 vector-based vaccines did not protect macaques from infection after SHIV89.6P challenge but did cause a substantial reduction in viral load and a preservation of CD4+ T cell counts after infection, findings that were not reproduced in the human trials. Although the SIV challenge model is incompletely validated, we propose that its expanded use can help facilitate the prioritization of candidate HIV-1 vaccines, ensuring that resources are focused on the most promising candidates. Vaccine designers must now develop T cell vaccine strategies that reduce viral load after heterologous challenge.", + "TAG_DATA": [ + "44, macaque {'context': 'I-organism'}", + "45, model. {'context': 'I-organism'}", + "62, macaques {'context': 'B-organism'}", + "76, macaques {'context': 'B-organism'}", + "95, CD4+ {'context': 'B-cells'}", + "96, T {'context': 'I-cells'}", + "97, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "44, macaque ['l0']", + "45, model. ['l0']", + "62, macaques ['l1']", + "76, macaques ['l1', 'l2', 'l3']", + "95, CD4+ ['l4', 'l5']", + "96, T ['l2', 'l4', 'l6']", + "97, cell ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18516053", + "TEXT": "Leptin (encoded by Lep) controls body weight by regulating food intake and fuel partitioning. Obesity is characterized by leptin resistance and increased endocannabinoid tone. Here we show that leptin infused into the mediobasal hypothalamus (MBH) of rats inhibits white adipose tissue (WAT) lipogenesis, which occurs independently of signal transducer and activator of transcription-3 (STAT3) signaling. Correspondingly, transgenic inactivation of STAT3 signaling by mutation of the leptin receptor (s/s mice) leads to reduced adipose mass compared to db/db mice (complete abrogation of leptin receptor signaling). Conversely, the ability of hypothalamic leptin to suppress WAT lipogenesis in rats is lost when hypothalamic phosphoinositide 3-kinase signaling is prevented or when sympathetic denervation of adipose tissue is performed. MBH leptin suppresses the endocannabinoid anandamide in WAT, and, when this suppression of endocannabinoid tone is prevented by systemic CB1 receptor activation, MBH leptin fails to suppress WAT lipogenesis. These data suggest that the increased endocannabinoid tone observed in obesity is linked to a failure of central leptin signaling to restrain peripheral endocannabinoids.", + "TAG_DATA": [ + "33, hypothalamus {'context': 'I-tissue/organ'}", + "34, (MBH) {'context': 'I-tissue/organ'}", + "36, rats {'context': 'B-organism'}", + "56, transgenic {'perturbing_action': 'B-gene loss-of-function'}", + "57, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "58, of {'perturbing_action': 'I-gene loss-of-function'}", + "59, STAT3 {'perturbing_action': 'I-gene loss-of-function'}", + "60, signaling {'perturbing_action': 'I-gene loss-of-function'}", + "61, by {'perturbing_action': 'I-gene loss-of-function'}", + "62, mutation {'perturbing_action': 'I-gene loss-of-function'}", + "63, of {'perturbing_action': 'I-gene loss-of-function'}", + "64, the {'perturbing_action': 'I-gene loss-of-function'}", + "65, leptin {'perturbing_action': 'I-other'}", + "66, receptor {'perturbing_action': 'I-other'}", + "67, (s/s {'perturbing_action': 'I-gene loss-of-function'}", + "68, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "76, db/db {'context': 'B-organism'}", + "77, mice {'context': 'I-organism'}", + "95, rats {'context': 'B-organism'}", + "110, adipose {'context': 'B-cells'}", + "111, tissue {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "32, mediobasal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "33, hypothalamus ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "34, (MBH) ['l1', 'l17', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "36, rats ['l2', 'l18', 'l32', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "56, transgenic ['l3', 'l19', 'l33', 'l46', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "57, inactivation ['l4', 'l20', 'l34', 'l47', 'l59', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "58, of ['l5', 'l21', 'l35', 'l48', 'l60', 'l73', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "59, STAT3 ['l6', 'l22', 'l36', 'l49', 'l61', 'l74', 'l87', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "60, signaling ['l7', 'l23', 'l37', 'l50', 'l62', 'l75', 'l88', 'l100', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "61, by ['l8', 'l24', 'l38', 'l51', 'l63', 'l76', 'l89', 'l101', 'l112', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "62, mutation ['l9', 'l25', 'l39', 'l52', 'l64', 'l77', 'l90', 'l102', 'l113', 'l123', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141']", + "63, of ['l10', 'l26', 'l40', 'l53', 'l65', 'l78', 'l91', 'l103', 'l114', 'l124', 'l133', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "64, the ['l11', 'l27', 'l41', 'l54', 'l66', 'l79', 'l92', 'l104', 'l115', 'l125', 'l134', 'l142', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156']", + "65, leptin ['l12', 'l28', 'l42', 'l55', 'l67', 'l80', 'l93', 'l105', 'l116', 'l126', 'l135', 'l143', 'l150', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162']", + "66, receptor ['l13', 'l29', 'l43', 'l56', 'l68', 'l81', 'l94', 'l106', 'l117', 'l127', 'l136', 'l144', 'l151', 'l157', 'l163', 'l164', 'l165', 'l166', 'l167']", + "67, (s/s ['l14', 'l30', 'l44', 'l57', 'l69', 'l82', 'l95', 'l107', 'l118', 'l128', 'l137', 'l145', 'l152', 'l158', 'l163', 'l168', 'l169', 'l170']", + "68, mice) ['l15', 'l31', 'l45', 'l58', 'l70', 'l83', 'l96', 'l108', 'l119', 'l129', 'l138', 'l146', 'l153', 'l159', 'l164', 'l168', 'l171']", + "76, db/db ['l71', 'l84', 'l97', 'l109', 'l120', 'l130', 'l139', 'l147', 'l154', 'l160', 'l165', 'l169', 'l172', 'l173']", + "77, mice ['l16', 'l72', 'l85', 'l98', 'l110', 'l121', 'l131', 'l140', 'l148', 'l155', 'l161', 'l166', 'l170', 'l171', 'l172', 'l174']", + "95, rats ['l86', 'l99', 'l111', 'l122', 'l132', 'l141', 'l149', 'l156', 'l162', 'l167', 'l173', 'l174']", + "110, adipose ['l175']", + "111, tissue ['l175']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "hypothalamus", + "(MBH)" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "transgenic", + "inactivation", + "of", + "STAT3", + "signaling", + "by", + "mutation", + "the", + "(s/s", + "mice)" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "hypothalamus", + "(MBH)" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "leptin", + "receptor" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rats", + "db/db", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "transgenic", + "inactivation", + "of", + "STAT3", + "signaling", + "by", + "mutation", + "the", + "(s/s", + "mice)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rats", + "db/db", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "leptin", + "receptor" + ] + } + } + ] + }, + { + "PMID": "18516052", + "TEXT": "More than 500 million people worldwide are persistently infected with hepatitis B virus or hepatitis C virus. Although both viruses are poorly cytopathic, persistence of either virus carries a risk of chronic liver inflammation, potentially resulting in liver steatosis, liver cirrhosis, end-stage liver failure or hepatocellular carcinoma. Virus-specific T cells are a major determinant of the outcome of hepatitis, as they contribute to the early control of chronic hepatitis viruses, but they also mediate immunopathology during persistent virus infection. We have analyzed the role of platelet-derived vasoactive serotonin during virus-induced CD8(+) T cell-dependent immunopathological hepatitis in mice infected with the noncytopathic lymphocytic choriomeningitis virus. After virus infection, platelets were recruited to the liver, and their activation correlated with severely reduced sinusoidal microcirculation, delayed virus elimination and increased immunopathological liver cell damage. Lack of platelet-derived serotonin in serotonin-deficient mice normalized hepatic microcirculatory dysfunction, accelerated virus clearance in the liver and reduced CD8(+) T cell-dependent liver cell damage. In keeping with these observations, serotonin treatment of infected mice delayed entry of activated CD8(+) T cells into the liver, delayed virus control and aggravated immunopathological hepatitis. Thus, vasoactive serotonin supports virus persistence in the liver and aggravates virus-induced immunopathology.", + "TAG_DATA": [ + "96, mice {'context': 'B-organism'}", + "128, liver {'context': 'B-cells'}", + "129, cell {'context': 'I-cells'}", + "136, serotonin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "137, mice {'context': 'B-organism'}", + "147, liver {'context': 'B-tissue/organ'}", + "153, liver {'context': 'B-cells'}", + "154, cell {'context': 'I-cells'}", + "165, mice {'context': 'B-organism'}", + "170, CD8(+) {'context': 'B-cells'}", + "171, T {'context': 'I-cells'}", + "172, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "96, mice ['l0', 'l1']", + "128, liver ['l0', 'l2']", + "129, cell ['l1', 'l2']", + "136, serotonin-deficient ['l3', 'l4', 'l5', 'l6']", + "137, mice ['l3', 'l7', 'l8', 'l9']", + "147, liver ['l4', 'l7']", + "153, liver ['l5', 'l8', 'l10']", + "154, cell ['l6', 'l9', 'l10']", + "165, mice ['l11', 'l12', 'l13']", + "170, CD8(+) ['l11', 'l14', 'l15']", + "171, T ['l12', 'l14', 'l16']", + "172, cells ['l13', 'l15', 'l16']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "serotonin-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "serotonin-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "serotonin-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "liver", + "cell" + ] + } + } + ] + }, + { + "PMID": "18516051", + "TEXT": "Alzheimer's disease is the most common dementia and is pathologically characterized by deposition of amyloid-beta peptide (Abeta) into beta-amyloid plaques, neuronal injury and low-level, chronic activation of brain immunity. Transforming growth factor-betas (TGF-betas) are pleiotropic cytokines that have key roles in immune cell activation, inflammation and repair after injury. We genetically interrupted TGF-beta and downstream Smad2/3 signaling (TGF-beta-Smad2/3) in innate immune cells by inducing expression of CD11c promoter-driven dominant-negative TGF-beta receptor type II in C57BL/6 mice (CD11c-DNR), crossed these mice with mice overexpressing mutant human amyloid precursor protein, the Tg2576 Alzheimer's disease mouse model, and evaluated Alzheimer's disease-like pathology. Aged double-transgenic mice showed complete mitigation of Tg2576-associated hyperactivity and partial mitigation of defective spatial working memory. Brain parenchymal and cerebrovascular beta-amyloid deposits and Abeta abundance were markedly (up to 90%) attenuated in Tg2576-CD11c-DNR mice. This was associated with increased infiltration of Abeta-containing peripheral macrophages around cerebral vessels and beta-amyloid plaques. In vitro, cultures of peripheral macrophages, but not microglia, from CD11c-DNR mice showed blockade of classical TGF-beta-activated Smad2/3 but also showed hyperactivation of alternative bone morphogenic protein-activated Smad1/5/8 signaling and increased Abeta phagocytosis. Similar effects were noted after pharmacological inhibition of activin-like kinase-5, a type I TGF-beta receptor. Taken together, our results suggest that blockade of TGF-beta-Smad2/3 signaling in peripheral macrophages represents a new therapeutic target for Alzheimer's disease.", + "TAG_DATA": [ + "59, innate {'context': 'B-cells'}", + "60, immune {'context': 'I-cells'}", + "61, cells {'context': 'I-cells'}", + "63, inducing {'perturbing_action': 'B-other'}", + "64, expression {'perturbing_action': 'I-other'}", + "65, of {'perturbing_action': 'I-other'}", + "66, CD11c {'perturbing_action': 'I-other'}", + "67, promoter-driven {'perturbing_action': 'I-other'}", + "68, dominant-negative {'perturbing_action': 'I-other'}", + "69, TGF-beta {'perturbing_action': 'I-other'}", + "70, receptor {'perturbing_action': 'I-other'}", + "71, type {'perturbing_action': 'I-other'}", + "72, II {'perturbing_action': 'I-other'}", + "74, C57BL/6 {'context': 'B-organism'}", + "75, mice {'context': 'I-organism'}", + "79, mice {'context': 'B-organism'}", + "81, mice {'context': 'B-organism'}", + "82, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "83, mutant {'perturbing_action': 'I-gene gain-of-function'}", + "84, human {'perturbing_action': 'I-gene gain-of-function'}", + "85, amyloid {'perturbing_action': 'I-gene gain-of-function'}", + "86, precursor {'perturbing_action': 'I-gene gain-of-function'}", + "87, protein, {'perturbing_action': 'I-gene gain-of-function'}", + "101, mice {'context': 'B-organism'}", + "132, Tg2576-CD11c-DNR {'perturbing_action': 'B-other'}", + "133, mice. {'context': 'B-organism'}", + "142, peripheral {'context': 'B-cells'}", + "143, macrophages {'context': 'I-cells'}", + "150, In {'context': 'B-in vitro'}", + "151, vitro, {'context': 'I-in vitro'}", + "154, peripheral {'context': 'B-cells'}", + "155, macrophages, {'context': 'I-cells'}", + "158, microglia, {'context': 'B-cells'}", + "161, mice {'context': 'B-organism'}", + "188, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "189, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "190, of {'perturbing_action': 'I-pharmacological inhibition'}", + "191, activin-like {'perturbing_action': 'I-pharmacological inhibition'}", + "192, kinase-5, {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "59, innate ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "60, immune ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "61, cells ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "63, inducing ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "64, expression ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "65, of ['l4', 'l17', 'l29', 'l40', 'l50', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "66, CD11c ['l5', 'l18', 'l30', 'l41', 'l51', 'l61', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "67, promoter-driven ['l6', 'l19', 'l31', 'l42', 'l52', 'l62', 'l71', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "68, dominant-negative ['l7', 'l20', 'l32', 'l43', 'l53', 'l63', 'l72', 'l80', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "69, TGF-beta ['l8', 'l21', 'l33', 'l44', 'l54', 'l64', 'l73', 'l81', 'l88', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "70, receptor ['l9', 'l22', 'l34', 'l45', 'l55', 'l65', 'l74', 'l82', 'l89', 'l95', 'l101', 'l102', 'l103', 'l104', 'l105']", + "71, type ['l10', 'l23', 'l35', 'l46', 'l56', 'l66', 'l75', 'l83', 'l90', 'l96', 'l101', 'l106', 'l107', 'l108', 'l109']", + "72, II ['l11', 'l24', 'l36', 'l47', 'l57', 'l67', 'l76', 'l84', 'l91', 'l97', 'l102', 'l106', 'l110', 'l111', 'l112']", + "74, C57BL/6 ['l12', 'l25', 'l37', 'l48', 'l58', 'l68', 'l77', 'l85', 'l92', 'l98', 'l103', 'l107', 'l110', 'l113', 'l114']", + "75, mice ['l13', 'l26', 'l38', 'l49', 'l59', 'l69', 'l78', 'l86', 'l93', 'l99', 'l104', 'l108', 'l111', 'l113']", + "79, mice ['l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "81, mice ['l115', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "82, overexpressing ['l116', 'l123', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "83, mutant ['l117', 'l124', 'l134', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "84, human ['l118', 'l125', 'l135', 'l144', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160']", + "85, amyloid ['l119', 'l126', 'l136', 'l145', 'l153', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "86, precursor ['l120', 'l127', 'l137', 'l146', 'l154', 'l161', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "87, protein, ['l121', 'l128', 'l138', 'l147', 'l155', 'l162', 'l168', 'l174', 'l175', 'l176', 'l177', 'l178']", + "101, mice ['l60', 'l70', 'l79', 'l87', 'l94', 'l100', 'l105', 'l109', 'l112', 'l114', 'l122', 'l129', 'l139', 'l148', 'l156', 'l163', 'l169', 'l174']", + "132, Tg2576-CD11c-DNR ['l130', 'l140', 'l149', 'l157', 'l164', 'l170', 'l175', 'l179', 'l180', 'l181']", + "133, mice. ['l131', 'l141', 'l150', 'l158', 'l165', 'l171', 'l176', 'l179', 'l182', 'l183']", + "142, peripheral ['l132', 'l142', 'l151', 'l159', 'l166', 'l172', 'l177', 'l180', 'l182', 'l184']", + "143, macrophages ['l133', 'l143', 'l152', 'l160', 'l167', 'l173', 'l178', 'l181', 'l183', 'l184']", + "150, In ['l185', 'l186', 'l187', 'l188', 'l189']", + "151, vitro, ['l185', 'l190', 'l191', 'l192', 'l193']", + "154, peripheral ['l186', 'l190', 'l194', 'l195', 'l196']", + "155, macrophages, ['l187', 'l191', 'l194', 'l197', 'l198']", + "158, microglia, ['l188', 'l192', 'l195', 'l197', 'l199']", + "161, mice ['l189', 'l193', 'l196', 'l198', 'l199']", + "188, pharmacological ['l200', 'l201', 'l202', 'l203']", + "189, inhibition ['l200', 'l204', 'l205', 'l206']", + "190, of ['l201', 'l204', 'l207', 'l208']", + "191, activin-like ['l202', 'l205', 'l207', 'l209']", + "192, kinase-5, ['l203', 'l206', 'l208', 'l209']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "innate", + "immune", + "cells", + "peripheral", + "macrophages" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "inducing", + "expression", + "of", + "CD11c", + "promoter-driven", + "dominant-negative", + "TGF-beta", + "receptor", + "type", + "II", + "Tg2576-CD11c-DNR" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "inducing", + "expression", + "of", + "CD11c", + "promoter-driven", + "dominant-negative", + "TGF-beta", + "receptor", + "type", + "II", + "Tg2576-CD11c-DNR" + ] + }, + "context": { + "val": "organism", + "words": [ + "C57BL/6", + "mice", + "mice." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "mutant", + "human", + "amyloid", + "precursor", + "protein," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "mutant", + "human", + "amyloid", + "precursor", + "protein," + ] + }, + "context": { + "val": "cells", + "words": [ + "peripheral", + "macrophages" + ] + } + } + ] + }, + { + "PMID": "18488037", + "TEXT": "The Ashwell receptor, the major lectin of hepatocytes, rapidly clears from blood circulation glycoproteins bearing glycan ligands that include galactose and N-acetylgalactosamine. This asialoglycoprotein receptor activity remains a key factor in the development and administration of glycoprotein pharmaceuticals, yet a biological purpose of the Ashwell receptor has remained elusive. We have identified endogenous ligands of the Ashwell receptor as glycoproteins and regulatory components in blood coagulation and thrombosis that include von Willebrand factor (vWF) and platelets. The Ashwell receptor normally modulates vWF homeostasis and is responsible for thrombocytopenia during systemic Streptococcus pneumoniae infection by eliminating platelets desialylated by the bacterium's neuraminidase. Hemostatic adaptation by the Ashwell receptor moderates the onset and severity of disseminated intravascular coagulation during sepsis and improves the probability of host survival.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "18469826", + "TEXT": "An ideal vaccination strategy against tumors relies on specific antigens that are required for tumor maintenance. For lymphoma, vaccination with subject-specific immunoglobulin idiotypes has had the most promising results. Here we show that DNA vaccination with plasmids encoding portions of the cytoplasmic domain of anaplastic lymphoma kinase (ALK), which has been translocated in different fusion proteins necessary for the growth of anaplastic large cell lymphoma (ALCL), protects mice from local and systemic lymphoma growth. The protection is potent and long lasting and elicits ALK-specific interferon-gamma responses and CD8+ T cell-mediated cytotoxicity. A combination of chemotherapy and vaccination significantly enhanced the survival of mice challenged with ALK+ lymphomas. These findings indicate that ALK represents an ideal tumor antigen for vaccination-based therapies of ALCL and possibly other ALK+ human tumors.", + "TAG_DATA": [ + "36, plasmids {'perturbing_action': 'B-gene gain-of-function'}", + "37, encoding {'perturbing_action': 'I-gene gain-of-function'}", + "38, portions {'perturbing_action': 'I-gene gain-of-function'}", + "39, of {'perturbing_action': 'I-rnai/knockdown'}", + "40, the {'perturbing_action': 'I-rnai/knockdown'}", + "41, cytoplasmic {'perturbing_action': 'I-rnai/knockdown'}", + "42, domain {'perturbing_action': 'I-gene gain-of-function'}", + "43, of {'perturbing_action': 'I-rnai/knockdown'}", + "44, anaplastic {'perturbing_action': 'I-rnai/knockdown'}", + "45, lymphoma {'perturbing_action': 'I-rnai/knockdown'}", + "46, kinase {'perturbing_action': 'I-gene gain-of-function'}", + "47, (ALK), {'perturbing_action': 'I-rnai/knockdown'}", + "67, mice {'context': 'B-organism'}", + "72, lymphoma {'context': 'B-neoplasm'}", + "102, mice {'context': 'B-organism'}", + "105, ALK+ {'context': 'B-neoplasm'}", + "106, lymphomas. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "36, plasmids ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "37, encoding ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "38, portions ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "39, of ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "40, the ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "41, cytoplasmic ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "42, domain ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "43, of ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "44, anaplastic ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "45, lymphoma ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "46, kinase ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "47, (ALK), ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "67, mice ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "72, lymphoma ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']", + "102, mice ['l91', 'l92']", + "105, ALK+ ['l91', 'l93']", + "106, lymphomas. ['l92', 'l93']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "plasmids", + "encoding", + "portions", + "domain", + "kinase" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "plasmids", + "encoding", + "portions", + "domain", + "kinase" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lymphoma" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "the", + "cytoplasmic", + "anaplastic", + "lymphoma", + "(ALK)," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "the", + "cytoplasmic", + "anaplastic", + "lymphoma", + "(ALK)," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lymphoma" + ] + } + } + ] + }, + { + "PMID": "18469825", + "TEXT": "Neurodegeneration and brain edema are hallmarks of human malignant brain tumors. Here we show that genetic or pharmacological inhibition of the glutamate transporter xCT (X(c-) system, encoded by SLC7a11) in vivo leads to abrogated neurodegeneration, attenuated perifocal edema and prolonged survival. These results show a crucial role for xCT in glioma-induced neurodegeneration and brain edema, corroborating the concept that edema formation may be in part a consequence of peritumoral cell death.", + "TAG_DATA": [ + "17, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "18, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "19, of {'perturbing_action': 'I-pharmacological inhibition'}", + "20, the {'perturbing_action': 'I-pharmacological inhibition'}", + "21, glutamate {'perturbing_action': 'I-pharmacological inhibition'}", + "22, transporter {'perturbing_action': 'I-pharmacological inhibition'}", + "23, xCT {'perturbing_action': 'I-pharmacological inhibition'}", + "24, (X(c-) {'perturbing_action': 'I-pharmacological inhibition'}", + "25, system, {'perturbing_action': 'I-pharmacological inhibition'}", + "26, encoded {'perturbing_action': 'I-pharmacological inhibition'}", + "27, by {'perturbing_action': 'I-pharmacological inhibition'}", + "28, SLC7a11) {'perturbing_action': 'I-pharmacological inhibition'}", + "29, in {'context': 'B-in vivo'}", + "30, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "17, pharmacological ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "18, inhibition ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "19, of ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "20, the ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "21, glutamate ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "22, transporter ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "23, xCT ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "24, (X(c-) ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "25, system, ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "26, encoded ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "27, by ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "28, SLC7a11) ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "29, in ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "30, vivo ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "the", + "glutamate", + "transporter", + "xCT", + "(X(c-)", + "system,", + "encoded", + "by", + "SLC7a11)" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "18438414", + "TEXT": "Secondary bacterial infection often occurs after pulmonary virus infection and is a common cause of severe disease in humans, yet the mechanisms responsible for this viral-bacterial synergy in the lung are only poorly understood. We now report that pulmonary interferon-gamma (IFN-gamma) produced during T cell responses to influenza infection in mice inhibits initial bacterial clearance from the lung by alveolar macrophages. This suppression of phagocytosis correlates with lung IFN-gamma abundance, but not viral burden, and leads to enhanced susceptibility to secondary pneumococcal infection, which can be prevented by IFN-gamma neutralization after influenza infection. Direct inoculation of IFN-gamma can mimic influenza infection and downregulate the expression of the class A scavenger receptor MARCO on alveolar macrophages. Thus, IFN-gamma, although probably facilitating induction of specific anti-influenza adaptive immunity, suppresses innate protection against extracellular bacterial pathogens in the lung.", + "TAG_DATA": [ + "43, T {'context': 'B-cells'}", + "44, cell {'context': 'B-cells'}", + "50, mice {'context': 'B-organism'}", + "59, alveolar {'context': 'B-cells'}", + "60, macrophages. {'context': 'I-cells'}", + "113, alveolar {'context': 'B-cells'}", + "114, macrophages. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "43, T ['l0', 'l1', 'l2', 'l3']", + "44, cell ['l0', 'l4', 'l5', 'l6']", + "50, mice ['l1', 'l4', 'l7', 'l8']", + "59, alveolar ['l2', 'l5', 'l7', 'l9']", + "60, macrophages. ['l3', 'l6', 'l8', 'l9']", + "113, alveolar ['l10']", + "114, macrophages. ['l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18391961", + "TEXT": "Postmortem analysis of five subjects with Parkinson's disease 9-14 years after transplantation of fetal midbrain cell suspensions revealed surviving grafts that included dopamine and serotonin neurons without pathology. These findings are important for the understanding of the etiopathogenesis of midbrain dopamine neuron degeneration and future use of cell replacement therapies.", + "TAG_DATA": [ + "13, fetal {'context': 'B-cells'}", + "14, midbrain {'context': 'I-cells'}", + "15, cell {'context': 'I-cells'}", + "16, suspensions {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "13, fetal ['l0', 'l1', 'l2']", + "14, midbrain ['l0', 'l3', 'l4']", + "15, cell ['l1', 'l3', 'l5']", + "16, suspensions ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18376408", + "TEXT": "Sepsis is a complex, incompletely understood and often fatal disorder, typically accompanied by hypotension, that is considered to represent a dysregulated host response to infection. Neurotensin (NT) is a 13-amino-acid peptide that, among its multiple effects, induces hypotension. We find that intraperitoneal and plasma concentrations of NT are increased in mice after severe cecal ligation and puncture (CLP), a model of sepsis, and that mice treated with a pharmacological antagonist of NT, or NT-deficient mice, show reduced mortality during severe CLP. In mice, mast cells can degrade NT and reduce NT-induced hypotension and CLP-associated mortality, and optimal expression of these effects requires mast cell expression of neurotensin receptor 1 and neurolysin. These findings show that NT contributes to sepsis-related mortality in mice during severe CLP and that mast cells can lower NT concentrations, and suggest that mast cell-dependent reduction in NT levels contributes to the ability of mast cells to enhance survival after CLP.", + "TAG_DATA": [ + "50, mice {'context': 'B-organism'}", + "64, mice {'context': 'B-organism'}", + "68, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "69, antagonist {'perturbing_action': 'I-pharmacological inhibition'}", + "70, of {'perturbing_action': 'I-pharmacological inhibition'}", + "71, NT, {'perturbing_action': 'I-pharmacological inhibition'}", + "73, NT-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "74, mice, {'context': 'B-organism'}", + "82, mice, {'context': 'B-organism'}", + "83, mast {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "64, mice ['l0', 'l1', 'l2', 'l3']", + "68, pharmacological ['l0', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "69, antagonist ['l1', 'l4', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "70, of ['l2', 'l5', 'l11', 'l17', 'l18', 'l19', 'l20', 'l21']", + "71, NT, ['l3', 'l6', 'l12', 'l17', 'l22', 'l23', 'l24', 'l25']", + "73, NT-deficient ['l7', 'l13', 'l18', 'l22', 'l26', 'l27', 'l28']", + "74, mice, ['l8', 'l14', 'l19', 'l23', 'l26', 'l29', 'l30']", + "82, mice, ['l9', 'l15', 'l20', 'l24', 'l27', 'l29', 'l31']", + "83, mast ['l10', 'l16', 'l21', 'l25', 'l28', 'l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "antagonist", + "of", + "NT," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "antagonist", + "of", + "NT," + ] + }, + "context": { + "val": "cells", + "words": [ + "mast" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NT-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NT-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "mast" + ] + } + } + ] + }, + { + "PMID": "18376404", + "TEXT": "Microbial lung infections are the major cause of morbidity and mortality in the hereditary metabolic disorder cystic fibrosis, yet the molecular mechanisms leading from the mutation of cystic fibrosis transmembrane conductance regulator (CFTR) to lung infection are still unclear. Here, we show that ceramide age-dependently accumulates in the respiratory tract of uninfected Cftr-deficient mice owing to an alkalinization of intracellular vesicles in Cftr-deficient cells. This change in pH results in an imbalance between acid sphingomyelinase (Asm) cleavage of sphingomyelin to ceramide and acid ceramidase consumption of ceramide, resulting in the higher levels of ceramide. The accumulation of ceramide causes Cftr-deficient mice to suffer from constitutive age-dependent pulmonary inflammation, death of respiratory epithelial cells, deposits of DNA in bronchi and high susceptibility to severe Pseudomonas aeruginosa infections. Partial genetic deficiency of Asm in Cftr(-/-)Smpd1(+/-) mice or pharmacological treatment of Cftr-deficient mice with the Asm blocker amitriptyline normalizes pulmonary ceramide and prevents all pathological findings, including susceptibility to infection. These data suggest inhibition of Asm as a new treatment strategy for cystic fibrosis.", + "TAG_DATA": [ + "52, Cftr-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "53, mice {'context': 'B-organism'}", + "62, Cftr-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "63, cells. {'context': 'B-cells'}", + "99, Cftr-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "100, mice {'context': 'B-organism'}", + "110, respiratory {'context': 'B-cells'}", + "111, epithelial {'context': 'I-cells'}", + "112, cells, {'context': 'I-cells'}", + "126, Partial {'perturbing_action': 'B-gene loss-of-function'}", + "127, genetic {'perturbing_action': 'I-gene loss-of-function'}", + "128, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "129, of {'perturbing_action': 'I-gene loss-of-function'}", + "130, Asm {'perturbing_action': 'I-gene loss-of-function'}", + "132, Cftr(-/-)Smpd1(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "133, mice {'context': 'B-organism'}", + "138, Cftr-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "139, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "52, Cftr-deficient ['l0', 'l1', 'l2', 'l3']", + "53, mice ['l0', 'l4', 'l5', 'l6']", + "62, Cftr-deficient ['l1', 'l4', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "63, cells. ['l2', 'l5', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "99, Cftr-deficient ['l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "100, mice ['l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "110, respiratory ['l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "111, epithelial ['l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "112, cells, ['l3', 'l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "126, Partial ['l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "127, genetic ['l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "128, deficiency ['l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "129, of ['l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "130, Asm ['l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "132, Cftr(-/-)Smpd1(+/-) ['l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "133, mice ['l33', 'l38', 'l42', 'l45', 'l47', 'l48']", + "138, Cftr-deficient ['l49']", + "139, mice ['l49']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cftr-deficient", + "Partial", + "genetic", + "deficiency", + "of", + "Asm", + "Cftr(-/-)Smpd1(+/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cftr-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells.", + "cells,", + "respiratory", + "epithelial" + ] + } + } + ] + }, + { + "PMID": "18311150", + "TEXT": "Regulatory T cells (T(reg) cells) suppress autoreactive immune responses and limit the efficacy of tumor vaccines; however, it remains a challenge to selectively eliminate or inhibit T(reg) cells. In this study, the zinc-finger A20, a negative regulator of the Toll-like receptor and tumor necrosis factor receptor signaling pathways, was found to play a crucial part in controlling the maturation, cytokine production and immunostimulatory potency of dendritic cells (DCs). A20-silenced DCs showed spontaneous and enhanced expression of costimulatory molecules and proinflammatory cytokines and had different effects on T cell subsets: they inhibited T(reg) cells and hyperactivated tumor-infiltrating cytotoxic T lymphocytes and T helper cells that produced interleukin-6 and tumor necrosis factor-alpha and were refractory to T(reg) cell-mediated suppression. Hence, this study identifies A20 as an antigen presentation attenuator in control of antitumor immune responses during both the priming and the effector phases and provides a strategy to overcome T(reg) cell-mediated suppression in an antigen-specific manner, reducing the need to directly target T(reg) cells.", + "TAG_DATA": [ + "68, A20-silenced {'perturbing_action': 'B-rnai/knockdown'}", + "69, DCs {'context': 'B-cells'}", + "86, T {'context': 'B-cells'}", + "87, cell {'context': 'B-cells'}", + "88, subsets: {'context': 'I-cells'}", + "91, T(reg) {'context': 'B-cells'}", + "92, cells {'context': 'I-cells'}", + "98, lymphocytes {'context': 'I-cells'}", + "100, T {'context': 'B-cells'}", + "101, helper {'context': 'I-cells'}", + "102, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "68, A20-silenced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "69, DCs ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "86, T ['l1', 'l6', 'l11', 'l12', 'l13', 'l14', 'l15']", + "87, cell ['l2', 'l7', 'l11', 'l16', 'l17', 'l18', 'l19']", + "88, subsets: ['l3', 'l8', 'l12', 'l16', 'l20', 'l21', 'l22']", + "91, T(reg) ['l4', 'l9', 'l13', 'l17', 'l20', 'l23', 'l24']", + "92, cells ['l5', 'l10', 'l14', 'l18', 'l21', 'l23']", + "98, lymphocytes ['l15', 'l19', 'l22', 'l24', 'l25', 'l26', 'l27']", + "100, T ['l25', 'l28', 'l29']", + "101, helper ['l26', 'l28', 'l30']", + "102, cells ['l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "A20-silenced" + ] + }, + "context": { + "val": "cells", + "words": [ + "DCs", + "T", + "cell", + "subsets:", + "T(reg)", + "cells" + ] + } + } + ] + }, + { + "PMID": "18311149", + "TEXT": "The persistence of central memory CD4(+) T cells (T(CM) cells) is a major correlate of immunological protection in HIV/AIDS, as the rate of T(CM) cell decline predicts HIV disease progression. In this study, we show that T(CM) cells and effector memory CD4(+) T cells (T(EM) cells) from HIV(+) elite controller (EC) subjects are less susceptible to Fas-mediated apoptosis and persist longer after multiple rounds of T cell receptor triggering when compared to T(CM) and T(EM) cells from aviremic successfully treated (ST) subjects or from HIV(-) donors. We show that persistence of T(CM) cells from EC subjects is a direct consequence of inactivation of the FOXO3a pathway. Silencing the transcriptionally active form of FOXO3a by small interfering RNA or by introducing a FOXO3a dominant-negative form (FOXO3a Nt) extended the long-term survival of T(CM) cells from ST subjects to a length of time similar to that of T(CM) cells from EC subjects. The crucial role of FOXO3a in the survival of memory cells will help shed light on the underlying immunological mechanisms that control viral replication in EC subjects.", + "TAG_DATA": [ + "36, T(CM) {'context': 'B-cells'}", + "37, cells {'context': 'I-cells'}", + "39, effector {'context': 'B-cells'}", + "40, memory {'context': 'I-cells'}", + "41, CD4(+) {'context': 'I-cells'}", + "42, T {'context': 'I-cells'}", + "43, cells {'context': 'I-cells'}", + "44, (T(EM) {'context': 'I-cells'}", + "45, cells) {'context': 'I-cells'}", + "72, T(CM) {'context': 'B-cells'}", + "73, and {'context': 'I-cells'}", + "74, T(EM) {'context': 'I-cells'}", + "75, cells {'context': 'I-cells'}", + "91, T(CM) {'context': 'B-cells'}", + "92, cells {'context': 'I-cells'}", + "106, Silencing {'perturbing_action': 'B-rnai/knockdown'}", + "107, the {'perturbing_action': 'I-rnai/knockdown'}", + "108, transcriptionally {'perturbing_action': 'I-rnai/knockdown'}", + "109, active {'perturbing_action': 'I-rnai/knockdown'}", + "110, form {'perturbing_action': 'I-rnai/knockdown'}", + "111, of {'perturbing_action': 'I-rnai/knockdown'}", + "112, FOXO3a {'perturbing_action': 'I-rnai/knockdown'}", + "113, by {'perturbing_action': 'I-rnai/knockdown'}", + "114, small {'perturbing_action': 'I-rnai/knockdown'}", + "115, interfering {'perturbing_action': 'I-rnai/knockdown'}", + "116, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "119, introducing {'perturbing_action': 'B-other'}", + "120, a {'perturbing_action': 'I-other'}", + "121, FOXO3a {'perturbing_action': 'I-other'}", + "122, dominant-negative {'perturbing_action': 'I-other'}", + "123, form {'perturbing_action': 'I-other'}", + "124, (FOXO3a {'perturbing_action': 'I-other'}", + "125, Nt) {'perturbing_action': 'I-other'}", + "131, T(CM) {'context': 'B-cells'}", + "132, cells {'context': 'I-cells'}", + "145, T(CM) {'context': 'B-cells'}", + "146, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "36, T(CM) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "37, cells ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "39, effector ['l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "40, memory ['l14', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "41, CD4(+) ['l15', 'l26', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "42, T ['l16', 'l27', 'l37', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "43, cells ['l1', 'l8', 'l17', 'l28', 'l38', 'l47', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "44, (T(EM) ['l2', 'l9', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "45, cells) ['l3', 'l10', 'l19', 'l30', 'l40', 'l49', 'l57', 'l63', 'l69', 'l70', 'l71', 'l72', 'l73']", + "72, T(CM) ['l4', 'l11', 'l20', 'l31', 'l41', 'l50', 'l58', 'l64', 'l69', 'l74', 'l75', 'l76', 'l77']", + "73, and ['l5', 'l12', 'l21', 'l32', 'l42', 'l51', 'l59', 'l65', 'l70', 'l74', 'l78', 'l79']", + "74, T(EM) ['l6', 'l22', 'l33', 'l43', 'l52', 'l60', 'l66', 'l71', 'l75', 'l78', 'l80', 'l81']", + "75, cells ['l7', 'l13', 'l23', 'l34', 'l44', 'l53', 'l61', 'l67', 'l72', 'l76', 'l79', 'l80']", + "91, T(CM) ['l24', 'l35', 'l45', 'l54', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "92, cells ['l25', 'l36', 'l46', 'l55', 'l62', 'l68', 'l73', 'l77', 'l81', 'l82', 'l92']", + "106, Silencing ['l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "107, the ['l83', 'l93', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "108, transcriptionally ['l94', 'l106', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "109, active ['l84', 'l95', 'l107', 'l117', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "110, form ['l85', 'l96', 'l108', 'l118', 'l127', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "111, of ['l86', 'l97', 'l109', 'l119', 'l128', 'l136', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "112, FOXO3a ['l87', 'l98', 'l110', 'l120', 'l129', 'l137', 'l143', 'l149', 'l150', 'l151', 'l152', 'l153']", + "113, by ['l88', 'l99', 'l111', 'l121', 'l130', 'l138', 'l144', 'l149', 'l154', 'l155', 'l156', 'l157']", + "114, small ['l89', 'l100', 'l112', 'l122', 'l131', 'l139', 'l145', 'l150', 'l154', 'l158', 'l159', 'l160']", + "115, interfering ['l90', 'l92', 'l101', 'l113', 'l123', 'l132', 'l140', 'l146', 'l151', 'l155', 'l158', 'l161']", + "116, RNA ['l91', 'l102', 'l114', 'l124', 'l133', 'l141', 'l147', 'l152', 'l156', 'l159', 'l161']", + "119, introducing ['l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171']", + "120, a ['l162', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180']", + "121, FOXO3a ['l163', 'l172', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "122, dominant-negative ['l164', 'l173', 'l181', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195']", + "123, form ['l165', 'l174', 'l182', 'l189', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201']", + "124, (FOXO3a ['l166', 'l175', 'l183', 'l190', 'l196', 'l202', 'l203', 'l204', 'l205', 'l206']", + "125, Nt) ['l167', 'l176', 'l184', 'l191', 'l197', 'l202', 'l207', 'l208', 'l209', 'l210']", + "131, T(CM) ['l103', 'l115', 'l125', 'l134', 'l168', 'l177', 'l185', 'l192', 'l198', 'l203', 'l207', 'l211', 'l212', 'l213']", + "132, cells ['l104', 'l116', 'l126', 'l135', 'l142', 'l148', 'l153', 'l157', 'l160', 'l169', 'l178', 'l186', 'l193', 'l199', 'l204', 'l208', 'l211', 'l214', 'l215']", + "145, T(CM) ['l170', 'l179', 'l187', 'l194', 'l200', 'l205', 'l209', 'l212', 'l214', 'l216']", + "146, cells ['l105', 'l171', 'l180', 'l188', 'l195', 'l201', 'l206', 'l210', 'l213', 'l215', 'l216']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T(CM)", + "cells" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "the", + "active", + "form", + "of", + "FOXO3a", + "by", + "small", + "interfering", + "RNA", + "Silencing", + "transcriptionally" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "introducing", + "a", + "FOXO3a", + "dominant-negative", + "form", + "(FOXO3a", + "Nt)" + ] + }, + "context": { + "val": "cells", + "words": [ + "T(CM)", + "cells" + ] + } + } + ] + }, + { + "PMID": "18297083", + "TEXT": "Postnatal bone marrow houses mesenchymal progenitor cells that are osteoblast precursors. These cells have established therapeutic potential, but they are difficult to maintain and expand in vitro, presumably because little is known about the mechanisms controlling their fate decisions. To investigate the potential role of Notch signaling in osteoblastogenesis, we used conditional alleles to genetically remove components of the Notch signaling system during skeletal development. We found that disruption of Notch signaling in the limb skeletogenic mesenchyme markedly increased trabecular bone mass in adolescent mice. Notably, mesenchymal progenitors were undetectable in the bone marrow of mice with high bone mass. As a result, these mice developed severe osteopenia as they aged. Moreover, Notch signaling seemed to inhibit osteoblast differentiation through Hes or Hey proteins, which diminished Runx2 transcriptional activity via physical interaction. These results support a model wherein Notch signaling in bone marrow normally acts to maintain a pool of mesenchymal progenitors by suppressing osteoblast differentiation. Thus, mesenchymal progenitors may be expanded in vitro by activating the Notch pathway, whereas bone formation in vivo may be enhanced by transiently suppressing this pathway.", + "TAG_DATA": [ + "74, limb {'context': 'B-tissue/organ'}", + "75, skeletogenic {'context': 'I-tissue/organ'}", + "76, mesenchyme {'context': 'I-tissue/organ'}", + "83, adolescent {'context': 'B-organism'}", + "84, mice. {'context': 'I-organism'}", + "95, mice {'context': 'B-organism'}", + "104, mice {'context': 'B-organism'}", + "116, inhibit {'effect': 'B-negative'}", + "117, osteoblast {'context': 'B-cells'}", + "118, differentiation {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "74, limb ['l0', 'l1', 'l2', 'l3', 'l4']", + "75, skeletogenic ['l0', 'l5', 'l6', 'l7', 'l8']", + "76, mesenchyme ['l1', 'l5', 'l9', 'l10', 'l11']", + "83, adolescent ['l2', 'l6', 'l9', 'l12']", + "84, mice. ['l3', 'l7', 'l10', 'l12']", + "95, mice ['l4', 'l8', 'l11']", + "116, inhibit ['l13', 'l14']", + "117, osteoblast ['l13', 'l15']", + "118, differentiation ['l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoblast" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoblast" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "18278052", + "TEXT": "Normalization of tumor vasculature is an emerging strategy to improve cytotoxic therapies. Here we show that eliminating nitric oxide (NO) production from tumor cells via neuronal NO synthase silencing or inhibition establishes perivascular gradients of NO in human glioma xenografts in mice and normalizes the tumor vasculature, resulting in improved tumor oxygenation and response to radiation treatment. Creation of perivascular NO gradients may be an effective strategy for normalizing abnormal vasculature.", + "TAG_DATA": [ + "25, neuronal {'perturbing_action': 'B-rnai/knockdown'}", + "26, NO {'perturbing_action': 'I-rnai/knockdown'}", + "27, synthase {'perturbing_action': 'I-rnai/knockdown'}", + "28, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "37, human {'context': 'B-xenograft'}", + "38, glioma {'context': 'I-xenograft'}", + "39, xenografts {'context': 'I-xenograft'}", + "41, mice {'context': 'B-organism'}", + "45, tumor {'context': 'B-neoplasm'}", + "50, tumor {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "25, neuronal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "26, NO ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "27, synthase ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "28, silencing ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "37, human ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "38, glioma ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32', 'l33']", + "39, xenografts ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l34', 'l35']", + "41, mice ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l34', 'l36']", + "45, tumor ['l32', 'l37']", + "50, tumor ['l7', 'l14', 'l20', 'l25', 'l29', 'l33', 'l35', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "neuronal", + "NO", + "synthase", + "silencing" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "human", + "glioma", + "xenografts" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "neuronal", + "NO", + "synthase", + "silencing" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "neuronal", + "NO", + "synthase", + "silencing" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + } + ] + }, + { + "PMID": "18246080", + "TEXT": "Beta-catenin is a central molecule in the Wnt pathway. Expression of a stable form of beta-catenin on CD4+CD25+ regulatory T (T(reg)) cells resulted in a marked enhancement of survival of these cells in vitro. Furthermore, stable beta-catenin-expressing CD4+CD25+ T(reg) cells outcompeted control T(reg) cells in vivo, and the number of T(reg) cells necessary for protection against inflammatory bowel disease could be substantially reduced when stable beta-catenin-expressing CD4+CD25+ T(reg) cells were used instead of control T(reg) cells. Expression of stable beta-catenin on potentially pathogenic CD4+CD25- T cells rendered these cells anergic, and the beta-catenin-mediated induction of anergy occurred even in Foxp3-deficient T cells. Thus, through enhanced survival of existing regulatory T cells, and through induction of unresponsiveness in precursors of T effector cells, beta-catenin stabilization has a powerful effect on the prevention of inflammatory disease.", + "TAG_DATA": [ + "10, of {'perturbing_action': 'I-gene gain-of-function'}", + "11, a {'perturbing_action': 'I-gene gain-of-function'}", + "12, stable {'perturbing_action': 'I-gene gain-of-function'}", + "13, form {'perturbing_action': 'I-gene gain-of-function'}", + "14, of {'perturbing_action': 'I-gene gain-of-function'}", + "15, beta-catenin {'perturbing_action': 'I-gene gain-of-function'}", + "17, CD4+CD25+ {'context': 'B-cells'}", + "18, regulatory {'context': 'I-cells'}", + "19, T {'context': 'I-cells'}", + "20, (T(reg)) {'context': 'I-cells'}", + "21, cells {'context': 'I-cells'}", + "31, cells {'context': 'B-cells'}", + "32, in {'context': 'B-in vitro'}", + "33, vitro. {'context': 'I-in vitro'}", + "37, CD4+CD25+ {'context': 'I-cells'}", + "38, T(reg) {'context': 'I-cells'}", + "39, cells {'context': 'I-cells'}", + "42, T(reg) {'context': 'B-cells'}", + "43, cells {'context': 'I-cells'}", + "44, in {'context': 'B-in vivo'}", + "45, vivo, {'context': 'I-in vivo'}", + "50, T(reg) {'context': 'B-cells'}", + "51, cells {'context': 'I-cells'}", + "66, CD4+CD25+ {'context': 'I-cells'}", + "67, T(reg) {'context': 'I-cells'}", + "68, cells {'context': 'I-cells'}", + "74, T(reg) {'context': 'B-cells'}", + "76, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "77, of {'perturbing_action': 'I-gene gain-of-function'}", + "78, stable {'perturbing_action': 'I-gene gain-of-function'}", + "79, beta-catenin {'perturbing_action': 'I-gene gain-of-function'}", + "83, CD4+CD25- {'context': 'B-cells'}", + "84, T {'context': 'I-cells'}", + "85, cells {'context': 'I-cells'}", + "88, cells {'context': 'B-cells'}", + "99, Foxp3-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "100, T {'context': 'B-cells'}", + "101, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "10, of ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "11, a ['l0', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "12, stable ['l1', 'l22', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "13, form ['l2', 'l23', 'l43', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "14, of ['l3', 'l24', 'l44', 'l63', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "15, beta-catenin ['l4', 'l25', 'l45', 'l64', 'l82', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "17, CD4+CD25+ ['l5', 'l26', 'l46', 'l65', 'l83', 'l100', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "18, regulatory ['l6', 'l27', 'l47', 'l66', 'l84', 'l101', 'l117', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139']", + "19, T ['l7', 'l28', 'l48', 'l67', 'l85', 'l102', 'l118', 'l130', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146']", + "20, (T(reg)) ['l8', 'l29', 'l49', 'l68', 'l86', 'l103', 'l119', 'l131', 'l140', 'l147', 'l148', 'l149', 'l150']", + "21, cells ['l9', 'l30', 'l50', 'l69', 'l87', 'l104', 'l120', 'l132', 'l141', 'l147', 'l151', 'l152', 'l153']", + "31, cells ['l10', 'l31', 'l51', 'l70', 'l88', 'l105', 'l121', 'l133', 'l142', 'l148', 'l151']", + "32, in ['l11', 'l32', 'l52', 'l71', 'l89', 'l106', 'l122', 'l134', 'l143', 'l149', 'l152', 'l154']", + "33, vitro. ['l12', 'l33', 'l53', 'l72', 'l90', 'l107', 'l123', 'l135', 'l144', 'l150', 'l153', 'l154']", + "37, CD4+CD25+ ['l13', 'l34', 'l54', 'l73', 'l91', 'l108', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168']", + "38, T(reg) ['l14', 'l35', 'l55', 'l74', 'l92', 'l109', 'l155', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180']", + "39, cells ['l15', 'l36', 'l56', 'l75', 'l93', 'l110', 'l124', 'l136', 'l156', 'l169', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "42, T(reg) ['l16', 'l37', 'l57', 'l76', 'l94', 'l111', 'l157', 'l170', 'l181', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196']", + "43, cells ['l17', 'l38', 'l58', 'l77', 'l95', 'l112', 'l125', 'l137', 'l145', 'l158', 'l171', 'l182', 'l189', 'l197', 'l198', 'l199', 'l200']", + "44, in ['l18', 'l39', 'l59', 'l78', 'l96', 'l113', 'l126', 'l159', 'l172', 'l183', 'l190', 'l197', 'l201', 'l202', 'l203', 'l204']", + "45, vivo, ['l19', 'l40', 'l60', 'l79', 'l97', 'l114', 'l127', 'l160', 'l173', 'l184', 'l191', 'l198', 'l201', 'l205', 'l206']", + "50, T(reg) ['l20', 'l41', 'l61', 'l80', 'l98', 'l115', 'l128', 'l138', 'l161', 'l174', 'l185', 'l192', 'l199', 'l202', 'l205', 'l207', 'l208', 'l209', 'l210']", + "51, cells ['l21', 'l42', 'l62', 'l81', 'l99', 'l116', 'l129', 'l139', 'l146', 'l162', 'l175', 'l186', 'l193', 'l200', 'l203', 'l206', 'l207', 'l211']", + "66, CD4+CD25+ ['l163', 'l176', 'l194', 'l208', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218']", + "67, T(reg) ['l164', 'l177', 'l187', 'l195', 'l209', 'l212', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224']", + "68, cells ['l165', 'l178', 'l188', 'l196', 'l204', 'l210', 'l211', 'l213', 'l219', 'l225', 'l226', 'l227', 'l228']", + "74, T(reg) ['l166', 'l179', 'l214', 'l220', 'l225', 'l229', 'l230', 'l231', 'l232']", + "76, Expression ['l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242']", + "77, of ['l233', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251']", + "78, stable ['l234', 'l243', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259']", + "79, beta-catenin ['l235', 'l244', 'l252', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266']", + "83, CD4+CD25- ['l215', 'l221', 'l229', 'l236', 'l245', 'l253', 'l260', 'l267', 'l268', 'l269', 'l270', 'l271']", + "84, T ['l167', 'l216', 'l222', 'l226', 'l230', 'l237', 'l246', 'l254', 'l261', 'l267', 'l272', 'l273']", + "85, cells ['l168', 'l180', 'l217', 'l223', 'l227', 'l231', 'l238', 'l247', 'l255', 'l262', 'l268', 'l272', 'l274']", + "88, cells ['l218', 'l224', 'l228', 'l232', 'l239', 'l248', 'l256', 'l263', 'l269', 'l273', 'l274']", + "99, Foxp3-deficient ['l240', 'l249', 'l257', 'l264', 'l275', 'l276']", + "100, T ['l241', 'l250', 'l258', 'l265', 'l270', 'l275', 'l277']", + "101, cells. ['l242', 'l251', 'l259', 'l266', 'l271', 'l276', 'l277']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "a", + "stable", + "form", + "beta-catenin", + "Expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+CD25+", + "regulatory", + "T", + "(T(reg))", + "cells", + "T(reg)", + "CD4+CD25-", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "a", + "stable", + "form", + "beta-catenin" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "a", + "stable", + "form", + "beta-catenin" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Foxp3-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells." + ] + } + } + ] + }, + { + "PMID": "18246079", + "TEXT": "Rhinoviruses cause serious morbidity and mortality as the major etiological agents of asthma exacerbations and the common cold. A major obstacle to understanding disease pathogenesis and to the development of effective therapies has been the lack of a small-animal model for rhinovirus infection. Of the 100 known rhinovirus serotypes, 90% (the major group) use human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor and do not bind mouse ICAM-1; the remaining 10% (the minor group) use a member of the low-density lipoprotein receptor family and can bind the mouse counterpart. Here we describe three novel mouse models of rhinovirus infection: minor-group rhinovirus infection of BALB/c mice, major-group rhinovirus infection of transgenic BALB/c mice expressing a mouse-human ICAM-1 chimera and rhinovirus-induced exacerbation of allergic airway inflammation. These models have features similar to those observed in rhinovirus infection in humans, including augmentation of allergic airway inflammation, and will be useful in the development of future therapies for colds and asthma exacerbations.", + "TAG_DATA": [ + "104, BALB/c {'context': 'B-organism'}", + "105, mice, {'context': 'I-organism'}", + "110, transgenic {'context': 'B-organism'}", + "111, BALB/c {'context': 'I-organism'}", + "112, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "104, BALB/c ['l0']", + "105, mice, ['l0']", + "110, transgenic ['l1', 'l2']", + "111, BALB/c ['l1', 'l3']", + "112, mice ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18204461", + "TEXT": "Little progress has been made toward the use of embryonic stem (ES) cells to study and isolate skeletal muscle progenitors. This is due to the paucity of paraxial mesoderm formation during embryoid body (EB) in vitro differentiation and to the lack of reliable identification and isolation criteria for skeletal muscle precursors. Here we show that expression of the transcription factor Pax3 during embryoid body differentiation enhances both paraxial mesoderm formation and the myogenic potential of the cells within this population. Transplantation of Pax3-induced cells results in teratomas, however, indicating the presence of residual undifferentiated cells. By sorting for the PDGF-alpha receptor, a marker of paraxial mesoderm, and for the absence of Flk-1, a marker of lateral plate mesoderm, we derive a cell population from differentiating ES cell cultures that has substantial muscle regeneration potential. Intramuscular and systemic transplantation of these cells into dystrophic mice results in extensive engraftment of adult myofibers with enhanced contractile function without the formation of teratomas. These data demonstrate the therapeutic potential of ES cells in muscular dystrophy.", + "TAG_DATA": [ + "83, cells {'context': 'B-cells'}", + "84, results {'effect': 'B-positive'}", + "85, in {'effect': 'I-positive'}", + "86, teratomas, {'phenotype': 'B-tumourigenesis'}", + "142, dystrophic {'context': 'B-organism'}", + "143, mice {'context': 'I-organism'}", + "149, adult {'context': 'B-cells'}", + "150, myofibers {'context': 'I-cells'}", + "155, without {'effect': 'B-no effect'}", + "156, the {'effect': 'I-no effect'}", + "157, formation {'effect': 'I-no effect'}", + "159, teratomas. {'phenotype': 'B-tumourigenesis'}" + ], + "LINK_DATA": [ + "83, cells ['l0', 'l1', 'l2']", + "84, results ['l0', 'l3', 'l4']", + "85, in ['l1', 'l3', 'l5']", + "86, teratomas, ['l2', 'l4', 'l5']", + "126, cell ['l6', 'l7', 'l8', 'l9', 'l10']", + "142, dystrophic ['l6', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "143, mice ['l7', 'l11', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "149, adult ['l8', 'l12', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "150, myofibers ['l9', 'l13', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32']", + "155, without ['l10', 'l14', 'l20', 'l25', 'l29', 'l33', 'l34', 'l35']", + "156, the ['l15', 'l21', 'l26', 'l30', 'l33', 'l36', 'l37']", + "157, formation ['l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l38']", + "159, teratomas. ['l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "adult", + "myofibers" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "teratomas,", + "teratomas." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "teratomas," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "dystrophic", + "mice" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "without", + "the", + "formation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "dystrophic", + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "teratomas." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "adult", + "myofibers" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "without", + "the", + "formation" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "without", + "the", + "formation" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "teratomas." + ] + } + } + ] + }, + { + "PMID": "18204460", + "TEXT": "Insulin receptor substrate (IRS)-1 and IRS-2 have dominant roles in the action of insulin, but other substrates of the insulin receptor kinase, such as Gab1, c-Cbl, SH2-B and APS, are also of physiological relevance. Although the protein downstream of tyrosine kinases-1 (Dok1) is known to function as a multisite adapter molecule in insulin signaling, its role in energy homeostasis has remained unclear. Here we show that Dok1 regulates adiposity. Expression of Dok1 in white adipose tissue was markedly increased in mice fed a high-fat diet, whereas adipocytes lacking this adapter were smaller and showed a reduced hypertrophic response to this dietary manipulation. Dok1-deficient mice were leaner and showed improved glucose tolerance and insulin sensitivity compared with wild-type mice. Embryonic fibroblasts from Dok1-deficient mice were impaired in adipogenic differentiation, and this defect was accompanied by an increased activity of the protein kinase ERK and a consequent increase in the phosphorylation of peroxisome proliferator-activated receptor (PPAR)-gamma on Ser112. Mutation of this negative regulatory site for the transactivation activity of PPAR-gamma blocked development of the lean phenotype caused by Dok1 ablation. These results indicate that Dok1 promotes adipocyte hypertrophy by counteracting the inhibitory effect of ERK on PPAR-gamma and may thus confer predisposition to diet-induced obesity.", + "TAG_DATA": [ + "80, mice {'context': 'B-organism'}", + "86, adipocytes {'context': 'B-cells'}", + "102, Dok1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "103, mice {'context': 'B-organism'}", + "118, Embryonic {'context': 'B-cells'}", + "119, fibroblasts {'context': 'I-cells'}", + "121, Dok1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "122, mice {'context': 'B-organism'}", + "124, impaired {'effect': 'B-negative'}", + "126, adipogenic {'phenotype': 'B-differentiation'}", + "127, differentiation, {'phenotype': 'I-differentiation'}", + "156, Mutation {'perturbing_action': 'B-other'}", + "157, of {'perturbing_action': 'I-other'}", + "158, this {'perturbing_action': 'I-other'}", + "159, negative {'perturbing_action': 'I-other'}", + "160, regulatory {'perturbing_action': 'I-other'}", + "161, site {'perturbing_action': 'I-other'}", + "162, for {'perturbing_action': 'I-other'}", + "163, the {'perturbing_action': 'I-other'}", + "164, transactivation {'perturbing_action': 'I-other'}", + "165, activity {'perturbing_action': 'I-other'}", + "166, of {'perturbing_action': 'I-other'}", + "167, PPAR-gamma {'perturbing_action': 'I-other'}", + "176, Dok1 {'perturbing_action': 'B-gene loss-of-function'}", + "177, ablation. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "80, mice ['l0']", + "86, adipocytes ['l0']", + "102, Dok1-deficient ['l1', 'l2', 'l3', 'l4']", + "103, mice ['l1', 'l5']", + "118, Embryonic ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "119, fibroblasts ['l6', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "121, Dok1-deficient ['l7', 'l22', 'l37', 'l38', 'l39', 'l40']", + "122, mice ['l8', 'l23', 'l37', 'l41', 'l42', 'l43']", + "124, impaired ['l2', 'l9', 'l24', 'l38', 'l41', 'l44', 'l45']", + "126, adipogenic ['l3', 'l10', 'l25', 'l39', 'l42', 'l44', 'l46']", + "127, differentiation, ['l4', 'l5', 'l11', 'l26', 'l40', 'l43', 'l45', 'l46']", + "156, Mutation ['l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "157, of ['l47', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "158, this ['l12', 'l27', 'l48', 'l60', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "159, negative ['l13', 'l28', 'l49', 'l61', 'l72', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "160, regulatory ['l14', 'l29', 'l50', 'l62', 'l73', 'l83', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "161, site ['l15', 'l30', 'l51', 'l63', 'l74', 'l84', 'l93', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "162, for ['l16', 'l31', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "163, the ['l17', 'l32', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "164, transactivation ['l18', 'l33', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l123', 'l124', 'l125', 'l126', 'l127']", + "165, activity ['l19', 'l34', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l118', 'l123', 'l128', 'l129', 'l130', 'l131']", + "166, of ['l20', 'l35', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l113', 'l119', 'l124', 'l128', 'l132', 'l133', 'l134']", + "167, PPAR-gamma ['l21', 'l36', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l129', 'l132', 'l135', 'l136']", + "176, Dok1 ['l58', 'l70', 'l81', 'l91', 'l100', 'l108', 'l115', 'l121', 'l126', 'l130', 'l133', 'l135', 'l137']", + "177, ablation. ['l59', 'l71', 'l82', 'l92', 'l101', 'l109', 'l116', 'l122', 'l127', 'l131', 'l134', 'l136', 'l137']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dok1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dok1-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dok1-deficient" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "adipogenic", + "differentiation," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation,", + "adipogenic" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Embryonic", + "fibroblasts" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dok1-deficient" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Embryonic", + "fibroblasts" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Embryonic", + "fibroblasts" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "adipogenic", + "differentiation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Embryonic", + "fibroblasts" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "this", + "negative", + "regulatory", + "site", + "for", + "the", + "transactivation", + "activity", + "of", + "PPAR-gamma" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "adipogenic", + "differentiation," + ] + } + } + ] + }, + { + "PMID": "18193059", + "TEXT": "About 3,000 individuals in the United States are awaiting a donor heart; worldwide, 22 million individuals are living with heart failure. A bioartificial heart is a theoretical alternative to transplantation or mechanical left ventricular support. Generating a bioartificial heart requires engineering of cardiac architecture, appropriate cellular constituents and pump function. We decellularized hearts by coronary perfusion with detergents, preserved the underlying extracellular matrix, and produced an acellular, perfusable vascular architecture, competent acellular valves and intact chamber geometry. To mimic cardiac cell composition, we reseeded these constructs with cardiac or endothelial cells. To establish function, we maintained eight constructs for up to 28 d by coronary perfusion in a bioreactor that simulated cardiac physiology. By day 4, we observed macroscopic contractions. By day 8, under physiological load and electrical stimulation, constructs could generate pump function (equivalent to about 2% of adult or 25% of 16-week fetal heart function) in a modified working heart preparation.", + "TAG_DATA": [ + "52, hearts {'context': 'B-tissue/organ'}", + "87, cardiac {'context': 'B-cells'}", + "88, or {'context': 'I-cells'}", + "89, endothelial {'context': 'I-cells'}", + "90, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "87, cardiac ['l0', 'l1', 'l2']", + "88, or ['l0', 'l3', 'l4']", + "89, endothelial ['l1', 'l3', 'l5']", + "90, cells. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18193058", + "TEXT": "The capacity to direct migration ('homing') of blood-borne cells to a predetermined anatomic compartment is vital to stem cell-based tissue engineering and other adoptive cellular therapies. Although multipotent mesenchymal stromal cells (MSCs, also termed 'mesenchymal stem cells') hold the potential for curing generalized skeletal diseases, their clinical effectiveness is constrained by the poor osteotropism of infused MSCs (refs. 1-3). Cellular recruitment to bone occurs within specialized marrow vessels that constitutively express vascular E-selectin, a lectin that recognizes sialofucosylated determinants on its various ligands. We show here that human MSCs do not express E-selectin ligands, but express a CD44 glycoform bearing alpha-2,3-sialyl modifications. Using an alpha-1,3-fucosyltransferase preparation and enzymatic conditions specifically designed for treating live cells, we converted the native CD44 glycoform on MSCs into hematopoietic cell E-selectin/L-selectin ligand (HCELL), which conferred potent E-selectin binding without effects on cell viability or multipotency. Real-time intravital microscopy in immunocompromised (NOD/SCID) mice showed that intravenously infused HCELL(+) MSCs infiltrated marrow within hours of infusion, with ensuing rare foci of endosteally localized cells and human osteoid generation. These findings establish that the HCELL glycoform of CD44 confers tropism to bone and unveil a readily translatable roadmap for programming cellular trafficking by chemical engineering of glycans on a distinct membrane glycoprotein.", + "TAG_DATA": [ + "122, MSCs {'context': 'B-cells'}", + "134, without {'effect': 'B-no effect'}", + "135, effects {'effect': 'I-no effect'}", + "137, cell {'phenotype': 'B-cell survival'}", + "138, viability {'phenotype': 'I-cell survival'}", + "145, immunocompromised {'context': 'B-organism'}", + "146, (NOD/SCID) {'context': 'I-organism'}", + "147, mice {'context': 'B-organism'}", + "152, HCELL(+) {'context': 'B-cells'}", + "153, MSCs {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "122, MSCs ['l0', 'l1', 'l2', 'l3']", + "134, without ['l0', 'l4', 'l5', 'l6']", + "135, effects ['l1', 'l4', 'l7', 'l8']", + "137, cell ['l2', 'l5', 'l7', 'l9']", + "138, viability ['l3', 'l6', 'l8', 'l9']", + "145, immunocompromised ['l10', 'l11', 'l12', 'l13']", + "146, (NOD/SCID) ['l10', 'l14', 'l15', 'l16']", + "147, mice ['l11', 'l14', 'l17']", + "152, HCELL(+) ['l12', 'l15', 'l18']", + "153, MSCs ['l13', 'l16', 'l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "MSCs" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "without", + "effects" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "MSCs" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "viability" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "without", + "effects" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "viability" + ] + } + } + ] + }, + { + "PMID": "18157143", + "TEXT": "Spinal cord injuries (SCIs) in humans and experimental animals are often associated with varying degrees of spontaneous functional recovery during the first months after injury. Such recovery is widely attributed to axons spared from injury that descend from the brain and bypass incomplete lesions, but its mechanisms are uncertain. To investigate the neural basis of spontaneous recovery, we used kinematic, physiological and anatomical analyses to evaluate mice with various combinations of spatially and temporally separated lateral hemisections with or without the excitotoxic ablation of intrinsic spinal cord neurons. We show that propriospinal relay connections that bypass one or more injury sites are able to mediate spontaneous functional recovery and supraspinal control of stepping, even when there has been essentially total and irreversible interruption of long descending supraspinal pathways in mice. Our findings show that pronounced functional recovery can occur after severe SCI without the maintenance or regeneration of direct projections from the brain past the lesion and can be mediated by the reorganization of descending and propriospinal connections. Targeting interventions toward augmenting the remodeling of relay connections may provide new therapeutic strategies to bypass lesions and restore function after SCI and in other conditions such as stroke and multiple sclerosis.", + "TAG_DATA": [ + "66, mice {'context': 'B-organism'}", + "82, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "84, intrinsic {'context': 'B-cells'}", + "85, spinal {'context': 'I-cells'}", + "86, cord {'context': 'I-cells'}", + "87, neurons. {'context': 'I-cells'}", + "129, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "82, ablation ['l0', 'l1', 'l2', 'l3', 'l4']", + "84, intrinsic ['l0', 'l5', 'l6', 'l7', 'l8']", + "85, spinal ['l1', 'l5', 'l9', 'l10', 'l11']", + "86, cord ['l2', 'l6', 'l9', 'l12', 'l13']", + "87, neurons. ['l3', 'l7', 'l10', 'l12', 'l14']", + "129, mice. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablation" + ] + }, + "context": { + "val": "cells", + "words": [ + "intrinsic", + "spinal", + "cord", + "neurons." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "18157142", + "TEXT": "In spite of their having sufficient immunogenicity, tumor vaccines remain largely ineffective. The mechanisms underlying this lack of efficacy are still unclear. Here we report a previously undescribed mechanism by which the tumor endothelium prevents T cell homing and hinders tumor immunotherapy. Transcriptional profiling of microdissected tumor endothelial cells from human ovarian cancers revealed genes associated with the absence or presence of tumor-infiltrating lymphocytes (TILs). Overexpression of the endothelin B receptor (ET(B)R) was associated with the absence of TILs and short patient survival time. The ET(B)R inhibitor BQ-788 increased T cell adhesion to human endothelium in vitro, an effect countered by intercellular adhesion molecule-1 (ICAM-1) blockade or treatment with NO donors. In mice, ET(B)R neutralization by BQ-788 increased T cell homing to tumors; this homing required ICAM-1 and enabled tumor response to otherwise ineffective immunotherapy in vivo without changes in systemic antitumor immune response. These findings highlight a molecular mechanism with the potential to be pharmacologically manipulated to enhance the efficacy of tumor immunotherapy in humans.", + "TAG_DATA": [ + "65, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "66, of {'perturbing_action': 'I-gene gain-of-function'}", + "67, the {'perturbing_action': 'I-gene gain-of-function'}", + "68, endothelin {'perturbing_action': 'I-gene gain-of-function'}", + "69, B {'perturbing_action': 'I-gene gain-of-function'}", + "70, receptor {'perturbing_action': 'I-gene gain-of-function'}", + "71, (ET(B)R) {'perturbing_action': 'I-gene gain-of-function'}", + "85, ET(B)R {'perturbing_action': 'B-pharmacological inhibition'}", + "86, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "87, BQ-788 {'perturbing_action': 'I-pharmacological inhibition'}", + "88, increased {'effect': 'B-positive'}", + "89, T {'context': 'B-cells'}", + "90, cell {'context': 'B-cells'}", + "91, adhesion {'phenotype': 'B-adhesion'}", + "93, human {'context': 'B-tissue/organ'}", + "94, endothelium {'context': 'I-tissue/organ'}", + "95, in {'context': 'B-in vitro'}", + "96, vitro, {'context': 'I-in vitro'}", + "112, mice, {'context': 'B-organism'}", + "113, ET(B)R {'perturbing_action': 'B-pharmacological inhibition'}", + "114, neutralization {'perturbing_action': 'I-pharmacological inhibition'}", + "115, by {'perturbing_action': 'I-pharmacological inhibition'}", + "116, BQ-788 {'perturbing_action': 'I-pharmacological inhibition'}", + "118, T {'context': 'B-cells'}", + "119, cell {'context': 'B-cells'}", + "122, tumors; {'context': 'B-neoplasm'}", + "129, tumor {'context': 'B-neoplasm'}", + "135, in {'context': 'B-in vivo'}", + "136, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "65, Overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "66, of ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "67, the ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "68, endothelin ['l2', 'l16', 'l29', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "69, B ['l3', 'l17', 'l30', 'l44', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "70, receptor ['l4', 'l18', 'l31', 'l45', 'l58', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "71, (ET(B)R) ['l5', 'l19', 'l32', 'l46', 'l59', 'l71', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "85, ET(B)R ['l33', 'l47', 'l60', 'l72', 'l83', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "86, inhibitor ['l34', 'l48', 'l61', 'l73', 'l84', 'l94', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "87, BQ-788 ['l6', 'l20', 'l35', 'l49', 'l62', 'l74', 'l85', 'l95', 'l104', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "88, increased ['l7', 'l21', 'l36', 'l50', 'l63', 'l75', 'l86', 'l96', 'l105', 'l113', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127']", + "89, T ['l8', 'l22', 'l37', 'l51', 'l64', 'l76', 'l87', 'l97', 'l106', 'l114', 'l121', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "90, cell ['l9', 'l23', 'l38', 'l52', 'l65', 'l77', 'l88', 'l98', 'l107', 'l115', 'l122', 'l128', 'l134', 'l135', 'l136', 'l137', 'l138']", + "91, adhesion ['l10', 'l24', 'l39', 'l53', 'l66', 'l78', 'l89', 'l99', 'l108', 'l116', 'l123', 'l129', 'l134', 'l139', 'l140', 'l141', 'l142']", + "93, human ['l11', 'l25', 'l40', 'l54', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l124', 'l130', 'l135', 'l139', 'l143', 'l144', 'l145']", + "94, endothelium ['l12', 'l26', 'l41', 'l55', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l125', 'l131', 'l136', 'l140', 'l143', 'l146', 'l147']", + "95, in ['l13', 'l27', 'l42', 'l56', 'l69', 'l81', 'l92', 'l102', 'l111', 'l119', 'l126', 'l132', 'l137', 'l141', 'l144', 'l146', 'l148']", + "96, vitro, ['l14', 'l28', 'l43', 'l57', 'l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l127', 'l133', 'l138', 'l142', 'l145', 'l147', 'l148']", + "112, mice, ['l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158']", + "113, ET(B)R ['l149', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "114, neutralization ['l150', 'l159', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175']", + "115, by ['l151', 'l160', 'l168', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "116, BQ-788 ['l152', 'l161', 'l169', 'l176', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "118, T ['l153', 'l162', 'l170', 'l177', 'l183', 'l189', 'l190', 'l191', 'l192', 'l193']", + "119, cell ['l154', 'l163', 'l171', 'l178', 'l184', 'l189', 'l194', 'l195', 'l196', 'l197']", + "122, tumors; ['l155', 'l164', 'l172', 'l179', 'l185', 'l190', 'l194', 'l198', 'l199', 'l200']", + "129, tumor ['l156', 'l165', 'l173', 'l180', 'l186', 'l191', 'l195', 'l198', 'l201', 'l202']", + "135, in ['l157', 'l166', 'l174', 'l181', 'l187', 'l192', 'l196', 'l199', 'l201', 'l203']", + "136, vivo ['l158', 'l167', 'l175', 'l182', 'l188', 'l193', 'l197', 'l200', 'l202', 'l203']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "the", + "endothelin", + "B", + "receptor", + "(ET(B)R)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "the", + "endothelin", + "B", + "receptor", + "(ET(B)R)" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "the", + "endothelin", + "B", + "receptor", + "(ET(B)R)" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "the", + "endothelin", + "B", + "receptor", + "(ET(B)R)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "human", + "endothelium" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "the", + "endothelin", + "B", + "receptor", + "(ET(B)R)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ET(B)R", + "inhibitor", + "BQ-788" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ET(B)R", + "inhibitor", + "BQ-788", + "neutralization", + "by" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ET(B)R", + "inhibitor", + "BQ-788" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ET(B)R", + "inhibitor", + "BQ-788" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "human", + "endothelium" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ET(B)R", + "inhibitor", + "BQ-788" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "human", + "endothelium" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "human", + "endothelium" + ] + } + }, + { + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ET(B)R", + "neutralization", + "by", + "BQ-788" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ET(B)R", + "neutralization", + "by", + "BQ-788" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors;", + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ET(B)R", + "neutralization", + "by", + "BQ-788" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "18084302", + "TEXT": "The tone of vascular smooth muscle cells is a primary determinant of the total peripheral vascular resistance and hence the arterial blood pressure. Most forms of hypertension ultimately result from an increased vascular tone that leads to an elevated total peripheral resistance. Regulation of vascular resistance under normotensive and hypertensive conditions involves multiple mediators, many of which act through G protein-coupled receptors on vascular smooth muscle cells. Receptors that mediate vasoconstriction couple with the G-proteins G(q)-G11 and G12-G13 to stimulate phosphorylation of myosin light chain (MLC) via the Ca2+/MLC kinase- and Rho/Rho kinase-mediated signaling pathways, respectively. Using genetically altered mouse models that allow for the acute abrogation of both signaling pathways by inducible Cre/loxP-mediated mutagenesis in smooth muscle cells, we show that G(q)-G11-mediated signaling in smooth muscle cells is required for maintenance of basal blood pressure and for the development of salt-induced hypertension. In contrast, lack of G12-G13, as well as of their major effector, the leukemia-associated Rho guanine nucleotide exchange factor (LARG), did not alter normal blood pressure regulation but did block the development of salt-induced hypertension. This identifies the G12-G13-LARG-mediated signaling pathway as a new target for antihypertensive therapies that would be expected to leave normal blood pressure regulation unaffected.", + "TAG_DATA": [ + "99, mouse {'context': 'B-organism'}", + "100, models {'context': 'I-organism'}", + "116, smooth {'context': 'B-cells'}", + "117, muscle {'context': 'I-cells'}", + "118, cells, {'context': 'I-cells'}", + "145, lack {'perturbing_action': 'B-gene loss-of-function'}", + "146, of {'perturbing_action': 'I-gene loss-of-function'}", + "147, G12-G13, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "99, mouse ['l0', 'l1', 'l2', 'l3']", + "100, models ['l0', 'l4', 'l5', 'l6']", + "116, smooth ['l1', 'l4', 'l7', 'l8']", + "117, muscle ['l2', 'l5', 'l7', 'l9']", + "118, cells, ['l3', 'l6', 'l8', 'l9']", + "145, lack ['l10', 'l11']", + "146, of ['l10', 'l12']", + "147, G12-G13, ['l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18066075", + "TEXT": "Aberrant wound-healing responses to injury have been implicated in the development of pulmonary fibrosis, but the mediators directing these pathologic responses have yet to be fully identified. We show that lysophosphatidic acid levels increase in bronchoalveolar lavage fluid following lung injury in the bleomycin model of pulmonary fibrosis, and that mice lacking one of its receptors, LPA1, are markedly protected from fibrosis and mortality in this model. The absence of LPA1 led to reduced fibroblast recruitment and vascular leak, two responses that may be excessive when injury leads to fibrosis rather than to repair, whereas leukocyte recruitment was preserved during the first week after injury. In persons with idiopathic pulmonary fibrosis, lysophosphatidic acid levels in bronchoalveolar lavage fluid were also increased, and inhibition of LPA1 markedly reduced fibroblast responses to the chemotactic activity of this fluid. LPA1 therefore represents a new therapeutic target for diseases in which aberrant responses to injury contribute to fibrosis, such as idiopathic pulmonary fibrosis.", + "TAG_DATA": [ + "50, mice {'context': 'B-organism'}", + "51, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "52, one {'perturbing_action': 'I-gene loss-of-function'}", + "53, of {'perturbing_action': 'I-gene loss-of-function'}", + "54, its {'perturbing_action': 'I-gene loss-of-function'}", + "55, receptors, {'perturbing_action': 'I-gene loss-of-function'}", + "56, LPA1, {'perturbing_action': 'I-gene loss-of-function'}", + "68, absence {'perturbing_action': 'B-gene loss-of-function'}", + "69, of {'perturbing_action': 'I-gene loss-of-function'}", + "70, LPA1 {'perturbing_action': 'I-gene loss-of-function'}", + "74, fibroblast {'context': 'B-cells'}", + "122, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "123, of {'perturbing_action': 'I-pharmacological inhibition'}", + "124, LPA1 {'perturbing_action': 'I-pharmacological inhibition'}", + "127, fibroblast {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "50, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "51, lacking ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "52, one ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "53, of ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "54, its ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "55, receptors, ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "56, LPA1, ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "68, absence ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "69, of ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "70, LPA1 ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "74, fibroblast ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "122, inhibition ['l55', 'l56', 'l57']", + "123, of ['l55', 'l58', 'l59']", + "124, LPA1 ['l56', 'l58', 'l60']", + "127, fibroblast ['l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "one", + "of", + "its", + "receptors,", + "LPA1,", + "absence", + "LPA1" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "one", + "of", + "its", + "receptors,", + "LPA1,", + "absence", + "LPA1" + ] + }, + "context": { + "val": "cells", + "words": [ + "fibroblast" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "LPA1" + ] + }, + "context": { + "val": "cells", + "words": [ + "fibroblast" + ] + } + } + ] + }, + { + "PMID": "17994102", + "TEXT": "Methicillin-resistant Staphylococcus aureus (MRSA) remains a major human pathogen. Traditionally, MRSA infections occurred exclusively in hospitals and were limited to immunocompromised patients or individuals with predisposing risk factors. However, recently there has been an alarming epidemic caused by community-associated (CA)-MRSA strains, which can cause severe infections that can result in necrotizing fasciitis or even death in otherwise healthy adults outside of healthcare settings. In the US, CA-MRSA is now the cause of the majority of infections that result in trips to the emergency room. It is unclear what makes CA-MRSA strains more successful in causing human disease compared with their hospital-associated counterparts. Here we describe a class of secreted staphylococcal peptides that have a remarkable ability to recruit, activate and subsequently lyse human neutrophils, thus eliminating the main cellular defense against S. aureus infection. These peptides are produced at high concentrations by standard CA-MRSA strains and contribute significantly to the strains' ability to cause disease in animal models of infection. Our study reveals a previously uncharacterized set of S. aureus virulence factors that account at least in part for the enhanced virulence of CA-MRSA.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17994101", + "TEXT": "Multiple sclerosis is a neuroinflammatory disease associated with axonal degeneration. The neuronally expressed, proton-gated acid-sensing ion channel-1 (ASIC1) is permeable to Na+ and Ca2+, and excessive accumulation of these ions is associated with axonal degeneration. We tested the hypothesis that ASIC1 contributes to axonal degeneration in inflammatory lesions of the central nervous system (CNS). After induction of experimental autoimmune encephalomyelitis (EAE), Asic1-/- mice showed both a markedly reduced clinical deficit and reduced axonal degeneration compared to wild-type mice. Consistently with acidosis-mediated injury, pH measurements in the spinal cord of EAE mice showed tissue acidosis sufficient to open ASIC1. The acidosis-related protective effect of Asic1 disruption was also observed in nerve explants in vitro. Amiloride, a licensed and clinically safe blocker of ASICs, was equally neuroprotective in nerve explants and in EAE. Although ASICs are also expressed by immune cells, this expression is unlikely to explain the neuroprotective effect of Asic1 inactivation, as CNS inflammation was similar in wild-type and Asic1-/- mice. In addition, adoptive transfer of T cells from wild-type mice did not affect the protection mediated by Asic1 disruption. These results suggest that ASIC1 blockers could provide neuroprotection in multiple sclerosis.", + "TAG_DATA": [ + "61, Asic1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "62, mice {'context': 'B-organism'}", + "77, mice. {'context': 'B-organism'}", + "86, spinal {'context': 'B-tissue/organ'}", + "87, cord {'context': 'I-tissue/organ'}", + "90, mice {'context': 'B-organism'}", + "109, nerve {'context': 'B-cells'}", + "110, explants {'context': 'I-cells'}", + "111, in {'context': 'B-in vitro'}", + "112, vitro. {'context': 'I-in vitro'}", + "126, nerve {'context': 'B-tissue/organ'}", + "127, explants {'context': 'I-tissue/organ'}", + "159, Asic1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "160, mice. {'context': 'B-organism'}", + "166, T {'context': 'B-cells'}", + "167, cells {'context': 'I-cells'}", + "170, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "61, Asic1-/- ['l0', 'l1']", + "62, mice ['l0', 'l2']", + "77, mice. ['l1', 'l2']", + "86, spinal ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "87, cord ['l3', 'l9', 'l10', 'l11', 'l12', 'l13']", + "90, mice ['l4', 'l9', 'l14', 'l15', 'l16', 'l17']", + "109, nerve ['l5', 'l10', 'l14', 'l18', 'l19', 'l20']", + "110, explants ['l6', 'l11', 'l15', 'l18', 'l21', 'l22']", + "111, in ['l7', 'l12', 'l16', 'l19', 'l21', 'l23']", + "112, vitro. ['l8', 'l13', 'l17', 'l20', 'l22', 'l23']", + "126, nerve ['l24']", + "127, explants ['l24']", + "159, Asic1-/- ['l25']", + "160, mice. ['l25']", + "166, T ['l26', 'l27']", + "167, cells ['l26', 'l28']", + "170, mice ['l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Asic1-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "17987025", + "TEXT": "Mesenchymal stem cells promote the dissemination of neoplastic cells in a mouse model of breast cancer. The findings sound a cautionary toll for anticancer therapies that rely on these cells and provoke a re-evaluation of how metastases form.", + "TAG_DATA": [ + "11, mouse {'context': 'B-neoplasm'}", + "12, model {'context': 'I-neoplasm'}", + "13, of {'context': 'I-neoplasm'}", + "14, breast {'context': 'I-neoplasm'}", + "15, cancer. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "11, mouse ['l0', 'l1', 'l2', 'l3']", + "12, model ['l0', 'l4', 'l5', 'l6']", + "13, of ['l1', 'l4', 'l7', 'l8']", + "14, breast ['l2', 'l5', 'l7', 'l9']", + "15, cancer. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17952092", + "TEXT": "Atopic allergy is characterized by an increase in IgE antibodies that signal through the high-affinity Fcepsilon receptor (FcepsilonRI) to induce the release of inflammatory mediators from mast cells. For unknown reasons, the prevalence of allergic diseases has recently increased steeply in the developed world. However, this increase has not been mirrored in developing countries, even though IgE concentrations are often greatly elevated in individuals from these countries, owing to nonspecific IgE induction by universally present parasitic worms. Here we offer one explanation for this paradox based on the properties of ES-62, a molecule secreted by filarial nematodes. We found that highly purified, endotoxin-free ES-62 directly inhibits the FcepsilonRI-induced release of allergy mediators from human mast cells by selectively blocking key signal transduction events, including phospholipase D-coupled, sphingosine kinase-mediated calcium mobilization and nuclear factor-kappaB activation. ES-62 mediates these effects by forming a complex with Toll-like receptor 4, which results in the sequestration of protein kinase C-alpha (PKC-alpha). This causes caveolae/lipid raft-mediated, proteasome-independent degradation of PKC-alpha, a molecule important for the coupling of FcepsilonRI to phospholipase D and mast cell activation. We also show that ES-62 is able to protect mice from mast cell-dependent hypersensitivity in the skin and lungs, indicating that it has potential as a novel therapeutic for allergy.", + "TAG_DATA": [ + "113, human {'context': 'B-cells'}", + "114, mast {'context': 'I-cells'}", + "115, cells {'context': 'I-cells'}", + "188, mice {'context': 'B-organism'}", + "197, lungs, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "113, human ['l0', 'l1']", + "114, mast ['l0', 'l2']", + "115, cells ['l1', 'l2']", + "188, mice ['l3']", + "197, lungs, ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17917657", + "TEXT": "The innate and adaptive immune systems act in concert to effectively combat infection while minimizing collater al damage caused by the host immune response. T cells of the adaptive immune system have now been shown to suppress overzealous early innate responses to infection that can lead to 'cytokine storm'–mediated death (pages 1248–1252).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17891146", + "TEXT": "Toll-like receptors (TLRs) recognize conserved microbial structures called pathogen-associated molecular patterns. Signaling from TLRs leads to upregulation of co-stimulatory molecules for better priming of T cells and secretion of inflammatory cytokines by innate immune cells. Lymphocyte-deficient hosts often die of acute infection, presumably owing to their lack of an adaptive immune response to effectively clear pathogens. However, we show here that an unleashed innate immune response due to the absence of residential T cells can also be a direct cause of death. Viral infection or administration of poly(I:C), a ligand for TLR3, led to cytokine storm in T-cell- or lymphocyte-deficient mice in a fashion dependent on NK cells and tumor necrosis factor. We have further shown, through the depletion of CD4+ and CD8+ cells in wild-type mice and the transfer of T lymphocytes into Rag-1-deficient mice, respectively, that T cells are both necessary and sufficient to temper the early innate response. In addition to the effects of natural regulatory T cells, close contact of resting CD4+CD25-Foxp3- or CD8+ T cells with innate cells could also suppress the cytokine surge by various innate cells in an antigen-independent fashion. Therefore, adaptive immune cells have an unexpected role in tempering initial innate responses.", + "TAG_DATA": [ + "97, T-cell- {'perturbing_action': 'B-gene loss-of-function'}", + "98, or {'perturbing_action': 'I-gene loss-of-function'}", + "99, lymphocyte-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "100, mice {'context': 'B-organism'}", + "120, CD4+ {'context': 'B-cells'}", + "121, and {'context': 'I-cells'}", + "122, CD8+ {'context': 'I-cells'}", + "123, cells {'context': 'I-cells'}", + "126, mice {'context': 'B-organism'}", + "131, T {'context': 'B-cells'}", + "132, lymphocytes {'context': 'I-cells'}", + "134, Rag-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "135, mice, {'context': 'B-organism'}", + "181, innate {'context': 'B-cells'}", + "182, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "97, T-cell- ['l0', 'l1', 'l2']", + "98, or ['l0', 'l3', 'l4']", + "99, lymphocyte-deficient ['l1', 'l3', 'l5', 'l6', 'l7', 'l8']", + "100, mice ['l2', 'l4', 'l5']", + "120, CD4+ ['l9', 'l10', 'l11', 'l12', 'l13']", + "121, and ['l6', 'l9', 'l14', 'l15', 'l16', 'l17']", + "122, CD8+ ['l7', 'l10', 'l14', 'l18', 'l19', 'l20']", + "123, cells ['l8', 'l11', 'l15', 'l18', 'l21']", + "126, mice ['l12', 'l16', 'l19', 'l21', 'l22']", + "131, T ['l23', 'l24', 'l25', 'l26', 'l27']", + "132, lymphocytes ['l23', 'l28', 'l29', 'l30', 'l31']", + "134, Rag-1-deficient ['l24', 'l28', 'l32', 'l33', 'l34']", + "135, mice, ['l13', 'l17', 'l20', 'l22', 'l25', 'l29', 'l32', 'l35', 'l36']", + "181, innate ['l26', 'l30', 'l33', 'l35', 'l37']", + "182, cells ['l27', 'l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "T-cell-", + "or", + "lymphocyte-deficient", + "Rag-1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lymphocyte-deficient", + "Rag-1-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "and", + "CD8+", + "cells", + "T", + "lymphocytes", + "innate" + ] + } + } + ] + }, + { + "PMID": "17891145", + "TEXT": "It is assumed that a timely mass administration of antiviral drugs, backed by quarantines and social distancing, could contain a nascent influenza epidemic at its source, provided that the first clusters of cases were localized within a short time. However, effective routine surveillance may be impossible in countries lacking basic public health resources. For a global containment strategy to be successful, low-cost, easy-to-use handheld units that permit decentralized testing would be vital. Here we present a microfluidic platform that can detect the highly pathogenic avian influenza virus H5N1 in a throat swab sample by using magnetic forces to manipulate a free droplet containing superparamagnetic particles. In a sequential process, the viral RNA is isolated, purified, preconcentrated by 50,000% and subjected to ultrafast real-time RT-PCR. Compared to commercially available tests, the bioassay is equally sensitive and is 440% faster and 2,000-5,000% cheaper.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17873882", + "TEXT": "Gain-of-function mutations in NOTCH1 are common in T-cell lymphoblastic leukemias and lymphomas (T-ALL), making this receptor a promising target for drugs such as gamma-secretase inhibitors, which block a proteolytic cleavage required for NOTCH1 activation. However, the enthusiasm for these therapies has been tempered by tumor resistance and the paucity of information on the oncogenic programs regulated by oncogenic NOTCH1. Here we show that NOTCH1 regulates the expression of PTEN (encoding phosphatase and tensin homolog) and the activity of the phosphoinositol-3 kinase (PI3K)-AKT signaling pathway in normal and leukemic T cells. Notch signaling and the PI3K-AKT pathway synergize in vivo in a Drosophila melanogaster model of Notch-induced tumorigenesis, and mutational loss of PTEN is associated with human T-ALL resistance to pharmacological inhibition of NOTCH1. Overall, these findings identify transcriptional control of PTEN and regulation of the PI3K-AKT pathway as key elements of the leukemogenic program activated by NOTCH1 and provide the basis for the design of new therapeutic strategies for T-ALL.", + "TAG_DATA": [ + "97, in {'context': 'B-in vivo'}", + "98, vivo {'context': 'I-in vivo'}", + "101, Drosophila {'context': 'B-organism'}", + "102, melanogaster {'context': 'I-organism'}", + "103, model {'context': 'I-organism'}", + "105, Notch-induced {'effect': 'B-positive'}", + "106, tumorigenesis, {'phenotype': 'B-tumourigenesis'}", + "108, mutational {'perturbing_action': 'B-gene loss-of-function'}", + "109, loss {'perturbing_action': 'I-gene loss-of-function'}", + "110, of {'perturbing_action': 'I-gene loss-of-function'}", + "111, PTEN {'perturbing_action': 'I-gene loss-of-function'}", + "120, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "121, of {'perturbing_action': 'I-pharmacological inhibition'}", + "122, NOTCH1. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "97, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "98, vivo ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "101, Drosophila ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "102, melanogaster ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "103, model ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "105, Notch-induced ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "106, tumorigenesis, ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "108, mutational ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "109, loss ['l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "110, of ['l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "111, PTEN ['l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "116, T-ALL ['l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "120, inhibition ['l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "121, of ['l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "122, NOTCH1. ['l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "Notch-induced" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Drosophila", + "melanogaster", + "model" + ] + }, + "effect": { + "val": "positive", + "words": [ + "Notch-induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Drosophila", + "melanogaster", + "model" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Notch-induced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis," + ] + } + } + ] + }, + { + "PMID": "17873881", + "TEXT": "Bone remodeling, the function affected in osteoporosis, the most common of bone diseases, comprises two phases: bone formation by matrix-producing osteoblasts and bone resorption by osteoclasts. The demonstration that the anorexigenic hormone leptin inhibits bone formation through a hypothalamic relay suggests that other molecules that affect energy metabolism in the hypothalamus could also modulate bone mass. Neuromedin U (NMU) is an anorexigenic neuropeptide that acts independently of leptin through poorly defined mechanisms. Here we show that Nmu-deficient (Nmu-/-) mice have high bone mass owing to an increase in bone formation; this is more prominent in male mice than female mice. Physiological and cell-based assays indicate that NMU acts in the central nervous system, rather than directly on bone cells, to regulate bone remodeling. Notably, leptin- or sympathetic nervous system-mediated inhibition of bone formation was abolished in Nmu-/- mice, which show an altered bone expression of molecular clock genes (mediators of the inhibition of bone formation by leptin). Moreover, treatment of wild-type mice with a natural agonist for the NMU receptor decreased bone mass. Collectively, these results suggest that NMU may be the first central mediator of leptin-dependent regulation of bone mass identified to date. Given the existence of inhibitors and activators of NMU action, our results may influence the treatment of diseases involving low bone mass, such as osteoporosis.", + "TAG_DATA": [ + "76, Nmu-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "77, (Nmu-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "78, mice {'context': 'B-organism'}", + "95, male {'context': 'B-organism'}", + "96, mice {'context': 'I-organism'}", + "136, Nmu-/- {'perturbing_action': 'B-gene loss-of-function'}", + "137, mice, {'context': 'B-organism'}", + "161, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "76, Nmu-deficient ['l0', 'l1', 'l2', 'l3']", + "77, (Nmu-/-) ['l0', 'l4', 'l5', 'l6']", + "78, mice ['l1', 'l4', 'l7', 'l8']", + "95, male ['l2', 'l5', 'l7', 'l9']", + "96, mice ['l3', 'l6', 'l8', 'l9']", + "136, Nmu-/- ['l10']", + "137, mice, ['l10']", + "161, mice ['l11']", + "165, agonist ['l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nmu-deficient", + "(Nmu-/-)", + "Nmu-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "male", + "mice," + ] + } + } + ] + }, + { + "PMID": "17873880", + "TEXT": "The cardioprotective effects of estrogen are mediated by receptors expressed in vascular cells. Here we show that 27-hydroxycholesterol (27HC), an abundant cholesterol metabolite that is elevated with hypercholesterolemia and found in atherosclerotic lesions, is a competitive antagonist of estrogen receptor action in the vasculature. 27HC inhibited both the transcription-mediated and the non-transcription-mediated estrogen-dependent production of nitric oxide by vascular cells, resulting in reduced estrogen-induced vasorelaxation of rat aorta. Furthermore, increasing 27HC levels in mice by diet-induced hypercholesterolemia, pharmacologic administration or genetic manipulation (by knocking out the gene encoding the catabolic enzyme CYP7B1) decreased estrogen-dependent expression of vascular nitric oxide synthase and repressed carotid artery reendothelialization. As well as antiestrogenic effects, there were proestrogenic actions of 27HC that were cell-type specific, indicating that 27HC functions as an endogenous selective estrogen receptor modulator (SERM). Taken together, these studies point to 27HC as a contributing factor in the loss of estrogen protection from vascular disease.", + "TAG_DATA": [ + "58, vascular {'context': 'B-cells'}", + "59, cells, {'context': 'I-cells'}", + "66, rat {'context': 'B-tissue/organ'}", + "67, aorta. {'context': 'I-tissue/organ'}", + "73, mice {'context': 'B-organism'}", + "83, knocking {'perturbing_action': 'B-gene loss-of-function'}", + "84, out {'perturbing_action': 'I-gene loss-of-function'}", + "85, the {'perturbing_action': 'I-gene loss-of-function'}", + "86, gene {'perturbing_action': 'I-gene loss-of-function'}", + "87, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "88, the {'perturbing_action': 'I-gene loss-of-function'}", + "89, catabolic {'perturbing_action': 'I-gene loss-of-function'}", + "90, enzyme {'perturbing_action': 'I-gene loss-of-function'}", + "91, CYP7B1) {'perturbing_action': 'I-gene loss-of-function'}", + "102, carotid {'context': 'B-tissue/organ'}", + "103, artery {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "58, vascular ['l0', 'l1', 'l2']", + "59, cells, ['l0', 'l3', 'l4']", + "66, rat ['l1', 'l3', 'l5']", + "67, aorta. ['l2', 'l4', 'l5']", + "83, knocking ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "84, out ['l6', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "85, the ['l7', 'l16', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "86, gene ['l8', 'l17', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "87, encoding ['l9', 'l18', 'l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "88, the ['l10', 'l19', 'l27', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "89, catabolic ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "90, enzyme ['l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57']", + "91, CYP7B1) ['l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l58', 'l59']", + "102, carotid ['l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58', 'l60']", + "103, artery ['l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knocking", + "out", + "the", + "gene", + "encoding", + "catabolic", + "enzyme", + "CYP7B1)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "carotid", + "artery" + ] + } + } + ] + }, + { + "PMID": "17828274", + "TEXT": "The repair of injured tendons remains a great challenge, largely owing to a lack of in-depth characterization of tendon cells and their precursors. We show that human and mouse tendons harbor a unique cell population, termed tendon stem/progenitor cells (TSPCs), that has universal stem cell characteristics such as clonogenicity, multipotency and self-renewal capacity. The isolated TSPCs could regenerate tendon-like tissues after extended expansion in vitro and transplantation in vivo. Moreover, we show that TSPCs reside within a unique niche predominantly comprised of an extracellular matrix, and we identify biglycan (Bgn) and fibromodulin (Fmod) as two critical components that organize this niche. Depletion of Bgn and Fmod affects the differentiation of TSPCs by modulating bone morphogenetic protein signaling and impairs tendon formation in vivo. Our results, while offering new insights into the biology of tendon cells, may assist in future strategies to treat tendon diseases.", + "TAG_DATA": [ + "55, TSPCs {'context': 'B-cells'}", + "63, in {'context': 'B-in vitro'}", + "64, vitro {'context': 'I-in vitro'}", + "67, in {'context': 'B-in vivo'}", + "68, vivo. {'context': 'I-in vivo'}", + "101, Depletion {'perturbing_action': 'B-gene loss-of-function'}", + "102, of {'perturbing_action': 'I-gene loss-of-function'}", + "103, Bgn {'perturbing_action': 'I-gene loss-of-function'}", + "104, and {'perturbing_action': 'I-gene loss-of-function'}", + "105, Fmod {'perturbing_action': 'I-gene loss-of-function'}", + "106, affects {'effect': 'B-regulates'}", + "108, differentiation {'phenotype': 'B-differentiation'}", + "110, TSPCs {'context': 'B-cells'}", + "118, impairs {'effect': 'B-negative'}", + "119, tendon {'context': 'B-tissue/organ', 'phenotype': 'B-tumourigenesis'}", + "120, formation {'phenotype': 'I-tumourigenesis'}", + "121, in {'context': 'B-in vivo'}", + "122, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "55, TSPCs ['l0', 'l1', 'l2', 'l3']", + "63, in ['l0', 'l4']", + "64, vitro ['l1', 'l4']", + "67, in ['l2', 'l5']", + "68, vivo. ['l3', 'l5']", + "101, Depletion ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "102, of ['l6', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "103, Bgn ['l7', 'l18', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "104, and ['l8', 'l19', 'l29', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "105, Fmod ['l9', 'l20', 'l30', 'l39', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "106, affects ['l10', 'l21', 'l31', 'l40', 'l48', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "108, differentiation ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "110, TSPCs ['l12', 'l23', 'l33', 'l42', 'l50', 'l57', 'l63', 'l69', 'l70', 'l71', 'l72', 'l73']", + "118, impairs ['l13', 'l24', 'l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l74', 'l75', 'l76', 'l77']", + "119, tendon ['l14', 'l25', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l78', 'l79', 'l80']", + "120, formation ['l15', 'l26', 'l36', 'l45', 'l53', 'l60', 'l66', 'l71', 'l75', 'l78', 'l81', 'l82']", + "121, in ['l16', 'l27', 'l37', 'l46', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l81', 'l83']", + "122, vivo. 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RNA interference of GALNT14 reduced cellular Apo2L/TRAIL sensitivity, whereas overexpression increased responsiveness. Biochemical analysis of DR5 identified several ectodomain O-(N-acetyl galactosamine-galactose-sialic acid) structures. Sequence comparison predicted conserved extracellular DR4 and DR5 O-glycosylation sites; progressive mutation of the DR5 sites attenuated apoptotic signaling. O-glycosylation promoted ligand-stimulated clustering of DR4 and DR5, which mediated recruitment and activation of the apoptosis-initiating protease caspase-8. These results uncover a new link between death-receptor O-glycosylation and apoptotic signaling, providing potential predictive biomarkers for Apo2L/TRAIL-based cancer therapy.", + "TAG_DATA": [ + "43, melanoma {'context': 'B-transformed cells'}", + "44, cell {'context': 'I-transformed cells'}", + "45, lines, {'context': 'I-transformed cells'}", + "59, RNA {'perturbing_action': 'B-rnai/knockdown'}", + "60, interference {'perturbing_action': 'B-rnai/knockdown'}", + "61, of {'perturbing_action': 'I-rnai/knockdown'}", + "62, GALNT14 {'perturbing_action': 'I-rnai/knockdown'}", + "68, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "93, mutation {'perturbing_action': 'I-other'}", + "94, of {'perturbing_action': 'I-other'}", + "95, the {'perturbing_action': 'I-other'}", + "96, DR5 {'perturbing_action': 'I-other'}", + "97, sites {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "43, melanoma ['l0', 'l1']", + "44, cell ['l0', 'l2']", + "45, lines, ['l1', 'l2']", + "59, RNA ['l3', 'l4', 'l5']", + "60, interference ['l3', 'l6', 'l7']", + "61, of ['l4', 'l6', 'l8']", + "62, GALNT14 ['l5', 'l7', 'l8']", + "93, mutation ['l9', 'l10', 'l11', 'l12']", + "94, of ['l9', 'l13', 'l14', 'l15']", + "95, the ['l10', 'l13', 'l16', 'l17']", + "96, DR5 ['l11', 'l14', 'l16', 'l18']", + "97, sites ['l12', 'l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17721547", + "TEXT": "Cytokine hormones have a short plasma half-life and require frequent administration. For example, growth hormone replacement involves daily injections. In common with other cytokines, the extracellular domain of the growth hormone receptor circulates as a binding protein, which naturally prolongs the biological half-life of growth hormone. Here we have studied the biological actions of a ligand-receptor fusion of growth hormone and the extracellular domain of its receptor. The genetically engineered ligand-receptor fusion protein was purified from mammalian cell culture. In rats, the ligand-receptor fusion had a 300-times reduced clearance as compared to native growth hormone, and a single injection promoted growth for 10 d, far exceeding the growth seen after administration of native growth hormone. The ligand-receptor fusion forms a reciprocal, head-to-tail dimer that provides a reservoir of inactive hormone similar to the natural reservoir of growth hormone and its binding protein. In conclusion, a ligand-receptor fusion of cytokine to its extracellular receptor generates a potent, long-acting agonist with exceptionally slow absorption and elimination. This approach could be easily applied to other cytokines.", + "TAG_DATA": [ + "76, mammalian {'context': 'B-cells'}", + "77, cell {'context': 'I-cells'}", + "78, culture. {'context': 'I-cells'}", + "80, rats, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "76, mammalian ['l0', 'l1', 'l2']", + "77, cell ['l0', 'l3', 'l4']", + "78, culture. ['l1', 'l3', 'l5']", + "80, rats, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17704785", + "TEXT": "Hepatocytes in fatty livers are hypersensitive to apoptosis and undergo escalated apoptotic activity via death receptor-mediated pathways, particularly that of Fas-FasL, causing hepatic injury that can eventually proceed to cirrhosis and end-stage liver disease. Here we report that the hepatocyte growth factor receptor, Met, plays an important part in preventing Fas-mediated apoptosis of hepatocytes by sequestering Fas. We also show that Fas antagonism by Met is abrogated in human fatty liver disease (FLD). Through structure-function studies, we found that a YLGA amino-acid motif located near the extracellular N terminus of the Met alpha-subunit is necessary and sufficient to specifically bind the extracellular portion of Fas and to act as a potent FasL antagonist and inhibitor of Fas trimerization. Using mouse models of FLD, we show that synthetic YLGA peptide tempers hepatocyte apoptosis and liver damage and therefore has therapeutic potential.", + "TAG_DATA": [ + "119, mouse {'context': 'B-organism'}", + "120, models {'context': 'I-organism'}", + "129, tempers {'effect': 'B-negative'}", + "130, hepatocyte {'context': 'B-cells'}", + "131, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "119, mouse ['l0', 'l1', 'l2', 'l3']", + "120, models ['l0', 'l4', 'l5', 'l6']", + "129, tempers ['l1', 'l4', 'l7', 'l8']", + "130, hepatocyte ['l2', 'l5', 'l7', 'l9']", + "131, apoptosis ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "effect": { + "val": "negative", + "words": [ + "tempers" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "tempers" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocyte" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "tempers" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hepatocyte" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "17694066", + "TEXT": "Low-density lipoprotein receptor-related protein-1 (LRP) on brain capillaries clears amyloid beta-peptide (Abeta) from brain. Here, we show that soluble circulating LRP (sLRP) provides key endogenous peripheral 'sink' activity for Abeta in humans. Recombinant LRP cluster IV (LRP-IV) bound Abeta in plasma in mice and Alzheimer's disease-affected humans with compromised sLRP-mediated Abeta binding, and reduced Abeta-related pathology and dysfunction in a mouse model of Alzheimer disease, suggesting that LRP-IV can effectively replace native sLRP and clear Abeta.", + "TAG_DATA": [ + "42, mice {'context': 'B-organism'}", + "60, mouse {'context': 'B-organism'}", + "61, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "60, mouse ['l0']", + "61, model ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17676050", + "TEXT": "Treatment with glatiramer acetate (GA, copolymer-1, Copaxone), a drug approved for multiple sclerosis (MS), in a mouse model promoted development of anti-inflammatory type II monocytes, characterized by increased secretion of interleukin (IL)-10 and transforming growth factor (TGF)-beta, and decreased production of IL-12 and tumor necrosis factor (TNF). This anti-inflammatory cytokine shift was associated with reduced STAT-1 signaling. Type II monocytes directed differentiation of T(H)2 cells and CD4+CD25+FoxP3+ regulatory T cells (T(reg)) independent of antigen specificity. Type II monocyte-induced regulatory T cells specific for a foreign antigen ameliorated experimental autoimmune encephalomyelitis (EAE), indicating that neither GA specificity nor recognition of self-antigen was required for their therapeutic effect. Adoptive transfer of type II monocytes reversed EAE, suppressed T(H)17 cell development and promoted both T(H)2 differentiation and expansion of T(reg) cells in recipient mice. This demonstration of adoptive immunotherapy by type II monocytes identifies a central role for these cells in T cell immune modulation of autoimmunity.", + "TAG_DATA": [ + "16, mouse {'context': 'B-organism'}", + "17, model {'context': 'I-organism'}", + "61, differentiation {'phenotype': 'B-differentiation'}", + "63, T(H)2 {'context': 'B-cells'}", + "64, cells {'context': 'I-cells'}", + "76, II {'context': 'B-cells'}", + "77, monocyte-induced {'context': 'I-cells'}", + "78, regulatory {'context': 'I-cells'}", + "79, T {'context': 'I-cells'}", + "80, cells {'context': 'I-cells'}", + "109, type {'context': 'B-cells'}", + "110, II {'context': 'B-cells'}", + "111, monocytes {'context': 'I-cells'}", + "115, T(H)17 {'context': 'B-cells'}", + "116, cell {'context': 'I-cells'}", + "119, promoted {'effect': 'B-positive'}", + "121, T(H)2 {'context': 'B-cells'}", + "122, differentiation {'phenotype': 'B-differentiation'}", + "126, T(reg) {'context': 'B-cells'}", + "127, cells {'context': 'I-cells'}", + "130, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "16, mouse ['l0', 'l1', 'l2', 'l3']", + "17, model ['l0', 'l4', 'l5']", + "61, differentiation ['l1', 'l6', 'l7']", + "63, T(H)2 ['l2', 'l4', 'l6', 'l8']", + "64, cells ['l3', 'l5', 'l7', 'l8']", + "76, II ['l9', 'l10', 'l11', 'l12']", + "77, monocyte-induced ['l9', 'l13', 'l14', 'l15']", + "78, regulatory ['l10', 'l13', 'l16', 'l17']", + "79, T ['l11', 'l14', 'l16', 'l18']", + "80, cells ['l12', 'l15', 'l17', 'l18']", + "109, type ['l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "110, II ['l19', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "111, monocytes ['l20', 'l29', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "115, T(H)17 ['l21', 'l30', 'l38', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "116, cell ['l22', 'l31', 'l39', 'l46', 'l53']", + "119, promoted ['l23', 'l32', 'l40', 'l47', 'l54', 'l55', 'l56', 'l57', 'l58']", + "121, T(H)2 ['l24', 'l33', 'l41', 'l48', 'l54', 'l59', 'l60', 'l61', 'l62']", + "122, differentiation ['l25', 'l34', 'l42', 'l49', 'l55', 'l59', 'l63', 'l64', 'l65']", + "126, T(reg) ['l26', 'l35', 'l43', 'l50', 'l56', 'l60', 'l63', 'l66', 'l67']", + "127, cells ['l27', 'l36', 'l44', 'l51', 'l53', 'l57', 'l61', 'l64', 'l66', 'l68']", + "130, mice. ['l28', 'l37', 'l45', 'l52', 'l58', 'l62', 'l65', 'l67', 'l68']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "mice." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "T(H)2", + "cells", + "type", + "II", + "monocytes", + "T(H)17", + "T(reg)" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "type", + "II", + "monocytes", + "T(H)17", + "T(H)2", + "T(reg)", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "17632526", + "TEXT": "Extracellular ATP serves as a danger signal to alert the immune system of tissue damage by acting on P2X or P2Y receptors. Here we show that allergen challenge causes acute accumulation of ATP in the airways of asthmatic subjects and mice with experimentally induced asthma. All the cardinal features of asthma, including eosinophilic airway inflammation, Th2 cytokine production and bronchial hyper-reactivity, were abrogated when lung ATP levels were locally neutralized using apyrase or when mice were treated with broad-spectrum P2-receptor antagonists. In addition to these effects of ATP in established inflammation, Th2 sensitization to inhaled antigen was enhanced by endogenous or exogenous ATP. The adjuvant effects of ATP were due to the recruitment and activation of lung myeloid dendritic cells that induced Th2 responses in the mediastinal nodes. Together these data show that purinergic signaling has a key role in allergen-driven lung inflammation that is likely to be amenable to therapeutic intervention.", + "TAG_DATA": [ + "40, mice {'context': 'B-organism'}", + "74, mice {'context': 'B-organism'}", + "116, lung {'context': 'B-cells'}", + "117, myeloid {'context': 'I-cells'}", + "118, dendritic {'context': 'I-cells'}", + "119, cells {'context': 'I-cells'}", + "126, mediastinal {'context': 'B-tissue/organ'}", + "127, nodes. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "116, lung ['l0', 'l1', 'l2', 'l3', 'l4']", + "117, myeloid ['l0', 'l5', 'l6', 'l7', 'l8']", + "118, dendritic ['l1', 'l5', 'l9', 'l10', 'l11']", + "119, cells ['l2', 'l6', 'l9', 'l12', 'l13']", + "126, mediastinal ['l3', 'l7', 'l10', 'l12', 'l14']", + "127, nodes. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17603494", + "TEXT": "Psoriasis is a common T cell-mediated autoimmune inflammatory disease. We show that blocking the interaction of alpha1beta1 integrin (VLA-1) with collagen prevented accumulation of epidermal T cells and immunopathology of psoriasis. Alpha1beta1 integrin, a major collagen-binding surface receptor, was exclusively expressed by epidermal but not dermal T cells. Alpha1beta1-positive T cells showed characteristic surface markers of effector memory cells and contained high levels of interferon-gamma but not interleukin-4. Blockade of alpha1beta1 inhibited migration of T cells into the epidermis in a clinically relevant xenotransplantation model. This was paralleled by a complete inhibition of psoriasis development, comparable to that caused by tumor necrosis factor-alpha blockers. These results define a crucial role for alpha1beta1 in controlling the accumulation of epidermal type 1 polarized effector memory T cells in a common human immunopathology and provide the basis for new strategies in psoriasis treatment focusing on T cell-extracellular matrix interactions.", + "TAG_DATA": [ + "24, epidermal {'context': 'B-cells'}", + "25, T {'context': 'I-cells'}", + "26, cells {'context': 'I-cells'}", + "68, Blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "69, of {'perturbing_action': 'I-pharmacological inhibition'}", + "70, alpha1beta1 {'perturbing_action': 'I-pharmacological inhibition'}", + "71, inhibited {'effect': 'B-negative'}", + "72, migration {'phenotype': 'B-migration'}", + "74, T {'context': 'B-cells'}", + "75, cells {'context': 'B-cells'}", + "78, epidermis {'context': 'B-tissue/organ'}", + "83, xenotransplantation {'context': 'B-xenograft'}", + "84, model. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "24, epidermal ['l0', 'l1', 'l2', 'l3', 'l4']", + "25, T ['l0', 'l5']", + "26, cells ['l1', 'l5']", + "68, Blockade ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "69, of ['l6', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "70, alpha1beta1 ['l7', 'l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "71, inhibited ['l8', 'l16', 'l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "72, migration ['l2', 'l9', 'l17', 'l24', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "74, T ['l3', 'l10', 'l18', 'l25', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "75, cells ['l4', 'l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l45', 'l46', 'l47']", + "78, epidermis ['l12', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l48', 'l49']", + "83, xenotransplantation ['l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l50']", + "84, model. ['l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l50']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "epidermal", + "T", + "cells" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "alpha1beta1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "alpha1beta1" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "alpha1beta1" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "alpha1beta1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "epidermis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "alpha1beta1" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenotransplantation", + "model." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "epidermis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenotransplantation", + "model." + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "epidermis" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenotransplantation", + "model." + ] + } + } + ] + }, + { + "PMID": "17589520", + "TEXT": "Gamma-aminobutyric acid (GABA) is an important neurotransmitter that, through the subtype A GABA receptor (GABAAR), induces inhibition in the adult brain. Here we show that an excitatory, rather than inhibitory, GABAergic system exists in airway epithelial cells. Both GABAARs and the GABA synthetic enzyme glutamic acid decarboxylase (GAD) are expressed in pulmonary epithelial cells. Activation of GABAARs depolarized these cells. The expression of GAD in the cytosol and GABAARs in the apical membranes of airway epithelial cells increased markedly when mice were sensitized and then challenged with ovalbumin, an approach for inducing allergic asthmatic reactions. Similarly, GAD and GABAARs in airway epithelial cells of humans with asthma increased after allergen inhalation challenge. Intranasal application of selective GABAAR inhibitors suppressed the hyperplasia of goblet cells and the overproduction of mucus induced by ovalbumin or interleukin-13 in mice. These findings show that a previously unknown epithelial GABAergic system has an essential role in asthma.", + "TAG_DATA": [ + "74, airway {'context': 'B-cells'}", + "75, epithelial {'context': 'I-cells'}", + "76, cells {'context': 'I-cells'}", + "80, mice {'context': 'B-organism'}", + "100, airway {'context': 'B-cells'}", + "101, epithelial {'context': 'I-cells'}", + "102, cells {'context': 'I-cells'}", + "104, humans {'context': 'B-cells'}", + "115, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "116, GABAAR {'perturbing_action': 'I-pharmacological inhibition'}", + "117, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "122, goblet {'context': 'B-cells'}", + "123, cells {'context': 'I-cells'}", + "135, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "74, airway ['l0', 'l1', 'l2']", + "75, epithelial ['l0', 'l3', 'l4']", + "76, cells ['l1', 'l3', 'l5']", + "80, mice ['l2', 'l4', 'l5', 'l6']", + "100, airway ['l7', 'l8', 'l9']", + "101, epithelial ['l7', 'l10', 'l11']", + "102, cells ['l6', 'l8', 'l10', 'l12']", + "104, humans ['l9', 'l11', 'l12']", + "115, selective ['l13', 'l14', 'l15', 'l16', 'l17']", + "116, GABAAR ['l13', 'l18', 'l19', 'l20', 'l21']", + "117, inhibitors ['l14', 'l18', 'l22', 'l23', 'l24']", + "122, goblet ['l15', 'l19', 'l22', 'l25']", + "123, cells ['l16', 'l20', 'l23', 'l25']", + "135, mice. ['l17', 'l21', 'l24']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "GABAAR", + "inhibitors" + ] + }, + "context": { + "val": "cells", + "words": [ + "goblet", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "GABAAR", + "inhibitors" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "17529981", + "TEXT": "The metabolism of vitamin A and the diverse effects of its metabolites are tightly controlled by distinct retinoid-generating enzymes, retinoid-binding proteins and retinoid-activated nuclear receptors. Retinoic acid regulates differentiation and metabolism by activating the retinoic acid receptor and retinoid X receptor (RXR), indirectly influencing RXR heterodimeric partners. Retinoic acid is formed solely from retinaldehyde (Rald), which in turn is derived from vitamin A. Rald currently has no defined biologic role outside the eye. Here we show that Rald is present in rodent fat, binds retinol-binding proteins (CRBP1, RBP4), inhibits adipogenesis and suppresses peroxisome proliferator-activated receptor-gamma and RXR responses. In vivo, mice lacking the Rald-catabolizing enzyme retinaldehyde dehydrogenase 1 (Raldh1) resisted diet-induced obesity and insulin resistance and showed increased energy dissipation. In ob/ob mice, administrating Rald or a Raldh inhibitor reduced fat and increased insulin sensitivity. These results identify Rald as a distinct transcriptional regulator of the metabolic responses to a high-fat diet.", + "TAG_DATA": [ + "98, In {'context': 'B-in vivo'}", + "99, vivo, {'context': 'I-in vivo'}", + "100, mice {'context': 'B-organism'}", + "101, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "102, the {'perturbing_action': 'I-gene loss-of-function'}", + "103, Rald-catabolizing {'perturbing_action': 'I-gene loss-of-function'}", + "104, enzyme {'perturbing_action': 'I-gene loss-of-function'}", + "105, retinaldehyde {'perturbing_action': 'I-gene loss-of-function'}", + "106, dehydrogenase {'perturbing_action': 'I-gene loss-of-function'}", + "107, 1 {'perturbing_action': 'I-gene loss-of-function'}", + "108, (Raldh1) {'perturbing_action': 'I-gene loss-of-function'}", + "121, ob/ob {'context': 'B-organism'}", + "122, mice, {'context': 'I-organism'}", + "123, administrating {'perturbing_action': 'B-gene gain-of-function'}", + "124, Rald {'perturbing_action': 'I-gene gain-of-function'}", + "127, Raldh {'perturbing_action': 'B-pharmacological inhibition'}", + "128, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "98, In ['l0']", + "99, vivo, ['l0']", + "100, mice ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "101, lacking ['l1', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "102, the ['l2', 'l9', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "103, Rald-catabolizing ['l3', 'l10', 'l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "104, enzyme ['l4', 'l11', 'l17', 'l22', 'l27', 'l28', 'l29', 'l30']", + "105, retinaldehyde ['l5', 'l12', 'l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "106, dehydrogenase ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "107, 1 ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "108, (Raldh1) ['l8', 'l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l36']", + "121, ob/ob ['l37', 'l38', 'l39', 'l40', 'l41']", + "122, mice, ['l37', 'l42', 'l43']", + "123, administrating ['l38', 'l44', 'l45', 'l46']", + "124, Rald ['l39', 'l42', 'l44', 'l47', 'l48']", + "127, Raldh ['l40', 'l45', 'l47', 'l49']", + "128, inhibitor ['l41', 'l43', 'l46', 'l48', 'l49']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "Rald-catabolizing", + "enzyme", + "retinaldehyde", + "dehydrogenase", + "1", + "(Raldh1)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "ob/ob", + "mice," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "administrating", + "Rald" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "ob/ob", + "mice," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Raldh", + "inhibitor" + ] + } + } + ] + }, + { + "PMID": "17450150", + "TEXT": "Autophagy, an evolutionarily conserved process for the bulk degradation of cytoplasmic components, serves as a cell survival mechanism in starving cells. Although altered autophagy has been observed in various heart diseases, including cardiac hypertrophy and heart failure, it remains unclear whether autophagy plays a beneficial or detrimental role in the heart. Here, we report that the cardiac-specific loss of autophagy causes cardiomyopathy in mice. In adult mice, temporally controlled cardiac-specific deficiency of Atg5 (autophagy-related 5), a protein required for autophagy, led to cardiac hypertrophy, left ventricular dilatation and contractile dysfunction, accompanied by increased levels of ubiquitination. Furthermore, Atg5-deficient hearts showed disorganized sarcomere structure and mitochondrial misalignment and aggregation. On the other hand, cardiac-specific deficiency of Atg5 early in cardiogenesis showed no such cardiac phenotypes under baseline conditions, but developed cardiac dysfunction and left ventricular dilatation one week after treatment with pressure overload. These results indicate that constitutive autophagy in the heart under baseline conditions is a homeostatic mechanism for maintaining cardiomyocyte size and global cardiac structure and function, and that upregulation of autophagy in failing hearts is an adaptive response for protecting cells from hemodynamic stress.", + "TAG_DATA": [ + "63, mice. {'context': 'B-organism'}", + "65, adult {'context': 'B-organism'}", + "66, mice, {'context': 'I-organism'}", + "69, cardiac-specific {'perturbing_action': 'I-gene loss-of-function'}", + "70, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "71, of {'perturbing_action': 'I-gene loss-of-function'}", + "72, Atg5 {'perturbing_action': 'I-gene loss-of-function'}", + "73, (autophagy-related {'perturbing_action': 'I-gene loss-of-function'}", + "74, 5), {'perturbing_action': 'I-gene loss-of-function'}", + "97, Atg5-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "98, hearts {'context': 'B-tissue/organ'}", + "112, cardiac-specific {'perturbing_action': 'B-gene loss-of-function'}", + "113, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "114, of {'perturbing_action': 'I-gene loss-of-function'}", + "115, Atg5 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "63, mice. ['l0', 'l1']", + "65, adult ['l0', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "66, mice, ['l1', 'l2', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "69, cardiac-specific ['l3', 'l9', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "70, deficiency ['l4', 'l10', 'l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "71, of ['l5', 'l11', 'l16', 'l22', 'l28', 'l29', 'l30', 'l31', 'l32']", + "72, Atg5 ['l6', 'l12', 'l17', 'l23', 'l28', 'l33', 'l34', 'l35', 'l36']", + "73, (autophagy-related ['l7', 'l13', 'l18', 'l24', 'l29', 'l33', 'l37', 'l38', 'l39']", + "74, 5), ['l8', 'l14', 'l19', 'l25', 'l30', 'l34', 'l37', 'l40', 'l41']", + "97, Atg5-deficient ['l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l42']", + "98, hearts ['l21', 'l27', 'l32', 'l36', 'l39', 'l41', 'l42']", + "112, cardiac-specific ['l43', 'l44', 'l45']", + "113, deficiency ['l43', 'l46', 'l47']", + "114, of ['l44', 'l46', 'l48']", + "115, Atg5 ['l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "adult", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cardiac-specific", + "deficiency", + "of", + "Atg5", + "(autophagy-related", + "5)," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cardiac-specific", + "deficiency", + "of", + "Atg5", + "(autophagy-related", + "5),", + "Atg5-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hearts" + ] + } + } + ] + }, + { + "PMID": "17417650", + "TEXT": "Sympathetic innervation is critical for effective cardiac function. However, the developmental and regulatory mechanisms determining the density and patterning of cardiac sympathetic innervation remain unclear, as does the role of this innervation in arrhythmogenesis. Here we show that a neural chemorepellent, Sema3a, establishes cardiac sympathetic innervation patterning. Sema3a is abundantly expressed in the trabecular layer in early-stage embryos but is restricted to Purkinje fibers after birth, forming an epicardial-to-endocardial transmural sympathetic innervation patterning. Sema3a(-/-) mice lacked a cardiac sympathetic innervation gradient and exhibited stellate ganglia malformation, which led to marked sinus bradycardia due to sympathetic dysfunction. Cardiac-specific overexpression of Sema3a in transgenic mice (SemaTG) was associated with reduced sympathetic innervation and attenuation of the epicardial-to-endocardial innervation gradient. SemaTG mice demonstrated sudden death and susceptibility to ventricular tachycardia, due to catecholamine supersensitivity and prolongation of the action potential duration. We conclude that appropriate cardiac Sema3a expression is needed for sympathetic innervation patterning and is critical for heart rate control.", + "TAG_DATA": [ + "73, Sema3a(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "74, mice {'context': 'B-organism'}", + "96, Cardiac-specific {'perturbing_action': 'B-gene gain-of-function'}", + "97, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "98, of {'perturbing_action': 'I-gene gain-of-function'}", + "99, Sema3a {'perturbing_action': 'I-gene gain-of-function'}", + "101, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "102, mice {'context': 'I-organism'}", + "117, SemaTG {'perturbing_action': 'B-gene loss-of-function'}", + "118, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, Sema3a(-/-) ['l0']", + "74, mice ['l0']", + "96, Cardiac-specific ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "97, overexpression ['l1', 'l7', 'l8', 'l9', 'l10']", + "98, of ['l2', 'l7', 'l11', 'l12', 'l13']", + "99, Sema3a ['l3', 'l8', 'l11', 'l14', 'l15']", + "101, transgenic ['l4', 'l9', 'l12', 'l14', 'l16']", + "102, mice ['l5', 'l10', 'l13', 'l15', 'l16']", + "117, SemaTG ['l17']", + "118, mice ['l6', 'l17']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sema3a(-/-)", + "SemaTG" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Cardiac-specific", + "overexpression", + "of", + "Sema3a", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "17401377", + "TEXT": "The germinal matrix of premature infants is selectively vulnerable to hemorrhage within the first 48 h of life. To assess the role of vascular immaturity in germinal matrix hemorrhage (GMH), we evaluated germinal matrix angiogenesis in human fetuses and premature infants, as well as in premature rabbit pups, and noted active vessel remodeling in all three. Vascular endothelial growth factor (VEGF), angiopoietin-2 and endothelial cell proliferation were present at consistently higher levels in the germinal matrix relative to the white matter anlagen and cortical mantle. On that basis, we asked whether prenatal treatment with either of two angiogenic inhibitors, the COX-2 inhibitor celecoxib, or the VEGFR2 inhibitor ZD6474, could suppress the incidence of GMH in premature rabbit pups. Celecoxib treatment decreased angiopoietin-2 and VEGF levels as well as germinal matrix endothelial proliferation. Furthermore, treatment with celecoxib or ZD6474 substantially decreased the incidence of GMH. Thus, by suppressing germinal matrix angiogenesis, prenatal celecoxib or ZD6474 treatment may be able to reduce both the incidence and severity of GMH in susceptible premature infants.", + "TAG_DATA": [ + "45, premature {'context': 'B-organism'}", + "46, rabbit {'context': 'I-organism'}", + "47, pups, {'context': 'I-organism'}", + "100, COX-2 {'perturbing_action': 'B-pharmacological inhibition'}", + "101, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "102, celecoxib, {'perturbing_action': 'I-pharmacological inhibition'}", + "105, VEGFR2 {'perturbing_action': 'B-pharmacological inhibition'}", + "106, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "107, ZD6474, {'perturbing_action': 'I-pharmacological inhibition'}", + "115, premature {'context': 'B-organism'}", + "116, rabbit {'context': 'I-organism'}", + "117, pups. {'context': 'I-organism'}", + "120, decreased {'effect': 'B-negative'}", + "128, germinal {'context': 'B-cells'}", + "129, matrix {'context': 'I-cells'}", + "130, endothelial {'context': 'I-cells'}", + "131, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "45, premature ['l0', 'l1']", + "46, rabbit ['l0', 'l2']", + "47, pups, ['l1', 'l2']", + "100, COX-2 ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "101, inhibitor ['l3', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "102, celecoxib, ['l4', 'l16', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "105, VEGFR2 ['l5', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "106, inhibitor ['l6', 'l17', 'l35', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "107, ZD6474, ['l7', 'l18', 'l27', 'l36', 'l45', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "115, premature ['l8', 'l19', 'l28', 'l37', 'l46', 'l54', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "116, rabbit ['l9', 'l20', 'l29', 'l38', 'l47', 'l55', 'l62', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "117, pups. ['l10', 'l21', 'l30', 'l39', 'l48', 'l56', 'l63', 'l69', 'l75', 'l76', 'l77', 'l78', 'l79']", + "120, decreased ['l11', 'l22', 'l31', 'l40', 'l49', 'l57', 'l64', 'l70', 'l75', 'l80', 'l81', 'l82', 'l83']", + "128, germinal ['l12', 'l23', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l84', 'l85', 'l86']", + "129, matrix ['l13', 'l24', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l87', 'l88']", + "130, endothelial ['l14', 'l25', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l87', 'l89']", + "131, proliferation. ['l15', 'l26', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l89']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "COX-2", + "inhibitor", + "celecoxib,", + "VEGFR2", + "ZD6474," + ] + }, + "context": { + "val": "organism", + "words": [ + "premature", + "rabbit", + "pups." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "COX-2", + "inhibitor", + "celecoxib,", + "VEGFR2", + "ZD6474," + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "COX-2", + "inhibitor", + "celecoxib,", + "VEGFR2", + "ZD6474," + ] + }, + "context": { + "val": "cells", + "words": [ + "germinal", + "matrix", + "endothelial" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "COX-2", + "inhibitor", + "celecoxib,", + "VEGFR2", + "ZD6474," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "premature", + "rabbit", + "pups." + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "premature", + "rabbit", + "pups." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "context": { + "val": "cells", + "words": [ + "germinal", + "matrix", + "endothelial" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "germinal", + "matrix", + "endothelial" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "17401376", + "TEXT": "The cannabinoid system is immunomodulatory and has been targeted as a treatment for the central nervous system (CNS) autoimmune disease multiple sclerosis. Using an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), we investigated the role of the CB(1) and CB(2) cannabinoid receptors in regulating CNS autoimmunity. We found that CB(1) receptor expression by neurons, but not T cells, was required for cannabinoid-mediated EAE suppression. In contrast, CB(2) receptor expression by encephalitogenic T cells was critical for controlling inflammation associated with EAE. CB(2)-deficient T cells in the CNS during EAE exhibited reduced levels of apoptosis, a higher rate of proliferation and increased production of inflammatory cytokines, resulting in severe clinical disease. Together, our results demonstrate that the cannabinoid system within the CNS plays a critical role in regulating autoimmune inflammation, with the CNS directly suppressing T-cell effector function via the CB(2) receptor.", + "TAG_DATA": [ + "83, CB(2)-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "84, T {'context': 'B-cells'}", + "85, cells {'context': 'I-cells'}", + "88, CNS {'context': 'B-tissue/organ'}", + "92, reduced {'effect': 'B-negative'}", + "93, levels {'effect': 'I-positive'}", + "95, apoptosis, {'phenotype': 'B-apoptosis'}", + "97, higher {'effect': 'B-positive'}", + "98, rate {'effect': 'I-positive'}", + "100, proliferation {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "83, CB(2)-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "84, T ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "85, cells ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "88, CNS ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "92, reduced ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "93, levels ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "95, apoptosis, ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "97, higher ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "98, rate ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "100, proliferation ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CB(2)-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CB(2)-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "CNS" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CB(2)-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CB(2)-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "levels", + "higher", + "rate" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CB(2)-deficient" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CB(2)-deficient" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "levels", + "higher", + "rate" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "CNS" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "CNS" + ] + }, + "effect": { + "val": "positive", + "words": [ + "levels", + "higher", + "rate" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "CNS" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "CNS" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "levels", + "higher", + "rate" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "levels", + "higher", + "rate" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "17351624", + "TEXT": "Cbl-associated protein (Cap) is a member of a phosphatidylinositol 3-kinase-independent pathway for insulin-stimulated translocation of the glucose transporter GLUT4. Despite this positive role of Cap in glucose uptake, here we show that deletion of the gene encoding Cap (official gene name: Sorbs1) protects against high-fat diet (HFD)-induced insulin resistance in mice while also having an opposite, insulin-sensitizing effect, accompanied by reduced tissue markers of inflammation. Given the emerging role of chronic inflammation in insulin resistance and the macrophage in initiating this inflammatory process, we considered that Sorbs1 deletion from macrophages may have resulted in the observed protection from HFD-induced insulin resistance. Using bone marrow transplantation to generate functional Sorbs1-null macrophages, we show that the insulin-sensitive phenotype can be transferred to wild-type mice by transplantation of Sorbs1-null bone marrow. These studies show that macrophages are an important cell type in the induction of insulin resistance and that Cap has a modulatory role in this function.", + "TAG_DATA": [ + "32, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "33, of {'perturbing_action': 'I-gene loss-of-function'}", + "34, the {'perturbing_action': 'I-gene loss-of-function'}", + "35, gene {'perturbing_action': 'I-gene loss-of-function'}", + "36, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "37, Cap {'perturbing_action': 'I-gene loss-of-function'}", + "38, (official {'perturbing_action': 'I-gene loss-of-function'}", + "39, gene {'perturbing_action': 'I-gene loss-of-function'}", + "40, name: {'perturbing_action': 'I-gene loss-of-function'}", + "41, Sorbs1) {'perturbing_action': 'I-gene loss-of-function'}", + "50, mice {'context': 'B-organism'}", + "86, Sorbs1 {'perturbing_action': 'B-gene loss-of-function'}", + "87, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "89, macrophages {'context': 'B-cells'}", + "108, Sorbs1-null {'perturbing_action': 'B-gene loss-of-function'}", + "109, macrophages, {'context': 'B-cells'}", + "121, mice {'context': 'B-organism'}", + "125, Sorbs1-null {'perturbing_action': 'B-gene loss-of-function'}", + "126, bone {'context': 'B-cells'}", + "127, marrow. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "32, deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "33, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "34, the ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "35, gene ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "36, encoding ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "37, Cap ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "38, (official ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "39, gene ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "40, name: ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "41, Sorbs1) ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "50, mice ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81']", + "86, Sorbs1 ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l86', 'l87']", + "87, deletion ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l85', 'l88']", + "89, macrophages ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l86', 'l88']", + "102, bone ['l89', 'l90', 'l91']", + "103, marrow ['l87', 'l89', 'l92', 'l93']", + "108, Sorbs1-null ['l90', 'l92', 'l94']", + "109, macrophages, ['l91', 'l93', 'l94']", + "121, mice ['l95', 'l96', 'l97']", + "125, Sorbs1-null ['l95', 'l98', 'l99']", + "126, bone ['l96', 'l98', 'l100']", + "127, marrow. ['l97', 'l99', 'l100']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "gene", + "encoding", + "Cap", + "(official", + "name:", + "Sorbs1)", + "Sorbs1-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "gene", + "encoding", + "Cap", + "(official", + "name:", + "Sorbs1)", + "Sorbs1", + "Sorbs1-null" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages", + "macrophages,", + "bone", + "marrow." + ] + } + } + ] + }, + { + "PMID": "17334371", + "TEXT": "Protective cell-mediated immune responses in cancer are critically dependent on T-helper type 1 (T(H)1) cytokines such as interferon-gamma (IFN-gamma). We have previously shown that the combination of CD40 stimulation and interleukin-2 (IL-2) leads to synergistic antitumor responses in several models of advanced metastatic disease. We now report that after this treatment and other immunotherapy regimens, the CD4+ T-cell population, in contrast to CD8+ T cells, did not significantly increase but rather exhibited a substantial level of apoptosis that was dependent on IFN-gamma. Mice immunized with tumor cells and treated with an immunotherapy regimen that was initially protective were later unable to mount effective memory responses compared with immunized mice not receiving immunotherapy. Immunotherapy given to tumor-bearing Ifngr-/- mice resulted in restoration of secondary responses. Thus, although immunotherapeutic regimens inducing strong IFN-gamma responses can lead to successful early antitumor efficacy, they may also impair the development of durable antitumor responses.", + "TAG_DATA": [ + "56, CD4+ {'context': 'B-cells'}", + "57, T-cell {'context': 'I-cells'}", + "71, exhibited {'effect': 'B-positive'}", + "76, apoptosis {'phenotype': 'B-apoptosis'}", + "82, Mice {'context': 'B-organism'}", + "85, tumor {'context': 'B-transformed cells'}", + "86, cells {'context': 'I-transformed cells'}", + "108, mice {'context': 'B-organism'}", + "116, Ifngr-/- {'perturbing_action': 'B-gene loss-of-function'}", + "117, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, CD4+ ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "57, T-cell ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "58, population, ['l1', 'l7', 'l13', 'l14', 'l15', 'l16']", + "71, exhibited ['l2', 'l8', 'l13', 'l17']", + "76, apoptosis ['l3', 'l9', 'l14', 'l17', 'l18']", + "82, Mice ['l4', 'l10', 'l19', 'l20']", + "85, tumor ['l5', 'l11', 'l15', 'l19', 'l21']", + "86, cells ['l6', 'l12', 'l16', 'l18', 'l20', 'l21']", + "116, Ifngr-/- ['l22']", + "117, mice ['l22']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD4+", + "T-cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "exhibited" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4+", + "T-cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "exhibited" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ifngr-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "17322896", + "TEXT": "Type 2 diabetes is characterized by both peripheral insulin resistance and reduced insulin secretion by beta-cells. The reasons for beta-cell dysfunction in this disease are incompletely understood but may include the accumulation of toxic lipids within this cell type. We examined the role of Abca1, a cellular cholesterol transporter, in cholesterol homeostasis and insulin secretion in beta-cells. Mice with specific inactivation of Abca1 in beta-cells had markedly impaired glucose tolerance and defective insulin secretion but normal insulin sensitivity. Islets isolated from these mice showed altered cholesterol homeostasis and impaired insulin secretion in vitro. We found that rosiglitazone, an activator of the peroxisome proliferator-activated receptor-gamma, which upregulates Abca1 in beta-cells, requires beta-cell Abca1 for its beneficial effects on glucose tolerance. These experiments establish a new role for Abca1 in beta-cell cholesterol homeostasis and insulin secretion, and suggest that cholesterol accumulation may contribute to beta-cell dysfunction in type 2 diabetes.", + "TAG_DATA": [ + "57, Mice {'context': 'B-organism'}", + "59, specific {'perturbing_action': 'B-gene loss-of-function'}", + "60, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "61, of {'perturbing_action': 'I-gene loss-of-function'}", + "62, Abca1 {'perturbing_action': 'I-gene loss-of-function'}", + "64, beta-cells {'context': 'B-cells'}", + "78, Islets {'context': 'B-cells'}", + "82, mice {'context': 'B-organism'}", + "91, in {'context': 'B-in vitro'}", + "92, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "57, Mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "59, specific ['l0', 'l5', 'l6', 'l7', 'l8']", + "60, inactivation ['l1', 'l5', 'l9', 'l10', 'l11']", + "61, of ['l2', 'l6', 'l9', 'l12', 'l13']", + "62, Abca1 ['l3', 'l7', 'l10', 'l12', 'l14']", + "64, beta-cells ['l4', 'l8', 'l11', 'l13', 'l14']", + "78, Islets ['l15', 'l16', 'l17']", + "82, mice ['l15', 'l18', 'l19']", + "91, in ['l16', 'l18', 'l20']", + "92, vitro. ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "specific", + "inactivation", + "of", + "Abca1" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "specific", + "inactivation", + "of", + "Abca1" + ] + }, + "context": { + "val": "cells", + "words": [ + "beta-cells" + ] + } + } + ] + }, + { + "PMID": "17322895", + "TEXT": "In the adult heart, a variety of stresses induce re-expression of a fetal gene program in association with myocyte hypertrophy and heart failure. Here we show that histone deacetylase-2 (Hdac2) regulates expression of many fetal cardiac isoforms. Hdac2 deficiency or chemical histone deacetylase (HDAC) inhibition prevented the re-expression of fetal genes and attenuated cardiac hypertrophy in hearts exposed to hypertrophic stimuli. Resistance to hypertrophy was associated with increased expression of the gene encoding inositol polyphosphate-5-phosphatase f (Inpp5f) resulting in constitutive activation of glycogen synthase kinase 3beta (Gsk3beta) via inactivation of thymoma viral proto-oncogene (Akt) and 3-phosphoinositide-dependent protein kinase-1 (Pdk1). In contrast, Hdac2 transgenic mice had augmented hypertrophy associated with inactivated Gsk3beta. Chemical inhibition of activated Gsk3beta allowed Hdac2-deficient adults to become sensitive to hypertrophic stimulation. These results suggest that Hdac2 is an important molecular target of HDAC inhibitors in the heart and that Hdac2 and Gsk3beta are components of a regulatory pathway providing an attractive therapeutic target for the treatment of cardiac hypertrophy and heart failure.", + "TAG_DATA": [ + "37, Hdac2 {'perturbing_action': 'B-gene loss-of-function'}", + "38, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "56, hearts {'context': 'B-tissue/organ'}", + "101, Hdac2 {'perturbing_action': 'B-gene gain-of-function'}", + "102, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "103, mice {'context': 'B-organism'}", + "114, activated {'perturbing_action': 'I-pharmacological inhibition'}", + "117, Hdac2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "118, adults {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "37, Hdac2 ['l0', 'l1']", + "38, deficiency ['l0', 'l2']", + "56, hearts ['l1', 'l2']", + "101, Hdac2 ['l3', 'l4']", + "102, transgenic ['l3', 'l5']", + "103, mice ['l4', 'l5']", + "114, activated ['l6', 'l7']", + "117, Hdac2-deficient ['l6', 'l8']", + "118, adults ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hdac2", + "deficiency" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hearts" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Hdac2", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "activated" + ] + }, + "context": { + "val": "organism", + "words": [ + "adults" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hdac2-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "adults" + ] + } + } + ] + }, + { + "PMID": "17322894", + "TEXT": "Cardiac overstimulation by the sympathetic nervous system (SNS) is a salient characteristic of heart failure, reflected by elevated circulating levels of catecholamines. The success of beta-adrenergic receptor (betaAR) antagonists in heart failure argues for SNS hyperactivity being pathogenic; however, sympatholytic agents targeting alpha2AR-mediated catecholamine inhibition have been unsuccessful. By investigating adrenal adrenergic receptor signaling in heart failure models, we found molecular mechanisms to explain the failure of sympatholytic agents and discovered a new strategy to lower SNS activity. During heart failure, there is substantial alpha2AR dysregulation in the adrenal gland, triggered by increased expression and activity of G protein-coupled receptor kinase 2 (GRK2). Adrenal gland-specific GRK2 inhibition reversed alpha2AR dysregulation in heart failure, resulting in lowered plasma catecholamine levels, improved cardiac betaAR signaling and function, and increased sympatholytic efficacy of a alpha2AR agonist. This is the first demonstration, to our knowledge, of a molecular mechanism for SNS hyperactivity in heart failure, and our study identifies adrenal GRK2 activity as a new sympatholytic target.", + "TAG_DATA": [ + "103, Adrenal {'perturbing_action': 'B-pharmacological inhibition'}", + "104, gland-specific {'perturbing_action': 'I-pharmacological inhibition'}", + "105, GRK2 {'perturbing_action': 'I-pharmacological inhibition'}", + "106, inhibition {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "103, Adrenal ['l0', 'l1', 'l2']", + "104, gland-specific ['l0', 'l3', 'l4']", + "105, GRK2 ['l1', 'l3', 'l5']", + "106, inhibition ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17273170", + "TEXT": "Increased production of very low-density lipoprotein (VLDL) is a critical feature of the metabolic syndrome. Here we report that a selective increase in brain glucose lowered circulating triglycerides (TG) through the inhibition of TG-VLDL secretion by the liver. We found that the effect of glucose required its conversion to lactate, leading to activation of ATP-sensitive potassium channels and to decreased hepatic activity of stearoyl-CoA desaturase-1 (SCD1). SCD1 catalyzed the synthesis of oleyl-CoA from stearoyl-CoA. Curtailing the liver activity of SCD1 was sufficient to lower the hepatic levels of oleyl-CoA and to recapitulate the effects of central glucose administration on VLDL secretion. Notably, portal infusion of oleic acid restored hepatic oleyl-CoA to control levels and negated the effects of both central glucose and SCD1 deficiency on TG-VLDL secretion. These central effects of glucose (but not those of lactate) were rapidly lost in diet-induced obesity. These findings indicate that a defect in brain glucose sensing could play a critical role in the etiology of the metabolic syndrome.", + "TAG_DATA": [ + "76, liver {'context': 'B-tissue/organ'}", + "77, activity {'perturbing_action': 'I-other'}", + "78, of {'perturbing_action': 'I-other'}", + "79, SCD1 {'perturbing_action': 'I-other'}", + "122, SCD1 {'perturbing_action': 'B-gene loss-of-function'}", + "123, deficiency {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "75, the ['l0', 'l1', 'l2', 'l3']", + "76, liver ['l0', 'l4', 'l5', 'l6']", + "77, activity ['l1', 'l4', 'l7', 'l8']", + "78, of ['l2', 'l5', 'l7', 'l9']", + "79, SCD1 ['l3', 'l6', 'l8', 'l9']", + "122, SCD1 ['l10']", + "123, deficiency ['l10']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "activity", + "of", + "SCD1" + ] + } + } + ] + }, + { + "PMID": "17273169", + "TEXT": "Asymmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA) are endogenously produced amino acids that inhibit all three isoforms of nitric oxide synthase (NOS). ADMA accumulates in various disease states, including renal failure, diabetes and pulmonary hypertension, and its concentration in plasma is strongly predictive of premature cardiovascular disease and death. Both L-NMMA and ADMA are eliminated largely through active metabolism by dimethylarginine dimethylaminohydrolase (DDAH) and thus DDAH dysfunction may be a crucial unifying feature of increased cardiovascular risk. However, despite considerable interest in this pathway and in the role of ADMA as a cardiovascular risk factor, there is little evidence to support a causal role of ADMA in pathophysiology. Here we reveal the structure of human DDAH-1 and probe the function of DDAH-1 both by deleting the DDAH1 gene in mice and by using DDAH-specific inhibitors which, as we demonstrate by crystallography, bind to the active site of human DDAH-1. We show that loss of DDAH-1 activity leads to accumulation of ADMA and reduction in NO signaling. This in turn causes vascular pathophysiology, including endothelial dysfunction, increased systemic vascular resistance and elevated systemic and pulmonary blood pressure. Our results also suggest that DDAH inhibition could be harnessed therapeutically to reduce the vascular collapse associated with sepsis.", + "TAG_DATA": [ + "124, deleting {'perturbing_action': 'B-gene loss-of-function'}", + "125, the {'perturbing_action': 'I-gene loss-of-function'}", + "126, DDAH1 {'perturbing_action': 'I-gene loss-of-function'}", + "127, gene {'perturbing_action': 'I-gene loss-of-function'}", + "129, mice {'context': 'B-organism'}", + "133, DDAH-specific {'perturbing_action': 'B-pharmacological inhibition'}", + "134, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "152, loss {'perturbing_action': 'B-gene loss-of-function'}", + "153, of {'perturbing_action': 'I-gene loss-of-function'}", + "154, DDAH-1 {'perturbing_action': 'I-gene loss-of-function'}", + "155, activity {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "124, deleting ['l0', 'l1', 'l2', 'l3']", + "125, the ['l0', 'l4', 'l5', 'l6']", + "126, DDAH1 ['l1', 'l4', 'l7', 'l8']", + "127, gene ['l2', 'l5', 'l7', 'l9']", + "129, mice ['l3', 'l6', 'l8', 'l9']", + "133, DDAH-specific ['l10', 'l11', 'l12', 'l13', 'l14']", + "134, inhibitors ['l10', 'l15', 'l16', 'l17', 'l18']", + "152, loss ['l11', 'l15', 'l19', 'l20', 'l21']", + "153, of ['l12', 'l16', 'l19', 'l22', 'l23']", + "154, DDAH-1 ['l13', 'l17', 'l20', 'l22', 'l24']", + "155, activity ['l14', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deleting", + "the", + "DDAH1", + "gene" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "17237795", + "TEXT": "The role of autoantibodies in the pathogenesis of multiple sclerosis (MS) and other demyelinating diseases is controversial, in part because widely used western blotting and ELISA methods either do not permit the detection of conformation-sensitive antibodies or do not distinguish them from conformation-independent antibodies. We developed a sensitive assay based on self-assembling radiolabeled tetramers that allows discrimination of antibodies against folded or denatured myelin oligodendrocyte glycoprotein (MOG) by selective unfolding of the antigen domain. The tetramer radioimmunoassay (RIA) was more sensitive for MOG autoantibody detection than other methodologies, including monomer-based RIA, ELISA or fluorescent-activated cell sorting (FACS). Autoantibodies from individuals with acute disseminated encephalomyelitis (ADEM) selectively bound the folded MOG tetramer, whereas sera from mice with experimental autoimmune encephalomyelitis induced with MOG peptide immunoprecipitated only the unfolded tetramer. MOG-specific autoantibodies were identified in a subset of ADEM but only rarely in adult-onset MS cases, indicating that MOG is a more prominent target antigen in ADEM than MS.", + "TAG_DATA": [ + "114, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17206148", + "TEXT": "Current methods for prenatal diagnosis of chromosomal aneuploidies involve the invasive sampling of fetal materials using procedures such as amniocentesis or chorionic villus sampling and constitute a finite risk to the fetus. Here, we outline a strategy for fetal chromosome dosage assessment that can be performed noninvasively through analysis of placental expressed mRNA in maternal plasma. We achieved noninvasive prenatal diagnosis of fetal trisomy 21 by determining the ratio between alleles of a single-nucleotide polymorphism (SNP) in PLAC4 mRNA, which is transcribed from chromosome 21 and expressed by the placenta, in maternal plasma. PLAC4 mRNA in maternal plasma was fetal derived and cleared after delivery. The allelic ratios in maternal plasma correlated with those in the placenta. Fetal trisomy 21 was detected noninvasively in 90% of cases and excluded in 96.5% of controls.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17206114", + "TEXT": "He is so soft-spoken you may have to strain to catch his words, but on the topic of recognition for scientists in resource-poor regions, Menno de Jong is ready for a fistfight.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17187072", + "TEXT": "Anthracyclin-treated tumor cells are particularly effective in eliciting an anticancer immune response, whereas other DNA-damaging agents such as etoposide and mitomycin C do not induce immunogenic cell death. Here we show that anthracyclins induce the rapid, preapoptotic translocation of calreticulin (CRT) to the cell surface. Blockade or knockdown of CRT suppressed the phagocytosis of anthracyclin-treated tumor cells by dendritic cells and abolished their immunogenicity in mice. The anthracyclin-induced CRT translocation was mimicked by inhibition of the protein phosphatase 1/GADD34 complex. Administration of recombinant CRT or inhibitors of protein phosphatase 1/GADD34 restored the immunogenicity of cell death elicited by etoposide and mitomycin C, and enhanced their antitumor effects in vivo. These data identify CRT as a key feature determining anticancer immune responses and delineate a possible strategy for immunogenic chemotherapy.", + "TAG_DATA": [ + "47, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "48, of {'perturbing_action': 'I-rnai/knockdown'}", + "49, CRT {'perturbing_action': 'I-rnai/knockdown'}", + "50, suppressed {'effect': 'B-negative'}", + "52, phagocytosis {'phenotype': 'B-mitophagy'}", + "55, tumor {'context': 'B-transformed cells'}", + "56, cells {'context': 'I-transformed cells'}", + "58, dendritic {'context': 'B-cells'}", + "59, cells {'context': 'I-cells'}", + "65, mice. {'context': 'B-organism'}", + "85, inhibitors {'perturbing_action': 'B-pharmacological inhibition'}", + "86, of {'perturbing_action': 'I-pharmacological inhibition'}", + "87, protein {'perturbing_action': 'I-pharmacological inhibition'}", + "88, phosphatase {'perturbing_action': 'I-pharmacological inhibition'}", + "89, 1/GADD34 {'perturbing_action': 'I-pharmacological inhibition'}", + "90, restored {'effect': 'B-rescues'}", + "94, cell {'phenotype': 'B-cell death'}", + "95, death {'phenotype': 'I-cell death'}", + "107, in {'context': 'B-in vivo'}", + "108, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "47, knockdown ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "48, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "49, CRT ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "50, suppressed ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28']", + "52, phagocytosis ['l3', 'l11', 'l18', 'l24', 'l29', 'l30', 'l31', 'l32', 'l33']", + "55, tumor ['l4', 'l12', 'l19', 'l25', 'l29', 'l34', 'l35', 'l36', 'l37']", + "56, cells ['l5', 'l13', 'l20', 'l26', 'l30', 'l34', 'l38', 'l39', 'l40']", + "58, dendritic ['l6', 'l14', 'l21', 'l27', 'l31', 'l35', 'l38', 'l41', 'l42']", + "59, cells ['l7', 'l15', 'l22', 'l28', 'l32', 'l36', 'l39', 'l41', 'l43']", + "65, mice. ['l8', 'l16', 'l23', 'l33', 'l37', 'l40', 'l42', 'l43']", + "85, inhibitors ['l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "86, of ['l44', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "87, protein ['l45', 'l53', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "88, phosphatase ['l46', 'l54', 'l61', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "89, 1/GADD34 ['l47', 'l55', 'l62', 'l68', 'l74', 'l75', 'l76', 'l77', 'l78']", + "90, restored ['l48', 'l56', 'l63', 'l69', 'l74', 'l79', 'l80']", + "94, cell ['l49', 'l57', 'l64', 'l70', 'l75', 'l79', 'l81']", + "95, death ['l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l81']", + "107, in ['l51', 'l59', 'l66', 'l72', 'l77', 'l82']", + "108, vivo. ['l52', 'l60', 'l67', 'l73', 'l78', 'l82']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "CRT" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "CRT" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "CRT" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "CRT" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "CRT" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells" + ] + } + }, + { + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells" + ] + } + }, + { + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "protein", + "phosphatase", + "1/GADD34" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "protein", + "phosphatase", + "1/GADD34" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "protein", + "phosphatase", + "1/GADD34" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + } + ] + }, + { + "PMID": "17173050", + "TEXT": "T-cell acute lymphoblastic leukemia (T-ALL), unlike other ALL types, is only infrequently associated with chromosomal aberrations, but it was recently shown that most individuals with T-ALL carry activating mutations in the NOTCH1 gene. However, the signaling pathways and target genes responsible for Notch1-induced neoplastic transformation remain undefined. We report here that constitutively active Notch1 activates the NF-kappaB pathway transcriptionally and via the IkappaB kinase (IKK) complex, thereby causing increased expression of several well characterized target genes of NF-kappaB in bone marrow hematopoietic stem cells and progenitors. Our observations demonstrate that the NF-kappaB pathway is highly active in established human T-ALL and that inhibition of the pathway can efficiently restrict tumor growth both in vitro and in vivo. These findings identify NF-kappaB as one of the major mediators of Notch1-induced transformation and suggest that the NF-kappaB pathway is a potential target of future therapies of T-ALL.", + "TAG_DATA": [ + "51, constitutively {'perturbing_action': 'B-gene gain-of-function'}", + "52, active {'perturbing_action': 'I-gene gain-of-function'}", + "53, Notch1 {'perturbing_action': 'I-gene gain-of-function'}", + "108, restrict {'effect': 'B-negative'}", + "109, tumor {'phenotype': 'B-tumour growth'}", + "110, growth {'phenotype': 'I-tumour growth'}", + "112, in {'context': 'B-in vitro'}", + "113, vitro {'context': 'I-in vitro'}", + "115, in {'context': 'B-in vivo'}", + "116, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "51, constitutively ['l0', 'l1']", + "52, active ['l0', 'l2']", + "53, Notch1 ['l1', 'l2']", + "108, restrict ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "109, tumor ['l3', 'l9', 'l10', 'l11', 'l12', 'l13']", + "110, growth ['l4', 'l9', 'l14', 'l15', 'l16', 'l17']", + "112, in ['l5', 'l10', 'l14', 'l18', 'l19', 'l20']", + "113, vitro ['l6', 'l11', 'l15', 'l18', 'l21', 'l22']", + "115, in ['l7', 'l12', 'l16', 'l19', 'l21', 'l23']", + "116, vivo. ['l8', 'l13', 'l17', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "restrict" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "restrict" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "restrict" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "17159987", + "TEXT": "Cancer immunoresistance and immune escape may play important roles in tumor progression and pose obstacles for immunotherapy. Expression of the immunosuppressive protein B7 homolog 1 (B7-H1), also known as programmed death ligand-1 (PD-L1), is increased in many pathological conditions, including cancer. Here we show that expression of the gene encoding B7-H1 increases post transcriptionally in human glioma after loss of phosphatase and tensin homolog (PTEN) and activation of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway. Tumor specimens from individuals with glioblastoma multiforme (GBM) had levels of B7-H1 protein that correlated with PTEN loss, and tumor-specific T cells lysed human glioma targets expressing wild-type PTEN more effectively than those expressing mutant PTEN. These data identify a previously unrecognized mechanism linking loss of the tumor suppressor PTEN with immunoresistance, mediated in part by B7-H1.", + "TAG_DATA": [ + "92, tumor-specific {'context': 'B-cells'}", + "93, T {'context': 'I-cells'}", + "94, cells {'context': 'I-cells'}", + "96, human {'context': 'B-neoplasm'}", + "97, glioma {'context': 'I-neoplasm'}", + "98, targets {'context': 'I-neoplasm'}", + "107, mutant {'perturbing_action': 'B-other'}", + "108, PTEN. {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "92, tumor-specific ['l0', 'l1', 'l2', 'l3', 'l4']", + "93, T ['l0', 'l5', 'l6', 'l7', 'l8']", + "94, cells ['l1', 'l5', 'l9', 'l10', 'l11']", + "96, human ['l2', 'l6', 'l9', 'l12', 'l13']", + "97, glioma ['l3', 'l7', 'l10', 'l12', 'l14']", + "98, targets ['l4', 'l8', 'l11', 'l13', 'l14']", + "107, mutant ['l15']", + "108, PTEN. ['l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17159986", + "TEXT": "Advanced breast cancers frequently metastasize to bone, resulting in osteolytic lesions, yet the underlying mechanisms are poorly understood. Here we report that nuclear factor-kappaB (NF-kappaB) plays a crucial role in the osteolytic bone metastasis of breast cancer by stimulating osteoclastogenesis. Using an in vivo bone metastasis model, we found that constitutive NF-kappaB activity in breast cancer cells is crucial for the bone resorption characteristic of osteolytic bone metastasis. We identified the gene encoding granulocyte macrophage-colony stimulating factor (GM-CSF) as a key target of NF-kappaB and found that it mediates osteolytic bone metastasis of breast cancer by stimulating osteoclast development. Moreover, we observed that the expression of GM-CSF correlated with NF-kappaB activation in bone-metastatic tumor tissues from individuals with breast cancer. These results uncover a new and specific role of NF-kappaB in osteolytic bone metastasis through GM-CSF induction, suggesting that NF-kappaB is a potential target for the treatment of breast cancer and the prevention of skeletal metastasis.", + "TAG_DATA": [ + "42, in {'context': 'B-in vivo'}", + "43, vivo {'context': 'B-in vivo'}", + "44, bone {'context': 'B-in vivo', 'phenotype': 'B-metastasis'}", + "45, metastasis {'phenotype': 'I-metastasis'}", + "46, model, {'phenotype': 'I-metastasis'}", + "54, breast {'context': 'B-transformed cells'}", + "55, cancer {'context': 'I-transformed cells'}", + "56, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "42, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "43, vivo ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "44, bone ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "45, metastasis ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "46, model, ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "54, breast ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "55, cancer ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "56, cells ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "bone" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "bone", + "metastasis", + "model," + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "bone", + "metastasis", + "model," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "breast", + "cancer", + "cells" + ] + } + } + ] + }, + { + "PMID": "17151671", + "TEXT": "Declining research budgets make for difficult funding decisions. Can the cuts be justified?", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17128270", + "TEXT": "Matrix-producing osteoblasts and bone-resorbing osteoclasts maintain bone homeostasis. Osteoclasts are multinucleated, giant cells of hematopoietic origin formed by the fusion of mononuclear pre-osteoclasts derived from myeloid cells. Fusion-mediated giant cell formation is critical for osteoclast maturation; without it, bone resorption is inefficient. To understand how osteoclasts differ from other myeloid lineage cells, we previously compared global mRNA expression patterns in these cells and identified genes of unknown function predominantly expressed in osteoclasts, one of which is the d2 isoform of vacuolar (H(+)) ATPase (v-ATPase) V(0) domain (Atp6v0d2). Here we show that inactivation of Atp6v0d2 in mice results in markedly increased bone mass due to defective osteoclasts and enhanced bone formation. Atp6v0d2 deficiency did not affect differentiation or the v-ATPase activity of osteoclasts. Rather, Atp6v0d2 was required for efficient pre-osteoclast fusion. Increased bone formation was probably due to osteoblast-extrinsic factors, as Atp6v02 was not expressed in osteoblasts and their differentiation ex vivo was not altered in the absence of Atp6v02. Our results identify Atp6v0d2 as a regulator of osteoclast fusion and bone formation, and provide genetic data showing that it is possible to simultaneously inhibit osteoclast maturation and stimulate bone formation by therapeutically targeting the function of a single gene.", + "TAG_DATA": [ + "91, inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "92, of {'perturbing_action': 'I-gene loss-of-function'}", + "93, Atp6v0d2 {'perturbing_action': 'I-gene loss-of-function'}", + "95, mice {'context': 'B-organism'}", + "105, osteoclasts {'context': 'B-cells'}", + "110, Atp6v0d2 {'perturbing_action': 'B-gene loss-of-function'}", + "111, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "112, did {'effect': 'B-no effect'}", + "113, not {'effect': 'I-no effect'}", + "114, affect {'effect': 'I-no effect'}", + "115, differentiation {'phenotype': 'B-differentiation'}", + "121, osteoclasts. {'context': 'B-cells'}", + "148, differentiation {'phenotype': 'B-differentiation'}", + "153, altered {'effect': 'B-no effect'}", + "156, absence {'perturbing_action': 'B-gene loss-of-function'}", + "157, of {'perturbing_action': 'I-gene loss-of-function'}", + "158, Atp6v02. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "91, inactivation ['l0', 'l1', 'l2', 'l3']", + "92, of ['l0', 'l4', 'l5', 'l6']", + "93, Atp6v0d2 ['l1', 'l4', 'l7', 'l8']", + "95, mice ['l2', 'l5', 'l7', 'l9']", + "105, osteoclasts ['l3', 'l6', 'l8', 'l9']", + "110, Atp6v0d2 ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "111, deficiency ['l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "112, did ['l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "113, not ['l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "114, affect ['l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "115, differentiation ['l14', 'l19', 'l23', 'l26', 'l28', 'l30']", + "121, osteoclasts. ['l15', 'l20', 'l24', 'l27', 'l29', 'l30']", + "148, differentiation ['l31', 'l32', 'l33', 'l34']", + "153, altered ['l31', 'l35', 'l36', 'l37']", + "156, absence ['l32', 'l35', 'l38', 'l39']", + "157, of ['l33', 'l36', 'l38', 'l40']", + "158, Atp6v02. ['l34', 'l37', 'l39', 'l40']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "Atp6v0d2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "Atp6v0d2", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclasts", + "osteoclasts." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atp6v0d2", + "deficiency", + "absence", + "of", + "Atp6v02." + ] + }, + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "affect", + "altered" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atp6v0d2", + "deficiency", + "absence", + "of", + "Atp6v02." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "affect", + "altered" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "affect" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclasts." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclasts." + ] + } + } + ] + }, + { + "PMID": "17115048", + "TEXT": "Amyloid plaque is the hallmark and primary cause of Alzheimer disease. Mutations of presenilin-1, the gamma-secretase catalytic subunit, can affect amyloid-beta (Abeta) production and Alzheimer disease pathogenesis. However, it is largely unknown whether and how gamma-secretase activity and amyloid plaque formation are regulated by environmental factors such as stress, which is mediated by receptors including beta(2)-adrenergic receptor (beta(2)-AR). Here we report that activation of beta(2)-AR enhanced gamma-secretase activity and thus Abeta production. This enhancement involved the association of beta(2)-AR with presenilin-1 and required agonist-induced endocytosis of beta(2)-AR and subsequent trafficking of gamma-secretase to late endosomes and lysosomes, where Abeta production was elevated. Similar effects were observed after activation of delta-opioid receptor. Furthermore, chronic treatment with beta(2)-AR agonists increased cerebral amyloid plaques in an Alzheimer disease mouse model. Thus, beta(2)-AR activation can stimulate gamma-secretase activity and amyloid plaque formation, which suggests that abnormal activation of beta(2)-AR might contribute to Abeta accumulation in Alzheimer disease pathogenesis.", + "TAG_DATA": [ + "62, activation {'perturbing_action': 'B-pharmacological augmentation'}", + "63, of {'perturbing_action': 'I-pharmacological augmentation'}", + "64, beta(2)-AR {'perturbing_action': 'I-pharmacological augmentation'}", + "107, activation {'perturbing_action': 'B-pharmacological augmentation'}", + "110, receptor. {'perturbing_action': 'I-pharmacological augmentation'}", + "115, beta(2)-AR {'perturbing_action': 'B-pharmacological augmentation'}", + "116, agonists {'perturbing_action': 'I-pharmacological augmentation'}", + "123, Alzheimer {'context': 'B-organism'}", + "124, disease {'context': 'I-organism'}", + "125, mouse {'context': 'I-organism'}", + "126, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "62, activation ['l0', 'l1']", + "63, of ['l0', 'l2']", + "64, beta(2)-AR ['l1', 'l2']", + "107, activation ['l3', 'l4']", + "110, receptor. ['l3', 'l5', 'l6', 'l7']", + "115, beta(2)-AR ['l8', 'l9', 'l10', 'l11', 'l12']", + "116, agonists ['l8', 'l13', 'l14', 'l15', 'l16']", + "123, Alzheimer ['l5', 'l9', 'l13', 'l17', 'l18', 'l19']", + "124, disease ['l6', 'l10', 'l14', 'l17', 'l20', 'l21']", + "125, mouse ['l11', 'l15', 'l18', 'l20', 'l22']", + "126, model. ['l4', 'l7', 'l12', 'l16', 'l19', 'l21', 'l22']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "receptor.", + "beta(2)-AR", + "agonists" + ] + }, + "context": { + "val": "organism", + "words": [ + "model.", + "Alzheimer", + "disease", + "mouse" + ] + } + } + ] + }, + { + "PMID": "17099709", + "TEXT": "Axons in the adult mammalian central nervous system (CNS) exhibit little regeneration after injury. It has been suggested that several axonal growth inhibitors prevent CNS axonal regeneration. Recent research has demonstrated that semaphorin3A (Sema3A) is one of the major inhibitors of axonal regeneration. We identified a strong and selective inhibitor of Sema3A, SM-216289, from the fermentation broth of a fungal strain. To examine the effect of SM-216289 in vivo, we transected the spinal cord of adult rats and administered SM-216289 into the lesion site for 4 weeks. Rats treated with SM-216289 showed substantially enhanced regeneration and/or preservation of injured axons, robust Schwann cell-mediated myelination and axonal regeneration in the lesion site, appreciable decreases in apoptotic cell number and marked enhancement of angiogenesis, resulting in considerably better functional recovery. Thus, Sema3A is essential for the inhibition of axonal regeneration and other regenerative responses after spinal cord injury (SCI). These results support the possibility of using Sema3A inhibitors in the treatment of human SCI.", + "TAG_DATA": [ + "67, in {'context': 'B-in vivo'}", + "68, vivo, {'context': 'I-in vivo'}", + "72, spinal {'context': 'B-tissue/organ'}", + "73, cord {'context': 'I-tissue/organ'}", + "75, adult {'context': 'B-organism'}", + "76, rats {'context': 'I-organism'}", + "87, Rats {'context': 'B-organism'}", + "99, axons, {'context': 'B-cells'}", + "112, decreases {'effect': 'B-negative'}", + "114, apoptotic {'phenotype': 'B-apoptosis'}", + "115, cell {'phenotype': 'I-apoptosis'}" + ], + "LINK_DATA": [ + "67, in ['l0', 'l1', 'l2', 'l3', 'l4']", + "68, vivo, ['l0', 'l5', 'l6', 'l7', 'l8']", + "72, spinal ['l1', 'l5', 'l9', 'l10', 'l11']", + "73, cord ['l2', 'l6', 'l9', 'l12', 'l13']", + "75, adult ['l3', 'l7', 'l10', 'l12', 'l14']", + "76, rats ['l4', 'l8', 'l11', 'l13', 'l14']", + "87, Rats ['l15']", + "99, axons, ['l15']", + "112, decreases ['l16', 'l17']", + "114, apoptotic ['l16', 'l18']", + "115, cell ['l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "decreases" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell" + ] + } + } + ] + }, + { + "PMID": "17072310", + "TEXT": "The cycle of gallbladder filling and emptying controls the flow of bile into the intestine for digestion. Here we show that fibroblast growth factor-15, a hormone made by the distal small intestine in response to bile acids, is required for gallbladder filling. These studies demonstrate that gallbladder filling is actively regulated by an endocrine pathway and suggest a postprandial timing mechanism that controls gallbladder motility.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17063141", + "TEXT": "We demonstrate here that lymphoid enhancer-binding factor 1 (LEF-1) mediates the proliferation, survival and differentiation of granulocyte progenitor cells. We initially documented the importance of this transcription factor in the bone marrow of individuals with severe congenital neutropenia (CN) with a 'differentiation block' at the promyelocytic stage of myelopoiesis. LEF-1 expression was greatly reduced or even absent in CN arrested promyelocytes, resulting in defective expression of the LEF-1 target genes CCND1, MYC and BIRC5, encoding cyclin D1 (ref. 2), c-Myc and survivin, respectively. In contrast, healthy individuals showed highest LEF-1 expression in promyelocytes. Reconstitution of LEF-1 in early hematopoietic progenitors of two individuals with CN corrected the defective myelopoiesis and resulted in the differentiation of these progenitors into mature granulocytes. Repression of endogenous LEF-1 by specific short hairpin RNA inhibited proliferation and induced apoptosis of CD34(+) progenitors from healthy individuals and of cells from two myeloid lines (HL-60 and K562). C/EBPalpha, a key transcription factor in granulopoiesis, was directly regulated by LEF-1. These observations indicate that LEF-1 is an instructive factor regulating neutrophilic granulopoiesis whose absence plays a critical role in the defective maturation program of myeloid progenitors in individuals with CN.", + "TAG_DATA": [ + "60, promyelocytes, {'context': 'B-cells'}", + "93, Reconstitution {'perturbing_action': 'B-gene gain-of-function'}", + "94, of {'perturbing_action': 'I-gene gain-of-function'}", + "95, LEF-1 {'perturbing_action': 'I-gene gain-of-function'}", + "97, early {'context': 'B-cells'}", + "98, hematopoietic {'context': 'B-cells'}", + "99, progenitors {'context': 'I-cells'}", + "110, resulted {'effect': 'B-positive'}", + "111, in {'effect': 'I-positive'}", + "113, differentiation {'phenotype': 'B-differentiation'}", + "116, progenitors {'context': 'B-cells'}", + "120, Repression {'perturbing_action': 'B-rnai/knockdown'}", + "121, of {'perturbing_action': 'I-rnai/knockdown'}", + "122, endogenous {'perturbing_action': 'I-rnai/knockdown'}", + "123, LEF-1 {'perturbing_action': 'I-rnai/knockdown'}", + "124, by {'perturbing_action': 'I-rnai/knockdown'}", + "125, specific {'perturbing_action': 'I-rnai/knockdown'}", + "126, short {'perturbing_action': 'I-rnai/knockdown'}", + "127, hairpin {'perturbing_action': 'I-rnai/knockdown'}", + "128, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "129, inhibited {'effect': 'B-negative'}", + "130, proliferation {'phenotype': 'B-proliferation'}", + "132, induced {'effect': 'B-positive'}", + "133, apoptosis {'phenotype': 'B-apoptosis'}", + "135, CD34(+) {'context': 'B-cells'}", + "136, progenitors {'context': 'I-cells'}", + "142, cells {'context': 'B-cells'}", + "143, from {'context': 'I-cells'}", + "144, two {'context': 'I-cells'}", + "145, myeloid {'context': 'B-cells'}", + "146, lines {'context': 'I-cells'}", + "147, (HL-60 {'context': 'I-cells'}", + "148, and {'context': 'I-cells'}", + "149, K562). {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "93, Reconstitution ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "94, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "95, LEF-1 ['l1', 'l13', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "97, early ['l2', 'l14', 'l23', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "98, hematopoietic ['l3', 'l15', 'l24', 'l32', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "99, progenitors ['l4', 'l16', 'l25', 'l33', 'l40', 'l47', 'l48', 'l49', 'l50', 'l51']", + "110, resulted ['l5', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l53', 'l54', 'l55']", + "111, in ['l6', 'l18', 'l27', 'l35', 'l42', 'l48', 'l52', 'l56', 'l57', 'l58']", + "113, differentiation ['l7', 'l19', 'l28', 'l36', 'l43', 'l49', 'l53', 'l56', 'l59', 'l60']", + "116, progenitors ['l8', 'l20', 'l29', 'l37', 'l44', 'l50', 'l54', 'l57', 'l59', 'l61']", + "119, granulocytes. ['l9', 'l21', 'l30', 'l38', 'l45', 'l51', 'l55', 'l58', 'l60', 'l61']", + "120, Repression ['l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "121, of ['l62', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "122, endogenous ['l63', 'l84', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "123, LEF-1 ['l64', 'l85', 'l105', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "124, by ['l65', 'l86', 'l106', 'l125', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "125, specific ['l66', 'l87', 'l107', 'l126', 'l144', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "126, short ['l67', 'l88', 'l108', 'l127', 'l145', 'l162', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "127, hairpin ['l68', 'l89', 'l109', 'l128', 'l146', 'l163', 'l179', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209']", + "128, RNA ['l69', 'l90', 'l110', 'l129', 'l147', 'l164', 'l180', 'l195', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223']", + "129, inhibited ['l70', 'l91', 'l111', 'l130', 'l148', 'l165', 'l181', 'l196', 'l210', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236']", + "130, proliferation ['l10', 'l71', 'l92', 'l112', 'l131', 'l149', 'l166', 'l182', 'l197', 'l211', 'l224', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244']", + "132, induced ['l72', 'l93', 'l113', 'l132', 'l150', 'l167', 'l183', 'l198', 'l212', 'l225', 'l237', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255']", + "133, apoptosis ['l73', 'l94', 'l114', 'l133', 'l151', 'l168', 'l184', 'l199', 'l213', 'l226', 'l238', 'l245', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265']", + "135, CD34(+) ['l11', 'l74', 'l95', 'l115', 'l134', 'l152', 'l169', 'l185', 'l200', 'l214', 'l227', 'l239', 'l246', 'l256', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274']", + "136, progenitors ['l12', 'l22', 'l31', 'l39', 'l46', 'l75', 'l96', 'l116', 'l135', 'l153', 'l170', 'l186', 'l201', 'l215', 'l228', 'l240', 'l247', 'l257', 'l266', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280']", + "142, cells ['l76', 'l97', 'l117', 'l136', 'l154', 'l171', 'l187', 'l202', 'l216', 'l229', 'l248', 'l258', 'l267', 'l275', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286', 'l287']", + "143, from ['l77', 'l98', 'l118', 'l137', 'l155', 'l172', 'l188', 'l203', 'l217', 'l230', 'l249', 'l259', 'l268', 'l276', 'l281', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293']", + "144, two ['l78', 'l99', 'l119', 'l138', 'l156', 'l173', 'l189', 'l204', 'l218', 'l231', 'l250', 'l260', 'l269', 'l282', 'l288', 'l294', 'l295', 'l296', 'l297', 'l298']", + "145, myeloid ['l79', 'l100', 'l120', 'l139', 'l157', 'l174', 'l190', 'l205', 'l219', 'l232', 'l251', 'l261', 'l270', 'l283', 'l289', 'l294', 'l299', 'l300', 'l301', 'l302']", + "146, lines ['l80', 'l101', 'l121', 'l140', 'l158', 'l175', 'l191', 'l206', 'l220', 'l233', 'l241', 'l252', 'l262', 'l271', 'l277', 'l284', 'l290', 'l295', 'l299', 'l303', 'l304', 'l305']", + "147, (HL-60 ['l81', 'l102', 'l122', 'l141', 'l159', 'l176', 'l192', 'l207', 'l221', 'l234', 'l242', 'l253', 'l263', 'l272', 'l278', 'l285', 'l291', 'l296', 'l300', 'l303', 'l306', 'l307']", + "148, and ['l82', 'l103', 'l123', 'l142', 'l160', 'l177', 'l193', 'l208', 'l222', 'l235', 'l243', 'l254', 'l264', 'l273', 'l279', 'l286', 'l292', 'l297', 'l301', 'l304', 'l306', 'l308']", + "149, K562). ['l83', 'l104', 'l124', 'l143', 'l161', 'l178', 'l194', 'l209', 'l223', 'l236', 'l244', 'l255', 'l265', 'l274', 'l280', 'l287', 'l293', 'l298', 'l302', 'l305', 'l307', 'l308']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reconstitution", + "of", + "LEF-1" + ] + }, + "context": { + "val": "cells", + "words": [ + "early", + "hematopoietic", + "progenitors", + "CD34(+)" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reconstitution", + "of", + "LEF-1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reconstitution", + "of", + "LEF-1" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reconstitution" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "early", + "hematopoietic", + "progenitors", + "CD34(+)", + "cells", + "from", + "two", + "myeloid", + "lines", + "(HL-60", + "and", + "K562)." + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulted", + "in", + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "early", + "hematopoietic", + "progenitors" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Repression", + "of", + "endogenous", + "LEF-1", + "by", + "specific", + "short", + "hairpin", + "RNA" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Repression", + "of", + "endogenous", + "LEF-1", + "by", + "specific", + "short", + "hairpin", + "RNA" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Repression", + "of", + "endogenous", + "LEF-1", + "by", + "specific", + "short", + "hairpin", + "RNA" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Repression", + "of", + "endogenous", + "LEF-1", + "by", + "specific", + "short", + "hairpin", + "RNA" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Repression", + "of", + "endogenous", + "LEF-1", + "by", + "specific", + "short", + "hairpin", + "RNA" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD34(+)", + "progenitors", + "cells", + "from", + "two", + "myeloid", + "lines", + "(HL-60", + "and", + "K562)." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD34(+)", + "progenitors", + "cells", + "from", + "two", + "myeloid", + "lines", + "(HL-60", + "and", + "K562)." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD34(+)", + "progenitors", + "lines", + "(HL-60", + "and", + "K562)." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD34(+)", + "progenitors", + "cells", + "from", + "two", + "myeloid", + "lines", + "(HL-60", + "and", + "K562)." + ] + } + } + ] + }, + { + "PMID": "17057709", + "TEXT": "To direct human embryonic stem (HES) cells to a dopaminergic neuronal fate, we cocultured HES cells that were exposed to both sonic hedgehog and fibroblast growth factor 8 with telomerase-immortalized human fetal midbrain astrocytes. These astrocytes substantially potentiated dopaminergic neurogenesis by both WA09 and WA01 HES cells, biasing them to the A9 nigrostriatal phenotype. When transplanted into the neostriata of 6-hydroxydopamine-lesioned parkinsonian rats, the dopaminergic implants yielded a significant, substantial and long-lasting restitution of motor function. However, although rich in donor-derived tyrosine hydroxylase-expressing neurons, the grafts exhibited expanding cores of undifferentiated mitotic neuroepithelial cells, which can be tumorigenic. These results show the utility of recreating the cellular environment of the developing human midbrain while driving dopaminergic neurogenesis from HES cells, and they demonstrate the potential of the resultant cells to mediate substantial functional recovery in a model of Parkinson disease. Yet these data also mandate caution in the clinical application of HES cell-derived grafts, given their potential for phenotypic instability and undifferentiated expansion.", + "TAG_DATA": [ + "14, HES {'context': 'B-cells'}", + "15, cells {'context': 'I-cells'}", + "30, human {'context': 'B-cells'}", + "31, fetal {'context': 'I-cells'}", + "32, midbrain {'context': 'I-cells'}", + "33, astrocytes. {'context': 'I-cells'}", + "35, astrocytes {'context': 'B-cells'}", + "42, WA09 {'context': 'B-cells'}", + "43, and {'context': 'I-cells'}", + "44, WA01 {'context': 'I-cells'}", + "45, HES {'context': 'I-cells'}", + "46, cells, {'context': 'I-cells'}", + "58, neostriata {'context': 'I-tissue/organ'}", + "61, parkinsonian {'context': 'B-organism'}", + "62, rats, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "14, HES ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "15, cells ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "30, human ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "31, fetal ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "32, midbrain ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "33, astrocytes. ['l4', 'l17', 'l29', 'l40', 'l50', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "35, astrocytes ['l5', 'l18', 'l30', 'l41', 'l51', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "42, WA09 ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "43, and ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "44, WA01 ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l90', 'l91', 'l92', 'l93', 'l94']", + "45, HES ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l95', 'l96', 'l97', 'l98']", + "46, cells, ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l95']", + "58, neostriata ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l100']", + "61, parkinsonian ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l99', 'l101']", + "62, rats, ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l100', 'l101']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16998484", + "TEXT": "The long-term survival of patients with acute myeloid leukemia (AML) is dismally poor. A permanent cure of AML requires elimination of leukemic stem cells (LSCs), the only cell type capable of initiating and maintaining the leukemic clonal hierarchy. We report a therapeutic approach using an activating monoclonal antibody directed to the adhesion molecule CD44. In vivo administration of this antibody to nonobese diabetic-severe combined immune-deficient mice transplanted with human AML markedly reduced leukemic repopulation. Absence of leukemia in serially transplanted mice demonstrated that AML LSCs are directly targeted. Mechanisms underlying this eradication included interference with transport to stem cell-supportive microenvironmental niches and alteration of AML-LSC fate, identifying CD44 as a key regulator of AML LSCs. The finding that AML LSCs require interaction with a niche to maintain their stem cell properties provides a therapeutic strategy to eliminate quiescent AML LSCs and may be applicable to other types of cancer stem cells.", + "TAG_DATA": [ + "54, In {'context': 'B-in vivo'}", + "55, vivo {'context': 'I-in vivo'}", + "61, nonobese {'context': 'B-organism'}", + "62, diabetic-severe {'context': 'I-organism'}", + "63, combined {'context': 'I-organism'}", + "64, immune-deficient {'context': 'I-organism'}", + "65, mice {'context': 'I-organism'}", + "76, leukemia {'phenotype': 'B-tumourigenesis'}", + "80, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "54, In ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "55, vivo ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "61, nonobese ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "62, diabetic-severe ['l2', 'l8', 'l13', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "63, combined ['l3', 'l9', 'l14', 'l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "64, immune-deficient ['l4', 'l10', 'l15', 'l21', 'l26', 'l31', 'l32', 'l33', 'l34']", + "65, mice ['l5', 'l11', 'l16', 'l22', 'l27', 'l31', 'l35']", + "69, AML ['l6', 'l12', 'l17', 'l23', 'l28', 'l32', 'l35']", + "76, leukemia ['l18', 'l24', 'l29', 'l33', 'l36']", + "80, mice ['l19', 'l25', 'l30', 'l34', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "nonobese", + "diabetic-severe", + "combined", + "immune-deficient", + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia" + ] + } + } + ] + }, + { + "PMID": "16980968", + "TEXT": "Pharmacological interventions that increase myofiber size counter the functional decline of dystrophic muscles. We show that deacetylase inhibitors increase the size of myofibers in dystrophin-deficient (MDX) and alpha-sarcoglycan (alpha-SG)-deficient mice by inducing the expression of the myostatin antagonist follistatin in satellite cells. Deacetylase inhibitor treatment conferred on dystrophic muscles resistance to contraction-coupled degeneration and alleviated both morphological and functional consequences of the primary genetic defect. These results provide a rationale for using deacetylase inhibitors in the pharmacological therapy of muscular dystrophies.", + "TAG_DATA": [ + "22, myofibers {'context': 'B-cells'}", + "24, dystrophin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "25, (MDX) {'perturbing_action': 'I-gene loss-of-function'}", + "27, alpha-sarcoglycan {'perturbing_action': 'B-gene loss-of-function'}", + "28, (alpha-SG)-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "29, mice {'context': 'B-organism'}", + "40, satellite {'context': 'B-cells'}", + "41, cells. {'context': 'I-cells'}", + "47, dystrophic {'context': 'B-tissue/organ'}", + "48, muscles {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "22, myofibers ['l0', 'l1', 'l2']", + "24, dystrophin-deficient ['l0', 'l3', 'l4', 'l5', 'l6']", + "25, (MDX) ['l1', 'l3', 'l7', 'l8']", + "27, alpha-sarcoglycan ['l9', 'l10', 'l11', 'l12', 'l13']", + "28, (alpha-SG)-deficient ['l9', 'l14', 'l15', 'l16', 'l17', 'l18']", + "29, mice ['l2', 'l4', 'l7', 'l10', 'l14', 'l19', 'l20']", + "40, satellite ['l5', 'l11', 'l15', 'l19', 'l21', 'l22']", + "41, cells. ['l6', 'l8', 'l12', 'l16', 'l20', 'l21']", + "47, dystrophic ['l17', 'l23']", + "48, muscles ['l13', 'l18', 'l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "myofibers", + "satellite", + "cells." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient", + "(MDX)", + "alpha-sarcoglycan", + "(alpha-SG)-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient", + "(MDX)", + "alpha-sarcoglycan", + "(alpha-SG)-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha-sarcoglycan", + "(alpha-SG)-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscles", + "dystrophic" + ] + } + } + ] + }, + { + "PMID": "16917489", + "TEXT": "The engagement of programmed death 1 (PD-1) to its ligands, PD-L1 and PD-L2, inhibits proliferation and cytokine production mediated by antibodies to CD3 (refs. 5,6,7). Blocking the PD-1-PD-L1 pathway in mice chronically infected with lymphocytic choriomeningitis virus restores the capacity of exhausted CD8(+) T cells to undergo proliferation, cytokine production and cytotoxic activity and, consequently, results in reduced viral load. During chronic HIV infection, HIV-specific CD8(+) T cells are functionally impaired, showing a reduced capacity to produce cytokines and effector molecules as well as an impaired capacity to proliferate. Here, we found that PD-1 was upregulated on HIV-specific CD8(+) T cells; PD-1 expression levels were significantly correlated both with viral load and with the reduced capacity for cytokine production and proliferation of HIV-specific CD8(+) T cells. Notably, cytomegalovirus (CMV)-specific CD8(+) T cells from the same donors did not upregulate PD-1 and maintained the production of high levels of cytokines. Blocking PD-1 engagement to its ligand (PD-L1) enhanced the capacity of HIV-specific CD8(+) T cells to survive and proliferate and led to an increased production of cytokines and cytotoxic molecules in response to cognate antigen. The accumulation of HIV-specific dysfunctional CD8(+) T cells in the infected host could prevent the renewal of a functionally competent HIV-specific CD8(+) repertoire.", + "TAG_DATA": [ + "30, mice {'context': 'B-organism'}", + "43, T {'context': 'I-cells'}", + "44, cells {'context': 'I-cells'}", + "114, reduced {'effect': 'B-negative'}", + "123, CD8(+) {'context': 'I-cells'}", + "124, T {'context': 'I-cells'}", + "125, cells. {'context': 'I-cells'}", + "129, CD8(+) {'context': 'B-cells'}", + "130, T {'context': 'I-cells'}", + "131, cells {'context': 'I-cells'}", + "160, HIV-specific {'context': 'B-cells'}", + "161, CD8(+) {'context': 'I-cells'}", + "162, T {'context': 'I-cells'}", + "163, cells {'context': 'I-cells'}", + "167, proliferate {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "30, mice ['l0', 'l1']", + "43, T ['l0', 'l2']", + "44, cells ['l1', 'l2']", + "114, reduced ['l3', 'l4', 'l5', 'l6']", + "123, CD8(+) ['l3', 'l7', 'l8', 'l9', 'l10', 'l11']", + "124, T ['l4', 'l7', 'l12', 'l13', 'l14', 'l15']", + "125, cells. ['l5', 'l8', 'l12', 'l16']", + "129, CD8(+) ['l9', 'l13', 'l17', 'l18', 'l19', 'l20']", + "130, T ['l10', 'l14', 'l17', 'l21']", + "131, cells ['l6', 'l11', 'l15', 'l16', 'l18', 'l21']", + "160, HIV-specific ['l22', 'l23', 'l24', 'l25']", + "161, CD8(+) ['l22', 'l26', 'l27', 'l28']", + "162, T ['l19', 'l23', 'l26', 'l29', 'l30']", + "163, cells ['l20', 'l24', 'l27', 'l29', 'l31']", + "167, proliferate ['l25', 'l28', 'l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "T", + "cells.", + "cells" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HIV-specific", + "CD8(+)", + "T", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate" + ] + } + } + ] + }, + { + "PMID": "16906154", + "TEXT": "Hepatic glucose production is crucial for glucose homeostasis, and its dysregulation contributes to the pathogenesis of diabetes. Here, we show that members of the NR4A family of ligand-independent orphan nuclear receptors are downstream mediators of cAMP action in the hormonal control of gluconeogenesis. Hepatic expression of Nur77, Nurr1 and NOR1 is induced by the cAMP axis in response to glucagon and fasting in vivo and is increased in diabetic mice that exhibit elevated gluconeogenesis. Adenoviral expression of Nur77 induces genes involved in gluconeogenesis, stimulates glucose production both in vitro and in vivo, and raises blood glucose levels. Conversely, expression of an inhibitory mutant Nur77 receptor antagonizes gluconeogenic gene expression and lowers blood glucose levels in db/db mice. These results outline a previously unrecognized role for orphan nuclear receptors in the transcriptional control of glucose homeostasis.", + "TAG_DATA": [ + "74, Adenoviral {'perturbing_action': 'B-gene gain-of-function'}", + "75, expression {'perturbing_action': 'I-gene gain-of-function'}", + "76, of {'perturbing_action': 'I-gene gain-of-function'}", + "77, Nur77 {'perturbing_action': 'I-gene gain-of-function'}", + "87, in {'context': 'B-in vitro'}", + "88, vitro {'context': 'I-in vitro'}", + "90, in {'context': 'B-in vivo'}", + "91, vivo, {'context': 'I-in vivo'}", + "98, expression {'perturbing_action': 'B-other'}", + "99, of {'perturbing_action': 'I-other'}", + "100, an {'perturbing_action': 'I-other'}", + "101, inhibitory {'perturbing_action': 'I-other'}", + "102, mutant {'perturbing_action': 'I-other'}", + "103, Nur77 {'perturbing_action': 'I-other'}", + "104, receptor {'perturbing_action': 'I-other'}", + "115, db/db {'context': 'B-organism'}", + "116, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "74, Adenoviral ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "75, expression ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "76, of ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "77, Nur77 ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "87, in ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "88, vitro ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "90, in ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "91, vivo, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "98, expression ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "99, of ['l28', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "100, an ['l29', 'l36', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "101, inhibitory ['l30', 'l37', 'l43', 'l49', 'l50', 'l51', 'l52', 'l53']", + "102, mutant ['l31', 'l38', 'l44', 'l49', 'l54', 'l55', 'l56', 'l57']", + "103, Nur77 ['l32', 'l39', 'l45', 'l50', 'l54', 'l58', 'l59', 'l60']", + "104, receptor ['l33', 'l40', 'l46', 'l51', 'l55', 'l58', 'l61', 'l62']", + "115, db/db ['l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l61', 'l63']", + "116, mice. ['l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l62', 'l63']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenoviral", + "expression", + "of", + "Nur77" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenoviral", + "expression", + "of", + "Nur77" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "an", + "inhibitory", + "mutant", + "Nur77", + "receptor" + ] + }, + "context": { + "val": "organism", + "words": [ + "db/db", + "mice." + ] + } + } + ] + }, + { + "PMID": "16892061", + "TEXT": "Vascular smooth muscle cell (VSMC) apoptosis occurs in many arterial diseases, including aneurysm formation, angioplasty restenosis and atherosclerosis. Although VSMC apoptosis promotes vessel remodeling, coagulation and inflammation, its precise contribution to these diseases is unknown, given that apoptosis frequently accompanies vessel injury or alterations to flow. To study the direct consequences of VSMC apoptosis, we generated transgenic mice expressing the human diphtheria toxin receptor (hDTR, encoded by HBEGF) from a minimal Tagln (also known as SM22alpha) promoter. Despite apoptosis inducing loss of 50-70% of VSMCs, normal arteries showed no inflammation, reactive proliferation, thrombosis, remodeling or aneurysm formation. In contrast, VSMC apoptosis in atherosclerotic plaques of SM22alpha-hDTR Apoe-/- mice induced marked thinning of fibrous cap, loss of collagen and matrix, accumulation of cell debris and intense intimal inflammation. We conclude that VSMC apoptosis is 'silent' in normal arteries, which have a large capacity to withstand cell loss. In contrast, VSMC apoptosis alone is sufficient to induce features of plaque vulnerability in atherosclerosis. SM22alpha-hDTR Apoe-/- mice may represent an important new model to test agents proposed to stabilize atherosclerotic plaques.", + "TAG_DATA": [ + "56, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "57, mice {'context': 'B-organism'}", + "58, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "59, the {'perturbing_action': 'I-gene gain-of-function'}", + "60, human {'perturbing_action': 'I-gene gain-of-function'}", + "61, diphtheria {'perturbing_action': 'I-gene gain-of-function'}", + "62, toxin {'perturbing_action': 'I-gene gain-of-function'}", + "63, receptor {'perturbing_action': 'I-gene gain-of-function'}", + "64, (hDTR, {'perturbing_action': 'I-gene gain-of-function'}", + "65, encoded {'perturbing_action': 'I-gene gain-of-function'}", + "66, by {'perturbing_action': 'I-gene gain-of-function'}", + "67, HBEGF) {'perturbing_action': 'I-gene gain-of-function'}", + "68, from {'perturbing_action': 'I-gene gain-of-function'}", + "69, a {'perturbing_action': 'I-gene gain-of-function'}", + "76, promoter. {'perturbing_action': 'I-gene gain-of-function'}", + "84, VSMCs, {'context': 'B-cells'}", + "86, arteries {'context': 'B-tissue/organ'}", + "88, no {'effect': 'B-no effect'}", + "91, proliferation, {'phenotype': 'B-proliferation'}", + "99, VSMC {'context': 'B-cells'}", + "100, apoptosis {'phenotype': 'B-apoptosis'}", + "105, SM22alpha-hDTR {'perturbing_action': 'B-gene loss-of-function'}", + "106, Apoe-/- {'perturbing_action': 'B-gene loss-of-function'}", + "107, mice {'context': 'B-organism'}", + "161, SM22alpha-hDTR {'perturbing_action': 'B-gene loss-of-function'}", + "162, Apoe-/- {'perturbing_action': 'B-gene loss-of-function'}", + "163, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "57, mice ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "58, expressing ['l1', 'l20', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "59, the ['l2', 'l21', 'l38', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "60, human ['l3', 'l22', 'l39', 'l56', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "61, diphtheria ['l4', 'l23', 'l40', 'l57', 'l73', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "62, toxin ['l5', 'l24', 'l41', 'l58', 'l74', 'l89', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "63, receptor ['l6', 'l25', 'l42', 'l59', 'l75', 'l90', 'l104', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "64, (hDTR, ['l7', 'l26', 'l43', 'l60', 'l76', 'l91', 'l105', 'l118', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "65, encoded ['l8', 'l27', 'l44', 'l61', 'l77', 'l92', 'l106', 'l119', 'l131', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "66, by ['l9', 'l28', 'l45', 'l62', 'l78', 'l93', 'l107', 'l120', 'l132', 'l143', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163']", + "67, HBEGF) ['l10', 'l29', 'l46', 'l63', 'l79', 'l94', 'l108', 'l121', 'l133', 'l144', 'l154', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "68, from ['l11', 'l30', 'l47', 'l64', 'l80', 'l95', 'l109', 'l122', 'l134', 'l145', 'l155', 'l164', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180']", + "69, a ['l12', 'l31', 'l48', 'l65', 'l81', 'l96', 'l110', 'l123', 'l135', 'l146', 'l156', 'l165', 'l173', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "70, minimal ['l13', 'l32', 'l49', 'l66', 'l82', 'l97', 'l111', 'l124', 'l136', 'l147', 'l157', 'l166', 'l174', 'l181', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "71, Tagln ['l14', 'l50', 'l67', 'l83', 'l98', 'l112', 'l125', 'l137', 'l148', 'l158', 'l167', 'l175', 'l182', 'l188', 'l194', 'l195', 'l196', 'l197', 'l198']", + "76, promoter. ['l15', 'l33', 'l51', 'l68', 'l84', 'l99', 'l113', 'l126', 'l138', 'l149', 'l159', 'l168', 'l176', 'l183', 'l189', 'l194', 'l199', 'l200', 'l201', 'l202']", + "84, VSMCs, ['l16', 'l34', 'l52', 'l69', 'l85', 'l100', 'l114', 'l127', 'l139', 'l150', 'l160', 'l169', 'l177', 'l184', 'l190', 'l195', 'l199', 'l203', 'l204', 'l205']", + "86, arteries ['l17', 'l35', 'l53', 'l70', 'l86', 'l101', 'l115', 'l128', 'l140', 'l151', 'l161', 'l170', 'l178', 'l185', 'l191', 'l196', 'l200', 'l203', 'l206', 'l207']", + "88, no ['l18', 'l36', 'l54', 'l71', 'l87', 'l102', 'l116', 'l129', 'l141', 'l152', 'l162', 'l171', 'l179', 'l186', 'l192', 'l197', 'l201', 'l204', 'l206', 'l208']", + "91, proliferation, ['l19', 'l37', 'l55', 'l72', 'l88', 'l103', 'l117', 'l130', 'l142', 'l153', 'l163', 'l172', 'l180', 'l187', 'l193', 'l198', 'l202', 'l205', 'l207', 'l208']", + "99, VSMC ['l209', 'l210', 'l211', 'l212']", + "100, apoptosis ['l209', 'l213', 'l214', 'l215']", + "105, SM22alpha-hDTR ['l210', 'l213', 'l216', 'l217']", + "106, Apoe-/- ['l211', 'l214', 'l216', 'l218']", + "107, mice ['l212', 'l215', 'l217', 'l218']", + "161, SM22alpha-hDTR ['l219', 'l220']", + "162, Apoe-/- ['l219', 'l221']", + "163, mice ['l220', 'l221']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "the", + "human", + "diphtheria", + "toxin", + "receptor", + "(hDTR,", + "encoded", + "by", + "HBEGF)", + "from", + "a", + "promoter." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "the", + "human", + "diphtheria", + "toxin", + "receptor", + "(hDTR,", + "encoded", + "by", + "HBEGF)", + "from", + "a", + "promoter." + ] + }, + "context": { + "val": "cells", + "words": [ + "VSMCs," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "the", + "human", + "diphtheria", + "toxin", + "receptor", + "(hDTR,", + "encoded", + "by", + "HBEGF)", + "from", + "a", + "promoter." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "arteries" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "the", + "human", + "diphtheria", + "toxin", + "receptor", + "(hDTR,", + "encoded", + "by", + "HBEGF)", + "from", + "a", + "promoter." + ] + }, + "effect": { + "val": "no effect", + "words": [ + "no" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "the", + "human", + "diphtheria", + "toxin", + "receptor", + "(hDTR,", + "encoded", + "by", + "HBEGF)", + "from", + "a", + "promoter." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "no" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "VSMCs," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "no" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "VSMCs," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "arteries" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "no" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "arteries" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "no" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "VSMC" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "VSMC" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SM22alpha-hDTR", + "Apoe-/-" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SM22alpha-hDTR", + "Apoe-/-" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SM22alpha-hDTR", + "Apoe-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "16892036", + "TEXT": "Bidirectional cellular communication is integral to both cancer progression and embryological development. In addition, aggressive tumor cells are phenotypically plastic, sharing many properties with embryonic cells. Owing to the similarities between these two types of cells, the developing zebrafish can be used as a biosensor for tumor-derived signals. Using this system, we show that aggressive melanoma cells secrete Nodal (a potent embryonic morphogen) and consequently can induce ectopic formation of the embryonic axis. We further show that Nodal is present in human metastatic tumors, but not in normal skin, and thus may be involved in melanoma pathogenesis. Inhibition of Nodal signaling reduces melanoma cell invasiveness, colony formation and tumorigenicity. Nodal inhibition also promotes the reversion of melanoma cells toward a melanocytic phenotype. These data suggest that Nodal signaling has a key role in melanoma cell plasticity and tumorigenicity, thereby providing a previously unknown molecular target for regulating tumor progression.", + "TAG_DATA": [ + "101, reduces {'effect': 'B-negative'}", + "102, melanoma {'context': 'B-transformed cells'}", + "103, cell {'context': 'I-transformed cells'}", + "104, invasiveness, {'phenotype': 'B-invasion'}", + "105, colony {'phenotype': 'B-colony formation'}", + "106, formation {'phenotype': 'I-colony formation'}", + "108, tumorigenicity. {'phenotype': 'B-tumourigenesis'}", + "109, Nodal {'perturbing_action': 'B-pharmacological inhibition'}", + "110, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "116, melanoma {'context': 'B-transformed cells'}", + "117, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "101, reduces ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "102, melanoma ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "103, cell ['l1', 'l6', 'l11', 'l12', 'l13']", + "104, invasiveness, ['l2', 'l7', 'l11', 'l14', 'l15', 'l16']", + "105, colony ['l3', 'l8', 'l12', 'l14', 'l17', 'l18']", + "106, formation ['l4', 'l9', 'l13', 'l15', 'l17', 'l19']", + "108, tumorigenicity. ['l5', 'l10', 'l16', 'l18', 'l19']", + "109, Nodal ['l20', 'l21', 'l22']", + "110, inhibition ['l20', 'l23', 'l24']", + "116, melanoma ['l21', 'l23', 'l25']", + "117, cells ['l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "colony", + "formation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cell" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cell" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "colony", + "formation" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "melanoma" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Nodal", + "inhibition" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cells" + ] + } + } + ] + }, + { + "PMID": "16862156", + "TEXT": "Immune responses arise from a wide variety of cells expressing unique combinations of multiple cell-surface proteins. Detailed characterization is hampered, however, by limitations in available probes and instrumentation. Here, we use the unique spectral properties of semiconductor nanocrystals (quantum dots) to extend the capabilities of polychromatic flow cytometry to resolve 17 fluorescence emissions. We show the need for this power by analyzing, in detail, the phenotype of multiple antigen-specific T-cell populations, revealing variations within complex phenotypic patterns that would otherwise remain obscure. For example, T cells specific for distinct epitopes from one pathogen, and even those specific for the same epitope, can have markedly different phenotypes. The technology we describe, encompassing the detection of eight quantum dots in conjunction with conventional fluorophores, should expand the horizons of flow cytometry, as well as our ability to characterize the intricacies of both adaptive and innate cellular immune responses.", + "TAG_DATA": [ + "84, T {'context': 'B-cells'}", + "85, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "84, T ['l0']", + "85, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16862155", + "TEXT": "A genetic polymorphism in the human gene encoding connexin37 (CX37, encoded by GJA4, also known as CX37) has been reported as a potential prognostic marker for atherosclerosis. The expression of this gap-junction protein is altered in mouse and human atherosclerotic lesions: it disappears from the endothelium of advanced plaques but is detected in macrophages recruited to the lesions. The role of CX37 in atherogenesis, however, remains unknown. Here we have investigated the effect of deleting the mouse connexin37 (Cx37) gene (Gja4, also known as Cx37) on atherosclerosis in apolipoprotein E-deficient (Apoe(-/-)) mice, an animal model of this disease. We find that Gja4(-/-)Apoe(-/-) mice develop more aortic lesions than Gja4(+/+)Apoe(-/-) mice that express Cx37. Using in vivo adoptive transfer, we show that monocyte and macrophage recruitment is enhanced by eliminating expression of Cx37 in these leukocytes but not by eliminating its expression in the endothelium. We further show that Cx37 hemichannel activity in primary monocytes, macrophages and a macrophage cell line (H36.12j) inhibits leukocyte adhesion. This antiadhesive effect is mediated by release of ATP into the extracellular space. Thus, Cx37 hemichannels may control initiation of the development of atherosclerotic plaques by regulating monocyte adhesion. H36.12j macrophages expressing either of the two CX37 proteins encoded by a polymorphism in the human GJA4 gene show differential ATP-dependent adhesion. These results provide a potential mechanism by which a polymorphism in CX37 protects against atherosclerosis.", + "TAG_DATA": [ + "74, deleting {'perturbing_action': 'B-gene loss-of-function'}", + "75, the {'perturbing_action': 'I-gene loss-of-function'}", + "76, mouse {'perturbing_action': 'I-gene loss-of-function'}", + "77, connexin37 {'perturbing_action': 'I-gene loss-of-function'}", + "78, (Cx37) {'perturbing_action': 'I-gene loss-of-function'}", + "79, gene {'perturbing_action': 'I-gene loss-of-function'}", + "80, (Gja4, {'perturbing_action': 'I-gene loss-of-function'}", + "81, also {'perturbing_action': 'I-gene loss-of-function'}", + "84, Cx37) {'perturbing_action': 'I-gene loss-of-function'}", + "88, apolipoprotein {'perturbing_action': 'B-gene loss-of-function'}", + "89, E-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "90, (Apoe(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "91, mice, {'context': 'B-organism'}", + "101, Gja4(-/-)Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "102, mice {'context': 'B-organism'}", + "108, Gja4(+/+)Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "109, mice {'context': 'B-organism'}", + "114, in {'context': 'B-in vivo'}", + "115, vivo {'context': 'I-in vivo'}", + "128, eliminating {'perturbing_action': 'B-gene loss-of-function'}", + "129, expression {'perturbing_action': 'I-gene loss-of-function'}", + "130, of {'perturbing_action': 'I-gene loss-of-function'}", + "131, Cx37 {'perturbing_action': 'I-gene loss-of-function'}", + "134, leukocytes {'context': 'B-cells'}", + "152, primary {'context': 'B-cells'}", + "153, monocytes, {'context': 'I-cells'}", + "154, macrophages {'context': 'I-cells'}", + "157, macrophage {'context': 'B-cells'}", + "158, cell {'context': 'I-cells'}", + "159, line {'context': 'I-cells'}", + "160, (H36.12j) {'context': 'I-cells'}", + "161, inhibits {'effect': 'B-negative'}", + "162, leukocyte {'context': 'B-cells'}", + "163, adhesion. {'phenotype': 'B-adhesion'}" + ], + "LINK_DATA": [ + "74, deleting ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "75, the ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "76, mouse ['l1', 'l12', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "77, connexin37 ['l2', 'l13', 'l26', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "78, (Cx37) ['l3', 'l14', 'l27', 'l39', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "79, gene ['l4', 'l15', 'l28', 'l40', 'l51', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "80, (Gja4, ['l5', 'l16', 'l29', 'l41', 'l52', 'l62', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "81, also ['l6', 'l17', 'l30', 'l42', 'l53', 'l63', 'l71', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "84, Cx37) ['l7', 'l18', 'l31', 'l43', 'l54', 'l64', 'l72', 'l77', 'l83', 'l84', 'l85', 'l86']", + "88, apolipoprotein ['l8', 'l19', 'l32', 'l44', 'l55', 'l65', 'l73', 'l78', 'l83', 'l87', 'l88', 'l89']", + "89, E-deficient ['l9', 'l20', 'l33', 'l45', 'l56', 'l66', 'l74', 'l79', 'l84', 'l87', 'l90', 'l91']", + "90, (Apoe(-/-)) ['l10', 'l21', 'l34', 'l46', 'l57', 'l67', 'l75', 'l80', 'l85', 'l88', 'l90', 'l92']", + "91, mice, ['l11', 'l22', 'l35', 'l47', 'l58', 'l68', 'l76', 'l81', 'l86', 'l89', 'l91', 'l92']", + "101, Gja4(-/-)Apoe(-/-) ['l23', 'l36', 'l48', 'l59', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "102, mice ['l24', 'l37', 'l49', 'l60', 'l69', 'l82', 'l93', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "108, Gja4(+/+)Apoe(-/-) ['l94', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "109, mice ['l95', 'l112', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "114, in ['l96', 'l105', 'l113', 'l123', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "115, vivo ['l97', 'l106', 'l114', 'l124', 'l133', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "128, eliminating ['l98', 'l107', 'l115', 'l125', 'l134', 'l141', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "129, expression ['l99', 'l108', 'l116', 'l126', 'l135', 'l142', 'l148', 'l155', 'l156', 'l157', 'l158', 'l159']", + "130, of ['l100', 'l109', 'l117', 'l127', 'l136', 'l143', 'l149', 'l155', 'l160', 'l161', 'l162', 'l163']", + "131, Cx37 ['l101', 'l110', 'l118', 'l128', 'l137', 'l144', 'l150', 'l156', 'l160', 'l164', 'l165', 'l166']", + "134, leukocytes ['l25', 'l38', 'l50', 'l61', 'l70', 'l102', 'l111', 'l119', 'l129', 'l138', 'l145', 'l151', 'l157', 'l161', 'l164', 'l167', 'l168']", + "152, primary ['l120', 'l130', 'l152', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177']", + "153, monocytes, ['l103', 'l121', 'l131', 'l139', 'l146', 'l153', 'l158', 'l162', 'l165', 'l167', 'l169', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185']", + "154, macrophages ['l104', 'l122', 'l132', 'l140', 'l147', 'l154', 'l159', 'l163', 'l166', 'l168', 'l170', 'l178', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192']", + "157, macrophage ['l171', 'l179', 'l186', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198']", + "158, cell ['l172', 'l180', 'l187', 'l193', 'l199', 'l200', 'l201', 'l202', 'l203']", + "159, line ['l173', 'l181', 'l188', 'l194', 'l199', 'l204', 'l205', 'l206', 'l207']", + "160, (H36.12j) ['l174', 'l182', 'l189', 'l195', 'l200', 'l204', 'l208', 'l209', 'l210']", + "161, inhibits ['l175', 'l183', 'l190', 'l196', 'l201', 'l205', 'l208', 'l211', 'l212']", + "162, leukocyte ['l176', 'l184', 'l191', 'l197', 'l202', 'l206', 'l209', 'l211', 'l213']", + "163, adhesion. ['l177', 'l185', 'l192', 'l198', 'l203', 'l207', 'l210', 'l212', 'l213']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deleting", + "the", + "mouse", + "connexin37", + "(Cx37)", + "gene", + "(Gja4,", + "also", + "Cx37)", + "apolipoprotein", + "E-deficient", + "(Apoe(-/-))", + "Gja4(-/-)Apoe(-/-)", + "eliminating", + "expression", + "of", + "Cx37", + "Gja4(+/+)Apoe(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "mouse", + "connexin37", + "(Cx37)", + "gene", + "Gja4(-/-)Apoe(-/-)", + "Gja4(+/+)Apoe(-/-)", + "eliminating", + "expression", + "of", + "Cx37" + ] + }, + "context": { + "val": "cells", + "words": [ + "leukocytes", + "monocytes,", + "macrophages", + "primary" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gja4(-/-)Apoe(-/-)", + "Gja4(+/+)Apoe(-/-)", + "eliminating", + "expression", + "of", + "Cx37" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "primary", + "monocytes,", + "macrophages", + "macrophage", + "cell", + "line", + "(H36.12j)", + "leukocyte" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "primary", + "monocytes,", + "macrophages", + "macrophage", + "cell", + "line", + "(H36.12j)", + "leukocyte" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion." + ] + } + } + ] + }, + { + "PMID": "16862153", + "TEXT": "Imatinib mesylate (Gleevec) is a small-molecule inhibitor of the fusion protein Bcr-Abl, the causal agent in chronic myelogenous leukemia. Here we report ten individuals who developed severe congestive heart failure while on imatinib and we show that imatinib-treated mice develop left ventricular contractile dysfunction. Transmission electron micrographs from humans and mice treated with imatinib show mitochondrial abnormalities and accumulation of membrane whorls in both vacuoles and the sarco- (endo-) plasmic reticulum, findings suggestive of a toxic myopathy. With imatinib treatment, cardiomyocytes in culture show activation of the endoplasmic reticulum (ER) stress response, collapse of the mitochondrial membrane potential, release of cytochrome c into the cytosol, reduction in cellular ATP content and cell death. Retroviral gene transfer of an imatinib-resistant mutant of c-Abl, alleviation of ER stress or inhibition of Jun amino-terminal kinases, which are activated as a consequence of ER stress, largely rescues cardiomyocytes from imatinib-induced death. Thus, cardiotoxicity is an unanticipated side effect of inhibition of c-Abl by imatinib.", + "TAG_DATA": [ + "38, mice {'context': 'B-organism'}", + "48, humans {'context': 'B-organism'}", + "50, mice {'context': 'B-organism'}", + "80, cardiomyocytes {'context': 'B-cells'}", + "82, culture {'context': 'I-in vitro'}", + "111, cell {'phenotype': 'B-cell death'}", + "112, death. {'phenotype': 'I-cell death'}", + "113, Retroviral {'perturbing_action': 'B-other'}", + "114, gene {'perturbing_action': 'I-other'}", + "115, transfer {'perturbing_action': 'I-other'}", + "116, of {'perturbing_action': 'I-other'}", + "117, an {'perturbing_action': 'I-other'}", + "118, imatinib-resistant {'perturbing_action': 'I-other'}", + "119, mutant {'perturbing_action': 'I-other'}", + "120, of {'perturbing_action': 'I-other'}", + "121, c-Abl, {'perturbing_action': 'I-other'}", + "143, cardiomyocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "38, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "48, humans ['l0', 'l5', 'l6', 'l7', 'l8']", + "50, mice ['l1', 'l5', 'l9', 'l10', 'l11']", + "80, cardiomyocytes ['l12', 'l13', 'l14']", + "82, culture ['l2', 'l6', 'l9', 'l12', 'l15', 'l16']", + "111, cell ['l3', 'l7', 'l10', 'l13', 'l15', 'l17']", + "112, death. ['l4', 'l8', 'l11', 'l14', 'l16', 'l17']", + "113, Retroviral ['l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "114, gene ['l18', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "115, transfer ['l19', 'l27', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "116, of ['l20', 'l28', 'l35', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "117, an ['l21', 'l29', 'l36', 'l42', 'l48', 'l49', 'l50', 'l51', 'l52']", + "118, imatinib-resistant ['l22', 'l30', 'l37', 'l43', 'l48', 'l53', 'l54', 'l55', 'l56']", + "119, mutant ['l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l57', 'l58', 'l59']", + "120, of ['l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l60', 'l61']", + "121, c-Abl, ['l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l58', 'l60', 'l62']", + "143, cardiomyocytes ['l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "humans" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cardiomyocytes" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Retroviral", + "gene", + "transfer", + "of", + "an", + "imatinib-resistant", + "mutant", + "c-Abl," + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes" + ] + } + } + ] + }, + { + "PMID": "16862152", + "TEXT": "Stress can alter immunological, neurochemical and endocrinological functions, but its role in cancer progression is not well understood. Here, we show that chronic behavioral stress results in higher levels of tissue catecholamines, greater tumor burden and more invasive growth of ovarian carcinoma cells in an orthotopic mouse model. These effects are mediated primarily through activation of the tumor cell cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway by the beta(2) adrenergic receptor (encoded by ADRB2). Tumors in stressed animals showed markedly increased vascularization and enhanced expression of VEGF, MMP2 and MMP9, and we found that angiogenic processes mediated the effects of stress on tumor growth in vivo. These data identify beta-adrenergic activation of the cAMP-PKA signaling pathway as a major mechanism by which behavioral stress can enhance tumor angiogenesis in vivo and thereby promote malignant cell growth. These data also suggest that blocking ADRB-mediated angiogenesis could have therapeutic implications for the management of ovarian cancer.", + "TAG_DATA": [ + "32, greater {'effect': 'B-positive'}", + "33, tumor {'phenotype': 'B-tumourigenesis'}", + "34, burden {'phenotype': 'I-tumourigenesis'}", + "36, more {'effect': 'B-positive'}", + "37, invasive {'phenotype': 'B-tumour growth'}", + "38, growth {'phenotype': 'I-invasion'}", + "40, ovarian {'context': 'B-transformed cells'}", + "41, carcinoma {'context': 'I-transformed cells'}", + "42, cells {'context': 'I-transformed cells'}", + "45, orthotopic {'context': 'B-organism'}", + "46, mouse {'context': 'I-organism'}", + "47, model. {'context': 'I-organism'}", + "75, Tumors {'context': 'B-neoplasm'}", + "78, animals {'context': 'B-organism'}", + "103, tumor {'phenotype': 'B-tumour growth'}", + "104, growth {'phenotype': 'I-tumour growth'}", + "105, in {'context': 'B-in vivo'}", + "106, vivo. {'context': 'I-in vivo'}", + "129, in {'context': 'B-in vivo'}", + "130, vivo {'context': 'I-in vivo'}", + "133, promote {'effect': 'B-positive'}", + "135, cell {'phenotype': 'B-cell growth'}", + "136, growth. {'phenotype': 'I-cell growth'}" + ], + "LINK_DATA": [ + "32, greater ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "33, tumor ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "34, burden ['l1', 'l7', 'l12', 'l13', 'l14', 'l15']", + "36, more ['l2', 'l8', 'l12', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "37, invasive ['l3', 'l9', 'l13', 'l16', 'l23', 'l24', 'l25', 'l26', 'l27']", + "38, growth ['l4', 'l10', 'l14', 'l17', 'l23', 'l28', 'l29', 'l30', 'l31']", + "40, ovarian ['l5', 'l18', 'l24', 'l28', 'l32', 'l33', 'l34', 'l35']", + "41, carcinoma ['l19', 'l25', 'l29', 'l32', 'l36', 'l37', 'l38', 'l39']", + "42, cells ['l6', 'l11', 'l15', 'l20', 'l26', 'l30', 'l33', 'l36', 'l40']", + "45, orthotopic ['l37', 'l41', 'l42', 'l43', 'l44']", + "46, mouse ['l21', 'l34', 'l38', 'l41', 'l45']", + "47, model. ['l22', 'l27', 'l31', 'l35', 'l39', 'l40', 'l42', 'l45']", + "75, Tumors ['l43', 'l46']", + "78, animals ['l44', 'l46']", + "103, tumor ['l47', 'l48', 'l49']", + "104, growth ['l47', 'l50', 'l51']", + "105, in ['l48', 'l50', 'l52']", + "106, vivo. ['l49', 'l51', 'l52']", + "129, in ['l53', 'l54', 'l55', 'l56']", + "130, vivo ['l53', 'l57', 'l58', 'l59']", + "133, promote ['l54', 'l57', 'l60', 'l61']", + "135, cell ['l55', 'l58', 'l60', 'l62']", + "136, growth. ['l56', 'l59', 'l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "greater", + "more" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "burden" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "greater", + "more" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "invasive" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "greater", + "more" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "greater", + "more" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "cells", + "carcinoma" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "burden" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "more" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "invasive" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "carcinoma", + "cells" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "invasive" + ] + }, + "context": { + "val": "organism", + "words": [ + "model." + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "growth" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "carcinoma", + "cells" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "model." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promote" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth." + ] + } + } + ] + }, + { + "PMID": "16845389", + "TEXT": "Obesity is a major health problem and a risk factor for type 2 diabetes. Leptin, an adipocyte-secreted hormone, acts on the hypothalamus to inhibit food intake and increase energy expenditure. Most obese individuals develop hyperleptinemia and leptin resistance, limiting the therapeutic efficacy of exogenously administered leptin. Mice lacking the tyrosine phosphatase PTP1B are protected from diet-induced obesity and are hypersensitive to leptin, but the site and mechanism for these effects remain controversial. We generated tissue-specific PTP1B knockout (Ptpn1(-/-)) mice. Neuronal Ptpn1(-/-) mice have reduced weight and adiposity, and increased activity and energy expenditure. In contrast, adipose PTP1B deficiency increases body weight, whereas PTP1B deletion in muscle or liver does not affect weight. Neuronal Ptpn1(-/-) mice are hypersensitive to leptin, despite paradoxically elevated leptin levels, and show improved glucose homeostasis. Thus, PTP1B regulates body mass and adiposity primarily through actions in the brain. Furthermore, neuronal PTP1B regulates adipocyte leptin production and probably is essential for the development of leptin resistance.", + "TAG_DATA": [ + "74, tissue-specific {'perturbing_action': 'B-gene loss-of-function'}", + "75, PTP1B {'perturbing_action': 'I-gene loss-of-function'}", + "76, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "77, (Ptpn1(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "78, mice. {'context': 'B-organism'}", + "79, Neuronal {'perturbing_action': 'B-gene loss-of-function'}", + "80, Ptpn1(-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "81, mice {'context': 'B-organism'}", + "95, adipose {'perturbing_action': 'B-gene loss-of-function'}", + "96, PTP1B {'perturbing_action': 'I-gene loss-of-function'}", + "97, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "102, PTP1B {'perturbing_action': 'B-gene loss-of-function'}", + "103, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "105, muscle {'context': 'B-tissue/organ'}", + "107, liver {'context': 'B-tissue/organ'}", + "112, Neuronal {'perturbing_action': 'B-gene loss-of-function'}", + "113, Ptpn1(-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "114, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "74, tissue-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "75, PTP1B ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "76, knockout ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "77, (Ptpn1(-/-)) ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "78, mice. ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "79, Neuronal ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "80, Ptpn1(-/-) ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27', 'l28']", + "81, mice ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "95, adipose ['l29', 'l30']", + "96, PTP1B ['l29', 'l31', 'l32', 'l33']", + "97, deficiency ['l28', 'l30', 'l31']", + "102, PTP1B ['l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "103, deletion ['l34', 'l40', 'l41', 'l42']", + "105, muscle ['l35', 'l40', 'l43', 'l44']", + "106, or ['l32', 'l36', 'l41', 'l43', 'l45']", + "107, liver ['l33', 'l37', 'l42', 'l44', 'l45']", + "112, Neuronal ['l46', 'l47']", + "113, Ptpn1(-/-) ['l38', 'l46', 'l48']", + "114, mice ['l39', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "tissue-specific", + "PTP1B", + "knockout", + "(Ptpn1(-/-))", + "Neuronal", + "Ptpn1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PTP1B", + "deletion" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver", + "muscle" + ] + } + } + ] + }, + { + "PMID": "16819551", + "TEXT": "In rodents, after spinal lesion, neutralizing the neurite growth inhibitor Nogo-A promotes axonal sprouting and functional recovery. To evaluate this treatment in primates, 12 monkeys were subjected to cervical lesion. Recovery of manual dexterity and sprouting of corticospinal axons were enhanced in monkeys treated with Nogo-A-specific antibody as compared to monkeys treated with control antibody.", + "TAG_DATA": [ + "22, primates, {'context': 'B-organism'}", + "24, monkeys {'context': 'B-organism'}", + "37, corticospinal {'context': 'B-cells'}", + "38, axons {'context': 'I-cells'}", + "42, monkeys {'context': 'B-organism'}", + "50, monkeys {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "22, primates, ['l0', 'l1']", + "24, monkeys ['l0']", + "37, corticospinal ['l2', 'l3', 'l4']", + "38, axons ['l1', 'l2', 'l5', 'l6']", + "42, monkeys ['l3', 'l5', 'l7']", + "50, monkeys ['l4', 'l6', 'l7']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16799556", + "TEXT": "The sensitivity of conventional DNA sequencing in tumor biopsies is limited by stromal contamination and by genetic heterogeneity within the cancer. Here, we show that microreactor-based pyrosequencing can detect rare cancer-associated sequence variations by independent and parallel sampling of multiple representatives of a given DNA fragment. This technology can thereby facilitate accurate molecular diagnosis of heterogeneous cancer specimens and enable patient selection for targeted cancer therapies.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16783371", + "TEXT": "Schistosomes are blood-dwelling flukes that infect 200 million people worldwide and are responsible for hundreds of thousands of deaths annually. Using a signal sequence trap, we cloned from Schistosoma mansoni two cDNAs, Sm-tsp-1 and Sm-tsp-2, encoding the tetraspanin (TSP) integral membrane proteins TSP-1 and TSP-2. We raised antibodies to recombinant TSP fusion proteins and showed that both proteins are exposed on the surface of S. mansoni. Recombinant TSP-2, but not TSP-1, is strongly recognized by IgG1 and IgG3 (but not IgE) from naturally resistant individuals but is not recognized by IgG from chronically infected or unexposed individuals. Vaccination of mice with the recombinant proteins followed by challenge infection with S. mansoni resulted in reductions of 57% and 64% (TSP-2) and 34% and 52% (TSP-1) for mean adult worm burdens and liver egg burdens, respectively, over two independent trials. Fecal egg counts were reduced by 65-69% in both test groups. TSP-2 in particular provided protection in excess of the 40% benchmark set by the World Health Organization for progression of schistosome vaccine antigens into clinical trials. When coupled with its selective recognition by naturally resistant people, TSP-2 seems to be an effective vaccine antigen against S. mansoni.", + "TAG_DATA": [ + "99, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16767099", + "TEXT": "Recent molecular genetics studies implicate neuregulin 1 (NRG1) and its receptor erbB in the pathophysiology of schizophrenia. Among NRG1 receptors, erbB4 is of particular interest because of its crucial roles in neurodevelopment and in the modulation of N-methyl-D-aspartate (NMDA) receptor signaling. Here, using a new postmortem tissue-stimulation approach, we show a marked increase in NRG1-induced activation of erbB4 in the prefrontal cortex in schizophrenia. Levels of NRG1 and erbB4, however, did not differ between schizophrenia and control groups. To evaluate possible causes for this hyperactivation of erbB4 signaling, we examined the association of erbB4 with PSD-95 (postsynaptic density protein of 95 kDa), as this association has been shown to facilitate activation of erbB4. Schizophrenia subjects showed substantial increases in erbB4-PSD-95 interactions. We found that NRG1 stimulation suppresses NMDA receptor activation in the human prefrontal cortex, as previously reported in the rodent cortex. NRG1-induced suppression of NMDA receptor activation was more pronounced in schizophrenia subjects than in controls, consistent with enhanced NRG1-erbB4 signaling seen in this illness. Therefore, these findings suggest that enhanced NRG1 signaling may contribute to NMDA hypofunction in schizophrenia.", + "TAG_DATA": [ + "132, human {'context': 'B-tissue/organ'}", + "133, prefrontal {'context': 'I-tissue/organ'}", + "134, cortex, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "132, human ['l0', 'l1']", + "133, prefrontal ['l0', 'l2']", + "134, cortex, ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16751768", + "TEXT": "The urinary tract functions in close proximity to the outside environment, yet must remain free of microbial colonization to avoid disease. The mechanisms for establishing an antimicrobial barrier in this area are not completely understood. Here, we describe the production and function of the cathelicidin antimicrobial peptides LL-37, its precursor hCAP-18 and its ortholog CRAMP in epithelial cells of human and mouse urinary tract, respectively. Bacterial contact with epithelial cells resulted in rapid production and secretion of the respective peptides, and in humans LL-37/hCAP-18 was released into urine. Epithelium-derived cathelicidin substantially contributed to the protection of the urinary tract against infection, as shown using CRAMP-deficient and neutrophil-depleted mice. In addition, clinical E. coli strains that were more resistant to LL-37 caused more severe urinary tract infections than did susceptible strains. Thus, cathelicidin seems to be a key factor in mucosal immunity of the urinary tract.", + "TAG_DATA": [ + "56, epithelial {'context': 'B-cells'}", + "57, cells {'context': 'I-cells'}", + "59, human {'context': 'B-tissue/organ'}", + "60, and {'context': 'I-tissue/organ'}", + "61, mouse {'context': 'I-tissue/organ'}", + "62, urinary {'context': 'I-tissue/organ'}", + "63, tract, {'context': 'I-tissue/organ'}", + "97, urinary {'context': 'B-tissue/organ'}", + "98, tract {'context': 'I-tissue/organ'}", + "104, CRAMP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "107, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, epithelial ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "57, cells ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "59, human ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "60, and ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "61, mouse ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "62, urinary ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "63, tract, ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "97, urinary ['l21', 'l22']", + "98, tract ['l21', 'l23']", + "104, CRAMP-deficient ['l24']", + "107, mice. ['l22', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CRAMP-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "16751767", + "TEXT": "Preeclampsia is a pregnancy-specific hypertensive syndrome that causes substantial maternal and fetal morbidity and mortality. Maternal endothelial dysfunction mediated by excess placenta-derived soluble VEGF receptor 1 (sVEGFR1 or sFlt1) is emerging as a prominent component in disease pathogenesis. We report a novel placenta-derived soluble TGF-beta coreceptor, endoglin (sEng), which is elevated in the sera of preeclamptic individuals, correlates with disease severity and falls after delivery. sEng inhibits formation of capillary tubes in vitro and induces vascular permeability and hypertension in vivo. Its effects in pregnant rats are amplified by coadministration of sFlt1, leading to severe preeclampsia including the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and restriction of fetal growth. sEng impairs binding of TGF-beta1 to its receptors and downstream signaling including effects on activation of eNOS and vasodilation, suggesting that sEng leads to dysregulated TGF-beta signaling in the vasculature. Our results suggest that sEng may act in concert with sFlt1 to induce severe preeclampsia.", + "TAG_DATA": [ + "71, in {'context': 'B-in vitro'}", + "72, vitro {'context': 'I-in vitro'}", + "79, in {'context': 'B-in vivo'}", + "80, vivo. {'context': 'I-in vivo'}", + "84, pregnant {'context': 'B-organism'}", + "85, rats {'context': 'I-organism'}", + "90, of {'perturbing_action': 'I-gene gain-of-function'}", + "91, sFlt1, {'perturbing_action': 'I-gene gain-of-function'}", + "107, restriction {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "71, in ['l0']", + "72, vitro ['l0']", + "79, in ['l1']", + "80, vivo. ['l1']", + "84, pregnant ['l2', 'l3', 'l4', 'l5']", + "85, rats ['l2', 'l6', 'l7']", + "90, of ['l3', 'l6', 'l8', 'l9']", + "91, sFlt1, ['l4', 'l7', 'l8', 'l10']", + "107, restriction ['l5', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "pregnant", + "rats" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "sFlt1," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "pregnant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "restriction" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "sFlt1," + ] + }, + "effect": { + "val": "negative", + "words": [ + "restriction" + ] + } + } + ] + }, + { + "PMID": "16732282", + "TEXT": "Selective inhibitors of cyclooxygenase-2 (COX2) have attracted widespread media attention because of evidence of an elevated risk of cardiovascular complications in placebo-controlled trials, resulting in the market withdrawal of some members of this class. These drugs block the cyclooxygenase activity of prostaglandin H synthase-2 (PGHS2), but do not affect the associated peroxidase function. They were developed with the rationale of conserving the anti-inflammatory and analgesic actions of traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) while sparing the ability of PGHS1-derived prostaglandins to afford gastric cytoprotection. PGHS1 and PGHS2 coexist in the vasculature and in macrophages, and are upregulated together in inflammatory tissues such as rheumatoid synovia and atherosclerotic plaque. They are each believed to function as homodimers. Here, we developed a new genetic mouse model of selective COX2 inhibition using a gene-targeted point mutation, resulting in a Y385F substitution. Structural modeling and biochemical assays showed the ability of PGHS1 and PGHS2 to heterodimerize and form prostaglandins. The heterodimerization of PGHS1-PGHS2 may explain how the ductus arteriosus closes normally at birth in mice expressing PGHS2 Y385F, but not in PGHS2-null mice.", + "TAG_DATA": [ + "121, mouse {'context': 'I-organism'}", + "122, model {'context': 'I-organism'}", + "124, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "125, COX2 {'perturbing_action': 'I-pharmacological inhibition'}", + "126, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "129, gene-targeted {'perturbing_action': 'B-other'}", + "130, point {'perturbing_action': 'I-other'}", + "131, mutation, {'perturbing_action': 'I-other'}", + "169, mice {'context': 'B-organism'}", + "176, PGHS2-null {'perturbing_action': 'B-gene loss-of-function'}", + "177, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "121, mouse ['l0', 'l1', 'l2', 'l3', 'l4']", + "122, model ['l0', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "124, selective ['l1', 'l5', 'l11', 'l12', 'l13', 'l14', 'l15']", + "125, COX2 ['l2', 'l6', 'l11', 'l16', 'l17', 'l18', 'l19']", + "126, inhibition ['l3', 'l7', 'l12', 'l16', 'l20', 'l21', 'l22']", + "129, gene-targeted ['l8', 'l13', 'l17', 'l20', 'l23', 'l24']", + "130, point ['l4', 'l9', 'l14', 'l18', 'l21', 'l23', 'l25']", + "131, mutation, ['l10', 'l15', 'l19', 'l22', 'l24', 'l25']", + "169, mice ['l26', 'l27']", + "176, PGHS2-null ['l26', 'l28']", + "177, mice. ['l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "COX2", + "inhibition" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "point", + "gene-targeted", + "mutation," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PGHS2-null" + ] + } + } + ] + }, + { + "PMID": "16604089", + "TEXT": "The hypothalamus responds to circulating leptin and insulin in the control of food intake and body weight. A number of neurotransmitters in the hypothalamus, including gamma-aminobutyric acid (GABA), also have key roles in feeding. Huntingtin-associated protein 1 (Hap1) is expressed more abundantly in the hypothalamus than in other brain regions, and lack of Hap1 in mice leads to early postnatal death. Hap1 is also involved in intracellular trafficking of the GABA(A) receptor. Here, we report that fasting upregulates the expression of Hap1 in the rodent hypothalamus, whereas intracerebroventricular administration of insulin downregulates Hap1 by increasing its degradation through ubiquitination. Decreasing the expression of mouse hypothalamic Hap1 by siRNA reduces the level and activity of hypothalamic GABA(A) receptors and causes a decrease in food intake and body weight. These findings provide evidence linking hypothalamic Hap1 to GABA in the stimulation of feeding and suggest that this mechanism is involved in the feeding-inhibitory actions of insulin in the brain.", + "TAG_DATA": [ + "84, rodent {'context': 'B-tissue/organ'}", + "85, hypothalamus, {'context': 'I-tissue/organ'}", + "99, Decreasing {'perturbing_action': 'B-rnai/knockdown'}", + "100, the {'perturbing_action': 'I-rnai/knockdown'}", + "101, expression {'perturbing_action': 'I-rnai/knockdown'}", + "102, of {'perturbing_action': 'I-rnai/knockdown'}", + "103, mouse {'perturbing_action': 'I-rnai/knockdown', 'context': 'B-tissue/organ'}", + "104, hypothalamic {'perturbing_action': 'I-rnai/knockdown', 'context': 'I-tissue/organ'}", + "105, Hap1 {'perturbing_action': 'I-rnai/knockdown'}", + "106, by {'perturbing_action': 'I-rnai/knockdown'}", + "107, siRNA {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "84, rodent ['l0']", + "85, hypothalamus, ['l0']", + "99, Decreasing ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "100, the ['l1', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "101, expression ['l2', 'l9', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "102, of ['l3', 'l10', 'l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "103, mouse ['l4', 'l11', 'l17', 'l22', 'l27', 'l28', 'l29', 'l30']", + "104, hypothalamic ['l5', 'l12', 'l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "105, Hap1 ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "106, by ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "107, siRNA ['l8', 'l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Decreasing", + "the", + "expression", + "of", + "mouse", + "hypothalamic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "hypothalamic" + ] + } + } + ] + }, + { + "PMID": "16604087", + "TEXT": "CTLA-4 is a negative regulator of T-cell activation, and its inhibitory effects can be accomplished either by competition with CD28 or by transmitting negative signals through its intracellular domain. To utilize the cytoplasmic domain of CTLA-4 to suppress allergic inflammation, we fused it to a novel protein-transduction domain in the human transcriptional factor Hph-1. Transduction efficiency was verified in vitro and in vivo after ocular, intranasal and intradermal administration. After transduction into T cells, the Hph-1-ctCTLA-4 fusion protein inhibited the production of interleukin (IL)-2, and downregulated CD69 and CD25. Intranasal administration of Hph-1-ctCTLA-4 resulted in markedly reduced infiltration of inflammatory cells, secretion of T helper type 2 (T(H)2) cytokines, serum IgE levels and airway hyper-responsiveness in a mouse model of allergic airway inflammation. These results indicated that Hph-1-ctCTLA-4 constitutes an effective immunosuppressive protein drug for potential use in the treatment of allergic asthma, via nasal administration.", + "TAG_DATA": [ + "58, in {'context': 'B-in vitro'}", + "59, vitro {'context': 'I-in vitro'}", + "61, in {'context': 'B-in vivo'}", + "62, vivo {'context': 'I-in vivo'}", + "72, T {'context': 'B-cells'}", + "73, cells, {'context': 'I-cells'}", + "100, cells, {'context': 'B-cells'}", + "117, mouse {'context': 'B-organism'}", + "118, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "58, in ['l0']", + "59, vitro ['l0']", + "61, in ['l1', 'l2', 'l3']", + "62, vivo ['l1', 'l4', 'l5']", + "72, T ['l2', 'l4', 'l6']", + "73, cells, ['l3', 'l5', 'l6']", + "117, mouse ['l7']", + "118, model ['l7']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16604086", + "TEXT": "Leptin controls food intake by regulating the transcription of key neuropeptides in the hypothalamus. The mechanism by which leptin regulates gene expression is unclear, however. Here we show that delivery of adenovirus encoding a constitutively nuclear mutant FoxO1, a transcription factor known to control liver metabolism and pancreatic beta-cell function, to the hypothalamic arcuate nucleus of rodents results in a loss of the ability of leptin to curtail food intake and suppress expression of Agrp. Conversely, a transactivation-deficient FoxO1 mutant prevents induction of Agrp by fasting. We also find that FoxO1 and the transcription factor Stat3 exert opposing actions on the expression of Agrp and Pomc through transcriptional squelching. FoxO1 promotes opposite patterns of coactivator-corepressor exchange at the Pomc and Agrp promoters, resulting in activation of Agrp and inhibition of Pomc. Thus, FoxO1 represents a shared component of pathways integrating food intake and peripheral metabolism.", + "TAG_DATA": [ + "31, adenovirus {'perturbing_action': 'B-other'}", + "32, encoding {'perturbing_action': 'I-other'}", + "33, a {'perturbing_action': 'I-other'}", + "34, constitutively {'perturbing_action': 'I-other'}", + "35, nuclear {'perturbing_action': 'I-other'}", + "36, mutant {'perturbing_action': 'I-other'}", + "37, FoxO1, {'perturbing_action': 'I-other'}", + "52, hypothalamic {'context': 'B-tissue/organ'}", + "53, arcuate {'context': 'I-tissue/organ'}", + "54, nucleus {'context': 'I-tissue/organ'}", + "56, rodents {'context': 'B-organism'}", + "77, transactivation-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "78, FoxO1 {'perturbing_action': 'I-other'}", + "79, mutant {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "31, adenovirus ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "32, encoding ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "33, a ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "34, constitutively ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "35, nuclear ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "36, mutant ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "37, FoxO1, ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "52, hypothalamic ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "53, arcuate ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "54, nucleus ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "56, rodents ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "77, transactivation-deficient ['l55', 'l56']", + "78, FoxO1 ['l55', 'l57']", + "79, mutant ['l56', 'l57']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "adenovirus", + "encoding", + "a", + "constitutively", + "nuclear", + "mutant", + "FoxO1," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hypothalamic", + "arcuate", + "nucleus" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "adenovirus", + "encoding", + "a", + "constitutively", + "nuclear", + "mutant", + "FoxO1," + ] + }, + "context": { + "val": "organism", + "words": [ + "rodents" + ] + } + } + ] + }, + { + "PMID": "16604085", + "TEXT": "High systemic drug toxicity and increasing prevalence of drug resistance hampers efficient treatment of human African trypanosomiasis (HAT). Hence, development of new highly specific trypanocidal drugs is necessary. Normal human serum (NHS) contains apolipoprotein L-I (apoL-I), which lyses African trypanosomes except resistant forms such as Trypanosoma brucei rhodesiense. T. b. rhodesiense expresses the apoL-I-neutralizing serum resistance-associated (SRA) protein, endowing this parasite with the ability to infect humans and cause HAT. A truncated apoL-I (Tr-apoL-I) has been engineered by deleting its SRA-interacting domain, which makes it lytic for T. b. rhodesiense. Here, we conjugated Tr-apoL-I with a single-domain antibody (nanobody) that efficiently targets conserved cryptic epitopes of the variant surface glycoprotein (VSG) of trypanosomes to generate a new manmade type of immunotoxin with potential for trypanosomiasis therapy. Treatment with this engineered conjugate resulted in clear curative and alleviating effects on acute and chronic infections of mice with both NHS-resistant and NHS-sensitive trypanosomes.", + "TAG_DATA": [ + "144, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "79, its ['l0', 'l1']", + "80, SRA-interacting ['l0', 'l2']", + "81, domain, ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16565724", + "TEXT": "We found that one-third of human sebaceous tumors examined had double-nucleotide substitutions in the same LEF1 allele, irrespective of DNA mismatch repair status. The mutations impaired both LEF1 binding to beta-catenin and transcriptional activation, and are the first tumor-associated mutations that inactivate Wnt signaling. Mutant LEF1 not only inhibited expression of beta-catenin target genes but also stimulated expression of sebocyte markers, suggesting that it may determine the differentiated characteristics of sebaceous tumors.", + "TAG_DATA": [ + "5, human {'context': 'B-neoplasm'}", + "6, sebaceous {'context': 'I-neoplasm'}", + "44, Mutant {'perturbing_action': 'B-other'}", + "45, LEF1 {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "5, human ['l0', 'l1']", + "6, sebaceous ['l0', 'l2']", + "7, tumors ['l1', 'l2']", + "44, Mutant ['l3']", + "45, LEF1 ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16565723", + "TEXT": "Matrix metalloproteinases (MMPs) are zinc-endopeptidases with multifactorial actions in central nervous system (CNS) physiology and pathology. Accumulating data suggest that MMPs have a deleterious role in stroke. By degrading neurovascular matrix, MMPs promote injury of the blood-brain barrier, edema and hemorrhage. By disrupting cell-matrix signaling and homeostasis, MMPs trigger brain cell death. Hence, there is a movement toward the development of MMP inhibitors for acute stroke therapy. But MMPs may have a different role during delayed phases after stroke. Because MMPs modulate brain matrix, they may mediate beneficial plasticity and remodeling during stroke recovery. Here, we show that MMPs participate in delayed cortical responses after focal cerebral ischemia in rats. MMP-9 is upregulated in peri-infarct cortex at 7-14 days after stroke and is colocalized with markers of neurovascular remodeling. Treatment with MMP inhibitors at 7 days after stroke suppresses neurovascular remodeling, increases ischemic brain injury and impairs functional recovery at 14 days. MMP processing of bioavailable VEGF may be involved because inhibition of MMPs reduces endogenous VEGF signals, whereas additional treatment with exogenous VEGF prevents MMP inhibitor-induced worsening of infarction. These data suggest that, contrary to MMP inhibitor therapies for acute stroke, strategies that modulate MMPs may be needed for promoting stroke recovery.", + "TAG_DATA": [ + "109, rats. {'context': 'B-organism'}", + "131, MMP {'perturbing_action': 'B-pharmacological inhibition'}", + "132, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "131, MMP ['l0']", + "132, inhibitors ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16565722", + "TEXT": "Hematopoietic stem cells (HSCs) undergo self-renewing cell divisions and maintain blood production for their lifetime. Appropriate control of HSC self-renewal is crucial for the maintenance of hematopoietic homeostasis. Here we show that activation of p38 MAPK in response to increasing levels of reactive oxygen species (ROS) limits the lifespan of HSCs in vivo. In Atm(-/-) mice, elevation of ROS levels induces HSC-specific phosphorylation of p38 MAPK accompanied by a defect in the maintenance of HSC quiescence. Inhibition of p38 MAPK rescued ROS-induced defects in HSC repopulating capacity and in the maintenance of HSC quiescence, indicating that the ROS-p38 MAPK pathway contributes to exhaustion of the stem cell population. Furthermore, prolonged treatment with an antioxidant or an inhibitor of p38 MAPK extended the lifespan of HSCs from wild-type mice in serial transplantation experiments. These data show that inactivation of p38 MAPK protects HSCs against loss of self-renewal capacity. Our characterization of molecular mechanisms that limit HSC lifespan may lead to beneficial therapies for human disease.", + "TAG_DATA": [ + "51, in {'context': 'B-in vivo'}", + "52, vivo. {'context': 'I-in vivo'}", + "54, Atm(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "55, mice, {'context': 'B-organism'}", + "72, maintenance {'effect': 'B-negative'}", + "74, HSC {'context': 'B-cells'}", + "75, quiescence. {'phenotype': 'B-quiescence'}", + "76, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "77, of {'perturbing_action': 'I-pharmacological inhibition'}", + "78, p38 {'perturbing_action': 'I-pharmacological inhibition'}", + "79, MAPK {'perturbing_action': 'I-pharmacological inhibition'}", + "84, HSC {'context': 'B-cells'}", + "90, maintenance {'effect': 'B-regulates'}", + "92, HSC {'context': 'B-cells'}", + "93, quiescence, {'phenotype': 'B-quiescence'}", + "116, inhibitor {'perturbing_action': 'B-pharmacological inhibition'}", + "117, of {'perturbing_action': 'I-pharmacological inhibition'}", + "118, p38 {'perturbing_action': 'I-pharmacological inhibition'}", + "119, MAPK {'perturbing_action': 'I-pharmacological inhibition'}", + "124, HSCs {'context': 'B-cells'}", + "127, mice {'context': 'B-organism'}", + "136, inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "137, of {'perturbing_action': 'I-gene loss-of-function'}", + "138, p38 {'perturbing_action': 'I-gene loss-of-function'}", + "139, MAPK {'perturbing_action': 'I-gene loss-of-function'}", + "141, HSCs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "51, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "52, vivo. ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "54, Atm(-/-) ['l1', 'l6', 'l11', 'l12', 'l13', 'l14', 'l15']", + "55, mice, ['l2', 'l7', 'l11', 'l16', 'l17', 'l18']", + "72, maintenance ['l3', 'l8', 'l12', 'l16', 'l19', 'l20']", + "74, HSC ['l4', 'l9', 'l13', 'l17', 'l19', 'l21']", + "75, quiescence. ['l5', 'l10', 'l14', 'l18', 'l20', 'l21']", + "76, Inhibition ['l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "77, of ['l22', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "78, p38 ['l23', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "79, MAPK ['l24', 'l30', 'l35', 'l40', 'l41', 'l42', 'l43']", + "84, HSC ['l15', 'l25', 'l31', 'l36', 'l40', 'l44', 'l45', 'l46']", + "90, maintenance ['l26', 'l32', 'l37', 'l41', 'l44', 'l47', 'l48']", + "92, HSC ['l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l49']", + "93, quiescence, ['l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l49']", + "116, inhibitor ['l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "117, of ['l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "118, p38 ['l51', 'l57', 'l63', 'l64', 'l65', 'l66']", + "119, MAPK ['l52', 'l58', 'l63', 'l67', 'l68', 'l69']", + "124, HSCs ['l53', 'l59', 'l64', 'l67', 'l70']", + "127, mice ['l54', 'l60', 'l65', 'l68', 'l70']", + "136, inactivation ['l55', 'l61', 'l71', 'l72', 'l73', 'l74']", + "137, of ['l71', 'l75', 'l76', 'l77']", + "138, p38 ['l72', 'l75', 'l78', 'l79']", + "139, MAPK ['l73', 'l76', 'l78', 'l80']", + "141, HSCs ['l56', 'l62', 'l66', 'l69', 'l74', 'l77', 'l79', 'l80']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atm(-/-)" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "effect": { + "val": "negative", + "words": [ + "maintenance" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atm(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atm(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "maintenance" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atm(-/-)", + "inactivation", + "of", + "p38", + "MAPK" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC", + "HSCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atm(-/-)" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "negative", + "words": [ + "maintenance" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "maintenance" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "maintenance" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSC" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence.", + "quiescence," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "p38", + "MAPK", + "inhibitor" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC", + "HSCs" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "p38", + "MAPK" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "maintenance" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "p38", + "MAPK" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSC" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "maintenance" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "maintenance" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitor", + "of", + "p38", + "MAPK" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "16520777", + "TEXT": "Cancer develops from normal tissues through the accumulation of genetic alterations that act in concert to confer malignant phenotypes. Although we have now identified some of the genes that when mutated initiate tumor formation and drive cancer progression, the identity of the cell population(s) susceptible to such transforming events remains undefined for the majority of human cancers. Recent work indicates that a small population of cells endowed with unique self-renewal properties and tumorigenic potential is present in some, and perhaps all, tumors. Although our understanding of the biology of these putative cancer stem cells remains rudimentary, the existence of such cells has implications for current conceptualizations of malignant transformation and therapeutic approaches to cancer.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16520776", + "TEXT": "Upon transmission to a new host, HIV targets CCR5+ CD4+ effector memory T cells, resulting in acute, massive depletion of these cells from mucosal effector sites. This depletion does not initially compromise the regenerative capacity of the immune system because naive and most central memory T cells are spared. Here, we discuss evidence suggesting that frequent activation of these spared cells during the chronic phase of HIV infection supplies mucosal tissues with short-lived CCR5+ CD4+ effector cells that prevent life-threatening infections. This immune activation also facilitates continued viral replication, but infection and killing of target T cells by HIV are selective and the impact on effector-cell lifespan is limited. We propose, however, that persistent activation progressively disrupts the functional organization of the immune system, reducing its regenerative capacity and facilitating viral evolution that leads to loss of the exquisite target cell-sparing selectivity of viral replication, ultimately resulting in AIDS.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16491085", + "TEXT": "We show here that children with pyridoxine-dependent seizures (PDS) have mutations in the ALDH7A1 gene, which encodes antiquitin; these mutations abolish the activity of antiquitin as a delta1-piperideine-6-carboxylate (P6C)-alpha-aminoadipic semialdehyde (alpha-AASA) dehydrogenase. The accumulating P6C inactivates pyridoxal 5'-phosphate (PLP) by forming a Knoevenagel condensation product. Measurement of urinary alpha-AASA provides a simple way of confirming the diagnosis of PDS and ALDH7A1 gene analysis provides a means for prenatal diagnosis.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16474399", + "TEXT": "CD8+ T cells can mediate eradication of established tumors, and strategies to amplify tumor-reactive T-cell numbers by immunization or ex vivo expansion followed by adoptive transfer are currently being explored in individuals with cancer. Generating effective CD8+ T cell-mediated responses to tumors is often impeded by T-cell tolerance to relevant tumor antigens, as most of these antigens are also expressed in normal tissues. We examined whether such tolerant T cells could be rescued and functionally restored for use in therapy of established tumors. We used a transgenic T-cell receptor (TCR) mouse model in which peripheral CD8+ T cells specific for a candidate tumor antigen also expressed in liver are tolerant, failing to proliferate or secrete interleukin (IL)-2 in response to antigen. Molecular and cellular analysis showed that these tolerant T cells expressed the IL-15 receptor alpha chain, and could be induced to proliferate in vitro in response to exogenous IL-15. Such proliferation abrogated tolerance and the rescued cells became effective in treating leukemia. Therefore, high-affinity CD8+ T cells are not necessarily deleted by encounter with self-antigen in the periphery, and can potentially be rescued and expanded for use in tumor immunotherapy.", + "TAG_DATA": [ + "86, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "87, T-cell {'perturbing_action': 'I-gene gain-of-function'}", + "88, receptor {'perturbing_action': 'I-gene gain-of-function'}", + "89, (TCR) {'perturbing_action': 'I-gene gain-of-function'}", + "90, mouse {'context': 'B-organism'}", + "91, model {'context': 'I-organism'}", + "94, peripheral {'context': 'B-cells'}", + "95, CD8+ {'context': 'I-cells'}", + "96, T {'context': 'I-cells'}", + "97, cells {'context': 'I-cells'}", + "110, failing {'effect': 'B-negative'}", + "111, to {'effect': 'I-negative'}", + "112, proliferate {'phenotype': 'B-proliferation'}", + "129, T {'context': 'B-cells'}", + "130, cells {'context': 'I-cells'}", + "140, induced {'effect': 'B-positive'}", + "142, proliferate {'phenotype': 'B-proliferation'}", + "143, in {'context': 'B-in vitro'}", + "144, vitro {'context': 'I-in vitro'}", + "151, proliferation {'phenotype': 'B-proliferation'}", + "157, cells {'context': 'B-cells'}", + "162, leukemia. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "86, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "87, T-cell ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "88, receptor ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "89, (TCR) ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "90, mouse ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "91, model ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "94, peripheral ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "95, CD8+ ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "96, T ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "97, cells ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "110, failing ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "111, to ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "112, proliferate ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "129, T ['l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "130, cells ['l78', 'l84', 'l85', 'l86', 'l87']", + "140, induced ['l79', 'l84', 'l88', 'l89', 'l90', 'l91']", + "142, proliferate ['l80', 'l85', 'l88', 'l92', 'l93', 'l94']", + "143, in ['l81', 'l86', 'l89', 'l92', 'l95', 'l96']", + "144, vitro ['l82', 'l87', 'l90', 'l93', 'l95', 'l97']", + "151, proliferation ['l83', 'l91', 'l94', 'l96', 'l97']", + "157, cells ['l98']", + "162, leukemia. ['l98']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "T-cell", + "receptor", + "(TCR)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "T-cell", + "receptor", + "(TCR)" + ] + }, + "context": { + "val": "cells", + "words": [ + "peripheral", + "CD8+", + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "T-cell", + "receptor", + "(TCR)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "failing", + "to" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "T-cell", + "receptor", + "(TCR)" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "effect": { + "val": "negative", + "words": [ + "failing", + "to" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "peripheral", + "CD8+", + "T", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "failing", + "to" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "peripheral", + "CD8+", + "T", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate", + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "failing", + "to" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate", + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate", + "proliferation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "16462801", + "TEXT": "Three percent of the world's population is chronically infected with the hepatitis C virus (HCV) and at risk of developing liver cancer. Effective cellular immune responses are deemed essential for spontaneous resolution of acute hepatitis C and long-term protection. Here we describe a new T-cell HCV genetic vaccine capable of protecting chimpanzees from acute hepatitis induced by challenge with heterologous virus. Suppression of acute viremia in vaccinated chimpanzees occurred as a result of massive expansion of peripheral and intrahepatic HCV-specific CD8(+) T lymphocytes that cross-reacted with vaccine and virus epitopes. These findings show that it is possible to elicit effective immunity against heterologous HCV strains by stimulating only the cellular arm of the immune system, and suggest a path for new immunotherapy against highly variable human pathogens like HCV, HIV or malaria, which can evade humoral responses.", + "TAG_DATA": [ + "51, chimpanzees {'context': 'B-organism'}", + "67, chimpanzees {'context': 'B-organism'}", + "80, CD8(+) {'context': 'B-cells'}", + "81, T {'context': 'I-cells'}", + "82, lymphocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "67, chimpanzees ['l0', 'l1', 'l2']", + "80, CD8(+) ['l0', 'l3', 'l4']", + "81, T ['l1', 'l3', 'l5']", + "82, lymphocytes ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16444267", + "TEXT": "For the majority of Duchenne muscular dystrophy (DMD) mutations, antisense oligonucleotide (AON)-mediated exon skipping has the potential to restore a functional protein. Here we show that weekly intravenous injections of morpholino phosphorodiamidate (morpholino) AONs induce expression of functional levels of dystrophin in body-wide skeletal muscles of the dystrophic mdx mouse, with resulting improvement in muscle function. Although the level of dystrophin expression achieved varies considerably between muscles, antisense therapy may provide a realistic hope for the treatment of a majority of individuals with DMD.", + "TAG_DATA": [ + "43, skeletal {'context': 'I-tissue/organ'}", + "44, muscles {'context': 'I-tissue/organ'}", + "47, dystrophic {'context': 'B-organism'}", + "48, mdx {'context': 'I-organism'}", + "49, mouse, {'context': 'I-organism'}", + "54, muscle {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "43, skeletal ['l0', 'l1', 'l2', 'l3', 'l4']", + "44, muscles ['l0', 'l5', 'l6', 'l7', 'l8']", + "47, dystrophic ['l1', 'l5', 'l9', 'l10', 'l11']", + "48, mdx ['l2', 'l6', 'l9', 'l12', 'l13']", + "49, mouse, ['l3', 'l7', 'l10', 'l12', 'l14']", + "54, muscle ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16341242", + "TEXT": "The in vivo regulation of hematopoietic stem cell (HSC) function is poorly understood. Here, we show that hematopoietic repopulation can be augmented by administration of a glycogen synthase kinase-3 (GSK-3) inhibitor to recipient mice transplanted with mouse or human HSCs. GSK-3 inhibitor treatment improved neutrophil and megakaryocyte recovery, recipient survival and resulted in enhanced sustained long-term repopulation. The output of primitive Lin(-)c-Kit(+)Sca-1(+) cells and progenitors from HSCs increased upon GSK-3 inhibitor treatment without altering secondary repopulating ability, suggesting that the HSC pool is maintained while overall hematopoietic reconstitution is increased. GSK-3 inhibitors were found to modulate gene targets of Wnt, Hedgehog and Notch pathways in cells comprising the primitive hematopoietic compartment without affecting mature cells. Our study establishes GSK-3 as a specific in vivo modulator of HSC activity, and suggests that administration of GSK-3 inhibitors may provide a clinical means to directly enhance the repopulating capacity of transplanted HSCs.", + "TAG_DATA": [ + "26, glycogen {'perturbing_action': 'B-pharmacological inhibition'}", + "27, synthase {'perturbing_action': 'I-pharmacological inhibition'}", + "28, kinase-3 {'perturbing_action': 'I-pharmacological inhibition'}", + "29, (GSK-3) {'perturbing_action': 'I-pharmacological inhibition'}", + "30, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "33, mice {'context': 'B-organism'}", + "36, mouse {'context': 'B-transformed cells'}", + "37, or {'context': 'I-cells'}", + "38, human {'context': 'I-cells'}", + "39, HSCs. {'context': 'I-cells'}", + "40, GSK-3 {'perturbing_action': 'B-pharmacological inhibition'}", + "41, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "42, treatment {'perturbing_action': 'I-pharmacological inhibition'}", + "62, cells {'context': 'I-cells'}", + "66, HSCs {'context': 'B-cells'}", + "69, GSK-3 {'perturbing_action': 'B-pharmacological inhibition'}", + "70, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "71, treatment {'perturbing_action': 'I-pharmacological inhibition'}", + "90, GSK-3 {'perturbing_action': 'B-pharmacological inhibition'}", + "91, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "105, cells {'context': 'B-cells'}", + "106, comprising {'context': 'I-cells'}", + "109, hematopoietic {'context': 'I-cells'}", + "110, compartment {'context': 'I-cells'}", + "113, mature {'context': 'B-cells'}", + "114, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "26, glycogen ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "27, synthase ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "28, kinase-3 ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "29, (GSK-3) ['l2', 'l13', 'l23', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "30, inhibitor ['l3', 'l14', 'l24', 'l31', 'l38', 'l39', 'l40', 'l41', 'l42']", + "33, mice ['l4', 'l15', 'l25', 'l32', 'l38']", + "36, mouse ['l5', 'l16', 'l26', 'l33', 'l39', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "37, or ['l6', 'l17', 'l27', 'l34', 'l40', 'l43', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "38, human ['l7', 'l18', 'l28', 'l35', 'l41', 'l44', 'l49', 'l55', 'l56', 'l57', 'l58', 'l59']", + "39, HSCs. ['l8', 'l19', 'l29', 'l36', 'l42', 'l45', 'l50', 'l55', 'l60', 'l61', 'l62', 'l63']", + "40, GSK-3 ['l51', 'l56', 'l60', 'l64', 'l65', 'l66', 'l67', 'l68']", + "41, inhibitor ['l9', 'l20', 'l46', 'l52', 'l57', 'l61', 'l64', 'l69', 'l70', 'l71']", + "42, treatment ['l10', 'l21', 'l30', 'l37', 'l47', 'l53', 'l58', 'l62', 'l65', 'l69', 'l72', 'l73']", + "62, cells ['l11', 'l22', 'l48', 'l54', 'l59', 'l63', 'l66', 'l70', 'l72', 'l74', 'l75', 'l76']", + "66, HSCs ['l67', 'l71', 'l73', 'l74', 'l77', 'l78', 'l79']", + "69, GSK-3 ['l77', 'l80', 'l81']", + "70, inhibitor ['l75', 'l78', 'l80', 'l82']", + "71, treatment ['l68', 'l76', 'l79', 'l81', 'l82']", + "90, GSK-3 ['l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "91, inhibitors ['l83', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "105, cells ['l84', 'l91', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "106, comprising ['l85', 'l92', 'l98', 'l104', 'l105', 'l106', 'l107', 'l108']", + "107, the ['l86', 'l93', 'l99', 'l104', 'l109', 'l110', 'l111', 'l112']", + "109, hematopoietic ['l87', 'l94', 'l100', 'l105', 'l109', 'l113', 'l114', 'l115']", + "110, compartment ['l88', 'l95', 'l101', 'l106', 'l110', 'l113', 'l116', 'l117']", + "113, mature ['l89', 'l96', 'l102', 'l107', 'l111', 'l114', 'l116', 'l118']", + "114, cells. ['l90', 'l97', 'l103', 'l108', 'l112', 'l115', 'l117', 'l118']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "glycogen", + "synthase", + "kinase-3", + "(GSK-3)", + "inhibitor" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "glycogen", + "synthase", + "kinase-3", + "(GSK-3)", + "inhibitor", + "treatment" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "glycogen", + "synthase", + "kinase-3", + "(GSK-3)", + "inhibitor", + "GSK-3", + "treatment", + "inhibitors" + ] + }, + "context": { + "val": "cells", + "words": [ + "or", + "human", + "HSCs.", + "cells", + "HSCs", + "comprising", + "hematopoietic", + "compartment", + "mature", + "cells." + ] + } + } + ] + }, + { + "PMID": "16311604", + "TEXT": "We transplanted kidneys from alpha1,3-galactosyltransferase knockout (GalT-KO) pigs into six baboons using two different immunosuppressive regimens, but most of the baboons died from severe acute humoral xenograft rejection. Circulating induced antibodies to non-Gal antigens were markedly elevated at rejection, which mediated strong complement-dependent cytotoxicity against GalT-KO porcine target cells. These data suggest that antibodies to non-Gal antigens will present an additional barrier to transplantation of organs from GalT-KO pigs to humans.", + "TAG_DATA": [ + "2, kidneys {'context': 'I-tissue/organ'}", + "4, alpha1,3-galactosyltransferase {'perturbing_action': 'B-gene loss-of-function'}", + "5, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "6, (GalT-KO) {'perturbing_action': 'I-gene loss-of-function'}", + "7, pigs {'context': 'B-tissue/organ'}", + "10, baboons {'context': 'B-organism'}", + "20, baboons {'context': 'B-organism'}", + "26, xenograft {'context': 'B-xenograft'}", + "45, GalT-KO {'perturbing_action': 'B-gene loss-of-function'}", + "46, porcine {'context': 'B-cells'}", + "47, target {'context': 'I-cells'}", + "48, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "2, kidneys ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "4, alpha1,3-galactosyltransferase ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "5, knockout ['l1', 'l7', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "6, (GalT-KO) ['l2', 'l8', 'l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "7, pigs ['l3', 'l9', 'l16', 'l22', 'l28', 'l29', 'l30']", + "10, baboons ['l4', 'l10', 'l17', 'l23', 'l28', 'l31']", + "20, baboons ['l5', 'l11', 'l18', 'l24', 'l29', 'l32']", + "26, xenograft ['l6', 'l12', 'l19', 'l25', 'l30', 'l31', 'l32']", + "45, GalT-KO ['l33', 'l34', 'l35']", + "46, porcine ['l33', 'l36', 'l37']", + "47, target ['l13', 'l20', 'l26', 'l34', 'l36', 'l38']", + "48, cells. ['l14', 'l21', 'l27', 'l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "kidneys", + "pigs" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha1,3-galactosyltransferase", + "knockout", + "(GalT-KO)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha1,3-galactosyltransferase", + "knockout", + "(GalT-KO)" + ] + }, + "context": { + "val": "organism", + "words": [ + "baboons" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha1,3-galactosyltransferase", + "knockout", + "(GalT-KO)" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha1,3-galactosyltransferase", + "knockout", + "(GalT-KO)", + "GalT-KO" + ] + }, + "context": { + "val": "cells", + "words": [ + "target", + "cells.", + "porcine" + ] + } + } + ] + }, + { + "PMID": "16311603", + "TEXT": "Abdominal aortic aneurysm (AAA) is a common disease among elderly people that, when surgical treatment is inapplicable, results in progressive expansion and rupture of the aorta with high mortality. Although nonsurgical treatment for AAA is much awaited, few options are available because its molecular pathogenesis remains elusive. Here, we identify JNK as a proximal signaling molecule in the pathogenesis of AAA. Human AAA tissue showed a high level of phosphorylated JNK. We show that JNK programs a gene expression pattern in different cell types that cooperatively enhances the degradation of the extracellular matrix while suppressing biosynthetic enzymes of the extracellular matrix. Selective inhibition of JNK in vivo not only prevented the development of AAA but also caused regression of established AAA in two mouse models. Thus, JNK promotes abnormal extracellular matrix metabolism in the tissue of AAA and may represent a therapeutic target.", + "TAG_DATA": [ + "101, Selective {'perturbing_action': 'B-pharmacological inhibition'}", + "102, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "103, of {'perturbing_action': 'I-pharmacological inhibition'}", + "104, JNK {'perturbing_action': 'I-pharmacological inhibition'}", + "105, in {'context': 'B-in vivo'}", + "106, vivo {'context': 'I-in vivo'}", + "109, prevented {'effect': 'B-negative'}", + "116, caused {'effect': 'B-positive'}", + "117, regression {'phenotype': 'B-tumour regression'}", + "118, of {'phenotype': 'I-tumour regression'}", + "120, AAA {'context': 'B-neoplasm'}", + "123, mouse {'context': 'B-organism'}", + "124, models. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "101, Selective ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "102, inhibition ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "103, of ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "104, JNK ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "105, in ['l3', 'l15', 'l26', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "106, vivo ['l4', 'l16', 'l27', 'l37', 'l45', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "109, prevented ['l5', 'l17', 'l28', 'l38', 'l46', 'l54', 'l61', 'l62']", + "113, AAA ['l6', 'l18', 'l29', 'l39', 'l47', 'l55', 'l61']", + "116, caused ['l7', 'l19', 'l30', 'l40', 'l48', 'l56', 'l62', 'l63', 'l64', 'l65']", + "117, regression ['l8', 'l20', 'l31', 'l41', 'l49', 'l57', 'l63', 'l66', 'l67', 'l68', 'l69']", + "118, of ['l9', 'l21', 'l32', 'l42', 'l50', 'l58', 'l64', 'l66', 'l70', 'l71', 'l72']", + "120, AAA ['l10', 'l22', 'l33', 'l43', 'l51', 'l59', 'l65', 'l67', 'l70', 'l73', 'l74']", + "123, mouse ['l11', 'l23', 'l34', 'l52', 'l68', 'l71', 'l73', 'l75']", + "124, models. ['l12', 'l24', 'l35', 'l44', 'l53', 'l60', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Selective", + "inhibition", + "of", + "JNK" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Selective", + "inhibition", + "of", + "JNK" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Selective", + "inhibition", + "of", + "JNK" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Selective", + "inhibition", + "of", + "JNK" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression", + "of" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Selective", + "inhibition", + "of", + "JNK" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "AAA" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Selective", + "inhibition", + "of", + "JNK" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression", + "of" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression", + "of" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "AAA" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression", + "of" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "AAA" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + } + ] + }, + { + "PMID": "16311602", + "TEXT": "Nitrative stress has an important role in microvascular degeneration leading to ischemia in conditions such as diabetic retinopathy and retinopathy of prematurity. Thus far, mediators of nitrative stress have been poorly characterized. We recently described that trans-arachidonic acids are major products of NO(2)(*)-mediated isomerization of arachidonic acid within the cell membrane, but their biological relevance is unknown. Here we show that trans-arachidonic acids are generated in a model of retinal microangiopathy in vivo in a NO(*)-dependent manner. They induce a selective time- and concentration-dependent apoptosis of microvascular endothelial cells in vitro, and result in retinal microvascular degeneration ex vivo and in vivo. These effects are mediated by an upregulation of the antiangiogenic factor thrombospondin-1, independently of classical arachidonic acid metabolism. Our findings provide new insight into the molecular mechanisms of nitrative stress in microvascular injury and suggest new therapeutic avenues in the management of disorders involving nitrative stress, such as ischemic retinopathies and encephalopathies.", + "TAG_DATA": [ + "78, induce {'effect': 'B-positive'}", + "84, apoptosis {'phenotype': 'B-apoptosis'}", + "86, microvascular {'context': 'B-cells'}", + "87, endothelial {'context': 'I-cells'}", + "88, cells {'context': 'I-cells'}", + "89, in {'context': 'B-in vitro'}", + "90, vitro, {'context': 'I-in vitro'}", + "100, in {'context': 'B-in vivo'}", + "101, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "78, induce ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "84, apoptosis ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "86, microvascular ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "87, endothelial ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "88, cells ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "89, in ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "90, vitro, ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "100, in ['l21']", + "101, vivo. ['l21']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "microvascular", + "endothelial", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "microvascular", + "endothelial", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + } + ] + }, + { + "PMID": "16286923", + "TEXT": "R-Ras is a small GTPase of the Ras family that regulates cell survival and integrin activity. Despite a number of in vitro studies, the in vivo function of R-Ras remains unclear. Here, we used R-Ras-null mice to explore the in vivo function of this small GTPase. Our results show a role for R-Ras as a regulator of vascular differentiation that primarily affects the remodeling of blood vessels. We show that R-Ras-null mice, although otherwise phenotypically normal, mount excessive vascular responses. We found that in vivo R-Ras expression is largely confined to fully differentiated smooth muscle cells, including those of blood vessels, and to endothelial cells. Challenging the R-Ras-null mice with arterial injury or tumor implantation showed exaggerated neointimal thickening in response to the injury and increased angiogenesis in the tumors. In wild-type mice, R-Ras expression was greatly reduced in hyperplastic neointimal smooth muscle cells and in angiogenic endothelial cells. Forced expression of activated R-Ras suppressed mitogenic and invasive activities of growth factor-stimulated vascular cells. These results establish an unexpected role for R-Ras in blood vessel homeostasis and suggest that R-Ras signaling may offer a target for therapeutic intervention in vascular diseases.", + "TAG_DATA": [ + "34, R-Ras-null {'perturbing_action': 'B-gene loss-of-function'}", + "70, R-Ras-null {'perturbing_action': 'B-gene loss-of-function'}", + "71, mice, {'context': 'B-organism'}", + "83, in {'context': 'B-in vivo'}", + "84, vivo {'context': 'I-in vivo'}", + "107, R-Ras-null {'perturbing_action': 'B-gene loss-of-function'}", + "108, mice {'context': 'B-organism'}", + "129, tumors. {'context': 'B-neoplasm'}", + "132, mice, {'context': 'B-organism'}", + "139, hyperplastic {'context': 'B-cells'}", + "140, neointimal {'context': 'I-cells'}", + "141, smooth {'context': 'I-cells'}", + "142, muscle {'context': 'I-cells'}", + "143, cells {'context': 'I-cells'}", + "146, angiogenic {'context': 'B-cells'}", + "147, endothelial {'context': 'I-cells'}", + "148, cells. {'context': 'I-cells'}", + "149, Forced {'perturbing_action': 'B-gene gain-of-function'}", + "150, expression {'perturbing_action': 'I-gene gain-of-function'}", + "151, of {'perturbing_action': 'I-gene gain-of-function'}", + "152, activated {'perturbing_action': 'I-gene gain-of-function'}", + "153, R-Ras {'perturbing_action': 'I-gene gain-of-function'}", + "162, vascular {'context': 'B-cells'}", + "163, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "34, R-Ras-null ['l0', 'l1', 'l2', 'l3']", + "70, R-Ras-null ['l0', 'l4', 'l5', 'l6']", + "71, mice, ['l1', 'l4', 'l7', 'l8']", + "83, in ['l2', 'l5', 'l7', 'l9']", + "84, vivo ['l3', 'l6', 'l8', 'l9']", + "107, R-Ras-null ['l10', 'l11', 'l12', 'l13', 'l14']", + "108, mice ['l10', 'l15']", + "129, tumors. ['l11', 'l15', 'l16', 'l17', 'l18']", + "132, mice, ['l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "139, hyperplastic ['l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "140, neointimal ['l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "141, smooth ['l12', 'l16', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "142, muscle ['l13', 'l17', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "143, cells ['l14', 'l18', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "146, angiogenic ['l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "147, endothelial ['l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "148, cells. ['l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "149, Forced ['l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "150, expression ['l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "151, of ['l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "152, activated ['l57', 'l62', 'l66', 'l70', 'l71', 'l72']", + "153, R-Ras ['l58', 'l63', 'l67', 'l70', 'l73', 'l74']", + "162, vascular ['l59', 'l64', 'l68', 'l71', 'l73', 'l75']", + "163, cells. ['l60', 'l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "R-Ras-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "R-Ras-null" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "R-Ras-null" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "R-Ras-null" + ] + }, + "context": { + "val": "cells", + "words": [ + "smooth", + "muscle", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "expression", + "of", + "activated", + "R-Ras" + ] + }, + "context": { + "val": "cells", + "words": [ + "vascular", + "cells." + ] + } + } + ] + }, + { + "PMID": "16273102", + "TEXT": "Pre-exposure oral prophylaxis with antiviral drugs is a potential method for preventing transmission of human immunodeficiency virus type 1 (HIV-1). We show that oral delivery of CMPD167, a small molecule that binds to the CCR5 coreceptor, for 10-14 d can protect a substantial proportion of macaques from vaginal infection with a CCR5-using virus (SHIV-162P3). The macaques that became infected despite receiving CMPD167 had reduced plasma viremia levels during the earliest stages of infection.", + "TAG_DATA": [ + "45, macaques {'context': 'B-organism'}", + "55, macaques {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16186817", + "TEXT": "Recently activated, but not resting, CD4(+) T cells express CD154, providing costimulatory signals to B cells and antigen-presenting cells (APCs). Therefore, de novo CD154 expression after stimulation identifies antigen-specific CD4(+) T cells. Previous assays were limited by the transient nature of surface CD154 expression; we overcame this by including fluorescently conjugated CD154-specific antibody during stimulation. Our assay is fully compatible with intracellular cytokine staining, and can be used for stimulations as long as 24 h. Notably, it is nonlethal, providing a means to purify viable antigen-specific CD4(+) T cells for further analysis. Using this assay, we found that stimulated cells expressing tumor necrosis factor (TNF)-alpha, interleukin (IL)-2 or interferon (IFN)-gamma were predominantly CD154(+). Furthermore, some cells expressing none of these cytokines also expressed CD154, suggesting that CD154 marks cells with other effector functions. For vaccine- or pathogen-specific responses, we found substantial heterogeneity in expression of CD154 and cytokines, suggesting previously unrecognized diversity in abilities of responding cells to stimulate APCs through CD40.", + "TAG_DATA": [ + "99, cells {'context': 'B-cells'}", + "115, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16170322", + "TEXT": "Antigen-specific T cells circulate freely and accumulate specifically at sites of antigen expression. To enhance the survival and targeting of systemically delivered viral vectors, we exploited the observation that retroviral particles adhere nonspecifically, or 'hitchhike,' to the surface of T cells. Adoptive transfer of antigen-specific T cells, loaded with viruses encoding interleukin (IL)-12 or Herpes Simplex Virus thymidine kinase (HSVtk), cured established metastatic disease where adoptive T-cell transfer alone was not effective. Productive hand off correlated with local heparanase expression either from malignant tumor cells and/or as a result of T-cell activation by antigen, providing high levels of selectivity for viral transfer to metastatic tumors in vivo. Protection, concentration and targeting of viruses by adsorption to cell carriers represent a new technique for systemic delivery of vectors, in fully immunocompetent hosts, for a variety of diseases in which delivery of genes may be therapeutically beneficial.", + "TAG_DATA": [ + "44, antigen-specific {'context': 'B-cells'}", + "45, T {'context': 'I-cells'}", + "46, cells, {'context': 'I-cells'}", + "62, metastatic {'context': 'B-neoplasm'}", + "63, disease {'context': 'I-neoplasm', 'phenotype': 'I-metastasis'}", + "103, metastatic {'context': 'B-neoplasm'}", + "104, tumors {'context': 'I-neoplasm'}", + "105, in {'context': 'B-in vivo'}", + "106, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "44, antigen-specific ['l0', 'l1', 'l2', 'l3']", + "45, T ['l0', 'l4', 'l5', 'l6']", + "46, cells, ['l1', 'l4', 'l7', 'l8']", + "62, metastatic ['l2', 'l5', 'l7', 'l9']", + "63, disease ['l3', 'l6', 'l8', 'l9']", + "90, T-cell ['l10', 'l11', 'l12', 'l13']", + "103, metastatic ['l10', 'l14', 'l15', 'l16']", + "104, tumors ['l11', 'l14', 'l17', 'l18']", + "105, in ['l12', 'l15', 'l17', 'l19']", + "106, vivo. ['l13', 'l16', 'l18', 'l19']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "antigen-specific", + "T", + "cells," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "disease" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "disease", + "metastatic" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "disease" + ] + } + } + ] + }, + { + "PMID": "16170321", + "TEXT": "Tumor necrosis factor (TNF)-alpha has an important role in the pathogenesis of autoimmune and inflammatory diseases such as rheumatoid and septic arthritis. The biological effects of TNF-alpha are mediated by binding to TNF receptors TNFR1 (also known as P60) or TNFR2 (also known as P80). The pre-ligand assembly domain (PLAD) is a portion of the extracellular region of TNFRs that mediates receptor-chain association essential for signaling. We found that soluble versions of PLAD, especially those derived from P60, block the biochemical effects of TNF-alpha in vitro and potently inhibit arthritis in animal models. Thus, targeting the PLAD may have clinical value in the treatment of human arthritis and other disorders involving receptors of the TNFR superfamily.", + "TAG_DATA": [ + "84, in {'context': 'B-in vitro'}", + "85, vitro {'context': 'I-in vitro'}", + "91, animal {'context': 'B-organism'}", + "92, models. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "84, in ['l0']", + "85, vitro ['l0']", + "91, animal ['l1']", + "92, models. ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16155577", + "TEXT": "Heat-shock protein 90 (Hsp90) functions as part of a multichaperone complex that folds, activates and assembles its client proteins. Androgen receptor (AR), a pathogenic gene product in spinal and bulbar muscular atrophy (SBMA), is one of the Hsp90 client proteins. We examined the therapeutic effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG), a potent Hsp90 inhibitor, and its ability to degrade polyglutamine-expanded mutant AR. Administration of 17-AAG markedly ameliorated motor impairments in the SBMA transgenic mouse model without detectable toxicity, by reducing amounts of monomeric and aggregated mutant AR. The mutant AR showed a higher affinity for Hsp90-p23 and preferentially formed an Hsp90 chaperone complex as compared to wild-type AR; mutant AR was preferentially degraded in the presence of 17-AAG in both cells and transgenic mice as compared to wild-type AR. 17-AAG also mildly induced Hsp70 and Hsp40. 17-AAG would thus provide a new therapeutic approach to SBMA and probably to other related neurodegenerative diseases.", + "TAG_DATA": [ + "69, SBMA {'perturbing_action': 'B-gene gain-of-function'}", + "70, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "71, mouse {'context': 'I-organism'}", + "72, model {'context': 'I-organism'}", + "86, mutant {'perturbing_action': 'B-other'}", + "87, AR {'perturbing_action': 'I-other'}", + "118, cells {'context': 'B-cells'}", + "120, transgenic {'perturbing_action': 'B-gene gain-of-function', 'context': 'B-xenograft'}", + "121, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "69, SBMA ['l0', 'l1', 'l2']", + "70, transgenic ['l0', 'l3', 'l4']", + "71, mouse ['l1', 'l3', 'l5']", + "72, model ['l2', 'l4', 'l5']", + "86, mutant ['l6', 'l7']", + "87, AR ['l6', 'l8']", + "118, cells ['l7', 'l8', 'l9', 'l10']", + "120, transgenic ['l9', 'l11']", + "121, mice ['l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "SBMA", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "AR" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "transgenic" + ] + } + } + ] + }, + { + "PMID": "16127434", + "TEXT": "Hypoxia inducible factor-1 (HIF-1) is considered a crucial mediator of the cellular response to hypoxia through its regulation of genes that control angiogenesis. It represents an attractive therapeutic target in colon cancer, one of the few tumor types that shows a clinical response to antiangiogenic therapy. But it is unclear whether inhibition of HIF-1 alone is sufficient to block tumor angiogenesis. In HIF-1alpha knockdown DLD-1 colon cancer cells (DLD-1(HIF-kd)), the hypoxic induction of vascular endothelial growth factor (VEGF) was only partially blocked. Xenografts remained highly vascularized with microvessel densities identical to DLD-1 tumors that had wild-type HIF-1alpha (DLD-1(HIF-wt)). In addition to the preserved expression of VEGF, the proangiogenic cytokine interleukin (IL)-8 was induced by hypoxia in DLD-1(HIF-kd) but not DLD-1(HIF-wt) cells. This induction was mediated by the production of hydrogen peroxide and subsequent activation of NF-kappaB. Furthermore, the KRAS oncogene, which is commonly mutated in colon cancer, enhanced the hypoxic induction of IL-8. A neutralizing antibody to IL-8 substantially inhibited angiogenesis and tumor growth in DLD-1(HIF-kd) but not DLD-1(HIF-wt) xenografts, verifying the functional significance of this IL-8 response. Thus, compensatory pathways can be activated to preserve the tumor angiogenic response, and strategies that inhibit HIF-1alpha may be most effective when IL-8 is simultaneously targeted.", + "TAG_DATA": [ + "62, HIF-1alpha {'perturbing_action': 'B-rnai/knockdown'}", + "63, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "64, DLD-1 {'context': 'B-transformed cells'}", + "65, colon {'context': 'I-transformed cells'}", + "66, cancer {'context': 'I-transformed cells'}", + "67, cells {'context': 'I-transformed cells'}", + "68, (DLD-1(HIF-kd)), {'context': 'I-transformed cells'}", + "82, Xenografts {'context': 'B-xenograft'}", + "120, cells. {'context': 'B-cells'}", + "159, inhibited {'effect': 'B-negative'}", + "162, tumor {'phenotype': 'B-tumour growth'}", + "163, growth {'phenotype': 'I-tumour growth'}", + "168, DLD-1(HIF-wt) {'context': 'B-xenograft'}", + "169, xenografts, {'context': 'B-xenograft'}" + ], + "LINK_DATA": [ + "62, HIF-1alpha ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "63, knockdown ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "64, DLD-1 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "65, colon ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "66, cancer ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "67, cells ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "68, (DLD-1(HIF-kd)), ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "82, Xenografts ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "159, inhibited ['l28', 'l29', 'l30', 'l31', 'l32']", + "162, tumor ['l28', 'l33', 'l34', 'l35', 'l36']", + "163, growth ['l29', 'l33', 'l37', 'l38', 'l39']", + "165, DLD-1(HIF-kd) ['l30', 'l34', 'l37', 'l40', 'l41']", + "168, DLD-1(HIF-wt) ['l31', 'l35', 'l38', 'l40', 'l42']", + "169, xenografts, ['l32', 'l36', 'l39', 'l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "HIF-1alpha", + "knockdown" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "DLD-1", + "colon", + "cancer", + "cells", + "(DLD-1(HIF-kd))," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "HIF-1alpha", + "knockdown" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "Xenografts" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "DLD-1(HIF-wt)", + "xenografts," + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "DLD-1(HIF-wt)", + "xenografts," + ] + } + } + ] + }, + { + "PMID": "16116431", + "TEXT": "Lymph vessels control fluid homeostasis, immunity and metastasis. Unraveling the molecular basis of lymphangiogenesis has been hampered by the lack of a small animal model that can be genetically manipulated. Here, we show that Xenopus tadpoles develop lymph vessels from lymphangioblasts or, through transdifferentiation, from venous endothelial cells. Lymphangiography showed that these lymph vessels drain lymph, through the lymph heart, to the venous circulation. Morpholino-mediated knockdown of the lymphangiogenic factor Prox1 caused lymph vessel defects and lymphedema by impairing lymphatic commitment. Knockdown of vascular endothelial growth factor C (VEGF-C) also induced lymph vessel defects and lymphedema, but primarily by affecting migration of lymphatic endothelial cells. Knockdown of VEGF-C also resulted in aberrant blood vessel formation in tadpoles. This tadpole model offers opportunities for the discovery of new regulators of lymphangiogenesis.", + "TAG_DATA": [ + "34, Xenopus {'context': 'B-organism'}", + "35, tadpoles {'context': 'I-organism'}", + "64, Morpholino-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "65, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "66, of {'perturbing_action': 'I-rnai/knockdown'}", + "67, the {'perturbing_action': 'I-rnai/knockdown'}", + "68, lymphangiogenic {'perturbing_action': 'I-rnai/knockdown'}", + "69, factor {'perturbing_action': 'I-rnai/knockdown'}", + "70, Prox1 {'perturbing_action': 'I-rnai/knockdown'}", + "81, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "82, of {'perturbing_action': 'I-rnai/knockdown'}", + "83, vascular {'perturbing_action': 'I-rnai/knockdown'}", + "84, endothelial {'perturbing_action': 'I-rnai/knockdown'}", + "85, growth {'perturbing_action': 'I-rnai/knockdown'}", + "86, factor {'perturbing_action': 'I-rnai/knockdown'}", + "87, C {'perturbing_action': 'I-rnai/knockdown'}", + "88, (VEGF-C) {'perturbing_action': 'I-rnai/knockdown'}", + "99, affecting {'effect': 'B-regulates'}", + "100, migration {'phenotype': 'B-migration'}", + "102, lymphatic {'context': 'B-cells'}", + "103, endothelial {'context': 'I-cells'}", + "104, cells. {'context': 'I-cells'}", + "105, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "106, of {'perturbing_action': 'I-rnai/knockdown'}", + "107, VEGF-C {'perturbing_action': 'I-rnai/knockdown'}", + "116, tadpoles. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "34, Xenopus ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "35, tadpoles ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "64, Morpholino-mediated ['l1', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "65, knockdown ['l2', 'l8', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "66, of ['l3', 'l9', 'l15', 'l20', 'l25', 'l26', 'l27', 'l28']", + "67, the ['l4', 'l10', 'l16', 'l21', 'l25', 'l29', 'l30', 'l31']", + "68, lymphangiogenic ['l5', 'l11', 'l17', 'l22', 'l26', 'l29', 'l32', 'l33']", + "69, factor ['l6', 'l12', 'l18', 'l23', 'l27', 'l30', 'l32', 'l34']", + "70, Prox1 ['l7', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l34']", + "81, Knockdown ['l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "82, of ['l35', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "83, vascular ['l36', 'l47', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "84, endothelial ['l37', 'l48', 'l58', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "85, growth ['l38', 'l49', 'l59', 'l68', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "86, factor ['l39', 'l50', 'l60', 'l69', 'l77', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "87, C ['l40', 'l51', 'l61', 'l70', 'l78', 'l85', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "88, (VEGF-C) ['l41', 'l52', 'l62', 'l71', 'l79', 'l86', 'l92', 'l98', 'l99', 'l100', 'l101', 'l102']", + "99, affecting ['l42', 'l53', 'l63', 'l72', 'l80', 'l87', 'l93', 'l98', 'l103', 'l104', 'l105', 'l106']", + "100, migration ['l43', 'l54', 'l64', 'l73', 'l81', 'l88', 'l94', 'l99', 'l103', 'l107', 'l108', 'l109']", + "102, lymphatic ['l44', 'l55', 'l65', 'l74', 'l82', 'l89', 'l95', 'l100', 'l104', 'l107', 'l110', 'l111']", + "103, endothelial ['l45', 'l56', 'l66', 'l75', 'l83', 'l90', 'l96', 'l101', 'l105', 'l108', 'l110', 'l112']", + "104, cells. ['l46', 'l57', 'l67', 'l76', 'l84', 'l91', 'l97', 'l102', 'l106', 'l109', 'l111', 'l112']", + "105, Knockdown ['l113', 'l114', 'l115']", + "106, of ['l113', 'l116', 'l117']", + "107, VEGF-C ['l114', 'l116', 'l118']", + "116, tadpoles. ['l115', 'l117', 'l118']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Xenopus", + "tadpoles", + "tadpoles." + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Morpholino-mediated", + "knockdown", + "of", + "the", + "lymphangiogenic", + "factor", + "Prox1", + "Knockdown", + "VEGF-C" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "vascular", + "endothelial", + "growth", + "factor", + "C", + "(VEGF-C)" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "affecting" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "vascular", + "endothelial", + "growth", + "factor", + "C", + "(VEGF-C)" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "vascular", + "endothelial", + "growth", + "factor", + "C", + "(VEGF-C)" + ] + }, + "context": { + "val": "cells", + "words": [ + "lymphatic", + "endothelial", + "cells." + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "affecting" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "affecting" + ] + }, + "context": { + "val": "cells", + "words": [ + "lymphatic", + "endothelial", + "cells." + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "cells", + "words": [ + "lymphatic", + "endothelial", + "cells." + ] + } + } + ] + }, + { + "PMID": "16116430", + "TEXT": "Neurovascular dysfunction substantially contributes to Alzheimer disease. Here, we show that transcriptional profiling of human brain endothelial cells (BECs) defines a subset of genes whose expression is age-independent but is considerably altered in Alzheimer disease, including the homeobox gene MEOX2 (also known as GAX), a regulator of vascular differentiation, whose expression is low in Alzheimer disease. By using viral-mediated MEOX2 gene silencing and transfer, we show that restoring expression of the protein it encodes, GAX, in BECs from individuals with Alzheimer disease stimulates angiogenesis, transcriptionally suppresses AFX1 forkhead transcription factor-mediated apoptosis and increases the levels of a major amyloid-beta peptide (Abeta) clearance receptor, the low-density lipoprotein receptor-related protein 1 (LRP), at the blood-brain barrier. In mice, deletion of Meox2 (also known as Gax) results in reductions in brain capillary density and resting cerebral blood flow, loss of the angiogenic response to hypoxia in the brain and an impaired Abeta efflux from brain caused by reduced LRP levels. The link of MEOX2 to neurovascular dysfunction in Alzheimer disease provides new mechanistic and therapeutic insights into this illness.", + "TAG_DATA": [ + "58, viral-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "59, MEOX2 {'perturbing_action': 'I-rnai/knockdown'}", + "60, gene {'perturbing_action': 'I-rnai/knockdown'}", + "61, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "67, restoring {'perturbing_action': 'B-gene gain-of-function'}", + "68, expression {'perturbing_action': 'I-gene gain-of-function'}", + "69, of {'perturbing_action': 'I-gene gain-of-function'}", + "70, the {'perturbing_action': 'I-gene gain-of-function'}", + "71, protein {'perturbing_action': 'I-gene gain-of-function'}", + "72, it {'perturbing_action': 'I-gene gain-of-function'}", + "73, encodes, {'perturbing_action': 'I-gene gain-of-function'}", + "74, GAX, {'perturbing_action': 'I-gene gain-of-function'}", + "76, BECs {'context': 'B-cells'}", + "85, suppresses {'effect': 'B-negative'}", + "89, factor-mediated {'effect': 'B-regulates'}", + "90, apoptosis {'phenotype': 'B-apoptosis'}", + "115, mice, {'context': 'B-organism'}", + "116, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "117, of {'perturbing_action': 'I-gene loss-of-function'}", + "118, Meox2 {'perturbing_action': 'I-gene loss-of-function'}", + "119, (also {'perturbing_action': 'I-gene loss-of-function'}", + "120, known {'perturbing_action': 'I-gene loss-of-function'}", + "121, as {'perturbing_action': 'I-gene loss-of-function'}", + "122, Gax) {'perturbing_action': 'I-gene loss-of-function'}", + "127, brain {'context': 'B-tissue/organ'}", + "144, brain {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "58, viral-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "59, MEOX2 ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "60, gene ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19']", + "61, silencing ['l2', 'l9', 'l15', 'l20', 'l21', 'l22', 'l23']", + "67, restoring ['l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "68, expression ['l24', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "69, of ['l25', 'l35', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "70, the ['l26', 'l36', 'l45', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "71, protein ['l27', 'l37', 'l46', 'l54', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "72, it ['l28', 'l38', 'l47', 'l55', 'l62', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "73, encodes, ['l29', 'l39', 'l48', 'l56', 'l63', 'l69', 'l75', 'l76', 'l77', 'l78', 'l79']", + "74, GAX, ['l3', 'l10', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l75', 'l80', 'l81', 'l82', 'l83']", + "76, BECs ['l4', 'l11', 'l16', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l84', 'l85', 'l86']", + "85, suppresses ['l5', 'l12', 'l17', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l87', 'l88']", + "89, factor-mediated ['l6', 'l13', 'l18', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l87', 'l89']", + "90, apoptosis ['l7', 'l14', 'l19', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l89']", + "115, mice, ['l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "116, deletion ['l90', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "117, of ['l91', 'l99', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "118, Meox2 ['l92', 'l100', 'l107', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "119, (also ['l93', 'l101', 'l108', 'l114', 'l120', 'l121', 'l122', 'l123', 'l124']", + "120, known ['l94', 'l102', 'l109', 'l115', 'l120', 'l125', 'l126', 'l127', 'l128']", + "121, as ['l95', 'l103', 'l110', 'l116', 'l121', 'l125', 'l129', 'l130', 'l131']", + "122, Gax) ['l96', 'l104', 'l111', 'l117', 'l122', 'l126', 'l129', 'l132', 'l133']", + "127, brain ['l97', 'l105', 'l112', 'l118', 'l123', 'l127', 'l130', 'l132', 'l134']", + "144, brain ['l98', 'l106', 'l113', 'l119', 'l124', 'l128', 'l131', 'l133', 'l134']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "viral-mediated", + "MEOX2", + "gene", + "silencing" + ] + }, + "context": { + "val": "cells", + "words": [ + "BECs" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "viral-mediated", + "MEOX2", + "gene", + "silencing" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "viral-mediated", + "MEOX2", + "gene", + "silencing" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "factor-mediated" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "viral-mediated", + "MEOX2", + "gene", + "silencing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "restoring", + "expression", + "of", + "the", + "protein", + "it", + "encodes,", + "GAX," + ] + }, + "context": { + "val": "cells", + "words": [ + "BECs" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "restoring", + "expression", + "of", + "the", + "protein", + "it", + "encodes,", + "GAX," + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "restoring", + "expression", + "of", + "the", + "protein", + "it", + "encodes,", + "GAX," + ] + }, + "effect": { + "val": "regulates", + "words": [ + "factor-mediated" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "restoring", + "expression", + "of", + "the", + "protein", + "it", + "encodes,", + "GAX," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "BECs" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "BECs" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "factor-mediated" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "BECs" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "factor-mediated" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Meox2", + "(also", + "known", + "as", + "Gax)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Meox2", + "(also", + "known", + "as", + "Gax)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain" + ] + } + } + ] + }, + { + "PMID": "16086023", + "TEXT": "Demyelination is the hallmark of numerous neurodegenerative conditions, including multiple sclerosis. Oligodendrocyte progenitors (OPCs), which normally mature into myelin-forming oligodendrocytes, are typically present around demyelinated lesions but do not remyelinate affected axons. Here, we find that the glycosaminoglycan hyaluronan accumulates in demyelinated lesions from individuals with multiple sclerosis and in mice with experimental autoimmune encephalomyelitis. A high molecular weight (HMW) form of hyaluronan synthesized by astrocytes accumulates in chronic demyelinated lesions. This form of hyaluronan inhibits remyelination after lysolecithin-induced white matter demyelination. OPCs accrue and do not mature into myelin-forming cells in demyelinating lesions where HMW hyaluronan is present. Furthermore, the addition of HMW hyaluronan to OPC cultures reversibly inhibits progenitor-cell maturation, whereas degrading hyaluronan in astrocyte-OPC cocultures promotes oligodendrocyte maturation. HMW hyaluronan may therefore contribute substantially to remyelination failure by preventing the maturation of OPCs that are recruited to demyelinating lesions.", + "TAG_DATA": [ + "82, OPCs {'context': 'B-cells'}", + "106, OPC {'context': 'B-cells'}", + "107, cultures {'context': 'I-cells'}", + "110, progenitor-cell {'context': 'B-cells'}", + "116, astrocyte-OPC {'context': 'B-cells'}", + "117, cocultures {'context': 'I-cells'}", + "119, oligodendrocyte {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "82, OPCs ['l0']", + "106, OPC ['l0', 'l1', 'l2']", + "107, cultures ['l1', 'l3']", + "110, progenitor-cell ['l2', 'l3']", + "116, astrocyte-OPC ['l4', 'l5']", + "117, cocultures ['l4', 'l6']", + "119, oligodendrocyte ['l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16079870", + "TEXT": "Two studies show how the enzyme ACE2 protects against lung injury caused by SARS and other agents. ACE2 seems to counteract the effects of ACE, which are more damaging (pages 875–879).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16007097", + "TEXT": "During several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world. A new coronavirus (SARS-CoV) was identified as the SARS pathogen, which triggered severe pneumonia and acute, often lethal, lung failure. Moreover, among infected individuals influenza such as the Spanish flu and the emergence of new respiratory disease viruses have caused high lethality resulting from acute lung failure. In cell lines, angiotensin-converting enzyme 2 (ACE2) has been identified as a potential SARS-CoV receptor. The high lethality of SARS-CoV infections, its enormous economic and social impact, fears of renewed outbreaks as well as the potential misuse of such viruses as biologic weapons make it paramount to understand the pathogenesis of SARS-CoV. Here we provide the first genetic proof that ACE2 is a crucial SARS-CoV receptor in vivo. SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway. These results provide a molecular explanation why SARS-CoV infections cause severe and often lethal lung failure and suggest a rational therapy for SARS and possibly other respiratory disease viruses.", + "TAG_DATA": [ + "153, mice {'context': 'B-organism'}", + "156, lung {'context': 'B-tissue/organ'}", + "158, in {'context': 'B-in vivo'}", + "159, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "153, mice ['l0', 'l1', 'l2']", + "156, lung ['l0', 'l3', 'l4']", + "158, in ['l1', 'l3', 'l5']", + "159, vivo ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16007095", + "TEXT": "Thiazolidinediones (TZDs) are widely used to treat type 2 diabetes mellitus; however, their use is complicated by systemic fluid retention. Along the nephron, the pharmacological target of TZDs, peroxisome proliferator-activated receptor-gamma (PPARgamma, encoded by Pparg), is most abundant in the collecting duct. Here we show that mice treated with TZDs experience early weight gain from increased total body water. Weight gain was blocked by the collecting duct-specific diuretic amiloride and was also prevented by deletion of Pparg from the collecting duct, using Pparg (flox/flox) mice. Deletion of collecting duct Pparg decreased renal Na(+) avidity and increased plasma aldosterone. Treating cultured collecting ducts with TZDs increased amiloride-sensitive Na(+) absorption and Scnn1g mRNA (encoding the epithelial Na(+) channel ENaCgamma) expression through a PPARgamma-dependent pathway. These studies identify Scnn1g as a PPARgamma target gene in the collecting duct. Activation of this pathway mediates fluid retention associated with TZDs, and suggests amiloride might provide a specific therapy.", + "TAG_DATA": [ + "46, mice {'context': 'B-organism'}", + "74, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "75, of {'perturbing_action': 'I-gene loss-of-function'}", + "76, Pparg {'perturbing_action': 'I-gene loss-of-function'}", + "77, from {'perturbing_action': 'I-gene loss-of-function'}", + "78, the {'perturbing_action': 'I-gene loss-of-function'}", + "79, collecting {'perturbing_action': 'I-gene loss-of-function'}", + "80, duct, {'perturbing_action': 'I-gene loss-of-function'}", + "82, Pparg {'perturbing_action': 'B-gene loss-of-function'}", + "83, (flox/flox) {'perturbing_action': 'B-gene loss-of-function'}", + "84, mice. {'context': 'B-organism'}", + "85, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "86, of {'perturbing_action': 'I-gene loss-of-function'}", + "87, collecting {'perturbing_action': 'I-gene loss-of-function'}", + "88, duct {'perturbing_action': 'I-gene loss-of-function'}", + "89, Pparg {'perturbing_action': 'I-gene loss-of-function'}", + "99, cultured {'context': 'B-cells'}", + "100, collecting {'context': 'I-cells'}", + "101, ducts {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "74, deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "75, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "76, Pparg ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "77, from ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "78, the ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "79, collecting ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "80, duct, ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "82, Pparg ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "83, (flox/flox) ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "84, mice. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l49', 'l55', 'l56', 'l57']", + "85, Deletion ['l44', 'l50', 'l58', 'l59', 'l60', 'l61']", + "86, of ['l45', 'l51', 'l58', 'l62', 'l63', 'l64']", + "87, collecting ['l46', 'l52', 'l55', 'l59', 'l62', 'l65', 'l66']", + "88, duct ['l47', 'l53', 'l56', 'l60', 'l63', 'l65', 'l67']", + "89, Pparg ['l48', 'l54', 'l57', 'l61', 'l64', 'l66', 'l67']", + "99, cultured ['l68', 'l69']", + "100, collecting ['l68', 'l70']", + "101, ducts ['l69', 'l70']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Pparg", + "from", + "the", + "collecting", + "duct,", + "(flox/flox)", + "duct" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "15980865", + "TEXT": "The Poxviridae family members vaccinia and variola virus enter mammalian cells, replicate outside the nucleus and produce virions that travel to the cell surface along microtubules, fuse with the plasma membrane and egress from infected cells toward apposing cells on actin-filled membranous protrusions. We show that cell-associated enveloped virions (CEV) use Abl- and Src-family tyrosine kinases for actin motility, and that these kinases act in a redundant fashion, perhaps permitting motility in a greater range of cell types. Additionally, release of CEV from the cell requires Abl- but not Src-family tyrosine kinases, and is blocked by STI-571 (Gleevec), an Abl-family kinase inhibitor used to treat chronic myelogenous leukemia in humans. Finally, we show that STI-571 reduces viral dissemination by five orders of magnitude and promotes survival in infected mice, suggesting possible use for this drug in treating smallpox or complications associated with vaccination. This therapeutic approach may prove generally efficacious in treating microbial infections that rely on host tyrosine kinases, and, because the drug targets host but not viral molecules, this strategy is much less likely to engender resistance compared to conventional antimicrobial therapies.", + "TAG_DATA": [ + "128, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15980864", + "TEXT": "Premature aging syndromes often result from mutations in nuclear proteins involved in the maintenance of genomic integrity. Lamin A is a major component of the nuclear lamina and nuclear skeleton. Truncation in lamin A causes Hutchinson-Gilford progerial syndrome (HGPS), a severe form of early-onset premature aging. Lack of functional Zmpste24, a metalloproteinase responsible for the maturation of prelamin A, also results in progeroid phenotypes in mice and humans. We found that Zmpste24-deficient mouse embryonic fibroblasts (MEFs) show increased DNA damage and chromosome aberrations and are more sensitive to DNA-damaging agents. Bone marrow cells isolated from Zmpste24-/- mice show increased aneuploidy and the mice are more sensitive to DNA-damaging agents. Recruitment of p53 binding protein 1 (53BP1) and Rad51 to sites of DNA lesion is impaired in Zmpste24-/- MEFs and in HGPS fibroblasts, resulting in delayed checkpoint response and defective DNA repair. Wild-type MEFs ectopically expressing unprocessible prelamin A show similar defects in checkpoint response and DNA repair. Our results indicate that unprocessed prelamin A and truncated lamin A act dominant negatively to perturb DNA damage response and repair, resulting in genomic instability which might contribute to laminopathy-based premature aging.", + "TAG_DATA": [ + "71, Zmpste24-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "72, mouse {'context': 'B-cells'}", + "73, embryonic {'context': 'I-cells'}", + "74, fibroblasts {'context': 'I-cells'}", + "75, (MEFs) {'context': 'I-cells'}", + "90, Bone {'context': 'B-cells'}", + "91, marrow {'context': 'I-cells'}", + "92, cells {'context': 'I-cells'}", + "95, Zmpste24-/- {'perturbing_action': 'B-gene loss-of-function'}", + "96, mice {'context': 'B-organism'}", + "102, mice {'context': 'B-organism'}", + "126, Zmpste24-/- {'perturbing_action': 'B-gene loss-of-function'}", + "127, MEFs {'context': 'B-cells'}", + "130, HGPS {'context': 'B-cells'}", + "131, fibroblasts, {'context': 'I-cells'}", + "142, MEFs {'context': 'B-cells'}", + "143, ectopically {'perturbing_action': 'B-gene gain-of-function'}", + "144, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "145, unprocessible {'perturbing_action': 'I-gene gain-of-function'}", + "146, prelamin {'perturbing_action': 'I-gene gain-of-function'}", + "147, A {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "71, Zmpste24-deficient ['l0', 'l1', 'l2', 'l3']", + "72, mouse ['l0', 'l4', 'l5', 'l6']", + "73, embryonic ['l1', 'l4', 'l7', 'l8']", + "74, fibroblasts ['l2', 'l5', 'l7', 'l9']", + "75, (MEFs) ['l3', 'l6', 'l8', 'l9']", + "90, Bone ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "91, marrow ['l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "92, cells ['l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "95, Zmpste24-/- ['l12', 'l20', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "96, mice ['l13', 'l21', 'l28', 'l33', 'l39', 'l40', 'l41']", + "102, mice ['l14', 'l22', 'l29', 'l34', 'l39', 'l42', 'l43', 'l44', 'l45']", + "126, Zmpste24-/- ['l15', 'l23', 'l35', 'l42', 'l46', 'l47', 'l48']", + "127, MEFs ['l16', 'l24', 'l30', 'l36', 'l40', 'l43', 'l46', 'l49', 'l50']", + "130, HGPS ['l17', 'l25', 'l31', 'l37', 'l44', 'l47', 'l49', 'l51']", + "131, fibroblasts, ['l18', 'l26', 'l32', 'l38', 'l41', 'l45', 'l48', 'l50', 'l51']", + "142, MEFs ['l52', 'l53', 'l54', 'l55', 'l56']", + "143, ectopically ['l52', 'l57', 'l58', 'l59', 'l60']", + "144, expressing ['l53', 'l57', 'l61', 'l62', 'l63']", + "145, unprocessible ['l54', 'l58', 'l61', 'l64', 'l65']", + "146, prelamin ['l55', 'l59', 'l62', 'l64', 'l66']", + "147, A ['l56', 'l60', 'l63', 'l65', 'l66']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Zmpste24-deficient", + "Zmpste24-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "embryonic", + "fibroblasts", + "(MEFs)", + "Bone", + "marrow", + "cells", + "MEFs", + "HGPS", + "fibroblasts," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Zmpste24-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "MEFs" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopically", + "expressing", + "unprocessible", + "prelamin", + "A" + ] + } + } + ] + }, + { + "PMID": "15924147", + "TEXT": "Type 2 diabetes mellitus is a widespread disease, affecting millions of people globally. Although genetics and environmental factors seem to have a role, the cause of this metabolic disorder is largely unknown. Here we report a genetic flaw that markedly reduced the intracellular expression of the high mobility group A1 (HMGA1) protein, and adversely affected insulin receptor expression in cells and tissues from four subjects with insulin resistance and type 2 diabetes. Restoration of HMGA1 protein expression in subjects' cells enhanced INSR gene transcription, and restored cell-surface insulin receptor protein expression and insulin-binding capacity. Loss of Hmga1 expression, induced in mice by disrupting the Hmga1 gene, considerably decreased insulin receptor expression in the major targets of insulin action, largely impaired insulin signaling and severely reduced insulin secretion, causing a phenotype characteristic of human type 2 diabetes.", + "TAG_DATA": [ + "72, Restoration {'perturbing_action': 'B-gene gain-of-function'}", + "73, of {'perturbing_action': 'I-gene gain-of-function'}", + "74, HMGA1 {'perturbing_action': 'I-gene gain-of-function'}", + "75, protein {'perturbing_action': 'I-gene gain-of-function'}", + "76, expression {'perturbing_action': 'I-gene gain-of-function'}", + "78, subjects' {'context': 'B-cells'}", + "79, cells {'context': 'I-cells'}", + "94, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "95, of {'perturbing_action': 'I-gene loss-of-function'}", + "96, Hmga1 {'perturbing_action': 'I-gene loss-of-function'}", + "97, expression, {'perturbing_action': 'I-gene loss-of-function'}", + "100, mice {'context': 'B-organism'}", + "102, disrupting {'perturbing_action': 'B-gene loss-of-function'}", + "103, the {'perturbing_action': 'I-gene loss-of-function'}", + "104, Hmga1 {'perturbing_action': 'I-gene loss-of-function'}", + "105, gene, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "72, Restoration ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "73, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "74, HMGA1 ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "75, protein ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "76, expression ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "78, subjects' ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "79, cells ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "94, Loss ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "95, of ['l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "96, Hmga1 ['l22', 'l29', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "97, expression, ['l23', 'l30', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "100, mice ['l24', 'l31', 'l37', 'l42', 'l47', 'l48', 'l49', 'l50']", + "102, disrupting ['l25', 'l32', 'l38', 'l43', 'l47', 'l51', 'l52', 'l53']", + "103, the ['l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l54', 'l55']", + "104, Hmga1 ['l27', 'l34', 'l40', 'l45', 'l49', 'l52', 'l54', 'l56']", + "105, gene, ['l28', 'l35', 'l41', 'l46', 'l50', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoration", + "of", + "HMGA1", + "protein", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "subjects'", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Loss", + "of", + "Hmga1", + "expression,", + "disrupting", + "the", + "gene," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15924146", + "TEXT": "A promising approach to reduce the impact of influenza is the use of an attenuated, live virus as a vaccine. Using reverse genetics, we generated a mutant of strain A/WSN/33 with a modified cleavage site within its hemagglutinin, which depends on proteolytic activation by elastase. Unlike the wild-type, which requires trypsin, this mutant is strictly dependent on elastase. Both viruses grow equally well in cell culture. In contrast to the lethal wild-type virus, the mutant is entirely attenuated in mice. At a dose of 10(5) plaque-forming units, it induced complete protection against lethal challenge. This approach allows the conversion of any epidemic strain into a genetically homologous attenuated virus.", + "TAG_DATA": [ + "64, cell {'context': 'B-cells'}", + "65, culture. {'context': 'I-cells'}", + "79, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "64, cell ['l0']", + "65, culture. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15895073", + "TEXT": "Anaplastic large cell lymphomas (ALCLs) are caused by chromosomal translocations that juxtapose the anaplastic lymphoma kinase (ALK) proto-oncogene to a dimerization partner, resulting in constitutive expression of ALK and ALK tyrosine kinase activity. One substrate of activated ALK in human ALCLs is the transcription factor Stat3, and its phosphorylation is accurately recapitulated in a new nucleophosmin (NPM)-ALK transgenic mouse model of lymphomagenesis. Here we show by gene targeting that Stat3 is required for the transformation of mouse embryonic fibroblasts in vitro, for the development of B-cell lymphoma in transgenic mice and for the growth and survival of both human and mouse NPM-ALK-transformed B and T cells. Ablation of Stat3 expression by antisense oligonucleotides significantly (P < 0.0001) impaired the growth of human and mouse NPM-ALK tumors in vivo. Pharmacological ablation of Stat3 represents a new candidate approach for the treatment of human lymphoma", + "TAG_DATA": [ + "74, transformation {'phenotype': 'B-transformation'}", + "76, mouse {'context': 'B-cells'}", + "77, embryonic {'context': 'I-cells'}", + "78, fibroblasts {'context': 'I-cells'}", + "79, in {'context': 'B-in vitro'}", + "80, vitro, {'context': 'I-in vitro'}", + "85, B-cell {'phenotype': 'B-tumourigenesis'}", + "86, lymphoma {'phenotype': 'I-tumourigenesis'}", + "88, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "89, mice {'context': 'I-organism'}", + "102, B {'context': 'B-cells'}", + "103, and {'context': 'I-cells'}", + "104, T {'context': 'I-cells'}", + "105, cells. {'context': 'I-cells'}", + "106, Ablation {'perturbing_action': 'B-gene loss-of-function'}", + "107, of {'perturbing_action': 'I-gene loss-of-function'}", + "108, Stat3 {'perturbing_action': 'I-gene loss-of-function'}", + "109, expression {'perturbing_action': 'I-gene loss-of-function'}", + "121, human {'context': 'B-neoplasm'}", + "122, and {'context': 'I-neoplasm'}", + "123, mouse {'context': 'I-neoplasm'}", + "124, NPM-ALK {'context': 'I-neoplasm'}", + "125, tumors {'context': 'I-neoplasm'}", + "126, in {'context': 'B-in vivo'}", + "127, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "74, transformation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "76, mouse ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "77, embryonic ['l1', 'l7', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "78, fibroblasts ['l2', 'l8', 'l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "79, in ['l3', 'l9', 'l16', 'l23', 'l29', 'l30', 'l31', 'l32']", + "80, vitro, ['l4', 'l10', 'l17', 'l24', 'l29', 'l33', 'l34']", + "83, development ['l5', 'l11', 'l18', 'l25', 'l30', 'l33', 'l35', 'l36', 'l37', 'l38']", + "85, B-cell ['l12', 'l19', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41', 'l42']", + "86, lymphoma ['l6', 'l13', 'l20', 'l27', 'l32', 'l34', 'l36', 'l39', 'l43', 'l44']", + "88, transgenic ['l21', 'l37', 'l40', 'l43', 'l45', 'l46']", + "89, mice ['l14', 'l22', 'l28', 'l38', 'l41', 'l44', 'l45']", + "102, B ['l47', 'l48', 'l49']", + "103, and ['l47', 'l50', 'l51']", + "104, T ['l48', 'l50', 'l52']", + "105, cells. ['l42', 'l46', 'l49', 'l51', 'l52']", + "106, Ablation ['l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "107, of ['l53', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "108, Stat3 ['l54', 'l63', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "109, expression ['l55', 'l64', 'l72', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "121, human ['l56', 'l65', 'l73', 'l80', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "122, and ['l57', 'l66', 'l74', 'l81', 'l87', 'l93', 'l94', 'l95', 'l96', 'l97']", + "123, mouse ['l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l98', 'l99', 'l100', 'l101']", + "124, NPM-ALK ['l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l102', 'l103', 'l104']", + "125, tumors ['l60', 'l69', 'l77', 'l84', 'l90', 'l95', 'l99', 'l102', 'l105', 'l106']", + "126, in ['l61', 'l70', 'l78', 'l85', 'l91', 'l96', 'l100', 'l103', 'l105', 'l107']", + "127, vivo. ['l62', 'l71', 'l79', 'l86', 'l92', 'l97', 'l101', 'l104', 'l106', 'l107']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "embryonic", + "fibroblasts" + ] + } + }, + { + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "embryonic", + "fibroblasts", + "cells." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "B-cell", + "lymphoma" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "embryonic", + "cells." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "B-cell", + "lymphoma" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "B-cell", + "lymphoma" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "B-cell", + "lymphoma" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "Stat3", + "expression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "and", + "mouse", + "NPM-ALK", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "Stat3", + "expression" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "15895072", + "TEXT": "Genes involved in fatty acid catabolism have undergone extensive duplication in the genus Mycobacterium, which includes the etiologic agents of leprosy and tuberculosis. Here, we show that prokaryotic- and eukaryotic-like isoforms of the glyoxylate cycle enzyme isocitrate lyase (ICL) are jointly required for fatty acid catabolism and virulence in Mycobacterium tuberculosis. Although deletion of icl1 or icl2, the genes that encode ICL1 and ICL2, respectively, had little effect on bacterial growth in macrophages and mice, deletion of both genes resulted in complete impairment of intracellular replication and rapid elimination from the lungs. The feasibility of targeting ICL1 and ICL2 for chemical inhibition was shown using a dual-specific ICL inhibitor, which blocked growth of M. tuberculosis on fatty acids and in macrophages. The absence of ICL orthologs in mammals should facilitate the development of glyoxylate cycle inhibitors as new drugs for the treatment of tuberculosis.", + "TAG_DATA": [ + "52, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "53, of {'perturbing_action': 'I-gene loss-of-function'}", + "54, icl1 {'perturbing_action': 'I-gene loss-of-function'}", + "55, or {'perturbing_action': 'I-gene loss-of-function'}", + "56, icl2, {'perturbing_action': 'I-gene loss-of-function'}", + "66, little {'effect': 'B-no effect'}", + "67, effect {'effect': 'I-no effect'}", + "72, macrophages {'context': 'B-cells'}", + "74, mice, {'context': 'B-organism'}", + "75, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "76, of {'perturbing_action': 'I-gene loss-of-function'}", + "77, both {'perturbing_action': 'I-gene loss-of-function'}", + "78, genes {'perturbing_action': 'I-gene loss-of-function'}", + "106, dual-specific {'perturbing_action': 'B-pharmacological inhibition'}", + "107, ICL {'perturbing_action': 'I-pharmacological inhibition'}", + "108, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "113, M. {'context': 'B-organism'}", + "114, tuberculosis {'context': 'I-organism'}", + "120, macrophages. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "52, deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "53, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "54, icl1 ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "55, or ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "56, icl2, ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "66, little ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37']", + "67, effect ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l39']", + "72, macrophages ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l38', 'l40']", + "74, mice, ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l39', 'l40']", + "75, deletion ['l41', 'l42', 'l43', 'l44']", + "76, of ['l41', 'l45', 'l46', 'l47']", + "77, both ['l42', 'l45', 'l48', 'l49']", + "78, genes ['l43', 'l46', 'l48', 'l50']", + "91, lungs. ['l8', 'l16', 'l23', 'l29', 'l34', 'l44', 'l47', 'l49', 'l50']", + "106, dual-specific ['l51', 'l52', 'l53', 'l54', 'l55']", + "107, ICL ['l51', 'l56', 'l57', 'l58', 'l59']", + "108, inhibitor, ['l52', 'l56', 'l60', 'l61', 'l62']", + "113, M. ['l53', 'l57', 'l60', 'l63', 'l64']", + "114, tuberculosis ['l54', 'l58', 'l61', 'l63', 'l65']", + "120, macrophages. ['l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "icl1", + "or", + "icl2," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "little", + "effect" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "icl1", + "or", + "icl2," + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "icl1", + "or", + "icl2," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "little", + "effect" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "little", + "effect" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "dual-specific", + "ICL", + "inhibitor," + ] + }, + "context": { + "val": "organism", + "words": [ + "M.", + "tuberculosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "dual-specific", + "ICL", + "inhibitor," + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages." + ] + } + } + ] + }, + { + "PMID": "15880120", + "TEXT": "To determine the protective potential of the humoral immune response against HIV-1 in vivo we evaluated the potency of three neutralizing antibodies (2G12, 2F5 and 4E10) in suppressing viral rebound in six acutely and eight chronically HIV-1-infected individuals undergoing interruption of antiretroviral treatment (ART). Only two of eight chronically infected individuals showed evidence of a delay in viral rebound during the passive immunization. Rebound in antibody-treated acutely infected individuals upon cessation of ART was substantially later than in a control group of 12 individuals with acute infection. Escape mutant analysis showed that the activity of 2G12 was crucial for the in vivo effect of the neutralizing antibody cocktail. By providing further direct evidence of the potency, breadth and titers of neutralizing antibodies that are required for in vivo activity, these data underline both the potential and the limits of humoral immunity in controlling HIV-1 infection.", + "TAG_DATA": [ + "68, individuals {'context': 'B-patient'}", + "100, in {'context': 'B-in vivo'}", + "101, vivo {'context': 'B-in vivo'}" + ], + "LINK_DATA": [ + "100, in ['l0']", + "101, vivo ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15864313", + "TEXT": "The muscular dystrophies are a heterogeneous group of disorders for which there are currently no cures. Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late-onset, progressive disease that generally presents in the fifth or sixth decade with dysphagia, ptosis and proximal limb weakness. OPMD is caused by the abnormal expansion of a (GCG)n trinucleotide repeat in the coding region of the poly-(A) binding protein nuclear 1 (PABPN1) gene. In unaffected individuals, (GCG)6 codes for the first six alanines in a homopolymeric stretch of ten alanines. In most individuals with OPMD this (GCG)6 repeat is expanded to (GCG)8-13, leading to a stretch of 12-17 alanines in mutant PABPN1. PABPN1 with an expanded polyalanine tract forms aggregates consisting of tubular filaments within the nuclei of skeletal muscle fibers. We have developed a transgenic mouse model of OPMD that manifests progressive muscle weakness accompanied by intranuclear aggregates and TUNEL-stained nuclei in skeletal muscle fibers. The onset and severity of these abnormalities were substantially delayed and attenuated by doxycycline treatment, which may exert its therapeutic effect by reducing aggregates and by distinct antiapoptotic properties. Doxycycline may represent a safe and feasible therapeutic for this disease.", + "TAG_DATA": [ + "130, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "131, mouse {'context': 'I-organism'}", + "132, model {'context': 'I-organism'}", + "148, skeletal {'context': 'B-cells'}", + "149, muscle {'context': 'I-cells'}", + "150, fibers. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "130, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "131, mouse ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "132, model ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "133, of ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "134, OPMD ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "148, skeletal ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "149, muscle ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "150, fibers. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "skeletal", + "muscle", + "fibers." + ] + } + } + ] + }, + { + "PMID": "15834425", + "TEXT": "Human cytomegalovirus (HCMV) is a widespread opportunistic pathogen that causes birth defects in newborns and severe disease in immunocompromised individuals. The broad tropism of HCMV infection suggests that it uses multiple receptors. We recently showed that the epidermal growth factor receptor (EGFR) serves as a receptor for HCMV. Here we show that HCMV also uses integrin alphavbeta3 as a coreceptor. Upon infection, HCMV glycoproteins gB and gH independently bind to EGFR and alphavbeta3, respectively, to initiate viral entry and signaling. Alphavbeta3 then translocates to lipid rafts where it interacts with EGFR to induce coordinated signaling. The coordination between EGFR and alphavbeta3 is essential for the early events of HCMV infection, including viral entry, RhoA downregulation, stress-fiber disassembly and viral nuclear trafficking. Our findings support a model in which EGFR and alphavbeta3 work together as coreceptors for HCMV entry and signaling. This discovery is fundamental to understanding HCMV pathogenesis and developing treatment strategies targeted to viral receptors.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15812485", + "TEXT": "Preventive vaccines are widely acknowledged as the best hope for protection against infectious pathogens such as avian flu, HIV and SARS. As a result, they have received much recent attention in the media that has exposed some of the challenges involved in optimally using vaccine technology.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15812482", + "TEXT": "Infectious diseases are thought to account for nearly 25% of all deaths worldwide, and extract a disproportionate toll in developing countries. Moreover, infectious diseases are now appreciated to be major causes of the poverty and economic underdevelopment that characterize the world's poorest countries. Development and deployment of new vaccines to prevent infectious diseases in developing countries have therefore become high priorities in the global health agenda.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15778721", + "TEXT": "We report a new platform technology for visualizing transgene expression in living subjects using magnetic resonance imaging (MRI). Using a vector, we introduced an MRI reporter, a metalloprotein from the ferritin family, into specific host tissues. The reporter is made superparamagnetic as the cell sequesters endogenous iron from the organism. In this new approach, the cells construct the MRI contrast agent in situ using genetic instructions introduced by the vector. No exogenous metal-complexed contrast agent is required, thereby simplifying intracellular delivery. We used a replication-defective adenovirus vector to deliver the ferritin transgenes. Following focal inoculation of the vector into the mouse brain, we monitored the reporter activity using in vivo time-lapse MRI. We observed robust contrast in virus-transduced neurons and glia for several weeks. This technology is adaptable to monitor transgene expression in vivo in many tissue types and has numerous biomedical applications, such as visualizing preclinical therapeutic gene delivery.", + "TAG_DATA": [ + "100, mouse {'context': 'B-tissue/organ'}", + "101, brain, {'context': 'I-tissue/organ'}", + "108, in {'context': 'B-in vivo'}", + "109, vivo {'context': 'B-in vivo'}", + "118, neurons {'context': 'B-cells'}", + "120, glia {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "100, mouse ['l0', 'l1', 'l2']", + "101, brain, ['l0', 'l3', 'l4']", + "108, in ['l1', 'l3', 'l5']", + "109, vivo ['l2', 'l4', 'l5']", + "118, neurons ['l6']", + "120, glia ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15735652", + "TEXT": "Increased glucose production is a hallmark of type 2 diabetes and alterations in lipid metabolism have a causative role in its pathophysiology. Here we postulate that physiological increments in plasma fatty acids can be sensed within the hypothalamus and that this sensing is required to balance their direct stimulatory action on hepatic gluconeogenesis. In the presence of physiologically-relevant increases in the levels of plasma fatty acids, negating their central action on hepatic glucose fluxes through (i) inhibition of the hypothalamic esterification of fatty acids, (ii) genetic deletion (Sur1-deficient mice) of hypothalamic K(ATP) channels or pharmacological blockade (K(ATP) blocker) of their activation by fatty acids, or (iii) surgical resection of the hepatic branch of the vagus nerve led to a marked increase in liver glucose production. These findings indicate that a physiological elevation in circulating lipids can be sensed within the hypothalamus and that a defect in hypothalamic lipid sensing disrupts glucose homeostasis.", + "TAG_DATA": [ + "85, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "86, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "87, (Sur1-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "88, mice) {'context': 'B-organism'}", + "89, of {'perturbing_action': 'I-gene loss-of-function'}", + "90, hypothalamic {'perturbing_action': 'I-gene loss-of-function'}", + "91, K(ATP) {'perturbing_action': 'I-gene loss-of-function'}", + "92, channels {'perturbing_action': 'I-gene loss-of-function'}", + "94, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "96, (K(ATP) {'perturbing_action': 'I-pharmacological inhibition'}", + "97, blocker) {'perturbing_action': 'I-pharmacological inhibition'}", + "106, surgical {'perturbing_action': 'B-gene loss-of-function'}", + "107, resection {'perturbing_action': 'I-gene loss-of-function'}", + "108, of {'perturbing_action': 'I-gene loss-of-function'}", + "109, the {'perturbing_action': 'I-gene loss-of-function'}", + "110, hepatic {'perturbing_action': 'I-gene loss-of-function'}", + "111, branch {'perturbing_action': 'I-gene loss-of-function'}", + "112, of {'perturbing_action': 'I-gene loss-of-function'}", + "113, the {'perturbing_action': 'I-gene loss-of-function'}", + "114, vagus {'perturbing_action': 'I-gene loss-of-function'}", + "115, nerve {'perturbing_action': 'I-gene loss-of-function'}", + "122, liver {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "85, genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "86, deletion ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "87, (Sur1-deficient ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "88, mice) ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "89, of ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "90, hypothalamic ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26', 'l27', 'l28']", + "91, K(ATP) ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l29', 'l30', 'l31']", + "92, channels ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l29']", + "94, pharmacological ['l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "96, (K(ATP) ['l32', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "97, blocker) ['l33', 'l45', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "106, surgical ['l34', 'l46', 'l57', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "107, resection ['l35', 'l47', 'l58', 'l68', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "108, of ['l36', 'l48', 'l59', 'l69', 'l78', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "109, the ['l37', 'l49', 'l60', 'l70', 'l79', 'l87', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "110, hepatic ['l38', 'l50', 'l61', 'l71', 'l80', 'l88', 'l95', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "111, branch ['l39', 'l51', 'l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l108', 'l109', 'l110', 'l111', 'l112']", + "112, of ['l40', 'l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l108', 'l113', 'l114', 'l115', 'l116']", + "113, the ['l41', 'l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l109', 'l113', 'l117', 'l118', 'l119']", + "114, vagus ['l42', 'l54', 'l65', 'l75', 'l84', 'l92', 'l99', 'l105', 'l110', 'l114', 'l117', 'l120', 'l121']", + "115, nerve ['l27', 'l30', 'l43', 'l55', 'l66', 'l76', 'l85', 'l93', 'l100', 'l106', 'l111', 'l115', 'l118', 'l120', 'l122']", + "122, liver ['l28', 'l31', 'l44', 'l56', 'l67', 'l77', 'l86', 'l94', 'l101', 'l107', 'l112', 'l116', 'l119', 'l121', 'l122']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "(Sur1-deficient", + "of", + "hypothalamic", + "K(ATP)", + "channels" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "hypothalamic", + "K(ATP)", + "surgical", + "resection", + "of", + "the", + "hepatic", + "branch", + "vagus", + "nerve" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "(K(ATP)", + "blocker)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "15723071", + "TEXT": "It has been shown that bone marrow-derived stem cells can form a major fraction of the tumor endothelium in mouse tumors. To determine the role of such cells in human tumor angiogenesis, we studied six individuals who developed cancers after bone marrow transplantation with donor cells derived from individuals of the opposite sex. By performing fluorescence in situ hybridization (FISH) with sex chromosome-specific probes in conjunction with fluorescent antibody staining, we found that such stem cells indeed contributed to tumor endothelium, but at low levels, averaging only 4.9% of the total. These results illustrate substantial differences between human tumors and many mouse models with respect to angiogenesis and have important implications for the translation of experimental antiangiogenic therapies to the clinic.", + "TAG_DATA": [ + "38, cancers {'phenotype': 'B-tumourigenesis'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15685171", + "TEXT": "Estrogen sulfotransferase (EST, encoded by SULT1E1) catalyzes the sulfoconjugation and inactivation of estrogens. Despite decades of biochemical study and the recognition that high levels of estrogen sulfates circulate in the blood of pregnant and nonpregnant women, the physiological role of estrogen sulfation remains poorly understood. Here we show that ablation of the mouse Sult1e1 gene caused placental thrombosis and spontaneous fetal loss. This phenotype was associated with elevated free estrogen levels systemically and in the amniotic fluid, increased tissue factor expression in the placenta and heightened platelet sensitivity to agonist-induced activation ex vivo. Treatment of pregnant Sult1e1-null mice with either an anticoagulant or antiestrogen prevented the fetal loss phenotype. Our results thus identify Est as a critical estrogen modulator in the placenta and suggest a link between estrogen excess and thrombotic fetal loss. These findings may have implications for understanding and treating human pregnancy failure and intrauterine growth retardation.", + "TAG_DATA": [ + "49, ablation {'perturbing_action': 'B-gene loss-of-function'}", + "50, of {'perturbing_action': 'I-gene loss-of-function'}", + "51, the {'perturbing_action': 'I-gene loss-of-function'}", + "52, mouse {'perturbing_action': 'I-gene loss-of-function'}", + "53, Sult1e1 {'perturbing_action': 'I-gene loss-of-function'}", + "54, gene {'perturbing_action': 'I-gene loss-of-function'}", + "86, platelet {'context': 'B-cells'}", + "96, Sult1e1-null {'perturbing_action': 'B-gene loss-of-function'}", + "97, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "49, ablation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "50, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "51, the ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "52, mouse ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "53, Sult1e1 ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "54, gene ['l4', 'l9', 'l13', 'l16', 'l18']", + "86, platelet ['l5', 'l10', 'l14', 'l17', 'l19']", + "96, Sult1e1-null ['l20']", + "97, mice ['l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablation", + "of", + "the", + "mouse", + "Sult1e1" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelet" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sult1e1-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15685169", + "TEXT": "Contamination of milk with drugs, pesticides and other xenotoxins can pose a major health risk to breast-fed infants and dairy consumers. Here we show that the multidrug transporter BCRP (encoded by ABCG2) is strongly induced in the mammary gland of mice, cows and humans during lactation and that it is responsible for the active secretion of clinically and toxicologically important substrates such as the dietary carcinogen PhIP, the anticancer drug topotecan and the antiulcerative cimetidine into mouse milk.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15665833", + "TEXT": "Although microglial activation occurs in inflammatory, degenerative and neoplastic central nervous system (CNS) disorders, its role in pathogenesis is unclear. We studied this question by generating CD11b-HSVTK transgenic mice, which express herpes simplex thymidine kinase in macrophages and microglia. Ganciclovir treatment of organotypic brain slice cultures derived from CD11b-HSVTK mice abolished microglial release of nitrite, proinflammatory cytokines and chemokines. Systemic ganciclovir administration to CD11b-HSVTK mice elicited hematopoietic toxicity, which was prevented by transfer of wild-type bone marrow. In bone marrow chimeras, ganciclovir blocked microglial activation in the facial nucleus upon axotomy and repressed the development of experimental autoimmune encephalomyelitis. We conclude that microglial paralysis inhibits the development and maintenance of inflammatory CNS lesions. The microglial compartment thus provides a potential therapeutic target in inflammatory CNS disorders. These results validate CD11b-HSVTK mice as a tool to study the impact of microglial activation on CNS diseases in vivo.", + "TAG_DATA": [ + "26, CD11b-HSVTK {'perturbing_action': 'B-gene gain-of-function'}", + "27, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "28, mice, {'context': 'B-organism'}", + "42, organotypic {'context': 'B-cells'}", + "43, brain {'context': 'I-cells'}", + "44, slice {'context': 'I-cells'}", + "45, cultures {'context': 'I-cells'}", + "48, CD11b-HSVTK {'perturbing_action': 'B-other'}", + "49, mice {'context': 'B-organism'}", + "63, CD11b-HSVTK {'perturbing_action': 'B-other'}", + "64, mice {'context': 'B-organism'}", + "78, bone {'context': 'B-cells'}", + "79, marrow {'context': 'I-cells'}", + "87, facial {'context': 'B-tissue/organ'}", + "88, nucleus {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "26, CD11b-HSVTK ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "27, transgenic ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "28, mice, ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "42, organotypic ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "43, brain ['l3', 'l10', 'l16', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "44, slice ['l4', 'l11', 'l17', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "45, cultures ['l5', 'l12', 'l18', 'l23', 'l28', 'l32', 'l36', 'l37', 'l38']", + "48, CD11b-HSVTK ['l6', 'l13', 'l19', 'l24', 'l29', 'l33', 'l36', 'l39', 'l40']", + "49, mice ['l7', 'l14', 'l20', 'l25', 'l30', 'l34', 'l37', 'l39']", + "63, CD11b-HSVTK ['l41']", + "64, mice ['l26', 'l31', 'l35', 'l38', 'l40', 'l41']", + "78, bone ['l42', 'l43', 'l44', 'l45']", + "79, marrow ['l42', 'l46', 'l47', 'l48']", + "80, chimeras, ['l43', 'l46', 'l49', 'l50']", + "87, facial ['l44', 'l47', 'l49', 'l51']", + "88, nucleus ['l45', 'l48', 'l50', 'l51']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "CD11b-HSVTK", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "CD11b-HSVTK", + "transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "organotypic", + "brain", + "slice", + "cultures" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "CD11b-HSVTK" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "organotypic", + "brain", + "slice", + "cultures" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "CD11b-HSVTK" + ] + } + } + ] + }, + { + "PMID": "15665830", + "TEXT": "Modest clinical outcomes of dendritic-cell (DC) vaccine trials call for the refinement of DC vaccine design. Although many potential antigens have been identified, development of methods to enhance antigen presentation by DCs has lagged. We have engineered a potent, drug-inducible CD40 (iCD40) receptor that permits temporally controlled, lymphoid-localized, DC-specific activation. iCD40 is comprised of a membrane-localized cytoplasmic domain of CD40 fused to drug-binding domains. This allows it to respond to a lipid-permeable, high-affinity dimerizer drug while circumventing ectodomain-dependent negative-feedback mechanisms. These modifications permit prolonged activation of iCD40-expressing DCs in vivo, resulting in more potent CD8(+) T-cell effector responses, including the eradication of previously established solid tumors, relative to activation of DCs ex vivo (P < 0.01), typical of most clinical DC protocols. In addition, iCD40-mediated DC activation exceeded that achieved by stimulating the full-length, endogenous CD40 receptor both in vitro and in vivo. Because iCD40 is insulated from the extracellular environment and can be activated within the context of an immunological synapse, iCD40-expressing DCs have a prolonged lifespan and should lead to more potent vaccines, perhaps even in immune-compromised patients.", + "TAG_DATA": [ + "86, iCD40-expressing {'context': 'B-cells'}", + "87, DCs {'context': 'I-cells'}", + "88, in {'context': 'B-in vivo'}", + "89, vivo, {'context': 'I-in vivo'}", + "94, CD8(+) {'context': 'B-cells'}", + "95, T-cell {'context': 'I-cells'}", + "104, solid {'context': 'B-neoplasm'}", + "105, tumors, {'context': 'I-neoplasm'}", + "110, DCs {'context': 'B-cells'}", + "125, DC {'context': 'B-cells'}", + "138, in {'context': 'B-in vitro'}", + "139, vitro {'context': 'I-in vitro'}", + "141, in {'context': 'B-in vivo'}", + "142, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "86, iCD40-expressing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "87, DCs ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "88, in ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "89, vivo, ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "94, CD8(+) ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24', 'l25']", + "95, T-cell ['l4', 'l10', 'l15', 'l19', 'l22', 'l26', 'l27', 'l28']", + "104, solid ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l29', 'l30']", + "105, tumors, ['l6', 'l12', 'l17', 'l21', 'l24', 'l27', 'l29']", + "110, DCs ['l25', 'l28', 'l30']", + "125, DC ['l31', 'l32', 'l33', 'l34', 'l35']", + "136, receptor ['l31', 'l36', 'l37', 'l38', 'l39']", + "138, in ['l32', 'l36', 'l40', 'l41', 'l42']", + "139, vitro ['l33', 'l37', 'l40', 'l43', 'l44']", + "141, in ['l34', 'l38', 'l41', 'l43', 'l45']", + "142, vivo. ['l35', 'l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15619627", + "TEXT": "The use of animal organs could potentially alleviate the critical worldwide shortage of donor organs for clinical transplantation. Because of the strong immune response to xenografts, success will probably depend upon new strategies of immune suppression and induction of tolerance. Here we report our initial results using alpha-1,3-galactosyltransferase knockout (GalT-KO) donors and a tolerance induction approach. We have achieved life-supporting pig-to-baboon renal xenograft survivals of up to 83 d with normal creatinine levels.", + "TAG_DATA": [ + "47, alpha-1,3-galactosyltransferase {'perturbing_action': 'B-gene loss-of-function'}", + "48, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "49, (GalT-KO) {'perturbing_action': 'I-gene loss-of-function'}", + "60, pig-to-baboon {'context': 'B-xenograft'}", + "61, renal {'context': 'I-xenograft'}", + "62, xenograft {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "47, alpha-1,3-galactosyltransferase ['l0', 'l1', 'l2', 'l3', 'l4']", + "48, knockout ['l0', 'l5', 'l6', 'l7', 'l8']", + "49, (GalT-KO) ['l1', 'l5', 'l9', 'l10', 'l11']", + "60, pig-to-baboon ['l2', 'l6', 'l9', 'l12', 'l13']", + "61, renal ['l3', 'l7', 'l10', 'l12', 'l14']", + "62, xenograft ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha-1,3-galactosyltransferase", + "knockout", + "(GalT-KO)" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "pig-to-baboon", + "renal", + "xenograft" + ] + } + } + ] + }, + { + "PMID": "15531891", + "TEXT": "Innate immune responses provide the host with an early protection barrier against infectious agents, including viruses, and help shape the nature and quality of the subsequent adaptive immune responses of the host. Expression of ISG15 (UCRP), a ubiquitin-like protein, and protein ISGylation are highly increased upon viral infection. We have identified UBP43 (USP18) as an ISG15 deconjugating protease. Protein ISGylation is enhanced in cells deficient in UBP43 (ref. 6). Here we have examined the role of UBP43, encoded by the gene Usp18, in innate immunity to virus infection. Usp18(-/-) mice were resistant to the fatal lymphocytic choriomeningitis and myeloencephalitis that developed in wild-type mice after intracerebral inoculation with lymphocytic choriomeningitis virus (LCMV) or vesicular stomatitis virus (VSV), respectively. Survival of Usp18(-/-) mice after intracerebral LCMV infection correlated with a severe inhibition of LCMV RNA replication and antigen expression in the brain and increased levels of protein ISGylation. Consistent with these findings, mouse embryonic fibroblasts (MEF) and bone marrow-derived macrophages from Usp18(-/-) mice showed restricted LCMV replication. Moreover, MEF from Usp18(-/-) mice showed enhanced interferon-mediated resistance to the cytopathic effect caused by VSV and Sindbis virus (SNV). This report provides the first direct evidence that the ISG15 protease UBP43 and possibly protein ISGylation have a role in innate immunity against viral infection.", + "TAG_DATA": [ + "88, Usp18(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "89, mice {'context': 'B-organism'}", + "103, mice {'context': 'B-organism'}", + "120, Usp18(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "121, mice {'context': 'B-organism'}", + "151, mouse {'context': 'B-cells'}", + "152, embryonic {'context': 'I-cells'}", + "153, fibroblasts {'context': 'I-cells'}", + "154, (MEF) {'context': 'I-cells'}", + "156, bone {'context': 'B-cells'}", + "157, marrow-derived {'context': 'I-cells'}", + "158, macrophages {'context': 'I-cells'}", + "160, Usp18(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "161, mice {'context': 'B-organism'}", + "167, MEF {'context': 'B-cells'}", + "169, Usp18(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "170, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "88, Usp18(-/-) ['l0']", + "89, mice ['l0']", + "120, Usp18(-/-) ['l1', 'l2', 'l3', 'l4']", + "121, mice ['l1', 'l5', 'l6']", + "151, mouse ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "152, embryonic ['l2', 'l7', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "153, fibroblasts ['l3', 'l5', 'l8', 'l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "154, (MEF) ['l4', 'l6', 'l9', 'l16', 'l22', 'l28', 'l29', 'l30', 'l31', 'l32']", + "156, bone ['l10', 'l17', 'l23', 'l28', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "157, marrow-derived ['l11', 'l18', 'l24', 'l29', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "158, macrophages ['l12', 'l19', 'l25', 'l30', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47']", + "160, Usp18(-/-) ['l13', 'l20', 'l26', 'l31', 'l35', 'l40', 'l44', 'l48']", + "161, mice ['l14', 'l21', 'l27', 'l32', 'l36', 'l41', 'l45', 'l48']", + "167, MEF ['l49', 'l50']", + "169, Usp18(-/-) ['l37', 'l42', 'l46', 'l49', 'l51']", + "170, mice ['l38', 'l43', 'l47', 'l50', 'l51']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Usp18(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Usp18(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "embryonic", + "fibroblasts", + "(MEF)", + "mouse", + "bone", + "marrow-derived", + "macrophages", + "MEF" + ] + } + } + ] + }, + { + "PMID": "15502844", + "TEXT": "The Arctic mutation within the amyloid-beta (Abeta) peptide causes Alzheimer disease. In vitro, Arctic-mutant Abeta forms (proto)fibrils more effectively than wild-type Abeta. We generated transgenic mouse lines expressing Arctic-mutant human amyloid precursor proteins (hAPP). Amyloid plaques formed faster and were more extensive in Arctic mice than in hAPP mice expressing wild-type Abeta, even though Arctic mice had lower Abeta(1-42/1-40) ratios. Thus, the Arctic mutation is highly amyloidogenic in vivo.", + "TAG_DATA": [ + "24, transgenic {'perturbing_action': 'B-gene gain-of-function', 'context': 'B-xenograft'}", + "25, mouse {'context': 'I-organism'}", + "26, lines {'context': 'I-organism'}", + "28, Arctic-mutant {'perturbing_action': 'B-other'}", + "29, human {'perturbing_action': 'I-other'}", + "30, amyloid {'perturbing_action': 'I-other'}", + "31, precursor {'perturbing_action': 'I-other'}", + "32, proteins {'perturbing_action': 'I-other'}", + "33, (hAPP). {'perturbing_action': 'I-other'}", + "44, mice {'context': 'B-organism'}", + "48, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "24, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "25, mouse ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "26, lines ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "28, Arctic-mutant ['l2', 'l10', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "29, human ['l3', 'l11', 'l18', 'l23', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "30, amyloid ['l4', 'l12', 'l19', 'l24', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "31, precursor ['l5', 'l13', 'l20', 'l25', 'l30', 'l35', 'l40', 'l41', 'l42', 'l43']", + "32, proteins ['l6', 'l14', 'l21', 'l26', 'l31', 'l36', 'l40', 'l44', 'l45']", + "33, (hAPP). ['l7', 'l15', 'l22', 'l27', 'l32', 'l37', 'l41', 'l44', 'l46']", + "44, mice ['l8', 'l16', 'l28', 'l33', 'l38', 'l42', 'l45', 'l46']", + "48, mice ['l34', 'l39', 'l43']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "lines", + "mice" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "transgenic" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Arctic-mutant", + "human", + "amyloid", + "precursor", + "proteins", + "(hAPP)." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "lines", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Arctic-mutant", + "human", + "amyloid", + "precursor", + "proteins", + "(hAPP)." + ] + } + } + ] + }, + { + "PMID": "15502842", + "TEXT": "High-density array comparative genomic hybridization (CGH) showed amplification of chromosome 1q22 centered on the RAB25 small GTPase, which is implicated in apical vesicle trafficking, in approximately half of ovarian and breast cancers. RAB25 mRNA levels were selectively increased in stage III and IV serous epithelial ovarian cancers compared to other genes within the amplified region, implicating RAB25 as a driving event in the development of the amplicon. Increased DNA copy number or RNA level of RAB25 was associated with markedly decreased disease-free survival or overall survival in ovarian and breast cancers, respectively. Forced expression of RAB25 markedly increased anchorage-dependent and anchorage-independent cell proliferation, prevented apoptosis and anoikis, including that induced by chemotherapy, and increased aggressiveness of cancer cells in vivo. The inhibition of apoptosis was associated with a decrease in expression of the proapoptotic molecules, BAK and BAX, and activation of the antiapoptotic phosphatidylinositol 3 kinase (PI3K) and AKT pathway, providing potential mechanisms for the effects of RAB25 on tumor aggressiveness. Overall, these studies implicate RAB25, and thus the RAB family of small G proteins, in aggressiveness of epithelial cancers.", + "TAG_DATA": [ + "92, Forced {'perturbing_action': 'B-gene gain-of-function'}", + "93, expression {'perturbing_action': 'I-gene gain-of-function'}", + "94, of {'perturbing_action': 'I-gene gain-of-function'}", + "95, RAB25 {'perturbing_action': 'I-gene gain-of-function'}", + "97, increased {'effect': 'B-positive'}", + "101, cell {'context': 'I-cells'}", + "102, proliferation, {'phenotype': 'B-proliferation'}", + "103, prevented {'effect': 'B-negative'}", + "104, apoptosis {'phenotype': 'B-apoptosis'}", + "116, cancer {'context': 'B-transformed cells'}", + "117, cells {'context': 'I-transformed cells'}", + "118, in {'context': 'B-in vivo'}", + "119, vivo. {'context': 'I-in vivo'}", + "121, inhibition {'effect': 'B-negative'}", + "123, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "92, Forced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "93, expression ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "94, of ['l1', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "95, RAB25 ['l2', 'l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "97, increased ['l3', 'l14', 'l23', 'l31', 'l37', 'l38']", + "101, cell ['l4', 'l15', 'l24', 'l32', 'l37', 'l39']", + "102, proliferation, ['l5', 'l16', 'l25', 'l33', 'l38', 'l39']", + "103, prevented ['l6', 'l17', 'l26', 'l34', 'l40']", + "104, apoptosis ['l7', 'l18', 'l27', 'l35', 'l40']", + "116, cancer ['l8', 'l19', 'l28', 'l41', 'l42', 'l43']", + "117, cells ['l9', 'l20', 'l29', 'l36', 'l41', 'l44', 'l45']", + "118, in ['l10', 'l42', 'l44', 'l46']", + "119, vivo. ['l11', 'l21', 'l30', 'l43', 'l45', 'l46']", + "121, inhibition ['l47']", + "123, apoptosis ['l47']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "expression", + "of", + "RAB25" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "expression", + "of", + "RAB25" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "expression", + "of", + "RAB25" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "expression", + "of", + "RAB25" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "expression", + "of", + "RAB25" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "expression", + "of", + "RAB25" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "expression", + "of" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented", + "inhibition" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "15489859", + "TEXT": "Nitric oxide (NO) physiologically stimulates the sarco/endoplasmic reticulum calcium (Ca(2+)) ATPase (SERCA) to decrease intracellular Ca(2+) concentration and relax cardiac, skeletal and vascular smooth muscle. Here, we show that NO-derived peroxynitrite (ONOO(-)) directly increases SERCA activity by S-glutathiolation and that this modification of SERCA is blocked by irreversible oxidation of the relevant cysteine thiols during atherosclerosis. Purified SERCA was S-glutathiolated by ONOO(-) and the increase in Ca(2+)-uptake activity of SERCA reconstituted in phospholipid vesicles required the presence of glutathione. Mutation of the SERCA-reactive Cys674 to serine abolished these effects. Because superoxide scavengers decreased S-glutathiolation of SERCA and arterial relaxation by NO, ONOO(-) is implicated as the intracellular mediator. NO-dependent relaxation as well as S-glutathiolation and activation of SERCA were decreased by atherosclerosis and Cys674 was found to be oxidized to sulfonic acid. Thus, irreversible oxidation of key thiol(s) in disease impairs NO-induced relaxation by preventing reversible S-glutathiolation and activation of SERCA by NO/ONOO(-).", + "TAG_DATA": [ + "79, Mutation {'perturbing_action': 'B-other'}", + "80, of {'perturbing_action': 'I-other'}", + "81, the {'perturbing_action': 'I-other'}", + "82, SERCA-reactive {'perturbing_action': 'I-other'}", + "83, Cys674 {'perturbing_action': 'I-other'}", + "84, to {'perturbing_action': 'I-other'}", + "85, serine {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "79, Mutation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "80, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "81, the ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "82, SERCA-reactive ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "83, Cys674 ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "84, to ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "85, serine ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15489858", + "TEXT": "The antiphospholipid syndrome (APS) is defined by thrombosis and recurrent pregnancy loss in the presence of antiphospholipid (aPL) antibodies and is generally treated with anticoagulation therapy. Because complement activation is essential and causative in aPL antibody-induced fetal injury, we hypothesized that heparin protects pregnant APS patients from complications through inhibition of complement. Treatment with heparin (unfractionated or low molecular weight) prevented complement activation in vivo and in vitro and protected mice from pregnancy complications induced by aPL antibodies. Neither fondaparinux nor hirudin, other anticoagulants, inhibited the generation of complement split products or prevented pregnancy loss, demonstrating that anticoagulation therapy is insufficient protection against APS-associated miscarriage. Our data indicate that heparins prevent obstetrical complications in women with APS because they block activation of complement induced by aPL antibodies targeted to decidual tissues, rather than by their anticoagulant effects.", + "TAG_DATA": [ + "63, in {'context': 'B-in vivo'}", + "64, vivo {'context': 'I-in vivo'}", + "66, in {'context': 'B-in vitro'}", + "67, vitro {'context': 'I-in vitro'}", + "70, mice {'context': 'B-organism'}", + "92, prevented {'effect': 'B-negative'}", + "93, pregnancy {'phenotype': 'B-cell survival'}", + "94, loss, {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "63, in ['l0', 'l1', 'l2', 'l3']", + "64, vivo ['l0', 'l4', 'l5']", + "66, in ['l1', 'l6', 'l7']", + "67, vitro ['l2', 'l4', 'l6', 'l8']", + "70, mice ['l3', 'l5', 'l7', 'l8']", + "92, prevented ['l9', 'l10']", + "93, pregnancy ['l9', 'l11']", + "94, loss, ['l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "pregnancy" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "loss," + ] + } + } + ] + }, + { + "PMID": "15448683", + "TEXT": "Inactivation of the adenosine A(2A) receptor (A(2A)R) consistently protects against ischemic brain injury and other neural insults, but the relative contribution of A(2A)Rs on peripheral inflammatory cells versus A(2A)Rs expressed on neurons and glia is unknown. We created a chimeric mouse model in which A(2A)Rs on bone marrow-derived cells (BMDCs) were selectively inactivated or reconstituted by bone marrow transplantation. Selective reconstitution of A(2A)Rs on BMDCs (A(2A)R knockout mice transplanted with wild-type bone marrow cells) largely reinstates ischemic brain injury in global A(2A)R knockout mice. Conversely, selective inactivation of A(2A)Rs on BMDCs (wild-type mice transplanted with A(2A)R knockout bone marrow cells) attenuates infarct volumes and ischemia-induced expression of several proinflammatory cytokines in the brain, but exacerbates ischemic liver injury. These results indicate that the A(2A)R-stimulated cascade in BMDCs is an important modulator of ischemic brain injury and that ischemic brain and liver injuries are regulated distinctly by A(2A)Rs on BMDCs.", + "TAG_DATA": [ + "39, chimeric {'context': 'B-organism'}", + "40, mouse {'context': 'I-organism'}", + "41, model {'context': 'I-organism'}", + "46, bone {'context': 'B-cells'}", + "47, marrow-derived {'context': 'I-cells'}", + "48, cells {'context': 'I-cells'}", + "49, (BMDCs) {'context': 'I-cells'}", + "64, BMDCs {'context': 'B-cells'}", + "66, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "67, mice {'context': 'B-organism'}", + "71, bone {'context': 'B-cells'}", + "72, marrow {'context': 'I-cells'}", + "73, cells) {'context': 'I-cells'}", + "80, global {'perturbing_action': 'B-gene loss-of-function'}", + "81, A(2A)R {'perturbing_action': 'B-gene loss-of-function'}", + "82, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "83, mice. {'context': 'B-organism'}", + "85, selective {'perturbing_action': 'B-gene loss-of-function'}", + "86, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "87, of {'perturbing_action': 'I-gene loss-of-function'}", + "88, A(2A)Rs {'perturbing_action': 'I-gene loss-of-function'}", + "90, BMDCs {'context': 'B-cells'}", + "92, mice {'context': 'B-organism'}", + "95, A(2A)R {'perturbing_action': 'B-gene loss-of-function'}", + "96, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "97, bone {'context': 'B-cells'}", + "98, marrow {'context': 'I-cells'}", + "99, cells) {'context': 'I-cells'}", + "112, brain, {'context': 'B-tissue/organ'}", + "116, liver {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "39, chimeric ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "40, mouse ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "41, model ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "46, bone ['l2', 'l7', 'l11', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "47, marrow-derived ['l3', 'l8', 'l12', 'l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "48, cells ['l4', 'l9', 'l13', 'l16', 'l22', 'l28', 'l29', 'l30']", + "49, (BMDCs) ['l5', 'l10', 'l14', 'l17', 'l23', 'l28', 'l31', 'l32', 'l33']", + "64, BMDCs ['l18', 'l24', 'l29', 'l31', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "66, knockout ['l19', 'l25', 'l34', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "67, mice ['l35', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "71, bone ['l36', 'l44', 'l51', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "72, marrow ['l37', 'l45', 'l52', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "73, cells) ['l38', 'l46', 'l53', 'l59', 'l64', 'l69', 'l70', 'l71', 'l72']", + "80, global ['l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l73', 'l74', 'l75']", + "81, A(2A)R ['l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l76', 'l77']", + "82, knockout ['l20', 'l26', 'l30', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l78']", + "83, mice. ['l21', 'l27', 'l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l77', 'l78']", + "85, selective ['l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "86, inactivation ['l79', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "87, of ['l80', 'l91', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "88, A(2A)Rs ['l81', 'l92', 'l102', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "90, BMDCs ['l82', 'l93', 'l103', 'l112', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "92, mice ['l83', 'l94', 'l104', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "95, A(2A)R ['l84', 'l95', 'l105', 'l113', 'l120', 'l127', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139']", + "96, knockout ['l85', 'l96', 'l106', 'l114', 'l121', 'l128', 'l134', 'l140', 'l141', 'l142', 'l143', 'l144']", + "97, bone ['l86', 'l97', 'l107', 'l115', 'l122', 'l129', 'l135', 'l140', 'l145', 'l146', 'l147', 'l148']", + "98, marrow ['l87', 'l98', 'l108', 'l116', 'l123', 'l130', 'l136', 'l141', 'l145', 'l149', 'l150', 'l151']", + "99, cells) ['l88', 'l99', 'l109', 'l117', 'l124', 'l131', 'l137', 'l142', 'l146', 'l149', 'l152', 'l153']", + "112, brain, ['l89', 'l100', 'l110', 'l118', 'l125', 'l132', 'l138', 'l143', 'l147', 'l150', 'l152', 'l154']", + "116, liver ['l90', 'l101', 'l111', 'l119', 'l126', 'l133', 'l139', 'l144', 'l148', 'l151', 'l153', 'l154']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "bone", + "marrow-derived", + "cells", + "(BMDCs)", + "BMDCs", + "marrow", + "cells)" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout", + "global", + "A(2A)R", + "selective", + "inactivation", + "of", + "A(2A)Rs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout", + "global", + "A(2A)R", + "selective", + "inactivation", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "inactivation", + "of", + "A(2A)Rs", + "A(2A)R", + "knockout" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain,", + "liver" + ] + } + } + ] + }, + { + "PMID": "15378054", + "TEXT": "Ectopic pregnancy is a major reproductive health issue. Although other underlying causes remain largely unknown, one cause of ectopic pregnancy is embryo retention in the fallopian tube. Here we show that genetic or pharmacologic silencing of cannabinoid receptor CB1 causes retention of a large number of embryos in the mouse oviduct, eventually leading to pregnancy failure. This is reversed by isoproterenol, a beta-adrenergic receptor agonist. Impaired oviductal embryo transport is also observed in wild-type mice treated with methanandamide. Collectively, the results suggest that aberrant cannabinoid signaling impedes coordinated oviductal smooth muscle contraction and relaxation crucial to normal oviductal embryo transport. Colocalization of CB1 and beta2-adrenergic receptors in the oviduct muscularis implies that a basal endocannabinoid tone in collaboration with adrenergic receptors coordinates oviductal motility for normal journey of embryos into the uterus. Besides uncovering a new regulatory mechanism, this study could be clinically relevant to ectopic pregnancy.", + "TAG_DATA": [ + "33, pharmacologic {'perturbing_action': 'B-rnai/knockdown'}", + "34, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "35, of {'perturbing_action': 'I-rnai/knockdown'}", + "36, cannabinoid {'perturbing_action': 'I-rnai/knockdown'}", + "37, receptor {'perturbing_action': 'I-rnai/knockdown'}", + "38, CB1 {'perturbing_action': 'I-rnai/knockdown'}", + "49, mouse {'context': 'B-tissue/organ'}", + "50, oviduct, {'context': 'I-tissue/organ'}", + "74, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "33, pharmacologic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "34, silencing ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "35, of ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "36, cannabinoid ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "37, receptor ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "38, CB1 ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "49, mouse ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "50, oviduct, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "pharmacologic", + "silencing", + "of", + "cannabinoid", + "receptor", + "CB1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "oviduct," + ] + } + } + ] + }, + { + "PMID": "15340416", + "TEXT": "Great progress has been made in the field of tumor immunology in the past decade, but optimism about the clinical application of currently available cancer vaccine approaches is based more on surrogate endpoints than on clinical tumor regression. In our cancer vaccine trials of 440 patients, the objective response rate was low (2.6%), and comparable to the results obtained by others. We consider here results in cancer vaccine trials and highlight alternate strategies that mediate cancer regression in preclinical and clinical models.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15311275", + "TEXT": "Bronchus-associated lymphoid tissue (BALT) is occasionally found in the lungs of mice and humans; however, its role in respiratory immunity is unknown. Here we show that mice lacking spleen, lymph nodes and Peyer's patches generate unexpectedly robust primary B- and T-cell responses to influenza, which seem to be initiated at sites of induced BALT (iBALT). Areas of iBALT have distinct B-cell follicles and T-cell areas, and support T and B-cell proliferation. The homeostatic chemokines CXCL13 and CCL21 are expressed independently of TNFalpha and lymphotoxin at sites of iBALT formation. In addition, mice with iBALT, but lacking peripheral lymphoid organs, clear influenza infection and survive higher doses of virus than do normal mice, indicating that immune responses generated in iBALT are not only protective, but potentially less pathologic, than systemic immune responses. Thus, iBALT functions as an inducible secondary lymphoid tissue for respiratory immune responses.", + "TAG_DATA": [ + "26, mice {'context': 'B-organism'}", + "70, proliferation. {'phenotype': 'B-proliferation'}", + "91, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "26, mice ['l0', 'l1']", + "28, spleen, ['l0', 'l2']", + "30, nodes ['l1', 'l2']", + "91, mice ['l3']", + "97, lymphoid ['l4']", + "98, organs, ['l3', 'l4']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15273748", + "TEXT": "X-linked immunodeficiency with hyper-IgM (HIGM1), characterized by failure of immunoglobulin isotype switching, is caused by mutations of the CD40 ligand (CD40L), which is normally expressed on activated CD4(+) T cells. As constitutive expression of CD40L induces lymphomas, we corrected the mutation while preserving the natural regulation of CD40L using pre-mRNA trans-splicing. Bone marrow from mice lacking CD40L was modified with a lentivirus trans-splicer encoding the normal CD40L exons 2-5 and was administered to syngenic CD40L-knockout mice. Recipient mice had corrected CD40L mRNA, antigen-specific IgG1 responses to keyhole limpet hemocyanin immunization, regulated CD4(+) T-cell CD40L expression after CD3 stimulation in primary and secondary transplanted mice, attenuation of Pneumocystis carinii pneumonia, and no evidence of lymphoproliferative disease over 1 year. Thus, HIGM1 can be corrected by CD40L trans-splicing, leading to functional correction of the genetic defect without the adverse consequences of unregulated expression of the CD40L gene.", + "TAG_DATA": [ + "51, Bone {'context': 'B-cells'}", + "52, marrow {'context': 'I-cells'}", + "54, mice {'context': 'B-organism'}", + "55, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "56, CD40L {'perturbing_action': 'I-gene loss-of-function'}", + "73, syngenic {'perturbing_action': 'B-gene loss-of-function'}", + "74, CD40L-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "75, mice. {'context': 'B-organism'}", + "77, mice {'context': 'I-organism'}", + "91, CD4(+) {'context': 'B-cells'}", + "100, and {'context': 'I-cells'}", + "101, secondary {'context': 'I-cells'}", + "103, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "51, Bone ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "52, marrow ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "54, mice ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "55, lacking ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "56, CD40L ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "73, syngenic ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "74, CD40L-knockout ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27', 'l28']", + "75, mice. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "77, mice ['l28', 'l29', 'l30', 'l31', 'l32']", + "91, CD4(+) ['l33', 'l34', 'l35', 'l36']", + "100, and ['l29', 'l33', 'l37', 'l38', 'l39']", + "101, secondary ['l30', 'l34', 'l37', 'l40', 'l41']", + "102, transplanted ['l31', 'l35', 'l38', 'l40', 'l42']", + "103, mice, ['l32', 'l36', 'l39', 'l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Bone", + "marrow" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "CD40L", + "syngenic", + "CD40L-knockout" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "CD40L", + "syngenic", + "CD40L-knockout" + ] + } + } + ] + }, + { + "PMID": "15247912", + "TEXT": "Staphylococcus aureus is a major human pathogen that is associated with diverse types of local and systemic infection characterized by inflammation dominated by polymorphonuclear leukocytes. Staphylococci frequently cause pneumonia, and these clinical isolates often have increased expression of protein A, suggesting that this protein may have a role in virulence. Here we show that TNFR1, a receptor for tumor-necrosis factor-alpha (TNF-alpha) that is widely distributed on the airway epithelium, is a receptor for protein A. We also show that the protein A-TNFR1 signaling pathway has a central role in the pathogenesis of staphylococcal pneumonia.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15247911", + "TEXT": "Here we show, in a double-blind, randomized, placebo-controlled trial in 37,107 fully immunized infants in Soweto, South Africa, that a 9-valent pneumococcal conjugate vaccine, PncCV, prevents 31% (95% confidence interval = 15-43%) of pneumonias associated with any of seven respiratory viruses in children in hospital. These data suggest that the pneumococcus has a major role in the development of pneumonia associated with these viruses and that viruses contribute to the pathogenesis of bacterial pneumonia.", + "TAG_DATA": [ + "13, infants {'context': 'B-organism'}", + "42, children {'context': 'B-patient'}", + "43, in {'context': 'B-in vitro'}", + "44, hospital. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "13, infants ['l0']", + "42, children ['l1', 'l2']", + "43, in ['l0', 'l1', 'l3']", + "44, hospital. ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15229512", + "TEXT": "Cannabinoids inhibit motility and secretion in the intestine. They are now assigned the additional task of curbing excessive inflammation, suggesting that drugs targeting the endogenous cannabinoid system could be exploited for inflammatory bowel disease.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15195089", + "TEXT": "Dystrophic epidermolysis bullosa (DEB) is a family of inherited mechano-bullous disorders that are caused by mutations in the type VII collagen gene and for which ex vivo gene therapy has been considered. To develop a simpler approach for treating DEB, we evaluated the feasibility of protein-based therapy by intradermally injecting human recombinant type VII collagen into mouse skin and a DEB human skin equivalent transplanted onto mice. The injected collagen localized to the basement membrane zone of both types of tissues, was organized into human anchoring fibril structures and reversed the features of DEB disease in the DEB skin equivalent.", + "TAG_DATA": [ + "56, mouse {'context': 'B-tissue/organ'}", + "57, skin {'context': 'I-tissue/organ'}", + "66, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, mouse ['l0']", + "57, skin ['l0']", + "61, human ['l1', 'l2', 'l3']", + "62, skin ['l1', 'l4', 'l5']", + "63, equivalent ['l2', 'l4', 'l6']", + "66, mice. ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15184894", + "TEXT": "Several congenital muscular dystrophies caused by defects in known or putative glycosyltransferases are commonly associated with hypoglycosylation of alpha-dystroglycan (alpha-DG) and a marked reduction of its receptor function. We have investigated changes in the processing and function of alpha-DG resulting from genetic manipulation of LARGE, the putative glycosyltransferase mutated both in Large(myd) mice and in humans with congenital muscular dystrophy 1D (MDC1D). Here we show that overexpression of LARGE ameliorates the dystrophic phenotype of Large(myd) mice and induces the synthesis of glycan-enriched alpha-DG with high affinity for extracellular ligands. Notably, LARGE circumvents the alpha-DG glycosylation defect in cells from individuals with genetically distinct types of congenital muscular dystrophy. Gene transfer of LARGE into the cells of individuals with congenital muscular dystrophies restores alpha-DG receptor function, whereby glycan-enriched alpha-DG coordinates the organization of laminin on the cell surface. Our findings indicate that modulation of LARGE expression or activity is a viable therapeutic strategy for glycosyltransferase-deficient congenital muscular dystrophies.", + "TAG_DATA": [ + "66, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "67, of {'perturbing_action': 'I-gene gain-of-function'}", + "68, LARGE {'perturbing_action': 'I-gene gain-of-function'}", + "74, Large(myd) {'perturbing_action': 'B-other'}", + "75, mice {'context': 'B-organism'}", + "97, cells {'context': 'B-cells'}", + "108, Gene {'perturbing_action': 'B-gene gain-of-function'}", + "109, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "110, of {'perturbing_action': 'I-gene gain-of-function'}", + "111, LARGE {'perturbing_action': 'I-gene gain-of-function'}", + "114, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "66, overexpression ['l0', 'l1', 'l2', 'l3', 'l4']", + "67, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "68, LARGE ['l1', 'l5', 'l9', 'l10', 'l11']", + "74, Large(myd) ['l2', 'l6', 'l9', 'l12', 'l13']", + "75, mice ['l3', 'l7', 'l10', 'l12']", + "97, cells ['l4', 'l8', 'l11', 'l13']", + "108, Gene ['l14', 'l15', 'l16', 'l17']", + "109, transfer ['l14', 'l18', 'l19', 'l20']", + "110, of ['l15', 'l18', 'l21', 'l22']", + "111, LARGE ['l16', 'l19', 'l21', 'l23']", + "114, cells ['l17', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "LARGE" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "LARGE", + "Gene", + "transfer" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Large(myd)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Large(myd)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "15156204", + "TEXT": "Central neurons regenerate axons if a permissive environment is provided; after spinal cord injury, however, inhibitory molecules are present that make the local environment nonpermissive. A promising new strategy for inducing neurons to overcome inhibitory signals is to activate cAMP signaling. Here we show that cAMP levels fall in the rostral spinal cord, sensorimotor cortex and brainstem after spinal cord contusion. Inhibition of cAMP hydrolysis by the phosphodiesterase IV inhibitor rolipram prevents this decrease and when combined with Schwann cell grafts promotes significant supraspinal and proprioceptive axon sparing and myelination. Furthermore, combining rolipram with an injection of db-cAMP near the graft not only prevents the drop in cAMP levels but increases them above those in uninjured controls. This further enhances axonal sparing and myelination, promotes growth of serotonergic fibers into and beyond grafts, and significantly improves locomotion. These findings show that cAMP levels are key for protection, growth and myelination of injured CNS axons in vivo and recovery of function.", + "TAG_DATA": [ + "78, Schwann {'context': 'B-xenograft'}", + "79, cell {'context': 'I-xenograft'}", + "80, grafts {'context': 'I-xenograft'}", + "127, serotonergic {'context': 'B-cells'}", + "128, fibers {'context': 'I-cells'}", + "135, improves {'effect': 'B-positive'}", + "136, locomotion. {'phenotype': 'B-autophagy'}" + ], + "LINK_DATA": [ + "78, Schwann ['l0', 'l1']", + "79, cell ['l0', 'l2']", + "80, grafts ['l1', 'l2']", + "127, serotonergic ['l3', 'l4', 'l5']", + "128, fibers ['l3', 'l6', 'l7']", + "135, improves ['l4', 'l6', 'l8']", + "136, locomotion. ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "serotonergic", + "fibers" + ] + }, + "effect": { + "val": "positive", + "words": [ + "improves" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "serotonergic", + "fibers" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "locomotion." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "improves" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "locomotion." + ] + } + } + ] + }, + { + "PMID": "15133506", + "TEXT": "Obesity is an increasingly prevalent human condition in developed societies. Despite major progress in the understanding of the molecular mechanisms leading to obesity, no safe and effective treatment has yet been found. Here, we report an antiobesity therapy based on targeted induction of apoptosis in the vasculature of adipose tissue. We used in vivo phage display to isolate a peptide motif (sequence CKGGRAKDC) that homes to white fat vasculature. We show that the CKGGRAKDC peptide associates with prohibitin, a multifunctional membrane protein, and establish prohibitin as a vascular marker of adipose tissue. Targeting a proapoptotic peptide to prohibitin in the adipose vasculature caused ablation of white fat. Resorption of established white adipose tissue and normalization of metabolism resulted in rapid obesity reversal without detectable adverse effects. Because prohibitin is also expressed in blood vessels of human white fat, this work may lead to the development of targeted drugs for treatment of obese patients.", + "TAG_DATA": [ + "52, in {'context': 'B-in vivo'}", + "53, vivo {'context': 'B-in vivo'}", + "100, adipose {'context': 'B-tissue/organ'}", + "101, vasculature {'context': 'I-tissue/organ'}", + "106, fat. {'context': 'I-tissue/organ'}", + "110, white {'context': 'B-tissue/organ'}", + "111, adipose {'context': 'I-tissue/organ'}", + "112, tissue {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "52, in ['l0', 'l1', 'l2', 'l3', 'l4']", + "53, vivo ['l0', 'l5', 'l6', 'l7', 'l8']", + "100, adipose ['l1', 'l5', 'l9', 'l10', 'l11']", + "101, vasculature ['l2', 'l6', 'l9', 'l12', 'l13']", + "105, white ['l3', 'l7', 'l10', 'l12', 'l14']", + "106, fat. ['l4', 'l8', 'l11', 'l13', 'l14']", + "110, white ['l15', 'l16']", + "111, adipose ['l15', 'l17']", + "112, tissue ['l16', 'l17']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15122251", + "TEXT": "Many proteins and pathways of pharmaceutical interest impinge on ubiquitin ligases or their substrates. The cyclin-dependent kinase (Cdk) inhibitor p27, for example, is polyubiquitylated in a cell cycle-dependent manner by a ubiquitin ligase complex containing the F-box protein Skp2. Regulated turnover of p27 is due, at least partly, to its phosphorylation by Cdk2 on threonine 187, which generates a Skp2-binding site. We made a p27-luciferase (p27Luc) fusion protein and show here that its abundance, like that of p27, is regulated by Skp2 in a cell cycle-dependent manner. As predicted, p27Luc levels increased after blocking Cdk2 activity with inhibitory proteins, peptides or small interfering RNA (siRNA). Accumulation of p27Luc in response to Cdk2 inhibitory drugs (flavopiridol and R-roscovitine) was demonstrable in human tumor cells in vivo using noninvasive bioluminescent imaging. In theory, the approach described here could be used to develop bioluminescent reporters for any drug target that directly or indirectly affects the turnover of a ubiquitin ligase substrate.", + "TAG_DATA": [ + "93, blocking {'perturbing_action': 'B-pharmacological inhibition'}", + "94, Cdk2 {'perturbing_action': 'I-pharmacological inhibition'}", + "95, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "96, with {'perturbing_action': 'I-pharmacological inhibition'}", + "111, Cdk2 {'perturbing_action': 'B-pharmacological inhibition'}", + "112, inhibitory {'perturbing_action': 'I-pharmacological inhibition'}", + "113, drugs {'perturbing_action': 'I-pharmacological inhibition'}", + "120, human {'context': 'B-transformed cells'}", + "121, tumor {'context': 'I-transformed cells'}", + "122, cells {'context': 'I-transformed cells'}", + "123, in {'context': 'B-in vivo'}", + "124, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "93, blocking ['l0', 'l1', 'l2']", + "94, Cdk2 ['l0', 'l3', 'l4']", + "95, activity ['l1', 'l3', 'l5']", + "96, with ['l2', 'l4', 'l5']", + "111, Cdk2 ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "112, inhibitory ['l6', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "113, drugs ['l7', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "120, human ['l8', 'l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "121, tumor ['l9', 'l15', 'l20', 'l24', 'l28', 'l29', 'l30']", + "122, cells ['l10', 'l16', 'l21', 'l25', 'l28', 'l31', 'l32']", + "123, in ['l11', 'l17', 'l22', 'l26', 'l29', 'l31', 'l33']", + "124, vivo ['l12', 'l18', 'l23', 'l27', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Cdk2", + "inhibitory", + "drugs" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Cdk2", + "inhibitory", + "drugs" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "15107843", + "TEXT": "CD1d is a major histocompatibility complex (MHC) class I-related molecule that functions in glycolipid antigen presentation to distinct subsets of T cells that express natural killer receptors and an invariant T-cell receptor-alpha chain (invariant NKT cells). The acquisition of glycolipid antigens by CD1d occurs, in part, in endosomes through the function of resident lipid transfer proteins, namely saposins. Here we show that microsomal triglyceride transfer protein (MTP), a protein that resides in the endoplasmic reticulum of hepatocytes and intestinal epithelial cells (IECs) and is essential for lipidation of apolipoprotein B, associates with CD1d in hepatocytes. Hepatocytes from animals in which Mttp (the gene encoding MTP) has been conditionally deleted, and IECs in which Mttp gene products have been silenced, are unable to activate invariant NKT cells. Conditional deletion of the Mttp gene in hepatocytes is associated with a redistribution of CD1d expression, and Mttp-deleted mice are resistant to immunopathologies associated with invariant NKT cell-mediated hepatitis and colitis. These studies indicate that the CD1d-regulating function of MTP in the endoplasmic reticulum is complementary to that of the saposins in endosomes in vivo.", + "TAG_DATA": [ + "95, Hepatocytes {'context': 'B-cells'}", + "97, animals {'context': 'B-organism'}", + "100, Mttp {'perturbing_action': 'B-gene loss-of-function'}", + "101, (the {'perturbing_action': 'I-gene loss-of-function'}", + "102, gene {'perturbing_action': 'I-gene loss-of-function'}", + "103, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "104, MTP) {'perturbing_action': 'I-gene loss-of-function'}", + "105, has {'perturbing_action': 'I-gene loss-of-function'}", + "106, been {'perturbing_action': 'I-gene loss-of-function'}", + "107, conditionally {'perturbing_action': 'I-gene loss-of-function'}", + "108, deleted, {'perturbing_action': 'I-gene loss-of-function'}", + "110, IECs {'context': 'B-cells'}", + "113, Mttp {'perturbing_action': 'B-rnai/knockdown'}", + "114, gene {'perturbing_action': 'I-rnai/knockdown'}", + "115, products {'perturbing_action': 'I-rnai/knockdown'}", + "116, have {'perturbing_action': 'I-rnai/knockdown'}", + "117, been {'perturbing_action': 'I-rnai/knockdown'}", + "118, silenced, {'perturbing_action': 'I-rnai/knockdown'}", + "120, unable {'effect': 'B-no effect'}", + "123, invariant {'context': 'B-cells'}", + "124, NKT {'context': 'I-cells'}", + "125, cells. {'context': 'I-cells'}", + "126, Conditional {'perturbing_action': 'B-gene loss-of-function'}", + "127, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "128, of {'perturbing_action': 'I-gene loss-of-function'}", + "129, the {'perturbing_action': 'I-gene loss-of-function'}", + "130, Mttp {'perturbing_action': 'I-gene loss-of-function'}", + "131, gene {'perturbing_action': 'I-gene loss-of-function'}", + "133, hepatocytes {'context': 'B-cells'}", + "143, Mttp-deleted {'perturbing_action': 'B-gene loss-of-function'}", + "144, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "95, Hepatocytes ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "97, animals ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "100, Mttp ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "101, (the ['l2', 'l16', 'l29', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "102, gene ['l3', 'l17', 'l30', 'l43', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "103, encoding ['l4', 'l18', 'l31', 'l44', 'l56', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "104, MTP) ['l5', 'l19', 'l32', 'l45', 'l57', 'l68', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "105, has ['l6', 'l20', 'l33', 'l46', 'l58', 'l69', 'l79', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "106, been ['l7', 'l21', 'l34', 'l47', 'l59', 'l70', 'l80', 'l89', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "107, conditionally ['l8', 'l22', 'l35', 'l48', 'l60', 'l71', 'l81', 'l90', 'l98', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "108, deleted, ['l9', 'l23', 'l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l99', 'l106', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "110, IECs ['l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l100', 'l107', 'l113', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "113, Mttp ['l119', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "114, gene ['l120', 'l137', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "115, products ['l121', 'l138', 'l154', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184']", + "116, have ['l122', 'l139', 'l155', 'l170', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198']", + "117, been ['l123', 'l140', 'l156', 'l171', 'l185', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211']", + "118, silenced, ['l124', 'l141', 'l157', 'l172', 'l186', 'l199', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223']", + "120, unable ['l10', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l108', 'l114', 'l125', 'l142', 'l158', 'l173', 'l187', 'l200', 'l212', 'l224', 'l225', 'l226', 'l227']", + "122, activate ['l11', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l115', 'l126', 'l143', 'l159', 'l174', 'l188', 'l201', 'l213', 'l224', 'l228', 'l229', 'l230']", + "123, invariant ['l12', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l127', 'l144', 'l160', 'l175', 'l189', 'l202', 'l214', 'l225', 'l228', 'l231', 'l232']", + "124, NKT ['l13', 'l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l128', 'l145', 'l161', 'l176', 'l190', 'l203', 'l215', 'l226', 'l229', 'l231', 'l233']", + "125, cells. ['l14', 'l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l118', 'l129', 'l146', 'l162', 'l177', 'l191', 'l204', 'l216', 'l227', 'l230', 'l232', 'l233']", + "126, Conditional ['l130', 'l147', 'l163', 'l178', 'l192', 'l205', 'l217', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239']", + "127, deletion ['l131', 'l148', 'l164', 'l179', 'l193', 'l206', 'l218', 'l234', 'l240', 'l241', 'l242', 'l243', 'l244']", + "128, of ['l132', 'l149', 'l165', 'l180', 'l194', 'l207', 'l219', 'l235', 'l240', 'l245', 'l246', 'l247', 'l248']", + "129, the ['l133', 'l150', 'l166', 'l181', 'l195', 'l208', 'l220', 'l236', 'l241', 'l245', 'l249', 'l250', 'l251']", + "130, Mttp ['l134', 'l151', 'l167', 'l182', 'l196', 'l209', 'l221', 'l237', 'l242', 'l246', 'l249', 'l252', 'l253']", + "131, gene ['l135', 'l152', 'l168', 'l183', 'l197', 'l210', 'l222', 'l238', 'l243', 'l247', 'l250', 'l252', 'l254']", + "133, hepatocytes ['l136', 'l153', 'l169', 'l184', 'l198', 'l211', 'l223', 'l239', 'l244', 'l248', 'l251', 'l253', 'l254']", + "143, Mttp-deleted ['l255']", + "144, mice ['l255']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Hepatocytes", + "IECs", + "invariant", + "NKT", + "cells.", + "hepatocytes" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mttp", + "(the", + "gene", + "encoding", + "MTP)", + "has", + "been", + "conditionally", + "deleted,", + "Conditional", + "deletion", + "of", + "the" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Hepatocytes", + "IECs", + "invariant", + "NKT", + "cells." + ] + }, + "effect": { + "val": "no effect", + "words": [ + "unable" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animals", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mttp", + "(the", + "gene", + "encoding", + "MTP)", + "has", + "been", + "conditionally", + "deleted,", + "Mttp-deleted" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animals" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "unable" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mttp", + "(the", + "gene", + "encoding", + "MTP)", + "has", + "been", + "conditionally", + "deleted," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "unable" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "IECs", + "invariant", + "NKT", + "cells.", + "hepatocytes" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Mttp", + "gene", + "products", + "have", + "been", + "silenced," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Mttp", + "gene", + "products", + "have", + "been", + "silenced," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "unable" + ] + } + } + ] + }, + { + "PMID": "15107842", + "TEXT": "The congenital disorders of glycosylation (CDG) are characterized by defects in N-linked glycan biosynthesis that result from mutations in genes encoding proteins directly involved in the glycosylation pathway. Here we describe two siblings with a fatal form of CDG caused by a mutation in the gene encoding COG-7, a subunit of the conserved oligomeric Golgi (COG) complex. The mutation impairs integrity of the COG complex and alters Golgi trafficking, resulting in disruption of multiple glycosylation pathways. These cases represent a new type of CDG in which the molecular defect lies in a protein that affects the trafficking and function of the glycosylation machinery.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15048110", + "TEXT": "Peroxisome proliferator-activated receptor-delta (PPAR-delta; also known as PPAR-beta) is expressed at high levels in colon tumors, but its contribution to colon cancer is unclear. We examined the role of PPAR-delta in colon carcinogenesis using PPAR-delta-deficient (Ppard(-/-)) mice. In both the Min mutant and chemically induced mouse models, colon polyp formation was significantly greater in mice nullizygous for PPAR-delta. In contrast to previous reports suggesting that activation of PPAR-delta potentiates colon polyp formation, here we show that PPAR-delta attenuates colon carcinogenesis.", + "TAG_DATA": [ + "34, PPAR-delta-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "35, (Ppard(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "36, mice. {'context': 'B-organism'}", + "45, mouse {'context': 'B-organism'}", + "46, models, {'context': 'I-organism'}", + "54, mice {'context': 'B-organism'}", + "55, nullizygous {'perturbing_action': 'B-gene loss-of-function'}", + "56, for {'perturbing_action': 'I-gene gain-of-function'}", + "57, PPAR-delta. {'perturbing_action': 'I-gene gain-of-function'}", + "77, attenuates {'effect': 'B-negative'}", + "78, colon {'context': 'B-tissue/organ'}", + "79, carcinogenesis. {'phenotype': 'B-tumourigenesis'}" + ], + "LINK_DATA": [ + "34, PPAR-delta-deficient ['l0', 'l1', 'l2', 'l3', 'l4']", + "35, (Ppard(-/-)) ['l0', 'l5', 'l6', 'l7']", + "36, mice. ['l1', 'l5']", + "41, mutant ['l2', 'l6', 'l8']", + "45, mouse ['l3', 'l9', 'l10', 'l11']", + "46, models, ['l4', 'l7', 'l8', 'l9']", + "54, mice ['l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "55, nullizygous ['l12', 'l18', 'l19', 'l20', 'l21', 'l22']", + "56, for ['l13', 'l18', 'l23', 'l24', 'l25', 'l26']", + "57, PPAR-delta. ['l14', 'l19', 'l23', 'l27', 'l28', 'l29']", + "77, attenuates ['l15', 'l20', 'l24', 'l27', 'l30', 'l31']", + "78, colon ['l10', 'l16', 'l21', 'l25', 'l28', 'l30', 'l32']", + "79, carcinogenesis. ['l11', 'l17', 'l22', 'l26', 'l29', 'l31', 'l32']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PPAR-delta-deficient", + "(Ppard(-/-))", + "nullizygous" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mouse", + "models,", + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "carcinogenesis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "for", + "PPAR-delta." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuates" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nullizygous" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuates" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nullizygous" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "colon" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nullizygous" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "carcinogenesis." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "for", + "PPAR-delta." + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuates" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "for", + "PPAR-delta." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "colon" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "for", + "PPAR-delta." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "carcinogenesis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuates" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "colon" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuates" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "carcinogenesis." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "colon" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "carcinogenesis." + ] + } + } + ] + }, + { + "PMID": "14991049", + "TEXT": "Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of end-stage renal disease. The vasopressin V2 receptor (VPV2R) antagonist OPC31260 has been effective in two animal models of PKD with pathologies that are probably related. Here we show, in a mouse model of ADPKD (Pkd2(-/tm1Som)), a similar cellular phenotype and response to OPC31260 treatment, with reduction of renal cyclic AMP (cAMP) levels, prevention of renal enlargement, marked inhibition of cystogenesis and protection of renal function.", + "TAG_DATA": [ + "41, mouse {'context': 'B-organism'}", + "42, model {'context': 'I-organism'}", + "43, of {'context': 'I-organism'}", + "44, ADPKD {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "41, mouse ['l0', 'l1', 'l2']", + "42, model ['l0', 'l3', 'l4']", + "43, of ['l1', 'l3', 'l5']", + "44, ADPKD ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14981512", + "TEXT": "Angiogenesis is crucial for tumor growth. Angiogenesis inhibitors, such as O-(chloracetyl-carbamoyl) fumagillol (TNP-470), are thus emerging as a new class of anticancer drugs. In clinical trials, TNP-470 slowed tumor growth in patients with metastatic cancer. However, at higher doses necessary for tumor regression, many patients experienced neurotoxicity. We therefore synthesized and characterized a water-soluble conjugate of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer, Gly-Phe-Leu-Gly linker and TNP-470. This conjugate accumulated selectively in tumor vessels because of the enhanced permeability and retention (EPR) effect. HPMA copolymer-TNP-470 substantially enhanced and prolonged the activity of TNP-470 in vivo in tumor and hepatectomy models. Polymer conjugation prevented TNP-470 from crossing the blood-brain barrier (BBB) and decreased its accumulation in normal organs, thereby avoiding drug-related toxicities. Treatment with TNP-470 caused weight loss and neurotoxic effects in mice, whereas treatment with the conjugate did not. This new approach for targeting angiogenesis inhibitors specifically to the tumor vasculature may provide a new strategy for the rational design of cancer therapies.", + "TAG_DATA": [ + "89, in {'context': 'B-in vivo'}", + "90, vivo {'context': 'I-in vivo'}", + "92, tumor {'context': 'B-neoplasm'}", + "94, hepatectomy {'context': 'B-tissue/organ'}", + "95, models. {'context': 'I-neoplasm'}", + "127, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "89, in ['l0', 'l1', 'l2', 'l3']", + "90, vivo ['l0', 'l4', 'l5', 'l6']", + "92, tumor ['l1', 'l4', 'l7', 'l8']", + "94, hepatectomy ['l2', 'l5', 'l7', 'l9']", + "95, models. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14966520", + "TEXT": "Engendering cytotoxic T-lymphocyte (CTL) responses is likely to be an important goal of HIV vaccines. However, CTLs select for viral variants that escape immune detection. Maintenance of such escape variants in human populations could pose an obstacle to HIV vaccine development. We first observed that escape mutations in a heterogeneous simian immunodeficiency virus (SIV) isolate were lost upon passage to new animals. We therefore infected macaques with a cloned SIV bearing escape mutations in three immunodominant CTL epitopes, and followed viral evolution after infection. Here we show that each mutant epitope sequence continued to evolve in vivo, often re-establishing the original, CTL-susceptible sequence. We conclude that escape from CTL responses may exact a cost to viral fitness. In the absence of selective pressure upon transmission to new hosts, these original escape mutations can be lost. This suggests that some HIV CTL epitopes will be maintained in human populations.", + "TAG_DATA": [ + "65, macaques {'context': 'B-organism'}", + "95, in {'context': 'B-in vivo'}", + "96, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "95, in ['l0']", + "96, vivo, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14966518", + "TEXT": "The protein kinase C (PKC) family of serine/threonine kinases functions downstream of nearly all membrane-associated signal transduction pathways. Here we identify PKC-alpha as a fundamental regulator of cardiac contractility and Ca(2+) handling in myocytes. Hearts of Prkca-deficient mice are hypercontractile, whereas those of transgenic mice overexpressing Prkca are hypocontractile. Adenoviral gene transfer of dominant-negative or wild-type PKC-alpha into cardiac myocytes enhances or reduces contractility, respectively. Mechanistically, modulation of PKC-alpha activity affects dephosphorylation of the sarcoplasmic reticulum Ca(2+) ATPase-2 (SERCA-2) pump inhibitory protein phospholamban (PLB), and alters sarcoplasmic reticulum Ca(2+) loading and the Ca(2+) transient. PKC-alpha directly phosphorylates protein phosphatase inhibitor-1 (I-1), altering the activity of protein phosphatase-1 (PP-1), which may account for the effects of PKC-alpha on PLB phosphorylation. Hypercontractility caused by Prkca deletion protects against heart failure induced by pressure overload, and against dilated cardiomyopathy induced by deleting the gene encoding muscle LIM protein (Csrp3). Deletion of Prkca also rescues cardiomyopathy associated with overexpression of PP-1. Thus, PKC-alpha functions as a nodal integrator of cardiac contractility by sensing intracellular Ca(2+) and signal transduction events, which can profoundly affect propensity toward heart failure.", + "TAG_DATA": [ + "34, Hearts {'context': 'B-tissue/organ'}", + "36, Prkca-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "37, mice {'context': 'B-organism'}", + "43, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "44, mice {'perturbing_action': 'I-gene gain-of-function', 'context': 'I-organism'}", + "45, overexpressing {'perturbing_action': 'I-gene gain-of-function'}", + "46, Prkca {'perturbing_action': 'I-gene gain-of-function'}", + "49, Adenoviral {'perturbing_action': 'B-other'}", + "50, gene {'perturbing_action': 'I-other'}", + "51, transfer {'perturbing_action': 'I-other'}", + "52, of {'perturbing_action': 'I-other'}", + "53, dominant-negative {'perturbing_action': 'I-other'}", + "54, or {'perturbing_action': 'I-other'}", + "55, wild-type {'perturbing_action': 'I-other'}", + "56, PKC-alpha {'perturbing_action': 'I-other'}", + "58, cardiac {'context': 'B-cells'}", + "59, myocytes {'context': 'I-cells'}", + "122, Prkca {'perturbing_action': 'B-gene loss-of-function'}", + "123, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "138, deleting {'perturbing_action': 'B-gene loss-of-function'}", + "139, the {'perturbing_action': 'I-gene loss-of-function'}", + "140, gene {'perturbing_action': 'I-gene loss-of-function'}", + "141, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "142, muscle {'perturbing_action': 'I-gene loss-of-function'}", + "143, LIM {'perturbing_action': 'I-gene loss-of-function'}", + "144, protein {'perturbing_action': 'I-gene loss-of-function'}", + "145, (Csrp3). {'perturbing_action': 'I-gene loss-of-function'}", + "146, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "147, of {'perturbing_action': 'I-gene loss-of-function'}", + "148, Prkca {'perturbing_action': 'I-gene loss-of-function'}", + "154, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "155, of {'perturbing_action': 'I-gene gain-of-function'}", + "156, PP-1. {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "34, Hearts ['l0', 'l1', 'l2', 'l3']", + "36, Prkca-deficient ['l0', 'l4', 'l5', 'l6', 'l7']", + "37, mice ['l1', 'l4', 'l8', 'l9']", + "43, transgenic ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "44, mice ['l10', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "45, overexpressing ['l11', 'l23', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "46, Prkca ['l5', 'l12', 'l24', 'l35', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "49, Adenoviral ['l13', 'l25', 'l36', 'l46', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "50, gene ['l14', 'l26', 'l37', 'l47', 'l56', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "51, transfer ['l15', 'l27', 'l38', 'l48', 'l57', 'l65', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "52, of ['l16', 'l28', 'l39', 'l49', 'l58', 'l66', 'l73', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "53, dominant-negative ['l17', 'l29', 'l40', 'l50', 'l59', 'l67', 'l74', 'l80', 'l86', 'l87', 'l88', 'l89', 'l90']", + "54, or ['l18', 'l30', 'l41', 'l51', 'l60', 'l68', 'l75', 'l81', 'l86', 'l91', 'l92', 'l93', 'l94']", + "55, wild-type ['l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l76', 'l82', 'l87', 'l91', 'l95', 'l96', 'l97']", + "56, PKC-alpha ['l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l83', 'l88', 'l92', 'l95', 'l98', 'l99']", + "58, cardiac ['l2', 'l6', 'l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l89', 'l93', 'l96', 'l98', 'l100']", + "59, myocytes ['l3', 'l7', 'l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l94', 'l97', 'l99', 'l100']", + "122, Prkca ['l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "123, deletion ['l101', 'l110', 'l111', 'l112']", + "138, deleting ['l102', 'l110', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "139, the ['l103', 'l113', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "140, gene ['l104', 'l114', 'l120', 'l126', 'l127', 'l128', 'l129', 'l130']", + "141, encoding ['l105', 'l115', 'l121', 'l126', 'l131', 'l132', 'l133', 'l134', 'l135']", + "142, muscle ['l106', 'l116', 'l122', 'l127', 'l131', 'l136', 'l137', 'l138', 'l139']", + "143, LIM ['l107', 'l117', 'l123', 'l128', 'l132', 'l136', 'l140', 'l141', 'l142']", + "144, protein ['l108', 'l111', 'l118', 'l124', 'l129', 'l133', 'l137', 'l140', 'l143', 'l144']", + "145, (Csrp3). ['l109', 'l112', 'l119', 'l125', 'l130', 'l134', 'l138', 'l141', 'l143', 'l145']", + "146, Deletion ['l146', 'l147', 'l148', 'l149', 'l150']", + "147, of ['l146', 'l151', 'l152', 'l153', 'l154']", + "148, Prkca ['l135', 'l139', 'l142', 'l144', 'l145', 'l147', 'l151', 'l155', 'l156', 'l157']", + "154, overexpression ['l148', 'l152', 'l155', 'l158', 'l159']", + "155, of ['l149', 'l153', 'l156', 'l158', 'l160']", + "156, PP-1. ['l150', 'l154', 'l157', 'l159', 'l160']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "Hearts" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Prkca-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Prkca-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Prkca-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiac", + "myocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "mice" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "mice", + "overexpressing", + "Prkca" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiac", + "myocytes" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Adenoviral", + "gene", + "transfer", + "of", + "dominant-negative", + "or", + "wild-type", + "PKC-alpha" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Adenoviral", + "gene", + "transfer", + "of", + "dominant-negative", + "or", + "wild-type", + "PKC-alpha" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiac", + "myocytes" + ] + } + } + ] + }, + { + "PMID": "14760422", + "TEXT": "The first X-ray crystal structures of gp41, the protein that mediates fusion of HIV-1 to target cells, were solved in the mid-1990s. The structures provide a foundation for understanding viral entry and the mechanism of action of compounds that block fusion. The first fusion inhibitor has recently entered the clinic, and the hope is that more potent and broadly active compounds, based on molecular design, will follow.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "14745444", + "TEXT": "The effects of vascular endothelial growth factor (VEGF) blockade on the vascular biology of human tumors are not known. Here we show here that a single infusion of the VEGF-specific antibody bevacizumab decreases tumor perfusion, vascular volume, microvascular density, interstitial fluid pressure and the number of viable, circulating endothelial and progenitor cells, and increases the fraction of vessels with pericyte coverage in rectal carcinoma patients. These data indicate that VEGF blockade has a direct and rapid antivascular effect in human tumors.", + "TAG_DATA": [ + "33, tumor {'context': 'B-neoplasm'}", + "46, viable, {'context': 'B-cells'}", + "47, circulating {'context': 'I-cells'}", + "48, endothelial {'context': 'I-cells'}", + "49, and {'context': 'I-cells'}", + "50, progenitor {'context': 'I-cells'}", + "51, cells, {'context': 'I-cells'}", + "59, pericyte {'context': 'B-cells'}", + "62, rectal {'context': 'B-neoplasm'}", + "63, carcinoma {'context': 'I-neoplasm'}", + "64, patients. {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "33, tumor ['l0']", + "46, viable, ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "47, circulating ['l1', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "48, endothelial ['l2', 'l9', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "49, and ['l3', 'l10', 'l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "50, progenitor ['l4', 'l11', 'l17', 'l22', 'l27', 'l28', 'l29', 'l30', 'l31']", + "51, cells, ['l0', 'l5', 'l12', 'l18', 'l23', 'l27', 'l32', 'l33']", + "59, pericyte ['l28', 'l34', 'l35', 'l36']", + "62, rectal ['l6', 'l13', 'l19', 'l24', 'l29', 'l34', 'l37', 'l38']", + "63, carcinoma ['l7', 'l14', 'l20', 'l25', 'l30', 'l32', 'l35', 'l37', 'l39']", + "64, patients. ['l8', 'l15', 'l21', 'l26', 'l31', 'l33', 'l36', 'l38', 'l39']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14745443", + "TEXT": "DNA containing unmethylated cytidyl guanosyl (CpG) sequences, which are underrepresented in mammalian genomes but prevalent in prokaryotes, is endocytosed by cells of the innate immune system, including macrophages, monocytes and dendritic cells, and activates a pathway involving Toll-like receptor-9 (TLR9). CpG-containing oligodeoxynucleotides (CpG-ODN) are potent stimulators of innate immunity, and are currently being tested as adjuvants of antimicrobial, antiallergic, anticancer and antiprion immunotherapy. Little is known, however, about the consequences of repeated CpG-ODN administration, which is advocated for some of these applications. Here we report that daily injection of 60 microg CpG-ODN dramatically alters the morphology and functionality of mouse lymphoid organs. By day 7, lymphoid follicles were poorly defined; follicular dendritic cells (FDC) and germinal center B lymphocytes were suppressed. Accordingly, CpG-ODN treatment for > or =7 d strongly reduced primary humoral immune responses and immunoglobulin class switching. By day 20, mice developed multifocal liver necrosis and hemorrhagic ascites. All untoward effects were strictly dependent on CpG and TLR9, as neither the CpG-ODN treatment of Tlr9(-/-) mice nor the repetitive challenge of wild-type mice with nonstimulatory ODN (AT-ODN) or with the TLR3 agonist polyinosinic:cytidylic acid (polyI:C) were immunotoxic or hepatotoxic.", + "TAG_DATA": [ + "99, mouse {'context': 'B-tissue/organ'}", + "100, lymphoid {'context': 'I-tissue/organ'}", + "101, organs. {'context': 'I-tissue/organ'}", + "110, follicular {'context': 'B-cells'}", + "111, dendritic {'context': 'I-cells'}", + "112, cells {'context': 'I-cells'}", + "113, (FDC) {'context': 'I-cells'}", + "115, germinal {'context': 'B-cells'}", + "116, center {'context': 'I-cells'}", + "117, B {'context': 'I-cells'}", + "118, lymphocytes {'context': 'I-cells'}", + "142, mice {'context': 'B-organism'}", + "145, liver {'context': 'B-tissue/organ'}", + "146, necrosis {'phenotype': 'B-necrosis'}", + "166, Tlr9(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "167, mice {'context': 'B-organism'}", + "174, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "99, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "100, lymphoid ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "101, organs. ['l1', 'l9', 'l17', 'l18', 'l19', 'l20']", + "110, follicular ['l2', 'l10', 'l17', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "111, dendritic ['l3', 'l11', 'l18', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "112, cells ['l4', 'l12', 'l19', 'l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "113, (FDC) ['l5', 'l13', 'l20', 'l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "115, germinal ['l6', 'l14', 'l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "116, center ['l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "117, B ['l7', 'l15', 'l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "118, lymphocytes ['l8', 'l16', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l48']", + "142, mice ['l49', 'l50']", + "145, liver ['l49', 'l51']", + "146, necrosis ['l50', 'l51']", + "166, Tlr9(-/-) ['l52', 'l53']", + "167, mice ['l52', 'l54']", + "174, mice ['l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tlr9(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "14716306", + "TEXT": "Transport parameters determine the access of drugs to tumors. However, technical difficulties preclude the measurement of these parameters deep inside living tissues. To this end, we adapted and further optimized two-photon fluorescence correlation microscopy (TPFCM) for in vivo measurement of transport parameters in tumors. TPFCM extends the detectable range of diffusion coefficients in tumors by one order of magnitude, and reveals both a fast and a slow component of diffusion. The ratio of these two components depends on molecular size and can be altered in vivo with hyaluronidase and collagenase. These studies indicate that TPFCM is a promising tool to dissect the barriers to drug delivery in tumors.", + "TAG_DATA": [ + "53, tumors {'context': 'B-neoplasm'}", + "84, in {'context': 'B-in vivo'}", + "85, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "84, in ['l0']", + "85, vivo ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14702635", + "TEXT": "Human and mouse embryonic stem cells (HESCs and MESCs, respectively) self-renew indefinitely while maintaining the ability to generate all three germ-layer derivatives. Despite the importance of ESCs in developmental biology and their potential impact on tissue replacement therapy, the molecular mechanism underlying ESC self-renewal is poorly understood. Here we show that activation of the canonical Wnt pathway is sufficient to maintain self-renewal of both HESCs and MESCs. Although Stat-3 signaling is involved in MESC self-renewal, stimulation of this pathway does not support self-renewal of HESCs. Instead we find that Wnt pathway activation by 6-bromoindirubin-3'-oxime (BIO), a specific pharmacological inhibitor of glycogen synthase kinase-3 (GSK-3), maintains the undifferentiated phenotype in both types of ESCs and sustains expression of the pluripotent state-specific transcription factors Oct-3/4, Rex-1 and Nanog. Wnt signaling is endogenously activated in undifferentiated MESCs and is downregulated upon differentiation. In addition, BIO-mediated Wnt activation is functionally reversible, as withdrawal of the compound leads to normal multidifferentiation programs in both HESCs and MESCs. These results suggest that the use of GSK-3-specific inhibitors such as BIO may have practical applications in regenerative medicine.", + "TAG_DATA": [ + "95, a {'perturbing_action': 'I-pharmacological inhibition'}", + "96, specific {'perturbing_action': 'I-pharmacological inhibition'}", + "97, pharmacological {'perturbing_action': 'I-pharmacological inhibition'}", + "98, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "99, of {'perturbing_action': 'I-pharmacological inhibition'}", + "100, glycogen {'perturbing_action': 'I-pharmacological inhibition'}", + "101, synthase {'perturbing_action': 'I-pharmacological inhibition'}", + "102, kinase-3 {'perturbing_action': 'I-pharmacological inhibition'}", + "103, (GSK-3), {'perturbing_action': 'I-pharmacological inhibition'}", + "104, maintains {'effect': 'B-positive'}", + "106, undifferentiated {'phenotype': 'B-differentiation'}", + "107, phenotype {'phenotype': 'I-differentiation'}", + "112, ESCs {'context': 'B-cells'}", + "152, leads {'effect': 'B-positive'}", + "153, to {'effect': 'I-positive'}", + "155, multidifferentiation {'phenotype': 'B-differentiation'}", + "156, programs {'phenotype': 'I-differentiation'}", + "159, HESCs {'context': 'B-cells'}", + "161, MESCs. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "95, a ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "96, specific ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "97, pharmacological ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "98, inhibitor ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "99, of ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "100, glycogen ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "101, synthase ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "102, kinase-3 ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "103, (GSK-3), ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "104, maintains ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "106, undifferentiated ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "107, phenotype ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "112, ESCs ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "152, leads ['l78', 'l79', 'l80', 'l81', 'l82']", + "153, to ['l78', 'l83', 'l84', 'l85', 'l86']", + "155, multidifferentiation ['l79', 'l83', 'l87', 'l88', 'l89']", + "156, programs ['l80', 'l84', 'l87', 'l90', 'l91']", + "159, HESCs ['l81', 'l85', 'l88', 'l90', 'l92']", + "161, MESCs. ['l82', 'l86', 'l89', 'l91', 'l92']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "a", + "specific", + "pharmacological", + "inhibitor", + "of", + "glycogen", + "synthase", + "kinase-3", + "(GSK-3)," + ] + }, + "effect": { + "val": "positive", + "words": [ + "maintains" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "a", + "specific", + "pharmacological", + "inhibitor", + "of", + "glycogen", + "synthase", + "kinase-3", + "(GSK-3)," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "undifferentiated", + "phenotype" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "a", + "specific", + "pharmacological", + "inhibitor", + "of", + "glycogen", + "synthase", + "kinase-3", + "(GSK-3)," + ] + }, + "context": { + "val": "cells", + "words": [ + "ESCs" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "maintains", + "leads", + "to" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "undifferentiated", + "phenotype", + "multidifferentiation", + "programs" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "maintains", + "leads", + "to" + ] + }, + "context": { + "val": "cells", + "words": [ + "ESCs", + "HESCs", + "MESCs." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "undifferentiated", + "phenotype", + "multidifferentiation", + "programs" + ] + }, + "context": { + "val": "cells", + "words": [ + "ESCs", + "HESCs", + "MESCs." + ] + } + } + ] + }, + { + "PMID": "14702632", + "TEXT": "Using microarray-based profiling of isogenic prostate cancer xenograft models, we found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy. This increase in androgen receptor mRNA and protein was both necessary and sufficient to convert prostate cancer growth from a hormone-sensitive to a hormone-refractory stage, and was dependent on a functional ligand-binding domain. Androgen receptor antagonists showed agonistic activity in cells with increased androgen receptor levels; this antagonist-agonist conversion was associated with alterations in the recruitment of coactivators and corepressors to the promoters of androgen receptor target genes. Increased levels of androgen receptor confer resistance to antiandrogens by amplifying signal output from low levels of residual ligand, and by altering the normal response to antagonists. These findings provide insight toward the design of new antiandrogens.", + "TAG_DATA": [ + "4, isogenic {'context': 'B-xenograft'}", + "5, prostate {'context': 'I-xenograft'}", + "6, cancer {'context': 'I-xenograft'}", + "7, xenograft {'context': 'I-xenograft'}", + "8, models, {'context': 'I-xenograft'}", + "48, prostate {'context': 'B-neoplasm'}", + "49, cancer {'context': 'I-neoplasm', 'phenotype': 'B-tumour growth'}", + "50, growth {'phenotype': 'I-tumour growth'}", + "73, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "4, isogenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "5, prostate ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "6, cancer ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "7, xenograft ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "8, models, ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "48, prostate ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "49, cancer ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "50, growth ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "xenograft", + "words": [ + "isogenic", + "prostate", + "cancer", + "xenograft", + "models," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "cancer", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "cancer", + "prostate" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "cancer", + "growth" + ] + } + } + ] + }, + { + "PMID": "14661018", + "TEXT": "It remains unclear how and why autoimmunity occurs. Here we show evidence for a previously unrecognized and possibly general mechanism of autoimmunity. This new finding was discovered serendipitously using material from patients with inflammatory vascular disease caused by antineutrophil cytoplasmic autoantibodies (ANCA) with specificity for proteinase-3 (PR-3). Such patients harbor not only antibodies to the autoantigen (PR-3), but also antibodies to a peptide translated from the antisense DNA strand of PR-3 (complementary PR-3, cPR-3) or to a mimic of this peptide. Immunization of mice with the middle region of cPR-3 resulted in production of antibodies not only to cPR-3, but also to the immunogen's sense peptide counterpart, PR-3. Both human and mouse antibodies to PR-3 and cPR-3 bound to each other, indicating idiotypic relationships. These findings indicate that autoimmunity can be initiated through an immune response against a peptide that is antisense or complementary to the autoantigen, which then induces anti-idiotypic antibodies (autoantibodies) that cross-react with the autoantigen.", + "TAG_DATA": [ + "83, mice {'context': 'B-organism'}", + "109, human {'context': 'B-cells'}", + "110, and {'context': 'I-cells'}", + "111, mouse {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "109, human ['l0', 'l1']", + "110, and ['l0', 'l2']", + "111, mouse ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14608378", + "TEXT": "Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy. The predominant subtype, CMT-1A, accounts for more than 50% of all cases and is associated with an interstitial chromosomal duplication of 17p12 (refs. 2,3). We have generated a model of CMT-1A by introducing extra copies of the responsible disease gene, Pmp22 (encoding the peripheral myelin protein of 22 kDa), into transgenic rats. Here, we used this model to test whether progesterone, a regulator of the myelin genes Pmp22 and myelin protein zero (Mpz) in cultured Schwann cells, can modulate the progressive neuropathy caused by moderate overexpression of Pmp22. Male transgenic rats (n = 84) were randomly assigned into three treatment groups: progesterone, progesterone antagonist (onapristone) and placebo control. Daily administration of progesterone elevated the steady-state levels of Pmp22 and Mpz mRNA in the sciatic nerve, resulting in enhanced Schwann cell pathology and a more progressive clinical neuropathy. In contrast, administration of the selective progesterone receptor antagonist reduced overexpression of Pmp22 and improved the CMT phenotype, without obvious side effects, in wild-type or transgenic rats. Taken together, these data provide proof of principle that the progesterone receptor of myelin-forming Schwann cells is a promising pharmacological target for therapy of CMT-1A.", + "TAG_DATA": [ + "84, Schwann {'context': 'I-cells'}", + "85, cells, {'context': 'I-cells'}", + "94, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "97, Male {'context': 'B-organism'}", + "98, transgenic {'context': 'I-organism'}", + "99, rats {'context': 'I-organism'}", + "100, (n {'context': 'I-organism'}", + "132, sciatic {'context': 'B-tissue/organ'}", + "133, nerve, {'context': 'I-tissue/organ'}", + "137, Schwann {'context': 'B-cells'}", + "138, cell {'context': 'I-cells'}", + "151, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "153, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "160, improved {'effect': 'B-positive'}", + "162, CMT {'phenotype': 'B-epithelial-mesenchymal transition'}", + "163, phenotype, {'phenotype': 'I-senescence'}", + "171, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "172, rats. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "84, Schwann ['l0', 'l1', 'l2', 'l3']", + "85, cells, ['l0', 'l4', 'l5', 'l6']", + "94, overexpression ['l1', 'l4', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "97, Male ['l7', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "98, transgenic ['l8', 'l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "99, rats ['l9', 'l16', 'l22', 'l28', 'l29', 'l30', 'l31', 'l32']", + "100, (n ['l10', 'l17', 'l23', 'l28', 'l33', 'l34', 'l35', 'l36']", + "132, sciatic ['l11', 'l18', 'l24', 'l29', 'l33', 'l37', 'l38', 'l39']", + "133, nerve, ['l2', 'l5', 'l12', 'l19', 'l25', 'l30', 'l34', 'l37', 'l40', 'l41']", + "137, Schwann ['l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l42']", + "138, cell ['l3', 'l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l41', 'l42']", + "151, selective ['l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "152, progesterone ['l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "153, receptor ['l44', 'l51', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "154, antagonist ['l45', 'l52', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "160, improved ['l46', 'l53', 'l59', 'l64', 'l69', 'l70', 'l71', 'l72']", + "162, CMT ['l47', 'l54', 'l60', 'l65', 'l69', 'l73', 'l74', 'l75']", + "163, phenotype, ['l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l76', 'l77']", + "171, transgenic ['l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l78']", + "172, rats. ['l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l77', 'l78']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Schwann", + "cells,", + "cell" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "Male", + "transgenic", + "rats", + "(n", + "rats." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "sciatic", + "nerve," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "receptor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "improved" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "receptor" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "CMT" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "receptor" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "phenotype," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "receptor" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "improved" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "CMT" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "improved" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "phenotype," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "improved" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "improved" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats." + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "CMT" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "CMT" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats." + ] + } + }, + { + "phenotype": { + "val": "senescence", + "words": [ + "phenotype," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + } + }, + { + "phenotype": { + "val": "senescence", + "words": [ + "phenotype," + ] + }, + "context": { + "val": "organism", + "words": [ + "rats." + ] + } + } + ] + }, + { + "PMID": "14595408", + "TEXT": "We recently reported that mice deficient in the programmed cell death-1 (PD-1) immunoinhibitory coreceptor develop autoimmune dilated cardiomyopathy (DCM), with production of high-titer autoantibodies against a heart-specific, 30-kDa protein. In this study, we purified the 30-kDa protein from heart extract and identified it as cardiac troponin I (cTnI), encoded by a gene in which mutations can cause familial hypertrophic cardiomyopathy (HCM). Administration of monoclonal antibodies to cTnI induced dilatation and dysfunction of hearts in wild-type mice. Monoclonal antibodies to cTnI stained the surface of cardiomyocytes and augmented the voltage-dependent L-type Ca2+ current of normal cardiomyocytes. These findings suggest that antibodies to cTnI induce heart dysfunction and dilatation by chronic stimulation of Ca2+ influx in cardiomyocytes.", + "TAG_DATA": [ + "72, hearts {'context': 'B-tissue/organ'}", + "75, mice. {'context': 'B-organism'}", + "84, cardiomyocytes {'context': 'B-cells'}", + "94, cardiomyocytes. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "72, hearts ['l0']", + "75, mice. ['l0']", + "84, cardiomyocytes ['l1']", + "94, cardiomyocytes. ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14578882", + "TEXT": "Expansion of human hematopoietic stem cells (HSCs) is a major challenge in cellular therapy, and currently relies on the use of recombinant cytokines or on gene transfer of transcription factors. Of these, the HOXB4 homeoprotein protein is of particular interests as it promotes the expansion of mouse HSCs without inducing the development of leukemia. To eliminate any deleterious effects that might be associated with stable HOXB4 gene transfer into human cells, we took advantage of the ability of HOX proteins to passively translocate through cell membranes. Here we show that when cultured on stromal cells genetically engineered to secrete HOXB4, human long-term culture-initiating cells (LTC-ICs) and nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mouse repopulating cells (SRCs) were expanded by more than 20- and 2.5-fold, respectively, over their input numbers. This expansion was associated with enhanced stem cell repopulating capacity in vivo and maintenance of pluripotentiality. This method provides a basis for developing cell therapy strategies using expanded HSCs that are not genetically modified.", + "TAG_DATA": [ + "93, stromal {'context': 'B-cells'}", + "94, cells {'context': 'I-cells'}", + "95, genetically {'perturbing_action': 'B-gene gain-of-function'}", + "96, engineered {'perturbing_action': 'I-gene gain-of-function'}", + "97, to {'perturbing_action': 'I-gene gain-of-function'}", + "98, secrete {'perturbing_action': 'I-gene gain-of-function'}", + "99, HOXB4, {'perturbing_action': 'I-gene gain-of-function'}", + "100, human {'context': 'B-cells'}", + "101, long-term {'context': 'I-cells'}", + "102, culture-initiating {'context': 'I-cells'}", + "103, cells {'context': 'I-cells'}", + "104, (LTC-ICs) {'context': 'I-cells'}", + "106, nonobese {'context': 'B-cells'}", + "107, diabetic-severe {'context': 'I-cells'}", + "108, combined {'context': 'I-cells'}", + "109, immunodeficiency {'context': 'I-cells'}", + "110, (NOD-SCID) {'context': 'I-cells'}", + "111, mouse {'context': 'I-cells'}", + "112, repopulating {'context': 'I-cells'}", + "113, cells {'context': 'I-cells'}", + "114, (SRCs) {'context': 'I-cells'}", + "134, stem {'context': 'B-cells'}", + "138, in {'context': 'B-in vivo'}", + "139, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "93, stromal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "94, cells ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "95, genetically ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "96, engineered ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "97, to ['l3', 'l13', 'l22', 'l30', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "98, secrete ['l4', 'l14', 'l23', 'l31', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "99, HOXB4, ['l5', 'l15', 'l24', 'l32', 'l40', 'l46', 'l52', 'l53', 'l54', 'l55', 'l56']", + "100, human ['l6', 'l16', 'l25', 'l33', 'l41', 'l47', 'l52', 'l57', 'l58', 'l59', 'l60']", + "101, long-term ['l7', 'l17', 'l26', 'l34', 'l42', 'l48', 'l53', 'l57', 'l61', 'l62', 'l63']", + "102, culture-initiating ['l8', 'l18', 'l27', 'l35', 'l43', 'l49', 'l54', 'l58', 'l61', 'l64', 'l65']", + "103, cells ['l9', 'l19', 'l28', 'l36', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l66']", + "104, (LTC-ICs) ['l10', 'l20', 'l29', 'l37', 'l45', 'l51', 'l56', 'l60', 'l63', 'l65', 'l66']", + "106, nonobese ['l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "107, diabetic-severe ['l67', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "108, combined ['l68', 'l78', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "109, immunodeficiency ['l38', 'l69', 'l79', 'l88', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "110, (NOD-SCID) ['l70', 'l80', 'l89', 'l97', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "111, mouse ['l71', 'l81', 'l90', 'l98', 'l105', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "112, repopulating ['l72', 'l82', 'l91', 'l99', 'l106', 'l112', 'l118', 'l119', 'l120', 'l121', 'l122']", + "113, cells ['l73', 'l83', 'l92', 'l100', 'l107', 'l113', 'l118', 'l123']", + "114, (SRCs) ['l74', 'l84', 'l93', 'l101', 'l108', 'l114', 'l119', 'l123', 'l124', 'l125']", + "134, stem ['l75', 'l85', 'l94', 'l102', 'l109', 'l115', 'l120', 'l124', 'l126', 'l127']", + "138, in ['l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l121', 'l125', 'l126', 'l128']", + "139, vivo ['l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l127', 'l128']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "stromal", + "cells", + "human", + "long-term", + "culture-initiating", + "(LTC-ICs)", + "immunodeficiency" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "genetically", + "engineered", + "to", + "secrete", + "HOXB4," + ] + } + } + ] + }, + { + "PMID": "14566334", + "TEXT": "The study and treatment of age-related macular degeneration (AMD), a leading cause of blindness, has been hampered by a lack of animal models. Here we report that mice deficient either in monocyte chemoattractant protein-1 (Ccl-2; also known as MCP-1) or its cognate C-C chemokine receptor-2 (Ccr-2) develop cardinal features of AMD, including accumulation of lipofuscin in and drusen beneath the retinal pigmented epithelium (RPE), photoreceptor atrophy and choroidal neovascularization (CNV). Complement and IgG deposition in RPE and choroid accompanies senescence in this model, as in human AMD. RPE or choroidal endothelial production of Ccl-2 induced by complement C5a and IgG may mediate choroidal macrophage infiltration into aged wild-type choroids. Wild-type choroidal macrophages degrade C5 and IgG in eye sections of Ccl2(-/-) or Ccr2(-/-) mice. Impaired macrophage recruitment may allow accumulation of C5a and IgG, which induces vascular endothelial growth factor (VEGF) production by RPE, possibly mediating development of CNV. These models implicate macrophage dysfunction in AMD pathogenesis and may be useful as a platform for validating therapies.", + "TAG_DATA": [ + "27, mice {'context': 'B-organism'}", + "79, senescence {'phenotype': 'B-senescence'}", + "109, Wild-type {'context': 'B-cells'}", + "110, choroidal {'context': 'I-cells'}", + "111, macrophages {'context': 'I-cells'}", + "117, eye {'context': 'B-tissue/organ'}", + "120, Ccl2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "122, Ccr2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "123, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "27, mice ['l0']", + "79, senescence ['l0']", + "109, Wild-type ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "110, choroidal ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "111, macrophages ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "117, eye ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "120, Ccl2(-/-) ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "122, Ccr2(-/-) ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "123, mice. ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Wild-type", + "choroidal", + "macrophages" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ccl2(-/-)", + "Ccr2(-/-)" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "eye" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ccl2(-/-)", + "Ccr2(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ccl2(-/-)", + "Ccr2(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "14528301", + "TEXT": "The viral infectivity factor (Vif) encoded by HIV-1 neutralizes a potent antiviral pathway that occurs in human T lymphocytes and several leukemic T-cell lines termed nonpermissive, but not in other cells termed permissive. In the absence of Vif, this antiviral pathway efficiently inactivates HIV-1. It was recently reported that APOBEC3G (also known as CEM-15), a cytidine deaminase nucleic acid-editing enzyme, confers this antiviral phenotype on permissive cells. Here we describe evidence that Vif binds APOBEC3G and induces its rapid degradation, thus eliminating it from cells and preventing its incorporation into HIV-1 virions. Studies of Vif mutants imply that it contains two domains, one that binds APOBEC3G and another with a conserved SLQ(Y/F)LA motif that mediates APOBEC3G degradation by a proteasome-dependent pathway. These results provide promising approaches for drug discovery.", + "TAG_DATA": [ + "84, cells {'context': 'B-cells'}", + "94, Vif {'perturbing_action': 'B-other'}", + "95, mutants {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "94, Vif ['l0']", + "95, mutants ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14528299", + "TEXT": "The clinical management of neuropathic pain is particularly challenging. Current therapies for neuropathic pain modulate nerve impulse propagation or synaptic transmission; these therapies are of limited benefit and have undesirable side effects. Injuries to peripheral nerves result in a host of pathophysiological changes associated with the sustained expression of abnormal pain. Here we show that systemic, intermittent administration of artemin produces dose- and time-related reversal of nerve injury-induced pain behavior, together with partial to complete normalization of multiple morphological and neurochemical features of the injury state. These effects of artemin were sustained for at least 28 days. Higher doses of artemin than those completely reversing experimental neuropathic pain did not elicit sensory or motor abnormalities. Our results indicate that the behavioral symptoms of neuropathic pain states can be treated successfully, and that partial to complete reversal of associated morphological and neurochemical changes is achievable with artemin.", + "TAG_DATA": [ + "66, nerve {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "14502283", + "TEXT": "The polycystic kidney diseases (PKDs) are a group of genetic disorders causing significant renal failure and death in children and adults. There are no effective treatments. Two childhood forms, autosomal recessive PKD (ARPKD) and nephronophthisis (NPH), are characterized by collecting-duct cysts. We used animal models orthologous to the human disorders to test whether a vasopressin V2 receptor (VPV2R) antagonist, OPC31260, would be effective against early or established disease. Adenosine-3',5'-cyclic monophosphate (cAMP) has a major role in cystogenesis, and the VPV2R is the major cAMP agonist in the collecting duct. OPC31260 administration lowered renal cAMP, inhibited disease development and either halted progression or caused regression of established disease. These results indicate that OPC31260 may be an effective treatment for these disorders and that clinical trials should be considered.", + "TAG_DATA": [ + "43, animal {'context': 'B-organism'}", + "44, models {'context': 'I-organism'}", + "54, vasopressin {'perturbing_action': 'B-pharmacological inhibition'}", + "55, V2 {'perturbing_action': 'I-pharmacological inhibition'}", + "56, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "57, (VPV2R) {'perturbing_action': 'I-pharmacological inhibition'}", + "58, antagonist, {'perturbing_action': 'I-pharmacological inhibition'}", + "59, OPC31260, {'perturbing_action': 'I-pharmacological inhibition'}", + "94, inhibited {'effect': 'B-negative'}", + "102, caused {'effect': 'B-positive'}" + ], + "LINK_DATA": [ + "43, animal ['l0', 'l1']", + "44, models ['l0', 'l2']", + "54, vasopressin ['l3', 'l4', 'l5', 'l6', 'l7']", + "55, V2 ['l3', 'l8', 'l9', 'l10', 'l11']", + "56, receptor ['l4', 'l8', 'l12', 'l13', 'l14']", + "57, (VPV2R) ['l5', 'l9', 'l12', 'l15', 'l16']", + "58, antagonist, ['l6', 'l10', 'l13', 'l15', 'l17']", + "59, OPC31260, ['l1', 'l2', 'l7', 'l11', 'l14', 'l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "animal", + "models" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "OPC31260," + ] + } + } + ] + }, + { + "PMID": "14502282", + "TEXT": "T lymphocytes undergo proliferation arrest when exposed to tryptophan shortage, which can be provoked by indoleamine 2,3-dioxygenase (IDO), an enzyme that is expressed in placenta and catalyzes tryptophan degradation. Here we show that most human tumors constitutively express IDO. We also observed that expression of IDO by immunogenic mouse tumor cells prevents their rejection by preimmunized mice. This effect is accompanied by a lack of accumulation of specific T cells at the tumor site and can be partly reverted by systemic treatment of mice with an inhibitor of IDO, in the absence of noticeable toxicity. These results suggest that the efficacy of therapeutic vaccination of cancer patients might be improved by concomitant administration of an IDO inhibitor.", + "TAG_DATA": [ + "43, expression {'perturbing_action': 'B-gene gain-of-function'}", + "44, of {'perturbing_action': 'I-gene gain-of-function'}", + "45, IDO {'perturbing_action': 'I-gene gain-of-function'}", + "46, by {'perturbing_action': 'I-gene gain-of-function'}", + "47, immunogenic {'context': 'B-transformed cells'}", + "48, mouse {'context': 'I-transformed cells'}", + "49, tumor {'context': 'I-transformed cells'}", + "50, cells {'context': 'I-transformed cells'}", + "56, mice. {'context': 'B-organism'}", + "68, T {'context': 'B-cells'}", + "69, cells {'context': 'B-cells'}", + "72, tumor {'context': 'B-neoplasm'}", + "83, mice {'context': 'B-organism'}", + "86, inhibitor {'perturbing_action': 'B-pharmacological inhibition'}", + "87, of {'perturbing_action': 'I-pharmacological inhibition'}", + "88, IDO, {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "43, expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "44, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "45, IDO ['l1', 'l11', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "46, by ['l2', 'l12', 'l20', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "47, immunogenic ['l3', 'l13', 'l21', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "48, mouse ['l4', 'l14', 'l22', 'l28', 'l33', 'l38', 'l39', 'l40']", + "49, tumor ['l5', 'l15', 'l23', 'l29', 'l34', 'l38', 'l41', 'l42']", + "50, cells ['l6', 'l16', 'l24', 'l30', 'l35', 'l39', 'l41', 'l43']", + "56, mice. ['l7', 'l17', 'l25', 'l31', 'l36', 'l40', 'l42', 'l43']", + "68, T ['l8', 'l44', 'l45']", + "69, cells ['l9', 'l18', 'l26', 'l32', 'l37', 'l44', 'l46']", + "72, tumor ['l10', 'l19', 'l45', 'l46']", + "83, mice ['l47', 'l48', 'l49']", + "86, inhibitor ['l47', 'l50', 'l51']", + "87, of ['l48', 'l50', 'l52']", + "88, IDO, ['l49', 'l51', 'l52']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "IDO", + "by" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "immunogenic", + "mouse", + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "IDO", + "by" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "IDO", + "by" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitor", + "of", + "IDO," + ] + } + } + ] + }, + { + "PMID": "12960962", + "TEXT": "Inhibition of the kinase suppressor of ras-1 (KSR1) gene by continuous infusion of phosphorothioate antisense oligonucleotides (ODNs) prevented growth of K-Ras-dependent human PANC-1 pancreatic and A549 non-small-cell lung carcinoma xenografts in nude mice, effected regression of established PANC-1 tumors and inhibited A549 lung metastases, all without apparent toxicity. These studies suggest KSR1 antisense ODNs as a treatment for Ras-dependent human malignancies, in particular pancreatic cancer, which lacks effective curative therapy.", + "TAG_DATA": [ + "21, human {'context': 'B-xenograft'}", + "22, PANC-1 {'context': 'I-xenograft'}", + "23, pancreatic {'context': 'I-xenograft'}", + "24, and {'context': 'I-xenograft'}", + "25, A549 {'context': 'I-xenograft'}", + "26, non-small-cell {'context': 'I-xenograft'}", + "27, lung {'context': 'I-xenograft'}", + "28, carcinoma {'context': 'I-xenograft'}", + "29, xenografts {'context': 'I-xenograft'}", + "31, nude {'context': 'B-organism'}", + "32, mice, {'context': 'I-organism'}", + "33, effected {'effect': 'B-positive'}", + "34, regression {'phenotype': 'B-tumour regression'}", + "37, PANC-1 {'context': 'B-neoplasm'}", + "38, tumors {'context': 'I-neoplasm'}", + "40, inhibited {'effect': 'B-negative'}", + "41, A549 {'context': 'B-neoplasm'}", + "42, lung {'phenotype': 'I-metastasis'}", + "43, metastases, {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "21, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "22, PANC-1 ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "23, pancreatic ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "24, and ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "25, A549 ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "26, non-small-cell ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "27, lung ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l47', 'l48', 'l49', 'l50']", + "28, carcinoma ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l47', 'l51', 'l52', 'l53']", + "29, xenografts ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l48', 'l51', 'l54', 'l55']", + "31, nude ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l49', 'l52', 'l54', 'l56']", + "32, mice, ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l50', 'l53', 'l55', 'l56']", + "33, effected ['l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "34, regression ['l57', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "35, of ['l45', 'l58', 'l65', 'l72', 'l73']", + "37, PANC-1 ['l59', 'l66', 'l72', 'l74', 'l75', 'l76', 'l77', 'l78']", + "38, tumors ['l46', 'l60', 'l67', 'l73', 'l74']", + "40, inhibited ['l61', 'l68', 'l75', 'l79', 'l80', 'l81']", + "41, A549 ['l62', 'l69', 'l76', 'l79', 'l82', 'l83']", + "42, lung ['l63', 'l70', 'l77', 'l80', 'l82', 'l84']", + "43, metastases, ['l64', 'l71', 'l78', 'l81', 'l83', 'l84']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "effected" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "effected" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "PANC-1", + "tumors", + "A549" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "effected" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "lung", + "metastases," + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "PANC-1", + "tumors", + "A549" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "PANC-1", + "A549" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "PANC-1", + "A549" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "lung", + "metastases," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "lung", + "metastases," + ] + } + } + ] + }, + { + "PMID": "12937416", + "TEXT": "CD3-specific antibodies have the unique capacity to restore self-tolerance in established autoimmunity. They induce long-term remission of overt diabetes in nonobese diabetic (NOD) mice and in human type I diabetes. The underlying mechanisms had been unclear until now. Here we report that treatment with CD3epsilon-specific antibodies induces transferable T-cell-mediated tolerance involving CD4+CD25+ cells. However, these CD4+CD25+ T cells are distinct from naturally occurring regulatory T cells that control physiological autoreactivity. CD3-specific antibody treatment induced remission in NOD Cd28-/- mice that were devoid of such regulatory cells. Remission of diabetes was abrogated by coadministration of a neutralizing transforming growth factor (TGF)-beta-specific antibody. The central role of TGF-beta was further suggested by its increased, long-lasting production by CD4+ T cells from tolerant mice. These data explain the intriguing tolerogenic effect of CD3-specific antibodies and position them as the first clinically applicable pharmacological stimulant of TGF-beta-producing regulatory CD4+ T cells.", + "TAG_DATA": [ + "76, NOD {'context': 'B-organism'}", + "77, Cd28-/- {'perturbing_action': 'B-gene loss-of-function'}", + "78, mice {'context': 'B-organism'}", + "84, regulatory {'context': 'B-cells'}", + "85, cells. {'context': 'I-cells'}", + "115, CD4+ {'context': 'B-cells'}", + "116, T {'context': 'I-cells'}", + "117, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "76, NOD ['l0', 'l1', 'l2', 'l3']", + "77, Cd28-/- ['l0', 'l4', 'l5', 'l6']", + "78, mice ['l1', 'l4', 'l7', 'l8']", + "84, regulatory ['l2', 'l5', 'l7', 'l9']", + "85, cells. ['l3', 'l6', 'l8', 'l9']", + "115, CD4+ ['l10', 'l11']", + "116, T ['l10', 'l12']", + "117, cells ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "NOD", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cd28-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cd28-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "regulatory", + "cells." + ] + } + } + ] + }, + { + "PMID": "12937415", + "TEXT": "Prion epizoonoses spread from animals consumed by humans raise the question of which pathways lead to prion neuroinvasion after oral exposure of humans. Here we show that neurons of sympathetic ganglia of patients with variant Creutzfeldt-Jakob disease (vCJD) accumulate the abnormal isoform of the protein prion. This observation shows the involvement of the sympathetic nervous system in the pathogenesis of vCJD and suggests a role for GUT-associated sympathetic neurons in prion propagation in humans after oral contamination.", + "TAG_DATA": [ + "27, neurons {'context': 'B-cells'}", + "28, of {'context': 'I-cells'}", + "29, sympathetic {'context': 'I-cells'}", + "30, ganglia {'context': 'I-cells'}", + "32, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "27, neurons ['l0', 'l1', 'l2', 'l3']", + "28, of ['l0', 'l4', 'l5', 'l6']", + "29, sympathetic ['l1', 'l4', 'l7', 'l8']", + "30, ganglia ['l2', 'l5', 'l7', 'l9']", + "32, patients ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12937414", + "TEXT": "Chronic idiopathic thrombocytopenic purpura (ITP) is a bleeding disorder that is characterized by increased platelet destruction and is believed to be autoantibody mediated. In this study, CD3+ T cells from ITP patients had increased expression of genes involved in cell-mediated cytotoxicity. In addition, cytotoxic cell-mediated lysis of autologous platelets was shown in active ITP. Our data suggest that T-cell-mediated cytotoxicity is an alternative mechanism for platelet destruction in ITP.", + "TAG_DATA": [ + "26, CD3+ {'context': 'B-cells'}", + "27, T {'context': 'I-cells'}", + "28, cells {'context': 'I-cells'}", + "47, autologous {'context': 'B-xenograft'}", + "48, platelets {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "26, CD3+ ['l0', 'l1']", + "27, T ['l0', 'l2']", + "28, cells ['l1', 'l2']", + "47, autologous ['l3']", + "48, platelets ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12925849", + "TEXT": "Fusion of tumor cells with antigen-presenting cells (APCs) has been proposed for the preparation of cancer vaccines. However, generation of these hybrids, using physical or chemical methods such as electrofusion or polyethylene glycol (PEG), has been difficult to standardize. Characterization of cell fusion has also been problematic because of difficulties in differentiating fusion from cell aggregation, leakage of cellular dyes and dendritic-cell (DC) phagocytosis of tumor material. In this report, we describe a new method to generate hybrid cell vaccines, based on gene transfer of a viral fusogenic membrane glycoprotein (FMG) into tumor cells, and incorporate a genetic method by which true hybrid formation can be unambiguously detected. We describe a new class of tumor cell-DC hybrid that can be rapidly isolated after cell fusion. These hybrids are highly potent in in vitro antigen presentation assays, target lymph nodes in vivo and are powerful immunogens against established metastatic disease.", + "TAG_DATA": [ + "92, tumor {'context': 'B-transformed cells'}", + "93, cells, {'context': 'I-transformed cells'}", + "137, lymph {'context': 'B-tissue/organ'}", + "138, nodes {'context': 'B-tissue/organ'}", + "139, in {'context': 'B-in vivo'}", + "140, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "92, tumor ['l0']", + "93, cells, ['l0']", + "137, lymph ['l1', 'l2', 'l3']", + "138, nodes ['l1', 'l4', 'l5']", + "139, in ['l2', 'l4', 'l6']", + "140, vivo ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12897779", + "TEXT": "Many mammalian species express restriction factors that confer host resistance to retroviral infection. Here we show that HIV-1 sensitivity to restriction factors is modulated by cyclophilin A (CypA), a host cell protein that binds the HIV-1 capsid protein (CA). In certain nonhuman primate cells, the CA-CypA interaction is essential for restriction: HIV-1 infectivity is increased >100-fold by cyclosporin A (CsA), a competitive inhibitor of the interaction, or by an HIV-1 CA mutation that disrupts CypA binding. Conversely, disruption of CA-CypA interaction in human cells reveals that CypA protects HIV-1 from the Ref-1 restriction factor. These findings suggest that HIV-1 has co-opted a host cell protein to counteract restriction factors expressed by human cells and that this adaptation can confer sensitivity to restriction in unnatural hosts. Manipulation of HIV-1 CA recognition by restriction factors promises to advance animal models and new therapeutic strategies for HIV-1 and AIDS.", + "TAG_DATA": [ + "69, HIV-1 {'perturbing_action': 'B-other'}", + "70, CA {'perturbing_action': 'I-other'}", + "71, mutation {'perturbing_action': 'I-other'}", + "82, human {'context': 'B-cells'}", + "83, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "69, HIV-1 ['l0', 'l1', 'l2', 'l3']", + "70, CA ['l0', 'l4', 'l5']", + "71, mutation ['l1', 'l4', 'l6', 'l7']", + "82, human ['l2', 'l6', 'l8']", + "83, cells ['l3', 'l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "HIV-1", + "CA", + "mutation" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "cells" + ] + } + } + ] + }, + { + "PMID": "12872164", + "TEXT": "The mechanisms of retinoid activity in tumors remain largely unknown. Here we establish that retinoids cause extensive apoptosis of medulloblastoma cells. In a xenograft model, retinoids largely abrogated tumor growth. Using receptor-specific retinoid agonists, we defined a subset of mRNAs that were induced by all active retinoids in retinoid-sensitive cell lines. We also identified bone morphogenetic protein-2 (BMP-2) as a candidate mediator of retinoid activity. BMP-2 protein induced medulloblastoma cell apoptosis, whereas the BMP-2 antagonist noggin blocked both retinoid and BMP-2-induced apoptosis. BMP-2 also induced p38 mitogen-activated protein kinase (MAPK), which is necessary for BMP-2- and retinoid-induced apoptosis. Retinoid-resistant medulloblastoma cells underwent apoptosis when treated with BMP-2 or when cultured with retinoid-sensitive medulloblastoma cells. Retinoid-induced expression of BMP-2 is thus necessary and sufficient for apoptosis of retinoid-responsive cells, and expression of BMP-2 by retinoid-sensitive cells is sufficient to induce apoptosis in surrounding retinoid-resistant cells.", + "TAG_DATA": [ + "23, xenograft {'context': 'B-xenograft'}", + "24, model, {'context': 'I-xenograft'}", + "27, abrogated {'effect': 'B-negative'}", + "28, tumor {'phenotype': 'B-tumour growth'}", + "29, growth. {'phenotype': 'I-tumour growth'}", + "49, cell {'context': 'I-cells'}", + "50, lines. {'context': 'I-cells'}", + "67, induced {'effect': 'B-positive'}", + "68, medulloblastoma {'context': 'B-transformed cells'}", + "69, cell {'context': 'I-transformed cells'}", + "70, apoptosis, {'phenotype': 'B-apoptosis'}", + "76, blocked {'effect': 'B-negative'}", + "80, BMP-2-induced {'effect': 'B-positive'}", + "81, apoptosis. {'phenotype': 'B-apoptosis'}", + "96, retinoid-induced {'effect': 'B-positive'}", + "97, apoptosis. {'phenotype': 'B-apoptosis'}", + "98, Retinoid-resistant {'context': 'B-transformed cells'}", + "99, medulloblastoma {'context': 'I-transformed cells'}", + "100, cells {'context': 'I-transformed cells'}", + "102, apoptosis {'phenotype': 'B-apoptosis'}", + "111, retinoid-sensitive {'context': 'B-transformed cells'}", + "112, medulloblastoma {'context': 'I-transformed cells'}", + "113, cells. {'context': 'I-transformed cells'}", + "133, retinoid-sensitive {'context': 'B-cells'}", + "134, cells {'context': 'I-cells'}", + "138, induce {'effect': 'B-positive'}", + "139, apoptosis {'phenotype': 'B-apoptosis'}", + "142, retinoid-resistant {'context': 'B-cells'}", + "143, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "23, xenograft ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "24, model, ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "27, abrogated ['l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "28, tumor ['l1', 'l9', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "29, growth. ['l2', 'l10', 'l18', 'l25', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "49, cell ['l3', 'l11', 'l19', 'l26', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "50, lines. ['l4', 'l12', 'l20', 'l27', 'l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "67, induced ['l5', 'l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "68, medulloblastoma ['l6', 'l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "69, cell ['l7', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "70, apoptosis, ['l8', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l52']", + "76, blocked ['l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "80, BMP-2-induced ['l53', 'l59', 'l60', 'l61', 'l62', 'l63']", + "81, apoptosis. ['l54', 'l59', 'l64', 'l65', 'l66']", + "96, retinoid-induced ['l55', 'l60', 'l64', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "97, apoptosis. ['l56', 'l61', 'l65', 'l67', 'l73', 'l74', 'l75']", + "98, Retinoid-resistant ['l68', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "99, medulloblastoma ['l57', 'l62', 'l69', 'l73', 'l76', 'l83', 'l84', 'l85', 'l86']", + "100, cells ['l58', 'l63', 'l66', 'l70', 'l74', 'l77', 'l83', 'l87', 'l88']", + "101, underwent ['l71', 'l75', 'l78', 'l84', 'l87', 'l89', 'l90']", + "102, apoptosis ['l72', 'l79', 'l85', 'l88', 'l89', 'l91']", + "111, retinoid-sensitive ['l80', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "112, medulloblastoma ['l81', 'l92', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "113, cells. ['l82', 'l86', 'l90', 'l91', 'l93', 'l98', 'l104', 'l105']", + "133, retinoid-sensitive ['l106', 'l107', 'l108', 'l109', 'l110']", + "134, cells ['l94', 'l99', 'l104', 'l106', 'l111', 'l112', 'l113', 'l114']", + "138, induce ['l95', 'l100', 'l107', 'l111', 'l115', 'l116', 'l117']", + "139, apoptosis ['l96', 'l101', 'l108', 'l112', 'l115', 'l118', 'l119']", + "142, retinoid-resistant ['l102', 'l109', 'l113', 'l116', 'l118', 'l120']", + "143, cells. ['l97', 'l103', 'l105', 'l110', 'l114', 'l117', 'l119', 'l120']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "model," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "model," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "model," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogated" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogated" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "lines." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogated", + "blocked" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "medulloblastoma", + "cell", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogated", + "blocked" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis,", + "apoptosis." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "lines." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "medulloblastoma", + "cell" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell", + "lines.", + "retinoid-sensitive", + "cells", + "retinoid-resistant", + "cells." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "induce" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell", + "lines.", + "retinoid-sensitive", + "cells", + "retinoid-resistant", + "cells." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis,", + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "BMP-2-induced", + "retinoid-induced", + "induce" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "medulloblastoma", + "cell", + "cells", + "Retinoid-resistant", + "retinoid-sensitive" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "BMP-2-induced", + "retinoid-induced", + "induce" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis,", + "apoptosis.", + "apoptosis" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "medulloblastoma", + "cell", + "cells", + "Retinoid-resistant", + "cells.", + "retinoid-sensitive" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis,", + "apoptosis.", + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "12858167", + "TEXT": "High plasma levels of soluble P-selectin are associated with thrombotic disorders and may predict future cardiovascular events. Mice with high levels of soluble P-selectin have more microparticles in their plasma than do normal mice. Here we show that chimeras of P-selectin and immunoglobulin (P-sel-Ig) induced formation of procoagulant microparticles in human blood through P-selectin glycoprotein ligand-1 (PSGL-1; encoded by the Psgl1 gene, officially known as Selpl). In addition, Psgl1-/- mice produced fewer microparticles after P-sel-Ig infusion and did not spontaneously increase their microparticle count in old age as do wild-type mice. Injected microparticles specifically bound to thrombi and thus could be involved in thrombin generation at sites of injury. Infusion of P-sel-Ig into hemophilia A mice produced a 20-fold increase over control immunoglobulin in microparticles containing tissue factor. This significantly improved the kinetics of fibrin formation in the hemophilia A mice and normalized their tail-bleeding time. P-sel-Ig treatment could become a new approach to sustained control of bleeding in hemophilia.", + "TAG_DATA": [ + "51, blood {'context': 'I-tissue/organ'}", + "68, Psgl1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "69, mice {'context': 'B-organism'}", + "90, mice. {'context': 'B-organism'}", + "113, hemophilia {'context': 'B-organism'}", + "114, A {'context': 'I-organism'}", + "115, mice {'context': 'I-organism'}", + "138, hemophilia {'context': 'B-organism'}", + "139, A {'context': 'I-organism'}", + "140, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "50, human ['l0']", + "51, blood ['l0']", + "68, Psgl1-/- ['l1']", + "69, mice ['l1']", + "113, hemophilia ['l2', 'l3', 'l4', 'l5', 'l6']", + "114, A ['l2', 'l7', 'l8', 'l9']", + "115, mice ['l3', 'l7', 'l10', 'l11', 'l12']", + "138, hemophilia ['l4', 'l10', 'l13', 'l14']", + "139, A ['l5', 'l8', 'l11', 'l13', 'l15']", + "140, mice ['l6', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Psgl1-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "12847519", + "TEXT": "Endothelin-1 (ET-1) is a newly described pain mediator that is involved in the pathogenesis of pain states ranging from trauma to cancer. ET-1 is synthesized by keratinocytes in normal skin and is locally released after cutaneous injury. While it is able to trigger pain through its actions on endothelin-A (ET(A)) receptors of local nociceptors, it can coincidentally produce analgesia through endothelin-B (ET(B)) receptors. Here we map a new endogenous analgesic circuit, in which ET(B) receptor activation induces the release of beta-endorphin from keratinocytes and the activation of G-protein-coupled inwardly rectifying potassium channels (GIRKs, also named Kir-3) linked to opioid receptors on nociceptors. These results indicate the existence of an intrinsic feedback mechanism to control peripheral pain in skin, and establish keratinocytes as an ET(B) receptor-operated opioid pool.", + "TAG_DATA": [ + "82, keratinocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12819780", + "TEXT": "The ubiquitin-proteasome pathway is the central mediator of regulated proteolysis in cells, and defects in this pathway are associated with cancer and neurodegenerative diseases. To assess 26S proteasome function in living animals, we developed a ubiquitin-luciferase reporter for bioluminescence imaging. The reporter was degraded rapidly under steady-state conditions and stabilized in a dose- and time-dependent manner in response to proteasome inhibitors. Using bioluminescence imaging after one dose of the chemo-therapeutic proteasome inhibitor bortezomib (PS-341), proteasome function in tumor xenografts was blocked within 30 min and returned to nearly baseline by 46 h. After a 2-week regimen of bortezomib, however, imaging of target tumors showed significantly enhanced proteasome inhibition that no longer returned to baseline. The ubiquitin-luciferase reporter enables repetitive tissue-specific analysis of 26S proteasome activity in vivo and should facilitate development and validation of proteasome inhibitors in mouse models, as well as investigations of the ubiquitin-proteasome pathway in disease pathogenesis.", + "TAG_DATA": [ + "77, tumor {'context': 'B-xenograft'}", + "78, xenografts {'context': 'I-xenograft'}", + "102, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "77, tumor ['l0']", + "78, xenografts ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12808451", + "TEXT": "Generation of arachidonic acid by the ubiquitously expressed cytosolic phospholipase A2 (PLA2) has a fundamental role in the regulation of cellular homeostasis, inflammation and tumorigenesis. Here we report that cytosolic PLA2 is a negative regulator of growth, specifically of striated muscle. We find that normal growth of skeletal muscle, as well as normal and pathologic stress-induced hypertrophic growth of the heart, are exaggerated in Pla2g4a-/- mice, which lack the gene encoding cytosolic PLA2. The mechanism underlying this phenotype is that cytosolic PLA2 negatively regulates insulin-like growth factor (IGF)-1 signaling. Absence of cytosolic PLA2 leads to sustained activation of the IGF-1 pathway, which results from the failure of 3-phosphoinositide-dependent protein kinase (PDK)-1 to recruit and phosphorylate protein kinase C (PKC)-zeta, a negative regulator of IGF-1 signaling. Arachidonic acid restores activation of PKC-zeta, correcting the exaggerated IGF-1 signaling. These results indicate that cytosolic PLA2 and arachidonic acid regulate striated muscle growth by modulating multiple growth-regulatory pathways.", + "TAG_DATA": [ + "47, skeletal {'context': 'B-tissue/organ'}", + "48, muscle, {'context': 'I-tissue/organ'}", + "64, Pla2g4a-/- {'perturbing_action': 'B-gene loss-of-function'}", + "65, mice, {'context': 'B-organism'}", + "67, lack {'perturbing_action': 'B-gene loss-of-function'}", + "68, the {'perturbing_action': 'I-gene loss-of-function'}", + "69, gene {'perturbing_action': 'I-gene loss-of-function'}", + "70, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "71, cytosolic {'perturbing_action': 'I-gene loss-of-function'}", + "72, PLA2. {'perturbing_action': 'I-gene loss-of-function'}", + "89, Absence {'perturbing_action': 'B-gene loss-of-function'}", + "90, of {'perturbing_action': 'I-gene loss-of-function'}", + "91, cytosolic {'perturbing_action': 'I-gene loss-of-function'}", + "92, PLA2 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "47, skeletal ['l0']", + "48, muscle, ['l0']", + "64, Pla2g4a-/- ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "65, mice, ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "67, lack ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "68, the ['l3', 'l9', 'l14', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "69, gene ['l4', 'l10', 'l15', 'l23', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "70, encoding ['l5', 'l11', 'l16', 'l24', 'l31', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "71, cytosolic ['l6', 'l12', 'l17', 'l25', 'l32', 'l38', 'l44', 'l45', 'l46', 'l47', 'l48']", + "72, PLA2. ['l7', 'l13', 'l18', 'l26', 'l33', 'l39', 'l44', 'l49', 'l50', 'l51', 'l52']", + "89, Absence ['l19', 'l27', 'l34', 'l40', 'l45', 'l49', 'l53', 'l54', 'l55']", + "90, of ['l20', 'l28', 'l35', 'l41', 'l46', 'l50', 'l53', 'l56', 'l57']", + "91, cytosolic ['l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l54', 'l56', 'l58']", + "92, PLA2 ['l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l57', 'l58']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pla2g4a-/-", + "lack", + "the", + "gene", + "encoding", + "cytosolic", + "PLA2." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "12808450", + "TEXT": "Amyloid-beta peptide (Abeta) interacts with the vasculature to influence Abeta levels in the brain and cerebral blood flow, providing a means of amplifying the Abeta-induced cellular stress underlying neuronal dysfunction and dementia. Systemic Abeta infusion and studies in genetically manipulated mice show that Abeta interaction with receptor for advanced glycation end products (RAGE)-bearing cells in the vessel wall results in transport of Abeta across the blood-brain barrier (BBB) and expression of proinflammatory cytokines and endothelin-1 (ET-1), the latter mediating Abeta-induced vasoconstriction. Inhibition of RAGE-ligand interaction suppresses accumulation of Abeta in brain parenchyma in a mouse transgenic model. These findings suggest that vascular RAGE is a target for inhibiting pathogenic consequences of Abeta-vascular interactions, including development of cerebral amyloidosis.", + "TAG_DATA": [ + "38, genetically {'context': 'B-organism'}", + "39, manipulated {'context': 'I-organism'}", + "40, mice {'context': 'I-organism'}", + "90, brain {'context': 'B-tissue/organ'}", + "91, parenchyma {'context': 'I-tissue/organ'}", + "94, mouse {'context': 'B-organism'}", + "95, transgenic {'context': 'I-organism'}", + "96, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "38, genetically ['l0', 'l1']", + "39, manipulated ['l0', 'l2']", + "40, mice ['l1', 'l2']", + "90, brain ['l3', 'l4', 'l5', 'l6']", + "91, parenchyma ['l3', 'l7', 'l8', 'l9']", + "94, mouse ['l4', 'l7', 'l10', 'l11']", + "95, transgenic ['l5', 'l8', 'l10', 'l12']", + "96, model. ['l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12778137", + "TEXT": "A major focus of cancer immunotherapy is to develop strategies to induce T-cell responses through presentation of tumor antigens by dendritic cells (DCs). Current vaccines are limited in their ability to efficiently transfer antigens to DCs in vivo. Ex vivo-generated DCs can be efficiently loaded with antigen but after reinjection, few DCs traffic to secondary lymphoid organs, the critical sites for antigen presentation. To enhance efficiency and durability of antigen presentation by DCs, we transduced hematopoietic stem-progenitor cells (HSCs) with a model tumor antigen and then transplanted the gene-modified cells into irradiated recipient mice, which resulted in efficient expression of the transgene in a large proportion of donor derived DCs in lymphoid organs. The combination of bone marrow transplantation (BMT) using transduced HSCs, systemic agents that generate and activate DCs, and mature T-cell infusion resulted in substantial expansion and activation of antigen-specific T cells. This tripartite strategy provided potent antigen-specific immunotherapy for an aggressive established tumor.", + "TAG_DATA": [ + "75, hematopoietic {'context': 'B-cells'}", + "76, stem-progenitor {'context': 'I-cells'}", + "77, cells {'context': 'I-cells'}", + "78, (HSCs) {'context': 'I-cells'}", + "93, mice, {'context': 'I-organism'}", + "107, donor {'context': 'B-cells'}", + "108, derived {'context': 'I-cells'}", + "109, DCs {'context': 'I-cells'}", + "111, lymphoid {'context': 'B-tissue/organ'}", + "112, organs. {'context': 'I-tissue/organ'}", + "122, HSCs, {'context': 'B-cells'}", + "129, DCs, {'context': 'B-cells'}", + "141, antigen-specific {'context': 'B-cells'}", + "142, T {'context': 'I-cells'}", + "143, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "75, hematopoietic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "76, stem-progenitor ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "77, cells ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "78, (HSCs) ['l2', 'l9', 'l15', 'l21', 'l22', 'l23']", + "93, mice, ['l3', 'l10', 'l16', 'l21', 'l24', 'l25', 'l26', 'l27', 'l28']", + "107, donor ['l24', 'l29', 'l30', 'l31', 'l32']", + "108, derived ['l4', 'l11', 'l17', 'l25', 'l29', 'l33', 'l34', 'l35']", + "109, DCs ['l5', 'l12', 'l18', 'l22', 'l26', 'l30', 'l33', 'l36', 'l37']", + "111, lymphoid ['l6', 'l13', 'l19', 'l27', 'l31', 'l34', 'l36', 'l38']", + "112, organs. ['l7', 'l14', 'l20', 'l23', 'l28', 'l32', 'l35', 'l37', 'l38']", + "122, HSCs, ['l39', 'l40', 'l41', 'l42']", + "129, DCs, ['l39', 'l43', 'l44', 'l45']", + "141, antigen-specific ['l40', 'l43', 'l46', 'l47']", + "142, T ['l41', 'l44', 'l46', 'l48']", + "143, cells. ['l42', 'l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12754503", + "TEXT": "The content and structure of collagen is essential in governing the delivery of therapeutic molecules in tumors. Thus, simple histological staining of tumor tissue biopsies for collagen could be used to assess the accessibility of molecular therapeutics in tumors. Here we show that it is possible to optically image fibrillar collagen in tumors growing in mice using second-harmonic generation (SHG). Using this noninvasive technique, we estimated relative diffusive hindrance, quantified the dynamics of collagen modification after pharmacologic intervention and provided mechanistic insight into improved diffusive transport induced by the hormone relaxin. This technology could offer basic scientists and clinicians an enhanced ability to estimate the relative penetrabilities of molecular therapeutics.", + "TAG_DATA": [ + "52, tumors {'context': 'B-neoplasm'}", + "53, growing {'context': 'I-neoplasm', 'phenotype': 'I-tumour growth'}", + "55, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "52, tumors ['l0', 'l1']", + "53, growing ['l0', 'l2']", + "55, mice ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "growing" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growing" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "growing" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "12754502", + "TEXT": "Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease that affects males. It is caused by the expansion of a polyglutamine (polyQ) tract in androgen receptors. Female carriers are usually asymptomatic. No specific treatment has been established. Our transgenic mouse model carrying a full-length human androgen receptor with expanded polyQ has considerable gender-related motor impairment. This phenotype was abrogated by castration, which prevented nuclear translocation of mutant androgen receptors. We examined the effect of androgen-blockade drugs on our mouse model. Leuprorelin, a lutenizing hormone-releasing hormone (LHRH) agonist that reduces testosterone release from the testis, rescued motor dysfunction and nuclear accumulation of mutant androgen receptors in male transgenic mice. Moreover, leuprorelin treatment reversed the behavioral and histopathological phenotypes that were once caused by transient increases in serum testosterone. Flutamide, an androgen antagonist promoting nuclear translocation of androgen receptors, yielded no therapeutic effect. Leuprorelin thus seems to be a promising candidate for the treatment of SBMA.", + "TAG_DATA": [ + "42, mouse {'context': 'I-organism'}", + "43, model {'context': 'I-organism'}", + "46, full-length {'perturbing_action': 'I-other'}", + "47, human {'perturbing_action': 'I-other'}", + "81, mouse {'context': 'B-organism'}", + "82, model. {'context': 'I-organism'}", + "108, male {'context': 'B-organism'}", + "109, transgenic {'context': 'I-organism'}", + "110, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "42, mouse ['l0', 'l1', 'l2', 'l3']", + "43, model ['l0', 'l4', 'l5', 'l6', 'l7']", + "46, full-length ['l1', 'l4', 'l8', 'l9', 'l10']", + "47, human ['l2', 'l5', 'l8', 'l11', 'l12']", + "81, mouse ['l6', 'l9', 'l11', 'l13']", + "82, model. ['l3', 'l7', 'l10', 'l12', 'l13']", + "108, male ['l14', 'l15']", + "109, transgenic ['l14', 'l16']", + "110, mice. ['l15', 'l16']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "model." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "full-length", + "human" + ] + } + } + ] + }, + { + "PMID": "12692539", + "TEXT": "Ovarian tumor cells are often genomically unstable and hypersensitive to cisplatin. To understand the molecular basis for this phenotype, we examined the integrity of the Fanconi anemia-BRCA (FANC-BRCA) pathway in those cells. This pathway regulates cisplatin sensitivity and is governed by the coordinate activity of six genes associated with Fanconi anemia (FANCA, FANCC, FANCD2, FANCE, FANCF and FANCG) as well as BRCA1 and BRCA2 (FANCD1). Here we show that the FANC-BRCA pathway is disrupted in a subset of ovarian tumor lines. Mono-ubiquitination of FANCD2, a measure of the function of this pathway, and cisplatin resistance were restored by functional complementation with FANCF, a gene that is upstream in this pathway. FANCF inactivation in ovarian tumors resulted from methylation of its CpG island, and acquired cisplatin resistance correlated with demethylation of FANCF. We propose a model for ovarian tumor progression in which the initial methylation of FANCF is followed by FANCF demethylation and ultimately results in cisplatin resistance.", + "TAG_DATA": [ + "110, FANCF {'perturbing_action': 'B-gene loss-of-function'}", + "111, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "113, ovarian {'context': 'B-neoplasm'}", + "114, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "110, FANCF ['l0', 'l1', 'l2']", + "111, inactivation ['l0', 'l3', 'l4']", + "113, ovarian ['l1', 'l3', 'l5']", + "114, tumors ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FANCF", + "inactivation" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "ovarian", + "tumors" + ] + } + } + ] + }, + { + "PMID": "12669034", + "TEXT": "Using natural killer T (NKT) cell-deficient mice, we show here that allergen-induced airway hyperreactivity (AHR), a cardinal feature of asthma, does not develop in the absence of V(alpha)14i NKT cells. The failure of NKT cell-deficient mice to develop AHR is not due to an inability of these mice to produce type 2 T-helper (Th2) responses because NKT cell-deficient mice that are immunized subcutaneously at non-mucosal sites produce normal Th2-biased responses. The failure to develop AHR can be reversed by the adoptive transfer of tetramer-purified NKT cells producing interleukin (IL)-4 and IL-13 to Ja281(-/-) mice, which lack the invariant T-cell receptor (TCR) of NKT cells, or by the administration to Cd1d(-/-) mice of recombinant IL-13, which directly affects airway smooth muscle cells. Thus, pulmonary V(alpha)14i NKT cells crucially regulate the development of asthma and Th2-biased respiratory immunity against nominal exogenous antigens. Therapies that target V(alpha)14i NKT cells may be clinically effective in limiting the development of AHR and asthma.", + "TAG_DATA": [ + "33, NKT {'perturbing_action': 'B-gene loss-of-function'}", + "34, cell-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "35, mice {'context': 'B-organism'}", + "47, mice {'context': 'B-organism'}", + "56, NKT {'perturbing_action': 'B-gene loss-of-function'}", + "57, cell-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "58, mice {'context': 'B-organism'}", + "84, NKT {'context': 'B-cells'}", + "85, cells {'context': 'I-cells'}", + "92, Ja281(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "93, mice, {'context': 'B-organism'}", + "109, Cd1d(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "110, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "33, NKT ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "34, cell-deficient ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "35, mice ['l1', 'l6', 'l11', 'l12']", + "47, mice ['l2', 'l7', 'l11']", + "56, NKT ['l3', 'l8', 'l13', 'l14', 'l15', 'l16', 'l17']", + "57, cell-deficient ['l4', 'l9', 'l12', 'l13', 'l18', 'l19', 'l20']", + "58, mice ['l5', 'l10', 'l14', 'l18', 'l21', 'l22']", + "84, NKT ['l15', 'l19', 'l21', 'l23', 'l24', 'l25']", + "85, cells ['l16', 'l20', 'l22', 'l23', 'l26', 'l27']", + "92, Ja281(-/-) ['l17', 'l24', 'l26', 'l28']", + "93, mice, ['l25', 'l27', 'l28']", + "109, Cd1d(-/-) ['l29']", + "110, mice ['l29']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NKT", + "cell-deficient", + "Ja281(-/-)", + "Cd1d(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NKT", + "cell-deficient", + "Ja281(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "NKT", + "cells" + ] + } + } + ] + }, + { + "PMID": "12652294", + "TEXT": "Antigen-specific CD8+ T cells acquire peptide-major histocompatibility complex (MHC) clusters through T-cell receptor (TCR)-mediated endocytosis after specific antigen stimulation. We generated an antigen-presenting cell (APC) expressing human leukocyte antigen (HLA)-A*201 coupled to the enhanced green fluorescent protein (GFP), which delivered GFP to an antigen-specific T cell when pulsed with antigenic peptide. We quantitatively identified human T-cell lymphotropic virus type I (HTLV-I) Tax(11-19) peptide-specific T-cell populations in peripheral blood mononuclear cells (PBMCs) from patients with HTLV-I-associated neurologic disease and defined a new CD8+ T-cell epitope in the HTLV-I envelope region. Acquisition of peptide-HLA-GFP complexes by antigen-specific T cells could distinguish, with respect to phenotype and perforin production, T cells from the chronic viral infections cytomegalovirus and HTLV-I. This approach will be a powerful tool in understanding the role of antigen-specific T-cell responses in health and disease.", + "TAG_DATA": [ + "66, peripheral {'context': 'B-cells'}", + "67, blood {'context': 'I-cells'}", + "68, mononuclear {'context': 'I-cells'}", + "69, cells {'context': 'I-cells'}", + "70, (PBMCs) {'context': 'I-cells'}", + "94, antigen-specific {'context': 'B-cells'}", + "95, T {'context': 'I-cells'}", + "96, cells {'context': 'I-cells'}", + "106, T {'context': 'B-cells'}", + "107, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "45, cell ['l0', 'l1']", + "66, peripheral ['l2', 'l3', 'l4', 'l5']", + "67, blood ['l2', 'l6', 'l7', 'l8']", + "68, mononuclear ['l3', 'l6', 'l9', 'l10']", + "69, cells ['l0', 'l4', 'l7', 'l9', 'l11']", + "70, (PBMCs) ['l1', 'l5', 'l8', 'l10', 'l11']", + "94, antigen-specific ['l12', 'l13', 'l14', 'l15']", + "95, T ['l12', 'l16', 'l17', 'l18']", + "96, cells ['l13', 'l16', 'l19', 'l20']", + "106, T ['l14', 'l17', 'l19', 'l21']", + "107, cells ['l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12652293", + "TEXT": "Tissue factor (TF) is an essential enzyme activator that forms a catalytic complex with FVII(a) and initiates coagulation by activating FIX and FX, ultimately resulting in thrombin formation. TF is found in adventitia of blood vessels and the lipid core of atherosclerotic plaques. In unstable coronary syndromes, plaque rupture initiates coagulation by exposing TF to blood. Biologically active TF has been detected in vessel walls and circulating blood. Elevated intravascular TF has been reported in diverse pro-thrombotic syndromes such as myocardial infarction, sepsis, anti-phospholipid syndrome and sickle-cell disease. It is unclear how TF circulates, although it may be present in pro-coagulant microparticles. We now report identification of a form of human TF generated by alternative splicing. Our studies indicate that alternatively spliced human tissue factor (asHTF) contains most of the extracellular domain of TF but lacks a transmembrane domain and terminates with a unique peptide sequence. asHTF is soluble, circulates in blood, exhibits pro-coagulant activity when exposed to phospholipids, and is incorporated into thrombi. We propose that binding of asHTF to the edge of thrombi contributes to thrombus growth by creating a surface that both initiates and propagates coagulation.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12640447", + "TEXT": "Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies. Its high mortality rate is mainly a result of intra-hepatic metastases. We analyzed the expression profiles of HCC samples without or with intra-hepatic metastases. Using a supervised machine-learning algorithm, we generated for the first time a molecular signature that can classify metastatic HCC patients and identified genes that were relevant to metastasis and patient survival. We found that the gene expression signature of primary HCCs with accompanying metastasis was very similar to that of their corresponding metastases, implying that genes favoring metastasis progression were initiated in the primary tumors. Osteopontin, which was identified as a lead gene in the signature, was over-expressed in metastatic HCC; an osteopontin-specific antibody effectively blocked HCC cell invasion in vitro and inhibited pulmonary metastasis of HCC cells in nude mice. Thus, osteopontin acts as both a diagnostic marker and a potential therapeutic target for metastatic HCC.", + "TAG_DATA": [ + "122, blocked {'effect': 'B-negative'}", + "123, HCC {'context': 'B-transformed cells'}", + "124, cell {'context': 'I-transformed cells'}", + "125, invasion {'phenotype': 'B-invasion'}", + "126, in {'context': 'B-in vitro'}", + "127, vitro {'context': 'I-in vitro'}", + "129, inhibited {'effect': 'B-negative'}", + "130, pulmonary {'phenotype': 'B-metastasis'}", + "131, metastasis {'phenotype': 'I-metastasis'}", + "133, HCC {'context': 'B-transformed cells'}", + "134, cells {'context': 'I-transformed cells'}", + "136, nude {'context': 'B-organism'}", + "137, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "122, blocked ['l0', 'l1', 'l2', 'l3', 'l4']", + "123, HCC ['l0', 'l5', 'l6', 'l7', 'l8']", + "124, cell ['l1', 'l5', 'l9', 'l10', 'l11']", + "125, invasion ['l2', 'l6', 'l9', 'l12', 'l13']", + "126, in ['l3', 'l7', 'l10', 'l12', 'l14']", + "127, vitro ['l4', 'l8', 'l11', 'l13', 'l14']", + "129, inhibited ['l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "130, pulmonary ['l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "131, metastasis ['l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "133, HCC ['l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "134, cells ['l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "136, nude ['l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "137, mice. ['l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "blocked", + "inhibited" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HCC", + "cell", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "HCC", + "cell" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "pulmonary", + "metastasis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice." + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "pulmonary", + "metastasis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HCC", + "cells" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "pulmonary", + "metastasis" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice." + ] + } + } + ] + }, + { + "PMID": "12640446", + "TEXT": "Amyloid-beta peptide (Abeta) has a key role in the pathogenesis of Alzheimer disease (AD). Immunization with Abeta in a transgenic mouse model of AD reduces both age-related accumulation of Abeta in the brain and associated cognitive impairment. Here we present the first analysis of human neuropathology after immunization with Abeta (AN-1792). Comparison with unimmunized cases of AD (n = 7) revealed the following unusual features in the immunized case, despite diagnostic neuropathological features of AD: (i) there were extensive areas of neocortex with very few Abeta plaques; (ii) those areas of cortex that were devoid of Abeta plaques contained densities of tangles, neuropil threads and cerebral amyloid angiopathy (CAA) similar to unimmunized AD, but lacked plaque-associated dystrophic neurites and astrocyte clusters; (iii) in some regions devoid of plaques, Abeta-immunoreactivity was associated with microglia; (iv) T-lymphocyte meningoencephalitis was present; and (v) cerebral white matter showed infiltration by macrophages. Findings (i)-(iii) strongly resemble the changes seen after Abeta immunotherapy in mouse models of AD and suggest that the immune response generated against the peptide elicited clearance of Abeta plaques in this patient. The T-lymphocyte meningoencephalitis is likely to correspond to the side effect seen in some other patients who received AN-1792 (refs. 7-9).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12579196", + "TEXT": "The genetic transfer of antigen receptors provides a means to rapidly generate autologous tumor-reactive T lymphocytes. However, recognition of tumor antigens by cytotoxic T cells is only one step towards effective cancer immunotherapy. Other crucial biological prerequisites must be fulfilled to expand tumor-reactive T cells that retain a functional phenotype, including in vivo cytolytic activity and the ability to travel to tumor sites without prematurely succumbing to apoptosis. We show that these requirements are met by expanding peripheral blood T cells genetically targeted to the CD19 antigen in the presence of CD80 and interleukin-15 (IL-15). T cells expanded in the presence of IL-15 uniquely persist in tumor-bearing severe combined immunodeficiency (SCID)-Beige mice and eradicate disseminated intramedullary tumors. Their anti-tumor activity is further enhanced by in vivo co-stimulation. In addition, transduced T cells from patients with chronic lymphocytic leukemia (CLL) effectively lyse autologous tumor cells. These findings strongly support the clinical feasibility of this therapeutic strategy.", + "TAG_DATA": [ + "77, peripheral {'context': 'B-cells'}", + "78, blood {'context': 'I-cells'}", + "79, T {'context': 'I-cells'}", + "80, cells {'context': 'I-cells'}", + "95, T {'context': 'B-cells'}", + "96, cells {'context': 'B-cells'}", + "106, tumor-bearing {'context': 'B-organism'}", + "107, severe {'context': 'I-organism'}", + "108, combined {'context': 'I-organism'}", + "109, immunodeficiency {'context': 'I-organism'}", + "110, (SCID)-Beige {'context': 'I-organism'}", + "111, mice {'context': 'I-organism'}", + "116, tumors. {'context': 'I-neoplasm'}", + "124, in {'context': 'B-in vivo'}", + "125, vivo {'context': 'I-in vivo'}", + "130, T {'context': 'B-cells'}", + "131, cells {'context': 'I-cells'}", + "133, patients {'context': 'B-transformed cells'}", + "141, autologous {'context': 'B-xenograft'}", + "142, tumor {'context': 'I-transformed cells'}", + "143, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "77, peripheral ['l0', 'l1', 'l2']", + "78, blood ['l0', 'l3', 'l4']", + "79, T ['l1', 'l3', 'l5']", + "80, cells ['l2', 'l4', 'l5']", + "95, T ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "96, cells ['l6', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "106, tumor-bearing ['l7', 'l16', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "107, severe ['l8', 'l17', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "108, combined ['l9', 'l18', 'l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "109, immunodeficiency ['l10', 'l19', 'l27', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "110, (SCID)-Beige ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "111, mice ['l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l55']", + "114, disseminated ['l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l56', 'l57']", + "115, intramedullary ['l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58']", + "116, tumors. ['l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l55', 'l57', 'l58']", + "124, in ['l59']", + "125, vivo ['l59']", + "130, T ['l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "131, cells ['l60', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "133, patients ['l61', 'l67', 'l73', 'l74', 'l75', 'l76', 'l77']", + "136, lymphocytic ['l62', 'l68', 'l73', 'l78', 'l79', 'l80', 'l81']", + "137, leukemia ['l63', 'l69', 'l74', 'l78', 'l82', 'l83', 'l84']", + "141, autologous ['l64', 'l70', 'l75', 'l79', 'l82', 'l85', 'l86']", + "142, tumor ['l65', 'l71', 'l76', 'l80', 'l83', 'l85', 'l87']", + "143, cells. ['l66', 'l72', 'l77', 'l81', 'l84', 'l86', 'l87']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12579195", + "TEXT": "Disruption of the mouse gene encoding the blood coagulation inhibitor thrombomodulin (Thbd) leads to embryonic lethality caused by an unknown defect in the placenta. We show that the abortion of thrombomodulin-deficient embryos is caused by tissue factor-initiated activation of the blood coagulation cascade at the feto-maternal interface. Activated coagulation factors induce cell death and growth inhibition of placental trophoblast cells by two distinct mechanisms. The death of giant trophoblast cells is caused by conversion of the thrombin substrate fibrinogen to fibrin and subsequent formation of fibrin degradation products. In contrast, the growth arrest of trophoblast cells is not mediated by fibrin, but is a likely result of engagement of protease-activated receptors (PAR)-2 and PAR-4 by coagulation factors. These findings show a new function for the thrombomodulin-protein C system in controlling the growth and survival of trophoblast cells in the placenta. This function is essential for the maintenance of pregnancy.", + "TAG_DATA": [ + "30, thrombomodulin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "31, embryos {'context': 'B-organism'}", + "50, induce {'effect': 'B-positive'}", + "51, cell {'phenotype': 'B-cell death'}", + "52, death {'phenotype': 'I-cell death'}", + "55, inhibition {'effect': 'B-negative'}", + "57, placental {'context': 'B-cells'}", + "58, trophoblast {'context': 'I-cells'}", + "59, cells {'context': 'I-cells'}", + "67, giant {'context': 'B-cells'}", + "68, trophoblast {'context': 'I-cells'}", + "69, cells {'context': 'I-cells'}", + "91, growth {'phenotype': 'B-cell growth'}", + "92, arrest {'effect': 'B-negative'}", + "94, trophoblast {'context': 'B-cells'}", + "95, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "30, thrombomodulin-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "31, embryos ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "50, induce ['l1', 'l11', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "51, cell ['l2', 'l12', 'l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "52, death ['l3', 'l13', 'l21', 'l29', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "55, inhibition ['l4', 'l14', 'l22', 'l30', 'l37', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "57, placental ['l5', 'l15', 'l23', 'l31', 'l38', 'l44', 'l50', 'l51', 'l52', 'l53', 'l54']", + "58, trophoblast ['l6', 'l16', 'l24', 'l32', 'l39', 'l45', 'l50', 'l55', 'l56', 'l57', 'l58']", + "59, cells ['l7', 'l17', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l59', 'l60', 'l61']", + "67, giant ['l8', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l62', 'l63']", + "68, trophoblast ['l9', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l62', 'l64']", + "69, cells ['l10', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l64']", + "91, growth ['l65', 'l66', 'l67']", + "92, arrest ['l65', 'l68', 'l69']", + "94, trophoblast ['l66', 'l68', 'l70']", + "95, cells ['l67', 'l69', 'l70']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "thrombomodulin-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "embryos" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "thrombomodulin-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "thrombomodulin-deficient" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "thrombomodulin-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "thrombomodulin-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "placental", + "trophoblast", + "cells", + "giant" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "embryos" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "embryos" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "embryos" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "placental", + "trophoblast", + "cells", + "giant" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "placental", + "trophoblast", + "cells", + "giant" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition", + "arrest" + ] + }, + "context": { + "val": "cells", + "words": [ + "placental", + "trophoblast", + "cells", + "giant" + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest" + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + }, + "context": { + "val": "cells", + "words": [ + "trophoblast", + "cells" + ] + } + } + ] + }, + { + "PMID": "12563314", + "TEXT": "Pseudomonas aeruginosa infection is a serious complication in patients with cystic fibrosis and in immunocompromised individuals. Here we show that P. aeruginosa infection triggers activation of the acid sphingomyelinase and the release of ceramide in sphingolipid-rich rafts. Ceramide reorganizes these rafts into larger signaling platforms that are required to internalize P. aeruginosa, induce apoptosis and regulate the cytokine response in infected cells. Failure to generate ceramide-enriched membrane platforms in infected cells results in an unabated inflammatory response, massive release of interleukin (IL)-1 and septic death of mice. Our findings show that ceramide-enriched membrane platforms are central to the host defense against this potentially lethal pathogen.", + "TAG_DATA": [ + "52, induce {'effect': 'B-positive'}", + "53, apoptosis {'phenotype': 'B-apoptosis'}", + "61, cells. {'context': 'B-cells'}", + "70, cells {'context': 'B-cells'}", + "86, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "52, induce ['l0', 'l1']", + "53, apoptosis ['l0', 'l2']", + "61, cells. ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "12539042", + "TEXT": "Immature dendritic cells are among the first cells infected by retroviruses after mucosal exposure. We explored the effects of human immunodeficiency virus-1 (HIV-1) and its Tat transactivator on these primary antigen-presenting cells using DNA microarray analysis and functional assays. We found that HIV-1 infection or Tat expression induces interferon (IFN)-responsive gene expression in immature human dendritic cells without inducing maturation. Among the induced gene products are chemokines that recruit activated T cells and macrophages, the ultimate target cells for the virus. Dendritic cells in the lymph nodes of macaques infected with simian immunodeficiency virus (SIV) have elevated levels of monocyte chemoattractant protein 2 (MCP-2), demonstrating that chemokine induction also occurs during retroviral infection in vivo. These results show that HIV-1 Tat reprograms host dendritic cell gene expression to facilitate expansion of HIV-1 infection.", + "TAG_DATA": [ + "45, Tat {'perturbing_action': 'B-gene gain-of-function'}", + "46, expression {'perturbing_action': 'I-gene gain-of-function'}", + "53, immature {'context': 'B-cells'}", + "54, human {'context': 'I-cells'}", + "55, dendritic {'context': 'I-cells'}", + "56, cells {'context': 'I-cells'}", + "81, Dendritic {'context': 'B-cells'}", + "82, cells {'context': 'I-cells'}", + "85, lymph {'context': 'B-tissue/organ'}", + "86, nodes {'context': 'I-tissue/organ'}", + "88, macaques {'context': 'B-organism'}", + "113, in {'context': 'B-in vivo'}", + "114, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "45, Tat ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "46, expression ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "53, immature ['l1', 'l8', 'l14', 'l15', 'l16']", + "54, human ['l2', 'l9', 'l14', 'l17', 'l18']", + "55, dendritic ['l3', 'l10', 'l15', 'l17', 'l19']", + "56, cells ['l4', 'l11', 'l16', 'l18', 'l19']", + "81, Dendritic ['l5', 'l12', 'l20', 'l21', 'l22', 'l23']", + "82, cells ['l6', 'l13', 'l20', 'l24', 'l25', 'l26']", + "85, lymph ['l21', 'l24', 'l27', 'l28']", + "86, nodes ['l7', 'l22', 'l25', 'l27', 'l29']", + "88, macaques ['l23', 'l26', 'l28', 'l29']", + "113, in ['l30']", + "114, vivo. ['l30']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Tat", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "immature", + "human", + "dendritic", + "cells", + "Dendritic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Tat" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "nodes" + ] + } + } + ] + }, + { + "PMID": "12539041", + "TEXT": "Antigen-specific T cells demonstrate several potent effector functions during immune responses. Direct killing of infected cells is crucial for clearing viruses and other intracellular pathogens, but it has been difficult to measure the frequency of cytolytic cells. We have now developed a single-cell assay to measure the number of cytotoxic cells in a population, using a herpes simplex virus amplicon vector to express Escherichia coli beta-galactosidase in mouse or human target cells, and an Elispot to detect release of beta-galactosidase from killed target cells. This antigen-specific, perforin-dependent Lysispot assay has been combined with a cytokine Elispot in a two-color assay to confirm that cytotoxicity and interferon-gamma secretion are regulated independently. The simultaneous enumeration of cytokine-secreting and cytotoxic cells should be invaluable for ex vivo analysis of immune responses during infection and autoimmunity.", + "TAG_DATA": [ + "67, mouse {'context': 'B-cells'}", + "68, or {'context': 'I-cells'}", + "69, human {'context': 'I-cells'}", + "70, target {'context': 'I-cells'}", + "71, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "67, mouse ['l0', 'l1', 'l2', 'l3']", + "68, or ['l0', 'l4', 'l5', 'l6']", + "69, human ['l1', 'l4', 'l7', 'l8']", + "70, target ['l2', 'l5', 'l7', 'l9']", + "71, cells, ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12524533", + "TEXT": "Annually, 1.25 million individuals suffer burns in the United States and 6.5 million experience chronic skin ulcers, often from diabetes, pressure or venous stasis. Growth factors are essential mediators of wound repair, but their success as therapeutics in wound treatment has, so far, been limited. Therefore, there is a need to identify new wound-response regulatory factors, but few have appeared in recent years. Progranulin (also called granulin or epithelin precursor, acrogranin or PC-derived growth factor) is a growth factor involved in tumorigenesis and development. Peptides derived from progranulin have been isolated from inflammatory cells, which led to suggestions that progranulin gene products are involved in the wound response, but this remains undemonstrated. We report that in murine transcutaneous puncture wounds, progranulin mRNA is expressed in the inflammatory infiltrate and is highly induced in dermal fibroblasts and endothelia following injury. When applied to a cutaneous wound, progranulin increased the accumulation of neutrophils, macrophages, blood vessels and fibroblasts in the wound. It acts directly on isolated dermal fibroblasts and endothelial cells to promote division, migration and the formation of capillary-like tubule structures. Progranulin is, therefore, a probable wound-related growth factor.", + "TAG_DATA": [ + "155, fibroblasts {'context': 'B-cells'}", + "164, dermal {'context': 'B-cells'}", + "165, fibroblasts {'context': 'I-cells'}", + "167, endothelial {'context': 'B-cells'}", + "168, cells {'context': 'I-cells'}", + "170, promote {'effect': 'B-positive'}", + "171, division, {'phenotype': 'B-proliferation'}", + "172, migration {'phenotype': 'B-migration'}" + ], + "LINK_DATA": [ + "164, dermal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "165, fibroblasts ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "167, endothelial ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "168, cells ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "170, promote ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "171, division, ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "172, migration ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "dermal", + "fibroblasts", + "endothelial", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promote" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "dermal", + "fibroblasts", + "endothelial", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "division," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "dermal", + "fibroblasts", + "endothelial", + "cells" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "division," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + } + ] + }, + { + "PMID": "12496959", + "TEXT": "An effective immune response against human immunodeficiency virus or simian immunodeficiency virus (SIV) is critical in achieving control of viral replication. Here, we show in SIV-infected rhesus monkeys that an effective and durable SIV-specific cellular and humoral immunity is elicited by a vaccination with chemically inactivated SIV-pulsed dendritic cells. After three immunizations made at two-week intervals, the animals exhibited a 50-fold decrease of SIV DNA and a 1,000-fold decrease of SIV RNA in peripheral blood. Such reduced viral load levels were maintained over the remaining 34 weeks of the study. Molecular and cellular analyses of axillary and inguinal node lymphocytes of vaccinated monkeys revealed a correlation between decreased SIV DNA and RNA levels and increased SIV-specific T-cell responses. Neutralizing antibody responses were augmented and remained elevated. Inactivated whole virus-pulsed dendritic cell vaccines are promising means to control diseases caused by immuno- deficiency viruses.", + "TAG_DATA": [ + "26, rhesus {'context': 'B-organism'}", + "27, monkeys {'context': 'I-organism'}", + "47, dendritic {'context': 'B-cells'}", + "48, cells. {'context': 'I-cells'}", + "57, animals {'context': 'B-organism'}", + "95, axillary {'context': 'B-cells'}", + "96, and {'context': 'I-cells'}", + "97, inguinal {'context': 'I-cells'}", + "98, node {'context': 'I-cells'}", + "99, lymphocytes {'context': 'I-cells'}", + "102, monkeys {'context': 'B-organism'}", + "116, T-cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "26, rhesus ['l0', 'l1']", + "27, monkeys ['l0', 'l2']", + "47, dendritic ['l3', 'l4']", + "48, cells. ['l1', 'l2', 'l3', 'l5']", + "57, animals ['l4', 'l5']", + "95, axillary ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "96, and ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "97, inguinal ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "98, node ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "99, lymphocytes ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "102, monkeys ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "116, T-cell ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12483205", + "TEXT": "Plasmodium sporozoites are transmitted through the bite of infected mosquitoes and first invade the liver of the mammalian host, as an obligatory step of the life cycle of the malaria parasite. Within hepatocytes, Plasmodium sporozoites reside in a membrane-bound vacuole, where they differentiate into exoerythrocytic forms and merozoites that subsequently infect erythrocytes and cause the malaria disease. Plasmodium sporozoite targeting to the liver is mediated by the specific binding of major sporozoite surface proteins, the circumsporozoite protein and the thrombospondin-related anonymous protein, to glycosaminoglycans on the hepatocyte surface. Still, the molecular mechanisms underlying sporozoite entry and differentiation within hepatocytes are largely unknown. Here we show that the tetraspanin CD81, a putative receptor for hepatitis C virus, is required on hepatocytes for human Plasmodium falciparum and rodent Plasmodium yoelii sporozoite infectivity. P. yoelii sporozoites fail to infect CD81-deficient mouse hepatocytes, in vivo and in vitro, and antibodies against mouse and human CD81 inhibit in vitro the hepatic development of P. yoelii and P. falciparum, respectively. We further demonstrate that the requirement for CD81 is linked to sporozoite entry into hepatocytes by formation of a parasitophorous vacuole, which is essential for parasite differentiation into exoerythrocytic forms.", + "TAG_DATA": [ + "136, CD81-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "137, mouse {'context': 'B-cells'}", + "138, hepatocytes, {'context': 'I-cells'}", + "139, in {'context': 'B-in vivo'}", + "140, vivo {'context': 'I-in vivo'}", + "142, in {'context': 'B-in vitro'}", + "143, vitro, {'context': 'I-in vitro'}", + "152, in {'context': 'B-in vitro'}", + "153, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "136, CD81-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "137, mouse ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "138, hepatocytes, ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "139, in ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "140, vivo ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "142, in ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "143, vitro, ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "146, against ['l21', 'l22', 'l23', 'l24']", + "147, mouse ['l21', 'l25', 'l26', 'l27']", + "149, human ['l22', 'l25', 'l28', 'l29']", + "152, in ['l23', 'l26', 'l28', 'l30']", + "153, vitro ['l24', 'l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD81-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "hepatocytes," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD81-deficient" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD81-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + } + ] + }, + { + "PMID": "12426560", + "TEXT": "Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that exhibits specific tumoricidal activity against a variety of tumors. It is expressed on different cells of the immune system and plays a role in natural killer cell-mediated tumor surveillance. In allogeneic hematopoietic-cell transplantation, the reactivity of the donor T cell against malignant cells is essential for the graft-versus-tumor (GVT) effect. Cytolytic activity of T cells is primarily mediated through the Fas-Fas ligand and perforin-granzyme pathways. However, T cells deficient for both Fas ligand and perforin can still exert GVT activity in vivo in mouse models. To uncover a potential role for TRAIL in donor T cell-mediated GVT activity, we compared donor T cells from TRAIL-deficient and wild-type mice in clinically relevant mouse bone-marrow transplantation models. We found that alloreactive T cells can express TRAIL, but the absence of TRAIL had no effect on their proliferative and cytokine response to alloantigens. TRAIL-deficient T cells showed significantly lower GVT activity than did TRAIL-expressing T cells, but no important differences in graft-versus-host disease, a major complication of allogeneic hematopoietic cell transplantation, were observed. These data suggest that strategies to enhance TRAIL-mediated GVT activity could decrease relapse rates of malignancies after hematopoietic cell transplantation without exacerbation of graft-versus-host disease.", + "TAG_DATA": [ + "81, T {'context': 'B-cells'}", + "82, cells {'context': 'B-cells'}", + "95, in {'context': 'B-in vivo'}", + "96, vivo {'context': 'I-in vivo'}", + "98, mouse {'context': 'B-organism'}", + "99, models. {'context': 'I-organism'}", + "115, donor {'context': 'B-cells'}", + "116, T {'context': 'I-cells'}", + "117, cells {'context': 'I-cells'}", + "119, TRAIL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "122, mice {'context': 'B-organism'}", + "133, alloreactive {'context': 'B-cells'}", + "134, T {'context': 'I-cells'}", + "135, cells {'context': 'I-cells'}", + "141, absence {'perturbing_action': 'B-gene loss-of-function'}", + "142, of {'perturbing_action': 'I-gene loss-of-function'}", + "143, TRAIL {'perturbing_action': 'I-gene loss-of-function'}", + "155, TRAIL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "156, T {'context': 'B-cells'}", + "157, cells {'context': 'I-cells'}", + "165, TRAIL-expressing {'context': 'B-cells'}", + "166, T {'context': 'I-cells'}", + "167, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "81, T ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "82, cells ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "95, in ['l1', 'l7', 'l15', 'l16', 'l17']", + "96, vivo ['l2', 'l8', 'l15', 'l18', 'l19']", + "98, mouse ['l3', 'l9', 'l16', 'l18', 'l20']", + "99, models. ['l4', 'l10', 'l17', 'l19', 'l20']", + "115, donor ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "116, T ['l5', 'l11', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "117, cells ['l6', 'l12', 'l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "119, TRAIL-deficient ['l13', 'l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "122, mice ['l14', 'l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "133, alloreactive ['l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47', 'l48', 'l49', 'l50']", + "134, T ['l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l51', 'l52', 'l53']", + "135, cells ['l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l51', 'l54', 'l55']", + "141, absence ['l48', 'l56', 'l57', 'l58', 'l59']", + "142, of ['l49', 'l52', 'l54', 'l56', 'l60', 'l61', 'l62']", + "143, TRAIL ['l50', 'l53', 'l55', 'l57', 'l60', 'l63', 'l64']", + "155, TRAIL-deficient ['l65', 'l66', 'l67', 'l68', 'l69']", + "156, T ['l58', 'l61', 'l63', 'l65', 'l70', 'l71', 'l72']", + "157, cells ['l59', 'l62', 'l64', 'l66', 'l70', 'l73', 'l74']", + "165, TRAIL-expressing ['l67', 'l75', 'l76']", + "166, T ['l68', 'l71', 'l73', 'l75', 'l77']", + "167, cells, ['l69', 'l72', 'l74', 'l76', 'l77']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells", + "donor", + "T", + "alloreactive", + "TRAIL-expressing", + "cells," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TRAIL-deficient", + "absence", + "of", + "TRAIL" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TRAIL-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "12415261", + "TEXT": "Tumor cells are elusive targets for immunotherapy due to their heterogeneity and genetic instability. Here we describe a novel, oral DNA vaccine that targets stable, proliferating endothelial cells in the tumor vasculature rather than tumor cells. Targeting occurs through upregulated vascular-endothelial growth factor receptor 2 (FLK-1) of proliferating endothelial cells in the tumor vasculature. This vaccine effectively protected mice from lethal challenges with melanoma, colon carcinoma and lung carcinoma cells and reduced growth of established metastases in a therapeutic setting. CTL-mediated killing of endothelial cells indicated breaking of peripheral immune tolerance against this self antigen, resulting in markedly reduced dissemination of spontaneous and experimental pulmonary metastases. Angiogenesis in the tumor vasculature was suppressed without impairment of fertility, neuromuscular performance or hematopoiesis, albeit with a slight delay in wound healing. Our strategy circumvents problems in targeting of genetically unstable tumor cells. This approach may provide a new strategy for the rational design of cancer therapies.", + "TAG_DATA": [ + "58, mice {'context': 'B-organism'}", + "63, melanoma, {'context': 'B-neoplasm'}", + "64, colon {'context': 'B-neoplasm'}", + "65, carcinoma {'context': 'I-neoplasm'}", + "67, lung {'context': 'B-transformed cells'}", + "68, carcinoma {'context': 'I-transformed cells'}", + "69, cells {'context': 'I-transformed cells'}", + "71, reduced {'effect': 'B-negative'}", + "75, metastases {'phenotype': 'B-metastasis'}", + "83, endothelial {'context': 'B-cells'}", + "84, cells {'context': 'I-cells'}", + "104, pulmonary {'phenotype': 'B-metastasis'}", + "105, metastases. {'phenotype': 'I-metastasis'}", + "109, tumor {'context': 'B-tissue/organ'}", + "110, vasculature {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "58, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "63, melanoma, ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "64, colon ['l1', 'l7', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "65, carcinoma ['l2', 'l8', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "67, lung ['l3', 'l9', 'l15', 'l20', 'l25', 'l26', 'l27', 'l28']", + "68, carcinoma ['l4', 'l10', 'l16', 'l21', 'l25', 'l29', 'l30', 'l31']", + "69, cells ['l5', 'l11', 'l17', 'l22', 'l26', 'l29', 'l32']", + "71, reduced ['l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "75, metastases ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l32', 'l33', 'l35']", + "83, endothelial ['l36', 'l37', 'l38']", + "84, cells ['l34', 'l35', 'l36', 'l39', 'l40']", + "104, pulmonary ['l37', 'l39', 'l41']", + "105, metastases. ['l38', 'l40', 'l41']", + "109, tumor ['l42']", + "110, vasculature ['l42']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "melanoma,", + "colon", + "carcinoma" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "melanoma,", + "colon", + "carcinoma" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "lung", + "carcinoma" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "lung", + "carcinoma", + "cells" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastases", + "pulmonary", + "metastases." + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "endothelial" + ] + } + } + ] + }, + { + "PMID": "12389040", + "TEXT": "The recent development of tissue microarrays-composed of hundreds of tissue sections from different tumors arrayed on a single glass slide-facilitates rapid evaluation of large-scale outcome studies. Realization of this potential depends on the ability to rapidly and precisely quantify the protein expression within each tissue spot. We have developed a set of algorithms that allow the rapid, automated, continuous and quantitative analysis of tissue microarrays, including the separation of tumor from stromal elements and the sub-cellular localization of signals. Validation studies using estrogen receptor in breast carcinoma show that automated analysis matches or exceeds the results of conventional pathologist-based scoring. Automated analysis and sub-cellular localization of beta-catenin in colon cancer identifies two novel, prognostically significant tumor subsets, not detected by traditional pathologist-based scoring. Development of automated analysis technology empowers tissue microarrays for use in discovery-type experiments (more typical of cDNA microarrays), with the added advantage of inclusion of long-term demographic and patient outcome information.", + "TAG_DATA": [ + "85, breast {'context': 'B-neoplasm'}", + "86, carcinoma {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "85, breast ['l0']", + "86, carcinoma ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12368907", + "TEXT": "Adiponectin (Ad) is a hormone secreted by adipocytes that regulates energy homeostasis and glucose and lipid metabolism. However, the signaling pathways that mediate the metabolic effects of Ad remain poorly identified. Here we show that phosphorylation and activation of the 5'-AMP-activated protein kinase (AMPK) are stimulated with globular and full-length Ad in skeletal muscle and only with full-length Ad in the liver. In parallel with its activation of AMPK, Ad stimulates phosphorylation of acetyl coenzyme A carboxylase (ACC), fatty-acid oxidation, glucose uptake and lactate production in myocytes, phosphorylation of ACC and reduction of molecules involved in gluconeogenesis in the liver, and reduction of glucose levels in vivo. Blocking AMPK activation by dominant-negative mutant inhibits each of these effects, indicating that stimulation of glucose utilization and fatty-acid oxidation by Ad occurs through activation of AMPK. Our data may provide a novel paradigm that an adipocyte-derived antidiabetic hormone, Ad, activates AMPK, thereby directly regulating glucose metabolism and insulin sensitivity in vitro and in vivo.", + "TAG_DATA": [ + "86, myocytes, {'context': 'B-cells'}", + "99, liver, {'context': 'B-tissue/organ'}", + "105, in {'context': 'B-in vivo'}", + "106, vivo. {'context': 'I-in vivo'}", + "107, Blocking {'perturbing_action': 'B-other'}", + "108, AMPK {'perturbing_action': 'I-other'}", + "109, activation {'perturbing_action': 'I-other'}", + "110, by {'perturbing_action': 'I-other'}", + "111, dominant-negative {'perturbing_action': 'I-other'}", + "112, mutant {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "86, myocytes, ['l0']", + "99, liver, ['l0', 'l1', 'l2']", + "105, in ['l1', 'l3']", + "106, vivo. ['l2', 'l3']", + "107, Blocking ['l4', 'l5', 'l6', 'l7', 'l8']", + "108, AMPK ['l4', 'l9', 'l10', 'l11', 'l12']", + "109, activation ['l5', 'l9', 'l13', 'l14', 'l15']", + "110, by ['l6', 'l10', 'l13', 'l16', 'l17']", + "111, dominant-negative ['l7', 'l11', 'l14', 'l16', 'l18']", + "112, mutant ['l8', 'l12', 'l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12244306", + "TEXT": "We have used confocal and widefield microscopy to image thrombus formation in real time in the microcirculation of a living mouse. This system provides high-speed, near-simultaneous acquisition of images of multiple fluorescent probes and of a brightfield channel. Vascular injury is induced with a laser focused through the microscope optics. We observed platelet deposition, tissue factor accumulation and fibrin generation after laser-induced endothelial injury in a single developing thrombus. The initiation of blood coagulation in vivo entailed the initial accumulation of tissue factor on the upstream and thrombus-vessel wall interface of the developing thrombus. Subsequently tissue factor was associated with the interior of the thrombus. Tissue factor was biologically active, and was associated with fibrin generation within the thrombus.", + "TAG_DATA": [ + "74, in {'context': 'B-in vivo'}", + "75, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "74, in ['l0']", + "75, vivo ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12195436", + "TEXT": "The H5N1 influenza viruses transmitted to humans in 1997 were highly virulent, but the mechanism of their virulence in humans is largely unknown. Here we show that lethal H5N1 influenza viruses, unlike other human, avian and swine influenza viruses, are resistant to the antiviral effects of interferons and tumor necrosis factor alpha. The nonstructural (NS) gene of H5N1 viruses is associated with this resistance. Pigs infected with recombinant human H1N1 influenza virus that carried the H5N1 NS gene experienced significantly greater and more prolonged viremia, fever and weight loss than did pigs infected with wild-type human H1N1 influenza virus. These effects required the presence of glutamic acid at position 92 of the NS1 molecule. These findings may explain the mechanism of the high virulence of H5N1 influenza viruses in humans.", + "TAG_DATA": [ + "64, Pigs {'context': 'B-organism'}", + "91, pigs {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12161749", + "TEXT": "The hematopoietic-restricted protein Src homology 2-containing inositol-5-phosphatase (SHIP) blunts phosphatidylinositol-3-kinase-initiated signaling by dephosphorylating its major substrate, phosphatidylinositol-3,4,5-trisphosphate. As SHIP(-/-) mice contain increased numbers of osteoclast precursors, that is, macrophages, we examined bones from these animals and found that osteoclast number is increased two-fold. This increased number is due to the prolonged life span of these cells and to hypersensitivity of precursors to macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappa B ligand (RANKL). Similar to pagetic osteoclasts, SHIP(-/-) osteoclasts are enlarged, containing upwards of 100 nuclei, and exhibit enhanced resorptive activity. Moreover, as in Paget disease, serum levels of interleukin-6 are markedly increased in SHIP(-/-) mice. Consistent with accelerated resorptive activity, 3D trabecular volume fraction, trabecular thickness, number and connectivity density of SHIP(-/-) long bones are reduced, resulting in a 22% loss of bone-mineral density and a 49% decrease in fracture energy. Thus, SHIP negatively regulates osteoclast formation and function and the absence of this enzyme results in severe osteoporosis.", + "TAG_DATA": [ + "18, SHIP(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "79, SHIP(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "80, osteoclasts {'context': 'B-cells'}", + "106, SHIP(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "107, mice. {'context': 'B-organism'}", + "124, SHIP(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "125, long {'context': 'B-tissue/organ'}", + "126, bones {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "79, SHIP(-/-) ['l0', 'l1', 'l2']", + "80, osteoclasts ['l0', 'l3']", + "106, SHIP(-/-) ['l1', 'l4']", + "107, mice. ['l2', 'l3', 'l4']", + "124, SHIP(-/-) ['l5', 'l6']", + "125, long ['l5', 'l7']", + "126, bones ['l6', 'l7']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHIP(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclasts" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHIP(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHIP(-/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "long", + "bones" + ] + } + } + ] + }, + { + "PMID": "12161748", + "TEXT": "In both pediatric and adult patients, cranial radiation therapy causes a debilitating cognitive decline that is poorly understood and currently untreatable. This decline is characterized by hippocampal dysfunction, and seems to involve a radiation-induced decrease in postnatal hippocampal neurogenesis. Here we show that the deficit in neurogenesis reflects alterations in the microenvironment that regulates progenitor-cell fate, as well as a defect in the proliferative capacity of the neural progenitor-cell population. Not only is hippocampal neurogenesis ablated, but the remaining neural precursors adopt glial fates and transplants of non-irradiated neural precursor cells fail to differentiate into neurons in the irradiated hippocampus. The inhibition of neurogenesis is accompanied by marked alterations in the neurogenic microenvironment, including disruption of the microvascular angiogenesis associated with adult neurogenesis and a marked increase in the number and activation status of microglia within the neurogenic zone. These findings provide clear targets for future therapeutic interventions.", + "TAG_DATA": [ + "79, neural {'context': 'B-cells'}", + "80, precursors {'context': 'I-cells'}", + "88, neural {'context': 'B-cells'}", + "89, precursor {'context': 'I-cells'}", + "90, cells {'context': 'I-cells'}", + "91, fail {'effect': 'B-negative'}", + "92, to {'effect': 'I-negative'}", + "93, differentiate {'phenotype': 'B-differentiation'}", + "95, neurons {'context': 'B-cells', 'phenotype': 'B-differentiation'}", + "99, hippocampus. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "79, neural ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "80, precursors ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "88, neural ['l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "89, precursor ['l12', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "90, cells ['l1', 'l13', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "91, fail ['l2', 'l7', 'l14', 'l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "92, to ['l3', 'l8', 'l15', 'l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "93, differentiate ['l4', 'l9', 'l16', 'l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "95, neurons ['l5', 'l10', 'l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "99, hippocampus. ['l6', 'l11', 'l18', 'l24', 'l29', 'l33', 'l36', 'l38', 'l39']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "neural", + "precursors", + "precursor", + "cells", + "neurons" + ] + }, + "effect": { + "val": "negative", + "words": [ + "fail", + "to" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neural", + "precursors", + "precursor", + "cells", + "neurons" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate", + "neurons" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "fail", + "to" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate", + "neurons" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "fail", + "to" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate", + "neurons" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus." + ] + } + } + ] + }, + { + "PMID": "12161747", + "TEXT": "In the adult brain, new neurons are continuously generated in the subventricular zone and dentate gyrus, but it is unknown whether these neurons can replace those lost following damage or disease. Here we show that stroke, caused by transient middle cerebral artery occlusion in adult rats, leads to a marked increase of cell proliferation in the subventricular zone. Stroke-generated new neurons, as well as neuroblasts probably already formed before the insult, migrate into the severely damaged area of the striatum, where they express markers of developing and mature, striatal medium-sized spiny neurons. Thus, stroke induces differentiation of new neurons into the phenotype of most of the neurons destroyed by the ischemic lesion. Here we show that the adult brain has the capacity for self-repair after insults causing extensive neuronal death. If the new neurons are functional and their formation can be stimulated, a novel therapeutic strategy might be developed for stroke in humans.", + "TAG_DATA": [ + "44, adult {'context': 'B-organism'}", + "45, rats, {'context': 'I-organism'}", + "50, increase {'effect': 'B-positive'}", + "52, cell {'context': 'B-cells'}", + "53, proliferation {'phenotype': 'B-proliferation'}", + "57, zone. {'context': 'I-tissue/organ'}", + "59, new {'context': 'B-cells'}", + "60, neurons, {'context': 'B-cells'}", + "94, induces {'effect': 'B-positive'}", + "95, differentiation {'phenotype': 'B-differentiation'}", + "97, new {'context': 'B-cells'}", + "98, neurons {'context': 'I-cells'}", + "106, neurons {'context': 'B-cells'}", + "118, brain {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "44, adult ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "45, rats, ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "50, increase ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "52, cell ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "53, proliferation ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "56, subventricular ['l4', 'l9', 'l13', 'l16', 'l18', 'l20', 'l21', 'l22']", + "57, zone. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20', 'l23']", + "59, new ['l21', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "60, neurons, ['l22', 'l23', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "94, induces ['l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "95, differentiation ['l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "97, new ['l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "98, neurons ['l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "106, neurons ['l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "117, adult ['l45']", + "118, brain ['l45']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "adult", + "rats," + ] + }, + "effect": { + "val": "positive", + "words": [ + "increase" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "adult", + "rats," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase", + "induces" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "new", + "neurons,", + "neurons" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "zone." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "zone." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "new", + "neurons,", + "neurons" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "12134144", + "TEXT": "Non-invasive imaging and transcriptional targeting can improve the safety of therapeutic approaches in cancer. Here we demonstrate the ability to identify metastases in a human-prostate cancer model, employing a prostate-specific adenovirus vector (AdPSE-BC-luc) and a charge-coupled device-imaging system. AdPSE-BC-luc, which expresses firefly luciferase from an enhanced prostate-specific antigen promoter, restricted expression in the liver but produced robust signals in prostate tumors. In fact, expression was higher in advanced, androgen-independent tumors than in androgen-dependent lesions. Repetitive imaging over a three-week period after AdPSE-BC-luc injection into tumor-bearing mice revealed that the virus could locate and illuminate metastases in the lung and spine. Systemic injection of low doses of AdPSE-BC-luc illuminated lung metastasis. These results demonstrate the potential use of a non-invasive imaging modality in therapeutic and diagnostic strategies to manage prostate cancer.", + "TAG_DATA": [ + "59, prostate {'context': 'B-neoplasm'}", + "60, tumors. {'context': 'I-neoplasm'}", + "84, tumor-bearing {'context': 'B-organism'}", + "85, mice {'context': 'I-organism'}", + "94, metastases {'phenotype': 'B-metastasis'}", + "97, lung {'context': 'B-tissue/organ'}", + "99, spine. {'context': 'B-tissue/organ'}", + "108, lung {'phenotype': 'B-metastasis'}", + "109, metastasis. {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "59, prostate ['l0']", + "60, tumors. ['l0']", + "84, tumor-bearing ['l1', 'l2', 'l3', 'l4']", + "85, mice ['l1', 'l5', 'l6', 'l7']", + "94, metastases ['l2', 'l5', 'l8', 'l9']", + "97, lung ['l3', 'l6', 'l8', 'l10']", + "99, spine. ['l4', 'l7', 'l9', 'l10']", + "107, illuminated ['l11', 'l12']", + "108, lung ['l11', 'l13']", + "109, metastasis. ['l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "tumor-bearing", + "mice" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung", + "spine." + ] + } + } + ] + }, + { + "PMID": "12134143", + "TEXT": "Heart septation and valve malformations constitute the most common anatomical birth defects. These structures arise from the endocardial cushions within the atrioventricular canal (AVC) through dynamic interactions between cushion cells and the extracellular matrix (termed cardiac jelly). Transformation of endothelial cells to mesenchymal cells is essential for the proper development of the AVC and subsequent septation and valve formation. Atrioventricular septal defects can result from incomplete endocardial cushion morphogenesis. We show that hyaluronan-deficient AVC explants from Has2(-/-) embryos, which normally lack mesenchyme formation, are rescued by heregulin treatment, which restores phosphorylation of ErbB2 and ErbB3. These events were blocked using a soluble ErbB3 molecule, as well as with an inhibitor of ErbB2, herstatin. We show further that ErbB3 is activated during hyaluronan treatment of Has2(-/-) explants. These data provide a link between extracellular matrix-hyaluronan and ErbB receptor activation during development of early heart-valve and septal mesenchyme.", + "TAG_DATA": [ + "73, AVC {'context': 'B-tissue/organ'}", + "74, explants {'context': 'I-tissue/organ'}", + "76, Has2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "77, embryos, {'context': 'B-organism'}", + "109, inhibitor {'perturbing_action': 'B-pharmacological inhibition'}", + "110, of {'perturbing_action': 'I-pharmacological inhibition'}", + "111, ErbB2, {'perturbing_action': 'I-pharmacological inhibition'}", + "112, herstatin. {'perturbing_action': 'I-pharmacological inhibition'}", + "124, Has2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "125, explants. {'context': 'B-organoid'}" + ], + "LINK_DATA": [ + "73, AVC ['l0', 'l1', 'l2']", + "74, explants ['l0', 'l3', 'l4']", + "76, Has2(-/-) ['l1', 'l3', 'l5']", + "77, embryos, ['l2', 'l4', 'l5']", + "109, inhibitor ['l6', 'l7', 'l8', 'l9', 'l10']", + "110, of ['l6', 'l11', 'l12', 'l13', 'l14']", + "111, ErbB2, ['l7', 'l11', 'l15', 'l16', 'l17']", + "112, herstatin. ['l8', 'l12', 'l15', 'l18', 'l19']", + "124, Has2(-/-) ['l9', 'l13', 'l16', 'l18', 'l20']", + "125, explants. ['l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "AVC", + "explants" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Has2(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Has2(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "embryos," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitor", + "of", + "ErbB2,", + "herstatin." + ] + }, + "context": { + "val": "organoid", + "words": [ + "explants." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Has2(-/-)" + ] + }, + "context": { + "val": "organoid", + "words": [ + "explants." + ] + } + } + ] + }, + { + "PMID": "12118246", + "TEXT": "Both enteroviral infection of the heart and mutations in the dystrophin gene can cause cardiomyopathy. Little is known, however, about the interaction between genetic and acquired forms of cardiomyopathy. We previously demonstrated that the enteroviral protease 2A cleaves dystrophin; therefore, we hypothesized that dystrophin deficiency would predispose to enterovirus-induced cardiomyopathy. We observed more severe cardiomyopathy, worsening over time, and greater viral replication in dystrophin-deficient mice infected with enterovirus than in infected wild-type mice. This difference appears to be a result of more efficient release of the virus from dystrophin-deficient myocytes. In addition, we found that expression of wild-type dystrophin in cultured cells decreased the cytopathic effect of enteroviral infection and the release of virus from the cell. We also found that expression of a cleavage-resistant mutant dystrophin further inhibited the virally mediated cytopathic effect and viral release. These results indicate that viral infection can influence the severity and penetrance of the cardiomyopathy that occurs in the hearts of dystrophin-deficient individuals.", + "TAG_DATA": [ + "63, dystrophin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "64, mice {'context': 'B-organism'}", + "72, mice. {'context': 'B-organism'}", + "88, dystrophin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "89, myocytes. {'context': 'B-cells'}", + "95, expression {'perturbing_action': 'B-other'}", + "96, of {'perturbing_action': 'I-other'}", + "97, wild-type {'perturbing_action': 'I-other'}", + "98, dystrophin {'perturbing_action': 'I-other'}", + "100, cultured {'context': 'B-cells'}", + "101, cells {'context': 'I-cells'}", + "116, cell. {'context': 'B-cells'}", + "121, expression {'perturbing_action': 'B-other'}", + "122, of {'perturbing_action': 'I-other'}", + "123, a {'perturbing_action': 'I-other'}", + "124, cleavage-resistant {'perturbing_action': 'I-other'}", + "125, mutant {'perturbing_action': 'I-other'}", + "126, dystrophin {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "63, dystrophin-deficient ['l0', 'l1', 'l2', 'l3']", + "64, mice ['l0', 'l4', 'l5']", + "72, mice. ['l1', 'l4', 'l6', 'l7', 'l8']", + "88, dystrophin-deficient ['l2', 'l6', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "89, myocytes. ['l3', 'l5', 'l7', 'l9', 'l17']", + "95, expression ['l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "96, of ['l11', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "97, wild-type ['l12', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32']", + "98, dystrophin ['l13', 'l20', 'l25', 'l29', 'l33', 'l34', 'l35']", + "100, cultured ['l14', 'l21', 'l26', 'l30', 'l33', 'l36', 'l37']", + "101, cells ['l8', 'l15', 'l17', 'l22', 'l27', 'l31', 'l34', 'l36', 'l38']", + "116, cell. ['l16', 'l23', 'l28', 'l32', 'l35', 'l37', 'l38']", + "121, expression ['l39', 'l40', 'l41', 'l42', 'l43']", + "122, of ['l39', 'l44', 'l45', 'l46', 'l47']", + "123, a ['l40', 'l44', 'l48', 'l49', 'l50']", + "124, cleavage-resistant ['l41', 'l45', 'l48', 'l51', 'l52']", + "125, mutant ['l42', 'l46', 'l49', 'l51', 'l53']", + "126, dystrophin ['l43', 'l47', 'l50', 'l52', 'l53']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "myocytes.", + "cultured", + "cells", + "cell." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "wild-type", + "dystrophin" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "cells", + "cell." + ] + } + } + ] + }, + { + "PMID": "12101409", + "TEXT": "We recently isolated a Krüppel-like zinc-finger transcription factor 5 (KLF5; also known as BTEB2 and IKLF), which is markedly induced in activated vascular smooth-muscle cells and fibroblasts. Here we describe our analysis of the in vivo function of KLF5 using heterozygous KLF5-knockout mice (Klf5(+/-)). In response to external stress, Klf5(+/-) mice showed diminished levels of arterial-wall thickening, angiogenesis, cardiac hypertrophy and interstitial fibrosis. Also, angiotensin II induced expression of KLF5, which in turn activated platelet-derived growth factor-A (PDGF-A) and transforming growth factor-beta (TGF-beta) expression. In addition, we determined that KLF5 interacted with the retinoic-acid receptor (RAR), that synthetic RAR ligands modulated KLF5 transcriptional activity, and that in vivo administration of RAR ligands affected stress responses in the cardiovascular system in a KLF5-dependent manner. KLF5 thus seems to be a key element linking external stress and cardiovascular remodeling.", + "TAG_DATA": [ + "40, heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "41, KLF5-knockout {'perturbing_action': 'I-gene loss-of-function'}", + "42, mice {'context': 'B-organism'}", + "43, (Klf5(+/-)). {'perturbing_action': 'I-gene loss-of-function'}", + "49, Klf5(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "50, mice {'context': 'B-organism'}", + "106, in {'context': 'B-in vivo'}", + "107, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "40, heterozygous ['l0', 'l1', 'l2', 'l3', 'l4']", + "41, KLF5-knockout ['l0', 'l5', 'l6', 'l7', 'l8']", + "42, mice ['l1', 'l5', 'l9', 'l10', 'l11']", + "43, (Klf5(+/-)). ['l2', 'l6', 'l9', 'l12', 'l13']", + "49, Klf5(+/-) ['l3', 'l7', 'l10', 'l12', 'l14']", + "50, mice ['l4', 'l8', 'l11', 'l13', 'l14']", + "106, in ['l15']", + "107, vivo ['l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "heterozygous", + "KLF5-knockout", + "(Klf5(+/-)).", + "Klf5(+/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "12068287", + "TEXT": "Immunoglobulin (Ig)-free light chains IgLC are present in serum and their production is augmented under pathological conditions such as multiple sclerosis, rheumatoid arthritis and neurological disorders. Until now, no (patho)physiological function has been ascribed to circulating Ig light chains. Here we show that IgLCs can confer mast cell dependent hypersensitivity in mice. Antigenic stimulation results in plasma extravasation, cutaneous swelling and mast-cell degranulation. We show that IgLCs have a crucial role in development of contact sensitivity, which could be completely prevented by a novel IgLC antagonist. Although IgE and IgG(1) are central to the induction of immediate hypersensitivity reactions, our results show that IgLCs have similar activity. IgLCs may therefore be a novel factor in the humoral immune response to antigen exposure. Our findings open new avenues in investigating the pathogenesis of autoimmune diseases and their treatments.", + "TAG_DATA": [ + "51, mice. {'context': 'B-organism'}", + "61, mast-cell {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12053176", + "TEXT": "Respiratory distress syndrome (RDS) due to insufficient production of surfactant is a common and severe complication of preterm delivery. Here, we report that loss of the hypoxia-inducible transcription factor-2alpha (HIF-2alpha) caused fatal RDS in neonatal mice due to insufficient surfactant production by alveolar type 2 cells. VEGF, a target of HIF-2alpha, regulates fetal lung maturation: because VEGF levels in alveolar cells were reduced in HIF-2alpha-deficient fetuses; mice with a deficiency of the VEGF(164) and VEGF(188) isoforms or of the HIF-binding site in the VEGF promotor died of RDS; intrauterine delivery of anti-VEGF-receptor-2 antibodies caused RDS and VEGF stimulated production of surfactant proteins by cultured type 2 pneumocytes. Intrauterine delivery or postnatal intratracheal instillation of VEGF stimulated conversion of glycogen to surfactant and protected preterm mice against RDS. The pneumotrophic effect of VEGF may have therapeutic potential for lung maturation in preterm infants.", + "TAG_DATA": [ + "23, loss {'perturbing_action': 'B-gene loss-of-function'}", + "24, of {'perturbing_action': 'I-gene loss-of-function'}", + "25, the {'perturbing_action': 'I-gene loss-of-function'}", + "26, hypoxia-inducible {'perturbing_action': 'I-gene loss-of-function'}", + "27, transcription {'perturbing_action': 'I-gene loss-of-function'}", + "28, factor-2alpha {'perturbing_action': 'I-gene loss-of-function'}", + "29, (HIF-2alpha) {'perturbing_action': 'I-gene loss-of-function'}", + "34, neonatal {'context': 'B-organism'}", + "35, mice {'context': 'I-organism'}", + "64, HIF-2alpha-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "66, mice {'context': 'B-organism'}", + "69, deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "70, of {'perturbing_action': 'I-gene loss-of-function'}", + "71, the {'perturbing_action': 'I-gene loss-of-function'}", + "72, VEGF(164) {'perturbing_action': 'I-gene loss-of-function'}", + "73, and {'perturbing_action': 'I-gene loss-of-function'}", + "74, VEGF(188) {'perturbing_action': 'I-gene loss-of-function'}", + "75, isoforms {'perturbing_action': 'I-gene loss-of-function'}", + "76, or {'perturbing_action': 'I-gene loss-of-function'}", + "77, of {'perturbing_action': 'I-gene loss-of-function'}", + "78, the {'perturbing_action': 'I-gene loss-of-function'}", + "79, HIF-binding {'perturbing_action': 'I-gene loss-of-function'}", + "80, site {'perturbing_action': 'I-gene loss-of-function'}", + "81, in {'perturbing_action': 'I-gene loss-of-function'}", + "82, the {'perturbing_action': 'I-gene loss-of-function'}", + "83, VEGF {'perturbing_action': 'I-gene loss-of-function'}", + "84, promotor {'perturbing_action': 'I-gene loss-of-function'}", + "104, type {'context': 'B-cells'}", + "105, 2 {'context': 'I-cells'}", + "106, pneumocytes. {'context': 'I-cells'}", + "123, preterm {'context': 'B-organism'}", + "124, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "23, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "24, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "25, the ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "26, hypoxia-inducible ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "27, transcription ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "28, factor-2alpha ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "29, (HIF-2alpha) ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "34, neonatal ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "35, mice ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "64, HIF-2alpha-deficient ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "66, mice ['l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "69, deficiency ['l45', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "70, of ['l46', 'l59', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "71, the ['l47', 'l60', 'l77', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "72, VEGF(164) ['l48', 'l61', 'l78', 'l94', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "73, and ['l49', 'l62', 'l79', 'l95', 'l110', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "74, VEGF(188) ['l50', 'l63', 'l80', 'l96', 'l111', 'l125', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151']", + "75, isoforms ['l51', 'l64', 'l81', 'l97', 'l112', 'l126', 'l139', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163']", + "76, or ['l52', 'l65', 'l82', 'l98', 'l113', 'l127', 'l140', 'l152', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "77, of ['l66', 'l83', 'l99', 'l114', 'l128', 'l141', 'l153', 'l164', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184']", + "78, the ['l67', 'l84', 'l100', 'l115', 'l129', 'l142', 'l154', 'l165', 'l175', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "79, HIF-binding ['l68', 'l85', 'l101', 'l116', 'l130', 'l143', 'l155', 'l166', 'l176', 'l185', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201']", + "80, site ['l69', 'l86', 'l102', 'l117', 'l131', 'l144', 'l156', 'l167', 'l177', 'l186', 'l194', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208']", + "81, in ['l70', 'l87', 'l103', 'l118', 'l132', 'l145', 'l157', 'l168', 'l178', 'l187', 'l195', 'l202', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214']", + "82, the ['l53', 'l71', 'l88', 'l104', 'l119', 'l133', 'l146', 'l158', 'l169', 'l179', 'l188', 'l196', 'l203', 'l209', 'l215', 'l216', 'l217', 'l218', 'l219']", + "83, VEGF ['l54', 'l72', 'l89', 'l105', 'l120', 'l134', 'l147', 'l159', 'l170', 'l180', 'l189', 'l197', 'l204', 'l210', 'l215', 'l220', 'l221', 'l222', 'l223']", + "84, promotor ['l55', 'l73', 'l90', 'l106', 'l121', 'l135', 'l148', 'l160', 'l171', 'l181', 'l190', 'l198', 'l205', 'l211', 'l216', 'l220', 'l224', 'l225', 'l226']", + "104, type ['l56', 'l74', 'l91', 'l107', 'l122', 'l136', 'l149', 'l161', 'l172', 'l182', 'l191', 'l199', 'l206', 'l212', 'l217', 'l221', 'l224', 'l227', 'l228']", + "105, 2 ['l57', 'l75', 'l92', 'l108', 'l123', 'l137', 'l150', 'l162', 'l173', 'l183', 'l192', 'l200', 'l207', 'l213', 'l218', 'l222', 'l225', 'l227', 'l229']", + "106, pneumocytes. ['l58', 'l76', 'l93', 'l109', 'l124', 'l138', 'l151', 'l163', 'l174', 'l184', 'l193', 'l201', 'l208', 'l214', 'l219', 'l223', 'l226', 'l228', 'l229']", + "123, preterm ['l230']", + "124, mice ['l230']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "hypoxia-inducible", + "transcription", + "factor-2alpha", + "(HIF-2alpha)", + "HIF-2alpha-deficient", + "deficiency", + "VEGF(164)", + "and", + "VEGF(188)", + "isoforms", + "or", + "VEGF", + "promotor" + ] + }, + "context": { + "val": "organism", + "words": [ + "neonatal", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "of", + "the", + "VEGF(164)", + "and", + "VEGF(188)", + "isoforms", + "or", + "HIF-binding", + "site", + "in", + "VEGF", + "promotor" + ] + }, + "context": { + "val": "cells", + "words": [ + "type", + "2", + "pneumocytes." + ] + } + } + ] + }, + { + "PMID": "12053174", + "TEXT": "Loss of cardiomyocytes through programmed cell death is a key event in the development of heart failure, but the inciting molecular mechanisms are largely unknown. We used microarray analysis to identify a genetic program for myocardial apoptosis in Gq-mediated and pressure-overload cardiac hypertrophy. A critical component of this apoptotic program was Nix/Bnip3L. Nix localized to mitochondria and caused release of cytochrome c, activation of caspase-3 and apoptotic cell death, when expressed in HEK293 fibroblasts. A previously undescribed truncated Nix isoform, termed sNix, was not targeted to mitochondria but heterodimerized with Nix and protected against Nix-mediated apoptosis. Forced in vivo myocardial expression of Nix resulted in apoptotic cardiomyopathy and rapid death. Conversely, sNix protected against apoptotic peripartum cardiomyopathy in G(alpha)q-overexpressors. Thus, Nix/Bnip3L is upregulated in myocardial hypertrophy, and is both necessary and sufficient for Gq-mediated apoptosis of cardiomyocytes and resulting hypertrophy decompensation.", + "TAG_DATA": [ + "66, apoptotic {'phenotype': 'B-apoptosis'}", + "67, cell {'phenotype': 'I-apoptosis'}", + "68, death, {'phenotype': 'I-apoptosis'}", + "72, HEK293 {'context': 'B-cells'}", + "73, fibroblasts. {'context': 'I-cells'}", + "92, protected {'effect': 'B-negative'}", + "93, against {'effect': 'I-negative'}", + "94, Nix-mediated {'effect': 'B-regulates'}", + "95, apoptosis. {'phenotype': 'B-apoptosis'}", + "96, Forced {'perturbing_action': 'B-gene gain-of-function'}", + "97, in {'context': 'B-in vivo'}", + "98, vivo {'context': 'I-in vivo'}", + "99, myocardial {'perturbing_action': 'I-gene gain-of-function'}", + "100, expression {'perturbing_action': 'I-gene gain-of-function'}", + "101, of {'perturbing_action': 'I-gene gain-of-function'}", + "102, Nix {'perturbing_action': 'I-gene gain-of-function'}", + "118, G(alpha)q-overexpressors. {'perturbing_action': 'B-gene gain-of-function'}" + ], + "LINK_DATA": [ + "66, apoptotic ['l0', 'l1', 'l2', 'l3']", + "67, cell ['l0', 'l4', 'l5', 'l6']", + "68, death, ['l1', 'l4', 'l7', 'l8']", + "72, HEK293 ['l2', 'l5', 'l7', 'l9']", + "73, fibroblasts. ['l3', 'l6', 'l8', 'l9']", + "92, protected ['l10', 'l11', 'l12']", + "93, against ['l10', 'l13', 'l14']", + "94, Nix-mediated ['l11', 'l13', 'l15']", + "95, apoptosis. ['l12', 'l14', 'l15']", + "96, Forced ['l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "97, in ['l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "98, vivo ['l17', 'l22', 'l27', 'l28', 'l29', 'l30']", + "99, myocardial ['l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "100, expression ['l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "101, of ['l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "102, Nix ['l21', 'l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death," + ] + }, + "context": { + "val": "cells", + "words": [ + "HEK293", + "fibroblasts." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "protected", + "against" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "Nix-mediated" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "myocardial", + "expression", + "of", + "Nix" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "12042815", + "TEXT": "Allergic asthma is a chronic inflammatory disease and despite the introduction of potent and effective drugs, the prevalence has increased substantially over the past few decades. The explanation that has attracted the most attention is the 'hygiene hypothesis', which suggests that the increase in allergic diseases is caused by a cleaner environment and fewer childhood infections. Indeed, certain mycobacterial strains can cause a shift from T-helper cell 2 (Th2) to Th1 immune responses, which may subsequently prevent the development of allergy in mice. Although the reconstitution of the balance between Th1 and Th2 is an attractive theory, it is unlikely to explain the whole story, as autoimmune diseases characterized by Th1 responses can also benefit from treatment with mycobacteria and their prevalence has also increased in parallel to allergies. Here we show that treatment of mice with SRP299, a killed Mycobacterium vaccae-suspension, gives rise to allergen-specific CD4+CD45RB(Lo) regulatory T cells, which confer protection against airway inflammation. This specific inhibition was mediated through interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta), as antibodies against IL-10 and TGF-beta completely reversed the inhibitory effect of CD4+CD45RB(Lo) T cells. Thus, regulatory T cells generated by mycobacteria treatment may have an essential role in restoring the balance of the immune system to prevent and treat allergic diseases.", + "TAG_DATA": [ + "135, mice {'context': 'B-organism'}", + "147, regulatory {'context': 'I-cells'}", + "148, T {'context': 'I-cells'}", + "149, cells, {'context': 'I-cells'}", + "181, CD4+CD45RB(Lo) {'context': 'B-cells'}", + "182, T {'context': 'I-cells'}", + "183, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "135, mice ['l0', 'l1', 'l2']", + "147, regulatory ['l0', 'l3', 'l4']", + "148, T ['l1', 'l3', 'l5']", + "149, cells, ['l2', 'l4', 'l5']", + "181, CD4+CD45RB(Lo) ['l6', 'l7']", + "182, T ['l6', 'l8']", + "183, cells. ['l7', 'l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12042810", + "TEXT": "Epstein-Barr virus is ubiquitous and is causally implicated in lymphoid and epithelial malignancies. Virus invades oropharyngeal mucosa and establishes latency in B lymphocytes. Reactivating lymphocytes shed virus into saliva for spread to new hosts. A complex of three virus glycoproteins, gH, gL and gp42, is essential for entry. B-cell entry requires binding of gp42 to human leukocyte antigen (HLA) class II whereas entry into epithelial cells lacking HLA class II requires complexes without gp42. To accommodate infection of each, the virus carries both three-part and two-part complexes. We show here that HLA class II in the virus-producing cell alters the ratio of three-part to two-part complexes. As a consequence, virus originating in epithelial cells efficiently infects B cells whereas B-cell derived virus better infects epithelial cells. This molecular switch is a novel strategy that could alter tropism of virus from epithelium to B cells and then back to epithelium in a new host.", + "TAG_DATA": [ + "112, epithelial {'context': 'B-cells'}", + "113, cells {'context': 'I-cells'}", + "116, B {'context': 'B-cells'}", + "117, cells {'context': 'I-cells'}", + "124, epithelial {'context': 'B-cells'}", + "125, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "112, epithelial ['l0', 'l1', 'l2']", + "113, cells ['l0', 'l3', 'l4']", + "116, B ['l1', 'l3', 'l5']", + "117, cells ['l2', 'l4', 'l5']", + "124, epithelial ['l6']", + "125, cells. ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11984599", + "TEXT": "HIV-associated nephropathy is a clinicopathologic entity that includes proteinuria, focal segmental glomerulosclerosis often of the collapsing variant, and microcystic tubulointerstitial disease. Increasing evidence supports a role for HIV-1 infection of renal epithelium in the pathogenesis of HIV-associated nephropathy. Using in situ hybridization, we previously demonstrated HIV-1 gag and nef mRNA in renal epithelial cells of patients with HIV-associated nephropathy. Here, to investigate whether renal epithelial cells were productively infected by HIV-1, we examined renal tissue for the presence of HIV-1 DNA and mRNA by in situ hybridization and PCR, and we molecularly characterized the HIV-1 quasispecies in the renal compartment. Infected renal epithelial cells were removed by laser-capture microdissection from biopsies of two patients, DNA was extracted, and HIV-1 V3-loop or gp120-envelope sequences were amplified from individually dissected cells by nested PCR. Phylogenetic analysis of kidney-derived sequences as well as corresponding sequences from peripheral blood mononuclear cells of the same patients revealed evidence of tissue-specific viral evolution. In phylogenetic trees constructed from V3 and gp120 sequences, kidney-derived sequences formed tissue-specific subclusters within the radiation of blood mononuclear cell-derived viral sequences from both patients. These data, along with the detection of HIV-1-specific proviral DNA and mRNA in tubular epithelium cells, argue strongly for localized replication of HIV-1 in the kidney and the existence of a renal viral reservoir.", + "TAG_DATA": [ + "63, renal {'context': 'B-cells'}", + "64, epithelial {'context': 'I-cells'}", + "65, cells {'context': 'I-cells'}", + "101, renal {'context': 'B-cells'}", + "102, epithelial {'context': 'I-cells'}", + "103, cells {'context': 'I-cells'}", + "128, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "63, renal ['l0', 'l1', 'l2']", + "64, epithelial ['l0', 'l3', 'l4']", + "65, cells ['l1', 'l3', 'l5']", + "101, renal ['l6', 'l7', 'l8']", + "102, epithelial ['l6', 'l9', 'l10']", + "103, cells ['l2', 'l4', 'l5', 'l7', 'l9', 'l11']", + "128, cells ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11984597", + "TEXT": "The only proven requirement for ascorbic acid (vitamin C) is in preventing scurvy, presumably because it is a cofactor for hydroxylases required for post-translational modifications that stabilize collagen. We have created mice deficient in the mouse ortholog (solute carrier family 23 member 1 or Slc23a1) of a rat ascorbic-acid transporter, Svct2 (ref. 4). Cultured embryonic fibroblasts from homozygous Slc23a1(-/-) mice had less than 5% of normal ascorbic-acid uptake. Ascorbic-acid levels were undetectable or markedly reduced in the blood and tissues of Slc23a1(-/-) mice. Prenatal supplementation of pregnant females did not elevate blood ascorbic acid in Slc23a1(-/-) fetuses, suggesting Slc23a1 is important in placental ascorbic-acid transport. Slc23a1(-/-) mice died within a few minutes of birth with respiratory failure and intraparenchymal brain hemorrhage. Lungs showed no postnatal expansion but had normal surfactant protein B levels. Brain hemorrhage was unlikely to be simply a form of scurvy since Slc23a1(-/-) mice showed no hemorrhage in any other tissues and their skin had normal skin 4-hydroxyproline levels despite low ascorbic-acid content. We conclude that Slc23a1 is required for transport of ascorbic acid into many tissues and across the placenta. Deficiency of the transporter is lethal in newborn mice, thereby revealing a previously unrecognized requirement for ascorbic acid in the perinatal period.", + "TAG_DATA": [ + "31, mice {'context': 'B-organism'}", + "32, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "33, in {'perturbing_action': 'I-gene loss-of-function'}", + "34, the {'perturbing_action': 'I-gene loss-of-function'}", + "35, mouse {'perturbing_action': 'I-gene loss-of-function'}", + "36, ortholog {'perturbing_action': 'I-gene loss-of-function'}", + "37, (solute {'perturbing_action': 'I-gene loss-of-function'}", + "38, carrier {'perturbing_action': 'I-gene loss-of-function'}", + "39, family {'perturbing_action': 'I-gene loss-of-function'}", + "40, 23 {'perturbing_action': 'I-gene loss-of-function'}", + "41, member {'perturbing_action': 'I-gene loss-of-function'}", + "42, 1 {'perturbing_action': 'I-gene loss-of-function'}", + "43, or {'perturbing_action': 'I-gene loss-of-function'}", + "44, Slc23a1) {'perturbing_action': 'I-gene loss-of-function'}", + "45, of {'perturbing_action': 'I-gene loss-of-function'}", + "54, embryonic {'context': 'I-cells'}", + "55, fibroblasts {'context': 'I-cells'}", + "57, homozygous {'perturbing_action': 'B-gene loss-of-function'}", + "58, Slc23a1(-/-) {'perturbing_action': 'I-other'}", + "59, mice {'context': 'B-organism'}", + "81, Slc23a1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "82, mice. {'context': 'B-organism'}", + "87, females {'context': 'I-organism'}", + "95, Slc23a1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "96, fetuses, {'context': 'B-organism'}", + "105, Slc23a1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "106, mice {'context': 'B-organism'}", + "121, Lungs {'context': 'B-tissue/organ'}", + "145, Slc23a1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "146, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "31, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "32, deficient ['l0', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "33, in ['l1', 'l21', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "34, the ['l2', 'l22', 'l41', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "35, mouse ['l3', 'l23', 'l42', 'l60', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "36, ortholog ['l4', 'l24', 'l43', 'l61', 'l79', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "37, (solute ['l5', 'l25', 'l44', 'l62', 'l80', 'l98', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "38, carrier ['l6', 'l26', 'l45', 'l63', 'l81', 'l99', 'l117', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "39, family ['l7', 'l27', 'l46', 'l64', 'l82', 'l100', 'l118', 'l136', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171']", + "40, 23 ['l8', 'l28', 'l47', 'l65', 'l83', 'l101', 'l119', 'l137', 'l154', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "41, member ['l9', 'l29', 'l48', 'l66', 'l84', 'l102', 'l120', 'l138', 'l155', 'l172', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "42, 1 ['l10', 'l30', 'l49', 'l67', 'l85', 'l103', 'l121', 'l139', 'l156', 'l173', 'l189', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218']", + "43, or ['l11', 'l31', 'l50', 'l68', 'l86', 'l104', 'l122', 'l140', 'l157', 'l174', 'l190', 'l205', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230']", + "44, Slc23a1) ['l12', 'l32', 'l51', 'l69', 'l87', 'l105', 'l123', 'l141', 'l158', 'l175', 'l191', 'l206', 'l219', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241']", + "45, of ['l13', 'l33', 'l52', 'l70', 'l88', 'l106', 'l124', 'l142', 'l159', 'l176', 'l192', 'l207', 'l220', 'l231', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249']", + "54, embryonic ['l14', 'l34', 'l53', 'l71', 'l89', 'l107', 'l125', 'l143', 'l160', 'l177', 'l193', 'l208', 'l221', 'l232', 'l242', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255']", + "55, fibroblasts ['l15', 'l35', 'l54', 'l72', 'l90', 'l108', 'l126', 'l144', 'l161', 'l178', 'l194', 'l209', 'l222', 'l233', 'l243', 'l250', 'l256', 'l257', 'l258', 'l259', 'l260']", + "57, homozygous ['l16', 'l36', 'l55', 'l73', 'l91', 'l109', 'l127', 'l145', 'l162', 'l179', 'l195', 'l210', 'l223', 'l234', 'l244', 'l251', 'l256', 'l261', 'l262', 'l263', 'l264']", + "58, Slc23a1(-/-) ['l17', 'l37', 'l56', 'l74', 'l92', 'l110', 'l128', 'l146', 'l163', 'l180', 'l196', 'l211', 'l224', 'l235', 'l245', 'l252', 'l257', 'l261', 'l265', 'l266', 'l267']", + "59, mice ['l18', 'l38', 'l57', 'l75', 'l93', 'l111', 'l129', 'l147', 'l164', 'l181', 'l197', 'l212', 'l225', 'l236', 'l246', 'l253', 'l258', 'l262', 'l265', 'l268']", + "81, Slc23a1(-/-) ['l19', 'l39', 'l58', 'l76', 'l94', 'l112', 'l130', 'l148', 'l165', 'l182', 'l198', 'l213', 'l226', 'l237', 'l247', 'l254', 'l259', 'l263', 'l266', 'l269']", + "82, mice. ['l20', 'l40', 'l59', 'l77', 'l95', 'l113', 'l131', 'l149', 'l166', 'l183', 'l199', 'l214', 'l227', 'l238', 'l248', 'l255', 'l260', 'l264', 'l267', 'l268', 'l269']", + "87, females ['l78', 'l96', 'l114', 'l132', 'l150', 'l167', 'l184', 'l200', 'l215', 'l228', 'l239', 'l249', 'l270', 'l271', 'l272', 'l273', 'l274']", + "95, Slc23a1(-/-) ['l168', 'l185', 'l201', 'l270', 'l275', 'l276', 'l277', 'l278']", + "96, fetuses, ['l115', 'l133', 'l151', 'l169', 'l186', 'l202', 'l216', 'l229', 'l240', 'l271', 'l275', 'l279', 'l280', 'l281']", + "105, Slc23a1(-/-) ['l134', 'l152', 'l170', 'l187', 'l203', 'l217', 'l272', 'l276', 'l279', 'l282', 'l283']", + "106, mice ['l97', 'l116', 'l135', 'l153', 'l171', 'l188', 'l204', 'l218', 'l230', 'l241', 'l273', 'l277', 'l280', 'l282', 'l284']", + "121, Lungs ['l274', 'l278', 'l281', 'l283', 'l284']", + "145, Slc23a1(-/-) ['l285']", + "146, mice ['l285']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "females", + "fetuses," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "the", + "mouse", + "ortholog", + "(solute", + "carrier", + "family", + "23", + "member", + "1", + "or", + "Slc23a1)", + "of", + "homozygous", + "Slc23a1(-/-)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Slc23a1(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "the", + "mouse", + "ortholog", + "(solute", + "carrier", + "family", + "23", + "member", + "1", + "or", + "Slc23a1)", + "of", + "homozygous", + "Slc23a1(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "embryonic", + "fibroblasts" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "embryonic", + "fibroblasts" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Slc23a1(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Slc23a1(-/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "Lungs" + ] + } + } + ] + }, + { + "PMID": "11984596", + "TEXT": "One hypothesis that couples infection with autoimmune disease is molecular mimicry. Molecular mimicry is characterized by an immune response to an environmental agent that cross-reacts with a host antigen, resulting in disease. This hypothesis has been implicated in the pathogenesis of diabetes, lupus and multiple sclerosis (MS). There is limited direct evidence linking causative agents with pathogenic immune reactions in these diseases. Our study establishes a clear link between viral infection, autoimmunity and neurological disease in humans. As a model for molecular mimicry, we studied patients with human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a disease that can be indistinguishable from MS (refs. 5,6,7). HAM/TSP patients develop antibodies to neurons. We hypothesized these antibodies would identify a central nervous system (CNS) autoantigen. Immunoglobulin G isolated from HAM/TSP patients identified heterogeneous nuclear ribonuclear protein-A1 (hnRNP-A1) as the autoantigen. Antibodies to hnRNP-A1 cross-reacted with HTLV-1-tax, the immune response to which is associated with HAM/TSP (refs. 5,9). Immunoglobulin G specifically stained human Betz cells, whose axons are preferentially damaged. Infusion of autoantibodies in brain sections inhibited neuronal firing, indicative of their pathogenic nature. These data demonstrate the importance of molecular mimicry between an infecting agent and hnRNP-A1 in autoimmune disease of the CNS.", + "TAG_DATA": [ + "161, human {'context': 'B-cells'}", + "162, Betz {'context': 'I-cells'}", + "163, cells, {'context': 'I-cells'}", + "173, brain {'context': 'B-tissue/organ'}", + "174, sections {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "161, human ['l0', 'l1']", + "162, Betz ['l0', 'l2']", + "163, cells, ['l1', 'l2']", + "173, brain ['l3']", + "174, sections ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11927939", + "TEXT": "Monoclonal antibodies against the T-cell activation molecule 4-1BB have been effective in the treatment of established mouse tumors. To create a vaccine that stimulates the immune system similarly to the efficacious monoclonal anti-4-1BB antibody, 1D8, we constructed a vector encoding cell-bound single-chain Fv fragments from 1D8. We transfected the vector into cells from the K1735 melanoma, selected because of its low immunogenicity and very low expression of major histocompatibility complex class I. The transfected cells induced a strong type 1 T-helper cell response, for which CD4+ but not CD8+ T lymphocytes were necessary and that involved natural killer cells. Vaccinated mice rejected established wild-type K1735 tumors growing as subcutaneous nodules or in the lung. An analogous approach may be effective against micrometastases in human patients, including tumors whose expression of major histocompatibility complex class I is very low.", + "TAG_DATA": [ + "51, cells {'context': 'B-cells'}", + "52, from {'context': 'I-cells'}", + "54, K1735 {'context': 'B-neoplasm'}", + "55, melanoma, {'context': 'I-neoplasm'}", + "74, cells {'context': 'B-cells'}", + "100, mice {'context': 'B-organism'}", + "104, K1735 {'context': 'B-neoplasm'}", + "105, tumors {'context': 'I-neoplasm'}", + "113, lung. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "51, cells ['l0', 'l1', 'l2', 'l3']", + "52, from ['l0', 'l4', 'l5', 'l6']", + "54, K1735 ['l1', 'l4', 'l7', 'l8']", + "55, melanoma, ['l2', 'l5', 'l7', 'l9']", + "74, cells ['l3', 'l6', 'l8', 'l9']", + "100, mice ['l10', 'l11']", + "104, K1735 ['l10', 'l12', 'l13']", + "105, tumors ['l11', 'l12', 'l14']", + "113, lung. ['l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11875494", + "TEXT": "The mechanisms underlying the action of the potent anti-inflammatory interleukin-10 (IL-10) are poorly understood. Here we show that, in murine macrophages, IL-10 induces expression of heme oxygenase-1 (HO-1), a stress-inducible protein with potential anti-inflammatory effect, via a p38 mitogen-activated protein kinase-dependent pathway. Inhibition of HO-1 protein synthesis or activity significantly reversed the inhibitory effect of IL-10 on production of tumor necrosis factor-alpha induced by lipopolysaccharide (LPS). Additional experiments revealed the involvement of carbon monoxide, one of the products of HO-1-mediated heme degradation, in the anti-inflammatory effect of IL-10 in vitro. Induction of HO-1 by IL-10 was also evident in vivo. IL-10-mediated protection against LPS-induced septic shock in mice was significantly attenuated by cotreatment with the HO inhibitor, zinc protoporphyrin. The identification of HO-1 as a downstream effector of IL-10 provides new possibilities for improved therapeutic approaches for treating inflammatory diseases.", + "TAG_DATA": [ + "19, murine {'context': 'B-cells'}", + "20, macrophages, {'context': 'I-cells'}", + "88, in {'context': 'B-in vitro'}", + "89, vitro. {'context': 'I-in vitro'}", + "98, in {'context': 'B-in vivo'}", + "99, vivo. {'context': 'I-in vivo'}", + "107, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "19, murine ['l0']", + "20, macrophages, ['l0']", + "88, in ['l1']", + "89, vitro. ['l1']", + "98, in ['l2']", + "99, vivo. ['l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11875493", + "TEXT": "Despite evidence that human non-hematopoietic cells, such as vascular endothelium, can activate allogeneic T lymphocytes in vitro, the prevailing view has been that hematopoietic antigen-presenting cells are required to trigger alloimmune responses in vivo. Here we report that mouse non-hematopoietic cells activate alloreactive CD8+ T lymphocytes in vitro and in vivo. We also show that vascularized cardiac allografts are acutely rejected via CD8+ direct allorecognition even if the alloantigen is not presented by hematopoietic professional antigen-presenting cells. Because activation of alloreactive CD8+ T cells by donor-type non-hematopoietic cells can continue for the life of the allograft, these findings present a new clinically relevant mechanism of allorecognition and should be taken into consideration when developing strategies to prevent allograft vasculopathy or to induce tolerance.", + "TAG_DATA": [ + "38, mouse {'context': 'B-cells'}", + "39, non-hematopoietic {'context': 'I-cells'}", + "40, cells {'context': 'I-cells'}", + "43, CD8+ {'context': 'B-cells'}", + "44, T {'context': 'I-cells'}", + "45, lymphocytes {'context': 'I-cells'}", + "46, in {'context': 'B-in vitro'}", + "47, vitro {'context': 'I-in vitro'}", + "49, in {'context': 'B-in vivo'}", + "50, vivo. {'context': 'I-in vivo'}", + "55, vascularized {'context': 'B-xenograft'}", + "56, cardiac {'context': 'I-xenograft'}", + "57, allografts {'context': 'I-xenograft'}", + "81, CD8+ {'context': 'B-cells'}", + "82, T {'context': 'I-cells'}", + "83, cells {'context': 'I-cells'}", + "85, donor-type {'context': 'B-cells'}", + "86, non-hematopoietic {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "38, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "39, non-hematopoietic ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "40, cells ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "43, CD8+ ['l2', 'l13', 'l23', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "44, T ['l3', 'l14', 'l24', 'l32', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "45, lymphocytes ['l4', 'l15', 'l25', 'l33', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "46, in ['l5', 'l16', 'l26', 'l34', 'l41', 'l46', 'l51', 'l52', 'l53']", + "47, vitro ['l6', 'l17', 'l27', 'l35', 'l42', 'l47', 'l51', 'l54', 'l55']", + "49, in ['l7', 'l18', 'l28', 'l36', 'l43', 'l48', 'l52', 'l54', 'l56', 'l57']", + "50, vivo. ['l8', 'l19', 'l29', 'l37', 'l44', 'l49', 'l53', 'l55', 'l56', 'l58']", + "55, vascularized ['l9', 'l20', 'l59', 'l60']", + "56, cardiac ['l10', 'l21', 'l30', 'l38', 'l59', 'l61']", + "57, allografts ['l11', 'l22', 'l31', 'l39', 'l45', 'l50', 'l57', 'l58', 'l60', 'l61']", + "81, CD8+ ['l62', 'l63', 'l64', 'l65', 'l66']", + "82, T ['l62', 'l67', 'l68', 'l69', 'l70']", + "83, cells ['l63', 'l67', 'l71', 'l72', 'l73']", + "85, donor-type ['l64', 'l68', 'l71', 'l74', 'l75']", + "86, non-hematopoietic ['l65', 'l69', 'l72', 'l74', 'l76']", + "87, cells ['l66', 'l70', 'l73', 'l75', 'l76']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11875489", + "TEXT": "Interactions between recipient T cells and donor endothelial graft cells may be an important mechanism for both acute and chronic rejection of vascularized allografts. This finding provides a starting point for investigations to develop novel ways of inducing long-lasting immunologic tolerance to donor antigens.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11821904", + "TEXT": "We have developed a non-radioactive flow-cytometry assay to monitor and quantify the target-cell killing activities mediated by cytotoxic T lymphocytes (CTLs). This flow-cytometry CTL (FCC) assay is predicated on measurement of CTL-induced caspase activation in target cells through detection of the specific cleavage of fluorogenic caspase substrates. Here we show that this assay reliably detects antigen-specific CTL killing of target cells, and demonstrate that it provides a more sensitive, more informative and safer alternative to the standard 51Cr-release assay most often used to quantify CTL responses. The FCC assay can be used to study CTL-mediated killing of primary host target cells of different cell lineages, and enables the study of antigen-specific cellular immune responses in real time at the single-cell level. As such, the FCC assay can provide a valuable tool for studies of infectious disease pathogenesis and development of new vaccines and immunotherapies.", + "TAG_DATA": [ + "59, target {'context': 'B-cells'}", + "60, cells, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "59, target ['l0']", + "60, cells, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11821902", + "TEXT": "Hematopoietic stem cells have been successfully employed for tolerance induction in a variety of rodent and large animal studies. However, clinical transplantation of fully allogeneic bone marrow or blood-borne stem cells is still associated with major obstacles, such as graft-versus-host disease or cytoreductive conditioning-related toxicity. Here we show that when rat embryonic stem cell-like cells of WKY origin are injected intraportally into fully MHC-mismatched DA rats, they engraft permanently (>150 days) without supplementary host conditioning. This deviation of a potentially alloreactive immune response sets the basis for long-term graft acceptance of second-set transplanted WKY cardiac allografts. Graft survival was strictly correlated with a state of mixed chimerism, which required functional thymic host competence. Our results provide a rationale for using preimplantation-stage stem cells as vehicles in gene therapy and for the induction of long-term graft acceptance.", + "TAG_DATA": [ + "50, rat {'context': 'B-cells'}", + "51, embryonic {'context': 'I-cells'}", + "52, stem {'context': 'I-cells'}", + "53, cell-like {'context': 'I-cells'}", + "54, cells {'context': 'I-cells'}", + "55, of {'context': 'I-cells'}", + "56, WKY {'context': 'I-cells'}", + "57, origin {'context': 'I-cells'}", + "65, rats, {'context': 'B-organism'}", + "93, WKY {'context': 'B-xenograft'}", + "94, cardiac {'context': 'I-xenograft'}", + "95, allografts. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "50, rat ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "51, embryonic ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "52, stem ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "53, cell-like ['l2', 'l12', 'l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "54, cells ['l3', 'l13', 'l22', 'l29', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "55, of ['l4', 'l14', 'l23', 'l30', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "56, WKY ['l5', 'l15', 'l24', 'l31', 'l37', 'l42', 'l47', 'l48', 'l49', 'l50']", + "57, origin ['l6', 'l16', 'l25', 'l32', 'l38', 'l43', 'l47', 'l51', 'l52']", + "65, rats, ['l7', 'l17', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51']", + "93, WKY ['l8', 'l18', 'l53', 'l54']", + "94, cardiac ['l9', 'l19', 'l27', 'l34', 'l40', 'l45', 'l49', 'l53', 'l55']", + "95, allografts. ['l10', 'l20', 'l28', 'l35', 'l41', 'l46', 'l50', 'l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11821899", + "TEXT": "The upper gastrointestinal tract is a principal route of HIV-1 entry in vertical transmission and after oral-genital contact. The phenotype of the newly acquired virus is predominantly R5 (CCR5-tropic) and not X4 (CXCR4-tropic), although both R5 and X4 viruses are frequently inoculated onto the mucosa. Here we show that primary intestinal (jejunal) epithelial cells express galactosylceramide, an alternative primary receptor for HIV-1, and CCR5 but not CXCR4. Moreover, we show that intestinal epithelial cells transfer R5, but not X4, viruses to CCR5+ indicator cells, which can efficiently replicate and amplify virus expression. Transfer was remarkably efficient and was not inhibited by the fusion blocker T-20, but was substantially reduced by colchicine and low (4 degrees C) temperature, suggesting endocytotic uptake and microtubule-dependent transcytosis of HIV-1. Our finding that CCR5+ intestinal epithelial cells select and transfer exclusively R5 viruses indicates a mechanism for the selective transmission of R5 HIV-1 in primary infection acquired through the upper gastrointestinal tract.", + "TAG_DATA": [ + "49, primary {'context': 'B-cells'}", + "50, intestinal {'context': 'I-cells'}", + "51, (jejunal) {'context': 'I-cells'}", + "52, epithelial {'context': 'I-cells'}", + "53, cells {'context': 'I-cells'}", + "71, intestinal {'context': 'B-cells'}", + "72, epithelial {'context': 'I-cells'}", + "73, cells {'context': 'I-cells'}", + "81, CCR5+ {'context': 'B-cells'}", + "82, indicator {'context': 'I-cells'}", + "83, cells, {'context': 'I-cells'}", + "129, intestinal {'context': 'I-cells'}", + "130, epithelial {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "49, primary ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "50, intestinal ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "51, (jejunal) ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "52, epithelial ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "53, cells ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "71, intestinal ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26', 'l27', 'l28', 'l29']", + "72, epithelial ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l30', 'l31', 'l32', 'l33']", + "73, cells ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l30', 'l34']", + "81, CCR5+ ['l27', 'l31', 'l35', 'l36']", + "82, indicator ['l28', 'l32', 'l35', 'l37']", + "83, cells, ['l29', 'l33', 'l34', 'l36', 'l37']", + "129, intestinal ['l38', 'l39']", + "130, epithelial ['l38', 'l40']", + "131, cells ['l39', 'l40']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11821898", + "TEXT": "An expanded polyglutamine domain in huntingtin underlies the pathogenic events in Huntington disease (HD), characterized by chorea, dementia and severe weight loss, culminating in death. Transglutaminase (TGase) may be critical in the pathogenesis, via cross-linking huntingtin. Administration of the TGase competitive inhibitor, cystamine, to transgenic mice expressing exon 1 of huntingtin containing an expanded polyglutamine repeat, altered the course of their HD-like disease. Cystamine given intraperitoneally entered brain where it inhibited TGase activity. When treatment began after the appearance of abnormal movements, cystamine extended survival, reduced associated tremor and abnormal movements and ameliorated weight loss. Treatment did not influence the appearance or frequency of neuronal nuclear inclusions. Unexpectedly, cystamine treatment increased transcription of one of the two genes shown to be neuroprotective for polyglutamine toxicity in Drosophila, dnaj (also known as HDJ1 and Hsp40 in humans and mice, respectively). Inhibition of TGase provides a new treatment strategy for HD and other polyglutamine diseases.", + "TAG_DATA": [ + "44, transgenic {'context': 'B-organism'}", + "45, mice {'context': 'I-organism'}", + "46, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "47, exon {'perturbing_action': 'I-other'}", + "48, 1 {'perturbing_action': 'I-other'}", + "49, of {'perturbing_action': 'I-other'}", + "50, huntingtin {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "44, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "45, mice ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "46, expressing ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "47, exon ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "48, 1 ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "49, of ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "50, huntingtin ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "exon", + "1", + "of", + "huntingtin" + ] + } + } + ] + }, + { + "PMID": "11821897", + "TEXT": "Although the trigeminal nerve innervates the meninges and participates in the genesis of migraine headaches, triggering mechanisms remain controversial and poorly understood. Here we establish a link between migraine aura and headache by demonstrating that cortical spreading depression, implicated in migraine visual aura, activates trigeminovascular afferents and evokes a series of cortical meningeal and brainstem events consistent with the development of headache. Cortical spreading depression caused long-lasting blood-flow enhancement selectively within the middle meningeal artery dependent upon trigeminal and parasympathetic activation, and plasma protein leakage within the dura mater in part by a neurokinin-1-receptor mechanism. Our findings provide a neural mechanism by which extracerebral cephalic blood flow couples to brain events; this mechanism explains vasodilation during headache and links intense neurometabolic brain activity with the transmission of headache pain by the trigeminal nerve.", + "TAG_DATA": [ + "72, middle {'context': 'B-tissue/organ'}", + "73, meningeal {'context': 'I-tissue/organ'}", + "74, artery {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "72, middle ['l0', 'l1']", + "73, meningeal ['l0', 'l2']", + "74, artery ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11786905", + "TEXT": "In the lungs of cystic fibrosis patients, overproduction of mucus leads to morbidity and mortality by obstructing airflow and shielding bacteria from antibiotics. Here we demonstrate that overproduction of mucus is a direct result of the activation of mucin gene expression by Gram-positive bacteria. Bacterial lipoteichoic acid activates the platelet-activating factor receptor, which is G protein-coupled. This results in activation of a disintegrin and metalloproteinase (ADAM10), kuzbanian, cleavage of pro heparin-binding epidermal growth factor and activation of the epidermal growth factor receptor. Unlike responses in macrophages, the epithelial-cell response to lipoteichoic acid does not require Toll-like receptor 2 or 4.", + "TAG_DATA": [ + "87, epithelial-cell {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11726977", + "TEXT": "We report a novel real-time imaging model to visualize apoptotic membrane changes of single cardiomyocytes in the injured heart of the living mouse, using fluorescent labeled annexin-V. Annexin-V binds to externalized phosphatidylserine (PS) of cells undergoing programmed cell death. With high-magnification (x100-160) real-time imaging, we visualized the binding of annexin-V to single cardiomyocytes. Kinetic studies at the single-cell level revealed that cardiomyocytes started to bind annexin-V within minutes after reperfusion, following an ischemic period of 30 minutes. The amount of bound annexin-V increased rapidly and reached a maximum within 20-25 minutes. Caspase inhibitors decreased the number of annexin-V-positive cardiomyocytes and slowed down the rate of PS exposure of cardiomyocytes that still bound annexin-V. This technology to study cell biology in the natural environment will enhance knowledge of intracellular signaling pathways relevant for cell-death regulation and strategies to manipulate these pathways for therapeutic effect.", + "TAG_DATA": [ + "61, cardiomyocytes {'context': 'B-cells'}", + "98, cardiomyocytes {'context': 'I-cells'}", + "108, cardiomyocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11689890", + "TEXT": "The C2 domain of synaptotagmin I, which binds to anionic phospholipids in cell membranes, was shown to bind to the plasma membrane of apoptotic cells by both flow cytometry and confocal microscopy. Conjugation of the protein to superparamagnetic iron oxide nanoparticles allowed detection of this binding using magnetic resonance imaging. Detection of apoptotic cells, using this novel contrast agent, was demonstrated both in vitro, with isolated apoptotic tumor cells, and in vivo, in a tumor treated with chemotherapeutic drugs.", + "TAG_DATA": [ + "53, cells, {'phenotype': 'I-apoptosis'}", + "62, in {'context': 'B-in vitro'}", + "63, vitro, {'context': 'I-in vitro'}", + "66, apoptotic {'context': 'B-transformed cells'}", + "67, tumor {'context': 'I-transformed cells'}", + "68, cells, {'context': 'I-transformed cells'}", + "70, in {'context': 'B-in vivo'}", + "71, vivo, {'context': 'I-in vivo'}", + "74, tumor {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "53, cells, ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "62, in ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "63, vitro, ['l1', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "66, apoptotic ['l2', 'l9', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "67, tumor ['l3', 'l10', 'l15', 'l20', 'l25', 'l26', 'l27']", + "68, cells, ['l4', 'l11', 'l16', 'l21', 'l25']", + "70, in ['l5', 'l17', 'l22', 'l28', 'l29']", + "71, vivo, ['l6', 'l12', 'l18', 'l23', 'l26', 'l28', 'l30']", + "74, tumor ['l7', 'l13', 'l19', 'l24', 'l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "apoptosis", + "words": [ + "cells," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "cells," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "apoptotic", + "tumor", + "cells," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "cells," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "cells," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + } + ] + }, + { + "PMID": "11689887", + "TEXT": "The antigenic polymorphism of HIV-1 is a major obstacle in developing an effective vaccine. Accordingly, we screened random peptide libraries (RPLs) displayed on phage with antibodies from HIV-infected individuals and identified an array of HIV-specific epitopes that behave as antigenic mimics of conformational epitopes of gp120 and gp41 proteins. We report that the selected epitopes are shared by a collection of HIV-1 isolates of clades A-F. The phage-borne epitopes are immunogenic in rhesus macaques, where they elicit envelope-specific antibody responses. Upon intravenous challenge with 60 MID50 of pathogenic SHIV-89.6PD, all monkeys became infected; however, in contrast to the naive and mock-immunized monkeys, four of five mimotope-immunized monkeys experienced lower levels of peak viremia, followed by viral set points of undetectable or transient levels of viremia and a mild decline of CD4+ T cells, and were protected from progression to AIDS-like illness. These results provide a new approach to the design of broadly protective HIV-1 vaccines.", + "TAG_DATA": [ + "90, monkeys {'context': 'B-organism'}", + "101, monkeys, {'context': 'B-organism'}", + "106, monkeys {'context': 'B-organism'}", + "130, CD4+ {'context': 'B-cells'}", + "131, T {'context': 'I-cells'}", + "132, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "101, monkeys, ['l0', 'l1', 'l2', 'l3']", + "106, monkeys ['l0', 'l4', 'l5', 'l6']", + "130, CD4+ ['l1', 'l4', 'l7', 'l8']", + "131, T ['l2', 'l5', 'l7', 'l9']", + "132, cells, ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11689883", + "TEXT": "The role of bone marrow (BM)-derived precursor cells in tumor angiogenesis is not known. We demonstrate here that tumor angiogenesis is associated with recruitment of hematopoietic and circulating endothelial precursor cells (CEPs). We used the angiogenic defective, tumor resistant Id-mutant mice to show that transplantation of wild-type BM or vascular endothelial growth factor (VEGF)-mobilized stem cells restore tumor angiogenesis and growth. We detected donor-derived CEPs throughout the neovessels of tumors and Matrigel-plugs in an Id1+/-Id3-/- host, which were associated with VEGF-receptor-1-positive (VEGFR1+) myeloid cells. The angiogenic defect in Id-mutant mice was due to impaired VEGF-driven mobilization of VEGFR2+ CEPs and impaired proliferation and incorporation of VEGFR1+ cells. Although targeting of either VEGFR1 or VEGFR2 alone partially blocks the growth of tumors, inhibition of both VEGFR1 and VEGFR2 was necessary to completely ablate tumor growth. These data demonstrate that recruitment of VEGF-responsive BM-derived precursors is necessary and sufficient for tumor angiogenesis and suggest new clinical strategies to block tumor growth.", + "TAG_DATA": [ + "40, mice {'context': 'B-organism'}", + "55, cells {'context': 'I-cells'}", + "57, tumor {'context': 'B-neoplasm'}", + "74, Id1+/-Id3-/- {'perturbing_action': 'B-gene loss-of-function'}", + "75, host, {'context': 'B-organism'}", + "88, Id-mutant {'perturbing_action': 'B-other'}", + "89, mice {'context': 'B-organism'}", + "100, impaired {'effect': 'B-negative'}", + "101, proliferation {'phenotype': 'B-proliferation'}", + "108, targeting {'perturbing_action': 'B-other'}", + "109, of {'perturbing_action': 'I-other'}", + "110, either {'perturbing_action': 'I-other'}", + "111, VEGFR1 {'perturbing_action': 'I-other'}", + "112, or {'perturbing_action': 'I-other'}", + "113, VEGFR2 {'perturbing_action': 'I-other'}", + "120, tumors, {'context': 'B-neoplasm'}", + "121, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "122, of {'perturbing_action': 'I-pharmacological inhibition'}", + "123, both {'perturbing_action': 'I-pharmacological inhibition'}", + "124, VEGFR1 {'perturbing_action': 'I-pharmacological inhibition'}", + "125, and {'perturbing_action': 'I-pharmacological inhibition'}", + "126, VEGFR2 {'perturbing_action': 'I-pharmacological inhibition'}", + "131, ablate {'effect': 'B-negative'}", + "132, tumor {'phenotype': 'B-tumour growth'}", + "133, growth. {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "40, mice ['l0']", + "55, cells ['l1', 'l2', 'l3', 'l4']", + "57, tumor ['l0', 'l1']", + "74, Id1+/-Id3-/- ['l2', 'l5', 'l6', 'l7']", + "75, host, ['l3', 'l5', 'l8']", + "88, Id-mutant ['l9', 'l10', 'l11']", + "89, mice ['l9', 'l12', 'l13']", + "100, impaired ['l6', 'l10', 'l12', 'l14']", + "101, proliferation ['l4', 'l7', 'l8', 'l11', 'l13', 'l14']", + "108, targeting ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "109, of ['l15', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "110, either ['l16', 'l24', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "111, VEGFR1 ['l17', 'l25', 'l32', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "112, or ['l18', 'l26', 'l33', 'l39', 'l45', 'l46', 'l47', 'l48', 'l49']", + "113, VEGFR2 ['l19', 'l27', 'l34', 'l40', 'l45', 'l50', 'l51', 'l52', 'l53']", + "120, tumors, ['l20', 'l28', 'l35', 'l41', 'l46', 'l50', 'l54', 'l55', 'l56']", + "121, inhibition ['l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "122, of ['l57', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "123, both ['l58', 'l65', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "124, VEGFR1 ['l59', 'l66', 'l72', 'l78', 'l79', 'l80', 'l81', 'l82']", + "125, and ['l60', 'l67', 'l73', 'l78', 'l83', 'l84', 'l85', 'l86']", + "126, VEGFR2 ['l61', 'l68', 'l74', 'l79', 'l83', 'l87', 'l88', 'l89']", + "131, ablate ['l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l90', 'l91']", + "132, tumor ['l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l63', 'l70', 'l76', 'l81', 'l85', 'l88', 'l90', 'l92']", + "133, growth. ['l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l64', 'l71', 'l77', 'l82', 'l86', 'l89', 'l91', 'l92']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Id1+/-Id3-/-" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Id1+/-Id3-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "host," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Id1+/-Id3-/-" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Id1+/-Id3-/-" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "host,", + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Id-mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Id-mutant", + "targeting", + "of", + "either", + "VEGFR1", + "or", + "VEGFR2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired", + "ablate" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Id-mutant" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "targeting", + "of", + "either", + "VEGFR1", + "or", + "VEGFR2" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "targeting", + "of", + "either", + "VEGFR1", + "or", + "VEGFR2" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors," + ] + }, + "effect": { + "val": "negative", + "words": [ + "ablate" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "both", + "VEGFR1", + "and", + "VEGFR2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "ablate" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "both", + "VEGFR1", + "and", + "VEGFR2" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "ablate" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + } + ] + }, + { + "PMID": "11689871", + "TEXT": "Prizes in science don't come any bigger than the Nobels, and more often than not this award catapults its recipients from the general research milieu into the realms of scientific stardom. In this, its centenary year, the Nobel committee for Physiology or Medicine decided to honor investigators who have identified vital components of the cell cycle. Nature Medicine talked to one of the winners, Sir Paul Nurse.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11590437", + "TEXT": "The physiological performance of an organ depends on an interplay between changes in cellular function and organ size, determined by cell growth, proliferation and death. Nowhere is this more evident than in the endocrine pancreas, where disturbances in function or mass result in severe disease. Recently, the insulin signal-transduction pathway has been implicated in both the regulation of hormone secretion from beta cells in mammals as well as the determination of cell and organ size in Drosophila melanogaster. A prominent mediator of the actions of insulin and insulin-like growth factor 1 (IGF-1) is the 3'-phosphoinositide-dependent protein kinase Akt, also known as protein kinase B (PKB). Here we report that overexpression of active Akt1 in the mouse beta cell substantially affects compartment size and function. There was a significant increase in both beta-cell size and total islet mass, accompanied by improved glucose tolerance and complete resistance to experimental diabetes.", + "TAG_DATA": [ + "109, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "110, of {'perturbing_action': 'I-gene gain-of-function'}", + "111, active {'perturbing_action': 'I-gene gain-of-function'}", + "112, Akt1 {'perturbing_action': 'I-gene gain-of-function'}", + "115, mouse {'context': 'B-cells'}", + "116, beta {'context': 'I-cells'}", + "117, cell {'context': 'I-cells'}", + "131, beta-cell {'context': 'B-cells'}", + "135, islet {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "109, overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "110, of ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "111, active ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "112, Akt1 ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "115, mouse ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28']", + "116, beta ['l4', 'l11', 'l17', 'l22', 'l26', 'l29', 'l30', 'l31']", + "117, cell ['l5', 'l12', 'l18', 'l23', 'l27', 'l29']", + "131, beta-cell ['l6', 'l13', 'l19', 'l24', 'l30', 'l32']", + "135, islet ['l7', 'l14', 'l20', 'l25', 'l28', 'l31', 'l32']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "active", + "Akt1" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "beta", + "cell", + "beta-cell", + "islet" + ] + } + } + ] + }, + { + "PMID": "11590436", + "TEXT": "All nuclear-encoded mRNAs contain a 5' cap structure (m7GpppN, where N is any nucleotide), which is recognized by the eukaryotic translation initiation factor 4E (eIF4E) subunit of the eIF4F complex. The eIF4E-binding proteins constitute a family of three polypeptides that reversibly repress cap-dependent translation by binding to eIF4E, thus preventing the formation of the eIF4F complex. We investigated the biological function of 4E-BP1 by disrupting its gene (Eif4ebp1) in the mouse. Eif4ebp1-/- mice manifest markedly smaller white fat pads than wild-type animals, and knockout males display an increase in metabolic rate. The males' white adipose tissue contains cells that exhibit the distinctive multilocular appearance of brown adipocytes, and expresses the uncoupling protein 1 (UCP1), a specific marker of brown fat. Consistent with these observations, translation of the peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC1), a transcriptional co-activator implicated in mitochondrial biogenesis and adaptive thermogenesis, is increased in white adipose tissue of Eif4ebp1-/- mice. These findings demonstrate that 4E-BP1 is a novel regulator of adipogenesis and metabolism in mammals.", + "TAG_DATA": [ + "64, disrupting {'perturbing_action': 'B-gene loss-of-function'}", + "65, its {'perturbing_action': 'I-gene loss-of-function'}", + "66, gene {'perturbing_action': 'I-gene loss-of-function'}", + "67, (Eif4ebp1) {'perturbing_action': 'I-gene loss-of-function'}", + "70, mouse. {'context': 'B-organism'}", + "71, Eif4ebp1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "72, mice {'context': 'B-organism'}", + "81, animals, {'context': 'B-organism'}", + "83, knockout {'perturbing_action': 'B-gene loss-of-function'}", + "84, males {'context': 'B-organism'}", + "92, males' {'context': 'B-tissue/organ'}", + "93, white {'context': 'I-tissue/organ'}", + "94, adipose {'context': 'I-tissue/organ'}", + "95, tissue {'context': 'I-tissue/organ'}", + "146, white {'context': 'B-tissue/organ'}", + "147, adipose {'context': 'I-tissue/organ'}", + "148, tissue {'context': 'I-tissue/organ'}", + "150, Eif4ebp1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "151, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "64, disrupting ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "65, its ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "66, gene ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "67, (Eif4ebp1) ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "70, mouse. ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "71, Eif4ebp1-/- ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "72, mice ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "81, animals, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "83, knockout ['l28', 'l29', 'l30', 'l31']", + "84, males ['l28', 'l32', 'l33', 'l34']", + "92, males' ['l29', 'l32', 'l35', 'l36', 'l37']", + "93, white ['l35', 'l38', 'l39']", + "94, adipose ['l30', 'l33', 'l36', 'l38', 'l40']", + "95, tissue ['l31', 'l34', 'l37', 'l39', 'l40']", + "146, white ['l41', 'l42', 'l43', 'l44']", + "147, adipose ['l41', 'l45', 'l46', 'l47']", + "148, tissue ['l42', 'l45', 'l48', 'l49']", + "150, Eif4ebp1-/- ['l43', 'l46', 'l48', 'l50']", + "151, mice. ['l44', 'l47', 'l49', 'l50']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "disrupting", + "its", + "gene", + "(Eif4ebp1)", + "Eif4ebp1-/-", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse.", + "mice", + "animals,", + "males", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout", + "Eif4ebp1-/-" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "males'", + "adipose", + "tissue", + "white" + ] + } + } + ] + }, + { + "PMID": "11533709", + "TEXT": "Arachidonic acid is metabolized to prostaglandin H(2) (PGH(2)) by cyclooxygenase (COX). COX-2, the inducible COX isozyme, has a key role in intestinal polyposis. Among the metabolites of PGH(2), PGE(2) is implicated in tumorigenesis because its level is markedly elevated in tissues of intestinal adenoma and colon cancer. Here we show that homozygous deletion of the gene encoding a cell-surface receptor of PGE(2), EP2, causes decreases in number and size of intestinal polyps in Apc(Delta 716) mice (a mouse model for human familial adenomatous polyposis). This effect is similar to that of COX-2 gene disruption. We also show that COX-2 expression is boosted by PGE(2) through the EP2 receptor via a positive feedback loop. Homozygous gene knockout for other PGE(2) receptors, EP1 or EP3, did not affect intestinal polyp formation in Apc(Delta 716) mice. We conclude that EP2 is the major receptor mediating the PGE2 signal generated by COX-2 upregulation in intestinal polyposis, and that increased cellular cAMP stimulates expression of more COX-2 and vascular endothelial growth factor in the polyp stroma.", + "TAG_DATA": [ + "51, homozygous {'perturbing_action': 'B-gene loss-of-function'}", + "52, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "53, of {'perturbing_action': 'I-gene loss-of-function'}", + "54, the {'perturbing_action': 'I-gene loss-of-function'}", + "55, gene {'perturbing_action': 'I-gene loss-of-function'}", + "56, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "57, a {'perturbing_action': 'I-gene loss-of-function'}", + "58, cell-surface {'perturbing_action': 'I-gene loss-of-function'}", + "59, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "60, of {'perturbing_action': 'I-gene loss-of-function'}", + "61, PGE(2), {'perturbing_action': 'I-gene loss-of-function'}", + "62, EP2, {'perturbing_action': 'I-gene loss-of-function'}", + "73, Apc(Delta {'perturbing_action': 'B-other'}", + "74, 716) {'perturbing_action': 'I-other'}", + "75, mice {'context': 'B-organism'}", + "76, (a {'context': 'B-organism'}", + "113, Homozygous {'perturbing_action': 'B-gene loss-of-function'}", + "114, gene {'perturbing_action': 'I-gene loss-of-function'}", + "115, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "116, for {'perturbing_action': 'I-gene loss-of-function'}", + "117, other {'perturbing_action': 'I-gene loss-of-function'}", + "118, PGE(2) {'perturbing_action': 'I-gene loss-of-function'}", + "119, receptors, {'perturbing_action': 'I-gene loss-of-function'}", + "120, EP1 {'perturbing_action': 'I-gene loss-of-function'}", + "121, or {'perturbing_action': 'I-gene loss-of-function'}", + "122, EP3, {'perturbing_action': 'I-gene loss-of-function'}", + "130, Apc(Delta {'perturbing_action': 'B-other'}", + "131, 716) {'perturbing_action': 'I-other'}", + "132, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "51, homozygous ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "52, deletion ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "53, of ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "54, the ['l2', 'l16', 'l29', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "55, gene ['l3', 'l17', 'l30', 'l42', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "56, encoding ['l4', 'l18', 'l31', 'l43', 'l54', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "57, a ['l5', 'l19', 'l32', 'l44', 'l55', 'l65', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "58, cell-surface ['l6', 'l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "59, receptor ['l7', 'l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l84', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "60, of ['l8', 'l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "61, PGE(2), ['l9', 'l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l86', 'l93', 'l99', 'l105', 'l106', 'l107', 'l108', 'l109']", + "62, EP2, ['l10', 'l24', 'l37', 'l49', 'l60', 'l70', 'l79', 'l87', 'l94', 'l100', 'l105', 'l110', 'l111', 'l112', 'l113']", + "73, Apc(Delta ['l11', 'l25', 'l38', 'l50', 'l61', 'l71', 'l80', 'l88', 'l95', 'l101', 'l106', 'l110', 'l114', 'l115', 'l116']", + "74, 716) ['l12', 'l26', 'l39', 'l51', 'l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l107', 'l111', 'l114', 'l117', 'l118']", + "75, mice ['l13', 'l27', 'l40', 'l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l108', 'l112', 'l115', 'l117', 'l119']", + "76, (a ['l14', 'l28', 'l41', 'l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l109', 'l113', 'l116', 'l118', 'l119']", + "113, Homozygous ['l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "114, gene ['l120', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "115, knockout ['l121', 'l132', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "116, for ['l122', 'l133', 'l143', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "117, other ['l123', 'l134', 'l144', 'l153', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "118, PGE(2) ['l124', 'l135', 'l145', 'l154', 'l162', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176']", + "119, receptors, ['l125', 'l136', 'l146', 'l155', 'l163', 'l170', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "120, EP1 ['l126', 'l137', 'l147', 'l156', 'l164', 'l171', 'l177', 'l183', 'l184', 'l185', 'l186', 'l187']", + "121, or ['l127', 'l138', 'l148', 'l157', 'l165', 'l172', 'l178', 'l183', 'l188', 'l189', 'l190', 'l191']", + "122, EP3, ['l128', 'l139', 'l149', 'l158', 'l166', 'l173', 'l179', 'l184', 'l188', 'l192', 'l193', 'l194']", + "130, Apc(Delta ['l129', 'l140', 'l150', 'l159', 'l167', 'l174', 'l180', 'l185', 'l189', 'l192', 'l195', 'l196']", + "131, 716) ['l130', 'l141', 'l151', 'l160', 'l168', 'l175', 'l181', 'l186', 'l190', 'l193', 'l195', 'l197']", + "132, mice. ['l131', 'l142', 'l152', 'l161', 'l169', 'l176', 'l182', 'l187', 'l191', 'l194', 'l196', 'l197']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "homozygous", + "deletion", + "of", + "the", + "gene", + "encoding", + "a", + "cell-surface", + "receptor", + "PGE(2),", + "EP2,", + "Homozygous", + "knockout", + "for", + "other", + "PGE(2)", + "receptors,", + "EP1", + "or", + "EP3," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "(a", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Apc(Delta", + "716)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "(a", + "mice." + ] + } + } + ] + }, + { + "PMID": "11533702", + "TEXT": "Several examples of functional G-protein-coupled receptor heterodimers have been identified. However, it is not known whether receptor heterodimerization is involved in the pathogenesis of human disorders. Here we show that in preeclamptic hypertensive women, a significant increase in heterodimerization occurs between the AT(1)-receptor for the vasopressor angiotensin II and the B(2)-receptor for the vasodepressor bradykinin. AT(1)-B(2)-receptor heterodimerization in preeclampsia correlated with a 4-5-fold increase in B(2)-receptor protein levels. Expression of the AT(1)-B(2) heterodimer increased the responsiveness to angiotensin II and conferred resistance in AT(1)-receptors to inactivation by reactive oxygen species raised in normotensive and preeclamptic pregnancies. We suggest that AT(1)-B(2) heterodimers contribute to angiotensin II hypersensitivity in preeclampsia. Moreover, we identify preeclampsia as the first disorder associated with altered G-protein-coupled receptor heterodimerization.", + "TAG_DATA": [ + "68, Expression {'perturbing_action': 'B-other'}", + "69, of {'perturbing_action': 'I-other'}", + "70, the {'perturbing_action': 'I-other'}", + "71, AT(1)-B(2) {'perturbing_action': 'I-other'}", + "72, heterodimer {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "68, Expression ['l0', 'l1', 'l2', 'l3']", + "69, of ['l0', 'l4', 'l5', 'l6']", + "70, the ['l1', 'l4', 'l7', 'l8']", + "71, AT(1)-B(2) ['l2', 'l5', 'l7', 'l9']", + "72, heterodimer ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11479630", + "TEXT": "While investigating the novel anticancer drug ecteinascidin 743 (Et743), a natural marine product isolated from the Caribbean sea squirt, we discovered a new cell-killing mechanism mediated by DNA nucleotide excision repair (NER). A cancer cell line selected for resistance to Et743 had chromosome alterations in a region that included the gene implicated in the hereditary disease xeroderma pigmentosum (XPG, also known as Ercc5). Complementation with wild-type XPG restored the drug sensitivity. Xeroderma pigmentosum cells deficient in the NER genes XPG, XPA, XPD or XPF were resistant to Et743, and sensitivity was restored by complementation with wild-type genes. Moreover, studies of cells deficient in XPC or in the genes implicated in Cockayne syndrome (CSA and CSB) indicated that the drug sensitivity is specifically dependent on the transcription-coupled pathway of NER. We found that Et743 interacts with the transcription-coupled NER machinery to induce lethal DNA strand breaks.", + "TAG_DATA": [ + "33, cancer {'context': 'B-transformed cells'}", + "34, cell {'context': 'I-transformed cells'}", + "35, line {'context': 'I-transformed cells'}", + "71, Xeroderma {'context': 'B-transformed cells'}", + "72, pigmentosum {'context': 'I-transformed cells'}", + "73, cells {'context': 'I-transformed cells'}", + "74, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "75, in {'perturbing_action': 'I-gene loss-of-function'}", + "100, cells {'context': 'B-cells'}", + "101, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "102, in {'perturbing_action': 'I-gene loss-of-function'}", + "103, XPC {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "33, cancer ['l0', 'l1']", + "34, cell ['l0', 'l2']", + "35, line ['l1', 'l2']", + "71, Xeroderma ['l3', 'l4', 'l5', 'l6']", + "72, pigmentosum ['l3', 'l7', 'l8', 'l9']", + "73, cells ['l4', 'l7', 'l10', 'l11']", + "74, deficient ['l5', 'l8', 'l10', 'l12']", + "75, in ['l6', 'l9', 'l11', 'l12']", + "100, cells ['l13', 'l14', 'l15']", + "101, deficient ['l13', 'l16', 'l17']", + "102, in ['l14', 'l16', 'l18']", + "103, XPC ['l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "Xeroderma", + "pigmentosum", + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "XPC" + ] + } + } + ] + }, + { + "PMID": "11479629", + "TEXT": "A novel anti-human DR5 monoclonal antibody, TRA-8, induces apoptosis of most tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-sensitive tumor cells both in vitro and in vivo. In contrast to both the membrane-bound form of human TRAIL, which induced severe hepatitis in mice, and the soluble form of human TRAIL, which induced apoptosis of normal human hepatocytes in vitro, TRA-8 did not induce significant cell death of normal human hepatocytes. However, both primary hepatocellular carcinoma cells and an established liver cancer cell line were highly susceptible to the killing mediated by TRA-8. We show here that elevated levels of cell-surface expression of DR5 and increased susceptibility to DR5-mediated apoptosis are characteristics of malignant tumor cells. In contrast, DR5 alone is not sufficient to trigger apoptosis of normal hepatocytes. Therefore, selective, specific targeting of DR5 with an agonistic antibody might be a safe and effective strategy for cancer therapy.", + "TAG_DATA": [ + "20, in {'context': 'B-in vitro'}", + "21, vitro {'context': 'I-in vitro'}", + "23, in {'context': 'B-in vivo'}", + "24, vivo. {'context': 'I-in vivo'}", + "49, induced {'effect': 'B-positive'}", + "50, apoptosis {'phenotype': 'B-apoptosis'}", + "52, normal {'context': 'B-cells'}", + "53, human {'context': 'I-cells'}", + "54, hepatocytes {'context': 'I-cells'}", + "55, in {'context': 'B-in vitro'}", + "56, vitro, {'context': 'I-in vitro'}", + "59, not {'effect': 'I-no effect'}", + "60, induce {'effect': 'I-no effect'}", + "62, cell {'phenotype': 'B-cell death'}", + "63, death {'phenotype': 'I-cell death'}", + "65, normal {'context': 'B-cells'}", + "66, human {'context': 'I-cells'}", + "67, hepatocytes. {'context': 'I-cells'}", + "70, primary {'context': 'B-transformed cells'}", + "71, hepatocellular {'context': 'I-transformed cells'}", + "72, carcinoma {'context': 'I-transformed cells'}", + "73, cells {'context': 'I-transformed cells'}", + "77, liver {'context': 'B-transformed cells'}", + "78, cancer {'context': 'I-transformed cells'}", + "79, cell {'context': 'I-transformed cells'}", + "80, line {'context': 'I-transformed cells'}", + "103, susceptibility {'effect': 'I-positive'}", + "105, DR5-mediated {'effect': 'B-regulates'}", + "106, apoptosis {'phenotype': 'B-apoptosis'}", + "121, trigger {'effect': 'B-positive'}", + "122, apoptosis {'phenotype': 'B-apoptosis'}", + "124, normal {'context': 'B-cells'}", + "125, hepatocytes. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "20, in ['l0', 'l1', 'l2', 'l3']", + "21, vitro ['l0', 'l4', 'l5', 'l6']", + "23, in ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "24, vivo. ['l7', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "49, induced ['l8', 'l21', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "50, apoptosis ['l9', 'l22', 'l34', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "52, normal ['l1', 'l4', 'l10', 'l23', 'l35', 'l48', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "53, human ['l2', 'l5', 'l11', 'l24', 'l36', 'l49', 'l61', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "54, hepatocytes ['l3', 'l6', 'l12', 'l25', 'l37', 'l50', 'l62', 'l71', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "55, in ['l13', 'l26', 'l38', 'l51', 'l63', 'l72', 'l82', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "56, vitro, ['l14', 'l27', 'l39', 'l52', 'l64', 'l73', 'l83', 'l92', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "58, did ['l40', 'l53', 'l74', 'l84', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "59, not ['l41', 'l54', 'l75', 'l85', 'l93', 'l106', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "60, induce ['l15', 'l28', 'l42', 'l55', 'l65', 'l76', 'l86', 'l94', 'l100', 'l107', 'l116', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "62, cell ['l16', 'l29', 'l43', 'l56', 'l66', 'l77', 'l87', 'l95', 'l101', 'l108', 'l117', 'l125', 'l131', 'l132', 'l133', 'l134']", + "63, death ['l17', 'l30', 'l44', 'l57', 'l67', 'l78', 'l88', 'l96', 'l102', 'l109', 'l118', 'l126', 'l131', 'l135', 'l136', 'l137']", + "65, normal ['l18', 'l31', 'l45', 'l58', 'l68', 'l79', 'l89', 'l97', 'l103', 'l110', 'l119', 'l127', 'l132', 'l135', 'l138', 'l139', 'l140', 'l141']", + "66, human ['l19', 'l32', 'l46', 'l59', 'l69', 'l80', 'l90', 'l98', 'l104', 'l111', 'l120', 'l128', 'l133', 'l136', 'l138', 'l142', 'l143', 'l144']", + "67, hepatocytes. ['l20', 'l33', 'l47', 'l60', 'l70', 'l81', 'l91', 'l99', 'l105', 'l112', 'l121', 'l129', 'l134', 'l137', 'l139', 'l142', 'l145', 'l146']", + "70, primary ['l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "71, hepatocellular ['l113', 'l122', 'l147', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159']", + "72, carcinoma ['l114', 'l123', 'l140', 'l143', 'l145', 'l148', 'l154', 'l160', 'l161', 'l162', 'l163', 'l164']", + "73, cells ['l115', 'l124', 'l130', 'l141', 'l144', 'l146', 'l149', 'l155', 'l160', 'l165', 'l166', 'l167', 'l168']", + "77, liver ['l150', 'l156', 'l161', 'l165', 'l169', 'l170', 'l171']", + "78, cancer ['l151', 'l157', 'l162', 'l166', 'l169', 'l172', 'l173']", + "79, cell ['l152', 'l158', 'l163', 'l167', 'l170', 'l172', 'l174']", + "80, line ['l153', 'l159', 'l164', 'l168', 'l171', 'l173', 'l174']", + "103, susceptibility ['l175', 'l176', 'l177', 'l178', 'l179', 'l180']", + "105, DR5-mediated ['l175', 'l181', 'l182', 'l183', 'l184', 'l185']", + "106, apoptosis ['l176', 'l181', 'l186', 'l187', 'l188', 'l189']", + "121, trigger ['l177', 'l182', 'l186', 'l190', 'l191', 'l192']", + "122, apoptosis ['l178', 'l183', 'l187', 'l190', 'l193', 'l194']", + "124, normal ['l179', 'l184', 'l188', 'l191', 'l193', 'l195']", + "125, hepatocytes. ['l180', 'l185', 'l189', 'l192', 'l194', 'l195']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "effect": { + "val": "no effect", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "susceptibility", + "trigger" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "susceptibility", + "trigger" + ] + }, + "context": { + "val": "cells", + "words": [ + "normal", + "human", + "hepatocytes", + "hepatocytes." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "normal", + "human", + "hepatocytes", + "hepatocytes." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "induce" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "normal", + "human", + "hepatocytes", + "hepatocytes." + ] + }, + "effect": { + "val": "no effect", + "words": [ + "induce", + "not" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "normal", + "human", + "hepatocytes", + "hepatocytes." + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "induce" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "induce" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "induce" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "hepatocellular", + "carcinoma", + "cells" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "DR5-mediated" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "DR5-mediated" + ] + }, + "context": { + "val": "cells", + "words": [ + "normal", + "hepatocytes." + ] + } + } + ] + }, + { + "PMID": "11479628", + "TEXT": "Acrp30 is a circulating protein synthesized in adipose tissue. A single injection in mice of purified recombinant Acrp30 leads to a 2-3-fold elevation in circulating Acrp30 levels, which triggers a transient decrease in basal glucose levels. Similar treatment in ob/ob, NOD (non-obese diabetic) or streptozotocin-treated mice transiently abolishes hyperglycemia. This effect on glucose is not associated with an increase in insulin levels. Moreover, in isolated hepatocytes, Acrp30 increases the ability of sub-physiological levels of insulin to suppress glucose production. We thus propose that Acrp30 is a potent insulin enhancer linking adipose tissue and whole-body glucose metabolism.", + "TAG_DATA": [ + "13, mice {'context': 'B-organism'}", + "39, ob/ob, {'context': 'B-organism'}", + "45, mice {'context': 'B-organism'}", + "65, hepatocytes, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "39, ob/ob, ['l0', 'l1', 'l2', 'l3']", + "40, NOD ['l0', 'l4', 'l5', 'l6']", + "41, (non-obese ['l1', 'l4', 'l7', 'l8']", + "42, diabetic) ['l2', 'l5', 'l7', 'l9']", + "45, mice ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11479624", + "TEXT": "Integase interactor 1 (INI1), also known as hSNF5, is a protein that interacts with HIV-1 integrase. We report here that a cytoplasmically localized fragment of INI1 (S6; aa183-294) containing the minimal integrase-interaction domain potently inhibits HIV-1 particle production and replication. Mutations in S6 or integrase that disrupt integrase-INI1 interaction abrogated the inhibitory effect. An integrase-deficient HIV-1 transcomplemented with integrase fused to Vpr was not affected by S6. INI1 was specifically incorporated into virions and was required for efficient HIV-1 particle production. These results indicate that INI1 is required for late events in the viral life cycle, and that ectopic expression of S6 inhibits HIV-1 replication in a transdominant manner via its specific interaction with integrase within the context of Gag-Pol, providing a novel strategy to control HIV-1 replication.", + "TAG_DATA": [ + "40, Mutations {'perturbing_action': 'B-other'}", + "41, in {'perturbing_action': 'I-other'}", + "42, S6 {'perturbing_action': 'I-other'}", + "54, integrase-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "55, HIV-1 {'context': 'B-cells'}", + "56, transcomplemented {'context': 'I-xenograft'}", + "58, integrase {'perturbing_action': 'I-other'}", + "59, fused {'perturbing_action': 'I-other'}", + "60, to {'perturbing_action': 'I-other'}", + "61, Vpr {'perturbing_action': 'I-other'}", + "98, ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "99, expression {'perturbing_action': 'I-gene gain-of-function'}", + "100, of {'perturbing_action': 'I-gene gain-of-function'}", + "101, S6 {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "40, Mutations ['l0', 'l1', 'l2', 'l3', 'l4']", + "41, in ['l0', 'l5', 'l6']", + "42, S6 ['l1', 'l5']", + "44, integrase ['l2', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "54, integrase-deficient ['l7', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "55, HIV-1 ['l8', 'l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "56, transcomplemented ['l9', 'l16', 'l22', 'l28', 'l29', 'l30', 'l31', 'l32']", + "57, with ['l10', 'l17', 'l23', 'l28', 'l33', 'l34', 'l35', 'l36']", + "58, integrase ['l11', 'l18', 'l24', 'l29', 'l33', 'l37', 'l38', 'l39']", + "59, fused ['l12', 'l19', 'l25', 'l30', 'l34', 'l37', 'l40', 'l41']", + "60, to ['l3', 'l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l42']", + "61, Vpr ['l4', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l41', 'l42']", + "98, ectopic ['l43', 'l44', 'l45']", + "99, expression ['l43', 'l46', 'l47']", + "100, of ['l44', 'l46', 'l48']", + "101, S6 ['l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "integrase-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "HIV-1" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "integrase-deficient" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "transcomplemented" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HIV-1" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "integrase", + "fused", + "to", + "Vpr" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "transcomplemented" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "integrase", + "fused", + "to", + "Vpr" + ] + } + } + ] + }, + { + "PMID": "11479623", + "TEXT": "Emerging evidence indicates that CD8+ and CD4+ T-cell immunity is differentially regulated. Here we have delineated differences and commonalities among antiviral T-cell responses by enumeration and functional profiling of eight specific CD8+ and CD4+ T-cell populations during primary, memory and recall responses. A high degree of coordinate regulation among all specific T-cell populations stood out against an approximately 20-fold lower peak expansion and prolonged contraction phase of specific CD4+ T-cell populations. Surprisingly, although CD8+ T-cell memory was stably maintained for life, levels of specific CD4+ memory T cells gradually declined. However, this decay, which seemed to result from less efficient rescue from apoptosis, did not affect functionality of surviving virus-specific CD4+ T cells. Our results indicate that CD4+ T-cell memory might become limiting under physiological conditions and that conditions precipitating CD4+ T-cell loss might compromise protective immunity even in the presence of unimpaired CD8+ T-cell responses.", + "TAG_DATA": [ + "84, CD4+ {'context': 'B-cells'}", + "85, memory {'context': 'I-cells'}", + "86, T {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}", + "98, less {'effect': 'B-negative'}", + "100, rescue {'effect': 'B-rescues'}", + "102, apoptosis, {'phenotype': 'B-apoptosis'}", + "110, CD4+ {'context': 'B-cells'}", + "111, T {'context': 'I-cells'}", + "112, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "84, CD4+ ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "85, memory ['l0', 'l6', 'l7', 'l8']", + "86, T ['l1', 'l6', 'l9']", + "87, cells ['l2', 'l7', 'l9']", + "98, less ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "99, efficient ['l3', 'l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "100, rescue ['l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "101, from ['l4', 'l8', 'l12', 'l18', 'l23', 'l28', 'l29', 'l30', 'l31']", + "102, apoptosis, ['l5', 'l13', 'l19', 'l24', 'l28', 'l32', 'l33', 'l34']", + "110, CD4+ ['l14', 'l20', 'l25', 'l29', 'l32', 'l35', 'l36']", + "111, T ['l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l37']", + "112, cells. ['l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "less" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "less" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells." + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescue" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescue" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells." + ] + } + } + ] + }, + { + "PMID": "11479609", + "TEXT": "At the age of 10, Alfred Gilman wanted to go to the moon; on a visit to New York's Hayden Planetarium with his parents, he signed up to be an astronaut. Fifty years later, Gilman is preparing to take on a different, yet equally astronomical task. Instead of traveling to outer space, he is heading up a research program to detail the workings of cellular space.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11433347", + "TEXT": "Using a combined pharmacological and gene-deletion approach, we have delineated a novel mechanism of neurokinin-1 (NK-1) receptor-dependent hyperalgesia induced by proteinase-activated receptor-2 (PAR2), a G-protein-coupled receptor expressed on nociceptive primary afferent neurons. Injections into the paw of sub-inflammatory doses of PAR2 agonists in rats and mice induced a prolonged thermal and mechanical hyperalgesia and elevated spinal Fos protein expression. This hyperalgesia was markedly diminished or absent in mice lacking the NK-1 receptor, preprotachykinin-A or PAR2 genes, or in rats treated with a centrally acting cyclooxygenase inhibitor or treated by spinal cord injection of NK-1 antagonists. Here we identify a previously unrecognized nociceptive pathway with important therapeutic implications, and our results point to a direct role for proteinases and their receptors in pain transmission.", + "TAG_DATA": [ + "40, PAR2 {'perturbing_action': 'B-pharmacological augmentation'}", + "41, agonists {'perturbing_action': 'I-pharmacological augmentation'}", + "43, rats {'context': 'B-organism'}", + "45, mice {'context': 'B-organism'}", + "67, mice {'context': 'B-organism'}", + "68, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "69, the {'perturbing_action': 'I-gene loss-of-function'}", + "70, NK-1 {'perturbing_action': 'I-gene loss-of-function'}", + "71, receptor, {'perturbing_action': 'I-gene loss-of-function'}", + "72, preprotachykinin-A {'perturbing_action': 'I-rnai/knockdown'}", + "75, genes, {'perturbing_action': 'I-gene loss-of-function'}", + "78, rats {'context': 'B-organism'}", + "93, NK-1 {'perturbing_action': 'B-pharmacological inhibition'}", + "94, antagonists. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "40, PAR2 ['l0', 'l1', 'l2']", + "41, agonists ['l0', 'l3', 'l4']", + "43, rats ['l1', 'l3', 'l5']", + "45, mice ['l2', 'l4', 'l5']", + "67, mice ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "68, lacking ['l6', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "69, the ['l7', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "70, NK-1 ['l8', 'l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "71, receptor, ['l9', 'l15', 'l20', 'l24', 'l28', 'l29', 'l30']", + "72, preprotachykinin-A ['l10', 'l16', 'l21', 'l25', 'l28', 'l31', 'l32']", + "75, genes, ['l11', 'l17', 'l22', 'l26', 'l29', 'l31', 'l33']", + "78, rats ['l12', 'l18', 'l23', 'l27', 'l30', 'l32', 'l33']", + "93, NK-1 ['l34']", + "94, antagonists. ['l34']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "PAR2", + "agonists" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats", + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "rats" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "NK-1", + "receptor,", + "genes," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "rats" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "preprotachykinin-A" + ] + } + } + ] + }, + { + "PMID": "11433346", + "TEXT": "The Fanconi anemia group C protein (FANCC) plays an important role in hematopoiesis by ensuring the survival of hematopoietic progenitor cells through an unknown mechanism. We investigated the function of FANCC by identifying FANCC-binding proteins in hematopoietic cells. Here we show that glutathione S-transferase P1-1 (GSTP1) interacts with FANCC, and that overexpression of both proteins in a myeloid progenitor cell line prevents apoptosis following factor deprivation. FANCC increases GSTP1 activity after the induction of apoptosis. GSTP1 is an enzyme that catalyzes the detoxification of xenobiotics and by-products of oxidative stress, and it is frequently upregulated in neoplastic cells. Although FANCC lacks homology with conventional disulfide reductases, it functions by preventing the formation of inactivating disulfide bonds within GSTP1 during apoptosis. The prevention of protein oxidation by FANCC reveals a novel mechanism of enzyme regulation during apoptosis and has implications for the treatment of degenerative diseases with thiol reducing agents.", + "TAG_DATA": [ + "51, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "52, of {'perturbing_action': 'I-gene gain-of-function'}", + "53, both {'perturbing_action': 'I-gene gain-of-function'}", + "54, proteins {'perturbing_action': 'I-gene gain-of-function'}", + "57, myeloid {'context': 'B-cells'}", + "58, progenitor {'context': 'I-cells'}", + "59, cell {'context': 'I-cells'}", + "60, line {'context': 'I-cells'}", + "61, prevents {'effect': 'B-negative'}", + "62, apoptosis {'phenotype': 'B-apoptosis'}", + "72, induction {'effect': 'B-positive'}", + "74, apoptosis. {'phenotype': 'B-apoptosis'}", + "119, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "51, overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "52, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "53, both ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "54, proteins ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "57, myeloid ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "58, progenitor ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "59, cell ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "60, line ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "61, prevents ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "62, apoptosis ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "72, induction ['l45']", + "74, apoptosis. ['l45']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "both", + "proteins" + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "progenitor", + "cell", + "line" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "both", + "proteins" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "both", + "proteins" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "myeloid", + "progenitor", + "cell", + "line" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "myeloid", + "progenitor", + "cell", + "line" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "11433344", + "TEXT": "To assess the role of complement in renal infection, we studied a model of Escherichia coli-induced pyelonephritis in mice deficient in complement components C3 and C4. Renal infection occurred less frequently in C3- and C4-deficient mice compared with wild-type mice. In vitro, renal epithelial cells internalized fewer bacteria in the absence of C3 or in the presence of blockade of C3 bound to the bacteria. Moreover, upregulation of epithelial C3 production by stimulation with lipopolysaccharide enhanced bacterial internalization. Here we provide evidence that uropathogenic E. coli might use host C3 to invade the renal epithelium and that local complement production is sufficient for the bacteria to achieve this effect.", + "TAG_DATA": [ + "18, mice {'context': 'B-organism'}", + "19, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "32, C3- {'perturbing_action': 'B-gene loss-of-function'}", + "33, and {'perturbing_action': 'I-gene loss-of-function'}", + "34, C4-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "35, mice {'context': 'B-organism'}", + "40, In {'context': 'B-in vitro'}", + "41, vitro, {'context': 'I-in vitro'}", + "42, renal {'context': 'B-cells'}", + "43, epithelial {'context': 'I-cells'}", + "44, cells {'context': 'I-cells'}", + "66, upregulation {'perturbing_action': 'B-gene gain-of-function'}", + "67, of {'perturbing_action': 'I-gene gain-of-function'}", + "68, epithelial {'perturbing_action': 'I-gene gain-of-function'}", + "69, C3 {'perturbing_action': 'I-gene gain-of-function'}", + "70, production {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "18, mice ['l0']", + "19, deficient ['l0', 'l1', 'l2', 'l3']", + "32, C3- ['l1', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "33, and ['l4', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "34, C4-deficient ['l5', 'l12', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "35, mice ['l2', 'l6', 'l13', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "40, In ['l7', 'l14', 'l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "41, vitro, ['l8', 'l15', 'l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "42, renal ['l9', 'l16', 'l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "43, epithelial ['l10', 'l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "44, cells ['l3', 'l11', 'l18', 'l24', 'l29', 'l33', 'l36', 'l38', 'l39']", + "66, upregulation ['l40', 'l41', 'l42', 'l43']", + "67, of ['l40', 'l44', 'l45', 'l46']", + "68, epithelial ['l41', 'l44', 'l47', 'l48']", + "69, C3 ['l42', 'l45', 'l47', 'l49']", + "70, production ['l43', 'l46', 'l48', 'l49']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "C3-", + "and", + "C4-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "C3-", + "and", + "C4-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "renal", + "epithelial" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "C3-", + "and", + "C4-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + } + } + ] + }, + { + "PMID": "11433342", + "TEXT": "Adoptive transfer of T cells reactive to minor histocompatibility antigens has the unmatched ability to eradicate malignant hematopoietic cells. Unfortunately, its use is hampered by the associated graft-versus-host disease. The critical issue of a possible dissociation of the antileukemic effect and graft-versus-host disease by targeting specific minor histocompatibility antigens remains unresolved because of the unknown nature and number of minor histocompatibility antigens necessary or sufficient to elicit anti-leukemic activity and graft-versus-host disease. We found that injection of T lymphocytes primed against a single major histocompatibility complex class I-restricted immunodominant minor histocompatibility antigen (B6dom1) caused no graft-versus-host disease but produced a curative anti-leukemic response. Avoidance of graft-versus-host disease required that no other host-reactive T cells be co-injected with T cells primed with B6dom1. Here we show that effective and non-toxic immunotherapy of hematologic malignancies can be achieved by targeting a single immunodominant minor histocompatibility antigen.", + "TAG_DATA": [ + "77, T {'context': 'B-cells'}", + "78, lymphocytes {'context': 'I-cells'}", + "111, host-reactive {'context': 'B-cells'}", + "112, T {'context': 'I-cells'}", + "113, cells {'context': 'I-cells'}", + "117, T {'context': 'B-cells'}", + "118, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "77, T ['l0']", + "78, lymphocytes ['l0']", + "111, host-reactive ['l1', 'l2', 'l3', 'l4']", + "112, T ['l1', 'l5', 'l6', 'l7']", + "113, cells ['l2', 'l5', 'l8', 'l9']", + "117, T ['l3', 'l6', 'l8', 'l10']", + "118, cells ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11433329", + "TEXT": "As dendritic cells increasingly become the adjuvant of choice in new approaches to cancer immunotherapy, a degree of protocol standardization is required to aid future large-scale clinical trials.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11385512", + "TEXT": "Elevated expression of heat-shock proteins (HSPs) can benefit a microbial pathogen struggling to penetrate host defenses during infection, but at the same time might provide a crucial signal alerting the host immune system to its presence. To determine which of these effects predominate, we constructed a mutant strain of Mycobacterium tuberculosis that constitutively overexpresses Hsp70 proteins. Although the mutant was fully virulent in the initial stage of infection, it was significantly impaired in its ability to persist during the subsequent chronic phase. Induction of microbial genes encoding HSPs might provide a novel strategy to boost the immune response of individuals with latent tuberculosis infection.", + "TAG_DATA": [ + "46, mutant {'perturbing_action': 'B-other'}", + "47, strain {'perturbing_action': 'I-other'}", + "48, of {'perturbing_action': 'I-other'}", + "49, Mycobacterium {'perturbing_action': 'I-other'}", + "50, tuberculosis {'perturbing_action': 'I-other', 'context': 'I-organism'}" + ], + "LINK_DATA": [ + "46, mutant ['l0', 'l1', 'l2', 'l3']", + "47, strain ['l0', 'l4', 'l5', 'l6']", + "48, of ['l1', 'l4', 'l7', 'l8']", + "49, Mycobacterium ['l2', 'l5', 'l7', 'l9']", + "50, tuberculosis ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "strain", + "of", + "Mycobacterium" + ] + }, + "context": { + "val": "organism", + "words": [ + "tuberculosis" + ] + } + } + ] + }, + { + "PMID": "11385508", + "TEXT": "Sonic hedgehog (Shh) is a prototypical morphogen known to regulate epithelial/mesenchymal interactions during embryonic development. We found that the hedgehog-signaling pathway is present in adult cardiovascular tissues and can be activated in vivo. Shh was able to induce robust angiogenesis, characterized by distinct large-diameter vessels. Shh also augmented blood-flow recovery and limb salvage following operatively induced hind-limb ischemia in aged mice. In vitro, Shh had no effect on endothelial-cell migration or proliferation; instead, it induced expression of two families of angiogenic cytokines, including all three vascular endothelial growth factor-1 isoforms and angiopoietins-1 and -2 from interstitial mesenchymal cells. These findings reveal a novel role for Shh as an indirect angiogenic factor regulating expression of multiple angiogenic cytokines and indicate that Shh might have potential therapeutic use for ischemic disorders.", + "TAG_DATA": [ + "59, aged {'context': 'B-organism'}", + "60, mice. {'context': 'I-organism'}", + "61, In {'context': 'B-in vitro'}", + "62, vitro, {'context': 'I-in vitro'}", + "65, no {'effect': 'B-no effect'}", + "66, effect {'effect': 'I-no effect'}", + "68, endothelial-cell {'context': 'B-cells'}", + "69, migration {'phenotype': 'B-migration'}", + "71, proliferation; {'phenotype': 'B-proliferation'}", + "95, interstitial {'context': 'B-cells'}", + "96, mesenchymal {'context': 'I-cells'}", + "97, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "59, aged ['l0', 'l1', 'l2', 'l3']", + "60, mice. ['l0', 'l4']", + "61, In ['l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "62, vitro, ['l5', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "65, no ['l6', 'l13', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "66, effect ['l7', 'l14', 'l20', 'l26', 'l27', 'l28', 'l29']", + "68, endothelial-cell ['l1', 'l8', 'l15', 'l21', 'l26', 'l30', 'l31']", + "69, migration ['l2', 'l4', 'l9', 'l16', 'l22', 'l27', 'l30', 'l32']", + "71, proliferation; ['l3', 'l10', 'l17', 'l23', 'l28', 'l31', 'l32']", + "95, interstitial ['l33', 'l34']", + "96, mesenchymal ['l11', 'l18', 'l24', 'l33', 'l35']", + "97, cells. ['l12', 'l19', 'l25', 'l29', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "aged", + "mice." + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "aged" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation;" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "no", + "effect" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation;" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "no", + "effect" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial-cell", + "mesenchymal", + "cells." + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "no", + "effect" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "no", + "effect" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation;" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial-cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial-cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation;" + ] + } + } + ] + }, + { + "PMID": "11329066", + "TEXT": "There is currently a need for vaccines that stimulate cell-mediated immunity-particularly that mediated by CD8+ cytotoxic T lymphocytes (CTLs)-against viral and tumor antigens. The optimal induction of cell-mediated immunity requires the presentation of antigens by specialized cells of the immune system called dendritic cells (DCs). DCs are unique in their ability to process exogenous antigens via the major histocompatibility complex (MHC) class I pathway as well as in their ability to activate naive, antigen-specific CD8+ and CD4+ T cells. Vaccine strategies that target or activate DCs in order to elicit potent CTL-mediated immunity are the subject of intense research. We report here that whole recombinant Saccharomyces cerevisiae yeast expressing tumor or HIV-1 antigens potently induced antigen-specific, CTL responses, including those mediating tumor protection, in vaccinated animals. Interactions between yeast and DCs led to DC maturation, IL-12 production and the efficient priming of MHC class I- and class II-restricted, antigen-specific T-cell responses. Yeast exerted a strong adjuvant effect, augmenting DC presentation of exogenous whole-protein antigen to MHC class I- and class II-restricted T cells. Recombinant yeast represent a novel vaccine strategy for the induction of broad-based cellular immune responses.", + "TAG_DATA": [ + "106, cerevisiae {'context': 'I-organism'}", + "116, CTL {'context': 'B-cells'}", + "125, animals. {'context': 'B-organism'}", + "133, DC {'context': 'B-cells'}", + "149, T-cell {'context': 'B-cells'}", + "158, DC {'context': 'B-cells'}", + "171, T {'context': 'B-cells'}", + "172, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "105, Saccharomyces ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "106, cerevisiae ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "107, yeast ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "116, CTL ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "125, animals. ['l3', 'l8', 'l12', 'l15', 'l18']", + "133, DC ['l4', 'l9', 'l13', 'l16', 'l18', 'l19']", + "149, T-cell ['l5', 'l10', 'l14', 'l17', 'l19']", + "158, DC ['l20', 'l21']", + "171, T ['l20', 'l22']", + "172, cells. ['l21', 'l22']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11329065", + "TEXT": "Hepatitis-B virus infection is globally ubiquitous, but its distribution is very heterogeneous, with prevalence of serological markers in various nations ranging from less than 1% to more than 90%. We propose an explanation for this diversity using a mathematical model of hepatitis-B virus transmission dynamics that shows, for the first time, 'catastrophic' behavior using realistic epidemiological processes and parameters. Our major conclusion is that the prevalence of infection is largely determined by a feedback mechanism that relates the rate of transmission, average age at infection and age-related probability of developing carriage following infection. Using the model we identify possible, highly non-linear, consequences of chemotherapy and immunization interventions, for which the starting prevalence of carriers is the most influential, predictive quantity. Taken together, our results demand a re-evaluation of public health policy towards hepatitis-B.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11329064", + "TEXT": "Abnormal accumulation of the amyloid-beta peptide (Abeta) in the brain appears crucial to pathogenesis in all forms of Alzheimer disease (AD), but the underlying mechanisms in the sporadic forms of AD remain unknown. Transforming growth factor beta1 (TGF-beta1), a key regulator of the brain's responses to injury and inflammation, has been implicated in Abeta deposition in vivo. Here we demonstrate that a modest increase in astroglial TGF-beta1 production in aged transgenic mice expressing the human beta-amyloid precursor protein (hAPP) results in a three-fold reduction in the number of parenchymal amyloid plaques, a 50% reduction in the overall Abeta load in the hippocampus and neocortex, and a decrease in the number of dystrophic neurites. In mice expressing hAPP and TGF-beta1, Abeta accumulated substantially in cerebral blood vessels, but not in parenchymal plaques. In human cases of AD, Abeta immunoreactivity associated with parenchymal plaques was inversely correlated with Abeta in blood vessels and cortical TGF-beta1 mRNA levels. The reduction of parenchymal plaques in hAPP/TGF-beta1 mice was associated with a strong activation of microglia and an increase in inflammatory mediators. Recombinant TGF-beta1 stimulated Abeta clearance in microglial cell cultures. These results demonstrate that TGF-beta1 is an important modifier of amyloid deposition in vivo and indicate that TGF-beta1 might promote microglial processes that inhibit the accumulation of Abeta in the brain parenchyma.", + "TAG_DATA": [ + "69, aged {'context': 'B-organism'}", + "70, transgenic {'context': 'I-organism'}", + "71, mice {'context': 'I-organism'}", + "72, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "73, the {'perturbing_action': 'I-gene gain-of-function'}", + "74, human {'perturbing_action': 'I-gene gain-of-function'}", + "75, beta-amyloid {'perturbing_action': 'I-gene gain-of-function'}", + "76, precursor {'perturbing_action': 'I-gene gain-of-function'}", + "77, protein {'perturbing_action': 'I-gene gain-of-function'}", + "78, (hAPP) {'perturbing_action': 'I-gene gain-of-function'}", + "101, hippocampus {'context': 'B-tissue/organ'}", + "103, neocortex, {'context': 'B-tissue/organ'}", + "114, mice {'context': 'B-organism'}", + "162, mice {'context': 'B-organism'}", + "170, microglia {'context': 'B-cells'}", + "183, microglial {'context': 'B-cells'}", + "184, cell {'context': 'I-cells'}", + "185, cultures. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "69, aged ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "70, transgenic ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "71, mice ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "72, expressing ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "73, the ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "74, human ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "75, beta-amyloid ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "76, precursor ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "77, protein ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "78, (hAPP) ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "101, hippocampus ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "103, neocortex, ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "162, mice ['l66']", + "170, microglia ['l66']", + "183, microglial ['l67', 'l68']", + "184, cell ['l67', 'l69']", + "185, cultures. ['l68', 'l69']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "aged", + "transgenic", + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "the", + "human", + "beta-amyloid", + "precursor", + "protein", + "(hAPP)" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "the", + "human", + "beta-amyloid", + "precursor", + "protein", + "(hAPP)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus", + "neocortex," + ] + } + } + ] + }, + { + "PMID": "11329060", + "TEXT": "Cytochrome P450 3A4 is an important mediator of drug catabolism that can be regulated by the steroid and xenobiotic receptor (SXR). We show here that SXR also regulates drug efflux by activating expression of the gene MDR1, which encodes the protein P-glycoprotein (ABCB1). Paclitaxel (Taxol), a commonly used chemotherapeutic agent, activated SXR and enhanced P-glycoprotein-mediated drug clearance. In contrast, docetaxel (Taxotere), a closely related antineoplastic agent, did not activate SXR and displayed superior pharmacokinetic properties. Docetaxel's silent properties reflect its inability to displace transcriptional corepressors from SXR. We also found that ET-743, a potent antineoplastic agent, suppressed MDR1 transcription by acting as an inhibitor of SXR. These findings demonstrate how the molecular activities of SXR can be manipulated to control drug clearance.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11283678", + "TEXT": "New-variant Creutzfeldt-Jakob disease and scrapie are typically initiated by extracerebral exposure to the causative agent, and exhibit early prion replication in lymphoid organs. In mouse scrapie, depletion of B-lymphocytes prevents neuropathogenesis after intraperitoneal inoculation, probably due to impaired lymphotoxin-dependent maturation of follicular dendritic cells (FDCs), which are a major extracerebral prion reservoir. FDCs trap immune complexes with Fc-gamma receptors and C3d/C4b-opsonized antigens with CD21/CD35 complement receptors. We examined whether these mechanisms participate in peripheral prion pathogenesis. Depletion of circulating immunoglobulins or of individual Fc-gamma receptors had no effect on scrapie pathogenesis if B-cell maturation was unaffected. However, mice deficient in C3, C1q, Bf/C2, combinations thereof or complement receptors were partially or fully protected against spongiform encephalopathy upon intraperitoneal exposure to limiting amounts of prions. Splenic accumulation of prion infectivity and PrPSc was delayed, indicating that activation of specific complement components is involved in the initial trapping of prions in lymphoreticular organs early after infection.", + "TAG_DATA": [ + "92, B-cell {'context': 'B-cells'}", + "97, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "97, mice ['l0']", + "124, Splenic ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11283673", + "TEXT": "The use of combination antiretroviral therapy results in a substantial reduction in viremia, a rebound of CD4+ T cells and increased survival for HIV-infected individuals. However, this treatment does not result in the total eradication of HIV. Rather, the virus is thought to remain latent in a subset of cells, where it avoids elimination by the immune system. In this state the virus is capable of reactivation of productive infection following cessation of therapy. These latently infected cells are very few in number and it has thus been difficult to determine their origin and to study the molecular nature of the latent viral genome. HIV replication is linked to cellular gene transcription and requires target cell activation. Therefore, should an activated, infected cell become transcriptionally inactive prior to cytopathic effects, the viral genome might be maintained in a latent state. We used the SCID-hu (Thy/Liv) mouse model to establish that activation-inducible HIV can be generated at high frequency during thymopoiesis, a process where previously activated cells mature towards quiescence. Moreover, we showed that these cells can be exported into the periphery where the virus remains latent until T-cell receptor stimulation, indicating that the thymus might be a source of latent HIV in humans.", + "TAG_DATA": [ + "143, SCID-hu {'perturbing_action': 'B-other'}", + "144, (Thy/Liv) {'perturbing_action': 'I-other'}", + "145, mouse {'context': 'B-organism'}", + "146, model {'context': 'I-organism'}", + "165, cells {'context': 'B-cells'}", + "168, quiescence. {'phenotype': 'B-quiescence'}" + ], + "LINK_DATA": [ + "143, SCID-hu ['l0', 'l1', 'l2', 'l3']", + "144, (Thy/Liv) ['l0', 'l4', 'l5']", + "145, mouse ['l1', 'l4', 'l6']", + "146, model ['l2', 'l5', 'l6']", + "165, cells ['l3', 'l7']", + "168, quiescence. ['l7']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "SCID-hu", + "(Thy/Liv)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "SCID-hu" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence." + ] + } + } + ] + }, + { + "PMID": "11283672", + "TEXT": "In an analysis of 84 primary-operated breast cancer patients and 11 healthy donors, we found that the bone marrow of most patients contained memory T cells with specificity for tumor-associated antigens. Patients' bone marrow and peripheral blood contained CD8+ T cells that specifically bound HLA/peptide tetramers. In short-term culture with autologous dendritic cells pre-pulsed with tumor lysates, patients' memory T cells from bone marrow (but not peripheral blood) could be specifically reactivated to interferon-gamma-producing and cytotoxic effector cells. A single transfer of restimulated bone-marrow T cells into NOD/SCID mice caused regression of autologous tumor xenotransplants associated with infiltration by human T cells and tumor-cell apoptosis and necrosis. T cells from peripheral blood showed much lower anti-tumor reactivity. Our findings reveal an innate, specific recognition of breast cancer antigens and point to a possible novel cancer therapy using patients' bone-marrow-derived memory T cells.", + "TAG_DATA": [ + "50, autologous {'context': 'B-cells'}", + "51, dendritic {'context': 'I-cells'}", + "52, cells {'context': 'I-cells'}", + "57, patients' {'context': 'B-cells'}", + "58, memory {'context': 'I-cells'}", + "59, T {'context': 'I-cells'}", + "60, cells {'context': 'I-cells'}", + "61, from {'context': 'I-cells'}", + "62, bone {'context': 'I-cells'}", + "63, marrow {'context': 'I-cells'}", + "83, bone-marrow {'context': 'B-cells'}", + "84, T {'context': 'I-cells'}", + "85, cells {'context': 'I-cells'}", + "87, NOD/SCID {'context': 'B-organism'}", + "88, mice {'context': 'I-organism'}", + "89, caused {'effect': 'B-positive'}", + "90, regression {'phenotype': 'B-tumour regression'}", + "92, autologous {'context': 'B-xenograft'}", + "93, tumor {'context': 'I-xenograft'}", + "94, xenotransplants {'context': 'I-xenograft'}", + "99, human {'context': 'B-cells'}", + "100, T {'context': 'I-cells'}", + "101, cells {'context': 'I-cells'}", + "103, tumor-cell {'context': 'B-transformed cells'}", + "104, apoptosis {'phenotype': 'B-apoptosis'}", + "106, necrosis. {'phenotype': 'B-necrosis'}", + "107, T {'context': 'B-cells'}", + "108, cells {'context': 'I-cells'}", + "109, from {'context': 'I-cells'}", + "110, peripheral {'context': 'I-cells'}", + "111, blood {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "50, autologous ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "51, dendritic ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "52, cells ['l1', 'l15', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "57, patients' ['l2', 'l16', 'l33', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "58, memory ['l3', 'l17', 'l34', 'l47', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "59, T ['l4', 'l18', 'l35', 'l48', 'l56', 'l64', 'l65', 'l66', 'l67', 'l68']", + "60, cells ['l5', 'l19', 'l36', 'l49', 'l57', 'l64', 'l69', 'l70', 'l71', 'l72']", + "61, from ['l6', 'l20', 'l37', 'l50', 'l58', 'l65', 'l69', 'l73', 'l74', 'l75']", + "62, bone ['l7', 'l21', 'l38', 'l51', 'l59', 'l66', 'l70', 'l73', 'l76']", + "63, marrow ['l8', 'l22', 'l39', 'l52', 'l60', 'l67', 'l71', 'l74', 'l76']", + "83, bone-marrow ['l23', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "84, T ['l9', 'l24', 'l40', 'l77', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "85, cells ['l10', 'l25', 'l41', 'l53', 'l61', 'l78', 'l92', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "87, NOD/SCID ['l79', 'l93', 'l106', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "88, mice ['l11', 'l26', 'l42', 'l80', 'l94', 'l107', 'l119', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139']", + "89, caused ['l27', 'l81', 'l95', 'l108', 'l120', 'l131', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "90, regression ['l82', 'l96', 'l109', 'l121', 'l132', 'l140', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156']", + "92, autologous ['l83', 'l97', 'l110', 'l122', 'l133', 'l141', 'l148', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162']", + "93, tumor ['l12', 'l28', 'l43', 'l84', 'l98', 'l111', 'l123', 'l134', 'l142', 'l149', 'l157', 'l163', 'l164', 'l165', 'l166', 'l167']", + "94, xenotransplants ['l29', 'l85', 'l99', 'l112', 'l124', 'l135', 'l143', 'l150', 'l158', 'l163', 'l168', 'l169', 'l170', 'l171']", + "99, human ['l30', 'l44', 'l86', 'l100', 'l113', 'l125', 'l136', 'l144', 'l151', 'l159', 'l164', 'l168', 'l172', 'l173', 'l174']", + "100, T ['l13', 'l31', 'l45', 'l54', 'l62', 'l87', 'l101', 'l114', 'l126', 'l137', 'l145', 'l152', 'l160', 'l165', 'l169', 'l172', 'l175', 'l176']", + "101, cells ['l14', 'l32', 'l46', 'l55', 'l63', 'l68', 'l72', 'l75', 'l88', 'l102', 'l115', 'l127', 'l138', 'l146', 'l153', 'l161', 'l166', 'l170', 'l173', 'l175']", + "103, tumor-cell ['l89', 'l103', 'l116', 'l128', 'l154', 'l177', 'l178']", + "104, apoptosis ['l90', 'l104', 'l117', 'l129', 'l139', 'l147', 'l155', 'l162', 'l167', 'l171', 'l174', 'l176', 'l177', 'l179']", + "106, necrosis. ['l91', 'l105', 'l118', 'l130', 'l156', 'l178', 'l179']", + "107, T ['l180', 'l181', 'l182', 'l183']", + "108, cells ['l180', 'l184', 'l185', 'l186']", + "109, from ['l181', 'l184', 'l187', 'l188']", + "110, peripheral ['l182', 'l185', 'l187', 'l189']", + "111, blood ['l183', 'l186', 'l188', 'l189']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "dendritic", + "bone-marrow", + "T", + "cells", + "human" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "bone-marrow", + "T", + "cells", + "human" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "bone-marrow", + "T", + "cells", + "human" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "bone-marrow", + "T", + "cells" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "NOD/SCID", + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "NOD/SCID", + "mice" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "NOD/SCID", + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "NOD/SCID" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "autologous", + "tumor", + "xenotransplants" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "autologous", + "tumor", + "xenotransplants" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor-cell" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "autologous", + "tumor", + "xenotransplants" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor-cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor-cell" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis." + ] + } + } + ] + }, + { + "PMID": "11231637", + "TEXT": "Transmissible spongiform encephalopathies (TSE) are a group of invariably fatal neurodegenerative diseases and include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease in deer and elk, and Kuru disease, Creutzfeldt-Jakob disease (CJD) and variant CJD in humans. The pathological effects of disease occur predominantly in the CNS (central nervous system), where common hallmarks include vacuolation, gliosis, accumulation of a protease-resistant, abnormally folded isoform of the prion protein (PrPSc) and neuronal cell death. Lack of understanding of the molecular mechanisms underlying disease pathogenesis, particularly in non-CNS tissues, means that there are currently no effective strategies for early diagnosis or therapeutic intervention of TSEs. Here we report the first identification of a molecular marker that is easily detectable in readily accessible tissues. We demonstrate that a dramatic decrease in expression of a transcript specific to erythroid lineage cells is a common feature of TSEs. Our findings indicate a previously unrecognized role for involvement of the erythroid lineage in the etiology of TSE pathogenesis and should provide a new focus for research into diagnostic and therapeutic strategies.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11231636", + "TEXT": "The effectiveness and toxicity of many drugs vary depending on the relationship between the dosing schedule and the 24-hour rhythms of biochemical, physiological and behavioral processes. In addition, several drugs can cause alterations to the 24-hour rhythms leading to illness and altered homeostatic regulation. However, the mechanisms of this drug-based disruption of circadian 'clock' genes remain unclear. Here, we show the disruptive effect of interferon-alpha on the rhythm of locomotor activity, body temperature and clock-gene mRNA expression in the periphery and suprachiasmatic nuclei, a primary circadian pacemaker. The rhythmicity of clock genes and the photic induction of the Per gene in suprachiasmatic nuclei were disturbed by the repetitive administration of interferon-alpha. Moreover, alteration of clock function, a new concept of adverse effects, can be overcome by optimizing the dosing schedule to minimize adverse drug effects.", + "TAG_DATA": [ + "101, suprachiasmatic {'context': 'B-tissue/organ'}", + "102, nuclei {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "101, suprachiasmatic ['l0']", + "102, nuclei ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11231631", + "TEXT": "Fibronectin performs essential roles in embryonic development and is prominently expressed during tissue repair. Two forms of fibronectin have been identified: plasma fibronectin (pFn), which is expressed by hepatocytes and secreted in soluble form into plasma; and cellular fibronectin (cFn), an insoluble form expressed locally by fibroblasts and other cell types and deposited and assembled into the extracellular matrix. To investigate the role of pFn in vivo, we generated pFn-deficient adult mice using Cre-loxP conditional gene-knockout technology. Here we show that pFn-deficient mice show increased neuronal apoptosis and larger infarction areas following transient focal cerebral ischemia. However, pFn is dispensable for skin-wound healing and hemostasis.", + "TAG_DATA": [ + "69, pFn-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "70, adult {'context': 'B-organism'}", + "71, mice {'context': 'I-organism'}", + "73, Cre-loxP {'perturbing_action': 'B-gene loss-of-function'}", + "74, conditional {'perturbing_action': 'I-gene loss-of-function'}", + "75, gene-knockout {'perturbing_action': 'I-gene loss-of-function'}", + "81, pFn-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "82, mice {'context': 'B-organism'}", + "84, increased {'effect': 'B-positive'}", + "86, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "69, pFn-deficient ['l0', 'l1', 'l2', 'l3', 'l4']", + "70, adult ['l0', 'l5', 'l6', 'l7', 'l8']", + "71, mice ['l1', 'l5', 'l9', 'l10', 'l11']", + "73, Cre-loxP ['l2', 'l6', 'l9', 'l12', 'l13', 'l14', 'l15']", + "74, conditional ['l3', 'l7', 'l10', 'l12', 'l16', 'l17', 'l18']", + "75, gene-knockout ['l4', 'l8', 'l11', 'l13', 'l16', 'l19', 'l20']", + "81, pFn-deficient ['l21', 'l22', 'l23']", + "82, mice ['l21', 'l24', 'l25']", + "84, increased ['l14', 'l17', 'l19', 'l22', 'l24', 'l26']", + "86, apoptosis ['l15', 'l18', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pFn-deficient", + "Cre-loxP", + "conditional", + "gene-knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "adult", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cre-loxP", + "conditional", + "gene-knockout", + "pFn-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cre-loxP", + "conditional", + "gene-knockout", + "pFn-deficient" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "11231612", + "TEXT": "Society has entered uncharted territory regarding how, when and where genetic information can be used. This article discusses the major issues raised by increased access to genomic information, which will ultimately be resolved by legislation or the courts.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11175855", + "TEXT": "The chimeric BCR-ABL oncoprotein is the molecular hallmark of chronic myelogenous leukemia (CML). BCR-ABL contains nuclear import and export signals but it is localized only in the cytoplasm where it activates mitogenic and anti-apoptotic pathways. We have found that inhibition of the BCR-ABL tyrosine kinase, either by mutation or by the drug STI571, can stimulate its nuclear entry. By combining STI571 with leptomycin B (LMB) to block nuclear export, we trapped BCR-ABL in the nucleus and the nuclear BCR-ABL tyrosine kinase activates apoptosis. As a result, the combined treatment with STI571 and LMB causes the irreversible and complete killing of BCR-ABL transformed cells, whereas the effect of either drug alone is fully reversible. The combined treatment with STI571 and LMB also preferentially eliminates mouse bone marrow cells that express BCR-ABL. These results indicate that nuclear entrapment of BCR-ABL can be used as a therapeutic strategy to selectively kill chronic myelogenous leukemia cells.", + "TAG_DATA": [ + "39, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "40, of {'perturbing_action': 'I-pharmacological inhibition'}", + "41, the {'perturbing_action': 'I-pharmacological inhibition'}", + "42, BCR-ABL {'perturbing_action': 'I-pharmacological inhibition'}", + "43, tyrosine {'perturbing_action': 'I-pharmacological inhibition'}", + "44, kinase, {'perturbing_action': 'I-pharmacological inhibition'}", + "47, mutation {'perturbing_action': 'I-pharmacological inhibition'}", + "81, activates {'effect': 'B-positive'}", + "82, apoptosis. {'phenotype': 'B-apoptosis'}", + "101, transformed {'context': 'B-transformed cells'}", + "102, cells, {'context': 'B-cells'}", + "123, mouse {'context': 'B-cells'}", + "124, bone {'context': 'I-cells'}", + "125, marrow {'context': 'I-cells'}", + "126, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "39, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "40, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "41, the ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "42, BCR-ABL ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "43, tyrosine ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "44, kinase, ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "46, by ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "47, mutation ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "81, activates ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "82, apoptosis. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "100, BCR-ABL ['l45', 'l46']", + "101, transformed ['l45', 'l47']", + "102, cells, ['l46', 'l47']", + "123, mouse ['l48', 'l49', 'l50']", + "124, bone ['l48', 'l51', 'l52']", + "125, marrow ['l49', 'l51', 'l53']", + "126, cells ['l50', 'l52', 'l53']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "the", + "BCR-ABL", + "tyrosine", + "kinase,", + "mutation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "activates" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "the", + "BCR-ABL", + "tyrosine", + "kinase,", + "mutation" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "activates" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "11175854", + "TEXT": "Vascular endothelial growth factor (VEGF), an angiogenic factor produced in response to ischemic injury, promotes vascular permeability (VP). Evidence is provided that Src kinase regulates VEGF-mediated VP in the brain following stroke and that suppression of Src activity decreases VP thereby minimizing brain injury. Mice lacking pp60c-src are resistant to VEGF-induced VP and show decreased infarct volumes after stroke whereas mice deficient in pp59c-fyn, another Src family member, have normal VEGF-mediated VP and infarct size. Systemic application of a Src-inhibitor given up to six hours following stroke suppressed VP protecting wild-type mice from ischemia-induced brain damage without influencing VEGF expression. This was associated with reduced edema, improved cerebral perfusion and decreased infarct volume 24 hours after injury as measured by magnetic resonance imaging and histological analysis. Thus, Src represents a key intermediate and novel therapeutic target in the pathophysiology of cerebral ischemia where it appears to regulate neuronal damage by influencing VEGF-mediated VP.", + "TAG_DATA": [ + "44, Mice {'context': 'B-organism'}", + "45, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "46, pp60c-src {'perturbing_action': 'I-gene loss-of-function'}", + "60, mice {'context': 'B-organism'}", + "61, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "62, in {'perturbing_action': 'I-gene loss-of-function'}", + "63, pp59c-fyn, {'perturbing_action': 'I-gene loss-of-function'}", + "79, Src-inhibitor {'perturbing_action': 'B-pharmacological inhibition'}", + "91, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "44, Mice ['l0', 'l1']", + "45, lacking ['l0', 'l2', 'l3']", + "46, pp60c-src ['l1', 'l2', 'l4', 'l5']", + "60, mice ['l3', 'l4', 'l6', 'l7', 'l8', 'l9', 'l10']", + "61, deficient ['l6', 'l11', 'l12', 'l13', 'l14']", + "62, in ['l7', 'l11', 'l15', 'l16', 'l17']", + "63, pp59c-fyn, ['l8', 'l12', 'l15', 'l18', 'l19']", + "79, Src-inhibitor ['l9', 'l13', 'l16', 'l18', 'l20']", + "91, mice ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "pp60c-src", + "deficient", + "in", + "pp59c-fyn," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Src-inhibitor" + ] + } + } + ] + }, + { + "PMID": "11175852", + "TEXT": "The mechanism underlying suppression of immune responses by interleukin-4 (IL-4) has remained unexplained. Here we show that the antigen-presenting dendritic cell is central to counter-regulation of autoimmune disease by IL-4. IL-4 acts at the locus of the dendritic cell to decrease the cytolytic T-cell response, preventing autoimmunity. Stimulation of cytotoxic precursors by antigen pulsed dendritic cells induces their differentiation but the process is blocked by IL-4. IL-4-influenced DC produce distinct effects on CD8+ T cells depending on their state of activation. The molecular basis for this regulation is the alteration of the expression ratio of the costimulatory ligands B7.1/B7.2 on dendritic cells. Our findings demonstrate that B7.2 induces expansion of CD8+ T cells and B7.1 governs their acquisition of cytolytic activity. IL-4 influences the dendritic cell to elicit qualitative differences in T-cell responses, providing the basis for counter-regulation mediated by IL-4.", + "TAG_DATA": [ + "54, dendritic {'context': 'B-cells'}", + "55, cells {'context': 'I-cells'}", + "56, induces {'effect': 'B-positive'}", + "58, differentiation {'phenotype': 'B-differentiation'}", + "67, DC {'context': 'B-cells'}", + "72, CD8+ {'context': 'B-cells'}", + "73, T {'context': 'I-cells'}", + "74, cells {'context': 'I-cells'}", + "110, CD8+ {'context': 'B-cells'}", + "111, T {'context': 'I-cells'}", + "112, cells {'context': 'I-cells'}", + "124, dendritic {'context': 'B-cells'}", + "125, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "54, dendritic ['l0', 'l1', 'l2', 'l3']", + "55, cells ['l0', 'l4', 'l5']", + "56, induces ['l1', 'l4', 'l6']", + "58, differentiation ['l2', 'l5', 'l6']", + "67, DC ['l7', 'l8', 'l9']", + "72, CD8+ ['l7', 'l10', 'l11']", + "73, T ['l8', 'l10', 'l12']", + "74, cells ['l3', 'l9', 'l11', 'l12']", + "110, CD8+ ['l13', 'l14']", + "111, T ['l13', 'l15']", + "112, cells ['l14', 'l15']", + "124, dendritic ['l16']", + "125, cell ['l16']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "11135615", + "TEXT": "Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is highly expressed in lipid-accumulating macrophages of the coronary artery. In light of this, the wide-spread clinical use of thiazolidinediones (TZDs) in the treatment of type II diabetes raises concerns about the role of PPAR-gamma in macrophage function and disease progression. To define the role of PPAR-gamma in macrophage biology, we used homologous recombination to create embryonic stem cells that were homozygous for a null mutation in the PPAR-gamma gene. We demonstrate here that PPAR-gamma is neither essential for nor substantially affects the development of the macrophage lineage both in vitro and in vivo. In contrast, we show it is an important regulator of the scavenger receptor CD36, which has been genetically linked to lipid accumulation in macrophages. Both 15-deoxy-Delta12,14prostaglandin J2 and thiazolidinediones have anti-inflammatory effects that are independent of PPAR-gamma. We show that PPAR-gamma is required for positive effects of its ligands in modulating macrophage lipid metabolism, but that inhibitory effects on cytokine production and inflammation may be receptor independent.", + "TAG_DATA": [ + "60, embryonic {'context': 'B-cells'}", + "61, stem {'context': 'I-cells'}", + "62, cells {'context': 'I-cells'}", + "68, null {'perturbing_action': 'B-gene loss-of-function'}", + "69, mutation {'perturbing_action': 'I-gene loss-of-function'}", + "70, in {'perturbing_action': 'I-gene loss-of-function'}", + "71, the {'perturbing_action': 'I-gene loss-of-function'}", + "72, PPAR-gamma {'perturbing_action': 'I-gene loss-of-function'}", + "73, gene. {'perturbing_action': 'I-gene loss-of-function'}", + "93, in {'context': 'B-in vitro'}", + "94, vitro {'context': 'I-in vitro'}", + "96, in {'context': 'B-in vivo'}", + "97, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "60, embryonic ['l0', 'l1', 'l2', 'l3', 'l4']", + "61, stem ['l0', 'l5', 'l6', 'l7']", + "62, cells ['l1', 'l5', 'l8', 'l9']", + "66, for ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "67, a ['l10', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "68, null ['l11', 'l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "69, mutation ['l12', 'l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "70, in ['l13', 'l23', 'l32', 'l40', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "71, the ['l14', 'l24', 'l33', 'l41', 'l48', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "72, PPAR-gamma ['l15', 'l25', 'l34', 'l42', 'l49', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "73, gene. ['l2', 'l16', 'l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "93, in ['l3', 'l6', 'l8', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l70']", + "94, vitro ['l4', 'l7', 'l9', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l70']", + "96, in ['l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71']", + "97, vivo. ['l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l71']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "embryonic" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "gene." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "null", + "mutation", + "in", + "the", + "PPAR-gamma", + "gene." + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "null", + "mutation", + "in", + "the", + "PPAR-gamma", + "gene." + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "11135614", + "TEXT": "Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), the transcription factor target of the anti-diabetic thiazolidinedione (TZD) drugs, is reported to mediate macrophage differentiation and inflammatory responses. Using PPAR-gamma-deficient stem cells, we demonstrate that PPAR-gamma is neither essential for myeloid development, nor for such mature macrophage functions as phagocytosis and inflammatory cytokine production. PPAR-gamma is required for basal expression of CD36, but not for expression of the other major scavenger receptor responsible for uptake of modified lipoproteins, SR-A. In wild-type macrophages, TZD treatment divergently regulated CD36 and class A macrophage-scavenger receptor expression and failed to induce significant cellular cholesterol accumulation, indicating that TZDs may not exacerbate macrophage foam-cell formation.", + "TAG_DATA": [ + "24, PPAR-gamma-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "25, stem {'context': 'B-cells'}", + "26, cells, {'context': 'I-cells'}", + "76, macrophages, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "24, PPAR-gamma-deficient ['l0', 'l1']", + "25, stem ['l0', 'l2']", + "26, cells, ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PPAR-gamma-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "stem", + "cells," + ] + } + } + ] + }, + { + "PMID": "11135608", + "TEXT": "Migratory cells can lead to both rejection and tolerance following organ transplantation, suggesting a direction for pro-tolerant immunomodulatory therapies.", + "TAG_DATA": [ + "1, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11135600", + "TEXT": "The World Health Organization estimates that tobacco will become the largest single health problem by 2020, causing an estimated 8.4 million deaths annually. But the smoking burden will not be distributed evenly across the globe; deaths in developed nations are set to rise 50% to 2.4 million while those in Asia will soar fourfold to an estimated 4.2 million in 2020. In the face of such discrepancy, Martin Raw, Honorary Lecturer in evidence-based treatment at Guys, Kings and St Thomas' School of Medicine, London, explains why attention can not be focused solely on Asia and why efforts are still needed to stop smoking in Europe.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11100123", + "TEXT": "The ribonucleoside analog ribavirin (1-beta-D-ribofuranosyl-1,2, 4-triazole-3-carboxamide) shows antiviral activity against a variety of RNA viruses and is used in combination with interferon-alpha to treat hepatitis C virus infection. Here we show in vitro use of ribavirin triphosphate by a model viral RNA polymerase, poliovirus 3Dpol. Ribavirin incorporation is mutagenic, as it templates incorporation of cytidine and uridine with equal efficiency. Ribavirin reduces infectious poliovirus production to as little as 0. 00001% in cell culture. The antiviral activity of ribavirin correlates directly with its mutagenic activity. These data indicate that ribavirin forces the virus into 'error catastrophe'. Thus, mutagenic ribonucleosides may represent an important class of anti-RNA virus agents.", + "TAG_DATA": [ + "31, in {'context': 'B-in vitro'}", + "32, vitro {'context': 'I-in vitro'}", + "72, cell {'context': 'B-cells'}", + "73, culture. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "31, in ['l0']", + "32, vitro ['l0']", + "72, cell ['l1']", + "73, culture. ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11100121", + "TEXT": "Caveolin-1, the primary coat protein of caveolae, has been implicated as a regulator of signal transduction through binding of its \"scaffolding domain\" to key signaling molecules. However, the physiological importance of caveolin-1 in regulating signaling has been difficult to distinguish from its traditional functions in caveolae assembly, transcytosis, and cholesterol transport. To directly address the importance of the caveolin scaffolding domain in vivo, we generated a chimeric peptide with a cellular internalization sequence fused to the caveolin-1 scaffolding domain (amino acids 82-101). The chimeric peptide was efficiently taken up into blood vessels and endothelial cells, resulting in selective inhibition of acetylcholine (Ach)-induced vasodilation and nitric oxide (NO) production, respectively. More importantly, systemic administration of the peptide to mice suppressed acute inflammation and vascular leak to the same extent as a glucocorticoid or an endothelial nitric oxide synthase (eNOS) inhibitor. These data imply that the caveolin-1 scaffolding domain can selectively regulate signal transduction to eNOS in endothelial cells and that small-molecule mimicry of this domain may provide a new therapeutic approach.", + "TAG_DATA": [ + "117, mice {'context': 'B-organism'}", + "133, endothelial {'perturbing_action': 'B-pharmacological inhibition'}", + "134, nitric {'perturbing_action': 'I-pharmacological inhibition'}", + "135, oxide {'perturbing_action': 'I-pharmacological inhibition'}", + "136, synthase {'perturbing_action': 'I-pharmacological inhibition'}", + "137, (eNOS) {'perturbing_action': 'I-pharmacological inhibition'}", + "138, inhibitor. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "117, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "133, endothelial ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "134, nitric ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "135, oxide ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "136, synthase ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "137, (eNOS) ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "138, inhibitor. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "endothelial", + "nitric", + "oxide", + "synthase", + "(eNOS)", + "inhibitor." + ] + } + } + ] + }, + { + "PMID": "11062537", + "TEXT": "Many systemically effective drugs such as cyclosporin A are ineffective topically because of their poor penetration into skin. To surmount this problem, we conjugated a heptamer of arginine to cyclosporin A through a pH-sensitive linker to produce R7-CsA. In contrast to unmodified cyclosporin A, which fails to penetrate skin, topically applied R7-CsA was efficiently transported into cells in mouse and human skin. R7-CsA reached dermal T lymphocytes and inhibited cutaneous inflammation. These data establish a general strategy for enhancing delivery of poorly absorbed drugs across tissue barriers and provide a new topical approach to the treatment of inflammatory skin disorders.", + "TAG_DATA": [ + "56, cells {'context': 'B-cells'}", + "58, mouse {'context': 'B-tissue/organ'}", + "59, and {'context': 'I-tissue/organ'}", + "60, human {'context': 'I-tissue/organ'}", + "61, skin. {'context': 'I-tissue/organ'}", + "64, dermal {'context': 'B-cells'}", + "65, T {'context': 'I-cells'}", + "66, lymphocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "56, cells ['l0', 'l1', 'l2', 'l3']", + "58, mouse ['l0', 'l4', 'l5', 'l6']", + "59, and ['l1', 'l4', 'l7', 'l8']", + "60, human ['l2', 'l5', 'l7', 'l9']", + "61, skin. ['l3', 'l6', 'l8', 'l9']", + "64, dermal ['l10', 'l11']", + "65, T ['l10', 'l12']", + "66, lymphocytes ['l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11062533", + "TEXT": "The characterization of hepatic progenitor cells is of great scientific and clinical interest. Here we report that intravenous injection of adult bone marrow cells in the FAH(-/-) mouse, an animal model of tyrosinemia type I, rescued the mouse and restored the biochemical function of its liver. Moreover, within bone marrow, only rigorously purified hematopoietic stem cells gave rise to donor-derived hematopoietic and hepatic regeneration. This result seems to contradict the conventional assumptions of the germ layer origins of tissues such as the liver, and raises the question of whether the cells of the hematopoietic stem cell phenotype are pluripotent hematopoietic cells that retain the ability to transdifferentiate, or whether they are more primitive multipotent cells.", + "TAG_DATA": [ + "20, adult {'context': 'B-cells'}", + "21, bone {'context': 'I-cells'}", + "22, marrow {'context': 'I-cells'}", + "23, cells {'context': 'I-cells'}", + "26, FAH(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "27, mouse, {'context': 'B-organism'}", + "37, mouse {'context': 'B-organism'}", + "45, liver. {'context': 'B-tissue/organ'}", + "53, hematopoietic {'context': 'B-cells'}", + "54, stem {'context': 'I-cells'}", + "55, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "20, adult ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "21, bone ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "22, marrow ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "23, cells ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "26, FAH(-/-) ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "27, mouse, ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "37, mouse ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "45, liver. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "53, hematopoietic ['l28', 'l29']", + "54, stem ['l28', 'l30']", + "55, cells ['l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "adult", + "bone", + "marrow", + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FAH(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FAH(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse,", + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FAH(-/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver." + ] + } + } + ] + }, + { + "PMID": "11017144", + "TEXT": "The adenovirus mutant dl1520 (ONYX-015) does not express the E1B-55K protein that binds and inactivates p53. This virus replicates in tumor cells with mutant p53, but not in normal cells with functional p53. Although intra-tumoral injection of dl1520 shows promising responses in patients with solid tumors, previous in vitro studies have not established a close correlation between p53 status and dl1520 replication. Here we identify loss of p14ARF as a mechanism that allows dl1520 replication in tumor cells retaining wild-type p53. We demonstrate that the re-introduction of p14ARF into tumor cells with wild-type p53 suppresses replication of dl1520 in a p53-dependent manner. Our study supports the therapeutic use of dl1520 in tumors with lesions within the p53 pathway other than mutation of p53.", + "TAG_DATA": [ + "76, tumor {'context': 'B-transformed cells'}", + "77, cells {'context': 'I-transformed cells'}", + "85, re-introduction {'perturbing_action': 'B-gene gain-of-function'}", + "86, of {'perturbing_action': 'I-gene gain-of-function'}", + "87, p14ARF {'perturbing_action': 'I-gene gain-of-function'}", + "89, tumor {'context': 'B-transformed cells'}", + "90, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "76, tumor ['l0']", + "77, cells ['l0']", + "85, re-introduction ['l1', 'l2', 'l3', 'l4']", + "86, of ['l1', 'l5', 'l6', 'l7']", + "87, p14ARF ['l2', 'l5', 'l8', 'l9']", + "89, tumor ['l3', 'l6', 'l8', 'l10']", + "90, cells ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "re-introduction", + "of", + "p14ARF" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + } + ] + }, + { + "PMID": "10973327", + "TEXT": "Galanin is widely distributed in enteric nerve terminals lining the gastrointestinal tract. We previously showed that pathogenic Escherichia coli, but not normal commensal organisms, increase galanin-1 receptor expression by epithelial cells lining the colon (i.e., colonocytes). When present, galanin-1 receptor activation by ligand causes colonocyte Cl- secretion. We herein demonstrate that disparate pathogens including Salmonella typhimurium and Shigella flexerii also increase colonocyte galanin-1 receptor expression, whose activation is responsible for a principal component of the increased colonic fluid secretion observed. Although eliminating the GAL1R gene by homologous recombination does not alter basal colonic fluid secretion, removal of one or both alleles completely attenuates the increase in fluid secretion due to infection with enteric pathogens. Galanin-1 receptor up-regulation therefore represents a novel mechanism accounting for the increased colonic fluid secretion observed in infectious diarrhea due to several different pathogens.", + "TAG_DATA": [ + "81, eliminating {'perturbing_action': 'B-gene loss-of-function'}", + "82, the {'perturbing_action': 'I-gene loss-of-function'}", + "83, GAL1R {'perturbing_action': 'I-gene loss-of-function'}", + "84, gene {'perturbing_action': 'I-gene loss-of-function'}", + "85, by {'perturbing_action': 'I-gene loss-of-function'}", + "86, homologous {'perturbing_action': 'I-gene loss-of-function'}", + "87, recombination {'perturbing_action': 'I-gene loss-of-function'}", + "95, removal {'perturbing_action': 'B-gene loss-of-function'}", + "96, of {'perturbing_action': 'I-gene loss-of-function'}", + "97, one {'perturbing_action': 'I-gene loss-of-function'}", + "98, or {'perturbing_action': 'I-gene loss-of-function'}", + "99, both {'perturbing_action': 'I-gene loss-of-function'}", + "100, alleles {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "81, eliminating ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "82, the ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "83, GAL1R ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "84, gene ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "85, by ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "86, homologous ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "87, recombination ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "95, removal ['l21', 'l22', 'l23', 'l24', 'l25']", + "96, of ['l21', 'l26', 'l27', 'l28', 'l29']", + "97, one ['l22', 'l26', 'l30', 'l31', 'l32']", + "98, or ['l23', 'l27', 'l30', 'l33', 'l34']", + "99, both ['l24', 'l28', 'l31', 'l33', 'l35']", + "100, alleles ['l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10973319", + "TEXT": "There is no known treatment for fatty liver, a ubiquitous cause of chronic liver disease. However, because it is associated with hyperinsulinemia and insulin-resistance, insulin-sensitizing agents might be beneficial. To evaluate this possibility, insulin-resistant ob/ob mice with fatty livers were treated with metformin, an agent that improves hepatic insulin-resistance. Metformin improved fatty liver disease, reversing hepatomegaly, steatosis and aminotransferase abnormalities. The therapeutic mechanism likely involves inhibited hepatic expression of tumor necrosis factor (TNF) alpha and TNF-inducible factors that promote hepatic lipid accumulation and ATP depletion. These findings suggest a mechanism of action for metformin and identify novel therapeutic targets in insulin-resistant states.", + "TAG_DATA": [ + "33, insulin-resistant {'context': 'B-organism'}", + "34, ob/ob {'context': 'I-organism'}", + "35, mice {'context': 'I-organism'}", + "37, fatty {'context': 'B-tissue/organ'}", + "38, livers {'context': 'I-tissue/organ'}", + "51, fatty {'context': 'B-tissue/organ'}", + "52, liver {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "33, insulin-resistant ['l0', 'l1', 'l2', 'l3']", + "34, ob/ob ['l0', 'l4', 'l5', 'l6']", + "35, mice ['l1', 'l4', 'l7', 'l8']", + "37, fatty ['l2', 'l5', 'l7', 'l9', 'l10']", + "38, livers ['l3', 'l6', 'l8', 'l9']", + "51, fatty ['l11']", + "52, liver ['l10', 'l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10973317", + "TEXT": "Members of the AP-1 family of transcription factors participate in the regulation of bone cell proliferation and differentiation. We report here a potent AP-1-related regulator of osteoblast function: DeltaFosB, a naturally occurring truncated form of FosB that arises from alternative splicing of the fosB transcript and is expressed in osteoblasts. Overexpression of DeltaFosB in transgenic mice leads to increased bone formation throughout the skeleton and a continuous post-developmental increase in bone mass, leading to osteosclerosis. In contrast, DeltaFosB inhibits adipogenesis both in vivo and in vitro, and downregulates the expression of early markers of adipocyte differentiation. Because osteoblasts and adipocytes are thought to share a common precursor, it is concluded that DeltaFosB transcriptionally regulates osteoblastogenesis, possibly at the expense of adipogenesis.", + "TAG_DATA": [ + "50, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "51, of {'perturbing_action': 'I-gene gain-of-function'}", + "52, DeltaFosB {'perturbing_action': 'I-gene gain-of-function'}", + "54, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "55, mice {'context': 'I-organism'}", + "81, in {'context': 'B-in vivo'}", + "82, vivo {'context': 'I-in vivo'}", + "84, in {'context': 'B-in vitro'}", + "85, vitro, {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "50, Overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "51, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "52, DeltaFosB ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "54, transgenic ['l2', 'l7', 'l11', 'l15']", + "55, mice ['l3', 'l8', 'l12', 'l15']", + "81, in ['l4', 'l9', 'l13', 'l16', 'l17', 'l18']", + "82, vivo ['l5', 'l10', 'l14', 'l16']", + "84, in ['l17', 'l19']", + "85, vitro, ['l18', 'l19']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "DeltaFosB", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "DeltaFosB" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "10932229", + "TEXT": "Repeated administration of morphine substantially increases its locomotor-enhancing activity, a phenomenon termed locomotor sensitization. Here we show that secreted protein acidic and rich in cysteine (SPARC), an anti-adhesive glycoprotein present in the basolateral amygdala, contributes to the establishment of locomotor sensitization. The morphine-induced increase in SPARC levels in the basolateral amygdala persisted after morphine withdrawal and coincided with the duration of locomotor sensitization. Moreover, a single injection of morphine after SPARC infusion into the basolateral amygdala of previously uninjected mice substantially enhanced locomotor activity. Thus, SPARC may be an important element for establishing locomotor sensitization to morphine.", + "TAG_DATA": [ + "49, basolateral {'context': 'B-tissue/organ'}", + "50, amygdala {'context': 'I-tissue/organ'}", + "74, basolateral {'context': 'B-tissue/organ'}", + "75, amygdala {'context': 'I-tissue/organ'}", + "79, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "49, basolateral ['l0']", + "50, amygdala ['l0']", + "71, infusion ['l1', 'l2', 'l3']", + "74, basolateral ['l1', 'l4', 'l5']", + "75, amygdala ['l2', 'l4', 'l6']", + "79, mice ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10932227", + "TEXT": "The parasite Plasmodium berghei imports the enzyme delta-aminolevulinate dehydratase (ALAD), and perhaps the subsequent enzymes of the pathway from the host red blood cell to sustain heme synthesis. Here we have studied the mechanism of this import. A 65-kDa protein on the P. berghei membrane specifically bound to mouse red blood cell ALAD, and a 93-amino-acid fragment (ALAD-DeltaNC) of the host erythrocyte ALAD was able to compete with the full-length enzyme for binding to the P. berghei membrane. ALAD-DeltaNC was taken up by the infected red blood cell when added to a culture of P. falciparum and this led to a substantial decrease in ALAD protein and enzyme activity and, subsequently, heme synthesis in the parasite, resulting in its death.", + "TAG_DATA": [ + "85, red {'context': 'B-cells'}", + "86, blood {'context': 'I-cells'}", + "87, cell {'context': 'I-cells'}", + "115, parasite, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "85, red ['l0', 'l1', 'l2']", + "86, blood ['l0', 'l3', 'l4']", + "87, cell ['l1', 'l3', 'l5']", + "115, parasite, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10932226", + "TEXT": "Lymphocyte polyclonal activation is a generalized mechanism of immune evasion among pathogens. In a mouse model of Trypanosoma cruzi infection (American trypanosomiasis), reduced levels of polyclonal lymphocyte responses correlate with resistance to infection and cardiopathy. We report here the characterization of a parasite protein with B-cell mitogenic properties in culture supernatants of infective forms, the cloning of the corresponding gene and the analysis of the biological properties of its product. We characterized the protein as a co-factor-independent proline racemase, and show that its expression as a cytoplasmic and/or membrane-associated protein is life-stage specific. Inhibition studies indicate that availability of the racemase active site is necessary for mitogenic activity. This is the first report to our knowledge of a eukaryotic amino acid racemase gene. Our findings have potential consequences for the development of new immune therapies and drug design against pathogens.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10932224", + "TEXT": "ONYX-015 is an adenovirus with the E1B 55-kDa gene deleted, engineered to selectively replicate in and lyse p53-deficient cancer cells while sparing normal cells. Although ONYX-015 and chemotherapy have demonstrated anti-tumoral activity in patients with recurrent head and neck cancer, disease recurs rapidly with either therapy alone. We undertook a phase II trial of a combination of intratumoral ONYX-015 injection with cisplatin and 5-fluorouracil in patients with recurrent squamous cell cancer of the head and neck. There were substantial objective responses, including a high proportion of complete responses. By 6 months, none of the responding tumors had progressed, whereas all non-injected tumors treated with chemotherapy alone had progressed. The toxic effects that occurred were acceptable. Tumor biopsies obtained after treatment showed tumor-selective viral replication and necrosis induction.", + "TAG_DATA": [ + "65, patients {'context': 'B-patient'}", + "67, recurrent {'context': 'B-neoplasm'}", + "68, squamous {'context': 'I-neoplasm'}", + "69, cell {'context': 'I-neoplasm'}", + "70, cancer {'context': 'I-neoplasm'}", + "71, of {'context': 'I-neoplasm'}", + "72, the {'context': 'I-neoplasm'}", + "73, head {'context': 'I-neoplasm'}", + "74, and {'context': 'I-neoplasm'}", + "75, neck. {'context': 'I-neoplasm'}", + "95, tumors {'context': 'B-neoplasm'}", + "101, tumors {'context': 'B-neoplasm'}", + "115, Tumor {'context': 'B-neoplasm'}", + "125, necrosis {'phenotype': 'B-necrosis'}", + "126, induction. {'effect': 'B-positive'}" + ], + "LINK_DATA": [ + "65, patients ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "67, recurrent ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "68, squamous ['l1', 'l9', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "69, cell ['l2', 'l10', 'l18', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "70, cancer ['l3', 'l11', 'l19', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "71, of ['l4', 'l12', 'l20', 'l27', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "72, the ['l5', 'l13', 'l21', 'l28', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47']", + "73, head ['l6', 'l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l48', 'l49']", + "74, and ['l7', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l50']", + "75, neck. ['l8', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l50']", + "95, tumors ['l17', 'l25', 'l32', 'l38', 'l43', 'l47']", + "101, tumors ['l51']", + "115, Tumor ['l52', 'l53']", + "125, necrosis ['l52', 'l54']", + "126, induction. ['l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "Tumor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "Tumor" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction." + ] + } + } + ] + }, + { + "PMID": "10932223", + "TEXT": "The sodium/iodide symporter mediates active iodide transport in both healthy and cancerous thyroid tissue. By exploiting this activity, radioiodide has been used for decades with considerable success in the detection and treatment of thyroid cancer. Here we show that a specialized form of the sodium/iodide symporter in the mammary gland mediates active iodide transport in healthy lactating (but not in nonlactating) mammary gland and in mammary tumors. In addition to characterizing the hormonal regulation of the mammary gland sodium/iodide symporter, we demonstrate by scintigraphy that mammary adenocarcinomas in transgenic mice bearing Ras or Neu oncogenes actively accumulate iodide by this symporter in vivo. Moreover, more than 80% of the human breast cancer samples we analyzed by immunohistochemistry expressed the symporter, compared with none of the normal (nonlactating) samples from reductive mammoplasties. These results indicate that the mammary gland sodium/iodide symporter may be an essential breast cancer marker and that radioiodide should be studied as a possible option in the diagnosis and treatment of breast cancer.", + "TAG_DATA": [ + "85, mammary {'context': 'B-neoplasm'}", + "86, adenocarcinomas {'context': 'I-neoplasm'}", + "88, transgenic {'context': 'B-organism'}", + "89, mice {'context': 'I-organism'}", + "91, Ras {'perturbing_action': 'I-other'}", + "92, or {'perturbing_action': 'I-other'}", + "93, Neu {'perturbing_action': 'I-other'}", + "94, oncogenes {'perturbing_action': 'I-other'}", + "101, in {'context': 'B-in vivo'}", + "102, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "85, mammary ['l0', 'l1', 'l2', 'l3', 'l4']", + "86, adenocarcinomas ['l0', 'l5', 'l6']", + "88, transgenic ['l1', 'l5', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "89, mice ['l2', 'l6', 'l7', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "91, Ras ['l8', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "92, or ['l9', 'l15', 'l20', 'l25', 'l26', 'l27', 'l28']", + "93, Neu ['l3', 'l10', 'l16', 'l21', 'l25', 'l29', 'l30', 'l31']", + "94, oncogenes ['l11', 'l17', 'l22', 'l26', 'l29', 'l32', 'l33']", + "101, in ['l12', 'l18', 'l23', 'l27', 'l30', 'l32', 'l34']", + "102, vivo. ['l4', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l34']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "mammary" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Neu" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Ras", + "or", + "Neu", + "oncogenes" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Ras", + "or", + "Neu", + "oncogenes" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "10888931", + "TEXT": "Reversible blockade of sodium channels by endogenous substances has been claimed to account for the fast exacerbations and relapses commonly seen in demyelinating autoimmune diseases. Evidence has been provided that in the cerebrospinal fluid of patients with multiple sclerosis or Guillain-Barré syndrome, a sodium-channel-blocking factor exists that has properties of local anesthetic agents. This factor could contribute to the nerve conduction block and paresis seen in these disorders. We describe here a previously unknown endogenous substance in human cerebrospinal fluid with distinct channel-blocking properties even at very low (0.00001 M) concentrations. The pentapeptide with the sequence Gln-Tyr-Asn-Ala-Asp exerted its blocking action by shifting the steady-state inactivation curve of the sodium channels to more-negative potentials, as most local anesthetics do. In the cerebrospinal fluid of healthy individuals, its concentration was about 3 microM, whereas in patients with multiple sclerosis and Guillain-Barré syndrome, it increased 300-1,400%. At these concentrations, the peptide's blocking efficacy was higher than that of 50 microM lidocaine. At a concentration of 10 microM, lidocaine is able to 'unmask' subclinical lesions in multiple sclerosis; thus, the endogenous pentapeptide may well contribute to the fast changes of symptoms. Furthermore, it may become valuable as a marker of disease activity.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10888928", + "TEXT": "Apoptosis of smooth muscle cells is a common feature of vascular lesions but its pathophysiological significance is not known. We demonstrate that signals initiated by regulated Fas-associated death domain protein overexpression in rat vascular smooth muscle cells in the carotid artery induce expression of monocyte-chemoattractant protein-1 and interleukin-8, and cause massive immigration of macrophages in vivo. These chemokines, and a specific set of other pro-inflammatory genes, are also upregulated in human vascular smooth muscle cells during Fas-induced apoptosis, in part through a process that requires interleukin-1alpha activation. Induction of a pro-inflammatory program by apoptotic vascular smooth muscle cells may thus contribute to the pathogenesis of vascular disease.", + "TAG_DATA": [ + "32, rat {'context': 'B-cells'}", + "33, vascular {'context': 'I-cells'}", + "34, smooth {'context': 'I-cells'}", + "35, muscle {'context': 'I-cells'}", + "36, cells {'context': 'I-cells'}", + "39, carotid {'context': 'B-tissue/organ'}", + "40, artery {'context': 'I-tissue/organ'}", + "53, macrophages {'context': 'B-cells'}", + "54, in {'context': 'B-in vivo'}", + "55, vivo. {'context': 'I-in vivo'}", + "70, human {'context': 'B-cells'}", + "71, vascular {'context': 'I-cells'}", + "72, smooth {'context': 'I-cells'}", + "73, muscle {'context': 'I-cells'}", + "74, cells {'context': 'I-cells'}", + "76, Fas-induced {'effect': 'B-positive'}", + "77, apoptosis, {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "32, rat ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "33, vascular ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "34, smooth ['l1', 'l9', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "35, muscle ['l2', 'l10', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "36, cells ['l3', 'l11', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "39, carotid ['l4', 'l12', 'l17', 'l22', 'l26', 'l30']", + "40, artery ['l5', 'l13', 'l18', 'l23', 'l27', 'l30']", + "53, macrophages ['l6', 'l14', 'l19', 'l24', 'l28', 'l31', 'l32']", + "54, in ['l7', 'l31', 'l33']", + "55, vivo. ['l8', 'l20', 'l25', 'l29', 'l32', 'l33']", + "70, human ['l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "71, vascular ['l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "72, smooth ['l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "73, muscle ['l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "74, cells ['l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "76, Fas-induced ['l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "77, apoptosis, ['l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "vascular", + "smooth", + "muscle", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "Fas-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "vascular", + "smooth", + "muscle", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Fas-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + } + ] + }, + { + "PMID": "10888925", + "TEXT": "The release of microparticles from eukaryotic cells is a well-recognized phenomenon. We demonstrate here that the chemokine receptor CCR5, the principal co-receptor for macrophage-tropic human immunodeficiency virus (HIV)-1, can be released through microparticles from the surface of CCR5+ Chinese hamster ovary cells and peripheral blood mononuclear cells. Microparticles containing CCR5 can transfer the receptor to CCR5- cells and render them CCR5+. The CCR5 transfer to CCR5-deficient peripheral blood mononuclear cells homozygous for a 32-base-pair deletion in the CCR5 gene enabled infection of these cells with macrophage-tropic HIV-1. In monocytes, the transfer of CCR5 could be inhibited by cytochalasin D, and transferred CCR5 could be downmodulated by chemokines. A transfer of CCR5 from peripheral blood mononuclear cells to endothelial cells during transendothelial migration could be demonstrated. Thus, the transfer of CCR5 may lead to infection of tissues without endogenous CCR5 expression. Moreover, the intercellular transfer of membrane proteins by microparticles might have broader consequences for intercellular communication beyond the effects seen for HIV-1.", + "TAG_DATA": [ + "65, CCR5-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "66, peripheral {'context': 'B-cells'}", + "67, blood {'context': 'I-cells'}", + "68, mononuclear {'context': 'I-cells'}", + "69, cells {'context': 'I-cells'}", + "70, homozygous {'perturbing_action': 'B-other'}", + "71, for {'perturbing_action': 'I-other'}", + "72, a {'perturbing_action': 'I-other'}", + "73, 32-base-pair {'perturbing_action': 'I-other'}", + "74, deletion {'perturbing_action': 'I-other'}", + "75, in {'perturbing_action': 'I-other'}", + "76, the {'perturbing_action': 'I-other'}", + "77, CCR5 {'perturbing_action': 'I-other'}", + "78, gene {'perturbing_action': 'I-other'}", + "83, cells {'context': 'B-cells'}", + "88, monocytes, {'context': 'B-cells'}", + "112, peripheral {'context': 'B-cells'}", + "113, blood {'context': 'I-cells'}", + "114, mononuclear {'context': 'I-cells'}", + "115, cells {'context': 'I-cells'}", + "117, endothelial {'context': 'B-cells'}", + "118, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "65, CCR5-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "66, peripheral ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "67, blood ['l1', 'l10', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "68, mononuclear ['l2', 'l11', 'l24', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "69, cells ['l3', 'l12', 'l25', 'l37', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "70, homozygous ['l4', 'l13', 'l26', 'l38', 'l49', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "71, for ['l14', 'l27', 'l39', 'l50', 'l60', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "72, a ['l15', 'l28', 'l40', 'l51', 'l61', 'l70', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "73, 32-base-pair ['l16', 'l29', 'l41', 'l52', 'l62', 'l71', 'l79', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "74, deletion ['l17', 'l30', 'l42', 'l53', 'l63', 'l72', 'l80', 'l87', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "75, in ['l5', 'l18', 'l31', 'l43', 'l54', 'l64', 'l73', 'l81', 'l88', 'l94', 'l100', 'l101', 'l102', 'l103', 'l104']", + "76, the ['l6', 'l19', 'l32', 'l44', 'l55', 'l65', 'l74', 'l82', 'l89', 'l95', 'l100', 'l105', 'l106', 'l107', 'l108']", + "77, CCR5 ['l7', 'l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l83', 'l90', 'l96', 'l101', 'l105', 'l109', 'l110', 'l111']", + "78, gene ['l8', 'l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l84', 'l91', 'l97', 'l102', 'l106', 'l109', 'l112', 'l113']", + "83, cells ['l9', 'l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l98', 'l103', 'l107', 'l110', 'l112']", + "88, monocytes, ['l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l86', 'l93', 'l99', 'l104', 'l108', 'l111', 'l113']", + "112, peripheral ['l114', 'l115', 'l116', 'l117', 'l118']", + "113, blood ['l114', 'l119', 'l120', 'l121', 'l122']", + "114, mononuclear ['l115', 'l119', 'l123', 'l124', 'l125']", + "115, cells ['l116', 'l120', 'l123', 'l126', 'l127']", + "117, endothelial ['l117', 'l121', 'l124', 'l126', 'l128']", + "118, cells ['l118', 'l122', 'l125', 'l127', 'l128']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CCR5-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "peripheral", + "blood", + "mononuclear", + "cells" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "peripheral", + "blood", + "mononuclear", + "cells", + "monocytes," + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "homozygous", + "for", + "a", + "32-base-pair", + "deletion", + "in", + "the", + "CCR5", + "gene" + ] + } + } + ] + }, + { + "PMID": "10835690", + "TEXT": "The androgen receptor (AR) is involved in the development, growth and progression of prostate cancer (CaP). CaP often progresses from an androgen-dependent to an androgen-independent tumor, making androgen ablation therapy ineffective. However, the mechanisms for the development of androgen-independent CaP are unclear. More than 80% of clinically androgen-independent prostate tumors show high levels of AR expression. In some CaPs, AR levels are increased because of gene amplification and/or overexpression, whereas in others, the AR is mutated. Nonetheless, the involvement of the AR in the transition of CaP to androgen-independent growth and the subsequent failure of endocrine therapy are not fully understood. Here we show that in CaP cells from a patient who failed androgen ablation therapy, a doubly mutated AR functioned as a high-affinity cortisol/cortisone receptor (ARccr). Cortisol, the main circulating glucocorticoid, and its metabolite, cortisone, both equally stimulate the growth of these CaP cells and increase the secretion of prostate-specific antigen in the absence of androgens. The physiological concentrations of free cortisol and total cortisone in men greatly exceed the binding affinity of the ARccr and would activate the receptor, promoting CaP cell proliferation. Our data demonstrate a previously unknown mechanism for the androgen-independent growth of advanced CaP. Understanding this mechanism and recognizing the presence of glucocorticoid-responsive AR mutants are important for the development of new forms of therapy for the treatment of this subset of CaP.", + "TAG_DATA": [ + "106, CaP {'context': 'B-transformed cells'}", + "107, cells {'context': 'I-transformed cells'}", + "117, doubly {'perturbing_action': 'B-other'}", + "118, mutated {'perturbing_action': 'B-other'}", + "119, AR {'perturbing_action': 'I-other'}", + "143, CaP {'context': 'B-transformed cells'}", + "144, cells {'context': 'I-transformed cells'}", + "181, promoting {'effect': 'B-positive'}", + "182, CaP {'context': 'B-transformed cells'}", + "183, cell {'context': 'I-transformed cells'}", + "184, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "106, CaP ['l0', 'l1', 'l2']", + "107, cells ['l0', 'l3', 'l4']", + "117, doubly ['l5', 'l6', 'l7', 'l8']", + "118, mutated ['l5', 'l9', 'l10', 'l11']", + "119, AR ['l6', 'l9', 'l12', 'l13']", + "143, CaP ['l1', 'l3', 'l7', 'l10', 'l12', 'l14']", + "144, cells ['l2', 'l4', 'l8', 'l11', 'l13', 'l14']", + "181, promoting ['l15', 'l16', 'l17']", + "182, CaP ['l15', 'l18', 'l19']", + "183, cell ['l16', 'l18', 'l20']", + "184, proliferation. ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "doubly", + "mutated", + "AR" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "CaP", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "CaP", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CaP", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "10835688", + "TEXT": "Cardiovascular disease is one of the leading causes of death worldwide, and has been associated with many environmental risk factors. Recent evidence has indicated the involvement of pathogens such as viruses as causative agents, and specifically identified the coxsackievirus B serogroup as the leading culprit. Not only has coxsackievirus B3 (CB3) been identified from patients with cardiovascular disease, but also infection of mice with CB3 strains can reproduce human clinical heart disease in rodents. Several mechanisms have been proposed in an attempt to distinguish between pathology mediated by direct viral destruction of cardiac muscle cells or by the virus-induced immune response directed at infected myocytes or at 'mimicked' epitopes shared between viral and cardiac antigens. To distinguish between these mechanisms, we infected a unique mouse that diminishes the extent of infection and spread of the virus, but allows complete immunity to the virus. Transgenic mice expressing interferon-gamma in their pancreatic beta cells failed to develop CB-3-induced myocarditis. This work challenges the idea of the function of the immune response and 'molecular mimicry' in the CB-3-induced autoimmune myocarditis model, and instead favors the idea of virus-mediated damage. These results emphasize the benefit of reducing the level of viremia early during infection, thereby reducing the incidence of virus-mediated heart damage and autoimmunity.", + "TAG_DATA": [ + "124, mouse {'context': 'B-organism'}", + "143, Transgenic {'context': 'B-organism'}", + "144, mice {'context': 'I-organism'}", + "149, pancreatic {'context': 'B-cells'}", + "150, beta {'context': 'I-cells'}", + "151, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "143, Transgenic ['l0', 'l1', 'l2', 'l3']", + "144, mice ['l0', 'l4', 'l5', 'l6']", + "149, pancreatic ['l1', 'l4', 'l7', 'l8']", + "150, beta ['l2', 'l5', 'l7', 'l9']", + "151, cells ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10835686", + "TEXT": "Secondary lymphoid organs (the spleen, lymph nodes and mucosal lymphoid tissues) provide the proper environment for antigen-presenting cells to interact with and activate naive T and B lymphocytes. Although it is generally accepted that secondary lymphoid organs are essential for initiating immune responses to microbial antigens and to skin allografts, the prevailing view has been that the immune response to primarily vascularized organ transplants such as hearts and kidneys does not require the presence of secondary lymphoid tissue. The assumption has been that the immune response to such organs is initiated in the graft itself when recipient lymphocytes encounter foreign histocompatibility antigens presented by the graft's endothelial cells. In contrast to this view, we show here that cardiac allografts are accepted indefinitely in recipient mice that lack secondary lymphoid tissue, indicating that the alloimmune response to a vascularized organ transplant cannot be initiated in the graft itself. Moreover, we demonstrate that the permanent acceptance of these grafts is not due to tolerance but is because of immunologic 'ignorance'.", + "TAG_DATA": [ + "117, cardiac {'context': 'B-xenograft'}", + "118, allografts {'context': 'I-xenograft'}", + "124, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "117, cardiac ['l0', 'l1']", + "118, allografts ['l0', 'l2']", + "124, mice ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10835685", + "TEXT": "Despite the well-recognized involvement of immunoglobulin (Ig) A in mucosal immunity, the function of its receptor, FcalphaRI (CD89), is poorly understood. The ability of FcalphaRI to activate leukocytes seems to conflict with the proposed anti-inflammatory activity of secretory IgA. We show here that in a transgenic mouse model, inflammatory mediators induced expression of FcalphaRI on Kupffer cells, which enabled efficient phagocytosis in vivo of bacteria coated with serum IgA. Secretory IgA did not initiate phagocytosis. Therefore, interactions between serum IgA and FcalphaRI on Kupffer cells may provide a 'second line of defense' in mucosal immunity, by eliminating invasive bacteria entering through the portal circulation and thus preventing disease.", + "TAG_DATA": [ + "45, transgenic {'context': 'B-organism'}", + "46, mouse {'context': 'I-organism'}", + "47, model, {'context': 'I-organism'}", + "55, Kupffer {'context': 'B-cells'}", + "56, cells, {'context': 'I-cells'}", + "61, in {'context': 'B-in vivo'}", + "62, vivo {'context': 'I-in vivo'}", + "72, not {'effect': 'I-no effect'}", + "73, initiate {'effect': 'I-no effect'}" + ], + "LINK_DATA": [ + "45, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "46, mouse ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "47, model, ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "55, Kupffer ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "56, cells, ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "58, enabled ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "61, in ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "62, vivo ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "72, not ['l28']", + "73, initiate ['l28']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10835683", + "TEXT": "Although the idiotypic structures of immunoglobulin from malignant B cells were the first tumor-specific determinants recognized, and clinical vaccination trials have demonstrated induction of tumor-specific immunity, the function of immunoglobulin-specific CD8+ cytotoxic T lymphocytes in tumor rejection remains elusive. Here, we combined bioinformatics and a T cell-expansion system to identify human immunoglobulin-derived peptides capable of inducing cytotoxic T-lymphocyte responses. Immunogenic peptides were derived from framework regions of the variable regions of the immunoglobulin that were shared among patients. Human-leukocyte-antigen-matched and autologous cytotoxic T lymphocytes specific for these peptides killed primary malignant B cells, demonstrating that malignant B cells are capable of processing and presenting such peptides. Targeting shared peptides to induce T-cell responses might further improve current vaccination strategies in B-cell malignancies.", + "TAG_DATA": [ + "89, primary {'context': 'B-transformed cells'}", + "90, malignant {'context': 'I-transformed cells'}", + "91, B {'context': 'I-transformed cells'}", + "92, cells, {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "89, primary ['l0', 'l1', 'l2']", + "90, malignant ['l0', 'l3', 'l4']", + "91, B ['l1', 'l3', 'l5']", + "92, cells, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10835681", + "TEXT": "Pre-clinical studies indicate that efficient retrovirus-mediated gene transfer into hematopoietic stem cells and progenitor cells can be achieved by co-localizing retroviral particles and target cells on specific adhesion domains of fibronectin. In this pilot study, we used this technique to transfer the human multidrug resistance 1 gene into stem and progenitor cells of patients with germ cell tumors undergoing autologous transplantation. There was efficient gene transfer into stem and progenitor cells in the presence of recombinant fibronectin fragment CH-296. The infusion of these cells was associated with no harmful effects and led to prompt hematopoietic recovery. There was in vivo vector expression, but it may have been limited by the high rate of aberrant splicing of the multidrug resistance 1 gene in the vector. Gene marking has persisted more than a year at levels higher than previously reported in humans.", + "TAG_DATA": [ + "48, stem {'context': 'B-cells'}", + "49, and {'context': 'I-cells'}", + "50, progenitor {'context': 'I-cells'}", + "51, cells {'context': 'I-cells'}", + "53, patients {'context': 'B-patient'}", + "54, with {'context': 'I-patient'}", + "55, germ {'context': 'B-neoplasm'}", + "56, cell {'context': 'I-neoplasm'}", + "57, tumors {'context': 'I-neoplasm'}", + "67, stem {'context': 'B-cells'}", + "68, and {'context': 'I-cells'}", + "69, progenitor {'context': 'I-cells'}", + "70, cells {'context': 'I-cells'}", + "83, cells {'context': 'B-cells'}", + "98, in {'context': 'B-in vivo'}", + "99, vivo {'context': 'B-in vivo'}" + ], + "LINK_DATA": [ + "48, stem ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "49, and ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "50, progenitor ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "51, cells ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "53, patients ['l3', 'l14', 'l24', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "54, with ['l4', 'l15', 'l25', 'l34', 'l40', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "55, germ ['l5', 'l16', 'l26', 'l35', 'l41', 'l48', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "56, cell ['l6', 'l17', 'l27', 'l36', 'l42', 'l49', 'l56', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "57, tumors ['l7', 'l18', 'l28', 'l37', 'l43', 'l50', 'l57', 'l63', 'l69', 'l70', 'l71', 'l72', 'l73']", + "67, stem ['l8', 'l19', 'l29', 'l44', 'l51', 'l58', 'l64', 'l69', 'l74', 'l75', 'l76', 'l77']", + "68, and ['l9', 'l20', 'l30', 'l38', 'l45', 'l52', 'l59', 'l65', 'l70', 'l74', 'l78', 'l79', 'l80']", + "69, progenitor ['l10', 'l21', 'l31', 'l46', 'l53', 'l60', 'l66', 'l71', 'l75', 'l78', 'l81', 'l82']", + "70, cells ['l11', 'l22', 'l32', 'l39', 'l47', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l81', 'l83']", + "83, cells ['l55', 'l62', 'l68', 'l73', 'l77', 'l80', 'l82', 'l83']", + "98, in ['l84']", + "99, vivo ['l84']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10835680", + "TEXT": "Accumulation of fibrils composed of amyloid A in tissues resulting in displacement of normal structures and cellular dysfunction is the characteristic feature of systemic amyloidoses. Here we show that RAGE, a multiligand immunoglobulin superfamily cell surface molecule, is a receptor for the amyloidogenic form of serum amyloid A. Interactions between RAGE and amyloid A induced cellular perturbation. In a mouse model, amyloid A accumulation, evidence of cell stress and expression of RAGE were closely linked. Antagonizing RAGE suppressed cell stress and amyloid deposition in mouse spleens. These data indicate that RAGE is a potential target for inhibiting accumulation of amyloid A and for limiting cellular dysfunction induced by amyloid A.", + "TAG_DATA": [ + "59, mouse {'context': 'B-organism'}", + "60, model, {'context': 'I-organism'}", + "75, Antagonizing {'perturbing_action': 'B-pharmacological inhibition'}", + "76, RAGE {'perturbing_action': 'I-pharmacological inhibition'}", + "84, mouse {'context': 'B-tissue/organ'}", + "85, spleens. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "59, mouse ['l0']", + "60, model, ['l0']", + "75, Antagonizing ['l1', 'l2', 'l3']", + "76, RAGE ['l1', 'l4', 'l5']", + "84, mouse ['l2', 'l4', 'l6']", + "85, spleens. ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Antagonizing", + "RAGE" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "spleens." + ] + } + } + ] + }, + { + "PMID": "10802711", + "TEXT": "Recent advances using transgenic animals or exogenous complement inhibitors have demonstrated prevention of hyperacute rejection of vascularized organs, but not graft loss due to acute vascular rejection. Using various wild-type and cytokine-deficient mice strains, we have examined the mechanisms of acute vascular rejection. C57BL/6 mice deficient in interleukin12 or gamma interferon showed faster acute vascular rejection than did wild-type mice. Furthermore, mice defective in B-cell development showed no acute vascular rejection. These results demonstrate that the axis of interleukin 12 and gamma interferon provides a survival advantage in vascularized xenografts by delaying or preventing acute vascular rejection caused by a B cell-dependent mechanism.", + "TAG_DATA": [ + "43, C57BL/6 {'context': 'B-organism'}", + "44, mice {'context': 'I-organism'}", + "45, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "46, in {'perturbing_action': 'I-gene loss-of-function'}", + "47, interleukin12 {'perturbing_action': 'I-gene loss-of-function'}", + "59, mice. {'context': 'B-organism'}", + "61, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "43, C57BL/6 ['l0', 'l1', 'l2', 'l3', 'l4']", + "44, mice ['l0', 'l5', 'l6', 'l7', 'l8']", + "45, deficient ['l1', 'l5', 'l9', 'l10', 'l11']", + "46, in ['l2', 'l6', 'l9', 'l12', 'l13']", + "47, interleukin12 ['l3', 'l7', 'l10', 'l12', 'l14']", + "59, mice. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "C57BL/6", + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "interleukin12" + ] + } + } + ] + }, + { + "PMID": "10802709", + "TEXT": "Helicobacter pylori is causally associated with gastritis and gastric cancer. Some developing countries with a high prevalence of infection have high gastric cancer rates, whereas in others, these rates are low. The progression of helicobacter-induced gastritis and gastric atrophy mediated by type 1 T-helper cells may be modulated by concurrent parasitic infection. Here, in mice with concurrent helminth infection, helicobacter-associated gastric atrophy was reduced considerably despite chronic inflammation and high helicobacter colonization. This correlated with a substantial reduction in mRNA for cytokines and chemokines associated with a gastric inflammatory response of type 1 T-helper cells. Thus, concurrent enteric helminth infection can attenuate gastric atrophy, a premalignant lesion.", + "TAG_DATA": [ + "54, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10802692", + "TEXT": "Based on early studies, it was hypothesized that expression of Fas ligand (FasL) by tumor cells enabled them to counterattack the immune system, and that transplant rejection could be prevented by expressing FasL on transplanted organs. More recent studies have indicated that the notion of FasL as a mediator of immune privilege needed to be reconsidered, and taught a valuable lesson about making broad conclusions based on small amounts of data.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10742157", + "TEXT": "Allogeneic bone marrow transplantation (in immunocompetent adults) has always required cytoreductive treatment of recipients with irradiation or cytotoxic drugs to achieve lasting engraftment at levels detectable by non-PCR-based techniques ('macrochimerism' or 'mixed chimerism'). Only syngeneic marrow engraftment at such levels has been achieved in unconditioned hosts. This requirement for potentially toxic myelosuppressive host pre-conditioning has precluded the clinical use of allogeneic bone marrow transplantation for many indications other than malignancies, including tolerance induction. We demonstrate here that treatment of naive mice with a high dose of fully major histocompatibility complex-mismatched allogeneic bone marrow, followed by one injection each of monoclonal antibody against CD154 and cytotoxic T-lymphocyte antigen 4 immunoglobulin, resulted in multi-lineage hematopoietic macrochimerism (of about 15%) that persisted for up to 34 weeks. Long-term chimeras developed donor-specific tolerance (donor skin graft survival of more than 145 days) and demonstrated ongoing intrathymic deletion of donor-reactive T cells. A protocol of high-dose bone marrow transplantation and co-stimulatory blockade can thus achieve allogeneic bone marrow engraftment without cytoreduction or T-cell depletion of the host, and eliminates a principal barrier to the more widespread use of allogeneic bone marrow transplantation. Although efforts have been made to minimize host pre-treatment for allogeneic bone marrow transplantation for tolerance induction, so far none have succeeded in eliminating pre-treatment completely. Our demonstration that this can be achieved provides the rationale for a safe approach for inducing robust transplantation tolerance in large animals and humans.", + "TAG_DATA": [ + "79, naive {'context': 'B-organism'}", + "80, mice {'context': 'I-organism'}", + "144, donor-reactive {'context': 'B-cells'}", + "145, T {'context': 'I-cells'}", + "146, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "79, naive ['l0']", + "80, mice ['l0']", + "144, donor-reactive ['l1', 'l2']", + "145, T ['l1', 'l3']", + "146, cells. ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10742154", + "TEXT": "Wild-type varicella zoster virus (VZV) causes chickenpox, a common childhood illness characterized by fever and a vesicular rash and rare serious complications. Wild-type VZV persists in a latent form in the sensory ganglia, and can re-activate to cause herpes zoster. More than 10 million American children have received the live attenuated Oka strain VZV vaccine (OkaVZV) since its licensure in 1995. Pre-licensure clinical studies showed that mean serum anti-VZV levels among vaccinees continued to increase with time after vaccination. This was attributed to immunologic boosting caused by exposure to wild-type VZV in the community. Here, we examine the alternative, that large-scale asymptomatic reactivation of OkaVZV might occur in vaccinees. We analyzed serum antibody levels and infection rates for 4 years of follow-up in 4,631 children immunized with OkaVZV. Anti-VZV titers decreased over time in high-responder subjects, but rose in vaccinees with low titers. Among subjects with low anti-VZV titers, the frequency of clinical infection and immunological boosting substantially exceeded the 13%-per-year rate of exposure to wild-type varicella. These findings indicate that OkaVZV persisted in vivo and reactivated as serum antibody titers decreased after vaccination. This has salient consequences for individuals immunized with OkaVZV.", + "TAG_DATA": [ + "124, children {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10700239", + "TEXT": "The hematopoietic-specific transmembrane protein tyrosine phosphatase CD45 functions to regulate Src kinases required for T- and B-cell antigen receptor signal transduction. So far, there have been no reports to our knowledge of a human deficiency in a tyrosine-specific phosphatase. Here, we identified a male patient with a deficiency in CD45 due to a large deletion at one allele and a point mutation at the other. The point mutation resulted in the alteration of intervening sequence 13 donor splice site. The patient presented at 2 months of age with severe combined immunodeficiency disease. The population of peripheral blood T lymphocytes was greatly diminished and unresponsive to mitogen stimulation. Despite normal B-lymphocyte numbers, serum immunoglobulin levels decreased with age. Thus, CD45 deficiency in humans results in T- and B-lymphocyte dysfunction.", + "TAG_DATA": [ + "95, peripheral {'context': 'B-cells'}", + "96, blood {'context': 'I-cells'}", + "97, T {'context': 'I-cells'}", + "98, lymphocytes {'context': 'I-cells'}", + "109, B-lymphocyte {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "43, male ['l0']", + "44, patient ['l0']", + "95, peripheral ['l1', 'l2', 'l3']", + "96, blood ['l1', 'l4', 'l5']", + "97, T ['l2', 'l4', 'l6']", + "98, lymphocytes ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10700235", + "TEXT": "To provide long-term therapy in patients with severe toxin-induced hepatic parenchymal damage, donor hepatocytes would need to replicate and replace a large portion of the damaged parenchyma. Using a mouse model developed to reproduce this type of hepatic injury, we found that hepatocyte transplantation only slightly improved survival after transplantation despite the fact that many non-survivors showed moderate liver repopulation by donor cells. Perhaps accounting for this outcome, donor parenchyma in non-survivors did not have typical lobular organization. These results indicate that the re-creation of functional parenchyma by transplanted hepatocytes requires time, during which donor cells proliferate and then establish normal parenchymal architecture.", + "TAG_DATA": [ + "29, mouse {'context': 'B-organism'}", + "30, model {'context': 'I-organism'}", + "42, hepatocyte {'context': 'B-cells'}", + "58, liver {'context': 'B-tissue/organ'}", + "62, cells. {'context': 'I-cells'}", + "94, donor {'context': 'B-cells'}", + "95, cells {'context': 'I-cells'}", + "96, proliferate {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "29, mouse ['l0']", + "30, model ['l0']", + "42, hepatocyte ['l1', 'l2']", + "58, liver ['l1', 'l3']", + "62, cells. ['l2', 'l3']", + "94, donor ['l4', 'l5']", + "95, cells ['l4', 'l6']", + "96, proliferate ['l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "donor", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate" + ] + } + } + ] + }, + { + "PMID": "10700229", + "TEXT": "Ductal structures of the adult pancreas contain stem cells that differentiate into islets of Langerhans. Here, we grew pancreatic ductal epithelial cells isolated from prediabetic adult non-obese diabetic mice in long-term cultures, where they were induced to produce functioning islets containing alpha, beta and delta cells. These in vitro-generated islets showed temporal changes in mRNA transcripts for islet cell-associated differentiation markers, responded in vitro to glucose challenge, and reversed insulin-dependent diabetes after being implanted into diabetic non-obese diabetic mice. The ability to control growth and differentiation of islet stem cells provides an abundant islet source for beta-cell reconstitution in type I diabetes.", + "TAG_DATA": [ + "18, pancreatic {'context': 'B-cells'}", + "19, ductal {'context': 'I-cells'}", + "20, epithelial {'context': 'I-cells'}", + "21, cells {'context': 'I-cells'}", + "22, isolated {'context': 'I-cells'}", + "24, prediabetic {'context': 'B-organism'}", + "25, adult {'context': 'I-organism'}", + "26, non-obese {'context': 'I-organism'}", + "27, diabetic {'context': 'I-organism'}", + "28, mice {'context': 'I-organism'}", + "45, cells. {'context': 'I-cells'}", + "47, in {'context': 'B-in vitro'}", + "48, vitro-generated {'context': 'I-in vitro'}", + "49, islets {'context': 'B-cells'}", + "62, in {'context': 'B-in vitro'}", + "63, vitro {'context': 'I-in vitro'}", + "75, diabetic {'context': 'B-organism'}", + "76, non-obese {'context': 'I-organism'}", + "77, diabetic {'context': 'I-organism'}", + "78, mice. {'context': 'I-organism'}", + "87, islet {'context': 'B-cells'}", + "88, stem {'context': 'I-cells'}", + "89, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "18, pancreatic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "19, ductal ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "20, epithelial ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "21, cells ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "22, isolated ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "24, prediabetic ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "25, adult ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66']", + "26, non-obese ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l67', 'l68', 'l69', 'l70']", + "27, diabetic ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l67', 'l71', 'l72', 'l73', 'l74']", + "28, mice ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l68', 'l71']", + "42, beta ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l69', 'l72', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "43, and ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l73', 'l75', 'l81', 'l82', 'l83', 'l84', 'l85']", + "44, delta ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l76', 'l81', 'l86', 'l87', 'l88', 'l89']", + "45, cells. ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l66', 'l70', 'l74', 'l77', 'l82', 'l86', 'l90', 'l91', 'l92']", + "47, in ['l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "48, vitro-generated ['l93', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "49, islets ['l78', 'l83', 'l87', 'l90', 'l94', 'l101', 'l108', 'l109']", + "62, in ['l79', 'l84', 'l88', 'l91', 'l95', 'l102', 'l108', 'l110']", + "63, vitro ['l80', 'l85', 'l89', 'l92', 'l96', 'l103', 'l109', 'l110']", + "75, diabetic ['l97', 'l104', 'l111', 'l112', 'l113']", + "76, non-obese ['l98', 'l105', 'l111', 'l114', 'l115']", + "77, diabetic ['l99', 'l106', 'l112', 'l114', 'l116']", + "78, mice. ['l100', 'l107', 'l113', 'l115', 'l116']", + "87, islet ['l117', 'l118']", + "88, stem ['l117', 'l119']", + "89, cells ['l118', 'l119']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10700227", + "TEXT": "Gastrointestinal disease caused by Shiga toxin-producing bacteria (such as Escherichia coli O157:H7 and Shigella dysenteriae) is often complicated by life-threatening toxin-induced systemic sequelae, including hemolytic-uremic syndrome. Such infections can now be diagnosed very early in the course of the disease, but at present no effective therapeutic intervention is possible. Here, we constructed a recombinant bacterium that displayed a Shiga toxin receptor mimic on its surface, and it adsorbed and neutralized Shiga toxins with very high efficiency. Moreover, oral administration of the recombinant bacterium completely protected mice from challenge with an otherwise 100%-fatal dose of Shiga toxigenic E. coli. Thus, the bacterium shows great promise as a 'probiotic' treatment for Shiga toxigenic E. coli infections and dysentery.", + "TAG_DATA": [ + "85, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10655114", + "TEXT": "Thromboxane (Tx) A2 is a platelet agonist, smooth muscle cell constrictor, and mitogen. Urinary Tx metabolite (Tx-M) excretion is increased in syndromes of platelet activation and early in both normal pregnancies and in pregnancy-induced hypertension. A further increment occurs in patients presenting with severe preeclampsia, in whom Tx-M correlates with other indices of disease severity. TxA2 exerts its effects through a membrane receptor (TP), of which two isoforms (alpha and beta; refs. 5,6) have been cloned. Overexpression of TP in the vasculature under the control of the pre-proendothelin-1 promoter results in a murine model of intrauterine growth retardation (IUGR), which is rescued by timed suppression of Tx synthesis with indomethacin. IUGR is commonly associated with maternal diabetes or cigarette smoking, both conditions associated with increased TxA2 biosynthesis.", + "TAG_DATA": [ + "76, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "77, of {'perturbing_action': 'I-gene gain-of-function'}", + "78, TP {'perturbing_action': 'I-gene gain-of-function'}", + "81, vasculature {'context': 'B-tissue/organ'}", + "82, under {'perturbing_action': 'I-gene gain-of-function'}", + "84, control {'perturbing_action': 'I-gene gain-of-function'}", + "92, murine {'context': 'B-organism'}", + "93, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "76, Overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "77, of ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "78, TP ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "79, in ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "80, the ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "81, vasculature ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "82, under ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "84, control ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "88, promoter ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "92, murine ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "93, model ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "TP", + "under", + "control" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "vasculature" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "TP", + "under", + "control" + ] + }, + "context": { + "val": "organism", + "words": [ + "murine", + "model" + ] + } + } + ] + }, + { + "PMID": "10655111", + "TEXT": "The development of the human immunodeficiency virus-1 (HIV-1)/simian immunodeficiency virus (SIV) chimeric virus macaque model (SHIV) permits the in vivo evaluation of anti-HIV-1 envelope glycoprotein immune responses. Using this model, others, and we have shown that passively infused antibody can protect against an intravenous challenge. However, HIV-1 is most often transmitted across mucosal surfaces and the intravenous challenge model may not accurately predict the role of antibody in protection against mucosal exposure. After controlling the macaque estrous cycle with progesterone, anti-HIV-1 neutralizing monoclonal antibodies 2F5 and 2G12, and HIV immune globulin were tested. Whereas all five control monkeys displayed high plasma viremia and rapid CD4 cell decline, 14 antibody-treated macaques were either completely protected against infection or against pathogenic manifestations of SHIV-infection. Infusion of all three antibodies together provided the greatest amount of protection, but a single monoclonal antibody, with modest virus neutralizing activity, was also protective. Compared with our previous intravenous challenge study with the same virus and antibodies, the data indicated that greater protection was achieved after vaginal challenge. This study demonstrates that antibodies can affect transmission and subsequent disease course after vaginal SHIV-challenge; the data begin to define the type of antibody response that could play a role in protection against mucosal transmission of HIV-1.", + "TAG_DATA": [ + "75, macaque {'context': 'B-organism'}", + "97, monkeys {'context': 'B-organism'}", + "104, CD4 {'context': 'B-cells'}", + "109, macaques {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "97, monkeys ['l0']", + "104, CD4 ['l0', 'l1']", + "109, macaques ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10613828", + "TEXT": "Treatment of HIV-1-infected individuals with a combination of anti-retroviral agents results in sustained suppression of HIV-1 replication, as evidenced by a reduction in plasma viral RNA to levels below the limit of detection of available assays. However, even in patients whose plasma viral RNA levels have been suppressed to below detectable levels for up to 30 months, replication-competent virus can routinely be recovered from patient peripheral blood mononuclear cells and from semen. A reservoir of latently infected cells established early in infection may be involved in the maintenance of viral persistence despite highly active anti-retroviral therapy. However, whether virus replication persists in such patients is unknown. HIV-1 cDNA episomes are labile products of virus infection and indicative of recent infection events. Using episome-specific PCR, we demonstrate here ongoing virus replication in a large percentage of infected individuals on highly active anti-retroviral therapy, despite sustained undetectable levels of plasma viral RNA. The presence of a reservoir of 'covert' virus replication in patients on highly active anti-retroviral therapy has important implications for the clinical management of HIV-1-infected individuals and for the development of virus eradication strategies.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10613827", + "TEXT": "To develop an HIV-1 vaccine with global efficacy, it is important to identify and characterize the viruses that are transmitted, particularly to individuals living in areas of high incidence. Several studies have shown that virus from the blood of acutely infected adults was homogeneous, even when the virus population in the index case was genetically diverse. In contrast to those results with mainly male cohorts in America and Europe, in several cases a heterogeneous virus population has been found early in infection in women in Africa. Thus, we more closely compared the diversity of transmitted HIV-1 in men and women who became infected through heterosexual contact. We found that women from Kenya were often infected by multiple virus variants, whereas men from Kenya were not. Moreover, a heterogeneous virus was present in the women before their seroconversion, and in each woman it was derived from a single index case, indicating that diversity was most likely to be the result of transmission of multiple variants. Our data indicate that there are important differences in the transmitted virus populations in women and men, even when cohorts from the same geographic region who are infected with the same subtypes of HIV-1 are compared.", + "TAG_DATA": [ + "109, women {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "109, women ['l0']", + "120, men ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10613826", + "TEXT": "Glutamate excitotoxicity mediated by the AMPA/kainate type of glutamate receptors damages not only neurons but also the myelin-producing cell of the central nervous system, the oligodendrocyte. In multiple sclerosis, myelin, oligodendrocytes and some axons are lost as a result of an inflammatory attack on the central nervous system. Because glutamate is released in large quantities by activated immune cells, we expected that during inflammation in MS, glutamate excitotoxicity might contribute to the lesion. We addressed this by using the AMPA/kainate antagonist NBQX to treat mice sensitized for experimental autoimmune encephalomyelitis, a demyelinating model that mimics many of the clinical and pathologic features of multiple sclerosis. Treatment resulted in substantial amelioration of disease, increased oligodendrocyte survival and reduced dephosphorylation of neurofilament H, an indicator of axonal damage. Despite the clinical differences, treatment with NBQX had no effect on lesion size and did not reduce the degree of central nervous system inflammation. In addition, NBQX did not alter the proliferative activity of antigen-primed T cells in vitro, further indicating a lack of effect on the immune system. Thus, glutamate excitotoxicity seems to be an important mechanism in autoimmune demyelination, and its prevention with AMPA/kainate antagonists may prove to be an effective therapy for multiple sclerosis.", + "TAG_DATA": [ + "84, mice {'context': 'B-organism'}", + "113, oligodendrocyte {'context': 'B-cells'}", + "153, did {'effect': 'B-no effect'}", + "154, not {'effect': 'I-no effect'}", + "155, alter {'effect': 'I-no effect'}", + "157, proliferative {'phenotype': 'B-proliferation'}", + "158, activity {'phenotype': 'I-proliferation'}", + "161, T {'context': 'B-cells'}", + "162, cells {'context': 'B-cells'}", + "163, in {'context': 'B-in vitro'}", + "164, vitro, {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "84, mice ['l0']", + "113, oligodendrocyte ['l0']", + "153, did ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "154, not ['l1', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "155, alter ['l2', 'l9', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "157, proliferative ['l3', 'l10', 'l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "158, activity ['l4', 'l11', 'l17', 'l22', 'l27', 'l28', 'l29', 'l30']", + "161, T ['l5', 'l12', 'l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "162, cells ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "163, in ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "164, vitro, ['l8', 'l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "alter" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "activity" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "alter" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "alter" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "activity" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "activity" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + } + ] + }, + { + "PMID": "10613823", + "TEXT": "Although tissue injury and inflammation are considered essential for the induction of angiogenesis, the molecular controls of this cascade are mostly unknown. Here we show that a macrophage-derived peptide, PR39, inhibited the ubiquitin-proteasome-dependent degradation of hypoxia-inducible factor-1alpha protein, resulting in accelerated formation of vascular structures in vitro and increased myocardial vasculature in mice. For the latter, coronary flow studies demonstrated that PR39-induced angiogenesis resulted in the production of functional blood vessels. These findings show that PR39 and related compounds can be used as potent inductors of angiogenesis, and that selective inhibition of hypoxia-inducible factor-1alpha degradation may underlie the mechanism of inflammation-induced angiogenesis.", + "TAG_DATA": [ + "45, in {'context': 'B-in vitro'}", + "46, vitro {'context': 'I-in vitro'}", + "52, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "45, in ['l0']", + "46, vitro ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10613815", + "TEXT": "The search for methods to detect in vivo the histopathology of Alzheimer disease moves a step closer with a recent demonstration that amyloid plaques in autopsy specimens can be visualized with magnetic resonance microscopy.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10581081", + "TEXT": "Although insulin-like growth factor 1 (IGF-1) has been associated with retinopathy, proof of a direct relationship has been lacking. Here we show that an IGF-1 receptor antagonist suppresses retinal neovascularization in vivo, and infer that interactions between IGF-1 and the IGF-1 receptor are necessary for induction of maximal neovascularization by vascular endothelial growth factor (VEGF). IGF-1 receptor regulation of VEGF action is mediated at least in part through control of VEGF activation of p44/42 mitogen-activated protein kinase, establishing a hierarchical relationship between IGF-1 and VEGF receptors. These findings establish an essential role for IGF-1 in angiogenesis and demonstrate a new target for control of retinopathy. They also explain why diabetic retinopathy initially increases with the onset of insulin treatment. IGF-1 levels, low in untreated diabetes, rise with insulin therapy, permitting VEGF-induced retinopathy.", + "TAG_DATA": [ + "24, IGF-1 {'perturbing_action': 'B-pharmacological inhibition'}", + "25, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "26, antagonist {'perturbing_action': 'I-pharmacological inhibition'}", + "30, in {'context': 'B-in vivo'}", + "31, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "24, IGF-1 ['l0', 'l1', 'l2', 'l3']", + "25, receptor ['l0', 'l4', 'l5', 'l6']", + "26, antagonist ['l1', 'l4', 'l7', 'l8']", + "30, in ['l2', 'l5', 'l7', 'l9']", + "31, vivo, ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "IGF-1", + "receptor", + "antagonist" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + } + ] + }, + { + "PMID": "10546001", + "TEXT": "Pituitary tumors are commonly encountered, and result from clonal expansion of a single mutated cell. Hypothalamic hormones, local growth factors and circulating sex steroid hormones promote pituitary tumor growth and expansion into large invasive tumors. Estrogen acting directly through its receptor and by stimulation of fibroblast growth factor regulates prolactin synthesis and secretion. Fibroblast growth factor-2 (bFGF) modulates angiogenesis, tumor formation and progression in many tissues, including the anterior pituitary. A pituitary tumor-derived transforming gene (PTTG) has been isolated, which is tumorigenic in vivo, regulates bFGF secretion, and inhibits chromatid separation. The human PTTG family consists of at least three homologous genes, of which PTTG1 is located on chromosome 5q33 and is expressed at low levels in most normal human tissues but is highly expressed in malignant human cell lines and in pituitary tumors. We report here that pituitary pttg is regulated in vivo and in vitro by estrogen. Maximal induction of rat pituitary pttg mRNA in vivo occurred early in pituitary transformation (normal cell to hypertrophic/hyperplastic cell), coincident with bFGF and vascular endothelial growth factor induction and pituitary angiogenesis. We also demonstrate that pttg expression is induced by bFGF, and show concordant pttg and bFGF expression in experimental and human pituitary adenomas. As bFGF and estrogen both induce pttg, and pttg expression coincides with the early lactotrophic hyperplastic response, angiogenesis and prolactinoma development, we propose a previously unknown paracrine growth factor-mediated mechanism for pituitary tumor pathogenesis and potentially other estrogen-regulated tumors.", + "TAG_DATA": [ + "152, rat {'context': 'B-tissue/organ'}", + "153, pituitary {'context': 'I-tissue/organ'}", + "156, in {'context': 'B-in vivo'}", + "157, vivo {'context': 'I-in vivo'}", + "162, transformation {'phenotype': 'B-transformation'}" + ], + "LINK_DATA": [ + "152, rat ['l0', 'l1', 'l2', 'l3', 'l4']", + "153, pituitary ['l0', 'l5', 'l6', 'l7', 'l8']", + "156, in ['l1', 'l5', 'l9', 'l10', 'l11']", + "157, vivo ['l2', 'l6', 'l9', 'l12', 'l13']", + "161, pituitary ['l3', 'l7', 'l10', 'l12', 'l14']", + "162, transformation ['l4', 'l8', 'l11', 'l13', 'l14']", + "201, pituitary ['l15']", + "202, adenomas. ['l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "pituitary" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + } + } + ] + }, + { + "PMID": "10545999", + "TEXT": "The immune system is central in the pathogenesis of scrapie and other transmissible spongiform encephalopathies (TSEs) or 'prion' diseases. After infecting by peripheral (intraperitoneal or oral) routes, most TSE agents replicate in spleen and lymph nodes before neuroinvasion. Characterization of the cells supporting replication in these tissues is essential to understanding early pathogenesis and may indicate potential targets for therapy, for example, in 'new variant' Creutzfeldt-Jakob disease. The host 'prion' protein (PrP) is required for TSE agent replication and accumulates in modified forms in infected tissues. Abnormal PrP is detected readily on follicular dendritic cells (FDCs) in lymphoid tissues of patients with 'new variant' Creutzfeldt-Jakob disease, sheep with natural scrapie and mice experimentally infected with scrapie. The normal protein is present on FDCs in uninfected mice and, at lower levels, on lymphocytes. Studies using severe combined immunodeficiency (SCID) mice, with and without bone marrow (BM) grafts, have indicated involvement of FDCs and/or lymphocytes in scrapie pathogenesis. To clarify the separate roles of FDCs and lymphocytes, we produced chimeric mice with a mismatch in PrP status between FDCs and other cells of the immune system, by grafting bone marrow from PrP-deficient knockout mice into PrP-expressing mice and vice versa. Using these chimeric models, we obtained strong evidence that FDCs themselves produce PrP and that replication of a mouse-passaged scrapie strain in spleen depends on PrP-expressing FDCs rather than on lymphocytes or other bone marrow-derived cells.", + "TAG_DATA": [ + "138, mice, {'context': 'B-organism'}", + "167, chimeric {'context': 'B-organism'}", + "168, mice {'context': 'I-organism'}", + "187, marrow {'context': 'I-cells'}", + "189, PrP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "190, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "191, mice {'context': 'B-organism'}", + "193, PrP-expressing {'context': 'B-cells'}", + "194, mice {'context': 'I-organism'}", + "220, spleen {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "167, chimeric ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "168, mice ['l0', 'l8', 'l9']", + "186, bone ['l1', 'l8', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "187, marrow ['l2', 'l9', 'l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "189, PrP-deficient ['l3', 'l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "190, knockout ['l4', 'l12', 'l18', 'l23', 'l28', 'l29', 'l30', 'l31']", + "191, mice ['l5', 'l13', 'l19', 'l24', 'l28', 'l32', 'l33']", + "193, PrP-expressing ['l6', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "194, mice ['l7', 'l15', 'l21', 'l26', 'l30', 'l33', 'l34', 'l36']", + "220, spleen ['l16', 'l22', 'l27', 'l31', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "chimeric", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PrP-deficient", + "knockout" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "marrow", + "PrP-expressing" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PrP-deficient", + "knockout" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PrP-deficient", + "knockout" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "spleen" + ] + } + } + ] + }, + { + "PMID": "10545995", + "TEXT": "Basal cell carcinomas, the commonest human skin cancers, consistently have abnormalities of the hedgehog signaling pathway and often have PTCH gene mutations. We report here that Ptch+/- mice develop primordial follicular neoplasms resembling human trichoblastomas, and that exposure to ultraviolet radiation or ionizing radiation results in an increase in the number and size of these tumors and a shift in their histologic features so that they more closely resemble human basal cell carcinoma. The mouse basal cell carcinomas and trichoblastoma-like tumors resemble human basal cell carcinomas in their loss of normal hemidesmosomal components, presence of p53 mutations, frequent loss of the normal remaining Ptch allele, and activation of hedgehog target gene transcription. The Ptch mutant mice provide the first mouse model, to our knowledge, of ultraviolet and ionizing radiation-induced basal cell carcinoma-like tumors, and also demonstrate that Ptch inactivation and hedgehog target gene activation are essential for basal cell carcinoma tumorigenesis.", + "TAG_DATA": [ + "26, Ptch+/- {'perturbing_action': 'B-gene loss-of-function'}", + "27, mice {'context': 'B-organism'}", + "31, neoplasms {'phenotype': 'I-tumourigenesis'}", + "113, Ptch {'perturbing_action': 'B-other'}", + "114, mutant {'perturbing_action': 'I-other'}", + "115, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "26, Ptch+/- ['l0', 'l1']", + "27, mice ['l0', 'l2']", + "31, neoplasms ['l1', 'l2']", + "75, basal ['l3', 'l4']", + "76, cell ['l3', 'l5']", + "77, carcinomas ['l4', 'l5']", + "113, Ptch ['l6', 'l7']", + "114, mutant ['l6', 'l8']", + "115, mice ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ptch+/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ptch+/-" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasms" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasms" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Ptch", + "mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "10545983", + "TEXT": "The lymphoid system is known to be involved in the propagation and spread of scrapie. However, the identity of the cell type responsible for scrapie replication remains controversial. A new study provides evidence that the follicular dendritic cells in the spleen are the targets of this infectious form of prion (pages 1308-1312).", + "TAG_DATA": [ + "35, follicular {'context': 'B-cells'}", + "36, dendritic {'context': 'I-cells'}", + "37, cells {'context': 'I-cells'}", + "38, in {'context': 'I-cells'}", + "39, the {'context': 'I-cells'}", + "40, spleen {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "35, follicular ['l0', 'l1', 'l2', 'l3', 'l4']", + "36, dendritic ['l0', 'l5', 'l6', 'l7', 'l8']", + "37, cells ['l1', 'l5', 'l9', 'l10', 'l11']", + "38, in ['l2', 'l6', 'l9', 'l12', 'l13']", + "39, the ['l3', 'l7', 'l10', 'l12', 'l14']", + "40, spleen ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10502821", + "TEXT": "Lymphomas express a tumor-specific antigen which can be targeted by cancer vaccination. We evaluated the ability of a new idiotype protein vaccine formulation to eradicate residual t(14;18)+ lymphoma cells in 20 patients in a homogeneous, chemotherapy-induced first clinical complete remission. All 11 patients with detectable translocations in their primary tumors had cells from the malignant clone detectable in their blood by PCR both at diagnosis and after chemotherapy, despite being in complete remission. However, 8 of 11 patients converted to lacking cells in their blood from the malignant clone detectable by PCR after vaccination and sustained their molecular remissions. Tumor-specific cytotoxic CD8+ and CD4+ T cells were uniformly found (19 of 20 patients), whereas antibodies were detected, but apparently were not required for molecular remission. Vaccination was thus associated with clearance of residual tumor cells from blood and long-term disease-free survival. The demonstration of molecular remissions, analysis of cytotoxic T lymphocytes against autologous tumor targets, and addition of granulocyte-monocyte colony-stimulating factor to the vaccine formulation provide principles relevant to the design of future clinical trials of other cancer vaccines administered in a minimal residual disease setting.", + "TAG_DATA": [ + "48, primary {'context': 'B-neoplasm'}", + "49, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "48, primary ['l0']", + "49, tumors ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10470088", + "TEXT": "APC is often cited as a prime example of a tumor suppressor gene. Truncating germline and somatic mutations (or, infrequently, allelic loss) occur in tumors in FAP (familial adenomatous polyposis). Most sporadic colorectal cancers also have two APC mutations. Clues from attenuated polyposis, missense germline variants with mild disease and the somatic mutation cluster region (codons 1,250-1,450) indicate, however, that APC mutations might not result in simple loss of protein function. We have found that FAP patients with germline APC mutations within a small region (codons 1,194-1,392 at most) mainly show allelic loss in their colorectal adenomas, in contrast to other FAP patients, whose 'second hits' tend to occur by truncating mutations in the mutation cluster region. Our results indicate that different APC mutations provide cells with different selective advantages, with mutations close to codon 1,300 providing the greatest advantage. Allelic loss is selected strongly in cells with one mutation near codon 1,300. A different germline-somatic APC mutation association exists in FAP desmoids. APC is not, therefore, a classical tumor suppressor. Our findings also indicate a new mechanism for disease severity: if a broader spectrum of mutations is selected in tumors, the somatic mutation rate is effectively higher and more tumors grow.", + "TAG_DATA": [ + "95, colorectal {'context': 'B-neoplasm'}", + "96, adenomas, {'context': 'I-neoplasm'}", + "125, cells {'context': 'B-cells'}", + "146, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "95, colorectal ['l0']", + "96, adenomas, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10470084", + "TEXT": "The human parvovirus adeno-associated virus type 2 (AAV2) has many features that make it attractive as a vector for gene therapy. However, the broad host range of AAV2 might represent a limitation for some applications in vivo, because recombinant AAV vector (rAAV)-mediated gene transfer would not be specific for the tissue of interest. This host range is determined by the binding of the AAV2 capsid to specific cellular receptors and/or co-receptors. The tropism of AAV2 might be changed by genetically introducing a ligand peptide into the viral capsid, thereby redirecting the binding of AAV2 to other cellular receptors. We generated six AAV2 capsid mutants by inserting a 14-amino-acid targeting peptide, L14, into six different putative loops of the AAV2 capsid protein identified by comparison with the known three-dimensional structure of canine parvovirus. All mutants were efficiently packaged. Three mutants expressed L14 on the capsid surface, and one efficiently infected wild-type AAV2-resistant cell lines that expressed the integrin receptor recognized by L14. The results demonstrate that the AAV2 capsid tolerates the insertion of a nonviral ligand sequence. This might open new perspectives for the design of targeted AAV2 vectors for human somatic gene therapy.", + "TAG_DATA": [ + "150, AAV2-resistant {'context': 'B-cells'}", + "151, cell {'context': 'I-cells'}", + "152, lines {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "150, AAV2-resistant ['l0', 'l1']", + "151, cell ['l0', 'l2']", + "152, lines ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10470079", + "TEXT": "Type 1 diabetes is an autoimmune disease in which the insulin-producing pancreatic beta cells are destroyed at an early age by an immune process that involves both CD4 and CD8 T lymphocytes. The identification of autoantigens in diabetes is very important for the design of antigen-specific immunotherapy. By screening a pancreatic islet cDNA library, we have identified the autoantigen recognized by highly pathogenic CD8 T cells in the non-obese diabetic mouse, one of the best animal models for human diabetes. This is the first identification, to our knowledge, of a CD8 T-cell epitope in an autoimmune disease. The peptide recognized by the cells is in the same region of the insulin B chain as the epitope recognized by previously isolated pathogenic CD4 T cells. This has very important implications for the potential use of insulin in preventative therapy.", + "TAG_DATA": [ + "68, non-obese {'context': 'B-organism'}", + "69, diabetic {'context': 'I-organism'}", + "70, mouse, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "50, pancreatic ['l0', 'l1', 'l2', 'l3']", + "51, islet ['l0', 'l4', 'l5', 'l6']", + "68, non-obese ['l1', 'l4', 'l7', 'l8']", + "69, diabetic ['l2', 'l5', 'l7', 'l9']", + "70, mouse, ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10470076", + "TEXT": "We assessed the potential for an allogeneic-based vaccine against HIV infection in women who were allo-immunized with their partners' mononuclear leucocytes to prevent spontaneous recurrent abortion. Within 1 month of allo-immunization, there was significant upregulation in the concentrations of CD8 cell-derived suppressor factor activity, RANTES, and macrophage inflammatory proteins 1alpha and 1beta. Allo-immunization also downregulated the proportion of cells with CCR5 and CXCR4 receptors. We also found a dose-dependent decrease in HIV infectivity of CD4+ cells in vitro after allo-immunization with both primary and T-cell line adapted HIV-1. This study provides a rational basis for an alternative or complementary strategy of allo-immunization against HIV infection.", + "TAG_DATA": [ + "58, cells {'context': 'B-cells'}", + "74, CD4+ {'context': 'B-cells'}", + "75, cells {'context': 'I-cells'}", + "76, in {'context': 'B-in vitro'}", + "77, vitro {'context': 'I-in vitro'}", + "82, primary {'context': 'B-cells'}", + "83, and {'context': 'I-cells'}", + "84, T-cell {'context': 'I-cells'}", + "85, line {'context': 'I-cells'}", + "86, adapted {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "74, CD4+ ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "75, cells ['l0', 'l8', 'l9']", + "76, in ['l1', 'l8', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "77, vitro ['l2', 'l9', 'l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "82, primary ['l3', 'l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "83, and ['l4', 'l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "84, T-cell ['l5', 'l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "85, line ['l6', 'l14', 'l19', 'l23', 'l26', 'l28', 'l30']", + "86, adapted ['l7', 'l15', 'l20', 'l24', 'l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10426322", + "TEXT": "In recent years, genetic defects of the mitochondrial genome (mtDNA) were shown to be associated with a heterogeneous group of disorders, known as mitochondrial diseases, but the cellular events deriving from the molecular lesions and the mechanistic basis of the specificity of the syndromes are still incompletely understood. Mitochondrial calcium (Ca2+) homeostasis depends on close contacts with the endoplasmic reticulum and is essential in modulating organelle function. Given the strong dependence of mitochondrial Ca2+ uptake on the membrane potential and the intracellular distribution of the organelle, both of which may be altered in mitochondrial diseases, we investigated the occurrence of defects in mitochondrial Ca2+ handling in living cells with either the tRNALys mutation of MERRF (myoclonic epilepsy with ragged-red fibers) or the ATPase mutation of NARP (neurogenic muscle weakness, ataxia and retinitis pigmentosa). There was a derangement of mitochondrial Ca2+ homeostasis in MERRF, but not in NARP cells, whereas cytosolic Ca2+ responses were normal in both cell types. Treatment of MERRF cells with drugs affecting organellar Ca2+ transport mostly restored both the agonist-dependent mitochondrial Ca2+ uptake and the ensuing stimulation of ATP production. These results emphasize the differences in the cellular pathogenesis of the various mtDNA defects and indicate specific pharmacological approaches to the treatment of some mitochondrial diseases.", + "TAG_DATA": [ + "106, living {'context': 'B-cells'}", + "107, cells {'context': 'I-cells'}", + "111, tRNALys {'perturbing_action': 'B-other'}", + "112, mutation {'perturbing_action': 'I-other'}", + "113, of {'perturbing_action': 'I-other'}", + "114, MERRF {'perturbing_action': 'I-other'}", + "122, ATPase {'perturbing_action': 'B-other'}", + "123, mutation {'perturbing_action': 'I-other'}", + "124, of {'perturbing_action': 'I-other'}", + "146, NARP {'context': 'B-cells'}", + "147, cells, {'context': 'I-cells'}", + "156, cell {'context': 'B-cells'}", + "157, types. {'context': 'I-cells'}", + "160, MERRF {'context': 'B-cells'}", + "161, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "106, living ['l0', 'l1', 'l2', 'l3', 'l4']", + "107, cells ['l0', 'l5', 'l6', 'l7', 'l8']", + "111, tRNALys ['l1', 'l5', 'l9', 'l10', 'l11', 'l12']", + "112, mutation ['l2', 'l6', 'l9', 'l13', 'l14', 'l15', 'l16', 'l17']", + "113, of ['l3', 'l7', 'l10', 'l13', 'l18', 'l19', 'l20']", + "114, MERRF ['l4', 'l8', 'l11', 'l14', 'l18', 'l21', 'l22', 'l23']", + "122, ATPase ['l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "123, mutation ['l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "124, of ['l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "146, NARP ['l15', 'l19', 'l21', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "147, cells, ['l12', 'l16', 'l20', 'l22', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "156, cell ['l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "157, types. ['l17', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "160, MERRF ['l45']", + "161, cells ['l45']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "living", + "cells", + "cells,", + "NARP", + "types.", + "cell" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "tRNALys", + "mutation", + "of", + "MERRF", + "ATPase" + ] + } + } + ] + }, + { + "PMID": "10426318", + "TEXT": "Dendritic cells (DCs) are special subsets of antigen-presenting cells characterized by their highly potent capacity to activate immunologically naive T cells. Here we report that DCs that are transfected with CD95 ligand (CD95L) cDNA, called 'killer' DCs, deliver death signals, instead of activation signals, to T cells after antigen-specific interaction. Injection of antigen-pulsed killer DCs into mice before sensitization induced antigen-specific immunosuppression. When administered after sensitization, killer DCs suppressed immune responses almost completely after subsequent challenge. Thus, killer DCs represent an entirely new immunomodulatory protocol, which may become directly applicable in preventing and even treating T cell-mediated inflammatory diseases.", + "TAG_DATA": [ + "25, DCs {'context': 'B-cells'}", + "28, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "29, with {'perturbing_action': 'I-gene gain-of-function'}", + "30, CD95 {'perturbing_action': 'I-gene gain-of-function'}", + "31, ligand {'perturbing_action': 'I-gene gain-of-function'}", + "32, (CD95L) {'perturbing_action': 'I-gene gain-of-function'}", + "33, cDNA, {'perturbing_action': 'I-gene gain-of-function'}", + "45, T {'context': 'B-cells'}", + "46, cells {'context': 'B-cells'}", + "53, killer {'context': 'B-cells'}", + "54, DCs {'context': 'I-cells'}", + "56, mice {'context': 'B-organism'}", + "66, killer {'context': 'B-cells'}", + "67, DCs {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "25, DCs ['l0', 'l1']", + "28, transfected ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "29, with ['l2', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "30, CD95 ['l3', 'l12', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "31, ligand ['l4', 'l13', 'l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "32, (CD95L) ['l5', 'l14', 'l22', 'l29', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "33, cDNA, ['l6', 'l15', 'l23', 'l30', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "45, T ['l0', 'l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l47', 'l48']", + "46, cells ['l1', 'l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47']", + "53, killer ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l49', 'l50']", + "54, DCs ['l10', 'l19', 'l27', 'l34', 'l40', 'l45', 'l48', 'l49', 'l51']", + "56, mice ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l50', 'l51']", + "66, killer ['l52']", + "67, DCs ['l52']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "CD95", + "ligand", + "(CD95L)", + "cDNA," + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "killer", + "DCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "CD95", + "ligand", + "(CD95L)", + "cDNA," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "10426316", + "TEXT": "We have identified two cell subsets in human blood based on the lack of lineage markers (lin-) and the differential expression of immunoglobulin-like transcript receptor 1 (ILT1) and ILT3. One subset (lin-/ILT3+/ILT1+) is related to myeloid dendritic cells. The other subset (lin-/ILT3+/ILT1+) corresponds to 'plasmacytoid monocytes'. These cells are found in inflamed lymph nodes in and around the high endothelial venules. They express CD62L and CXCR3, and produce extremely large amounts of type I interferon after stimulation with influenza virus or CD40L. These results, with the distinct cell phenotype, indicate that plasmacytoid monocytes represent a specialized cell lineage that enters inflamed lymph nodes at high endothelial venules, where it produces type I interferon. Plasmacytoid monocytes may protect other cells from viral infections and promote survival of antigen-activated T cells.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10395333", + "TEXT": "Graft-versus-host disease (GvHD) is a chief complication of allogeneic bone marrow transplantation. In HLA-identical bone marrow transplantation, GvHD may be induced by disparities in minor histocompatibility antigens (mHags) between the donor and the recipient, with the antigen being present in the recipient and not in the donor. Cytotoxic T lymphocytes (CTLs) specific for mHags of the recipients can be isolated from the blood of recipients with severe GvHD (ref. 3). A retrospective study demonstrated an association between mismatch for mHags HA-1, -2, -4 and -5 and the occurrence of GvHD in adult recipients of bone marrow from HLA genotypically identical donors. Tetrameric HLA-peptide complexes have been used to visualize and quantitate antigen-specific CTLs in HIV-infected individuals and during Epstein-Barr virus and lymphocytic choriomeningitis virus infections. Here we show the direct ex vivo visualization of mHag-specific CTLs during GvHD using tetrameric HLA-class and I-mHag HA-1 and HY peptide complexes. In the peripheral blood of 17 HA-1 or HY mismatched marrow recipients, HA-1- and HY-specific CTLs were detected as early as 14 days after bone marrow transplantation. The tetrameric complexes demonstrated a significant increase in HA-1- and HY-specific CTLs during acute and chronic GvHD, which decreased after successful GvHD treatment. HLA class I-mHag peptide tetramers may serve as clinical tools for the diagnosis and monitoring of GvHD patients.", + "TAG_DATA": [ + "151, blood {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "150, peripheral ['l0']", + "151, blood ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10395331", + "TEXT": "The Bax protein is widely known as a pro-apoptotic Bcl-2 family member that when overexpressed can trigger apoptosis in multiple cell types and is important for the developmental cell death of neurons. However, Bax was found here to be a potent inhibitor of neuronal cell death in mice infected with Sindbis virus. Newborn mice, which are highly susceptible to a fatal infection with neurotropic Sindbis virus, were significantly protected from neuronal apoptosis and fatal disease when infected with a recombinant Sindbis virus encoding Bax. Deletion of the N terminus of Bax, which mimics cleaved Bax, converted Bax into a pro-apoptotic factor in vivo. As mice mature during the first week after birth, they acquire resistance to a fatal Sindbis virus infection. However, Bax-deficient mice remained very sensitive to fatal disease compared with their control littermates, indicating that endogenous Bax functions as a survival factor and contributes to age-dependent resistance to Sindbis virus-induced mortality. The protective effects of Bax were reproduced in cultured hippocampal neurons but not in cultured dorsal root ganglia neurons. These findings indicate that cell-specific factors determine the anti-apoptotic versus pro-apoptotic function of Bax.", + "TAG_DATA": [ + "52, Newborn {'context': 'B-organism'}", + "53, mice, {'context': 'I-organism'}", + "68, protected {'effect': 'B-negative'}", + "71, apoptosis {'phenotype': 'B-apoptosis'}", + "84, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "85, of {'perturbing_action': 'I-gene loss-of-function'}", + "86, the {'perturbing_action': 'I-gene loss-of-function'}", + "87, N {'perturbing_action': 'I-gene loss-of-function'}", + "88, terminus {'perturbing_action': 'I-gene loss-of-function'}", + "89, of {'perturbing_action': 'I-gene loss-of-function'}", + "90, Bax, {'perturbing_action': 'I-gene loss-of-function'}", + "101, in {'context': 'B-in vivo'}", + "102, vivo. {'context': 'I-in vivo'}", + "104, mice {'context': 'B-organism'}", + "122, Bax-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "123, mice {'context': 'B-organism'}", + "162, hippocampal {'context': 'I-cells'}", + "163, neurons {'context': 'I-cells'}", + "167, cultured {'context': 'B-cells'}", + "168, dorsal {'context': 'I-cells'}", + "169, root {'context': 'I-cells'}", + "170, ganglia {'context': 'I-cells'}", + "171, neurons. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "52, Newborn ['l0', 'l1', 'l2']", + "53, mice, ['l0', 'l3', 'l4']", + "68, protected ['l1', 'l3', 'l5']", + "71, apoptosis ['l2', 'l4', 'l5']", + "84, Deletion ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "85, of ['l6', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "86, the ['l7', 'l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "87, N ['l8', 'l16', 'l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "88, terminus ['l9', 'l17', 'l24', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "89, of ['l10', 'l18', 'l25', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "90, Bax, ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l45', 'l46', 'l47']", + "101, in ['l12', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l48', 'l49']", + "102, vivo. ['l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l50']", + "104, mice ['l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l50']", + "122, Bax-deficient ['l51']", + "123, mice ['l51']", + "162, hippocampal ['l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "163, neurons ['l52', 'l58', 'l59', 'l60', 'l61', 'l62']", + "167, cultured ['l53', 'l58', 'l63', 'l64', 'l65', 'l66']", + "168, dorsal ['l54', 'l59', 'l63', 'l67', 'l68', 'l69']", + "169, root ['l55', 'l60', 'l64', 'l67', 'l70', 'l71']", + "170, ganglia ['l56', 'l61', 'l65', 'l68', 'l70', 'l72']", + "171, neurons. ['l57', 'l62', 'l66', 'l69', 'l71', 'l72']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Newborn", + "mice," + ] + }, + "effect": { + "val": "negative", + "words": [ + "protected" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Newborn", + "mice," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "protected" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "N", + "terminus", + "Bax," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "N", + "terminus", + "Bax,", + "Bax-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "10395330", + "TEXT": "Given the associations between chronic inflammation and epithelial cancer, we studied susceptibility to skin carcinogenesis in mice deficient for the pro-inflammatory cytokine TNF-alpha (refs. 5,6). TNF-alpha(-/-) mice were resistant to development of benign and malignant skin tumors, whether induced by initiation with DMBA and promotion with TPA or by repeated dosing with DMBA. TNF-alpha(-/-) mice developed 5-10% the number of tumors developed by wild-type mice during initiation/promotion and 25% of those in wild-type mice after repeated carcinogen treatment. TNF-alpha could influence tumor and stromal cells during tumor development. The early stages of TPA promotion are characterized by keratinocyte hyperproliferation and inflammation. These were diminished in TNF-alpha(-/-) mice. TNF-alpha was extensively induced in the epidermis, but not the dermis, in TPA-treated wild-type skin, indicating that dermal inflammation is controlled by keratinocyte TNF-alpha production. Deletion of a TNF-alpha inducible chemokine also conferred some resistance to skin tumor development. TNF-alpha has little influence on later stages of carcinogenesis, as tumors in wild-type and TNF-alpha(-/-) mice had similar rates of malignant progression. These data provide evidence that a pro-inflammatory cytokine is required for de novo carcinogenesis and that TNF-alpha is important to the early stages of tumor promotion. Strategies that neutralize TNF-alpha production may be useful in cancer treatment and prevention.", + "TAG_DATA": [ + "16, mice {'context': 'B-organism'}", + "17, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "18, for {'perturbing_action': 'I-gene loss-of-function'}", + "25, TNF-alpha(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "26, mice {'context': 'B-organism'}", + "28, resistant {'effect': 'B-negative'}", + "30, development {'phenotype': 'B-tumourigenesis'}", + "32, benign {'phenotype': 'B-tumourigenesis'}", + "33, and {'context': 'I-neoplasm', 'phenotype': 'I-tumourigenesis'}", + "34, malignant {'context': 'I-neoplasm', 'phenotype': 'I-tumourigenesis'}", + "35, skin {'context': 'I-neoplasm'}", + "36, tumors, {'context': 'I-neoplasm', 'phenotype': 'I-tumourigenesis'}", + "38, induced {'effect': 'B-positive'}", + "53, TNF-alpha(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "54, mice {'context': 'B-organism'}", + "60, tumors {'phenotype': 'B-tumourigenesis'}", + "64, mice {'context': 'B-organism'}", + "73, mice {'context': 'B-organism'}", + "81, tumor {'context': 'B-neoplasm'}", + "86, tumor {'phenotype': 'B-tumourigenesis'}", + "87, development. {'phenotype': 'I-tumourigenesis'}", + "105, TNF-alpha(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "106, mice. {'context': 'B-organism'}", + "113, epidermis, {'context': 'B-tissue/organ'}", + "121, skin, {'context': 'B-tissue/organ'}", + "132, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "133, of {'perturbing_action': 'I-gene loss-of-function'}", + "134, a {'perturbing_action': 'I-gene loss-of-function'}", + "135, TNF-alpha {'perturbing_action': 'I-gene loss-of-function'}", + "136, inducible {'perturbing_action': 'I-gene loss-of-function'}", + "137, chemokine {'perturbing_action': 'I-gene loss-of-function'}", + "141, resistance {'effect': 'B-negative'}", + "143, skin {'context': 'B-tissue/organ'}", + "144, tumor {'phenotype': 'B-tumourigenesis'}", + "145, development. {'phenotype': 'I-tumourigenesis'}", + "156, tumors {'context': 'B-neoplasm'}", + "160, TNF-alpha(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "161, mice {'context': 'B-organism'}", + "163, similar {'effect': 'B-no effect'}", + "164, rates {'effect': 'B-negative'}", + "166, malignant {'phenotype': 'B-tumourigenesis'}", + "167, progression. {'phenotype': 'I-tumour progression'}" + ], + "LINK_DATA": [ + "16, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "17, deficient ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "18, for ['l1', 'l16', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "25, TNF-alpha(-/-) ['l2', 'l17', 'l34', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "26, mice ['l3', 'l18', 'l35', 'l52', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "28, resistant ['l4', 'l19', 'l36', 'l53', 'l68', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "29, to ['l5', 'l20', 'l37', 'l54', 'l69', 'l80', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "30, development ['l6', 'l21', 'l38', 'l55', 'l70', 'l81', 'l91', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "32, benign ['l7', 'l22', 'l39', 'l56', 'l71', 'l82', 'l92', 'l101', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "33, and ['l8', 'l23', 'l40', 'l57', 'l72', 'l83', 'l93', 'l102', 'l109', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "34, malignant ['l9', 'l24', 'l41', 'l58', 'l73', 'l84', 'l94', 'l103', 'l110', 'l116', 'l122', 'l123', 'l124', 'l125', 'l126']", + "35, skin ['l10', 'l25', 'l42', 'l59', 'l74', 'l85', 'l95', 'l104', 'l111', 'l117', 'l122', 'l127', 'l128', 'l129']", + "36, tumors, ['l11', 'l26', 'l43', 'l60', 'l75', 'l86', 'l96', 'l105', 'l112', 'l118', 'l123', 'l127', 'l130']", + "38, induced ['l12', 'l27', 'l44', 'l61', 'l76', 'l87', 'l97', 'l106', 'l113', 'l119', 'l124', 'l128', 'l130', 'l131', 'l132']", + "53, TNF-alpha(-/-) ['l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "54, mice ['l133', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "55, developed ['l28', 'l45', 'l62', 'l134', 'l145', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160']", + "60, tumors ['l29', 'l46', 'l63', 'l135', 'l146', 'l155', 'l161', 'l162', 'l163', 'l164', 'l165']", + "64, mice ['l30', 'l47', 'l64', 'l136', 'l147', 'l156', 'l161', 'l166', 'l167', 'l168', 'l169']", + "73, mice ['l48', 'l137', 'l148', 'l157', 'l162', 'l166', 'l170', 'l171', 'l172']", + "81, tumor ['l13', 'l31', 'l49', 'l65', 'l77', 'l88', 'l98', 'l138', 'l149', 'l158', 'l163', 'l167', 'l170', 'l173', 'l174']", + "86, tumor ['l14', 'l32', 'l50', 'l66', 'l78', 'l89', 'l99', 'l107', 'l114', 'l120', 'l125', 'l131', 'l139', 'l150', 'l159', 'l164', 'l168', 'l171', 'l173', 'l175']", + "87, development. ['l15', 'l33', 'l51', 'l67', 'l79', 'l90', 'l100', 'l108', 'l115', 'l121', 'l126', 'l129', 'l132', 'l140', 'l151', 'l160', 'l165', 'l169', 'l172', 'l174', 'l175']", + "105, TNF-alpha(-/-) ['l141', 'l152', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "106, mice. ['l142', 'l153', 'l176', 'l183', 'l184']", + "113, epidermis, ['l143', 'l177', 'l183', 'l185', 'l186', 'l187', 'l188', 'l189']", + "121, skin, ['l144', 'l154', 'l178', 'l184', 'l185', 'l190', 'l191', 'l192', 'l193']", + "132, Deletion ['l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209']", + "133, of ['l194', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224']", + "134, a ['l195', 'l210', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237']", + "135, TNF-alpha ['l196', 'l211', 'l225', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249']", + "136, inducible ['l197', 'l212', 'l226', 'l238', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259']", + "137, chemokine ['l198', 'l213', 'l227', 'l239', 'l250', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266']", + "141, resistance ['l179', 'l186', 'l190', 'l199', 'l214', 'l228', 'l240', 'l251', 'l260', 'l267', 'l268', 'l269']", + "143, skin ['l180', 'l187', 'l191', 'l200', 'l215', 'l229', 'l241', 'l252', 'l261', 'l267', 'l270', 'l271']", + "144, tumor ['l181', 'l188', 'l192', 'l201', 'l216', 'l230', 'l242', 'l253', 'l262', 'l268', 'l270', 'l272']", + "145, development. ['l182', 'l189', 'l193', 'l202', 'l217', 'l231', 'l243', 'l254', 'l263', 'l269', 'l271', 'l272']", + "156, tumors ['l203', 'l218', 'l232', 'l244', 'l255', 'l264', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278']", + "160, TNF-alpha(-/-) ['l204', 'l219', 'l273', 'l279', 'l280', 'l281', 'l282', 'l283']", + "161, mice ['l205', 'l220', 'l233', 'l245', 'l256', 'l274', 'l279', 'l284', 'l285', 'l286', 'l287']", + "163, similar ['l206', 'l221', 'l234', 'l246', 'l257', 'l265', 'l275', 'l280', 'l284', 'l288', 'l289', 'l290']", + "164, rates ['l207', 'l222', 'l235', 'l247', 'l258', 'l266', 'l276', 'l281', 'l285', 'l288', 'l291', 'l292']", + "166, malignant ['l208', 'l223', 'l236', 'l248', 'l277', 'l282', 'l286', 'l289', 'l291', 'l293']", + "167, progression. ['l209', 'l224', 'l237', 'l249', 'l259', 'l278', 'l283', 'l287', 'l290', 'l292', 'l293']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "TNF-alpha(-/-)", + "Deletion", + "of", + "a", + "TNF-alpha", + "inducible" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant", + "rates" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development", + "benign", + "and", + "malignant", + "tumors,", + "tumor", + "development.", + "tumors" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "and", + "malignant", + "tumors,", + "skin", + "tumor", + "tumors" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "and", + "malignant", + "tumors,", + "development", + "benign", + "development.", + "tumors", + "tumor" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "TNF-alpha(-/-)", + "Deletion", + "of", + "a", + "TNF-alpha", + "inducible", + "chemokine" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant", + "resistance", + "rates" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "TNF-alpha(-/-)", + "Deletion", + "of", + "a", + "TNF-alpha", + "inducible", + "chemokine" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development", + "benign", + "and", + "malignant", + "tumors,", + "tumors", + "tumor", + "development." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "TNF-alpha(-/-)", + "Deletion", + "of", + "a", + "TNF-alpha", + "inducible", + "chemokine" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "and", + "malignant", + "skin", + "tumors,", + "tumor", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "TNF-alpha(-/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistant", + "resistance", + "rates" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development", + "benign", + "and", + "malignant", + "tumors,", + "tumor", + "development." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistant", + "rates" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "and", + "malignant", + "skin", + "tumors,", + "tumor", + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development", + "benign", + "and", + "malignant", + "tumors,", + "tumor", + "development." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "and", + "malignant", + "skin", + "tumors," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TNF-alpha(-/-)", + "Deletion", + "of", + "a", + "TNF-alpha", + "inducible", + "chemokine" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "epidermis,", + "skin,", + "skin" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "epidermis,", + "skin,", + "skin" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "epidermis,", + "skin,", + "skin" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "a", + "TNF-alpha", + "inducible", + "chemokine", + "TNF-alpha(-/-)" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "similar" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "a", + "TNF-alpha", + "inducible", + "TNF-alpha(-/-)" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "progression." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "similar" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "progression." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "similar" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "progression." + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "similar" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "malignant" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "similar" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "progression." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "rates" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "progression." + ] + } + } + ] + }, + { + "PMID": "10395327", + "TEXT": "The mitogen-activated protein kinase pathway is thought to be essential in cellular growth and differentiation. Here we report the discovery of a highly potent and selective inhibitor of the upstream kinase MEK that is orally active. Tumor growth was inhibited as much as 80% in mice with colon carcinomas of both mouse and human origin after treatment with this inhibitor. Efficacy was achieved with a wide range of doses with no signs of toxicity, and correlated with a reduction in the levels of activated mitogen-activated protein kinase in excised tumors. These data indicate that MEK inhibitors represent a promising, noncytotoxic approach to the clinical management of colon cancer.", + "TAG_DATA": [ + "36, Tumor {'phenotype': 'B-tumour growth'}", + "37, growth {'phenotype': 'I-tumour growth'}", + "39, inhibited {'effect': 'B-negative'}", + "45, mice {'context': 'B-organism'}", + "47, colon {'context': 'B-neoplasm'}", + "48, carcinomas {'context': 'I-neoplasm'}", + "51, mouse {'context': 'I-neoplasm'}", + "52, and {'context': 'I-neoplasm'}", + "53, human {'context': 'I-neoplasm'}", + "54, origin {'context': 'I-neoplasm'}", + "89, tumors. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "36, Tumor ['l0', 'l1']", + "37, growth ['l0', 'l2']", + "39, inhibited ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "45, mice ['l3', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "47, colon ['l4', 'l12', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "48, carcinomas ['l5', 'l13', 'l20', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "49, of ['l6', 'l14', 'l21', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "50, both ['l7', 'l15', 'l22', 'l28', 'l33', 'l38', 'l39', 'l40', 'l41']", + "51, mouse ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l42', 'l43', 'l44']", + "52, and ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l45', 'l46']", + "53, human ['l10', 'l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l47']", + "54, origin ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "tumour growth", + "words": [ + "Tumor", + "growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "colon", + "carcinomas", + "mouse", + "and", + "human", + "origin" + ] + } + } + ] + }, + { + "PMID": "10395325", + "TEXT": "Heparan sulfate proteoglycans interact with many extracellular matrix constituents, growth factors and enzymes. Degradation of heparan sulfate by endoglycosidic heparanase cleavage affects a variety of biological processes. We have purified a 50-kDa heparanase from human hepatoma and placenta, and now report cloning of the cDNA and gene encoding this enzyme. Expression of the cloned cDNA in insect and mammalian cells yielded 65-kDa and 50-kDa recombinant heparanase proteins. The 50-kDa enzyme represents an N-terminally processed enzyme, at least 100-fold more active than the 65-kDa form. The heparanase mRNA and protein are preferentially expressed in metastatic cell lines and specimens of human breast, colon and liver carcinomas. Low metastatic murine T-lymphoma and melanoma cells transfected with the heparanase cDNA acquired a highly metastatic phenotype in vivo, reflected by a massive liver and lung colonization. This represents the first cloned mammalian heparanase, to our knowledge, and provides direct evidence for its role in tumor metastasis. Cloning of the heparanase gene enables the development of specific molecular probes for early detection and treatment of cancer metastasis and autoimmune disorders.", + "TAG_DATA": [ + "56, insect {'context': 'B-cells'}", + "58, mammalian {'context': 'B-cells'}", + "59, cells {'context': 'I-cells'}", + "105, Low {'context': 'B-neoplasm'}", + "106, metastatic {'context': 'I-neoplasm'}", + "107, murine {'context': 'I-neoplasm'}", + "108, T-lymphoma {'context': 'I-neoplasm'}", + "110, melanoma {'context': 'B-transformed cells'}", + "111, cells {'context': 'I-transformed cells'}", + "112, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "113, with {'perturbing_action': 'I-gene gain-of-function'}", + "114, the {'perturbing_action': 'I-gene gain-of-function'}", + "115, heparanase {'perturbing_action': 'I-gene gain-of-function'}", + "116, cDNA {'perturbing_action': 'I-gene gain-of-function'}", + "120, metastatic {'phenotype': 'B-metastasis'}", + "121, phenotype {'phenotype': 'I-metastasis'}", + "122, in {'context': 'B-in vivo'}", + "123, vivo, {'context': 'I-in vivo'}", + "128, liver {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "56, insect ['l0', 'l1']", + "58, mammalian ['l0', 'l2']", + "59, cells ['l1', 'l2']", + "105, Low ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "106, metastatic ['l3', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "107, murine ['l4', 'l12', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "108, T-lymphoma ['l5', 'l13', 'l20', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "110, melanoma ['l6', 'l14', 'l21', 'l34', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "111, cells ['l7', 'l15', 'l22', 'l35', 'l47', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "112, transfected ['l23', 'l36', 'l48', 'l59', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "113, with ['l24', 'l37', 'l49', 'l60', 'l70', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "114, the ['l25', 'l38', 'l50', 'l61', 'l71', 'l80', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "115, heparanase ['l26', 'l39', 'l51', 'l62', 'l72', 'l81', 'l89', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "116, cDNA ['l27', 'l40', 'l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "120, metastatic ['l8', 'l16', 'l28', 'l41', 'l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l110', 'l111', 'l112', 'l113', 'l114']", + "121, phenotype ['l9', 'l17', 'l29', 'l42', 'l54', 'l65', 'l75', 'l84', 'l92', 'l99', 'l105', 'l110', 'l115', 'l116', 'l117', 'l118']", + "122, in ['l10', 'l18', 'l30', 'l43', 'l55', 'l66', 'l76', 'l85', 'l93', 'l100', 'l106', 'l111', 'l115', 'l119', 'l120', 'l121']", + "123, vivo, ['l11', 'l19', 'l31', 'l44', 'l56', 'l67', 'l77', 'l86', 'l94', 'l101', 'l107', 'l112', 'l116', 'l119', 'l122', 'l123']", + "128, liver ['l32', 'l45', 'l57', 'l68', 'l78', 'l87', 'l95', 'l102', 'l108', 'l113', 'l117', 'l120', 'l122', 'l124']", + "130, lung ['l33', 'l46', 'l58', 'l69', 'l79', 'l88', 'l96', 'l103', 'l109', 'l114', 'l118', 'l121', 'l123', 'l124']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "Low", + "metastatic", + "murine", + "T-lymphoma" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "phenotype" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "murine", + "T-lymphoma" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "the", + "heparanase", + "cDNA" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "the", + "heparanase", + "cDNA" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cells" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "phenotype" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "the", + "heparanase", + "cDNA" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "phenotype" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "the", + "heparanase", + "cDNA" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "the", + "heparanase", + "cDNA" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "phenotype" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "phenotype" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "10395323", + "TEXT": "Tumor antigen-specific T-cell tolerance limits the efficacy of therapeutic cancer vaccines. Antigen-presenting cells mediate the induction of T-cell tolerance to self-antigens. We therefore assessed the fate of tumor-specific CD4+ T cells in tumor-bearing recipients after in vivo activation of antigen-presenting cells with antibodies against CD40. Such treatment not only preserved the responsiveness of this population, but resulted in their endogenous activation. Established tumors regressed in vaccinated mice treated with antibody against CD40 at a time when no response was achieved with vaccination alone. These results indicate that modulation of antigen-presenting cells may be a useful strategy for enhancing responsiveness to immunization.", + "TAG_DATA": [ + "32, tumor-bearing {'context': 'B-organism'}", + "33, recipients {'context': 'I-organism'}", + "35, in {'context': 'B-in vivo'}", + "36, vivo {'context': 'I-in vivo'}", + "39, antigen-presenting {'context': 'B-cells'}", + "40, cells {'context': 'I-cells'}", + "62, tumors {'context': 'B-neoplasm'}", + "63, regressed {'phenotype': 'B-necrosis'}", + "66, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "32, tumor-bearing ['l0']", + "33, recipients ['l0']", + "35, in ['l1', 'l2', 'l3']", + "36, vivo ['l1', 'l4', 'l5']", + "39, antigen-presenting ['l2', 'l4', 'l6']", + "40, cells ['l3', 'l5', 'l6']", + "62, tumors ['l7', 'l8']", + "63, regressed ['l7', 'l9']", + "66, mice ['l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "regressed" + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "regressed" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "10395322", + "TEXT": "The outcome of antigen recognition by naive CD8+ cytotoxic T lymphocytes (CTLs) in the periphery is orchestrated by CD4+ T-helper cells, and can either lead to priming or tolerization. The presence of T-helper cells favors the induction of CTL immunity, whereas the absence of T-helper cells can result in CTL tolerance. The action of T helper cells in CTL priming is mediated by CD40-CD40 ligand interactions. We demonstrate here that triggering of CD40 in vivo can considerably enhance the efficacy of peptide-based anti-tumor vaccines. The combination of a tolerogenic peptide vaccine containing a minimal essential CTL epitope with an activating antibody against CD40 converts tolerization into strong CTL priming. Moreover, CD40 ligation can provide an already protective tumor-specific peptide vaccine with the capacity to induce therapeutic CTL immunity in tumor-bearing mice. These findings indicate that the CD40-CD40 ligand pair can act as a 'switch', determining whether naive peripheral CTLs are primed or tolerized, and support the clinical use of CD40-stimulating agents as components of anti-cancer vaccines.", + "TAG_DATA": [ + "73, in {'context': 'B-in vivo'}", + "74, vivo {'context': 'I-in vivo'}", + "129, tumor-bearing {'context': 'B-organism'}", + "130, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "73, in ['l0']", + "74, vivo ['l0']", + "129, tumor-bearing ['l1']", + "130, mice. ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10395319", + "TEXT": "The inability to deliver growth factors locally in a transient but sustained manner is a substantial barrier to tissue regeneration. Systems capable of localized plasmid gene delivery for prolonged times may offer lower toxicity and should be well-suited for growth factor therapeutics. We investigated the potency of plasmid gene delivery from genes physically entrapped in a polymer matrix (gene activated matrix) using bone regeneration as the endpoint in vivo. Implantation of gene activated matrices at sites of bone injury was associated with retention and expression of plasmid DNA for at least 6 weeks, and with the induction of centimeters of normal new bone in a stable, reproducible, dose- and time-dependent manner.", + "TAG_DATA": [ + "67, in {'context': 'B-in vivo'}", + "68, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "67, in ['l0']", + "68, vivo. ['l0']", + "101, new ['l1']", + "102, bone ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10371511", + "TEXT": "Unmethylated CpG motifs are often found in bacterial DNA, and exert immunostimulatory effects on hematopoietic cells. Bacteria produce severe joint inflammation in septic and reactive arthritides; bacterial DNA may be involved in this process. We injected bacterial DNA originating from Escherichia coli and Staphylococcus aureus and oligonucleotides containing CpG directly into the knee joints of mice of different strains. Arthritis was seen by histopathology within 2 hours and lasted for at least 14 days. Unmethylated CpG motifs were responsible for this induction of arthritis, as oligonucleotides containing these motifs produced the arthritis. The arthritis was characterized by an influx of monocytic, Mac-1+ cells and by a lack of T lymphocytes. Depletion of monocytes resulted in abrogation of the synovial inflammation. Tumor necrosis factor (TNF)-alpha, a cytokine produced by cells of the monocyte/macrophage lineage, is an important mediator of this disease, as expression of mRNA for TNF-alpha was evident in the inflamed joints, and the CpG-mediated inflammation was abrogated in mice genetically unable to produce this cytokine. These findings demonstrate that bacterial DNA containing unmethylated CpG motifs induces arthritis, and indicate an important pathogenic role for bacterial DNA in septic arthritis.", + "TAG_DATA": [ + "55, mice {'context': 'B-organism'}", + "108, T {'context': 'B-cells'}", + "109, lymphocytes. {'context': 'I-cells'}", + "112, monocytes {'context': 'B-cells'}", + "159, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "108, T ['l0', 'l1']", + "109, lymphocytes. ['l0', 'l2']", + "112, monocytes ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10371510", + "TEXT": "Cyclooxygenase (COX) has two isoforms. Generally, COX 1 is constitutively expressed in most tissues, where it maintains physiological processes; inducible COX 2 is considered a pro-inflammatory enzyme and a chief target for the treatment of inflammatory diseases. Here we present evidence that COX 2 may have anti-inflammatory properties. In carrageenin-induced pleurisy in rats, the predominant cells at 2 hours are polymorphonuclear leucocytes, whereas mononuclear cells dominate from 24 hours until resolution at 48 hours. In this model, COX 2 protein expression peaked initially at 2 hours, associated with maximal prostaglandin E2 synthesis. However, at 48 hours there was a second increase in COX 2 expression, 350% greater than that at 2 hours. Paradoxically, this coincided with inflammatory resolution and was associated with minimal prostaglandin E2 synthesis. In contrast, levels of prostaglandin D2, and 15deoxy delta(12-14)prostaglandin J2 were high at 2 hours, decreased as inflammation increased, but were increased again at 48 hours. The selective COX 2 inhibitor NS-398 and the dual COX 1/COX 2 inhibitor indomethacin inhibited inflammation at 2 hours but significantly exacerbated inflammation at 48 hours. This exacerbation was associated with reduced exudate prostaglandin D2 and 15deoxy delta(12-14)prostaglandin J2 concentrations, and was reversed by replacement of these prostaglandins. Thus, COX 2 may be pro-inflammatory during the early phase of a carrageenin-induced pleurisy, dominated by polymorphonuclear leucocytes, but may aid resolution at the later, mononuclear cell-dominated phase by generating an alternative set of anti-inflammatory prostaglandins.", + "TAG_DATA": [ + "153, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "154, COX {'perturbing_action': 'I-pharmacological inhibition'}", + "155, 2 {'perturbing_action': 'I-pharmacological inhibition'}", + "156, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "157, NS-398 {'perturbing_action': 'I-pharmacological inhibition'}", + "160, dual {'perturbing_action': 'B-pharmacological inhibition'}", + "161, COX {'perturbing_action': 'I-pharmacological inhibition'}", + "162, 1/COX {'perturbing_action': 'I-pharmacological inhibition'}", + "163, 2 {'perturbing_action': 'I-pharmacological inhibition'}", + "164, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "165, indomethacin {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "153, selective ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "154, COX ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "155, 2 ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "156, inhibitor ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "157, NS-398 ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "160, dual ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "161, COX ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "162, 1/COX ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "163, 2 ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "164, inhibitor ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "165, indomethacin ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10371508", + "TEXT": "CD154 is the ligand for the receptor CD40. This ligand-receptor pair mediates endothelial and antigen-presenting cell activation, and facilitates the interaction of these cells with T cells and platelets. We demonstrate here that administration of a CD154-specific monoclonal antibody (hu5C8) allows for renal allotransplantation in outbred, MHC-mismatched rhesus monkeys without acute rejection. The effect persisted for more than 10 months after therapy termination, and no additional drug was required to achieve extended graft survival. Indeed, the use of tacrolimus or chronic steroids seemed to antagonize the anti-rejection effect. Monkeys treated with antibody against CD154 remained healthy during and after therapy. The mechanism of action does not require global depletion of T or B cells. Long-term survivors lost their mixed lymphocyte reactivity in a donor-specific manner, but still formed donor-specific antibody and generated T cells that infiltrated the grafted organ without any obvious effect on graft function. Thus, therapy with antibody against CD154 is a promising agent for clinical use in human allotransplantation.", + "TAG_DATA": [ + "45, outbred, {'context': 'B-organism'}", + "47, rhesus {'context': 'B-organism'}", + "48, monkeys {'context': 'I-organism'}", + "88, Monkeys {'context': 'B-organism'}", + "111, or {'context': 'I-cells'}", + "112, B {'context': 'I-cells'}", + "113, cells. {'context': 'I-cells'}", + "132, T {'context': 'B-cells'}", + "133, cells {'context': 'I-cells'}", + "138, organ {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "45, outbred, ['l0', 'l1', 'l2']", + "46, MHC-mismatched ['l0', 'l3', 'l4']", + "47, rhesus ['l1', 'l3', 'l5']", + "48, monkeys ['l2', 'l4', 'l5']", + "88, Monkeys ['l6', 'l7', 'l8', 'l9', 'l10']", + "111, or ['l6', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "112, B ['l7', 'l11', 'l17', 'l18', 'l19', 'l20', 'l21']", + "113, cells. ['l8', 'l12', 'l17', 'l22', 'l23']", + "132, T ['l13', 'l18', 'l24', 'l25', 'l26']", + "133, cells ['l9', 'l14', 'l19', 'l22', 'l24', 'l27', 'l28']", + "138, organ ['l10', 'l15', 'l20', 'l23', 'l25', 'l27', 'l29']", + "144, graft ['l16', 'l21', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10229237", + "TEXT": "Most chronic carriers of hepatitis B virus (HBV) do not respond to interferon (IFN) treatment. This limitation of IFN therapy may be due in part to scant expression of IFN receptor in the liver. Because the asialoglycoprotein (ASGP) receptor is specifically expressed in the liver at high density, the ASGP receptor-binding domain was generated within an N-glycosylated human IFN-beta molecule by the removal of sialic acid to direct this cytokine to the liver. This modified IFN (asialo-IFN-beta) demonstrated greater inhibition of HBV production in ASGP receptor-positive human liver cells transfected with a replication-competent HBV construct than did conventional IFN-alpha or IFN-beta. Furthermore, the enhanced antiviral effect of asialo-IFN-beta was supported by induction of the 2'-5' oligoadenylate synthetase, an indicator of IFN activity, at a level significantly higher than that produced by conventional IFN-beta. Moreover, mouse asialo-IFN-beta profoundly reduced viremia in vivo in HBV-transfected athymic nude mice, in contrast to conventional IFN-beta, which had no substantial effect. These experiments demonstrate that directing IFN to ASGP receptor facilitates its signaling in the liver and augments its antiviral effect, and is therefore useful in overcoming the limited antiviral effect of conventional IFNs.", + "TAG_DATA": [ + "84, ASGP {'context': 'B-cells'}", + "85, receptor-positive {'context': 'I-cells'}", + "86, human {'context': 'I-cells'}", + "87, liver {'context': 'I-cells'}", + "88, cells {'context': 'I-cells'}", + "89, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "90, with {'perturbing_action': 'I-gene gain-of-function'}", + "91, a {'perturbing_action': 'I-gene gain-of-function'}", + "92, replication-competent {'perturbing_action': 'I-gene gain-of-function'}", + "93, HBV {'perturbing_action': 'I-gene gain-of-function'}", + "94, construct {'perturbing_action': 'I-gene gain-of-function'}", + "139, in {'context': 'B-in vivo'}", + "140, vivo {'context': 'I-in vivo'}", + "142, HBV-transfected {'perturbing_action': 'B-gene gain-of-function'}", + "143, athymic {'context': 'B-organism'}", + "144, nude {'context': 'I-organism'}", + "145, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "84, ASGP ['l0', 'l1', 'l2', 'l3', 'l4']", + "85, receptor-positive ['l0', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "86, human ['l1', 'l5', 'l13', 'l14', 'l15']", + "87, liver ['l2', 'l6', 'l13', 'l16']", + "88, cells ['l3', 'l7', 'l14', 'l16']", + "89, transfected ['l4', 'l8', 'l15', 'l17', 'l18', 'l19', 'l20', 'l21']", + "90, with ['l9', 'l17', 'l22', 'l23', 'l24', 'l25']", + "91, a ['l10', 'l18', 'l22', 'l26', 'l27', 'l28']", + "92, replication-competent ['l19', 'l23', 'l26', 'l29', 'l30']", + "93, HBV ['l11', 'l20', 'l24', 'l27', 'l29', 'l31']", + "94, construct ['l12', 'l21', 'l25', 'l28', 'l30', 'l31']", + "139, in ['l32', 'l33', 'l34', 'l35', 'l36']", + "140, vivo ['l32', 'l37', 'l38', 'l39', 'l40']", + "142, HBV-transfected ['l33', 'l37', 'l41', 'l42', 'l43']", + "143, athymic ['l34', 'l38', 'l41', 'l44', 'l45']", + "144, nude ['l35', 'l39', 'l42', 'l44', 'l46']", + "145, mice, ['l36', 'l40', 'l43', 'l45', 'l46']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "ASGP", + "receptor-positive", + "human" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "a", + "HBV", + "construct" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "HBV-transfected" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "HBV-transfected" + ] + }, + "context": { + "val": "organism", + "words": [ + "athymic", + "nude", + "mice," + ] + } + } + ] + }, + { + "PMID": "10229235", + "TEXT": "Variation in epitopes of infectious pathogens inhibits various effector functions of T lymphocytes through antagonism of the T-cell receptor. However, a more powerful strategy for immune evasion would be to prevent the induction of T-cell responses. We report here mutual 'interference' with the priming of human T-cell responses by a pair of naturally occurring variants of a malaria cytotoxic T-cell epitope. Interference with priming also occurs in vivo for a murine malaria T-cell epitope. Reshaping of the T-cell repertoire by such immune interference during naive T-cell induction may provide a general mechanism for observed patterns of immunodominance and persistence by many polymorphic pathogens.", + "TAG_DATA": [ + "45, human {'context': 'B-cells'}", + "46, T-cell {'context': 'I-cells'}", + "66, in {'context': 'B-in vivo'}", + "67, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "45, human ['l0']", + "46, T-cell ['l0']", + "66, in ['l1', 'l2']", + "67, vivo ['l1', 'l3']", + "71, malaria ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10229232", + "TEXT": "CD40 is essential in enabling antigen-presenting cells to process and present antigen effectively to T cells. We demonstrate here that when antibody against CD40 is used to treat mice with syngeneic lymphoma, a rapid cytotoxic T-cell response independent of T-helper cells occurs, with tenfold expansion of CD8+ T cells over a period of 5 days. This response eradicates the lymphoma and provides protection against tumor rechallenge without further antibody treatment. Thus, it seems that by treating mice with monoclonal antibody against CD40, we are immunizing against syngeneic tumors. The phenomenon proved reproducible with two antibodies against CD40 (3/23 and FGK-45) in three CD40+ lymphomas (A20, A31 and BCL1) and gave partial protection in one of two CD40- lymphomas (EL4 and Ten1). Although the nature of the target antigens on these lymphomas is unknown, CD8+ T cells recovered from responding mice showed powerful cytotoxic activity against the target B-cell lymphoma in vitro.", + "TAG_DATA": [ + "39, T-helper {'context': 'B-cells'}", + "40, cells {'context': 'I-cells'}", + "46, CD8+ {'context': 'B-cells'}", + "47, T {'context': 'I-cells'}", + "48, cells {'context': 'I-cells'}", + "59, lymphoma {'context': 'B-neoplasm'}", + "76, mice {'context': 'B-organism'}", + "102, CD40+ {'context': 'B-neoplasm'}", + "103, lymphomas {'context': 'I-neoplasm'}", + "116, CD40- {'context': 'B-neoplasm'}", + "117, lymphomas {'context': 'B-neoplasm'}", + "133, CD8+ {'context': 'B-cells'}", + "134, T {'context': 'I-cells'}", + "135, cells {'context': 'I-cells'}", + "139, mice {'context': 'B-organism'}", + "147, B-cell {'context': 'B-neoplasm'}", + "148, lymphoma {'context': 'I-neoplasm'}", + "149, in {'context': 'B-in vitro'}", + "150, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "39, T-helper ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "40, cells ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "46, CD8+ ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "47, T ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "48, cells ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "59, lymphoma ['l4', 'l9', 'l13', 'l16', 'l18']", + "76, mice ['l5', 'l10', 'l14', 'l17', 'l19']", + "102, CD40+ ['l20']", + "103, lymphomas ['l20']", + "116, CD40- ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "117, lymphomas ['l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "133, CD8+ ['l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "134, T ['l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "135, cells ['l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "139, mice ['l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "147, B-cell ['l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "148, lymphoma ['l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "149, in ['l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "150, vitro. ['l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10229229", + "TEXT": "Eight different protocols were compared for their ability to raise protection against immunodeficiency virus challenges in rhesus macaques. The most promising containment of challenge infections was achieved by intradermal DNA priming followed by recombinant fowl pox virus booster immunizations. This containment did not require neutralizing antibody and was active for a series of challenges ending with a highly virulent virus with a primary isolate envelope heterologous to the immunizing strain.", + "TAG_DATA": [ + "16, rhesus {'context': 'B-organism'}", + "17, macaques. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "16, rhesus ['l0']", + "17, macaques. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10229228", + "TEXT": "The role of HIV-1-specific CD4+ T-cell responses in controlling HIV-1 infection remains unclear. Previous work has suggested that such cells are eliminated in the early stages of infection in most subjects, and thus cannot substantially contribute to host defense against HIV-1. Here, using flow cytometric detection of antigen-induced intracellular cytokines, we show that significant frequencies of gag specific, T-helper-1 CD4+ memory T cells are detectable in most subjects with active/progressive HIV-1 infection (median frequency, 0.12% of memory subset; range, 0-0.66%). Median frequencies of these cells were considerably higher in nonprogressive HIV-1 disease (0.40%), but there was substantial overlap between the two groups (range of nonprogressors, 0.10-1.7%). Continuous HIV-1 suppression with anti-retroviral therapy was associated with a time-dependent reduction in median frequencies of gag-specific CD4+ memory T cells: 0.08% in subjects treated for 4-24 weeks, and 0.03% in subjects treated for 47-112 weeks. Thus, functional HIV-1-specific CD4+ T cells are commonly available for support of anti-HIV-1 effector responses in active disease, but their decline with anti-retroviral therapy indicates that immunologic participation in long-term HIV-1 control will probably require effective vaccination strategies.", + "TAG_DATA": [ + "123, CD4+ {'context': 'B-cells'}", + "124, memory {'context': 'I-cells'}", + "125, T {'context': 'I-cells'}", + "126, cells: {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "123, CD4+ ['l0', 'l1', 'l2']", + "124, memory ['l0', 'l3', 'l4']", + "125, T ['l1', 'l3', 'l5']", + "126, cells: ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10202935", + "TEXT": "Endothelial progenitor cells (EPCs) have been isolated from circulating mononuclear cells in human peripheral blood and shown to be incorporated into foci of neovascularization, consistent with postnatal vasculogenesis. We determined whether endogenous stimuli (tissue ischemia) and exogenous cytokine therapy (granulocyte macrophage-colony stimulating factor, GM-CSF) mobilize EPCs and thereby contribute to neovascularization of ischemic tissues. The development of regional ischemia in both mice and rabbits increased the frequency of circulating EPCs. In mice, the effect of ischemia-induced EPC mobilization was demonstrated by enhanced ocular neovascularization after cornea micropocket surgery in mice with hindlimb ischemia compared with that in non-ischemic control mice. In rabbits with hindlimb ischemia, circulating EPCs were further augmented after pretreatment with GM-CSF, with a corresponding improvement in hindlimb neovascularization. There was direct evidence that EPCs that contributed to enhanced corneal neovascularization were specifically mobilized from the bone marrow in response to ischemia and GM-CSF in mice transplanted with bone marrow from transgenic donors expressing beta-galactosidase transcriptionally regulated by the endothelial cell-specific Tie-2 promoter. These findings indicate that circulating EPCs are mobilized endogenously in response to tissue ischemia or exogenously by cytokine therapy and thereby augment neovascularization of ischemic tissues.", + "TAG_DATA": [ + "61, mice {'context': 'B-organism'}", + "63, rabbits {'context': 'B-organism'}", + "71, mice, {'context': 'B-organism'}", + "89, mice {'context': 'B-organism'}", + "99, mice. {'context': 'B-organism'}", + "101, rabbits {'context': 'B-organism'}", + "106, EPCs {'context': 'I-cells'}", + "147, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "61, mice ['l0', 'l1']", + "63, rabbits ['l0']", + "71, mice, ['l1']", + "89, mice ['l2']", + "99, mice. ['l2']", + "101, rabbits ['l3']", + "106, EPCs ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10202932", + "TEXT": "Ebola virus is very pathogenic in humans. It induces an acute hemorrhagic fever that leads to death in about 70% of patients. We compared the immune responses of patients who died from Ebola virus disease with those who survived during two large outbreaks in 1996 in Gabon. In survivors, early and increasing levels of IgG, directed mainly against the nucleoprotein and the 40-kDa viral protein, were followed by clearance of circulating viral antigen and activation of cytotoxic T cells, which was indicated by the upregulation of FasL, perforin, CD28 and gamma interferon mRNA in peripheral blood mononuclear cells. In contrast, fatal infection was characterized by impaired humoral responses, with absent specific IgG and barely detectable IgM. Early activation of T cells, indicated by mRNA patterns in peripheral blood mononuclear cells and considerable release of gamma interferon in plasma, was followed in the days preceding death by the disappearance of T cell-related mRNA (including CD3 and CD8). DNA fragmentation in blood leukocytes and release of 41/7 nuclear matrix protein in plasma indicated that massive intravascular apoptosis proceeded relentlessly during the last 5 days of life. Thus, events very early in Ebola virus infection determine the control of viral replication and recovery or catastrophic illness and death.", + "TAG_DATA": [ + "119, T {'context': 'B-cells'}", + "120, cells, {'context': 'B-cells'}", + "127, blood {'context': 'I-cells'}", + "128, mononuclear {'context': 'I-cells'}", + "129, cells {'context': 'I-cells'}", + "159, blood {'context': 'B-cells'}", + "160, leukocytes {'context': 'I-cells'}", + "174, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "119, T ['l0', 'l1', 'l2', 'l3']", + "120, cells, ['l0', 'l4', 'l5', 'l6']", + "127, blood ['l1', 'l4', 'l7', 'l8']", + "128, mononuclear ['l2', 'l5', 'l7', 'l9']", + "129, cells ['l3', 'l6', 'l8', 'l9']", + "159, blood ['l10', 'l11']", + "160, leukocytes ['l10', 'l12']", + "174, apoptosis ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "blood", + "leukocytes" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "10202929", + "TEXT": "Cytotoxic T lymphocytes and natural killer cells are essential effectors of anti-tumor immune responses in vivo. Dendritic cells (DC) 'prime' tumor antigen-specific cytotoxic T lymphocytes; thus, we investigated whether DC might also trigger the innate, NK cell-mediated anti-tumor immunity. In mice with MHC class I-negative tumors, adoptively transferred- or Flt3 ligand-expanded DC promoted NK cell-dependent anti-tumor effects. In vitro studies demonstrated a cell-to-cell contact between DC and resting NK cells that resulted in a substantial increase in both NK cell cytolytic activity and IFN-gamma production. Thus, DC are involved in the interaction between innate and adaptive immune responses.", + "TAG_DATA": [ + "40, mice {'context': 'B-organism'}", + "42, MHC {'context': 'B-neoplasm'}", + "43, class {'context': 'B-neoplasm'}", + "45, tumors, {'context': 'B-neoplasm'}", + "51, DC {'context': 'B-cells'}", + "57, In {'context': 'B-in vitro'}", + "58, vitro {'context': 'I-in vitro'}", + "65, DC {'context': 'B-cells'}", + "67, resting {'context': 'B-cells'}", + "68, NK {'context': 'I-cells'}", + "69, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "40, mice ['l0', 'l1', 'l2', 'l3']", + "42, MHC ['l0', 'l4', 'l5', 'l6', 'l7']", + "43, class ['l1', 'l4', 'l8', 'l9', 'l10']", + "44, I-negative ['l2', 'l5', 'l8', 'l11', 'l12']", + "45, tumors, ['l3', 'l6', 'l9', 'l11', 'l13']", + "51, DC ['l7', 'l10', 'l12', 'l13', 'l14']", + "57, In ['l15', 'l16', 'l17', 'l18', 'l19']", + "58, vitro ['l15', 'l20', 'l21', 'l22', 'l23']", + "65, DC ['l16', 'l20', 'l24', 'l25', 'l26']", + "67, resting ['l17', 'l21', 'l24', 'l27', 'l28']", + "68, NK ['l18', 'l22', 'l25', 'l27', 'l29']", + "69, cells ['l14', 'l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10202928", + "TEXT": "The CD8 co-receptor is important in the differentiation and selection of class I MHC-restricted T cells during thymic development, and in the activation of mature T lymphocytes in response to antigen. Here we show that soluble CD8alphaalpha receptor, despite an extremely low affinity for MHC, inhibits activation of cytotoxic lymphocytes by obstructing CD3 zeta-chain phosphorylation. We propose a model for this effect that involves interference of productive receptor multimerization at the T-cell surface. These results provide new insights into the mechanism of T-cell activation and evidence that CD8 function is exquisitely sensitive to disruption, an effect that might be exploited by molecular therapeutics.", + "TAG_DATA": [ + "48, cytotoxic {'context': 'B-cells'}", + "49, lymphocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "48, cytotoxic ['l0']", + "49, lymphocytes ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10086395", + "TEXT": "Mitochondria are particularly vulnerable to oxidative stress, and mitochondrial swelling and vacuolization are among the earliest pathologic features found in two strains of transgenic amyotrophic lateral sclerosis (ALS) mice with SOD1 mutations. Mice with the G93A human SOD1 mutation have altered electron transport enzymes, and expression of the mutant enzyme in vitro results in a loss of mitochondrial membrane potential and elevated cytosolic calcium concentration. Mitochondrial dysfunction may lead to ATP depletion, which may contribute to cell death. If this is true, then buffering intracellular energy levels could exert neuroprotective effects. Creatine kinase and its substrates creatine and phosphocreatine constitute an intricate cellular energy buffering and transport system connecting sites of energy production (mitochondria) with sites of energy consumption, and creatine administration stabilizes the mitochondrial creatine kinase and inhibits opening of the mitochondrial transition pore. We found that oral administration of creatine produced a dose-dependent improvement in motor performance and extended survival in G93A transgenic mice, and it protected mice from loss of both motor neurons and substantia nigra neurons at 120 days of age. Creatine administration protected G93A transgenic mice from increases in biochemical indices of oxidative damage. Therefore, creatine administration may be a new therapeutic strategy for ALS.", + "TAG_DATA": [ + "48, mutant {'perturbing_action': 'I-other'}", + "49, enzyme {'perturbing_action': 'I-other'}", + "153, G93A {'perturbing_action': 'B-gene gain-of-function'}", + "154, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "155, mice, {'context': 'B-organism'}", + "159, mice {'context': 'B-organism'}", + "164, motor {'context': 'B-cells'}", + "165, neurons {'context': 'I-cells'}", + "167, substantia {'context': 'B-cells'}", + "168, nigra {'context': 'I-cells'}", + "169, neurons {'context': 'I-cells'}", + "178, G93A {'perturbing_action': 'B-gene gain-of-function'}", + "179, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "180, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "48, mutant ['l0', 'l1', 'l2', 'l3', 'l4']", + "49, enzyme ['l0', 'l5', 'l6', 'l7']", + "51, vitro ['l1', 'l5', 'l8']", + "153, G93A ['l2', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "154, transgenic ['l3', 'l6', 'l9', 'l16', 'l17']", + "155, mice, ['l4', 'l7', 'l8', 'l10', 'l16']", + "159, mice ['l11', 'l18', 'l19', 'l20', 'l21', 'l22']", + "164, motor ['l12', 'l18', 'l23', 'l24', 'l25', 'l26']", + "165, neurons ['l13', 'l17', 'l19', 'l23', 'l27', 'l28', 'l29']", + "167, substantia ['l20', 'l24', 'l27', 'l30', 'l31']", + "168, nigra ['l14', 'l21', 'l25', 'l28', 'l30', 'l32']", + "169, neurons ['l15', 'l22', 'l26', 'l29', 'l31', 'l32']", + "178, G93A ['l33', 'l34']", + "179, transgenic ['l33', 'l35']", + "180, mice ['l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "enzyme" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "G93A", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "G93A", + "transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "motor", + "neurons", + "nigra" + ] + } + } + ] + }, + { + "PMID": "10086389", + "TEXT": "Enteroviruses such as Coxsackievirus B3 can cause dilated cardiomyopathy, but the mechanism of this pathology is unknown. Mutations in cytoskeletal proteins such as dystrophin cause hereditary dilated cardiomyopathy, but it is unclear if similar mechanisms underlie acquired forms of heart failure. We demonstrate here that purified Coxsackievirus protease 2A cleaves dystrophin in vitro as predicted by computer analysis. Dystrophin is also cleaved during Coxsackievirus infection of cultured myocytes and in infected mouse hearts, leading to impaired dystrophin function. In vivo, dystrophin and the dystrophin-associated glycoproteins alpha-sarcoglycan and beta-dystroglycan are morphologically disrupted in infected myocytes. We suggest a molecular mechanism through which enteroviral infection contributes to the pathogenesis of acquired forms of dilated cardiomyopathy.", + "TAG_DATA": [ + "51, in {'context': 'B-in vitro'}", + "52, vitro {'context': 'I-in vitro'}", + "66, cultured {'context': 'B-cells'}", + "67, myocytes {'context': 'I-cells'}", + "71, mouse {'context': 'B-tissue/organ'}", + "72, hearts, {'context': 'I-tissue/organ'}", + "78, In {'context': 'B-in vivo'}", + "79, vivo, {'context': 'I-in vivo'}", + "93, myocytes. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "51, in ['l0', 'l1', 'l2', 'l3']", + "52, vitro ['l0', 'l4', 'l5', 'l6']", + "66, cultured ['l1', 'l4', 'l7', 'l8', 'l9']", + "67, myocytes ['l2', 'l5', 'l7', 'l10', 'l11']", + "71, mouse ['l8', 'l10', 'l12']", + "72, hearts, ['l3', 'l6', 'l9', 'l11', 'l12']", + "78, In ['l13', 'l14']", + "79, vivo, ['l13', 'l15']", + "93, myocytes. ['l14', 'l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10086388", + "TEXT": "Human type 1 diabetes results from the selective destruction of insulin-producing pancreatic beta cells during islet inflammation. Cytokines and reactive radicals released during this process contribute to beta-cell death. Here we show that mice with a disrupted gene coding for poly (ADP-ribose) polymerase (PARP-/- mice) are completely resistant to the development of diabetes induced by the beta-cell toxin streptozocin. The mice remained normoglycemic and maintained normal levels of total pancreatic insulin content and normal islet ultrastructure. Cultivated PARP-/- islet cells resisted streptozocin-induced lysis and maintained intracellular NAD+ levels. Our results identify NAD+ depletion caused by PARP activation as the dominant metabolic event in islet-cell destruction, and provide information for the development of strategies to prevent the progression or manifestation of the disease in individuals at risk of developing type 1 diabetes.", + "TAG_DATA": [ + "33, mice {'context': 'B-organism'}", + "35, a {'perturbing_action': 'B-gene loss-of-function'}", + "36, disrupted {'perturbing_action': 'B-gene loss-of-function'}", + "37, gene {'perturbing_action': 'I-gene loss-of-function'}", + "38, coding {'perturbing_action': 'I-gene loss-of-function'}", + "39, for {'perturbing_action': 'I-gene loss-of-function'}", + "40, poly {'perturbing_action': 'I-gene loss-of-function'}", + "41, (ADP-ribose) {'perturbing_action': 'I-gene loss-of-function'}", + "42, polymerase {'perturbing_action': 'I-gene loss-of-function'}", + "44, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "60, mice {'context': 'B-organism'}", + "77, PARP-/- {'perturbing_action': 'B-gene loss-of-function'}", + "78, islet {'context': 'B-cells'}", + "79, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "33, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "35, a ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "36, disrupted ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "37, gene ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "38, coding ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "39, for ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "40, poly ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "41, (ADP-ribose) ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "42, polymerase ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "44, mice) ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "60, mice ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "77, PARP-/- ['l55', 'l56']", + "78, islet ['l55', 'l57']", + "79, cells ['l56', 'l57']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "a", + "disrupted", + "gene", + "coding", + "for", + "poly", + "(ADP-ribose)", + "polymerase", + "mice)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PARP-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "islet", + "cells" + ] + } + } + ] + }, + { + "PMID": "10086387", + "TEXT": "In principle, transplantation of mesenchymal progenitor cells would attenuate or possibly correct genetic disorders of bone, cartilage and muscle, but clinical support for this concept is lacking. Here we describe the initial results of allogeneic bone marrow transplantation in three children with osteogenesis imperfecta, a genetic disorder in which osteoblasts produce defective type I collagen, leading to osteopenia, multiple fractures, severe bony deformities and considerably shortened stature. Three months after osteoblast engraftment (1.5-2.0% donor cells), representative specimens of trabecular bone showed histologic changes indicative of new dense bone formation. All patients had increases in total body bone mineral content ranging from 21 to 29 grams (median, 28), compared with predicted values of 0 to 4 grams (median, 0) for healthy children with similar changes in weight. These improvements were associated with increases in growth velocity and reduced frequencies of bone fracture. Thus, allogeneic bone marrow transplantation can lead to engraftment of functional mesenchymal progenitor cells, indicating the feasibility of this strategy in the treatment of osteogenesis imperfecta and perhaps other mesenchymal stem cell disorders as well.", + "TAG_DATA": [ + "40, children {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9930874", + "TEXT": "The beta2 integrin LFA-1 (lymphocyte function associated antigen; CD11a/CD18) is the common ligand for the intercellular adhesion molecules (ICAMs). Integrins support cell function by providing co-stimulatory second signals that are a precondition for full cell activation first described for ICAM-1-binding to LFA-1 in lymphocytes. Integrins can also serve to activate functions associated with distinct subunits of other integrins. In addition to LFA-1, neutrophils express the beta2 integrin Mac-1 (CD11b/CD18; CR3) that apparently contains multiple sites that bind invading microbes directly or through surface-fixed C3, resulting in activation of the phagocyte function. Expression of the LFA-1 counter-receptor ICAM-1 on endothelial cells occurs only at the site of inflammation. Therefore, in neutrophils, ICAM-1 ligand binding could, as with lymphocytes, also play a part as a co-stimulatory signal to induce full phagocytotic function. We show that in neutrophils, the LFA-1 ligand interaction is the stimulatory signal to express full phagocytotic activation. This is best demonstrated by the rapid association of Streptococcus pyogenes with neutrophils, followed by ingestion, strong oxidative-burst induction and enhanced killing of these bacteria, which are well-known for their resistance to human neutrophil defense. These findings may contribute to the development of therapeutic strategies targeting the modulation of ICAM-1-leukocyte interaction.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9930873", + "TEXT": "Liver cirrhosis is the irreversible end result of fibrous scarring and hepatocellular regeneration, characterized by diffuse disorganization of the normal hepatic structure of regenerative nodules and fibrotic tissue. It is associated with prominent morbidity and mortality, and is induced by many factors, including chronic hepatitis virus infections, alcohol drinking and drug abuse. Hepatocyte growth factor (HGF), originally identified and cloned as a potent mitogen for hepatocytes, shows mitogenic, motogenic and morphogenic activities for a wide variety of cells. Moreover, HGF plays an essential part in the development and regeneration of the liver, and shows anti-apoptotic activity in hepatocytes. In a rat model of lethal liver cirrhosis produced by dimethylnitrosamine administrations, repeated transfections of the human HGF gene into skeletal muscles induced a high plasma level of human as well as enodogenous rat HGF, and tyrosine phosphorylation of the c-Met/HGF receptor. Transduction with the HGF gene also suppressed the increase of transforming growth factor-beta1 (TGF-beta1), which plays an essential part in the progression of liver cirrhosis, inhibited fibrogenesis and hepatocyte apoptosis, and produced the complete resolution of fibrosis in the cirrhotic liver, thereby improving the survival rate of rats with this severe illness. Thus, HGF gene therapy may be potentially useful for the treatment of patients with liver cirrhosis, which is otherwise fatal and untreatable by conventional therapy.", + "TAG_DATA": [ + "100, rat {'context': 'B-organism'}", + "101, model {'context': 'I-organism'}", + "111, transfections {'perturbing_action': 'B-gene gain-of-function'}", + "112, of {'perturbing_action': 'I-gene gain-of-function'}", + "113, the {'perturbing_action': 'I-gene gain-of-function'}", + "114, human {'perturbing_action': 'I-gene gain-of-function'}", + "115, HGF {'perturbing_action': 'I-gene gain-of-function'}", + "116, gene {'perturbing_action': 'I-gene gain-of-function'}", + "118, skeletal {'context': 'B-tissue/organ'}", + "119, muscles {'context': 'I-tissue/organ'}", + "140, Transduction {'perturbing_action': 'B-gene gain-of-function'}", + "141, with {'perturbing_action': 'I-gene gain-of-function'}", + "142, the {'perturbing_action': 'I-gene gain-of-function'}", + "143, HGF {'perturbing_action': 'I-gene gain-of-function'}", + "144, gene {'perturbing_action': 'I-gene gain-of-function'}", + "165, inhibited {'effect': 'B-negative'}", + "168, hepatocyte {'context': 'B-cells'}", + "169, apoptosis, {'phenotype': 'B-apoptosis'}", + "180, liver, {'context': 'I-tissue/organ'}", + "187, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "100, rat ['l0', 'l1', 'l2', 'l3', 'l4']", + "101, model ['l0', 'l5', 'l6', 'l7']", + "111, transfections ['l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "112, of ['l8', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "113, the ['l9', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "114, human ['l1', 'l10', 'l18', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "115, HGF ['l2', 'l5', 'l11', 'l19', 'l26', 'l33', 'l39', 'l40', 'l41', 'l42']", + "116, gene ['l12', 'l20', 'l27', 'l34', 'l39', 'l43', 'l44', 'l45']", + "118, skeletal ['l3', 'l6', 'l13', 'l21', 'l28', 'l35', 'l40', 'l43', 'l46']", + "119, muscles ['l4', 'l7', 'l14', 'l22', 'l29', 'l36', 'l41', 'l44', 'l46']", + "140, Transduction ['l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "141, with ['l47', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "142, the ['l48', 'l56', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "143, HGF ['l49', 'l57', 'l65', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "144, gene ['l50', 'l58', 'l66', 'l72', 'l78', 'l79', 'l80', 'l81', 'l82']", + "165, inhibited ['l15', 'l23', 'l30', 'l37', 'l42', 'l45', 'l51', 'l59', 'l67', 'l73', 'l78', 'l83', 'l84', 'l85']", + "168, hepatocyte ['l31', 'l52', 'l60', 'l68', 'l74', 'l79', 'l83', 'l86', 'l87']", + "169, apoptosis, ['l16', 'l24', 'l32', 'l38', 'l53', 'l61', 'l69', 'l75', 'l80', 'l84', 'l86', 'l88']", + "179, cirrhotic ['l54', 'l62', 'l70', 'l76', 'l81', 'l89', 'l90']", + "180, liver, ['l55', 'l63', 'l71', 'l77', 'l82', 'l85', 'l87', 'l88', 'l89']", + "187, rats ['l64', 'l90']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "rat", + "model", + "rats" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "human", + "HGF", + "with" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfections", + "of", + "the", + "human", + "HGF", + "gene", + "Transduction", + "with" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skeletal", + "muscles", + "liver," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfections", + "of", + "the", + "human", + "HGF", + "gene", + "Transduction", + "with" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfections", + "of", + "the", + "human", + "Transduction", + "with", + "HGF", + "gene" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "the", + "Transduction", + "with", + "HGF", + "gene" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocyte" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocyte" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hepatocyte" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver," + ] + } + } + ] + }, + { + "PMID": "9930870", + "TEXT": "The concentration of human immunodeficiency virus type 1 (HIV-1) particles in blood plasma is very predictive of the subsequent disease course in an infected individual; its measurement has become one of the most important parameters for monitoring clinical status. Steady-state virus levels in plasma reflect a balance between the rates of virions entering and leaving the peripheral blood. We analyzed the rate of virus clearance in the general circulation in rhesus macaques receiving a continuous infusion of cell-free particles in the presence and absence of virus-specific antibodies. Here we show, by measuring virion RNA, particle-associated p24 Gag protein and virus infectivity, that the clearance of physical and infectious particles from a primary, dual-tropic virus isolate, HIV-1DH12, is very rapid in naive animals, with half-lives ranging from 13 to 26 minutes. In the presence of high-titer HIV-1DH12-specific neutralizing antibodies, the half-life of virion RNA was considerably reduced (to 3.9-7.2 minutes), and infectious virus in the blood became undetectable. Although physical virus particles were eliminated extravascularly, the loss of virus infectivity in the blood reflected the combined effects of extravascular clearance and intravascular inactivation of HIV-1 infectivity due to antibody binding.", + "TAG_DATA": [ + "70, rhesus {'context': 'B-organism'}", + "71, macaques {'context': 'I-organism'}", + "121, animals, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "70, rhesus ['l0']", + "71, macaques ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9930865", + "TEXT": "Closure of the ductus arteriosus requires prenatal formation of intimal cushions, which occlude the vessel lumen at birth. Survival of newborns with severe congenital heart defects, however, depends on ductal patency. We used a gene transfer approach to create a patent ductus arteriosus by targeting the fibronectin-dependent smooth muscle cell migration required for intimal cushion formation. Fetal lamb ductus arteriosus was transfected in utero with hemagglutinating virus of Japan liposomes containing plasmid encoding 'decoy' RNA to sequester the fibronectin mRNA binding protein. Fibronectin translation was inhibited and intimal cushion formation was prevented. We thus established the essential role of fibronectin-dependent smooth muscle cell migration in intimal cushion formation in the intact animal and the feasibility of incorporating biological engineering in the management of congenital heart disease.", + "TAG_DATA": [ + "47, smooth {'context': 'B-cells'}", + "48, muscle {'context': 'I-cells'}", + "49, cell {'context': 'I-cells'}", + "56, Fetal {'context': 'B-organism'}", + "57, lamb {'context': 'I-organism'}", + "58, ductus {'context': 'I-tissue/organ'}", + "59, arteriosus {'context': 'I-tissue/organ'}", + "61, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "62, in {'context': 'B-in vivo'}", + "63, utero {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "47, smooth ['l0', 'l1', 'l2', 'l3']", + "48, muscle ['l0', 'l4', 'l5', 'l6']", + "49, cell ['l1', 'l4']", + "56, Fetal ['l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "57, lamb ['l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "58, ductus ['l2', 'l5', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "59, arteriosus ['l3', 'l6', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "61, transfected ['l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "62, in ['l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "63, utero ['l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Fetal", + "lamb" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "ductus", + "arteriosus" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "utero" + ] + } + } + ] + }, + { + "PMID": "9883848", + "TEXT": "Severe thrombocytopenia frequently occurs in patients receiving chemotherapy and in patients with autoimmune disorders. Thrombocytopenia is associated with bleeding, which may be serious and life threatening. Current treatment strategies for thrombocytopenia may require transfusion of allogeneic platelets, which is associated with serious drawbacks. These include the occurrence of anti-platelet antibodies, which may result in refractoriness to further platelet transfusions, and the potential risk of transfer of blood-borne diseases. Therefore, we have recently developed a platelet substitute product (Synthocytes), which is composed of human albumin microcapsules with fibrinogen immobilized on their surface. Here we show that the intravenous administration of these microcapsules not only corrects the prolonged bleeding time in rabbits rendered thrombocytopenic either by anti-platelet antibodies or by chemotherapy, but also reduces bleeding from surgical wounds inflicted in the abdominal skin and musculature. No potential systemic prothrombotic effect of the microcapsules was observed in a model of rabbit venous thrombosis. As for the mechanism of action, experiments with normal and thrombocytopenic human blood in an endothelial cell matrix-coated perfusion chamber demonstrated an interaction between the fibrinogen-coated albumin microcapsules and native platelets. It was shown that the fibrinogen-coated albumin microcapsules could facilitate platelet adhesion to endothelial cell matrix and correct the impaired formation of platelet aggregates in relatively platelet-poor blood. This study indicates that fibrinogen-coated albumin microcapsules can act to improve primary hemostasis under thrombocytopenic conditions and may eventually be a promising agent for prophylaxis and treatment of bleeding in patients with severe thrombocytopenia.", + "TAG_DATA": [ + "109, rabbits {'context': 'B-organism'}", + "147, rabbit {'context': 'B-tissue/organ'}", + "165, endothelial {'context': 'B-cells'}", + "166, cell {'context': 'I-cells'}", + "180, platelets. {'context': 'B-cells'}", + "191, platelet {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "147, rabbit ['l0']", + "165, endothelial ['l1', 'l2']", + "166, cell ['l0', 'l1', 'l3']", + "180, platelets. ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9883846", + "TEXT": "Transplantation of embryonic nigral tissue ameliorates functional deficiencies in Parkinson disease. The main practical constraints of neural grafting are the shortage of human donor tissue and the poor survival of dopaminergic neurons grafted into patients, which is estimated at 5-10% (refs. 3,4). The required amount of human tissue could be considerably reduced if the neuronal survival was augmented. Studies in rats indicate that most implanted embryonic neurons die within 1 week of transplantation, and that most of this cell death is apoptotic. Modified peptides, such as acetyl-tyrosinyl-valyl-alanyl-aspartyl-chloro-methylketone (Ac-YVAD-cmk), that specifically inhibit proteases of the caspase family effectively block apoptosis in a plethora of experimental paradigms, such as growth factor withdrawal, excitotoxicity, axotomy, cerebral ischemia and brain trauma. Here we examined the effects of caspase inhibition by Ac-YVAD-cmk on cell death immediately after donor tissue preparation and on long-term graft survival. Treatment of the embryonic nigral cell suspension with Ac-YVAD-cmk mitigated DNA fragmentation and reduced apoptosis in transplants. It also increased survival of dopaminergic neurons grafted to hemiparkinsonian rats, and thereby substantially improved functional recovery.", + "TAG_DATA": [ + "97, block {'effect': 'B-negative'}", + "98, apoptosis {'phenotype': 'B-apoptosis'}", + "128, cell {'phenotype': 'B-cell death'}", + "129, death {'phenotype': 'I-cell death'}", + "143, embryonic {'context': 'B-cells'}", + "144, nigral {'context': 'I-cells'}", + "145, cell {'context': 'I-cells'}", + "146, suspension {'context': 'I-cells'}", + "153, reduced {'effect': 'B-negative'}", + "154, apoptosis {'phenotype': 'B-apoptosis'}", + "156, transplants. {'context': 'B-organoid'}", + "162, dopaminergic {'context': 'B-cells'}", + "163, neurons {'context': 'I-cells'}", + "166, hemiparkinsonian {'context': 'B-organism'}", + "167, rats, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "97, block ['l0', 'l1', 'l2']", + "98, apoptosis ['l0', 'l3', 'l4']", + "128, cell ['l1', 'l3', 'l5']", + "129, death ['l2', 'l4', 'l5']", + "143, embryonic ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "144, nigral ['l6', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "145, cell ['l7', 'l16', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "146, suspension ['l8', 'l17', 'l23', 'l29', 'l30', 'l31', 'l32', 'l33']", + "153, reduced ['l9', 'l18', 'l24', 'l29', 'l34', 'l35']", + "154, apoptosis ['l10', 'l19', 'l25', 'l30', 'l34', 'l36']", + "156, transplants. ['l11', 'l20', 'l26', 'l31', 'l35', 'l36']", + "162, dopaminergic ['l12', 'l37', 'l38', 'l39']", + "163, neurons ['l13', 'l21', 'l27', 'l32', 'l37', 'l40', 'l41']", + "166, hemiparkinsonian ['l14', 'l38', 'l40', 'l42']", + "167, rats, ['l15', 'l22', 'l28', 'l33', 'l39', 'l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "block", + "reduced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "block" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "embryonic", + "nigral", + "cell", + "suspension" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "embryonic", + "nigral", + "cell", + "suspension" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "organoid", + "words": [ + "transplants." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "organoid", + "words": [ + "transplants." + ] + } + } + ] + }, + { + "PMID": "9883840", + "TEXT": "Hemophilia B is a severe X-linked bleeding diathesis caused by the absence of functional blood coagulation factor IX, and is an excellent candidate for treatment of a genetic disease by gene therapy. Using an adeno-associated viral vector, we demonstrate sustained expression (>17 months) of factor IX in a large-animal model at levels that would have a therapeutic effect in humans (up to 70 ng/ml, adequate to achieve phenotypic correction, in an animal injected with 8.5x10(12) vector particles/kg). The five hemophilia B dogs treated showed stable, vector dose-dependent partial correction of the whole blood clotting time and, at higher doses, of the activated partial thromboplastin time. In contrast to other viral gene delivery systems, this minimally invasive procedure, consisting of a series of percutaneous intramuscular injections at a single timepoint, was not associated with local or systemic toxicity. Efficient gene transfer to muscle was shown by immunofluorescence staining and DNA analysis of biopsied tissue. Immune responses against factor IX were either absent or transient. These data provide strong support for the feasibility of the approach for therapy of human subjects.", + "TAG_DATA": [ + "48, large-animal {'context': 'B-organism'}", + "49, model {'context': 'I-organism'}", + "71, animal {'context': 'B-organism'}", + "79, hemophilia {'context': 'B-organism'}", + "80, B {'context': 'I-organism'}", + "81, dogs {'context': 'I-organism'}", + "141, muscle {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "48, large-animal ['l0']", + "49, model ['l0']", + "71, animal ['l1', 'l2', 'l3']", + "79, hemophilia ['l1', 'l4', 'l5']", + "80, B ['l2', 'l4', 'l6']", + "81, dogs ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9846585", + "TEXT": "Live virus vaccines have in many cases proven to be an extremely effective tool for the prevention of viral diseases. However, the production of conventional live vaccines in eukaryotic cell cultures has many disadvantages, including the potential for contamination with adventitious agents and genetic alterations during propagation, making it necessary to do extensive testing before distribution. Based on results obtained with a flavivirus (tick-borne encephalitis virus) in an experimental animal system, we propose a novel live attenuated virus vaccination strategy consisting of the application of in vitro-synthesized infectious RNA instead of the live virus itself. When administered using the GeneGun, less than 1 ng of RNA was required to initiate replication of virus that was attenuated by a specifically engineered deletion and this induced a protective immunity in laboratory mice. Because this approach uses RNA, it does not have the potential drawbacks of DNA vaccines and thus combines the advantages of conventional live virus vaccines (for example, mimicking natural infection and inducing long-lasting immunity) with those of nucleic acid-based vaccines (for example, ease of production without a requirement for eukaryotic cell culture, stability and purity).", + "TAG_DATA": [ + "128, laboratory {'context': 'B-organism'}", + "129, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "128, laboratory ['l0']", + "129, mice. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9846581", + "TEXT": "Although perinatal mortality rates have improved for pregnant diabetic women because of insulin therapy and tight metabolic control, infants of diabetics still experience significantly higher rates of congenital malformations and spontaneous miscarriages compared with those of non-diabetic women. Our results here indicate that hyperglycemic conditions, either in vivo or in vitro, modulate the expression of an apoptosis regulatory gene as early as the pre-implantation blastocyst stage in the mouse. Apoptosis in the mammalian pre-implantation blastocyst is a normal process, thought to protect the early embryo by eliminating abnormal cells. Here we demonstrate that expression of Bax, a Bcl-2-like protein, is increased at the blastocyst stage in the presence of high concentrations of glucose, and that these changes correlate morphologically with increased DNA fragmentation. Expression of Bax and caspase are necessary for this in vitro glucose-induced apoptotic event, and ceramide is involved in mediating this embryotoxic effect of glucose. We also show that these apoptotic cellular changes can be prevented in vivo by treating hyperglycemic mice with insulin before and immediately after conception. These findings emphasize the importance of tight glycemic control in diabetic women at the earliest stages after conception.", + "TAG_DATA": [ + "132, in {'context': 'B-in vitro'}", + "133, vitro {'context': 'I-in vitro'}", + "134, glucose-induced {'effect': 'B-positive'}", + "135, apoptotic {'phenotype': 'B-apoptosis'}", + "136, event, {'phenotype': 'I-apoptosis'}", + "159, in {'context': 'B-in vivo'}", + "160, vivo {'context': 'I-in vivo'}", + "164, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "132, in ['l0', 'l1', 'l2', 'l3']", + "133, vitro ['l0', 'l4', 'l5', 'l6']", + "134, glucose-induced ['l1', 'l4', 'l7', 'l8']", + "135, apoptotic ['l2', 'l5', 'l7', 'l9']", + "136, event, ['l3', 'l6', 'l8', 'l9']", + "159, in ['l10', 'l11']", + "160, vivo ['l10', 'l12']", + "164, mice ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "glucose-induced" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "event," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "glucose-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "event," + ] + } + } + ] + }, + { + "PMID": "9809561", + "TEXT": "Positron emission tomography (PET) is now regularly used in the diagnosis and staging of cancer. These uses and its ability to monitor treatment response would be aided by the development of imaging agents that can be used to measure tissue and tumor proliferation. We have developed and tested [F-18]FLT (3'-deoxy-3'-fluorothymidine); it is resistant to degradation, is retained in proliferating tissues by the action of thymidine kinase 1 (TK), and produces high-contrast images of normal marrow and tumors in canine and human subjects.", + "TAG_DATA": [ + "74, marrow {'context': 'I-tissue/organ'}", + "76, tumors {'context': 'B-neoplasm'}", + "78, canine {'context': 'B-organism'}", + "79, and {'context': 'I-organism'}", + "80, human {'context': 'I-organism'}", + "81, subjects. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "73, normal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "74, marrow ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "76, tumors ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "78, canine ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "79, and ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "80, human ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "81, subjects. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9809560", + "TEXT": "The present study describes a technique for quantitation of mRNA in a few isotypic cells obtained from an intact organ structure by combining laser-assisted cell picking and real-time PCR. The microscopically controlled lasering of selected cells in stained tissue sections was applied to lung alveolar macrophages, which are unique in that they can alternatively be gathered as a pure cell population from intact lungs by bronchoalveolar lavage as a reference technique. TNF-alpha was chosen as the transcriptionally inducible target gene to be quantified in alveolar macrophages of control rat lung, as well as low- and high-challenge lungs stimulated by endotoxin and IFN-gamma nebulization. Online fluorescence detection for quantitation of the number of amplified copies was based on 5' nuclease activity of Taq polymerase cleaving a sequence-specific dual-labeled fluorogenic hybridization probe. A pseudogene-free sequence of PBGD served as an internal calibrator for comparative quantitation of target. A quick procedure and minimized loss of template were achieved by avoiding RNA extraction, DNase digestion and nested-PCR. Using this approach, we demonstrated dose-dependent manifold upregulation of the ratio of TNF-alpha mRNA copies per one copy of PBGD mRNA in alveolar macrophages of the challenged lungs. The quantitative data obtained from laser-picked alveolar macrophages were well matched with those of lavaged alveolar macrophages carried out in parallel. We suggest that this new combination of laser-assisted cell picking and real-time PCR has great promise for quantifying mRNA expression in a few single cells or oligocellular clusters in intact organs, allowing assessment of transcriptional regulation in defined cell populations.", + "TAG_DATA": [ + "84, alveolar {'context': 'B-cells'}", + "85, macrophages {'context': 'I-cells'}", + "88, rat {'context': 'B-tissue/organ'}", + "89, lung, {'context': 'I-tissue/organ'}", + "96, lungs {'context': 'B-tissue/organ'}", + "185, alveolar {'context': 'B-cells'}", + "186, macrophages {'context': 'I-cells'}", + "190, lungs. {'context': 'B-tissue/organ'}", + "197, alveolar {'context': 'B-cells'}", + "198, macrophages {'context': 'I-cells'}", + "206, alveolar {'context': 'B-cells'}", + "207, macrophages {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "84, alveolar ['l0', 'l1', 'l2', 'l3']", + "85, macrophages ['l0', 'l4', 'l5', 'l6']", + "88, rat ['l1', 'l4', 'l7', 'l8']", + "89, lung, ['l2', 'l5', 'l7', 'l9']", + "96, lungs ['l3', 'l6', 'l8', 'l9']", + "185, alveolar ['l10', 'l11']", + "186, macrophages ['l10', 'l12']", + "190, lungs. ['l11', 'l12']", + "197, alveolar ['l13', 'l14', 'l15']", + "198, macrophages ['l13', 'l16', 'l17']", + "206, alveolar ['l14', 'l16', 'l18']", + "207, macrophages ['l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9771754", + "TEXT": "Hepatocyte transplantation might represent a potential therapeutic alternative to liver transplantation in the future; however, transplanted cells have a limited capacity to repopulate the liver, as they do not proliferate under normal conditions. Recently, studies in urokinase (uPA) transgenic mice and in fumarylacetoacetate hydrolase (FAH)-deficient mice have shown that the liver can be repopulated by genetically engineered hepatocytes harboring a selective advantage over resident hepatocytes. We have reported that transgenic mice expressing human Bcl-2 in their hepatocytes are protected from Fas/CD95-mediated liver apoptosis. We now show that Bcl-2 transplanted hepatocytes selectively repopulate the liver of mice treated with nonlethal doses of the anti-Fas antibody Jo2. FK 506 immunosuppressed mice were transplanted by splenic injection with Bcl-2 hepatocytes. The livers of female recipients were repopulated by male Bcl-2 transgenic hepatocytes, as much as 16%, after 8 to 12 administrations of Jo2. This only occurred after anti-Fas treatment, confirming that resistance to Fas-induced apoptosis constituted the selective advantage of these transplanted hepatocytes. Thus, we have demonstrated a method for increasing genetic reconstitution of the liver through selective repopulation with modified transgenic hepatocytes, which will allow optimization of cell and gene therapy in the liver.", + "TAG_DATA": [ + "36, urokinase {'perturbing_action': 'B-gene gain-of-function'}", + "38, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "39, mice {'context': 'B-organism'}", + "42, fumarylacetoacetate {'perturbing_action': 'B-gene loss-of-function'}", + "43, hydrolase {'perturbing_action': 'I-gene loss-of-function'}", + "44, (FAH)-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "45, mice {'context': 'B-organism'}", + "69, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "70, mice {'context': 'I-organism'}", + "71, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "72, human {'perturbing_action': 'I-gene gain-of-function'}", + "73, Bcl-2 {'perturbing_action': 'I-gene gain-of-function'}", + "76, hepatocytes {'context': 'B-cells'}", + "78, protected {'effect': 'B-negative'}", + "87, Bcl-2 {'perturbing_action': 'B-gene gain-of-function'}", + "88, transplanted {'perturbing_action': 'I-gene gain-of-function'}", + "89, hepatocytes {'context': 'B-cells'}", + "93, liver {'context': 'B-tissue/organ'}", + "95, mice {'context': 'B-organism'}", + "108, mice {'context': 'B-organism'}", + "118, livers {'context': 'B-tissue/organ'}", + "120, female {'context': 'B-organism'}", + "121, recipients {'context': 'I-organism'}", + "125, male {'perturbing_action': 'B-gene gain-of-function'}", + "126, Bcl-2 {'perturbing_action': 'I-gene gain-of-function'}", + "127, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "128, hepatocytes, {'context': 'I-cells'}", + "148, resistance {'effect': 'B-negative'}", + "150, Fas-induced {'effect': 'B-positive'}", + "151, apoptosis {'phenotype': 'B-apoptosis'}", + "159, hepatocytes. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "36, urokinase ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "38, transgenic ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "39, mice ['l1', 'l15', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "42, fumarylacetoacetate ['l2', 'l16', 'l28', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "43, hydrolase ['l3', 'l17', 'l29', 'l40', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "44, (FAH)-deficient ['l4', 'l18', 'l30', 'l41', 'l55', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "45, mice ['l5', 'l19', 'l31', 'l42', 'l56', 'l69', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "69, transgenic ['l6', 'l20', 'l32', 'l43', 'l57', 'l70', 'l82', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "70, mice ['l7', 'l21', 'l33', 'l44', 'l58', 'l71', 'l83', 'l92', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "71, expressing ['l8', 'l22', 'l34', 'l45', 'l59', 'l72', 'l84', 'l93', 'l101', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "72, human ['l9', 'l23', 'l35', 'l46', 'l60', 'l73', 'l85', 'l94', 'l102', 'l108', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "73, Bcl-2 ['l10', 'l24', 'l36', 'l47', 'l61', 'l74', 'l86', 'l95', 'l103', 'l109', 'l117', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "76, hepatocytes ['l11', 'l25', 'l37', 'l48', 'l62', 'l75', 'l87', 'l96', 'l104', 'l110', 'l118', 'l125', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "78, protected ['l12', 'l26', 'l38', 'l49', 'l63', 'l76', 'l88', 'l97', 'l105', 'l111', 'l119', 'l126', 'l132', 'l138']", + "87, Bcl-2 ['l50', 'l64', 'l77', 'l112', 'l120', 'l127', 'l133', 'l139', 'l140', 'l141', 'l142']", + "88, transplanted ['l51', 'l65', 'l78', 'l89', 'l98', 'l113', 'l121', 'l128', 'l134', 'l139', 'l143', 'l144', 'l145']", + "89, hepatocytes ['l13', 'l27', 'l39', 'l52', 'l66', 'l79', 'l90', 'l99', 'l106', 'l114', 'l122', 'l129', 'l135', 'l138', 'l140', 'l143', 'l146', 'l147']", + "93, liver ['l14', 'l53', 'l67', 'l80', 'l91', 'l100', 'l107', 'l115', 'l123', 'l130', 'l136', 'l141', 'l144', 'l146', 'l148']", + "95, mice ['l54', 'l68', 'l81', 'l116', 'l124', 'l131', 'l137', 'l142', 'l145', 'l147', 'l148']", + "118, livers ['l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "120, female ['l149', 'l155', 'l156', 'l157', 'l158', 'l159']", + "121, recipients ['l150', 'l155', 'l160', 'l161', 'l162', 'l163']", + "125, male ['l151', 'l156', 'l160', 'l164', 'l165', 'l166', 'l167', 'l168']", + "126, Bcl-2 ['l152', 'l157', 'l161', 'l164', 'l169', 'l170', 'l171', 'l172', 'l173']", + "127, transgenic ['l153', 'l158', 'l162', 'l165', 'l169', 'l174', 'l175']", + "128, hepatocytes, ['l154', 'l159', 'l163', 'l166', 'l170', 'l174', 'l176', 'l177']", + "148, resistance ['l167', 'l171', 'l176', 'l178', 'l179', 'l180']", + "150, Fas-induced ['l172', 'l178', 'l181', 'l182']", + "151, apoptosis ['l168', 'l173', 'l175', 'l177', 'l179', 'l181', 'l183']", + "159, hepatocytes. ['l180', 'l182', 'l183']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "urokinase", + "transgenic", + "expressing", + "human", + "Bcl-2", + "transplanted", + "male" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "female", + "recipients" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "urokinase", + "transgenic", + "expressing", + "human", + "Bcl-2", + "transplanted", + "male" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes", + "hepatocytes," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "urokinase", + "transgenic", + "expressing", + "human", + "Bcl-2", + "male" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protected", + "resistance" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "urokinase", + "transgenic", + "expressing", + "human", + "Bcl-2", + "transplanted", + "male" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver", + "livers" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "fumarylacetoacetate", + "hydrolase", + "(FAH)-deficient" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protected" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "fumarylacetoacetate", + "hydrolase", + "(FAH)-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "fumarylacetoacetate", + "hydrolase", + "(FAH)-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protected" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "fumarylacetoacetate", + "hydrolase", + "(FAH)-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hepatocytes", + "hepatocytes,", + "hepatocytes." + ] + }, + "effect": { + "val": "negative", + "words": [ + "protected", + "resistance" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "male", + "Bcl-2", + "transgenic" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Bcl-2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "Fas-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hepatocytes,", + "hepatocytes." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Fas-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Fas-induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes." + ] + } + } + ] + }, + { + "PMID": "9771749", + "TEXT": "Variations in prions, which cause different incubation times and deposition patterns of the prion protein isoform called PrP(Sc), are often referred to as 'strains'. We report here a highly sensitive, conformation-dependent immunoassay that discriminates PrP(Sc) molecules among eight different prion strains propagated in Syrian hamsters. This immunoassay quantifies PrP isoforms by simultaneously following antibody binding to the denatured and native forms of a protein. In a plot of the ratio of antibody binding to denatured/native PrP graphed as a function of the concentration of PrP(Sc), each strain occupies a unique position, indicative of a particular PrP(Sc) conformation. This conclusion is supported by a unique pattern of equilibrium unfolding of PrP(Sc) found with each strain. Our findings indicate that each of the eight prion strains has a PrP(Sc) molecule with a unique conformation and, in accordance with earlier results, indicate the biological properties of prion strains are 'enciphered' in the conformation of PrP(Sc) and that the variation in incubation times is related to the relative protease sensitivity of PrP(Sc) in each strain.", + "TAG_DATA": [ + "43, Syrian {'context': 'B-organism'}", + "44, hamsters. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "43, Syrian ['l0']", + "44, hamsters. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9771747", + "TEXT": "We have investigated the molecular effects of passive maternal cigarette exposure in a newborn population and consider the possible implications of the observed genetic changes in the development of neoplastic diseases in children. We present a distribution analysis of somatic mutational events in a reporter gene, HPRT, in cord blood T lymphocytes from newborns after transplacental exposure to cigarette smoke. Analysis of 30 HPRT mutant isolates from 12 newborn infants born to mothers with no evidence of environmental exposure to cigarette smoke and 37 HPRT mutant isolates from 12 infants born to mothers exposed to passive cigarette smoke showed a significant difference in the HPRT mutational spectrum in those exposed in utero to cigarette smoke. The most notable change was an increase in 'illegitimate' genomic deletions mediated by V(D)J recombinase, a recombination event associated with hematopoietic malignancies in early childhood. Recent epidemiological studies of maternal and paternal cigarette smoke exposure and childhood cancers may need to be re-interpreted, given these results.", + "TAG_DATA": [ + "68, newborn {'context': 'B-organism'}", + "69, infants {'context': 'I-organism'}", + "89, infants {'context': 'B-organism'}", + "110, in {'context': 'B-in vivo'}", + "111, utero {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "68, newborn ['l0']", + "69, infants ['l0']", + "89, infants ['l1', 'l2']", + "110, in ['l1', 'l3']", + "111, utero ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9771745", + "TEXT": "Gene therapy is usually reserved for severe and medically refractory disorders because of the toxicity, potential long-term risks and invasiveness of most gene transfer protocols. Here we show that an orally administered adeno-associated viral vector leads to persistent expression of a beta-galactosidase transgene in both gut epithelial and lamina propria cells, and that this approach results in long-term phenotypic recovery in an animal model of lactose intolerance. A gene 'pill' associated with highly efficient and stable gene expression might be a practical and cost-effective strategy for even relatively mild disorders, such as lactase deficiency.", + "TAG_DATA": [ + "45, gut {'context': 'B-cells'}", + "46, epithelial {'context': 'I-cells'}", + "47, and {'context': 'I-cells'}", + "48, lamina {'context': 'I-cells'}", + "49, propria {'context': 'I-cells'}", + "50, cells, {'context': 'I-cells'}", + "62, animal {'context': 'B-organism'}", + "63, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "45, gut ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "46, epithelial ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "47, and ['l1', 'l6', 'l11', 'l12', 'l13']", + "48, lamina ['l2', 'l7', 'l11', 'l14', 'l15', 'l16', 'l17']", + "49, propria ['l3', 'l8', 'l12', 'l14', 'l18', 'l19', 'l20']", + "50, cells, ['l4', 'l9', 'l13', 'l15', 'l18']", + "62, animal ['l16', 'l19', 'l21']", + "63, model ['l5', 'l10', 'l17', 'l20', 'l21']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9734404", + "TEXT": "The rejection of concordant xenografts, such as mouse-to-rat cardiac xenografts, is very similar to the delayed rejection of porcine-to-primate discordant xenografts. In concordant models, this type of rejection is prevented by brief complement inhibition by cobra venom factor (CVF) and sustained T-cell immunosuppression by cyclosporin A (CyA). Mouse hearts that survive indefinitely in rats treated with CVF plus CyA express the anti-inflammatory gene heme oxygenase-1 (HO-1) in their endothelial cells and smooth muscle cells. The anti-inflammatory properties of HO-1 are thought to rely on the ability of this enzyme to degrade heme and generate bilirubin, free iron and carbon monoxide. Bilirubin is a potent anti-oxidant, free iron upregulates the transcription of the cytoprotective gene, ferritin, and carbon monoxide is thought to be essential in regulating vascular relaxation in a manner similar to nitric oxide. We show here that the expression of the HO-1 gene is functionally associated with xenograft survival, and that rapid expression of HO-1 in cardiac xenografts can be essential to ensure long-term xenograft survival.", + "TAG_DATA": [ + "47, Mouse {'context': 'B-tissue/organ'}", + "48, hearts {'context': 'I-tissue/organ'}", + "53, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "47, Mouse ['l0', 'l1']", + "48, hearts ['l0', 'l2']", + "53, rats ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9734401", + "TEXT": "Although prostate cancer cells are often initially sensitive to androgen ablation, they eventually lose this response and continue to survive, grow and spread in the absence of androgenic steroids. The mechanism(s) that underlie resistance to androgen ablation therapy remain mostly unknown. We have demonstrated that elevated caveolin protein levels are associated with human prostate cancer progression in pathological specimens. Here we show that suppression of caveolin expression by a stably transfected antisense caveolin-1 cDNA vector converted androgen-insensitive metastatic mouse prostate cancer cells to an androgen-sensitive phenotype. Orthotopically grown tumors and low-density cell cultures derived from antisense caveolin clones had increased apoptosis in the absence of androgenic steroids, whereas similarly grown tumors and cells from vector (control) clones and parental cells were not sensitive to androgens. Studies using a representative antisense caveolin clone showed that selection for androgen resistance in vivo correlated with increased caveolin levels, and that adenovirus-mediated caveolin expression blocked androgen sensitivity. Our results identify a new candidate gene for hormone-resistant prostate cancer in man and indicate that androgen insensitivity can be an inherent property of metastatic prostate cancer.", + "TAG_DATA": [ + "63, suppression {'perturbing_action': 'B-other'}", + "64, of {'perturbing_action': 'I-other'}", + "65, caveolin {'perturbing_action': 'I-other'}", + "66, expression {'perturbing_action': 'I-other'}", + "67, by {'perturbing_action': 'I-rnai/knockdown'}", + "68, a {'perturbing_action': 'I-rnai/knockdown'}", + "69, stably {'perturbing_action': 'B-rnai/knockdown'}", + "70, transfected {'perturbing_action': 'I-rnai/knockdown'}", + "71, antisense {'perturbing_action': 'I-rnai/knockdown'}", + "72, caveolin-1 {'perturbing_action': 'I-rnai/knockdown'}", + "73, cDNA {'perturbing_action': 'I-rnai/knockdown'}", + "74, vector {'perturbing_action': 'I-rnai/knockdown'}", + "77, metastatic {'context': 'B-transformed cells'}", + "78, mouse {'context': 'I-transformed cells'}", + "79, prostate {'context': 'I-transformed cells'}", + "80, cancer {'context': 'I-transformed cells'}", + "81, cells {'context': 'I-transformed cells'}", + "88, tumors {'context': 'B-neoplasm'}", + "90, low-density {'context': 'B-cells'}", + "91, cell {'context': 'I-cells'}", + "92, cultures {'context': 'I-cells'}", + "99, increased {'effect': 'B-positive'}", + "100, apoptosis {'phenotype': 'B-apoptosis'}", + "110, tumors {'context': 'B-neoplasm'}", + "112, cells {'context': 'B-cells'}", + "118, parental {'context': 'B-cells'}", + "119, cells {'context': 'I-cells'}", + "147, adenovirus-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "148, caveolin {'perturbing_action': 'I-gene gain-of-function'}", + "149, expression {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "63, suppression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "64, of ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "65, caveolin ['l1', 'l17', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "66, expression ['l2', 'l18', 'l33', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "67, by ['l3', 'l19', 'l34', 'l48', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "68, a ['l4', 'l20', 'l35', 'l49', 'l62', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "69, stably ['l5', 'l21', 'l36', 'l50', 'l63', 'l75', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "70, transfected ['l6', 'l22', 'l37', 'l51', 'l64', 'l76', 'l90', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "71, antisense ['l7', 'l23', 'l38', 'l52', 'l65', 'l77', 'l91', 'l105', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "72, caveolin-1 ['l8', 'l24', 'l39', 'l53', 'l66', 'l78', 'l92', 'l106', 'l119', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "73, cDNA ['l9', 'l25', 'l40', 'l54', 'l67', 'l79', 'l93', 'l107', 'l120', 'l131', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "74, vector ['l10', 'l26', 'l41', 'l55', 'l68', 'l80', 'l94', 'l108', 'l121', 'l132', 'l141', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "77, metastatic ['l11', 'l27', 'l42', 'l56', 'l69', 'l81', 'l95', 'l109', 'l122', 'l133', 'l142', 'l150', 'l156', 'l157', 'l158', 'l159']", + "78, mouse ['l12', 'l28', 'l43', 'l57', 'l70', 'l82', 'l96', 'l110', 'l123', 'l134', 'l143', 'l151', 'l156', 'l160', 'l161', 'l162']", + "79, prostate ['l13', 'l29', 'l44', 'l58', 'l71', 'l83', 'l97', 'l111', 'l124', 'l135', 'l144', 'l152', 'l157', 'l160', 'l163', 'l164']", + "80, cancer ['l14', 'l30', 'l45', 'l59', 'l72', 'l84', 'l98', 'l112', 'l125', 'l136', 'l145', 'l153', 'l158', 'l161', 'l163', 'l165']", + "81, cells ['l15', 'l31', 'l46', 'l60', 'l73', 'l85', 'l99', 'l113', 'l126', 'l137', 'l146', 'l154', 'l159', 'l162', 'l164', 'l165']", + "88, tumors ['l16', 'l32', 'l47', 'l61', 'l74', 'l86', 'l100', 'l114', 'l127', 'l138', 'l147', 'l155', 'l166', 'l167', 'l168', 'l169', 'l170']", + "90, low-density ['l101', 'l115', 'l166', 'l171', 'l172', 'l173', 'l174']", + "91, cell ['l87', 'l102', 'l116', 'l128', 'l139', 'l148', 'l167', 'l171', 'l175', 'l176', 'l177']", + "92, cultures ['l88', 'l103', 'l117', 'l129', 'l140', 'l149', 'l168', 'l172', 'l175', 'l178', 'l179']", + "99, increased ['l89', 'l104', 'l118', 'l130', 'l169', 'l173', 'l176', 'l178', 'l180']", + "100, apoptosis ['l170', 'l174', 'l177', 'l179', 'l180']", + "110, tumors ['l181', 'l182']", + "112, cells ['l181', 'l183']", + "118, parental ['l184']", + "119, cells ['l182', 'l183', 'l184']", + "147, adenovirus-mediated ['l185', 'l186']", + "148, caveolin ['l185', 'l187']", + "149, expression ['l186', 'l187']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "suppression", + "of", + "caveolin", + "expression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "metastatic", + "mouse", + "prostate", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "suppression", + "of", + "caveolin", + "expression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "by", + "a", + "stably", + "transfected", + "antisense", + "caveolin-1", + "cDNA", + "vector" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "metastatic", + "mouse", + "prostate", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "by", + "a", + "stably", + "transfected", + "antisense", + "caveolin-1", + "cDNA", + "vector" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "a", + "stably", + "transfected", + "antisense", + "caveolin-1", + "cDNA" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "cultures", + "low-density" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "a", + "stably", + "transfected", + "antisense" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "low-density", + "cell", + "cultures" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "low-density", + "cell", + "cultures" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "9734393", + "TEXT": "We studied antigen-specific T-cell tolerization therapy using skin transplantation across a defined minor histocompatibility antigen difference. Specific tolerization protocols using short-lived peptide or long-lived spleen cells presenting the peptide as antigen prevented graft rejection without immunosuppression when started before or as long as 10 days after transplantation. Peptide-induced T-cell tolerance was transient, and antigen presentation by the graft was not sufficient to maintain tolerance. In contrast, transfer of antigen-expressing lymphoid cells induced long-lasting tolerance correlating with donor cell chimerism. These findings show that antigen-specific tolerization can induce graft acceptance even when begun after transplantation and that long-term graft survival depends on persistence of the tolerizing antigen.", + "TAG_DATA": [ + "23, long-lived {'context': 'B-cells'}", + "24, spleen {'context': 'I-cells'}", + "25, cells {'context': 'I-cells'}", + "32, graft {'context': 'B-xenograft'}", + "48, T-cell {'context': 'B-cells'}", + "57, graft {'context': 'B-cells'}", + "68, antigen-expressing {'context': 'B-cells'}", + "69, lymphoid {'context': 'I-cells'}", + "70, cells {'context': 'I-cells'}", + "76, donor {'context': 'B-cells'}", + "77, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "23, long-lived ['l0', 'l1', 'l2', 'l3', 'l4']", + "24, spleen ['l0', 'l5', 'l6', 'l7', 'l8']", + "25, cells ['l1', 'l5', 'l9', 'l10', 'l11']", + "32, graft ['l2', 'l6', 'l9']", + "48, T-cell ['l3', 'l7', 'l10', 'l12']", + "57, graft ['l4', 'l8', 'l11', 'l12', 'l13', 'l14']", + "68, antigen-expressing ['l15', 'l16', 'l17', 'l18']", + "69, lymphoid ['l15', 'l19', 'l20', 'l21']", + "70, cells ['l16', 'l19', 'l22', 'l23']", + "76, donor ['l13', 'l17', 'l20', 'l22', 'l24']", + "77, cell ['l14', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9701252", + "TEXT": "Substitutive therapy using fetal striatal grafts in animal models of Huntington disease (HD) have already demonstrated obvious beneficial effects on motor indices. Using a new phenotypic model of HD recently designed in primates, we demonstrate here complete and persistent recovery in a frontal-type cognitive task two to five months after intrastriatal allografting. The striatal allografts also reduce the occurrence of dystonia, a major abnormal movement associated with HD. These results show the capacity of fetal neurons to provide a renewed substrate for both cognitive and motor systems in the lesioned adult brain. They also support the use of neural transplantation as a potential therapy for HD.", + "TAG_DATA": [ + "54, allografts {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "50, intrastriatal ['l0']", + "51, allografting. ['l0']", + "53, striatal ['l1']", + "54, allografts ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9701250", + "TEXT": "Recent studies of subjects infected with human immunodeficiency virus (HIV-1) have produced conflicting results about the extent of reconstitution possible in the CD4+ lymphocyte repertoire after highly active antiretroviral therapy (HAART). The effect of HAART on the incidence of opportunistic infections will probably depend on reconstitution of antigen-specific CD4+ lymphocyte responses to important pathogens, including cytomegalovirus (CMV), the leading cause of blindness in AIDS. Several studies have demonstrated an important role for CD4+ lymphocytes in controlling CMV replication in vitro and in clinical studies. It is now possible to quantitate antigen-specific CD4+ lymphocyte responses by flow cytometry. Using this method, we studied CMV-specific CD4+ lymphocyte responses in individuals infected with HIV-1 with and without a history of active CMV-associated end organ disease (EOD), and in those with quiescent CMV EOD after ganciclovir therapy and HAART. The presence of active CMV-associated EOD strongly correlated with loss of CMV-specific lymphocyte responses (P = 0.0004). In contrast, patients with no history of CMV-associated EOD and most patients with quiescent EOD after HAART demonstrated strong CMV-specific CD4+ lymphocyte responses. These data indicate that the loss of CMV-specific CD4+ lymphocyte responses in individuals infected with HIV-1 who have active CMV EOD may be restored after ganciclovir therapy and HAART, which provides evidence for functional immune reconstitution to an important pathogen.", + "TAG_DATA": [ + "107, individuals {'context': 'B-patient'}", + "154, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9701247", + "TEXT": "The Epstein-Barr virus nuclear antigen 1 contains a glycine-alanine repeat that inhibits in cis MHC class I-restricted presentation. We report here that insertion of a minimal glycine-alanine repeat motif in different positions of I kappaB alpha protects this NF-kappaB inhibitor from signal-induced degradation dependent on ubiquitin-proteasome, and decreases its basal turnover in vivo resulting in constitutive dominant-negative mutants. The chimeras are phosphorylated and ubiquitinated in response to tumor necrosis factor alpha, but are then released from NF-kappaB and fail to associate with the proteasome. This explains how functionally competent I kappaB alpha is protected from proteasomal disruption and identifies the glycine-alanine repeat as a new regulator of proteolysis.", + "TAG_DATA": [ + "51, in {'context': 'B-in vivo'}", + "52, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "51, in ['l0']", + "52, vivo ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9701244", + "TEXT": "Acquisition of invasive/metastatic potential through protease expression is an essential event in tumor progression. High levels of components of the plasminogen activation system, including urokinase, but paradoxically also its inhibitor, plasminogen activator inhibitor 1 (PAI1), have been correlated with a poor prognosis for some cancers. We report here that deficient PAI1 expression in host mice prevented local invasion and tumor vascularization of transplanted malignant keratinocytes. When this PAI1 deficiency was circumvented by intravenous injection of a replication-defective adenoviral vector expressing human PAI1, invasion and associated angiogenesis were restored. This experimental evidence demonstrates that host-produced PAI is essential for cancer cell invasion and angiogenesis.", + "TAG_DATA": [ + "49, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "50, PAI1 {'perturbing_action': 'I-gene loss-of-function'}", + "51, expression {'perturbing_action': 'I-gene loss-of-function'}", + "54, mice {'context': 'I-organism'}", + "55, prevented {'effect': 'B-negative'}", + "57, invasion {'phenotype': 'B-invasion'}", + "59, tumor {'context': 'B-neoplasm'}", + "63, malignant {'context': 'B-cells'}", + "64, keratinocytes. {'context': 'I-cells'}", + "67, PAI1 {'perturbing_action': 'B-gene loss-of-function'}", + "68, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "76, replication-defective {'perturbing_action': 'B-gene gain-of-function'}", + "77, adenoviral {'perturbing_action': 'I-gene gain-of-function'}", + "78, vector {'perturbing_action': 'I-gene gain-of-function'}", + "79, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "80, human {'perturbing_action': 'I-gene gain-of-function'}", + "81, PAI1, {'perturbing_action': 'I-gene gain-of-function'}", + "82, invasion {'phenotype': 'B-invasion'}", + "87, restored. {'effect': 'B-rescues'}" + ], + "LINK_DATA": [ + "49, deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "50, PAI1 ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "51, expression ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "54, mice ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "55, prevented ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "57, invasion ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "59, tumor ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "63, malignant ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "64, keratinocytes. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "67, PAI1 ['l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "68, deficiency ['l36', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "76, replication-defective ['l37', 'l45', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "77, adenoviral ['l38', 'l46', 'l53', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "78, vector ['l39', 'l47', 'l54', 'l60', 'l66', 'l67', 'l68', 'l69', 'l70']", + "79, expressing ['l40', 'l48', 'l55', 'l61', 'l66', 'l71', 'l72', 'l73', 'l74']", + "80, human ['l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l75', 'l76', 'l77']", + "81, PAI1, ['l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l78', 'l79']", + "82, invasion ['l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l76', 'l78', 'l80']", + "87, restored. ['l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l79', 'l80']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "PAI1", + "expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "PAI1", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "PAI1", + "expression", + "deficiency" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "PAI1", + "expression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "PAI1", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "malignant", + "keratinocytes." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "cells", + "words": [ + "malignant", + "keratinocytes." + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "cells", + "words": [ + "malignant", + "keratinocytes." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PAI1", + "deficiency" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "replication-defective", + "adenoviral", + "vector", + "expressing", + "human", + "PAI1," + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "replication-defective", + "adenoviral", + "vector", + "expressing", + "human", + "PAI1," + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored." + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored." + ] + } + } + ] + }, + { + "PMID": "9701243", + "TEXT": "Neurofibromatosis type 2 (NF2) protein, also known as merlin or schwannomin, is a tumor suppressor, and NF2 is mutated in most schwannomas and meningiomas. Although these tumors are dependent on NF2, some lack detectable NF2 mutations, which indicates that alternative mechanisms exist for inactivating merlin. Here, we demonstrate cleavage of merlin by the ubiquitous protease calpain and considerable activation of the calpain system resulting in the loss of merlin expression in these tumors. Increased proteolysis of merlin by calpain in some schwannomas and meningiomas exemplifies tumorigenesis linked to the calpain-mediated proteolytic pathway.", + "TAG_DATA": [ + "72, tumors. {'context': 'B-neoplasm'}", + "81, schwannomas {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9701242", + "TEXT": "Although the involvement of soluble and matrix-immobilized proteases in tumor cell invasion and metastasis is well recognized, the role of proteolytically activated cell surface receptors has not been elucidated. We report here that thrombin receptor, a member of the protease-activated receptor family, is preferentially expressed in highly metastatic human breast carcinoma cell lines and breast carcinoma biopsy specimens. Introduction of thrombin receptor antisense cDNA considerably inhibited the invasion of metastatic breast carcinoma cells in culture through a reconstituted basement membrane. During placental implantation of the human embryo, thrombin receptor is transiently expressed in the invading cytotrophoblasts. These results emphasize the involvement of thrombin receptor in cell invasion associated with tumor progression and normal embryonic development.", + "TAG_DATA": [ + "61, receptor {'perturbing_action': 'I-rnai/knockdown'}", + "62, antisense {'perturbing_action': 'I-rnai/knockdown'}", + "63, cDNA {'perturbing_action': 'I-rnai/knockdown'}", + "65, inhibited {'effect': 'B-negative'}", + "67, invasion {'phenotype': 'B-invasion'}", + "69, metastatic {'context': 'B-transformed cells'}", + "70, breast {'context': 'I-transformed cells'}", + "71, carcinoma {'context': 'I-transformed cells'}", + "72, cells {'context': 'I-transformed cells'}", + "74, culture {'context': 'I-in vitro'}", + "85, human {'context': 'B-organism'}", + "86, embryo, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "61, receptor ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "62, antisense ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "63, cDNA ['l1', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "65, inhibited ['l2', 'l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "67, invasion ['l3', 'l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "69, metastatic ['l4', 'l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "70, breast ['l5', 'l14', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "71, carcinoma ['l6', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "72, cells ['l7', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "74, culture ['l8', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']", + "85, human ['l46']", + "86, embryo, ['l9', 'l46']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "receptor", + "antisense", + "cDNA" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "receptor", + "antisense", + "cDNA" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "receptor", + "antisense", + "cDNA" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "metastatic", + "breast", + "carcinoma", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "receptor", + "antisense", + "cDNA" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "receptor" + ] + }, + "context": { + "val": "organism", + "words": [ + "embryo," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "metastatic", + "breast", + "carcinoma", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "metastatic", + "breast", + "carcinoma", + "cells" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + } + ] + }, + { + "PMID": "9662380", + "TEXT": "Networks of interstitial cells of Cajal embedded in the musculature of the gastrointestinal tract are involved in the generation of electrical pacemaker activity for gastrointestinal motility. This pacemaker activity manifests itself as rhythmic slow waves in membrane potential, and controls the frequency and propagation characteristics of gut contractile activity. Mice that lack a functional Kit receptor fail to develop the network of interstitial cells of Cajal associated with Auerbach's plexus in the mouse small intestine and do not generate slow wave activity. These cells could provide an essential component of slow wave activity (for example, a biochemical trigger that would be transferred to smooth muscle cells), or provide an actual pacemaker current that could initiate slow waves. Here we provide direct evidence that a single cell, identified as an interstitial cell of Cajal by light microscopy, electron microscopy and expression of Kit mRNA, generates spontaneous contractions and a rhythmic inward current that is insensitive to L-type calcium channel blockers. Identification of the pacemaker of gut motility will aid in the elucidation of the pathophysiology of intestinal motor disorders, and provide a target cell for pharmacological treatment.", + "TAG_DATA": [ + "49, Mice {'context': 'B-organism'}", + "72, mouse {'context': 'B-tissue/organ'}", + "73, small {'context': 'I-tissue/organ'}", + "74, intestine {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "49, Mice ['l0', 'l1', 'l2']", + "72, mouse ['l0', 'l3', 'l4']", + "73, small ['l1', 'l3', 'l5']", + "74, intestine ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9662372", + "TEXT": "The mechanism of immunodepression after brain injury is not yet clear. Here we demonstrate rapid systemic release of the immunoinhibitory cytokine interleukin-10, monocytic deactivation and a high incidence of infection in patients with 'sympathetic storm' due to acute accidental or iatrogenic brain trauma. In vitro studies showed that within minutes catecholamines trigger the secretion of interleukin-10 from unstimulated monocytes through a beta-adrenoreceptor-mediated, cAMP/protein kinase A-dependent pathway. We found that in a rat model of acute brain injury, the beta-receptor antagonist propranolol prevented the increase of interleukin-10 plasma levels. Rapid monocytic interleukin-10 release after sympathetic activation may represent a common pathway for immunodepression induced by stress and injury.", + "TAG_DATA": [ + "43, In {'context': 'B-in vitro'}", + "44, vitro {'context': 'I-in vitro'}", + "58, monocytes {'context': 'B-cells'}", + "71, rat {'context': 'B-organism'}", + "72, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "43, In ['l0', 'l1']", + "44, vitro ['l0', 'l2']", + "58, monocytes ['l1', 'l2']", + "71, rat ['l3']", + "72, model ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9623986", + "TEXT": "Ordered assembly of the amyloid-beta protein (A beta) into amyloid fibrils is a critical step in Alzheimer's disease (AD). To release the amyloidogenic peptide A beta from the Alzheimer amyloid precursor protein (APP), two secretases act sequentially: first, beta-secretase cleaves close to the membrane within the ectodomain and then gamma-secretase cuts within the transmembrane domain. The sites of gamma-secretase cleavage are after residues 40 or 42 of A beta. Except in those rare cases of AD caused by a mutation, levels of secreted A beta are not elevated; thus, the secretory pathway may be unaffected, and factors other than the extracellular concentration of A beta may contribute to the aggregation properties of the peptide. A beta is also present in intracellular compartments. The two gamma-secretase cleavage products, A beta42 and A beta40, were found in different compartments: A beta42 in the endoplasmic reticulum (ER)/intermediate compartment, and A beta40 in the trans-Golgi network (TGN). The cellular compartments that harbor A beta are target sites for therapeutic intervention. Here we report that in the brain, the principal compartment in which A beta resides is a detergent-insoluble glycolipid-enriched membrane domain (DIG). Also present in the DIG fractions are the endoproteolytic fragments of presenilin-1 (PS1) and APP. The presence of these proteins, which all contribute to the generation of A beta, indicates that the DIG fraction is probably where the intramembranous cleavage of APP occurs.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9623982", + "TEXT": "The action of tissue Transglutaminase (TGase) on specific protein-bound glutamine residues plays a critical role in numerous biological processes. Here we provide evidence for a new role of this enzyme in the common, HLA-DQ2 (and DQ8) associated enteropathy, celiac disease (CD). The intestinal inflammation in CD is precipitated by exposure to wheat gliadin in the diet and is associated with increased mucosal activity of TGase. This enzyme has also been identified as the main target for CD-associated anti-endomysium autoantibodies, and is known to accept gliadin as one of its few substrates. We have examined the possibility that TGase could be involved in modulating the reactivity of gliadin specific T cells. This could establish a link between previous reports of the role of TGase in CD and the prevailing view of CD as a T-cell mediated disorder. We found a specific effect of TGase on T-cell recognition of gliadin. This effect was limited to gliadin-specific T cells isolated from intestinal CD lesions. We demonstrate that TGase mediates its effect through an ordered and specific deamidation of gliadins. This deamidation creates an epitope that binds efficiently to DQ2 and is recognized by gut-derived T cells. Generation of epitopes by enzymatic modification is a new mechanism that may be relevant for breaking of tolerance and initiation of autoimmune disease.", + "TAG_DATA": [ + "154, T {'context': 'B-cells'}", + "155, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "154, T ['l0']", + "155, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9623981", + "TEXT": "The p53 molecule might serve as a common tumor-associated antigen, as the tumor suppressor gene p53 is mutated and the p53 protein is often over-expressed in tumor cells. We report that effective immunity to p53 can be induced through an idiotypic network by immunization of mice with a monoclonal antibody (PAb-240) specific for mutated p53, or with a peptide derived from the complementarity determining region (CDR) 3 of the variable domain of the light chain (VL) of this antibody. The immunized mice produced IgG antibodies to p53 and mounted a cytotoxic reaction to a tumor line bearing mutated p53. The idiotypically immunized mice were resistant to challenge with the tumor cells. Thus antibodies to p53 might serve as immunogens for activating resistance to some tumors. At the basic level, these findings indicate that a network of p53 immunity may be organized naturally within the immune system.", + "TAG_DATA": [ + "45, mice {'context': 'B-organism'}", + "81, mice {'context': 'B-organism'}", + "94, tumor {'context': 'B-transformed cells'}", + "95, line {'context': 'I-transformed cells'}", + "97, mutated {'perturbing_action': 'I-other'}", + "98, p53. {'perturbing_action': 'I-other'}", + "102, mice {'context': 'B-organism'}", + "109, tumor {'context': 'B-transformed cells'}", + "110, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "45, mice ['l0', 'l1']", + "81, mice ['l0', 'l2', 'l3', 'l4', 'l5']", + "94, tumor ['l2', 'l6', 'l7', 'l8']", + "95, line ['l1', 'l3', 'l6', 'l9', 'l10']", + "97, mutated ['l4', 'l7', 'l9', 'l11']", + "98, p53. ['l5', 'l8', 'l10', 'l11']", + "102, mice ['l12', 'l13']", + "109, tumor ['l12', 'l14']", + "110, cells. ['l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "p53." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "line" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "p53." + ] + } + } + ] + }, + { + "PMID": "9623980", + "TEXT": "We investigated whether immunization with recombinant anti-idiotypic antibody fragments mimicking the conformation of the capsular antigen can protect against infection by group B streptococcus, an important neonatal pathogen. Single-chain fragment-variable anti-idiotypes competed with the type III carbohydrate for binding to type-specific antibodies and elicited, in mice, the production of protective immunoglobulins reacting against the type III polysaccharide. Moreover, maternal immunization with soluble or phage-displayed fragments protected neonatal mice against streptococcal infection. These data indicate that recombinant anti-idiotypic antibodies may be useful in developing protein images of relevant carbohydrate epitopes and, ultimately, in preventing infections by encapsulated bacteria.", + "TAG_DATA": [ + "45, mice, {'context': 'B-organism'}", + "66, neonatal {'context': 'B-organism'}", + "67, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "66, neonatal ['l0']", + "67, mice ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9585241", + "TEXT": "Cytotoxic T lymphocyte (CTL) mediated tumor immunity against major histocompatibility antigen (MHC) class I-positive but class II-negative tumors often requires help from CD4+ T cells. These CD4 cells are activated by MHC class II-positive cells that present tumor derived antigens. Considering that different antigen presenting cells, such as B cells, macrophages and dendritic cells compete for antigen and influence the outcome of an immune response, we analyzed tumor immunity in B cell-deficient mice. These mice appear normal with regard to T cell immunity and tolerance to some pure foreign antigens. We show here that the low immunogenicity of tumors is caused by B cells whose presence in the priming phase results in disabled CD4+ T cell help for CTL mediated tumor immunity. Instead, in the presence of B cells, a non-protective humoral immune response is induced. Our results may explain the enigmatic observation that tumor-reactive antibodies occur frequently in cancer patients.", + "TAG_DATA": [ + "70, B {'perturbing_action': 'B-gene loss-of-function'}", + "71, cell-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "72, mice. {'context': 'B-organism'}", + "74, mice {'context': 'B-organism'}", + "113, CD4+ {'context': 'B-cells'}", + "114, T {'context': 'I-cells'}", + "115, cell {'context': 'I-cells'}", + "127, B {'context': 'B-cells'}", + "128, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "70, B ['l0', 'l1']", + "71, cell-deficient ['l0', 'l2', 'l3']", + "72, mice. ['l1', 'l2', 'l4']", + "74, mice ['l3', 'l4']", + "113, CD4+ ['l5', 'l6']", + "114, T ['l5', 'l7']", + "115, cell ['l6', 'l7']", + "127, B ['l8']", + "128, cells, ['l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "B", + "cell-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + } + ] + }, + { + "PMID": "9585234", + "TEXT": "Dendritic cells (DCs) are professional antigen presenting cells with the unique capacity to induce primary and secondary immune responses in vivo. Here, we show that DCs secrete antigen presenting vesicles, called exosomes, which express functional Major Histocompatibility Complex class I and class II, and T-cell costimulatory molecules. Tumor peptide-pulsed DC-derived exosomes prime specific cytotoxic T lymphocytes in vivo and eradicate or suppress growth of established murine tumors in a T cell-dependent manner. Exosome-based cell-free vaccines represent an alternative to DC adoptive therapy for suppressing tumor growth.", + "TAG_DATA": [ + "56, in {'context': 'B-in vivo'}", + "57, vivo {'context': 'I-in vivo'}", + "65, murine {'context': 'B-neoplasm'}", + "66, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "56, in ['l0', 'l1', 'l2']", + "57, vivo ['l0', 'l3']", + "65, murine ['l1', 'l4']", + "66, tumors ['l2', 'l3', 'l4']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9585230", + "TEXT": "Parkinson's disease symptoms can be improved by transplanting fetal dopamine cells into the putamen of parkinsonian patients. Because the supply of human donor tissue is limited and variable, an alternative and genetically modifiable non-human source of tissue would be valuable. We have generated cloned transgenic bovine embryos, 42% of which developed beyond 40 days. Dopamine cells collected from the ventral mesencephalon of the cloned fetuses 42 to 50 days post-conception survived transplantation into immunosuppressed parkinsonian rats and cells from cloned and wild-type embryos improved motor performance. Somatic cell cloning can efficiently produce transgenic animal tissue for treating parkinsonism.", + "TAG_DATA": [ + "45, bovine {'context': 'B-organism'}", + "46, embryos, {'context': 'I-organism'}", + "54, Dopamine {'context': 'B-cells'}", + "55, cells {'context': 'I-cells'}", + "56, collected {'context': 'I-cells'}", + "57, from {'context': 'I-cells'}", + "58, the {'context': 'I-cells'}", + "59, ventral {'context': 'I-cells'}", + "60, mesencephalon {'context': 'I-cells'}", + "64, fetuses {'context': 'I-organism'}", + "75, rats {'context': 'I-organism'}", + "77, cells {'context': 'B-cells'}", + "82, embryos {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "45, bovine ['l0', 'l1', 'l2', 'l3']", + "46, embryos, ['l0']", + "54, Dopamine ['l1', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "55, cells ['l2', 'l4', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "56, collected ['l5', 'l12', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "57, from ['l6', 'l13', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "58, the ['l7', 'l14', 'l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "59, ventral ['l8', 'l15', 'l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "60, mesencephalon ['l3', 'l9', 'l16', 'l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "64, fetuses ['l10', 'l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "75, rats ['l11', 'l18', 'l24', 'l29', 'l33', 'l36', 'l38', 'l39']", + "77, cells ['l40']", + "82, embryos ['l40']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9546790", + "TEXT": "The human CD4 molecule (hCD4) is expressed on T lymphocytes and macrophages and acts as a key component of the cellular receptor for HIV. At baseline, hCD4 transgenic mice expressed hCD4 on microglia, the resident mononuclear phagocytes of the brain, and showed no neuronal damage. Activation of brain microglia by peripheral immune challenges elicited neurodegeneration in hCD4 mice but not in nontransgenic controls. In post-mortem brain tissues from AIDS patients with opportunistic infections, but without typical HIV encephalitis, hCD4 expression correlated with neurodegeneration. We conclude that hCD4 may function as an important mediator of indirect neuronal damage in infectious and immune-mediated diseases of the central nervous system.", + "TAG_DATA": [ + "26, hCD4 {'perturbing_action': 'B-gene gain-of-function'}", + "27, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "28, mice {'context': 'B-organism'}", + "32, microglia, {'context': 'B-cells'}", + "47, brain {'context': 'B-cells'}", + "48, microglia {'context': 'I-cells'}", + "56, hCD4 {'perturbing_action': 'B-gene gain-of-function'}", + "57, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "26, hCD4 ['l0', 'l1', 'l2', 'l3', 'l4']", + "27, transgenic ['l0', 'l5', 'l6', 'l7']", + "28, mice ['l1', 'l5', 'l8']", + "32, microglia, ['l2', 'l6', 'l8']", + "47, brain ['l3', 'l9', 'l10', 'l11']", + "48, microglia ['l4', 'l7', 'l9', 'l12', 'l13']", + "56, hCD4 ['l10', 'l12', 'l14']", + "57, mice ['l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hCD4", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hCD4", + "transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "microglia,", + "brain", + "microglia" + ] + } + } + ] + }, + { + "PMID": "9546784", + "TEXT": "Studying the transmission of simian retroviruses to humans can help define the importance of these infections to public health. We identified a substantial prevalence (4/231, 1.8%) of infection with simian foamy viruses (SFV) among humans occupationally exposed to nonhuman primates. Evidence of SFV infection included seropositivity, proviral DNA detection and isolation of foamy virus. The infecting SFV originated from an African green monkey (one person) and baboons (three people). These infections have not as yet resulted in either disease or sexual transmission, and may represent benign endpoint infections.", + "TAG_DATA": [ + "60, African {'context': 'B-organism'}", + "61, green {'context': 'I-organism'}", + "62, monkey {'context': 'I-organism'}", + "66, baboons {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "60, African ['l0', 'l1', 'l2']", + "61, green ['l0', 'l3', 'l4']", + "62, monkey ['l1', 'l3', 'l5']", + "66, baboons ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9546771", + "TEXT": "PIP: Health officials in the Indian state of Maharashtra have ordered the compulsory testing of all girls 12 years and older who live in designated \"destitute homes.\" The officials also plan to tattoo a symbol on the thighs of all HIV-positive prostitutes. By April 1998, this December 1997 order had resulted in the compulsory testing of women living in 50 boarding houses and the transfer of several found to be HIV-positive to a separate institution 200 miles from the state capital. Nongovernment organizations (NGOs) have mounted a protest over this statute, but state governments in India are free to enact their own health laws. The Maharashtran government is also seeking to legalize prostitution and to force prostitutes to register with a Board that will be able to order compulsory HIV tests and tattooing. Women with HIV who continue to engage in prostitution will be quarantined, and their clients will be jailed. In response, prostitutes in the capital city of Mumbai have threatened to release a list of their client's names to the press. The only recourse available to NGOs who oppose this action is to generate a large enough public outcry to stop it. A Mumbai-based attorney noted that many private companies are also requiring HIV testing and dismissing those who test positive.", + "TAG_DATA": [ + "56, women {'context': 'B-cells'}", + "133, Women {'context': 'B-patient'}", + "153, prostitutes {'context': 'B-cells'}", + "157, city {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "153, prostitutes ['l0', 'l1', 'l2', 'l3']", + "156, capital ['l0', 'l4', 'l5', 'l6']", + "157, city ['l1', 'l4', 'l7', 'l8']", + "158, of ['l2', 'l5', 'l7', 'l9']", + "159, Mumbai ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9500609", + "TEXT": "The development and endocrine function of the ovarian corpus luteum (CL) are dependent on the growth of new capillary vessels. Although several molecules have been implicated as mediators of CL angiogenesis, at present there is no direct evidence for the involvement of any. Here we report the unexpected finding that treatment with truncated soluble Flt-1 receptors, which inhibit vascular endothelial growth factor (VEGF) bioactivity, resulted in virtually complete suppression of CL angiogenesis in a rat model of hormonally induced ovulation. This effect was associated with inhibition of CL development and progesterone release. Failure of maturation of the endometrium was also observed. Areas of ischemic necrosis were demonstrated in the corpora lutea (CLs) of treated animals. However, no effect on the preexisting ovarian vasculature was observed. These findings demonstrate that, in spite of the redundancy of potential mediators, VEGF is essential for CL angiogenesis. Furthermore, they have implications for the control of fertility and the treatment of ovarian disorders characterized by hypervascularity and hyperplasia.", + "TAG_DATA": [ + "52, truncated {'perturbing_action': 'B-other'}", + "53, soluble {'perturbing_action': 'I-other'}", + "54, Flt-1 {'perturbing_action': 'I-other'}", + "55, receptors, {'perturbing_action': 'I-other'}", + "74, rat {'context': 'B-organism'}", + "75, model {'context': 'I-organism'}", + "77, hormonally {'effect': 'B-positive'}", + "78, induced {'effect': 'B-positive'}", + "104, necrosis {'phenotype': 'B-necrosis'}", + "109, corpora {'context': 'B-tissue/organ'}", + "110, lutea {'context': 'I-tissue/organ'}", + "114, animals. {'context': 'B-organism'}", + "121, ovarian {'context': 'B-tissue/organ'}", + "122, vasculature {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "52, truncated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "53, soluble ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "54, Flt-1 ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "55, receptors, ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "74, rat ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45']", + "75, model ['l4', 'l15', 'l25', 'l34', 'l42', 'l46', 'l47', 'l48']", + "77, hormonally ['l5', 'l16', 'l26', 'l35', 'l43', 'l46', 'l49', 'l50']", + "78, induced ['l6', 'l17', 'l27', 'l36', 'l44', 'l47', 'l49', 'l51']", + "79, ovulation. ['l7', 'l18', 'l28', 'l37', 'l45', 'l48', 'l50', 'l51']", + "104, necrosis ['l8', 'l19', 'l29', 'l38', 'l52', 'l53', 'l54', 'l55']", + "109, corpora ['l9', 'l20', 'l30', 'l39', 'l52', 'l56', 'l57', 'l58']", + "110, lutea ['l10', 'l21', 'l31', 'l40', 'l53', 'l56', 'l59', 'l60']", + "111, (CLs) ['l11', 'l22', 'l32', 'l41', 'l54', 'l57', 'l59', 'l61']", + "114, animals. ['l55', 'l58', 'l60', 'l61']", + "121, ovarian ['l62']", + "122, vasculature ['l62']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "truncated", + "soluble", + "Flt-1", + "receptors," + ] + }, + "context": { + "val": "organism", + "words": [ + "rat", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "truncated", + "soluble", + "Flt-1", + "receptors," + ] + }, + "effect": { + "val": "positive", + "words": [ + "hormonally", + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "truncated", + "soluble", + "Flt-1", + "receptors," + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "truncated", + "soluble", + "Flt-1", + "receptors," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "corpora", + "lutea" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rat", + "model" + ] + }, + "effect": { + "val": "positive", + "words": [ + "hormonally", + "induced" + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "corpora", + "lutea" + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "animals." + ] + } + } + ] + }, + { + "PMID": "9500602", + "TEXT": "Fever, hypotension and bleeding disorders are common symptoms of sepsis and septic shock. The activation of the contact-phase system is thought to contribute to the development of these severe disease states by triggering proinflammatory and procoagulatory cascades; however, the underlying molecular mechanisms are obscure. Here we report that the components of the contact-phase system are assembled on the surface of Escherichia coli and Salmonella through their specific interactions with fibrous bacterial surface proteins, curli and fimbriae. As a consequence, the proinflammatory pathway is activated through the release of bradykinin, a potent inducer of fever, pain and hypotension. Absorption of contact-phase proteins and fibrinogen by bacterial surface proteins depletes relevant coagulation factors and causes a hypocoagulatory state. Thus, the complex interplay of microbe surface proteins and host contact-phase factors may contribute to the symptoms of sepsis and septic shock.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9461199", + "TEXT": "Malignant melanoma is a prime example of cancers that respond poorly to various treatment modalities including chemotherapy. A number of chemotherapeutic agents have been shown recently to act by inducing apoptosis, a type of cell death antagonized by the bcl-2 gene. Human melanoma expresses Bcl-2 in up to 90% of all cases. In the present study we demonstrate that bcl-2 antisense oligonucleotide treatment improves the chemosensitivity of human melanoma grown in severe combined immunodeficient (SCID) mice. Our findings suggest that reduction of Bcl-2 in melanoma, and possibly also in a variety of other tumors, may be a novel and rational approach to improve chemosensitivity and treatment outcome.", + "TAG_DATA": [ + "67, human {'context': 'B-neoplasm'}", + "68, melanoma {'context': 'I-neoplasm'}", + "71, severe {'context': 'B-organism'}", + "72, combined {'context': 'I-organism'}", + "73, immunodeficient {'context': 'I-organism'}", + "74, (SCID) {'context': 'I-organism'}", + "75, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "67, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "68, melanoma ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "71, severe ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "72, combined ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "73, immunodeficient ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "74, (SCID) ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "75, mice. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9461194", + "TEXT": "Vascular tone control is essential in blood pressure regulation, shock, ischemia-reperfusion, inflammation, vessel injury/repair, wound healing, temperature regulation, digestion, exercise physiology, and metabolism. Here we show that a well-known growth factor, FGF2, long thought to be involved in many developmental and homeostatic processes, including growth of the tissue layers of vessel walls, functions in vascular tone control. Fgf2 knockout mice are morphologically normal and display decreased vascular smooth muscle contractility, low blood pressure and thrombocytosis. Following intra-arterial mechanical injury, FGF2-deficient vessels undergo a normal hyperplastic response. These results force us to reconsider the function of FGF2 in vascular development and homeostasis in terms of vascular tone control.", + "TAG_DATA": [ + "57, Fgf2 {'perturbing_action': 'B-gene loss-of-function'}", + "58, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "59, mice {'context': 'B-organism'}", + "66, vascular {'context': 'B-cells'}", + "79, FGF2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "80, vessels {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "57, Fgf2 ['l0', 'l1', 'l2', 'l3']", + "58, knockout ['l0', 'l4', 'l5', 'l6']", + "59, mice ['l1', 'l4', 'l7', 'l8']", + "66, vascular ['l2', 'l5', 'l7', 'l9']", + "67, smooth ['l3', 'l6', 'l8', 'l9']", + "79, FGF2-deficient ['l10']", + "80, vessels ['l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fgf2", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fgf2", + "knockout" + ] + }, + "context": { + "val": "cells", + "words": [ + "vascular" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FGF2-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "vessels" + ] + } + } + ] + }, + { + "PMID": "9461191", + "TEXT": "Simian immunodeficiency virus (SIV) infection of nonhuman primates is one of the most relevant animals models of HIV infection in humans. To test a potential anti-HIV gene therapy strategy in this model, CD4-enriched lymphocytes from three rhesus macaques were subjected to retrovirally mediated gene transfer with a vector expressing an antisense tat/rev gene. This group of animals and three control macaques were subsequently infected with SIVmac239. Blood and lymph nodes from all macaques were sampled for more than a year to monitor the progress of infection. Although all animals became infected, the animals that received the lymphocytes engineered with the antisense vector demonstrated a significant reduction in viral load in both peripheral blood and lymph nodes, had sustained numbers of CD4+ cells, and exhibited little disruption of lymph node architecture.", + "TAG_DATA": [ + "32, CD4-enriched {'context': 'B-cells'}", + "33, lymphocytes {'context': 'I-cells'}", + "36, rhesus {'context': 'B-organism'}", + "37, macaques {'context': 'I-organism'}", + "56, animals {'context': 'B-organism'}", + "60, macaques {'context': 'B-organism'}", + "72, macaques {'context': 'B-organism'}", + "88, animals {'context': 'B-organism'}", + "92, animals {'context': 'B-organism'}", + "96, lymphocytes {'context': 'B-cells'}", + "111, peripheral {'context': 'B-tissue/organ'}", + "112, blood {'context': 'I-tissue/organ'}", + "114, lymph {'context': 'B-tissue/organ'}", + "115, nodes, {'context': 'I-tissue/organ'}", + "120, CD4+ {'context': 'B-cells'}", + "121, cells, {'context': 'I-cells'}", + "127, lymph {'context': 'B-tissue/organ'}", + "128, node {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "32, CD4-enriched ['l0', 'l1', 'l2']", + "33, lymphocytes ['l0', 'l3', 'l4']", + "36, rhesus ['l1', 'l3', 'l5']", + "37, macaques ['l2', 'l4', 'l5']", + "56, animals ['l6', 'l7', 'l8', 'l9']", + "60, macaques ['l6', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "72, macaques ['l7', 'l10', 'l17', 'l18', 'l19', 'l20', 'l21']", + "88, animals ['l8', 'l11', 'l17', 'l22', 'l23']", + "92, animals ['l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "96, lymphocytes ['l24', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "111, peripheral ['l12', 'l18', 'l25', 'l32', 'l40', 'l41', 'l42', 'l43', 'l44']", + "112, blood ['l13', 'l19', 'l22', 'l26', 'l33', 'l40', 'l45', 'l46', 'l47', 'l48']", + "114, lymph ['l14', 'l20', 'l27', 'l34', 'l41', 'l45', 'l49', 'l50', 'l51']", + "115, nodes, ['l9', 'l15', 'l21', 'l23', 'l28', 'l35', 'l42', 'l46', 'l49', 'l52']", + "120, CD4+ ['l29', 'l36', 'l43', 'l47', 'l50', 'l53', 'l54', 'l55']", + "121, cells, ['l16', 'l30', 'l37', 'l44', 'l48', 'l51', 'l52', 'l53']", + "127, lymph ['l38', 'l54', 'l56']", + "128, node ['l31', 'l39', 'l55', 'l56']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9461188", + "TEXT": "The ability to measure the effects of local alterations in blood flow, blood volume and oxygenation by nuclear magnetic resonance has stimulated a surge of activity in functional MRI of many organs, particularly in its application to cognitive neuroscience. However, the exact description of these effects in terms of the interrelations between the MRI signal changes and the basic physiological parameters has remained an elusive goal. We here present this fundamental theory for spin-echo signal changes in perfused tissue and validate it in vivo in the cat brain by using the physiological alteration of hypoxic hypoxia. These experiments show that high-resolution absolute blood volume images can be obtained by using hemoglobin as a natural intravascular contrast agent. The theory also correctly predicts the magnitude of spin-echo MRI signal intensity changes on brain activation and thereby provides a sound physiological basis for these types of studies.", + "TAG_DATA": [ + "82, in {'context': 'B-in vivo'}", + "83, vivo {'context': 'I-in vivo'}", + "86, cat {'context': 'B-tissue/organ'}", + "87, brain {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "82, in ['l0', 'l1', 'l2']", + "83, vivo ['l0', 'l3', 'l4']", + "86, cat ['l1', 'l3', 'l5']", + "87, brain ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9427610", + "TEXT": "Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by localized areas of demyelination. Although the etiology and pathogenesis of MS remain largely unknown, it is generally assumed that immune responses to myelin antigens contribute to the disease process. The exact sequence of events, as well as the molecular mediators that lead to myelin destruction, is yet to be defined. As a potent mediator of inflammation, the cytopathic cytokine, tumor necrosis factor (TNF) has been considered to be a strong candidate in the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). However, its role in immune-mediated demyelination remains to be elucidated. To determine the contribution of TNF to the pathogenesis of the MS-like disease provoked by the myelin oligodendrocyte glycoprotein (MOG), we have tested mice with an homologous disruption of the gene encoding TNF. Here we report that upon immunization with MOG, mice lacking TNF develop severe neurological impairment with high mortality and extensive inflammation and demyelination. We show further that inactivation of the TNF gene converts MOG-resistant mice to a state of high susceptibility. Furthermore, treatment with TNF dramatically reduces disease severity in both TNF-/- mice and in other TNF+/+ mice highly susceptible to the MOG-induced disease. These findings indicate that TNF is not essential for the induction and expression of inflammatory and demyelinating lesions, and that it may limit the extent and duration of severe CNS pathology.", + "TAG_DATA": [ + "132, mice {'context': 'B-organism'}", + "150, mice {'context': 'B-organism'}", + "151, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "152, TNF {'perturbing_action': 'I-gene loss-of-function'}", + "169, inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "170, of {'perturbing_action': 'I-gene loss-of-function'}", + "171, the {'perturbing_action': 'I-gene loss-of-function'}", + "172, TNF {'perturbing_action': 'I-gene loss-of-function'}", + "173, gene {'perturbing_action': 'I-gene loss-of-function'}", + "175, MOG-resistant {'context': 'B-organism'}", + "176, mice {'context': 'B-organism'}", + "193, TNF-/- {'perturbing_action': 'B-gene loss-of-function'}", + "194, mice {'context': 'B-organism'}", + "198, TNF+/+ {'perturbing_action': 'B-gene gain-of-function'}", + "199, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "132, mice ['l0', 'l1', 'l2']", + "150, mice ['l0', 'l3', 'l4']", + "151, lacking ['l1', 'l3', 'l5']", + "152, TNF ['l2', 'l4', 'l5']", + "169, inactivation ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "170, of ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "171, the ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "172, TNF ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "173, gene ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "175, MOG-resistant ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "176, mice ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']", + "193, TNF-/- ['l27', 'l28', 'l29']", + "194, mice ['l27']", + "198, TNF+/+ ['l28', 'l30']", + "199, mice ['l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "MOG-resistant" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "TNF", + "inactivation", + "of", + "the", + "gene", + "TNF-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "TNF+/+" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "9427607", + "TEXT": "Janus kinase-3 (JAK3) deficiency has recently been identified as a cause of severe combined immunodeficiency (SCID) in humans. We used a mouse model of Jak3-deficient SCID to test a gene therapy approach for treatment of this disease. Transfer of a Jak3 retroviral vector to repopulating hematopoietic stem cells resulted in increased numbers of T and B lymphocytes, reversal of hypogammaglobulinemia, restoration of T-cell activation upon stimulation with mitogens, and development of an antigen-specific immune response after immunization. Analysis for vector copy number in lymphoid and myeloid populations showed a large in vivo selective advantage for Jak3-expressing lymphoid cells. These results show that gene replacement is a feasible treatment strategy for this disease and that naturally occurring in vivo selection of corrected cells is an important advantage of this approach.", + "TAG_DATA": [ + "21, mouse {'context': 'B-organism'}", + "22, model {'context': 'I-organism'}", + "24, Jak3-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "40, Jak3 {'perturbing_action': 'I-gene gain-of-function'}", + "41, retroviral {'perturbing_action': 'I-gene gain-of-function'}", + "42, vector {'perturbing_action': 'I-gene gain-of-function'}", + "45, hematopoietic {'context': 'I-cells'}", + "46, stem {'context': 'I-cells'}", + "47, cells {'context': 'I-cells'}", + "53, T {'context': 'B-cells'}", + "54, and {'context': 'I-cells'}", + "55, B {'context': 'I-cells'}", + "56, lymphocytes, {'context': 'I-cells'}", + "62, T-cell {'context': 'B-cells'}", + "83, lymphoid {'context': 'B-cells'}", + "84, and {'context': 'I-cells'}", + "85, myeloid {'context': 'I-cells'}", + "86, populations {'context': 'I-cells'}", + "90, in {'context': 'B-in vivo'}", + "91, vivo {'context': 'I-in vivo'}", + "95, Jak3-expressing {'context': 'B-cells'}", + "96, lymphoid {'context': 'I-cells'}", + "97, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "21, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "22, model ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "24, Jak3-deficient ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "40, Jak3 ['l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "41, retroviral ['l19', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "42, vector ['l20', 'l29', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "45, hematopoietic ['l21', 'l30', 'l38', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "46, stem ['l22', 'l31', 'l39', 'l46', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "47, cells ['l13', 'l23', 'l32', 'l40', 'l47', 'l53', 'l59', 'l60', 'l61', 'l62', 'l63']", + "53, T ['l2', 'l8', 'l14', 'l24', 'l33', 'l41', 'l48', 'l54', 'l59', 'l64', 'l65', 'l66', 'l67']", + "54, and ['l3', 'l9', 'l15', 'l25', 'l34', 'l42', 'l49', 'l55', 'l60', 'l64', 'l68', 'l69', 'l70']", + "55, B ['l4', 'l10', 'l16', 'l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l71', 'l72']", + "56, lymphocytes, ['l5', 'l11', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l69', 'l71', 'l73']", + "62, T-cell ['l6', 'l12', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l70', 'l72', 'l73']", + "83, lymphoid ['l74', 'l75', 'l76']", + "84, and ['l74', 'l77', 'l78']", + "85, myeloid ['l75', 'l77', 'l79']", + "86, populations ['l76', 'l78', 'l79']", + "90, in ['l80', 'l81', 'l82', 'l83']", + "91, vivo ['l80', 'l84', 'l85', 'l86']", + "95, Jak3-expressing ['l81', 'l84', 'l87', 'l88']", + "96, lymphoid ['l82', 'l85', 'l87', 'l89']", + "97, cells. ['l83', 'l86', 'l88', 'l89']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Jak3-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Jak3-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "T", + "and", + "B", + "lymphocytes,", + "T-cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Jak3", + "retroviral", + "vector" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cells", + "T", + "and", + "B", + "lymphocytes,", + "T-cell" + ] + } + } + ] + }, + { + "PMID": "9427585", + "TEXT": "PIP: UNAIDS believes that more than 3 million Indians are infected with HIV, approximately 200,000 of which have AIDS. Failing in its attempt to check the spread of HIV/AIDS through disease prevention messages and the promotion of condom use, the government of India has launched a program to develop a vaccine against HIV/AIDS. Some see the development of a vaccine as the only viable course of action against HIV/AIDS in India, for educational campaigns have failed and AIDS drugs are unaffordable even for wealthy Indians. Interest in producing an indigenous vaccine stems from concern that vaccines being developed in the West may not be effective in India due to differences in HIV subtypes. A 5-year extension of an existing Indo-US program started in 1987 to develop vaccines against a range of infectious diseases was signed in December 1997, with AIDS added to the list of original program diseases. This revised agreement includes collaboration with US vaccine research groups and possible US funding, but details of the terms have yet to be disclosed. The following Indian teams are working on the project: the government Department of Biotechnology (DBT), the All India Institute of Medical Sciences, the National Institute of Communicable Diseases (New Delhi), Christian Medical College (Vellore), and the National AIDS Research Institute (Pune). The DBT argues that there will be enough funding even without a US contribution. Indian scientists plan to develop a DNA vaccine mixture containing the desired gene sequences of the HIV subtypes which are prevalent in India.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9396609", + "TEXT": "Prions are thought to consist of infectious proteins that cause transmissible spongiform encephalopathies. According to overwhelming evidence, the pathogenic prion protein PrPSc converts its host encoded isoform PrPC into insoluble aggregates of PrPSc, concomitant with pathological modifications (for review, see refs. 1-3). Although the physiological role of PrPC is poorly understood, studies with PrP knockout mice demonstrated that PrPC is required for the development of prion diseases. Using the yeast two-hybrid technology in Saccharomyces cerevisiae, we identified the 37-kDa laminin receptor precursor (LRP) as interacting with the cellular prion protein PrPC. Mapping analysis of the LRP-PrP interaction site in S. cerevisiae revealed that PrP and laminin share the same binding domain (amino acids 161 to 180) on LRP. The LRP-PrP interaction was confirmed in vivo in insect (Sf9) and mammalian cells (COS-7). The LRP level was increased in scrapie-infected murine N2a cells and in brain and spleen of scrapie-infected mice. In contrast, the LRP concentration was not significantly altered in these organs from mice infected with the bovine spongiform encephalopathic agent (BSE), which have a lower PrPSc accumulation. LRP levels, however, were dramatically increased in brain and pancreas, slightly increased in the spleen and not altered in the liver of crapie-infected hamsters. These data show that enhanced LRP concentrations are correlated with PrPSc accumulation in organs from mice and hamsters. The laminin receptor precursor, which is highly conserved among mammals and is located on the cell surface, may act as a receptor or co-receptor for the prion protein on mammalian cells.", + "TAG_DATA": [ + "73, Saccharomyces {'context': 'B-organism'}", + "74, cerevisiae, {'context': 'I-organism'}", + "123, in {'context': 'B-in vivo'}", + "124, vivo {'context': 'I-in vivo'}", + "126, insect {'context': 'B-organism'}", + "129, mammalian {'context': 'B-cells'}", + "130, cells {'context': 'I-cells'}", + "131, (COS-7). {'context': 'I-cells'}", + "139, murine {'context': 'B-cells'}", + "140, N2a {'context': 'I-cells'}", + "141, cells {'context': 'I-cells'}", + "144, brain {'context': 'B-tissue/organ'}", + "146, spleen {'context': 'I-tissue/organ'}", + "149, mice. {'context': 'B-organism'}", + "163, mice {'context': 'B-organism'}", + "185, brain {'context': 'B-tissue/organ'}", + "187, pancreas, {'context': 'B-tissue/organ'}", + "192, spleen {'context': 'B-tissue/organ'}", + "198, liver {'context': 'B-tissue/organ'}", + "201, hamsters. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, Saccharomyces ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "74, cerevisiae, ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "123, in ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "124, vivo ['l2', 'l12', 'l21', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "126, insect ['l3', 'l13', 'l22', 'l33', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "127, (Sf9) ['l4', 'l14', 'l23', 'l34', 'l44', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "129, mammalian ['l5', 'l15', 'l24', 'l35', 'l45', 'l54', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "130, cells ['l6', 'l16', 'l25', 'l36', 'l46', 'l55', 'l63', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "131, (COS-7). ['l7', 'l17', 'l26', 'l37', 'l47', 'l56', 'l64', 'l71', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "139, murine ['l8', 'l18', 'l27', 'l38', 'l48', 'l57', 'l65', 'l72', 'l78', 'l84', 'l85', 'l86', 'l87', 'l88']", + "140, N2a ['l9', 'l19', 'l28', 'l39', 'l49', 'l58', 'l66', 'l73', 'l79', 'l84', 'l89', 'l90', 'l91', 'l92']", + "141, cells ['l10', 'l20', 'l29', 'l40', 'l50', 'l59', 'l67', 'l74', 'l80', 'l85', 'l89', 'l93']", + "144, brain ['l30', 'l41', 'l51', 'l60', 'l68', 'l75', 'l81', 'l86', 'l90', 'l93', 'l94', 'l95']", + "146, spleen ['l31', 'l42', 'l52', 'l61', 'l69', 'l76', 'l82', 'l87', 'l91', 'l94', 'l96']", + "149, mice. ['l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l83', 'l88', 'l92', 'l95', 'l96']", + "185, brain ['l97', 'l98']", + "187, pancreas, ['l97', 'l99']", + "192, spleen ['l98', 'l99', 'l100', 'l101']", + "198, liver ['l100', 'l102']", + "201, hamsters. ['l101', 'l102']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9396608", + "TEXT": "Prions, the etiological agents for infectious degenerative encephalopathies, act by entering the cell and inducing conformational changes in PrPC (a normal cell membrane sialoglycoprotein), which result in cell death. A specific cell-surface receptor to mediate PrPC and prion endocytosis has been predicted. Complementary hydropathy let us generate a hypothetical peptide mimicking the receptor binding site. Antibodies raised against this peptide stain the surface of mouse neurons and recognize a 66-kDa membrane protein that binds PrPC both in vitro and in vivo. Furthermore, both the complementary prion peptide and antiserum against it inhibit the toxicity of a prion-derived peptide toward neuronal cells in culture. Such reagents might therefore have therapeutic applications.", + "TAG_DATA": [ + "64, mouse {'context': 'B-cells'}", + "65, neurons {'context': 'I-cells'}", + "77, vitro {'context': 'I-in vitro'}", + "79, in {'context': 'B-in vivo'}", + "80, vivo. {'context': 'I-in vivo'}", + "99, neuronal {'context': 'B-cells'}", + "100, cells {'context': 'I-cells'}", + "101, in {'context': 'B-in vitro'}", + "102, culture. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "64, mouse ['l0', 'l1', 'l2', 'l3']", + "65, neurons ['l0', 'l4', 'l5', 'l6']", + "77, vitro ['l1', 'l4', 'l7', 'l8']", + "79, in ['l2', 'l5', 'l7', 'l9']", + "80, vivo. ['l3', 'l6', 'l8', 'l9']", + "99, neuronal ['l10', 'l11', 'l12']", + "100, cells ['l10', 'l13', 'l14']", + "101, in ['l11', 'l13', 'l15']", + "102, culture. ['l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9396605", + "TEXT": "Intratumoral implantation of murine cells modified to produce retroviral vectors containing the herpes simplex virus-thymidine kinase (HSV-TK) gene induces regression of experimental brain tumors in rodents after ganciclovir (GCV) administration. We evaluated this approach in 15 patients with progressive growth of recurrent malignant brain tumors. Antitumor activity was detected in five of the smaller tumors (1.4 +/- 0.5 ml). In situ hybridization for HSV-TK demonstrated survival of vector-producing cells (VPCs) at 7 days but indicated limited gene transfer to tumors, suggesting that indirect, \"bystander,\" mechanisms provide local antitumor activity in human tumors. However, the response of only very small tumors in which a high density of vector-producing cells had been placed suggests that techniques to improve delivery and distribution of the therapeutic gene will need to be developed if clinical utility is to be achieved with this approach.", + "TAG_DATA": [ + "3, murine {'context': 'B-cells'}", + "4, cells {'context': 'I-cells'}", + "18, induces {'effect': 'B-positive'}", + "19, regression {'phenotype': 'B-tumour regression'}", + "22, brain {'context': 'B-neoplasm'}", + "23, tumors {'context': 'I-neoplasm'}", + "25, rodents {'context': 'B-organism'}", + "41, recurrent {'context': 'B-neoplasm'}", + "42, malignant {'context': 'B-neoplasm'}", + "43, brain {'context': 'I-neoplasm'}", + "44, tumors. {'context': 'I-neoplasm'}", + "54, tumors {'context': 'B-neoplasm'}", + "67, vector-producing {'context': 'B-cells'}", + "68, cells {'context': 'I-cells'}", + "79, tumors, {'context': 'B-neoplasm'}", + "90, human {'context': 'B-neoplasm'}", + "91, tumors. {'context': 'I-neoplasm'}", + "99, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "3, murine ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "4, cells ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "18, induces ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "19, regression ['l2', 'l12', 'l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "22, brain ['l3', 'l13', 'l22', 'l29', 'l37', 'l38', 'l39', 'l40']", + "23, tumors ['l4', 'l14', 'l23', 'l30', 'l37', 'l41', 'l42', 'l43']", + "25, rodents ['l5', 'l15', 'l24', 'l31', 'l38', 'l41', 'l44', 'l45']", + "41, recurrent ['l6', 'l16', 'l25', 'l32', 'l46', 'l47', 'l48', 'l49']", + "42, malignant ['l7', 'l17', 'l26', 'l33', 'l46', 'l50', 'l51', 'l52']", + "43, brain ['l8', 'l18', 'l27', 'l34', 'l39', 'l42', 'l44', 'l47', 'l50', 'l53', 'l54']", + "44, tumors. ['l9', 'l19', 'l28', 'l35', 'l40', 'l43', 'l45', 'l48', 'l51', 'l53', 'l55']", + "54, tumors ['l10', 'l20', 'l36', 'l49', 'l52', 'l54', 'l55']", + "67, vector-producing ['l56', 'l57', 'l58', 'l59']", + "68, cells ['l56', 'l60', 'l61', 'l62']", + "79, tumors, ['l57', 'l60', 'l63', 'l64']", + "90, human ['l58', 'l61', 'l63', 'l65']", + "91, tumors. ['l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "murine", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "murine", + "cells" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "brain", + "tumors", + "recurrent", + "malignant", + "tumors." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "organism", + "words": [ + "rodents" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "brain", + "tumors", + "recurrent", + "malignant", + "tumors." + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "organism", + "words": [ + "rodents" + ] + } + } + ] + }, + { + "PMID": "9359704", + "TEXT": "The gradual loss of DNA from the ends of telomeres has been implicated in the control of cellular proliferative potential. Telomerase is an enzyme that restores telomeric DNA sequences, and expression of its activity was thought to be essential for the immortalization of human cells, both in vitro and in tumor progression in vivo. Telomerase activity has been detected in 50-100% of tumors of different types, but not in most normal adult somatic tissues. It has also been detected in about 70% of human cell lines immortalized in vitro and in all tumor-derived cell lines examined to date. It has previously been shown that in vitro immortalized telomerase-negative cell lines acquire very long and heterogeneous telomeres in association with immortalization presumably via one or more novel telomere-lengthening mechanisms that we refer to as ALT (alternative lengthening of telomeres). Here we report evidence for the presence of ALT in a subset of tumor-derived cell lines and tumors. The maintenance of telomeres by a mechanism other than telomerase, even in a minority of cancers, has major implications for therapeutic uses of telomerase inhibitors.", + "TAG_DATA": [ + "104, in {'context': 'B-in vitro'}", + "105, vitro {'context': 'I-in vitro'}", + "107, telomerase-negative {'context': 'B-cells'}", + "108, cell {'context': 'I-cells'}", + "109, lines {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "104, in ['l0', 'l1', 'l2', 'l3']", + "105, vitro ['l0', 'l4', 'l5', 'l6']", + "107, telomerase-negative ['l1', 'l4', 'l7', 'l8']", + "108, cell ['l2', 'l5', 'l7', 'l9']", + "109, lines ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9334719", + "TEXT": "Nitric oxide (NO) and peroxynitrite, formed from NO and superoxide anion, have been implicated as mediators of neuronal damage following focal ischemia, but their molecular targets have not been defined. One candidate pathway is DNA damage leading to activation of the nuclear enzyme, poly(ADP-ribose) polymerase (PARP), which catalyzes attachment of ADP ribose units from NAD to nuclear proteins following DNA damage. Excessive activation of PARP can deplete NAD and ATP, which is consumed in regeneration of NAD, leading to cell death by energy depletion. We show that genetic disruption of PARP provides profound protection against glutamate-NO-mediated ischemic insults in vitro and major decreases in infarct volume after reversible middle cerebral artery occlusion. These results provide compelling evidence for a primary involvement of PARP activation in neuronal damage following focal ischemia and suggest that therapies designed towards inhibiting PARP may provide benefit in the treatment of cerebrovascular disease.", + "TAG_DATA": [ + "79, cell {'phenotype': 'B-cell death'}", + "80, death {'phenotype': 'I-cell death'}", + "87, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "88, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "89, of {'perturbing_action': 'I-gene loss-of-function'}", + "90, PARP {'perturbing_action': 'I-gene loss-of-function'}", + "98, in {'context': 'B-in vitro'}", + "99, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "79, cell ['l0', 'l1', 'l2']", + "80, death ['l0', 'l3', 'l4']", + "87, genetic ['l5', 'l6', 'l7', 'l8', 'l9']", + "88, disruption ['l5', 'l10', 'l11', 'l12', 'l13']", + "89, of ['l6', 'l10', 'l14', 'l15', 'l16']", + "90, PARP ['l7', 'l11', 'l14', 'l17', 'l18']", + "98, in ['l1', 'l3', 'l8', 'l12', 'l15', 'l17', 'l19']", + "99, vitro ['l2', 'l4', 'l9', 'l13', 'l16', 'l18', 'l19']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "disruption", + "of", + "PARP" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "9288734", + "TEXT": "In response to anticancer therapeutics, human colon cancer cells growing in vitro either enter into a stable arrest or die, depending on the integrity of their cell-cycle checkpoints. To test whether altered checkpoints can modulate sensitivity to treatment in vivo, xenografts were established from isogenic lines differing only in their p21 checkpoint status. Although all tumors with intact checkpoint function underwent regrowth after treatment with gamma-radiation, a significant fraction of checkpoint-deficient tumors were completely cured. This difference in sensitivity was not detected by the clonogenic survival assay, because both arrest and death preclude outgrowth of colonies. These results demonstrate that checkpoint status affects sensitivity to anticancer treatments in vivo, and these findings have important implications for identifying and testing new therapeutic compounds.", + "TAG_DATA": [ + "5, human {'context': 'B-transformed cells'}", + "6, colon {'context': 'I-transformed cells'}", + "7, cancer {'context': 'I-transformed cells'}", + "8, cells {'context': 'I-transformed cells'}", + "10, in {'context': 'B-in vitro'}", + "11, vitro {'context': 'I-in vitro'}", + "38, in {'context': 'B-in vivo'}", + "39, vivo, {'context': 'I-in vivo'}", + "40, xenografts {'context': 'B-xenograft'}", + "55, tumors {'context': 'B-neoplasm'}", + "71, tumors {'context': 'B-neoplasm'}", + "92, preclude {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "5, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "6, colon ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "7, cancer ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "8, cells ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "10, in ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "11, vitro ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "38, in ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "39, vivo, ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "40, xenografts ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "71, tumors ['l36']", + "92, preclude ['l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "effect": { + "val": "negative", + "words": [ + "preclude" + ] + } + } + ] + }, + { + "PMID": "9288733", + "TEXT": "Leptin is a circulating hormone that is expressed abundantly and specifically in the adipose tissue. It is involved in the regulation of energy homeostasis, as well as the neuroendocrine and reproductive systems. Here, we demonstrate production of leptin by nonadipose tissue, namely, placental trophoblasts and amnion cells from uteri of pregnant women. We show that pregnant women secrete a considerable amount of leptin from the placenta into the maternal circulation as compared with nonpregnant obese women. Leptin production was also detected in a cultured human choriocarcinoma cell line, BeWo cells, and was augmented during the course of forskolin-induced differentiation of cytotrophoblasts into syncytiotrophoblasts. Plasma leptin levels were markedly elevated in patients with hydatidiform mole or choriocarcinoma and were reduced after surgical treatment or chemotherapy. Leptin is also produced by primary cultured human amnion cells and is secreted into the amniotic fluid. The present study provides evidence for leptin as a novel placenta-derived hormone in humans and suggests the physiologic and pathophysiologic significance of leptin in normal pregnancy and gestational trophoblastic neoplasms.", + "TAG_DATA": [ + "84, human {'context': 'B-transformed cells'}", + "85, choriocarcinoma {'context': 'I-transformed cells'}", + "86, cell {'context': 'I-transformed cells'}", + "87, line, {'context': 'I-transformed cells'}", + "88, BeWo {'context': 'I-cells'}", + "89, cells, {'context': 'I-cells'}", + "97, forskolin-induced {'effect': 'B-positive'}", + "98, differentiation {'phenotype': 'B-differentiation'}", + "100, cytotrophoblasts {'context': 'B-cells'}", + "131, human {'context': 'B-cells'}", + "132, amnion {'context': 'I-cells'}", + "133, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "84, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "85, choriocarcinoma ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "86, cell ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "87, line, ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "88, BeWo ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "89, cells, ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31']", + "97, forskolin-induced ['l5', 'l12', 'l18', 'l23', 'l27', 'l32', 'l33']", + "98, differentiation ['l6', 'l13', 'l19', 'l24', 'l28', 'l30', 'l32', 'l34']", + "100, cytotrophoblasts ['l7', 'l14', 'l20', 'l25', 'l29', 'l31', 'l33', 'l34']", + "131, human ['l35', 'l36']", + "132, amnion ['l35', 'l37']", + "133, cells ['l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "choriocarcinoma", + "cell", + "line," + ] + }, + "effect": { + "val": "positive", + "words": [ + "forskolin-induced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "choriocarcinoma", + "cell", + "line," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "BeWo", + "cytotrophoblasts" + ] + }, + "effect": { + "val": "positive", + "words": [ + "forskolin-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "BeWo", + "cells,", + "cytotrophoblasts" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "forskolin-induced" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "9288732", + "TEXT": "Cataract is responsible for rendering several million people blind throughout the world and is also by far the most common cause of low visual acuity. Although cataract surgery is common, routine and effective, posterior capsule opacification (PCO) occurs in 30-50% of patients following modern cataract surgery. This condition arises from stimulated cell growth within the capsular bag after surgery. The resulting decline in visual acuity requires expensive laser treatment, and PCO therefore prevents modern cataract surgery from being carried out routinely in underdeveloped countries. The present study, using a human lens capsular bag culture system, has confirmed that cells from a wide age range of donors proliferate in the absence of added serum protein and explains why PCO is such a common problem even in aged patients. This study also provides one possible solution for PCO by using polymethylmethacrylate (PMMA) implanted intraocular lenses as a drug delivery system. PMMA lenses coated with thapsigargin, a hydrophobic inhibitor of endoplasmic reticulum (ER) (Ca2+)-ATPase, greatly reduced cell growth in the capsular bag at relatively low coating concentrations (200 nM) but, more significantly, induced total cell death of the residual anterior epithelial cells at higher concentrations (>2 microM).", + "TAG_DATA": [ + "98, cells {'context': 'B-cells'}", + "106, proliferate {'phenotype': 'B-proliferation'}", + "162, reduced {'effect': 'B-negative'}", + "163, cell {'phenotype': 'B-cell growth'}", + "164, growth {'phenotype': 'I-cell growth'}", + "167, capsular {'context': 'B-tissue/organ'}", + "168, bag {'context': 'I-tissue/organ'}", + "179, induced {'effect': 'B-positive'}", + "181, cell {'phenotype': 'B-cell death'}", + "182, death {'phenotype': 'I-cell death'}", + "185, residual {'context': 'B-cells'}", + "186, anterior {'context': 'I-cells'}", + "187, epithelial {'context': 'I-cells'}", + "188, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "98, cells ['l0']", + "106, proliferate ['l0']", + "162, reduced ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "163, cell ['l1', 'l7', 'l8', 'l9', 'l10']", + "164, growth ['l2', 'l7', 'l11', 'l12']", + "167, capsular ['l3', 'l8', 'l11', 'l13', 'l14', 'l15', 'l16']", + "168, bag ['l4', 'l9', 'l12', 'l13', 'l17', 'l18']", + "179, induced ['l5', 'l14', 'l17', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "181, cell ['l15', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "182, death ['l6', 'l10', 'l16', 'l18', 'l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "185, residual ['l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "186, anterior ['l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "187, epithelial ['l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "188, cells ['l24', 'l29', 'l33', 'l36', 'l38', 'l39']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "capsular", + "bag" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "death" + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "capsular", + "bag" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "capsular", + "bag" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "capsular", + "bag" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "residual", + "anterior", + "epithelial", + "cells" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "residual", + "anterior", + "epithelial", + "cells" + ] + } + } + ] + }, + { + "PMID": "9288730", + "TEXT": "Alzheimer's disease (AD) is a neurodegenerative disorder involving the florid deposition of vascular and cerebral plaques composed chiefly of amyloid beta-peptide (A beta) derived from cleavage of the amyloid precursor protein (APP). Varying in length from 39 to 43 amino acids, A beta, particularly the longer A beta(42), is thought to play a significant role in AD pathogenesis. To better understand AD it is important to identify the subcellular organelles generating A beta. Studies using agents that disrupt endosomal/lysosomal function suggest that A beta is generated late in the secretory and endocytic pathways. However, much of what is known about A beta biosynthesis has been inferred by monitoring extracellular A beta levels since intracellular A beta is undetectable in most cell types. Consequently, the precise site or sites that generate A beta, or whether A beta(1-40) and A beta(1-42) are generated at the same point in the biosynthetic pathway, is not known. Using human NT2N neurons, we found that retention of APP in the endoplasmic reticulum/intermediate compartment (ER/IC) by three independent approaches eliminated production of intracellular A beta(1-40), but did not alter intracellular A beta(1-42) synthesis. These findings suggest that the ER/IC may be an important site for generating this highly amyloidogenic species of A beta.", + "TAG_DATA": [ + "153, human {'context': 'B-cells'}", + "154, NT2N {'context': 'I-cells'}", + "155, neurons, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "153, human ['l0', 'l1']", + "154, NT2N ['l0', 'l2']", + "155, neurons, ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9288729", + "TEXT": "The Alzheimer amyloid precursor protein (APP) is cleaved by several proteases, the most studied, but still unidentified ones, are those involved in the release of a fragment of APP, the amyloidogenic beta-protein A beta. Proteolysis by gamma-secretase is the last processing step resulting in release of A beta. Cleavage occurs after residue 40 of A beta [A beta(1-40)], occasionally after residue 42 [A beta(1-42)]. Even slightly increased amounts of this A beta(1-42) might be sufficient to cause Alzheimer's disease (AD) (reviewed in ref. 1, 2). It is thus generally believed that inhibition of this enzyme could aid in prevention of AD. Unexpectedly we have identified in neurons the endoplasmic reticulum (ER) as the site for generation of A beta(1-42) and the trans-Golgi network (TGN) as the site for A beta(1-40) generation. It is interesting that intracellular generation of A beta seemed to be unique to neurons, because we found that nonneuronal cells produced significant amounts of A beta(1-40) and A beta(1-42) only at the cell surface. The specific production of the critical A beta isoform in the ER of neurons links this compartment with the generation of A beta and explains why primarily ER localized (mutant) proteins such as the presenilins could induce AD. We suggest that the earliest event taking place in AD might be the generation of A beta(1-42) in the ER.", + "TAG_DATA": [ + "150, nonneuronal {'context': 'B-cells'}", + "151, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "150, nonneuronal ['l0']", + "151, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9288727", + "TEXT": "Mortality from atherosclerotic cardiovascular disease is lower in premenopausal women than in age-matched men. It is also lower in postmenopausal women who take estrogens and progestins together rather than estrogens alone. Progesterone receptors were detected in human and rat aortic smooth muscle cells in vivo and in vitro (in subculture). We examined the effect of progesterone on proliferation of smooth muscle cells, important constituents of atherosclerotic plaques. Progesterone at physiologic levels inhibited DNA synthesis and proliferation in these cells in a dose-dependent manner, and pretreatment with the progesterone receptor antagonist RU486 blocked inhibition. Cyclin A and E messenger RNA levels decreased after progesterone treatment but those of cyclin B and D1 did not change. This cell cycle-dependent inhibition of arterial smooth muscle cell proliferation by progesterone may represent a mechanism for the hormone's protective effect against atherosclerosis.", + "TAG_DATA": [ + "36, human {'context': 'B-cells'}", + "37, and {'context': 'I-cells'}", + "38, rat {'context': 'I-cells'}", + "39, aortic {'context': 'I-cells'}", + "40, smooth {'context': 'I-cells'}", + "41, muscle {'context': 'I-cells'}", + "42, cells {'context': 'I-cells'}", + "71, inhibited {'effect': 'B-negative'}", + "75, proliferation {'phenotype': 'B-proliferation'}", + "78, cells {'context': 'B-cells'}", + "117, inhibition {'effect': 'B-negative'}", + "119, arterial {'context': 'B-cells'}", + "120, smooth {'context': 'I-cells'}", + "121, muscle {'context': 'I-cells'}", + "122, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "36, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "37, and ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "38, rat ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "39, aortic ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "40, smooth ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "41, muscle ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "42, cells ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "71, inhibited ['l21', 'l22']", + "75, proliferation ['l21', 'l23']", + "78, cells ['l22', 'l23']", + "117, inhibition ['l24', 'l25', 'l26', 'l27']", + "119, arterial ['l24', 'l28', 'l29', 'l30']", + "120, smooth ['l25', 'l28', 'l31', 'l32']", + "121, muscle ['l26', 'l29', 'l31', 'l33']", + "122, cell ['l27', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "arterial", + "smooth", + "muscle", + "cell" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "9288724", + "TEXT": "Patients with B-cell chronic lymphocytic leukemia (CLL) acquire an immunodeficiency with many characteristics similar to those of persons with inherited defects in the gene encoding the CD40-ligand (CD154). We found that the blood and splenic CD4+ T cells of patients with CLL failed to express surface CD154 after CD3 ligation. However, using an enzyme-linked immunosorbent assay (ELISA)-based quantitative competitive polymerase chain reaction (PCR), we noted that CD3 ligation could induce such T cells to express CD154 messenger RNA at levels similar to that of CD3-activated T cells from normal donors. Moreover, addition of increasing numbers of CLL B cells to activated normal donor T cells rapidly resulted in progressively greater down-modulation of CD154. Such down-modulation of CD154 could be blocked by addition of CD40 monoclonal antibody to cultures in vitro. We propose that leukemia cell-mediated down-modulation of CD154 on activated T cells accounts for some of the acquired immune defects of patients with CLL.", + "TAG_DATA": [ + "32, blood {'context': 'B-cells'}", + "33, and {'context': 'I-cells'}", + "34, splenic {'context': 'I-cells'}", + "35, CD4+ {'context': 'I-cells'}", + "36, T {'context': 'I-cells'}", + "37, cells {'context': 'I-cells'}", + "71, T {'context': 'B-cells'}", + "72, cells {'context': 'B-cells'}", + "85, T {'context': 'I-cells'}", + "86, cells {'context': 'I-cells'}", + "96, CLL {'context': 'B-transformed cells'}", + "97, B {'context': 'I-transformed cells'}", + "98, cells {'context': 'I-transformed cells'}", + "101, normal {'context': 'B-cells'}", + "102, donor {'context': 'I-cells'}", + "103, T {'context': 'I-cells'}", + "104, cells {'context': 'I-cells'}", + "127, cultures {'context': 'B-cells'}", + "128, in {'context': 'B-in vitro'}", + "129, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "32, blood ['l0', 'l1', 'l2', 'l3', 'l4']", + "33, and ['l0', 'l5', 'l6', 'l7', 'l8']", + "34, splenic ['l1', 'l5', 'l9', 'l10', 'l11', 'l12']", + "35, CD4+ ['l2', 'l6', 'l9', 'l13', 'l14', 'l15']", + "36, T ['l3', 'l7', 'l10', 'l13', 'l16']", + "37, cells ['l4', 'l8', 'l11', 'l14', 'l16']", + "71, T ['l17', 'l18', 'l19']", + "72, cells ['l12', 'l15', 'l17', 'l20', 'l21']", + "85, T ['l18', 'l20', 'l22']", + "86, cells ['l19', 'l21', 'l22']", + "96, CLL ['l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "97, B ['l23', 'l29', 'l30', 'l31', 'l32', 'l33']", + "98, cells ['l24', 'l29', 'l34', 'l35', 'l36', 'l37']", + "101, normal ['l25', 'l30', 'l34', 'l38', 'l39', 'l40']", + "102, donor ['l26', 'l31', 'l35', 'l38', 'l41', 'l42']", + "103, T ['l27', 'l32', 'l36', 'l39', 'l41', 'l43']", + "104, cells ['l28', 'l33', 'l37', 'l40', 'l42', 'l43']", + "127, cultures ['l44', 'l45']", + "128, in ['l44', 'l46']", + "129, vitro. ['l45', 'l46']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9256287", + "TEXT": "Nucleoside-based inhibitors of reverse transcriptase were the first drugs to be used in the chemotherapy of AIDS. After entering the cell, these substances are activated to their triphosphate form by cellular kinases, after which they are potent chain terminators for the growing viral DNA. The two main factors limiting their efficacy are probably interrelated. These are the insufficient degree of reduction of viral load at the commencement of treatment and the emergence of resistant variants of the virus. The reason for the relatively poor suppression of viral replication appears to be inefficient metabolic activation. Thus, for the most extensively used drug, 3'-azido-3'-deoxythymidine (AZT), whereas phosphorylation to the monophosphate is facile, the product is a very poor substrate for the next kinase in the cascade, thymidylate kinase. Because of this, although high concentrations of the monophosphate can be reached in the cell, the achievable concentration of the active triphosphate is several orders of magnitude lower. Determination of the structure of thymidylate kinase as a complex with AZT monophosphate (AZTMP) together with studies on the kinetics of its phosphorylation have now led to a detailed understanding of the reasons for and consequences of the poor substrate properties.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9256285", + "TEXT": "The oncoprotein of simian virus-40, SV40 large T-antigen (Tag), is reported to target and to inactivate growth suppressive proteins such as the retinoblastoma family and p53 (ref. 4, 5), leading to transformation of human cell lines in vitro, tumor production in rodents, and detection of Tag in several human cancers including mesotheliomas. The retinoblastoma family contains three members, pRb, p107 and pRb2/p130 (ref. 9), that are phosphorylated in a cell cycle-dependent manner, have cell growth suppressive properties and bind to specific members of the E2F family and various cyclins. Even though mesotheliomas are among the most aggressive human cancers, alterations of important cell-cycle \"controllers,\" such as the Rb family genes, have never been reported in these tumors. We found the presence of SV40-like sequences in 86% of 35 archival specimens of mesothelioma. We also demonstrated that SV40 Tag, isolated from frozen biopsies of human mesothelioma, binds each of the retinoblastoma family proteins, pRb, p107 and pRb2/p130, in four of four specimens. We propose that the tumorigenic potential of SV40 Tag in some human mesotheliomas may arise from its ability to interact with and thereby inactivate several tumor and/or growth suppressive proteins.", + "TAG_DATA": [ + "33, human {'context': 'B-cells'}", + "34, cell {'context': 'I-cells'}", + "35, lines {'context': 'I-cells'}", + "36, in {'context': 'B-in vitro'}", + "37, vitro, {'context': 'I-in vitro'}", + "39, production {'phenotype': 'I-tumourigenesis'}" + ], + "LINK_DATA": [ + "33, human ['l0', 'l1', 'l2', 'l3']", + "34, cell ['l0', 'l4', 'l5', 'l6']", + "35, lines ['l1', 'l4', 'l7', 'l8']", + "36, in ['l2', 'l5', 'l7', 'l9']", + "37, vitro, ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9256284", + "TEXT": "We found that simian virus 40 (SV40) induces mesotheliomas in hamsters and that 60% of human mesotheliomas contain and express SV40 sequences, results now confirmed by others [ref. 3-5, and presentations by D. Griffiths & R. Weiss, F. Galateau-SallE, and H.I.P. at \"Simian virus 40: A possible human polyoma virus,\" NIH workshop, 27-28 January 1997, Bethesda, MD (transcript available through SAG Corp., Washington, DC 20008)]. Mesothelioma, an aggressive malignancy resistant to therapy, originates from the serosal lining of the pleural, pericardial and peritoneal cavities. The incidence of mesothelioma continues to increase worldwide because of exposure to crocidolite asbestos. However, at least 20% of mesotheliomas in the United States are not associated with asbestos exposure, and only a minority of people exposed to high concentrations of asbestos develop mesothelioma. Thus, other carcinogens may induce mesothelioma in individuals not exposed to asbestos, and/or may render particular individuals more susceptible to the carcinogenic effect of asbestos. We investigated whether the expression of the SV40 large T-antigen (Tag) interferes with the normal expression of the tumor suppressor gene p53 in human mesotheliomas. We found that SV40 Tag retains its ability to bind and to inactivate p53, a cellular protein that when normally expressed plays an important role in suppressing tumor growth and in inducing sensitivity to therapy. Our findings do not establish a cause-and-effect relation, but indicate that the possibility that SV40 contributes to the development of human mesotheliomas should be carefully investigated.", + "TAG_DATA": [ + "176, human {'context': 'B-neoplasm'}", + "177, mesotheliomas. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "176, human ['l0']", + "177, mesotheliomas. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9256283", + "TEXT": "Plasma extravasation from postcapillary venules is one of the earliest steps of inflammation. Substance P (SP) and bradykinin (BK) mediate extravasation and cause hypotension. The cell-surface enzyme neutral endopeptidase (NEP) inactivates both peptides. Thus, absence of NEP may predispose development of inflammation and hypotension. We examined these possibilities in mice in which the NEP gene was deleted by homologous recombination. There was widespread basal plasma extravasation in postcapillary venular endothelia in NEP-/- mice, which was reversed by recombinant NEP and antagonists of SP (NK1) and BK (B2) receptors. Mean arterial blood pressure was 20% lower in NEP-/- animals, but this was unaffected by reintroduction of recombinant NEP and the kinin receptor antagonists. The hypotension was also independent of nitric oxide (NO), because NEP-/- mice treated with a NO synthase inhibitor remained hypotensive relative to the wild type. Thus, NEP has important roles in regulating basal microvascular permeability by degrading SP and BK, and may regulate blood pressure set point through a mechanism that is independent of SP, BK and NO. The use of NEP antagonists as candidate drugs in cardiovascular disease is suggested by the blood pressure data reported herein.", + "TAG_DATA": [ + "49, mice {'context': 'B-organism'}", + "52, the {'perturbing_action': 'I-gene loss-of-function'}", + "53, NEP {'perturbing_action': 'I-gene loss-of-function'}", + "54, gene {'perturbing_action': 'I-gene loss-of-function'}", + "55, was {'perturbing_action': 'I-gene loss-of-function'}", + "56, deleted {'perturbing_action': 'I-gene loss-of-function'}", + "71, NEP-/- {'perturbing_action': 'B-gene loss-of-function'}", + "72, mice, {'context': 'B-organism'}", + "80, antagonists {'perturbing_action': 'B-pharmacological inhibition'}", + "81, of {'perturbing_action': 'I-pharmacological inhibition'}", + "82, SP {'perturbing_action': 'I-pharmacological inhibition'}", + "83, (NK1) {'perturbing_action': 'I-pharmacological inhibition'}", + "84, and {'perturbing_action': 'I-pharmacological inhibition'}", + "85, BK {'perturbing_action': 'I-pharmacological inhibition'}", + "86, (B2) {'perturbing_action': 'I-pharmacological inhibition'}", + "87, receptors. {'perturbing_action': 'I-pharmacological inhibition'}", + "96, NEP-/- {'perturbing_action': 'B-gene loss-of-function'}", + "97, animals, {'context': 'B-organism'}", + "103, reintroduction {'perturbing_action': 'B-gene gain-of-function'}", + "104, of {'perturbing_action': 'I-gene gain-of-function'}", + "105, recombinant {'perturbing_action': 'I-gene gain-of-function'}", + "106, NEP {'perturbing_action': 'I-gene gain-of-function'}", + "122, NEP-/- {'perturbing_action': 'B-gene loss-of-function'}", + "123, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "49, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "52, the ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "53, NEP ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "54, gene ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "55, was ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "56, deleted ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "71, NEP-/- ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "72, mice, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "80, antagonists ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "81, of ['l28', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "82, SP ['l29', 'l39', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "83, (NK1) ['l30', 'l40', 'l51', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "84, and ['l31', 'l41', 'l52', 'l62', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "85, BK ['l32', 'l42', 'l53', 'l63', 'l71', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "86, (B2) ['l33', 'l43', 'l54', 'l64', 'l72', 'l80', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "87, receptors. ['l34', 'l44', 'l55', 'l65', 'l73', 'l81', 'l88', 'l95', 'l96', 'l97', 'l98']", + "96, NEP-/- ['l35', 'l45', 'l56', 'l66', 'l74', 'l82', 'l89', 'l95', 'l99', 'l100', 'l101']", + "97, animals, ['l36', 'l46', 'l57', 'l67', 'l75', 'l83', 'l90', 'l96', 'l99']", + "103, reintroduction ['l47', 'l58', 'l76', 'l84', 'l91', 'l102', 'l103', 'l104']", + "104, of ['l37', 'l48', 'l59', 'l68', 'l77', 'l85', 'l92', 'l97', 'l100', 'l102', 'l105', 'l106']", + "105, recombinant ['l49', 'l60', 'l69', 'l78', 'l86', 'l93', 'l103', 'l105', 'l107']", + "106, NEP ['l38', 'l50', 'l61', 'l70', 'l79', 'l87', 'l94', 'l98', 'l101', 'l104', 'l106', 'l107']", + "122, NEP-/- ['l108']", + "123, mice ['l108']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice,", + "animals," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "NEP", + "gene", + "was", + "deleted", + "NEP-/-" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antagonists", + "of", + "SP", + "(NK1)", + "and", + "BK", + "(B2)", + "receptors." + ] + }, + "context": { + "val": "organism", + "words": [ + "animals," + ] + } + } + ] + }, + { + "PMID": "9256282", + "TEXT": "Graft coronary arteriosclerosis, which limits the long-term survival of allograft recipients, is characterized by diffuse intimal thickening composed of proliferative smooth muscle cells. We observed that messenger RNA of the cell cycle regulatory enzyme cyclin-dependent kinase (cdk) 2 kinase, which mediates smooth muscle cell proliferation, was elevated in the thickened intima of coronary arteries of murine heterotopic cardiac allografts. We studied the effects of antisense phosphorothioate oligodeoxynucleotide (ODN) against this enzyme using gene transfer mediated by a hemagglutinating virus of Japan (HVJ)-liposome complex intraluminally delivered to inhibit the intimal hyperplasia. At 30 days after transplantation, antisense cdk2 kinase ODN treatment had dramatically inhibited neointimal formation in the allografts. Expression of vascular cell adhesion molecule-1 was also suppressed by antisense cdk2 kinase. However, these effects were not observed in the sense or scrambled ODN-treated allografts. Thus, an intraluminal administration of antisense ODN directed to a specific cell cycle regulatory gene can inhibit neointimal formation after cardiac transplantation.", + "TAG_DATA": [ + "107, allografts. {'context': 'B-xenograft'}", + "119, cdk2 {'perturbing_action': 'I-pharmacological augmentation'}", + "120, kinase. {'perturbing_action': 'I-pharmacological augmentation'}", + "133, allografts. {'context': 'B-xenograft'}" + ], + "LINK_DATA": [ + "119, cdk2 ['l0', 'l1']", + "120, kinase. ['l0', 'l2']", + "133, allografts. ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "cdk2", + "kinase." + ] + }, + "context": { + "val": "xenograft", + "words": [ + "allografts." + ] + } + } + ] + }, + { + "PMID": "9256275", + "TEXT": "The tissue amyloid deposits that characterize systemic amyloidosis, Alzheimer's disease and the transmissible spongiform encephalopathies always contain serum amyloid P component (SAP) bound to the amyloid fibrils. We have previously proposed that this normal plasma protein may contribute to amyloidogenesis by stabilizing the deposits. Here we show that the induction of reactive amyloidosis is retarded in mice with targeted deletion of the SAP gene. This first demonstration of the participation of SAP in pathogenesis of amyloidosis in vivo confirms that inhibition of SAP binding to amyloid fibrils is an attractive therapeutic target in a range of serious human diseases.", + "TAG_DATA": [ + "56, mice {'context': 'B-organism'}", + "58, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "59, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "60, of {'perturbing_action': 'I-gene loss-of-function'}", + "61, the {'perturbing_action': 'I-gene loss-of-function'}", + "62, SAP {'perturbing_action': 'I-gene loss-of-function'}", + "63, gene. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "56, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "58, targeted ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "59, deletion ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "60, of ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "61, the ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "62, SAP ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "63, gene. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "deletion", + "of", + "the", + "SAP", + "gene." + ] + } + } + ] + }, + { + "PMID": "9256274", + "TEXT": "An adjuvant role for certain short bacterial immunostimulatory DNA sequences (ISSs) has recently been proposed on the basis of their ability to stimulate T helper-1 (Th1) responses in gene-vaccinated animals. We report here that noncoding, ISS-enriched plasmid DNAs or ISS oligonucleotides (ISS-ODNs) potently stimulate immune responses to coadministered antigens. The ISS-DNAs suppress IgE synthesis, but promote IgG and interferon-gamma (IFN-gamma) production. They furthermore initiate the production of IFN-gamma, IFN-alpha, IFN-beta, and interleukins 12 and 18, all of which foster Th1 responses and enhance cell-mediated immunity. Consideration should be given to adding noncoding DNA adjuvants to inactivated or subunit viral vaccines that, by themselves, provide only partial protection from infection.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9256273", + "TEXT": "We investigated the effect of Fas/APO1-ligand (CD95L) gene transfer on allogeneic immune responses in vivo. A colon carcinoma cell line from BALB/c mice, CT26, was stably transfected with a vector encoding mouse CD95L and was inoculated into C57BL/6 mice. CD95L expression markedly reduced allogeneic cytotoxic T lymphocyte and helper T lymphocyte activity directed toward CT26. Strikingly, expression of CD95L on these allogeneic tumors completely inhibited the generation of alloantibodies of both IgM and IgG subclasses. Thus, CD95L inhibited alloantibody production and conferred localized immune suppression through this mechanism. These results provide insight into the role of CD95L in regulating the alloantibody response and the generation of local immune responses.", + "TAG_DATA": [ + "16, colon {'context': 'B-transformed cells'}", + "17, carcinoma {'context': 'I-transformed cells'}", + "18, cell {'context': 'I-transformed cells'}", + "19, line {'context': 'I-transformed cells'}", + "20, from {'context': 'I-transformed cells'}", + "21, BALB/c {'context': 'I-organism'}", + "22, mice, {'context': 'I-transformed cells'}", + "23, CT26, {'context': 'I-transformed cells'}", + "25, stably {'perturbing_action': 'B-gene gain-of-function'}", + "26, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "27, with {'perturbing_action': 'I-gene gain-of-function'}", + "28, a {'perturbing_action': 'I-gene gain-of-function'}", + "29, vector {'perturbing_action': 'I-gene gain-of-function'}", + "30, encoding {'perturbing_action': 'I-gene gain-of-function'}", + "31, mouse {'perturbing_action': 'I-gene gain-of-function'}", + "32, CD95L {'perturbing_action': 'I-gene gain-of-function'}", + "37, C57BL/6 {'context': 'B-organism'}", + "38, mice. {'context': 'I-organism'}", + "39, CD95L {'perturbing_action': 'B-gene gain-of-function'}", + "40, expression {'perturbing_action': 'I-gene gain-of-function'}", + "48, helper {'context': 'B-cells'}", + "49, T {'context': 'I-cells'}", + "50, lymphocyte {'context': 'I-cells'}", + "56, expression {'perturbing_action': 'B-gene gain-of-function'}", + "57, of {'perturbing_action': 'I-gene gain-of-function'}", + "58, CD95L {'perturbing_action': 'I-gene gain-of-function'}", + "61, allogeneic {'context': 'B-neoplasm'}", + "62, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "16, colon ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "17, carcinoma ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "18, cell ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "19, line ['l2', 'l11', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "20, from ['l3', 'l12', 'l20', 'l26', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "21, BALB/c ['l4', 'l13', 'l21', 'l27', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "22, mice, ['l5', 'l14', 'l22', 'l28', 'l33', 'l38', 'l45', 'l46', 'l47']", + "23, CT26, ['l6', 'l15', 'l23', 'l29', 'l34', 'l39', 'l45', 'l48']", + "25, stably ['l7', 'l16', 'l24', 'l30', 'l35', 'l40', 'l46', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "26, transfected ['l8', 'l17', 'l36', 'l41', 'l49', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "27, with ['l50', 'l63', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "28, a ['l51', 'l64', 'l76', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "29, vector ['l52', 'l65', 'l77', 'l89', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "30, encoding ['l53', 'l66', 'l78', 'l90', 'l101', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "31, mouse ['l54', 'l67', 'l79', 'l91', 'l102', 'l113', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "32, CD95L ['l42', 'l55', 'l68', 'l80', 'l92', 'l103', 'l114', 'l124', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "37, C57BL/6 ['l56', 'l69', 'l81', 'l93', 'l104', 'l115', 'l125', 'l134', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150']", + "38, mice. ['l9', 'l18', 'l25', 'l31', 'l37', 'l43', 'l47', 'l48', 'l57', 'l70', 'l82', 'l94', 'l105', 'l116', 'l126', 'l135', 'l143', 'l151', 'l152', 'l153', 'l154']", + "39, CD95L ['l58', 'l71', 'l83', 'l95', 'l106', 'l117', 'l127', 'l136', 'l144', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160']", + "40, expression ['l59', 'l72', 'l84', 'l96', 'l107', 'l118', 'l128', 'l137', 'l145', 'l151', 'l155', 'l161', 'l162', 'l163', 'l164', 'l165']", + "48, helper ['l60', 'l73', 'l85', 'l97', 'l108', 'l119', 'l129', 'l138', 'l146', 'l152', 'l156', 'l161', 'l166', 'l167', 'l168']", + "49, T ['l61', 'l74', 'l86', 'l98', 'l109', 'l120', 'l130', 'l139', 'l147', 'l153', 'l157', 'l162', 'l166', 'l169', 'l170']", + "50, lymphocyte ['l44', 'l62', 'l75', 'l87', 'l99', 'l110', 'l121', 'l131', 'l140', 'l148', 'l154', 'l158', 'l163', 'l167', 'l169', 'l171']", + "56, expression ['l172', 'l173', 'l174', 'l175']", + "57, of ['l172', 'l176', 'l177', 'l178']", + "58, CD95L ['l173', 'l176', 'l179', 'l180']", + "61, allogeneic ['l111', 'l122', 'l132', 'l141', 'l149', 'l159', 'l164', 'l174', 'l177', 'l179', 'l181']", + "62, tumors ['l88', 'l100', 'l112', 'l123', 'l133', 'l142', 'l150', 'l160', 'l165', 'l168', 'l170', 'l171', 'l175', 'l178', 'l180', 'l181']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "colon", + "carcinoma", + "cell", + "line", + "from", + "mice," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "stably", + "transfected" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "BALB/c", + "C57BL/6", + "mice." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "stably", + "transfected", + "CD95L", + "with", + "a", + "vector", + "encoding", + "mouse", + "expression" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "stably", + "transfected", + "with", + "a", + "vector", + "encoding", + "mouse", + "CD95L", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "helper", + "T", + "lymphocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "with", + "a", + "vector", + "encoding", + "mouse", + "CD95L", + "expression", + "of" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "allogeneic" + ] + } + } + ] + }, + { + "PMID": "9212110", + "TEXT": "Oral administration of protein can induce antigen-specific immune hyporesponsiveness. However, the utility of oral tolerance to autoantigens in the treatment of autoimmune diseases may be limited when candidate autoantigens cannot be produced by conventional systems in quantities sufficient for clinical studies. Plants may be ideally suited for this purpose, as they can synthesize, glycosylate and assemble mammalian proteins to provide huge quantities of relatively low cost soluble proteins. Furthermore, edible transgenic plants could provide a simple and direct method of autoantigen delivery for oral tolerance. Therefore, the aim of this study was to determine whether a transgenic plant expression system was capable of synthesizing the diabetes-associated autoantigen, glutamic acid decarboxylase (GAD) in an immunogenic form and whether the oral administration of an autoantigen expressed by a plant could directly induce protective immune responses in a mouse model of diabetes. We show that a GAD-expressing transgenic plant, given as a dietary supplement, inhibits the development of diabetes in the non-obese diabetic (NOD) mouse.", + "TAG_DATA": [ + "143, GAD-expressing {'perturbing_action': 'B-gene gain-of-function'}", + "144, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "145, plant, {'perturbing_action': 'I-gene gain-of-function'}", + "158, non-obese {'context': 'B-organism'}", + "159, diabetic {'context': 'I-organism'}", + "160, (NOD) {'context': 'I-organism'}", + "161, mouse. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "143, GAD-expressing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "144, transgenic ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "145, plant, ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "158, non-obese ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "159, diabetic ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "160, (NOD) ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "161, mouse. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GAD-expressing", + "transgenic", + "plant," + ] + }, + "context": { + "val": "organism", + "words": [ + "non-obese", + "diabetic", + "(NOD)", + "mouse." + ] + } + } + ] + }, + { + "PMID": "9176497", + "TEXT": "Neutralization of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) or interleukin-1 (IL-1), decreases mortality in several animal models of sepsis. However, recent clinical trials did not show an unequivocal improvement in survival. In contrast to animals, which succumb to shock during the first 72 hours, we found that many patients die much later with signs of opportunistic infections accompanied by downregulation of their monocytic HLA-DR expression and reduced ability to produce lipopolysaccharide (LPS)-induced TNF-alpha in vitro. This phenomenon of monocyte deactivation in septic patients with fatal outcome shows similarities to experimental monocytic refractoriness induced by LPS desensitization or by pretreatment with its endogenous mediators IL-10 and transforming growth factor-beta (TGF-beta). In order to strengthen their antimicrobial defense, here we tested whether interferon-gamma (IFN-gamma) can improve monocytic functions in these patients and in experimental monocytic deactivation. The considerably lowered in vitro levels of LPS-induced TNF-alpha in these situations were significantly enhanced by IFN-gamma, but did not reach the extremely high levels of IFN-gamma primed naive cells from healthy donors. Moreover, IFN-gamma applied to septic patients with low monocytic HLA-DR expression restored the deficient HLA-DR expression and in vitro LPS-induced TNF-alpha secretion. Recovery of monocyte function resulted in clearance of sepsis in eight of nine patients. These data suggest that IFN-gamma treatment in carefully selected septic patients is a novel therapeutic strategy worth pursuing.", + "TAG_DATA": [ + "75, in {'context': 'B-in vitro'}", + "76, vitro. {'context': 'I-in vitro'}", + "139, in {'context': 'B-in vitro'}", + "140, vitro {'context': 'I-in vitro'}", + "164, naive {'context': 'B-cells'}", + "165, cells {'context': 'I-cells'}", + "168, donors. {'context': 'I-cells'}", + "186, in {'context': 'B-in vitro'}", + "187, vitro {'context': 'I-in vitro'}", + "193, monocyte {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "75, in ['l0']", + "76, vitro. ['l0']", + "139, in ['l1']", + "140, vitro ['l1']", + "164, naive ['l2', 'l3']", + "165, cells ['l2', 'l4']", + "168, donors. ['l3', 'l4']", + "186, in ['l5']", + "187, vitro ['l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9176496", + "TEXT": "Pulmonary emphysema is a common disease in which destruction of the lung's gas-exchange structures (alveoli) leads to inadequate oxygenation, disability and frequently death; lung transplantation provides its only remediation. Because treatment of normal rats with all-trans-retinoic acid increases the number of alveoli, we tested whether a similar effect would occur in rats with emphysema. Elastase was instilled into rat lungs, producing changes characteristic of human and experimental emphysema: increased lung volume reflecting a loss of lung elastic recoil, larger but fewer alveoli and diminished volume-corrected alveolar surface area due to destruction of alveolar walls. Treatment with all-trans-retinoic acid reversed these changes providing nonsurgical remediation of emphysema and suggesting the possibility of a similar effect in humans.", + "TAG_DATA": [ + "33, rats {'context': 'I-organism'}", + "58, rat {'context': 'B-tissue/organ'}", + "59, lungs, {'context': 'I-tissue/organ'}", + "69, lung {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "33, rats ['l0', 'l1', 'l2']", + "58, rat ['l0', 'l3', 'l4']", + "59, lungs, ['l1', 'l3', 'l5']", + "69, lung ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9176495", + "TEXT": "Studies of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in monkeys suggest that excessive inhibitory outflow from the internal segment of the globus pallidus (GPi) suppresses the motor thalamus, which reduces activation of the cerebral cortex motor system, resulting in the slowness and poverty of movement of Parkinson's disease (PD). This hypothesis is supported by reports of high rates of spontaneous neuronal discharges and hypermetabolism in GPi (ref. 4-7) and impaired activation of the supplementary motor area (SMA) and dorsolateral prefrontal regions in PD patients. Furthermore, lesion or chronic high-frequency electrical (likely inactivating) stimulation of GPi (ref. 10-14) is associated with marked improvements in akinesia and rigidity, and the impaired activation of SMA is reversed when the akinesia is treated with dopamine agonists. To test whether improvement in motor function with pallidal surgery can be attributed to increased activity in premotor cortical regions, we assessed the changes in regional cerebral blood flow (rCBF) and parkinsonian symptoms during disruption of GPi activity with high-frequency stimulation delivered through implanted brain electrodes. Positron emission tomography (PET) revealed an increase in rCBF in ipsilateral premotor cortical areas during GPi stimulation, which improved rigidity and bradykinesia. These results suggest that disrupting the excessive inhibitory output of the basal ganglia reverses parkinsonism, via a thalamic relay, by activation of brain areas involved in the initiation of movement.", + "TAG_DATA": [ + "175, ipsilateral {'context': 'B-cells'}", + "176, premotor {'context': 'I-cells'}", + "177, cortical {'context': 'I-cells'}", + "178, areas {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "175, ipsilateral ['l0', 'l1', 'l2']", + "176, premotor ['l0', 'l3', 'l4']", + "177, cortical ['l1', 'l3', 'l5']", + "178, areas ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9176490", + "TEXT": "The 55-kilodalton (kDa) protein from the E1B-region of adenovirus binds to and inactivates the p53 gene, which is mutated in half of human cancers. We have previously shown that the replication and cytopathogenicity of an E1B, 55-kDa gene-attenuated adenovirus, ONYX-015, is blocked by functional p53 in RKO and U20S carcinoma lines. We now report that normal human cells were highly resistant to ONYX-015-mediated, replication-dependent cytolysis. In contrast, a wide range of human tumor cells, including numerous carcinoma lines with either mutant or normal p53 gene sequences (exons 5-9), were efficiently destroyed. Antitumoral efficacy was documented following intratumoral or intravenous administration of ONYX-015 to nude mouse-human tumor xenografts; efficacy with ONYX-015 plus chemotherapy (cisplatin, 5-fluorouracil) was significantly greater than with either agent alone.", + "TAG_DATA": [ + "48, U20S {'context': 'I-transformed cells'}", + "49, carcinoma {'context': 'I-transformed cells'}", + "50, lines. {'context': 'I-transformed cells'}", + "55, normal {'context': 'B-cells'}", + "56, human {'context': 'I-cells'}", + "57, cells {'context': 'I-cells'}", + "71, human {'context': 'B-transformed cells'}", + "72, tumor {'context': 'I-transformed cells'}", + "73, cells, {'context': 'I-transformed cells'}", + "76, carcinoma {'context': 'B-transformed cells'}", + "77, lines {'context': 'I-transformed cells'}", + "103, nude {'context': 'B-xenograft'}", + "104, mouse-human {'context': 'I-xenograft'}", + "105, tumor {'context': 'I-xenograft'}", + "106, xenografts; {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "48, U20S ['l0', 'l1', 'l2', 'l3', 'l4']", + "49, carcinoma ['l0', 'l5', 'l6', 'l7', 'l8']", + "50, lines. ['l1', 'l5', 'l9', 'l10']", + "55, normal ['l2', 'l6', 'l11', 'l12']", + "56, human ['l3', 'l7', 'l9', 'l11', 'l13']", + "57, cells ['l4', 'l8', 'l10', 'l12', 'l13']", + "71, human ['l14', 'l15', 'l16', 'l17']", + "72, tumor ['l14', 'l18', 'l19', 'l20']", + "73, cells, ['l15', 'l18', 'l21', 'l22']", + "76, carcinoma ['l16', 'l19', 'l21', 'l23']", + "77, lines ['l17', 'l20', 'l22', 'l23']", + "103, nude ['l24', 'l25', 'l26']", + "104, mouse-human ['l24', 'l27', 'l28']", + "105, tumor ['l25', 'l27', 'l29']", + "106, xenografts; ['l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9176488", + "TEXT": "Daily treatment of mice with recombinant human Flt3 ligand (huFlt3L) results in a dramatic numerical increase in the number of dendritic cells (DCs) in vivo. Since DCs are pivotal in the induction of immune responses, we tested whether Flt3L treatment of mice challenged with a syngeneic methylcholanthrene (MCA)-induced fibrosarcoma would augment the generation of effective antitumor immune responses in vivo. Flt3L treatment not only induced complete tumor regression in a significant proportion of mice, but also decreased tumor growth rate in the remaining mice. A preliminary characterization of the cellular mechanisms involved suggests that Flt3L may be important in the treatment of cancer in situ through the generation of specific antitumor immune responses.", + "TAG_DATA": [ + "41, mice {'context': 'B-organism'}", + "48, fibrosarcoma {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}", + "58, in {'context': 'B-in vivo'}", + "59, vivo. {'context': 'I-in vivo'}", + "64, induced {'effect': 'B-positive'}", + "66, tumor {'phenotype': 'B-tumour regression'}", + "67, regression {'phenotype': 'I-tumour regression'}", + "73, mice, {'context': 'B-organism'}", + "76, decreased {'effect': 'B-negative'}", + "77, tumor {'phenotype': 'B-tumour growth'}", + "78, growth {'phenotype': 'I-tumour growth'}", + "83, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "41, mice ['l0', 'l1', 'l2']", + "48, fibrosarcoma ['l0', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "58, in ['l1', 'l3', 'l9']", + "59, vivo. ['l2', 'l4', 'l9']", + "64, induced ['l5', 'l10', 'l11', 'l12']", + "66, tumor ['l6', 'l10', 'l13', 'l14']", + "67, regression ['l7', 'l11', 'l13', 'l15']", + "73, mice, ['l8', 'l12', 'l14', 'l15']", + "76, decreased ['l16', 'l17', 'l18']", + "77, tumor ['l16', 'l19', 'l20']", + "78, growth ['l17', 'l19', 'l21']", + "83, mice. ['l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "fibrosarcoma" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "fibrosarcoma" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "fibrosarcoma" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "fibrosarcoma" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "fibrosarcoma" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "fibrosarcoma" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "fibrosarcoma" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "9176487", + "TEXT": "A reliable, noninvasive method for monitoring patients with transitional cell carcinoma (TCC) of the bladder would be of great clinical benefit. Cystoscopy is currently the \"gold standard,\" but it is invasive, expensive and uncomfortable for the patient. Recently, we demonstrated a novel approach for the detection of primary bladder cancer based on microsatellite analysis of urine DNA. To determine the feasibility of this technique for following-up patients with TCC, we tested serial urine samples from 21 patients who had been treated for bladder cancer with 20 polymorphic microsatellite markers in a blinded fashion. We detected recurrent lesions in 10 out of 11 patients and correctly predicted the existence of a neoplastic cell population in the urine of two patients, 4 and 6 months before cystoscopic evidence of the tumor. The assay was negative in 10 of 10 patients who had no evident cancer. Microsatellite analysis of urine sediment represents a novel and potentially powerful clinical tool for the detection of recurrent bladder cancer.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9142132", + "TEXT": "Secreted proteins are a therapeutic cornerstone of the biotechnology industry, and numerous recombinant products, including human growth hormone, human erythropoietin and granulocyte-colony stimulating factor, are now widely prescribed. In addition to bioprocessing applications, GMD technology should benefit the emerging fields of cellular and gene therapy. The ability to assess rapidly and precisely the productivity of cells for ex vivo cell screening and expansion is a unique approach with numerous research and therapeutic uses.", + "TAG_DATA": [ + "55, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9142131", + "TEXT": "Leptin communicates nutritional status to regulatory centers in the brain. Because peripheral leptin influences the activity of the highly pulsatile adrenal and gonadal axes, we sought to determine whether leptin levels in the blood are pulsatile. We measured circulating leptin levels every 7 minutes for 24 hours, in six healthy men, and found that total circulating leptin levels exhibited a pattern indicative of pulsatile release, with 32.0 +/- 1.5 pulses every 24 hours and a pulse duration of 32.8 +/- 1.6 minutes. We also show an inverse relation between rapid fluctuations in plasma levels of leptin and those of adrenocorticotropic hormone (ACTH) and cortisol that could not be accounted for on the basis of glucocorticoid suppression of leptin. As leptin levels are pulsatile, we propose that a key function of the CNS is regulated by a peripheral pulsatile signal. In a separate pilot study we compared leptin pulsatility in 414 plasma samples collected every 7 minutes for 24 hours from one obese woman and one normal-weight woman. We found that high leptin levels in the obese subject were due solely to increased leptin pulse height; all concentration-independent pulsatility parameters were almost identical in the two women. Leptin pulsatility therefore can be preserved in the obese.", + "TAG_DATA": [ + "49, healthy {'context': 'B-organism'}", + "50, men, {'context': 'I-organism'}", + "162, woman {'context': 'I-organism'}", + "166, woman. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "49, healthy ['l0']", + "50, men, ['l0']", + "162, woman ['l1', 'l2']", + "165, normal-weight ['l1', 'l3']", + "166, woman. ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9142128", + "TEXT": "Leukotoxin is a linoleic acic oxide produced by leukocytes and has been associated with the multiple organ failure and adult respiratory distress syndrome seen in some severe burn patients. Leukotoxin has been reported to be toxic when injected into animals intravenously. Herein, we report that this lipid is not directly cytotoxic in at least two in vitro systems. Using a baculovirus expression system we demonstrate that leukotoxin is only cytotoxic in the presence of epoxide hydrolases. In addition, it is the diol metabolite that proves toxic to pulmonary alveolar epithelial cells, suggesting a critical role for the diol in leukotoxin-associated respiratory disease. In vivo data also support the toxicity of leukotoxin diol. For the first time we demonstrate that soluble epoxide hydrolase can bioactivate epoxides to diols that are apparently cytotoxic. Thus leukotoxin should be regarded as a protoxin corresponding to the more toxic diol. This clearly has implications for designing new clinical interventions.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9142121", + "TEXT": "Novel approaches for the generation of more effective vaccines for HIV-1 are of significant importance. In this report we analyze the immunogenicity and efficacy of an HIV-1 DNA vaccine encoding env, rev and gag/pol in a chimpanzee model system. The immunized animals developed specific cellular and humoral immune responses. Animals were challenged with a heterologous chimpanzee titered stock of HIV-1 SF2 virus and followed for 48 weeks after challenge. Polymerase chain reaction coupled with reverse transcription (RT-PCR) results indicated infection in the control animal, whereas those animals vaccinated with the DNA constructs were protected from the establishment of infection. These studies serve as an important benchmark for the use of DNA vaccine technology for the production of protective immune responses.", + "TAG_DATA": [ + "36, chimpanzee {'context': 'B-organism'}", + "37, model {'context': 'I-organism'}", + "41, animals {'context': 'B-organism'}", + "49, Animals {'context': 'B-organism'}", + "83, animal, {'context': 'B-organism'}", + "86, animals {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "36, chimpanzee ['l0', 'l1']", + "37, model ['l0', 'l2']", + "38, system. ['l1', 'l2']", + "49, Animals ['l3']", + "83, animal, ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9095179", + "TEXT": "Angiogenesis, the growth of new blood vessels, occurs normally in female reproductive organs. We tested the hypothesis that angiogenesis inhibition may affect fertility by studying the reproductive system in either pregnant or nonpregnant cycling mice after treatment with the angiogenesis inhibitor AGM-1470. Administration of AGM-1470 to pregnant mice resulted in complete failure of embryonic growth due to interference with decidualization, placental and yolk sac formation, and embryonic vascular development. When nonpregnant cycling female mice were chronically treated with AGM-1470, inhibition of endometrial maturation and corpora lutea was observed. These data suggest that processes in reproduction can be controlled through angiogenesis inhibition.", + "TAG_DATA": [ + "32, nonpregnant {'context': 'B-organism'}", + "33, cycling {'context': 'I-organism'}", + "34, mice {'context': 'I-organism'}", + "46, pregnant {'context': 'B-organism'}", + "47, mice {'context': 'I-organism'}", + "51, failure {'effect': 'B-negative'}", + "53, embryonic {'phenotype': 'B-tumourigenesis'}", + "54, growth {'phenotype': 'I-cell growth'}", + "57, interference {'effect': 'B-negative'}", + "70, nonpregnant {'context': 'B-organism'}", + "71, cycling {'context': 'I-organism'}", + "72, female {'context': 'I-organism'}", + "73, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "32, nonpregnant ['l0', 'l1', 'l2']", + "33, cycling ['l0', 'l3']", + "34, mice ['l1', 'l3']", + "46, pregnant ['l4', 'l5', 'l6', 'l7', 'l8']", + "47, mice ['l4', 'l9', 'l10', 'l11', 'l12']", + "51, failure ['l5', 'l9', 'l13', 'l14', 'l15']", + "53, embryonic ['l6', 'l10', 'l13', 'l16', 'l17']", + "54, growth ['l2', 'l7', 'l11', 'l14', 'l16', 'l18']", + "57, interference ['l8', 'l12', 'l15', 'l17', 'l18']", + "70, nonpregnant ['l19', 'l20', 'l21']", + "71, cycling ['l19', 'l22', 'l23']", + "72, female ['l20', 'l22', 'l24']", + "73, mice ['l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "nonpregnant", + "pregnant", + "mice" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "pregnant", + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "failure", + "interference" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "pregnant", + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "embryonic" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "failure", + "interference" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "embryonic" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "failure", + "interference" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + } + ] + }, + { + "PMID": "9095176", + "TEXT": "We show that the nonimmunosuppressive analogues of the immunosuppressive drugs FK506, rapamycin and cyclosporin A promote neurite outgrowth both in PC12 cells and sensory neuronal cultures of dorsal root ganglia with potencies resembling their immunosuppressive homologues. Neurotrophic potencies of the immunophilin ligands resemble their potencies in binding to and inhibiting the rotamase activity of FKBP-12 of cyclophilin. Since nonimmunosuppressive immunophilin ligands, which are devoid of calcineurin inhibitory activity, are equally neurotrophic, inhibition of calcineurin activity is not the mediator of the neurotrophic effects. The immunophilin ligands are neurotrophic in intact animals. FK506 and L-685,818 (the C18-hydroxy, C21-ethyl derivative of FK506) treatment of rats with crushed sciatic nerves enhances both functional and morphologic recovery. The striking potency of these agents, their bioavailability and the dissociation of neurotrophic from immunosuppressant actions argue for their therapeutic relevance in the treatment of neurodegenerative diseases.", + "TAG_DATA": [ + "20, PC12 {'context': 'B-cells'}", + "21, cells {'context': 'I-cells'}", + "23, sensory {'context': 'B-cells'}", + "24, neuronal {'context': 'I-cells'}", + "25, cultures {'context': 'I-cells'}", + "26, of {'context': 'I-cells'}", + "27, dorsal {'context': 'I-cells'}", + "28, root {'context': 'I-cells'}", + "29, ganglia {'context': 'I-cells'}", + "102, rats {'context': 'B-organism'}", + "105, sciatic {'context': 'B-tissue/organ'}", + "106, nerves {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "20, PC12 ['l0', 'l1']", + "21, cells ['l0']", + "23, sensory ['l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "24, neuronal ['l2', 'l8', 'l9', 'l10', 'l11', 'l12']", + "25, cultures ['l1', 'l3', 'l8', 'l13', 'l14', 'l15', 'l16']", + "26, of ['l4', 'l9', 'l13', 'l17', 'l18', 'l19']", + "27, dorsal ['l5', 'l10', 'l14', 'l17', 'l20', 'l21']", + "28, root ['l6', 'l11', 'l15', 'l18', 'l20', 'l22']", + "29, ganglia ['l7', 'l12', 'l16', 'l19', 'l21', 'l22']", + "102, rats ['l23', 'l24']", + "105, sciatic ['l23', 'l25']", + "106, nerves ['l24', 'l25']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9095174", + "TEXT": "The Fas ligand (FasL) is expressed in activated T cells and induces apoptosis in Fas-bearing cells. A cytotoxic T lymphocyte (CTL) clone specific for hepatitis B surface antigen (HBsAg) causes an acute liver disease in HBsAg transgenic mice. Here we observed that the CTL clone killed hepatocytes expressing HBsAg in a Fas-dependent manner. Administration of the soluble form of Fas into HBsAg transgenic mice prevented the CTL-induced liver disease. In the second model, mice were primed with Propionibacterium acnes. A subsequent challenge with lipopolysaccharide (LPS) killed the mice by inducing liver injury. Neutralization of FasL rescued the mice from LPS-induced mortality, and Fas-null mice were resistant to LPS-induced mortality. These results suggest that FasL has an essential role in the development of hepatitis.", + "TAG_DATA": [ + "46, hepatocytes {'context': 'B-cells'}", + "61, HBsAg {'perturbing_action': 'B-gene gain-of-function'}", + "62, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "63, mice {'context': 'B-organism'}", + "67, liver {'context': 'B-tissue/organ'}", + "73, mice {'context': 'B-organism'}", + "87, mice {'context': 'B-organism'}", + "90, liver {'context': 'B-tissue/organ'}", + "92, Neutralization {'perturbing_action': 'B-pharmacological inhibition'}", + "93, of {'perturbing_action': 'I-rnai/knockdown'}", + "94, FasL {'perturbing_action': 'I-rnai/knockdown'}", + "97, mice {'context': 'B-organism'}", + "102, Fas-null {'perturbing_action': 'B-gene loss-of-function'}", + "103, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "46, hepatocytes ['l0']", + "61, HBsAg ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "62, transgenic ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "63, mice ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "67, liver ['l0', 'l3', 'l8', 'l12']", + "73, mice ['l4', 'l9', 'l13', 'l16', 'l17']", + "87, mice ['l5', 'l10', 'l14', 'l16', 'l18']", + "90, liver ['l6', 'l11', 'l15', 'l17', 'l18']", + "92, Neutralization ['l19', 'l20', 'l21', 'l22']", + "93, of ['l19', 'l23', 'l24']", + "94, FasL ['l20', 'l23', 'l25']", + "97, mice ['l21', 'l24', 'l25']", + "102, Fas-null ['l26']", + "103, mice ['l22', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "HBsAg", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "HBsAg", + "transgenic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Neutralization" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "FasL" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fas-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "9055868", + "TEXT": "HSV has a unique relationship with neurons which the virus naturally utilizes for efficient gene transfer and long-term gene expression. Progress in developing defective viral mutants with reduced cytotoxicity, and increasing insight into the state of the viral genome during latency and the functional elements of the latency promoter system, suggest that HSV vectors may be developed in which these natural features are exploited for effective transgene expression in brain.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9055865", + "TEXT": "Nucleocapsid p7 (NCp7) proteins of human immunodeficiency virus type 1 (HIV-1) contain two zinc binding domains of the sequence Cys-(X)2-Cys-(X)4-His-(X)4-Cys (CCHC). The spacing pattern and metal-chelating residues (3 Cys, 1 His) of these nucleocapside CCHC zinc fingers are highly conserved among retroviruses. These CCHC domains are required during both the early and late phases of retroviral replication, making them attractive targets for antiviral agents. toward that end, we have identified a number of antiviral chemotypes that electrophilically attack the sulfur atoms of the zinc-coordinating cysteine residues of the domains. Such nucleocapside inhibitors were directly virucidal by preventing the initiation of reverse transcription and blocked formation of infectious virus from cells through modification of CCHC domains within Gag precursors. Herein we report that azodicarbonamide (ADA) represents a new compound that inhibits HIV-1 and a broad range of retroviruses by targeting the the nucleocapsid CCHC domains. Vandevelde et al. also recently disclosed that ADA inhibits HIV-1 infection via an unidentified mechanism and that ADA was introduced into Phase I/II clinical trials in Europe for advanced AIDS. These studies distinguish ADA as the first known nucleocapsid inhibitor to progress to human trials and provide a lead compound for drug optimization.", + "TAG_DATA": [ + "96, preventing {'effect': 'B-negative'}", + "109, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "96, preventing ['l0']", + "109, cells ['l0']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "preventing" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "9055863", + "TEXT": "Accelerated programmed cell death, or apoptosis, contributes to the CD4+ T-cell depletion characteristic of infection by human immunodeficiency virus (HIV). It has therefore been proposed that limiting apoptosis may represent a therapeutic modality for HIV infection. We found, however, that T leukemia cells or peripheral blood mononuclear cells (PBMCs) exposed to HIV-1 underwent enhanced viral replication in the presence of the cell death inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-AVD-fmk). Furthermore, z-VAD-fmk, which targets the pro-apoptotic interleukin-1 beta-converting enzyme (ICE)-like proteases, stimulated endogenous virus production in activated PBMCs derived from HIV-1-infected asymptomatic individuals. These findings suggest that programmed cell death may serve as a beneficial host mechanism to limit HIV spread and that strategies to inhibit it may have deleterious consequences for the infected host.", + "TAG_DATA": [ + "40, T {'context': 'B-transformed cells'}", + "41, leukemia {'context': 'I-transformed cells'}", + "42, cells {'context': 'I-transformed cells'}", + "44, peripheral {'context': 'B-cells'}", + "45, blood {'context': 'I-cells'}", + "46, mononuclear {'context': 'I-cells'}", + "47, cells {'context': 'I-cells'}", + "48, (PBMCs) {'context': 'I-cells'}", + "83, PBMCs {'context': 'B-cells'}", + "88, individuals. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "40, T ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "41, leukemia ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "42, cells ['l1', 'l7', 'l13', 'l14']", + "44, peripheral ['l2', 'l8', 'l15', 'l16', 'l17', 'l18']", + "45, blood ['l3', 'l9', 'l15', 'l19', 'l20', 'l21']", + "46, mononuclear ['l4', 'l10', 'l16', 'l19', 'l22', 'l23']", + "47, cells ['l5', 'l11', 'l13', 'l17', 'l20', 'l22', 'l24']", + "48, (PBMCs) ['l6', 'l12', 'l14', 'l18', 'l21', 'l23', 'l24']", + "83, PBMCs ['l25']", + "88, individuals. ['l25']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9018243", + "TEXT": "Mutations in certain genes that regulate the cell cycle, such as p16 and p53, are frequently found in human cancers. However, tumor-specific mutations are uncommon in genes encoding cyclin E and the CDK inhibitor p27Kip1, two cell-cycle regulators that are also thought to contribute to tumor progression. It is now known that levels of both cyclin E and p27 can be controlled by posttranscriptional mechanisms, indicating that expression of these proteins can be altered by means other than simply mutation of their respective genes. Thus, changes in p27 and cyclin E protein levels in tumors might be more common than previously anticipated and may be indicators of tumor behavior.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9018241", + "TEXT": "The precise role played by HIV-specific cytotoxic T lymphocytes (CTL) in HIV infection remains controversial. Despite strong CTL responses being generated during the asymptomatic phase, the virus persists and AIDS ultimately develops. It has been argued that the virus is so variable, and the virus turnover so great that escape from CTL recognition would occur continually, but so far there is limited evidence for CTL escape. The opposing argument is that evidence for CTL escape is present but hard to find because multiple anti-HIV immune responses are acting simultaneously during the asymptomatic phase of infection. We describe six donors who make a strong CTL response to an immunodominant HLA-B27-restricted epitope. In the two donors who progressed to AIDS, CTL escape to fixation by the same mutation was observed, but only after 9-12 years of epitope stability. CTL escape may play an important role in the pathogenesis of HIV infection.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9018237", + "TEXT": "Psoriasis is a complex disorder involving alterations of many cell types. Although evidence suggests a T-cell pathogenesis for psoriasis, a primary role of T cells has not been directly demonstrated. Here, we show that reconstitution of scid/scid mice with minor histocompatibility mismatched naive CD4+ T lymphocytes resulted in skin alterations that strikingly resembled human psoriasis clinically, histopathologically and in cytokine expression. This skin disorder was diminished when memory T cells were coinjected. Thus, a subset of dysregulated CD4+ T cells can cause tissue alterations seen in psoriasis without the presence of CD8+ cells or a primary epithelial abnormality.", + "TAG_DATA": [ + "36, scid/scid {'perturbing_action': 'B-gene loss-of-function'}", + "37, mice {'context': 'B-organism'}", + "42, naive {'context': 'B-cells'}", + "43, CD4+ {'context': 'I-cells'}", + "44, T {'context': 'I-cells'}", + "45, lymphocytes {'context': 'I-cells'}", + "67, memory {'context': 'B-cells'}", + "68, T {'context': 'I-cells'}", + "69, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "36, scid/scid ['l0', 'l1', 'l2', 'l3', 'l4']", + "37, mice ['l0', 'l5', 'l6', 'l7', 'l8']", + "42, naive ['l1', 'l5', 'l9', 'l10', 'l11']", + "43, CD4+ ['l2', 'l6', 'l9', 'l12', 'l13']", + "44, T ['l3', 'l7', 'l10', 'l12', 'l14']", + "45, lymphocytes ['l4', 'l8', 'l11', 'l13', 'l14']", + "67, memory ['l15', 'l16']", + "68, T ['l15', 'l17']", + "69, cells ['l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "scid/scid" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "scid/scid" + ] + }, + "context": { + "val": "cells", + "words": [ + "naive", + "CD4+", + "T", + "lymphocytes" + ] + } + } + ] + }, + { + "PMID": "8946840", + "TEXT": "Genetic alterations in malignant tissues are potential targets for gene-based cancer therapies. Alternatively, aberrant expression of certain specific genes associated with malignant transformation may be envisioned to enhance the expression of chemosensitizing drugs. Epstein-Barr virus (EBV)-related B-cell lymphomas are fatal complications of immunosuppression due to AIDS, organ transplantation or congenital immune abnormalities. The malignant cells latently infected with EBV typically express the transcription factor EBNA2 as one of nine latent viral genes. We tested whether an EBNA2-responsive EBV promoter may selectively target EBV-related lymphoma cells by virus-regulated expression of a suicide gene. Using the BamC promoter driving a hygromycin-thymidine kinase fusion gene or controls, we demonstrated that sensitivity to ganciclovir was selectively enhanced in cells expressing EBNA2. Further, there was complete macroscopic regression of established B-cell lymphomas in mice with severe combined immunodeficiency disease (SCID mice) treated with a single course of ganciclovir. These data provide in vitro and in vivo support for a model of exploiting the molecular basis of tumor development to enhance the specificity of gene therapy.", + "TAG_DATA": [ + "114, cells {'context': 'B-cells'}", + "122, regression {'phenotype': 'I-tumour regression'}", + "125, B-cell {'context': 'B-neoplasm'}", + "126, lymphomas {'context': 'I-neoplasm'}", + "128, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "122, regression ['l0', 'l1', 'l2']", + "125, B-cell ['l0', 'l3', 'l4']", + "126, lymphomas ['l1', 'l3', 'l5']", + "128, mice ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "B-cell", + "lymphomas" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "8946833", + "TEXT": "Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a disorder of childhood associated with inappropriate hypersecretion of insulin by the pancreas. The pathogenesis of the condition has hitherto remained controversial. We show here that insulin-secreting cells from a homogeneous group of five infants with PHHI lack ATP-sensitive K+ channel (KATP) activity. As a consequence, PHHI beta-cells are spontaneously electrically active with high basal cytosolic Ca2+ concentrations due to Ca2+ influx. Our findings define the pathogenesis of this disease as a novel K+ channel disorder.", + "TAG_DATA": [ + "33, insulin-secreting {'context': 'B-cells'}", + "34, cells {'context': 'I-cells'}", + "53, PHHI {'context': 'B-cells'}", + "54, beta-cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "33, insulin-secreting ['l0']", + "34, cells ['l0']", + "53, PHHI ['l1']", + "54, beta-cells ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8946832", + "TEXT": "The use of aminoglycoside antibiotics is limited by ototoxicity that can produce permanent hearing loss. We report that concurrent administration of N-methyl-D-aspartate (NMDA) antagonists markedly attenuates both the hearing loss and destruction of cochlear hair cells in guinea pigs treated with aminoglycoside antibiotics. These findings indicate that aminoglycoside-induced hearing loss is mediated, in part, through an excitotoxic process. The high correlation (Spearman correlation coefficient: 0.928; P < 0.01) obtained between the relative cochleotoxicities of a series of aminoglycosides in humans and the potencies of these compounds to produce a polyamine-like enhancement of [3H]dizocilpine binding to NMDA receptors is consistent with this hypothesis, and provides a simple in vitro assay that can predict this aspect of aminoglycoside-induced ototoxicity.", + "TAG_DATA": [ + "33, cochlear {'context': 'B-cells'}", + "34, hair {'context': 'I-cells'}", + "35, cells {'context': 'I-cells'}", + "37, guinea {'context': 'B-organism'}", + "38, pigs {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "33, cochlear ['l0', 'l1', 'l2', 'l3']", + "34, hair ['l0', 'l4', 'l5', 'l6']", + "35, cells ['l1', 'l4', 'l7', 'l8']", + "37, guinea ['l2', 'l5', 'l7', 'l9']", + "38, pigs ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8898757", + "TEXT": "Polymorphonuclear leukocyte (PMN) migration into sites of inflammation is fundamental to the host defense response. Activation of endothelial cells and PMNs increases the expression or activation of adhesion molecules, culminating in rolling and subsequent adherence of these cells to the vascular wall. Further activation of adherent PMNs, possibly by endothelial cell ligands, leads, within a few minutes, to extravasation itself. This process is not clearly understood, but adhesion molecules or related proteins, as well as endogenous chemokines, may play an important role. The anti-inflammatory glucocorticoids delay extravasation, which implies that an inhibitory regulatory system exists. Resting PMNs contain abundant cytoplasmic lipocortin 1 (LC1, also called annexin I)', and the activity profile of this protein suggests that it could reduce PMN responsiveness. To investigate this we have assessed neutrophil transmigration both in vivo and in vitro and examined the content and subcellular distribution of LC1 in PMNs by fluorescence-activated cell-sorting (FACS) analysis, western blotting and confocal microscopy. We report that LC1 is mobilized and externalized following PMN adhesion to endothelial monolayers in vitro or to venular endothelium in vivo and that the end point of this process is a negative regulation of PMN transendothelial passage.", + "TAG_DATA": [ + "131, vivo {'context': 'I-in vivo'}", + "134, vitro {'context': 'I-in vitro'}", + "165, PMN {'context': 'B-cells'}", + "168, endothelial {'context': 'B-cells'}", + "169, monolayers {'context': 'I-cells'}", + "170, in {'context': 'B-in vitro'}", + "171, vitro {'context': 'I-in vitro'}", + "174, venular {'context': 'B-cells'}", + "175, endothelium {'context': 'I-cells'}", + "176, in {'context': 'B-in vivo'}", + "177, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "131, vivo ['l0']", + "134, vitro ['l0']", + "165, PMN ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "168, endothelial ['l1', 'l8', 'l9', 'l10']", + "169, monolayers ['l2', 'l8', 'l11', 'l12']", + "170, in ['l3', 'l9', 'l11', 'l13']", + "171, vitro ['l4', 'l10', 'l12', 'l13']", + "174, venular ['l14', 'l15', 'l16']", + "175, endothelium ['l5', 'l14', 'l17', 'l18']", + "176, in ['l6', 'l15', 'l17', 'l19']", + "177, vivo ['l7', 'l16', 'l18', 'l19']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8898756", + "TEXT": "Glucagon-like peptide 1 (GLP1) is postulated to regulate blood glucose and satiety, but the biological importance of GLP1 as an incretin and neuropeptide remains controversal. The regulation of nutrient-induced insulin secretion is dependent on the secretion of incretins, gut-derived peptides that potentiate insulin secretion from the pancreatic islets. To ascertain the relative physiological importance of GLP1 as a regulator of feeding behavior and insulin secretion, we have generated mice with a targeted disruption of the GLP1 receptor gene (GLP1R). These GLP1R-/- mice are viable, develop normally but exhibit increased levels of blood glucose following oral glucose challenge in association with diminished levels of circulating insulin. It is surprising that they also exhibit abnormal levels of blood glucose following intraperitoneal glucose challenge. Intracerebroventricular administration of GLP1 inhibited feeding in wild-type mice but not in GLP1R-/- mice; however, no evidence for abnormal body weight or feeding behavior was observed in GLP1R-/- mice. These observations demonstrate that GLP1 plays a central role in the regulation of glycemia; however, disruption of GLP1/GLP1R signaling in the central nervous system is not associated with perturbation of feeding behavior or obesity in vivo.", + "TAG_DATA": [ + "68, mice {'context': 'B-organism'}", + "71, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "72, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "73, of {'perturbing_action': 'I-gene loss-of-function'}", + "74, the {'perturbing_action': 'I-gene loss-of-function'}", + "75, GLP1 {'perturbing_action': 'I-gene loss-of-function'}", + "76, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "77, gene {'perturbing_action': 'I-gene loss-of-function'}", + "78, (GLP1R). {'perturbing_action': 'I-gene loss-of-function'}", + "80, GLP1R-/- {'perturbing_action': 'B-gene loss-of-function'}", + "81, mice {'context': 'B-organism'}", + "129, mice {'context': 'B-organism'}", + "133, GLP1R-/- {'perturbing_action': 'B-gene loss-of-function'}", + "134, mice; {'context': 'B-organism'}", + "148, GLP1R-/- {'perturbing_action': 'B-gene loss-of-function'}", + "149, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "68, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "71, targeted ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "72, disruption ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "73, of ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "74, the ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "75, GLP1 ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "76, receptor ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "77, gene ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "78, (GLP1R). ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "80, GLP1R-/- ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "81, mice ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "129, mice ['l55', 'l56']", + "133, GLP1R-/- ['l55', 'l57']", + "134, mice; ['l56', 'l57']", + "148, GLP1R-/- ['l58']", + "149, mice. ['l58']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice;", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "disruption", + "of", + "the", + "GLP1", + "receptor", + "gene", + "(GLP1R).", + "GLP1R-/-" + ] + } + } + ] + }, + { + "PMID": "8898754", + "TEXT": "Sex differences in human responses to nociceptive stimuli and painful pathological conditions have generally indicated that women report higher pain levels or exhibit less tolerance than men for given stimulus intensities (reviewed in ref. 1 and 2). However, studies have not evaluated sex differences in analgesic responses. We recently reported that the opioid agonist-antagonist pentazocine, which acts predominantly at kappa-receptors, produced significantly better postoperative analgesia in females than in males in patients who underwent surgery for the removal of their third molars (wisdom teeth). In the current study, we evaluated the hypothesis that this sex difference is a characteristic of kappa-opioid agonism. In order to determine whether there are sex differences associated with kappa-opioid agonism, the analgesic efficacy of two other predominantly kappa-opioid analgesics, nalbuphine and butorphanol; was compared in males and females who underwent surgery for the removal of third molar teeth. We found that both nalbuphine and butorphanol produced significantly greater analgesia in females as compared with males. Considering our earlier findings, we conclude that kappa-opioid analgesia is greater in females than in males, probably reflecting a difference in kappa-opioid-activated endogenous pain modulating circuits.", + "TAG_DATA": [ + "71, patients {'context': 'B-patient'}", + "130, males {'context': 'B-patient'}", + "132, females {'context': 'B-patient'}", + "155, females {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "130, males ['l0']", + "132, females ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8898751", + "TEXT": "The imaging of regional ventilation in the lungs is essential for the evaluation of a variety of pathological conditions, such as emphysema, pneumonia and pulmonary embolism. We propose a novel approach for ventilation scanning, using magnetic resonance imaging (MRI) and inhaled molecular oxygen as a contrast agent, that directly depicts transfer of oxygen across the alveolus into the pulmonary vasculature. Molecular oxygen is only weakly paramagnetic but produces substantial signal changes in the lungs because of their large surface area. Ventilation defects were shown in a patient with bullous emphysema, and ventilation-perfusion mismatches were shown in two patients with pulmonary embolism.", + "TAG_DATA": [ + "86, patient {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8898749", + "TEXT": "The endogenous opioid system has been recently implicated in the reinforcing actions of cocaine and other addictive drugs. In this study we examined mu opioid receptor binding in ten cocaine-dependent men and seven nonaddicted controls using positron emission tomography and [11C] carfentanil. Mu opioid binding was increased in several brain regions of the cocaine addicts studied 1-4 days after their last use of cocaine. Binding was positively correlated with the severity of cocaine craving experienced at the time. The upregulation of mu opioid receptor binding persisted after 4 weeks of monitored cocaine abstinence. These findings demonstrate for the first time the involvement of the endogenous opioid system in cocaine dependence and cocaine craving in living human subjects.", + "TAG_DATA": [ + "30, men {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "53, cocaine ['l0']", + "54, addicts ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8898746", + "TEXT": "A low proliferating fraction in solid tumors limits the effectiveness of cell cycle-dependent chemotherapeutic agents. To understand the molecular basis of such \"kinetic\" resistance we cultured tumor cells as multicellular spheroids and examined levels of p27Kip1, a cyclin-dependent kinase inhibitor known to be upregulated by intercellular contact in normal cells. When transferred from monolayer to three-dimensional culture, a consistent upregulation (up to 15-fold) of p27 protein was observed in a panel of mouse and human carcinoma cell lines. Antisense-oligonucleotide-mediated downregulation of p27 in EMT-6 mammary tumor cell spheroids reduced intercellular adhesion, increased cell proliferation, sensitized tumor cells to 4-hydroperoxycyclophosphamide, and restored drug- or radiation-induced cell-cycle perturbations repressed in spheroid culture. Our results implicate p27 as a regulator of drug resistance in solid tumors and suggest that tumor-targeted p27 antagonists may be useful chemosensitizers in conjunction with conventional anticancer therapy.", + "TAG_DATA": [ + "26, tumor {'context': 'B-transformed cells'}", + "27, cells {'context': 'I-transformed cells'}", + "72, mouse {'context': 'B-transformed cells'}", + "73, and {'context': 'I-transformed cells'}", + "74, human {'context': 'I-transformed cells'}", + "75, carcinoma {'context': 'I-transformed cells'}", + "76, cell {'context': 'I-transformed cells'}", + "77, lines. {'context': 'I-transformed cells'}", + "78, Antisense-oligonucleotide-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "79, downregulation {'perturbing_action': 'I-rnai/knockdown'}", + "80, of {'perturbing_action': 'I-rnai/knockdown'}", + "81, p27 {'perturbing_action': 'I-rnai/knockdown'}", + "83, EMT-6 {'context': 'B-transformed cells'}", + "84, mammary {'context': 'I-neoplasm'}", + "85, tumor {'context': 'I-neoplasm'}", + "86, cell {'context': 'I-neoplasm'}", + "87, spheroids {'context': 'I-organoid'}", + "88, reduced {'effect': 'B-negative'}", + "90, adhesion, {'phenotype': 'B-adhesion'}", + "91, increased {'effect': 'B-positive'}", + "92, cell {'context': 'B-cells'}", + "93, proliferation, {'phenotype': 'B-proliferation'}", + "95, tumor {'context': 'B-transformed cells'}", + "96, cells {'context': 'I-transformed cells'}", + "108, spheroid {'context': 'B-organoid'}", + "109, culture. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "26, tumor ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "27, cells ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "72, mouse ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "73, and ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "74, human ['l3', 'l9', 'l14', 'l18', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "75, carcinoma ['l4', 'l10', 'l15', 'l19', 'l26', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "76, cell ['l5', 'l11', 'l16', 'l20', 'l27', 'l34', 'l41']", + "77, lines. ['l6', 'l12', 'l17', 'l21', 'l28', 'l35', 'l41']", + "78, Antisense-oligonucleotide-mediated ['l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "79, downregulation ['l42', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "80, of ['l43', 'l58', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "81, p27 ['l44', 'l59', 'l73', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "83, EMT-6 ['l45', 'l60', 'l74', 'l87', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "84, mammary ['l46', 'l61', 'l75', 'l88', 'l100', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "85, tumor ['l22', 'l29', 'l36', 'l47', 'l62', 'l76', 'l89', 'l101', 'l112', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "86, cell ['l23', 'l30', 'l37', 'l48', 'l63', 'l77', 'l90', 'l102', 'l113', 'l123', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141']", + "87, spheroids ['l49', 'l64', 'l78', 'l91', 'l103', 'l114', 'l124', 'l133', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "88, reduced ['l24', 'l31', 'l38', 'l50', 'l65', 'l79', 'l92', 'l104', 'l115', 'l125', 'l134', 'l142', 'l150', 'l151', 'l152', 'l153', 'l154']", + "89, intercellular ['l32', 'l39', 'l51', 'l66', 'l80', 'l93', 'l105', 'l116', 'l126', 'l135', 'l143', 'l150', 'l155', 'l156', 'l157', 'l158']", + "90, adhesion, ['l25', 'l33', 'l40', 'l52', 'l67', 'l81', 'l94', 'l106', 'l117', 'l127', 'l136', 'l144', 'l151', 'l155', 'l159', 'l160', 'l161']", + "91, increased ['l53', 'l68', 'l82', 'l95', 'l107', 'l118', 'l128', 'l137', 'l145', 'l152', 'l156', 'l159', 'l162', 'l163']", + "92, cell ['l54', 'l69', 'l83', 'l96', 'l108', 'l119', 'l129', 'l138', 'l146', 'l153', 'l157', 'l160', 'l162', 'l164']", + "93, proliferation, ['l55', 'l70', 'l84', 'l97', 'l109', 'l120', 'l130', 'l139', 'l147', 'l154', 'l158', 'l161', 'l163', 'l164']", + "95, tumor ['l56', 'l71', 'l85', 'l98', 'l110', 'l121', 'l131', 'l140', 'l148', 'l165']", + "96, cells ['l57', 'l72', 'l86', 'l99', 'l111', 'l122', 'l132', 'l141', 'l149', 'l165']", + "108, spheroid ['l166']", + "109, culture. ['l166']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "and", + "human", + "carcinoma", + "EMT-6" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "and", + "human", + "carcinoma", + "EMT-6" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antisense-oligonucleotide-mediated", + "downregulation", + "of", + "p27" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "EMT-6", + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antisense-oligonucleotide-mediated", + "downregulation", + "of", + "p27" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mammary", + "tumor", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antisense-oligonucleotide-mediated", + "downregulation", + "of", + "p27" + ] + }, + "context": { + "val": "organoid", + "words": [ + "spheroids" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antisense-oligonucleotide-mediated", + "downregulation", + "of", + "p27" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antisense-oligonucleotide-mediated", + "downregulation", + "of", + "p27" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antisense-oligonucleotide-mediated", + "downregulation", + "of", + "p27" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antisense-oligonucleotide-mediated", + "downregulation", + "of", + "p27" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antisense-oligonucleotide-mediated", + "downregulation", + "of", + "p27" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "EMT-6" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "EMT-6" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mammary", + "tumor", + "cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mammary", + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mammary", + "tumor", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mammary", + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "spheroids" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "spheroids" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "spheroids" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "spheroids" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + } + ] + }, + { + "PMID": "8837614", + "TEXT": "Loss of receptor hair cells in the cochlea accounts for a significant proportion of hearing impairment in the population. Hair cells can be lost as a consequence of viral or bacterial insult, aging, and damage from intense sound or aminoglycoside antibiotics. The generation of replacement hair cells following damage by sound or drugs has been clearly demonstrated in birds; the chick is the best-studied model for auditory hair cell regeneration. New hair cells arise as progeny from an otherwise nondividing supporting cell population induced to proliferate by the damage. Functional recovery of hearing accompanies this cellular recovery process. The signals and pathways responsible for regenerative proliferation are unknown. Here we show that proliferation is induced in the undamaged receptor epithelium by agents that increase cyclic AMP levels, and that following this stimulation hair cells become labeled with proliferation markers. This remarkable proliferative response is blocked by inhibitors of the cAMP-regulated protein kinase A (PKA). In addition we show that the proliferative response induced by in vitro gentamicin damage is also significantly blocked by PKA inhibitors. These observations are the first to identify a signaling pathway that plays a role in regenerative proliferation in the auditory receptor epithelium.", + "TAG_DATA": [ + "112, proliferation {'phenotype': 'B-proliferation'}", + "114, induced {'effect': 'B-positive'}", + "118, receptor {'context': 'B-tissue/organ'}", + "119, epithelium {'context': 'I-tissue/organ'}", + "132, hair {'context': 'B-cells'}", + "133, cells {'context': 'I-cells'}", + "141, proliferative {'phenotype': 'B-proliferation'}", + "142, response {'phenotype': 'I-proliferation'}", + "144, blocked {'effect': 'B-negative'}", + "160, proliferative {'phenotype': 'B-proliferation'}", + "161, response {'phenotype': 'I-proliferation'}", + "162, induced {'effect': 'B-positive'}", + "164, in {'context': 'B-in vitro'}", + "165, vitro {'context': 'I-in vitro'}", + "171, blocked {'effect': 'B-negative'}", + "173, PKA {'perturbing_action': 'B-pharmacological inhibition'}", + "174, inhibitors. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "112, proliferation ['l0', 'l1', 'l2']", + "114, induced ['l0', 'l3', 'l4']", + "118, receptor ['l1', 'l3', 'l5', 'l6', 'l7']", + "119, epithelium ['l2', 'l4', 'l5', 'l8', 'l9']", + "132, hair ['l6', 'l8', 'l10', 'l11']", + "133, cells ['l7', 'l9', 'l10']", + "141, proliferative ['l12', 'l13']", + "142, response ['l11', 'l12', 'l14']", + "144, blocked ['l13', 'l14']", + "160, proliferative ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "161, response ['l15', 'l22', 'l23', 'l24', 'l25']", + "162, induced ['l16', 'l22', 'l26', 'l27', 'l28']", + "164, in ['l17', 'l23', 'l26', 'l29', 'l30']", + "165, vitro ['l18', 'l24', 'l27', 'l29', 'l31', 'l32']", + "171, blocked ['l19', 'l25', 'l28', 'l30', 'l31', 'l33', 'l34']", + "173, PKA ['l20', 'l33', 'l35']", + "174, inhibitors. ['l21', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation", + "proliferative", + "response" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "receptor", + "epithelium" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "receptor", + "epithelium" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hair" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "response" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "response" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "response" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PKA", + "inhibitors." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "vitro" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PKA", + "inhibitors." + ] + } + } + ] + }, + { + "PMID": "8837606", + "TEXT": "The probability of producing a specific antitumor response should be increased by multiplying the number of T lymphocytes that encounter the malignant cells. We tested this prediction in a murine model, using a recently discovered T-cell chemokine, lymphotactin (Lptn). This chemokine increased tumor cell infiltration with CD4+ lymphocytes but generated little antitumor activity. Coexpression of the T-cell growth factor interleukin-2, however, greatly expanded the T lymphocytes attracted by Lptn, affording protection from the growth of established tumor in a CD4+ and CD8+ T cell-dependent manner. Lesser synergy was seen with GM-CSF. Hence coexpression of a T-cell chemokine and T-cell growth factor potentiates antitumor responses in vivo, suggesting a general strategy to improve cancer immunotherapy.", + "TAG_DATA": [ + "29, murine {'context': 'B-organism'}", + "30, model, {'context': 'I-organism'}", + "42, tumor {'context': 'B-transformed cells'}", + "43, cell {'context': 'I-transformed cells'}", + "46, CD4+ {'context': 'B-cells'}", + "47, lymphocytes {'context': 'I-cells'}", + "53, Coexpression {'perturbing_action': 'B-gene gain-of-function'}", + "54, of {'perturbing_action': 'I-gene gain-of-function'}", + "55, the {'perturbing_action': 'I-gene gain-of-function'}", + "56, T-cell {'perturbing_action': 'I-gene gain-of-function'}", + "57, growth {'perturbing_action': 'I-gene gain-of-function'}", + "58, factor {'perturbing_action': 'I-gene gain-of-function'}", + "59, interleukin-2, {'perturbing_action': 'I-gene gain-of-function'}", + "64, T {'context': 'B-cells'}", + "65, lymphocytes {'context': 'I-cells'}", + "70, protection {'effect': 'B-negative'}", + "73, growth {'phenotype': 'B-cell growth'}", + "76, tumor {'context': 'B-neoplasm'}", + "104, in {'context': 'B-in vivo'}", + "105, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "29, murine ['l0', 'l1', 'l2', 'l3', 'l4']", + "30, model, ['l0', 'l5', 'l6', 'l7', 'l8']", + "42, tumor ['l1', 'l5', 'l9', 'l10', 'l11']", + "43, cell ['l2', 'l6', 'l9', 'l12', 'l13']", + "46, CD4+ ['l3', 'l7', 'l10', 'l12', 'l14']", + "47, lymphocytes ['l4', 'l8', 'l11', 'l13', 'l14']", + "53, Coexpression ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "54, of ['l15', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "55, the ['l16', 'l26', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "56, T-cell ['l17', 'l27', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "57, growth ['l18', 'l28', 'l37', 'l45', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "58, factor ['l19', 'l29', 'l38', 'l46', 'l53', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "59, interleukin-2, ['l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l66', 'l67', 'l68', 'l69', 'l70']", + "64, T ['l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l71', 'l72', 'l73', 'l74']", + "65, lymphocytes ['l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l75', 'l76', 'l77']", + "70, protection ['l23', 'l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l78', 'l79']", + "73, growth ['l24', 'l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l76', 'l78', 'l80']", + "76, tumor ['l25', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l79', 'l80']", + "99, growth ['l81', 'l82', 'l83']", + "100, factor ['l81', 'l84', 'l85']", + "104, in ['l82', 'l84', 'l86']", + "105, vivo, ['l83', 'l85', 'l86']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Coexpression", + "of", + "the", + "T-cell", + "growth", + "factor", + "interleukin-2," + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "lymphocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Coexpression", + "of", + "the", + "T-cell", + "growth", + "factor", + "interleukin-2," + ] + }, + "effect": { + "val": "negative", + "words": [ + "protection" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Coexpression", + "of", + "the", + "T-cell", + "growth", + "factor", + "interleukin-2," + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Coexpression", + "of", + "the", + "T-cell", + "growth", + "factor", + "interleukin-2," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "lymphocytes" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protection" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "lymphocytes" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "protection" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "protection" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + } + ] + }, + { + "PMID": "8782463", + "TEXT": "Microsatellite instability is an important characteristic of many tumor types especially those associated with hereditary non-polyposis colorectal carcinoma (HNPCC) syndrome. Microsatellite alterations in 50% of primary small cell lung carcinoma (SCLC) have been found. These alterations were also found in the sputum. Because neoplastic characteristics such as decreased strand stability9 and ras mutations have been found in the plasma DNA of cancer patients, we looked for microsatellite alterations in the plasma of SCLC patients. A microsatellite alteration was present in 16 out of 21 (76%) SCLC tumors and in 15 out of 21 (71%) plasma samples. In one case, the alteration was present only in the plasma DNA. If confirmed in larger studies, microsatellite analysis of plasma DNA might constitute a new tool for tumor staging, management and, possibly, detection.", + "TAG_DATA": [ + "85, SCLC {'context': 'B-neoplasm'}", + "86, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "85, SCLC ['l0']", + "86, tumors ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8782460", + "TEXT": "1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces clinical, biochemical and neuropathologic changes reminiscent of those which occur in idiopathic Parkinson's disease. 7-Nitroindazole (7-NI) is a relatively selective inhibitor of the neuronal isoform of nitric oxide synthase (NOS) that blocks MPTP neurotoxicity in mice. We now show that 7-NI protects against profound striatal dopamine depletions and loss of tyrosine hydroxylase-positive neurons in the substantia nigra in MPTP-treated baboons. Furthermore, 7-NI protected against MPTP-induced motor and frontal-type cognitive deficits. These results strongly implicate a role of nitric oxide in MPTP neurotoxicity and suggest that inhibitors of neuronal NOS might be useful in treating Parkinson's disease.", + "TAG_DATA": [ + "55, neurons {'context': 'I-cells'}", + "56, in {'context': 'I-cells'}", + "57, the {'context': 'I-cells'}", + "58, substantia {'context': 'I-cells'}", + "59, nigra {'context': 'I-cells'}", + "62, baboons. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "55, neurons ['l0', 'l1', 'l2', 'l3', 'l4']", + "56, in ['l0', 'l5', 'l6', 'l7', 'l8']", + "57, the ['l1', 'l5', 'l9', 'l10', 'l11']", + "58, substantia ['l2', 'l6', 'l9', 'l12', 'l13']", + "59, nigra ['l3', 'l7', 'l10', 'l12', 'l14']", + "62, baboons. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8705864", + "TEXT": "A major controversy regarding Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8) is whether or not it is a ubiquitous infection of humans. Immunoassays based on KSHV- and Epstein-Barr virus (EBV)-coinfected cell lines show that most US AIDS-KS patients have specific antibodies to KSHV-related antigens. We have developed a sensitive indirect immunofluorescence assay (IFA) based on an EBV-negative, KSHV-infected cell line, BCP-1. When we used this IFA assay, KSHV-related antibodies were found in 71-88% of serum samples from US, Italian and Ugandan AIDS-KS patients, as well as all serum samples examined from HIV-seronegative KS patients. Although none of the US blood donors examined were KSHV seropositive by IFA, intermediate and high seroprevalence rates were found in Italian and Ugandan control populations. Antibody kinetics showed that more than half of the AIDS-KS patients who were examined IgG-seroconverted before KS development, and antibody levels did not decline after seroconversion. For these patients, seropositivity rates increased linearly with time, suggesting that the rate of infection was constant and that the risk of developing KS once infected with KSHV is not highly dependent on the duration of infection. These data strongly suggest that KSHV is not ubiquitous in most populations and that the virus may be under strict immunologic control in healthy KSHV-infected persons.", + "TAG_DATA": [ + "97, US {'context': 'B-cells'}", + "98, blood {'context': 'I-cells'}", + "99, donors {'context': 'I-cells'}", + "128, AIDS-KS {'context': 'B-patient'}", + "129, patients {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "97, US ['l0', 'l1', 'l2', 'l3']", + "98, blood ['l0', 'l4', 'l5', 'l6']", + "99, donors ['l1', 'l4', 'l7', 'l8']", + "128, AIDS-KS ['l2', 'l5', 'l7', 'l9']", + "129, patients ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8705858", + "TEXT": "There are 3 million deaths per annum worldwide due to tuberculosis, and AIDS is compounding the problem. A better vaccine than the live mycobacterium currently in use, bacillus Calmette-Guérin (BCG), is needed. When mice were injected with plasmid DNA encoding a single mycobacterial antigen (65-kDa heat shock protein, hsp65) they made specific cellular and humoral responses to the protein and became immune to subsequent challenge with Mycobacterium tuberculosis. Protection was equivalent to that obtained by vaccinating with live BCG, whereas immunizing with the protein was ineffective. Protection was also obtained with DNA encoding another mycobacterial antigen (36-kDa proline-rich antigen). These results suggest that DNA vaccination might yield improved vaccines to replace BCG.", + "TAG_DATA": [ + "33, mice {'context': 'B-organism'}", + "37, plasmid {'perturbing_action': 'B-gene gain-of-function'}", + "38, DNA {'perturbing_action': 'I-rnai/knockdown'}", + "39, encoding {'perturbing_action': 'I-rnai/knockdown'}", + "40, a {'perturbing_action': 'I-rnai/knockdown'}", + "41, single {'perturbing_action': 'I-rnai/knockdown'}", + "42, mycobacterial {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "33, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "37, plasmid ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "38, DNA ['l0', 'l6', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "39, encoding ['l7', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "40, a ['l1', 'l8', 'l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "41, single ['l2', 'l9', 'l15', 'l20', 'l24', 'l28', 'l29', 'l30']", + "42, mycobacterial ['l3', 'l10', 'l16', 'l21', 'l25', 'l28', 'l31', 'l32']", + "43, antigen ['l4', 'l11', 'l17', 'l22', 'l26', 'l29', 'l31', 'l33']", + "44, (65-kDa ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "DNA", + "a", + "single", + "mycobacterial" + ] + } + } + ] + }, + { + "PMID": "8705856", + "TEXT": "Hematopoietic cells are important targets for genetic modification with retroviral vectors. Attempts at human gene therapy of stem cells have achieved limited success partly because of low gene transfer efficiency. Chymotryptic fragments of the extracellular matrix molecule fibronectin used during infection have been shown to increase transduction of human hematopoietic progenitor cells. Here, we demonstrate that this enhanced gene transfer into mammalian target cells is due to direct binding of retroviral particles to sequences within the fibronectin molecule. Transduction of mammalian cells, including murine long-term repopulating hematopoietic cells, is greatly enhanced when cells are adherent to chimeric fragments containing these retroviral binding sequences. In addition, colocalization of retrovirus and target cells on fibronectin peptides allows targeted transduction of specific cell types by exploiting unique ligand/receptor interactions.", + "TAG_DATA": [ + "80, mammalian {'context': 'B-cells'}", + "81, cells, {'context': 'I-cells'}", + "83, murine {'context': 'B-cells'}", + "84, long-term {'context': 'I-cells'}", + "85, repopulating {'context': 'I-cells'}", + "86, hematopoietic {'context': 'I-cells'}", + "87, cells, {'context': 'I-cells'}", + "92, cells {'context': 'B-cells'}", + "119, cell {'context': 'B-cells'}", + "120, types {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "80, mammalian ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "81, cells, ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "83, murine ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "84, long-term ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "85, repopulating ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "86, hematopoietic ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "87, cells, ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "92, cells ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "119, cell ['l28']", + "120, types ['l28']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8673930", + "TEXT": "Cough accompanied by an increased sensitivity of the cough reflex is the most common symptom of inflammatory airway disease. This symptom is also frequently reported in patients receiving angiotensin-converting enzyme (ACE) inhibitors as therapy for heart failure or hypertension, although the underlying mechanism is unknown. We have investigated the possibility that the inflammatory peptide bradykinin, normally degraded by ACE, causes sensitization of airway sensory nerves and an enhancement of the cough reflex in conscious guinea pigs. Treatment of guinea pigs for two weeks with captopril led to an increased cough response to inhaled citric acid, which was prevented by concomitant treatment with the bradykinin receptor antagonist icatibant. A similar icatibant-sensitive enhancement of citric acid-evoked cough was seen in untreated animals after prior inhalation of bradykinin, although cough evoked by hypertonic saline was unaffected. In electrophysiological studies performed in vitro, responses of single vagal C fibers to capsaicin, applied to receptive fields of single-fiber units in the trachea, were also markedly increased after perfusion with bradykinin, whereas A delta fiber responses to hypertonic saline were unaffected. These results indicate that bradykinin-evoked sensitization of airway sensory nerves may underlie the pathogenesis of ACE-inhibitor cough. Bradykinin receptor antagonists may be of benefit in treating chronic cough seen with this and other inflammatory conditions.", + "TAG_DATA": [ + "73, conscious {'context': 'B-organism'}", + "74, guinea {'context': 'I-organism'}", + "75, pigs. {'context': 'I-organism'}", + "78, guinea {'context': 'B-organism'}", + "79, pigs {'context': 'I-organism'}", + "119, animals {'context': 'B-organism'}", + "137, in {'context': 'B-in vitro'}", + "138, vitro, {'context': 'I-in vitro'}", + "142, vagal {'context': 'I-cells'}", + "143, C {'context': 'I-cells'}", + "144, fibers {'context': 'I-cells'}", + "152, single-fiber {'context': 'B-cells'}", + "153, units {'context': 'I-cells'}", + "156, trachea, {'context': 'B-tissue/organ'}", + "166, A {'context': 'B-cells'}", + "167, delta {'context': 'I-cells'}", + "168, fiber {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "73, conscious ['l0', 'l1', 'l2', 'l3']", + "74, guinea ['l0', 'l4', 'l5', 'l6']", + "75, pigs. ['l1', 'l4', 'l7', 'l8']", + "78, guinea ['l2', 'l5', 'l7', 'l9']", + "79, pigs ['l3', 'l6', 'l8', 'l9']", + "119, animals ['l10', 'l11', 'l12']", + "137, in ['l10', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "138, vitro, ['l13', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "142, vagal ['l14', 'l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "143, C ['l11', 'l15', 'l21', 'l26', 'l31', 'l32', 'l33', 'l34']", + "144, fibers ['l12', 'l16', 'l22', 'l27', 'l31', 'l35', 'l36', 'l37']", + "152, single-fiber ['l17', 'l23', 'l28', 'l32', 'l35', 'l38', 'l39']", + "153, units ['l18', 'l24', 'l29', 'l33', 'l36', 'l38', 'l40']", + "156, trachea, ['l19', 'l25', 'l30', 'l34', 'l37', 'l39', 'l40']", + "166, A ['l41', 'l42']", + "167, delta ['l41', 'l43']", + "168, fiber ['l42', 'l43']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8673927", + "TEXT": "The presence of obesity increases the risk of thrombotic vascular diseases. The role of fat accumulation and its effect on plasminogen activator inhibitor-1 (PAI-1) levels was investigated in humans and animals. Plasma PAI-1 levels were closely correlated with visceral fat area but not with subcutaneous fat area in human subjects. PAI-1 mRNA was detected in both types of fat tissue in obese rats but increased only in visceral fat during the development of obesity. These data suggest that an enhanced expression of the PAI-1 gene in visceral fat may increase plasma levels and may have a role in the development of vascular disease in visceral obesity.", + "TAG_DATA": [ + "61, obese {'context': 'B-organism'}", + "62, rats {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "61, obese ['l0']", + "62, rats ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8673926", + "TEXT": "An injectable sustained-release form of human growth hormone (hGH) was developed by stabilizing and encapsulating the protein, without altering its integrity, into biodegradable microspheres using a novel cryogenic process. A single injection of microspheres in monkeys resulted in elevated serum levels of recombinant hGH (rhGH) for more than one month. Insulin-like growth factor-I (IGF-I) and its binding protein IGFBP-3, both of which are induced by hGH, were also elevated for four weeks by the rhGH containing microspheres to a level greater than that induced by the same amount of rhGH administered by daily injections. These results show that, by using appropriate methods of stabilization and encapsulation, the advantages of sustained-release formulations previously demonstrated for low-molecular-weight drugs can now be extended to protein therapeutics.", + "TAG_DATA": [ + "35, monkeys {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8640561", + "TEXT": "Neuroblastoma (NB) is the most common extracranial solid neoplasm of infancy and is associated with very poor prognosis in patients with advanced disease. Current therapeutic regimens of advanced NB which combine surgical resection with radiation therapy and/or chemotherapy brought some improvements, but in a significant number of patients, a cure remains elusive. Normal human serum of healthy adults contains natural IgM antibodies that are cytotoxic for human NB cells. In this study, we evaluated the anti-NB activity of these natural IgM antibodies in nude rats bearing solid human NB tumors. A single intravenous (i.v.) injection of purified cytotoxic IgM led to uptake of IgM into the tumors with massive perivascular complement activation and accumulation of neutrophil granulocytes after 24 hours. Five consecutive i.v. injections of purified cytotoxic IgM into NB-bearing animals resulted in complete growth arrest of even large and established solid tumors which lasted for several weeks after discontinuation of the injections, whereas tumors of control animals continued to grow exponentially during the observation period. These studies suggest that natural anti-NB IgM may have a potential as a novel therapeutic modality in the treatment of human NB.", + "TAG_DATA": [ + "83, nude {'context': 'B-organism'}", + "84, rats {'context': 'I-organism'}", + "86, solid {'context': 'B-neoplasm'}", + "87, human {'context': 'I-neoplasm'}", + "88, NB {'context': 'I-neoplasm'}", + "89, tumors. {'context': 'I-neoplasm'}", + "106, tumors {'context': 'B-neoplasm'}", + "129, NB-bearing {'context': 'B-organism'}", + "130, animals {'context': 'I-organism'}", + "141, solid {'context': 'B-neoplasm'}", + "142, tumors {'context': 'I-neoplasm'}", + "154, tumors {'context': 'B-neoplasm'}", + "157, animals {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "83, nude ['l0', 'l1', 'l2', 'l3', 'l4']", + "84, rats ['l0', 'l5', 'l6', 'l7', 'l8']", + "86, solid ['l1', 'l5', 'l9', 'l10', 'l11']", + "87, human ['l2', 'l6', 'l9', 'l12', 'l13', 'l14']", + "88, NB ['l3', 'l7', 'l10', 'l12', 'l15', 'l16']", + "89, tumors. ['l4', 'l8', 'l11', 'l13', 'l15']", + "106, tumors ['l14', 'l16']", + "129, NB-bearing ['l17', 'l18', 'l19']", + "130, animals ['l17', 'l20', 'l21']", + "141, solid ['l18', 'l20', 'l22']", + "142, tumors ['l19', 'l21', 'l22']", + "154, tumors ['l23']", + "157, animals ['l23']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8640560", + "TEXT": "To better understand genetic alterations in oral premalignant lesions, we examined 84 oral leukoplakia samples from 37 patients who had been enrolled in a chemoprevention trial. The samples were analyzed for two microsatellite markers located at chromosomes 9p21 and 3p14. Loss of heterozygosity (LOH) at either or both loci was identified in 19 of the 37 (51%) patients. Of these 19 patients, seven (37%) have developed head and neck squamous cell carcinoma (HNSCC) while only one of 18 (6%) of patients without LOH developed HNSCC. Our data suggest that clonal genetic alterations are common in oral premalignant lesions; that multiple genetic alterations have already occurred in oral premalignant lesions, allowing at least a focal clonal expansion; and that losses of the 9p21 and 3p14 regions may be related to early processes of tumorigenesis in HNSCC. These genetic alterations in premalignant tissues may serve as markers for cancer risk assessment.", + "TAG_DATA": [ + "84, HNSCC. {'phenotype': 'B-tumourigenesis'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8640555", + "TEXT": "Mutations in the beta subunit of the cGMP phosphodiesterase gene (beta PDE) can cause a recessively inherited retinal degeneration in several species, including mice, dogs and humans. We tested the possibility of altering the course of retinal degeneration in the rd mouse through subretinal injection of a recombinant replication-defective adenovirus that contains the murine cDNA for wild-type (beta PDE, Ad.CMV beta PDE. Subretinal injection of Ad.CMV beta PDE results in beta PDE transcripts and increased PDE activity and delays photoreceptor cell death by six weeks. The findings demonstrate cell rescue by in vivo gene transfer, thus supporting the feasibility of treating an inherited retinal degeneration by somatic gene therapy.", + "TAG_DATA": [ + "40, rd {'context': 'B-organism'}", + "41, mouse {'context': 'I-organism'}", + "78, delays {'effect': 'B-negative'}", + "79, photoreceptor {'context': 'B-cells'}", + "80, cell {'phenotype': 'B-cell death'}", + "81, death {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "40, rd ['l0']", + "41, mouse ['l0']", + "78, delays ['l1', 'l2', 'l3']", + "79, photoreceptor ['l1', 'l4', 'l5']", + "80, cell ['l2', 'l4', 'l6']", + "81, death ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "delays" + ] + }, + "context": { + "val": "cells", + "words": [ + "photoreceptor" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "delays" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "photoreceptor" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + } + ] + }, + { + "PMID": "8616720", + "TEXT": "Inducible nitric oxide synthase (iNOS) is a transcriptionally regulated enzyme that synthesizes nitric oxide from L-arginine that has a key role in the pathophysiology of systemic inflammation and sepsis. Transgenic animals with a null mutation for the iNOS gene are resistant to hypotension and death caused by Escherichia coli lipopolysaccharide (LPS). The regulation of peripheral iNOS has been well studied in sepsis, but little is known about iNOS regulation in the brain during systemic inflammation or sepsis. We know that at baseline there is no detectable iNOS gene expression in the brain, but a detailed neuroanatomical study reveals that early in the course of systemic inflammation there is a profound induction of iNOS messenger RNA in vascular, glial and neuronal structures of the rat brain, accompanied by the production of nitric oxide (NO) metabolites in brain parenchyma and cerebrospinal fluid (CSF). We propose that the spillover of nitrite into the CSF has the potential to be a diagnostic marker for systemic inflammation and sepsis. Pharmacological interventions aimed at regulating iNOS function in the brain might represent a new treatment strategy in sepsis. Brain iNOS may be relevant to the pathophysiology, diagnosis and treatment of systemic inflammation and sepsis.", + "TAG_DATA": [ + "33, null {'perturbing_action': 'B-gene loss-of-function'}", + "34, mutation {'perturbing_action': 'I-gene loss-of-function'}", + "35, for {'perturbing_action': 'I-gene loss-of-function'}", + "36, the {'perturbing_action': 'I-gene loss-of-function'}", + "37, iNOS {'perturbing_action': 'I-gene loss-of-function'}", + "38, gene {'perturbing_action': 'I-gene loss-of-function'}", + "123, rat {'context': 'B-tissue/organ'}", + "124, brain, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "33, null ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "34, mutation ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "35, for ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "36, the ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "37, iNOS ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "38, gene ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "123, rat ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "124, brain, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "null", + "mutation", + "for", + "the", + "iNOS", + "gene" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "brain," + ] + } + } + ] + }, + { + "PMID": "8616719", + "TEXT": "About half of human conceptions are estimated not to be implanted in the uterus, resulting in unrecognizable spontaneous abortions, and about 5% of human births have a recognizable malformation. In order to find clues to the mechanisms of malformation and abortion, we compared the incidences of radiation-induced malformations and abortions in p53 null (p53-/-) and wild-type (p53+/+) mice. After X-irradiation with 2 Gy on day 9.5 of gestation, p53-/- mice showed a 70% incidence of anomalies and a 7% incidence of deaths, whereas p53+/+ mice had a 20% incidence of anomalies and a 60% incidence of deaths. Similar results were obtained after irradiation on day 3.5 of gestation. This reciprocal relationship of radiosensitivity to anomalies and to embryonic or fetal lethality supports the notion that embryonic or fetal tissues have a p53-dependent \"guardian\" of the tissue that aborts cells bearing radiation-induced teratogenic DNA damage. In fact, after X-irradiation, the number of cells with apoptotic DNA fragments was greatly increased in tissues of the p53+/+ fetuses but not in those of the p53-/- fetuses.", + "TAG_DATA": [ + "51, p53 {'perturbing_action': 'B-gene loss-of-function'}", + "52, null {'perturbing_action': 'I-gene loss-of-function'}", + "53, (p53-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "57, mice. {'context': 'B-organism'}", + "68, p53-/- {'perturbing_action': 'B-gene loss-of-function'}", + "69, mice {'context': 'B-organism'}", + "83, p53+/+ {'perturbing_action': 'B-gene loss-of-function'}", + "84, mice {'context': 'B-organism'}", + "151, cells {'context': 'B-cells'}", + "163, p53+/+ {'perturbing_action': 'B-gene loss-of-function'}", + "171, p53-/- {'perturbing_action': 'B-gene loss-of-function'}" + ], + "LINK_DATA": [ + "51, p53 ['l0', 'l1', 'l2', 'l3', 'l4']", + "52, null ['l0', 'l5', 'l6', 'l7', 'l8']", + "53, (p53-/-) ['l1', 'l5', 'l9', 'l10', 'l11']", + "57, mice. ['l2', 'l6', 'l9', 'l12']", + "68, p53-/- ['l3', 'l7', 'l10', 'l12', 'l13']", + "69, mice ['l4', 'l8', 'l11', 'l13']", + "83, p53+/+ ['l14']", + "84, mice ['l14']", + "151, cells ['l15', 'l16', 'l17', 'l18', 'l19']", + "160, tissues ['l15', 'l20', 'l21', 'l22', 'l23']", + "163, p53+/+ ['l16', 'l20', 'l24', 'l25', 'l26']", + "164, fetuses ['l17', 'l21', 'l24', 'l27', 'l28']", + "171, p53-/- ['l18', 'l22', 'l25', 'l27', 'l29']", + "172, fetuses. ['l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53", + "null", + "(p53-/-)", + "p53-/-", + "p53+/+" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53+/+", + "p53-/-" + ] + } + } + ] + }, + { + "PMID": "8597958", + "TEXT": "Colorectal cancer is one of the commonest malignant tumors and has a relatively poor prognosis. The outcome depends on the extent of local and particularly metastatic tumor spread. The matrix metalloproteinases (MMPs) are a family of closely related enzymes that degrade the extracellular matrix and are considered to be important in facilitating tumor invasion and spread (1-3). Using immunohistochemistry we have investigated the occurrence in colorectal cancer of MMP-1 (interstitial collagenase). Our monoclonal antibody was prepared against a synthetic peptide corresponding to an amino acid sequence specific for MMP-1 and was selected to react in formalin-fixed wax-embedded sections, thus allowing use in diagnostic histopathology and also enabling access to archival material. We found that the presence of MMP-1 in colorectal cancer is associated with a poor prognosis (P = 0.006) and has prognostic value independent of Dukes stage. One MMP inhibitor that strongly inhibits MMP-1 has already been shown to inhibit growth of human colon cancer xenografts in nude mice (4). Our results suggest that treatment of those individuals whose colon tumors produce MMP-1 with MMP inhibitors is a therapeutic strategy worth pursuing.", + "TAG_DATA": [ + "153, human {'context': 'B-xenograft'}", + "154, colon {'context': 'I-xenograft'}", + "155, cancer {'context': 'I-xenograft'}", + "156, xenografts {'context': 'I-xenograft'}", + "158, nude {'context': 'B-organism'}", + "159, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "153, human ['l0', 'l1', 'l2', 'l3', 'l4']", + "154, colon ['l0', 'l5', 'l6', 'l7', 'l8']", + "155, cancer ['l1', 'l5', 'l9', 'l10', 'l11']", + "156, xenografts ['l2', 'l6', 'l9', 'l12', 'l13']", + "158, nude ['l3', 'l7', 'l10', 'l12', 'l14']", + "159, mice ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8597957", + "TEXT": "Alcohol consumption is associated with increased morbidity and mortality related to infectious diseases and malignancy (1-5), although immune mediation of these relationships is controversial. Specifically, the activity of natural killer (NK) cells, which are involved in the resistance to infections and metastasis, can be suppressed in the presence of ethanol in vitro. However, acute consumption or infusion of ethanol in vivo exerts no effects on NK activity assessed in vitro thereafter. Therefore, we have developed and used a method to study the effects of ethanol on NK activity in living rats by using an NK-sensitive metastatic process and selective depletion of NK cells in vivo. Acute ethanol intoxication caused a marked suppression of NK activity in vivo and a tenfold increase in the number of MADB106 tumor metastases. Ethanol had no effect in rats selectively depleted of NK cells or when an NK-insensitive tumor (C4047) was used. These findings suggest that even acute ethanol intoxication markedly suppresses NK activity in the living organism. This suppression may underlie some aspects of the association between alcoholism, infectious disease and malignancies.", + "TAG_DATA": [ + "90, rats {'context': 'I-organism'}", + "103, in {'context': 'B-in vivo'}", + "104, vivo. {'context': 'I-in vivo'}", + "115, in {'context': 'B-in vivo'}", + "116, vivo {'context': 'I-in vivo'}", + "120, increase {'effect': 'B-positive'}", + "125, MADB106 {'context': 'B-neoplasm'}", + "126, tumor {'phenotype': 'B-tumour growth'}", + "127, metastases. {'phenotype': 'I-metastasis'}", + "133, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "103, in ['l0', 'l1', 'l2', 'l3']", + "104, vivo. ['l0', 'l4', 'l5', 'l6']", + "115, in ['l1', 'l4', 'l7', 'l8', 'l9', 'l10']", + "116, vivo ['l2', 'l5', 'l7', 'l11', 'l12', 'l13']", + "120, increase ['l3', 'l6', 'l8', 'l11', 'l14', 'l15', 'l16']", + "125, MADB106 ['l14', 'l17', 'l18']", + "126, tumor ['l9', 'l12', 'l15', 'l17', 'l19']", + "127, metastases. ['l10', 'l13', 'l16', 'l18', 'l19']", + "133, rats ['l20']", + "143, tumor ['l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo.", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increase" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "MADB106" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "MADB106" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "MADB106" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases." + ] + } + } + ] + }, + { + "PMID": "8597955", + "TEXT": "The endocrine mechanism involved in term and preterm delivery in primates, including pregnant women, are poorly understood. In the term monkey, fetal plasma androgen concentration rises to two hundred times the maternal concentration which remains unchanged. Placental conversion of androgen to estrogen results in increased maternal plasma estrogen concentration at term in both pregnant nonhuman primates and women. In the present study, continuous infusion of androstenedione to 0.8 gestation monkeys resulted in the premature occurrence of labor-type myometrial activity and increases in maternal plasma estrogen, oxytocin and amnion fibronectin concentrations similar to those measured at normal-term labor. Androstenedione induction of these normal-term biochemical and endocrine changes accompanied by fetal membrane rupture, cervical dilatation and live delivery provides a rich opportunity to study the molecular and physiological mechanisms of both term and preterm labor in primates.", + "TAG_DATA": [ + "54, nonhuman {'context': 'I-organism'}", + "55, primates {'context': 'I-organism'}", + "69, monkeys {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "54, nonhuman ['l0']", + "55, primates ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8597953", + "TEXT": "A nonhuman primate model of tuberculosis that closely resembles human disease is urgently needed. We have evaluated the Philippine cynomolgus monkey, Macaca fasicularis, as a model of TB. Cynomolgus monkeys challenged intratracheally with extremely high doses of Mycobacterium tuberculosis (10(5) or 10(4) CFU) developed an acute, rapidly progressive, highly fatal multilobar pneumonia. However, monkeys challenged with moderate or low doses of M. tuberculosis (A mutation, which causes human Usher syndrome, the leading genetic cause of combined deafness and blindness. Treatment of neonatal mice with a single systemic dose of ASO partially corrects Ush1c c.216G>A splicing, increases protein expression, improves stereocilia organization in the cochlea, and rescues cochlear hair cells, vestibular function and low-frequency hearing in mice. These effects were sustained for several months, providing evidence that congenital deafness can be effectively overcome by treatment early in development to correct gene expression and demonstrating the therapeutic potential of ASOs in the treatment of deafness.", + "TAG_DATA": [ + "63, mouse {'context': 'B-organism'}", + "64, model {'context': 'I-organism'}", + "106, neonatal {'context': 'B-organism'}", + "107, mice {'context': 'I-organism'}", + "124, stereocilia {'context': 'B-cells'}", + "128, cochlea, {'context': 'B-tissue/organ'}", + "131, cochlear {'context': 'B-cells'}", + "132, hair {'context': 'I-cells'}", + "133, cells, {'context': 'I-cells'}", + "140, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "63, mouse ['l0']", + "64, model ['l0']", + "106, neonatal ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "107, mice ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "124, stereocilia ['l2', 'l8', 'l14', 'l15', 'l16']", + "128, cochlea, ['l3', 'l9', 'l14', 'l17', 'l18']", + "131, cochlear ['l4', 'l10', 'l19', 'l20', 'l21']", + "132, hair ['l5', 'l11', 'l15', 'l17', 'l19', 'l22', 'l23']", + "133, cells, ['l6', 'l12', 'l16', 'l18', 'l20', 'l22', 'l24']", + "140, mice. ['l7', 'l13', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22281806", + "TEXT": "Mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) have been shown to be present in most World Health Organization grade 2 and grade 3 gliomas in adults. These mutations are associated with the accumulation of 2-hydroxyglutarate (2HG) in the tumor. Here we report the noninvasive detection of 2HG by proton magnetic resonance spectroscopy (MRS). We developed and optimized the pulse sequence with numerical and phantom analyses for 2HG detection, and we estimated the concentrations of 2HG using spectral fitting in the tumors of 30 subjects. Detection of 2HG correlated with mutations in IDH1 or IDH2 and with increased levels of D-2HG by mass spectrometry of the resected tumors. Noninvasive detection of 2HG may prove to be a valuable diagnostic and prognostic biomarker.", + "TAG_DATA": [ + "83, tumors {'context': 'B-neoplasm'}", + "109, tumors. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22037645", + "TEXT": "Exercise, obesity and type 2 diabetes are associated with elevated plasma concentrations of interleukin-6 (IL-6). Glucagon-like peptide-1 (GLP-1) is a hormone that induces insulin secretion. Here we show that administration of IL-6 or elevated IL-6 concentrations in response to exercise stimulate GLP-1 secretion from intestinal L cells and pancreatic alpha cells, improving insulin secretion and glycemia. IL-6 increased GLP-1 production from alpha cells through increased proglucagon (which is encoded by GCG) and prohormone convertase 1/3 expression. In models of type 2 diabetes, the beneficial effects of IL-6 were maintained, and IL-6 neutralization resulted in further elevation of glycemia and reduced pancreatic GLP-1. Hence, IL-6 mediates crosstalk between insulin-sensitive tissues, intestinal L cells and pancreatic islets to adapt to changes in insulin demand. This previously unidentified endocrine loop implicates IL-6 in the regulation of insulin secretion and suggests that drugs modulating this loop may be useful in type 2 diabetes.", + "TAG_DATA": [ + "44, intestinal {'context': 'B-cells'}", + "45, L {'context': 'I-cells'}", + "46, cells {'context': 'I-cells'}", + "48, pancreatic {'context': 'B-cells'}", + "49, alpha {'context': 'I-cells'}", + "50, cells, {'context': 'I-cells'}", + "61, alpha {'context': 'B-cells'}", + "62, cells {'context': 'I-cells'}", + "90, IL-6 {'perturbing_action': 'B-rnai/knockdown'}", + "91, neutralization {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "44, intestinal ['l0', 'l1', 'l2', 'l3', 'l4']", + "45, L ['l0', 'l5', 'l6', 'l7', 'l8']", + "46, cells ['l1', 'l5', 'l9', 'l10', 'l11']", + "48, pancreatic ['l2', 'l6', 'l9', 'l12', 'l13', 'l14']", + "49, alpha ['l3', 'l7', 'l10', 'l12', 'l15', 'l16']", + "50, cells, ['l4', 'l8', 'l11', 'l13', 'l15']", + "61, alpha ['l17']", + "62, cells ['l14', 'l16', 'l17']", + "90, IL-6 ['l18']", + "91, neutralization ['l18']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19198614", + "TEXT": "Duchenne muscular dystrophy is characterized by progressive muscle weakness and early death resulting from dystrophin deficiency. Loss of dystrophin results in disruption of a large dystrophin glycoprotein complex, leading to pathological calcium (Ca2+)-dependent signals that damage muscle cells. We have identified a structural and functional defect in the ryanodine receptor (RyR1), a sarcoplasmic reticulum Ca2+ release channel, in the mdx mouse model of muscular dystrophy that contributes to altered Ca2+ homeostasis in dystrophic muscles. RyR1 isolated from mdx skeletal muscle showed an age-dependent increase in S-nitrosylation coincident with dystrophic changes in the muscle. RyR1 S-nitrosylation depleted the channel complex of FKBP12 (also known as calstabin-1, for calcium channel stabilizing binding protein), resulting in 'leaky' channels. Preventing calstabin-1 depletion from RyR1 with S107, a compound that binds the RyR1 channel and enhances the binding affinity of calstabin-1 to the nitrosylated channel, inhibited sarcoplasmic reticulum Ca2+ leak, reduced biochemical and histological evidence of muscle damage, improved muscle function and increased exercise performance in mdx mice. On the basis of these findings, we propose that sarcoplasmic reticulum Ca2+ leak via RyR1 due to S-nitrosylation of the channel and calstabin-1 depletion contributes to muscle weakness in muscular dystrophy, and that preventing the RyR1-mediated sarcoplasmic reticulum Ca2+ leak may provide a new therapeutic approach.", + "TAG_DATA": [ + "78, skeletal {'context': 'I-tissue/organ'}", + "79, muscle {'context': 'I-tissue/organ'}", + "119, RyR1 {'perturbing_action': 'I-gene loss-of-function'}", + "154, muscle {'context': 'B-tissue/organ'}", + "161, mdx {'context': 'B-organism'}", + "162, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "77, mdx ['l0', 'l1']", + "78, skeletal ['l0', 'l2']", + "79, muscle ['l1', 'l2']", + "119, RyR1 ['l3', 'l4', 'l5']", + "154, muscle ['l3', 'l6', 'l7']", + "161, mdx ['l4', 'l6', 'l8']", + "162, mice. ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "RyR1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscle" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "RyR1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mdx", + "mice." + ] + } + } + ] + }, + { + "PMID": "15864314", + "TEXT": "Although stem cells succumbing to reproductive death are assumed to be the single relevant targets in radiation tissue damage, recent studies showed intestinal stem cell damage is conditionally linked to crypt endothelial apoptosis, defining a two-target model. Here we report that when mouse intestines were protected against microvascular apoptosis, radiation switched as the dose escalated to a previously unrecognized crypt stem cell target, activating ceramide synthase-mediated apoptosis to initiate intestinal damage. Whereas ataxia telangiectasia-mutated (ATM) kinase normally represses ceramide synthase, its derepression in Atm(-/-) mice increased crypt stem cell radiosensitivity 3.7-fold without sensitizing the microvascular response. Discovery of this intestinal radiosensitivity mechanism allowed design of an antisense Atm oligonucleotide treatment which phenocopied the Atm(-/-) mouse, reordering ceramide synthase-mediated stem cell death to become the first-line gastrointestinal response of wild-type littermates. These experiments indicate that tissues operate multiple potential targets activated consecutively according to their inherent radiosensitivities that may be reordered therapeutically to control radiation tissue responses.", + "TAG_DATA": [ + "42, mouse {'context': 'B-tissue/organ'}", + "43, intestines {'context': 'I-tissue/organ'}", + "46, against {'effect': 'I-negative'}", + "63, activating {'effect': 'B-positive'}", + "66, apoptosis {'phenotype': 'B-apoptosis'}", + "83, Atm(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "84, mice {'context': 'B-organism'}", + "86, crypt {'context': 'B-cells'}", + "87, stem {'context': 'I-cells'}", + "88, cell {'context': 'I-cells'}", + "113, Atm(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "114, mouse, {'context': 'B-organism'}", + "118, stem {'context': 'B-cells'}", + "119, cell {'phenotype': 'B-cell death'}", + "120, death {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "42, mouse ['l0', 'l1', 'l2', 'l3']", + "43, intestines ['l0', 'l4', 'l5', 'l6']", + "46, against ['l1', 'l4', 'l7', 'l8']", + "63, activating ['l2', 'l5', 'l7', 'l9']", + "66, apoptosis ['l3', 'l6', 'l8', 'l9']", + "83, Atm(-/-) ['l10', 'l11', 'l12', 'l13']", + "84, mice ['l10', 'l14', 'l15', 'l16']", + "86, crypt ['l11', 'l14', 'l17', 'l18']", + "87, stem ['l12', 'l15', 'l17', 'l19']", + "88, cell ['l13', 'l16', 'l18', 'l19']", + "113, Atm(-/-) ['l20', 'l21', 'l22', 'l23']", + "114, mouse, ['l20', 'l24', 'l25', 'l26']", + "118, stem ['l21', 'l24', 'l27', 'l28']", + "119, cell ['l22', 'l25', 'l27', 'l29']", + "120, death ['l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "intestines" + ] + }, + "effect": { + "val": "negative", + "words": [ + "against" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "intestines" + ] + }, + "effect": { + "val": "positive", + "words": [ + "activating" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "intestines" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "against" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "activating" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atm(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mouse," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atm(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "crypt", + "stem", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atm(-/-)" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "stem" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + } + ] + }, + { + "PMID": "15558058", + "TEXT": "Patients with diabetes and other obesity-linked conditions have increased susceptibility to cardiovascular disorders. The adipocytokine adiponectin is decreased in patients with obesity-linked diseases. Here, we found that pressure overload in adiponectin-deficient mice resulted in enhanced concentric cardiac hypertrophy and increased mortality that was associated with increased extracellular signal-regulated kinase (ERK) and diminished AMP-activated protein kinase (AMPK) signaling in the myocardium. Adenovirus-mediated supplemention of adiponectin attenuated cardiac hypertrophy in response to pressure overload in adiponectin-deficient, wild-type and diabetic db/db mice. In cultures of cardiac myocytes, adiponectin activated AMPK and inhibited agonist-stimulated hypertrophy and ERK activation. Transduction with a dominant-negative form of AMPK reversed these effects, suggesting that adiponectin inhibits hypertrophic signaling in the myocardium through activation of AMPK signaling. Adiponectin may have utility for the treatment of hypertrophic cardiomyopathy associated with diabetes and other obesity-related diseases.", + "TAG_DATA": [ + "30, adiponectin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "31, mice {'context': 'B-organism'}", + "73, adiponectin-deficient, {'perturbing_action': 'B-gene loss-of-function'}", + "76, diabetic {'context': 'B-organism'}", + "77, db/db {'context': 'I-organism'}", + "78, mice. {'context': 'I-organism'}", + "80, cultures {'context': 'B-in vitro'}", + "82, cardiac {'context': 'B-cells'}", + "83, myocytes, {'context': 'I-cells'}", + "94, Transduction {'perturbing_action': 'B-other'}", + "95, with {'perturbing_action': 'I-other'}", + "96, a {'perturbing_action': 'I-other'}", + "97, dominant-negative {'perturbing_action': 'I-other'}", + "98, form {'perturbing_action': 'I-other'}", + "99, of {'perturbing_action': 'I-other'}", + "100, AMPK {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "30, adiponectin-deficient ['l0']", + "31, mice ['l0']", + "73, adiponectin-deficient, ['l1', 'l2', 'l3', 'l4']", + "76, diabetic ['l1', 'l5', 'l6', 'l7', 'l8', 'l9']", + "77, db/db ['l2', 'l5', 'l10', 'l11', 'l12', 'l13']", + "78, mice. ['l3', 'l6', 'l10', 'l14', 'l15', 'l16']", + "80, cultures ['l7', 'l11', 'l14', 'l17', 'l18']", + "82, cardiac ['l8', 'l12', 'l15', 'l17', 'l19']", + "83, myocytes, ['l4', 'l9', 'l13', 'l16', 'l18', 'l19']", + "94, Transduction ['l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "95, with ['l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "96, a ['l21', 'l26', 'l31', 'l32', 'l33', 'l34']", + "97, dominant-negative ['l22', 'l27', 'l31', 'l35', 'l36', 'l37']", + "98, form ['l23', 'l28', 'l32', 'l35', 'l38', 'l39']", + "99, of ['l24', 'l29', 'l33', 'l36', 'l38', 'l40']", + "100, AMPK ['l25', 'l30', 'l34', 'l37', 'l39', 'l40']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adiponectin-deficient", + "adiponectin-deficient," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "diabetic", + "db/db", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adiponectin-deficient," + ] + }, + "context": { + "val": "cells", + "words": [ + "myocytes," + ] + } + } + ] + }, + { + "PMID": "11984598", + "TEXT": "Human mast cells and basophils that express the high-affinity immunoglobulin E (IgE) receptor, Fc epsilon receptor 1 (Fc epsilon RI), have key roles in allergic diseases. Fc epsilon RI cross-linking stimulates the release of allergic mediators. Mast cells and basophils co-express Fc gamma RIIb, a low affinity receptor containing an immunoreceptor tyrosine-based inhibitory motif and whose co-aggregation with Fc epsilon RI can block Fc epsilon RI-mediated reactivity. Here we designed, expressed and tested the human basophil and mast-cell inhibitory function of a novel chimeric fusion protein, whose structure is gamma Hinge-CH gamma 2-CH gamma 3-15aa linker-CH epsilon 2-CH epsilon 3-CH epsilon 4. This Fc gamma Fc epsilon fusion protein was expressed as the predicted 140-kappa D dimer that reacted with anti-human epsilon- and gamma-chain specific antibodies. Fc gamma Fc epsilon bound to both human Fc epsilon RI and Fc gamma RII. It also showed dose- and time-dependent inhibition of antigen-driven IgE-mediated histamine release from fresh human basophils sensitized with IgE directed against NIP (4-hydroxy-3-iodo-5-nitrophenylacetyl). This was associated with altered Syk signaling. The fusion protein also showed increased inhibition of human anti-NP (4-hydroxy-3-nitrophenylacetyl) and anti-dansyl IgE-mediated passive cutaneous anaphylaxis in transgenic mice expressing human Fc epsilon RI alpha. Our results show that this chimeric protein is able to form complexes with both Fc epsilon RI and Fc gamma RII, and inhibit mast-cell and basophil function. This approach, using a Fc gamma Fc epsilon fusion protein to co-aggregate Fc epsilon RI with a receptor containing an immunoreceptor tyrosine-based inhibition motif, has therapeutic potential in", + "TAG_DATA": [ + "155, human {'context': 'B-cells'}", + "156, basophils {'context': 'I-cells'}", + "189, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "190, mice {'context': 'I-organism'}", + "191, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "192, human {'perturbing_action': 'I-gene gain-of-function'}", + "193, Fc {'perturbing_action': 'I-gene gain-of-function'}", + "194, epsilon {'perturbing_action': 'I-gene gain-of-function'}", + "195, RI {'perturbing_action': 'I-gene gain-of-function'}", + "196, alpha. {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "155, human ['l0']", + "156, basophils ['l0']", + "189, transgenic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "190, mice ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "191, expressing ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "192, human ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "193, Fc ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "194, epsilon ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "195, RI ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "196, alpha. ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "human", + "Fc", + "epsilon", + "RI", + "alpha." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "11017152", + "TEXT": "Systemic sclerosis is an autoimmune disease characterized by immunological and vascular abnormalities. Autoantibodies against intracellular antigens are associated with particular clinical features of the disease, whereas autoantibodies against cell surface antigens may be pathogenic by inducing endothelial cell damage, considered the primary event in the pathogenesis of the disease. Latent human cytomegalovirus infection may contribute to progression of systemic sclerosis through its ability to infect endothelial cells; however, direct links between human cytomegalovirus infection and systemic sclerosis are still lacking. Molecular mimicry is one of the mechanisms that account for the link between infection and autoimmunity. Here we have identified an immunodominant peptide using systemic sclerosis serum screening of a random peptide library; such peptide shares homology with autoantigens and with the human cytomegalovirus late protein UL94 (ref. 9). Immunoglobulin G antibodies against the peptide affinity-purified from the sera of patients with systemic sclerosis specifically recognized the viral product and autoantigens; moreover, such antibodies induced endothelial cell apoptosis through specific interaction with the cell surface integrin-NAG-2 protein complex. Our results provide evidence that antibodies against human cytomegalovirus cause apoptosis of endothelial cells, considered the initial pathogenic event of systemic sclerosis, and indicate a previously unknown mechanism for the etiological link between human cytomegalovirus infection and autoimmunity.", + "TAG_DATA": [ + "154, induced {'effect': 'B-positive'}", + "155, endothelial {'context': 'B-cells'}", + "156, cell {'context': 'I-cells'}", + "157, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "154, induced ['l0', 'l1', 'l2']", + "155, endothelial ['l0', 'l3', 'l4']", + "156, cell ['l1', 'l3', 'l5']", + "157, apoptosis ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "10581079", + "TEXT": "Elucidating the cellular immune response to infectious agents is a prerequisite for understanding disease pathogenesis and designing effective vaccines. In the identification of microbial T-cell epitopes, the availability of purified or recombinant bacterial proteins has been a chief limiting factor. In chronic infectious diseases such as Lyme disease, immune-mediated damage may add to the effects of direct infection by means of molecular mimicry to tissue autoantigens. Here, we describe a new method to effectively identify both microbial epitopes and candidate autoantigens. The approach combines data acquisition by positional scanning peptide combinatorial libraries and biometric data analysis by generation of scoring matrices. In a patient with chronic neuroborreliosis, we show that this strategy leads to the identification of potentially relevant T-cell targets derived from both Borrelia burgdorferi and the host. We also found that the antigen specificity of a single T-cell clone can be degenerate and yet the clone can preferentially recognize different peptides derived from the same organism, thus demonstrating that flexibility in T-cell recognition does not preclude specificity. This approach has potential applications in the identification of ligands in infectious diseases, tumors and autoimmune diseases.", + "TAG_DATA": [ + "103, patient {'context': 'B-patient'}", + "139, T-cell {'context': 'B-cells'}", + "140, clone {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "139, T-cell ['l0']", + "140, clone ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11536795", + "TEXT": "How does one treat in a seriously injured astronaut in outer space or even another planet? To answer such a question, the US National Aeronautical Space Administration (NASA) has embarked on a program of growing tissues--and possibly whole organs--in space. NASA has developed a unique rotating bioreactor that allow cells to be grown in a microgravity environment that eliminates almost all shear forces placed upon a cell culture system while entering space. Back on earth, this novel bioreactor has led to exciting discoveries and applications by scientists trying to get cells to differentiate and form their natural three-dimensional tissue matrices--the holy grail of tissue engineers. NASA's bioreactor has allowed various labs to culture cells and even viruses previously impossible to grow using traditional methods. These successes are attributed to the bioreactor's ability to provide an unique environment that closely resembles tissue differentiation during embryogenesis, and thus allowing cellular expression of surface epitopes similar to that of intact tissues. It also appears that cells grown in a microgravity, low-shear environment allows for greater chemical signaling, probably as a result of more surface contact between cells. Realizing the bioreactor's commercial potential, Santa Monica, California-based VivoRx licensed exclusive rights from NASA for both therapeutic and diagnostic commercial applications. VivoRx has, in the past, successfully transplanted encapsulated islet cells from cadavers and porcine pancreas into insulin-dependent diabetics, perhaps a major breakthrough in the treatment of diabetes. However, pancreas from cadavers are in very short supply. The bioreactor may be the answer; VivoRx hopes the bioreactor will allow them to propagate enough human islet cells to use their cell-based approach to treat a large diabetic population. The company has already successfully grown islet cells generated from the bioreactors, and is beginning FDA-approved Phase I/II clinical trials.", + "TAG_DATA": [ + "162, cells {'context': 'B-cells'}", + "213, islet {'context': 'I-cells'}", + "214, cells {'context': 'I-cells'}", + "218, porcine {'context': 'B-tissue/organ'}", + "219, pancreas {'context': 'I-tissue/organ'}", + "222, diabetics, {'context': 'I-organism'}", + "257, human {'context': 'B-cells'}", + "258, islet {'context': 'I-cells'}", + "259, cells {'context': 'I-cells'}", + "277, islet {'context': 'B-cells'}", + "278, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "162, cells ['l0', 'l1', 'l2']", + "213, islet ['l0', 'l3', 'l4', 'l5', 'l6']", + "214, cells ['l1', 'l3', 'l7']", + "216, cadavers ['l2', 'l4', 'l7', 'l8', 'l9']", + "218, porcine ['l10', 'l11', 'l12']", + "219, pancreas ['l5', 'l8', 'l10', 'l13']", + "222, diabetics, ['l6', 'l9', 'l11', 'l13', 'l14']", + "257, human ['l15', 'l16', 'l17']", + "258, islet ['l15', 'l18', 'l19']", + "259, cells ['l12', 'l14', 'l16', 'l18']", + "277, islet ['l20']", + "278, cells ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7585092", + "TEXT": "Psoriasis is a hyperproliferative and inflammatory skin disorder of unknown aetiology. A fusion protein composed of human interleukin-2 and fragments of diphtheria toxin (DAB389IL-2), which selectively blocks the growth of activated lymphocytes but not keratinocytes, was administered systemically to ten patients to gauge the contribution of activated T cells to the disease. Four patients showed striking clinical improvement and four moderate improvement, after two cycle of low dose IL-2-toxin. The reversal of several molecular markers of epidermal dysfunction was associated with a marked reduction in intraepidermal CD3+ and CD8+ T cells, suggesting a primary immunological basis for this widespread disorder.", + "TAG_DATA": [ + "31, lymphocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "7585001", + "TEXT": "Contemporary psychiatric misdirections derived primarily from standard medical errors of oversimplification, misplaced emphasis, and invention are reviewed. These particular errors, however, were in part prompted and sustained by the sociocultural fads and fashions of the day. The results have been disastrous for everyone--patients, families, the public and psychiatry itself.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32770166", + "TEXT": "Type 1 diabetes (T1D)-an autoimmune disease that destroys the pancreatic islets, resulting in insulin deficiency-often begins early in life when islet autoantibody appearance signals high risk1. However, clinical diabetes can follow in weeks or only after decades, and is very difficult to predict. Ketoacidosis at onset remains common2,3 and is most severe in the very young4,5, in whom it can be life threatening and difficult to treat6-9. Autoantibody surveillance programs effectively prevent most ketoacidosis10-12 but require frequent evaluations whose expense limits public health adoption13. Prevention therapies applied before onset, when greater islet mass remains, have rarely been feasible14 because individuals at greatest risk of impending T1D are difficult to identify. To remedy this, we sought accurate, cost-effective estimation of future T1D risk by developing a combined risk score incorporating both fixed and variable factors (genetic, clinical and immunological) in 7,798 high-risk children followed closely from birth for 9.3 years. Compared with autoantibodies alone, the combined model dramatically improves T1D prediction at ≥2 years of age over horizons up to 8 years of age (area under the receiver operating characteristic curve ≥ 0.9), doubles the estimated efficiency of population-based newborn screening to prevent ketoacidosis, and enables individualized risk estimates for better prevention trial selection.", + "TAG_DATA": [ + "140, high-risk {'context': 'B-organism'}", + "141, children {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "140, high-risk ['l0']", + "141, children ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32747827", + "TEXT": "Artemisinin resistance (delayed P. falciparum clearance following artemisinin-based combination therapy), is widespread across Southeast Asia but to date has not been reported in Africa1-4. Here we genotyped the P. falciparum K13 (Pfkelch13) propeller domain, mutations in which can mediate artemisinin resistance5,6, in pretreatment samples collected from recent dihydroarteminisin-piperaquine and artemether-lumefantrine efficacy trials in Rwanda7. While cure rates were >95% in both treatment arms, the Pfkelch13 R561H mutation was identified in 19 of 257 (7.4%) patients at Masaka. Phylogenetic analysis revealed the expansion of an indigenous R561H lineage. Gene editing confirmed that this mutation can drive artemisinin resistance in vitro. This study provides evidence for the de novo emergence of Pfkelch13-mediated artemisinin resistance in Rwanda, potentially compromising the continued success of antimalarial chemotherapy in Africa.", + "TAG_DATA": [ + "97, in {'context': 'B-in vitro'}", + "98, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "97, in ['l0']", + "98, vitro. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32665655", + "TEXT": "Many European countries have responded to the COVID-19 pandemic by implementing nationwide protection measures and lockdowns1. However, the epidemic could rebound when such measures are relaxed, possibly leading to a requirement for a second or more, repeated lockdowns2. Here, we present results of a stochastic agent-based microsimulation model of the COVID-19 epidemic in France. We examined the potential impact of post-lockdown measures, including physical distancing, mask-wearing and shielding individuals who are the most vulnerable to severe COVID-19 infection, on cumulative disease incidence and mortality, and on intensive care unit (ICU)-bed occupancy. While lockdown is effective in containing the viral spread, once lifted, regardless of duration, it would be unlikely to prevent a rebound. Both physical distancing and mask-wearing, although effective in slowing the epidemic and in reducing mortality, would also be ineffective in ultimately preventing ICUs from becoming overwhelmed and a subsequent second lockdown. However, these measures coupled with the shielding of vulnerable people would be associated with better outcomes, including lower mortality and maintaining an adequate ICU capacity to prevent a second lockdown. Benefits would nonetheless be markedly reduced if most people do not adhere to these measures, or if they are not maintained for a sufficiently long period.", + "TAG_DATA": [ + "135, ICUs {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32661393", + "TEXT": "The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has dramatically expedited global vaccine development efforts1-3, most targeting the viral 'spike' glycoprotein (S). S localizes on the virion surface and mediates recognition of cellular receptor angiotensin-converting enzyme 2 (ACE2)4-6. Eliciting neutralizing antibodies that block S-ACE2 interaction7-9, or indirectly prevent membrane fusion10, constitute an attractive modality for vaccine-elicited protection11. However, although prototypic S-based vaccines show promise in animal models12-14, the immunogenic properties of S in humans are poorly resolved. In this study, we characterized humoral and circulating follicular helper T cell (cTFH) immunity against spike in recovered patients with coronavirus disease 2019 (COVID-19). We found that S-specific antibodies, memory B cells and cTFH are consistently elicited after SARS-CoV-2 infection, demarking robust humoral immunity and positively associated with plasma neutralizing activity. Comparatively low frequencies of B cells or cTFH specific for the receptor binding domain of S were elicited. Notably, the phenotype of S-specific cTFH differentiated subjects with potent neutralizing responses, providing a potential biomarker of potency for S-based vaccines entering the clinic. Overall, although patients who recovered from COVID-19 displayed multiple hallmarks of effective immune recognition of S, the wide spectrum of neutralizing activity observed suggests that vaccines might require strategies to selectively target the most potent neutralizing epitopes.", + "TAG_DATA": [ + "107, memory {'context': 'B-cells'}", + "108, B {'context': 'I-cells'}", + "109, cells {'context': 'I-cells'}", + "133, B {'context': 'B-cells'}", + "134, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "107, memory ['l0', 'l1']", + "108, B ['l0', 'l2']", + "109, cells ['l1', 'l2']", + "133, B ['l3']", + "134, cells ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32661391", + "TEXT": "Cancer cachexia is a highly prevalent condition associated with poor quality of life and reduced survival1. Tumor-induced perturbations in the endocrine, immune and nervous systems drive anorexia and catabolic changes in adipose tissue and skeletal muscle, hallmarks of cancer cachexia2-4. However, the molecular mechanisms driving cachexia remain poorly defined, and there are currently no approved drugs for the condition. Elevation in circulating growth differentiation factor 15 (GDF15) correlates with cachexia and reduced survival in patients with cancer5-8, and a GDNF family receptor alpha like (GFRAL)-Ret proto-oncogene (RET) signaling complex in brainstem neurons that mediates GDF15-induced weight loss in mice has recently been described9-12. Here we report a therapeutic antagonistic monoclonal antibody, 3P10, that targets GFRAL and inhibits RET signaling by preventing the GDF15-driven interaction of RET with GFRAL on the cell surface. Treatment with 3P10 reverses excessive lipid oxidation in tumor-bearing mice and prevents cancer cachexia, even under calorie-restricted conditions. Mechanistically, activation of the GFRAL-RET pathway induces expression of genes involved in lipid metabolism in adipose tissues, and both peripheral chemical sympathectomy and loss of adipose triglyceride lipase protect mice from GDF15-induced weight loss. These data uncover a peripheral sympathetic axis by which GDF15 elicits a lipolytic response in adipose tissue independently of anorexia, leading to reduced adipose and muscle mass and function in tumor-bearing mice.", + "TAG_DATA": [ + "140, tumor-bearing {'context': 'B-organism'}", + "141, mice {'context': 'I-organism'}", + "179, mice {'context': 'B-organism'}", + "214, tumor-bearing {'context': 'B-organism'}", + "215, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "140, tumor-bearing ['l0']", + "141, mice ['l0']", + "179, mice ['l1', 'l2']", + "214, tumor-bearing ['l1', 'l3']", + "215, mice. ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32651581", + "TEXT": "Antibodies are a principal determinant of immunity for most RNA viruses and have promise to reduce infection or disease during major epidemics. The novel coronavirus SARS-CoV-2 has caused a global pandemic with millions of infections and hundreds of thousands of deaths to date1,2. In response, we used a rapid antibody discovery platform to isolate hundreds of human monoclonal antibodies (mAbs) against the SARS-CoV-2 spike (S) protein. We stratify these mAbs into five major classes on the basis of their reactivity to subdomains of S protein as well as their cross-reactivity to SARS-CoV. Many of these mAbs inhibit infection of authentic SARS-CoV-2 virus, with most neutralizing mAbs recognizing the receptor-binding domain (RBD) of S. This work defines sites of vulnerability on SARS-CoV-2 S and demonstrates the speed and robustness of advanced antibody discovery platforms.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32647358", + "TEXT": "In January 2020, a novel betacoronavirus (family Coronaviridae), named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the etiological agent of a cluster of pneumonia cases occurring in Wuhan City, Hubei Province, China1,2. The disease arising from SARS-CoV-2 infection, coronavirus disease 2019 (COVID-19), subsequently spread rapidly causing a worldwide pandemic. Here we examine the added value of near real-time genome sequencing of SARS-CoV-2 in a subpopulation of infected patients during the first 10 weeks of COVID-19 containment in Australia and compare findings from genomic surveillance with predictions of a computational agent-based model (ABM). Using the Australian census data, the ABM generates over 24 million software agents representing the population of Australia, each with demographic attributes of an anonymous individual. It then simulates transmission of the disease over time, spreading from specific infection sources, using contact rates of individuals within different social contexts. We report that the prospective sequencing of SARS-CoV-2 clarified the probable source of infection in cases where epidemiological links could not be determined, significantly decreased the proportion of COVID-19 cases with contentious links, documented genomically similar cases associated with concurrent transmission in several institutions and identified previously unsuspected links. Only a quarter of sequenced cases appeared to be locally acquired and were concordant with predictions from the ABM. These high-resolution genomic data are crucial to track cases with locally acquired COVID-19 and for timely recognition of independent importations once border restrictions are lifted and trade and travel resume.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32581323", + "TEXT": "As of 10 April 2020, New York State had 180,458 cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and 9,385 reported deaths. Patients with cancer comprised 8.4% of deceased individuals1. Population-based studies from China and Italy suggested a higher coronavirus disease 2019 (COVID-19) death rate in patients with cancer2,3, although there is a knowledge gap as to which aspects of cancer and its treatment confer risk of severe COVID-194. This information is critical to balance the competing safety considerations of reducing SARS-CoV-2 exposure and cancer treatment continuation. From 10 March to 7 April 2020, 423 cases of symptomatic COVID-19 were diagnosed at Memorial Sloan Kettering Cancer Center (from a total of 2,035 patients with cancer tested). Of these, 40% were hospitalized for COVID-19, 20% developed severe respiratory illness (including 9% who required mechanical ventilation) and 12% died within 30 d. Age older than 65 years and treatment with immune checkpoint inhibitors (ICIs) were predictors for hospitalization and severe disease, whereas receipt of chemotherapy and major surgery were not. Overall, COVID-19 in patients with cancer is marked by substantial rates of hospitalization and severe outcomes. The association observed between ICI and COVID-19 outcomes in our study will need further interrogation in tumor-specific cohorts.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32572266", + "TEXT": "Improving early cancer detection has the potential to substantially reduce cancer-related mortality. Cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) is a highly sensitive assay capable of detecting early-stage tumors. We report accurate classification of patients across all stages of renal cell carcinoma (RCC) in plasma (area under the receiver operating characteristic (AUROC) curve of 0.99) and demonstrate the validity of this assay to identify patients with RCC using urine cell-free DNA (cfDNA; AUROC of 0.86).", + "TAG_DATA": [ + "40, renal {'context': 'B-neoplasm'}", + "41, cell {'context': 'I-neoplasm'}", + "42, carcinoma {'context': 'I-neoplasm'}", + "43, (RCC) {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "40, renal ['l0', 'l1', 'l2']", + "41, cell ['l0', 'l3', 'l4']", + "42, carcinoma ['l1', 'l3', 'l5']", + "43, (RCC) ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32528151", + "TEXT": "Metabolic responses to food influence risk of cardiometabolic disease, but large-scale high-resolution studies are lacking. We recruited n = 1,002 twins and unrelated healthy adults in the United Kingdom to the PREDICT 1 study and assessed postprandial metabolic responses in a clinical setting and at home. We observed large inter-individual variability (as measured by the population coefficient of variation (s.d./mean, %)) in postprandial responses of blood triglyceride (103%), glucose (68%) and insulin (59%) following identical meals. Person-specific factors, such as gut microbiome, had a greater influence (7.1% of variance) than did meal macronutrients (3.6%) for postprandial lipemia, but not for postprandial glycemia (6.0% and 15.4%, respectively); genetic variants had a modest impact on predictions (9.5% for glucose, 0.8% for triglyceride, 0.2% for C-peptide). Findings were independently validated in a US cohort (n = 100 people). We developed a machine-learning model that predicted both triglyceride (r = 0.47) and glycemic (r = 0.77) responses to food intake. These findings may be informative for developing personalized diet strategies. The ClinicalTrials.gov registration identifier is NCT03479866.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32504052", + "TEXT": "Detection of asymptomatic or subclinical novel human coronavirus SARS-CoV-2 infection is critical for understanding the overall prevalence and infection potential of COVID-19. To estimate the cumulative prevalence of SARS-CoV-2 infection in China, we evaluated the host serologic response, measured by the levels of immunoglobulins M and G in 17,368 individuals, in the city of Wuhan, the epicenter of the COVID-19 pandemic in China, and geographic regions in the country, during the period from 9 March 2020 to 10 April 2020. In our cohorts, the seropositivity in Wuhan varied between 3.2% and 3.8% in different subcohorts. Seroposivity progressively decreased in other cities as the distance to the epicenter increased. Patients who visited a hospital for maintenance hemodialysis and healthcare workers also had a higher seroprevalence of 3.3% (51 of 1,542, 2.5-4.3%, 95% confidence interval (CI)) and 1.8% (81 of 4,384, 1.5-2.3%, 95% CI), respectively. More studies are needed to determine whether these results are generalizable to other populations and geographic locations, as well as to determine at what rate seroprevalence is increasing with the progress of the COVID-19 pandemic. Serologic surveillance has the potential to provide a more faithful cumulative viral attack rate for the first season of this novel SARS-CoV-2 infection.", + "TAG_DATA": [ + "108, Patients {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32451499", + "TEXT": "Understanding of the factors governing immune responses in cancer remains incomplete, limiting patient benefit. In this study, we used mass cytometry to define the systemic immune landscape in response to tumor development across five tissues in eight mouse tumor models. Systemic immunity was dramatically altered across models and time, with consistent findings in the peripheral blood of patients with breast cancer. Changes in peripheral tissues differed from those in the tumor microenvironment. Mice with tumor-experienced immune systems mounted dampened responses to orthogonal challenges, including reduced T cell activation during viral or bacterial infection. Antigen-presenting cells (APCs) mounted weaker responses in this context, whereas promoting APC activation rescued T cell activity. Systemic immune changes were reversed with surgical tumor resection, and many were prevented by interleukin-1 or granulocyte colony-stimulating factor blockade, revealing remarkable plasticity in the systemic immune state. These results demonstrate that tumor development dynamically reshapes the composition and function of the immune macroenvironment.", + "TAG_DATA": [ + "72, Mice {'context': 'B-organism'}", + "85, T {'context': 'B-cells'}", + "86, cell {'context': 'B-cells'}", + "93, Antigen-presenting {'context': 'B-cells'}", + "94, cells {'context': 'I-cells'}", + "104, APC {'context': 'B-cells'}", + "107, T {'context': 'B-cells'}", + "108, cell {'context': 'B-cells'}", + "117, tumor {'perturbing_action': 'I-gene loss-of-function'}", + "118, resection, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "72, Mice ['l0', 'l1', 'l2', 'l3']", + "85, T ['l0', 'l4']", + "86, cell ['l1', 'l4']", + "93, Antigen-presenting ['l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "94, cells ['l2', 'l5', 'l11', 'l12', 'l13', 'l14']", + "104, APC ['l6', 'l11', 'l15', 'l16', 'l17', 'l18']", + "107, T ['l7', 'l12', 'l15', 'l19', 'l20']", + "108, cell ['l3', 'l8', 'l13', 'l16', 'l19']", + "117, tumor ['l9', 'l17', 'l21']", + "118, resection, ['l10', 'l14', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Antigen-presenting", + "cells", + "APC", + "T" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "tumor", + "resection," + ] + } + } + ] + }, + { + "PMID": "32424212", + "TEXT": "Skin conditions affect 1.9 billion people. Because of a shortage of dermatologists, most cases are seen instead by general practitioners with lower diagnostic accuracy. We present a deep learning system (DLS) to provide a differential diagnosis of skin conditions using 16,114 de-identified cases (photographs and clinical data) from a teledermatology practice serving 17 sites. The DLS distinguishes between 26 common skin conditions, representing 80% of cases seen in primary care, while also providing a secondary prediction covering 419 skin conditions. On 963 validation cases, where a rotating panel of three board-certified dermatologists defined the reference standard, the DLS was non-inferior to six other dermatologists and superior to six primary care physicians (PCPs) and six nurse practitioners (NPs) (top-1 accuracy: 0.66 DLS, 0.63 dermatologists, 0.44 PCPs and 0.40 NPs). These results highlight the potential of the DLS to assist general practitioners in diagnosing skin conditions.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32405055", + "TEXT": "In just a few weeks’ time, leaders across the globe will have to start making decisions about lifting lockdown policies, with considerable social, economic and political consequences. We propose a framework for what is arguably the most difficult health challenge that governments have faced since the beginning of this century: a responsible lockdown exit strategy.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32405028", + "TEXT": "A novel coronavirus-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-emerged in humans in Wuhan, China, in December 2019 and has since disseminated globally1,2. As of April 16, 2020, the confirmed case count of coronavirus disease 2019 (COVID-19) had surpassed 2 million. Based on full-genome sequence analysis, SARS-CoV-2 shows high homology to SARS-related coronaviruses identified in horseshoe bats1,2. Here we show the establishment and characterization of expandable intestinal organoids derived from horseshoe bats of the Rhinolophus sinicus species that can recapitulate bat intestinal epithelium. These bat enteroids are fully susceptible to SARS-CoV-2 infection and sustain robust viral replication. Development of gastrointestinal symptoms in some patients with COVID-19 and detection of viral RNA in fecal specimens suggest that SARS-CoV-2 might cause enteric, in addition to respiratory, infection3,4. Here we demonstrate active replication of SARS-CoV-2 in human intestinal organoids and isolation of infectious virus from the stool specimen of a patient with diarrheal COVID-19. Collectively, we established the first expandable organoid culture system of bat intestinal epithelium and present evidence that SARS-CoV-2 can infect bat intestinal cells. The robust SARS-CoV-2 replication in human intestinal organoids suggests that the human intestinal tract might be a transmission route of SARS-CoV-2.", + "TAG_DATA": [ + "83, bat {'context': 'B-organoid'}", + "84, enteroids {'context': 'I-organoid'}", + "132, human {'context': 'B-organoid'}", + "133, intestinal {'context': 'I-organoid'}", + "134, organoids {'context': 'I-organoid'}", + "170, bat {'context': 'B-cells'}", + "171, intestinal {'context': 'I-cells'}", + "172, cells. {'context': 'I-cells'}", + "178, human {'context': 'B-organoid'}", + "179, intestinal {'context': 'I-organoid'}", + "180, organoids {'context': 'I-organoid'}" + ], + "LINK_DATA": [ + "66, organoids ['l0']", + "83, bat ['l1']", + "84, enteroids ['l0', 'l1']", + "132, human ['l2', 'l3']", + "133, intestinal ['l2', 'l4']", + "134, organoids ['l3', 'l4']", + "170, bat ['l5', 'l6', 'l7', 'l8', 'l9']", + "171, intestinal ['l5', 'l10', 'l11', 'l12', 'l13']", + "172, cells. ['l6', 'l10', 'l14', 'l15', 'l16']", + "178, human ['l7', 'l11', 'l14', 'l17', 'l18']", + "179, intestinal ['l8', 'l12', 'l15', 'l17', 'l19']", + "180, organoids ['l9', 'l13', 'l16', 'l18', 'l19']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32398876", + "TEXT": "Here, we describe a serological enzyme-linked immunosorbent assay for the screening and identification of human SARS-CoV-2 seroconverters. This assay does not require the handling of infectious virus, can be adjusted to detect different antibody types in serum and plasma and is amenable to scaling. Serological assays are of critical importance to help define previous exposure to SARS-CoV-2 in populations, identify highly reactive human donors for convalescent plasma therapy and investigate correlates of protection.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32393800", + "TEXT": "Recent efforts toward an HIV vaccine focus on inducing broadly neutralizing antibodies, but eliciting both neutralizing antibodies (nAbs) and cellular responses may be superior. Here, we immunized macaques with an HIV envelope trimer, either alone to induce nAbs, or together with a heterologous viral vector regimen to elicit nAbs and cellular immunity, including CD8+ tissue-resident memory T cells. After ten vaginal challenges with autologous virus, protection was observed in both vaccine groups at 53.3% and 66.7%, respectively. A nAb titer >300 was generally associated with protection but in the heterologous viral vector + nAb group, titers <300 were sufficient. In this group, protection was durable as the animals resisted six more challenges 5 months later. Antigen stimulation of T cells in ex vivo vaginal tissue cultures triggered antiviral responses in myeloid and CD4+ T cells. We propose that cellular immune responses reduce the threshold of nAbs required to confer superior and durable protection.", + "TAG_DATA": [ + "27, macaques {'context': 'B-organism'}", + "105, animals {'context': 'B-organism'}", + "116, T {'context': 'B-cells'}", + "117, cells {'context': 'I-cells'}", + "119, ex {'context': 'B-in vitro'}", + "120, vivo {'context': 'B-in vitro'}", + "121, vaginal {'context': 'B-organoid'}", + "122, tissue {'context': 'I-cells'}", + "123, cultures {'context': 'I-cells'}", + "128, myeloid {'context': 'B-cells'}", + "129, and {'context': 'I-cells'}", + "130, CD4+ {'context': 'I-cells'}", + "131, T {'context': 'I-cells'}", + "132, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "116, T ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "117, cells ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "119, ex ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "120, vivo ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "121, vaginal ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "122, tissue ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "123, cultures ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "128, myeloid ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "129, and ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "130, CD4+ ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "131, T ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "132, cells. ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32393799", + "TEXT": "The electrocardiogram (ECG) is a widely used medical test, consisting of voltage versus time traces collected from surface recordings over the heart1. Here we hypothesized that a deep neural network (DNN) can predict an important future clinical event, 1-year all-cause mortality, from ECG voltage-time traces. By using ECGs collected over a 34-year period in a large regional health system, we trained a DNN with 1,169,662 12-lead resting ECGs obtained from 253,397 patients, in which 99,371 events occurred. The model achieved an area under the curve (AUC) of 0.88 on a held-out test set of 168,914 patients, in which 14,207 events occurred. Even within the large subset of patients (n = 45,285) with ECGs interpreted as 'normal' by a physician, the performance of the model in predicting 1-year mortality remained high (AUC = 0.85). A blinded survey of cardiologists demonstrated that many of the discriminating features of these normal ECGs were not apparent to expert reviewers. Finally, a Cox proportional-hazard model revealed a hazard ratio of 9.5 (P < 0.005) for the two predicted groups (dead versus alive 1 year after ECG) over a 25-year follow-up period. These results show that deep learning can add substantial prognostic information to the interpretation of 12-lead resting ECGs, even in cases that are interpreted as normal by physicians.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32350462", + "TEXT": "We report acute antibody responses to SARS-CoV-2 in 285 patients with COVID-19. Within 19 days after symptom onset, 100% of patients tested positive for antiviral immunoglobulin-G (IgG). Seroconversion for IgG and IgM occurred simultaneously or sequentially. Both IgG and IgM titers plateaued within 6 days after seroconversion. Serological testing may be helpful for the diagnosis of suspected patients with negative RT-PCR results and for the identification of asymptomatic infections.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32341578", + "TEXT": "Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 editing of immune checkpoint genes could improve the efficacy of T cell therapy, but the first necessary undertaking is to understand the safety and feasibility. Here, we report results from a first-in-human phase I clinical trial of CRISPR-Cas9 PD-1-edited T cells in patients with advanced non-small-cell lung cancer (ClinicalTrials.gov NCT02793856). Primary endpoints were safety and feasibility, and the secondary endpoint was efficacy. The exploratory objectives included tracking of edited T cells. All prespecified endpoints were met. PD-1-edited T cells were manufactured ex vivo by cotransfection using electroporation of Cas9 and single guide RNA plasmids. A total of 22 patients were enrolled; 17 had sufficient edited T cells for infusion, and 12 were able to receive treatment. All treatment-related adverse events were grade 1/2. Edited T cells were detectable in peripheral blood after infusion. The median progression-free survival was 7.7 weeks (95% confidence interval, 6.9 to 8.5 weeks) and median overall survival was 42.6 weeks (95% confidence interval, 10.3-74.9 weeks). The median mutation frequency of off-target events was 0.05% (range, 0-0.25%) at 18 candidate sites by next generation sequencing. We conclude that clinical application of CRISPR-Cas9 gene-edited T cells is generally safe and feasible. Future trials should use superior gene editing approaches to improve therapeutic efficacy.", + "TAG_DATA": [ + "46, T {'context': 'B-cells'}", + "47, cells {'context': 'B-cells'}", + "49, patients {'context': 'B-patient'}", + "51, advanced {'context': 'B-neoplasm'}", + "52, non-small-cell {'context': 'I-neoplasm'}", + "53, lung {'context': 'I-neoplasm'}", + "54, cancer {'context': 'I-neoplasm'}", + "84, T {'context': 'B-cells'}", + "85, cells {'context': 'I-cells'}", + "112, T {'context': 'B-cells'}", + "113, cells {'context': 'I-cells'}", + "131, T {'context': 'B-cells'}", + "132, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "46, T ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "47, cells ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "49, patients ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "51, advanced ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "52, non-small-cell ['l3', 'l8', 'l12', 'l15', 'l18', 'l19', 'l20']", + "53, lung ['l4', 'l9', 'l13', 'l16', 'l18', 'l21']", + "54, cancer ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "84, T ['l22', 'l23', 'l24']", + "85, cells ['l20', 'l22', 'l25']", + "112, T ['l23', 'l26', 'l27', 'l28']", + "113, cells ['l24', 'l25', 'l26', 'l29', 'l30']", + "131, T ['l27', 'l29', 'l31']", + "132, cells ['l28', 'l30', 'l31']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32313250", + "TEXT": "Phase 3 trials are the mainstay of drug development across medicine but have often not met expectations set by preceding phase 2 studies. A systematic meta-analysis evaluated all randomized controlled, double-blind trials investigating targeted disease-modifying anti-rheumatic drugs in rheumatoid and psoriatic arthritis. Primary outcomes of American College of Rheumatology (ACR) 20 responses were compared by mixed-model logistic regression, including exploration of potential determinants of efficacy overestimation. In rheumatoid arthritis, phase 2 trial outcomes systematically overestimated subsequent phase 3 results (odds ratio comparing ACR20 in phase 2 versus phase 3: 1.39, 95% confidence interval: 1.25-1.57, P < 0.001). Data for psoriatic arthritis trials were similar, but not statistically significant (odds ratio comparing ACR20 in phase 2 versus phase 3: 1.35, 95% confidence interval: 0.94-1.94, P = 0.09). Differences in inclusion criteria largely explained the observed differences in efficacy findings. Our findings have implications for all stakeholders in new therapeutic development and testing, as well as potential ethical implications.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32296168", + "TEXT": "We report temporal patterns of viral shedding in 94 patients with laboratory-confirmed COVID-19 and modeled COVID-19 infectiousness profiles from a separate sample of 77 infector-infectee transmission pairs. We observed the highest viral load in throat swabs at the time of symptom onset, and inferred that infectiousness peaked on or before symptom onset. We estimated that 44% (95% confidence interval, 25-69%) of secondary cases were infected during the index cases' presymptomatic stage, in settings with substantial household clustering, active case finding and quarantine outside the home. Disease control measures should be adjusted to account for probable substantial presymptomatic transmission.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32284613", + "TEXT": "We report epidemiological and clinical investigations on ten pediatric SARS-CoV-2 infection cases confirmed by real-time reverse transcription PCR assay of SARS-CoV-2 RNA. Symptoms in these cases were nonspecific and no children required respiratory support or intensive care. Chest X-rays lacked definite signs of pneumonia, a defining feature of the infection in adult cases. Notably, eight children persistently tested positive on rectal swabs even after nasopharyngeal testing was negative, raising the possibility of fecal-oral transmission.", + "TAG_DATA": [ + "55, children {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32284588", + "TEXT": "Although immunotherapy has revolutionized cancer treatment, only a subset of patients demonstrate durable clinical benefit. Definitive predictive biomarkers and targets to overcome resistance remain unidentified, underscoring the urgency to develop reliable immunocompetent models for mechanistic assessment. Here we characterize a panel of syngeneic mouse models, representing a variety of molecular and phenotypic subtypes of human melanomas and exhibiting their diverse range of responses to immune checkpoint blockade (ICB). Comparative analysis of genomic, transcriptomic and tumor-infiltrating immune cell profiles demonstrated alignment with clinical observations and validated the correlation of T cell dysfunction and exclusion programs with resistance. Notably, genome-wide expression analysis uncovered a melanocytic plasticity signature predictive of patient outcome in response to ICB, suggesting that the multipotency and differentiation status of melanoma can determine ICB benefit. Our comparative preclinical platform recapitulates melanoma clinical behavior and can be employed to identify mechanisms and treatment strategies to improve patient care.", + "TAG_DATA": [ + "43, mouse {'context': 'I-organism'}", + "44, models, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "43, mouse ['l0']", + "44, models, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32251400", + "TEXT": "PD-1 plus CTLA-4 blockade is highly effective in advanced-stage, mismatch repair (MMR)-deficient (dMMR) colorectal cancers, yet not in MMR-proficient (pMMR) tumors. We postulated a higher efficacy of neoadjuvant immunotherapy in early-stage colon cancers. In the exploratory NICHE study (ClinicalTrials.gov: NCT03026140), patients with dMMR or pMMR tumors received a single dose of ipilimumab and two doses of nivolumab before surgery, the pMMR group with or without celecoxib. The primary objective was safety and feasibility; 40 patients with 21 dMMR and 20 pMMR tumors were treated, and 3 patients received nivolumab monotherapy in the safety run-in. Treatment was well tolerated and all patients underwent radical resections without delays, meeting the primary endpoint. Of the patients who received ipilimumab + nivolumab (20 dMMR and 15 pMMR tumors), 35 were evaluable for efficacy and translational endpoints. Pathological response was observed in 20/20 (100%; 95% exact confidence interval (CI): 86-100%) dMMR tumors, with 19 major pathological responses (MPRs, ≤10% residual viable tumor) and 12 pathological complete responses. In pMMR tumors, 4/15 (27%; 95% exact CI: 8-55%) showed pathological responses, with 3 MPRs and 1 partial response. CD8+PD-1+ T cell infiltration was predictive of response in pMMR tumors. These data indicate that neoadjuvant immunotherapy may have the potential to become the standard of care for a defined group of colon cancer patients when validated in larger studies with at least 3 years of disease-free survival data.", + "TAG_DATA": [ + "40, patients {'context': 'B-patient'}", + "42, dMMR {'context': 'B-neoplasm'}", + "44, pMMR {'context': 'I-neoplasm'}", + "45, tumors {'context': 'I-neoplasm'}", + "74, patients {'context': 'B-patient'}", + "77, dMMR {'context': 'B-neoplasm'}", + "80, pMMR {'context': 'B-neoplasm'}", + "81, tumors {'context': 'I-neoplasm'}", + "143, dMMR {'context': 'B-neoplasm'}", + "144, tumors, {'context': 'I-neoplasm'}", + "161, pMMR {'context': 'B-neoplasm'}", + "162, tumors, {'context': 'I-neoplasm'}", + "188, pMMR {'context': 'B-neoplasm'}", + "189, tumors. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "40, patients ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "42, dMMR ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "43, or ['l1', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "44, pMMR ['l2', 'l9', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "45, tumors ['l3', 'l10', 'l15', 'l20', 'l25', 'l26', 'l27']", + "74, patients ['l4', 'l11', 'l16', 'l21', 'l25', 'l28', 'l29', 'l30']", + "77, dMMR ['l5', 'l12', 'l17', 'l22', 'l26', 'l28', 'l31', 'l32']", + "80, pMMR ['l6', 'l18', 'l23', 'l29', 'l31', 'l33']", + "81, tumors ['l7', 'l13', 'l19', 'l24', 'l27', 'l30', 'l32', 'l33']", + "143, dMMR ['l34']", + "144, tumors, ['l34']", + "161, pMMR ['l35']", + "162, tumors, ['l35']", + "188, pMMR ['l36']", + "189, tumors. ['l36']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32242125", + "TEXT": "A trial of a therapeutic vaccine against HIV induces cellular immunity and, although it provides hope, it highlights the hurdles for the development of such strategies.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32235883", + "TEXT": "We administered Ad26, modified vaccinia Ankara vectors containing mosaic HIV-1 antigens or placebo in 26 individuals who initiated antiretroviral therapy during acute human immunodeficiency virus infection as an exploratory study to determine the safety and duration of viremic control after treatment interruption. The vaccine was safe and generated robust immune responses, but delayed time to viral rebound compared to that in placebo recipients by only several days and did not lead to viremic control after treatment interruption (clinical trial NCT02919306).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32161413", + "TEXT": "Fetal growth restriction (FGR) is the major single cause of stillbirth1 and is also associated with neonatal morbidity and mortality2,3, impaired health and educational achievement in childhood4,5 and with a range of diseases in later life6. Effective screening and intervention for FGR is an unmet clinical need. Here, we performed ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) metabolomics on maternal serum at 12, 20 and 28 weeks of gestational age (wkGA) using 175 cases of term FGR and 299 controls from the Pregnancy Outcome Prediction (POP) study, conducted in Cambridge, UK, to identify predictive metabolites. Internal validation using 36 wkGA samples demonstrated that a ratio of the products of the relative concentrations of two positively associated metabolites (1-(1-enyl-stearoyl)-2-oleoyl-GPC (P-18:0/18:1) and 1,5-anhydroglucitol) to the product of the relative concentrations of two negatively associated metabolites (5α-androstan-3α,17α-diol disulfate and N1,N12-diacetylspermine) predicted FGR at term. The ratio had approximately double the discrimination as compared to a previously developed angiogenic biomarker7, the soluble fms-like tyrosine kinase 1:placental growth factor (sFLT1:PlGF) ratio (AUC 0.78 versus 0.64, P = 0.0001). We validated the predictive performance of the metabolite ratio in two sub-samples of a demographically dissimilar cohort, Born in Bradford (BiB), conducted in Bradford, UK (P = 0.0002). Screening and intervention using this metabolite ratio in conjunction with ultrasonic imaging at around 36 wkGA could plausibly prevent adverse events through enhanced fetal monitoring and targeted induction of labor.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32066973", + "TEXT": "Replacement of regular salt with potassium-enriched substitutes reduces blood pressure in controlled situations, mainly among people with hypertension. We report on a population-wide implementation of this strategy in a stepped-wedge cluster randomized trial (NCT01960972). The regular salt in enrolled households was retrieved and replaced, free of charge, with a combination of 75% NaCl and 25% KCl. A total of 2,376 participants were enrolled in 6 villages in Tumbes, Peru. The fully adjusted intention-to-treat analysis showed an average reduction of 1.29 mm Hg (95% confidence interval (95% CI) (-2.17, -0.41)) in systolic and 0.76 mm Hg (95% CI (-1.39, -0.13)) in diastolic blood pressure. Among participants without hypertension at baseline, in the time- and cluster-adjusted model, the use of the salt substitute was associated with a 51% (95% CI (29%, 66%)) reduced risk of developing hypertension compared with the control group. In 24-h urine samples, there was no evidence of differences in sodium levels (mean difference 0.01; 95% CI (0.25, -0.23)), but potassium levels were higher at the end of the study than at baseline (mean difference 0.63; 95% CI (0.78, 0.47)). Our results support a case for implementing a pragmatic, population-wide, salt-substitution strategy for reducing blood pressure and hypertension incidence.", + "TAG_DATA": [ + "101, participants {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32042193", + "TEXT": "Disrupted molecular pathways are often robustly associated with disease outcome in cancer1-3. Although biologically informative transcriptional pathways can be revealed by RNA sequencing (RNA-seq) at up to hundreds of folds reduction in conventionally used coverage4-6, it remains unknown how low-depth sequencing datasets perform in the challenging context of developing transcriptional signatures to predict clinical outcomes. Here we assessed the possibility of cancer prognosis with shallow tumor RNA-seq, which would potentially enable cost-effective assessment of much larger numbers of samples for deeper biological and predictive insights. By statistically modeling the relative risk of an adverse outcome for thousands of subjects in The Cancer Genome Atlas7-13, we present evidence that subsampled tumor RNA-seq data with a few hundred thousand reads per sample provide sufficient information for outcome prediction in several types of cancer. Analysis of predictive models revealed robust contributions from pathways known to be associated with outcomes. Our findings indicate that predictive models of outcomes in cancer may be developed with dramatically increases in sample numbers at low cost, thus potentially enabling the development of more realistic predictive models that incorporate diverse variables and their interactions. This strategy could also be used, for example, in longitudinal analysis of multiple regions of a tumor alongside treatment for quantitative modeling and prediction of outcome in personalized oncology.", + "TAG_DATA": [ + "129, of {'context': 'B-neoplasm'}", + "130, cancer. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "129, of ['l0']", + "130, cancer. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32015557", + "TEXT": "Zika virus (ZIKV) has caused significant disease, with widespread cases of neurological pathology and congenital neurologic defects. Rapid vaccine development has led to a number of candidates capable of eliciting potent ZIKV-neutralizing antibodies (reviewed in refs. 1-3). Despite advances in vaccine development, it remains unclear how ZIKV vaccination affects immune responses in humans with prior flavivirus immunity. Here we show that a single-dose immunization of ZIKV purified inactivated vaccine (ZPIV)4-7 in a dengue virus (DENV)-experienced human elicited potent cross-neutralizing antibodies to both ZIKV and DENV. Using a unique ZIKV virion-based sorting strategy, we isolated and characterized multiple antibodies, including one termed MZ4, which targets a novel site of vulnerability centered on the Envelope (E) domain I/III linker region and protects mice from viremia and viral dissemination following ZIKV or DENV-2 challenge. These data demonstrate that Zika vaccination in a DENV-experienced individual can boost pre-existing flavivirus immunity and elicit protective responses against both ZIKV and DENV. ZPIV vaccination in Puerto Rican individuals with prior flavivirus experience yielded similar cross-neutralizing potency after a single vaccination, highlighting the potential benefit of ZIKV vaccination in flavivirus-endemic areas.", + "TAG_DATA": [ + "75, human {'context': 'B-organism'}", + "120, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31959988", + "TEXT": "Although aberrations in the number and function of glutamate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors are thought to underlie neuropsychiatric disorders, no methods are currently available for visualizing AMPA receptors in the living human brain. Here we developed a positron emission tomography (PET) tracer for AMPA receptors. A derivative of 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide radiolabeled with 11C ([11C]K-2) showed specific binding to AMPA receptors. Our clinical trial with healthy human participants confirmed reversible binding of [11C]K-2 in the brain according to Logan graphical analysis (UMIN000020975; study design: non-randomized, single arm; primary outcome: dynamics and distribution volumes of [11C]K-2 in the brain; secondary outcome: adverse events of [11C]K-2 during the 4-10 d following dosing; this trial met prespecified endpoints). In an exploratory clinical study including patients with epilepsy, we detected increased [11C]K-2 uptake in the epileptogenic focus of patients with mesial temporal lobe epilepsy, which was closely correlated with the local AMPA receptor protein distribution in surgical specimens from the same individuals (UMIN000025090; study design: non-randomized, single arm; primary outcome: correlation between [11C]K-2 uptake measured with PET before surgery and AMPA receptor protein density examined by biochemical study after surgery; secondary outcome: adverse events during the 7 d following PET scan; this trial met prespecified endpoints). Thus, [11C]K-2 is a potent PET tracer for AMPA receptors, potentially providing a tool to examine the involvement of AMPA receptors in neuropsychiatric disorders.", + "TAG_DATA": [ + "64, healthy {'context': 'B-organism'}", + "65, human {'context': 'I-organism'}", + "66, participants {'context': 'I-organism'}", + "74, brain {'context': 'B-tissue/organ'}", + "132, patients {'context': 'B-patient'}", + "134, mesial {'context': 'B-neoplasm'}", + "135, temporal {'context': 'I-neoplasm'}", + "136, lobe {'context': 'I-neoplasm'}", + "137, epilepsy, {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "64, healthy ['l0', 'l1', 'l2']", + "65, human ['l0', 'l3', 'l4']", + "66, participants ['l1', 'l3', 'l5']", + "74, brain ['l2', 'l4', 'l5']", + "132, patients ['l6', 'l7', 'l8', 'l9']", + "134, mesial ['l6', 'l10', 'l11', 'l12']", + "135, temporal ['l7', 'l10', 'l13', 'l14']", + "136, lobe ['l8', 'l11', 'l13', 'l15']", + "137, epilepsy, ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31932802", + "TEXT": "MET exon 14 alterations are oncogenic drivers of non-small-cell lung cancers (NSCLCs)1. These alterations are associated with increased MET activity and preclinical sensitivity to MET inhibition2. Crizotinib is a multikinase inhibitor with potent activity against MET3. The antitumor activity and safety of crizotinib were assessed in 69 patients with advanced NSCLCs harboring MET exon 14 alterations. Objective response rate was 32% (95% confidence interval (CI), 21-45) among 65 response-evaluable patients. Objective responses were observed independent of the molecular heterogeneity that characterizes these cancers and did not vary by splice-site region and mutation type of the MET exon 14 alteration, concurrent increased MET copy number or the detection of a MET exon 14 alteration in circulating tumor DNA. The median duration of response was 9.1 months (95% CI, 6.4-12.7). The median progression-free survival was 7.3 months (95% CI, 5.4-9.1). MET exon 14 alteration defines a molecular subgroup of NSCLCs for which MET inhibition with crizotinib is active. These results address an unmet need for targeted therapy in people with lung cancers with MET exon 14 alterations and adds to an expanding list of genomically driven therapies for oncogenic subsets of NSCLC.", + "TAG_DATA": [ + "47, patients {'context': 'B-patient'}", + "49, advanced {'context': 'I-neoplasm'}", + "50, NSCLCs {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "47, patients ['l0', 'l1']", + "49, advanced ['l0', 'l2']", + "50, NSCLCs ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31932800", + "TEXT": "Temperatures that deviate from the long-term local norm affect human health, and are projected to become more frequent as the global climate changes1. There are limited data on how such anomalies affect deaths from injuries. In the present study, we used data on mortality and temperature over 38 years (1980-2017) in the contiguous USA and formulated a Bayesian spatio-temporal model to quantify how anomalous temperatures, defined as deviations of monthly temperature from the local average monthly temperature over the entire analysis period, affect deaths from unintentional (transport, falls and drownings) and intentional (assault and suicide) injuries, by age group and sex. We found that a 1.5 °C anomalously warm year, as envisioned under the Paris Climate Agreement2, would be associated with an estimated 1,601 (95% credible interval 1,430-1,776) additional injury deaths. Of these additional deaths, 84% would occur in males, mostly in adolescence to middle age. These would comprise increases in deaths from drownings, transport, assault and suicide, offset partly by a decline in deaths from falls in older ages. The findings demonstrate the need for targeted interventions against injuries during periods of anomalously warm temperatures, especially as these episodes are likely to increase with global climate change.", + "TAG_DATA": [ + "137, males, {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31907460", + "TEXT": "Intraoperative diagnosis is essential for providing safe and effective care during cancer surgery1. The existing workflow for intraoperative diagnosis based on hematoxylin and eosin staining of processed tissue is time, resource and labor intensive2,3. Moreover, interpretation of intraoperative histologic images is dependent on a contracting, unevenly distributed, pathology workforce4. In the present study, we report a parallel workflow that combines stimulated Raman histology (SRH)5-7, a label-free optical imaging method and deep convolutional neural networks (CNNs) to predict diagnosis at the bedside in near real-time in an automated fashion. Specifically, our CNNs, trained on over 2.5 million SRH images, predict brain tumor diagnosis in the operating room in under 150 s, an order of magnitude faster than conventional techniques (for example, 20-30 min)2. In a multicenter, prospective clinical trial (n = 278), we demonstrated that CNN-based diagnosis of SRH images was noninferior to pathologist-based interpretation of conventional histologic images (overall accuracy, 94.6% versus 93.9%). Our CNNs learned a hierarchy of recognizable histologic feature representations to classify the major histopathologic classes of brain tumors. In addition, we implemented a semantic segmentation method to identify tumor-infiltrated diagnostic regions within SRH images. These results demonstrate how intraoperative cancer diagnosis can be streamlined, creating a complementary pathway for tissue diagnosis that is independent of a traditional pathology laboratory.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31873310", + "TEXT": "De novo mutations arising on the paternal chromosome make the largest known contribution to autism risk, and correlate with paternal age at the time of conception. The recurrence risk for autism spectrum disorders is substantial, leading many families to decline future pregnancies, but the potential impact of assessing parental gonadal mosaicism has not been considered. We measured sperm mosaicism using deep-whole-genome sequencing, for variants both present in an offspring and evident only in father's sperm, and identified single-nucleotide, structural and short tandem-repeat variants. We found that mosaicism quantification can stratify autism spectrum disorders recurrence risk due to de novo mutations into a vast majority with near 0% recurrence and a small fraction with a substantially higher and quantifiable risk, and we identify novel mosaic variants at risk for transmission to a future offspring. This suggests, therefore, that genetic counseling would benefit from the addition of sperm mosaicism assessment.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31806906", + "TEXT": "Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is typically sporadic. Inborn errors of TLR3- and DBR1-mediated central nervous system cell-intrinsic immunity can account for forebrain and brainstem HSE, respectively. We report five unrelated patients with forebrain HSE, each heterozygous for one of four rare variants of SNORA31, encoding a small nucleolar RNA of the H/ACA class that are predicted to direct the isomerization of uridine residues to pseudouridine in small nuclear RNA and ribosomal RNA. We show that CRISPR/Cas9-introduced bi- and monoallelic SNORA31 deletions render human pluripotent stem cell (hPSC)-derived cortical neurons susceptible to HSV-1. Accordingly, SNORA31-mutated patient hPSC-derived cortical neurons are susceptible to HSV-1, like those from TLR3- or STAT1-deficient patients. Exogenous interferon (IFN)-β renders SNORA31- and TLR3- but not STAT1-mutated neurons resistant to HSV-1. Finally, transcriptome analysis of SNORA31-mutated neurons revealed normal responses to TLR3 and IFN-α/β stimulation but abnormal responses to HSV-1. Human SNORA31 thus controls central nervous system neuron-intrinsic immunity to HSV-1 by a distinctive mechanism.", + "TAG_DATA": [ + "77, CRISPR/Cas9-introduced {'perturbing_action': 'B-gene loss-of-function'}", + "80, monoallelic {'perturbing_action': 'I-gene loss-of-function'}", + "81, SNORA31 {'perturbing_action': 'I-gene loss-of-function'}", + "82, deletions {'perturbing_action': 'I-gene loss-of-function'}", + "84, human {'context': 'B-cells'}", + "85, pluripotent {'context': 'I-cells'}", + "86, stem {'context': 'I-cells'}", + "87, cell {'context': 'I-cells'}", + "88, (hPSC)-derived {'context': 'I-cells'}", + "89, cortical {'context': 'I-cells'}", + "90, neurons {'context': 'I-cells'}", + "95, SNORA31-mutated {'perturbing_action': 'B-other'}", + "96, patient {'context': 'B-cells'}", + "97, hPSC-derived {'context': 'I-cells'}", + "98, cortical {'context': 'I-cells'}", + "99, neurons {'context': 'I-cells'}", + "107, TLR3- {'perturbing_action': 'B-gene loss-of-function'}", + "108, or {'perturbing_action': 'I-gene loss-of-function'}", + "109, STAT1-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "121, neurons {'context': 'B-cells'}", + "129, SNORA31-mutated {'perturbing_action': 'B-other'}", + "130, neurons {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "77, CRISPR/Cas9-introduced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "80, monoallelic ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "81, SNORA31 ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "82, deletions ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "84, human ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "85, pluripotent ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "86, stem ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "87, cell ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l53', 'l59', 'l60', 'l61', 'l62', 'l63']", + "88, (hPSC)-derived ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l54', 'l59', 'l64', 'l65', 'l66', 'l67']", + "89, cortical ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l55', 'l60', 'l64', 'l68']", + "90, neurons ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l56', 'l61', 'l65', 'l68']", + "95, SNORA31-mutated ['l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "96, patient ['l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "97, hPSC-derived ['l50', 'l70', 'l77', 'l83', 'l84', 'l85', 'l86', 'l87']", + "98, cortical ['l51', 'l57', 'l62', 'l66', 'l71', 'l78', 'l83', 'l88', 'l89', 'l90', 'l91']", + "99, neurons ['l10', 'l20', 'l29', 'l37', 'l44', 'l52', 'l58', 'l63', 'l67', 'l72', 'l79', 'l84', 'l88', 'l92', 'l93', 'l94']", + "107, TLR3- ['l73', 'l80', 'l85', 'l89', 'l92', 'l95', 'l96', 'l97']", + "108, or ['l74', 'l81', 'l86', 'l90', 'l93', 'l95', 'l98', 'l99']", + "109, STAT1-deficient ['l75', 'l82', 'l87', 'l91', 'l94', 'l96', 'l98', 'l100']", + "121, neurons ['l76', 'l97', 'l99', 'l100']", + "129, SNORA31-mutated ['l101']", + "130, neurons ['l101']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CRISPR/Cas9-introduced", + "monoallelic", + "SNORA31", + "deletions", + "TLR3-", + "or", + "STAT1-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "pluripotent", + "stem", + "cell", + "(hPSC)-derived", + "cortical", + "neurons", + "patient", + "hPSC-derived" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "SNORA31-mutated" + ] + }, + "context": { + "val": "cells", + "words": [ + "patient", + "hPSC-derived", + "cortical", + "neurons" + ] + } + } + ] + }, + { + "PMID": "31792459", + "TEXT": "How obesity and elevated androgen levels in women with polycystic ovary syndrome (PCOS) affect their offspring is unclear. In a Swedish nationwide register-based cohort and a clinical case-control study from Chile, we found that daughters of mothers with PCOS were more likely to be diagnosed with PCOS. Furthermore, female mice (F0) with PCOS-like traits induced by late-gestation injection of dihydrotestosterone, with and without obesity, produced female F1-F3 offspring with PCOS-like reproductive and metabolic phenotypes. Sequencing of single metaphase II oocytes from F1-F3 offspring revealed common and unique altered gene expression across all generations. Notably, four genes were also differentially expressed in serum samples from daughters in the case-control study and unrelated women with PCOS. Our findings provide evidence of transgenerational effects in female offspring of mothers with PCOS and identify possible candidate genes for the prediction of a PCOS phenotype in future generations.", + "TAG_DATA": [ + "48, female {'context': 'B-organism'}", + "49, mice {'context': 'I-organism'}", + "50, (F0) {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "48, female ['l0', 'l1']", + "49, mice ['l0', 'l2']", + "50, (F0) ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31792456", + "TEXT": "Viruses are implicated in autoimmune destruction of pancreatic islet β cells, which results in insulin deficiency and type 1 diabetes (T1D)1-4. Certain enteroviruses can infect β cells in vitro5, have been detected in the pancreatic islets of patients with T1D6 and have shown an association with T1D in meta-analyses4. However, establishing consistency in findings across studies has proven difficult. Obstacles to convincingly linking RNA viruses to islet autoimmunity may be attributed to rapid viral mutation rates, the cyclical periodicity of viruses7 and the selection of variants with altered pathogenicity and ability to spread in populations. β cells strongly express cell-surface coxsackie and adenovirus receptor (CXADR) genes, which can facilitate enterovirus infection8. Studies of human pancreata and cultured islets have shown significant variation in enteroviral virulence to β cells between serotypes and within the same serotype9,10. In this large-scale study of known eukaryotic DNA and RNA viruses in stools from children, we evaluated fecally shed viruses in relation to islet autoimmunity and T1D. This study showed that prolonged enterovirus B rather than independent, short-duration enterovirus B infections may be involved in the development of islet autoimmunity, but not T1D, in some young children. Furthermore, we found that fewer early-life human mastadenovirus C infections, as well as CXADR rs6517774, independently correlated with islet autoimmunity.", + "TAG_DATA": [ + "113, human {'context': 'B-tissue/organ'}", + "114, pancreata {'context': 'I-tissue/organ'}", + "116, cultured {'context': 'B-cells'}", + "117, islets {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "113, human ['l0', 'l1', 'l2']", + "114, pancreata ['l0', 'l3', 'l4']", + "116, cultured ['l1', 'l3', 'l5']", + "117, islets ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31700186", + "TEXT": "Anthracyclines are a highly effective component of curative breast cancer chemotherapy but are associated with substantial morbidity1,2. Because anthracyclines work in part by inhibiting topoisomerase-II (TOP2) on accessible DNA3,4, we hypothesized that chromatin regulatory genes (CRGs) that mediate DNA accessibility might predict anthracycline response. We studied the role of CRGs in anthracycline sensitivity in breast cancer through integrative analysis of patient and cell line data. We identified a consensus set of 38 CRGs associated with anthracycline response across ten cell line datasets. By evaluating the interaction between expression and treatment in predicting survival in a metacohort of 1006 patients with early-stage breast cancer, we identified 54 CRGs whose expression levels dictate anthracycline benefit across the clinical subgroups; of these CRGs, 12 overlapped with those identified in vitro. CRGs that promote DNA accessibility, including Trithorax complex members, were associated with anthracycline sensitivity when highly expressed, whereas CRGs that reduce accessibility, such as Polycomb complex proteins, were associated with decreased anthracycline sensitivity. We show that KDM4B modulates TOP2 accessibility to chromatin, elucidating a mechanism of TOP2 inhibitor sensitivity. These findings indicate that CRGs mediate anthracycline benefit by altering DNA accessibility, with implications for the stratification of patients with breast cancer and treatment decision making.", + "TAG_DATA": [ + "98, patients {'context': 'B-patient'}", + "99, with {'context': 'I-patient'}", + "100, early-stage {'context': 'I-neoplasm'}", + "101, breast {'context': 'I-neoplasm'}", + "102, cancer, {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "98, patients ['l0', 'l1', 'l2', 'l3']", + "99, with ['l0', 'l4', 'l5', 'l6']", + "100, early-stage ['l1', 'l4', 'l7', 'l8']", + "101, breast ['l2', 'l5', 'l7', 'l9']", + "102, cancer, ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31700183", + "TEXT": "Type 2 diabetes is characterized by insulin resistance and a gradual loss of pancreatic beta cell mass and function1,2. Currently, there are no therapies proven to prevent beta cell loss and some, namely insulin secretagogues, have been linked to accelerated beta cell failure, thereby limiting their use in type 2 diabetes3,4. The adipokine adipsin/complement factor D controls the alternative complement pathway and generation of complement component C3a, which acts to augment beta cell insulin secretion5. In contrast to other insulin secretagogues, we show that chronic replenishment of adipsin in diabetic db/db mice ameliorates hyperglycemia and increases insulin levels while preserving beta cells by blocking dedifferentiation and death. Mechanistically, we find that adipsin/C3a decreases the phosphatase Dusp26; forced expression of Dusp26 in beta cells decreases expression of core beta cell identity genes and sensitizes to cell death. In contrast, pharmacological inhibition of DUSP26 improves hyperglycemia in diabetic mice and protects human islet cells from cell death. Pertaining to human health, we show that higher concentrations of circulating adipsin are associated with a significantly lower risk of developing future diabetes among middle-aged adults after adjusting for body mass index (BMI). Collectively, these data suggest that adipsin/C3a and DUSP26-directed therapies may represent a novel approach to achieve beta cell health to treat and prevent type 2 diabetes.", + "TAG_DATA": [ + "89, diabetic {'context': 'B-organism'}", + "90, db/db {'context': 'I-organism'}", + "91, mice {'context': 'I-organism'}", + "100, beta {'context': 'B-cells'}", + "101, cells {'context': 'I-cells'}", + "103, blocking {'effect': 'B-negative'}", + "104, dedifferentiation {'phenotype': 'B-differentiation'}", + "116, forced {'perturbing_action': 'B-gene gain-of-function'}", + "117, expression {'perturbing_action': 'I-gene gain-of-function'}", + "118, of {'perturbing_action': 'I-gene gain-of-function'}", + "119, Dusp26 {'perturbing_action': 'I-gene gain-of-function'}", + "121, beta {'context': 'B-cells'}", + "122, cells {'context': 'I-cells'}", + "132, sensitizes {'effect': 'B-positive'}", + "134, cell {'phenotype': 'B-cell death'}", + "135, death. {'phenotype': 'I-cell death'}", + "138, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "139, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "140, of {'perturbing_action': 'I-pharmacological inhibition'}", + "141, DUSP26 {'perturbing_action': 'I-pharmacological inhibition'}", + "145, diabetic {'context': 'B-organism'}", + "146, mice {'context': 'I-organism'}", + "148, protects {'effect': 'B-negative'}", + "149, human {'context': 'B-cells'}", + "150, islet {'context': 'I-cells'}", + "151, cells {'context': 'I-cells'}", + "153, cell {'phenotype': 'B-cell death'}", + "154, death. {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "89, diabetic ['l0', 'l1', 'l2', 'l3', 'l4']", + "90, db/db ['l0', 'l5', 'l6', 'l7', 'l8', 'l9']", + "91, mice ['l1', 'l5', 'l10', 'l11']", + "100, beta ['l2', 'l6', 'l10', 'l12', 'l13', 'l14']", + "101, cells ['l3', 'l7', 'l11', 'l12', 'l15']", + "103, blocking ['l4', 'l8', 'l13', 'l15', 'l16', 'l17']", + "104, dedifferentiation ['l9', 'l14', 'l16', 'l18', 'l19', 'l20', 'l21']", + "116, forced ['l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "117, expression ['l22', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "118, of ['l23', 'l35', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "119, Dusp26 ['l24', 'l36', 'l46', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "121, beta ['l25', 'l37', 'l47', 'l56', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "122, cells ['l18', 'l26', 'l38', 'l48', 'l57', 'l65', 'l71', 'l72', 'l73', 'l74', 'l75']", + "132, sensitizes ['l19', 'l27', 'l39', 'l49', 'l58', 'l66', 'l71', 'l76', 'l77', 'l78', 'l79']", + "134, cell ['l20', 'l28', 'l40', 'l50', 'l59', 'l67', 'l72', 'l76', 'l80', 'l81']", + "135, death. ['l17', 'l21', 'l29', 'l41', 'l51', 'l60', 'l68', 'l73', 'l77', 'l80']", + "138, pharmacological ['l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "139, inhibition ['l82', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "140, of ['l83', 'l93', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "141, DUSP26 ['l84', 'l94', 'l103', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "145, diabetic ['l30', 'l42', 'l52', 'l61', 'l69', 'l74', 'l78', 'l85', 'l95', 'l104', 'l112', 'l120', 'l121', 'l122', 'l123', 'l124']", + "146, mice ['l31', 'l43', 'l53', 'l62', 'l70', 'l75', 'l79', 'l81', 'l86', 'l96', 'l105', 'l113', 'l120']", + "148, protects ['l32', 'l44', 'l54', 'l63', 'l87', 'l97', 'l106', 'l114', 'l121', 'l125', 'l126', 'l127', 'l128', 'l129']", + "149, human ['l88', 'l98', 'l107', 'l115', 'l125', 'l130', 'l131', 'l132', 'l133']", + "150, islet ['l33', 'l89', 'l99', 'l108', 'l116', 'l122', 'l126', 'l130', 'l134', 'l135', 'l136']", + "151, cells ['l34', 'l45', 'l55', 'l64', 'l90', 'l100', 'l109', 'l117', 'l123', 'l127', 'l131', 'l134', 'l137', 'l138']", + "153, cell ['l91', 'l101', 'l110', 'l118', 'l128', 'l132', 'l135', 'l137', 'l139']", + "154, death. ['l92', 'l102', 'l111', 'l119', 'l124', 'l129', 'l133', 'l136', 'l138', 'l139']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "diabetic", + "db/db" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocking", + "protects" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "db/db" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "dedifferentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "beta", + "cells", + "human", + "islet" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocking", + "protects" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "beta", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "dedifferentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocking" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "dedifferentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocking", + "protects" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "death.", + "cell" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "dedifferentiation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitizes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "forced", + "expression", + "of", + "Dusp26" + ] + }, + "context": { + "val": "cells", + "words": [ + "beta", + "cells", + "islet" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "forced", + "expression", + "of", + "Dusp26" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitizes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "forced", + "expression", + "of", + "Dusp26" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "forced", + "expression", + "of", + "Dusp26" + ] + }, + "context": { + "val": "organism", + "words": [ + "diabetic", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "forced", + "expression", + "of", + "Dusp26" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protects" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "beta", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitizes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "beta", + "cells", + "human", + "islet" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitizes" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitizes" + ] + }, + "context": { + "val": "organism", + "words": [ + "diabetic", + "mice" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "diabetic" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "DUSP26" + ] + }, + "context": { + "val": "organism", + "words": [ + "diabetic", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "DUSP26" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protects" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "DUSP26" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "islet", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "DUSP26" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "31686036", + "TEXT": "Antibodies targeting PD-1 or its ligand 1 PD-L1 such as atezolizumab, have great efficacy in a proportion of metastatic urothelial cancers1,2. Biomarkers may facilitate identification of these responding tumors3. Neoadjuvant use of these agents is associated with pathological complete response in a spectrum of tumors, including urothelial cancer4-7. Sequential tissue sampling from these studies allowed for detailed on-treatment biomarker analysis. Here, we present a single-arm phase 2 study, investigating two cycles of atezolizumab before cystectomy in 95 patients with muscle-invasive urothelial cancer (ClinicalTrials.gov identifier: NCT02662309). Pathological complete response was the primary endpoint. Secondary endpoints focused on safety, relapse-free survival and biomarker analysis. The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-β and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.", + "TAG_DATA": [ + "77, patients {'context': 'B-patient'}", + "79, muscle-invasive {'context': 'B-neoplasm'}", + "80, urothelial {'context': 'I-neoplasm'}", + "81, cancer {'context': 'I-neoplasm'}", + "127, T {'context': 'I-cells'}", + "128, cells {'context': 'I-cells'}", + "178, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "77, patients ['l0', 'l1', 'l2']", + "79, muscle-invasive ['l0', 'l3', 'l4', 'l5', 'l6']", + "80, urothelial ['l1', 'l3', 'l7', 'l8', 'l9']", + "81, cancer ['l2', 'l4', 'l7']", + "127, T ['l5', 'l8', 'l10']", + "128, cells ['l6', 'l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31591605", + "TEXT": "Recombinant vesicular stomatitis virus-Zaire Ebola virus (rVSV-ZEBOV) is the most advanced Ebola virus vaccine candidate and is currently being used to combat the outbreak of Ebola virus disease (EVD) in the Democratic Republic of the Congo (DRC). Here we examine the humoral immune response in a subset of human volunteers enrolled in a phase 1 rVSV-ZEBOV vaccination trial by performing comprehensive single B cell and electron microscopy structure analyses. Four studied vaccinees show polyclonal, yet reproducible and convergent B cell responses with shared sequence characteristics. EBOV-targeting antibodies cross-react with other Ebolavirus species, and detailed epitope mapping revealed overlapping target epitopes with antibodies isolated from EVD survivors. Moreover, in all vaccinees, we detected highly potent EBOV-neutralizing antibodies with activities comparable or superior to the monoclonal antibodies currently used in clinical trials. These include antibodies combining the IGHV3-15/IGLV1-40 immunoglobulin gene segments that were identified in all investigated individuals. Our findings will help to evaluate and direct current and future vaccination strategies and offer opportunities for novel EVD therapies.", + "TAG_DATA": [ + "48, human {'context': 'B-organism'}", + "49, volunteers {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "48, human ['l0']", + "49, volunteers ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31591599", + "TEXT": "We report the results of a first exploratory study testing the use of vaginal microbiome transplantation (VMT) from healthy donors as a therapeutic alternative for patients suffering from symptomatic, intractable and recurrent bacterial vaginosis (ClinicalTrials.gov NCT02236429 ). In our case series, five patients were treated, and in four of them VMT was associated with full long-term remission until the end of follow-up at 5-21 months after VMT, defined as marked improvement of symptoms, Amsel criteria, microscopic vaginal fluid appearance and reconstitution of a Lactobacillus-dominated vaginal microbiome. One patient presented with incomplete remission in clinical and laboratory features. No adverse effects were observed in any of the five women. Notably, remission in three patients necessitated repeated VMT, including a donor change in one patient, to elicit a long-standing clinical response. The therapeutic efficacy of VMT in women with intractable and recurrent bacterial vaginosis should be further determined in randomized, placebo-controlled clinical trials.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31591597", + "TEXT": "Rectal cancer (RC) is a challenging disease to treat that requires chemotherapy, radiation and surgery to optimize outcomes for individual patients. No accurate model of RC exists to answer fundamental research questions relevant to patients. We established a biorepository of 65 patient-derived RC organoid cultures (tumoroids) from patients with primary, metastatic or recurrent disease. RC tumoroids retained molecular features of the tumors from which they were derived, and their ex vivo responses to clinically relevant chemotherapy and radiation treatment correlated with the clinical responses noted in individual patients' tumors. Upon engraftment into murine rectal mucosa, human RC tumoroids gave rise to invasive RC followed by metastasis to lung and liver. Importantly, engrafted tumors displayed the heterogenous sensitivity to chemotherapy observed clinically. Thus, the biology and drug sensitivity of RC clinical isolates can be efficiently interrogated using an organoid-based, ex vivo platform coupled with in vivo endoluminal propagation in animals.", + "TAG_DATA": [ + "92, murine {'context': 'B-tissue/organ'}", + "93, rectal {'context': 'I-tissue/organ'}", + "94, mucosa, {'context': 'I-tissue/organ'}", + "95, human {'context': 'B-organoid'}", + "96, RC {'context': 'I-organoid'}", + "97, tumoroids {'context': 'I-organoid'}", + "98, gave {'effect': 'B-positive'}", + "99, rise {'effect': 'I-positive'}", + "105, metastasis {'phenotype': 'B-metastasis'}", + "106, to {'phenotype': 'I-metastasis'}", + "107, lung {'phenotype': 'I-metastasis'}", + "108, and {'phenotype': 'I-metastasis'}", + "109, liver. {'phenotype': 'I-metastasis'}", + "112, tumors {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "92, murine ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "93, rectal ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "94, mucosa, ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "95, human ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "96, RC ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "97, tumoroids ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "98, gave ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "99, rise ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "103, followed ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "105, metastasis ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "106, to ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "107, lung ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "108, and ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "109, liver. ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "murine", + "rectal", + "mucosa," + ] + }, + "effect": { + "val": "positive", + "words": [ + "gave", + "rise" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "murine", + "rectal", + "mucosa," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "to", + "lung", + "and", + "liver." + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "human", + "RC", + "tumoroids" + ] + }, + "effect": { + "val": "positive", + "words": [ + "gave", + "rise" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "human", + "RC", + "tumoroids" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "to", + "lung", + "and", + "liver." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "gave", + "rise" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "to", + "lung", + "and", + "liver." + ] + } + } + ] + }, + { + "PMID": "31591595", + "TEXT": "Approximately 50% of patients with early-stage non-small-cell lung cancer (NSCLC) who undergo surgery with curative intent will relapse within 5 years1,2. Detection of circulating tumor cells (CTCs) at the time of surgery may represent a tool to identify patients at higher risk of recurrence for whom more frequent monitoring is advised. Here we asked whether CellSearch-detected pulmonary venous CTCs (PV-CTCs) at surgical resection of early-stage NSCLC represent subclones responsible for subsequent disease relapse. PV-CTCs were detected in 48% of 100 patients enrolled into the TRACERx study3, were associated with lung-cancer-specific relapse and remained an independent predictor of relapse in multivariate analysis adjusted for tumor stage. In a case study, genomic profiling of single PV-CTCs collected at surgery revealed higher mutation overlap with metastasis detected 10 months later (91%) than with the primary tumor (79%), suggesting that early-disseminating PV-CTCs were responsible for disease relapse. Together, PV-CTC enumeration and genomic profiling highlight the potential of PV-CTCs as early predictors of NSCLC recurrence after surgery. However, the limited sensitivity of PV-CTCs in predicting relapse suggests that further studies using a larger, independent cohort are warranted to confirm and better define the potential clinical utility of PV-CTCs in early-stage NSCLC.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31591592", + "TEXT": "The increasing availability of large healthcare databases is fueling an intense debate on whether real-world data should play a role in the assessment of the benefit-risk of medical treatments. In many observational studies, for example, statin users were found to have a substantially lower risk of cancer than in meta-analyses of randomized trials. Although such discrepancies are often attributed to a lack of randomization in the observational studies, they might be explained by flaws that can be avoided by explicitly emulating a target trial (the randomized trial that would answer the question of interest). Using the electronic health records of 733,804 UK adults, we emulated a target trial of statins and cancer and compared our estimates with those obtained using previously applied analytic approaches. Over the 10-yr follow-up, 28,408 individuals developed cancer. Under the target trial approach, estimated observational analogs of intention-to-treat and per-protocol 10-yr cancer-free survival differences were -0.5% (95% confidence interval (CI) -1.0%, 0.0%) and -0.3% (95% CI -1.5%, 0.5%), respectively. By contrast, previous analytic approaches yielded estimates that appeared to be strongly protective. Our findings highlight the importance of explicitly emulating a target trial to reduce bias in the effect estimates derived from observational analyses.", + "TAG_DATA": [ + "102, adults, {'context': 'I-organism'}", + "131, cancer. {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}" + ], + "LINK_DATA": [ + "101, UK ['l0', 'l1', 'l2']", + "102, adults, ['l0', 'l3']", + "130, developed ['l1', 'l4']", + "131, cancer. ['l2', 'l3', 'l4']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "cancer." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "cancer." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "adults," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "cancer." + ] + } + } + ] + }, + { + "PMID": "31591582", + "TEXT": "Sherene Loi is a medical oncologist and clinician scientist at the Peter MacCallum Cancer Centre in Melbourne, Australia. Her laboratory studies the cancer genome in breast cancer and its interface with the immune microenvironment in order to develop more effective drugs and rational combinations.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31501600", + "TEXT": "Conventional leg prostheses do not convey sensory information about motion or interaction with the ground to above-knee amputees, thereby reducing confidence and walking speed in the users that is associated with high mental and physical fatigue1-4. The lack of physiological feedback from the remaining extremity to the brain also contributes to the generation of phantom limb pain from the missing leg5,6. To determine whether neural sensory feedback restoration addresses these issues, we conducted a study with two transfemoral amputees, implanted with four intraneural stimulation electrodes7 in the remaining tibial nerve (ClinicalTrials.gov identifier NCT03350061). Participants were evaluated while using a neuroprosthetic device consisting of a prosthetic leg equipped with foot and knee sensors. These sensors drive neural stimulation, which elicits sensations of knee motion and the sole of the foot touching the ground. We found that walking speed and self-reported confidence increased while mental and physical fatigue decreased for both participants during neural sensory feedback compared to the no stimulation trials. Furthermore, participants exhibited reduced phantom limb pain with neural sensory feedback. The results from these proof-of-concept cases provide the rationale for larger population studies investigating the clinical utility of neuroprostheses that restore sensory feedback.", + "TAG_DATA": [ + "77, transfemoral {'context': 'B-tissue/organ'}", + "78, amputees, {'context': 'I-xenograft'}", + "89, nerve {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "77, transfemoral ['l0', 'l1', 'l2', 'l3']", + "78, amputees, ['l0', 'l4', 'l5', 'l6']", + "87, remaining ['l1', 'l4', 'l7', 'l8']", + "88, tibial ['l2', 'l5', 'l7', 'l9']", + "89, nerve ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31406349", + "TEXT": "The MORDOR I trial1, conducted in Niger, Malawi and Tanzania, demonstrated that mass azithromycin distribution to preschool children reduced childhood mortality1. However, the large but simple trial design precluded determination of the mechanisms involved. Here we examined the gut microbiome of preschool children from 30 Nigerien communities randomized to either biannual azithromycin or placebo. Gut microbiome γ-diversity was not significantly altered (P = 0.08), but the relative abundances of two Campylobacter species, along with another 33 gut bacteria, were significantly reduced in children treated with azithromycin at the 24-month follow-up. Metagenomic analysis revealed functional differences in gut bacteria between treatment groups. Resistome analysis showed an increase in macrolide resistance gene expression in gut microbiota in communities treated with azithromycin (P = 0.004). These results suggest that prolonged mass azithromycin distribution to reduce childhood mortality reduces certain gut bacteria, including known pathogens, while selecting for antibiotic resistance.", + "TAG_DATA": [ + "41, preschool {'context': 'B-organism'}", + "42, children {'context': 'I-organism'}", + "45, Nigerien {'context': 'B-tissue/organ'}", + "46, communities {'context': 'I-tissue/organ'}", + "80, children {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "41, preschool ['l0', 'l1', 'l2']", + "42, children ['l0', 'l3', 'l4']", + "45, Nigerien ['l1', 'l3', 'l5', 'l6']", + "46, communities ['l2', 'l4', 'l5']", + "80, children ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31388180", + "TEXT": "Particular bacteria from the gut microbiota metabolize Levodopa (L-dopa), reducing bioavailability of the drug for treating Parkinson’s disease.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31359004", + "TEXT": "TCF21, a gene associated with coronary heart disease, promotes plaque stability and reduces clinical events by enhancing smooth muscle cell phenotype modulation into “fibromyocytes” in atherosclerosis.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31332393", + "TEXT": "Exclusive breastfeeding (EBF)-giving infants only breast-milk (and medications, oral rehydration salts and vitamins as needed) with no additional food or drink for their first six months of life-is one of the most effective strategies for preventing child mortality1-4. Despite these advantages, only 37% of infants under 6 months of age in Africa were exclusively breastfed in 20175, and the practice of EBF varies by population. Here, we present a fine-scale geospatial analysis of EBF prevalence and trends in 49 African countries from 2000-2017, providing policy-relevant administrative- and national-level estimates. Previous national-level analyses found that most countries will not meet the World Health Organization's Global Nutrition Target of 50% EBF prevalence by 20256. Our analyses show that even fewer will achieve this ambition in all subnational areas. Our estimates provide the ability to visualize subnational EBF variability and identify populations in need of additional breastfeeding support.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31308506", + "TEXT": "Flaviviral infections result in a wide spectrum of clinical outcomes, ranging from asymptomatic infection to severe disease. Although the correlates of severe disease have been explored1-4, the pathophysiology that differentiates symptomatic from asymptomatic infection remains undefined. To understand the molecular underpinnings of symptomatic infection, the blood transcriptomic and metabolomic profiles of individuals were examined before and after inoculation with the live yellow fever viral vaccine (YF17D). It was found that individuals with adaptive endoplasmic reticulum (ER) stress and reduced tricarboxylic acid cycle activity at baseline showed increased susceptibility to symptomatic outcome. YF17D infection in these individuals induced maladaptive ER stress, triggering downstream proinflammatory responses that correlated with symptomatic outcome. The findings of the present study thus suggest that the ER stress response and immunometabolism underpin symptomatic yellow fever and possibly even other flaviviral infections. Modulating either ER stress or metabolism could be exploited for prophylaxis against symptomatic flaviviral infection outcome.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31273328", + "TEXT": "Antibiotic resistance is prevalent among the bacterial pathogens causing urinary tract infections. However, antimicrobial treatment is often prescribed 'empirically', in the absence of antibiotic susceptibility testing, risking mismatched and therefore ineffective treatment. Here, linking a 10-year longitudinal data set of over 700,000 community-acquired urinary tract infections with over 5,000,000 individually resolved records of antibiotic purchases, we identify strong associations of antibiotic resistance with the demographics, records of past urine cultures and history of drug purchases of the patients. When combined together, these associations allow for machine-learning-based personalized drug-specific predictions of antibiotic resistance, thereby enabling drug-prescribing algorithms that match an antibiotic treatment recommendation to the expected resistance of each sample. Applying these algorithms retrospectively, over a 1-year test period, we find that they greatly reduce the risk of mismatched treatment compared with the current standard of care. The clinical application of such algorithms may help improve the effectiveness of antimicrobial treatments.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31270502", + "TEXT": "Bladder cancer is lethal in its advanced, muscle-invasive phase with very limited therapeutic advances1,2. Recent molecular characterization has defined new (epi)genetic drivers and potential targets for bladder cancer3,4. The immune checkpoint inhibitors have shown remarkable efficacy but only in a limited fraction of bladder cancer patients5-8. Here, we show that high G9a (EHMT2) expression is associated with poor clinical outcome in bladder cancer and that targeting G9a/DNMT methyltransferase activity with a novel inhibitor (CM-272) induces apoptosis and immunogenic cell death. Using an immunocompetent quadruple-knockout (PtenloxP/loxP; Trp53loxP/loxP; Rb1loxP/loxP; Rbl1-/-) transgenic mouse model of aggressive metastatic, muscle-invasive bladder cancer, we demonstrate that CM-272 + cisplatin treatment results in statistically significant regression of established tumors and metastases. The antitumor effect is significantly improved when CM-272 is combined with anti-programmed cell death ligand 1, even in the absence of cisplatin. These effects are associated with an endogenous antitumor immune response and immunogenic cell death with the conversion of a cold immune tumor into a hot tumor. Finally, increased G9a expression was associated with resistance to programmed cell death protein 1 inhibition in a cohort of patients with bladder cancer. In summary, these findings support new and promising opportunities for the treatment of bladder cancer using a combination of epigenetic inhibitors and immune checkpoint blockade.", + "TAG_DATA": [ + "74, induces {'effect': 'B-positive'}", + "75, apoptosis {'phenotype': 'B-apoptosis'}", + "78, cell {'phenotype': 'B-cell death'}", + "79, death. {'phenotype': 'I-cell death'}", + "82, immunocompetent {'perturbing_action': 'B-gene loss-of-function'}", + "83, quadruple-knockout {'perturbing_action': 'I-gene loss-of-function'}", + "84, (PtenloxP/loxP; {'perturbing_action': 'I-gene loss-of-function'}", + "85, Trp53loxP/loxP; {'perturbing_action': 'I-gene loss-of-function'}", + "86, Rb1loxP/loxP; {'perturbing_action': 'I-gene loss-of-function'}", + "87, Rbl1-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "88, transgenic {'perturbing_action': 'I-gene loss-of-function'}", + "89, mouse {'context': 'B-organism'}", + "90, model {'context': 'I-neoplasm'}", + "92, aggressive {'context': 'B-neoplasm'}", + "93, metastatic, {'context': 'I-neoplasm'}", + "94, muscle-invasive {'context': 'I-neoplasm'}", + "95, bladder {'context': 'I-neoplasm'}", + "96, cancer, {'context': 'I-neoplasm'}", + "102, results {'effect': 'B-positive'}", + "103, in {'effect': 'I-positive'}", + "106, regression {'phenotype': 'B-tumour regression'}", + "109, tumors {'context': 'B-neoplasm'}", + "111, metastases. {'phenotype': 'B-metastasis'}", + "147, death {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "74, induces ['l0', 'l1', 'l2']", + "75, apoptosis ['l0', 'l3', 'l4']", + "78, cell ['l1', 'l3', 'l5']", + "79, death. ['l2', 'l4', 'l5']", + "82, immunocompetent ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "83, quadruple-knockout ['l6', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "84, (PtenloxP/loxP; ['l7', 'l24', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "85, Trp53loxP/loxP; ['l8', 'l25', 'l42', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "86, Rb1loxP/loxP; ['l9', 'l26', 'l43', 'l59', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "87, Rbl1-/-) ['l10', 'l27', 'l44', 'l60', 'l75', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "88, transgenic ['l11', 'l28', 'l45', 'l61', 'l76', 'l90', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "89, mouse ['l12', 'l29', 'l46', 'l62', 'l77', 'l91', 'l104', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "90, model ['l13', 'l30', 'l47', 'l63', 'l78', 'l92', 'l105', 'l117', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "91, of ['l14', 'l31', 'l48', 'l64', 'l79', 'l93', 'l106', 'l118', 'l127', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "92, aggressive ['l15', 'l32', 'l49', 'l65', 'l80', 'l94', 'l107', 'l119', 'l128', 'l136', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150']", + "93, metastatic, ['l16', 'l33', 'l50', 'l66', 'l81', 'l95', 'l108', 'l120', 'l129', 'l137', 'l144', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156']", + "94, muscle-invasive ['l17', 'l34', 'l51', 'l67', 'l82', 'l96', 'l109', 'l121', 'l130', 'l138', 'l145', 'l151', 'l157', 'l158', 'l159', 'l160', 'l161']", + "95, bladder ['l18', 'l35', 'l52', 'l68', 'l83', 'l97', 'l110', 'l122', 'l131', 'l139', 'l146', 'l152', 'l157', 'l162', 'l163', 'l164', 'l165']", + "96, cancer, ['l19', 'l36', 'l53', 'l69', 'l84', 'l98', 'l111', 'l123', 'l132', 'l140', 'l147', 'l153', 'l158', 'l162']", + "102, results ['l20', 'l37', 'l54', 'l70', 'l85', 'l99', 'l112', 'l124', 'l133', 'l141', 'l148', 'l154', 'l159', 'l163', 'l166', 'l167', 'l168', 'l169']", + "103, in ['l21', 'l38', 'l55', 'l71', 'l86', 'l100', 'l113', 'l125', 'l134', 'l142', 'l149', 'l155', 'l160', 'l164', 'l166', 'l170', 'l171', 'l172']", + "106, regression ['l22', 'l39', 'l56', 'l72', 'l87', 'l101', 'l114', 'l167', 'l170', 'l173', 'l174']", + "109, tumors ['l23', 'l40', 'l57', 'l73', 'l88', 'l102', 'l115', 'l126', 'l135', 'l143', 'l150', 'l156', 'l161', 'l165', 'l168', 'l171', 'l173', 'l175']", + "111, metastases. ['l41', 'l58', 'l74', 'l89', 'l103', 'l116', 'l169', 'l172', 'l174', 'l175']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immunocompetent", + "quadruple-knockout", + "(PtenloxP/loxP;", + "Trp53loxP/loxP;", + "Rb1loxP/loxP;", + "Rbl1-/-)", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immunocompetent", + "quadruple-knockout", + "(PtenloxP/loxP;", + "Trp53loxP/loxP;", + "Rb1loxP/loxP;", + "Rbl1-/-)", + "transgenic" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "model", + "aggressive", + "metastatic,", + "muscle-invasive", + "bladder", + "cancer,", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immunocompetent", + "quadruple-knockout", + "(PtenloxP/loxP;", + "Trp53loxP/loxP;", + "Rb1loxP/loxP;", + "Rbl1-/-)", + "transgenic" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immunocompetent", + "quadruple-knockout", + "(PtenloxP/loxP;", + "Trp53loxP/loxP;", + "Rb1loxP/loxP;", + "Rbl1-/-)", + "transgenic" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "quadruple-knockout", + "(PtenloxP/loxP;", + "Trp53loxP/loxP;", + "Rb1loxP/loxP;", + "Rbl1-/-)", + "transgenic" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "model", + "aggressive", + "metastatic,", + "muscle-invasive", + "bladder", + "tumors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases." + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases." + ] + } + } + ] + }, + { + "PMID": "31270493", + "TEXT": "Petter Brodin is a pediatrician at the Karolinska University Hospital and an immunologist at Science for Life Laboratory. His lab combines state-of-the-art experimental methods and computational tools to monitor human immune systems in the most comprehensive way possible.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31209334", + "TEXT": "Asthma prevalence has increased in epidemic proportions with urbanization, but growing up on traditional farms offers protection even today1. The asthma-protective effect of farms appears to be associated with rich home dust microbiota2,3, which could be used to model a health-promoting indoor microbiome. Here we show by modeling differences in house dust microbiota composition between farm and non-farm homes of Finnish birth cohorts4 that in children who grow up in non-farm homes, asthma risk decreases as the similarity of their home bacterial microbiota composition to that of farm homes increases. The protective microbiota had a low abundance of Streptococcaceae relative to outdoor-associated bacterial taxa. The protective effect was independent of richness and total bacterial load and was associated with reduced proinflammatory cytokine responses against bacterial cell wall components ex vivo. We were able to reproduce these findings in a study among rural German children2 and showed that children living in German non-farm homes with an indoor microbiota more similar to Finnish farm homes have decreased asthma risk. The indoor dust microbiota composition appears to be a definable, reproducible predictor of asthma risk and a potential modifiable target for asthma prevention.", + "TAG_DATA": [ + "65, children {'context': 'B-patient'}", + "141, rural {'context': 'B-cells'}", + "142, German {'context': 'I-cells'}", + "143, children2 {'context': 'I-cells'}", + "147, children {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "141, rural ['l0', 'l1']", + "142, German ['l0', 'l2']", + "143, children2 ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31171880", + "TEXT": "In most cases of sporadic colorectal cancers, tumorigenesis is a multistep process, involving genomic alterations in parallel with morphologic changes. In addition, accumulating evidence suggests that the human gut microbiome is linked to the development of colorectal cancer. Here we performed fecal metagenomic and metabolomic studies on samples from a large cohort of 616 participants who underwent colonoscopy to assess taxonomic and functional characteristics of gut microbiota and metabolites. Microbiome and metabolome shifts were apparent in cases of multiple polypoid adenomas and intramucosal carcinomas, in addition to more advanced lesions. We found two distinct patterns of microbiome elevations. First, the relative abundance of Fusobacterium nucleatum spp. was significantly (P < 0.005) elevated continuously from intramucosal carcinoma to more advanced stages. Second, Atopobium parvulum and Actinomyces odontolyticus, which co-occurred in intramucosal carcinomas, were significantly (P < 0.005) increased only in multiple polypoid adenomas and/or intramucosal carcinomas. Metabolome analyses showed that branched-chain amino acids and phenylalanine were significantly (P < 0.005) increased in intramucosal carcinomas and bile acids, including deoxycholate, were significantly (P < 0.005) elevated in multiple polypoid adenomas and/or intramucosal carcinomas. We identified metagenomic and metabolomic markers to discriminate cases of intramucosal carcinoma from the healthy controls. Our large-cohort multi-omics data indicate that shifts in the microbiome and metabolome occur from the very early stages of the development of colorectal cancer, which is of possible etiological and diagnostic importance.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31171878", + "TEXT": "Blocking programmed death 1 (PD-1) may enhance the durability of anti-tumor responses that are induced by the combined inhibition of BRAF and MEK1. Here we performed a randomized phase 2 trial ( NCT02130466 ), in which patients with treatment-naive BRAFV600E/K-mutant, advanced melanoma received the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib together with the PD-1-blocking antibody pembrolizumab (triplet; n = 60) or placebo (doublet; n = 60). The primary end point of progression-free survival was numerically improved in the triplet group-16.0 months-compared with 10.3 months in the doublet group (hazard ratio, 0.66; P = 0.043); however, the trial did not reach the planned benefit for a statistically significant improvement. Median duration of response was 18.7 months (95% confidence interval, 10.1-22.1) and 12.5 months (95% confidence interval, 6.0-14.1); 59.8 and 27.8% of responses were estimated to have lasted for more than 18 months for triplet and doublet treatment, respectively. Grade 3-5 treatment-related adverse events occurred in 58.3 and 26.7% of patients treated with triplet and doublet therapies, respectively, which were most commonly fever, increased transaminase levels and rash. One patient who received triplet therapy died of pneumonitis. In summary, triplet therapy with dabrafenib, trametinib and pembrolizumab conferred numerically longer progression-free survival and duration of response with a higher rate of grade 3/4 adverse events compared with the doublet therapy of dabrafenib, trametinib and placebo.", + "TAG_DATA": [ + "36, patients {'context': 'B-patient'}", + "39, BRAFV600E/K-mutant, {'perturbing_action': 'B-other'}", + "40, advanced {'context': 'I-neoplasm'}", + "41, melanoma {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "36, patients ['l0', 'l1', 'l2']", + "39, BRAFV600E/K-mutant, ['l0', 'l3', 'l4']", + "40, advanced ['l1', 'l3', 'l5']", + "41, melanoma ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "BRAFV600E/K-mutant," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BRAFV600E/K-mutant," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "advanced", + "melanoma" + ] + } + } + ] + }, + { + "PMID": "31142849", + "TEXT": "The incidence of preterm birth exceeds 10% worldwide. There are significant disparities in the frequency of preterm birth among populations within countries, and women of African ancestry disproportionately bear the burden of risk in the United States. In the present study, we report a community resource that includes 'omics' data from approximately 12,000 samples as part of the integrative Human Microbiome Project. Longitudinal analyses of 16S ribosomal RNA, metagenomic, metatranscriptomic and cytokine profiles from 45 preterm and 90 term birth controls identified harbingers of preterm birth in this cohort of women predominantly of African ancestry. Women who delivered preterm exhibited significantly lower vaginal levels of Lactobacillus crispatus and higher levels of BVAB1, Sneathia amnii, TM7-H1, a group of Prevotella species and nine additional taxa. The first representative genomes of BVAB1 and TM7-H1 are described. Preterm-birth-associated taxa were correlated with proinflammatory cytokines in vaginal fluid. These findings highlight new opportunities for assessment of the risk of preterm birth.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31114058", + "TEXT": "In the version of this article originally published, there is an error in Fig. 5a. Originally, 'MAT2A' appeared between 'Methionine' and 'Homocysteine'. 'MAT2A' should have been 'MTR'. The error has been corrected in the PDF and HTML versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31068711", + "TEXT": "Precision health relies on the ability to assess disease risk at an individual level, detect early preclinical conditions and initiate preventive strategies. Recent technological advances in omics and wearable monitoring enable deep molecular and physiological profiling and may provide important tools for precision health. We explored the ability of deep longitudinal profiling to make health-related discoveries, identify clinically relevant molecular pathways and affect behavior in a prospective longitudinal cohort (n = 109) enriched for risk of type 2 diabetes mellitus. The cohort underwent integrative personalized omics profiling from samples collected quarterly for up to 8 years (median, 2.8 years) using clinical measures and emerging technologies including genome, immunome, transcriptome, proteome, metabolome, microbiome and wearable monitoring. We discovered more than 67 clinically actionable health discoveries and identified multiple molecular pathways associated with metabolic, cardiovascular and oncologic pathophysiology. We developed prediction models for insulin resistance by using omics measurements, illustrating their potential to replace burdensome tests. Finally, study participation led the majority of participants to implement diet and exercise changes. Altogether, we conclude that deep longitudinal profiling can lead to actionable health discoveries and provide relevant information for precision health.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31068703", + "TEXT": "Despite considerable efforts to identify cancer metabolic alterations that might unveil druggable vulnerabilities, systematic characterizations of metabolism as it relates to functional genomic features and associated dependencies remain uncommon. To further understand the metabolic diversity of cancer, we profiled 225 metabolites in 928 cell lines from more than 20 cancer types in the Cancer Cell Line Encyclopedia (CCLE) using liquid chromatography-mass spectrometry (LC-MS). This resource enables unbiased association analysis linking the cancer metabolome to genetic alterations, epigenetic features and gene dependencies. Additionally, by screening barcoded cell lines, we demonstrated that aberrant ASNS hypermethylation sensitizes subsets of gastric and hepatic cancers to asparaginase therapy. Finally, our analysis revealed distinct synthesis and secretion patterns of kynurenine, an immune-suppressive metabolite, in model cancer cell lines. Together, these findings and related methodology provide comprehensive resources that will help clarify the landscape of cancer metabolism.", + "TAG_DATA": [ + "85, cell {'context': 'B-cells'}", + "86, lines, {'context': 'I-cells'}", + "96, gastric {'context': 'B-neoplasm'}", + "97, and {'context': 'I-neoplasm'}", + "98, hepatic {'context': 'I-neoplasm'}", + "99, cancers {'context': 'I-neoplasm'}", + "119, cancer {'context': 'B-transformed cells'}", + "120, cell {'context': 'I-transformed cells'}", + "121, lines. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "85, cell ['l0', 'l1', 'l2', 'l3', 'l4']", + "86, lines, ['l0', 'l5', 'l6', 'l7']", + "96, gastric ['l1', 'l8', 'l9', 'l10']", + "97, and ['l2', 'l5', 'l8', 'l11', 'l12']", + "98, hepatic ['l3', 'l6', 'l9', 'l11', 'l13']", + "99, cancers ['l4', 'l7', 'l10', 'l12', 'l13']", + "119, cancer ['l14', 'l15']", + "120, cell ['l14', 'l16']", + "121, lines. ['l15', 'l16']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31011207", + "TEXT": "Anti-CD19 chimeric antigen receptor (CAR) T cell therapies can cause severe cytokine-release syndrome (CRS) and neurotoxicity, impeding their therapeutic application. Here we generated a new anti-CD19 CAR molecule (CD19-BBz(86)) derived from the CD19-BBz prototype bearing co-stimulatory 4-1BB and CD3ζ domains. We found that CD19-BBz(86) CAR T cells produced lower levels of cytokines, expressed higher levels of antiapoptotic molecules and proliferated more slowly than the prototype CD19-BBz CAR T cells, although they retained potent cytolytic activity. We performed a phase 1 trial of CD19-BBz(86) CAR T cell therapy in patients with B cell lymphoma (ClinicalTrials.gov identifier NCT02842138 ). Complete remission occurred in 6 of 11 patients (54.5%) who each received a dose of 2 × 108-4 × 108 CD19-BBz(86) CAR T cells. Notably, no neurological toxicity or CRS (greater than grade 1) occurred in any of the 25 patients treated. No significant elevation in serum cytokine levels after CAR T cell infusion was detected in the patients treated, including in those who achieved complete remission. CD19-BBz(86) CAR T cells persistently proliferated and differentiated into memory cells in vivo. Thus, therapy with the new CD19-BBz(86) CAR T cells produces a potent and durable antilymphoma response without causing neurotoxicity or severe CRS, representing a safe and potent anti-CD19 CAR T cell therapy.", + "TAG_DATA": [ + "59, proliferated {'phenotype': 'B-proliferation'}", + "88, patients {'context': 'B-patient'}", + "90, B {'context': 'B-neoplasm'}", + "91, cell {'context': 'I-neoplasm'}", + "92, lymphoma {'context': 'I-neoplasm'}", + "162, T {'context': 'I-cells'}", + "163, cells {'context': 'I-cells'}", + "165, proliferated {'phenotype': 'B-proliferation'}", + "167, differentiated {'phenotype': 'B-differentiation'}", + "169, memory {'context': 'B-cells', 'phenotype': 'B-differentiation'}", + "170, cells {'context': 'I-cells'}", + "171, in {'context': 'B-in vivo'}", + "172, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "88, patients ['l0', 'l1', 'l2']", + "90, B ['l0', 'l3', 'l4']", + "91, cell ['l1', 'l3', 'l5']", + "92, lymphoma ['l2', 'l4', 'l5']", + "162, T ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "163, cells ['l6', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "165, proliferated ['l7', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "167, differentiated ['l8', 'l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "169, memory ['l9', 'l15', 'l20', 'l24', 'l28', 'l29', 'l30']", + "170, cells ['l10', 'l16', 'l21', 'l25', 'l28', 'l31', 'l32']", + "171, in ['l11', 'l17', 'l22', 'l26', 'l29', 'l31', 'l33']", + "172, vivo. ['l12', 'l18', 'l23', 'l27', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "memory" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferated" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "memory" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiated", + "memory" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferated" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiated", + "memory" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "31011204", + "TEXT": "Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) supports blood-based genomic profiling but is not yet routinely implemented in the setting of a phase I trials clinic. TARGET is a molecular profiling program with the primary aim to match patients with a broad range of advanced cancers to early phase clinical trials on the basis of analysis of both somatic mutations and copy number alterations (CNA) across a 641 cancer-associated-gene panel in a single ctDNA assay. For the first 100 TARGET patients, ctDNA data showed good concordance with matched tumor and results were turned round within a clinically acceptable timeframe for Molecular Tumor Board (MTB) review. When a 2.5% variant allele frequency (VAF) threshold was applied, actionable mutations were identified in 41 of 100 patients, and 11 of these patients received a matched therapy. These data support the application of ctDNA in this early phase trial setting where broad genomic profiling of contemporaneous tumor material enhances patient stratification to novel therapies and provides a practical template for bringing routinely applied blood-based analyses to the clinic.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30996326", + "TEXT": "In the version of this article originally published, the graph in Extended Data Fig. 2c was a duplication of Extended Data Fig. 2b. The correct version of Extended Data Fig. 2c is now available online.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30944418", + "TEXT": "In the version of this article initially published, Table 1 had several errors. In the 'Immortalized cell lines column, the 'Expansion/Scalability' was listed as 'very high' and should have been 'unlimited'. In the 'Conditional reprogramming' column 'derivation time' was listed as '2-6 months' and should have been 'a few weeks', Expansion/Scalabilty was listed as 'Unknown' and should have been 'high', 'Amenability to high throughput' was listed as 'Unknown' and should have been 'moderate', 'Modeling early stage cancer and premalignancy' was listed as 'Unknown' and should have been 'Yes', 'Amenability to genetic manipulation' was listed as 'Unknown' and should have been 'possible', 'Autologous normal controls' was listed as 'Unknown' and should have been 'yes'. In the 'Tumor-derived iPSCs' column, Expansion/Scalability was listed as 'very high' and should have been 'Unlimited'.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30911134", + "TEXT": "Transplantation of hematopoietic cells from a healthy individual (allogeneic hematopoietic cell transplantation (allo-HCT)) demonstrates that adoptive immunotherapy can cure blood cancers: still, post-transplantation relapses remain frequent. To explain their drivers, we analyzed the genomic and gene expression profiles of acute myeloid leukemia (AML) blasts purified from patients at serial time-points during their disease history. We identified a transcriptional signature specific for post-transplantation relapses and highly enriched in immune-related processes, including T cell costimulation and antigen presentation. In two independent patient cohorts we confirmed the deregulation of multiple costimulatory ligands on AML blasts at post-transplantation relapse (PD-L1, B7-H3, CD80, PVRL2), mirrored by concomitant changes in circulating donor T cells. Likewise, we documented the frequent loss of surface expression of HLA-DR, -DQ and -DP on leukemia cells, due to downregulation of the HLA class II regulator CIITA. We show that loss of HLA class II expression and upregulation of inhibitory checkpoint molecules represent alternative modalities to abolish AML recognition from donor-derived T cells, and can be counteracted by interferon-γ or checkpoint blockade, respectively. Our results demonstrate that the deregulation of pathways involved in T cell-mediated allorecognition is a distinctive feature and driver of AML relapses after allo-HCT, which can be rapidly translated into personalized therapies.", + "TAG_DATA": [ + "123, leukemia {'context': 'B-transformed cells'}", + "124, cells, {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "123, leukemia ['l0']", + "124, cells, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30846883", + "TEXT": "Owing to an error during typesetting, a number of references were deleted from the Methods reference list. This altered all of the references in the Methods section and some of the references in Extended Data Fig. 5, making them inaccurate. References 121-134 were added back into the Methods reference list, and the references in the Methods section and in Extended Data Fig. 5 were renumbered accordingly. The error has been corrected in the PDF and HTML versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30833750", + "TEXT": "Overexpression of the B7-H1 (PD-L1) molecule in the tumor microenvironment (TME) is a major immune evasion mechanism in some patients with cancer, and antibody blockade of the B7-H1/PD-1 interaction can normalize compromised immunity without excessive side-effects. Using a genome-scale T cell activity array, we identified Siglec-15 as a critical immune suppressor. While only expressed on some myeloid cells normally, Siglec-15 is broadly upregulated on human cancer cells and tumor-infiltrating myeloid cells, and its expression is mutually exclusive to B7-H1, partially due to its induction by macrophage colony-stimulating factor and downregulation by IFN-γ. We demonstrate that Siglec-15 suppresses antigen-specific T cell responses in vitro and in vivo. Genetic ablation or antibody blockade of Siglec-15 amplifies anti-tumor immunity in the TME and inhibits tumor growth in some mouse models. Taken together, our results support Siglec-15 as a potential target for normalization cancer immunotherapy.", + "TAG_DATA": [ + "98, T {'context': 'B-cells'}", + "99, cell {'context': 'I-cells'}", + "101, in {'context': 'B-in vitro'}", + "102, vitro {'context': 'I-in vitro'}", + "104, in {'context': 'B-in vivo'}", + "105, vivo. {'context': 'I-in vivo'}", + "109, antibody {'perturbing_action': 'B-pharmacological inhibition'}", + "110, blockade {'perturbing_action': 'I-pharmacological inhibition'}", + "111, of {'perturbing_action': 'I-rnai/knockdown'}", + "112, Siglec-15 {'perturbing_action': 'I-rnai/knockdown'}", + "120, inhibits {'effect': 'B-negative'}", + "121, tumor {'phenotype': 'B-tumour growth'}", + "122, growth {'phenotype': 'I-tumour growth'}", + "125, mouse {'context': 'B-organism'}", + "126, models. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "98, T ['l0', 'l1', 'l2', 'l3', 'l4']", + "99, cell ['l0', 'l5', 'l6', 'l7']", + "101, in ['l1', 'l5', 'l8', 'l9', 'l10']", + "102, vitro ['l2', 'l6', 'l8', 'l11', 'l12']", + "104, in ['l3', 'l9', 'l11', 'l13']", + "105, vivo. ['l4', 'l7', 'l10', 'l12', 'l13']", + "109, antibody ['l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "110, blockade ['l14', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "111, of ['l15', 'l22', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "112, Siglec-15 ['l16', 'l23', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "120, inhibits ['l17', 'l24', 'l30', 'l35', 'l40', 'l41', 'l42', 'l43']", + "121, tumor ['l18', 'l25', 'l31', 'l36', 'l40', 'l44', 'l45', 'l46']", + "122, growth ['l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l47', 'l48']", + "125, mouse ['l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l49']", + "126, models. ['l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l49']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antibody", + "blockade" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antibody", + "blockade" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antibody", + "blockade" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "Siglec-15" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "Siglec-15" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "Siglec-15" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + } + ] + }, + { + "PMID": "30742121", + "TEXT": "Artificial intelligence (AI)-based methods have emerged as powerful tools to transform medical care. Although machine learning classifiers (MLCs) have already demonstrated strong performance in image-based diagnoses, analysis of diverse and massive electronic health record (EHR) data remains challenging. Here, we show that MLCs can query EHRs in a manner similar to the hypothetico-deductive reasoning used by physicians and unearth associations that previous statistical methods have not found. Our model applies an automated natural language processing system using deep learning techniques to extract clinically relevant information from EHRs. In total, 101.6 million data points from 1,362,559 pediatric patient visits presenting to a major referral center were analyzed to train and validate the framework. Our model demonstrates high diagnostic accuracy across multiple organ systems and is comparable to experienced pediatricians in diagnosing common childhood diseases. Our study provides a proof of concept for implementing an AI-based system as a means to aid physicians in tackling large amounts of data, augmenting diagnostic evaluations, and to provide clinical decision support in cases of diagnostic uncertainty or complexity. Although this impact may be most evident in areas where healthcare providers are in relative shortage, the benefits of such an AI system are likely to be universal.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30742119", + "TEXT": "Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor's clonal evolution during treatment.", + "TAG_DATA": [ + "89, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30705421", + "TEXT": "In the version of this article originally published, the color key in Fig. 1a was wrong. In the Cytogenetics key, the box over t(8;21) originally was green. It should have been red, matching the color of the sections of the pie graphs below the key that were labeled with 15% and 19%.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30700866", + "TEXT": "In the version of this article originally published, there were several errors in Fig. 4. In Fig. 4a, the title read '3D repeated optical inhibition after CSDS.' It should have read '3-day repeated optical inhibition after CSDS.' In Fig. 4c, two labels that should have been aligned with the time axis appeared in the wrong place in the figure. The ticks labeled 'SI' and 'Fiber implant' should have also been labeled with '10' and '14,' respectively. Additionally, in Fig. 4j, a label that should have been aligned with the time axis appeared in the wrong place in the figure. The tick labeled 'Fiber implant' should have also been labeled with '14.' The errors have been corrected in the print, PDF and HTML versions of the manuscript.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30670876", + "TEXT": "In the version of this article originally published, the figure callout in this sentence was incorrect: \"Furthermore, in S1P1-KI mice themselves, whereas PD-1 blockade was ineffectual as monotherapy, the effects of 4-1BB agonism and checkpoint blockade proved additive, with the combination prolonging median survival and producing a 50% long-term survival rate (Fig. 6f).\" The callout should have been to Supplementary Fig. 6b. The error has been corrected in the PDF and HTML versions of the article.", + "TAG_DATA": [ + "18, S1P1-KI {'perturbing_action': 'B-pharmacological inhibition'}", + "19, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "18, S1P1-KI ['l0']", + "19, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "S1P1-KI" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "30664783", + "TEXT": "Inflammatory bowel diseases (IBD) can be broadly divided into Crohn's disease (CD) and ulcerative colitis (UC) from their clinical phenotypes. Over 150 host susceptibility genes have been described, although most overlap between CD, UC and their subtypes, and they do not adequately account for the overall incidence or the highly variable severity of disease. Replicating key findings between two long-term IBD cohorts, we have defined distinct networks of taxa associations within intestinal biopsies of CD and UC patients. Disturbances in an association network containing taxa of the Lachnospiraceae and Ruminococcaceae families, typically producing short chain fatty acids, characterize frequently relapsing disease and poor responses to treatment with anti-TNF-α therapeutic antibodies. Alterations of taxa within this network also characterize risk of later disease recurrence of patients in remission after the active inflamed segment of CD has been surgically removed.", + "TAG_DATA": [ + "124, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30664779", + "TEXT": "Chordoma is a primary bone cancer with no approved therapy1. The identification of therapeutic targets in this disease has been challenging due to the infrequent occurrence of clinically actionable somatic mutations in chordoma tumors2,3. Here we describe the discovery of therapeutically targetable chordoma dependencies via genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling. These systematic approaches reveal that the developmental transcription factor T (brachyury; TBXT) is the top selectively essential gene in chordoma, and that transcriptional cyclin-dependent kinase (CDK) inhibitors targeting CDK7/12/13 and CDK9 potently suppress chordoma cell proliferation. In other cancer types, transcriptional CDK inhibitors have been observed to downregulate highly expressed, enhancer-associated oncogenic transcription factors4,5. In chordoma, we find that T is associated with a 1.5-Mb region containing 'super-enhancers' and is the most highly expressed super-enhancer-associated transcription factor. Notably, transcriptional CDK inhibition leads to preferential and concentration-dependent downregulation of cellular brachyury protein levels in all models tested. In vivo, CDK7/12/13-inhibitor treatment substantially reduces tumor growth. Together, these data demonstrate small-molecule targeting of brachyury transcription factor addiction in chordoma, identify a mechanism of T gene regulation that underlies this therapeutic strategy, and provide a blueprint for applying systematic genetic and chemical screening approaches to discover vulnerabilities in genomically quiet cancers.", + "TAG_DATA": [ + "75, transcriptional {'perturbing_action': 'B-pharmacological inhibition'}", + "76, cyclin-dependent {'perturbing_action': 'I-pharmacological inhibition'}", + "77, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "78, (CDK) {'perturbing_action': 'I-pharmacological inhibition'}", + "79, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "80, targeting {'perturbing_action': 'I-pharmacological inhibition'}", + "81, CDK7/12/13 {'perturbing_action': 'I-pharmacological inhibition'}", + "82, and {'perturbing_action': 'I-pharmacological inhibition'}", + "83, CDK9 {'perturbing_action': 'I-pharmacological inhibition'}", + "85, suppress {'effect': 'B-negative'}", + "86, chordoma {'context': 'B-transformed cells'}", + "87, cell {'context': 'I-transformed cells'}", + "88, proliferation. {'phenotype': 'B-proliferation'}", + "131, transcriptional {'perturbing_action': 'B-pharmacological inhibition'}", + "132, CDK {'perturbing_action': 'I-pharmacological inhibition'}", + "133, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "149, In {'context': 'B-in vivo'}", + "150, vivo, {'context': 'I-in vivo'}", + "151, CDK7/12/13-inhibitor {'perturbing_action': 'B-pharmacological inhibition'}", + "152, treatment {'perturbing_action': 'I-pharmacological inhibition'}", + "154, reduces {'effect': 'B-negative'}", + "155, tumor {'phenotype': 'B-tumour growth'}", + "156, growth. {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "75, transcriptional ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "76, cyclin-dependent ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "77, kinase ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "78, (CDK) ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "79, inhibitors ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "80, targeting ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "81, CDK7/12/13 ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "82, and ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "83, CDK9 ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "85, suppress ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "86, chordoma ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "87, cell ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "88, proliferation. ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "95, inhibitors ['l78', 'l79', 'l80']", + "131, transcriptional ['l78', 'l81', 'l82']", + "132, CDK ['l79', 'l81', 'l83']", + "133, inhibition ['l80', 'l82', 'l83']", + "149, In ['l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "150, vivo, ['l84', 'l90', 'l91', 'l92', 'l93', 'l94']", + "151, CDK7/12/13-inhibitor ['l85', 'l90', 'l95', 'l96', 'l97', 'l98']", + "152, treatment ['l86', 'l91', 'l95', 'l99', 'l100', 'l101']", + "154, reduces ['l87', 'l92', 'l96', 'l99', 'l102', 'l103']", + "155, tumor ['l88', 'l93', 'l97', 'l100', 'l102', 'l104']", + "156, growth. ['l89', 'l94', 'l98', 'l101', 'l103', 'l104']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "transcriptional", + "cyclin-dependent", + "kinase", + "(CDK)", + "inhibitors", + "targeting", + "CDK7/12/13", + "and", + "CDK9", + "CDK7/12/13-inhibitor", + "treatment" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppress", + "reduces" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "transcriptional", + "cyclin-dependent", + "kinase", + "(CDK)", + "inhibitors", + "targeting", + "CDK7/12/13", + "and", + "CDK9" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "chordoma", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "transcriptional", + "cyclin-dependent", + "kinase", + "(CDK)", + "inhibitors", + "targeting", + "CDK7/12/13", + "and", + "CDK9" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppress" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "chordoma", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppress" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "chordoma", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK7/12/13-inhibitor", + "treatment" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK7/12/13-inhibitor", + "treatment" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + } + ] + }, + { + "PMID": "30643286", + "TEXT": "Cancer cells develop mechanisms to escape immunosurveillance, among which modulating the expression of immune suppressive messenger RNAs is most well-documented. However, how this is molecularly achieved remains largely unresolved. Here, we develop an in vivo mouse model of liver cancer to study oncogene cooperation in immunosurveillance. We show that MYC overexpression (MYCTg) synergizes with KRASG12D to induce an aggressive liver tumor leading to metastasis formation and reduced mouse survival compared with KRASG12D alone. Genome-wide ribosomal footprinting of MYCTg;KRASG12 tumors compared with KRASG12D revealed potential alterations in translation of mRNAs, including programmed-death-ligand 1 (PD-L1). Further analysis revealed that PD-L1 translation is repressed in KRASG12D tumors by functional, non-canonical upstream open reading frames in its 5' untranslated region, which is bypassed in MYCTg;KRASG12D tumors to evade immune attack. We show that this mechanism of PD-L1 translational upregulation was effectively targeted by a potent, clinical compound that inhibits eIF4E phosphorylation, eFT508, which reverses the aggressive and metastatic characteristics of MYCTg;KRASG12D tumors. Together, these studies reveal how immune-checkpoint proteins are manipulated by distinct oncogenes at the level of mRNA translation, which can be exploited for new immunotherapies.", + "TAG_DATA": [ + "49, MYC {'perturbing_action': 'B-gene gain-of-function'}", + "50, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "51, (MYCTg) {'perturbing_action': 'I-gene gain-of-function'}", + "56, induce {'effect': 'B-positive'}", + "59, liver {'context': 'B-neoplasm'}", + "60, tumor {'context': 'I-neoplasm'}", + "61, leading {'effect': 'B-positive'}", + "62, to {'effect': 'I-positive'}", + "63, metastasis {'phenotype': 'B-metastasis'}", + "64, formation {'phenotype': 'I-metastasis'}", + "67, mouse {'context': 'B-organism'}", + "156, MYCTg;KRASG12D {'perturbing_action': 'B-other'}", + "157, tumors. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "49, MYC ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "50, overexpression ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "51, (MYCTg) ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "56, induce ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "59, liver ['l3', 'l12', 'l20', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "60, tumor ['l4', 'l13', 'l21', 'l28', 'l33', 'l38', 'l39', 'l40', 'l41']", + "61, leading ['l5', 'l14', 'l22', 'l29', 'l34', 'l38', 'l42', 'l43', 'l44']", + "62, to ['l6', 'l15', 'l23', 'l30', 'l35', 'l39', 'l42', 'l45', 'l46']", + "63, metastasis ['l7', 'l16', 'l24', 'l31', 'l36', 'l40', 'l43', 'l45', 'l47', 'l48']", + "64, formation ['l8', 'l17', 'l25', 'l32', 'l37', 'l41', 'l44', 'l46', 'l47']", + "67, mouse ['l9', 'l18', 'l26', 'l48']", + "156, MYCTg;KRASG12D ['l49']", + "157, tumors. ['l49']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "MYC", + "overexpression", + "(MYCTg)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce", + "leading", + "to" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "MYC", + "overexpression", + "(MYCTg)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "liver", + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "MYC", + "overexpression", + "(MYCTg)" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "formation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "MYC", + "overexpression", + "(MYCTg)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce", + "leading", + "to" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "liver", + "tumor" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce", + "leading", + "to" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "formation" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "liver", + "tumor" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "formation" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "MYCTg;KRASG12D" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors." + ] + } + } + ] + }, + { + "PMID": "30643285", + "TEXT": "Current methods for bioprinting functional tissue lack appropriate biofabrication techniques to build complex 3D microarchitectures essential for guiding cell growth and promoting tissue maturation1. 3D printing of central nervous system (CNS) structures has not been accomplished, possibly owing to the complexity of CNS architecture. Here, we report the use of a microscale continuous projection printing method (μCPP) to create a complex CNS structure for regenerative medicine applications in the spinal cord. μCPP can print 3D biomimetic hydrogel scaffolds tailored to the dimensions of the rodent spinal cord in 1.6 s and is scalable to human spinal cord sizes and lesion geometries. We tested the ability of µCPP 3D-printed scaffolds loaded with neural progenitor cells (NPCs) to support axon regeneration and form new 'neural relays' across sites of complete spinal cord injury in vivo in rodents1,2. We find that injured host axons regenerate into 3D biomimetic scaffolds and synapse onto NPCs implanted into the device and that implanted NPCs in turn extend axons out of the scaffold and into the host spinal cord below the injury to restore synaptic transmission and significantly improve functional outcomes. Thus, 3D biomimetic scaffolds offer a means of enhancing CNS regeneration through precision medicine.", + "TAG_DATA": [ + "110, neural {'context': 'B-cells'}", + "111, progenitor {'context': 'I-cells'}", + "112, cells {'context': 'I-cells'}", + "113, (NPCs) {'context': 'I-cells'}", + "130, in {'context': 'B-in vivo'}", + "131, vivo {'context': 'I-in vivo'}", + "133, rodents1,2. {'context': 'B-organism'}", + "138, host {'context': 'B-cells'}", + "139, axons {'context': 'I-cells'}", + "148, NPCs {'context': 'B-cells'}", + "156, NPCs {'context': 'B-cells'}", + "160, axons {'context': 'B-cells'}", + "169, spinal {'context': 'I-tissue/organ'}", + "170, cord {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "110, neural ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "111, progenitor ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "112, cells ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "113, (NPCs) ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "130, in ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28']", + "131, vivo ['l4', 'l11', 'l17', 'l22', 'l26', 'l29']", + "133, rodents1,2. ['l5', 'l12', 'l18', 'l23', 'l27', 'l29', 'l30', 'l31']", + "138, host ['l6', 'l13', 'l19', 'l24', 'l30', 'l32', 'l33']", + "139, axons ['l7', 'l14', 'l20', 'l25', 'l28', 'l31', 'l32', 'l34']", + "148, NPCs ['l33', 'l34']", + "156, NPCs ['l35', 'l36', 'l37']", + "160, axons ['l35', 'l38', 'l39']", + "169, spinal ['l36', 'l38', 'l40']", + "170, cord ['l37', 'l39', 'l40']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30568307", + "TEXT": "In the version of this article originally published, Ulrich Steidl's name was listed as \"and Ulrich Steidl.\" His name has been updated to \"Ulrich Steidl.\" The error has been fixed in the print, PDF and HTML versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30560902", + "TEXT": "In the version of this article originally published, Extended Data Fig. 3 was incorrect. A duplicate of Extended Data Fig. 4 was uploaded in place of Extended Data Fig. 3. Extended Data Fig. 3 has now been uploaded. The error has been fixed in the PDF and HTML versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30559421", + "TEXT": "Chimeric antigen receptors (CARs) are synthetic receptors that target and reprogram T cells to acquire augmented antitumor properties1. CD19-specific CARs that comprise CD28 and CD3ζ signaling motifs2 have induced remarkable responses in patients with refractory leukemia3-5 and lymphoma6 and were recently approved by the US Food and Drug Administration7. These CARs program highly performing effector functions that mediate potent tumor elimination4,8 despite the limited persistence they confer on T cells3-6,8. Extending their functional persistence without compromising their potency should improve current CAR therapies. Strong T cell activation drives exhaustion9,10, which may be accentuated by the redundancy of CD28 and CD3ζ signaling11,12 as well as the spatiotemporal constraints imparted by the structure of second-generation CARs2. Thus, we hypothesized that calibrating the activation potential of CD28-based CARs would differentially reprogram T cell function and differentiation. Here, we show that CARs encoding a single immunoreceptor tyrosine-based activation motif direct T cells to different fates by balancing effector and memory programs, thereby yielding CAR designs with enhanced therapeutic profiles.", + "TAG_DATA": [ + "84, T {'context': 'B-cells'}", + "85, cell {'context': 'B-cells'}", + "146, T {'context': 'B-cells'}", + "147, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "84, T ['l0']", + "85, cell ['l0']", + "146, T ['l1']", + "147, cells ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30523328", + "TEXT": "Multiple myeloma, a plasma cell malignancy, is the second most common blood cancer. Despite extensive research, disease heterogeneity is poorly characterized, hampering efforts for early diagnosis and improved treatments. Here, we apply single cell RNA sequencing to study the heterogeneity of 40 individuals along the multiple myeloma progression spectrum, including 11 healthy controls, demonstrating high interindividual variability that can be explained by expression of known multiple myeloma drivers and additional putative factors. We identify extensive subclonal structures for 10 of 29 individuals with multiple myeloma. In asymptomatic individuals with early disease and in those with minimal residual disease post-treatment, we detect rare tumor plasma cells with molecular characteristics similar to those of active myeloma, with possible implications for personalized therapies. Single cell analysis of rare circulating tumor cells allows for accurate liquid biopsy and detection of malignant plasma cells, which reflect bone marrow disease. Our work establishes single cell RNA sequencing for dissecting blood malignancies and devising detailed molecular characterization of tumor cells in symptomatic and asymptomatic patients.", + "TAG_DATA": [ + "103, plasma {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "103, plasma ['l0']", + "104, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30531922", + "TEXT": "Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma). We found that the predisposing germline mutation of the NF1 gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1 wild-type subgroup enriched with ATRX mutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30478422", + "TEXT": "Understanding the mechanisms underlying autoantibody development will accelerate therapeutic target identification in autoimmune diseases such as systemic lupus erythematosus (SLE)1. Follicular helper T cells (TFH cells) have long been implicated in SLE pathogenesis. Yet a fraction of autoantibodies in individuals with SLE are unmutated, supporting that autoreactive B cells also differentiate outside germinal centers2. Here, we describe a CXCR5-CXCR3+ programmed death 1 (PD1)hiCD4+ helper T cell population distinct from TFH cells and expanded in both SLE blood and the tubulointerstitial areas of individuals with proliferative lupus nephritis. These cells produce interleukin-10 (IL-10) and accumulate mitochondrial reactive oxygen species as the result of reverse electron transport fueled by succinate. Furthermore, they provide B cell help, independently of IL-21, through IL-10 and succinate. Similar cells are generated in vitro upon priming naive CD4+ T cells with plasmacytoid dendritic cells activated with oxidized mitochondrial DNA, a distinct class of interferogenic toll-like receptor 9 ligand3. Targeting this pathway might blunt the initiation and/or perpetuation of extrafollicular humoral responses in SLE.", + "TAG_DATA": [ + "125, in {'context': 'B-in vitro'}", + "126, vitro {'context': 'I-in vitro'}", + "129, naive {'context': 'B-cells'}", + "130, CD4+ {'context': 'I-cells'}", + "131, T {'context': 'I-cells'}", + "132, cells {'context': 'I-cells'}", + "134, plasmacytoid {'context': 'B-cells'}", + "135, dendritic {'context': 'I-cells'}", + "136, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "125, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "126, vitro ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "129, naive ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "130, CD4+ ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "131, T ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "132, cells ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "134, plasmacytoid ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "135, dendritic ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "136, cells ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30420753", + "TEXT": "The recent successes of immunotherapy have shifted the paradigm in cancer treatment, but because only a percentage of patients are responsive to immunotherapy, it is imperative to identify factors impacting outcome. Obesity is reaching pandemic proportions and is a major risk factor for certain malignancies, but the impact of obesity on immune responses, in general and in cancer immunotherapy, is poorly understood. Here, we demonstrate, across multiple species and tumor models, that obesity results in increased immune aging, tumor progression and PD-1-mediated T cell dysfunction which is driven, at least in part, by leptin. However, obesity is also associated with increased efficacy of PD-1/PD-L1 blockade in both tumor-bearing mice and clinical cancer patients. These findings advance our understanding of obesity-induced immune dysfunction and its consequences in cancer and highlight obesity as a biomarker for some cancer immunotherapies. These data indicate a paradoxical impact of obesity on cancer. There is heightened immune dysfunction and tumor progression but also greater anti-tumor efficacy and survival after checkpoint blockade which directly targets some of the pathways activated in obesity.", + "TAG_DATA": [ + "69, tumor {'context': 'B-neoplasm'}", + "70, models, {'context': 'I-neoplasm'}", + "78, tumor {'phenotype': 'B-tumour progression'}", + "79, progression {'phenotype': 'I-tumour progression'}", + "107, tumor-bearing {'context': 'B-organism'}", + "108, mice {'context': 'I-organism'}", + "110, clinical {'context': 'B-transformed cells'}", + "111, cancer {'context': 'I-transformed cells'}", + "112, patients. {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "69, tumor ['l0', 'l1', 'l2']", + "70, models, ['l0', 'l3', 'l4']", + "78, tumor ['l1', 'l3', 'l5']", + "79, progression ['l2', 'l4', 'l5']", + "107, tumor-bearing ['l6', 'l7', 'l8', 'l9']", + "108, mice ['l6']", + "110, clinical ['l7', 'l10', 'l11']", + "111, cancer ['l8', 'l10', 'l12']", + "112, patients. ['l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "tumor", + "models," + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + } + ] + }, + { + "PMID": "30397356", + "TEXT": "The anti-hyperglycemic effect of metformin is believed to be caused by its direct action on signaling processes in hepatocytes, leading to lower hepatic gluconeogenesis. Recently, metformin was reported to alter the gut microbiota community in humans, suggesting that the hyperglycemia-lowering action of the drug could be the result of modulating the population of gut microbiota. However, the critical microbial signaling metabolites and the host targets associated with the metabolic benefits of metformin remained elusive. Here, we performed metagenomic and metabolomic analysis of samples from individuals with newly diagnosed type 2 diabetes (T2D) naively treated with metformin for 3 d, which revealed that Bacteroides fragilis was decreased and the bile acid glycoursodeoxycholic acid (GUDCA) was increased in the gut. These changes were accompanied by inhibition of intestinal farnesoid X receptor (FXR) signaling. We further found that high-fat-diet (HFD)-fed mice colonized with B. fragilis were predisposed to more severe glucose intolerance, and the metabolic benefits of metformin treatment on glucose intolerance were abrogated. GUDCA was further identified as an intestinal FXR antagonist that improved various metabolic endpoints in mice with established obesity. Thus, we conclude that metformin acts in part through a B. fragilis-GUDCA-intestinal FXR axis to improve metabolic dysfunction, including hyperglycemia.", + "TAG_DATA": [ + "137, mice {'context': 'B-organism'}", + "176, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30374198", + "TEXT": "Commensal gut bacterial communities (microbiomes) are predicted to influence human health and disease1,2. Neonatal gut microbiomes are colonized with maternal and environmental flora and mature toward a stable composition over 2-3 years3,4. To study pre- and postnatal determinants of infant microbiome development, we analyzed 402 fecal metagenomes from 60 infants aged 0-8 months, using longitudinal generalized linear mixed models (GLMMs). Distinct microbiome signatures correlated with breastfeeding, formula ingredients, and maternal gestational weight gain (GWG). Amino acid synthesis pathway accretion in breastfed microbiomes complemented normative breastmilk composition. Prebiotic oligosaccharides, designed to promote breastfed-like microflora5, predicted functional pathways distinct from breastfed infant microbiomes. Soy formula in six infants was positively associated with Lachnospiraceae and pathways suggesting a short-chain fatty acid (SCFA)-rich environment, including glycerol to 1-butanol fermentation, which is potentially dysbiotic. GWG correlated with altered carbohydrate degradation and enriched vitamin synthesis pathways. Maternal and postnatal antibiotics predicted microbiome alterations, while delivery route had no persistent effects. Domestic water source correlates suggest water may be an underappreciated determinant of microbiome acquisition. Clinically important microbial pathways with statistically significant dietary correlates included dysbiotic markers6,7, core enterotype features8, and synthesis pathways for enteroprotective9 and immunomodulatory10,11 metabolites, epigenetic mediators1, and developmentally critical vitamins12, warranting further investigation.", + "TAG_DATA": [ + "48, infants {'context': 'B-organism'}", + "49, aged {'context': 'I-organism'}", + "50, 0-8 months, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "48, infants ['l0', 'l1']", + "49, aged ['l0', 'l2']", + "50, 0-8 months, ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30361510", + "TEXT": "In the version of this article originally published, there was an error in Fig. 2b. RECIST ORR and pCR were both listed as 25%. RECIST ORR was actually 73%, and pCR was 45%. Also, an author's name was incorrect in the author list. Danny K. Wells should have been listed as Daniel K. Wells. The errors have been corrected in the print, HTML and PDF versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30297909", + "TEXT": "Preclinical studies suggest that treatment with neoadjuvant immune checkpoint blockade is associated with enhanced survival and antigen-specific T cell responses compared with adjuvant treatment1; however, optimal regimens have not been defined. Here we report results from a randomized phase 2 study of neoadjuvant nivolumab versus combined ipilimumab with nivolumab in 23 patients with high-risk resectable melanoma ( NCT02519322 ). RECIST overall response rates (ORR), pathologic complete response rates (pCR), treatment-related adverse events (trAEs) and immune correlates of response were assessed. Treatment with combined ipilimumab and nivolumab yielded high response rates (RECIST ORR 73%, pCR 45%) but substantial toxicity (73% grade 3 trAEs), whereas treatment with nivolumab monotherapy yielded modest responses (ORR 25%, pCR 25%) and low toxicity (8% grade 3 trAEs). Immune correlates of response were identified, demonstrating higher lymphoid infiltrates in responders to both therapies and a more clonal and diverse T cell infiltrate in responders to nivolumab monotherapy. These results describe the feasibility of neoadjuvant immune checkpoint blockade in melanoma and emphasize the need for additional studies to optimize treatment regimens and to validate putative biomarkers.", + "TAG_DATA": [ + "51, patients {'context': 'B-patient'}", + "52, with {'context': 'I-patient'}", + "53, high-risk {'context': 'B-neoplasm'}", + "54, resectable {'context': 'I-neoplasm'}", + "55, melanoma {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "51, patients ['l0', 'l1', 'l2', 'l3']", + "52, with ['l0', 'l4', 'l5', 'l6']", + "53, high-risk ['l1', 'l4', 'l7', 'l8']", + "54, resectable ['l2', 'l5', 'l7', 'l9']", + "55, melanoma ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30275568", + "TEXT": "We report a patient relapsing 9 months after CD19-targeted CAR T cell (CTL019) infusion with CD19- leukemia that aberrantly expressed the anti-CD19 CAR. The CAR gene was unintentionally introduced into a single leukemic B cell during T cell manufacturing, and its product bound in cis to the CD19 epitope on the surface of leukemic cells, masking it from recognition by and conferring resistance to CTL019.", + "TAG_DATA": [ + "15, CD19- {'context': 'B-neoplasm'}", + "16, leukemia {'context': 'B-neoplasm'}", + "32, leukemic {'context': 'B-cells'}", + "33, B {'context': 'I-cells'}", + "34, cell {'context': 'I-cells'}", + "53, leukemic {'context': 'B-transformed cells'}", + "54, cells, {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "15, CD19- ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "16, leukemia ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "32, leukemic ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "33, B ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "34, cell ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "53, leukemic ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "54, cells, ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30194412", + "TEXT": "To address a critical roadblock that can occur in translational and clinical research, the National Cancer Institute and the Food and Drug Administration, in coordination with the DREAM Challenges, are launching the first computational challenge using multi-omics datasets to detect and correct specimen mislabeling.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30150719", + "TEXT": "Metformin is a first-line drug for the treatment of individuals with type 2 diabetes, yet its precise mechanism of action remains unclear. Metformin exerts its antihyperglycemic action primarily through lowering hepatic glucose production (HGP). This suppression is thought to be mediated through inhibition of mitochondrial respiratory complex I, and thus elevation of 5'-adenosine monophosphate (AMP) levels and the activation of AMP-activated protein kinase (AMPK), though this proposition has been challenged given results in mice lacking hepatic AMPK. Here we report that the AMP-inhibited enzyme fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis, functions as a major contributor to the therapeutic action of metformin. We identified a point mutation in FBP1 that renders it insensitive to AMP while sparing regulation by fructose-2,6-bisphosphate (F-2,6-P2), and knock-in (KI) of this mutant in mice significantly reduces their response to metformin treatment. We observe this during a metformin tolerance test and in a metformin-euglycemic clamp that we have developed. The antihyperglycemic effect of metformin in high-fat diet-fed diabetic FBP1-KI mice was also significantly blunted compared to wild-type controls. Collectively, we show a new mechanism of action for metformin and provide further evidence that molecular targeting of FBP1 can have antihyperglycemic effects.", + "TAG_DATA": [ + "105, point {'perturbing_action': 'B-other'}", + "106, mutation {'perturbing_action': 'I-other'}", + "107, in {'perturbing_action': 'I-other'}", + "108, FBP1 {'perturbing_action': 'I-other'}", + "122, knock-in {'perturbing_action': 'B-rnai/knockdown'}", + "123, (KI) {'perturbing_action': 'I-rnai/knockdown'}", + "124, of {'perturbing_action': 'I-rnai/knockdown'}", + "125, this {'perturbing_action': 'I-rnai/knockdown'}", + "126, mutant {'perturbing_action': 'I-rnai/knockdown'}", + "128, mice {'context': 'B-organism'}", + "161, diabetic {'perturbing_action': 'B-other'}", + "162, FBP1-KI {'perturbing_action': 'B-other'}", + "163, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "105, point ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "106, mutation ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "107, in ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "108, FBP1 ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "122, knock-in ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "123, (KI) ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "124, of ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "125, this ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "126, mutant ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "128, mice ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "161, diabetic ['l45', 'l46']", + "162, FBP1-KI ['l45', 'l47']", + "163, mice ['l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "point", + "mutation", + "in", + "FBP1", + "diabetic", + "FBP1-KI" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knock-in", + "(KI)", + "of", + "this", + "mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "30150717", + "TEXT": "Trillions of microorganisms inhabit the human gut and are regarded as potential key factors for health1,2. Characteristics such as diet, lifestyle, or genetics can shape the composition of the gut microbiota2-6 and are usually shared by individuals from comparable ethnic origin. So far, most studies assessing how ethnicity relates to the intestinal microbiota compared small groups living at separate geographical locations7-10. Using fecal 16S ribosomal RNA gene sequencing in 2,084 participants of the Healthy Life in an Urban Setting (HELIUS) study11,12, we show that individuals living in the same city tend to share similar gut microbiota characteristics with others of their ethnic background. Ethnicity contributed to explain the interindividual dissimilarities in gut microbiota composition, with three main poles primarily characterized by operational taxonomic units (OTUs) classified as Prevotella (Moroccans, Turks, Ghanaians), Bacteroides (African Surinamese, South-Asian Surinamese), and Clostridiales (Dutch). The Dutch exhibited the greatest gut microbiota α-diversity and the South-Asian Surinamese the smallest, with corresponding enrichment or depletion in numerous OTUs. Ethnic differences in α-diversity and interindividual dissimilarities were independent of metabolic health and only partly explained by ethnic-related characteristics including sociodemographic, lifestyle, or diet factors. Hence, the ethnic origin of individuals may be an important factor to consider in microbiome research and its potential future applications in ethnic-diverse societies.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30127393", + "TEXT": "Cancer treatment by immune checkpoint blockade (ICB) can bring long-lasting clinical benefits, but only a fraction of patients respond to treatment. To predict ICB response, we developed TIDE, a computational method to model two primary mechanisms of tumor immune evasion: the induction of T cell dysfunction in tumors with high infiltration of cytotoxic T lymphocytes (CTL) and the prevention of T cell infiltration in tumors with low CTL level. We identified signatures of T cell dysfunction from large tumor cohorts by testing how the expression of each gene in tumors interacts with the CTL infiltration level to influence patient survival. We also modeled factors that exclude T cell infiltration into tumors using expression signatures from immunosuppressive cells. Using this framework and pre-treatment RNA-Seq or NanoString tumor expression profiles, TIDE predicted the outcome of melanoma patients treated with first-line anti-PD1 or anti-CTLA4 more accurately than other biomarkers such as PD-L1 level and mutation load. TIDE also revealed new candidate ICB resistance regulators, such as SERPINB9, demonstrating utility for immunotherapy research.", + "TAG_DATA": [ + "133, melanoma {'context': 'B-patient'}", + "134, patients {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "133, melanoma ['l0']", + "134, patients ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30093729", + "TEXT": "In the version of this article originally published, the P statistic described in Fig. 3d was incorrect. It was described as \"P < 22 × 10-16\". It should have been \"P < 2.2 × 10-16\". Also, the \"CD8+ Treg\" label in Fig. 4f was incorrect. It should have been \"CD4+ Treg\". The errors have been corrected in the HTML and PDF versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30082871", + "TEXT": "Translation of the CRISPR-Cas9 system to human therapeutics holds high promise. However, specificity remains a concern especially when modifying stem cell populations. We show that existing rationally engineered Cas9 high-fidelity variants have reduced on-target activity when using the therapeutically relevant ribonucleoprotein (RNP) delivery method. Therefore, we devised an unbiased bacterial screen to isolate variants that retain activity in the RNP format. Introduction of a single point mutation, p.R691A, in Cas9 (high-fidelity (HiFi) Cas9) retained the high on-target activity of Cas9 while reducing off-target editing. HiFi Cas9 induces robust AAV6-mediated gene targeting at five therapeutically relevant loci (HBB, IL2RG, CCR5, HEXB, and TRAC) in human CD34+ hematopoietic stem and progenitor cells (HSPCs) as well as primary T cells. We also show that HiFi Cas9 mediates high-level correction of the sickle cell disease (SCD)-causing p.E6V mutation in HSPCs derived from patients with SCD. We anticipate that HiFi Cas9 will have wide utility for both basic science and therapeutic genome-editing applications.", + "TAG_DATA": [ + "61, Introduction {'perturbing_action': 'B-other'}", + "62, of {'perturbing_action': 'I-other'}", + "63, a {'perturbing_action': 'I-other'}", + "64, single {'perturbing_action': 'I-other'}", + "65, point {'perturbing_action': 'I-other'}", + "66, mutation, {'perturbing_action': 'I-other'}", + "67, p.R691A, {'perturbing_action': 'I-other'}", + "68, in {'perturbing_action': 'I-other'}", + "69, Cas9 {'perturbing_action': 'I-other'}", + "70, (high-fidelity {'perturbing_action': 'I-other'}", + "103, human {'context': 'B-cells'}", + "104, CD34+ {'context': 'I-cells'}", + "105, hematopoietic {'context': 'I-cells'}", + "106, stem {'context': 'I-cells'}", + "107, and {'context': 'I-cells'}", + "108, progenitor {'context': 'I-cells'}", + "109, cells {'context': 'I-cells'}", + "110, (HSPCs) {'context': 'I-cells'}", + "114, primary {'context': 'B-cells'}", + "115, T {'context': 'I-cells'}", + "116, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "61, Introduction ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "62, of ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "63, a ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "64, single ['l2', 'l21', 'l39', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "65, point ['l3', 'l22', 'l40', 'l57', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "66, mutation, ['l4', 'l23', 'l41', 'l58', 'l74', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "67, p.R691A, ['l5', 'l24', 'l42', 'l59', 'l75', 'l90', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "68, in ['l6', 'l25', 'l43', 'l60', 'l76', 'l91', 'l105', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "69, Cas9 ['l7', 'l26', 'l44', 'l61', 'l77', 'l92', 'l106', 'l119', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "70, (high-fidelity ['l8', 'l27', 'l45', 'l62', 'l78', 'l93', 'l107', 'l120', 'l130', 'l139', 'l140']", + "103, human ['l9', 'l28', 'l46', 'l63', 'l79', 'l94', 'l108', 'l121', 'l131', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150']", + "104, CD34+ ['l10', 'l29', 'l47', 'l64', 'l80', 'l95', 'l109', 'l122', 'l132', 'l141', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159']", + "105, hematopoietic ['l11', 'l30', 'l48', 'l65', 'l81', 'l96', 'l110', 'l123', 'l133', 'l142', 'l151', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "106, stem ['l12', 'l31', 'l49', 'l66', 'l82', 'l97', 'l111', 'l124', 'l134', 'l143', 'l152', 'l160', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "107, and ['l13', 'l32', 'l50', 'l67', 'l83', 'l98', 'l112', 'l125', 'l135', 'l144', 'l153', 'l161', 'l168', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180']", + "108, progenitor ['l14', 'l33', 'l51', 'l68', 'l84', 'l99', 'l113', 'l126', 'l136', 'l145', 'l154', 'l162', 'l169', 'l175', 'l181', 'l182', 'l183', 'l184', 'l185']", + "109, cells ['l15', 'l34', 'l52', 'l69', 'l85', 'l100', 'l114', 'l127', 'l137', 'l139', 'l146', 'l155', 'l163', 'l170', 'l176', 'l181', 'l186', 'l187', 'l188', 'l189']", + "110, (HSPCs) ['l16', 'l35', 'l53', 'l70', 'l86', 'l101', 'l115', 'l128', 'l138', 'l140', 'l147', 'l156', 'l164', 'l171', 'l177', 'l182', 'l186', 'l190', 'l191', 'l192']", + "114, primary ['l17', 'l36', 'l54', 'l71', 'l87', 'l102', 'l116', 'l148', 'l157', 'l165', 'l172', 'l178', 'l183', 'l187', 'l190', 'l193', 'l194']", + "115, T ['l18', 'l37', 'l55', 'l72', 'l88', 'l103', 'l117', 'l149', 'l158', 'l166', 'l173', 'l179', 'l184', 'l188', 'l191', 'l193', 'l195']", + "116, cells. ['l19', 'l38', 'l56', 'l73', 'l89', 'l104', 'l118', 'l129', 'l150', 'l159', 'l167', 'l174', 'l180', 'l185', 'l189', 'l192', 'l194', 'l195']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Introduction", + "of", + "a", + "single", + "point", + "mutation,", + "p.R691A,", + "in", + "Cas9", + "(high-fidelity" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "CD34+", + "hematopoietic", + "stem", + "and", + "progenitor", + "cells", + "(HSPCs)", + "primary", + "T", + "cells." + ] + } + } + ] + }, + { + "PMID": "30082860", + "TEXT": "Intratumoral infusion of a nonpathogenic replication-competent recombinant polio-rhinovirus chimera for recurrent glioblastoma demonstrates safety and promising preliminary treatment responses.", + "TAG_DATA": [ + "10, recurrent {'context': 'B-neoplasm'}", + "11, glioblastoma {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "10, recurrent ['l0']", + "11, glioblastoma ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30038219", + "TEXT": "Metformin, the universal first-line treatment for type 2 diabetes, exerts its therapeutic glucose-lowering effects by inhibiting hepatic gluconeogenesis. However, the primary molecular mechanism of this biguanide remains unclear, though it has been suggested to act, at least partially, by mitochondrial complex I inhibition. Here we show that clinically relevant concentrations of plasma metformin achieved by acute intravenous, acute intraportal or chronic oral administration in awake normal and diabetic rats inhibit gluconeogenesis from lactate and glycerol but not from pyruvate and alanine, implicating an increased cytosolic redox state in mediating metformin's antihyperglycemic effect. All of these effects occurred independently of complex I inhibition, evidenced by unaltered hepatic energy charge and citrate synthase flux. Normalizing the cytosolic redox state by infusion of methylene blue or substrates that contribute to gluconeogenesis independently of the cytosolic redox state abrogated metformin-mediated inhibition of gluconeogenesis in vivo. Additionally, in mice expressing constitutively active acetyl-CoA carboxylase, metformin acutely decreased hepatic glucose production and increased the hepatic cytosolic redox state without altering hepatic triglyceride content or gluconeogenic enzyme expression. These studies demonstrate that metformin, at clinically relevant plasma concentrations, inhibits hepatic gluconeogenesis in a redox-dependent manner independently of reductions in citrate synthase flux, hepatic nucleotide concentrations, acetyl-CoA carboxylase activity, or gluconeogenic enzyme protein expression.", + "TAG_DATA": [ + "67, diabetic {'context': 'B-organism'}", + "68, rats {'context': 'I-organism'}", + "139, in {'context': 'B-in vivo'}", + "140, vivo. {'context': 'I-in vivo'}", + "143, mice {'context': 'B-organism'}", + "144, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "145, constitutively {'perturbing_action': 'I-gene gain-of-function'}", + "146, active {'perturbing_action': 'I-gene gain-of-function'}", + "147, acetyl-CoA {'perturbing_action': 'I-gene gain-of-function'}", + "148, carboxylase, {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "65, normal ['l0', 'l1']", + "67, diabetic ['l0', 'l2']", + "68, rats ['l1', 'l2']", + "139, in ['l3']", + "140, vivo. ['l3']", + "143, mice ['l4', 'l5', 'l6', 'l7', 'l8']", + "144, expressing ['l4', 'l9', 'l10', 'l11', 'l12']", + "145, constitutively ['l5', 'l9', 'l13', 'l14', 'l15']", + "146, active ['l6', 'l10', 'l13', 'l16', 'l17']", + "147, acetyl-CoA ['l7', 'l11', 'l14', 'l16', 'l18']", + "148, carboxylase, ['l8', 'l12', 'l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "constitutively", + "active", + "acetyl-CoA", + "carboxylase," + ] + } + } + ] + }, + { + "PMID": "30038217", + "TEXT": "Plasmodium vivax causes approximately 100 million clinical malaria cases yearly1,2. The basis of protective immunity is poorly understood and thought to be mediated by antibodies3,4. Cytotoxic CD8+ T cells protect against other intracellular parasites by detecting parasite peptides presented by human leukocyte antigen class I on host cells. Cytotoxic CD8+ T cells kill parasite-infected mammalian cells and intracellular parasites by releasing their cytotoxic granules5,6. Perforin delivers the antimicrobial peptide granulysin and death-inducing granzymes into the host cell, and granulysin then delivers granzymes into the parasite. Cytotoxic CD8+ T cells were thought to have no role against Plasmodium spp. blood stages because red blood cells generally do not express human leukocyte antigen class I7. However, P. vivax infects reticulocytes that retain the protein translation machinery. Here we show that P. vivax-infected reticulocytes express human leukocyte antigen class I. Infected patient circulating CD8+ T cells highly express cytotoxic proteins and recognize and form immunological synapses with P. vivax-infected reticulocytes in a human leukocyte antigen-dependent manner, releasing their cytotoxic granules to kill both host cell and intracellular parasite, preventing reinvasion. P. vivax-infected reticulocytes and parasite killing is perforin independent, but depends on granulysin, which generally efficiently forms pores only in microbial membranes8. We find that P. vivax depletes cholesterol from the P. vivax-infected reticulocyte cell membrane, rendering it granulysin-susceptible. This unexpected T cell defense might be mobilized to improve P. vivax vaccine efficacy.", + "TAG_DATA": [ + "130, reticulocytes {'context': 'B-cells'}", + "138, patient {'context': 'B-cells'}", + "139, circulating {'context': 'I-cells'}", + "140, CD8+ {'context': 'I-cells'}", + "141, T {'context': 'I-cells'}", + "142, cells {'context': 'I-cells'}", + "156, reticulocytes {'context': 'B-cells'}", + "179, reticulocytes {'context': 'B-cells'}", + "181, parasite {'context': 'B-organism'}", + "210, reticulocyte {'context': 'B-cells'}", + "211, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "130, reticulocytes ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "138, patient ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "139, circulating ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "140, CD8+ ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "141, T ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "142, cells ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "156, reticulocytes ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "181, parasite ['l21', 'l22']", + "210, reticulocyte ['l21', 'l23']", + "211, cell ['l22', 'l23']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30013198", + "TEXT": "Mutations in the gene encoding isocitrate dehydrogenase 2 (IDH2) occur in several types of cancer, including acute myeloid leukemia (AML). In model systems, mutant IDH2 causes hematopoietic differentiation arrest. Enasidenib, a selective small-molecule inhibitor of mutant IDH2, produces a clinical response in 40% of treated patients with relapsed/refractory AML by promoting leukemic cell differentiation. Here, we studied the clonal basis of response and acquired resistance to enasidenib treatment. Using sequential patient samples, we determined the clonal structure of hematopoietic cell populations at different stages of differentiation. Before therapy, IDH2-mutant clones showed variable differentiation arrest. Enasidenib treatment promoted hematopoietic differentiation from either terminal or ancestral mutant clones; less frequently, treatment promoted differentiation of nonmutant cells. Analysis of paired diagnosis/relapse samples did not identify second-site mutations in IDH2 at relapse. Instead, relapse arose by clonal evolution or selection of terminal or ancestral clones, thus highlighting multiple bypass pathways that could potentially be targeted to restore differentiation arrest. These results show how mapping of clonal structure in cell populations at different stages of differentiation can reveal the response and evolution of clones during treatment response and relapse.", + "TAG_DATA": [ + "88, IDH2-mutant {'perturbing_action': 'B-other'}", + "92, differentiation {'phenotype': 'B-differentiation'}", + "93, arrest. {'effect': 'B-positive', 'phenotype': 'I-senescence'}", + "96, promoted {'effect': 'B-positive'}", + "97, hematopoietic {'phenotype': 'B-differentiation'}", + "98, differentiation {'phenotype': 'I-differentiation'}", + "109, promoted {'effect': 'B-positive'}", + "110, differentiation {'phenotype': 'B-differentiation'}", + "112, nonmutant {'context': 'B-cells'}", + "113, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "88, IDH2-mutant ['l0', 'l1']", + "92, differentiation ['l0', 'l2']", + "93, arrest. ['l1', 'l2']", + "96, promoted ['l3', 'l4']", + "97, hematopoietic ['l3', 'l5']", + "98, differentiation ['l4', 'l5']", + "109, promoted ['l6', 'l7', 'l8']", + "110, differentiation ['l6', 'l9', 'l10']", + "112, nonmutant ['l7', 'l9', 'l11']", + "113, cells. ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "IDH2-mutant" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "IDH2-mutant" + ] + }, + "effect": { + "val": "positive", + "words": [ + "arrest." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "IDH2-mutant" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "arrest." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "arrest." + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "arrest." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "hematopoietic" + ] + }, + "effect": { + "val": "positive", + "words": [ + "arrest.", + "promoted" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "cells", + "words": [ + "nonmutant", + "cells." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "nonmutant", + "cells." + ] + } + } + ] + }, + { + "PMID": "29967352", + "TEXT": "The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments.", + "TAG_DATA": [ + "61, vitro {'context': 'I-in vitro'}", + "63, in {'context': 'B-in vivo'}", + "64, vivo. {'context': 'I-in vivo'}", + "123, confer {'effect': 'B-positive'}", + "124, increased {'effect': 'B-positive'}", + "125, invasion {'phenotype': 'B-invasion'}", + "127, migration {'phenotype': 'B-migration'}", + "130, cells, {'context': 'B-cells'}", + "131, in {'context': 'B-in vitro'}", + "132, vitro {'context': 'I-in vitro'}", + "134, in {'context': 'B-in vivo'}", + "135, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "61, vitro ['l0', 'l1']", + "63, in ['l0', 'l2']", + "64, vivo. ['l1', 'l2']", + "123, confer ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "124, increased ['l3', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "125, invasion ['l4', 'l11', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "127, migration ['l5', 'l12', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "130, cells, ['l6', 'l13', 'l18', 'l23', 'l28', 'l29']", + "131, in ['l7', 'l14', 'l19', 'l24', 'l28', 'l30', 'l31']", + "132, vitro ['l8', 'l15', 'l20', 'l25', 'l29', 'l30', 'l32']", + "134, in ['l9', 'l21', 'l26', 'l33']", + "135, vivo, ['l10', 'l16', 'l22', 'l27', 'l31', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "confer", + "increased" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "confer", + "increased" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "confer", + "increased" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "confer", + "increased" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "confer", + "increased" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells," + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells," + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + } + ] + }, + { + "PMID": "29967349", + "TEXT": "Small-molecule inhibitors of the serine dipeptidases DPP8 and DPP9 (DPP8/9) induce a lytic form of cell death called pyroptosis in mouse and human monocytes and macrophages1,2. In mouse myeloid cells, Dpp8/9 inhibition activates the inflammasome sensor Nlrp1b, which in turn activates pro-caspase-1 to mediate cell death3, but the mechanism of DPP8/9 inhibitor-induced pyroptosis in human myeloid cells is not yet known. Here we show that the CARD-containing protein CARD8 mediates DPP8/9 inhibitor-induced pro-caspase-1-dependent pyroptosis in human myeloid cells. We further show that DPP8/9 inhibitors induce pyroptosis in the majority of human acute myeloid leukemia (AML) cell lines and primary AML samples, but not in cells from many other lineages, and that these inhibitors inhibit human AML progression in mouse models. Overall, this work identifies an activator of CARD8 in human cells and indicates that its activation by small-molecule DPP8/9 inhibitors represents a new potential therapeutic strategy for AML.", + "TAG_DATA": [ + "69, mediates {'effect': 'B-regulates'}", + "71, inhibitor-induced {'perturbing_action': 'I-pharmacological inhibition', 'effect': 'B-positive'}", + "73, pyroptosis {'phenotype': 'B-pyroptosis'}", + "75, human {'context': 'B-cells'}", + "76, myeloid {'context': 'I-cells'}", + "77, cells. {'context': 'I-cells'}", + "82, DPP8/9 {'perturbing_action': 'B-pharmacological inhibition'}", + "83, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "84, induce {'effect': 'B-positive'}", + "85, pyroptosis {'phenotype': 'B-pyroptosis'}", + "90, human {'context': 'B-transformed cells'}", + "91, acute {'context': 'I-transformed cells'}", + "92, myeloid {'context': 'I-transformed cells'}", + "93, leukemia {'context': 'I-transformed cells'}", + "94, (AML) {'context': 'I-transformed cells'}", + "95, cell {'context': 'I-transformed cells'}", + "96, lines {'context': 'I-transformed cells'}", + "98, primary {'context': 'B-transformed cells'}", + "99, AML {'context': 'I-transformed cells'}", + "100, samples, {'context': 'I-transformed cells'}", + "104, cells {'context': 'B-cells'}", + "105, from {'context': 'I-cells'}", + "108, lineages, {'context': 'I-cells'}", + "114, human {'context': 'B-neoplasm'}", + "115, AML {'context': 'I-neoplasm'}", + "118, mouse {'context': 'B-organism'}", + "119, models. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "69, mediates ['l0', 'l1', 'l2', 'l3', 'l4']", + "71, inhibitor-induced ['l0', 'l5', 'l6', 'l7', 'l8']", + "73, pyroptosis ['l1', 'l5', 'l9', 'l10', 'l11']", + "75, human ['l2', 'l6', 'l9', 'l12', 'l13']", + "76, myeloid ['l3', 'l7', 'l10', 'l12', 'l14']", + "77, cells. ['l4', 'l8', 'l11', 'l13', 'l14']", + "82, DPP8/9 ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "83, inhibitors ['l15', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "84, induce ['l16', 'l31', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "85, pyroptosis ['l17', 'l32', 'l46', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "90, human ['l18', 'l33', 'l47', 'l59', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "91, acute ['l19', 'l34', 'l48', 'l60', 'l72', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "92, myeloid ['l20', 'l35', 'l49', 'l61', 'l73', 'l84', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "93, leukemia ['l21', 'l36', 'l50', 'l62', 'l74', 'l85', 'l95', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "94, (AML) ['l22', 'l37', 'l51', 'l63', 'l75', 'l86', 'l96', 'l105', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "95, cell ['l23', 'l38', 'l52', 'l64', 'l76', 'l87', 'l97', 'l106', 'l114', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127']", + "96, lines ['l24', 'l39', 'l53', 'l65', 'l77', 'l88', 'l98', 'l107', 'l115', 'l122', 'l128', 'l129', 'l130', 'l131']", + "98, primary ['l25', 'l40', 'l54', 'l66', 'l78', 'l89', 'l99', 'l108', 'l116', 'l123', 'l128', 'l132', 'l133', 'l134', 'l135', 'l136']", + "99, AML ['l26', 'l41', 'l55', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l124', 'l129', 'l132', 'l137', 'l138', 'l139', 'l140']", + "100, samples, ['l27', 'l42', 'l56', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l125', 'l130', 'l133', 'l137', 'l141', 'l142', 'l143']", + "104, cells ['l28', 'l43', 'l57', 'l69', 'l81', 'l92', 'l102', 'l111', 'l119', 'l126', 'l131', 'l134', 'l138', 'l141', 'l144', 'l145']", + "105, from ['l29', 'l44', 'l58', 'l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l127', 'l135', 'l139', 'l142', 'l144', 'l146']", + "108, lineages, ['l30', 'l45', 'l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l136', 'l140', 'l143', 'l145', 'l146']", + "114, human ['l147', 'l148', 'l149']", + "115, AML ['l147', 'l150', 'l151']", + "118, mouse ['l148', 'l150', 'l152']", + "119, models. ['l149', 'l151', 'l152']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "regulates", + "words": [ + "mediates" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitor-induced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitor-induced", + "DPP8/9", + "inhibitors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inhibitor-induced", + "induce" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "mediates" + ] + }, + "phenotype": { + "val": "pyroptosis", + "words": [ + "pyroptosis" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "mediates" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "myeloid", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitor-induced", + "DPP8/9", + "inhibitors" + ] + }, + "phenotype": { + "val": "pyroptosis", + "words": [ + "pyroptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inhibitor-induced", + "induce" + ] + }, + "phenotype": { + "val": "pyroptosis", + "words": [ + "pyroptosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitor-induced", + "DPP8/9", + "inhibitors" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "myeloid", + "cells.", + "cells", + "from", + "lineages," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inhibitor-induced", + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "myeloid", + "cells.", + "cells", + "from" + ] + } + }, + { + "phenotype": { + "val": "pyroptosis", + "words": [ + "pyroptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "myeloid", + "cells.", + "cells", + "from", + "lineages," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "DPP8/9", + "inhibitors" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "acute", + "myeloid", + "leukemia", + "(AML)", + "cell", + "lines", + "primary", + "AML", + "samples," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "acute", + "myeloid", + "leukemia", + "(AML)", + "cell", + "lines", + "primary", + "AML", + "samples," + ] + } + }, + { + "phenotype": { + "val": "pyroptosis", + "words": [ + "pyroptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "acute", + "myeloid", + "leukemia", + "(AML)", + "cell", + "lines", + "primary", + "AML", + "samples," + ] + } + } + ] + }, + { + "PMID": "29942096", + "TEXT": "Hepatic steatosis is a multifactorial condition that is often observed in obese patients and is a prelude to non-alcoholic fatty liver disease. Here, we combine shotgun sequencing of fecal metagenomes with molecular phenomics (hepatic transcriptome and plasma and urine metabolomes) in two well-characterized cohorts of morbidly obese women recruited to the FLORINASH study. We reveal molecular networks linking the gut microbiome and the host phenome to hepatic steatosis. Patients with steatosis have low microbial gene richness and increased genetic potential for the processing of dietary lipids and endotoxin biosynthesis (notably from Proteobacteria), hepatic inflammation and dysregulation of aromatic and branched-chain amino acid metabolism. We demonstrated that fecal microbiota transplants and chronic treatment with phenylacetic acid, a microbial product of aromatic amino acid metabolism, successfully trigger steatosis and branched-chain amino acid metabolism. Molecular phenomic signatures were predictive (area under the curve = 87%) and consistent with the gut microbiome having an effect on the steatosis phenome (>75% shared variation) and, therefore, actionable via microbiome-based therapies.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "29942092", + "TEXT": "The quantity of tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) is a robust prognostic factor for improved patient survival, particularly in triple-negative and HER2-overexpressing BC subtypes1. Although T cells are the predominant TIL population2, the relationship between quantitative and qualitative differences in T cell subpopulations and patient prognosis remains unknown. We performed single-cell RNA sequencing (scRNA-seq) of 6,311 T cells isolated from human BCs and show that significant heterogeneity exists in the infiltrating T cell population. We demonstrate that BCs with a high number of TILs contained CD8+ T cells with features of tissue-resident memory T (TRM) cell differentiation and that these CD8+ TRM cells expressed high levels of immune checkpoint molecules and effector proteins. A CD8+ TRM gene signature developed from the scRNA-seq data was significantly associated with improved patient survival in early-stage triple-negative breast cancer (TNBC) and provided better prognostication than CD8 expression alone. Our data suggest that CD8+ TRM cells contribute to BC immunosurveillance and are the key targets of modulation by immune checkpoint inhibition. Further understanding of the development, maintenance and regulation of TRM cells will be crucial for successful immunotherapeutic development in BC.", + "TAG_DATA": [ + "86, CD8+ {'context': 'B-cells'}", + "87, T {'context': 'I-cells'}", + "88, cells {'context': 'I-cells'}", + "94, T {'context': 'I-cells'}", + "101, CD8+ {'context': 'B-cells'}", + "102, TRM {'context': 'I-cells'}", + "103, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "86, CD8+ ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "87, T ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "88, cells ['l1', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "93, memory ['l2', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "94, T ['l3', 'l10', 'l15', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "95, (TRM) ['l4', 'l11', 'l16', 'l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "96, cell ['l5', 'l12', 'l17', 'l21', 'l26', 'l30', 'l34']", + "101, CD8+ ['l22', 'l27', 'l31', 'l35', 'l36']", + "102, TRM ['l6', 'l23', 'l28', 'l32', 'l35', 'l37']", + "103, cells ['l7', 'l13', 'l18', 'l24', 'l29', 'l33', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29892070", + "TEXT": "Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors.", + "TAG_DATA": [ + "76, inhibited {'effect': 'B-negative'}", + "77, proliferation {'phenotype': 'B-proliferation'}", + "79, induced {'effect': 'B-positive'}", + "80, apoptosis {'phenotype': 'B-apoptosis'}", + "82, models {'context': 'B-neoplasm'}", + "83, of {'context': 'I-neoplasm'}", + "84, brain {'context': 'I-neoplasm'}", + "85, cancer {'context': 'I-neoplasm'}", + "87, acute {'context': 'B-neoplasm'}", + "88, myeloid {'context': 'I-neoplasm'}", + "89, leukemia {'context': 'I-neoplasm'}", + "90, (AML) {'context': 'I-neoplasm'}", + "113, models {'context': 'B-neoplasm'}", + "114, of {'context': 'I-neoplasm'}", + "115, brain {'context': 'I-neoplasm'}", + "116, cancer {'context': 'I-neoplasm'}", + "118, AML, {'context': 'I-neoplasm'}", + "119, tumor {'phenotype': 'B-tumour growth'}", + "120, growth {'phenotype': 'I-tumour growth'}", + "123, inhibited {'effect': 'B-negative'}", + "124, in {'context': 'B-in vivo'}", + "125, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "76, inhibited ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "77, proliferation ['l0', 'l7', 'l8', 'l9', 'l10']", + "79, induced ['l1', 'l7', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "80, apoptosis ['l2', 'l11', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "82, models ['l3', 'l12', 'l20', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "83, of ['l4', 'l8', 'l13', 'l21', 'l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "84, brain ['l5', 'l9', 'l14', 'l22', 'l29', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "85, cancer ['l6', 'l10', 'l15', 'l23', 'l30', 'l36', 'l41', 'l46', 'l47', 'l48', 'l49']", + "87, acute ['l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l50', 'l51', 'l52']", + "88, myeloid ['l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "89, leukemia ['l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l59', 'l60', 'l61', 'l62', 'l63']", + "90, (AML) ['l19', 'l27', 'l34', 'l40', 'l45', 'l49', 'l52', 'l54', 'l59', 'l64']", + "113, models ['l65', 'l66', 'l67', 'l68', 'l69']", + "114, of ['l55', 'l60', 'l65', 'l70', 'l71', 'l72']", + "115, brain ['l56', 'l61', 'l66', 'l70', 'l73', 'l74']", + "116, cancer ['l57', 'l62', 'l64', 'l67', 'l71', 'l73', 'l75']", + "118, AML, ['l58', 'l63', 'l68', 'l72', 'l74', 'l75']", + "119, tumor ['l76', 'l77', 'l78', 'l79']", + "120, growth ['l69', 'l76', 'l80', 'l81', 'l82']", + "123, inhibited ['l77', 'l80', 'l83', 'l84']", + "124, in ['l78', 'l81', 'l83', 'l85']", + "125, vivo ['l79', 'l82', 'l84', 'l85']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models", + "of", + "brain", + "cancer" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "of", + "brain", + "cancer" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models", + "of", + "brain", + "cancer", + "acute", + "myeloid", + "leukemia", + "(AML)" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models", + "of", + "brain", + "cancer", + "acute", + "myeloid", + "leukemia", + "(AML)" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "models" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "29892066", + "TEXT": "Activation of microglia by classical inflammatory mediators can convert astrocytes into a neurotoxic A1 phenotype in a variety of neurological diseases1,2. Development of agents that could inhibit the formation of A1 reactive astrocytes could be used to treat these diseases for which there are no disease-modifying therapies. Glucagon-like peptide-1 receptor (GLP1R) agonists have been indicated as potential neuroprotective agents for neurologic disorders such as Alzheimer's disease and Parkinson's disease3-13. The mechanisms by which GLP1R agonists are neuroprotective are not known. Here we show that a potent, brain-penetrant long-acting GLP1R agonist, NLY01, protects against the loss of dopaminergic neurons and behavioral deficits in the α-synuclein preformed fibril (α-syn PFF) mouse model of sporadic Parkinson's disease14,15. NLY01 also prolongs the life and reduces the behavioral deficits and neuropathological abnormalities in the human A53T α-synuclein (hA53T) transgenic mouse model of α-synucleinopathy-induced neurodegeneration16. We found that NLY01 is a potent GLP1R agonist with favorable properties that is neuroprotective through the direct prevention of microglial-mediated conversion of astrocytes to an A1 neurotoxic phenotype. In light of its favorable properties, NLY01 should be evaluated in the treatment of Parkinson's disease and related neurologic disorders characterized by microglial activation.", + "TAG_DATA": [ + "96, dopaminergic {'context': 'B-cells'}", + "97, neurons {'context': 'I-cells'}", + "108, mouse {'context': 'B-organism'}", + "109, model {'context': 'I-organism'}", + "129, human {'perturbing_action': 'B-gene gain-of-function'}", + "130, A53T {'perturbing_action': 'I-gene gain-of-function'}", + "131, α-synuclein {'perturbing_action': 'I-gene gain-of-function'}", + "132, (hA53T) {'perturbing_action': 'I-gene gain-of-function'}", + "133, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "134, mouse {'context': 'B-organism'}", + "135, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "96, dopaminergic ['l0', 'l1', 'l2']", + "97, neurons ['l0', 'l3']", + "108, mouse ['l1', 'l4']", + "109, model ['l2', 'l3', 'l4']", + "129, human ['l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "130, A53T ['l5', 'l11', 'l12', 'l13', 'l14', 'l15']", + "131, α-synuclein ['l6', 'l11', 'l16', 'l17', 'l18', 'l19']", + "132, (hA53T) ['l7', 'l12', 'l16', 'l20', 'l21', 'l22']", + "133, transgenic ['l8', 'l13', 'l17', 'l20', 'l23', 'l24']", + "134, mouse ['l9', 'l14', 'l18', 'l21', 'l23', 'l25']", + "135, model ['l10', 'l15', 'l19', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "human", + "A53T", + "α-synuclein", + "(hA53T)", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + } + ] + }, + { + "PMID": "29892065", + "TEXT": "Evidence from mouse chronic viral infection models suggests that CD8+ T cell subsets characterized by distinct expression levels of the receptor PD-1 diverge in their state of exhaustion and potential for reinvigoration by PD-1 blockade. However, it remains unknown whether T cells in human cancer adopt a similar spectrum of exhausted states based on PD-1 expression levels. We compared transcriptional, metabolic and functional signatures of intratumoral CD8+ T lymphocyte populations with high (PD-1T), intermediate (PD-1N) and no PD-1 expression (PD-1-) from non-small-cell lung cancer patients. PD-1T T cells showed a markedly different transcriptional and metabolic profile from PD-1N and PD-1- lymphocytes, as well as an intrinsically high capacity for tumor recognition. Furthermore, while PD-1T lymphocytes were impaired in classical effector cytokine production, they produced CXCL13, which mediates immune cell recruitment to tertiary lymphoid structures. Strikingly, the presence of PD-1T cells was strongly predictive for both response and survival in a small cohort of non-small-cell lung cancer patients treated with PD-1 blockade. The characterization of a distinct state of tumor-reactive, PD-1-bright lymphocytes in human cancer, which only partially resembles that seen in chronic infection, provides potential avenues for therapeutic intervention.", + "TAG_DATA": [ + "86, T {'context': 'B-cells'}", + "87, cells {'context': 'I-cells'}", + "114, lymphocytes {'context': 'B-cells'}", + "153, non-small-cell {'context': 'B-transformed cells'}", + "154, lung {'context': 'I-patient'}", + "155, cancer {'context': 'I-patient'}", + "156, patients {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "86, T ['l0']", + "87, cells ['l0']", + "153, non-small-cell ['l1', 'l2', 'l3']", + "154, lung ['l1', 'l4', 'l5']", + "155, cancer ['l2', 'l4', 'l6']", + "156, patients ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29892063", + "TEXT": "Antiretroviral therapy during the earliest stage of acute HIV infection (Fiebig I) might minimize establishment of a latent HIV reservoir and thereby facilitate viremic control after analytical treatment interruption. We show that 8 participants, who initiated treatment during Fiebig I and were treated for a median of 2.8 years, all experienced rapid viral load rebound following analytical treatment interruption, indicating that additional strategies are required to control or eradicate HIV.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "29892062", + "TEXT": "CRISPR/Cas9 has revolutionized our ability to engineer genomes and conduct genome-wide screens in human cells1-3. Whereas some cell types are amenable to genome engineering, genomes of human pluripotent stem cells (hPSCs) have been difficult to engineer, with reduced efficiencies relative to tumour cell lines or mouse embryonic stem cells3-13. Here, using hPSC lines with stable integration of Cas9 or transient delivery of Cas9-ribonucleoproteins (RNPs), we achieved an average insertion or deletion (indel) efficiency greater than 80%. This high efficiency of indel generation revealed that double-strand breaks (DSBs) induced by Cas9 are toxic and kill most hPSCs. In previous studies, the toxicity of Cas9 in hPSCs was less apparent because of low transfection efficiency and subsequently low DSB induction3. The toxic response to DSBs was P53/TP53-dependent, such that the efficiency of precise genome engineering in hPSCs with a wild-type P53 gene was severely reduced. Our results indicate that Cas9 toxicity creates an obstacle to the high-throughput use of CRISPR/Cas9 for genome engineering and screening in hPSCs. Moreover, as hPSCs can acquire P53 mutations14, cell replacement therapies using CRISPR/Cas9-enginereed hPSCs should proceed with caution, and such engineered hPSCs should be monitored for P53 function.", + "TAG_DATA": [ + "51, hPSC {'context': 'B-cells'}", + "52, lines {'context': 'I-cells'}", + "95, hPSCs. {'context': 'B-cells'}", + "104, hPSCs {'context': 'B-cells'}", + "134, hPSCs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "51, hPSC ['l0', 'l1']", + "52, lines ['l0', 'l2']", + "95, hPSCs. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29892060", + "TEXT": "It has long been assumed that p53 suppresses tumor development through induction of apoptosis, possibly with contributions by cell cycle arrest and cell senescence1,2. However, combined deficiency in these three processes does not result in spontaneous tumor formation as observed upon loss of p53, suggesting the existence of additional mechanisms that are critical mediators of p53-dependent tumor suppression function3-5. To define such mechanisms, we performed in vivo shRNA screens targeting p53-regulated genes in sensitized genetic backgrounds. We found that knockdown of Zmat3, Ctsf and Cav1, promoted lymphoma/leukemia development only when PUMA and p21, the critical effectors of p53-driven apoptosis, cell cycle arrest and senescence, were also absent. Notably, loss of the DNA repair gene Mlh1 caused lymphoma in a wild-type background, and its enforced expression was able to delay tumor development driven by loss of p53. Further examination of direct p53 target genes implicated in DNA repair showed that knockdown of Mlh1, Msh2, Rnf144b, Cav1 and Ddit4 accelerated MYC-driven lymphoma development to a similar extent as knockdown of p53. Collectively, these findings demonstrate that extensive functional overlap of several p53-regulated processes safeguards against cancer and that coordination of DNA repair appears to be an important process by which p53 suppresses tumor development.", + "TAG_DATA": [ + "65, in {'context': 'B-in vivo'}", + "66, vivo {'context': 'B-in vivo'}", + "79, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "80, of {'perturbing_action': 'I-rnai/knockdown'}", + "81, Zmat3, {'perturbing_action': 'I-rnai/knockdown'}", + "82, Ctsf {'perturbing_action': 'I-rnai/knockdown'}", + "83, and {'perturbing_action': 'I-rnai/knockdown'}", + "84, Cav1, {'perturbing_action': 'I-rnai/knockdown'}", + "85, promoted {'effect': 'B-positive'}", + "86, lymphoma/leukemia {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}", + "98, apoptosis, {'phenotype': 'B-apoptosis'}", + "99, cell {'phenotype': 'B-cell cycle arrest'}", + "100, cycle {'phenotype': 'I-cell cycle arrest'}", + "101, arrest {'phenotype': 'I-cell cycle arrest'}", + "103, senescence, {'phenotype': 'B-senescence'}", + "108, loss {'perturbing_action': 'B-gene loss-of-function'}", + "109, of {'perturbing_action': 'I-gene loss-of-function'}", + "110, the {'perturbing_action': 'I-gene loss-of-function'}", + "111, DNA {'perturbing_action': 'I-gene loss-of-function'}", + "112, repair {'perturbing_action': 'I-gene loss-of-function'}", + "113, gene {'perturbing_action': 'I-gene loss-of-function'}", + "114, Mlh1 {'perturbing_action': 'I-gene loss-of-function'}", + "115, caused {'effect': 'B-positive'}", + "116, lymphoma {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}", + "128, delay {'effect': 'B-negative'}", + "129, tumor {'phenotype': 'B-tumourigenesis'}", + "130, development {'phenotype': 'I-tumourigenesis'}", + "133, loss {'perturbing_action': 'B-gene loss-of-function'}", + "134, of {'perturbing_action': 'I-gene loss-of-function'}", + "135, p53. {'perturbing_action': 'I-gene loss-of-function'}", + "149, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "150, of {'perturbing_action': 'I-rnai/knockdown'}", + "151, Mlh1, {'perturbing_action': 'I-rnai/knockdown'}", + "152, Msh2, {'perturbing_action': 'I-rnai/knockdown'}", + "153, Rnf144b, {'perturbing_action': 'I-rnai/knockdown'}", + "154, Cav1 {'perturbing_action': 'I-rnai/knockdown'}", + "155, and {'perturbing_action': 'I-rnai/knockdown'}", + "156, Ddit4 {'perturbing_action': 'I-rnai/knockdown'}", + "157, accelerated {'effect': 'B-positive'}", + "159, lymphoma {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}", + "166, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "167, of {'perturbing_action': 'I-rnai/knockdown'}", + "168, p53. {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "65, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "66, vivo ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "79, knockdown ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "80, of ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "81, Zmat3, ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "82, Ctsf ['l4', 'l17', 'l29', 'l40', 'l50', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "83, and ['l5', 'l18', 'l30', 'l41', 'l51', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "84, Cav1, ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "85, promoted ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "86, lymphoma/leukemia ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l90', 'l91', 'l92', 'l93', 'l94']", + "98, apoptosis, ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l95', 'l96', 'l97', 'l98']", + "99, cell ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l99', 'l100', 'l101']", + "100, cycle ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l102', 'l103']", + "101, arrest ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l104']", + "103, senescence, ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l104']", + "108, loss ['l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "109, of ['l105', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "110, the ['l106', 'l119', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "111, DNA ['l107', 'l120', 'l132', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "112, repair ['l108', 'l121', 'l133', 'l144', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164']", + "113, gene ['l109', 'l122', 'l134', 'l145', 'l155', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "114, Mlh1 ['l110', 'l123', 'l135', 'l146', 'l156', 'l165', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181']", + "115, caused ['l111', 'l124', 'l136', 'l147', 'l157', 'l166', 'l174', 'l182']", + "116, lymphoma ['l112', 'l125', 'l137', 'l148', 'l158', 'l167', 'l175', 'l182']", + "128, delay ['l113', 'l126', 'l138', 'l149', 'l159', 'l168', 'l176', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190']", + "129, tumor ['l114', 'l127', 'l139', 'l150', 'l160', 'l169', 'l177', 'l183', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196']", + "130, development ['l115', 'l128', 'l140', 'l151', 'l161', 'l170', 'l178', 'l184', 'l191', 'l197', 'l198', 'l199']", + "133, loss ['l116', 'l129', 'l141', 'l152', 'l162', 'l171', 'l179', 'l185', 'l192', 'l197', 'l200', 'l201']", + "134, of ['l117', 'l130', 'l142', 'l153', 'l163', 'l172', 'l180', 'l186', 'l193', 'l198', 'l200', 'l202']", + "135, p53. ['l118', 'l131', 'l143', 'l154', 'l164', 'l173', 'l181', 'l187', 'l194', 'l199', 'l201', 'l202']", + "149, knockdown ['l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214']", + "150, of ['l203', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225']", + "151, Mlh1, ['l204', 'l215', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235']", + "152, Msh2, ['l188', 'l195', 'l205', 'l216', 'l226', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244']", + "153, Rnf144b, ['l189', 'l196', 'l206', 'l217', 'l227', 'l236', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252']", + "154, Cav1 ['l190', 'l207', 'l218', 'l228', 'l237', 'l245', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259']", + "155, and ['l208', 'l219', 'l229', 'l238', 'l246', 'l253', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265']", + "156, Ddit4 ['l209', 'l220', 'l230', 'l239', 'l247', 'l254', 'l260', 'l266', 'l267', 'l268', 'l269', 'l270']", + "157, accelerated ['l210', 'l221', 'l231', 'l240', 'l248', 'l255', 'l261', 'l266', 'l271', 'l272', 'l273', 'l274']", + "159, lymphoma ['l211', 'l222', 'l232', 'l241', 'l249', 'l256', 'l262', 'l267', 'l271', 'l275', 'l276', 'l277']", + "166, knockdown ['l212', 'l223', 'l233', 'l242', 'l250', 'l257', 'l263', 'l268', 'l272', 'l275', 'l278', 'l279']", + "167, of ['l213', 'l224', 'l234', 'l243', 'l251', 'l258', 'l264', 'l269', 'l273', 'l276', 'l278', 'l280']", + "168, p53. ['l214', 'l225', 'l235', 'l244', 'l252', 'l259', 'l265', 'l270', 'l274', 'l277', 'l279', 'l280']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "Zmat3,", + "Ctsf", + "and", + "Cav1," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma/leukemia" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "lymphoma/leukemia", + "lymphoma" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma/leukemia", + "lymphoma" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "Zmat3,", + "Ctsf", + "and", + "Cav1,", + "Mlh1,", + "Msh2,", + "Rnf144b,", + "Cav1", + "Ddit4", + "p53." + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted", + "accelerated" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "Zmat3,", + "Ctsf", + "and", + "Cav1,", + "Mlh1,", + "Msh2,", + "Rnf144b,", + "Cav1", + "Ddit4", + "p53." + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lymphoma/leukemia", + "lymphoma" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "Zmat3,", + "Ctsf", + "and", + "Cav1,", + "Msh2,", + "Rnf144b,", + "Mlh1,", + "Cav1", + "Ddit4", + "p53." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma/leukemia", + "tumor", + "lymphoma" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "Zmat3,", + "Ctsf", + "and", + "Cav1," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "Zmat3,", + "Ctsf", + "and", + "Cav1," + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "Zmat3,", + "Ctsf", + "and", + "Cav1," + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted", + "caused", + "accelerated" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lymphoma/leukemia", + "lymphoma" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted", + "caused", + "accelerated" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma/leukemia", + "lymphoma" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "lymphoma/leukemia" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "lymphoma/leukemia" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "lymphoma/leukemia" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "DNA", + "repair", + "gene", + "Mlh1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "DNA", + "repair", + "gene", + "Mlh1" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lymphoma" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "DNA", + "repair", + "gene", + "Mlh1", + "p53." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma", + "tumor", + "development" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "DNA", + "repair", + "gene", + "Mlh1", + "p53." + ] + }, + "effect": { + "val": "negative", + "words": [ + "delay" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "delay" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "delay" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Msh2,", + "Rnf144b,", + "Cav1" + ] + } + } + ] + }, + { + "PMID": "29867235", + "TEXT": "A central goal of HIV-1 vaccine research is the elicitation of antibodies capable of neutralizing diverse primary isolates of HIV-1. Here we show that focusing the immune response to exposed N-terminal residues of the fusion peptide, a critical component of the viral entry machinery and the epitope of antibodies elicited by HIV-1 infection, through immunization with fusion peptide-coupled carriers and prefusion stabilized envelope trimers, induces cross-clade neutralizing responses. In mice, these immunogens elicited monoclonal antibodies capable of neutralizing up to 31% of a cross-clade panel of 208 HIV-1 strains. Crystal and cryoelectron microscopy structures of these antibodies revealed fusion peptide conformational diversity as a molecular explanation for the cross-clade neutralization. Immunization of guinea pigs and rhesus macaques induced similarly broad fusion peptide-directed neutralizing responses, suggesting translatability. The N terminus of the HIV-1 fusion peptide is thus a promising target of vaccine efforts aimed at eliciting broadly neutralizing antibodies.", + "TAG_DATA": [ + "69, mice, {'context': 'B-organism'}", + "112, guinea {'context': 'B-organism'}", + "113, pigs {'context': 'I-organism'}", + "115, rhesus {'context': 'B-organism'}", + "116, macaques {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "112, guinea ['l0', 'l1', 'l2']", + "113, pigs ['l0', 'l3', 'l4']", + "115, rhesus ['l1', 'l3', 'l5']", + "116, macaques ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29867232", + "TEXT": "Unsuppressed hepatic glucose production (HGP) contributes substantially to glucose intolerance and diabetes, which can be modeled by the genetic inactivation of hepatic insulin receptor substrate 1 (Irs1) and Irs2 (LDKO mice). We previously showed that glucose intolerance in LDKO mice is resolved by hepatic inactivation of the transcription factor FoxO1 (that is, LTKO mice)-even though the liver remains insensitive to insulin. Here, we report that insulin sensitivity in the white adipose tissue of LDKO mice is also impaired but is restored in LTKO mice in conjunction with normal suppression of HGP by insulin. To establish the mechanism by which white adipose tissue insulin signaling and HGP was regulated by hepatic FoxO1, we identified putative hepatokines-including excess follistatin (Fst)-that were dysregulated in LDKO mice but normalized in LTKO mice. Knockdown of hepatic Fst in the LDKO mouse liver restored glucose tolerance, white adipose tissue insulin signaling and the suppression of HGP by insulin; however, the expression of Fst in the liver of healthy LTKO mice had the opposite effect. Of potential clinical significance, knockdown of Fst also improved glucose tolerance in high-fat-fed obese mice, and the level of serum Fst was reduced in parallel with glycated hemoglobin in obese individuals with diabetes who underwent therapeutic gastric bypass surgery. We conclude that Fst is a pathological hepatokine that might be targeted for diabetes therapy during hepatic insulin resistance.", + "TAG_DATA": [ + "127, mice. {'context': 'B-organism'}", + "128, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "129, of {'perturbing_action': 'I-rnai/knockdown'}", + "130, hepatic {'perturbing_action': 'I-rnai/knockdown'}", + "131, Fst {'perturbing_action': 'I-rnai/knockdown'}", + "134, LDKO {'context': 'B-cells'}", + "135, mouse {'context': 'I-tissue/organ'}", + "136, liver {'context': 'I-tissue/organ'}", + "141, adipose {'context': 'I-tissue/organ'}", + "159, liver {'context': 'B-tissue/organ'}", + "163, mice {'context': 'I-organism'}", + "172, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "173, of {'perturbing_action': 'I-rnai/knockdown'}", + "174, Fst {'perturbing_action': 'I-rnai/knockdown'}", + "181, obese {'context': 'I-organism'}", + "182, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "127, mice. ['l0', 'l1', 'l2', 'l3']", + "128, Knockdown ['l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "129, of ['l4', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "130, hepatic ['l5', 'l12', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "131, Fst ['l6', 'l13', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "134, LDKO ['l0', 'l7', 'l14', 'l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "135, mouse ['l1', 'l8', 'l15', 'l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "136, liver ['l2', 'l9', 'l16', 'l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "141, adipose ['l10', 'l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "142, tissue ['l3', 'l11', 'l18', 'l24', 'l29', 'l33', 'l36', 'l38', 'l39']", + "159, liver ['l40', 'l41', 'l42', 'l43', 'l44']", + "163, mice ['l40', 'l45', 'l46', 'l47']", + "172, knockdown ['l48', 'l49', 'l50', 'l51', 'l52']", + "173, of ['l41', 'l48', 'l53', 'l54', 'l55', 'l56']", + "174, Fst ['l42', 'l45', 'l49', 'l53', 'l57', 'l58', 'l59']", + "181, obese ['l43', 'l46', 'l50', 'l54', 'l57', 'l60']", + "182, mice, ['l44', 'l47', 'l51', 'l55', 'l58', 'l60']", + "198, individuals ['l52', 'l56', 'l59']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "hepatic", + "Fst" + ] + }, + "context": { + "val": "cells", + "words": [ + "LDKO" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "hepatic", + "Fst" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "liver", + "adipose" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "obese", + "mice," + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Fst", + "knockdown", + "of" + ] + } + } + ] + }, + { + "PMID": "29867227", + "TEXT": "Immunotherapy using either checkpoint blockade or the adoptive transfer of antitumor lymphocytes has shown effectiveness in treating cancers with high levels of somatic mutations-such as melanoma, smoking-induced lung cancers and bladder cancer-with little effect in other common epithelial cancers that have lower mutation rates, such as those arising in the gastrointestinal tract, breast and ovary1-7. Adoptive transfer of autologous lymphocytes that specifically target proteins encoded by somatically mutated genes has mediated substantial objective clinical regressions in patients with metastatic bile duct, colon and cervical cancers8-11. We present a patient with chemorefractory hormone receptor (HR)-positive metastatic breast cancer who was treated with tumor-infiltrating lymphocytes (TILs) reactive against mutant versions of four proteins-SLC3A2, KIAA0368, CADPS2 and CTSB. Adoptive transfer of these mutant-protein-specific TILs in conjunction with interleukin (IL)-2 and checkpoint blockade mediated the complete durable regression of metastatic breast cancer, which is now ongoing for >22 months, and it represents a new immunotherapy approach for the treatment of these patients.", + "TAG_DATA": [ + "88, patient {'context': 'B-patient'}", + "91, hormone {'context': 'B-neoplasm'}", + "92, receptor {'context': 'I-neoplasm'}", + "93, (HR)-positive {'context': 'I-neoplasm'}", + "94, metastatic {'context': 'I-neoplasm'}", + "95, breast {'context': 'I-neoplasm'}", + "96, cancer {'context': 'I-neoplasm'}", + "101, tumor-infiltrating {'context': 'B-cells'}", + "102, lymphocytes {'context': 'I-cells'}", + "103, (TILs) {'context': 'I-cells'}", + "135, metastatic {'context': 'B-neoplasm'}", + "136, breast {'context': 'I-neoplasm'}", + "137, cancer, {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "88, patient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "91, hormone ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "92, receptor ['l1', 'l7', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "93, (HR)-positive ['l2', 'l8', 'l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "94, metastatic ['l3', 'l9', 'l16', 'l22', 'l28', 'l29', 'l30', 'l31', 'l32']", + "95, breast ['l4', 'l10', 'l17', 'l23', 'l28', 'l33', 'l34', 'l35', 'l36']", + "96, cancer ['l5', 'l11', 'l18', 'l24', 'l29', 'l33', 'l37', 'l38', 'l39']", + "101, tumor-infiltrating ['l12', 'l19', 'l25', 'l30', 'l34', 'l37', 'l40', 'l41']", + "102, lymphocytes ['l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l42']", + "103, (TILs) ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l41', 'l42']", + "135, metastatic ['l43', 'l44']", + "136, breast ['l43', 'l45']", + "137, cancer, ['l44', 'l45']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29808009", + "TEXT": "The ubiquitously expressed non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, is involved in signal transduction downstream of multiple growth factor, cytokine and integrin receptors1. Its requirement for complete RAS-MAPK activation and its role as a negative regulator of JAK-STAT signaling have established SHP2 as an essential player in oncogenic signaling pathways1-7. Recently, a novel potent allosteric SHP2 inhibitor was presented as a viable therapeutic option for receptor tyrosine kinase-driven cancers, but was shown to be ineffective in KRAS-mutant tumor cell lines in vitro8. Here, we report a central and indispensable role for SHP2 in oncogenic KRAS-driven tumors. Genetic deletion of Ptpn11 profoundly inhibited tumor development in mutant KRAS-driven murine models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. We provide evidence for a critical dependence of mutant KRAS on SHP2 during carcinogenesis. Deletion or inhibition of SHP2 in established tumors delayed tumor progression but was not sufficient to achieve tumor regression. However, SHP2 was necessary for resistance mechanisms upon blockade of MEK. Synergy was observed when both SHP2 and MEK were targeted, resulting in sustained tumor growth control in murine and human patient-derived organoids and xenograft models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. Our data indicate the clinical utility of dual SHP2/MEK inhibition as a targeted therapy approach for KRAS-mutant cancers.", + "TAG_DATA": [ + "98, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "99, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "100, of {'perturbing_action': 'I-gene loss-of-function'}", + "101, Ptpn11 {'perturbing_action': 'I-gene loss-of-function'}", + "103, inhibited {'effect': 'B-negative'}", + "104, tumor {'phenotype': 'B-tumourigenesis'}", + "105, development {'phenotype': 'I-tumourigenesis'}", + "107, mutant {'perturbing_action': 'B-other'}", + "108, KRAS-driven {'perturbing_action': 'B-other'}", + "109, murine {'context': 'B-neoplasm'}", + "110, models {'context': 'I-neoplasm'}", + "111, of {'context': 'I-neoplasm'}", + "112, pancreatic {'context': 'I-neoplasm'}", + "113, ductal {'context': 'I-neoplasm'}", + "114, adenocarcinoma {'context': 'I-neoplasm'}", + "116, non-small-cell {'context': 'B-neoplasm'}", + "117, lung {'context': 'I-neoplasm'}", + "118, cancer. {'context': 'I-neoplasm'}", + "135, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "136, of {'perturbing_action': 'I-pharmacological inhibition'}", + "137, SHP2 {'perturbing_action': 'I-pharmacological inhibition'}", + "140, tumors {'context': 'B-neoplasm'}", + "141, delayed {'effect': 'B-negative'}", + "142, tumor {'phenotype': 'B-tumour progression'}", + "143, progression {'phenotype': 'I-tumour progression'}", + "149, achieve {'effect': 'I-positive'}", + "150, tumor {'phenotype': 'B-tumour regression'}", + "151, regression. {'phenotype': 'I-tumour regression'}", + "176, tumor {'phenotype': 'B-tumour growth'}", + "177, growth {'phenotype': 'I-tumour growth'}", + "178, control {'effect': 'B-regulates'}", + "180, murine {'context': 'B-organoid'}", + "181, and {'context': 'I-organoid'}", + "182, human {'context': 'I-organoid'}", + "183, patient-derived {'context': 'I-organoid'}", + "184, organoids {'context': 'I-organoid'}", + "186, xenograft {'context': 'B-xenograft'}", + "187, models {'context': 'I-xenograft'}", + "189, pancreatic {'context': 'I-xenograft'}", + "190, ductal {'context': 'I-neoplasm'}", + "191, adenocarcinoma {'context': 'I-neoplasm'}", + "193, non-small-cell {'context': 'B-neoplasm'}", + "194, lung {'context': 'I-neoplasm'}", + "195, cancer. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "98, Genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "99, deletion ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "100, of ['l1', 'l17', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "101, Ptpn11 ['l2', 'l18', 'l33', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "103, inhibited ['l3', 'l19', 'l34', 'l48', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "104, tumor ['l4', 'l20', 'l35', 'l49', 'l62', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "105, development ['l5', 'l21', 'l36', 'l50', 'l63', 'l75', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "107, mutant ['l6', 'l22', 'l37', 'l51', 'l64', 'l76', 'l87', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "108, KRAS-driven ['l7', 'l23', 'l38', 'l52', 'l65', 'l77', 'l88', 'l97', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "109, murine ['l8', 'l24', 'l39', 'l53', 'l66', 'l78', 'l89', 'l98', 'l107', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "110, models ['l9', 'l25', 'l40', 'l54', 'l67', 'l79', 'l90', 'l99', 'l108', 'l116', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "111, of ['l10', 'l26', 'l41', 'l55', 'l68', 'l80', 'l91', 'l100', 'l109', 'l117', 'l124', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "112, pancreatic ['l11', 'l27', 'l42', 'l56', 'l69', 'l81', 'l92', 'l101', 'l110', 'l118', 'l125', 'l131', 'l137', 'l138', 'l139', 'l140', 'l141']", + "113, ductal ['l12', 'l28', 'l43', 'l57', 'l70', 'l82', 'l93', 'l102', 'l111', 'l119', 'l126', 'l132', 'l137', 'l142', 'l143', 'l144', 'l145']", + "114, adenocarcinoma ['l13', 'l29', 'l44', 'l58', 'l71', 'l83', 'l94', 'l103', 'l112', 'l120', 'l127', 'l133', 'l138', 'l142', 'l146', 'l147', 'l148']", + "116, non-small-cell ['l14', 'l30', 'l45', 'l59', 'l72', 'l84', 'l104', 'l113', 'l121', 'l128', 'l134', 'l139', 'l143', 'l146', 'l149', 'l150']", + "117, lung ['l15', 'l31', 'l46', 'l60', 'l73', 'l85', 'l95', 'l105', 'l114', 'l122', 'l129', 'l135', 'l140', 'l144', 'l147', 'l149', 'l151']", + "118, cancer. ['l16', 'l32', 'l47', 'l61', 'l74', 'l86', 'l96', 'l106', 'l115', 'l123', 'l130', 'l136', 'l141', 'l145', 'l148', 'l150', 'l151']", + "135, inhibition ['l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "136, of ['l152', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "137, SHP2 ['l153', 'l166', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189']", + "140, tumors ['l154', 'l167', 'l179', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195']", + "141, delayed ['l155', 'l168', 'l180', 'l190', 'l196', 'l197', 'l198', 'l199', 'l200']", + "142, tumor ['l156', 'l169', 'l181', 'l191', 'l196', 'l201', 'l202', 'l203', 'l204']", + "143, progression ['l157', 'l170', 'l182', 'l192', 'l197', 'l201', 'l205', 'l206', 'l207']", + "149, achieve ['l158', 'l171', 'l183', 'l193', 'l198', 'l202', 'l205', 'l208', 'l209']", + "150, tumor ['l159', 'l172', 'l184', 'l194', 'l199', 'l203', 'l206', 'l208', 'l210']", + "151, regression. ['l160', 'l173', 'l185', 'l195', 'l200', 'l204', 'l207', 'l209', 'l210']", + "170, MEK ['l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227']", + "176, tumor ['l211', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243']", + "177, growth ['l212', 'l228', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258']", + "178, control ['l213', 'l229', 'l244', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272']", + "180, murine ['l161', 'l174', 'l214', 'l230', 'l245', 'l259', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285']", + "181, and ['l162', 'l175', 'l186', 'l215', 'l231', 'l246', 'l260', 'l273', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297']", + "182, human ['l163', 'l176', 'l187', 'l216', 'l232', 'l247', 'l261', 'l274', 'l286', 'l298', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304', 'l305', 'l306', 'l307', 'l308']", + "183, patient-derived ['l164', 'l177', 'l188', 'l217', 'l233', 'l248', 'l262', 'l275', 'l287', 'l298', 'l309', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315', 'l316', 'l317', 'l318']", + "184, organoids ['l165', 'l178', 'l189', 'l218', 'l234', 'l249', 'l263', 'l276', 'l288', 'l299', 'l309', 'l319', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327']", + "186, xenograft ['l219', 'l235', 'l250', 'l264', 'l277', 'l289', 'l300', 'l310', 'l319', 'l328', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334', 'l335']", + "187, models ['l220', 'l236', 'l251', 'l265', 'l278', 'l290', 'l301', 'l311', 'l320', 'l328', 'l336', 'l337', 'l338', 'l339', 'l340', 'l341', 'l342']", + "188, of ['l221', 'l237', 'l252', 'l266', 'l279', 'l291', 'l302', 'l312', 'l321', 'l329', 'l336', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348']", + "189, pancreatic ['l222', 'l238', 'l253', 'l267', 'l280', 'l292', 'l303', 'l313', 'l322', 'l330', 'l337', 'l343', 'l349', 'l350', 'l351', 'l352', 'l353']", + "190, ductal ['l223', 'l239', 'l254', 'l268', 'l281', 'l293', 'l304', 'l314', 'l323', 'l331', 'l338', 'l344', 'l349', 'l354', 'l355', 'l356', 'l357']", + "191, adenocarcinoma ['l224', 'l240', 'l255', 'l269', 'l282', 'l294', 'l305', 'l315', 'l324', 'l332', 'l339', 'l345', 'l350', 'l354', 'l358', 'l359', 'l360']", + "193, non-small-cell ['l225', 'l241', 'l256', 'l270', 'l283', 'l295', 'l306', 'l316', 'l325', 'l333', 'l340', 'l346', 'l351', 'l355', 'l358', 'l361', 'l362']", + "194, lung ['l226', 'l242', 'l257', 'l271', 'l284', 'l296', 'l307', 'l317', 'l326', 'l334', 'l341', 'l347', 'l352', 'l356', 'l359', 'l361', 'l363']", + "195, cancer. ['l227', 'l243', 'l258', 'l272', 'l285', 'l297', 'l308', 'l318', 'l327', 'l335', 'l342', 'l348', 'l353', 'l357', 'l360', 'l362', 'l363']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "deletion", + "of", + "Ptpn11" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "deletion", + "of", + "Ptpn11" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "deletion", + "of", + "Ptpn11" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "murine", + "models", + "of", + "pancreatic", + "ductal", + "adenocarcinoma", + "non-small-cell", + "lung", + "cancer." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "KRAS-driven" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "delayed" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "murine", + "models", + "of", + "pancreatic", + "ductal", + "adenocarcinoma", + "non-small-cell", + "lung", + "cancer.", + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "KRAS-driven" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "murine", + "models", + "of", + "pancreatic", + "ductal", + "adenocarcinoma", + "non-small-cell", + "lung", + "cancer." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "KRAS-driven" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "murine", + "models", + "of", + "pancreatic", + "ductal", + "adenocarcinoma", + "non-small-cell", + "lung", + "cancer." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "delayed" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "achieve" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2" + ] + }, + "context": { + "val": "organoid", + "words": [ + "murine", + "and", + "human", + "patient-derived", + "organoids" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "achieve" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "delayed" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "delayed" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression." + ] + } + }, + { + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "achieve" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "achieve" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "control" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organoid", + "words": [ + "murine", + "and", + "human", + "patient-derived", + "organoids" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "models", + "pancreatic" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "ductal", + "adenocarcinoma", + "non-small-cell", + "lung", + "cancer." + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "control" + ] + }, + "context": { + "val": "organoid", + "words": [ + "murine", + "and", + "human", + "patient-derived", + "organoids" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "control" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "models", + "pancreatic" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "control" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "ductal", + "adenocarcinoma", + "non-small-cell", + "lung", + "cancer." + ] + } + } + ] + }, + { + "PMID": "29736028", + "TEXT": "The chances to develop Alzheimer's disease (AD) result from a combination of genetic and non-genetic risk factors 1 , the latter likely being mediated by epigenetic mechanisms 2 . In the past, genome-wide association studies (GWAS) have identified an important number of risk loci associated with AD pathology 3 , but a causal relationship remains difficult to establish. In contrast, locus-specific or epigenome-wide association studies (EWAS) have revealed site-specific epigenetic alterations, which provide mechanistic insights for a particular risk gene but often lack the statistical power of GWAS 4 . Here, combining both approaches, we report a previously unidentified association of the peptidase M20-domain-containing protein 1 (PM20D1) with AD. We find that PM20D1 is a methylation and expression quantitative trait locus coupled to an AD-risk associated haplotype, which displays enhancer-like characteristics and contacts the PM20D1 promoter via a haplotype-dependent, CCCTC-binding-factor-mediated chromatin loop. Furthermore, PM20D1 is increased following AD-related neurotoxic insults at symptomatic stages in the APP/PS1 mouse model of AD and in human patients with AD who are carriers of the non-risk haplotype. In line, genetically increasing or decreasing the expression of PM20D1 reduces and aggravates AD-related pathologies, respectively. These findings suggest that in a particular genetic background, PM20D1 contributes to neuroprotection against AD.", + "TAG_DATA": [ + "156, mouse {'context': 'I-organism'}", + "157, model {'context': 'I-organism'}", + "176, increasing {'perturbing_action': 'B-gene gain-of-function'}", + "178, decreasing {'perturbing_action': 'B-gene loss-of-function'}", + "179, the {'perturbing_action': 'I-gene loss-of-function'}", + "180, expression {'perturbing_action': 'I-gene loss-of-function'}", + "181, of {'perturbing_action': 'I-gene loss-of-function'}", + "182, PM20D1 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "156, mouse ['l0']", + "157, model ['l0']", + "176, increasing ['l1', 'l2', 'l3', 'l4', 'l5']", + "178, decreasing ['l1', 'l6', 'l7', 'l8', 'l9']", + "179, the ['l2', 'l6', 'l10', 'l11', 'l12']", + "180, expression ['l3', 'l7', 'l10', 'l13', 'l14']", + "181, of ['l4', 'l8', 'l11', 'l13', 'l15']", + "182, PM20D1 ['l5', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29736026", + "TEXT": "ARID1A (the AT-rich interaction domain 1A, also known as BAF250a) is one of the most commonly mutated genes in cancer1,2. The majority of ARID1A mutations are inactivating mutations and lead to loss of ARID1A expression 3 , which makes ARID1A a poor therapeutic target. Therefore, it is of clinical importance to identify molecular consequences of ARID1A deficiency that create therapeutic vulnerabilities in ARID1A-mutant tumors. In a proteomic screen, we found that ARID1A interacts with mismatch repair (MMR) protein MSH2. ARID1A recruited MSH2 to chromatin during DNA replication and promoted MMR. Conversely, ARID1A inactivation compromised MMR and increased mutagenesis. ARID1A deficiency correlated with microsatellite instability genomic signature and a predominant C>T mutation pattern and increased mutation load across multiple human cancer types. Tumors formed by an ARID1A-deficient ovarian cancer cell line in syngeneic mice displayed increased mutation load, elevated numbers of tumor-infiltrating lymphocytes, and PD-L1 expression. Notably, treatment with anti-PD-L1 antibody reduced tumor burden and prolonged survival of mice bearing ARID1A-deficient but not ARID1A-wild-type ovarian tumors. Together, these results suggest ARID1A deficiency contributes to impaired MMR and mutator phenotype in cancer, and may cooperate with immune checkpoint blockade therapy.", + "TAG_DATA": [ + "91, ARID1A {'perturbing_action': 'B-gene loss-of-function'}", + "92, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "98, ARID1A {'perturbing_action': 'B-gene loss-of-function'}", + "99, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "125, ARID1A-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "126, ovarian {'context': 'B-transformed cells'}", + "127, cancer {'context': 'I-transformed cells'}", + "128, cell {'context': 'I-transformed cells'}", + "129, line {'context': 'I-transformed cells'}", + "131, syngeneic {'context': 'B-organism'}", + "132, mice {'context': 'I-organism'}", + "151, tumor {'phenotype': 'B-tumourigenesis'}", + "152, burden {'phenotype': 'I-tumourigenesis'}", + "157, mice {'context': 'B-organism'}", + "159, ARID1A-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "163, ovarian {'context': 'B-neoplasm'}", + "164, tumors. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "91, ARID1A ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "92, inactivation ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "98, ARID1A ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "99, deficiency ['l2', 'l11', 'l19', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "121, Tumors ['l3', 'l12', 'l20', 'l28', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "125, ARID1A-deficient ['l4', 'l13', 'l21', 'l29', 'l36', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "126, ovarian ['l5', 'l14', 'l22', 'l30', 'l37', 'l43', 'l49', 'l50', 'l51', 'l52', 'l53']", + "127, cancer ['l6', 'l15', 'l23', 'l31', 'l38', 'l44', 'l49', 'l54', 'l55', 'l56', 'l57']", + "128, cell ['l7', 'l16', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l58', 'l59', 'l60']", + "129, line ['l8', 'l17', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l58', 'l61', 'l62']", + "131, syngeneic ['l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l61', 'l63']", + "132, mice ['l9', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l62', 'l63']", + "151, tumor ['l64', 'l65', 'l66', 'l67', 'l68']", + "152, burden ['l64', 'l69']", + "157, mice ['l65', 'l70', 'l71', 'l72']", + "159, ARID1A-deficient ['l66', 'l70', 'l73', 'l74']", + "163, ovarian ['l67', 'l71', 'l73', 'l75']", + "164, tumors. ['l68', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ARID1A", + "inactivation", + "deficiency", + "ARID1A-deficient" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "cancer", + "cell", + "line" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ARID1A", + "inactivation", + "deficiency", + "ARID1A-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "syngeneic" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ARID1A-deficient" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "burden" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "ovarian", + "tumors." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ARID1A-deficient" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "ovarian", + "tumors." + ] + } + } + ] + }, + { + "PMID": "29736023", + "TEXT": "Genetic defects underlying the melanocortin-4 receptor (MC4R) signaling pathway lead to severe obesity. Three severely obese LEPR-deficient individuals were administered the MC4R agonist setmelanotide, resulting in substantial and durable reductions in hyperphagia and body weight over an observation period of 45-61 weeks. Compared to formerly developed and tested MC4R agonists, setmelanotide has the unique capability of activating nuclear factor of activated T cell (NFAT) signaling and restoring function of this signaling pathway for selected MC4R variants. Our data demonstrate the potency of setmelanotide in treatment of individuals with diverse MC4R-related pathway deficiencies.", + "TAG_DATA": [ + "14, severely {'perturbing_action': 'B-gene loss-of-function', 'context': 'B-organism'}", + "15, obese {'perturbing_action': 'B-gene loss-of-function', 'context': 'I-organism'}", + "16, LEPR-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "17, individuals {'context': 'I-organism'}", + "21, MC4R {'perturbing_action': 'B-pharmacological augmentation'}", + "22, agonist {'perturbing_action': 'I-pharmacological augmentation'}" + ], + "LINK_DATA": [ + "14, severely ['l0', 'l1', 'l2', 'l3', 'l4']", + "15, obese ['l0', 'l5', 'l6', 'l7', 'l8']", + "16, LEPR-deficient ['l1', 'l5', 'l9', 'l10', 'l11']", + "17, individuals ['l2', 'l6', 'l9', 'l12', 'l13']", + "21, MC4R ['l3', 'l7', 'l10', 'l12', 'l14']", + "22, agonist ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "severely", + "obese", + "LEPR-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "severely", + "obese", + "individuals" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "severely", + "obese", + "individuals" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "MC4R", + "agonist" + ] + } + } + ] + }, + { + "PMID": "29736022", + "TEXT": "Aging of hematopoietic stem cells (HSCs) is associated with a decline in their regenerative capacity and multilineage differentiation potential, contributing to the development of blood disorders. The bone marrow microenvironment has recently been suggested to influence HSC aging, but the underlying mechanisms remain largely unknown. Here we show that HSC aging critically depends on bone marrow innervation by the sympathetic nervous system (SNS), as loss of SNS nerves or adrenoreceptor β3 signaling in the bone marrow microenvironment of young mice led to premature HSC aging, as evidenced by appearance of HSC phenotypes reminiscent of physiological aging. Strikingly, supplementation of a sympathomimetic acting selectively on adrenoreceptor β3 to old mice significantly rejuvenated the in vivo function of aged HSCs, suggesting that the preservation or restitution of bone marrow SNS innervation during aging may hold the potential for new HSC rejuvenation strategies.", + "TAG_DATA": [ + "63, loss {'perturbing_action': 'B-gene loss-of-function'}", + "64, of {'perturbing_action': 'I-gene loss-of-function'}", + "65, SNS nerves {'perturbing_action': 'I-gene loss-of-function'}", + "76, young {'context': 'B-organism'}", + "77, mice {'context': 'I-organism'}", + "81, HSC {'context': 'B-cells'}", + "105, old {'context': 'B-organism'}", + "106, mice {'context': 'I-organism'}", + "110, in {'context': 'B-in vivo'}", + "111, vivo {'context': 'I-in vivo'}", + "114, aged {'context': 'B-cells'}", + "115, HSCs, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "63, loss ['l0', 'l1', 'l2', 'l3', 'l4']", + "64, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "65, SNS nerves ['l1', 'l5', 'l9', 'l10', 'l11']", + "76, young ['l2', 'l6', 'l9', 'l12', 'l13']", + "77, mice ['l3', 'l7', 'l10', 'l12', 'l14']", + "81, HSC ['l4', 'l8', 'l11', 'l13', 'l14']", + "105, old ['l15', 'l16', 'l17', 'l18', 'l19']", + "106, mice ['l15', 'l20', 'l21', 'l22', 'l23']", + "110, in ['l16', 'l20', 'l24', 'l25', 'l26']", + "111, vivo ['l17', 'l21', 'l24', 'l27', 'l28']", + "114, aged ['l18', 'l22', 'l25', 'l27', 'l29']", + "115, HSCs, ['l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "SNS nerves" + ] + }, + "context": { + "val": "organism", + "words": [ + "young", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "SNS nerves" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC" + ] + } + } + ] + }, + { + "PMID": "29713085", + "TEXT": "Tolerance to self-antigens prevents the elimination of cancer by the immune system1,2. We used synthetic chimeric antigen receptors (CARs) to overcome immunological tolerance and mediate tumor rejection in patients with chronic lymphocytic leukemia (CLL). Remission was induced in a subset of subjects, but most did not respond. Comprehensive assessment of patient-derived CAR T cells to identify mechanisms of therapeutic success and failure has not been explored. We performed genomic, phenotypic and functional evaluations to identify determinants of response. Transcriptomic profiling revealed that CAR T cells from complete-responding patients with CLL were enriched in memory-related genes, including IL-6/STAT3 signatures, whereas T cells from nonresponders upregulated programs involved in effector differentiation, glycolysis, exhaustion and apoptosis. Sustained remission was associated with an elevated frequency of CD27+CD45RO-CD8+ T cells before CAR T cell generation, and these lymphocytes possessed memory-like characteristics. Highly functional CAR T cells from patients produced STAT3-related cytokines, and serum IL-6 correlated with CAR T cell expansion. IL-6/STAT3 blockade diminished CAR T cell proliferation. Furthermore, a mechanistically relevant population of CD27+PD-1-CD8+ CAR T cells expressing high levels of the IL-6 receptor predicts therapeutic response and is responsible for tumor control. These findings uncover new features of CAR T cell biology and underscore the potential of using pretreatment biomarkers of response to advance immunotherapies.", + "TAG_DATA": [ + "99, T {'context': 'B-cells'}", + "100, cells {'context': 'B-cells'}", + "132, lymphocytes {'context': 'B-cells'}", + "157, diminished {'effect': 'B-negative'}", + "158, CAR {'context': 'B-cells'}", + "159, T {'context': 'I-cells'}", + "160, cell {'context': 'I-cells'}", + "161, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "99, T ['l0', 'l1', 'l2']", + "100, cells ['l0', 'l3', 'l4']", + "112, apoptosis. ['l1', 'l3']", + "132, lymphocytes ['l2', 'l4']", + "157, diminished ['l5', 'l6', 'l7', 'l8']", + "158, CAR ['l5', 'l9', 'l10', 'l11']", + "159, T ['l6', 'l9', 'l12', 'l13']", + "160, cell ['l7', 'l10', 'l12', 'l14']", + "161, proliferation. ['l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "diminished" + ] + }, + "context": { + "val": "cells", + "words": [ + "CAR", + "T", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "diminished" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CAR", + "T", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "29662199", + "TEXT": "In the absence of an effective and safe vaccine against HIV-1, the administration of broadly neutralizing antibodies (bNAbs) represents a logical alternative approach to prevent virus transmission. Here, we introduced two mutations encoding amino acid substitutions (M428L and N434S, collectively referred to as 'LS') into the genes encoding the crystallizable fragment domains of the highly potent HIV-specific 3BNC117 and 10-1074 bNAbs to increase their half-lives and evaluated their efficacy in blocking infection following repeated low-dose mucosal challenges of rhesus macaques (Macaca mulatta) with the tier 2 SHIVAD8-EO. A single intravenous infusion of 10-1074-LS monoclonal antibodies markedly delayed virus acquisition for 18 to 37 weeks (median, 27 weeks), whereas the protective effect of the 3BNC117-LS bNAb was more modest (provided protection for 11-23 weeks; median, 17 weeks). Serum concentrations of the 10-1074-LS monoclonal antibody gradually declined and became undetectable in all recipients between weeks 26 and 41, whereas the 3BNC117-LS bNAb exhibited a shorter half-life. To model immunoprophylaxis against genetically diverse and/or neutralization-resistant HIV-1 strains, a combination of the 3BNC117-LS plus 10-1074-LS monoclonal antibodies was injected into macaques via the more clinically relevant subcutaneous route. Even though the administered mixture contained an amount of each bNAb that was nearly threefold less than the quantity of the single monoclonal antibody in the intravenous injections, the monoclonal antibody combination still protected macaques for a median of 20 weeks. The extended period of protection observed in macaques for the 3BNC117-LS plus 10-1074-LS combination could translate into an effective semiannual or annual immunoprophylaxis regimen for preventing HIV-1 infections in humans.", + "TAG_DATA": [ + "78, rhesus {'context': 'B-organism'}", + "79, macaques {'context': 'I-organism'}", + "80, (Macaca {'context': 'I-organism'}", + "81, mulatta) {'context': 'I-organism'}", + "176, macaques {'context': 'B-organism'}", + "218, macaques {'context': 'B-organism'}", + "232, macaques {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "78, rhesus ['l0', 'l1', 'l2']", + "79, macaques ['l0', 'l3', 'l4']", + "80, (Macaca ['l1', 'l3', 'l5']", + "81, mulatta) ['l2', 'l4', 'l5']", + "218, macaques ['l6']", + "232, macaques ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29554083", + "TEXT": "Development of a highly effective vaccine or antibodies for the prevention and ultimately elimination of malaria is urgently needed. Here we report the isolation of a number of human monoclonal antibodies directed against the Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) from several subjects immunized with an attenuated Pf whole-sporozoite (SPZ) vaccine (Sanaria PfSPZ Vaccine). Passive transfer of one of these antibodies, monoclonal antibody CIS43, conferred high-level, sterile protection in two different mouse models of malaria infection. The affinity and stoichiometry of CIS43 binding to PfCSP indicate that there are two sequential multivalent binding events encompassing the repeat domain. The first binding event is to a unique 'junctional' epitope positioned between the N terminus and the central repeat domain of PfCSP. Moreover, CIS43 prevented proteolytic cleavage of PfCSP on PfSPZ. Analysis of crystal structures of the CIS43 antigen-binding fragment in complex with the junctional epitope determined the molecular interactions of binding, revealed the epitope's conformational flexibility and defined Asn-Pro-Asn (NPN) as the structural repeat motif. The demonstration that CIS43 is highly effective for passive prevention of malaria has potential application for use in travelers, military personnel and elimination campaigns and identifies a new and conserved site of vulnerability on PfCSP for next-generation rational vaccine design.", + "TAG_DATA": [ + "71, mouse {'context': 'B-organism'}", + "72, models {'context': 'I-organism'}", + "74, malaria {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "71, mouse ['l0', 'l1']", + "72, models ['l0', 'l2']", + "74, malaria ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29505030", + "TEXT": "Spinal bulbar muscular atrophy (SBMA) is a motor neuron disease caused by toxic gain of function of the androgen receptor (AR). Previously, we found that co-regulator binding through the activation function-2 (AF2) domain of AR is essential for pathogenesis, suggesting that AF2 may be a potential drug target for selective modulation of toxic AR activity. We screened previously identified AF2 modulators for their ability to rescue toxicity in a Drosophila model of SBMA. We identified two compounds, tolfenamic acid (TA) and 1-[2-(4-methylphenoxy)ethyl]-2-[(2-phenoxyethyl)sulfanyl]-1H-benzimidazole (MEPB), as top candidates for rescuing lethality, locomotor function and neuromuscular junction defects in SBMA flies. Pharmacokinetic analyses in mice revealed a more favorable bioavailability and tissue retention of MEPB compared with TA in muscle, brain and spinal cord. In a preclinical trial in a new mouse model of SBMA, MEPB treatment yielded a dose-dependent rescue from loss of body weight, rotarod activity and grip strength. In addition, MEPB ameliorated neuronal loss, neurogenic atrophy and testicular atrophy, validating AF2 modulation as a potent androgen-sparing strategy for SBMA therapy.", + "TAG_DATA": [ + "97, flies. {'context': 'B-organism'}", + "101, mice {'context': 'B-organism'}", + "116, muscle, {'context': 'B-tissue/organ'}", + "128, mouse {'context': 'B-organism'}", + "129, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "101, mice ['l0', 'l1']", + "116, muscle, ['l0', 'l2', 'l3']", + "128, mouse ['l2', 'l4']", + "129, model ['l1', 'l3', 'l4']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29431745", + "TEXT": "Immunotherapy offers new options for cancer treatment, but efficacy varies across cancer types. Colorectal cancers (CRCs) are largely refractory to immune-checkpoint blockade, which suggests the presence of yet uncharacterized immune-suppressive mechanisms. Here we report that the loss of adenomatosis polyposis coli (APC) in intestinal tumor cells or of the tumor suppressor PTEN in melanoma cells upregulates the expression of Dickkopf-related protein 2 (DKK2), which, together with its receptor LRP5, provides an unconventional mechanism for tumor immune evasion. DKK2 secreted by tumor cells acts on cytotoxic lymphocytes, inhibiting STAT5 signaling by impeding STAT5 nuclear localization via LRP5, but independently of LRP6 and the Wnt-β-catenin pathway. Genetic or antibody-mediated ablation of DKK2 activates natural killer (NK) cells and CD8+ T cells in tumors, impedes tumor progression, and enhances the effects of PD-1 blockade. Thus, we have identified a previously unknown tumor immune-suppressive mechanism and immunotherapeutic targets particularly relevant for CRCs and a subset of melanomas.", + "TAG_DATA": [ + "36, loss {'perturbing_action': 'B-gene loss-of-function'}", + "37, of {'perturbing_action': 'I-gene loss-of-function'}", + "38, adenomatosis {'perturbing_action': 'I-gene loss-of-function'}", + "39, polyposis {'perturbing_action': 'I-gene loss-of-function'}", + "40, coli {'perturbing_action': 'I-gene loss-of-function'}", + "41, (APC) {'perturbing_action': 'I-gene loss-of-function'}", + "43, intestinal {'context': 'B-transformed cells'}", + "44, tumor {'context': 'I-transformed cells'}", + "45, cells {'context': 'I-transformed cells'}", + "47, of {'perturbing_action': 'I-gene loss-of-function'}", + "48, the {'perturbing_action': 'I-gene loss-of-function'}", + "49, tumor {'perturbing_action': 'I-gene loss-of-function'}", + "50, suppressor {'perturbing_action': 'I-gene loss-of-function'}", + "51, PTEN {'perturbing_action': 'I-gene loss-of-function'}", + "53, melanoma {'context': 'B-transformed cells'}", + "54, cells {'context': 'I-transformed cells'}", + "106, antibody-mediated {'perturbing_action': 'B-gene loss-of-function'}", + "107, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "108, of {'perturbing_action': 'I-gene loss-of-function'}", + "109, DKK2 {'perturbing_action': 'I-gene loss-of-function'}", + "111, natural {'context': 'B-cells'}", + "112, killer {'context': 'I-cells'}", + "113, (NK) {'context': 'I-cells'}", + "114, cells {'context': 'I-cells'}", + "116, CD8+ {'context': 'B-cells'}", + "117, T {'context': 'I-cells'}", + "118, cells {'context': 'I-cells'}", + "120, tumors, {'context': 'B-neoplasm'}", + "121, impedes {'effect': 'B-negative'}", + "122, tumor {'phenotype': 'B-tumour progression'}", + "123, progression, {'phenotype': 'I-tumour progression'}" + ], + "LINK_DATA": [ + "36, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "37, of ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "38, adenomatosis ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "39, polyposis ['l2', 'l16', 'l29', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "40, coli ['l3', 'l17', 'l30', 'l42', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "41, (APC) ['l4', 'l18', 'l31', 'l43', 'l54', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "43, intestinal ['l5', 'l19', 'l32', 'l44', 'l55', 'l65', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "44, tumor ['l6', 'l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l81', 'l82', 'l83']", + "45, cells ['l7', 'l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l81', 'l84', 'l85']", + "47, of ['l8', 'l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "48, the ['l9', 'l23', 'l36', 'l48', 'l59', 'l69', 'l86', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "49, tumor ['l10', 'l24', 'l37', 'l49', 'l60', 'l70', 'l87', 'l92', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "50, suppressor ['l11', 'l25', 'l38', 'l50', 'l61', 'l71', 'l88', 'l93', 'l99', 'l106', 'l107', 'l108', 'l109', 'l110']", + "51, PTEN ['l12', 'l26', 'l39', 'l51', 'l62', 'l72', 'l78', 'l89', 'l94', 'l100', 'l106', 'l111', 'l112', 'l113']", + "53, melanoma ['l13', 'l27', 'l40', 'l52', 'l63', 'l73', 'l79', 'l82', 'l84', 'l90', 'l95', 'l101', 'l107', 'l111', 'l114']", + "54, cells ['l14', 'l28', 'l41', 'l53', 'l64', 'l74', 'l80', 'l83', 'l85', 'l91', 'l96', 'l102', 'l108', 'l112', 'l114']", + "106, antibody-mediated ['l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "107, ablation ['l115', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141']", + "108, of ['l116', 'l129', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "109, DKK2 ['l117', 'l130', 'l142', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164']", + "111, natural ['l118', 'l131', 'l143', 'l154', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "112, killer ['l119', 'l132', 'l144', 'l155', 'l165', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183']", + "113, (NK) ['l103', 'l120', 'l133', 'l145', 'l156', 'l166', 'l175', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191']", + "114, cells ['l97', 'l104', 'l109', 'l113', 'l121', 'l134', 'l146', 'l157', 'l167', 'l176', 'l184', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198']", + "116, CD8+ ['l122', 'l135', 'l147', 'l158', 'l168', 'l177', 'l185', 'l192', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "117, T ['l123', 'l136', 'l148', 'l159', 'l169', 'l178', 'l186', 'l193', 'l199', 'l205', 'l206', 'l207', 'l208', 'l209']", + "118, cells ['l98', 'l105', 'l110', 'l124', 'l137', 'l149', 'l160', 'l170', 'l179', 'l187', 'l194', 'l200', 'l205', 'l210', 'l211', 'l212', 'l213']", + "120, tumors, ['l125', 'l138', 'l150', 'l161', 'l171', 'l180', 'l188', 'l195', 'l201', 'l206', 'l210', 'l214', 'l215', 'l216']", + "121, impedes ['l126', 'l139', 'l151', 'l162', 'l172', 'l181', 'l189', 'l196', 'l202', 'l207', 'l211', 'l214', 'l217', 'l218']", + "122, tumor ['l127', 'l140', 'l152', 'l163', 'l173', 'l182', 'l190', 'l197', 'l203', 'l208', 'l212', 'l215', 'l217', 'l219']", + "123, progression, ['l128', 'l141', 'l153', 'l164', 'l174', 'l183', 'l191', 'l198', 'l204', 'l209', 'l213', 'l216', 'l218', 'l219']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "adenomatosis", + "polyposis", + "coli", + "(APC)", + "PTEN", + "the", + "tumor", + "suppressor" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "intestinal", + "tumor", + "cells", + "melanoma" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "tumor", + "suppressor", + "PTEN", + "antibody-mediated", + "ablation", + "of", + "DKK2" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "(NK)", + "natural", + "killer", + "CD8+", + "T" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "antibody-mediated", + "ablation", + "of", + "DKK2" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "antibody-mediated", + "ablation", + "of", + "DKK2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impedes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "antibody-mediated", + "ablation", + "of", + "DKK2" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "natural", + "killer", + "(NK)", + "cells", + "CD8+", + "T" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impedes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "natural", + "killer", + "(NK)", + "cells", + "CD8+", + "T" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors," + ] + }, + "effect": { + "val": "negative", + "words": [ + "impedes" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors," + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impedes" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression," + ] + } + } + ] + }, + { + "PMID": "29431742", + "TEXT": "Nuclear receptors regulate gene expression in response to environmental cues, but the molecular events governing the cell type specificity of nuclear receptors remain poorly understood. Here we outline a role for a long noncoding RNA (lncRNA) in modulating the cell type-specific actions of liver X receptors (LXRs), sterol-activated nuclear receptors that regulate the expression of genes involved in cholesterol homeostasis and that have been causally linked to the pathogenesis of atherosclerosis. We identify the lncRNA MeXis as an amplifier of LXR-dependent transcription of the gene Abca1, which is critical for regulation of cholesterol efflux. Mice lacking the MeXis gene show reduced Abca1 expression in a tissue-selective manner. Furthermore, loss of MeXis in mouse bone marrow cells alters chromosome architecture at the Abca1 locus, impairs cellular responses to cholesterol overload, and accelerates the development of atherosclerosis. Mechanistic studies reveal that MeXis interacts with and guides promoter binding of the transcriptional coactivator DDX17. The identification of MeXis as a lncRNA modulator of LXR-dependent gene expression expands understanding of the mechanisms underlying cell type-selective actions of nuclear receptors in physiology and disease.", + "TAG_DATA": [ + "94, Mice {'context': 'B-organism'}", + "95, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "96, the {'perturbing_action': 'I-gene loss-of-function'}", + "97, MeXis {'perturbing_action': 'I-gene loss-of-function'}", + "98, gene {'perturbing_action': 'I-gene loss-of-function'}", + "108, loss {'perturbing_action': 'B-gene loss-of-function'}", + "109, of {'perturbing_action': 'I-gene loss-of-function'}", + "110, MeXis {'perturbing_action': 'I-gene loss-of-function'}", + "112, mouse {'context': 'B-cells'}", + "113, bone {'context': 'I-cells'}", + "114, marrow {'context': 'I-cells'}", + "115, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "94, Mice ['l0', 'l1', 'l2', 'l3']", + "95, lacking ['l0', 'l4', 'l5', 'l6']", + "96, the ['l1', 'l4', 'l7', 'l8']", + "97, MeXis ['l2', 'l5', 'l7', 'l9']", + "98, gene ['l3', 'l6', 'l8', 'l9']", + "108, loss ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "109, of ['l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "110, MeXis ['l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "112, mouse ['l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "113, bone ['l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "114, marrow ['l14', 'l19', 'l23', 'l26', 'l28', 'l30']", + "115, cells ['l15', 'l20', 'l24', 'l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "MeXis", + "gene" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "MeXis" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "bone", + "marrow", + "cells" + ] + } + } + ] + }, + { + "PMID": "29400714", + "TEXT": "An intronic GGGGCC repeat expansion in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the pathogenic mechanism of this repeat remains unclear. Using human induced motor neurons (iMNs), we found that repeat-expanded C9ORF72 was haploinsufficient in ALS. We found that C9ORF72 interacted with endosomes and was required for normal vesicle trafficking and lysosomal biogenesis in motor neurons. Repeat expansion reduced C9ORF72 expression, triggering neurodegeneration through two mechanisms: accumulation of glutamate receptors, leading to excitotoxicity, and impaired clearance of neurotoxic dipeptide repeat proteins derived from the repeat expansion. Thus, cooperativity between gain- and loss-of-function mechanisms led to neurodegeneration. Restoring C9ORF72 levels or augmenting its function with constitutively active RAB5 or chemical modulators of RAB5 effectors rescued patient neuron survival and ameliorated neurodegenerative processes in both gain- and loss-of-function C9ORF72 mouse models. Thus, modulating vesicle trafficking was able to rescue neurodegeneration caused by the C9ORF72 repeat expansion. Coupled with rare mutations in ALS2, FIG4, CHMP2B, OPTN and SQSTM1, our results reveal mechanistic convergence on vesicle trafficking in ALS and FTD.", + "TAG_DATA": [ + "31, human {'context': 'B-cells'}", + "32, induced {'context': 'I-cells'}", + "33, motor {'context': 'I-cells'}", + "34, neurons {'context': 'I-cells'}", + "35, (iMNs), {'context': 'I-cells'}", + "109, augmenting {'perturbing_action': 'B-gene gain-of-function'}", + "111, function {'perturbing_action': 'I-gene gain-of-function'}", + "112, with {'perturbing_action': 'I-gene gain-of-function'}", + "113, constitutively {'perturbing_action': 'I-gene gain-of-function'}", + "114, active {'perturbing_action': 'I-gene gain-of-function'}", + "115, RAB5 {'perturbing_action': 'I-gene gain-of-function'}", + "117, chemical {'perturbing_action': 'B-pharmacological inhibition'}", + "118, modulators {'perturbing_action': 'I-pharmacological inhibition'}", + "119, of {'perturbing_action': 'I-pharmacological inhibition'}", + "120, RAB5 {'perturbing_action': 'I-pharmacological augmentation'}", + "121, effectors {'perturbing_action': 'I-pharmacological inhibition'}", + "124, neuron {'context': 'I-cells'}", + "132, gain- {'perturbing_action': 'B-gene gain-of-function'}", + "133, and {'perturbing_action': 'B-gene loss-of-function'}", + "134, loss-of-function {'perturbing_action': 'B-gene loss-of-function'}", + "135, C9ORF72 {'perturbing_action': 'B-gene gain-of-function'}", + "136, mouse {'context': 'B-organism'}", + "137, models. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "31, human ['l0', 'l1', 'l2', 'l3']", + "32, induced ['l0', 'l4', 'l5', 'l6']", + "33, motor ['l1', 'l4', 'l7', 'l8']", + "34, neurons ['l2', 'l5', 'l7', 'l9']", + "35, (iMNs), ['l3', 'l6', 'l8', 'l9']", + "109, augmenting ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "111, function ['l10', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "112, with ['l11', 'l27', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "113, constitutively ['l12', 'l28', 'l43', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "114, active ['l13', 'l29', 'l44', 'l58', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "115, RAB5 ['l14', 'l30', 'l45', 'l59', 'l72', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "117, chemical ['l15', 'l31', 'l46', 'l60', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "118, modulators ['l16', 'l32', 'l47', 'l61', 'l93', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "119, of ['l17', 'l33', 'l48', 'l62', 'l73', 'l83', 'l94', 'l104', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "120, RAB5 ['l18', 'l34', 'l49', 'l63', 'l74', 'l84', 'l95', 'l105', 'l114', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "121, effectors ['l19', 'l35', 'l50', 'l64', 'l75', 'l85', 'l96', 'l106', 'l115', 'l123', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "124, neuron ['l20', 'l36', 'l51', 'l65', 'l76', 'l86', 'l97', 'l107', 'l116', 'l124', 'l131']", + "132, gain- ['l21', 'l37', 'l52', 'l66', 'l77', 'l87', 'l98', 'l108', 'l117', 'l125', 'l132', 'l138', 'l139', 'l140', 'l141', 'l142']", + "133, and ['l22', 'l38', 'l53', 'l67', 'l78', 'l88', 'l99', 'l109', 'l118', 'l126', 'l133', 'l138', 'l143', 'l144', 'l145', 'l146']", + "134, loss-of-function ['l23', 'l39', 'l54', 'l68', 'l79', 'l89', 'l100', 'l110', 'l119', 'l127', 'l134', 'l139', 'l143', 'l147', 'l148', 'l149']", + "135, C9ORF72 ['l24', 'l40', 'l55', 'l69', 'l80', 'l90', 'l101', 'l111', 'l120', 'l128', 'l135', 'l140', 'l144', 'l147', 'l150', 'l151']", + "136, mouse ['l25', 'l41', 'l56', 'l70', 'l81', 'l91', 'l102', 'l112', 'l121', 'l129', 'l136', 'l141', 'l145', 'l148', 'l150', 'l152']", + "137, models. ['l26', 'l42', 'l57', 'l71', 'l82', 'l92', 'l103', 'l113', 'l122', 'l130', 'l137', 'l142', 'l146', 'l149', 'l151', 'l152']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "augmenting", + "function", + "with", + "constitutively", + "active", + "RAB5" + ] + }, + "context": { + "val": "cells", + "words": [ + "neuron" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "augmenting", + "function", + "with", + "constitutively", + "active", + "RAB5", + "gain-", + "C9ORF72" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "chemical", + "modulators", + "of", + "effectors" + ] + }, + "context": { + "val": "cells", + "words": [ + "neuron" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "chemical", + "modulators", + "of", + "effectors" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "RAB5" + ] + }, + "context": { + "val": "cells", + "words": [ + "neuron" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "RAB5" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "and", + "loss-of-function" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + } + ] + }, + { + "PMID": "29400712", + "TEXT": "Hedgehog pathway-dependent cancers can escape Smoothened (SMO) inhibition through mutations in genes encoding canonical hedgehog pathway components; however, around 50% of drug-resistant basal cell carcinomas (BCCs) lack additional variants of these genes. Here we use multidimensional genomics analysis of human and mouse drug-resistant BCCs to identify a noncanonical hedgehog activation pathway driven by the transcription factor serum response factor (SRF). Active SRF along with its coactivator megakaryoblastic leukemia 1 (MKL1) binds DNA near hedgehog target genes and forms a previously unknown protein complex with the hedgehog transcription factor glioma-associated oncogene family zinc finger-1 (GLI1), causing amplification of GLI1 transcriptional activity. We show that cytoskeletal activation through Rho and the formin family member Diaphanous (mDia) is required for SRF-MKL-driven GLI1 activation and for tumor cell viability. Remarkably, nuclear MKL1 staining served as a biomarker in tumors from mice and human subjects to predict tumor responsiveness to MKL inhibitors, highlighting the therapeutic potential of targeting this pathway. Thus, our study illuminates, for the first time, cytoskeletal-activation-driven transcription as a personalized therapeutic target for combatting drug-resistant malignancies.", + "TAG_DATA": [ + "122, tumor {'context': 'B-neoplasm'}", + "123, cell {'phenotype': 'B-cell survival'}", + "124, viability. {'phenotype': 'I-cell survival'}" + ], + "LINK_DATA": [ + "122, tumor ['l0', 'l1']", + "123, cell ['l0', 'l2']", + "124, viability. ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "viability." + ] + } + } + ] + }, + { + "PMID": "29334373", + "TEXT": "Despite widespread use of the bacille Calmette-Guérin (BCG) vaccine, tuberculosis (TB) remains a leading cause of global mortality from a single infectious agent (Mycobacterium tuberculosis or Mtb). Here, over two independent Mtb challenge studies, we demonstrate that subcutaneous vaccination of rhesus macaques (RMs) with rhesus cytomegalovirus vectors encoding Mtb antigen inserts (hereafter referred to as RhCMV/TB)-which elicit and maintain highly effector-differentiated, circulating and tissue-resident Mtb-specific CD4+ and CD8+ memory T cell responses-can reduce the overall (pulmonary and extrapulmonary) extent of Mtb infection and disease by 68%, as compared to that in unvaccinated controls, after intrabronchial challenge with the Erdman strain of Mtb at ∼1 year after the first vaccination. Fourteen of 34 RhCMV/TB-vaccinated RMs (41%) across both studies showed no TB disease by computed tomography scans or at necropsy after challenge (as compared to 0 of 17 unvaccinated controls), and ten of these RMs were Mtb-culture-negative for all tissues, an exceptional long-term vaccine effect in the RM challenge model with the Erdman strain of Mtb. These results suggest that complete vaccine-mediated immune control of highly pathogenic Mtb is possible if immune effector responses can intercept Mtb infection at its earliest stages.", + "TAG_DATA": [ + "40, rhesus {'context': 'B-organism'}", + "41, macaques {'context': 'I-organism'}", + "42, (RMs) {'context': 'I-organism'}", + "113, RMs {'context': 'B-cells'}", + "143, RMs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "40, rhesus ['l0', 'l1']", + "41, macaques ['l0', 'l2']", + "42, (RMs) ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29309058", + "TEXT": "Multiple immune-cell types can infiltrate tumors and promote progression and metastasis through different mechanisms, including immunosuppression. How distinct genetic alterations in tumors affect the composition of the immune landscape is currently unclear. Here, we characterized the immune-cell composition of prostate cancers driven by the loss of the critical tumor suppressor gene Pten, either alone or in combination with the loss of Trp53, Zbtb7a or Pml. We observed a striking quantitative and qualitative heterogeneity that was directly dependent on the specific genetic events in the tumor and ranged from 'cold', noninflamed tumors to massively infiltrated landscapes-results with important therapeutic implications. Further, we showed these qualitative differences in transcriptomic analysis of human prostate cancer samples. These data suggest that patient stratification on the basis of integrated genotypic-immunophenotypic analyses may be necessary for successful clinical trials and tailored precision immunological therapies.", + "TAG_DATA": [ + "39, prostate {'context': 'B-neoplasm'}", + "40, cancers {'context': 'I-neoplasm'}", + "44, loss {'perturbing_action': 'B-gene loss-of-function'}", + "45, of {'perturbing_action': 'I-gene loss-of-function'}", + "46, the {'perturbing_action': 'I-gene loss-of-function'}", + "47, critical {'perturbing_action': 'I-gene loss-of-function'}", + "48, tumor {'perturbing_action': 'I-gene loss-of-function'}", + "49, suppressor {'perturbing_action': 'I-gene loss-of-function'}", + "50, gene {'perturbing_action': 'I-gene loss-of-function'}", + "51, Pten, {'perturbing_action': 'I-gene loss-of-function'}", + "59, loss {'perturbing_action': 'B-gene loss-of-function'}", + "60, of {'perturbing_action': 'I-gene loss-of-function'}", + "61, Trp53, {'perturbing_action': 'I-gene loss-of-function'}", + "62, Zbtb7a {'perturbing_action': 'I-gene loss-of-function'}", + "63, or {'perturbing_action': 'I-gene loss-of-function'}", + "64, Pml. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "39, prostate ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "40, cancers ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "44, loss ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "45, of ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "46, the ['l3', 'l11', 'l18', 'l24', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "47, critical ['l4', 'l12', 'l19', 'l25', 'l31', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "48, tumor ['l5', 'l13', 'l20', 'l26', 'l32', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49']", + "49, suppressor ['l6', 'l14', 'l21', 'l27', 'l33', 'l39', 'l45', 'l50', 'l51', 'l52', 'l53', 'l54']", + "50, gene ['l7', 'l15', 'l22', 'l28', 'l34', 'l40', 'l46', 'l50', 'l55']", + "51, Pten, ['l8', 'l16', 'l23', 'l29', 'l35', 'l41', 'l47', 'l51', 'l55']", + "59, loss ['l56', 'l57', 'l58', 'l59', 'l60']", + "60, of ['l56', 'l61', 'l62', 'l63', 'l64']", + "61, Trp53, ['l57', 'l61', 'l65', 'l66', 'l67']", + "62, Zbtb7a ['l42', 'l52', 'l58', 'l62', 'l65', 'l68', 'l69']", + "63, or ['l36', 'l43', 'l48', 'l53', 'l59', 'l63', 'l66', 'l68', 'l70']", + "64, Pml. ['l30', 'l37', 'l44', 'l49', 'l54', 'l60', 'l64', 'l67', 'l69', 'l70']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "prostate", + "cancers" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "critical", + "tumor", + "suppressor", + "gene", + "Pten," + ] + } + } + ] + }, + { + "PMID": "29216041", + "TEXT": "In an article published recently in Nature Medicine, the authors generate organoid models of liver neoplasia. In doing so, they highlight both the diversity of current organoid methodologies and their application to cancer modeling and therapeutics discovery.", + "TAG_DATA": [ + "11, organoid {'context': 'B-organoid'}", + "12, models {'context': 'I-organoid'}", + "14, liver {'context': 'B-tissue/organ'}", + "15, neoplasia. {'phenotype': 'B-tumourigenesis'}" + ], + "LINK_DATA": [ + "11, organoid ['l0', 'l1', 'l2']", + "12, models ['l0', 'l3', 'l4']", + "14, liver ['l1', 'l3', 'l5']", + "15, neoplasia. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organoid", + "words": [ + "organoid", + "models" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasia." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasia." + ] + } + } + ] + }, + { + "PMID": "29200204", + "TEXT": "Thyroid hormone (TH) is critical for the maintenance of cellular homeostasis during stress responses, but its role in lung fibrosis is unknown. Here we found that the activity and expression of iodothyronine deiodinase 2 (DIO2), an enzyme that activates TH, were higher in lungs from patients with idiopathic pulmonary fibrosis than in control individuals and were correlated with disease severity. We also found that Dio2-knockout mice exhibited enhanced bleomycin-induced lung fibrosis. Aerosolized TH delivery increased survival and resolved fibrosis in two models of pulmonary fibrosis in mice (intratracheal bleomycin and inducible TGF-β1). Sobetirome, a TH mimetic, also blunted bleomycin-induced lung fibrosis. After bleomycin-induced injury, TH promoted mitochondrial biogenesis, improved mitochondrial bioenergetics and attenuated mitochondria-regulated apoptosis in alveolar epithelial cells both in vivo and in vitro. TH did not blunt fibrosis in Ppargc1a- or Pink1-knockout mice, suggesting dependence on these pathways. We conclude that the antifibrotic properties of TH are associated with protection of alveolar epithelial cells and restoration of mitochondrial function and that TH may thus represent a potential therapy for pulmonary fibrosis.", + "TAG_DATA": [ + "64, Dio2-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "65, mice {'context': 'B-organism'}", + "86, mice {'context': 'B-organism'}", + "99, lung {'context': 'B-tissue/organ'}", + "112, attenuated {'effect': 'B-negative'}", + "114, apoptosis {'phenotype': 'B-apoptosis'}", + "116, alveolar {'context': 'B-cells'}", + "117, epithelial {'context': 'I-cells'}", + "118, cells {'context': 'I-cells'}", + "120, in {'context': 'B-in vivo'}", + "121, vivo {'context': 'I-in vivo'}", + "123, in {'context': 'B-in vitro'}", + "124, vitro. {'context': 'I-in vitro'}", + "131, Ppargc1a- {'perturbing_action': 'B-gene loss-of-function'}", + "132, or {'perturbing_action': 'I-gene loss-of-function'}", + "133, Pink1-knockout {'perturbing_action': 'I-gene loss-of-function'}", + "134, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "64, Dio2-knockout ['l0']", + "65, mice ['l0']", + "99, lung ['l1', 'l2', 'l3', 'l4']", + "112, attenuated ['l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "114, apoptosis ['l1', 'l5', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "116, alveolar ['l2', 'l6', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "117, epithelial ['l3', 'l7', 'l14', 'l19', 'l25', 'l26', 'l27', 'l28']", + "118, cells ['l4', 'l8', 'l15', 'l20', 'l25', 'l29', 'l30']", + "120, in ['l9', 'l16', 'l21', 'l26', 'l29', 'l31', 'l32', 'l33']", + "121, vivo ['l10', 'l17', 'l22', 'l27', 'l30', 'l31', 'l34', 'l35']", + "123, in ['l11', 'l18', 'l23', 'l28', 'l32', 'l34', 'l36']", + "124, vitro. ['l12', 'l24', 'l33', 'l35', 'l36']", + "131, Ppargc1a- ['l37', 'l38', 'l39']", + "132, or ['l37', 'l40', 'l41']", + "133, Pink1-knockout ['l38', 'l40', 'l42']", + "134, mice, ['l39', 'l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dio2-knockout", + "Ppargc1a-", + "or", + "Pink1-knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + }, + "context": { + "val": "cells", + "words": [ + "alveolar", + "epithelial", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "alveolar", + "epithelial", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in" + ] + } + } + ] + }, + { + "PMID": "29131157", + "TEXT": "Mature T cell cancers are typically aggressive, treatment resistant and associated with poor prognosis. Clinical application of immunotherapeutic approaches has been limited by a lack of target antigens that discriminate malignant from healthy (normal) T cells. Unlike B cell depletion, pan-T cell aplasia is prohibitively toxic. We report a new targeting strategy based on the mutually exclusive expression of T cell receptor β-chain constant domains 1 and 2 (TRBC1 and TRBC2). We identify an antibody with unique TRBC1 specificity and use it to demonstrate that normal and virus-specific T cell populations contain both TRBC1+ and TRBC2+ compartments, whereas malignancies are restricted to only one. As proof of concept for anti-TRBC immunotherapy, we developed anti-TRBC1 chimeric antigen receptor (CAR) T cells, which recognized and killed normal and malignant TRBC1+, but not TRBC2+, T cells in vitro and in a disseminated mouse model of leukemia. Unlike nonselective approaches targeting the entire T cell population, TRBC-targeted immunotherapy could eradicate a T cell malignancy while preserving sufficient normal T cells to maintain cellular immunity.", + "TAG_DATA": [ + "118, T {'context': 'B-cells'}", + "119, cells, {'context': 'B-cells'}", + "127, TRBC1+, {'context': 'B-cells'}", + "131, T {'context': 'B-cells'}", + "132, cells {'context': 'I-cells'}", + "133, in {'context': 'B-in vitro'}", + "134, vitro {'context': 'I-in vitro'}", + "138, disseminated {'context': 'B-neoplasm'}", + "139, mouse {'context': 'I-neoplasm'}", + "140, model {'context': 'I-neoplasm'}", + "141, of {'context': 'I-neoplasm'}", + "142, leukemia. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "118, T ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "119, cells, ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "127, TRBC1+, ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "131, T ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "132, cells ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "133, in ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "134, vitro ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "138, disseminated ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "139, mouse ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "140, model ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "141, of ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "142, leukemia. ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29035365", + "TEXT": "Critical to the function of mast cells in immune responses including allergy is their production of lipid mediators, among which only omega-6 (ω-6) arachidonate-derived eicosanoids have been well characterized. Here, by employing comprehensive lipidomics, we identify omega-3 (ω-3) fatty acid epoxides as new mast cell-derived lipid mediators and show that they are produced by PAF-AH2, an oxidized-phospholipid-selective phospholipase A2. Genetic or pharmacological deletion of PAF-AH2 reduced the steady-state production of ω-3 epoxides, leading to attenuated mast cell activation and anaphylaxis following FcɛRI cross-linking. Mechanistically, the ω-3 epoxides promote IgE-mediated activation of mast cells by downregulating Srcin1, a Src-inhibitory protein that counteracts FcɛRI signaling, through a pathway involving PPARg. Thus, the PAF-AH2-ω-3 epoxide-Srcin1 axis presents new potential drug targets for allergic diseases.", + "TAG_DATA": [ + "61, pharmacological {'perturbing_action': 'B-gene loss-of-function'}", + "62, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "63, of {'perturbing_action': 'I-gene loss-of-function'}", + "64, PAF-AH2 {'perturbing_action': 'I-gene loss-of-function'}", + "75, mast {'context': 'B-cells'}", + "76, cell {'context': 'I-cells'}", + "91, mast {'context': 'B-cells'}", + "92, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "61, pharmacological ['l0', 'l1', 'l2', 'l3', 'l4']", + "62, deletion ['l0', 'l5', 'l6', 'l7', 'l8']", + "63, of ['l1', 'l5', 'l9', 'l10', 'l11']", + "64, PAF-AH2 ['l2', 'l6', 'l9', 'l12', 'l13']", + "75, mast ['l3', 'l7', 'l10', 'l12', 'l14']", + "76, cell ['l4', 'l8', 'l11', 'l13', 'l14']", + "91, mast ['l15']", + "92, cells ['l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pharmacological", + "deletion", + "of", + "PAF-AH2" + ] + }, + "context": { + "val": "cells", + "words": [ + "mast", + "cell" + ] + } + } + ] + }, + { + "PMID": "28892065", + "TEXT": "Malaria, caused by the protozoan Plasmodium, is a devastating mosquito-borne disease with the potential to affect nearly half the world's population. Despite mounting substantial T and B cell responses, humans fail to efficiently control blood-stage malaria or develop sterilizing immunity to reinfections. Although forkhead box P3 (FOXP3)+CD4+ regulatory T (Treg) cells form a part of these responses, their influence remains disputed and their mode of action is unknown. Here we show that Treg cells expand in both humans and mice in blood-stage malaria and interfere with conventional T helper cell responses and follicular T helper (TFH)-B cell interactions in germinal centers. Mechanistically, Treg cells function in a critical temporal window to impede protective immunity through cytotoxic-T-lymphocyte-associated protein-4 (CTLA-4). Targeting Treg cells or CTLA-4 in this precise window accelerated parasite clearance and generated species-transcending immunity to blood-stage malaria in mice. Our study uncovers a critical mechanism of immunosuppression associated with blood-stage malaria that delays parasite clearance and prevents development of potent adaptive immunity to reinfection. These data also reveal a temporally discrete and potentially therapeutically amenable functional role for Treg cells and CTLA-4 in limiting antimalarial immunity.", + "TAG_DATA": [ + "77, humans {'context': 'B-organism'}", + "79, mice {'context': 'B-organism'}", + "119, Treg {'context': 'B-cells'}", + "120, cells {'context': 'I-cells'}", + "138, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "77, humans ['l0']", + "79, mice ['l0']", + "119, Treg ['l1', 'l2']", + "120, cells ['l1', 'l3']", + "138, mice. ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28869610", + "TEXT": "Basal cell carcinoma (BCC), the most common human cancer, results from aberrant activation of the Hedgehog signaling pathway. Although most cases of BCC are sporadic, some forms are inherited, such as Bazex-Dupré-Christol syndrome (BDCS)-a cancer-prone genodermatosis with an X-linked, dominant inheritance pattern. We have identified mutations in the ACTRT1 gene, which encodes actin-related protein T1 (ARP-T1), in two of the six families with BDCS that were examined in this study. High-throughput sequencing in the four remaining families identified germline mutations in noncoding sequences surrounding ACTRT1. These mutations were located in transcribed sequences encoding enhancer RNAs (eRNAs) and were shown to impair enhancer activity and ACTRT1 expression. ARP-T1 was found to directly bind to the GLI1 promoter, thus inhibiting GLI1 expression, and loss of ARP-T1 led to activation of the Hedgehog pathway in individuals with BDCS. Moreover, exogenous expression of ACTRT1 reduced the in vitro and in vivo proliferation rates of cell lines with aberrant activation of the Hedgehog signaling pathway. In summary, our study identifies a disease mechanism in BCC involving mutations in regulatory noncoding elements and uncovers the tumor-suppressor properties of ACTRT1.", + "TAG_DATA": [ + "121, loss {'perturbing_action': 'B-gene loss-of-function'}", + "122, of {'perturbing_action': 'I-gene loss-of-function'}", + "123, ARP-T1 {'perturbing_action': 'I-gene loss-of-function'}", + "136, exogenous {'perturbing_action': 'B-gene gain-of-function'}", + "137, expression {'perturbing_action': 'I-gene gain-of-function'}", + "138, of {'perturbing_action': 'I-gene gain-of-function'}", + "139, ACTRT1 {'perturbing_action': 'I-gene gain-of-function'}", + "140, reduced {'effect': 'B-negative'}", + "142, in {'context': 'B-in vitro'}", + "143, vitro {'context': 'I-in vitro'}", + "145, in {'context': 'B-in vivo'}", + "146, vivo {'context': 'I-in vivo'}", + "147, proliferation {'phenotype': 'B-proliferation'}", + "150, cell {'context': 'B-cells'}", + "151, lines {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "121, loss ['l0', 'l1']", + "122, of ['l0', 'l2']", + "123, ARP-T1 ['l1', 'l2']", + "136, exogenous ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "137, expression ['l3', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "138, of ['l4', 'l14', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "139, ACTRT1 ['l5', 'l15', 'l24', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "140, reduced ['l6', 'l16', 'l25', 'l33', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "142, in ['l7', 'l17', 'l26', 'l34', 'l41', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "143, vitro ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l54', 'l55', 'l56', 'l57', 'l58']", + "145, in ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l59', 'l60', 'l61', 'l62']", + "146, vivo ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l63', 'l64', 'l65']", + "147, proliferation ['l11', 'l21', 'l30', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l66', 'l67']", + "150, cell ['l12', 'l22', 'l31', 'l39', 'l46', 'l52', 'l57', 'l61', 'l64', 'l66', 'l68']", + "151, lines ['l13', 'l23', 'l32', 'l40', 'l47', 'l53', 'l58', 'l62', 'l65', 'l67', 'l68']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "exogenous", + "expression", + "of", + "ACTRT1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "exogenous", + "expression", + "of", + "ACTRT1" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "exogenous", + "expression", + "of", + "ACTRT1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "exogenous", + "expression", + "of", + "ACTRT1" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "exogenous", + "expression", + "of", + "ACTRT1" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "lines" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "lines" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "lines" + ] + } + } + ] + }, + { + "PMID": "28825717", + "TEXT": "Recent large-scale genetic sequencing efforts have identified rare coding variants in genes in the triglyceride-rich lipoprotein (TRL) clearance pathway that are protective against coronary heart disease (CHD), independently of LDL cholesterol (LDL-C) levels. Insight into the mechanisms of protection of these variants may facilitate the development of new therapies for lowering TRL levels. The gene APOC3 encodes apoC-III, a critical inhibitor of triglyceride (TG) lipolysis and remnant TRL clearance. Here we report a detailed interrogation of the mechanism of TRL lowering by the APOC3 Ala43Thr (A43T) variant, the only missense (rather than protein-truncating) variant in APOC3 reported to be TG lowering and protective against CHD. We found that both human APOC3 A43T heterozygotes and mice expressing human APOC3 A43T display markedly reduced circulating apoC-III levels. In mice, this reduction is due to impaired binding of A43T apoC-III to lipoproteins and accelerated renal catabolism of free apoC-III. Moreover, the reduced content of apoC-III in TRLs resulted in accelerated clearance of circulating TRLs. On the basis of this protective mechanism, we developed a monoclonal antibody targeting lipoprotein-bound human apoC-III that promotes circulating apoC-III clearance in mice expressing human APOC3 and enhances TRL catabolism in vivo. These data reveal the molecular mechanism by which a missense variant in APOC3 causes reduced circulating TG levels and, hence, protects from CHD. This protective mechanism has the potential to be exploited as a new therapeutic approach to reduce apoC-III levels and circulating TRL burden.", + "TAG_DATA": [ + "109, human {'perturbing_action': 'B-other'}", + "110, APOC3 {'perturbing_action': 'I-other'}", + "111, A43T {'perturbing_action': 'I-other'}", + "112, heterozygotes {'perturbing_action': 'I-other'}", + "114, mice {'context': 'B-organism'}", + "115, expressing {'perturbing_action': 'B-other'}", + "116, human {'perturbing_action': 'I-other'}", + "117, APOC3 {'perturbing_action': 'I-other'}", + "118, A43T {'perturbing_action': 'I-other'}", + "126, mice, {'context': 'B-organism'}", + "183, mice {'context': 'B-organism'}", + "184, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "185, human {'perturbing_action': 'I-gene gain-of-function'}", + "186, APOC3 {'perturbing_action': 'I-gene gain-of-function'}", + "191, in {'context': 'B-in vivo'}", + "192, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "109, human ['l0', 'l1', 'l2', 'l3', 'l4']", + "110, APOC3 ['l0', 'l5', 'l6', 'l7', 'l8']", + "111, A43T ['l1', 'l5', 'l9', 'l10', 'l11']", + "112, heterozygotes ['l2', 'l6', 'l9', 'l12', 'l13']", + "114, mice ['l14', 'l15', 'l16', 'l17', 'l18']", + "115, expressing ['l14', 'l19', 'l20', 'l21', 'l22']", + "116, human ['l15', 'l19', 'l23', 'l24', 'l25']", + "117, APOC3 ['l16', 'l20', 'l23', 'l26', 'l27']", + "118, A43T ['l3', 'l7', 'l10', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "126, mice, ['l4', 'l8', 'l11', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']", + "183, mice ['l29', 'l30', 'l31', 'l32', 'l33']", + "184, expressing ['l29', 'l34', 'l35', 'l36', 'l37']", + "185, human ['l30', 'l34', 'l38', 'l39', 'l40']", + "186, APOC3 ['l31', 'l35', 'l38', 'l41', 'l42']", + "191, in ['l32', 'l36', 'l39', 'l41', 'l43']", + "192, vivo. ['l33', 'l37', 'l40', 'l42', 'l43']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "human", + "APOC3", + "A43T", + "heterozygotes", + "expressing" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "human", + "APOC3" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "human", + "APOC3" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "28759052", + "TEXT": "D-mannose, a C-2 epimer of glucose, exists naturally in many plants and fruits, and is found in human blood at concentrations less than one-fiftieth of that of glucose. However, although the roles of glucose in T cell metabolism, diabetes and obesity are well characterized, the function of D-mannose in T cell immune responses remains unknown. Here we show that supraphysiological levels of D-mannose safely achievable by drinking-water supplementation suppressed immunopathology in mouse models of autoimmune diabetes and airway inflammation, and increased the proportion of Foxp3+ regulatory T cells (Treg cells) in mice. In vitro, D-mannose stimulated Treg cell differentiation in human and mouse cells by promoting TGF-β activation, which in turn was mediated by upregulation of integrin αvβ8 and reactive oxygen species generated by increased fatty acid oxidation. This previously unrecognized immunoregulatory function of D-mannose may have clinical applications for immunopathology.", + "TAG_DATA": [ + "71, mouse {'context': 'B-organism'}", + "72, models {'context': 'I-organism'}", + "84, Foxp3+ {'context': 'B-cells'}", + "85, regulatory {'context': 'I-cells'}", + "86, T {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}", + "88, (Treg {'context': 'I-cells'}", + "89, cells) {'context': 'I-cells'}", + "91, mice. {'context': 'B-organism'}", + "92, In {'context': 'B-in vitro'}", + "93, vitro, {'context': 'I-in vitro'}", + "95, stimulated {'effect': 'B-positive'}", + "96, Treg {'context': 'B-cells'}", + "97, cell {'context': 'I-cells'}", + "98, differentiation {'phenotype': 'B-differentiation'}", + "100, human {'context': 'B-cells'}", + "101, and {'context': 'I-cells'}", + "102, mouse {'context': 'I-cells'}", + "103, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "71, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "72, models ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "84, Foxp3+ ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "85, regulatory ['l2', 'l8', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "86, T ['l3', 'l9', 'l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "87, cells ['l4', 'l10', 'l15', 'l20', 'l24', 'l28', 'l29', 'l30']", + "88, (Treg ['l5', 'l11', 'l16', 'l21', 'l25', 'l28', 'l31', 'l32']", + "89, cells) ['l6', 'l12', 'l17', 'l22', 'l26', 'l29', 'l31', 'l33']", + "91, mice. ['l18', 'l23', 'l27', 'l30', 'l32', 'l33']", + "92, In ['l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "93, vitro, ['l34', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "95, stimulated ['l35', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "96, Treg ['l36', 'l44', 'l51', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "97, cell ['l37', 'l45', 'l52', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "98, differentiation ['l38', 'l46', 'l53', 'l59', 'l64', 'l69', 'l70', 'l71', 'l72']", + "100, human ['l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l73', 'l74', 'l75']", + "101, and ['l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l76', 'l77']", + "102, mouse ['l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l78']", + "103, cells ['l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l77', 'l78']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + }, + "context": { + "val": "cells", + "words": [ + "Treg", + "cell", + "human", + "and", + "mouse", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Treg", + "cell", + "human", + "and", + "mouse", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "28759051", + "TEXT": "CRISPR-Cas genome-editing methods hold immense potential as therapeutic tools to fix disease-causing mutations at the level of DNA. In contrast to typical drug development strategies aimed at targets that are highly conserved among individual patients, treatment at the genomic level must contend with substantial inter-individual natural genetic variation. Here we analyze the recently released ExAC and 1000 Genomes data sets to determine how human genetic variation impacts target choice for Cas endonucleases in the context of therapeutic genome editing. We find that this genetic variation confounds the target sites of certain Cas endonucleases more than others, and we provide a compendium of guide RNAs predicted to have high efficacy in diverse patient populations. For further analysis, we focus on 12 therapeutically relevant genes and consider how genetic variation affects off-target candidates for these loci. Our analysis suggests that, in large populations of individuals, most candidate off-target sites will be rare, underscoring the need for prescreening of patients through whole-genome sequencing to ensure safety. This information can be integrated with empirical methods for guide RNA selection into a framework for designing CRISPR-based therapeutics that maximizes efficacy and safety across patient populations.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28650457", + "TEXT": "The endocrine-derived hormone fibroblast growth factor (FGF) 19 has recently emerged as a potential target for treating metabolic disease. Given that skeletal muscle is a key metabolic organ, we explored the role of FGF19 in that tissue. Here we report a novel function of FGF19 in regulating skeletal muscle mass through enlargement of muscle fiber size, and in protecting muscle from atrophy. Treatment with FGF19 causes skeletal muscle hypertrophy in mice, while physiological and pharmacological doses of FGF19 substantially increase the size of human myotubes in vitro. These effects were not elicited by FGF21, a closely related endocrine FGF member. Both in vitro and in vivo, FGF19 stimulates the phosphorylation of the extracellular-signal-regulated protein kinase 1/2 (ERK1/2) and the ribosomal protein S6 kinase (S6K1), an mTOR-dependent master regulator of muscle cell growth. Moreover, mice with a skeletal-muscle-specific genetic deficiency of β-Klotho (KLB), an obligate co-receptor for FGF15/19 (refs. 2,3), were unresponsive to the hypertrophic effect of FGF19. Finally, in mice, FGF19 ameliorates skeletal muscle atrophy induced by glucocorticoid treatment or obesity, as well as sarcopenia. Taken together, these findings provide evidence that the enterokine FGF19 is a novel factor in the regulation of skeletal muscle mass, and that it has therapeutic potential for the treatment of muscle wasting.", + "TAG_DATA": [ + "70, mice, {'context': 'B-organism'}", + "83, human {'context': 'B-cells'}", + "84, myotubes {'context': 'I-cells'}", + "85, in {'context': 'B-in vitro'}", + "86, vitro. {'context': 'I-in vitro'}", + "101, in {'context': 'B-in vitro'}", + "102, vitro {'context': 'I-in vitro'}", + "104, in {'context': 'B-in vivo'}", + "105, vivo, {'context': 'I-in vivo'}", + "133, mice {'context': 'B-organism'}", + "136, skeletal-muscle-specific {'perturbing_action': 'B-gene loss-of-function'}", + "137, genetic {'perturbing_action': 'I-gene loss-of-function'}", + "138, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "139, of {'perturbing_action': 'I-gene loss-of-function'}", + "140, β-Klotho {'perturbing_action': 'I-gene loss-of-function'}", + "141, (KLB), {'perturbing_action': 'I-gene loss-of-function'}", + "159, mice, {'context': 'B-organism'}", + "162, skeletal {'context': 'B-tissue/organ'}", + "163, muscle {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "83, human ['l0', 'l1', 'l2']", + "84, myotubes ['l0', 'l3', 'l4']", + "85, in ['l1', 'l3', 'l5']", + "86, vitro. ['l2', 'l4', 'l5']", + "101, in ['l6', 'l7', 'l8']", + "102, vitro ['l6', 'l9', 'l10']", + "104, in ['l7', 'l9', 'l11']", + "105, vivo, ['l8', 'l10', 'l11']", + "133, mice ['l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "136, skeletal-muscle-specific ['l12', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "137, genetic ['l13', 'l18', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "138, deficiency ['l14', 'l19', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "139, of ['l15', 'l20', 'l27', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "140, β-Klotho ['l16', 'l21', 'l28', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47']", + "141, (KLB), ['l17', 'l22', 'l29', 'l35', 'l40', 'l44', 'l48', 'l49', 'l50']", + "159, mice, ['l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l51', 'l52']", + "162, skeletal ['l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l53']", + "163, muscle ['l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l53']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "skeletal-muscle-specific", + "genetic", + "deficiency", + "of", + "β-Klotho", + "(KLB)," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "skeletal-muscle-specific", + "genetic", + "deficiency", + "of", + "β-Klotho", + "(KLB)," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skeletal", + "muscle" + ] + } + } + ] + }, + { + "PMID": "28553933", + "TEXT": "Although antiretroviral therapy can suppress HIV-1 infection to undetectable levels of plasma viremia, integrated latent HIV-1 genomes that encode replication-competent virus persist in resting CD4+ T cells. This latent HIV-1 reservoir represents a major barrier to a cure. Currently, there are substantial efforts to identify therapeutic approaches that will eliminate or reduce the size of this latent HIV-1 reservoir. In this regard, a sensitive assay that can accurately and rapidly quantify inducible, replication-competent latent HIV-1 from resting CD4+ T cells is essential for HIV-1 eradication studies. Here we describe a reporter cell-based assay to quantify inducible, replication-competent latent HIV-1. This assay has several advantages over existing technology in that it (i) is sensitive; (ii) requires only a small blood volume; (iii) is faster, less labor intensive, and less expensive; and (iv) can be readily adapted into a high-throughput format. Using this assay, we show that the size of the inducible latent HIV-1 reservoir in aviremic participants on therapy is approximately 70-fold larger than previous estimates.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28504723", + "TEXT": "Impaired learning and cognitive function often occurs during systemic infection or inflammation. Although activation of the innate immune system has been linked to the behavioral and cognitive effects that are associated with infection, the underlying mechanisms remain poorly understood. Here we mimicked viral immune activation with poly(I:C), a synthetic analog of double-stranded RNA, and longitudinally imaged postsynaptic dendritic spines of layer V pyramidal neurons in the mouse primary motor cortex using two-photon microscopy. We found that peripheral immune activation caused dendritic spine loss, impairments in learning-dependent dendritic spine formation and deficits in multiple learning tasks in mice. These observed synaptic alterations in the cortex were mediated by peripheral-monocyte-derived cells and did not require microglial function in the central nervous system. Furthermore, activation of CX3CR1highLy6Clow monocytes impaired motor learning and learning-related dendritic spine plasticity through tumor necrosis factor (TNF)-α-dependent mechanisms. Taken together, our results highlight CX3CR1high monocytes and TNF-α as potential therapeutic targets for preventing infection-induced cognitive dysfunction.", + "TAG_DATA": [ + "60, layer {'context': 'B-cells'}", + "61, V {'context': 'I-cells'}", + "62, pyramidal {'context': 'I-cells'}", + "63, neurons {'context': 'I-cells'}", + "64, in {'context': 'I-cells'}", + "65, the {'context': 'I-cells'}", + "66, mouse {'context': 'I-cells'}", + "67, primary {'context': 'I-cells'}", + "68, motor {'context': 'I-cells'}", + "69, cortex {'context': 'I-cells'}", + "96, mice. {'context': 'B-organism'}", + "121, activation {'perturbing_action': 'B-pharmacological augmentation'}", + "122, of {'perturbing_action': 'I-pharmacological augmentation'}", + "123, CX3CR1highLy6Clow {'perturbing_action': 'I-other'}", + "124, monocytes {'context': 'B-cells'}", + "125, impaired {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "60, layer ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "61, V ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "62, pyramidal ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "63, neurons ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "64, in ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "65, the ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "66, mouse ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "67, primary ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "68, motor ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "69, cortex ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "121, activation ['l45', 'l46', 'l47', 'l48']", + "122, of ['l45', 'l49', 'l50', 'l51']", + "123, CX3CR1highLy6Clow ['l46', 'l49', 'l52', 'l53']", + "124, monocytes ['l47', 'l50', 'l52', 'l54']", + "125, impaired ['l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "of" + ] + }, + "context": { + "val": "cells", + "words": [ + "monocytes" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "of" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "CX3CR1highLy6Clow" + ] + }, + "context": { + "val": "cells", + "words": [ + "monocytes" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "CX3CR1highLy6Clow" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "monocytes" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + } + ] + }, + { + "PMID": "28481359", + "TEXT": "Tumor molecular profiling is a fundamental component of precision oncology, enabling the identification of genomic alterations in genes and pathways that can be targeted therapeutically. The existence of recurrent targetable alterations across distinct histologically defined tumor types, coupled with an expanding portfolio of molecularly targeted therapies, demands flexible and comprehensive approaches to profile clinically relevant genes across the full spectrum of cancers. We established a large-scale, prospective clinical sequencing initiative using a comprehensive assay, MSK-IMPACT, through which we have compiled tumor and matched normal sequence data from a unique cohort of more than 10,000 patients with advanced cancer and available pathological and clinical annotations. Using these data, we identified clinically relevant somatic mutations, novel noncoding alterations, and mutational signatures that were shared by common and rare tumor types. Patients were enrolled on genomically matched clinical trials at a rate of 11%. To enable discovery of novel biomarkers and deeper investigation into rare alterations and tumor types, all results are publicly accessible.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28481358", + "TEXT": "Extended daytime and nighttime activities are major contributors to the growing sleep deficiency epidemic, as is the high prevalence of sleep disorders like insomnia. The consequences of chronic insufficient sleep for health remain uncertain. Sleep quality and duration predict presence of pain the next day in healthy subjects, suggesting that sleep disturbances alone may worsen pain, and experimental sleep deprivation in humans supports this claim. We demonstrate that sleep loss, but not sleep fragmentation, in healthy mice increases sensitivity to noxious stimuli (referred to as 'pain') without general sensory hyper-responsiveness. Moderate daily repeated sleep loss leads to a progressive accumulation of sleep debt and also to exaggerated pain responses, both of which are rescued after restoration of normal sleep. Caffeine and modafinil, two wake-promoting agents that have no analgesic activity in rested mice, immediately normalize pain sensitivity in sleep-deprived animals, without affecting sleep debt. The reversibility of mild sleep-loss-induced pain by wake-promoting agents reveals an unsuspected role for alertness in setting pain sensitivity. Clinically, insufficient or poor-quality sleep may worsen pain and this enhanced pain may be reduced not by analgesics, whose effectiveness is reduced, but by increasing alertness or providing better sleep.", + "TAG_DATA": [ + "76, mice {'context': 'I-organism'}", + "132, mice, {'context': 'B-organism'}", + "139, animals, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "132, mice, ['l0']", + "139, animals, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28394333", + "TEXT": "Heart failure is a complex clinical syndrome characterized by insufficient cardiac function. In addition to abnormalities intrinsic to the heart, dysfunction of other organs and dysregulation of systemic factors greatly affect the development and consequences of heart failure. Here we show that the heart and kidneys function cooperatively in generating an adaptive response to cardiac pressure overload. In mice subjected to pressure overload in the heart, sympathetic nerve activation led to activation of renal collecting-duct (CD) epithelial cells. Cell-cell interactions among activated CD cells, tissue macrophages and endothelial cells within the kidney led to secretion of the cytokine CSF2, which in turn stimulated cardiac-resident Ly6Clo macrophages, which are essential for the myocardial adaptive response to pressure overload. The renal response to cardiac pressure overload was disrupted by renal sympathetic denervation, adrenergic β2-receptor blockade or CD-cell-specific deficiency of the transcription factor KLF5. Moreover, we identified amphiregulin as an essential cardioprotective mediator produced by cardiac Ly6Clo macrophages. Our results demonstrate a dynamic interplay between the heart, brain and kidneys that is necessary for adaptation to cardiac stress, and they highlight the homeostatic functions of tissue macrophages and the sympathetic nervous system.", + "TAG_DATA": [ + "58, mice {'context': 'B-organism'}", + "73, renal {'context': 'B-cells'}", + "74, collecting-duct {'context': 'I-cells'}", + "75, (CD) {'context': 'I-cells'}", + "76, epithelial {'context': 'I-cells'}", + "77, cells. {'context': 'I-cells'}", + "128, sympathetic {'perturbing_action': 'I-gene loss-of-function'}", + "129, denervation, {'perturbing_action': 'I-gene loss-of-function'}", + "134, CD-cell-specific {'perturbing_action': 'B-gene loss-of-function'}", + "135, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "136, of {'perturbing_action': 'I-gene loss-of-function'}", + "137, the {'perturbing_action': 'I-gene loss-of-function'}", + "138, transcription {'perturbing_action': 'I-gene loss-of-function'}", + "139, factor {'perturbing_action': 'I-gene loss-of-function'}", + "140, KLF5. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "58, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "73, renal ['l0', 'l5', 'l6', 'l7', 'l8']", + "74, collecting-duct ['l1', 'l5', 'l9', 'l10', 'l11']", + "75, (CD) ['l2', 'l6', 'l9', 'l12', 'l13']", + "76, epithelial ['l3', 'l7', 'l10', 'l12', 'l14']", + "77, cells. ['l4', 'l8', 'l11', 'l13', 'l14']", + "128, sympathetic ['l15']", + "129, denervation, ['l15']", + "134, CD-cell-specific ['l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "135, deficiency ['l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "136, of ['l17', 'l22', 'l27', 'l28', 'l29', 'l30']", + "137, the ['l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "138, transcription ['l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "139, factor ['l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "140, KLF5. ['l21', 'l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28394332", + "TEXT": "Damage-associated molecular patterns (DAMPs) trigger sterile inflammation after tissue injury, but the mechanisms underlying the resolution of inflammation remain unclear. In this study, we demonstrate that common DAMPs, such as high-mobility-group box 1 (HMGB1), peroxiredoxins (PRXs), and S100A8 and S100A9, were internalized through the class A scavenger receptors MSR1 and MARCO in vitro. In ischemic murine brain, DAMP internalization was largely mediated by MSR1. An elevation of MSR1 levels in infiltrating myeloid cells observed 3 d after experimental stroke was dependent on the transcription factor Mafb. Combined deficiency for Msr1 and Marco, or for Mafb alone, in infiltrating myeloid cells caused impaired clearance of DAMPs, more severe inflammation, and exacerbated neuronal injury in a murine model of ischemic stroke. The retinoic acid receptor (RAR) agonist Am80 increased the expression of Mafb, thereby enhancing MSR1 expression. Am80 exhibited therapeutic efficacy when administered, even at 24 h after the onset of experimental stroke. Our findings uncover cellular mechanisms contributing to DAMP clearance in resolution of the sterile inflammation triggered by tissue injury.", + "TAG_DATA": [ + "55, murine {'context': 'B-tissue/organ'}", + "56, brain, {'context': 'I-tissue/organ'}", + "86, Combined {'perturbing_action': 'B-gene loss-of-function'}", + "87, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "88, for {'perturbing_action': 'I-gene loss-of-function'}", + "89, Msr1 {'perturbing_action': 'I-gene loss-of-function'}", + "90, and {'perturbing_action': 'I-gene loss-of-function'}", + "91, Marco, {'perturbing_action': 'I-gene loss-of-function'}", + "98, myeloid {'context': 'B-cells'}", + "99, cells {'context': 'I-cells'}", + "114, murine {'context': 'B-organism'}", + "115, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "55, murine ['l0']", + "56, brain, ['l0']", + "86, Combined ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "87, deficiency ['l1', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "88, for ['l2', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "89, Msr1 ['l3', 'l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "90, and ['l4', 'l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "91, Marco, ['l5', 'l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "98, myeloid ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "99, cells ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "114, murine ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "115, model ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Combined", + "deficiency", + "for", + "Msr1", + "and", + "Marco," + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Combined", + "deficiency", + "for", + "Msr1", + "and", + "Marco," + ] + }, + "context": { + "val": "organism", + "words": [ + "murine", + "model" + ] + } + } + ] + }, + { + "PMID": "28394330", + "TEXT": "Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that compromise its chloride channel activity. The most common mutation, p.Phe508del, results in the production of a misfolded CFTR protein, which has residual channel activity but is prematurely degraded. Because of the inherent complexity of the pathogenetic mechanisms involved in CF, which include impaired chloride permeability and persistent lung inflammation, a multidrug approach is required for efficacious CF therapy. To date, no individual drug with pleiotropic beneficial effects is available for CF. Here we report on the ability of thymosin alpha 1 (Tα1)-a naturally occurring polypeptide with an excellent safety profile in the clinic when used as an adjuvant or an immunotherapeutic agent-to rectify the multiple tissue defects in mice with CF as well as in cells from subjects with the p.Phe508del mutation. Tα1 displayed two combined properties that favorably opposed CF symptomatology: it reduced inflammation and increased CFTR maturation, stability and activity. By virtue of this two-pronged action, Tα1 has strong potential to be an efficacious single-molecule-based therapeutic agent for CF.", + "TAG_DATA": [ + "127, mice {'context': 'B-organism'}", + "129, CF {'context': 'I-patient'}", + "134, cells {'context': 'B-cells'}", + "139, p.Phe508del {'perturbing_action': 'B-other'}", + "140, mutation. {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "127, mice ['l0']", + "129, CF ['l0', 'l1']", + "134, cells ['l1']", + "139, p.Phe508del ['l2']", + "140, mutation. ['l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28319094", + "TEXT": "Tyrosine-kinase inhibitor (TKI) therapy for human cancers is not curative, and relapse occurs owing to the continued presence of tumor cells, referred to as minimal residual disease (MRD). The survival of MRD stem or progenitor cells in the absence of oncogenic kinase signaling, a phenomenon referred to as intrinsic resistance, depends on diverse growth factors. Here we report that oncogenic kinase and growth-factor signaling converge to induce the expression of the signaling proteins FBJ osteosarcoma oncogene (c-FOS, encoded by Fos) and dual-specificity phosphatase 1 (DUSP1). Genetic deletion of Fos and Dusp1 suppressed tumor growth in a BCR-ABL fusion protein kinase-induced mouse model of chronic myeloid leukemia (CML). Pharmacological inhibition of c-FOS, DUSP1 and BCR-ABL eradicated MRD in multiple in vivo models, as well as in mice xenotransplanted with patient-derived primary CML cells. Growth-factor signaling also conferred TKI resistance and induced FOS and DUSP1 expression in tumor cells modeling other types of kinase-driven leukemias. Our data demonstrate that c-FOS and DUSP1 expression levels determine the threshold of TKI efficacy, such that growth-factor-induced expression of c-FOS and DUSP1 confers intrinsic resistance to TKI therapy in a wide-ranging set of leukemias, and might represent a unifying Achilles' heel of kinase-driven cancers.", + "TAG_DATA": [ + "85, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "86, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "87, of {'perturbing_action': 'I-gene loss-of-function'}", + "88, Fos {'perturbing_action': 'I-gene loss-of-function'}", + "89, and {'perturbing_action': 'I-gene loss-of-function'}", + "90, Dusp1 {'perturbing_action': 'I-gene loss-of-function'}", + "91, suppressed {'effect': 'B-negative'}", + "92, tumor {'phenotype': 'B-tumour growth'}", + "93, growth {'phenotype': 'I-tumour growth'}", + "100, mouse {'context': 'B-neoplasm'}", + "101, model {'context': 'I-neoplasm'}", + "102, of {'context': 'I-neoplasm'}", + "103, chronic {'context': 'I-neoplasm'}", + "104, myeloid {'context': 'I-neoplasm'}", + "105, leukemia {'context': 'I-neoplasm'}", + "106, (CML). {'context': 'I-neoplasm'}", + "107, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "108, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "109, of {'perturbing_action': 'I-pharmacological inhibition'}", + "110, c-FOS, {'perturbing_action': 'I-pharmacological inhibition'}", + "111, DUSP1 {'perturbing_action': 'I-pharmacological inhibition'}", + "112, and {'perturbing_action': 'I-pharmacological inhibition'}", + "113, BCR-ABL {'perturbing_action': 'I-pharmacological inhibition'}", + "118, in {'context': 'B-in vivo'}", + "119, vivo {'context': 'I-in vivo'}", + "125, mice {'context': 'B-organism'}", + "126, xenotransplanted {'context': 'I-xenograft'}", + "127, with {'context': 'I-xenograft'}", + "128, patient-derived {'context': 'I-xenograft'}", + "129, primary {'context': 'I-xenograft'}", + "130, CML {'context': 'I-xenograft'}", + "131, cells. {'context': 'I-xenograft'}", + "145, tumor {'context': 'B-transformed cells'}", + "146, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "85, Genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "86, deletion ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "87, of ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "88, Fos ['l2', 'l16', 'l29', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "89, and ['l3', 'l17', 'l30', 'l42', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "90, Dusp1 ['l4', 'l18', 'l31', 'l43', 'l54', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "91, suppressed ['l5', 'l19', 'l32', 'l44', 'l55', 'l65', 'l75', 'l76', 'l77']", + "92, tumor ['l6', 'l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l78']", + "93, growth ['l7', 'l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l78']", + "100, mouse ['l8', 'l22', 'l35', 'l47', 'l58', 'l68', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "101, model ['l9', 'l23', 'l36', 'l48', 'l59', 'l69', 'l79', 'l85', 'l86', 'l87', 'l88', 'l89']", + "102, of ['l10', 'l24', 'l37', 'l49', 'l60', 'l70', 'l77', 'l80', 'l85', 'l90', 'l91', 'l92', 'l93']", + "103, chronic ['l11', 'l25', 'l38', 'l50', 'l61', 'l71', 'l81', 'l86', 'l90', 'l94', 'l95', 'l96']", + "104, myeloid ['l12', 'l26', 'l39', 'l51', 'l62', 'l72', 'l82', 'l87', 'l91', 'l94', 'l97', 'l98']", + "105, leukemia ['l13', 'l27', 'l40', 'l52', 'l63', 'l73', 'l83', 'l88', 'l92', 'l95', 'l97', 'l99']", + "106, (CML). ['l14', 'l28', 'l41', 'l53', 'l64', 'l74', 'l84', 'l89', 'l93', 'l96', 'l98', 'l99']", + "107, Pharmacological ['l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "108, inhibition ['l100', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "109, of ['l101', 'l117', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "110, c-FOS, ['l102', 'l118', 'l133', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "111, DUSP1 ['l103', 'l119', 'l134', 'l148', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "112, and ['l104', 'l120', 'l135', 'l149', 'l162', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184']", + "113, BCR-ABL ['l105', 'l121', 'l136', 'l150', 'l163', 'l174', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "118, in ['l106', 'l122', 'l137', 'l151', 'l164', 'l175', 'l185', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202']", + "119, vivo ['l107', 'l123', 'l138', 'l152', 'l165', 'l176', 'l186', 'l195', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209']", + "125, mice ['l108', 'l124', 'l139', 'l153', 'l166', 'l177', 'l187', 'l196', 'l203', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215']", + "126, xenotransplanted ['l109', 'l125', 'l140', 'l154', 'l167', 'l178', 'l188', 'l197', 'l204', 'l210', 'l216', 'l217', 'l218', 'l219', 'l220']", + "127, with ['l110', 'l126', 'l141', 'l155', 'l168', 'l179', 'l189', 'l198', 'l205', 'l211', 'l216', 'l221', 'l222', 'l223', 'l224']", + "128, patient-derived ['l111', 'l127', 'l142', 'l156', 'l169', 'l180', 'l190', 'l199', 'l206', 'l212', 'l217', 'l221', 'l225', 'l226', 'l227', 'l228', 'l229']", + "129, primary ['l112', 'l128', 'l143', 'l157', 'l170', 'l181', 'l191', 'l200', 'l207', 'l213', 'l218', 'l222', 'l225', 'l230', 'l231']", + "130, CML ['l113', 'l129', 'l144', 'l158', 'l171', 'l182', 'l192', 'l201', 'l208', 'l214', 'l219', 'l223', 'l226', 'l230', 'l232']", + "131, cells. ['l114', 'l130', 'l145', 'l159', 'l172', 'l183', 'l193', 'l202', 'l209', 'l215', 'l220', 'l224', 'l227', 'l231', 'l232']", + "145, tumor ['l115', 'l131', 'l146', 'l160', 'l228', 'l233']", + "146, cells ['l116', 'l132', 'l147', 'l161', 'l173', 'l184', 'l194', 'l229', 'l233']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "deletion", + "of", + "Fos", + "and", + "Dusp1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "deletion", + "of", + "Fos", + "and", + "Dusp1" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "deletion", + "of", + "Fos", + "and", + "Dusp1" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "chronic", + "myeloid", + "leukemia", + "(CML)." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "of" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "c-FOS,", + "DUSP1", + "and", + "BCR-ABL" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "c-FOS,", + "DUSP1", + "and", + "BCR-ABL" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "c-FOS,", + "DUSP1", + "and", + "BCR-ABL" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenotransplanted", + "with", + "patient-derived", + "primary", + "CML", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "c-FOS,", + "DUSP1", + "and", + "BCR-ABL" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + } + ] + }, + { + "PMID": "28263312", + "TEXT": "We developed a multiplexed assay on a plasmonic-gold platform for measuring IgG and IgA antibodies and IgG avidity against both Zika virus (ZIKV) and dengue virus (DENV) infections. In contrast to IgM cross-reactivity, IgG and IgA antibodies against ZIKV nonstructural protein 1 (NS1) antigen were specific to ZIKV infection, and IgG avidity revealed recent ZIKV infection and past DENV-2 infection in patients in dengue-endemic regions. This assay could enable specific diagnosis of ZIKV infection over other flaviviral infections.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28263309", + "TEXT": "Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor that is located in the pons and primarily affects children. Nearly 80% of DIPGs harbor mutations in histone H3 genes, wherein lysine 27 is substituted with methionine (H3K27M). H3K27M has been shown to inhibit polycomb repressive complex 2 (PRC2), a multiprotein complex responsible for the methylation of H3 at lysine 27 (H3K27me), by binding to its catalytic subunit EZH2. Although DIPGs with the H3K27M mutation show global loss of H3K27me3, several genes retain H3K27me3. Here we describe a mouse model of DIPG in which H3K27M potentiates tumorigenesis. Using this model and primary patient-derived DIPG cell lines, we show that H3K27M-expressing tumors require PRC2 for proliferation. Furthermore, we demonstrate that small-molecule EZH2 inhibitors abolish tumor cell growth through a mechanism that is dependent on the induction of the tumor-suppressor protein p16INK4A. Genome-wide enrichment analyses show that the genes that retain H3K27me3 in H3K27M cells are strong polycomb targets. Furthermore, we find a highly significant overlap between genes that retain H3K27me3 in the DIPG mouse model and in human primary DIPGs expressing H3K27M. Taken together, these results show that residual PRC2 activity is required for the proliferation of H3K27M-expressing DIPGs, and that inhibition of EZH2 is a potential therapeutic strategy for the treatment of these tumors.", + "TAG_DATA": [ + "88, mouse {'context': 'B-organism'}", + "89, model {'context': 'I-organism'}", + "95, potentiates {'effect': 'B-positive'}", + "96, tumorigenesis. {'phenotype': 'B-tumourigenesis'}", + "101, primary {'context': 'B-transformed cells'}", + "102, patient-derived {'context': 'I-transformed cells'}", + "103, DIPG {'context': 'I-transformed cells'}", + "104, cell {'context': 'I-transformed cells'}", + "105, lines, {'context': 'I-transformed cells'}", + "119, small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "120, EZH2 {'perturbing_action': 'I-pharmacological inhibition'}", + "121, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "122, abolish {'effect': 'B-negative'}", + "123, tumor {'context': 'B-neoplasm'}", + "124, cell {'phenotype': 'B-cell growth'}", + "125, growth {'phenotype': 'I-cell growth'}" + ], + "LINK_DATA": [ + "88, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "89, model ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "91, DIPG ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "95, potentiates ['l2', 'l8', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "96, tumorigenesis. ['l3', 'l9', 'l14', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30']", + "101, primary ['l4', 'l10', 'l15', 'l20', 'l26', 'l31', 'l32', 'l33', 'l34', 'l35']", + "102, patient-derived ['l21', 'l27', 'l31', 'l36', 'l37', 'l38', 'l39']", + "103, DIPG ['l16', 'l22', 'l28', 'l32', 'l36', 'l40', 'l41', 'l42']", + "104, cell ['l5', 'l11', 'l17', 'l23', 'l29', 'l33', 'l37', 'l40', 'l43', 'l44']", + "105, lines, ['l6', 'l12', 'l18', 'l24', 'l30', 'l34', 'l38', 'l41', 'l43', 'l45']", + "110, tumors ['l25', 'l35', 'l39', 'l42', 'l44', 'l45']", + "119, small-molecule ['l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "120, EZH2 ['l46', 'l52', 'l53', 'l54', 'l55', 'l56']", + "121, inhibitors ['l47', 'l52', 'l57', 'l58', 'l59', 'l60']", + "122, abolish ['l48', 'l53', 'l57', 'l61', 'l62', 'l63']", + "123, tumor ['l49', 'l54', 'l58', 'l61', 'l64', 'l65']", + "124, cell ['l50', 'l55', 'l59', 'l62', 'l64', 'l66']", + "125, growth ['l51', 'l56', 'l60', 'l63', 'l65', 'l66']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "effect": { + "val": "positive", + "words": [ + "potentiates" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "potentiates" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "potentiates" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "patient-derived", + "DIPG", + "cell", + "lines," + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "patient-derived", + "DIPG", + "cell", + "lines," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "EZH2", + "inhibitors" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abolish" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "EZH2", + "inhibitors" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "EZH2", + "inhibitors" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abolish" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abolish" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + } + ] + }, + { + "PMID": "28263307", + "TEXT": "Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor characterized by rapid and uniform patient demise. A heterozygous point mutation of histone H3 occurs in more than 80% of these tumors and results in a lysine-to-methionine substitution (H3K27M). Expression of this histone mutant is accompanied by a reduction in the levels of polycomb repressive complex 2 (PRC2)-mediated H3K27 trimethylation (H3K27me3), and this is hypothesized to be a driving event of DIPG oncogenesis. Despite a major loss of H3K27me3, PRC2 activity is still detected in DIPG cells positive for H3K27M. To investigate the functional roles of H3K27M and PRC2 in DIPG pathogenesis, we profiled the epigenome of H3K27M-mutant DIPG cells and found that H3K27M associates with increased H3K27 acetylation (H3K27ac). In accordance with previous biochemical data, the majority of the heterotypic H3K27M-K27ac nucleosomes colocalize with bromodomain proteins at the loci of actively transcribed genes, whereas PRC2 is excluded from these regions; this suggests that H3K27M does not sequester PRC2 on chromatin. Residual PRC2 activity is required to maintain DIPG proliferative potential, by repressing neuronal differentiation and function. Finally, to examine the therapeutic potential of blocking the recruitment of bromodomain proteins by heterotypic H3K27M-K27ac nucleosomes in DIPG cells, we performed treatments in vivo with BET bromodomain inhibitors and demonstrate that they efficiently inhibit tumor progression, thus identifying this class of compounds as potential therapeutics in DIPG.", + "TAG_DATA": [ + "109, H3K27M-mutant {'perturbing_action': 'B-other'}", + "110, DIPG {'context': 'B-transformed cells'}", + "111, cells {'context': 'I-transformed cells'}", + "171, proliferative {'phenotype': 'B-proliferation'}", + "172, potential, {'phenotype': 'I-proliferation'}", + "174, repressing {'effect': 'B-negative'}", + "176, differentiation {'phenotype': 'B-differentiation'}", + "197, DIPG {'context': 'B-transformed cells'}", + "198, cells, {'context': 'I-transformed cells'}", + "202, in {'context': 'B-in vivo'}", + "203, vivo {'context': 'I-in vivo'}", + "213, inhibit {'effect': 'B-negative'}", + "214, tumor {'phenotype': 'B-tumour progression'}", + "215, progression, {'phenotype': 'I-tumour progression'}" + ], + "LINK_DATA": [ + "109, H3K27M-mutant ['l0', 'l1']", + "110, DIPG ['l0', 'l2']", + "111, cells ['l1', 'l2']", + "171, proliferative ['l3', 'l4', 'l5', 'l6', 'l7']", + "172, potential, ['l3', 'l8', 'l9', 'l10', 'l11']", + "174, repressing ['l4', 'l8', 'l12', 'l13', 'l14', 'l15', 'l16']", + "176, differentiation ['l5', 'l9', 'l12', 'l17', 'l18']", + "197, DIPG ['l6', 'l10', 'l13', 'l17', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "198, cells, ['l7', 'l11', 'l14', 'l18', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "202, in ['l15', 'l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "203, vivo ['l16', 'l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "213, inhibit ['l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "214, tumor ['l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "215, progression, ['l24', 'l29', 'l33', 'l36', 'l38', 'l39']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "H3K27M-mutant" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "DIPG", + "cells" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "potential," + ] + }, + "effect": { + "val": "negative", + "words": [ + "repressing" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "potential," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "DIPG", + "cells," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "repressing" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "repressing", + "inhibit" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "DIPG", + "cells," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "repressing", + "inhibit" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "DIPG", + "cells," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "DIPG", + "cells," + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression," + ] + } + } + ] + }, + { + "PMID": "28218919", + "TEXT": "Nonalcoholic steatohepatitis (NASH) is a progressive disease that is often accompanied by metabolic syndrome and poses a high risk of severe liver damage. However, no effective pharmacological treatment is currently available for NASH. Here we report that CASP8 and FADD-like apoptosis regulator (CFLAR) is a key suppressor of steatohepatitis and its metabolic disorders. We provide mechanistic evidence that CFLAR directly targets the kinase MAP3K5 (also known as ASK1) and interrupts its N-terminus-mediated dimerization, thereby blocking signaling involving ASK1 and the kinase MAPK8 (also known as JNK1). Furthermore, we identified a small peptide segment in CFLAR that effectively attenuates the progression of steatohepatitis and metabolic disorders in both mice and monkeys by disrupting the N-terminus-mediated dimerization of ASK1 when the peptide is expressed from an injected adenovirus-associated virus 8-based vector. Taken together, these findings establish CFLAR as a key suppressor of steatohepatitis and indicate that the development of CFLAR-peptide-mimicking drugs and the screening of small-molecular inhibitors that specifically block ASK1 dimerization are new and feasible approaches for NASH treatment.", + "TAG_DATA": [ + "107, mice {'context': 'B-organism'}", + "109, monkeys {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28191886", + "TEXT": "The voltage-gated cardiac Na+ channel (Nav1.5), encoded by the SCN5A gene, conducts the inward depolarizing cardiac Na+ current (INa) and is vital for normal cardiac electrical activity. Inherited loss-of-function mutations in SCN5A lead to defects in the generation and conduction of the cardiac electrical impulse and are associated with various arrhythmia phenotypes. Here we show that sirtuin 1 deacetylase (Sirt1) deacetylates Nav1.5 at lysine 1479 (K1479) and stimulates INa via lysine-deacetylation-mediated trafficking of Nav1.5 to the plasma membrane. Cardiac Sirt1 deficiency in mice induces hyperacetylation of K1479 in Nav1.5, decreases expression of Nav1.5 on the cardiomyocyte membrane, reduces INa and leads to cardiac conduction abnormalities and premature death owing to arrhythmia. The arrhythmic phenotype of cardiac-Sirt1-deficient mice recapitulated human cardiac arrhythmias resulting from loss of function of Nav1.5. Increased Sirt1 activity or expression results in decreased lysine acetylation of Nav1.5, which promotes the trafficking of Nav1.5 to the plasma membrane and stimulation of INa. As compared to wild-type Nav1.5, Nav1.5 with K1479 mutated to a nonacetylatable residue increases peak INa and is not regulated by Sirt1, whereas Nav1.5 with K1479 mutated to mimic acetylation decreases INa. Nav1.5 is hyperacetylated on K1479 in the hearts of patients with cardiomyopathy and clinical conduction disease. Thus, Sirt1, by deacetylating Nav1.5, plays an essential part in the regulation of INa and cardiac electrical activity.", + "TAG_DATA": [ + "78, Cardiac {'perturbing_action': 'B-gene loss-of-function'}", + "79, Sirt1 {'perturbing_action': 'I-gene loss-of-function'}", + "80, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "82, mice {'context': 'B-organism'}", + "115, cardiac-Sirt1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "116, mice {'context': 'B-organism'}", + "123, loss {'perturbing_action': 'B-gene loss-of-function'}", + "124, of {'perturbing_action': 'I-gene loss-of-function'}", + "125, function {'perturbing_action': 'I-gene loss-of-function'}", + "126, of {'perturbing_action': 'I-gene loss-of-function'}", + "127, Nav1.5. {'perturbing_action': 'I-gene loss-of-function'}", + "161, K1479 {'perturbing_action': 'I-other'}", + "162, mutated {'perturbing_action': 'I-other'}", + "179, K1479 {'perturbing_action': 'I-other'}", + "180, mutated {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "78, Cardiac ['l0', 'l1', 'l2']", + "79, Sirt1 ['l0', 'l3', 'l4']", + "80, deficiency ['l1', 'l3', 'l5']", + "82, mice ['l2', 'l4', 'l5']", + "115, cardiac-Sirt1-deficient ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "116, mice ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "123, loss ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "124, of ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "125, function ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "126, of ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "127, Nav1.5. ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']", + "161, K1479 ['l27', 'l28', 'l29']", + "162, mutated ['l27', 'l30', 'l31']", + "179, K1479 ['l28', 'l30', 'l32']", + "180, mutated ['l29', 'l31', 'l32']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cardiac", + "Sirt1", + "deficiency", + "cardiac-Sirt1-deficient", + "loss", + "of", + "function", + "Nav1.5." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "28165480", + "TEXT": "Cystinuria is an incompletely dominant disorder characterized by defective urinary cystine reabsorption that results in the formation of cystine-based urinary stones. Current treatment options are limited in their effectiveness at preventing stone recurrence and are often poorly tolerated. We report that the nutritional supplement α-lipoic acid inhibits cystine stone formation in the Slc3a1-/- mouse model of cystinuria by increasing the solubility of urinary cystine. These findings identify a novel therapeutic strategy for the clinical treatment of cystinuria.", + "TAG_DATA": [ + "46, inhibits {'effect': 'B-negative'}", + "49, formation {'phenotype': 'I-tumourigenesis'}", + "52, Slc3a1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "53, mouse {'context': 'B-organism'}", + "54, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "46, inhibits ['l0', 'l1', 'l2', 'l3']", + "49, formation ['l0', 'l4', 'l5']", + "52, Slc3a1-/- ['l1', 'l6', 'l7']", + "53, mouse ['l2', 'l4', 'l6', 'l8']", + "54, model ['l3', 'l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Slc3a1-/-" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Slc3a1-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + } + ] + }, + { + "PMID": "28134926", + "TEXT": "Developmental tumors in children and young adults carry few genetic alterations, yet they have diverse clinical presentation. Focusing on Ewing sarcoma, we sought to establish the prevalence and characteristics of epigenetic heterogeneity in genetically homogeneous cancers. We performed genome-scale DNA methylation sequencing for a large cohort of Ewing sarcoma tumors and analyzed epigenetic heterogeneity on three levels: between cancers, between tumors, and within tumors. We observed consistent DNA hypomethylation at enhancers regulated by the disease-defining EWS-FLI1 fusion protein, thus establishing epigenomic enhancer reprogramming as a ubiquitous and characteristic feature of Ewing sarcoma. DNA methylation differences between tumors identified a continuous disease spectrum underlying Ewing sarcoma, which reflected the strength of an EWS-FLI1 regulatory signature and a continuum between mesenchymal and stem cell signatures. There was substantial epigenetic heterogeneity within tumors, particularly in patients with metastatic disease. In summary, our study provides a comprehensive assessment of epigenetic heterogeneity in Ewing sarcoma and thereby highlights the importance of considering nongenetic aspects of tumor heterogeneity in the context of cancer biology and personalized medicine.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28112734", + "TEXT": "Opportunistic fungal infections are a leading cause of death among immune-compromised patients, and there is a pressing need to develop new antifungal therapeutic agents because of toxicity and resistance to the antifungal drugs currently in use. Although C-type lectin receptor- and Toll-like receptor-induced signaling pathways are key activators of host antifungal immunity, little is known about the mechanisms that negatively regulate host immune responses to a fungal infection. Here we found that JNK1 activation suppresses antifungal immunity in mice. We showed that JNK1-deficient mice had a significantly higher survival rate than wild-type control mice in response to Candida albicans infection, and the expression of JNK1 in hematopoietic innate immune cells was critical for this effect. JNK1 deficiency leads to significantly higher induction of CD23, a novel C-type lectin receptor, through NFATc1-mediated regulation of the CD23 gene promoter. Blocking either CD23 upregulation or CD23-dependent nitric oxide production eliminated the enhanced antifungal response found in JNK1-deficient mice. Notably, JNK inhibitors exerted potent antifungal therapeutic effects in both mouse and human cells infected with C. albicans, indicating that JNK1 may be a therapeutic target for treating fungal infection.", + "TAG_DATA": [ + "78, mice. {'context': 'B-organism'}", + "82, JNK1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "83, mice {'context': 'B-organism'}", + "93, mice {'context': 'B-organism'}", + "106, hematopoietic {'context': 'B-cells'}", + "107, innate {'context': 'I-cells'}", + "108, immune {'context': 'I-cells'}", + "109, cells {'context': 'I-cells'}", + "115, JNK1 {'perturbing_action': 'B-gene loss-of-function'}", + "116, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "153, JNK1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "154, mice. {'context': 'B-organism'}", + "156, JNK {'perturbing_action': 'B-pharmacological inhibition'}", + "157, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "165, mouse {'context': 'B-cells'}", + "166, and {'context': 'I-cells'}", + "167, human {'context': 'I-cells'}", + "168, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "78, mice. ['l0', 'l1', 'l2']", + "82, JNK1-deficient ['l0', 'l3', 'l4', 'l5', 'l6']", + "83, mice ['l1', 'l3', 'l7']", + "93, mice ['l2', 'l4', 'l7', 'l8']", + "106, hematopoietic ['l9', 'l10', 'l11', 'l12', 'l13']", + "107, innate ['l9', 'l14', 'l15', 'l16', 'l17']", + "108, immune ['l5', 'l10', 'l14', 'l18', 'l19']", + "109, cells ['l6', 'l8', 'l11', 'l15', 'l18']", + "115, JNK1 ['l12', 'l16', 'l20']", + "116, deficiency ['l13', 'l17', 'l19', 'l20']", + "153, JNK1-deficient ['l21']", + "154, mice. ['l21']", + "156, JNK ['l22', 'l23', 'l24', 'l25', 'l26']", + "157, inhibitors ['l22', 'l27', 'l28', 'l29', 'l30']", + "165, mouse ['l23', 'l27', 'l31', 'l32', 'l33']", + "166, and ['l24', 'l28', 'l31', 'l34', 'l35']", + "167, human ['l25', 'l29', 'l32', 'l34', 'l36']", + "168, cells ['l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "JNK1-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "JNK1-deficient", + "JNK1", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "immune", + "cells", + "hematopoietic", + "innate" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "JNK", + "inhibitors" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "and", + "human", + "cells" + ] + } + } + ] + }, + { + "PMID": "28060803", + "TEXT": "A new study shows that fasting induces the differentiation and elimination of some types of leukemia, which implicates fasting or its mimetics as a novel strategy for the treatment of leukemia.", + "TAG_DATA": [ + "6, induces {'effect': 'B-positive'}", + "8, differentiation {'phenotype': 'B-differentiation'}", + "14, of {'context': 'B-neoplasm'}", + "15, leukemia, {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "6, induces ['l0', 'l1', 'l2']", + "8, differentiation ['l0', 'l3', 'l4']", + "14, of ['l1', 'l3', 'l5']", + "15, leukemia, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "of", + "leukemia," + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "of", + "leukemia," + ] + } + } + ] + }, + { + "PMID": "28024083", + "TEXT": "Mammalian tissues rely on a variety of nutrients to support their physiological functions. It is known that altered metabolism is involved in the pathogenesis of cancer, but which nutrients support the inappropriate growth of intact malignant tumors is incompletely understood. Amino acids are essential nutrients for many cancer cells that can be obtained through the scavenging and catabolism of extracellular protein via macropinocytosis. In particular, macropinocytosis can be a nutrient source for pancreatic cancer cells, but it is not fully understood how the tumor environment influences metabolic phenotypes and whether macropinocytosis supports the maintenance of amino acid levels within pancreatic tumors. Here we utilize miniaturized plasma exchange to deliver labeled albumin to tissues in live mice, and we demonstrate that breakdown of albumin contributes to the supply of free amino acids in pancreatic tumors. We also deliver albumin directly into tumors using an implantable microdevice, which was adapted and modified from ref. 9. Following implantation, we directly observe protein catabolism and macropinocytosis in situ by pancreatic cancer cells, but not by adjacent, non-cancerous pancreatic tissue. In addition, we find that intratumoral inhibition of macropinocytosis decreases amino acid levels. Taken together, these data suggest that pancreatic cancer cells consume extracellular protein, including albumin, and that this consumption serves as an important source of amino acids for pancreatic cancer cells in vivo.", + "TAG_DATA": [ + "115, mice, {'context': 'B-organism'}", + "132, pancreatic {'context': 'B-neoplasm'}", + "133, tumors. {'context': 'I-neoplasm'}", + "140, tumors {'context': 'B-neoplasm'}", + "165, pancreatic {'context': 'B-transformed cells'}", + "166, cancer {'context': 'I-transformed cells'}", + "167, cells, {'context': 'I-transformed cells'}", + "172, non-cancerous {'context': 'I-tissue/organ'}", + "173, pancreatic {'context': 'I-tissue/organ'}", + "174, tissue. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "115, mice, ['l0', 'l1']", + "132, pancreatic ['l0', 'l2', 'l3', 'l4']", + "133, tumors. ['l1', 'l2']", + "140, tumors ['l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "165, pancreatic ['l5', 'l11', 'l12', 'l13', 'l14', 'l15']", + "166, cancer ['l3', 'l6', 'l11', 'l16', 'l17', 'l18', 'l19']", + "167, cells, ['l4', 'l7', 'l12', 'l16', 'l20']", + "172, non-cancerous ['l8', 'l13', 'l17', 'l21', 'l22']", + "173, pancreatic ['l9', 'l14', 'l18', 'l21', 'l23']", + "174, tissue. ['l10', 'l15', 'l19', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27991919", + "TEXT": "The nucleoside analog cytarabine (Ara-C) is an essential component of primary and salvage chemotherapy regimens for acute myeloid leukemia (AML). After cellular uptake, Ara-C is converted into its therapeutically active triphosphate metabolite, Ara-CTP, which exerts antileukemic effects, primarily by inhibiting DNA synthesis in proliferating cells. Currently, a substantial fraction of patients with AML fail to respond effectively to Ara-C therapy, and reliable biomarkers for predicting the therapeutic response to Ara-C are lacking. SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate. Although it has been postulated that SAMHD1 sensitizes cancer cells to nucleoside-analog derivatives through the depletion of competing dNTPs, we show here that SAMHD1 reduces Ara-C cytotoxicity in AML cells. Mechanistically, dGTP-activated SAMHD1 hydrolyzes Ara-CTP, which results in a drastic reduction of Ara-CTP in leukemic cells. Loss of SAMHD1 activity-through genetic depletion, mutational inactivation of its triphosphohydrolase activity or proteasomal degradation using specialized, virus-like particles-potentiates the cytotoxicity of Ara-C in AML cells. In mouse models of retroviral AML transplantation, as well as in retrospective analyses of adult patients with AML, the response to Ara-C-containing therapy was inversely correlated with SAMHD1 expression. These results identify SAMHD1 as a potential biomarker for the stratification of patients with AML who might best respond to Ara-C-based therapy and as a target for treating Ara-C-refractory AML.", + "TAG_DATA": [ + "116, AML {'context': 'B-transformed cells'}", + "117, cells. {'context': 'I-transformed cells'}", + "132, leukemic {'context': 'B-transformed cells'}", + "133, cells. {'context': 'I-transformed cells'}", + "134, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "135, of {'perturbing_action': 'I-gene loss-of-function'}", + "136, SAMHD1 {'perturbing_action': 'I-gene loss-of-function'}", + "137, activity-through {'perturbing_action': 'I-gene loss-of-function'}", + "158, AML {'context': 'B-transformed cells'}", + "159, cells. {'context': 'I-transformed cells'}", + "161, mouse {'context': 'B-organism'}", + "162, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "116, AML ['l0', 'l1', 'l2']", + "117, cells. ['l0', 'l3']", + "132, leukemic ['l1', 'l4']", + "133, cells. ['l2', 'l3', 'l4']", + "134, Loss ['l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "135, of ['l5', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "136, SAMHD1 ['l6', 'l12', 'l18', 'l19', 'l20', 'l21', 'l22']", + "137, activity-through ['l7', 'l13', 'l18', 'l23', 'l24', 'l25', 'l26']", + "158, AML ['l8', 'l14', 'l19', 'l23', 'l27']", + "159, cells. ['l9', 'l15', 'l20', 'l24', 'l27']", + "161, mouse ['l10', 'l16', 'l21', 'l25', 'l28']", + "162, models ['l11', 'l17', 'l22', 'l26', 'l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Loss", + "of", + "SAMHD1", + "activity-through" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "AML", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Loss", + "of", + "SAMHD1", + "activity-through" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + } + } + ] + }, + { + "PMID": "27918562", + "TEXT": "Biomarkers have transformed modern medicine but remain largely elusive in psychiatry, partly because there is a weak correspondence between diagnostic labels and their neurobiological substrates. Like other neuropsychiatric disorders, depression is not a unitary disease, but rather a heterogeneous syndrome that encompasses varied, co-occurring symptoms and divergent responses to treatment. By using functional magnetic resonance imaging (fMRI) in a large multisite sample (n = 1,188), we show here that patients with depression can be subdivided into four neurophysiological subtypes ('biotypes') defined by distinct patterns of dysfunctional connectivity in limbic and frontostriatal networks. Clustering patients on this basis enabled the development of diagnostic classifiers (biomarkers) with high (82-93%) sensitivity and specificity for depression subtypes in multisite validation (n = 711) and out-of-sample replication (n = 477) data sets. These biotypes cannot be differentiated solely on the basis of clinical features, but they are associated with differing clinical-symptom profiles. They also predict responsiveness to transcranial magnetic stimulation therapy (n = 154). Our results define novel subtypes of depression that transcend current diagnostic boundaries and may be useful for identifying the individuals who are most likely to benefit from targeted neurostimulation therapies.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27892954", + "TEXT": "Obesity and type 2 diabetes are associated with low-grade inflammation and specific changes in gut microbiota composition. We previously demonstrated that administration of Akkermansia muciniphila to mice prevents the development of obesity and associated complications. However, the underlying mechanisms of this protective effect remain unclear. Moreover, the sensitivity of A. muciniphila to oxygen and the presence of animal-derived compounds in its growth medium currently limit the development of translational approaches for human medicine. We have addressed these issues here by showing that A. muciniphila retains its efficacy when grown on a synthetic medium compatible with human administration. Unexpectedly, we discovered that pasteurization of A. muciniphila enhanced its capacity to reduce fat mass development, insulin resistance and dyslipidemia in mice. These improvements were notably associated with a modulation of the host urinary metabolomics profile and intestinal energy absorption. We demonstrated that Amuc_1100, a specific protein isolated from the outer membrane of A. muciniphila, interacts with Toll-like receptor 2, is stable at temperatures used for pasteurization, improves the gut barrier and partly recapitulates the beneficial effects of the bacterium. Finally, we showed that administration of live or pasteurized A. muciniphila grown on the synthetic medium is safe in humans. These findings provide support for the use of different preparations of A. muciniphila as therapeutic options to target human obesity and associated disorders.", + "TAG_DATA": [ + "118, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27892953", + "TEXT": "Although 22q11.2 deletion syndrome (22q11DS) is associated with early-life behavioral abnormalities, affected individuals are also at high risk for the development of schizophrenia symptoms, including psychosis, later in life. Auditory thalamocortical (TC) projections recently emerged as a neural circuit that is specifically disrupted in mouse models of 22q11DS (hereafter referred to as 22q11DS mice), in which haploinsufficiency of the microRNA (miRNA)-processing-factor-encoding gene Dgcr8 results in the elevation of the dopamine receptor Drd2 in the auditory thalamus, an abnormal sensitivity of thalamocortical projections to antipsychotics, and an abnormal acoustic-startle response. Here we show that these auditory TC phenotypes have a delayed onset in 22q11DS mice and are associated with an age-dependent reduction of miR-338-3p, a miRNA that targets Drd2 and is enriched in the thalamus of both humans and mice. Replenishing depleted miR-338-3p in mature 22q11DS mice rescued the TC abnormalities, and deletion of Mir338 (which encodes miR-338-3p) or reduction of miR-338-3p expression mimicked the TC and behavioral deficits and eliminated the age dependence of these deficits. Therefore, miR-338-3p depletion is necessary and sufficient to disrupt auditory TC signaling in 22q11DS mice, and it may mediate the pathogenic mechanism of 22q11DS-related psychosis and control its late onset.", + "TAG_DATA": [ + "131, miR-338-3p {'perturbing_action': 'I-rnai/knockdown'}", + "134, 22q11DS {'context': 'B-organism'}", + "135, mice {'context': 'I-organism'}", + "141, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "142, of {'perturbing_action': 'I-gene loss-of-function'}", + "143, Mir338 {'perturbing_action': 'I-gene loss-of-function'}", + "144, (which {'perturbing_action': 'I-gene loss-of-function'}", + "145, encodes {'perturbing_action': 'I-gene loss-of-function'}", + "146, miR-338-3p) {'perturbing_action': 'I-gene loss-of-function'}", + "148, reduction {'perturbing_action': 'B-gene loss-of-function'}", + "149, of {'perturbing_action': 'I-gene loss-of-function'}", + "150, miR-338-3p {'perturbing_action': 'I-gene loss-of-function'}", + "151, expression {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "131, miR-338-3p ['l0', 'l1']", + "134, 22q11DS ['l0', 'l2']", + "135, mice ['l1', 'l2']", + "141, deletion ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "142, of ['l3', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "143, Mir338 ['l4', 'l12', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "144, (which ['l5', 'l13', 'l20', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "145, encodes ['l6', 'l14', 'l21', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "146, miR-338-3p) ['l7', 'l15', 'l22', 'l28', 'l33', 'l38', 'l39', 'l40', 'l41']", + "148, reduction ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l42', 'l43', 'l44']", + "149, of ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l45', 'l46']", + "150, miR-338-3p ['l10', 'l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l47']", + "151, expression ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "miR-338-3p" + ] + }, + "context": { + "val": "organism", + "words": [ + "22q11DS", + "mice" + ] + } + } + ] + }, + { + "PMID": "27841874", + "TEXT": "Hepatitis C virus (HCV) infects 200 million people globally, and 60-80% of cases persist as a chronic infection that will progress to cirrhosis and liver cancer in 2-10% of patients. We recently demonstrated that HCV induces aberrant expression of two host microRNAs (miRNAs), miR-208b and miR-499a-5p, encoded by myosin genes in infected hepatocytes. These miRNAs, along with AU-rich-element-mediated decay, suppress IFNL2 and IFNL3, members of the type III interferon (IFN) gene family, to support viral persistence. In this study, we show that miR-208b and miR-499a-5p also dampen type I IFN signaling in HCV-infected hepatocytes by directly down-regulating expression of the type I IFN receptor chain, IFNAR1. Inhibition of these miRNAs by using miRNA inhibitors during HCV infection increased expression of IFNAR1. Additionally, inhibition rescued the antiviral response to exogenous type I IFN, as measured by a marked increase in IFN-stimulated genes and a decrease in HCV load. Treatment of HCV-infected hepatocytes with type I IFN increased expression of myosins over HCV infection alone. Since these miRNAs can suppress type III IFN family members, these data collectively define a novel cross-regulation between type I and III IFNs during HCV infection.", + "TAG_DATA": [ + "93, hepatocytes {'context': 'B-cells'}", + "150, hepatocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27798615", + "TEXT": "Development of an effective vaccine against Ebola virus is of high priority. However, knowledge about potential correlates of protection and the durability of immune response after vaccination is limited. Here, we elucidate the human antibody repertoire after administration of vesicular stomatitis virus (VSV)-Ebola vaccine at 3 million, 20 million and 100 million plaque-forming units (PFU) and homologous VSV-Ebola vaccine boost in healthy adult volunteers. Whole genome-fragment phage display libraries, expressing linear and conformational epitopes of Ebola glycoprotein (GP), showed higher diversity of antibody epitopes in individuals vaccinated with 20 million PFU than in those vaccinated with 3 million or 100 million PFU. Surface plasmon resonance kinetics showed higher levels of GP-binding antibodies after a single vaccination with 20 million or 100 million PFU than with 3 million PFU, and these correlated strongly with neutralization titers. A second vaccination did not boost antibody or virus neutralization titers, which declined rapidly, and induced only minimal antibody affinity maturation. Isotype analysis revealed a predominant IgM response even after the second vaccination, which contributed substantially to virus neutralization in vitro. These findings may help identify new vaccine targets and aid development and evaluation of effective countermeasures against Ebola.", + "TAG_DATA": [ + "61, healthy {'context': 'B-organism'}", + "62, adult {'context': 'I-organism'}", + "63, volunteers. {'context': 'I-organism'}", + "174, in {'context': 'B-in vitro'}", + "175, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "61, healthy ['l0', 'l1']", + "62, adult ['l0', 'l2']", + "63, volunteers. ['l1', 'l2']", + "174, in ['l3']", + "175, vitro. ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27783068", + "TEXT": "People diagnosed with neuropsychiatric disorders such as depression, anxiety, addiction or schizophrenia often have dysregulated memory, mood, pattern separation and/or reward processing. These symptoms are indicative of a disrupted function of the dentate gyrus (DG) subregion of the brain, and they improve with treatment and remission. The dysfunction of the DG is accompanied by structural maladaptations, including dysregulation of adult-generated neurons. An increasing number of studies using modern inducible approaches to manipulate new neurons show that the behavioral symptoms in animal models of neuropsychiatric disorders can be produced or exacerbated by the inhibition of DG neurogenesis. Thus, here we posit that the connection between neuropsychiatric disorders and dysregulated DG neurogenesis is beyond correlation or epiphenomenon, and that the regulation of adult-generated DG neurogenesis merits continued and focused attention in the ongoing effort to develop novel treatments for neuropsychiatric disorders.", + "TAG_DATA": [ + "81, models {'context': 'I-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27668935", + "TEXT": "At low levels, carbon monoxide (CO) has physiological roles as a second messenger and neuromodulator. Here we assess the effects of CO in a mouse model of traumatic brain injury (TBI). Treatment with CO-releasing molecule (CORM)-3 reduced pericyte death and ameliorated the progression of neurological deficits. In contrast, although treatment with the radical scavenger N-tert-butyl-a-phenylnitrone (PBN) also reduced pericyte death, neurological outcomes were not rescued. As compared to vehicle-treated control and PBN-treated mice, CORM-3-treated mice showed higher levels of phosphorylated neural nitric oxide synthase within neural stem cells (NSCs). Inhibition of nitric oxide synthase diminished the CORM-3-mediated increase in the number of cells that stained positive for both the neuronal marker NeuN and 5-bromo-2'-deoxyuridine (BrdU; a marker for proliferating cells) in vivo, consequently interfering with neurological recovery after TBI. Because NSCs seemed to be in close proximity to pericytes, we asked whether cross-talk between pericytes and NSCs was induced by CORM-3, thereby promoting neurogenesis. In pericyte cultures that were undergoing oxygen and glucose deprivation, conditioned cell culture medium collected after CORM-3 treatment enhanced the in vitro differentiation of NSCs into mature neurons. Taken together, these findings suggest that CO treatment may provide a therapeutic approach for TBI by preventing pericyte death, rescuing cross-talk with NSCs and promoting neurogenesis.", + "TAG_DATA": [ + "37, pericyte {'context': 'B-cells'}", + "58, pericyte {'context': 'B-cells'}", + "72, mice, {'context': 'B-organism'}", + "74, mice {'context': 'B-organism'}", + "85, neural {'context': 'B-cells'}", + "86, stem {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}", + "102, cells {'context': 'B-cells'}", + "120, in {'context': 'B-in vivo'}", + "121, vivo, {'context': 'I-in vivo'}", + "155, pericyte {'context': 'B-cells'}", + "156, cultures {'context': 'I-cells'}", + "172, enhanced {'effect': 'B-positive'}", + "174, in {'context': 'B-in vitro'}", + "175, vitro {'context': 'I-in vitro'}", + "176, differentiation {'phenotype': 'B-differentiation'}", + "178, NSCs {'context': 'B-cells'}", + "180, mature {'context': 'B-cells'}", + "181, neurons. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "37, pericyte ['l0']", + "58, pericyte ['l0', 'l1']", + "72, mice, ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "74, mice ['l2', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "85, neural ['l3', 'l9', 'l15', 'l16', 'l17', 'l18', 'l19']", + "86, stem ['l4', 'l10', 'l15', 'l20', 'l21', 'l22', 'l23']", + "87, cells ['l1', 'l5', 'l11', 'l16', 'l20', 'l24', 'l25', 'l26']", + "102, cells ['l6', 'l12', 'l17', 'l21', 'l24', 'l27', 'l28']", + "120, in ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l29']", + "121, vivo, ['l8', 'l14', 'l19', 'l23', 'l26', 'l28', 'l29']", + "155, pericyte ['l30', 'l31', 'l32']", + "156, cultures ['l30']", + "172, enhanced ['l31', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "174, in ['l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "175, vitro ['l34', 'l39', 'l44', 'l45', 'l46', 'l47']", + "176, differentiation ['l35', 'l40', 'l44', 'l48', 'l49', 'l50']", + "178, NSCs ['l32', 'l36', 'l41', 'l45', 'l48', 'l51', 'l52']", + "180, mature ['l37', 'l42', 'l46', 'l49', 'l51', 'l53']", + "181, neurons. ['l38', 'l43', 'l47', 'l50', 'l52', 'l53']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "pericyte", + "NSCs", + "mature", + "neurons." + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "NSCs", + "mature", + "neurons." + ] + } + } + ] + }, + { + "PMID": "27595323", + "TEXT": "In view of the high proportion of individuals with resistance to antihypertensive medication and/or poor compliance or tolerance of this medication, new drugs to treat hypertension are urgently needed. Here we show that peripheral chemoreceptors generate aberrant signaling that contributes to high blood pressure in hypertension. We discovered that purinergic receptor P2X3 (P2rx3, also known as P2x3) mRNA expression is upregulated substantially in chemoreceptive petrosal sensory neurons in rats with hypertension. These neurons generate both tonic drive and hyperreflexia in hypertensive (but not normotensive) rats, and both phenomena are normalized by the blockade of P2X3 receptors. Antagonism of P2X3 receptors also reduces arterial pressure and basal sympathetic activity and normalizes carotid body hyperreflexia in conscious rats with hypertension; no effect was observed in rats without hypertension. We verified P2X3 receptor expression in human carotid bodies and observed hyperactivity of carotid bodies in individuals with hypertension. These data support the identification of the P2X3 receptor as a potential new target for the control of human hypertension.", + "TAG_DATA": [ + "84, rats, {'context': 'B-organism'}", + "92, blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "93, of {'perturbing_action': 'I-pharmacological inhibition'}", + "94, P2X3 {'perturbing_action': 'I-pharmacological inhibition'}", + "95, receptors. {'perturbing_action': 'I-pharmacological inhibition'}", + "96, Antagonism {'perturbing_action': 'B-pharmacological inhibition'}", + "97, of {'perturbing_action': 'I-pharmacological inhibition'}", + "98, P2X3 {'perturbing_action': 'I-pharmacological inhibition'}", + "99, receptors {'perturbing_action': 'I-pharmacological inhibition'}", + "110, carotid {'context': 'B-tissue/organ'}", + "111, body {'context': 'I-tissue/organ'}", + "114, conscious {'context': 'B-organism'}", + "115, rats {'context': 'I-organism'}", + "123, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "92, blockade ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "93, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "94, P2X3 ['l1', 'l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "95, receptors. ['l2', 'l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "96, Antagonism ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "97, of ['l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "98, P2X3 ['l22', 'l29', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "99, receptors ['l23', 'l30', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "110, carotid ['l3', 'l8', 'l13', 'l17', 'l24', 'l31', 'l37', 'l42', 'l47', 'l48', 'l49']", + "111, body ['l4', 'l9', 'l14', 'l18', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l51']", + "114, conscious ['l5', 'l10', 'l15', 'l19', 'l26', 'l33', 'l39', 'l44', 'l48', 'l50', 'l52']", + "115, rats ['l11', 'l16', 'l20', 'l27', 'l34', 'l40', 'l45', 'l49', 'l51', 'l52']", + "123, rats ['l28', 'l35', 'l41', 'l46']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "P2X3", + "receptors.", + "Antagonism", + "receptors" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "carotid", + "body" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "P2X3", + "receptors.", + "Antagonism", + "receptors" + ] + }, + "context": { + "val": "organism", + "words": [ + "conscious", + "rats" + ] + } + } + ] + }, + { + "PMID": "27571349", + "TEXT": "In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ∼6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds; we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and three-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, a category B anthelmintic drug approved by the US Food and Drug Administration, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.", + "TAG_DATA": [ + "60, neural {'context': 'B-cells'}", + "61, cells. {'context': 'I-cells'}", + "74, human {'context': 'B-cells'}", + "75, cortical {'context': 'I-cells'}", + "76, neural {'context': 'I-cells'}", + "77, progenitors {'context': 'I-cells'}", + "82, three-dimensional {'context': 'B-organoid'}", + "83, organoid {'context': 'I-organoid'}", + "84, cultures. {'context': 'I-organoid'}", + "127, protection {'effect': 'B-negative'}", + "129, human {'context': 'B-cells'}", + "130, neural {'context': 'I-cells'}", + "131, progenitors {'context': 'I-cells'}", + "133, astrocytes {'context': 'B-cells'}", + "135, ZIKV-induced {'effect': 'B-positive'}", + "136, cell {'phenotype': 'B-cell death'}", + "137, death. {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "60, neural ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "61, cells. ['l0', 'l6', 'l7', 'l8', 'l9']", + "74, human ['l1', 'l6', 'l10', 'l11', 'l12', 'l13', 'l14']", + "75, cortical ['l2', 'l7', 'l10', 'l15', 'l16', 'l17', 'l18']", + "76, neural ['l3', 'l8', 'l11', 'l15', 'l19', 'l20', 'l21']", + "77, progenitors ['l4', 'l9', 'l12', 'l16', 'l19', 'l22']", + "82, three-dimensional ['l23', 'l24']", + "83, organoid ['l13', 'l17', 'l20', 'l23', 'l25']", + "84, cultures. ['l5', 'l14', 'l18', 'l21', 'l22', 'l24', 'l25']", + "127, protection ['l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "129, human ['l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "130, neural ['l27', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "131, progenitors ['l28', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47']", + "133, astrocytes ['l29', 'l35', 'l40', 'l44', 'l48', 'l49', 'l50']", + "135, ZIKV-induced ['l30', 'l36', 'l41', 'l45', 'l48', 'l51', 'l52']", + "136, cell ['l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l53']", + "137, death. ['l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l53']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "protection" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "neural", + "progenitors", + "astrocytes" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "protection" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "neural", + "progenitors", + "astrocytes" + ] + }, + "effect": { + "val": "positive", + "words": [ + "ZIKV-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "neural", + "progenitors", + "astrocytes" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "ZIKV-induced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "27455510", + "TEXT": "Altered metabolism has been implicated in the pathogenesis of inflammatory diseases. NADPH oxidase 4 (NOX4), a source of cellular superoxide anions, has multiple biological functions that may be of importance in inflammation and in the pathogenesis of human metabolic diseases, including diabetes. However, the mechanisms by which NOX4-dependent metabolic regulation affect the innate immune response remain unclear. Here we show that deficiency of NOX4 resulted in reduced expression of carnitine palmitoyltransferase 1A (CPT1A), which is a key mitochondrial enzyme in the fatty acid oxidation (FAO) pathway. The reduced FAO resulted in less activation of the nucleotide-binding domain, leucine-rich-repeat-containing receptor (NLR), pyrin-domain-containing 3 (NLRP3) inflammasome in human and mouse macrophages. In contrast, NOX4 deficiency did not inhibit the activation of the NLR family, CARD-domain-containing 4 (NLRC4), the NLRP1 or the absent in melanoma 2 (AIM2) inflammasomes. We also found that inhibition of FAO by etomoxir treatment suppressed NLRP3 inflammasome activation. Furthermore, Nox4-deficient mice showed substantial reduction in caspase-1 activation and in interleukin (IL)-1β and IL-18 production, and there was improved survival in a mouse model of NLRP3-mediated Streptococcus pneumoniae infection. The pharmacologic inhibition of NOX4 by either GKT137831, which is currently in phase 2 clinical trials, or VAS-2870 attenuated NLRP3 inflammasome activation. Our results suggest that NOX4-mediated FAO promotes NLRP3 inflammasome activation.", + "TAG_DATA": [ + "61, deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "62, of {'perturbing_action': 'I-gene loss-of-function'}", + "63, NOX4 {'perturbing_action': 'I-gene loss-of-function'}", + "105, human {'context': 'B-cells'}", + "106, and {'context': 'I-cells'}", + "107, mouse {'context': 'I-cells'}", + "108, macrophages. {'context': 'I-cells'}", + "111, NOX4 {'perturbing_action': 'B-gene loss-of-function'}", + "112, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "140, of {'perturbing_action': 'I-pharmacological inhibition'}", + "141, FAO {'perturbing_action': 'I-pharmacological inhibition'}", + "150, Nox4-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "151, mice {'context': 'B-organism'}", + "172, mouse {'context': 'B-organism'}", + "173, model {'context': 'I-organism'}", + "180, pharmacologic {'perturbing_action': 'B-pharmacological inhibition'}", + "181, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "182, of {'perturbing_action': 'I-pharmacological inhibition'}", + "183, NOX4 {'perturbing_action': 'I-pharmacological inhibition'}", + "184, by {'perturbing_action': 'I-pharmacological inhibition'}", + "185, either {'perturbing_action': 'I-pharmacological inhibition'}", + "186, GKT137831, {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "61, deficiency ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "62, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "63, NOX4 ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "105, human ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "106, and ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "107, mouse ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "108, macrophages. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "111, NOX4 ['l21']", + "112, deficiency ['l21']", + "140, of ['l22', 'l23', 'l24', 'l25', 'l26']", + "141, FAO ['l22', 'l27', 'l28', 'l29', 'l30']", + "150, Nox4-deficient ['l23', 'l27', 'l31', 'l32', 'l33']", + "151, mice ['l24', 'l28', 'l31', 'l34', 'l35']", + "172, mouse ['l25', 'l29', 'l32', 'l34', 'l36']", + "173, model ['l26', 'l30', 'l33', 'l35', 'l36']", + "180, pharmacologic ['l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "181, inhibition ['l37', 'l43', 'l44', 'l45', 'l46', 'l47']", + "182, of ['l38', 'l43', 'l48', 'l49', 'l50', 'l51']", + "183, NOX4 ['l39', 'l44', 'l48', 'l52', 'l53', 'l54']", + "184, by ['l40', 'l45', 'l49', 'l52', 'l55', 'l56']", + "185, either ['l41', 'l46', 'l50', 'l53', 'l55', 'l57']", + "186, GKT137831, ['l42', 'l47', 'l51', 'l54', 'l56', 'l57']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "of", + "NOX4" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "and", + "mouse", + "macrophages." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "of", + "FAO" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nox4-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "model" + ] + } + } + ] + }, + { + "PMID": "27400264", + "TEXT": "Antiretroviral therapy is not curative. Given the challenges in providing lifelong therapy to a global population of more than 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. This Perspective summarizes the group's strategy.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27387881", + "TEXT": "As part of the World Health Organization (WHO) R&D Blueprint initiative, leading stakeholders on Middle East respiratory syndrome coronavirus (MERS-CoV) convened to agree on strategic public-health goals and global priority research activities that are needed to combat MERS-CoV.SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nm.4131) contains supplementary material, which is available to authorized users.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27376578", + "TEXT": "In a search for mediators of the p53 tumor suppressor pathway, which induces pleiotropic and often antagonistic cellular responses, we identified the long noncoding RNA (lncRNA) NEAT1. NEAT1 is an essential architectural component of paraspeckle nuclear bodies, whose pathophysiological relevance remains unclear. Activation of p53, pharmacologically or by oncogene-induced replication stress, stimulated the formation of paraspeckles in mouse and human cells. Silencing Neat1 expression in mice, which prevents paraspeckle formation, sensitized preneoplastic cells to DNA-damage-induced cell death and impaired skin tumorigenesis. We provide mechanistic evidence that NEAT1 promotes ATR signaling in response to replication stress and is thereby engaged in a negative feedback loop that attenuates oncogene-dependent activation of p53. NEAT1 targeting in established human cancer cell lines induced synthetic lethality with genotoxic chemotherapeutics, including PARP inhibitors, and nongenotoxic activation of p53. This study establishes a key genetic link between NEAT1 paraspeckles, p53 biology and tumorigenesis and identifies NEAT1 as a promising target to enhance sensitivity of cancer cells to both chemotherapy and p53 reactivation therapy.", + "TAG_DATA": [ + "42, Activation {'perturbing_action': 'B-pharmacological augmentation'}", + "43, of {'perturbing_action': 'I-pharmacological augmentation'}", + "44, p53, {'perturbing_action': 'I-pharmacological augmentation'}", + "57, mouse {'context': 'B-cells'}", + "58, and {'context': 'I-cells'}", + "59, human {'context': 'I-cells'}", + "60, cells. {'context': 'I-cells'}", + "61, Silencing {'perturbing_action': 'B-rnai/knockdown'}", + "62, Neat1 {'perturbing_action': 'I-rnai/knockdown'}", + "63, expression {'perturbing_action': 'I-rnai/knockdown'}", + "65, mice, {'context': 'B-organism'}", + "70, sensitized {'effect': 'B-positive'}", + "71, preneoplastic {'context': 'B-transformed cells'}", + "72, cells {'context': 'I-transformed cells'}", + "75, cell {'phenotype': 'B-cell death'}", + "76, death {'phenotype': 'I-cell death'}", + "78, impaired {'effect': 'B-negative'}", + "79, skin {'context': 'B-tissue/organ'}", + "80, tumorigenesis. {'phenotype': 'B-tumourigenesis'}", + "110, NEAT1 {'perturbing_action': 'B-rnai/knockdown'}", + "111, targeting {'perturbing_action': 'I-other'}", + "114, human {'context': 'B-transformed cells'}", + "115, cancer {'context': 'I-transformed cells'}", + "116, cell {'context': 'I-transformed cells'}", + "117, lines {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "42, Activation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "43, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "44, p53, ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "57, mouse ['l2', 'l12', 'l21', 'l30', 'l31', 'l32']", + "58, and ['l3', 'l13', 'l22', 'l30', 'l33', 'l34']", + "59, human ['l4', 'l14', 'l23', 'l31', 'l33', 'l35']", + "60, cells. ['l5', 'l15', 'l24', 'l32', 'l34', 'l35']", + "61, Silencing ['l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "62, Neat1 ['l36', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "63, expression ['l37', 'l47', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "65, mice, ['l38', 'l48', 'l57', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "70, sensitized ['l6', 'l16', 'l25', 'l39', 'l49', 'l58', 'l66', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "71, preneoplastic ['l7', 'l17', 'l26', 'l40', 'l50', 'l59', 'l67', 'l74', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "72, cells ['l8', 'l18', 'l27', 'l41', 'l51', 'l60', 'l68', 'l75', 'l81', 'l87', 'l88', 'l89', 'l90']", + "75, cell ['l9', 'l19', 'l28', 'l42', 'l52', 'l61', 'l69', 'l76', 'l82', 'l87', 'l91', 'l92', 'l93', 'l94']", + "76, death ['l10', 'l20', 'l29', 'l43', 'l53', 'l62', 'l70', 'l77', 'l83', 'l88', 'l91', 'l95', 'l96', 'l97']", + "78, impaired ['l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l89', 'l92', 'l95', 'l98', 'l99']", + "79, skin ['l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l93', 'l96', 'l98', 'l100']", + "80, tumorigenesis. ['l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l90', 'l94', 'l97', 'l99', 'l100']", + "110, NEAT1 ['l101', 'l102', 'l103', 'l104', 'l105']", + "111, targeting ['l101', 'l106', 'l107', 'l108', 'l109']", + "114, human ['l102', 'l106', 'l110', 'l111', 'l112']", + "115, cancer ['l103', 'l107', 'l110', 'l113', 'l114']", + "116, cell ['l104', 'l108', 'l111', 'l113', 'l115']", + "117, lines ['l105', 'l109', 'l112', 'l114', 'l115']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "p53," + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "and", + "human", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "p53," + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "p53," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "preneoplastic", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "p53," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "Neat1", + "expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "Neat1", + "expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "Neat1", + "expression", + "NEAT1" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "preneoplastic", + "cells", + "human", + "cancer", + "cell", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "Neat1", + "expression" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "Neat1", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "Neat1", + "expression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skin" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "Neat1", + "expression" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "preneoplastic", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skin" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "preneoplastic", + "cells" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "preneoplastic", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "preneoplastic", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skin" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skin" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "skin" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "targeting" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "cancer", + "cell", + "lines" + ] + } + } + ] + }, + { + "PMID": "27376576", + "TEXT": "Single-agent immunotherapy has achieved limited clinical benefit to date in patients with pancreatic ductal adenocarcinoma (PDAC). This may be a result of the presence of a uniquely immunosuppressive tumor microenvironment (TME). Critical obstacles to immunotherapy in PDAC tumors include a high number of tumor-associated immunosuppressive cells and a uniquely desmoplastic stroma that functions as a barrier to T cell infiltration. We identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as an important regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlated with high levels of fibrosis and poor CD8(+) cytotoxic T cell infiltration. Single-agent FAK inhibition using the selective FAK inhibitor VS-4718 substantially limited tumor progression, resulting in a doubling of survival in the p48-Cre;LSL-Kras(G12D);Trp53(flox/+) (KPC) mouse model of human PDAC. This delay in tumor progression was associated with markedly reduced tumor fibrosis and decreased numbers of tumor-infiltrating immunosuppressive cells. We also found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to T cell immunotherapy and PD-1 antagonists. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and renders tumors responsive to immunotherapy.", + "TAG_DATA": [ + "107, Single-agent {'perturbing_action': 'B-pharmacological inhibition'}", + "108, FAK {'perturbing_action': 'I-pharmacological inhibition'}", + "109, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "110, using {'perturbing_action': 'I-pharmacological inhibition'}", + "111, the {'perturbing_action': 'I-pharmacological inhibition'}", + "112, selective {'perturbing_action': 'I-pharmacological inhibition'}", + "113, FAK {'perturbing_action': 'I-pharmacological inhibition'}", + "114, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "115, VS-4718 {'perturbing_action': 'I-pharmacological inhibition'}", + "117, limited {'effect': 'B-negative'}", + "118, tumor {'phenotype': 'B-tumour progression'}", + "119, progression, {'phenotype': 'I-tumour progression'}", + "128, p48-Cre;LSL-Kras(G12D);Trp53(flox/+) {'perturbing_action': 'B-other'}", + "129, (KPC) {'perturbing_action': 'I-other'}", + "130, mouse {'context': 'B-neoplasm'}", + "131, model {'context': 'I-neoplasm'}", + "132, of {'context': 'I-neoplasm'}", + "133, human {'context': 'I-neoplasm'}", + "134, PDAC. {'context': 'I-neoplasm'}", + "136, delay {'effect': 'B-negative'}", + "138, tumor {'phenotype': 'B-tumour progression'}", + "139, progression {'phenotype': 'I-tumour progression'}", + "152, immunosuppressive {'context': 'B-cells'}", + "153, cells. {'context': 'I-cells'}", + "158, FAK {'perturbing_action': 'B-pharmacological inhibition'}", + "159, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "164, KPC {'context': 'B-organism'}", + "165, mouse {'context': 'B-organism'}", + "166, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "107, Single-agent ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "108, FAK ['l0', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "109, inhibition ['l1', 'l22', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "110, using ['l2', 'l23', 'l42', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "111, the ['l3', 'l24', 'l43', 'l60', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "112, selective ['l4', 'l25', 'l44', 'l61', 'l77', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "113, FAK ['l5', 'l26', 'l45', 'l62', 'l78', 'l94', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "114, inhibitor ['l6', 'l27', 'l46', 'l63', 'l79', 'l95', 'l110', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "115, VS-4718 ['l7', 'l28', 'l47', 'l64', 'l80', 'l96', 'l111', 'l125', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "117, limited ['l8', 'l29', 'l48', 'l65', 'l81', 'l97', 'l112', 'l126', 'l138', 'l148', 'l149']", + "118, tumor ['l9', 'l30', 'l49', 'l66', 'l82', 'l98', 'l113', 'l127', 'l139', 'l148', 'l150']", + "119, progression, ['l10', 'l31', 'l50', 'l67', 'l83', 'l99', 'l114', 'l128', 'l140', 'l149', 'l150']", + "128, p48-Cre;LSL-Kras(G12D);Trp53(flox/+) ['l11', 'l32', 'l51', 'l68', 'l84', 'l100', 'l115', 'l129', 'l141', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "129, (KPC) ['l12', 'l33', 'l52', 'l69', 'l85', 'l101', 'l116', 'l130', 'l142', 'l151', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171']", + "130, mouse ['l13', 'l34', 'l53', 'l70', 'l86', 'l102', 'l117', 'l131', 'l143', 'l152', 'l162', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180']", + "131, model ['l14', 'l35', 'l54', 'l71', 'l87', 'l103', 'l118', 'l132', 'l144', 'l153', 'l163', 'l172', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "132, of ['l15', 'l36', 'l55', 'l72', 'l88', 'l104', 'l119', 'l133', 'l145', 'l154', 'l164', 'l173', 'l181', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "133, human ['l16', 'l37', 'l56', 'l73', 'l89', 'l105', 'l120', 'l134', 'l146', 'l155', 'l165', 'l174', 'l182', 'l188', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199']", + "134, PDAC. ['l17', 'l38', 'l57', 'l74', 'l90', 'l106', 'l121', 'l135', 'l147', 'l156', 'l166', 'l175', 'l183', 'l189', 'l194', 'l200', 'l201', 'l202', 'l203', 'l204']", + "136, delay ['l18', 'l39', 'l58', 'l75', 'l91', 'l107', 'l122', 'l136', 'l157', 'l167', 'l176', 'l184', 'l190', 'l195', 'l200', 'l205', 'l206', 'l207', 'l208']", + "138, tumor ['l19', 'l40', 'l92', 'l108', 'l123', 'l158', 'l168', 'l177', 'l185', 'l191', 'l196', 'l201', 'l205', 'l209', 'l210', 'l211']", + "139, progression ['l20', 'l41', 'l59', 'l76', 'l93', 'l109', 'l124', 'l137', 'l159', 'l169', 'l178', 'l186', 'l192', 'l197', 'l202', 'l206', 'l209', 'l212', 'l213']", + "152, immunosuppressive ['l160', 'l170', 'l179', 'l198', 'l203', 'l207', 'l210', 'l212', 'l214']", + "153, cells. ['l21', 'l161', 'l171', 'l180', 'l187', 'l193', 'l199', 'l204', 'l208', 'l211', 'l213', 'l214']", + "158, FAK ['l215', 'l216', 'l217', 'l218']", + "159, inhibition ['l215', 'l219', 'l220', 'l221']", + "164, KPC ['l216', 'l219', 'l222', 'l223']", + "165, mouse ['l217', 'l220', 'l222', 'l224']", + "166, model ['l218', 'l221', 'l223', 'l224']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Single-agent", + "FAK", + "inhibition", + "using", + "the", + "selective", + "inhibitor", + "VS-4718" + ] + }, + "effect": { + "val": "negative", + "words": [ + "limited", + "delay" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Single-agent", + "FAK", + "inhibition", + "using", + "the", + "selective", + "inhibitor", + "VS-4718" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression,", + "progression" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Single-agent", + "FAK", + "inhibition", + "using", + "the", + "selective", + "inhibitor", + "VS-4718" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "human", + "PDAC." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Single-agent" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limited", + "delay" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression,", + "progression" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "p48-Cre;LSL-Kras(G12D);Trp53(flox/+)", + "(KPC)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "human", + "PDAC." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "p48-Cre;LSL-Kras(G12D);Trp53(flox/+)", + "(KPC)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "delay" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "p48-Cre;LSL-Kras(G12D);Trp53(flox/+)", + "(KPC)" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "p48-Cre;LSL-Kras(G12D);Trp53(flox/+)", + "(KPC)" + ] + }, + "context": { + "val": "cells", + "words": [ + "immunosuppressive", + "cells." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "human", + "PDAC." + ] + }, + "effect": { + "val": "negative", + "words": [ + "delay" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "human", + "PDAC." + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "delay" + ] + }, + "context": { + "val": "cells", + "words": [ + "immunosuppressive", + "cells." + ] + } + }, + { + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + }, + "context": { + "val": "cells", + "words": [ + "immunosuppressive", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "FAK", + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "KPC", + "mouse", + "model" + ] + } + } + ] + }, + { + "PMID": "27348499", + "TEXT": "Genetic mutations in TAR DNA-binding protein 43 (TARDBP, also known as TDP-43) cause amyotrophic lateral sclerosis (ALS), and an increase in the presence of TDP-43 (encoded by TARDBP) in the cytoplasm is a prominent histopathological feature of degenerating neurons in various neurodegenerative diseases. However, the molecular mechanisms by which TDP-43 contributes to ALS pathophysiology remain elusive. Here we have found that TDP-43 accumulates in the mitochondria of neurons in subjects with ALS or frontotemporal dementia (FTD). Disease-associated mutations increase TDP-43 mitochondrial localization. In mitochondria, wild-type (WT) and mutant TDP-43 preferentially bind mitochondria-transcribed messenger RNAs (mRNAs) encoding respiratory complex I subunits ND3 and ND6, impair their expression and specifically cause complex I disassembly. The suppression of TDP-43 mitochondrial localization abolishes WT and mutant TDP-43-induced mitochondrial dysfunction and neuronal loss, and improves phenotypes of transgenic mutant TDP-43 mice. Thus, our studies link TDP-43 toxicity directly to mitochondrial bioenergetics and propose the targeting of TDP-43 mitochondrial localization as a promising therapeutic approach for neurodegeneration.", + "TAG_DATA": [ + "132, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "133, mutant {'perturbing_action': 'I-other'}", + "134, TDP-43 {'perturbing_action': 'I-other'}", + "135, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "132, transgenic ['l0', 'l1', 'l2']", + "133, mutant ['l0', 'l3', 'l4']", + "134, TDP-43 ['l1', 'l3', 'l5']", + "135, mice. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "TDP-43" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "27294876", + "TEXT": "Immunomodulatory drugs (IMiDs), such as thalidomide and its derivatives lenalidomide and pomalidomide, are key treatment modalities for hematologic malignancies, particularly multiple myeloma (MM) and del(5q) myelodysplastic syndrome (MDS). Cereblon (CRBN), a substrate receptor of the CRL4 ubiquitin ligase complex, is the primary target by which IMiDs mediate anticancer and teratogenic effects. Here we identify a ubiquitin-independent physiological chaperone-like function of CRBN that promotes maturation of the basigin (BSG; also known as CD147) and solute carrier family 16 member 1 (SLC16A1; also known as MCT1) proteins. This process allows for the formation and activation of the CD147-MCT1 transmembrane complex, which promotes various biological functions, including angiogenesis, proliferation, invasion and lactate export. We found that IMiDs outcompete CRBN for binding to CD147 and MCT1, leading to destabilization of the CD147-MCT1 complex. Accordingly, IMiD-sensitive MM cells lose CD147 and MCT1 expression after being exposed to IMiDs, whereas IMiD-resistant cells retain their expression. Furthermore, del(5q) MDS cells have elevated CD147 expression, which is attenuated after IMiD treatment. Finally, we show that BSG (CD147) knockdown phenocopies the teratogenic effects of thalidomide exposure in zebrafish. These findings provide a common mechanistic framework to explain both the teratogenic and pleiotropic antitumor effects of IMiDs.", + "TAG_DATA": [ + "130, IMiD-sensitive {'context': 'B-transformed cells'}", + "131, MM {'context': 'B-transformed cells'}", + "132, cells {'context': 'I-transformed cells'}", + "144, IMiD-resistant {'context': 'B-cells'}", + "145, cells {'context': 'I-cells'}", + "150, del(5q) {'perturbing_action': 'B-gene loss-of-function'}", + "151, MDS {'context': 'B-transformed cells'}", + "152, cells {'context': 'I-transformed cells'}", + "167, BSG {'perturbing_action': 'B-rnai/knockdown'}", + "168, (CD147) {'perturbing_action': 'I-rnai/knockdown'}", + "169, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "178, zebrafish. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "130, IMiD-sensitive ['l0', 'l1']", + "131, MM ['l0', 'l2']", + "132, cells ['l1', 'l2']", + "144, IMiD-resistant ['l3']", + "145, cells ['l3']", + "150, del(5q) ['l4', 'l5', 'l6']", + "151, MDS ['l4', 'l7', 'l8']", + "152, cells ['l5', 'l7']", + "167, BSG ['l9', 'l10', 'l11']", + "168, (CD147) ['l9', 'l12', 'l13']", + "169, knockdown ['l10', 'l12', 'l14']", + "178, zebrafish. ['l6', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "del(5q)" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MDS", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "del(5q)" + ] + }, + "context": { + "val": "organism", + "words": [ + "zebrafish." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "BSG", + "(CD147)", + "knockdown" + ] + }, + "context": { + "val": "organism", + "words": [ + "zebrafish." + ] + } + } + ] + }, + { + "PMID": "27294875", + "TEXT": "The persistence of latent HIV proviruses in long-lived CD4(+) T cells despite antiretroviral therapy (ART) is a major obstacle to viral eradication. Because current candidate latency-reversing agents (LRAs) induce HIV transcription, but fail to clear these cellular reservoirs, new approaches for killing these reactivated latent HIV reservoir cells are urgently needed. HIV latency depends upon the transcriptional quiescence of the integrated provirus and the circumvention of immune defense mechanisms. These defenses include cell-intrinsic innate responses that use pattern-recognition receptors (PRRs) to detect viral pathogens, and that subsequently induce apoptosis of the infected cell. Retinoic acid (RA)-inducible gene I (RIG-I, encoded by DDX58) forms one class of PRRs that mediates apoptosis and the elimination of infected cells after recognition of viral RNA. Here we show that acitretin, an RA derivative approved by the US Food and Drug Administration (FDA), enhances RIG-I signaling ex vivo, increases HIV transcription, and induces preferential apoptosis of HIV-infected cells. These effects are abrogated by DDX58 knockdown. Acitretin also decreases proviral DNA levels in CD4(+) T cells from HIV-positive subjects on suppressive ART, an effect that is amplified when combined with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor. Pharmacological enhancement of an innate cellular-defense network could provide a means by which to eliminate reactivated cells in the latent HIV reservoir.", + "TAG_DATA": [ + "147, induces {'effect': 'B-positive'}", + "149, apoptosis {'phenotype': 'B-apoptosis'}", + "152, cells. {'context': 'B-cells'}", + "158, DDX58 {'perturbing_action': 'B-rnai/knockdown'}", + "159, knockdown. {'perturbing_action': 'I-rnai/knockdown'}", + "167, CD4(+) {'context': 'B-cells'}", + "168, T {'context': 'I-cells'}", + "169, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "147, induces ['l0', 'l1']", + "149, apoptosis ['l0', 'l2']", + "152, cells. ['l1', 'l2']", + "158, DDX58 ['l3']", + "159, knockdown. ['l3']", + "167, CD4(+) ['l4', 'l5']", + "168, T ['l4', 'l6']", + "169, cells ['l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "27239761", + "TEXT": "A recombinant vaccine containing Aventis Pasteur's canarypox vector (ALVAC)-HIV and gp120 alum decreased the risk of HIV acquisition in the RV144 vaccine trial. The substitution of alum with the more immunogenic MF59 adjuvant is under consideration for the next efficacy human trial. We found here that an ALVAC-simian immunodeficiency virus (SIV) and gp120 alum (ALVAC-SIV + gp120) equivalent vaccine, but not an ALVAC-SIV + gp120 MF59 vaccine, was efficacious in delaying the onset of SIVmac251 in rhesus macaques, despite the higher immunogenicity of the latter adjuvant. Vaccine efficacy was associated with alum-induced, but not with MF59-induced, envelope (Env)-dependent mucosal innate lymphoid cells (ILCs) that produce interleukin (IL)-17, as well as with mucosal IgG to the gp120 variable region 2 (V2) and the expression of 12 genes, ten of which are part of the RAS pathway. The association between RAS activation and vaccine efficacy was also observed in an independent efficacious SIV-vaccine approach. Whether RAS activation, mucosal ILCs and antibodies to V2 are also important hallmarks of HIV-vaccine efficacy in humans will require further studies.", + "TAG_DATA": [ + "76, rhesus {'context': 'B-organism'}", + "77, macaques, {'context': 'I-organism'}", + "98, mucosal {'context': 'B-cells'}", + "99, innate {'context': 'I-cells'}", + "100, lymphoid {'context': 'I-cells'}", + "101, cells {'context': 'I-cells'}", + "102, (ILCs) {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "76, rhesus ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "77, macaques, ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "98, mucosal ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "99, innate ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "100, lymphoid ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "101, cells ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "102, (ILCs) ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27183216", + "TEXT": "Although somatic cell activation of the embryonic stem cell (ESC) pluripotency factor OCT4 has been reported, this previous work has been controversial and has not demonstrated a functional role for OCT4 in somatic cells. Here we demonstrate that smooth muscle cell (SMC)-specific conditional knockout of Oct4 in Apoe(-/-) mice resulted in increased lesion size and changes in lesion composition that are consistent with decreased plaque stability, including a thinner fibrous cap, increased necrotic core area, and increased intraplaque hemorrhage. Results of SMC-lineage-tracing studies showed that these effects were probably the result of marked reductions in SMC numbers within lesions and SMC investment within the fibrous cap, which may result from impaired SMC migration. The reactivation of Oct4 within SMCs was associated with hydroxymethylation of the Oct4 promoter and was hypoxia inducible factor-1α (HIF-1α, encoded by HIF1A) and Krüppel-like factor-4 (KLF4)-dependent. These results provide the first direct evidence that OCT4 has a functional role in somatic cells, and they highlight the potential role of OCT4 in normal and diseased somatic cells.", + "TAG_DATA": [ + "38, smooth {'perturbing_action': 'B-gene loss-of-function'}", + "39, muscle {'perturbing_action': 'B-gene loss-of-function'}", + "40, cell {'perturbing_action': 'I-gene loss-of-function'}", + "41, (SMC)-specific {'perturbing_action': 'I-gene loss-of-function'}", + "42, conditional {'perturbing_action': 'I-gene loss-of-function'}", + "43, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "44, of {'perturbing_action': 'I-gene loss-of-function'}", + "45, Oct4 {'perturbing_action': 'I-gene loss-of-function'}", + "47, Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "48, mice {'context': 'B-organism'}", + "95, SMC {'context': 'B-cells'}", + "110, impaired {'effect': 'B-negative'}", + "111, SMC {'context': 'B-cells'}", + "112, migration. {'phenotype': 'B-migration'}", + "118, SMCs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "38, smooth ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "39, muscle ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "40, cell ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "41, (SMC)-specific ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "42, conditional ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "43, knockout ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "44, of ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "45, Oct4 ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "47, Apoe(-/-) ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "48, mice ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "110, impaired ['l45', 'l46']", + "111, SMC ['l45', 'l47']", + "112, migration. ['l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "smooth", + "muscle", + "cell", + "(SMC)-specific", + "conditional", + "knockout", + "of", + "Oct4", + "Apoe(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "cells", + "words": [ + "SMC" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "SMC" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + } + ] + }, + { + "PMID": "27135741", + "TEXT": "Cetuximab is a monoclonal antibody that is effective in the treatment of metastatic colorectal cancer (mCRC). Cetuximab blocks epidermal growth factor receptor (EGFR)-ligand interaction and inhibits downstream RAS-ERK activation. However, only some activating mutations in RAS affect cetuximab efficacy, and it is not clear what else mediates treatment success. Here we hypothesized that cetuximab induces immunogenic cell death (ICD) that activates a potent antitumor response. We found that cetuximab, in combination with chemotherapy, fostered ICD in CRC cells, which we measured via the endoplasmic reticulum (ER) stress response and an increase in phagocytosis by dendritic cells. ICD induction depended on the mutational status of the EGFR signaling pathway and on the inhibition of the splicing of X-box binding protein 1 (XBP1), an unfolded protein response (UPR) mediator. We confirmed the enhanced immunogenicity elicited by cetuximab in a mouse model of human EGFR-expressing CRC. Overall, we demonstrate a new, immune-related mechanism of action of cetuximab that may help to tailor personalized medicine.", + "TAG_DATA": [ + "54, induces {'effect': 'B-positive'}", + "76, CRC {'context': 'B-transformed cells'}", + "77, cells, {'context': 'I-transformed cells'}", + "90, increase {'effect': 'B-positive'}", + "92, phagocytosis {'phenotype': 'B-mitophagy'}", + "94, dendritic {'context': 'B-cells'}", + "95, cells. {'context': 'I-cells'}", + "137, mouse {'context': 'B-organism'}", + "138, model {'context': 'I-neoplasm'}", + "139, of {'context': 'I-neoplasm'}", + "140, human {'context': 'I-neoplasm'}", + "141, EGFR-expressing {'context': 'I-neoplasm'}", + "142, CRC. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "54, induces ['l0', 'l1']", + "76, CRC ['l0', 'l2', 'l3', 'l4', 'l5', 'l6']", + "77, cells, ['l1', 'l2', 'l7']", + "90, increase ['l3', 'l8', 'l9', 'l10']", + "92, phagocytosis ['l4', 'l8', 'l11', 'l12']", + "94, dendritic ['l5', 'l9', 'l11', 'l13']", + "95, cells. ['l6', 'l7', 'l10', 'l12', 'l13']", + "137, mouse ['l14', 'l15', 'l16', 'l17', 'l18']", + "138, model ['l14', 'l19', 'l20', 'l21', 'l22']", + "139, of ['l15', 'l19', 'l23', 'l24', 'l25']", + "140, human ['l16', 'l20', 'l23', 'l26', 'l27']", + "141, EGFR-expressing ['l17', 'l21', 'l24', 'l26', 'l28']", + "142, CRC. ['l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induces", + "increase" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "CRC", + "cells," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CRC" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells." + ] + } + }, + { + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells." + ] + } + } + ] + }, + { + "PMID": "27135739", + "TEXT": "Cachexia is a devastating muscle-wasting syndrome that occurs in patients who have chronic diseases. It is most commonly observed in individuals with advanced cancer, presenting in 80% of these patients, and it is one of the primary causes of morbidity and mortality associated with cancer. Additionally, although many people with cachexia show hypermetabolism, the causative role of metabolism in muscle atrophy has been unclear. To understand the molecular basis of cachexia-associated muscle atrophy, it is necessary to develop accurate models of the condition. By using transcriptomics and cytokine profiling of human muscle stem cell-based models and human cancer-induced cachexia models in mice, we found that cachectic cancer cells secreted many inflammatory factors that rapidly led to high levels of fatty acid metabolism and to the activation of a p38 stress-response signature in skeletal muscles, before manifestation of cachectic muscle atrophy occurred. Metabolomics profiling revealed that factors secreted by cachectic cancer cells rapidly induce excessive fatty acid oxidation in human myotubes, which leads to oxidative stress, p38 activation and impaired muscle growth. Pharmacological blockade of fatty acid oxidation not only rescued human myotubes, but also improved muscle mass and body weight in cancer cachexia models in vivo. Therefore, fatty acid-induced oxidative stress could be targeted to prevent cancer-induced cachexia.", + "TAG_DATA": [ + "101, mice, {'context': 'B-organism'}", + "132, skeletal {'context': 'B-tissue/organ'}", + "133, muscles, {'context': 'I-tissue/organ'}", + "158, human {'context': 'B-cells'}", + "159, myotubes, {'context': 'I-cells'}", + "168, impaired {'effect': 'B-negative'}", + "169, muscle {'phenotype': 'B-tumour growth'}", + "170, growth. {'phenotype': 'I-tumour growth'}", + "180, human {'context': 'B-cells'}", + "181, myotubes, {'context': 'I-cells'}", + "194, in {'context': 'B-in vivo'}", + "195, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "101, mice, ['l0', 'l1']", + "132, skeletal ['l0', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "133, muscles, ['l1', 'l2', 'l8', 'l9', 'l10', 'l11', 'l12']", + "158, human ['l3', 'l8', 'l13', 'l14', 'l15', 'l16']", + "159, myotubes, ['l4', 'l9', 'l13', 'l17', 'l18', 'l19']", + "168, impaired ['l5', 'l10', 'l14', 'l17', 'l20', 'l21']", + "169, muscle ['l6', 'l11', 'l15', 'l18', 'l20', 'l22']", + "170, growth. ['l7', 'l12', 'l16', 'l19', 'l21', 'l22']", + "180, human ['l23']", + "181, myotubes, ['l23']", + "194, in ['l24']", + "195, vivo. ['l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "skeletal", + "muscles," + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "skeletal", + "muscles," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "muscle", + "growth." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "myotubes," + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "myotubes," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "muscle", + "growth." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "muscle", + "growth." + ] + } + } + ] + }, + { + "PMID": "27135738", + "TEXT": "B cell lymphoma and melanoma harbor recurrent mutations in the gene encoding the EZH2 histone methyltransferase (EZH2), but the carcinogenic role of these mutations is unclear. Here we describe a mouse model in which the most common somatic Ezh2 gain-of-function mutation (EZH2(Y646F) in human; Ezh2(Y641F) in mouse) is conditionally expressed. Expression of Ezh2(Y641F) in mouse B cells or melanocytes caused high-penetrance lymphoma or melanoma, respectively. Overexpression of the anti-apoptotic protein Bcl2, but not the oncoprotein Myc, or loss of the tumor suppressor protein p53 (encoded by Trp53 in mice) further accelerated lymphoma progression. Expression of the mutant Braf but not the mutant Nras oncoprotein further accelerated melanoma progression. Although expression of Ezh2(Y641F) globally increased the abundance of trimethylated Lys27 of histone H3 (H3K27me3), it also caused a widespread redistribution of this repressive mark, including a loss of H3K27me3 that was associated with increased transcription at many loci. These results suggest that Ezh2(Y641F) induces lymphoma and melanoma through a vast reorganization of chromatin structure, inducing both repression and activation of polycomb-regulated loci.", + "TAG_DATA": [ + "30, mouse {'context': 'B-organism'}", + "31, model {'context': 'I-organism'}", + "39, gain-of-function {'perturbing_action': 'I-other'}", + "40, mutation {'perturbing_action': 'I-other'}", + "50, Expression {'perturbing_action': 'B-other'}", + "51, of {'perturbing_action': 'I-other'}", + "52, Ezh2(Y641F) {'perturbing_action': 'I-other'}", + "54, mouse {'context': 'B-cells'}", + "55, B {'context': 'I-cells'}", + "56, cells {'context': 'I-cells'}", + "58, melanocytes {'context': 'B-cells'}", + "65, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "66, of {'perturbing_action': 'I-gene gain-of-function'}", + "67, the {'perturbing_action': 'I-gene gain-of-function'}", + "68, anti-apoptotic {'perturbing_action': 'I-gene gain-of-function'}", + "69, protein {'perturbing_action': 'I-gene gain-of-function'}", + "70, Bcl2, {'perturbing_action': 'I-gene gain-of-function'}", + "77, loss {'perturbing_action': 'B-gene loss-of-function'}", + "78, of {'perturbing_action': 'I-gene loss-of-function'}", + "79, the {'perturbing_action': 'I-gene loss-of-function'}", + "80, tumor {'perturbing_action': 'I-gene loss-of-function'}", + "81, suppressor {'perturbing_action': 'I-gene loss-of-function'}", + "82, protein {'perturbing_action': 'I-gene loss-of-function'}", + "83, p53 {'perturbing_action': 'I-gene loss-of-function'}", + "84, (encoded {'perturbing_action': 'I-gene loss-of-function'}", + "85, by {'perturbing_action': 'I-gene loss-of-function'}", + "86, Trp53 {'perturbing_action': 'I-gene loss-of-function'}", + "87, in {'perturbing_action': 'I-gene loss-of-function'}", + "88, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "91, lymphoma {'context': 'B-neoplasm'}", + "93, Expression {'perturbing_action': 'B-other'}", + "94, of {'perturbing_action': 'I-other'}", + "95, the {'perturbing_action': 'I-other'}", + "96, mutant {'perturbing_action': 'I-other'}", + "97, Braf {'perturbing_action': 'I-other'}", + "101, mutant {'perturbing_action': 'B-other'}", + "106, melanoma {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "30, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "31, model ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "38, Ezh2 ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "39, gain-of-function ['l2', 'l15', 'l27', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "40, mutation ['l3', 'l16', 'l28', 'l45', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "50, Expression ['l4', 'l17', 'l29', 'l46', 'l62', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "51, of ['l5', 'l18', 'l30', 'l47', 'l63', 'l78', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "52, Ezh2(Y641F) ['l6', 'l19', 'l31', 'l48', 'l64', 'l79', 'l92', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "53, in ['l7', 'l20', 'l32', 'l49', 'l65', 'l80', 'l93', 'l105', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "54, mouse ['l8', 'l21', 'l33', 'l50', 'l66', 'l81', 'l94', 'l106', 'l118', 'l127', 'l128', 'l129', 'l130']", + "55, B ['l9', 'l22', 'l34', 'l51', 'l67', 'l82', 'l95', 'l107', 'l119', 'l127', 'l131', 'l132', 'l133']", + "56, cells ['l10', 'l23', 'l35', 'l52', 'l68', 'l83', 'l96', 'l108', 'l120', 'l128', 'l131', 'l134', 'l135']", + "58, melanocytes ['l11', 'l24', 'l36', 'l53', 'l69', 'l84', 'l97', 'l109', 'l121', 'l129', 'l132', 'l134', 'l136']", + "61, lymphoma ['l12', 'l25', 'l37', 'l54', 'l70', 'l85', 'l98', 'l110', 'l122', 'l130', 'l133', 'l135', 'l136']", + "65, Overexpression ['l38', 'l55', 'l71', 'l86', 'l99', 'l111', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "66, of ['l39', 'l56', 'l72', 'l87', 'l100', 'l112', 'l137', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171']", + "67, the ['l40', 'l57', 'l73', 'l88', 'l101', 'l113', 'l123', 'l138', 'l155', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "68, anti-apoptotic ['l41', 'l58', 'l74', 'l89', 'l102', 'l114', 'l124', 'l139', 'l156', 'l172', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202']", + "69, protein ['l42', 'l59', 'l75', 'l90', 'l103', 'l115', 'l125', 'l140', 'l157', 'l173', 'l188', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216']", + "70, Bcl2, ['l13', 'l26', 'l43', 'l60', 'l76', 'l91', 'l104', 'l116', 'l126', 'l141', 'l158', 'l174', 'l189', 'l203', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229']", + "77, loss ['l142', 'l159', 'l175', 'l190', 'l204', 'l217', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241']", + "78, of ['l143', 'l160', 'l176', 'l191', 'l205', 'l218', 'l230', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252']", + "79, the ['l144', 'l161', 'l177', 'l192', 'l206', 'l219', 'l231', 'l242', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262']", + "80, tumor ['l145', 'l162', 'l178', 'l193', 'l207', 'l220', 'l232', 'l243', 'l253', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271']", + "81, suppressor ['l146', 'l163', 'l179', 'l194', 'l208', 'l221', 'l233', 'l244', 'l254', 'l263', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279']", + "82, protein ['l147', 'l164', 'l180', 'l195', 'l209', 'l222', 'l234', 'l245', 'l255', 'l264', 'l272', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286']", + "83, p53 ['l148', 'l165', 'l181', 'l196', 'l210', 'l223', 'l235', 'l246', 'l256', 'l265', 'l273', 'l280', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292']", + "84, (encoded ['l149', 'l166', 'l182', 'l197', 'l211', 'l224', 'l236', 'l247', 'l257', 'l266', 'l274', 'l281', 'l287', 'l293', 'l294', 'l295', 'l296', 'l297']", + "85, by ['l150', 'l167', 'l183', 'l198', 'l212', 'l225', 'l237', 'l248', 'l258', 'l267', 'l275', 'l282', 'l288', 'l293', 'l298', 'l299', 'l300', 'l301']", + "86, Trp53 ['l151', 'l168', 'l184', 'l199', 'l213', 'l226', 'l238', 'l249', 'l259', 'l268', 'l276', 'l283', 'l289', 'l294', 'l298', 'l302', 'l303', 'l304']", + "87, in ['l152', 'l169', 'l185', 'l200', 'l214', 'l227', 'l239', 'l250', 'l260', 'l269', 'l277', 'l284', 'l290', 'l295', 'l299', 'l302', 'l305', 'l306']", + "88, mice) ['l153', 'l170', 'l186', 'l201', 'l215', 'l228', 'l240', 'l251', 'l261', 'l270', 'l278', 'l285', 'l291', 'l296', 'l300', 'l303', 'l305', 'l307']", + "91, lymphoma ['l44', 'l61', 'l77', 'l117', 'l154', 'l171', 'l187', 'l202', 'l216', 'l229', 'l241', 'l252', 'l262', 'l271', 'l279', 'l286', 'l292', 'l297', 'l301', 'l304', 'l306', 'l307']", + "93, Expression ['l308', 'l309', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315']", + "94, of ['l308', 'l316', 'l317', 'l318', 'l319', 'l320', 'l321', 'l322']", + "95, the ['l309', 'l316', 'l323', 'l324', 'l325', 'l326', 'l327', 'l328']", + "96, mutant ['l310', 'l317', 'l323', 'l329', 'l330', 'l331', 'l332', 'l333']", + "97, Braf ['l311', 'l318', 'l324', 'l329', 'l334', 'l335', 'l336', 'l337']", + "101, mutant ['l312', 'l319', 'l325', 'l330', 'l334', 'l338', 'l339', 'l340']", + "106, melanoma ['l313', 'l320', 'l326', 'l331', 'l335', 'l338']", + "110, of ['l314', 'l321', 'l327', 'l332', 'l336', 'l339', 'l341']", + "111, Ezh2(Y641F) ['l315', 'l322', 'l328', 'l333', 'l337', 'l340', 'l341']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "gain-of-function", + "mutation", + "Expression", + "of", + "Ezh2(Y641F)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Bcl2," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "gain-of-function", + "mutation", + "Expression", + "of", + "Ezh2(Y641F)" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "B", + "cells", + "melanocytes" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "gain-of-function", + "mutation", + "Ezh2(Y641F)", + "Expression", + "of", + "the", + "mutant", + "Braf" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lymphoma", + "melanoma" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "the", + "anti-apoptotic", + "protein", + "Bcl2," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lymphoma" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "tumor", + "suppressor", + "protein", + "p53", + "(encoded", + "by", + "Trp53", + "in", + "mice)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lymphoma" + ] + } + } + ] + }, + { + "PMID": "27111281", + "TEXT": "Interactions between the hippocampus and the cortex are critical for memory. Interictal epileptiform discharges (IEDs) identify epileptic brain regions and can impair memory, but the mechanisms by which they interact with physiological patterns of network activity are mostly undefined. We show in a rat model of temporal lobe epilepsy that spontaneous hippocampal IEDs correlate with impaired memory consolidation, and that they are precisely coordinated with spindle oscillations in the prefrontal cortex during nonrapid-eye-movement (NREM) sleep. This coordination surpasses the normal physiological ripple-spindle coupling and is accompanied by decreased ripple occurrence. IEDs also induce spindles during rapid-eye movement (REM) sleep and wakefulness-behavioral states that do not naturally express these oscillations-by generating a cortical 'down' state. In a pilot clinical examination of four subjects with focal epilepsy, we confirm a similar correlation of temporofrontal IEDs with spindles over anatomically restricted cortical regions. These findings imply that IEDs may impair memory via the misappropriation of physiological mechanisms for hippocampal-cortical coupling, which suggests a target for the treatment of memory impairment in epilepsy.", + "TAG_DATA": [ + "43, rat {'context': 'B-organism'}", + "44, model {'context': 'I-organism'}", + "45, of {'context': 'I-organism'}", + "46, temporal {'context': 'I-organism'}", + "47, lobe {'context': 'I-organism'}", + "48, epilepsy {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "43, rat ['l0', 'l1', 'l2', 'l3', 'l4']", + "44, model ['l0', 'l5', 'l6', 'l7', 'l8']", + "45, of ['l1', 'l5', 'l9', 'l10', 'l11']", + "46, temporal ['l2', 'l6', 'l9', 'l12', 'l13']", + "47, lobe ['l3', 'l7', 'l10', 'l12', 'l14']", + "48, epilepsy ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27089514", + "TEXT": "Doxorubicin is an anthracycline chemotherapy agent effective in treating a wide range of malignancies, but it causes a dose-related cardiotoxicity that can lead to heart failure in a subset of patients. At present, it is not possible to predict which patients will be affected by doxorubicin-induced cardiotoxicity (DIC). Here we demonstrate that patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can recapitulate the predilection to DIC of individual patients at the cellular level. hiPSC-CMs derived from individuals with breast cancer who experienced DIC were consistently more sensitive to doxorubicin toxicity than hiPSC-CMs from patients who did not experience DIC, with decreased cell viability, impaired mitochondrial and metabolic function, impaired calcium handling, decreased antioxidant pathway activity, and increased reactive oxygen species production. Taken together, our data indicate that hiPSC-CMs are a suitable platform to identify and characterize the genetic basis and molecular mechanisms of DIC.", + "TAG_DATA": [ + "53, human {'context': 'I-cells'}", + "54, induced {'context': 'I-cells'}", + "55, pluripotent {'context': 'I-cells'}", + "56, stem {'context': 'I-cells'}", + "57, cell-derived {'context': 'I-cells'}", + "58, cardiomyocytes {'context': 'I-cells'}", + "73, hiPSC-CMs {'context': 'B-cells'}", + "78, breast {'context': 'B-neoplasm'}", + "79, cancer {'context': 'I-neoplasm'}", + "91, hiPSC-CMs {'context': 'B-cells'}", + "100, decreased {'effect': 'B-negative'}", + "101, cell {'phenotype': 'B-cell survival'}", + "102, viability, {'phenotype': 'I-cell survival'}" + ], + "LINK_DATA": [ + "53, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "54, induced ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "55, pluripotent ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "56, stem ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "57, cell-derived ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "58, cardiomyocytes ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "73, hiPSC-CMs ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "78, breast ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "79, cancer ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "91, hiPSC-CMs ['l36', 'l37', 'l38']", + "100, decreased ['l36', 'l39', 'l40']", + "101, cell ['l37', 'l39', 'l41']", + "102, viability, ['l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "hiPSC-CMs" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hiPSC-CMs" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "viability," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "viability," + ] + } + } + ] + }, + { + "PMID": "27064448", + "TEXT": "Cholera toxin (CT) is a potent adjuvant for inducing mucosal immune responses. However, the mechanism by which CT induces adjuvant activity remains unclear. Here we show that the microbiota is critical for inducing antigen-specific IgG production after intranasal immunization. After mucosal vaccination with CT, both antibiotic-treated and germ-free (GF) mice had reduced amounts of antigen-specific IgG, smaller recall-stimulated cytokine responses, impaired follicular helper T (TFH) cell responses and reduced numbers of plasma cells. Recognition of symbiotic bacteria via the nucleotide-binding oligomerization domain containing 2 (Nod2) sensor in cells that express the integrin CD11c (encoded by Itgax) was required for the adjuvanticity of CT. Reconstitution of GF mice with a Nod2 agonist or monocolonization with Staphylococcus sciuri, which has high Nod2-stimulatory activity, was sufficient to promote robust CT adjuvant activity, whereas bacteria with low Nod2-stimulatory activity did not. Mechanistically, CT enhanced Nod2-mediated cytokine production in dendritic cells via intracellular cyclic AMP. These results show a role for the microbiota and the intracellular receptor Nod2 in promoting the mucosal adjuvant activity of CT.", + "TAG_DATA": [ + "49, mice {'context': 'B-organism'}", + "61, follicular {'context': 'B-cells'}", + "62, helper {'context': 'I-cells'}", + "63, T {'context': 'I-cells'}", + "64, (TFH) {'context': 'I-cells'}", + "65, cell {'context': 'I-cells'}", + "71, plasma {'context': 'B-cells'}", + "72, cells. {'context': 'I-cells'}", + "87, cells {'context': 'B-cells'}", + "105, GF {'context': 'B-organism'}", + "106, mice {'context': 'I-organism'}", + "109, Nod2 {'perturbing_action': 'B-pharmacological augmentation'}", + "110, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "144, dendritic {'context': 'B-cells'}", + "145, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "49, mice ['l0']", + "61, follicular ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "62, helper ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "63, T ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "64, (TFH) ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "65, cell ['l0', 'l4', 'l10', 'l15', 'l19', 'l23', 'l24']", + "71, plasma ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l26']", + "72, cells. ['l6', 'l12', 'l17', 'l21', 'l24', 'l25']", + "87, cells ['l7', 'l13', 'l18', 'l22', 'l26', 'l27', 'l28', 'l29', 'l30']", + "105, GF ['l27', 'l31', 'l32', 'l33']", + "106, mice ['l28', 'l31', 'l34', 'l35']", + "109, Nod2 ['l29', 'l32', 'l34', 'l36']", + "110, agonist ['l30', 'l33', 'l35', 'l36']", + "144, dendritic ['l37']", + "145, cells ['l37']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Nod2", + "agonist" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "GF", + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Nod2", + "agonist" + ] + } + } + ] + }, + { + "PMID": "26974308", + "TEXT": "Tissues with high metabolic rates often use lipids, as well as glucose, for energy, conferring a survival advantage during feast and famine. Current dogma suggests that high-energy-consuming photoreceptors depend on glucose. Here we show that the retina also uses fatty acid β-oxidation for energy. Moreover, we identify a lipid sensor, free fatty acid receptor 1 (Ffar1), that curbs glucose uptake when fatty acids are available. Very-low-density lipoprotein receptor (Vldlr), which is present in photoreceptors and is expressed in other tissues with a high metabolic rate, facilitates the uptake of triglyceride-derived fatty acid. In the retinas of Vldlr(-/-) mice with low fatty acid uptake but high circulating lipid levels, we found that Ffar1 suppresses expression of the glucose transporter Glut1. Impaired glucose entry into photoreceptors results in a dual (lipid and glucose) fuel shortage and a reduction in the levels of the Krebs cycle intermediate α-ketoglutarate (α-KG). Low α-KG levels promotes stabilization of hypoxia-induced factor 1a (Hif1a) and secretion of vascular endothelial growth factor A (Vegfa) by starved Vldlr(-/-) photoreceptors, leading to neovascularization. The aberrant vessels in the Vldlr(-/-) retinas, which invade normally avascular photoreceptors, are reminiscent of the vascular defects in retinal angiomatous proliferation, a subset of neovascular age-related macular degeneration (AMD), which is associated with high vitreous VEGFA levels in humans. Dysregulated lipid and glucose photoreceptor energy metabolism may therefore be a driving force in macular telangiectasia, neovascular AMD and other retinal diseases.", + "TAG_DATA": [ + "94, retinas {'context': 'B-tissue/organ'}", + "96, Vldlr(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "97, mice {'context': 'B-organism'}", + "167, Vldlr(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "168, photoreceptors, {'context': 'B-cells'}", + "177, Vldlr(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "178, retinas, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "94, retinas ['l0', 'l1']", + "96, Vldlr(-/-) ['l0', 'l2']", + "97, mice ['l1', 'l2']", + "167, Vldlr(-/-) ['l3']", + "168, photoreceptors, ['l3']", + "177, Vldlr(-/-) ['l4']", + "178, retinas, ['l4']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "retinas", + "retinas," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Vldlr(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Vldlr(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Vldlr(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "photoreceptors," + ] + } + } + ] + }, + { + "PMID": "26928463", + "TEXT": "Tumor heterogeneity may reduce the efficacy of molecularly guided systemic therapy for cancers that have metastasized. To determine whether the genomic alterations in a single metastasis provide a reasonable assessment of the major oncogenic drivers of other dispersed metastases in an individual, we analyzed multiple tumors from men with disseminated prostate cancer through whole-exome sequencing, array comparative genomic hybridization (CGH) and RNA transcript profiling, and we compared the genomic diversity within and between individuals. In contrast to the substantial heterogeneity between men, there was limited diversity among metastases within an individual. The number of somatic mutations, the burden of genomic copy number alterations and aberrations in known oncogenic drivers were all highly concordant, as were metrics of androgen receptor (AR) activity and cell cycle activity. AR activity was inversely associated with cell proliferation, whereas the expression of Fanconi anemia (FA)-complex genes was correlated with elevated cell cycle progression, expression of the E2F transcription factor 1 (E2F1) and loss of retinoblastoma 1 (RB1). Men with somatic aberrations in FA-complex genes or in ATM serine/threonine kinase (ATM) exhibited significantly longer treatment-response durations to carboplatin than did men without defects in genes encoding DNA-repair proteins. Collectively, these data indicate that although exceptions exist, evaluating a single metastasis provides a reasonable assessment of the major oncogenic driver alterations that are present in disseminated tumors within an individual, and thus may be useful for selecting treatments on the basis of predicted molecular vulnerabilities.", + "TAG_DATA": [ + "131, cell {'context': 'B-cells'}", + "132, proliferation, {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "131, cell ['l0']", + "132, proliferation, ['l0']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + } + ] + }, + { + "PMID": "26901407", + "TEXT": "Detection of lymphocytes that target tumor-specific mutant neoantigens--derived from products encoded by mutated genes in the tumor--is mostly limited to tumor-resident lymphocytes, but whether these lymphocytes often occur in the circulation is unclear. We recently reported that intratumoral expression of the programmed cell death 1 (PD-1) receptor can guide the identification of the patient-specific repertoire of tumor-reactive CD8(+) lymphocytes that reside in the tumor. In view of these findings, we investigated whether PD-1 expression on peripheral blood lymphocytes could be used as a biomarker to detect T cells that target neoantigens. By using a high-throughput personalized screening approach, we identified neoantigen-specific lymphocytes in the peripheral blood of three of four melanoma patients. Despite their low frequency in the circulation, we found that CD8(+)PD-1(+), but not CD8(+)PD-1(-), cell populations had lymphocytes that targeted 3, 3 and 1 unique, patient-specific neoantigens, respectively. We show that neoantigen-specific T cells and gene-engineered lymphocytes expressing neoantigen-specific T cell receptors (TCRs) isolated from peripheral blood recognized autologous tumors. Notably, the tumor-antigen specificities and TCR repertoires of the circulating and tumor-infiltrating CD8(+)PD-1(+) cells appeared similar, implying that the circulating CD8(+)PD-1(+) lymphocytes could provide a window into the tumor-resident antitumor lymphocytes. Thus, expression of PD-1 identifies a diverse and patient-specific antitumor T cell response in peripheral blood, providing a novel noninvasive strategy to develop personalized therapies using neoantigen-reactive lymphocytes or TCRs to treat cancer.", + "TAG_DATA": [ + "129, lymphocytes {'context': 'B-cells'}", + "143, neoantigen-specific {'context': 'B-cells'}", + "144, T {'context': 'I-cells'}", + "145, cells {'context': 'I-cells'}", + "147, gene-engineered {'context': 'B-cells'}", + "148, lymphocytes {'context': 'I-cells'}", + "174, CD8(+)PD-1(+) {'context': 'B-cells'}", + "175, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "129, lymphocytes ['l0', 'l1']", + "143, neoantigen-specific ['l2', 'l3']", + "144, T ['l0', 'l2', 'l4']", + "145, cells ['l1', 'l3', 'l4']", + "147, gene-engineered ['l5', 'l6', 'l7']", + "148, lymphocytes ['l5', 'l8', 'l9']", + "174, CD8(+)PD-1(+) ['l6', 'l8', 'l10']", + "175, cells ['l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26855150", + "TEXT": "Although subtypes of pancreatic ductal adenocarcinoma (PDAC) have been described, this malignancy is clinically still treated as a single disease. Here we present patient-derived models representing the full spectrum of previously identified quasi-mesenchymal (QM-PDA), classical and exocrine-like PDAC subtypes, and identify two markers--HNF1A and KRT81--that enable stratification of tumors into different subtypes by using immunohistochemistry. Individuals with tumors of these subtypes showed substantial differences in overall survival, and their tumors differed in drug sensitivity, with the exocrine-like subtype being resistant to tyrosine kinase inhibitors and paclitaxel. Cytochrome P450 3A5 (CYP3A5) metabolizes these compounds in tumors of the exocrine-like subtype, and pharmacological or short hairpin RNA (shRNA)-mediated CYP3A5 inhibition sensitizes tumor cells to these drugs. Whereas hepatocyte nuclear factor 4, alpha (HNF4A) controls basal expression of CYP3A5, drug-induced CYP3A5 upregulation is mediated by the nuclear receptor NR1I2. CYP3A5 also contributes to acquired drug resistance in QM-PDA and classical PDAC, and it is highly expressed in several additional malignancies. These findings designate CYP3A5 as a predictor of therapy response and as a tumor cell-autonomous detoxification mechanism that must be overcome to prevent drug resistance.", + "TAG_DATA": [ + "102, short {'perturbing_action': 'B-rnai/knockdown'}", + "103, hairpin {'perturbing_action': 'I-rnai/knockdown'}", + "104, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "105, (shRNA)-mediated {'perturbing_action': 'I-rnai/knockdown'}", + "106, CYP3A5 {'perturbing_action': 'I-rnai/knockdown'}", + "107, inhibition {'perturbing_action': 'I-rnai/knockdown'}", + "109, tumor {'context': 'B-transformed cells'}", + "110, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "102, short ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "103, hairpin ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "104, RNA ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "105, (shRNA)-mediated ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "106, CYP3A5 ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "107, inhibition ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "109, tumor ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "110, cells ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "short", + "hairpin", + "RNA", + "(shRNA)-mediated", + "CYP3A5", + "inhibition" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + } + ] + }, + { + "PMID": "26808348", + "TEXT": "Uncoupling protein 1 (UCP1) is highly expressed in brown adipose tissue, where it generates heat by uncoupling electron transport from ATP production. UCP1 is also found outside classical brown adipose tissue depots, in adipocytes that are termed 'brite' (brown-in-white) or 'beige'. In humans, the presence of brite or beige (brite/beige) adipocytes is correlated with a lean, metabolically healthy phenotype, but whether a causal relationship exists is not clear. Here we report that human brite/beige adipocyte progenitors proliferate in response to pro-angiogenic factors, in association with expanding capillary networks. Adipocytes formed from these progenitors transform in response to adenylate cyclase activation from being UCP1 negative to being UCP1 positive, which is a defining feature of the beige/brite phenotype, while displaying uncoupled respiration. When implanted into normal chow-fed, or into high-fat diet (HFD)-fed, glucose-intolerant NOD-scid IL2rg(null) (NSG) mice, brite/beige adipocytes activated in vitro enhance systemic glucose tolerance. These adipocytes express neuroendocrine and secreted factors, including the pro-protein convertase PCSK1, which is strongly associated with human obesity. Pro-angiogenic conditions therefore drive the proliferation of human beige/brite adipocyte progenitors, and activated beige/brite adipocytes can affect systemic glucose homeostasis, potentially through a neuroendocrine mechanism.", + "TAG_DATA": [ + "76, proliferate {'phenotype': 'B-proliferation'}", + "132, NOD-scid {'perturbing_action': 'B-gene loss-of-function'}", + "133, IL2rg(null) {'perturbing_action': 'I-gene loss-of-function'}", + "134, (NSG) {'perturbing_action': 'I-gene loss-of-function'}", + "135, mice, {'context': 'B-organism'}", + "136, brite/beige {'context': 'B-cells'}", + "137, adipocytes {'context': 'I-cells'}", + "139, in {'context': 'B-in vitro'}", + "140, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "132, NOD-scid ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "133, IL2rg(null) ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "134, (NSG) ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "135, mice, ['l2', 'l8', 'l13', 'l18', 'l19']", + "136, brite/beige ['l3', 'l9', 'l14', 'l18', 'l20', 'l21', 'l22']", + "137, adipocytes ['l4', 'l10', 'l15', 'l19', 'l20', 'l23', 'l24']", + "139, in ['l5', 'l11', 'l16', 'l21', 'l23', 'l25']", + "140, vitro ['l6', 'l12', 'l17', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NOD-scid", + "IL2rg(null)", + "(NSG)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NOD-scid", + "IL2rg(null)", + "(NSG)" + ] + }, + "context": { + "val": "cells", + "words": [ + "brite/beige", + "adipocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NOD-scid", + "IL2rg(null)", + "(NSG)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "26808347", + "TEXT": "The lateral habenula (LHb) encodes aversive signals, and its aberrant activity contributes to depression-like symptoms. However, a limited understanding of the cellular mechanisms underlying LHb hyperactivity has precluded the development of pharmacological strategies to ameliorate depression-like phenotypes. Here we report that an aversive experience in mice, such as foot-shock exposure (FsE), induces LHb neuronal hyperactivity and depression-like symptoms. This occurs along with increased protein phosphatase 2A (PP2A) activity, a known regulator of GABAB receptor (GABABR) and G protein-gated inwardly rectifying potassium (GIRK) channel surface expression. Accordingly, FsE triggers GABAB1 and GIRK2 internalization, leading to rapid and persistent weakening of GABAB-activated GIRK-mediated (GABAB-GIRK) currents. Pharmacological inhibition of PP2A restores both GABAB-GIRK function and neuronal excitability. As a consequence, PP2A inhibition ameliorates depression-like symptoms after FsE and in a learned-helplessness model of depression. Thus, GABAB-GIRK plasticity in the LHb represents a cellular substrate for aversive experience. Furthermore, its reversal by PP2A inhibition may provide a novel therapeutic approach to alleviate symptoms of depression in disorders that are characterized by LHb hyperactivity.", + "TAG_DATA": [ + "45, mice, {'context': 'B-organism'}", + "52, LHb {'context': 'B-cells'}", + "103, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "104, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "105, of {'perturbing_action': 'I-pharmacological inhibition'}", + "106, PP2A {'perturbing_action': 'I-pharmacological inhibition'}", + "117, PP2A {'perturbing_action': 'B-pharmacological inhibition'}", + "118, inhibition {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "45, mice, ['l0']", + "52, LHb ['l0']", + "103, Pharmacological ['l1', 'l2', 'l3', 'l4', 'l5']", + "104, inhibition ['l1', 'l6', 'l7', 'l8', 'l9']", + "105, of ['l2', 'l6', 'l10', 'l11', 'l12']", + "106, PP2A ['l3', 'l7', 'l10', 'l13', 'l14']", + "117, PP2A ['l4', 'l8', 'l11', 'l13', 'l15']", + "118, inhibition ['l5', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26808346", + "TEXT": "The transplantation of glucose-responsive, insulin-producing cells offers the potential for restoring glycemic control in individuals with diabetes. Pancreas transplantation and the infusion of cadaveric islets are currently implemented clinically, but these approaches are limited by the adverse effects of immunosuppressive therapy over the lifetime of the recipient and the limited supply of donor tissue. The latter concern may be addressed by recently described glucose-responsive mature beta cells that are derived from human embryonic stem cells (referred to as SC-β cells), which may represent an unlimited source of human cells for pancreas replacement therapy. Strategies to address the immunosuppression concerns include immunoisolation of insulin-producing cells with porous biomaterials that function as an immune barrier. However, clinical implementation has been challenging because of host immune responses to the implant materials. Here we report the first long-term glycemic correction of a diabetic, immunocompetent animal model using human SC-β cells. SC-β cells were encapsulated with alginate derivatives capable of mitigating foreign-body responses in vivo and implanted into the intraperitoneal space of C57BL/6J mice treated with streptozotocin, which is an animal model for chemically induced type 1 diabetes. These implants induced glycemic correction without any immunosuppression until their removal at 174 d after implantation. Human C-peptide concentrations and in vivo glucose responsiveness demonstrated therapeutically relevant glycemic control. Implants retrieved after 174 d contained viable insulin-producing cells.", + "TAG_DATA": [ + "138, diabetic, {'context': 'B-organism'}", + "139, immunocompetent {'context': 'I-organism'}", + "140, animal {'context': 'I-organism'}", + "141, model {'context': 'I-organism'}", + "143, human {'context': 'B-cells'}", + "144, SC-β {'context': 'I-cells'}", + "145, cells. {'context': 'I-cells'}", + "146, SC-β {'context': 'B-cells'}", + "147, cells {'context': 'I-cells'}", + "158, in {'context': 'B-in vivo'}", + "159, vivo {'context': 'I-in vivo'}", + "167, C57BL/6J {'context': 'B-organism'}", + "168, mice {'context': 'I-organism'}", + "203, in {'context': 'B-in vivo'}", + "204, vivo {'context': 'I-in vivo'}", + "219, insulin-producing {'context': 'B-cells'}", + "220, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "138, diabetic, ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "139, immunocompetent ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "140, animal ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "141, model ['l2', 'l13', 'l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "143, human ['l3', 'l14', 'l24', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "144, SC-β ['l4', 'l15', 'l25', 'l31', 'l36', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "145, cells. ['l5', 'l16', 'l26', 'l32', 'l37', 'l44', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "146, SC-β ['l6', 'l17', 'l38', 'l45', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "147, cells ['l7', 'l18', 'l27', 'l33', 'l39', 'l46', 'l52', 'l57', 'l62', 'l63', 'l64', 'l65']", + "158, in ['l8', 'l19', 'l28', 'l34', 'l40', 'l47', 'l53', 'l58', 'l62', 'l66', 'l67', 'l68']", + "159, vivo ['l9', 'l20', 'l29', 'l35', 'l41', 'l48', 'l54', 'l59', 'l63', 'l66', 'l69', 'l70']", + "167, C57BL/6J ['l10', 'l21', 'l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l71']", + "168, mice ['l11', 'l22', 'l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l71']", + "203, in ['l72', 'l73', 'l74']", + "204, vivo ['l72', 'l75', 'l76']", + "219, insulin-producing ['l73', 'l75', 'l77']", + "220, cells. ['l74', 'l76', 'l77']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26779815", + "TEXT": "Electrical neuromodulation of lumbar segments improves motor control after spinal cord injury in animal models and humans. However, the physiological principles underlying the effect of this intervention remain poorly understood, which has limited the therapeutic approach to continuous stimulation applied to restricted spinal cord locations. Here we developed stimulation protocols that reproduce the natural dynamics of motoneuron activation during locomotion. For this, we computed the spatiotemporal activation pattern of muscle synergies during locomotion in healthy rats. Computer simulations identified optimal electrode locations to target each synergy through the recruitment of proprioceptive feedback circuits. This framework steered the design of spatially selective spinal implants and real-time control software that modulate extensor and flexor synergies with precise temporal resolution. Spatiotemporal neuromodulation therapies improved gait quality, weight-bearing capacity, endurance and skilled locomotion in several rodent models of spinal cord injury. These new concepts are directly translatable to strategies to improve motor control in humans.", + "TAG_DATA": [ + "74, healthy {'context': 'B-organism'}", + "75, rats. {'context': 'I-organism'}", + "128, locomotion {'phenotype': 'B-migration'}", + "131, rodent {'context': 'B-organism'}", + "132, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "74, healthy ['l0']", + "75, rats. ['l0']", + "128, locomotion ['l1', 'l2']", + "131, rodent ['l1', 'l3']", + "132, models ['l2', 'l3']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "migration", + "words": [ + "locomotion" + ] + }, + "context": { + "val": "organism", + "words": [ + "rodent", + "models" + ] + } + } + ] + }, + { + "PMID": "26752519", + "TEXT": "Chronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and genetic determinants. We have previously identified iron-responsive element-binding protein 2 (IRP2) as an important COPD susceptibility gene and have shown that IRP2 protein is increased in the lungs of individuals with COPD. Here we demonstrate that mice deficient in Irp2 were protected from cigarette smoke (CS)-induced experimental COPD. By integrating RNA immunoprecipitation followed by sequencing (RIP-seq), RNA sequencing (RNA-seq), and gene expression and functional enrichment clustering analysis, we identified Irp2 as a regulator of mitochondrial function in the lungs of mice. Irp2 increased mitochondrial iron loading and levels of cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD. Frataxin-deficient mice, which had higher mitochondrial iron loading, showed impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas mice deficient in the synthesis of cytochrome c oxidase, which have reduced COX, were protected from CS-induced pulmonary inflammation and impairment of MCC. Mice treated with a mitochondrial iron chelator or mice fed a low-iron diet were protected from CS-induced COPD. Mitochondrial iron chelation also alleviated CS-induced impairment of MCC, CS-induced pulmonary inflammation and CS-associated lung injury in mice with established COPD, suggesting a critical functional role and potential therapeutic intervention for the mitochondrial-iron axis in COPD.", + "TAG_DATA": [ + "48, mice {'context': 'B-organism'}", + "49, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "50, in {'perturbing_action': 'I-gene loss-of-function'}", + "51, Irp2 {'perturbing_action': 'I-gene loss-of-function'}", + "114, Frataxin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "115, mice, {'context': 'B-organism'}", + "135, mice {'context': 'B-organism'}", + "158, Mice {'context': 'B-organism'}", + "166, mice {'context': 'B-organism'}", + "193, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "48, mice ['l0', 'l1', 'l2']", + "49, deficient ['l0', 'l3', 'l4']", + "50, in ['l1', 'l3', 'l5']", + "51, Irp2 ['l2', 'l4', 'l5']", + "114, Frataxin-deficient ['l6']", + "115, mice, ['l6']", + "158, Mice ['l7']", + "166, mice ['l7', 'l8']", + "193, mice ['l8']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Irp2", + "Frataxin-deficient" + ] + } + } + ] + }, + { + "PMID": "26657142", + "TEXT": "Complex insertions and deletions (indels) are formed by simultaneously deleting and inserting DNA fragments of different sizes at a common genomic location. Here we present a systematic analysis of somatic complex indels in the coding sequences of samples from over 8,000 cancer cases using Pindel-C. We discovered 285 complex indels in cancer-associated genes (such as PIK3R1, TP53, ARID1A, GATA3 and KMT2D) in approximately 3.5% of cases analyzed; nearly all instances of complex indels were overlooked (81.1%) or misannotated (17.6%) in previous reports of 2,199 samples. In-frame complex indels are enriched in PIK3R1 and EGFR, whereas frameshifts are prevalent in VHL, GATA3, TP53, ARID1A, PTEN and ATRX. Furthermore, complex indels display strong tissue specificity (such as VHL in kidney cancer samples and GATA3 in breast cancer samples). Finally, structural analyses support findings of previously missed, but potentially druggable, mutations in the EGFR, MET and KIT oncogenes. This study indicates the critical importance of improving complex indel discovery and interpretation in medical research.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "26646495", + "TEXT": "Aging is a risk factor for several of the world's most prevalent diseases, including neurodegenerative disorders, cancer, cardiovascular disease and metabolic disease. Although our understanding of the molecular pathways that contribute to the aging process and age-related disease is progressing through the use of model organisms, how to apply this knowledge in the clinic is less clear. In September, Nature Medicine, in collaboration with the Volkswagen Foundation, hosted a conference at the beautiful Herrenhausen Palace in Hannover, Germany with the goal of broadening our understanding of the aging process and its meaning as a 'risk factor' in disease. Here, several of the speakers at that conference answer questions posed by Nature Medicine.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "26618723", + "TEXT": "Intratumor heterogeneity (ITH) drives neoplastic progression and therapeutic resistance. We used the bioinformatics tools 'expanding ploidy and allele frequency on nested subpopulations' (EXPANDS) and PyClone to detect clones that are present at a ≥10% frequency in 1,165 exome sequences from tumors in The Cancer Genome Atlas. 86% of tumors across 12 cancer types had at least two clones. ITH in the morphology of nuclei was associated with genetic ITH (Spearman's correlation coefficient, ρ = 0.24-0.41; P < 0.001). Mutation of a driver gene that typically appears in smaller clones was a survival risk factor (hazard ratio (HR) = 2.15, 95% confidence interval (CI): 1.71-2.69). The risk of mortality also increased when >2 clones coexisted in the same tumor sample (HR = 1.49, 95% CI: 1.20-1.87). In two independent data sets, copy-number alterations affecting either <25% or >75% of a tumor's genome predicted reduced risk (HR = 0.15, 95% CI: 0.08-0.29). Mortality risk also declined when >4 clones coexisted in the sample, suggesting a trade-off between the costs and benefits of genomic instability. ITH and genomic instability thus have the potential to be useful measures that can universally be applied to all cancers.", + "TAG_DATA": [ + "117, tumor {'context': 'B-neoplasm'}", + "118, sample {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "117, tumor ['l0']", + "118, sample ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26569381", + "TEXT": "Dystrophin is expressed in differentiated myofibers, in which it is required for sarcolemmal integrity, and loss-of-function mutations in the gene that encodes it result in Duchenne muscular dystrophy (DMD), a disease characterized by progressive and severe skeletal muscle degeneration. Here we found that dystrophin is also highly expressed in activated muscle stem cells (also known as satellite cells), in which it associates with the serine-threonine kinase Mark2 (also known as Par1b), an important regulator of cell polarity. In the absence of dystrophin, expression of Mark2 protein is downregulated, resulting in the inability to localize the cell polarity regulator Pard3 to the opposite side of the cell. Consequently, the number of asymmetric divisions is strikingly reduced in dystrophin-deficient satellite cells, which also display a loss of polarity, abnormal division patterns (including centrosome amplification), impaired mitotic spindle orientation and prolonged cell divisions. Altogether, these intrinsic defects strongly reduce the generation of myogenic progenitors that are needed for proper muscle regeneration. Therefore, we conclude that dystrophin has an essential role in the regulation of satellite cell polarity and asymmetric division. Our findings indicate that muscle wasting in DMD not only is caused by myofiber fragility, but also is exacerbated by impaired regeneration owing to intrinsic satellite cell dysfunction.", + "TAG_DATA": [ + "79, absence {'perturbing_action': 'B-gene loss-of-function'}", + "80, of {'perturbing_action': 'I-gene loss-of-function'}", + "81, dystrophin, {'perturbing_action': 'I-gene loss-of-function'}", + "116, dystrophin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "117, satellite {'context': 'B-cells'}", + "118, cells, {'context': 'I-cells'}", + "139, divisions. {'phenotype': 'I-proliferation'}" + ], + "LINK_DATA": [ + "79, absence ['l0', 'l1', 'l2']", + "80, of ['l0', 'l3', 'l4']", + "81, dystrophin, ['l1', 'l3', 'l5']", + "116, dystrophin-deficient ['l6', 'l7', 'l8', 'l9']", + "117, satellite ['l6', 'l10', 'l11']", + "118, cells, ['l2', 'l4', 'l5', 'l7', 'l10', 'l12']", + "138, cell ['l8', 'l13']", + "139, divisions. ['l9', 'l11', 'l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "dystrophin,", + "dystrophin-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells,", + "satellite" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "divisions." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "satellite", + "cells," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "divisions." + ] + } + } + ] + }, + { + "PMID": "26552008", + "TEXT": "The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome (MERS)-CoV underscores the threat of cross-species transmission events leading to outbreaks in humans. Here we examine the disease potential of a SARS-like virus, SHC014-CoV, which is currently circulating in Chinese horseshoe bat populations. Using the SARS-CoV reverse genetics system, we generated and characterized a chimeric virus expressing the spike of bat coronavirus SHC014 in a mouse-adapted SARS-CoV backbone. The results indicate that group 2b viruses encoding the SHC014 spike in a wild-type backbone can efficiently use multiple orthologs of the SARS receptor human angiotensin converting enzyme II (ACE2), replicate efficiently in primary human airway cells and achieve in vitro titers equivalent to epidemic strains of SARS-CoV. Additionally, in vivo experiments demonstrate replication of the chimeric virus in mouse lung with notable pathogenesis. Evaluation of available SARS-based immune-therapeutic and prophylactic modalities revealed poor efficacy; both monoclonal antibody and vaccine approaches failed to neutralize and protect from infection with CoVs using the novel spike protein. On the basis of these findings, we synthetically re-derived an infectious full-length SHC014 recombinant virus and demonstrate robust viral replication both in vitro and in vivo. Our work suggests a potential risk of SARS-CoV re-emergence from viruses currently circulating in bat populations.", + "TAG_DATA": [ + "105, primary {'context': 'B-cells'}", + "106, human {'context': 'I-cells'}", + "107, airway {'context': 'I-cells'}", + "108, cells {'context': 'I-cells'}", + "111, in {'context': 'B-in vitro'}", + "112, vitro {'context': 'I-in vitro'}", + "121, in {'context': 'B-in vivo'}", + "122, vivo {'context': 'I-in vivo'}", + "131, mouse {'context': 'B-tissue/organ'}", + "132, lung {'context': 'I-tissue/organ'}", + "188, in {'context': 'B-in vitro'}", + "189, vitro {'context': 'I-in vitro'}", + "191, in {'context': 'B-in vivo'}", + "192, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "105, primary ['l0', 'l1', 'l2', 'l3', 'l4']", + "106, human ['l0', 'l5', 'l6', 'l7', 'l8']", + "107, airway ['l1', 'l5', 'l9', 'l10', 'l11']", + "108, cells ['l2', 'l6', 'l9', 'l12']", + "111, in ['l3', 'l7', 'l10', 'l13']", + "112, vitro ['l4', 'l8', 'l11', 'l12', 'l13']", + "121, in ['l14', 'l15', 'l16']", + "122, vivo ['l14', 'l17', 'l18']", + "131, mouse ['l15', 'l17', 'l19']", + "132, lung ['l16', 'l18', 'l19']", + "188, in ['l20', 'l21', 'l22']", + "189, vitro ['l20', 'l23', 'l24']", + "191, in ['l21', 'l23', 'l25']", + "192, vivo. ['l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26523971", + "TEXT": "Focal malformations of cortical development (FMCDs) account for the majority of drug-resistant pediatric epilepsy. Postzygotic somatic mutations activating the phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway are found in a wide range of brain diseases, including FMCDs. It remains unclear how a mutation in a small fraction of cells disrupts the architecture of the entire hemisphere. Within human FMCD-affected brain, we found that cells showing activation of the PI3K-AKT-mTOR pathway were enriched for the AKT3(E17K) mutation. Introducing the FMCD-causing mutation into mouse brain resulted in electrographic seizures and impaired hemispheric architecture. Mutation-expressing neural progenitors showed misexpression of reelin, which led to a non-cell autonomous migration defect in neighboring cells, due at least in part to derepression of reelin transcription in a manner dependent on the forkhead box (FOX) transcription factor FOXG1. Treatments aimed at either blocking downstream AKT signaling or inactivating reelin restored migration. These findings suggest a central AKT-FOXG1-reelin signaling pathway in FMCD and support pathway inhibitors as potential treatments or therapies for some forms of focal epilepsy.", + "TAG_DATA": [ + "66, cells {'context': 'B-cells'}", + "79, Introducing {'perturbing_action': 'B-other'}", + "80, the {'perturbing_action': 'I-other'}", + "81, FMCD-causing {'perturbing_action': 'I-other'}", + "82, mutation {'perturbing_action': 'I-other'}", + "84, mouse {'context': 'B-tissue/organ'}", + "85, brain {'context': 'I-tissue/organ'}", + "94, Mutation-expressing {'context': 'B-cells'}", + "95, neural {'context': 'I-cells'}", + "96, progenitors {'context': 'I-cells'}", + "107, migration {'phenotype': 'B-migration'}", + "108, defect {'effect': 'B-negative'}", + "111, cells, {'context': 'B-cells'}", + "143, inactivating {'perturbing_action': 'B-gene loss-of-function'}", + "144, reelin {'perturbing_action': 'I-gene loss-of-function'}", + "145, restored {'effect': 'B-rescues'}", + "146, migration. {'phenotype': 'B-migration'}" + ], + "LINK_DATA": [ + "79, Introducing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "80, the ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "81, FMCD-causing ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "82, mutation ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "84, mouse ['l3', 'l12', 'l20', 'l27', 'l34']", + "85, brain ['l4', 'l13', 'l21', 'l28', 'l34']", + "94, Mutation-expressing ['l35', 'l36', 'l37', 'l38', 'l39']", + "95, neural ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l41', 'l42', 'l43']", + "96, progenitors ['l6', 'l15', 'l23', 'l30', 'l36', 'l40', 'l44', 'l45', 'l46']", + "107, migration ['l7', 'l16', 'l24', 'l31', 'l37', 'l41', 'l44', 'l47', 'l48']", + "108, defect ['l8', 'l17', 'l25', 'l32', 'l38', 'l42', 'l45', 'l47', 'l49']", + "111, cells, ['l9', 'l18', 'l26', 'l33', 'l39', 'l43', 'l46', 'l48', 'l49']", + "143, inactivating ['l50', 'l51', 'l52']", + "144, reelin ['l50', 'l53', 'l54']", + "145, restored ['l51', 'l53', 'l55']", + "146, migration. ['l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Introducing", + "the", + "FMCD-causing", + "mutation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "brain" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Introducing", + "the", + "FMCD-causing", + "mutation" + ] + }, + "context": { + "val": "cells", + "words": [ + "neural", + "progenitors", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Introducing", + "the", + "FMCD-causing", + "mutation" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Introducing", + "the", + "FMCD-causing", + "mutation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defect" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Mutation-expressing", + "neural", + "progenitors", + "cells," + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Mutation-expressing", + "neural", + "progenitors", + "cells," + ] + }, + "effect": { + "val": "negative", + "words": [ + "defect" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defect" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivating", + "reelin" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivating", + "reelin" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + } + ] + }, + { + "PMID": "26523970", + "TEXT": "The TAM receptors Tyro3, Axl and Mertk are receptor tyrosine kinases that dampen host innate immune responses following engagement with their ligands Gas6 and Protein S, which recognize phosphatidylserine on apoptotic cells. In a form of apoptotic mimicry, many enveloped viruses display phosphatidylserine on the outer leaflet of their membranes, enabling TAM receptor activation and downregulation of antiviral responses. Accordingly, we hypothesized that a deficiency of TAM receptors would enhance antiviral responses and protect against viral infection. Unexpectedly, mice lacking Mertk and/or Axl, but not Tyro3, exhibited greater vulnerability to infection with neuroinvasive West Nile and La Crosse encephalitis viruses. This phenotype was associated with increased blood-brain barrier permeability, which enhanced virus entry into and infection of the brain. Activation of Mertk synergized with interferon-β to tighten cell junctions and prevent virus transit across brain microvascular endothelial cells. Because TAM receptors restrict pathogenesis of neuroinvasive viruses, these findings have implications for TAM antagonists that are currently in clinical development.", + "TAG_DATA": [ + "78, mice {'context': 'B-organism'}", + "79, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "80, Mertk {'perturbing_action': 'I-gene loss-of-function'}", + "81, and/or {'perturbing_action': 'I-gene loss-of-function'}", + "82, Axl, {'perturbing_action': 'I-gene loss-of-function'}", + "118, brain. {'context': 'B-tissue/organ'}", + "119, Activation {'perturbing_action': 'B-pharmacological augmentation'}", + "120, of {'perturbing_action': 'I-pharmacological augmentation'}", + "121, Mertk {'perturbing_action': 'I-pharmacological augmentation'}", + "134, brain {'context': 'B-cells'}", + "135, microvascular {'context': 'I-cells'}", + "136, endothelial {'context': 'I-cells'}", + "137, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "78, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "79, lacking ['l0', 'l5', 'l6', 'l7', 'l8']", + "80, Mertk ['l1', 'l5', 'l9', 'l10', 'l11']", + "81, and/or ['l2', 'l6', 'l9', 'l12', 'l13']", + "82, Axl, ['l3', 'l7', 'l10', 'l12', 'l14']", + "118, brain. ['l4', 'l8', 'l11', 'l13', 'l14']", + "119, Activation ['l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "120, of ['l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "121, Mertk ['l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "134, brain ['l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "135, microvascular ['l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "136, endothelial ['l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "137, cells. ['l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "Mertk", + "and/or", + "Axl," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "Mertk", + "and/or", + "Axl," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "Mertk" + ] + }, + "context": { + "val": "cells", + "words": [ + "brain", + "microvascular", + "endothelial", + "cells." + ] + } + } + ] + }, + { + "PMID": "26501191", + "TEXT": "There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53(R175H) induces cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. We also define culture conditions for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture and phenotypic heterogeneity of the primary tumor and retain patient-specific physiological changes, including hypoxia, oxygen consumption, epigenetic marks and differences in sensitivity to inhibition of the histone methyltransferase EZH2. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies.", + "TAG_DATA": [ + "26, human {'context': 'B-cells'}", + "43, in {'context': 'B-in vivo'}", + "44, vivo. {'context': 'I-in vivo'}", + "45, Expression {'perturbing_action': 'B-other'}", + "46, of {'perturbing_action': 'I-other'}", + "47, mutant {'perturbing_action': 'I-other'}", + "48, KRAS {'perturbing_action': 'I-other'}", + "49, or {'perturbing_action': 'I-other'}", + "50, TP53 {'perturbing_action': 'I-other'}", + "52, progenitor {'context': 'B-organoid'}", + "53, organoids {'context': 'I-organoid'}", + "58, culture {'context': 'I-in vitro'}", + "60, in {'context': 'B-in vivo'}", + "61, vivo. {'context': 'I-in vivo'}", + "62, Expression {'perturbing_action': 'B-other'}", + "63, of {'perturbing_action': 'I-other'}", + "64, TP53(R175H) {'perturbing_action': 'I-other'}", + "70, patient {'context': 'B-neoplasm'}", + "71, tumors {'context': 'I-neoplasm'}", + "73, TP53 {'perturbing_action': 'I-other'}", + "74, mutations, {'perturbing_action': 'I-other'}", + "89, generation {'phenotype': 'I-colony formation'}", + "91, tumor {'context': 'B-organoid'}", + "92, organoids {'context': 'I-organoid'}", + "96, PDAC. {'context': 'B-neoplasm'}", + "97, Tumor {'context': 'B-organoid'}", + "98, organoids {'context': 'I-organoid'}", + "99, maintain {'effect': 'B-positive'}", + "101, differentiation {'phenotype': 'B-differentiation'}", + "102, status, {'phenotype': 'I-differentiation'}", + "109, primary {'context': 'B-neoplasm'}", + "110, tumor {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "26, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "43, in ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "44, vivo. ['l1', 'l7', 'l12', 'l13', 'l14', 'l15']", + "45, Expression ['l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "46, of ['l16', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "47, mutant ['l17', 'l33', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "48, KRAS ['l18', 'l34', 'l48', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "49, or ['l19', 'l35', 'l49', 'l61', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "50, TP53 ['l20', 'l36', 'l50', 'l62', 'l70', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "52, progenitor ['l2', 'l8', 'l12', 'l21', 'l37', 'l51', 'l63', 'l71', 'l81', 'l91', 'l92', 'l93', 'l94', 'l95']", + "53, organoids ['l3', 'l9', 'l13', 'l22', 'l38', 'l52', 'l64', 'l72', 'l82', 'l91', 'l96', 'l97', 'l98']", + "58, culture ['l4', 'l10', 'l14', 'l23', 'l39', 'l53', 'l65', 'l73', 'l83', 'l92', 'l96', 'l99']", + "60, in ['l5', 'l24', 'l40', 'l54', 'l66', 'l74', 'l84', 'l93', 'l97', 'l100']", + "61, vivo. ['l6', 'l11', 'l15', 'l25', 'l41', 'l55', 'l67', 'l75', 'l85', 'l94', 'l98', 'l99', 'l100']", + "62, Expression ['l26', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "63, of ['l27', 'l42', 'l56', 'l76', 'l86', 'l101', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "64, TP53(R175H) ['l28', 'l43', 'l57', 'l77', 'l87', 'l102', 'l113', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "70, patient ['l29', 'l44', 'l58', 'l68', 'l78', 'l88', 'l103', 'l114', 'l125', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "71, tumors ['l30', 'l45', 'l59', 'l69', 'l79', 'l89', 'l95', 'l104', 'l115', 'l126', 'l135', 'l141', 'l142']", + "73, TP53 ['l31', 'l46', 'l105', 'l116', 'l127', 'l136', 'l141', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "74, mutations, ['l32', 'l47', 'l60', 'l80', 'l90', 'l106', 'l117', 'l128', 'l137', 'l142', 'l143', 'l150', 'l151', 'l152', 'l153']", + "89, generation ['l107', 'l118', 'l129', 'l138', 'l144', 'l150', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160']", + "91, tumor ['l108', 'l119', 'l130', 'l145', 'l151', 'l154', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "92, organoids ['l109', 'l120', 'l131', 'l139', 'l146', 'l152', 'l155', 'l161', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "96, PDAC. ['l110', 'l121', 'l132', 'l140', 'l147', 'l153', 'l156', 'l162', 'l168', 'l174', 'l175', 'l176', 'l177', 'l178']", + "97, Tumor ['l179', 'l180', 'l181', 'l182', 'l183', 'l184']", + "98, organoids ['l179', 'l185', 'l186', 'l187', 'l188', 'l189']", + "99, maintain ['l163', 'l169', 'l174', 'l180', 'l185', 'l190', 'l191', 'l192', 'l193']", + "101, differentiation ['l122', 'l157', 'l164', 'l170', 'l175', 'l181', 'l186', 'l190', 'l194', 'l195', 'l196']", + "102, status, ['l111', 'l123', 'l133', 'l148', 'l158', 'l165', 'l171', 'l176', 'l182', 'l187', 'l191', 'l194', 'l197', 'l198']", + "109, primary ['l159', 'l166', 'l172', 'l177', 'l183', 'l188', 'l192', 'l195', 'l197', 'l199']", + "110, tumor ['l112', 'l124', 'l134', 'l149', 'l160', 'l167', 'l173', 'l178', 'l184', 'l189', 'l193', 'l196', 'l198', 'l199']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Expression", + "of", + "mutant", + "KRAS", + "or", + "TP53", + "TP53(R175H)", + "mutations," + ] + }, + "context": { + "val": "organoid", + "words": [ + "progenitor", + "organoids", + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Expression", + "of", + "mutant", + "KRAS", + "or", + "TP53" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Expression", + "of", + "mutant", + "KRAS", + "or", + "TP53" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Expression", + "of", + "mutant", + "KRAS", + "or", + "TP53", + "TP53(R175H)", + "mutations," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "patient", + "tumors", + "PDAC.", + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Expression", + "of", + "TP53(R175H)", + "TP53", + "mutations," + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "generation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Expression", + "of", + "TP53(R175H)", + "TP53" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "status,", + "differentiation" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "patient", + "PDAC.", + "primary", + "tumor" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "generation" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "generation" + ] + }, + "context": { + "val": "organoid", + "words": [ + "tumor", + "organoids" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "tumor", + "organoids", + "Tumor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "maintain" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "tumor", + "organoids", + "Tumor" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "status," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "PDAC.", + "primary", + "tumor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "maintain" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "PDAC.", + "primary", + "tumor" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "status," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "maintain" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "status," + ] + } + } + ] + }, + { + "PMID": "26479925", + "TEXT": "Mechanical allodynia, induced by normally innocuous low-threshold mechanical stimulation, represents a cardinal feature of neuropathic pain. Blockade or ablation of high-threshold, small-diameter unmyelinated group C nerve fibers (C-fibers) has limited effects on mechanical allodynia. Although large, myelinated group A fibers, in particular Aβ-fibers, have previously been implicated in mechanical allodynia, an A-fiber-selective pharmacological blocker is still lacking. Here we report a new method for targeted silencing of A-fibers in neuropathic pain. We found that Toll-like receptor 5 (TLR5) is co-expressed with neurofilament-200 in large-diameter A-fiber neurons in the dorsal root ganglion (DRG). Activation of TLR5 with its ligand flagellin results in neuronal entry of the membrane-impermeable lidocaine derivative QX-314, leading to TLR5-dependent blockade of sodium currents, predominantly in A-fiber neurons of mouse DRGs. Intraplantar co-application of flagellin and QX-314 (flagellin/QX-314) dose-dependently suppresses mechanical allodynia after chemotherapy, nerve injury, and diabetic neuropathy, but this blockade is abrogated in Tlr5-deficient mice. In vivo electrophysiology demonstrated that co-application of flagellin/QX-314 selectively suppressed Aβ-fiber conduction in naive and chemotherapy-treated mice. TLR5-mediated Aβ-fiber blockade, but not capsaicin-mediated C-fiber blockade, also reduced chemotherapy-induced ongoing pain without impairing motor function. Finally, flagellin/QX-314 co-application suppressed sodium currents in large-diameter human DRG neurons. Thus, our findings provide a new tool for targeted silencing of Aβ-fibers and neuropathic pain treatment.", + "TAG_DATA": [ + "118, A-fiber {'context': 'B-cells'}", + "119, neurons {'context': 'I-cells'}", + "120, of {'context': 'I-cells'}", + "121, mouse {'context': 'I-cells'}", + "122, DRGs. {'context': 'I-cells'}", + "147, Tlr5-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "148, mice. {'context': 'B-organism'}", + "149, In {'context': 'B-in vivo'}", + "150, vivo {'context': 'I-in vivo'}", + "165, mice. {'context': 'B-organism'}", + "190, large-diameter {'context': 'B-cells'}", + "191, human {'context': 'I-cells'}", + "192, DRG {'context': 'I-cells'}", + "193, neurons. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "118, A-fiber ['l0', 'l1', 'l2', 'l3']", + "119, neurons ['l0', 'l4', 'l5', 'l6']", + "120, of ['l1', 'l4', 'l7', 'l8']", + "121, mouse ['l2', 'l5', 'l7', 'l9']", + "122, DRGs. ['l3', 'l6', 'l8', 'l9']", + "147, Tlr5-deficient ['l10', 'l11']", + "148, mice. ['l10', 'l12']", + "149, In ['l13', 'l14']", + "150, vivo ['l13', 'l15']", + "165, mice. ['l11', 'l12', 'l14', 'l15']", + "190, large-diameter ['l16', 'l17', 'l18']", + "191, human ['l16', 'l19', 'l20']", + "192, DRG ['l17', 'l19', 'l21']", + "193, neurons. ['l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tlr5-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "26479924", + "TEXT": "In heart failure therapy, it is generally assumed that attempts to produce a long-term increase in cardiac contractile force are almost always accompanied by structural and functional damage. Here we show that modest overexpression of the Raf kinase inhibitor protein (RKIP), encoded by Pebp1 in mice, produces a well-tolerated, persistent increase in cardiac contractility that is mediated by the β1-adrenoceptor (β1AR). This result is unexpected, as β1AR activation, a major driver of cardiac contractility, usually has long-term adverse effects. RKIP overexpression achieves this tolerance via simultaneous activation of the β2AR subtype. Analogously, RKIP deficiency exaggerates pressure overload-induced cardiac failure. We find that RKIP expression is upregulated in mouse and human heart failure, indicative of an adaptive role for RKIP. Pebp1 gene transfer in a mouse model of heart failure has beneficial effects, suggesting a new therapeutic strategy for heart failure therapy.", + "TAG_DATA": [ + "32, modest {'perturbing_action': 'B-gene gain-of-function'}", + "33, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "34, of {'perturbing_action': 'I-gene gain-of-function'}", + "35, the {'perturbing_action': 'I-gene gain-of-function'}", + "36, Raf {'perturbing_action': 'I-gene gain-of-function'}", + "37, kinase {'perturbing_action': 'I-gene gain-of-function'}", + "38, inhibitor {'perturbing_action': 'I-gene gain-of-function'}", + "39, protein {'perturbing_action': 'I-gene gain-of-function'}", + "40, (RKIP), {'perturbing_action': 'I-gene gain-of-function'}", + "41, encoded {'perturbing_action': 'I-gene gain-of-function'}", + "42, by {'perturbing_action': 'I-gene gain-of-function'}", + "43, Pebp1 {'perturbing_action': 'I-gene gain-of-function'}", + "45, mice, {'context': 'B-organism'}", + "79, RKIP {'perturbing_action': 'B-gene gain-of-function'}", + "80, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "92, RKIP {'perturbing_action': 'B-gene loss-of-function'}", + "93, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "119, Pebp1 {'perturbing_action': 'B-gene gain-of-function'}", + "120, gene {'perturbing_action': 'I-gene gain-of-function'}", + "121, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "124, mouse {'context': 'B-organism'}", + "125, model {'context': 'I-organism'}", + "126, of {'context': 'I-patient'}", + "127, heart {'context': 'I-tissue/organ'}", + "128, failure {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "32, modest ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "33, overexpression ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "34, of ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "35, the ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "36, Raf ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "37, kinase ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "38, inhibitor ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "39, protein ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "40, (RKIP), ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "41, encoded ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "42, by ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "43, Pebp1 ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "45, mice, ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "79, RKIP ['l78', 'l79', 'l80']", + "80, overexpression ['l78', 'l81', 'l82']", + "92, RKIP ['l79', 'l81', 'l83']", + "93, deficiency ['l80', 'l82', 'l83']", + "119, Pebp1 ['l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "120, gene ['l84', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "121, transfer ['l85', 'l91', 'l97', 'l98', 'l99', 'l100', 'l101']", + "124, mouse ['l86', 'l92', 'l97', 'l102', 'l103', 'l104', 'l105']", + "125, model ['l87', 'l93', 'l98', 'l102', 'l106', 'l107', 'l108']", + "126, of ['l88', 'l94', 'l99', 'l103', 'l106', 'l109', 'l110']", + "127, heart ['l89', 'l95', 'l100', 'l104', 'l107', 'l109', 'l111']", + "128, failure ['l90', 'l96', 'l101', 'l105', 'l108', 'l110', 'l111']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "modest", + "overexpression", + "of", + "the", + "Raf", + "kinase", + "inhibitor", + "protein", + "(RKIP),", + "encoded", + "by", + "Pebp1", + "gene", + "transfer" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Pebp1", + "gene", + "transfer" + ] + }, + "context": { + "val": "patient", + "words": [ + "of", + "failure" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Pebp1", + "gene", + "transfer" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "heart" + ] + } + } + ] + }, + { + "PMID": "26457757", + "TEXT": "Retention of long-term repopulating hematopoietic stem cells (LT-HSCs) in the bone marrow is essential for hematopoiesis and for protection from myelotoxic injury. We report that signaling cascades that are traditionally viewed as coagulation related also control retention of endothelial protein C receptor-positive (EPCR(+)) LT-HSCs in the bone marrow and their recruitment to the blood via two pathways mediated by protease activated receptor 1 (PAR1). Thrombin-PAR1 signaling induces nitric oxide (NO) production, leading to EPCR shedding mediated by tumor necrosis factor-α-converting enzyme (TACE), enhanced CXCL12-CXCR4-induced motility and rapid stem and progenitor cell mobilization. Conversely, bone marrow blood vessels provide a microenvironment enriched with activated protein C (aPC) that retains EPCR(+) LT-HSCs by limiting NO generation, reducing Cdc42 activity and enhancing integrin VLA4 affinity and adhesion. Inhibition of NO production by aPC-EPCR-PAR1 signaling reduces progenitor cell egress from the bone marrow, increases retention of bone marrow NO(low) EPCR(+) LT-HSCs and protects mice from chemotherapy-induced hematological failure and death. Our study reveals new roles for PAR1 and EPCR in controlling NO production to balance maintenance and recruitment of bone marrow EPCR(+) LT-HSCs, with potential clinical relevance for stem cell transplantation.", + "TAG_DATA": [ + "84, motility {'phenotype': 'B-migration'}", + "87, stem {'context': 'B-cells'}", + "88, and {'context': 'I-cells'}", + "89, progenitor {'context': 'I-cells'}", + "90, cell {'context': 'I-cells'}", + "132, progenitor {'context': 'B-cells'}", + "133, cell {'context': 'I-cells'}", + "149, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "84, motility ['l0', 'l1', 'l2', 'l3']", + "87, stem ['l0', 'l4', 'l5', 'l6']", + "88, and ['l1', 'l4', 'l7', 'l8']", + "89, progenitor ['l2', 'l5', 'l7', 'l9']", + "90, cell ['l3', 'l6', 'l8', 'l9']", + "132, progenitor ['l10']", + "133, cell ['l10']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "migration", + "words": [ + "motility" + ] + }, + "context": { + "val": "cells", + "words": [ + "stem", + "and", + "progenitor", + "cell" + ] + } + } + ] + }, + { + "PMID": "26413781", + "TEXT": "Neural prostheses have the potential to improve the quality of life of individuals with paralysis by directly mapping neural activity to limb- and computer-control signals. We translated a neural prosthetic system previously developed in animal model studies for use by two individuals with amyotrophic lateral sclerosis who had intracortical microelectrode arrays placed in motor cortex. Measured more than 1 year after implant, the neural cursor-control system showed the highest published performance achieved by a person to date, more than double that of previous pilot clinical trial participants.", + "TAG_DATA": [ + "41, individuals {'context': 'B-patient'}", + "53, motor {'context': 'B-cells'}", + "54, cortex. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "41, individuals ['l0', 'l1']", + "53, motor ['l0', 'l2']", + "54, cortex. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26390243", + "TEXT": "Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and shows resistance to any therapeutic strategy used. Here we tested small-molecule inhibitors targeting chromatin regulators as possible therapeutic agents in PDAC. We show that JQ1, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, suppresses PDAC development in mice by inhibiting both MYC activity and inflammatory signals. The histone deacetylase (HDAC) inhibitor SAHA synergizes with JQ1 to augment cell death and more potently suppress advanced PDAC. Finally, using a CRISPR-Cas9-based method for gene editing directly in the mouse adult pancreas, we show that de-repression of p57 (also known as KIP2 or CDKN1C) upon combined BET and HDAC inhibition is required for the induction of combination therapy-induced cell death in PDAC. SAHA is approved for human use, and molecules similar to JQ1 are being tested in clinical trials. Thus, these studies identify a promising epigenetic-based therapeutic strategy that may be rapidly implemented in fatal human tumors.", + "TAG_DATA": [ + "50, PDAC {'context': 'B-neoplasm'}", + "53, mice {'context': 'B-organism'}", + "72, augment {'effect': 'B-positive'}", + "73, cell {'phenotype': 'B-cell death'}", + "74, death {'phenotype': 'I-cell death'}", + "80, PDAC. {'context': 'B-neoplasm'}", + "92, mouse {'context': 'B-tissue/organ'}", + "93, adult {'context': 'I-tissue/organ'}", + "94, pancreas, {'context': 'I-tissue/organ'}", + "98, de-repression {'perturbing_action': 'B-gene loss-of-function'}", + "99, of {'perturbing_action': 'I-gene loss-of-function'}", + "100, p57 {'perturbing_action': 'I-gene loss-of-function'}", + "101, (also {'perturbing_action': 'I-gene loss-of-function'}", + "104, KIP2 {'perturbing_action': 'I-rnai/knockdown'}", + "106, CDKN1C) {'perturbing_action': 'I-rnai/knockdown'}", + "117, induction {'effect': 'B-positive'}", + "120, therapy-induced {'effect': 'B-positive'}", + "121, cell {'phenotype': 'B-cell death'}", + "122, death {'phenotype': 'I-cell death'}", + "124, PDAC. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "50, PDAC ['l0']", + "53, mice ['l0']", + "72, augment ['l1', 'l2', 'l3']", + "73, cell ['l1', 'l4', 'l5']", + "74, death ['l2', 'l4', 'l6']", + "80, PDAC. ['l3', 'l5', 'l6']", + "92, mouse ['l7', 'l8']", + "93, adult ['l7', 'l9']", + "94, pancreas, ['l8', 'l9']", + "98, de-repression ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "99, of ['l10', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "100, p57 ['l11', 'l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "101, (also ['l12', 'l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "103, as ['l13', 'l23', 'l32', 'l40', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "104, KIP2 ['l14', 'l24', 'l33', 'l41', 'l48', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "106, CDKN1C) ['l15', 'l25', 'l34', 'l42', 'l49', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "117, induction ['l16', 'l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "120, therapy-induced ['l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l70', 'l71', 'l72']", + "121, cell ['l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l70', 'l73', 'l74']", + "122, death ['l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l73', 'l75']", + "124, PDAC. ['l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "augment", + "induction", + "therapy-induced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "augment", + "induction", + "therapy-induced" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "PDAC." + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "PDAC." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "de-repression", + "of", + "p57", + "(also" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction", + "therapy-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "de-repression", + "of", + "p57", + "(also" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "de-repression", + "of", + "p57", + "(also" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "PDAC." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "KIP2", + "CDKN1C)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction", + "therapy-induced" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "KIP2", + "CDKN1C)" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "KIP2", + "CDKN1C)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "PDAC." + ] + } + } + ] + }, + { + "PMID": "26366711", + "TEXT": "The early years of life are important for immune development and influence health in adulthood. Although it has been established that the gut bacterial microbiome is rapidly acquired after birth, less is known about the viral microbiome (or 'virome'), consisting of bacteriophages and eukaryotic RNA and DNA viruses, during the first years of life. Here, we characterized the gut virome and bacterial microbiome in a longitudinal cohort of healthy infant twins. The virome and bacterial microbiome were more similar between co-twins than between unrelated infants. From birth to 2 years of age, the eukaryotic virome and the bacterial microbiome expanded, but this was accompanied by a contraction of and shift in the bacteriophage virome composition. The bacteriophage-bacteria relationship begins from birth with a high predator-low prey dynamic, consistent with the Lotka-Volterra prey model. Thus, in contrast to the stable microbiome observed in adults, the infant microbiome is highly dynamic and associated with early life changes in the composition of bacteria, viruses and bacteriophages with age.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "26301690", + "TEXT": "Endothelial dysfunction is a critical factor in many cardiovascular diseases, including hypertension. Although lipid signaling has been implicated in endothelial dysfunction and cardiovascular disease, specific molecular mechanisms are poorly understood. Here we report that Nogo-B, a membrane protein of the endoplasmic reticulum, regulates endothelial sphingolipid biosynthesis with direct effects on vascular function and blood pressure. Nogo-B inhibits serine palmitoyltransferase, the rate-limiting enzyme of the de novo sphingolipid biosynthetic pathway, thereby controlling production of endothelial sphingosine 1-phosphate and autocrine, G protein-coupled receptor-dependent signaling by this metabolite. Mice lacking Nogo-B either systemically or specifically in endothelial cells are hypotensive, resistant to angiotensin II-induced hypertension and have preserved endothelial function and nitric oxide release. In mice that lack Nogo-B, pharmacological inhibition of serine palmitoyltransferase with myriocin reinstates endothelial dysfunction and angiotensin II-induced hypertension. Our study identifies Nogo-B as a key inhibitor of local sphingolipid synthesis and shows that autocrine sphingolipid signaling within the endothelium is critical for vascular function and blood pressure homeostasis.", + "TAG_DATA": [ + "85, Mice {'context': 'B-organism'}", + "86, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "87, Nogo-B {'perturbing_action': 'I-gene loss-of-function'}", + "89, systemically {'perturbing_action': 'I-gene loss-of-function'}", + "93, endothelial {'context': 'B-cells'}", + "94, cells {'context': 'I-cells'}", + "112, mice {'context': 'B-organism'}", + "114, lack {'perturbing_action': 'B-gene loss-of-function'}", + "115, Nogo-B, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "85, Mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "86, lacking ['l0', 'l5', 'l6', 'l7', 'l8']", + "87, Nogo-B ['l1', 'l5', 'l9', 'l10', 'l11']", + "89, systemically ['l2', 'l6', 'l9', 'l12', 'l13']", + "93, endothelial ['l3', 'l7', 'l10', 'l12', 'l14']", + "94, cells ['l4', 'l8', 'l11', 'l13', 'l14']", + "112, mice ['l15', 'l16']", + "114, lack ['l15', 'l17']", + "115, Nogo-B, ['l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "Nogo-B", + "systemically", + "lack", + "Nogo-B," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "Nogo-B", + "systemically" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + } + } + ] + }, + { + "PMID": "26301689", + "TEXT": "One strategy for combating cancer-drug resistance is to deploy rational polytherapy up front that suppresses the survival and emergence of resistant tumor cells. Here we demonstrate in models of lung adenocarcinoma harboring the oncogenic fusion of ALK and EML4 that the GTPase RAS-mitogen-activated protein kinase (MAPK) pathway, but not other known ALK effectors, is required for tumor-cell survival. EML4-ALK activated RAS-MAPK signaling by engaging all three major RAS isoforms through the HELP domain of EML4. Reactivation of the MAPK pathway via either a gain in the number of copies of the gene encoding wild-type K-RAS (KRAS(WT)) or decreased expression of the MAPK phosphatase DUSP6 promoted resistance to ALK inhibitors in vitro, and each was associated with resistance to ALK inhibitors in individuals with EML4-ALK-positive lung adenocarcinoma. Upfront inhibition of both ALK and the kinase MEK enhanced both the magnitude and duration of the initial response in preclinical models of EML4-ALK lung adenocarcinoma. Our findings identify RAS-MAPK dependence as a hallmark of EML4-ALK lung adenocarcinoma and provide a rationale for the upfront inhibition of both ALK and MEK to forestall resistance and improve patient outcomes.", + "TAG_DATA": [ + "107, ALK {'perturbing_action': 'B-pharmacological inhibition'}", + "108, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "109, in {'context': 'B-in vitro'}", + "110, vitro, {'context': 'B-in vitro'}", + "118, ALK {'perturbing_action': 'B-pharmacological inhibition'}", + "119, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "123, EML4-ALK-positive {'context': 'B-neoplasm'}", + "124, lung {'context': 'I-neoplasm'}", + "125, adenocarcinoma. {'context': 'I-neoplasm'}", + "126, Upfront {'perturbing_action': 'B-pharmacological inhibition'}", + "127, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "128, of {'perturbing_action': 'I-pharmacological inhibition'}", + "129, both {'perturbing_action': 'I-pharmacological inhibition'}", + "130, ALK {'perturbing_action': 'I-pharmacological inhibition'}", + "131, and {'perturbing_action': 'I-pharmacological inhibition'}", + "132, the {'perturbing_action': 'I-pharmacological inhibition'}", + "133, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "134, MEK {'perturbing_action': 'I-pharmacological inhibition'}", + "146, preclinical {'context': 'B-neoplasm'}", + "147, models {'context': 'I-neoplasm'}", + "148, of {'context': 'I-neoplasm'}", + "149, EML4-ALK {'context': 'I-neoplasm'}", + "150, lung {'context': 'I-neoplasm'}", + "151, adenocarcinoma. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "107, ALK ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "108, inhibitors ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "109, in ['l1', 'l7', 'l12']", + "110, vitro, ['l2', 'l8', 'l12']", + "118, ALK ['l3', 'l9', 'l13', 'l14', 'l15', 'l16']", + "119, inhibitors ['l4', 'l10', 'l13', 'l17', 'l18', 'l19']", + "123, EML4-ALK-positive ['l14', 'l17', 'l20', 'l21']", + "124, lung ['l5', 'l15', 'l18', 'l20', 'l22']", + "125, adenocarcinoma. ['l6', 'l11', 'l16', 'l19', 'l21', 'l22']", + "126, Upfront ['l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "127, inhibition ['l23', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "128, of ['l24', 'l37', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "129, both ['l25', 'l38', 'l50', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "130, ALK ['l26', 'l39', 'l51', 'l62', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "131, and ['l27', 'l40', 'l52', 'l63', 'l73', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "132, the ['l28', 'l41', 'l53', 'l64', 'l74', 'l83', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "133, kinase ['l29', 'l42', 'l54', 'l65', 'l75', 'l84', 'l92', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "134, MEK ['l30', 'l43', 'l55', 'l66', 'l76', 'l85', 'l93', 'l100', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "146, preclinical ['l31', 'l44', 'l56', 'l67', 'l77', 'l86', 'l94', 'l101', 'l107', 'l113', 'l114', 'l115', 'l116', 'l117']", + "147, models ['l32', 'l45', 'l57', 'l68', 'l78', 'l87', 'l95', 'l102', 'l108', 'l113', 'l118', 'l119', 'l120', 'l121']", + "148, of ['l33', 'l46', 'l58', 'l69', 'l79', 'l88', 'l96', 'l103', 'l109', 'l114', 'l118', 'l122', 'l123', 'l124']", + "149, EML4-ALK ['l34', 'l47', 'l59', 'l70', 'l80', 'l89', 'l97', 'l104', 'l110', 'l115', 'l119', 'l122', 'l125', 'l126']", + "150, lung ['l35', 'l48', 'l60', 'l71', 'l81', 'l90', 'l98', 'l105', 'l111', 'l116', 'l120', 'l123', 'l125', 'l127']", + "151, adenocarcinoma. ['l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l99', 'l106', 'l112', 'l117', 'l121', 'l124', 'l126', 'l127']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ALK", + "inhibitors" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ALK", + "inhibitors", + "Upfront", + "inhibition", + "of", + "both", + "and", + "the", + "kinase", + "MEK" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lung", + "adenocarcinoma.", + "EML4-ALK-positive", + "preclinical", + "models", + "of", + "EML4-ALK" + ] + } + } + ] + }, + { + "PMID": "26280122", + "TEXT": "An increase in amyloid-β (Aβ) production is a major pathogenic mechanism associated with Alzheimer's disease (AD), but little is known about possible homeostatic control of the amyloidogenic pathway. Here we report that the amyloid precursor protein (APP) intracellular domain (AICD) downregulates Wiskott-Aldrich syndrome protein (WASP)-family verprolin homologous protein 1 (WAVE1 or WASF1) as part of a negative feedback mechanism to limit Aβ production. The AICD binds to the Wasf1 promoter, negatively regulates its transcription and downregulates Wasf1 mRNA and protein expression in Neuro 2a (N2a) cells. WAVE1 interacts and colocalizes with APP in the Golgi apparatus. Experimentally reducing WAVE1 in N2a cells decreased the budding of APP-containing vesicles and reduced cell-surface APP, thereby reducing the production of Aβ. WAVE1 downregulation was observed in mouse models of AD. Reduction of Wasf1 gene expression dramatically reduced Aβ levels and restored memory deficits in a mouse model of AD. A decrease in amounts of WASF1 mRNA was also observed in human AD brains, suggesting clinical relevance of the negative feedback circuit involved in homeostatic regulation of Aβ production.", + "TAG_DATA": [ + "96, Experimentally {'perturbing_action': 'B-gene loss-of-function'}", + "97, reducing {'perturbing_action': 'B-gene loss-of-function'}", + "98, WAVE1 {'perturbing_action': 'I-gene loss-of-function'}", + "100, N2a {'context': 'B-cells'}", + "101, cells {'context': 'I-cells'}", + "118, WAVE1 {'perturbing_action': 'B-gene loss-of-function'}", + "119, downregulation {'perturbing_action': 'I-rnai/knockdown'}", + "123, mouse {'context': 'B-organism'}", + "124, models {'context': 'I-organism'}", + "127, Reduction {'perturbing_action': 'B-gene loss-of-function'}", + "128, of {'perturbing_action': 'I-rnai/knockdown'}", + "129, Wasf1 {'perturbing_action': 'I-rnai/knockdown'}", + "130, gene {'perturbing_action': 'I-rnai/knockdown'}", + "131, expression {'perturbing_action': 'I-rnai/knockdown'}", + "142, mouse {'context': 'B-organism'}", + "143, model {'context': 'I-organism'}", + "144, of {'context': 'I-organism'}", + "145, AD. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "96, Experimentally ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "97, reducing ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "98, WAVE1 ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "100, N2a ['l2', 'l9', 'l15', 'l21', 'l22', 'l23']", + "101, cells ['l3', 'l10', 'l16', 'l21', 'l24']", + "118, WAVE1 ['l4', 'l11', 'l17', 'l25', 'l26', 'l27']", + "119, downregulation ['l5', 'l12', 'l18', 'l25', 'l28', 'l29']", + "123, mouse ['l6', 'l13', 'l19', 'l22', 'l26', 'l28', 'l30']", + "124, models ['l7', 'l14', 'l20', 'l23', 'l24', 'l27', 'l29', 'l30']", + "127, Reduction ['l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "128, of ['l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "129, Wasf1 ['l32', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "130, gene ['l33', 'l40', 'l46', 'l52', 'l53', 'l54', 'l55', 'l56']", + "131, expression ['l34', 'l41', 'l47', 'l52', 'l57', 'l58', 'l59', 'l60']", + "142, mouse ['l35', 'l42', 'l48', 'l53', 'l57', 'l61', 'l62', 'l63']", + "143, model ['l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l64', 'l65']", + "144, of ['l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l66']", + "145, AD. ['l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l65', 'l66']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Experimentally", + "reducing", + "WAVE1" + ] + }, + "context": { + "val": "cells", + "words": [ + "N2a", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Experimentally", + "reducing", + "WAVE1", + "Reduction" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "model", + "of", + "AD." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "downregulation", + "of", + "Wasf1", + "gene", + "expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "model", + "of", + "AD." + ] + } + } + ] + }, + { + "PMID": "26280119", + "TEXT": "T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) elicits antitumor activity in various tumor models; however, the underlying mechanism of action remains unclear. Here we demonstrate a crucial role for interleukin (IL)-9 in antitumor immunity generated by the GITR agonistic antibody DTA-1. IL-4 receptor knockout (Il4ra(-/-)) mice, which have reduced expression of IL-9, were resistant to tumor growth inhibition by DTA-1. Notably, neutralization of IL-9 considerably impaired tumor rejection induced by DTA-1. In particular, DTA-1-induced IL-9 promoted tumor-specific cytotoxic T lymphocyte (CTL) responses by enhancing the function of dendritic cells in vivo. Furthermore, GITR signaling enhanced the differentiation of IL-9-producing CD4(+) T-helper (TH9) cells in a TNFR-associated factor 6 (TRAF6)- and NF-κB-dependent manner and inhibited the generation of induced regulatory T cells in vitro. Our findings demonstrate that GITR co-stimulation mediates antitumor immunity by promoting TH9 cell differentiation and enhancing CTL responses and thus provide a mechanism of action for GITR agonist-mediated cancer immunotherapies.", + "TAG_DATA": [ + "46, IL-4 {'perturbing_action': 'B-gene loss-of-function'}", + "47, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "48, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "49, (Il4ra(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "50, mice, {'context': 'B-organism'}", + "58, resistant {'effect': 'B-negative'}", + "60, tumor {'phenotype': 'B-tumour growth'}", + "61, growth {'phenotype': 'I-tumour growth'}", + "62, inhibition {'effect': 'B-negative'}", + "66, neutralization {'perturbing_action': 'B-pharmacological inhibition'}", + "70, impaired {'effect': 'B-negative'}", + "71, tumor {'phenotype': 'B-tumour growth'}", + "72, rejection {'phenotype': 'I-tumour regression'}", + "92, dendritic {'context': 'B-cells'}", + "93, cells {'context': 'I-cells'}", + "94, in {'context': 'B-in vivo'}", + "95, vivo. {'context': 'I-in vivo'}", + "99, enhanced {'effect': 'B-positive'}", + "101, differentiation {'phenotype': 'B-differentiation'}", + "104, CD4(+) {'context': 'B-cells'}", + "105, T-helper {'context': 'I-cells'}", + "106, (TH9) {'context': 'I-cells'}", + "107, cells {'context': 'I-cells'}", + "123, regulatory {'context': 'B-cells'}", + "124, T {'context': 'I-cells'}", + "125, cells {'context': 'I-cells'}", + "126, in {'context': 'B-in vitro'}", + "127, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "46, IL-4 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "47, receptor ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "48, knockout ['l1', 'l15', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "49, (Il4ra(-/-)) ['l2', 'l16', 'l30', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "50, mice, ['l3', 'l17', 'l31', 'l43', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "58, resistant ['l4', 'l18', 'l32', 'l44', 'l55', 'l64', 'l65', 'l66', 'l67']", + "60, tumor ['l5', 'l19', 'l33', 'l45', 'l56', 'l64', 'l68', 'l69']", + "61, growth ['l6', 'l20', 'l34', 'l46', 'l57', 'l65', 'l68', 'l70']", + "62, inhibition ['l7', 'l21', 'l35', 'l47', 'l58', 'l66', 'l69', 'l70']", + "66, neutralization ['l22', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "70, impaired ['l8', 'l23', 'l36', 'l48', 'l59', 'l71', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "71, tumor ['l9', 'l24', 'l37', 'l49', 'l60', 'l72', 'l81', 'l87', 'l88', 'l89', 'l90', 'l91']", + "72, rejection ['l10', 'l25', 'l38', 'l50', 'l61', 'l67', 'l73', 'l82', 'l87', 'l92', 'l93']", + "92, dendritic ['l11', 'l26', 'l39', 'l51', 'l74', 'l83', 'l88', 'l94', 'l95', 'l96']", + "93, cells ['l12', 'l27', 'l40', 'l52', 'l62', 'l75', 'l84', 'l89', 'l92', 'l94', 'l97', 'l98']", + "94, in ['l13', 'l28', 'l41', 'l53', 'l76', 'l85', 'l90', 'l95', 'l97', 'l99']", + "95, vivo. ['l14', 'l29', 'l42', 'l54', 'l63', 'l77', 'l86', 'l91', 'l93', 'l96', 'l98', 'l99']", + "99, enhanced ['l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "101, differentiation ['l100', 'l107', 'l108', 'l109', 'l110', 'l111']", + "104, CD4(+) ['l101', 'l107', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "105, T-helper ['l78', 'l102', 'l108', 'l112', 'l118', 'l119', 'l120', 'l121']", + "106, (TH9) ['l79', 'l103', 'l109', 'l113', 'l118', 'l122', 'l123', 'l124']", + "107, cells ['l80', 'l104', 'l110', 'l114', 'l119', 'l122']", + "123, regulatory ['l115', 'l125', 'l126', 'l127', 'l128']", + "124, T ['l105', 'l116', 'l120', 'l123', 'l125', 'l129', 'l130', 'l131']", + "125, cells ['l106', 'l111', 'l117', 'l121', 'l124', 'l126', 'l129', 'l132', 'l133']", + "126, in ['l127', 'l130', 'l132', 'l134']", + "127, vitro. ['l128', 'l131', 'l133', 'l134']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IL-4", + "receptor", + "knockout", + "(Il4ra(-/-))" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IL-4", + "receptor", + "knockout", + "(Il4ra(-/-))" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant", + "inhibition", + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IL-4", + "receptor", + "knockout", + "(Il4ra(-/-))" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IL-4", + "receptor", + "knockout", + "(Il4ra(-/-))" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "rejection" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IL-4", + "receptor", + "knockout", + "(Il4ra(-/-))" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IL-4", + "receptor", + "knockout", + "(Il4ra(-/-))" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant", + "inhibition", + "impaired" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "rejection" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistant", + "inhibition", + "impaired" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistant", + "impaired" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "rejection" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "neutralization" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "neutralization" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "neutralization" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "rejection" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "neutralization" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells", + "T-helper", + "(TH9)" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "neutralization" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "rejection" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "rejection" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T-helper", + "(TH9)", + "cells", + "T" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T-helper", + "(TH9)", + "cells" + ] + } + } + ] + }, + { + "PMID": "26259033", + "TEXT": "Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed after the disease has metastasized; it is among the most lethal forms of cancer. We recently described aberrant expression of an open reading frame 1 protein, ORF1p, encoded by long interspersed element-1 (LINE-1; L1) retrotransposon, in PDAC. To test whether LINE-1 expression leads to somatic insertions of this mobile DNA, we used a targeted method to sequence LINE-1 insertion sites in matched PDAC and normal samples. We found evidence of 465 somatic LINE-1 insertions in 20 PDAC genomes, which were absent from corresponding normal samples. In cases in which matched normal tissue, primary PDAC and metastatic disease sites were available, insertions were found in primary and metastatic tissues in differing proportions. Two adenocarcinomas secondarily involving the pancreas, but originating in the stomach and duodenum, acquired insertions with a similar discordance between primary and metastatic sites. Together, our findings show that LINE-1 contributes to the genetic evolution of PDAC and suggest that somatic insertions are acquired discontinuously in gastrointestinal neoplasms.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "26259032", + "TEXT": "Hypertension is the most common cardiovascular disease, afflicting >30% of adults. The cause of hypertension in most individuals remains unknown, suggesting that additional contributing factors have yet to be discovered. Corin is a serine protease that activates the natriuretic peptides, thereby regulating blood pressure. It is synthesized as a zymogen that is activated by proteolytic cleavage. CORIN variants and mutations impairing corin activation have been identified in people with hypertension and pre-eclampsia. To date, however, the identity of the protease that activates corin remains elusive. Here we show that proprotein convertase subtilisin/kexin-6 (PCSK6, also named PACE4; ref. 10) cleaves and activates corin. In cultured cells, we found that corin activation was inhibited by inhibitors of PCSK family proteases and by small interfering RNAs blocking PCSK6 expression. Conversely, PCSK6 overexpression enhanced corin activation. In addition, purified PCSK6 cleaved wild-type corin but not the R801A variant that lacks the conserved activation site. Pcsk6-knockout mice developed salt-sensitive hypertension, and corin activation and pro-atrial natriuretic peptide processing activity were undetectable in these mice. Moreover, we found that CORIN variants in individuals with hypertension and pre-eclampsia were defective in PCSK6-mediated activation. We also identified a PCSK6 mutation that impaired corin activation activity in a hypertensive patient. Our results indicate that PCSK6 is the long-sought corin activator and is important for sodium homeostasis and normal blood pressure.", + "TAG_DATA": [ + "103, cultured {'context': 'B-cells'}", + "104, cells, {'context': 'I-cells'}", + "120, small {'perturbing_action': 'B-rnai/knockdown'}", + "121, interfering {'perturbing_action': 'I-rnai/knockdown'}", + "122, RNAs {'perturbing_action': 'I-rnai/knockdown'}", + "123, blocking {'perturbing_action': 'I-rnai/knockdown'}", + "124, PCSK6 {'perturbing_action': 'I-rnai/knockdown'}", + "125, expression. {'perturbing_action': 'I-rnai/knockdown'}", + "127, PCSK6 {'perturbing_action': 'B-gene gain-of-function'}", + "128, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "150, Pcsk6-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "151, mice {'context': 'B-organism'}", + "168, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "103, cultured ['l0']", + "104, cells, ['l0']", + "120, small ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "121, interfering ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "122, RNAs ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "123, blocking ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "124, PCSK6 ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "125, expression. ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "127, PCSK6 ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28', 'l29']", + "128, overexpression ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']", + "150, Pcsk6-knockout ['l30', 'l31']", + "151, mice ['l29', 'l30', 'l32']", + "168, mice. ['l31', 'l32']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PCSK6" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pcsk6-knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "26248267", + "TEXT": "The extent of tumor heterogeneity is an emerging theme that researchers are only beginning to understand. How genetic and epigenetic heterogeneity affects tumor evolution and clinical progression is unknown. The precise nature of the environmental factors that influence this heterogeneity is also yet to be characterized. Nature Medicine, Nature Biotechnology and the Volkswagen Foundation organized a meeting focused on identifying the obstacles that need to be overcome to advance translational research in and tumor heterogeneity. Once these key questions were established, the attendees devised potential solutions. Their ideas are presented here.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "26193344", + "TEXT": "Despite recent therapeutic advances, multiple myeloma (MM) remains largely incurable. Here we report results of a phase I/II trial to evaluate the safety and activity of autologous T cells engineered to express an affinity-enhanced T cell receptor (TCR) recognizing a naturally processed peptide shared by the cancer-testis antigens NY-ESO-1 and LAGE-1. Twenty patients with antigen-positive MM received an average 2.4 × 10(9) engineered T cells 2 d after autologous stem cell transplant. Infusions were well tolerated without clinically apparent cytokine-release syndrome, despite high IL-6 levels. Engineered T cells expanded, persisted, trafficked to marrow and exhibited a cytotoxic phenotype. Persistence of engineered T cells in blood was inversely associated with NY-ESO-1 levels in the marrow. Disease progression was associated with loss of T cell persistence or antigen escape, in accordance with the expected mechanism of action of the transferred T cells. Encouraging clinical responses were observed in 16 of 20 patients (80%) with advanced disease, with a median progression-free survival of 19.1 months. NY-ESO-1-LAGE-1 TCR-engineered T cells were safe, trafficked to marrow and showed extended persistence that correlated with clinical activity against antigen-positive myeloma.", + "TAG_DATA": [ + "52, patients {'context': 'B-patient'}", + "53, with {'context': 'I-patient'}", + "54, antigen-positive {'context': 'I-patient'}", + "55, MM {'context': 'I-neoplasm'}", + "86, T {'context': 'B-cells'}", + "87, cells {'context': 'I-cells'}", + "101, T {'context': 'B-cells'}", + "102, cells {'context': 'I-cells'}", + "121, T {'context': 'B-cells'}", + "122, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "52, patients ['l0', 'l1', 'l2', 'l3']", + "53, with ['l0', 'l4', 'l5', 'l6', 'l7']", + "54, antigen-positive ['l1', 'l4', 'l8', 'l9', 'l10']", + "55, MM ['l2', 'l5', 'l8', 'l11']", + "86, T ['l6', 'l9', 'l12']", + "87, cells ['l3', 'l7', 'l10', 'l11', 'l12']", + "101, T ['l13']", + "102, cells ['l13']", + "121, T ['l14']", + "122, cell ['l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26168292", + "TEXT": "Unraveling the fate specification of resident stem cells during lung regeneration is of clinical importance. It has been reported that c-kit(+) progenitor cells resident in the human lung regenerate epithelial lineages upon transplantation into injured mouse lung. Here we test the lineage potential of c-kit(+) cells by inducible genetic lineage tracing. We find that c-kit(+) cells do not contribute to lung epithelium during homeostasis and repair, and instead maintain a vascular endothelial cell fate. These findings call attention to the clinical application of c-kit(+) stem cells as lung epithelial progenitors for the treatment of pulmonary disease.", + "TAG_DATA": [ + "54, c-kit(+) {'context': 'B-cells'}", + "55, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "54, c-kit(+) ['l0']", + "55, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26168291", + "TEXT": "Mouse models of cancers are routinely used to study cancer biology. However, it remains unclear whether carcinogenesis in mice is driven by the same spectrum of genomic alterations found in humans. Here we conducted a comprehensive genomic analysis of 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced skin cancer, the most commonly used skin cancer model, which appears as benign papillomas that progress into squamous cell carcinomas (SCCs). We also studied genetically induced SCCs that expressed G12D mutant Kras (Kras G12D) but were deficient for p53. Using whole-exome sequencing, we uncovered a characteristic mutational signature of DMBA-induced SCCs. We found that the vast majority of DMBA-induced SCCs presented recurrent mutations in Hras, Kras or Rras2 and mutations in several additional putative oncogenes and tumor-suppressor genes. Similar genes were recurrently mutated in mouse and human SCCs that were from different organs or had been exposed to different carcinogens. Invasive SCCs, but not papillomas, presented substantial chromosomal aberrations, especially in DMBA-induced and genetically induced Trp53-mutated SCCs. Metastasis occurred through sequential spreading, with relatively few additional genetic events. This study provides a framework for future functional cancer genomic studies in mice.", + "TAG_DATA": [ + "67, SCCs {'context': 'B-transformed cells'}", + "100, SCCs {'context': 'B-neoplasm'}", + "158, Metastasis {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "142, SCCs, ['l0']", + "157, SCCs. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26147761", + "TEXT": "Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain. Here we identify β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner. B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice and young heterochronic parabionts. Exogenous B2M injected systemically, or locally in the hippocampus, impairs hippocampal-dependent cognitive function and neurogenesis in young mice. The negative effects of B2M and heterochronic parabiosis are, in part, mitigated in the hippocampus of young transporter associated with antigen processing 1 (Tap1)-deficient mice with reduced cell surface expression of MHC I. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.", + "TAG_DATA": [ + "124, young {'context': 'B-organism'}", + "125, mice. {'context': 'I-organism'}", + "140, hippocampus {'context': 'B-tissue/organ'}", + "143, transporter {'perturbing_action': 'B-gene loss-of-function'}", + "144, associated {'perturbing_action': 'I-gene loss-of-function'}", + "145, with {'perturbing_action': 'I-gene loss-of-function'}", + "146, antigen {'perturbing_action': 'I-gene loss-of-function'}", + "147, processing {'perturbing_action': 'I-gene loss-of-function'}", + "148, 1 {'perturbing_action': 'I-gene loss-of-function'}", + "149, (Tap1)-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "150, mice {'context': 'B-organism'}", + "162, endogenous {'perturbing_action': 'I-gene loss-of-function'}", + "163, B2M {'perturbing_action': 'I-gene loss-of-function'}", + "164, expression {'perturbing_action': 'I-gene loss-of-function'}", + "173, aged {'context': 'B-organism'}", + "174, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "124, young ['l0']", + "125, mice. ['l0']", + "140, hippocampus ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "143, transporter ['l1', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "144, associated ['l2', 'l9', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "145, with ['l3', 'l10', 'l18', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "146, antigen ['l4', 'l11', 'l19', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "147, processing ['l5', 'l12', 'l20', 'l27', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "148, 1 ['l6', 'l13', 'l21', 'l28', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47']", + "149, (Tap1)-deficient ['l7', 'l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l48', 'l49', 'l50']", + "150, mice ['l8', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l51', 'l52']", + "161, of ['l53', 'l54', 'l55', 'l56', 'l57']", + "162, endogenous ['l53', 'l58', 'l59', 'l60', 'l61']", + "163, B2M ['l54', 'l58', 'l62', 'l63', 'l64']", + "164, expression ['l55', 'l59', 'l62', 'l65', 'l66']", + "173, aged ['l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l56', 'l60', 'l63', 'l65', 'l67']", + "174, mice. ['l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l57', 'l61', 'l64', 'l66', 'l67']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "transporter", + "associated", + "with", + "antigen", + "processing", + "1", + "(Tap1)-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "transporter", + "associated", + "with", + "antigen", + "processing", + "1", + "(Tap1)-deficient", + "endogenous", + "B2M", + "expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "aged", + "mice." + ] + } + } + ] + }, + { + "PMID": "26147760", + "TEXT": "Cold exposure may be a potential therapy for diabetes by increasing brown adipose tissue (BAT) mass and activity. Here we report that 10 d of cold acclimation (14-15 °C) increased peripheral insulin sensitivity by ∼43% in eight type 2 diabetes subjects. Basal skeletal muscle GLUT4 translocation markedly increased, without effects on insulin signaling or AMP-activated protein kinase (AMPK) activation and only a minor increase in BAT glucose uptake.", + "TAG_DATA": [ + "37, type {'context': 'B-patient'}", + "38, 2 {'context': 'B-patient'}", + "39, diabetes {'context': 'I-patient'}", + "40, subjects. {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "37, type ['l0', 'l1', 'l2']", + "38, 2 ['l0', 'l3', 'l4']", + "39, diabetes ['l1', 'l3', 'l5']", + "40, subjects. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26076038", + "TEXT": "Genetic evidence implicates the loss of bone morphogenetic protein type II receptor (BMPR-II) signaling in the endothelium as an initiating factor in pulmonary arterial hypertension (PAH). However, selective targeting of this signaling pathway using BMP ligands has not yet been explored as a therapeutic strategy. Here, we identify BMP9 as the preferred ligand for preventing apoptosis and enhancing monolayer integrity in both pulmonary arterial endothelial cells and blood outgrowth endothelial cells from subjects with PAH who bear mutations in the gene encoding BMPR-II, BMPR2. Mice bearing a heterozygous knock-in allele of a human BMPR2 mutation, R899X, which we generated as an animal model of PAH caused by BMPR-II deficiency, spontaneously developed PAH. Administration of BMP9 reversed established PAH in these mice, as well as in two other experimental PAH models, in which PAH develops in response to either monocrotaline or VEGF receptor inhibition combined with chronic hypoxia. These results demonstrate the promise of direct enhancement of endothelial BMP signaling as a new therapeutic strategy for PAH.", + "TAG_DATA": [ + "84, Mice {'context': 'B-organism'}", + "86, a {'perturbing_action': 'B-other'}", + "87, heterozygous {'perturbing_action': 'B-other'}", + "88, knock-in {'perturbing_action': 'I-other'}", + "89, allele {'perturbing_action': 'I-other'}", + "90, of {'perturbing_action': 'I-other'}", + "91, a {'perturbing_action': 'I-other'}", + "92, human {'perturbing_action': 'I-other'}", + "93, BMPR2 {'perturbing_action': 'I-other'}", + "94, mutation, {'perturbing_action': 'I-other'}", + "95, R899X, {'perturbing_action': 'I-other'}", + "107, BMPR-II {'perturbing_action': 'B-gene loss-of-function'}", + "108, deficiency, {'perturbing_action': 'I-gene loss-of-function'}", + "120, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "84, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "86, a ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "87, heterozygous ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "88, knock-in ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "89, allele ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "90, of ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "91, a ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "92, human ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "93, BMPR2 ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "94, mutation, ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "95, R899X, ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "107, BMPR-II ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "108, deficiency, ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "a", + "heterozygous", + "knock-in", + "allele", + "of", + "human", + "BMPR2", + "mutation,", + "R899X," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "BMPR-II", + "deficiency," + ] + } + } + ] + }, + { + "PMID": "25985364", + "TEXT": "Previous studies investigating the role of smooth muscle cells (SMCs) and macrophages in the pathogenesis of atherosclerosis have provided controversial results owing to the use of unreliable methods for clearly identifying each of these cell types. Here, using Myh11-CreER(T2) ROSA floxed STOP eYFP Apoe(-/-) mice to perform SMC lineage tracing, we find that traditional methods for detecting SMCs based on immunostaining for SMC markers fail to detect >80% of SMC-derived cells within advanced atherosclerotic lesions. These unidentified SMC-derived cells exhibit phenotypes of other cell lineages, including macrophages and mesenchymal stem cells (MSCs). SMC-specific conditional knockout of Krüppel-like factor 4 (Klf4) resulted in reduced numbers of SMC-derived MSC- and macrophage-like cells, a marked reduction in lesion size, and increases in multiple indices of plaque stability, including an increase in fibrous cap thickness as compared to wild-type controls. On the basis of in vivo KLF4 chromatin immunoprecipitation-sequencing (ChIP-seq) analyses and studies of cholesterol-treated cultured SMCs, we identified >800 KLF4 target genes, including many that regulate pro-inflammatory responses of SMCs. Our findings indicate that the contribution of SMCs to atherosclerotic plaques has been greatly underestimated, and that KLF4-dependent transitions in SMC phenotype are critical in lesion pathogenesis.", + "TAG_DATA": [ + "38, Myh11-CreER(T2) {'perturbing_action': 'B-gene loss-of-function'}", + "39, ROSA {'perturbing_action': 'I-gene loss-of-function'}", + "40, floxed {'perturbing_action': 'I-gene loss-of-function'}", + "41, STOP {'perturbing_action': 'I-gene loss-of-function'}", + "42, eYFP {'perturbing_action': 'I-gene loss-of-function'}", + "43, Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "44, mice {'context': 'B-organism'}", + "92, SMC-specific {'perturbing_action': 'B-gene loss-of-function'}", + "93, conditional {'perturbing_action': 'I-gene loss-of-function'}", + "94, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "95, of {'perturbing_action': 'I-gene loss-of-function'}", + "96, Krüppel-like {'perturbing_action': 'I-gene loss-of-function'}", + "97, factor {'perturbing_action': 'I-gene loss-of-function'}", + "98, 4 {'perturbing_action': 'I-gene loss-of-function'}", + "99, (Klf4) {'perturbing_action': 'I-gene loss-of-function'}", + "105, SMC-derived {'context': 'B-cells'}", + "106, MSC- {'context': 'I-cells'}", + "107, and {'context': 'I-cells'}", + "108, macrophage-like {'context': 'I-cells'}", + "109, cells, {'context': 'I-cells'}", + "140, in {'context': 'B-in vivo'}", + "141, vivo {'context': 'I-in vivo'}", + "152, SMCs, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "38, Myh11-CreER(T2) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "39, ROSA ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "40, floxed ['l1', 'l7', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "41, STOP ['l2', 'l8', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "42, eYFP ['l3', 'l9', 'l18', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "43, Apoe(-/-) ['l4', 'l10', 'l19', 'l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "44, mice ['l5', 'l11', 'l20', 'l27', 'l34', 'l40']", + "92, SMC-specific ['l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "93, conditional ['l46', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "94, knockout ['l47', 'l58', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "95, of ['l48', 'l59', 'l69', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "96, Krüppel-like ['l49', 'l60', 'l70', 'l79', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "97, factor ['l50', 'l61', 'l71', 'l80', 'l88', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "98, 4 ['l51', 'l62', 'l72', 'l81', 'l89', 'l96', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "99, (Klf4) ['l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l109', 'l110', 'l111', 'l112', 'l113']", + "105, SMC-derived ['l12', 'l21', 'l28', 'l35', 'l41', 'l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l109', 'l114', 'l115', 'l116', 'l117']", + "106, MSC- ['l13', 'l22', 'l29', 'l36', 'l42', 'l54', 'l65', 'l75', 'l84', 'l92', 'l99', 'l105', 'l110', 'l114', 'l118', 'l119', 'l120']", + "107, and ['l14', 'l23', 'l30', 'l37', 'l43', 'l55', 'l66', 'l76', 'l85', 'l93', 'l100', 'l106', 'l111', 'l115', 'l118', 'l121', 'l122']", + "108, macrophage-like ['l15', 'l31', 'l38', 'l44', 'l56', 'l67', 'l77', 'l86', 'l94', 'l101', 'l107', 'l112', 'l116', 'l119', 'l121', 'l123']", + "109, cells, ['l6', 'l16', 'l24', 'l32', 'l39', 'l45', 'l57', 'l68', 'l78', 'l87', 'l95', 'l102', 'l108', 'l113', 'l117', 'l120', 'l122', 'l123']", + "140, in ['l124', 'l125']", + "141, vivo ['l124', 'l126']", + "152, SMCs, ['l125', 'l126']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Myh11-CreER(T2)", + "ROSA", + "floxed", + "STOP", + "eYFP", + "Apoe(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Myh11-CreER(T2)", + "ROSA", + "floxed", + "STOP", + "eYFP", + "Apoe(-/-)", + "SMC-specific", + "conditional", + "knockout", + "of", + "Krüppel-like", + "factor", + "4", + "(Klf4)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells,", + "SMC-derived", + "MSC-", + "and", + "macrophage-like" + ] + } + } + ] + }, + { + "PMID": "25962122", + "TEXT": "Central memory T (TCM) cells in lymph nodes (LNs) and resident memory T (TRM) cells in peripheral tissues have distinct roles in protective immunity. Both are generated after primary infections, but their clonal origins have been unclear. To address this question, we immunized mice through the skin with a protein antigen, a chemical hapten, or a non-replicating poxvirus. We then analyzed antigen-activated T cells from different tissues using high-throughput sequencing (HTS) of the gene encoding the T cell receptor (TCR) β-chain (Trb, also known as Tcrb) using CDR3 sequences to simultaneously track thousands of unique T cells. For every abundant TRM cell clone generated in the skin, an abundant TCM cell clone bearing the identical TCR was present in the LNs. Thus, antigen-reactive skin TRM and LN TCM cell clones were derived from a common naive T cell precursor after skin immunization, generating overlapping TCR repertoires. Although they bore the same TCR, TRM cells mediated rapid contact hypersensitivity responses, whereas TCM cells mediated delayed and attenuated responses. Studies in human subjects confirmed the generation of skin TRM cells in allergic contact dermatitis. Thus, immunization through skin simultaneously generates skin TRM and LN TCM cells in similar numbers from the same naive T cells.", + "TAG_DATA": [ + "43, mice {'context': 'B-organism'}", + "152, TRM {'context': 'B-cells'}", + "153, cells {'context': 'I-cells'}", + "160, TCM {'context': 'B-cells'}", + "161, cells {'context': 'I-cells'}", + "201, T {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "152, TRM ['l0', 'l1', 'l2']", + "153, cells ['l0']", + "160, TCM ['l1', 'l3']", + "161, cells ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25939061", + "TEXT": "Here we studied cell-free plasma DNA (cfDNA) collected from subjects with advanced lung cancer whose tumors had developed resistance to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) AZD9291. We first performed next-generation sequencing of cfDNA from seven subjects and detected an acquired EGFR C797S mutation in one; expression of this mutant EGFR construct in a cell line rendered it resistant to AZD9291. We then performed droplet digital PCR on serial cfDNA specimens collected from 15 AZD9291-treated subjects. All were positive for the T790M mutation before treatment, but upon developing AZD9291 resistance three molecular subtypes emerged: six cases acquired the C797S mutation, five cases maintained the T790M mutation but did not acquire the C797S mutation and four cases lost the T790M mutation despite the presence of the underlying EGFR activating mutation. Our findings provide insight into the diversity of mechanisms through which tumors acquire resistance to AZD9291 and highlight the need for therapies that are able to overcome resistance mediated by the EGFR C797S mutation.", + "TAG_DATA": [ + "50, expression {'perturbing_action': 'B-other'}", + "51, of {'perturbing_action': 'I-other'}", + "52, this {'perturbing_action': 'I-other'}", + "53, mutant {'perturbing_action': 'I-other'}", + "54, EGFR {'perturbing_action': 'I-other'}", + "55, construct {'perturbing_action': 'I-other'}", + "58, cell {'context': 'B-cells'}", + "59, line {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "50, expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "51, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "52, this ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "53, mutant ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "54, EGFR ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "55, construct ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "58, cell ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "59, line ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "this", + "mutant", + "EGFR", + "construct" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "line" + ] + } + } + ] + }, + { + "PMID": "25915832", + "TEXT": "Patients with retinal degeneration lose sight due to the gradual demise of photoreceptors. Electrical stimulation of surviving retinal neurons provides an alternative route for the delivery of visual information. We demonstrate that subretinal implants with 70-μm-wide photovoltaic pixels provide highly localized stimulation of retinal neurons in rats. The electrical receptive fields recorded in retinal ganglion cells were similar in size to the natural visual receptive fields. Similarly to normal vision, the retinal response to prosthetic stimulation exhibited flicker fusion at high frequencies, adaptation to static images and nonlinear spatial summation. In rats with retinal degeneration, these photovoltaic arrays elicited retinal responses with a spatial resolution of 64 ± 11 μm, corresponding to half of the normal visual acuity in healthy rats. The ease of implantation of these wireless and modular arrays, combined with their high resolution, opens the door to the functional restoration of sight in patients blinded by retinal degeneration.", + "TAG_DATA": [ + "46, rats. {'context': 'B-organism'}", + "53, retinal {'context': 'B-cells'}", + "54, ganglion {'context': 'I-cells'}", + "55, cells {'context': 'I-cells'}", + "91, rats {'context': 'B-organism'}", + "120, rats. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "46, rats. ['l0', 'l1']", + "53, retinal ['l2', 'l3']", + "54, ganglion ['l0', 'l2', 'l4']", + "55, cells ['l1', 'l3', 'l4']", + "91, rats ['l5']", + "120, rats. ['l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25849134", + "TEXT": "Adoptive transfer of chimeric antigen receptor (CAR)-redirected T lymphocytes (CAR-T cells) has had less striking therapeutic effects in solid tumors than in lymphoid malignancies. Although active tumor-mediated immunosuppression may have a role in limiting the efficacy of CAR-T cells, functional changes in T lymphocytes after their ex vivo manipulation may also account for the reduced ability of cultured CAR-T cells to penetrate stroma-rich solid tumors compared with lymphoid tissues. We therefore studied the capacity of human in vitro-cultured CAR-T cells to degrade components of the extracellular matrix (ECM). In contrast to freshly isolated T lymphocytes, we found that in vitro-cultured T lymphocytes lack expression of the enzyme heparanase (HPSE), which degrades heparan sulfate proteoglycans, the main components of ECM. We found that HPSE mRNA is downregulated in in vitro-expanded T cells, which may be a consequence of p53 (officially known as TP53, encoding tumor protein 53) binding to the HPSE gene promoter. We therefore engineered CAR-T cells to express HPSE and showed their improved capacity to degrade the ECM, which promoted tumor T cell infiltration and antitumor activity. The use of this strategy may enhance the activity of CAR-T cells in individuals with stroma-rich solid tumors.", + "TAG_DATA": [ + "98, in {'context': 'B-in vitro'}", + "99, vitro-cultured {'context': 'I-in vitro'}", + "100, T {'context': 'I-cells'}", + "101, lymphocytes {'context': 'I-cells'}", + "128, vitro-expanded {'context': 'I-in vitro'}", + "129, T {'context': 'B-cells'}", + "130, cells, {'context': 'I-cells'}", + "155, CAR-T {'context': 'B-cells'}", + "156, cells {'context': 'I-cells'}", + "171, tumor {'context': 'B-transformed cells'}", + "172, T {'context': 'I-transformed cells'}", + "173, cell {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "98, in ['l0', 'l1', 'l2', 'l3', 'l4']", + "99, vitro-cultured ['l0', 'l5', 'l6', 'l7', 'l8']", + "100, T ['l1', 'l5', 'l9', 'l10', 'l11']", + "101, lymphocytes ['l2', 'l6', 'l9', 'l12']", + "128, vitro-expanded ['l13', 'l14', 'l15', 'l16', 'l17']", + "129, T ['l3', 'l7', 'l10', 'l13', 'l18', 'l19', 'l20']", + "130, cells, ['l4', 'l8', 'l11', 'l12', 'l14', 'l18', 'l21']", + "155, CAR-T ['l22', 'l23', 'l24', 'l25']", + "156, cells ['l22', 'l26', 'l27', 'l28']", + "171, tumor ['l15', 'l23', 'l26', 'l29', 'l30']", + "172, T ['l16', 'l19', 'l24', 'l27', 'l29', 'l31']", + "173, cell ['l17', 'l20', 'l21', 'l25', 'l28', 'l30', 'l31']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25849131", + "TEXT": "Resveratrol improves insulin sensitivity and lowers hepatic glucose production (HGP) in rat models of obesity and diabetes, but the underlying mechanisms for these antidiabetic effects remain elusive. One process that is considered a key feature of resveratrol action is the activation of the nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase sirtuin 1 (SIRT1) in various tissues. However, the low bioavailability of resveratrol raises questions about whether the antidiabetic effects of oral resveratrol can act directly on these tissues. We show here that acute intraduodenal infusion of resveratrol reversed a 3 d high fat diet (HFD)-induced reduction in duodenal-mucosal Sirt1 protein levels while also enhancing insulin sensitivity and lowering HGP. Further, we found that duodenum-specific knockdown of Sirt1 expression for 14 d was sufficient to induce hepatic insulin resistance in rats fed normal chow. We also found that the glucoregulatory role of duodenally acting resveratrol required activation of Sirt1 and AMP-activated protein kinase (Ampk) in this tissue to initiate a gut-brain-liver neuronal axis that improved hypothalamic insulin sensitivity and in turn, reduced HGP. In addition to the effects of duodenally acting resveratrol in an acute 3 d HFD-fed model of insulin resistance, we also found that short-term infusion of resveratrol into the duodenum lowered HGP in two other rat models of insulin resistance--a 28 d HFD-induced model of obesity and a nicotinamide (NA)-streptozotocin (STZ)-HFD-induced model of mild type 2 diabetes. Together, these studies highlight the therapeutic relevance of targeting duodenal SIRT1 to reverse insulin resistance and improve glucose homeostasis in obesity and diabetes.", + "TAG_DATA": [ + "111, duodenum-specific {'perturbing_action': 'B-rnai/knockdown'}", + "112, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "113, of {'perturbing_action': 'I-rnai/knockdown'}", + "114, Sirt1 {'perturbing_action': 'I-rnai/knockdown'}", + "115, expression {'perturbing_action': 'I-rnai/knockdown'}", + "127, rats {'context': 'B-organism'}", + "205, rat {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "111, duodenum-specific ['l0', 'l1', 'l2', 'l3', 'l4']", + "112, knockdown ['l0', 'l5', 'l6', 'l7', 'l8']", + "113, of ['l1', 'l5', 'l9', 'l10', 'l11']", + "114, Sirt1 ['l2', 'l6', 'l9', 'l12', 'l13']", + "115, expression ['l3', 'l7', 'l10', 'l12', 'l14']", + "127, rats ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "duodenum-specific", + "knockdown", + "of", + "Sirt1", + "expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + } + ] + }, + { + "PMID": "25799228", + "TEXT": "More than 10% of the world's population is chronically infected with HIV, hepatitis C virus (HCV) or hepatitis B virus (HBV), all of which can cause severe disease and death. These viruses persist in part because continuous antigenic stimulation causes the deterioration of virus-specific cytotoxic T lymphocyte (CTL) function and survival. Additionally, antiviral CTLs autonomously suppress their responses to limit immunopathology by upregulating inhibitory receptors such as programmed cell death 1 (PD-1). Identification and blockade of the pathways that induce CTL dysfunction may facilitate the clearance of chronic viral infections. We found that the prostaglandin E2 (PGE₂) receptors EP2 and EP4 were upregulated on virus-specific CTLs during chronic lymphocytic choriomeningitis virus (LCMV) infection and suppressed CTL survival and function. We show that the combined blockade of PGE₂ and PD-1 signaling was therapeutic in terms of improving viral control and augmenting the numbers of functional virus-specific CTLs. Thus, PGE₂ inhibition is both an independent candidate therapeutic target and a promising adjunct therapy to PD-1 blockade for the treatment of HIV and other chronic viral infections.", + "TAG_DATA": [ + "115, CTL {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25751816", + "TEXT": "Rosetting is a virulent Plasmodium falciparum phenomenon associated with severe malaria. Here we demonstrate that P. falciparum-encoded repetitive interspersed families of polypeptides (RIFINs) are expressed on the surface of infected red blood cells (iRBCs), where they bind to RBCs--preferentially of blood group A--to form large rosettes and mediate microvascular binding of iRBCs. We suggest that RIFINs have a fundamental role in the development of severe malaria and thereby contribute to the varying global distribution of ABO blood groups in the human population.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25751815", + "TEXT": "Types 1 and 2 diabetes affect some 380 million people worldwide. Both ultimately result from a deficiency of functional pancreatic insulin-producing beta cells. Beta cells proliferate in humans during a brief temporal window beginning around the time of birth, with a peak percentage (∼2%) engaged in the cell cycle in the first year of life. In embryonic life and after early childhood, beta cell replication is barely detectable. Whereas beta cell expansion seems an obvious therapeutic approach to beta cell deficiency, adult human beta cells have proven recalcitrant to such efforts. Hence, there remains an urgent need for antidiabetic therapeutic agents that can induce regeneration and expansion of adult human beta cells in vivo or ex vivo. Here, using a high-throughput small-molecule screen (HTS), we find that analogs of the small molecule harmine function as a new class of human beta cell mitogenic compounds. We also define dual-specificity tyrosine-regulated kinase-1a (DYRK1A) as the likely target of harmine and the nuclear factors of activated T cells (NFAT) family of transcription factors as likely mediators of human beta cell proliferation and differentiation. Using three different mouse and human islet in vivo-based models, we show that harmine is able to induce beta cell proliferation, increase islet mass and improve glycemic control. These observations suggest that harmine analogs may have unique therapeutic promise for human diabetes therapy. Enhancing the potency and beta cell specificity of these compounds are important future challenges.", + "TAG_DATA": [ + "183, mouse {'context': 'B-cells'}", + "184, and {'context': 'I-cells'}", + "185, human {'context': 'I-cells'}", + "186, islet {'context': 'I-cells'}", + "187, in {'context': 'B-in vivo'}", + "188, vivo-based {'context': 'I-in vivo'}", + "189, models, {'context': 'I-xenograft'}", + "197, induce {'effect': 'B-positive'}", + "198, beta {'context': 'B-cells'}", + "199, cell {'context': 'I-cells'}", + "200, proliferation, {'phenotype': 'B-proliferation'}", + "202, islet {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "183, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "184, and ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "185, human ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "186, islet ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "187, in ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "188, vivo-based ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "189, models, ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54']", + "197, induce ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l56', 'l57', 'l58']", + "198, beta ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l55', 'l59', 'l60', 'l61']", + "199, cell ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l56', 'l59', 'l62', 'l63']", + "200, proliferation, ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l57', 'l60', 'l62', 'l64']", + "202, islet ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l58', 'l61', 'l63', 'l64']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "mouse", + "and", + "human", + "islet", + "beta", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "and", + "human", + "islet", + "beta", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo-based" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo-based" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "models," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "models," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + } + ] + }, + { + "PMID": "25686104", + "TEXT": "The gene encoding ARID1A, a chromatin remodeler, shows one of the highest mutation rates across many cancer types. Notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas, which currently have no effective therapy. To date, clinically applicable targeted cancer therapy based on ARID1A mutational status has not been described. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer cells and that ARID1A mutational status correlated with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct target of ARID1A and EZH2 that is upregulated by EZH2 inhibition and contributed to the observed synthetic lethality by inhibiting PI3K-AKT signaling. Importantly, EZH2 inhibition caused regression of ARID1A-mutated ovarian tumors in vivo. To our knowledge, this is the first data set to demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. Our data indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for cancers involving ARID1A mutations.", + "TAG_DATA": [ + "69, ovarian {'context': 'B-transformed cells'}", + "70, cancer {'context': 'I-transformed cells'}", + "71, cells {'context': 'I-transformed cells'}", + "82, EZH2 {'perturbing_action': 'B-pharmacological inhibition'}", + "83, inhibitor. {'perturbing_action': 'I-pharmacological inhibition'}", + "99, EZH2 {'perturbing_action': 'B-pharmacological inhibition'}", + "100, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "113, EZH2 {'perturbing_action': 'B-pharmacological inhibition'}", + "114, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "115, caused {'effect': 'B-positive'}", + "116, regression {'phenotype': 'B-tumour regression'}", + "119, ovarian {'context': 'B-neoplasm'}", + "120, tumors {'context': 'I-neoplasm'}", + "121, in {'context': 'B-in vivo'}", + "122, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "69, ovarian ['l0', 'l1']", + "70, cancer ['l0', 'l2']", + "71, cells ['l1', 'l2']", + "82, EZH2 ['l3', 'l4', 'l5']", + "83, inhibitor. ['l3', 'l6', 'l7']", + "99, EZH2 ['l4', 'l6', 'l8']", + "100, inhibition ['l5', 'l7', 'l8']", + "113, EZH2 ['l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "114, inhibition ['l9', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "115, caused ['l10', 'l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "116, regression ['l11', 'l17', 'l22', 'l27', 'l28', 'l29', 'l30']", + "119, ovarian ['l12', 'l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "120, tumors ['l13', 'l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "121, in ['l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "122, vivo. ['l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EZH2", + "inhibition" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EZH2", + "inhibition" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EZH2", + "inhibition" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "ovarian", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EZH2", + "inhibition" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "ovarian", + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "ovarian", + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "25642938", + "TEXT": "Antisense oligonucleotides (AONs) hold promise for therapeutic correction of many genetic diseases via exon skipping, and the first AON-based drugs have entered clinical trials for neuromuscular disorders. However, despite advances in AON chemistry and design, systemic use of AONs is limited because of poor tissue uptake, and recent clinical reports confirm that sufficient therapeutic efficacy has not yet been achieved. Here we present a new class of AONs made of tricyclo-DNA (tcDNA), which displays unique pharmacological properties and unprecedented uptake by many tissues after systemic administration. We demonstrate these properties in two mouse models of Duchenne muscular dystrophy (DMD), a neurogenetic disease typically caused by frame-shifting deletions or nonsense mutations in the gene encoding dystrophin and characterized by progressive muscle weakness, cardiomyopathy, respiratory failure and neurocognitive impairment. Although current naked AONs do not enter the heart or cross the blood-brain barrier to any substantial extent, we show that systemic delivery of tcDNA-AONs promotes a high degree of rescue of dystrophin expression in skeletal muscles, the heart and, to a lesser extent, the brain. Our results demonstrate for the first time a physiological improvement of cardio-respiratory functions and a correction of behavioral features in DMD model mice. This makes tcDNA-AON chemistry particularly attractive as a potential future therapy for patients with DMD and other neuromuscular disorders or with other diseases that are eligible for exon-skipping approaches requiring whole-body treatment.", + "TAG_DATA": [ + "92, mouse {'context': 'B-organism'}", + "93, models {'context': 'I-organism'}", + "162, skeletal {'context': 'B-tissue/organ'}", + "163, muscles, {'context': 'I-tissue/organ'}", + "165, heart {'context': 'B-tissue/organ'}", + "172, brain. {'context': 'B-tissue/organ'}", + "195, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "92, mouse ['l0', 'l1', 'l2']", + "93, models ['l0', 'l3', 'l4']", + "96, muscular ['l1', 'l3', 'l5']", + "97, dystrophy ['l2', 'l4', 'l5']", + "162, skeletal ['l6', 'l7', 'l8']", + "163, muscles, ['l6', 'l9', 'l10']", + "165, heart ['l7', 'l9', 'l11']", + "172, brain. ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25599133", + "TEXT": "Mutant isocitrate dehydrogenase (IDH) 1 and 2 proteins alter the epigenetic landscape in acute myeloid leukemia (AML) cells through production of the oncometabolite (R)-2-hydroxyglutarate (2-HG). Here we performed a large-scale RNA interference (RNAi) screen to identify genes that are synthetic lethal to the IDH1(R132H) mutation in AML and identified the anti-apoptotic gene BCL-2. IDH1- and IDH2-mutant primary human AML cells were more sensitive than IDH1/2 wild-type cells to ABT-199, a highly specific BCL-2 inhibitor that is currently in clinical trials for hematologic malignancies, both ex vivo and in xenotransplant models. This sensitization effect was induced by (R)-2-HG-mediated inhibition of the activity of cytochrome c oxidase (COX) in the mitochondrial electron transport chain (ETC); suppression of COX activity lowered the mitochondrial threshold to trigger apoptosis upon BCL-2 inhibition. Our findings indicate that IDH1/2 mutation status may identify patients that are likely to respond to pharmacologic BCL-2 inhibition and form the rational basis for combining agents that disrupt ETC activity with ABT-199 in future clinical studies.", + "TAG_DATA": [ + "53, IDH1- {'perturbing_action': 'B-other'}", + "54, and {'perturbing_action': 'I-other'}", + "55, IDH2-mutant {'perturbing_action': 'I-other'}", + "56, primary {'context': 'B-transformed cells'}", + "57, human {'context': 'I-transformed cells'}", + "58, AML {'context': 'I-transformed cells'}", + "59, cells {'context': 'I-transformed cells'}", + "66, cells {'context': 'B-cells'}", + "72, BCL-2 {'perturbing_action': 'I-pharmacological inhibition'}", + "73, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "88, xenotransplant {'context': 'B-xenograft'}", + "89, models. {'context': 'I-xenograft'}", + "122, trigger {'effect': 'B-positive'}", + "123, apoptosis {'phenotype': 'B-apoptosis'}", + "125, BCL-2 {'perturbing_action': 'B-pharmacological inhibition'}", + "126, inhibition. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "53, IDH1- ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "54, and ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "55, IDH2-mutant ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "56, primary ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "57, human ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "58, AML ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "59, cells ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54']", + "66, cells ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l56', 'l57', 'l58']", + "72, BCL-2 ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l55', 'l59', 'l60', 'l61']", + "73, inhibitor ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l56', 'l59', 'l62', 'l63']", + "88, xenotransplant ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l57', 'l60', 'l62', 'l64']", + "89, models. ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l54', 'l58', 'l61', 'l63', 'l64']", + "116, activity ['l65', 'l66', 'l67', 'l68']", + "122, trigger ['l65', 'l69', 'l70', 'l71']", + "123, apoptosis ['l66', 'l69', 'l72', 'l73']", + "125, BCL-2 ['l67', 'l70', 'l72', 'l74']", + "126, inhibition. ['l68', 'l71', 'l73', 'l74']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "IDH1-", + "and", + "IDH2-mutant" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "human", + "AML", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "IDH1-", + "and", + "IDH2-mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "IDH1-", + "and", + "IDH2-mutant" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenotransplant", + "models." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "primary", + "human", + "AML", + "cells" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BCL-2", + "inhibitor" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BCL-2", + "inhibitor" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BCL-2", + "inhibitor" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenotransplant", + "models." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "trigger" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "trigger" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BCL-2", + "inhibition." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BCL-2", + "inhibition." + ] + } + } + ] + }, + { + "PMID": "25531942", + "TEXT": "Tumor-specific neo-antigens that arise as a consequence of mutations are thought to be important for the therapeutic efficacy of cancer immunotherapies. Accumulating evidence suggests that neo-antigens may be commonly recognized by intratumoral CD8+ T cells, but it is unclear whether neo-antigen-specific CD4+ T cells also frequently reside within human tumors. In view of the accepted role of tumor-specific CD4+ T-cell responses in tumor control, we addressed whether neo-antigen-specific CD4+ T-cell reactivity is a common property in human melanoma.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25501908", + "TEXT": "High-throughput immune repertoire sequencing has emerged as a critical step in the understanding of adaptive responses following infection or vaccination or in autoimmunity. However, determination of native antibody variable heavy-light pairs (VH-VL pairs) remains a major challenge, and no technologies exist to adequately interrogate the >1 × 10(6) B cells in typical specimens. We developed a low-cost, single-cell, emulsion-based technology for sequencing antibody VH-VL repertoires from >2 × 10(6) B cells per experiment with demonstrated pairing precision >97%. A simple flow-focusing apparatus was used to sequester single B cells into emulsion droplets containing lysis buffer and magnetic beads for mRNA capture; subsequent emulsion RT-PCR generated VH-VL amplicons for next-generation sequencing. Massive VH-VL repertoire analyses of three human donors provided new immunological insights including (i) the identity, frequency and pairing propensity of shared, or 'public', VL genes, (ii) the detection of allelic inclusion (an implicated autoimmune mechanism) in healthy individuals and (iii) the occurrence of antibodies with features, in terms of gene usage and CDR3 length, associated with broadly neutralizing antibodies to rapidly evolving viruses such as HIV-1 and influenza.", + "TAG_DATA": [ + "87, B {'context': 'B-cells'}", + "88, cells {'context': 'I-cells'}", + "116, human {'context': 'B-organism'}", + "117, donors {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "87, B ['l0']", + "88, cells ['l0']", + "116, human ['l1']", + "117, donors ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25473904", + "TEXT": "Investigational drugs can save or extend lives, and seriously ill patients not able to take part in clinical trials should have access to such drugs whenever possible. In a climate of increased public pressure for this access - often termed compassionate use - five states in the US have passed so-called ‘right to try’ legislation. These laws are ill advised, as they are not likely to substantially increase access and have the potential to compromise the clinical trial system.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25419709", + "TEXT": "We searched for genetic alterations in human B cell lymphoma that affect the ubiquitin-proteasome system. This approach identified FBXO25 within a minimal common region of frequent deletion in mantle cell lymphoma (MCL). FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)(FBXO25) ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase Cδ (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1. Our analyses in primary human MCL identify monoallelic loss of FBXO25 and stabilizing HAX1 phosphodegron mutations. Accordingly, FBXO25 re-expression in FBXO25-deleted MCL cells promotes cell death, whereas expression of the HAX-1 phosphodegron mutant inhibits apoptosis. In addition, knockdown of FBXO25 significantly accelerated lymphoma development in Eμ-Myc mice and in a human MCL xenotransplant model. Together we identify a PRKCD-dependent proapoptotic mechanism controlling HAX-1 stability, and we propose that FBXO25 functions as a haploinsufficient tumor suppressor and that HAX1 is a proto-oncogene in MCL.", + "TAG_DATA": [ + "111, FBXO25 {'perturbing_action': 'B-gene gain-of-function'}", + "112, re-expression {'perturbing_action': 'I-gene gain-of-function'}", + "114, FBXO25-deleted {'perturbing_action': 'B-gene loss-of-function'}", + "115, MCL {'context': 'B-transformed cells'}", + "116, cells {'context': 'I-transformed cells'}", + "117, promotes {'effect': 'B-positive'}", + "118, cell {'phenotype': 'B-cell death'}", + "119, death, {'phenotype': 'I-cell death'}", + "121, expression {'perturbing_action': 'B-other'}", + "122, of {'perturbing_action': 'I-other'}", + "123, the {'perturbing_action': 'I-other'}", + "124, HAX-1 {'perturbing_action': 'I-other'}", + "125, phosphodegron {'perturbing_action': 'I-other'}", + "126, mutant {'perturbing_action': 'I-other'}", + "127, inhibits {'effect': 'B-negative'}", + "128, apoptosis. {'phenotype': 'B-apoptosis'}", + "131, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "132, of {'perturbing_action': 'I-rnai/knockdown'}", + "133, FBXO25 {'perturbing_action': 'I-rnai/knockdown'}", + "135, accelerated {'effect': 'B-positive'}", + "136, lymphoma {'phenotype': 'B-tumourigenesis'}", + "139, Eμ-Myc {'perturbing_action': 'B-gene loss-of-function', 'context': 'B-organism'}", + "140, mice {'context': 'B-organism'}", + "144, human {'context': 'B-xenograft'}", + "145, MCL {'context': 'I-xenograft'}", + "146, xenotransplant {'context': 'I-xenograft'}", + "147, model. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "111, FBXO25 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "112, re-expression ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "114, FBXO25-deleted ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "115, MCL ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27']", + "116, cells ['l3', 'l11', 'l18', 'l24', 'l28', 'l29', 'l30']", + "117, promotes ['l4', 'l12', 'l19', 'l25', 'l28', 'l31', 'l32']", + "118, cell ['l5', 'l13', 'l20', 'l26', 'l29', 'l31', 'l33', 'l34']", + "119, death, ['l6', 'l14', 'l21', 'l27', 'l30', 'l32', 'l33']", + "121, expression ['l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "122, of ['l35', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "123, the ['l36', 'l42', 'l48', 'l49', 'l50', 'l51', 'l52']", + "124, HAX-1 ['l37', 'l43', 'l48', 'l53', 'l54', 'l55', 'l56']", + "125, phosphodegron ['l38', 'l44', 'l49', 'l53', 'l57', 'l58', 'l59']", + "126, mutant ['l39', 'l45', 'l50', 'l54', 'l57', 'l60', 'l61']", + "127, inhibits ['l7', 'l15', 'l22', 'l40', 'l46', 'l51', 'l55', 'l58', 'l60', 'l62']", + "128, apoptosis. ['l8', 'l16', 'l23', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l61', 'l62']", + "131, knockdown ['l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "132, of ['l63', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "133, FBXO25 ['l64', 'l73', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "135, accelerated ['l65', 'l74', 'l82', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "136, lymphoma ['l66', 'l75', 'l83', 'l90', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "139, Eμ-Myc ['l67', 'l76', 'l84', 'l91', 'l97', 'l103', 'l104', 'l105', 'l106', 'l107']", + "140, mice ['l68', 'l77', 'l85', 'l92', 'l98', 'l103', 'l108', 'l109', 'l110', 'l111']", + "144, human ['l69', 'l78', 'l86', 'l93', 'l99', 'l104', 'l108', 'l112', 'l113', 'l114']", + "145, MCL ['l70', 'l79', 'l87', 'l94', 'l100', 'l105', 'l109', 'l112', 'l115', 'l116']", + "146, xenotransplant ['l71', 'l80', 'l88', 'l95', 'l101', 'l106', 'l110', 'l113', 'l115', 'l117']", + "147, model. ['l72', 'l81', 'l89', 'l96', 'l102', 'l107', 'l111', 'l114', 'l116', 'l117']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "FBXO25", + "re-expression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MCL", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "FBXO25", + "re-expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "FBXO25", + "re-expression" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "FBXO25", + "re-expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "FBXO25", + "re-expression" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FBXO25-deleted" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MCL", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FBXO25-deleted", + "Eμ-Myc" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes", + "accelerated" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FBXO25-deleted" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FBXO25-deleted" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FBXO25-deleted" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "MCL", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "MCL", + "cells" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "the", + "HAX-1", + "phosphodegron", + "mutant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "the", + "HAX-1", + "phosphodegron", + "mutant" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "FBXO25" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerated" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "FBXO25" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "FBXO25" + ] + }, + "context": { + "val": "organism", + "words": [ + "Eμ-Myc", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Eμ-Myc" + ] + }, + "context": { + "val": "organism", + "words": [ + "Eμ-Myc" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "FBXO25" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "human", + "MCL", + "xenotransplant", + "model." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "accelerated" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "accelerated" + ] + }, + "context": { + "val": "organism", + "words": [ + "Eμ-Myc", + "mice" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "accelerated" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "human", + "MCL", + "xenotransplant", + "model." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Eμ-Myc" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + }, + "context": { + "val": "organism", + "words": [ + "Eμ-Myc", + "mice" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "human", + "MCL", + "xenotransplant", + "model." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Eμ-Myc" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "human", + "MCL", + "xenotransplant", + "model." + ] + } + } + ] + }, + { + "PMID": "25419707", + "TEXT": "Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps.", + "TAG_DATA": [ + "45, mouse {'context': 'B-organism'}", + "46, model {'context': 'I-organism'}", + "85, Lgr5-negative {'context': 'B-cells'}", + "86, progenitor {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}", + "96, cells {'context': 'B-cells'}", + "100, proliferate, {'phenotype': 'B-proliferation'}", + "106, initiate {'effect': 'B-positive'}", + "107, intestinal {'context': 'B-tissue/organ'}", + "108, neoplasia, {'phenotype': 'I-tumourigenesis'}" + ], + "LINK_DATA": [ + "45, mouse ['l0', 'l1', 'l2', 'l3']", + "46, model ['l0', 'l4', 'l5', 'l6']", + "85, Lgr5-negative ['l1', 'l4', 'l7', 'l8', 'l9', 'l10']", + "86, progenitor ['l2', 'l5', 'l7', 'l11', 'l12', 'l13']", + "87, cells ['l3', 'l6', 'l8', 'l11', 'l14']", + "96, cells ['l9', 'l12', 'l14', 'l15', 'l16', 'l17', 'l18']", + "100, proliferate, ['l10', 'l13', 'l15', 'l19', 'l20', 'l21']", + "106, initiate ['l16', 'l19', 'l22', 'l23']", + "107, intestinal ['l17', 'l20', 'l22', 'l24']", + "108, neoplasia, ['l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Lgr5-negative", + "progenitor", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasia," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate," + ] + }, + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "intestinal" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "intestinal" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasia," + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "intestinal" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasia," + ] + } + } + ] + }, + { + "PMID": "25384086", + "TEXT": "Antibodies are critical for defense against a variety of microbes, but they may also be pathogenic in some autoimmune diseases. Many effector functions of antibodies are mediated by Fcγ receptors (FcγRs), which are found on most immune cells, including dendritic cells (DCs)-important antigen-presenting cells that play a central role in inducing antigen-specific tolerance or immunity. Following antigen acquisition in peripheral tissues, DCs migrate to draining lymph nodes via the lymphatics to present antigen to T cells. Here we demonstrate that FcγR engagement by IgG immune complexes (ICs) stimulates DC migration from peripheral tissues to the paracortex of draining lymph nodes. In vitro, IC-stimulated mouse and human DCs showed greater directional migration in a chemokine (C-C) ligand 19 (CCL19) gradient and increased chemokine (C-C) receptor 7 (CCR7) expression. Using intravital two-photon microscopy, we observed that local administration of IC resulted in dermal DC mobilization. We confirmed that dermal DC migration to lymph nodes depended on CCR7 and increased in the absence of the inhibitory receptor FcγRIIB. These observations have relevance to autoimmunity because autoantibody-containing serum from humans with systemic lupus erythematosus (SLE) and from a mouse model of SLE also increased dermal DC migration in vivo, suggesting that this process may occur in lupus, potentially driving the inappropriate localization of autoantigen-bearing DCs.", + "TAG_DATA": [ + "88, DC {'context': 'B-cells'}", + "100, In {'context': 'B-in vitro'}", + "101, vitro, {'context': 'I-in vitro'}", + "103, mouse {'context': 'B-cells'}", + "104, and {'context': 'I-cells'}", + "105, human {'context': 'I-cells'}", + "106, DCs {'context': 'I-cells'}", + "140, dermal {'context': 'B-cells'}", + "141, DC {'context': 'B-cells'}", + "146, dermal {'context': 'B-cells'}", + "147, DC {'context': 'B-cells'}", + "190, dermal {'context': 'B-cells'}", + "191, DC {'context': 'B-cells'}", + "193, in {'context': 'B-in vivo'}", + "194, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "100, In ['l0', 'l1', 'l2', 'l3', 'l4']", + "101, vitro, ['l0', 'l5', 'l6', 'l7', 'l8']", + "103, mouse ['l1', 'l5', 'l9', 'l10', 'l11']", + "104, and ['l2', 'l6', 'l9', 'l12', 'l13']", + "105, human ['l3', 'l7', 'l10', 'l12', 'l14']", + "106, DCs ['l4', 'l8', 'l11', 'l13', 'l14']", + "140, dermal ['l15']", + "141, DC ['l15']", + "146, dermal ['l16']", + "147, DC ['l16']", + "190, dermal ['l17', 'l18', 'l19']", + "191, DC ['l17', 'l20', 'l21']", + "193, in ['l18', 'l20', 'l22']", + "194, vivo, ['l19', 'l21', 'l22']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25384085", + "TEXT": "We describe a rapid target enrichment method for next-generation sequencing, termed anchored multiplex PCR (AMP), that is compatible with low nucleic acid input from formalin-fixed paraffin-embedded (FFPE) specimens. AMP is effective in detecting gene rearrangements (without prior knowledge of the fusion partners), single nucleotide variants, insertions, deletions and copy number changes. Validation of a gene rearrangement panel using 319 FFPE samples showed 100% sensitivity (95% confidence limit: 96.5-100%) and 100% specificity (95% confidence limit: 99.3-100%) compared with reference assays. On the basis of our experience with performing AMP on 986 clinical FFPE samples, we show its potential as both a robust clinical assay and a powerful discovery tool, which we used to identify new therapeutically important gene fusions: ARHGEF2-NTRK1 and CHTOP-NTRK1 in glioblastoma, MSN-ROS1, TRIM4-BRAF, VAMP2-NRG1, TPM3-NTRK1 and RUFY2-RET in lung cancer, FGFR2-CREB5 in cholangiocarcinoma and PPL-NTRK1 in thyroid carcinoma. AMP is a scalable and efficient next-generation sequencing target enrichment method for research and clinical applications.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25375910", + "TEXT": "The international response to the ongoing Ebola epidemic has in many respects been more reactive than proactive. But there are changes that, if made, may shift the balance toward future readiness.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25326804", + "TEXT": "Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. The Cancer Genome Atlas (TCGA) provides a unique resource for comprehensive discovery of mutations and genes in blood that may contribute to the clonal expansion of hematopoietic stem/progenitor cells. Here, we analyzed blood-derived sequence data from 2,728 individuals from TCGA and discovered 77 blood-specific mutations in cancer-associated genes, the majority being associated with advanced age. Remarkably, 83% of these mutations were from 19 leukemia and/or lymphoma-associated genes, and nine were recurrently mutated (DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1 and SF3B1). We identified 14 additional mutations in a very small fraction of blood cells, possibly representing the earliest stages of clonal expansion in hematopoietic stem cells. Comparison of these findings to mutations in hematological malignancies identified several recurrently mutated genes that may be disease initiators. Our analyses show that the blood cells of more than 2% of individuals (5-6% of people older than 70 years) contain mutations that may represent premalignant events that cause clonal hematopoietic expansion.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25326799", + "TEXT": "Genetically engineered mouse models (GEMMs) have dramatically improved our understanding of tumor evolution and therapeutic resistance. However, sequential genetic manipulation of gene expression and targeting of the host is almost impossible using conventional Cre-loxP-based models. We have developed an inducible dual-recombinase system by combining flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies to improve GEMMs of pancreatic cancer. This enables investigation of multistep carcinogenesis, genetic manipulation of tumor subpopulations (such as cancer stem cells), selective targeting of the tumor microenvironment and genetic validation of therapeutic targets in autochthonous tumors on a genome-wide scale. As a proof of concept, we performed tumor cell-autonomous and nonautonomous targeting, recapitulated hallmarks of human multistep carcinogenesis, validated genetic therapy by 3-phosphoinositide-dependent protein kinase inactivation as well as cancer cell depletion and show that mast cells in the tumor microenvironment, which had been thought to be key oncogenic players, are dispensable for tumor formation.", + "TAG_DATA": [ + "120, cancer {'context': 'B-transformed cells'}", + "121, cell {'context': 'I-transformed cells'}", + "144, tumor {'phenotype': 'B-tumourigenesis'}", + "145, formation. {'phenotype': 'I-tumourigenesis'}" + ], + "LINK_DATA": [ + "120, cancer ['l0', 'l1', 'l2']", + "121, cell ['l0', 'l3', 'l4']", + "144, tumor ['l1', 'l3', 'l5']", + "145, formation. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cell" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "formation." + ] + } + } + ] + }, + { + "PMID": "25326798", + "TEXT": "Multiple bone marrow stromal cell types have been identified as hematopoietic stem cell (HSC)-regulating niche cells. However, whether HSC progeny can serve directly as HSC niche cells has not previously been shown. Here we report a dichotomous role of megakaryocytes (MKs) in both maintaining HSC quiescence during homeostasis and promoting HSC regeneration after chemotherapeutic stress. We show that MKs are physically associated with HSCs in the bone marrow of mice and that MK ablation led to activation of quiescent HSCs and increased HSC proliferation. RNA sequencing (RNA-seq) analysis revealed that transforming growth factor β1 (encoded by Tgfb1) is expressed at higher levels in MKs as compared to other stromal niche cells. MK ablation led to reduced levels of biologically active TGF-β1 protein in the bone marrow and nuclear-localized phosphorylated SMAD2/3 (pSMAD2/3) in HSCs, suggesting that MKs maintain HSC quiescence through TGF-β-SMAD signaling. Indeed, TGF-β1 injection into mice in which MKs had been ablated restored HSC quiescence, and conditional deletion of Tgfb1 in MKs increased HSC activation and proliferation. These data demonstrate that TGF-β1 is a dominant signal emanating from MKs that maintains HSC quiescence. However, under conditions of chemotherapeutic challenge, MK ablation resulted in a severe defect in HSC expansion. In response to stress, fibroblast growth factor 1 (FGF1) signaling from MKs transiently dominates over TGF-β inhibitory signaling to stimulate HSC expansion. Overall, these observations demonstrate that MKs serve as HSC-derived niche cells to dynamically regulate HSC function.", + "TAG_DATA": [ + "72, MK {'perturbing_action': 'B-gene loss-of-function'}", + "73, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "79, HSCs {'context': 'B-cells'}", + "81, increased {'effect': 'B-positive'}", + "82, HSC {'context': 'B-transformed cells'}", + "83, proliferation. {'phenotype': 'B-proliferation'}", + "111, MK {'perturbing_action': 'B-gene loss-of-function'}", + "112, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "132, HSCs, {'context': 'B-cells'}", + "146, mice {'context': 'B-organism'}", + "149, MKs {'perturbing_action': 'B-gene loss-of-function'}", + "151, been {'perturbing_action': 'I-gene loss-of-function'}", + "152, ablated {'perturbing_action': 'I-gene loss-of-function'}", + "153, restored {'effect': 'B-rescues'}", + "154, HSC {'context': 'B-cells'}", + "155, quiescence, {'phenotype': 'B-quiescence'}", + "157, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "158, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "159, of {'perturbing_action': 'I-gene loss-of-function'}", + "160, Tgfb1 {'perturbing_action': 'I-gene loss-of-function'}", + "162, MKs {'context': 'B-cells'}", + "163, increased {'effect': 'B-positive'}", + "164, HSC {'context': 'B-cells'}", + "167, proliferation. {'phenotype': 'B-proliferation'}", + "190, MK {'perturbing_action': 'B-gene loss-of-function'}", + "191, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "198, HSC {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "72, MK ['l0', 'l1', 'l2', 'l3', 'l4']", + "73, ablation ['l0', 'l5', 'l6', 'l7', 'l8']", + "79, HSCs ['l1', 'l5', 'l9', 'l10', 'l11']", + "81, increased ['l2', 'l6', 'l9', 'l12', 'l13']", + "82, HSC ['l3', 'l7', 'l10', 'l12', 'l14']", + "83, proliferation. ['l4', 'l8', 'l11', 'l13', 'l14']", + "111, MK ['l15', 'l16', 'l17']", + "112, ablation ['l15', 'l18', 'l19']", + "132, HSCs, ['l16', 'l18', 'l20']", + "146, mice ['l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "149, MKs ['l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "151, been ['l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "152, ablated ['l23', 'l28', 'l32', 'l36', 'l37', 'l38']", + "153, restored ['l17', 'l19', 'l20', 'l24', 'l29', 'l33', 'l36', 'l39', 'l40']", + "154, HSC ['l25', 'l30', 'l34', 'l37', 'l39', 'l41']", + "155, quiescence, ['l26', 'l31', 'l35', 'l38', 'l40', 'l41']", + "157, conditional ['l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "158, deletion ['l42', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "159, of ['l43', 'l52', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "160, Tgfb1 ['l44', 'l53', 'l61', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "162, MKs ['l45', 'l54', 'l62', 'l69', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "163, increased ['l46', 'l55', 'l63', 'l70', 'l76', 'l82', 'l83']", + "164, HSC ['l47', 'l56', 'l64', 'l71', 'l77', 'l82', 'l84']", + "167, proliferation. ['l48', 'l57', 'l65', 'l72', 'l78', 'l83', 'l84']", + "190, MK ['l49', 'l58', 'l66', 'l73', 'l79', 'l85', 'l86']", + "191, ablation ['l50', 'l59', 'l67', 'l74', 'l80', 'l85', 'l87']", + "198, HSC ['l51', 'l60', 'l68', 'l75', 'l81', 'l86', 'l87']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MK", + "ablation", + "MKs", + "been", + "ablated", + "conditional", + "deletion", + "of", + "Tgfb1" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSCs", + "HSCs,", + "HSC", + "MKs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MK", + "ablation", + "conditional", + "deletion", + "of", + "Tgfb1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MK", + "ablation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MK", + "ablation", + "conditional", + "deletion", + "of", + "Tgfb1" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSCs", + "MKs", + "HSC" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSCs", + "MKs", + "HSC" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MK", + "ablation", + "MKs", + "been", + "ablated" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSCs,", + "HSC" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MKs", + "been", + "ablated" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MKs", + "been", + "ablated" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence," + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSC" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence," + ] + } + } + ] + }, + { + "PMID": "25306233", + "TEXT": "The WNT16 locus is a major determinant of cortical bone thickness and nonvertebral fracture risk in humans. The disability, mortality and costs caused by osteoporosis-induced nonvertebral fractures are enormous. We demonstrate here that Wnt16-deficient mice develop spontaneous fractures as a result of low cortical thickness and high cortical porosity. In contrast, trabecular bone volume is not altered in these mice. Mechanistic studies revealed that WNT16 is osteoblast derived and inhibits human and mouse osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts. The signaling pathway activated by WNT16 in osteoclast progenitors is noncanonical, whereas the pathway activated in osteoblasts is both canonical and noncanonical. Conditional Wnt16 inactivation revealed that osteoblast-lineage cells are the principal source of WNT16, and its targeted deletion in osteoblasts increases fracture susceptibility. Thus, osteoblast-derived WNT16 is a previously unreported key regulator of osteoclastogenesis and fracture susceptibility. These findings open new avenues for the specific prevention or treatment of nonvertebral fractures, a substantial unmet medical need.", + "TAG_DATA": [ + "33, Wnt16-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "34, mice {'context': 'B-organism'}", + "59, mice. {'context': 'B-organism'}", + "69, inhibits {'effect': 'B-negative'}", + "70, human {'context': 'B-organism'}", + "71, and {'context': 'I-organism'}", + "72, mouse {'context': 'I-organism'}", + "73, osteoclastogenesis {'phenotype': 'B-mitophagy'}", + "113, Conditional {'perturbing_action': 'B-gene loss-of-function'}", + "114, Wnt16 {'perturbing_action': 'I-gene loss-of-function'}", + "115, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "118, osteoblast-lineage {'context': 'B-cells'}", + "119, cells {'context': 'I-cells'}", + "131, osteoblasts {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "33, Wnt16-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "34, mice ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "59, mice. ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "69, inhibits ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "70, human ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "71, and ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "72, mouse ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "73, osteoclastogenesis ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "113, Conditional ['l28', 'l29', 'l30', 'l31', 'l32']", + "114, Wnt16 ['l28', 'l33', 'l34', 'l35', 'l36']", + "115, inactivation ['l29', 'l33', 'l37', 'l38', 'l39']", + "118, osteoblast-lineage ['l30', 'l34', 'l37', 'l40', 'l41']", + "119, cells ['l31', 'l35', 'l38', 'l40', 'l42']", + "131, osteoblasts ['l32', 'l36', 'l39', 'l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Wnt16-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "human", + "and", + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Wnt16-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Wnt16-deficient" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "osteoclastogenesis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "human", + "and", + "mouse" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "human", + "and", + "mouse" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "osteoclastogenesis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "osteoclastogenesis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "Wnt16", + "inactivation" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoblast-lineage", + "cells", + "osteoblasts" + ] + } + } + ] + }, + { + "PMID": "25295923", + "TEXT": "The Ice Bucket Challenge, a social media-driven fundraiser for the Amyotrophic Lateral Sclerosis (ALS) Association, has raised over $100 million to date. Despite criticisms of this fundraiser, efforts to understand why it has been so successful and how to sustain its momentum would benefit its cause--research funding--and may inform future charitable campaigns.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25282357", + "TEXT": "Type 2 diabetes (T2D) has reached an epidemic level globally. Most current treatments ameliorate the hyperglycemic symptom of the disease but are not effective in correcting its underlying cause. One important causal factor of T2D is ectopic accumulation of lipids in metabolically sensitive organs such as liver and muscle. Mitochondrial uncoupling, which reduces cellular energy efficiency and increases lipid oxidation, is an appealing therapeutic strategy. The challenge, however, is to discover safe mitochondrial uncouplers for practical use. Niclosamide is an anthelmintic drug approved by the US Food and Drug Administration that uncouples the mitochondria of parasitic worms. Here we show that niclosamide ethanolamine salt (NEN) uncouples mammalian mitochondria at upper nanomolar concentrations. Oral NEN increases energy expenditure and lipid metabolism in mice. It is also efficacious in preventing and treating hepatic steatosis and insulin resistance induced by a high-fat diet. Moreover, it improves glycemic control and delays disease progression in db/db mice. Given the well-documented safety profile of NEN, our study provides a potentially new and practical pharmacological approach for treating T2D.", + "TAG_DATA": [ + "121, mice. {'context': 'B-organism'}", + "150, db/db {'context': 'B-organism'}", + "151, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "150, db/db ['l0']", + "151, mice. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25261995", + "TEXT": "Haploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD) and modulates an innate immune response in humans and in mouse models. GRN polymorphism may be linked to late-onset Alzheimer's disease (AD). However, the role of PGRN in AD pathogenesis is unknown. Here we show that PGRN inhibits amyloid β (Aβ) deposition. Selectively reducing microglial expression of PGRN in AD mouse models impaired phagocytosis, increased plaque load threefold and exacerbated cognitive deficits. Lentivirus-mediated PGRN overexpression lowered plaque load in AD mice with aggressive amyloid plaque pathology. Aβ plaque load correlated negatively with levels of hippocampal PGRN, showing the dose-dependent inhibitory effects of PGRN on plaque deposition. PGRN also protected against Aβ toxicity. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. The protective effects of PGRN against Aβ deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTLD and AD.", + "TAG_DATA": [ + "55, Selectively {'perturbing_action': 'B-rnai/knockdown'}", + "56, reducing {'perturbing_action': 'I-rnai/knockdown'}", + "57, microglial {'perturbing_action': 'I-rnai/knockdown'}", + "58, expression {'perturbing_action': 'I-rnai/knockdown'}", + "59, of {'perturbing_action': 'I-rnai/knockdown'}", + "60, PGRN {'perturbing_action': 'I-rnai/knockdown'}", + "62, AD {'context': 'B-organism'}", + "63, mouse {'context': 'I-organism'}", + "64, models {'context': 'I-organism'}", + "75, Lentivirus-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "76, PGRN {'perturbing_action': 'I-gene gain-of-function'}", + "77, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "82, AD {'context': 'B-organism'}", + "83, mice {'context': 'I-organism'}", + "115, Lentivirus-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "116, PGRN {'perturbing_action': 'I-gene gain-of-function'}", + "117, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "127, AD {'context': 'B-organism'}", + "128, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "55, Selectively ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "56, reducing ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "57, microglial ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "58, expression ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "59, of ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "60, PGRN ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "62, AD ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "63, mouse ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "64, models ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "75, Lentivirus-mediated ['l36', 'l37', 'l38', 'l39']", + "76, PGRN ['l36', 'l40', 'l41', 'l42']", + "77, overexpression ['l37', 'l40', 'l43', 'l44']", + "82, AD ['l38', 'l41', 'l43', 'l45']", + "83, mice ['l39', 'l42', 'l44', 'l45']", + "115, Lentivirus-mediated ['l46', 'l47', 'l48', 'l49']", + "116, PGRN ['l46', 'l50', 'l51', 'l52']", + "117, overexpression ['l47', 'l50', 'l53', 'l54']", + "127, AD ['l48', 'l51', 'l53', 'l55']", + "128, mice. ['l49', 'l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Selectively", + "reducing", + "microglial", + "expression", + "of", + "PGRN" + ] + }, + "context": { + "val": "organism", + "words": [ + "AD", + "mouse", + "models" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Lentivirus-mediated", + "PGRN", + "overexpression" + ] + }, + "context": { + "val": "organism", + "words": [ + "AD", + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "25216638", + "TEXT": "In solid tumors, resistance to therapy inevitably develops upon treatment with cytotoxic drugs or molecularly targeted therapies. Here, we describe a system that enables pooled shRNA screening directly in mouse hepatocellular carcinomas (HCC) in vivo to identify genes likely to be involved in therapy resistance. Using a focused shRNA library targeting genes located within focal genomic amplifications of human HCC, we screened for genes whose inhibition increased the therapeutic efficacy of the multikinase inhibitor sorafenib. Both shRNA-mediated and pharmacological silencing of Mapk14 (p38α) were found to sensitize mouse HCC to sorafenib therapy and prolong survival by abrogating Mapk14-dependent activation of Mek-Erk and Atf2 signaling. Elevated Mapk14-Atf2 signaling predicted poor response to sorafenib therapy in human HCC, and sorafenib resistance of p-Mapk14-expressing HCC cells could be reverted by silencing Mapk14. Our results suggest that a combination of sorafenib and Mapk14 blockade is a promising approach to overcoming therapy resistance of human HCC.", + "TAG_DATA": [ + "78, pharmacological {'perturbing_action': 'B-rnai/knockdown'}", + "79, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "80, of {'perturbing_action': 'I-rnai/knockdown'}", + "81, Mapk14 {'perturbing_action': 'I-rnai/knockdown'}", + "82, (p38α) {'perturbing_action': 'I-rnai/knockdown'}", + "87, mouse {'context': 'B-neoplasm'}", + "88, HCC {'context': 'I-neoplasm'}", + "121, HCC {'context': 'B-transformed cells'}", + "122, cells {'context': 'I-transformed cells'}", + "127, silencing {'perturbing_action': 'B-rnai/knockdown'}", + "128, Mapk14. {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "78, pharmacological ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "79, silencing ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "80, of ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "81, Mapk14 ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "82, (p38α) ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "87, mouse ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "88, HCC ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "120, p-Mapk14-expressing ['l21', 'l22', 'l23', 'l24']", + "121, HCC ['l21', 'l25', 'l26', 'l27']", + "122, cells ['l22', 'l25', 'l28', 'l29']", + "127, silencing ['l23', 'l26', 'l28', 'l30']", + "128, Mapk14. ['l24', 'l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "pharmacological", + "silencing", + "of", + "Mapk14", + "(p38α)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "HCC" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "HCC", + "cells" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "Mapk14." + ] + } + } + ] + }, + { + "PMID": "25216635", + "TEXT": "Here we describe a blood-cleansing device for sepsis therapy inspired by the spleen, which can continuously remove pathogens and toxins from blood without first identifying the infectious agent. Blood flowing from an infected individual is mixed with magnetic nanobeads coated with an engineered human opsonin--mannose-binding lectin (MBL)--that captures a broad range of pathogens and toxins without activating complement factors or coagulation. Magnets pull the opsonin-bound pathogens and toxins from the blood; the cleansed blood is then returned back to the individual. The biospleen efficiently removes multiple Gram-negative and Gram-positive bacteria, fungi and endotoxins from whole human blood flowing through a single biospleen unit at up to 1.25 liters per h in vitro. In rats infected with Staphylococcus aureus or Escherichia coli, the biospleen cleared >90% of bacteria from blood, reduced pathogen and immune cell infiltration in multiple organs and decreased inflammatory cytokine levels. In a model of endotoxemic shock, the biospleen increased survival rates after a 5-h treatment.", + "TAG_DATA": [ + "110, in {'context': 'B-in vitro'}", + "111, vitro. {'context': 'I-in vitro'}", + "113, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "110, in ['l0']", + "111, vitro. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25194568", + "TEXT": "The Notch signaling pathway controls cell fates through interactions between neighboring cells by positively or negatively affecting the processes of proliferation, differentiation and apoptosis in a context-dependent manner. This pathway has been implicated in human cancer as both an oncogene and a tumor suppressor. Here we report new inactivating mutations in Notch pathway components in over 40% of human bladder cancers examined. Bladder cancer is the fourth most commonly diagnosed malignancy in the male population of the United States. Thus far, driver mutations in fibroblast growth factor receptor 3 (FGFR3) and, less commonly, in RAS proteins have been identified. We show that Notch activation in bladder cancer cells suppresses proliferation both in vitro and in vivo by directly upregulating dual-specificity phosphatases (DUSPs), thus reducing the phosphorylation of ERK1 and ERK2 (ERK1/2). In mouse models, genetic inactivation of Notch signaling leads to Erk1/2 phosphorylation, resulting in tumorigenesis in the urinary tract. Collectively our findings show that loss of Notch activity is a driving event in urothelial cancer.", + "TAG_DATA": [ + "105, bladder {'context': 'B-transformed cells'}", + "106, cancer {'context': 'I-transformed cells'}", + "107, cells {'context': 'I-transformed cells'}", + "108, suppresses {'effect': 'B-negative'}", + "109, proliferation {'phenotype': 'B-proliferation'}", + "111, in {'context': 'B-in vitro'}", + "112, vitro {'context': 'I-in vitro'}", + "114, in {'context': 'B-in vivo'}", + "115, vivo {'context': 'I-in vivo'}", + "132, mouse {'context': 'B-organism'}", + "133, models, {'context': 'I-organism'}", + "134, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "135, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "136, of {'perturbing_action': 'I-gene loss-of-function'}", + "137, Notch {'perturbing_action': 'I-gene loss-of-function'}", + "138, signaling {'perturbing_action': 'I-gene loss-of-function'}", + "143, resulting {'effect': 'B-positive'}", + "144, in {'effect': 'I-positive'}", + "145, tumorigenesis {'phenotype': 'B-tumourigenesis'}", + "148, urinary {'context': 'B-tissue/organ'}", + "149, tract. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "105, bladder ['l0', 'l1', 'l2', 'l3']", + "106, cancer ['l0', 'l4', 'l5', 'l6']", + "107, cells ['l1', 'l4', 'l7', 'l8']", + "108, suppresses ['l2', 'l5', 'l7', 'l9', 'l10', 'l11']", + "109, proliferation ['l3', 'l6', 'l8', 'l9', 'l12', 'l13']", + "111, in ['l10', 'l12', 'l14']", + "112, vitro ['l11', 'l13', 'l14']", + "114, in ['l15']", + "115, vivo ['l15']", + "132, mouse ['l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "133, models, ['l16', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "134, genetic ['l17', 'l27', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "135, inactivation ['l18', 'l28', 'l37', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "136, of ['l19', 'l29', 'l38', 'l46', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "137, Notch ['l20', 'l30', 'l39', 'l47', 'l54', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "138, signaling ['l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l67', 'l68', 'l69', 'l70', 'l71']", + "143, resulting ['l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l72', 'l73', 'l74', 'l75']", + "144, in ['l23', 'l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l76', 'l77', 'l78']", + "145, tumorigenesis ['l24', 'l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l76', 'l79', 'l80']", + "148, urinary ['l25', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l79', 'l81']", + "149, tract. ['l26', 'l36', 'l45', 'l53', 'l60', 'l66', 'l71', 'l75', 'l78', 'l80', 'l81']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "bladder", + "cancer", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "bladder", + "cancer", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inactivation", + "of", + "Notch", + "signaling" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models," + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inactivation", + "of", + "Notch", + "signaling" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inactivation", + "of", + "Notch", + "signaling" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inactivation", + "of", + "Notch", + "signaling" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "urinary", + "tract." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "urinary", + "tract." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "urinary", + "tract." + ] + } + } + ] + }, + { + "PMID": "25108525", + "TEXT": "Most mutations that truncate the reading frame of the DMD gene cause loss of dystrophin expression and lead to Duchenne muscular dystrophy. However, amelioration of disease severity has been shown to result from alternative translation initiation beginning in DMD exon 6 that leads to expression of a highly functional N-truncated dystrophin. Here we demonstrate that this isoform results from usage of an internal ribosome entry site (IRES) within exon 5 that is glucocorticoid inducible. We confirmed IRES activity by both peptide sequencing and ribosome profiling in muscle from individuals with minimal symptoms despite the presence of truncating mutations. We generated a truncated reading frame upstream of the IRES by exon skipping, which led to synthesis of a functional N-truncated isoform in both human subject-derived cell lines and in a new DMD mouse model, where expression of the truncated isoform protected muscle from contraction-induced injury and corrected muscle force to the same level as that observed in control mice. These results support a potential therapeutic approach for patients with mutations within the 5' exons of DMD.", + "TAG_DATA": [ + "122, human {'context': 'B-cells'}", + "123, subject-derived {'context': 'I-cells'}", + "124, cell {'context': 'I-cells'}", + "125, lines {'context': 'I-cells'}", + "130, DMD {'context': 'B-patient'}", + "131, mouse {'context': 'I-organism'}", + "132, model, {'context': 'I-organism'}", + "140, muscle {'context': 'B-tissue/organ'}", + "157, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "122, human ['l0', 'l1', 'l2', 'l3']", + "123, subject-derived ['l0', 'l4', 'l5', 'l6', 'l7']", + "124, cell ['l1', 'l4', 'l8', 'l9']", + "125, lines ['l2', 'l5', 'l8', 'l10']", + "130, DMD ['l11', 'l12', 'l13', 'l14']", + "131, mouse ['l11', 'l15', 'l16', 'l17']", + "132, model, ['l6', 'l12', 'l15', 'l18', 'l19']", + "140, muscle ['l3', 'l7', 'l9', 'l10', 'l13', 'l16', 'l18']", + "157, mice. ['l14', 'l17', 'l19']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25064127", + "TEXT": "Oxidative tissue injury often accompanies viral infection, yet there is little understanding of how it influences virus replication. We show that multiple hepatitis C virus (HCV) genotypes are exquisitely sensitive to oxidative membrane damage, a property distinguishing them from other pathogenic RNA viruses. Lipid peroxidation, regulated in part through sphingosine kinase-2, severely restricts HCV replication in Huh-7 cells and primary human hepatoblasts. Endogenous oxidative membrane damage lowers the 50% effective concentration of direct-acting antivirals in vitro, suggesting critical regulation of the conformation of the NS3-4A protease and the NS5B polymerase, membrane-bound HCV replicase components. Resistance to lipid peroxidation maps genetically to transmembrane and membrane-proximal residues within these proteins and is essential for robust replication in cell culture, as exemplified by the atypical JFH1 strain of HCV. Thus, the typical, wild-type HCV replicase is uniquely regulated by lipid peroxidation, providing a mechanism for attenuating replication in stressed tissue and possibly facilitating long-term viral persistence.", + "TAG_DATA": [ + "56, Huh-7 {'context': 'B-cells'}", + "57, cells {'context': 'I-cells'}", + "59, primary {'context': 'B-cells'}", + "60, human {'context': 'I-cells'}", + "61, hepatoblasts. {'context': 'I-cells'}", + "74, in {'context': 'B-in vitro'}", + "75, vitro, {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "56, Huh-7 ['l0', 'l1', 'l2', 'l3']", + "57, cells ['l0', 'l4']", + "59, primary ['l1', 'l4', 'l5', 'l6']", + "60, human ['l2', 'l5', 'l7']", + "61, hepatoblasts. ['l3', 'l6', 'l7']", + "74, in ['l8']", + "75, vitro, ['l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25064126", + "TEXT": "The nonsense-mediated mRNA decay (NMD) pathway selectively eliminates aberrant transcripts containing premature translation termination codons and regulates the levels of a number of physiological mRNAs. NMD modulates the clinical outcome of a variety of human diseases, including cancer and many genetic disorders, and may represent a target for therapeutic intervention. Here, we have developed a new multicolored bioluminescence-based reporter system that can specifically and effectively assay NMD in live human cells. Using this reporter system, we conducted a robust high-throughput small-molecule screen in human cells and, unpredictably, identified a group of cardiac glycosides, including ouabain and digoxin, as potent inhibitors of NMD. Cardiac glycoside-mediated effects on NMD are dependent on binding and inhibiting the sodium-potassium ATPase on the plasma membrane and subsequent elevation of intracellular calcium levels. Induction of calcium release from the endoplasmic reticulum also leads to inhibition of NMD. Thus, this study reveals intracellular calcium as a key regulator of NMD and has implications for exploiting NMD in the treatment of disease.", + "TAG_DATA": [ + "83, human {'context': 'B-cells'}", + "84, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "83, human ['l0']", + "84, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25038826", + "TEXT": "Beige adipocytes in white adipose tissue (WAT) are similar to classical brown adipocytes in that they can burn lipids to produce heat. Thus, an increase in beige adipocyte content in WAT browning would raise energy expenditure and reduce adiposity. Here we report that adipose-specific inactivation of Notch1 or its signaling mediator Rbpj in mice results in browning of WAT and elevated expression of uncoupling protein 1 (Ucp1), a key regulator of thermogenesis. Consequently, as compared to wild-type mice, Notch mutants exhibit elevated energy expenditure, better glucose tolerance and improved insulin sensitivity and are more resistant to high fat diet-induced obesity. By contrast, adipose-specific activation of Notch1 leads to the opposite phenotypes. At the molecular level, constitutive activation of Notch signaling inhibits, whereas Notch inhibition induces, Ppargc1a and Prdm16 transcription in white adipocytes. Notably, pharmacological inhibition of Notch signaling in obese mice ameliorates obesity, reduces blood glucose and increases Ucp1 expression in white fat. Therefore, Notch signaling may be therapeutically targeted to treat obesity and type 2 diabetes.", + "TAG_DATA": [ + "43, adipose-specific {'perturbing_action': 'B-gene loss-of-function'}", + "44, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "45, of {'perturbing_action': 'I-gene loss-of-function'}", + "46, Notch1 {'perturbing_action': 'I-gene loss-of-function'}", + "47, or {'perturbing_action': 'I-gene loss-of-function'}", + "48, its {'perturbing_action': 'I-gene loss-of-function'}", + "49, signaling {'perturbing_action': 'I-gene loss-of-function'}", + "50, mediator {'perturbing_action': 'I-gene loss-of-function'}", + "51, Rbpj {'perturbing_action': 'I-gene loss-of-function'}", + "53, mice {'context': 'B-organism'}", + "78, Notch {'perturbing_action': 'B-other'}", + "79, mutants {'perturbing_action': 'I-other'}", + "102, adipose-specific {'perturbing_action': 'B-pharmacological augmentation'}", + "103, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "104, of {'perturbing_action': 'I-pharmacological augmentation'}", + "105, Notch1 {'perturbing_action': 'I-pharmacological augmentation'}", + "115, constitutive {'perturbing_action': 'B-gene gain-of-function'}", + "116, activation {'perturbing_action': 'I-gene gain-of-function'}", + "122, Notch {'perturbing_action': 'B-pharmacological inhibition'}", + "123, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "130, white {'context': 'B-cells'}", + "131, adipocytes. {'context': 'I-cells'}", + "133, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "134, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "135, of {'perturbing_action': 'I-pharmacological inhibition'}", + "136, Notch {'perturbing_action': 'I-pharmacological inhibition'}", + "137, signaling {'perturbing_action': 'I-pharmacological inhibition'}", + "139, obese {'context': 'B-organism'}", + "140, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "43, adipose-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "44, inactivation ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "45, of ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "46, Notch1 ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "47, or ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "48, its ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "49, signaling ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "50, mediator ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "51, Rbpj ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "53, mice ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "78, Notch ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "79, mutants ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "102, adipose-specific ['l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "103, activation ['l66', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "104, of ['l67', 'l77', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "105, Notch1 ['l68', 'l78', 'l86', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "115, constitutive ['l69', 'l79', 'l87', 'l94', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "116, activation ['l70', 'l80', 'l88', 'l95', 'l101', 'l107', 'l108', 'l109', 'l110', 'l111']", + "119, signaling ['l71', 'l81', 'l89', 'l96', 'l102', 'l107', 'l112', 'l113', 'l114', 'l115']", + "122, Notch ['l72', 'l82', 'l90', 'l97', 'l103', 'l108', 'l112', 'l116', 'l117', 'l118']", + "123, inhibition ['l73', 'l83', 'l91', 'l98', 'l104', 'l109', 'l113', 'l116', 'l119', 'l120']", + "130, white ['l74', 'l84', 'l92', 'l99', 'l105', 'l110', 'l114', 'l117', 'l119', 'l121']", + "131, adipocytes. ['l75', 'l85', 'l93', 'l100', 'l106', 'l111', 'l115', 'l118', 'l120', 'l121']", + "133, pharmacological ['l122', 'l123', 'l124', 'l125', 'l126', 'l127']", + "134, inhibition ['l122', 'l128', 'l129', 'l130', 'l131', 'l132']", + "135, of ['l123', 'l128', 'l133', 'l134', 'l135', 'l136']", + "136, Notch ['l124', 'l129', 'l133', 'l137', 'l138', 'l139']", + "137, signaling ['l125', 'l130', 'l134', 'l137', 'l140', 'l141']", + "139, obese ['l126', 'l131', 'l135', 'l138', 'l140', 'l142']", + "140, mice ['l76', 'l127', 'l132', 'l136', 'l139', 'l141', 'l142']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adipose-specific", + "inactivation", + "of", + "Notch1", + "or", + "its", + "signaling", + "mediator", + "Rbpj" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Notch", + "mutants" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "adipose-specific", + "activation", + "of", + "Notch1" + ] + }, + "context": { + "val": "cells", + "words": [ + "white", + "adipocytes." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "adipose-specific" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutive", + "activation" + ] + }, + "context": { + "val": "cells", + "words": [ + "white", + "adipocytes." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Notch", + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "white", + "adipocytes." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "Notch", + "signaling" + ] + }, + "context": { + "val": "organism", + "words": [ + "obese", + "mice" + ] + } + } + ] + }, + { + "PMID": "24997607", + "TEXT": "Functional screening for compounds that promote remyelination represents a major hurdle in the development of rational therapeutics for multiple sclerosis. Screening for remyelination is problematic, as myelination requires the presence of axons. Standard methods do not resolve cell-autonomous effects and are not suited for high-throughput formats. Here we describe a binary indicant for myelination using micropillar arrays (BIMA). Engineered with conical dimensions, micropillars permit resolution of the extent and length of membrane wrapping from a single two-dimensional image. Confocal imaging acquired from the base to the tip of the pillars allows for detection of concentric wrapping observed as 'rings' of myelin. The platform is formatted in 96-well plates, amenable to semiautomated random acquisition and automated detection and quantification. Upon screening 1,000 bioactive molecules, we identified a cluster of antimuscarinic compounds that enhance oligodendrocyte differentiation and remyelination. Our findings demonstrate a new high-throughput screening platform for potential regenerative therapeutics in multiple sclerosis.", + "TAG_DATA": [ + "131, enhance {'effect': 'B-positive'}", + "132, oligodendrocyte {'context': 'B-cells'}", + "133, differentiation {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "131, enhance ['l0', 'l1']", + "132, oligodendrocyte ['l0', 'l2']", + "133, differentiation ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "enhance" + ] + }, + "context": { + "val": "cells", + "words": [ + "oligodendrocyte" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhance" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "oligodendrocyte" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "24973920", + "TEXT": "Hedgehog signaling drives oncogenesis in several cancers, and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened (SMO). However, resistance to Smoothened inhibitors occurs by genetic changes of Smoothened or other downstream Hedgehog components. Here we overcome these resistance mechanisms by modulating GLI transcription through inhibition of bromo and extra C-terminal (BET) bromodomain proteins. We show that BRD4 and other BET bromodomain proteins regulate GLI transcription downstream of SMO and suppressor of fused (SUFU), and chromatin immunoprecipitation studies reveal that BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites after treatment with JQ1, a small-molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM (genetically engineered mouse model)-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists. Altogether, our results reveal BET proteins as critical regulators of Hedgehog pathway transcriptional output and nominate BET bromodomain inhibitors as a strategy for treating Hedgehog-driven tumors with emerged or a priori resistance to Smoothened antagonists.", + "TAG_DATA": [ + "103, JQ1, {'perturbing_action': 'B-pharmacological inhibition'}", + "104, a {'perturbing_action': 'I-pharmacological inhibition'}", + "105, small-molecule {'perturbing_action': 'I-pharmacological inhibition'}", + "106, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "107, targeting {'perturbing_action': 'I-pharmacological inhibition'}", + "108, BRD4. {'perturbing_action': 'I-pharmacological inhibition'}", + "140, Hedgehog-driven {'context': 'I-neoplasm'}", + "141, tumors {'context': 'I-neoplasm'}", + "142, (basal {'context': 'I-neoplasm'}", + "143, cell {'context': 'I-neoplasm'}", + "144, carcinoma, {'context': 'I-neoplasm'}", + "145, medulloblastoma {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "103, JQ1, ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "104, a ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "105, small-molecule ['l1', 'l10', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "106, inhibitor ['l2', 'l11', 'l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "107, targeting ['l3', 'l12', 'l21', 'l29', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "108, BRD4. ['l4', 'l13', 'l22', 'l30', 'l37', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "140, Hedgehog-driven ['l5', 'l14', 'l23', 'l31', 'l38', 'l44', 'l50', 'l51', 'l52', 'l53', 'l54']", + "141, tumors ['l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l55', 'l56', 'l57', 'l58']", + "142, (basal ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l59', 'l60', 'l61']", + "143, cell ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l62', 'l63']", + "144, carcinoma, ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l62', 'l64']", + "145, medulloblastoma ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l64']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "JQ1,", + "a", + "small-molecule", + "inhibitor", + "targeting", + "BRD4." + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "Hedgehog-driven", + "(basal", + "cell", + "carcinoma,", + "medulloblastoma", + "tumors" + ] + } + } + ] + }, + { + "PMID": "24952647", + "TEXT": "Two-photon excitation microscopy can image retinal molecular processes in vivo. Intrinsically fluorescent retinyl esters in subcellular structures called retinosomes are an integral part of the visual chromophore regeneration pathway. Fluorescent condensation products of all-trans-retinal accumulate in the eye with age and are also associated with age-related macular degeneration (AMD). Here, we report repetitive, dynamic imaging of these compounds in live mice through the pupil of the eye. By leveraging advanced adaptive optics, we developed a data acquisition algorithm that permitted the identification of retinosomes and condensation products in the retinal pigment epithelium by their characteristic localization, spectral properties and absence in genetically modified or drug-treated mice. This imaging approach has the potential to detect early molecular changes in retinoid metabolism that trigger light- and AMD-induced retinal defects and to assess the effectiveness of treatments for these conditions.", + "TAG_DATA": [ + "59, live {'context': 'B-organism'}", + "60, mice {'context': 'I-organism'}", + "105, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "59, live ['l0']", + "60, mice ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24859531", + "TEXT": "Pancreatic adenosquamous carcinoma (ASC) is an enigmatic and aggressive tumor that has a worse prognosis and higher metastatic potential than its adenocarcinoma counterpart. Here we report that ASC tumors frequently harbor somatically acquired mutations in the UPF1 gene, which encodes the core component of the nonsense-mediated RNA decay (NMD) pathway. These tumor-specific mutations alter UPF1 RNA splicing and perturb NMD, leading to upregulated levels of NMD substrate mRNAs. UPF1 mutations are, to our knowledge, the first known unique molecular signatures of pancreatic ASC.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24859530", + "TEXT": "Immune evasion is an emerging hallmark of cancer progression. However, functional studies to understand the role of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment are limited by the lack of available specific cell surface markers. We adapted a competitive peptide phage display platform to identify candidate peptides binding MDSCs specifically and generated peptide-Fc fusion proteins (peptibodies). In multiple tumor models, intravenous peptibody injection completely depleted blood, splenic and intratumoral MDSCs in tumor-bearing mice without affecting proinflammatory immune cell types, such as dendritic cells. Whereas control Gr-1-specific antibody primarily depleted granulocytic MDSCs, peptibodies depleted both granulocytic and monocytic MDSC subsets. Peptibody treatment was associated with inhibition of tumor growth in vivo, which was superior to that achieved with Gr-1-specific antibody. Immunoprecipitation of MDSC membrane proteins identified S100 family proteins as candidate targets. Our strategy may be useful to identify new diagnostic and therapeutic surface targets on rare cell subtypes, including human MDSCs.", + "TAG_DATA": [ + "59, tumor {'context': 'B-neoplasm'}", + "60, models, {'context': 'I-neoplasm'}", + "70, MDSCs {'context': 'B-cells'}", + "72, tumor-bearing {'context': 'B-organism'}", + "73, mice {'context': 'I-organism'}", + "90, granulocytic {'context': 'B-cells'}", + "91, MDSCs, {'context': 'I-cells'}", + "95, granulocytic {'context': 'B-cells'}", + "96, and {'context': 'I-cells'}", + "97, monocytic {'context': 'I-cells'}", + "98, MDSC {'context': 'I-cells'}", + "99, subsets. {'context': 'I-cells'}", + "105, inhibition {'effect': 'B-negative'}", + "107, tumor {'phenotype': 'B-tumour growth'}", + "108, growth {'phenotype': 'I-tumour growth'}", + "109, in {'context': 'B-in vivo'}", + "110, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "59, tumor ['l0', 'l1']", + "60, models, ['l0', 'l2']", + "70, MDSCs ['l1', 'l2', 'l3']", + "72, tumor-bearing ['l4']", + "73, mice ['l3', 'l4']", + "90, granulocytic ['l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "91, MDSCs, ['l5', 'l11']", + "95, granulocytic ['l6', 'l12', 'l13', 'l14', 'l15']", + "96, and ['l7', 'l12', 'l16', 'l17', 'l18']", + "97, monocytic ['l8', 'l13', 'l16', 'l19', 'l20']", + "98, MDSC ['l9', 'l14', 'l17', 'l19', 'l21']", + "99, subsets. ['l10', 'l11', 'l15', 'l18', 'l20', 'l21']", + "105, inhibition ['l22', 'l23', 'l24', 'l25']", + "107, tumor ['l22', 'l26', 'l27', 'l28']", + "108, growth ['l23', 'l26', 'l29', 'l30']", + "109, in ['l24', 'l27', 'l29', 'l31']", + "110, vivo, ['l25', 'l28', 'l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + } + ] + }, + { + "PMID": "24836577", + "TEXT": "Cardiomyocyte T tubules are important for regulating ion flux. Bridging integrator 1 (BIN1) is a T-tubule protein associated with calcium channel trafficking that is downregulated in failing hearts. Here we find that cardiac T tubules normally contain dense protective inner membrane folds that are formed by a cardiac isoform of BIN1. In mice with cardiac Bin1 deletion, T-tubule folding is decreased, which does not change overall cardiomyocyte morphology but leads to free diffusion of local extracellular calcium and potassium ions, prolonging action-potential duration and increasing susceptibility to ventricular arrhythmias. We also found that T-tubule inner folds are rescued by expression of the BIN1 isoform BIN1+13+17, which promotes N-WASP-dependent actin polymerization to stabilize the T-tubule membrane at cardiac Z discs. BIN1+13+17 recruits actin to fold the T-tubule membrane, creating a 'fuzzy space' that protectively restricts ion flux. When the amount of the BIN1+13+17 isoform is decreased, as occurs in acquired cardiomyopathy, T-tubule morphology is altered, and arrhythmia can result.", + "TAG_DATA": [ + "52, mice {'context': 'B-organism'}", + "54, cardiac {'perturbing_action': 'B-gene loss-of-function'}", + "55, Bin1 {'perturbing_action': 'I-gene loss-of-function'}", + "56, deletion, {'perturbing_action': 'I-gene loss-of-function'}", + "99, expression {'perturbing_action': 'B-other'}", + "100, of {'perturbing_action': 'I-other'}", + "101, the {'perturbing_action': 'I-other'}", + "102, BIN1 {'perturbing_action': 'I-other'}", + "103, isoform {'perturbing_action': 'I-other'}", + "104, BIN1+13+17, {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "52, mice ['l0', 'l1', 'l2']", + "54, cardiac ['l0', 'l3', 'l4']", + "55, Bin1 ['l1', 'l3', 'l5']", + "56, deletion, ['l2', 'l4', 'l5']", + "99, expression ['l6', 'l7', 'l8', 'l9', 'l10']", + "100, of ['l6', 'l11', 'l12', 'l13', 'l14']", + "101, the ['l7', 'l11', 'l15', 'l16', 'l17']", + "102, BIN1 ['l8', 'l12', 'l15', 'l18', 'l19']", + "103, isoform ['l9', 'l13', 'l16', 'l18', 'l20']", + "104, BIN1+13+17, ['l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cardiac", + "Bin1", + "deletion," + ] + } + } + ] + }, + { + "PMID": "24813252", + "TEXT": "Study of monogenic mitochondrial cardiomyopathies may yield insights into mitochondrial roles in cardiac development and disease. Here, we combined patient-derived and genetically engineered induced pluripotent stem cells (iPSCs) with tissue engineering to elucidate the pathophysiology underlying the cardiomyopathy of Barth syndrome (BTHS), a mitochondrial disorder caused by mutation of the gene encoding tafazzin (TAZ). Using BTHS iPSC-derived cardiomyocytes (iPSC-CMs), we defined metabolic, structural and functional abnormalities associated with TAZ mutation. BTHS iPSC-CMs assembled sparse and irregular sarcomeres, and engineered BTHS 'heart-on-chip' tissues contracted weakly. Gene replacement and genome editing demonstrated that TAZ mutation is necessary and sufficient for these phenotypes. Sarcomere assembly and myocardial contraction abnormalities occurred in the context of normal whole-cell ATP levels. Excess levels of reactive oxygen species mechanistically linked TAZ mutation to impaired cardiomyocyte function. Our study provides new insights into the pathogenesis of Barth syndrome, suggests new treatment strategies and advances iPSC-based in vitro modeling of cardiomyopathy.", + "TAG_DATA": [ + "55, BTHS {'context': 'B-cells'}", + "56, iPSC-derived {'context': 'I-cells'}", + "57, cardiomyocytes {'context': 'I-cells'}", + "58, (iPSC-CMs), {'context': 'I-cells'}", + "70, BTHS {'context': 'B-cells'}", + "71, iPSC-CMs {'context': 'I-cells'}", + "79, BTHS {'context': 'B-organoid'}", + "91, TAZ {'perturbing_action': 'B-other'}", + "92, mutation {'perturbing_action': 'I-other'}", + "127, cardiomyocyte {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "55, BTHS ['l0', 'l1', 'l2']", + "56, iPSC-derived ['l0', 'l3', 'l4']", + "57, cardiomyocytes ['l1', 'l3', 'l5']", + "58, (iPSC-CMs), ['l2', 'l4', 'l5']", + "70, BTHS ['l6', 'l7']", + "71, iPSC-CMs ['l6', 'l8']", + "79, BTHS ['l9']", + "81, tissues ['l7', 'l8', 'l9']", + "91, TAZ ['l10']", + "92, mutation ['l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24813251", + "TEXT": "Oncogene-induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and the mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies, including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53-independent, proapoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway coactivator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1-induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine-threonine kinase, STK4. Notably, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a new synthetic-lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels.", + "TAG_DATA": [ + "74, triggers {'effect': 'B-positive'}", + "75, cell {'phenotype': 'B-cell death'}", + "76, death {'phenotype': 'I-cell death'}", + "87, normal {'context': 'B-cells'}", + "88, cells, {'context': 'I-cells'}", + "95, prevent {'effect': 'B-negative'}", + "97, ABL1-induced {'effect': 'B-positive'}", + "98, apoptosis {'phenotype': 'B-apoptosis'}", + "101, hematologic {'context': 'B-neoplasm'}", + "102, malignancies. {'context': 'I-neoplasm'}", + "114, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "115, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "116, of {'perturbing_action': 'I-gene loss-of-function'}", + "117, STK4 {'perturbing_action': 'I-gene loss-of-function'}", + "121, triggering {'effect': 'B-positive'}", + "122, cell {'phenotype': 'B-cell death'}", + "123, death {'phenotype': 'I-cell death'}", + "124, in {'context': 'B-in vitro'}", + "125, vitro {'context': 'I-in vitro'}", + "127, in {'context': 'B-in vivo'}", + "128, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "74, triggers ['l0', 'l1', 'l2', 'l3']", + "75, cell ['l0', 'l4', 'l5', 'l6']", + "76, death ['l1', 'l4', 'l7', 'l8']", + "87, normal ['l2', 'l5', 'l7', 'l9']", + "88, cells, ['l3', 'l6', 'l8', 'l9']", + "95, prevent ['l10', 'l11', 'l12', 'l13']", + "97, ABL1-induced ['l10', 'l14', 'l15', 'l16']", + "98, apoptosis ['l11', 'l14', 'l17', 'l18']", + "101, hematologic ['l12', 'l15', 'l17', 'l19']", + "102, malignancies. ['l13', 'l16', 'l18', 'l19']", + "114, genetic ['l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "115, inactivation ['l20', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "116, of ['l21', 'l30', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "117, STK4 ['l22', 'l31', 'l39', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "121, triggering ['l23', 'l32', 'l40', 'l47', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "122, cell ['l24', 'l33', 'l41', 'l48', 'l54', 'l60', 'l61', 'l62', 'l63', 'l64']", + "123, death ['l25', 'l34', 'l42', 'l49', 'l55', 'l60', 'l65', 'l66', 'l67']", + "124, in ['l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l69', 'l70']", + "125, vitro ['l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l68', 'l71', 'l72']", + "127, in ['l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l69', 'l71', 'l73']", + "128, vivo. ['l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l67', 'l70', 'l72', 'l73']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "triggers", + "triggering" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "context": { + "val": "cells", + "words": [ + "normal", + "cells," + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "normal", + "cells," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "hematologic", + "malignancies." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "ABL1-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "ABL1-induced" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "hematologic", + "malignancies." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "hematologic", + "malignancies." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inactivation", + "of", + "STK4" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inactivation", + "of", + "STK4" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inactivation", + "of", + "STK4" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inactivation", + "of", + "STK4" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "24793239", + "TEXT": "We describe a new mechanism regulating the tumor endothelial barrier and T cell infiltration into tumors. We detected selective expression of the death mediator Fas ligand (FasL, also called CD95L) in the vasculature of human and mouse solid tumors but not in normal vasculature. In these tumors, FasL expression was associated with scarce CD8(+) infiltration and a predominance of FoxP3(+) T regulatory (Treg) cells. Tumor-derived vascular endothelial growth factor A (VEGF-A), interleukin 10 (IL-10) and prostaglandin E2 (PGE2) cooperatively induced FasL expression in endothelial cells, which acquired the ability to kill effector CD8(+) T cells but not Treg cells because of higher levels of c-FLIP expression in Treg cells. In mice, genetic or pharmacologic suppression of FasL produced a substantial increase in the influx of tumor-rejecting CD8(+) over FoxP3(+) T cells. Pharmacologic inhibition of VEGF and PGE2 produced a marked increase in the influx of tumor-rejecting CD8(+) over FoxP3(+) T cells that was dependent on attenuation of FasL expression and led to CD8-dependent tumor growth suppression. Thus, tumor paracrine mechanisms establish a tumor endothelial death barrier, which has a critical role in establishing immune tolerance and determining the fate of tumors.", + "TAG_DATA": [ + "83, endothelial {'context': 'B-cells'}", + "84, cells, {'context': 'I-cells'}", + "110, mice, {'context': 'B-organism'}", + "113, pharmacologic {'perturbing_action': 'B-pharmacological inhibition'}", + "114, suppression {'perturbing_action': 'I-pharmacological inhibition'}", + "115, of {'perturbing_action': 'I-pharmacological inhibition'}", + "116, FasL {'perturbing_action': 'I-pharmacological inhibition'}", + "125, tumor-rejecting {'context': 'B-neoplasm'}", + "126, CD8(+) {'context': 'I-cells'}", + "128, FoxP3(+) {'context': 'B-cells'}", + "129, T {'context': 'I-cells'}", + "130, cells. {'context': 'I-cells'}", + "131, Pharmacologic {'perturbing_action': 'B-pharmacological inhibition'}", + "132, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "133, of {'perturbing_action': 'I-pharmacological inhibition'}", + "134, VEGF {'perturbing_action': 'I-pharmacological inhibition'}", + "135, and {'perturbing_action': 'I-pharmacological inhibition'}", + "136, PGE2 {'perturbing_action': 'I-pharmacological inhibition'}", + "146, CD8(+) {'context': 'I-cells'}", + "148, FoxP3(+) {'context': 'B-cells'}", + "149, T {'context': 'I-cells'}", + "150, cells {'context': 'I-cells'}", + "163, tumor {'phenotype': 'B-tumour growth'}", + "164, growth {'phenotype': 'I-tumour growth'}", + "165, suppression. {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "83, endothelial ['l0', 'l1', 'l2']", + "84, cells, ['l0']", + "110, mice, ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "113, pharmacologic ['l3', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "114, suppression ['l4', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "115, of ['l5', 'l13', 'l23', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "116, FasL ['l6', 'l14', 'l24', 'l32', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "125, tumor-rejecting ['l7', 'l15', 'l25', 'l33', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "126, CD8(+) ['l8', 'l16', 'l26', 'l34', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "128, FoxP3(+) ['l9', 'l17', 'l27', 'l35', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57']", + "129, T ['l1', 'l10', 'l18', 'l28', 'l36', 'l43', 'l48', 'l52', 'l55', 'l58']", + "130, cells. ['l2', 'l11', 'l19', 'l29', 'l37', 'l44', 'l49', 'l53', 'l56', 'l58']", + "131, Pharmacologic ['l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "132, inhibition ['l59', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "133, of ['l60', 'l72', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "134, VEGF ['l61', 'l73', 'l84', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "135, and ['l62', 'l74', 'l85', 'l95', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "136, PGE2 ['l20', 'l63', 'l75', 'l86', 'l96', 'l105', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "145, tumor-rejecting ['l64', 'l76', 'l87', 'l97', 'l106', 'l114', 'l122', 'l123', 'l124', 'l125', 'l126']", + "146, CD8(+) ['l65', 'l77', 'l88', 'l98', 'l107', 'l115', 'l122', 'l127', 'l128', 'l129', 'l130', 'l131']", + "148, FoxP3(+) ['l66', 'l78', 'l89', 'l99', 'l108', 'l116', 'l123', 'l127', 'l132', 'l133', 'l134', 'l135', 'l136']", + "149, T ['l21', 'l30', 'l38', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l124', 'l128', 'l132', 'l137']", + "150, cells ['l22', 'l31', 'l39', 'l45', 'l50', 'l54', 'l57', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l125', 'l129', 'l133', 'l137']", + "163, tumor ['l69', 'l81', 'l92', 'l102', 'l111', 'l119', 'l134', 'l138', 'l139']", + "164, growth ['l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l130', 'l135', 'l138', 'l140']", + "165, suppression. ['l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l126', 'l131', 'l136', 'l139', 'l140']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "suppression", + "of", + "FasL" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "suppression", + "of", + "FasL" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor-rejecting" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "suppression", + "of", + "FasL", + "Pharmacologic", + "inhibition", + "VEGF", + "and", + "PGE2" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "FoxP3(+)", + "T", + "cells.", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacologic", + "inhibition", + "of", + "VEGF", + "and", + "PGE2" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacologic", + "inhibition", + "of", + "VEGF", + "and", + "PGE2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppression." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "FoxP3(+)" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth", + "tumor" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "FoxP3(+)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppression." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppression." + ] + } + } + ] + }, + { + "PMID": "24793238", + "TEXT": "As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts--in which circulatory systems of young and aged animals are connected--identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.", + "TAG_DATA": [ + "113, aged {'context': 'B-organism'}", + "114, mice {'context': 'I-organism'}", + "126, learning {'phenotype': 'I-metastasis'}", + "156, aged {'context': 'B-tissue/organ'}", + "157, hippocampus. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "113, aged ['l0', 'l1', 'l2', 'l3', 'l4']", + "114, mice ['l0', 'l5', 'l6', 'l7', 'l8']", + "125, spatial ['l1', 'l5', 'l9', 'l10', 'l11']", + "126, learning ['l2', 'l6', 'l9', 'l12', 'l13']", + "127, and ['l3', 'l7', 'l10', 'l12', 'l14']", + "128, memory. ['l4', 'l8', 'l11', 'l13', 'l14']", + "156, aged ['l15']", + "157, hippocampus. ['l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "aged", + "mice" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "learning" + ] + } + } + ] + }, + { + "PMID": "24793237", + "TEXT": "Osteogenesis imperfecta (OI) is a heritable disorder, in both a dominant and recessive manner, of connective tissue characterized by brittle bones, fractures and extraskeletal manifestations. How structural mutations of type I collagen (dominant OI) or of its post-translational modification machinery (recessive OI) can cause abnormal quality and quantity of bone is poorly understood. Notably, the clinical overlap between dominant and recessive forms of OI suggests common molecular pathomechanisms. Here, we show that excessive transforming growth factor-β (TGF-β) signaling is a mechanism of OI in both recessive (Crtap(-/-)) and dominant (Col1a2(tm1.1Mcbr)) OI mouse models. In the skeleton, we find higher expression of TGF-β target genes, higher ratio of phosphorylated Smad2 to total Smad2 protein and higher in vivo Smad2 reporter activity. Moreover, the type I collagen of Crtap(-/-) mice shows reduced binding to the small leucine-rich proteoglycan decorin, a known regulator of TGF-β activity. Anti-TGF-β treatment using the neutralizing antibody 1D11 corrects the bone phenotype in both forms of OI and improves the lung abnormalities in Crtap(-/-) mice. Hence, altered TGF-β matrix-cell signaling is a primary mechanism in the pathogenesis of OI and could be a promising target for the treatment of OI.", + "TAG_DATA": [ + "85, recessive {'perturbing_action': 'B-gene loss-of-function'}", + "86, (Crtap(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "91, mouse {'context': 'B-organism'}", + "92, models. {'context': 'I-organism'}", + "115, in {'context': 'B-in vivo'}", + "116, vivo {'context': 'I-in vivo'}", + "126, Crtap(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "127, mice {'context': 'B-organism'}", + "162, lung {'context': 'B-tissue/organ'}", + "165, Crtap(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "166, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "85, recessive ['l0', 'l1', 'l2', 'l3']", + "86, (Crtap(-/-)) ['l0', 'l4', 'l5', 'l6']", + "91, mouse ['l1', 'l4', 'l7', 'l8']", + "92, models. ['l2', 'l5', 'l7', 'l9']", + "95, skeleton, ['l3', 'l6', 'l8', 'l9', 'l10']", + "115, in ['l11', 'l12']", + "116, vivo ['l10', 'l11', 'l13']", + "126, Crtap(-/-) ['l14']", + "127, mice ['l12', 'l13', 'l14']", + "162, lung ['l15', 'l16']", + "165, Crtap(-/-) ['l15', 'l17']", + "166, mice. ['l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "recessive", + "(Crtap(-/-))", + "Crtap(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models.", + "mice", + "mice." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Crtap(-/-)" + ] + } + } + ] + }, + { + "PMID": "24728411", + "TEXT": "Major depressive disorder (MDD) affects up to 17% of the population, causing profound personal suffering and economic loss. Clinical and preclinical studies have revealed that prolonged stress and MDD are associated with neuronal atrophy of cortical and limbic brain regions, but the molecular mechanisms underlying these morphological alterations have not yet been identified. Here, we show that stress increases levels of REDD1 (regulated in development and DNA damage responses-1), an inhibitor of mTORC1 (mammalian target of rapamycin complex-1; ref. 10), in rat prefrontal cortex (PFC). This is concurrent with a decrease in phosphorylation of signaling targets of mTORC1, which is implicated in protein synthesis-dependent synaptic plasticity. We also found that REDD1 levels are increased in the postmortem PFC of human subjects with MDD relative to matched controls. Mutant mice with a deletion of the gene encoding REDD1 are resilient to the behavioral, synaptic and mTORC1 signaling deficits caused by chronic unpredictable stress, whereas viral-mediated overexpression of REDD1 in rat PFC is sufficient to cause anxiety- and depressive-like behaviors and neuronal atrophy. Taken together, these postmortem and preclinical findings identify REDD1 as a critical mediator of the atrophy of neurons and depressive behavior caused by chronic stress exposure.", + "TAG_DATA": [ + "81, rat {'context': 'B-tissue/organ'}", + "82, prefrontal {'context': 'I-tissue/organ'}", + "83, cortex {'context': 'I-tissue/organ'}", + "84, (PFC). {'context': 'I-tissue/organ'}", + "127, Mutant {'context': 'B-organism'}", + "128, mice {'context': 'B-organism'}", + "131, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "132, of {'perturbing_action': 'I-gene loss-of-function'}", + "133, the {'perturbing_action': 'I-gene loss-of-function'}", + "134, gene {'perturbing_action': 'I-gene loss-of-function'}", + "135, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "136, REDD1 {'perturbing_action': 'I-gene loss-of-function'}", + "153, viral-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "154, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "155, of {'perturbing_action': 'I-gene gain-of-function'}", + "156, REDD1 {'perturbing_action': 'I-gene gain-of-function'}", + "158, rat {'context': 'B-tissue/organ'}", + "159, PFC {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "81, rat ['l0', 'l1', 'l2']", + "82, prefrontal ['l0', 'l3', 'l4']", + "83, cortex ['l1', 'l3', 'l5']", + "84, (PFC). ['l2', 'l4', 'l5']", + "127, Mutant ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "128, mice ['l6', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "131, deletion ['l7', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "132, of ['l8', 'l14', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "133, the ['l9', 'l15', 'l20', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37']", + "134, gene ['l10', 'l16', 'l21', 'l27', 'l33', 'l38', 'l39', 'l40', 'l41']", + "135, encoding ['l11', 'l17', 'l22', 'l28', 'l34', 'l38', 'l42', 'l43', 'l44']", + "136, REDD1 ['l12', 'l18', 'l23', 'l29', 'l35', 'l39', 'l42', 'l45', 'l46']", + "153, viral-mediated ['l47', 'l48', 'l49', 'l50', 'l51']", + "154, overexpression ['l47', 'l52', 'l53', 'l54', 'l55']", + "155, of ['l48', 'l52', 'l56', 'l57', 'l58']", + "156, REDD1 ['l30', 'l49', 'l53', 'l56', 'l59', 'l60']", + "158, rat ['l24', 'l31', 'l36', 'l40', 'l43', 'l45', 'l50', 'l54', 'l57', 'l59', 'l61']", + "159, PFC ['l25', 'l32', 'l37', 'l41', 'l44', 'l46', 'l51', 'l55', 'l58', 'l60', 'l61']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mutant", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "gene", + "encoding", + "REDD1" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "gene", + "encoding", + "REDD1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "PFC" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "viral-mediated", + "overexpression", + "of", + "REDD1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "PFC" + ] + } + } + ] + }, + { + "PMID": "24710362", + "TEXT": "Efficacious new drugs to treat hepatitis C virus infection offer the potential to halt this epidemic. But their exorbitant cost may prove prohibitive for most patients in need. Strong patient and government advocacy will be necessary to ensure that accessibility to treatments is a right, not a privilege.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24705333", + "TEXT": "Circulating tumor DNA (ctDNA) is a promising biomarker for noninvasive assessment of cancer burden, but existing ctDNA detection methods have insufficient sensitivity or patient coverage for broad clinical applicability. Here we introduce cancer personalized profiling by deep sequencing (CAPP-Seq), an economical and ultrasensitive method for quantifying ctDNA. We implemented CAPP-Seq for non-small-cell lung cancer (NSCLC) with a design covering multiple classes of somatic alterations that identified mutations in >95% of tumors. We detected ctDNA in 100% of patients with stage II-IV NSCLC and in 50% of patients with stage I, with 96% specificity for mutant allele fractions down to ∼0.02%. Levels of ctDNA were highly correlated with tumor volume and distinguished between residual disease and treatment-related imaging changes, and measurement of ctDNA levels allowed for earlier response assessment than radiographic approaches. Finally, we evaluated biopsy-free tumor screening and genotyping with CAPP-Seq. We envision that CAPP-Seq could be routinely applied clinically to detect and monitor diverse malignancies, thus facilitating personalized cancer therapy.", + "TAG_DATA": [ + "51, non-small-cell {'context': 'B-neoplasm'}", + "52, lung {'context': 'I-neoplasm'}", + "53, cancer {'context': 'I-neoplasm'}", + "54, (NSCLC) {'context': 'I-neoplasm'}", + "79, stage {'context': 'B-neoplasm'}", + "80, II-IV {'context': 'I-neoplasm'}", + "81, NSCLC {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "51, non-small-cell ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "52, lung ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "53, cancer ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "54, (NSCLC) ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "79, stage ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "80, II-IV ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "81, NSCLC ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24681598", + "TEXT": "We report a newly developed technique for high-resolution in vivo imaging of myelinated axons in the brain, spinal cord and peripheral nerve that requires no fluorescent labeling. This method, based on spectral confocal reflectance microscopy (SCoRe), uses a conventional laser-scanning confocal system to generate images by merging the simultaneously reflected signals from multiple lasers of different wavelengths. Striking color patterns unique to individual myelinated fibers are generated that facilitate their tracing in dense axonal areas. These patterns highlight nodes of Ranvier and Schmidt-Lanterman incisures and can be used to detect various myelin pathologies. Using SCoRe we carried out chronic brain imaging up to 400 μm deep, capturing de novo myelination of mouse cortical axons in vivo. We also established the feasibility of imaging myelinated axons in the human cerebral cortex. SCoRe adds a powerful component to the evolving toolbox for imaging myelination in living animals and potentially in humans.", + "TAG_DATA": [ + "111, mouse {'context': 'B-cells'}", + "112, cortical {'context': 'I-cells'}", + "113, axons {'context': 'I-cells'}", + "114, in {'context': 'B-in vivo'}", + "115, vivo. {'context': 'I-in vivo'}", + "127, human {'context': 'B-tissue/organ'}", + "128, cerebral {'context': 'I-tissue/organ'}", + "129, cortex. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "111, mouse ['l0', 'l1', 'l2', 'l3']", + "112, cortical ['l0', 'l4', 'l5', 'l6']", + "113, axons ['l1', 'l4', 'l7', 'l8']", + "114, in ['l2', 'l5', 'l7', 'l9']", + "115, vivo. ['l3', 'l6', 'l8', 'l9']", + "127, human ['l10', 'l11']", + "128, cerebral ['l10', 'l12']", + "129, cortex. ['l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24658078", + "TEXT": "Erythropoietin (EPO) stimulates proliferation of early-stage erythrocyte precursors and is widely used for the treatment of chronic anemia. However, several types of EPO-resistant anemia are characterized by defects in late-stage erythropoiesis, which is EPO independent. Here we investigated regulation of erythropoiesis using a ligand-trapping fusion protein (ACE-536) containing the extracellular domain of human activin receptor type IIB (ActRIIB) modified to reduce activin binding. ACE-536, or its mouse version RAP-536, produced rapid and robust increases in erythrocyte numbers in multiple species under basal conditions and reduced or prevented anemia in murine models. Unlike EPO, RAP-536 promoted maturation of late-stage erythroid precursors in vivo. Cotreatment with ACE-536 and EPO produced a synergistic erythropoietic response. ACE-536 bound growth differentiation factor-11 (GDF11) and potently inhibited GDF11-mediated Smad2/3 signaling. GDF11 inhibited erythroid maturation in mice in vivo and ex vivo. Expression of GDF11 and ActRIIB in erythroid precursors decreased progressively with maturation, suggesting an inhibitory role for GDF11 in late-stage erythroid differentiation. RAP-536 treatment also reduced Smad2/3 activation, anemia, erythroid hyperplasia and ineffective erythropoiesis in a mouse model of myelodysplastic syndromes (MDS). These findings implicate transforming growth factor-β (TGF-β) superfamily signaling in erythroid maturation and identify ACE-536 as a new potential treatment for anemia, including that caused by ineffective erythropoiesis.", + "TAG_DATA": [ + "89, murine {'context': 'B-organism'}", + "90, models. {'context': 'I-organism'}", + "97, late-stage {'context': 'B-cells'}", + "98, erythroid {'context': 'I-cells'}", + "99, precursors {'context': 'I-cells'}", + "100, in {'context': 'B-in vivo'}", + "101, vivo. {'context': 'I-in vivo'}", + "129, mice {'context': 'B-organism'}", + "130, in {'context': 'B-in vivo'}", + "131, vivo {'context': 'I-in vivo'}", + "141, erythroid {'context': 'B-cells'}", + "142, precursors {'context': 'I-cells'}", + "171, mouse {'context': 'B-organism'}", + "172, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "89, murine ['l0', 'l1']", + "90, models. ['l0']", + "97, late-stage ['l2', 'l3', 'l4', 'l5']", + "98, erythroid ['l2', 'l6', 'l7', 'l8']", + "99, precursors ['l1', 'l3', 'l6', 'l9', 'l10']", + "100, in ['l4', 'l7', 'l9', 'l11']", + "101, vivo. ['l5', 'l8', 'l10', 'l11']", + "129, mice ['l12', 'l13']", + "130, in ['l12', 'l14']", + "131, vivo ['l13', 'l14']", + "141, erythroid ['l15']", + "142, precursors ['l15']", + "171, mouse ['l16']", + "172, model ['l16']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24658074", + "TEXT": "Assessment of KRAS status is mandatory in patients with metastatic colorectal cancer (mCRC) before applying targeted therapy. We describe here a blinded prospective study to compare KRAS and BRAF mutation status data obtained from the analysis of tumor tissue by routine gold-standard methods and of plasma DNA using a quantitative PCR-based method specifically designed to analyze circulating cell-free DNA (cfDNA). The mutation status was determined by both methods from 106 patient samples. cfDNA analysis showed 100% specificity and sensitivity for the BRAF V600E mutation. For the seven tested KRAS point mutations, the method exhibited 98% specificity and 92% sensitivity with a concordance value of 96%. Mutation load, expressed as the proportion of mutant alleles in cfDNA, was highly variable (0.5-64.1%, median 10.5%) among mutated samples. CfDNA was detected in 100% of patients with mCRC. This study shows that liquid biopsy through cfDNA analysis could advantageously replace tumor-section analysis and expand the scope of personalized medicine for patients with cancer.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24633305", + "TEXT": "Apoptotic cell death is a hallmark of the loss of insulin-producing beta cells in all forms of diabetes mellitus. Current treatments fail to halt the decline in functional beta cell mass, and strategies to prevent beta cell apoptosis and dysfunction are urgently needed. Here, we identified mammalian sterile 20-like kinase-1 (MST1) as a critical regulator of apoptotic beta cell death and function. Under diabetogenic conditions, MST1 was strongly activated in beta cells in human and mouse islets and specifically induced the mitochondrial-dependent pathway of apoptosis through upregulation of the BCL-2 homology-3 (BH3)-only protein BIM. MST1 directly phosphorylated the beta cell transcription factor PDX1 at T11, resulting in the latter's ubiquitination and degradation and thus in impaired insulin secretion. MST1 deficiency completely restored normoglycemia, beta cell function and survival in vitro and in vivo. We show MST1 as a proapoptotic kinase and key mediator of apoptotic signaling and beta cell dysfunction and suggest that it may serve as target for the development of new therapies for diabetes.", + "TAG_DATA": [ + "70, beta {'context': 'B-cells'}", + "71, cells {'context': 'I-cells'}", + "73, human {'context': 'B-cells'}", + "74, and {'context': 'I-cells'}", + "75, mouse {'context': 'I-cells'}", + "76, islets {'context': 'I-cells'}", + "79, induced {'effect': 'B-positive'}", + "84, apoptosis {'phenotype': 'B-apoptosis'}", + "118, MST1 {'perturbing_action': 'B-gene loss-of-function'}", + "119, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "123, beta {'context': 'B-cells'}", + "124, cell {'context': 'I-cells'}", + "128, in {'context': 'B-in vitro'}", + "129, vitro {'context': 'I-in vitro'}", + "131, in {'context': 'B-in vivo'}", + "132, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "70, beta ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "71, cells ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "73, human ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "74, and ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "75, mouse ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "76, islets ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "79, induced ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "84, apoptosis ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "118, MST1 ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "119, deficiency ['l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "123, beta ['l29', 'l35', 'l41', 'l42', 'l43']", + "124, cell ['l30', 'l36', 'l41', 'l44', 'l45']", + "128, in ['l31', 'l37', 'l42', 'l44', 'l46']", + "129, vitro ['l32', 'l38', 'l43', 'l45', 'l46']", + "131, in ['l33', 'l39', 'l47']", + "132, vivo. ['l34', 'l40', 'l47']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "beta", + "cells", + "human", + "and", + "mouse", + "islets" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "beta", + "cells", + "human", + "and", + "mouse", + "islets" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MST1", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "beta", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MST1", + "deficiency" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MST1", + "deficiency" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "24584118", + "TEXT": "During obesity, macrophage accumulation in adipose tissue propagates the chronic inflammation and insulin resistance associated with type 2 diabetes. The factors, however, that regulate the accrual of macrophages in adipose tissue are not well understood. Here we show that the neuroimmune guidance cue netrin-1 is highly expressed in obese but not lean adipose tissue of humans and mice, where it directs the retention of macrophages. Netrin-1, whose expression is induced in macrophages by the saturated fatty acid palmitate, acts via its receptor Unc5b to block their migration. In a mouse model of diet-induced obesity, we show that adipose tissue macrophages exhibit reduced migratory capacity, which can be restored by blocking netrin-1. Furthermore, hematopoietic deletion of Ntn1 facilitates adipose tissue macrophage emigration, reduces inflammation and improves insulin sensitivity. Collectively, these findings identify netrin-1 as a macrophage retention signal in adipose tissue during obesity that promotes chronic inflammation and insulin resistance.", + "TAG_DATA": [ + "89, mouse {'context': 'B-organism'}", + "90, model {'context': 'I-organism'}", + "97, adipose {'context': 'B-cells'}", + "98, tissue {'context': 'I-cells'}", + "99, macrophages {'context': 'I-cells'}", + "101, reduced {'effect': 'B-negative'}", + "102, migratory {'phenotype': 'B-migration'}", + "103, capacity, {'phenotype': 'I-migration'}", + "109, blocking {'perturbing_action': 'B-pharmacological inhibition'}", + "110, netrin-1. {'perturbing_action': 'I-pharmacological inhibition'}", + "112, hematopoietic {'perturbing_action': 'B-gene loss-of-function'}", + "113, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "114, of {'perturbing_action': 'I-gene loss-of-function'}", + "115, Ntn1 {'perturbing_action': 'I-gene loss-of-function'}", + "117, adipose {'context': 'B-cells'}", + "118, tissue {'context': 'I-cells'}", + "119, macrophage {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "89, mouse ['l0', 'l1']", + "90, model ['l0', 'l2', 'l3']", + "97, adipose ['l4', 'l5', 'l6', 'l7', 'l8']", + "98, tissue ['l1', 'l2', 'l4', 'l9', 'l10', 'l11', 'l12']", + "99, macrophages ['l3', 'l5', 'l9', 'l13', 'l14', 'l15']", + "101, reduced ['l6', 'l10', 'l13', 'l16', 'l17']", + "102, migratory ['l7', 'l11', 'l14', 'l16', 'l18']", + "103, capacity, ['l8', 'l12', 'l15', 'l17', 'l18']", + "109, blocking ['l19']", + "110, netrin-1. ['l19']", + "112, hematopoietic ['l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "113, deletion ['l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "114, of ['l21', 'l26', 'l31', 'l32', 'l33', 'l34']", + "115, Ntn1 ['l22', 'l27', 'l31', 'l35', 'l36', 'l37']", + "117, adipose ['l23', 'l28', 'l32', 'l35', 'l38', 'l39']", + "118, tissue ['l24', 'l29', 'l33', 'l36', 'l38', 'l40']", + "119, macrophage ['l25', 'l30', 'l34', 'l37', 'l39', 'l40']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "adipose", + "tissue", + "macrophages" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "adipose", + "tissue", + "macrophages" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migratory", + "capacity," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migratory", + "capacity," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "hematopoietic", + "deletion", + "of", + "Ntn1" + ] + }, + "context": { + "val": "cells", + "words": [ + "adipose", + "tissue", + "macrophage" + ] + } + } + ] + }, + { + "PMID": "24584117", + "TEXT": "Atherosclerosis, a hyperlipidemia-induced chronic inflammatory process of the arterial wall, develops preferentially at sites where disturbed laminar flow compromises endothelial cell (EC) function. Here we show that endothelial miR-126-5p maintains a proliferative reserve in ECs through suppression of the Notch1 inhibitor delta-like 1 homolog (Dlk1) and thereby prevents atherosclerotic lesion formation. Endothelial recovery after denudation was impaired in Mir126(-/-) mice because lack of miR-126-5p, but not miR-126-3p, reduced EC proliferation by derepressing Dlk1. At nonpredilection sites, high miR-126-5p levels in endothelial cells confer a proliferative reserve that compensates for the antiproliferative effects of hyperlipidemia, such that atherosclerosis was exacerbated in Mir126(-/-) mice. In contrast, downregulation of miR-126-5p by disturbed flow abrogated EC proliferation at predilection sites in response to hyperlipidemic stress through upregulation of Dlk1 expression. Administration of miR-126-5p rescued EC proliferation at predilection sites and limited atherosclerosis, introducing a potential therapeutic approach.", + "TAG_DATA": [ + "58, Mir126(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "59, mice {'context': 'B-organism'}", + "61, lack {'perturbing_action': 'B-gene loss-of-function'}", + "62, of {'perturbing_action': 'I-gene loss-of-function'}", + "63, miR-126-5p, {'perturbing_action': 'I-gene loss-of-function'}", + "67, reduced {'effect': 'B-negative'}", + "68, EC {'context': 'B-cells'}", + "69, proliferation {'phenotype': 'B-proliferation'}", + "80, endothelial {'context': 'B-cells'}", + "81, cells {'context': 'I-cells'}", + "100, Mir126(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "101, mice. {'context': 'B-organism'}", + "104, downregulation {'perturbing_action': 'B-gene loss-of-function'}", + "105, of {'perturbing_action': 'I-gene loss-of-function'}", + "106, miR-126-5p {'perturbing_action': 'I-gene loss-of-function'}", + "110, abrogated {'effect': 'B-negative'}", + "111, EC {'context': 'B-cells'}", + "112, proliferation {'phenotype': 'B-proliferation'}", + "129, rescued {'effect': 'B-rescues'}", + "130, EC {'context': 'B-cells'}", + "131, proliferation {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "58, Mir126(-/-) ['l0', 'l1', 'l2']", + "59, mice ['l0', 'l3']", + "61, lack ['l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "62, of ['l4', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "63, miR-126-5p, ['l5', 'l13', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "67, reduced ['l6', 'l14', 'l21', 'l28', 'l29', 'l30']", + "68, EC ['l1', 'l3', 'l7', 'l15', 'l22', 'l28', 'l31']", + "69, proliferation ['l2', 'l8', 'l16', 'l23', 'l29', 'l31', 'l32']", + "80, endothelial ['l9', 'l17', 'l24', 'l33', 'l34', 'l35', 'l36']", + "81, cells ['l10', 'l18', 'l25', 'l30', 'l32', 'l33', 'l37', 'l38']", + "100, Mir126(-/-) ['l11', 'l19', 'l26', 'l34', 'l37', 'l39', 'l40', 'l41', 'l42']", + "101, mice. ['l12', 'l20', 'l27', 'l35', 'l38', 'l39', 'l43']", + "104, downregulation ['l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "105, of ['l44', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "106, miR-126-5p ['l45', 'l52', 'l59', 'l60', 'l61', 'l62', 'l63']", + "110, abrogated ['l40', 'l46', 'l53', 'l59', 'l64', 'l65']", + "111, EC ['l41', 'l47', 'l54', 'l60', 'l64', 'l66']", + "112, proliferation ['l36', 'l42', 'l43', 'l48', 'l55', 'l61', 'l65', 'l66']", + "129, rescued ['l49', 'l56', 'l67', 'l68']", + "130, EC ['l50', 'l57', 'l62', 'l67', 'l69']", + "131, proliferation ['l51', 'l58', 'l63', 'l68', 'l69']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mir126(-/-)", + "lack", + "of", + "miR-126-5p," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mir126(-/-)", + "lack", + "of", + "miR-126-5p,", + "downregulation", + "miR-126-5p" + ] + }, + "context": { + "val": "cells", + "words": [ + "EC", + "endothelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mir126(-/-)", + "lack", + "of", + "miR-126-5p,", + "downregulation", + "miR-126-5p" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "miR-126-5p,", + "Mir126(-/-)", + "downregulation", + "miR-126-5p" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced", + "abrogated" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced", + "abrogated" + ] + }, + "context": { + "val": "cells", + "words": [ + "EC", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced", + "abrogated" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "EC", + "cells", + "endothelial" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "downregulation", + "of" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "context": { + "val": "cells", + "words": [ + "EC" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "24562383", + "TEXT": "Recent studies have revealed that ARID1A, encoding AT-rich interactive domain 1A (SWI-like), is frequently mutated across a variety of human cancers and also has bona fide tumor suppressor properties. Consequently, identification of vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. Here, using a broad screening approach, we identify ARID1B, an ARID1A homolog whose gene product is mutually exclusive with ARID1A in SWI/SNF complexes, as the number 1 gene preferentially required for the survival of ARID1A-mutant cancer cell lines. We show that loss of ARID1B in ARID1A-deficient backgrounds destabilizes SWI/SNF and impairs proliferation in both cancer cells and primary cells. We also find that ARID1A and ARID1B are frequently co-mutated in cancer but that ARID1A-deficient cancers retain at least one functional ARID1B allele. These results suggest that loss of ARID1A and ARID1B alleles cooperatively promotes cancer formation but also results in a unique functional dependence. The results further identify ARID1B as a potential therapeutic target for ARID1A-mutant cancers.", + "TAG_DATA": [ + "85, loss {'perturbing_action': 'B-gene loss-of-function'}", + "86, of {'perturbing_action': 'I-gene loss-of-function'}", + "87, ARID1B {'perturbing_action': 'I-gene loss-of-function'}", + "89, ARID1A-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "90, backgrounds {'context': 'B-neoplasm'}", + "94, impairs {'effect': 'B-negative'}", + "95, proliferation {'phenotype': 'B-proliferation'}", + "98, cancer {'context': 'B-transformed cells'}", + "99, cells {'context': 'I-transformed cells'}", + "101, primary {'context': 'B-transformed cells'}", + "102, cells. {'context': 'I-transformed cells'}", + "117, ARID1A-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "118, cancers {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "85, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "86, of ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "87, ARID1B ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "89, ARID1A-deficient ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "90, backgrounds ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "94, impairs ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "95, proliferation ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "98, cancer ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "99, cells ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52']", + "101, primary ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l53']", + "102, cells. ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l52', 'l53']", + "117, ARID1A-deficient ['l54']", + "118, cancers ['l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "ARID1B", + "ARID1A-deficient" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "backgrounds", + "cancers" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "ARID1B", + "ARID1A-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "ARID1B", + "ARID1A-deficient" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "ARID1B", + "ARID1A-deficient" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells", + "primary", + "cells." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "backgrounds" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "backgrounds" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells", + "primary", + "cells." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells", + "primary", + "cells." + ] + } + } + ] + }, + { + "PMID": "24441827", + "TEXT": "Gaucher's disease (GD), an inherited metabolic disorder caused by mutations in the glucocerebrosidase gene (GBA), is the most common lysosomal storage disease. Heterozygous mutations in GBA are a major risk factor for Parkinson's disease. GD is divided into three clinical subtypes based on the absence (type 1) or presence (types 2 and 3) of neurological signs. Type 1 GD was the first lysosomal storage disease (LSD) for which enzyme therapy became available, and although infusions of recombinant glucocerebrosidase (GCase) ameliorate the systemic effects of GD, the lack of efficacy for the neurological manifestations, along with the considerable expense and inconvenience of enzyme therapy for patients, renders the search for alternative or complementary therapies paramount. Glucosylceramide and glucosylsphingosine accumulation in the brain leads to massive neuronal loss in patients with neuronopathic GD (nGD) and in nGD mouse models. However, the mode of neuronal death is not known. Here, we show that modulating the receptor-interacting protein kinase-3 (Ripk3) pathway markedly improves neurological and systemic disease in a mouse model of GD. Notably, Ripk3 deficiency substantially improved the clinical course of GD mice, with increased survival and motor coordination and salutary effects on cerebral as well as hepatic injury.", + "TAG_DATA": [ + "165, mouse {'context': 'B-organism'}", + "166, model {'context': 'I-organism'}", + "167, of {'context': 'I-organism'}", + "168, GD. {'context': 'I-organism'}", + "170, Ripk3 {'perturbing_action': 'B-gene loss-of-function'}", + "171, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "179, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "165, mouse ['l0', 'l1', 'l2']", + "166, model ['l0', 'l3', 'l4']", + "167, of ['l1', 'l3', 'l5']", + "168, GD. ['l2', 'l4', 'l5']", + "170, Ripk3 ['l6', 'l7']", + "171, deficiency ['l6', 'l8']", + "179, mice, ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ripk3", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "24412924", + "TEXT": "ATP derived from the conversion of phosphocreatine to creatine by creatine kinase provides an essential chemical energy source that governs myocardial contraction. Here, we demonstrate that the exchange of amine protons from creatine with protons in bulk water can be exploited to image creatine through chemical exchange saturation transfer (CrEST) in myocardial tissue. We show that CrEST provides about two orders of magnitude higher sensitivity compared to (1)H magnetic resonance spectroscopy. Results of CrEST studies from ex vivo myocardial tissue strongly correlate with results from (1)H and (31)P magnetic resonance spectroscopy and biochemical analysis. We demonstrate the feasibility of CrEST measurement in healthy and infarcted myocardium in animal models in vivo on a 3-T clinical scanner. As proof of principle, we show the conversion of phosphocreatine to creatine by spatiotemporal mapping of creatine changes in the exercised human calf muscle. We also discuss the potential utility of CrEST in studying myocardial disorders.", + "TAG_DATA": [ + "105, myocardium {'context': 'B-tissue/organ'}", + "107, animal {'context': 'B-organism'}", + "108, models {'context': 'I-organism'}", + "109, in {'context': 'B-in vivo'}", + "110, vivo {'context': 'I-in vivo'}", + "137, human {'context': 'B-tissue/organ'}", + "138, calf {'context': 'I-tissue/organ'}", + "139, muscle. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "105, myocardium ['l0', 'l1']", + "107, animal ['l0', 'l2', 'l3', 'l4']", + "108, models ['l1', 'l2', 'l5', 'l6']", + "109, in ['l3', 'l5', 'l7']", + "110, vivo ['l4', 'l6', 'l7']", + "137, human ['l8', 'l9']", + "138, calf ['l8', 'l10']", + "139, muscle. ['l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24412922", + "TEXT": "Neutralizing antibodies against influenza viruses have traditionally been thought to provide protection exclusively through their variable region; the contributions of mechanisms conferred by the Fc domain remain controversial. We investigated the in vivo contributions of Fc interactions with their cognate receptors for a collection of neutralizing anti-influenza antibodies. Whereas five broadly neutralizing monoclonal antibodies (bNAbs) targeting the conserved stalk region of hemagglutinin (HA) required interactions between the antibody Fc and Fc receptors for IgG (FcγRs) to confer protection from lethal H1N1 challenge, three strain-specific monoclonal Abs (mAbs) against the variable head domain of HA were equally protective in the presence or absence of FcγR interactions. Although all antibodies blocked infection, only anti-stalk bNAbs were capable of mediating cytotoxicity of infected cells, which accounts for their FcγR dependence. Immune complexes generated with anti-HA stalk mAb efficiently interacted with FcγRs, but anti-HA head immune complexes did not. These results suggest that FcγR binding capacity by anti-HA antibodies was dependent on the interaction of the cognate Fab with antigen. We exploited these disparate mechanisms of mAb-mediated protection to reengineer an anti-stalk bNAb to selectively enhance FcγR engagement to augment its protective activity. These findings reveal a previously uncharacterized property of bNAbs and guide an approach toward enhancing mAb-mediated antiviral therapeutics.", + "TAG_DATA": [ + "120, cells, {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24362935", + "TEXT": "Mantle cell lymphoma (MCL) is an aggressive malignancy that is characterized by poor prognosis. Large-scale pharmacological profiling across more than 100 hematological cell line models identified a subset of MCL cell lines that are highly sensitive to the B cell receptor (BCR) signaling inhibitors ibrutinib and sotrastaurin. Sensitive MCL models exhibited chronic activation of the BCR-driven classical nuclear factor-κB (NF-κB) pathway, whereas insensitive cell lines displayed activation of the alternative NF-κB pathway. Transcriptome sequencing revealed genetic lesions in alternative NF-κB pathway signaling components in ibrutinib-insensitive cell lines, and sequencing of 165 samples from patients with MCL identified recurrent mutations in TRAF2 or BIRC3 in 15% of these individuals. Although they are associated with insensitivity to ibrutinib, lesions in the alternative NF-κB pathway conferred dependence on the protein kinase NIK (also called mitogen-activated protein 3 kinase 14 or MAP3K14) both in vitro and in vivo. Thus, NIK is a new therapeutic target for MCL treatment, particularly for lymphomas that are refractory to BCR pathway inhibitors. Our findings reveal a pattern of mutually exclusive activation of the BCR-NF-κB or NIK-NF-κB pathways in MCL and provide critical insights into patient stratification strategies for NF-κB pathway-targeted agents.", + "TAG_DATA": [ + "29, MCL {'context': 'B-transformed cells'}", + "48, MCL {'context': 'B-neoplasm'}", + "49, models {'context': 'I-neoplasm'}", + "63, cell {'context': 'B-cells'}", + "64, lines {'context': 'I-cells'}", + "86, lines, {'context': 'I-cells'}", + "139, in {'context': 'B-in vitro'}", + "140, vitro {'context': 'I-in vitro'}", + "142, in {'context': 'B-in vivo'}", + "143, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "29, MCL ['l0']", + "48, MCL ['l1', 'l2', 'l3']", + "49, models ['l0', 'l1', 'l4']", + "63, cell ['l5', 'l6']", + "64, lines ['l2', 'l5', 'l7']", + "86, lines, ['l3', 'l4', 'l6', 'l7']", + "139, in ['l8', 'l9', 'l10']", + "140, vitro ['l8', 'l11', 'l12']", + "142, in ['l9', 'l11', 'l13']", + "143, vivo. ['l10', 'l12', 'l13']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24336249", + "TEXT": "Obesity is associated with the development of asthma, which is often difficult to control. To understand the immunological pathways that lead to obesity-associated asthma, we fed mice a high-fat diet for 12 weeks, which resulted in obesity and the development of airway hyperreactivity (AHR), a cardinal feature of asthma. This AHR was independent of adaptive immunity, as it occurred in obese Rag1(-/-) mice, which lack B and T cells, and was dependent on interleukin-17A (IL-17A) and the NLRP3 inflammasome, as it did not develop in obese Il17a(-/-) or Nlrp3(-/-) mice. AHR was also associated with the expansion of CCR6(+) type 3 innate lymphoid cells (ILCs) producing IL-17A (ILC3 cells) in the lung, which could by themselves mediate AHR when adoptively transferred into Rag2(-/-); Il2rg(-/-) mice treated with recombinant IL-1β. Macrophage-derived IL-1β production was induced by HFD and expanded the number of lung ILC3 cells. Blockade of IL-1β with an IL-1 receptor antagonist abolished obesity-induced AHR and reduced the number of ILC3 cells. As we found ILC3-like cells in the bronchoalveolar lavage fluid of individuals with asthma, we suggest that obesity-associated asthma is facilitated by inflammation mediated by NLRP3, IL-1β and ILC3 cells.", + "TAG_DATA": [ + "26, mice {'context': 'B-organism'}", + "60, obese {'perturbing_action': 'B-gene loss-of-function'}", + "61, Rag1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "62, mice, {'context': 'B-organism'}", + "85, obese {'perturbing_action': 'B-gene loss-of-function'}", + "86, Il17a(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "87, or {'perturbing_action': 'B-gene loss-of-function'}", + "88, Nlrp3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "89, mice. {'context': 'B-organism'}", + "111, lung, {'context': 'B-tissue/organ'}", + "122, Rag2(-/-); {'perturbing_action': 'B-gene loss-of-function'}", + "123, Il2rg(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "124, mice {'context': 'B-organism'}", + "141, lung {'context': 'B-cells'}", + "142, ILC3 {'context': 'I-cells'}", + "143, cells. {'context': 'I-cells'}", + "160, ILC3 {'context': 'B-cells'}", + "161, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "26, mice ['l0', 'l1', 'l2']", + "60, obese ['l0', 'l3', 'l4', 'l5', 'l6']", + "61, Rag1(-/-) ['l1', 'l3', 'l7', 'l8', 'l9']", + "62, mice, ['l2', 'l4', 'l7']", + "85, obese ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "86, Il17a(-/-) ['l5', 'l8', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "87, or ['l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "88, Nlrp3(-/-) ['l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "89, mice. ['l13', 'l20', 'l26', 'l31', 'l39', 'l40', 'l41', 'l42']", + "111, lung, ['l6', 'l9', 'l14', 'l21', 'l27', 'l32', 'l39', 'l43', 'l44', 'l45']", + "122, Rag2(-/-); ['l33', 'l46', 'l47', 'l48', 'l49', 'l50']", + "123, Il2rg(-/-) ['l34', 'l46', 'l51', 'l52', 'l53', 'l54']", + "124, mice ['l35', 'l47', 'l51', 'l55', 'l56', 'l57']", + "141, lung ['l15', 'l22', 'l28', 'l36', 'l40', 'l43', 'l48', 'l52', 'l55', 'l58', 'l59']", + "142, ILC3 ['l16', 'l23', 'l29', 'l37', 'l41', 'l44', 'l49', 'l53', 'l56', 'l58', 'l60']", + "143, cells. ['l17', 'l24', 'l30', 'l38', 'l42', 'l45', 'l50', 'l54', 'l57', 'l59', 'l60']", + "160, ILC3 ['l61']", + "161, cells. ['l61']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice,", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "obese", + "Rag1(-/-)", + "Il17a(-/-)", + "or", + "Nlrp3(-/-)", + "Rag2(-/-);", + "Il2rg(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "obese", + "Rag1(-/-)", + "Il17a(-/-)", + "or", + "Nlrp3(-/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "obese", + "Il17a(-/-)", + "or", + "Nlrp3(-/-)", + "Rag2(-/-);", + "Il2rg(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "lung", + "ILC3", + "cells." + ] + } + } + ] + }, + { + "PMID": "24336248", + "TEXT": "Over 30% of the world's population is infected with Mycobacterium tuberculosis (Mtb), yet only ∼5-10% will develop clinical disease. Despite considerable effort, researchers understand little about what distinguishes individuals whose infection progresses to active tuberculosis (TB) from those whose infection remains latent for decades. The variable course of disease is recapitulated in cynomolgus macaques infected with Mtb. Active disease occurs in ∼45% of infected macaques and is defined by clinical, microbiologic and immunologic signs, whereas the remaining infected animals are clinically asymptomatic. Here, we use individually marked Mtb isolates and quantitative measures of culturable and cumulative bacterial burden to show that most lung lesions are probably founded by a single bacterium and reach similar maximum burdens. Despite this observation, the fate of individual lesions varies substantially within the same host. Notably, in active disease, the host sterilizes some lesions even while others progress. Our data suggest that lesional heterogeneity arises, in part, through differential killing of bacteria after the onset of adaptive immunity. Thus, individual lesions follow diverse and overlapping trajectories, suggesting that critical responses occur at a lesional level to ultimately determine the clinical outcome of infection. Defining the local factors that dictate outcome will be useful in developing effective interventions to prevent active TB.", + "TAG_DATA": [ + "52, cynomolgus {'context': 'B-organism'}", + "53, macaques {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "52, cynomolgus ['l0']", + "53, macaques ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24317117", + "TEXT": "The molecular link between proteinuria and hyperlipidemia in nephrotic syndrome is not known. We show in the present study that plasma angiopoietin-like 4 (Angptl4) links proteinuria with hypertriglyceridemia through two negative feedback loops. In previous studies in a rat model that mimics human minimal change disease, we observed localized secretion by podocytes of hyposialylated Angptl4, a pro-proteinuric form of the protein. But in this study we noted high serum levels of Angptl4 (presumably normosialylated based on a neutral isoelectric point) in other glomerular diseases as well. Circulating Angptl4 was secreted by extrarenal organs in response to an elevated plasma ratio of free fatty acids (FFAs) to albumin when proteinuria reached nephrotic range. In a systemic feedback loop, these circulating pools of Angptl4 reduced proteinuria by interacting with glomerular endothelial αvβ5 integrin. Blocking the Angptl4-β5 integrin interaction or global knockout of Angptl4 or β5 integrin delayed recovery from peak proteinuria in animal models. But at the same time, in a local feedback loop, the elevated extrarenal pools of Angptl4 reduced tissue FFA uptake in skeletal muscle, heart and adipose tissue, subsequently resulting in hypertriglyceridemia, by inhibiting lipoprotein lipase (LPL)-mediated hydrolysis of plasma triglycerides to FFAs. Injecting recombinant human ANGPTL4 modified at a key LPL interacting site into nephrotic Buffalo Mna and Zucker Diabetic Fatty rats reduced proteinuria through the systemic loop but, by bypassing the local loop, without increasing plasma triglyceride levels. These data show that increases in circulating Angptl4 in response to nephrotic-range proteinuria reduces the degree of this pathology, but at the cost of inducing hypertriglyceridemia, while also suggesting a possible therapy to treat these linked pathologies.", + "TAG_DATA": [ + "137, global {'perturbing_action': 'B-gene loss-of-function'}", + "138, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "139, of {'perturbing_action': 'I-gene loss-of-function'}", + "140, Angptl4 {'perturbing_action': 'I-gene loss-of-function'}", + "141, or {'perturbing_action': 'I-gene loss-of-function'}", + "142, β5 {'perturbing_action': 'I-gene loss-of-function'}", + "143, integrin {'perturbing_action': 'I-gene loss-of-function'}", + "150, animal {'context': 'B-organism'}", + "151, models. {'context': 'I-organism'}", + "173, skeletal {'context': 'B-tissue/organ'}", + "174, muscle, {'context': 'I-tissue/organ'}", + "175, heart {'context': 'B-tissue/organ'}", + "177, adipose {'context': 'B-tissue/organ'}", + "178, tissue, {'context': 'I-tissue/organ'}", + "211, Diabetic {'context': 'I-organism'}", + "212, Fatty {'context': 'I-organism'}", + "213, rats {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "137, global ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "138, knockout ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "139, of ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "140, Angptl4 ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "141, or ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "142, β5 ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "143, integrin ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "150, animal ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "151, models. ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "173, skeletal ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "174, muscle, ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "175, heart ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "177, adipose ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "178, tissue, ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']", + "211, Diabetic ['l91', 'l92']", + "212, Fatty ['l91', 'l93']", + "213, rats ['l92', 'l93']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "global", + "knockout", + "of", + "Angptl4", + "or", + "β5", + "integrin" + ] + }, + "context": { + "val": "organism", + "words": [ + "animal", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "global", + "knockout", + "of", + "Angptl4", + "or", + "β5", + "integrin" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skeletal", + "muscle,", + "heart", + "adipose", + "tissue," + ] + } + } + ] + }, + { + "PMID": "24216753", + "TEXT": "Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not been developed. We report that Cre under control of the promoter of Pdgfrb (Pdgfrb-Cre) inactivates loxP-flanked genes in mouse HSCs with high efficiency. We used this system to delete the gene encoding α(v) integrin subunit because various α(v)-containing integrins have been suggested as central mediators of fibrosis in multiple organs. Such depletion protected mice from carbon tetrachloride-induced hepatic fibrosis, whereas global loss of β₃, β₅ or β₆ integrins or conditional loss of β₈ integrins in HSCs did not. We also found that Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of the α(v) integrin subunit using this system was protective in other models of organ fibrosis, including pulmonary and renal fibrosis. Pharmacological blockade of α(v)-containing integrins by a small molecule (CWHM 12) attenuated both liver and lung fibrosis, including in a therapeutic manner. These data identify a core pathway that regulates fibrosis and suggest that pharmacological targeting of all α(v) integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.", + "TAG_DATA": [ + "47, Cre {'perturbing_action': 'B-gene loss-of-function'}", + "48, under {'perturbing_action': 'I-gene gain-of-function'}", + "49, control {'perturbing_action': 'I-gene gain-of-function'}", + "50, of {'perturbing_action': 'I-gene gain-of-function'}", + "51, the {'perturbing_action': 'I-gene gain-of-function'}", + "52, promoter {'perturbing_action': 'I-gene gain-of-function'}", + "53, of {'perturbing_action': 'I-gene gain-of-function'}", + "54, Pdgfrb {'perturbing_action': 'I-gene gain-of-function'}", + "55, (Pdgfrb-Cre) {'perturbing_action': 'I-gene loss-of-function'}", + "60, mouse {'context': 'B-cells'}", + "61, HSCs {'context': 'I-cells'}", + "95, mice {'context': 'B-organism'}", + "111, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "112, loss {'perturbing_action': 'I-gene loss-of-function'}", + "113, of {'perturbing_action': 'I-gene loss-of-function'}", + "114, β₈ {'perturbing_action': 'I-gene loss-of-function'}", + "115, integrins {'perturbing_action': 'I-gene loss-of-function'}", + "117, HSCs {'context': 'B-cells'}", + "127, myofibroblasts {'context': 'B-cells'}", + "167, liver {'context': 'B-tissue/organ'}", + "168, and {'context': 'B-tissue/organ'}", + "169, lung {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "47, Cre ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "48, under ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "49, control ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "50, of ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "51, the ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "52, promoter ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "53, of ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "54, Pdgfrb ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "55, (Pdgfrb-Cre) ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "60, mouse ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63']", + "61, HSCs ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63']", + "95, mice ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62']", + "111, conditional ['l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "112, loss ['l64', 'l70', 'l71', 'l72', 'l73', 'l74']", + "113, of ['l65', 'l70', 'l75', 'l76', 'l77', 'l78']", + "114, β₈ ['l66', 'l71', 'l75', 'l79', 'l80', 'l81']", + "115, integrins ['l67', 'l72', 'l76', 'l79', 'l82', 'l83']", + "117, HSCs ['l68', 'l73', 'l77', 'l80', 'l82', 'l84']", + "127, myofibroblasts ['l69', 'l74', 'l78', 'l81', 'l83', 'l84']", + "167, liver ['l85', 'l86']", + "168, and ['l85', 'l87']", + "169, lung ['l86', 'l87']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cre", + "(Pdgfrb-Cre)", + "conditional", + "loss", + "of", + "β₈", + "integrins" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "HSCs", + "myofibroblasts" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cre", + "(Pdgfrb-Cre)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "under", + "control", + "of", + "the", + "promoter", + "Pdgfrb" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "HSCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "under", + "control", + "of", + "the", + "promoter", + "Pdgfrb" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "24202377", + "TEXT": "Neuroscience, in recent years, has started to look like a graveyard for drug development, with many large pharmaceutical companies either eliminating their brain disorder programs or cutting back heavily on such research. Novartis seemed to have made exactly this kind of drastic change two years ago when the company announced plans to shutter its neuroscience operations at its global headquarters in Basel, Switzerland. But the company made it known then that its intention was to ultimately set up a new neuroscience division at the company's US base in Cambridge, Massachusetts. The US site was initially picked to take advantage of the local academic strength in the field of psychiatric genetics. Now, it seems that Novartis is also looking to add stem cell technologies to the mix with the appointment in August of Ricardo Dolmetsch as the company's global head of neurosciences-the first new hire for the company's reincarnated division. As a professor at California's Stanford University School of Medicine for the past ten years, Dolmetsch made his name using induced pluripotent stem (iPS) cells to study a rare form of autism known as Timothy syndrome. Elie Dolgin met with Dolmetsch at the Novartis Institutes for BioMedical Research in the Technology Square area of Cambridge to discuss how he plans to succeed where so many others have failed.", + "TAG_DATA": [ + "169, induced {'context': 'B-cells'}", + "170, pluripotent {'context': 'I-cells'}", + "171, stem {'context': 'I-cells'}", + "172, (iPS) {'context': 'I-cells'}", + "173, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "169, induced ['l0', 'l1', 'l2', 'l3']", + "170, pluripotent ['l0', 'l4', 'l5', 'l6']", + "171, stem ['l1', 'l4', 'l7', 'l8']", + "172, (iPS) ['l2', 'l5', 'l7', 'l9']", + "173, cells ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24100978", + "TEXT": "After myocardial infarction (MI), circulating B cells produce the chemokine Ccl7, which mobilizes inflammatory monocytes from the bone marrow into the blood, after which they are then recruited to the injured heart, a new study shows. B cell depletion after MI limits myocardial injury and improves heart function, suggesting a new approach for the management of acute MI (pages 1273–1280).", + "TAG_DATA": [ + "36, B {'perturbing_action': 'B-gene loss-of-function'}", + "37, cell {'perturbing_action': 'I-gene loss-of-function'}", + "38, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "46, heart {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "36, B ['l0', 'l1', 'l2']", + "37, cell ['l0', 'l3', 'l4']", + "38, depletion ['l1', 'l3', 'l5']", + "46, heart ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "B", + "cell", + "depletion" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "heart" + ] + } + } + ] + }, + { + "PMID": "24100971", + "TEXT": "The Framingham Heart Study (FHS) has long been a beacon of biomedical research, yielding landmark findings on everything from the links between elevated blood pressure and stroke to the genetic risk factors underlying cardiac arrhythmias. Now, the fabled 65-year-long study of cardiovascular disease is the beacon of a more modern trend in science: tight budgets. Thanks to the automatic cuts in US government spending known as sequestration, the approximately $9-million-per-year contract the FHS receives from the US National Heart, Lung, and Blood Institute (NHLBI) was reduced by $4 million on 1 August. The renewal of the contract, scheduled for 2015, is expected to run for only two or three years, instead of the usual seven as it has been in the past. And next month, the most visible effects of the cuts will take hold, when 19 layoffs (out of a total of 90 total staff members) go into effect. Overseeing the budget-related turbulence is Daniel Levy, a medical officer at the NHLBI who joined the FHS nearly 30 years ago and has served as the study's director since 1994. Elie Dolgin met with Levy in Framingham, on the outskirts of Boston, to discuss how he's taking the new funding realities to heart.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24076664", + "TEXT": "Heterotopic ossification, the pathologic formation of extraskeletal bone, occurs as a common complication of trauma or in genetic disorders and can be disabling and lethal. However, the underlying molecular mechanisms are largely unknown. Here we demonstrate that Gαs restricts bone formation to the skeleton by inhibiting Hedgehog signaling in mesenchymal progenitor cells. In progressive osseous heteroplasia, a human disease caused by null mutations in GNAS, which encodes Gαs, Hedgehog signaling is upregulated in ectopic osteoblasts and progenitor cells. In animal models, we show that genetically-mediated ectopic Hedgehog signaling is sufficient to induce heterotopic ossification, whereas inhibition of this signaling pathway by genetic or pharmacological means strongly reduces the severity of this condition. As our previous work has shown that GNAS gain-of-function mutations upregulate WNT-β-catenin signaling in osteoblast progenitor cells, resulting in their defective differentiation and fibrous dysplasia, we identify Gαs as a key regulator of proper osteoblast differentiation through its maintenance of a balance between the Wnt-β-catenin and Hedgehog pathways. Also, given the results here of the pharmacological studies in our mouse model, we propose that Hedgehog inhibitors currently used in the clinic for other conditions, such as cancer, may possibly be repurposed for treating heterotopic ossification and other diseases caused by GNAS inactivation.", + "TAG_DATA": [ + "49, mesenchymal {'context': 'B-cells'}", + "50, progenitor {'context': 'I-cells'}", + "51, cells. {'context': 'I-cells'}", + "79, animal {'context': 'B-organism'}", + "80, models, {'context': 'I-organism'}", + "119, GNAS {'perturbing_action': 'B-gene gain-of-function'}", + "120, gain-of-function {'perturbing_action': 'I-gene gain-of-function'}", + "121, mutations {'perturbing_action': 'I-gene gain-of-function'}", + "126, osteoblast {'context': 'B-cells'}", + "127, progenitor {'context': 'I-cells'}", + "128, cells, {'context': 'I-cells'}", + "132, defective {'effect': 'B-negative'}", + "133, differentiation {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "49, mesenchymal ['l0', 'l1', 'l2', 'l3']", + "50, progenitor ['l0', 'l4', 'l5', 'l6']", + "51, cells. ['l1', 'l4', 'l7', 'l8']", + "79, animal ['l2', 'l5', 'l7', 'l9']", + "80, models, ['l3', 'l6', 'l8', 'l9']", + "119, GNAS ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "120, gain-of-function ['l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "121, mutations ['l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "126, osteoblast ['l12', 'l18', 'l23', 'l28', 'l29', 'l30', 'l31']", + "127, progenitor ['l13', 'l19', 'l24', 'l28', 'l32', 'l33', 'l34']", + "128, cells, ['l14', 'l20', 'l25', 'l29', 'l32', 'l35', 'l36']", + "132, defective ['l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l37']", + "133, differentiation ['l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GNAS", + "gain-of-function", + "mutations" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoblast", + "progenitor", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GNAS", + "gain-of-function", + "mutations" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GNAS", + "gain-of-function", + "mutations" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoblast", + "progenitor", + "cells," + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoblast", + "progenitor", + "cells," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "defective" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "24056770", + "TEXT": "In chronic kidney disease (CKD), loss of functional nephrons results in metabolic and mechanical stress in the remaining ones, resulting in further nephron loss. Here we show that Akt2 activation has an essential role in podocyte protection after nephron reduction. Glomerulosclerosis and albuminuria were substantially worsened in Akt2(-/-) but not in Akt1(-/-) mice as compared to wild-type mice. Specific deletion of Akt2 or its regulator Rictor in podocytes revealed that Akt2 has an intrinsic function in podocytes. Mechanistically, Akt2 triggers a compensatory program that involves mouse double minute 2 homolog (Mdm2), glycogen synthase kinase 3 (Gsk3) and Rac1. The defective activation of this pathway after nephron reduction leads to apoptosis and foot process effacement of the podocytes. We further show that AKT2 activation by mammalian target of rapamycin complex 2 (mTORC2) is also required for podocyte survival in human CKD. More notably, we elucidate the events underlying the adverse renal effect of sirolimus and provide a criterion for the rational use of this drug. Thus, our results disclose a new function of Akt2 and identify a potential therapeutic target for preserving glomerular function in CKD.", + "TAG_DATA": [ + "47, Akt2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "51, Akt1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "52, mice {'context': 'B-organism'}", + "57, mice. {'context': 'B-organism'}", + "58, Specific {'perturbing_action': 'B-gene loss-of-function'}", + "59, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "60, of {'perturbing_action': 'I-gene loss-of-function'}", + "61, Akt2 {'perturbing_action': 'I-gene loss-of-function'}", + "62, or {'perturbing_action': 'I-gene loss-of-function'}", + "63, its {'perturbing_action': 'I-gene loss-of-function'}", + "64, regulator {'perturbing_action': 'I-gene loss-of-function'}", + "65, Rictor {'perturbing_action': 'I-gene loss-of-function'}", + "67, podocytes {'context': 'B-cells'}", + "109, apoptosis {'phenotype': 'B-apoptosis'}", + "116, podocytes. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "47, Akt2(-/-) ['l0', 'l1']", + "51, Akt1(-/-) ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "52, mice ['l0', 'l2', 'l15']", + "57, mice. ['l3', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "58, Specific ['l4', 'l16', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "59, deletion ['l5', 'l17', 'l24', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "60, of ['l6', 'l18', 'l25', 'l34', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "61, Akt2 ['l7', 'l19', 'l26', 'l35', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "62, or ['l8', 'l20', 'l27', 'l36', 'l44', 'l51', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "63, its ['l9', 'l21', 'l28', 'l37', 'l45', 'l52', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "64, regulator ['l10', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l69', 'l70', 'l71', 'l72']", + "65, Rictor ['l11', 'l22', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l73', 'l74', 'l75']", + "67, podocytes ['l1', 'l12', 'l15', 'l23', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73']", + "109, apoptosis ['l13', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76']", + "116, podocytes. ['l14', 'l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l76']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Akt2(-/-)", + "Akt1(-/-)", + "Specific", + "deletion", + "of", + "Akt2", + "or", + "its", + "Rictor" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Akt2(-/-)", + "Akt1(-/-)", + "Specific", + "deletion", + "of", + "Akt2", + "or", + "its", + "regulator", + "Rictor" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocytes", + "podocytes." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Akt1(-/-)", + "Specific", + "deletion", + "of", + "Akt2", + "or", + "its", + "regulator", + "Rictor" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocytes." + ] + } + } + ] + }, + { + "PMID": "24037092", + "TEXT": "Neutralizing antibodies (inhibitors) to replacement factor VIII (FVIII, either plasma derived or recombinant) impair the effective management of hemophilia A. Individuals with hemophilia A due to major deletions of the FVIII gene (F8) lack antigenically cross-reactive material in their plasma (\"CRM-negative\"), and the prevalence of inhibitors in these individuals may be as high as 90%. Conversely, individuals with hemophilia A caused by F8 missense mutations are CRM-positive, and their overall prevalence of inhibitors is <10% (ref. 2). Individuals with the F8 intron 22 inversion (found in ∼50% of individuals with severe hemophilia A) have been grouped with the former on the basis of their genetic defect and CRM-negative status. However, only ∼20% of these individuals develop inhibitors. Here we demonstrate that the levels of F8 mRNA and intracellular FVIII protein in B lymphoblastoid cells and liver biopsies from individuals with the intron 22 inversion are comparable to those in healthy controls. These results support the hypothesis that most individuals with the intron 22 inversion are tolerized to FVIII and thus do not develop inhibitors. Furthermore, we developed a new pharmacogenetic algorithm that permits the stratification of inhibitor risk for individuals and subpopulations by predicting the immunogenicity of replacement FVIII using, as input, the number of putative T cell epitopes in the infused protein and the competence of major histocompatibility complex class II molecules to present such epitopes. This algorithm showed statistically significant accuracy in predicting the presence of inhibitors in 25 unrelated individuals with the intron 22 inversion.", + "TAG_DATA": [ + "131, B {'context': 'B-cells'}", + "132, lymphoblastoid {'context': 'I-cells'}", + "133, cells {'context': 'I-cells'}", + "141, intron {'perturbing_action': 'B-other'}", + "142, 22 {'perturbing_action': 'I-other'}", + "143, inversion {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "131, B ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "132, lymphoblastoid ['l0', 'l6', 'l7', 'l8', 'l9']", + "133, cells ['l1', 'l6', 'l10']", + "135, liver ['l2', 'l7', 'l10', 'l11', 'l12', 'l13']", + "141, intron ['l3', 'l11', 'l14', 'l15']", + "142, 22 ['l4', 'l8', 'l12', 'l14', 'l16']", + "143, inversion ['l5', 'l9', 'l13', 'l15', 'l16']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "B", + "lymphoblastoid" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "intron", + "22", + "inversion" + ] + } + } + ] + }, + { + "PMID": "24013744", + "TEXT": "The fibroblast growth factor 21 (FGF21)-β-Klotho pathway orchestrates a switch to oxidative metabolism during fasting and starvation and has been implicated as a signal connecting nutrition, growth, reproduction and longevity. Two new studies in mice show that Fgf21 interacts directly with the brain circadian clock to coordinate activity and reproduction as part of the adaptation to fasting.", + "TAG_DATA": [ + "34, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24013700", + "TEXT": "The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) is of global concern: the virus has caused severe respiratory illness, with 111 confirmed cases and 52 deaths at the time of this article's publication. Therapeutic interventions have not been evaluated in vivo; thus, patient management relies exclusively on supportive care, which, given the high case-fatality rate, is not highly effective. The rhesus macaque is the only known model organism for MERS-CoV infection, developing an acute localized to widespread pneumonia with transient clinical disease that recapitulates mild to moderate human MERS-CoV cases. The combination of interferon-α2b and ribavirin was effective in reducing MERS-CoV replication in vitro; therefore, we initiated this treatment 8 h after inoculation of rhesus macaques. In contrast to untreated, infected macaques, treated animals did not develop breathing abnormalities and showed no or very mild radiographic evidence of pneumonia. Moreover, treated animals showed lower levels of systemic (serum) and local (lung) proinflammatory markers, in addition to fewer viral genome copies, distinct gene expression and less severe histopathological changes in the lungs. Taken together, these data suggest that treatment of MERS-CoV infected rhesus macaques with IFN-α2b and ribavirin reduces virus replication, moderates the host response and improves clinical outcome. As these two drugs are already used in combination in the clinic for other infections, IFN-α2b and ribavirin should be considered for the management of MERS-CoV cases.", + "TAG_DATA": [ + "103, in {'context': 'B-in vitro'}", + "104, vitro; {'context': 'I-in vitro'}", + "115, rhesus {'context': 'B-organism'}", + "116, macaques. {'context': 'I-organism'}", + "122, macaques, {'context': 'B-organism'}", + "124, animals {'context': 'B-organism'}", + "142, animals {'context': 'B-organism'}", + "182, rhesus {'context': 'B-organism'}", + "183, macaques {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "103, in ['l0']", + "104, vitro; ['l0']", + "115, rhesus ['l1']", + "116, macaques. ['l1']", + "122, macaques, ['l2', 'l3']", + "124, animals ['l2']", + "142, animals ['l3']", + "182, rhesus ['l4']", + "183, macaques ['l4']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23995282", + "TEXT": "White adipose tissue displays high plasticity. We developed a system for the inducible, permanent labeling of mature adipocytes that we called the AdipoChaser mouse. We monitored adipogenesis during development, high-fat diet (HFD) feeding and cold exposure. During cold-induced 'browning' of subcutaneous fat, most 'beige' adipocytes stem from de novo-differentiated adipocytes. During HFD feeding, epididymal fat initiates adipogenesis after 4 weeks, whereas subcutaneous fat undergoes hypertrophy for a period of up to 12 weeks. Gonadal fat develops postnatally, whereas subcutaneous fat develops between embryonic days 14 and 18. Our results highlight the extensive differences in adipogenic potential in various fat depots.", + "TAG_DATA": [ + "44, adipocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23975025", + "TEXT": "Combined positron emission tomography (PET) and magnetic resonance imaging (MRI) is a new tool to study functional processes in the brain. Here we study brain function in response to a barrel-field stimulus simultaneously using PET, which traces changes in glucose metabolism on a slow time scale, and functional MRI (fMRI), which assesses fast vascular and oxygenation changes during activation. We found spatial and quantitative discrepancies between the PET and the fMRI activation data. The functional connectivity of the rat brain was assessed by both modalities: the fMRI approach determined a total of nine known neural networks, whereas the PET method identified seven glucose metabolism-related networks. These results demonstrate the feasibility of combined PET-MRI for the simultaneous study of the brain at activation and rest, revealing comprehensive and complementary information to further decode brain function and brain networks.", + "TAG_DATA": [ + "78, rat {'context': 'B-tissue/organ'}", + "79, brain {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "78, rat ['l0']", + "79, brain ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23955711", + "TEXT": "Forkhead box P3 (Foxp3)(+) T regulatory (T(reg)) cells maintain immune homeostasis and limit autoimmunity but can also curtail host immune responses to various types of tumors. Foxp3(+) T(reg) cells are therefore considered promising targets to enhance antitumor immunity, and approaches for their therapeutic modulation are being developed. However, although studies showing that experimentally depleting Foxp3(+) T(reg) cells can enhance antitumor responses provide proof of principle, these studies lack clear translational potential and have various shortcomings. Histone/protein acetyltransferases (HATs) promote chromatin accessibility, gene transcription and the function of multiple transcription factors and nonhistone proteins. We now report that conditional deletion or pharmacologic inhibition of one HAT, p300 (also known as Ep300 or KAT3B), in Foxp3(+) T(reg) cells increased T cell receptor-induced apoptosis in T(reg) cells, impaired T(reg) cell suppressive function and peripheral T(reg) cell induction, and limited tumor growth in immunocompetent but not in immunodeficient mice. Our data thereby demonstrate that p300 is important for Foxp3(+) T(reg) cell function and homeostasis in vivo and in vitro, and identify mechanisms by which appropriate small-molecule inhibitors can diminish T(reg) cell function without overtly impairing T effector cell responses or inducing autoimmunity. Collectively, these data suggest a new approach for cancer immunotherapy.", + "TAG_DATA": [ + "100, pharmacologic {'perturbing_action': 'B-pharmacological inhibition'}", + "101, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "102, of {'perturbing_action': 'I-pharmacological inhibition'}", + "103, one {'perturbing_action': 'I-pharmacological inhibition'}", + "104, HAT, {'perturbing_action': 'I-pharmacological inhibition'}", + "105, p300 {'perturbing_action': 'I-pharmacological inhibition'}", + "106, (also {'perturbing_action': 'I-pharmacological inhibition'}", + "111, KAT3B), {'perturbing_action': 'I-pharmacological inhibition'}", + "113, Foxp3(+) {'context': 'B-cells'}", + "114, T(reg) {'context': 'I-cells'}", + "115, cells {'context': 'I-cells'}", + "116, increased {'effect': 'B-positive'}", + "118, cell {'effect': 'B-positive'}", + "119, receptor-induced {'effect': 'B-positive'}", + "120, apoptosis {'phenotype': 'B-apoptosis'}", + "122, T(reg) {'context': 'B-cells'}", + "123, cells, {'context': 'I-cells'}", + "125, T(reg) {'context': 'B-cells'}", + "130, peripheral {'context': 'B-cells'}", + "131, T(reg) {'context': 'I-cells'}", + "132, cell {'context': 'I-cells'}", + "135, limited {'effect': 'B-negative'}", + "136, tumor {'phenotype': 'B-tumour growth'}", + "137, growth {'phenotype': 'I-tumour growth'}", + "139, immunocompetent {'context': 'B-organism'}", + "143, immunodeficient {'context': 'B-organism'}", + "144, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "100, pharmacologic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "101, inhibition ['l0', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "102, of ['l1', 'l28', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "103, one ['l2', 'l29', 'l55', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "104, HAT, ['l3', 'l30', 'l56', 'l81', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127']", + "105, p300 ['l4', 'l31', 'l57', 'l82', 'l105', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "106, (also ['l5', 'l32', 'l58', 'l83', 'l106', 'l128', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170']", + "109, Ep300 ['l6', 'l33', 'l59', 'l84', 'l107', 'l129', 'l150', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190']", + "111, KAT3B), ['l7', 'l34', 'l60', 'l85', 'l108', 'l130', 'l151', 'l171', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209']", + "113, Foxp3(+) ['l8', 'l35', 'l61', 'l86', 'l109', 'l131', 'l152', 'l172', 'l191', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220']", + "114, T(reg) ['l9', 'l36', 'l62', 'l87', 'l110', 'l132', 'l153', 'l173', 'l192', 'l210', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230']", + "115, cells ['l10', 'l37', 'l63', 'l88', 'l111', 'l133', 'l154', 'l174', 'l193', 'l211', 'l221', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237']", + "116, increased ['l11', 'l38', 'l64', 'l89', 'l112', 'l134', 'l155', 'l175', 'l194', 'l212', 'l222', 'l231', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243']", + "117, T ['l12', 'l39', 'l65', 'l90', 'l113', 'l135', 'l156', 'l176', 'l195', 'l213', 'l223', 'l232', 'l238', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249']", + "118, cell ['l13', 'l40', 'l66', 'l91', 'l114', 'l136', 'l157', 'l177', 'l196', 'l214', 'l224', 'l233', 'l239', 'l244', 'l250', 'l251', 'l252', 'l253', 'l254']", + "119, receptor-induced ['l14', 'l41', 'l67', 'l92', 'l115', 'l137', 'l158', 'l178', 'l197', 'l215', 'l225', 'l234', 'l240', 'l245', 'l250', 'l255', 'l256', 'l257', 'l258']", + "120, apoptosis ['l15', 'l42', 'l68', 'l93', 'l116', 'l138', 'l159', 'l179', 'l198', 'l216', 'l226', 'l235', 'l241', 'l246', 'l251', 'l255', 'l259', 'l260', 'l261']", + "122, T(reg) ['l16', 'l43', 'l69', 'l94', 'l117', 'l139', 'l160', 'l180', 'l199', 'l217', 'l227', 'l236', 'l242', 'l247', 'l252', 'l256', 'l259', 'l262', 'l263', 'l264']", + "123, cells, ['l17', 'l44', 'l70', 'l95', 'l118', 'l140', 'l161', 'l181', 'l200', 'l218', 'l228', 'l237', 'l243', 'l248', 'l253', 'l257', 'l260', 'l262']", + "125, T(reg) ['l18', 'l45', 'l71', 'l96', 'l119', 'l141', 'l162', 'l182', 'l201', 'l219', 'l229', 'l249', 'l254', 'l258', 'l261', 'l263', 'l265', 'l266', 'l267']", + "130, peripheral ['l19', 'l46', 'l72', 'l97', 'l120', 'l142', 'l163', 'l183', 'l202', 'l265', 'l268', 'l269', 'l270', 'l271']", + "131, T(reg) ['l20', 'l47', 'l73', 'l98', 'l121', 'l143', 'l164', 'l184', 'l203', 'l266', 'l268', 'l272', 'l273', 'l274']", + "132, cell ['l21', 'l48', 'l74', 'l99', 'l122', 'l144', 'l165', 'l185', 'l204', 'l220', 'l230', 'l264', 'l267', 'l269', 'l272']", + "135, limited ['l22', 'l49', 'l75', 'l100', 'l123', 'l145', 'l166', 'l186', 'l205', 'l270', 'l273', 'l275', 'l276', 'l277', 'l278', 'l279']", + "136, tumor ['l23', 'l50', 'l76', 'l101', 'l124', 'l146', 'l167', 'l187', 'l206', 'l275', 'l280', 'l281', 'l282', 'l283']", + "137, growth ['l24', 'l51', 'l77', 'l102', 'l125', 'l147', 'l168', 'l188', 'l207', 'l271', 'l274', 'l276', 'l280', 'l284', 'l285']", + "139, immunocompetent ['l25', 'l52', 'l78', 'l103', 'l126', 'l148', 'l169', 'l189', 'l208', 'l277', 'l281', 'l284', 'l286', 'l287']", + "143, immunodeficient ['l26', 'l53', 'l79', 'l278', 'l282', 'l286', 'l288']", + "144, mice. ['l27', 'l54', 'l80', 'l104', 'l127', 'l149', 'l170', 'l190', 'l209', 'l279', 'l283', 'l285', 'l287', 'l288']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "one", + "HAT,", + "p300", + "(also", + "KAT3B)," + ] + }, + "context": { + "val": "cells", + "words": [ + "Foxp3(+)", + "T(reg)", + "cells", + "cells,", + "peripheral", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "one", + "HAT,", + "p300", + "(also", + "KAT3B)," + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "cell", + "receptor-induced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "one", + "HAT,", + "p300", + "(also", + "KAT3B)," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "one", + "HAT,", + "p300", + "(also", + "KAT3B)," + ] + }, + "effect": { + "val": "negative", + "words": [ + "limited" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "one", + "HAT,", + "p300", + "(also", + "KAT3B)," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "one", + "HAT,", + "p300", + "(also", + "KAT3B)," + ] + }, + "context": { + "val": "organism", + "words": [ + "immunocompetent", + "immunodeficient", + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Foxp3(+)", + "T(reg)", + "cells", + "cells," + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "cell", + "receptor-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Foxp3(+)", + "T(reg)", + "cells", + "cells," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased", + "cell", + "receptor-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "peripheral", + "T(reg)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "limited" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "peripheral", + "T(reg)" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limited" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limited" + ] + }, + "context": { + "val": "organism", + "words": [ + "immunocompetent", + "immunodeficient", + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "immunocompetent", + "immunodeficient", + "mice." + ] + } + } + ] + }, + { + "PMID": "23933984", + "TEXT": "Fibroblast growth factor 21 (FGF21) is a hepatokine that acts as a global starvation signal to modulate fuel partitioning and metabolism and repress growth; however, the site of action of these diverse effects remains unclear. FGF21 signals through a heteromeric cell-surface receptor composed of one of three FGF receptors (FGFR1c, FGFR2c or FGFR3c) in complex with β-Klotho, a single-pass transmembrane protein that is enriched in metabolic tissues. Here we show that in addition to its known effects on peripheral metabolism, FGF21 increases systemic glucocorticoid levels, suppresses physical activity and alters circadian behavior, which are all features of the adaptive starvation response. These effects are mediated through β-Klotho expression in the suprachiasmatic nucleus of the hypothalamus and the dorsal vagal complex of the hindbrain. Mice lacking the gene encoding β-Klotho (Klb) in these regions are refractory to these effects, as well as those on metabolism, insulin and growth. These findings demonstrate a crucial role for the nervous system in mediating the diverse physiologic and pharmacologic actions of FGF21.", + "TAG_DATA": [ + "123, Mice {'context': 'B-organism'}", + "124, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "125, the {'perturbing_action': 'I-gene loss-of-function'}", + "126, gene {'perturbing_action': 'I-gene loss-of-function'}", + "127, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "128, β-Klotho {'perturbing_action': 'I-gene loss-of-function'}", + "129, (Klb) {'perturbing_action': 'I-gene loss-of-function'}", + "130, in {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "123, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "124, lacking ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "125, the ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "126, gene ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "127, encoding ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "128, β-Klotho ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "129, (Klb) ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "130, in ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "gene", + "encoding", + "β-Klotho", + "(Klb)", + "in" + ] + } + } + ] + }, + { + "PMID": "23933982", + "TEXT": "During the inflammatory response that drives atherogenesis, macrophages accumulate progressively in the expanding arterial wall. The observation that circulating monocytes give rise to lesional macrophages has reinforced the concept that monocyte infiltration dictates macrophage buildup. Recent work has indicated, however, that macrophage accumulation does not depend on monocyte recruitment in some inflammatory contexts. We therefore revisited the mechanism underlying macrophage accumulation in atherosclerosis. In murine atherosclerotic lesions, we found that macrophages turn over rapidly, after 4 weeks. Replenishment of macrophages in these experimental atheromata depends predominantly on local macrophage proliferation rather than monocyte influx. The microenvironment orchestrates macrophage proliferation through the involvement of scavenger receptor A (SR-A). Our study reveals macrophage proliferation as a key event in atherosclerosis and identifies macrophage self-renewal as a therapeutic target for cardiovascular disease.", + "TAG_DATA": [ + "70, macrophages {'context': 'B-cells'}", + "79, macrophages {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23933981", + "TEXT": "The blood-brain barrier (BBB) is an integral part of the neurovascular unit (NVU). The NVU is comprised of endothelial cells that are interconnected by tight junctions resting on a parenchymal basement membrane ensheathed by pericytes, smooth muscle cells and a layer of astrocyte end feet. Circulating blood cells, such as leukocytes, complete the NVU. BBB disruption is common in several neurological diseases, but the molecular mechanisms involved remain largely unknown. We analyzed the role of TWIK-related potassium channel-1 (TREK1, encoded by KCNK2) in human and mouse endothelial cells and the BBB. TREK1 was downregulated in endothelial cells by treatment with interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). Blocking TREK1 increased leukocyte transmigration, whereas TREK1 activation had the opposite effect. We identified altered mitogen-activated protein (MAP) kinase signaling, actin remodeling and upregulation of cellular adhesion molecules as potential mechanisms of increased migration in TREK1-deficient (Kcnk2(-/-)) cells. In Kcnk2(-/-) mice, brain endothelial cells showed an upregulation of the cellular adhesion molecules ICAM1, VCAM1 and PECAM1 and facilitated leukocyte trafficking into the CNS. Following the induction of experimental autoimmune encephalomyelitis (EAE) by immunization with a myelin oligodendrocyte protein (MOG)35-55 peptide, Kcnk2(-/-) mice showed higher EAE severity scores that were accompanied by increased cellular infiltrates in the central nervous system (CNS). The severity of EAE was attenuated in mice given the amyotrophic lateral sclerosis drug riluzole or fed a diet enriched with linseed oil (which contains the TREK-1 activating omega-3 fatty acid α-linolenic acid). These beneficial effects were reduced in Kcnk2(-/-) mice, suggesting TREK-1", + "TAG_DATA": [ + "95, endothelial {'context': 'B-cells'}", + "96, cells {'context': 'I-cells'}", + "107, Blocking {'perturbing_action': 'B-pharmacological inhibition'}", + "108, TREK1 {'perturbing_action': 'I-pharmacological inhibition'}", + "110, leukocyte {'context': 'B-cells'}", + "113, TREK1 {'perturbing_action': 'B-pharmacological augmentation'}", + "114, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "139, increased {'effect': 'B-positive'}", + "140, migration {'phenotype': 'B-migration'}", + "142, TREK1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "143, (Kcnk2(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "144, cells. {'context': 'B-cells'}", + "146, Kcnk2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "147, mice, {'context': 'B-organism'}", + "148, brain {'context': 'B-cells'}", + "149, endothelial {'context': 'I-cells'}", + "150, cells {'context': 'I-cells'}", + "187, Kcnk2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "188, mice {'context': 'B-organism'}", + "214, mice {'context': 'B-organism'}", + "246, Kcnk2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "247, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "95, endothelial ['l0', 'l1']", + "96, cells ['l0', 'l2']", + "107, Blocking ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "108, TREK1 ['l3', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "110, leukocyte ['l1', 'l2', 'l4', 'l14', 'l23', 'l24', 'l25']", + "113, TREK1 ['l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "114, activation ['l5', 'l26', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "139, increased ['l6', 'l15', 'l23', 'l27', 'l37', 'l47', 'l48', 'l49', 'l50']", + "140, migration ['l7', 'l16', 'l24', 'l28', 'l38', 'l47', 'l51', 'l52', 'l53']", + "142, TREK1-deficient ['l8', 'l17', 'l29', 'l39', 'l48', 'l51', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "143, (Kcnk2(-/-)) ['l9', 'l18', 'l30', 'l40', 'l49', 'l52', 'l54', 'l60', 'l61', 'l62']", + "144, cells. ['l10', 'l19', 'l25', 'l31', 'l41', 'l50', 'l53', 'l55', 'l60']", + "146, Kcnk2(-/-) ['l32', 'l42', 'l63', 'l64', 'l65', 'l66']", + "147, mice, ['l11', 'l20', 'l33', 'l43', 'l56', 'l61', 'l63', 'l67', 'l68', 'l69']", + "148, brain ['l34', 'l44', 'l57', 'l64', 'l67', 'l70', 'l71']", + "149, endothelial ['l12', 'l21', 'l35', 'l45', 'l58', 'l65', 'l68', 'l70', 'l72']", + "150, cells ['l13', 'l22', 'l36', 'l46', 'l59', 'l62', 'l66', 'l69', 'l71', 'l72']", + "187, Kcnk2(-/-) ['l73']", + "188, mice ['l73']", + "214, mice ['l74', 'l75']", + "246, Kcnk2(-/-) ['l74', 'l76']", + "247, mice, ['l75', 'l76']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blocking", + "TREK1" + ] + }, + "context": { + "val": "cells", + "words": [ + "leukocyte", + "cells.", + "endothelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blocking", + "TREK1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blocking", + "TREK1" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blocking", + "TREK1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "leukocyte", + "cells." + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "leukocyte", + "cells." + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "TREK1", + "activation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "TREK1", + "activation" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "TREK1", + "activation" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells.", + "brain", + "endothelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "TREK1", + "activation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TREK1-deficient", + "(Kcnk2(-/-))" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TREK1-deficient", + "(Kcnk2(-/-))" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TREK1-deficient", + "(Kcnk2(-/-))", + "Kcnk2(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells.", + "brain", + "endothelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TREK1-deficient", + "(Kcnk2(-/-))", + "Kcnk2(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + } + ] + }, + { + "PMID": "23913125", + "TEXT": "Mitochondrial diseases are commonly caused by mutated mitochondrial DNA (mtDNA), which in most cases coexists with wild-type mtDNA, resulting in mtDNA heteroplasmy. We have engineered transcription activator-like effector nucleases (TALENs) to localize to mitochondria and cleave different classes of pathogenic mtDNA mutations. Mitochondria-targeted TALEN (mitoTALEN) expression led to permanent reductions in deletion or point-mutant mtDNA in patient-derived cells, raising the possibility that these mitochondrial nucleases can be therapeutic for some mitochondrial diseases.", + "TAG_DATA": [ + "42, Mitochondria-targeted {'perturbing_action': 'B-gene gain-of-function'}", + "43, TALEN {'perturbing_action': 'I-gene gain-of-function'}", + "44, (mitoTALEN) {'perturbing_action': 'I-gene gain-of-function'}", + "45, expression {'perturbing_action': 'I-gene gain-of-function'}", + "56, patient-derived {'context': 'B-cells'}", + "57, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "42, Mitochondria-targeted ['l0', 'l1', 'l2', 'l3', 'l4']", + "43, TALEN ['l0', 'l5', 'l6', 'l7', 'l8']", + "44, (mitoTALEN) ['l1', 'l5', 'l9', 'l10', 'l11']", + "45, expression ['l2', 'l6', 'l9', 'l12', 'l13']", + "56, patient-derived ['l3', 'l7', 'l10', 'l12', 'l14']", + "57, cells, ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Mitochondria-targeted", + "TALEN", + "(mitoTALEN)", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "patient-derived", + "cells," + ] + } + } + ] + }, + { + "PMID": "23913124", + "TEXT": "Although angiogenesis inhibitors have provided substantial clinical benefit as cancer therapeutics, their use is limited by resistance to their therapeutic effects. While ample evidence indicates that such resistance can be influenced by the tumor microenvironment, the underlying mechanisms remain incompletely understood. Here, we have uncovered a paracrine signaling network between the adaptive and innate immune systems that is associated with resistance in multiple tumor models: lymphoma, lung and colon. Tumor-infiltrating T helper type 17 (T(H)17) cells and interleukin-17 (IL-17) induced the expression of granulocyte colony-stimulating factor (G-CSF) through nuclear factor κB (NF-κB) and extracellular-related kinase (ERK) signaling, leading to immature myeloid-cell mobilization and recruitment into the tumor microenvironment. The occurrence of T(H)17 cells and Bv8-positive granulocytes was also observed in clinical tumor specimens. Tumors resistant to treatment with antibodies to VEGF were rendered sensitive in IL-17 receptor (IL-17R)-knockout hosts deficient in T(H)17 effector function. Furthermore, pharmacological blockade of T(H)17 cell function sensitized resistant tumors to therapy with antibodies to VEGF. These findings indicate that IL-17 promotes tumor resistance to VEGF inhibition, suggesting that immunomodulatory strategies could improve the efficacy of anti-angiogenic therapy.", + "TAG_DATA": [ + "123, Tumors {'context': 'B-neoplasm'}", + "135, IL-17 {'perturbing_action': 'B-gene loss-of-function'}", + "136, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "137, (IL-17R)-knockout {'perturbing_action': 'I-gene loss-of-function'}", + "148, T(H)17 {'context': 'B-cells'}", + "149, cell {'context': 'I-cells'}", + "153, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "123, Tumors ['l0', 'l1', 'l2']", + "135, IL-17 ['l0', 'l3', 'l4']", + "136, receptor ['l1', 'l3', 'l5', 'l6']", + "137, (IL-17R)-knockout ['l2', 'l4', 'l5']", + "148, T(H)17 ['l7', 'l8', 'l9']", + "149, cell ['l7', 'l10', 'l11']", + "150, function ['l8', 'l10', 'l12']", + "153, tumors ['l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "Tumors", + "tumors" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IL-17", + "receptor", + "(IL-17R)-knockout" + ] + } + } + ] + }, + { + "PMID": "23852340", + "TEXT": "Huntington's disease is caused by an expanded polyglutamine repeat in the huntingtin protein (HTT), but the pathophysiological sequence of events that trigger synaptic failure and neuronal loss are not fully understood. Alterations in N-methyl-D-aspartate (NMDA)-type glutamate receptors (NMDARs) have been implicated. Yet, it remains unclear how the HTT mutation affects NMDAR function, and direct evidence for a causative role is missing. Here we show that mutant HTT redirects an intracellular store of juvenile NMDARs containing GluN3A subunits to the surface of striatal neurons by sequestering and disrupting the subcellular localization of the endocytic adaptor PACSIN1, which is specific for GluN3A. Overexpressing GluN3A in wild-type mouse striatum mimicked the synapse loss observed in Huntington's disease mouse models, whereas genetic deletion of GluN3A prevented synapse degeneration, ameliorated motor and cognitive decline and reduced striatal atrophy and neuronal loss in the YAC128 Huntington's disease mouse model. Furthermore, GluN3A deletion corrected the abnormally enhanced NMDAR currents, which have been linked to cell death in Huntington's disease and other neurodegenerative conditions. Our findings reveal an early pathogenic role of GluN3A dysregulation in Huntington's disease and suggest that therapies targeting GluN3A or pathogenic HTT-PACSIN1 interactions might prevent or delay disease progression.", + "TAG_DATA": [ + "100, Overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "101, GluN3A {'perturbing_action': 'I-gene gain-of-function'}", + "104, mouse {'context': 'B-tissue/organ'}", + "105, striatum {'context': 'I-tissue/organ'}", + "115, models, {'context': 'I-organism'}", + "117, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "118, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "119, of {'perturbing_action': 'I-gene loss-of-function'}", + "120, GluN3A {'perturbing_action': 'I-gene loss-of-function'}", + "140, disease {'context': 'I-organism'}", + "141, mouse {'context': 'I-organism'}", + "142, model. {'context': 'I-organism'}", + "144, GluN3A {'perturbing_action': 'B-gene loss-of-function'}", + "145, deletion {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "100, Overexpressing ['l0', 'l1', 'l2', 'l3']", + "101, GluN3A ['l0', 'l4', 'l5', 'l6']", + "104, mouse ['l1', 'l4', 'l7', 'l8']", + "105, striatum ['l2', 'l5', 'l7', 'l9']", + "115, models, ['l3', 'l6', 'l8', 'l9']", + "117, genetic ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "118, deletion ['l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "119, of ['l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "120, GluN3A ['l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "140, disease ['l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "141, mouse ['l14', 'l19', 'l23', 'l26', 'l28', 'l30']", + "142, model. ['l15', 'l20', 'l24', 'l27', 'l29', 'l30']", + "144, GluN3A ['l31']", + "145, deletion ['l31']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpressing", + "GluN3A" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "striatum" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpressing", + "GluN3A" + ] + }, + "context": { + "val": "organism", + "words": [ + "models," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "GluN3A" + ] + }, + "context": { + "val": "organism", + "words": [ + "disease", + "mouse", + "model." + ] + } + } + ] + }, + { + "PMID": "23852339", + "TEXT": "The nuclear receptor Rev-erb-α modulates hepatic lipid and glucose metabolism, adipogenesis and the inflammatory response in macrophages. We show here that Rev-erb-α is highly expressed in oxidative skeletal muscle and that its deficiency in muscle leads to reduced mitochondrial content and oxidative function, as well as upregulation of autophagy. These cellular effects resulted in both impaired mitochondrial biogenesis and increased clearance of this organelle, leading to compromised exercise capacity. On a molecular level, Rev-erb-α deficiency resulted in deactivation of the Lkb1-Ampk-Sirt1-Ppargc-1α signaling pathway. These effects were recapitulated in isolated fibers and in muscle cells after knockdown of the gene encoding Rev-erb-α, Nr1d1. In complementary experiments, Rev-erb-α overexpression in vitro increased the number of mitochondria and improved respiratory capacity, whereas muscle overexpression or pharmacological activation of Rev-erb-α in vivo increased exercise capacity. This study identifies Rev-erb-α as a pharmacological target that improves muscle oxidative function by modulating gene networks controlling mitochondrial number and function.", + "TAG_DATA": [ + "73, Rev-erb-α {'perturbing_action': 'B-gene loss-of-function'}", + "74, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "89, fibers {'context': 'B-cells'}", + "92, muscle {'context': 'B-cells'}", + "93, cells {'context': 'I-cells'}", + "95, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "96, of {'perturbing_action': 'I-rnai/knockdown'}", + "97, the {'perturbing_action': 'I-rnai/knockdown'}", + "98, gene {'perturbing_action': 'I-rnai/knockdown'}", + "99, encoding {'perturbing_action': 'I-rnai/knockdown'}", + "100, Rev-erb-α, {'perturbing_action': 'I-rnai/knockdown'}", + "101, Nr1d1. {'perturbing_action': 'I-rnai/knockdown'}", + "105, Rev-erb-α {'perturbing_action': 'B-gene gain-of-function'}", + "106, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "107, in {'context': 'B-in vitro'}", + "108, vitro {'context': 'I-in vitro'}", + "119, muscle {'perturbing_action': 'B-gene gain-of-function'}", + "120, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "122, pharmacological {'perturbing_action': 'B-pharmacological augmentation'}", + "123, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "124, of {'perturbing_action': 'I-pharmacological augmentation'}", + "125, Rev-erb-α {'perturbing_action': 'I-pharmacological augmentation'}", + "126, in {'context': 'B-in vivo'}", + "127, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "73, Rev-erb-α ['l0', 'l1', 'l2']", + "74, deficiency ['l0', 'l3']", + "89, fibers ['l1', 'l3']", + "92, muscle ['l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "93, cells ['l2', 'l4', 'l11']", + "95, knockdown ['l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "96, of ['l5', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "97, the ['l6', 'l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "98, gene ['l7', 'l14', 'l23', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "99, encoding ['l8', 'l15', 'l24', 'l32', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "100, Rev-erb-α, ['l9', 'l16', 'l25', 'l33', 'l40', 'l46', 'l52', 'l53', 'l54', 'l55', 'l56']", + "101, Nr1d1. ['l10', 'l11', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l57', 'l58', 'l59', 'l60']", + "105, Rev-erb-α ['l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l61', 'l62', 'l63']", + "106, overexpression ['l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l64', 'l65']", + "107, in ['l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l66']", + "108, vitro ['l21', 'l30', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l65', 'l66']", + "119, muscle ['l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "120, overexpression ['l67', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "122, pharmacological ['l68', 'l74', 'l80', 'l81', 'l82', 'l83', 'l84']", + "123, activation ['l69', 'l75', 'l80', 'l85', 'l86', 'l87', 'l88']", + "124, of ['l70', 'l76', 'l81', 'l85', 'l89', 'l90', 'l91']", + "125, Rev-erb-α ['l71', 'l77', 'l82', 'l86', 'l89', 'l92', 'l93']", + "126, in ['l72', 'l78', 'l83', 'l87', 'l90', 'l92', 'l94']", + "127, vivo ['l73', 'l79', 'l84', 'l88', 'l91', 'l93', 'l94']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rev-erb-α", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "fibers", + "cells" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "muscle", + "cells" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "the", + "gene", + "encoding", + "Rev-erb-α,", + "Nr1d1." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "the", + "gene", + "encoding", + "Rev-erb-α,", + "Nr1d1." + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Rev-erb-α", + "overexpression" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "muscle", + "overexpression" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "pharmacological", + "activation", + "of", + "Rev-erb-α" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "23836199", + "TEXT": "Public health and research efforts directed at managing and targeting viral hepatitis have borne fruit in recent decades. However, more work is necessary to meet the goals of preventing transmission and treating infection to eliminate the enormous burden of hepatitis worldwide.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23832089", + "TEXT": "Increased hepatic lipid content is an early correlate of insulin resistance and can be caused by nutrient-induced activation of mammalian target of rapamycin (mTor). This activation of mTor increases basal Akt activity, leading to a self-perpetuating lipogenic cycle. We have previously shown that the developmental Notch pathway has metabolic functions in adult mouse liver. Acute or chronic inhibition of Notch dampens hepatic glucose production and increases Akt activity and may therefore be predicted to increase hepatic lipid content. Here we now show that constitutive liver-specific ablation of Notch signaling, or its acute inhibition with a decoy Notch1 receptor, prevents hepatosteatosis by blocking mTor complex 1 (mTorc1) activity. Conversely, Notch gain of function causes fatty liver through constitutive activation of mTorc1, an effect that is reversible by treatment with rapamycin. We demonstrate that Notch signaling increases mTorc1 complex stability, augmenting mTorc1 function and sterol regulatory element binding transcription factor 1c (Srebp1c)-mediated lipogenesis. These data identify Notch as a therapeutically actionable branch point of metabolic signaling at which Akt activation in the liver can be uncoupled from hepatosteatosis.", + "TAG_DATA": [ + "83, constitutive {'perturbing_action': 'B-gene loss-of-function'}", + "84, liver-specific {'perturbing_action': 'I-gene loss-of-function'}", + "85, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "86, of {'perturbing_action': 'I-gene loss-of-function'}", + "87, Notch {'perturbing_action': 'I-gene loss-of-function'}", + "88, signaling, {'perturbing_action': 'I-gene loss-of-function'}", + "96, Notch1 {'perturbing_action': 'I-rnai/knockdown'}", + "108, Notch {'perturbing_action': 'B-gene gain-of-function'}", + "109, gain {'perturbing_action': 'I-gene gain-of-function'}", + "110, of {'perturbing_action': 'I-gene gain-of-function'}", + "111, function {'perturbing_action': 'I-gene gain-of-function'}", + "113, fatty {'context': 'B-tissue/organ'}", + "114, liver {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "83, constitutive ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "84, liver-specific ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "85, ablation ['l1', 'l7', 'l12', 'l13', 'l14']", + "86, of ['l2', 'l8', 'l12', 'l15', 'l16']", + "87, Notch ['l3', 'l9', 'l13', 'l15', 'l17']", + "88, signaling, ['l4', 'l10', 'l14', 'l16', 'l17']", + "96, Notch1 ['l5', 'l18', 'l19', 'l20']", + "97, receptor, ['l6', 'l11', 'l18', 'l21', 'l22']", + "108, Notch ['l23', 'l24', 'l25', 'l26', 'l27']", + "109, gain ['l23', 'l28', 'l29', 'l30', 'l31']", + "110, of ['l24', 'l28', 'l32', 'l33', 'l34']", + "111, function ['l25', 'l29', 'l32', 'l35', 'l36']", + "113, fatty ['l19', 'l21', 'l26', 'l30', 'l33', 'l35', 'l37']", + "114, liver ['l20', 'l22', 'l27', 'l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Notch1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "fatty", + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Notch", + "gain", + "of", + "function" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "fatty", + "liver" + ] + } + } + ] + }, + { + "PMID": "23749231", + "TEXT": "Hyperlipidemia is a risk factor for various cardiovascular and metabolic disorders. Overproduction of lipoproteins, a process that is dependent on microsomal triglyceride transfer protein (MTP), can contribute to hyperlipidemia. We show that microRNA-30c (miR-30c) interacts with the 3' untranslated region of MTP mRNA and induces its degradation, leading to reductions in MTP activity and in apolipoprotein B (APOB) secretion. miR-30c also reduces lipid synthesis independently of MTP. Hepatic overexpression of miR-30c reduced hyperlipidemia in Western diet-fed mice by decreasing lipid synthesis and the secretion of triglyceride-rich ApoB-containing lipoproteins and decreased atherosclerosis in Apoe(-/-) mice. Furthermore, inhibition of hepatic miR-30c by anti-miR-30c increased hyperlipidemia and atherosclerosis. Therefore, miR-30c coordinately reduces lipid biosynthesis and lipoprotein secretion, thereby regulating hepatic and plasma lipid concentrations. Raising miR-30c levels might be useful in treating hyperlipidemias and associated disorders.", + "TAG_DATA": [ + "67, Hepatic {'perturbing_action': 'B-gene gain-of-function'}", + "68, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "69, of {'perturbing_action': 'I-gene gain-of-function'}", + "70, miR-30c {'perturbing_action': 'I-gene gain-of-function'}", + "76, mice {'context': 'B-organism'}", + "89, decreased {'effect': 'B-negative'}", + "92, Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "93, mice. {'context': 'B-organism'}", + "95, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "96, of {'perturbing_action': 'I-pharmacological inhibition'}", + "97, hepatic {'perturbing_action': 'I-pharmacological inhibition'}", + "98, miR-30c {'perturbing_action': 'I-pharmacological inhibition'}", + "99, by {'perturbing_action': 'I-pharmacological inhibition'}", + "100, anti-miR-30c {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "67, Hepatic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "68, overexpression ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "69, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "70, miR-30c ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "76, mice ['l3', 'l10', 'l16', 'l21']", + "89, decreased ['l4', 'l11', 'l17', 'l22', 'l26', 'l27', 'l28']", + "90, atherosclerosis ['l5', 'l12', 'l18', 'l23', 'l26', 'l29', 'l30']", + "92, Apoe(-/-) ['l6', 'l13', 'l19', 'l24', 'l27', 'l29', 'l31']", + "93, mice. ['l7', 'l14', 'l20', 'l25', 'l28', 'l30', 'l31']", + "95, inhibition ['l32', 'l33', 'l34', 'l35', 'l36']", + "96, of ['l32', 'l37', 'l38', 'l39', 'l40']", + "97, hepatic ['l33', 'l37', 'l41', 'l42', 'l43']", + "98, miR-30c ['l34', 'l38', 'l41', 'l44', 'l45']", + "99, by ['l35', 'l39', 'l42', 'l44', 'l46']", + "100, anti-miR-30c ['l36', 'l40', 'l43', 'l45', 'l46']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Hepatic", + "overexpression", + "of", + "miR-30c" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Hepatic", + "overexpression", + "of", + "miR-30c" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apoe(-/-)" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apoe(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "23744148", + "TEXT": "Using brain surgery, specific areas in the brain can be stimulated with electrical impulses to reversibly change their activity and alleviate symptoms related to mental illnesses. This so-called deep brain stimulation and other methodological advances that even more selectively activate specific groups of neurons can give us clues as to what neural circuitry is involved in a particular mental disorder and whether therapeutic activation of these brain areas and neurons may be effective. In \"Bedside to Bench\", Eric Nestler discusses two trials of individuals with anorexia nervosa in which deep brain stimulation of different brain areas resulted in improvement of behavioral domains associated with the syndrome. The results and potential of this technique in animals and humans may bring us closer to understanding the neurobiology of anorexia nervosa, which still remains a mystery and poses a challenge for treatment. In \"Bench to Bedside\", Jennifer Warner-Schmidt peruses recent findings that uncover the functional connectivity of brain regions involved in depression and how activation of cortical regions can result in antidepressant effects that can compensate for the malfunction of other brain circuits that results in depression.", + "TAG_DATA": [ + "83, individuals {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "83, individuals ['l0', 'l1']", + "85, anorexia ['l0', 'l2']", + "86, nervosa ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23708292", + "TEXT": "Hepatitis C virus (HCV) interacts extensively with host factors to not only establish productive infection but also trigger unique pathological processes. Our recent genome-wide siRNA screen demonstrated that IκB kinase-α (IKK-α) is a crucial host factor for HCV. Here we describe a new nuclear factor κB (NF-κB)-independent and kinase-mediated nuclear function of IKK-α in HCV assembly. HCV, through its 3' untranslated region, interacts with DEAD box polypeptide 3, X-linked (DDX3X) to activate IKK-α, which translocates to the nucleus and induces a CBP/p300-mediated transcriptional program involving sterol regulatory element-binding proteins (SREBPs). This innate pathway induces lipogenic genes and enhances core-associated lipid droplet formation to facilitate viral assembly. Chemical inhibitors of IKK-α suppress HCV infection and IKK-α-induced lipogenesis, offering a proof-of-concept approach for new HCV therapeutic development. Our results show that HCV uses a novel mechanism to exploit intrinsic innate responses and hijack lipid metabolism, which may contribute to high chronicity rates and the pathological hallmark of steatosis in HCV infection.", + "TAG_DATA": [ + "106, Chemical {'perturbing_action': 'B-pharmacological inhibition'}", + "107, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "108, of {'perturbing_action': 'I-pharmacological inhibition'}", + "109, IKK-α {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "106, Chemical ['l0', 'l1', 'l2']", + "107, inhibitors ['l0', 'l3', 'l4']", + "108, of ['l1', 'l3', 'l5']", + "109, IKK-α ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23685842", + "TEXT": "Total anomalous pulmonary venous connection (TAPVC) is a potentially lethal congenital disorder that occurs when the pulmonary veins do not connect normally to the left atrium, allowing mixing of pulmonary and systemic blood. In contrast to the extensive knowledge of arterial vascular patterning, little is known about the patterning of veins. Here we show that the secreted guidance molecule semaphorin 3d (Sema3d) is crucial for the normal patterning of pulmonary veins. Prevailing models suggest that TAPVC occurs when the midpharyngeal endothelial strand (MES), the precursor of the common pulmonary vein, does not form at the proper location on the dorsal surface of the embryonic common atrium. However, we found that TAPVC occurs in Sema3d mutant mice despite normal formation of the MES. In these embryos, the maturing pulmonary venous plexus does not anastomose uniquely with the properly formed MES. In the absence of Sema3d, endothelial tubes form in a region that is normally avascular, resulting in aberrant connections. Normally, Sema3d provides a repulsive cue to endothelial cells in this area, establishing a boundary. Sequencing of SEMA3D in individuals with anomalous pulmonary veins identified a phenylalanine-to-leucine substitution that adversely affects SEMA3D function. These results identify Sema3d as a crucial pulmonary venous patterning cue and provide experimental evidence for an alternate developmental model to explain abnormal pulmonary venous connections.", + "TAG_DATA": [ + "113, Sema3d {'perturbing_action': 'B-other'}", + "114, mutant {'perturbing_action': 'I-other'}", + "115, mice {'context': 'B-organism'}", + "124, embryos, {'context': 'B-organism'}", + "141, absence {'perturbing_action': 'B-gene loss-of-function'}", + "142, of {'perturbing_action': 'I-gene loss-of-function'}", + "143, Sema3d, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "113, Sema3d ['l0', 'l1']", + "114, mutant ['l0', 'l2']", + "115, mice ['l1', 'l2']", + "124, embryos, ['l3', 'l4', 'l5']", + "141, absence ['l3', 'l6', 'l7']", + "142, of ['l4', 'l6', 'l8']", + "143, Sema3d, ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Sema3d", + "mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "embryos," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "Sema3d," + ] + } + } + ] + }, + { + "PMID": "23685839", + "TEXT": "Glucagon activates hepatic protein kinase A (PKA) to increase glucose production, but the gluco-stimulatory effect is transient even in the presence of continuous intravenous glucagon infusion. Continuous intravenous infusion of insulin, however, inhibits glucose production through its sustained actions in both the liver and the mediobasal hypothalamus (MBH). In a pancreatic clamp setting, MBH infusion with glucagon activated MBH PKA and inhibited hepatic glucose production (HGP) in rats, as did central glucagon infusion in mice. Inhibition of glucagon receptor-PKA signaling in the MBH and hepatic vagotomy each negated the effect of MBH glucagon in rats, whereas the central effect of glucagon was diminished in glucagon receptor knockout mice. A sustained rise in plasma glucagon concentrations transiently increased HGP, and this transiency was abolished in rats with negated MBH glucagon action. In a nonclamp setting, MBH glucagon infusion improved glucose tolerance, and inhibition of glucagon receptor-PKA signaling in the MBH enhanced the ability of intravenous glucagon injection to increase plasma glucose concentrations. We also detected a similar enhancement of glucose concentrations that was associated with a disruption in MBH glucagon signaling in rats fed a high-fat diet. We show that hypothalamic glucagon signaling inhibits HGP and suggest that hypothalamic glucagon resistance contributes to hyperglycemia in diabetes and obesity.", + "TAG_DATA": [ + "67, rats, {'context': 'B-organism'}", + "74, mice. {'context': 'B-organism'}", + "94, rats, {'context': 'B-organism'}", + "104, glucagon {'perturbing_action': 'B-gene loss-of-function'}", + "105, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "106, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "107, mice. {'context': 'B-organism'}", + "124, rats {'context': 'B-organism'}", + "181, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "67, rats, ['l0']", + "74, mice. ['l0']", + "104, glucagon ['l1', 'l2', 'l3', 'l4']", + "105, receptor ['l1', 'l5', 'l6', 'l7']", + "106, knockout ['l2', 'l5', 'l8', 'l9']", + "107, mice. ['l3', 'l6', 'l8', 'l10']", + "124, rats ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "glucagon", + "receptor", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "rats" + ] + } + } + ] + }, + { + "PMID": "23652101", + "TEXT": "GLP-1R agonists are novel new drugs for patients with type 2 diabetes mellitus (T2DM). An intriguing connection between these agents such as liraglutide and native GLP-1 from the gut and the release of the blood pressure lowering cardiac hormone atrial natriuretic peptide (ANP) establishes a new gut – heart connection not only for glycemic control in diabetes, but in overall cardiovascular homeostasis.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23644514", + "TEXT": "Anticancer chemotherapy drugs challenge hematopoietic tissues to regenerate but commonly produce long-term sequelae. Chemotherapy-induced deficits in hematopoietic stem or stromal cell function have been described, but the mechanisms mediating hematopoietic dysfunction remain unclear. Administration of multiple cycles of cisplatin chemotherapy causes substantial sensory neuropathy. Here we demonstrate that chemotherapy-induced nerve injury in the bone marrow of mice is a crucial lesion impairing hematopoietic regeneration. Using pharmacological and genetic models, we show that the selective loss of adrenergic innervation in the bone marrow alters its regeneration after genotoxic insult. Sympathetic nerves in the marrow promote the survival of constituents of the stem cell niche that initiate recovery. Neuroprotection by deletion of Trp53 in sympathetic neurons or neuroregeneration by administration of 4-methylcatechol or glial-derived neurotrophic factor (GDNF) promotes hematopoietic recovery. These results demonstrate the potential benefit of adrenergic nerve protection for shielding hematopoietic niches from injury.", + "TAG_DATA": [ + "73, selective {'perturbing_action': 'B-gene loss-of-function'}", + "74, loss {'perturbing_action': 'I-gene loss-of-function'}", + "75, of {'perturbing_action': 'I-gene loss-of-function'}", + "76, adrenergic {'perturbing_action': 'I-gene loss-of-function'}", + "77, innervation {'perturbing_action': 'I-gene loss-of-function'}", + "78, in {'perturbing_action': 'I-gene loss-of-function'}", + "79, the {'perturbing_action': 'I-gene loss-of-function'}", + "80, bone {'perturbing_action': 'I-gene loss-of-function'}", + "81, marrow {'perturbing_action': 'I-gene loss-of-function'}", + "108, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "109, of {'perturbing_action': 'I-gene loss-of-function'}", + "110, Trp53 {'perturbing_action': 'I-gene loss-of-function'}", + "112, sympathetic {'context': 'B-cells'}", + "113, neurons {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "73, selective ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "74, loss ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "75, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "76, adrenergic ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "77, innervation ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "78, in ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "79, the ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "80, bone ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "81, marrow ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "108, deletion ['l36', 'l37', 'l38', 'l39']", + "109, of ['l36', 'l40', 'l41', 'l42']", + "110, Trp53 ['l37', 'l40', 'l43', 'l44']", + "112, sympathetic ['l38', 'l41', 'l43', 'l45']", + "113, neurons ['l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Trp53" + ] + }, + "context": { + "val": "cells", + "words": [ + "sympathetic", + "neurons" + ] + } + } + ] + }, + { + "PMID": "23603816", + "TEXT": "Upregulation of the ERK1 and ERK2 (ERK1/2) MAP kinase (MAPK) cascade occurs in >30% of cancers, often through mutational activation of receptor tyrosine kinases or other upstream genes, including KRAS and BRAF. Efforts to target endogenous MAPKs are challenged by the fact that these kinases are required for viability in mammals. Additionally, the effectiveness of new inhibitors of mutant BRAF has been diminished by acquired tumor resistance through selection for BRAF-independent mechanisms of ERK1/2 induction. Furthermore, recently identified ERK1/2-inducing mutations in MEK1 and MEK2 (MEK1/2) MAPK genes in melanoma confer resistance to emerging therapeutic MEK inhibitors, underscoring the challenges facing direct kinase inhibition in cancer. MAPK scaffolds, such as IQ motif-containing GTPase activating protein 1 (IQGAP1), assemble pathway kinases to affect signal transmission, and disrupting scaffold function therefore offers an orthogonal approach to MAPK cascade inhibition. Consistent with this, we found a requirement for IQGAP1 in RAS-driven tumorigenesis in mouse and human tissue. In addition, the ERK1/2-binding IQGAP1 WW domain peptide disrupted IQGAP1-ERK1/2 interactions, inhibited RAS- and RAF-driven tumorigenesis, bypassed acquired resistance to the BRAF inhibitor vemurafenib (PLX-4032) and acted as a systemically deliverable therapeutic to significantly increase the lifespan of tumor-bearing mice. Scaffold-kinase interaction blockade acts by a mechanism distinct from direct kinase inhibition and may be a strategy to target overactive oncogenic kinase cascades in cancer.", + "TAG_DATA": [ + "164, inhibited {'effect': 'B-negative'}", + "168, tumorigenesis, {'phenotype': 'B-tumourigenesis'}", + "191, tumor-bearing {'context': 'B-organism'}", + "192, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "164, inhibited ['l0']", + "168, tumorigenesis, ['l0']", + "191, tumor-bearing ['l1']", + "192, mice. ['l1']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis," + ] + } + } + ] + }, + { + "PMID": "23603814", + "TEXT": "Microglia are crucial for the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Here we show that the E3 ubiquitin ligase Peli1 is abundantly expressed in microglia and promotes microglial activation during the course of EAE induction. Peli1 mediates the induction of chemokines and proinflammatory cytokines in microglia and thereby promotes recruitment of T cells into the central nervous system. The severity of EAE is reduced in Peli1-deficient mice despite their competent induction of inflammatory T cells in the peripheral lymphoid organs. Notably, Peli1 regulates Toll-like receptor (TLR) pathway signaling by promoting degradation of TNF receptor-associated factor 3 (Traf3), a potent inhibitor of mitogen-activated protein kinase (MAPK) activation and gene induction. Ablation of Traf3 restores microglial activation and CNS inflammation after the induction of EAE in Peli1-deficient mice. These findings establish Peli1 as a microglia-specific mediator of autoimmune neuroinflammation and suggest a previously unknown signaling mechanism of Peli1 function.", + "TAG_DATA": [ + "71, Peli1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "72, mice {'context': 'B-organism'}", + "115, Ablation {'perturbing_action': 'B-gene loss-of-function'}", + "116, of {'perturbing_action': 'I-gene loss-of-function'}", + "117, Traf3 {'perturbing_action': 'I-gene loss-of-function'}", + "122, CNS {'context': 'B-tissue/organ'}", + "130, Peli1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "131, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "71, Peli1-deficient ['l0']", + "72, mice ['l0']", + "115, Ablation ['l1', 'l2', 'l3', 'l4', 'l5']", + "116, of ['l1', 'l6', 'l7', 'l8', 'l9']", + "117, Traf3 ['l2', 'l6', 'l10']", + "122, CNS ['l3', 'l7', 'l10', 'l11', 'l12']", + "130, Peli1-deficient ['l4', 'l8', 'l11', 'l13']", + "131, mice. ['l5', 'l9', 'l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Peli1-deficient", + "Ablation", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "Traf3", + "Peli1-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "CNS" + ] + } + } + ] + }, + { + "PMID": "23542788", + "TEXT": "Glucagon-like peptide-1 receptor (GLP-1R) agonists exert antihypertensive actions through incompletely understood mechanisms. Here we demonstrate that cardiac Glp1r expression is localized to cardiac atria and that GLP-1R activation promotes the secretion of atrial natriuretic peptide (ANP) and a reduction of blood pressure. Consistent with an indirect ANP-dependent mechanism for the antihypertensive effects of GLP-1R activation, the GLP-1R agonist liraglutide did not directly increase the amount of cyclic GMP (cGMP) or relax preconstricted aortic rings; however, conditioned medium from liraglutide-treated hearts relaxed aortic rings in an endothelium-independent, GLP-1R-dependent manner. Liraglutide did not induce ANP secretion, vasorelaxation or lower blood pressure in Glp1r(-/-) or Nppa(-/-) mice. Cardiomyocyte GLP-1R activation promoted the translocation of the Rap guanine nucleotide exchange factor Epac2 (also known as Rapgef4) to the membrane, whereas Epac2 deficiency eliminated GLP-1R-dependent stimulation of ANP secretion. Plasma ANP concentrations were increased after refeeding in wild-type but not Glp1r(-/-) mice, and liraglutide increased urine sodium excretion in wild-type but not Nppa(-/-) mice. These findings define a gut-heart GLP-1R-dependent and ANP-dependent axis that regulates blood pressure.", + "TAG_DATA": [ + "72, aortic {'context': 'B-tissue/organ'}", + "73, rings; {'context': 'I-tissue/organ'}", + "79, hearts {'context': 'B-tissue/organ'}", + "81, aortic {'context': 'B-tissue/organ'}", + "82, rings {'context': 'I-tissue/organ'}", + "100, Glp1r(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "102, Nppa(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "103, mice. {'context': 'B-organism'}", + "104, Cardiomyocyte {'context': 'B-cells'}", + "126, Epac2 {'perturbing_action': 'B-gene loss-of-function'}", + "127, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "145, Glp1r(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "146, mice, {'context': 'B-organism'}", + "157, Nppa(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "158, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "72, aortic ['l0']", + "73, rings; ['l0']", + "79, hearts ['l1', 'l2']", + "81, aortic ['l1', 'l3']", + "82, rings ['l2', 'l3']", + "100, Glp1r(-/-) ['l4', 'l5', 'l6']", + "102, Nppa(-/-) ['l4', 'l7', 'l8']", + "103, mice. ['l5', 'l7', 'l9']", + "104, Cardiomyocyte ['l6', 'l8', 'l9', 'l10', 'l11']", + "126, Epac2 ['l12', 'l13', 'l14']", + "127, deficiency ['l10', 'l12', 'l15', 'l16']", + "145, Glp1r(-/-) ['l13', 'l15', 'l17']", + "146, mice, ['l11', 'l14', 'l16', 'l17']", + "157, Nppa(-/-) ['l18']", + "158, mice. ['l18']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Glp1r(-/-)", + "Nppa(-/-)", + "Epac2", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Glp1r(-/-)", + "Nppa(-/-)", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "Cardiomyocyte" + ] + } + } + ] + }, + { + "PMID": "23524342", + "TEXT": "Adenovirus type 5 (Ad5) specifically binds coagulation factor X (FX), and FX is normally essential for intravenously injected Ad5 vectors to transduce the liver. We demonstrate that the ability of FX to enhance liver transduction by Ad5 vectors is due to an unexpected ability of FX to protect Ad5 from attack by the classical complement pathway. In vitro, naive mouse serum neutralized Ad5 when FX was blocked from binding Ad5. This neutralization was mediated by natural IgM and the classical complement pathway. In vivo, FX was essential for Ad5 vectors to transduce the livers of wild-type mice, but FX was not required for liver transduction in mice that lack antibodies, C1q or C4. We conclude that Ad5 recruits FX as a defense against complement and that the sensitivity of Ad5 to inactivation by complement must be taken into account when designing vectors for systemic gene therapy.", + "TAG_DATA": [ + "56, In {'context': 'B-in vitro'}", + "57, vitro, {'context': 'I-in vitro'}", + "59, mouse {'context': 'I-cells'}", + "82, In {'context': 'B-in vivo'}", + "83, vivo, {'context': 'I-in vivo'}", + "93, livers {'context': 'B-tissue/organ'}", + "96, mice, {'context': 'B-organism'}", + "103, liver {'context': 'B-tissue/organ'}", + "106, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, In ['l0', 'l1']", + "57, vitro, ['l0', 'l2']", + "59, mouse ['l1', 'l2', 'l3']", + "82, In ['l4', 'l5', 'l6']", + "83, vivo, ['l4', 'l7', 'l8']", + "93, livers ['l3', 'l5', 'l7', 'l9']", + "96, mice, ['l6', 'l8', 'l9']", + "103, liver ['l10']", + "106, mice ['l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23502962", + "TEXT": "A role for macrophages in erythropoiesis was suggested several decades ago when erythroblastic islands in the bone marrow, composed of a central macrophage surrounded by developing erythroblasts, were described. However, the in vivo role of macrophages in erythropoiesis under homeostatic conditions or in disease remains unclear. We found that specific depletion of CD169(+) macrophages markedly reduced the number of erythroblasts in the bone marrow but did not result in overt anemia under homeostatic conditions, probably because of concomitant alterations in red blood cell clearance. However, CD169(+) macrophage depletion significantly impaired erythropoietic recovery from hemolytic anemia, acute blood loss and myeloablation. Furthermore, macrophage depletion normalized the erythroid compartment in a JAK2(V617F)-driven mouse model of polycythemia vera, suggesting that erythropoiesis in polycythemia vera remains under the control of macrophages in the bone marrow and splenic microenvironments. These results indicate that CD169(+) macrophages promote late erythroid maturation and that modulation of the macrophage compartment may be a new strategy to treat erythropoietic disorders.", + "TAG_DATA": [ + "50, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "51, of {'perturbing_action': 'I-gene loss-of-function'}", + "52, CD169(+) {'context': 'B-cells'}", + "53, macrophages {'context': 'I-cells'}", + "59, erythroblasts {'context': 'B-cells'}", + "62, bone {'context': 'B-tissue/organ'}", + "63, marrow {'context': 'I-tissue/organ'}", + "85, CD169(+) {'context': 'B-cells'}", + "86, macrophage {'context': 'I-cells'}", + "87, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "102, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "110, mouse {'context': 'B-organism'}", + "111, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "50, depletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "51, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "52, CD169(+) ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "53, macrophages ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "59, erythroblasts ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "62, bone ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "63, marrow ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "85, CD169(+) ['l21', 'l22']", + "86, macrophage ['l21', 'l23']", + "87, depletion ['l22', 'l23']", + "102, depletion ['l24', 'l25', 'l26']", + "109, JAK2(V617F)-driven ['l24', 'l27', 'l28']", + "110, mouse ['l25', 'l27', 'l29']", + "111, model ['l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD169(+)", + "macrophages", + "erythroblasts", + "macrophage" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "bone", + "marrow" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + } + ] + }, + { + "PMID": "23502960", + "TEXT": "Focal segmental glomerulosclerosis (FSGS) is a frequent and severe glomerular disease characterized by destabilization of podocyte foot processes. We report that transgenic expression of the microRNA miR-193a in mice rapidly induces FSGS with extensive podocyte foot process effacement. Mechanistically, miR-193a inhibits the expression of the Wilms' tumor protein (WT1), a transcription factor and master regulator of podocyte differentiation and homeostasis. Decreased expression levels of WT1 lead to downregulation of its target genes PODXL (podocalyxin) and NPHS1 (nephrin), as well as several other genes crucial for the architecture of podocytes, initiating a catastrophic collapse of the entire podocyte-stabilizing system. We found upregulation of miR-193a in isolated glomeruli from individuals with FSGS compared to normal kidneys or individuals with other glomerular diseases. Thus, upregulation of miR-193a provides a new pathogenic mechanism for FSGS and is a potential therapeutic target.", + "TAG_DATA": [ + "21, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "22, expression {'perturbing_action': 'I-gene gain-of-function'}", + "23, of {'perturbing_action': 'I-gene gain-of-function'}", + "24, the {'perturbing_action': 'I-gene gain-of-function'}", + "25, microRNA {'perturbing_action': 'I-gene gain-of-function'}", + "26, miR-193a {'perturbing_action': 'I-gene gain-of-function'}", + "28, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "21, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "22, expression ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "23, of ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "24, the ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "25, microRNA ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "26, miR-193a ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "28, mice ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "of", + "the", + "microRNA", + "miR-193a" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23475203", + "TEXT": "Co-therapy with rifampicin (RIF) and isoniazid (INH) used to treat tuberculosis in humans frequently causes liver injury. Here, using a pregnane X receptor (PXR)-humanized mouse model, we found that co-treatment with RIF and INH causes accumulation of the endogenous hepatotoxin protoporphyrin IX in the liver through PXR-mediated alteration of the heme biosynthesis pathway. These results provide insight into the mechanism of liver injury induced by co-treatment with these compounds and may lead to their safer use in the clinic.", + "TAG_DATA": [ + "24, mouse {'context': 'B-organism'}", + "25, model, {'context': 'I-organism'}", + "44, liver {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "20, pregnane ['l0', 'l1', 'l2', 'l3', 'l4']", + "21, X ['l0', 'l5', 'l6', 'l7', 'l8']", + "22, receptor ['l1', 'l5', 'l9', 'l10', 'l11']", + "23, (PXR)-humanized ['l2', 'l6', 'l9', 'l12', 'l13']", + "24, mouse ['l3', 'l7', 'l10', 'l12', 'l14']", + "25, model, ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23455714", + "TEXT": "Inhibitors of coagulation factor Xa (fXa) have emerged as a new class of antithrombotics but lack effective antidotes for patients experiencing serious bleeding. We designed and expressed a modified form of fXa as an antidote for fXa inhibitors. This recombinant protein (r-Antidote, PRT064445) is catalytically inactive and lacks the membrane-binding γ-carboxyglutamic acid domain of native fXa but retains the ability of native fXa to bind direct fXa inhibitors as well as low molecular weight heparin-activated antithrombin III (ATIII). r-Antidote dose-dependently reversed the inhibition of fXa by direct fXa inhibitors and corrected the prolongation of ex vivo clotting times by such inhibitors. In rabbits treated with the direct fXa inhibitor rivaroxaban, r-Antidote restored hemostasis in a liver laceration model. The effect of r-Antidote was mediated by reducing plasma anti-fXa activity and the non-protein bound fraction of the fXa inhibitor in plasma. In rats, r-Antidote administration dose-dependently and completely corrected increases in blood loss resulting from ATIII-dependent anticoagulation by enoxaparin or fondaparinux. r-Antidote has the potential to be used as a universal antidote for a broad range of fXa inhibitors.", + "TAG_DATA": [ + "102, rabbits {'context': 'B-organism'}", + "115, liver {'context': 'B-tissue/organ'}", + "141, rats, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "102, rabbits ['l0']", + "115, liver ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23455713", + "TEXT": "To understand why cancer vaccine-induced T cells often do not eradicate tumors, we studied immune responses in mice vaccinated with gp100 melanoma peptide in incomplete Freund's adjuvant (peptide/IFA), which is commonly used in clinical cancer vaccine trials. Peptide/IFA vaccination primed tumor-specific CD8(+) T cells, which accumulated not in tumors but rather at the persisting, antigen-rich vaccination site. Once there, primed T cells became dysfunctional and underwent antigen-driven, interferon-γ (IFN-γ)- and Fas ligand (FasL)-mediated apoptosis, resulting in hyporesponsiveness to subsequent vaccination. Provision of CD40-specific antibody, Toll-like receptor 7 (TLR7) agonist and interleukin-2 (IL-2) reduced T cell apoptosis but did not prevent vaccination-site sequestration. A nonpersisting vaccine formulation shifted T cell localization toward tumors, inducing superior antitumor activity while reducing systemic T cell dysfunction and promoting memory formation. These data show that persisting vaccine depots can induce specific T cell sequestration, dysfunction and deletion at vaccination sites; short-lived formulations may overcome these limitations and result in greater therapeutic efficacy of peptide-based cancer vaccines.", + "TAG_DATA": [ + "17, mice {'context': 'B-organism'}", + "41, CD8(+) {'context': 'B-cells'}", + "42, T {'context': 'I-cells'}", + "43, cells, {'context': 'I-cells'}", + "60, T {'context': 'B-cells'}", + "61, cells {'context': 'B-cells'}", + "73, apoptosis, {'phenotype': 'B-apoptosis'}", + "92, reduced {'effect': 'B-negative'}", + "93, T {'context': 'B-cells'}", + "94, cell {'context': 'B-cells'}", + "95, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "17, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "41, CD8(+) ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "42, T ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "43, cells, ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "60, T ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "61, cells ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "73, apoptosis, ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "92, reduced ['l21', 'l22', 'l23']", + "93, T ['l21', 'l24', 'l25']", + "94, cell ['l22', 'l24', 'l26']", + "95, apoptosis ['l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "T", + "cells,", + "cells", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis,", + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "23435170", + "TEXT": "Delayed T cell recovery and restricted T cell receptor (TCR) diversity after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are associated with increased risks of infection and cancer relapse. Technical challenges have limited faithful measurement of TCR diversity after allo-HSCT. Here we combined 5' rapid amplification of complementary DNA ends PCR with deep sequencing to quantify TCR diversity in 28 recipients of allo-HSCT using a single oligonucleotide pair. Analysis of duplicate blood samples confirmed that we accurately determined the frequency of individual TCRs. After 6 months, cord blood-graft recipients approximated the TCR diversity of healthy individuals, whereas recipients of T cell-depleted peripheral-blood stem cell grafts had 28-fold and 14-fold lower CD4(+) and CD8(+) T cell diversities, respectively. After 12 months, these deficiencies had improved for the CD4(+) but not the CD8(+) T cell compartment. Overall, this method provides unprecedented views of T cell repertoire recovery after allo-HSCT and may identify patients at high risk of infection or relapse.", + "TAG_DATA": [ + "100, peripheral-blood {'context': 'I-xenograft'}", + "101, stem {'context': 'I-cells'}", + "102, cell {'context': 'I-cells'}", + "103, grafts {'context': 'I-xenograft'}", + "112, T {'context': 'I-cells'}", + "113, cell {'context': 'I-cells'}", + "125, CD4(+) {'context': 'B-cells'}", + "129, CD8(+) {'context': 'B-cells'}", + "130, T {'context': 'I-cells'}", + "131, cell {'context': 'I-cells'}", + "132, compartment. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "98, T ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "100, peripheral-blood ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "101, stem ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "102, cell ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "103, grafts ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "111, CD8(+) ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "112, T ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "113, cell ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "125, CD4(+) ['l28', 'l29', 'l30', 'l31']", + "129, CD8(+) ['l28', 'l32', 'l33', 'l34']", + "130, T ['l29', 'l32', 'l35', 'l36']", + "131, cell ['l30', 'l33', 'l35', 'l37']", + "132, compartment. ['l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23396211", + "TEXT": "Emerging evidence suggests that inflammation provides a link between obesity and insulin resistance. The noncanonical IκB kinases IKK-ɛ and TANK-binding kinase 1 (TBK1) are induced in liver and fat by NF-κB activation upon high-fat diet feeding and in turn initiate a program of counterinflammation that preserves energy storage. Here we report that amlexanox, an approved small-molecule therapeutic presently used in the clinic to treat aphthous ulcers and asthma, is an inhibitor of these kinases. Treatment of obese mice with amlexanox elevates energy expenditure through increased thermogenesis, producing weight loss, improved insulin sensitivity and decreased steatosis. Because of its record of safety in patients, amlexanox may be an interesting candidate for clinical evaluation in the treatment of obesity and related disorders.", + "TAG_DATA": [ + "76, obese {'context': 'B-organism'}", + "77, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "76, obese ['l0']", + "77, mice ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23291631", + "TEXT": "A better understanding of human hepatocellular carcinoma (HCC) pathogenesis at the molecular level will facilitate the discovery of tumor-initiating events. Transcriptome sequencing revealed that adenosine-to-inosine (A→I) RNA editing of AZIN1 (encoding antizyme inhibitor 1) is increased in HCC specimens. A→I editing of AZIN1 transcripts, specifically regulated by ADAR1 (encoding adenosine deaminase acting on RNA-1), results in a serine-to-glycine substitution at residue 367 of AZIN1, located in β-strand 15 (β15) and predicted to cause a conformational change, induced a cytoplasmic-to-nuclear translocation and conferred gain-of-function phenotypes that were manifested by augmented tumor-initiating potential and more aggressive behavior. Compared with wild-type AZIN1 protein, the edited form has a stronger affinity to antizyme, and the resultant higher AZIN1 protein stability promotes cell proliferation through the neutralization of antizyme-mediated degradation of ornithine decarboxylase (ODC) and cyclin D1 (CCND1). Collectively, A→I RNA editing of AZIN1 may be a potential driver in the pathogenesis of human cancers, particularly HCC.", + "TAG_DATA": [ + "88, augmented {'effect': 'B-positive'}", + "89, tumor-initiating {'phenotype': 'B-tumour initiation'}", + "90, potential {'phenotype': 'I-tumour initiation'}", + "116, promotes {'effect': 'B-positive'}", + "117, cell {'context': 'B-cells'}", + "118, proliferation {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "88, augmented ['l0', 'l1']", + "89, tumor-initiating ['l0', 'l2']", + "90, potential ['l1', 'l2']", + "116, promotes ['l3', 'l4']", + "117, cell ['l3', 'l5']", + "118, proliferation ['l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "augmented" + ] + }, + "phenotype": { + "val": "tumour initiation", + "words": [ + "tumor-initiating", + "potential" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "23223058", + "TEXT": "There is a growing appreciation of the importance of circadian regulation in energy homeostasis, and the dysregulation of the circadian clock has been associated with obesity and metabolic abnormalities. A new study shows that adipocyte-specific deletion of a core circadian clock gene, Bmal1, in mice shifts the timing of their feeding behavior, resulting in obesity (aaa-bbb).", + "TAG_DATA": [ + "34, adipocyte-specific {'perturbing_action': 'B-gene loss-of-function'}", + "35, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "36, of {'perturbing_action': 'I-gene loss-of-function'}", + "37, a {'perturbing_action': 'I-gene loss-of-function'}", + "38, core {'perturbing_action': 'I-gene loss-of-function'}", + "39, circadian {'perturbing_action': 'I-gene loss-of-function'}", + "40, clock {'perturbing_action': 'I-gene loss-of-function'}", + "41, gene, {'perturbing_action': 'I-gene loss-of-function'}", + "42, Bmal1, {'perturbing_action': 'I-gene loss-of-function'}", + "44, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "34, adipocyte-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "35, deletion ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "36, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "37, a ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "38, core ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "39, circadian ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "40, clock ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "41, gene, ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "42, Bmal1, ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "44, mice ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adipocyte-specific", + "deletion", + "of", + "a", + "core", + "circadian", + "clock", + "gene,", + "Bmal1," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23202294", + "TEXT": "Skeletal muscle atrophy occurs in aging and pathological conditions, including cancer, diabetes and AIDS. Treatment of atrophy is based on either preventing protein-degradation pathways, which are activated during atrophy, or activating protein-synthesis pathways, which induce muscle hypertrophy. Here we show that neuronal nitric oxide synthase (nNOS) regulates load-induced hypertrophy by activating transient receptor potential cation channel, subfamily V, member 1 (TRPV1). The overload-induced hypertrophy was prevented in nNOS-null mice. nNOS was transiently activated within 3 min after overload. This activation promoted formation of peroxynitrite, a reaction product of nitric oxide with superoxide, which was derived from NADPH oxidase 4 (Nox4). Nitric oxide and peroxynitrite then activated Trpv1, resulting in an increase of intracellular Ca(2+) concentration ([Ca(2+)](i)) that subsequently triggered activation of mammalian target of rapamycin (mTOR). Notably, administration of the TRPV1 agonist capsaicin induced hypertrophy without overload and alleviated unloading- or denervation-induced atrophy. These findings identify nitric oxide, peroxynitrite and [Ca(2+)](i) as the crucial mediators that convert a mechanical load into an intracellular signaling pathway and lead us to suggest that TRPV1 could be a new therapeutic target for treating muscle atrophy.", + "TAG_DATA": [ + "67, nNOS-null {'perturbing_action': 'B-gene loss-of-function'}", + "68, mice. {'context': 'B-organism'}", + "130, TRPV1 {'perturbing_action': 'B-pharmacological augmentation'}", + "131, agonist {'perturbing_action': 'I-pharmacological augmentation'}" + ], + "LINK_DATA": [ + "67, nNOS-null ['l0']", + "68, mice. ['l0']", + "130, TRPV1 ['l1']", + "131, agonist ['l1']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nNOS-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "23142821", + "TEXT": "Live, attenuated RNA virus vaccines are efficacious but subject to reversion to virulence. Among RNA viruses, replication fidelity is recognized as a key determinant of virulence and escape from antiviral therapy; increased fidelity is attenuating for some viruses. Coronavirus (CoV) replication fidelity is approximately 20-fold greater than that of other RNA viruses and is mediated by a 3'→5' exonuclease (ExoN) activity that probably functions in RNA proofreading. In this study we demonstrate that engineered inactivation of severe acute respiratory syndrome (SARS)-CoV ExoN activity results in a stable mutator phenotype with profoundly decreased fidelity in vivo and attenuation of pathogenesis in young, aged and immunocompromised mice. The ExoN inactivation genotype and mutator phenotype are stable and do not revert to virulence, even after serial passage or long-term persistent infection in vivo. ExoN inactivation has potential for broad applications in the stable attenuation of CoVs and, perhaps, other RNA viruses.", + "TAG_DATA": [ + "73, engineered {'perturbing_action': 'B-gene loss-of-function'}", + "74, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "75, of {'perturbing_action': 'I-gene loss-of-function'}", + "76, severe {'perturbing_action': 'I-gene loss-of-function'}", + "77, acute {'perturbing_action': 'I-gene loss-of-function'}", + "78, respiratory {'perturbing_action': 'I-gene loss-of-function'}", + "79, syndrome {'perturbing_action': 'I-gene loss-of-function'}", + "80, (SARS)-CoV {'perturbing_action': 'I-gene loss-of-function'}", + "81, ExoN {'perturbing_action': 'I-gene loss-of-function'}", + "82, activity {'perturbing_action': 'I-gene loss-of-function'}", + "93, in {'context': 'B-in vivo'}", + "94, vivo {'context': 'I-in vivo'}", + "96, attenuation {'effect': 'B-negative'}", + "100, young, {'context': 'B-organism'}", + "101, aged {'context': 'I-organism'}", + "103, immunocompromised {'context': 'I-organism'}", + "104, mice. {'context': 'I-organism'}", + "106, ExoN {'perturbing_action': 'B-gene loss-of-function'}", + "107, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "128, in {'context': 'B-in vivo'}", + "129, vivo. {'context': 'I-in vivo'}", + "130, ExoN {'perturbing_action': 'B-gene loss-of-function'}", + "131, inactivation {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "73, engineered ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "74, inactivation ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "75, of ['l1', 'l17', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "76, severe ['l2', 'l18', 'l33', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "77, acute ['l3', 'l19', 'l34', 'l48', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "78, respiratory ['l4', 'l20', 'l35', 'l49', 'l62', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "79, syndrome ['l5', 'l21', 'l36', 'l50', 'l63', 'l75', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "80, (SARS)-CoV ['l6', 'l22', 'l37', 'l51', 'l64', 'l76', 'l87', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "81, ExoN ['l7', 'l23', 'l38', 'l52', 'l65', 'l77', 'l88', 'l98', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "82, activity ['l8', 'l24', 'l39', 'l53', 'l66', 'l78', 'l89', 'l99', 'l108', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "93, in ['l9', 'l25', 'l40', 'l54', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l125']", + "94, vivo ['l10', 'l26', 'l41', 'l55', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l125']", + "96, attenuation ['l11', 'l27', 'l42', 'l56', 'l69', 'l81', 'l92', 'l102', 'l111', 'l119', 'l126', 'l127', 'l128', 'l129', 'l130']", + "100, young, ['l12', 'l28', 'l43', 'l57', 'l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l126', 'l131', 'l132', 'l133', 'l134']", + "101, aged ['l13', 'l29', 'l44', 'l58', 'l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l127', 'l131', 'l135', 'l136', 'l137']", + "102, and ['l14', 'l30', 'l45', 'l59', 'l72', 'l84', 'l95', 'l105', 'l114', 'l122', 'l128', 'l132', 'l135', 'l138', 'l139']", + "103, immunocompromised ['l15', 'l31', 'l46', 'l60', 'l73', 'l85', 'l96', 'l106', 'l115', 'l123', 'l129', 'l133', 'l136', 'l138', 'l140']", + "104, mice. ['l16', 'l32', 'l47', 'l61', 'l74', 'l86', 'l97', 'l107', 'l116', 'l124', 'l130', 'l134', 'l137', 'l139', 'l140']", + "106, ExoN ['l141', 'l142', 'l143']", + "107, inactivation ['l141', 'l144', 'l145']", + "128, in ['l142', 'l144', 'l146']", + "129, vivo. ['l143', 'l145', 'l146']", + "130, ExoN ['l147']", + "131, inactivation ['l147']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "engineered", + "inactivation", + "of", + "severe", + "acute", + "respiratory", + "syndrome", + "(SARS)-CoV", + "ExoN", + "activity" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "engineered", + "inactivation", + "of", + "severe", + "acute", + "respiratory", + "syndrome", + "(SARS)-CoV", + "ExoN", + "activity" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "engineered", + "inactivation", + "of", + "severe", + "acute", + "respiratory", + "syndrome", + "(SARS)-CoV", + "ExoN", + "activity" + ] + }, + "context": { + "val": "organism", + "words": [ + "young,", + "aged", + "immunocompromised", + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuation" + ] + }, + "context": { + "val": "organism", + "words": [ + "young,", + "aged", + "immunocompromised", + "mice." + ] + } + } + ] + }, + { + "PMID": "23142819", + "TEXT": "Adipocytes store excess energy in the form of triglycerides and signal the levels of stored energy to the brain. Here we show that adipocyte-specific deletion of Arntl (also known as Bmal1), a gene encoding a core molecular clock component, results in obesity in mice with a shift in the diurnal rhythm of food intake, a result that is not seen when the gene is disrupted in hepatocytes or pancreatic islets. Changes in the expression of hypothalamic neuropeptides that regulate appetite are consistent with feedback from the adipocyte to the central nervous system to time feeding behavior. Ablation of the adipocyte clock is associated with a reduced number of polyunsaturated fatty acids in adipocyte triglycerides. This difference between mutant and wild-type mice is reflected in the circulating concentrations of polyunsaturated fatty acids and nonesterified polyunsaturated fatty acids in hypothalamic neurons that regulate food intake. Thus, this study reveals a role for the adipocyte clock in the temporal organization of energy regulation, highlights timing as a modulator of the adipocyte-hypothalamic axis and shows the impact of timing of food intake on body weight.", + "TAG_DATA": [ + "23, adipocyte-specific {'perturbing_action': 'B-gene loss-of-function'}", + "24, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "25, of {'perturbing_action': 'I-gene loss-of-function'}", + "26, Arntl {'perturbing_action': 'I-gene loss-of-function'}", + "27, (also {'perturbing_action': 'I-gene loss-of-function'}", + "29, as {'perturbing_action': 'I-gene loss-of-function'}", + "30, Bmal1), {'perturbing_action': 'I-gene loss-of-function'}", + "43, mice {'context': 'B-organism'}", + "64, disrupted {'perturbing_action': 'I-gene loss-of-function'}", + "66, hepatocytes {'context': 'B-cells'}", + "68, pancreatic {'context': 'B-cells'}", + "69, islets. {'context': 'I-cells'}", + "120, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "23, adipocyte-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "24, deletion ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "25, of ['l1', 'l10', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "26, Arntl ['l2', 'l11', 'l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "27, (also ['l3', 'l12', 'l21', 'l29', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "29, as ['l4', 'l13', 'l22', 'l30', 'l37', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "30, Bmal1), ['l5', 'l14', 'l23', 'l31', 'l38', 'l44', 'l50', 'l51', 'l52', 'l53', 'l54']", + "43, mice ['l6', 'l15', 'l24', 'l32', 'l39', 'l45', 'l50']", + "64, disrupted ['l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l56', 'l57']", + "66, hepatocytes ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l55', 'l58', 'l59']", + "68, pancreatic ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l56', 'l58', 'l60']", + "69, islets. ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adipocyte-specific", + "deletion", + "of", + "Arntl", + "(also", + "as", + "Bmal1)," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adipocyte-specific", + "deletion", + "of", + "Arntl", + "(also", + "as", + "Bmal1),", + "disrupted" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes", + "pancreatic", + "islets." + ] + } + } + ] + }, + { + "PMID": "23142818", + "TEXT": "Glioblastomas shed large quantities of small, membrane-bound microvesicles into the circulation. Although these hold promise as potential biomarkers of therapeutic response, their identification and quantification remain challenging. Here, we describe a highly sensitive and rapid analytical technique for profiling circulating microvesicles directly from blood samples of patients with glioblastoma. Microvesicles, introduced onto a dedicated microfluidic chip, are labeled with target-specific magnetic nanoparticles and detected by a miniaturized nuclear magnetic resonance system. Compared with current methods, this integrated system has a much higher detection sensitivity and can differentiate glioblastoma multiforme (GBM) microvesicles from nontumor host cell-derived microvesicles. We also show that circulating GBM microvesicles can be used to analyze primary tumor mutations and as a predictive metric of treatment-induced changes. This platform could provide both an early indicator of drug efficacy and a potential molecular stratifier for human clinical trials.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23135524", + "TEXT": "Next-generation sequencing of DNA from human tumors or individuals with developmental abnormalities has led to the discovery of a process we term chromoanagenesis, in which large numbers of complex rearrangements occur at one or a few chromosomal loci in a single catastrophic event. Two mechanisms underlie these rearrangements, both of which can be facilitated by a mitotic chromosome segregation error to produce a micronucleus containing the chromosome to undergo rearrangement. In the first, chromosome shattering (chromothripsis) is produced by mitotic entry before completion of DNA replication within the micronucleus, with a failure to disassemble the micronuclear envelope encapsulating the chromosomal fragments for random reassembly in the subsequent interphase. Alternatively, locally defective DNA replication initiates serial, microhomology-mediated template switching (chromoanasynthesis) that produces local rearrangements with altered gene copy numbers. Complex rearrangements are present in a broad spectrum of tumors and in individuals with congenital or developmental defects, highlighting the impact of chromoanagenesis on human disease.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23135513", + "TEXT": "An imaging technique adapted to differentiate between chronic obstructive pulmonary disease phenotypes can identify small-airway pathophysiology, locate the disease and potentially track disease progression. This approach may be used as a biomarker to identify the small-airway lesion in chronic obstructive pulmonary disease, at an individual level in the clinic (pages 1711-1715).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23135511", + "TEXT": "The production of cross-reactive neutralizing antibodies is the ultimate goal in HIV vaccine development, but no immunogen other than HIV itself has been able to elicit this type of humoral immunity. In natural HIV infections, these antibodies take several years to develop. A new study sheds light on what may be causing this delay in neutralizing antibody development (pages 1688-1692).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23104131", + "TEXT": "Parasitic worms express host-like glycans to attenuate the immune response of human hosts. The therapeutic potential of this immunomodulatory mechanism in controlling the metabolic dysfunction that is associated with chronic inflammation remains unexplored. We demonstrate here that administration of lacto-N-fucopentaose III (LNFPIII), a Lewis(X)-containing immunomodulatory glycan found in human milk and on parasitic helminths, improves glucose tolerance and insulin sensitivity in diet-induced obese mice. This effect is mediated partly through increased interleukin-10 (Il-10) production by LNFPIII-activated macrophages and dendritic cells, which reduces white adipose tissue inflammation and sensitizes the insulin response of adipocytes. Concurrently, LNFPIII treatment upregulates nuclear receptor subfamily 1, group H, member 4 (Fxr-α, also known as Nr1h4) to suppress lipogenesis in the liver, conferring protection against hepatosteatosis. At the signaling level, the extracellular signal-regulated kinase (Erk)-activator protein 1 (Ap1) pathway seems to mediate the effects of LNFPIII on both inflammatory and metabolic pathways. Our results suggest that LNFPIII may provide new therapeutic approaches to treat metabolic diseases.", + "TAG_DATA": [ + "62, obese {'context': 'B-organism'}", + "63, mice. {'context': 'I-organism'}", + "76, macrophages {'context': 'B-cells'}", + "78, dendritic {'context': 'B-cells'}", + "79, cells, {'context': 'I-cells'}", + "83, adipose {'context': 'I-tissue/organ'}", + "84, tissue {'context': 'I-tissue/organ'}", + "92, adipocytes. {'context': 'B-cells'}", + "115, liver, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "62, obese ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "63, mice. ['l0', 'l7', 'l8', 'l9', 'l10']", + "76, macrophages ['l1', 'l7', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "78, dendritic ['l2', 'l8', 'l11', 'l17', 'l18', 'l19', 'l20', 'l21']", + "79, cells, ['l3', 'l9', 'l12', 'l17', 'l22', 'l23', 'l24', 'l25']", + "82, white ['l4', 'l13', 'l18', 'l22', 'l26', 'l27', 'l28']", + "83, adipose ['l5', 'l14', 'l19', 'l23', 'l26', 'l29', 'l30']", + "84, tissue ['l6', 'l10', 'l15', 'l20', 'l24', 'l27', 'l29', 'l31']", + "92, adipocytes. ['l16', 'l21', 'l25', 'l28', 'l30', 'l31']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23064464", + "TEXT": "Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin's lymphoma found in children and young adults. ALCLs frequently carry a chromosomal translocation that results in expression of the oncoprotein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The key molecular downstream events required for NPM-ALK-triggered lymphoma growth have been only partly unveiled. Here we show that the activator protein 1 family members JUN and JUNB promote lymphoma development and tumor dissemination through transcriptional regulation of platelet-derived growth factor receptor-β (PDGFRB) in a mouse model of NPM-ALK-triggered lymphomagenesis. Therapeutic inhibition of PDGFRB markedly prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor in transplanted NPM-ALK tumors. Notably, inhibition of PDGFRA and PDGFRB in a patient with refractory late-stage NPM-ALK(+) ALCL resulted in rapid, complete and sustained remission. Together, our data identify PDGFRB as a previously unknown JUN and JUNB target that could be a highly effective therapy for ALCL.", + "TAG_DATA": [ + "78, mouse {'context': 'B-organism'}", + "79, model {'context': 'I-organism'}", + "83, Therapeutic {'perturbing_action': 'B-pharmacological inhibition'}", + "84, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "85, of {'perturbing_action': 'I-pharmacological inhibition'}", + "86, PDGFRB {'perturbing_action': 'I-pharmacological inhibition'}", + "91, NPM-ALK {'perturbing_action': 'B-gene gain-of-function'}", + "92, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "93, mice {'context': 'B-organism'}", + "100, ALK-specific {'perturbing_action': 'B-pharmacological inhibition'}", + "101, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "103, transplanted {'context': 'B-xenograft'}", + "104, NPM-ALK {'context': 'B-neoplasm'}", + "105, tumors. {'context': 'I-neoplasm'}", + "107, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "108, of {'perturbing_action': 'I-pharmacological inhibition'}", + "109, PDGFRA {'perturbing_action': 'I-pharmacological inhibition'}", + "110, and {'perturbing_action': 'I-pharmacological inhibition'}", + "111, PDGFRB {'perturbing_action': 'I-pharmacological inhibition'}", + "114, patient {'context': 'B-patient'}", + "119, ALCL {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "78, mouse ['l0']", + "79, model ['l0']", + "83, Therapeutic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "84, inhibition ['l1', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "85, of ['l2', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "86, PDGFRB ['l3', 'l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "91, NPM-ALK ['l4', 'l14', 'l23', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43']", + "92, transgenic ['l5', 'l15', 'l24', 'l32', 'l39', 'l44', 'l45', 'l46']", + "93, mice ['l6', 'l16', 'l25', 'l33', 'l40', 'l44']", + "100, ALK-specific ['l7', 'l17', 'l26', 'l34', 'l47', 'l48', 'l49', 'l50']", + "101, inhibitor ['l8', 'l18', 'l27', 'l35', 'l47', 'l51', 'l52', 'l53']", + "103, transplanted ['l9', 'l19', 'l28', 'l36', 'l41', 'l48', 'l51', 'l54', 'l55']", + "104, NPM-ALK ['l10', 'l20', 'l29', 'l37', 'l42', 'l45', 'l49', 'l52', 'l54', 'l56']", + "105, tumors. ['l11', 'l21', 'l30', 'l38', 'l43', 'l46', 'l50', 'l53', 'l55', 'l56']", + "107, inhibition ['l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "108, of ['l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "109, PDGFRA ['l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "110, and ['l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "111, PDGFRB ['l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "114, patient ['l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "119, ALCL ['l62', 'l67', 'l71', 'l74', 'l76', 'l77']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Therapeutic", + "inhibition", + "of", + "PDGFRB" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Therapeutic", + "inhibition", + "of", + "PDGFRB", + "ALK-specific", + "inhibitor" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "transplanted" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Therapeutic", + "inhibition", + "of", + "PDGFRB", + "ALK-specific", + "inhibitor", + "PDGFRA", + "and" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "NPM-ALK", + "tumors.", + "ALCL" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "NPM-ALK", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "NPM-ALK" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "transplanted" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "NPM-ALK", + "transgenic" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "NPM-ALK", + "tumors." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "PDGFRA", + "and", + "PDGFRB" + ] + }, + "context": { + "val": "patient", + "words": [ + "patient" + ] + } + } + ] + }, + { + "PMID": "23023499", + "TEXT": "Spinal and bulbar muscular atrophy (SBMA) is a motor neuron disease caused by the expansion of the CAG triplet repeat within the androgen receptor (AR) gene. Here, we demonstrated that pathogenic AR upregulates the gene encoding calcitonin gene-related peptide α (CGRP1). In neuronal cells, overexpression of CGRP1 induced cellular damage via the activation of the c-Jun N-terminal kinase (JNK) pathway, whereas pharmacological suppression of CGRP1 or JNK attenuated the neurotoxic effects of pathogenic AR. The depletion of CGRP1 inactivated JNK and suppressed neurodegeneration in a mouse model of SBMA. Naratriptan, a serotonin 1B/1D (5-hydroxytryptamine 1B/1D, or 5-HT1B/1D) receptor agonist, decreased CGRP1 expression via the induction of dual-specificity protein phosphatase 1 (DUSP1), attenuated JNK activity and mitigated pathogenic AR-mediated neuronal damage in cellular and mouse SBMA models. These observations suggest that pharmacological activation of the 5-HT1B/1D receptor may be used therapeutically to treat SBMA and other polyglutamine-related neurodegenerative diseases.", + "TAG_DATA": [ + "42, neuronal {'context': 'B-cells'}", + "43, cells, {'context': 'I-cells'}", + "44, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "45, of {'perturbing_action': 'I-gene gain-of-function'}", + "46, CGRP1 {'perturbing_action': 'I-gene gain-of-function'}", + "61, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "62, suppression {'perturbing_action': 'I-pharmacological inhibition'}", + "63, of {'perturbing_action': 'I-pharmacological inhibition'}", + "64, CGRP1 {'perturbing_action': 'I-pharmacological inhibition'}", + "65, or {'perturbing_action': 'I-pharmacological inhibition'}", + "66, JNK {'perturbing_action': 'I-pharmacological inhibition'}", + "75, depletion {'perturbing_action': 'B-gene loss-of-function'}", + "76, of {'perturbing_action': 'I-gene loss-of-function'}", + "77, CGRP1 {'perturbing_action': 'I-gene loss-of-function'}", + "85, mouse {'context': 'B-organism'}", + "86, model {'context': 'I-organism'}", + "87, of {'context': 'I-organism'}", + "88, SBMA. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "42, neuronal ['l0', 'l1', 'l2', 'l3']", + "43, cells, ['l0', 'l4', 'l5', 'l6']", + "44, overexpression ['l1', 'l4', 'l7', 'l8']", + "45, of ['l2', 'l5', 'l7', 'l9']", + "46, CGRP1 ['l3', 'l6', 'l8', 'l9']", + "61, pharmacological ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "62, suppression ['l10', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "63, of ['l11', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "64, CGRP1 ['l12', 'l23', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "65, or ['l13', 'l24', 'l32', 'l40', 'l48', 'l49', 'l50', 'l51', 'l52']", + "66, JNK ['l14', 'l25', 'l33', 'l41', 'l48', 'l53', 'l54', 'l55', 'l56', 'l57']", + "75, depletion ['l15', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "76, of ['l16', 'l34', 'l42', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "77, CGRP1 ['l17', 'l26', 'l35', 'l43', 'l53', 'l59', 'l64', 'l69', 'l70', 'l71', 'l72']", + "85, mouse ['l18', 'l27', 'l36', 'l44', 'l49', 'l54', 'l60', 'l65', 'l69', 'l73', 'l74', 'l75']", + "86, model ['l19', 'l28', 'l37', 'l45', 'l50', 'l55', 'l61', 'l66', 'l70', 'l73', 'l76', 'l77']", + "87, of ['l20', 'l29', 'l38', 'l46', 'l51', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l78']", + "88, SBMA. ['l21', 'l30', 'l39', 'l47', 'l52', 'l57', 'l63', 'l68', 'l72', 'l75', 'l77', 'l78']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "neuronal", + "cells," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "CGRP1" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "suppression", + "of", + "CGRP1", + "or", + "JNK" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "SBMA." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "CGRP1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "SBMA." + ] + } + } + ] + }, + { + "PMID": "23001183", + "TEXT": "There is a pressing need to identify prognostic markers of metastatic disease and targets for treatment. Combining high-throughput RNA sequencing, functional characterization, mechanistic studies and clinical validation, we identify leukemia inhibitory factor receptor (LIFR) as a breast cancer metastasis suppressor downstream of the microRNA miR-9 and upstream of Hippo signaling. Restoring LIFR expression in highly malignant tumor cells suppresses metastasis by triggering a Hippo kinase cascade that leads to phosphorylation, cytoplasmic retention and functional inactivation of the transcriptional coactivator YES-associated protein (YAP). Conversely, loss of LIFR in nonmetastatic breast cancer cells induces migration, invasion and metastatic colonization through activation of YAP. LIFR is downregulated in human breast carcinomas and inversely correlates with metastasis. Notably, in approximately 1,000 nonmetastatic breast tumors, LIFR expression status correlated with metastasis-free, recurrence-free and overall survival outcomes in the patients. These findings identify LIFR as a metastasis suppressor that functions through the Hippo-YAP pathway and has significant prognostic power.", + "TAG_DATA": [ + "58, suppresses {'effect': 'B-negative'}", + "59, metastasis {'phenotype': 'B-metastasis'}", + "83, loss {'perturbing_action': 'B-gene loss-of-function'}", + "84, of {'perturbing_action': 'I-gene loss-of-function'}", + "85, LIFR {'perturbing_action': 'I-gene loss-of-function'}", + "87, nonmetastatic {'context': 'B-transformed cells'}", + "88, breast {'context': 'I-transformed cells'}", + "89, cancer {'context': 'I-transformed cells'}", + "90, cells {'context': 'I-transformed cells'}", + "91, induces {'effect': 'B-positive'}", + "92, migration, {'phenotype': 'B-migration'}", + "93, invasion {'phenotype': 'B-invasion'}", + "95, metastatic {'phenotype': 'B-metastasis'}", + "96, colonization {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "58, suppresses ['l0']", + "59, metastasis ['l0', 'l1', 'l2', 'l3']", + "83, loss ['l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "84, of ['l4', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "85, LIFR ['l5', 'l15', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "87, nonmetastatic ['l6', 'l16', 'l25', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "88, breast ['l1', 'l7', 'l17', 'l26', 'l34', 'l42', 'l43', 'l44', 'l45', 'l46']", + "89, cancer ['l2', 'l8', 'l18', 'l27', 'l35', 'l42', 'l47', 'l48', 'l49', 'l50']", + "90, cells ['l3', 'l9', 'l19', 'l28', 'l36', 'l43', 'l47', 'l51', 'l52', 'l53']", + "91, induces ['l10', 'l20', 'l29', 'l37', 'l44', 'l48', 'l51', 'l54', 'l55']", + "92, migration, ['l11', 'l21', 'l30', 'l38', 'l45', 'l49', 'l52', 'l54', 'l56']", + "93, invasion ['l12', 'l22', 'l31', 'l39', 'l46', 'l50', 'l53', 'l55', 'l56']", + "95, metastatic ['l13', 'l23', 'l32', 'l40', 'l57']", + "96, colonization ['l14', 'l24', 'l33', 'l41', 'l57']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "metastatic", + "colonization" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "breast", + "cancer", + "cells", + "nonmetastatic" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "LIFR" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "nonmetastatic", + "breast", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "LIFR" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "LIFR" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "LIFR" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "LIFR" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "colonization" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "nonmetastatic", + "breast", + "cancer", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "nonmetastatic", + "breast", + "cancer", + "cells" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "nonmetastatic", + "breast", + "cancer", + "cells" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + } + ] + }, + { + "PMID": "22983395", + "TEXT": "The class II α-isoform of phosphatidylinositol 3-kinase (PI3K-C2α) is localized in endosomes, the trans-Golgi network and clathrin-coated vesicles; however, its functional role is not well understood. Global or endothelial-cell-specific deficiency of PI3K-C2α resulted in embryonic lethality caused by defects in sprouting angiogenesis and vascular maturation. PI3K-C2α knockdown in endothelial cells resulted in a decrease in the number of PI3-phosphate-enriched endosomes, impaired endosomal trafficking, defective delivery of VE-cadherin to endothelial cell junctions and defective junction assembly. PI3K-C2α knockdown also impaired endothelial cell signaling, including vascular endothelial growth factor receptor internalization and endosomal RhoA activation. Together, the effects of PI3K-C2α knockdown led to defective endothelial cell migration, proliferation, tube formation and barrier integrity. Endothelial PI3K-C2α deficiency in vivo suppressed postischemic and tumor angiogenesis and diminished vascular barrier function with a greatly augmented susceptibility to anaphylaxis and a higher incidence of dissecting aortic aneurysm formation in response to angiotensin II infusion. Thus, PI3K-C2α has a crucial role in vascular formation and barrier integrity and represents a new therapeutic target for vascular disease.", + "TAG_DATA": [ + "28, endothelial-cell-specific {'perturbing_action': 'B-gene loss-of-function'}", + "29, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "30, of {'perturbing_action': 'I-gene loss-of-function'}", + "31, PI3K-C2α {'perturbing_action': 'I-gene loss-of-function'}", + "45, PI3K-C2α {'perturbing_action': 'B-rnai/knockdown'}", + "46, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "48, endothelial {'context': 'B-cells'}", + "49, cells {'context': 'I-cells'}", + "75, PI3K-C2α {'perturbing_action': 'B-rnai/knockdown'}", + "76, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "79, endothelial {'context': 'B-cells'}", + "80, cell {'context': 'I-cells'}", + "97, PI3K-C2α {'perturbing_action': 'B-rnai/knockdown'}", + "98, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "101, defective {'effect': 'B-negative'}", + "102, endothelial {'context': 'B-cells'}", + "103, cell {'context': 'I-cells'}", + "104, migration, {'phenotype': 'B-migration'}", + "105, proliferation, {'phenotype': 'B-proliferation'}", + "111, Endothelial {'perturbing_action': 'B-gene loss-of-function'}", + "112, PI3K-C2α {'perturbing_action': 'I-gene loss-of-function'}", + "113, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "114, in {'context': 'B-in vivo'}", + "115, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "28, endothelial-cell-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "29, deficiency ['l0', 'l8', 'l9', 'l10', 'l11']", + "30, of ['l1', 'l8', 'l12', 'l13', 'l14', 'l15']", + "31, PI3K-C2α ['l2', 'l9', 'l12', 'l16', 'l17', 'l18', 'l19']", + "45, PI3K-C2α ['l3', 'l16', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "46, knockdown ['l4', 'l13', 'l17', 'l20', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "48, endothelial ['l5', 'l10', 'l14', 'l18', 'l21', 'l30', 'l37', 'l38', 'l39', 'l40']", + "49, cells ['l6', 'l11', 'l15', 'l19', 'l22', 'l31', 'l37']", + "75, PI3K-C2α ['l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "76, knockdown ['l41', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "79, endothelial ['l23', 'l42', 'l51', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "80, cell ['l24', 'l32', 'l38', 'l43', 'l52', 'l60', 'l67', 'l68', 'l69', 'l70', 'l71']", + "97, PI3K-C2α ['l44', 'l53', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "98, knockdown ['l45', 'l54', 'l61', 'l72', 'l78', 'l79', 'l80', 'l81', 'l82']", + "101, defective ['l25', 'l46', 'l55', 'l62', 'l67', 'l73', 'l78', 'l83', 'l84', 'l85', 'l86']", + "102, endothelial ['l26', 'l33', 'l47', 'l56', 'l63', 'l68', 'l74', 'l79', 'l83', 'l87', 'l88', 'l89']", + "103, cell ['l7', 'l27', 'l34', 'l39', 'l48', 'l57', 'l64', 'l69', 'l75', 'l80', 'l84', 'l87', 'l90', 'l91']", + "104, migration, ['l28', 'l35', 'l40', 'l49', 'l58', 'l65', 'l70', 'l76', 'l81', 'l85', 'l88', 'l90', 'l92']", + "105, proliferation, ['l29', 'l36', 'l50', 'l59', 'l66', 'l71', 'l77', 'l82', 'l86', 'l89', 'l91', 'l92']", + "111, Endothelial ['l93', 'l94', 'l95', 'l96']", + "112, PI3K-C2α ['l93', 'l97', 'l98', 'l99']", + "113, deficiency ['l94', 'l97', 'l100', 'l101']", + "114, in ['l95', 'l98', 'l100', 'l102']", + "115, vivo ['l96', 'l99', 'l101', 'l102']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "endothelial-cell-specific", + "deficiency", + "of", + "PI3K-C2α" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PI3K-C2α", + "knockdown" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PI3K-C2α", + "knockdown" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PI3K-C2α", + "knockdown" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PI3K-C2α", + "knockdown" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "defective" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "defective" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Endothelial", + "PI3K-C2α", + "deficiency" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "22972397", + "TEXT": "Unlike activated CD4(+) T cells, resting CD4(+) T cells are highly resistant to productive HIV-1 infection. Early after HIV-1 entry, a major block limits reverse transcription of incoming viral genomes. Here we show that the deoxynucleoside triphosphate triphosphohydrolase SAMHD1 prevents reverse transcription of HIV-1 RNA in resting CD4(+) T cells. SAMHD1 is abundantly expressed in resting CD4(+) T cells circulating in peripheral blood and residing in lymphoid organs. The early restriction to infection in unstimulated CD4(+) T cells is overcome by HIV-1 or HIV-2 virions into which viral Vpx is artificially or naturally packaged, respectively, or by addition of exogenous deoxynucleosides. Vpx-mediated proteasomal degradation of SAMHD1 and elevation of intracellular deoxynucleotide pools precede successful infection by Vpx-carrying HIV. Resting CD4(+) T cells from healthy donors following SAMHD1 silencing or from a patient with Aicardi-Goutières syndrome homozygous for a nonsense mutation in SAMHD1 were permissive for HIV-1 infection. Thus, SAMHD1 imposes an effective restriction to HIV-1 infection in the large pool of noncycling CD4(+) T cells in vivo. Bypassing SAMHD1 was insufficient for the release of viral progeny, implicating other barriers at later stages of HIV replication. Together, these findings may unveil new ways to interfere with the immune evasion and T cell immunopathology of pandemic HIV-1.", + "TAG_DATA": [ + "75, CD4(+) {'context': 'B-cells'}", + "76, T {'context': 'I-cells'}", + "77, cells {'context': 'I-cells'}", + "118, Resting {'context': 'B-cells'}", + "119, CD4(+) {'context': 'I-cells'}", + "120, T {'context': 'I-cells'}", + "121, cells {'context': 'I-cells'}", + "124, donors {'context': 'I-cells'}", + "126, SAMHD1 {'perturbing_action': 'B-rnai/knockdown'}", + "127, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "131, patient {'context': 'B-patient'}", + "135, homozygous {'perturbing_action': 'B-other'}", + "136, for {'perturbing_action': 'I-other'}", + "137, a {'perturbing_action': 'I-other'}", + "138, nonsense {'perturbing_action': 'I-other'}", + "139, mutation {'perturbing_action': 'I-other'}", + "140, in {'perturbing_action': 'I-other'}", + "141, SAMHD1 {'perturbing_action': 'I-other'}", + "161, noncycling {'context': 'B-cells'}", + "162, CD4(+) {'context': 'I-cells'}", + "163, T {'context': 'I-cells'}", + "164, cells {'context': 'I-cells'}", + "165, in {'context': 'B-in vivo'}", + "166, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "75, CD4(+) ['l0', 'l1']", + "76, T ['l0', 'l2']", + "77, cells ['l1', 'l2']", + "118, Resting ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "119, CD4(+) ['l3', 'l9', 'l10', 'l11', 'l12', 'l13']", + "120, T ['l4', 'l9', 'l14', 'l15', 'l16', 'l17']", + "121, cells ['l5', 'l10', 'l14', 'l18', 'l19', 'l20']", + "124, donors ['l6', 'l11', 'l15', 'l18', 'l21', 'l22']", + "126, SAMHD1 ['l7', 'l12', 'l16', 'l19', 'l21', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "127, silencing ['l8', 'l13', 'l17', 'l20', 'l22', 'l23', 'l29', 'l30', 'l31', 'l32', 'l33']", + "131, patient ['l24', 'l29', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "135, homozygous ['l34', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "136, for ['l35', 'l47', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "137, a ['l36', 'l48', 'l59', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "138, nonsense ['l37', 'l49', 'l60', 'l70', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "139, mutation ['l38', 'l50', 'l61', 'l71', 'l80', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "140, in ['l25', 'l30', 'l39', 'l51', 'l62', 'l72', 'l81', 'l89', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "141, SAMHD1 ['l26', 'l31', 'l40', 'l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "161, noncycling ['l41', 'l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l110', 'l111', 'l112', 'l113', 'l114']", + "162, CD4(+) ['l42', 'l54', 'l65', 'l75', 'l84', 'l92', 'l99', 'l105', 'l110', 'l115', 'l116', 'l117', 'l118']", + "163, T ['l27', 'l32', 'l43', 'l55', 'l66', 'l76', 'l85', 'l93', 'l100', 'l106', 'l111', 'l115', 'l119', 'l120', 'l121']", + "164, cells ['l28', 'l33', 'l44', 'l56', 'l67', 'l77', 'l86', 'l94', 'l101', 'l107', 'l112', 'l116', 'l119', 'l122', 'l123']", + "165, in ['l45', 'l57', 'l68', 'l78', 'l87', 'l95', 'l102', 'l108', 'l113', 'l117', 'l120', 'l122', 'l124']", + "166, vivo. ['l46', 'l58', 'l69', 'l79', 'l88', 'l96', 'l103', 'l109', 'l114', 'l118', 'l121', 'l123', 'l124']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Resting", + "CD4(+)", + "T", + "cells", + "donors" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "SAMHD1", + "silencing" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "SAMHD1", + "silencing" + ] + }, + "context": { + "val": "patient", + "words": [ + "patient" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patient" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "homozygous", + "for", + "a", + "nonsense", + "mutation", + "in", + "SAMHD1" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "homozygous", + "for", + "a", + "nonsense", + "mutation", + "in", + "SAMHD1" + ] + }, + "context": { + "val": "cells", + "words": [ + "noncycling", + "CD4(+)", + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "homozygous", + "for", + "a", + "nonsense", + "mutation", + "in", + "SAMHD1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "22961107", + "TEXT": "Immune tolerance is instituted early in life, during which time regulatory T (T(reg)) cells have an important role. Recurrent infections with respiratory syncytial virus (RSV) in early life increase the risk for asthma in adult life. Repeated infection of infant mice tolerized to ovalbumin (OVA) through their mother's milk with RSV induced allergic airway disease in response to OVA sensitization and challenge, including airway inflammation, hyper-reactivity and higher OVA-specific IgE, as compared to uninfected tolerized control mice. Virus infection induced GATA-3 expression and T helper type 2 (T(H)2) cytokine production in forkhead box P3 (FOXP3)(+) T(reg) cells and compromised the suppressive function of pulmonary T(reg) cells in a manner that was dependent on interleukin-4 receptor α (IL-4Rα) expression in the host. Thus, by promoting a T(H)2-type inflammatory response in the lung, RSV induced a T(H)2-like effector phenotype in T(reg) cells and attenuated tolerance to an unrelated antigen (allergen). Our findings highlight a mechanism by which viral infection targets a host-protective mechanism in early life and increases susceptibility to allergic disease.", + "TAG_DATA": [ + "39, infant {'context': 'B-organism'}", + "40, mice {'context': 'I-organism'}", + "76, mice. {'context': 'I-organism'}", + "95, T(reg) {'context': 'I-cells'}", + "96, cells {'context': 'I-cells'}", + "103, pulmonary {'context': 'B-cells'}", + "104, T(reg) {'context': 'I-cells'}", + "105, cells {'context': 'I-cells'}", + "138, T(reg) {'context': 'B-cells'}", + "139, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "39, infant ['l0', 'l1', 'l2', 'l3']", + "40, mice ['l0', 'l4']", + "76, mice. ['l1', 'l5', 'l6']", + "95, T(reg) ['l2', 'l5', 'l7', 'l8']", + "96, cells ['l3', 'l4', 'l6', 'l7']", + "103, pulmonary ['l9', 'l10']", + "104, T(reg) ['l9', 'l11']", + "105, cells ['l8', 'l10', 'l11']", + "138, T(reg) ['l12']", + "139, cells ['l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22922412", + "TEXT": "Hypertension is a cardiovascular risk factor present in over two-thirds of people over age 60 in North America; elevated blood pressure correlates with increased risk of heart attack, stroke and progression to heart and kidney failure. Current therapies are insufficient to control blood pressure in almost half of these patients. The mineralocorticoid receptor (MR), acting in the kidney, is known to regulate blood pressure through aldosterone binding and stimulation of sodium retention. However, recent studies support the concept that the MR also has extrarenal actions and that defects in sodium handling alone do not fully explain the development of hypertension and associated cardiovascular mortality. We and others have identified functional MR in human vascular smooth muscle cells (SMCs), suggesting that vascular MR might directly regulate blood pressure. Here we show that mice with SMC-specific deficiency of the MR have decreased blood pressure as they age without defects in renal sodium handling or vascular structure. Aged mice lacking MR in SMCs (SMC-MR) have reduced vascular myogenic tone, agonist-dependent contraction and expression and activity of L-type calcium channels. Moreover, SMC-MR contributes to angiotensin II–induced vascular oxidative stress, vascular contraction and hypertension. This study identifies a new role for vascular MR in blood pressure control and in vascular aging and supports the emerging hypothesis that vascular tone contributes directly to systemic blood pressure.", + "TAG_DATA": [ + "131, mice {'context': 'B-organism'}", + "133, SMC-specific {'perturbing_action': 'B-gene loss-of-function'}", + "134, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "135, of {'perturbing_action': 'I-gene loss-of-function'}", + "136, the {'perturbing_action': 'I-gene loss-of-function'}", + "137, MR {'perturbing_action': 'I-gene loss-of-function'}", + "155, mice {'context': 'I-organism'}", + "156, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "157, MR {'perturbing_action': 'I-gene loss-of-function'}", + "158, in {'perturbing_action': 'I-gene loss-of-function'}", + "159, SMCs {'context': 'B-cells'}", + "160, (SMC-MR) {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "131, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "133, SMC-specific ['l0', 'l5', 'l6', 'l7', 'l8']", + "134, deficiency ['l1', 'l5', 'l9', 'l10', 'l11']", + "135, of ['l2', 'l6', 'l9', 'l12', 'l13']", + "136, the ['l3', 'l7', 'l10', 'l12', 'l14']", + "137, MR ['l4', 'l8', 'l11', 'l13', 'l14']", + "155, mice ['l15', 'l16', 'l17', 'l18', 'l19']", + "156, lacking ['l15', 'l20', 'l21', 'l22', 'l23']", + "157, MR ['l16', 'l20', 'l24', 'l25', 'l26']", + "158, in ['l17', 'l21', 'l24', 'l27', 'l28']", + "159, SMCs ['l18', 'l22', 'l25', 'l27', 'l29']", + "160, (SMC-MR) ['l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SMC-specific", + "deficiency", + "of", + "the", + "MR", + "lacking", + "in", + "(SMC-MR)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "MR", + "in", + "(SMC-MR)" + ] + }, + "context": { + "val": "cells", + "words": [ + "SMCs" + ] + } + } + ] + }, + { + "PMID": "22869175", + "TEXT": "The US Supreme Court's ruling in late June to uphold most of the Patient Protection and Affordable Care Act of 2010 decided more than just the fate of the law's individual mandate for health care. It also allowed many of the other provisions of the legislation to safely go ahead. Chief among those was the establishment of a comparative-effectiveness research hub called the Patient-Centered Outcomes Research Institute (PCORI), located in Washington, DC. With a budget of $3.3 billion over the next seven years and an independent status, PCORI is now tasked with creating the evidence base to help patients and doctors make more informed decisions about their medical choices. Leading the fledgling institute is executive director Joe Selby. A family physician and clinical epidemiologist, Selby joined PCORI in July 2011 after 13 years as head of research at Kaiser Permanente, the California-based health provider. Even amid all the uncertainty that surrounded the future of US healthcare reform, Selby, together with PCORI's board of directors, managed to help craft the institute's first research agenda and to fund 50 pilot projects totaling $30 million, all in the spring of this year. Elie Dolgin spoke with Selby to discuss how PCORI will influence the debate about which treatments work best.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22842478", + "TEXT": "IMA901 is the first therapeutic vaccine for renal cell cancer (RCC) consisting of multiple tumor-associated peptides (TUMAPs) confirmed to be naturally presented in human cancer tissue. We treated a total of 96 human leukocyte antigen A (HLA-A)*02(+) subjects with advanced RCC with IMA901 in two consecutive studies. In the phase 1 study, the T cell responses of the patients to multiple TUMAPs were associated with better disease control and lower numbers of prevaccine forkhead box P3 (FOXP3)(+) regulatory T (T(reg)) cells. The randomized phase 2 trial showed that a single dose of cyclophosphamide reduced the number of T(reg) cells and confirmed that immune responses to multiple TUMAPs were associated with longer overall survival. Furthermore, among six predefined populations of myeloid-derived suppressor cells, two were prognostic for overall survival, and among over 300 serum biomarkers, we identified apolipoprotein A-I (APOA1) and chemokine (C-C motif) ligand 17 (CCL17) as being predictive for both immune response to IMA901 and overall survival. A randomized phase 3 study to determine the clinical benefit of treatment with IMA901 is ongoing.", + "TAG_DATA": [ + "39, advanced {'context': 'B-neoplasm'}", + "40, RCC {'context': 'I-neoplasm'}", + "97, T(reg) {'context': 'B-cells'}", + "98, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "39, advanced ['l0']", + "40, RCC ['l0']", + "97, T(reg) ['l1']", + "98, cells ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22842475", + "TEXT": "Pressure-induced vasodilation (PIV) delays the decrease in cutaneous blood flow produced by local application of low pressure to the skin, a physiologically appropriate adjustment of local vasomotor function. Individuals without a normal PIV response have a high risk of ulceration. Here we demonstrate that acid-sensing ion channel 3 (Asic3) is an essential neuronal sensor for the vasodilation response to direct pressure in both humans and rodents and for protecting against pressure ulcers in mice.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22820644", + "TEXT": "Sepsis, a systemic inflammatory response to infection, commonly progresses to acute lung injury (ALI), an inflammatory lung disease with high morbidity. We postulated that sepsis-associated ALI is initiated by degradation of the pulmonary endothelial glycocalyx, leading to neutrophil adherence and inflammation. Using intravital microscopy, we found that endotoxemia in mice rapidly induced pulmonary microvascular glycocalyx degradation via tumor necrosis factor-α (TNF-α)-dependent mechanisms. Glycocalyx degradation involved the specific loss of heparan sulfate and coincided with activation of endothelial heparanase, a TNF-α-responsive, heparan sulfate-specific glucuronidase. Glycocalyx degradation increased the availability of endothelial surface adhesion molecules to circulating microspheres and contributed to neutrophil adhesion. Heparanase inhibition prevented endotoxemia-associated glycocalyx loss and neutrophil adhesion and, accordingly, attenuated sepsis-induced ALI and mortality in mice. These findings are potentially relevant to human disease, as sepsis-associated respiratory failure in humans was associated with higher plasma heparan sulfate degradation activity; moreover, heparanase content was higher in human lung biopsies showing diffuse alveolar damage than in normal human lung tissue.", + "TAG_DATA": [ + "49, mice {'context': 'B-organism'}", + "99, neutrophil {'context': 'B-cells'}", + "101, Heparanase {'perturbing_action': 'B-pharmacological inhibition'}", + "102, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "108, neutrophil {'context': 'B-cells'}", + "109, adhesion {'phenotype': 'B-adhesion'}", + "118, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "99, neutrophil ['l0']", + "101, Heparanase ['l1', 'l2', 'l3', 'l4']", + "102, inhibition ['l1', 'l5', 'l6', 'l7']", + "108, neutrophil ['l2', 'l5', 'l8']", + "109, adhesion ['l0', 'l3', 'l6', 'l8']", + "118, mice. ['l4', 'l7']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "neutrophil" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Heparanase", + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "neutrophil" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Heparanase", + "inhibition" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Heparanase", + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "22729286", + "TEXT": "Tissue damage induced by ionizing radiation in the hematopoietic and gastrointestinal systems is the major cause of lethality in radiological emergency scenarios and underlies some deleterious side effects in patients undergoing radiation therapy. The identification of target-specific interventions that confer radiomitigating activity is an unmet challenge. Here we identify the thrombomodulin (Thbd)-activated protein C (aPC) pathway as a new mechanism for the mitigation of total body irradiation (TBI)-induced mortality. Although the effects of the endogenous Thbd-aPC pathway were largely confined to the local microenvironment of Thbd-expressing cells, systemic administration of soluble Thbd or aPC could reproduce and augment the radioprotective effect of the endogenous Thbd-aPC pathway. Therapeutic administration of recombinant, soluble Thbd or aPC to lethally irradiated wild-type mice resulted in an accelerated recovery of hematopoietic progenitor activity in bone marrow and a mitigation of lethal TBI. Starting infusion of aPC as late as 24 h after exposure to radiation was sufficient to mitigate radiation-induced mortality in these mice. These findings suggest that pharmacologic augmentation of the activity of the Thbd-aPC pathway by recombinant Thbd or aPC might offer a rational approach to the mitigation of tissue injury and lethality caused by ionizing radiation.", + "TAG_DATA": [ + "118, mice {'context': 'B-organism'}", + "129, bone {'context': 'B-tissue/organ'}", + "130, marrow {'context': 'I-tissue/organ'}", + "158, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "118, mice ['l0', 'l1']", + "129, bone ['l0', 'l2']", + "130, marrow ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22683779", + "TEXT": "Temporal lobe epilepsy is a common, chronic neurological disorder characterized by recurrent spontaneous seizures. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate post-transcriptional expression of protein-coding mRNAs, which may have key roles in the pathogenesis of neurological disorders. In experimental models of prolonged, injurious seizures (status epilepticus) and in human epilepsy, we found upregulation of miR-134, a brain-specific, activity-regulated miRNA that has been implicated in the control of dendritic spine morphology. Silencing of miR-134 expression in vivo using antagomirs reduced hippocampal CA3 pyramidal neuron dendrite spine density by 21% and rendered mice refractory to seizures and hippocampal injury caused by status epilepticus. Depletion of miR-134 after status epilepticus in mice reduced the later occurrence of spontaneous seizures by over 90% and mitigated the attendant pathological features of temporal lobe epilepsy. Thus, silencing miR-134 exerts prolonged seizure-suppressant and neuroprotective actions; determining whether these are anticonvulsant effects or are truly antiepileptogenic effects requires additional experimentation.", + "TAG_DATA": [ + "71, Silencing {'perturbing_action': 'B-rnai/knockdown'}", + "72, of {'perturbing_action': 'I-rnai/knockdown'}", + "73, miR-134 {'perturbing_action': 'I-rnai/knockdown'}", + "74, expression {'perturbing_action': 'I-rnai/knockdown'}", + "75, in {'context': 'B-in vivo'}", + "76, vivo {'context': 'I-in vivo'}", + "80, hippocampal {'context': 'B-cells'}", + "81, CA3 {'context': 'I-cells'}", + "82, pyramidal {'context': 'I-cells'}", + "83, neuron {'context': 'I-cells'}", + "91, mice {'context': 'B-organism'}", + "102, Depletion {'perturbing_action': 'B-gene loss-of-function'}", + "103, of {'perturbing_action': 'I-gene loss-of-function'}", + "104, miR-134 {'perturbing_action': 'I-gene loss-of-function'}", + "109, mice {'context': 'B-organism'}", + "131, silencing {'perturbing_action': 'B-rnai/knockdown'}", + "132, miR-134 {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "71, Silencing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "72, of ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "73, miR-134 ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "74, expression ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "75, in ['l3', 'l12', 'l20', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "76, vivo ['l4', 'l13', 'l21', 'l28', 'l33', 'l39', 'l40', 'l41', 'l42']", + "80, hippocampal ['l5', 'l14', 'l22', 'l29', 'l34', 'l39', 'l43', 'l44', 'l45']", + "81, CA3 ['l6', 'l15', 'l23', 'l30', 'l35', 'l40', 'l43', 'l46', 'l47', 'l48']", + "82, pyramidal ['l7', 'l16', 'l24', 'l31', 'l36', 'l41', 'l44', 'l46', 'l49', 'l50']", + "83, neuron ['l8', 'l17', 'l25', 'l32', 'l37', 'l42', 'l45', 'l47', 'l49', 'l51']", + "91, mice ['l9', 'l18', 'l26', 'l38', 'l48', 'l50', 'l51']", + "102, Depletion ['l52', 'l53', 'l54', 'l55', 'l56']", + "103, of ['l52', 'l57', 'l58', 'l59', 'l60']", + "104, miR-134 ['l53', 'l57', 'l61', 'l62']", + "109, mice ['l54', 'l58', 'l61']", + "131, silencing ['l55', 'l59', 'l63']", + "132, miR-134 ['l56', 'l60', 'l62', 'l63']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "miR-134", + "expression" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "miR-134", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "hippocampal", + "CA3", + "pyramidal", + "neuron" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "miR-134" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Depletion", + "of", + "miR-134" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "22653117", + "TEXT": "Central nervous system (CNS) disorders distinctly impair locomotor pattern generation and balance, but technical limitations prevent independent assessment and rehabilitation of these subfunctions. Here we introduce a versatile robotic interface to evaluate, enable and train pattern generation and balance independently during natural walking behaviors in rats. In evaluation mode, the robotic interface affords detailed assessments of pattern generation and dynamic equilibrium after spinal cord injury (SCI) and stroke. In enabling mode,the robot acts as a propulsive or postural neuroprosthesis that instantly promotes unexpected locomotor capacities including overground walking after complete SCI, stair climbing following partial SCI and precise paw placement shortly after stroke. In training mode, robot-enabled rehabilitation, epidural electrical stimulation and monoamine agonists reestablish weight-supported locomotion, coordinated steering and balance in rats with a paralyzing SCI. This new robotic technology and associated concepts have broad implications for both assessing and restoring motor functions after CNS disorders, both in animals and in humans.", + "TAG_DATA": [ + "122, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22635007", + "TEXT": "Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma(1), a highly vascularized tumor originating from lymphatic endothelial cells, and of at least two different B cell malignancies(2,3). A dimeric complex formed by the envelope glycoproteins H and L (gH-gL) is required for entry of herpesviruses into host cells(4). We show that the ephrin receptor tyrosine kinase A2 (EphA2) is a cellular receptor for KSHV gH-gL. EphA2 co-precipitated with both gH-gL and KSHV virions. Infection of human epithelial cells with a GFP-expressing recombinant KSHV strain, as measured by FACS analysis, was increased upon overexpression of EphA2. Antibodies against EphA(2) and siRNAs directed against EphA2 inhibited infection of endothelial cells. Pretreatment of KSHV with soluble EphA2 resulted in inhibition of KSHV infection by up to 90%. This marked reduction of KSHV infection was seen with all the different epithelial and endothelial cells used in this study. Similarly, pretreating epithelial or endothelial cells with the soluble EphA2 ligand ephrinA4 impaired KSHV infection. Deletion of the gene encoding EphA2 essentially abolished KSHV infection of mouse endothelial cells. Binding of gH-gL to EphA2 triggered EphA2 phosphorylation and endocytosis, a major pathway of KSHV entry(5,6). Quantitative RT-PCR and in situ histochemistry revealed a close correlation between KSHV infection and EphA2 expression both in cultured cells derived from human Kaposi's sarcoma lesions or unaffected human lymphatic endothelium, and in situ in Kaposi's sarcoma specimens, respectively. Taken together, our results identify EphA2, a tyrosine", + "TAG_DATA": [ + "77, human {'context': 'B-cells'}", + "78, epithelial {'context': 'I-cells'}", + "79, cells {'context': 'I-cells'}", + "94, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "95, of {'perturbing_action': 'I-gene gain-of-function'}", + "96, EphA2. {'perturbing_action': 'I-gene gain-of-function'}", + "101, siRNAs {'perturbing_action': 'B-rnai/knockdown'}", + "102, directed {'perturbing_action': 'I-rnai/knockdown'}", + "103, against {'perturbing_action': 'I-rnai/knockdown'}", + "104, EphA2 {'perturbing_action': 'I-rnai/knockdown'}", + "108, endothelial {'context': 'B-cells'}", + "109, cells. {'context': 'I-cells'}", + "138, epithelial {'context': 'B-cells'}", + "139, and {'context': 'I-cells'}", + "140, endothelial {'context': 'I-cells'}", + "141, cells {'context': 'I-cells'}", + "148, epithelial {'context': 'B-cells'}", + "149, or {'context': 'I-cells'}", + "150, endothelial {'context': 'I-cells'}", + "151, cells {'context': 'I-cells'}", + "161, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "162, of {'perturbing_action': 'I-gene loss-of-function'}", + "163, the {'perturbing_action': 'I-gene loss-of-function'}", + "164, gene {'perturbing_action': 'I-gene loss-of-function'}", + "165, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "166, EphA2 {'perturbing_action': 'I-gene loss-of-function'}", + "172, mouse {'context': 'B-cells'}", + "173, endothelial {'context': 'I-cells'}", + "174, cells. {'context': 'I-cells'}", + "210, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "77, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "78, epithelial ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "79, cells ['l1', 'l6', 'l11']", + "94, overexpression ['l12', 'l13', 'l14', 'l15']", + "95, of ['l2', 'l7', 'l12', 'l16', 'l17', 'l18']", + "96, EphA2. ['l3', 'l8', 'l13', 'l16', 'l19', 'l20']", + "101, siRNAs ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "102, directed ['l21', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "103, against ['l22', 'l34', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "104, EphA2 ['l23', 'l35', 'l46', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "108, endothelial ['l4', 'l9', 'l14', 'l17', 'l19', 'l24', 'l36', 'l47', 'l57', 'l67']", + "109, cells. ['l5', 'l10', 'l11', 'l15', 'l18', 'l20', 'l25', 'l37', 'l48', 'l58', 'l67']", + "138, epithelial ['l26', 'l38', 'l49', 'l59', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "139, and ['l27', 'l39', 'l50', 'l60', 'l68', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "140, endothelial ['l28', 'l40', 'l51', 'l61', 'l69', 'l75', 'l81', 'l82', 'l83', 'l84', 'l85']", + "141, cells ['l29', 'l41', 'l52', 'l62', 'l70', 'l76', 'l81', 'l86', 'l87', 'l88', 'l89']", + "148, epithelial ['l30', 'l42', 'l53', 'l63', 'l71', 'l77', 'l82', 'l86', 'l90', 'l91', 'l92']", + "149, or ['l31', 'l43', 'l54', 'l64', 'l72', 'l78', 'l83', 'l87', 'l90', 'l93', 'l94']", + "150, endothelial ['l32', 'l44', 'l55', 'l65', 'l73', 'l79', 'l84', 'l88', 'l91', 'l93', 'l95']", + "151, cells ['l33', 'l45', 'l56', 'l66', 'l74', 'l80', 'l85', 'l89', 'l92', 'l94', 'l95']", + "161, Deletion ['l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "162, of ['l96', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "163, the ['l97', 'l105', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "164, gene ['l98', 'l106', 'l113', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "165, encoding ['l99', 'l107', 'l114', 'l120', 'l126', 'l127', 'l128', 'l129', 'l130']", + "166, EphA2 ['l100', 'l108', 'l115', 'l121', 'l126', 'l131', 'l132', 'l133', 'l134']", + "172, mouse ['l101', 'l109', 'l116', 'l122', 'l127', 'l131', 'l135', 'l136', 'l137']", + "173, endothelial ['l102', 'l110', 'l117', 'l123', 'l128', 'l132', 'l135', 'l138', 'l139']", + "174, cells. ['l103', 'l111', 'l118', 'l124', 'l129', 'l133', 'l136', 'l138', 'l140']", + "210, cells ['l104', 'l112', 'l119', 'l125', 'l130', 'l134', 'l137', 'l139', 'l140']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "epithelial", + "endothelial", + "cells." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "EphA2.", + "overexpression" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNAs", + "directed", + "against", + "EphA2" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells.", + "epithelial", + "and", + "cells", + "or" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "gene", + "encoding", + "EphA2" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "endothelial", + "cells.", + "cells" + ] + } + } + ] + }, + { + "PMID": "22610279", + "TEXT": "Gastrointestinal bypass surgeries restore metabolic homeostasis in patients with type 2 diabetes and obesity(1), but the underlying mechanisms remain elusive. Duodenal-jejunal bypass surgery (DJB), an experimental surgical technique that excludes the duodenum and proximal jejunum from nutrient transit(1,2), lowers glucose concentrations in nonobese type 2 diabetic rats(2–5). Given that DJB redirects and enhances nutrient flow into the jejunum and that jejunal nutrient sensing affects feeding(6,7), the repositioned jejunum after DJB represents a junction at which nutrients could regulate glucose homeostasis. Here we found that intrajejunal nutrient administration lowered endogenous glucose production in normal rats through a gut-brain-liver network in the presence of basal plasma insulin concentrations. Inhibition of jejunal glucose uptake or formation of long chain fatty acyl-coA negated the metabolic effects of glucose or lipid, respectively, in normal rats, and altered the rapid (2 d) glucose-lowering effect induced by DJB in streptozotocin (STZ)-induced uncontrolled diabetic rats during refeeding. Lastly, in insulin-deficient autoimmune type 1 diabetic rats and STZ-induced diabetic rats, DJB lowered glucose concentrations in 2 d independently of changes in plasma insulin concentrations, food intake and body weight. These data unveil a glucoregulatory role of jejunal nutrient sensing and its relevance in the early improvement of glycemic control after DJB in rat models of uncontrolled diabetes.", + "TAG_DATA": [ + "93, rats {'context': 'I-organism'}", + "129, rats, {'context': 'I-organism'}", + "145, diabetic {'context': 'B-organism'}", + "146, rats {'context': 'I-organism'}", + "151, insulin-deficient {'perturbing_action': 'B-gene loss-of-function', 'context': 'B-organism'}", + "152, autoimmune {'context': 'I-organism'}", + "153, type {'context': 'I-organism'}", + "154, 1 {'context': 'I-organism'}", + "155, diabetic {'context': 'I-organism'}", + "156, rats {'context': 'I-organism'}", + "160, rats, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "129, rats, ['l0', 'l1']", + "145, diabetic ['l0', 'l2']", + "146, rats ['l1', 'l2']", + "151, insulin-deficient ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "152, autoimmune ['l3', 'l9', 'l10', 'l11', 'l12', 'l13']", + "153, type ['l4', 'l9', 'l14', 'l15', 'l16', 'l17']", + "154, 1 ['l5', 'l10', 'l14', 'l18', 'l19', 'l20']", + "155, diabetic ['l6', 'l11', 'l15', 'l18', 'l21', 'l22']", + "156, rats ['l7', 'l12', 'l16', 'l19', 'l21']", + "160, rats, ['l8', 'l13', 'l17', 'l20', 'l22']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "insulin-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "insulin-deficient" + ] + } + } + ] + }, + { + "PMID": "22581287", + "TEXT": "The canonical inhibitor of nuclear factor κB kinase subunit β (IKK-β)–nuclear factor of κ light polypeptide gene enhancer in B cells 1 (NF-κB1) pathway has been well documented to promote insulin resistance; however, the noncanonical NF-κB–inducing kinase (NIK)–NF-κB2 pathway is not well understood in obesity. Additionally, the contribution of counter-regulatory hormones, particularly glucagon, to hyperglycemia in obesity is unclear. Here we show that NIK promotes glucagon responses in obesity. Hepatic NIK was abnormally activated in mice with dietary or genetic obesity. Systemic deletion of Map3k14, encoding NIK, resulted in reduced glucagon responses and hepatic glucose production (HGP). Obesity is associated with high glucagon responses, and liver-specific inhibition of NIK led to lower glucagon responses and HGP and protected against hyperglycemia and glucose intolerance in obese mice. Conversely, hepatocyte-specific overexpression of NIK resulted in higher glucagon responses and HGP. In isolated mouse livers and primary hepatocytes, NIK also promoted glucagon action and glucose production, at least in part by increasing cAMP response element-binding (CREB) stability. Therefore, overactivation of liver NIK in obesity promotes hyperglycemia and glucose intolerance by increasing the hyperglycemic response to glucagon and other factors that activate CREB.", + "TAG_DATA": [ + "75, mice {'context': 'B-organism'}", + "81, Systemic {'perturbing_action': 'B-gene loss-of-function'}", + "82, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "83, of {'perturbing_action': 'I-gene loss-of-function'}", + "84, Map3k14, {'perturbing_action': 'I-gene loss-of-function'}", + "85, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "86, NIK, {'perturbing_action': 'I-gene loss-of-function'}", + "105, liver-specific {'perturbing_action': 'B-pharmacological inhibition'}", + "106, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "107, of {'perturbing_action': 'I-pharmacological inhibition'}", + "108, NIK {'perturbing_action': 'I-pharmacological inhibition'}", + "124, obese {'context': 'B-organism'}", + "125, mice. {'context': 'I-organism'}", + "127, hepatocyte-specific {'perturbing_action': 'B-gene gain-of-function'}", + "128, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "129, of {'perturbing_action': 'I-gene gain-of-function'}", + "130, NIK {'perturbing_action': 'I-gene gain-of-function'}", + "140, mouse {'context': 'B-tissue/organ'}", + "141, livers {'context': 'I-tissue/organ'}", + "143, primary {'context': 'B-cells'}", + "144, hepatocytes, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "81, Systemic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "82, deletion ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "83, of ['l1', 'l10', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "84, Map3k14, ['l2', 'l11', 'l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "85, encoding ['l3', 'l12', 'l21', 'l29', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "86, NIK, ['l4', 'l13', 'l22', 'l30', 'l37', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "105, liver-specific ['l5', 'l14', 'l23', 'l31', 'l38', 'l44', 'l50', 'l51', 'l52', 'l53', 'l54']", + "106, inhibition ['l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l55', 'l56', 'l57', 'l58']", + "107, of ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l59', 'l60', 'l61']", + "108, NIK ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l62', 'l63']", + "124, obese ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l62', 'l64']", + "125, mice. ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l64']", + "127, hepatocyte-specific ['l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "128, overexpression ['l65', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "129, of ['l66', 'l72', 'l78', 'l79', 'l80', 'l81', 'l82']", + "130, NIK ['l67', 'l73', 'l78', 'l83']", + "140, mouse ['l68', 'l74', 'l79', 'l84', 'l85', 'l86']", + "141, livers ['l69', 'l75', 'l80', 'l83', 'l84', 'l87', 'l88']", + "143, primary ['l70', 'l76', 'l81', 'l85', 'l87', 'l89']", + "144, hepatocytes, ['l71', 'l77', 'l82', 'l86', 'l88', 'l89']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Systemic", + "deletion", + "of", + "Map3k14,", + "encoding", + "NIK," + ] + }, + "context": { + "val": "organism", + "words": [ + "obese", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "liver-specific", + "inhibition", + "of", + "NIK" + ] + }, + "context": { + "val": "organism", + "words": [ + "obese", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hepatocyte-specific", + "overexpression", + "of", + "NIK" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "livers" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hepatocyte-specific", + "overexpression", + "of" + ] + }, + "context": { + "val": "cells", + "words": [ + "primary", + "hepatocytes," + ] + } + } + ] + }, + { + "PMID": "22561819", + "TEXT": "Age-related macular degeneration (AMD) is the most common cause of blindness in the elderly. AMD progression is associated with alterations in inflammatory pathways and the immune system. A new study identifies a protective role for inflammasomes in AMD, suggesting that inflammasome activation might be manipulated as a potential therapeutic strategy for this condition (pages 791-798).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22561685", + "TEXT": "Promoting brown adipose tissue (BAT) formation and function may reduce obesity. Recent data link retinoids to energy balance, but a specific role for retinoid metabolism in white versus brown fat is unknown. Retinaldehyde dehydrogenases (Aldhs), also known as aldehyde dehydrogenases, are rate-limiting enzymes that convert retinaldehyde (Rald) to retinoic acid. Here we show that Aldh1a1 is expressed predominately in white adipose tissue (WAT), including visceral depots in mice and humans. Deficiency of the Aldh1a1 gene induced a BAT-like transcriptional program in WAT that drove uncoupled respiration and adaptive thermogenesis. WAT-selective Aldh1a1 knockdown conferred this BAT program in obese mice, limiting weight gain and improving glucose homeostasis. Rald induced uncoupling protein-1 (Ucp1) mRNA and protein levels in white adipocytes by selectively activating the retinoic acid receptor (RAR), recruiting the coactivator PGC-1α and inducing Ucp1 promoter activity. These data establish Aldh1a1 and its substrate Rald as previously unrecognized determinants of adipocyte plasticity and adaptive thermogenesis, which may have potential therapeutic implications.", + "TAG_DATA": [ + "70, Deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "71, of {'perturbing_action': 'I-gene loss-of-function'}", + "72, the {'perturbing_action': 'I-gene loss-of-function'}", + "73, Aldh1a1 {'perturbing_action': 'I-gene loss-of-function'}", + "74, gene {'perturbing_action': 'I-gene loss-of-function'}", + "89, WAT-selective {'perturbing_action': 'B-rnai/knockdown'}", + "90, Aldh1a1 {'perturbing_action': 'I-rnai/knockdown'}", + "91, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "97, obese {'context': 'B-organism'}", + "98, mice, {'context': 'I-organism'}", + "116, white {'context': 'B-cells'}", + "117, adipocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "70, Deficiency ['l0', 'l1', 'l2', 'l3']", + "71, of ['l0', 'l4', 'l5', 'l6']", + "72, the ['l1', 'l4', 'l7', 'l8']", + "73, Aldh1a1 ['l2', 'l5', 'l7', 'l9']", + "74, gene ['l3', 'l6', 'l8', 'l9']", + "89, WAT-selective ['l10', 'l11', 'l12', 'l13']", + "90, Aldh1a1 ['l10', 'l14', 'l15', 'l16']", + "91, knockdown ['l11', 'l14', 'l17', 'l18']", + "97, obese ['l12', 'l15', 'l17', 'l19']", + "98, mice, ['l13', 'l16', 'l18', 'l19']", + "116, white ['l20']", + "117, adipocytes ['l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "WAT-selective", + "Aldh1a1", + "knockdown" + ] + }, + "context": { + "val": "organism", + "words": [ + "obese", + "mice," + ] + } + } + ] + }, + { + "PMID": "22522561", + "TEXT": "The molecular processes underlying epidemic waves of methicillin-resistant Staphylococcus aureus (MRSA) infection are poorly understood(1). Although a major role has been attributed to the acquisition of virulence determinants by horizontal gene transfer(2), there are insufficient epidemiological and functional data supporting that concept. We here report the spread of clones containing a previously extremely rare(3,4) mobile genetic element–encoded gene, sasX. We demonstrate that sasX has a key role in MRSA colonization and pathogenesis, substantially enhancing nasal colonization, lung disease and abscess formation and promoting mechanisms of immune evasion. Moreover, we observed the recent spread of sasX from sequence type 239 (ST239) to invasive clones belonging to other sequence types. Our study identifies sasX as a quickly spreading crucial determinant of MRSA pathogenic success and a promising target for therapeutic interference. Our results provide proof of principle that horizontal gene transfer of key virulence determinants drives MRSA epidemic waves.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22504485", + "TEXT": "Bone marrow-derived stromal cells (BMSCs) protect against acute lung injury (ALI). To determine the role of BMSC mitochondria in this protection, we airway-instilled mice first with lipopolysaccharide (LPS) and then with either mouse BMSCs (mBMSCs) or human BMSCs (hBMSCs). Live optical studies revealed that the mBMSCs formed connexin 43 (Cx43)-containing gap junctional channels (GJCs) with the alveolar epithelia in these mice, releasing mitochondria-containing microvesicles that the epithelia engulfed. The presence of BMSC-derived mitochondria in the epithelia was evident optically, as well as by the presence of human mitochondrial DNA in mouse lungs instilled with hBMSCs. The mitochondrial transfer resulted in increased alveolar ATP concentrations. LPS-induced ALI, as indicated by alveolar leukocytosis and protein leak, inhibition of surfactant secretion and high mortality, was markedly abrogated by the instillation of wild-type mBMSCs but not of mutant, GJC-incompetent mBMSCs or mBMSCs with dysfunctional mitochondria. This is the first evidence, to our knowledge, that BMSCs protect against ALI by restituting alveolar bioenergetics through Cx43-dependent alveolar attachment and mitochondrial transfer.", + "TAG_DATA": [ + "23, mice {'context': 'B-organism'}", + "32, mouse {'context': 'B-cells'}", + "33, BMSCs {'context': 'I-cells'}", + "34, (mBMSCs) {'context': 'I-cells'}", + "36, human {'context': 'B-cells'}", + "37, BMSCs {'context': 'I-cells'}", + "38, (hBMSCs). {'context': 'I-cells'}", + "60, mice, {'context': 'B-organism'}", + "90, mouse {'context': 'B-tissue/organ'}", + "91, lungs {'context': 'I-tissue/organ'}", + "94, hBMSCs. {'context': 'B-cells'}", + "129, mBMSCs {'context': 'B-cells'}", + "135, mBMSCs {'context': 'I-cells'}", + "137, mBMSCs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "23, mice ['l0']", + "32, mouse ['l1', 'l2', 'l3', 'l4', 'l5']", + "33, BMSCs ['l1', 'l6', 'l7', 'l8', 'l9', 'l10']", + "34, (mBMSCs) ['l2', 'l6', 'l11', 'l12']", + "36, human ['l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "37, BMSCs ['l3', 'l8', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "38, (hBMSCs). ['l4', 'l9', 'l11', 'l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "60, mice, ['l0', 'l5', 'l10', 'l12', 'l15', 'l20', 'l24']", + "90, mouse ['l16', 'l21', 'l25', 'l28', 'l29']", + "91, lungs ['l17', 'l22', 'l26', 'l28', 'l30']", + "94, hBMSCs. ['l18', 'l23', 'l27', 'l29', 'l30']", + "129, mBMSCs ['l31']", + "135, mBMSCs ['l31', 'l32']", + "137, mBMSCs ['l32']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22504483", + "TEXT": "Adenosine signaling has been implicated in cardiac adaptation to limited oxygen availability. In a wide search for adenosine receptor A2b (Adora2b)-elicited cardioadaptive responses, we identified the circadian rhythm protein period 2 (Per2) as an Adora2b target. Adora2b signaling led to Per2 stabilization during myocardial ischemia, and in this setting, Per2(-/-) mice had larger infarct sizes compared to wild-type mice and loss of the cardioprotection conferred by ischemic preconditioning. Metabolic studies uncovered a limited ability of ischemic hearts in Per2(-/-) mice to use carbohydrates for oxygen-efficient glycolysis. This impairment was caused by a failure to stabilize hypoxia-inducible factor-1α (Hif-1α). Moreover, stabilization of Per2 in the heart by exposing mice to intense light resulted in the transcriptional induction of glycolytic enzymes and Per2-dependent cardioprotection from ischemia. Together, these studies identify adenosine-elicited stabilization of Per2 in the control of HIF-dependent cardiac metabolism and ischemia tolerance and implicate Per2 stabilization as a potential new strategy for treating myocardial ischemia.", + "TAG_DATA": [ + "49, Per2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "50, mice {'context': 'B-organism'}", + "58, mice {'context': 'B-organism'}", + "76, hearts {'context': 'B-tissue/organ'}", + "78, Per2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "79, mice {'context': 'B-organism'}", + "104, heart {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "49, Per2(-/-) ['l0', 'l1', 'l2']", + "50, mice ['l0', 'l3']", + "58, mice ['l1', 'l3']", + "76, hearts ['l2', 'l4', 'l5']", + "78, Per2(-/-) ['l4', 'l6']", + "79, mice ['l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Per2(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Per2(-/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hearts" + ] + } + } + ] + }, + { + "PMID": "22484808", + "TEXT": "Age-related macular degeneration (AMD) is the leading cause of central vision loss worldwide. Drusen accumulation is the major pathological hallmark common to both dry and wet AMD. Although activation of the immune system has been implicated in disease progression, the pathways involved are unclear. Here we show that drusen isolated from donor AMD eyes activates the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, causing secretion of interleukin-1b (IL-1b) and IL-18. Drusen component C1Q also activates the NLRP3 inflammasome. Moreover, the oxidative-stress-related protein-modification carboxyethylpyrrole (CEP), a biomarker of AMD, primes the inflammasome. We found cleaved caspase-1 and NLRP3 in activated macrophages in the retinas of mice immunized with CEP-adducted mouse serum albumin, modeling a dry-AMD–like pathology. We show that laser-induced choroidal neovascularization (CNV), a mouse model of wet AMD, is exacerbated in Nlrp3(-/-) but not Il1r1(-/-) mice, directly implicating IL-18 in the regulation of CNV development. These findings indicate a protective role for NLRP3 and IL-18 in the progression of AMD.", + "TAG_DATA": [ + "101, macrophages {'context': 'B-cells'}", + "104, retinas {'context': 'B-tissue/organ'}", + "106, mice {'context': 'B-organism'}", + "133, Nlrp3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "136, Il1r1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "137, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "101, macrophages ['l0', 'l1']", + "104, retinas ['l0', 'l2']", + "106, mice ['l1', 'l2']", + "133, Nlrp3(-/-) ['l3', 'l4']", + "136, Il1r1(-/-) ['l3', 'l5']", + "137, mice, ['l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nlrp3(-/-)", + "Il1r1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "22447076", + "TEXT": "It is unclear whether the ability of the innate immune system to recognize distinct ligands from a single microbial pathogen via multiple pattern recognition receptors (PRRs) triggers common pathways or differentially triggers specific host responses. In the human mycobacterial infection leprosy, we found that activation of monocytes via nucleotide-binding oligomerization domain-containing protein 2 (NOD2) by its ligand muramyl dipeptide, as compared to activation via heterodimeric Toll-like receptor 2 and Toll-like receptor 1 (TLR2/1) by triacylated lipopeptide, preferentially induced differentiation into dendritic cells (DCs), which was dependent on a previously unknown interleukin-32 (IL-32)-dependent mechanism. Notably, IL-32 was sufficient to induce monocytes to rapidly differentiate into DCs, which were more efficient than granulocyte-macrophage colony-stimulating factor (GM-CSF)-derived DCs in presenting antigen to major histocompatibility complex (MHC) class I-restricted CD8(+) T cells. Expression of NOD2 and IL-32 and the frequency of CD1b(+) DCs at the site of leprosy infection correlated with the clinical presentation; they were greater in patients with limited as compared to progressive disease. The addition of recombinant IL-32 restored NOD2-induced DC differentiation in patients with the progressive form of leprosy. In conclusion, the NOD2 ligand-induced, IL-32-dependent DC differentiation pathway contributes a key and specific mechanism for host defense against microbial infection in humans.", + "TAG_DATA": [ + "77, induced {'effect': 'B-positive'}", + "78, differentiation {'phenotype': 'B-differentiation'}", + "80, dendritic {'context': 'B-cells'}", + "81, cells {'context': 'I-cells'}", + "98, induce {'effect': 'B-positive'}", + "99, monocytes {'context': 'B-cells'}", + "102, differentiate {'phenotype': 'B-differentiation'}", + "104, DCs, {'context': 'B-cells'}", + "114, DCs {'context': 'I-cells'}", + "125, CD8(+) {'context': 'B-cells'}", + "126, T {'context': 'I-cells'}", + "127, cells. {'context': 'I-cells'}", + "167, restored {'effect': 'B-rescues'}", + "169, DC {'context': 'B-cells'}", + "170, differentiation {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "77, induced ['l0', 'l1', 'l2']", + "78, differentiation ['l0', 'l3', 'l4']", + "80, dendritic ['l1', 'l3', 'l5', 'l6', 'l7', 'l8', 'l9']", + "81, cells ['l2', 'l4', 'l5', 'l10', 'l11']", + "98, induce ['l6', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "99, monocytes ['l7', 'l12', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "102, differentiate ['l8', 'l10', 'l13', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "104, DCs, ['l9', 'l11', 'l14', 'l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "114, DCs ['l15', 'l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "125, CD8(+) ['l16', 'l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "126, T ['l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "127, cells. ['l18', 'l24', 'l29', 'l33', 'l36', 'l38', 'l39']", + "167, restored ['l40', 'l41']", + "169, DC ['l40', 'l42']", + "170, differentiation ['l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced", + "induce" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "differentiate" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells", + "monocytes", + "DCs,", + "DCs", + "CD8(+)", + "T", + "cells." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "differentiate" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells", + "monocytes", + "DCs,", + "DCs", + "CD8(+)", + "T", + "cells.", + "DC" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + }, + "context": { + "val": "cells", + "words": [ + "DC" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "22406747", + "TEXT": "Acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML), characterized by the t(15;17)-associated PML-RARA fusion, has been successfully treated with therapy utilizing all-trans-retinoic acid (ATRA) to differentiate leukemic blasts. However, among patients with non-APL AML, ATRA-based treatment has not been effective. Here we show that, through epigenetic reprogramming, inhibitors of lysine-specific demethylase 1 (LSD1, also called KDM1A), including tranylcypromine (TCP), unlocked the ATRA-driven therapeutic response in non-APL AML. LSD1 inhibition did not lead to a large-scale increase in histone 3 Lys4 dimethylation (H3K4(me2)) across the genome, but it did increase H3K4(me2) and expression of myeloid-differentiation-associated genes. Notably, treatment with ATRA plus TCP markedly diminished the engraftment of primary human AML cells in vivo in nonobese diabetic (NOD)-severe combined immunodeficient (SCID) mice, suggesting that ATRA in combination with TCP may target leukemia-initiating cells. Furthermore, initiation of ATRA plus TCP treatment 15 d after engraftment of human AML cells in NOD-SCID γ (with interleukin-2 (IL-2) receptor γ chain deficiency) mice also revealed the ATRA plus TCP drug combination to have a potent anti-leukemic effect that was superior to treatment with either drug alone. These data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to AML pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for new combinatorial therapies for AML.", + "TAG_DATA": [ + "72, LSD1 {'perturbing_action': 'B-pharmacological inhibition'}", + "73, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "111, primary {'context': 'B-transformed cells'}", + "112, human {'context': 'I-transformed cells'}", + "113, AML {'context': 'I-transformed cells'}", + "114, cells {'context': 'I-transformed cells'}", + "115, in {'context': 'B-in vivo'}", + "116, vivo {'context': 'I-in vivo'}", + "118, nonobese {'context': 'B-organism'}", + "119, diabetic {'context': 'I-organism'}", + "120, (NOD)-severe {'context': 'I-organism'}", + "121, combined {'context': 'I-organism'}", + "122, immunodeficient {'context': 'I-organism'}", + "123, (SCID) {'context': 'I-organism'}", + "124, mice, {'context': 'I-organism'}", + "148, human {'context': 'B-transformed cells'}", + "149, AML {'context': 'I-transformed cells'}", + "150, cells {'context': 'I-transformed cells'}", + "152, NOD-SCID {'context': 'B-organism'}", + "153, γ {'context': 'I-organism'}", + "161, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "72, LSD1 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "73, inhibition ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "111, primary ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "112, human ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "113, AML ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54']", + "114, cells ['l4', 'l17', 'l29', 'l40', 'l50', 'l55', 'l56', 'l57']", + "115, in ['l5', 'l18', 'l30', 'l41', 'l51', 'l55', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "116, vivo ['l6', 'l19', 'l31', 'l42', 'l52', 'l56', 'l58', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "118, nonobese ['l7', 'l20', 'l32', 'l43', 'l59', 'l66', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "119, diabetic ['l8', 'l21', 'l33', 'l44', 'l60', 'l67', 'l73', 'l79', 'l80', 'l81', 'l82', 'l83']", + "120, (NOD)-severe ['l9', 'l22', 'l34', 'l45', 'l61', 'l68', 'l74', 'l79', 'l84', 'l85', 'l86', 'l87']", + "121, combined ['l10', 'l23', 'l35', 'l46', 'l62', 'l69', 'l75', 'l80', 'l84', 'l88', 'l89', 'l90']", + "122, immunodeficient ['l11', 'l24', 'l36', 'l47', 'l63', 'l70', 'l76', 'l81', 'l85', 'l88', 'l91', 'l92']", + "123, (SCID) ['l12', 'l25', 'l37', 'l48', 'l53', 'l64', 'l71', 'l77', 'l82', 'l86', 'l89', 'l91', 'l93']", + "124, mice, ['l13', 'l26', 'l38', 'l49', 'l54', 'l57', 'l65', 'l72', 'l78', 'l83', 'l87', 'l90', 'l92', 'l93']", + "148, human ['l94', 'l95']", + "149, AML ['l94', 'l96']", + "150, cells ['l95', 'l96']", + "152, NOD-SCID ['l97', 'l98']", + "153, γ ['l97', 'l99']", + "161, mice ['l98', 'l99']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "LSD1", + "inhibition" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "human", + "AML", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "LSD1", + "inhibition" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "LSD1", + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "nonobese", + "diabetic", + "(NOD)-severe", + "combined", + "immunodeficient", + "(SCID)", + "mice," + ] + } + } + ] + }, + { + "PMID": "22406746", + "TEXT": "Kidney fibrosis is a common process that leads to the progression of various types of kidney disease. We used an integrated computational and experimental systems biology approach to identify protein kinases that regulate gene expression changes in the kidneys of human immunodeficiency virus (HIV) transgenic mice (Tg26 mice), which have both tubulointerstitial fibrosis and glomerulosclerosis. We identified homeo-domain interacting protein kinase 2 (HIPK2) as a key regulator of kidney fibrosis. HIPK2 was upregulated in the kidneys of Tg26 mice and in those of patients with various kidney diseases. HIV infection increased the protein concentrations of HIPK2 by promoting oxidative stress, which inhibited the seven in absentia homolog 1 (SIAH1)-mediated proteasomal degradation of HIPK2. HIPK2 induced apoptosis and the expression of epithelial-to-mesenchymal transition markers in kidney epithelial cells by activating the p53, transforming growth factor β (TGF-β)-SMAD family member 3 (Smad3) and Wnt-Notch pathways. Knockout of HIPK2 improved renal function and attenuated proteinuria and kidney fibrosis in Tg26 mice, as well as in other murine models of kidney fibrosis. We therefore conclude that HIPK2 is a potential target for anti-fibrosis therapy.", + "TAG_DATA": [ + "45, mice {'context': 'B-organism'}", + "114, induced {'effect': 'B-positive'}", + "115, apoptosis {'phenotype': 'B-apoptosis'}", + "124, kidney {'context': 'B-cells'}", + "125, epithelial {'context': 'I-cells'}", + "126, cells {'context': 'I-cells'}", + "143, Knockout {'perturbing_action': 'B-gene loss-of-function'}", + "144, of {'perturbing_action': 'I-gene loss-of-function'}", + "145, HIPK2 {'perturbing_action': 'I-gene loss-of-function'}", + "156, Tg26 {'context': 'B-organism'}", + "157, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "114, induced ['l0', 'l1', 'l2', 'l3']", + "115, apoptosis ['l0', 'l4', 'l5', 'l6']", + "124, kidney ['l1', 'l4', 'l7', 'l8']", + "125, epithelial ['l2', 'l5', 'l7', 'l9']", + "126, cells ['l3', 'l6', 'l8', 'l9']", + "143, Knockout ['l10', 'l11', 'l12', 'l13']", + "144, of ['l10', 'l14', 'l15', 'l16']", + "145, HIPK2 ['l11', 'l14', 'l17', 'l18']", + "156, Tg26 ['l12', 'l15', 'l17', 'l19']", + "157, mice, ['l13', 'l16', 'l18', 'l19']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "kidney", + "epithelial", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "kidney", + "epithelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Knockout", + "of", + "HIPK2" + ] + }, + "context": { + "val": "organism", + "words": [ + "Tg26", + "mice," + ] + } + } + ] + }, + { + "PMID": "22388090", + "TEXT": "Bone homeostasis is maintained by the balance between osteoblastic bone formation and osteoclastic bone resorption. Osteoclasts are multinucleated cells that are formed by mononuclear preosteoclast fusion. Fat-soluble vitamins such as vitamin D are pivotal in maintaining skeletal integrity. However, the role of vitamin E in bone remodeling is unknown. Here, we show that mice deficient in α-tocopherol transfer protein (Ttpa(-/-) mice), a mouse model of genetic vitamin E deficiency, have high bone mass as a result of a decrease in bone resorption. Cell-based assays indicated that α-tocopherol stimulated osteoclast fusion, independent of its antioxidant capacity, by inducing the expression of dendritic-cell-specific transmembrane protein, an essential molecule for osteoclast fusion, through activation of mitogen-activated protein kinase 14 (p38) and microphthalmia-associated transcription factor, as well as its direct recruitment to the Tm7sf4 (a gene encoding DC-STAMP) promoter. Indeed, the bone abnormality seen in Ttpa(-/-) mice was rescued by a Tm7sf4 transgene. Moreover, wild-type mice or rats fed an α-tocopherol-supplemented diet, which contains a comparable amount of α-tocopherol to supplements consumed by many people, lost bone mass. These results show that serum vitamin E is a determinant of bone mass through its regulation of osteoclast fusion.", + "TAG_DATA": [ + "53, mice {'context': 'B-organism'}", + "54, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "55, in {'perturbing_action': 'I-gene loss-of-function'}", + "56, α-tocopherol {'perturbing_action': 'I-gene loss-of-function'}", + "57, transfer {'perturbing_action': 'I-gene loss-of-function'}", + "58, protein {'perturbing_action': 'I-gene loss-of-function'}", + "59, (Ttpa(-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "60, mice), {'perturbing_action': 'I-gene loss-of-function'}", + "141, Ttpa(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "142, mice {'context': 'B-organism'}", + "147, Tm7sf4 {'perturbing_action': 'B-gene gain-of-function'}", + "148, transgene. {'perturbing_action': 'I-gene gain-of-function'}", + "151, mice {'context': 'B-organism'}", + "153, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "53, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "54, deficient ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "55, in ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "56, α-tocopherol ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "57, transfer ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "58, protein ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "59, (Ttpa(-/-) ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "60, mice), ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "141, Ttpa(-/-) ['l28', 'l29', 'l30']", + "142, mice ['l28']", + "147, Tm7sf4 ['l29', 'l31']", + "148, transgene. ['l30', 'l31']", + "151, mice ['l32']", + "153, rats ['l32']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "α-tocopherol", + "transfer", + "protein", + "(Ttpa(-/-)", + "mice),", + "Ttpa(-/-)" + ] + } + } + ] + }, + { + "PMID": "22366952", + "TEXT": "Celiac disease is an immune-mediated disorder in which mucosal autoantibodies to the enzyme transglutaminase 2 (TG2) are generated in response to the exogenous antigen gluten in individuals who express human leukocyte antigen HLA-DQ2 or HLA-DQ8 (ref. 3). We assessed in a comprehensive and nonbiased manner the IgA anti-TG2 response by expression cloning of the antibody repertoire of ex vivo-isolated intestinal antibody-secreting cells (ASCs). We found that TG2-specific plasma cells are markedly expanded within the duodenal mucosa in individuals with active celiac disease. TG2-specific antibodies were of high affinity yet showed little adaptation by somatic mutations. Unlike infection-induced peripheral blood plasmablasts, the TG2-specific ASCs had not recently proliferated and were not short-lived ex vivo. Altogether, these observations demonstrate that there is a germline repertoire with high affinity for TG2 that may favor massive generation of autoreactive B cells. TG2-specific antibodies did not block enzymatic activity and served as substrates for TG2-mediated crosslinking when expressed as IgD or IgM but not as IgA1 or IgG1. This could result in preferential recruitment of plasma cells from naive IgD- and IgM-expressing B cells, thus possibly explaining why the antibody response to TG2 bears signs of a primary immune response despite the disease chronicity.", + "TAG_DATA": [ + "97, peripheral {'context': 'B-cells'}", + "98, blood {'context': 'I-cells'}", + "99, plasmablasts, {'context': 'I-cells'}", + "102, ASCs {'context': 'B-cells'}", + "104, not {'effect': 'B-no effect'}", + "105, recently {'effect': 'I-no effect'}", + "106, proliferated {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "97, peripheral ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "98, blood ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "99, plasmablasts, ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "102, ASCs ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "104, not ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "105, recently ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "106, proliferated ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "peripheral", + "blood", + "plasmablasts,", + "ASCs" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "recently" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "peripheral", + "blood", + "plasmablasts,", + "ASCs" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferated" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "recently" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferated" + ] + } + } + ] + }, + { + "PMID": "22366949", + "TEXT": "The TLX1 and TLX3 transcription factor oncogenes have a key role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL). Here we used reverse engineering of global transcriptional networks to decipher the oncogenic regulatory circuit controlled by TLX1 and TLX3. This systems biology analysis defined T cell leukemia homeobox 1 (TLX1) and TLX3 as master regulators of an oncogenic transcriptional circuit governing T-ALL. Notably, a network structure analysis of this hierarchical network identified RUNX1 as a key mediator of the T-ALL induced by TLX1 and TLX3 and predicted a tumor-suppressor role for RUNX1 in T cell transformation. Consistent with these results, we identified recurrent somatic loss-of-function mutations in RUNX1 in human T-ALL. Overall, these results place TLX1 and TLX3 at the top of an oncogenic transcriptional network controlling leukemia development, show the power of network analyses to identify key elements in the regulatory circuits governing human cancer and identify RUNX1 as a tumor-suppressor gene in T-ALL.", + "TAG_DATA": [ + "95, T {'context': 'B-cells'}", + "96, cell {'context': 'B-cells'}", + "97, transformation. {'phenotype': 'B-transformation'}" + ], + "LINK_DATA": [ + "95, T ['l0', 'l1']", + "96, cell ['l0', 'l2']", + "97, transformation. ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation." + ] + } + } + ] + }, + { + "PMID": "22344297", + "TEXT": "For centuries, opioid drugs have been the mainstay of chronic pain treatment. However, over time analgesic tolerance develops, leaving few treatment options. Here we show that platelet-derived growth factor receptor-β (PDGFR-β)-mediated signaling plays a key role in morphine tolerance. PDGFR-β inhibition selectively eliminates morphine tolerance in rats. PDGFR-β inhibitors are widely used and well tolerated, suggesting that clinical translation of our findings could reduce the suffering endured by individuals with intractable pain.", + "TAG_DATA": [ + "39, PDGFR-β {'perturbing_action': 'B-pharmacological inhibition'}", + "40, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "46, rats. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "39, PDGFR-β ['l0', 'l1']", + "40, inhibition ['l0', 'l2']", + "46, rats. ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PDGFR-β", + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats." + ] + } + } + ] + }, + { + "PMID": "22327624", + "TEXT": "We identified in-frame fusion transcripts of KIF5B (the kinesin family 5B gene) and the RET oncogene, which are present in 1-2% of lung adenocarcinomas (LADCs) from people from Japan and the United States, using whole-transcriptome sequencing. The KIF5B-RET fusion leads to aberrant activation of RET kinase and is considered to be a new driver mutation of LADC because it segregates from mutations or fusions in EGFR, KRAS, HER2 and ALK, and a RET tyrosine kinase inhibitor, vandetanib, suppresses the fusion-induced anchorage-independent growth activity of NIH3T3 cells.", + "TAG_DATA": [ + "77, suppresses {'effect': 'B-negative'}", + "80, anchorage-independent {'phenotype': 'B-autophagy'}", + "81, growth {'phenotype': 'I-cell growth'}", + "84, NIH3T3 {'context': 'B-cells'}", + "85, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "77, suppresses ['l0', 'l1', 'l2', 'l3']", + "80, anchorage-independent ['l0', 'l4', 'l5', 'l6']", + "81, growth ['l1', 'l4', 'l7', 'l8']", + "84, NIH3T3 ['l2', 'l5', 'l7', 'l9']", + "85, cells. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "anchorage-independent" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + }, + "context": { + "val": "cells", + "words": [ + "NIH3T3", + "cells." + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "anchorage-independent" + ] + }, + "context": { + "val": "cells", + "words": [ + "NIH3T3", + "cells." + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + }, + "context": { + "val": "cells", + "words": [ + "NIH3T3", + "cells." + ] + } + } + ] + }, + { + "PMID": "22327623", + "TEXT": "Through an integrated molecular- and histopathology-based screening system, we performed a screening for fusions of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1, receptor tyrosine kinase (ROS1) in 1,529 lung cancers and identified 44 ALK-fusion-positive and 13 ROS1-fusion-positive adenocarcinomas, including for unidentified fusion partners for ROS1. In addition, we discovered previously unidentified kinase fusions that may be promising for molecular-targeted therapy, kinesin family member 5B (KIF5B)-ret proto-oncogene (RET) and coiled-coil domain containing 6 (CCDC6)-RET, in 14 adenocarcinomas. A multivariate analysis of 1,116 adenocarcinomas containing these 71 kinase-fusion-positive adenocarcinomas identified four independent factors that are indicators of poor prognosis: age ≥ 50 years, male sex, high pathological stage and negative kinase-fusion status.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22327622", + "TEXT": "Applying a next-generation sequencing assay targeting 145 cancer-relevant genes in 40 colorectal cancer and 24 non-small cell lung cancer formalin-fixed paraffin-embedded tissue specimens identified at least one clinically relevant genomic alteration in 59% of the samples and revealed two gene fusions, C2orf44-ALK in a colorectal cancer sample and KIF5B-RET in a lung adenocarcinoma. Further screening of 561 lung adenocarcinomas identified 11 additional tumors with KIF5B-RET gene fusions (2.0%; 95% CI 0.8-3.1%). Cells expressing oncogenic KIF5B-RET are sensitive to multi-kinase inhibitors that inhibit RET.", + "TAG_DATA": [ + "45, cancer {'context': 'I-transformed cells'}", + "51, lung {'context': 'B-neoplasm'}", + "52, adenocarcinoma. {'context': 'I-neoplasm'}", + "57, lung {'context': 'B-neoplasm'}", + "58, adenocarcinomas {'context': 'I-neoplasm'}", + "71, Cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "44, colorectal ['l0', 'l1', 'l2']", + "45, cancer ['l0', 'l3', 'l4']", + "51, lung ['l1', 'l3', 'l5']", + "52, adenocarcinoma. ['l2', 'l4', 'l5']", + "57, lung ['l6']", + "58, adenocarcinomas ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22245782", + "TEXT": "Blood pressure regulation is crucial for the maintenance of health, and hypertension is a risk factor for myocardial infarction, heart failure, stroke and renal disease. Nitric oxide (NO) and prostacyclin trigger well-defined vasodilator pathways; however, substantial vasorelaxation in response to agents such as acetylcholine persists when the synthesis of these molecules is prevented. This remaining vasorelaxation activity, termed endothelium-derived hyperpolarizing factor (EDHF), is more prevalent in resistance than in conduit blood vessels and is considered a major mechanism for blood pressure control. Hydrogen peroxide (H2O2) has been shown to be a major component of EDHF in several vascular beds in multiple species, including in humans. H2O2 causes the formation of a disulfide bond between the two α subunits of protein kinase G I-α (PKGI-α), which activates the kinase independently of the NO-cyclic guanosine monophosphate (cGMP) pathway and is coupled to vasodilation. To test the importance of PKGI-α oxidation in the EDHF mechanism and blood pressure control in vivo, we generated a knock-in mouse expressing only a C42S 'redox-dead' version of PKGI-α. This amino acid substitution, a single-atom change (an oxygen atom replacing a sulfur atom), blocked the vasodilatory action of H2O2 on resistance vessels and resulted in hypertension in vivo.", + "TAG_DATA": [ + "161, knock-in {'perturbing_action': 'B-rnai/knockdown'}", + "162, mouse {'context': 'B-organism'}", + "170, PKGI-α. {'perturbing_action': 'I-rnai/knockdown'}", + "192, resistance {'context': 'B-tissue/organ'}", + "193, vessels {'context': 'I-tissue/organ'}", + "198, in {'context': 'B-in vivo'}", + "199, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "161, knock-in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "162, mouse ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "164, only ['l1', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "165, a ['l2', 'l10', 'l16', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "168, version ['l3', 'l11', 'l17', 'l24', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "169, of ['l4', 'l12', 'l18', 'l25', 'l31', 'l37', 'l38', 'l39', 'l40', 'l41']", + "170, PKGI-α. ['l5', 'l13', 'l19', 'l26', 'l32', 'l37', 'l42', 'l43', 'l44', 'l45']", + "192, resistance ['l6', 'l14', 'l20', 'l27', 'l33', 'l38', 'l42', 'l46', 'l47', 'l48']", + "193, vessels ['l7', 'l15', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l49', 'l50']", + "198, in ['l8', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l51']", + "199, vivo. ['l9', 'l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l51']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knock-in", + "PKGI-α." + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knock-in", + "PKGI-α." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "resistance", + "vessels" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knock-in", + "PKGI-α." + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "22179318", + "TEXT": "In sub-Saharan Africa, invasive nontyphoid Salmonella (NTS) infection is a common and often fatal complication of Plasmodium falciparum infection. Induction of heme oxygenase-1 (HO-1) mediates tolerance to the cytotoxic effects of heme during malarial hemolysis but might impair resistance to NTS by limiting production of bactericidal reactive oxygen species. We show that co-infection of mice with Plasmodium yoelii 17XNL (Py17XNL) and Salmonella enterica serovar Typhimurium 12023 (Salmonella typhimurium) causes acute, fatal bacteremia with high bacterial load, features reproduced by phenylhydrazine-induced hemolysis or hemin administration. S. typhimurium localized predominantly in granulocytes. Py17XNL, phenylhydrazine and hemin caused premature mobilization of granulocytes from bone marrow with a quantitative defect in the oxidative burst. Inhibition of HO by tin protoporphyrin abrogated the impairment of resistance to S. typhimurium by hemolysis. Thus, a mechanism of tolerance to one infection, malaria, impairs resistance to another, NTS. Furthermore, HO inhibitors may be useful adjunctive therapy for NTS infection in the context of hemolysis.", + "TAG_DATA": [ + "54, mice {'context': 'B-organism'}", + "98, granulocytes {'context': 'B-cells'}", + "100, bone {'context': 'B-cells'}", + "101, marrow {'context': 'I-tissue/organ'}", + "110, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "111, of {'perturbing_action': 'I-pharmacological inhibition'}", + "112, HO {'perturbing_action': 'I-pharmacological inhibition'}", + "113, by {'perturbing_action': 'I-pharmacological inhibition'}", + "114, tin {'perturbing_action': 'I-pharmacological inhibition'}", + "115, protoporphyrin {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "98, granulocytes ['l0', 'l1']", + "100, bone ['l0', 'l2']", + "101, marrow ['l1', 'l2']", + "110, Inhibition ['l3', 'l4', 'l5', 'l6', 'l7']", + "111, of ['l3', 'l8', 'l9', 'l10', 'l11']", + "112, HO ['l4', 'l8', 'l12', 'l13', 'l14']", + "113, by ['l5', 'l9', 'l12', 'l15', 'l16']", + "114, tin ['l6', 'l10', 'l13', 'l15', 'l17']", + "115, protoporphyrin ['l7', 'l11', 'l14', 'l16', 'l17']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22157681", + "TEXT": "The involvement of the MET oncogene in de novo and acquired resistance of non-small cell lung cancers (NSCLCs) to tyrosine kinase inhibitors (TKIs) has previously been reported, but the precise mechanism by which MET overexpression contributes to TKI-resistant NSCLC remains unclear. MicroRNAs (miRNAs) negatively regulate gene expression, and their dysregulation has been implicated in tumorigenesis. To understand their role in TKI-resistant NSCLCs, we examined changes in miRNA that are mediated by tyrosine kinase receptors. Here we report that miR-30b, miR-30c, miR-221 and miR-222 are modulated by both epidermal growth factor (EGF) and MET receptors, whereas miR-103 and miR-203 are controlled only by MET. We showed that these miRNAs have important roles in gefitinib-induced apoptosis and epithelial-mesenchymal transition of NSCLC cells in vitro and in vivo by inhibiting the expression of the genes encoding BCL2-like 11 (BIM), apoptotic peptidase activating factor 1 (APAF-1), protein kinase C ɛ (PKC-ɛ) and sarcoma viral oncogene homolog (SRC). These findings suggest that modulation of specific miRNAs may provide a therapeutic approach for the treatment of NSCLCs.", + "TAG_DATA": [ + "112, gefitinib-induced {'effect': 'B-positive'}", + "113, apoptosis {'phenotype': 'B-apoptosis'}", + "115, epithelial-mesenchymal {'phenotype': 'B-epithelial-mesenchymal transition'}", + "116, transition {'phenotype': 'I-epithelial-mesenchymal transition'}", + "118, NSCLC {'context': 'B-transformed cells'}", + "119, cells {'context': 'I-transformed cells'}", + "120, in {'context': 'B-in vitro'}", + "121, vitro {'context': 'I-in vitro'}", + "123, in {'context': 'B-in vivo'}", + "124, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "112, gefitinib-induced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "113, apoptosis ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "115, epithelial-mesenchymal ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "116, transition ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "118, NSCLC ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "119, cells ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "120, in ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "121, vitro ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "123, in ['l28']", + "124, vivo ['l28']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "gefitinib-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "gefitinib-induced" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "epithelial-mesenchymal", + "transition" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "gefitinib-induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "NSCLC", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "gefitinib-induced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "NSCLC", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "epithelial-mesenchymal", + "transition" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "NSCLC", + "cells" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "epithelial-mesenchymal", + "transition" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "22138753", + "TEXT": "Studies of ligand-receptor binding and the development of receptor antagonists would benefit greatly from imaging techniques that translate directly from cell-based assays to living animals. We used Gaussia luciferase protein fragment complementation to quantify the binding of chemokine (C-X-C motif) ligand 12 (CXCL12) to chemokine (C-X-C motif) receptor 4 (CXCR4) and CXCR7. Studies established that small-molecule inhibitors of CXCR4 or CXCR7 specifically blocked CXCL12 binding in cell-based assays and revealed differences in kinetics of inhibiting chemokine binding to each receptor. Bioluminescence imaging showed CXCL12-CXCR7 binding in primary and metastatic tumors in a mouse model of breast cancer. We used this imaging technique to quantify drug-mediated inhibition of CXCL12-CXCR4 binding in living mice. We expect this imaging technology to advance research in areas such as ligand-receptor interactions and the development of new therapeutic agents in cell-based assays and small animals.", + "TAG_DATA": [ + "55, small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "56, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "57, of {'perturbing_action': 'I-pharmacological inhibition'}", + "58, CXCR4 {'perturbing_action': 'I-pharmacological inhibition'}", + "59, or {'perturbing_action': 'I-pharmacological inhibition'}", + "60, CXCR7 {'perturbing_action': 'I-pharmacological inhibition'}", + "86, primary {'context': 'B-neoplasm'}", + "87, and {'context': 'I-neoplasm'}", + "88, metastatic {'context': 'I-neoplasm'}", + "89, tumors {'context': 'I-neoplasm'}", + "92, mouse {'context': 'B-neoplasm'}", + "93, model {'context': 'I-neoplasm'}", + "94, of {'context': 'I-neoplasm'}", + "95, breast {'context': 'I-neoplasm'}", + "96, cancer. {'context': 'I-neoplasm'}", + "110, living {'context': 'B-organism'}", + "111, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "55, small-molecule ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "56, inhibitors ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "57, of ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "58, CXCR4 ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "59, or ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "60, CXCR7 ['l4', 'l17', 'l29', 'l40', 'l50', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "86, primary ['l5', 'l18', 'l30', 'l41', 'l51', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "87, and ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "88, metastatic ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "89, tumors ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l90', 'l91', 'l92', 'l93', 'l94']", + "92, mouse ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l95', 'l96', 'l97', 'l98']", + "93, model ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l99', 'l100', 'l101']", + "94, of ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l102', 'l103']", + "95, breast ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l104']", + "96, cancer. ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l104']", + "110, living ['l105']", + "111, mice. ['l105']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "inhibitors", + "of", + "CXCR4", + "or", + "CXCR7" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "primary", + "and", + "metastatic", + "tumors", + "mouse", + "model", + "of", + "breast", + "cancer." + ] + } + } + ] + }, + { + "PMID": "22138752", + "TEXT": "Malignant transformation, invasion and angiogenesis rely on the coordinated reprogramming of gene expression in the cells from which the tumor originated. Although deregulated gene expression has been extensively studied at genomic and epigenetic scales, the contribution of the regulation of mRNA-specific translation to this reprogramming is not well understood. Here we show that cytoplasmic polyadenylation element binding protein 4 (CPEB4), an RNA binding protein that mediates meiotic mRNA cytoplasmic polyadenylation and translation, is overexpressed in pancreatic ductal adenocarcinomas and glioblastomas, where it supports tumor growth, vascularization and invasion. We also show that, in pancreatic tumors, the pro-oncogenic functions of CPEB4 originate in the translational activation of mRNAs that are silenced in normal tissue, including the mRNA of tissue plasminogen activator, a key contributor to pancreatic ductal adenocarcinoma malignancy. Taken together, our results document a key role for post-transcriptional gene regulation in tumor development and describe a detailed mechanism for gene expression reprogramming underlying malignant tumor progression.", + "TAG_DATA": [ + "82, supports {'effect': 'B-positive'}", + "83, tumor {'phenotype': 'B-tumour growth'}", + "84, growth, {'phenotype': 'I-tumour growth'}", + "87, invasion. {'phenotype': 'B-invasion'}" + ], + "LINK_DATA": [ + "82, supports ['l0', 'l1', 'l2']", + "83, tumor ['l0', 'l3', 'l4']", + "84, growth, ['l1', 'l3', 'l5']", + "87, invasion. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "supports" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "supports" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion." + ] + } + } + ] + }, + { + "PMID": "22127134", + "TEXT": "The presentation pathways by which allogeneic peptides induce graft-versus-host disease (GVHD) are unclear. We developed a bone marrow transplant (BMT) system in mice whereby presentation of a processed recipient peptide within major histocompatibility complex (MHC) class II molecules could be spatially and temporally quantified. Whereas donor antigen presenting cells (APCs) could induce lethal acute GVHD via MHC class II, recipient APCs were 100-1,000 times more potent in this regard. After myeloablative irradiation, T cell activation and memory differentiation occurred in lymphoid organs independently of alloantigen. Unexpectedly, professional hematopoietic-derived recipient APCs within lymphoid organs had only a limited capacity to induce GVHD, and dendritic cells were not required. In contrast, nonhematopoietic recipient APCs within target organs induced universal GVHD mortality and promoted marked alloreactive donor T cell expansion within the gastrointestinal tract and inflammatory cytokine generation. These data challenge current paradigms, suggesting that experimental lethal acute GVHD can be induced by nonhematopoietic recipient APCs.", + "TAG_DATA": [ + "22, mice {'context': 'B-organism'}", + "72, T {'context': 'B-cells'}", + "73, cell {'context': 'B-cells'}", + "76, memory {'phenotype': 'B-differentiation'}", + "77, differentiation {'phenotype': 'I-differentiation'}", + "80, lymphoid {'context': 'B-tissue/organ'}", + "81, organs {'context': 'I-tissue/organ'}", + "87, hematopoietic-derived {'context': 'I-cells'}", + "88, recipient {'context': 'I-cells'}", + "89, APCs {'context': 'I-cells'}", + "91, lymphoid {'context': 'B-tissue/organ'}", + "92, organs {'context': 'I-tissue/organ'}", + "102, dendritic {'context': 'B-cells'}", + "103, cells {'context': 'I-cells'}", + "109, nonhematopoietic {'context': 'B-cells'}", + "110, recipient {'context': 'I-cells'}", + "111, APCs {'context': 'I-cells'}", + "114, organs {'context': 'I-tissue/organ'}", + "122, alloreactive {'context': 'B-cells'}", + "123, donor {'context': 'I-cells'}", + "124, T {'context': 'I-cells'}", + "125, cell {'context': 'I-cells'}", + "129, gastrointestinal {'context': 'B-tissue/organ'}", + "130, tract {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "22, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "72, T ['l0', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "73, cell ['l1', 'l5', 'l11', 'l12', 'l13', 'l14', 'l15']", + "74, activation ['l2', 'l6', 'l11', 'l16', 'l17', 'l18', 'l19']", + "76, memory ['l7', 'l12', 'l16', 'l20', 'l21', 'l22']", + "77, differentiation ['l3', 'l8', 'l13', 'l17', 'l20', 'l23', 'l24']", + "80, lymphoid ['l9', 'l14', 'l18', 'l21', 'l23', 'l25']", + "81, organs ['l4', 'l10', 'l15', 'l19', 'l22', 'l24', 'l25']", + "87, hematopoietic-derived ['l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "88, recipient ['l26', 'l32', 'l33', 'l34', 'l35', 'l36']", + "89, APCs ['l27', 'l32', 'l37', 'l38', 'l39', 'l40']", + "91, lymphoid ['l28', 'l33', 'l37', 'l41', 'l42', 'l43']", + "92, organs ['l29', 'l34', 'l38', 'l41', 'l44']", + "102, dendritic ['l30', 'l35', 'l39', 'l42', 'l45']", + "103, cells ['l31', 'l36', 'l40', 'l43', 'l44', 'l45']", + "109, nonhematopoietic ['l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "110, recipient ['l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "111, APCs ['l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "114, organs ['l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "122, alloreactive ['l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "123, donor ['l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "124, T ['l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "125, cell ['l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "129, gastrointestinal ['l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "130, tract ['l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "memory", + "differentiation" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "memory", + "differentiation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lymphoid", + "organs" + ] + } + } + ] + }, + { + "PMID": "22120178", + "TEXT": "Monogenic neurodevelopmental disorders provide key insights into the pathogenesis of disease and help us understand how specific genes control the development of the human brain. Timothy syndrome is caused by a missense mutation in the L-type calcium channel Ca(v)1.2 that is associated with developmental delay and autism. We generated cortical neuronal precursor cells and neurons from induced pluripotent stem cells derived from individuals with Timothy syndrome. Cells from these individuals have defects in calcium (Ca(2+)) signaling and activity-dependent gene expression. They also show abnormalities in differentiation, including decreased expression of genes that are expressed in lower cortical layers and in callosal projection neurons. In addition, neurons derived from individuals with Timothy syndrome show abnormal expression of tyrosine hydroxylase and increased production of norepinephrine and dopamine. This phenotype can be reversed by treatment with roscovitine, a cyclin-dependent kinase inhibitor and atypical L-type-channel blocker. These findings provide strong evidence that Ca(v)1.2 regulates the differentiation of cortical neurons in humans and offer new insights into the causes of autism in individuals with Timothy syndrome.", + "TAG_DATA": [ + "49, cortical {'context': 'B-cells'}", + "50, neuronal {'context': 'I-cells'}", + "51, precursor {'context': 'I-cells'}", + "52, cells {'context': 'I-cells'}", + "54, neurons {'context': 'B-cells'}", + "55, from {'context': 'I-cells'}", + "56, induced {'context': 'I-cells'}", + "57, pluripotent {'context': 'I-cells'}", + "58, stem {'context': 'I-cells'}", + "59, cells {'context': 'I-cells'}", + "105, neurons {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "49, cortical ['l0', 'l1', 'l2']", + "50, neuronal ['l0', 'l3', 'l4']", + "51, precursor ['l1', 'l3', 'l5']", + "52, cells ['l2', 'l4', 'l5']", + "54, neurons ['l6', 'l7', 'l8', 'l9', 'l10']", + "55, from ['l6', 'l11', 'l12', 'l13', 'l14']", + "56, induced ['l7', 'l11', 'l15', 'l16', 'l17']", + "57, pluripotent ['l8', 'l12', 'l15', 'l18', 'l19']", + "58, stem ['l9', 'l13', 'l16', 'l18', 'l20']", + "59, cells ['l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22101769", + "TEXT": "Glycoconjugate vaccines have provided enormous health benefits globally, but they have been less successful in some populations at high risk for developing disease. To identify new approaches to enhancing glycoconjugate effectiveness, we investigated molecular and cellular mechanisms governing the immune response to a prototypical glycoconjugate vaccine. We found that in antigen-presenting cells a carbohydrate epitope is generated upon endolysosomal processing of group B streptococcal type III polysaccharide coupled to a carrier protein. In conjunction with a carrier protein-derived peptide, this carbohydrate epitope binds major histocompatibility class II (MHCII) and stimulates carbohydrate-specific CD4(+) T cell clones to produce interleukins 2 and 4-cytokines essential for providing T cell help to antibody-producing B cells. An archetypical glycoconjugate vaccine that we constructed to maximize the presentation of carbohydrate-specific T cell epitopes is 50-100 times more potent and substantially more protective in a neonatal mouse model of group B Streptococcus infection than a vaccine constructed by methods currently used by the vaccine industry. Our discovery of how glycoconjugates are processed resulting in presentation of carbohydrate epitopes that stimulate CD4(+) T cells has key implications for glycoconjugate vaccine design that could result in greatly enhanced vaccine efficacy.", + "TAG_DATA": [ + "91, CD4(+) {'context': 'B-cells'}", + "92, T {'context': 'I-cells'}", + "93, cell {'context': 'I-cells'}", + "94, clones {'context': 'I-cells'}", + "108, antibody-producing {'context': 'B-cells'}", + "109, B {'context': 'I-cells'}", + "110, cells. {'context': 'I-cells'}", + "138, neonatal {'context': 'B-organism'}", + "139, mouse {'context': 'I-organism'}", + "140, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "91, CD4(+) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "92, T ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "93, cell ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "94, clones ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "108, antibody-producing ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "109, B ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "110, cells. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "138, neonatal ['l21', 'l22']", + "139, mouse ['l21', 'l23']", + "140, model ['l22', 'l23']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22101766", + "TEXT": "Breast cancer is a heterogeneous disease that has a wide range of molecular aberrations and clinical outcomes. Here we used paired-end transcriptome sequencing to explore the landscape of gene fusions in a panel of breast cancer cell lines and tissues. We observed that individual breast cancers have a variety of expressed gene fusions. We identified two classes of recurrent gene rearrangements involving genes encoding microtubule-associated serine-threonine kinase (MAST) and members of the Notch family. Both MAST and Notch-family gene fusions have substantial phenotypic effects in breast epithelial cells. Breast cancer cell lines harboring Notch gene rearrangements are uniquely sensitive to inhibition of Notch signaling, and overexpression of MAST1 or MAST2 gene fusions has a proliferative effect both in vitro and in vivo. These findings show that recurrent gene rearrangements have key roles in subsets of carcinomas and suggest that transcriptome sequencing could identify individuals with rare, targetable gene fusions.", + "TAG_DATA": [ + "85, breast {'context': 'B-cells'}", + "86, epithelial {'context': 'I-cells'}", + "87, cells. {'context': 'I-cells'}", + "88, Breast {'context': 'B-transformed cells'}", + "89, cancer {'context': 'I-transformed cells'}", + "90, cell {'context': 'I-transformed cells'}", + "91, lines {'context': 'I-transformed cells'}", + "105, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "106, of {'perturbing_action': 'I-gene gain-of-function'}", + "107, MAST1 {'perturbing_action': 'I-gene gain-of-function'}", + "108, or {'perturbing_action': 'I-gene gain-of-function'}", + "109, MAST2 {'perturbing_action': 'I-gene gain-of-function'}", + "110, gene {'perturbing_action': 'I-gene gain-of-function'}", + "111, fusions {'perturbing_action': 'I-gene gain-of-function'}", + "114, proliferative {'phenotype': 'B-proliferation'}", + "115, effect {'phenotype': 'I-proliferation'}", + "117, in {'context': 'B-in vitro'}", + "118, vitro {'context': 'I-in vitro'}", + "120, in {'context': 'B-in vivo'}", + "121, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "85, breast ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "86, epithelial ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "87, cells. ['l1', 'l6', 'l11']", + "88, Breast ['l2', 'l7', 'l12', 'l13', 'l14']", + "89, cancer ['l3', 'l8', 'l12', 'l15', 'l16']", + "90, cell ['l4', 'l9', 'l11', 'l13', 'l15', 'l17']", + "91, lines ['l5', 'l10', 'l14', 'l16', 'l17']", + "105, overexpression ['l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "106, of ['l18', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "107, MAST1 ['l19', 'l30', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "108, or ['l20', 'l31', 'l41', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "109, MAST2 ['l21', 'l32', 'l42', 'l51', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "110, gene ['l22', 'l33', 'l43', 'l52', 'l60', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "111, fusions ['l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "114, proliferative ['l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l81', 'l82', 'l83', 'l84', 'l85']", + "115, effect ['l25', 'l36', 'l46', 'l55', 'l63', 'l70', 'l76', 'l81', 'l86', 'l87', 'l88', 'l89']", + "117, in ['l26', 'l37', 'l47', 'l56', 'l64', 'l71', 'l77', 'l82', 'l86', 'l90', 'l91', 'l92']", + "118, vitro ['l27', 'l38', 'l48', 'l57', 'l65', 'l72', 'l78', 'l83', 'l87', 'l90', 'l93', 'l94']", + "120, in ['l28', 'l39', 'l49', 'l58', 'l66', 'l73', 'l79', 'l84', 'l88', 'l91', 'l93', 'l95']", + "121, vivo. ['l29', 'l40', 'l50', 'l59', 'l67', 'l74', 'l80', 'l85', 'l89', 'l92', 'l94', 'l95']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "MAST1", + "or", + "MAST2", + "gene", + "fusions" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "effect" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "MAST1", + "or", + "MAST2", + "gene", + "fusions" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "MAST1", + "or", + "MAST2", + "gene", + "fusions" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "effect" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "effect" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "22081025", + "TEXT": "Excessive activation of the β-adrenergic, angiotensin II (Ang II) and aldosterone signaling pathways promotes mortality after myocardial infarction, and antagonists targeting these pathways are core therapies for treating this condition. Catecholamines and Ang II activate the multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), the inhibition of which prevents isoproterenol-mediated and Ang II-mediated cardiomyopathy. Here we show that aldosterone exerts direct toxic actions on myocardium by oxidative activation of CaMKII, causing cardiac rupture and increased mortality in mice after myocardial infarction. Aldosterone induces CaMKII oxidation by recruiting NADPH oxidase, and this oxidized and activated CaMKII promotes matrix metalloproteinase 9 (MMP9) expression in cardiomyocytes. Myocardial CaMKII inhibition, overexpression of methionine sulfoxide reductase A (an enzyme that reduces oxidized CaMKII) or NADPH oxidase deficiency prevented aldosterone-enhanced cardiac rupture after myocardial infarction. These findings show that oxidized myocardial CaMKII mediates the cardiotoxic effects of aldosterone on the cardiac matrix and establish CaMKII as a nodal signal for the neurohumoral pathways associated with poor outcomes after myocardial infarction.", + "TAG_DATA": [ + "75, mice {'context': 'B-organism'}", + "100, cardiomyocytes. {'context': 'B-cells'}", + "101, Myocardial {'perturbing_action': 'B-pharmacological inhibition'}", + "102, CaMKII {'perturbing_action': 'I-pharmacological inhibition'}", + "103, inhibition, {'perturbing_action': 'I-pharmacological inhibition'}", + "104, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "105, of {'perturbing_action': 'I-gene gain-of-function'}", + "106, methionine {'perturbing_action': 'I-gene gain-of-function'}", + "107, sulfoxide {'perturbing_action': 'I-gene gain-of-function'}", + "108, reductase {'perturbing_action': 'I-gene gain-of-function'}", + "109, A {'perturbing_action': 'I-gene gain-of-function'}", + "110, (an {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "75, mice ['l0']", + "100, cardiomyocytes. ['l0']", + "101, Myocardial ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "102, CaMKII ['l1', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "103, inhibition, ['l2', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "104, overexpression ['l3', 'l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "105, of ['l4', 'l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "106, methionine ['l5', 'l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "107, sulfoxide ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "108, reductase ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "109, A ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "110, (an ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22081023", + "TEXT": "Met is the transmembrane tyrosine kinase cell surface receptor for hepatocyte growth factor (HGF) and is structurally related to the insulin receptor (INSR) tyrosine kinase. Here we report that the HGF-Met axis regulates metabolism by stimulating hepatic glucose uptake and suppressing hepatic glucose output. We show that Met is essential for an optimal hepatic insulin response by directly engaging INSR to form a Met-INSR hybrid complex, which culminates in a robust signal output. We also found that the HGF-Met system restores insulin responsiveness in a mouse model of insulin refractoriness. These results provide new insights into the molecular basis of hepatic insulin resistance and suggest that HGF may have therapeutic potential for type 2 diabetes in the clinical setting.", + "TAG_DATA": [ + "85, mouse {'context': 'B-organism'}", + "86, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "85, mouse ['l0']", + "86, model ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22081022", + "TEXT": "Mature dendritic cells (DCs) are crucial for the induction of adaptive immune responses and perturbed DC homeostasis can result in autoimmune disease. Either uncontrolled expansion or enhanced survival of DCs can result in a variety of autoimmune diseases in mouse models. In addition, increased maturation signals, through overexpression of surface Toll-like receptors (TLRs) or stimulation by type I interferon (IFN), has been associated with systemic autoimmunity. Whereas recent studies have focused on identifying factors required for initiating the maturation process, the possibility that resting DCs also express molecules that 'hold' them in an immature state has generally not been considered. Here we show that nuclear factor-κB1 (NF-κB1) is crucial for maintaining the resting state of DCs. Self-antigen-pulsed unstimulated DCs that do not express NF-κB1 were able to activate CD8(+) T lymphocytes and induce autoimmunity. We further show that NF-κB1 negatively regulates the spontaneous production of tumor necrosis factor-α (TNF-α), which is associated with increased granzyme B expression in cytotoxic T lymphocytes (CTLs). These findings provide a new perspective on functional DC maturation and a potential mechanism that may account for pathologic T cell activation.", + "TAG_DATA": [ + "118, DCs {'context': 'B-cells'}", + "128, CD8(+) {'context': 'B-cells'}", + "129, T {'context': 'I-cells'}", + "130, lymphocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "118, DCs ['l0', 'l1', 'l2']", + "128, CD8(+) ['l0', 'l3', 'l4']", + "129, T ['l1', 'l3', 'l5']", + "130, lymphocytes ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22057347", + "TEXT": "Ubiquitin-tagged substrates are degraded by the 26S proteasome, which is a multisubunit complex comprising a proteolytic 20S core particle capped by 19S regulatory particles. The approval of bortezomib for the treatment of multiple myeloma validated the 20S core particle as an anticancer drug target. Here we describe the small molecule b-AP15 as a previously unidentified class of proteasome inhibitor that abrogates the deubiquitinating activity of the 19S regulatory particle. b-AP15 inhibited the activity of two 19S regulatory-particle-associated deubiquitinases, ubiquitin C-terminal hydrolase 5 (UCHL5) and ubiquitin-specific peptidase 14 (USP14), resulting in accumulation of polyubiquitin. b-AP15 induced tumor cell apoptosis that was insensitive to TP53 status and overexpression of the apoptosis inhibitor BCL2. We show that treatment with b-AP15 inhibited tumor progression in four different in vivo solid tumor models and inhibited organ infiltration in an acute myeloid leukemia model. Our results show that the deubiquitinating activity of the 19S regulatory particle is a new anticancer drug target.", + "TAG_DATA": [ + "94, induced {'effect': 'B-positive'}", + "95, tumor {'context': 'B-transformed cells'}", + "96, cell {'context': 'I-transformed cells'}", + "97, apoptosis {'phenotype': 'B-apoptosis'}", + "105, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "106, of {'perturbing_action': 'I-gene gain-of-function'}", + "107, the {'perturbing_action': 'I-gene gain-of-function'}", + "108, apoptosis {'perturbing_action': 'I-gene gain-of-function'}", + "109, inhibitor {'perturbing_action': 'I-gene gain-of-function'}", + "110, BCL2. {'perturbing_action': 'I-gene gain-of-function'}", + "117, inhibited {'effect': 'B-negative'}", + "118, tumor {'phenotype': 'B-tumour progression'}", + "119, progression {'phenotype': 'I-tumour progression'}", + "123, in {'context': 'B-in vivo'}", + "124, vivo {'context': 'B-in vivo'}", + "125, solid {'context': 'B-neoplasm'}", + "126, tumor {'context': 'I-neoplasm'}", + "127, models {'context': 'I-neoplasm'}", + "134, acute {'context': 'B-neoplasm'}", + "135, myeloid {'context': 'I-neoplasm'}", + "136, leukemia {'context': 'I-neoplasm'}", + "137, model. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "94, induced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "95, tumor ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "96, cell ['l1', 'l8', 'l16', 'l17', 'l18']", + "97, apoptosis ['l2', 'l9', 'l16', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "105, overexpression ['l10', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "106, of ['l3', 'l11', 'l20', 'l25', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "107, the ['l4', 'l12', 'l21', 'l26', 'l37', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "108, apoptosis ['l5', 'l13', 'l22', 'l27', 'l38', 'l49', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "109, inhibitor ['l6', 'l14', 'l17', 'l23', 'l28', 'l39', 'l50', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "110, BCL2. ['l7', 'l15', 'l18', 'l24', 'l29', 'l40', 'l51', 'l61', 'l69', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "117, inhibited ['l41', 'l52', 'l70', 'l78', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "118, tumor ['l30', 'l42', 'l53', 'l62', 'l71', 'l79', 'l86', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "119, progression ['l31', 'l43', 'l54', 'l63', 'l72', 'l80', 'l87', 'l97', 'l103', 'l104', 'l105', 'l106', 'l107']", + "123, in ['l32', 'l44', 'l55', 'l64', 'l73', 'l81', 'l88', 'l98', 'l103', 'l108', 'l109', 'l110', 'l111']", + "124, vivo ['l33', 'l45', 'l56', 'l65', 'l74', 'l82', 'l89', 'l99', 'l104', 'l108', 'l112', 'l113', 'l114']", + "125, solid ['l34', 'l46', 'l57', 'l66', 'l75', 'l83', 'l90', 'l100', 'l105', 'l109', 'l112', 'l115', 'l116']", + "126, tumor ['l35', 'l47', 'l58', 'l67', 'l76', 'l84', 'l91', 'l101', 'l106', 'l110', 'l113', 'l115', 'l117']", + "127, models ['l36', 'l48', 'l59', 'l68', 'l77', 'l85', 'l92', 'l102', 'l107', 'l111', 'l114', 'l116', 'l117']", + "134, acute ['l93', 'l118', 'l119', 'l120']", + "135, myeloid ['l94', 'l118', 'l121', 'l122']", + "136, leukemia ['l95', 'l119', 'l121', 'l123']", + "137, model. ['l96', 'l120', 'l122', 'l123']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "the", + "apoptosis", + "inhibitor", + "BCL2." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "the", + "apoptosis", + "inhibitor", + "BCL2." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "the", + "apoptosis", + "inhibitor", + "BCL2." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "the", + "apoptosis", + "inhibitor", + "BCL2." + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "the", + "apoptosis", + "inhibitor", + "BCL2." + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "the", + "apoptosis", + "inhibitor", + "BCL2." + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "solid", + "tumor", + "models" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "the", + "inhibitor", + "BCL2." + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "solid", + "tumor", + "models", + "acute", + "myeloid", + "leukemia", + "model." + ] + } + }, + { + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "solid", + "tumor", + "models" + ] + } + } + ] + }, + { + "PMID": "22057345", + "TEXT": "Advancing understanding of human coronary artery disease requires new methods that can be used in patients for studying atherosclerotic plaque microstructure in relation to the molecular mechanisms that underlie its initiation, progression and clinical complications, including myocardial infarction and sudden cardiac death. Here we report a dual-modality intra-arterial catheter for simultaneous microstructural and molecular imaging in vivo using a combination of optical frequency domain imaging (OFDI) and near-infrared fluorescence (NIRF) imaging. By providing simultaneous molecular information in the context of the surrounding tissue microstructure, this new catheter could provide new opportunities for investigating coronary atherosclerosis and stent healing and for identifying high-risk biological and structural coronary arterial plaques in vivo.", + "TAG_DATA": [ + "55, in {'context': 'B-in vivo'}", + "56, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "55, in ['l0']", + "56, vivo ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22019887", + "TEXT": "Development and preclinical testing of new cancer therapies is limited by the scarcity of in vivo models that authentically reproduce tumor growth and metastatic progression. We report new models for breast tumor growth and metastasis in the form of transplantable tumors derived directly from individuals undergoing treatment for breast cancer. These tumor grafts illustrate the diversity of human breast cancer and maintain essential features of the original tumors, including metastasis to specific sites. Co-engraftment of primary human mesenchymal stem cells maintains phenotypic stability of the grafts and increases tumor growth by promoting angiogenesis. We also report that tumor engraftment is a prognostic indicator of disease outcome for women with newly diagnosed breast cancer; orthotopic breast tumor grafting is a step toward individualized models for tumor growth, metastasis and prognosis. This bank of tumor grafts also serves as a publicly available resource for new models in which to study the biology of breast cancer.", + "TAG_DATA": [ + "75, primary {'context': 'B-cells'}", + "76, human {'context': 'I-cells'}", + "77, mesenchymal {'context': 'I-cells'}", + "78, stem {'context': 'I-cells'}", + "79, cells {'context': 'I-cells'}", + "87, increases {'effect': 'B-positive'}", + "88, tumor {'phenotype': 'B-tumour growth'}", + "89, growth {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "75, primary ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "76, human ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "77, mesenchymal ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "78, stem ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "79, cells ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "87, increases ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "88, tumor ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "89, growth ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "primary", + "human", + "mesenchymal", + "stem", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increases" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "primary", + "human", + "mesenchymal", + "stem", + "cells" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + } + ] + }, + { + "PMID": "22001908", + "TEXT": "Infertility and recurrent pregnancy loss (RPL) are prevalent but distinct causes of reproductive failure that often remain unexplained despite extensive investigations. Analysis of midsecretory endometrial samples revealed that SGK1, a kinase involved in epithelial ion transport and cell survival, is upregulated in unexplained infertility, most prominently in the luminal epithelium, but downregulated in the endometrium of women suffering from RPL. To determine the functional importance of these observations, we first expressed a constitutively active SGK1 mutant in the luminal epithelium of the mouse uterus. This prevented expression of certain endometrial receptivity genes, perturbed uterine fluid handling and abolished embryo implantation. By contrast, implantation was unhindered in Sgk1-/- mice, but pregnancy was often complicated by bleeding at the decidual-placental interface and fetal growth retardation and subsequent demise. Compared to wild-type mice, Sgk1-/- mice had gross impairment of pregnancy-dependent induction of genes involved in oxidative stress defenses. Relative SGK1 deficiency was also a hallmark of decidualizing stromal cells from human subjects with RPL and sensitized these cells to oxidative cell death. Thus, depending on the cellular compartment, deregulated SGK1 activity in cycling endometrium interferes with embryo implantation, leading to infertility, or predisposes to pregnancy complications by rendering the feto-maternal interface vulnerable to oxidative damage.", + "TAG_DATA": [ + "72, constitutively {'perturbing_action': 'I-other'}", + "73, active {'perturbing_action': 'I-other'}", + "74, SGK1 {'perturbing_action': 'I-other'}", + "75, mutant {'perturbing_action': 'I-other'}", + "76, in {'perturbing_action': 'I-other'}", + "77, the {'perturbing_action': 'I-other'}", + "78, luminal {'perturbing_action': 'I-other'}", + "79, epithelium {'perturbing_action': 'I-other', 'context': 'I-tissue/organ'}", + "80, of {'perturbing_action': 'I-other'}", + "82, mouse {'context': 'B-tissue/organ'}", + "83, uterus. {'context': 'I-tissue/organ'}", + "97, abolished {'effect': 'B-negative'}", + "102, implantation {'phenotype': 'B-autophagy'}", + "106, Sgk1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "107, mice, {'context': 'B-organism'}", + "129, mice, {'context': 'B-organism'}", + "130, Sgk1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "131, mice {'context': 'B-organism'}", + "146, SGK1 {'perturbing_action': 'B-gene loss-of-function'}", + "147, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "162, sensitized {'effect': 'B-positive'}", + "164, cells {'context': 'B-cells'}", + "167, cell {'phenotype': 'B-cell death'}", + "168, death. {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "72, constitutively ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "73, active ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "74, SGK1 ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "75, mutant ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "76, in ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "77, the ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "78, luminal ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "79, epithelium ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "80, of ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "82, mouse ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "83, uterus. ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "97, abolished ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "99, implantation. ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "102, implantation ['l78', 'l79']", + "106, Sgk1-/- ['l78', 'l80']", + "107, mice, ['l79', 'l80']", + "129, mice, ['l81', 'l82', 'l83', 'l84', 'l85']", + "130, Sgk1-/- ['l81', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "131, mice ['l82', 'l86', 'l92', 'l93', 'l94']", + "146, SGK1 ['l95', 'l96', 'l97', 'l98', 'l99']", + "147, deficiency ['l87', 'l95', 'l100', 'l101', 'l102', 'l103']", + "162, sensitized ['l88', 'l96', 'l100', 'l104', 'l105', 'l106']", + "164, cells ['l83', 'l89', 'l92', 'l97', 'l101', 'l104', 'l107', 'l108']", + "167, cell ['l84', 'l90', 'l93', 'l98', 'l102', 'l105', 'l107', 'l109']", + "168, death. ['l85', 'l91', 'l94', 'l99', 'l103', 'l106', 'l108', 'l109']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "constitutively", + "active", + "SGK1", + "mutant", + "in", + "the", + "luminal", + "epithelium", + "of" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "epithelium", + "mouse", + "uterus." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "constitutively", + "active", + "SGK1", + "mutant", + "in", + "the", + "luminal", + "epithelium", + "of" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abolished" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "epithelium", + "mouse", + "uterus." + ] + }, + "effect": { + "val": "negative", + "words": [ + "abolished" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "implantation" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sgk1-/-" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "implantation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sgk1-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sgk1-/-", + "SGK1", + "deficiency" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sgk1-/-", + "SGK1", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sgk1-/-", + "SGK1", + "deficiency" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "21983856", + "TEXT": "Chronic pain is a common neurological disease involving lasting, multifaceted maladaptations ranging from gene modulation to synaptic dysfunction and emotional disorders. Sustained pathological stimuli in many diseases alter the output activities of certain genes through epigenetic modifications, but it is unclear how epigenetic mechanisms operate in the development of chronic pain. We show here that in the rat brainstem nucleus raphe magnus, which is important for central mechanisms of chronic pain, persistent inflammatory and neuropathic pain epigenetically suppresses Gad2 (encoding glutamic acid decarboxylase 65 (GAD65)) transcription through histone deacetylase (HDAC)-mediated histone hypoacetylation, resulting in impaired γ-aminobutyric acid (GABA) synaptic inhibition. Gad2 knockout mice showed sensitized pain behavior and impaired GABA synaptic function in their brainstem neurons. In wild-type but not Gad2 knockout mice, HDAC inhibitors strongly increased GAD65 activity, restored GABA synaptic function and relieved sensitized pain behavior. These findings suggest GAD65 and HDACs as potential therapeutic targets in an epigenetic approach to the treatment of chronic pain.", + "TAG_DATA": [ + "58, brainstem {'context': 'I-tissue/organ'}", + "59, nucleus {'context': 'I-tissue/organ'}", + "60, raphe {'context': 'I-tissue/organ'}", + "61, magnus, {'context': 'I-tissue/organ'}", + "100, Gad2 {'perturbing_action': 'B-gene loss-of-function'}", + "101, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "102, mice {'context': 'B-organism'}", + "114, brainstem {'context': 'B-cells'}", + "115, neurons. {'context': 'I-cells'}", + "120, Gad2 {'perturbing_action': 'B-gene loss-of-function'}", + "121, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "122, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "58, brainstem ['l0', 'l1', 'l2']", + "59, nucleus ['l0', 'l3', 'l4', 'l5']", + "60, raphe ['l1', 'l3', 'l6']", + "61, magnus, ['l2', 'l4', 'l6', 'l7']", + "100, Gad2 ['l8', 'l9', 'l10', 'l11']", + "101, knockout ['l5', 'l7', 'l8', 'l12', 'l13', 'l14']", + "102, mice ['l9', 'l12', 'l15', 'l16']", + "114, brainstem ['l10', 'l13', 'l15', 'l17']", + "115, neurons. ['l11', 'l14', 'l16', 'l17']", + "120, Gad2 ['l18', 'l19']", + "121, knockout ['l18', 'l20']", + "122, mice, ['l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "nucleus", + "magnus," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gad2", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gad2", + "knockout" + ] + }, + "context": { + "val": "cells", + "words": [ + "brainstem", + "neurons." + ] + } + } + ] + }, + { + "PMID": "21946539", + "TEXT": "Heat shock proteins (HSPs) are necessary for cancer cell survival. We identified a mutant of HSP110 (HSP110ΔE9) in colorectal cancer showing microsatellite instability (MSI CRC), generated from an aberrantly spliced mRNA and lacking the HSP110 substrate-binding domain. This mutant was expressed at variable levels in almost all MSI CRC cell lines and primary tumors tested. HSP110ΔE9 impaired both the normal cellular localization of HSP110 and its interaction with other HSPs, thus abrogating the chaperone activity and antiapoptotic function of HSP110 in a dominant-negative manner. HSP110ΔE9 overexpression caused the sensitization of cells to anticancer agents such as oxaliplatin and 5-fluorouracil, which are routinely prescribed in the adjuvant treatment of people with CRC. The survival and response to chemotherapy of subjects with MSI CRCs was associated with the tumor expression level of HSP110ΔE9. HSP110 may thus constitute a major determinant for both prognosis and treatment response in CRC.", + "TAG_DATA": [ + "84, HSP110ΔE9 {'perturbing_action': 'B-gene gain-of-function'}", + "85, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "90, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "84, HSP110ΔE9 ['l0', 'l1']", + "85, overexpression ['l0', 'l2']", + "90, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "HSP110ΔE9", + "overexpression" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "21946538", + "TEXT": "Rapidly progressive glomerulonephritis (RPGN) is a life-threatening clinical syndrome and a morphological manifestation of severe glomerular injury that is marked by a proliferative histological pattern ('crescents') with accumulation of T cells and macrophages and proliferation of intrinsic glomerular cells. We show de novo induction of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in intrinsic glomerular epithelial cells (podocytes) from both mice and humans with RPGN. HB-EGF induction increases phosphorylation of the epidermal growth factor receptor (EGFR, also known as ErbB1) in mice with RPGN. In HB-EGF-deficient mice, EGFR activation in glomeruli is absent and the course of RPGN is improved. Autocrine HB-EGF induces a phenotypic switch in podocytes in vitro. Conditional deletion of the Egfr gene from podocytes of mice alleviates the severity of RPGN. Likewise, pharmacological blockade of EGFR also improves the course of RPGN, even when started 4 d after the induction of experimental RPGN. This suggests that targeting the HB-EGF-EGFR pathway could also be beneficial in treatment of human RPGN.", + "TAG_DATA": [ + "53, intrinsic {'context': 'B-cells'}", + "54, glomerular {'context': 'I-cells'}", + "55, epithelial {'context': 'I-cells'}", + "56, cells {'context': 'I-cells'}", + "57, (podocytes) {'context': 'I-cells'}", + "81, mice {'context': 'B-organism'}", + "85, HB-EGF-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "86, mice, {'context': 'B-organism'}", + "90, glomeruli {'context': 'B-tissue/organ'}", + "107, podocytes {'context': 'B-cells'}", + "108, in {'context': 'B-in vitro'}", + "109, vitro. {'context': 'I-in vitro'}", + "110, Conditional {'perturbing_action': 'B-gene loss-of-function'}", + "111, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "112, of {'perturbing_action': 'I-gene loss-of-function'}", + "113, the {'perturbing_action': 'I-gene loss-of-function'}", + "114, Egfr {'perturbing_action': 'I-gene loss-of-function'}", + "115, gene {'perturbing_action': 'I-gene loss-of-function'}", + "117, podocytes {'context': 'B-cells'}", + "119, mice {'context': 'B-organism'}", + "126, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "127, blockade {'perturbing_action': 'I-pharmacological inhibition'}", + "128, of {'perturbing_action': 'I-pharmacological inhibition'}", + "129, EGFR {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "53, intrinsic ['l0', 'l1', 'l2', 'l3', 'l4']", + "54, glomerular ['l0', 'l5', 'l6', 'l7', 'l8']", + "55, epithelial ['l1', 'l5', 'l9', 'l10', 'l11']", + "56, cells ['l2', 'l6', 'l9', 'l12', 'l13']", + "57, (podocytes) ['l3', 'l7', 'l10', 'l12', 'l14']", + "81, mice ['l4', 'l8', 'l11', 'l13', 'l14']", + "85, HB-EGF-deficient ['l15', 'l16', 'l17', 'l18', 'l19']", + "86, mice, ['l15', 'l20']", + "90, glomeruli ['l16', 'l20', 'l21']", + "107, podocytes ['l17', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "108, in ['l18', 'l22', 'l27', 'l28']", + "109, vitro. ['l19', 'l23', 'l27', 'l29']", + "110, Conditional ['l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "111, deletion ['l30', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "112, of ['l31', 'l37', 'l43', 'l44', 'l45', 'l46', 'l47']", + "113, the ['l32', 'l38', 'l43', 'l48', 'l49', 'l50', 'l51']", + "114, Egfr ['l33', 'l39', 'l44', 'l48', 'l52', 'l53', 'l54']", + "115, gene ['l24', 'l34', 'l40', 'l45', 'l49', 'l52', 'l55', 'l56']", + "117, podocytes ['l25', 'l35', 'l41', 'l46', 'l50', 'l53', 'l55', 'l57']", + "119, mice ['l26', 'l28', 'l29', 'l36', 'l42', 'l47', 'l51', 'l54', 'l56', 'l57']", + "126, pharmacological ['l58', 'l59', 'l60']", + "127, blockade ['l58', 'l61', 'l62']", + "128, of ['l59', 'l61', 'l63']", + "129, EGFR ['l60', 'l62', 'l63']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "HB-EGF-deficient", + "Conditional", + "deletion", + "of", + "the", + "Egfr", + "gene" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "HB-EGF-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "glomeruli" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "HB-EGF-deficient", + "gene", + "Conditional", + "deletion", + "of", + "the", + "Egfr" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "HB-EGF-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "21946537", + "TEXT": "DNA mismatch repair enzymes (for example, MSH2) maintain genomic integrity, and their deficiency predisposes to several human cancers and to drug resistance. We found that leukemia cells from a substantial proportion of children (∼11%) with newly diagnosed acute lymphoblastic leukemia have low or undetectable MSH2 protein levels, despite abundant wild-type MSH2 mRNA. Leukemia cells with low levels of MSH2 contained partial or complete somatic deletions of one to four genes that regulate MSH2 degradation (FRAP1 (also known as MTOR), HERC1, PRKCZ and PIK3C2B); we also found these deletions in individuals with adult acute lymphoblastic leukemia (16%) and sporadic colorectal cancer (13.5%). Knockdown of these genes in human leukemia cells recapitulated the MSH2 protein deficiency by enhancing MSH2 degradation, leading to substantial reduction in DNA mismatch repair and increased resistance to thiopurines. These findings reveal a previously unrecognized mechanism whereby somatic deletions of genes regulating MSH2 degradation result in undetectable levels of MSH2 protein in leukemia cells, DNA mismatch repair deficiency and drug resistance.", + "TAG_DATA": [ + "52, Leukemia {'context': 'B-transformed cells'}", + "53, cells {'context': 'I-transformed cells'}", + "101, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "102, of {'perturbing_action': 'I-rnai/knockdown'}", + "103, these {'perturbing_action': 'I-rnai/knockdown'}", + "104, genes {'perturbing_action': 'I-rnai/knockdown'}", + "106, human {'context': 'B-transformed cells'}", + "107, leukemia {'context': 'I-transformed cells'}", + "108, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "52, Leukemia ['l0', 'l1', 'l2']", + "53, cells ['l0', 'l3']", + "92, acute ['l4', 'l5', 'l6', 'l7']", + "93, lymphoblastic ['l1', 'l4', 'l8', 'l9', 'l10']", + "94, leukemia ['l2', 'l3', 'l5', 'l8', 'l11', 'l12']", + "98, colorectal ['l6', 'l9', 'l11', 'l13']", + "99, cancer ['l7', 'l10', 'l12', 'l13']", + "101, Knockdown ['l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "102, of ['l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "103, these ['l15', 'l20', 'l25', 'l26', 'l27', 'l28']", + "104, genes ['l16', 'l21', 'l25', 'l29', 'l30', 'l31']", + "106, human ['l17', 'l22', 'l26', 'l29', 'l32', 'l33']", + "107, leukemia ['l18', 'l23', 'l27', 'l30', 'l32', 'l34']", + "108, cells ['l19', 'l24', 'l28', 'l31', 'l33', 'l34']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "these", + "genes" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "leukemia", + "cells" + ] + } + } + ] + }, + { + "PMID": "21926976", + "TEXT": "The prognosis in advanced-stage ovarian cancer remains poor. Tumor-specific intraoperative fluorescence imaging may improve staging and debulking efforts in cytoreductive surgery and thereby improve prognosis. The overexpression of folate receptor-α (FR-α) in 90-95% of epithelial ovarian cancers prompted the investigation of intraoperative tumor-specific fluorescence imaging in ovarian cancer surgery using an FR-α-targeted fluorescent agent. In patients with ovarian cancer, intraoperative tumor-specific fluorescence imaging with an FR-α-targeted fluorescent agent showcased the potential applications in patients with ovarian cancer for improved intraoperative staging and more radical cytoreductive surgery.", + "TAG_DATA": [ + "55, patients {'context': 'B-patient'}", + "58, cancer, {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "55, patients ['l0']", + "58, cancer, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21892180", + "TEXT": "We report the involvement of an evolutionarily conserved set of mycobacterial genes, the esx-3 region, in evasion of bacterial killing by innate immunity. Whereas high-dose intravenous infections of mice with the rapidly growing mycobacterial species Mycobacterium smegmatis bearing an intact esx-3 locus were rapidly lethal, infection with an M. smegmatis Δesx-3 mutant (here designated as the IKE strain) was controlled and cleared by a MyD88-dependent bactericidal immune response. Introduction of the orthologous Mycobacterium tuberculosis esx-3 genes into the IKE strain resulted in a strain, designated IKEPLUS, that remained susceptible to innate immune killing and was highly attenuated in mice but had a marked ability to stimulate bactericidal immunity against challenge with virulent M. tuberculosis. Analysis of these adaptive immune responses indicated that the highly protective bactericidal immunity elicited by IKEPLUS was dependent on CD4(+) memory T cells and involved a distinct shift in the pattern of cytokine responses by CD4(+) cells. Our results establish a role for the esx-3 locus in promoting mycobacterial virulence and also identify the IKE strain as a potentially powerful candidate vaccine vector for eliciting protective immunity to M. tuberculosis.", + "TAG_DATA": [ + "28, mice {'context': 'B-organism'}", + "48, M. {'perturbing_action': 'B-other', 'context': 'B-organism'}", + "49, smegmatis {'perturbing_action': 'B-other'}", + "50, Δesx-3 {'perturbing_action': 'B-other'}", + "51, mutant {'perturbing_action': 'I-other'}", + "52, (here {'perturbing_action': 'I-other'}", + "68, Introduction {'perturbing_action': 'B-other'}", + "69, of {'perturbing_action': 'I-other'}", + "70, the {'perturbing_action': 'I-other'}", + "71, orthologous {'perturbing_action': 'I-other'}", + "72, Mycobacterium {'perturbing_action': 'I-other'}", + "73, tuberculosis {'perturbing_action': 'I-other'}", + "74, esx-3 {'perturbing_action': 'I-other'}", + "75, genes {'perturbing_action': 'I-other'}", + "76, into {'perturbing_action': 'I-other'}", + "98, mice {'context': 'B-organism'}", + "133, CD4(+) {'context': 'B-cells'}", + "134, memory {'context': 'I-cells'}", + "135, T {'context': 'I-cells'}", + "136, cells {'context': 'I-cells'}", + "149, CD4(+) {'context': 'B-cells'}", + "150, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "48, M. ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "49, smegmatis ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "50, Δesx-3 ['l1', 'l14', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "51, mutant ['l2', 'l15', 'l26', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "52, (here ['l3', 'l16', 'l27', 'l39', 'l49', 'l50']", + "68, Introduction ['l28', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "69, of ['l4', 'l17', 'l29', 'l40', 'l51', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "70, the ['l5', 'l18', 'l30', 'l41', 'l52', 'l61', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "71, orthologous ['l6', 'l19', 'l31', 'l42', 'l53', 'l62', 'l70', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "72, Mycobacterium ['l7', 'l20', 'l32', 'l43', 'l54', 'l63', 'l71', 'l78', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "73, tuberculosis ['l8', 'l21', 'l33', 'l44', 'l49', 'l55', 'l64', 'l72', 'l79', 'l85', 'l91', 'l92', 'l93', 'l94', 'l95']", + "74, esx-3 ['l9', 'l22', 'l34', 'l45', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l96', 'l97', 'l98', 'l99']", + "75, genes ['l10', 'l23', 'l35', 'l46', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l100', 'l101', 'l102']", + "76, into ['l11', 'l36', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l103', 'l104']", + "78, IKE ['l12', 'l24', 'l37', 'l47', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l105']", + "98, mice ['l13', 'l25', 'l38', 'l48', 'l50', 'l60', 'l69', 'l77', 'l84', 'l90', 'l95', 'l99', 'l102', 'l104', 'l105']", + "133, CD4(+) ['l106', 'l107', 'l108', 'l109', 'l110']", + "134, memory ['l106', 'l111', 'l112', 'l113', 'l114']", + "135, T ['l107', 'l111', 'l115', 'l116', 'l117']", + "136, cells ['l108', 'l112', 'l115', 'l118', 'l119']", + "149, CD4(+) ['l109', 'l113', 'l116', 'l118', 'l120']", + "150, cells. ['l110', 'l114', 'l117', 'l119', 'l120']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "M.", + "smegmatis", + "Δesx-3", + "mutant", + "(here", + "Introduction", + "of", + "the", + "orthologous", + "Mycobacterium", + "tuberculosis", + "esx-3", + "genes", + "into" + ] + }, + "context": { + "val": "organism", + "words": [ + "M.", + "mice" + ] + } + } + ] + }, + { + "PMID": "21857652", + "TEXT": "Coagulase-positive Staphylococcus aureus (S. aureus) is the major causal pathogen of acute endocarditis, a rapidly progressing, destructive infection of the heart valves. Bacterial colonization occurs at sites of endothelial damage, where, together with fibrin and platelets, the bacteria initiate the formation of abnormal growths known as vegetations. Here we report that an engineered analog of prothrombin could be used to detect S. aureus in endocarditic vegetations via noninvasive fluorescence or positron emission tomography (PET) imaging. These prothrombin derivatives bound staphylocoagulase and intercalated into growing bacterial vegetations. We also present evidence for bacterial quorum sensing in the regulation of staphylocoagulase expression by S. aureus. Staphylocoagulase expression was limited to the growing edge of mature vegetations, where it was exposed to the host and co-localized with the imaging probe. When endocarditis was induced with an S. aureus strain with genetic deletion of coagulases, survival of mice improved, highlighting the role of staphylocoagulase as a virulence factor.", + "TAG_DATA": [ + "133, S. {'context': 'B-transformed cells'}", + "135, strain {'context': 'I-transformed cells'}", + "137, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "138, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "139, of {'perturbing_action': 'I-gene loss-of-function'}", + "140, coagulases, {'perturbing_action': 'I-gene loss-of-function'}", + "143, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "133, S. ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "134, aureus ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "135, strain ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "137, genetic ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "138, deletion ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "139, of ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "140, coagulases, ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "143, mice ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "S.", + "strain" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "coagulases," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "coagulases," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "21822285", + "TEXT": "The prognosis of breast cancer in young women is influenced by reproductive history. Women diagnosed within 5 years postpartum have worse prognosis than nulliparous women or women diagnosed during pregnancy. Here we describe a mouse model of postpartum breast cancer that identifies mammary gland involution as a driving force of tumor progression. In this model, human breast cancer cells exposed to the involuting mammary microenvironment form large tumors that are characterized by abundant fibrillar collagen, high cyclooxygenase-2 (COX-2) expression and an invasive phenotype. In culture, tumor cells are invasive in a fibrillar collagen and COX-2-dependent manner. In the involuting mammary gland, inhibition of COX-2 reduces the collagen fibrillogenesis associated with involution, as well as tumor growth and tumor cell infiltration to the lung. These data support further research to determine whether women at high risk for postpartum breast cancer would benefit from treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) during postpartum involution.", + "TAG_DATA": [ + "55, human {'context': 'B-transformed cells'}", + "56, breast {'context': 'I-transformed cells'}", + "57, cancer {'context': 'I-transformed cells'}", + "58, cells {'context': 'I-transformed cells'}", + "85, tumor {'context': 'B-transformed cells'}", + "86, cells {'context': 'I-transformed cells'}", + "98, involuting {'context': 'B-tissue/organ'}", + "99, mammary {'context': 'I-tissue/organ'}", + "100, gland, {'context': 'I-tissue/organ'}", + "101, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "102, of {'perturbing_action': 'I-pharmacological inhibition'}", + "103, COX-2 {'perturbing_action': 'I-pharmacological inhibition'}", + "114, tumor {'phenotype': 'B-tumour growth'}", + "115, growth {'phenotype': 'I-tumour growth'}", + "117, tumor {'context': 'B-transformed cells'}", + "118, cell {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "55, human ['l0', 'l1', 'l2']", + "56, breast ['l0', 'l3', 'l4']", + "57, cancer ['l1', 'l3', 'l5']", + "58, cells ['l2', 'l4', 'l5']", + "85, tumor ['l6']", + "86, cells ['l6']", + "98, involuting ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "99, mammary ['l7', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "100, gland, ['l8', 'l16', 'l23', 'l24', 'l25', 'l26']", + "101, inhibition ['l9', 'l17', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "102, of ['l10', 'l18', 'l23', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "103, COX-2 ['l11', 'l19', 'l24', 'l28', 'l33', 'l38', 'l39', 'l40', 'l41']", + "114, tumor ['l12', 'l20', 'l25', 'l29', 'l34', 'l38', 'l42', 'l43', 'l44']", + "115, growth ['l13', 'l21', 'l26', 'l30', 'l35', 'l39', 'l42', 'l45', 'l46']", + "117, tumor ['l14', 'l31', 'l36', 'l40', 'l43', 'l45', 'l47']", + "118, cell ['l15', 'l22', 'l32', 'l37', 'l41', 'l44', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "involuting", + "mammary", + "gland," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "COX-2" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "involuting", + "mammary", + "gland," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "COX-2" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "COX-2" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + } + ] + }, + { + "PMID": "21804542", + "TEXT": "PICT1 (also known as GLTSCR2) is considered a tumor suppressor because it stabilizes phosphatase and tensin homolog (PTEN), but individuals with oligodendrogliomas lacking chromosome 19q13, where PICT1 is located, have better prognoses than other oligodendroglioma patients. To clarify the function of PICT1, we generated Pict1-deficient mice and embryonic stem (ES) cells. Pict1 is a nucleolar protein essential for embryogenesis and ES cell survival. Even without DNA damage, Pict1 loss led to p53-dependent arrest of cell cycle phase G(1) and apoptosis. Pict1-deficient cells accumulated p53, owing to impaired Mdm2 function. Pict1 binds Rpl11, and Rpl11 is released from nucleoli in the absence of Pict1. In Pict1-deficient cells, increased binding of Rpl11 to Mdm2 blocks Mdm2-mediated ubiquitination of p53. In human cancer, individuals whose tumors express less PICT1 have better prognoses. When PICT1 is depleted in tumor cells with intact P53 signaling, the cells grow more slowly and accumulate P53. Thus, PICT1 is a potent regulator of the MDM2-P53 pathway and promotes tumor progression by retaining RPL11 in the nucleolus.", + "TAG_DATA": [ + "44, Pict1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "45, mice {'context': 'B-organism'}", + "47, embryonic {'context': 'B-cells'}", + "48, stem {'context': 'I-cells'}", + "49, (ES) {'context': 'I-cells'}", + "50, cells. {'context': 'I-cells'}", + "67, Pict1 {'perturbing_action': 'B-gene loss-of-function'}", + "68, loss {'perturbing_action': 'I-gene loss-of-function'}", + "69, led {'effect': 'B-positive'}", + "70, to {'effect': 'I-positive'}", + "72, arrest {'phenotype': 'B-cell cycle arrest'}", + "73, of {'phenotype': 'I-cell cycle arrest'}", + "74, cell {'phenotype': 'I-cell cycle arrest'}", + "75, cycle {'phenotype': 'I-cell cycle arrest'}", + "76, phase {'phenotype': 'I-cell cycle arrest'}", + "77, G(1) {'phenotype': 'I-cell cycle arrest'}", + "79, apoptosis. {'phenotype': 'B-apoptosis'}", + "80, Pict1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "81, cells {'context': 'B-cells'}", + "104, Pict1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "105, cells, {'context': 'B-cells'}", + "141, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "44, Pict1-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "45, mice ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "47, embryonic ['l1', 'l16', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "48, stem ['l2', 'l17', 'l31', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "49, (ES) ['l3', 'l18', 'l32', 'l45', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "50, cells. ['l4', 'l19', 'l33', 'l46', 'l58', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "67, Pict1 ['l5', 'l20', 'l34', 'l47', 'l59', 'l70', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "68, loss ['l6', 'l21', 'l35', 'l48', 'l60', 'l71', 'l81', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "69, led ['l7', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "70, to ['l8', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l100', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "72, arrest ['l9', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l108', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "73, of ['l10', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l115', 'l121', 'l122', 'l123', 'l124', 'l125']", + "74, cell ['l11', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l121', 'l126', 'l127', 'l128', 'l129']", + "75, cycle ['l12', 'l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l126', 'l130', 'l131', 'l132']", + "76, phase ['l13', 'l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l118', 'l123', 'l127', 'l130', 'l133', 'l134']", + "77, G(1) ['l14', 'l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l113', 'l119', 'l124', 'l128', 'l131', 'l133', 'l135']", + "79, apoptosis. ['l15', 'l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l129', 'l132', 'l134', 'l135']", + "80, Pict1-deficient ['l136']", + "81, cells ['l136']", + "104, Pict1-deficient ['l137', 'l138']", + "105, cells, ['l137']", + "141, cells ['l138']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pict1-deficient", + "Pict1", + "loss" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pict1-deficient", + "Pict1", + "loss" + ] + }, + "context": { + "val": "cells", + "words": [ + "embryonic", + "stem", + "(ES)", + "cells.", + "cells", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pict1-deficient", + "Pict1", + "loss" + ] + }, + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pict1-deficient", + "Pict1", + "loss" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest", + "of", + "cell", + "cycle", + "phase", + "G(1)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pict1-deficient", + "Pict1", + "loss" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest", + "of", + "cell", + "cycle", + "phase", + "G(1)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "embryonic", + "stem", + "(ES)", + "cells." + ] + }, + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "embryonic", + "stem", + "(ES)", + "cells." + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest", + "of", + "cell", + "cycle", + "phase", + "G(1)" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "embryonic", + "stem", + "(ES)", + "cells." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest", + "of", + "cell", + "cycle", + "phase", + "G(1)" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "21785433", + "TEXT": "Follicular helper (T(FH)) cells provide crucial signals to germinal center B cells undergoing somatic hypermutation and selection that results in affinity maturation. Tight control of T(FH) numbers maintains self tolerance. We describe a population of Foxp3(+)Blimp-1(+)CD4(+) T cells constituting 10-25% of the CXCR5(high)PD-1(high)CD4(+) T cells found in the germinal center after immunization with protein antigens. These follicular regulatory T (T(FR)) cells share phenotypic characteristics with T(FH) and conventional Foxp3(+) regulatory T (T(reg)) cells yet are distinct from both. Similar to T(FH) cells, T(FR) cell development depends on Bcl-6, SLAM-associated protein (SAP), CD28 and B cells; however, T(FR) cells originate from thymic-derived Foxp3(+) precursors, not naive or T(FH) cells. T(FR) cells are suppressive in vitro and limit T(FH) cell and germinal center B cell numbers in vivo. In the absence of T(FR) cells, an outgrowth of non-antigen-specific B cells in germinal centers leads to fewer antigen-specific cells. Thus, the T(FH) differentiation pathway is co-opted by T(reg) cells to control the germinal center response.", + "TAG_DATA": [ + "108, T(FR) {'context': 'B-cells'}", + "112, in {'context': 'B-in vitro'}", + "113, vitro {'context': 'I-in vitro'}", + "116, T(FH) {'context': 'B-cells'}", + "119, germinal {'context': 'B-cells'}", + "120, center {'context': 'I-cells'}", + "121, B {'context': 'I-cells'}", + "122, cell {'context': 'I-cells'}", + "124, in {'context': 'B-in vivo'}", + "125, vivo. {'context': 'I-in vivo'}", + "128, absence {'perturbing_action': 'B-gene loss-of-function'}", + "130, T(FR) {'context': 'B-cells'}", + "131, cells, {'context': 'I-cells'}", + "135, non-antigen-specific {'context': 'B-cells'}", + "136, B {'context': 'I-cells'}", + "137, cells {'context': 'I-cells'}", + "144, antigen-specific {'context': 'B-cells'}", + "145, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "108, T(FR) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "112, in ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "113, vitro ['l1', 'l14', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "116, T(FH) ['l2', 'l15', 'l22', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "119, germinal ['l3', 'l16', 'l23', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "120, center ['l4', 'l17', 'l24', 'l30', 'l35', 'l40', 'l41', 'l42', 'l43']", + "121, B ['l5', 'l18', 'l25', 'l31', 'l36', 'l40', 'l44', 'l45', 'l46']", + "122, cell ['l6', 'l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l47']", + "124, in ['l7', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l48']", + "125, vivo. ['l8', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48']", + "128, absence ['l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "130, T(FR) ['l49', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "131, cells, ['l9', 'l50', 'l56', 'l62', 'l63', 'l64', 'l65', 'l66']", + "135, non-antigen-specific ['l10', 'l51', 'l57', 'l62', 'l67', 'l68', 'l69', 'l70']", + "136, B ['l11', 'l52', 'l58', 'l63', 'l67', 'l71', 'l72', 'l73']", + "137, cells ['l12', 'l53', 'l59', 'l64', 'l68', 'l71', 'l74', 'l75']", + "144, antigen-specific ['l54', 'l60', 'l65', 'l69', 'l72', 'l74', 'l76']", + "145, cells. ['l13', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l76']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence" + ] + }, + "context": { + "val": "cells", + "words": [ + "T(FR)", + "cells,", + "non-antigen-specific", + "B", + "cells", + "antigen-specific", + "cells." + ] + } + } + ] + }, + { + "PMID": "21785432", + "TEXT": "Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. Mutations in the 27-kDa small heat-shock protein gene (HSPB1) cause axonal CMT or distal hereditary motor neuropathy (distal HMN). We developed and characterized transgenic mice expressing two different HSPB1 mutations (S135F and P182L) in neurons only. These mice showed all features of CMT or distal HMN dependent on the mutation. Expression of mutant HSPB1 decreased acetylated α-tubulin abundance and induced severe axonal transport deficits. An increase of α-tubulin acetylation induced by pharmacological inhibition of histone deacetylase 6 (HDAC6) corrected the axonal transport defects caused by HSPB1 mutations and rescued the CMT phenotype of symptomatic mutant HSPB1 mice. Our findings demonstrate the pathogenic role of α-tubulin deacetylation in mutant HSPB1-induced neuropathies and offer perspectives for using HDAC6 inhibitors as a therapeutic strategy for hereditary axonopathies.", + "TAG_DATA": [ + "37, transgenic {'context': 'B-organism'}", + "38, mice {'context': 'I-organism'}", + "40, two {'perturbing_action': 'I-other'}", + "41, different {'perturbing_action': 'I-other'}", + "42, HSPB1 {'perturbing_action': 'I-other'}", + "43, mutations {'perturbing_action': 'I-other'}", + "44, (S135F {'perturbing_action': 'I-other'}", + "45, and {'perturbing_action': 'I-other'}", + "46, P182L) {'perturbing_action': 'I-other'}", + "48, neurons {'context': 'B-cells'}", + "49, only. {'context': 'B-cells'}", + "51, mice {'context': 'B-organism'}", + "64, Expression {'perturbing_action': 'B-other'}", + "65, of {'perturbing_action': 'I-other'}", + "66, mutant {'perturbing_action': 'I-other'}", + "67, HSPB1 {'perturbing_action': 'I-other'}", + "85, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "86, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "87, of {'perturbing_action': 'I-pharmacological inhibition'}", + "88, histone {'perturbing_action': 'I-pharmacological inhibition'}", + "89, deacetylase {'perturbing_action': 'I-pharmacological inhibition'}", + "90, 6 {'perturbing_action': 'I-pharmacological inhibition'}", + "91, (HDAC6) {'perturbing_action': 'I-pharmacological inhibition'}", + "99, HSPB1 {'perturbing_action': 'B-other'}", + "100, mutations {'perturbing_action': 'I-other'}", + "102, rescued {'effect': 'B-rescues'}", + "104, CMT {'phenotype': 'B-epithelial-mesenchymal transition'}", + "105, phenotype {'phenotype': 'I-senescence'}", + "107, symptomatic {'perturbing_action': 'B-other'}", + "108, mutant {'perturbing_action': 'I-other'}", + "109, HSPB1 {'perturbing_action': 'I-other'}", + "110, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "37, transgenic ['l0', 'l1', 'l2', 'l3']", + "38, mice ['l0', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "40, two ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "41, different ['l10', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "42, HSPB1 ['l11', 'l23', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "43, mutations ['l12', 'l24', 'l35', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "44, (S135F ['l4', 'l13', 'l25', 'l36', 'l46', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "45, and ['l5', 'l14', 'l26', 'l37', 'l47', 'l56', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "46, P182L) ['l15', 'l27', 'l38', 'l48', 'l57', 'l65', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "48, neurons ['l1', 'l6', 'l16', 'l28', 'l39', 'l49', 'l58', 'l66', 'l73', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "49, only. ['l2', 'l7', 'l17', 'l29', 'l40', 'l50', 'l59', 'l67', 'l74', 'l80', 'l86', 'l87', 'l88']", + "51, mice ['l3', 'l8', 'l18', 'l30', 'l41', 'l51', 'l60', 'l68', 'l75', 'l81', 'l86', 'l89', 'l90', 'l91', 'l92']", + "64, Expression ['l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l76', 'l82', 'l89', 'l93', 'l94', 'l95']", + "65, of ['l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l83', 'l90', 'l93', 'l96', 'l97']", + "66, mutant ['l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l87', 'l91', 'l94', 'l96', 'l98']", + "67, HSPB1 ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l88', 'l92', 'l95', 'l97', 'l98']", + "85, pharmacological ['l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "86, inhibition ['l99', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "87, of ['l100', 'l110', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "88, histone ['l101', 'l111', 'l120', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "89, deacetylase ['l102', 'l112', 'l121', 'l129', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "90, 6 ['l103', 'l113', 'l122', 'l130', 'l136', 'l143', 'l144', 'l145', 'l146', 'l147']", + "91, (HDAC6) ['l104', 'l114', 'l123', 'l131', 'l137', 'l143', 'l148', 'l149', 'l150', 'l151', 'l152']", + "99, HSPB1 ['l105', 'l115', 'l124', 'l132', 'l138', 'l144', 'l148', 'l153']", + "100, mutations ['l106', 'l116', 'l125', 'l133', 'l139', 'l145', 'l149', 'l153']", + "102, rescued ['l107', 'l117', 'l126', 'l134', 'l140', 'l146', 'l150', 'l154', 'l155', 'l156']", + "104, CMT ['l108', 'l118', 'l127', 'l141', 'l151', 'l154', 'l157', 'l158', 'l159', 'l160', 'l161']", + "105, phenotype ['l109', 'l119', 'l128', 'l135', 'l142', 'l147', 'l152', 'l155', 'l157', 'l162', 'l163', 'l164', 'l165']", + "107, symptomatic ['l158', 'l162', 'l166', 'l167', 'l168']", + "108, mutant ['l159', 'l163', 'l166', 'l169', 'l170']", + "109, HSPB1 ['l160', 'l164', 'l167', 'l169', 'l171']", + "110, mice. ['l156', 'l161', 'l165', 'l168', 'l170', 'l171']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "(S135F", + "and", + "HSPB1", + "two", + "different", + "mutations", + "P182L)", + "Expression", + "of", + "mutant", + "symptomatic" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "two", + "different", + "HSPB1", + "mutations", + "(S135F", + "and", + "P182L)", + "Expression", + "of", + "mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons", + "only." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "histone", + "deacetylase", + "6", + "(HDAC6)" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "deacetylase", + "(HDAC6)" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "CMT" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "histone", + "deacetylase", + "6", + "(HDAC6)" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "phenotype" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "CMT" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "phenotype" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "CMT" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "symptomatic", + "mutant", + "HSPB1" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "CMT" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "senescence", + "words": [ + "phenotype" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "symptomatic", + "mutant", + "HSPB1" + ] + } + }, + { + "phenotype": { + "val": "senescence", + "words": [ + "phenotype" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "21765404", + "TEXT": "Aluminum-based adjuvants (aluminum salts or alum) are widely used in human vaccination, although their mechanisms of action are poorly understood. Here we report that, in mice, alum causes cell death and the subsequent release of host cell DNA, which acts as a potent endogenous immunostimulatory signal mediating alum adjuvant activity. Furthermore, we propose that host DNA signaling differentially regulates IgE and IgG1 production after alum-adjuvanted immunization. We suggest that, on the one hand, host DNA induces primary B cell responses, including IgG1 production, through interferon response factor 3 (Irf3)-independent mechanisms. On the other hand, we suggest that host DNA also stimulates 'canonical' T helper type 2 (T(H)2) responses, associated with IgE isotype switching and peripheral effector responses, through Irf3-dependent mechanisms. The finding that host DNA released from dying cells acts as a damage-associated molecular pattern that mediates alum adjuvant activity may increase our understanding of the mechanisms of action of current vaccines and help in the design of new adjuvants.", + "TAG_DATA": [ + "25, mice, {'context': 'B-organism'}", + "27, causes {'effect': 'B-positive'}", + "28, cell {'phenotype': 'B-cell death'}", + "29, death {'phenotype': 'I-cell death'}", + "77, B {'context': 'B-cells'}", + "78, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "25, mice, ['l0', 'l1', 'l2', 'l3', 'l4']", + "27, causes ['l0', 'l5', 'l6', 'l7', 'l8']", + "28, cell ['l1', 'l5', 'l9', 'l10', 'l11']", + "29, death ['l2', 'l6', 'l9', 'l12', 'l13']", + "77, B ['l3', 'l7', 'l10', 'l12', 'l14']", + "78, cell ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "positive", + "words": [ + "causes" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes" + ] + }, + "context": { + "val": "cells", + "words": [ + "B", + "cell" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "B", + "cell" + ] + } + } + ] + }, + { + "PMID": "21765403", + "TEXT": "Specific human leukocyte antigens (HLAs), notably HLA-B*27 and HLA-B*57 allele groups, have long been associated with control of HIV-1. Although the majority of HIV-specific CD8(+) T cells lose proliferative capacity during chronic infection, T cells restricted by HLA-B*27 or HLA-B*57 allele groups do not. Here we show that CD8(+) T cells restricted by 'protective' HLA allele groups are not suppressed by T(reg) cells, whereas, within the same individual, T cells restricted by 'nonprotective' alleles are highly suppressed ex vivo. This differential sensitivity of HIV-specific CD8(+) T cells to T(reg) cell-mediated suppression correlates with their expression of the inhibitory receptor T cell immunoglobulin domain and mucin domain 3 (Tim-3) after stimulation with their cognate epitopes. Furthermore, we show that HLA-B*27- and HLA-B*57-restricted effectors also evade T(reg) cell-mediated suppression by directly killing T(reg) cells they encounter in a granzyme B (GzmB)-dependent manner. This study uncovers a previously unknown explanation for why HLA-B*27 and HLA-B*57 allele groups are associated with delayed HIV-1 disease progression.", + "TAG_DATA": [ + "48, CD8(+) {'context': 'B-cells'}", + "49, T {'context': 'I-cells'}", + "50, cells {'context': 'I-cells'}", + "68, T {'context': 'B-cells'}", + "69, cells {'context': 'B-cells'}", + "84, CD8(+) {'context': 'I-cells'}", + "85, T {'context': 'I-cells'}", + "86, cells {'context': 'I-cells'}", + "130, T(reg) {'context': 'B-cells'}", + "131, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "48, CD8(+) ['l0', 'l1']", + "49, T ['l0', 'l2']", + "50, cells ['l1', 'l2']", + "68, T ['l3', 'l4', 'l5']", + "69, cells ['l3', 'l6', 'l7', 'l8']", + "84, CD8(+) ['l6', 'l9', 'l10']", + "85, T ['l4', 'l7', 'l9', 'l11']", + "86, cells ['l5', 'l8', 'l10', 'l11']", + "130, T(reg) ['l12']", + "131, cells ['l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21743453", + "TEXT": "Carvedilol is one of the most effective beta blockers for preventing ventricular tachyarrhythmias in heart failure, but the mechanisms underlying its favorable antiarrhythmic benefits remain unclear. Spontaneous Ca(2+) waves, also called store overload-induced Ca(2+) release (SOICR), evoke ventricular tachyarrhythmias in individuals with heart failure. Here we show that carvedilol is the only beta blocker tested that effectively suppresses SOICR by directly reducing the open duration of the cardiac ryanodine receptor (RyR2). This unique anti-SOICR activity of carvedilol, combined with its beta-blocking activity, probably contributes to its favorable antiarrhythmic effect. To enable optimal titration of carvedilol's actions as a beta blocker and as a suppressor of SOICR separately, we developed a new SOICR-inhibiting, minimally beta-blocking carvedilol analog, VK-II-86. VK-II-86 prevented stress-induced ventricular tachyarrhythmias in RyR2-mutant mice and did so more effectively when combined with either of the selective beta blockers metoprolol or bisoprolol. Combining SOICR inhibition with optimal beta blockade has the potential to provide antiarrhythmic therapy that can be tailored to individual patients.", + "TAG_DATA": [ + "123, RyR2-mutant {'perturbing_action': 'B-other'}", + "124, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "123, RyR2-mutant ['l0']", + "124, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "RyR2-mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "21743452", + "TEXT": "Progress in understanding, diagnosis, and treatment of coronary artery disease (CAD) has been hindered by our inability to observe cells and extracellular components associated with human coronary atherosclerosis in situ. The current standards for microstructural investigation, histology and electron microscopy are destructive and prone to artifacts. The highest-resolution intracoronary imaging modality, optical coherence tomography (OCT), has a resolution of ~10 μm, which is too coarse for visualizing most cells. Here we report a new form of OCT, termed micro-optical coherence tomography (μOCT), whose resolution is improved by an order of magnitude. We show that μOCT images of cadaver coronary arteries provide clear pictures of cellular and subcellular features associated with atherogenesis, thrombosis and responses to interventional therapy. These results suggest that μOCT can complement existing diagnostic techniques for investigating atherosclerotic specimens, and that μOCT may eventually become a useful tool for cellular and subcellular characterization of the human coronary wall in vivo.", + "TAG_DATA": [ + "97, cadaver {'context': 'B-tissue/organ'}", + "98, coronary {'context': 'I-tissue/organ'}", + "99, arteries {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "97, cadaver ['l0', 'l1']", + "98, coronary ['l0', 'l2']", + "99, arteries ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21738147", + "TEXT": "With an eye to tackling the growing problem of antimicrobial drug resistance, uS lawmakers last month proposed new incentives to jump-start the ailing antibiotic industry. but the legislation as written is not likely to have the intended consequences, as it fails to adequately shield companies from competition with generic drugs. To truly entice investment and research from the drug industry, the bill needs to simplify the path to regulatory approval, provide greater protection from generic competition and aid drug companies with intellectual property extensions, tax relief and guaranteed market commitments.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21642978", + "TEXT": "Obesity-related hypertension has become an epidemic health problem and a major risk factor for the development of cardiovascular disease (CVD). Recent research on the pathophysiology of obesity has implicated a role for the hypothalamus in the pathogenesis of this condition. However, it remains unknown whether the often-seen coupling of hypertension with obesity can also be explained by hypothalamic dysfunction, despite the emerging appreciation that many forms of hypertension are neurogenic in origin. Our studies here revealed that acute activation of the proinflammatory protein nuclear factor κB (NF-κB) and its upstream activator IκB kinase-β (IKK-β, encoded by Ikbkb) in the mediobasal hypothalamus rapidly elevated blood pressure in mice independently of obesity. This form of hypothalamic inflammation-induced hypertension involved the sympathetic upregulation of hemodynamics and was reversed by sympathetic suppression. Loss-of-function studies further showed that NF-κB inhibition in the mediobasal hypothalamus counteracted obesity-related hypertension in a manner that was dissociable from changes in body weight. In addition, we found that pro-opiomelanocortin (POMC) neurons were crucial for the hypertensive effects of the activation of hypothalamic IKK-β and NF-κB, which underlie obesity-related hypertension. In conclusion, obesity-associated activation of IKK-β and NF-κB in the mediobasal hypothalamus--particularly in the hypothalamic POMC neurons--is a primary pathogenic link between obesity and hypertension. Breaking this pathogenic link may represent an avenue for controlling obesity-related hypertension and CVD without requiring obesity control.", + "TAG_DATA": [ + "99, mediobasal {'context': 'B-tissue/organ'}", + "100, hypothalamus {'context': 'I-tissue/organ'}", + "106, mice {'context': 'B-organism'}", + "133, NF-κB {'perturbing_action': 'B-pharmacological inhibition'}", + "134, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "137, mediobasal {'context': 'B-tissue/organ'}", + "138, hypothalamus {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "99, mediobasal ['l0', 'l1']", + "100, hypothalamus ['l0', 'l2']", + "106, mice ['l1', 'l2']", + "133, NF-κB ['l3', 'l4', 'l5']", + "134, inhibition ['l3', 'l6', 'l7']", + "137, mediobasal ['l4', 'l6', 'l8']", + "138, hypothalamus ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NF-κB", + "inhibition" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mediobasal", + "hypothalamus" + ] + } + } + ] + }, + { + "PMID": "21623381", + "TEXT": "Myotonic dystrophy is the most common muscular dystrophy in adults and the first recognized example of an RNA-mediated disease. Congenital myotonic dystrophy (CDM1) and myotonic dystrophy of type 1 (DM1) or of type 2 (DM2) are caused by the expression of mutant RNAs containing expanded CUG or CCUG repeats, respectively. These mutant RNAs sequester the splicing regulator Muscleblind-like-1 (MBNL1), resulting in specific misregulation of the alternative splicing of other pre-mRNAs. We found that alternative splicing of the bridging integrator-1 (BIN1) pre-mRNA is altered in skeletal muscle samples of people with CDM1, DM1 and DM2. BIN1 is involved in tubular invaginations of membranes and is required for the biogenesis of muscle T tubules, which are specialized skeletal muscle membrane structures essential for excitation-contraction coupling. Mutations in the BIN1 gene cause centronuclear myopathy, which shares some histopathological features with myotonic dystrophy. We found that MBNL1 binds the BIN1 pre-mRNA and regulates its alternative splicing. BIN1 missplicing results in expression of an inactive form of BIN1 lacking phosphatidylinositol 5-phosphate-binding and membrane-tubulating activities. Consistent with a defect of BIN1, muscle T tubules are altered in people with myotonic dystrophy, and membrane structures are restored upon expression of the normal splicing form of BIN1 in muscle cells of such individuals. Finally, reproducing BIN1 splicing alteration in mice is sufficient to promote T tubule alterations and muscle weakness, a predominant feature of myotonic dystrophy.", + "TAG_DATA": [ + "160, form {'perturbing_action': 'I-other'}", + "200, muscle {'context': 'B-cells'}", + "201, cells {'context': 'I-cells'}", + "211, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "160, form ['l0', 'l1']", + "200, muscle ['l0', 'l2', 'l3']", + "201, cells ['l1', 'l2']", + "211, mice ['l3']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "form" + ] + }, + "context": { + "val": "cells", + "words": [ + "muscle", + "cells" + ] + } + } + ] + }, + { + "PMID": "21572426", + "TEXT": "Transplant rejection involves a coordinated attack of the innate and the adaptive immune systems of the host. To investigate this dynamic process and the contributions of both donor and host cells, we developed an ear skin graft model suitable for intravital imaging. We found that donor dermal dendritic cells (DCs) migrated rapidly from the graft and were replaced by host CD11b(+) mononuclear cells. The infiltrating host cells captured donor antigen, reached the draining lymph node and cross-primed graft-reactive CD8(+) T cells. Furthermore, we defined the mechanisms by which host T cells target graft cells. We found that primed T cells entered the graft from the surrounding tissue and localized selectively at the dermis-epidermis junction. Later, CD8(+) T cells disseminated throughout the graft and many became arrested. These results provide insights into the antigen presentation pathway and the stepwise progression of CD8(+) T cell activity, thereby offering a framework for evaluating how immunotherapy might abrogate the key steps in allograft rejection.", + "TAG_DATA": [ + "45, donor {'context': 'B-cells'}", + "46, dermal {'context': 'I-cells'}", + "47, dendritic {'context': 'I-cells'}", + "48, cells {'context': 'I-cells'}", + "49, (DCs) {'context': 'I-cells'}", + "65, host {'context': 'B-cells'}", + "66, cells {'context': 'I-cells'}", + "78, CD8(+) {'context': 'B-cells'}", + "79, T {'context': 'I-cells'}", + "80, cells. {'context': 'I-cells'}", + "98, T {'context': 'B-cells'}", + "99, cells {'context': 'I-cells'}", + "115, CD8(+) {'context': 'B-cells'}", + "116, T {'context': 'I-cells'}", + "117, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, donor ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "46, dermal ['l0', 'l7', 'l8', 'l9', 'l10']", + "47, dendritic ['l1', 'l7', 'l11', 'l12', 'l13', 'l14', 'l15']", + "48, cells ['l2', 'l8', 'l11', 'l16', 'l17']", + "49, (DCs) ['l3', 'l9', 'l12', 'l16', 'l18']", + "65, host ['l4', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "66, cells ['l5', 'l10', 'l14', 'l17', 'l18', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "78, CD8(+) ['l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "79, T ['l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "80, cells. ['l6', 'l15', 'l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "98, T ['l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "99, cells ['l24', 'l29', 'l33', 'l36', 'l38', 'l39']", + "115, CD8(+) ['l40', 'l41']", + "116, T ['l40', 'l42']", + "117, cells ['l41', 'l42']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21552268", + "TEXT": "The natural killer (NK) cell receptor NKp30 is involved in the recognition of tumor and dendritic cells (DCs). Here we describe the influence of three NKp30 splice variants on the prognosis of gastrointestinal sarcoma (GIST), a malignancy that expresses NKp30 ligands and that is treated with NK-stimulatory KIT tyrosine kinase inhibitors. Healthy individuals and those with GIST show distinct patterns of transcription of functionally different NKp30 isoforms. In a retrospective analysis of 80 individuals with GIST, predominant expression of the immunosuppressive NKp30c isoform (over the immunostimulatory NKp30a and NKp30b isoforms) was associated with reduced survival of subjects, decreased NKp30-dependent tumor necrosis factor-α (TNF-α) and CD107a release, and defective interferon-γ (IFN-γ) and interleukin-12 (IL-12) secretion in the NK-DC cross-talk that could be restored by blocking of IL-10. Preferential NKp30c expression resulted partly from a single-nucleotide polymorphism at position 3790 in the 3' untranslated region of the gene encoding NKp30. The genetically determined NKp30 status predicts the clinical outcomes of individuals with GIST independently from KIT mutation.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21546971", + "TEXT": "Moderate to severe asthma is difficult to treat because recurring bouts of inflammation in the lungs induce fibrosis, which reduces lung elasticity, gas exchange and responses to conventional therapy. A recent study identifies the tumor necrosis factor family member LIGHT as an essential mediator of airway fibrosis in a mouse model of chronic asthma (pages 596–603).", + "TAG_DATA": [ + "49, mouse {'context': 'B-organism'}", + "50, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "49, mouse ['l0']", + "50, model ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21499270", + "TEXT": "How high salt intake increases blood pressure is a key question in the study of hypertension. Salt intake induces increased renal sympathetic activity resulting in sodium retention. However, the mechanisms underlying the sympathetic control of renal sodium excretion remain unclear. In this study, we found that β(2)-adrenergic receptor (β(2)AR) stimulation led to decreased transcription of the gene encoding WNK4, a regulator of sodium reabsorption. β(2)AR stimulation resulted in cyclic AMP-dependent inhibition of histone deacetylase-8 (HDAC8) activity and increased histone acetylation, leading to binding of the glucocorticoid receptor to a negative glucocorticoid-responsive element in the promoter region. In rat models of salt-sensitive hypertension and sympathetic overactivity, salt loading suppressed renal WNK4 expression, activated the Na(+)-Cl(-) cotransporter and induced salt-dependent hypertension. These findings implicate the epigenetic modulation of WNK4 transcription in the development of salt-sensitive hypertension. The renal β(2)AR-WNK4 pathway may be a therapeutic target for salt-sensitive hypertension.", + "TAG_DATA": [ + "97, rat {'context': 'B-organism'}", + "98, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "97, rat ['l0']", + "98, models ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21499268", + "TEXT": "Attention deficit hyperactivity disorder (ADHD) is a psychiatric disorder that affects ~5% of school-aged children; however, the mechanisms underlying ADHD remain largely unclear. Here we report a previously unidentified association between G protein-coupled receptor kinase-interacting protein-1 (GIT1) and ADHD in humans. An intronic single-nucleotide polymorphism in GIT1, the minor allele of which causes reduced GIT1 expression, shows a strong association with ADHD susceptibility in humans. Git1-deficient mice show ADHD-like phenotypes, with traits including hyperactivity, enhanced electroencephalogram theta rhythms and impaired learning and memory. Hyperactivity in Git1(-/-) mice is reversed by amphetamine and methylphenidate, psychostimulants commonly used to treat ADHD. In addition, amphetamine normalizes enhanced theta rhythms and impaired memory. GIT1 deficiency in mice leads to decreases in ras-related C3 botulinum toxin substrate-1 (RAC1) signaling and inhibitory presynaptic input; furthermore, it shifts the neuronal excitation-inhibition balance in postsynaptic neurons toward excitation. Our study identifies a previously unknown involvement of GIT1 in human ADHD and shows that GIT1 deficiency in mice causes psychostimulant-responsive ADHD-like phenotypes.", + "TAG_DATA": [ + "65, Git1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "66, mice {'context': 'B-organism'}", + "85, Git1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "86, mice {'context': 'B-organism'}", + "109, GIT1 {'perturbing_action': 'B-gene loss-of-function'}", + "110, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "112, mice {'context': 'B-organism'}", + "155, GIT1 {'perturbing_action': 'B-gene loss-of-function'}", + "156, deficiency {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "65, Git1-deficient ['l0']", + "66, mice ['l0']", + "85, Git1(-/-) ['l1']", + "86, mice ['l1']", + "109, GIT1 ['l2', 'l3', 'l4']", + "110, deficiency ['l2', 'l5']", + "112, mice ['l3', 'l5']", + "155, GIT1 ['l6']", + "156, deficiency ['l4', 'l6']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Git1-deficient", + "Git1(-/-)", + "GIT1", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "21475240", + "TEXT": "Overwhelming evidence that relationships between universities, physicians and the medical products industry benefit patients explains the ubiquitous calls to encourage such relationships. Yet accumulating 'conflict of interest' regulations in academic health centers, government and industry have had the opposite effect. Justifications underlying the regulations lack quantitative rigor, and the rules they enforce impose costly bureaucratic requirements of dubious benefit. Evidence shows that they have diminished the collaborations deemed beneficial to health enhancement.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21475239", + "TEXT": "Concerns about conflicts of interest have driven a wedge between academia and the pharmaceutical and devices industries. Although elevated concern for bias is justified, particularly when academics may affect drug sales, partnerships between industry and academia are essential to achieve the full promise of health improvement from the public investment in biomedical research. New models for such partnerships are developing and should be encouraged.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21475232", + "TEXT": "Retinoic acid receptors inhibit chondrogenesis, but their ability to block the cartilaginous scaffold of heterotopic endochondral ossification has not been explored. A study in mice shows that agonists of retinoic acid receptor-γ potently inhibit heterotopic endochondral ossification, suggesting therapeutic potential in people with this condition (pages 454–460).", + "TAG_DATA": [ + "24, mice {'context': 'B-organism'}", + "27, agonists {'perturbing_action': 'B-pharmacological augmentation'}", + "28, of {'perturbing_action': 'I-pharmacological augmentation'}", + "29, retinoic {'perturbing_action': 'I-pharmacological augmentation'}", + "30, acid {'perturbing_action': 'I-pharmacological augmentation'}", + "31, receptor-γ {'perturbing_action': 'I-pharmacological augmentation'}" + ], + "LINK_DATA": [ + "27, agonists ['l0', 'l1', 'l2', 'l3']", + "28, of ['l0', 'l4', 'l5', 'l6']", + "29, retinoic ['l1', 'l4', 'l7', 'l8']", + "30, acid ['l2', 'l5', 'l7', 'l9']", + "31, receptor-γ ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21441916", + "TEXT": "In multiple sclerosis, a common inflammatory disease of the central nervous system, immune-mediated axon damage is responsible for permanent neurological deficits. How axon damage is initiated is not known. Here we use in vivo imaging to identify a previously undescribed variant of axon damage in a mouse model of multiple sclerosis. This process, termed 'focal axonal degeneration' (FAD), is characterized by sequential stages, beginning with focal swellings and progressing to axon fragmentation. Notably, most swollen axons persist unchanged for several days, and some recover spontaneously. Early stages of FAD can be observed in axons with intact myelin sheaths. Thus, contrary to the classical view, demyelination-a hallmark of multiple sclerosis-is not a prerequisite for axon damage. Instead, focal intra-axonal mitochondrial pathology is the earliest ultrastructural sign of damage, and it precedes changes in axon morphology. Molecular imaging and pharmacological experiments show that macrophage-derived reactive oxygen and nitrogen species (ROS and RNS) can trigger mitochondrial pathology and initiate FAD. Indeed, neutralization of ROS and RNS rescues axons that have already entered the degenerative process. Finally, axonal changes consistent with FAD can be detected in acute human multiple sclerosis lesions. In summary, our data suggest that inflammatory axon damage might be spontaneously reversible and thus a potential target for therapy.", + "TAG_DATA": [ + "164, axons {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21423182", + "TEXT": "In multiple sclerosis, activated CD4(+) T cells initiate an immune response in the brain and spinal cord, resulting in demyelination, degeneration and progressive paralysis. Repulsive guidance molecule-a (RGMa) is an axon guidance molecule that has a role in the visual system and in neural tube closure. Our study shows that RGMa is expressed in bone marrow-derived dendritic cells (BMDCs) and that CD4(+) T cells express neogenin, a receptor for RGMa. Binding of RGMa to CD4(+) T cells led to activation of the small GTPase Rap1 and increased adhesion of T cells to intracellular adhesion molecule-1 (ICAM-1). Neutralizing antibodies to RGMa attenuated clinical symptoms of mouse myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) and reduced invasion of inflammatory cells into the CNS. Silencing of RGMa in MOG-pulsed BMDCs reduced their capacity to induce EAE following adoptive transfer to naive C57BL/6 mice. CD4(+) T cells isolated from mice treated with an RGMa-specific antibody showed diminished proliferative responses and reduced interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-4 and IL-17 secretion. Incubation of PBMCs from patients with multiple sclerosis with an RGMa-specific antibody reduced proliferative responses and pro-inflammatory cytokine expression. These results demonstrate that an RGMa-specific antibody suppresses T cell responses, and suggest that RGMa could be a promising molecular target for the treatment of multiple sclerosis.", + "TAG_DATA": [ + "74, CD4(+) {'context': 'B-cells'}", + "75, T {'context': 'I-cells'}", + "76, cells {'context': 'I-cells'}", + "86, increased {'effect': 'B-positive'}", + "89, T {'context': 'B-cells'}", + "90, cells {'context': 'B-cells'}", + "117, inflammatory {'context': 'B-cells'}", + "118, cells {'context': 'I-cells'}", + "122, Silencing {'perturbing_action': 'B-rnai/knockdown'}", + "123, of {'perturbing_action': 'I-rnai/knockdown'}", + "124, RGMa {'perturbing_action': 'I-rnai/knockdown'}", + "127, BMDCs {'context': 'B-cells'}", + "139, C57BL/6 {'context': 'I-organism'}", + "140, mice. {'context': 'I-organism'}", + "141, CD4(+) {'context': 'B-cells'}", + "142, T {'context': 'I-cells'}", + "143, cells {'context': 'I-cells'}", + "146, mice {'context': 'B-organism'}", + "153, diminished {'effect': 'B-negative'}", + "154, proliferative {'phenotype': 'B-proliferation'}", + "155, responses {'phenotype': 'I-proliferation'}", + "168, PBMCs {'context': 'B-cells'}", + "169, from {'context': 'I-patient'}", + "170, patients {'context': 'I-patient'}", + "171, with {'context': 'I-patient'}", + "178, reduced {'effect': 'B-negative'}", + "179, proliferative {'phenotype': 'B-proliferation'}", + "180, responses {'phenotype': 'I-proliferation'}" + ], + "LINK_DATA": [ + "74, CD4(+) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "75, T ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "76, cells ['l1', 'l7', 'l12', 'l13', 'l14']", + "86, increased ['l2', 'l8', 'l12', 'l15', 'l16']", + "89, T ['l3', 'l9', 'l13', 'l15', 'l17', 'l18']", + "90, cells ['l4', 'l10', 'l14', 'l16', 'l17', 'l19']", + "117, inflammatory ['l5', 'l20']", + "118, cells ['l6', 'l11', 'l18', 'l19', 'l20']", + "122, Silencing ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "123, of ['l21', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "124, RGMa ['l22', 'l33', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "127, BMDCs ['l23', 'l34', 'l44', 'l52', 'l53']", + "139, C57BL/6 ['l24', 'l35', 'l45', 'l52', 'l54']", + "140, mice. ['l25', 'l36', 'l46', 'l53', 'l54']", + "141, CD4(+) ['l26', 'l37', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "142, T ['l27', 'l38', 'l47', 'l55', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "143, cells ['l28', 'l39', 'l48', 'l56', 'l64', 'l70', 'l71', 'l72', 'l73']", + "146, mice ['l29', 'l40', 'l57', 'l65', 'l70', 'l74', 'l75', 'l76', 'l77']", + "153, diminished ['l30', 'l41', 'l49', 'l58', 'l66', 'l71', 'l74', 'l78', 'l79']", + "154, proliferative ['l31', 'l42', 'l50', 'l59', 'l67', 'l72', 'l75', 'l78', 'l80']", + "155, responses ['l32', 'l43', 'l51', 'l60', 'l68', 'l73', 'l76', 'l79', 'l80']", + "168, PBMCs ['l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "169, from ['l61', 'l81', 'l87', 'l88', 'l89', 'l90', 'l91']", + "170, patients ['l82', 'l87', 'l92', 'l93', 'l94', 'l95']", + "171, with ['l83', 'l88', 'l92', 'l96', 'l97', 'l98']", + "178, reduced ['l84', 'l89', 'l93', 'l96', 'l99', 'l100']", + "179, proliferative ['l62', 'l85', 'l90', 'l94', 'l97', 'l99', 'l101']", + "180, responses ['l63', 'l69', 'l77', 'l86', 'l91', 'l95', 'l98', 'l100', 'l101']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "RGMa" + ] + }, + "context": { + "val": "cells", + "words": [ + "BMDCs", + "CD4(+)", + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "RGMa" + ] + }, + "context": { + "val": "organism", + "words": [ + "C57BL/6", + "mice.", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "RGMa" + ] + }, + "effect": { + "val": "negative", + "words": [ + "diminished" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "RGMa" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "responses" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cells", + "PBMCs" + ] + }, + "effect": { + "val": "negative", + "words": [ + "diminished", + "reduced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cells", + "PBMCs" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "responses" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "diminished" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "responses" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "diminished", + "reduced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "responses" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "from", + "patients", + "with" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "from", + "patients", + "with" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "responses" + ] + } + } + ] + }, + { + "PMID": "21383718", + "TEXT": "Finding mechanisms of viral resistance and new ways to tackle chronic hepatitis will help find a cure for this disease. In ‘Bench to Bedside’, Christopher Walker and Benoît Callendret highlight studies showing that overcoming immune exhaustion during chronic infection by blocking several inhibitory pathways of T cells may restore an adequate immune response. In ‘Bedside to Bench’, Lawrence Corey, Joshua Schiffer and John Scott discuss recent advances in antiviral therapy with protease inhibitors and the findings of a mathematical model that predicts possible single and double mutations prior to antiviral therapy.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21378977", + "TEXT": "The trials performed worldwide toward noninvasive prenatal diagnosis (NIPD) of Down's syndrome (or trisomy 21) have shown the commercial and medical potential of NIPD compared to the currently used invasive prenatal diagnostic procedures. Extensive investigation of methylation differences between the mother and the fetus has led to the identification of differentially methylated regions (DMRs). In this study, we present a strategy using the methylated DNA immunoprecipitation (MeDiP) methodology in combination with real-time quantitative PCR (qPCR) to achieve fetal chromosome dosage assessment, which can be performed noninvasively through the analysis of fetal-specific DMRs. We achieved noninvasive prenatal detection of trisomy 21 by determining the methylation ratio of normal and trisomy 21 cases for each tested fetal-specific DMR present in maternal peripheral blood, followed by further statistical analysis. The application of this fetal-specific methylation ratio approach provided correct diagnosis of 14 trisomy 21 and 26 normal cases.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21358627", + "TEXT": "We analyzed HIV-1 genome sequences from 68 newly infected volunteers in the STEP HIV-1 vaccine trial. To determine whether the vaccine exerted selective T cell pressure on breakthrough viruses, we identified potential T cell epitopes in the founder sequences and compared them to epitopes in the vaccine. We found greater distances to the vaccine sequence for sequences from vaccine recipients than from placebo recipients. The most significant signature site distinguishing vaccine from placebo recipients was Gag amino acid 84, a site encompassed by several epitopes contained in the vaccine and restricted by human leukocyte antigen (HLA) alleles common in the study cohort. Moreover, the extended divergence was confined to the vaccine components of the virus (HIV-1 Gag, Pol and Nef) and not found in other HIV-1 proteins. These results represent what is to our knowledge the first evidence of selective pressure from vaccine-induced T cell responses on HIV-1 infection in humans.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21336285", + "TEXT": "Rapid diagnosis of active Mycobacterium tuberculosis (Mtb) infection remains a clinical and laboratory challenge. We have analyzed the cytokine profile (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2)) of Mtb-specific T cells by polychromatic flow cytometry. We studied Mtb-specific CD4+ T cell responses in subjects with latent Mtb infection and active tuberculosis disease. The results showed substantial increase in the proportion of single-positive TNF-α Mtb-specific CD4+ T cells in subjects with active disease, and this parameter was the strongest predictor of diagnosis of active disease versus latent infection. We validated the use of this parameter in a cohort of 101 subjects with tuberculosis diagnosis unknown to the investigator. The sensitivity and specificity of the flow cytometry-based assay were 67% and 92%, respectively, the positive predictive value was 80% and the negative predictive value was 92.4%. Therefore, the proportion of single-positive TNF-α Mtb-specific CD4+ T cells is a new tool for the rapid diagnosis of active tuberculosis disease.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21336284", + "TEXT": "Huntington's disease is an inherited and incurable neurodegenerative disorder caused by an abnormal polyglutamine (polyQ) expansion in huntingtin (encoded by HTT). PolyQ length determines disease onset and severity, with a longer expansion causing earlier onset. The mechanisms of mutant huntingtin-mediated neurotoxicity remain unclear; however, mitochondrial dysfunction is a key event in Huntington's disease pathogenesis. Here we tested whether mutant huntingtin impairs the mitochondrial fission-fusion balance and thereby causes neuronal injury. We show that mutant huntingtin triggers mitochondrial fragmentation in rat neurons and fibroblasts of individuals with Huntington's disease in vitro and in a mouse model of Huntington's disease in vivo before the presence of neurological deficits and huntingtin aggregates. Mutant huntingtin abnormally interacts with the mitochondrial fission GTPase dynamin-related protein-1 (DRP1) in mice and humans with Huntington's disease, which, in turn, stimulates its enzymatic activity. Mutant huntingtin-mediated mitochondrial fragmentation, defects in anterograde and retrograde mitochondrial transport and neuronal cell death are all rescued by reducing DRP1 GTPase activity with the dominant-negative DRP1 K38A mutant. Thus, DRP1 might represent a new therapeutic target to combat neurodegeneration in Huntington's disease.", + "TAG_DATA": [ + "73, mutant {'perturbing_action': 'B-other'}", + "74, huntingtin {'perturbing_action': 'I-other'}", + "79, rat {'context': 'B-cells'}", + "80, neurons {'context': 'I-cells'}", + "82, fibroblasts {'context': 'B-cells'}", + "84, individuals {'context': 'B-patient'}", + "88, in {'context': 'B-in vitro'}", + "89, vitro {'context': 'I-in vitro'}", + "93, mouse {'context': 'B-organism'}", + "94, model {'context': 'I-organism'}", + "95, of {'context': 'I-organism'}", + "96, Huntington's {'context': 'I-organism'}", + "97, disease {'context': 'I-organism'}", + "98, in {'context': 'B-in vivo'}", + "99, vivo {'context': 'I-in vivo'}", + "148, cell {'phenotype': 'B-cell death'}", + "149, death {'phenotype': 'I-cell death'}", + "160, dominant-negative {'perturbing_action': 'B-other'}", + "161, DRP1 {'perturbing_action': 'I-other'}", + "162, K38A {'perturbing_action': 'I-other'}", + "163, mutant. {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "73, mutant ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "74, huntingtin ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "79, rat ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "80, neurons ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "82, fibroblasts ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "84, individuals ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "88, in ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "89, vitro ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "93, mouse ['l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "94, model ['l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "95, of ['l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "96, Huntington's ['l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "97, disease ['l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "98, in ['l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "99, vivo ['l33', 'l38', 'l42', 'l45', 'l47', 'l48']", + "148, cell ['l49']", + "149, death ['l49']", + "160, dominant-negative ['l50', 'l51', 'l52']", + "161, DRP1 ['l50', 'l53', 'l54']", + "162, K38A ['l51', 'l53', 'l55']", + "163, mutant. ['l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "huntingtin" + ] + }, + "context": { + "val": "cells", + "words": [ + "rat", + "neurons", + "fibroblasts" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "huntingtin" + ] + }, + "context": { + "val": "patient", + "words": [ + "individuals" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "huntingtin" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "21297617", + "TEXT": "Pseudomonas aeruginosa is a Gram-negative pathogen that causes severe infections in immunocompromised individuals and individuals with cystic fibrosis or chronic obstructive pulmonary disease (COPD). Here we show that kinase suppressor of Ras-1 (Ksr1)-deficient mice are highly susceptible to pulmonary P. aeruginosa infection accompanied by uncontrolled pulmonary cytokine release, sepsis and death, whereas wild-type mice clear the infection. Ksr1 recruits and assembles inducible nitric oxide (NO) synthase (iNOS) and heat shock protein-90 (Hsp90) to enhance iNOS activity and to release NO upon infection. Ksr1 deficiency prevents lung alveolar macrophages and neutrophils from activating iNOS, producing NO and killing bacteria. Restoring NO production restores the bactericidal capability of Ksr1-deficient lung alveolar macrophages and neutrophils and rescues Ksr1-deficient mice from P. aeruginosa infection. Our findings suggest that Ksr1 functions as a previously unknown scaffold that enhances iNOS activity and is therefore crucial for the pulmonary response to P. aeruginosa infections.", + "TAG_DATA": [ + "28, kinase {'perturbing_action': 'B-gene loss-of-function'}", + "29, suppressor {'perturbing_action': 'I-gene loss-of-function'}", + "30, of {'perturbing_action': 'I-gene loss-of-function'}", + "31, Ras-1 {'perturbing_action': 'I-gene loss-of-function'}", + "32, (Ksr1)-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "33, mice {'context': 'B-organism'}", + "82, Ksr1 {'perturbing_action': 'B-gene loss-of-function'}", + "83, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "85, lung {'context': 'B-cells'}", + "86, alveolar {'context': 'I-cells'}", + "87, macrophages {'context': 'I-cells'}", + "89, neutrophils {'context': 'B-cells'}", + "106, Ksr1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "107, lung {'context': 'B-cells'}", + "108, alveolar {'context': 'I-cells'}", + "109, macrophages {'context': 'I-cells'}", + "111, neutrophils {'context': 'B-cells'}", + "114, Ksr1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "115, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "28, kinase ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "29, suppressor ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "30, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "31, Ras-1 ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "32, (Ksr1)-deficient ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "33, mice ['l4', 'l12', 'l19', 'l25', 'l30']", + "82, Ksr1 ['l35', 'l36', 'l37', 'l38', 'l39']", + "83, deficiency ['l35', 'l40', 'l41', 'l42', 'l43']", + "85, lung ['l5', 'l13', 'l20', 'l26', 'l31', 'l36', 'l40', 'l44', 'l45', 'l46']", + "86, alveolar ['l6', 'l14', 'l21', 'l27', 'l32', 'l37', 'l41', 'l44', 'l47', 'l48']", + "87, macrophages ['l7', 'l15', 'l22', 'l28', 'l33', 'l38', 'l42', 'l45', 'l47', 'l49']", + "89, neutrophils ['l8', 'l16', 'l23', 'l29', 'l34', 'l39', 'l43', 'l46', 'l48', 'l49']", + "106, Ksr1-deficient ['l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "107, lung ['l50', 'l56', 'l57', 'l58', 'l59', 'l60']", + "108, alveolar ['l51', 'l56', 'l61', 'l62', 'l63', 'l64']", + "109, macrophages ['l52', 'l57', 'l61', 'l65', 'l66', 'l67']", + "111, neutrophils ['l53', 'l58', 'l62', 'l65', 'l68', 'l69']", + "114, Ksr1-deficient ['l54', 'l59', 'l63', 'l66', 'l68', 'l70']", + "115, mice ['l55', 'l60', 'l64', 'l67', 'l69', 'l70']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "kinase", + "suppressor", + "of", + "Ras-1", + "(Ksr1)-deficient", + "Ksr1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "kinase", + "suppressor", + "of", + "Ras-1", + "(Ksr1)-deficient", + "Ksr1", + "deficiency", + "Ksr1-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "lung", + "alveolar", + "macrophages", + "neutrophils" + ] + } + } + ] + }, + { + "PMID": "21258338", + "TEXT": "All tuberculosis vaccines currently in clinical trials are designed as prophylactic vaccines based on early expressed antigens. We have developed a multistage vaccination strategy in which the early antigens Ag85B and 6-kDa early secretory antigenic target (ESAT-6) are combined with the latency-associated protein Rv2660c (H56 vaccine). In CB6F1 mice we show that Rv2660c is stably expressed in late stages of infection despite an overall reduced transcription. The H56 vaccine promotes a T cell response against all protein components that is characterized by a high proportion of polyfunctional CD4(+) T cells. In three different pre-exposure mouse models, H56 confers protective immunity characterized by a more efficient containment of late-stage infection than the Ag85B-ESAT6 vaccine (H1) and BCG. In two mouse models of latent tuberculosis, we show that H56 vaccination after exposure is able to control reactivation and significantly lower the bacterial load compared to adjuvant control mice.", + "TAG_DATA": [ + "47, CB6F1 {'context': 'B-organism'}", + "48, mice {'context': 'I-organism'}", + "71, T {'context': 'B-cells'}", + "72, cell {'context': 'B-cells'}", + "94, mouse {'context': 'B-organism'}", + "95, models, {'context': 'I-organism'}", + "118, mouse {'context': 'B-organism'}", + "119, models {'context': 'I-organism'}", + "121, latent {'context': 'I-organism'}", + "122, tuberculosis, {'context': 'I-organism'}", + "145, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "47, CB6F1 ['l0', 'l1', 'l2']", + "48, mice ['l0', 'l3', 'l4']", + "71, T ['l1', 'l3', 'l5', 'l6']", + "72, cell ['l2', 'l4', 'l5', 'l7']", + "94, mouse ['l8']", + "95, models, ['l6', 'l7', 'l8']", + "118, mouse ['l9', 'l10', 'l11', 'l12']", + "119, models ['l9', 'l13', 'l14', 'l15']", + "121, latent ['l10', 'l13', 'l16', 'l17']", + "122, tuberculosis, ['l11', 'l14', 'l16', 'l18']", + "145, mice. ['l12', 'l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21170047", + "TEXT": "Clinical efficacy of the antiplatelet drug clopidogrel is hampered by its variable biotransformation into the active metabolite. The variability in the clinical response to clopidogrel treatment has been attributed to genetic factors, but the specific genes and mechanisms underlying clopidogrel bioactivation remain unclear. Using in vitro metabolomic profiling techniques, we identified paraoxonase-1 (PON1) as the crucial enzyme for clopidogrel bioactivation, with its common Q192R polymorphism determining the rate of active metabolite formation. We tested the clinical relevance of the PON1 Q192R genotype in a population of individuals with coronary artery disease who underwent stent implantation and received clopidogrel therapy. PON1 QQ192 homozygous individuals showed a considerably higher risk than RR192 homozygous individuals of stent thrombosis, lower PON1 plasma activity, lower plasma concentrations of active metabolite and lower platelet inhibition. Thus, we identified PON1 as a key factor for the bioactivation and clinical activity of clopidogrel. These findings have therapeutic implications and may be exploited to prospectively assess the clinical efficacy of clopidogrel.", + "TAG_DATA": [ + "86, individuals {'context': 'B-patient'}", + "99, PON1 {'perturbing_action': 'B-other'}", + "100, QQ192 {'perturbing_action': 'I-other'}", + "101, homozygous {'perturbing_action': 'I-other'}", + "109, RR192 {'perturbing_action': 'B-other'}", + "110, homozygous {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "86, individuals ['l0', 'l1', 'l2']", + "88, coronary ['l0', 'l3', 'l4']", + "89, artery ['l1', 'l3', 'l5']", + "90, disease ['l2', 'l4', 'l5']", + "99, PON1 ['l6', 'l7', 'l8', 'l9']", + "100, QQ192 ['l6', 'l10', 'l11', 'l12']", + "101, homozygous ['l7', 'l10']", + "109, RR192 ['l8', 'l11', 'l13']", + "110, homozygous ['l9', 'l12', 'l13']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21151138", + "TEXT": "The main manifestations of nephrotic syndrome include proteinuria, hypoalbuminemia, edema, hyperlipidemia and lipiduria. Common causes of nephrotic syndrome are diabetic nephropathy, minimal change disease (MCD), focal and segmental glomerulosclerosis (FSGS) and membranous nephropathy. Among the primary glomerular diseases, MCD is usually sensitive to glucocorticoid treatment, whereas the other diseases show variable responses. Despite the identification of key structural proteins in the glomerular capillary loop which may contribute to defects in ultrafiltration, many of the disease mechanisms of nephrotic syndrome remain unresolved. In this study, we show that the glomerular expression of angiopoietin-like-4 (Angptl4), a secreted glycoprotein, is glucocorticoid sensitive and is highly upregulated in the serum and in podocytes in experimental models of MCD and in the human disease. Podocyte-specific transgenic overexpression of Angptl4 (NPHS2-Angptl4) in rats induced nephrotic-range, and selective, proteinuria (over 500-fold increase in albuminuria), loss of glomerular basement membrane (GBM) charge and foot process effacement, whereas transgenic expression specifically in the adipose tissue (aP2-Angptl4) resulted in increased circulating Angptl4, but no proteinuria. Angptl4(-/-) mice that were injected with lipopolysaccharide (LPS) or nephritogenic antisera developed markedly less proteinuria than did control mice. Angptl4 secreted from podocytes in some forms of nephrotic syndrome lacks normal sialylation. When we fed the sialic acid precursor N-acetyl-D-mannosamine (ManNAc) to NPHS2-Angptl4 transgenic rats it increased the sialylation of Angptl4 and decreased albuminuria by more than 40%. These results suggest that podocyte-secreted Angptl4 has a key role in nephrotic syndrome.", + "TAG_DATA": [ + "119, Podocyte-specific {'perturbing_action': 'B-gene gain-of-function'}", + "120, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "121, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "122, of {'perturbing_action': 'I-gene gain-of-function'}", + "123, Angptl4 {'perturbing_action': 'I-gene gain-of-function'}", + "124, (NPHS2-Angptl4) {'perturbing_action': 'I-gene gain-of-function'}", + "126, rats {'context': 'B-organism'}", + "149, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "150, expression {'perturbing_action': 'I-gene gain-of-function'}", + "151, specifically {'perturbing_action': 'I-gene gain-of-function'}", + "152, in {'perturbing_action': 'I-gene gain-of-function'}", + "153, the {'perturbing_action': 'I-gene gain-of-function'}", + "154, adipose {'perturbing_action': 'I-gene gain-of-function'}", + "155, tissue {'perturbing_action': 'I-gene gain-of-function'}", + "156, (aP2-Angptl4) {'perturbing_action': 'I-gene gain-of-function'}", + "165, Angptl4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "166, mice {'context': 'B-organism'}", + "183, mice. {'context': 'B-organism'}", + "207, NPHS2-Angptl4 {'perturbing_action': 'B-gene gain-of-function'}", + "208, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "209, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "119, Podocyte-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "120, transgenic ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "121, overexpression ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "122, of ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "123, Angptl4 ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "124, (NPHS2-Angptl4) ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "126, rats ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "149, transgenic ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "150, expression ['l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "151, specifically ['l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "152, in ['l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "153, the ['l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "154, adipose ['l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "155, tissue ['l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "156, (aP2-Angptl4) ['l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l48']", + "165, Angptl4(-/-) ['l49', 'l50']", + "166, mice ['l49', 'l51']", + "183, mice. ['l50', 'l51']", + "207, NPHS2-Angptl4 ['l52', 'l53']", + "208, transgenic ['l52', 'l54']", + "209, rats ['l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Podocyte-specific", + "transgenic", + "overexpression", + "of", + "Angptl4", + "(NPHS2-Angptl4)", + "NPHS2-Angptl4" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Angptl4(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "21135852", + "TEXT": "The immune system normally responds to influenza virus by making neutralizing antibodies to regions of the viral spike, the hemagglutinin, that vary year to year. This natural response protects against circulating subtypes but necessitates production of new vaccines annually. Newer vaccine approaches have succeeded in eliciting broadly neutralizing antibodies to highly conserved yet vulnerable regions of the hemagglutinin and suggest potential pathways for the development of universal influenza vaccines.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21135826", + "TEXT": "In July, the global health financing mechanism UNITAID established an intellectual property-sharing scheme focused on scaling up access to new and lower-priced antiretroviral drugs in the developing world. The initiative-called the Medicines Patent Pool (MPP)-aims to streamline licensing processes, drive the combination of multiple HIV medicines into one pill and foster the development of drug formulations for children. In September, the US National Institutes of Health (NIH) became the first contributor to the venture, licensing a suite of patents related to protease inhibitors that are used to treat HIV. The task of bringing drug firms and other key stakeholders into the fold now falls on Ellen 't Hoen, a lawyer who became MPP's executive director last month after previously heading up Médecins Sans Frontières' Campaign for Access to Essential Medicines. Asher Mullard spoke to Hoen about the challenges of encouraging companies to share their intellectual property in a normally guarded sector.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21131957", + "TEXT": "MicroRNAs are a family of regulatory molecules involved in many physiological processes, including differentiation and activation of cells of the immune system. We found that brain-specific miR-124 is expressed in microglia but not in peripheral monocytes or macrophages. When overexpressed in macrophages, miR-124 directly inhibited the transcription factor CCAAT/enhancer-binding protein-α (C/EBP-α) and its downstream target PU.1, resulting in transformation of these cells from an activated phenotype into a quiescent CD45(low), major histocompatibility complex (MHC) class II(low) phenotype resembling resting microglia. During experimental autoimmune encephalomyelitis (EAE), miR-124 was downregulated in activated microglia. Peripheral administration of miR-124 in EAE caused systemic deactivation of macrophages, reduced activation of myelin-specific T cells and marked suppression of disease. Conversely, knockdown of miR-124 in microglia and macrophages resulted in activation of these cells in vitro and in vivo. These findings identify miR-124 both as a key regulator of microglia quiescence in the central nervous system and as a previously unknown modulator of monocyte and macrophage activation.", + "TAG_DATA": [ + "41, macrophages, {'context': 'B-cells'}", + "61, cells {'context': 'B-cells'}", + "90, microglia. {'context': 'B-cells'}", + "101, macrophages, {'context': 'B-cells'}", + "105, myelin-specific {'context': 'B-cells'}", + "106, T {'context': 'I-cells'}", + "107, cells {'context': 'I-cells'}", + "114, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "115, of {'perturbing_action': 'I-rnai/knockdown'}", + "116, miR-124 {'perturbing_action': 'I-rnai/knockdown'}", + "118, microglia {'context': 'B-cells'}", + "120, macrophages {'context': 'B-cells'}", + "126, cells {'context': 'B-cells'}", + "127, in {'context': 'B-in vitro'}", + "128, vitro {'context': 'I-in vitro'}", + "130, in {'context': 'B-in vivo'}", + "131, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "41, macrophages, ['l0']", + "61, cells ['l0']", + "90, microglia. ['l1', 'l2', 'l3']", + "101, macrophages, ['l1', 'l4', 'l5', 'l6']", + "105, myelin-specific ['l4', 'l7', 'l8']", + "106, T ['l2', 'l5', 'l7', 'l9']", + "107, cells ['l3', 'l6', 'l8', 'l9']", + "114, knockdown ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "115, of ['l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "116, miR-124 ['l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "118, microglia ['l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "120, macrophages ['l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "126, cells ['l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "127, in ['l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "128, vitro ['l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "130, in ['l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "131, vivo. ['l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "miR-124" + ] + }, + "context": { + "val": "cells", + "words": [ + "microglia", + "macrophages", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "miR-124" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "miR-124" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "21076394", + "TEXT": "Basal tearing is crucial to maintaining ocular surface wetness. Corneal cold thermoreceptors sense small oscillations in ambient temperature and change their discharge accordingly. Deletion of the cold-transducing ion channel Transient receptor potential cation channel subfamily M member 8 (TRPM8) in mice abrogates cold responsiveness and reduces basal tearing without affecting nociceptor-mediated irritative tearing. Warming of the cornea in humans also decreases tearing rate. These findings indicate that TRPM8-dependent impulse activity in corneal cold receptors contributes to regulating basal tear flow.", + "TAG_DATA": [ + "23, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "24, of {'perturbing_action': 'I-gene loss-of-function'}", + "25, the {'perturbing_action': 'I-gene loss-of-function'}", + "26, cold-transducing {'perturbing_action': 'I-gene loss-of-function'}", + "27, ion {'perturbing_action': 'I-gene loss-of-function'}", + "28, channel {'perturbing_action': 'I-gene loss-of-function'}", + "29, Transient {'perturbing_action': 'I-gene loss-of-function'}", + "30, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "31, potential {'perturbing_action': 'I-gene loss-of-function'}", + "32, cation {'perturbing_action': 'I-gene loss-of-function'}", + "33, channel {'perturbing_action': 'I-gene loss-of-function'}", + "34, subfamily {'perturbing_action': 'I-gene loss-of-function'}", + "35, M {'perturbing_action': 'I-gene loss-of-function'}", + "36, member {'perturbing_action': 'I-gene loss-of-function'}", + "37, 8 {'perturbing_action': 'I-gene loss-of-function'}", + "38, (TRPM8) {'perturbing_action': 'I-gene loss-of-function'}", + "40, mice {'context': 'B-organism'}", + "56, cornea {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "23, Deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "24, of ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "25, the ['l1', 'l17', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "26, cold-transducing ['l2', 'l18', 'l33', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "27, ion ['l3', 'l19', 'l34', 'l48', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "28, channel ['l4', 'l20', 'l35', 'l49', 'l62', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "29, Transient ['l5', 'l21', 'l36', 'l50', 'l63', 'l75', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "30, receptor ['l6', 'l22', 'l37', 'l51', 'l64', 'l76', 'l87', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "31, potential ['l7', 'l23', 'l38', 'l52', 'l65', 'l77', 'l88', 'l98', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "32, cation ['l8', 'l24', 'l39', 'l53', 'l66', 'l78', 'l89', 'l99', 'l108', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "33, channel ['l9', 'l25', 'l40', 'l54', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "34, subfamily ['l10', 'l26', 'l41', 'l55', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l125', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "35, M ['l11', 'l27', 'l42', 'l56', 'l69', 'l81', 'l92', 'l102', 'l111', 'l119', 'l126', 'l132', 'l138', 'l139', 'l140', 'l141', 'l142']", + "36, member ['l12', 'l28', 'l43', 'l57', 'l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l127', 'l133', 'l138', 'l143', 'l144', 'l145', 'l146']", + "37, 8 ['l13', 'l29', 'l44', 'l58', 'l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l128', 'l134', 'l139', 'l143', 'l147', 'l148', 'l149']", + "38, (TRPM8) ['l14', 'l30', 'l45', 'l59', 'l72', 'l84', 'l95', 'l105', 'l114', 'l122', 'l129', 'l135', 'l140', 'l144', 'l147', 'l150', 'l151']", + "40, mice ['l15', 'l31', 'l46', 'l60', 'l73', 'l85', 'l96', 'l106', 'l115', 'l123', 'l130', 'l136', 'l141', 'l145', 'l148', 'l150']", + "56, cornea ['l16', 'l32', 'l47', 'l61', 'l74', 'l86', 'l97', 'l107', 'l116', 'l124', 'l131', 'l137', 'l142', 'l146', 'l149', 'l151']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "cold-transducing", + "ion", + "channel", + "Transient", + "receptor", + "potential", + "cation", + "subfamily", + "M", + "member", + "8", + "(TRPM8)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "cold-transducing", + "ion", + "channel", + "Transient", + "receptor", + "potential", + "cation", + "subfamily", + "M", + "member", + "8", + "(TRPM8)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "cornea" + ] + } + } + ] + }, + { + "PMID": "21057494", + "TEXT": "The transition from androgen-dependent to castration-resistant prostate cancer (CRPC) is a lethal event of uncertain molecular etiology. Comparing gene expression in isogenic androgen-dependent and CRPC xenografts, we found a reproducible increase in N-cadherin expression, which was also elevated in primary and metastatic tumors of individuals with CRPC. Ectopic expression of N-cadherin in nonmetastatic, androgen-dependent prostate cancer models caused castration resistance, invasion and metastasis. Monoclonal antibodies against the ectodomain of N-cadherin reduced proliferation, adhesion and invasion of prostate cancer cells in vitro. In vivo, these antibodies slowed the growth of multiple established CRPC xenografts, blocked local invasion and metastasis and, at higher doses, led to complete regression. N-cadherin-specific antibodies markedly delayed the time to emergence of castration resistance, markedly affected tumor histology and angiogenesis, and reduced both AKT serine-threonine kinase activity and serum interleukin-8 (IL-8) secretion. These data indicate that N-cadherin is a major cause of both prostate cancer metastasis and castration resistance. Therapeutic targeting of this factor with monoclonal antibodies may have considerable clinical benefit.", + "TAG_DATA": [ + "47, Ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "48, expression {'perturbing_action': 'I-gene gain-of-function'}", + "49, of {'perturbing_action': 'I-gene gain-of-function'}", + "50, N-cadherin {'perturbing_action': 'I-gene gain-of-function'}", + "52, nonmetastatic, {'context': 'B-neoplasm'}", + "53, androgen-dependent {'context': 'I-neoplasm'}", + "54, prostate {'context': 'I-neoplasm'}", + "55, cancer {'context': 'I-neoplasm'}", + "56, models {'context': 'I-neoplasm'}", + "57, caused {'effect': 'B-positive'}", + "60, invasion {'phenotype': 'B-invasion'}", + "62, metastasis. {'phenotype': 'B-metastasis'}", + "63, Monoclonal {'perturbing_action': 'B-rnai/knockdown'}", + "64, antibodies {'perturbing_action': 'I-rnai/knockdown'}", + "65, against {'perturbing_action': 'I-rnai/knockdown'}", + "66, the {'perturbing_action': 'I-rnai/knockdown'}", + "67, ectodomain {'perturbing_action': 'I-rnai/knockdown'}", + "68, of {'perturbing_action': 'I-rnai/knockdown'}", + "69, N-cadherin {'perturbing_action': 'I-rnai/knockdown'}", + "70, reduced {'effect': 'B-negative'}", + "71, proliferation, {'phenotype': 'B-proliferation'}", + "72, adhesion {'phenotype': 'B-adhesion'}", + "74, invasion {'phenotype': 'B-invasion'}", + "76, prostate {'context': 'B-transformed cells'}", + "77, cancer {'context': 'I-transformed cells'}", + "78, cells {'context': 'I-transformed cells'}", + "79, in {'context': 'B-in vitro'}", + "80, vitro. {'context': 'I-in vitro'}", + "81, In {'context': 'B-in vivo'}", + "82, vivo, {'context': 'I-in vivo'}", + "91, CRPC {'context': 'B-xenograft'}", + "92, xenografts, {'context': 'I-xenograft'}", + "93, blocked {'effect': 'B-negative'}", + "95, invasion {'phenotype': 'B-invasion'}", + "97, metastasis {'phenotype': 'B-metastasis'}", + "102, led {'effect': 'B-positive'}", + "103, to {'effect': 'I-positive'}", + "105, regression. {'phenotype': 'I-tumour regression'}", + "119, tumor {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "47, Ectopic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "48, expression ['l0', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "49, of ['l1', 'l27', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "50, N-cadherin ['l2', 'l28', 'l48', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "52, nonmetastatic, ['l3', 'l29', 'l49', 'l68', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "53, androgen-dependent ['l4', 'l30', 'l50', 'l69', 'l86', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "54, prostate ['l5', 'l31', 'l51', 'l70', 'l87', 'l102', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "55, cancer ['l6', 'l32', 'l52', 'l71', 'l88', 'l103', 'l117', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "56, models ['l7', 'l33', 'l53', 'l72', 'l89', 'l104', 'l118', 'l130', 'l141', 'l142', 'l143', 'l144', 'l145']", + "57, caused ['l8', 'l34', 'l54', 'l73', 'l90', 'l105', 'l119', 'l131', 'l141', 'l146', 'l147', 'l148']", + "60, invasion ['l9', 'l35', 'l55', 'l74', 'l91', 'l106', 'l120', 'l132', 'l142', 'l146', 'l149']", + "62, metastasis. ['l10', 'l36', 'l56', 'l75', 'l92', 'l107', 'l121', 'l133', 'l143', 'l147', 'l149', 'l150', 'l151']", + "63, Monoclonal ['l11', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "64, antibodies ['l12', 'l152', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "65, against ['l13', 'l153', 'l174', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215']", + "66, the ['l14', 'l154', 'l175', 'l195', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234']", + "67, ectodomain ['l15', 'l155', 'l176', 'l196', 'l216', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253']", + "68, of ['l16', 'l37', 'l57', 'l156', 'l177', 'l197', 'l217', 'l235', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270']", + "69, N-cadherin ['l17', 'l38', 'l58', 'l76', 'l157', 'l178', 'l198', 'l218', 'l236', 'l254', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286']", + "70, reduced ['l18', 'l39', 'l59', 'l77', 'l93', 'l108', 'l122', 'l134', 'l158', 'l179', 'l199', 'l219', 'l237', 'l255', 'l271', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294']", + "71, proliferation, ['l19', 'l40', 'l60', 'l78', 'l94', 'l109', 'l123', 'l135', 'l159', 'l180', 'l200', 'l220', 'l238', 'l256', 'l272', 'l287', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301']", + "72, adhesion ['l20', 'l41', 'l61', 'l79', 'l95', 'l110', 'l124', 'l136', 'l160', 'l181', 'l201', 'l221', 'l239', 'l257', 'l273', 'l288', 'l295', 'l302', 'l303', 'l304', 'l305', 'l306', 'l307']", + "74, invasion ['l21', 'l42', 'l62', 'l80', 'l96', 'l111', 'l125', 'l137', 'l161', 'l182', 'l202', 'l222', 'l240', 'l258', 'l274', 'l289', 'l296', 'l302', 'l308', 'l309', 'l310', 'l311']", + "76, prostate ['l22', 'l43', 'l63', 'l81', 'l97', 'l112', 'l126', 'l138', 'l162', 'l183', 'l203', 'l223', 'l241', 'l259', 'l275', 'l290', 'l297', 'l303', 'l308', 'l312', 'l313', 'l314', 'l315']", + "77, cancer ['l23', 'l44', 'l64', 'l82', 'l98', 'l113', 'l127', 'l139', 'l144', 'l150', 'l163', 'l184', 'l204', 'l224', 'l242', 'l260', 'l276', 'l291', 'l298', 'l304', 'l309', 'l312', 'l316', 'l317', 'l318']", + "78, cells ['l24', 'l45', 'l65', 'l83', 'l99', 'l114', 'l128', 'l140', 'l145', 'l148', 'l151', 'l164', 'l185', 'l205', 'l225', 'l243', 'l261', 'l277', 'l292', 'l299', 'l305', 'l310', 'l313', 'l316']", + "79, in ['l25', 'l46', 'l66', 'l84', 'l100', 'l115', 'l165', 'l186', 'l206', 'l226', 'l244', 'l262', 'l278', 'l293', 'l300', 'l306', 'l314', 'l317', 'l319']", + "80, vitro. ['l26', 'l47', 'l67', 'l85', 'l101', 'l116', 'l129', 'l166', 'l187', 'l207', 'l227', 'l245', 'l263', 'l279', 'l294', 'l301', 'l307', 'l311', 'l315', 'l318', 'l319']", + "81, In ['l167', 'l188', 'l208', 'l228', 'l246', 'l264', 'l280', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327']", + "82, vivo, ['l168', 'l189', 'l209', 'l229', 'l247', 'l265', 'l281', 'l320', 'l328', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334']", + "91, CRPC ['l169', 'l190', 'l210', 'l230', 'l248', 'l266', 'l282', 'l321', 'l328', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340', 'l341']", + "92, xenografts, ['l170', 'l191', 'l211', 'l231', 'l249', 'l267', 'l283', 'l322', 'l329', 'l335', 'l342', 'l343', 'l344', 'l345', 'l346']", + "93, blocked ['l171', 'l192', 'l212', 'l232', 'l250', 'l268', 'l284', 'l323', 'l330', 'l336', 'l342', 'l347', 'l348', 'l349', 'l350']", + "95, invasion ['l172', 'l193', 'l213', 'l233', 'l251', 'l269', 'l285', 'l324', 'l331', 'l337', 'l343', 'l347', 'l351', 'l352', 'l353']", + "97, metastasis ['l173', 'l194', 'l214', 'l234', 'l252', 'l270', 'l286', 'l325', 'l332', 'l338', 'l344', 'l348', 'l351', 'l354', 'l355', 'l356']", + "102, led ['l215', 'l253', 'l326', 'l333', 'l339', 'l345', 'l349', 'l352', 'l354', 'l357', 'l358']", + "103, to ['l327', 'l334', 'l340', 'l346', 'l350', 'l353', 'l355', 'l357', 'l359']", + "105, regression. ['l341', 'l356', 'l358', 'l359']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "N-cadherin" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "nonmetastatic,", + "androgen-dependent", + "prostate", + "cancer", + "models" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "N-cadherin" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "N-cadherin" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "N-cadherin" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "N-cadherin" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "N-cadherin" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "N-cadherin" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "N-cadherin" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "N-cadherin" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "nonmetastatic,", + "androgen-dependent", + "prostate", + "cancer", + "models" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "nonmetastatic,", + "androgen-dependent", + "prostate", + "cancer", + "models" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "nonmetastatic,", + "androgen-dependent", + "prostate", + "cancer", + "models" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "nonmetastatic,", + "androgen-dependent", + "prostate", + "cancer" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "nonmetastatic,", + "androgen-dependent", + "prostate", + "cancer" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "nonmetastatic,", + "androgen-dependent", + "prostate", + "cancer" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused", + "led", + "to" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused", + "led", + "to" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis.", + "metastasis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Monoclonal", + "antibodies", + "against", + "the", + "ectodomain", + "of", + "N-cadherin" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced", + "blocked" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Monoclonal", + "antibodies", + "against", + "the", + "ectodomain", + "of", + "N-cadherin" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Monoclonal", + "antibodies", + "against", + "the", + "ectodomain", + "of", + "N-cadherin" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Monoclonal", + "antibodies", + "against", + "the", + "ectodomain", + "of", + "N-cadherin" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Monoclonal", + "antibodies", + "against", + "the", + "ectodomain", + "of", + "N-cadherin" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Monoclonal", + "antibodies", + "against", + "the", + "ectodomain", + "of", + "N-cadherin" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Monoclonal", + "antibodies", + "against", + "the", + "ectodomain", + "of", + "N-cadherin" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Monoclonal", + "antibodies", + "against", + "the", + "ectodomain", + "of", + "N-cadherin" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "CRPC", + "xenografts," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Monoclonal", + "antibodies", + "against", + "the", + "ectodomain", + "of", + "N-cadherin" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "against", + "ectodomain" + ] + }, + "effect": { + "val": "positive", + "words": [ + "led" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced", + "blocked" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cells" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cells" + ] + } + }, + { + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cells" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "vitro." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "CRPC", + "xenografts," + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "CRPC", + "xenografts," + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "CRPC", + "xenografts," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "CRPC", + "xenografts," + ] + }, + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "CRPC" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression." + ] + } + } + ] + }, + { + "PMID": "21052077", + "TEXT": "Biomarkers may be of great value in Alzheimer's disease drug development to select the most optimal drug candidates for large and expensive phase 3 clinical trials. Biomarkers will also be important to provide evidence that a drug affects the underlying pathophysiology of the disease, which, together with a beneficial effect on the clinical course, will be essential for labeling the drug as having a disease-modifying effect.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21052061", + "TEXT": "Portuguese businessman António Champalimaud surprised his family when his will, opened after his 2004 death, revealed that he was bequeathing €500 million ($690 million), about a quarter of his estate, to establish a foundation for applied biomedical research. He also surprised law professor and one-time Portuguese Health Minister Leonor Beleza, whom he named to lead the foundation. Beleza, who met Champalimaud just once, agreed in principle to run his proposed foundation during a phone call in 2000 but did not hear any further until his death. She has now returned from a global tour of medical research institutions and foundations lasting over a year to determine how best to spend Champalimaud's millions.On 5 October, the Champalimaud Foundation opened its seaside Center for the Unknown in Lisbon, Portugal. The center will host about 600 researchers and physicians and 300 patients when it reaches full staffing levels. Lucas Laursen recently called Beleza to ask how she laid the groundwork and what lies ahead.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21037587", + "TEXT": "Allergic asthma is a T helper type 2 (T(H)2)-dominated disease of the lung. In people with asthma, a fraction of CD4(+) T cells express the CX3CL1 receptor, CX3CR1, and CX3CL1 expression is increased in airway smooth muscle, lung endothelium and epithelium upon allergen challenge. Here we found that untreated CX3CR1-deficient mice or wild-type (WT) mice treated with CX3CR1-blocking reagents show reduced lung disease upon allergen sensitization and challenge. Transfer of WT CD4(+) T cells into CX3CR1-deficient mice restored the cardinal features of asthma, and CX3CR1-blocking reagents prevented airway inflammation in CX3CR1-deficient recipients injected with WT T(H)2 cells. We found that CX3CR1 signaling promoted T(H)2 survival in the inflamed lungs, and injection of B cell leukemia/lymphoma-2 protein (BCl-2)-transduced CX3CR1-deficient T(H)2 cells into CX3CR1-deficient mice restored asthma. CX3CR1-induced survival was also observed for T(H)1 cells upon airway inflammation but not under homeostatic conditions or upon peripheral inflammation. Therefore, CX3CR1 and CX3CL1 may represent attractive therapeutic targets in asthma.", + "TAG_DATA": [ + "49, CX3CR1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "50, mice {'context': 'B-organism'}", + "54, mice {'context': 'B-organism'}", + "61, lung {'context': 'B-tissue/organ'}", + "71, CD4(+) {'context': 'B-cells'}", + "72, T {'context': 'I-cells'}", + "73, cells {'context': 'I-cells'}", + "75, CX3CR1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "76, mice {'context': 'B-organism'}", + "90, CX3CR1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "91, recipients {'context': 'B-organism'}", + "95, T(H)2 {'context': 'B-cells'}", + "96, cells. {'context': 'I-cells'}", + "103, T(H)2 {'context': 'B-cells'}", + "108, lungs, {'context': 'B-tissue/organ'}", + "115, protein {'perturbing_action': 'I-gene gain-of-function'}", + "116, (BCl-2)-transduced {'perturbing_action': 'I-gene gain-of-function'}", + "117, CX3CR1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "118, T(H)2 {'context': 'B-cells'}", + "119, cells {'context': 'I-cells'}", + "121, CX3CR1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "122, mice {'context': 'B-organism'}", + "131, T(H)1 {'context': 'B-cells'}", + "132, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "49, CX3CR1-deficient ['l0', 'l1']", + "50, mice ['l0', 'l2']", + "54, mice ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "61, lung ['l1', 'l2', 'l3']", + "71, CD4(+) ['l4', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "72, T ['l5', 'l9', 'l15', 'l16', 'l17', 'l18']", + "73, cells ['l6', 'l10', 'l15', 'l19', 'l20']", + "75, CX3CR1-deficient ['l7', 'l11', 'l16', 'l19', 'l21', 'l22']", + "76, mice ['l8', 'l12', 'l17', 'l20', 'l21']", + "90, CX3CR1-deficient ['l23', 'l24', 'l25', 'l26', 'l27']", + "91, recipients ['l23', 'l28', 'l29', 'l30', 'l31']", + "95, T(H)2 ['l24', 'l28', 'l32', 'l33', 'l34']", + "96, cells. ['l13', 'l18', 'l22', 'l25', 'l29', 'l32', 'l35', 'l36']", + "103, T(H)2 ['l26', 'l30', 'l33', 'l35', 'l37']", + "108, lungs, ['l14', 'l27', 'l31', 'l34', 'l36', 'l37']", + "112, B ['l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "113, cell ['l38', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "114, leukemia/lymphoma-2 ['l39', 'l49', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "115, protein ['l40', 'l50', 'l59', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "116, (BCl-2)-transduced ['l41', 'l51', 'l60', 'l68', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "117, CX3CR1-deficient ['l42', 'l52', 'l61', 'l69', 'l76', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "118, T(H)2 ['l43', 'l53', 'l62', 'l70', 'l77', 'l83', 'l89', 'l90', 'l91', 'l92', 'l93']", + "119, cells ['l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l89', 'l94', 'l95', 'l96']", + "121, CX3CR1-deficient ['l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l94', 'l97', 'l98', 'l99']", + "122, mice ['l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l97']", + "131, T(H)1 ['l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l98', 'l100']", + "132, cells ['l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l96', 'l99', 'l100']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CX3CR1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "recipients" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CX3CR1-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung", + "lungs," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cells", + "cells.", + "T(H)2", + "T(H)1" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CX3CR1-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "protein", + "(BCl-2)-transduced" + ] + }, + "context": { + "val": "cells", + "words": [ + "T(H)2", + "cells", + "T(H)1" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "protein", + "(BCl-2)-transduced" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "20948535", + "TEXT": "Immune cells and glia interact with neurons to alter pain sensitivity and to mediate the transition from acute to chronic pain. In response to injury, resident immune cells are activated and blood-borne immune cells are recruited to the site of injury. Immune cells not only contribute to immune protection but also initiate the sensitization of peripheral nociceptors. Through the synthesis and release of inflammatory mediators and interactions with neurotransmitters and their receptors, the immune cells, glia and neurons form an integrated network that coordinates immune responses and modulates the excitability of pain pathways. The immune system also reduces sensitization by producing immune-derived analgesic and anti-inflammatory or proresolution agents. A greater understanding of the role of the immune system in pain processing and modulation reveals potential targets for analgesic drug development and new therapeutic opportunities for managing chronic pain.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20948533", + "TEXT": "The perception of pain is subject to powerful influences. Understanding how these are mediated at a neuroanatomical and neurobiological level provides us with valuable information that has a direct impact on our ability to harness positive and minimize negative effects therapeutically, as well as optimize clinical trial designs when developing new analgesics. This is particularly relevant for placebo and nocebo effects. New research findings have directly contributed to an increased understanding of how placebo and nocebo effects are produced and what biological and psychological factors influence variances in the magnitude of the effect. The findings have relevance for chronic pain states and other disorders, where abnormal functioning of crucial brain regions might affect analgesic outcome even in the normal therapeutic setting.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20890291", + "TEXT": "CD8(+) T cells in chronic viral infections such as HIV develop functional defects including loss of interleukin-2 (IL-2) secretion and decreased proliferative potential that are collectively termed 'exhaustion'. Exhausted T cells express increased amounts of multiple inhibitory receptors, such as programmed death-1 (PD-1), that contribute to impaired virus-specific T cell function. Although reversing PD-1 inhibition is therefore an attractive therapeutic strategy, the cellular mechanisms by which PD-1 ligation results in T cell inhibition are not fully understood. PD-1 is thought to limit T cell activation by attenuating T cell receptor (TCR) signaling. It is not known whether PD-1 also acts by upregulating genes in exhausted T cells that impair their function. Here we analyzed gene expression profiles from HIV-specific CD8(+) T cells in individuals with HIV and show that PD-1 coordinately upregulates a program of genes in exhausted CD8(+) T cells from humans and mice. This program includes upregulation of basic leucine transcription factor, ATF-like (BATF), a transcription factor in the AP-1 family. Enforced expression of BATF was sufficient to impair T cell proliferation and cytokine secretion, whereas BATF knockdown reduced PD-1 inhibition. Silencing BATF in T cells from individuals with chronic viremia rescued HIV-specific T cell function. Thus, inhibitory receptors can cause T cell exhaustion by upregulating genes--such as BATF--that inhibit T cell function. Such genes may provide new therapeutic opportunities to improve T cell immunity to HIV.", + "TAG_DATA": [ + "163, Enforced {'perturbing_action': 'B-gene gain-of-function'}", + "164, expression {'perturbing_action': 'I-gene gain-of-function'}", + "165, of {'perturbing_action': 'I-gene gain-of-function'}", + "166, BATF {'perturbing_action': 'I-gene gain-of-function'}", + "170, impair {'effect': 'B-negative'}", + "171, T {'context': 'B-cells'}", + "172, cell {'context': 'B-cells'}", + "173, proliferation {'phenotype': 'B-proliferation'}", + "178, BATF {'perturbing_action': 'B-rnai/knockdown'}", + "179, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "183, Silencing {'perturbing_action': 'B-rnai/knockdown'}", + "184, BATF {'perturbing_action': 'I-rnai/knockdown'}", + "186, T {'context': 'B-cells'}", + "187, cells {'context': 'I-cells'}", + "194, HIV-specific {'context': 'B-cells'}", + "195, T {'context': 'I-cells'}", + "196, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "163, Enforced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "164, expression ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "165, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "166, BATF ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27']", + "170, impair ['l3', 'l11', 'l18', 'l24', 'l28', 'l29', 'l30']", + "171, T ['l4', 'l12', 'l19', 'l25', 'l28', 'l31', 'l32']", + "172, cell ['l5', 'l13', 'l20', 'l26', 'l29', 'l31', 'l33']", + "173, proliferation ['l6', 'l14', 'l21', 'l27', 'l30', 'l32', 'l33']", + "178, BATF ['l7', 'l15', 'l22', 'l34']", + "179, knockdown ['l8', 'l16', 'l23', 'l34']", + "183, Silencing ['l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "184, BATF ['l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "186, T ['l36', 'l41', 'l46', 'l47', 'l48', 'l49']", + "187, cells ['l37', 'l42', 'l46', 'l50', 'l51', 'l52']", + "194, HIV-specific ['l38', 'l43', 'l47', 'l50', 'l53', 'l54']", + "195, T ['l39', 'l44', 'l48', 'l51', 'l53', 'l55']", + "196, cell ['l40', 'l45', 'l49', 'l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced", + "expression", + "of", + "BATF" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impair" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced", + "expression", + "of", + "BATF" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced", + "expression", + "of", + "BATF" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impair" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impair" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "BATF" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "HIV-specific", + "cell" + ] + } + } + ] + }, + { + "PMID": "20818376", + "TEXT": "We have identified a new role for the matrix enzyme lysyl oxidase-like-2 (LOXL2) in the creation and maintenance of the pathologic microenvironment of cancer and fibrotic disease. Our analysis of biopsies from human tumors and fibrotic lung and liver tissues revealed an increase in LOXL2 in disease-associated stroma and limited expression in healthy tissues. Targeting LOXL2 with an inhibitory monoclonal antibody (AB0023) was efficacious in both primary and metastatic xenograft models of cancer, as well as in liver and lung fibrosis models. Inhibition of LOXL2 resulted in a marked reduction in activated fibroblasts, desmoplasia and endothelial cells, decreased production of growth factors and cytokines and decreased transforming growth factor-beta (TGF-beta) pathway signaling. AB0023 outperformed the small-molecule lysyl oxidase inhibitor beta-aminoproprionitrile. The efficacy and safety of LOXL2-specific AB0023 represents a new therapeutic approach with broad applicability in oncologic and fibrotic diseases.", + "TAG_DATA": [ + "54, Targeting {'perturbing_action': 'B-other'}", + "55, LOXL2 {'perturbing_action': 'I-other'}", + "56, with {'perturbing_action': 'I-other'}", + "57, an {'perturbing_action': 'I-rnai/knockdown'}", + "58, inhibitory {'perturbing_action': 'I-pharmacological inhibition'}", + "59, monoclonal {'perturbing_action': 'I-rnai/knockdown'}", + "60, antibody {'perturbing_action': 'I-rnai/knockdown'}", + "61, (AB0023) {'perturbing_action': 'I-other'}", + "66, primary {'context': 'B-xenograft'}", + "67, and {'context': 'I-xenograft'}", + "68, metastatic {'context': 'I-xenograft'}", + "69, xenograft {'context': 'I-xenograft'}", + "70, models {'context': 'I-xenograft'}", + "71, of {'context': 'I-xenograft'}", + "72, cancer, {'context': 'I-xenograft'}", + "77, liver {'context': 'B-tissue/organ'}", + "78, and {'context': 'I-tissue/organ'}", + "79, lung {'context': 'I-tissue/organ'}", + "82, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "83, of {'perturbing_action': 'I-pharmacological inhibition'}", + "84, LOXL2 {'perturbing_action': 'I-pharmacological inhibition'}", + "91, activated {'context': 'B-cells'}", + "92, fibroblasts, {'context': 'B-cells'}", + "95, endothelial {'context': 'B-cells'}", + "96, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "54, Targeting ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "55, LOXL2 ['l0', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "56, with ['l1', 'l27', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "57, an ['l2', 'l28', 'l51', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "58, inhibitory ['l3', 'l29', 'l52', 'l75', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "59, monoclonal ['l4', 'l30', 'l53', 'l76', 'l99', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "60, antibody ['l5', 'l31', 'l54', 'l77', 'l100', 'l122', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163']", + "61, (AB0023) ['l6', 'l32', 'l55', 'l78', 'l101', 'l123', 'l144', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "66, primary ['l7', 'l33', 'l56', 'l79', 'l102', 'l124', 'l145', 'l164', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190']", + "67, and ['l8', 'l34', 'l57', 'l80', 'l103', 'l125', 'l146', 'l165', 'l183', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196']", + "68, metastatic ['l9', 'l35', 'l58', 'l81', 'l104', 'l126', 'l147', 'l166', 'l184', 'l191', 'l197', 'l198', 'l199', 'l200', 'l201']", + "69, xenograft ['l10', 'l36', 'l59', 'l82', 'l105', 'l127', 'l148', 'l167', 'l185', 'l192', 'l197', 'l202', 'l203', 'l204']", + "70, models ['l11', 'l37', 'l60', 'l83', 'l106', 'l128', 'l149', 'l168', 'l186', 'l193', 'l198', 'l202', 'l205', 'l206']", + "71, of ['l12', 'l38', 'l61', 'l84', 'l107', 'l129', 'l150', 'l169', 'l187', 'l194', 'l199', 'l203', 'l205', 'l207']", + "72, cancer, ['l13', 'l39', 'l62', 'l85', 'l108', 'l130', 'l151', 'l170', 'l188', 'l195', 'l200', 'l204', 'l206', 'l207']", + "77, liver ['l14', 'l40', 'l63', 'l86', 'l109', 'l131', 'l152', 'l171', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216']", + "78, and ['l15', 'l41', 'l64', 'l87', 'l110', 'l132', 'l153', 'l172', 'l208', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224']", + "79, lung ['l16', 'l42', 'l65', 'l88', 'l111', 'l133', 'l154', 'l173', 'l209', 'l217', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231']", + "80, fibrosis ['l17', 'l43', 'l66', 'l89', 'l112', 'l134', 'l155', 'l174', 'l210', 'l218', 'l225', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237']", + "81, models. ['l18', 'l44', 'l67', 'l90', 'l113', 'l135', 'l156', 'l175', 'l189', 'l211', 'l219', 'l226', 'l232', 'l238', 'l239', 'l240', 'l241', 'l242']", + "82, Inhibition ['l19', 'l91', 'l114', 'l136', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249']", + "83, of ['l20', 'l68', 'l92', 'l115', 'l137', 'l157', 'l176', 'l243', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255']", + "84, LOXL2 ['l21', 'l45', 'l69', 'l93', 'l116', 'l138', 'l158', 'l177', 'l244', 'l250', 'l256', 'l257', 'l258', 'l259', 'l260']", + "91, activated ['l22', 'l46', 'l70', 'l94', 'l117', 'l139', 'l159', 'l178', 'l212', 'l220', 'l227', 'l233', 'l238', 'l245', 'l251', 'l256', 'l261', 'l262', 'l263', 'l264']", + "92, fibroblasts, ['l23', 'l47', 'l71', 'l95', 'l118', 'l140', 'l160', 'l179', 'l213', 'l221', 'l228', 'l234', 'l239', 'l246', 'l252', 'l257', 'l261', 'l265', 'l266', 'l267']", + "93, desmoplasia ['l24', 'l48', 'l72', 'l96', 'l119', 'l141', 'l161', 'l180', 'l214', 'l222', 'l229', 'l235', 'l240', 'l247', 'l253', 'l258', 'l262', 'l265', 'l268', 'l269']", + "95, endothelial ['l25', 'l49', 'l73', 'l97', 'l120', 'l142', 'l162', 'l181', 'l215', 'l223', 'l230', 'l236', 'l241', 'l248', 'l254', 'l259', 'l263', 'l266', 'l268', 'l270']", + "96, cells, ['l26', 'l50', 'l74', 'l98', 'l121', 'l143', 'l163', 'l182', 'l190', 'l196', 'l201', 'l216', 'l224', 'l231', 'l237', 'l242', 'l249', 'l255', 'l260', 'l264', 'l267', 'l269', 'l270']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Targeting", + "LOXL2", + "with", + "(AB0023)" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "primary", + "and", + "metastatic", + "xenograft", + "models", + "of", + "cancer," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Targeting", + "LOXL2", + "with", + "(AB0023)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver", + "and", + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Targeting", + "LOXL2", + "with", + "(AB0023)" + ] + }, + "context": { + "val": "cells", + "words": [ + "activated", + "fibroblasts,", + "endothelial", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "an", + "monoclonal", + "antibody" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "primary", + "and", + "metastatic", + "xenograft", + "models", + "of", + "cancer," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "an", + "monoclonal", + "antibody" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver", + "and", + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "an", + "monoclonal", + "antibody" + ] + }, + "context": { + "val": "cells", + "words": [ + "activated", + "fibroblasts,", + "endothelial", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitory" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "primary", + "and", + "metastatic", + "xenograft", + "models", + "of", + "cancer," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitory" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver", + "and", + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitory", + "Inhibition", + "of", + "LOXL2" + ] + }, + "context": { + "val": "cells", + "words": [ + "activated", + "fibroblasts,", + "endothelial", + "cells," + ] + } + } + ] + }, + { + "PMID": "20729864", + "TEXT": "Leucine-rich repeat kinase-2 (LRRK2) mutations are a common cause of Parkinson's disease. Here we identify inhibitors of LRRK2 kinase that are protective in in vitro and in vivo models of LRRK2-induced neurodegeneration. These results establish that LRRK2-induced degeneration of neurons in vivo is kinase dependent and that LRRK2 kinase inhibition provides a potential new neuroprotective paradigm for the treatment of Parkinson's disease.", + "TAG_DATA": [ + "15, inhibitors {'perturbing_action': 'B-pharmacological inhibition'}", + "16, of {'perturbing_action': 'I-pharmacological inhibition'}", + "17, LRRK2 {'perturbing_action': 'I-pharmacological inhibition'}", + "18, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "23, in {'context': 'B-in vitro'}", + "24, vitro {'context': 'I-in vitro'}", + "26, in {'context': 'B-in vivo'}", + "27, vivo {'context': 'I-in vivo'}", + "39, neurons {'context': 'B-cells'}", + "40, in {'context': 'B-in vivo'}", + "41, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "15, inhibitors ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "16, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "17, LRRK2 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "18, kinase ['l2', 'l8', 'l13', 'l19', 'l20', 'l21', 'l22']", + "23, in ['l3', 'l9', 'l14', 'l19', 'l23']", + "24, vitro ['l4', 'l10', 'l15', 'l20', 'l23']", + "26, in ['l5', 'l11', 'l16', 'l21', 'l24']", + "27, vivo ['l6', 'l12', 'l17', 'l22', 'l24']", + "39, neurons ['l18', 'l25', 'l26']", + "40, in ['l25', 'l27']", + "41, vivo ['l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "LRRK2", + "kinase" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "LRRK2", + "kinase" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "LRRK2" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons" + ] + } + } + ] + }, + { + "PMID": "20693993", + "TEXT": "Because of tolerance mechanisms, it has been hard to identify the T cell receptors (TCRs) of high-avidity T cells against self (for example, tumor) antigens. TCRs that are specific for foreign human antigens from the nontolerant T cell repertoire can be identified in mice. Moreover, if mice are constructed to express the human TCR repertoire, they can be used to analyze the unskewed repertoire against human self antigens. Here we generated transgenic mice with the entire human TCRalphabeta gene loci (1.1 and 0.7 Mb), whose T cells express a diverse human TCR repertoire that compensates for mouse TCR deficiency. A human major histocompatibility class I transgene increases the generation of CD8+ T cells with human compared to mouse TCRs. Functional CD8+ T cells against several human tumor antigens were induced, and those against the Melan-A melanoma antigen used similar TCRs to those that have been detected in T cell clones from individuals with autoimmune vitiligo or melanoma. These mice will allow researchers to identify pathogenic and therapeutic human TCRs.", + "TAG_DATA": [ + "72, mice {'context': 'B-organism'}", + "85, T {'context': 'B-cells'}", + "86, cells {'context': 'B-cells'}", + "110, CD8+ {'context': 'B-cells'}", + "111, T {'context': 'I-cells'}", + "112, cells {'context': 'I-cells'}", + "120, CD8+ {'context': 'B-cells'}", + "121, T {'context': 'I-cells'}", + "122, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "72, mice ['l0', 'l1']", + "85, T ['l0', 'l2']", + "86, cells ['l1', 'l2']", + "110, CD8+ ['l3', 'l4']", + "111, T ['l3', 'l5']", + "112, cells ['l4', 'l5']", + "120, CD8+ ['l6', 'l7']", + "121, T ['l6', 'l8']", + "122, cells ['l7', 'l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20676107", + "TEXT": "Blood neutrophils provide the first line of defense against pathogens but have also been implicated in thrombotic processes. This dual function of neutrophils could reflect an evolutionarily conserved association between blood coagulation and antimicrobial defense, although the molecular determinants and in vivo significance of this association remain unclear. Here we show that major microbicidal effectors of neutrophils, the serine proteases neutrophil elastase and cathepsin G, together with externalized nucleosomes, promote coagulation and intravascular thrombus growth in vivo. The serine proteases and extracellular nucleosomes enhance tissue factor- and factor XII-dependent coagulation in a process involving local proteolysis of the coagulation suppressor tissue factor pathway inhibitor. During systemic infection, activation of coagulation fosters compartmentalization of bacteria in liver microvessels and reduces bacterial invasion into tissue. In the absence of a pathogen challenge, neutrophil-derived serine proteases and nucleosomes can contribute to large-vessel thrombosis, the main trigger of myocardial infarction and stroke. The ability of coagulation to suppress pathogen dissemination indicates that microvessel thrombosis represents a physiological tool of host defense.", + "TAG_DATA": [ + "75, in {'context': 'B-in vivo'}", + "76, vivo. {'context': 'I-in vivo'}", + "115, liver {'context': 'B-tissue/organ'}", + "116, microvessels {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "75, in ['l0']", + "76, vivo. ['l0']", + "115, liver ['l1']", + "116, microvessels ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20676106", + "TEXT": "Although it is well established that tumors initiate an angiogenic switch, the molecular basis of this process remains incompletely understood. Here we show that the miRNA miR-132 acts as an angiogenic switch by targeting p120RasGAP in the endothelium and thereby inducing neovascularization. We identified miR-132 as a highly upregulated miRNA in a human embryonic stem cell model of vasculogenesis and found that miR-132 was highly expressed in the endothelium of human tumors and hemangiomas but was undetectable in normal endothelium. Ectopic expression of miR-132 in endothelial cells in vitro increased their proliferation and tube-forming capacity, whereas intraocular injection of an antagomir targeting miR-132, anti-miR-132, reduced postnatal retinal vascular development in mice. Among the top-ranking predicted targets of miR-132 was p120RasGAP, which we found to be expressed in normal but not tumor endothelium. Endothelial expression of miR-132 suppressed p120RasGAP expression and increased Ras activity, whereas a miRNA-resistant version of p120RasGAP reversed the vascular response induced by miR-132. Notably, administration of anti-miR-132 inhibited angiogenesis in wild-type mice but not in mice with an inducible deletion of Rasa1 (encoding p120RasGAP). Finally, vessel-targeted nanoparticle delivery of anti-miR-132 restored p120RasGAP expression in the tumor endothelium, suppressed angiogenesis and decreased tumor burden in an orthotopic xenograft mouse model of human breast carcinoma. We conclude that miR-132 acts as an angiogenic switch by suppressing endothelial p120RasGAP expression, leading to Ras activation and the induction of neovascularization, whereas the application of anti-miR-132 inhibits neovascularization by maintaining vessels in the resting state.", + "TAG_DATA": [ + "80, Ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "81, expression {'perturbing_action': 'I-gene gain-of-function'}", + "82, of {'perturbing_action': 'I-gene gain-of-function'}", + "83, miR-132 {'perturbing_action': 'I-gene gain-of-function'}", + "85, endothelial {'context': 'B-cells'}", + "86, cells {'context': 'I-cells'}", + "87, in {'context': 'B-in vitro'}", + "88, vitro {'context': 'I-in vitro'}", + "89, increased {'effect': 'B-positive'}", + "91, proliferation {'phenotype': 'B-proliferation'}", + "93, tube-forming {'phenotype': 'B-colony formation'}", + "94, capacity, {'phenotype': 'I-colony formation'}", + "100, antagomir {'perturbing_action': 'B-rnai/knockdown'}", + "101, targeting {'perturbing_action': 'I-rnai/knockdown'}", + "102, miR-132, {'perturbing_action': 'I-rnai/knockdown'}", + "103, anti-miR-132, {'perturbing_action': 'I-rnai/knockdown'}", + "110, mice. {'context': 'B-organism'}", + "132, Endothelial {'perturbing_action': 'B-gene gain-of-function'}", + "133, expression {'perturbing_action': 'I-gene gain-of-function'}", + "134, of {'perturbing_action': 'I-gene gain-of-function'}", + "135, miR-132 {'perturbing_action': 'I-gene gain-of-function'}", + "164, mice {'context': 'B-organism'}", + "168, mice {'context': 'B-organism'}", + "171, inducible {'perturbing_action': 'B-gene loss-of-function'}", + "172, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "173, of {'perturbing_action': 'I-gene loss-of-function'}", + "174, Rasa1 {'perturbing_action': 'I-gene loss-of-function'}", + "175, (encoding {'perturbing_action': 'I-gene loss-of-function'}", + "176, p120RasGAP). {'perturbing_action': 'I-gene loss-of-function'}", + "188, tumor {'context': 'B-tissue/organ'}", + "189, endothelium, {'context': 'I-tissue/organ'}", + "193, decreased {'effect': 'B-negative'}", + "194, tumor {'phenotype': 'B-tumourigenesis'}", + "195, burden {'phenotype': 'I-tumourigenesis'}", + "198, orthotopic {'context': 'B-xenograft'}", + "199, xenograft {'context': 'I-xenograft'}", + "200, mouse {'context': 'I-xenograft'}", + "201, model {'context': 'I-xenograft'}", + "202, of {'context': 'I-xenograft'}", + "203, human {'context': 'I-xenograft'}", + "204, breast {'context': 'I-xenograft'}", + "205, carcinoma. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "80, Ectopic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "81, expression ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "82, of ['l1', 'l14', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "83, miR-132 ['l2', 'l15', 'l24', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "85, endothelial ['l3', 'l16', 'l25', 'l33', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "86, cells ['l4', 'l17', 'l26', 'l34', 'l41', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "87, in ['l5', 'l18', 'l27', 'l35', 'l42', 'l48', 'l54', 'l55', 'l56', 'l57', 'l58']", + "88, vitro ['l6', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l59', 'l60', 'l61', 'l62']", + "89, increased ['l7', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l63', 'l64', 'l65']", + "91, proliferation ['l8', 'l21', 'l30', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l66', 'l67']", + "93, tube-forming ['l9', 'l22', 'l31', 'l39', 'l46', 'l52', 'l57', 'l61', 'l64', 'l66', 'l68']", + "94, capacity, ['l10', 'l23', 'l32', 'l40', 'l47', 'l53', 'l58', 'l62', 'l65', 'l67', 'l68']", + "100, antagomir ['l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "101, targeting ['l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "102, miR-132, ['l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "103, anti-miR-132, ['l71', 'l78', 'l84', 'l90', 'l91', 'l92', 'l93', 'l94']", + "110, mice. ['l72', 'l79', 'l85', 'l90', 'l95', 'l96', 'l97', 'l98']", + "132, Endothelial ['l11', 'l73', 'l80', 'l86', 'l91', 'l95', 'l99', 'l100', 'l101']", + "133, expression ['l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l102', 'l103']", + "134, of ['l12', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l104']", + "135, miR-132 ['l13', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l104']", + "164, mice ['l105', 'l106', 'l107', 'l108', 'l109']", + "168, mice ['l105', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "171, inducible ['l110', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "172, deletion ['l111', 'l120', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "173, of ['l106', 'l112', 'l121', 'l138', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170']", + "174, Rasa1 ['l107', 'l113', 'l122', 'l139', 'l155', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185']", + "175, (encoding ['l108', 'l114', 'l123', 'l140', 'l156', 'l171', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199']", + "176, p120RasGAP). ['l109', 'l115', 'l124', 'l141', 'l157', 'l172', 'l186', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212']", + "188, tumor ['l125', 'l142', 'l158', 'l173', 'l187', 'l200', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224']", + "189, endothelium, ['l116', 'l126', 'l143', 'l159', 'l174', 'l188', 'l201', 'l213', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235']", + "193, decreased ['l117', 'l127', 'l144', 'l160', 'l175', 'l189', 'l202', 'l214', 'l225', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245']", + "194, tumor ['l118', 'l128', 'l145', 'l161', 'l176', 'l190', 'l203', 'l215', 'l226', 'l236', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254']", + "195, burden ['l119', 'l129', 'l146', 'l162', 'l177', 'l191', 'l204', 'l216', 'l227', 'l237', 'l246', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262']", + "198, orthotopic ['l130', 'l147', 'l163', 'l178', 'l192', 'l205', 'l217', 'l228', 'l238', 'l247', 'l255', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269']", + "199, xenograft ['l131', 'l148', 'l164', 'l179', 'l193', 'l206', 'l218', 'l229', 'l239', 'l248', 'l256', 'l263', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275']", + "200, mouse ['l132', 'l149', 'l165', 'l180', 'l194', 'l207', 'l219', 'l230', 'l240', 'l249', 'l257', 'l264', 'l270', 'l276', 'l277', 'l278', 'l279', 'l280']", + "201, model ['l133', 'l150', 'l166', 'l181', 'l195', 'l208', 'l220', 'l231', 'l241', 'l250', 'l258', 'l265', 'l271', 'l276', 'l281', 'l282', 'l283', 'l284']", + "202, of ['l134', 'l151', 'l167', 'l182', 'l196', 'l209', 'l221', 'l232', 'l242', 'l251', 'l259', 'l266', 'l272', 'l277', 'l281', 'l285', 'l286', 'l287']", + "203, human ['l135', 'l152', 'l168', 'l183', 'l197', 'l210', 'l222', 'l233', 'l243', 'l252', 'l260', 'l267', 'l273', 'l278', 'l282', 'l285', 'l288', 'l289']", + "204, breast ['l136', 'l153', 'l169', 'l184', 'l198', 'l211', 'l223', 'l234', 'l244', 'l253', 'l261', 'l268', 'l274', 'l279', 'l283', 'l286', 'l288', 'l290']", + "205, carcinoma. ['l137', 'l154', 'l170', 'l185', 'l199', 'l212', 'l224', 'l235', 'l245', 'l254', 'l262', 'l269', 'l275', 'l280', 'l284', 'l287', 'l289', 'l290']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "miR-132" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "miR-132" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "miR-132" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "miR-132" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "miR-132" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "tube-forming", + "capacity," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "tube-forming", + "capacity," + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "tube-forming", + "capacity," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "tube-forming", + "capacity," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antagomir", + "targeting", + "miR-132,", + "anti-miR-132," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Endothelial", + "expression", + "of", + "miR-132" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "Rasa1", + "(encoding", + "p120RasGAP).", + "inducible", + "deletion" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "burden" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inducible", + "deletion", + "of", + "Rasa1", + "(encoding", + "p120RasGAP)." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tumor", + "endothelium," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inducible", + "deletion", + "of", + "Rasa1", + "(encoding", + "p120RasGAP)." + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inducible", + "deletion", + "of", + "Rasa1", + "(encoding", + "p120RasGAP)." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "burden" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inducible", + "deletion", + "of", + "Rasa1", + "(encoding", + "p120RasGAP)." + ] + }, + "context": { + "val": "xenograft", + "words": [ + "orthotopic", + "xenograft", + "mouse", + "model", + "of", + "human", + "breast", + "carcinoma." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "tumor", + "endothelium," + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "tumor", + "endothelium," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "burden" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "burden" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "orthotopic", + "xenograft", + "mouse", + "model", + "of", + "human", + "breast", + "carcinoma." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "burden" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "orthotopic", + "xenograft", + "mouse", + "model", + "of", + "human", + "breast", + "carcinoma." + ] + } + } + ] + }, + { + "PMID": "20657580", + "TEXT": "Ethylmalonic encephalopathy is caused by mutations in ETHE1, a mitochondrial matrix sulfur dioxygenase, leading to failure to detoxify sulfide, a product of intestinal anaerobes and, in trace amounts, tissues. Metronidazole, a bactericide, or N-acetylcysteine, a precursor of sulfide-buffering glutathione, substantially prolonged the lifespan of Ethe1-deficient mice, with the combined treatment being additive. The same dual treatment caused marked clinical improvement in five affected children, with hardly any adverse or side effects.", + "TAG_DATA": [ + "44, Ethe1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "45, mice, {'context': 'B-organism'}", + "63, children, {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "44, Ethe1-deficient ['l0']", + "45, mice, ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ethe1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "20622859", + "TEXT": "Dendritic cells (DCs), a type of professional antigen-presenting cells, are responsible for initiation and maintenance of immune responses. Here we report that a substantial proportion of DCs in tumor-bearing mice and people with cancer have high amounts of triglycerides as compared with DCs from tumor-free mice and healthy individuals. In our studies, lipid accumulation in DCs was caused by increased uptake of extracellular lipids due to upregulation of scavenger receptor A. DCs with high lipid content were not able to effectively stimulate allogeneic T cells or present tumor-associated antigens. DCs with high and normal lipid levels did not differ in expression of major histocompatibility complex and co-stimulatory molecules. However, lipid-laden DCs had a reduced capacity to process antigens. Pharmacological normalization of lipid abundance in DCs with an inhibitor of acetyl-CoA carboxylase restored the functional activity of DCs and substantially enhanced the effects of cancer vaccines. These findings suggest that immune responses in cancer can be improved by manipulating the lipid levels in DCs.", + "TAG_DATA": [ + "71, DCs {'context': 'B-cells'}", + "82, allogeneic {'context': 'B-cells'}", + "83, T {'context': 'I-cells'}", + "84, cells {'context': 'I-cells'}", + "89, DCs {'context': 'B-cells'}", + "110, DCs {'context': 'B-cells'}", + "124, DCs {'context': 'B-cells'}", + "136, DCs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "71, DCs ['l0', 'l1', 'l2']", + "82, allogeneic ['l0', 'l3', 'l4']", + "83, T ['l1', 'l3', 'l5']", + "84, cells ['l2', 'l4', 'l5']", + "89, DCs ['l6']", + "110, DCs ['l6']", + "124, DCs ['l7']", + "136, DCs ['l7']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20613727", + "TEXT": "A more transparent drug approval process has the potential to reduce cost and duplicated effort, as well as ultimately improve access to effective treatments for patients.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20581836", + "TEXT": "Sarcomas are heterogeneous and aggressive mesenchymal tumors. Histological grading has so far been the best predictor for metastasis-free survival, but it has several limitations, such as moderate reproducibility and poor prognostic value for some histological types. To improve patient grading, we performed genomic and expression profiling in a training set of 183 sarcomas and established a prognostic gene expression signature, complexity index in sarcomas (CINSARC), composed of 67 genes related to mitosis and chromosome management. In a multivariate analysis, CINSARC predicts metastasis outcome in the training set and in an independent 127 sarcomas validation set. It is superior to the Fédération Francaise des Centres de Lutte Contre le Cancer grading system in determining metastatic outcome for sarcoma patients. Furthermore, it also predicts outcome for gastrointestinal stromal tumors (GISTs), breast carcinomas and lymphomas. Application of the signature will permit more selective use of adjuvant therapies for people with sarcomas, leading to decreased iatrogenic morbidity and improved outcomes for such individuals.", + "TAG_DATA": [ + "80, predicts {'effect': 'B-regulates'}", + "81, metastasis {'phenotype': 'B-metastasis'}", + "82, outcome {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "80, predicts ['l0', 'l1']", + "81, metastasis ['l0', 'l2']", + "82, outcome ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "regulates", + "words": [ + "predicts" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "outcome" + ] + } + } + ] + }, + { + "PMID": "20526316", + "TEXT": "There is no cure for osteoarthritis—the most common disease of the joints. By piecing together the molecular events that drive the progression of this debilitating disease, recent studies published in Nature Medicine put hypoxia-inducible factor-2α (HIF-2α) in the driver's seat, opening up new avenues for early detection and treatment (pages 678–686 and 687–693).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20512126", + "TEXT": "Muscle paralysis after spinal cord injury is partly caused by a loss of brainstem-derived serotonin (5-HT), which normally maintains motoneuron excitability by regulating crucial persistent calcium currents. Here we examine how over time motoneurons compensate for lost 5-HT to regain excitability. We find that, months after a spinal transection in rats, changes in post-transcriptional editing of 5-HT2C receptor mRNA lead to increased expression of 5-HT2C receptor isoforms that are spontaneously active (constitutively active) without 5-HT. Such constitutive receptor activity restores large persistent calcium currents in motoneurons in the absence of 5-HT. We show that this helps motoneurons recover their ability to produce sustained muscle contractions and ultimately enables recovery of motor functions such as locomotion. However, without regulation from the brain, these sustained contractions can also cause debilitating muscle spasms. Accordingly, blocking constitutively active 5-HT2C receptors with SB206553 or cyproheptadine, in both rats and humans, largely eliminates these calcium currents and muscle spasms, providing a new rationale for antispastic drug therapy.", + "TAG_DATA": [ + "48, transection {'perturbing_action': 'I-gene loss-of-function'}", + "50, rats, {'context': 'B-organism'}", + "85, motoneurons {'context': 'B-cells'}", + "96, motoneurons {'context': 'B-cells'}", + "131, blocking {'perturbing_action': 'B-pharmacological inhibition'}", + "132, constitutively {'perturbing_action': 'I-gene gain-of-function'}", + "133, active {'perturbing_action': 'I-pharmacological augmentation'}", + "134, 5-HT2C {'perturbing_action': 'I-pharmacological augmentation'}", + "135, receptors {'perturbing_action': 'I-pharmacological augmentation'}", + "136, with {'perturbing_action': 'I-pharmacological inhibition'}", + "137, SB206553 {'perturbing_action': 'I-pharmacological inhibition'}", + "138, or {'perturbing_action': 'I-pharmacological inhibition'}", + "139, cyproheptadine, {'perturbing_action': 'I-pharmacological inhibition'}", + "142, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "48, transection ['l0', 'l1']", + "50, rats, ['l0']", + "85, motoneurons ['l1', 'l2']", + "96, motoneurons ['l2']", + "131, blocking ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "132, constitutively ['l3', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "133, active ['l4', 'l12', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "134, 5-HT2C ['l5', 'l13', 'l20', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "135, receptors ['l6', 'l14', 'l21', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "136, with ['l7', 'l15', 'l22', 'l28', 'l33', 'l38', 'l39', 'l40', 'l41']", + "137, SB206553 ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l42', 'l43', 'l44']", + "138, or ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l45', 'l46']", + "139, cyproheptadine, ['l10', 'l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l47']", + "142, rats ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "transection" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "transection" + ] + }, + "context": { + "val": "cells", + "words": [ + "motoneurons" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blocking", + "with", + "SB206553", + "or", + "cyproheptadine," + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutively" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "active", + "5-HT2C", + "receptors" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + } + ] + }, + { + "PMID": "20495570", + "TEXT": "Chondrocyte hypertrophy followed by cartilage matrix degradation and vascular invasion, characterized by expression of type X collagen (COL10A1), matrix metalloproteinase-13 (MMP-13) and vascular endothelial growth factor (VEGF), respectively, are central steps of endochondral ossification during normal skeletal growth and osteoarthritis development. A COL10A1 promoter assay identified hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by EPAS1) as the most potent transactivator of COL10A1. HIF-2alpha enhanced promoter activities of COL10A1, MMP13 and VEGFA through specific binding to the respective hypoxia-responsive elements. HIF-2alpha, independently of oxygen-dependent hydroxylation, was essential for endochondral ossification of cultured chondrocytes and embryonic skeletal growth in mice. HIF-2alpha expression was higher in osteoarthritic cartilages versus nondiseased cartilages of mice and humans. Epas1-heterozygous deficient mice showed resistance to osteoarthritis development, and a functional single nucleotide polymorphism (SNP) in the human EPAS1 gene was associated with knee osteoarthritis in a Japanese population. The EPAS1 promoter assay identified RELA, a nuclear factor-kappaB (NF-kappaB) family member, as a potent inducer of HIF-2alpha expression. Hence, HIF-2alpha is a central transactivator that targets several crucial genes for endochondral ossification and may represent a therapeutic target for osteoarthritis.", + "TAG_DATA": [ + "88, chondrocytes {'context': 'I-cells'}", + "109, Epas1-heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "110, deficient {'perturbing_action': 'I-gene loss-of-function'}", + "111, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "109, Epas1-heterozygous ['l0', 'l1']", + "110, deficient ['l0', 'l2']", + "111, mice ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Epas1-heterozygous", + "deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "20400962", + "TEXT": "The transfer of T cell receptor (TCR) genes can be used to induce immune reactivity toward defined antigens to which endogenous T cells are insufficiently reactive. This approach, which is called TCR gene therapy, is being developed to target tumors and pathogens, and its clinical testing has commenced in patients with cancer. In this study we show that lethal cytokine-driven autoimmune pathology can occur in mouse models of TCR gene therapy under conditions that closely mimic the clinical setting. We show that the pairing of introduced and endogenous TCR chains in TCR gene-modified T cells leads to the formation of self-reactive TCRs that are responsible for the observed autoimmunity. Furthermore, we demonstrate that adjustments in the design of gene therapy vectors and target T cell populations can be used to reduce the risk of TCR gene therapy-induced autoimmune pathology.", + "TAG_DATA": [ + "65, mouse {'context': 'B-organism'}", + "66, models {'context': 'I-organism'}", + "93, T {'context': 'B-cells'}", + "94, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "65, mouse ['l0', 'l1']", + "66, models ['l0', 'l2']", + "93, T ['l3']", + "94, cells ['l1', 'l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20400961", + "TEXT": "Autoimmune diseases are common and debilitating, but their severe manifestations could be reduced if biomarkers were available to allow individual tailoring of potentially toxic immunosuppressive therapy. Gene expression-based biomarkers facilitating such tailoring of chemotherapy in cancer, but not autoimmunity, have been identified and translated into clinical practice. We show that transcriptional profiling of purified CD8(+) T cells, which avoids the confounding influences of unseparated cells, identifies two distinct subject subgroups predicting long-term prognosis in two autoimmune diseases, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), a chronic, severe disease characterized by inflammation of medium-sized and small blood vessels, and systemic lupus erythematosus (SLE), characterized by autoantibodies, immune complex deposition and diverse clinical manifestations ranging from glomerulonephritis to neurological dysfunction. We show that the subset of genes defining the poor prognostic group is enriched for genes involved in the interleukin-7 receptor (IL-7R) pathway and T cell receptor (TCR) signaling and those expressed by memory T cells. Furthermore, the poor prognostic group is associated with an expanded CD8(+) T cell memory population. These subgroups, which are also found in the normal population and can be identified by measuring expression of only three genes, raise the prospect of individualized therapy and suggest new potential therapeutic targets in autoimmunity.", + "TAG_DATA": [ + "55, T {'context': 'I-cells'}", + "56, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "55, T ['l0']", + "56, cells, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20383155", + "TEXT": "Esophageal cancer is increasing in frequency in the United States faster than any other cancer. Barrett's esophagus, an otherwise benign complication of esophageal reflux, affects approximately three million Americans and precedes almost all cases of esophageal cancer. If detected as high-grade dysplasia (HGD), most esophageal cancers can be prevented. Standard-of-care screening for dysplasia uses visual endoscopy and a prescribed pattern of biopsy. This procedure, in which a tiny fraction of the affected tissue is selected for pathological examination, has a low probability of detection because dysplasia is highly focal and visually indistinguishable. We developed a system called endoscopic polarized scanning spectroscopy (EPSS), which performs rapid optical scanning and multispectral imaging of the entire esophageal surface and provides diagnoses in near real time. By detecting and mapping suspicious sites, guided biopsy of invisible, precancerous dysplasia becomes practicable. Here we report the development of EPSS and its application in several clinical cases, one of which merits special consideration.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20376035", + "TEXT": "Counterfeiting medicine has become such a sophisticated crime that it has attracted the attention of the world's largest police organization, Interpol. In November, these top cops wrapped up an operation in South East Asia, in which they helped seize around 20 million counterfeit drugs and arrested more than 30 people. To further stem the tide of phoney, dangerous, unregistered and illegal medical products, Interpol has placed French police officer Aline Plançon at the helm of its dedicated Medical Products Counterfeiting and Pharmaceutical Crime (MPCPC) unit, which was created in January. Working closely with the World Health Organization's (WHO's) International Medical Products Anti-Counterfeiting Taskforce (IMPACT)-a four-year-old inter-agency partnership developing global, collaborative anticounterfeiting solutions-Plançon is tasked with supporting and coordinating enforcement activities around the world. Asher Mullard spoke with Plançon about her role in combating a deadly international scourge.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20348925", + "TEXT": "Interferon-beta (IFN-beta) is the major treatment for multiple sclerosis. However, this treatment is not always effective. Here we have found congruence in outcome between responses to IFN-beta in experimental autoimmune encephalomyelitis (EAE) and relapsing-remitting multiple sclerosis (RRMS). IFN-beta was effective in reducing EAE symptoms induced by T helper type 1 (T(H)1) cells but exacerbated disease induced by T(H)17 cells. Effective treatment in T(H)1-induced EAE correlated with increased interleukin-10 (IL-10) production by splenocytes. In T(H)17-induced disease, the amount of IL-10 was unaltered by treatment, although, unexpectedly, IFN-beta treatment still reduced IL-17 production without benefit. Both inhibition of IL-17 and induction of IL-10 depended on IFN-gamma. In the absence of IFN-gamma signaling, IFN-beta therapy was ineffective in EAE. In RRMS patients, IFN-beta nonresponders had higher IL-17F concentrations in serum compared to responders. Nonresponders had worse disease with more steroid usage and more relapses than did responders. Hence, IFN-beta is proinflammatory in T(H)17-induced EAE. Moreover, a high IL-17F concentration in the serum of people with RRMS is associated with nonresponsiveness to therapy with IFN-beta.", + "TAG_DATA": [ + "46, T {'context': 'B-cells'}", + "47, helper {'context': 'I-cells'}", + "48, type {'context': 'I-cells'}", + "49, 1 {'context': 'I-cells'}", + "50, (T(H)1) {'context': 'I-cells'}", + "51, cells {'context': 'I-cells'}", + "57, T(H)17 {'context': 'B-cells'}", + "58, cells. {'context': 'I-cells'}", + "71, splenocytes. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "46, T ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "47, helper ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "48, type ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "49, 1 ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "50, (T(H)1) ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "51, cells ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31']", + "57, T(H)17 ['l5', 'l12', 'l18', 'l23', 'l27', 'l32', 'l33']", + "58, cells. ['l6', 'l13', 'l19', 'l24', 'l28', 'l30', 'l32', 'l34']", + "71, splenocytes. ['l7', 'l14', 'l20', 'l25', 'l29', 'l31', 'l33', 'l34']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20348924", + "TEXT": "Hypothalamic neuron circuits regulating energy balance are highly plastic and develop in response to nutrient and hormonal cues. To identify processes that might be susceptible to gestational influences in mice, we characterized the ontogeny of proopiomelanocortin (POMC) and neuropeptide Y (NPY) cell populations, which exert opposing influences on food intake and body weight. These analyses revealed that Pomc is broadly expressed in immature hypothalamic neurons and that half of embryonic Pomc-expressing precursors subsequently adopt a non-POMC fate in adult mice. Moreover, nearly one quarter of the mature NPY+ cell population shares a common progenitor with POMC+ cells.", + "TAG_DATA": [ + "78, adult {'context': 'B-organism'}", + "79, mice. {'context': 'I-organism'}", + "87, NPY+ {'context': 'I-cells'}", + "88, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "78, adult ['l0']", + "79, mice. ['l0']", + "87, NPY+ ['l1']", + "88, cell ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20228817", + "TEXT": "Highly active antiretroviral therapy (HAART) results in potent and durable suppression of HIV-1 viremia. However, HIV-1 replication resumes if therapy is interrupted. Although it is generally believed that active replication has been halted in individuals on HAART, immune activation and inflammation continue at abnormal levels, suggesting continued, low-level viral replication. To assess whether active replication might be driving immune activation in HAART, we examined the impact of treatment intensification with the integrase inhibitor raltegravir on viral complementary DNA and immune activation parameters. In the presence of raltegravir, linear HIV-1 cDNA is prevented from integrating into chromatin and is subsequently converted to episomal cDNAs. Raltegravir intensification of a three-drug suppressive HAART regimen resulted in a specific and transient increase in episomal DNAs in a large percentage of HAART-suppressed subjects. Furthermore, in subjects with these episomal DNAs, immune activation was higher at baseline and was subsequently normalized after raltegravir intensification. These results suggest that, despite suppressive HAART, active replication persists in some infected individuals and drives immune activation. The ability of raltegravir intensification to perturb the reservoir that supports active replication has implications for therapeutic strategies aimed at achieving viral eradication.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20208541", + "TEXT": "HIV causes a chronic infection characterized by depletion of CD4(+) T lymphocytes and the development of opportunistic infections. Despite drugs that inhibit viral spread, HIV infection has been difficult to cure because of uncharacterized reservoirs of infected cells that are resistant to highly active antiretroviral therapy (HAART) and the immune response. Here we used CD34(+) cells from infected people as well as in vitro studies of wild-type HIV to show infection and killing of CD34(+) multipotent hematopoietic progenitor cells (HPCs). In some HPCs, we detected latent infection that stably persisted in cell culture until viral gene expression was activated by differentiation factors. A unique reporter HIV that directly detects latently infected cells in vitro confirmed the presence of distinct populations of active and latently infected HPCs. These findings have major implications for understanding HIV bone marrow pathology and the mechanisms by which HIV causes persistent infection.", + "TAG_DATA": [ + "54, CD34(+) {'context': 'B-cells'}", + "55, cells {'context': 'I-cells'}", + "62, in {'context': 'B-in vitro'}", + "63, vitro {'context': 'I-in vitro'}", + "74, CD34(+) {'context': 'B-cells'}", + "75, multipotent {'context': 'I-cells'}", + "76, hematopoietic {'context': 'I-cells'}", + "77, progenitor {'context': 'I-cells'}", + "78, cells {'context': 'I-cells'}", + "79, (HPCs). {'context': 'I-cells'}", + "82, HPCs, {'context': 'B-cells'}", + "91, cell {'context': 'B-in vitro'}", + "92, culture {'context': 'I-in vitro'}", + "111, cells {'context': 'B-cells'}", + "112, in {'context': 'B-in vitro'}", + "113, vitro {'context': 'I-in vitro'}", + "125, HPCs. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "54, CD34(+) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "55, cells ['l0', 'l8', 'l9', 'l10']", + "62, in ['l1', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "63, vitro ['l2', 'l8', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "74, CD34(+) ['l3', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "75, multipotent ['l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "76, hematopoietic ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "77, progenitor ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "78, cells ['l6', 'l9', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "79, (HPCs). ['l7', 'l10', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "82, HPCs, ['l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "91, cell ['l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "92, culture ['l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "111, cells ['l66', 'l67', 'l68']", + "112, in ['l66', 'l69', 'l70']", + "113, vitro ['l67', 'l69', 'l71']", + "125, HPCs. ['l68', 'l70', 'l71']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20208514", + "TEXT": "Thinking about how asthma and allergic diseases arise is undergoing several shifts. In ‘Bedside to Bench’, Clare M. Lloyd and Sejal Saglani examine how recent human studies are putting the focus on the epithelium as a major contributor to asthma. The findings shift the emphasis away from the T helper type 2 immune response, and call into question the utility of current animal models of the disease. Although asthma and other allergic disorders are known to have origins in infancy, some researchers are looking even earlier, to effects in utero and before conception. In ‘Bench to Bedside’, Catherine Hawrylowicz and Kimuli Ryanna highlight animal studies that outline some of the effects of the maternal environment, and they examine the potential implications for prevention of disease.", + "TAG_DATA": [ + "103, animal {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20173754", + "TEXT": "An effective HIV vaccine must elicit immune responses that recognize genetically diverse viruses. It must generate CD8+ T lymphocytes that control HIV replication and CD4+ T lymphocytes that provide help for the generation and maintenance of both cellular and humoral immune responses against the virus. Creating immunogens that can elicit cellular immune responses against the genetically varied circulating isolates of HIV presents a key challenge for creating an HIV vaccine. Polyvalent mosaic immunogens derived by in silico recombination of natural strains of HIV are designed to induce cellular immune responses that recognize genetically diverse circulating virus isolates. Here we immunized rhesus monkeys by plasmid DNA prime and recombinant vaccinia virus boost with vaccine constructs expressing either consensus or polyvalent mosaic proteins. As compared to consensus immunogens, the mosaic immunogens elicited CD8+ T lymphocyte responses to more epitopes of each viral protein than did the consensus immunogens and to more variant sequences of CD8+ T lymphocyte epitopes. This increased breadth and depth of epitope recognition may contribute both to protection against infection by genetically diverse viruses and to the control of variant viruses that emerge as they mutate away from recognition by cytotoxic T lymphocytes.", + "TAG_DATA": [ + "100, rhesus {'context': 'B-organism'}", + "101, monkeys {'context': 'I-organism'}", + "130, CD8+ {'context': 'B-cells'}", + "131, T {'context': 'I-cells'}", + "132, lymphocyte {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "100, rhesus ['l0']", + "101, monkeys ['l0']", + "130, CD8+ ['l1', 'l2']", + "131, T ['l1', 'l3']", + "132, lymphocyte ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20154696", + "TEXT": "The expression of ABO(H) blood group antigens causes deletion of cells that generate self-specific antibodies to these antigens but this deletion limits adaptive immunity toward pathogens bearing cognate blood group antigens. To explore potential defense mechanisms against such pathogens, given these limitations in adaptive immunity, we screened for innate proteins that could recognize human blood group antigens. Here we report that two innate immune lectins, galectin-4 (Gal-4) and Gal-8, which are expressed in the intestinal tract, recognize and kill human blood group antigen-expressing Escherichia coli while failing to alter the viability of other E. coli strains or other Gram-negative or Gram-positive organisms both in vitro and in vivo. The killing activity of both Gal-4 and Gal-8 is mediated by their C-terminal domains, occurs rapidly and independently of complement and is accompanied by disruption of membrane integrity. These results demonstrate that innate defense lectins can provide immunity against pathogens that express blood group-like antigens on their surface.", + "TAG_DATA": [ + "98, Gram-negative {'context': 'B-cells'}", + "103, in {'context': 'B-in vitro'}", + "104, vitro {'context': 'I-in vitro'}", + "106, in {'context': 'B-in vivo'}", + "107, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "93, E. ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "95, strains ['l0', 'l7', 'l8', 'l9', 'l10']", + "98, Gram-negative ['l1', 'l7', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "99, or ['l2', 'l11', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "100, Gram-positive ['l3', 'l12', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "101, organisms ['l4', 'l8', 'l13', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32']", + "103, in ['l5', 'l9', 'l14', 'l20', 'l25', 'l29', 'l33']", + "104, vitro ['l6', 'l10', 'l15', 'l21', 'l26', 'l30', 'l33']", + "106, in ['l16', 'l22', 'l27', 'l31', 'l34']", + "107, vivo. ['l17', 'l23', 'l28', 'l32', 'l34']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20134460", + "TEXT": "How should clinical trials be improved? Ken Getz, a senior fellow at the Tufts Center for the Study of Drug Development, has been thinking up answers to this question for two decades. In 2003, Getz took on a new challenge when he launched the Center for Information & Study on Clinical Research, a nonprofit focused on providing education and outreach on clinical research to the public. Cassandra Willyard asked Getz for his thoughts on trial recruitment, financial conflicts of interest and keeping trial participants safe.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20098432", + "TEXT": "Individuals with beta-thalassemia develop progressive systemic iron overload, resulting in high morbidity and mortality. These complications are caused by labile plasma iron, which is taken up by parenchymal cells in a dysregulated manner; in contrast, erythropoiesis depends on transferrin-bound iron uptake via the transferrin receptor. We hypothesized that the ineffective erythropoiesis and anemia observed in beta-thalassemia might be ameliorated by increasing the amount of circulating transferrin. We tested the ability of transferrin injections to modulate iron metabolism and erythropoiesis in Hbb(th1/th1) mice, an experimental model of beta-thalassemia. Injected transferrin reversed or markedly improved the thalassemia phenotype in these mice. Specifically, transferrin injections normalized labile plasma iron concentrations, increased hepcidin expression, normalized red blood cell survival and increased hemoglobin production; this treatment concomitantly decreased reticulocytosis, erythropoietin abundance and splenomegaly. These results indicate that transferrin is a limiting factor contributing to anemia in these mice and suggest that transferrin therapy might be beneficial in human beta-thalassemia.", + "TAG_DATA": [ + "80, Hbb(th1/th1) {'perturbing_action': 'B-other'}", + "81, mice, {'context': 'B-organism'}", + "98, mice. {'context': 'B-organism'}", + "111, red {'context': 'B-cells'}", + "112, blood {'context': 'I-cells'}", + "113, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "80, Hbb(th1/th1) ['l0']", + "81, mice, ['l0']", + "98, mice. ['l1', 'l2', 'l3']", + "111, red ['l1', 'l4', 'l5']", + "112, blood ['l2', 'l4', 'l6']", + "113, cell ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Hbb(th1/th1)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "20098431", + "TEXT": "Gene-modified autologous hematopoietic stem cells (HSC) can provide ample clinical benefits to subjects suffering from X-linked chronic granulomatous disease (X-CGD), a rare inherited immunodeficiency characterized by recurrent, often life-threatening bacterial and fungal infections. Here we report on the molecular and cellular events observed in two young adults with X-CGD treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both subjects showed silencing of transgene expression due to methylation of the viral promoter, and myelodysplasia with monosomy 7 as a result of insertional activation of ecotropic viral integration site 1 (EVI1). One subject died from overwhelming sepsis 27 months after gene therapy, whereas a second subject underwent an allogeneic HSC transplantation. Our data show that forced overexpression of EVI1 in human cells disrupts normal centrosome duplication, linking EVI1 activation to the development of genomic instability, monosomy 7 and clonal progression toward myelodysplasia.", + "TAG_DATA": [ + "46, adults {'context': 'I-organism'}", + "113, allogeneic {'context': 'B-xenograft'}", + "114, HSC {'context': 'I-xenograft'}", + "120, forced {'perturbing_action': 'B-gene gain-of-function'}", + "121, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "122, of {'perturbing_action': 'I-gene gain-of-function'}", + "123, EVI1 {'perturbing_action': 'I-gene gain-of-function'}", + "125, human {'context': 'B-cells'}", + "126, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "113, allogeneic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "114, HSC ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "115, transplantation. ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "120, forced ['l15', 'l16', 'l17', 'l18', 'l19']", + "121, overexpression ['l15', 'l20', 'l21', 'l22', 'l23']", + "122, of ['l2', 'l7', 'l11', 'l16', 'l20', 'l24', 'l25', 'l26']", + "123, EVI1 ['l3', 'l8', 'l12', 'l17', 'l21', 'l24', 'l27', 'l28']", + "125, human ['l4', 'l9', 'l13', 'l18', 'l22', 'l25', 'l27', 'l29']", + "126, cells ['l5', 'l10', 'l14', 'l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "xenograft", + "words": [ + "allogeneic", + "HSC" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "EVI1" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "forced", + "overexpression", + "of", + "EVI1" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "cells" + ] + } + } + ] + }, + { + "PMID": "20098430", + "TEXT": "Hypertension is one of the most frequent pathologies in the industrialized world. Although recognized to be dependent on a combination of genetic and environmental factors, its molecular basis remains elusive. Increased activity of the monomeric G protein RhoA in arteries is a common feature of hypertension. However, how RhoA is activated and whether it has a causative role in hypertension remains unclear. Here we provide evidence that Arhgef1 is the RhoA guanine exchange factor specifically responsible for angiotensin II-induced activation of RhoA signaling in arterial smooth muscle cells. We found that angiotensin II activates Arhgef1 through a previously undescribed mechanism in which Jak2 phosphorylates Tyr738 of Arhgef1. Arhgef1 inactivation in smooth muscle induced resistance to angiotensin II-dependent hypertension in mice, but did not affect normal blood pressure regulation. Our results show that control of RhoA signaling through Arhgef1 is central to the development of angiotensin II-dependent hypertension and identify Arhgef1 as a potential target for the treatment of hypertension.", + "TAG_DATA": [ + "107, Arhgef1 {'perturbing_action': 'B-gene loss-of-function'}", + "108, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "110, smooth {'context': 'B-cells'}", + "111, muscle {'context': 'I-cells'}", + "119, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "107, Arhgef1 ['l0', 'l1', 'l2', 'l3']", + "108, inactivation ['l0', 'l4', 'l5', 'l6']", + "110, smooth ['l1', 'l4', 'l7', 'l8']", + "111, muscle ['l2', 'l5', 'l7', 'l9']", + "119, mice, ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Arhgef1", + "inactivation" + ] + }, + "context": { + "val": "cells", + "words": [ + "smooth", + "muscle" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Arhgef1", + "inactivation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "20098429", + "TEXT": "Adjuvant chemotherapy for breast cancer after surgery has effectively lowered metastatic recurrence rates. However, a considerable proportion of women suffer recurrent cancer at distant metastatic sites despite adjuvant treatment. Identification of the genes crucial for tumor response to specific chemotherapy drugs is a challenge but is necessary to improve outcomes. By using integrated genomics, we identified a small number of overexpressed and amplified genes from chromosome 8q22 that were associated with early disease recurrence despite anthracycline-based adjuvant chemotherapy. We confirmed the association in an analysis of multiple independent cohorts. SiRNA-mediated knockdown of either of two of these genes, the antiapoptotic gene YWHAZ and a lysosomal gene LAPTM4B, sensitized tumor cells to anthracyclines, and overexpression of either of the genes induced anthracycline resistance. Overexpression of LAPTM4B resulted in sequestration of the anthracycline doxorubicin, delaying its appearance in the nucleus. Overexpression of these two genes was associated with poor tumor response to anthracycline treatment in a neoadjuvant chemotherapy trial in women with primary breast cancer. Our results suggest that 8q22 amplification and overexpression of LAPTM4B and YWHAZ contribute to de novo chemoresistance to anthracyclines and are permissive for metastatic recurrence. Overexpression of these two genes may predict anthracycline resistance and influence selection of chemotherapy.", + "TAG_DATA": [ + "89, SiRNA-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "90, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "91, of {'perturbing_action': 'I-rnai/knockdown'}", + "92, either {'perturbing_action': 'I-rnai/knockdown'}", + "93, of {'perturbing_action': 'I-rnai/knockdown'}", + "94, two {'perturbing_action': 'I-rnai/knockdown'}", + "95, of {'perturbing_action': 'I-rnai/knockdown'}", + "96, these {'perturbing_action': 'I-rnai/knockdown'}", + "97, genes, {'perturbing_action': 'I-rnai/knockdown'}", + "98, the {'perturbing_action': 'I-rnai/knockdown'}", + "99, antiapoptotic {'perturbing_action': 'I-rnai/knockdown'}", + "100, gene {'perturbing_action': 'I-rnai/knockdown'}", + "101, YWHAZ {'perturbing_action': 'I-rnai/knockdown'}", + "102, and {'perturbing_action': 'I-rnai/knockdown'}", + "103, a {'perturbing_action': 'I-rnai/knockdown'}", + "104, lysosomal {'perturbing_action': 'I-rnai/knockdown'}", + "105, gene {'perturbing_action': 'I-rnai/knockdown'}", + "106, LAPTM4B, {'perturbing_action': 'I-rnai/knockdown'}", + "108, tumor {'context': 'B-transformed cells'}", + "109, cells {'context': 'I-transformed cells'}", + "113, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "114, of {'perturbing_action': 'I-gene gain-of-function'}", + "115, either {'perturbing_action': 'I-gene gain-of-function'}", + "116, of {'perturbing_action': 'I-gene gain-of-function'}", + "117, the {'perturbing_action': 'I-gene gain-of-function'}", + "118, genes {'perturbing_action': 'I-gene gain-of-function'}", + "122, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "123, of {'perturbing_action': 'I-gene gain-of-function'}", + "124, LAPTM4B {'perturbing_action': 'I-gene gain-of-function'}", + "138, Overexpression {'perturbing_action': 'B-gene gain-of-function'}" + ], + "LINK_DATA": [ + "89, SiRNA-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "90, knockdown ['l0', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "91, of ['l1', 'l19', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "92, either ['l2', 'l20', 'l37', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "93, of ['l3', 'l21', 'l38', 'l54', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "94, two ['l4', 'l22', 'l39', 'l55', 'l70', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "95, of ['l5', 'l23', 'l40', 'l56', 'l71', 'l85', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "96, these ['l6', 'l24', 'l41', 'l57', 'l72', 'l86', 'l99', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "97, genes, ['l7', 'l25', 'l42', 'l58', 'l73', 'l87', 'l100', 'l112', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "98, the ['l8', 'l26', 'l43', 'l59', 'l74', 'l88', 'l101', 'l113', 'l124', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "99, antiapoptotic ['l9', 'l27', 'l44', 'l60', 'l75', 'l89', 'l102', 'l114', 'l125', 'l135', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "100, gene ['l10', 'l28', 'l45', 'l61', 'l76', 'l90', 'l103', 'l115', 'l126', 'l136', 'l145', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "101, YWHAZ ['l11', 'l29', 'l46', 'l62', 'l77', 'l91', 'l104', 'l116', 'l127', 'l137', 'l146', 'l154', 'l162', 'l163', 'l164', 'l165', 'l166']", + "102, and ['l12', 'l30', 'l47', 'l63', 'l78', 'l92', 'l105', 'l117', 'l128', 'l138', 'l147', 'l155', 'l162', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "103, a ['l13', 'l31', 'l48', 'l64', 'l79', 'l93', 'l106', 'l118', 'l129', 'l139', 'l148', 'l156', 'l163', 'l167', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "104, lysosomal ['l14', 'l32', 'l49', 'l65', 'l80', 'l94', 'l107', 'l119', 'l130', 'l140', 'l149', 'l157', 'l168', 'l173', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184']", + "105, gene ['l15', 'l33', 'l50', 'l66', 'l81', 'l95', 'l108', 'l120', 'l131', 'l141', 'l150', 'l158', 'l169', 'l174', 'l179', 'l185', 'l186', 'l187', 'l188', 'l189']", + "106, LAPTM4B, ['l16', 'l34', 'l51', 'l67', 'l82', 'l96', 'l109', 'l121', 'l132', 'l142', 'l151', 'l159', 'l164', 'l170', 'l175', 'l180', 'l185', 'l190', 'l191', 'l192']", + "108, tumor ['l17', 'l35', 'l52', 'l68', 'l83', 'l97', 'l110', 'l122', 'l133', 'l143', 'l152', 'l160', 'l165', 'l171', 'l176', 'l181', 'l186', 'l190', 'l193']", + "109, cells ['l18', 'l36', 'l53', 'l69', 'l84', 'l98', 'l111', 'l123', 'l134', 'l144', 'l153', 'l161', 'l166', 'l172', 'l177', 'l182', 'l187', 'l191', 'l193']", + "113, overexpression ['l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201']", + "114, of ['l194', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208']", + "115, either ['l195', 'l202', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214']", + "116, of ['l196', 'l203', 'l209', 'l215', 'l216', 'l217', 'l218', 'l219']", + "117, the ['l183', 'l188', 'l197', 'l204', 'l210', 'l215', 'l220', 'l221', 'l222', 'l223']", + "118, genes ['l178', 'l184', 'l189', 'l192', 'l198', 'l205', 'l211', 'l216', 'l220', 'l224', 'l225', 'l226']", + "122, Overexpression ['l199', 'l206', 'l212', 'l217', 'l221', 'l224', 'l227', 'l228']", + "123, of ['l200', 'l207', 'l213', 'l218', 'l222', 'l225', 'l227', 'l229']", + "124, LAPTM4B ['l201', 'l208', 'l214', 'l219', 'l223', 'l226', 'l228', 'l229']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "SiRNA-mediated", + "knockdown", + "of", + "either", + "two", + "these", + "genes,", + "the", + "antiapoptotic", + "gene", + "YWHAZ", + "and", + "a", + "lysosomal", + "LAPTM4B," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + } + ] + }, + { + "PMID": "20081863", + "TEXT": "Humans are colonized by a large and diverse bacterial flora (the microbiota) essential for the development of the gut immune system. A broader role for the microbiota as a major modulator of systemic immunity has been proposed; however, evidence and a mechanism for this role have remained elusive. We show that the microbiota are a source of peptidoglycan that systemically primes the innate immune system, enhancing killing by bone marrow-derived neutrophils of two major pathogens: Streptococcus pneumoniae and Staphylococcus aureus. This requires signaling via the pattern recognition receptor nucleotide-binding, oligomerization domain-containing protein-1 (Nod1, which recognizes meso-diaminopimelic acid (mesoDAP)-containing peptidoglycan found predominantly in Gram-negative bacteria), but not Nod2 (which detects peptidoglycan found in Gram-positive and Gram-negative bacteria) or Toll-like receptor 4 (Tlr4, which recognizes lipopolysaccharide). We show translocation of peptidoglycan from the gut to neutrophils in the bone marrow and show that peptidoglycan concentrations in sera correlate with neutrophil function. In vivo administration of Nod1 ligands is sufficient to restore neutrophil function after microbiota depletion. Nod1(-/-) mice are more susceptible than wild-type mice to early pneumococcal sepsis, demonstrating a role for Nod1 in priming innate defenses facilitating a rapid response to infection. These data establish a mechanism for systemic immunomodulation by the microbiota and highlight potential adverse consequences of microbiota disruption by broad-spectrum antibiotics on innate immune defense to infection.", + "TAG_DATA": [ + "149, In {'context': 'B-in vivo'}", + "150, vivo {'context': 'I-in vivo'}", + "164, Nod1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "165, mice {'context': 'B-organism'}", + "171, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "149, In ['l0']", + "150, vivo ['l0']", + "164, Nod1(-/-) ['l1', 'l2']", + "165, mice ['l1', 'l3']", + "171, mice ['l2', 'l3']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nod1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "20081862", + "TEXT": "Delayed myeloid engraftment after cord blood transplantation (CBT) is thought to result from inadequate numbers of progenitor cells in the graft and is associated with increased early transplant-related morbidity and mortality. New culture strategies that increase the number of cord blood progenitors capable of rapid myeloid engraftment after CBT would allow more widespread use of this stem cell source for transplantation. Here we report the development of a clinically relevant Notch-mediated ex vivo expansion system for human CD34(+) cord blood progenitors that results in a marked increase in the absolute number of stem/progenitor cells, including those capable of enhanced repopulation in the marrow of immunodeficient nonobese diabetic-severe combined immunodeficient (NOD-SCID) mice. Furthermore, when cord blood progenitors expanded ex vivo in the presence of Notch ligand were infused in a clinical setting after a myeloablative preparative regimen for stem cell transplantation, the time to neutrophil recovery was substantially shortened. To our knowledge, this is the first instance of rapid engraftment derived from ex vivo expanded stem/progenitor cells in humans.", + "TAG_DATA": [ + "76, human {'context': 'B-cells'}", + "77, CD34(+) {'context': 'I-cells'}", + "78, cord {'context': 'I-cells'}", + "79, blood {'context': 'I-cells'}", + "92, stem/progenitor {'context': 'B-cells'}", + "93, cells, {'context': 'I-cells'}", + "104, immunodeficient {'context': 'B-organism'}", + "105, nonobese {'context': 'I-organism'}", + "106, diabetic-severe {'context': 'I-organism'}", + "107, combined {'context': 'I-organism'}", + "108, immunodeficient {'context': 'I-organism'}", + "109, (NOD-SCID) {'context': 'I-organism'}", + "110, mice. {'context': 'I-organism'}", + "113, cord {'context': 'B-cells'}", + "114, blood {'context': 'I-cells'}", + "115, progenitors {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "76, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "77, CD34(+) ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "78, cord ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "79, blood ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "92, stem/progenitor ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "93, cells, ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "104, immunodeficient ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27', 'l28', 'l29', 'l30']", + "105, nonobese ['l27', 'l31', 'l32', 'l33', 'l34', 'l35']", + "106, diabetic-severe ['l28', 'l31', 'l36', 'l37', 'l38', 'l39']", + "107, combined ['l32', 'l36', 'l40', 'l41', 'l42']", + "108, immunodeficient ['l33', 'l37', 'l40', 'l43', 'l44']", + "109, (NOD-SCID) ['l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "110, mice. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']", + "113, cord ['l46', 'l47']", + "114, blood ['l46', 'l48']", + "115, progenitors ['l47', 'l48']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20072130", + "TEXT": "Targeting the mammalian target of rapamycin (mTOR) protein is a promising strategy for cancer therapy. The mTOR kinase functions in two complexes, TORC1 (target of rapamycin complex-1) and TORC2 (target of rapamycin complex-2); however, neither of these complexes is fully inhibited by the allosteric inhibitor rapamycin or its analogs. We compared rapamycin with PP242, an inhibitor of the active site of mTOR in both TORC1 and TORC2 (hereafter referred to as TORC1/2), in models of acute leukemia harboring the Philadelphia chromosome (Ph) translocation. We demonstrate that PP242, but not rapamycin, causes death of mouse and human leukemia cells. In vivo, PP242 delays leukemia onset and augments the effects of the current front-line tyrosine kinase inhibitors more effectively than does rapamycin. Unexpectedly, PP242 has much weaker effects than rapamycin on the proliferation and function of normal lymphocytes. PI-103, a less selective TORC1/2 inhibitor that also targets phosphoinositide 3-kinase (PI3K), is more immunosuppressive than PP242. These findings establish that Ph(+) transformed cells are more sensitive than normal lymphocytes to selective TORC1/2 inhibitors and support the development of such inhibitors for leukemia therapy.", + "TAG_DATA": [ + "53, PP242, {'perturbing_action': 'B-pharmacological inhibition'}", + "54, an {'perturbing_action': 'I-pharmacological inhibition'}", + "55, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "56, of {'perturbing_action': 'I-pharmacological inhibition'}", + "57, the {'perturbing_action': 'I-pharmacological inhibition'}", + "58, active {'perturbing_action': 'I-pharmacological inhibition'}", + "59, site {'perturbing_action': 'I-pharmacological inhibition'}", + "60, of {'perturbing_action': 'I-pharmacological inhibition'}", + "61, mTOR {'perturbing_action': 'I-pharmacological inhibition'}", + "62, in {'perturbing_action': 'I-pharmacological inhibition'}", + "63, both {'perturbing_action': 'I-pharmacological inhibition'}", + "64, TORC1 {'perturbing_action': 'I-pharmacological inhibition'}", + "73, models {'context': 'B-neoplasm'}", + "75, acute {'context': 'B-neoplasm'}", + "76, leukemia {'context': 'I-neoplasm'}", + "93, mouse {'context': 'B-transformed cells'}", + "94, and {'context': 'I-transformed cells'}", + "95, human {'context': 'I-transformed cells'}", + "96, leukemia {'context': 'I-transformed cells'}", + "97, cells. {'context': 'I-transformed cells'}", + "98, In {'context': 'B-in vivo'}", + "99, vivo, {'context': 'I-in vivo'}", + "102, leukemia {'context': 'B-neoplasm'}", + "130, proliferation {'phenotype': 'B-proliferation'}", + "134, normal {'context': 'B-cells'}", + "135, lymphocytes. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "53, PP242, ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "54, an ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "55, inhibitor ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "56, of ['l2', 'l21', 'l39', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "57, the ['l3', 'l22', 'l40', 'l57', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "58, active ['l4', 'l23', 'l41', 'l58', 'l75', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "59, site ['l5', 'l24', 'l42', 'l59', 'l76', 'l92', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "60, of ['l6', 'l25', 'l43', 'l60', 'l77', 'l93', 'l107', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "61, mTOR ['l7', 'l26', 'l44', 'l61', 'l78', 'l94', 'l108', 'l122', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146']", + "62, in ['l8', 'l27', 'l45', 'l62', 'l79', 'l95', 'l109', 'l123', 'l135', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "63, both ['l9', 'l28', 'l46', 'l63', 'l80', 'l96', 'l110', 'l124', 'l136', 'l147', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "64, TORC1 ['l10', 'l29', 'l47', 'l64', 'l81', 'l97', 'l111', 'l125', 'l137', 'l148', 'l158', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176']", + "73, models ['l11', 'l30', 'l48', 'l65', 'l82', 'l98', 'l112', 'l126', 'l138', 'l149', 'l159', 'l168', 'l177', 'l178', 'l179', 'l180']", + "74, of ['l12', 'l31', 'l49', 'l66', 'l83', 'l99', 'l113', 'l127', 'l139', 'l150', 'l160', 'l169', 'l177', 'l181', 'l182', 'l183']", + "75, acute ['l13', 'l32', 'l50', 'l67', 'l84', 'l100', 'l114', 'l128', 'l140', 'l151', 'l161', 'l170', 'l178', 'l181', 'l184', 'l185']", + "76, leukemia ['l14', 'l33', 'l51', 'l68', 'l85', 'l101', 'l115', 'l129', 'l141', 'l152', 'l162', 'l171', 'l179', 'l182', 'l184', 'l186', 'l187']", + "93, mouse ['l15', 'l34', 'l52', 'l69', 'l86', 'l102', 'l116', 'l130', 'l142', 'l153', 'l163', 'l172', 'l188', 'l189', 'l190', 'l191']", + "94, and ['l16', 'l35', 'l53', 'l70', 'l87', 'l103', 'l117', 'l131', 'l143', 'l154', 'l164', 'l173', 'l186', 'l188', 'l192', 'l193', 'l194']", + "95, human ['l17', 'l36', 'l54', 'l71', 'l88', 'l104', 'l118', 'l132', 'l144', 'l155', 'l165', 'l174', 'l189', 'l192', 'l195', 'l196']", + "96, leukemia ['l18', 'l37', 'l55', 'l72', 'l89', 'l105', 'l119', 'l133', 'l145', 'l156', 'l166', 'l175', 'l190', 'l193', 'l195', 'l197']", + "97, cells. ['l19', 'l38', 'l56', 'l73', 'l90', 'l106', 'l120', 'l134', 'l146', 'l157', 'l167', 'l176', 'l180', 'l183', 'l185', 'l187', 'l191', 'l194', 'l196', 'l197']", + "98, In ['l198', 'l199']", + "99, vivo, ['l74', 'l91', 'l121', 'l198', 'l200']", + "102, leukemia ['l199', 'l200']", + "125, effects ['l201', 'l202', 'l203']", + "130, proliferation ['l201', 'l204', 'l205']", + "134, normal ['l202', 'l204', 'l206']", + "135, lymphocytes. ['l203', 'l205', 'l206']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PP242,", + "an", + "inhibitor", + "of", + "the", + "active", + "site", + "mTOR", + "in", + "both", + "TORC1" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models", + "acute", + "leukemia" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PP242,", + "an", + "inhibitor", + "of", + "the", + "active", + "site", + "mTOR", + "in", + "both", + "TORC1" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "mouse", + "and", + "human", + "leukemia", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "of", + "the", + "site" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "normal", + "lymphocytes." + ] + } + } + ] + }, + { + "PMID": "20037593", + "TEXT": "Panic disorder is a severe anxiety disorder with recurrent, debilitating panic attacks. In individuals with panic disorder there is evidence of decreased central gamma-aminobutyric acid (GABA) activity as well as marked increases in autonomic and respiratory responses after intravenous infusions of hypertonic sodium lactate. In a rat model of panic disorder, chronic inhibition of GABA synthesis in the dorsomedial-perifornical hypothalamus of rats produces anxiety-like states and a similar vulnerability to sodium lactate-induced cardioexcitatory responses. The dorsomedial-perifornical hypothalamus is enriched in neurons containing orexin (ORX, also known as hypocretin), which have a crucial role in arousal, vigilance and central autonomic mobilization, all of which are key components of panic. Here we show that activation of ORX-synthesizing neurons is necessary for developing a panic-prone state in the rat panic model, and either silencing of the hypothalamic gene encoding ORX (Hcrt) with RNAi or systemic ORX-1 receptor antagonists blocks the panic responses. Moreover, we show that human subjects with panic anxiety have elevated levels of ORX in the cerebrospinal fluid compared to subjects without panic anxiety. Taken together, our results suggest that the ORX system may be involved in the pathophysiology of panic anxiety and that ORX antagonists constitute a potential new treatment strategy for panic disorder.", + "TAG_DATA": [ + "61, rats {'context': 'B-organism'}", + "130, silencing {'perturbing_action': 'B-rnai/knockdown'}", + "131, of {'perturbing_action': 'I-rnai/knockdown'}", + "132, the {'perturbing_action': 'I-rnai/knockdown'}", + "133, hypothalamic {'perturbing_action': 'I-rnai/knockdown'}", + "134, gene {'perturbing_action': 'I-rnai/knockdown'}", + "135, encoding {'perturbing_action': 'I-rnai/knockdown'}", + "136, ORX {'perturbing_action': 'I-rnai/knockdown'}", + "137, (Hcrt) {'perturbing_action': 'I-rnai/knockdown'}", + "138, with {'perturbing_action': 'I-rnai/knockdown'}", + "139, RNAi {'perturbing_action': 'I-rnai/knockdown'}", + "141, systemic {'perturbing_action': 'B-pharmacological inhibition'}", + "142, ORX-1 {'perturbing_action': 'I-pharmacological inhibition'}", + "143, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "144, antagonists {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "130, silencing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "131, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "132, the ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "133, hypothalamic ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "134, gene ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "135, encoding ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "136, ORX ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "137, (Hcrt) ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "138, with ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "139, RNAi ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "141, systemic ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "142, ORX-1 ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "143, receptor ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "144, antagonists ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19966813", + "TEXT": "The ductus arteriosus (DA) is a fetal shunt vessel between the pulmonary artery and the aorta that closes promptly after birth. Failure of postnatal DA closure is a major cause of morbidity and mortality particularly in preterm neonates. The events leading to DA closure are incompletely understood. Here we show that platelets have an essential role in DA closure. Using intravital microscopy of neonatal mice, we observed that platelets are recruited to the luminal aspect of the DA during closure. DA closure is impaired in neonates with malfunctioning platelet adhesion or aggregation or with defective platelet biogenesis. Defective DA closure resulted in a left-to-right shunt with increased pulmonary perfusion, pulmonary vascular remodeling and right ventricular hypertrophy. Our findings indicate that platelets are crucial for DA closure by promoting thrombotic sealing of the constricted DA and by supporting luminal remodeling. A retrospective clinical study revealed that thrombocytopenia is an independent predictor for failure of DA closure in preterm human newborns, indicating that platelets are likely to contribute to DA closure in humans.", + "TAG_DATA": [ + "63, neonatal {'context': 'B-organism'}", + "64, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "63, neonatal ['l0']", + "64, mice, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19966812", + "TEXT": "Nucleotide-binding oligomerization domain-containing-2 (NOD2) acts as a bacterial sensor in dendritic cells (DCs), but it is not clear how bacterial recognition links with antigen presentation after NOD2 stimulation. NOD2 variants are associated with Crohn's disease, where breakdown in self-recognition of commensal bacteria leads to gastrointestinal inflammation. Here we show NOD2 triggering by muramyldipeptide induces autophagy in DCs. This effect requires receptor-interacting serine-threonine kinase-2 (RIPK-2), autophagy-related protein-5 (ATG5), ATG7 and ATG16L1 but not NLR family, pyrin domain containing-3 (NALP3).We show that NOD2-mediated autophagy is required for both bacterial handling and generation of major histocompatibility complex (MHC) class II antigen-specific CD4(+) T cell responses in DCs. DCs from individuals with Crohn's disease expressing Crohn's disease-associated NOD2 or ATG16L1 risk variants are defective in autophagy induction, bacterial trafficking and antigen presentation. Our findings link two Crohn's disease-associated susceptibility genes in a single functional pathway and reveal defects in this pathway in Crohn's disease DCs that could lead to bacterial persistence via impaired lysosomal destruction and immune mediated clearance.", + "TAG_DATA": [ + "50, triggering {'perturbing_action': 'I-pharmacological augmentation'}", + "53, induces {'effect': 'B-positive'}", + "54, autophagy {'phenotype': 'B-autophagy'}", + "56, DCs. {'context': 'B-cells'}", + "81, autophagy {'phenotype': 'B-autophagy'}", + "103, DCs. {'context': 'B-cells'}", + "104, DCs {'context': 'B-cells'}", + "121, autophagy {'phenotype': 'B-autophagy'}", + "122, induction, {'effect': 'B-positive'}" + ], + "LINK_DATA": [ + "50, triggering ['l0', 'l1', 'l2', 'l3']", + "53, induces ['l0', 'l4', 'l5', 'l6']", + "54, autophagy ['l1', 'l4', 'l7', 'l8']", + "56, DCs. ['l2', 'l5', 'l7', 'l9']", + "81, autophagy ['l10']", + "103, DCs. ['l3', 'l6', 'l8', 'l9', 'l10']", + "104, DCs ['l11', 'l12']", + "121, autophagy ['l11', 'l13']", + "122, induction, ['l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "triggering" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "triggering" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "triggering" + ] + }, + "context": { + "val": "cells", + "words": [ + "DCs." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "induction," + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "induction," + ] + }, + "context": { + "val": "cells", + "words": [ + "DCs.", + "DCs" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + }, + "context": { + "val": "cells", + "words": [ + "DCs.", + "DCs" + ] + } + } + ] + }, + { + "PMID": "19893557", + "TEXT": "The wide-spread resistance of influenza virus isolates to existing antivirals and the lack of a universal influenza vaccine makes imperative the development of new antivirals to treat influenza, more especially during pandemic years. Two recent publications that determine the crystal structure of the unique endonuclease domain of the influenza virus polymerase open the possibility for the rational design of novel influenza virus inhibitors. [after I edit kanta’s piece I will be writing a subhead that also include her commentary, you can comment on that subhead in proofs]", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19855399", + "TEXT": "Reversible methylation of histone tails serves as either a positive signal recognized by transcriptional assemblies or a negative signal that result in repression. Invading viral pathogens that depend upon the host cell's transcriptional apparatus are also subject to the regulatory impact of chromatin assembly and modifications. Here we show that infection by the alpha-herpesviruses, herpes simplex virus (HSV) and varicella zoster virus (VZV), results in the rapid accumulation of chromatin bearing repressive histone H3 Lys9 methylation. To enable expression of viral immediate early (IE) genes, both viruses use the cellular transcriptional coactivator host cell factor-1 (HCF-1) to recruit the lysine-specific demethylase-1 (LSD1) to the viral immediate early promoters. Depletion of LSD1 or inhibition of its activity with monoamine oxidase inhibitors (MAOIs) results in the accumulation of repressive chromatin and a block to viral gene expression. As HCF-1 is a component of the Set1 and MLL1 histone H3 Lys4 methyltransferase complexes, it thus coordinates modulation of repressive H3 Lys9 methylation levels with addition of activating H3 Lys4 trimethylation marks. Strikingly, MAOIs also block the reactivation of HSV from latency in sensory neurons, indicating that the HCF-1 complex is a crucial component of the reactivation mechanism. The results support pharmaceutical control of histone modifying enzymes as a strategy for controlling herpesvirus infections.", + "TAG_DATA": [ + "108, Depletion {'perturbing_action': 'B-gene loss-of-function'}", + "109, of {'perturbing_action': 'I-gene loss-of-function'}", + "110, LSD1 {'perturbing_action': 'I-gene loss-of-function'}", + "179, sensory {'context': 'B-cells'}", + "180, neurons, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "108, Depletion ['l0', 'l1']", + "109, of ['l0', 'l2']", + "110, LSD1 ['l1', 'l2']", + "179, sensory ['l3']", + "180, neurons, ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19855398", + "TEXT": "We report that infection of draining lymph nodes (DLNs) by Salmonella typhimurium results in the specific downregulation of the homeostatic chemokines CCL21 and CXCL13, which are essential for normal DLN organization and function. Our data reveal that the mechanism of this suppression is dependent on S. typhimurium LPS (sLPS). The decrease in CCL21 expression involves interaction between sLPS and CCL21-producing cells within DLNs, triggering a distinct Toll-like receptor 4 (TLR4)-mediated host signaling response. In this response, suppressor of cytokine signaling-3 (Socs3) is upregulated, which negatively regulates mothers against decapentaplegic homolog-3 (Smad3)-initiated production of CCL21. Disruption of lymph node architecture and cellular trafficking enhances S. typhimurium virulence and could represent a mechanism of immune suppression used by pathogens that primarily target lymphoid tissue.", + "TAG_DATA": [], + "LINK_DATA": [ + "6, lymph ['l0']", + "7, nodes ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19855397", + "TEXT": "Hyperinflammatory responses can lead to a variety of diseases, including sepsis. We now report that extracellular histones released in response to inflammatory challenge contribute to endothelial dysfunction, organ failure and death during sepsis. They can be targeted pharmacologically by antibody to histone or by activated protein C (APC). Antibody to histone reduced the mortality of mice in lipopolysaccharide (LPS), tumor necrosis factor (TNF) or cecal ligation and puncture models of sepsis. Extracellular histones are cytotoxic toward endothelium in vitro and are lethal in mice. In vivo, histone administration resulted in neutrophil margination, vacuolated endothelium, intra-alveolar hemorrhage and macro- and microvascular thrombosis. We detected histone in the circulation of baboons challenged with Escherichia coli, and the increase in histone levels was accompanied by the onset of renal dysfunction. APC cleaves histones and reduces their cytotoxicity. Co-infusion of APC with E. coli in baboons or histones in mice prevented lethality. Blockade of protein C activation exacerbated sublethal LPS challenge into lethality, which was reversed by treatment with antibody to histone. We conclude that extracellular histones are potential molecular targets for therapeutics for sepsis and other inflammatory diseases.", + "TAG_DATA": [ + "55, mice {'context': 'B-organism'}", + "84, In {'context': 'B-in vivo'}", + "85, vivo, {'context': 'I-in vivo'}", + "108, baboons {'context': 'B-organism'}", + "141, baboons {'context': 'B-organism'}", + "145, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "84, In ['l0', 'l1']", + "85, vivo, ['l0', 'l2']", + "108, baboons ['l1', 'l2', 'l3', 'l4']", + "141, baboons ['l3', 'l5']", + "145, mice ['l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19783996", + "TEXT": "Germ cells are sensitive to genotoxins, and ovarian failure and infertility are major side effects of chemotherapy in young patients with cancer. Here we describe the c-Abl-TAp63 pathway activated by chemotherapeutic DNA-damaging drugs in model human cell lines and in mouse oocytes and its role in cell death. In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters. Similarly, in oocytes, cisplatin rapidly promotes TAp63 accumulation and eventually cell death. Treatment with the c-Abl kinase inhibitor imatinib counteracts these cisplatin-induced effects. Taken together, these data support a model in which signals initiated by DNA double-strand breaks are detected by c-Abl, which, through its kinase activity, modulates the p63 transcriptional output. Moreover, they suggest a new use for imatinib, aimed at preserving oocytes of the follicle reserve during chemotherapeutic treatments.", + "TAG_DATA": [ + "40, mouse {'context': 'B-cells'}", + "41, oocytes {'context': 'I-cells'}", + "49, cell {'context': 'B-cells'}", + "50, lines, {'context': 'I-cells'}", + "76, oocytes, {'context': 'B-cells'}", + "79, promotes {'effect': 'B-positive'}", + "84, cell {'phenotype': 'B-cell death'}", + "85, death. {'phenotype': 'I-cell death'}", + "89, c-Abl {'perturbing_action': 'I-pharmacological inhibition'}", + "90, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "91, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "40, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "41, oocytes ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "49, cell ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "50, lines, ['l2', 'l8', 'l13', 'l18', 'l19', 'l20']", + "76, oocytes, ['l3', 'l9', 'l14', 'l18', 'l21', 'l22', 'l23']", + "79, promotes ['l4', 'l10', 'l15', 'l19', 'l21', 'l24', 'l25']", + "84, cell ['l5', 'l11', 'l16', 'l22', 'l24', 'l26']", + "85, death. ['l6', 'l12', 'l17', 'l20', 'l23', 'l25', 'l26']", + "89, c-Abl ['l27', 'l28']", + "90, kinase ['l27', 'l29']", + "91, inhibitor ['l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "mouse", + "oocytes", + "cell", + "lines,", + "oocytes," + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "oocytes", + "cell", + "lines,", + "oocytes," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "19767734", + "TEXT": "Reduced food intake brings about an adaptive decrease in energy expenditure that contributes to the recidivism of obesity after weight loss. Insulin and leptin inhibit food intake through actions in the central nervous system that are partly mediated by the transcription factor FoxO1. We show that FoxO1 ablation in pro-opiomelanocortin (Pomc)-expressing neurons in mice (here called Pomc-Foxo1(-/-) mice) increases Carboxypeptidase E (Cpe) expression, resulting in selective increases of alpha-melanocyte-stimulating hormone (alpha-Msh) and carboxy-cleaved beta-endorphin, the products of Cpe-dependent processing of Pomc. This neuropeptide profile is associated with decreased food intake and normal energy expenditure in Pomc-Foxo1(-/-) mice. We show that Cpe expression is downregulated by diet-induced obesity and that FoxO1 deletion offsets the decrease, protecting against weight gain. Moreover, moderate Cpe overexpression in the arcuate nucleus phenocopies features of the FoxO1 mutation. The dissociation of food intake from energy expenditure in Pomc-Foxo1(-/-) mice represents a model for therapeutic intervention in obesity and raises the possibility of targeting Cpe to develop weight loss medications.", + "TAG_DATA": [ + "46, FoxO1 {'perturbing_action': 'B-gene loss-of-function'}", + "47, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "49, pro-opiomelanocortin {'context': 'B-cells'}", + "50, (Pomc)-expressing {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "51, neurons {'context': 'I-cells'}", + "53, mice {'context': 'B-organism'}", + "56, Pomc-Foxo1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "95, Pomc-Foxo1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "96, mice. {'context': 'B-organism'}", + "109, FoxO1 {'perturbing_action': 'B-gene loss-of-function'}", + "110, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "119, moderate {'perturbing_action': 'B-gene gain-of-function'}", + "120, Cpe {'perturbing_action': 'I-gene gain-of-function'}", + "121, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "124, arcuate {'context': 'B-tissue/organ'}", + "125, nucleus {'context': 'I-tissue/organ'}", + "130, FoxO1 {'perturbing_action': 'B-other'}", + "131, mutation. {'perturbing_action': 'I-other'}", + "141, Pomc-Foxo1(-/-) {'perturbing_action': 'B-gene loss-of-function'}" + ], + "LINK_DATA": [ + "46, FoxO1 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "47, ablation ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "49, pro-opiomelanocortin ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "50, (Pomc)-expressing ['l2', 'l8', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "51, neurons ['l3', 'l9', 'l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "53, mice ['l4', 'l10', 'l15', 'l20', 'l24', 'l28', 'l29']", + "56, Pomc-Foxo1(-/-) ['l5', 'l11', 'l16', 'l21', 'l25', 'l28', 'l30', 'l31']", + "95, Pomc-Foxo1(-/-) ['l17', 'l22', 'l26', 'l30', 'l32']", + "96, mice. ['l6', 'l12', 'l18', 'l23', 'l27', 'l29', 'l31', 'l32']", + "109, FoxO1 ['l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "110, deletion ['l33', 'l41', 'l42', 'l43', 'l44', 'l45']", + "119, moderate ['l34', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "120, Cpe ['l35', 'l46', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "121, overexpression ['l36', 'l41', 'l47', 'l53', 'l59', 'l60', 'l61', 'l62', 'l63']", + "124, arcuate ['l37', 'l42', 'l48', 'l54', 'l59', 'l64', 'l65', 'l66']", + "125, nucleus ['l38', 'l43', 'l49', 'l55', 'l60', 'l64', 'l67', 'l68']", + "130, FoxO1 ['l39', 'l44', 'l50', 'l56', 'l61', 'l65', 'l67', 'l69']", + "131, mutation. ['l40', 'l45', 'l51', 'l57', 'l62', 'l66', 'l68', 'l69']", + "141, Pomc-Foxo1(-/-) ['l52', 'l58', 'l63']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FoxO1", + "ablation", + "(Pomc)-expressing", + "Pomc-Foxo1(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "pro-opiomelanocortin", + "(Pomc)-expressing", + "neurons" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FoxO1", + "ablation", + "(Pomc)-expressing", + "Pomc-Foxo1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FoxO1", + "deletion" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "arcuate", + "nucleus" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "moderate", + "Cpe", + "overexpression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "arcuate", + "nucleus" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "arcuate", + "nucleus" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "FoxO1", + "mutation." + ] + } + } + ] + }, + { + "PMID": "19734861", + "TEXT": "How do you sequence a virus that no one has identified before? With the right technology, it's not as difficult a task as it might seem, says Ian Lipkin, director of the Center for Infection and Immunity at Columbia University's Mailman School of Public Health. Lipkin has been working on the technology involved with viral discovery since the late 1980s, when he became the first researcher to identify a microbe using only molecular tools. He and the Center's team of about 50 researchers have identified close to 200 new viruses so far. Most recently, Lipkin and his colleague Thomas Briese identified a new hemorrhagic fever virus that killed several patients in southern Africa last year. Now, in addition to processing samples from around the world, Lipkin has been working to export his sequencing technology-and the expertise needed to use it-to the developing world. Erica Westly spoke with Lipkin about how the viral discovery techniques he uses could help prevent future viral disease outbreaks, from swine flu to the unknown.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19718040", + "TEXT": "Here we show that ischemia induces sustained contraction of pericytes on microvessels in the intact mouse brain. Pericytes remain contracted despite successful reopening of the middle cerebral artery after 2 h of ischemia. Pericyte contraction causes capillary constriction and obstructs erythrocyte flow. Suppression of oxidative-nitrative stress relieves pericyte contraction, reduces erythrocyte entrapment and restores microvascular patency; hence, tissue survival improves. In contrast, peroxynitrite application causes pericyte contraction. We also show that the microvessel wall is the major source of oxygen and nitrogen radicals causing ischemia and reperfusion-induced microvascular dysfunction. These findings point to a major but previously not recognized pathophysiological mechanism; ischemia and reperfusion-induced injury to pericytes may impair microcirculatory reflow and negatively affect survival by limiting substrate and drug delivery to tissue already under metabolic stress, despite recanalization of an occluded artery. Agents that can restore pericyte dysfunction and microvascular patency may increase the success of thrombolytic and neuroprotective treatments.", + "TAG_DATA": [ + "9, pericytes {'context': 'B-cells'}", + "14, intact {'context': 'B-tissue/organ'}", + "15, mouse {'context': 'I-tissue/organ'}", + "16, brain. {'context': 'I-tissue/organ'}", + "17, Pericytes {'context': 'B-cells'}", + "26, cerebral {'context': 'I-tissue/organ'}", + "33, Pericyte {'context': 'B-cells'}", + "47, pericyte {'context': 'B-cells'}", + "65, pericyte {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "9, pericytes ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "14, intact ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "15, mouse ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "16, brain. ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "17, Pericytes ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "26, cerebral ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "33, Pericyte ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "47, pericyte ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19701203", + "TEXT": "Recent work has shown that primary cilia are essential for Hedgehog (Hh) signaling during mammalian development. It is also known that aberrant Hh signaling can lead to cancer, but the role of primary cilia in oncogenesis is not known. Cerebellar granule neuron precursors (GNPs) can give rise to medulloblastomas, the most common malignant brain tumor in children. The primary cilium and Hh signaling are required for GNP proliferation. We asked whether primary cilia in GNPs have a role in medulloblastoma growth in mice. Genetic ablation of primary cilia blocked medulloblastoma formation when this tumor was driven by a constitutively active Smoothened protein (Smo), an upstream activator of Hh signaling. In contrast, removal of cilia was required for medulloblastoma growth by a constitutively active glioma-associated oncogene family zinc finger-2 (GLI2), a downstream transcription factor. Thus, primary cilia are either required for or inhibit medulloblastoma formation, depending on the initiating oncogenic event. Remarkably, the presence or absence of cilia was associated with specific variants of human medulloblastomas; primary cilia were found in medulloblastomas with activation in HH or WNT signaling but not in most medulloblastomas in other distinct molecular subgroups. Primary cilia could serve as a diagnostic tool and provide new insights into the mechanism of tumorigenesis.", + "TAG_DATA": [ + "83, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "84, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "85, of {'perturbing_action': 'I-gene loss-of-function'}", + "86, primary {'perturbing_action': 'I-gene loss-of-function'}", + "87, cilia {'perturbing_action': 'I-gene loss-of-function'}", + "88, blocked {'effect': 'B-negative'}", + "89, medulloblastoma {'phenotype': 'B-tumourigenesis'}", + "90, formation {'phenotype': 'I-tumourigenesis'}", + "93, tumor {'context': 'B-neoplasm'}", + "98, constitutively {'perturbing_action': 'B-gene gain-of-function'}", + "117, medulloblastoma {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}" + ], + "LINK_DATA": [ + "83, Genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "84, ablation ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "85, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "86, primary ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "87, cilia ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "88, blocked ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37']", + "89, medulloblastoma ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l39']", + "90, formation ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l38']", + "93, tumor ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l39', 'l40']", + "98, constitutively ['l8', 'l16', 'l23', 'l29', 'l34', 'l40']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "ablation", + "of", + "primary", + "cilia" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "ablation", + "of", + "primary", + "cilia" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "medulloblastoma", + "formation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "ablation", + "of", + "primary", + "cilia" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "medulloblastoma", + "formation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "medulloblastoma" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutively" + ] + } + } + ] + }, + { + "PMID": "19668192", + "TEXT": "Disruption of the precise balance of positive and negative molecular regulators of blood and lymphatic vessel growth can lead to myriad diseases. Although dozens of natural inhibitors of hemangiogenesis have been identified, an endogenous selective inhibitor of lymphatic vessel growth has not to our knowledge been previously described. We report the existence of a splice variant of the gene encoding vascular endothelial growth factor receptor-2 (Vegfr-2) that encodes a secreted form of the protein, designated soluble Vegfr-2 (sVegfr-2), that inhibits developmental and reparative lymphangiogenesis by blocking Vegf-c function. Tissue-specific loss of sVegfr-2 in mice induced, at birth, spontaneous lymphatic invasion of the normally alymphatic cornea and hyperplasia of skin lymphatics without affecting blood vasculature. Administration of sVegfr-2 inhibited lymphangiogenesis but not hemangiogenesis induced by corneal suture injury or transplantation, enhanced corneal allograft survival and suppressed lymphangioma cellular proliferation. Naturally occurring sVegfr-2 thus acts as a molecular uncoupler of blood and lymphatic vessels; modulation of sVegfr-2 might have therapeutic effects in treating lymphatic vascular malformations, transplantation rejection and, potentially, tumor lymphangiogenesis and lymphedema (pages 993-994).", + "TAG_DATA": [ + "88, Tissue-specific {'perturbing_action': 'B-gene loss-of-function'}", + "89, loss {'perturbing_action': 'I-gene loss-of-function'}", + "90, of {'perturbing_action': 'I-gene loss-of-function'}", + "91, sVegfr-2 {'perturbing_action': 'I-gene loss-of-function'}", + "93, mice {'context': 'B-organism'}", + "130, corneal {'context': 'B-xenograft'}", + "131, allograft {'context': 'I-xenograft'}", + "134, suppressed {'effect': 'B-negative'}", + "135, lymphangioma {'context': 'B-neoplasm'}", + "136, cellular {'context': 'I-transformed cells', 'phenotype': 'B-proliferation'}", + "137, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "88, Tissue-specific ['l0', 'l1', 'l2', 'l3']", + "89, loss ['l0', 'l4', 'l5', 'l6']", + "90, of ['l1', 'l4', 'l7', 'l8']", + "91, sVegfr-2 ['l2', 'l5', 'l7', 'l9']", + "93, mice ['l3', 'l6', 'l8', 'l9']", + "130, corneal ['l10', 'l11', 'l12', 'l13', 'l14']", + "131, allograft ['l10', 'l15', 'l16', 'l17', 'l18']", + "134, suppressed ['l11', 'l15', 'l19', 'l20', 'l21']", + "135, lymphangioma ['l12', 'l16', 'l19', 'l22', 'l23']", + "136, cellular ['l13', 'l17', 'l20', 'l22', 'l24']", + "137, proliferation. ['l14', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tissue-specific", + "loss", + "of", + "sVegfr-2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "corneal", + "allograft" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "corneal", + "allograft" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cellular", + "proliferation." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "cellular" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cellular" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lymphangioma" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cellular" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cellular", + "proliferation." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "lymphangioma" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cellular", + "proliferation." + ] + } + } + ] + }, + { + "PMID": "19648930", + "TEXT": "To explore the mechanism by which herpes simplex virus (HSV)-2 infection is related to HIV-1 acquisition, we conducted in situ analysis of the cellular infiltrate from sequential biopsies of HSV-2 lesions from patients on and off antiviral therapy. CD4(+) and CD8(+) T cells and a mixed population of plasmacytoid and myeloid dendritic cells (DCs), including cells expressing the C-type lectin receptor DC-SIGN, persisted at sites of HSV-2 reactivation for months after healing, even with daily antiviral therapy. The CD4(+) T cells that persisted reacted to HSV-2 antigen, were enriched for expression of the chemokine receptor CCR5, and were contiguous to DCs expressing the interleukin-3 receptor CD123 or DC-SIGN. Ex vivo infection with a CCR5-tropic strain of HIV-1 revealed greater concentrations of integrated HIV-1 DNA in cells derived from healed genital lesion biopsies than in cells from control skin biopsies. The persistence and enrichment of HIV receptor-positive inflammatory cells in the genitalia help explain the inability of anti-HSV-2 therapy to reduce HIV acquisition.", + "TAG_DATA": [ + "38, CD4(+) {'context': 'B-cells'}", + "39, and {'context': 'I-cells'}", + "40, CD8(+) {'context': 'I-cells'}", + "41, T {'context': 'I-cells'}", + "42, cells {'context': 'I-cells'}", + "48, plasmacytoid {'context': 'B-cells'}", + "49, and {'context': 'I-cells'}", + "50, myeloid {'context': 'I-cells'}", + "51, dendritic {'context': 'I-cells'}", + "52, cells {'context': 'I-cells'}", + "53, (DCs), {'context': 'I-cells'}", + "55, cells {'context': 'B-cells'}", + "78, CD4(+) {'context': 'B-cells'}", + "79, T {'context': 'I-cells'}", + "80, cells {'context': 'I-cells'}", + "100, DCs {'context': 'B-cells'}", + "125, cells {'context': 'B-cells'}", + "134, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "38, CD4(+) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "39, and ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "40, CD8(+) ['l1', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "41, T ['l2', 'l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "42, cells ['l3', 'l14', 'l23', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "48, plasmacytoid ['l4', 'l15', 'l24', 'l32', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "49, and ['l5', 'l16', 'l25', 'l33', 'l40', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "50, myeloid ['l6', 'l17', 'l26', 'l34', 'l41', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "51, dendritic ['l7', 'l18', 'l27', 'l35', 'l42', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "52, cells ['l8', 'l19', 'l28', 'l36', 'l43', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "53, (DCs), ['l9', 'l20', 'l29', 'l37', 'l44', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "55, cells ['l10', 'l21', 'l30', 'l38', 'l45', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "78, CD4(+) ['l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89', 'l90']", + "79, T ['l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l91', 'l92']", + "80, cells ['l11', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l91', 'l93']", + "100, DCs ['l90', 'l92', 'l93']", + "113, CCR5-tropic ['l94', 'l95']", + "125, cells ['l94', 'l96']", + "134, cells ['l95', 'l96']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19648929", + "TEXT": "Lymphocyte recruitment and activation have been implicated in the progression of cerebral ischemia-reperfusion (I/R) injury, but the roles of specific lymphocyte subpopulations and cytokines during stroke remain to be clarified. Here we demonstrate that the infiltration of T cells into the brain, as well as the cytokines interleukin-23 (IL-23) and IL-17, have pivotal roles in the evolution of brain infarction and accompanying neurological deficits. Blockade of T cell infiltration into the brain by the immunosuppressant FTY720 reduced I/R-induced brain damage. The expression of IL-23, which was derived mostly from infiltrated macrophages, increased on day 1 after I/R, whereas IL-17 levels were elevated after day 3, and this induction of IL-17 was dependent on IL-23. These data, together with analysis of mice genetically disrupted for IL-17 and IL-23, suggest that IL-23 functions in the immediate stage of I/R brain injury, whereas IL-17 has an important role in the delayed phase of I/R injury during which apoptotic neuronal death occurs in the penumbra. Intracellular cytokine staining revealed that gammadeltaT lymphocytes, but not CD4(+) helper T cells, were a major source of IL-17. Moreover, depletion of gammadeltaT lymphocytes ameliorated the I/R injury. We propose that T lymphocytes, including gammadeltaT lymphocytes, could be a therapeutic target for mitigating the inflammatory events that amplify the initial damage in cerebral ischemia.", + "TAG_DATA": [ + "78, brain {'context': 'B-tissue/organ'}", + "120, mice {'context': 'B-organism'}", + "121, genetically {'perturbing_action': 'I-gene loss-of-function'}", + "122, disrupted {'perturbing_action': 'I-gene loss-of-function'}", + "166, gammadeltaT {'context': 'B-cells'}", + "167, lymphocytes, {'context': 'I-cells'}", + "170, CD4(+) {'context': 'B-cells'}", + "171, helper {'context': 'I-cells'}", + "172, T {'context': 'I-cells'}", + "173, cells, {'context': 'I-cells'}", + "183, gammadeltaT {'context': 'B-cells'}", + "184, lymphocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "120, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "121, genetically ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "122, disrupted ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "166, gammadeltaT ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "167, lymphocytes, ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "170, CD4(+) ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32', 'l33']", + "171, helper ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l34', 'l35', 'l36']", + "172, T ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l34', 'l37']", + "173, cells, ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l35', 'l37']", + "183, gammadeltaT ['l38']", + "184, lymphocytes ['l33', 'l36', 'l38']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetically", + "disrupted" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetically", + "disrupted" + ] + }, + "context": { + "val": "cells", + "words": [ + "gammadeltaT", + "lymphocytes,", + "CD4(+)", + "helper", + "T", + "cells," + ] + } + } + ] + }, + { + "PMID": "19633657", + "TEXT": "Obesity and its associated metabolic syndromes represent a growing global challenge, yet mechanistic understanding of this pathology and current therapeutics are unsatisfactory. We discovered that CD4(+) T lymphocytes, resident in visceral adipose tissue (VAT), control insulin resistance in mice with diet-induced obesity (DIO). Analyses of human tissue suggest that a similar process may also occur in humans. DIO VAT-associated T cells show severely biased T cell receptor V(alpha) repertoires, suggesting antigen-specific expansion. CD4(+) T lymphocyte control of glucose homeostasis is compromised in DIO progression, when VAT accumulates pathogenic interferon-gamma (IFN-gamma)-secreting T helper type 1 (T(H)1) cells, overwhelming static numbers of T(H)2 (CD4(+)GATA-binding protein-3 (GATA-3)(+)) and regulatory forkhead box P3 (Foxp3)(+) T cells. CD4(+) (but not CD8(+)) T cell transfer into lymphocyte-free Rag1-null DIO mice reversed weight gain and insulin resistance, predominantly through T(H)2 cells. In obese WT and ob/ob (leptin-deficient) mice, brief treatment with CD3-specific antibody or its F(ab')(2) fragment, reduces the predominance of T(H)1 cells over Foxp3(+) cells, reversing insulin resistance for months, despite continuation of a high-fat diet. Our data suggest that the progression of obesity-associated metabolic abnormalities is under the pathophysiological control of CD4(+) T cells. The eventual failure of this control, with expanding adiposity and pathogenic VAT T cells, can successfully be reversed by immunotherapy.", + "TAG_DATA": [ + "116, T {'context': 'I-cells'}", + "120, lymphocyte-free {'perturbing_action': 'B-gene loss-of-function'}", + "121, Rag1-null {'perturbing_action': 'B-gene loss-of-function'}", + "123, mice {'context': 'B-organism'}", + "132, T(H)2 {'context': 'B-cells'}", + "133, cells. {'context': 'I-cells'}", + "138, ob/ob {'perturbing_action': 'B-gene loss-of-function'}", + "139, (leptin-deficient) {'perturbing_action': 'I-gene loss-of-function'}", + "140, mice, {'context': 'B-organism'}", + "154, T(H)1 {'context': 'B-cells'}", + "155, cells {'context': 'I-cells'}", + "157, Foxp3(+) {'context': 'B-cells'}", + "158, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "113, (but ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "116, T ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "120, lymphocyte-free ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "121, Rag1-null ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "123, mice ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "132, T(H)2 ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "133, cells. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "136, WT ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "138, ob/ob ['l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "139, (leptin-deficient) ['l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "140, mice, ['l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "154, T(H)1 ['l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "155, cells ['l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "157, Foxp3(+) ['l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "158, cells, ['l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "T(H)2", + "cells.", + "T(H)1", + "cells", + "Foxp3(+)", + "cells," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lymphocyte-free", + "Rag1-null", + "ob/ob", + "(leptin-deficient)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lymphocyte-free", + "Rag1-null", + "ob/ob", + "(leptin-deficient)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + } + ] + }, + { + "PMID": "19633656", + "TEXT": "Obesity is accompanied by chronic, low-grade inflammation of adipose tissue, which promotes insulin resistance and type-2 diabetes. These findings raise the question of how fat inflammation can escape the powerful armamentarium of cells and molecules normally responsible for guarding against a runaway immune response. CD4(+) Foxp3(+) T regulatory (T(reg)) cells with a unique phenotype were highly enriched in the abdominal fat of normal mice, but their numbers were strikingly and specifically reduced at this site in insulin-resistant models of obesity. Loss-of-function and gain-of-function experiments revealed that these T(reg) cells influenced the inflammatory state of adipose tissue and, thus, insulin resistance. Cytokines differentially synthesized by fat-resident regulatory and conventional T cells directly affected the synthesis of inflammatory mediators and glucose uptake by cultured adipocytes. These observations suggest that harnessing the anti-inflammatory properties of T(reg) cells to inhibit elements of the metabolic syndrome may have therapeutic potential.", + "TAG_DATA": [ + "87, T(reg) {'context': 'B-cells'}", + "88, cells {'context': 'I-cells'}", + "122, adipocytes. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "87, T(reg) ['l0']", + "88, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19633655", + "TEXT": "Although mast cell functions have classically been related to allergic responses, recent studies indicate that these cells contribute to other common diseases such as multiple sclerosis, rheumatoid arthritis, atherosclerosis, aortic aneurysm and cancer. This study presents evidence that mast cells also contribute to diet-induced obesity and diabetes. For example, white adipose tissue (WAT) from obese humans and mice contain more mast cells than WAT from their lean counterparts. Furthermore, in the context of mice on a Western diet, genetically induced deficiency of mast cells, or their pharmacological stabilization, reduces body weight gain and levels of inflammatory cytokines, chemokines and proteases in serum and WAT, in concert with improved glucose homeostasis and energy expenditure. Mechanistic studies reveal that mast cells contribute to WAT and muscle angiogenesis and associated cell apoptosis and cathepsin activity. Adoptive transfer experiments of cytokine-deficient mast cells show that these cells, by producing interleukin-6 (IL-6) and interferon-gamma (IFN-gamma), contribute to mouse adipose tissue cysteine protease cathepsin expression, apoptosis and angiogenesis, thereby promoting diet-induced obesity and glucose intolerance. Our results showing reduced obesity and diabetes in mice treated with clinically available mast cell-stabilizing agents suggest the potential of developing new therapies for these common human metabolic disorders.", + "TAG_DATA": [ + "73, mice {'context': 'B-organism'}", + "80, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "82, mast {'context': 'B-cells'}", + "83, cells, {'context': 'I-cells'}", + "128, apoptosis {'phenotype': 'B-apoptosis'}", + "136, cytokine-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "137, mast {'context': 'B-cells'}", + "138, cells {'context': 'I-cells'}", + "142, cells, {'context': 'B-cells'}", + "152, mouse {'context': 'B-tissue/organ'}", + "153, adipose {'context': 'I-tissue/organ'}", + "154, tissue {'context': 'I-tissue/organ'}", + "159, apoptosis {'phenotype': 'B-apoptosis'}", + "177, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, mice ['l0']", + "80, deficiency ['l1', 'l2', 'l3']", + "82, mast ['l1', 'l4', 'l5']", + "83, cells, ['l0', 'l2', 'l4', 'l6']", + "128, apoptosis ['l3', 'l5', 'l6']", + "136, cytokine-deficient ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "137, mast ['l7', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "138, cells ['l8', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "142, cells, ['l9', 'l15', 'l20', 'l25', 'l26', 'l27', 'l28']", + "152, mouse ['l10', 'l16', 'l21', 'l25', 'l29', 'l30', 'l31']", + "153, adipose ['l11', 'l17', 'l22', 'l26', 'l29', 'l32', 'l33']", + "154, tissue ['l12', 'l18', 'l23', 'l27', 'l30', 'l32', 'l34']", + "159, apoptosis ['l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l34']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "cytokine-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "mast", + "cells,", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "cytokine-deficient" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mast", + "cells,", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cytokine-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "adipose", + "tissue" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "adipose", + "tissue" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "19620962", + "TEXT": "The mechanisms underlying possible increased HIV-1 acquisition in adenovirus 5 (Ad5)-seropositive subjects vaccinated with Ad5-HIV-1 vectors in the Merck STEP trial remain unclear. We find that Ad5 serostatus does not predict Ad5-specific CD4(+) T cell frequency, and we did not observe durable significant differences in Ad5-specific CD4(+) T cells between Ad5-seropositive and Ad5-seronegative subjects after vaccination. These findings indicate no causative role for Ad5-specific CD4(+) T cells in increasing HIV-1 susceptibility in the STEP trial.", + "TAG_DATA": [ + "46, CD4(+) {'context': 'I-cells'}", + "47, T {'context': 'I-cells'}", + "48, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "46, CD4(+) ['l0', 'l1']", + "47, T ['l0', 'l2']", + "48, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19597506", + "TEXT": "Imaging agents that enable direct visualization and quantification of apoptosis in vivo have great potential value for monitoring chemotherapeutic response as well as for early diagnosis and disease monitoring. We describe here the development of fluorescently labeled activity-based probes (ABPs) that covalently label active caspases in vivo. We used these probes to monitor apoptosis in the thymi of mice treated with dexamethasone as well as in tumor-bearing mice treated with the apoptosis-inducing monoclonal antibody Apomab (Genentech). Caspase ABPs provided direct readouts of the kinetics of apoptosis in live mice, whole organs and tissue extracts. The probes produced a maximum fluorescent signal that could be monitored noninvasively and that coincided with the peak in caspase activity, as measured by gel analysis. Overall, these studies demonstrate that caspase-specific ABPs have the potential to be used for noninvasive imaging of apoptosis in both preclinical and clinical settings.", + "TAG_DATA": [ + "53, apoptosis {'phenotype': 'B-apoptosis'}", + "56, thymi {'context': 'B-tissue/organ'}", + "58, mice {'context': 'B-organism'}", + "66, tumor-bearing {'context': 'B-organism'}", + "67, mice {'context': 'I-organism'}", + "85, apoptosis {'phenotype': 'B-apoptosis'}", + "88, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "53, apoptosis ['l0', 'l1']", + "56, thymi ['l0', 'l2']", + "58, mice ['l1', 'l2']", + "66, tumor-bearing ['l3', 'l4', 'l5']", + "67, mice ['l3', 'l6', 'l7']", + "85, apoptosis ['l4', 'l6', 'l8']", + "88, mice, ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "thymi" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "tumor-bearing", + "mice," + ] + } + } + ] + }, + { + "PMID": "19584859", + "TEXT": "Manipulation of cell renewal pathways creates T memory stem cells that can generate a sustained and targeted immune response. These findings have broad implications for vaccine development and immunotherapy.", + "TAG_DATA": [ + "6, T {'context': 'B-cells'}", + "7, memory {'context': 'I-cells'}", + "8, stem {'context': 'I-cells'}", + "9, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "6, T ['l0', 'l1', 'l2']", + "7, memory ['l0', 'l3', 'l4']", + "8, stem ['l1', 'l3', 'l5']", + "9, cells ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19561618", + "TEXT": "Uncontrolled T helper type 1 (T(H)1) and T(H)17 cells are associated with autoimmune responses. We identify surface lymphotoxin-alpha (LT-alpha) as common to T(H)0, T(H)1 and T(H)17 cells and employ a unique strategy to target these subsets using a depleting monoclonal antibody (mAb) directed to surface LT-alpha. Depleting LT-alpha-specific mAb inhibited T cell-mediated models of delayed-type hypersensitivity and experimental autoimmune encephalomyelitis. In collagen-induced arthritis (CIA), preventive and therapeutic administration of LT-alpha-specific mAb inhibited disease, and immunoablated T cells expressing interleukin-17 (IL-17), interferon-gamma and tumor necrosis factor-alpha (TNF-alpha), whereas decoy lymphotoxin-beta receptor (LT-betaR) fusion protein had no effect. A mutation in the Fc tail, rendering the antibody incapable of Fcgamma receptor binding and antibody-dependent cellular cytotoxicity activity, abolished all in vivo effects. Efficacy in CIA was preceded by a loss of rheumatoid-associated cytokines IL-6, IL-1beta and TNF-alpha within joints. These data indicate that depleting LT-alpha-expressing lymphocytes with LT-alpha-specific mAb may be beneficial in the treatment of autoimmune disease.", + "TAG_DATA": [ + "75, T {'context': 'B-cells'}", + "76, cells {'context': 'I-cells'}", + "97, mutation {'perturbing_action': 'B-other'}", + "98, in {'perturbing_action': 'I-other'}", + "99, the {'perturbing_action': 'I-other'}", + "100, Fc {'perturbing_action': 'I-other'}", + "101, tail, {'perturbing_action': 'I-other'}", + "117, in {'context': 'B-in vivo'}", + "118, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "75, T ['l0']", + "76, cells ['l0']", + "97, mutation ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "98, in ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "99, the ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "100, Fc ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "101, tail, ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "117, in ['l5', 'l11', 'l16', 'l20', 'l23', 'l26']", + "118, vivo ['l6', 'l12', 'l17', 'l21', 'l24', 'l26']", + "136, joints. ['l7', 'l13', 'l18', 'l22', 'l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "in", + "the", + "Fc", + "tail," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "19561617", + "TEXT": "Although there have been major advances in the treatment of rheumatoid arthritis with the advent of biological agents, the mechanisms that drive cytokine production and sustain disease chronicity remain unknown. Tenascin-C (encoded by Tnc) is an extracellular matrix glycoprotein specifically expressed at areas of inflammation and tissue damage in inflamed rheumatoid joints. Here we show that mice that do not express tenascin-C show rapid resolution of acute joint inflammation and are protected from erosive arthritis. Intra-articular injection of tenascin-C promotes joint inflammation in vivo in mice, and addition of exogenous tenascin-C induces cytokine synthesis in explant cultures from inflamed synovia of individuals with rheumatoid arthritis. Moreover, in human macrophages and fibroblasts from synovia of individuals with rheumatoid arthritis, tenascin-C induces synthesis of proinflammatory cytokines via activation of Toll-like receptor 4 (TLR4). Thus, we have identified tenascin-C as a novel endogenous activator of TLR4-mediated immunity that mediates persistent synovial inflammation and tissue destruction in arthritic joint disease.", + "TAG_DATA": [ + "56, mice {'context': 'B-organism'}", + "82, in {'context': 'B-in vivo'}", + "83, vivo {'context': 'I-in vivo'}", + "85, mice, {'context': 'B-organism'}", + "95, explant {'context': 'B-in vitro'}", + "96, cultures {'context': 'I-cells'}", + "99, synovia {'context': 'I-tissue/organ'}", + "107, human {'context': 'B-cells'}", + "108, macrophages {'context': 'I-cells'}", + "110, fibroblasts {'context': 'B-cells'}", + "111, from {'context': 'I-cells'}", + "112, synovia {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "56, mice ['l0', 'l1', 'l2']", + "82, in ['l0', 'l3', 'l4']", + "83, vivo ['l1', 'l3', 'l5']", + "85, mice, ['l2', 'l4', 'l5']", + "95, explant ['l6', 'l7']", + "96, cultures ['l6', 'l8']", + "99, synovia ['l7', 'l8']", + "107, human ['l9', 'l10', 'l11', 'l12']", + "108, macrophages ['l9', 'l13', 'l14', 'l15']", + "110, fibroblasts ['l10', 'l13', 'l16', 'l17']", + "111, from ['l11', 'l14', 'l16', 'l18']", + "112, synovia ['l12', 'l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19525966", + "TEXT": "Pain is one of the most severe and debilitating symptoms associated with several forms of cancer. Various types of carcinomas and sarcomas metastasize to skeletal bones and cause spontaneous bone pain and hyperalgesia, which is accompanied by bone degradation and remodeling of peripheral nerves. Despite recent advances, the molecular mechanisms underlying the development and maintenance of cancer-evoked pain are not well understood. Several types of non-hematopoietic tumors secrete hematopoietic colony-stimulating factors that act on myeloid cells and tumor cells. Here we report that receptors and signaling mediators of granulocyte- and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF) are also functionally expressed on sensory nerves. GM-CSF sensitized nerves to mechanical stimuli in vitro and in vivo, potentiated CGRP release and caused sprouting of sensory nerve endings in the skin. Interruption of G-CSF and GM-CSF signaling in vivo led to reduced tumor growth and nerve remodeling, and abrogated bone cancer pain. The key significance of GM-CSF signaling in sensory neurons was revealed by an attenuation of tumor-evoked pain following a sensory nerve-specific knockdown of GM-CSF receptors. These results show that G-CSF and GM-CSF are important in tumor-nerve interactions and suggest that their receptors on primary afferent nerve fibers constitute potential therapeutic targets in cancer pain.", + "TAG_DATA": [ + "105, nerves {'context': 'B-cells'}", + "109, in {'context': 'B-in vitro'}", + "110, vitro {'context': 'I-in vitro'}", + "112, in {'context': 'B-in vivo'}", + "113, vivo, {'context': 'I-in vivo'}", + "121, sensory {'context': 'B-cells'}", + "122, nerve {'context': 'I-cells'}", + "123, endings {'context': 'I-cells'}", + "126, skin. {'context': 'B-tissue/organ'}", + "133, in {'context': 'B-in vivo'}", + "134, vivo {'context': 'I-in vivo'}", + "137, reduced {'effect': 'B-negative'}", + "138, tumor {'phenotype': 'B-tumour growth'}", + "139, growth {'phenotype': 'I-tumour growth'}", + "145, bone {'context': 'B-neoplasm'}", + "167, sensory {'perturbing_action': 'B-rnai/knockdown'}", + "168, nerve-specific {'perturbing_action': 'I-rnai/knockdown'}", + "169, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "170, of {'perturbing_action': 'I-rnai/knockdown'}", + "171, GM-CSF {'perturbing_action': 'I-rnai/knockdown'}", + "172, receptors. {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "105, nerves ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "109, in ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "110, vitro ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "112, in ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "113, vivo, ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "121, sensory ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "122, nerve ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "123, endings ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "126, skin. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "133, in ['l36', 'l37', 'l38', 'l39', 'l40']", + "134, vivo ['l36', 'l41', 'l42', 'l43', 'l44']", + "137, reduced ['l37', 'l41', 'l45', 'l46', 'l47']", + "138, tumor ['l38', 'l42', 'l45', 'l48', 'l49']", + "139, growth ['l39', 'l43', 'l46', 'l48', 'l50']", + "145, bone ['l40', 'l44', 'l47', 'l49', 'l50']", + "167, sensory ['l51', 'l52', 'l53', 'l54', 'l55']", + "168, nerve-specific ['l51', 'l56', 'l57', 'l58', 'l59']", + "169, knockdown ['l52', 'l56', 'l60', 'l61', 'l62']", + "170, of ['l53', 'l57', 'l60', 'l63', 'l64']", + "171, GM-CSF ['l54', 'l58', 'l61', 'l63', 'l65']", + "172, receptors. ['l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "bone" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "bone" + ] + } + } + ] + }, + { + "PMID": "19503064", + "TEXT": "Central nervous system nutrient sensing and afferent endocrine signaling have been established as parallel systems communicating metabolic status and energy availability in vertebrates. The only afferent endocrine signal known to require modification with a fatty acid side chain is the orexigenic hormone ghrelin. We find that the ghrelin O-acyl transferase (GOAT), which is essential for ghrelin acylation, is regulated by nutrient availability, depends on specific dietary lipids as acylation substrates and links ingested lipids to energy expenditure and body fat mass. These data implicate the ghrelin-GOAT system as a signaling pathway that alerts the central nervous system to the presence of dietary calories, rather than to their absence as is commonly accepted.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19483695", + "TEXT": "Type I interferons (IFNs), a family of cytokines, orchestrate numerous biological and cellular processes1, 2, 3. Although it is well known that type I IFNs are essential for establishing the host antiviral state4, their role in hematopoietic homeostasis has not been studied. Here we show that type I IFNs induce proliferation and exhaustion in hematopoietic stem cells (HSCs) and that interferon regulatory factor-2 (IRF2), a transcriptional suppressor of type I IFN signaling5, 6, preserves the self-renewal and multilineage differentiation capacity of HSCs. HSCs were substantially less abundant in the bone marrow of Irf2-/- as compared to Irf2+/- mice. Irf2-/- HSCs showed enhanced cell cycling status and failed to produce hematopoietic cells in competitive repopulation assays, and the reconstituting capacity of Irf2-/- HSCs was restored by disabling type I IFN signaling in these cells. In wild-type mice, injection of poly(I:C), an inducer of type I IFN signaling, or IFN- induced HSC proliferation, and chronic type I IFN signaling further reduced the number of quiescent HSCs. Notably, combined poly(I:C) and 5-fluorouracil (5-FU) treatment allowed exogenous HSC engraftment and hematopoietic reconstitution in WT mice. Our findings provide insight into the molecular basis for the maintenance of HSC quiescence and may lead to improvements in bone marrow transplantation and type I IFN-based therapies for viral infection and cancer.", + "TAG_DATA": [ + "92, Irf2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "96, Irf2+/- {'perturbing_action': 'B-gene loss-of-function'}", + "97, mice. {'context': 'B-organism'}", + "98, Irf2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "99, HSCs {'context': 'B-cells'}", + "109, hematopoietic {'context': 'B-cells'}", + "110, cells {'context': 'I-cells'}", + "120, Irf2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "121, HSCs {'context': 'B-cells'}", + "132, cells. {'context': 'B-cells'}", + "135, mice, {'context': 'B-organism'}", + "147, IFN- {'effect': 'B-positive'}", + "148, induced {'effect': 'B-positive'}", + "149, HSC {'context': 'B-cells'}", + "150, proliferation, {'phenotype': 'B-proliferation'}", + "158, reduced {'effect': 'B-negative'}", + "162, quiescent {'phenotype': 'B-quiescence'}", + "163, HSCs. {'context': 'B-cells'}", + "173, HSC {'context': 'B-cells'}", + "180, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "92, Irf2-/- ['l0', 'l1', 'l2', 'l3']", + "96, Irf2+/- ['l0', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "97, mice. ['l1', 'l4', 'l11', 'l12']", + "98, Irf2-/- ['l5', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "99, HSCs ['l2', 'l6', 'l11', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "109, hematopoietic ['l7', 'l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "110, cells ['l3', 'l8', 'l12', 'l15', 'l20', 'l24', 'l28']", + "120, Irf2-/- ['l16', 'l21', 'l25', 'l29', 'l30']", + "121, HSCs ['l9', 'l17', 'l22', 'l26', 'l29', 'l31']", + "132, cells. ['l10', 'l18', 'l23', 'l27', 'l28', 'l30', 'l31']", + "135, mice, ['l32', 'l33', 'l34', 'l35', 'l36']", + "147, IFN- ['l32', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "148, induced ['l33', 'l37', 'l43', 'l44']", + "149, HSC ['l34', 'l38', 'l43', 'l45', 'l46', 'l47', 'l48']", + "150, proliferation, ['l35', 'l39', 'l44', 'l45']", + "158, reduced ['l40', 'l46', 'l49', 'l50']", + "162, quiescent ['l41', 'l47', 'l49', 'l51']", + "163, HSCs. ['l36', 'l42', 'l48', 'l50', 'l51']", + "173, HSC ['l52']", + "180, mice. ['l52']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Irf2-/-", + "Irf2+/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Irf2-/-", + "Irf2+/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSCs", + "cells", + "hematopoietic", + "cells." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "positive", + "words": [ + "IFN-", + "induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "IFN-", + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC", + "HSCs." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "IFN-", + "induced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "IFN-" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescent" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSC" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSC", + "HSCs." + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSC", + "HSCs." + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescent" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescent" + ] + } + } + ] + }, + { + "PMID": "19483693", + "TEXT": "Formation of new vessels in granulation tissue during wound healing has been assumed to occur solely through sprouting angiogenesis. In contrast, we show here that neovascularization can be accomplished by nonangiogenic expansion of preexisting vessels. Using neovascularization models based on the chick chorioallantoic membrane and the healing mouse cornea, we found that tissue tension generated by activated fibroblasts or myofibroblasts during wound contraction mediated and directed translocation of the vasculature. These mechanical forces pulled vessels from the preexisting vascular bed as vascular loops with functional circulation that expanded as an integral part of the growing granulation tissue through vessel enlargement and elongation. Blockade of vascular endothelial growth factor receptor-2 confirmed that biomechanical forces were sufficient to mediate the initial vascular growth independently of endothelial sprouting or proliferation. The neovascular network was further remodeled by splitting, sprouting and regression of individual vessels. This model explains the rapid appearance of large functional vessels in granulation tissue during wound healing.", + "TAG_DATA": [ + "47, mouse {'context': 'B-tissue/organ'}", + "48, cornea, {'context': 'I-tissue/organ'}", + "102, Blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "103, of {'perturbing_action': 'I-pharmacological inhibition'}", + "104, vascular {'perturbing_action': 'I-pharmacological inhibition'}", + "105, endothelial {'perturbing_action': 'I-pharmacological inhibition'}", + "106, growth {'perturbing_action': 'I-pharmacological inhibition'}", + "107, factor {'perturbing_action': 'I-pharmacological inhibition'}", + "108, receptor-2 {'perturbing_action': 'I-pharmacological inhibition'}", + "126, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "47, mouse ['l0']", + "48, cornea, ['l0']", + "102, Blockade ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "103, of ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "104, vascular ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "105, endothelial ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "106, growth ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "107, factor ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "108, receptor-2 ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "126, proliferation. ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "vascular", + "endothelial", + "growth", + "factor", + "receptor-2" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "19448636", + "TEXT": "Small-vessel vasculitis (SVV) is a chronic autoinflammatory condition linked to antineutrophil cytoplasm autoantibodies (ANCAs). Here we show that chromatin fibers, so-called neutrophil extracellular traps (NETs), are released by ANCA-stimulated neutrophils and contain the targeted autoantigens proteinase-3 (PR3) and myeloperoxidase (MPO). Deposition of NETs in inflamed kidneys and circulating MPO-DNA complexes suggest that NET formation triggers vasculitis and promotes the autoimmune response against neutrophil components in individuals with SVV.", + "TAG_DATA": [ + "45, kidneys {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19424209", + "TEXT": "The immune response goes haywire during sepsis, a deadly condition triggered by infection. Richard S. Hotchkiss and his colleagues take the focus off of the prevailing view that the key aspect of this response is an exuberant inflammatory reaction. They assess recent human studies bolstering the notion that immunosuppression is also a major contributor to the disease. Many people with sepsis succumb to cardiac dysfunction, a process examined by Peter Ward. He showcases the factors that cause cardiomyocyte contractility to wane during the disease.", + "TAG_DATA": [ + "77, cardiomyocyte {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19424205", + "TEXT": "Studies of schizophrenia have been plagued by shortcomings such as weak genetic association with disease, inadequate animal models and limited replication of gene expression findings. Future success may lie not in overcoming any one of these limitations but in a broad approach strengthening the evidence in each area. Using such an approach, neuroscientists have uncovered a new gene behind the disease (pages 509–518).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19412174", + "TEXT": "The side effects associated with tuberculosis therapy bring with them the risk of noncompliance and subsequent drug resistance. Increasing the therapeutic index of antituberculosis drugs should thus improve treatment effectiveness. Several antituberculosis compounds require in situ metabolic activation to become inhibitory. Various thiocarbamide-containing drugs, including ethionamide, are activated by the mycobacterial monooxygenase EthA, the production of which is controlled by the transcriptional repressor EthR. Here we identify drug-like inhibitors of EthR that boost the bioactivation of ethionamide. Compounds designed and screened for their capacity to inhibit EthR-DNA interaction were co-crystallized with EthR. We exploited the three-dimensional structures of the complexes for the synthesis of improved analogs that boosted the ethionamide potency in culture more than tenfold. In Mycobacterium tuberculosis-infected mice, one of these analogs, BDM31343, enabled a substantially reduced dose of ethionamide to lessen the mycobacterial load as efficiently as the conventional higher-dose treatment. This provides proof of concept that inhibiting EthR improves the therapeutic index of thiocarbamide derivatives, which should prompt reconsideration of their use as first-line drugs.", + "TAG_DATA": [ + "118, tuberculosis-infected {'context': 'I-organism'}", + "119, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "118, tuberculosis-infected ['l0']", + "119, mice, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19396175", + "TEXT": "Chromosome instability is a hallmark of tumorigenesis. This study establishes that chromosome instability is also common during early human embryogenesis. A new array-based method allowed screening of genome-wide copy number and loss of heterozygosity in single cells. This revealed not only mosaicism for whole-chromosome aneuploidies and uniparental disomies in most cleavage-stage embryos but also frequent segmental deletions, duplications and amplifications that were reciprocal in sister blastomeres, implying the occurrence of breakage-fusion-bridge cycles. This explains the low human fecundity and identifies post-zygotic chromosome instability as a leading cause of constitutional chromosomal disorders.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19396173", + "TEXT": "Specific inhibition of the entry of encephalitogenic T lymphocytes into the central nervous system in multiple sclerosis would provide a means of inhibiting disease without compromising innate immune responses. We show here that targeting lymphocyte interactions with endothelial basement membrane laminins provides such a possibility. In mouse experimental autoimmune encephalomyelitis, T lymphocyte extravasation correlates with sites expressing laminin alpha4 and small amounts of laminin alpha5. In mice lacking laminin alpha4, laminin alpha5 is ubiquitously expressed along the vascular tree, resulting in marked and selective reduction of T lymphocyte infiltration into the brain and reduced disease susceptibility and severity. Vessel phenotype and immune response were not affected in these mice. Rather, laminin alpha5 directly inhibited integrin alpha(6)beta(1)-mediated migration of T lymphocytes through laminin alpha4. The data indicate that T lymphocytes use mechanisms distinct from other immune cells to penetrate the endothelial basement membrane barrier, permitting specific targeting of this immune cell population.", + "TAG_DATA": [ + "66, mice {'context': 'B-organism'}", + "67, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "68, laminin {'perturbing_action': 'I-gene loss-of-function'}", + "69, alpha4, {'perturbing_action': 'I-gene loss-of-function'}", + "98, Vessel {'context': 'B-tissue/organ'}", + "108, mice. {'context': 'B-organism'}", + "113, inhibited {'effect': 'B-negative'}", + "116, migration {'phenotype': 'B-migration'}", + "118, T {'context': 'B-cells'}", + "119, lymphocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "66, mice ['l0', 'l1', 'l2']", + "67, lacking ['l0', 'l3', 'l4']", + "68, laminin ['l1', 'l3', 'l5']", + "69, alpha4, ['l2', 'l4', 'l5']", + "98, Vessel ['l6']", + "108, mice. ['l6']", + "113, inhibited ['l7', 'l8', 'l9']", + "116, migration ['l7', 'l10', 'l11']", + "118, T ['l8', 'l10', 'l12']", + "119, lymphocytes ['l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "laminin", + "alpha4," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "lymphocytes" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "lymphocytes" + ] + } + } + ] + }, + { + "PMID": "19377487", + "TEXT": "Here we describe the parametric response map (PRM), a voxel-wise approach for image analysis and quantification of hemodynamic alterations during treatment for 44 patients with high-grade glioma. Relative cerebral blood volume (rCBV) and flow (rCBF) maps were acquired before treatment and after 1 and 3 weeks of therapy. We compared the standard approach using region-of-interest analysis for change in rCBV or rCBF to the change in perfusion parameters on the basis of PRM (PRM(rCBV) and PRM(rCBF)) for their accuracy in predicting overall survival. Neither the percentage change of rCBV or rCBF predicted survival, whereas the regional response evaluations made on the basis of PRM were highly predictive of survival. Even when accounting for baseline rCBV, which is prognostic, PRM(rCBV) proved more predictive of overall survival.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19330010", + "TEXT": "Understanding the mechanisms of osteoclastogenesis is crucial for developing new drugs to treat diseases associated with bone loss, such as osteoporosis. Here we report that the C-C chemokine receptor-2 (CCR2) is crucially involved in balancing bone mass. CCR2-knockout mice have high bone mass owing to a decrease in number, size and function of osteoclasts. In normal mice, activation of CCR2 in osteoclast progenitor cells results in both nuclear factor-kappaB (NF-kappaB) and extracellular signal-related kinase 1 and 2 (ERK1/2) signaling but not that of p38 mitogen-activated protein kinase or c-Jun N-terminal kinase. The induction of NF-kappaB and ERK1/2 signaling in turn leads to increased surface expression of receptor activator of NF-kappaB (RANK, encoded by Tnfrsf11a), making the progenitor cells more susceptible to RANK ligand-induced osteoclastogenesis. In ovariectomized mice, a model of postmenopausal osteoporosis, CCR2 is upregulated on wild-type preosteoclasts, thus increasing the surface expression of RANK on these cells and their osteoclastogenic potential, whereas CCR2-knockout mice are resistant to ovariectomy-induced bone loss. These data reveal a previously undescribed pathway by which RANK, osteoclasts and bone homeostasis are regulated in health and disease.", + "TAG_DATA": [ + "37, CCR2-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "38, mice {'context': 'B-organism'}", + "55, normal {'context': 'B-organism'}", + "56, mice, {'context': 'I-organism'}", + "57, activation {'perturbing_action': 'B-pharmacological augmentation'}", + "58, of {'perturbing_action': 'I-pharmacological augmentation'}", + "59, CCR2 {'perturbing_action': 'I-pharmacological augmentation'}", + "61, osteoclast {'context': 'B-cells'}", + "62, progenitor {'context': 'I-cells'}", + "63, cells {'context': 'I-cells'}", + "116, progenitor {'context': 'B-cells'}", + "117, cells {'context': 'I-cells'}", + "126, mice, {'context': 'B-organism'}", + "153, CCR2-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "154, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "37, CCR2-knockout ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "38, mice ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "55, normal ['l1', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "56, mice, ['l2', 'l11', 'l18', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "57, activation ['l3', 'l12', 'l19', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "58, of ['l4', 'l13', 'l20', 'l27', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "59, CCR2 ['l5', 'l14', 'l21', 'l28', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "61, osteoclast ['l6', 'l15', 'l22', 'l29', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53']", + "62, progenitor ['l7', 'l16', 'l23', 'l30', 'l36', 'l42', 'l47', 'l51', 'l54', 'l55']", + "63, cells ['l8', 'l17', 'l24', 'l31', 'l37', 'l43', 'l48', 'l52', 'l54', 'l56']", + "116, progenitor ['l38', 'l44', 'l49', 'l57', 'l58']", + "117, cells ['l9', 'l25', 'l32', 'l39', 'l45', 'l50', 'l53', 'l55', 'l56', 'l57', 'l59']", + "126, mice, ['l58', 'l59']", + "153, CCR2-knockout ['l60']", + "154, mice ['l60']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CCR2-knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "normal", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CCR2-knockout" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast", + "progenitor", + "cells" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "normal", + "mice," + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "of", + "CCR2" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "of", + "CCR2" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast", + "progenitor", + "cells" + ] + } + } + ] + }, + { + "PMID": "19270710", + "TEXT": "Hypothalamic brain-derived neurotrophic factor (BDNF) is a key element in the regulation of energy balance. Here we investigated the therapeutic efficacy of BDNF by gene transfer in mouse models of obesity and diabetes. Gene transfer of BDNF led to marked weight loss and alleviation of obesity-associated insulin resistance. To facilitate clinical translation and ensure that BDNF protein expression was appropriately decreased as weight loss progressed, thus preventing cachexia, we developed a molecular autoregulatory system involving a single recombinant adeno-associated virus vector harboring two expression cassettes, one constitutively driving BDNF and the other driving a specific microRNA targeting BDNF. The microRNA element was controlled by a promoter (that controlling the Agrp gene encoding agouti-related peptide) responsive to BDNF-induced physiological changes. Hence, as body weight decreased and agouti-related protein is induced, microRNA expression was activated, inhibiting transgene expression. In contrast to the progressive weight loss associated with a nonregulated approach, this microRNA-approach led to a sustainable plateau of body weight after notable weight loss was achieved. This strategy mimics the body's endogenous physiological feedback mechanisms, thereby resetting the hypothalamic set point to reverse obesity and metabolic syndrome.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19270709", + "TEXT": "Tissue injury may create a specific microenvironment for inducing the systemic participation of stromal-like cells in the repair process. Here we show that substance P is an injury-inducible factor that acts early in the wound healing process to induce CD29(+) stromal-like cell mobilization. Likewise, mobilization of such cells also occurs in uninjured mice, rats and rabbits if substance P is intravenously injected. Upon further characterization these substance P-mobilized CD29(+) cells were found to be similar to stromal cells from a number of connective tissues, including bone marrow (that is, bone marrow stromal cells, or BMSCs). Both substance P injection and transfusion of autologously derived substance P-mobilized CD29(+) cells from uninjured rabbits accelerated wound healing in an alkali burn model. Also, epithelial engraftment of the transfused cells into the injured tissue occurred during the wound healing. Finally, using human BMSCs as a test population, we show that substance P stimulates transmigration, cell proliferation, activation of the extracellular signal-related kinases (Erk) 1 and 2 and nuclear translocation of beta-catenin in vitro. This finding highlights a previously undescribed function of substance P as a systemically acting messenger of injury and a mobilizer of CD29(+) stromal-like cells to participate in wound healing.", + "TAG_DATA": [ + "51, uninjured {'context': 'B-organism'}", + "52, mice, {'context': 'I-organism'}", + "53, rats {'context': 'B-organism'}", + "55, rabbits {'context': 'B-organism'}", + "106, CD29(+) {'context': 'B-cells'}", + "107, cells {'context': 'I-cells'}", + "109, uninjured {'context': 'B-organism'}", + "110, rabbits {'context': 'I-organism'}", + "125, cells {'context': 'B-cells'}", + "137, human {'context': 'B-cells'}", + "138, BMSCs {'context': 'I-cells'}", + "148, stimulates {'effect': 'B-positive'}", + "150, cell {'context': 'B-cells'}", + "151, proliferation, {'phenotype': 'B-proliferation'}", + "167, in {'context': 'B-in vitro'}", + "168, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "51, uninjured ['l0', 'l1', 'l2']", + "52, mice, ['l0', 'l3', 'l4']", + "53, rats ['l1', 'l3', 'l5']", + "55, rabbits ['l2', 'l4', 'l5']", + "106, CD29(+) ['l6', 'l7', 'l8', 'l9']", + "107, cells ['l6', 'l10', 'l11', 'l12']", + "109, uninjured ['l7', 'l10', 'l13']", + "110, rabbits ['l8', 'l11', 'l13']", + "125, cells ['l9', 'l12', 'l14']", + "137, human ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "138, BMSCs ['l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "148, stimulates ['l16', 'l22', 'l28', 'l29', 'l30', 'l31', 'l32']", + "149, transmigration, ['l17', 'l23', 'l28', 'l33', 'l34', 'l35', 'l36']", + "150, cell ['l14', 'l18', 'l24', 'l29', 'l33', 'l37']", + "151, proliferation, ['l19', 'l25', 'l30', 'l34', 'l37']", + "167, in ['l20', 'l26', 'l31', 'l35', 'l38']", + "168, vitro. ['l21', 'l27', 'l32', 'l36', 'l38']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "BMSCs", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "BMSCs", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "19252503", + "TEXT": "The variable efficacy of Bacille Calmette Guerin (BCG) vaccination against tuberculosis has prompted efforts to improve the vaccine. In this study, we used autophagy to enhance vaccine efficacy against tuberculosis in a mouse model. We examined the effect of autophagy on the processing of the immunodominant mycobacterial antigen Ag85B by antigen presenting cells (APCs), macrophages and dendritic cells (DCs). We found that rapamycin-induced autophagy enhanced Ag85B presentation by APCs infected with wild-type Mycobacterium tuberculosis H37Rv, H37Rv-derived DeltafbpA attenuated candidate vaccine or BCG. Furthermore, rapamycin enhanced localization of mycobacteria with autophagosomes and lysosomes. Rapamycin-enhanced antigen presentation was attenuated when autophagy was suppressed by 3-methyladenine or by small interfering RNA against beclin-1. Notably, mice immunized with rapamycin-treated DCs infected with either DeltafbpA or BCG showed enhanced T helper type 1-mediated protection when challenged with virulent Mycobacterium tuberculosis. Finally, overexpression of Ag85B in BCG induced autophagy in APCs and enhanced immunogenicity in mice, suggesting that vaccine efficacy can be enhanced by augmenting autophagy-mediated antigen presentation.", + "TAG_DATA": [ + "63, autophagy {'phenotype': 'B-autophagy'}", + "68, APCs {'context': 'B-cells'}", + "98, autophagy {'phenotype': 'B-autophagy'}", + "100, suppressed {'effect': 'B-negative'}", + "105, small {'perturbing_action': 'B-rnai/knockdown'}", + "106, interfering {'perturbing_action': 'I-rnai/knockdown'}", + "107, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "108, against {'perturbing_action': 'I-rnai/knockdown'}", + "109, beclin-1. {'perturbing_action': 'I-rnai/knockdown'}", + "111, mice {'context': 'B-organism'}", + "115, DCs {'context': 'B-cells'}", + "136, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "137, of {'perturbing_action': 'I-gene gain-of-function'}", + "138, Ag85B {'perturbing_action': 'I-gene gain-of-function'}", + "139, in {'perturbing_action': 'I-gene gain-of-function'}", + "140, BCG {'perturbing_action': 'I-gene gain-of-function'}", + "141, induced {'effect': 'B-positive'}", + "142, autophagy {'phenotype': 'B-autophagy'}", + "144, APCs {'context': 'B-cells'}", + "149, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "63, autophagy ['l0']", + "68, APCs ['l0']", + "98, autophagy ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "100, suppressed ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "105, small ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "106, interfering ['l3', 'l9', 'l14', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "107, RNA ['l4', 'l10', 'l15', 'l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "108, against ['l5', 'l11', 'l16', 'l24', 'l30', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "109, beclin-1. ['l6', 'l12', 'l17', 'l25', 'l31', 'l37', 'l43', 'l44']", + "111, mice ['l7', 'l13', 'l18', 'l26', 'l32', 'l38', 'l43', 'l45', 'l46', 'l47', 'l48']", + "115, DCs ['l19', 'l27', 'l33', 'l39', 'l44', 'l45', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "136, overexpression ['l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "137, of ['l56', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "138, Ag85B ['l49', 'l57', 'l64', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "139, in ['l50', 'l58', 'l65', 'l71', 'l77', 'l78', 'l79', 'l80', 'l81']", + "140, BCG ['l51', 'l59', 'l66', 'l72', 'l77', 'l82', 'l83', 'l84', 'l85']", + "141, induced ['l20', 'l28', 'l34', 'l40', 'l46', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l86', 'l87', 'l88']", + "142, autophagy ['l21', 'l35', 'l41', 'l47', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l89', 'l90']", + "144, APCs ['l22', 'l29', 'l36', 'l42', 'l48', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l91']", + "149, mice, ['l55', 'l63', 'l70', 'l76', 'l81', 'l85', 'l88', 'l90', 'l91']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + }, + "context": { + "val": "cells", + "words": [ + "APCs", + "DCs" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "small", + "interfering", + "RNA", + "against", + "beclin-1." + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "small", + "interfering", + "RNA", + "against", + "beclin-1." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "small", + "interfering", + "RNA", + "against", + "beclin-1." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "small", + "interfering", + "RNA", + "against", + "beclin-1." + ] + }, + "context": { + "val": "cells", + "words": [ + "DCs", + "APCs" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "small", + "interfering", + "RNA", + "against" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "DCs", + "APCs" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ag85B", + "in", + "BCG", + "overexpression", + "of" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "DCs", + "APCs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Ag85B", + "in", + "BCG" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Ag85B", + "in", + "BCG" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Ag85B", + "in", + "BCG" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + } + ] + }, + { + "PMID": "19252500", + "TEXT": "Immune sensing of a microbe occurs via multiple receptors. How signals from different receptors are coordinated to yield a specific immune response is poorly understood. We show that two pathogen recognition receptors, Toll-like receptor 2 (TLR2) and dectin-1, recognizing the same microbial stimulus, stimulate distinct innate and adaptive responses. TLR2 signaling induced splenic dendritic cells (DCs) to express the retinoic acid metabolizing enzyme retinaldehyde dehydrogenase type 2 and interleukin-10 (IL-10) and to metabolize vitamin A and stimulate Foxp3(+) T regulatory cells (T(reg) cells). Retinoic acid acted on DCs to induce suppressor of cytokine signaling-3 expression, which suppressed activation of p38 mitogen-activated protein kinase and proinflammatory cytokines. Consistent with this finding, TLR2 signaling induced T(reg) cells and suppressed IL-23 and T helper type 17 (T(H)17) and T(H)1-mediated autoimmune responses in vivo. In contrast, dectin-1 signaling mostly induced IL-23 and proinflammatory cytokines and augmented T(H)17 and T(H)1-mediated autoimmune responses in vivo. These data define a new mechanism for the systemic induction of retinoic acid and immune suppression against autoimmunity.", + "TAG_DATA": [ + "52, splenic {'context': 'B-cells'}", + "53, dendritic {'context': 'I-cells'}", + "54, cells {'context': 'I-cells'}", + "55, (DCs) {'context': 'I-cells'}", + "77, Foxp3(+) {'context': 'B-cells'}", + "78, T {'context': 'I-cells'}", + "79, regulatory {'context': 'I-cells'}", + "80, cells {'context': 'I-cells'}", + "82, cells). {'context': 'I-cells'}", + "87, DCs {'context': 'B-cells'}", + "113, T(reg) {'context': 'B-cells'}", + "114, cells {'context': 'I-cells'}", + "128, in {'context': 'B-in vivo'}", + "129, vivo. {'context': 'I-in vivo'}", + "147, in {'context': 'B-in vivo'}", + "148, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "52, splenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "53, dendritic ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "54, cells ['l1', 'l9', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "55, (DCs) ['l2', 'l10', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "77, Foxp3(+) ['l3', 'l11', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32']", + "78, T ['l4', 'l12', 'l20', 'l25', 'l29', 'l33', 'l34', 'l35', 'l36']", + "79, regulatory ['l5', 'l13', 'l21', 'l26', 'l30', 'l33', 'l37', 'l38', 'l39']", + "80, cells ['l6', 'l14', 'l22', 'l27', 'l31', 'l34', 'l37', 'l40']", + "82, cells). ['l7', 'l15', 'l23', 'l28', 'l32', 'l35', 'l38', 'l40']", + "87, DCs ['l8', 'l16', 'l36', 'l39', 'l41', 'l42', 'l43', 'l44']", + "113, T(reg) ['l41', 'l45', 'l46', 'l47']", + "114, cells ['l17', 'l42', 'l45', 'l48', 'l49']", + "128, in ['l43', 'l46', 'l48', 'l50']", + "129, vivo. ['l44', 'l47', 'l49', 'l50']", + "147, in ['l51']", + "148, vivo. ['l51']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19234463", + "TEXT": "Integrins are the major adhesion receptors of leukocytes and platelets. Beta1 and beta2 integrin function on leukocytes is crucial for a successful immune response and the platelet integrin alpha(IIb)beta3 initiates the process of blood clotting through binding fibrinogen. Integrins on circulating cells bind poorly to their ligands but become active after 'inside-out' signaling through other membrane receptors. Subjects with leukocyte adhesion deficiency-1 (LAD-I) do not express beta2 integrins because of mutations in the gene specifying the beta2 subunit, and they suffer recurrent bacterial infections. Mutations affecting alpha(IIb)beta3 integrin cause the bleeding disorder termed Glanzmann's thrombasthenia. Subjects with LAD-III show symptoms of both LAD-I and Glanzmann's thrombasthenia. Their hematopoietically-derived cells express beta1, beta2 and beta3 integrins, but defective inside-out signaling causes immune deficiency and bleeding problems. The LAD-III lesion has been attributed to a C --> A mutation in the gene encoding calcium and diacylglycerol guanine nucleotide exchange factor (CALDAGGEF1; official symbol RASGRP2) specifying the CALDAG-GEF1 protein, but we show that this change is not responsible for the LAD-III disorder. Instead, we identify mutations in the KINDLIN3 (official symbol FERMT3) gene specifying the KINDLIN-3 protein as the cause of LAD-III in Maltese and Turkish subjects. Two independent mutations result in decreased KINDLIN3 messenger RNA levels and loss of protein expression. Notably, transfection of the subjects' lymphocytes with KINDLIN3 complementary DNA but not CALDAGGEF1 cDNA reverses the LAD-III defect, restoring integrin-mediated adhesion and migration.", + "TAG_DATA": [ + "210, transfection {'perturbing_action': 'B-gene gain-of-function'}", + "213, subjects' {'context': 'B-cells'}", + "214, lymphocytes {'context': 'B-cells'}", + "215, with {'perturbing_action': 'I-gene gain-of-function'}", + "216, KINDLIN3 {'perturbing_action': 'I-gene gain-of-function'}", + "217, complementary {'perturbing_action': 'I-gene gain-of-function'}", + "218, DNA {'perturbing_action': 'I-gene gain-of-function'}", + "227, restoring {'effect': 'B-rescues'}", + "229, adhesion {'phenotype': 'B-adhesion'}", + "231, migration. {'phenotype': 'B-migration'}" + ], + "LINK_DATA": [ + "210, transfection ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "213, subjects' ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "214, lymphocytes ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "215, with ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "216, KINDLIN3 ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "217, complementary ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "218, DNA ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "227, restoring ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "229, adhesion ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "231, migration. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfection", + "with", + "KINDLIN3", + "complementary", + "DNA" + ] + }, + "context": { + "val": "cells", + "words": [ + "subjects'", + "lymphocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfection", + "with", + "KINDLIN3", + "complementary", + "DNA" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restoring" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfection", + "with", + "KINDLIN3", + "complementary", + "DNA" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfection", + "with", + "KINDLIN3", + "complementary", + "DNA" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "subjects'", + "lymphocytes" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restoring" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "subjects'", + "lymphocytes" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "subjects'", + "lymphocytes" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restoring" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restoring" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + } + ] + }, + { + "PMID": "19234461", + "TEXT": "Integrin activation is essential for the function of all blood cells, including platelets and leukocytes. The blood cell-specific FERM domain protein Kindlin-3 is required for the activation of the beta1 and beta3 integrins on platelets. Impaired activation of beta1, beta2 and beta3 integrins on platelets and leukocytes is the hallmark of a rare autosomal recessive leukocyte adhesion deficiency syndrome in humans called LAD-III, characterized by severe bleeding and impaired adhesion of leukocytes to inflamed endothelia. Here we show that Kindlin-3 also binds the beta2 integrin cytoplasmic domain and is essential for neutrophil binding and spreading on beta2 integrin-dependent ligands such as intercellular adhesion molecule-1 and the complement C3 activation product iC3b. Moreover, loss of Kindlin-3 expression abolished firm adhesion and arrest of neutrophils on activated endothelial cells in vitro and in vivo, whereas selectin-mediated rolling was unaffected. Thus, Kindlin-3 is essential to activate the beta1, beta2 and beta3 integrin classes, and loss of Kindlin-3 function is sufficient to cause a LAD-III-like phenotype in mice.", + "TAG_DATA": [ + "112, loss {'perturbing_action': 'B-gene loss-of-function'}", + "113, of {'perturbing_action': 'I-gene loss-of-function'}", + "114, Kindlin-3 {'perturbing_action': 'I-gene loss-of-function'}", + "115, expression {'perturbing_action': 'I-gene loss-of-function'}", + "116, abolished {'effect': 'B-negative'}", + "125, endothelial {'context': 'B-cells'}", + "126, cells {'context': 'I-cells'}", + "127, in {'context': 'B-in vitro'}", + "128, vitro {'context': 'I-in vitro'}", + "130, in {'context': 'B-in vivo'}", + "131, vivo, {'context': 'I-in vivo'}", + "136, unaffected. {'effect': 'B-no effect'}", + "151, loss {'perturbing_action': 'B-gene loss-of-function'}", + "152, of {'perturbing_action': 'I-gene loss-of-function'}", + "153, Kindlin-3 {'perturbing_action': 'I-gene loss-of-function'}", + "154, function {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "112, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "113, of ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "114, Kindlin-3 ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "115, expression ['l2', 'l9', 'l15', 'l22', 'l23', 'l24', 'l25', 'l26']", + "116, abolished ['l3', 'l10', 'l16', 'l22', 'l27', 'l28', 'l29', 'l30']", + "125, endothelial ['l4', 'l11', 'l17', 'l23', 'l27', 'l31', 'l32', 'l33']", + "126, cells ['l5', 'l12', 'l18', 'l24', 'l28', 'l31', 'l34', 'l35']", + "127, in ['l6', 'l13', 'l19', 'l25', 'l29', 'l32', 'l34', 'l36']", + "128, vitro ['l7', 'l14', 'l20', 'l26', 'l30', 'l33', 'l35', 'l36']", + "130, in ['l37']", + "131, vivo, ['l21', 'l37']", + "151, loss ['l38', 'l39', 'l40']", + "152, of ['l38', 'l41', 'l42']", + "153, Kindlin-3 ['l39', 'l41', 'l43']", + "154, function ['l40', 'l42', 'l43']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Kindlin-3", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abolished" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Kindlin-3", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Kindlin-3", + "expression" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Kindlin-3" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abolished" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abolished" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "19219024", + "TEXT": "The rapid onset of massive, systemic viral replication during primary HIV or simian immunodeficiency virus (SIV) infection and the immune evasion capabilities of these viruses pose fundamental problems for vaccines that depend upon initial viral replication to stimulate effector T cell expansion and differentiation. We hypothesized that vaccines designed to maintain differentiated effector memory T cell (TEM cell) responses at viral entry sites might improve efficacy by impairing viral replication at its earliest stage, and we have therefore developed SIV protein-encoding vectors based on rhesus cytomegalovirus (RhCMV), the prototypical inducer of life-long TEM cell responses. RhCMV vectors expressing SIV Gag, Rev-Tat-Nef and Env persistently infected rhesus macaques, regardless of preexisting RhCMV immunity, and primed and maintained robust, SIV-specific CD4+ and CD8+ TEM cell responses (characterized by coordinate tumor necrosis factor, interferon-gamma and macrophage inflammatory protein-1beta expression, cytotoxic degranulation and accumulation at extralymphoid sites) in the absence of neutralizing antibodies. Compared to control rhesus macaques, these vaccinated rhesus macaques showed increased resistance to acquisition of progressive SIVmac239 infection upon repeated limiting-dose intrarectal challenge, including four macaques who controlled rectal mucosal infection without progressive systemic dissemination. These data suggest a new paradigm for AIDS vaccine development--vaccines capable of generating and maintaining HIV-specific TEM cells might decrease the incidence of HIV acquisition after sexual exposure.", + "TAG_DATA": [ + "95, RhCMV {'perturbing_action': 'B-gene gain-of-function'}", + "96, vectors {'perturbing_action': 'I-gene gain-of-function'}", + "97, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "98, SIV {'perturbing_action': 'I-gene gain-of-function'}", + "99, Gag, {'perturbing_action': 'I-gene gain-of-function'}", + "100, Rev-Tat-Nef {'perturbing_action': 'I-gene gain-of-function'}", + "101, and {'perturbing_action': 'I-gene gain-of-function'}", + "102, Env {'perturbing_action': 'I-gene gain-of-function'}", + "105, rhesus {'context': 'B-organism'}", + "106, macaques, {'context': 'I-organism'}", + "118, CD4+ {'context': 'B-cells'}", + "119, and {'context': 'I-cells'}", + "120, CD8+ {'context': 'I-cells'}", + "121, TEM {'context': 'I-cells'}", + "122, cell {'context': 'I-cells'}", + "152, rhesus {'context': 'B-organism'}", + "153, macaques, {'context': 'I-organism'}", + "156, rhesus {'context': 'B-organism'}", + "157, macaques {'context': 'I-organism'}", + "174, macaques {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "95, RhCMV ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "96, vectors ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "97, expressing ['l1', 'l14', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "98, SIV ['l2', 'l15', 'l25', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "99, Gag, ['l3', 'l16', 'l26', 'l37', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "100, Rev-Tat-Nef ['l4', 'l17', 'l27', 'l38', 'l48', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "101, and ['l5', 'l18', 'l28', 'l39', 'l49', 'l58', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "102, Env ['l6', 'l19', 'l29', 'l40', 'l50', 'l59', 'l67', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "105, rhesus ['l7', 'l20', 'l30', 'l41', 'l51', 'l60', 'l68', 'l73', 'l79']", + "106, macaques, ['l8', 'l21', 'l31', 'l42', 'l52', 'l61', 'l69', 'l74', 'l79']", + "118, CD4+ ['l9', 'l32', 'l43', 'l53', 'l62', 'l75', 'l80', 'l81', 'l82', 'l83']", + "119, and ['l10', 'l22', 'l33', 'l44', 'l54', 'l63', 'l70', 'l76', 'l80', 'l84', 'l85', 'l86']", + "120, CD8+ ['l11', 'l34', 'l45', 'l55', 'l64', 'l81', 'l84', 'l87', 'l88']", + "121, TEM ['l12', 'l23', 'l35', 'l46', 'l56', 'l65', 'l71', 'l77', 'l82', 'l85', 'l87', 'l89']", + "122, cell ['l13', 'l24', 'l36', 'l47', 'l57', 'l66', 'l72', 'l78', 'l83', 'l86', 'l88', 'l89']", + "152, rhesus ['l90', 'l91', 'l92']", + "153, macaques, ['l90', 'l93', 'l94']", + "156, rhesus ['l91', 'l93', 'l95']", + "157, macaques ['l92', 'l94', 'l95']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "RhCMV", + "vectors", + "expressing", + "SIV", + "Gag,", + "Rev-Tat-Nef", + "and", + "Env" + ] + }, + "context": { + "val": "organism", + "words": [ + "rhesus", + "macaques," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "RhCMV", + "vectors", + "expressing", + "SIV", + "Gag,", + "Rev-Tat-Nef", + "and", + "Env" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "and", + "CD8+", + "TEM", + "cell" + ] + } + } + ] + }, + { + "PMID": "19219023", + "TEXT": "We developed a new approach to bioluminescent T cell imaging using a membrane-anchored form of the Gaussia luciferase (GLuc) enzyme, termed extGLuc, which we could stably express in both mouse and human primary T cells. In vitro, extGLuc+ cells emitted significantly higher bioluminescent signal when compared to cells expressing GLuc, Renilla luciferase (RLuc) or membrane-anchored RLuc (extRLuc). In vivo, mouse extGLuc+ T cells showed higher bioluminescent signal when compared to GLuc+ and RLuc+ T cells. Application of this imaging approach to human T cells genetically modified to express tumor-specific chimeric antigen receptors (CARs) enabled us to show in vivo CAR-mediated T cell accumulation in tumor, T cell persistence over time and concomitant imaging of T cells and tumor cells modified to express firefly luciferase. This sensitive imaging technology has application to many in vivo cell-based studies in a wide array of mouse models.", + "TAG_DATA": [ + "35, In {'context': 'B-in vitro'}", + "36, vitro, {'context': 'I-in vitro'}", + "37, extGLuc+ {'context': 'B-cells'}", + "38, cells {'context': 'I-cells'}", + "47, cells {'context': 'B-cells'}", + "57, In {'context': 'B-in vivo'}", + "58, vivo, {'context': 'I-in vivo'}", + "59, mouse {'context': 'B-cells'}", + "60, extGLuc+ {'context': 'I-cells'}", + "61, T {'context': 'I-cells'}", + "62, cells {'context': 'I-cells'}", + "81, human {'context': 'B-cells'}", + "82, T {'context': 'I-cells'}", + "83, cells {'context': 'I-cells'}", + "84, genetically {'perturbing_action': 'B-other'}", + "85, modified {'perturbing_action': 'B-other'}", + "86, to {'perturbing_action': 'I-other'}", + "87, express {'perturbing_action': 'I-other'}", + "88, tumor-specific {'perturbing_action': 'I-other'}", + "89, chimeric {'perturbing_action': 'I-other'}", + "97, in {'context': 'B-in vivo'}", + "98, vivo {'context': 'I-in vivo'}", + "100, T {'context': 'B-cells'}", + "101, cell {'context': 'I-cells'}", + "104, tumor, {'context': 'B-neoplasm'}", + "105, T {'context': 'B-cells'}", + "106, cell {'context': 'I-cells'}", + "114, T {'context': 'B-cells'}", + "115, cells {'context': 'B-cells'}", + "117, tumor {'context': 'B-transformed cells'}", + "118, cells {'context': 'I-transformed cells'}", + "119, modified {'perturbing_action': 'B-other'}" + ], + "LINK_DATA": [ + "35, In ['l0', 'l1', 'l2', 'l3']", + "36, vitro, ['l0', 'l4', 'l5', 'l6']", + "37, extGLuc+ ['l1', 'l4', 'l7', 'l8']", + "38, cells ['l2', 'l5', 'l7', 'l9']", + "47, cells ['l3', 'l6', 'l8', 'l9']", + "57, In ['l10', 'l11', 'l12', 'l13', 'l14']", + "58, vivo, ['l10', 'l15', 'l16', 'l17', 'l18']", + "59, mouse ['l11', 'l15', 'l19', 'l20', 'l21']", + "60, extGLuc+ ['l12', 'l16', 'l19', 'l22', 'l23']", + "61, T ['l13', 'l17', 'l20', 'l22', 'l24']", + "62, cells ['l14', 'l18', 'l21', 'l23', 'l24']", + "81, human ['l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "82, T ['l25', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "83, cells ['l26', 'l44', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "84, genetically ['l27', 'l45', 'l62', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "85, modified ['l28', 'l46', 'l63', 'l78', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "86, to ['l29', 'l47', 'l64', 'l79', 'l97', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "87, express ['l30', 'l48', 'l65', 'l80', 'l98', 'l117', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "88, tumor-specific ['l31', 'l49', 'l66', 'l81', 'l99', 'l118', 'l136', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "89, chimeric ['l32', 'l50', 'l67', 'l82', 'l100', 'l119', 'l137', 'l154', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184']", + "90, antigen ['l33', 'l51', 'l68', 'l83', 'l101', 'l120', 'l138', 'l155', 'l170', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196']", + "91, receptors ['l34', 'l52', 'l69', 'l84', 'l102', 'l121', 'l139', 'l156', 'l171', 'l185', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208']", + "92, (CARs) ['l35', 'l53', 'l70', 'l85', 'l103', 'l122', 'l140', 'l157', 'l172', 'l186', 'l197', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218']", + "97, in ['l36', 'l54', 'l71', 'l86', 'l104', 'l123', 'l141', 'l158', 'l173', 'l187', 'l198', 'l209', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226']", + "98, vivo ['l37', 'l55', 'l72', 'l87', 'l105', 'l124', 'l142', 'l159', 'l174', 'l188', 'l199', 'l210', 'l219', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233']", + "100, T ['l38', 'l56', 'l73', 'l88', 'l106', 'l125', 'l143', 'l160', 'l175', 'l189', 'l200', 'l211', 'l220', 'l227', 'l234', 'l235', 'l236', 'l237']", + "101, cell ['l39', 'l57', 'l74', 'l89', 'l107', 'l126', 'l144', 'l161', 'l176', 'l190', 'l201', 'l212', 'l221', 'l228', 'l234', 'l238', 'l239', 'l240']", + "104, tumor, ['l40', 'l58', 'l75', 'l90', 'l108', 'l127', 'l145', 'l162', 'l177', 'l191', 'l202', 'l213', 'l222', 'l229', 'l235', 'l238']", + "105, T ['l41', 'l59', 'l76', 'l91', 'l109', 'l128', 'l146', 'l163', 'l178', 'l192', 'l203', 'l214', 'l223', 'l230', 'l236', 'l239', 'l241', 'l242', 'l243', 'l244', 'l245']", + "106, cell ['l42', 'l60', 'l77', 'l92', 'l110', 'l129', 'l147', 'l164', 'l179', 'l193', 'l204', 'l215', 'l224', 'l231', 'l237', 'l240', 'l241', 'l246', 'l247']", + "114, T ['l93', 'l111', 'l130', 'l148', 'l165', 'l180', 'l194', 'l205', 'l216', 'l225', 'l232', 'l242', 'l246', 'l248', 'l249', 'l250', 'l251', 'l252']", + "115, cells ['l43', 'l61', 'l94', 'l112', 'l131', 'l149', 'l166', 'l181', 'l195', 'l206', 'l217', 'l226', 'l233', 'l243', 'l247', 'l248', 'l253', 'l254', 'l255', 'l256']", + "117, tumor ['l95', 'l113', 'l132', 'l150', 'l167', 'l182', 'l207', 'l244', 'l249', 'l253', 'l257', 'l258', 'l259']", + "118, cells ['l96', 'l114', 'l133', 'l151', 'l168', 'l183', 'l196', 'l208', 'l218', 'l245', 'l250', 'l254', 'l257', 'l260', 'l261']", + "119, modified ['l115', 'l134', 'l152', 'l251', 'l255', 'l258', 'l260', 'l262']", + "120, to ['l116', 'l135', 'l153', 'l169', 'l184', 'l252', 'l256', 'l259', 'l261', 'l262']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "T", + "cells", + "cell" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "genetically", + "modified", + "to", + "express", + "tumor-specific", + "chimeric" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetically", + "modified", + "to", + "express", + "tumor-specific", + "chimeric" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetically", + "modified", + "to", + "express", + "tumor-specific", + "chimeric" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetically", + "modified", + "to", + "express", + "tumor-specific", + "chimeric" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + } + ] + }, + { + "PMID": "19182797", + "TEXT": "We identified nicotinamide phosphoribosyltransferase (NAMPT), also known as pre-B cell colony enhancing factor (PBEF), as an essential enzyme mediating granulocyte colony-stimulating factor (G-CSF)-triggered granulopoiesis in healthy individuals and in individuals with severe congenital neutropenia. Intracellular NAMPT and NAD(+) amounts in myeloid cells, as well as plasma NAMPT and NAD(+) levels, were increased by G-CSF treatment of both healthy volunteers and individuals with congenital neutropenia. NAMPT administered both extracellularly and intracellularly induced granulocytic differentiation of CD34(+) hematopoietic progenitor cells and of the promyelocytic leukemia cell line HL-60. Treatment of healthy individuals with high doses of vitamin B3 (nicotinamide), a substrate of NAMPT, induced neutrophilic granulocyte differentiation. The molecular events triggered by NAMPT include NAD(+)-dependent sirtuin-1 activation, subsequent induction of CCAAT/enhancer binding protein-alpha and CCAAT/enhancer binding protein-beta, and, ultimately, upregulation of G-CSF synthesis and G-CSF receptor expression. G-CSF, in turn, further increases NAMPT levels. These results reveal a decisive role of the NAD(+) metabolic pathway in G-CSF-triggered myelopoiesis.", + "TAG_DATA": [ + "70, induced {'effect': 'B-positive'}", + "72, differentiation {'phenotype': 'I-differentiation'}", + "74, CD34(+) {'context': 'B-cells'}", + "75, hematopoietic {'context': 'I-cells'}", + "76, progenitor {'context': 'I-cells'}", + "77, cells {'context': 'I-cells'}", + "81, promyelocytic {'context': 'B-transformed cells'}", + "82, leukemia {'context': 'I-transformed cells'}", + "83, cell {'context': 'I-transformed cells'}", + "84, line {'context': 'I-transformed cells'}", + "85, HL-60. {'context': 'I-transformed cells'}", + "101, induced {'effect': 'B-positive'}", + "102, neutrophilic {'context': 'B-cells'}", + "103, granulocyte {'context': 'I-cells'}", + "104, differentiation. {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "70, induced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "72, differentiation ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "74, CD34(+) ['l1', 'l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "75, hematopoietic ['l2', 'l11', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "76, progenitor ['l3', 'l12', 'l18', 'l25', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "77, cells ['l4', 'l13', 'l19', 'l26', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "81, promyelocytic ['l5', 'l20', 'l27', 'l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "82, leukemia ['l6', 'l21', 'l28', 'l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "83, cell ['l7', 'l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "84, line ['l8', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "85, HL-60. ['l9', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l52']", + "101, induced ['l53', 'l54', 'l55']", + "102, neutrophilic ['l53', 'l56', 'l57']", + "103, granulocyte ['l54', 'l56', 'l58']", + "104, differentiation. ['l55', 'l57', 'l58']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "differentiation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD34(+)", + "hematopoietic", + "progenitor", + "cells", + "neutrophilic", + "granulocyte" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "promyelocytic", + "leukemia", + "cell", + "line", + "HL-60." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "differentiation." + ] + }, + "context": { + "val": "cells", + "words": [ + "CD34(+)", + "hematopoietic", + "progenitor", + "cells", + "neutrophilic", + "granulocyte" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cell", + "line", + "HL-60." + ] + } + } + ] + }, + { + "PMID": "19098909", + "TEXT": "Disorders of neuronal migration can lead to malformations of the cerebral neocortex that greatly increase the risk of seizures. It remains untested whether malformations caused by disorders in neuronal migration can be reduced by reactivating cellular migration and whether such repair can decrease seizure risk. Here we show, in a rat model of subcortical band heterotopia (SBH) generated by in utero RNA interference of the Dcx gene, that aberrantly positioned neurons can be stimulated to migrate by reexpressing Dcx after birth. Restarting migration in this way both reduces neocortical malformations and restores neuronal patterning. We further find that the capacity to reduce SBH continues into early postnatal development. Moreover, intervention after birth reduces the convulsant-induced seizure threshold to a level similar to that in malformation-free controls. These results suggest that disorders of neuronal migration may be eventually treatable by reengaging developmental programs both to reduce the size of cortical malformations and to reduce seizure risk.", + "TAG_DATA": [ + "50, rat {'context': 'B-organism'}", + "51, model {'context': 'I-organism'}", + "61, RNA {'perturbing_action': 'B-rnai/knockdown'}", + "62, interference {'perturbing_action': 'I-rnai/knockdown'}", + "63, of {'perturbing_action': 'I-rnai/knockdown'}", + "64, the {'perturbing_action': 'I-rnai/knockdown'}", + "65, Dcx {'perturbing_action': 'I-rnai/knockdown'}", + "66, gene, {'perturbing_action': 'I-rnai/knockdown'}", + "70, neurons {'context': 'B-cells'}", + "73, stimulated {'effect': 'B-positive'}", + "75, migrate {'phenotype': 'B-migration'}", + "77, reexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "78, Dcx {'perturbing_action': 'I-gene gain-of-function'}", + "82, migration {'phenotype': 'B-migration'}" + ], + "LINK_DATA": [ + "50, rat ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "51, model ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "52, of ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "53, subcortical ['l2', 'l16', 'l29', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "54, band ['l3', 'l17', 'l30', 'l42', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "55, heterotopia ['l4', 'l18', 'l31', 'l43', 'l55', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "59, in ['l5', 'l19', 'l32', 'l44', 'l56', 'l66', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "61, RNA ['l6', 'l20', 'l33', 'l45', 'l57', 'l67', 'l77', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "62, interference ['l7', 'l21', 'l34', 'l46', 'l58', 'l68', 'l78', 'l87', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "63, of ['l8', 'l22', 'l35', 'l47', 'l59', 'l69', 'l79', 'l88', 'l97', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "64, the ['l9', 'l23', 'l36', 'l48', 'l60', 'l70', 'l80', 'l89', 'l98', 'l106', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "65, Dcx ['l10', 'l24', 'l37', 'l49', 'l61', 'l71', 'l81', 'l90', 'l99', 'l107', 'l114', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "66, gene, ['l11', 'l25', 'l38', 'l50', 'l62', 'l72', 'l82', 'l91', 'l100', 'l108', 'l115', 'l121', 'l127', 'l128', 'l129', 'l130', 'l131']", + "70, neurons ['l12', 'l26', 'l39', 'l51', 'l63', 'l73', 'l83', 'l92', 'l101', 'l109', 'l116', 'l122', 'l127', 'l132', 'l133', 'l134', 'l135', 'l136']", + "73, stimulated ['l13', 'l27', 'l40', 'l52', 'l64', 'l74', 'l84', 'l93', 'l102', 'l110', 'l117', 'l123', 'l128', 'l132', 'l137', 'l138', 'l139', 'l140']", + "75, migrate ['l14', 'l28', 'l41', 'l53', 'l65', 'l75', 'l85', 'l94', 'l103', 'l111', 'l118', 'l124', 'l129', 'l133', 'l137', 'l141', 'l142', 'l143']", + "77, reexpressing ['l134', 'l138', 'l141', 'l144', 'l145']", + "78, Dcx ['l95', 'l104', 'l112', 'l119', 'l125', 'l130', 'l135', 'l139', 'l142', 'l144', 'l146']", + "82, migration ['l54', 'l76', 'l86', 'l96', 'l105', 'l113', 'l120', 'l126', 'l131', 'l136', 'l140', 'l143', 'l145', 'l146']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "rat", + "model" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "RNA", + "interference", + "of", + "the", + "Dcx", + "gene," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rat", + "model" + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rat", + "model" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migrate" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "RNA", + "interference", + "of", + "the", + "Dcx", + "gene," + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "RNA", + "interference", + "of", + "the", + "Dcx", + "gene," + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "RNA", + "interference", + "of", + "the", + "Dcx", + "gene," + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migrate", + "migration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neurons" + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neurons" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migrate", + "migration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neurons" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "reexpressing", + "Dcx" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migrate", + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "reexpressing", + "Dcx" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migrate", + "migration" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "reexpressing", + "Dcx" + ] + } + } + ] + }, + { + "PMID": "19098908", + "TEXT": "We identified a previously undescribed gene associated with colon cancer by genome-wide expression analysis in primary and metastatic carcinomas: metastasis-associated in colon cancer-1, MACC1. MACC1 expression in tumor specimens is an independent prognostic indicator of metastasis formation and metastasis-free survival. We show that the gene encoding the hepatocyte growth factor (HGF) receptor, MET, is a transcriptional target of MACC1. MACC1 promotes proliferation, invasion and HGF-induced scattering of colon cancer cells in cell culture and tumor growth and metastasis in mouse models. These phenotypes are lost in cells expressing MACC1 mutants lacking the SH3 domain or the proline-rich motif. For clinical practice, MACC1 will be useful for the identification of poor prognosis subjects with colorectal cancer and is a promising new target for intervention in metastasis formation.", + "TAG_DATA": [ + "60, promotes {'effect': 'B-positive'}", + "61, proliferation, {'phenotype': 'B-proliferation'}", + "62, invasion {'phenotype': 'B-invasion'}", + "67, colon {'context': 'B-transformed cells'}", + "68, cancer {'context': 'I-transformed cells'}", + "69, cells {'context': 'I-transformed cells'}", + "71, cell {'context': 'B-cells'}", + "72, culture {'context': 'I-in vitro'}", + "74, tumor {'phenotype': 'B-tumour growth'}", + "75, growth {'phenotype': 'I-tumour growth'}", + "77, metastasis {'phenotype': 'B-metastasis'}", + "79, mouse {'context': 'B-organism'}", + "80, models. {'context': 'I-organism'}", + "86, cells {'context': 'B-cells'}", + "88, MACC1 {'perturbing_action': 'B-other'}", + "89, mutants {'perturbing_action': 'I-other'}", + "90, lacking {'perturbing_action': 'I-other'}", + "93, domain {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "60, promotes ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "61, proliferation, ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "62, invasion ['l1', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "67, colon ['l2', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22', 'l23']", + "68, cancer ['l3', 'l10', 'l15', 'l19', 'l24', 'l25', 'l26']", + "69, cells ['l4', 'l11', 'l16', 'l20', 'l24', 'l27', 'l28']", + "71, cell ['l5', 'l12', 'l17', 'l21', 'l25', 'l27', 'l29', 'l30']", + "72, culture ['l6', 'l13', 'l18', 'l22', 'l26', 'l28', 'l29']", + "74, tumor ['l31', 'l32', 'l33', 'l34']", + "75, growth ['l7', 'l23', 'l30', 'l31', 'l35', 'l36', 'l37']", + "77, metastasis ['l32', 'l35', 'l38', 'l39']", + "79, mouse ['l33', 'l36', 'l38', 'l40']", + "80, models. ['l34', 'l37', 'l39', 'l40']", + "86, cells ['l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "88, MACC1 ['l41', 'l47', 'l48', 'l49', 'l50', 'l51']", + "89, mutants ['l42', 'l47', 'l52', 'l53', 'l54', 'l55']", + "90, lacking ['l43', 'l48', 'l52', 'l56', 'l57', 'l58']", + "91, the ['l44', 'l49', 'l53', 'l56', 'l59', 'l60']", + "92, SH3 ['l45', 'l50', 'l54', 'l57', 'l59', 'l61']", + "93, domain ['l46', 'l51', 'l55', 'l58', 'l60', 'l61']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "colon", + "cancer", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "colon", + "cancer", + "cells" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "colon", + "cancer", + "cells" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "colon" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "MACC1", + "mutants", + "lacking", + "domain" + ] + } + } + ] + }, + { + "PMID": "19098906", + "TEXT": "Sepsis causes over 200,000 deaths yearly in the US; better treatments are urgently needed. Administering bone marrow stromal cells (BMSCs -- also known as mesenchymal stem cells) to mice before or shortly after inducing sepsis by cecal ligation and puncture reduced mortality and improved organ function. The beneficial effect of BMSCs was eliminated by macrophage depletion or pretreatment with antibodies specific for interleukin-10 (IL-10) or IL-10 receptor. Monocytes and/or macrophages from septic lungs made more IL-10 when prepared from mice treated with BMSCs versus untreated mice. Lipopolysaccharide (LPS)-stimulated macrophages produced more IL-10 when cultured with BMSCs, but this effect was eliminated if the BMSCs lacked the genes encoding Toll-like receptor 4, myeloid differentiation primary response gene-88, tumor necrosis factor (TNF) receptor-1a or cyclooxygenase-2. Our results suggest that BMSCs (activated by LPS or TNF-alpha) reprogram macrophages by releasing prostaglandin E(2) that acts on the macrophages through the prostaglandin EP2 and EP4 receptors. Because BMSCs have been successfully given to humans and can easily be cultured and might be used without human leukocyte antigen matching, we suggest that cultured, banked human BMSCs may be effective in treating sepsis in high-risk patient groups.", + "TAG_DATA": [ + "28, mice {'context': 'B-organism'}", + "67, Monocytes {'context': 'B-cells'}", + "69, macrophages {'context': 'B-cells'}", + "79, mice {'context': 'B-organism'}", + "85, mice. {'context': 'B-organism'}", + "88, macrophages {'context': 'B-cells'}", + "103, BMSCs {'context': 'B-cells'}", + "134, macrophages {'context': 'B-cells'}", + "143, macrophages {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "28, mice ['l0', 'l1']", + "67, Monocytes ['l0', 'l2', 'l3', 'l4']", + "69, macrophages ['l1', 'l2', 'l5', 'l6']", + "79, mice ['l3', 'l5', 'l7']", + "85, mice. ['l4', 'l6', 'l7']", + "103, BMSCs ['l8', 'l9']", + "134, macrophages ['l8', 'l10']", + "143, macrophages ['l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19079256", + "TEXT": "Respiratory syncytial virus (RSV) is a leading cause of hospitalization in infants. A formalin-inactivated RSV vaccine was used to immunize children and elicited nonprotective, pathogenic antibody. Immunized infants experienced increased morbidity after subsequent RSV exposure. No vaccine has been licensed since that time. A widely accepted hypothesis attributed the vaccine failure to formalin disruption of protective antigens. Here we show that the lack of protection was not due to alterations caused by formalin but instead to low antibody avidity for protective epitopes. Lack of antibody affinity maturation followed poor Toll-like receptor (TLR) stimulation. This study explains why the inactivated RSV vaccine did not protect the children and consequently led to severe disease, hampering vaccine development for 42 years. It also suggests that inactivated RSV vaccines may be rendered safe and effective by inclusion of TLR agonists in their formulation, and it identifies affinity maturation as a key factor for the safe immunization of infants.", + "TAG_DATA": [ + "105, children {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19029985", + "TEXT": "The mechanisms involved in the pathogenesis of epilepsy, a chronic neurological disorder that affects approximately one percent of the world population, are not well understood. Using a mouse model of epilepsy, we show that seizures induce elevated expression of vascular cell adhesion molecules and enhanced leukocyte rolling and arrest in brain vessels mediated by the leukocyte mucin P-selectin glycoprotein ligand-1 (PSGL-1, encoded by Selplg) and leukocyte integrins alpha(4)beta(1) and alpha(L)beta(2). Inhibition of leukocyte-vascular interactions, either with blocking antibodies or by genetically interfering with PSGL-1 function in mice, markedly reduced seizures. Treatment with blocking antibodies after acute seizures prevented the development of epilepsy. Neutrophil depletion also inhibited acute seizure induction and chronic spontaneous recurrent seizures. Blood-brain barrier (BBB) leakage, which is known to enhance neuronal excitability, was induced by acute seizure activity but was prevented by blockade of leukocyte-vascular adhesion, suggesting a pathogenetic link between leukocyte-vascular interactions, BBB damage and seizure generation. Consistent with the potential leukocyte involvement in epilepsy in humans, leukocytes were more abundant in brains of individuals with epilepsy than in controls. Our results suggest leukocyte-endothelial interaction as a potential target for the prevention and treatment of epilepsy.", + "TAG_DATA": [ + "51, vessels {'context': 'I-tissue/organ'}", + "80, genetically {'perturbing_action': 'B-other'}", + "81, interfering {'perturbing_action': 'B-other'}", + "82, with {'perturbing_action': 'I-other'}", + "83, PSGL-1 {'perturbing_action': 'I-other'}", + "84, function {'perturbing_action': 'I-other'}", + "86, mice, {'context': 'B-organism'}", + "105, inhibited {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "50, brain ['l0']", + "51, vessels ['l0']", + "80, genetically ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "81, interfering ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "82, with ['l2', 'l7', 'l12', 'l13', 'l14']", + "83, PSGL-1 ['l3', 'l8', 'l12', 'l15', 'l16']", + "84, function ['l4', 'l9', 'l13', 'l15', 'l17']", + "86, mice, ['l5', 'l10', 'l14', 'l16', 'l17']", + "105, inhibited ['l6', 'l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "genetically", + "interfering", + "with", + "PSGL-1", + "function" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetically", + "interfering" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + } + ] + }, + { + "PMID": "19029984", + "TEXT": "Blockade of mineralocorticoid receptor has been shown to improve the clinical outcomes of proteinuric kidney diseases. However, little is known about the regulation of mineralocorticoid receptor-dependent transcriptional activity in renal disease. Here we identify a new role for Rac1, a member of the Rho family GTPases, as a potent activator of mineralocorticoid receptor signal transduction both in vitro and in vivo. Transient transfection assays in HEK 293 cells revealed that constitutively active Rac1 (CA-Rac1) enhanced mineralocorticoid receptor-dependent reporter activity, which was accompanied by increased nuclear translocation of mineralocorticoid receptor. CA-Rac1 facilitated mineralocorticoid receptor nuclear accumulation also in podocytes via p21-activated kinase phosphorylation. In mice lacking Rho GDP-dissociation inhibitor-alpha (Arhgdia(-/-) mice), renal abnormalities, including heavy albuminuria and podocyte damage, were associated with increased Rac1 (but not RhoA) and mineralocorticoid receptor signaling in the kidney, without alteration in systemic aldosterone status. Pharmacological intervention with a Rac-specific small-molecule inhibitor diminished mineralocorticoid receptor overactivity and renal damage in this model. Furthermore, albuminuria and histological changes in Arhgdia(-/-) mice were suppressed by mineralocorticoid receptor blockade, confirming the pathological role of Rac1-mineralocorticoid receptor interaction. Our results provide evidence that signaling cross-talk between Rac1 and mineralocorticoid receptor modulates mineralocorticoid receptor activity and identify Rac1 as a therapeutic target for chronic kidney disease.", + "TAG_DATA": [ + "65, HEK {'context': 'B-cells'}", + "66, 293 {'context': 'I-cells'}", + "67, cells {'context': 'I-cells'}", + "70, constitutively {'perturbing_action': 'B-gene gain-of-function'}", + "71, active {'perturbing_action': 'I-gene gain-of-function'}", + "72, Rac1 {'perturbing_action': 'I-gene gain-of-function'}", + "73, (CA-Rac1) {'perturbing_action': 'I-gene gain-of-function'}", + "97, podocytes {'context': 'B-cells'}", + "103, mice {'context': 'B-organism'}", + "104, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "105, Rho {'perturbing_action': 'I-gene loss-of-function'}", + "106, GDP-dissociation {'perturbing_action': 'I-gene loss-of-function'}", + "107, inhibitor-alpha {'perturbing_action': 'I-gene loss-of-function'}", + "109, mice), {'perturbing_action': 'I-gene loss-of-function'}", + "143, Rac-specific {'perturbing_action': 'B-pharmacological inhibition'}", + "144, small-molecule {'perturbing_action': 'I-pharmacological inhibition'}", + "145, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "162, Arhgdia(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "163, mice {'context': 'B-organism'}", + "167, mineralocorticoid {'perturbing_action': 'B-pharmacological inhibition'}", + "168, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "169, blockade, {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "65, HEK ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "66, 293 ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "67, cells ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "70, constitutively ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "71, active ['l3', 'l9', 'l14', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "72, Rac1 ['l4', 'l10', 'l15', 'l19', 'l24', 'l29', 'l30', 'l31']", + "73, (CA-Rac1) ['l5', 'l11', 'l16', 'l20', 'l25', 'l29', 'l32', 'l33']", + "97, podocytes ['l6', 'l12', 'l17', 'l21', 'l26', 'l30', 'l32', 'l34']", + "103, mice ['l22', 'l27', 'l35', 'l36', 'l37', 'l38', 'l39']", + "104, lacking ['l35', 'l40', 'l41', 'l42', 'l43']", + "105, Rho ['l36', 'l40', 'l44', 'l45', 'l46']", + "106, GDP-dissociation ['l37', 'l41', 'l44', 'l47', 'l48']", + "107, inhibitor-alpha ['l38', 'l42', 'l45', 'l47', 'l49']", + "109, mice), ['l23', 'l28', 'l31', 'l33', 'l34', 'l39', 'l43', 'l46', 'l48', 'l49']", + "143, Rac-specific ['l50', 'l51', 'l52', 'l53']", + "144, small-molecule ['l50', 'l54', 'l55', 'l56']", + "145, inhibitor ['l51', 'l54', 'l57', 'l58']", + "162, Arhgdia(-/-) ['l52', 'l55', 'l57', 'l59', 'l60', 'l61', 'l62']", + "163, mice ['l53', 'l56', 'l58', 'l59']", + "167, mineralocorticoid ['l60', 'l63', 'l64']", + "168, receptor ['l61', 'l63', 'l65']", + "169, blockade, ['l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "HEK", + "293", + "cells", + "podocytes" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutively", + "active", + "Rac1", + "(CA-Rac1)" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutively", + "active" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "podocytes" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "mice)," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "Rho", + "GDP-dissociation", + "inhibitor-alpha", + "mice),", + "Arhgdia(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Rac-specific", + "small-molecule", + "inhibitor" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "19029980", + "TEXT": "Retinoic acid and arsenic trioxide target the protein stability and transcriptional repression activity of the fusion oncoprotein PML-RARA, resulting in regression of acute promyelocytic leukemia (APL). Phenotypically, retinoic acid induces differentiation of APL cells. Here we show that retinoic acid also triggers growth arrest of leukemia-initiating cells (LICs) ex vivo and their clearance in PML-RARA mouse APL in vivo. Retinoic acid treatment of mouse APLs expressing the fusion protein PLZF-RARA triggers full differentiation, but not LIC loss or disease remission, establishing that differentiation and LIC loss can be uncoupled. Although retinoic acid and arsenic synergize to clear LICs through cooperative PML-RARA degradation, this combination does not enhance differentiation. A cyclic AMP (cAMP)-dependent phosphorylation site in PML-RARA is crucial for retinoic acid-induced PML-RARA degradation and LIC clearance. Moreover, activation of cAMP signaling enhances LIC loss by retinoic acid, identifying cAMP as another potential APL therapy. Thus, whereas transcriptional activation of PML-RARA is likely to control differentiation, its catabolism triggers LIC eradication and long-term remission of mouse APL. Therapy-triggered degradation of oncoproteins could be a general strategy to eradicate cancer stem cells.", + "TAG_DATA": [ + "41, triggers {'effect': 'B-positive'}", + "42, growth {'phenotype': 'B-cell cycle arrest'}", + "43, arrest {'phenotype': 'I-cell cycle arrest'}", + "45, leukemia-initiating {'context': 'B-cells'}", + "46, cells {'context': 'I-cells'}", + "47, (LICs) {'context': 'I-cells'}", + "55, mouse {'context': 'B-transformed cells'}", + "56, APL {'context': 'I-transformed cells'}", + "57, in {'context': 'B-in vivo'}", + "58, vivo. {'context': 'I-in vivo'}", + "63, mouse {'context': 'B-transformed cells'}", + "64, APLs {'context': 'I-transformed cells'}", + "65, expressing {'perturbing_action': 'B-other'}", + "66, the {'perturbing_action': 'I-other'}", + "67, fusion {'perturbing_action': 'I-other'}", + "68, protein {'perturbing_action': 'I-other'}", + "69, PLZF-RARA {'perturbing_action': 'I-other'}", + "70, triggers {'effect': 'B-positive'}", + "72, differentiation, {'phenotype': 'B-differentiation'}", + "82, differentiation {'phenotype': 'B-differentiation'}", + "106, enhance {'effect': 'B-positive'}", + "107, differentiation. {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "41, triggers ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "42, growth ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "43, arrest ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "45, leukemia-initiating ['l2', 'l10', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "46, cells ['l3', 'l11', 'l18', 'l23', 'l29', 'l30', 'l31', 'l32', 'l33']", + "47, (LICs) ['l4', 'l12', 'l19', 'l24', 'l29', 'l34', 'l35', 'l36', 'l37']", + "55, mouse ['l5', 'l13', 'l25', 'l30', 'l34', 'l38', 'l39', 'l40']", + "56, APL ['l6', 'l14', 'l20', 'l26', 'l31', 'l35', 'l38', 'l41', 'l42']", + "57, in ['l7', 'l15', 'l21', 'l27', 'l32', 'l36', 'l39', 'l41', 'l43']", + "58, vivo. ['l8', 'l16', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l43']", + "63, mouse ['l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "64, APLs ['l44', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "65, expressing ['l45', 'l53', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "66, the ['l46', 'l54', 'l61', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "67, fusion ['l47', 'l55', 'l62', 'l68', 'l74', 'l75', 'l76', 'l77', 'l78']", + "68, protein ['l48', 'l56', 'l63', 'l69', 'l74', 'l79', 'l80', 'l81', 'l82']", + "69, PLZF-RARA ['l49', 'l57', 'l64', 'l70', 'l75', 'l79', 'l83', 'l84', 'l85']", + "70, triggers ['l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l83', 'l86', 'l87']", + "72, differentiation, ['l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l86', 'l88']", + "82, differentiation ['l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l87', 'l88']", + "106, enhance ['l89']", + "107, differentiation. ['l89']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "growth", + "arrest" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "context": { + "val": "cells", + "words": [ + "leukemia-initiating", + "cells", + "(LICs)" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "mouse", + "APL", + "APLs" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "growth", + "arrest" + ] + }, + "context": { + "val": "cells", + "words": [ + "leukemia-initiating", + "cells", + "(LICs)" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "growth", + "arrest" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "mouse", + "APL" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "growth", + "arrest" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "mouse", + "APLs" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "the", + "fusion", + "protein", + "PLZF-RARA" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "mouse", + "APLs" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation,", + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "the", + "fusion", + "protein", + "PLZF-RARA" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "the", + "fusion", + "protein", + "PLZF-RARA" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation,", + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggers", + "enhance" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation,", + "differentiation", + "differentiation." + ] + } + } + ] + }, + { + "PMID": "18989303", + "TEXT": "Although it has been thought that female mammals develop all the eggs they will ever have by the time they are born, new research suggesting otherwise has now sparked a debate.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "18931683", + "TEXT": "MicroRNAs (miRNAs) are noncoding small RNAs that repress protein translation by targeting specific messenger RNAs. miR-15a and miR-16-1 act as putative tumor suppressors by targeting the oncogene BCL2. These miRNAs form a cluster at the chromosomal region 13q14, which is frequently deleted in cancer. Here, we report that the miR-15a and miR-16-1 cluster targets CCND1 (encoding cyclin D1) and WNT3A, which promotes several tumorigenic features such as survival, proliferation and invasion. In cancer cells of advanced prostate tumors, the miR-15a and miR-16 level is significantly decreased, whereas the expression of BCL2, CCND1 and WNT3A is inversely upregulated. Delivery of antagomirs specific for miR-15a and miR-16 to normal mouse prostate results in marked hyperplasia, and knockdown of miR-15a and miR-16 promotes survival, proliferation and invasiveness of untransformed prostate cells, which become tumorigenic in immunodeficient NOD-SCID mice. Conversely, reconstitution of miR-15a and miR-16-1 expression results in growth arrest, apoptosis and marked regression of prostate tumor xenografts. Altogether, we propose that miR-15a and miR-16 act as tumor suppressor genes in prostate cancer through the control of cell survival, proliferation and invasion. These findings have therapeutic implications and may be exploited for future treatment of prostate cancer.", + "TAG_DATA": [ + "99, antagomirs {'perturbing_action': 'B-rnai/knockdown'}", + "100, specific {'perturbing_action': 'I-rnai/knockdown'}", + "101, for {'perturbing_action': 'I-rnai/knockdown'}", + "102, miR-15a {'perturbing_action': 'I-rnai/knockdown'}", + "103, and {'perturbing_action': 'I-rnai/knockdown'}", + "104, miR-16 {'perturbing_action': 'I-rnai/knockdown'}", + "106, normal {'context': 'B-tissue/organ'}", + "107, mouse {'context': 'I-tissue/organ'}", + "108, prostate {'context': 'I-tissue/organ'}", + "114, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "115, of {'perturbing_action': 'I-rnai/knockdown'}", + "116, miR-15a {'perturbing_action': 'I-rnai/knockdown'}", + "117, and {'perturbing_action': 'I-rnai/knockdown'}", + "118, miR-16 {'perturbing_action': 'I-rnai/knockdown'}", + "119, promotes {'effect': 'B-positive'}", + "121, proliferation {'phenotype': 'B-proliferation'}", + "123, invasiveness {'phenotype': 'B-invasion'}", + "125, untransformed {'context': 'B-cells'}", + "126, prostate {'context': 'I-transformed cells'}", + "127, cells, {'context': 'I-transformed cells'}", + "132, immunodeficient {'context': 'B-organism'}", + "133, NOD-SCID {'context': 'I-organism'}", + "134, mice. {'context': 'I-organism'}", + "136, reconstitution {'perturbing_action': 'B-gene gain-of-function'}", + "137, of {'perturbing_action': 'I-gene gain-of-function'}", + "138, miR-15a {'perturbing_action': 'I-gene gain-of-function'}", + "139, and {'perturbing_action': 'I-gene gain-of-function'}", + "140, miR-16-1 {'perturbing_action': 'I-gene gain-of-function'}", + "141, expression {'perturbing_action': 'I-gene gain-of-function'}", + "145, arrest, {'effect': 'B-negative'}", + "146, apoptosis {'phenotype': 'B-apoptosis'}", + "151, prostate {'context': 'B-xenograft'}", + "152, tumor {'context': 'I-xenograft'}", + "153, xenografts. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "99, antagomirs ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "100, specific ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "101, for ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "102, miR-15a ['l2', 'l21', 'l39', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "103, and ['l3', 'l22', 'l40', 'l57', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "104, miR-16 ['l4', 'l23', 'l41', 'l58', 'l73', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "106, normal ['l5', 'l24', 'l42', 'l59', 'l74', 'l87', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "107, mouse ['l6', 'l25', 'l43', 'l60', 'l75', 'l88', 'l99', 'l105', 'l106', 'l107', 'l108', 'l109']", + "108, prostate ['l7', 'l26', 'l44', 'l61', 'l76', 'l89', 'l100', 'l105', 'l110', 'l111', 'l112', 'l113']", + "114, knockdown ['l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "115, of ['l114', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "116, miR-15a ['l8', 'l27', 'l45', 'l115', 'l129', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "117, and ['l9', 'l28', 'l46', 'l62', 'l116', 'l130', 'l143', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "118, miR-16 ['l10', 'l29', 'l47', 'l63', 'l77', 'l117', 'l131', 'l144', 'l155', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175']", + "119, promotes ['l11', 'l30', 'l48', 'l64', 'l78', 'l90', 'l101', 'l106', 'l110', 'l118', 'l132', 'l145', 'l156', 'l166', 'l176', 'l177', 'l178', 'l179', 'l180']", + "121, proliferation ['l12', 'l31', 'l49', 'l65', 'l79', 'l91', 'l102', 'l107', 'l111', 'l119', 'l133', 'l146', 'l157', 'l167', 'l176', 'l181', 'l182', 'l183', 'l184']", + "123, invasiveness ['l13', 'l32', 'l50', 'l66', 'l80', 'l92', 'l103', 'l108', 'l112', 'l120', 'l134', 'l147', 'l158', 'l168', 'l177', 'l181', 'l185', 'l186', 'l187', 'l188', 'l189']", + "125, untransformed ['l14', 'l33', 'l51', 'l67', 'l81', 'l93', 'l121', 'l135', 'l148', 'l159', 'l169', 'l178', 'l182', 'l185', 'l190', 'l191', 'l192', 'l193', 'l194']", + "126, prostate ['l15', 'l34', 'l52', 'l68', 'l82', 'l94', 'l122', 'l136', 'l149', 'l160', 'l170', 'l179', 'l183', 'l186', 'l190', 'l195', 'l196', 'l197', 'l198']", + "127, cells, ['l16', 'l35', 'l53', 'l69', 'l83', 'l95', 'l104', 'l109', 'l113', 'l123', 'l137', 'l150', 'l161', 'l171', 'l180', 'l184', 'l187', 'l191', 'l195', 'l199', 'l200']", + "132, immunodeficient ['l17', 'l36', 'l54', 'l70', 'l84', 'l96', 'l124', 'l138', 'l151', 'l162', 'l172', 'l188', 'l192', 'l196', 'l199', 'l201', 'l202']", + "133, NOD-SCID ['l18', 'l37', 'l55', 'l71', 'l85', 'l97', 'l125', 'l139', 'l152', 'l163', 'l173', 'l193', 'l197', 'l201', 'l203']", + "134, mice. ['l19', 'l38', 'l56', 'l72', 'l86', 'l98', 'l126', 'l140', 'l153', 'l164', 'l174', 'l189', 'l194', 'l198', 'l200', 'l202', 'l203']", + "136, reconstitution ['l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213']", + "137, of ['l204', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222']", + "138, miR-15a ['l205', 'l214', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230']", + "139, and ['l206', 'l215', 'l223', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237']", + "140, miR-16-1 ['l207', 'l216', 'l224', 'l231', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243']", + "141, expression ['l208', 'l217', 'l225', 'l232', 'l238', 'l244', 'l245', 'l246', 'l247', 'l248']", + "145, arrest, ['l127', 'l141', 'l154', 'l165', 'l175', 'l209', 'l218', 'l226', 'l233', 'l239', 'l244', 'l249']", + "146, apoptosis ['l128', 'l142', 'l210', 'l219', 'l227', 'l234', 'l240', 'l245', 'l249']", + "151, prostate ['l211', 'l220', 'l228', 'l235', 'l241', 'l246', 'l250', 'l251']", + "152, tumor ['l212', 'l221', 'l229', 'l236', 'l242', 'l247', 'l250', 'l252']", + "153, xenografts. ['l213', 'l222', 'l230', 'l237', 'l243', 'l248', 'l251', 'l252']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antagomirs", + "specific", + "for", + "miR-15a", + "and", + "miR-16" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "normal", + "mouse", + "prostate" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antagomirs", + "specific", + "for", + "miR-15a", + "and", + "miR-16", + "knockdown", + "of" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antagomirs", + "specific", + "for", + "miR-15a", + "and", + "miR-16", + "knockdown", + "of" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antagomirs", + "specific", + "for", + "miR-15a", + "and", + "miR-16", + "knockdown", + "of" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antagomirs", + "specific", + "for", + "miR-15a", + "and", + "miR-16", + "knockdown", + "of" + ] + }, + "context": { + "val": "cells", + "words": [ + "untransformed" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antagomirs", + "specific", + "for", + "miR-15a", + "and", + "miR-16", + "knockdown", + "of" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antagomirs", + "specific", + "for", + "miR-15a", + "and", + "miR-16", + "knockdown", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "immunodeficient", + "NOD-SCID", + "mice." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "normal", + "mouse", + "prostate" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "normal", + "mouse", + "prostate" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "normal", + "mouse", + "prostate" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "miR-15a", + "and", + "miR-16" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "cells", + "words": [ + "untransformed" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cells," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "untransformed" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cells," + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness" + ] + }, + "context": { + "val": "cells", + "words": [ + "untransformed" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cells," + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness" + ] + }, + "context": { + "val": "organism", + "words": [ + "immunodeficient", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "reconstitution", + "of", + "miR-15a", + "and", + "miR-16-1", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "reconstitution", + "of", + "miR-15a", + "and", + "miR-16-1", + "expression" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "reconstitution", + "of", + "miR-15a", + "and", + "miR-16-1", + "expression" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "prostate", + "tumor", + "xenografts." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "arrest," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "18849997", + "TEXT": "We have developed a multianalyte fluid-phase protein array technology termed high-throughput immunophenotyping using transcription (HIT). This method employs a panel of monoclonal antibodies, each tagged with a unique oligonucleotide sequence that serves as a molecular bar code. After staining a sample, T7 polymerase amplifies the tags, which are then hybridized to a DNA microarray for indirect measurement of each analyte. Although there are many potential applications for this technology, here we report its suitability for profiling cytokines, intracellular molecules and cell surface markers. Using HIT, we profiled 90 surface markers on human naive T helper cells activated in vitro. The markers identified in this screen are consistent with previously described activation markers and were validated by flow cytometry. Additionally, a HIT screen of surface markers expressed on T helper cells activated in the presence of transforming growth factor-beta identified downregulation of CD26 in these cells. HIT arrays are an ideal platform for rapidly identifying markers for further characterization and therapeutic intervention.", + "TAG_DATA": [ + "91, human {'context': 'B-cells'}", + "92, naive {'context': 'I-cells'}", + "93, T {'context': 'I-cells'}", + "94, helper {'context': 'I-cells'}", + "95, cells {'context': 'I-cells'}", + "97, in {'context': 'B-in vitro'}", + "98, vitro. {'context': 'I-in vitro'}", + "127, T {'context': 'B-cells'}", + "128, helper {'context': 'I-cells'}", + "129, cells {'context': 'I-cells'}", + "144, cells. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "91, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "92, naive ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "93, T ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "94, helper ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "95, cells ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "97, in ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "98, vitro. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "127, T ['l21', 'l22', 'l23']", + "128, helper ['l21', 'l24', 'l25']", + "129, cells ['l22', 'l24', 'l26']", + "144, cells. ['l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18806802", + "TEXT": "Cyclophilin D (CypD, encoded by Ppif) is an integral part of the mitochondrial permeability transition pore, whose opening leads to cell death. Here we show that interaction of CypD with mitochondrial amyloid-beta protein (Abeta) potentiates mitochondrial, neuronal and synaptic stress. The CypD-deficient cortical mitochondria are resistant to Abeta- and Ca(2+)-induced mitochondrial swelling and permeability transition. Additionally, they have an increased calcium buffering capacity and generate fewer mitochondrial reactive oxygen species. Furthermore, the absence of CypD protects neurons from Abeta- and oxidative stress-induced cell death. Notably, CypD deficiency substantially improves learning and memory and synaptic function in an Alzheimer's disease mouse model and alleviates Abeta-mediated reduction of long-term potentiation. Thus, the CypD-mediated mitochondrial permeability transition pore is directly linked to the cellular and synaptic perturbations observed in the pathogenesis of Alzheimer's disease. Blockade of CypD may be a therapeutic strategy in Alzheimer's disease.", + "TAG_DATA": [ + "41, CypD-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "42, cortical {'context': 'B-cells'}", + "43, mitochondria {'context': 'I-cells'}", + "72, absence {'perturbing_action': 'B-gene loss-of-function'}", + "73, of {'perturbing_action': 'I-gene loss-of-function'}", + "74, CypD {'perturbing_action': 'I-gene loss-of-function'}", + "75, protects {'effect': 'B-negative'}", + "76, neurons {'context': 'B-cells'}", + "82, cell {'phenotype': 'B-cell death'}", + "83, death. {'phenotype': 'I-cell death'}", + "85, CypD {'perturbing_action': 'B-gene loss-of-function'}", + "86, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "97, Alzheimer's {'context': 'B-organism'}", + "98, disease {'context': 'I-organism'}", + "99, mouse {'context': 'I-organism'}", + "100, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "41, CypD-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "42, cortical ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "43, mitochondria ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "72, absence ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "73, of ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "74, CypD ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "75, protects ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "76, neurons ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "82, cell ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "83, death. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "85, CypD ['l45', 'l46', 'l47', 'l48', 'l49']", + "86, deficiency ['l45', 'l50', 'l51', 'l52', 'l53']", + "97, Alzheimer's ['l46', 'l50', 'l54', 'l55', 'l56']", + "98, disease ['l47', 'l51', 'l54', 'l57', 'l58']", + "99, mouse ['l48', 'l52', 'l55', 'l57', 'l59']", + "100, model ['l49', 'l53', 'l56', 'l58', 'l59']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CypD-deficient", + "absence", + "of", + "CypD" + ] + }, + "context": { + "val": "cells", + "words": [ + "cortical", + "mitochondria", + "neurons" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CypD-deficient", + "absence", + "of", + "CypD" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protects" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CypD-deficient", + "absence", + "of", + "CypD" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cortical", + "mitochondria", + "neurons" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protects" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cortical", + "mitochondria", + "neurons" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "protects" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CypD", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "Alzheimer's", + "disease", + "mouse", + "model" + ] + } + } + ] + }, + { + "PMID": "18806801", + "TEXT": "Increased lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity is associated with increased risk of cardiac events, but it is not known whether Lp-PLA(2) is a causative agent. Here we show that selective inhibition of Lp-PLA(2) with darapladib reduced development of advanced coronary atherosclerosis in diabetic and hypercholesterolemic swine. Darapladib markedly inhibited plasma and lesion Lp-PLA(2) activity and reduced lesion lysophosphatidylcholine content. Analysis of coronary gene expression showed that darapladib exerted a general anti-inflammatory action, substantially reducing the expression of 24 genes associated with macrophage and T lymphocyte functioning. Darapladib treatment resulted in a considerable decrease in plaque area and, notably, a markedly reduced necrotic core area and reduced medial destruction, resulting in fewer lesions with an unstable phenotype. These data show that selective inhibition of Lp-PLA(2) inhibits progression to advanced coronary atherosclerotic lesions and confirms a crucial role of vascular inflammation independent from hypercholesterolemia in the development of lesions implicated in the pathogenesis of myocardial infarction and stroke.", + "TAG_DATA": [ + "29, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "30, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "31, of {'perturbing_action': 'I-pharmacological inhibition'}", + "32, Lp-PLA(2) {'perturbing_action': 'I-pharmacological inhibition'}", + "33, with {'perturbing_action': 'I-pharmacological inhibition'}", + "34, darapladib {'perturbing_action': 'I-pharmacological inhibition'}", + "42, diabetic {'context': 'B-organism'}", + "43, and {'context': 'I-organism'}", + "45, swine. {'context': 'I-organism'}", + "120, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "121, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "122, of {'perturbing_action': 'I-pharmacological inhibition'}", + "123, Lp-PLA(2) {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "29, selective ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "30, inhibition ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "31, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "32, Lp-PLA(2) ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "33, with ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "34, darapladib ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "42, diabetic ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "43, and ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "45, swine. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "120, selective ['l36', 'l37', 'l38']", + "121, inhibition ['l36', 'l39', 'l40']", + "122, of ['l37', 'l39', 'l41']", + "123, Lp-PLA(2) ['l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "inhibition", + "of", + "Lp-PLA(2)", + "with", + "darapladib" + ] + }, + "context": { + "val": "organism", + "words": [ + "diabetic", + "and", + "swine." + ] + } + } + ] + }, + { + "PMID": "18724379", + "TEXT": "The immunosuppressive action of the calcineurin inhibitor cyclosporine A (CsA) stems from the inhibition of nuclear factor of activated T cells (NFAT) signaling in T cells. CsA is also used for the treatment of proteinuric kidney diseases. As it stands, the antiproteinuric effect of CsA is attributed to its immunosuppressive action. Here we show that the beneficial effect of CsA on proteinuria is not dependent on NFAT inhibition in T cells, but rather results from the stabilization of the actin cytoskeleton in kidney podocytes. CsA blocks the calcineurin-mediated dephosphorylation of synaptopodin, a regulator of Rho GTPases in podocytes, thereby preserving the phosphorylation-dependent synaptopodin-14-3-3 beta interaction. Preservation of this interaction, in turn, protects synaptopodin from cathepsin L-mediated degradation. These results represent a new view of calcineurin signaling and shed further light on the treatment of proteinuric kidney diseases. Novel calcineurin substrates such as synaptopodin may provide promising starting points for antiproteinuric drugs that avoid the serious side effects of long-term CsA treatment.", + "TAG_DATA": [ + "97, podocytes, {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "18724377", + "TEXT": "Osteoclasts differentiate from precursor cells of the monocyte-macrophage lineage and subsequently become activated to be competent for bone resorption through programs primarily governed by receptor activator of nuclear factor-kappaB ligand in cooperation with macrophage colony-stimulating factor. Proteins prominently expressed at late phases of osteoclastogenesis and with a supportive role in osteoclast function are potential therapeutic targets for bone-remodeling disorders. In this study, we used a proteomics approach to show that abundance of the brain-type cytoplasmic creatine kinase (Ckb) is greatly increased during osteoclastogenesis. Decreasing Ckb abundance by RNA interference or blocking its enzymatic activity with a pharmacological inhibitor, cyclocreatine, suppressed the bone-resorbing activity of osteoclasts grown in vitro via combined effects on actin ring formation, RhoA GTPase activity and vacuolar ATPase function. Activities of osteoclasts derived from Ckb-/- mice were similarly affected. In vivo studies showed that Ckb-/- mice were better protected against bone loss induced by ovariectomy, lipopolysaccharide challenge or interleukin-1 treatment than wild-type controls. Furthermore, administration of cyclocreatine or adenoviruses harboring Ckb small hairpin RNA attenuated bone loss in rat and mouse models. Our findings establish an important role for Ckb in the bone-resorbing function of osteoclasts and underscore its potential as a new molecular target for antiresorptive drug development.", + "TAG_DATA": [ + "83, Decreasing {'perturbing_action': 'B-rnai/knockdown'}", + "84, Ckb {'perturbing_action': 'I-rnai/knockdown'}", + "85, abundance {'perturbing_action': 'I-rnai/knockdown'}", + "86, by {'perturbing_action': 'I-rnai/knockdown'}", + "87, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "88, interference {'perturbing_action': 'I-rnai/knockdown'}", + "104, osteoclasts {'context': 'B-cells'}", + "106, in {'context': 'B-in vitro'}", + "107, vitro {'context': 'I-in vitro'}", + "124, osteoclasts {'context': 'B-cells'}", + "127, Ckb-/- {'perturbing_action': 'B-gene loss-of-function'}", + "128, mice {'context': 'B-organism'}", + "132, In {'context': 'B-in vivo'}", + "133, vivo {'context': 'I-in vivo'}", + "137, Ckb-/- {'perturbing_action': 'B-gene loss-of-function'}", + "138, mice {'context': 'B-organism'}", + "161, adenoviruses {'perturbing_action': 'B-rnai/knockdown'}", + "162, harboring {'perturbing_action': 'I-rnai/knockdown'}", + "163, Ckb {'perturbing_action': 'I-rnai/knockdown'}", + "164, small {'perturbing_action': 'I-rnai/knockdown'}", + "165, hairpin {'perturbing_action': 'I-rnai/knockdown'}", + "166, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "171, rat {'context': 'B-organism'}", + "172, and {'context': 'I-organism'}", + "173, mouse {'context': 'I-organism'}", + "174, models. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "83, Decreasing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "84, Ckb ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "85, abundance ['l1', 'l9', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "86, by ['l2', 'l10', 'l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "87, RNA ['l3', 'l11', 'l17', 'l22', 'l27', 'l28', 'l29', 'l30']", + "88, interference ['l4', 'l12', 'l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "104, osteoclasts ['l5', 'l13', 'l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "106, in ['l6', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "107, vitro ['l7', 'l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l36']", + "124, osteoclasts ['l8', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "127, Ckb-/- ['l37', 'l43', 'l44', 'l45', 'l46', 'l47']", + "128, mice ['l38', 'l43', 'l48', 'l49', 'l50']", + "132, In ['l39', 'l44', 'l48', 'l51', 'l52', 'l53']", + "133, vivo ['l40', 'l45', 'l49', 'l51', 'l54', 'l55']", + "137, Ckb-/- ['l41', 'l46', 'l52', 'l54', 'l56']", + "138, mice ['l42', 'l47', 'l50', 'l53', 'l55', 'l56']", + "161, adenoviruses ['l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "162, harboring ['l57', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "163, Ckb ['l58', 'l66', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "164, small ['l59', 'l67', 'l74', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "165, hairpin ['l60', 'l68', 'l75', 'l81', 'l87', 'l88', 'l89', 'l90', 'l91']", + "166, RNA ['l61', 'l69', 'l76', 'l82', 'l87', 'l92', 'l93', 'l94', 'l95']", + "171, rat ['l62', 'l70', 'l77', 'l83', 'l88', 'l92', 'l96', 'l97', 'l98']", + "172, and ['l63', 'l71', 'l78', 'l84', 'l89', 'l93', 'l96', 'l99', 'l100']", + "173, mouse ['l64', 'l72', 'l79', 'l85', 'l90', 'l94', 'l97', 'l99', 'l101']", + "174, models. ['l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l98', 'l100', 'l101']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Decreasing", + "Ckb", + "abundance", + "by", + "RNA", + "interference" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclasts" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Decreasing", + "Ckb", + "abundance", + "by", + "RNA", + "interference" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoclasts" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ckb-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ckb-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ckb-/-" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "adenoviruses", + "harboring", + "Ckb", + "small", + "hairpin", + "RNA" + ] + }, + "context": { + "val": "organism", + "words": [ + "rat", + "and", + "mouse", + "models." + ] + } + } + ] + }, + { + "PMID": "18690244", + "TEXT": "Although eosinophils are considered useful in defense mechanisms against parasites, their exact function in innate immunity remains unclear. The aim of this study is to better understand the role of eosinophils within the gastrointestinal immune system. We show here that lipopolysaccharide from Gram-negative bacteria activates interleukin-5 (IL-5)- or interferon-gamma-primed eosinophils to release mitochondrial DNA in a reactive oxygen species-dependent manner, but independent of eosinophil death. Notably, the process of DNA release occurs rapidly in a catapult-like manner--in less than one second. In the extracellular space, the mitochondrial DNA and the granule proteins form extracellular structures able to bind and kill bacteria both in vitro and under inflammatory conditions in vivo. Moreover, after cecal ligation and puncture, Il5-transgenic but not wild-type mice show intestinal eosinophil infiltration and extracellular DNA deposition in association with protection against microbial sepsis. These data suggest a previously undescribed mechanism of eosinophil-mediated innate immune responses that might be crucial for maintaining the intestinal barrier function after inflammation-associated epithelial cell damage, preventing the host from uncontrolled invasion of bacteria.", + "TAG_DATA": [ + "49, eosinophils {'context': 'B-cells'}", + "102, in {'context': 'B-in vitro'}", + "103, vitro {'context': 'I-in vitro'}", + "108, in {'context': 'B-in vivo'}", + "109, vivo. {'context': 'I-in vivo'}", + "116, Il5-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "120, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "49, eosinophils ['l0']", + "102, in ['l1', 'l2', 'l3']", + "103, vitro ['l0', 'l1', 'l4', 'l5']", + "108, in ['l2', 'l4', 'l6']", + "109, vivo. ['l3', 'l5', 'l6']", + "116, Il5-transgenic ['l7']", + "120, mice ['l7']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Il5-transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "18690243", + "TEXT": "Chaperone-mediated autophagy (CMA), a selective mechanism for degradation of cytosolic proteins in lysosomes, contributes to the removal of altered proteins as part of the cellular quality-control systems. We have previously found that CMA activity declines in aged organisms and have proposed that this failure in cellular clearance could contribute to the accumulation of altered proteins, the abnormal cellular homeostasis and, eventually, the functional loss characteristic of aged organisms. To determine whether these negative features of aging can be prevented by maintaining efficient autophagic activity until late in life, in this work we have corrected the CMA defect in aged rodents. We have generated a double transgenic mouse model in which the amount of the lysosomal receptor for CMA, previously shown to decrease in abundance with age, can be modulated. We have analyzed in this model the consequences of preventing the age-dependent decrease in receptor abundance in aged rodents at the cellular and organ levels. We show here that CMA activity is maintained until advanced ages if the decrease in the receptor abundance is prevented and that preservation of autophagic activity is associated with lower intracellular accumulation of damaged proteins, better ability to handle protein damage and improved organ function.", + "TAG_DATA": [ + "98, aged {'context': 'B-organism'}", + "99, rodents. {'context': 'I-organism'}", + "106, mouse {'context': 'B-organism'}", + "107, model {'context': 'I-organism'}", + "147, rodents {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "98, aged ['l0']", + "99, rodents. ['l0']", + "105, transgenic ['l1', 'l2']", + "106, mouse ['l1', 'l3']", + "107, model ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18660817", + "TEXT": "Sclerosis and reduced microvessel density characterize advanced stages of muscular dystrophy and hamper cell or gene delivery, precluding treatment of most individuals with Duchenne muscular dystrophy. Modified tendon fibroblasts expressing an angiogenic factor (placenta growth factor, PlGF) and a metalloproteinase (matrix metalloproteinase-9, MMP-9) are able to restore a vascular network and reduce collagen deposition, allowing efficient cell therapy in aged dystrophic mice. These data open the possibility of extending new therapies to currently untreatable individuals.", + "TAG_DATA": [ + "27, tendon {'context': 'B-cells'}", + "28, fibroblasts {'context': 'I-cells'}", + "59, aged {'context': 'B-organism'}", + "60, dystrophic {'context': 'I-organism'}", + "61, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "27, tendon ['l0', 'l1', 'l2', 'l3']", + "28, fibroblasts ['l0', 'l4', 'l5', 'l6']", + "59, aged ['l1', 'l4', 'l7', 'l8']", + "60, dystrophic ['l2', 'l5', 'l7', 'l9']", + "61, mice. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18607350", + "TEXT": "Rapid and accurate measurement of biomarkers in tissue and fluid samples is a major challenge in medicine. Here we report the development of a new, miniaturized diagnostic magnetic resonance (DMR) system for multiplexed, quantitative and rapid analysis. By using magnetic particles as a proximity sensor to amplify molecular interactions, the handheld DMR system can perform measurements on unprocessed biological samples. We show the capability of the DMR system by using it to detect bacteria with high sensitivity, identify small numbers of cells and analyze them on a molecular level in real time, and measure a series of protein biomarkers in parallel. The DMR technology shows promise as a robust and portable diagnostic device.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "18607349", + "TEXT": "Individuals with mutations in breast cancer susceptibility genes BRCA1 and BRCA2 have up to an 80% risk of developing breast cancer by the age of 70. Sequencing-based genetic tests are now available to identify mutation carriers in an effort to reduce mortality through prevention and early diagnosis. However, lack of a suitable functional assay hinders the risk assessment of more than 1,900 BRCA1 and BRCA2 variants in the Breast Cancer Information Core database that do not clearly disrupt the gene product. We have established a simple, versatile and reliable assay to test for the functional significance of mutations in BRCA2 using mouse embryonic stem cells (ES cells) and bacterial artificial chromosomes and have used it to classify 17 sequence variants. The assay is based on the ability of human BRCA2 to complement the loss of endogenous Brca2 in mouse ES cells. This technique may also serve as a paradigm for functional analysis of mutations found in other genes linked to human diseases.", + "TAG_DATA": [ + "101, mouse {'context': 'B-cells'}", + "102, embryonic {'context': 'I-cells'}", + "103, stem {'context': 'I-cells'}", + "104, cells {'context': 'I-cells'}", + "105, (ES {'context': 'I-cells'}", + "106, cells) {'context': 'I-cells'}", + "135, endogenous {'perturbing_action': 'I-gene loss-of-function'}", + "138, mouse {'context': 'B-cells'}", + "139, ES {'context': 'I-cells'}", + "140, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "101, mouse ['l0', 'l1', 'l2', 'l3', 'l4']", + "102, embryonic ['l0', 'l5', 'l6', 'l7', 'l8']", + "103, stem ['l1', 'l5', 'l9', 'l10', 'l11']", + "104, cells ['l2', 'l6', 'l9', 'l12', 'l13']", + "105, (ES ['l3', 'l7', 'l10', 'l12', 'l14']", + "106, cells) ['l4', 'l8', 'l11', 'l13', 'l14']", + "135, endogenous ['l15', 'l16', 'l17']", + "138, mouse ['l15', 'l18', 'l19']", + "139, ES ['l16', 'l18', 'l20']", + "140, cells. ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "endogenous" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "ES", + "cells." + ] + } + } + ] + }, + { + "PMID": "18587408", + "TEXT": "Recent efforts have revealed that numerous protein-coding messenger RNAs have natural antisense transcript partners, most of which seem to be noncoding RNAs. Here we identify a conserved noncoding antisense transcript for beta-secretase-1 (BACE1), a crucial enzyme in Alzheimer's disease pathophysiology. The BACE1-antisense transcript (BACE1-AS) regulates BACE1 mRNA and subsequently BACE1 protein expression in vitro and in vivo. Upon exposure to various cell stressors including amyloid-beta 1-42 (Abeta 1-42), expression of BACE1-AS becomes elevated, increasing BACE1 mRNA stability and generating additional Abeta 1-42 through a post-transcriptional feed-forward mechanism. BACE1-AS concentrations were elevated in subjects with Alzheimer's disease and in amyloid precursor protein transgenic mice. These data show that BACE1 mRNA expression is under the control of a regulatory noncoding RNA that may drive Alzheimer's disease-associated pathophysiology. In summary, we report that a long noncoding RNA is directly implicated in the increased abundance of Abeta 1-42 in Alzheimer's disease.", + "TAG_DATA": [ + "98, amyloid {'perturbing_action': 'B-gene gain-of-function'}", + "99, precursor {'perturbing_action': 'I-gene gain-of-function'}", + "100, protein {'perturbing_action': 'I-gene gain-of-function'}", + "101, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "102, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "98, amyloid ['l0', 'l1', 'l2', 'l3']", + "99, precursor ['l0', 'l4', 'l5', 'l6']", + "100, protein ['l1', 'l4', 'l7', 'l8']", + "101, transgenic ['l2', 'l5', 'l7', 'l9']", + "102, mice. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "amyloid", + "precursor", + "protein", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "18542049", + "TEXT": "Autoantibody-mediated diseases like myasthenia gravis, autoimmune hemolytic anemia and systemic lupus erythematosus represent a therapeutic challenge. In particular, long-lived plasma cells producing autoantibodies resist current therapeutic and experimental approaches. Recently, we showed that the sensitivity of myeloma cells toward proteasome inhibitors directly correlates with their immunoglobulin synthesis rates. Therefore, we hypothesized that normal plasma cells are also hypersensitive to proteasome inhibition owing to their extremely high amount of protein biosynthesis. Here we show that the proteasome inhibitor bortezomib, which is approved for the treatment of multiple myeloma, eliminates both short- and long-lived plasma cells by activation of the terminal unfolded protein response. Treatment with bortezomib depleted plasma cells producing antibodies to double-stranded DNA, eliminated autoantibody production, ameliorated glomerulonephritis and prolonged survival of two mouse strains with lupus-like disease, NZB/W F1 and MRL/lpr mice. Hence, the elimination of autoreactive plasma cells by proteasome inhibitors might represent a new treatment strategy for antibody-mediated diseases.", + "TAG_DATA": [ + "92, plasma {'context': 'B-cells'}", + "93, cells {'context': 'I-cells'}", + "106, plasma {'context': 'B-cells'}", + "107, cells {'context': 'I-cells'}", + "123, mouse {'context': 'B-organism'}", + "124, strains {'context': 'I-organism'}", + "132, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "92, plasma ['l0']", + "93, cells ['l0']", + "106, plasma ['l1']", + "107, cells ['l1']", + "123, mouse ['l2', 'l3']", + "124, strains ['l2', 'l4']", + "132, mice. ['l3', 'l4']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18500350", + "TEXT": "Obesity and metabolic syndrome are increasingly recognized as major risk factors for cardiovascular disease. Herein we show that Krüppel-like transcription factor 5 (KLF5) is a crucial regulator of energy metabolism. Klf5(+/-) mice were resistant to high fat-induced obesity, hypercholesterolemia and glucose intolerance, despite consuming more food than wild-type mice. This may in part reflect their enhanced energy expenditure. Expression of the genes involved in lipid oxidation and energy uncoupling, including those encoding carnitine-palmitoyl transferase-1b (Cpt1b) and uncoupling proteins 2 and 3 (Ucp2 and Ucp3), was upregulated in the soleus muscles of Klf5(+/-) mice. Under basal conditions, KLF5 modified with small ubiquitin-related modifier (SUMO) proteins was associated with transcriptionally repressive regulatory complexes containing unliganded peroxisome proliferator-activated receptor-delta (PPAR-delta) and co-repressors and thus inhibited Cpt1b, Ucp2 and Ucp3 expression. Upon agonist stimulation of PPAR-delta, KLF5 was deSUMOylated, and became associated with transcriptional activation complexes containing both the liganded PPAR-delta and CREB binding protein (CBP). This activation complex increased the expression of Cpt1b, Ucp2 and Ucp3. Thus, SUMOylation seems to be a molecular switch affecting function of KLF5 and the transcriptional regulatory programs governing lipid metabolism.", + "TAG_DATA": [ + "30, Klf5(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "31, mice {'context': 'B-organism'}", + "88, soleus {'context': 'B-tissue/organ'}", + "89, muscles {'context': 'I-tissue/organ'}", + "91, Klf5(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "92, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "30, Klf5(+/-) ['l0', 'l1', 'l2']", + "31, mice ['l0', 'l3', 'l4']", + "88, soleus ['l1', 'l3', 'l5', 'l6']", + "89, muscles ['l2', 'l4', 'l5']", + "91, Klf5(+/-) ['l7']", + "92, mice. ['l6', 'l7']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Klf5(+/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Klf5(+/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "soleus", + "muscles" + ] + } + } + ] + }, + { + "PMID": "18454155", + "TEXT": "Dendritic cells (DCs) are integral to the differentiation of T helper cells into T helper type 1 T(H)1, T(H)2 and T(H)17 subsets. Interleukin-6 (IL-6) plays an important part in regulating these three arms of the immune response by limiting the T(H)1 response and promoting the T(H)2 and T(H)17 responses. In this study, we investigated pathways in DCs that promote IL-6 production. We show that the allergen house dust mite (HDM) or the mucosal adjuvant cholera toxin promotes cell surface expression of c-Kit and its ligand, stem cell factor (SCF), on DCs. This dual upregulation of c-Kit and SCF results in sustained signaling downstream of c-Kit, promoting IL-6 secretion. Intranasal administration of antigen into c-Kit-mutant mice or neutralization of IL-6 in cultures established from the lung-draining lymph nodes of immunized wild-type mice blunted the T(H)2 and T(H)17 responses. DCs lacking functional c-Kit or those unable to express membrane-bound SCF secreted lower amounts of IL-6 in response to HDM or cholera toxin. DCs expressing nonfunctional c-Kit were unable to induce a robust T(H)2 or T(H)17 response and elicited diminished allergic airway inflammation when adoptively transferred into mice. Expression of the Notch ligand Jagged-2, which has been associated with T(H)2 differentiation, was blunted in DCs from c-Kit-mutant mice. c-Kit upregulation was specifically induced by T(H)2- and T(H)17-skewing stimuli, as the T(H)1-inducing adjuvant, CpG oligodeoxynucleotide, did not promote either c-Kit or Jagged-2 expression. DCs generated from mice expressing a catalytically inactive form of the p110delta subunit of phosphatidylinositol-3 (PI3) kinase (p110(D910A)) secreted lower amounts of IL-6 upon stimulation with cholera toxin.", + "TAG_DATA": [ + "113, c-Kit-mutant {'perturbing_action': 'B-other'}", + "114, mice {'context': 'B-organism'}", + "120, cultures {'context': 'B-cells'}", + "121, established {'context': 'I-cells'}", + "124, lung-draining {'context': 'B-tissue/organ'}", + "125, lymph {'context': 'I-tissue/organ'}", + "126, nodes {'context': 'I-tissue/organ'}", + "130, mice {'context': 'B-organism'}", + "137, DCs {'context': 'B-cells'}", + "138, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "139, functional {'perturbing_action': 'I-gene loss-of-function'}", + "140, c-Kit {'perturbing_action': 'I-gene loss-of-function'}", + "160, DCs {'context': 'B-cells'}", + "161, expressing {'perturbing_action': 'B-other'}", + "162, nonfunctional {'perturbing_action': 'B-other'}", + "163, c-Kit {'perturbing_action': 'I-other'}", + "184, mice. {'context': 'B-organism'}", + "201, DCs {'context': 'B-cells'}", + "203, c-Kit-mutant {'perturbing_action': 'B-other'}", + "204, mice. {'context': 'B-organism'}", + "229, DCs {'context': 'B-cells'}", + "232, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "113, c-Kit-mutant ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "114, mice ['l0', 'l6', 'l7', 'l8', 'l9']", + "120, cultures ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "121, established ['l10', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "122, from ['l11', 'l21', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "123, the ['l1', 'l12', 'l22', 'l32', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "124, lung-draining ['l2', 'l6', 'l13', 'l23', 'l33', 'l41', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "125, lymph ['l3', 'l7', 'l14', 'l24', 'l34', 'l42', 'l49', 'l56', 'l57', 'l58', 'l59', 'l60']", + "126, nodes ['l4', 'l8', 'l15', 'l25', 'l35', 'l43', 'l50', 'l56', 'l61', 'l62']", + "130, mice ['l5', 'l9', 'l16', 'l26', 'l36', 'l44', 'l51', 'l57', 'l61']", + "137, DCs ['l17', 'l27', 'l37', 'l45', 'l52', 'l58', 'l62', 'l63', 'l64', 'l65']", + "138, lacking ['l18', 'l28', 'l38', 'l46', 'l53', 'l63', 'l66', 'l67', 'l68']", + "139, functional ['l19', 'l29', 'l39', 'l47', 'l54', 'l59', 'l64', 'l66', 'l69', 'l70']", + "140, c-Kit ['l20', 'l30', 'l40', 'l48', 'l55', 'l60', 'l65', 'l67', 'l69', 'l71']", + "160, DCs ['l72', 'l73', 'l74']", + "161, expressing ['l72', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "162, nonfunctional ['l75', 'l81', 'l82', 'l83', 'l84', 'l85']", + "163, c-Kit ['l73', 'l76', 'l81', 'l86', 'l87', 'l88']", + "184, mice. ['l31', 'l68', 'l70', 'l71', 'l74', 'l77', 'l82', 'l86']", + "201, DCs ['l78', 'l83', 'l87', 'l89', 'l90']", + "203, c-Kit-mutant ['l79', 'l84', 'l89', 'l91']", + "204, mice. ['l80', 'l85', 'l88', 'l90', 'l91']", + "229, DCs ['l92']", + "232, mice ['l92']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "c-Kit-mutant", + "expressing", + "nonfunctional", + "c-Kit" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "c-Kit-mutant" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung-draining", + "lymph", + "nodes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultures", + "established", + "DCs" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "functional", + "c-Kit" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "lung-draining", + "lymph" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "functional", + "c-Kit" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "functional", + "c-Kit" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "DCs" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "c-Kit", + "nonfunctional", + "c-Kit-mutant" + ] + } + } + ] + }, + { + "PMID": "18438416", + "TEXT": "Intact CD3-specific antibody transiently depletes large numbers of T cells and subsequently induces long-term immune tolerance. The underlying mechanisms for the systemic tolerance, however, remain unclear. We show here that treatment of normal mice with intact antibody to CD3 increases systemic transforming growth factor-beta (TGF-beta) produced by phagocytes exposed to apoptotic T cells. Among the phagocytes, macrophages and immature dendritic cells (iDCs) secrete TGF-beta upon ingestion of apoptotic T cells, which induces CD4+Foxp3+ regulatory T cells in culture and contributes to immune tolerance mediated by CD3-specific antibody in vivo. In accordance with these results, depletion of macrophages and iDCs not only abrogates CD3-specific antibody-mediated prevention of myelin oligodendrocyte glycoprotein-induced acute experimental autoimmune encephalomyelitis (EAE), but also reverses the therapeutic effects of antibody to CD3 on established disease in a model of relapsing-remitting EAE. Thus, CD3-specific antibody-induced immune tolerance is associated with TGF-beta production in phagocytes involved in clearing apoptotic T cells, which suggests that apoptosis is linked to active suppression in immune tolerance.", + "TAG_DATA": [ + "32, normal {'context': 'B-organism'}", + "33, mice {'context': 'I-organism'}", + "47, phagocytes {'context': 'B-cells'}", + "55, phagocytes, {'context': 'B-cells'}", + "56, macrophages {'context': 'B-cells'}", + "58, immature {'context': 'B-cells'}", + "59, dendritic {'context': 'I-cells'}", + "60, cells {'context': 'I-cells'}", + "61, (iDCs) {'context': 'I-cells'}", + "77, culture {'context': 'I-in vitro'}", + "87, in {'context': 'B-in vivo'}", + "88, vivo. {'context': 'I-in vivo'}", + "96, macrophages {'context': 'B-cells'}", + "98, iDCs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "32, normal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "33, mice ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "47, phagocytes ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "55, phagocytes, ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "56, macrophages ['l3', 'l10', 'l16', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "58, immature ['l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "59, dendritic ['l23', 'l31', 'l38', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "60, cells ['l24', 'l32', 'l39', 'l47', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "61, (iDCs) ['l25', 'l33', 'l40', 'l48', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "76, in ['l4', 'l11', 'l17', 'l26', 'l34', 'l41', 'l49', 'l56', 'l61', 'l66', 'l67', 'l68']", + "77, culture ['l5', 'l12', 'l18', 'l27', 'l35', 'l42', 'l50', 'l57', 'l62', 'l66', 'l69', 'l70']", + "87, in ['l6', 'l13', 'l19', 'l28', 'l36', 'l43', 'l51', 'l58', 'l63', 'l67', 'l69', 'l71']", + "88, vivo. ['l7', 'l14', 'l20', 'l29', 'l37', 'l44', 'l52', 'l59', 'l64', 'l68', 'l70', 'l71']", + "96, macrophages ['l45', 'l53', 'l60', 'l65', 'l72']", + "98, iDCs ['l46', 'l54', 'l72']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18425131", + "TEXT": "In this study, we document the development of stable, antigen-independent CD8+ T cell memory after drug-induced cure of a chronic infection. By establishing a system for drug cure of chronic Trypanosoma cruzi infection, we present the first extensively documented case of total parasite clearance after drug treatment of this infection. Cure resulted in the emergence of a stable, parasite-specific CD8+ T cell population with the characteristics of central memory cells, based upon expression of CD62L, CCR7, CD127, CD122, Bcl-2 and a reduced immediate in vivo CTL function. CD8+ T cells from treated and cured mice also expanded more rapidly and provided greater protection following challenge than those from chronically infected mice. These results show that complete pathogen clearance results in stable, antigen-independent and protective T cell memory, despite the potentially exhausting effects of prior long-term exposure to antigen in this chronic infection.", + "TAG_DATA": [ + "59, CD8+ {'context': 'B-cells'}", + "60, T {'context': 'I-cells'}", + "61, cell {'context': 'I-cells'}", + "83, in {'context': 'B-in vivo'}", + "84, vivo {'context': 'B-in vivo'}", + "87, CD8+ {'context': 'B-cells'}", + "88, T {'context': 'I-cells'}", + "89, cells {'context': 'I-cells'}", + "94, mice {'context': 'B-organism'}", + "110, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "59, CD8+ ['l0', 'l1', 'l2', 'l3', 'l4']", + "60, T ['l0', 'l5', 'l6', 'l7']", + "61, cell ['l1', 'l5', 'l8', 'l9']", + "83, in ['l2', 'l6', 'l8', 'l10']", + "84, vivo ['l3', 'l7', 'l9', 'l10']", + "87, CD8+ ['l11', 'l12', 'l13', 'l14']", + "88, T ['l11', 'l15', 'l16', 'l17']", + "89, cells ['l4', 'l12', 'l15', 'l18']", + "94, mice ['l13', 'l16', 'l18']", + "110, mice. ['l14', 'l17']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18425130", + "TEXT": "Beta-adrenergic receptor (betaAR) blockade is a standard therapy for cardiac failure and ischemia. G protein-coupled receptor kinases (GRKs) desensitize betaARs, suggesting that genetic GRK variants might modify outcomes in these syndromes. Re-sequencing of GRK2 and GRK5 revealed a nonsynonymous polymorphism of GRK5, common in African Americans, in which leucine is substituted for glutamine at position 41. GRK5-Leu41 uncoupled isoproterenol-stimulated responses more effectively than did GRK5-Gln41 in transfected cells and transgenic mice, and, like pharmacological betaAR blockade, GRK5-Leu41 protected against experimental catecholamine-induced cardiomyopathy. Human association studies showed a pharmacogenomic interaction between GRK5-Leu41 and beta-blocker treatment, in which the presence of the GRK5-Leu41 polymorphism was associated with decreased mortality in African Americans with heart failure or cardiac ischemia. In 375 prospectively followed African-American subjects with heart failure, GRK5-Leu41 protected against death or cardiac transplantation. Enhanced betaAR desensitization of excessive catecholamine signaling by GRK5-Leu41 provides a 'genetic beta-blockade' that improves survival in African Americans with heart failure, suggesting a reason for conflicting results of beta-blocker clinical trials in this population.", + "TAG_DATA": [ + "66, transfected {'perturbing_action': 'B-gene gain-of-function', 'context': 'B-cells'}", + "67, cells {'context': 'B-cells'}", + "69, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "70, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "66, transfected ['l0']", + "67, cells ['l0']", + "69, transgenic ['l1']", + "70, mice, ['l1']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected" + ] + }, + "context": { + "val": "cells", + "words": [ + "transfected" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "18425129", + "TEXT": "Mast cells (MCs) have recently received recognition as prominent effectors in the regulation of immune cell migration to draining lymph nodes and lymphocyte activation. However, their role in the development of humoral immune responses is not clear. Here, we demonstrate that subcutaneous or nasal administration of small-molecule MC activators with vaccine antigens evokes large increases in antigen-specific serum immunoglobulin G (IgG) responses. These responses were MC dependent and correlated with increased dendritic cell and lymphocyte recruitment to draining lymph nodes. Nasal instillation of these formulations also evoked antigen-specific secretory IgA and provided protection against anthrax lethal toxin challenge in vitro and against vaccinia virus infection in vivo. Collectively, these results define the MC as an integral sensory arm of the adaptive immune system. Moreover, they highlight MC activators as a new class of vaccine adjuvants, capable of inducing protective antigen-specific immune responses through needle-free routes of administration.", + "TAG_DATA": [ + "98, in {'context': 'B-in vitro'}", + "99, vitro {'context': 'I-in vitro'}", + "105, in {'context': 'B-in vivo'}", + "106, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "98, in ['l0']", + "99, vitro ['l0']", + "105, in ['l1']", + "106, vivo. ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18376410", + "TEXT": "Noninvasive imaging at the molecular level is an emerging field in biomedical research. This paper introduces a new technology synergizing two leading imaging methodologies: positron emission tomography (PET) and magnetic resonance imaging (MRI). Although the value of PET lies in its high-sensitivity tracking of biomarkers in vivo, it lacks resolving morphology. MRI has lower sensitivity, but produces high soft-tissue contrast and provides spectroscopic information and functional MRI (fMRI). We have developed a three-dimensional animal PET scanner that is built into a 7-T MRI. Our evaluations show that both modalities preserve their functionality, even when operated isochronously. With this combined imaging system, we simultaneously acquired functional and morphological PET-MRI data from living mice. PET-MRI provides a powerful tool for studying biology and pathology in preclinical research and has great potential for clinical applications. Combining fMRI and spectroscopy with PET paves the way for a new perspective in molecular imaging.", + "TAG_DATA": [ + "111, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "18376406", + "TEXT": "Salmonella typhimurium causes a localized enteric infection in immunocompetent individuals, whereas HIV-infected individuals develop a life-threatening bacteremia. Here we show that simian immunodeficiency virus (SIV) infection results in depletion of T helper type 17 (TH17) cells in the ileal mucosa of rhesus macaques, thereby impairing mucosal barrier functions to S. typhimurium dissemination. In SIV-negative macaques, the gene expression profile induced by S. typhimurium in ligated ileal loops was dominated by TH17 responses, including the expression of interleukin-17 (IL-17) and IL-22. TH17 cells were markedly depleted in SIV-infected rhesus macaques, resulting in blunted TH17 responses to S. typhimurium infection and increased bacterial dissemination. IL-17 receptor-deficient mice showed increased systemic dissemination of S. typhimurium from the gut, suggesting that IL-17 deficiency causes defects in mucosal barrier function. We conclude that SIV infection impairs the IL-17 axis, an arm of the mucosal immune response preventing systemic microbial dissemination from the gastrointestinal tract.", + "TAG_DATA": [ + "39, mucosa {'context': 'I-tissue/organ'}", + "41, rhesus {'context': 'B-organism'}", + "42, macaques, {'context': 'I-organism'}", + "53, SIV-negative {'context': 'B-organism'}", + "54, macaques, {'context': 'I-organism'}", + "65, ileal {'context': 'B-tissue/organ'}", + "66, loops {'context': 'I-tissue/organ'}", + "80, TH17 {'context': 'B-cells'}", + "81, cells {'context': 'I-cells'}", + "87, rhesus {'context': 'B-organism'}", + "88, macaques, {'context': 'I-organism'}", + "102, IL-17 {'perturbing_action': 'B-gene loss-of-function'}", + "103, receptor-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "104, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "39, mucosa ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "41, rhesus ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "42, macaques, ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "53, SIV-negative ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "54, macaques, ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "65, ileal ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "66, loops ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "80, TH17 ['l21', 'l22', 'l23']", + "81, cells ['l21', 'l24', 'l25']", + "87, rhesus ['l22', 'l24', 'l26']", + "88, macaques, ['l23', 'l25', 'l26']", + "102, IL-17 ['l27', 'l28']", + "103, receptor-deficient ['l27', 'l29']", + "104, mice ['l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IL-17", + "receptor-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "18376405", + "TEXT": "Cell-free human T-lymphotropic virus type 1 (HTLV-1) virions are poorly infectious in vitro for their primary target cells, CD4(+) T cells. Here, we show that HTLV-1 can efficiently infect myeloid and plasmacytoid dendritic cells (DCs). Moreover, DCs exposed to HTLV-1, both before and after being productively infected, can rapidly, efficiently and reproducibly transfer virus to autologous primary CD4(+) T cells. This DC-mediated transfer of HTLV-1 involves heparan sulfate proteoglycans and neuropilin-1 and results in long-term productive infection and interleukin-2-independent transformation of the CD4(+) T cells. These studies, along with observations of HTLV-1-infected DCs in the peripheral blood of infected individuals, indicate that DCs have a central role in HTLV-1 transmission, dissemination and persistence in vivo. In addition to altering the current paradigm concerning how HTLV-1 transmission occurs, these studies suggest that impairment of DC function after HTLV-1 infection plays a part in pathogenesis.", + "TAG_DATA": [ + "29, myeloid {'context': 'B-cells'}", + "30, and {'context': 'I-cells'}", + "31, plasmacytoid {'context': 'I-cells'}", + "32, dendritic {'context': 'I-cells'}", + "33, cells {'context': 'I-cells'}", + "34, (DCs). {'context': 'I-cells'}", + "36, DCs {'context': 'B-cells'}", + "55, autologous {'context': 'B-xenograft'}", + "56, primary {'context': 'I-cells'}", + "57, CD4(+) {'context': 'I-cells'}", + "58, T {'context': 'I-cells'}", + "59, cells. {'context': 'I-cells'}", + "72, results {'effect': 'B-positive'}", + "73, in {'effect': 'I-positive'}", + "79, transformation {'phenotype': 'B-transformation'}", + "82, CD4(+) {'context': 'B-cells'}", + "83, T {'context': 'I-cells'}", + "84, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "29, myeloid ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "30, and ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "31, plasmacytoid ['l1', 'l10', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "32, dendritic ['l2', 'l11', 'l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "33, cells ['l3', 'l12', 'l21', 'l29', 'l37', 'l38', 'l39', 'l40']", + "34, (DCs). ['l4', 'l13', 'l22', 'l30', 'l37', 'l41', 'l42']", + "36, DCs ['l5', 'l14', 'l23', 'l31', 'l38', 'l41', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "55, autologous ['l15', 'l24', 'l32', 'l43', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "56, primary ['l6', 'l16', 'l25', 'l33', 'l44', 'l50', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "57, CD4(+) ['l7', 'l17', 'l26', 'l34', 'l45', 'l51', 'l58', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "58, T ['l8', 'l18', 'l27', 'l35', 'l39', 'l46', 'l52', 'l59', 'l65', 'l71', 'l72', 'l73', 'l74', 'l75']", + "59, cells. ['l9', 'l19', 'l28', 'l36', 'l40', 'l42', 'l47', 'l53', 'l60', 'l66', 'l71', 'l76', 'l77', 'l78']", + "72, results ['l48', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l80', 'l81', 'l82', 'l83']", + "73, in ['l49', 'l55', 'l62', 'l68', 'l73', 'l77', 'l79', 'l84', 'l85', 'l86', 'l87']", + "79, transformation ['l80', 'l84', 'l88', 'l89', 'l90']", + "82, CD4(+) ['l81', 'l85', 'l88', 'l91', 'l92']", + "83, T ['l56', 'l63', 'l69', 'l74', 'l82', 'l86', 'l89', 'l91', 'l93']", + "84, cells. ['l57', 'l64', 'l70', 'l75', 'l78', 'l83', 'l87', 'l90', 'l92', 'l93']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "DCs", + "primary", + "CD4(+)", + "T", + "cells." + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "autologous" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + } + }, + { + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cells." + ] + } + } + ] + }, + { + "PMID": "18345011", + "TEXT": "Muscular dystrophies comprise a diverse group of genetic disorders that lead to muscle wasting and, in many instances, premature death. Many mutations that cause muscular dystrophy compromise the support network that connects myofilament proteins within the cell to the basal lamina outside the cell, rendering the sarcolemma more permeable or leaky. Here we show that deletion of the gene encoding cyclophilin D (Ppif) rendered mitochondria largely insensitive to the calcium overload-induced swelling associated with a defective sarcolemma, thus reducing myofiber necrosis in two distinct models of muscular dystrophy. Mice lacking delta-sarcoglycan (Scgd(-/-) mice) showed markedly less dystrophic disease in both skeletal muscle and heart in the absence of Ppif. Moreover, the premature lethality associated with deletion of Lama2, encoding the alpha-2 chain of laminin-2, was rescued, as were other indices of dystrophic disease. Treatment with the cyclophilin inhibitor Debio-025 similarly reduced mitochondrial swelling and necrotic disease manifestations in mdx mice, a model of Duchenne muscular dystrophy, and in Scgd(-/-) mice. Thus, mitochondrial-dependent necrosis represents a prominent disease mechanism in muscular dystrophy, suggesting that inhibition of cyclophilin D could provide a new pharmacologic treatment strategy for these diseases.", + "TAG_DATA": [ + "55, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "56, of {'perturbing_action': 'I-gene loss-of-function'}", + "57, the {'perturbing_action': 'I-gene loss-of-function'}", + "58, gene {'perturbing_action': 'I-gene loss-of-function'}", + "59, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "60, cyclophilin {'perturbing_action': 'I-gene loss-of-function'}", + "61, D {'perturbing_action': 'I-gene loss-of-function'}", + "62, (Ppif) {'perturbing_action': 'I-gene loss-of-function'}", + "79, myofiber {'context': 'B-cells'}", + "88, Mice {'context': 'B-organism'}", + "89, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "90, delta-sarcoglycan {'perturbing_action': 'I-gene loss-of-function'}", + "92, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "100, skeletal {'context': 'B-tissue/organ'}", + "101, muscle {'context': 'I-tissue/organ'}", + "103, heart {'context': 'B-tissue/organ'}", + "106, absence {'perturbing_action': 'B-gene loss-of-function'}", + "107, of {'perturbing_action': 'I-gene loss-of-function'}", + "108, Ppif. {'perturbing_action': 'I-gene loss-of-function'}", + "115, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "116, of {'perturbing_action': 'I-gene loss-of-function'}", + "117, Lama2, {'perturbing_action': 'I-gene loss-of-function'}", + "148, mdx {'context': 'B-organism'}", + "149, mice, {'context': 'I-organism'}", + "158, Scgd(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "159, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "55, deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "56, of ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "57, the ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "58, gene ['l2', 'l16', 'l29', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "59, encoding ['l3', 'l17', 'l30', 'l42', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "60, cyclophilin ['l4', 'l18', 'l31', 'l43', 'l54', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "61, D ['l5', 'l19', 'l32', 'l44', 'l55', 'l66', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "62, (Ppif) ['l6', 'l20', 'l33', 'l45', 'l56', 'l67', 'l76', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "79, myofiber ['l7', 'l21', 'l34', 'l46', 'l57', 'l68', 'l77', 'l85']", + "88, Mice ['l8', 'l22', 'l35', 'l47', 'l58', 'l69', 'l78', 'l86', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "89, lacking ['l9', 'l23', 'l36', 'l48', 'l59', 'l70', 'l79', 'l87', 'l92', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "90, delta-sarcoglycan ['l10', 'l24', 'l37', 'l49', 'l60', 'l71', 'l80', 'l93', 'l101', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "92, mice) ['l11', 'l25', 'l38', 'l50', 'l61', 'l72', 'l81', 'l88', 'l94', 'l102', 'l109', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "100, skeletal ['l12', 'l26', 'l39', 'l51', 'l62', 'l73', 'l82', 'l89', 'l95', 'l103', 'l110', 'l116', 'l122', 'l123']", + "101, muscle ['l13', 'l27', 'l40', 'l52', 'l63', 'l74', 'l83', 'l90', 'l96', 'l104', 'l111', 'l117', 'l122', 'l124']", + "103, heart ['l14', 'l28', 'l41', 'l53', 'l64', 'l75', 'l84', 'l91', 'l97', 'l105', 'l112', 'l118', 'l123', 'l124', 'l125', 'l126']", + "106, absence ['l98', 'l106', 'l113', 'l119', 'l127', 'l128']", + "107, of ['l65', 'l99', 'l107', 'l114', 'l120', 'l125', 'l127', 'l129']", + "108, Ppif. ['l100', 'l108', 'l115', 'l121', 'l126', 'l128', 'l129']", + "115, deletion ['l130', 'l131', 'l132', 'l133']", + "116, of ['l130', 'l134', 'l135', 'l136']", + "117, Lama2, ['l131', 'l134', 'l137', 'l138']", + "148, mdx ['l132', 'l135', 'l137', 'l139']", + "149, mice, ['l133', 'l136', 'l138', 'l139']", + "158, Scgd(-/-) ['l140']", + "159, mice. ['l140']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "gene", + "encoding", + "cyclophilin", + "D", + "(Ppif)" + ] + }, + "context": { + "val": "cells", + "words": [ + "myofiber" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "gene", + "encoding", + "cyclophilin", + "D", + "(Ppif)", + "lacking", + "delta-sarcoglycan", + "mice)", + "absence", + "Ppif.", + "Lama2,", + "Scgd(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "Mice", + "mdx", + "mice,", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "gene", + "encoding", + "cyclophilin", + "D", + "(Ppif)", + "lacking", + "delta-sarcoglycan", + "mice)", + "Ppif." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skeletal", + "muscle", + "heart" + ] + } + } + ] + }, + { + "PMID": "18327267", + "TEXT": "Pathogenic microbes have evolved sophisticated molecular strategies to subvert host defenses. Here we show that virulent bacteria interfere directly with Toll-like receptor (TLR) function by secreting inhibitory homologs of the Toll/interleukin-1 receptor (TIR) domain. Genes encoding TIR domain containing-proteins (Tcps) were identified in Escherichia coli CFT073 (TcpC) and Brucella melitensis (TcpB). We found that TcpC is common in the most virulent uropathogenic E. coli strains and promotes bacterial survival and kidney pathology in vivo. In silico analysis predicted significant tertiary structure homology to the TIR domain of human TLR1, and we show that the Tcps impede TLR signaling through the myeloid differentiation factor 88 (MyD88) adaptor protein, owing to direct binding of Tcps to MyD88. Tcps represent a new class of virulence factors that act by inhibiting TLR- and MyD88-specific signaling, thus suppressing innate immunity and increasing virulence.", + "TAG_DATA": [ + "72, in {'context': 'B-in vivo'}", + "73, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "72, in ['l0']", + "73, vivo. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18323824", + "TEXT": "An Institute of Medicine report recommends that the United States government create a program to provide consistent guidelines for clinical interventions. The reliability of the guidelines will depend on the availability of the clinical data to be assessed.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "18311147", + "TEXT": "Albuminuria associated with sclerosis of the glomerulus leads to a progressive decline in renal function affecting millions of people. Here we report that activation of the Notch pathway, which is critical in glomerular patterning, contributes to the development of glomerular disease. Expression of the intracellular domain of Notch1 (ICN1) was increased in glomerular epithelial cells in diabetic nephropathy and in focal segmental glomerulosclerosis. Conditional re-expression of ICN1 in vivo exclusively in podocytes caused proteinuria and glomerulosclerosis. In vitro and in vivo studies showed that ICN1 induced apoptosis of podocytes through the activation of p53. Genetic deletion of a Notch transcriptional partner (Rbpj) specifically in podocytes or pharmacological inhibition of the Notch pathway (with a gamma-secretase inhibitor) protected rats with proteinuric kidney diseases. Collectively, our observations suggest that Notch activation in mature podocytes is a new mechanism in the pathogenesis of glomerular disease and thus could represent a new therapeutic target.", + "TAG_DATA": [ + "63, Conditional {'perturbing_action': 'B-gene gain-of-function'}", + "64, re-expression {'perturbing_action': 'I-gene gain-of-function'}", + "65, of {'perturbing_action': 'I-gene gain-of-function'}", + "66, ICN1 {'perturbing_action': 'I-gene gain-of-function'}", + "67, in {'context': 'B-in vivo'}", + "68, vivo {'context': 'I-in vivo'}", + "71, podocytes {'context': 'B-cells'}", + "76, In {'context': 'B-in vitro'}", + "77, vitro {'context': 'I-in vitro'}", + "79, in {'context': 'B-in vivo'}", + "80, vivo {'context': 'I-in vivo'}", + "85, induced {'effect': 'B-positive'}", + "86, apoptosis {'phenotype': 'B-apoptosis'}", + "88, podocytes {'context': 'B-cells'}", + "94, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "95, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "96, of {'perturbing_action': 'I-gene loss-of-function'}", + "97, a {'perturbing_action': 'I-gene loss-of-function'}", + "98, Notch {'perturbing_action': 'I-gene loss-of-function'}", + "99, transcriptional {'perturbing_action': 'I-gene loss-of-function'}", + "100, partner {'perturbing_action': 'I-gene loss-of-function'}", + "101, (Rbpj) {'perturbing_action': 'I-gene loss-of-function'}", + "102, specifically {'perturbing_action': 'I-gene loss-of-function'}", + "103, in {'perturbing_action': 'I-gene loss-of-function'}", + "104, podocytes {'context': 'B-cells'}", + "117, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "63, Conditional ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "64, re-expression ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "65, of ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "66, ICN1 ['l2', 'l13', 'l23', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "67, in ['l3', 'l14', 'l24', 'l32', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "68, vivo ['l4', 'l15', 'l25', 'l33', 'l40', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "71, podocytes ['l5', 'l16', 'l26', 'l34', 'l41', 'l47', 'l53', 'l54', 'l55', 'l56', 'l57']", + "76, In ['l6', 'l17', 'l27', 'l35', 'l42', 'l48', 'l53', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "77, vitro ['l7', 'l18', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "79, in ['l59', 'l64', 'l69', 'l70', 'l71', 'l72']", + "80, vivo ['l8', 'l19', 'l60', 'l65', 'l69', 'l73', 'l74', 'l75']", + "85, induced ['l9', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l61', 'l66', 'l70', 'l73', 'l76', 'l77']", + "86, apoptosis ['l10', 'l21', 'l30', 'l38', 'l45', 'l51', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l78']", + "88, podocytes ['l11', 'l22', 'l31', 'l39', 'l46', 'l52', 'l57', 'l63', 'l68', 'l72', 'l75', 'l77', 'l78']", + "94, Genetic ['l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "95, deletion ['l79', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "96, of ['l80', 'l90', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "97, a ['l81', 'l91', 'l100', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "98, Notch ['l82', 'l92', 'l101', 'l109', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "99, transcriptional ['l83', 'l93', 'l102', 'l110', 'l117', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "100, partner ['l84', 'l94', 'l103', 'l111', 'l118', 'l124', 'l130', 'l131', 'l132', 'l133', 'l134']", + "101, (Rbpj) ['l85', 'l95', 'l104', 'l112', 'l119', 'l125', 'l130', 'l135', 'l136', 'l137', 'l138']", + "102, specifically ['l86', 'l96', 'l105', 'l113', 'l120', 'l126', 'l131', 'l135', 'l139', 'l140', 'l141']", + "103, in ['l87', 'l97', 'l106', 'l114', 'l121', 'l127', 'l132', 'l136', 'l139', 'l142', 'l143']", + "104, podocytes ['l88', 'l98', 'l107', 'l115', 'l122', 'l128', 'l133', 'l137', 'l140', 'l142', 'l144']", + "117, rats ['l89', 'l99', 'l108', 'l116', 'l123', 'l129', 'l134', 'l138', 'l141', 'l143', 'l144']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Conditional", + "re-expression", + "of", + "ICN1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Conditional", + "re-expression", + "of", + "ICN1" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Conditional", + "re-expression", + "of", + "ICN1" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Conditional", + "re-expression", + "of", + "ICN1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Conditional", + "re-expression", + "of", + "ICN1" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "podocytes" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "podocytes" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "deletion", + "of", + "a", + "Notch", + "transcriptional", + "partner", + "(Rbpj)", + "specifically", + "in" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "deletion", + "of", + "a", + "Notch", + "transcriptional", + "partner", + "(Rbpj)", + "specifically", + "in" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + } + ] + }, + { + "PMID": "18264110", + "TEXT": "Emerging evidence supports the concept that T helper type 17 (T(H)17) cells, in addition to mediating autoimmunity, have key roles in mucosal immunity against extracellular pathogens. Interleukin-22 (IL-22) and IL-17A are both effector cytokines produced by the T(H)17 lineage, and both were crucial for maintaining local control of the Gram-negative pulmonary pathogen, Klebsiella pneumoniae. Although both cytokines regulated CXC chemokines and granulocyte colony-stimulating factor production in the lung, only IL-22 increased lung epithelial cell proliferation and increased transepithelial resistance to injury. These data support the concept that the T(H)17 cell lineage and its effector molecules have evolved to effect host defense against extracellular pathogens at mucosal sites.", + "TAG_DATA": [ + "67, lung, {'context': 'B-tissue/organ'}", + "70, increased {'effect': 'B-positive'}", + "71, lung {'context': 'B-cells'}", + "72, epithelial {'context': 'I-cells'}", + "73, cell {'context': 'I-cells'}", + "74, proliferation {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "67, lung, ['l0', 'l1', 'l2']", + "70, increased ['l0', 'l3', 'l4', 'l5', 'l6']", + "71, lung ['l3', 'l7', 'l8', 'l9']", + "72, epithelial ['l4', 'l7', 'l10', 'l11']", + "73, cell ['l1', 'l5', 'l8', 'l10', 'l12']", + "74, proliferation ['l2', 'l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "lung," + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "lung," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "cells", + "words": [ + "lung", + "epithelial", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "lung", + "epithelial", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "18246078", + "TEXT": "Treacher Collins syndrome (TCS) is a congenital disorder of craniofacial development arising from mutations in TCOF1, which encodes the nucleolar phosphoprotein Treacle. Haploinsufficiency of Tcof1 perturbs mature ribosome biogenesis, resulting in stabilization of p53 and the cyclin G1-mediated cell-cycle arrest that underpins the specificity of neuroepithelial apoptosis and neural crest cell hypoplasia characteristic of TCS. Here we show that inhibition of p53 prevents cyclin G1-driven apoptotic elimination of neural crest cells while rescuing the craniofacial abnormalities associated with mutations in Tcof1 and extending life span. These improvements, however, occur independently of the effects on ribosome biogenesis; thus suggesting that it is p53-dependent neuroepithelial apoptosis that is the primary mechanism underlying the pathogenesis of TCS. Our work further implies that neuroepithelial and neural crest cells are particularly sensitive to cellular stress during embryogenesis and that suppression of p53 function provides an attractive avenue for possible clinical prevention of TCS craniofacial birth defects and possibly those of other neurocristopathies.", + "TAG_DATA": [ + "59, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "60, of {'perturbing_action': 'I-pharmacological inhibition'}", + "61, p53 {'perturbing_action': 'I-pharmacological inhibition'}", + "62, prevents {'effect': 'B-negative'}", + "65, apoptotic {'phenotype': 'B-apoptosis'}", + "66, elimination {'phenotype': 'I-apoptosis'}", + "68, neural {'context': 'B-cells'}", + "69, crest {'context': 'I-cells'}", + "70, cells {'context': 'I-cells'}", + "78, mutations {'perturbing_action': 'B-other'}", + "79, in {'perturbing_action': 'I-other'}", + "80, Tcof1 {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "59, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "60, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "61, p53 ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "62, prevents ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34']", + "65, apoptotic ['l3', 'l13', 'l22', 'l30', 'l35', 'l36', 'l37', 'l38']", + "66, elimination ['l4', 'l14', 'l23', 'l31', 'l35', 'l39', 'l40', 'l41']", + "68, neural ['l5', 'l15', 'l24', 'l32', 'l36', 'l39', 'l42', 'l43']", + "69, crest ['l6', 'l16', 'l25', 'l33', 'l37', 'l40', 'l42', 'l44']", + "70, cells ['l7', 'l17', 'l26', 'l34', 'l38', 'l41', 'l43', 'l44']", + "78, mutations ['l8', 'l18', 'l27', 'l45', 'l46']", + "79, in ['l9', 'l19', 'l28', 'l45', 'l47']", + "80, Tcof1 ['l10', 'l20', 'l29', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "p53" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "p53" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "elimination" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "p53" + ] + }, + "context": { + "val": "cells", + "words": [ + "neural", + "crest", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "elimination" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "context": { + "val": "cells", + "words": [ + "neural", + "crest", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "elimination" + ] + }, + "context": { + "val": "cells", + "words": [ + "neural", + "crest", + "cells" + ] + } + } + ] + }, + { + "PMID": "18223656", + "TEXT": "Oxidative damage and inflammation are postulated to be involved in age-related macular degeneration (AMD). However, the molecular signal(s) linking oxidation to inflammation in this late-onset disease is unknown. Here we describe AMD-like lesions in mice after immunization with mouse serum albumin adducted with carboxyethylpyrrole, a unique oxidation fragment of docosahexaenoic acid that has previously been found adducting proteins in drusen from AMD donor eye tissues and in plasma samples from individuals with AMD. Immunized mice develop antibodies to this hapten, fix complement component-3 in Bruch's membrane, accumulate drusen below the retinal pigment epithelium during aging, and develop lesions in the retinal pigment epithelium mimicking geographic atrophy, the blinding end-stage condition characteristic of the dry form of AMD. We hypothesize that these mice are sensitized to the generation of carboxyethylpyrrole adducts in the outer retina, where docosahexaenoic acid is abundant and conditions for oxidative damage are permissive. This new model provides a platform for dissecting the molecular pathology of oxidative damage in the outer retina and the immune response contributing to AMD.", + "TAG_DATA": [ + "34, mice {'context': 'B-organism'}", + "74, mice {'context': 'B-organism'}", + "100, retinal {'context': 'B-tissue/organ'}", + "101, pigment {'context': 'I-tissue/organ'}", + "102, epithelium {'context': 'I-tissue/organ'}", + "121, mice {'context': 'B-organism'}", + "132, outer {'context': 'B-tissue/organ'}", + "133, retina, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "74, mice ['l0', 'l1']", + "91, pigment ['l0', 'l2']", + "92, epithelium ['l1', 'l2']", + "100, retinal ['l3', 'l4']", + "101, pigment ['l3', 'l5']", + "102, epithelium ['l4', 'l5']", + "121, mice ['l6', 'l7']", + "132, outer ['l6', 'l8']", + "133, retina, ['l7', 'l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18204462", + "TEXT": "The dendritic cell immunoreceptor (official gene symbol Clec4a2, called Dcir here) is a C-type lectin receptor expressed mainly in dendritic cells (DCs) that has a carbohydrate recognition domain in its extracellular portion and an immunoreceptor tyrosine-based inhibitory motif, which transduces negative signals into cells, in its cytoplasmic portion. We found high Dcir expression in the joints of two mouse rheumatoid arthritis models. Because the structural characteristics of Dcir suggest that it may have an immune regulatory role, and because autoimmune-related genes are mapped to the DCIR locus in humans, we generated Dcir-/- mice to learn more about the pathological roles of this molecule. We found that aged Dcir-/- mice spontaneously develop sialadenitis and enthesitis associated with elevated serum autoantibodies. Dcir-/- mice showed a markedly exacerbated response to collagen-induced arthritis. The DC population was expanded excessively in aged and type II collagen-immunized Dcir-/- mice. Upon treatment with granulocyte-macrophage colony-stimulating factor, Dcir-/- mouse-derived bone marrow cells (BMCs) differentiated into DCs more efficiently than did wild-type BMCs, owing to enhanced signal transducer and activator of transcription-5 phosphorylation. These observations indicate that Dcir is a negative regulator of DC expansion and has a crucial role in maintaining the homeostasis of the immune system.", + "TAG_DATA": [ + "91, Dcir-/- {'perturbing_action': 'B-gene loss-of-function'}", + "92, mice {'context': 'B-organism'}", + "107, Dcir-/- {'perturbing_action': 'B-gene loss-of-function'}", + "108, mice {'context': 'B-organism'}", + "119, Dcir-/- {'perturbing_action': 'B-gene loss-of-function'}", + "120, mice {'context': 'B-organism'}", + "130, DC {'context': 'B-cells'}", + "141, Dcir-/- {'perturbing_action': 'B-gene loss-of-function'}", + "142, mice. {'context': 'B-organism'}", + "149, Dcir-/- {'perturbing_action': 'B-gene loss-of-function'}", + "150, mouse-derived {'context': 'B-cells'}", + "151, bone {'context': 'I-cells'}", + "152, marrow {'context': 'I-cells'}", + "153, cells {'context': 'I-cells'}", + "154, (BMCs) {'context': 'I-cells'}", + "155, differentiated {'phenotype': 'B-differentiation'}", + "157, DCs {'context': 'B-cells'}", + "163, BMCs, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "91, Dcir-/- ['l0', 'l1', 'l2']", + "92, mice ['l0', 'l3', 'l4']", + "107, Dcir-/- ['l1', 'l3', 'l5']", + "108, mice ['l2', 'l4', 'l5']", + "119, Dcir-/- ['l6', 'l7', 'l8', 'l9']", + "120, mice ['l6', 'l10', 'l11', 'l12']", + "130, DC ['l7', 'l10', 'l13', 'l14']", + "141, Dcir-/- ['l8', 'l11', 'l13', 'l15']", + "142, mice. ['l9', 'l12', 'l14', 'l15']", + "149, Dcir-/- ['l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "150, mouse-derived ['l16', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "151, bone ['l17', 'l24', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "152, marrow ['l18', 'l25', 'l31', 'l37', 'l38', 'l39', 'l40']", + "153, cells ['l19', 'l26', 'l32', 'l37', 'l41', 'l42', 'l43']", + "154, (BMCs) ['l20', 'l27', 'l33', 'l38', 'l41', 'l44', 'l45', 'l46']", + "155, differentiated ['l21', 'l28', 'l34', 'l39', 'l42', 'l44', 'l47']", + "157, DCs ['l22', 'l29', 'l35', 'l40', 'l43', 'l45', 'l47', 'l48']", + "163, BMCs, ['l23', 'l30', 'l36', 'l46', 'l48']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dcir-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dcir-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "DC", + "mouse-derived", + "bone", + "marrow", + "cells", + "(BMCs)", + "DCs", + "BMCs," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dcir-/-" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiated" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse-derived", + "bone", + "marrow", + "cells", + "(BMCs)", + "DCs" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiated" + ] + } + } + ] + }, + { + "PMID": "18157140", + "TEXT": "Deep brain stimulation (DBS) is a widely used neurosurgical approach to treating tremor and other movement disorders. In addition, the use of DBS in a number of psychiatric diseases, including obsessive-compulsive disorders and depression, is currently being tested. Despite the rapid increase in the number of individuals with surgically implanted stimulation electrodes, the cellular pathways involved in mediating the effects of DBS remain unknown. Here we show that DBS is associated with a marked increase in the release of ATP, resulting in accumulation of its catabolic product, adenosine. Adenosine A1 receptor activation depresses excitatory transmission in the thalamus and reduces both tremor- and DBS-induced side effects. Intrathalamic infusion of A1 receptor agonists directly reduces tremor, whereas adenosine A1 receptor-null mice show involuntary movements and seizure at stimulation intensities below the therapeutic level. Furthermore, our data indicate that endogenous adenosine mechanisms are active in tremor, thus supporting the clinical notion that caffeine, a nonselective adenosine receptor antagonist, can trigger or exacerbate essential tremor. Our findings suggest that nonsynaptic mechanisms involving the activation of A1 receptors suppress tremor activity and limit stimulation-induced side effects, thereby providing a new pharmacological target to replace or improve the efficacy of DBS.", + "TAG_DATA": [ + "89, A1 {'perturbing_action': 'I-pharmacological augmentation'}", + "90, receptor {'perturbing_action': 'I-pharmacological augmentation'}", + "91, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "109, A1 {'perturbing_action': 'B-pharmacological augmentation'}", + "110, receptor {'perturbing_action': 'I-pharmacological augmentation'}", + "111, agonists {'perturbing_action': 'I-pharmacological augmentation'}", + "116, adenosine {'perturbing_action': 'B-gene loss-of-function'}", + "117, A1 {'perturbing_action': 'I-gene loss-of-function'}", + "118, receptor-null {'perturbing_action': 'I-gene loss-of-function'}", + "119, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "89, A1 ['l0', 'l1']", + "90, receptor ['l0', 'l2']", + "91, activation ['l1', 'l2']", + "109, A1 ['l3', 'l4']", + "110, receptor ['l3', 'l5']", + "111, agonists ['l4', 'l5']", + "116, adenosine ['l6', 'l7', 'l8']", + "117, A1 ['l6', 'l9', 'l10']", + "118, receptor-null ['l7', 'l9', 'l11']", + "119, mice ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adenosine", + "A1", + "receptor-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "18059282", + "TEXT": "Osteoclasts are bone-resorbing cells derived from hematopoietic precursors of the monocyte-macrophage lineage. Regulation of osteoclast function is central to the understanding of bone diseases such as osteoporosis, rheumatoid arthritis and osteopetrosis. Although peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been shown to inhibit osteoblast differentiation, its role, if any, in osteoclasts is unknown. This is a clinically crucial question because PPAR-gamma agonists, \"such as thiazolidinediones-\" a class of insulin-sensitizing drugs, have been reported to cause a higher rate of fractures in human patients. Here we have uncovered a pro-osteoclastogenic effect of PPAR-gamma by using a Tie2Cre/flox mouse model in which PPAR-gamma is deleted in osteoclasts but not in osteoblasts. These mice develop osteopetrosis characterized by increased bone mass, reduced medullary cavity space and extramedullary hematopoiesis in the spleen. These defects are the result of impaired osteoclast differentiation and compromised receptor activator of nuclear factor-kappaB ligand signaling and can be rescued by bone marrow transplantation. Moreover, ligand activation of PPAR-gamma by rosiglitazone exacerbates osteoclast differentiation in a receptor-dependent manner. Our examination of the underlying mechanisms suggested that PPAR-gamma functions as a direct regulator of c-fos expression, an essential mediator of osteoclastogenesis. Therefore, PPAR-gamma and its ligands have a previously unrecognized role in promoting osteoclast differentiation and bone resorption.", + "TAG_DATA": [ + "93, Tie2Cre/flox {'perturbing_action': 'B-gene loss-of-function'}", + "94, mouse {'context': 'B-organism'}", + "95, model {'context': 'I-organism'}", + "98, PPAR-gamma {'perturbing_action': 'I-gene loss-of-function'}", + "99, is {'perturbing_action': 'I-gene loss-of-function'}", + "100, deleted {'perturbing_action': 'I-gene loss-of-function'}", + "102, osteoclasts {'context': 'B-cells'}", + "106, osteoblasts. {'context': 'B-cells'}", + "108, mice {'context': 'B-organism'}", + "125, spleen. {'context': 'B-tissue/organ'}", + "132, impaired {'effect': 'B-negative'}", + "134, differentiation {'phenotype': 'B-differentiation'}", + "159, exacerbates {'effect': 'B-positive'}", + "160, osteoclast {'context': 'B-cells'}", + "161, differentiation {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "93, Tie2Cre/flox ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "94, mouse ['l0', 'l10', 'l11', 'l12', 'l13']", + "95, model ['l1', 'l10', 'l14', 'l15', 'l16']", + "98, PPAR-gamma ['l2', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "99, is ['l3', 'l11', 'l14', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "100, deleted ['l4', 'l18', 'l25', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "102, osteoclasts ['l5', 'l12', 'l15', 'l19', 'l26', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "106, osteoblasts. ['l6', 'l13', 'l16', 'l20', 'l27', 'l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "108, mice ['l7', 'l21', 'l28', 'l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "125, spleen. ['l8', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "132, impaired ['l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "134, differentiation ['l9', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l52']", + "159, exacerbates ['l53', 'l54']", + "160, osteoclast ['l53', 'l55']", + "161, differentiation ['l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tie2Cre/flox", + "is", + "PPAR-gamma", + "deleted" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tie2Cre/flox", + "PPAR-gamma", + "is", + "deleted" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclasts", + "osteoblasts." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tie2Cre/flox", + "PPAR-gamma", + "is", + "deleted" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "spleen." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tie2Cre/flox", + "PPAR-gamma", + "is", + "deleted" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PPAR-gamma", + "is", + "deleted" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoclasts", + "osteoblasts." + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoclasts", + "osteoblasts.", + "osteoclast" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "spleen." + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "spleen." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "exacerbates" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "exacerbates" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "18059281", + "TEXT": "The success of Mycobacterium tuberculosis (Mtb) as a human pathogen relies on its ability to resist eradication by the immune system. The identification of mechanisms that enable Mtb to persist is key for finding ways to limit latent tuberculosis, which affects one-third of the world's population. Here we show that conditional gene silencing can be used to determine whether an Mtb gene required for optimal growth in vitro is also important for virulence and, if so, during which phase of an infection it is required. Application of this approach to the prcBA genes, which encode the core of the mycobacterial proteasome, revealed an unpredicted requirement of the core proteasome for the persistence of Mtb during the chronic phase of infection in mice. Proteasome depletion also attenuated Mtb in interferon-gamma-deficient mice, pointing to a function of the proteasome beyond defense against the adaptive immune response. Genes that are essential for growth in vitro, in vivo or both account for approximately 20% of Mtb's genome. Conditional gene silencing could therefore facilitate the validation of up to 800 potential Mtb drug targets and improve our understanding of host-pathogen dynamics.", + "TAG_DATA": [ + "121, mice. {'context': 'B-organism'}", + "128, interferon-gamma-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "129, mice, {'context': 'B-organism'}", + "153, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "128, interferon-gamma-deficient ['l0']", + "129, mice, ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interferon-gamma-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "18059280", + "TEXT": "Surgery or radiation therapy of metastatic cancer often damages lymph nodes, leading to secondary lymphedema. Here we show, using a newly established mouse model, that collecting lymphatic vessels can be regenerated and fused to lymph node transplants after lymph node removal. Treatment of lymph node-excised mice with adenovirally delivered vascular endothelial growth factor-C (VEGF-C) or VEGF-D induced robust growth of the lymphatic capillaries, which gradually underwent intrinsic remodeling, differentiation and maturation into functional collecting lymphatic vessels, including the formation of uniform endothelial cell-cell junctions and intraluminal valves. The vessels also reacquired pericyte contacts, which downregulated lymphatic capillary markers during vessel maturation. Growth factor therapy improved the outcome of lymph node transplantation, including functional reconstitution of the immunological barrier against tumor metastasis. These results show that growth factor-induced maturation of lymphatic vessels is possible in adult mice and provide a basis for future therapy of lymphedema.", + "TAG_DATA": [ + "45, mice {'context': 'B-organism'}", + "47, adenovirally {'perturbing_action': 'B-gene gain-of-function'}", + "48, delivered {'perturbing_action': 'I-gene gain-of-function'}", + "49, vascular {'perturbing_action': 'I-gene gain-of-function'}", + "50, endothelial {'perturbing_action': 'I-gene gain-of-function'}", + "51, growth {'perturbing_action': 'I-gene gain-of-function'}", + "52, factor-C {'perturbing_action': 'I-gene gain-of-function'}", + "53, (VEGF-C) {'perturbing_action': 'I-gene gain-of-function'}", + "61, lymphatic {'context': 'B-tissue/organ'}", + "62, capillaries, {'context': 'I-tissue/organ'}", + "88, vessels {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "43, lymph ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "44, node-excised ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "45, mice ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "47, adenovirally ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "48, delivered ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "49, vascular ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "50, endothelial ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "51, growth ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "52, factor-C ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "53, (VEGF-C) ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "61, lymphatic ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75']", + "62, capillaries, ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75']", + "88, vessels ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirally", + "delivered", + "vascular", + "endothelial", + "growth", + "factor-C", + "(VEGF-C)" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirally", + "delivered", + "vascular", + "endothelial", + "growth", + "factor-C", + "(VEGF-C)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lymphatic", + "capillaries,", + "vessels" + ] + } + } + ] + }, + { + "PMID": "18059279", + "TEXT": "Interleukin-8 (IL-8) activates neutrophils via the chemokine receptors CXCR1 and CXCR2. However, the airways of individuals with cystic fibrosis are frequently colonized by bacterial pathogens, despite the presence of large numbers of neutrophils and IL-8. Here we show that IL-8 promotes bacterial killing by neutrophils through CXCR1 but not CXCR2. Unopposed proteolytic activity in the airways of individuals with cystic fibrosis cleaved CXCR1 on neutrophils and disabled their bacterial-killing capacity. These effects were protease concentration-dependent and also occurred to a lesser extent in individuals with chronic obstructive pulmonary disease. Receptor cleavage induced the release of glycosylated CXCR1 fragments that were capable of stimulating IL-8 production in bronchial epithelial cells via Toll-like receptor 2. In vivo inhibition of proteases by inhalation of alpha1-antitrypsin restored CXCR1 expression and improved bacterial killing in individuals with cystic fibrosis. The cleavage of CXCR1, the functional consequences of its cleavage, and the identification of soluble CXCR1 fragments that behave as bioactive components represent a new pathophysiologic mechanism in cystic fibrosis and other chronic lung diseases.", + "TAG_DATA": [ + "106, bronchial {'context': 'B-cells'}", + "107, epithelial {'context': 'I-cells'}", + "108, cells {'context': 'I-cells'}", + "113, In {'context': 'B-in vivo'}", + "114, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "106, bronchial ['l0', 'l1']", + "107, epithelial ['l0', 'l2']", + "108, cells ['l1', 'l2']", + "113, In ['l3']", + "114, vivo ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17982464", + "TEXT": "Data providing direct evidence for a causative link between endothelial dysfunction, microvascular disease and diabetic end-organ damage are scarce. Here we show that activated protein C (APC) formation, which is regulated by endothelial thrombomodulin, is reduced in diabetic mice and causally linked to nephropathy. Thrombomodulin-dependent APC formation mediates cytoprotection in diabetic nephropathy by inhibiting glomerular apoptosis. APC prevents glucose-induced apoptosis in endothelial cells and podocytes, the cellular components of the glomerular filtration barrier. APC modulates the mitochondrial apoptosis pathway via the protease-activated receptor PAR-1 and the endothelial protein C receptor EPCR in glucose-stressed cells. These experiments establish a new pathway, in which hyperglycemia impairs endothelial thrombomodulin-dependent APC formation. Loss of thrombomodulin-dependent APC formation interrupts cross-talk between the vascular compartment and podocytes, causing glomerular apoptosis and diabetic nephropathy. Conversely, maintaining high APC levels during long-term diabetes protects against diabetic nephropathy.", + "TAG_DATA": [ + "53, inhibiting {'effect': 'B-negative'}", + "55, apoptosis. {'phenotype': 'B-apoptosis'}", + "57, prevents {'effect': 'B-negative'}", + "58, glucose-induced {'effect': 'B-positive'}", + "59, apoptosis {'phenotype': 'B-apoptosis'}", + "61, endothelial {'context': 'B-cells'}", + "62, cells {'context': 'I-cells'}", + "64, podocytes, {'context': 'B-cells'}", + "74, modulates {'effect': 'B-regulates'}", + "77, apoptosis {'phenotype': 'B-apoptosis'}", + "78, pathway {'phenotype': 'I-apoptosis'}", + "93, cells. {'context': 'B-cells'}", + "121, causing {'effect': 'B-positive'}", + "123, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "53, inhibiting ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "55, apoptosis. ['l0', 'l6', 'l7', 'l8', 'l9']", + "57, prevents ['l1', 'l6', 'l10', 'l11', 'l12', 'l13', 'l14']", + "58, glucose-induced ['l2', 'l7', 'l10', 'l15', 'l16', 'l17', 'l18']", + "59, apoptosis ['l3', 'l11', 'l15', 'l19', 'l20', 'l21']", + "61, endothelial ['l4', 'l8', 'l12', 'l16', 'l19', 'l22', 'l23']", + "62, cells ['l5', 'l9', 'l13', 'l17', 'l20', 'l22', 'l24']", + "64, podocytes, ['l14', 'l18', 'l21', 'l23', 'l24', 'l25', 'l26']", + "74, modulates ['l27', 'l28', 'l29', 'l30', 'l31']", + "77, apoptosis ['l27', 'l32', 'l33', 'l34']", + "78, pathway ['l25', 'l28', 'l32', 'l35']", + "93, cells. ['l26', 'l29', 'l33', 'l35', 'l36', 'l37']", + "121, causing ['l30', 'l34', 'l36', 'l38']", + "123, apoptosis ['l31', 'l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibiting", + "prevents" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis.", + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibiting", + "prevents" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells", + "podocytes," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis.", + "apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "glucose-induced", + "causing" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis.", + "apoptosis", + "pathway" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells", + "podocytes,", + "cells." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "glucose-induced", + "causing" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells", + "podocytes,", + "cells." + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "modulates" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "pathway" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "modulates" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "17965722", + "TEXT": "Measurements of early tumor responses to therapy have been shown, in some cases, to predict treatment outcome. We show in lymphoma-bearing mice injected intravenously with hyperpolarized [1-(13)C]pyruvate that the lactate dehydrogenase-catalyzed flux of (13)C label between the carboxyl groups of pyruvate and lactate in the tumor can be measured using (13)C magnetic resonance spectroscopy and spectroscopic imaging, and that this flux is inhibited within 24 h of chemotherapy. The reduction in the measured flux after drug treatment and the induction of tumor cell death can be explained by loss of the coenzyme NAD(H) and decreases in concentrations of lactate and enzyme in the tumors. The technique could provide a new way to assess tumor responses to treatment in the clinic.", + "TAG_DATA": [ + "20, lymphoma-bearing {'context': 'B-organism'}", + "21, mice {'context': 'I-organism'}", + "45, tumor {'context': 'B-neoplasm'}", + "79, induction {'effect': 'B-positive'}", + "81, tumor {'context': 'B-neoplasm'}", + "82, cell {'phenotype': 'B-cell death'}", + "83, death {'phenotype': 'I-cell death'}", + "103, tumors. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "20, lymphoma-bearing ['l0', 'l1']", + "21, mice ['l0', 'l2']", + "45, tumor ['l1', 'l2']", + "79, induction ['l3', 'l4', 'l5']", + "81, tumor ['l3', 'l6', 'l7']", + "82, cell ['l4', 'l6', 'l8']", + "83, death ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + } + ] + }, + { + "PMID": "17952090", + "TEXT": "Hepatic injury is associated with a defective intestinal barrier and increased hepatic exposure to bacterial products. Here we report that the intestinal bacterial microflora and a functional Toll-like receptor 4 (TLR4), but not TLR2, are required for hepatic fibrogenesis. Using Tlr4-chimeric mice and in vivo lipopolysaccharide (LPS) challenge, we demonstrate that quiescent hepatic stellate cells (HSCs), the main precursors for myofibroblasts in the liver, are the predominant target through which TLR4 ligands promote fibrogenesis. In quiescent HSCs, TLR4 activation not only upregulates chemokine secretion and induces chemotaxis of Kupffer cells, but also downregulates the transforming growth factor (TGF)-beta pseudoreceptor Bambi to sensitize HSCs to TGF-beta-induced signals and allow for unrestricted activation by Kupffer cells. LPS-induced Bambi downregulation and sensitization to TGF-beta is mediated by a MyD88-NF-kappaB-dependent pathway. Accordingly, Myd88-deficient mice have decreased hepatic fibrosis. Thus, modulation of TGF-beta signaling by a TLR4-MyD88-NF-kappaB axis provides a novel link between proinflammatory and profibrogenic signals.", + "TAG_DATA": [ + "40, Tlr4-chimeric {'perturbing_action': 'B-other'}", + "41, mice {'context': 'I-organism'}", + "43, in {'context': 'B-in vivo'}", + "44, vivo {'context': 'I-in vivo'}", + "51, quiescent {'context': 'B-cells'}", + "52, hepatic {'context': 'I-cells'}", + "53, stellate {'context': 'I-cells'}", + "54, cells {'context': 'I-cells'}", + "55, (HSCs), {'context': 'I-cells'}", + "75, quiescent {'context': 'B-cells'}", + "76, HSCs, {'context': 'I-cells'}", + "85, induces {'effect': 'B-positive'}", + "86, chemotaxis {'phenotype': 'B-migration'}", + "88, Kupffer {'context': 'B-cells'}", + "89, cells, {'context': 'I-cells'}", + "102, HSCs {'context': 'B-cells'}", + "112, Kupffer {'context': 'B-cells'}", + "113, cells. {'context': 'I-cells'}", + "128, Myd88-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "129, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "40, Tlr4-chimeric ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "41, mice ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "43, in ['l1', 'l13', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "44, vivo ['l2', 'l14', 'l23', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "51, quiescent ['l3', 'l15', 'l24', 'l34', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "52, hepatic ['l4', 'l16', 'l25', 'l35', 'l44', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "53, stellate ['l5', 'l17', 'l26', 'l36', 'l45', 'l55', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "54, cells ['l6', 'l18', 'l27', 'l37', 'l46', 'l56', 'l65', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "55, (HSCs), ['l7', 'l19', 'l28', 'l38', 'l47', 'l57', 'l66', 'l74', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "75, quiescent ['l48', 'l58', 'l67', 'l80', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "76, HSCs, ['l8', 'l29', 'l39', 'l49', 'l59', 'l68', 'l75', 'l81', 'l86', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "85, induces ['l9', 'l20', 'l30', 'l40', 'l50', 'l60', 'l69', 'l76', 'l82', 'l87', 'l94', 'l101', 'l102', 'l103']", + "86, chemotaxis ['l10', 'l21', 'l31', 'l41', 'l51', 'l61', 'l70', 'l77', 'l83', 'l88', 'l95', 'l101', 'l104', 'l105', 'l106', 'l107']", + "88, Kupffer ['l11', 'l32', 'l42', 'l52', 'l62', 'l71', 'l78', 'l84', 'l89', 'l96', 'l102', 'l104', 'l108', 'l109', 'l110', 'l111']", + "89, cells, ['l12', 'l22', 'l33', 'l43', 'l53', 'l63', 'l72', 'l79', 'l85', 'l90', 'l97', 'l103', 'l105', 'l108', 'l112', 'l113']", + "102, HSCs ['l91', 'l98', 'l106', 'l109', 'l112', 'l114', 'l115']", + "112, Kupffer ['l92', 'l99', 'l110', 'l114', 'l116']", + "113, cells. ['l54', 'l64', 'l73', 'l93', 'l100', 'l107', 'l111', 'l113', 'l115', 'l116']", + "128, Myd88-deficient ['l117']", + "129, mice ['l117']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Tlr4-chimeric" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Tlr4-chimeric" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Tlr4-chimeric" + ] + }, + "context": { + "val": "cells", + "words": [ + "quiescent", + "hepatic", + "stellate", + "cells", + "(HSCs),", + "HSCs,", + "Kupffer", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Tlr4-chimeric" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Tlr4-chimeric" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "quiescent", + "hepatic", + "stellate", + "cells", + "(HSCs),", + "HSCs,", + "Kupffer", + "cells," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "quiescent", + "hepatic", + "stellate", + "cells", + "(HSCs),", + "HSCs,", + "Kupffer", + "cells,", + "HSCs", + "cells." + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Myd88-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "17922009", + "TEXT": "Although STAT5A and STAT5B have some nonredundant functional properties, their distinct contributions to carcinogenesis are not clearly defined. Here we report that STAT5A expression is selectively inhibited by DNA methylation of the STAT5A gene promoter region in cells expressing the oncogenic tyrosine kinase NPM1-ALK (also known as NPM-ALK). The DNA methylation is induced by NPM1-ALK itself via STAT3, and is associated with binding to the promoter of the gene encoding MeCP2 capping protein and with lack of binding of the STAT5A gene transcription activator SP1. Reversal of methylation by the DNA methyltransferase inhibitor 5'-aza-2'-deoxycytidine restores SP1 binding and STAT5A gene expression. Notably, the induced or exogenously expressed STAT5A protein binds to the enhancer and intron 14 of the NPM1-ALK gene and triggers selective suppression of NPM1-ALK expression. These results show that NPM1-ALK induces epigenetic silencing of STAT5A gene and that STAT5A protein can act as a key tumor suppressor by reciprocally inhibiting expression of NPM1-ALK.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17906637", + "TEXT": "The latency of human immunodeficiency virus type 1 (HIV-1) in resting primary CD4+ T cells is the major barrier for the eradication of the virus in patients on suppressive highly active antiretroviral therapy (HAART). Even with optimal HAART treatment, replication-competent HIV-1 still exists in resting primary CD4+ T cells. Multiple restriction factors that act upon various steps of the viral life cycle could contribute to viral latency. Here we show that cellular microRNAs (miRNAs) potently inhibit HIV-1 production in resting primary CD4+ T cells. We have found that the 3' ends of HIV-1 messenger RNAs are targeted by a cluster of cellular miRNAs including miR-28, miR-125b, miR-150, miR-223 and miR-382, which are enriched in resting CD4+ T cells as compared to activated CD4+ T cells. Specific inhibitors of these miRNAs substantially counteracted their effects on the target mRNAs, measured either as HIV-1 protein translation in resting CD4+ T cells transfected with HIV-1 infectious clones, or as HIV-1 virus production from resting CD4+ T cells isolated from HIV-1-infected individuals on suppressive HAART. Our data indicate that cellular miRNAs are pivotal in HIV-1 latency and suggest that manipulation of cellular miRNAs could be a novel approach for purging the HIV-1 reservoir.", + "TAG_DATA": [ + "79, resting {'context': 'B-cells'}", + "80, primary {'context': 'I-cells'}", + "81, CD4+ {'context': 'I-cells'}", + "82, T {'context': 'I-cells'}", + "83, cells. {'context': 'I-cells'}", + "145, resting {'context': 'B-cells'}", + "146, CD4+ {'context': 'I-cells'}", + "147, T {'context': 'I-cells'}", + "148, cells {'context': 'I-cells'}", + "149, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "150, with {'perturbing_action': 'I-gene gain-of-function'}", + "151, HIV-1 {'perturbing_action': 'I-gene gain-of-function'}", + "152, infectious {'perturbing_action': 'I-gene gain-of-function'}", + "153, clones, {'perturbing_action': 'I-gene gain-of-function'}", + "160, resting {'context': 'B-cells'}", + "161, CD4+ {'context': 'I-cells'}", + "162, T {'context': 'I-cells'}", + "163, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "79, resting ['l0', 'l1', 'l2', 'l3']", + "80, primary ['l0', 'l4', 'l5', 'l6']", + "81, CD4+ ['l1', 'l4', 'l7', 'l8']", + "82, T ['l2', 'l5', 'l7', 'l9']", + "83, cells. ['l3', 'l6', 'l8', 'l9']", + "145, resting ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "146, CD4+ ['l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "147, T ['l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "148, cells ['l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "149, transfected ['l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "150, with ['l14', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "151, HIV-1 ['l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "152, infectious ['l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "153, clones, ['l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']", + "160, resting ['l46', 'l47', 'l48']", + "161, CD4+ ['l46', 'l49', 'l50']", + "162, T ['l47', 'l49', 'l51']", + "163, cells ['l48', 'l50', 'l51']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "resting", + "CD4+", + "T", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "HIV-1", + "infectious", + "clones," + ] + } + } + ] + }, + { + "PMID": "17906636", + "TEXT": "An association between inflammation and cancer has long been recognized, but the cause and effect relationship linking the two remains unclear. Myc is a pleiotropic transcription factor that is overexpressed in many human cancers and instructs many extracellular aspects of the tumor tissue phenotype, including remodeling of tumor stroma and angiogenesis. Here we show in a beta-cell tumor model that activation of Myc in vivo triggers rapid recruitment of mast cells to the tumor site-a recruitment that is absolutely required for macroscopic tumor expansion. In addition, treatment of established beta-cell tumors with a mast cell inhibitor rapidly triggers hypoxia and cell death of tumor and endothelial cells. Inhibitors of mast cell function may therefore prove therapeutically useful in restraining expansion and survival of pancreatic and other cancers.", + "TAG_DATA": [ + "56, beta-cell {'context': 'B-neoplasm'}", + "57, tumor {'context': 'I-neoplasm'}", + "58, model {'context': 'I-neoplasm'}", + "60, activation {'perturbing_action': 'B-pharmacological augmentation'}", + "61, of {'perturbing_action': 'I-pharmacological augmentation'}", + "62, Myc {'perturbing_action': 'I-pharmacological augmentation'}", + "63, in {'context': 'B-in vivo'}", + "64, vivo {'context': 'I-in vivo'}", + "89, beta-cell {'context': 'B-neoplasm'}", + "90, tumors {'context': 'I-neoplasm'}", + "93, mast {'perturbing_action': 'B-pharmacological inhibition'}", + "95, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "97, triggers {'effect': 'B-positive'}", + "100, cell {'phenotype': 'B-cell death'}", + "101, death {'phenotype': 'I-cell death'}", + "103, tumor {'context': 'B-neoplasm'}", + "105, endothelial {'context': 'B-cells'}", + "106, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "56, beta-cell ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "57, tumor ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "58, model ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "60, activation ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "61, of ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "62, Myc ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "63, in ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "64, vivo ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "89, beta-cell ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "90, tumors ['l28', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "93, mast ['l29', 'l38', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "94, cell ['l30', 'l39', 'l47', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "95, inhibitor ['l31', 'l40', 'l48', 'l55', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "97, triggers ['l32', 'l41', 'l49', 'l56', 'l62', 'l68', 'l69', 'l70', 'l71', 'l72']", + "100, cell ['l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l73', 'l74', 'l75', 'l76']", + "101, death ['l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l77', 'l78', 'l79']", + "103, tumor ['l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l80', 'l81']", + "105, endothelial ['l36', 'l45', 'l53', 'l60', 'l66', 'l71', 'l75', 'l78', 'l80', 'l82']", + "106, cells. ['l37', 'l46', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l81', 'l82']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "beta-cell", + "tumor", + "model" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "of", + "Myc" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "of", + "Myc" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "beta-cell", + "tumors", + "tumor" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mast", + "inhibitor" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "beta-cell", + "tumors", + "tumor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "beta-cell", + "tumors", + "tumor" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mast", + "inhibitor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mast", + "inhibitor" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mast", + "inhibitor" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells." + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells." + ] + } + } + ] + }, + { + "PMID": "17906635", + "TEXT": "Insulin resistance is often associated with obesity and can precipitate type 2 diabetes. To date, most known approaches that improve insulin resistance must be preceded by the amelioration of obesity and hepatosteatosis. Here, we show that this provision is not mandatory; insulin resistance and hyperglycemia are improved by the modification of hepatic fatty acid composition, even in the presence of persistent obesity and hepatosteatosis. Mice deficient for Elovl6, the gene encoding the elongase that catalyzes the conversion of palmitate to stearate, were generated and shown to become obese and develop hepatosteatosis when fed a high-fat diet or mated to leptin-deficient ob/ob mice. However, they showed marked protection from hyperinsulinemia, hyperglycemia and hyperleptinemia. Amelioration of insulin resistance was associated with restoration of hepatic insulin receptor substrate-2 and suppression of hepatic protein kinase C epsilon activity resulting in restoration of Akt phosphorylation. Collectively, these data show that hepatic fatty acid composition is a new determinant for insulin sensitivity that acts independently of cellular energy balance and stress. Inhibition of this elongase could be a new therapeutic approach for ameliorating insulin resistance, diabetes and cardiovascular risks, even in the presence of a continuing state of obesity.", + "TAG_DATA": [ + "64, Mice {'context': 'B-organism'}", + "65, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "66, for {'perturbing_action': 'I-gene loss-of-function'}", + "67, Elovl6, {'perturbing_action': 'I-gene loss-of-function'}", + "99, leptin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "100, ob/ob {'perturbing_action': 'B-gene loss-of-function'}", + "101, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "64, Mice ['l0', 'l1', 'l2']", + "65, deficient ['l0', 'l3', 'l4', 'l5', 'l6', 'l7']", + "66, for ['l1', 'l3', 'l8', 'l9', 'l10', 'l11']", + "67, Elovl6, ['l2', 'l4', 'l8', 'l12', 'l13', 'l14']", + "99, leptin-deficient ['l5', 'l9', 'l12', 'l15', 'l16']", + "100, ob/ob ['l6', 'l10', 'l13', 'l15', 'l17']", + "101, mice. ['l7', 'l11', 'l14', 'l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "Elovl6,", + "leptin-deficient", + "ob/ob" + ] + } + } + ] + }, + { + "PMID": "17891147", + "TEXT": "Multiple sclerosis is a disease of the central nervous system that is associated with leukocyte recruitment and subsequent inflammation, demyelination and axonal loss. Endothelial vascular cell adhesion molecule-1 (VCAM-1) and its ligand, alpha4beta1 integrin, are key mediators of leukocyte recruitment, and selective inhibitors that bind to the alpha4 subunit of alpha4beta1 substantially reduce clinical relapse in multiple sclerosis. Urgently needed is a molecular imaging technique to accelerate diagnosis, to quantify disease activity and to guide specific therapy. Here we report in vivo detection of VCAM-1 in acute brain inflammation, by magnetic resonance imaging in a mouse model, at a time when pathology is otherwise undetectable. Antibody-conjugated microparticles carrying a large amount of iron oxide provide potent, quantifiable contrast effects that delineate the architecture of activated cerebral blood vessels. Their rapid clearance from blood results in minimal background contrast. This technology is adaptable to monitor the expression of endovascular molecules in vivo in various pathologies.", + "TAG_DATA": [ + "80, in {'context': 'B-in vivo'}", + "81, vivo {'context': 'I-in vivo'}", + "95, mouse {'context': 'B-organism'}", + "96, model, {'context': 'I-organism'}", + "125, cerebral {'context': 'B-tissue/organ'}", + "126, blood {'context': 'I-tissue/organ'}", + "127, vessels. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "80, in ['l0']", + "81, vivo ['l0']", + "95, mouse ['l1']", + "96, model, ['l1']", + "125, cerebral ['l2', 'l3']", + "126, blood ['l2', 'l4']", + "127, vessels. ['l3', 'l4']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17828272", + "TEXT": "T(H)17 lymphocytes appear to be essential in the pathogenesis of numerous inflammatory diseases. We demonstrate here the expression of IL-17 and IL-22 receptors on blood-brain barrier endothelial cells (BBB-ECs) in multiple sclerosis lesions, and show that IL-17 and IL-22 disrupt BBB tight junctions in vitro and in vivo. Furthermore, T(H)17 lymphocytes transmigrate efficiently across BBB-ECs, highly express granzyme B, kill human neurons and promote central nervous system inflammation through CD4+ lymphocyte recruitment.", + "TAG_DATA": [ + "43, in {'context': 'B-in vitro'}", + "44, vitro {'context': 'I-in vitro'}", + "46, in {'context': 'B-in vivo'}", + "47, vivo. {'context': 'I-in vivo'}", + "49, T(H)17 {'context': 'B-cells'}", + "50, lymphocytes {'context': 'I-cells'}", + "60, human {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "43, in ['l0']", + "44, vitro ['l0']", + "46, in ['l1', 'l2', 'l3']", + "47, vivo. ['l1', 'l4', 'l5']", + "49, T(H)17 ['l6', 'l7']", + "50, lymphocytes ['l2', 'l4', 'l6', 'l8']", + "60, human ['l3', 'l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17721545", + "TEXT": "Dyslipidemia is associated with a prothrombotic phenotype; however, the mechanisms responsible for enhanced platelet reactivity remain unclear. Proatherosclerotic lipid abnormalities are associated with both enhanced oxidant stress and the generation of biologically active oxidized lipids, including potential ligands for the scavenger receptor CD36, a major platelet glycoprotein. Using multiple mouse in vivo thrombosis models, we now demonstrate that genetic deletion of Cd36 protects mice from hyperlipidemia-associated enhanced platelet reactivity and the accompanying prothrombotic phenotype. Structurally defined oxidized choline glycerophospholipids that serve as high-affinity ligands for CD36 were at markedly increased levels in the plasma of hyperlipidemic mice and in the plasma of humans with low HDL levels, were able to bind platelets via CD36 and, at pathophysiological levels, promoted platelet activation via CD36. Thus, interactions of platelet CD36 with specific endogenous oxidized lipids play a crucial role in the well-known clinical associations between dyslipidemia, oxidant stress and a prothrombotic phenotype.", + "TAG_DATA": [ + "49, mouse {'context': 'B-organism'}", + "50, in {'context': 'B-in vivo'}", + "58, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "59, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "60, of {'perturbing_action': 'I-gene loss-of-function'}", + "61, Cd36 {'perturbing_action': 'I-gene loss-of-function'}", + "63, mice {'context': 'B-organism'}", + "96, mice {'context': 'B-organism'}", + "111, platelets {'context': 'B-cells'}", + "119, platelet {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "49, mouse ['l0', 'l1', 'l2', 'l3', 'l4']", + "50, in ['l0', 'l5', 'l6']", + "51, vivo ['l1', 'l5', 'l7']", + "58, genetic ['l8', 'l9', 'l10', 'l11']", + "59, deletion ['l8', 'l12', 'l13', 'l14', 'l15']", + "60, of ['l2', 'l9', 'l12', 'l16', 'l17']", + "61, Cd36 ['l3', 'l6', 'l7', 'l10', 'l13', 'l16', 'l18']", + "63, mice ['l4', 'l11', 'l14', 'l17', 'l18']", + "96, mice ['l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "Cd36", + "genetic", + "deletion" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cd36" + ] + } + } + ] + }, + { + "PMID": "17721544", + "TEXT": "In thalassemia, deficient globin-chain production during erythropoiesis results in anemia. Thalassemia may be further complicated by iron overload (frequently exacerbated by blood transfusion), which induces numerous endocrine diseases, hepatic cirrhosis, cardiac failure and even death. Accumulation of iron in the absence of blood transfusions may result from inappropriate suppression of the iron-regulating peptide hepcidin by an erythropoietic mechanism. To test this hypothesis, we examined erythroblast transcriptome profiles from 15 healthy, nonthalassemic donors. Growth differentiation factor 15 (GDF15), a member of the transforming growth factor-beta superfamily, showed increased expression and secretion during erythroblast maturation. Healthy volunteers had mean GDF15 serum concentrations of 450 +/- 50 pg/ml. In comparison, individuals with beta-thalassemia syndromes had elevated GDF15 serum levels (mean 66,000 +/- 9,600 pg/ml; range 4,800-248,000 pg/ml; P < 0.05) that were positively correlated with the levels of soluble transferrin receptor, erythropoietin and ferritin. Serum from thalassemia patients suppressed hepcidin mRNA expression in primary human hepatocytes, and depletion of GDF15 reversed hepcidin suppression. These results suggest that GDF15 overexpression arising from an expanded erythroid compartment contributes to iron overload in thalassemia syndromes by inhibiting hepcidin expression.", + "TAG_DATA": [ + "150, primary {'context': 'B-cells'}", + "151, human {'context': 'I-cells'}", + "152, hepatocytes, {'context': 'I-cells'}", + "154, depletion {'perturbing_action': 'B-gene loss-of-function'}", + "155, of {'perturbing_action': 'I-gene loss-of-function'}", + "156, GDF15 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "150, primary ['l0', 'l1']", + "151, human ['l0', 'l2']", + "152, hepatocytes, ['l1', 'l2']", + "154, depletion ['l3', 'l4']", + "155, of ['l3', 'l5']", + "156, GDF15 ['l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17694067", + "TEXT": "Transformation and cancer growth are regulated by the coordinate actions of oncogenes and tumor suppressors. Here, we show that the novel E3 ubiquitin ligase HACE1 is frequently downregulated in human tumors and maps to a region of chromosome 6q21 implicated in multiple human cancers. Genetic inactivation of HACE1 in mice results in the development of spontaneous, late-onset cancer. A second hit from either environmental triggers or genetic heterozygosity of another tumor suppressor, p53, markedly increased tumor incidence in a Hace1-deficient background. Re-expression of HACE1 in human tumor cells directly abrogates in vitro and in vivo tumor growth, whereas downregulation of HACE1 via siRNA allows non-tumorigenic human cells to form tumors in vivo. Mechanistically, the tumor-suppressor function of HACE1 is dependent on its E3 ligase activity and HACE1 controls adhesion-dependent growth and cell cycle progression during cell stress through degradation of cyclin D1. Thus, HACE1 is a candidate chromosome 6q21 tumor-suppressor gene involved in multiple cancers.", + "TAG_DATA": [ + "44, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "45, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "46, of {'perturbing_action': 'I-gene loss-of-function'}", + "47, HACE1 {'perturbing_action': 'I-gene loss-of-function'}", + "49, mice {'context': 'B-organism'}", + "57, cancer. {'phenotype': 'I-tumourigenesis'}", + "66, genetic {'perturbing_action': 'B-other'}", + "67, heterozygosity {'perturbing_action': 'I-other'}", + "68, of {'perturbing_action': 'I-other'}", + "69, another {'perturbing_action': 'I-other'}", + "70, tumor {'perturbing_action': 'I-other'}", + "71, suppressor, {'perturbing_action': 'I-other'}", + "72, p53, {'perturbing_action': 'I-other'}", + "74, increased {'effect': 'B-positive'}", + "75, tumor {'phenotype': 'B-tumourigenesis'}", + "76, incidence {'phenotype': 'I-tumourigenesis'}", + "79, Hace1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "81, Re-expression {'perturbing_action': 'B-gene gain-of-function'}", + "82, of {'perturbing_action': 'I-gene gain-of-function'}", + "83, HACE1 {'perturbing_action': 'I-gene gain-of-function'}", + "85, human {'context': 'B-transformed cells'}", + "86, tumor {'context': 'I-transformed cells'}", + "87, cells {'context': 'I-transformed cells'}", + "89, abrogates {'effect': 'B-negative'}", + "90, in {'context': 'B-in vitro'}", + "91, vitro {'context': 'I-in vitro'}", + "93, in {'context': 'B-in vivo'}", + "94, vivo {'context': 'I-in vivo'}", + "95, tumor {'phenotype': 'B-tumour growth'}", + "96, growth, {'phenotype': 'I-tumour growth'}", + "98, downregulation {'perturbing_action': 'B-rnai/knockdown'}", + "99, of {'perturbing_action': 'I-rnai/knockdown'}", + "100, HACE1 {'perturbing_action': 'I-rnai/knockdown'}", + "101, via {'perturbing_action': 'I-rnai/knockdown'}", + "102, siRNA {'perturbing_action': 'I-rnai/knockdown'}", + "103, allows {'effect': 'B-positive'}", + "104, non-tumorigenic {'context': 'B-cells'}", + "105, human {'context': 'I-cells'}", + "106, cells {'context': 'I-cells'}", + "108, form {'phenotype': 'B-tumourigenesis'}", + "109, tumors {'phenotype': 'B-tumourigenesis'}", + "110, in {'context': 'B-in vivo'}", + "111, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "44, Genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "45, inactivation ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "46, of ['l1', 'l12', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "47, HACE1 ['l2', 'l13', 'l26', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "49, mice ['l3', 'l14', 'l27', 'l37', 'l47', 'l48', 'l49', 'l50']", + "57, cancer. ['l4', 'l15', 'l28', 'l38', 'l47']", + "66, genetic ['l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "67, heterozygosity ['l51', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "68, of ['l52', 'l74', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "69, another ['l53', 'l75', 'l96', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "70, tumor ['l54', 'l76', 'l97', 'l117', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "71, suppressor, ['l55', 'l77', 'l98', 'l118', 'l137', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "72, p53, ['l16', 'l56', 'l78', 'l99', 'l119', 'l138', 'l156', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190']", + "74, increased ['l5', 'l17', 'l29', 'l39', 'l48', 'l57', 'l79', 'l100', 'l120', 'l139', 'l157', 'l174', 'l191', 'l192', 'l193', 'l194', 'l195']", + "75, tumor ['l6', 'l18', 'l30', 'l40', 'l49', 'l58', 'l80', 'l101', 'l121', 'l140', 'l158', 'l175', 'l191', 'l196', 'l197', 'l198']", + "76, incidence ['l7', 'l19', 'l31', 'l41', 'l50', 'l59', 'l81', 'l102', 'l122', 'l141', 'l159', 'l176', 'l192', 'l196', 'l199']", + "79, Hace1-deficient ['l8', 'l20', 'l32', 'l42', 'l60', 'l82', 'l103', 'l123', 'l142', 'l160', 'l177', 'l193', 'l197', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206']", + "81, Re-expression ['l61', 'l83', 'l104', 'l124', 'l143', 'l161', 'l178', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218']", + "82, of ['l62', 'l84', 'l105', 'l125', 'l144', 'l162', 'l179', 'l207', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229']", + "83, HACE1 ['l63', 'l85', 'l106', 'l126', 'l145', 'l163', 'l180', 'l208', 'l219', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239']", + "85, human ['l9', 'l21', 'l33', 'l43', 'l64', 'l86', 'l107', 'l127', 'l146', 'l164', 'l181', 'l194', 'l200', 'l209', 'l220', 'l230', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248']", + "86, tumor ['l10', 'l22', 'l34', 'l44', 'l65', 'l87', 'l108', 'l128', 'l147', 'l165', 'l182', 'l201', 'l210', 'l221', 'l231', 'l240', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256']", + "87, cells ['l11', 'l23', 'l35', 'l45', 'l66', 'l88', 'l109', 'l129', 'l148', 'l166', 'l183', 'l195', 'l198', 'l202', 'l211', 'l222', 'l232', 'l241', 'l249', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263']", + "89, abrogates ['l24', 'l67', 'l89', 'l110', 'l130', 'l149', 'l167', 'l184', 'l203', 'l212', 'l223', 'l233', 'l242', 'l250', 'l257', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269']", + "90, in ['l68', 'l90', 'l111', 'l131', 'l150', 'l168', 'l185', 'l213', 'l224', 'l234', 'l243', 'l251', 'l258', 'l264', 'l270', 'l271', 'l272', 'l273', 'l274']", + "91, vitro ['l69', 'l91', 'l112', 'l132', 'l151', 'l169', 'l186', 'l204', 'l214', 'l225', 'l235', 'l244', 'l252', 'l259', 'l265', 'l270', 'l275', 'l276', 'l277', 'l278']", + "93, in ['l70', 'l92', 'l113', 'l133', 'l152', 'l170', 'l187', 'l215', 'l226', 'l236', 'l245', 'l253', 'l260', 'l266', 'l271', 'l275', 'l279', 'l280', 'l281']", + "94, vivo ['l71', 'l93', 'l114', 'l134', 'l153', 'l171', 'l188', 'l216', 'l227', 'l237', 'l246', 'l254', 'l261', 'l267', 'l272', 'l276', 'l279', 'l282', 'l283']", + "95, tumor ['l72', 'l94', 'l115', 'l135', 'l154', 'l172', 'l189', 'l205', 'l217', 'l228', 'l238', 'l247', 'l255', 'l262', 'l268', 'l273', 'l277', 'l280', 'l282', 'l284']", + "96, growth, ['l25', 'l36', 'l46', 'l73', 'l95', 'l116', 'l136', 'l155', 'l173', 'l190', 'l206', 'l218', 'l229', 'l239', 'l248', 'l256', 'l263', 'l269', 'l274', 'l278', 'l281', 'l283', 'l284']", + "98, downregulation ['l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296']", + "99, of ['l285', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304', 'l305', 'l306', 'l307']", + "100, HACE1 ['l286', 'l297', 'l308', 'l309', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315', 'l316', 'l317']", + "101, via ['l287', 'l298', 'l308', 'l318', 'l319', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326']", + "102, siRNA ['l288', 'l299', 'l309', 'l318', 'l327', 'l328', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334']", + "103, allows ['l289', 'l300', 'l310', 'l319', 'l327', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340', 'l341']", + "104, non-tumorigenic ['l290', 'l301', 'l311', 'l320', 'l328', 'l335', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347']", + "105, human ['l291', 'l302', 'l312', 'l321', 'l329', 'l336', 'l342', 'l348', 'l349', 'l350', 'l351', 'l352']", + "106, cells ['l292', 'l303', 'l313', 'l322', 'l330', 'l337', 'l343', 'l348', 'l353', 'l354', 'l355', 'l356']", + "108, form ['l293', 'l304', 'l314', 'l323', 'l331', 'l338', 'l344', 'l349', 'l353', 'l357', 'l358', 'l359']", + "109, tumors ['l294', 'l305', 'l315', 'l324', 'l332', 'l339', 'l345', 'l350', 'l354', 'l357', 'l360', 'l361']", + "110, in ['l295', 'l306', 'l316', 'l325', 'l333', 'l340', 'l346', 'l351', 'l355', 'l358', 'l360', 'l362']", + "111, vivo. ['l296', 'l307', 'l317', 'l326', 'l334', 'l341', 'l347', 'l352', 'l356', 'l359', 'l361', 'l362']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "inactivation", + "of", + "HACE1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "inactivation", + "of", + "HACE1", + "Hace1-deficient" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "cancer.", + "tumor", + "incidence" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "inactivation", + "of", + "HACE1", + "Hace1-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "inactivation", + "of", + "HACE1", + "Hace1-deficient" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "Hace1-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "HACE1", + "Hace1-deficient" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth,", + "tumor" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "cancer.", + "tumor", + "incidence" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetic", + "heterozygosity", + "of", + "another", + "tumor", + "suppressor,", + "p53," + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetic", + "heterozygosity", + "of", + "another", + "tumor", + "suppressor,", + "p53," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "incidence" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetic", + "heterozygosity", + "of", + "another", + "tumor", + "suppressor,", + "p53," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetic", + "heterozygosity", + "of", + "another", + "tumor", + "suppressor,", + "p53," + ] + }, + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetic", + "heterozygosity", + "of", + "another", + "tumor", + "suppressor,", + "p53," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetic", + "heterozygosity", + "of", + "another", + "tumor", + "suppressor,", + "p53," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetic", + "heterozygosity", + "of", + "another", + "tumor", + "suppressor,", + "p53," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased", + "allows" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "incidence", + "form", + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "cells" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor" + ] 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+ ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Re-expression", + "of", + "HACE1" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "tumor", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "tumor", + "cells" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth," + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "downregulation", + "of", + "HACE1", + "via", + "siRNA" + ] + }, + "effect": { + "val": "positive", + "words": [ + "allows" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "downregulation", + "of", + "HACE1", + "via", + "siRNA" + ] + }, + "context": { + "val": "cells", + "words": [ + "non-tumorigenic", + "human", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "downregulation", + "of", + "HACE1", + "via", + "siRNA" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "downregulation", + "of", + "HACE1", + "via", + "siRNA" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "allows" + ] + }, + "context": { + "val": "cells", + "words": [ + "non-tumorigenic", + "human", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "allows" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "non-tumorigenic", + "human", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumors" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "17660827", + "TEXT": "An emerging concept is that the mammalian myocardium has the potential to regenerate, but that regeneration might be too inefficient to repair the extensive myocardial injury that is typical of human disease. However, the degree to which stem cells or precursor cells contribute to the renewal of adult mammalian cardiomyocytes remains controversial. Here we report evidence that stem cells or precursor cells contribute to the replacement of adult mammalian cardiomyocytes after injury but do not contribute significantly to cardiomyocyte renewal during normal aging. We generated double-transgenic mice to track the fate of adult cardiomyocytes in a 'pulse-chase' fashion: after a 4-OH-tamoxifen pulse, green fluorescent protein (GFP) expression was induced only in cardiomyocytes, with 82.7% of cardiomyocytes expressing GFP. During normal aging up to one year, the percentage of GFP+ cardiomyocytes remained unchanged, indicating that stem or precursor cells did not refresh uninjured cardiomyocytes at a significant rate during this period of time. By contrast, after myocardial infarction or pressure overload, the percentage of GFP+ cardiomyocytes decreased from 82.8% in heart tissue from sham-treated mice to 67.5% in areas bordering a myocardial infarction, 76.6% in areas away from a myocardial infarction, and 75.7% in hearts subjected to pressure overload, indicating that stem cells or precursor cells had refreshed the cardiomyocytes.", + "TAG_DATA": [ + "86, mice {'context': 'B-organism'}", + "92, adult {'context': 'B-cells'}", + "93, cardiomyocytes {'context': 'I-cells'}", + "111, cardiomyocytes, {'context': 'B-cells'}", + "115, cardiomyocytes {'context': 'B-cells'}", + "128, GFP+ {'context': 'B-cells'}", + "129, cardiomyocytes {'context': 'I-cells'}", + "134, stem {'context': 'B-cells'}", + "142, cardiomyocytes {'context': 'B-cells'}", + "163, GFP+ {'context': 'B-cells'}", + "164, cardiomyocytes {'context': 'I-cells'}", + "169, heart {'context': 'B-tissue/organ'}", + "170, tissue {'context': 'I-tissue/organ'}", + "173, mice {'context': 'B-organism'}", + "193, hearts {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "86, mice ['l0', 'l1', 'l2']", + "92, adult ['l0', 'l3', 'l4']", + "93, cardiomyocytes ['l1', 'l3', 'l5']", + "111, cardiomyocytes, ['l2', 'l4', 'l5', 'l6']", + "115, cardiomyocytes ['l6']", + "128, GFP+ ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "129, cardiomyocytes ['l7', 'l15', 'l16', 'l17']", + "134, stem ['l8', 'l15', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "142, cardiomyocytes ['l9', 'l16', 'l18', 'l24', 'l25', 'l26']", + "163, GFP+ ['l10', 'l19', 'l27', 'l28', 'l29', 'l30']", + "164, cardiomyocytes ['l11', 'l17', 'l20', 'l24', 'l27', 'l31', 'l32', 'l33']", + "169, heart ['l12', 'l21', 'l28', 'l31', 'l34', 'l35']", + "170, tissue ['l13', 'l22', 'l25', 'l29', 'l32', 'l34', 'l36']", + "173, mice ['l14', 'l23', 'l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17632525", + "TEXT": "Adult mammalian hearts respond to injury with scar formation and not with cardiomyocyte proliferation, the cellular basis of regeneration. Although cardiogenic progenitor cells may maintain myocardial turnover, they do not give rise to a robust regenerative response. Here we show that extracellular periostin induced reentry of differentiated mammalian cardiomyocytes into the cell cycle. Periostin stimulated mononucleated cardiomyocytes to go through the full mitotic cell cycle. Periostin activated alphaV, beta1, beta3 and beta5 integrins located in the cardiomyocyte cell membrane. Activation of phosphatidylinositol-3-OH kinase was required for periostin-induced reentry of cardiomyocytes into the cell cycle and was sufficient for cell-cycle reentry in the absence of periostin. After myocardial infarction, periostin-induced cardiomyocyte cell-cycle reentry and mitosis were associated with improved ventricular remodeling and myocardial function, reduced fibrosis and infarct size, and increased angiogenesis. Thus, periostin and the pathway that it regulates may provide a target for innovative strategies to treat heart failure.", + "TAG_DATA": [ + "46, differentiated {'context': 'B-cells'}", + "47, mammalian {'context': 'I-cells'}", + "48, cardiomyocytes {'context': 'I-cells'}", + "55, mononucleated {'context': 'B-cells'}", + "56, cardiomyocytes {'context': 'I-cells'}", + "89, cardiomyocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "46, differentiated ['l0', 'l1', 'l2', 'l3']", + "47, mammalian ['l0', 'l4', 'l5', 'l6']", + "48, cardiomyocytes ['l1', 'l4', 'l7', 'l8']", + "55, mononucleated ['l2', 'l5', 'l7', 'l9', 'l10']", + "56, cardiomyocytes ['l3', 'l6', 'l8', 'l9', 'l11']", + "89, cardiomyocytes ['l10', 'l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17603496", + "TEXT": "Here we describe a technique for measuring changes in Ca2+ in the cytosolic domain of mature compact myelin of live axons in the central nervous system (CNS). We label the myelin sheath of optic nerve and dorsal column axons by using the Ca2+ indicator X-rhod-1 coupled with DiOC6(3) to produce bright myelin counterstaining, thereby providing unambiguous identification of the myelin sheath for analysis of two-photon excited fluorescence. We present evidence for localization of the Ca2+ reporter to the cytosolic domain of myelin, obtained by using fluorescence lifetime, spectral measurements and Mn2+ quenching. Chemical ischemia increased myelinic X-rhod-1 fluorescence (approximately 50% after 30 min) in a manner dependent on extracellular Ca2+. Inhibiting Na+-dependent glutamate transporters (with TBOA) or glycine transporters (with sarcosine and ALX-1393) reduced the ischemia-induced increase in Ca2+. We show that myelinic N-methyl-D-aspartate (NMDA) receptors are activated by the two conventional coagonists glutamate and glycine, which are released by specific transporters under conditions of cellular Na+ loading and depolarization in injured white matter. This new technique facilitates detailed studies of living myelin, a vital component of the mammalian CNS.", + "TAG_DATA": [ + "163, matter. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17603495", + "TEXT": "Genital human papillomavirus (HPV) infection is the most common sexually transmitted infection, and virtually all cases of cervical cancer are attributable to infection by a subset of HPVs (reviewed in ref. 1). Despite the high incidence of HPV infection and the recent development of a prophylactic vaccine that confers protection against some HPV types, many features of HPV infection are poorly understood. It remains worthwhile to consider other interventions against genital HPVs, particularly those that target infections not prevented by the current vaccine. However, productive papillomavirus infection is species- and tissue-restricted, and traditional models use animal papillomaviruses that infect the skin or oral mucosa. Here we report the development of a mouse model of cervicovaginal infection with HPV16 that recapitulates the establishment phase of papillomavirus infection. Transduction of a reporter gene by an HPV16 pseudovirus was characterized by histology and quantified by whole-organ, multispectral imaging. Disruption of the integrity of the stratified or columnar genital epithelium was required for infection, which occurred after deposition of the virus on the basement membrane underlying basal keratinocytes. A widely used vaginal spermicide, nonoxynol-9 (N-9), greatly increased susceptibility to infection. In contrast, carrageenan, a polysaccharide present in some vaginal lubricants, prevented infection even in the presence of N-9, suggesting that carrageenan might serve as an effective topical HPV microbicide.", + "TAG_DATA": [ + "111, mouse {'context': 'B-organism'}", + "112, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "111, mouse ['l0']", + "112, model ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17603492", + "TEXT": "The relationship between stress and obesity remains elusive. In response to stress, some people lose weight, whereas others gain. Here we report that stress exaggerates diet-induced obesity through a peripheral mechanism in the abdominal white adipose tissue that is mediated by neuropeptide Y (NPY). Stressors such as exposure to cold or aggression lead to the release of NPY from sympathetic nerves, which in turn upregulates NPY and its Y2 receptors (NPY2R) in a glucocorticoid-dependent manner in the abdominal fat. This positive feedback response by NPY leads to the growth of abdominal fat. Release of NPY and activation of NPY2R stimulates fat angiogenesis, macrophage infiltration, and the proliferation and differentiation of new adipocytes, resulting in abdominal obesity and a metabolic syndrome-like condition. NPY, like stress, stimulates mouse and human fat growth, whereas pharmacological inhibition or fat-targeted knockdown of NPY2R is anti-angiogenic and anti-adipogenic, while reducing abdominal obesity and metabolic abnormalities. Thus, manipulations of NPY2R activity within fat tissue offer new ways to remodel fat and treat obesity and metabolic syndrome.", + "TAG_DATA": [ + "99, stimulates {'effect': 'B-positive'}", + "106, proliferation {'phenotype': 'B-proliferation'}", + "108, differentiation {'phenotype': 'B-differentiation'}", + "110, new {'context': 'B-cells'}", + "111, adipocytes, {'context': 'I-cells'}", + "125, mouse {'context': 'B-tissue/organ'}", + "126, and {'context': 'I-tissue/organ'}", + "127, human {'context': 'I-tissue/organ'}", + "134, fat-targeted {'perturbing_action': 'B-rnai/knockdown'}", + "135, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "136, of {'perturbing_action': 'I-rnai/knockdown'}", + "137, NPY2R {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "99, stimulates ['l0', 'l1', 'l2', 'l3']", + "106, proliferation ['l0', 'l4', 'l5', 'l6']", + "108, differentiation ['l1', 'l4', 'l7', 'l8']", + "110, new ['l2', 'l5', 'l7', 'l9']", + "111, adipocytes, ['l3', 'l6', 'l8', 'l9']", + "125, mouse ['l10', 'l11']", + "126, and ['l10', 'l12']", + "127, human ['l11', 'l12']", + "134, fat-targeted ['l13', 'l14', 'l15']", + "135, knockdown ['l13', 'l16', 'l17']", + "136, of ['l14', 'l16', 'l18']", + "137, NPY2R ['l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "context": { + "val": "cells", + "words": [ + "new", + "adipocytes," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "new", + "adipocytes," + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "new", + "adipocytes," + ] + } + } + ] + }, + { + "PMID": "17515897", + "TEXT": "Nur77 (NR4A1) and Nor-1 (NR4A3) are highly homologous orphan nuclear receptors that regulate the transcription of overlapping target genes. The transcriptional activity of both proteins is regulated in a ligand-independent manner by cell- and stimulus-specific gene induction and protein phosphorylation. Nor-1 and Nur77 have been implicated in a variety of cellular processes, including the transduction of hormonal, inflammatory, mitogenic, apoptotic and differentiative signals. Cellular responses to these proteins suggest that they may function as homeostatic regulators of proliferation, apoptosis and differentiation, and thus may regulate cellular susceptibility to tumorigenesis. Their physiological functions, however, remain poorly understood. Here we describe a previously unsuspected function of Nor-1 and Nur77-as critical tumor suppressors of myeloid leukemogenesis. The abrogation of these proteins in mice led to rapidly lethal acute myeloid leukemia (AML), involving abnormal expansion of hematopoietic stem cells (HSCs) and myeloid progenitors, decreased expression of the AP-1 transcription factors JunB and c-Jun and defective extrinsic apoptotic (Fas-L and TRAIL) signaling. We found that downregulation of NR4A3 ( NOR-1 ) and NR4A1 ( NUR77 ) was a common feature in leukemic blasts from human AML patients, irrespective of karyotype. Thus Nor-1 and Nur77 may provide potential targets for therapeutic intervention in AML.", + "TAG_DATA": [ + "119, mice {'context': 'B-organism'}", + "124, acute {'context': 'B-neoplasm'}", + "125, myeloid {'context': 'B-neoplasm'}", + "126, leukemia {'context': 'I-neoplasm'}", + "132, hematopoietic {'context': 'B-cells'}", + "133, stem {'context': 'I-cells'}", + "134, cells {'context': 'I-cells'}", + "135, (HSCs) {'context': 'I-cells'}", + "137, myeloid {'context': 'B-cells'}", + "138, progenitors, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "119, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "124, acute ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "125, myeloid ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "126, leukemia ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "127, (AML), ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "132, hematopoietic ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "133, stem ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "134, cells ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "135, (HSCs) ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "137, myeloid ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "138, progenitors, ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17515894", + "TEXT": "Loss of cone function in the central retina is a pivotal event in the development of severe vision impairment for many prevalent blinding diseases. Complete achromatopsia is a genetic defect resulting in cone vision loss in 1 in 30,000 individuals. Using adeno-associated virus (AAV) gene therapy, we show that it is possible to target cones and rescue both the cone-mediated electroretinogram response and visual acuity in the Gnat2 ( cpfl3 ) mouse model of achromatopsia.", + "TAG_DATA": [ + "54, cones {'context': 'B-cells'}", + "56, rescue {'effect': 'B-rescues'}", + "67, Gnat2 {'perturbing_action': 'B-other'}", + "68, ( {'perturbing_action': 'I-other'}", + "69, cpfl3 {'perturbing_action': 'I-other'}", + "70, ) {'perturbing_action': 'I-other'}", + "71, mouse {'context': 'B-organism'}", + "72, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "54, cones ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "56, rescue ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "67, Gnat2 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "68, ( ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "69, cpfl3 ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "70, ) ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "71, mouse ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "72, model ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cones" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescue" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cones" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Gnat2", + "(", + "cpfl3", + ")" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescue" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Gnat2", + "(", + "cpfl3", + ")" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescue" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Gnat2", + "(", + "cpfl3", + ")" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + } + ] + }, + { + "PMID": "17496901", + "TEXT": "We analyzed the PI3K-AKT signaling cascade in a cohort of sarcomas and found a marked induction of insulin receptor substrate-2 (IRS2) and phosphorylated AKT and a concomitant upregulation of downstream effectors in most leiomyosarcomas. To determine the role of aberrant PI3K-AKT signaling in leiomyosarcoma pathogenesis, we genetically inactivated Pten in the smooth muscle cell lineage by cross-breeding Pten(loxP/loxP) mice with Tagln-cre mice. Mice carrying homozygous deletion of Pten alleles developed widespread smooth muscle cell hyperplasia and abdominal leiomyosarcomas, with a very rapid onset and elevated incidence (approximately 80%) compared to other animal models. Constitutive mTOR activation was restricted to the leiomyosarcomas, revealing the requirement for additional molecular events besides Pten loss. The rapamycin derivative everolimus substantially decelerated tumor growth on Tagln-cre/Pten(loxP/loxP) mice and prolonged their lifespan. Our data show a new and critical role for the AKT-mTOR pathway in smooth muscle transformation and leiomyosarcoma genesis, and support treatment of selected sarcomas by the targeting of this pathway with new compounds or combinations of these with conventional chemotherapy agents.", + "TAG_DATA": [ + "46, genetically {'perturbing_action': 'B-gene loss-of-function'}", + "47, inactivated {'perturbing_action': 'I-gene loss-of-function'}", + "48, Pten {'perturbing_action': 'I-gene loss-of-function'}", + "51, smooth {'context': 'B-cells'}", + "52, muscle {'context': 'I-cells'}", + "53, cell {'context': 'I-cells'}", + "54, lineage {'context': 'I-cells'}", + "58, mice {'context': 'B-organism'}", + "62, Mice {'context': 'B-organism'}", + "64, homozygous {'perturbing_action': 'B-gene loss-of-function'}", + "65, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "66, of {'perturbing_action': 'I-gene loss-of-function'}", + "67, Pten {'perturbing_action': 'I-gene loss-of-function'}", + "68, alleles {'perturbing_action': 'I-gene loss-of-function'}", + "71, smooth {'context': 'B-cells'}", + "72, muscle {'context': 'I-cells'}", + "73, cell {'context': 'I-cells'}", + "77, leiomyosarcomas, {'phenotype': 'I-tumourigenesis'}", + "100, leiomyosarcomas, {'context': 'B-neoplasm'}", + "116, decelerated {'effect': 'B-negative'}", + "117, tumor {'phenotype': 'B-tumour growth'}", + "118, growth {'phenotype': 'I-tumour growth'}", + "120, Tagln-cre/Pten(loxP/loxP) {'perturbing_action': 'B-other'}", + "121, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "46, genetically ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "47, inactivated ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "48, Pten ['l1', 'l10', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "51, smooth ['l2', 'l11', 'l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "52, muscle ['l3', 'l12', 'l21', 'l29', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "53, cell ['l4', 'l13', 'l22', 'l30', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "54, lineage ['l5', 'l14', 'l23', 'l31', 'l37', 'l42', 'l47', 'l48', 'l49', 'l50']", + "58, mice ['l6', 'l15', 'l24', 'l32', 'l38', 'l43', 'l47', 'l51', 'l52', 'l53', 'l54', 'l55']", + "62, Mice ['l51', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "64, homozygous ['l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "65, deletion ['l56', 'l64', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "66, of ['l57', 'l65', 'l73', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "67, Pten ['l58', 'l66', 'l74', 'l81', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "68, alleles ['l59', 'l67', 'l75', 'l82', 'l88', 'l94', 'l95', 'l96', 'l97', 'l98']", + "71, smooth ['l7', 'l16', 'l25', 'l33', 'l39', 'l44', 'l48', 'l52', 'l60', 'l68', 'l76', 'l83', 'l89', 'l94', 'l99', 'l100', 'l101']", + "72, muscle ['l8', 'l17', 'l26', 'l34', 'l40', 'l45', 'l49', 'l53', 'l61', 'l69', 'l77', 'l84', 'l90', 'l95', 'l99', 'l102', 'l103']", + "73, cell ['l9', 'l18', 'l27', 'l35', 'l41', 'l46', 'l50', 'l54', 'l62', 'l70', 'l78', 'l85', 'l91', 'l96', 'l100', 'l102', 'l104']", + "77, leiomyosarcomas, ['l19', 'l28', 'l55', 'l63', 'l71', 'l79', 'l86', 'l92', 'l97', 'l101', 'l103', 'l104']", + "100, leiomyosarcomas, ['l72', 'l80', 'l87', 'l93', 'l98']", + "116, decelerated ['l105', 'l106', 'l107', 'l108']", + "117, tumor ['l105', 'l109', 'l110', 'l111']", + "118, growth ['l106', 'l109', 'l112', 'l113']", + "120, Tagln-cre/Pten(loxP/loxP) ['l107', 'l110', 'l112', 'l114']", + "121, mice ['l108', 'l111', 'l113', 'l114']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetically", + "inactivated", + "Pten", + "homozygous", + "deletion", + "of", + "alleles" + ] + }, + "context": { + "val": "cells", + "words": [ + "smooth", + "muscle", + "cell", + "lineage" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetically", + "inactivated", + "Pten", + "deletion", + "of", + "alleles" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "Mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivated", + "Pten", + "homozygous", + "deletion", + "of", + "alleles" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leiomyosarcomas," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "Mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leiomyosarcomas," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "homozygous", + "deletion", + "of", + "Pten", + "alleles" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leiomyosarcomas," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "smooth", + "muscle", + "cell" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leiomyosarcomas," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decelerated" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decelerated" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Tagln-cre/Pten(loxP/loxP)" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decelerated" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Tagln-cre/Pten(loxP/loxP)" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Tagln-cre/Pten(loxP/loxP)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "17496900", + "TEXT": "T-helper type 17 cells (T(H)17) are implicated in rodent models of immune-mediated diseases. Here we report their involvement in human uveitis and scleritis, and validate our findings in experimental autoimmune uveoretinitis (EAU), a model of uveitis. T(H)17 cells were present in human peripheral blood mononuclear cells (PBMC), and were expanded by interleukin (IL)-2 and inhibited by interferon (IFN)-gamma. Their numbers increased during active uveitis and scleritis and decreased following treatment. IL-17 was elevated in EAU and upregulated tumor necrosis factor (TNF)-alpha in retinal cells, suggesting a mechanism by which T(H)17 may contribute to ocular pathology. Furthermore, IL-27 was constitutively expressed in retinal ganglion and photoreceptor cells, was upregulated by IFN-gamma and inhibited proliferation of T(H)17. These findings suggest that T(H)1 cells may mitigate uveitis by antagonizing the T(H)17 phenotype through the IFN-gamma-mediated induction of IL-27 in target tissue. The finding that IL-2 promotes T(H)17 expansion provides explanations for the efficacy of IL-2R antibody therapy in uveitis, and suggests that antagonism of T(H)17 by IFN-gamma and/or IL-27 could be used for the treatment of chronic inflammation.", + "TAG_DATA": [ + "36, T(H)17 {'context': 'B-cells'}", + "37, cells {'context': 'I-cells'}", + "41, human {'context': 'B-cells'}", + "42, peripheral {'context': 'I-cells'}", + "43, blood {'context': 'I-cells'}", + "44, mononuclear {'context': 'I-cells'}", + "45, cells {'context': 'I-cells'}", + "46, (PBMC), {'context': 'I-cells'}", + "82, retinal {'context': 'B-cells'}", + "83, cells, {'context': 'I-cells'}", + "101, retinal {'context': 'B-cells'}", + "102, ganglion {'context': 'I-cells'}", + "103, and {'context': 'I-cells'}", + "104, photoreceptor {'context': 'I-cells'}", + "105, cells, {'context': 'I-cells'}", + "111, inhibited {'effect': 'B-negative'}", + "112, proliferation {'phenotype': 'B-proliferation'}", + "114, T(H)17. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "36, T(H)17 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "37, cells ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "41, human ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "42, peripheral ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "43, blood ['l3', 'l10', 'l16', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "44, mononuclear ['l4', 'l11', 'l17', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "45, cells ['l5', 'l12', 'l18', 'l23', 'l28', 'l32', 'l36', 'l37']", + "46, (PBMC), ['l6', 'l13', 'l19', 'l24', 'l29', 'l33', 'l36', 'l38', 'l39']", + "82, retinal ['l25', 'l30', 'l34', 'l38', 'l40', 'l41', 'l42', 'l43']", + "83, cells, ['l7', 'l14', 'l20', 'l26', 'l31', 'l35', 'l37', 'l39', 'l40']", + "101, retinal ['l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "102, ganglion ['l41', 'l44', 'l51', 'l52', 'l53', 'l54', 'l55']", + "103, and ['l42', 'l45', 'l51', 'l56', 'l57', 'l58', 'l59', 'l60']", + "104, photoreceptor ['l46', 'l52', 'l56', 'l61', 'l62', 'l63', 'l64']", + "105, cells, ['l43', 'l47', 'l53', 'l57', 'l61', 'l65']", + "111, inhibited ['l48', 'l54', 'l58', 'l62', 'l66', 'l67']", + "112, proliferation ['l49', 'l59', 'l63', 'l66', 'l68']", + "114, T(H)17. ['l50', 'l55', 'l60', 'l64', 'l65', 'l67', 'l68']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "retinal", + "ganglion", + "and", + "photoreceptor", + "T(H)17." + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "retinal", + "and", + "photoreceptor", + "T(H)17." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "17486090", + "TEXT": "Misfolding of Cu/Zn-superoxide dismutase (SOD1) is emerging as a mechanism underlying motor neuron degeneration in individuals with amyotrophic lateral sclerosis (ALS) who carry a mutant SOD1 gene (SOD1 ALS). Here we describe a structure-guided approach to developing an antibody that specifically recognizes monomer-misfolded forms of SOD1. We raised this antibody to an epitope that is normally buried in the SOD1 native homodimer interface. The SOD1 exposed dimer interface (SEDI) antibody recognizes only those SOD1 conformations in which the native dimer is disrupted or misfolded and thereby exposes the hydrophobic dimer interface. Using the SEDI antibody, we established the presence of monomer-misfolded SOD1 in three ALS mouse models, with G37R, G85R and G93A SOD1 mutations, and in a human individual with an A4V SOD1 mutation. Despite ubiquitous expression, misfolded SOD1 was found primarily within degenerating motor neurons. Misfolded SOD1 appeared before the onset of symptoms and decreased at the end stage of the disease, concomitant with motor neuron loss.", + "TAG_DATA": [ + "104, ALS {'context': 'B-organism'}", + "105, mouse {'context': 'I-organism'}", + "106, models, {'context': 'I-organism'}", + "117, human {'context': 'B-patient'}", + "118, individual {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "104, ALS ['l0', 'l1']", + "105, mouse ['l0', 'l2']", + "106, models, ['l1', 'l2']", + "117, human ['l3']", + "118, individual ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17435772", + "TEXT": "Mammalian cells have developed diverse strategies to restrict retroviral infection. Retroviruses have therefore evolved to counteract such restriction factors, in order to colonize their hosts. Tripartite motif-containing 5 isoform-alpha (TRIM5alpha) protein from rhesus monkey (TRIM5alpharh) restricts human immunodeficiency virus type 1 (HIV-1) infection at a postentry, preintegration stage in the viral life cycle, by recognizing the incoming capsid and promoting its premature disassembly. TRIM5alpha comprises an RBCC (RING, B-box 2 and coiled-coil motifs) domain and a B30.2(SPRY) domain. Sequences in the B30.2(SPRY) domain dictate the potency and specificity of the restriction. As TRIM5alpharh targets incoming mature HIV-1 capsid, but not precursor Gag, it was assumed that TRIM5alpharh did not affect HIV-1 production. Here we provide evidence that TRIM5alpharh, but not its human ortholog (TRIM5alphahu), blocks HIV-1 production through rapid degradation of HIV-1 Gag polyproteins. The specificity for this restriction is determined by sequences in the RBCC domain. Our observations suggest that TRIM5alpharh interacts with HIV-1 Gag during or before Gag assembly through a mechanism distinct from the well-characterized postentry restriction. This finding demonstrates a cellular factor blocking HIV-1 production by actively degrading a viral protein. Further understanding of this previously unknown restriction mechanism may reveal new targets for future anti-HIV-1 therapy.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17415356", + "TEXT": "Large-scale sequencing projects to identify mutations related to cancer and psychiatric disorders will generate a lot of data. But the usefulness of these results will be limited unless we have good models to test their contribution to disease.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17401375", + "TEXT": "Infection with Helicobacter pylori (H. pylori) is a risk factor for the development of gastric cancer. Here we show that infection of gastric epithelial cells with 'cag' pathogenicity island (cagPAI)-positive H. pylori induced aberrant expression of activation-induced cytidine deaminase (AID), a member of the cytidine-deaminase family that acts as a DNA- and RNA-editing enzyme, via the IkappaB kinase-dependent nuclear factor-kappaB activation pathway. H. pylori-mediated upregulation of AID resulted in the accumulation of nucleotide alterations in the TP53 tumor suppressor gene in gastric cells in vitro. Our findings provide evidence that aberrant AID expression caused by H. pylori infection might be a mechanism of mutation accumulation in the gastric mucosa during H. pylori-associated gastric carcinogenesis.", + "TAG_DATA": [ + "22, gastric {'context': 'B-cells'}", + "23, epithelial {'context': 'I-cells'}", + "24, cells {'context': 'I-cells'}", + "81, gastric {'context': 'B-cells'}", + "82, cells {'context': 'I-cells'}", + "83, in {'context': 'B-in vitro'}", + "84, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "22, gastric ['l0', 'l1']", + "23, epithelial ['l0', 'l2']", + "24, cells ['l1', 'l2']", + "81, gastric ['l3', 'l4', 'l5']", + "82, cells ['l3', 'l6', 'l7']", + "83, in ['l4', 'l6', 'l8']", + "84, vitro. ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17384648", + "TEXT": "It has been known for many years that neutrophils and platelets participate in the pathogenesis of severe sepsis, but the inter-relationship between these players is completely unknown. We report several cellular events that led to enhanced trapping of bacteria in blood vessels: platelet TLR4 detected TLR4 ligands in blood and induced platelet binding to adherent neutrophils. This led to robust neutrophil activation and formation of neutrophil extracellular traps (NETs). Plasma from severely septic humans also induced TLR4-dependent platelet-neutrophil interactions, leading to the production of NETs. The NETs retained their integrity under flow conditions and ensnared bacteria within the vasculature. The entire event occurred primarily in the liver sinusoids and pulmonary capillaries, where NETs have the greatest capacity for bacterial trapping. We propose that platelet TLR4 is a threshold switch for this new bacterial trapping mechanism in severe sepsis.", + "TAG_DATA": [ + "106, liver {'context': 'B-tissue/organ'}", + "107, sinusoids {'context': 'I-tissue/organ'}", + "109, pulmonary {'context': 'B-tissue/organ'}", + "110, capillaries, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "106, liver ['l0', 'l1', 'l2']", + "107, sinusoids ['l0', 'l3', 'l4']", + "109, pulmonary ['l1', 'l3', 'l5']", + "110, capillaries, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17334372", + "TEXT": "Motor neuron degeneration resulting from the aggregation of the androgen receptor with an expanded polyglutamine tract (AR-polyQ) has been linked to the development of spinal and bulbar muscular atrophy (SBMA or Kennedy disease). Here we report that adding 5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one (ASC-J9) disrupts the interaction between AR and its coregulators, and also increases cell survival by decreasing AR-polyQ nuclear aggregation and increasing AR-polyQ degradation in cultured cells. Intraperitoneal injection of ASC-J9 into AR-polyQ transgenic SBMA mice markedly improved disease symptoms, as seen by a reduction in muscular atrophy. Notably, unlike previous approaches in which surgical or chemical castration was used to reduce SBMA symptoms, ASC-J9 treatment ameliorated SBMA symptoms by decreasing AR-97Q aggregation and increasing VEGF164 expression with little change of serum testosterone. Moreover, mice treated with ASC-J9 retained normal sexual function and fertility. Collectively, our results point to a better therapeutic and preventative approach to treating SBMA, by disrupting the interaction between AR and AR coregulators.", + "TAG_DATA": [ + "50, increases {'effect': 'B-positive'}", + "51, cell {'phenotype': 'B-cell survival'}", + "52, survival {'phenotype': 'I-cell survival'}", + "63, cultured {'context': 'B-cells'}", + "64, cells. {'context': 'I-cells'}", + "70, AR-polyQ {'perturbing_action': 'B-gene gain-of-function'}", + "71, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "72, SBMA {'context': 'B-organism'}", + "73, mice {'context': 'I-organism'}", + "122, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, increases ['l0', 'l1', 'l2', 'l3']", + "51, cell ['l0', 'l4', 'l5', 'l6']", + "52, survival ['l1', 'l4', 'l7', 'l8']", + "63, cultured ['l2', 'l5', 'l7', 'l9']", + "64, cells. ['l3', 'l6', 'l8', 'l9']", + "70, AR-polyQ ['l10', 'l11', 'l12']", + "71, transgenic ['l10', 'l13', 'l14']", + "72, SBMA ['l11', 'l13', 'l15']", + "73, mice ['l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "survival" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "cells." + ] + } + }, + { + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "survival" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "AR-polyQ", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "SBMA", + "mice" + ] + } + } + ] + }, + { + "PMID": "17322898", + "TEXT": "With the increased potential of RNA interference (RNAi) as a therapeutic strategy, new noninvasive methods for detection of siRNA delivery and silencing are urgently needed. Here we describe the development of dual-purpose probes for in vivo transfer of siRNA and the simultaneous imaging of its accumulation in tumors by high-resolution magnetic resonance imaging (MRI) and near-infrared in vivo optical imaging (NIRF). These probes consisted of magnetic nanoparticles labeled with a near-infrared dye and covalently linked to siRNA molecules specific for model or therapeutic targets. Additionally, these nanoparticles were modified with a membrane translocation peptide for intracellular delivery. We show the feasibility of in vivo tracking of tumor uptake of these probes by MRI and optical imaging in two separate tumor models. We also used proof-of-principle optical imaging to corroborate the efficiency of the silencing process. These studies represent the first step toward the advancement of siRNA delivery and imaging strategies, essential for cancer therapeutic product development and optimization.", + "TAG_DATA": [ + "102, in {'context': 'B-in vivo'}", + "103, vivo {'context': 'B-in vivo'}", + "106, tumor {'context': 'B-neoplasm'}", + "119, tumor {'context': 'B-neoplasm'}", + "120, models. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "102, in ['l0', 'l1', 'l2', 'l3']", + "103, vivo ['l0', 'l4', 'l5', 'l6']", + "106, tumor ['l1', 'l4', 'l7', 'l8']", + "119, tumor ['l2', 'l5', 'l7', 'l9']", + "120, models. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17187074", + "TEXT": "HIV-1/AIDS vaccines must address the extreme diversity of HIV-1. We have designed new polyvalent vaccine antigens comprised of sets of 'mosaic' proteins, assembled from fragments of natural sequences via a computational optimization method. Mosaic proteins resemble natural proteins, and a mosaic set maximizes the coverage of potential T-cell epitopes (peptides of nine amino acids) for a viral population. We found that coverage of viral diversity using mosaics was greatly increased compared to coverage by natural-sequence vaccine candidates, for both variable and conserved proteins; for conserved HIV-1 proteins, global coverage may be feasible. For example, four mosaic proteins perfectly matched 74% of 9-amino-acid potential epitopes in global Gag sequences; 87% of potential epitopes matched at least 8 of 9 positions. In contrast, a single natural Gag protein covered only 37% (9 of 9) and 67% (8 of 9). Mosaics provide diversity coverage comparable to that afforded by thousands of separate peptides, but, because the fragments of natural proteins are compressed into a small number of native-like proteins, they are tractable for vaccines.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17173051", + "TEXT": "Selection of T-cell vaccine antigens for chronic persistent viral infections has been largely empirical. To define the relationship, at the population level, between the specificity of the cellular immune response and viral control for a relevant human pathogen, we performed a comprehensive analysis of the 160 dominant CD8(+) T-cell responses in 578 untreated HIV-infected individuals from KwaZulu-Natal, South Africa. Of the HIV proteins targeted, only Gag-specific responses were associated with lowering viremia. Env-specific and Accessory/Regulatory protein-specific responses were associated with higher viremia. Increasing breadth of Gag-specific responses was associated with decreasing viremia and increasing Env breadth with increasing viremia. Association of the specific CD8(+) T-cell response with low viremia was independent of HLA type and unrelated to epitope sequence conservation. These population-based data, suggesting the existence of both effective immune responses and responses lacking demonstrable biological impact in chronic HIV infection, are of relevance to HIV vaccine design and evaluation.", + "TAG_DATA": [ + "54, individuals {'context': 'I-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17143276", + "TEXT": "Regulatory CD4(+)CD25(+) T cells are important in suppressing immune responses. The requirements for the maintenance of peripheral CD4(+)CD25(+) T cells remain incompletely understood. Receptor activator of NF-kappaB (RANK) and its ligand (RANKL; also known as CD254, OPGL and TRANCE) are key regulators of bone remodeling, mammary gland formation, lymph node development and T-cell/dendritic cell communication. Here we report that RANKL is expressed in keratinocytes of the inflamed skin. RANKL overexpression in keratinocytes resulted in functional alterations of epidermal dendritic cells and systemic increases of regulatory CD4(+)CD25(+) T cells. Thus, epidermal RANKL expression can change dendritic cell functions to maintain the number of peripheral CD4(+)CD25(+) regulatory T cells. Epidermal RANKL mediated ultraviolet-induced immunosuppression and overexpression of epidermal RANKL suppressed allergic contact hypersensitivity responses and the development of systemic autoimmunity. Therefore, environmental stimuli at the skin can rewire the local and systemic immune system by means of RANKL.", + "TAG_DATA": [ + "68, RANKL {'perturbing_action': 'B-gene gain-of-function'}", + "69, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "71, keratinocytes {'context': 'B-cells'}", + "77, epidermal {'context': 'B-cells'}", + "78, dendritic {'context': 'I-cells'}", + "79, cells {'context': 'I-cells'}", + "113, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "114, of {'perturbing_action': 'I-gene gain-of-function'}", + "115, epidermal {'perturbing_action': 'I-gene gain-of-function'}", + "116, RANKL {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "68, RANKL ['l0', 'l1', 'l2', 'l3', 'l4']", + "69, overexpression ['l0', 'l5', 'l6', 'l7', 'l8']", + "71, keratinocytes ['l1', 'l5', 'l9', 'l10', 'l11']", + "77, epidermal ['l2', 'l6', 'l9', 'l12', 'l13']", + "78, dendritic ['l3', 'l7', 'l10', 'l12', 'l14']", + "79, cells ['l4', 'l8', 'l11', 'l13', 'l14']", + "113, overexpression ['l15', 'l16', 'l17']", + "114, of ['l15', 'l18', 'l19']", + "115, epidermal ['l16', 'l18', 'l20']", + "116, RANKL ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "RANKL", + "overexpression" + ] + }, + "context": { + "val": "cells", + "words": [ + "keratinocytes", + "epidermal", + "dendritic", + "cells" + ] + } + } + ] + }, + { + "PMID": "17099710", + "TEXT": "The role of nitric oxide (NO) in the genesis of cerebral malaria is controversial. Most investigators propose that the unfortunate consequence of the high concentrations of NO produced to kill the parasite is the development of cerebral malaria. Here we have tested this high NO bioavailability hypothesis in the setting of experimental cerebral malaria (ECM), but find instead that low NO bioavailability contributes to the genesis of ECM. Specifically, mice deficient in vascular NO synthase showed parasitemia and mortality similar to that observed in control mice. Exogenous NO did not affect parasitemia but provided marked protection against ECM; in fact, mice treated with exogenous NO were clinically indistinguishable from uninfected mice at a stage when control infected mice were moribund. Administration of exogenous NO restored NO-mediated signaling in the brain, decreased proinflammatory biomarkers in the blood, and markedly reduced vascular leak and petechial hemorrhage into the brain. Low NO bioavailability in the vasculature during ECM was caused in part by an increase in NO-scavenging free hemoglobin in the blood, by hypoargininemia, and by low blood and erythrocyte nitrite concentrations. Exogenous NO inactivated NO-scavenging free hemoglobin in the plasma and restored nitrite to concentrations observed in uninfected mice. We therefore conclude that low rather than high NO bioavailability contributes to the genesis of ECM.", + "TAG_DATA": [ + "69, mice {'context': 'B-organism'}", + "71, in {'perturbing_action': 'I-gene loss-of-function'}", + "72, vascular {'perturbing_action': 'I-gene loss-of-function'}", + "73, NO {'perturbing_action': 'I-gene loss-of-function'}", + "74, synthase {'perturbing_action': 'I-gene loss-of-function'}", + "100, mice {'context': 'B-organism'}", + "110, mice {'context': 'B-organism'}", + "117, mice {'context': 'B-organism'}", + "129, brain, {'context': 'B-tissue/organ'}", + "196, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "69, mice ['l0', 'l1', 'l2', 'l3']", + "71, in ['l0', 'l4', 'l5', 'l6', 'l7', 'l8']", + "72, vascular ['l1', 'l4', 'l9', 'l10', 'l11', 'l12']", + "73, NO ['l2', 'l5', 'l9', 'l13', 'l14', 'l15', 'l16']", + "74, synthase ['l3', 'l6', 'l10', 'l13', 'l17', 'l18', 'l19', 'l20']", + "100, mice ['l14', 'l17', 'l21', 'l22', 'l23']", + "110, mice ['l7', 'l11', 'l15', 'l18', 'l21', 'l24', 'l25']", + "117, mice ['l19', 'l22', 'l24', 'l26']", + "129, brain, ['l8', 'l12', 'l16', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "in", + "vascular", + "NO", + "synthase" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "in", + "vascular", + "NO", + "synthase" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain," + ] + } + } + ] + }, + { + "PMID": "17086190", + "TEXT": "Smallpox was eradicated without an adequate understanding of how vaccination induced protection. In response to possible bioterrorism with smallpox, the UK government vaccinated approximately 300 health care workers with vaccinia virus (VACV) strain Lister. Antibody responses were analyzed using ELISA for multiple surface antigens of the extracellular enveloped virus (EEV) and the intracellular mature virus (IMV), plaque reduction neutralization and a fluorescence-based flow cytometric neutralization assay. Antibody depletion experiments showed that the EEV surface protein B5 is the only target responsible for EEV neutralization in vaccinated humans, whereas multiple IMV surface proteins, including A27 and H3, are targets for IMV-neutralizing antibodies. These data suggest that it would be unwise to exclude the B5 protein from a future smallpox vaccine. Repeated vaccination provided significantly higher B5-specific and thus EEV-neutralizing antibody responses. These data provide a benchmark against which new, safer smallpox vaccines and residual immunity can be compared.", + "TAG_DATA": [ + "25, health {'context': 'B-cells'}", + "26, care {'context': 'B-cells'}", + "27, workers {'context': 'I-cells'}", + "86, humans, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "25, health ['l0', 'l1']", + "26, care ['l0', 'l2', 'l3']", + "27, workers ['l1', 'l2', 'l4']", + "86, humans, ['l3', 'l4']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17013385", + "TEXT": "Currently available methods for detection of tumors in vivo such as computed tomography and magnetic resonance imaging are not specific for tumors. Here we describe a new approach for visualizing tumors whose fluorescence can be detected using telomerase-specific replication-competent adenovirus expressing green fluorescent protein (GFP) (OBP-401). OBP-401 contains the replication cassette, in which the human telomerase reverse transcriptase (hTERT) promoter drives expression of E1 genes, and the GFP gene for monitoring viral replication. When OBP-401 was intratumorally injected into HT29 tumors orthotopically implanted into the rectum in BALB/c nu/nu mice, para-aortic lymph node metastasis could be visualized at laparotomy under a three-chip color cooled charged-coupled device camera. Our results indicate that OBP-401 causes viral spread into the regional lymphatic area and selectively replicates in neoplastic lesions, resulting in GFP expression in metastatic lymph nodes. This technology is adaptable to detect lymph node metastasis in vivo as a preclinical model of surgical navigation.", + "TAG_DATA": [ + "79, HT29 {'context': 'B-neoplasm'}", + "80, tumors {'context': 'I-neoplasm'}", + "87, BALB/c {'perturbing_action': 'B-other'}", + "88, nu/nu {'perturbing_action': 'B-other'}", + "89, mice, {'context': 'B-organism'}", + "90, para-aortic {'context': 'B-tissue/organ', 'phenotype': 'B-metastasis'}", + "91, lymph {'phenotype': 'I-metastasis'}", + "92, node {'phenotype': 'I-metastasis'}", + "93, metastasis {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "79, HT29 ['l0']", + "80, tumors ['l0']", + "87, BALB/c ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "88, nu/nu ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "89, mice, ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "90, para-aortic ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "91, lymph ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "92, node ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "93, metastasis ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "96, visualized ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "BALB/c", + "nu/nu" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BALB/c", + "nu/nu" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "para-aortic" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BALB/c", + "nu/nu" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "para-aortic", + "lymph", + "node", + "metastasis" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "para-aortic" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "para-aortic" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "para-aortic", + "lymph", + "node", + "metastasis" + ] + } + } + ] + }, + { + "PMID": "17013383", + "TEXT": "Treatment of chronic myeloid leukemia (CML) with the tyrosine kinase inhibitor imatinib represents a successful application of molecularly targeted cancer therapy. A rapid hematologic and cytogenetic response can be induced in the majority of people, even in advanced disease. However, complete eradication of malignant cells, which are characterized by the expression of the BCR-ABL1 fusion protein, is rare. Reasons for the persistence of the malignant clone are currently not known and provide a substantial challenge for clinicians and biologists. Based on a mathematical modeling approach that quantitatively explains a broad range of phenomena, we show for two independent datasets that clinically observed BCR-ABL1 transcript dynamics during imatinib treatment of CML can consistently be explained by a selective functional effect of imatinib on proliferative leukemia stem cells. Our results suggest the general potential of imatinib to induce a complete elimination of the malignant clone. Moreover, we predict that the therapeutic benefit of imatinib can, under certain circumstances, be accelerated by combination with proliferation-stimulating treatment strategies.", + "TAG_DATA": [ + "109, CML {'context': 'B-neoplasm'}", + "122, proliferative {'context': 'B-transformed cells'}", + "123, leukemia {'context': 'I-transformed cells'}", + "124, stem {'context': 'I-transformed cells'}", + "125, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "109, CML ['l0', 'l1', 'l2']", + "122, proliferative ['l3', 'l4', 'l5']", + "123, leukemia ['l0', 'l3', 'l6', 'l7']", + "124, stem ['l1', 'l4', 'l6', 'l8']", + "125, cells. ['l2', 'l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16998485", + "TEXT": "Immunocompromised individuals are at high risk for life-threatening diseases, especially those caused by cytomegalovirus (CMV), Epstein-Barr virus (EBV) and adenovirus. Conventional therapeutics are primarily active only against CMV, and resistance is frequent. Adoptive transfer of polyclonal cytotoxic T lymphocytes (CTLs) specific for CMV or EBV seems promising, but it is unclear whether this strategy can be extended to adenovirus, which comprises many serotypes. In addition, the preparation of a specific CTL line for each virus in every eligible individual would be impractical. Here we describe genetic modification of antigen-presenting cell lines to facilitate the production of CD4(+) and CD8(+) T lymphocytes specific for CMV, EBV and several serotypes of adenovirus from a single cell culture. When administered to immunocompromised individuals, the single T lymphocyte line expands into multiple discrete virus-specific populations that supply clinically measurable antiviral activity. Monoculture-derived multispecific CTL infusion could provide a safe and efficient means to restore virus-specific immunity in the immunocompromised host.", + "TAG_DATA": [ + "88, antigen-presenting {'context': 'B-cells'}", + "89, cell {'context': 'I-cells'}", + "90, lines {'context': 'I-cells'}", + "96, CD4(+) {'context': 'B-cells'}", + "97, and {'context': 'I-cells'}", + "98, CD8(+) {'context': 'I-cells'}", + "99, T {'context': 'I-cells'}", + "100, lymphocytes {'context': 'I-cells'}", + "113, cell {'context': 'B-cells'}", + "114, culture. {'context': 'I-cells'}", + "122, T {'context': 'B-cells'}", + "123, lymphocyte {'context': 'I-cells'}", + "124, line {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "88, antigen-presenting ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "89, cell ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "90, lines ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "96, CD4(+) ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "97, and ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "98, CD8(+) ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "99, T ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "100, lymphocytes ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "113, cell ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "114, culture. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "122, T ['l45', 'l46']", + "123, lymphocyte ['l45', 'l47']", + "124, line ['l46', 'l47']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16892063", + "TEXT": "Here, we describe a system for the exogenous control of gene expression in mammalian cells that relies on the control of translational termination. To achieve gene regulation, we modified protein-coding sequences by introduction of a translational termination codon just downstream from the initiator AUG codon. Translation of the resulting mRNA leads to potent reduction in expression of the desired gene product. Expression of the gene product can be controlled by treating cells that express the mRNA with either aminoglycoside antibiotics or several nonantibiotic compounds. We show that the extent of regulation of gene expression can be substantial (60-fold) and that regulation can be achieved in the case of a variety of different genes, in different cultured cell lines and in primary cells in vivo. This gene regulation strategy offers significant advantages over existing methods for controlling gene expression and should have both immediate experimental application and possible clinical application.", + "TAG_DATA": [ + "71, cells {'context': 'B-cells'}", + "115, cultured {'context': 'B-cells'}", + "116, cell {'context': 'I-cells'}", + "117, lines {'context': 'I-cells'}", + "120, primary {'context': 'B-cells'}", + "121, cells {'context': 'I-cells'}", + "122, in {'context': 'B-in vivo'}", + "123, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "71, cells ['l0', 'l1', 'l2']", + "115, cultured ['l0', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "116, cell ['l1', 'l3', 'l9', 'l10', 'l11', 'l12']", + "117, lines ['l2', 'l4', 'l9']", + "120, primary ['l5', 'l10', 'l13', 'l14', 'l15']", + "121, cells ['l6', 'l11', 'l13', 'l16', 'l17']", + "122, in ['l7', 'l14', 'l16', 'l18']", + "123, vivo. ['l8', 'l12', 'l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16892039", + "TEXT": "Demyelination is a common pathologic feature in many neurodegenerative diseases including infection with leprosy-causing Mycobacterium leprae. Because of the long incubation time and highly complex disease pathogenesis, the management of nerve damage in leprosy, as in other demyelinating diseases, is extremely difficult. Therefore, an important challenge in therapeutic interventions is to identify the molecular events that occur in the early phase before the progression of the disease. Here we provide evidence that M. leprae-induced demyelination is a result of direct bacterial ligation to and activation of ErbB2 receptor tyrosine kinase (RTK) signaling without ErbB2-ErbB3 heterodimerization, a previously unknown mechanism that bypasses the neuregulin-ErbB3-mediated ErbB2 phosphorylation. MEK-dependent Erk1 and Erk2 (hereafter referred to as Erk1/2) signaling is identified as a downstream target of M. leprae-induced ErbB2 activation that mediates demyelination. Herceptin (trastuzumab), a therapeutic humanized ErbB2-specific antibody, inhibits M. leprae binding to and activation of ErbB2 and Erk1/2 in human primary Schwann cells, and the blockade of ErbB2 activity by the small molecule dual ErbB1-ErbB2 kinase inhibitor PKI-166 (ref. 11) effectively abrogates M. leprae-induced myelin damage in in vitro and in vivo models. These results may have implications for the design of ErbB2 RTK-based therapies for both leprosy nerve damage and other demyelinating neurodegenerative diseases.", + "TAG_DATA": [ + "148, human {'context': 'B-cells'}", + "149, primary {'context': 'I-cells'}", + "150, Schwann {'context': 'I-cells'}", + "151, cells, {'context': 'I-cells'}", + "164, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "165, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "166, PKI-166 {'perturbing_action': 'I-pharmacological inhibition'}", + "176, in {'context': 'B-in vitro'}", + "177, vitro {'context': 'I-in vitro'}", + "179, in {'context': 'B-in vivo'}", + "180, vivo {'context': 'I-in vivo'}", + "181, models. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "148, human ['l0', 'l1', 'l2']", + "149, primary ['l0', 'l3', 'l4']", + "150, Schwann ['l1', 'l3', 'l5']", + "151, cells, ['l2', 'l4', 'l5']", + "163, ErbB1-ErbB2 ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "164, kinase ['l6', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "165, inhibitor ['l7', 'l14', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "166, PKI-166 ['l8', 'l15', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "176, in ['l9', 'l16', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "177, vitro ['l10', 'l17', 'l23', 'l28', 'l32', 'l36', 'l37', 'l38']", + "179, in ['l11', 'l18', 'l24', 'l29', 'l33', 'l36', 'l39', 'l40']", + "180, vivo ['l12', 'l19', 'l25', 'l30', 'l34', 'l37', 'l39', 'l41']", + "181, models. ['l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "kinase", + "inhibitor", + "PKI-166" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "kinase", + "inhibitor", + "PKI-166" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "models." + ] + } + } + ] + }, + { + "PMID": "16892037", + "TEXT": "The t(8;21)(q22;q22) translocation is one of the most common genetic abnormalities in acute myeloid leukemia (AML), identified in 15% of all cases of AML, including 40-50% of FAB M2 subtype and rare cases of M0, M1 and M4 subtypes. The most commonly known AML1-ETO fusion protein (full-length AML1-ETO) from this translocation has 752 amino acids and contains the N-terminal portion of RUNX1 (also known as AML1, CBFalpha2 or PEBP2alphaB), including its DNA binding domain, and almost the entire RUNX1T1 (also known as MTG8 or ETO) protein. Although alterations of gene expression and hematopoietic cell proliferation have been reported in the presence of AML1-ETO, its expression does not lead to the development of leukemia. Here, we report the identification of a previously unknown alternatively spliced isoform of the AML1-ETO transcript, AML1-ETO9a, that includes an extra exon, exon 9a, of the ETO gene. AML1-ETO9a encodes a C-terminally truncated AML1-ETO protein of 575 amino acids. Expression of AML1-ETO9a leads to rapid development of leukemia in a mouse retroviral transduction-transplantation model. More importantly, coexpression of AML1-ETO and AML1-ETO9a results in the substantially earlier onset of AML and blocks myeloid cell differentiation at a more immature stage. These results indicate that fusion proteins from alternatively spliced isoforms of a chromosomal translocation may work together to induce cancer development.", + "TAG_DATA": [ + "152, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "153, of {'perturbing_action': 'I-gene gain-of-function'}", + "154, AML1-ETO9a {'perturbing_action': 'I-gene gain-of-function'}", + "155, leads {'effect': 'B-positive'}", + "156, to {'effect': 'I-positive'}", + "160, leukemia {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}", + "163, mouse {'context': 'B-organism'}", + "164, retroviral {'context': 'I-xenograft'}", + "169, coexpression {'perturbing_action': 'B-gene gain-of-function'}", + "170, of {'perturbing_action': 'I-gene gain-of-function'}", + "171, AML1-ETO {'perturbing_action': 'I-gene gain-of-function'}", + "172, and {'perturbing_action': 'I-gene gain-of-function'}", + "173, AML1-ETO9a {'perturbing_action': 'I-gene gain-of-function'}", + "183, blocks {'effect': 'B-negative'}", + "184, myeloid {'context': 'B-cells'}", + "185, cell {'context': 'I-cells'}", + "186, differentiation {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "152, Expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "153, of ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "154, AML1-ETO9a ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "155, leads ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "156, to ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28']", + "160, leukemia ['l4', 'l11', 'l17', 'l22', 'l26', 'l29', 'l30', 'l31']", + "163, mouse ['l5', 'l12', 'l18', 'l23', 'l27', 'l29', 'l32', 'l33']", + "164, retroviral ['l6', 'l13', 'l19', 'l24', 'l30', 'l32', 'l34']", + "165, transduction-transplantation ['l7', 'l14', 'l20', 'l25', 'l28', 'l31', 'l33', 'l34']", + "169, coexpression ['l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "170, of ['l35', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "171, AML1-ETO ['l36', 'l43', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "172, and ['l37', 'l44', 'l50', 'l56', 'l57', 'l58', 'l59', 'l60']", + "173, AML1-ETO9a ['l38', 'l45', 'l51', 'l56', 'l61', 'l62', 'l63', 'l64']", + "183, blocks ['l39', 'l46', 'l52', 'l57', 'l61', 'l65', 'l66', 'l67']", + "184, myeloid ['l40', 'l47', 'l53', 'l58', 'l62', 'l65', 'l68', 'l69']", + "185, cell ['l41', 'l48', 'l54', 'l59', 'l63', 'l66', 'l68', 'l70']", + "186, differentiation ['l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l70']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "AML1-ETO9a" + ] + }, + "effect": { + "val": "positive", + "words": [ + "leads", + "to" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "AML1-ETO9a" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "AML1-ETO9a" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "leukemia" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "AML1-ETO9a" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "AML1-ETO9a" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "retroviral" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "leads", + "to" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "leads", + "to" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "leads", + "to" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "leads" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "retroviral" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "retroviral" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "coexpression", + "of", + "AML1-ETO", + "and", + "AML1-ETO9a" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "coexpression", + "of", + "AML1-ETO", + "and", + "AML1-ETO9a" + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "coexpression", + "of", + "AML1-ETO", + "and", + "AML1-ETO9a" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "myeloid", + "cell" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "16829910", + "TEXT": "An untested herbal product in South Africa is being touted as an effective AIDS treatment—with the full support of a local scientist. Natasha Bolognesi investigates.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16783372", + "TEXT": "In the injured central nervous system (CNS), reactive astrocytes form a glial scar and are considered to be detrimental for axonal regeneration, but their function remains elusive. Here we show that reactive astrocytes have a crucial role in wound healing and functional recovery by using mice with a selective deletion of the protein signal transducer and activator of transcription 3 (Stat3) or the protein suppressor of cytokine signaling 3 (Socs3) under the control of the Nes promoter-enhancer (Nes-Stat3(-/-), Nes-Socs3(-/-)). Reactive astrocytes in Nes-Stat3(-/-) mice showed limited migration and resulted in markedly widespread infiltration of inflammatory cells, neural disruption and demyelination with severe motor deficits after contusive spinal cord injury (SCI). On the contrary, we observed rapid migration of reactive astrocytes to seclude inflammatory cells, enhanced contraction of lesion area and notable improvement in functional recovery in Nes-Socs3(-/-) mice. These results suggest that Stat3 is a key regulator of reactive astrocytes in the healing process after SCI, providing a potential target for intervention in the treatment of CNS injury.", + "TAG_DATA": [ + "45, mice {'context': 'B-organism'}", + "48, selective {'perturbing_action': 'B-gene loss-of-function'}", + "49, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "50, of {'perturbing_action': 'I-gene loss-of-function'}", + "51, the {'perturbing_action': 'I-gene loss-of-function'}", + "52, protein {'perturbing_action': 'I-gene loss-of-function'}", + "53, signal {'perturbing_action': 'I-gene loss-of-function'}", + "55, and {'perturbing_action': 'I-gene loss-of-function'}", + "56, activator {'perturbing_action': 'I-gene loss-of-function'}", + "57, of {'perturbing_action': 'I-gene loss-of-function'}", + "58, transcription {'perturbing_action': 'I-gene loss-of-function'}", + "59, 3 {'perturbing_action': 'I-gene loss-of-function'}", + "60, (Stat3) {'perturbing_action': 'I-gene loss-of-function'}", + "61, or {'perturbing_action': 'I-gene loss-of-function'}", + "62, the {'perturbing_action': 'I-gene loss-of-function'}", + "63, protein {'perturbing_action': 'I-gene loss-of-function'}", + "64, suppressor {'perturbing_action': 'I-gene loss-of-function'}", + "65, of {'perturbing_action': 'I-gene loss-of-function'}", + "66, cytokine {'perturbing_action': 'I-gene loss-of-function'}", + "67, signaling {'perturbing_action': 'I-gene loss-of-function'}", + "68, 3 {'perturbing_action': 'I-gene loss-of-function'}", + "69, (Socs3) {'perturbing_action': 'I-gene loss-of-function'}", + "70, under {'perturbing_action': 'I-gene gain-of-function'}", + "71, the {'perturbing_action': 'I-gene loss-of-function'}", + "72, control {'perturbing_action': 'I-gene gain-of-function'}", + "73, of {'perturbing_action': 'I-gene loss-of-function'}", + "74, the {'perturbing_action': 'I-gene loss-of-function'}", + "75, Nes {'perturbing_action': 'I-gene loss-of-function'}", + "76, promoter-enhancer {'perturbing_action': 'I-gene gain-of-function'}", + "77, (Nes-Stat3(-/-), {'perturbing_action': 'I-gene loss-of-function'}", + "78, Nes-Socs3(-/-)). {'perturbing_action': 'I-gene loss-of-function'}", + "79, Reactive {'context': 'B-cells'}", + "80, astrocytes {'context': 'I-cells'}", + "82, Nes-Stat3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "83, mice {'context': 'B-organism'}", + "85, limited {'effect': 'B-negative'}", + "86, migration {'phenotype': 'B-migration'}", + "116, migration {'phenotype': 'B-migration'}", + "118, reactive {'context': 'B-cells'}", + "119, astrocytes {'context': 'I-cells'}", + "136, Nes-Socs3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "137, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "45, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "48, selective ['l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "49, deletion ['l5', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "50, of ['l6', 'l40', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "51, the ['l7', 'l41', 'l74', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "52, protein ['l8', 'l42', 'l75', 'l107', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "53, signal ['l9', 'l43', 'l76', 'l108', 'l139', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199']", + "55, and ['l10', 'l44', 'l77', 'l109', 'l140', 'l170', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228']", + "56, activator ['l11', 'l45', 'l78', 'l110', 'l141', 'l171', 'l200', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256']", + "57, of ['l0', 'l12', 'l46', 'l79', 'l111', 'l142', 'l172', 'l201', 'l229', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283']", + "58, transcription ['l1', 'l13', 'l47', 'l80', 'l112', 'l143', 'l173', 'l202', 'l230', 'l257', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304', 'l305', 'l306', 'l307', 'l308', 'l309']", + "59, 3 ['l2', 'l14', 'l48', 'l81', 'l113', 'l144', 'l174', 'l203', 'l231', 'l258', 'l284', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315', 'l316', 'l317', 'l318', 'l319', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327', 'l328', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334']", + "60, (Stat3) ['l3', 'l15', 'l49', 'l82', 'l114', 'l145', 'l175', 'l204', 'l232', 'l259', 'l285', 'l310', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340', 'l341', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348', 'l349', 'l350', 'l351', 'l352', 'l353', 'l354', 'l355', 'l356', 'l357', 'l358']", + "61, or ['l16', 'l50', 'l83', 'l115', 'l146', 'l176', 'l205', 'l233', 'l260', 'l286', 'l311', 'l335', 'l359', 'l360', 'l361', 'l362', 'l363', 'l364', 'l365', 'l366', 'l367', 'l368', 'l369', 'l370', 'l371', 'l372', 'l373', 'l374', 'l375', 'l376', 'l377', 'l378', 'l379', 'l380', 'l381']", + "62, the ['l17', 'l51', 'l84', 'l116', 'l147', 'l177', 'l206', 'l234', 'l261', 'l287', 'l312', 'l336', 'l359', 'l382', 'l383', 'l384', 'l385', 'l386', 'l387', 'l388', 'l389', 'l390', 'l391', 'l392', 'l393', 'l394', 'l395', 'l396', 'l397', 'l398', 'l399', 'l400', 'l401', 'l402', 'l403']", + "63, protein ['l18', 'l52', 'l85', 'l117', 'l148', 'l178', 'l207', 'l235', 'l262', 'l288', 'l313', 'l337', 'l360', 'l382', 'l404', 'l405', 'l406', 'l407', 'l408', 'l409', 'l410', 'l411', 'l412', 'l413', 'l414', 'l415', 'l416', 'l417', 'l418', 'l419', 'l420', 'l421', 'l422', 'l423', 'l424']", + "64, suppressor ['l19', 'l53', 'l86', 'l118', 'l149', 'l179', 'l208', 'l236', 'l263', 'l289', 'l314', 'l338', 'l361', 'l383', 'l404', 'l425', 'l426', 'l427', 'l428', 'l429', 'l430', 'l431', 'l432', 'l433', 'l434', 'l435', 'l436', 'l437', 'l438', 'l439', 'l440', 'l441', 'l442', 'l443', 'l444']", + "65, of ['l20', 'l54', 'l87', 'l119', 'l150', 'l180', 'l209', 'l237', 'l264', 'l290', 'l315', 'l339', 'l362', 'l384', 'l405', 'l425', 'l445', 'l446', 'l447', 'l448', 'l449', 'l450', 'l451', 'l452', 'l453', 'l454', 'l455', 'l456', 'l457', 'l458', 'l459', 'l460', 'l461', 'l462', 'l463']", + "66, cytokine ['l21', 'l55', 'l88', 'l120', 'l151', 'l181', 'l210', 'l238', 'l265', 'l291', 'l316', 'l340', 'l363', 'l385', 'l406', 'l426', 'l445', 'l464', 'l465', 'l466', 'l467', 'l468', 'l469', 'l470', 'l471', 'l472', 'l473', 'l474', 'l475', 'l476', 'l477', 'l478', 'l479', 'l480', 'l481']", + "67, signaling ['l22', 'l56', 'l89', 'l121', 'l152', 'l182', 'l211', 'l239', 'l266', 'l292', 'l317', 'l341', 'l364', 'l386', 'l407', 'l427', 'l446', 'l464', 'l482', 'l483', 'l484', 'l485', 'l486', 'l487', 'l488', 'l489', 'l490', 'l491', 'l492', 'l493', 'l494', 'l495', 'l496', 'l497', 'l498']", + "68, 3 ['l23', 'l57', 'l90', 'l122', 'l153', 'l183', 'l212', 'l240', 'l267', 'l293', 'l318', 'l342', 'l365', 'l387', 'l408', 'l428', 'l447', 'l465', 'l482', 'l499', 'l500', 'l501', 'l502', 'l503', 'l504', 'l505', 'l506', 'l507', 'l508', 'l509', 'l510', 'l511', 'l512', 'l513', 'l514']", + "69, (Socs3) ['l24', 'l58', 'l91', 'l123', 'l154', 'l184', 'l213', 'l241', 'l268', 'l294', 'l319', 'l343', 'l366', 'l388', 'l409', 'l429', 'l448', 'l466', 'l483', 'l499', 'l515', 'l516', 'l517', 'l518', 'l519', 'l520', 'l521', 'l522', 'l523', 'l524', 'l525', 'l526', 'l527', 'l528', 'l529']", + "70, under ['l25', 'l59', 'l92', 'l124', 'l155', 'l185', 'l214', 'l242', 'l269', 'l295', 'l320', 'l344', 'l367', 'l389', 'l410', 'l430', 'l449', 'l467', 'l484', 'l500', 'l515', 'l530', 'l531', 'l532', 'l533', 'l534', 'l535', 'l536', 'l537', 'l538', 'l539', 'l540', 'l541', 'l542', 'l543']", + "71, the ['l26', 'l60', 'l93', 'l125', 'l156', 'l186', 'l215', 'l243', 'l270', 'l296', 'l321', 'l345', 'l368', 'l390', 'l411', 'l431', 'l450', 'l468', 'l485', 'l501', 'l516', 'l530', 'l544', 'l545', 'l546', 'l547', 'l548', 'l549', 'l550', 'l551', 'l552', 'l553', 'l554', 'l555', 'l556']", + "72, control ['l27', 'l61', 'l94', 'l126', 'l157', 'l187', 'l216', 'l244', 'l271', 'l297', 'l322', 'l346', 'l369', 'l391', 'l412', 'l432', 'l451', 'l469', 'l486', 'l502', 'l517', 'l531', 'l544', 'l557', 'l558', 'l559', 'l560', 'l561', 'l562', 'l563', 'l564', 'l565', 'l566', 'l567', 'l568']", + "73, of ['l28', 'l62', 'l95', 'l127', 'l158', 'l188', 'l217', 'l245', 'l272', 'l298', 'l323', 'l347', 'l370', 'l392', 'l413', 'l433', 'l452', 'l470', 'l487', 'l503', 'l518', 'l532', 'l545', 'l557', 'l569', 'l570', 'l571', 'l572', 'l573', 'l574', 'l575', 'l576', 'l577', 'l578', 'l579']", + "74, the ['l29', 'l63', 'l96', 'l128', 'l159', 'l189', 'l218', 'l246', 'l273', 'l299', 'l324', 'l348', 'l371', 'l393', 'l414', 'l434', 'l453', 'l471', 'l488', 'l504', 'l519', 'l533', 'l546', 'l558', 'l569', 'l580', 'l581', 'l582', 'l583', 'l584', 'l585', 'l586', 'l587', 'l588', 'l589']", + "75, Nes ['l30', 'l64', 'l97', 'l129', 'l160', 'l190', 'l219', 'l247', 'l274', 'l300', 'l325', 'l349', 'l372', 'l394', 'l415', 'l435', 'l454', 'l472', 'l489', 'l505', 'l520', 'l534', 'l547', 'l559', 'l570', 'l580', 'l590', 'l591', 'l592', 'l593', 'l594', 'l595', 'l596', 'l597', 'l598']", + "76, promoter-enhancer ['l31', 'l65', 'l98', 'l130', 'l161', 'l191', 'l220', 'l248', 'l275', 'l301', 'l326', 'l350', 'l373', 'l395', 'l416', 'l436', 'l455', 'l473', 'l490', 'l506', 'l521', 'l535', 'l548', 'l560', 'l571', 'l581', 'l590', 'l599', 'l600', 'l601', 'l602', 'l603', 'l604', 'l605', 'l606']", + "77, (Nes-Stat3(-/-), ['l32', 'l66', 'l99', 'l131', 'l162', 'l192', 'l221', 'l249', 'l276', 'l302', 'l327', 'l351', 'l374', 'l396', 'l417', 'l437', 'l456', 'l474', 'l491', 'l507', 'l522', 'l536', 'l549', 'l561', 'l572', 'l582', 'l591', 'l599', 'l607', 'l608', 'l609', 'l610', 'l611', 'l612', 'l613']", + "78, Nes-Socs3(-/-)). ['l33', 'l67', 'l100', 'l132', 'l163', 'l193', 'l222', 'l250', 'l277', 'l303', 'l328', 'l352', 'l375', 'l397', 'l418', 'l438', 'l457', 'l475', 'l492', 'l508', 'l523', 'l537', 'l550', 'l562', 'l573', 'l583', 'l592', 'l600', 'l607', 'l614', 'l615', 'l616', 'l617', 'l618', 'l619']", + "79, Reactive ['l34', 'l68', 'l101', 'l133', 'l164', 'l194', 'l223', 'l251', 'l278', 'l304', 'l329', 'l353', 'l376', 'l398', 'l419', 'l439', 'l458', 'l476', 'l493', 'l509', 'l524', 'l538', 'l551', 'l563', 'l574', 'l584', 'l593', 'l601', 'l608', 'l614', 'l620', 'l621', 'l622', 'l623', 'l624']", + "80, astrocytes ['l4', 'l35', 'l69', 'l102', 'l134', 'l165', 'l195', 'l224', 'l252', 'l279', 'l305', 'l330', 'l354', 'l377', 'l399', 'l420', 'l440', 'l459', 'l477', 'l494', 'l510', 'l525', 'l539', 'l552', 'l564', 'l575', 'l585', 'l594', 'l602', 'l609', 'l615', 'l620', 'l625', 'l626', 'l627', 'l628']", + "82, Nes-Stat3(-/-) ['l36', 'l70', 'l103', 'l135', 'l166', 'l196', 'l225', 'l253', 'l280', 'l306', 'l331', 'l355', 'l378', 'l400', 'l421', 'l441', 'l460', 'l478', 'l495', 'l511', 'l526', 'l540', 'l553', 'l565', 'l576', 'l586', 'l595', 'l603', 'l610', 'l616', 'l621', 'l625', 'l629', 'l630', 'l631']", + "83, mice ['l37', 'l71', 'l104', 'l136', 'l167', 'l197', 'l226', 'l254', 'l281', 'l307', 'l332', 'l356', 'l379', 'l401', 'l422', 'l442', 'l461', 'l479', 'l496', 'l512', 'l527', 'l541', 'l554', 'l566', 'l577', 'l587', 'l596', 'l604', 'l611', 'l617', 'l622', 'l626', 'l629', 'l632', 'l633']", + "85, limited ['l38', 'l72', 'l105', 'l137', 'l168', 'l198', 'l227', 'l255', 'l282', 'l308', 'l333', 'l357', 'l380', 'l402', 'l423', 'l443', 'l462', 'l480', 'l497', 'l513', 'l528', 'l542', 'l555', 'l567', 'l578', 'l588', 'l597', 'l605', 'l612', 'l618', 'l623', 'l627', 'l630', 'l632', 'l634']", + "86, migration ['l39', 'l73', 'l106', 'l138', 'l169', 'l199', 'l228', 'l256', 'l283', 'l309', 'l334', 'l358', 'l381', 'l403', 'l424', 'l444', 'l463', 'l481', 'l498', 'l514', 'l529', 'l543', 'l556', 'l568', 'l579', 'l589', 'l598', 'l606', 'l613', 'l619', 'l624', 'l628', 'l631', 'l633', 'l634']", + "116, migration ['l635', 'l636', 'l637']", + "118, reactive ['l635', 'l638', 'l639', 'l640']", + "119, astrocytes ['l636', 'l638', 'l641', 'l642']", + "136, Nes-Socs3(-/-) ['l639', 'l641', 'l643']", + "137, mice. ['l637', 'l640', 'l642', 'l643']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "transcription", + "3", + "(Stat3)", + "selective", + "deletion", + "the", + "protein", + "signal", + "and", + "activator", + "or", + "suppressor", + "cytokine", + "signaling", + "(Socs3)", + "Nes", + "(Nes-Stat3(-/-),", + "Nes-Socs3(-/-)).", + "Nes-Stat3(-/-)", + "Nes-Socs3(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "deletion", + "of", + "the", + "protein", + "signal", + "and", + "activator", + "transcription", + "3", + "(Stat3)", + "or", + "suppressor", + "cytokine", + "signaling", + "(Socs3)", + "Nes", + "(Nes-Stat3(-/-),", + "Nes-Socs3(-/-)).", + "Nes-Stat3(-/-)", + "Nes-Socs3(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "Reactive", + "astrocytes", + "reactive" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "deletion", + "of", + "the", + "protein", + "signal", + "and", + "activator", + "transcription", + "3", + "(Stat3)", + "or", + "suppressor", + "cytokine", + "signaling", + "(Socs3)", + "Nes", + "(Nes-Stat3(-/-),", + "Nes-Socs3(-/-)).", + "Nes-Stat3(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "limited" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "deletion", + "of", + "the", + "protein", + "signal", + "and", + "activator", + "transcription", + "3", + "(Stat3)", + "or", + "suppressor", + "cytokine", + "signaling", + "(Socs3)", + "Nes", + "(Nes-Stat3(-/-),", + "Nes-Socs3(-/-)).", + "Nes-Stat3(-/-)" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "under", + "control", + "promoter-enhancer" + ] + }, + "context": { + "val": "cells", + "words": [ + "Reactive", + "astrocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "under", + "control", + "promoter-enhancer" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "under", + "control", + "promoter-enhancer" + ] + }, + "effect": { + "val": "negative", + "words": [ + "limited" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "under", + "control", + "promoter-enhancer" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Reactive", + "astrocytes" + ] + }, + "effect": { + "val": "negative", + "words": [ + "limited" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Reactive", + "astrocytes", + "reactive" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "limited" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limited" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + } + ] + }, + { + "PMID": "16715091", + "TEXT": "A major goal of immunotherapy for autoimmune diseases and transplantation is induction of regulatory T cells that mediate immunologic tolerance. The mucosal immune system is unique, as tolerance is preferentially induced after exposure to antigen, and induction of regulatory T cells is a primary mechanism of oral tolerance. Parenteral administration of CD3-specific monoclonal antibody is an approved therapy for transplantation in humans and is effective in autoimmune diabetes. We found that orally administered CD3-specific antibody is biologically active in the gut and suppresses autoimmune encephalomyelitis both before induction of disease and at the height of disease. Orally administered CD3-specific antibody induces CD4+ CD25- LAP+ regulatory T cells that contain latency-associated peptide (LAP) on their surface and that function in vitro and in vivo through a TGF-beta-dependent mechanism. These findings identify a new immunologic approach that is widely applicable for the treatment of human autoimmune conditions.", + "TAG_DATA": [ + "101, CD4+ {'context': 'B-cells'}", + "102, CD25- {'context': 'I-cells'}", + "103, LAP+ {'context': 'I-cells'}", + "104, regulatory {'context': 'I-cells'}", + "105, T {'context': 'I-cells'}", + "106, cells {'context': 'I-cells'}", + "118, in {'context': 'B-in vitro'}", + "119, vitro {'context': 'I-in vitro'}", + "121, in {'context': 'B-in vivo'}", + "122, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "101, CD4+ ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "102, CD25- ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "103, LAP+ ['l1', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "104, regulatory ['l2', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "105, T ['l3', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "106, cells ['l4', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "118, in ['l5', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28', 'l29', 'l30']", + "119, vitro ['l6', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28', 'l31', 'l32']", + "121, in ['l29', 'l31', 'l33']", + "122, vivo ['l7', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16715088", + "TEXT": "Complement-mediated tissue injury in humans occurs upon deposition of immune complexes, such as in autoimmune diseases and acute respiratory distress syndrome. Acute lung inflammatory injury in wild-type and C3-/- mice after deposition of IgG immune complexes was of equivalent intensity and was C5a dependent, but injury was greatly attenuated in Hc-/- mice (Hc encodes C5). Injury in lungs of C3-/- mice and C5a levels in bronchoalveolar lavage (BAL) fluids from these mice were greatly reduced in the presence of antithrombin III (ATIII) or hirudin but were not reduced in similarly treated C3+/+ mice. Plasma from C3-/- mice contained threefold higher levels of thrombin activity compared to plasma from C3+/+ mice. There were higher levels of F2 mRNA (encoding prothrombin) as well as prothrombin and thrombin protein in liver of C3-/- mice compared to C3+/+ mice. A potent solid-phase C5 convertase was generated using plasma from either C3+/+ or C3-/- mice. Human C5 incubated with thrombin generated C5a that was biologically active. These data suggest that, in the genetic absence of C3, thrombin substitutes for the C3-dependent C5 convertase. This linkage between the complement and coagulation pathways may represent a new pathway of complement activation.", + "TAG_DATA": [ + "28, C3-/- {'perturbing_action': 'B-gene loss-of-function'}", + "29, mice {'context': 'B-organism'}", + "50, Hc-/- {'perturbing_action': 'B-gene loss-of-function'}", + "51, mice {'context': 'B-organism'}", + "57, lungs {'context': 'B-tissue/organ'}", + "59, C3-/- {'perturbing_action': 'B-gene loss-of-function'}", + "60, mice {'context': 'B-organism'}", + "71, mice {'context': 'B-organism'}", + "95, C3-/- {'perturbing_action': 'B-gene loss-of-function'}", + "96, mice {'context': 'B-organism'}", + "127, liver {'context': 'B-tissue/organ'}", + "129, C3-/- {'perturbing_action': 'B-gene loss-of-function'}", + "130, mice {'context': 'B-organism'}", + "148, C3-/- {'perturbing_action': 'B-gene loss-of-function'}", + "149, mice. {'context': 'B-organism'}", + "150, Human {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "28, C3-/- ['l0', 'l1', 'l2', 'l3']", + "29, mice ['l0', 'l4']", + "50, Hc-/- ['l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "51, mice ['l5', 'l11', 'l12', 'l13', 'l14']", + "57, lungs ['l1', 'l4', 'l6', 'l11', 'l15', 'l16', 'l17']", + "59, C3-/- ['l2', 'l7', 'l12', 'l15', 'l18', 'l19']", + "60, mice ['l3', 'l8', 'l13', 'l16', 'l18', 'l20']", + "71, mice ['l9', 'l14', 'l17', 'l19', 'l20']", + "95, C3-/- ['l21', 'l22', 'l23']", + "96, mice ['l10', 'l21']", + "127, liver ['l22', 'l24', 'l25']", + "129, C3-/- ['l24', 'l26', 'l27']", + "130, mice ['l23', 'l25', 'l26']", + "148, C3-/- ['l28', 'l29', 'l30']", + "149, mice. ['l27', 'l28', 'l31', 'l32']", + "150, Human ['l29', 'l31', 'l33']", + "151, C5 ['l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "C3-/-", + "Hc-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "C3-/-", + "Hc-/-" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lungs", + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "C3-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "Human" + ] + } + } + ] + }, + { + "PMID": "16680148", + "TEXT": "Endochondral ossification is an essential process not only for physiological skeletal development and growth, but also for pathological disorders. We recently identified a novel cartilage-specific molecule, carminerin (also known as cystatin 10 and encoded by Cst10), which is upregulated in synchrony with cartilage maturation and stimulates the later differentiation of cultured chondrocytes. Although carminerin-deficient (Cst10-/-) mice developed and grew normally, they had a microscopic decrease in the calcification of hypertrophic chondrocytes at the growth plate. When we created experimental models of pathological endochondral ossification, we observed suppression of chondrocyte calcification during formation of osteoarthritic osteophytes, age-related ectopic ossification and healing of bone fractures in Cst10-/- mice. Cultured Cst10-/- chondrocytes showed a reduction in calcification with activation of an SRY site in the promoter of the gene encoding nucleotide pyrophosphatase phosphodiesterase 1 (NPP1, encoded by Enpp1). Functional NPP1 is required for carminerin deficiency to suppress the pathological endochondral ossifications listed above. Carminerin is the first cartilage-specific protein that contributes to chondrocyte calcification during endochondral ossification under physiological and pathological conditions through the transcriptional inhibition of NPP1.", + "TAG_DATA": [ + "53, carminerin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "54, (Cst10-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "55, mice {'context': 'B-organism'}", + "69, hypertrophic {'context': 'B-cells'}", + "70, chondrocytes {'context': 'I-cells'}", + "104, Cst10-/- {'perturbing_action': 'B-gene loss-of-function'}", + "105, mice. {'context': 'B-organism'}", + "107, Cst10-/- {'perturbing_action': 'B-gene loss-of-function'}", + "108, chondrocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "53, carminerin-deficient ['l0', 'l1', 'l2', 'l3']", + "54, (Cst10-/-) ['l0', 'l4', 'l5', 'l6']", + "55, mice ['l1', 'l4', 'l7', 'l8']", + "69, hypertrophic ['l2', 'l5', 'l7', 'l9']", + "70, chondrocytes ['l3', 'l6', 'l8', 'l9']", + "104, Cst10-/- ['l10']", + "105, mice. ['l10']", + "107, Cst10-/- ['l11']", + "108, chondrocytes ['l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "carminerin-deficient", + "(Cst10-/-)", + "Cst10-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "carminerin-deficient", + "(Cst10-/-)", + "Cst10-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "hypertrophic", + "chondrocytes" + ] + } + } + ] + }, + { + "PMID": "16633348", + "TEXT": "MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by repressing translation of target cellular transcripts. Increasing evidence indicates that miRNAs have distinct expression profiles and play crucial roles in numerous cellular processes, although the extent of miRNA regulation is not well known. By challenging mice with lentiviral vectors encoding target sequences of endogenous miRNAs, we show the efficiency of miRNAs in sharply segregating gene expression among different tissues. Transgene expression from vectors incorporating target sequences for mir-142-3p was effectively suppressed in intravascular and extravascular hematopoietic lineages, whereas expression was maintained in nonhematopoietic cells. This expression profile, which could not be attained until now, enabled stable gene transfer in immunocompetent mice, thus overcoming a major hurdle to successful gene therapy. Our results provide novel in situ evidence of miRNA regulation and demonstrate a new paradigm in vector design with applications for genetic engineering and therapeutic gene transfer.", + "TAG_DATA": [ + "46, mice {'context': 'B-organism'}", + "93, nonhematopoietic {'context': 'B-cells'}", + "94, cells. {'context': 'I-cells'}", + "110, immunocompetent {'context': 'B-organism'}", + "111, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "93, nonhematopoietic ['l0']", + "94, cells. ['l0']", + "110, immunocompetent ['l1']", + "111, mice, ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16617349", + "TEXT": "The protein tyrosine phosphatase SHP-1 is a well-known inhibitor of activation-promoting signaling cascades in hematopoietic cells but its potential role in insulin target tissues is unknown. Here we show that Ptpn6(me-v/me-v) (also known as viable motheaten) mice bearing a functionally deficient SHP-1 protein are markedly glucose tolerant and insulin sensitive as compared to wild-type littermates, as a result of enhanced insulin receptor signaling to IRS-PI3K-Akt in liver and muscle. Downregulation of SHP-1 activity in liver of normal mice by adenoviral expression of a catalytically inert mutant of SHP-1, or after small hairpin RNA-mediated SHP-1 silencing, further confirmed this phenotype. Tyrosine phosphorylation of CEACAM1, a modulator of hepatic insulin clearance, and clearance of serum [125I]-insulin were markedly increased in SHP-1-deficient mice or SHP-1-deficient hepatic cells in vitro. These findings show a novel role for SHP-1 in the regulation of glucose homeostasis through modulation of insulin signaling in liver and muscle as well as hepatic insulin clearance.", + "TAG_DATA": [ + "30, Ptpn6(me-v/me-v) {'perturbing_action': 'B-other'}", + "36, mice {'context': 'B-organism'}", + "39, functionally {'perturbing_action': 'B-gene loss-of-function'}", + "40, deficient {'perturbing_action': 'I-gene loss-of-function'}", + "41, SHP-1 {'perturbing_action': 'I-gene loss-of-function'}", + "42, protein {'perturbing_action': 'I-gene loss-of-function'}", + "69, Downregulation {'perturbing_action': 'B-other'}", + "70, of {'perturbing_action': 'I-gene loss-of-function'}", + "71, SHP-1 {'perturbing_action': 'I-gene loss-of-function'}", + "72, activity {'perturbing_action': 'I-gene loss-of-function'}", + "74, liver {'context': 'B-tissue/organ'}", + "77, mice {'context': 'B-organism'}", + "79, adenoviral {'perturbing_action': 'B-other'}", + "80, expression {'perturbing_action': 'I-other'}", + "81, of {'perturbing_action': 'I-other'}", + "82, a {'perturbing_action': 'I-other'}", + "83, catalytically {'perturbing_action': 'I-other'}", + "84, inert {'perturbing_action': 'I-other'}", + "85, mutant {'perturbing_action': 'I-other'}", + "86, of {'perturbing_action': 'I-other'}", + "87, SHP-1, {'perturbing_action': 'I-other'}", + "90, small {'perturbing_action': 'B-rnai/knockdown'}", + "91, hairpin {'perturbing_action': 'I-rnai/knockdown'}", + "92, RNA-mediated {'perturbing_action': 'I-rnai/knockdown'}", + "93, SHP-1 {'perturbing_action': 'I-rnai/knockdown'}", + "94, silencing, {'perturbing_action': 'I-rnai/knockdown'}", + "118, SHP-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "119, mice {'context': 'B-organism'}", + "121, SHP-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "122, hepatic {'context': 'B-cells'}", + "123, cells {'context': 'I-cells'}", + "124, in {'context': 'B-in vitro'}", + "125, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "30, Ptpn6(me-v/me-v) ['l0', 'l1', 'l2']", + "31, (also ['l0', 'l3', 'l4', 'l5']", + "36, mice ['l1', 'l3', 'l6']", + "39, functionally ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "40, deficient ['l7', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "41, SHP-1 ['l8', 'l25', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "42, protein ['l9', 'l26', 'l42', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "69, Downregulation ['l10', 'l27', 'l43', 'l58', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "70, of ['l11', 'l28', 'l44', 'l59', 'l73', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "71, SHP-1 ['l12', 'l29', 'l45', 'l60', 'l74', 'l87', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "72, activity ['l13', 'l30', 'l46', 'l61', 'l75', 'l88', 'l100', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "74, liver ['l2', 'l4', 'l6', 'l14', 'l31', 'l47', 'l62', 'l76', 'l89', 'l101', 'l112', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "77, mice ['l5', 'l15', 'l32', 'l48', 'l63', 'l77', 'l90', 'l102', 'l113', 'l123', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141']", + "79, adenoviral ['l16', 'l33', 'l49', 'l64', 'l78', 'l91', 'l103', 'l114', 'l124', 'l133', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "80, expression ['l17', 'l34', 'l50', 'l65', 'l79', 'l92', 'l104', 'l115', 'l125', 'l134', 'l142', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156']", + "81, of ['l18', 'l35', 'l51', 'l66', 'l80', 'l93', 'l105', 'l116', 'l126', 'l135', 'l143', 'l150', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162']", + "82, a ['l19', 'l36', 'l52', 'l67', 'l81', 'l94', 'l106', 'l117', 'l127', 'l136', 'l144', 'l151', 'l157', 'l163', 'l164', 'l165', 'l166', 'l167']", + "83, catalytically ['l20', 'l37', 'l53', 'l68', 'l82', 'l95', 'l107', 'l118', 'l128', 'l137', 'l145', 'l152', 'l158', 'l163', 'l168', 'l169', 'l170', 'l171']", + "84, inert ['l21', 'l38', 'l54', 'l69', 'l83', 'l96', 'l108', 'l119', 'l129', 'l138', 'l146', 'l153', 'l159', 'l164', 'l168', 'l172', 'l173', 'l174']", + "85, mutant ['l22', 'l39', 'l55', 'l70', 'l84', 'l97', 'l109', 'l120', 'l130', 'l139', 'l147', 'l154', 'l160', 'l165', 'l169', 'l172', 'l175', 'l176']", + "86, of ['l23', 'l40', 'l56', 'l71', 'l85', 'l98', 'l110', 'l121', 'l131', 'l140', 'l148', 'l155', 'l161', 'l166', 'l170', 'l173', 'l175', 'l177']", + "87, SHP-1, ['l24', 'l41', 'l57', 'l72', 'l86', 'l99', 'l111', 'l122', 'l132', 'l141', 'l149', 'l156', 'l162', 'l167', 'l171', 'l174', 'l176', 'l177']", + "90, small ['l178', 'l179', 'l180', 'l181', 'l182', 'l183']", + "91, hairpin ['l178', 'l184', 'l185', 'l186', 'l187', 'l188']", + "92, RNA-mediated ['l179', 'l184', 'l189', 'l190', 'l191', 'l192']", + "93, SHP-1 ['l180', 'l185', 'l189', 'l193', 'l194', 'l195']", + "94, silencing, ['l181', 'l186', 'l190', 'l193', 'l196', 'l197']", + "118, SHP-1-deficient ['l182', 'l187', 'l191', 'l194', 'l196', 'l198', 'l199', 'l200', 'l201', 'l202']", + "119, mice ['l183', 'l188', 'l192', 'l195', 'l197', 'l198']", + "121, SHP-1-deficient ['l199', 'l203', 'l204', 'l205', 'l206']", + "122, hepatic ['l200', 'l203', 'l207', 'l208', 'l209']", + "123, cells ['l201', 'l204', 'l207', 'l210', 'l211']", + "124, in ['l202', 'l205', 'l208', 'l210', 'l212']", + "125, vitro. ['l206', 'l209', 'l211', 'l212']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Ptpn6(me-v/me-v)", + "Downregulation", + "adenoviral", + "expression", + "of", + "a", + "catalytically", + "inert", + "mutant", + "SHP-1," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Ptpn6(me-v/me-v)", + "Downregulation", + "adenoviral", + "expression", + "of", + "a", + "catalytically", + "inert", + "mutant", + "SHP-1," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "functionally", + "deficient", + "SHP-1", + "protein", + "of", + "activity" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "functionally", + "deficient", + "SHP-1", + "protein", + "of", + "activity", + "SHP-1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "small", + "hairpin", + "RNA-mediated", + "SHP-1", + "silencing," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHP-1-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatic", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHP-1-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "16582917", + "TEXT": "Mesenchymal stem cells are multipotent cells that can differentiate into cardiomyocytes and vascular endothelial cells. Here we show, using cell sheet technology, that monolayered mesenchymal stem cells have multipotent and self-propagating properties after transplantation into infarcted rat hearts. We cultured adipose tissue-derived mesenchymal stem cells characterized by flow cytometry using temperature-responsive culture dishes. Four weeks after coronary ligation, we transplanted the monolayered mesenchymal stem cells onto the scarred myocardium. After transplantation, the engrafted sheet gradually grew to form a thick stratum that included newly formed vessels, undifferentiated cells and few cardiomyocytes. The mesenchymal stem cell sheet also acted through paracrine pathways to trigger angiogenesis. Unlike a fibroblast cell sheet, the monolayered mesenchymal stem cells reversed wall thinning in the scar area and improved cardiac function in rats with myocardial infarction. Thus, transplantation of monolayered mesenchymal stem cells may be a new therapeutic strategy for cardiac tissue regeneration.", + "TAG_DATA": [ + "40, adipose {'context': 'B-cells'}", + "41, tissue-derived {'context': 'I-cells'}", + "42, mesenchymal {'context': 'I-cells'}", + "43, stem {'context': 'I-cells'}", + "44, cells {'context': 'I-cells'}", + "61, monolayered {'context': 'B-cells'}", + "62, mesenchymal {'context': 'I-cells'}", + "63, stem {'context': 'I-cells'}", + "64, cells {'context': 'I-cells'}", + "67, scarred {'context': 'B-tissue/organ'}", + "68, myocardium. {'context': 'I-tissue/organ'}", + "90, cardiomyocytes. {'context': 'B-cells'}", + "110, monolayered {'context': 'B-cells'}", + "111, mesenchymal {'context': 'I-cells'}", + "112, stem {'context': 'I-cells'}", + "113, cells {'context': 'I-cells'}", + "126, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "40, adipose ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "41, tissue-derived ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "42, mesenchymal ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "43, stem ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "44, cells ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "61, monolayered ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "62, mesenchymal ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "63, stem ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "64, cells ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "67, scarred ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "68, myocardium. ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "87, cells ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65', 'l66']", + "90, cardiomyocytes. ['l66']", + "93, stem ['l67']", + "94, cell ['l67']", + "110, monolayered ['l68', 'l69', 'l70', 'l71']", + "111, mesenchymal ['l68', 'l72', 'l73', 'l74']", + "112, stem ['l69', 'l72', 'l75', 'l76']", + "113, cells ['l70', 'l73', 'l75', 'l77']", + "126, rats ['l71', 'l74', 'l76', 'l77']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16582915", + "TEXT": "The concept of regenerating diseased myocardium by implantation of tissue-engineered heart muscle is intriguing, but convincing evidence is lacking that heart tissues can be generated at a size and with contractile properties that would lend considerable support to failing hearts. Here we created large (thickness/diameter, 1-4 mm/15 mm), force-generating engineered heart tissue from neonatal rat heart cells. Engineered heart tissue formed thick cardiac muscle layers when implanted on myocardial infarcts in immune-suppressed rats. When evaluated 28 d later, engineered heart tissue showed undelayed electrical coupling to the native myocardium without evidence of arrhythmia induction. Moreover, engineered heart tissue prevented further dilation, induced systolic wall thickening of infarcted myocardial segments and improved fractional area shortening of infarcted hearts compared to controls (sham operation and noncontractile constructs). Thus, our study provides evidence that large contractile cardiac tissue grafts can be constructed in vitro, can survive after implantation and can support contractile function of infarcted hearts.", + "TAG_DATA": [ + "53, neonatal {'context': 'B-cells'}", + "54, rat {'context': 'I-cells'}", + "55, heart {'context': 'I-cells'}", + "56, cells. {'context': 'I-cells'}", + "71, immune-suppressed {'context': 'B-organism'}", + "72, rats. {'context': 'I-organism'}", + "78, engineered {'context': 'B-organoid'}", + "79, heart {'context': 'I-organoid'}", + "80, tissue {'context': 'I-organoid'}", + "95, engineered {'context': 'B-organoid'}", + "96, heart {'context': 'I-tissue/organ'}", + "97, tissue {'context': 'I-organoid'}", + "107, myocardial {'context': 'B-tissue/organ'}", + "108, segments {'context': 'I-tissue/organ'}", + "116, hearts {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "51, tissue ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "53, neonatal ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "54, rat ['l1', 'l9', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "55, heart ['l2', 'l10', 'l20', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "56, cells. ['l3', 'l11', 'l21', 'l30', 'l37', 'l38', 'l39', 'l40', 'l41']", + "58, heart ['l4', 'l12', 'l22', 'l31', 'l37', 'l42', 'l43', 'l44', 'l45', 'l46']", + "59, tissue ['l5', 'l13', 'l23', 'l32', 'l38', 'l42', 'l47', 'l48', 'l49']", + "71, immune-suppressed ['l6', 'l14', 'l24', 'l33', 'l39', 'l43', 'l47', 'l50', 'l51', 'l52']", + "72, rats. ['l7', 'l15', 'l25', 'l34', 'l40', 'l44', 'l48', 'l50', 'l53', 'l54']", + "78, engineered ['l16', 'l26', 'l55', 'l56', 'l57', 'l58', 'l59']", + "79, heart ['l17', 'l27', 'l55', 'l60', 'l61', 'l62', 'l63']", + "80, tissue ['l18', 'l28', 'l35', 'l45', 'l51', 'l53', 'l56', 'l60', 'l64', 'l65']", + "88, myocardium ['l8', 'l19', 'l29', 'l36', 'l41', 'l46', 'l49', 'l52', 'l54', 'l57', 'l61', 'l64', 'l66']", + "95, engineered ['l67', 'l68', 'l69', 'l70', 'l71']", + "96, heart ['l67', 'l72', 'l73', 'l74', 'l75']", + "97, tissue ['l68', 'l72', 'l76', 'l77', 'l78']", + "107, myocardial ['l58', 'l62', 'l69', 'l73', 'l76', 'l79']", + "108, segments ['l59', 'l63', 'l65', 'l66', 'l70', 'l74', 'l77', 'l79']", + "116, hearts ['l71', 'l75', 'l78']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16550189", + "TEXT": "We analyzed urinary polypeptides from individuals with neonatal ureteropelvic junction (UPJ) obstruction to predict which individuals with this condition will evolve toward obstruction that needs surgical correction. We identified polypeptides that enabled diagnosis of the severity of obstruction and validated these biomarkers in urine collected in a prospective blinded study. Using these noninvasive biomarkers, we were able to predict, several months in advance and with 94% precision, the clinical evolution of neonates with UPJ obstruction.", + "TAG_DATA": [ + "71, neonates {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16532003", + "TEXT": "The ability to detect antigens immunologically is limited by the affinity of the antibodies and the amount of antigens. We have now succeeded in creating a modular, facile amplification system, termed fluorescent amplification catalyzed by T7 polymerase technique (FACTT). Such a system can detect protein targets specifically at subfemtomolar levels ( approximately 0.08 fM). We describe here the detection of Her2 (also known as Neu) from rodent and human sera. FACTT is adaptable to high-throughput screening and automation and provides a practical method to enhance current ELISAs in medical practice.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16501571", + "TEXT": "A significant impediment to the widespread use of noninvasive in vivo vascular imaging techniques is the current lack of suitable intravital imaging probes. We describe here a new strategy to use viral nanoparticles as a platform for the multivalent display of fluorescent dyes to image tissues deep inside living organisms. The bioavailable cowpea mosaic virus (CPMV) can be fluorescently labeled to high densities with no measurable quenching, resulting in exceptionally bright particles with in vivo dispersion properties that allow high-resolution intravital imaging of vascular endothelium for periods of at least 72 h. We show that CPMV nanoparticles can be used to visualize the vasculature and blood flow in living mouse and chick embryos to a depth of up to 500 microm. Furthermore, we show that the intravital visualization of human fibrosarcoma-mediated tumor angiogenesis using fluorescent CPMV provides a means to identify arterial and venous vessels and to monitor the neovascularization of the tumor microenvironment.", + "TAG_DATA": [ + "109, mouse {'context': 'B-organism'}", + "110, and {'context': 'I-organism'}", + "111, chick {'context': 'B-organism'}", + "112, embryos {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "109, mouse ['l0', 'l1', 'l2']", + "110, and ['l0', 'l3', 'l4']", + "111, chick ['l1', 'l3', 'l5']", + "112, embryos ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16501570", + "TEXT": "We evaluated the ability of neonatal porcine islets to engraft and restore glucose control in pancreatectomized rhesus macaques. Although porcine islets transplanted into nonimmunosuppressed macaques were rapidly rejected by a process consistent with cellular rejection, recipients treated with a CD28-CD154 costimulation blockade regimen achieved sustained insulin independence (median survival, >140 days) without evidence of porcine endogenous retrovirus dissemination. Thus, neonatal porcine islets represent a promising solution to the crucial supply problem in clinical islet transplantation.", + "TAG_DATA": [ + "16, rhesus {'context': 'B-organism'}", + "17, macaques. {'context': 'I-organism'}", + "19, porcine {'context': 'B-cells'}", + "20, islets {'context': 'I-cells'}", + "23, nonimmunosuppressed {'context': 'B-organism'}", + "24, macaques {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "16, rhesus ['l0', 'l1', 'l2', 'l3', 'l4']", + "17, macaques. ['l0', 'l5', 'l6', 'l7', 'l8']", + "19, porcine ['l1', 'l5', 'l9', 'l10', 'l11']", + "20, islets ['l2', 'l6', 'l9', 'l12', 'l13']", + "23, nonimmunosuppressed ['l3', 'l7', 'l10', 'l12', 'l14']", + "24, macaques ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16474398", + "TEXT": "We describe the tripeptide neutrophil chemoattractant N-acetyl Pro-Gly-Pro (PGP), derived from the breakdown of extracellular matrix (ECM), which shares sequence and structural homology with an important domain on alpha chemokines. PGP caused chemotaxis and production of superoxide through CXC receptors, and administration of peptide caused recruitment of neutrophils (PMNs) into lungs of control, but not CXCR2-deficient mice. PGP was generated in mouse lung after exposure to lipopolysaccharide, and in vivo and in vitro blockade of PGP with monoclonal antibody suppressed PMN responses as much as chemokine-specific monoclonal antibody. Extended PGP treatment caused alveolar enlargement and right ventricular hypertrophy in mice. PGP was detectable in substantial concentrations in a majority of bronchoalveolar lavage samples from individuals with chronic obstructive pulmonary disease, but not control individuals. Thus, PGP's activity links degradation of ECM with neutrophil recruitment in airway inflammation, and PGP may be a biomarker and therapeutic target for neutrophilic inflammatory diseases.", + "TAG_DATA": [ + "55, CXCR2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "56, mice. {'context': 'B-organism'}", + "61, mouse {'context': 'B-tissue/organ'}", + "62, lung {'context': 'I-tissue/organ'}", + "68, in {'context': 'B-in vivo'}", + "69, vivo {'context': 'I-in vivo'}", + "71, in {'context': 'B-in vitro'}", + "72, vitro {'context': 'I-in vitro'}", + "80, PMN {'context': 'B-cells'}", + "99, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "55, CXCR2-deficient ['l0', 'l1', 'l2']", + "56, mice. ['l0', 'l3', 'l4']", + "61, mouse ['l1', 'l3', 'l5']", + "62, lung ['l2', 'l4', 'l5']", + "68, in ['l6', 'l7', 'l8', 'l9']", + "69, vivo ['l6', 'l10', 'l11', 'l12']", + "71, in ['l7', 'l10', 'l13', 'l14']", + "72, vitro ['l8', 'l11', 'l13', 'l15']", + "80, PMN ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CXCR2-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CXCR2-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "lung" + ] + } + } + ] + }, + { + "PMID": "16462803", + "TEXT": "Major histocompatibility complex (MHC) class I molecules associate with a variety of peptide ligands during biosynthesis and present these ligands on the cell surface for recognition by cytotoxic T cells. We have designed conditional MHC ligands that form stable complexes with MHC molecules but degrade on command, by exposure to a defined photostimulus. 'Empty MHC molecules' generated in this manner can be loaded with arrays of peptide ligands to determine MHC binding properties and to monitor antigen-specific T-cell responses in a high-throughput manner. We document the value of this approach by identifying cytotoxic T-cell epitopes within the H5N1 influenza A/Vietnam/1194/04 genome.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16444266", + "TEXT": "Natural killer (NK) cells and dendritic cells (DCs) are, respectively, central components of innate and adaptive immune responses. We describe here a third DC lineage, termed interferon-producing killer DCs (IKDCs), distinct from conventional DCs and plasmacytoid DCs and with the molecular expression profile of both NK cells and DCs. They produce substantial amounts of type I interferons (IFN) and interleukin (IL)-12 or IFN-gamma, depending on activation stimuli. Upon stimulation with CpG oligodeoxynucleotides, ligands for Toll-like receptor (TLR)-9, IKDCs kill typical NK target cells using NK-activating receptors. Their cytolytic capacity subsequently diminishes, associated with the loss of NKG2D receptor (also known as Klrk1) and its adaptors, Dap10 and Dap12. As cytotoxicity is lost, DC-like antigen-presenting activity is gained, associated with upregulation of surface major histocompatibility complex class II (MHC II) and costimulatory molecules, which formally distinguish them from classical NK cells. In vivo, splenic IKDCs preferentially show NK function and, upon systemic infection, migrate to lymph nodes, where they primarily show antigen-presenting cell activity. By virtue of their capacity to kill target cells, followed by antigen presentation, IKDCs provide a link between innate and adaptive immunity.", + "TAG_DATA": [ + "140, In {'context': 'B-in vivo'}", + "141, vivo, {'context': 'I-in vivo'}", + "142, splenic {'context': 'B-cells'}", + "143, IKDCs {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "140, In ['l0', 'l1', 'l2', 'l3']", + "141, vivo, ['l0', 'l4', 'l5', 'l6']", + "142, splenic ['l1', 'l4', 'l7', 'l8']", + "143, IKDCs ['l2', 'l5', 'l7', 'l9']", + "155, nodes, ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16432513", + "TEXT": "Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostanoid synthesis, has been implicated in the neurotoxicity resulting from hypoxia-ischemia, and its inhibition has therapeutic potential for ischemic stroke. However, COX-2 inhibitors increase the risk of cardiovascular complications. We therefore sought to identify the downstream effectors of COX-2 neurotoxicity, and found that prostaglandin E(2) EP1 receptors are essential for the neurotoxicity mediated by COX-2-derived prostaglandin E(2). EP1 receptors disrupt Ca(2+) homeostasis by impairing Na(+)-Ca(2+) exchange, a key mechanism by which neurons cope with excess Ca(2+) accumulation after an excitotoxic insult. Thus, EP1 receptors contribute to neurotoxicity by augmenting the Ca(2+) dysregulation underlying excitotoxic neuronal death. Pharmacological inhibition or gene inactivation of EP1 receptors ameliorates brain injury induced by excitotoxicity, oxygen glucose deprivation and middle cerebral artery (MCA) occlusion. An EP1 receptor inhibitor reduces brain injury when administered 6 hours after MCA occlusion, suggesting that EP1 receptor inhibition may be a viable therapeutic option in ischemic stroke.", + "TAG_DATA": [ + "105, gene {'perturbing_action': 'B-gene loss-of-function'}", + "106, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "107, of {'perturbing_action': 'I-gene loss-of-function'}", + "108, EP1 {'perturbing_action': 'I-gene loss-of-function'}", + "109, receptors {'perturbing_action': 'I-gene loss-of-function'}", + "111, brain {'context': 'B-tissue/organ'}", + "126, EP1 {'perturbing_action': 'B-pharmacological inhibition'}", + "127, receptor {'perturbing_action': 'B-pharmacological inhibition'}", + "128, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "130, brain {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "105, gene ['l0', 'l1', 'l2', 'l3', 'l4']", + "106, inactivation ['l0', 'l5', 'l6', 'l7', 'l8']", + "107, of ['l1', 'l5', 'l9', 'l10', 'l11']", + "108, EP1 ['l2', 'l6', 'l9', 'l12', 'l13']", + "109, receptors ['l3', 'l7', 'l10', 'l12', 'l14']", + "111, brain ['l4', 'l8', 'l11', 'l13', 'l14']", + "126, EP1 ['l15', 'l16', 'l17']", + "127, receptor ['l15', 'l18', 'l19']", + "128, inhibitor ['l16', 'l18', 'l20']", + "130, brain ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "gene", + "inactivation", + "of", + "EP1", + "receptors" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EP1", + "receptor", + "inhibitor" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain" + ] + } + } + ] + }, + { + "PMID": "16429144", + "TEXT": "Plasmodium, the parasite that causes malaria, is transmitted by a mosquito into the dermis and must reach the liver before infecting erythrocytes and causing disease. We present here a quantitative, real-time analysis of the fate of parasites transmitted in a rodent system. We show that only a proportion of the parasites enter blood capillaries, whereas others are drained by lymphatics. Lymph sporozoites stop at the proximal lymph node, where most are degraded inside dendritic leucocytes, but some can partially differentiate into exoerythrocytic stages. This previously unrecognized step of the parasite life cycle could influence the immune response of the host, and may have implications for vaccination strategies against the preerythrocytic stages of the parasite.", + "TAG_DATA": [ + "65, proximal {'context': 'B-tissue/organ'}", + "66, lymph {'context': 'I-tissue/organ'}", + "67, node, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "65, proximal ['l0', 'l1']", + "66, lymph ['l0', 'l2']", + "67, node, ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16415878", + "TEXT": "De novo lymphangiogenesis influences the course of different human diseases as diverse as chronic renal transplant rejection and tumor metastasis. The cellular mechanisms of lymphangiogenesis in human diseases are currently unknown, and could involve division of local preexisting endothelial cells or incorporation of circulating progenitors. We analyzed renal tissues of individuals with gender-mismatched transplants who had transplant rejection and high rates of overall lymphatic endothelial proliferation as well as massive chronic inflammation. Donor-derived cells were detected by in situ hybridization of the Y chromosome. We compared these tissues with biopsies of essentially normal skin and intestine, and two rare carcinomas with low rates of lymphatic endothelial proliferation that were derived from individuals with gender-mismatched bone marrow transplants. Here, we provide evidence for the participation of recipient-derived lymphatic progenitor cells in renal transplants. In contrast, lymphatic vessels of normal tissues and those around post-transplant carcinomas did not incorporate donor-derived progenitors. This indicates a stepwise mechanism of inflammation-associated de novo lymphangiogenesis, implying that potential lymphatic progenitor cells derive from the circulation, transmigrate through the connective tissue stroma, presumably in the form of macrophages, and finally incorporate into the growing lymphatic vessel.", + "TAG_DATA": [ + "72, Donor-derived {'context': 'B-cells'}", + "73, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "72, Donor-derived ['l0']", + "73, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16369542", + "TEXT": "Antimicrobial-modifying resistance enzymes have traditionally been class specific, having coevolved with the antibiotics they inactivate. Fluoroquinolones, antimicrobial agents used extensively in medicine and agriculture, are synthetic and have been considered safe from naturally occurring antimicrobial-modifying enzymes. We describe reduced susceptibility to ciprofloxacin in clinical bacterial isolates conferred by a variant of the gene encoding aminoglycoside acetyltransferase AAC(6')-Ib. This enzyme reduces the activity of ciprofloxacin by N-acetylation at the amino nitrogen on its piperazinyl substituent. Although approximately 30 variants of this gene have been reported since 1986, the two base-pair changes responsible for the ciprofloxacin modification phenotype are unique to this variant, first reported in 2003 and now widely disseminated. An intense increase in the medical use of ciprofloxacin seems to have been accompanied by a notable development: a single-function resistance enzyme has crossed class boundaries, and is now capable of enzymatically undermining two unrelated antimicrobial agents, one of them fully synthetic.", + "TAG_DATA": [ + "43, clinical {'context': 'B-transformed cells'}", + "44, bacterial {'context': 'I-transformed cells'}", + "45, isolates {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "43, clinical ['l0', 'l1']", + "44, bacterial ['l0', 'l2']", + "45, isolates ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16327803", + "TEXT": "Many heat-shock proteins (Hsp) are members of evolutionarily conserved families of chaperone proteins that inhibit the aggregation of unfolded polypeptides and refold denatured proteins, thereby remedying phenotypic effects that may result from protein aggregation or protein instability. Here we report that the mitochondrial chaperone Hsp40, also known as Dnaja3 or Tid1, is differentially expressed during cardiac development and pathological hypertrophy. Mice deficient in Dnaja3 developed dilated cardiomyopathy (DCM) and died before 10 weeks of age. Progressive respiratory chain deficiency and decreased copy number of mitochondrial DNA were evident in cardiomyocytes lacking Dnaja3. Profiling of Dnaja3-interacting proteins identified the alpha-subunit of DNA polymerase gamma (Polga) as a client protein. These findings suggest that Dnaja3 is crucial for mitochondrial biogenesis, at least in part, through its chaperone activity on Polga and provide genetic evidence of the necessity for mitochondrial Hsp40 in preventing DCM.", + "TAG_DATA": [ + "60, Mice {'context': 'B-organism'}", + "61, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "62, in {'perturbing_action': 'I-gene loss-of-function'}", + "63, Dnaja3 {'perturbing_action': 'I-gene loss-of-function'}", + "89, cardiomyocytes {'context': 'B-cells'}", + "90, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "91, Dnaja3. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "60, Mice ['l0', 'l1', 'l2']", + "61, deficient ['l0', 'l3', 'l4', 'l5', 'l6']", + "62, in ['l1', 'l3', 'l7', 'l8', 'l9']", + "63, Dnaja3 ['l2', 'l4', 'l7', 'l10', 'l11']", + "89, cardiomyocytes ['l5', 'l8', 'l10', 'l12', 'l13']", + "90, lacking ['l6', 'l9', 'l11', 'l12', 'l14']", + "91, Dnaja3. ['l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Dnaja3" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Dnaja3", + "lacking", + "Dnaja3." + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes" + ] + } + } + ] + }, + { + "PMID": "16327801", + "TEXT": "Using an expression cloning strategy, we have identified TFE3, a basic helix-loop-helix protein, as a transactivator of metabolic genes that are regulated through an E-box in their promoters. Adenovirus-mediated expression of TFE3 in hepatocytes in culture and in vivo strongly activated expression of IRS-2 and Akt and enhanced phosphorylation of insulin-signaling kinases such as Akt, glycogen synthase kinase 3beta and p70S6 kinase. TFE3 also induced hexokinase II (HK2) and insulin-induced gene 1 (INSIG1). These changes led to metabolic consequences, such as activation of glycogen and protein synthesis, but not lipogenesis, in liver. Collectively, plasma glucose levels were markedly reduced both in normal mice and in different mouse models of diabetes, including streptozotocin-treated, db/db and KK mice. Promoter analyses showed that IRS2, HK2 and INSIG1 are direct targets of TFE3. Activation of insulin signals in both insulin depletion and resistance suggests that TFE3 could be a therapeutic target for diabetes.", + "TAG_DATA": [ + "28, Adenovirus-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "29, expression {'perturbing_action': 'I-gene gain-of-function'}", + "30, of {'perturbing_action': 'I-gene gain-of-function'}", + "31, TFE3 {'perturbing_action': 'I-gene gain-of-function'}", + "33, hepatocytes {'context': 'B-cells'}", + "34, in {'context': 'B-in vitro'}", + "35, culture {'context': 'I-in vitro'}", + "37, in {'context': 'B-in vivo'}", + "38, vivo {'context': 'I-in vivo'}", + "91, liver. {'context': 'B-tissue/organ'}", + "102, mice {'context': 'B-organism'}", + "106, mouse {'context': 'B-organism'}", + "107, models {'context': 'I-organism'}", + "115, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "28, Adenovirus-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "29, expression ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "30, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "31, TFE3 ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "33, hepatocytes ['l3', 'l11', 'l18', 'l24', 'l30', 'l31']", + "34, in ['l4', 'l12', 'l19', 'l25', 'l30', 'l32']", + "35, culture ['l5', 'l13', 'l20', 'l26', 'l31', 'l32']", + "37, in ['l6', 'l14', 'l21', 'l27', 'l33', 'l34']", + "38, vivo ['l7', 'l15', 'l22', 'l28', 'l33', 'l35']", + "91, liver. ['l8', 'l16', 'l23', 'l29', 'l34', 'l35']", + "106, mouse ['l36', 'l37']", + "107, models ['l36', 'l38']", + "115, mice. ['l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenovirus-mediated", + "expression", + "of", + "TFE3" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenovirus-mediated", + "expression", + "of", + "TFE3" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "culture" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenovirus-mediated", + "expression", + "of", + "TFE3" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenovirus-mediated", + "expression", + "of", + "TFE3" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver." + ] + } + } + ] + }, + { + "PMID": "16311605", + "TEXT": "HIV DNA integration is favored in active genes, but the underlying mechanism is unclear. Cellular lens epithelium-derived growth factor (LEDGF/p75) binds both chromosomal DNA and HIV integrase, and might therefore direct integration by a tethering interaction. We analyzed HIV integration in cells depleted for LEDGF/p75, and found that integration was (i) less frequent in transcription units, (ii) less frequent in genes regulated by LEDGF/p75 and (iii) more frequent in GC-rich DNA. LEDGF is thus the first example of a cellular protein controlling the location of HIV integration in human cells.", + "TAG_DATA": [ + "41, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16288282", + "TEXT": "Graft-versus-host disease (GVHD) is caused by alloreactive donor T cells that trigger host tissue injury. GVHD develops over weeks or months, but how this immune response is maintained over time is unknown. In mouse models of human GVHD, we identify a new subset of postmitotic CD44(lo)CD62L(hi)CD8(+) T cells that generate and sustain all allogeneic T-cell subsets in GVHD reactions, including central memory, effector memory and effector CD8(+) T cells, while self-renewing. These cells express Sca-1, CD122 and Bcl-2, and induce GVHD upon transfer into secondary recipients. The postmitotic CD44(lo)CD62L(hi)CD8(+) T cells persist throughout the course of GVHD, are generated in the initial phase in response to alloantigens and dendritic cells and require interleukin-15. Thus, their long life, ability to self-renew and multipotentiality define these cells as candidate memory stem cells. Memory stem cells will be important targets for understanding and influencing diverse chronic immune reactions, including GVHD.", + "TAG_DATA": [ + "108, dendritic {'context': 'B-cells'}", + "109, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "108, dendritic ['l0']", + "109, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16288280", + "TEXT": "An effective acquired immune response to infectious agents mediated by HLA-restricted T-cell recognition can target different stages of disease pathogenesis. We show here that three distinct HLA alleles known to alter the overall rate of AIDS progression act during distinct intervals after HIV-1 infection. The discrete timing of HLA allele influence suggests alternative functional mechanisms in immune defense against this dynamic and chronic immunosuppressive disease.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16286924", + "TEXT": "The IkappaB kinase complex IKK is a central component of the signaling cascade that controls NF-kappaB-dependent gene transcription. So far, its function in the brain is largely unknown. Here, we show that IKK is activated in a mouse model of stroke. To investigate the function of IKK in brain ischemia we generated mice that contain a targeted deletion of Ikbkb (which encodes IKK2) in mouse neurons and mice that express a dominant inhibitor of IKK in neurons. In both lines, inhibition of IKK activity markedly reduced infarct size. In contrast, constitutive activation of IKK2 enlarged the infarct size. A selective small-molecule inhibitor of IKK mimicked the effect of genetic IKK inhibition in neurons, reducing the infarct volume and cell death in a therapeutic time window of 4.5 h. These data indicate a key function of IKK in ischemic brain damage and suggest a potential role for IKK inhibitors in stroke therapy.", + "TAG_DATA": [ + "52, mice {'context': 'B-organism'}", + "56, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "57, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "58, of {'perturbing_action': 'I-gene loss-of-function'}", + "59, Ikbkb {'perturbing_action': 'I-gene loss-of-function'}", + "60, (which {'perturbing_action': 'I-gene loss-of-function'}", + "64, mouse {'context': 'B-cells'}", + "65, neurons {'context': 'I-cells'}", + "67, mice {'context': 'B-organism'}", + "76, neurons. {'context': 'B-cells'}", + "80, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "81, of {'perturbing_action': 'I-pharmacological inhibition'}", + "82, IKK {'perturbing_action': 'I-pharmacological inhibition'}", + "83, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "90, constitutive {'perturbing_action': 'B-gene gain-of-function'}", + "91, activation {'perturbing_action': 'I-gene gain-of-function'}", + "92, of {'perturbing_action': 'I-gene gain-of-function'}", + "93, IKK2 {'perturbing_action': 'I-gene gain-of-function'}", + "99, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "100, small-molecule {'perturbing_action': 'I-pharmacological inhibition'}", + "101, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "102, of {'perturbing_action': 'I-pharmacological inhibition'}", + "103, IKK {'perturbing_action': 'I-pharmacological inhibition'}", + "108, genetic {'perturbing_action': 'B-pharmacological inhibition'}", + "109, IKK {'perturbing_action': 'I-pharmacological inhibition'}", + "110, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "112, neurons, {'context': 'B-cells'}", + "113, reducing {'effect': 'B-negative'}", + "118, cell {'phenotype': 'B-cell death'}", + "119, death {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "52, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "56, targeted ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "57, deletion ['l0', 'l6', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "58, of ['l1', 'l7', 'l18', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "59, Ikbkb ['l2', 'l8', 'l19', 'l29', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "60, (which ['l3', 'l9', 'l20', 'l30', 'l39', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "64, mouse ['l4', 'l10', 'l21', 'l31', 'l40', 'l48', 'l56', 'l57']", + "65, neurons ['l5', 'l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l58']", + "67, mice ['l12', 'l23', 'l33', 'l42', 'l50', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "76, neurons. ['l13', 'l24', 'l34', 'l43', 'l51', 'l57', 'l58', 'l59', 'l65', 'l66', 'l67', 'l68']", + "80, inhibition ['l14', 'l25', 'l35', 'l44', 'l52', 'l60', 'l65', 'l69', 'l70', 'l71', 'l72']", + "81, of ['l15', 'l26', 'l36', 'l45', 'l53', 'l61', 'l66', 'l69', 'l73', 'l74', 'l75', 'l76']", + "82, IKK ['l16', 'l27', 'l37', 'l46', 'l54', 'l62', 'l67', 'l70', 'l73', 'l77', 'l78', 'l79']", + "83, activity ['l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l68', 'l71', 'l74', 'l77']", + "90, constitutive ['l80', 'l81', 'l82']", + "91, activation ['l80', 'l83', 'l84']", + "92, of ['l75', 'l78', 'l81', 'l83', 'l85']", + "93, IKK2 ['l64', 'l72', 'l76', 'l79', 'l82', 'l84', 'l85']", + "99, selective ['l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "100, small-molecule ['l86', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "101, inhibitor ['l87', 'l97', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "102, of ['l88', 'l98', 'l107', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "103, IKK ['l89', 'l99', 'l108', 'l116', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "108, genetic ['l90', 'l100', 'l109', 'l117', 'l124', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "109, IKK ['l91', 'l101', 'l110', 'l118', 'l125', 'l131', 'l137', 'l138', 'l139', 'l140', 'l141']", + "110, inhibition ['l92', 'l102', 'l111', 'l119', 'l126', 'l132', 'l137', 'l142', 'l143', 'l144', 'l145']", + "112, neurons, ['l93', 'l103', 'l112', 'l120', 'l127', 'l133', 'l138', 'l142', 'l146', 'l147', 'l148']", + "113, reducing ['l94', 'l104', 'l113', 'l121', 'l128', 'l134', 'l139', 'l143', 'l146', 'l149', 'l150']", + "118, cell ['l95', 'l105', 'l114', 'l122', 'l129', 'l135', 'l140', 'l144', 'l147', 'l149', 'l151']", + "119, death ['l96', 'l106', 'l115', 'l123', 'l130', 'l136', 'l141', 'l145', 'l148', 'l150', 'l151']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Ikbkb", + "(which", + "targeted" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "deletion", + "of", + "Ikbkb", + "(which" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "neurons", + "neurons." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "IKK", + "activity" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "IKK2" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neurons.", + "neurons," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "IKK", + "activity", + "selective", + "small-molecule", + "inhibitor", + "genetic" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "small-molecule", + "inhibitor", + "of", + "IKK", + "genetic", + "inhibition" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reducing" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "small-molecule", + "inhibitor", + "of", + "IKK", + "genetic", + "inhibition" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neurons," + ] + }, + "effect": { + "val": "negative", + "words": [ + "reducing" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neurons," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reducing" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + } + ] + }, + { + "PMID": "16258538", + "TEXT": "We found that platelet depletion reduces intrahepatic accumulation of virus-specific cytotoxic T lymphocytes (CTLs) and organ damage in mouse models of acute viral hepatitis. Transfusion of normal but not activation-blocked platelets in platelet-depleted mice restored accumulation of CTLs and severity of disease. In contrast, anticoagulant treatment that prevented intrahepatic fibrin deposition without reducing platelet counts did not avert liver injury. Thus, activated platelets contribute to CTL-mediated liver immunopathology independently of procoagulant function.", + "TAG_DATA": [ + "18, mouse {'context': 'B-organism'}", + "19, models {'context': 'I-organism'}", + "33, mice {'context': 'B-organism'}", + "58, liver {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "18, mouse ['l0']", + "19, models ['l0']", + "32, platelet-depleted ['l1']", + "33, mice ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16244651", + "TEXT": "Mechanisms that regulate inflammation and repair after acute lung injury are incompletely understood. The extracellular matrix glycosaminoglycan hyaluronan is produced after tissue injury and impaired clearance results in unremitting inflammation. Here we report that hyaluronan degradation products require MyD88 and both Toll-like receptor (TLR)4 and TLR2 in vitro and in vivo to initiate inflammatory responses in acute lung injury. Hyaluronan fragments isolated from serum of individuals with acute lung injury stimulated macrophage chemokine production in a TLR4- and TLR2-dependent manner. Myd88(-/-) and Tlr4(-/-)Tlr2(-/-) mice showed impaired transepithelial migration of inflammatory cells but decreased survival and enhanced epithelial cell apoptosis after lung injury. Lung epithelial cell-specific overexpression of high-molecular-mass hyaluronan was protective against acute lung injury. Furthermore, epithelial cell-surface hyaluronan was protective against apoptosis, in part, through TLR-dependent basal activation of NF-kappaB. Hyaluronan-TLR2 and hyaluronan-TLR4 interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity and promote recovery from acute lung injury.", + "TAG_DATA": [ + "80, Myd88(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "82, Tlr4(-/-)Tlr2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "83, mice {'context': 'B-organism'}", + "85, impaired {'effect': 'B-negative'}", + "87, migration {'phenotype': 'B-migration'}", + "89, inflammatory {'context': 'B-cells'}", + "90, cells {'context': 'I-cells'}", + "95, enhanced {'effect': 'B-positive'}", + "96, epithelial {'context': 'B-cells'}", + "97, cell {'context': 'I-cells'}", + "98, apoptosis {'phenotype': 'B-apoptosis'}", + "102, Lung {'perturbing_action': 'B-gene gain-of-function'}", + "103, epithelial {'perturbing_action': 'I-gene gain-of-function'}", + "104, cell-specific {'perturbing_action': 'I-gene gain-of-function'}", + "105, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "106, of {'perturbing_action': 'I-gene gain-of-function'}", + "107, high-molecular-mass {'perturbing_action': 'I-gene gain-of-function'}", + "108, hyaluronan {'perturbing_action': 'I-gene gain-of-function'}", + "120, protective {'effect': 'B-negative'}", + "121, against {'effect': 'I-negative'}", + "122, apoptosis, {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "80, Myd88(-/-) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "82, Tlr4(-/-)Tlr2(-/-) ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "83, mice ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "85, impaired ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "87, migration ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36']", + "89, inflammatory ['l4', 'l13', 'l21', 'l28', 'l34', 'l37', 'l38', 'l39']", + "90, cells ['l5', 'l14', 'l22', 'l29', 'l35', 'l37', 'l40']", + "95, enhanced ['l6', 'l15', 'l23', 'l30', 'l38', 'l41', 'l42', 'l43']", + "96, epithelial ['l7', 'l16', 'l24', 'l31', 'l41', 'l44', 'l45']", + "97, cell ['l8', 'l17', 'l25', 'l32', 'l36', 'l39', 'l40', 'l42', 'l44', 'l46']", + "98, apoptosis ['l9', 'l18', 'l26', 'l33', 'l43', 'l45', 'l46']", + "102, Lung ['l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "103, epithelial ['l47', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "104, cell-specific ['l48', 'l56', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "105, overexpression ['l49', 'l57', 'l64', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "106, of ['l50', 'l58', 'l65', 'l71', 'l77', 'l78', 'l79', 'l80', 'l81']", + "107, high-molecular-mass ['l51', 'l59', 'l66', 'l72', 'l77', 'l82', 'l83', 'l84', 'l85']", + "108, hyaluronan ['l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l86', 'l87', 'l88']", + "120, protective ['l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l89', 'l90']", + "121, against ['l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l91']", + "122, apoptosis, ['l55', 'l63', 'l70', 'l76', 'l81', 'l85', 'l88', 'l90', 'l91']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Myd88(-/-)", + "Tlr4(-/-)Tlr2(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Myd88(-/-)", + "Tlr4(-/-)Tlr2(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Myd88(-/-)", + "Tlr4(-/-)Tlr2(-/-)" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Myd88(-/-)", + "Tlr4(-/-)Tlr2(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "inflammatory", + "cells", + "epithelial", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Myd88(-/-)", + "Tlr4(-/-)Tlr2(-/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Myd88(-/-)", + "Tlr4(-/-)Tlr2(-/-)" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "cells", + "words": [ + "inflammatory", + "cells", + "epithelial", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired", + "protective", + "against" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis," + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "cells", + "words": [ + "inflammatory", + "cells", + "cell" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "inflammatory", + "epithelial", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "epithelial", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Lung", + "epithelial", + "cell-specific", + "overexpression", + "of", + "high-molecular-mass", + "hyaluronan" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protective", + "against" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Lung", + "epithelial", + "cell-specific", + "overexpression", + "of", + "high-molecular-mass", + "hyaluronan" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + } + ] + }, + { + "PMID": "16227993", + "TEXT": "During development, activation of Cl(-)-permeable GABA(A) receptors (GABA(A)-R) excites neurons as a result of elevated intracellular Cl(-) levels and a depolarized Cl(-) equilibrium potential (E(Cl)). GABA becomes inhibitory as net outward neuronal transport of Cl(-) develops in a caudal-rostral progression. In line with this caudal-rostral developmental pattern, GABAergic anticonvulsant compounds inhibit motor manifestations of neonatal seizures but not cortical seizure activity. The Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) facilitates the accumulation of Cl(-) in neurons. The NKCC1 blocker bumetanide shifted E(Cl) negative in immature neurons, suppressed epileptiform activity in hippocampal slices in vitro and attenuated electrographic seizures in neonatal rats in vivo. Bumetanide had no effect in the presence of the GABA(A)-R antagonist bicuculline, nor in brain slices from NKCC1-knockout mice. NKCC1 expression level versus expression of the Cl(-)-extruding transporter (KCC2) in human and rat cortex showed that Cl(-) transport in perinatal human cortex is as immature as in the rat. Our results provide evidence that NKCC1 facilitates seizures in the developing brain and indicate that bumetanide should be useful in the treatment of neonatal seizures.", + "TAG_DATA": [ + "73, NKCC1 {'perturbing_action': 'B-pharmacological inhibition'}", + "74, blocker {'perturbing_action': 'I-pharmacological inhibition'}", + "75, bumetanide {'perturbing_action': 'I-pharmacological inhibition'}", + "80, immature {'context': 'B-cells'}", + "81, neurons, {'context': 'I-cells'}", + "86, hippocampal {'context': 'B-cells'}", + "87, slices {'context': 'I-cells'}", + "88, in {'context': 'B-in vitro'}", + "89, vitro {'context': 'I-in vitro'}", + "95, neonatal {'context': 'B-organism'}", + "96, rats {'context': 'I-organism'}", + "97, in {'context': 'B-in vivo'}", + "98, vivo. {'context': 'I-in vivo'}", + "113, brain {'context': 'B-tissue/organ'}", + "114, slices {'context': 'I-tissue/organ'}", + "116, NKCC1-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "117, mice. {'context': 'B-organism'}", + "129, human {'context': 'B-tissue/organ'}", + "130, and {'context': 'I-tissue/organ'}", + "131, rat {'context': 'I-tissue/organ'}", + "132, cortex {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "73, NKCC1 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "74, blocker ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "75, bumetanide ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "80, immature ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "81, neurons, ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46']", + "86, hippocampal ['l4', 'l15', 'l25', 'l34', 'l42', 'l47', 'l48', 'l49', 'l50', 'l51']", + "87, slices ['l5', 'l16', 'l26', 'l35', 'l43', 'l47', 'l52', 'l53', 'l54']", + "88, in ['l6', 'l17', 'l27', 'l36', 'l44', 'l48', 'l52', 'l55', 'l56']", + "89, vitro ['l7', 'l18', 'l28', 'l37', 'l45', 'l49', 'l53', 'l55', 'l57']", + "95, neonatal ['l8', 'l19', 'l29', 'l38', 'l58', 'l59', 'l60']", + "96, rats ['l9', 'l20', 'l30', 'l39', 'l46', 'l50', 'l54', 'l56', 'l57', 'l58', 'l61', 'l62']", + "97, in ['l10', 'l21', 'l31', 'l40', 'l59', 'l61', 'l63']", + "98, vivo. ['l11', 'l22', 'l32', 'l41', 'l51', 'l60', 'l62', 'l63']", + "113, brain ['l64', 'l65', 'l66']", + "114, slices ['l64', 'l67', 'l68']", + "116, NKCC1-knockout ['l65', 'l67', 'l69', 'l70', 'l71', 'l72', 'l73']", + "117, mice. ['l66', 'l68', 'l69', 'l74', 'l75', 'l76', 'l77']", + "129, human ['l70', 'l74', 'l78', 'l79', 'l80']", + "130, and ['l71', 'l75', 'l78', 'l81', 'l82']", + "131, rat ['l72', 'l76', 'l79', 'l81', 'l83']", + "132, cortex ['l73', 'l77', 'l80', 'l82', 'l83']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NKCC1", + "blocker", + "bumetanide" + ] + }, + "context": { + "val": "cells", + "words": [ + "immature", + "neurons,", + "hippocampal", + "slices" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NKCC1", + "blocker", + "bumetanide" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NKCC1", + "blocker", + "bumetanide" + ] + }, + "context": { + "val": "organism", + "words": [ + "neonatal", + "rats" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NKCC1", + "blocker", + "bumetanide" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "brain", + "slices", + "human", + "and", + "rat", + "cortex" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NKCC1-knockout" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NKCC1-knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "16227991", + "TEXT": "Graft-versus-leukemia (GVL) response after allogeneic bone marrow transplantation (BMT) represents one of the most potent forms of immunotherapy against malignant diseases. Antigen-presenting cells (APCs) are crucial for the induction of graft-versus-host disease (GVHD), the most serious complication of allogeneic BMT, but their role in GVL responses is unclear. Using a series of clinically relevant mouse GVL tumor models, we found that APCs and alloantigen expression on tumors are crucial for GVL. Moreover, APCs of host origin predominated in GVL responses although donor APCs contributed as the acuity of tumor burden decreased.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16227988", + "TEXT": "CD4(+)CD25(+) regulatory T (T(reg)) cells have a crucial role in maintaining immune tolerance. Mice and humans born lacking T(reg) cells develop severe autoimmune disease, and depletion of T(reg) cells in lymphopenic mice induces autoimmunity. Interleukin (IL)-2 signaling is required for thymic development, peripheral expansion and suppressive activity of T(reg) cells. Animals lacking IL-2 die of autoimmunity, which is prevented by administration of IL-2-responsive T(reg) cells. In light of the emerging evidence that one of the primary physiologic roles of IL-2 is to generate and maintain T(reg) cells, the question arises as to the effects of IL-2 therapy on them. We monitored T(reg) cells during immune reconstitution in individuals with cancer who did or did not receive IL-2 therapy. CD4(+)CD25(hi) cells underwent homeostatic peripheral expansion during immune reconstitution, and in lymphopenic individuals receiving IL-2, the T(reg) cell compartment was markedly increased. Mouse studies showed that IL-2 therapy induced expansion of existent T(reg) cells in normal hosts, and IL-2-induced T(reg) cell expansion was further augmented by lymphopenia. On a per-cell basis, T(reg) cells generated by IL-2 therapy expressed similar levels of FOXP3 and had similar potency for suppression compared to T(reg) cells present in normal hosts. These studies suggest that IL-2 and lymphopenia are primary modulators of CD4(+)CD25(+) T(reg) cell homeostasis.", + "TAG_DATA": [ + "118, CD4(+)CD25(hi) {'context': 'B-cells'}", + "119, cells {'context': 'I-cells'}", + "140, Mouse {'context': 'B-organism'}", + "150, T(reg) {'context': 'B-cells'}", + "151, cells {'context': 'I-cells'}", + "157, T(reg) {'context': 'B-cells'}", + "158, cell {'context': 'I-cells'}", + "169, T(reg) {'context': 'B-cells'}", + "170, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "118, CD4(+)CD25(hi) ['l0', 'l1', 'l2', 'l3']", + "119, cells ['l0', 'l4']", + "140, Mouse ['l1', 'l5', 'l6']", + "150, T(reg) ['l2', 'l5', 'l7']", + "151, cells ['l3', 'l4', 'l6', 'l7']", + "157, T(reg) ['l8']", + "158, cell ['l8']", + "169, T(reg) ['l9']", + "170, cells ['l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16205738", + "TEXT": "We assessed the efficacy and safety of 10-d monotherapy with the orally administered CCR5 antagonist maraviroc in 63 HIV-1-positive individuals prescreened for the absence of CXCR4-using virus. Maximum reduction in viral load occurred at a median of 10-15 d, with a mean reduction of >or=1.6 log(10) copies/ml at all twice daily doses >or=100 mg. These results provide proof of concept that CCR5 antagonism is a viable antiretroviral therapeutic approach.", + "TAG_DATA": [ + "18, HIV-1-positive {'context': 'B-organism'}", + "19, individuals {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "18, HIV-1-positive ['l0']", + "19, individuals ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16186818", + "TEXT": "The direct assessment of T helper (T(H))-cell responses specific for antigens is essential to evaluate pathogenic and protective immunity. Presently, analysis and isolation of antigen-specific T(H) cells is restricted to cells that produce cytokines, or can be performed only with a rare selection of specific peptide major histocompatibility complex class II (MHC II) multimers. Here we report a new method that enables the assessment and isolation of T(H) cells specific for a defined antigen according to CD154 expression induced after stimulation in vitro. We show that antigen-induced CD154 expression is highly sensitive and specific for human and mouse antigen-specific T(H) cells. Moreover, the isolation of antigen-specific CD154(+) T(H) cells necessitates only surface staining with antibodies, thereby enabling the fast generation of antigen-specific T(H) cell lines. Our approach allows assessment of T(H) cells with a defined specificity for the combined quantitative and qualitative analysis of T(H)-cell immunity as well as for the isolation of specific T(H) cells for targeted cellular immunotherapies.", + "TAG_DATA": [ + "81, in {'context': 'B-in vitro'}", + "82, vitro. {'context': 'I-in vitro'}", + "95, human {'context': 'B-cells'}", + "96, and {'context': 'I-cells'}", + "97, mouse {'context': 'I-cells'}", + "98, antigen-specific {'context': 'I-cells'}", + "99, T(H) {'context': 'I-cells'}", + "100, cells. {'context': 'I-cells'}", + "107, T(H) {'context': 'I-cells'}", + "108, cells {'context': 'I-cells'}", + "122, T(H) {'context': 'I-cells'}", + "123, cell {'context': 'I-cells'}", + "124, lines. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "81, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "82, vitro. ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "95, human ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "96, and ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "97, mouse ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "98, antigen-specific ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "99, T(H) ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "100, cells. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "107, T(H) ['l28', 'l29', 'l30', 'l31', 'l32']", + "108, cells ['l28', 'l33', 'l34']", + "121, antigen-specific ['l29', 'l35', 'l36', 'l37']", + "122, T(H) ['l30', 'l35', 'l38', 'l39']", + "123, cell ['l31', 'l33', 'l36', 'l38', 'l40']", + "124, lines. ['l32', 'l34', 'l37', 'l39', 'l40']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16155576", + "TEXT": "Tight glycemic control in individuals with diabetes mellitus is essential to prevent or delay its complications. Present treatments to reduce hyperglycemia mainly target the ATP-sensitive K(+) (K(ATP)) channel of pancreatic beta cells to increase insulin secretion. These current approaches are often associated with the side effect of hypoglycemia. Here we show that inhibition of the activity of cyclin-dependent kinase 5 (Cdk5) enhanced insulin secretion under conditions of stimulation by high glucose but not low glucose in MIN6 cells and pancreatic islets. The role of Cdk5 in regulation of insulin secretion was confirmed in pancreatic beta cells deficient in p35, an activator of Cdk5. p35-knockout mice also showed enhanced insulin secretion in response to a glucose challenge. Cdk5 kinase inhibition enhanced the inward whole-cell Ca(2+) channel current and increased Ca(2+) influx across the L-type voltage-dependent Ca(2+) channel (L-VDCC) upon stimulation with high glucose in beta cells, but had no effect on Ca(2+) influx without glucose stimulation. The inhibitory regulation by Cdk5 on the L-VDCC was attributed to the phosphorylation of loop II-III of the alpha(1C) subunit of L-VDCC at Ser783, which prevented the binding to SNARE proteins and subsequently resulted in a decrease of the activity of L-VDCC. These results suggest that Cdk5/p35 may be a drug target for the regulation of glucose-stimulated insulin secretion.", + "TAG_DATA": [ + "52, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "53, of {'perturbing_action': 'I-pharmacological inhibition'}", + "54, the {'perturbing_action': 'I-pharmacological inhibition'}", + "55, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "56, of {'perturbing_action': 'I-pharmacological inhibition'}", + "57, cyclin-dependent {'perturbing_action': 'I-pharmacological inhibition'}", + "58, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "59, 5 {'perturbing_action': 'I-pharmacological inhibition'}", + "60, (Cdk5) {'perturbing_action': 'I-pharmacological inhibition'}", + "76, MIN6 {'context': 'B-cells'}", + "77, cells {'context': 'I-cells'}", + "79, pancreatic {'context': 'B-cells'}", + "80, islets. {'context': 'I-cells'}", + "93, pancreatic {'context': 'B-cells'}", + "94, beta {'context': 'I-cells'}", + "95, cells {'context': 'I-cells'}", + "96, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "97, in {'perturbing_action': 'I-gene loss-of-function'}", + "98, p35, {'perturbing_action': 'I-gene loss-of-function'}", + "99, an {'perturbing_action': 'I-pharmacological inhibition'}", + "100, activator {'perturbing_action': 'I-pharmacological augmentation'}", + "101, of {'perturbing_action': 'I-pharmacological inhibition'}", + "102, Cdk5. {'perturbing_action': 'I-pharmacological augmentation'}", + "103, p35-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "104, mice {'context': 'B-organism'}", + "116, Cdk5 {'perturbing_action': 'B-pharmacological inhibition'}", + "117, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "118, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "143, beta {'context': 'B-cells'}", + "144, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "52, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "53, of ['l0', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "54, the ['l1', 'l18', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "55, activity ['l2', 'l19', 'l35', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "56, of ['l3', 'l20', 'l36', 'l51', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "57, cyclin-dependent ['l4', 'l21', 'l37', 'l52', 'l66', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "58, kinase ['l5', 'l22', 'l38', 'l53', 'l67', 'l80', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "59, 5 ['l6', 'l23', 'l39', 'l54', 'l68', 'l81', 'l93', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "60, (Cdk5) ['l7', 'l24', 'l40', 'l55', 'l69', 'l82', 'l94', 'l105', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "76, MIN6 ['l8', 'l25', 'l41', 'l56', 'l70', 'l83', 'l95', 'l106', 'l116', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "77, cells ['l9', 'l26', 'l42', 'l57', 'l71', 'l84', 'l96', 'l107', 'l117', 'l126', 'l132', 'l133', 'l134', 'l135', 'l136']", + "79, pancreatic ['l10', 'l27', 'l43', 'l58', 'l72', 'l85', 'l97', 'l108', 'l118', 'l127', 'l132', 'l137', 'l138', 'l139', 'l140', 'l141']", + "80, islets. ['l11', 'l28', 'l44', 'l59', 'l73', 'l86', 'l98', 'l109', 'l119', 'l128', 'l133', 'l137', 'l142', 'l143', 'l144', 'l145']", + "93, pancreatic ['l12', 'l29', 'l45', 'l60', 'l74', 'l87', 'l99', 'l110', 'l120', 'l129', 'l134', 'l138', 'l142', 'l146', 'l147', 'l148', 'l149', 'l150']", + "94, beta ['l13', 'l30', 'l46', 'l61', 'l75', 'l88', 'l100', 'l111', 'l121', 'l130', 'l135', 'l139', 'l143', 'l146', 'l151', 'l152']", + "95, cells ['l14', 'l31', 'l47', 'l62', 'l76', 'l89', 'l101', 'l112', 'l122', 'l131', 'l136', 'l140', 'l144', 'l147', 'l151', 'l153']", + "96, deficient ['l15', 'l32', 'l48', 'l63', 'l77', 'l90', 'l102', 'l113', 'l123', 'l141', 'l145', 'l148', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160']", + "97, in ['l16', 'l33', 'l49', 'l64', 'l78', 'l91', 'l103', 'l114', 'l124', 'l149', 'l154', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "98, p35, ['l17', 'l34', 'l50', 'l65', 'l79', 'l92', 'l104', 'l115', 'l125', 'l150', 'l155', 'l161', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "99, an ['l156', 'l162', 'l168', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180']", + "100, activator ['l157', 'l163', 'l169', 'l174', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186']", + "101, of ['l158', 'l164', 'l170', 'l175', 'l181', 'l187', 'l188', 'l189', 'l190', 'l191']", + "102, Cdk5. ['l159', 'l165', 'l171', 'l176', 'l182', 'l187', 'l192', 'l193', 'l194', 'l195']", + "103, p35-knockout ['l166', 'l172', 'l177', 'l183', 'l188', 'l192', 'l196', 'l197', 'l198']", + "104, mice ['l160', 'l167', 'l173', 'l178', 'l184', 'l189', 'l193', 'l196']", + "116, Cdk5 ['l199', 'l200', 'l201', 'l202']", + "117, kinase ['l199', 'l203', 'l204', 'l205']", + "118, inhibition ['l200', 'l203', 'l206', 'l207']", + "143, beta ['l179', 'l185', 'l190', 'l194', 'l197', 'l201', 'l204', 'l206', 'l208']", + "144, cells, ['l180', 'l186', 'l191', 'l195', 'l198', 'l202', 'l205', 'l207', 'l208']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "the", + "activity", + "cyclin-dependent", + "kinase", + "5", + "(Cdk5)", + "an", + "Cdk5" + ] + }, + "context": { + "val": "cells", + "words": [ + "MIN6", + "cells", + "pancreatic", + "islets.", + "beta", + "cells," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pancreatic", + "islets.", + "beta", + "cells", + "cells," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "p35,", + "p35-knockout" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "p35,", + "p35-knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "an", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activator", + "Cdk5." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activator", + "Cdk5." + ] + }, + "context": { + "val": "cells", + "words": [ + "beta", + "cells," + ] + } + } + ] + }, + { + "PMID": "16145568", + "TEXT": "Neurons in the brain of individuals with focal epilepsy exhibit sustained discharges, called paroxysmal depolarization shifts. Unexpected new evidence indicates that glutamate release from glia can generate these events, and may serve to synchronize the activity of neurons.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16127435", + "TEXT": "Systemic lupus erythematosus (SLE) is a chronic inflammatory disease generated by deregulation of T cell-mediated B-cell activation, which results in glomerulonephritis and renal failure. Disease is treated with immunosuppressants and cytostatic agents that have numerous side effects. Here we examine the use of inhibitors of phosphoinositide 3-kinase (PI3K) gamma, a lipid kinase that regulates inflammation, in the MRL-lpr mouse model of SLE. Treatment reduced glomerulonephritis and prolonged lifespan, suggesting that P13Kgamma may be a useful target in the treatment of chronic inflammation.", + "TAG_DATA": [ + "43, inhibitors {'perturbing_action': 'B-pharmacological inhibition'}", + "44, of {'perturbing_action': 'I-pharmacological inhibition'}", + "45, phosphoinositide {'perturbing_action': 'I-pharmacological inhibition'}", + "46, 3-kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "47, (PI3K) {'perturbing_action': 'I-pharmacological inhibition'}", + "48, gamma, {'perturbing_action': 'I-pharmacological inhibition'}", + "57, MRL-lpr {'perturbing_action': 'B-other', 'context': 'B-organism'}", + "58, mouse {'context': 'I-organism'}", + "59, model {'context': 'I-organism'}", + "60, of {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "43, inhibitors ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "44, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "45, phosphoinositide ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "46, 3-kinase ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "47, (PI3K) ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "48, gamma, ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "57, MRL-lpr ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "58, mouse ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "59, model ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "60, of ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "phosphoinositide", + "3-kinase", + "(PI3K)", + "gamma," + ] + }, + "context": { + "val": "organism", + "words": [ + "MRL-lpr", + "mouse", + "model", + "of" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "MRL-lpr" + ] + }, + "context": { + "val": "organism", + "words": [ + "MRL-lpr" + ] + } + } + ] + }, + { + "PMID": "16116432", + "TEXT": "Development of therapeutic agents for severe acute respiratory syndrome (SARS) viral infection using short interfering RNA (siRNA) inhibitors exemplifies a powerful new means to combat emerging infectious diseases. Potent siRNA inhibitors of SARS coronavirus (SCV) in vitro were further evaluated for efficacy and safety in a rhesus macaque (Macaca mulatta) SARS model using clinically viable delivery while comparing three dosing regimens. Observations of SARS-like symptoms, measurements of SCV RNA presence and lung histopathology and immunohistochemistry consistently showed siRNA-mediated anti-SARS efficacy by either prophylactic or therapeutic regimens. The siRNAs used provided relief from SCV infection-induced fever, diminished SCV viral levels and reduced acute diffuse alveoli damage. The 10-40 mg/kg accumulated dosages of siRNA did not show any sign of siRNA-induced toxicity. These results suggest that a clinical investigation is warranted and illustrate the prospects for siRNA to enable a massive reduction in development time for new targeted therapeutic agents.", + "TAG_DATA": [ + "29, siRNA {'perturbing_action': 'I-rnai/knockdown'}", + "30, inhibitors {'perturbing_action': 'I-rnai/knockdown'}", + "31, of {'perturbing_action': 'I-rnai/knockdown'}", + "32, SARS {'perturbing_action': 'I-rnai/knockdown'}", + "33, coronavirus {'perturbing_action': 'I-rnai/knockdown'}", + "34, (SCV) {'perturbing_action': 'I-rnai/knockdown'}", + "35, in {'context': 'B-in vitro'}", + "36, vitro {'context': 'B-in vitro'}", + "46, rhesus {'context': 'B-organism'}", + "47, macaque {'context': 'I-organism'}", + "48, (Macaca {'context': 'I-organism'}", + "49, mulatta) {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "29, siRNA ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "30, inhibitors ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "31, of ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "32, SARS ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "33, coronavirus ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "34, (SCV) ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "35, in ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "36, vitro ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "46, rhesus ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "47, macaque ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "48, (Macaca ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "49, mulatta) ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA", + "inhibitors", + "of", + "SARS", + "coronavirus", + "(SCV)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA", + "inhibitors", + "of", + "SARS", + "coronavirus", + "(SCV)" + ] + }, + "context": { + "val": "organism", + "words": [ + "rhesus", + "macaque", + "(Macaca", + "mulatta)" + ] + } + } + ] + }, + { + "PMID": "16116429", + "TEXT": "The role of B cells in T-cell priming is unclear, and the effects of B-cell depletion on immune responses to cancer vaccines are unknown. Although results from some mouse models suggest that B cells may inhibit induction of T cell-dependent immunity by competing with antigen-presenting cells for antigens, skewing T helper response toward a T helper 2 profile and/or inducing T-cell tolerance, results from others suggest that B cells are necessary for priming as well as generation of T-cell memory. We assessed immune responses to a well-characterized idiotype vaccine in individuals with severe B-cell depletion but normal T cells after CD20-specific antibody-based chemotherapy of mantle cell lymphoma in first remission. Humoral antigen- and tumor-specific responses were detectable but delayed, and they correlated with peripheral blood B-cell recovery. In contrast, vigorous CD4(+) and CD8(+) antitumor type I T-cell cytokine responses were induced in most individuals in the absence of circulating B cells. Analysis of relapsing tumors showed no mutations or change in expression of target antigen to explain escape from therapy. These results show that severe B-cell depletion does not impair T-cell priming in humans. Based on these results, it is justifiable to administer vaccines in the setting of B-cell depletion; however, vaccine boosts after B-cell recovery may be necessary for optimal humoral responses.", + "TAG_DATA": [ + "97, T {'context': 'B-cells'}", + "98, cells {'context': 'B-cells'}", + "104, mantle {'context': 'B-neoplasm'}", + "105, cell {'context': 'I-neoplasm'}", + "106, lymphoma {'context': 'I-neoplasm'}", + "148, circulating {'context': 'B-cells'}", + "149, B {'context': 'I-cells'}", + "150, cells. {'context': 'I-cells'}", + "153, relapsing {'context': 'B-neoplasm'}", + "154, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "97, T ['l0', 'l1', 'l2', 'l3']", + "98, cells ['l0', 'l4', 'l5', 'l6']", + "104, mantle ['l1', 'l4', 'l7', 'l8']", + "105, cell ['l2', 'l5', 'l7', 'l9']", + "106, lymphoma ['l3', 'l6', 'l8', 'l9']", + "148, circulating ['l10', 'l11']", + "149, B ['l10', 'l12']", + "150, cells. ['l11', 'l12']", + "153, relapsing ['l13']", + "154, tumors ['l13']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16041384", + "TEXT": "Immunosuppressants are crucial in the prevention of detrimental immune reactions associated with allogenic organ transplantation, but they often cause adverse effects in a number of biological systems, including the skeletal system. Calcineurin inhibitors FK506 and cyclosporin A inhibit nuclear factor of activated T cells (NFAT) activity and induce strong immunosuppression. Among NFAT proteins, NFATc1 is crucial for the differentiation of bone-resorbing osteoclasts. Here we show FK506 administration induces the reduction of bone mass despite a blockade of osteoclast differentiation. This reduction is caused by severe impairment of bone formation, suggesting that NFAT transcription factors also have an important role in the transcriptional program of osteoblasts. In fact, bone formation is inhibited in Nfatc1- and Nfatc2-deficient cells as well as in FK506-treated osteoblasts. Overexpression of NFATc1 stimulates Osterix-dependent activation of the Col1a1 (encoding type I collagen) promoter, but not Runx2-dependent activation of the Bglap1 (encoding osteocalcin) promoter. NFAT and Osterix form a complex that binds to DNA, and this interaction is important for the transcriptional activity of Osterix. Thus, NFAT and Osterix cooperatively control osteoblastic bone formation. These results may provide important insight into the management of post-transplantation osteoporosis as well as a new strategy for promoting bone regeneration in osteopenic disease.", + "TAG_DATA": [ + "75, blockade {'effect': 'B-negative'}", + "77, osteoclast {'context': 'B-cells'}", + "78, differentiation. {'phenotype': 'B-differentiation'}", + "107, bone {'phenotype': 'B-tumourigenesis'}", + "108, formation {'phenotype': 'I-tumourigenesis'}", + "110, inhibited {'effect': 'B-negative'}", + "112, Nfatc1- {'perturbing_action': 'B-gene loss-of-function'}", + "113, and {'perturbing_action': 'I-gene loss-of-function'}", + "114, Nfatc2-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "115, cells {'context': 'B-cells'}", + "121, osteoblasts. {'context': 'B-cells'}", + "122, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "123, of {'perturbing_action': 'I-gene gain-of-function'}", + "124, NFATc1 {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "75, blockade ['l0', 'l1', 'l2', 'l3']", + "77, osteoclast ['l0', 'l4', 'l5', 'l6']", + "78, differentiation. ['l1', 'l4']", + "107, bone ['l2', 'l5', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "108, formation ['l3', 'l6', 'l7', 'l13', 'l14', 'l15', 'l16']", + "110, inhibited ['l8', 'l13', 'l17', 'l18', 'l19', 'l20']", + "112, Nfatc1- ['l9', 'l14', 'l17', 'l21', 'l22', 'l23', 'l24']", + "113, and ['l10', 'l15', 'l18', 'l21', 'l25', 'l26', 'l27']", + "114, Nfatc2-deficient ['l11', 'l19', 'l22', 'l25', 'l28', 'l29']", + "115, cells ['l12', 'l16', 'l20', 'l23', 'l26', 'l28']", + "121, osteoblasts. ['l24', 'l27', 'l29']", + "122, Overexpression ['l30', 'l31']", + "123, of ['l30', 'l32']", + "124, NFATc1 ['l31', 'l32']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "blockade", + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blockade" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blockade", + "inhibited" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "bone", + "formation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoclast", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "bone", + "formation" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "bone", + "formation" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nfatc1-", + "and", + "Nfatc2-deficient" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nfatc1-", + "and", + "Nfatc2-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nfatc1-", + "and", + "Nfatc2-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "osteoblasts." + ] + } + } + ] + }, + { + "PMID": "16041383", + "TEXT": "Mechanisms of progression of chronic renal diseases, a major healthcare burden, are poorly understood. Angiotensin II (AngII), the major renin-angiotensin system effector, is known to be involved in renal deterioration, but the molecular pathways are still unknown. Here, we show that mice overexpressing a dominant negative isoform of epidermal growth factor receptor (EGFR) were protected from renal lesions during chronic AngII infusion. Transforming growth factor-alpha (TGF-alpha) and its sheddase, TACE (also known as ADAM17), were induced by AngII treatment, TACE was redistributed to apical membranes and EGFR was phosphorylated. AngII-induced lesions were substantially reduced in mice lacking TGF-alpha or in mice given a specific TACE inhibitor. Pharmacologic inhibition of AngII prevented TGF-alpha and TACE accumulation as well as renal lesions after nephron reduction. These findings indicate a crucial role for AngII-dependent EGFR transactivation in renal deterioration and identify in TACE inhibitors a new therapeutic strategy for preventing progression of chronic renal diseases.", + "TAG_DATA": [ + "41, mice {'context': 'B-organism'}", + "42, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "43, a {'perturbing_action': 'I-gene gain-of-function'}", + "44, dominant {'perturbing_action': 'I-gene gain-of-function'}", + "45, negative {'perturbing_action': 'I-gene gain-of-function'}", + "46, isoform {'perturbing_action': 'I-gene gain-of-function'}", + "47, of {'perturbing_action': 'I-gene gain-of-function'}", + "48, epidermal {'perturbing_action': 'I-gene gain-of-function'}", + "49, growth {'perturbing_action': 'I-gene gain-of-function'}", + "50, factor {'perturbing_action': 'I-gene gain-of-function'}", + "51, receptor {'perturbing_action': 'I-gene gain-of-function'}", + "52, (EGFR) {'perturbing_action': 'I-gene gain-of-function'}", + "95, mice {'context': 'B-organism'}", + "96, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "97, TGF-alpha {'perturbing_action': 'I-gene loss-of-function'}", + "100, mice {'context': 'B-organism'}", + "103, specific {'perturbing_action': 'B-pharmacological inhibition'}", + "104, TACE {'perturbing_action': 'I-pharmacological inhibition'}", + "105, inhibitor. {'perturbing_action': 'I-pharmacological inhibition'}", + "106, Pharmacologic {'perturbing_action': 'B-pharmacological inhibition'}", + "107, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "108, of {'perturbing_action': 'I-pharmacological inhibition'}", + "109, AngII {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "41, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "42, overexpressing ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "43, a ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "44, dominant ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "45, negative ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "46, isoform ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "47, of ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "48, epidermal ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "49, growth ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "50, factor ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "51, receptor ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "52, (EGFR) ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "95, mice ['l66', 'l67']", + "96, lacking ['l66', 'l68']", + "97, TGF-alpha ['l67', 'l68', 'l69']", + "100, mice ['l69', 'l70', 'l71', 'l72']", + "103, specific ['l70', 'l73', 'l74']", + "104, TACE ['l71', 'l73', 'l75']", + "105, inhibitor. ['l72', 'l74', 'l75']", + "106, Pharmacologic ['l76', 'l77', 'l78']", + "107, inhibition ['l76', 'l79', 'l80']", + "108, of ['l77', 'l79', 'l81']", + "109, AngII ['l78', 'l80', 'l81']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "a", + "dominant", + "negative", + "isoform", + "of", + "epidermal", + "growth", + "factor", + "receptor", + "(EGFR)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "TGF-alpha" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "TACE", + "inhibitor." + ] + } + } + ] + }, + { + "PMID": "16041381", + "TEXT": "The latent transcription factor Stat3 is activated by gp130, the common receptor for the interleukin (IL)-6 cytokine family and other growth factor and cytokine receptors. Ligand-induced dimerization of gp130 leads to activation of the Stat1, Stat3 and Shp2-Ras-Erk signaling pathways. Here we assess genetically the contribution of exaggerated Stat3 activation to the phenotype of gp130 (Y757F/Y757F) mice, in which a knock-in mutation disrupts the negative feedback mechanism on gp130-dependent Stat signaling. Compared to gp130 (Y757F/Y757F) mice, reduced Stat3 activation in gp130 (Y757F/Y757F) Stat3(+/-) mice increased their lifespan, prevented splenomegaly, normalized exaggerated hepatic acute-phase response and lymphocyte trafficking, and suppressed the growth of spontaneously arising gastric adenomas in young mice. These lesions share histological features of gastric polyps in aging mice with monoallelic null mutations in Smad4, which encodes the common transducer for transforming growth factor (TGF)-beta signaling. Indeed, hyperactivation of Stat3 desensitizes gp130 (Y757F/Y757F) cells to the cytostatic effect of TGF-beta through transcriptional induction of inhibitory Smad7, thereby providing a novel link for cross-talk between Stat and Smad signaling in gastric homeostasis.", + "TAG_DATA": [ + "80, gp130 {'perturbing_action': 'B-other'}", + "81, (Y757F/Y757F) {'perturbing_action': 'B-other'}", + "82, Stat3(+/-) {'perturbing_action': 'B-other'}", + "83, mice {'context': 'B-organism'}", + "95, lymphocyte {'context': 'B-cells'}", + "104, gastric {'context': 'B-neoplasm'}", + "105, adenomas {'context': 'I-neoplasm'}", + "107, young {'context': 'B-organism'}", + "108, mice. {'context': 'I-organism'}", + "142, gp130 {'context': 'B-cells'}", + "144, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "80, gp130 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "81, (Y757F/Y757F) ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "82, Stat3(+/-) ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "83, mice ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "95, lymphocyte ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28']", + "104, gastric ['l4', 'l11', 'l17', 'l22', 'l29', 'l30', 'l31']", + "105, adenomas ['l5', 'l12', 'l18', 'l23', 'l26', 'l29', 'l32', 'l33']", + "107, young ['l6', 'l13', 'l19', 'l24', 'l27', 'l30', 'l32', 'l34']", + "108, mice. ['l7', 'l14', 'l20', 'l25', 'l28', 'l31', 'l33', 'l34']", + "142, gp130 ['l35']", + "144, cells ['l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "gp130", + "(Y757F/Y757F)", + "Stat3(+/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "young", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "gp130", + "(Y757F/Y757F)", + "Stat3(+/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "lymphocyte" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "gp130", + "(Y757F/Y757F)", + "Stat3(+/-)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "gastric", + "adenomas" + ] + } + } + ] + }, + { + "PMID": "16025126", + "TEXT": "Hypertrophy represents the major physiological response of the heart to adapt to chronically enhanced workload, but is also crucial in the development of heart failure. Although we know of numerous inducers of cardiac hypertrophy, little is known about mechanisms that limit cardiac hypertrophy. Here, we describe the transcriptional repressor NAB1 as an endogenous regulator of cardiac growth. We identified NAB1 as being upregulated in both mouse and human heart failure. Nab1 is highly expressed in mammalian cardiac myocytes and it inhibited cardiomyocyte hypertrophy through repression of its targets, transcription factor Egr. Transgenic mice with cardiac-specific overexpression of Nab1 showed that Nab1 is a potent inhibitor of cardiac growth in response to pathological stimuli in vivo. Nab1 overexpression suppressed adrenergically induced and pressure overload-induced hypertrophy, whereas physiological growth during development and in response to exercise was not affected. These findings implicate the Nab1-Egr1 axis as a crucial regulator of pathological cardiac growth.", + "TAG_DATA": [ + "92, mice {'context': 'I-organism'}", + "94, cardiac-specific {'perturbing_action': 'B-gene gain-of-function'}", + "95, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "96, of {'perturbing_action': 'I-gene gain-of-function'}", + "97, Nab1 {'perturbing_action': 'I-gene gain-of-function'}", + "113, in {'context': 'B-in vivo'}", + "114, vivo. {'context': 'I-in vivo'}", + "115, Nab1 {'perturbing_action': 'B-gene gain-of-function'}", + "116, overexpression {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "92, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "94, cardiac-specific ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "95, overexpression ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "96, of ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "97, Nab1 ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "113, in ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "114, vivo. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "115, Nab1 ['l21']", + "116, overexpression ['l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "cardiac-specific", + "overexpression", + "of", + "Nab1" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "cardiac-specific", + "overexpression", + "of", + "Nab1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "16007096", + "TEXT": "Suppressor of cytokine signaling (SOCS) 3 attenuates proinflammatory signaling mediated by the signal transducer and activator of transcription (STAT) family of proteins. But acute inflammation can occur after exposure to pathogen-derived inducers staphylococcal enterotoxin B (SEB) and lipopolysaccharide (LPS), or the lectin concanavalin A (ConA), suggesting that physiologic levels of SOCS3 are insufficient to stem proinflammatory signaling under pathogenic circumstances. To test this hypothesis, we developed recombinant cell-penetrating forms of SOCS3 (CP-SOCS3) for intracellular delivery to counteract SEB-, LPS- and ConA-induced inflammation. We found that CP-SOCS3 was distributed in multiple organs within 2 h and persisted for at least 8 h in leukocytes and lymphocytes. CP-SOCS3 protected animals from lethal effects of SEB and LPS by reducing production of inflammatory cytokines and attenuating liver apoptosis and hemorrhagic necrosis. It also reduced ConA-induced liver apoptosis. Thus, replenishing the intracellular stores of SOCS3 with CP-SOCS3 effectively suppresses the devastating effects of acute inflammation.", + "TAG_DATA": [ + "102, leukocytes {'context': 'B-cells'}", + "104, lymphocytes. {'context': 'B-cells'}", + "107, animals {'context': 'B-organism'}", + "122, attenuating {'effect': 'B-negative'}", + "123, liver {'context': 'B-tissue/organ'}", + "124, apoptosis {'phenotype': 'B-apoptosis'}", + "127, necrosis. {'phenotype': 'B-necrosis'}", + "130, reduced {'effect': 'B-negative'}", + "131, ConA-induced {'effect': 'B-positive'}", + "132, liver {'context': 'B-tissue/organ'}", + "133, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "102, leukocytes ['l0', 'l1', 'l2', 'l3', 'l4']", + "104, lymphocytes. ['l0']", + "107, animals ['l1', 'l5', 'l6', 'l7', 'l8']", + "122, attenuating ['l2', 'l5', 'l9', 'l10', 'l11']", + "123, liver ['l3', 'l6', 'l9', 'l12', 'l13']", + "124, apoptosis ['l4', 'l7', 'l10', 'l12', 'l14']", + "127, necrosis. ['l8', 'l11', 'l13', 'l14']", + "130, reduced ['l15', 'l16', 'l17']", + "131, ConA-induced ['l15', 'l18', 'l19']", + "132, liver ['l16', 'l18', 'l20']", + "133, apoptosis. ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "leukocytes" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuating" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "leukocytes" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animals" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuating" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animals" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animals" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuating", + "reduced" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuating", + "reduced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuating" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "ConA-induced" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "ConA-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "15980866", + "TEXT": "Type 2 diabetes is a disorder of hyperglycemia resulting from failure of beta cells to produce adequate insulin to accommodate an increased metabolic demand. Here we show that regulation of mRNA translation through phosphorylation of eukaryotic initiation factor 2 (eIF2alpha) is essential to preserve the integrity of the endoplasmic reticulum (ER) and to increase insulin production to meet the demand imposed by a high-fat diet. Accumulation of unfolded proteins in the ER activates phosphorylation of eIF2alpha at Ser51 and inhibits translation. To elucidate the role of this pathway in beta-cell function we studied glucose homeostasis in Eif2s1(tm1Rjk) mutant mice, which have an alanine substitution at Ser51. Heterozygous (Eif2s1(+/tm1Rjk)) mice became obese and diabetic on a high-fat diet. Profound glucose intolerance resulted from reduced insulin secretion accompanied by abnormal distension of the ER lumen, defective trafficking of proinsulin, and a reduced number of insulin granules in beta cells. We propose that translational control couples insulin synthesis with folding capacity to maintain ER integrity and that this signal is essential to prevent diet-induced type 2 diabetes.", + "TAG_DATA": [ + "96, Eif2s1(tm1Rjk) {'perturbing_action': 'B-other'}", + "97, mutant {'perturbing_action': 'I-other'}", + "98, mice, {'context': 'B-organism'}", + "106, Heterozygous {'perturbing_action': 'B-other'}", + "107, (Eif2s1(+/tm1Rjk)) {'perturbing_action': 'I-other'}", + "108, mice {'context': 'B-organism'}", + "145, beta {'context': 'B-cells'}", + "146, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "96, Eif2s1(tm1Rjk) ['l0', 'l1']", + "97, mutant ['l0', 'l2']", + "98, mice, ['l1', 'l2']", + "106, Heterozygous ['l3', 'l4', 'l5']", + "107, (Eif2s1(+/tm1Rjk)) ['l3', 'l6', 'l7', 'l8']", + "108, mice ['l4', 'l6']", + "145, beta ['l7', 'l9']", + "146, cells. ['l5', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Eif2s1(tm1Rjk)", + "mutant", + "Heterozygous", + "(Eif2s1(+/tm1Rjk))" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Heterozygous", + "(Eif2s1(+/tm1Rjk))" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells.", + "beta" + ] + } + } + ] + }, + { + "PMID": "15965482", + "TEXT": "Induction of immunity after DNA vaccination is generally considered a slow process. Here we show that DNA delivery to the skin results in a highly transient pulse of antigen expression. Based on this information, we developed a new rapid and potent intradermal DNA vaccination method. By short-interval intradermal DNA delivery, robust T-cell responses, of a magnitude sufficient to reject established subcutaneous tumors, are generated within 12 d. Moreover, this vaccination strategy confers protecting humoral immunity against influenza A infection within 2 weeks after the start of vaccination. The strength and speed of this newly developed strategy will be beneficial in situations in which immunity is required in the shortest possible time.", + "TAG_DATA": [ + "51, T-cell {'context': 'B-cells'}", + "60, subcutaneous {'context': 'B-neoplasm'}", + "61, tumors, {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "51, T-cell ['l0', 'l1']", + "60, subcutaneous ['l0', 'l2']", + "61, tumors, ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15908957", + "TEXT": "Antigen therapy may hold great promise for the prevention of autoimmunity; however, most clinical trials have failed, suggesting that the principles guiding the choice of treatment remain ill defined. Here, we examine the antidiabetogenic properties of altered peptide ligands of CD8+ T cells recognizing an epitope of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP206-214), a prevalent population of autoreactive T cells in autoimmune diabetes. We show that islet-associated CD8+ T cells in nonobese diabetic mice recognize numerous IGRP epitopes, and that these cells have a role in the outcome of protocols designed to induce IGRP206-214-specific tolerance. Ligands targeting IGRP206-214-reactive T cells prevented disease, but only at doses that spared low-avidity clonotypes. Notably, near complete depletion of the IGRP206-214-reactive T-cell pool enhanced the recruitment of subdominant specificities and did not blunt diabetogenesis. Thus, peptide therapy in autoimmunity is most effective under conditions that foster occupation of the target organ lymphocyte niche by nonpathogenic, low-avidity clonotypes.", + "TAG_DATA": [ + "66, islet-associated {'context': 'B-cells'}", + "67, CD8+ {'context': 'I-cells'}", + "68, T {'context': 'I-cells'}", + "69, cells {'context': 'I-cells'}", + "71, nonobese {'context': 'B-organism'}", + "72, diabetic {'context': 'I-organism'}", + "73, mice {'context': 'I-organism'}", + "98, T {'context': 'I-cells'}", + "99, cells {'context': 'I-cells'}", + "117, T-cell {'context': 'B-cells'}", + "118, pool {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "66, islet-associated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "67, CD8+ ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "68, T ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "69, cells ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "71, nonobese ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "72, diabetic ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "73, mice ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "98, T ['l21']", + "99, cells ['l21']", + "117, T-cell ['l22']", + "118, pool ['l22']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15880119", + "TEXT": "We describe a new therapeutic approach for the treatment of lethal sepsis using cell-penetrating lipopeptides-termed pepducins-that target either individual or multiple chemokine receptors. Interleukin-8 (IL-8), a ligand for the CXCR1 and CXCR2 receptors, is the most potent endogenous proinflammatory chemokine in sepsis. IL-8 levels rise in blood and lung fluids to activate neutrophils and other cells, and correlate with shock, lung injury and high mortality. We show that pepducins derived from either the i1 or i3 intracellular loops of CXCR1 and CXCR2 prevent the IL-8 response of both receptors and reverse the lethal sequelae of sepsis, including disseminated intravascular coagulation and multi-organ failure in mice. Conversely, pepducins selective for CXCR4 cause a massive leukocytosis that does not affect survival. CXCR1 and CXCR2 pepducins conferred nearly 100% survival even when treatment was postponed, suggesting that our approach might be beneficial in the setting of advanced disease.", + "TAG_DATA": [ + "104, mice. {'context': 'B-organism'}", + "107, selective {'perturbing_action': 'I-pharmacological augmentation'}", + "108, for {'perturbing_action': 'I-other'}", + "109, CXCR4 {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "107, selective ['l0', 'l1']", + "108, for ['l0', 'l2']", + "109, CXCR4 ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15880117", + "TEXT": "A solid tumor is an organ composed of cancer and host cells embedded in an extracellular matrix and nourished by blood vessels. A prerequisite to understanding tumor pathophysiology is the ability to distinguish and monitor each component in dynamic studies. Standard fluorophores hamper simultaneous intravital imaging of these components. Here, we used multiphoton microscopy techniques and transgenic mice that expressed green fluorescent protein, and combined them with the use of quantum dot preparations. We show that these fluorescent semiconductor nanocrystals can be customized to concurrently image and differentiate tumor vessels from both the perivascular cells and the matrix. Moreover, we used them to measure the ability of particles of different sizes to access the tumor. Finally, we successfully monitored the recruitment of quantum dot-labeled bone marrow-derived precursor cells to the tumor vasculature. These examples show the versatility of quantum dots for studying tumor pathophysiology and creating avenues for treatment.", + "TAG_DATA": [ + "57, mice {'context': 'I-organism'}", + "124, bone {'context': 'B-cells'}", + "125, marrow-derived {'context': 'I-cells'}", + "126, precursor {'context': 'I-cells'}", + "127, cells {'context': 'I-cells'}", + "130, tumor {'context': 'B-neoplasm'}", + "131, vasculature. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "124, bone ['l0', 'l1', 'l2', 'l3', 'l4']", + "125, marrow-derived ['l0', 'l5', 'l6', 'l7', 'l8']", + "126, precursor ['l1', 'l5', 'l9', 'l10', 'l11']", + "127, cells ['l2', 'l6', 'l9', 'l12', 'l13']", + "130, tumor ['l3', 'l7', 'l10', 'l12', 'l14']", + "131, vasculature. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15834428", + "TEXT": "Vascular endothelial growth factor (VEGF)-induced blood vessel growth is involved in both physiological and pathological angiogenesis and requires integrin-mediated signaling. We now show that an integrin-binding protein initially described in milk-fat globule, MFG-E8 (also known as lactadherin), is expressed in and around blood vessels and has a crucial role in VEGF-dependent neovascularization in the adult mouse. Using neutralizing antibodies and lactadherin-deficient animals, we show that lactadherin interacts with alphavbeta3 and alphavbeta5 integrins and alters both VEGF-dependent Akt phosphorylation and neovascularization. In the absence of VEGF, lactadherin administration induced alphavbeta3- and alphavbeta5-dependent Akt phosphorylation in endothelial cells in vitro and strongly improved postischemic neovascularization in vivo. These results show a crucial role for lactadherin in VEGF-dependent neovascularization and identify lactadherin as an important target for the modulation of neovascularization.", + "TAG_DATA": [ + "60, lactadherin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "61, animals, {'context': 'B-organism'}", + "82, absence {'perturbing_action': 'B-gene loss-of-function'}", + "83, of {'perturbing_action': 'I-gene loss-of-function'}", + "84, VEGF, {'perturbing_action': 'I-gene loss-of-function'}", + "94, endothelial {'context': 'B-cells'}", + "95, cells {'context': 'I-cells'}", + "96, in {'context': 'B-in vitro'}", + "97, vitro {'context': 'I-in vitro'}", + "103, in {'context': 'B-in vivo'}", + "104, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "60, lactadherin-deficient ['l0', 'l1']", + "61, animals, ['l0', 'l2', 'l3']", + "82, absence ['l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "83, of ['l2', 'l4', 'l10', 'l11', 'l12', 'l13', 'l14']", + "84, VEGF, ['l5', 'l10', 'l15', 'l16', 'l17', 'l18']", + "94, endothelial ['l6', 'l11', 'l15', 'l19', 'l20', 'l21']", + "95, cells ['l1', 'l3', 'l7', 'l12', 'l16', 'l19', 'l22', 'l23']", + "96, in ['l8', 'l13', 'l17', 'l20', 'l22', 'l24']", + "97, vitro ['l9', 'l14', 'l18', 'l21', 'l23', 'l24']", + "103, in ['l25']", + "104, vivo. ['l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lactadherin-deficient", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "animals," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lactadherin-deficient", + "absence", + "of", + "VEGF," + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "endothelial" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "VEGF," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "15834426", + "TEXT": "Increased Abeta42 production has been linked to the development of Alzheimer disease. We now identify a number of compounds that raise Abeta42. Among the more potent Abeta42-raising agents identified are fenofibrate, an antilipidemic agent, and celecoxib, a COX-2-selective NSAID. Many COX-2-selective NSAIDs tested raised Abeta42, including multiple COX-2-selective derivatives of two Abeta42-lowering NSAIDs. Compounds devoid of COX activity and the endogenous isoprenoids FPP and GGPP also raised Abeta42. These compounds seem to target the gamma-secretase complex, increasing gamma-secretase-catalyzed production of Abeta42 in vitro. Short-term in vivo studies show that two Abeta42-raising compounds increase Abeta42 levels in the brains of mice. The elevations in Abeta42 by these compounds are comparable to the increases in Abeta42 induced by Alzheimer disease-causing mutations in the genes encoding amyloid beta protein precursor and presenilins, raising the possibility that exogenous compounds or naturally occurring isoprenoids might increase Abeta42 production in humans.", + "TAG_DATA": [ + "81, in {'context': 'B-in vitro'}", + "82, vitro. {'context': 'I-in vitro'}", + "84, in {'context': 'B-in vivo'}", + "85, vivo {'context': 'I-in vivo'}", + "97, brains {'context': 'B-tissue/organ'}", + "99, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "81, in ['l0']", + "82, vitro. ['l0']", + "84, in ['l1', 'l2', 'l3']", + "85, vivo ['l1', 'l4', 'l5']", + "97, brains ['l2', 'l4', 'l6']", + "99, mice. ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15821747", + "TEXT": "The poor response of central axons to transection underlies the bleak prognosis following spinal cord injury. Here, we monitor individual fluorescent axons in the spinal cords of living transgenic mice over several days after spinal injury. We find that within 30 min after trauma, axons die back hundreds of micrometers. This acute form of axonal degeneration is similar in mechanism to the more delayed Wallerian degeneration of the disconnected distal axon, but acute degeneration affects the proximal and distal axon ends equally. In vivo imaging further shows that many axons attempt regeneration within 6-24 h after lesion. This growth response, although robust, seems to fail as a result of the inability of axons to navigate in the proper direction. These results suggest that time-lapse imaging of spinal cord injury may provide a powerful analytical tool for assessing the pathogenesis of spinal cord injury and for evaluating therapies that enhance regeneration.", + "TAG_DATA": [ + "28, transgenic {'context': 'B-organism'}", + "29, mice {'context': 'I-organism'}", + "44, axons {'context': 'B-cells'}", + "82, In {'context': 'B-in vivo'}", + "83, vivo {'context': 'I-in vivo'}", + "89, axons {'context': 'B-cells'}", + "112, axons {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "28, transgenic ['l0', 'l1']", + "29, mice ['l0']", + "44, axons ['l1']", + "82, In ['l2', 'l3']", + "83, vivo ['l2', 'l4']", + "89, axons ['l3', 'l4']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15821746", + "TEXT": "Although epithelial ovarian cancers (EOCs) have been thought to arise from the simple epithelium lining the ovarian surface or inclusion cysts, the major subtypes of EOCs show morphologic features that resemble those of the müllerian duct-derived epithelia of the reproductive tract. We found that HOX genes, which normally regulate mullerian duct differentiation, are not expressed in normal ovarian surface epithelium (OSE), but are expressed in different EOC subtypes according to the pattern of mullerian-like differentiation of these cancers. Ectopic expression of Hoxa9 in tumorigenic mouse OSE cells gave rise to papillary tumors resembling serous EOCs. In contrast, Hoxa10 and Hoxa11 induced morphogenesis of endometrioid-like and mucinous-like EOCs, respectively. Hoxa7 showed no lineage specificity, but promoted the abilities of Hoxa9, Hoxa10 and Hoxa11 to induce differentiation along their respective pathways. Therefore, inappropriate activation of a molecular program that controls patterning of the reproductive tract could explain the morphologic heterogeneity of EOCs and their assumption of müllerian-like features.", + "TAG_DATA": [ + "78, Ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "79, expression {'perturbing_action': 'I-gene gain-of-function'}", + "80, of {'perturbing_action': 'I-gene gain-of-function'}", + "81, Hoxa9 {'perturbing_action': 'I-gene gain-of-function'}", + "83, tumorigenic {'context': 'B-transformed cells'}", + "84, mouse {'context': 'I-transformed cells'}", + "85, OSE {'context': 'I-transformed cells'}", + "86, cells {'context': 'I-transformed cells'}", + "87, gave {'effect': 'B-positive'}", + "88, rise {'effect': 'I-positive'}", + "89, to {'effect': 'I-positive'}", + "90, papillary {'phenotype': 'B-tumourigenesis'}", + "91, tumors {'phenotype': 'I-tumourigenesis'}", + "106, EOCs, {'context': 'B-neoplasm'}", + "123, induce {'effect': 'B-positive'}", + "124, differentiation {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "78, Ectopic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "79, expression ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "80, of ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "81, Hoxa9 ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "83, tumorigenic ['l3', 'l14', 'l24', 'l33', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "84, mouse ['l4', 'l15', 'l25', 'l34', 'l41', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "85, OSE ['l5', 'l16', 'l26', 'l35', 'l42', 'l49', 'l55', 'l56', 'l57', 'l58', 'l59']", + "86, cells ['l6', 'l17', 'l27', 'l36', 'l43', 'l50', 'l55', 'l60', 'l61', 'l62', 'l63']", + "87, gave ['l7', 'l18', 'l28', 'l37', 'l44', 'l51', 'l56', 'l60', 'l64', 'l65', 'l66', 'l67']", + "88, rise ['l8', 'l19', 'l29', 'l38', 'l45', 'l52', 'l57', 'l61', 'l64', 'l68', 'l69', 'l70']", + "89, to ['l9', 'l20', 'l30', 'l39', 'l46', 'l53', 'l58', 'l62', 'l65', 'l68', 'l71', 'l72']", + "90, papillary ['l10', 'l21', 'l31', 'l47', 'l66', 'l69', 'l71', 'l73']", + "91, tumors ['l11', 'l22', 'l32', 'l40', 'l48', 'l54', 'l59', 'l63', 'l67', 'l70', 'l72', 'l73']", + "123, induce ['l74']", + "124, differentiation ['l74']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "Hoxa9" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumorigenic", + "mouse", + "OSE", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "Hoxa9" + ] + }, + "effect": { + "val": "positive", + "words": [ + "gave", + "rise", + "to" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "Hoxa9" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "papillary", + "tumors" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumorigenic", + "mouse", + "OSE", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "gave", + "rise", + "to" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumorigenic", + "mouse", + "OSE", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "papillary", + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "gave", + "rise", + "to" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "papillary", + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "15812490", + "TEXT": "The vaccines developed over the first two hundred years since Jenner's lifetime have accomplished striking reductions of infection and disease wherever applied. Pasteur's early approaches to vaccine development, attenuation and inactivation, are even now the two poles of vaccine technology. Today, purification of microbial elements, genetic engineering and improved knowledge of immune protection allow direct creation of attenuated mutants, expression of vaccine proteins in live vectors, purification and even synthesis of microbial antigens, and induction of a variety of immune responses through manipulation of DNA, RNA, proteins and polysaccharides. Both noninfectious and infectious diseases are now within the realm of vaccinology. The profusion of new vaccines enables new populations to be targeted for vaccination, and requires the development of routes of administration additional to injection. With all this come new problems in the production, regulation and distribution of vaccines.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15812483", + "TEXT": "The challenges of vaccine development are not limited to identification of suitable antigens, adjuvants and delivery methods, but include regulatory, technical and manufacturing hurdles in translating a vaccine candidate to the clinic. Process development is the technological foundation that underlies the manufacture of new vaccines and is central to successful commercialization.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15793582", + "TEXT": "Beta-adrenergic receptor (betaAR) stimulation increases cytosolic Ca(2+) to physiologically augment cardiac contraction, whereas excessive betaAR activation causes adverse cardiac remodeling, including myocardial hypertrophy, dilation and dysfunction, in individuals with myocardial infarction. The Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) is a recently identified downstream element of the betaAR-initiated signaling cascade that is linked to pathological myocardial remodeling and to regulation of key proteins involved in cardiac excitation-contraction coupling. We developed a genetic mouse model of cardiac CaMKII inhibition to test the role of CaMKII in betaAR signaling in vivo. Here we show CaMKII inhibition substantially prevented maladaptive remodeling from excessive betaAR stimulation and myocardial infarction, and induced balanced changes in excitation-contraction coupling that preserved baseline and betaAR-stimulated physiological increases in cardiac function. These findings mark CaMKII as a determinant of clinically important heart disease phenotypes, and suggest CaMKII inhibition can be a highly selective approach for targeting adverse myocardial remodeling linked to betaAR signaling.", + "TAG_DATA": [ + "69, genetic {'context': 'B-organism'}", + "70, mouse {'context': 'I-organism'}", + "71, model {'context': 'I-organism'}", + "74, CaMKII {'perturbing_action': 'I-pharmacological inhibition'}", + "75, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "90, CaMKII {'perturbing_action': 'B-pharmacological inhibition'}", + "91, inhibition {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "69, genetic ['l0', 'l1', 'l2', 'l3']", + "70, mouse ['l0', 'l4', 'l5', 'l6']", + "71, model ['l1', 'l4', 'l7', 'l8']", + "74, CaMKII ['l2', 'l5', 'l7', 'l9']", + "75, inhibition ['l3', 'l6', 'l8', 'l9']", + "90, CaMKII ['l10']", + "91, inhibition ['l10']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "genetic", + "mouse", + "model" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CaMKII", + "inhibition" + ] + } + } + ] + }, + { + "PMID": "15793580", + "TEXT": "Animal allergens are an important cause of asthma and allergic rhinitis. We designed and tested a chimeric human-cat fusion protein composed of a truncated human IgG Fcgamma1 and the major cat allergen Fel d1, as a proof of concept for a new approach to allergy immunotherapy. This Fcgamma-Fel d1 protein induced dose-dependent inhibition of Fel d1-driven IgE-mediated histamine release from cat-allergic donors' basophils and sensitized human cord blood-derived mast cells. Such inhibition was associated with altered Syk and ERK signaling. The Fcgamma-Fel d1 protein also blocked in vivo reactivity in FcepsilonRIalpha transgenic mice passively sensitized with human IgE antibody to cat and in Balb/c mice actively sensitized against Fel d1. The Fcgamma-Fel d1 protein alone did not induce mediator release. Chimeric human Fcgamma-allergen fusion proteins may provide a new therapeutic platform for the immune-based therapy of allergic disease.", + "TAG_DATA": [ + "65, human {'context': 'B-cells'}", + "66, cord {'context': 'I-cells'}", + "67, blood-derived {'context': 'I-cells'}", + "68, mast {'context': 'I-cells'}", + "69, cells. {'context': 'I-cells'}", + "86, in {'context': 'B-in vivo'}", + "87, vivo {'context': 'I-in vivo'}", + "90, FcepsilonRIalpha {'perturbing_action': 'B-gene gain-of-function'}", + "91, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "92, mice {'context': 'B-organism'}", + "103, Balb/c {'context': 'B-organism'}", + "104, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "65, human ['l0', 'l1', 'l2', 'l3']", + "66, cord ['l0', 'l4', 'l5', 'l6', 'l7']", + "67, blood-derived ['l1', 'l4', 'l8', 'l9', 'l10']", + "68, mast ['l2', 'l5', 'l8', 'l11']", + "69, cells. ['l3', 'l6', 'l9', 'l11']", + "86, in ['l12', 'l13', 'l14', 'l15']", + "87, vivo ['l7', 'l10', 'l12', 'l16', 'l17', 'l18']", + "90, FcepsilonRIalpha ['l13', 'l16', 'l19', 'l20']", + "91, transgenic ['l14', 'l17', 'l19', 'l21']", + "92, mice ['l15', 'l18', 'l20', 'l21']", + "103, Balb/c ['l22']", + "104, mice ['l22']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "FcepsilonRIalpha", + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "FcepsilonRIalpha", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15750600", + "TEXT": "Hutchinson-Gilford progeria syndrome (HGPS) is a childhood premature aging disease caused by a spontaneous point mutation in lamin A (encoded by LMNA), one of the major architectural elements of the mammalian cell nucleus. The HGPS mutation activates an aberrant cryptic splice site in LMNA pre-mRNA, leading to synthesis of a truncated lamin A protein and concomitant reduction in wild-type lamin A. Fibroblasts from individuals with HGPS have severe morphological abnormalities in nuclear envelope structure. Here we show that the cellular disease phenotype is reversible in cells from individuals with HGPS. Introduction of wild-type lamin A protein does not rescue the cellular disease symptoms. The mutant LMNA mRNA and lamin A protein can be efficiently eliminated by correction of the aberrant splicing event using a modified oligonucleotide targeted to the activated cryptic splice site. Upon splicing correction, HGPS fibroblasts assume normal nuclear morphology, the aberrant nuclear distribution and cellular levels of lamina-associated proteins are rescued, defects in heterochromatin-specific histone modifications are corrected and proper expression of several misregulated genes is reestablished. Our results establish proof of principle for the correction of the premature aging phenotype in individuals with HGPS.", + "TAG_DATA": [ + "85, cells {'context': 'B-cells'}", + "92, wild-type {'perturbing_action': 'I-gene gain-of-function'}", + "93, lamin {'perturbing_action': 'I-gene gain-of-function'}", + "136, HGPS {'context': 'B-cells'}", + "137, fibroblasts {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "92, wild-type ['l0']", + "93, lamin ['l0']", + "136, HGPS ['l1']", + "137, fibroblasts ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15735651", + "TEXT": "Chronic progression of two T cell-mediated central nervous system (CNS) demyelinating models of multiple sclerosis, relapsing EAE (R-EAE) and Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is dependent on the activation of T cells to endogenous myelin epitopes (epitope spreading). Using transfer of carboxyfluorescein succinyl ester (CFSE)-labeled T-cell receptor (TCR)-transgenic T cells and mixed bone marrow chimeras, we show that activation of naive proteolipid protein (PLP)139-151-specific T cells in SJL mice undergoing PLP178-191-induced R-EAE or TMEV-IDD occurs directly in the CNS and not in the cervical lymph nodes or other peripheral lymphoid organs. Examination of the antigen-presentation capacity of antigen-presenting cell (APC) populations purified from the CNS of mice with PLP178-191-induced R-EAE shows that only F4/80-CD11c+CD45hi dendritic cells (DCs) efficiently present endogenous antigen to activate naive PLP139-151-specific T cells in vitro. In contrast, DCs as well as F4/80+CD45hi macrophages and F4/80+CD45lo microglia activate a PLP139-151-specific helper T cell line. The data suggest that naive T cells enter the inflamed CNS and are activated by local APCs, possibly DCs, to initiate epitope spreading.", + "TAG_DATA": [ + "50, T {'context': 'B-cells'}", + "51, cells {'context': 'B-cells'}", + "66, T {'context': 'I-cells'}", + "67, cells {'context': 'I-cells'}", + "69, SJL {'context': 'B-organism'}", + "70, mice {'context': 'I-organism'}", + "80, CNS {'context': 'B-tissue/organ'}", + "85, cervical {'context': 'B-tissue/organ'}", + "86, lymph {'context': 'I-tissue/organ'}", + "87, nodes {'context': 'I-tissue/organ'}", + "90, peripheral {'context': 'B-tissue/organ'}", + "91, lymphoid {'context': 'I-tissue/organ'}", + "92, organs. {'context': 'I-tissue/organ'}", + "108, mice {'context': 'B-organism'}", + "115, F4/80-CD11c+CD45hi {'context': 'B-cells'}", + "116, dendritic {'context': 'I-cells'}", + "117, cells {'context': 'I-cells'}", + "118, (DCs) {'context': 'I-cells'}", + "126, PLP139-151-specific {'context': 'I-cells'}", + "127, T {'context': 'I-cells'}", + "128, cells {'context': 'I-cells'}", + "129, in {'context': 'B-in vitro'}", + "130, vitro. {'context': 'I-in vitro'}", + "133, DCs {'context': 'B-cells'}", + "137, F4/80+CD45hi {'context': 'B-cells'}", + "138, macrophages {'context': 'I-cells'}", + "140, F4/80+CD45lo {'context': 'B-cells'}", + "141, microglia {'context': 'I-cells'}", + "145, helper {'context': 'I-cells'}", + "146, T {'context': 'I-cells'}", + "147, cell {'context': 'I-cells'}", + "148, line. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "50, T ['l0', 'l1', 'l2', 'l3', 'l4']", + "51, cells ['l0', 'l5', 'l6', 'l7', 'l8']", + "66, T ['l1', 'l5', 'l9', 'l10', 'l11']", + "67, cells ['l2', 'l6', 'l9', 'l12', 'l13']", + "69, SJL ['l3', 'l7', 'l10', 'l12', 'l14', 'l15', 'l16', 'l17']", + "70, mice ['l4', 'l8', 'l11', 'l13', 'l14']", + "80, CNS ['l15', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "85, cervical ['l18', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "86, lymph ['l16', 'l19', 'l24', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "87, nodes ['l17', 'l20', 'l25', 'l35', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "90, peripheral ['l21', 'l26', 'l36', 'l42', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "91, lymphoid ['l22', 'l27', 'l37', 'l43', 'l48', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "92, organs. ['l23', 'l28', 'l38', 'l44', 'l49', 'l57', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "108, mice ['l50', 'l58', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "115, F4/80-CD11c+CD45hi ['l29', 'l51', 'l59', 'l65', 'l71', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "116, dendritic ['l30', 'l52', 'l60', 'l66', 'l72', 'l80', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "117, cells ['l31', 'l39', 'l45', 'l53', 'l61', 'l67', 'l73', 'l81', 'l88', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "118, (DCs) ['l32', 'l40', 'l46', 'l54', 'l62', 'l68', 'l74', 'l82', 'l89', 'l95', 'l101', 'l102', 'l103', 'l104', 'l105']", + "126, PLP139-151-specific ['l75', 'l83', 'l90', 'l96', 'l101', 'l106', 'l107', 'l108', 'l109']", + "127, T ['l33', 'l55', 'l63', 'l69', 'l76', 'l84', 'l91', 'l97', 'l102', 'l106', 'l110', 'l111', 'l112']", + "128, cells ['l34', 'l41', 'l47', 'l56', 'l64', 'l70', 'l77', 'l85', 'l92', 'l98', 'l103', 'l107', 'l110', 'l113', 'l114']", + "129, in ['l78', 'l86', 'l93', 'l99', 'l104', 'l108', 'l111', 'l113', 'l115']", + "130, vitro. ['l79', 'l87', 'l94', 'l100', 'l105', 'l109', 'l112', 'l114', 'l115']", + "133, DCs ['l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "137, F4/80+CD45hi ['l116', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "138, macrophages ['l117', 'l124', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "140, F4/80+CD45lo ['l118', 'l125', 'l131', 'l137', 'l138', 'l139', 'l140', 'l141']", + "141, microglia ['l119', 'l126', 'l132', 'l137', 'l142', 'l143', 'l144', 'l145']", + "145, helper ['l120', 'l127', 'l133', 'l138', 'l142', 'l146', 'l147', 'l148']", + "146, T ['l121', 'l128', 'l134', 'l139', 'l143', 'l146', 'l149', 'l150']", + "147, cell ['l122', 'l129', 'l135', 'l140', 'l144', 'l147', 'l149', 'l151']", + "148, line. ['l123', 'l130', 'l136', 'l141', 'l145', 'l148', 'l150', 'l151']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15711560", + "TEXT": "Targeted gene transduction to specific tissues and organs through intravenous injection would be the ultimate preferred method of gene delivery. Here, we report successful targeting in a living animal through intravenous injection of a lentiviral vector pseudotyped with a modified chimeric Sindbis virus envelope (termed m168). m168 pseudotypes have high titer and high targeting specificity and, unlike other retroviral pseudotypes, have low nonspecific infectivity in liver and spleen. A mouse cancer model of metastatic melanoma was used to test intravenous targeting with m168. Human P-glycoprotein was ectopically expressed on the surface of melanoma cells and targeted by the m168 pseudotyped lentiviral vector conjugated with antibody specific for P-glycoprotein. m168 pseudotypes successfully targeted metastatic melanoma cells growing in the lung after systemic administration by tail vein injection. Further development of this targeting technology should result in applications not only for cancers but also for genetic, infectious and immune diseases.", + "TAG_DATA": [ + "27, living {'context': 'B-organism'}", + "28, animal {'context': 'I-organism'}", + "69, mouse {'context': 'B-neoplasm'}", + "70, cancer {'context': 'I-neoplasm'}", + "71, model {'context': 'I-neoplasm'}", + "72, of {'context': 'I-neoplasm'}", + "73, metastatic {'context': 'I-neoplasm'}", + "74, melanoma {'context': 'I-neoplasm'}", + "92, melanoma {'context': 'B-transformed cells'}", + "93, cells {'context': 'I-transformed cells'}", + "112, metastatic {'context': 'B-transformed cells'}", + "113, melanoma {'context': 'I-transformed cells'}", + "114, cells {'context': 'I-transformed cells'}", + "118, lung {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "27, living ['l0']", + "28, animal ['l0']", + "69, mouse ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "70, cancer ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "71, model ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "72, of ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "73, metastatic ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "74, melanoma ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "92, melanoma ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "93, cells ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']", + "112, metastatic ['l29', 'l30', 'l31']", + "113, melanoma ['l29', 'l32', 'l33']", + "114, cells ['l30', 'l32', 'l34']", + "118, lung ['l31', 'l33', 'l34']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15665834", + "TEXT": "Sustained cardiac pressure overload induces hypertrophy and pathological remodeling, frequently leading to heart failure. Genetically engineered hyperstimulation of guanosine 3',5'-cyclic monophosphate (cGMP) synthesis counters this response. Here, we show that blocking the intrinsic catabolism of cGMP with an oral phosphodiesterase-5A (PDE5A) inhibitor (sildenafil) suppresses chamber and myocyte hypertrophy, and improves in vivo heart function in mice exposed to chronic pressure overload induced by transverse aortic constriction. Sildenafil also reverses pre-established hypertrophy induced by pressure load while restoring chamber function to normal. cGMP catabolism by PDE5A increases in pressure-loaded hearts, leading to activation of cGMP-dependent protein kinase with inhibition of PDE5A. PDE5A inhibition deactivates multiple hypertrophy signaling pathways triggered by pressure load (the calcineurin/NFAT, phosphoinositide-3 kinase (PI3K)/Akt, and ERK1/2 signaling pathways). But it does not suppress hypertrophy induced by overexpression of calcineurin in vitro or Akt in vivo, suggesting upstream targeting of these pathways. PDE5A inhibition may provide a new treatment strategy for cardiac hypertrophy and remodeling.", + "TAG_DATA": [ + "38, oral {'perturbing_action': 'B-pharmacological inhibition'}", + "39, phosphodiesterase-5A {'perturbing_action': 'I-pharmacological inhibition'}", + "40, (PDE5A) {'perturbing_action': 'I-pharmacological inhibition'}", + "41, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "42, (sildenafil) {'perturbing_action': 'I-pharmacological inhibition'}", + "44, chamber {'context': 'B-cells'}", + "46, myocyte {'context': 'B-cells'}", + "50, in {'context': 'B-in vivo'}", + "51, vivo {'context': 'I-in vivo'}", + "52, heart {'context': 'B-tissue/organ'}", + "55, mice {'context': 'B-organism'}", + "77, chamber {'context': 'B-tissue/organ'}", + "88, hearts, {'context': 'B-tissue/organ'}", + "97, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "98, of {'perturbing_action': 'I-pharmacological inhibition'}", + "99, PDE5A. {'perturbing_action': 'I-pharmacological inhibition'}", + "100, PDE5A {'perturbing_action': 'B-pharmacological inhibition'}", + "101, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "128, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "129, of {'perturbing_action': 'I-gene gain-of-function'}", + "130, calcineurin {'perturbing_action': 'I-gene gain-of-function'}", + "131, in {'context': 'B-in vitro'}", + "132, vitro {'context': 'I-in vitro'}", + "135, in {'context': 'B-in vivo'}", + "136, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "38, oral ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "39, phosphodiesterase-5A ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "40, (PDE5A) ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "41, inhibitor ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "42, (sildenafil) ['l3', 'l14', 'l24', 'l33', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "44, chamber ['l4', 'l15', 'l25', 'l34', 'l41', 'l47', 'l48']", + "46, myocyte ['l5', 'l16', 'l26', 'l35', 'l42', 'l47']", + "50, in ['l6', 'l17', 'l27', 'l36', 'l43', 'l49', 'l50', 'l51']", + "51, vivo ['l7', 'l18', 'l28', 'l37', 'l44', 'l49', 'l52', 'l53']", + "52, heart ['l8', 'l19', 'l29', 'l38', 'l45', 'l48', 'l50', 'l52', 'l54']", + "55, mice ['l9', 'l20', 'l30', 'l39', 'l46', 'l51', 'l53', 'l54']", + "77, chamber ['l10', 'l21', 'l31', 'l55']", + "88, hearts, ['l11', 'l22', 'l32', 'l40', 'l55', 'l56', 'l57']", + "97, inhibition ['l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "98, of ['l56', 'l58', 'l65', 'l66', 'l67', 'l68']", + "99, PDE5A. ['l57', 'l59', 'l65', 'l69']", + "100, PDE5A ['l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "101, inhibition ['l60', 'l66', 'l70', 'l78', 'l79', 'l80', 'l81', 'l82']", + "128, overexpression ['l71', 'l78', 'l83', 'l84', 'l85', 'l86']", + "129, of ['l61', 'l67', 'l72', 'l79', 'l83', 'l87', 'l88', 'l89']", + "130, calcineurin ['l62', 'l68', 'l69', 'l73', 'l80', 'l84', 'l87', 'l90', 'l91']", + "131, in ['l63', 'l74', 'l81', 'l85', 'l88', 'l90', 'l92']", + "132, vitro ['l64', 'l75', 'l82', 'l86', 'l89', 'l91', 'l92']", + "135, in ['l76', 'l93']", + "136, vivo, ['l77', 'l93']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "oral", + "phosphodiesterase-5A", + "(PDE5A)", + "inhibitor", + "(sildenafil)" + ] + }, + "context": { + "val": "cells", + "words": [ + "chamber", + "myocyte" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "oral", + "phosphodiesterase-5A", + "(PDE5A)", + "inhibitor", + "(sildenafil)", + "PDE5A" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "oral", + "phosphodiesterase-5A", + "(PDE5A)", + "inhibitor", + "(sildenafil)", + "of", + "PDE5A." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "heart", + "chamber", + "hearts," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "oral", + "phosphodiesterase-5A", + "(PDE5A)", + "inhibitor", + "(sildenafil)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "PDE5A" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "calcineurin" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "15665831", + "TEXT": "Infusion of endothelial progenitor cells (EPC), but not of mature endothelial cells, promotes neovascularization after ischemia. We performed gene expression profiling of EPC and endothelial cells to identify genes that might be important for the neovascularization capacity of EPC. Notably, the protease cathepsin L (CathL) was highly expressed in EPC as opposed to endothelial cells and was essential for matrix degradation and invasion by EPC in vitro. CathL-deficient mice showed impaired functional recovery following hind limb ischemia, supporting the concept of a crucial role for CathL in postnatal neovascularization. Infused CathL-deficient progenitor cells neither homed to sites of ischemia nor augmented neovascularization. Forced expression of CathL in mature endothelial cells considerably enhanced their invasive activity and sufficed to confer their capacity for neovascularization in vivo. We concluded that CathL has a critical role in the integration of circulating EPC into ischemic tissue and is required for EPC-mediated neovascularization.", + "TAG_DATA": [ + "65, in {'context': 'B-in vitro'}", + "66, vitro. {'context': 'I-in vitro'}", + "67, CathL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "68, mice {'context': 'B-organism'}", + "90, CathL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "91, progenitor {'context': 'B-cells'}", + "92, cells {'context': 'I-cells'}", + "102, Forced {'perturbing_action': 'B-gene gain-of-function'}", + "103, expression {'perturbing_action': 'I-gene gain-of-function'}", + "104, of {'perturbing_action': 'I-gene gain-of-function'}", + "105, CathL {'perturbing_action': 'I-gene gain-of-function'}", + "107, mature {'context': 'B-cells'}", + "108, endothelial {'context': 'I-cells'}", + "109, cells {'context': 'I-cells'}", + "123, in {'context': 'B-in vivo'}", + "124, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "65, in ['l0']", + "66, vitro. ['l0']", + "67, CathL-deficient ['l1', 'l2']", + "68, mice ['l1']", + "90, CathL-deficient ['l3', 'l4']", + "91, progenitor ['l3', 'l5']", + "92, cells ['l2', 'l4', 'l5']", + "102, Forced ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "103, expression ['l6', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "104, of ['l7', 'l14', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "105, CathL ['l8', 'l15', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "107, mature ['l9', 'l16', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "108, endothelial ['l10', 'l17', 'l23', 'l28', 'l32', 'l36', 'l37', 'l38']", + "109, cells ['l11', 'l18', 'l24', 'l29', 'l33', 'l36', 'l39', 'l40']", + "123, in ['l12', 'l19', 'l25', 'l30', 'l34', 'l37', 'l39', 'l41']", + "124, vivo. ['l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CathL-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CathL-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "progenitor" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "expression", + "of", + "CathL" + ] + }, + "context": { + "val": "cells", + "words": [ + "mature", + "endothelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "expression", + "of", + "CathL" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "15665829", + "TEXT": "Beyond serving as a mechanical barrier, the endothelium has important regulatory functions. The discovery of nitric oxide revolutionized our understanding of vasoregulation. In contrast, the identity of endothelium-derived vasoconstrictive factors (EDCFs) remains unclear. The supernatant obtained from mechanically stimulated human endothelial cells obtained from dermal vessels elicited a vasoconstrictive response in an isolated perfused rat kidney. A purinoceptor blocker had a greater effect than an endothelin receptor blocker in decreasing endothelially derived vasoconstriction in the isolated perfused rat kidney. The nucleotide uridine adenosine tetraphosphate (Up(4)A) was isolated from the supernatant of stimulated human endothelium and identified by mass spectrometry. Up(4)A is likely to exert vasoconstriction predominantly through P2X1 receptors, and probably also through P2Y2 and P2Y4 receptors. Plasma concentrations of Up(4)A that cause vasoconstriction are found in healthy subjects. Stimulation with adenosine 5'-triphosphate (ATP), uridine 5'-triphosphate (UTP), acetylcholine, endothelin, A23187 and mechanical stress releases Up(4)A from endothelium, suggesting that Up(4)A contributes to vascular autoregulation. To our knowledge, Up(4)A is the first dinucleotide isolated from living organisms that contains both purine and pyrimidine moieties. We conclude that Up(4)A is a novel potent nonpeptidic EDCF. Its vasoactive effects, plasma concentrations and its release upon endothelial stimulation strongly suggest that Up(4)A has a functional vasoregulatory role.", + "TAG_DATA": [ + "39, human {'context': 'B-cells'}", + "40, endothelial {'context': 'I-cells'}", + "41, cells {'context': 'I-cells'}", + "53, perfused {'context': 'B-tissue/organ'}", + "54, rat {'context': 'B-tissue/organ'}", + "55, kidney. {'context': 'I-tissue/organ'}", + "76, perfused {'context': 'B-tissue/organ'}", + "77, rat {'context': 'I-tissue/organ'}", + "78, kidney. {'context': 'I-tissue/organ'}", + "92, human {'context': 'B-cells'}", + "93, endothelium {'context': 'I-cells'}", + "146, endothelium, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "39, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "40, endothelial ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "41, cells ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "53, perfused ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31']", + "54, rat ['l3', 'l12', 'l20', 'l27', 'l32', 'l33', 'l34']", + "55, kidney. ['l4', 'l13', 'l21', 'l28', 'l32', 'l35']", + "76, perfused ['l5', 'l14', 'l22', 'l29', 'l36', 'l37', 'l38', 'l39']", + "77, rat ['l6', 'l15', 'l23', 'l30', 'l33', 'l36', 'l40', 'l41', 'l42']", + "78, kidney. ['l7', 'l16', 'l24', 'l31', 'l34', 'l35', 'l37', 'l40', 'l43', 'l44']", + "92, human ['l8', 'l17', 'l25', 'l38', 'l41', 'l43', 'l45']", + "93, endothelium ['l9', 'l18', 'l26', 'l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15619634", + "TEXT": "Histone deacetylases (HDACs) regulate transcription and specific cellular functions, such as tumor suppression by p53, and are frequently altered in cancer. Inhibitors of HDACs (HDACIs) possess antitumor activity and are well tolerated, supporting the idea that their use might develop as a specific strategy for cancer treatment. The molecular basis for their selective antitumor activity is, however, unknown. We investigated the effects of HDACIs on leukemias expressing the PML-RAR or AML1-ETO oncoproteins, known to initiate leukemogenesis through deregulation of HDACs. Here we report that: (i) HDACIs induce apoptosis of leukemic blasts, although oncogene expression is not sufficient to confer HDACI sensitivity to normal cells; (ii) apoptosis is p53 independent and depends, both in vitro and in vivo, upon activation of the death receptor pathway (TRAIL and Fas signaling pathways); (iii) TRAIL, DR5, FasL and Fas are upregulated by HDACIs in the leukemic cells, but not in normal hematopoietic progenitors. These results show that sensitivity to HDACIs in leukemias is a property of the fully transformed phenotype and depends on activation of a specific death pathway.", + "TAG_DATA": [ + "86, induce {'effect': 'B-positive'}", + "87, apoptosis {'phenotype': 'B-apoptosis'}", + "89, leukemic {'context': 'B-transformed cells'}", + "90, blasts, {'context': 'I-transformed cells'}", + "103, cells; {'context': 'I-cells'}", + "105, apoptosis {'phenotype': 'B-apoptosis'}", + "112, in {'context': 'B-in vitro'}", + "113, vitro {'context': 'I-in vitro'}", + "115, in {'context': 'B-in vivo'}", + "116, vivo, {'context': 'I-in vivo'}", + "141, leukemic {'context': 'B-transformed cells'}", + "142, cells, {'context': 'I-transformed cells'}", + "147, hematopoietic {'context': 'I-cells'}", + "148, progenitors. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "86, induce ['l0', 'l1', 'l2', 'l3']", + "87, apoptosis ['l0', 'l4', 'l5', 'l6']", + "89, leukemic ['l1', 'l4', 'l7', 'l8']", + "90, blasts, ['l2', 'l5', 'l7']", + "103, cells; ['l3', 'l6', 'l8']", + "105, apoptosis ['l9', 'l10', 'l11', 'l12']", + "112, in ['l9', 'l13', 'l14', 'l15']", + "113, vitro ['l10', 'l13', 'l16', 'l17']", + "115, in ['l11', 'l14', 'l16', 'l18']", + "116, vivo, ['l12', 'l15', 'l17', 'l18', 'l19']", + "141, leukemic ['l20', 'l21', 'l22']", + "142, cells, ['l19', 'l20', 'l23', 'l24']", + "147, hematopoietic ['l21', 'l23', 'l25']", + "148, progenitors. ['l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "leukemic", + "blasts," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells;" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "leukemic", + "blasts," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells;" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + } + ] + }, + { + "PMID": "15619633", + "TEXT": "Chromatin is a dynamic macromolecular structure epigenetically modified to regulate specific gene expression. Altered chromatin function can lead to aberrant expression of growth regulators and may, ultimately, cause cancer. That many human diseases have epigenetic etiology has stimulated the development of 'epigenetic' therapies. Inhibitors of histone deacetylases (HDACIs) induce proliferation arrest, maturation and apoptosis of cancer cells, but not normal cells, in vitro and in vivo, and are currently being tested in clinical trials. We investigated the mechanism(s) underlying this tumor selectivity. We report that HDACIs induce, in addition to p21, expression of TRAIL (Apo2L, TNFSF10) by directly activating the TNFSF10 promoter, thereby triggering tumor-selective death signaling in acute myeloid leukemia (AML) cells and the blasts of individuals with AML. RNA interference revealed that the induction of p21, TRAIL and differentiation are separable activities of HDACIs. HDACIs induced proliferation arrest, TRAIL-mediated apoptosis and suppression of AML blast clonogenicity irrespective of French-American-British (FAB) classification status, karyotype and immunophenotype. No apoptosis was seen in normal CD34(+) progenitor cells. Our results identify TRAIL as a mediator of the anticancer action of HDACIs.", + "TAG_DATA": [ + "49, proliferation {'phenotype': 'B-proliferation'}", + "50, arrest, {'phenotype': 'I-cell cycle arrest'}", + "55, cancer {'context': 'B-transformed cells'}", + "56, cells, {'context': 'I-transformed cells'}", + "59, normal {'context': 'B-cells'}", + "60, cells, {'context': 'I-cells'}", + "108, acute {'context': 'B-transformed cells'}", + "109, myeloid {'context': 'I-transformed cells'}", + "110, leukemia {'context': 'I-transformed cells'}", + "111, (AML) {'context': 'I-transformed cells'}", + "112, cells {'context': 'I-transformed cells'}", + "137, induced {'effect': 'B-positive'}", + "138, proliferation {'phenotype': 'B-cell cycle arrest'}", + "139, arrest, {'phenotype': 'I-cell cycle arrest'}", + "141, apoptosis {'phenotype': 'B-apoptosis'}", + "143, suppression {'effect': 'B-negative'}", + "145, AML {'context': 'B-transformed cells'}", + "146, blast {'context': 'I-transformed cells'}", + "147, clonogenicity {'phenotype': 'B-colony formation'}", + "157, No {'effect': 'B-no effect'}", + "158, apoptosis {'phenotype': 'B-apoptosis'}", + "163, CD34(+) {'context': 'B-cells'}", + "164, progenitor {'context': 'I-cells'}", + "165, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "49, proliferation ['l0', 'l1', 'l2', 'l3', 'l4']", + "50, arrest, ['l0', 'l5', 'l6', 'l7', 'l8']", + "55, cancer ['l1', 'l5', 'l9', 'l10', 'l11']", + "56, cells, ['l2', 'l6', 'l9', 'l12', 'l13']", + "59, normal ['l3', 'l7', 'l10', 'l12', 'l14']", + "60, cells, ['l4', 'l8', 'l11', 'l13', 'l14']", + "108, acute ['l15', 'l16', 'l17', 'l18']", + "109, myeloid ['l15', 'l19', 'l20', 'l21']", + "110, leukemia ['l16', 'l19', 'l22', 'l23']", + "111, (AML) ['l17', 'l20', 'l22', 'l24']", + "112, cells ['l18', 'l21', 'l23', 'l24']", + "137, induced ['l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "138, proliferation ['l25', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "139, arrest, ['l26', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "141, apoptosis ['l27', 'l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "143, suppression ['l28', 'l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "145, AML ['l29', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "146, blast ['l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "147, clonogenicity ['l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l52']", + "157, No ['l53', 'l54', 'l55', 'l56']", + "158, apoptosis ['l53', 'l57', 'l58', 'l59']", + "163, CD34(+) ['l54', 'l57', 'l60', 'l61']", + "164, progenitor ['l55', 'l58', 'l60', 'l62']", + "165, cells. ['l56', 'l59', 'l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "normal", + "cells," + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest,", + "proliferation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells,", + "AML", + "blast" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest," + ] + }, + "context": { + "val": "cells", + "words": [ + "normal", + "cells," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "proliferation", + "arrest," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "AML", + "blast" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenicity" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "proliferation", + "arrest," + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppression" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppression" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "AML", + "blast" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "AML", + "blast" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppression" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenicity" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "AML", + "blast" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenicity" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "No" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "No" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD34(+)", + "progenitor", + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD34(+)", + "progenitor", + "cells." + ] + } + } + ] + }, + { + "PMID": "15619630", + "TEXT": "Diabetes, a disease in which the body does not produce or use insulin properly, is a serious global health problem. Gut polypeptides secreted in response to food intake, such as glucagon-like peptide-1 (GLP-1), are potent incretin hormones that enhance the glucose-dependent secretion of insulin from pancreatic beta cells. Free fatty acids (FFAs) provide an important energy source and also act as signaling molecules in various cellular processes, including the secretion of gut incretin peptides. Here we show that a G-protein-coupled receptor, GPR120, which is abundantly expressed in intestine, functions as a receptor for unsaturated long-chain FFAs. Furthermore, we show that the stimulation of GPR120 by FFAs promotes the secretion of GLP-1 in vitro and in vivo, and increases circulating insulin. Because GLP-1 is the most potent insulinotropic incretin, our results indicate that GPR120-mediated GLP-1 secretion induced by dietary FFAs is important in the treatment of diabetes.", + "TAG_DATA": [ + "111, in {'context': 'B-in vitro'}", + "112, vitro {'context': 'I-in vitro'}", + "114, in {'context': 'B-in vivo'}", + "115, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "111, in ['l0', 'l1', 'l2']", + "112, vitro ['l0', 'l3', 'l4']", + "114, in ['l1', 'l3', 'l5']", + "115, vivo, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15608650", + "TEXT": "Period (Per) genes are involved in regulation of the circadian clock and are thought to modulate several brain functions. We demonstrate that Per2(Brdm1) mutant mice, which have a deletion in the PAS domain of the Per2 protein, show alterations in the glutamatergic system. Lowered expression of the glutamate transporter Eaat1 is observed in these animals, leading to reduced uptake of glutamate by astrocytes. As a consequence, glutamate levels increase in the extracellular space of Per2(Brdm1) mutant mouse brains. This is accompanied by increased alcohol intake in these animals. In humans, variations of the PER2 gene are associated with regulation of alcohol consumption. Acamprosate, a drug used to prevent craving and relapse in alcoholic patients is thought to act by dampening a hyper-glutamatergic state. This drug reduced augmented glutamate levels and normalized increased alcohol consumption in Per2(Brdm1) mutant mice. Collectively, these data establish glutamate as a link between dysfunction of the circadian clock gene Per2 and enhanced alcohol intake.", + "TAG_DATA": [ + "22, Per2(Brdm1) {'perturbing_action': 'B-other'}", + "23, mutant {'perturbing_action': 'I-other'}", + "24, mice, {'context': 'B-organism'}", + "28, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "29, in {'perturbing_action': 'I-gene loss-of-function'}", + "30, the {'perturbing_action': 'I-gene loss-of-function'}", + "31, PAS {'perturbing_action': 'I-gene loss-of-function'}", + "32, domain {'perturbing_action': 'I-gene loss-of-function'}", + "33, of {'perturbing_action': 'I-gene loss-of-function'}", + "34, the {'perturbing_action': 'I-gene loss-of-function'}", + "35, Per2 {'perturbing_action': 'I-gene loss-of-function'}", + "36, protein, {'perturbing_action': 'I-gene loss-of-function'}", + "54, animals, {'context': 'B-organism'}", + "62, astrocytes. {'context': 'B-cells'}", + "74, Per2(Brdm1) {'perturbing_action': 'B-other'}", + "75, mutant {'perturbing_action': 'I-other'}", + "76, mouse {'context': 'B-tissue/organ'}", + "77, brains. {'context': 'I-tissue/organ'}", + "87, animals. {'context': 'B-organism'}", + "135, Per2(Brdm1) {'perturbing_action': 'B-other'}", + "136, mutant {'perturbing_action': 'I-other'}", + "137, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "22, Per2(Brdm1) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "23, mutant ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "24, mice, ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "28, deletion ['l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "29, in ['l30', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "30, the ['l31', 'l45', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "31, PAS ['l32', 'l46', 'l59', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "32, domain ['l33', 'l47', 'l60', 'l72', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "33, of ['l34', 'l48', 'l61', 'l73', 'l84', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "34, the ['l2', 'l13', 'l35', 'l49', 'l62', 'l74', 'l85', 'l95', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "35, Per2 ['l3', 'l14', 'l36', 'l50', 'l63', 'l75', 'l86', 'l96', 'l105', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "36, protein, ['l4', 'l15', 'l37', 'l51', 'l64', 'l76', 'l87', 'l97', 'l106', 'l114', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "54, animals, ['l5', 'l16', 'l23', 'l38', 'l52', 'l65', 'l77', 'l88', 'l98', 'l107', 'l115', 'l122', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "62, astrocytes. ['l6', 'l17', 'l24', 'l39', 'l53', 'l66', 'l78', 'l89', 'l99', 'l108', 'l116', 'l123', 'l129', 'l135', 'l136', 'l137', 'l138', 'l139']", + "74, Per2(Brdm1) ['l7', 'l18', 'l25', 'l40', 'l54', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l124', 'l130', 'l135', 'l140', 'l141', 'l142', 'l143']", + "75, mutant ['l8', 'l19', 'l26', 'l41', 'l55', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l125', 'l131', 'l136', 'l140', 'l144', 'l145', 'l146']", + "76, mouse ['l9', 'l20', 'l27', 'l42', 'l56', 'l69', 'l81', 'l92', 'l102', 'l111', 'l119', 'l126', 'l132', 'l137', 'l141', 'l144', 'l147', 'l148']", + "77, brains. ['l10', 'l21', 'l28', 'l43', 'l57', 'l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l127', 'l133', 'l138', 'l142', 'l145', 'l147', 'l149']", + "87, animals. ['l11', 'l22', 'l29', 'l44', 'l58', 'l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l128', 'l134', 'l139', 'l143', 'l146', 'l148', 'l149']", + "135, Per2(Brdm1) ['l150', 'l151']", + "136, mutant ['l150', 'l152']", + "137, mice. ['l151', 'l152']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Per2(Brdm1)", + "mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "animals,", + "animals.", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Per2(Brdm1)", + "mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "astrocytes." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Per2(Brdm1)", + "mutant" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "brains." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "in", + "the", + "PAS", + "domain", + "of", + "Per2", + "protein," + ] + }, + "context": { + "val": "organism", + "words": [ + "animals,", + "animals." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "in", + "the", + "PAS", + "domain", + "of", + "Per2", + "protein," + ] + }, + "context": { + "val": "cells", + "words": [ + "astrocytes." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "in", + "the", + "PAS", + "domain", + "of", + "Per2", + "protein," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "brains." + ] + } + } + ] + }, + { + "PMID": "15543153", + "TEXT": "Signaling by the calcium-dependent phosphatase calcineurin profoundly influences the growth and gene expression of cardiac and skeletal muscle. Calcineurin binds to calsarcins, a family of muscle-specific proteins of the sarcomeric Z-disc, a focal point in the pathogenesis of human cardiomyopathies. We show that calsarcin-1 negatively modulates the functions of calcineurin, such that calcineurin signaling was enhanced in striated muscles of mice that do not express calsarcin-1. As a consequence of inappropriate calcineurin activation, mice with a null mutation in calsarcin-1 showed an excess of slow skeletal muscle fibers. The absence of calsarcin-1 also activated a hypertrophic gene program, despite the absence of hypertrophy, and enhanced the cardiac growth response to pressure overload. In contrast, cardiac adaptation to other hypertrophic stimuli, such as chronic catecholamine stimulation or exercise, was not affected. These findings show important roles for calsarcins as modulators of calcineurin signaling and the transmission of a specific subset of stress signals leading to cardiac remodeling in vivo.", + "TAG_DATA": [ + "60, mice {'context': 'B-organism'}", + "73, mice {'context': 'B-organism'}", + "76, null {'perturbing_action': 'B-gene loss-of-function'}", + "77, mutation {'perturbing_action': 'I-gene loss-of-function'}", + "78, in {'perturbing_action': 'I-gene loss-of-function'}", + "79, calsarcin-1 {'perturbing_action': 'I-gene loss-of-function'}", + "85, skeletal {'context': 'I-cells'}", + "86, muscle {'context': 'I-cells'}", + "87, fibers. {'context': 'I-cells'}", + "89, absence {'perturbing_action': 'B-gene loss-of-function'}", + "90, of {'perturbing_action': 'I-gene loss-of-function'}", + "91, calsarcin-1 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "60, mice ['l0', 'l1', 'l2']", + "73, mice ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "76, null ['l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "77, mutation ['l4', 'l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "78, in ['l5', 'l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "79, calsarcin-1 ['l6', 'l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "85, skeletal ['l0', 'l7', 'l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "86, muscle ['l1', 'l8', 'l14', 'l19', 'l23', 'l26', 'l28', 'l30']", + "87, fibers. ['l2', 'l9', 'l15', 'l20', 'l24', 'l27', 'l29', 'l30']", + "89, absence ['l31', 'l32']", + "90, of ['l31', 'l33']", + "91, calsarcin-1 ['l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "null", + "mutation", + "in", + "calsarcin-1" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "null", + "mutation", + "in", + "calsarcin-1" + ] + }, + "context": { + "val": "cells", + "words": [ + "skeletal", + "muscle", + "fibers." + ] + } + } + ] + }, + { + "PMID": "15531890", + "TEXT": "The BTB/POZ transcriptional repressor and candidate oncogene BCL6 is frequently misregulated in B-cell lymphomas. The interface through which the BCL6 BTB domain mediates recruitment of the SMRT, NCoR and BCoR corepressors was recently identified. To determine the contribution of this interface to BCL6 transcriptional and biological properties, we generated a peptide that specifically binds BCL6 and blocks corepressor recruitment in vivo. This inhibitor disrupts BCL6-mediated repression and establishment of silenced chromatin, reactivates natural BCL6 target genes, and abrogates BCL6 biological function in B cells. In BCL6-positive lymphoma cells, peptide blockade caused apoptosis and cell cycle arrest. BTB domain peptide inhibitors may constitute a novel therapeutic agent for B-cell lymphomas.", + "TAG_DATA": [ + "59, in {'context': 'B-in vivo'}", + "60, vivo. {'context': 'I-in vivo'}", + "82, B {'context': 'B-cells'}", + "83, cells. {'context': 'I-cells'}", + "85, BCL6-positive {'context': 'B-transformed cells'}", + "86, lymphoma {'context': 'I-transformed cells'}", + "87, cells, {'context': 'I-transformed cells'}", + "90, caused {'effect': 'B-positive'}", + "91, apoptosis {'phenotype': 'B-apoptosis'}", + "93, cell {'phenotype': 'B-cell cycle arrest'}", + "94, cycle {'phenotype': 'I-cell cycle arrest'}", + "95, arrest. {'phenotype': 'I-cell cycle arrest'}" + ], + "LINK_DATA": [ + "59, in ['l0', 'l1', 'l2']", + "60, vivo. ['l0', 'l3', 'l4']", + "82, B ['l1', 'l3', 'l5']", + "83, cells. ['l2', 'l4', 'l5']", + "85, BCL6-positive ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "86, lymphoma ['l6', 'l13', 'l14', 'l15', 'l16']", + "87, cells, ['l7', 'l13', 'l17']", + "90, caused ['l8', 'l14', 'l17', 'l18', 'l19', 'l20', 'l21']", + "91, apoptosis ['l9', 'l15', 'l18', 'l22', 'l23', 'l24']", + "93, cell ['l10', 'l19', 'l22', 'l25', 'l26']", + "94, cycle ['l11', 'l20', 'l23', 'l25', 'l27']", + "95, arrest. ['l12', 'l16', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "BCL6-positive", + "lymphoma", + "cells," + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "BCL6-positive", + "lymphoma" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "BCL6-positive", + "lymphoma" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest." + ] + } + } + ] + }, + { + "PMID": "15531889", + "TEXT": "We identify berberine (BBR), a compound isolated from a Chinese herb, as a new cholesterol-lowering drug. Oral administration of BBR in 32 hypercholesterolemic patients for 3 months reduced serum cholesterol by 29%, triglycerides by 35% and LDL-cholesterol by 25%. Treatment of hyperlipidemic hamsters with BBR reduced serum cholesterol by 40% and LDL-cholesterol by 42%, with a 3.5-fold increase in hepatic LDLR mRNA and a 2.6-fold increase in hepatic LDLR protein. Using human hepatoma cells, we show that BBR upregulates LDLR expression independent of sterol regulatory element binding proteins, but dependent on ERK activation. BBR elevates LDLR expression through a post-transcriptional mechanism that stabilizes the mRNA. Using a heterologous system with luciferase as a reporter, we further identify the 5' proximal section of the LDLR mRNA 3' untranslated region responsible for the regulatory effect of BBR. These findings show BBR as a new hypolipidemic drug with a mechanism of action different from that of statin drugs.", + "TAG_DATA": [ + "41, hyperlipidemic {'context': 'B-organism'}", + "42, hamsters {'context': 'I-organism'}", + "71, human {'context': 'B-transformed cells'}", + "72, hepatoma {'context': 'I-transformed cells'}", + "73, cells, {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "41, hyperlipidemic ['l0', 'l1', 'l2', 'l3']", + "42, hamsters ['l0', 'l4', 'l5', 'l6']", + "71, human ['l1', 'l4', 'l7', 'l8']", + "72, hepatoma ['l2', 'l5', 'l7', 'l9']", + "73, cells, ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15502843", + "TEXT": "Physiological anti-inflammatory mechanisms can potentially be exploited for the treatment of inflammatory disorders. Here we report that the neurotransmitter acetylcholine inhibits HMGB1 release from human macrophages by signaling through a nicotinic acetylcholine receptor. Nicotine, a selective cholinergic agonist, is more efficient than acetylcholine and inhibits HMGB1 release induced by either endotoxin or tumor necrosis factor-alpha (TNF-alpha). Nicotinic stimulation prevents activation of the NF-kappaB pathway and inhibits HMGB1 secretion through a specific 'nicotinic anti-inflammatory pathway' that requires the alpha7 nicotinic acetylcholine receptor (alpha7nAChR). In vivo, treatment with nicotine attenuates serum HMGB1 levels and improves survival in experimental models of sepsis, even when treatment is started after the onset of the disease. These results reveal acetylcholine as the first known physiological inhibitor of HMGB1 release from human macrophages and suggest that selective nicotinic agonists for the alpha7nAChR might have therapeutic potential for the treatment of sepsis.", + "TAG_DATA": [ + "82, In {'context': 'B-in vivo'}", + "83, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "82, In ['l0']", + "83, vivo, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15502839", + "TEXT": "Protective immunity against Mycobacterium tuberculosis depends on the generation of a T(H)1-type cellular immune response, characterized by the secretion of interferon-gamma (IFN-gamma) from antigen-specific T cells. The induction of potent cellular immune responses by vaccination in humans has proven difficult. Recombinant viral vectors, especially poxviruses and adenoviruses, are particularly effective at boosting previously primed CD4(+) and CD8(+) T-cell responses against a number of intracellular pathogens in animal studies. In the first phase 1 study of any candidate subunit vaccine against tuberculosis, recombinant modified vaccinia virus Ankara (MVA) expressing antigen 85A (MVA85A) was found to induce high levels of antigen-specific IFN-gamma-secreting T cells when used alone in bacille Calmette-Guerin (BCG)-naive healthy volunteers. In volunteers who had been vaccinated 0.5-38 years previously with BCG, substantially higher levels of antigen-specific IFN-gamma-secreting T cells were induced, and at 24 weeks after vaccination these levels were 5-30 times greater than in vaccinees administered a single BCG vaccination. Boosting vaccinations with MVA85A could offer a practical and efficient strategy for enhancing and prolonging antimycobacterial immunity in tuberculosis-endemic areas.", + "TAG_DATA": [ + "100, T {'context': 'B-cells'}", + "101, cells {'context': 'I-cells'}", + "109, healthy {'context': 'B-cells'}", + "110, volunteers. {'context': 'I-cells'}", + "112, volunteers {'context': 'B-cells'}", + "128, T {'context': 'B-cells'}", + "129, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "87, expressing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "88, antigen ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "89, 85A ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "100, T ['l2', 'l10', 'l17', 'l24', 'l25', 'l26']", + "101, cells ['l3', 'l11', 'l18', 'l24', 'l27', 'l28']", + "109, healthy ['l4', 'l12', 'l19', 'l25', 'l27', 'l29']", + "110, volunteers. ['l5', 'l13', 'l20', 'l26', 'l28', 'l29']", + "112, volunteers ['l6', 'l14', 'l21', 'l30', 'l31']", + "128, T ['l7', 'l15', 'l22', 'l30', 'l32']", + "129, cells ['l8', 'l16', 'l23', 'l31', 'l32']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15448688", + "TEXT": "Recent reports suggest that some commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) unexpectedly shift the cleavage products of amyloid precursor protein (APP) to shorter, less fibrillogenic forms, although the underlying mechanism remains unknown. We now demonstrate, using a fluorescence resonance energy transfer method, that Abeta(42)-lowering NSAIDs specifically affect the proximity between APP and presenilin 1 and alter presenilin 1 conformation both in vitro and in vivo, suggesting a novel allosteric mechanism of action.", + "TAG_DATA": [ + "60, in {'context': 'B-in vitro'}", + "61, vitro {'context': 'I-in vitro'}", + "63, in {'context': 'B-in vivo'}", + "64, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "60, in ['l0', 'l1', 'l2']", + "61, vitro ['l0', 'l3', 'l4']", + "63, in ['l1', 'l3', 'l5']", + "64, vivo, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15448687", + "TEXT": "The JNK pathway is known to be activated in several tissues in the diabetic state, and is possibly involved in the development of insulin resistance and suppression of insulin biosynthesis. Here we show a potential new therapy for diabetes using cell-permeable JNK-inhibitory peptide. Intraperitoneal administration of the peptide led to its transduction into various tissues in vivo, and this treatment markedly improved insulin resistance and ameliorated glucose tolerance in diabetic mice. These data indicate that the JNK pathway is critically involved in diabetes and that the cell-permeable JNK-inhibitory peptide may have promise as a new therapeutic agent for diabetes.", + "TAG_DATA": [ + "55, in {'context': 'B-in vivo'}", + "56, vivo, {'context': 'I-in vivo'}", + "69, diabetic {'context': 'B-organism'}", + "70, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "55, in ['l0']", + "56, vivo, ['l0']", + "69, diabetic ['l1']", + "70, mice. ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15361864", + "TEXT": "Volumetric computed tomography (VCT) is a technology in which area detectors are used for imaging large volumes of a subject with isotropic imaging resolution. We are experimenting with a prototype VCT scanner that uses flat-panel X-ray detectors and is designed for high-resolution three-dimensional (3D) imaging. Using this technique, we have demonstrated microangiography of xeno-transplanted skin squamous cell carcinomas in nude mice. VCT shows the vessel architecture of tumors and animals with greater detail and plasticity than has previously been achieved, and is superior to contrast-enhanced magnetic resonance (MR) angiography. VCT and MR images correlate well for larger tumor vessels, which are tracked from their origin on 3D reconstructions of VCT images. When compared with histology, small tumor vessels with a diameter as small as 50 microm were clearly visualized. Furthermore, imaging small vessel networks inside the tumor tissue improved discrimination of vital and necrotic regions. Thus, VCT substantially improves imaging of vascularization in tumors and offers a promising tool for preclinical studies of tumor angiogenesis and antiangiogenic therapies.", + "TAG_DATA": [ + "53, xeno-transplanted {'context': 'B-xenograft'}", + "54, skin {'context': 'I-neoplasm'}", + "55, squamous {'context': 'I-neoplasm'}", + "56, cell {'context': 'I-neoplasm'}", + "57, carcinomas {'context': 'I-neoplasm'}", + "59, nude {'context': 'B-organism'}", + "60, mice. {'context': 'I-organism'}", + "136, tumor {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "53, xeno-transplanted ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "54, skin ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "55, squamous ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "56, cell ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "57, carcinomas ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "59, nude ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "60, mice. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "136, tumor ['l21']", + "137, tissue ['l21']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15340403", + "TEXT": "If battling a viral illness for a week can be tiring, being consumed by it for years can be downright exhausting. Still, Malik Peiris labors on in his quest to conquer the elusive infections.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15322537", + "TEXT": "Lymphatic vessels are essential for the removal of interstitial fluid and prevention of tissue edema. Lymphatic capillaries lack associated mural cells, and collecting lymphatic vessels have valves, which prevent lymph backflow. In lymphedema-distichiasis (LD), lymphatic vessel function fails because of mutations affecting the forkhead transcription factor FOXC2. We report that Foxc2(-/-) mice show abnormal lymphatic vascular patterning, increased pericyte investment of lymphatic vessels, agenesis of valves and lymphatic dysfunction. In addition, an abnormally large proportion of skin lymphatic vessels was covered with smooth muscle cells in individuals with LD and in mice heterozygous for Foxc2 and for the gene encoding lymphatic endothelial receptor, Vegfr3 (also known as Flt4). Our data show that Foxc2 is essential for the morphogenesis of lymphatic valves and the establishment of a pericyte-free lymphatic capillary network and that it cooperates with Vegfr3 in the latter process. Our results indicate that an abnormal interaction between the lymphatic endothelial cells and pericytes, as well as valve defects, underlie the pathogenesis of LD.", + "TAG_DATA": [ + "50, Foxc2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "51, mice {'context': 'B-organism'}", + "91, mice {'context': 'B-organism'}", + "92, heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "93, for {'perturbing_action': 'I-gene loss-of-function'}", + "94, Foxc2 {'perturbing_action': 'I-gene loss-of-function'}", + "95, and {'perturbing_action': 'I-gene loss-of-function'}", + "96, for {'perturbing_action': 'I-gene loss-of-function'}", + "97, the {'perturbing_action': 'I-gene loss-of-function'}", + "98, gene {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "50, Foxc2(-/-) ['l0']", + "51, mice ['l0']", + "91, mice ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "92, heterozygous ['l1', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "93, for ['l2', 'l13', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "94, Foxc2 ['l3', 'l14', 'l24', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "95, and ['l4', 'l15', 'l25', 'l34', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "96, for ['l5', 'l16', 'l26', 'l35', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "97, the ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "98, gene ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "99, encoding ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l69', 'l70', 'l71', 'l72']", + "100, lymphatic ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l73', 'l74', 'l75']", + "101, endothelial ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l76', 'l77']", + "102, receptor, ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l78']", + "103, Vegfr3 ['l12', 'l23', 'l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l77', 'l78']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Foxc2(-/-)", + "heterozygous", + "for", + "Foxc2", + "and", + "the", + "gene" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15300244", + "TEXT": "Although post-translational modifications of protein antigens may be important componenets of some B cell epitopes, the determinants of T cell immunity are generally nonmodified peptides. Here we show that methylation of the Mycobacterium tuberculosis heparin-binding hemagglutinin (HBHA) by the bacterium is essential for effective T cell immunity to this antigen in infected healthy humans and in mice. Methylated HBHA provides high levels of protection against M. tuberculosis challenge in mice, whereas nonmethylated HBHA does not. Protective immunity induced by methylated HBHA is comparable to that afforded by vaccination with bacille Calmette et Guérin, the only available anti-tuberculosis vaccine. Thus, post-translational modifications of proteins may be crucial for their ability to induce protective T cell-mediated immunity against infectious diseases such as tuberculosis.", + "TAG_DATA": [ + "56, mice. {'context': 'B-organism'}", + "69, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15273747", + "TEXT": "A major obstacle limiting gene therapy for diseases of the heart and skeletal muscles is an inability to deliver genes systemically to muscles of an adult organism. Systemic gene transfer to striated muscles is hampered by the vascular endothelium, which represents a barrier to distribution of vectors via the circulation. Here we show the first evidence of widespread transduction of both cardiac and skeletal muscles in an adult mammal, after a single intravenous administration of recombinant adeno-associated virus pseudotype 6 vectors. The inclusion of vascular endothelium growth factor/vascular permeability factor, to achieve acute permeabilization of the peripheral microvasculature, enhanced tissue transduction at lower vector doses. This technique enabled widespread muscle-specific expression of a functional micro-dystrophin in the skeletal muscles of dystrophin-deficient mdx mice, which model Duchenne muscular dystrophy. We propose that these methods may be applicable for systemic delivery of a wide variety of genes to the striated muscles of adult mammals.", + "TAG_DATA": [ + "61, cardiac {'context': 'B-tissue/organ'}", + "62, and {'context': 'I-tissue/organ'}", + "63, skeletal {'context': 'I-tissue/organ'}", + "64, muscles {'context': 'I-tissue/organ'}", + "67, adult {'context': 'B-organism'}", + "68, mammal, {'context': 'I-organism'}", + "117, skeletal {'context': 'B-tissue/organ'}", + "118, muscles {'context': 'I-tissue/organ'}", + "120, dystrophin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "121, mdx {'perturbing_action': 'B-gene loss-of-function'}", + "122, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "61, cardiac ['l0', 'l1', 'l2', 'l3', 'l4']", + "62, and ['l0', 'l5', 'l6', 'l7', 'l8']", + "63, skeletal ['l1', 'l5', 'l9', 'l10', 'l11']", + "64, muscles ['l2', 'l6', 'l9', 'l12', 'l13']", + "67, adult ['l3', 'l7', 'l10', 'l12', 'l14']", + "68, mammal, ['l4', 'l8', 'l11', 'l13', 'l14']", + "117, skeletal ['l15', 'l16', 'l17', 'l18']", + "118, muscles ['l15', 'l19', 'l20', 'l21']", + "120, dystrophin-deficient ['l16', 'l19', 'l22', 'l23']", + "121, mdx ['l17', 'l20', 'l22', 'l24']", + "122, mice, ['l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "skeletal", + "muscles" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient", + "mdx" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient", + "mdx" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "15235598", + "TEXT": "The dominant polyglutamine expansion diseases, which include spinocerebellar ataxia type 1 (SCA1) and Huntington disease, are progressive, untreatable, neurodegenerative disorders. In inducible mouse models of SCA1 and Huntington disease, repression of mutant allele expression improves disease phenotypes. Thus, therapies designed to inhibit expression of the mutant gene would be beneficial. Here we evaluate the ability of RNA interference (RNAi) to inhibit polyglutamine-induced neurodegeneration caused by mutant ataxin-1 in a mouse model of SCA1. Upon intracerebellar injection, recombinant adeno-associated virus (AAV) vectors expressing short hairpin RNAs profoundly improved motor coordination, restored cerebellar morphology and resolved characteristic ataxin-1 inclusions in Purkinje cells of SCA1 mice. Our data demonstrate in vivo the potential use of RNAi as therapy for dominant neurodegenerative disease.", + "TAG_DATA": [ + "65, mutant {'perturbing_action': 'B-other'}", + "66, ataxin-1 {'perturbing_action': 'I-other'}", + "69, mouse {'context': 'B-organism'}", + "70, model {'context': 'I-organism'}", + "71, of {'context': 'I-organism'}", + "72, SCA1. {'context': 'I-organism'}", + "76, recombinant {'perturbing_action': 'B-rnai/knockdown'}", + "77, adeno-associated {'perturbing_action': 'I-rnai/knockdown'}", + "78, virus {'perturbing_action': 'I-rnai/knockdown'}", + "79, (AAV) {'perturbing_action': 'I-rnai/knockdown'}", + "80, vectors {'perturbing_action': 'I-rnai/knockdown'}", + "81, expressing {'perturbing_action': 'I-rnai/knockdown'}", + "82, short {'perturbing_action': 'I-rnai/knockdown'}", + "83, hairpin {'perturbing_action': 'I-rnai/knockdown'}", + "98, Purkinje {'context': 'B-cells'}", + "99, cells {'context': 'I-cells'}", + "101, SCA1 {'context': 'B-organism'}", + "102, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "65, mutant ['l0', 'l1', 'l2', 'l3', 'l4']", + "66, ataxin-1 ['l0', 'l5', 'l6', 'l7', 'l8']", + "69, mouse ['l1', 'l5', 'l9', 'l10', 'l11']", + "70, model ['l2', 'l6', 'l9', 'l12', 'l13']", + "71, of ['l3', 'l7', 'l10', 'l12', 'l14']", + "72, SCA1. ['l4', 'l8', 'l11', 'l13', 'l14']", + "76, recombinant ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "77, adeno-associated ['l15', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "78, virus ['l16', 'l26', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "79, (AAV) ['l17', 'l27', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "80, vectors ['l18', 'l28', 'l37', 'l45', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "81, expressing ['l19', 'l29', 'l38', 'l46', 'l53', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "82, short ['l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l66', 'l67', 'l68', 'l69', 'l70']", + "83, hairpin ['l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l71', 'l72', 'l73', 'l74']", + "98, Purkinje ['l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l75', 'l76', 'l77']", + "99, cells ['l23', 'l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l78', 'l79']", + "101, SCA1 ['l24', 'l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l76', 'l78', 'l80']", + "102, mice. ['l25', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l79', 'l80']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "ataxin-1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "SCA1." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "recombinant", + "adeno-associated", + "virus", + "(AAV)", + "vectors", + "expressing", + "short", + "hairpin" + ] + }, + "context": { + "val": "cells", + "words": [ + "Purkinje", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "recombinant", + "adeno-associated", + "virus", + "(AAV)", + "vectors", + "expressing", + "short", + "hairpin" + ] + }, + "context": { + "val": "organism", + "words": [ + "SCA1", + "mice." + ] + } + } + ] + }, + { + "PMID": "15220914", + "TEXT": "Leptin is an adipocyte-derived hormone that regulates energy balance and neuroendocrine function primarily by acting on specific hypothalamic pathways. Resistance to the weight reducing effects of leptin is a feature of most cases of human and rodent obesity, yet the molecular basis of leptin resistance is poorly understood. We have previously identified suppressor of cytokine signaling-3 (Socs3) as a leptin-induced negative regulator of leptin receptor signaling and potential mediator of leptin resistance. However, due to the non-viability of mice with targeted disruption of Socs3 (ref. 6), the importance of Socs3 in leptin action in vivo was unclear. To determine the functional significance of Socs3 in energy balance in vivo we undertook studies in mice with heterozygous Socs3 deficiency (Socs3(+/-)). We report here that Socs3(+/-) mice display greater leptin sensitivity than wild-type control mice: Socs3(+/-) mice show both enhanced weight loss and increased hypothalamic leptin receptor signaling in response to exogenous leptin administration. Furthermore, Socs3(+/-) mice are significantly protected against the development of diet-induced obesity and associated metabolic complications. The level of Socs3 expression is thus a critical determinant of leptin sensitivity and obesity susceptibility in vivo and this molecule is a potential target for therapeutic intervention.", + "TAG_DATA": [ + "113, mice {'context': 'B-organism'}", + "115, heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "116, Socs3 {'perturbing_action': 'I-gene loss-of-function'}", + "117, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "118, (Socs3(+/-)). {'perturbing_action': 'I-gene loss-of-function'}", + "123, Socs3(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "124, mice {'context': 'B-organism'}", + "132, mice: {'context': 'B-organism'}", + "133, Socs3(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "134, mice {'context': 'B-organism'}", + "153, Socs3(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "154, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "113, mice ['l0', 'l1', 'l2', 'l3']", + "115, heterozygous ['l0', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "116, Socs3 ['l1', 'l4', 'l10', 'l11', 'l12', 'l13', 'l14']", + "117, deficiency ['l2', 'l5', 'l10', 'l15', 'l16', 'l17', 'l18']", + "118, (Socs3(+/-)). ['l3', 'l6', 'l11', 'l15', 'l19', 'l20', 'l21']", + "123, Socs3(+/-) ['l7', 'l12', 'l16', 'l19', 'l22', 'l23', 'l24']", + "124, mice ['l8', 'l13', 'l17', 'l20', 'l22', 'l25']", + "132, mice: ['l9', 'l14', 'l18', 'l21', 'l23', 'l25', 'l26']", + "133, Socs3(+/-) ['l27']", + "134, mice ['l24', 'l26', 'l27']", + "153, Socs3(+/-) ['l28']", + "154, mice ['l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice:" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "heterozygous", + "Socs3", + "deficiency", + "(Socs3(+/-)).", + "Socs3(+/-)" + ] + } + } + ] + }, + { + "PMID": "15208705", + "TEXT": "Leptin is an adipocyte-derived hormone that plays a key role in energy homeostasis, yet resistance to leptin is a feature of most cases of obesity in humans and rodents. In vitro analysis suggested that the suppressor of cytokine signaling-3 (Socs3) is a negative-feedback regulator of leptin signaling involved in leptin resistance. To determine the functional significance of Socs3 in vivo, we generated neural cell-specific SOCS3 conditional knockout mice using the Cre-loxP system. Compared to their wild-type littermates, Socs3-deficient mice showed enhanced leptin-induced hypothalamic Stat3 tyrosine phosphorylation as well as pro-opiomelanocortin (POMC) induction, and this resulted in a greater body weight loss and suppression of food intake. Moreover, the Socs3-deficient mice were resistant to high fat diet-induced weight gain and hyperleptinemia, and insulin-sensitivity was retained. These data indicate that Socs3 is a key regulator of diet-induced leptin as well as insulin resistance. Our study demonstrates the negative regulatory role of Socs3 in leptin signaling in vivo, and thus suppression of Socs3 in the brain is a potential therapy for leptin-resistance in obesity.", + "TAG_DATA": [ + "62, neural {'perturbing_action': 'B-gene loss-of-function'}", + "63, cell-specific {'perturbing_action': 'I-gene loss-of-function'}", + "64, SOCS3 {'perturbing_action': 'I-gene loss-of-function'}", + "65, conditional {'perturbing_action': 'I-gene loss-of-function'}", + "66, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "67, mice {'context': 'B-organism'}", + "77, Socs3-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "78, mice {'context': 'B-organism'}", + "108, Socs3-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "109, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "62, neural ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "63, cell-specific ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "64, SOCS3 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "65, conditional ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "66, knockout ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "67, mice ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "77, Socs3-deficient ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "78, mice ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "108, Socs3-deficient ['l28']", + "109, mice ['l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "neural", + "cell-specific", + "SOCS3", + "conditional", + "knockout", + "Socs3-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15195087", + "TEXT": "AMP-activated protein kinase (AMPK) functions as a fuel sensor in the cell and is activated when cellular energy is depleted. Here we report that alpha-lipoic acid (alpha-LA), a cofactor of mitochondrial enzymes, decreases hypothalamic AMPK activity and causes profound weight loss in rodents by reducing food intake and enhancing energy expenditure. Activation of hypothalamic AMPK reverses the effects of alpha-LA on food intake and energy expenditure. Intracerebroventricular (i.c.v.) administration of glucose decreases hypothalamic AMPK activity, whereas inhibition of intracellular glucose utilization through the administration of 2-deoxyglucose increases hypothalamic AMPK activity and food intake. The 2-deoxyglucose-induced hyperphagia is reversed by inhibiting hypothalamic AMPK. Our findings indicate that hypothalamic AMPK is important in the central regulation of food intake and energy expenditure and that alpha-LA exerts anti-obesity effects by suppressing hypothalamic AMPK activity.", + "TAG_DATA": [ + "42, rodents {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15170210", + "TEXT": "We determine here the functional integrity of auxiliary livers in containers fashioned from the small intestine. Liver microfragments from dipeptidyl peptidase 4 (DPP4)-deficient rats were transplanted into syngeneic normal animals with isolated intestinal segments characterized by mucosal denudation but intact vascular supply. Transplanted liver fragments were restored to confluent tissue with normal hepatic architecture and development of DPP4-positive vessels, indicating angiogenesis and revascularization. Auxiliary liver units expressed multiple hepatotrophic and angiogenic genes, and transplanted tissues remained intact for up to the 6-week duration of the studies with neither ischemic injury nor significant hepatocellular proliferation. Hepatic metabolic, transport and synthetic functions were preserved in auxiliary livers, including uptake and biliary excretion of (99m)Tc-mebrofenin in syngeneic recipients of liver from F344 rats, as well as secretion of albumin in allografted Nagase analbuminemic rats. This ability to produce functionally competent auxiliary livers in vascularized intestinal segments offers therapeutic potential for liver disease and genetic deficiency.", + "TAG_DATA": [ + "19, dipeptidyl {'perturbing_action': 'B-gene loss-of-function'}", + "20, peptidase {'perturbing_action': 'I-gene loss-of-function'}", + "21, 4 {'perturbing_action': 'I-gene loss-of-function'}", + "22, (DPP4)-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "23, rats {'context': 'B-organism'}", + "27, syngeneic {'context': 'B-organism'}", + "28, normal {'context': 'I-organism'}", + "29, animals {'context': 'I-organism'}", + "43, liver {'context': 'B-tissue/organ'}", + "44, fragments {'context': 'I-tissue/organ'}", + "93, proliferation. {'phenotype': 'B-proliferation'}", + "103, auxiliary {'context': 'B-tissue/organ'}", + "104, livers, {'context': 'I-tissue/organ'}", + "114, recipients {'context': 'I-tissue/organ'}", + "116, liver {'context': 'I-cells'}", + "118, F344 {'context': 'I-cells'}", + "119, rats, {'context': 'I-cells'}", + "130, rats. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "19, dipeptidyl ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "20, peptidase ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "21, 4 ['l1', 'l9', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "22, (DPP4)-deficient ['l2', 'l10', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "23, rats ['l3', 'l11', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "27, syngeneic ['l4', 'l12', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "28, normal ['l5', 'l13', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "29, animals ['l6', 'l14', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "43, liver ['l7', 'l15', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "44, fragments ['l8', 'l16', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']", + "93, proliferation. ['l17']", + "103, auxiliary ['l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "104, livers, ['l46', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "113, syngeneic ['l47', 'l53', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "114, recipients ['l48', 'l54', 'l59', 'l65', 'l66', 'l67', 'l68', 'l69']", + "115, of ['l49', 'l55', 'l60', 'l65', 'l70', 'l71', 'l72', 'l73']", + "116, liver ['l50', 'l56', 'l61', 'l66', 'l70', 'l74', 'l75', 'l76']", + "118, F344 ['l51', 'l57', 'l62', 'l67', 'l71', 'l74', 'l77', 'l78']", + "119, rats, ['l52', 'l58', 'l63', 'l68', 'l72', 'l75', 'l77', 'l79']", + "130, rats. ['l64', 'l69', 'l73', 'l76', 'l78', 'l79']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dipeptidyl", + "peptidase", + "4", + "(DPP4)-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats", + "syngeneic", + "normal", + "animals" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dipeptidyl", + "peptidase", + "4", + "(DPP4)-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver", + "fragments" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "peptidase" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "15156203", + "TEXT": "Because variant Creutzfeldt-Jakob disease (vCJD) in humans probably results from consumption of products contaminated with tissue from animals with bovine spongiform encephalopathy, whether infectious prion protein is present in ruminant muscles is a crucial question. Here we show that experimentally and naturally scrapie-affected sheep accumulate the prion protein PrP(Sc) in a myocyte subset. In naturally infected sheep, PrP(Sc) is detectable in muscle several months before clinical disease onset. The relative amounts of PrP(Sc) suggest a 5,000-fold lower infectivity for muscle as compared to brain.", + "TAG_DATA": [ + "43, sheep {'context': 'B-organism'}", + "51, myocyte {'context': 'B-cells'}", + "52, subset. {'context': 'I-cells'}", + "56, sheep, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "43, sheep ['l0', 'l1']", + "51, myocyte ['l0', 'l2']", + "52, subset. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15146179", + "TEXT": "Thyroxine (T(4)) is the predominant form of thyroid hormone (TH). Hyperthyroidism, a condition associated with excess TH, is characterized by increases in metabolic rate, core body temperature and cardiac performance. In target tissues, T(4) is enzymatically deiodinated to 3,5,3'-triiodothyronine (T(3)), a high-affinity ligand for the nuclear TH receptors TR alpha and TR beta, whose activation controls normal vertebrate development and physiology. T(3)-modulated transcription of target genes via activation of TR alpha and TR beta is a slow process, the effects of which manifest over hours and days. Although rapidly occurring effects of TH have been documented, the molecules that mediate these non-genomic effects remain obscure. Here we report the discovery of 3-iodothyronamine (T(1)AM), a naturally occurring derivative of TH that in vitro is a potent agonist of the G protein-coupled trace amine receptor TAR1. Administering T(1)AM in vivo induces profound hypothermia and bradycardia within minutes. T(1)AM treatment also rapidly reduces cardiac output in an ex vivo working heart preparation. These results suggest the existence of a new signaling pathway, stimulation of which leads to rapid physiological and behavioral consequences that are opposite those associated with excess TH.", + "TAG_DATA": [ + "136, in {'context': 'B-in vivo'}", + "137, vivo {'context': 'I-in vivo'}", + "156, working {'context': 'B-tissue/organ'}", + "157, heart {'context': 'I-cells'}", + "158, preparation. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "136, in ['l0']", + "137, vivo ['l0']", + "154, ex ['l1', 'l2', 'l3', 'l4']", + "155, vivo ['l1', 'l5', 'l6', 'l7']", + "156, working ['l2', 'l5', 'l8', 'l9']", + "157, heart ['l3', 'l6', 'l8', 'l10']", + "158, preparation. ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15107845", + "TEXT": "Macrophages play host to Leishmania major, a parasite that causes leishmaniasis in 500,000 people annually. Macrophage-expressed CD40, a costimulatory molecule, induces interleukin-12 (IL-12)-dependent and interferon-gamma (IFN-gamma)-dependent host-protective immune responses to Leishmania and other intracellular pathogens. Paradoxically, IL-10, another CD40-induced cytokine in macrophages, promotes Leishmania infection. How CD40 signaling regulates the secretion of these two counteractive cytokines remains unknown. Here we show that weak CD40 signals induce extracellular stress-related kinase-1/2 (ERK-1/2)-dependent IL-10 expression, whereas stronger signals induce p38 mitogen-activated protein kinase (p38MAPK)-dependent IL-12 production. p38MAPK and ERK-1/2 therefore have counter-regulatory actions. Leishmania skews CD40 signaling toward ERK-1/2, inducing IL-10, which inhibits activation of CD40-induced p38MAPK and expression of inducible nitric oxide synthase-2 (iNOS-2) and IL-12. ERK-1/2 inhibition or IL-10 neutralization restores CD40-induced p38MAPK activation and parasite killing in macrophages and the BALB/c mouse, a susceptible host. These data uncover a new immune evasion strategy, whereby Leishmania differentially modulates CD40-engaged, reciprocally functioning signaling modules, and provide a new conceptual framework for immune homeostasis.", + "TAG_DATA": [ + "114, ERK-1/2 {'perturbing_action': 'B-pharmacological inhibition'}", + "115, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "117, IL-10 {'perturbing_action': 'B-rnai/knockdown'}", + "118, neutralization {'perturbing_action': 'I-rnai/knockdown'}", + "127, macrophages {'context': 'B-cells'}", + "130, BALB/c {'context': 'B-organism'}", + "131, mouse, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "114, ERK-1/2 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "115, inhibition ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "117, IL-10 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "118, neutralization ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "124, parasite ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "127, macrophages ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "130, BALB/c ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "131, mouse, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ERK-1/2", + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ERK-1/2", + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "BALB/c", + "mouse," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "IL-10", + "neutralization" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "IL-10", + "neutralization" + ] + }, + "context": { + "val": "organism", + "words": [ + "BALB/c", + "mouse," + ] + } + } + ] + }, + { + "PMID": "15098027", + "TEXT": "Hemostasis initiates angiogenesis-dependent wound healing, and thrombosis is frequently associated with advanced cancer. Although activation of coagulation generates potent regulators of angiogenesis, little is known about how this pathway supports angiogenesis in vivo. Here we show that the tissue factor (TF)-VIIa protease complex, independent of triggering coagulation, can promote tumor and developmental angiogenesis through protease-activated receptor-2 (PAR-2) signaling. In this context, the TF cytoplasmic domain negatively regulates PAR-2 signaling. Mice from which the TF cytoplasmic domain has been deleted (TF Delta CT mice) show enhanced PAR-2-dependent angiogenesis, in synergy with platelet-derived growth factor BB (PDGF-BB). Ocular tissue from diabetic patients shows PAR-2 colocalization with phosphorylated TF specifically on neovasculature, suggesting that phosphorylation of the TF cytoplasmic domain releases its negative regulatory control of PAR-2 signaling in angiogenesis. Targeting the TF-VIIa signaling pathway may thus enhance the efficacy of angiostatic treatments for cancer and neovascular eye diseases.", + "TAG_DATA": [ + "69, Mice {'context': 'B-organism'}", + "72, the {'perturbing_action': 'I-gene loss-of-function'}", + "73, TF {'perturbing_action': 'I-gene loss-of-function'}", + "74, cytoplasmic {'perturbing_action': 'I-gene loss-of-function'}", + "75, domain {'perturbing_action': 'I-gene loss-of-function'}", + "76, has {'perturbing_action': 'I-gene loss-of-function'}", + "77, been {'perturbing_action': 'I-gene loss-of-function'}", + "78, deleted {'perturbing_action': 'I-gene loss-of-function'}", + "80, Delta {'perturbing_action': 'B-gene loss-of-function'}", + "81, CT {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "69, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "72, the ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "73, TF ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "74, cytoplasmic ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "75, domain ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "76, has ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "77, been ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "78, deleted ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "80, Delta ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "81, CT ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "TF", + "cytoplasmic", + "domain", + "has", + "been", + "deleted", + "Delta", + "CT" + ] + } + } + ] + }, + { + "PMID": "15077108", + "TEXT": "Adiponectin (ADP) is an adipocyte hormone involved in glucose and lipid metabolism. We detected a rise in ADP in cerebrospinal fluid after intravenous (i.v.) injection, consistent with brain transport. In contrast to leptin, intracerebroventricular (i.c.v.) administration of ADP decreased body weight mainly by stimulating energy expenditure. Full-length ADP, mutant ADP with Cys39 replaced with serine, and globular ADP were effective, whereas the collagenous tail fragment was not. Lep(ob/ob) mice were especially sensitive to i.c.v. and systemic ADP, which resulted in increased thermogenesis, weight loss and reduction in serum glucose and lipid levels. ADP also potentiated the effect of leptin on thermogenesis and lipid levels. While both hormones increased expression of hypothalamic corticotropin-releasing hormone (CRH), ADP had no substantial effect on other neuropeptide targets of leptin. In addition, ADP induced distinct Fos immunoreactivity. Agouti (A(y)/a) mice did not respond to ADP or leptin, indicating the melanocortin pathway may be a common target. These results show that ADP has unique central effects on energy homeostasis.", + "TAG_DATA": [ + "67, Lep(ob/ob) {'perturbing_action': 'B-gene loss-of-function'}", + "68, mice {'context': 'B-organism'}", + "132, Agouti {'perturbing_action': 'B-other'}", + "133, (A(y)/a) {'perturbing_action': 'B-other'}", + "134, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "67, Lep(ob/ob) ['l0']", + "68, mice ['l0']", + "132, Agouti ['l1', 'l2']", + "133, (A(y)/a) ['l1', 'l3']", + "134, mice ['l2', 'l3']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lep(ob/ob)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Agouti", + "(A(y)/a)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15034573", + "TEXT": "Charcot-Marie-Tooth disease (CMT) is the most common hereditary peripheral neuropathy, affecting 1 in 2,500 people. The only treatment currently available is rehabilitation or corrective surgery. The most frequent form of the disease, CMT-1A, involves abnormal myelination of the peripheral nerves. Here we used a mouse model of CMT-1A to test the ability of ascorbic acid, a known promoter of myelination, to correct the CMT-1A phenotype. Ascorbic acid treatment resulted in substantial amelioration of the CMT-1A phenotype, and reduced the expression of PMP22 to a level below what is necessary to induce the disease phenotype. As ascorbic acid has already been approved by the FDA for other clinical indications, it offers an immediate therapeutic possibility for patients with the disease.", + "TAG_DATA": [ + "44, mouse {'context': 'B-organism'}", + "45, model {'context': 'I-organism'}", + "46, of {'context': 'I-organism'}", + "47, CMT-1A {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "44, mouse ['l0', 'l1', 'l2']", + "45, model ['l0', 'l3', 'l4']", + "46, of ['l1', 'l3', 'l5']", + "47, CMT-1A ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15034569", + "TEXT": "Over 7 million people worldwide die annually from erratic heart rhythms (cardiac arrhythmias), and many more are disabled. Yet there is no imaging modality to identify patients at risk, provide accurate diagnosis and guide therapy. Standard diagnostic techniques such as the electrocardiogram (ECG) provide only low-resolution projections of cardiac electrical activity on the body surface. Here we demonstrate the successful application in humans of a new imaging modality called electrocardiographic imaging (ECGI), which noninvasively images cardiac electrical activity in the heart. In ECGI, a multielectrode vest records 224 body-surface electrocardiograms; electrical potentials, electrograms and isochrones are then reconstructed on the heart's surface using geometrical information from computed tomography (CT) and a mathematical algorithm. We provide examples of ECGI application during atrial and ventricular activation and ventricular repolarization in (i) normal heart (ii) heart with a conduction disorder (right bundle branch block) (iii) focal activation initiated by right or left ventricular pacing, and (iv) atrial flutter.", + "TAG_DATA": [ + "132, heart {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15034566", + "TEXT": "Atherosclerosis, the leading cause of death in developed countries, has been linked to hypercholesterolemia for decades. More recently, atherosclerotic lesion progression has been shown to depend on persistent, chronic inflammation in the artery wall. Although several studies have implicated infectious agents in this process, the role of infection in atherosclerosis remains controversial. Because the involvement of monocytes and macrophages in the pathogenesis of atherosclerosis is well established, we investigated the possibility that macrophage innate immunity signaling pathways normally activated by pathogens might also be activated in response to hyperlipidemia. We examined atherosclerotic lesion development in uninfected, hyperlipidemic mice lacking expression of either lipopolysaccharide (LPS) receptor CD14 or myeloid differentiation protein-88 (MyD88), which transduces cell signaling events downstream of the Toll-like receptors (TLRs), as well as receptors for interleukin-1 (IL-1) and IL-18. Whereas the MyD88-deficient mice evinced a marked reduction in early atherosclerosis, mice deficient in CD14 had no decrease in early lesion development. Inactivation of the MyD88 pathway led to a reduction in atherosclerosis through a decrease in macrophage recruitment to the artery wall that was associated with reduced chemokine levels. These findings link elevated serum lipid levels to a proinflammatory signaling cascade that is also engaged by microbial pathogens.", + "TAG_DATA": [ + "97, mice {'context': 'B-organism'}", + "98, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "99, expression {'perturbing_action': 'I-gene loss-of-function'}", + "100, of {'perturbing_action': 'I-gene loss-of-function'}", + "101, either {'perturbing_action': 'I-gene loss-of-function'}", + "102, lipopolysaccharide {'perturbing_action': 'I-gene loss-of-function'}", + "104, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "105, CD14 {'perturbing_action': 'I-gene loss-of-function'}", + "107, myeloid {'perturbing_action': 'I-gene loss-of-function'}", + "133, MyD88-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "134, mice {'context': 'B-organism'}", + "138, reduction {'effect': 'B-negative'}", + "142, mice {'context': 'B-organism'}", + "143, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "144, in {'perturbing_action': 'I-gene loss-of-function'}", + "145, CD14 {'perturbing_action': 'I-gene loss-of-function'}", + "153, Inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "154, of {'perturbing_action': 'I-gene loss-of-function'}", + "155, the {'perturbing_action': 'I-gene loss-of-function'}", + "156, MyD88 {'perturbing_action': 'I-gene loss-of-function'}", + "157, pathway {'perturbing_action': 'I-gene loss-of-function'}", + "161, reduction {'effect': 'B-negative'}", + "168, macrophage {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "97, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "98, lacking ['l0', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "99, expression ['l5', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "100, of ['l6', 'l12', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "101, either ['l1', 'l7', 'l13', 'l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "102, lipopolysaccharide ['l2', 'l8', 'l14', 'l22', 'l29', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "104, receptor ['l3', 'l9', 'l15', 'l23', 'l30', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "105, CD14 ['l4', 'l10', 'l16', 'l24', 'l31', 'l37', 'l42', 'l47', 'l48', 'l49', 'l50']", + "107, myeloid ['l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l51', 'l52', 'l53', 'l54']", + "133, MyD88-deficient ['l11', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l55', 'l56']", + "134, mice ['l19', 'l27', 'l34', 'l40', 'l45', 'l49', 'l52', 'l55', 'l57']", + "138, reduction ['l20', 'l28', 'l35', 'l41', 'l46', 'l50', 'l53', 'l56', 'l57']", + "142, mice ['l58', 'l59', 'l60']", + "143, deficient ['l58', 'l61', 'l62']", + "144, in ['l59', 'l61', 'l63']", + "145, CD14 ['l54', 'l60', 'l62', 'l63']", + "153, Inactivation ['l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "154, of ['l64', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "155, the ['l65', 'l71', 'l77', 'l78', 'l79', 'l80', 'l81']", + "156, MyD88 ['l66', 'l72', 'l77', 'l82', 'l83', 'l84', 'l85']", + "157, pathway ['l67', 'l73', 'l78', 'l82', 'l86', 'l87', 'l88']", + "161, reduction ['l68', 'l74', 'l79', 'l83', 'l86', 'l89', 'l90']", + "163, atherosclerosis ['l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l91']", + "168, macrophage ['l70', 'l76', 'l81', 'l85', 'l88', 'l90', 'l91']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "either", + "lipopolysaccharide", + "receptor", + "CD14", + "expression", + "of", + "myeloid", + "MyD88-deficient", + "deficient", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "expression", + "of", + "either", + "lipopolysaccharide", + "receptor", + "CD14", + "myeloid", + "MyD88-deficient", + "Inactivation", + "the", + "MyD88", + "pathway" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduction" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduction" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Inactivation", + "of", + "the", + "MyD88", + "pathway" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophage" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduction" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophage" + ] + } + } + ] + }, + { + "PMID": "14981513", + "TEXT": "The Aurora kinases are essential for the regulation of chromosome segregation and cytokinesis during mitosis. Aberrant expression and activity of these kinases occur in a wide range of human tumors, and lead to aneuploidy and tumorigenesis. Here we report the discovery of a highly potent and selective small-molecule inhibitor of Aurora kinases, VX-680, that blocks cell-cycle progression and induces apoptosis in a diverse range of human tumor types. This compound causes profound inhibition of tumor growth in a variety of in vivo xenograft models, leading to regression of leukemia, colon and pancreatic tumors at well-tolerated doses. Our data indicate that Aurora kinase inhibition provides a new approach for the treatment of multiple human malignancies.", + "TAG_DATA": [ + "44, potent {'perturbing_action': 'B-pharmacological inhibition'}", + "46, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "47, small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "48, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "49, of {'perturbing_action': 'I-pharmacological inhibition'}", + "50, Aurora {'perturbing_action': 'I-pharmacological inhibition'}", + "51, kinases, {'perturbing_action': 'I-pharmacological inhibition'}", + "52, VX-680, {'perturbing_action': 'I-pharmacological inhibition'}", + "58, induces {'effect': 'B-positive'}", + "59, apoptosis {'phenotype': 'B-apoptosis'}", + "65, human {'context': 'B-neoplasm'}", + "66, tumor {'context': 'I-neoplasm'}", + "67, types. {'context': 'I-neoplasm'}", + "72, inhibition {'effect': 'B-negative'}", + "74, tumor {'phenotype': 'B-tumour growth'}", + "75, growth {'phenotype': 'I-tumour growth'}", + "80, in {'context': 'B-xenograft'}", + "81, vivo {'context': 'B-in vivo'}", + "82, xenograft {'context': 'B-xenograft'}", + "83, models, {'context': 'I-xenograft'}", + "84, leading {'effect': 'B-positive'}", + "85, to {'effect': 'I-positive'}", + "86, regression {'phenotype': 'B-tumour regression'}", + "88, leukemia, {'context': 'B-neoplasm'}", + "89, colon {'context': 'I-neoplasm'}", + "90, and {'context': 'I-neoplasm'}", + "91, pancreatic {'context': 'I-neoplasm'}", + "92, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "44, potent ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "46, selective ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "47, small-molecule ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "48, inhibitor ['l2', 'l21', 'l39', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "49, of ['l3', 'l22', 'l40', 'l60', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "50, Aurora ['l4', 'l23', 'l41', 'l61', 'l80', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "51, kinases, ['l5', 'l24', 'l42', 'l62', 'l81', 'l101', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "52, VX-680, ['l6', 'l25', 'l43', 'l63', 'l82', 'l102', 'l119', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "58, induces ['l7', 'l26', 'l44', 'l64', 'l83', 'l103', 'l120', 'l136', 'l148', 'l149', 'l150', 'l151', 'l152']", + "59, apoptosis ['l8', 'l27', 'l45', 'l65', 'l84', 'l104', 'l121', 'l137', 'l148', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158']", + "65, human ['l9', 'l28', 'l46', 'l66', 'l85', 'l105', 'l122', 'l138', 'l149', 'l153', 'l159', 'l160', 'l161']", + "66, tumor ['l10', 'l29', 'l47', 'l67', 'l86', 'l106', 'l123', 'l139', 'l150', 'l154', 'l159', 'l162', 'l163']", + "67, types. ['l11', 'l30', 'l48', 'l68', 'l87', 'l107', 'l124', 'l140', 'l151', 'l155', 'l160', 'l162', 'l164']", + "72, inhibition ['l12', 'l31', 'l49', 'l69', 'l88', 'l108', 'l125', 'l141', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171']", + "74, tumor ['l13', 'l32', 'l50', 'l70', 'l89', 'l109', 'l126', 'l142', 'l156', 'l165', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177']", + "75, growth ['l14', 'l33', 'l51', 'l71', 'l90', 'l110', 'l127', 'l143', 'l152', 'l157', 'l161', 'l163', 'l164', 'l166', 'l172', 'l178', 'l179', 'l180', 'l181']", + "80, in ['l15', 'l34', 'l52', 'l72', 'l91', 'l111', 'l128', 'l144', 'l167', 'l173', 'l178', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "81, vivo ['l16', 'l35', 'l53', 'l73', 'l92', 'l112', 'l129', 'l145', 'l168', 'l174', 'l179', 'l182', 'l189', 'l190', 'l191']", + "82, xenograft ['l17', 'l36', 'l54', 'l74', 'l93', 'l113', 'l130', 'l146', 'l169', 'l175', 'l180', 'l183', 'l189', 'l192', 'l193', 'l194']", + "83, models, ['l18', 'l37', 'l55', 'l75', 'l94', 'l114', 'l131', 'l147', 'l158', 'l170', 'l176', 'l181', 'l184', 'l190', 'l192', 'l195']", + "84, leading ['l19', 'l38', 'l56', 'l76', 'l95', 'l115', 'l132', 'l171', 'l177', 'l185', 'l191', 'l193', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201']", + "85, to ['l57', 'l77', 'l96', 'l116', 'l133', 'l186', 'l196', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207']", + "86, regression ['l202', 'l208', 'l209', 'l210', 'l211', 'l212']", + "88, leukemia, ['l197', 'l203', 'l208', 'l213', 'l214', 'l215', 'l216']", + "89, colon ['l58', 'l78', 'l97', 'l117', 'l134', 'l187', 'l194', 'l198', 'l204', 'l209', 'l213', 'l217', 'l218', 'l219']", + "90, and ['l59', 'l79', 'l98', 'l118', 'l135', 'l188', 'l199', 'l205', 'l210', 'l214', 'l217', 'l220', 'l221']", + "91, pancreatic ['l99', 'l200', 'l206', 'l211', 'l215', 'l218', 'l220', 'l222']", + "92, tumors ['l100', 'l201', 'l207', 'l212', 'l216', 'l219', 'l221', 'l222']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "potent", + "selective", + "small-molecule", + "inhibitor", + "of", + "Aurora", + "kinases,", + "VX-680," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces", + "leading", + "to" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "potent", + "selective", + "small-molecule", + "inhibitor", + "of", + "Aurora", + "kinases,", + "VX-680," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "potent", + "selective", + "small-molecule", + "inhibitor", + "of", + "Aurora", + "kinases,", + "VX-680," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "tumor", + "types.", + "colon", + "and", + "pancreatic", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "potent", + "selective", + "small-molecule", + "inhibitor", + "of", + "Aurora", + "kinases,", + "VX-680," + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "potent", + "selective", + "small-molecule", + "inhibitor", + "of", + "Aurora", + "kinases,", + "VX-680," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "potent", + "selective", + "small-molecule", + "inhibitor", + "of", + "Aurora", + "kinases,", + "VX-680," + ] + }, + "context": { + "val": "xenograft", + "words": [ + "in", + "xenograft", + "models," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "potent", + "selective", + "small-molecule", + "inhibitor", + "of", + "Aurora", + "kinases,", + "VX-680," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "leading", + "to" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "tumor", + "types.", + "leukemia,", + "colon", + "and", + "pancreatic", + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "leading" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth", + "tumor" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "tumor", + "types." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "models," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "human", + "tumor", + "types." + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "in", + "xenograft", + "models," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "in", + "xenograft", + "models," + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "in", + "xenograft", + "models," + ] + }, + "effect": { + "val": "positive", + "words": [ + "leading", + "to" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "leading" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "to" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia,", + "colon", + "and", + "pancreatic", + "tumors" + ] + } + } + ] + }, + { + "PMID": "14770178", + "TEXT": "The TAT protein transduction domain (PTD) has been used to deliver a wide variety of biologically active cargo for the treatment of multiple preclinical disease models, including cancer and stroke. However, the mechanism of transduction remains unknown. Because of the TAT PTD's strong cell-surface binding, early assumptions regarding cellular uptake suggested a direct penetration mechanism across the lipid bilayer by a temperature- and energy-independent process. Here we show, using a transducible TAT-Cre recombinase reporter assay on live cells, that after an initial ionic cell-surface interaction, TAT-fusion proteins are rapidly internalized by lipid raft-dependent macropinocytosis. Transduction was independent of interleukin-2 receptor/raft-, caveolar- and clathrin-mediated endocytosis and phagocytosis. Using this information, we developed a transducible, pH-sensitive, fusogenic dTAT-HA2 peptide that markedly enhanced TAT-Cre escape from macropinosomes. Taken together, these observations provide a scientific basis for the development of new, biologically active, transducible therapeutic molecules.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "14770177", + "TEXT": "Lipid infusion or ingestion of a high-fat diet results in insulin resistance, but the mechanism underlying this phenomenon remains unclear. Here we show that, in rats fed a high-fat diet, whole-animal, muscle and liver insulin resistance is ameliorated following hepatic overexpression of malonyl-coenzyme A (CoA) decarboxylase (MCD), an enzyme that affects lipid partitioning. MCD overexpression decreased circulating free fatty acid (FFA) and liver triglyceride content. In skeletal muscle, levels of triglyceride and long-chain acyl-CoA (LC-CoA)-two candidate mediators of insulin resistance-were either increased or unchanged. Metabolic profiling of 36 acylcarnitine species by tandem mass spectrometry revealed a unique decrease in the concentration of one lipid-derived metabolite, beta-OH-butyrate, in muscle of MCD-overexpressing animals. The best explanation for our findings is that hepatic expression of MCD lowered circulating FFA levels, which led to lowering of muscle beta-OH-butyrate levels and improvement of insulin sensitivity.", + "TAG_DATA": [ + "25, rats {'context': 'B-organism'}", + "39, hepatic {'perturbing_action': 'B-gene gain-of-function'}", + "40, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "41, of {'perturbing_action': 'I-gene gain-of-function'}", + "42, malonyl-coenzyme {'perturbing_action': 'I-gene gain-of-function'}", + "43, A {'perturbing_action': 'I-gene gain-of-function'}", + "44, (CoA) {'perturbing_action': 'I-gene gain-of-function'}", + "45, decarboxylase {'perturbing_action': 'I-gene gain-of-function'}", + "46, (MCD), {'perturbing_action': 'I-gene gain-of-function'}", + "53, MCD {'perturbing_action': 'B-gene gain-of-function'}", + "54, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "62, liver {'context': 'B-tissue/organ'}", + "66, skeletal {'context': 'B-tissue/organ'}", + "67, muscle, {'context': 'I-tissue/organ'}", + "107, muscle {'context': 'B-tissue/organ'}", + "109, MCD-overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "110, animals. {'context': 'B-organism'}", + "119, hepatic {'perturbing_action': 'B-gene gain-of-function'}", + "120, expression {'perturbing_action': 'I-gene gain-of-function'}", + "121, of {'perturbing_action': 'I-gene gain-of-function'}", + "122, MCD {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "25, rats ['l0', 'l1', 'l2']", + "31, muscle ['l0', 'l3', 'l4']", + "33, liver ['l1', 'l3', 'l5']", + "39, hepatic ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "40, overexpression ['l6', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "41, of ['l7', 'l18', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "42, malonyl-coenzyme ['l8', 'l19', 'l29', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "43, A ['l9', 'l20', 'l30', 'l39', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "44, (CoA) ['l10', 'l21', 'l31', 'l40', 'l48', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "45, decarboxylase ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "46, (MCD), ['l12', 'l23', 'l33', 'l42', 'l50', 'l57', 'l63', 'l69', 'l70', 'l71', 'l72', 'l73']", + "53, MCD ['l13', 'l24', 'l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l74', 'l75', 'l76', 'l77']", + "54, overexpression ['l14', 'l25', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l78', 'l79', 'l80']", + "62, liver ['l2', 'l4', 'l5', 'l15', 'l26', 'l36', 'l45', 'l53', 'l60', 'l66', 'l71', 'l75', 'l78']", + "66, skeletal ['l16', 'l27', 'l37', 'l46', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l81']", + "67, muscle, ['l17', 'l28', 'l38', 'l47', 'l55', 'l62', 'l68', 'l73', 'l77', 'l80', 'l81']", + "107, muscle ['l82', 'l83']", + "109, MCD-overexpressing ['l82', 'l84']", + "110, animals. ['l83', 'l84']", + "119, hepatic ['l85', 'l86', 'l87']", + "120, expression ['l85', 'l88', 'l89']", + "121, of ['l86', 'l88', 'l90']", + "122, MCD ['l87', 'l89', 'l90']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hepatic", + "overexpression", + "of", + "malonyl-coenzyme", + "A", + "(CoA)", + "decarboxylase", + "(MCD),", + "MCD", + "MCD-overexpressing" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver", + "skeletal", + "muscle,", + "muscle" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "MCD-overexpressing" + ] + }, + "context": { + "val": "organism", + "words": [ + "animals." + ] + } + } + ] + }, + { + "PMID": "14758356", + "TEXT": "We treated Apc(min) mice, which are predisposed to intestinal polyposis, with a selective synthetic agonist of peroxisome proliferator-activated receptor-delta (PPAR-delta). Exposure of Apc(min) mice to the PPAR-delta ligand GW501516 resulted in a significant increase in the number and size of intestinal polyps. The most prominent effect was on polyp size; mice treated with the PPAR-delta activator had a fivefold increase in the number of polyps larger than 2 mm. Our results implicate PPAR-delta in the regulation of intestinal adenoma growth.", + "TAG_DATA": [ + "2, Apc(min) {'perturbing_action': 'B-other'}", + "3, mice, {'context': 'B-organism'}", + "22, Apc(min) {'perturbing_action': 'B-other'}", + "23, mice {'context': 'B-organism'}", + "27, ligand {'perturbing_action': 'I-pharmacological augmentation'}", + "50, mice {'context': 'B-organism'}", + "54, PPAR-delta {'perturbing_action': 'B-pharmacological augmentation'}", + "55, activator {'perturbing_action': 'I-pharmacological augmentation'}" + ], + "LINK_DATA": [ + "2, Apc(min) ['l0', 'l1', 'l2', 'l3']", + "3, mice, ['l0', 'l4', 'l5', 'l6']", + "22, Apc(min) ['l1', 'l4', 'l7', 'l8']", + "23, mice ['l2', 'l5', 'l7']", + "27, ligand ['l3', 'l6', 'l8']", + "50, mice ['l9', 'l10']", + "54, PPAR-delta ['l9', 'l11']", + "55, activator ['l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Apc(min)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "ligand", + "PPAR-delta", + "activator" + ] + } + } + ] + }, + { + "PMID": "14758355", + "TEXT": "Colonization of the anterior nares in approximately 37% of the population is a major risk factor for severe Staphylococcus aureus infections. Here we show that wall teichoic acid (WTA), a surface-exposed staphylococcal polymer, is essential for nasal colonization and mediates interaction with human nasal epithelial cells. WTA-deficient mutants were impaired in their adherence to nasal cells, and were completely unable to colonize cotton rat nares. This study describes the first essential factor for S. aureus nasal colonization.", + "TAG_DATA": [ + "46, WTA-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "49, impaired {'effect': 'B-negative'}", + "54, nasal {'context': 'B-cells'}", + "55, cells, {'context': 'I-cells'}", + "63, rat {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "46, WTA-deficient ['l0', 'l1', 'l2', 'l3']", + "49, impaired ['l0', 'l4', 'l5']", + "54, nasal ['l1', 'l4', 'l6']", + "55, cells, ['l2', 'l5', 'l6']", + "63, rat ['l3']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "WTA-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "WTA-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "nasal", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "WTA-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "cells", + "words": [ + "nasal", + "cells," + ] + } + } + ] + }, + { + "PMID": "14730358", + "TEXT": "Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) persists despite a vigorous virus-specific host immune response, and causes adult T-cell leukemia and lymphoma in approximately 2% of infected individuals. Here we report that HTLV-1 has evolved a genetic function to restrict its own replication by a novel post-transcriptional mechanism. The HTLV-1-encoded p30(II) is a nuclear-resident protein that binds to, and retains in the nucleus, the doubly spliced mRNA encoding the Tax and Rex proteins. Because Tex and Rex are positive regulators of viral gene expression, their inhibition by p30(II) reduces virion production. p30(II) inhibits virus expression by reducing Tax and Rex protein expression.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "14716308", + "TEXT": "Sepsis represents a major cause of death in intensive care units. Here we show that administration of lysophosphatidylcholine (LPC), an endogenous lysophospholipid, protected mice against lethality after cecal ligation and puncture (CLP) or intraperitoneal injection of Escherichia coli. In vivo treatment with LPC markedly enhanced clearance of intraperitoneal bacteria and blocked CLP-induced deactivation of neutrophils. In vitro, LPC increased bactericidal activity of neutrophils, but not macrophages, by enhancing H(2)O(2) production in neutrophils that ingested E. coli. Incubation with an antibody to the LPC receptor, G2A, inhibited LPC-induced protection from CLP lethality and inhibited the effects of LPC in neutrophils. G2A-specific antibody also blocked the inhibitory effects of LPC on certain actions of lipopolysaccharides (LPS), including lethality and the release of tumor necrosis factor-alpha (TNF-alpha) from neutrophils. These results suggest that LPC can effectively prevent and treat sepsis and microbial infections.", + "TAG_DATA": [ + "23, mice {'context': 'B-organism'}", + "38, In {'context': 'B-in vivo'}", + "39, vivo {'context': 'I-in vivo'}", + "55, In {'context': 'B-in vitro'}", + "56, vitro, {'context': 'I-in vitro'}", + "65, macrophages, {'context': 'B-cells'}", + "80, to {'perturbing_action': 'I-pharmacological inhibition'}", + "81, the {'perturbing_action': 'I-rnai/knockdown'}", + "82, LPC {'perturbing_action': 'I-rnai/knockdown'}", + "83, receptor, {'perturbing_action': 'I-pharmacological inhibition'}", + "84, G2A, {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "38, In ['l0', 'l1', 'l2', 'l3', 'l4']", + "39, vivo ['l0', 'l5', 'l6', 'l7', 'l8']", + "55, In ['l1', 'l5', 'l9', 'l10', 'l11']", + "56, vitro, ['l2', 'l6', 'l9', 'l12', 'l13']", + "62, neutrophils, ['l3', 'l7', 'l10', 'l12', 'l14']", + "65, macrophages, ['l4', 'l8', 'l11', 'l13', 'l14']", + "79, antibody ['l15', 'l16', 'l17', 'l18', 'l19']", + "80, to ['l15', 'l20', 'l21', 'l22', 'l23']", + "81, the ['l16', 'l20', 'l24', 'l25', 'l26']", + "82, LPC ['l17', 'l21', 'l24', 'l27', 'l28']", + "83, receptor, ['l18', 'l22', 'l25', 'l27', 'l29']", + "84, G2A, ['l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14716305", + "TEXT": "The transcription factor, signal transducer and activator of transcription-3 (STAT-3) contributes to various physiological processes. Here we show that mice with liver-specific deficiency in STAT-3, achieved using the Cre-loxP system, show insulin resistance associated with increased hepatic expression of gluconeogenic genes. Restoration of hepatic STAT-3 expression in these mice, using adenovirus-mediated gene transfer, corrected the metabolic abnormalities and the alterations in hepatic expression of gluconeogenic genes. Overexpression of STAT-3 in cultured hepatocytes inhibited gluconeogenic gene expression independently of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha), an upstream regulator of gluconeogenic genes. Liver-specific expression of a constitutively active form of STAT-3, achieved by infection with an adenovirus vector, markedly reduced blood glucose, plasma insulin concentrations and hepatic gluconeogenic gene expression in diabetic mice. Hepatic STAT-3 signaling is thus essential for normal glucose homeostasis and may provide new therapeutic targets for diabetes mellitus.", + "TAG_DATA": [ + "19, mice {'context': 'B-organism'}", + "21, liver-specific {'perturbing_action': 'B-gene loss-of-function'}", + "22, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "23, in {'perturbing_action': 'I-gene loss-of-function'}", + "24, STAT-3, {'perturbing_action': 'I-gene loss-of-function'}", + "41, Restoration {'perturbing_action': 'B-gene gain-of-function'}", + "42, of {'perturbing_action': 'I-gene gain-of-function'}", + "43, hepatic {'perturbing_action': 'I-gene gain-of-function'}", + "44, STAT-3 {'perturbing_action': 'I-gene gain-of-function'}", + "45, expression {'perturbing_action': 'I-gene gain-of-function'}", + "48, mice, {'context': 'B-organism'}", + "66, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "67, of {'perturbing_action': 'I-gene gain-of-function'}", + "68, STAT-3 {'perturbing_action': 'I-gene gain-of-function'}", + "70, cultured {'context': 'B-cells'}", + "71, hepatocytes {'context': 'I-cells'}", + "91, Liver-specific {'perturbing_action': 'B-gene gain-of-function'}", + "92, expression {'perturbing_action': 'I-gene gain-of-function'}", + "93, of {'perturbing_action': 'I-gene gain-of-function'}", + "94, a {'perturbing_action': 'I-gene gain-of-function'}", + "95, constitutively {'perturbing_action': 'I-gene gain-of-function'}", + "96, active {'perturbing_action': 'I-gene gain-of-function'}", + "97, form {'perturbing_action': 'I-gene gain-of-function'}", + "98, of {'perturbing_action': 'I-gene gain-of-function'}", + "99, STAT-3, {'perturbing_action': 'I-gene gain-of-function'}", + "120, diabetic {'context': 'B-organism'}", + "121, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "19, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "21, liver-specific ['l0', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "22, deficiency ['l1', 'l5', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "23, in ['l2', 'l6', 'l13', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "24, STAT-3, ['l3', 'l7', 'l14', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "41, Restoration ['l15', 'l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "42, of ['l8', 'l16', 'l23', 'l29', 'l34', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "43, hepatic ['l9', 'l17', 'l24', 'l30', 'l35', 'l44', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "44, STAT-3 ['l10', 'l18', 'l25', 'l31', 'l36', 'l45', 'l52', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "45, expression ['l11', 'l19', 'l26', 'l32', 'l37', 'l46', 'l53', 'l59', 'l65', 'l66', 'l67', 'l68', 'l69']", + "48, mice, ['l4', 'l12', 'l20', 'l27', 'l33', 'l38', 'l47', 'l54', 'l60', 'l65', 'l70']", + "66, Overexpression ['l39', 'l71', 'l72', 'l73', 'l74']", + "67, of ['l40', 'l48', 'l55', 'l61', 'l66', 'l71', 'l75', 'l76', 'l77']", + "68, STAT-3 ['l41', 'l49', 'l56', 'l62', 'l67', 'l72', 'l75', 'l78', 'l79']", + "70, cultured ['l42', 'l50', 'l57', 'l63', 'l68', 'l73', 'l76', 'l78', 'l80']", + "71, hepatocytes ['l43', 'l51', 'l58', 'l64', 'l69', 'l70', 'l74', 'l77', 'l79', 'l80']", + "91, Liver-specific ['l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "92, expression ['l81', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "93, of ['l82', 'l91', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "94, a ['l83', 'l92', 'l100', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "95, constitutively ['l84', 'l93', 'l101', 'l108', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "96, active ['l85', 'l94', 'l102', 'l109', 'l115', 'l121', 'l122', 'l123', 'l124', 'l125']", + "97, form ['l86', 'l95', 'l103', 'l110', 'l116', 'l121', 'l126', 'l127', 'l128', 'l129']", + "98, of ['l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l126', 'l130', 'l131', 'l132']", + "99, STAT-3, ['l88', 'l97', 'l105', 'l112', 'l118', 'l123', 'l127', 'l130', 'l133', 'l134']", + "120, diabetic ['l89', 'l98', 'l106', 'l113', 'l119', 'l124', 'l128', 'l131', 'l133', 'l135']", + "121, mice. ['l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l129', 'l132', 'l134', 'l135']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "liver-specific", + "deficiency", + "in", + "STAT-3," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoration", + "of", + "hepatic", + "STAT-3", + "expression", + "Liver-specific", + "a", + "constitutively", + "active", + "form", + "STAT-3," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "diabetic", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoration", + "of", + "hepatic", + "STAT-3", + "expression", + "Overexpression" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "hepatocytes" + ] + } + } + ] + }, + { + "PMID": "14647497", + "TEXT": "Patients taking fluoroquinolone antibiotics such as norfloxacin exhibit a low incidence of convulsions and anxiety. These side effects probably result from antagonism of the neurotransmitter gamma-aminobutyric acid (GABA) at the brain GABA(A) receptor complex (GRC). Modification of norfloxacin yields molecules such as compound 4 that potentiate GABA action with alpha(2) subunit selectivity. Compound 4 is anxiolytic but does not cause sedation, and may represent a new class of ligands that have anxiolytic activity without sedative liability.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "14647496", + "TEXT": "Despite the ease of inhibiting immune responses by blockade of T-cell costimulation in naive rodent models, it is difficult to suppress those responses in animals with memory cells. Studies demonstrating the importance of alloreactive T-cell deletion during tolerance induction have promoted use of peritransplant T-cell-depleting therapies in clinical trials. But potentially complicating wide-scale, nonspecific T-cell depletion is the finding that extensive T-cell proliferation can occur under conditions of lymphopenia. This process, termed homeostatic proliferation, may induce acquisition of functional memory T cells. Here, using clinically relevant mouse models of peripheral T-cell depletion, we show that residual nondepleted T cells undergo substantial homeostatic expansion. In this setting, costimulatory blockade neither significantly suppresses homeostatic proliferation nor prevents allograft rejection. In addition, T cells that have completed homeostatic proliferation show dominant resistance to tolerance when adoptively transferred into wild-type recipients, consistent with known properties of memory cells in vivo. These findings establish the importance of homeostatic proliferation in clinically relevant settings, demonstrate the barrier that homeostatic proliferation can present to the induction of transplantation tolerance, and have important implications for transplantation protocols that use partial or complete peripheral T-cell depletion.", + "TAG_DATA": [ + "97, T {'context': 'B-cells'}", + "98, cells {'context': 'I-cells'}", + "110, suppresses {'effect': 'B-negative'}", + "112, proliferation {'phenotype': 'B-proliferation'}", + "114, prevents {'effect': 'B-negative'}", + "115, allograft {'context': 'B-xenograft'}", + "119, T {'context': 'B-cells'}", + "120, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "97, T ['l0', 'l1', 'l2', 'l3', 'l4']", + "98, cells ['l0', 'l5', 'l6']", + "110, suppresses ['l1', 'l7', 'l8', 'l9']", + "112, proliferation ['l2', 'l5', 'l7', 'l10', 'l11']", + "114, prevents ['l3', 'l6', 'l8', 'l10', 'l12']", + "115, allograft ['l4', 'l9', 'l11', 'l12']", + "119, T ['l13']", + "120, cells ['l13']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppresses", + "prevents" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppresses", + "prevents" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppresses", + "prevents" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "allograft" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "allograft" + ] + } + } + ] + }, + { + "PMID": "14634645", + "TEXT": "Conditional mutant techniques that allow spatial and temporal control over gene expression can be used to create mice with restricted genetic modifications. These mice serve as powerful disease models in which gene function in adult tissues can be specifically dissected. Current strategies for conditional genetic manipulation are inefficient, however, and often lack sufficient spatial control. Here we use viral-mediated RNA interference (RNAi) to generate a specific knockdown of Th, the gene encoding the dopamine synthesis enzyme tyrosine hydroxylase, within midbrain neurons of adult mice. This localized gene knockdown resulted in behavioral changes, including a motor performance deficit and reduced response to a psychostimulant. These results underscore the potential of using viral-mediated RNAi for the rapid production and testing of new genetic disease models. Similar strategies may be used in other model species, and may ultimately find applications in human gene therapy.", + "TAG_DATA": [ + "58, viral-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "59, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "60, interference {'perturbing_action': 'I-rnai/knockdown'}", + "61, (RNAi) {'perturbing_action': 'I-rnai/knockdown'}", + "65, specific {'perturbing_action': 'B-rnai/knockdown'}", + "66, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "67, of {'perturbing_action': 'I-rnai/knockdown'}", + "68, Th, {'perturbing_action': 'I-rnai/knockdown'}", + "79, midbrain {'context': 'B-cells'}", + "80, neurons {'context': 'I-cells'}", + "82, adult {'context': 'B-organism'}", + "83, mice. {'context': 'I-organism'}", + "86, gene {'perturbing_action': 'I-rnai/knockdown'}", + "87, knockdown {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "58, viral-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "59, RNA ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "60, interference ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "61, (RNAi) ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "65, specific ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "66, knockdown ['l4', 'l16', 'l27', 'l37', 'l46', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "67, of ['l5', 'l17', 'l28', 'l38', 'l47', 'l53', 'l59', 'l60', 'l61', 'l62', 'l63']", + "68, Th, ['l6', 'l18', 'l29', 'l39', 'l48', 'l54', 'l59', 'l64', 'l65', 'l66', 'l67']", + "79, midbrain ['l7', 'l19', 'l30', 'l40', 'l49', 'l55', 'l60', 'l64', 'l68', 'l69', 'l70', 'l71', 'l72']", + "80, neurons ['l8', 'l20', 'l31', 'l41', 'l50', 'l56', 'l61', 'l65', 'l68', 'l73', 'l74', 'l75']", + "82, adult ['l9', 'l21', 'l32', 'l42', 'l51', 'l57', 'l62', 'l66', 'l69', 'l73', 'l76']", + "83, mice. ['l10', 'l22', 'l33', 'l43', 'l52', 'l58', 'l63', 'l67', 'l70', 'l74', 'l76']", + "86, gene ['l11', 'l23', 'l34', 'l44', 'l71', 'l77']", + "87, knockdown ['l12', 'l24', 'l35', 'l45', 'l72', 'l75', 'l77']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "viral-mediated", + "RNA", + "interference", + "(RNAi)", + "specific", + "knockdown", + "of", + "Th,", + "gene" + ] + }, + "context": { + "val": "cells", + "words": [ + "midbrain", + "neurons" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "viral-mediated", + "RNA", + "interference", + "(RNAi)", + "specific", + "knockdown", + "of", + "Th," + ] + }, + "context": { + "val": "organism", + "words": [ + "adult", + "mice." + ] + } + } + ] + }, + { + "PMID": "14625542", + "TEXT": "Thiazolidinediones (TZDs) are insulin-sensitizing drugs and are potent agonists of the nuclear peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Although muscle is the major organ responsible for insulin-stimulated glucose disposal, PPAR-gamma is more highly expressed in adipose tissue than in muscle. To address this issue, we used the Cre-loxP system to knock out Pparg, the gene encoding PPAR-gamma, in mouse skeletal muscle. As early as 4 months of age, mice with targeted disruption of PPAR-gamma in muscle showed glucose intolerance and progressive insulin resistance. Using the hyperinsulinemic-euglycemic clamp technique, the in vivo insulin-stimulated glucose disposal rate (IS-GDR) was reduced by approximately 80% and was unchanged by 3 weeks of TZD treatment. These effects reveal a crucial role for muscle PPAR-gamma in the maintenance of skeletal muscle insulin action, the etiology of insulin resistance and the action of TZDs.", + "TAG_DATA": [ + "48, knock {'perturbing_action': 'B-gene loss-of-function'}", + "49, out {'perturbing_action': 'I-gene loss-of-function'}", + "50, Pparg, {'perturbing_action': 'I-gene loss-of-function'}", + "56, mouse {'context': 'B-tissue/organ'}", + "57, skeletal {'context': 'I-tissue/organ'}", + "58, muscle. {'context': 'I-tissue/organ'}", + "66, mice {'context': 'B-organism'}", + "68, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "69, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "70, of {'perturbing_action': 'I-gene loss-of-function'}", + "71, PPAR-gamma {'perturbing_action': 'I-gene loss-of-function'}", + "72, in {'perturbing_action': 'I-gene loss-of-function'}", + "73, muscle {'perturbing_action': 'I-gene loss-of-function'}", + "87, in {'context': 'B-in vivo'}", + "88, vivo {'context': 'B-in vivo'}" + ], + "LINK_DATA": [ + "48, knock ['l0', 'l1', 'l2', 'l3', 'l4']", + "49, out ['l0', 'l5', 'l6', 'l7', 'l8']", + "50, Pparg, ['l1', 'l5', 'l9', 'l10', 'l11']", + "56, mouse ['l2', 'l6', 'l9', 'l12', 'l13']", + "57, skeletal ['l3', 'l7', 'l10', 'l12', 'l14']", + "58, muscle. ['l4', 'l8', 'l11', 'l13', 'l14']", + "66, mice ['l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "68, targeted ['l15', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "69, disruption ['l16', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "70, of ['l17', 'l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "71, PPAR-gamma ['l18', 'l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "72, in ['l19', 'l24', 'l30', 'l35', 'l39', 'l43']", + "73, muscle ['l20', 'l25', 'l31', 'l36', 'l40', 'l43']", + "87, in ['l26', 'l32', 'l37', 'l41', 'l44']", + "88, vivo ['l27', 'l33', 'l38', 'l42', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knock", + "out", + "Pparg," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "skeletal", + "muscle." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "disruption", + "of", + "PPAR-gamma", + "in", + "muscle" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "disruption", + "of", + "PPAR-gamma" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "14608380", + "TEXT": "The neural tube defects (NTDs) spina bifida and anencephaly are widely prevalent severe birth defects. The mouse mutant curly tail (ct/ct) has served as a model of NTDs for 50 years, even though the responsible genetic defect remained unrecognized. Here we show by gene targeting, mapping and genetic complementation studies that a mouse homolog of the Drosophila grainyhead (grh) gene, grainyhead-like-3 (Grhl3), is a compelling candidate for the gene underlying the curly tail phenotype. The NTDs in Grhl3-null mice are more severe than those in the curly tail strain, as the Grhl3 alleles in ct/ct mice are hypomorphic. Spina bifida in ct/ct mice is folate resistant, but its incidence can be markedly reduced by maternal inositol supplementation periconceptually. The NTDs in Grhl3-/- embryos are also folate resistant, but unlike those in ct/ct mice, they are resistant to inositol. These findings suggest that residual Grhl3 expression in ct/ct mice may be required for inositol rescue of folate-resistant NTDs.", + "TAG_DATA": [ + "77, Grhl3-null {'perturbing_action': 'B-gene loss-of-function'}", + "78, mice {'context': 'B-organism'}", + "94, ct/ct {'perturbing_action': 'B-gene loss-of-function'}", + "95, mice {'context': 'B-organism'}", + "101, ct/ct {'perturbing_action': 'B-gene loss-of-function'}", + "102, mice {'context': 'B-organism'}", + "121, Grhl3-/- {'perturbing_action': 'B-gene loss-of-function'}", + "122, embryos {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "77, Grhl3-null ['l0']", + "78, mice ['l0']", + "94, ct/ct ['l1', 'l2', 'l3']", + "95, mice ['l1', 'l4']", + "101, ct/ct ['l2', 'l5']", + "102, mice ['l3', 'l4', 'l5']", + "121, Grhl3-/- ['l6']", + "122, embryos ['l6']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Grhl3-null", + "ct/ct", + "Grhl3-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "embryos" + ] + } + } + ] + }, + { + "PMID": "14608379", + "TEXT": "Nitric oxide (NO) inhibits vascular contraction by activating cGMP-dependent protein kinase I-alpha (PKGI-alpha), which causes dephosphorylation of myosin light chain (MLC) and vascular smooth muscle relaxation. Here we show that PKGI-alpha attenuates signaling by the thrombin receptor protease-activated receptor-1 (PAR-1) through direct activation of regulator of G-protein signaling-2 (RGS-2). NO donors and cGMP cause cGMP-mediated inhibition of PAR-1 and membrane localization of RGS-2. PKGI-alpha binds directly to and phosphorylates RGS-2, which significantly increases GTPase activity of G(q), terminating PAR-1 signaling. Disruption of the RGS-2-PKGI-alpha interaction reverses inhibition of PAR-1 signaling by nitrovasodilators and cGMP. Rgs2-/- mice develop marked hypertension, and their blood vessels show enhanced contraction and decreased cGMP-mediated relaxation. Thus, PKGI-alpha binds to, phosphorylates and activates RGS-2, attenuating receptor-mediated vascular contraction. Our study shows that RGS-2 is required for normal vascular function and blood pressure and is a new drug development target for hypertension.", + "TAG_DATA": [ + "94, Rgs2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "95, mice {'context': 'B-organism'}", + "101, blood {'context': 'B-tissue/organ'}", + "102, vessels {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "94, Rgs2-/- ['l0', 'l1', 'l2']", + "95, mice ['l0', 'l3', 'l4']", + "101, blood ['l1', 'l3', 'l5']", + "102, vessels ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rgs2-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rgs2-/-" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "blood", + "vessels" + ] + } + } + ] + }, + { + "PMID": "14595431", + "TEXT": "The continuous evolution and adaptation of HIV to its host has produced extensive global viral diversity. Understanding the kinetics and directions of this continuing adaptation and its impact on viral fitness, immunogenicity and pathogenicity will be crucial to the successful design of effective HIV vaccines. Here we discuss some potential scenarios of viral and host coevolution.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "14556003", + "TEXT": "Endothelial nitric oxide synthase (eNOS) is essential for neovascularization. Here we show that the impaired neovascularization in mice lacking eNOS is related to a defect in progenitor cell mobilization. Mice deficient in eNOS (Nos3(-/-)) show reduced vascular endothelial growth factor (VEGF)-induced mobilization of endothelial progenitor cells (EPCs) and increased mortality after myelosuppression. Intravenous infusion of wild-type progenitor cells, but not bone marrow transplantation, rescued the defective neovascularization of Nos3(-/-) mice in a model of hind-limb ischemia, suggesting that progenitor mobilization from the bone marrow is impaired in Nos3(-/-) mice. Mechanistically, matrix metalloproteinase-9 (MMP-9), which is required for stem cell mobilization, was reduced in the bone marrow of Nos3(-/-) mice. These findings indicate that eNOS expressed by bone marrow stromal cells influences recruitment of stem and progenitor cells. This may contribute to impaired regeneration processes in ischemic heart disease patients, who are characterized by a reduced systemic NO bioactivity.", + "TAG_DATA": [ + "19, eNOS {'perturbing_action': 'I-gene loss-of-function'}", + "29, Mice {'context': 'B-organism'}", + "30, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "31, in {'perturbing_action': 'I-gene loss-of-function'}", + "32, eNOS {'perturbing_action': 'I-gene loss-of-function'}", + "33, (Nos3(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "43, endothelial {'context': 'B-cells'}", + "44, progenitor {'context': 'I-cells'}", + "45, cells {'context': 'I-cells'}", + "46, (EPCs) {'context': 'I-cells'}", + "56, progenitor {'context': 'B-cells'}", + "57, cells, {'context': 'I-cells'}", + "68, Nos3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "69, mice {'context': 'B-organism'}", + "87, Nos3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "88, mice. {'context': 'B-organism'}", + "104, bone {'context': 'B-tissue/organ'}", + "105, marrow {'context': 'I-tissue/organ'}", + "107, Nos3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "108, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "19, eNOS ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "29, Mice ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "30, deficient ['l6', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "31, in ['l7', 'l14', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "32, eNOS ['l8', 'l15', 'l23', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "33, (Nos3(-/-)) ['l1', 'l9', 'l16', 'l24', 'l32', 'l39', 'l40', 'l41', 'l42']", + "43, endothelial ['l2', 'l10', 'l17', 'l25', 'l33', 'l39', 'l43', 'l44', 'l45']", + "44, progenitor ['l3', 'l11', 'l18', 'l26', 'l34', 'l40', 'l43', 'l46', 'l47']", + "45, cells ['l4', 'l12', 'l19', 'l27', 'l35', 'l41', 'l44', 'l46', 'l48']", + "46, (EPCs) ['l5', 'l13', 'l20', 'l28', 'l36', 'l42', 'l45', 'l47', 'l48']", + "56, progenitor ['l49', 'l50', 'l51', 'l52', 'l53']", + "57, cells, ['l21', 'l29', 'l37', 'l49', 'l54', 'l55', 'l56', 'l57']", + "68, Nos3(-/-) ['l30', 'l50', 'l54', 'l58']", + "69, mice ['l22', 'l31', 'l38', 'l51', 'l55', 'l58']", + "87, Nos3(-/-) ['l52', 'l56', 'l59']", + "88, mice. ['l53', 'l57', 'l59']", + "104, bone ['l60', 'l61', 'l62']", + "105, marrow ['l60', 'l63', 'l64']", + "107, Nos3(-/-) ['l61', 'l63', 'l65']", + "108, mice. ['l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "eNOS", + "deficient", + "in", + "(Nos3(-/-))", + "Nos3(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "Mice", + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "eNOS", + "deficient", + "in", + "(Nos3(-/-))", + "Nos3(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "progenitor", + "cells", + "(EPCs)", + "cells," + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "bone", + "marrow" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nos3(-/-)" + ] + } + } + ] + }, + { + "PMID": "14556002", + "TEXT": "Plasmodium, the causative agent of malaria, must first infect hepatocytes to initiate a mammalian infection. Sporozoites migrate through several hepatocytes, by breaching their plasma membranes, before infection is finally established in one of them. Here we show that wounding of hepatocytes by sporozoite migration induces the secretion of hepatocyte growth factor (HGF), which renders hepatocytes susceptible to infection. Infection depends on activation of the HGF receptor, MET, by secreted HGF. The malaria parasite exploits MET not as a primary binding site, but as a mediator of signals that make the host cell susceptible to infection. HGF/MET signaling induces rearrangements of the host-cell actin cytoskeleton that are required for the early development of the parasites within hepatocytes. Our findings identify HGF and MET as potential targets for new approaches to malaria prevention.", + "TAG_DATA": [ + "40, hepatocytes {'context': 'B-cells'}", + "54, hepatocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "40, hepatocytes ['l0']", + "54, hepatocytes ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14528298", + "TEXT": "Platelet activation at sites of vascular injury is essential for primary hemostasis, but also underlies arterial thrombosis leading to myocardial infarction or stroke. Platelet activators such as adenosine diphosphate, thrombin or thromboxane A(2) (TXA(2)) activate receptors that are coupled to heterotrimeric G proteins. Activation of platelets through these receptors involves signaling through G(q), G(i) and G(z) (refs. 4-6). However, the role and relative importance of G(12) and G(13), which are activated by various platelet stimuli, are unclear. Here we show that lack of Galpha(13), but not Galpha(12), severely reduced the potency of thrombin, TXA(2) and collagen to induce platelet shape changes and aggregation in vitro. These defects were accompanied by reduced activation of RhoA and inability to form stable platelet thrombi under high shear stress ex vivo. Galpha(13) deficiency in platelets resulted in a severe defect in primary hemostasis and complete protection against arterial thrombosis in vivo. We conclude that G(13)-mediated signaling processes are required for normal hemostasis and thrombosis and may serve as a new target for antiplatelet drugs.", + "TAG_DATA": [ + "81, lack {'perturbing_action': 'B-gene loss-of-function'}", + "82, of {'perturbing_action': 'I-gene loss-of-function'}", + "83, Galpha(13), {'perturbing_action': 'I-gene loss-of-function'}", + "97, induce {'effect': 'B-positive'}", + "98, platelet {'context': 'B-cells'}", + "102, aggregation {'phenotype': 'B-autophagy'}", + "103, in {'context': 'B-in vitro'}", + "104, vitro. {'context': 'I-in vitro'}", + "127, Galpha(13) {'perturbing_action': 'B-gene loss-of-function'}", + "128, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "130, platelets {'context': 'B-cells'}", + "145, in {'context': 'B-in vivo'}", + "146, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "81, lack ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "82, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "83, Galpha(13), ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "97, induce ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "98, platelet ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "102, aggregation ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "103, in ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "104, vitro. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "127, Galpha(13) ['l28', 'l29', 'l30', 'l31']", + "128, deficiency ['l28', 'l32', 'l33', 'l34']", + "130, platelets ['l29', 'l32', 'l35', 'l36']", + "145, in ['l30', 'l33', 'l35', 'l37']", + "146, vivo. ['l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "Galpha(13)," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "Galpha(13),", + "Galpha(13)", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelet", + "platelets" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "Galpha(13)," + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "aggregation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "Galpha(13)," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelet" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "aggregation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "platelet" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "aggregation" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "aggregation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Galpha(13)", + "deficiency" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "14502278", + "TEXT": "Catecholamines stimulate cardiac contractility through beta(1)-adrenergic receptors (beta(1)-ARs), which in humans are polymorphic at amino acid residue 389 (Arg/Gly). We used cardiac-targeted transgenesis in a mouse model to delineate mechanisms accounting for the association of Arg389 with human heart failure phenotypes. Hearts from young Arg389 mice had enhanced receptor function and contractility compared with Gly389 hearts. Older Arg389 mice displayed a phenotypic switch, with decreased beta-agonist signaling to adenylyl cyclase and decreased cardiac contractility compared with Gly 389 hearts. Arg389 hearts had abnormal expression of fetal and hypertrophy genes and calcium-cycling proteins, decreased adenylyl cyclase and G alpha(s) expression, and fibrosis with heart failure This phenotype was recapitulated in homozygous, end-stage, failing human hearts. In addition, hemodynamic responses to beta-receptor blockade were greater in Arg389 mice, and homozygosity for Arg389 was associated with improvement in ventricular function during carvedilol treatment in heart failure patients. Thus the human Arg389 variant predisposes to heart failure by instigating hyperactive signaling programs leading to depressed receptor coupling and ventricular dysfunction, and influences the therapeutic response to beta-receptor blockade.", + "TAG_DATA": [ + "25, mouse {'context': 'B-organism'}", + "26, model {'context': 'I-organism'}", + "41, Hearts {'context': 'B-tissue/organ'}", + "45, mice {'context': 'I-organism'}", + "58, mice {'context': 'B-organism'}", + "80, hearts {'context': 'B-tissue/organ'}", + "112, human {'context': 'B-tissue/organ'}", + "113, hearts. {'context': 'I-tissue/organ'}", + "125, mice, {'context': 'B-organism'}", + "127, homozygosity {'perturbing_action': 'B-other'}", + "128, for {'perturbing_action': 'I-other'}", + "129, Arg389 {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "25, mouse ['l0', 'l1', 'l2']", + "26, model ['l0', 'l3', 'l4']", + "41, Hearts ['l1', 'l3', 'l5']", + "45, mice ['l2', 'l4', 'l5']", + "80, hearts ['l6', 'l7']", + "112, human ['l6', 'l8']", + "113, hearts. ['l7', 'l8']", + "127, homozygosity ['l9', 'l10']", + "128, for ['l9', 'l11']", + "129, Arg389 ['l10', 'l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12960963", + "TEXT": "The role of the nuclear peroxisome proliferator-activated receptor (PPAR)-gamma in cancer has been a subject of debate. The identification of loss-of-function mutations in PPARG in colon and prostate tumors has led to the idea that this gene may function as a tumor suppressor. We have directly tested this notion using a mouse model of prostate cancer. Neither hemizygous deletion of Pparg nor complete ablation of Ppara influenced the development of prostate cancer in our experimental context.", + "TAG_DATA": [ + "51, mouse {'context': 'B-neoplasm'}", + "52, model {'context': 'I-neoplasm'}", + "53, of {'context': 'I-neoplasm'}", + "54, prostate {'context': 'I-neoplasm'}", + "55, cancer. {'context': 'I-neoplasm'}", + "57, hemizygous {'perturbing_action': 'B-gene loss-of-function'}", + "58, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "59, of {'perturbing_action': 'I-gene loss-of-function'}", + "60, Pparg {'perturbing_action': 'I-gene loss-of-function'}", + "62, complete {'perturbing_action': 'B-gene loss-of-function'}", + "63, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "64, of {'perturbing_action': 'I-gene loss-of-function'}", + "65, Ppara {'perturbing_action': 'I-gene loss-of-function'}", + "70, prostate {'context': 'B-neoplasm'}", + "71, cancer {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "51, mouse ['l0', 'l1', 'l2', 'l3']", + "52, model ['l0', 'l4', 'l5', 'l6']", + "53, of ['l1', 'l4', 'l7', 'l8']", + "54, prostate ['l2', 'l5', 'l7', 'l9']", + "55, cancer. ['l3', 'l6', 'l8', 'l9']", + "57, hemizygous ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "58, deletion ['l10', 'l16', 'l17', 'l18', 'l19']", + "59, of ['l11', 'l16', 'l20', 'l21', 'l22']", + "60, Pparg ['l12', 'l17', 'l20', 'l23', 'l24']", + "62, complete ['l25', 'l26', 'l27', 'l28', 'l29']", + "63, ablation ['l25', 'l30', 'l31', 'l32', 'l33']", + "64, of ['l26', 'l30', 'l34', 'l35', 'l36']", + "65, Ppara ['l13', 'l27', 'l31', 'l34', 'l37', 'l38']", + "70, prostate ['l14', 'l18', 'l21', 'l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "71, cancer ['l15', 'l19', 'l22', 'l24', 'l29', 'l33', 'l36', 'l38', 'l39']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "hemizygous", + "deletion", + "of", + "Pparg", + "complete", + "ablation", + "Ppara" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "prostate", + "cancer" + ] + } + } + ] + }, + { + "PMID": "12937412", + "TEXT": "Neuronal death in cerebral ischemia is largely due to excitotoxic mechanisms, which are known to activate the c-Jun N-terminal kinase (JNK) pathway. We have evaluated the neuroprotective power of a cell-penetrating, protease-resistant peptide that blocks the access of JNK to many of its targets. We obtained strong protection in two models of middle cerebral artery occlusion (MCAO): transient occlusion in adult mice and permanent occlusion in 14-d-old rat pups. In the first model, intraventricular administration as late as 6 h after occlusion reduced the lesion volume by more than 90% for at least 14 d and prevented behavioral consequences. In the second model, systemic delivery reduced the lesion by 78% and 49% at 6 and 12 h after ischemia, respectively. Protection correlated with prevention of an increase in c-Jun activation and c-Fos transcription. In view of its potency and long therapeutic window, this protease-resistant peptide is a promising neuroprotective agent for stroke.", + "TAG_DATA": [ + "60, adult {'context': 'B-organism'}", + "61, mice {'context': 'I-organism'}", + "66, 14-d-old {'context': 'B-organism'}", + "67, rat {'context': 'I-organism'}", + "68, pups. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "60, adult ['l0', 'l1', 'l2', 'l3']", + "61, mice ['l0', 'l4']", + "66, 14-d-old ['l1', 'l5', 'l6']", + "67, rat ['l2', 'l5', 'l7']", + "68, pups. ['l3', 'l4', 'l6', 'l7']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12925844", + "TEXT": "Mature donor T cells cause graft-versus-host disease (GVHD), but they are also the main mediators of the beneficial graft-versus-tumor (GVT) activity of allogeneic bone marrow transplantation. Suppression of GVHD with maintenance of GVT activity is a desirable outcome for clinical transplantation. We have previously shown that donor-derived CD4+CD25+ regulatory T cells inhibit lethal GVHD after allogeneic bone marrow transplantation across major histocompatibility complex (MHC) class I and II barriers in mice. Here we demonstrate that in host mice with leukemia and lymphoma, CD4+CD25+ regulatory T cells suppress the early expansion of alloreactive donor T cells, their interleukin-2-receptor (IL-2R) alpha-chain expression and their capacity to induce GVHD without abrogating their GVT effector function, mediated primarily by the perforin lysis pathway. Thus, CD4+CD25+ T cells are potent regulatory cells that can separate GVHD from GVT activity mediated by conventional donor T cells.", + "TAG_DATA": [ + "70, mice. {'context': 'B-organism'}", + "77, mice {'context': 'B-organism'}", + "79, leukemia {'context': 'B-neoplasm'}", + "82, CD4+CD25+ {'context': 'B-cells'}", + "83, regulatory {'context': 'I-cells'}", + "84, T {'context': 'I-cells'}", + "85, cells {'context': 'I-cells'}", + "91, alloreactive {'context': 'B-cells'}", + "92, donor {'context': 'I-cells'}", + "93, T {'context': 'I-cells'}", + "94, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "77, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "79, leukemia ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "82, CD4+CD25+ ['l8', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "83, regulatory ['l1', 'l9', 'l16', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "84, T ['l2', 'l10', 'l17', 'l23', 'l29', 'l30', 'l31', 'l32', 'l33']", + "85, cells ['l3', 'l11', 'l18', 'l24', 'l29', 'l34', 'l35', 'l36', 'l37']", + "91, alloreactive ['l4', 'l12', 'l19', 'l25', 'l30', 'l34', 'l38', 'l39', 'l40']", + "92, donor ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l41', 'l42']", + "93, T ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l41', 'l43']", + "94, cells, ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l43']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12910263", + "TEXT": "The discovery of endogenous bioactive peptides has typically required a lengthy identification process. Computer-assisted analysis of cDNA and genomic DNA sequence information can markedly shorten the process. A bioinformatic analysis of full-length, enriched human cDNA libraries searching for previously unidentified bioactive peptides resulted in the identification and characterization of two related peptides of 28 and 20 amino acids, which we designated salusin-alpha and salusin-beta. Salusins are translated from an alternatively spliced mRNA of TOR2A, a gene encoding a protein of the torsion dystonia family. Intravenous administration of salusin-alpha or salusin-beta to rats causes rapid, profound hypotension and bradycardia. Salusins increase intracellular Ca2+, upregulate a variety of genes and induce cell mitogenesis. Salusin-beta stimulates the release of arginine-vasopressin from rat pituitary. Expression of TOR2A mRNA and its splicing into preprosalusin are ubiquitous, and immunoreactive salusin-alpha and salusin-beta are detected in many human tissues, plasma and urine, suggesting that salusins are endocrine and/or paracrine factors.", + "TAG_DATA": [ + "91, rats {'context': 'B-organism'}", + "108, induce {'effect': 'B-positive'}", + "109, cell {'context': 'B-cells'}", + "110, mitogenesis. {'phenotype': 'B-proliferation'}", + "118, rat {'context': 'B-tissue/organ'}", + "119, pituitary. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "91, rats ['l0', 'l1', 'l2']", + "108, induce ['l0', 'l3', 'l4']", + "109, cell ['l1', 'l3', 'l5']", + "110, mitogenesis. ['l2', 'l4', 'l5']", + "118, rat ['l6']", + "119, pituitary. ['l6']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "rats" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rats" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "mitogenesis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "mitogenesis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "mitogenesis." + ] + } + } + ] + }, + { + "PMID": "12897778", + "TEXT": "Bone-marrow minimal residual disease (MRD) causes relapse after chemotherapy in patients with acute myelogenous leukemia (AML). We postulate that the drug resistance is induced by the attachment of very late antigen (VLA)-4 on leukemic cells to fibronectin on bone-marrow stromal cells. We found that VLA-4-positive cells acquired resistance to anoikis (loss of anchorage) or drug-induced apoptosis through the phosphatidylinositol-3-kinase (PI-3K)/AKT/Bcl-2 signaling pathway, which is activated by the interaction of VLA-4 and fibronectin. This resistance was negated by VLA-4-specific antibodies. In a mouse model of MRD, we achieved a 100% survival rate by combining VLA-4-specific antibodies and cytosine arabinoside (AraC), whereas AraC alone prolonged survival only slightly. In addition, overall survival at 5 years was 100% for 10 VLA-4-negative patients and 44.4% for 15 VLA-4-positive patients. Thus, the interaction between VLA-4 on leukemic cells and fibronectin on stromal cells may be crucial in bone marrow MRD and AML prognosis.", + "TAG_DATA": [ + "44, VLA-4-positive {'context': 'B-cells'}", + "45, cells {'context': 'I-cells'}", + "54, drug-induced {'effect': 'B-positive'}", + "55, apoptosis {'phenotype': 'B-apoptosis'}", + "81, mouse {'context': 'B-organism'}", + "82, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "44, VLA-4-positive ['l0']", + "45, cells ['l0']", + "54, drug-induced ['l1', 'l2']", + "55, apoptosis ['l1']", + "81, mouse ['l3']", + "82, model ['l2', 'l3']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "drug-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "drug-induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "model" + ] + } + } + ] + }, + { + "PMID": "12835707", + "TEXT": "Antiretroviral therapy, where available, has transformed HIV-1 disease into a treatable and somewhat chronic infection. This article summarizes the accomplishments thus far and what lies ahead in our struggle to improve the treatment of, and possibly eliminate, HIV-1 infection.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12819779", + "TEXT": "The highly polymorphic human leukocyte antigen (HLA) class I molecules help to determine the specificity and repertoire of the immune response. The great diversity of these antigen-binding molecules confers differential advantages in responding to pathogens, but presents a major obstacle to distinguishing HLA allele-specific effects. HLA class I supertypes provide a functional classification for the many different HLA alleles that overlap in their peptide-binding specificities. We analyzed the association of these discrete HLA supertypes with HIV disease progression rates in a population of HIV-infected men. We found that HLA supertypes alone and in combination conferred a strong differential advantage in responding to HIV infection, independent of the contribution of single HLA alleles that associate with progression of the disease. The correlation of the frequency of the HLA supertypes with viral load suggests that HIV adapts to the most frequent alleles in the population, providing a selective advantage for those individuals who express rare alleles.", + "TAG_DATA": [ + "84, men. {'context': 'I-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12808449", + "TEXT": "The blood-brain barrier (BBB) is essential for maintaining brain homeostasis and low permeability. BBB maintenance is important in the central nervous system (CNS) because disruption of the BBB may contribute to many brain disorders, including Alzheimer disease and ischemic stroke. The molecular mechanisms of BBB development remain ill-defined, however. Here we report that src-suppressed C-kinase substrate (SSeCKS) decreases the expression of vascular endothelial growth factor (VEGF) through AP-1 reduction and stimulates expression of angiopoietin-1 (Ang-1), an antipermeability factor in astrocytes. Conditioned media from SSeCKS-overexpressing astrocytes (SSeCKS-CM) blocked angiogenesis in vivo and in vitro. Moreover, SSeCKS-CM increased tight junction proteins in endothelial cells, consequently decreasing [3H]sucrose permeability. Furthermore, immunoreactivity to SSeCKS gradually increased during the BBB maturation period, and SSeCKS-expressing astrocytes closely interacted with zonula occludens (ZO)-1-expressing blood vessels in vivo. Collectively, our results suggest that SSeCKS regulates BBB differentiation by modulating both brain angiogenesis and tight junction formation.", + "TAG_DATA": [ + "79, astrocytes. {'context': 'B-cells'}", + "83, SSeCKS-overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "84, astrocytes {'context': 'B-cells'}", + "88, in {'context': 'B-in vivo'}", + "89, vivo {'context': 'I-in vivo'}", + "91, in {'context': 'B-in vitro'}", + "92, vitro. {'context': 'I-in vitro'}", + "100, endothelial {'context': 'B-cells'}", + "101, cells, {'context': 'I-cells'}", + "118, SSeCKS-expressing {'context': 'B-cells'}", + "119, astrocytes {'context': 'I-cells'}", + "128, in {'context': 'B-in vivo'}", + "129, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "79, astrocytes. ['l0']", + "83, SSeCKS-overexpressing ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "84, astrocytes ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "88, in ['l2', 'l8', 'l14']", + "89, vivo ['l0', 'l3', 'l9', 'l14']", + "91, in ['l4', 'l10', 'l15', 'l16']", + "92, vitro. ['l5', 'l11', 'l15', 'l17']", + "100, endothelial ['l6', 'l12', 'l18']", + "101, cells, ['l7', 'l13', 'l16', 'l17', 'l18']", + "118, SSeCKS-expressing ['l19', 'l20', 'l21']", + "119, astrocytes ['l19', 'l22', 'l23']", + "128, in ['l20', 'l22', 'l24']", + "129, vivo. ['l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "SSeCKS-overexpressing" + ] + }, + "context": { + "val": "cells", + "words": [ + "astrocytes", + "endothelial", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "SSeCKS-overexpressing" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "SSeCKS-overexpressing" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "12766765", + "TEXT": "In animals, effective immune responses against malignancies and against several infectious pathogens, including malaria, are mediated by T cells. Here we show that a heterologous prime-boost vaccination regime of DNA either intramuscularly or epidermally, followed by intradermal recombinant modified vaccinia virus Ankara (MVA), induces high frequencies of interferon (IFN)-gamma-secreting, antigen-specific T-cell responses in humans to a pre-erythrocytic malaria antigen, thrombospondin-related adhesion protein (TRAP). These responses are five- to tenfold higher than the T-cell responses induced by the DNA vaccine or recombinant MVA vaccine alone, and produce partial protection manifest as delayed parasitemia after sporozoite challenge with a different strain of Plasmodium falciparum. Such heterologous prime-boost immunization approaches may provide a basis for preventative and therapeutic vaccination in humans.", + "TAG_DATA": [ + "50, T-cell {'context': 'B-cells'}", + "53, humans {'context': 'B-organism'}", + "72, T-cell {'context': 'B-cells'}", + "101, falciparum. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "50, T-cell ['l0']", + "53, humans ['l0']", + "90, delayed ['l1', 'l2']", + "100, Plasmodium ['l1', 'l3']", + "101, falciparum. ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12754504", + "TEXT": "Latent HIV-1 persists in resting memory CD4+ T cells, even in patients receiving highly active antiretroviral therapy (HAART). It has been unclear how stable this latent reservoir is and whether its persistence reflects replenishment by low-level viremia. Here we show that even in treated patients who have had no detectable viremia for as long as 7 years, the reservoir decays so slowly (t(1/2) = 44 months) that eradication is unlikely.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12730690", + "TEXT": "Retinal ischemia can cause vision-threatening pathological neovascularization. The mechanisms of retinal ischemia are not fully understood, however. Here we have shown that leukocytes prune the retinal vasculature during normal development and obliterate it in disease. Beginning at postnatal day 5 (P5) in the normal rat, vascular pruning began centrally and extended peripherally, leaving behind a less dense, smaller-caliber vasculature. The pruning was correlated with retinal vascular expression of intercellular adhesion molecule-1 (ICAM-1) and coincided with an outward-moving wave of adherent leukocytes composed in part of cytotoxic T lymphocytes. The leukocytes adhered to the vasculature through CD18 and remodeled it through Fas ligand (FasL)-mediated endothelial cell apoptosis. In a model of oxygen-induced ischemic retinopathy, this process was exaggerated. Leukocytes used CD18 and FasL to obliterate the retinal vasculature, leaving behind large areas of ischemic retina. In vitro, T lymphocytes isolated from oxygen-exposed neonates induced a FasL-mediated apoptosis of hyperoxygenated endothelial cells. Targeting these pathways may prove useful in the treatment of retinal ischemia, a leading cause of vision loss and blindness.", + "TAG_DATA": [ + "44, rat, {'context': 'B-organism'}", + "103, endothelial {'context': 'B-cells'}", + "104, cell {'context': 'I-cells'}", + "105, apoptosis. {'phenotype': 'B-apoptosis'}", + "117, Leukocytes {'context': 'B-cells'}", + "134, In {'context': 'B-in vitro'}", + "135, vitro, {'context': 'I-in vitro'}", + "136, T {'context': 'B-cells'}", + "137, lymphocytes {'context': 'I-cells'}", + "138, isolated {'context': 'I-cells'}", + "141, neonates {'context': 'B-organism'}", + "142, induced {'effect': 'B-positive'}", + "145, apoptosis {'phenotype': 'B-apoptosis'}", + "148, endothelial {'context': 'B-cells'}", + "149, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "103, endothelial ['l0', 'l1']", + "104, cell ['l0', 'l2']", + "105, apoptosis. ['l1', 'l2']", + "134, In ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "135, vitro, ['l3', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "136, T ['l4', 'l12', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "137, lymphocytes ['l5', 'l13', 'l20', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "138, isolated ['l6', 'l14', 'l21', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "141, neonates ['l7', 'l15', 'l22', 'l28', 'l33', 'l38', 'l39', 'l40', 'l41']", + "142, induced ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l42', 'l43', 'l44']", + "145, apoptosis ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l45', 'l46']", + "148, endothelial ['l10', 'l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l47']", + "149, cells. ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell", + "T", + "lymphocytes", + "isolated", + "cells." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis.", + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "lymphocytes", + "isolated", + "endothelial", + "cells." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "neonates" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "neonates" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "12730689", + "TEXT": "Interleukin-2 (IL-2) is used to treat metastatic renal cell carcinoma and malignant melanoma, but its use is limited by the severe hypotension it produces. We have shown here that M40403, a superoxide dismutase (SOD) mimetic, blocked IL-2-induced hypotension and allowed the dose of IL-2 to be increased in mice. The reversal of IL-2-mediated hypotension was associated with an increase in plasma catecholamines. In addition, M40403 increased lymphokine-activated killer (LAK) cell cytotoxicity in vitro and in vivo, through inhibition of macrophage superoxide production. Treatment of methylcholanthrene-induced (Meth A) ascites tumors with IL-2 and > or =3 mg per kg body weight M40403 induced 50% complete remissions lasting for more than 200 d, which was longer than those of untreated mice (15-d median survival) or mice treated with IL-2 alone (22-d median). Growth of subcutaneous implants of RENCA renal carcinoma was also inhibited by the combination of IL-2 and M40403. These results established that M40403 prevented IL-2 from causing dose-limiting hypotension, while enhancing its anticancer activity.", + "TAG_DATA": [ + "48, mice. {'context': 'B-organism'}", + "71, in {'context': 'B-in vitro'}", + "72, vitro {'context': 'I-in vitro'}", + "74, in {'context': 'B-in vivo'}", + "75, vivo, {'context': 'I-in vivo'}", + "84, methylcholanthrene-induced {'context': 'B-neoplasm'}", + "85, (Meth {'context': 'I-neoplasm'}", + "86, A) {'context': 'I-neoplasm'}", + "87, ascites {'context': 'I-neoplasm'}", + "88, tumors {'context': 'I-neoplasm'}", + "118, mice {'context': 'B-organism'}", + "123, mice {'context': 'B-organism'}", + "132, subcutaneous {'context': 'B-xenograft'}", + "133, implants {'context': 'I-xenograft'}", + "135, RENCA {'context': 'B-neoplasm'}", + "136, renal {'context': 'I-neoplasm'}", + "137, carcinoma {'context': 'I-neoplasm'}", + "140, inhibited {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "48, mice. ['l0', 'l1', 'l2']", + "71, in ['l0', 'l3', 'l4', 'l5']", + "72, vitro ['l1', 'l3', 'l6', 'l7']", + "74, in ['l4', 'l6', 'l8']", + "75, vivo, ['l2', 'l5', 'l7', 'l8']", + "84, methylcholanthrene-induced ['l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "85, (Meth ['l9', 'l15', 'l16', 'l17', 'l18', 'l19']", + "86, A) ['l10', 'l15', 'l20', 'l21', 'l22', 'l23']", + "87, ascites ['l11', 'l16', 'l20', 'l24', 'l25', 'l26']", + "88, tumors ['l12', 'l17', 'l21', 'l24', 'l27', 'l28']", + "118, mice ['l13', 'l18', 'l22', 'l25', 'l27', 'l29']", + "123, mice ['l14', 'l19', 'l23', 'l26', 'l28', 'l29']", + "132, subcutaneous ['l30', 'l31', 'l32', 'l33', 'l34']", + "133, implants ['l30', 'l35', 'l36', 'l37', 'l38']", + "135, RENCA ['l31', 'l35', 'l39', 'l40', 'l41']", + "136, renal ['l32', 'l36', 'l39', 'l42', 'l43']", + "137, carcinoma ['l33', 'l37', 'l40', 'l42', 'l44']", + "140, inhibited ['l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "xenograft", + "words": [ + "subcutaneous", + "implants" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "RENCA", + "renal", + "carcinoma" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + } + ] + }, + { + "PMID": "12704384", + "TEXT": "To explore induced islet neogenesis in the liver as a strategy for the treatment of diabetes, we used helper-dependent adenovirus (HDAD) to deliver the pancreatic duodenal homeobox-1 gene (Ipf1; also known as Pdx-1) to streptozotocin (STZ)-treated diabetic mice. HDAD is relatively nontoxic as it is devoid of genes encoding viral protein. Mice treated with HDAD-Ipf1 developed fulminant hepatitis, however, because of the exocrine-differentiating activity of Ipf1. The diabetes of STZ mice was partially reversed by HDAD-mediated transfer of NeuroD (Neurod), a factor downstream of Ipf1, and completely reversed by a combination of Neurod and betacellulin (Btc), without producing hepatitis. Treated mice were healthy and normoglycemic for the duration of the experiment (>120 d). We detected in the liver insulin and other islet-specific transcripts, including proinsulin-processing enzymes, beta-cell-specific glucokinase and sulfonylurea receptor. Immunocytochemistry detected the presence of insulin, glucagon, pancreatic polypeptide and somatostatin-producing cells organized into islet clusters; immuno-electron microscopy showed typical insulin-containing granules. Our data suggest that Neurod-Btc gene therapy is a promising regimen to induce islet neogenesis for the treatment of insulin-dependent diabetes.", + "TAG_DATA": [ + "36, diabetic {'context': 'B-organism'}", + "37, mice. {'context': 'I-organism'}", + "51, Mice {'context': 'B-organism'}", + "70, mice {'context': 'B-organism'}", + "100, mice {'context': 'B-organism'}", + "117, liver {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "36, diabetic ['l0', 'l1']", + "37, mice. ['l0', 'l2']", + "51, Mice ['l1', 'l2', 'l3']", + "70, mice ['l3']", + "100, mice ['l4']", + "117, liver ['l4']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12692546", + "TEXT": "Interleukin (IL)-2 is currently used to enhance T-cell immunity but can have both positive and negative effects on T cells. To determine whether these opposing results are due to IL-2 acting differently on T cells depending on their stage of differentiation, we examined the effects of IL-2 therapy during the expansion, contraction and memory phases of the T-cell response in lymphocytic choriomeningitis virus (LCMV)-infected mice. IL-2 treatment during the expansion phase was detrimental to the survival of rapidly dividing effector T cells. In contrast, IL-2 therapy was highly beneficial during the death phase, resulting in increased proliferation and survival of virus-specific T cells. IL-2 treatment also increased proliferation of resting memory T cells in mice that controlled the infection. Virus-specific T cells in chronically infected mice also responded to IL-2 resulting in decreased viral burden. Thus, timing of IL-2 administration and differentiation status of the T cell are critical parameters in designing IL-2 therapies.", + "TAG_DATA": [ + "64, mice. {'context': 'B-organism'}", + "79, effector {'context': 'I-cells'}", + "80, T {'context': 'I-cells'}", + "81, cells. {'context': 'I-cells'}", + "95, increased {'effect': 'B-positive'}", + "96, proliferation {'phenotype': 'B-proliferation'}", + "100, virus-specific {'context': 'B-cells'}", + "101, T {'context': 'I-cells'}", + "102, cells. {'context': 'I-cells'}", + "106, increased {'effect': 'B-positive'}", + "107, proliferation {'phenotype': 'B-proliferation'}", + "109, resting {'context': 'B-cells'}", + "110, memory {'context': 'I-cells'}", + "111, T {'context': 'I-cells'}", + "112, cells {'context': 'I-cells'}", + "114, mice {'context': 'B-organism'}", + "119, Virus-specific {'context': 'B-cells'}", + "120, T {'context': 'I-cells'}", + "121, cells {'context': 'I-cells'}", + "125, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "64, mice. ['l0', 'l1']", + "79, effector ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "80, T ['l0', 'l2', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "81, cells. ['l1', 'l3', 'l9', 'l15', 'l16', 'l17', 'l18']", + "95, increased ['l4', 'l10', 'l15', 'l19', 'l20', 'l21', 'l22']", + "96, proliferation ['l5', 'l11', 'l16', 'l19', 'l23', 'l24', 'l25']", + "100, virus-specific ['l6', 'l12', 'l20', 'l23', 'l26', 'l27']", + "101, T ['l7', 'l13', 'l17', 'l21', 'l24', 'l26', 'l28']", + "102, cells. ['l8', 'l14', 'l18', 'l22', 'l25', 'l27', 'l28']", + "106, increased ['l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "107, proliferation ['l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "109, resting ['l30', 'l35', 'l40', 'l41', 'l42', 'l43']", + "110, memory ['l31', 'l36', 'l40', 'l44', 'l45', 'l46']", + "111, T ['l32', 'l37', 'l41', 'l44', 'l47', 'l48']", + "112, cells ['l33', 'l38', 'l42', 'l45', 'l47', 'l49']", + "114, mice ['l34', 'l39', 'l43', 'l46', 'l48', 'l49']", + "119, Virus-specific ['l50', 'l51', 'l52']", + "120, T ['l50', 'l53', 'l54']", + "121, cells ['l51', 'l53', 'l55']", + "125, mice ['l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "effector", + "T", + "cells.", + "virus-specific", + "resting", + "memory", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "effector", + "T", + "cells.", + "virus-specific", + "resting", + "memory", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "12692538", + "TEXT": "We studied the role of NF-kappaB in acute inflammation caused by gut ischemia-reperfusion through selective ablation of IkappaB kinase (IKK)-beta, the catalytic subunit of IKK that is essential for NF-kappaB activation. Ablation of IKK-beta in enterocytes prevented the systemic inflammatory response, which culminates in multiple organ dysfunction syndrome (MODS) that is normally triggered by gut ischemia-reperfusion. IKK-beta removal from enterocytes, however, also resulted in severe apoptotic damage to the reperfused intestinal mucosa. These results show the dual function of the NF-kappaB system, which is responsible for both tissue protection and systemic inflammation, and underscore the caution that should be exerted in using NF-kappaB and IKK inhibitors.", + "TAG_DATA": [ + "31, Ablation {'perturbing_action': 'B-gene loss-of-function'}", + "32, of {'perturbing_action': 'I-gene loss-of-function'}", + "33, IKK-beta {'perturbing_action': 'I-gene loss-of-function'}", + "35, enterocytes {'context': 'B-cells'}", + "56, IKK-beta {'perturbing_action': 'B-gene loss-of-function'}", + "57, removal {'perturbing_action': 'I-gene loss-of-function'}", + "58, from {'perturbing_action': 'I-gene loss-of-function'}", + "59, enterocytes, {'context': 'B-cells'}", + "65, apoptotic {'phenotype': 'B-apoptosis'}", + "66, damage {'phenotype': 'I-apoptosis'}", + "70, intestinal {'context': 'B-tissue/organ'}", + "71, mucosa. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "31, Ablation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "32, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "33, IKK-beta ['l1', 'l7', 'l13', 'l14', 'l15', 'l16']", + "35, enterocytes ['l2', 'l8', 'l13']", + "56, IKK-beta ['l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "57, removal ['l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "58, from ['l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "59, enterocytes, ['l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "65, apoptotic ['l3', 'l9', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "66, damage ['l4', 'l10', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "70, intestinal ['l5', 'l11', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "71, mucosa. ['l6', 'l12', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "IKK-beta", + "removal", + "from" + ] + }, + "context": { + "val": "cells", + "words": [ + "enterocytes", + "enterocytes," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "IKK-beta", + "removal", + "from" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "damage" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "IKK-beta", + "removal", + "from" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "intestinal", + "mucosa." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "enterocytes," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "damage" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "damage" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "intestinal", + "mucosa." + ] + } + } + ] + }, + { + "PMID": "12669032", + "TEXT": "The establishment of functional and stable vascular networks is essential for angiogenic therapy. Here we report that a combination of two angiogenic factors, platelet-derived growth factor (PDGF)-BB and fibroblast growth factor (FGF)-2, synergistically induces vascular networks, which remain stable for more than a year even after depletion of angiogenic factors. In both rat and rabbit ischemic hind limb models, PDGF-BB and FGF-2 together markedly stimulated collateral arteriogenesis after ligation of the femoral artery, with a significant increase in vascularization and improvement in paw blood flow. A possible mechanism of angiogenic synergism between PDGF-BB and FGF-2 involves upregulation of the expression of PDGF receptor (PDGFR)-alpha and PDGFR-beta by FGF-2 in newly formed blood vessels. Our data show that a specific combination of angiogenic factors establishes functional and stable vascular networks, and provides guidance for the ongoing clinical trials of angiogenic factors for the treatment of ischemic diseases.", + "TAG_DATA": [ + "52, rat {'context': 'B-organism'}", + "53, and {'context': 'I-organism'}", + "54, rabbit {'context': 'I-organism'}", + "69, of {'perturbing_action': 'I-gene loss-of-function'}", + "70, the {'perturbing_action': 'I-gene loss-of-function'}", + "71, femoral {'perturbing_action': 'I-gene loss-of-function'}", + "72, artery, {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-tissue/organ'}", + "82, paw {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "52, rat ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "53, and ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "54, rabbit ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "56, hind ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "57, limb ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "68, ligation ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "69, of ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "70, the ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "71, femoral ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44', 'l45']", + "72, artery, ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "82, paw ['l45']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "rat", + "and", + "rabbit" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "the", + "femoral", + "artery," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "artery,", + "of", + "the", + "femoral" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "artery,", + "paw" + ] + } + } + ] + }, + { + "PMID": "12598894", + "TEXT": "Small polybasic peptides derived from the transduction domains of certain proteins, such as the third alpha-helix of the Antennapedia (Antp) homeodomain, can cross the cell membrane through a receptor-independent mechanism. These cell-permeable molecules have been used as 'Trojan horses' to introduce biologically active cargo molecules such as DNA, peptides or proteins into cells. Using these cell-permeable peptides, we have developed an efficient and simple method to increase virally mediated gene delivery and protein expression in vitro and in vivo. Here, we show that cell-permeable peptides increase viral cell entry, improve gene expression at reduced titers of virus and improve efficacy of therapeutically relevant genes in vivo.", + "TAG_DATA": [ + "104, in {'context': 'B-in vivo'}", + "105, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "104, in ['l0']", + "105, vivo. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12592403", + "TEXT": "Three of the major biochemical pathways implicated in the pathogenesis of hyperglycemia induced vascular damage (the hexosamine pathway, the advanced glycation end product (AGE) formation pathway and the diacylglycerol (DAG)-protein kinase C (PKC) pathway) are activated by increased availability of the glycolytic metabolites glyceraldehyde-3-phosphate and fructose-6-phosphate. We have discovered that the lipid-soluble thiamine derivative benfotiamine can inhibit these three pathways, as well as hyperglycemia-associated NF-kappaB activation, by activating the pentose phosphate pathway enzyme transketolase, which converts glyceraldehyde-3-phosphate and fructose-6-phosphate into pentose-5-phosphates and other sugars. In retinas of diabetic animals, benfotiamine treatment inhibited these three pathways and NF-kappaB activation by activating transketolase, and also prevented experimental diabetic retinopathy. The ability of benfotiamine to inhibit three major pathways simultaneously might be clinically useful in preventing the development and progression of diabetic complications.", + "TAG_DATA": [ + "85, retinas {'context': 'B-tissue/organ'}", + "87, diabetic {'context': 'B-organism'}", + "88, animals, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "85, retinas ['l0', 'l1']", + "87, diabetic ['l0', 'l2']", + "88, animals, ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12592402", + "TEXT": "Polymorphonuclear leukocytes (PMNs) are critical effector cells of the innate immune system that protect the host by migrating to inflammatory sites and killing pathogenic microbes. We addressed the role of chemokine receptor desensitization induced by G-protein-coupled receptor kinases (GRKs) in the feedback control of PMN migration. We show that the chemokine macrophage inflammatory protein-2 (MIP-2) induces GRK2 and GRK5 expression in PMNs through phosphoinositide-3-kinase (PI3K)-gamma signaling. We also show that lipopolysaccharide (LPS)-activated signaling through the Toll-like receptor (TLR)-4 pathway transcriptionally downregulates the expression of GRK2 and GRK5 in response to MIP-2. The reduced expression of GRKs lowers chemokine receptor desensitization and markedly augments the PMN migratory response. These data indicate that TLR4 modulation of PMN surface chemokine receptor expression subsequent to the downregulation of GRK2 and GRK5 expression is a critical determinant of PMN migration.", + "TAG_DATA": [ + "61, PMNs {'context': 'B-cells'}", + "95, GRKs {'perturbing_action': 'I-rnai/knockdown'}", + "102, augments {'effect': 'B-positive'}", + "104, PMN {'context': 'B-cells'}", + "105, migratory {'phenotype': 'B-migration'}", + "106, response. {'phenotype': 'I-migration'}" + ], + "LINK_DATA": [ + "95, GRKs ['l0', 'l1', 'l2', 'l3']", + "102, augments ['l0', 'l4', 'l5', 'l6']", + "104, PMN ['l1', 'l4', 'l7', 'l8']", + "105, migratory ['l2', 'l5', 'l7', 'l9']", + "106, response. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "GRKs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "augments" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "GRKs" + ] + }, + "context": { + "val": "cells", + "words": [ + "PMN" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "GRKs" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migratory", + "response." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "augments" + ] + }, + "context": { + "val": "cells", + "words": [ + "PMN" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "augments" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migratory", + "response." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "PMN" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migratory", + "response." + ] + } + } + ] + }, + { + "PMID": "12592401", + "TEXT": "Epstein-Barr virus (EBV) initially enters the body through the oropharyngeal mucosa and subsequently infects B lymphocytes through their CD21 (CR2) complement receptor. Mechanisms of EBV entry into and release from epithelial cells are poorly understood. To study EBV infection in mucosal oropharyngeal epithelial cells, we established human polarized tongue and pharyngeal epithelial cells in culture. We show that EBV enters these cells through three CD21-independent pathways: (i) by direct cell-to-cell contact of apical cell membranes with EBV-infected lymphocytes; (ii) by entry of cell-free virions through basolateral membranes, mediated in part through an interaction between beta1 or alpha5beta1 integrins and the EBV BMRF-2 protein; and (iii) after initial infection, by virus spread directly across lateral membranes to adjacent epithelial cells. Release of progeny virions from polarized cells occurs from both their apical and basolateral membranes. These data indicate that multiple approaches to prevention of epithelial infection with EBV will be necessary.", + "TAG_DATA": [ + "46, human {'context': 'B-tissue/organ'}", + "47, polarized {'context': 'I-tissue/organ'}", + "48, tongue {'context': 'I-tissue/organ'}", + "49, and {'context': 'I-cells'}", + "50, pharyngeal {'context': 'I-cells'}", + "51, epithelial {'context': 'I-cells'}", + "52, cells {'context': 'I-cells'}", + "53, in {'context': 'B-in vitro'}", + "54, culture. {'context': 'I-in vitro'}", + "61, cells {'context': 'B-cells'}", + "117, epithelial {'context': 'B-cells'}", + "118, cells. {'context': 'I-cells'}", + "124, polarized {'context': 'B-cells'}", + "125, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "46, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "47, polarized ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "48, tongue ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "49, and ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "50, pharyngeal ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "51, epithelial ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "52, cells ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "53, in ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "54, culture. ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "61, cells ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "117, epithelial ['l45']", + "118, cells. ['l45']", + "124, polarized ['l46']", + "125, cells ['l46']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12579198", + "TEXT": "A topical microbicide reduces the probability of virus transmission when applied to the vagina or rectum of a person at risk of sexually acquiring HIV-1 infection. An effective microbicide could significantly reduce the global spread of HIV-1, particularly if women were able to use it covertly to protect themselves. A microbicide could target the incoming virus and either permanently inactivate it or reduce its infectivity, or it could block receptors on susceptible cells near the sites of transmission. We describe here how vaginal administration of the broadly neutralizing human monoclonal antibody b12 can protect macaques from simian-human immunodeficiency virus (SHIV) infection through the vagina. Only 3 of 12 animals receiving 5 mg b12 vaginally in either saline or a gel and then challenged vaginally (up to 2 h later) with SHIV-162P4 became infected. In contrast, infection occurred in 12 of 13 animals given various control agents under similar conditions. Lower amounts of b12 were less effective, suggesting that protection was dose dependent. These observations support the concept that viral entry inhibitors can help prevent the sexual transmission of HIV-1 to humans.", + "TAG_DATA": [ + "94, macaques {'context': 'B-organism'}", + "108, animals {'context': 'B-organism'}", + "141, animals {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12579197", + "TEXT": "RNA interference (RNAi) is a powerful tool to silence gene expression post-transcriptionally. However, its potential to treat or prevent disease remains unproven. Fas-mediated apoptosis is implicated in a broad spectrum of liver diseases, where inhibiting hepatocyte death is life-saving. We investigated the in vivo silencing effect of small interfering RNA (siRNA) duplexes targeting the gene Fas (also known as Tnfrsf6), encoding the Fas receptor, to protect mice from liver failure and fibrosis in two models of autoimmune hepatitis. Intravenous injection of Fas siRNA specifically reduced Fas mRNA levels and expression of Fas protein in mouse hepatocytes, and the effects persisted without diminution for 10 days. Hepatocytes isolated from mice treated with Fas siRNA were resistant to apoptosis when exposed to Fas-specific antibody or co-cultured with concanavalin A (ConA)-stimulated hepatic mononuclear cells. Treatment with Fas siRNA 2 days before ConA challenge abrogated hepatocyte necrosis and inflammatory infiltration and markedly reduced serum concentrations of transaminases. Administering Fas siRNA beginning one week after initiating weekly ConA injections protected mice from liver fibrosis. In a more fulminant hepatitis induced by injecting agonistic Fas-specific antibody, 82% of mice treated with siRNA that effectively silenced Fas survived for 10 days of observation, whereas all control mice died within 3 days. Silencing Fas expression with RNAi holds therapeutic promise to prevent liver injury by protecting hepatocytes from cytotoxicity.", + "TAG_DATA": [ + "66, mice {'context': 'B-organism'}", + "81, Fas {'perturbing_action': 'B-rnai/knockdown'}", + "82, siRNA {'perturbing_action': 'I-rnai/knockdown'}", + "94, mouse {'context': 'B-cells'}", + "95, hepatocytes, {'context': 'I-cells'}", + "105, Hepatocytes {'context': 'B-cells'}", + "106, isolated {'context': 'I-cells'}", + "108, mice {'context': 'B-organism'}", + "111, Fas {'perturbing_action': 'B-rnai/knockdown'}", + "112, siRNA {'perturbing_action': 'I-rnai/knockdown'}", + "114, resistant {'effect': 'B-negative'}", + "116, apoptosis {'phenotype': 'B-apoptosis'}", + "128, hepatic {'context': 'B-cells'}", + "129, mononuclear {'context': 'I-cells'}", + "130, cells. {'context': 'I-cells'}", + "133, Fas {'perturbing_action': 'B-rnai/knockdown'}", + "134, siRNA {'perturbing_action': 'I-rnai/knockdown'}", + "140, abrogated {'effect': 'B-negative'}", + "141, hepatocyte {'context': 'B-cells'}", + "142, necrosis {'phenotype': 'B-necrosis'}", + "154, Fas {'perturbing_action': 'B-rnai/knockdown'}", + "155, siRNA {'perturbing_action': 'I-rnai/knockdown'}", + "165, mice {'context': 'B-organism'}", + "167, liver {'context': 'B-tissue/organ'}", + "182, mice {'context': 'B-organism'}", + "185, siRNA {'perturbing_action': 'B-rnai/knockdown'}", + "188, silenced {'perturbing_action': 'I-rnai/knockdown'}", + "189, Fas {'perturbing_action': 'I-rnai/knockdown'}", + "199, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "66, mice ['l0', 'l1', 'l2', 'l3']", + "81, Fas ['l0', 'l4', 'l5', 'l6']", + "82, siRNA ['l1', 'l4', 'l7', 'l8']", + "94, mouse ['l2', 'l5', 'l7', 'l9']", + "95, hepatocytes, ['l3', 'l6', 'l8', 'l9']", + "105, Hepatocytes ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "106, isolated ['l10', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "108, mice ['l11', 'l24', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "111, Fas ['l12', 'l25', 'l37', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "112, siRNA ['l13', 'l26', 'l38', 'l49', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "114, resistant ['l14', 'l27', 'l39', 'l50', 'l60', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "116, apoptosis ['l15', 'l28', 'l40', 'l51', 'l61', 'l70', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "128, hepatic ['l16', 'l29', 'l41', 'l52', 'l62', 'l71', 'l79', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "129, mononuclear ['l17', 'l30', 'l42', 'l53', 'l63', 'l72', 'l80', 'l87', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "130, cells. ['l18', 'l31', 'l43', 'l54', 'l64', 'l73', 'l81', 'l88', 'l94', 'l100', 'l101', 'l102', 'l103', 'l104']", + "133, Fas ['l19', 'l32', 'l44', 'l55', 'l65', 'l74', 'l82', 'l89', 'l95', 'l100', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "134, siRNA ['l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l83', 'l90', 'l96', 'l101', 'l105', 'l111', 'l112', 'l113', 'l114', 'l115']", + "140, abrogated ['l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l84', 'l91', 'l97', 'l102', 'l106', 'l111', 'l116', 'l117']", + "141, hepatocyte ['l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l98', 'l103', 'l107', 'l112', 'l116', 'l118']", + "142, necrosis ['l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l86', 'l93', 'l99', 'l104', 'l108', 'l113', 'l117', 'l118']", + "154, Fas ['l119', 'l120', 'l121']", + "155, siRNA ['l119', 'l122', 'l123']", + "165, mice ['l109', 'l114', 'l120', 'l122', 'l124']", + "167, liver ['l110', 'l115', 'l121', 'l123', 'l124']", + "182, mice ['l125', 'l126', 'l127', 'l128']", + "185, siRNA ['l125', 'l129', 'l130', 'l131']", + "188, silenced ['l126', 'l129', 'l132', 'l133']", + "189, Fas ['l127', 'l130', 'l132', 'l134']", + "199, mice ['l128', 'l131', 'l133', 'l134']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Fas", + "siRNA", + "silenced" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Fas", + "siRNA" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "hepatocytes,", + "Hepatocytes", + "isolated", + "hepatic", + "mononuclear", + "cells.", + "hepatocyte" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Hepatocytes", + "isolated", + "hepatic", + "mononuclear", + "cells.", + "hepatocyte" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant", + "abrogated" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Hepatocytes", + "isolated", + "hepatic", + "mononuclear", + "cells.", + "hepatocyte" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Hepatocytes", + "isolated", + "hepatic", + "mononuclear", + "cells.", + "hepatocyte" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant", + "abrogated" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Fas", + "siRNA" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant", + "abrogated" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Fas", + "siRNA" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Fas", + "siRNA" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistant", + "abrogated" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistant", + "abrogated" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Fas", + "siRNA" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "12539038", + "TEXT": "Carbon monoxide (CO), one of the products of heme oxygenase action on heme, prevents arteriosclerotic lesions that occur following aorta transplantation; pre-exposure to 250 parts per million of CO for 1 hour before injury suppresses stenosis after carotid balloon injury in rats as well as in mice. The protective effect of CO is associated with a profound inhibition of graft leukocyte infiltration/activation as well as with inhibition of smooth muscle cell proliferation. The anti-proliferative effect of CO in vitro requires the activation of guanylate cyclase, the generation of cGMP, the activation of p38 mitogen-activated protein kinases and the expression of the cell cycle inhibitor p21Cip1. These findings demonstrate a protective role for CO in vascular injury and support its use as a therapeutic agent.", + "TAG_DATA": [ + "41, rats {'context': 'B-organism'}", + "46, mice. {'context': 'B-organism'}", + "66, inhibition {'effect': 'B-negative'}", + "68, smooth {'context': 'B-cells'}", + "69, muscle {'context': 'I-cells'}", + "70, cell {'context': 'I-cells'}", + "71, proliferation. {'phenotype': 'B-proliferation'}", + "77, in {'context': 'B-in vitro'}", + "78, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "41, rats ['l0']", + "46, mice. ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "66, inhibition ['l1', 'l6', 'l7', 'l8', 'l9']", + "68, smooth ['l2', 'l6', 'l10', 'l11', 'l12']", + "69, muscle ['l3', 'l7', 'l10', 'l13', 'l14']", + "70, cell ['l4', 'l8', 'l11', 'l13', 'l15']", + "71, proliferation. ['l5', 'l9', 'l12', 'l14', 'l15']", + "77, in ['l16']", + "78, vitro ['l16']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "smooth", + "muscle", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "smooth", + "muscle", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "12514742", + "TEXT": "Systemic tolerance can be induced by the introduction of antigen into an immune-privileged site. Here we investigated the role of complement in the induction of tolerance after intraocular injection. We found that the development of antigen-specific tolerance is dependent on a complement activation product. The ligation of the complement C3 activation product iC3b to complement receptor type 3 (the iC3b receptor) on antigen-presenting cells resulted in the sequential production of transforming growth factor-beta2 and interleukin-10, which is essential for the induction of tolerance. These observations may extend to the development of both neonatal tolerance and other forms of acquired tolerance.", + "TAG_DATA": [ + "62, antigen-presenting {'context': 'B-cells'}", + "63, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "62, antigen-presenting ['l0']", + "63, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12496961", + "TEXT": "Cancer vaccines targeting 'self' antigens that are expressed at consistently high levels by tumor cells are potentially useful in immunotherapy, but immunological tolerance may block their function. Here, we describe a novel, naked DNA vaccine encoding an alphavirus replicon (self-replicating mRNA) and the self/tumor antigen tyrosinase-related protein-1. Unlike conventional DNA vaccines, this vaccine can break tolerance and provide immunity to melanoma. The vaccine mediates production of double-stranded RNA, as evidenced by the autophosphorylation of dsRNA-dependent protein kinase R (PKR). Double-stranded RNA is critical to vaccine function because both the immunogenicity and the anti-tumor activity of the vaccine are blocked in mice deficient for the RNase L enzyme, a key component of the 2',5'-linked oligoadenylate synthetase antiviral pathway involved in double-stranded RNA recognition. This study shows for the first time that alphaviral replicon-encoding DNA vaccines activate innate immune pathways known to drive antiviral immune responses, and points the way to strategies for improving the efficacy of immunization with naked DNA.", + "TAG_DATA": [ + "100, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "100, mice ['l0']", + "101, deficient ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12496960", + "TEXT": "Kidney transplantation has been one of the major medical advances of the past 30 years. However, tissue availability remains a major obstacle. This can potentially be overcome by the use of undifferentiated or partially developed kidney precursor cells derived from early embryos and fetal tissue. Here, transplantation in mice reveals the earliest gestational time point at which kidney precursor cells, of both human and pig origin, differentiate into functional nephrons and not into other, non-renal professional cell types. Moreover, successful organogenesis is achieved when using the early kidney precursors, but not later-gestation kidneys. The formed, miniature kidneys are functional as evidenced by the dilute urine they produce. In addition, decreased immunogenicity of the transplants of early human and pig kidney precursors compared with adult kidney transplants is demonstrated in vivo. Our data pinpoint a window of human and pig kidney organogenesis that may be optimal for transplantation in humans.", + "TAG_DATA": [ + "48, mice {'context': 'B-organism'}", + "57, kidney {'context': 'B-cells'}", + "58, precursor {'context': 'I-cells'}", + "59, cells, {'context': 'I-cells'}", + "116, human {'context': 'I-cells'}", + "117, and {'context': 'I-cells'}", + "118, pig {'context': 'I-cells'}", + "119, kidney {'context': 'I-cells'}", + "120, precursors {'context': 'I-cells'}", + "123, adult {'context': 'B-cells'}", + "124, kidney {'context': 'I-cells'}", + "128, in {'context': 'B-in vivo'}", + "129, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "48, mice ['l0', 'l1', 'l2']", + "57, kidney ['l0', 'l3', 'l4']", + "58, precursor ['l1', 'l3', 'l5']", + "59, cells, ['l2', 'l4', 'l5']", + "116, human ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "117, and ['l6', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "118, pig ['l7', 'l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "119, kidney ['l8', 'l16', 'l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "120, precursors ['l9', 'l17', 'l24', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "123, adult ['l10', 'l18', 'l25', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "124, kidney ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l45', 'l46', 'l47']", + "125, transplants ['l12', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l48', 'l49']", + "128, in ['l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l50']", + "129, vivo. ['l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l50']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12483207", + "TEXT": "We studied whether circulating activated platelets and platelet-leukocyte aggregates cause the development of atherosclerotic lesions in apolipoprotein-E-deficient (Apoe(-/-)) mice. Circulating activated platelets bound to leukocytes, preferentially monocytes, to form platelet-monocyte/leukocyte aggregates. Activated platelets and platelet-leukocyte aggregates interacted with atherosclerotic lesions. The interactions of activated platelets with monocytes and atherosclerotic arteries led to delivery of the platelet-derived chemokines CCL5 (regulated on activation, normal T cell expressed and secreted, RANTES) and CXCL4 (platelet factor 4) to the monocyte surface and endothelium of atherosclerotic arteries. The presence of activated platelets promoted leukocyte binding of vascular cell adhesion molecule-1 (VCAM-1) and increased their adhesiveness to inflamed or atherosclerotic endothelium. Injection of activated wild-type, but not P-selectin-deficient, platelets increased monocyte arrest on the surface of atherosclerotic lesions and the size of atherosclerotic lesions in Apoe(-/-) mice. Our results indicate that circulating activated platelets and platelet-leukocyte/monocyte aggregates promote formation of atherosclerotic lesions. This role of activated platelets in atherosclerosis is attributed to platelet P-selectin-mediated delivery of platelet-derived proinflammatory factors to monocytes/leukocytes and the vessel wall.", + "TAG_DATA": [ + "16, apolipoprotein-E-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "17, (Apoe(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "104, endothelium. {'context': 'I-tissue/organ'}", + "111, P-selectin-deficient, {'perturbing_action': 'B-gene loss-of-function'}", + "112, platelets {'context': 'B-cells'}", + "114, monocyte {'context': 'B-cells'}", + "129, Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "130, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "16, apolipoprotein-E-deficient ['l0', 'l1']", + "17, (Apoe(-/-)) ['l0', 'l2']", + "104, endothelium. ['l1', 'l2']", + "111, P-selectin-deficient, ['l3', 'l4', 'l5', 'l6']", + "112, platelets ['l3', 'l7', 'l8', 'l9']", + "114, monocyte ['l4', 'l7']", + "129, Apoe(-/-) ['l5', 'l8', 'l10']", + "130, mice. ['l6', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "apolipoprotein-E-deficient", + "(Apoe(-/-))" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "endothelium." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "P-selectin-deficient,", + "Apoe(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelets", + "monocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "P-selectin-deficient,", + "Apoe(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "12461523", + "TEXT": "The psychoactive constituent of cannabis, Delta(9)-tetrahydrocannabinol, produces in humans subjective responses mediated by CB1 cannabinoid receptors, indicating that endogenous cannabinoids may contribute to the control of emotion. But the variable effects of Delta(9)-tetrahydrocannabinol obscure the interpretation of these results and limit the therapeutic potential of direct cannabinoid agonists. An alternative approach may be to develop drugs that amplify the effects of endogenous cannabinoids by preventing their inactivation. Here we describe a class of potent, selective and systemically active inhibitors of fatty acid amide hydrolase, the enzyme responsible for the degradation of the endogenous cannabinoid anandamide. Like clinically used anti-anxiety drugs, in rats the inhibitors exhibit benzodiazepine-like properties in the elevated zero-maze test and suppress isolation-induced vocalizations. These effects are accompanied by augmented brain levels of anandamide and are prevented by CB1 receptor blockade. Our results indicate that anandamide participates in the modulation of emotional states and point to fatty acid amide hydrolase inhibition as an innovative approach to anti-anxiety therapy.", + "TAG_DATA": [ + "101, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12426559", + "TEXT": "Humans and mice deficient in Fas, a tumor necrosis factor (TNF)-receptor family member, cannot induce apoptosis of autoreactive cells, and consequently develop progressive lymphoproliferative disorders and lupus-like autoimmune diseases. Previous studies have shown that short-term administrations of agonistic monoclonal antibodies against CD137, another TNF-receptor family member, activate T cells and induce rejection of allografts and established tumors. Here we report that treatment with an agonistic monoclonal antibody to CD137 (2A) blocks lymphadenopathy and spontaneous autoimmune diseases in Fas-deficient MRL/lpr mice, ultimately leading to their prolonged survival. Notably, 2A treatment rapidly augments IFN-gamma production, and induces the depletion of autoreactive B cells and abnormal double-negative T cells, possibly by increasing their apoptosis through Fas- and TNF receptor-independent mechanisms. This study demonstrates that agonistic monoclonal antibodies specific for costimulatory molecules can be used as novel therapeutic agents to delete autoreactive lymphocytes and block autoimmune disease progression.", + "TAG_DATA": [ + "77, Fas-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "78, MRL/lpr {'context': 'B-organism'}", + "79, mice, {'context': 'I-organism'}", + "98, autoreactive {'context': 'B-cells'}", + "99, B {'context': 'I-cells'}", + "100, cells {'context': 'I-cells'}", + "103, double-negative {'context': 'B-cells'}", + "104, T {'context': 'I-cells'}", + "105, cells, {'context': 'I-cells'}", + "108, increasing {'effect': 'B-positive'}", + "110, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "77, Fas-deficient ['l0', 'l1']", + "78, MRL/lpr ['l0', 'l2']", + "79, mice, ['l1', 'l2']", + "98, autoreactive ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "99, B ['l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "100, cells ['l4', 'l10', 'l16', 'l17', 'l18', 'l19']", + "103, double-negative ['l5', 'l11', 'l20', 'l21', 'l22', 'l23']", + "104, T ['l6', 'l12', 'l16', 'l20', 'l24', 'l25', 'l26']", + "105, cells, ['l7', 'l13', 'l17', 'l21', 'l24', 'l27', 'l28']", + "108, increasing ['l8', 'l14', 'l18', 'l22', 'l25', 'l27', 'l29']", + "110, apoptosis ['l9', 'l15', 'l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fas-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "MRL/lpr", + "mice," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "autoreactive", + "B", + "cells", + "double-negative", + "T", + "cells," + ] + }, + "effect": { + "val": "positive", + "words": [ + "increasing" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "autoreactive", + "B", + "cells", + "double-negative", + "T", + "cells," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increasing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "12415262", + "TEXT": "The relationship between the structure of zinc-finger protein (ZFP) transcription factors and DNA sequence binding specificity has been extensively studied. Advances in this field have made it possible to design ZFPs de novo that will bind to specific targeted DNA sequences. It has been proposed that such designed ZFPs may eventually be useful in gene therapy. A principal advantage of this approach is that activation of an endogenous gene ensures expression of the natural array of splice variants. Preliminary studies in tissue culture have validated the feasibility of this approach. The studies reported here were intended to test whether engineered transcription factors are effective in a whole-organism model. ZFPs were designed to regulate the endogenous gene encoding vascular endothelial growth factor-A (Vegfa). Expression of these new ZFPs in vivo led to induced expression of the protein VEGF-A, stimulation of angiogenesis and acceleration of experimental wound healing. In addition, the neovasculature resulting from ZFP-induced expression of Vegfa was not hyperpermeable as was that produced by expression of murine Vegfa(164) cDNA. These data establish, for the first time, that specifically designed transcription factors can regulate an endogenous gene in vivo and evoke a potentially therapeutic biophysiologic effect.", + "TAG_DATA": [ + "127, in {'context': 'B-in vivo'}", + "128, vivo {'context': 'I-in vivo'}", + "141, acceleration {'effect': 'B-positive'}", + "164, expression {'perturbing_action': 'B-gene gain-of-function'}", + "165, of {'perturbing_action': 'I-gene gain-of-function'}", + "166, murine {'perturbing_action': 'I-gene gain-of-function'}", + "167, Vegfa(164) {'perturbing_action': 'I-gene gain-of-function'}", + "168, cDNA. {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "127, in ['l0', 'l1']", + "128, vivo ['l0', 'l2']", + "141, acceleration ['l1', 'l2']", + "164, expression ['l3', 'l4', 'l5', 'l6']", + "165, of ['l3', 'l7', 'l8', 'l9']", + "166, murine ['l4', 'l7', 'l10', 'l11']", + "167, Vegfa(164) ['l5', 'l8', 'l10', 'l12']", + "168, cDNA. ['l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "acceleration" + ] + } + } + ] + }, + { + "PMID": "12379848", + "TEXT": "Plasmodium sporozoites, the infective stage of the malaria parasite transmitted by mosquitoes, migrate through several hepatocytes before infecting a final one. Migration through hepatocytes occurs by breaching their plasma membranes, and final infection takes place with the formation of a vacuole around the sporozoite. Once in the liver, sporozoites have already reached their target cells, making migration through hepatocytes prior to infection seem unnecessary. Here we show that this migration is required for infection of hepatocytes. Migration through host cells, but not passive contact with hepatocytes, induces the exocytosis of sporozoite apical organelles, a prerequisite for infection with formation of a vacuole. Sporozoite activation induced by migration through host cells is an essential step of Plasmodium life cycle.", + "TAG_DATA": [], + "LINK_DATA": [ + "78, host ['l0']", + "79, cells, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12357248", + "TEXT": "Thiazolidinediones (TZDs) are effective therapies for type 2 diabetes, which has reached epidemic proportions in industrialized societies. TZD treatment reduces circulating free fatty acids (FFAs), which oppose insulin actions in skeletal muscle and other insulin target tissues. Here we report that TZDs, acting as ligands for the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-gamma, markedly induce adipocyte glycerol kinase (GyK) gene expression. This is surprising, as standard textbooks indicate that adipocytes lack GyK and thereby avoid futile cycles of triglyceride breakdown and resynthesis from glycerol and FFAs. By inducing GyK, TZDs markedly stimulate glycerol incorporation into triglyceride and reduce FFA secretion from adipocytes. The 'futile' fuel cycle resulting from expression of GyK in adipocytes is thus a novel mechanism contributing to reduced FFA levels and perhaps insulin sensitization by antidiabetic therapies.", + "TAG_DATA": [ + "101, adipocytes. {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12195435", + "TEXT": "Studies have shown that bone marrow cells have the potential to differentiate into a variety of cell types. Here we show that bone marrow cells can repopulate the epithelia of the human gastrointestinal tract. Epithelial cells of male donor origin were distributed in every part of the gastrointestinal tract of female bone marrow transplant recipients. Donor-derived epithelial cells substantially repopulated the gastrointestinal tract during epithelial regeneration after graft-versus-host disease or ulcer formation. Regeneration of gastrointestinal epithelia with donor-derived cells in humans shows a potential clinical application of bone marrow-derived cells for repairing severely damaged epithelia, not only in the gastrointestinal tract but also in other tissues.", + "TAG_DATA": [ + "55, Donor-derived {'context': 'B-cells'}", + "56, epithelial {'context': 'I-cells'}", + "57, cells {'context': 'I-cells'}", + "61, gastrointestinal {'context': 'B-tissue/organ'}", + "62, tract {'context': 'I-tissue/organ'}", + "77, donor-derived {'context': 'B-cells'}", + "78, cells {'context': 'I-cells'}", + "80, humans {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "35, cells ['l0']", + "55, Donor-derived ['l1', 'l2', 'l3', 'l4']", + "56, epithelial ['l1', 'l5', 'l6', 'l7']", + "57, cells ['l2', 'l5', 'l8', 'l9']", + "61, gastrointestinal ['l3', 'l6', 'l8', 'l10']", + "62, tract ['l0', 'l4', 'l7', 'l9', 'l10']", + "77, donor-derived ['l11', 'l12']", + "78, cells ['l11', 'l13']", + "80, humans ['l12', 'l13']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12185363", + "TEXT": "Analysis of the viability, differentiation, clonogenicity and function of human stem/progenitor cells requires suitable xenograft models. However, the identification of transplanted cells has been generally difficult. Fluorescence in situ hybridization is a tedious method for analyzing tissues, and localization of transplanted cells with X or Y chromosome probes is limited by the sparse signals produced. Therefore, we examined the possibility of generating either pan-nuclear signals with a total human DNA probe or multiple nuclear signals with a pan-centromeric human DNA probe. The probes were labeled with digoxigenin to make reaction products visible by light microscopy and to allow the use of immunohistochemistry methods incorporating various color schemes to demonstrate specific properties of transplanted cells. The ability to localize all types of nucleated human cells with such probes will facilitate studies of stem cell biology and cell and gene therapy, as well as the development of new animal models.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12185362", + "TEXT": "Truncated Notch receptors have transforming activity in vitro and in vivo. However, the role of wild-type Notch signaling in neoplastic transformation remains unclear. Ras signaling is deregulated in a large fraction of human malignancies and is a major target for the development of novel cancer treatments. We show that oncogenic Ras activates Notch signaling and that wild-type Notch-1 is necessary to maintain the neoplastic phenotype in Ras-transformed human cells in vitro and in vivo. Oncogenic Ras increases levels and activity of the intracellular form of wild-type Notch-1, and upregulates Notch ligand Delta-1 and also presenilin-1, a protein involved in Notch processing, through a p38-mediated pathway. These observations place Notch signaling among key downstream effectors of oncogenic Ras and suggest that it might be a novel therapeutic target.", + "TAG_DATA": [ + "66, Ras-transformed {'perturbing_action': 'B-other', 'phenotype': 'B-transformation'}", + "67, human {'context': 'B-cells'}", + "68, cells {'context': 'I-cells'}", + "69, in {'context': 'B-in vitro'}", + "70, vitro {'context': 'I-in vitro'}", + "72, in {'context': 'B-in vivo'}", + "73, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "61, maintain ['l0', 'l1', 'l2', 'l3', 'l4']", + "66, Ras-transformed ['l0', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "67, human ['l1', 'l5', 'l11', 'l12', 'l13']", + "68, cells ['l2', 'l6', 'l11', 'l14', 'l15']", + "69, in ['l3', 'l7', 'l12', 'l14', 'l16']", + "70, vitro ['l4', 'l8', 'l13', 'l15', 'l16']", + "72, in ['l9', 'l17']", + "73, vivo. ['l10', 'l17']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Ras-transformed" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "Ras-transformed" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Ras-transformed" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "cells" + ] + } + }, + { + "phenotype": { + "val": "transformation", + "words": [ + "Ras-transformed" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Ras-transformed" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "transformation", + "words": [ + "Ras-transformed" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Ras-transformed" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "transformation", + "words": [ + "Ras-transformed" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "12172543", + "TEXT": "Survivin (also termed Birc5) belongs to the family of genes known as inhibitors of apoptosis, and it has been implicated in both prevention of cell death and control of mitosis. The survivin pathway is exploited in cancer, but its potential role in vascular injury is unknown. Here, we show that balloon-mediated arterial injury in rabbits resulted in expression of survivin in vascular cells. Serum or PDGF-AB stimulated survivin expression in cultured smooth-muscle cells (SMCs), which suppressed apoptosis and prevented caspase activation. Adenoviral delivery of a phosphorylation-defective survivin mutant reversed the cytoprotective effect of PDGF in SMCs without affecting mitotic progression, suppressed neointimal formation in wire-injured mouse femoral arteries, and induced vascular cell apoptosis in vivo. These data identify survivin as a critical regulator of SMC apoptosis after acute vascular injury. Disrupting the survivin pathway may provide a novel therapy to limit pathological vessel-wall remodeling.", + "TAG_DATA": [ + "54, rabbits {'context': 'B-organism'}", + "61, vascular {'context': 'B-cells'}", + "62, cells. {'context': 'I-cells'}", + "70, cultured {'context': 'B-cells'}", + "71, smooth-muscle {'context': 'I-cells'}", + "72, cells {'context': 'I-cells'}", + "73, (SMCs), {'context': 'I-cells'}", + "75, suppressed {'effect': 'B-negative'}", + "76, apoptosis {'phenotype': 'B-apoptosis'}", + "81, Adenoviral {'perturbing_action': 'B-other'}", + "85, phosphorylation-defective {'perturbing_action': 'B-other'}", + "86, survivin {'perturbing_action': 'I-other'}", + "87, mutant {'perturbing_action': 'I-other'}", + "95, SMCs {'context': 'B-cells'}", + "96, without {'effect': 'B-no effect'}", + "97, affecting {'effect': 'I-no effect'}", + "105, mouse {'context': 'B-tissue/organ'}", + "106, femoral {'context': 'I-tissue/organ'}", + "107, arteries, {'context': 'I-tissue/organ'}", + "109, induced {'effect': 'B-positive'}", + "110, vascular {'context': 'B-cells'}", + "111, cell {'context': 'I-cells'}", + "112, apoptosis {'phenotype': 'B-apoptosis'}", + "113, in {'context': 'B-in vivo'}", + "114, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "54, rabbits ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "61, vascular ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "62, cells. ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "70, cultured ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "71, smooth-muscle ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "72, cells ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "73, (SMCs), ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "75, suppressed ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "76, apoptosis ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "81, Adenoviral ['l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "85, phosphorylation-defective ['l36', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "86, survivin ['l37', 'l51', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "87, mutant ['l38', 'l52', 'l65', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "95, SMCs ['l39', 'l53', 'l66', 'l78', 'l90', 'l91', 'l92']", + "96, without ['l40', 'l54', 'l67', 'l79', 'l90', 'l93']", + "97, affecting ['l41', 'l55', 'l68', 'l80', 'l91', 'l93', 'l94']", + "105, mouse ['l42', 'l56', 'l69', 'l81', 'l95', 'l96', 'l97']", + "106, femoral ['l43', 'l57', 'l70', 'l82', 'l95', 'l98', 'l99']", + "107, arteries, ['l44', 'l58', 'l71', 'l83', 'l92', 'l94', 'l96', 'l98']", + "109, induced ['l45', 'l59', 'l72', 'l84', 'l97', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "110, vascular ['l46', 'l60', 'l73', 'l85', 'l100', 'l105', 'l106', 'l107', 'l108']", + "111, cell ['l47', 'l61', 'l74', 'l86', 'l101', 'l105', 'l109', 'l110', 'l111']", + "112, apoptosis ['l48', 'l62', 'l75', 'l87', 'l102', 'l106', 'l109', 'l112', 'l113']", + "113, in ['l49', 'l63', 'l76', 'l88', 'l103', 'l107', 'l110', 'l112', 'l114']", + "114, vivo. ['l50', 'l64', 'l77', 'l89', 'l104', 'l108', 'l111', 'l113', 'l114']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "rabbits" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rabbits" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "vascular", + "cells.", + "cultured", + "smooth-muscle", + "cells", + "(SMCs)," + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "vascular", + "cells.", + "cultured", + "smooth-muscle", + "cells", + "(SMCs),", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Adenoviral", + "phosphorylation-defective", + "survivin", + "mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "SMCs", + "vascular", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Adenoviral", + "phosphorylation-defective", + "survivin", + "mutant" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "without", + "affecting" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Adenoviral", + "phosphorylation-defective", + "survivin", + "mutant" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "femoral", + "arteries," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Adenoviral", + "phosphorylation-defective", + "survivin", + "mutant" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Adenoviral", + "phosphorylation-defective", + "survivin", + "mutant" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Adenoviral", + "phosphorylation-defective", + "survivin", + "mutant" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "SMCs" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "without", + "affecting" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "affecting" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "arteries," + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "femoral" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "vascular", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "12145647", + "TEXT": "Asthma is caused by T-helper cell 2 (Th2)-driven immune responses, but the immunological mechanisms that protect against asthma development are poorly understood. T-cell tolerance, induced by respiratory exposure to allergen, can inhibit the development of airway hyperreactivity (AHR), a cardinal feature of asthma, and we show here that regulatory T (T(R)) cells can mediate this protective effect. Mature pulmonary dendritic cells in the bronchial lymph nodes of mice exposed to respiratory allergen induced the development of T(R) cells, in a process that required T-cell costimulation via the inducible costimulator (ICOS-ICOS-ligand pathway. The T(R) cells produced IL-10, and had potent inhibitory activity; when adoptively transferred into sensitized mice, T(R) cells blocked the development of AHR. Both the development and the inhibitory function of regulatory cells were dependent on the presence of IL-10 and on ICOS-ICOS-ligand interactions. These studies demonstrate that T(R) cells and the ICOS-ICOS-ligand signaling pathway are critically involved in respiratory tolerance and in downregulating pulmonary inflammation in asthma.", + "TAG_DATA": [ + "57, Mature {'context': 'B-cells'}", + "58, pulmonary {'context': 'I-cells'}", + "59, dendritic {'context': 'I-cells'}", + "60, cells {'context': 'I-cells'}", + "61, in {'context': 'I-cells'}", + "62, the {'context': 'I-tissue/organ'}", + "63, bronchial {'context': 'I-tissue/organ'}", + "64, lymph {'context': 'I-tissue/organ'}", + "65, nodes {'context': 'I-tissue/organ'}", + "67, mice {'context': 'B-organism'}", + "76, T(R) {'context': 'B-cells'}", + "77, cells, {'context': 'I-cells'}", + "92, T(R) {'context': 'B-cells'}", + "93, cells {'context': 'I-cells'}", + "106, mice, {'context': 'B-organism'}", + "107, T(R) {'context': 'B-cells'}", + "108, cells {'context': 'I-cells'}", + "122, regulatory {'context': 'B-cells'}", + "123, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "57, Mature ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "58, pulmonary ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "59, dendritic ['l1', 'l11', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "60, cells ['l2', 'l12', 'l22', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "61, in ['l3', 'l13', 'l23', 'l32', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "62, the ['l4', 'l14', 'l24', 'l33', 'l40', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "63, bronchial ['l5', 'l15', 'l25', 'l34', 'l41', 'l47', 'l53', 'l54', 'l55', 'l56', 'l57']", + "64, lymph ['l6', 'l16', 'l26', 'l35', 'l42', 'l48', 'l53', 'l58', 'l59', 'l60', 'l61']", + "65, nodes ['l7', 'l17', 'l27', 'l36', 'l43', 'l49', 'l54', 'l58', 'l62', 'l63', 'l64']", + "67, mice ['l8', 'l18', 'l28', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l65', 'l66']", + "76, T(R) ['l9', 'l19', 'l29', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l65', 'l67']", + "77, cells, ['l10', 'l20', 'l30', 'l39', 'l46', 'l52', 'l57', 'l61', 'l64', 'l66', 'l67']", + "92, T(R) ['l68']", + "93, cells ['l21', 'l31', 'l68']", + "106, mice, ['l69', 'l70']", + "107, T(R) ['l69', 'l71']", + "108, cells ['l70', 'l71']", + "122, regulatory ['l72']", + "123, cells ['l72']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12145646", + "TEXT": "Adult bone marrow (BM) contains cells capable of differentiating along hematopoietic (Lin(+)) or non-hematopoietic (Lin(-)) lineages. Lin(-) hematopoietic stem cells (HSCs) have recently been shown to contain a population of endothelial precursor cells (EPCs) capable of forming blood vessels. Here we show that intravitreally injected Lin(-) BM cells selectively target retinal astrocytes, cells that serve as a template for both developmental and injury-associated retinal angiogenesis. When Lin(-) BM cells were injected into neonatal mouse eyes, they extensively and stably incorporated into forming retinal vasculature. When EPC-enriched HSCs were injected into the eyes of neonatal rd/rd mice, whose vasculature ordinarily degenerates with age, they rescued and maintained a normal vasculature. In contrast, normal retinal angiogenesis was inhibited when EPCs expressing a potent angiostatic protein were injected. We have demonstrated that Lin(-) BM cells and astrocytes specifically interact with one another during normal angiogenesis and pathological vascular degeneration in the retina. Selective targeting with Lin(-) HSC may be a useful therapeutic approach for the treatment of many ocular diseases.", + "TAG_DATA": [ + "72, neonatal {'context': 'B-tissue/organ'}", + "73, mouse {'context': 'I-tissue/organ'}", + "74, eyes, {'context': 'I-tissue/organ'}", + "91, eyes {'context': 'B-tissue/organ'}", + "93, neonatal {'perturbing_action': 'B-other', 'context': 'B-organism'}", + "94, rd/rd {'perturbing_action': 'B-other', 'context': 'I-organism'}", + "95, mice, {'context': 'I-organism'}", + "117, EPCs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "67, BM ['l0', 'l1', 'l2', 'l3']", + "68, cells ['l0', 'l4', 'l5', 'l6']", + "72, neonatal ['l1', 'l4', 'l7', 'l8']", + "73, mouse ['l2', 'l5', 'l7', 'l9']", + "74, eyes, ['l3', 'l6', 'l8', 'l9']", + "91, eyes ['l10', 'l11', 'l12']", + "93, neonatal ['l10', 'l13', 'l14']", + "94, rd/rd ['l11', 'l13', 'l15']", + "95, mice, ['l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "eyes" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "neonatal", + "rd/rd" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "neonatal", + "rd/rd" + ] + }, + "context": { + "val": "organism", + "words": [ + "neonatal", + "rd/rd" + ] + } + } + ] + }, + { + "PMID": "12118245", + "TEXT": "A major concern in cancer therapy is resistance of tumors such as glioblastoma to current treatment protocols. Here, we report that transfer of the gene encoding second mitochondria-derived activator of caspase (Smac) or Smac peptides sensitized various tumor cells in vitro and malignant glioma cells in vivo for apoptosis induced by death-receptor ligation or cytotoxic drugs. Expression of a cytosolic active form of Smac or cell-permeable Smac peptides bypassed the Bcl-2 block, which prevented the release of Smac from mitochondria, and also sensitized resistant neuroblastoma or melanoma cells and patient-derived primary neuroblastoma cells ex vivo. Most importantly, Smac peptides strongly enhanced the antitumor activity of Apo-2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in an intracranial malignant glioma xenograft model in vivo. Complete eradication of established tumors and survival of mice was only achieved upon combined treatment with Smac peptides and Apo2L/TRAIL without detectable toxicity to normal brain tissue. Thus, Smac agonists are promising candidates for cancer therapy by potentiating cytotoxic therapies.", + "TAG_DATA": [ + "21, transfer {'perturbing_action': 'B-gene gain-of-function'}", + "22, of {'perturbing_action': 'I-gene gain-of-function'}", + "23, the {'perturbing_action': 'I-gene gain-of-function'}", + "24, gene {'perturbing_action': 'I-gene gain-of-function'}", + "25, encoding {'perturbing_action': 'I-gene gain-of-function'}", + "26, second {'perturbing_action': 'I-gene gain-of-function'}", + "27, mitochondria-derived {'perturbing_action': 'I-gene gain-of-function'}", + "37, tumor {'context': 'B-transformed cells'}", + "38, cells {'context': 'I-transformed cells'}", + "39, in {'context': 'B-in vitro'}", + "40, vitro {'context': 'I-in vitro'}", + "42, malignant {'context': 'B-transformed cells'}", + "43, glioma {'context': 'I-transformed cells'}", + "44, cells {'context': 'I-transformed cells'}", + "45, in {'context': 'B-in vivo'}", + "46, vivo {'context': 'I-in vivo'}", + "48, apoptosis {'phenotype': 'B-apoptosis'}", + "49, induced {'effect': 'B-positive'}", + "56, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "57, of {'perturbing_action': 'I-gene gain-of-function'}", + "58, a {'perturbing_action': 'I-gene gain-of-function'}", + "59, cytosolic {'perturbing_action': 'I-gene gain-of-function'}", + "60, active {'perturbing_action': 'I-gene gain-of-function'}", + "61, form {'perturbing_action': 'I-gene gain-of-function'}", + "62, of {'perturbing_action': 'I-gene gain-of-function'}", + "63, Smac {'perturbing_action': 'I-gene gain-of-function'}", + "83, resistant {'context': 'B-transformed cells'}", + "84, neuroblastoma {'context': 'I-transformed cells'}", + "85, or {'context': 'I-transformed cells'}", + "86, melanoma {'context': 'I-transformed cells'}", + "87, cells {'context': 'I-transformed cells'}", + "89, patient-derived {'context': 'B-transformed cells'}", + "90, primary {'context': 'I-transformed cells'}", + "91, neuroblastoma {'context': 'I-transformed cells'}", + "92, cells {'context': 'I-transformed cells'}", + "113, intracranial {'context': 'B-xenograft'}", + "114, malignant {'context': 'I-xenograft'}", + "115, glioma {'context': 'I-xenograft'}", + "116, xenograft {'context': 'I-xenograft'}", + "117, model {'context': 'I-xenograft'}", + "118, in {'context': 'B-in vivo'}", + "119, vivo. {'context': 'I-in vivo'}", + "124, tumors {'context': 'B-neoplasm'}", + "128, mice {'context': 'B-organism'}", + "145, brain {'context': 'I-tissue/organ'}", + "146, tissue. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "21, transfer ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "22, of ['l0', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "23, the ['l1', 'l23', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "24, gene ['l2', 'l24', 'l45', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "25, encoding ['l3', 'l25', 'l46', 'l66', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "26, second ['l4', 'l26', 'l47', 'l67', 'l86', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "27, mitochondria-derived ['l5', 'l27', 'l48', 'l68', 'l87', 'l105', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "28, activator ['l6', 'l28', 'l49', 'l69', 'l88', 'l106', 'l124', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156']", + "37, tumor ['l7', 'l29', 'l50', 'l70', 'l89', 'l107', 'l125', 'l141', 'l157', 'l158', 'l159']", + "38, cells ['l8', 'l30', 'l51', 'l71', 'l90', 'l108', 'l126', 'l142', 'l157', 'l160', 'l161']", + "39, in ['l9', 'l31', 'l52', 'l72', 'l91', 'l109', 'l127', 'l143', 'l158', 'l160', 'l162', 'l163', 'l164']", + "40, vitro ['l10', 'l32', 'l53', 'l73', 'l92', 'l110', 'l128', 'l144', 'l159', 'l161', 'l162']", + "42, malignant ['l11', 'l33', 'l54', 'l74', 'l93', 'l111', 'l129', 'l145', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "43, glioma ['l12', 'l34', 'l55', 'l75', 'l94', 'l112', 'l130', 'l146', 'l163', 'l165', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "44, cells ['l13', 'l35', 'l56', 'l76', 'l95', 'l113', 'l131', 'l147', 'l164', 'l166', 'l175', 'l183', 'l184', 'l185', 'l186']", + "45, in ['l14', 'l36', 'l57', 'l77', 'l96', 'l114', 'l132', 'l148', 'l167', 'l176', 'l183', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "46, vivo ['l15', 'l37', 'l58', 'l78', 'l97', 'l115', 'l133', 'l149', 'l168', 'l177', 'l184', 'l187', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201']", + "48, apoptosis ['l16', 'l38', 'l59', 'l79', 'l98', 'l116', 'l134', 'l150', 'l169', 'l178', 'l188', 'l195', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207']", + "49, induced ['l17', 'l39', 'l60', 'l80', 'l99', 'l117', 'l135', 'l151', 'l170', 'l179', 'l185', 'l189', 'l196', 'l202', 'l208', 'l209', 'l210', 'l211', 'l212']", + "56, Expression ['l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235']", + "57, of ['l213', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257']", + "58, a ['l214', 'l236', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278']", + "59, cytosolic ['l215', 'l237', 'l258', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298']", + "60, active ['l216', 'l238', 'l259', 'l279', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304', 'l305', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311', 'l312', 'l313', 'l314']", + "61, form ['l217', 'l239', 'l260', 'l280', 'l299', 'l315', 'l316', 'l317', 'l318', 'l319', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327', 'l328', 'l329']", + "62, of ['l218', 'l240', 'l261', 'l281', 'l300', 'l315', 'l330', 'l331', 'l332', 'l333', 'l334', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340', 'l341']", + "63, Smac ['l118', 'l219', 'l241', 'l262', 'l282', 'l301', 'l316', 'l330', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348', 'l349', 'l350']", + "83, resistant ['l18', 'l40', 'l61', 'l81', 'l100', 'l119', 'l136', 'l152', 'l190', 'l197', 'l203', 'l208', 'l220', 'l242', 'l263', 'l283', 'l302', 'l317', 'l331', 'l342', 'l351', 'l352', 'l353', 'l354', 'l355']", + "84, neuroblastoma ['l19', 'l41', 'l62', 'l82', 'l101', 'l120', 'l137', 'l153', 'l171', 'l191', 'l198', 'l204', 'l209', 'l221', 'l243', 'l264', 'l284', 'l303', 'l318', 'l332', 'l343', 'l351', 'l356', 'l357', 'l358', 'l359']", + "85, or ['l20', 'l42', 'l63', 'l83', 'l102', 'l121', 'l138', 'l154', 'l172', 'l180', 'l192', 'l199', 'l205', 'l210', 'l222', 'l244', 'l265', 'l285', 'l304', 'l319', 'l333', 'l344', 'l352', 'l356', 'l360', 'l361']", + "86, melanoma ['l21', 'l43', 'l64', 'l84', 'l103', 'l122', 'l139', 'l155', 'l173', 'l181', 'l193', 'l200', 'l206', 'l211', 'l223', 'l245', 'l266', 'l286', 'l305', 'l320', 'l334', 'l345', 'l353', 'l357', 'l360', 'l362', 'l363']", + "87, cells ['l22', 'l44', 'l65', 'l85', 'l104', 'l123', 'l140', 'l156', 'l174', 'l182', 'l186', 'l194', 'l201', 'l207', 'l212', 'l224', 'l246', 'l267', 'l287', 'l306', 'l321', 'l335', 'l346', 'l354', 'l358', 'l361', 'l362']", + "89, patient-derived ['l225', 'l247', 'l268', 'l288', 'l307', 'l322', 'l336', 'l347', 'l364', 'l365', 'l366', 'l367', 'l368', 'l369', 'l370']", + "90, primary ['l226', 'l248', 'l269', 'l289', 'l308', 'l323', 'l337', 'l348', 'l364', 'l371', 'l372', 'l373', 'l374', 'l375', 'l376']", + "91, neuroblastoma ['l227', 'l249', 'l270', 'l290', 'l309', 'l324', 'l338', 'l349', 'l365', 'l371', 'l377', 'l378', 'l379', 'l380', 'l381']", + "92, cells ['l228', 'l250', 'l271', 'l291', 'l310', 'l325', 'l339', 'l350', 'l355', 'l359', 'l363', 'l366', 'l372', 'l377']", + "113, intracranial ['l229', 'l251', 'l272', 'l292', 'l382', 'l383', 'l384', 'l385', 'l386', 'l387', 'l388']", + "114, malignant ['l230', 'l252', 'l273', 'l293', 'l311', 'l326', 'l367', 'l373', 'l378', 'l382', 'l389', 'l390', 'l391', 'l392', 'l393', 'l394']", + "115, glioma ['l231', 'l253', 'l274', 'l294', 'l312', 'l327', 'l340', 'l368', 'l374', 'l379', 'l383', 'l389', 'l395', 'l396', 'l397', 'l398', 'l399']", + "116, xenograft ['l232', 'l254', 'l275', 'l295', 'l313', 'l328', 'l369', 'l375', 'l380', 'l384', 'l390', 'l395', 'l400', 'l401', 'l402', 'l403']", + "117, model ['l233', 'l255', 'l276', 'l296', 'l314', 'l329', 'l341', 'l370', 'l376', 'l381', 'l385', 'l391', 'l396', 'l400', 'l404', 'l405', 'l406']", + "118, in ['l234', 'l256', 'l277', 'l297', 'l386', 'l392', 'l397', 'l401', 'l404', 'l407', 'l408']", + "119, vivo. ['l235', 'l257', 'l278', 'l298', 'l387', 'l393', 'l398', 'l402', 'l405', 'l407', 'l409']", + "124, tumors ['l388', 'l394', 'l399', 'l403', 'l406', 'l408', 'l409']", + "128, mice ['l410', 'l411', 'l412']", + "144, normal ['l410', 'l413', 'l414']", + "145, brain ['l411', 'l413', 'l415']", + "146, tissue. ['l412', 'l414', 'l415']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfer", + "of", + "the", + "gene", + "encoding", + "second", + "mitochondria-derived", + "Expression", + "a", + "cytosolic", + "active", + "form", + "Smac" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells", + "malignant", + "glioma", + "resistant", + "neuroblastoma", + "or", + "melanoma", + "patient-derived", + "primary" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfer", + "of", + "the", + "gene", + "encoding", + "second", + "mitochondria-derived" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfer", + "of", + "the", + "gene", + "encoding", + "second", + "mitochondria-derived", + "Expression", + "a", + "cytosolic" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfer", + "of", + "the", + "gene", + "encoding", + "second", + "mitochondria-derived" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfer", + "of", + "the", + "gene", + "encoding", + "second", + "mitochondria-derived" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "malignant", + "glioma", + "resistant", + "neuroblastoma", + "or", + "melanoma", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "malignant", + "glioma", + "cells", + "resistant", + "neuroblastoma", + "or", + "melanoma" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "a", + "cytosolic", + "active", + "form" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "intracranial", + "malignant", + "glioma", + "xenograft", + "model" + ] + } + } + ] + }, + { + "PMID": "12101408", + "TEXT": "The Human Combinatorial Antibody Library (HuCAL) was screened for antibodies specific to human leukocyte antigen-DR (HLA-DR) that induce programmed death of lymphoma/leukemia cells expressing the target antigen. The active Fab fragments were affinity-matured, and engineered to IgG(4) antibodies of sub-nanomolar affinity. The antibodies exhibited potent in vitro tumoricidal activity on several lymphoma and leukemia cell lines and on chronic lymphocytic leukemia patient samples. They were also active in vivo in xenograft models of non-Hodgkin lymphoma. Cell death occurred rapidly, without the need for exogenous immunological effector mechanisms, and was selective to activated/tumor-transformed cells. Although the expression of HLA-DR on normal hematopoietic cells is a potential safety concern, the antibodies caused no long-lasting hematological toxicity in primates, in vivo. Such monoclonal antibodies offer the potential for a novel therapeutic approach to lymphoid malignancies.", + "TAG_DATA": [ + "45, in {'context': 'B-in vitro'}", + "46, vitro {'context': 'I-in vitro'}", + "51, lymphoma {'context': 'B-transformed cells'}", + "52, and {'context': 'I-transformed cells'}", + "53, leukemia {'context': 'I-transformed cells'}", + "54, cell {'context': 'I-transformed cells'}", + "55, lines {'context': 'I-transformed cells'}", + "58, chronic {'context': 'B-transformed cells'}", + "59, lymphocytic {'context': 'I-transformed cells'}", + "60, leukemia {'context': 'I-transformed cells'}", + "61, patient {'context': 'I-transformed cells'}", + "62, samples. {'context': 'I-transformed cells'}", + "67, in {'context': 'B-in vivo'}", + "68, vivo {'context': 'I-in vivo'}", + "70, xenograft {'context': 'B-xenograft'}", + "71, models {'context': 'I-neoplasm'}", + "72, of {'context': 'I-neoplasm'}", + "73, non-Hodgkin {'context': 'I-neoplasm'}", + "74, lymphoma. {'context': 'I-neoplasm'}", + "75, Cell {'phenotype': 'B-cell death'}", + "76, death {'phenotype': 'I-cell death'}", + "91, activated/tumor-transformed {'context': 'B-cells'}", + "92, cells. {'context': 'I-cells'}", + "115, primates, {'context': 'B-organism'}", + "116, in {'context': 'B-in vivo'}", + "117, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "45, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "46, vitro ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "51, lymphoma ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "52, and ['l2', 'l11', 'l19', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "53, leukemia ['l3', 'l12', 'l20', 'l28', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "54, cell ['l4', 'l13', 'l21', 'l29', 'l36', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "55, lines ['l5', 'l14', 'l22', 'l30', 'l37', 'l43', 'l49', 'l50', 'l51', 'l52', 'l53']", + "58, chronic ['l23', 'l31', 'l38', 'l44', 'l49', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "59, lymphocytic ['l6', 'l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "60, leukemia ['l7', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l64', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "61, patient ['l8', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l65', 'l73', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "62, samples. ['l9', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l66', 'l74', 'l82', 'l88', 'l89']", + "67, in ['l58', 'l67', 'l75', 'l83', 'l88', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "68, vivo ['l59', 'l68', 'l76', 'l84', 'l89', 'l90', 'l98', 'l99', 'l100', 'l101', 'l102']", + "70, xenograft ['l60', 'l69', 'l77', 'l91', 'l98', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "71, models ['l61', 'l70', 'l78', 'l85', 'l92', 'l99', 'l103', 'l109', 'l110', 'l111', 'l112', 'l113']", + "72, of ['l62', 'l71', 'l79', 'l86', 'l93', 'l100', 'l104', 'l109', 'l114', 'l115', 'l116', 'l117']", + "73, non-Hodgkin ['l80', 'l94', 'l101', 'l105', 'l110', 'l114', 'l118', 'l119', 'l120', 'l121']", + "74, lymphoma. ['l63', 'l72', 'l81', 'l87', 'l95', 'l102', 'l106', 'l111', 'l115', 'l118', 'l122', 'l123', 'l124']", + "75, Cell ['l96', 'l107', 'l112', 'l116', 'l119', 'l122', 'l125', 'l126', 'l127']", + "76, death ['l97', 'l108', 'l113', 'l117', 'l120', 'l123', 'l125', 'l128']", + "91, activated/tumor-transformed ['l126', 'l129']", + "92, cells. ['l121', 'l124', 'l127', 'l128', 'l129']", + "115, primates, ['l130', 'l131']", + "116, in ['l130', 'l132']", + "117, vivo. ['l131', 'l132']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "Cell", + "death" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenograft" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "Cell", + "death" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "models", + "of", + "non-Hodgkin", + "lymphoma." + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "Cell", + "death" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "Cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "activated/tumor-transformed", + "cells." + ] + } + } + ] + }, + { + "PMID": "12091907", + "TEXT": "Systematic efforts are under way to develop novel technologies that would allow molecular sensing in intact organisms in vivo. Using near-infrared fluorescent molecular beacons and inversion techniques that take into account the diffuse nature of photon propagation in tissue, we were able to obtain three-dimensional in vivo images of a protease in orthopic gliomas. We demonstrate that enzyme-activatable fluorochromes can be detected with high positional accuracy in deep tissues, that molecular specificities of different beacons towards enzymes can be resolved and that tomography of beacon activation is linearly related to enzyme concentration. The tomographic imaging method offers a range of new capabilities for studying biological function; for example, identifying molecular-expression patterns by multispectral imaging or continuously monitoring the efficacy of therapeutic drugs.", + "TAG_DATA": [ + "45, in {'context': 'B-in vivo'}", + "46, vivo {'context': 'B-in vivo'}", + "52, orthopic {'context': 'B-neoplasm'}", + "53, gliomas. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "45, in ['l0', 'l1', 'l2']", + "46, vivo ['l0', 'l3', 'l4']", + "52, orthopic ['l1', 'l3', 'l5']", + "53, gliomas. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12091905", + "TEXT": "Staphylococcus aureus is a human pathogen that secretes proteins that contribute to bacterial colonization. Here we describe the extracellular adherence protein (Eap) as a novel anti-inflammatory factor that inhibits host leukocyte recruitment. Due to its direct interactions with the host adhesive proteins intercellular adhesion molecule 1 (ICAM-1), fibrinogen or vitronectin, Eap disrupted beta(2)-integrin and urokinase receptor mediated leukocyte adhesion in vitro. Whereas Eap-expressing S. aureus induced a 2 3-fold lower neutrophil recruitment in bacterial peritonitis in mice as compared with an Eap-negative strain, isolated Eap prevented beta(2)-integrin-dependent neutrophil recruitment in a mouse model of acute thioglycollate-induced peritonitis. Thus, the specific interactions with ICAM-1 and extracellular matrix proteins render Eap a potent anti-inflammatory factor, which may serve as a new therapeutic substance to block leukocyte extravasation in patients with hyperinflammatory pathologies.", + "TAG_DATA": [ + "57, leukocyte {'context': 'B-cells'}", + "59, in {'context': 'B-in vitro'}", + "60, vitro. {'context': 'I-in vitro'}", + "76, mice {'context': 'B-organism'}", + "91, mouse {'context': 'B-organism'}", + "92, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "57, leukocyte ['l0', 'l1', 'l2']", + "59, in ['l0', 'l3']", + "60, vitro. ['l1', 'l3']", + "76, mice ['l2']", + "91, mouse ['l4']", + "92, model ['l4']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12068289", + "TEXT": "Here we investigated the biological functions of adiponectin/ACRP30, a fat-derived hormone, by disrupting the gene that encodes it in mice. Adiponectin/ACRP30-knockout (KO) mice showed delayed clearance of free fatty acid in plasma, low levels of fatty-acid transport protein 1 (FATP-1) mRNA in muscle, high levels of tumor necrosis factor-alpha (TNF-alpha) mRNA in adipose tissue and high plasma TNF-alpha concentrations. The KO mice exhibited severe diet-induced insulin resistance with reduced insulin-receptor substrate 1 (IRS-1)-associated phosphatidylinositol 3 kinase (PI3-kinase) activity in muscle. Viral mediated adiponectin/ACRP30 expression in KO mice reversed the reduction of FATP-1 mRNA, the increase of adipose TNF-alpha mRNA and the diet-induced insulin resistance. In cultured myocytes, TNF-alpha decreased FATP-1 mRNA, IRS-1-associated PI3-kinase activity and glucose uptake, whereas adiponectin increased these parameters. Our results indicate that adiponectin/ACRP30 deficiency and high TNF-alpha levels in KO mice reduced muscle FATP-1 mRNA and IRS-1-mediated insulin signaling, resulting in severe diet-induced insulin resistance.", + "TAG_DATA": [ + "20, Adiponectin/ACRP30-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "21, (KO) {'perturbing_action': 'I-gene loss-of-function'}", + "22, mice {'context': 'B-organism'}", + "61, mice {'context': 'B-organism'}", + "80, Viral {'perturbing_action': 'B-gene gain-of-function'}", + "81, mediated {'perturbing_action': 'I-gene gain-of-function'}", + "82, adiponectin/ACRP30 {'perturbing_action': 'I-gene gain-of-function'}", + "83, expression {'perturbing_action': 'I-gene gain-of-function'}", + "85, KO {'perturbing_action': 'B-gene loss-of-function'}", + "86, mice {'context': 'B-organism'}", + "105, cultured {'context': 'B-cells'}", + "106, myocytes, {'context': 'I-cells'}", + "126, adiponectin/ACRP30 {'perturbing_action': 'B-gene loss-of-function'}", + "127, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "134, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "20, Adiponectin/ACRP30-knockout ['l0', 'l1', 'l2', 'l3']", + "21, (KO) ['l0', 'l4', 'l5']", + "22, mice ['l1', 'l4']", + "61, mice ['l2', 'l6']", + "79, muscle. ['l3', 'l5', 'l6']", + "80, Viral ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "81, mediated ['l7', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "82, adiponectin/ACRP30 ['l8', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "83, expression ['l9', 'l15', 'l20', 'l25', 'l26', 'l27', 'l28']", + "85, KO ['l10', 'l16', 'l21', 'l25', 'l29', 'l30', 'l31']", + "86, mice ['l11', 'l17', 'l22', 'l26', 'l29']", + "105, cultured ['l12', 'l18', 'l23', 'l27', 'l30', 'l32']", + "106, myocytes, ['l13', 'l19', 'l24', 'l28', 'l31', 'l32']", + "126, adiponectin/ACRP30 ['l33', 'l34']", + "127, deficiency ['l33', 'l35']", + "134, mice ['l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Adiponectin/ACRP30-knockout", + "(KO)", + "KO", + "adiponectin/ACRP30", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Viral", + "mediated", + "adiponectin/ACRP30", + "expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Viral", + "mediated", + "adiponectin/ACRP30", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "myocytes," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "KO" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "myocytes," + ] + } + } + ] + }, + { + "PMID": "12068288", + "TEXT": "Erythropoietin (Epo) is upregulated by hypoxia and provides protection against apoptosis of erythroid progenitors in bone marrow and brain neurons. Here we show in the adult mouse retina that acute hypoxia dose-dependently stimulates expression of Epo, fibroblast growth factor 2 and vascular endothelial growth factor via hypoxia-inducible factor-1alpha (HIF-1alpha) stabilization. Hypoxic preconditioning protects retinal morphology and function against light-induced apoptosis by interfering with caspase-1 activation, a downstream event in the intracellular death cascade. In contrast, induction of activator protein-1, an early event in the light-stressed retina, is not affected by hypoxia. The Epo receptor required for Epo signaling localizes to photoreceptor cells. The protective effect of hypoxic preconditioning is mimicked by systemically applied Epo that crosses the blood retina barrier and prevents apoptosis even when given therapeutically after light insult. Application of Epo may, through the inhibition of apoptosis, be beneficial for the treatment of different forms of retinal disease.", + "TAG_DATA": [ + "25, adult {'context': 'B-tissue/organ'}", + "26, mouse {'context': 'I-tissue/organ'}", + "27, retina {'context': 'I-tissue/organ'}", + "58, light-induced {'effect': 'B-positive'}", + "59, apoptosis {'phenotype': 'B-apoptosis'}", + "121, prevents {'effect': 'B-negative'}", + "122, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "25, adult ['l0', 'l1', 'l2', 'l3']", + "26, mouse ['l0', 'l4', 'l5', 'l6']", + "27, retina ['l1', 'l4', 'l7', 'l8']", + "58, light-induced ['l2', 'l5', 'l7', 'l9']", + "59, apoptosis ['l3', 'l6', 'l8', 'l9']", + "121, prevents ['l10']", + "122, apoptosis ['l10']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "adult", + "mouse", + "retina" + ] + }, + "effect": { + "val": "positive", + "words": [ + "light-induced" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "adult", + "mouse", + "retina" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "light-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "12042812", + "TEXT": "Adults maintain a reservoir of hematopoietic stem cells that can enter the circulation to reach organs in need of regeneration. We developed a novel model of retinal neovascularization in adult mice to examine the role of hematopoietic stem cells in revascularizing ischemic retinas. Adult mice were durably engrafted with hematopoietic stem cells isolated from transgenic mice expressing green fluorescent protein. We performed serial long-term transplants, to ensure activity arose from self-renewing stem cells, and single hematopoietic stem-cell transplants to show clonality. After durable hematopoietic engraftment was established, retinal ischemia was induced to promote neovascularization. Our results indicate that self-renewing adult hematopoietic stem cells have functional hemangioblast activity, that is, they can clonally differentiate into all hematopoietic cell lineages as well as endothelial cells that revascularize adult retina. We also show that recruitment of endothelial precursors to sites of ischemic injury has a significant role in neovascularization.", + "TAG_DATA": [ + "43, Adult {'context': 'B-organism'}", + "44, mice {'context': 'I-organism'}", + "49, hematopoietic {'context': 'B-cells'}", + "50, stem {'context': 'I-cells'}", + "51, cells {'context': 'I-cells'}", + "52, isolated {'context': 'I-cells'}", + "54, transgenic {'context': 'B-organism'}", + "55, mice {'context': 'I-organism'}", + "76, stem-cell {'context': 'I-cells'}", + "121, endothelial {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "43, Adult ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "44, mice ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "49, hematopoietic ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "50, stem ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "51, cells ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "52, isolated ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "54, transgenic ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "55, mice ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "75, hematopoietic ['l28']", + "76, stem-cell ['l28']", + "100, hematopoietic ['l29', 'l30']", + "101, stem ['l29', 'l31']", + "121, endothelial ['l30', 'l31']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12042807", + "TEXT": "Alloantigen expression on host antigen-presenting cells (APCs) is essential to initiate graft-versus-host disease (GvHD); therefore, alloantigen expression on host target epithelium is also thought to be essential for tissue damage. We tested this hypothesis in mouse models of GvHD using bone-marrow chimeras in which either major histocompatibility complex class I or class II alloantigen was expressed only on APCs. We found that acute GvHD does not require alloantigen expression on host target epithelium and that neutralization of tumor necrosis factor-alpha and interleukin-1 prevents acute GvHD. These results pertain particularly to CD4-mediated GvHD but also apply, at least in part, to CD8-mediated GvHD. These results challenge current paradigms about the antigen specificity of GvHD effector mechanisms and confirm the central roles of both host APCs and inflammatory cytokines in acute GvHD.", + "TAG_DATA": [ + "35, mouse {'context': 'B-organism'}", + "36, models {'context': 'I-organism'}", + "82, prevents {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "35, mouse ['l0', 'l1', 'l2']", + "36, models ['l0', 'l3', 'l4']", + "40, bone-marrow ['l1', 'l3', 'l5']", + "41, chimeras ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11927945", + "TEXT": "Herpes simplex virus infections are the cause of significant morbidity, and currently used therapeutics are largely based on modified nucleoside analogs that inhibit viral DNA polymerase function. To target this disease in a new way, we have identified and optimized selective thiazolylphenyl-containing inhibitors of the herpes simplex virus (HSV) helicase-primase enzyme. The most potent compounds inhibited the helicase, the primase and the DNA-dependent ATPase activities of the enzyme with IC50 (50% inhibitory concentration) values less than 100 nM. Inhibition of the enzymatic activities was through stabilization of the interaction between the helicase-primase and DNA substrates, preventing the progression through helicase or primase catalytic cycles. Helicase-primase inhibitors also prevented viral replication as demonstrated in viral growth assays. One compound, BILS 179 BS, displayed an EC50 (effective concentration inhibiting viral growth by 50%) of 27 nM against viral growth with a selectivity index greater than 2,000. Antiviral activity was also demonstrated for multiple strains of HSV, including strains resistant to nucleoside-based therapies. Most importantly, BILS 179 BS was orally active against HSV infections in murine models of HSV-1 and HSV-2 disease and more effective than acyclovir when the treatment frequency per day was reduced or when initiation of treatment was delayed up to 65 hours after infection. These studies validate the use of helicase-primase inhibitors for the treatment of acute herpesvirus infections and provide new lead compounds for optimization and design of superior anti-HSV agents.", + "TAG_DATA": [ + "107, prevented {'effect': 'B-negative'}", + "109, replication {'phenotype': 'I-colony formation'}", + "172, murine {'context': 'B-organism'}", + "173, models {'context': 'I-organism'}", + "174, of {'context': 'I-organism'}", + "175, HSV-1 {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "107, prevented ['l0']", + "109, replication ['l0']", + "172, murine ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "173, models ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "174, of ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "175, HSV-1 ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "176, and ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "177, HSV-2 ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "178, disease ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "replication" + ] + } + } + ] + }, + { + "PMID": "11875495", + "TEXT": "CD40L, a member of the tumor necrosis factor family of ligands, plays a major role in immune responses via its receptor, CD40. Recently, CD40L has been detected on the surfaces of activated platelets and shown to activate endothelium. Here we further addressed the function of platelet CD40L. We show that absence of CD40L affects the stability of arterial thrombi and delays arterial occlusion in vivo. Infusion of recombinant soluble (rs)CD40L restored normal thrombosis, whereas rsCD40L lacking the KGD integrin-recognition sequence did not. CD40-deficient mice exhibited normal thrombogenesis. rsCD40L specifically bound to purified integrin alphaIIbbeta3 and to activated platelets in a beta3-dependent manner and induced platelet spreading. In addition, rsCD40L promoted the aggregation of either human or mouse platelets under high shear rates. Thus, CD40L appears to be an alphaIIbbeta3 ligand, a platelet agonist, and necessary for stability of arterial thrombi.", + "TAG_DATA": [ + "50, absence {'perturbing_action': 'B-gene loss-of-function'}", + "51, of {'perturbing_action': 'I-gene loss-of-function'}", + "52, CD40L {'perturbing_action': 'I-gene loss-of-function'}", + "63, in {'context': 'B-in vivo'}", + "64, vivo. {'context': 'I-in vivo'}", + "75, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "76, the {'perturbing_action': 'I-gene loss-of-function'}", + "77, KGD {'perturbing_action': 'I-gene loss-of-function'}", + "78, integrin-recognition {'perturbing_action': 'I-gene loss-of-function'}", + "79, sequence {'perturbing_action': 'I-gene loss-of-function'}", + "82, CD40-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "83, mice {'context': 'B-organism'}", + "97, platelets {'context': 'B-cells'}", + "104, platelet {'context': 'B-cells'}", + "109, promoted {'effect': 'B-positive'}", + "111, aggregation {'phenotype': 'B-autophagy'}", + "114, human {'context': 'B-cells'}", + "115, or {'context': 'I-cells'}", + "116, mouse {'context': 'I-cells'}", + "117, platelets {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "50, absence ['l0', 'l1', 'l2', 'l3']", + "51, of ['l0', 'l4', 'l5', 'l6']", + "52, CD40L ['l1', 'l4', 'l7', 'l8']", + "63, in ['l2', 'l5', 'l7', 'l9']", + "64, vivo. ['l3', 'l6', 'l8', 'l9']", + "75, lacking ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "76, the ['l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "77, KGD ['l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "78, integrin-recognition ['l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "79, sequence ['l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "82, CD40-deficient ['l14', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "83, mice ['l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "97, platelets ['l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "104, platelet ['l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']", + "109, promoted ['l46', 'l47', 'l48', 'l49', 'l50']", + "111, aggregation ['l46', 'l51', 'l52', 'l53', 'l54']", + "114, human ['l47', 'l51', 'l55', 'l56', 'l57']", + "115, or ['l48', 'l52', 'l55', 'l58', 'l59']", + "116, mouse ['l49', 'l53', 'l56', 'l58', 'l60']", + "117, platelets ['l50', 'l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "CD40L" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "KGD", + "integrin-recognition", + "sequence", + "CD40-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "KGD", + "integrin-recognition", + "sequence", + "CD40-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelets", + "platelet" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "aggregation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "or", + "mouse", + "platelets" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "aggregation" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "or", + "mouse", + "platelets" + ] + } + } + ] + }, + { + "PMID": "11821903", + "TEXT": "Obesity and insulin resistance are major risk factors for a number of metabolic disorders, such as type 2 diabetes mellitus. Insulin has been suggested to function as one of the adiposity signals to the brain for modulation of energy balance. Administration of insulin into the brain reduces food intake and body weight, and mice with a genetic deletion of neuronal insulin receptors are hyperphagic and obese. However, insulin is also an anabolic factor; when administered systemically, pharmacological levels of insulin are associated with body weight gain in patients. In this study, we investigated the efficacy and feasibility of small molecule insulin mimetic compounds to regulate key parameters of energy homeostasis. Central intracerebroventricular (i.c.v.) administration of an insulin mimetic resulted in a dose-dependent reduction of food intake and body weight in rats, and altered the expression of hypothalamic genes known to regulate food intake and body weight. Oral administration of a mimetic in a mouse model of high-fat diet-induced obesity reduced body weight gain, adiposity and insulin resistance. Thus, insulin mimetics have a unique advantage over insulin in the control of body weight and hold potential as a novel anti-obesity treatment.", + "TAG_DATA": [ + "56, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "57, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "58, of {'perturbing_action': 'I-gene loss-of-function'}", + "59, neuronal {'perturbing_action': 'I-gene loss-of-function'}", + "60, insulin {'perturbing_action': 'I-gene loss-of-function'}", + "61, receptors {'perturbing_action': 'I-gene loss-of-function'}", + "130, rats, {'context': 'B-organism'}", + "153, mouse {'context': 'B-organism'}", + "154, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "56, genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "57, deletion ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "58, of ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "59, neuronal ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "60, insulin ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "61, receptors ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "130, rats, ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "153, mouse ['l21']", + "154, model ['l21']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "neuronal", + "insulin", + "receptors" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats," + ] + } + } + ] + }, + { + "PMID": "11821896", + "TEXT": "Conventional immunosuppressive drugs have been used effectively to prevent immunologic rejection in organ transplantation. Individuals taking these drugs are at risk, however, for the development and recurrence of cancer. In the present study we show that the new immunosuppressive drug rapamycin (RAPA) may reduce the risk of cancer development while simultaneously providing effective immunosuppression. Experimentally, RAPA inhibited metastatic tumor growth and angiogenesis in in vivo mouse models. In addition, normal immunosuppressive doses of RAPA effectively controlled the growth of established tumors. In contrast, the most widely recognized immunosuppressive drug, cyclosporine, promoted tumor growth. From a mechanistic perspective, RAPA showed antiangiogenic activities linked to a decrease in production of vascular endothelial growth factor (VEGF) and to a markedly inhibited response of vascular endothelial cells to stimulation by VEGF. Thus, the use of RAPA, instead of cyclosporine, may reduce the chance of recurrent or de novo cancer in high-risk transplant patients.", + "TAG_DATA": [ + "56, inhibited {'effect': 'B-negative'}", + "57, metastatic {'phenotype': 'B-tumour growth'}", + "58, tumor {'phenotype': 'B-tumour growth'}", + "59, growth {'phenotype': 'I-tumour growth'}", + "63, in {'context': 'B-in vivo'}", + "64, vivo {'context': 'I-in vivo'}", + "65, mouse {'context': 'I-in vivo'}", + "66, models. {'context': 'I-organism'}", + "80, tumors. {'context': 'B-neoplasm'}", + "90, promoted {'effect': 'B-positive'}", + "91, tumor {'phenotype': 'B-tumour growth'}", + "92, growth. {'phenotype': 'I-tumour growth'}", + "120, vascular {'context': 'B-cells'}", + "121, endothelial {'context': 'I-cells'}", + "122, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "56, inhibited ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "57, metastatic ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "58, tumor ['l1', 'l7', 'l13', 'l14', 'l15', 'l16']", + "59, growth ['l2', 'l8', 'l13', 'l17', 'l18', 'l19']", + "63, in ['l3', 'l9', 'l20', 'l21', 'l22']", + "64, vivo ['l4', 'l10', 'l14', 'l17', 'l20', 'l23', 'l24']", + "65, mouse ['l5', 'l11', 'l15', 'l18', 'l21', 'l23', 'l25']", + "66, models. ['l6', 'l12', 'l16', 'l19', 'l22', 'l24', 'l25']", + "90, promoted ['l26', 'l27']", + "91, tumor ['l26', 'l28']", + "92, growth. ['l27', 'l28']", + "120, vascular ['l29', 'l30']", + "121, endothelial ['l29', 'l31']", + "122, cells ['l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "metastatic", + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "mouse" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "organism", + "words": [ + "models." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "metastatic", + "tumor", + "growth" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "mouse" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "metastatic", + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "models." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + } + ] + }, + { + "PMID": "11786910", + "TEXT": "The immune-modulating cytokine interleukin-6 (IL-6) is expressed both in adipose tissue and centrally in hypothalamic nuclei that regulate body composition. We investigated the impact of loss of IL-6 on body composition in mice lacking the gene encoding IL-6 (Il6-/- mice) and found that they developed mature-onset obesity that was partly reversed by IL-6 replacement. The obese Il6-/- mice had disturbed carbohydrate and lipid metabolism, increased leptin levels and decreased responsiveness to leptin treatment. To investigate the possible mechanism and site of action of the anti-obesity effect of IL-6, we injected rats centrally and peripherally with IL-6 at low doses. Intracerebroventricular, but not intraperitoneal IL-6 treatment increased energy expenditure. In conclusion, centrally acting IL-6 exerts anti-obesity effects in rodents.", + "TAG_DATA": [ + "32, mice {'context': 'B-organism'}", + "33, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "34, the {'perturbing_action': 'I-gene loss-of-function'}", + "35, gene {'perturbing_action': 'I-gene loss-of-function'}", + "36, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "37, IL-6 {'perturbing_action': 'I-gene loss-of-function'}", + "38, (Il6-/- {'perturbing_action': 'I-gene loss-of-function'}", + "39, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "56, Il6-/- {'perturbing_action': 'B-gene loss-of-function'}", + "57, mice {'context': 'B-organism'}", + "90, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "32, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "33, lacking ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "34, the ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "35, gene ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "36, encoding ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "37, IL-6 ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "38, (Il6-/- ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "39, mice) ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "56, Il6-/- ['l28']", + "57, mice ['l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "gene", + "encoding", + "IL-6", + "(Il6-/-", + "mice)", + "Il6-/-" + ] + } + } + ] + }, + { + "PMID": "11786907", + "TEXT": "Respiratory syncytial virus (RSV) is a major cause of morbidity from respiratory infection in infants, young children and the elderly. No effective vaccine against RSV is currently available and studies of the natural history of RSV infection suggest repeated infections with antigenically related virus strains are common throughout an individual's lifetime. We have studied the CD8+ T-cell response during experimental murine RSV infection and found that RSV inhibits the expression of effector activity by activated RSV-specific CD8+ T cells infiltrating the lung parenchyma and the development of pulmonary CD8+ T-cell memory by interfering with TCR-mediated signaling. These data suggest a possible mechanism to explain the limited duration of protective immunity in RSV infection.", + "TAG_DATA": [ + "75, RSV-specific {'context': 'B-cells'}", + "76, CD8+ {'context': 'I-cells'}", + "77, T {'context': 'I-cells'}", + "78, cells {'context': 'I-cells'}", + "81, lung {'context': 'B-tissue/organ'}", + "82, parenchyma {'context': 'I-tissue/organ'}", + "89, T-cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "75, RSV-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "76, CD8+ ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "77, T ['l1', 'l6', 'l11', 'l12', 'l13']", + "78, cells ['l2', 'l7', 'l11', 'l14', 'l15']", + "81, lung ['l3', 'l8', 'l12', 'l14', 'l16']", + "82, parenchyma ['l4', 'l9', 'l13', 'l15', 'l16']", + "89, T-cell ['l5', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11726978", + "TEXT": "Gene therapy in the central nervous system (CNS) is hindered by the presence of the blood-brain barrier, which restricts access of serum constituents and peripheral cells to the brain parenchyma. Expression of exogenously administered genes in the CNS has been achieved in vivo using highly invasive routes, or ex vivo relying on the direct implantation of genetically modified cells into the brain. Here we provide evidence for a novel, noninvasive approach for targeting potential therapeutic factors to the CNS. Genetically-modified hematopoietic cells enter the CNS and differentiate into microglia after bone-marrow transplantation. Up to a quarter of the regional microglial population is donor-derived by four months after transplantation. Microglial engraftment is enhanced by neuropathology, and gene-modified myeloid cells are specifically attracted to the sites of neuronal damage. Thus, microglia may serve as vehicles for gene delivery to the nervous system.", + "TAG_DATA": [ + "80, hematopoietic {'context': 'B-cells'}", + "81, cells {'context': 'I-cells'}", + "86, differentiate {'phenotype': 'B-differentiation'}", + "116, myeloid {'context': 'B-cells'}", + "117, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "80, hematopoietic ['l0', 'l1']", + "81, cells ['l0', 'l2']", + "86, differentiate ['l1', 'l2']", + "116, myeloid ['l3']", + "117, cells ['l3']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate" + ] + } + } + ] + }, + { + "PMID": "11726976", + "TEXT": "Heart transplant rejection is characterized pathologically by myocyte necrosis and apoptosis associated with interstitial mononuclear cell infiltration. Any one of these components can be targeted for noninvasive detection of transplant rejection. During apoptotic cell death, phosphatidylserine, a phospholipid that is normally confined to the inner leaflet of cell membrane bilayer, gets exteriorized. Technetium-99m-labeled annexin-V, an endogenous protein that has high affinity for binding to phosphatidylserine, has been administered intravenously for noninvasive identification of apoptotic cell death. In the present study of 18 cardiac allograft recipients, 13 patients had negative and five had positive myocardial uptake of annexin. These latter five demonstrated at least moderate transplant rejection and caspase-3 staining, suggesting apoptosis in their biopsy specimens. This study reveals the clinical feasibility and safety of annexin-V imaging for noninvasive detection of transplant rejection by targeting cell membrane phospholipid alterations that are commonly associated with the process of apoptosis.", + "TAG_DATA": [ + "82, cardiac {'context': 'B-xenograft'}", + "83, allograft {'context': 'I-xenograft'}", + "84, recipients, {'context': 'I-xenograft'}", + "110, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "82, cardiac ['l0', 'l1']", + "83, allograft ['l0', 'l2']", + "84, recipients, ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11726974", + "TEXT": "Upregulation of low-density lipoprotein receptor (LDLr) is a key mechanism to control elevated plasma LDL-cholesterol levels. Here we identify a new class of compounds that directly binds to the sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP). We show that a 14C-labeled, photo-activatable analog specifically labeled both SCAP and a truncated form of SCAP containing the sterol-sensing domain. When administered to hyperlipidemic hamsters, SCAP ligands reduced both LDL cholesterol and triglycerides levels by up to 80% with a three-fold increase in LDLr mRNA in the livers. Using human hepatoma cells, we show that these compounds act through the sterol-responsive element of the LDLr promoter and activate the SCAP/SREBP pathway, leading to increased LDLr expression and activity, even in presence of excess of sterols. These findings have led to the identification of a class of compounds that represent a promising new class of hypolipidemic drugs.", + "TAG_DATA": [ + "62, hamsters, {'context': 'B-organism'}", + "85, livers. {'context': 'B-tissue/organ'}", + "87, human {'context': 'B-transformed cells'}", + "88, hepatoma {'context': 'I-transformed cells'}", + "89, cells, {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "62, hamsters, ['l0']", + "85, livers. ['l0']", + "87, human ['l1', 'l2']", + "88, hepatoma ['l1', 'l3']", + "89, cells, ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11726972", + "TEXT": "Given the mucosal transmission of HIV-1, we compared whether a mucosal vaccine could induce mucosal cytotoxic T lymphocytes (CTLs) and protect rhesus macaques against mucosal infection with simian/human immunodeficiency virus (SHIV) more effectively than the same vaccine given subcutaneously. Here we show that mucosal CTLs specific for simian immunodeficiency virus can be induced by intrarectal immunization of macaques with a synthetic-peptide vaccine incorporating the LT(R192G) adjuvant. This response correlated with the level of T-helper response. After intrarectal challenge with pathogenic SHIV-Ku2, viral titers were eliminated more completely (to undetectable levels) both in blood and intestine, a major reservoir for virus replication, in intrarectally immunized animals than in subcutaneously immunized or control macaques. Moreover, CD4+ T cells were better preserved. Thus, induction of CTLs in the intestinal mucosa, a key site of virus replication, with a mucosal AIDS vaccine ameliorates infection by SHIV in non-human primates.", + "TAG_DATA": [ + "57, macaques {'context': 'B-organism'}", + "92, blood {'context': 'B-tissue/organ'}", + "94, intestine, {'context': 'B-tissue/organ'}", + "104, animals {'context': 'B-organism'}", + "111, macaques. {'context': 'B-organism'}", + "113, CD4+ {'context': 'B-cells'}", + "114, T {'context': 'I-cells'}", + "115, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "92, blood ['l0', 'l1']", + "94, intestine, ['l0', 'l2']", + "104, animals ['l1', 'l2']", + "111, macaques. ['l3', 'l4']", + "113, CD4+ ['l5', 'l6']", + "114, T ['l3', 'l5', 'l7']", + "115, cells ['l4', 'l6', 'l7']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11689891", + "TEXT": "Biomedical imaging with light-scattering spectroscopy (LSS) is a novel optical technology developed to probe the structure of living epithelial cells in situ without need for tissue removal. LSS makes it possible to distinguish between single backscattering from epithelial-cell nuclei and multiply scattered light. The spectrum of the single backscattering component is further analyzed to provide quantitative information about the epithelial-cell nuclei such as nuclear size, degree of pleomorphism, degree of hyperchromasia and amount of chromatin. LSS imaging allows mapping these histological properties over wide areas of epithelial lining. Because nuclear enlargement, pleomorphism and hyperchromasia are principal features of nuclear atypia associated with precancerous and cancerous changes in virtually all epithelia, LSS imaging can be used to detect precancerous lesions in optically accessible organs.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11689888", + "TEXT": "HIV-1 infects target cells via a receptor complex formed by CD4 and a chemokine receptor, primarily CCR5 or CXCR4 (ref. 1). Commonly, HIV-1 transmission is mediated by CCR5-tropic variants, also designated slow/low, non-syncytia-inducer or macrophage-tropic, which dominate the early stages of HIV-1 infection and frequently persist during the entire course of the disease. In contrast, HIV-1 variants that use CXCR4 are typically detected at the later stages, and are associated with a rapid decline in CD4+ T cells and progression to AIDS (refs. 2,7-11). Disease progression is also associated with the emergence of concurrent infections that may affect the course of HIV disease by unknown mechanisms. A lymphotropic agent frequently reactivated in HIV-infected patients is human herpesvirus 6 (HHV-6), which has been proposed as a cofactor in AIDS progression. Here we show that in human lymphoid tissue ex vivo, HHV-6 affects HIV-1 infection in a coreceptor-dependent manner, suppressing CCR5-tropic but not CXCR4-tropic HIV-1 replication, as shown with both uncloned viral isolates and isogenic molecular chimeras. Furthermore, we demonstrate that HHV-6 increases the production of the CCR5 ligand RANTES ('regulated upon activation, normal T-cell expressed and secreted'), the most potent HIV-inhibitory CC chemokine, and that exogenous RANTES mimics the effects of HHV-6 on HIV-1, providing a mechanism for the selective blockade of CCR5-tropic HIV-1. Our data suggest that HHV-6 may profoundly influence the course of HIV-1 infection.", + "TAG_DATA": [ + "134, human {'context': 'B-tissue/organ'}", + "135, lymphoid {'context': 'I-tissue/organ'}", + "136, tissue {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "134, human ['l0', 'l1']", + "135, lymphoid ['l0', 'l2']", + "136, tissue ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11689884", + "TEXT": "Acute and fulminant liver failure induced by viral hepatitis, alcohol or other hepatotoxic drugs, are associated with tumor necrosis factor (TNF) production. In a mouse model of lethal hepatitis induced by TNF, apoptosis and necrosis of hepatocytes, but also lethality, hypothermia and influx of leukocytes into the liver, are prevented by a broad-spectrum matrix metalloproteinase (MMP) inhibitor, BB-94. Mice deficient in MMP-2, MMP-3 or MMP-9 had lower levels of apoptosis and necrosis of hepatocytes, and better survival. We found induction of MMP-9 activity and fibronectin degradation. Our findings suggest that several MMPs play a critical role in acute, fulminant hepatitis by degrading the extracellular matrix and allowing massive leukocyte influx in the liver. BB-94 also prevented lethality in TNF/interferon-gamma therapy in tumor-bearing mice. A broad-spectrum MMP inhibitor may be potentially useful for the treatment of patients with acute and perhaps chronic liver failure, and in cancer therapies using inflammatory cytokines.", + "TAG_DATA": [ + "32, apoptosis {'phenotype': 'B-apoptosis'}", + "34, necrosis {'phenotype': 'B-necrosis'}", + "36, hepatocytes, {'context': 'B-cells'}", + "52, broad-spectrum {'perturbing_action': 'B-pharmacological inhibition'}", + "53, matrix {'perturbing_action': 'I-pharmacological inhibition'}", + "54, metalloproteinase {'perturbing_action': 'I-pharmacological inhibition'}", + "55, (MMP) {'perturbing_action': 'I-pharmacological inhibition'}", + "56, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "57, BB-94. {'perturbing_action': 'I-pharmacological inhibition'}", + "58, Mice {'context': 'B-organism'}", + "59, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "60, in {'perturbing_action': 'I-gene loss-of-function'}", + "61, MMP-2, {'perturbing_action': 'I-gene loss-of-function'}", + "62, MMP-3 {'perturbing_action': 'I-gene loss-of-function'}", + "63, or {'perturbing_action': 'I-gene loss-of-function'}", + "64, MMP-9 {'perturbing_action': 'I-gene loss-of-function'}", + "66, lower {'effect': 'B-negative'}", + "67, levels {'effect': 'I-positive'}", + "69, apoptosis {'phenotype': 'B-apoptosis'}", + "71, necrosis {'phenotype': 'B-necrosis'}", + "73, hepatocytes, {'context': 'B-cells'}", + "121, tumor-bearing {'context': 'B-organism'}", + "122, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "32, apoptosis ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "34, necrosis ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "36, hepatocytes, ['l1', 'l8']", + "52, broad-spectrum ['l2', 'l9', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "53, matrix ['l3', 'l10', 'l15', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "54, metalloproteinase ['l16', 'l32', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "55, (MMP) ['l4', 'l11', 'l17', 'l33', 'l48', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "56, inhibitor, ['l18', 'l34', 'l49', 'l63', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "57, BB-94. ['l5', 'l12', 'l19', 'l35', 'l50', 'l64', 'l77', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "58, Mice ['l20', 'l36', 'l51', 'l65', 'l78', 'l90', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "59, deficient ['l21', 'l37', 'l52', 'l66', 'l79', 'l100', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "60, in ['l22', 'l38', 'l53', 'l67', 'l80', 'l101', 'l111', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "61, MMP-2, ['l23', 'l39', 'l54', 'l68', 'l81', 'l91', 'l102', 'l112', 'l121', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "62, MMP-3 ['l24', 'l40', 'l55', 'l69', 'l82', 'l92', 'l103', 'l113', 'l122', 'l130', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "63, or ['l25', 'l41', 'l56', 'l70', 'l83', 'l93', 'l104', 'l114', 'l123', 'l131', 'l138', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150']", + "64, MMP-9 ['l26', 'l42', 'l57', 'l71', 'l84', 'l94', 'l105', 'l115', 'l124', 'l132', 'l139', 'l145', 'l151', 'l152', 'l153', 'l154', 'l155']", + "66, lower ['l6', 'l13', 'l27', 'l43', 'l58', 'l72', 'l85', 'l95', 'l106', 'l116', 'l125', 'l133', 'l140', 'l146', 'l151', 'l156', 'l157', 'l158', 'l159']", + "67, levels ['l7', 'l14', 'l28', 'l44', 'l59', 'l73', 'l86', 'l96', 'l107', 'l117', 'l126', 'l134', 'l141', 'l147', 'l152', 'l156', 'l160', 'l161', 'l162']", + "69, apoptosis ['l29', 'l45', 'l60', 'l74', 'l87', 'l97', 'l108', 'l118', 'l127', 'l135', 'l142', 'l148', 'l153', 'l157', 'l160', 'l163', 'l164']", + "71, necrosis ['l30', 'l46', 'l61', 'l75', 'l88', 'l98', 'l109', 'l119', 'l128', 'l136', 'l143', 'l149', 'l154', 'l158', 'l161', 'l163', 'l165']", + "73, hepatocytes, ['l31', 'l47', 'l62', 'l76', 'l89', 'l99', 'l110', 'l120', 'l129', 'l137', 'l144', 'l150', 'l155', 'l159', 'l162', 'l164', 'l165']", + "121, tumor-bearing ['l166']", + "122, mice. ['l166']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "broad-spectrum", + "matrix", + "(MMP)", + "BB-94.", + "metalloproteinase", + "inhibitor," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "levels" + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes," + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "broad-spectrum", + "matrix", + "(MMP)", + "BB-94.", + "metalloproteinase", + "inhibitor," + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "levels" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "broad-spectrum", + "matrix", + "metalloproteinase", + "(MMP)", + "inhibitor,", + "BB-94." + ] + }, + "context": { + "val": "organism", + "words": [ + "Mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "broad-spectrum", + "matrix", + "metalloproteinase", + "(MMP)", + "inhibitor,", + "BB-94." + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "broad-spectrum", + "matrix", + "metalloproteinase", + "(MMP)", + "inhibitor,", + "BB-94." + ] + }, + "effect": { + "val": "positive", + "words": [ + "levels" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "broad-spectrum", + "matrix", + "metalloproteinase", + "(MMP)", + "inhibitor,", + "BB-94." + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "MMP-2,", + "MMP-3", + "or", + "MMP-9" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "levels" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "MMP-2,", + "MMP-3", + "or", + "MMP-9" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "MMP-2,", + "MMP-3", + "or", + "MMP-9" + ] + }, + "effect": { + "val": "positive", + "words": [ + "levels" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "MMP-2,", + "MMP-3", + "or", + "MMP-9" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "MMP-2,", + "MMP-3", + "or", + "MMP-9" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "MMP-2,", + "MMP-3", + "or", + "MMP-9" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "lower" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "levels" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes," + ] + } + } + ] + }, + { + "PMID": "11590439", + "TEXT": "Parkinson disease is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons and the presence of intracytoplasmic-ubiquitinated inclusions (Lewy bodies). Mutations in alpha-synuclein (A53T, A30P) and parkin cause familial Parkinson disease. Both these proteins are found in Lewy bodies. The absence of Lewy bodies in patients with parkin mutations suggests that parkin might be required for the formation of Lewy bodies. Here we show that parkin interacts with and ubiquitinates the alpha-synuclein-interacting protein, synphilin-1. Co-expression of alpha-synuclein, synphilin-1 and parkin result in the formation of Lewy-body-like ubiquitin-positive cytosolic inclusions. We further show that familial-linked mutations in parkin disrupt the ubiquitination of synphilin-1 and the formation of the ubiquitin-positive inclusions. These results provide a molecular basis for the ubiquitination of Lewy-body-associated proteins and link parkin and alpha-synuclein in a common pathogenic mechanism through their interaction with synphilin-1.", + "TAG_DATA": [ + "76, Co-expression {'perturbing_action': 'B-gene gain-of-function'}", + "77, of {'perturbing_action': 'I-gene gain-of-function'}", + "78, alpha-synuclein, {'perturbing_action': 'I-gene gain-of-function'}", + "79, synphilin-1 {'perturbing_action': 'I-gene gain-of-function'}", + "80, and {'perturbing_action': 'I-gene gain-of-function'}", + "81, parkin {'perturbing_action': 'I-gene gain-of-function'}", + "95, familial-linked {'perturbing_action': 'B-other'}", + "96, mutations {'perturbing_action': 'I-other'}", + "97, in {'perturbing_action': 'I-other'}", + "98, parkin {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "76, Co-expression ['l0', 'l1', 'l2', 'l3', 'l4']", + "77, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "78, alpha-synuclein, ['l1', 'l5', 'l9', 'l10', 'l11']", + "79, synphilin-1 ['l2', 'l6', 'l9', 'l12', 'l13']", + "80, and ['l3', 'l7', 'l10', 'l12', 'l14']", + "81, parkin ['l4', 'l8', 'l11', 'l13', 'l14']", + "95, familial-linked ['l15', 'l16', 'l17']", + "96, mutations ['l15', 'l18', 'l19']", + "97, in ['l16', 'l18', 'l20']", + "98, parkin ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11590438", + "TEXT": "Inducible nitric oxide synthase (iNOS) is induced by inflammatory cytokines in skeletal muscle and fat. It has been proposed that chronic iNOS induction may cause muscle insulin resistance. Here we show that iNOS expression is increased in muscle and fat of genetic and dietary models of obesity. Moreover, mice in which the gene encoding iNOS was disrupted (Nos2-/- mice) are protected from high-fat-induced insulin resistance. Whereas both wild-type and Nos2-/- mice developed obesity on the high-fat diet, obese Nos2-/- mice exhibited improved glucose tolerance, normal insulin sensitivity in vivo and normal insulin-stimulated glucose uptake in muscles. iNOS induction in obese wild-type mice was associated with impairments in phosphatidylinositol 3-kinase and Akt activation by insulin in muscle. These defects were fully prevented in obese Nos2-/- mice. These findings provide genetic evidence that iNOS is involved in the development of muscle insulin resistance in diet-induced obesity.", + "TAG_DATA": [ + "48, mice {'context': 'B-organism'}", + "51, the {'perturbing_action': 'I-gene loss-of-function'}", + "52, gene {'perturbing_action': 'I-gene loss-of-function'}", + "53, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "54, iNOS {'perturbing_action': 'I-gene loss-of-function'}", + "55, was {'perturbing_action': 'I-gene loss-of-function'}", + "56, disrupted {'perturbing_action': 'I-gene loss-of-function'}", + "58, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "69, Nos2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "70, mice {'context': 'B-organism'}", + "77, obese {'perturbing_action': 'B-gene loss-of-function'}", + "78, Nos2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "79, mice {'context': 'B-organism'}", + "87, in {'context': 'B-in vivo'}", + "88, vivo {'context': 'I-in vivo'}", + "95, muscles. {'context': 'B-tissue/organ'}", + "101, mice {'context': 'B-organism'}", + "115, muscle. {'context': 'B-tissue/organ'}", + "123, Nos2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "124, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "48, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "51, the ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "52, gene ['l1', 'l11', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "53, encoding ['l2', 'l12', 'l25', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "54, iNOS ['l3', 'l13', 'l26', 'l38', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "55, was ['l4', 'l14', 'l27', 'l39', 'l50', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "56, disrupted ['l5', 'l15', 'l28', 'l40', 'l51', 'l61', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "58, mice) ['l6', 'l16', 'l29', 'l41', 'l52', 'l62', 'l71', 'l80', 'l81', 'l82', 'l83']", + "69, Nos2-/- ['l7', 'l17', 'l30', 'l42', 'l53', 'l63', 'l72', 'l80', 'l84', 'l85', 'l86', 'l87', 'l88']", + "70, mice ['l8', 'l18', 'l31', 'l43', 'l54', 'l64', 'l73', 'l81', 'l84', 'l89', 'l90']", + "77, obese ['l19', 'l32', 'l44', 'l55', 'l65', 'l74', 'l91', 'l92', 'l93', 'l94', 'l95']", + "78, Nos2-/- ['l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l91', 'l96', 'l97', 'l98', 'l99']", + "79, mice ['l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l85', 'l92', 'l96', 'l100', 'l101', 'l102']", + "87, in ['l9', 'l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l82', 'l86', 'l89', 'l93', 'l97', 'l100', 'l103', 'l104']", + "88, vivo ['l10', 'l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l83', 'l87', 'l90', 'l94', 'l98', 'l101', 'l103']", + "95, muscles. ['l24', 'l37', 'l49', 'l60', 'l70', 'l79', 'l88', 'l95', 'l99', 'l102', 'l104']", + "101, mice ['l105']", + "115, muscle. ['l105']", + "123, Nos2-/- ['l106']", + "124, mice. ['l106']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "gene", + "encoding", + "iNOS", + "was", + "disrupted", + "mice)", + "Nos2-/-", + "obese" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "gene", + "encoding", + "iNOS", + "was", + "disrupted", + "mice)", + "Nos2-/-", + "obese" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "gene", + "encoding", + "iNOS", + "was", + "disrupted", + "Nos2-/-", + "obese" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscles." + ] + } + } + ] + }, + { + "PMID": "11590435", + "TEXT": "Polymorphonuclear leukocyte infiltration into tissues in host defense and inflammatory disease causes increased vascular permeability and edema formation through unknown mechanisms. Here, we report the involvement of a paracrine mechanism in neutrophil-evoked alteration in endothelial barrier function. We show that upon neutrophil adhesion to the endothelial lining, leukocytic beta2 integrin signaling triggers the release of neutrophil-borne heparin-binding protein (HBP), also known as CAP37/azurocidin, a member of the serprocidin family of neutrophil cationic proteins. HBP induced Ca++-dependent cytoskeletal rearrangement and intercellular gap formation in endothelial-cell monolayers in vitro, and increased macromolecular efflux in microvessels in vivo. Moreover, selective inactivation of HBP prevented the neutrophils from inducing endothelial hyperpermeability. Our data suggest a fundamental role of neutrophil-derived HBP in the vascular response to neutrophil trafficking in inflammation. Targeting this molecule in inflammatory disease conditions offers a new strategy for prevention of endothelial barrier dysfunction caused by misdirected leukocyte activation.", + "TAG_DATA": [ + "83, endothelial-cell {'context': 'B-cells'}", + "84, monolayers {'context': 'I-cells'}", + "85, in {'context': 'B-in vitro'}", + "86, vitro, {'context': 'I-in vitro'}", + "93, in {'context': 'B-in vivo'}", + "94, vivo. {'context': 'I-in vivo'}", + "96, selective {'perturbing_action': 'B-gene loss-of-function'}", + "97, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "98, of {'perturbing_action': 'I-gene loss-of-function'}", + "99, HBP {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "83, endothelial-cell ['l0', 'l1', 'l2', 'l3']", + "84, monolayers ['l0', 'l4', 'l5']", + "85, in ['l1', 'l4', 'l6']", + "86, vitro, ['l2', 'l5', 'l6']", + "92, microvessels ['l7', 'l8']", + "93, in ['l7', 'l9']", + "94, vivo. ['l3', 'l8', 'l9']", + "96, selective ['l10', 'l11', 'l12']", + "97, inactivation ['l10', 'l13', 'l14']", + "98, of ['l11', 'l13', 'l15']", + "99, HBP ['l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11533710", + "TEXT": "Diabetes in non-obese diabetic (NOD) mice is mediated by pathogenic T-helper type 1 (Th1) cells that arise because of a deficiency in regulatory or suppressor T cells. V alpha 14-J alpha 15 natural killer T (NKT) cells recognize lipid antigens presented by the major histocompatibility complex class I-like protein CD1d (refs. 3,4). We have previously shown that in vivo activation of V alpha 14 NKT cells by alpha-galactosylceramide (alpha-GalCer) and CD1d potentiates Th2-mediated adaptive immune responses. Here we show that alpha-GalCer prevents development of diabetes in wild-type but not CD1d-deficient NOD mice. Disease prevention correlated with the ability of alpha-GalCer to suppress interferon-gamma but not interleukin-4 production by NKT cells, to increase serum immunoglobulin E levels, and to promote the generation of islet autoantigen-specific Th2 cells. Because alpha-GalCer recognition by NKT cells is conserved among mice and humans, these findings indicate that alpha-GalCer might be useful for therapeutic intervention in human diseases characterized by Th1-mediated pathology such as Type 1 diabetes.", + "TAG_DATA": [ + "57, in {'context': 'B-in vivo'}", + "58, vivo {'context': 'I-in vivo'}", + "61, V {'context': 'B-cells'}", + "62, alpha {'context': 'I-cells'}", + "63, 14 {'context': 'B-cells'}", + "64, NKT {'context': 'I-cells'}", + "65, cells {'context': 'I-cells'}", + "89, CD1d-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "90, NOD {'context': 'B-organism'}", + "91, mice. {'context': 'I-organism'}", + "108, NKT {'context': 'B-cells'}", + "109, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "57, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "58, vivo ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "61, V ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "62, alpha ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "63, 14 ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "64, NKT ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "65, cells ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "89, CD1d-deficient ['l21', 'l22', 'l23', 'l24']", + "90, NOD ['l21', 'l25', 'l26', 'l27']", + "91, mice. ['l22', 'l25', 'l28', 'l29']", + "108, NKT ['l23', 'l26', 'l28', 'l30']", + "109, cells, ['l24', 'l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD1d-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "NOD", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD1d-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "NKT", + "cells," + ] + } + } + ] + }, + { + "PMID": "11533706", + "TEXT": "Stem cells from bone marrow, skeletal muscle and possibly other tissues can be identified by the 'side-population' (SP) phenotype. Although it has been assumed that expression of ABC transporters is responsible for this phenotype, the specific molecules involved have not been defined. Here we show that expression of the Bcrp1 (also known as Abcg2 murine/ABCG2 human) gene is a conserved feature of stem cells from a wide variety of sources. Bcrp1 mRNA was expressed at high levels in primitive murine hematopoietic stem cells, and was sharply downregulated with differentiation. Enforced expression of the ABCG2 cDNA directly conferred the SP phenotype to bone-marrow cells and caused a reduction in maturing progeny both in vitro and in transplantation-based assays. These results show that expression of the Bcrp1/ABCG2 gene is an important determinant of the SP phenotype, and that it might serve as a marker for stem cells from various sources.", + "TAG_DATA": [ + "89, Enforced {'perturbing_action': 'B-gene gain-of-function'}", + "90, expression {'perturbing_action': 'I-gene gain-of-function'}", + "91, of {'perturbing_action': 'I-gene gain-of-function'}", + "92, the {'perturbing_action': 'I-gene gain-of-function'}", + "93, ABCG2 {'perturbing_action': 'I-gene gain-of-function'}", + "94, cDNA {'perturbing_action': 'I-gene gain-of-function'}", + "101, bone-marrow {'context': 'B-cells'}", + "102, cells {'context': 'I-cells'}", + "111, in {'context': 'B-in vitro'}", + "112, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "89, Enforced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "90, expression ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "91, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "92, the ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "93, ABCG2 ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "94, cDNA ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "101, bone-marrow ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "102, cells ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39']", + "111, in ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42']", + "112, vitro ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced", + "expression", + "of", + "the", + "ABCG2", + "cDNA" + ] + }, + "context": { + "val": "cells", + "words": [ + "bone-marrow", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced", + "expression", + "of", + "the", + "ABCG2", + "cDNA" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "11533704", + "TEXT": "We use a mathematical model to understand (from 1996 to 2001) and to predict (from 2001 to 2005) the evolution of the epidemic of drug-resistant HIV in San Francisco. We predict the evolutionary trajectories for 1,000 different drug-resistant strains with each strain having a different fitness relative to a drug-sensitive strain. We calculate that the current prevalence of resistance is high, and predict it will continue to rise. In contrast, we calculate that transmission of resistance is currently low, and predict it will remain low. We show that the epidemic of resistance is being generated mainly by the conversion of drug-sensitive cases to drug-resistant cases, and not by the transmission of resistant strains. We also show that transmission of resistant strains has not increased the overall number of new HIV infections. Our results indicate that transmission of resistant strains is, and will remain, a relatively minor public health problem.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11479631", + "TEXT": "Many biological processes result in either cell death or cessation of cell growth. However, plasmid- and retrovirus-based mammalian expression vectors in which it has been possible to construct representative cDNA libraries cannot be readily recovered from cells that are not actively dividing. This has limited the efficiency of selection of recombinant genes that mediate either lytic events or growth arrest. Examples include genes that encode the target antigens of cytotoxic T cells, genes that promote stem-cell differentiation and pro-apoptotic genes. We have successfully constructed representative cDNA libraries in a poxvirus-based vector that can be recovered from cells that have undergone lethality-based selection. This strategy has been applied to selection of a gene that encodes a cytotoxic T-cell target antigen common to several independently derived tumors.", + "TAG_DATA": [ + "96, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11479627", + "TEXT": "Adiponectin is an adipocyte-derived hormone. Recent genome-wide scans have mapped a susceptibility locus for type 2 diabetes and metabolic syndrome to chromosome 3q27, where the gene encoding adiponectin is located. Here we show that decreased expression of adiponectin correlates with insulin resistance in mouse models of altered insulin sensitivity. Adiponectin decreases insulin resistance by decreasing triglyceride content in muscle and liver in obese mice. This effect results from increased expression of molecules involved in both fatty-acid combustion and energy dissipation in muscle. Moreover, insulin resistance in lipoatrophic mice was completely reversed by the combination of physiological doses of adiponectin and leptin, but only partially by either adiponectin or leptin alone. We conclude that decreased adiponectin is implicated in the development of insulin resistance in mouse models of both obesity and lipoatrophy. These data also indicate that the replenishment of adiponectin might provide a novel treatment modality for insulin resistance and type 2 diabetes.", + "TAG_DATA": [ + "58, muscle {'context': 'B-tissue/organ'}", + "60, liver {'context': 'B-tissue/organ'}", + "62, obese {'context': 'B-organism'}", + "63, mice. {'context': 'I-organism'}", + "87, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "58, muscle ['l0', 'l1', 'l2']", + "60, liver ['l0', 'l3', 'l4']", + "62, obese ['l1', 'l3', 'l5']", + "63, mice. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11479625", + "TEXT": "Lack of a small animal model of the human hepatitis C virus (HCV) has impeded development of antiviral therapies against this epidemic infection. By transplanting normal human hepatocytes into SCID mice carrying a plasminogen activator transgene (Alb-uPA), we generated mice with chimeric human livers. Homozygosity of Alb-uPA was associated with significantly higher levels of human hepatocyte engraftment, and these mice developed prolonged HCV infections with high viral titers after inoculation with infected human serum. Initial increases in total viral load were up to 1950-fold, with replication confirmed by detection of negative-strand viral RNA in transplanted livers. HCV viral proteins were localized to human hepatocyte nodules, and infection was serially passaged through three generations of mice confirming both synthesis and release of infectious viral particles. These chimeric mice represent the first murine model suitable for studying the human hepatitis C virus in vivo.", + "TAG_DATA": [ + "25, normal {'context': 'B-cells'}", + "26, human {'context': 'I-cells'}", + "27, hepatocytes {'context': 'I-cells'}", + "29, SCID {'context': 'B-organism'}", + "30, mice {'context': 'I-organism'}", + "34, activator {'perturbing_action': 'I-other'}", + "35, transgene {'perturbing_action': 'I-other'}", + "39, mice {'context': 'B-organism'}", + "43, livers. {'context': 'I-tissue/organ'}", + "44, Homozygosity {'perturbing_action': 'B-other'}", + "45, of {'perturbing_action': 'I-other'}", + "46, Alb-uPA {'perturbing_action': 'I-other'}", + "54, human {'context': 'B-cells'}", + "55, hepatocyte {'context': 'I-cells'}", + "59, mice {'context': 'B-organism'}", + "95, livers. {'context': 'B-tissue/organ'}", + "114, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "25, normal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "26, human ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "27, hepatocytes ['l1', 'l17', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "29, SCID ['l2', 'l18', 'l32', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "30, mice ['l3', 'l19', 'l33', 'l46', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "32, a ['l4', 'l20', 'l34', 'l47', 'l59', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "33, plasminogen ['l5', 'l21', 'l35', 'l48', 'l60', 'l71', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "34, activator ['l6', 'l22', 'l36', 'l49', 'l61', 'l72', 'l85', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "35, transgene ['l7', 'l23', 'l37', 'l50', 'l62', 'l73', 'l86', 'l98', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "36, (Alb-uPA), ['l8', 'l24', 'l38', 'l51', 'l63', 'l74', 'l87', 'l99', 'l110', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "39, mice ['l9', 'l25', 'l39', 'l52', 'l64', 'l75', 'l88', 'l100', 'l111', 'l121', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "42, human ['l10', 'l26', 'l40', 'l53', 'l65', 'l76', 'l89', 'l101', 'l112', 'l122', 'l131', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145']", + "43, livers. ['l11', 'l27', 'l41', 'l54', 'l66', 'l77', 'l90', 'l102', 'l113', 'l123', 'l132', 'l139', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151']", + "44, Homozygosity ['l78', 'l91', 'l103', 'l114', 'l124', 'l133', 'l140', 'l146', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "45, of ['l12', 'l79', 'l92', 'l104', 'l115', 'l125', 'l134', 'l141', 'l147', 'l152', 'l158', 'l159', 'l160', 'l161', 'l162']", + "46, Alb-uPA ['l13', 'l28', 'l42', 'l55', 'l67', 'l80', 'l93', 'l105', 'l116', 'l126', 'l135', 'l142', 'l148', 'l153', 'l158', 'l163', 'l164', 'l165', 'l166']", + "54, human ['l14', 'l29', 'l43', 'l56', 'l68', 'l81', 'l94', 'l106', 'l117', 'l127', 'l136', 'l143', 'l149', 'l154', 'l159', 'l163', 'l167', 'l168']", + "55, hepatocyte ['l15', 'l30', 'l44', 'l57', 'l69', 'l82', 'l95', 'l107', 'l118', 'l128', 'l137', 'l144', 'l150', 'l155', 'l160', 'l164', 'l167', 'l169']", + "59, mice ['l16', 'l31', 'l45', 'l58', 'l70', 'l83', 'l96', 'l108', 'l119', 'l129', 'l138', 'l145', 'l151', 'l156', 'l161', 'l165', 'l168', 'l169']", + "95, livers. ['l84', 'l97', 'l109', 'l120', 'l130', 'l157', 'l162', 'l166']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "normal", + "human", + "hepatocytes", + "hepatocyte" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "activator", + "transgene", + "of", + "Alb-uPA", + "Homozygosity" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "SCID", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "activator", + "transgene", + "Alb-uPA", + "Homozygosity", + "of" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "activator", + "transgene", + "Homozygosity", + "of", + "Alb-uPA" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "livers." + ] + } + } + ] + }, + { + "PMID": "11433352", + "TEXT": "Atherosclerosis is the primary cause of cardiovascular disease, and the risk for atherosclerosis is inversely proportional to circulating levels of high-density lipoprotein (HDL) cholesterol. However, the mechanisms by which HDL is atheroprotective are complex and not well understood. Here we show that HDL stimulates endothelial nitric oxide synthase (eNOS) in cultured endothelial cells. In contrast, eNOS is not activated by purified forms of the major HDL apolipoproteins ApoA-I and ApoA-II or by low-density lipoprotein. Heterologous expression experiments in Chinese hamster ovary cells reveal that scavenger receptor-BI (SR-BI) mediates the effects of HDL on the enzyme. HDL activation of eNOS is demonstrable in isolated endothelial-cell caveolae where SR-BI and eNOS are colocalized, and the response in isolated plasma membranes is blocked by antibodies to ApoA-I and SR-BI, but not by antibody to ApoA-II. HDL also enhances endothelium- and nitric-oxide-dependent relaxation in aortae from wild-type mice, but not in aortae from homozygous null SR-BI knockout mice. Thus, HDL activates eNOS via SR-BI through a process that requires ApoA-I binding. The resulting increase in nitric-oxide production might be critical to the atheroprotective properties of HDL and ApoA-I.", + "TAG_DATA": [ + "50, cultured {'context': 'B-cells'}", + "51, endothelial {'context': 'I-cells'}", + "52, cells. {'context': 'I-cells'}", + "78, Chinese {'context': 'B-cells'}", + "79, hamster {'context': 'I-cells'}", + "80, ovary {'context': 'I-cells'}", + "81, cells {'context': 'I-cells'}", + "140, aortae {'context': 'B-tissue/organ'}", + "143, mice, {'context': 'B-organism'}", + "147, aortae {'context': 'B-tissue/organ'}", + "149, homozygous {'perturbing_action': 'B-gene loss-of-function'}", + "150, null {'perturbing_action': 'I-gene loss-of-function'}", + "151, SR-BI {'perturbing_action': 'I-gene loss-of-function'}", + "152, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "153, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, cultured ['l0', 'l1']", + "51, endothelial ['l0', 'l2', 'l3']", + "52, cells. ['l1', 'l2', 'l4']", + "78, Chinese ['l5', 'l6', 'l7']", + "79, hamster ['l5', 'l8', 'l9']", + "80, ovary ['l6', 'l8', 'l10']", + "81, cells ['l3', 'l4', 'l7', 'l9', 'l10']", + "140, aortae ['l11']", + "143, mice, ['l11']", + "147, aortae ['l12', 'l13', 'l14', 'l15', 'l16']", + "149, homozygous ['l12', 'l17', 'l18', 'l19', 'l20']", + "150, null ['l13', 'l17', 'l21', 'l22', 'l23']", + "151, SR-BI ['l14', 'l18', 'l21', 'l24', 'l25']", + "152, knockout ['l15', 'l19', 'l22', 'l24', 'l26']", + "153, mice. ['l16', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "aortae" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "homozygous", + "null", + "SR-BI", + "knockout" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "homozygous", + "null", + "SR-BI", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "11433349", + "TEXT": "We provide anatomic and functional evidence that nicotine induces angiogenesis. We also show that nicotine accelerates the growth of tumor and atheroma in association with increased neovascularization. Nicotine increased endothelial-cell growth and tube formation in vitro, and accelerated fibrovascular growth in vivo. In a mouse model of hind-limb ischemia, nicotine increased capillary and collateral growth, and enhanced tissue perfusion. In mouse models of lung cancer and atherosclerosis, we found that nicotine enhanced lesion growth in association with an increase in lesion vascularity. These effects of nicotine were mediated through nicotinic acetylcholine receptors at nicotine concentrations that are pathophysiologically relevant. The endothelial production of nitric oxide, prostacyclin and vascular endothelial growth factor might have a role in these effects.", + "TAG_DATA": [ + "28, increased {'effect': 'B-positive'}", + "30, growth {'phenotype': 'I-cell growth'}", + "32, tube {'phenotype': 'B-tumourigenesis'}", + "33, formation {'phenotype': 'I-tumourigenesis'}", + "34, in {'context': 'B-in vitro'}", + "35, vitro, {'context': 'I-in vitro'}", + "40, in {'context': 'B-in vivo'}", + "41, vivo. {'context': 'I-in vivo'}", + "44, mouse {'context': 'B-organism'}", + "45, model {'context': 'I-organism'}", + "60, mouse {'context': 'B-neoplasm'}", + "61, models {'context': 'I-neoplasm'}", + "62, of {'context': 'I-neoplasm'}", + "63, lung {'context': 'I-neoplasm'}", + "64, cancer {'context': 'I-neoplasm'}", + "71, enhanced {'effect': 'B-positive'}", + "72, lesion {'context': 'B-neoplasm', 'phenotype': 'B-tumour growth'}", + "73, growth {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "19, tumor ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "28, increased ['l0', 'l8', 'l9', 'l10', 'l11', 'l12']", + "30, growth ['l1', 'l8', 'l13', 'l14', 'l15', 'l16']", + "32, tube ['l2', 'l9', 'l13', 'l17', 'l18', 'l19']", + "33, formation ['l3', 'l10', 'l14', 'l17', 'l20', 'l21']", + "34, in ['l4', 'l11', 'l15', 'l18', 'l20', 'l22']", + "35, vitro, ['l5', 'l12', 'l16', 'l19', 'l21', 'l22']", + "40, in ['l6', 'l23']", + "41, vivo. ['l7', 'l23']", + "44, mouse ['l24']", + "45, model ['l24']", + "60, mouse ['l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "61, models ['l25', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "62, of ['l26', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "63, lung ['l27', 'l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "64, cancer ['l28', 'l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "71, enhanced ['l29', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "72, lesion ['l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "73, growth ['l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l52']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tube", + "formation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tube", + "formation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "models", + "of", + "lung", + "cancer", + "lesion" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "models", + "of", + "lung", + "cancer", + "lesion" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "lesion", + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "lesion", + "growth" + ] + } + } + ] + }, + { + "PMID": "11433348", + "TEXT": "Advanced cirrhosis is associated with generalized vasodilation of unknown origin, which contributes to mortality. Cirrhotic patients are endotoxemic, and activation of vascular cannabinoid CB1 receptors has been implicated in endotoxin-induced hypotension. Here we show that rats with biliary cirrhosis have low blood pressure, which is elevated by the CB1 receptor antagonist SR141716A. The low blood pressure of rats with CCl4-induced cirrhosis was similarly reversed by SR141716A, which also reduced the elevated mesenteric blood flow and portal pressure. Monocytes from cirrhotic but not control patients or rats elicited SR141716A-sensitive hypotension in normal recipient rats and showed significantly elevated levels of anandamide. Compared with non-cirrhotic controls, in cirrhotic human livers there was a three-fold increase in CB1 receptors on isolated vascular endothelial cells. These results implicate anandamide and vascular CB1 receptors in the vasodilated state in advanced cirrhosis and indicate a novel approach for its management.", + "TAG_DATA": [ + "57, rats {'context': 'B-organism'}", + "77, Monocytes {'context': 'B-cells'}", + "85, rats {'context': 'B-organism'}", + "92, rats {'context': 'B-organism'}", + "105, cirrhotic {'context': 'B-tissue/organ'}", + "106, human {'context': 'I-tissue/organ'}", + "107, livers {'context': 'I-tissue/organ'}", + "118, vascular {'context': 'B-cells'}", + "119, endothelial {'context': 'I-cells'}", + "120, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "77, Monocytes ['l0', 'l1']", + "85, rats ['l0', 'l2']", + "92, rats ['l1', 'l2']", + "105, cirrhotic ['l3', 'l4', 'l5', 'l6', 'l7']", + "106, human ['l3', 'l8', 'l9', 'l10', 'l11']", + "107, livers ['l4', 'l8', 'l12', 'l13', 'l14']", + "118, vascular ['l5', 'l9', 'l12', 'l15', 'l16']", + "119, endothelial ['l6', 'l10', 'l13', 'l15', 'l17']", + "120, cells. ['l7', 'l11', 'l14', 'l16', 'l17']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11433328", + "TEXT": "Having originally researched the activities of the potent hematopeotic stimulator of bone-marrow cells, granulocyte colony stimulating factor, Shigekazu Nagata is better known for his work on apoptosis. Here, one of Japan's most renowned biomedical scientists outlines the path that has taken him full circle: from stimulating cells to grow, to finding out how they die, to tying the two processes together. (Interview by David Cyranoski.)", + "TAG_DATA": [ + "46, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11385511", + "TEXT": "Surface-contact-mediated signaling induced by the measles virus (MV) fusion and hemagglutinin glycoproteins is necessary and sufficient to induce T-cell unresponsiveness in vitro and in vivo. To define the intracellular pathways involved, we analyzed interleukin (IL)-2R signaling in primary human T cells and in Kit-225 cells. Unlike IL-2-dependent activation of JAK/STAT pathways, activation of Akt kinase was impaired after MV contact both in vitro and in vivo. MV interference with Akt activation was important for immunosuppression, as expression of a catalytically active Akt prevented negative signaling by the MV glycoproteins. Thus, we show here that MV exploits a novel strategy to interfere with T-cell activation during immunosuppression.", + "TAG_DATA": [ + "37, primary {'context': 'B-cells'}", + "38, human {'context': 'I-cells'}", + "39, T {'context': 'I-cells'}", + "40, cells {'context': 'I-cells'}", + "43, Kit-225 {'context': 'B-cells'}", + "44, cells. {'context': 'I-cells'}", + "61, in {'context': 'B-in vitro'}", + "62, vitro {'context': 'I-in vitro'}", + "64, in {'context': 'B-in vivo'}", + "65, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "37, primary ['l0', 'l1', 'l2', 'l3']", + "38, human ['l0', 'l4', 'l5', 'l6']", + "39, T ['l1', 'l4', 'l7', 'l8']", + "40, cells ['l2', 'l5', 'l7']", + "43, Kit-225 ['l9', 'l10', 'l11', 'l12', 'l13']", + "44, cells. ['l3', 'l6', 'l8', 'l9', 'l14', 'l15']", + "61, in ['l10', 'l14', 'l16', 'l17', 'l18']", + "62, vitro ['l11', 'l15', 'l16', 'l19', 'l20']", + "64, in ['l12', 'l17', 'l19', 'l21']", + "65, vivo. ['l13', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11385509", + "TEXT": "Many HIV-1-infected patients treated with protease inhibitors (PI) develop PI-resistant HIV-1 variants and rebounds in viremia, but their CD4+ T-cell counts often do not fall. We hypothesized that in these patients, T-cell counts remain elevated because PI-resistant virus spares intrathymic T-cell production. To test this, we studied recombinant HIV-1 clones containing wild-type or PI-resistant protease domains, as well as uncloned isolates from patients, in activated peripheral blood mononuclear cells, human thymic organ cultures and human thymus implants in SCID-hu Thy/Liv mice. In most cases, wild-type and PI-resistant HIV-1 isolates replicated to similar degrees in peripheral blood mononuclear cells. However, the replication of PI-resistant but not wild-type HIV-1 isolates was highly impaired in thymocytes. In addition, patients who had PI-resistant HIV-1 had abundant thymus tissue as assessed by computed tomography. We propose that the inability of PI-resistant HIV-1 to replicate efficiently in thymus contributes to the preservation of CD4+ T-cell counts in patients showing virologic rebound on PI therapy.", + "TAG_DATA": [ + "64, activated {'context': 'B-cells'}", + "65, peripheral {'context': 'I-cells'}", + "66, blood {'context': 'I-cells'}", + "67, mononuclear {'context': 'I-cells'}", + "68, cells, {'context': 'I-cells'}", + "69, human {'context': 'B-cells'}", + "70, thymic {'context': 'I-cells'}", + "71, organ {'context': 'I-cells'}", + "72, cultures {'context': 'I-cells'}", + "74, human {'context': 'B-tissue/organ'}", + "75, thymus {'context': 'I-tissue/organ'}", + "80, mice. {'context': 'B-organism'}", + "94, peripheral {'context': 'B-cells'}", + "95, blood {'context': 'I-cells'}", + "96, mononuclear {'context': 'I-cells'}", + "97, cells. {'context': 'I-cells'}", + "112, thymocytes. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "64, activated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "65, peripheral ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "66, blood ['l1', 'l11', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "67, mononuclear ['l2', 'l12', 'l22', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "68, cells, ['l3', 'l13', 'l23', 'l32', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "69, human ['l4', 'l14', 'l24', 'l33', 'l41', 'l47', 'l48', 'l49', 'l50', 'l51']", + "70, thymic ['l5', 'l15', 'l25', 'l34', 'l42', 'l47', 'l52', 'l53', 'l54']", + "71, organ ['l6', 'l16', 'l26', 'l35', 'l43', 'l48', 'l52', 'l55', 'l56', 'l57']", + "72, cultures ['l7', 'l17', 'l27', 'l36', 'l44', 'l49', 'l53', 'l55', 'l58']", + "74, human ['l8', 'l18', 'l28', 'l37', 'l45', 'l50', 'l54', 'l56', 'l58', 'l59', 'l60']", + "75, thymus ['l9', 'l19', 'l29', 'l38', 'l46', 'l51', 'l57', 'l59', 'l61', 'l62']", + "76, implants ['l10', 'l20', 'l30', 'l39', 'l60', 'l61', 'l63']", + "80, mice. ['l21', 'l31', 'l40', 'l62', 'l63']", + "94, peripheral ['l64', 'l65', 'l66']", + "95, blood ['l64', 'l67', 'l68']", + "96, mononuclear ['l65', 'l67', 'l69']", + "97, cells. ['l66', 'l68', 'l69']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11385503", + "TEXT": "The purpose of this study was to develop a method of classifying cancers to specific diagnostic categories based on their gene expression signatures using artificial neural networks (ANNs). We trained the ANNs using the small, round blue-cell tumors (SRBCTs) as a model. These cancers belong to four distinct diagnostic categories and often present diagnostic dilemmas in clinical practice. The ANNs correctly classified all samples and identified the genes most relevant to the classification. Expression of several of these genes has been reported in SRBCTs, but most have not been associated with these cancers. To test the ability of the trained ANN models to recognize SRBCTs, we analyzed additional blinded samples that were not previously used for the training procedure, and correctly classified them in all cases. This study demonstrates the potential applications of these methods for tumor diagnosis and the identification of candidate targets for therapy.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11329063", + "TEXT": "Adaptive stress responses mediated by the endocrine, autonomic, cardiovascular and immune systems are essential for the survival of the individual. Initial stress-induced responses provide a vital short-term metabolic lift, but prolonged or inappropriate exposure to stress can compromise homeostasis thereby leading to disease. This 'fight-or-flight' response is characterized by the activation of the corticotropin-releasing hormone (CRH)-adrenocorticotropin-glucocorticoid axis, mediated by the type 1 CRH receptor. In contrast, the type 2 CRH receptor mediates the stress-coping responses during the recovery phase of stress. We identified human stresscopin (SCP) and stresscopin-related peptide (SRP) as specific ligands for the type 2 CRH receptor. The genes encoding these peptides were expressed in diverse peripheral tissues as well as in the central nervous system. Treatment with SCP or SRP suppressed food intake, delayed gastric emptying and decreased heat-induced edema. Thus SCP and SRP might represent endogenous ligands for maintaining homeostasis after stress, and could allow the design of drugs to ameliorate stress-related diseases.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11329062", + "TEXT": "Carbon monoxide (CO) can arrest cellular respiration, but paradoxically, it is synthesized endogenously by heme oxygenase type 1 (Ho-1) in response to ischemic stress. Ho-1-deficient (Hmox1-/-) mice exhibited lethal ischemic lung injury, but were rescued from death by inhaled CO. CO drove ischemic protection by activating soluble guanylate cyclase and thereby suppressed hypoxic induction of the gene encoding plasminogen activator inhibitor-1 (PAI-1) in mononuclear phagocytes, which reduced accrual of microvascular fibrin. CO-mediated ischemic protection observed in wild-type mice was lost in mice null for the gene encoding PAI-1 (Serpine1). These data establish a fundamental link between CO and prevention of ischemic injury based on the ability of CO to derepress the fibrinolytic axis. These data also point to a potential therapeutic use for inhaled CO.", + "TAG_DATA": [ + "24, Ho-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "25, (Hmox1-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "26, mice {'context': 'B-organism'}", + "63, mononuclear {'context': 'B-cells'}", + "64, phagocytes, {'context': 'I-cells'}", + "77, mice {'context': 'B-organism'}", + "81, mice {'context': 'B-organism'}", + "82, null {'perturbing_action': 'B-gene loss-of-function'}", + "83, for {'perturbing_action': 'I-gene loss-of-function'}", + "84, the {'perturbing_action': 'I-gene loss-of-function'}", + "85, gene {'perturbing_action': 'I-gene loss-of-function'}", + "86, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "87, PAI-1 {'perturbing_action': 'I-gene loss-of-function'}", + "88, (Serpine1). {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "24, Ho-1-deficient ['l0', 'l1', 'l2', 'l3']", + "25, (Hmox1-/-) ['l0', 'l4', 'l5', 'l6']", + "26, mice ['l1', 'l4']", + "63, mononuclear ['l2', 'l5', 'l7']", + "64, phagocytes, ['l3', 'l6', 'l7']", + "81, mice ['l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "82, null ['l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "83, for ['l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "84, the ['l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "85, gene ['l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "86, encoding ['l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "87, PAI-1 ['l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "88, (Serpine1). ['l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ho-1-deficient", + "(Hmox1-/-)", + "null", + "for", + "the", + "gene", + "encoding", + "PAI-1", + "(Serpine1)." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ho-1-deficient", + "(Hmox1-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "mononuclear", + "phagocytes," + ] + } + } + ] + }, + { + "PMID": "11329059", + "TEXT": "Vascular endothelial growth factor (VEGF) stimulates angiogenesis by activating VEGF receptor-2 (VEGFR-2). The role of its homolog, placental growth factor (PlGF), remains unknown. Both VEGF and PlGF bind to VEGF receptor-1 (VEGFR-1), but it is unknown whether VEGFR-1, which exists as a soluble or a membrane-bound type, is an inert decoy or a signaling receptor for PlGF during angiogenesis. Here, we report that embryonic angiogenesis in mice was not affected by deficiency of PlGF (Pgf-/-). VEGF-B, another ligand of VEGFR-1, did not rescue development in Pgf-/- mice. However, loss of PlGF impaired angiogenesis, plasma extravasation and collateral growth during ischemia, inflammation, wound healing and cancer. Transplantation of wild-type bone marrow rescued the impaired angiogenesis and collateral growth in Pgf-/- mice, indicating that PlGF might have contributed to vessel growth in the adult by mobilizing bone-marrow-derived cells. The synergism between PlGF and VEGF was specific, as PlGF deficiency impaired the response to VEGF, but not to bFGF or histamine. VEGFR-1 was activated by PlGF, given that anti-VEGFR-1 antibodies and a Src-kinase inhibitor blocked the endothelial response to PlGF or VEGF/PlGF. By upregulating PlGF and the signaling subtype of VEGFR-1, endothelial cells amplify their responsiveness to VEGF during the 'angiogenic switch' in many pathological disorders.", + "TAG_DATA": [ + "66, mice {'context': 'B-organism'}", + "71, deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "72, of {'perturbing_action': 'I-gene loss-of-function'}", + "73, PlGF {'perturbing_action': 'I-gene loss-of-function'}", + "74, (Pgf-/-). {'perturbing_action': 'I-gene loss-of-function'}", + "85, Pgf-/- {'perturbing_action': 'B-gene loss-of-function'}", + "86, mice. {'context': 'B-organism'}", + "88, loss {'perturbing_action': 'B-gene loss-of-function'}", + "89, of {'perturbing_action': 'I-gene loss-of-function'}", + "90, PlGF {'perturbing_action': 'I-gene loss-of-function'}", + "105, Transplantation {'perturbing_action': 'B-gene gain-of-function'}", + "106, of {'perturbing_action': 'I-gene gain-of-function'}", + "107, wild-type {'perturbing_action': 'I-gene gain-of-function'}", + "108, bone {'perturbing_action': 'I-gene loss-of-function'}", + "109, marrow {'perturbing_action': 'I-gene gain-of-function'}", + "118, Pgf-/- {'perturbing_action': 'B-gene loss-of-function'}", + "119, mice, {'context': 'B-organism'}", + "134, bone-marrow-derived {'context': 'B-cells'}", + "135, cells. {'context': 'I-cells'}", + "145, PlGF {'perturbing_action': 'B-gene loss-of-function'}", + "146, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "169, Src-kinase {'perturbing_action': 'B-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "66, mice ['l0', 'l1', 'l2', 'l3']", + "71, deficiency ['l0', 'l4', 'l5', 'l6']", + "72, of ['l1', 'l4', 'l7', 'l8']", + "73, PlGF ['l2', 'l5', 'l7', 'l9']", + "74, (Pgf-/-). ['l3', 'l6', 'l8', 'l9']", + "85, Pgf-/- ['l10']", + "86, mice. ['l10']", + "88, loss ['l11', 'l12', 'l13']", + "89, of ['l11', 'l14', 'l15', 'l16']", + "90, PlGF ['l12', 'l14', 'l17', 'l18']", + "105, Transplantation ['l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "106, of ['l19', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "107, wild-type ['l20', 'l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "108, bone ['l21', 'l29', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "109, marrow ['l22', 'l30', 'l36', 'l41', 'l46', 'l47', 'l48', 'l49']", + "118, Pgf-/- ['l23', 'l31', 'l37', 'l42', 'l46', 'l50', 'l51', 'l52']", + "119, mice, ['l24', 'l32', 'l38', 'l43', 'l47', 'l50', 'l53', 'l54']", + "134, bone-marrow-derived ['l15', 'l17', 'l25', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l55']", + "135, cells. ['l13', 'l16', 'l18', 'l26', 'l34', 'l40', 'l45', 'l49', 'l52', 'l54', 'l55']", + "145, PlGF ['l56', 'l57', 'l58']", + "146, deficiency ['l27', 'l56']", + "169, Src-kinase ['l57', 'l59']", + "170, inhibitor ['l58', 'l59']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "of", + "PlGF", + "(Pgf-/-).", + "Pgf-/-", + "bone" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "PlGF", + "bone", + "Pgf-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells.", + "bone-marrow-derived" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transplantation", + "of", + "wild-type", + "marrow" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transplantation", + "of", + "wild-type", + "marrow" + ] + }, + "context": { + "val": "cells", + "words": [ + "bone-marrow-derived", + "cells." + ] + } + } + ] + }, + { + "PMID": "11329057", + "TEXT": "Rheumatoid arthritis (RA) is a chronic and debilitating autoimmune disease of unknown etiology, characterized by chronic inflammation in the joints and subsequent destruction of the cartilage and bone. We describe here a new strategy for the treatment of arthritis: administration of the neuropeptide vasoactive intestinal peptide (VIP). Treatment with VIP significantly reduced incidence and severity of arthritis in an experimental model, completely abrogating joint swelling and destruction of cartilage and bone. The therapeutic effect of VIP was associated with downregulation of both inflammatory and autoimmune components of the disease. Our data indicate VIP as a viable candidate for the development of treatments for RA.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11329056", + "TEXT": "Successful transplantation of allogeneic organs is an important objective in modern medicine. However, sophisticated immune defense mechanisms, primarily evolved to combat infections, often work against medical transplantation. To investigate the roles of natural and adaptive immune responses in transplant rejection, we functionally inactivated key effector systems of the innate (NK cells) and the adaptive immune system (CD28-mediated costimulation of T cells) in mice. Neither of these interventions alone led to acceptance of allogeneic vascularized cardiac grafts. In contrast, inhibition of NK-receptor-bearing cells combined with CD28-costimulation blockade established long-term graft acceptance. These results indicate a concerted interplay between innate and adaptive immune surveillance for graft rejection. Thus we suggest that inactivation of NK-receptor-bearing cells could be a new strategy for successful survival of solid-organ transplants.", + "TAG_DATA": [ + "62, mice. {'context': 'B-organism'}", + "72, allogeneic {'context': 'B-xenograft'}", + "73, vascularized {'context': 'I-xenograft'}", + "74, cardiac {'context': 'I-xenograft'}", + "75, grafts. {'context': 'I-xenograft'}", + "78, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "80, NK-receptor-bearing {'context': 'B-cells'}", + "81, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "62, mice. ['l0', 'l1']", + "72, allogeneic ['l2', 'l3', 'l4']", + "73, vascularized ['l2', 'l5', 'l6']", + "74, cardiac ['l0', 'l3', 'l5', 'l7']", + "75, grafts. ['l1', 'l4', 'l6', 'l7']", + "78, inhibition ['l8', 'l9']", + "80, NK-receptor-bearing ['l8', 'l10']", + "81, cells ['l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "NK-receptor-bearing", + "cells" + ] + } + } + ] + }, + { + "PMID": "11329042", + "TEXT": "Despite the availability of effective therapies in developed nations, infectious diseases continue to take a grave toll on the population and economy of sub-Saharan Africa. Aside from a few successes, the global donor community has not adequately helped African governments meet these health challenges. However, if annual donor contributions increased approximately 10-20-fold, millions of lives could be saved, helping Africa escape the cycle of disease and impoverishment.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11283670", + "TEXT": "Low oxygen tension influences tumor progression by enhancing angiogenesis; and histone deacetylases (HDAC) are implicated in alteration of chromatin assembly and tumorigenesis. Here we show induction of HDAC under hypoxia and elucidate a role for HDAC in the regulation of hypoxia-induced angiogenesis. Overexpressed wild-type HDAC1 downregulated expression of p53 and von Hippel-Lindau tumor suppressor genes and stimulated angiogenesis of human endothelial cells. A specific HDAC inhibitor, trichostatin A (TSA), upregulated p53 and von Hippel-Lindau expression and downregulated hypoxia-inducible factor-1alpha and vascular endothelial growth factor. TSA also blocked angiogenesis in vitro and in vivo. TSA specifically inhibited hypoxia-induced angiogenesis in the Lewis lung carcinoma model. These results indicate that hypoxia enhances HDAC function and that HDAC is closely involved in angiogenesis through suppression of hypoxia-responsive tumor suppressor genes.", + "TAG_DATA": [ + "42, Overexpressed {'perturbing_action': 'B-gene gain-of-function'}", + "43, wild-type {'perturbing_action': 'I-gene gain-of-function'}", + "44, HDAC1 {'perturbing_action': 'I-gene gain-of-function'}", + "59, human {'context': 'B-cells'}", + "60, endothelial {'context': 'I-cells'}", + "61, cells. {'context': 'I-cells'}", + "63, specific {'perturbing_action': 'B-pharmacological inhibition'}", + "64, HDAC {'perturbing_action': 'I-pharmacological inhibition'}", + "65, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "66, trichostatin {'perturbing_action': 'I-pharmacological inhibition'}", + "67, A {'perturbing_action': 'I-pharmacological inhibition'}", + "68, (TSA), {'perturbing_action': 'I-pharmacological inhibition'}", + "88, in {'context': 'B-in vitro'}", + "89, vitro {'context': 'I-in vitro'}", + "91, in {'context': 'B-in vivo'}", + "92, vivo. {'context': 'I-in vivo'}", + "100, Lewis {'context': 'B-neoplasm'}", + "101, lung {'context': 'I-neoplasm'}", + "102, carcinoma {'context': 'I-neoplasm'}", + "103, model. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "42, Overexpressed ['l0', 'l1', 'l2', 'l3', 'l4']", + "43, wild-type ['l0', 'l5', 'l6', 'l7', 'l8']", + "44, HDAC1 ['l1', 'l5', 'l9', 'l10', 'l11']", + "59, human ['l2', 'l6', 'l9', 'l12', 'l13']", + "60, endothelial ['l3', 'l7', 'l10', 'l12', 'l14']", + "61, cells. ['l4', 'l8', 'l11', 'l13', 'l14']", + "63, specific ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "64, HDAC ['l15', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "65, inhibitor, ['l16', 'l24', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "66, trichostatin ['l17', 'l25', 'l32', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "67, A ['l18', 'l26', 'l33', 'l39', 'l45', 'l46', 'l47', 'l48', 'l49']", + "68, (TSA), ['l19', 'l27', 'l34', 'l40', 'l45', 'l50', 'l51', 'l52', 'l53']", + "88, in ['l20', 'l28', 'l35', 'l41', 'l46', 'l50', 'l54', 'l55']", + "89, vitro ['l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l54', 'l56']", + "91, in ['l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l57']", + "92, vivo. ['l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l55', 'l56', 'l57']", + "100, Lewis ['l58', 'l59', 'l60']", + "101, lung ['l58', 'l61', 'l62']", + "102, carcinoma ['l59', 'l61', 'l63']", + "103, model. ['l60', 'l62', 'l63']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpressed", + "wild-type", + "HDAC1" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "endothelial", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "HDAC", + "inhibitor,", + "trichostatin", + "A", + "(TSA)," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "HDAC", + "inhibitor,", + "trichostatin", + "A", + "(TSA)," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "11231635", + "TEXT": "Epstein-Barr virus (EBV) is an oncogenic virus associated with a number of human malignancies including Burkitt lymphoma, nasopharyngeal carcinoma, lymphoproliferative disease and, though still debated, breast carcinoma. A subset of latent EBV antigens is required for mediating immortalization of primary B-lymphocytes. Here we demonstrate that the carboxy-terminal region of the essential latent antigen, EBNA-3C, interacts specifically with the human metastatic suppressor protein Nm23-H1. Moreover, EBNA-3C reverses the ability of Nm23-H1 to suppress the migration of Burkitt lymphoma cells and breast carcinoma cells. We propose that EBNA-3C contributes to EBV-associated human cancers by targeting and altering the role of the metastasis suppressor Nm23-H1.", + "TAG_DATA": [ + "71, suppress {'effect': 'B-negative'}", + "73, migration {'phenotype': 'B-migration'}", + "75, Burkitt {'context': 'B-transformed cells'}", + "76, lymphoma {'context': 'I-transformed cells'}", + "77, cells {'context': 'I-transformed cells'}", + "79, breast {'context': 'B-transformed cells'}", + "80, carcinoma {'context': 'I-transformed cells'}", + "81, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "71, suppress ['l0', 'l1', 'l2', 'l3']", + "73, migration ['l0', 'l4', 'l5', 'l6']", + "75, Burkitt ['l1', 'l4', 'l7', 'l8']", + "76, lymphoma ['l2', 'l5', 'l7', 'l9']", + "77, cells ['l3', 'l6', 'l8', 'l9']", + "79, breast ['l10', 'l11']", + "80, carcinoma ['l10', 'l12']", + "81, cells. ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "suppress" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppress" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "Burkitt", + "lymphoma", + "cells" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "Burkitt", + "lymphoma", + "cells" + ] + } + } + ] + }, + { + "PMID": "11231634", + "TEXT": "Dendritic cells and macrophages can process extracellular antigens for presentation by MHC-I molecules. This exogenous pathway may have a crucial role in the activation of CD8+ cytotoxic T lymphocytes during human viral infections. We show here that HIV-1 epitopes derived from incoming virions are presented through the exogenous MHC-I pathway in primary human dendritic cells, and to a lower extent in macrophages, leading to cytotoxic T-lymphocyte activation in the absence of viral protein synthesis. Exogenous antigen presentation required adequate virus-receptor interactions and fusion of viral and cellular membranes. These results provide new insights into how anti-HIV cytotoxic T lymphocytes can be activated and have implications for anti-HIV vaccine design.", + "TAG_DATA": [ + "51, primary {'context': 'B-cells'}", + "52, human {'context': 'I-cells'}", + "53, dendritic {'context': 'I-cells'}", + "54, cells, {'context': 'I-cells'}", + "61, macrophages, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "51, primary ['l0', 'l1', 'l2', 'l3']", + "52, human ['l0', 'l4', 'l5', 'l6']", + "53, dendritic ['l1', 'l4', 'l7', 'l8']", + "54, cells, ['l2', 'l5', 'l7']", + "61, macrophages, ['l3', 'l6', 'l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11175857", + "TEXT": "Clinical applications of tumor gene therapy require tumor-specific delivery or expression of therapeutic genes in order to maximize the oncolytic index and minimize side effects. This study demonstrates activation of transgene expression exclusively in hepatic metastases after systemic application of a modified first-generation (E1A/E1B-deleted) adenovirus vector (AdE1-) in mouse tumor models. The discrimination between tumors and normal liver tissue is based on selective DNA replication of AdE1- vectors in tumor cells. This new AdE1- based vector system uses homologous recombination between inverted repeats to mediate precise rearrangements within the viral genome. As a result of these rearrangements, a promoter is brought into conjunction with a reporter gene creating a functional expression cassette. Genomic rearrangements are dependent upon viral DNA replication, which in turn occurs specifically in tumor cells. In a mouse tumor model with liver metastases derived from human tumor cells, a single systemic administration of replication activated AdE1- vectors achieved transgene expression in every metastasis, whereas no extra-tumoral transgene induction was observed. Here we provide a new concept for tumor-specific gene expression that is also applicable for other conditionally replicating adenovirus vectors.", + "TAG_DATA": [ + "130, mouse {'context': 'B-neoplasm'}", + "131, tumor {'context': 'I-neoplasm'}", + "132, model {'context': 'I-neoplasm'}", + "134, liver {'phenotype': 'B-metastasis'}", + "135, metastases {'phenotype': 'I-metastasis'}", + "137, from {'context': 'I-transformed cells'}", + "138, human {'context': 'I-transformed cells'}", + "139, tumor {'context': 'I-transformed cells'}", + "140, cells, {'context': 'I-transformed cells'}", + "155, metastasis, {'context': 'B-neoplasm', 'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "130, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "131, tumor ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "132, model ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "134, liver ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "135, metastases ['l3', 'l11', 'l18', 'l24', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "136, derived ['l4', 'l12', 'l19', 'l25', 'l31', 'l37', 'l38', 'l39', 'l40', 'l41']", + "137, from ['l5', 'l13', 'l20', 'l26', 'l32', 'l37', 'l42', 'l43', 'l44', 'l45']", + "138, human ['l6', 'l14', 'l21', 'l27', 'l33', 'l38', 'l42', 'l46', 'l47', 'l48']", + "139, tumor ['l7', 'l15', 'l22', 'l28', 'l34', 'l39', 'l43', 'l46', 'l49', 'l50']", + "140, cells, ['l8', 'l16', 'l23', 'l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l51']", + "155, metastasis, ['l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l51']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "tumor", + "model", + "metastasis," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "liver", + "metastases", + "metastasis," + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "liver", + "metastases", + "metastasis," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "from", + "human", + "tumor", + "cells," + ] + } + } + ] + }, + { + "PMID": "11175856", + "TEXT": "Although the process of mammary tumorigenesis requires multiple genetic events, it is unclear to what extent carcinogenesis proceeds through preferred secondary pathways following a specific initiating oncogenic event. Similarly, the extent to which established mammary tumors remain dependent on individual mutations for maintenance of the transformed state is unknown. Here we use the tetracycline regulatory system to conditionally express the human c-MYC oncogene in the mammary epithelium of transgenic mice. MYC encodes a transcription factor implicated in multiple human cancers. In particular, amplification and overexpression of c-MYC in human breast cancers is associated with poor prognosis, although the genetic mechanisms by which c-MYC promotes tumor progression are poorly understood. We show that deregulated c-MYC expression in this inducible system results in the formation of invasive mammary adenocarcinomas, many of which fully regress following c-MYC deinduction. Approximately half of these tumors harbor spontaneous activating point mutations in the ras family of proto-oncogenes with a strong preference for Kras2 compared with Hras1. Nearly all tumors lacking activating ras mutations fully regressed following c-MYC deinduction, whereas tumors bearing ras mutations did not, suggesting that secondary mutations in ras contribute to tumor progression. These findings demonstrate that c-MYC-induced mammary tumorigenesis proceeds through a preferred secondary oncogenic pathway involving Kras2.", + "TAG_DATA": [ + "66, epithelium {'context': 'I-tissue/organ'}", + "68, transgenic {'context': 'B-organism'}", + "69, mice. {'context': 'I-organism'}", + "119, results {'effect': 'B-positive'}", + "125, mammary {'phenotype': 'B-tumourigenesis'}", + "126, adenocarcinomas, {'phenotype': 'I-tumourigenesis'}", + "139, tumors {'context': 'B-neoplasm'}", + "162, tumors {'context': 'B-neoplasm'}", + "173, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "65, mammary ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "66, epithelium ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "68, transgenic ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "69, mice. ['l2', 'l7', 'l11', 'l15', 'l16']", + "119, results ['l3', 'l8', 'l12', 'l15', 'l17', 'l18', 'l19']", + "125, mammary ['l4', 'l9', 'l13', 'l17', 'l20', 'l21']", + "126, adenocarcinomas, ['l5', 'l10', 'l14', 'l16', 'l18', 'l20', 'l22']", + "139, tumors ['l19', 'l21', 'l22']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "epithelium" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "epithelium" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "mammary", + "adenocarcinomas," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice." + ] + }, + "effect": { + "val": "positive", + "words": [ + "results" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "mammary", + "adenocarcinomas," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "mammary", + "adenocarcinomas," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "mammary", + "adenocarcinomas," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + } + ] + }, + { + "PMID": "11175851", + "TEXT": "The lymphatic vasculature transports extravasated tissue fluid, macromolecules and cells back into the blood circulation. Recent reports have focused on the molecular mechanisms regulating the lymphatic vessels. Vascular endothelial growth factor (VEGF)-C and VEGF-D have been shown to stimulate lymphangiogenesis and their receptor, VEGFR-3, has been linked to human hereditary lymphedema. Here we show that a soluble form of VEGFR-3 is a potent inhibitor of VEGF-C/VEGF-D signaling, and when expressed in the skin of transgenic mice, it inhibits fetal lymphangiogenesis and induces a regression of already formed lymphatic vessels, though the blood vasculature remains normal. Transgenic mice develop a lymphedema-like phenotype characterized by swelling of feet, edema and dermal fibrosis. They survive the neonatal period in spite of a virtually complete lack of lymphatic vessels in several tissues, and later show regeneration of the lymphatic vasculature, indicating that induction of lymphatic regeneration may also be possible in humans.", + "TAG_DATA": [ + "75, mice, {'context': 'I-organism'}", + "81, induces {'effect': 'B-positive'}", + "83, regression {'phenotype': 'B-tumour regression'}", + "96, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "72, skin ['l0', 'l1', 'l2', 'l3', 'l4']", + "75, mice, ['l0', 'l5', 'l6', 'l7', 'l8']", + "81, induces ['l1', 'l5', 'l9', 'l10', 'l11']", + "83, regression ['l2', 'l6', 'l9', 'l12', 'l13']", + "87, lymphatic ['l3', 'l7', 'l10', 'l12', 'l14']", + "88, vessels, ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + } + ] + }, + { + "PMID": "11175848", + "TEXT": "Antibacterial peptides are active defense components of innate immunity. Several studies confirm their importance at epithelial surfaces as immediate barrier effectors in preventing infection. Here we report that early in Shigella spp. infections, expression of the antibacterial peptides LL-37 and human beta-defensin-1 is reduced or turned off. The downregulation is detected in biopsies from patients with bacillary dysenteries and in Shigella- infected cell cultures of epithelial and monocyte origin. This downregulation of immediate defense effectors might promote bacterial adherence and invasion into host epithelium and could be an important virulence parameter. Analyses of bacterial molecules causing the downregulation indicate Shigella plasmid DNA as one mediator.", + "TAG_DATA": [ + "62, cell {'context': 'B-cells'}", + "63, cultures {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "62, cell ['l0', 'l1']", + "63, cultures ['l0', 'l2']", + "67, monocyte ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11135626", + "TEXT": "Relaxation of the smooth muscle cells in the cavernosal arterioles and sinuses results in increased blood flow into the penis, raising corpus cavernosum pressure to culminate in penile erection. Nitric oxide, released from non-adrenergic/non-cholinergic nerves, is considered the principle stimulator of cavernosal smooth muscle relaxation, however, the inhibition of vasoconstrictors (that is, norepinephrine and endothelin-1, refs. 5-9) cannot be ignored as a potential regulator of penile erection. The calcium-sensitizing rho-A/Rho-kinase pathway may play a synergistic role in cavernosal vasoconstriction to maintain penile flaccidity. Rho-kinase is known to inhibit myosin light chain phosphatase, and to directly phosphorylate myosin light-chain (in solution), altogether resulting in a net increase in activated myosin and the promotion of cellular contraction. Although Rho-kinase protein and mRNA have been detected in cavernosal tissue, the role of Rho-kinase in the regulation of cavernosal tone is unknown. Using pharmacologic antagonism (Y-27632, ref. 13, 18), we examined the role of Rho-kinase in cavernosal tone, based on the hypothesis that antagonism of Rho-kinase results in increased corpus cavernosum pressure, initiating the erectile response independently of nitric oxide. Our finding, that Rho-kinase antagonism stimulates rat penile erection independently of nitric oxide, introduces a potential alternate avenue for the treatment of erectile dysfunction.", + "TAG_DATA": [ + "159, antagonism {'perturbing_action': 'B-pharmacological inhibition'}", + "160, of {'perturbing_action': 'I-pharmacological inhibition'}", + "161, Rho-kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "179, Rho-kinase {'perturbing_action': 'B-pharmacological inhibition'}", + "180, antagonism {'perturbing_action': 'I-pharmacological inhibition'}", + "182, rat {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "159, antagonism ['l0', 'l1']", + "160, of ['l0', 'l2']", + "161, Rho-kinase ['l1', 'l2']", + "179, Rho-kinase ['l3', 'l4']", + "180, antagonism ['l3', 'l5']", + "182, rat ['l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Rho-kinase", + "antagonism" + ] + }, + "context": { + "val": "organism", + "words": [ + "rat" + ] + } + } + ] + }, + { + "PMID": "11135623", + "TEXT": "The transcription factor early growth response protein 1 (EGR1) is overexpressed in a majority of human prostate cancers and is implicated in the regulation of several genes important for prostate tumor progression. Here we have assessed the effect of Egr1 deficiency on tumor development in two transgenic mouse models of prostate cancer (CR2-T-Ag and TRAMP). Using a combination of high-resolution magnetic resonance imaging and histopathological and survival analyses, we show that tumor progression was significantly impaired in Egr1-/- mice. Tumor initiation and tumor growth rate were not affected by the lack of Egr1; however, Egr1 deficiency significantly delayed the progression from prostatic intra-epithelial neoplasia to invasive carcinoma. These results indicate a unique role for Egr1 in regulating the transition from localized, carcinoma in situ to invasive carcinoma.", + "TAG_DATA": [ + "39, Egr1 {'perturbing_action': 'B-gene loss-of-function'}", + "40, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "43, development {'phenotype': 'I-tumourigenesis'}", + "47, mouse {'context': 'I-organism'}", + "48, models {'context': 'I-neoplasm'}", + "49, of {'context': 'I-neoplasm'}", + "50, prostate {'context': 'I-neoplasm'}", + "51, cancer {'context': 'I-neoplasm'}", + "71, tumor {'phenotype': 'B-tumour progression'}", + "72, progression {'phenotype': 'I-tumour progression'}", + "75, impaired {'effect': 'B-negative'}", + "77, Egr1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "78, mice. {'context': 'B-organism'}", + "79, Tumor {'phenotype': 'B-tumour initiation'}", + "80, initiation {'phenotype': 'I-tumour initiation'}", + "82, tumor {'phenotype': 'B-tumour growth'}", + "83, growth {'phenotype': 'I-tumour growth'}", + "86, not {'effect': 'B-no effect'}", + "87, affected {'effect': 'I-no effect'}", + "90, lack {'perturbing_action': 'B-gene loss-of-function'}", + "91, of {'perturbing_action': 'I-gene loss-of-function'}", + "92, Egr1; {'perturbing_action': 'I-gene loss-of-function'}", + "94, Egr1 {'perturbing_action': 'B-gene loss-of-function'}", + "95, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "97, delayed {'effect': 'B-negative'}", + "102, intra-epithelial {'phenotype': 'I-epithelial-mesenchymal transition'}", + "103, neoplasia {'phenotype': 'I-epithelial-mesenchymal transition'}", + "105, invasive {'phenotype': 'B-tumourigenesis'}", + "106, carcinoma. {'phenotype': 'I-tumourigenesis'}" + ], + "LINK_DATA": [ + "39, Egr1 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "40, deficiency ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "43, development ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "47, mouse ['l2', 'l12', 'l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "48, models ['l3', 'l13', 'l22', 'l29', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "49, of ['l4', 'l14', 'l23', 'l30', 'l37', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "50, prostate ['l5', 'l15', 'l24', 'l31', 'l38', 'l44', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "51, cancer ['l6', 'l16', 'l25', 'l32', 'l39', 'l45', 'l50', 'l56', 'l57', 'l58', 'l59']", + "71, tumor ['l7', 'l17', 'l26', 'l33', 'l40', 'l46', 'l51', 'l56', 'l60', 'l61', 'l62']", + "72, progression ['l8', 'l18', 'l27', 'l34', 'l41', 'l47', 'l52', 'l57', 'l60', 'l63', 'l64']", + "75, impaired ['l9', 'l19', 'l28', 'l35', 'l42', 'l48', 'l53', 'l58', 'l61', 'l63', 'l65']", + "77, Egr1-/- ['l10', 'l20', 'l36', 'l43', 'l49', 'l54', 'l59', 'l62', 'l64', 'l65', 'l66']", + "78, mice. ['l55', 'l66']", + "79, Tumor ['l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "80, initiation ['l67', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "82, tumor ['l68', 'l78', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "83, growth ['l69', 'l79', 'l88', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "86, not ['l70', 'l80', 'l89', 'l97', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "87, affected ['l71', 'l81', 'l90', 'l98', 'l105', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "90, lack ['l72', 'l82', 'l91', 'l99', 'l106', 'l114', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "91, of ['l73', 'l83', 'l92', 'l100', 'l107', 'l115', 'l122', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "92, Egr1; ['l74', 'l84', 'l93', 'l101', 'l108', 'l116', 'l123', 'l129', 'l135', 'l136', 'l137']", + "94, Egr1 ['l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "95, deficiency ['l138', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150']", + "97, delayed ['l139', 'l145', 'l151', 'l152', 'l153', 'l154', 'l155']", + "101, prostatic ['l75', 'l85', 'l94', 'l102', 'l109', 'l117', 'l124', 'l130', 'l135', 'l140', 'l146', 'l151', 'l156', 'l157', 'l158', 'l159']", + "102, intra-epithelial ['l76', 'l86', 'l95', 'l103', 'l110', 'l118', 'l125', 'l131', 'l136', 'l141', 'l147', 'l152', 'l156', 'l160', 'l161', 'l162']", + "103, neoplasia ['l77', 'l87', 'l96', 'l104', 'l111', 'l119', 'l126', 'l132', 'l137', 'l142', 'l148', 'l153', 'l157', 'l160', 'l163', 'l164']", + "105, invasive ['l112', 'l120', 'l127', 'l133', 'l143', 'l149', 'l154', 'l158', 'l161', 'l163', 'l165']", + "106, carcinoma. ['l113', 'l121', 'l128', 'l134', 'l144', 'l150', 'l155', 'l159', 'l162', 'l164', 'l165']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Egr1", + "deficiency", + "lack", + "of" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development", + "invasive", + "carcinoma." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Egr1", + "deficiency", + "Egr1-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Egr1", + "deficiency", + "Egr1-/-" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models", + "of", + "prostate", + "cancer" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Egr1", + "deficiency", + "Egr1-/-" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Egr1", + "deficiency", + "Egr1-/-" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired", + "delayed" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models", + "of", + "prostate", + "cancer" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development", + "invasive", + "carcinoma." + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired", + "delayed" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "models", + "of", + "prostate", + "cancer" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "models", + "of", + "prostate", + "cancer" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "phenotype": { + "val": "tumour initiation", + "words": [ + "Tumor", + "initiation" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "affected" + ] + } + }, + { + "phenotype": { + "val": "tumour initiation", + "words": [ + "Tumor", + "initiation" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "Egr1;" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "affected" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "Egr1;" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "affected" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "Egr1;" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "affected" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "intra-epithelial", + "neoplasia" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "affected" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "invasive", + "carcinoma." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "Egr1;", + "Egr1", + "deficiency" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "intra-epithelial", + "neoplasia" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "delayed" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "intra-epithelial", + "neoplasia" + ] + } + } + ] + }, + { + "PMID": "11135620", + "TEXT": "Solid organ transplants contain small numbers of leukocytes that can migrate into the host and establish long-lasting microchimerism. Although such microchimerism is often associated with graft acceptance and tolerance, it has been difficult to demonstrate a true causal link. Using skin from mutant mice deficient for leukocyte subsets, we found that donor T-cell chimerism is a 'double-edged sword' that can result in very different outcomes depending on the host's immunological maturity and the antigenic disparities involved. In immunologically mature hosts, chimerism resulted in immunity and stronger graft rejection. In immature hosts, it resulted in tolerance to the chimeric T cells, but not to graft antigens not expressed by the chimeric cells. Clinical efforts aimed at augmenting chimerism to induce tolerance must take into account the maturation state of host T cells, the type of chimerism produced by each organ and the antigenic disparities involved, lest the result be increased rejection rather than tolerance.", + "TAG_DATA": [ + "40, skin {'context': 'B-tissue/organ'}", + "43, mice {'context': 'B-organism'}", + "89, immature {'context': 'B-organism'}", + "90, hosts, {'context': 'I-organism'}", + "97, chimeric {'context': 'B-cells'}", + "98, T {'context': 'I-cells'}", + "99, cells, {'context': 'I-cells'}", + "109, chimeric {'context': 'B-cells'}", + "110, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "40, skin ['l0']", + "43, mice ['l0']", + "89, immature ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "90, hosts, ['l1', 'l7', 'l8', 'l9', 'l10']", + "97, chimeric ['l2', 'l7', 'l11', 'l12', 'l13', 'l14']", + "98, T ['l3', 'l8', 'l11', 'l15', 'l16']", + "99, cells, ['l4', 'l9', 'l12', 'l15', 'l17']", + "109, chimeric ['l5', 'l13', 'l18']", + "110, cells. ['l6', 'l10', 'l14', 'l16', 'l17', 'l18']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11135616", + "TEXT": "Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate lipid and glucose metabolism and cellular differentiation. PPAR-alpha and PPAR-gamma are both expressed in human macrophages where they exert anti-inflammatory effects. The activation of PPAR-alpha may promote foam-cell formation by inducing expression of the macrophage scavenger receptor CD36. This prompted us to investigate the influence of different PPAR-activators on cholesterol metabolism and foam-cell formation of human primary and THP-1 macrophages. Here we show that PPAR-alpha and PPAR-gamma activators do not influence acetylated low density lipoprotein-induced foam-cell formation of human macrophages. In contrast, PPAR-alpha and PPAR-gamma activators induce the expression of the gene encoding ABCA1, a transporter that controls apoAI-mediated cholesterol efflux from macrophages. These effects are likely due to enhanced expression of liver-x-receptor alpha, an oxysterol-activated nuclear receptor which induces ABCA1-promoter transcription. Moreover, PPAR-alpha and PPAR-gamma activators increase apoAI-induced cholesterol efflux from normal macrophages. In contrast, PPAR-alpha or PPAR-gamma activation does not influence cholesterol efflux from macrophages isolated from patients with Tangier disease, which is due to a genetic defect in ABCA1. Here we identify a regulatory role for PPAR-alpha and PPAR-gamma in the first steps of the reverse-cholesterol-transport pathway through the activation of ABCA1-mediated cholesterol efflux in human macrophages.", + "TAG_DATA": [ + "73, PPAR-alpha {'perturbing_action': 'B-gene gain-of-function'}", + "74, and {'perturbing_action': 'I-pharmacological augmentation'}", + "75, PPAR-gamma {'perturbing_action': 'I-pharmacological augmentation'}", + "76, activators {'perturbing_action': 'I-pharmacological augmentation'}", + "78, not {'effect': 'I-no effect'}", + "79, influence {'effect': 'I-no effect'}", + "84, foam-cell {'phenotype': 'B-tumourigenesis'}", + "87, human {'context': 'B-cells'}", + "88, macrophages. {'context': 'I-cells'}", + "94, activators {'perturbing_action': 'I-pharmacological augmentation'}", + "135, activators {'perturbing_action': 'I-pharmacological augmentation'}", + "142, macrophages. {'context': 'B-cells'}", + "146, or {'perturbing_action': 'I-pharmacological augmentation'}", + "147, PPAR-gamma {'perturbing_action': 'I-pharmacological augmentation'}", + "148, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "155, macrophages {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "73, PPAR-alpha ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "74, and ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "75, PPAR-gamma ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "76, activators ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "78, not ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "79, influence ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "84, foam-cell ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "87, human ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "88, macrophages. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "91, PPAR-alpha ['l36']", + "94, activators ['l36']", + "135, activators ['l37']", + "142, macrophages. ['l37']", + "146, or ['l38', 'l39', 'l40']", + "147, PPAR-gamma ['l38', 'l41', 'l42']", + "148, activation ['l39', 'l41', 'l43']", + "155, macrophages ['l40', 'l42', 'l43']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PPAR-alpha" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "influence" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PPAR-alpha" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "foam-cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PPAR-alpha" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "macrophages." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "and", + "PPAR-gamma", + "activators" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "influence" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "and", + "PPAR-gamma", + "activators" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "foam-cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "and", + "PPAR-gamma", + "activators", + "or", + "activation" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "macrophages.", + "macrophages" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "influence" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "foam-cell" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "influence" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "macrophages." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "foam-cell" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "macrophages." + ] + } + } + ] + }, + { + "PMID": "11135610", + "TEXT": "A new investigation into Duchenne muscular dystrophy (DMD) pathogenesis suggests that at least part of the muscle degeneration observed in DMD patients may result from the reduced production of muscle membrane-associated neuronal nitric oxide synthase. This reduction may lead to impaired regulation of the vasoconstrictor response and eventual muscle damage.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11135605", + "TEXT": "Identification of HIV-1 variants capable of entering T cells via the CD8 receptor suggests a new mode of viral pathogenesis. But are these variants rare, aberrant viruses or a real problem?", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11135603", + "TEXT": "The clot-busting drug tissue plasminogen activator (tPA) is currently the only FDA-approved therapy for acute stroke. However, increasing evidence suggests that tPA can also contribute to excitotoxic neuronal damage in animal models of stroke.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11100129", + "TEXT": "Recent progress in molecular medicine has provided important tools to identify antigen-specific T cells. In most cases, the approach is based on oligomeric combinations of recombinant major histocompatibility complex-peptide complexes fixed to various rigid supports available for binding by the T-cell receptor. These tools have greatly increased our insight into mechanisms of immune responses mediated by CD8+ T cells. Examples of the diverse fields of application for this technology include immunization, viral infections and oral tolerance induction.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11100126", + "TEXT": "Modern treatment of cardiac arrhythmias is limited to pharmacotherapy, radiofrequency ablation, or implantable devices. Antiarrhythmic medications suppress arrhythmias, but their systemic effects are often poorly tolerated and their proarrhythmic tendencies increase mortality. Radiofrequency ablation can cure only a limited number of arrhythmias. Implantable devices can be curative for bradyarrhythmias and lifesaving for tachyarrhythmias, but require a lifetime commitment to repeated procedures, are a significant expense, and may lead to severe complications. One possibility is the use of gene therapy as an antiarrhythmic strategy. As an initial attempt to explore this option, we focused on genetic modification of the atrioventricular node. First, we developed an intracoronary perfusion model for gene delivery, building on our previous work in isolated cardiac myocytes and hearts perfused ex vivo. Using this method, we infected porcine hearts with Adbetagal (recombinant adenovirus expressing Escherichia coli beta-galactosidase) or with AdGi (adenovirus encoding the Galphai2 subunit). We hypothesized that excess Galphai2 would mimic the effects of beta-adreneric antagonists, in effect creating a localized beta-blockade. Galphai2 overexpression suppressed baseline atrioventricular conduction and slowed the heart rate during atrial fibrillation without producing complete heart block. In contrast, expression of the reporter gene beta-galactosidase had no electrophysiological effects. Our results demonstrate the feasibility of using myocardial gene transfer strategies to treat common arrhythmias.", + "TAG_DATA": [ + "117, cardiac {'context': 'B-cells'}", + "118, myocytes {'context': 'I-cells'}", + "120, hearts {'context': 'B-tissue/organ'}", + "129, porcine {'context': 'B-tissue/organ'}", + "130, hearts {'context': 'I-tissue/organ'}", + "165, Galphai2 {'perturbing_action': 'B-gene gain-of-function'}", + "166, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "186, expression {'perturbing_action': 'B-gene gain-of-function'}", + "187, of {'perturbing_action': 'I-gene gain-of-function'}", + "188, the {'perturbing_action': 'I-gene gain-of-function'}", + "189, reporter {'perturbing_action': 'I-gene gain-of-function'}", + "190, gene {'perturbing_action': 'I-gene gain-of-function'}", + "191, beta-galactosidase {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "117, cardiac ['l0', 'l1']", + "118, myocytes ['l0', 'l2']", + "120, hearts ['l1', 'l2', 'l3', 'l4']", + "129, porcine ['l3', 'l5']", + "130, hearts ['l4', 'l5']", + "165, Galphai2 ['l6']", + "166, overexpression ['l6']", + "186, expression ['l7', 'l8', 'l9', 'l10', 'l11']", + "187, of ['l7', 'l12', 'l13', 'l14', 'l15']", + "188, the ['l8', 'l12', 'l16', 'l17', 'l18']", + "189, reporter ['l9', 'l13', 'l16', 'l19', 'l20']", + "190, gene ['l10', 'l14', 'l17', 'l19', 'l21']", + "191, beta-galactosidase ['l11', 'l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11100122", + "TEXT": "Ovulatory dysfunction is the commonest cause of female infertility. Here we show that the co-repressor nuclear-receptor-interacting protein 1 (Nrip1; encoded by the gene Nrip1) is essential for ovulation. Mice null for this protein are viable, but female mice are infertile because of complete failure of mature follicles to release the oocyte at ovulation. In contrast, luteinization proceeds normally, resulting in a phenotype closely resembling that of luteinized unruptured follicle syndrome, often associated with infertility in women. Therefore, whereas the pre-ovulatory surge of luteinizing hormone induces both ovulation and luteinization, the ability to suppress the action of nuclear receptors is essential for the coordinated control of ovarian function with the essential process of oocyte release dependent on the activity of the transcriptional co-repressor Nrip1 (RIP40).", + "TAG_DATA": [ + "28, Mice {'context': 'B-organism'}", + "29, null {'perturbing_action': 'B-gene loss-of-function'}", + "30, for {'perturbing_action': 'I-gene loss-of-function'}", + "36, female {'context': 'B-organism'}", + "37, mice {'context': 'I-organism'}", + "45, mature {'context': 'B-cells'}", + "46, follicles {'context': 'I-cells'}", + "84, induces {'effect': 'B-positive'}" + ], + "LINK_DATA": [ + "28, Mice ['l0', 'l1', 'l2', 'l3']", + "29, null ['l0', 'l4', 'l5', 'l6']", + "30, for ['l1', 'l4', 'l7', 'l8']", + "36, female ['l9', 'l10', 'l11']", + "37, mice ['l9', 'l12', 'l13']", + "45, mature ['l2', 'l5', 'l7', 'l10', 'l12', 'l14']", + "46, follicles ['l3', 'l6', 'l8', 'l11', 'l13', 'l14']", + "84, induces ['l15']", + "88, luteinization, ['l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "null", + "for" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "null", + "for" + ] + }, + "context": { + "val": "cells", + "words": [ + "mature", + "follicles" + ] + } + } + ] + }, + { + "PMID": "11062540", + "TEXT": "The pathogenic bacterium Neisseria meningitidis is an important cause of septicemia and meningitis, especially in childhood. The establishment and maintenance of bacteremic infection is a pre-requisite for all the pathological sequelae of meningococcal infection. To further understand the genetic basis of this essential step in pathogenesis, we analyzed a library of 2,850 insertional mutants of N. meningitidis for their capacity to cause systemic infection in an infant rat model. The library was constructed by in vitro modification of Neisseria genomic DNA with the purified components of Tn10 transposition. We identified 73 genes in the N. meningitidis genome that are essential for bacteremic disease. Eight insertions were in genes encoding known pathogenicity factors. Involvement of the remaining 65 genes in meningocoocal pathogenesis has not been demonstrated previously, and the identification of these genes provides insights into the pathogenic mechanisms that underlie meningococcal infection. Our results provide a genome-wide analysis of the attributes of N. meningitidis required for disseminated infection, and may lead to new interventions to prevent and treat meningococcal infection.", + "TAG_DATA": [ + "66, infant {'context': 'B-organism'}", + "67, rat {'context': 'I-organism'}", + "68, model. {'context': 'I-organism'}", + "74, in {'context': 'B-in vitro'}", + "75, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "66, infant ['l0', 'l1']", + "67, rat ['l0', 'l2']", + "68, model. ['l1', 'l2']", + "74, in ['l3']", + "75, vitro ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11062539", + "TEXT": "A common pathological characteristic of Plasmodium falciparum infection is the cytoadhesion of mature-stage-infected erythrocytes (IE) to host endothelium and syncytiotrophoblasts. Massive accumulation of IE in the brain microvasculature or placenta is strongly correlated with severe forms of malaria. Extensive binding of IE to placental chondroitin sulfate A (CSA) is associated with physiopathology during pregnancy. The adhesive phenotype of IE correlates with the appearance of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) at the erythrocyte surface (approximately 16 h after merozoite invasion), so that only early blood-stage (ring-stage) IE appear in the peripheral blood. Here, we describe results that challenge the existing view of blood-stage IE biology by demonstrating the specific adhesion of IE, during the early ring-stage, to endothelial cell lines from the brain and lung and to placental syncytiotrophoblasts. Later, during blood-stage development of these IE, trophozoites switch to an exclusively CSA cytoadhesion phenotype. Therefore, adhesion to an individual endothelial cell or syncytiotrophoblast may occur throughout the blood-stage cycle, indicating the presence in malaria patients of noncirculating (cryptic) parasite subpopulations. We detected two previously unknown parasite proteins on the surface of ring-stage IE. These proteins disappear shortly after the start of PfEMP1-mediated adhesion.", + "TAG_DATA": [ + "118, endothelial {'context': 'B-cells'}", + "119, cell {'context': 'I-cells'}", + "120, lines {'context': 'I-cells'}", + "121, from {'context': 'I-cells'}", + "122, the {'context': 'I-cells'}", + "123, brain {'context': 'I-cells'}", + "124, and {'context': 'I-cells'}", + "125, lung {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "118, endothelial ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "119, cell ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "120, lines ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "121, from ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "122, the ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "123, brain ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "124, and ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "125, lung ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11062536", + "TEXT": "We covalently linked doxorubicin with a peptide that is hydrolyzable by prostate-specific antigen. In the presence of prostate tumor cells secreting prostate-specific antigen, the peptide moiety of this conjugate, L-377,202, was hydrolyzed, resulting in the release of leucine-doxorubicin and doxorubicin, which are both very cytotoxic to cancer cells. However, L-377,202 was much less cytotoxic than conventional doxorubicin to cells in culture that do not secrete prostate-specific antigen. L-377,202 was approximately 15 times more effective than was conventional doxorubicin at inhibiting the growth of human prostate cancer tumors in nude mice when both drugs were used at their maximally tolerated doses. Nude mice inoculated with human prostate tumor cells secreting prostate-specific antigen showed considerable reductions in tumor burden with minimal total body weight loss when treated with L-377, 202. This improvement in therapeutic index correlated with the selective localization of leucine-doxorubicin and free doxorubicin in tissues secreting prostate-specific antigen after exposure to L-377,202.", + "TAG_DATA": [ + "58, cells {'context': 'B-cells'}", + "60, culture {'context': 'I-cells'}", + "83, human {'context': 'B-neoplasm'}", + "84, prostate {'context': 'I-neoplasm'}", + "85, cancer {'context': 'I-neoplasm'}", + "86, tumors {'context': 'I-neoplasm'}", + "88, nude {'context': 'B-organism'}", + "89, mice {'context': 'I-organism'}", + "100, Nude {'context': 'B-organism'}", + "101, mice {'context': 'I-organism'}", + "104, human {'context': 'B-transformed cells'}", + "105, prostate {'context': 'I-transformed cells'}", + "106, tumor {'context': 'I-transformed cells'}", + "107, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "58, cells ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "60, culture ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "83, human ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "84, prostate ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "85, cancer ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "86, tumors ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "88, nude ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "89, mice ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "100, Nude ['l28', 'l29', 'l30', 'l31', 'l32']", + "101, mice ['l28', 'l33', 'l34', 'l35', 'l36']", + "104, human ['l29', 'l33', 'l37', 'l38', 'l39']", + "105, prostate ['l30', 'l34', 'l37', 'l40', 'l41']", + "106, tumor ['l31', 'l35', 'l38', 'l40', 'l42']", + "107, cells ['l32', 'l36', 'l39', 'l41', 'l42']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11017149", + "TEXT": "The breaking of immune tolerance against autologous angiogenic endothelial cells should be a useful approach for cancer therapy. Here we show that immunotherapy of tumors using fixed xenogeneic whole endothelial cells as a vaccine was effective in affording protection from tumor growth, inducing regression of established tumors and prolonging survival of tumor-bearing mice. Furthermore, autoreactive immunity targeting to microvessels in solid tumors was induced and was probably responsible for the anti-tumor activity. These observations may provide a new vaccine strategy for cancer therapy through the induction of an autoimmune response against the tumor endothelium in a cross-reaction.", + "TAG_DATA": [ + "38, protection {'effect': 'B-negative'}", + "40, tumor {'phenotype': 'B-tumour growth'}", + "41, growth, {'phenotype': 'I-tumour growth'}", + "42, inducing {'effect': 'B-positive'}", + "43, regression {'phenotype': 'B-tumour regression'}", + "44, of {'phenotype': 'I-tumour regression'}", + "45, established {'phenotype': 'I-tumour growth'}", + "46, tumors {'context': 'B-neoplasm'}", + "51, tumor-bearing {'context': 'B-organism'}", + "52, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "38, protection ['l0', 'l1']", + "40, tumor ['l0', 'l2']", + "41, growth, ['l1', 'l2']", + "42, inducing ['l3', 'l4', 'l5', 'l6']", + "43, regression ['l3', 'l7', 'l8', 'l9']", + "44, of ['l4', 'l7', 'l10', 'l11']", + "45, established ['l5', 'l8', 'l10', 'l12']", + "46, tumors ['l6', 'l9', 'l11', 'l12']", + "51, tumor-bearing ['l13']", + "52, mice. ['l13']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "protection" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression", + "of" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "established" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression", + "of" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "established" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + } + ] + }, + { + "PMID": "11017146", + "TEXT": "Prolonged antiretroviral therapy (ART) is not likely to eradicate human immunodeficiency virus type I (HIV-I) infection. Here we explore the effect of therapeutic immunization in the context of ART during primary infection using the simian immunodeficiency virus (SIV251) macaque model. Vaccination of rhesus macaques with the highly attenuated poxvirus-based NYVAC-SIV vaccine expressing structural genes elicited vigorous virus-specific CD4 + and CD8+ T cell responses in macaques that responded effectively to ART. Following discontinuation of a six-month ART regimen, viral rebound occurred in most animals, but was transient in six of eight vaccinated animals. Viral rebound was also transient in four of seven mock-vaccinated control animals. These data establish the importance of antiretroviral treatment during primary infection and demonstrate that virus-specific immune responses in the infected host can be expanded by therapeutic immunization.", + "TAG_DATA": [ + "42, rhesus {'context': 'B-organism'}", + "43, macaques {'context': 'I-organism'}", + "65, macaques {'context': 'B-organism'}", + "83, animals, {'context': 'B-organism'}", + "92, animals. {'context': 'B-organism'}", + "104, animals. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "42, rhesus ['l0', 'l1', 'l2', 'l3']", + "43, macaques ['l0', 'l4', 'l5']", + "65, macaques ['l1', 'l4', 'l6']", + "83, animals, ['l2', 'l5', 'l6', 'l7']", + "92, animals. ['l3', 'l7']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11017143", + "TEXT": "Kaposi sarcoma-associated herpesvirus (KSHV) is involved in the etiopathogenesis of Kaposi sar-coma and certain lymphoproliferative disorders. Open reading frame (ORF) 73 encodes the main immunogenic latent nuclear antigen (LNA-1) of KSHV. LNA-1 maintains the KSHV episome and tethers the viral genome to chromatin during mitosis. In addition, LNA-1 interacts with p53 and represses its transcriptional activity. Here we show that LNA-1 also interacts with the retinoblastoma protein. LNA-1 transactivated an artificial promoter carrying the cell cycle transcription factor E2F DNA-binding sequences and also upregulated the cyclin E (CCNEI) promoter, but not the B-myb (MYBL2) promoter. LNA-1 overcame the flat-cell phenotype induced by retinoblastoma protein in Saos2 cells. In cooperation with the cellular oncogene Harvey rat sarcoma viral oncogene homolog (Hras), LNA-1 transformed primary rat embryo fibroblasts and rendered them tumorigenic. These findings indicate that LNA-1 acts as a transcription co-factor and may contribute to KSHV-induced oncogenesis by targeting the retinoblastoma protein-E2F transcriptional regulatory pathway.", + "TAG_DATA": [ + "105, Saos2 {'context': 'B-cells'}", + "106, cells. {'context': 'I-cells'}", + "122, primary {'context': 'B-cells'}", + "123, rat {'context': 'I-cells'}", + "124, embryo {'context': 'I-cells'}", + "125, fibroblasts {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "105, Saos2 ['l0']", + "106, cells. ['l0']", + "122, primary ['l1', 'l2', 'l3']", + "123, rat ['l1', 'l4', 'l5']", + "124, embryo ['l2', 'l4', 'l6']", + "125, fibroblasts ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11017141", + "TEXT": "The time at which ovarian failure (menopause) occurs in females is determined by the size of the oocyte reserve provided at birth, as well as by the rate at which this endowment is depleted throughout post-natal life. Here we show that disruption of the gene for acid sphingomyelinase in female mice suppressed the normal apoptotic deletion of fetal oocytes, leading to neonatal ovarian hyperplasia. Ex vivo, oocytes lacking the gene for acid sphingomyelinase or wild-type oocytes treated with sphingosine-1-phosphate resisted developmental apoptosis and apoptosis induced by anti-cancer therapy, confirming cell autonomy of the death defect. Moreover, radiation-induced oocyte loss in adult wild-type female mice, the event that drives premature ovarian failure and infertility in female cancer patients, was completely prevented by in vivo therapy with sphingosine-1-phosphate. Thus, the sphingomyelin pathway regulates developmental death of oocytes, and sphingosine-1-phosphate provides a new approach to preserve ovarian function in vivo.", + "TAG_DATA": [ + "41, disruption {'perturbing_action': 'B-gene loss-of-function'}", + "42, of {'perturbing_action': 'I-gene loss-of-function'}", + "43, the {'perturbing_action': 'I-gene loss-of-function'}", + "44, gene {'perturbing_action': 'I-gene loss-of-function'}", + "45, for {'perturbing_action': 'I-gene loss-of-function'}", + "46, acid {'perturbing_action': 'I-gene loss-of-function'}", + "47, sphingomyelinase {'perturbing_action': 'I-gene loss-of-function'}", + "49, female {'context': 'B-organism'}", + "50, mice {'context': 'I-organism'}", + "51, suppressed {'effect': 'B-negative'}", + "55, deletion {'phenotype': 'I-apoptosis'}", + "57, fetal {'context': 'B-cells'}", + "58, oocytes, {'context': 'I-cells'}", + "66, oocytes {'context': 'B-cells'}", + "67, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "68, the {'perturbing_action': 'I-gene loss-of-function'}", + "69, gene {'perturbing_action': 'I-gene loss-of-function'}", + "70, for {'perturbing_action': 'I-gene loss-of-function'}", + "71, acid {'perturbing_action': 'I-gene loss-of-function'}", + "72, sphingomyelinase {'perturbing_action': 'I-gene loss-of-function'}", + "75, oocytes {'context': 'B-cells'}", + "79, resisted {'effect': 'B-negative'}", + "81, apoptosis {'phenotype': 'B-apoptosis'}", + "83, apoptosis {'phenotype': 'B-apoptosis'}", + "84, induced {'effect': 'B-positive'}", + "97, oocyte {'context': 'B-cells'}", + "100, adult {'context': 'B-organism'}", + "101, wild-type {'context': 'I-organism'}", + "102, female {'context': 'I-organism'}", + "103, mice, {'context': 'I-organism'}", + "121, in {'context': 'B-in vivo'}", + "122, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "41, disruption ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "42, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "43, the ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "44, gene ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "45, for ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "46, acid ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "47, sphingomyelinase ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "49, female ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "50, mice ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79']", + "51, suppressed ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l81', 'l82', 'l83']", + "54, apoptotic ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l80', 'l84', 'l85', 'l86']", + "55, deletion ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l77', 'l81', 'l84', 'l87', 'l88']", + "57, fetal ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l78', 'l82', 'l85', 'l87', 'l89']", + "58, oocytes, ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l79', 'l83', 'l86', 'l88', 'l89']", + "66, oocytes ['l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "67, lacking ['l90', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "68, the ['l91', 'l101', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "69, gene ['l92', 'l102', 'l111', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127']", + "70, for ['l93', 'l103', 'l112', 'l120', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "71, acid ['l94', 'l104', 'l113', 'l121', 'l128', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "72, sphingomyelinase ['l95', 'l105', 'l114', 'l122', 'l129', 'l135', 'l141', 'l142', 'l143', 'l144', 'l145']", + "75, oocytes ['l96', 'l106', 'l115', 'l123', 'l130', 'l136', 'l141', 'l146', 'l147', 'l148', 'l149']", + "79, resisted ['l97', 'l107', 'l116', 'l124', 'l131', 'l137', 'l142', 'l146', 'l150', 'l151', 'l152']", + "81, apoptosis ['l98', 'l108', 'l117', 'l125', 'l132', 'l138', 'l143', 'l147', 'l150', 'l153', 'l154']", + "83, apoptosis ['l99', 'l109', 'l118', 'l126', 'l133', 'l139', 'l144', 'l148', 'l151', 'l153', 'l155']", + "84, induced ['l100', 'l110', 'l119', 'l127', 'l134', 'l140', 'l145', 'l149', 'l152', 'l154', 'l155']", + "97, oocyte ['l156', 'l157', 'l158', 'l159']", + "100, adult ['l156', 'l160', 'l161', 'l162']", + "101, wild-type ['l157', 'l160', 'l163', 'l164']", + "102, female ['l158', 'l161', 'l163', 'l165']", + "103, mice, ['l159', 'l162', 'l164', 'l165']", + "121, in ['l166']", + "122, vivo ['l166']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "disruption", + "of", + "the", + "gene", + "for", + "acid", + "sphingomyelinase" + ] + }, + "context": { + "val": "organism", + "words": [ + "female", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "disruption", + "of", + "the", + "gene", + "for", + "acid", + "sphingomyelinase", + "lacking" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed", + "resisted" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "disruption", + "of", + "the", + "gene", + "for", + "acid", + "sphingomyelinase", + "lacking" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "deletion", + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "disruption", + "of", + "the", + "gene", + "for", + "acid", + "sphingomyelinase", + "lacking" + ] + }, + "context": { + "val": "cells", + "words": [ + "fetal", + "oocytes,", + "oocytes" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "female", + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "female", + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "deletion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed", + "resisted" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "deletion", + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed", + "resisted" + ] + }, + "context": { + "val": "cells", + "words": [ + "fetal", + "oocytes,", + "oocytes" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "deletion", + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "fetal", + "oocytes,", + "oocytes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "oocytes" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "gene", + "for", + "acid", + "sphingomyelinase" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "10973323", + "TEXT": "A combination of two drugs afforded remarkable protection from intestinal neoplasia in APC(Min/+) mice, a murine model of human familial adenomatous polyposis (FAP). One of the drugs was sulindac, a prototypical non-steroidal anti-inflammatory drug with established chemopreventative activity. The second drug was EKI-569, a newly developed, irreversible inhibitor of the epidermal growth factor receptor kinase. Although 100% of the untreated APC(Min/+) mice developed approximately 20 polyps, nearly half the mice treated with these two agents developed no polyps at all. These results suggest a powerful strategy for the chemoprevention of human colonic neoplasia.", + "TAG_DATA": [ + "7, protection {'effect': 'B-negative'}", + "10, neoplasia {'phenotype': 'B-tumourigenesis'}", + "12, APC(Min/+) {'perturbing_action': 'B-other'}", + "13, mice, {'context': 'B-organism'}", + "60, APC(Min/+) {'perturbing_action': 'B-gene loss-of-function'}", + "61, mice {'context': 'B-organism'}", + "69, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "7, protection ['l0', 'l1', 'l2', 'l3']", + "9, intestinal ['l0', 'l4', 'l5', 'l6']", + "10, neoplasia ['l1', 'l4', 'l7', 'l8']", + "12, APC(Min/+) ['l2', 'l5', 'l7', 'l9', 'l10', 'l11']", + "13, mice, ['l3', 'l6', 'l8', 'l9']", + "60, APC(Min/+) ['l10', 'l12', 'l13']", + "61, mice ['l11', 'l12']", + "69, mice ['l13']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "protection" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasia" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "protection" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "APC(Min/+)" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "protection" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasia" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "APC(Min/+)" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasia" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "APC(Min/+)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "APC(Min/+)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "10973321", + "TEXT": "The polypeptide component of telomerase (TERT) is an attractive candidate for a broadly expressed tumor rejection antigen because telomerase is silent in normal tissues but is reactivated in more than 85% of cancers. Here we show that immunization against TERT induces immunity against tumors of unrelated origin. Immunization of mice with TERT RNA-transfected dendritic cells (DC) stimulated cytotoxic T lymphocytes (CTL), which lysed melanoma and thymoma tumor cells and inhibited the growth of three unrelated tumors in mice of distinct genetic backgrounds. TERT RNA-transfected human DC stimulated TERT-specific CTL in vitro that lysed human tumor cells, including Epstein Barr virus (EBV)-transformed B cells as well as autologous tumor targets from patients with renal and prostate cancer. Tumor RNA-transfected DC were used as surrogate targets in the CTL assays, obviating the difficulties in obtaining tumor cells from cancer patients. In one instance, where a tumor cell line was successfully established in culture from a patient with renal cancer, the patient's tumor cells were efficiently lysed by the CTL. Immunization with tumor RNA was generally more effective than immunization with TERT RNA, suggesting that an optimal immunization protocol may have to include TERT as well as additional tumor antigens.", + "TAG_DATA": [ + "49, mice {'context': 'B-organism'}", + "51, TERT {'perturbing_action': 'B-gene gain-of-function'}", + "52, RNA-transfected {'perturbing_action': 'I-gene gain-of-function'}", + "53, dendritic {'context': 'B-cells'}", + "54, cells {'context': 'I-cells'}", + "55, (DC) {'context': 'I-cells'}", + "63, melanoma {'context': 'B-transformed cells'}", + "65, thymoma {'context': 'B-transformed cells'}", + "66, tumor {'context': 'I-transformed cells'}", + "67, cells {'context': 'I-transformed cells'}", + "75, tumors {'context': 'I-neoplasm'}", + "77, mice {'context': 'B-organism'}", + "82, TERT {'perturbing_action': 'B-gene gain-of-function'}", + "83, RNA-transfected {'perturbing_action': 'I-gene gain-of-function'}", + "84, human {'context': 'B-cells'}", + "85, DC {'context': 'I-cells'}", + "89, in {'context': 'B-in vitro'}", + "90, vitro {'context': 'I-in vitro'}", + "93, human {'context': 'B-transformed cells'}", + "94, tumor {'context': 'I-transformed cells'}", + "95, cells, {'context': 'I-transformed cells'}", + "97, Epstein {'context': 'B-transformed cells'}", + "98, Barr {'context': 'B-transformed cells'}", + "99, virus {'context': 'I-transformed cells'}", + "100, (EBV)-transformed {'context': 'I-transformed cells'}", + "101, B {'context': 'I-transformed cells'}", + "102, cells {'context': 'I-transformed cells'}", + "106, autologous {'context': 'B-neoplasm'}", + "107, tumor {'context': 'I-transformed cells'}", + "108, targets {'context': 'I-transformed cells'}", + "110, patients {'context': 'B-patient'}", + "112, renal {'context': 'I-neoplasm'}", + "113, and {'context': 'I-neoplasm'}", + "114, prostate {'context': 'I-neoplasm'}", + "115, cancer. {'context': 'I-neoplasm'}", + "118, DC {'context': 'B-cells'}", + "143, tumor {'context': 'B-transformed cells'}", + "144, cell {'context': 'I-transformed cells'}", + "145, line {'context': 'I-transformed cells'}", + "153, patient {'context': 'B-patient'}", + "158, patient's {'context': 'B-transformed cells'}", + "159, tumor {'context': 'I-transformed cells'}", + "160, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "49, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "51, TERT ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "52, RNA-transfected ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "53, dendritic ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "54, cells ['l3', 'l13', 'l22', 'l30', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "55, (DC) ['l4', 'l14', 'l23', 'l31', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "63, melanoma ['l5', 'l15', 'l24', 'l32', 'l40', 'l46', 'l52', 'l53', 'l54', 'l55', 'l56']", + "65, thymoma ['l6', 'l16', 'l25', 'l33', 'l41', 'l47', 'l52', 'l57', 'l58', 'l59', 'l60']", + "66, tumor ['l7', 'l17', 'l26', 'l34', 'l42', 'l48', 'l53', 'l57', 'l61', 'l62']", + "67, cells ['l8', 'l18', 'l27', 'l35', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63']", + "75, tumors ['l9', 'l19', 'l28', 'l36', 'l44', 'l50', 'l55', 'l59', 'l62', 'l63', 'l64']", + "77, mice ['l10', 'l20', 'l29', 'l37', 'l45', 'l51', 'l56', 'l60', 'l64']", + "82, TERT ['l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "83, RNA-transfected ['l65', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "84, human ['l66', 'l88', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "85, DC ['l67', 'l89', 'l110', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150']", + "89, in ['l68', 'l90', 'l111', 'l131', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "90, vitro ['l69', 'l91', 'l112', 'l132', 'l151', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "93, human ['l70', 'l92', 'l113', 'l133', 'l152', 'l170', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "94, tumor ['l71', 'l93', 'l114', 'l134', 'l153', 'l171', 'l188', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220']", + "95, cells, ['l72', 'l94', 'l115', 'l135', 'l154', 'l172', 'l189', 'l205', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235']", + "97, Epstein ['l73', 'l95', 'l116', 'l136', 'l155', 'l173', 'l190', 'l206', 'l221', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249']", + "98, Barr ['l74', 'l96', 'l117', 'l137', 'l156', 'l174', 'l191', 'l207', 'l222', 'l236', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265']", + "99, virus ['l75', 'l97', 'l118', 'l138', 'l157', 'l175', 'l192', 'l208', 'l223', 'l237', 'l250', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280']", + "100, (EBV)-transformed ['l76', 'l98', 'l119', 'l139', 'l158', 'l176', 'l193', 'l209', 'l224', 'l238', 'l251', 'l266', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294']", + "101, B ['l77', 'l99', 'l120', 'l140', 'l159', 'l177', 'l194', 'l210', 'l225', 'l239', 'l252', 'l267', 'l281', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304']", + "102, cells ['l38', 'l78', 'l100', 'l121', 'l141', 'l160', 'l178', 'l195', 'l211', 'l226', 'l240', 'l253', 'l268', 'l282', 'l295', 'l305', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311', 'l312', 'l313']", + "106, autologous ['l79', 'l101', 'l122', 'l142', 'l161', 'l179', 'l196', 'l212', 'l227', 'l241', 'l254', 'l269', 'l283', 'l296', 'l305', 'l314', 'l315', 'l316', 'l317', 'l318', 'l319', 'l320', 'l321', 'l322', 'l323']", + "107, tumor ['l80', 'l102', 'l123', 'l143', 'l162', 'l180', 'l197', 'l213', 'l228', 'l242', 'l255', 'l270', 'l284', 'l297', 'l306', 'l314', 'l324', 'l325', 'l326', 'l327', 'l328', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334']", + "108, targets ['l81', 'l103', 'l124', 'l144', 'l163', 'l181', 'l198', 'l214', 'l229', 'l243', 'l256', 'l271', 'l285', 'l298', 'l307', 'l315', 'l324', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340']", + "110, patients ['l82', 'l104', 'l125', 'l145', 'l164', 'l182', 'l199', 'l215', 'l230', 'l244', 'l257', 'l272', 'l286', 'l299', 'l308', 'l316', 'l325', 'l335', 'l341', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348', 'l349', 'l350', 'l351', 'l352', 'l353']", + "111, with ['l83', 'l105', 'l126', 'l146', 'l165', 'l183', 'l200', 'l216', 'l231', 'l245', 'l258', 'l273', 'l287', 'l300', 'l309', 'l317', 'l326', 'l336', 'l341', 'l354', 'l355', 'l356', 'l357', 'l358', 'l359', 'l360', 'l361', 'l362', 'l363', 'l364', 'l365']", + "112, renal ['l84', 'l106', 'l127', 'l147', 'l166', 'l184', 'l201', 'l217', 'l232', 'l246', 'l259', 'l274', 'l288', 'l301', 'l310', 'l318', 'l327', 'l337', 'l342', 'l354', 'l366', 'l367', 'l368', 'l369', 'l370', 'l371', 'l372', 'l373', 'l374', 'l375', 'l376']", + "113, and ['l85', 'l107', 'l128', 'l148', 'l167', 'l185', 'l202', 'l218', 'l233', 'l247', 'l260', 'l275', 'l289', 'l302', 'l311', 'l319', 'l328', 'l338', 'l343', 'l355', 'l366', 'l377', 'l378', 'l379', 'l380', 'l381', 'l382', 'l383', 'l384', 'l385', 'l386']", + "114, prostate ['l86', 'l108', 'l129', 'l149', 'l168', 'l186', 'l203', 'l219', 'l234', 'l248', 'l261', 'l276', 'l290', 'l303', 'l312', 'l320', 'l329', 'l339', 'l344', 'l356', 'l367', 'l377', 'l387', 'l388', 'l389', 'l390', 'l391', 'l392', 'l393', 'l394', 'l395']", + "115, cancer. ['l87', 'l109', 'l130', 'l150', 'l169', 'l187', 'l204', 'l220', 'l235', 'l249', 'l262', 'l277', 'l291', 'l304', 'l313', 'l321', 'l330', 'l340', 'l345', 'l357', 'l368', 'l378', 'l387', 'l396', 'l397', 'l398', 'l399', 'l400', 'l401', 'l402']", + "118, DC ['l331', 'l346', 'l358', 'l369', 'l379', 'l388', 'l396', 'l403', 'l404', 'l405', 'l406', 'l407', 'l408', 'l409', 'l410', 'l411']", + "143, tumor ['l347', 'l359', 'l370', 'l380', 'l389', 'l397', 'l403', 'l412', 'l413', 'l414', 'l415', 'l416', 'l417', 'l418', 'l419']", + "144, cell ['l263', 'l278', 'l292', 'l322', 'l332', 'l348', 'l360', 'l371', 'l381', 'l390', 'l398', 'l404', 'l412', 'l420', 'l421', 'l422', 'l423', 'l424', 'l425', 'l426']", + "145, line ['l264', 'l279', 'l293', 'l323', 'l333', 'l349', 'l361', 'l372', 'l382', 'l391', 'l399', 'l405', 'l413', 'l420', 'l427', 'l428', 'l429', 'l430', 'l431', 'l432']", + "153, patient ['l350', 'l362', 'l373', 'l383', 'l392', 'l400', 'l406', 'l414', 'l421', 'l427', 'l433', 'l434', 'l435', 'l436', 'l437']", + "155, renal ['l351', 'l363', 'l374', 'l384', 'l393', 'l401', 'l407', 'l415', 'l422', 'l428', 'l433', 'l438', 'l439', 'l440', 'l441']", + "156, cancer, ['l265', 'l280', 'l294', 'l334', 'l352', 'l364', 'l375', 'l385', 'l394', 'l402', 'l408', 'l416', 'l423', 'l429', 'l434', 'l438', 'l442', 'l443', 'l444']", + "158, patient's ['l409', 'l417', 'l424', 'l430', 'l435', 'l439', 'l442', 'l445', 'l446']", + "159, tumor ['l410', 'l418', 'l425', 'l431', 'l436', 'l440', 'l443', 'l445', 'l447']", + "160, cells ['l353', 'l365', 'l376', 'l386', 'l395', 'l411', 'l419', 'l426', 'l432', 'l437', 'l441', 'l444', 'l446', 'l447']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "TERT", + "RNA-transfected" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "TERT", + "RNA-transfected" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells", + "(DC)", + "human", + "DC" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "TERT", + "RNA-transfected" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "thymoma", + "tumor", + "cells", + "human", + "cells,", + "Epstein", + "Barr", + "virus", + "(EBV)-transformed", + "B", + "targets" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "TERT", + "RNA-transfected" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "autologous", + "renal", + "and", + "prostate", + "cancer." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "TERT", + "RNA-transfected" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "TERT", + "RNA-transfected" + ] + }, + "context": { + "val": "patient", + "words": [ + "patients" + ] + } + } + ] + }, + { + "PMID": "10973318", + "TEXT": "We explored the role of hypocretins in human narcolepsy through histopathology of six narcolepsy brains and mutation screening of Hcrt, Hcrtr1 and Hcrtr2 in 74 patients of various human leukocyte antigen and family history status. One Hcrt mutation, impairing peptide trafficking and processing, was found in a single case with early onset narcolepsy. In situ hybridization of the perifornical area and peptide radioimmunoassays indicated global loss of hypocretins, without gliosis or signs of inflammation in all human cases examined. Although hypocretin loci do not contribute significantly to genetic predisposition, most cases of human narcolepsy are associated with a deficient hypocretin system.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10932231", + "TEXT": "Fas (CD95) is a receptor involved in induction of apoptotic cell death of Fas-bearing cells, including hepatocytes and T cells. Injection of Fas-specific antibodies into mice leads to fulminant hepatic failure and death. Fas also transduces growth-promoting signals in proliferating T cells, fibroblasts and some tumor cells. Here we show that partial hepatectomy, which triggers the immediate onset of liver regeneration, protected mice against the lethal effects of Fas-specific antibodies and prevented hepatocyte apoptosis in response to Fas engagement in vivo. Furthermore, Fas engagement accelerated liver regeneration after partial hepatectomy. Liver regeneration kinetics were delayed in mutant mice with decreased cell surface Fas expression (lpr mice). In contrast, regeneration was not delayed in lpr-cg mutant mice, which have a Fas mutation that prevents Fas-induced death but not Fas-dependent proliferative stimulation. Our results indicate that Fas engagement on cells in regenerating or healing tissues may promote cell growth.", + "TAG_DATA": [ + "59, liver {'context': 'B-tissue/organ'}", + "62, mice {'context': 'B-organism'}", + "71, prevented {'effect': 'B-negative'}", + "72, hepatocyte {'context': 'B-cells'}", + "73, apoptosis {'phenotype': 'B-apoptosis'}", + "79, in {'context': 'B-in vivo'}", + "80, vivo. {'context': 'I-in vivo'}", + "84, accelerated {'effect': 'B-positive'}", + "85, liver {'context': 'B-tissue/organ'}", + "90, Liver {'context': 'B-tissue/organ'}", + "97, mice {'context': 'B-organism'}", + "113, lpr-cg {'perturbing_action': 'B-other'}", + "114, mutant {'perturbing_action': 'I-other'}", + "115, mice, {'context': 'B-organism'}", + "119, Fas {'perturbing_action': 'I-other'}", + "120, mutation {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "52, hepatectomy, ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "59, liver ['l0', 'l7', 'l8', 'l9', 'l10']", + "62, mice ['l1', 'l7', 'l11', 'l12', 'l13', 'l14', 'l15']", + "71, prevented ['l2', 'l8', 'l11', 'l16', 'l17', 'l18', 'l19']", + "72, hepatocyte ['l3', 'l9', 'l12', 'l16', 'l20', 'l21', 'l22']", + "73, apoptosis ['l4', 'l10', 'l13', 'l17', 'l20', 'l23', 'l24']", + "79, in ['l5', 'l14', 'l18', 'l21', 'l23', 'l25']", + "80, vivo. ['l6', 'l15', 'l19', 'l22', 'l24', 'l25']", + "84, accelerated ['l26']", + "85, liver ['l26']", + "90, Liver ['l27']", + "97, mice ['l27']", + "113, lpr-cg ['l28', 'l29', 'l30', 'l31']", + "114, mutant ['l28', 'l32', 'l33', 'l34']", + "115, mice, ['l29', 'l32', 'l35', 'l36']", + "119, Fas ['l30', 'l33', 'l35', 'l37']", + "120, mutation ['l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocyte" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hepatocyte" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "accelerated" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "lpr-cg", + "mutant", + "Fas", + "mutation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "10888935", + "TEXT": "Medulloblastoma is the most malignant pediatric brain tumor. It is believed to originate from the undifferentiated external granule layer cells in the cerebellum, but the mechanism of tumorigenesis remains unknown. Here we studied three types of human medulloblastoma cells that express markers corresponding to different levels of neuronal differentiation. They expressed the neuronal repressor element 1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF; refs. 7-10) at very high levels compared with either neuronal progenitor NTera2 (NT2) cells or fully differentiated human neuron teratocarcinoma (hNT cells). To counter the effect of REST/NRSF, we used a recombinant transcription factor, REST-VP16, constructed by replacing repressor domains of REST/NRSF with the activation domain of viral protein (VP16). Transient expression of REST-VP16 in medulloblastoma cells was able to compete with the endogenous REST/NRSF for DNA binding and stimulate neuronal promoters. High-efficiency expression of REST-VP16 mediated by adenovirus vectors (Ad.REST-VP16) in medulloblastoma cells was able to counter REST/NRSF-mediated repression of neuronal promoters, stimulate expression of endogenous neuronal genes and trigger apoptosis through the activation of caspase cascades. Furthermore, intratumoral injection of Ad.REST-VP16 in established medulloblastoma tumors in nude mice inhibited their growth. Therefore, REST/NRSF may serve as a new target for therapeutic interventions for medulloblastoma through agents such as REST-VP16.", + "TAG_DATA": [ + "113, Transient {'perturbing_action': 'B-gene gain-of-function'}", + "114, expression {'perturbing_action': 'I-gene gain-of-function'}", + "115, of {'perturbing_action': 'I-gene gain-of-function'}", + "116, REST-VP16 {'perturbing_action': 'I-gene gain-of-function'}", + "118, medulloblastoma {'context': 'B-transformed cells'}", + "119, cells {'context': 'I-transformed cells'}", + "136, expression {'perturbing_action': 'I-gene gain-of-function'}", + "137, of {'perturbing_action': 'I-gene gain-of-function'}", + "138, REST-VP16 {'perturbing_action': 'I-gene gain-of-function'}", + "145, medulloblastoma {'context': 'B-transformed cells'}", + "146, cells {'context': 'I-transformed cells'}", + "163, trigger {'effect': 'B-positive'}", + "164, apoptosis {'phenotype': 'B-apoptosis'}", + "178, medulloblastoma {'context': 'B-neoplasm'}", + "179, tumors {'context': 'I-neoplasm'}", + "181, nude {'context': 'B-organism'}", + "182, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "113, Transient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "114, expression ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "115, of ['l1', 'l7', 'l12', 'l13', 'l14', 'l15']", + "116, REST-VP16 ['l2', 'l8', 'l12', 'l16', 'l17', 'l18']", + "118, medulloblastoma ['l3', 'l9', 'l13', 'l16', 'l19']", + "119, cells ['l4', 'l10', 'l14', 'l17', 'l19']", + "136, expression ['l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "137, of ['l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "138, REST-VP16 ['l21', 'l26', 'l31', 'l32', 'l33', 'l34']", + "145, medulloblastoma ['l5', 'l22', 'l27', 'l31', 'l35', 'l36', 'l37']", + "146, cells ['l6', 'l11', 'l15', 'l18', 'l23', 'l28', 'l32', 'l35', 'l38', 'l39']", + "163, trigger ['l24', 'l29', 'l33', 'l36', 'l38', 'l40']", + "164, apoptosis ['l25', 'l30', 'l34', 'l37', 'l39', 'l40']", + "178, medulloblastoma ['l41', 'l42', 'l43']", + "179, tumors ['l41', 'l44', 'l45']", + "181, nude ['l42', 'l44', 'l46']", + "182, mice ['l43', 'l45', 'l46']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transient", + "expression", + "of", + "REST-VP16" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "medulloblastoma", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "REST-VP16" + ] + }, + "effect": { + "val": "positive", + "words": [ + "trigger" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "REST-VP16" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "medulloblastoma", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "trigger" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "medulloblastoma", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "trigger" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "10888932", + "TEXT": "Exogenous application of neurotrophic growth factors has emerged as a new and particularly promising approach not only to promote functional recovery after acute brain injury but also to protect neurons against the immediate effect of the injury. Among the various growth factors and cytokines studied so far, the neuroprotective and neurotrophic profile of basic fibroblast growth factor (bFGF) is the best documented. Using an animal model of acute excitotoxic brain injury, we report here that the neuroprotective action of bFGF, which is now being tested in stroke patients, depends on the induction of activin A, a member of the transforming growth factor-beta superfamily. Our evidence for this previously unknown mechanism of action of bFGF is that bFGF strongly enhanced lesion-associated induction of activin A; in the presence of the activin-neutralizing protein follistatin, bFGF was no longer capable of rescuing neurons from excitotoxic death; and recombinant activin A exerted a neuroprotective effect by itself. Our data indicate that the development of substances influencing activin expression or receptor binding should offer new ways to fight neuronal loss in ischemic and traumatic brain injury.", + "TAG_DATA": [ + "135, longer {'effect': 'I-no effect'}", + "136, capable {'effect': 'I-no effect'}", + "139, neurons {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "135, longer ['l0', 'l1']", + "136, capable ['l0', 'l2']", + "139, neurons ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "no effect", + "words": [ + "longer", + "capable" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons" + ] + } + } + ] + }, + { + "PMID": "10888924", + "TEXT": "Mycophenolic acid, a selective inhibitor of the de novo synthesis of guanosine nucleotides in T and B lymphocytes, has been proposed to inhibit human immunodeficiency virus (HIV) replication in vitro by depleting the substrate (guanosine nucleotides) for reverse transcriptase. Here we show that mycophenolic acid induced apoptosis and cell death in a large proportion of activated CD4+ T cells, thus indicating that it may inhibit HIV infection in vitro by both virological mechanisms and immunological mechanisms (depletion of the pool of activated CD4+ T lymphocytes). Administration of mycophenolate mophetil, the ester derivate of mycophenolic acid, to HIV-infected subjects treated with anti-retroviral therapy and with undetectable viremia resulted in the reduction of the number of dividing CD4 + and CD8+ T cells and in the inhibition of virus isolation from purified CD4+ T-cell populations. Based on these results, the potential use of mycophenolate mophetil in the treatment of HIV infection deserves further investigation in controlled clinical trials.", + "TAG_DATA": [ + "45, induced {'effect': 'B-positive'}", + "46, apoptosis {'phenotype': 'B-apoptosis'}", + "48, cell {'phenotype': 'B-cell death'}", + "49, death {'phenotype': 'I-cell death'}", + "56, CD4+ {'context': 'B-cells'}", + "57, T {'context': 'I-cells'}", + "58, cells, {'context': 'I-cells'}", + "96, HIV-infected {'context': 'B-patient'}", + "97, subjects {'context': 'I-patient'}", + "115, CD4 {'context': 'B-cells'}", + "116, + {'context': 'B-cells'}", + "117, and {'context': 'I-cells'}", + "118, CD8+ {'context': 'I-cells'}", + "119, T {'context': 'I-cells'}", + "120, cells {'context': 'I-cells'}", + "130, CD4+ {'context': 'B-cells'}", + "131, T-cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, induced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "46, apoptosis ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "48, cell ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "49, death ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "56, CD4+ ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "57, T ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "58, cells, ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "96, HIV-infected ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "97, subjects ['l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "115, CD4 ['l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "116, + ['l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "117, and ['l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "118, CD8+ ['l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47', 'l48']", + "119, T ['l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l49']", + "120, cells ['l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l49']", + "130, CD4+ ['l50']", + "131, T-cell ['l48', 'l50']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells," + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells," + ] + } + } + ] + }, + { + "PMID": "10888923", + "TEXT": "We examined the pathogenic significance of the latent viral reservoir in the resting CD4+ T cell compartment of HIV-1-infected individuals as well as its involvement in the rebound of plasma viremia after discontinuation of highly active anti-retroviral therapy (HAART). Using heteroduplex mobility and tracking assays, we show that the detectable pool of latently infected, resting CD4+ T cells does not account entirely for the early rebounding plasma HIV in infected individuals in whom HAART has been discontinued. In the majority of patients examined, the rebounding plasma virus was genetically distinct from both the cell-associated HIV RNA and the replication-competent virus within the detectable pool of latently infected, resting CD4 + T cells. These results indicate the existence of other persistent HIV reservoirs that could prompt rapid emergence of plasma viremia after cessation of HAART and underscore the necessity to develop therapies directed toward such populations of infected cells.", + "TAG_DATA": [ + "108, CD4 {'context': 'I-cells'}", + "109, + {'context': 'I-cells'}", + "110, T {'context': 'I-cells'}", + "111, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "108, CD4 ['l0', 'l1', 'l2']", + "109, + ['l0', 'l3', 'l4']", + "110, T ['l1', 'l3', 'l5']", + "111, cells. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10802718", + "TEXT": "Systemic infection with Listeria monocytogenes, a Gram-positive intracellular bacterium, has been used extensively to analyze the innate immune response. Macrophages are central to this response, acting as both the host for and principal defense against this bacterium. During pregnancy L. monocytogenes has a predilection for replication at the maternal-placental interface and consequently is an important cause of fetal morbidity and mortality. However, macrophages are mostly excluded from the murine placenta with neutrophils acting as the main immune effector cell against this bacterium. Colony stimulating factor (CSF)-1, a macrophage growth factor, is synthesized in high concentrations by the uterine epithelium during pregnancy, where it is targeted to trophoblast bearing CSF-1-receptors. To define the involvement of CSF-1 in placental immunity, we infected pregnant mice either homozygous or heterozygous for an inactivating recessive mutation in the gene for CSF-1 (osteopetrotic; Csfmop) with L. monocytogenes. CSF-1 was required to recruit neutrophils to the site of listerial infection in the decidua basalis, and infection by Listeria remained unrestrained in its absence. CSF-1 acted by inducing the trophoblast to synthesize the neutrophil chemoattractants (KC) and macrophage inflammatory protein (MIP)-2. Thus, during pregnancy, trophoblast responsive to CSF-1 acts to organize the maternal immune response to bacterial infection at the utero-placental interface. This previously unknown function indicates that the trophoblast acts as a pregnancy-specific component of the innate immune system.", + "TAG_DATA": [ + "120, pregnant {'context': 'B-organism'}", + "121, mice {'context': 'I-organism'}", + "125, heterozygous {'perturbing_action': 'B-other'}", + "126, for {'perturbing_action': 'I-other'}", + "127, an {'perturbing_action': 'I-other'}", + "128, inactivating {'perturbing_action': 'I-other'}", + "129, recessive {'perturbing_action': 'I-other'}", + "130, mutation {'perturbing_action': 'I-other'}", + "131, in {'perturbing_action': 'I-other'}", + "132, the {'perturbing_action': 'I-other'}", + "133, gene {'perturbing_action': 'I-other'}", + "134, for {'perturbing_action': 'I-other'}", + "135, CSF-1 {'perturbing_action': 'I-other'}", + "136, (osteopetrotic; {'perturbing_action': 'I-other'}", + "137, Csfmop) {'perturbing_action': 'I-other'}", + "171, trophoblast {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "120, pregnant ['l0']", + "121, mice ['l0']", + "125, heterozygous ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "126, for ['l1', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "127, an ['l2', 'l13', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "128, inactivating ['l3', 'l14', 'l24', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "129, recessive ['l4', 'l15', 'l25', 'l34', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "130, mutation ['l5', 'l16', 'l26', 'l35', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "131, in ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "132, the ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "133, gene ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l69', 'l70', 'l71', 'l72']", + "134, for ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l73', 'l74', 'l75']", + "135, CSF-1 ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l76', 'l77']", + "136, (osteopetrotic; ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l78']", + "137, Csfmop) ['l12', 'l23', 'l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l77', 'l78']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10802717", + "TEXT": "The pro-inflammatory cytokine interleukin (IL)-6 (refs. 1-5) can bind to cells lacking the IL-6 receptor (IL-6R) when it forms a complex with the soluble IL-6R (sIL-6R) (trans signaling). Here, we have assessed the contribution of this system to the increased resistance of mucosal T cells against apoptosis in Crohn disease (CD), a chronic inflammatory disease of the gastrointestinal tract. A neutralizing antibody against IL-6R suppressed established experimental colitis in various animal models of CD mediated by type 1 T-helper cells, by inducing apoptosis of lamina propria T cells. Similarly, specific neutralization of sIL-6R in vivo by a newly designed gp130-Fc fusion protein caused suppression of colitis activity and induction of apoptosis, indicating that sIL-6R prevents mucosal T-cell apoptosis. In patients with CD, mucosal T cells showed strong evidence for IL-6 trans signaling, with activation of signal transducer and activator of transcription 3, bcl-2 and bcl-xl. Blockade of IL-6 trans signaling caused T-cell apoptosis, indicating that the IL-6-sIL-6R system mediates the resistance of T cells to apoptosis in CD. These data indicate that a pathway of T-cell activation driven by IL-6-sIL-6R contributes to the perpetuation of chronic intestinal inflammation. Specific targeting of this pathway may be a promising new approach for the treatment of CD.", + "TAG_DATA": [ + "70, animal {'context': 'B-organism'}", + "71, models {'context': 'I-organism'}", + "73, CD {'context': 'I-organism'}", + "81, inducing {'effect': 'B-positive'}", + "82, apoptosis {'phenotype': 'B-apoptosis'}", + "84, lamina {'context': 'B-cells'}", + "86, T {'context': 'I-cells'}", + "87, cells. {'context': 'I-cells'}", + "89, specific {'perturbing_action': 'B-pharmacological inhibition'}", + "90, neutralization {'perturbing_action': 'I-pharmacological inhibition'}", + "91, of {'perturbing_action': 'I-pharmacological inhibition'}", + "92, sIL-6R {'perturbing_action': 'I-pharmacological inhibition'}", + "93, in {'context': 'B-in vivo'}", + "94, vivo {'context': 'I-in vivo'}", + "108, induction {'effect': 'B-positive'}", + "110, apoptosis, {'phenotype': 'B-apoptosis'}", + "114, prevents {'effect': 'B-negative'}", + "115, mucosal {'context': 'B-cells'}", + "116, T-cell {'context': 'I-cells'}", + "117, apoptosis. {'phenotype': 'B-apoptosis'}", + "122, mucosal {'context': 'B-cells'}", + "123, T {'context': 'I-cells'}", + "124, cells {'context': 'I-cells'}", + "150, caused {'effect': 'B-positive'}", + "151, T-cell {'context': 'B-cells'}", + "152, apoptosis, {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "60, neutralizing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "61, antibody ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "62, against ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "63, IL-6R ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "70, animal ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "71, models ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "72, of ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "73, CD ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "81, inducing ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "82, apoptosis ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "84, lamina ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "86, T ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "87, cells. ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "89, specific ['l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "90, neutralization ['l78', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "91, of ['l79', 'l93', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "92, sIL-6R ['l80', 'l94', 'l107', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "93, in ['l81', 'l95', 'l108', 'l120', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "94, vivo ['l82', 'l96', 'l109', 'l121', 'l132', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "101, protein ['l83', 'l97', 'l110', 'l122', 'l133', 'l143', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "108, induction ['l84', 'l98', 'l111', 'l123', 'l134', 'l144', 'l153', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168']", + "110, apoptosis, ['l85', 'l99', 'l112', 'l124', 'l135', 'l145', 'l154', 'l162', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175']", + "114, prevents ['l86', 'l100', 'l113', 'l125', 'l136', 'l146', 'l155', 'l163', 'l169', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181']", + "115, mucosal ['l87', 'l101', 'l114', 'l126', 'l137', 'l147', 'l156', 'l164', 'l170', 'l176', 'l182', 'l183', 'l184', 'l185', 'l186']", + "116, T-cell ['l88', 'l102', 'l115', 'l127', 'l138', 'l148', 'l157', 'l165', 'l171', 'l177', 'l182', 'l187', 'l188', 'l189', 'l190']", + "117, apoptosis. ['l89', 'l103', 'l116', 'l128', 'l139', 'l149', 'l158', 'l166', 'l172', 'l178', 'l183', 'l187', 'l191', 'l192', 'l193']", + "122, mucosal ['l90', 'l104', 'l117', 'l129', 'l140', 'l150', 'l159', 'l173', 'l179', 'l184', 'l188', 'l191', 'l194', 'l195']", + "123, T ['l91', 'l105', 'l118', 'l130', 'l141', 'l151', 'l160', 'l167', 'l174', 'l180', 'l185', 'l189', 'l192', 'l194', 'l196']", + "124, cells ['l92', 'l106', 'l119', 'l131', 'l142', 'l152', 'l161', 'l168', 'l175', 'l181', 'l186', 'l190', 'l193', 'l195', 'l196']", + "150, caused ['l197', 'l198']", + "151, T-cell ['l197', 'l199']", + "152, apoptosis, ['l198', 'l199']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "animal", + "models", + "CD" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animal", + "models", + "CD" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing", + "induction", + "caused" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis,", + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing", + "induction", + "caused" + ] + }, + "context": { + "val": "cells", + "words": [ + "lamina", + "T", + "cells.", + "mucosal", + "T-cell", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis,", + "apoptosis." + ] + }, + "context": { + "val": "cells", + "words": [ + "lamina", + "T", + "cells.", + "mucosal", + "T-cell", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "neutralization", + "of", + "sIL-6R" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "neutralization", + "of", + "sIL-6R" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "neutralization", + "of", + "sIL-6R" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis,", + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "neutralization", + "of", + "sIL-6R" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "neutralization", + "of", + "sIL-6R" + ] + }, + "context": { + "val": "cells", + "words": [ + "mucosal", + "T-cell", + "T", + "cells" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis,", + "apoptosis." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis,", + "apoptosis." + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "context": { + "val": "cells", + "words": [ + "mucosal", + "T-cell", + "T", + "cells" + ] + } + } + ] + }, + { + "PMID": "10802713", + "TEXT": "Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to induce apoptosis in various tumor cells but not in nontransformed, normal cells. Preclinical studies in mice and nonhuman primates have shown that administration of TRAIL can induce apoptosis in human tumors, but that no cytotoxicity to normal organs or tissues is found. The susceptibility of tumor cells to TRAIL and an apparent lack of activity in normal cells has lead to a proposal to use TRAIL in cancer therapy. Here, we assessed the sensitivity of hepatocytes from rat, mouse, rhesus monkey and human livers to TRAIL-induced apoptosis. TRAIL induced apoptosis in normal human hepatocytes in culture but not in hepatocytes isolated from the other species. Human hepatocytes showed characteristic features of apoptosis, including cytoplasmic shrinkage, the activation of caspases and DNA fragmentation. Apoptosis and cell death in human hepatocytes was massive and rapid, occurring in more than 60% of the cells exposed to TRAIL within 10 hours. These results indicate that there are species differences in sensitivity to TRAIL, and that substantial liver toxicity might result if TRAIL were used in human cancer therapy.", + "TAG_DATA": [ + "85, hepatocytes {'context': 'B-cells'}", + "88, mouse, {'context': 'I-organism'}", + "89, rhesus {'context': 'B-organism'}", + "90, monkey {'context': 'I-tissue/organ'}", + "92, human {'context': 'B-tissue/organ'}", + "93, livers {'context': 'I-tissue/organ'}", + "95, TRAIL-induced {'effect': 'B-positive'}", + "98, induced {'effect': 'B-positive'}", + "99, apoptosis {'phenotype': 'B-apoptosis'}", + "101, normal {'context': 'B-cells'}", + "102, human {'context': 'I-cells'}", + "103, hepatocytes {'context': 'I-cells'}", + "105, culture {'context': 'I-in vitro'}", + "109, hepatocytes {'context': 'B-cells'}", + "110, isolated {'context': 'I-cells'}", + "115, Human {'context': 'B-cells'}", + "116, hepatocytes {'context': 'I-cells'}", + "121, apoptosis, {'phenotype': 'B-apoptosis'}", + "132, Apoptosis {'phenotype': 'B-apoptosis'}", + "134, cell {'phenotype': 'B-cell death'}", + "135, death {'phenotype': 'I-cell death'}", + "137, human {'context': 'B-cells'}", + "138, hepatocytes {'context': 'I-cells'}", + "150, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "85, hepatocytes ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "88, mouse, ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "89, rhesus ['l1', 'l6', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "90, monkey ['l2', 'l7', 'l11', 'l18', 'l19', 'l20']", + "92, human ['l3', 'l8', 'l12', 'l18', 'l21', 'l22']", + "93, livers ['l4', 'l9', 'l13', 'l19', 'l21']", + "95, TRAIL-induced ['l5', 'l10', 'l14', 'l20', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "98, induced ['l15', 'l23', 'l28', 'l29', 'l30', 'l31', 'l32']", + "99, apoptosis ['l16', 'l24', 'l28', 'l33', 'l34', 'l35', 'l36']", + "101, normal ['l17', 'l25', 'l29', 'l33', 'l37', 'l38', 'l39']", + "102, human ['l26', 'l30', 'l34', 'l37', 'l40', 'l41']", + "103, hepatocytes ['l27', 'l31', 'l35', 'l38', 'l40', 'l42']", + "105, culture ['l32', 'l36', 'l39', 'l41', 'l42']", + "109, hepatocytes ['l43', 'l44', 'l45', 'l46']", + "110, isolated ['l43', 'l47', 'l48', 'l49']", + "115, Human ['l44', 'l47', 'l50', 'l51', 'l52']", + "116, hepatocytes ['l45', 'l48', 'l50', 'l53', 'l54']", + "121, apoptosis, ['l46', 'l49', 'l51', 'l53', 'l55']", + "132, Apoptosis ['l52', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "134, cell ['l56', 'l61', 'l62', 'l63', 'l64']", + "135, death ['l57', 'l61', 'l65', 'l66', 'l67']", + "137, human ['l58', 'l62', 'l65', 'l68', 'l69']", + "138, hepatocytes ['l59', 'l63', 'l66', 'l68', 'l70']", + "150, cells ['l60', 'l64', 'l67', 'l69', 'l70']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "hepatocytes", + "normal", + "human" + ] + }, + "effect": { + "val": "positive", + "words": [ + "TRAIL-induced", + "induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse,", + "rhesus" + ] + }, + "effect": { + "val": "positive", + "words": [ + "TRAIL-induced", + "induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rhesus" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "monkey", + "human" + ] + }, + "effect": { + "val": "positive", + "words": [ + "TRAIL-induced" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "TRAIL-induced", + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis,", + "Apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "normal", + "human", + "hepatocytes", + "isolated", + "Human", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "hepatocytes", + "cells" + ] + } + } + ] + }, + { + "PMID": "10802708", + "TEXT": "Caspase 8 is a cysteine protease regulated in both a death-receptor-dependent and -independent manner during apoptosis. Here, we report that the gene for caspase 8 is frequently inactivated in neuroblastoma, a childhood tumor of the peripheral nervous system. The gene is silenced through DNA methylation as well as through gene deletion. Complete inactivation of CASP8 occurred almost exclusively in neuroblastomas with amplification of the oncogene MYCN. Caspase 8-null neuroblastoma cells were resistant to death receptor- and doxorubicin-mediated apoptosis, deficits that were corrected by programmed expression of the enzyme. Thus, caspase 8 acts as a tumor suppressor in neuroblastomas with amplification of MYCN.", + "TAG_DATA": [ + "59, neuroblastomas {'context': 'B-neoplasm'}", + "66, Caspase {'perturbing_action': 'B-gene loss-of-function'}", + "67, 8-null {'perturbing_action': 'B-gene loss-of-function'}", + "68, neuroblastoma {'context': 'B-transformed cells'}", + "69, cells {'context': 'I-transformed cells'}", + "71, resistant {'effect': 'B-negative'}", + "77, apoptosis, {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "59, neuroblastomas ['l0']", + "66, Caspase ['l1', 'l2', 'l3', 'l4', 'l5']", + "67, 8-null ['l1', 'l6', 'l7', 'l8', 'l9']", + "68, neuroblastoma ['l2', 'l6', 'l10', 'l11', 'l12']", + "69, cells ['l0', 'l3', 'l7', 'l10', 'l13', 'l14']", + "71, resistant ['l4', 'l8', 'l11', 'l13', 'l15']", + "77, apoptosis, ['l5', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Caspase", + "8-null" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "neuroblastoma", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Caspase", + "8-null" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Caspase", + "8-null" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "neuroblastoma", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "neuroblastoma", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistant" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + } + ] + }, + { + "PMID": "10802707", + "TEXT": "Bone cancer pain is common among cancer patients and can have a devastating effect on their quality of life. A chief problem in designing new therapies for bone cancer pain is that it is unclear what mechanisms drive this distinct pain condition. Here we show that osteoprotegerin, a secreted 'decoy' receptor that inhibits osteoclast activity, also blocks behaviors indicative of pain in mice with bone cancer. A substantial part of the actions of osteoprotegerin seems to result from inhibition of tumor-induced bone destruction that in turn inhibits the neurochemical changes in the spinal cord that are thought to be involved in the generation and maintenance of cancer pain. These results demonstrate that excessive tumor-induced bone destruction is involved in the generation of bone cancer pain and that osteoprotegerin may provide an effective treatment for this common human condition.", + "TAG_DATA": [ + "62, mice {'context': 'B-organism'}", + "64, bone {'context': 'B-neoplasm'}", + "65, cancer. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "62, mice ['l0', 'l1']", + "64, bone ['l0', 'l2']", + "65, cancer. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10742146", + "TEXT": "The amyloid beta-protein precursor gives rise to the amyloid beta-protein, the principal constituent of senile plaques and a cytotoxic fragment involved in the pathogenesis of Alzheimer disease. Here we show that amyloid beta-protein precursor was proteolytically cleaved by caspases in the C terminus to generate a second unrelated peptide, called C31. The resultant C31 peptide was a potent inducer of apoptosis. Both caspase-cleaved amyloid beta-protein precursor and activated caspase-9 were present in brains of Alzheimer disease patients but not in control brains. These findings indicate the possibility that caspase cleavage of amyloid beta-protein precursor with the generation of C31 may be involved in the neuronal death associated with Alzheimer disease.", + "TAG_DATA": [ + "58, inducer {'effect': 'B-positive'}", + "60, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "58, inducer ['l0']", + "60, apoptosis. ['l0']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "inducer" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "10700238", + "TEXT": "Celiac disease (CD) is an increasingly diagnosed enteropathy (prevalence, 1:200-1:300) that is induced by dietary exposure to wheat gliadins (as well as related proteins in rye and barley) and is strongly associated with HLA-DQ2 (alpha1*0501, beta1*0201), which is present in over 90% of CD patients. Because a variety of gliadin peptides have been identified as epitopes for gliadin-specific T-cell clones and as bioactive sequences in feeding studies and in ex vivo CD intestinal biopsy challenge, it has been unclear whether a 'dominant' T-cell epitope is associated with CD. Here, we used fresh peripheral blood lymphocytes from individual subjects undergoing short-term antigen challenge and tissue transglutaminase-treated, overlapping synthetic peptides spanning A-gliadin to demonstrate a transient, disease-specific, DQ2-restricted, CD4 T-cell response to a single dominant epitope. Optimal gamma interferon release in an ELISPOT assay was elicited by a 17-amino-acid peptide corresponding to the partially deamidated peptide of A-gliadin amino acids 57-73 (Q65E). Consistent with earlier reports indicating that host tissue transglutaminase modification of gliadin enhances gliadin-specific CD T-cell responses, tissue transglutaminase specifically deamidated Q65 in the peptide of A-gliadin amino acids 56-75. Discovery of this dominant epitope may allow development of antigen-specific immunotherapy for CD.", + "TAG_DATA": [ + "92, peripheral {'context': 'B-cells'}", + "93, blood {'context': 'I-cells'}", + "94, lymphocytes {'context': 'I-cells'}", + "116, CD4 {'context': 'B-cells'}", + "117, T-cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "92, peripheral ['l0', 'l1']", + "93, blood ['l0', 'l2']", + "94, lymphocytes ['l1', 'l2']", + "116, CD4 ['l3']", + "117, T-cell ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10700234", + "TEXT": "Delta9-Tetrahydrocannabinol, the main active component of marijuana, induces apoptosis of transformed neural cells in culture. Here, we show that intratumoral administration of Delta9-tetrahydrocannabinol and the synthetic cannabinoid agonist WIN-55,212-2 induced a considerable regression of malignant gliomas in Wistar rats and in mice deficient in recombination activating gene 2. Cannabinoid treatment did not produce any substantial neurotoxic effect in the conditions used. Experiments with two subclones of C6 glioma cells in culture showed that cannabinoids signal apoptosis by a pathway involving cannabinoid receptors, sustained ceramide accumulation and Raf1/extracellular signal-regulated kinase activation. These results may provide the basis for a new therapeutic approach for the treatment of malignant gliomas.", + "TAG_DATA": [ + "29, induced {'effect': 'B-positive'}", + "32, regression {'phenotype': 'B-tumour regression'}", + "34, malignant {'context': 'B-neoplasm'}", + "35, gliomas {'context': 'I-neoplasm'}", + "37, Wistar {'context': 'B-organism'}", + "38, rats {'context': 'I-organism'}", + "41, mice {'context': 'B-organism'}", + "42, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "43, in {'perturbing_action': 'I-gene loss-of-function'}", + "44, recombination {'perturbing_action': 'I-gene loss-of-function'}", + "45, activating {'perturbing_action': 'I-gene loss-of-function'}", + "46, gene {'perturbing_action': 'I-gene loss-of-function'}", + "47, 2. {'perturbing_action': 'I-gene loss-of-function'}", + "66, C6 {'context': 'B-transformed cells'}", + "67, glioma {'context': 'I-transformed cells'}", + "68, cells {'context': 'I-transformed cells'}", + "70, culture {'context': 'I-in vitro'}", + "74, signal {'effect': 'B-regulates'}" + ], + "LINK_DATA": [ + "29, induced ['l0', 'l1', 'l2', 'l3', 'l4']", + "32, regression ['l0', 'l5', 'l6', 'l7', 'l8']", + "34, malignant ['l1', 'l5', 'l9', 'l10', 'l11']", + "35, gliomas ['l2', 'l6', 'l9', 'l12', 'l13']", + "37, Wistar ['l3', 'l7', 'l10', 'l12', 'l14']", + "38, rats ['l4', 'l8', 'l11', 'l13', 'l14']", + "41, mice ['l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "42, deficient ['l15', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "43, in ['l16', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "44, recombination ['l17', 'l22', 'l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "45, activating ['l18', 'l23', 'l29', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "46, gene ['l19', 'l24', 'l30', 'l36', 'l41', 'l46', 'l47', 'l48']", + "47, 2. ['l20', 'l25', 'l31', 'l37', 'l42', 'l46', 'l49', 'l50']", + "66, C6 ['l32', 'l38', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "67, glioma ['l26', 'l33', 'l39', 'l44', 'l47', 'l49', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "68, cells ['l27', 'l34', 'l40', 'l45', 'l48', 'l50', 'l52', 'l57', 'l62', 'l63']", + "69, in ['l53', 'l58', 'l62', 'l64', 'l65', 'l66']", + "70, culture ['l54', 'l59', 'l63', 'l64', 'l67', 'l68']", + "74, signal ['l55', 'l60', 'l65', 'l67', 'l69']", + "75, apoptosis ['l56', 'l61', 'l66', 'l68', 'l69']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "malignant", + "gliomas" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "Wistar", + "rats" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "malignant", + "gliomas" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "organism", + "words": [ + "Wistar", + "rats" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "recombination", + "activating", + "gene", + "2." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "recombination", + "activating", + "gene", + "2." + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "glioma", + "cells", + "C6" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "C6", + "glioma" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "signal" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "signal" + ] + } + } + ] + }, + { + "PMID": "10700233", + "TEXT": "Golgi beta1,6N-acetylglucosaminyltransferase V (MGAT5) is required in the biosynthesis of beta1,6GlcNAc-branched N-linked glycans attached to cell surface and secreted glycoproteins. Amounts of MGAT5 glycan products are commonly increased in malignancies, and correlate with disease progression. To study the functions of these N-glycans in development and disease, we generated mice deficient in Mgat5 by targeted gene mutation. These Mgat5-/- mice lacked Mgat5 products and appeared normal, but differed in their responses to certain extrinsic conditions. Mammary tumor growth and metastases induced by the polyomavirus middle T oncogene was considerably less in Mgat5-/- mice than in transgenic littermates expressing Mgat5. Furthermore, Mgat5 glycan products stimulated membrane ruffling and phosphatidylinositol 3 kinase-protein kinase B activation, fueling a positive feedback loop that amplified oncogene signaling and tumor growth in vivo. Our results indicate that inhibitors of MGAT5 might be useful in the treatment of malignancies by targeting their dependency on focal adhesion signaling for growth and metastasis.", + "TAG_DATA": [ + "48, mice {'context': 'B-organism'}", + "49, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "50, in {'perturbing_action': 'I-gene loss-of-function'}", + "51, Mgat5 {'perturbing_action': 'I-gene loss-of-function'}", + "53, targeted {'perturbing_action': 'B-other'}", + "54, gene {'perturbing_action': 'I-other'}", + "55, mutation. {'perturbing_action': 'I-other'}", + "57, Mgat5-/- {'perturbing_action': 'B-gene loss-of-function'}", + "58, mice {'context': 'B-organism'}", + "74, Mammary {'context': 'B-tissue/organ'}", + "75, tumor {'phenotype': 'B-tumour growth'}", + "76, growth {'phenotype': 'I-tumour growth'}", + "78, metastases {'phenotype': 'B-metastasis'}", + "79, induced {'effect': 'B-positive'}", + "88, less {'effect': 'B-negative'}", + "90, Mgat5-/- {'perturbing_action': 'B-gene loss-of-function'}", + "91, mice {'context': 'B-organism'}", + "94, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "96, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "97, Mgat5. {'perturbing_action': 'I-gene gain-of-function'}", + "122, tumor {'phenotype': 'B-tumour growth'}", + "123, growth {'phenotype': 'I-tumour growth'}", + "124, in {'context': 'B-in vivo'}", + "125, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "48, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "49, deficient ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "50, in ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "51, Mgat5 ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "53, targeted ['l3', 'l8', 'l12', 'l15', 'l18', 'l19', 'l20']", + "54, gene ['l4', 'l9', 'l13', 'l16', 'l18', 'l21', 'l22']", + "55, mutation. ['l5', 'l10', 'l14', 'l17', 'l19', 'l21', 'l23']", + "57, Mgat5-/- ['l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "58, mice ['l20', 'l22', 'l23', 'l24', 'l33', 'l34', 'l35', 'l36']", + "74, Mammary ['l25', 'l33', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "75, tumor ['l26', 'l34', 'l37', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "76, growth ['l27', 'l35', 'l38', 'l46', 'l52', 'l53', 'l54', 'l55']", + "78, metastases ['l28', 'l39', 'l47', 'l52', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "79, induced ['l29', 'l36', 'l40', 'l48', 'l53', 'l56', 'l62', 'l63', 'l64', 'l65']", + "83, middle ['l41', 'l57', 'l62', 'l66', 'l67', 'l68', 'l69', 'l70']", + "84, T ['l30', 'l42', 'l49', 'l58', 'l63', 'l66', 'l71', 'l72', 'l73', 'l74']", + "85, oncogene ['l31', 'l43', 'l50', 'l54', 'l59', 'l64', 'l67', 'l71', 'l75', 'l76', 'l77']", + "88, less ['l32', 'l44', 'l51', 'l55', 'l60', 'l65', 'l68', 'l72', 'l75', 'l78', 'l79']", + "90, Mgat5-/- ['l69', 'l73', 'l76', 'l78', 'l80', 'l81', 'l82']", + "91, mice ['l45', 'l61', 'l70', 'l74', 'l77', 'l79', 'l80']", + "94, transgenic ['l81', 'l83', 'l84', 'l85']", + "96, expressing ['l83', 'l86', 'l87', 'l88', 'l89', 'l90']", + "97, Mgat5. ['l82', 'l84', 'l86', 'l91', 'l92', 'l93', 'l94']", + "122, tumor ['l87', 'l91', 'l95', 'l96', 'l97']", + "123, growth ['l85', 'l88', 'l92', 'l95', 'l98', 'l99']", + "124, in ['l89', 'l93', 'l96', 'l98', 'l100']", + "125, vivo. ['l90', 'l94', 'l97', 'l99', 'l100']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Mgat5", + "Mgat5-/-" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "targeted", + "gene", + "mutation." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mgat5-/-" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "Mammary" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mgat5-/-" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mgat5-/-" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mgat5-/-" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mgat5-/-" + ] + }, + "effect": { + "val": "negative", + "words": [ + "less" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "Mammary" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "Mammary" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "Mammary" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "Mammary" + ] + }, + "effect": { + "val": "negative", + "words": [ + "less" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "less" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + }, + "effect": { + "val": "negative", + "words": [ + "less" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "less" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "Mgat5." + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth", + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "Mgat5." + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "10700231", + "TEXT": "Although recent in vitro studies have begun to decipher the molecular events that characterize the anergic state, their in vivo biologic relevance and potential clinical importance remain unclear. Here, using anergic human T-cell clones and tolerant alloreactive mouse T cells that do not induce graft-versus-host disease, we show that p27kip1 cyclin-dependent kinase inhibitor is an essential regulator responsible for the blockade of clonal expansion of anergic T cells in vitro and in vivo. Moreover, in anergic cells, p27kip1 associates with the c-Jun co-activator JAB1, resulting in defective transactivation of AP-1 and interleukin 2 transcription. Therefore, pharmacological agents that upregulate the expression of or prevent the degradation of p27kip1 during antigen recognition should be part of new therapeutic strategies to induce antigen-specific T-cell unresponsiveness.", + "TAG_DATA": [ + "30, anergic {'context': 'B-cells'}", + "31, human {'context': 'I-cells'}", + "32, T-cell {'context': 'I-cells'}", + "33, clones {'context': 'I-cells'}", + "36, alloreactive {'context': 'I-cells'}", + "37, mouse {'context': 'I-cells'}", + "38, T {'context': 'I-cells'}", + "39, cells {'context': 'I-cells'}", + "60, blockade {'effect': 'B-negative'}", + "62, clonal {'phenotype': 'B-colony formation'}", + "63, expansion {'phenotype': 'I-colony formation'}", + "65, anergic {'context': 'B-cells'}", + "66, T {'context': 'I-cells'}", + "67, cells {'context': 'I-cells'}", + "68, in {'context': 'B-in vitro'}", + "69, vitro {'context': 'I-in vitro'}", + "71, in {'context': 'B-in vivo'}", + "72, vivo. {'context': 'I-in vivo'}", + "75, anergic {'context': 'B-cells'}", + "76, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "30, anergic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "31, human ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "32, T-cell ['l1', 'l13', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "33, clones ['l2', 'l14', 'l22', 'l32', 'l33', 'l34', 'l35']", + "36, alloreactive ['l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "37, mouse ['l36', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "38, T ['l3', 'l15', 'l23', 'l37', 'l49', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "39, cells ['l4', 'l16', 'l24', 'l38', 'l50', 'l59', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "60, blockade ['l5', 'l39', 'l51', 'l60', 'l68', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "62, clonal ['l6', 'l17', 'l25', 'l40', 'l52', 'l61', 'l69', 'l76', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "63, expansion ['l7', 'l18', 'l26', 'l32', 'l41', 'l53', 'l62', 'l70', 'l77', 'l85', 'l91', 'l92', 'l93', 'l94', 'l95']", + "65, anergic ['l8', 'l19', 'l27', 'l33', 'l42', 'l54', 'l63', 'l71', 'l78', 'l86', 'l91', 'l96', 'l97', 'l98', 'l99']", + "66, T ['l9', 'l20', 'l28', 'l34', 'l43', 'l55', 'l64', 'l72', 'l79', 'l87', 'l92', 'l96', 'l100', 'l101', 'l102']", + "67, cells ['l10', 'l21', 'l29', 'l35', 'l44', 'l56', 'l65', 'l73', 'l80', 'l88', 'l93', 'l97', 'l100', 'l103', 'l104']", + "68, in ['l11', 'l30', 'l45', 'l57', 'l66', 'l74', 'l81', 'l89', 'l94', 'l98', 'l101', 'l103', 'l105']", + "69, vitro ['l12', 'l31', 'l46', 'l58', 'l67', 'l75', 'l82', 'l90', 'l95', 'l99', 'l102', 'l104', 'l105', 'l106']", + "71, in ['l47', 'l83', 'l107', 'l108']", + "72, vivo. ['l48', 'l84', 'l106', 'l107']", + "75, anergic ['l109']", + "76, cells, ['l108', 'l109']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "anergic", + "alloreactive", + "mouse", + "T", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blockade" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "anergic", + "human", + "T-cell", + "clones", + "alloreactive", + "mouse", + "T", + "cells" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonal", + "expansion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blockade" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonal", + "expansion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blockade" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blockade" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "clonal", + "expansion" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "10655113", + "TEXT": "The development of many autoimmune diseases has been etiologically linked to exposure to infectious agents. For example, a subset of patients with a history of Salmonella infection develop reactive arthritis. The persistence of bacterial antigen in arthritic tissue and the isolation of Salmonella or Yersinia reactive CD8+ T cells from the joints of patients with reactive arthritis support the etiological link between Gram-negative bacterial infection and autoimmune disease. Models proposed to account for the link between infection and autoimmunity include inflammation-induced presentation of cryptic self-epitopes, antigen persistence and molecular mimicry. Several studies support molecular mimicry as a mechanism for the involvement of class II epitopes in infectious disease-induced self-reactivity. Here, we have identified an immunodominant epitope derived from the S. typhimurium GroEL molecule. This epitope is presented by the mouse H2-T23-encoded class Ib molecule Qa-1 and was recognized by CD8+ cytotoxic T lymphocytes induced after natural infection. S. typhimurium-stimulated cytotoxic T lymphocytes recognizing the GroEL epitope cross-reacted with a peptide derived from mouse heat shock protein 60 and recognized stressed macrophages. Our results indicate involvement of MHC class Ib molecules in infection-induced autoimmune recognition and indicate a mechanism for the etiological link between Gram-negative bacterial infection and autoimmunity.", + "TAG_DATA": [ + "149, cytotoxic {'context': 'B-cells'}", + "150, T {'context': 'I-cells'}", + "151, lymphocytes {'context': 'I-cells'}", + "170, macrophages. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "149, cytotoxic ['l0', 'l1', 'l2']", + "150, T ['l0', 'l3', 'l4']", + "151, lymphocytes ['l1', 'l3', 'l5']", + "170, macrophages. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10655110", + "TEXT": "Although maternal human immunodeficiency virus type 1 (HIV-1) transmission occurs during gestation, intrapartum and postpartum (by breast-feeding), 50-70% of all infected children seem to acquire HIV-1 shortly before or during delivery. Epidemiological evidence indicates that mucosal exposure is an important aspect of intrapartum HIV transmission. A simian immunodeficiency virus (SIV) macaque model has been developed that mimics the mucosal exposure that can occur during intrapartum HIV-1 transmission. To develop immunoprophylaxis against intrapartum HIV-1 transmission, we used SHIV-vpu+ (refs. 5,6), a chimeric simian-human virus that encodes the env gene of HIV-IIIB. Several combinations of human monoclonal antibodies against HIV-1 have been identified that neutralize SHIV-vpu+ completely in vitro through synergistic interaction. Here, we treated four pregnant macaques with a triple combination of the human IgG1 monoclonal antibodies F105, 2G12 and 2F5. All four macaques were protected against intravenous SHIV-vpu+ challenge after delivery. The infants received monoclonal antibodies after birth and were challenged orally with SHIV-vpu+ shortly thereafter. We found no evidence of infection in any infant during 6 months of follow-up. This demonstrates that IgG1 monoclonal antibodies protect against mucosal lentivirus challenge in neonates. We conclude that epitopes recognized by the three monoclonal antibodies are important determinants for achieving substantial protection, thus providing a rational basis for AIDS vaccine development.", + "TAG_DATA": [ + "114, pregnant {'context': 'B-organism'}", + "115, macaques {'context': 'I-organism'}", + "132, macaques {'context': 'B-organism'}", + "142, infants {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "114, pregnant ['l0', 'l1']", + "115, macaques ['l0', 'l2']", + "132, macaques ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10655105", + "TEXT": "Here we show that the cell-cycle regulator p21 is involved in immune system function. T lymphocytes from p21-/- mice exhibit significant proliferative advantage over wild-type cells following prolonged stimulation, but not after primary activation. Consistent with this, p21-deficient mice accumulate abnormal amounts of CD4+ memory cells, and develop loss of tolerance towards nuclear antigens. Similar to human lupus, female p21-deficient mice develop antibodies against dsDNA, lymphadenopathy, and glomerulonephritis, leading to decreased viability. These data demonstrate a specialized role for p21 in the control of T-cell proliferation, tolerance to nuclear antigens, and female-prone lupus. These findings could be the basis for new therapeutic approaches to lupus.", + "TAG_DATA": [ + "14, T {'context': 'B-cells'}", + "15, lymphocytes {'context': 'I-cells'}", + "17, p21-/- {'perturbing_action': 'B-gene loss-of-function'}", + "18, mice {'context': 'B-organism'}", + "21, proliferative {'phenotype': 'B-proliferation'}", + "22, advantage {'phenotype': 'I-proliferation'}", + "25, cells {'context': 'B-cells'}", + "37, p21-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "38, mice {'context': 'B-organism'}", + "43, CD4+ {'context': 'B-cells'}", + "44, memory {'context': 'I-cells'}", + "45, cells, {'context': 'I-cells'}", + "58, female {'perturbing_action': 'B-gene loss-of-function'}", + "59, p21-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "60, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "14, T ['l0', 'l1', 'l2', 'l3', 'l4']", + "15, lymphocytes ['l0', 'l5', 'l6', 'l7', 'l8', 'l9']", + "17, p21-/- ['l5', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "18, mice ['l1', 'l6', 'l10', 'l17', 'l18', 'l19']", + "21, proliferative ['l2', 'l7', 'l11', 'l17', 'l20', 'l21']", + "22, advantage ['l3', 'l8', 'l12', 'l18', 'l20', 'l22']", + "25, cells ['l4', 'l9', 'l13', 'l19', 'l21', 'l22']", + "37, p21-deficient ['l23', 'l24', 'l25', 'l26', 'l27']", + "38, mice ['l23', 'l28', 'l29', 'l30']", + "43, CD4+ ['l14', 'l24', 'l28', 'l31', 'l32']", + "44, memory ['l15', 'l25', 'l29', 'l31', 'l33']", + "45, cells, ['l16', 'l26', 'l30', 'l32', 'l33']", + "58, female ['l34', 'l35']", + "59, p21-deficient ['l34', 'l36']", + "60, mice ['l27', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "lymphocytes", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "advantage" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "lymphocytes", + "cells", + "CD4+", + "memory", + "cells," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p21-/-", + "p21-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p21-/-", + "p21-deficient", + "female" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p21-/-" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "advantage" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "advantage" + ] + } + } + ] + }, + { + "PMID": "10613833", + "TEXT": "Metastasis is a frequent complication of cancer, yet the process through which circulating tumor cells form distant colonies is poorly understood. We have been able to observe the steps in early hematogenous metastasis by epifluorescence microscopy of tumor cells expressing green fluorescent protein in subpleural microvessels in intact, perfused mouse and rat lungs. Metastatic tumor cells attached to the endothelia of pulmonary pre-capillary arterioles and capillaries. Extravasation of tumor cells was rare, and it seemed that the transmigrated cells were cleared quickly by the lung, leaving only the endothelium-attached cells as the seeds of secondary tumors. Early colonies were entirely within the blood vessels. Although most models of metastasis include an extravasation step early in the process, here we show that in the lung, metastasis is initiated by attachment of tumor cells to the vascular endothelium and that hematogenous metastasis originates from the proliferation of attached intravascular tumor cells rather than from extravasated ones. Intravascular metastasis formation would make early colonies especially vulnerable to intravascular drugs, and this possibility has potential for the prevention of tumor cell attachment to the endothelium.", + "TAG_DATA": [ + "49, mouse {'context': 'B-tissue/organ'}", + "50, and {'context': 'I-tissue/organ'}", + "51, rat {'context': 'I-tissue/organ'}", + "52, lungs. {'context': 'I-tissue/organ'}", + "53, Metastatic {'context': 'B-transformed cells'}", + "54, tumor {'context': 'I-transformed cells'}", + "55, cells {'context': 'I-transformed cells'}", + "123, lung, {'context': 'B-tissue/organ'}", + "124, metastasis {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "49, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "50, and ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "51, rat ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "52, lungs. ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "53, Metastatic ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "54, tumor ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "55, cells ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "123, lung, ['l21']", + "124, metastasis ['l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "lung," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + } + ] + }, + { + "PMID": "10613832", + "TEXT": "Hepatocellular carcinoma (HCC) is one of the most common cancers in Asia and Africa, where hepatitis virus infection and exposure to specific liver carcinogens are prevalent. Although inactivation of some tumor suppressor genes such as p53 and p16INK4Ahas been identified, no known oncogene is commonly activated in hepatocellular carcinomas. Here we have isolated genes overexpressed in hepatocellular carcinomas by cDNA subtractive hybridization, and identified an oncoprotein consisting of six ankyrin repeats (gankyrin). The expression of gankyrin was increased in all 34 hepatocellular carcinomas studied. Gankyrin induced anchorage-independent growth and tumorigenicity in NIH/3T3 cells. Gankyrin bound to the product of the retinoblastoma gene (RB1), increasing its phosphorylation and releasing the activity of the transcription factor E2F-1. Gankyrin accelerated the degradation of RB1 in vitro and in vivo, and was identical to or interacted with a subunit of the 26S proteasome. These results demonstrate the importance of ubiquitin-proteasome pathway in the regulation of cell growth and oncogenic transformation, and indicate that gankyrin overexpression contributes to hepatocarcinogenesis by destabilizing RB1.", + "TAG_DATA": [ + "85, induced {'effect': 'B-positive'}", + "89, tumorigenicity {'phenotype': 'B-tumourigenesis'}", + "91, NIH/3T3 {'context': 'B-cells'}", + "92, cells. {'context': 'I-cells'}", + "121, in {'context': 'B-in vitro'}", + "122, vitro {'context': 'I-in vitro'}", + "124, in {'context': 'B-in vivo'}", + "125, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "85, induced ['l0', 'l1']", + "89, tumorigenicity ['l0', 'l2', 'l3']", + "91, NIH/3T3 ['l2', 'l4']", + "92, cells. ['l1', 'l3', 'l4']", + "121, in ['l5', 'l6', 'l7']", + "122, vitro ['l5', 'l8', 'l9']", + "124, in ['l6', 'l8', 'l10']", + "125, vivo, ['l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity" + ] + }, + "context": { + "val": "cells", + "words": [ + "NIH/3T3", + "cells." + ] + } + } + ] + }, + { + "PMID": "10613831", + "TEXT": "The C-terminal region of Plasmodium falciparum merozoite surface protein 1 (MSP-119) is at present a leading malaria vaccine candidate. Antibodies against the epidermal growth factor-like domains of MSP-1 19are associated with immunity to P. falciparum and active immunization with recombinant forms of the molecule protect against malaria challenge in various experimental systems. These findings, with the knowledge that epidermal growth factor-like domains in other molecules have essential binding functions, indicate the importance of this protein in merozoite invasion of red blood cells. Despite extensive molecular epidemiological investigations, only limited sequence polymorphism has been identified in P. falciparum MSP-119 (refs. 9-11). This indicates its sequence is functionally constrained, and is used in support of the use of MSP-119 as a vaccine. Here, we have successfully complemented the function of most of P. falciparum MSP-119 with the corresponding but highly divergent sequence from the rodent parasite P. chabaudi. The results indicate that the role of MSP-119 in red blood cell invasion is conserved across distantly related Plasmodium species and show that the sequence of P. falciparum MSP-119 is not constrained by function.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10613825", + "TEXT": "Multiple sclerosis is an immune-mediated disorder of the central nervous system leading to progressive decline of motor and sensory functions and permanent disability. The therapy of multiple sclerosis is only partially effective, despite anti-inflammatory, immunosuppresive and immunomodulatory measures. White matter inflammation and loss of myelin, the pathological hallmarks of multiple sclerosis, are thought to determine disease severity. Experimental autoimmune encephalomyelitis reproduces the features of multiple sclerosis in rodents and in nonhuman primates. The dominant early clinical symptom of acute autoimmune encephalomyelitis is progressive ascending muscle weakness. However, demyelination may not be profound and its extent may not correlate with severity of neurological decline, indicating that targets unrelated to myelin or oligodendrocytes may contribute to the pathogenesis of acute autoimmune encephalomyelitis. Here we report that within the spinal cord in the course of autoimmune encephalomyelitis not only myelin but also neurons are subject to lymphocyte attack and may degenerate. Blockade of glutamate AMPA receptors ameliorated the neurological sequelae of autoimmune encephalomyelitis, indicating the potential for AMPA antagonists in the therapy of multiple sclerosis.", + "TAG_DATA": [ + "67, rodents {'context': 'B-organism'}", + "70, nonhuman {'context': 'B-organism'}", + "71, primates. {'context': 'I-organism'}", + "139, neurons {'context': 'B-cells'}", + "148, Blockade {'perturbing_action': 'B-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "67, rodents ['l0', 'l1']", + "70, nonhuman ['l0', 'l2']", + "71, primates. ['l1', 'l2']", + "148, Blockade ['l3', 'l4', 'l5', 'l6']", + "149, of ['l3', 'l7', 'l8', 'l9']", + "150, glutamate ['l4', 'l7', 'l10', 'l11']", + "151, AMPA ['l5', 'l8', 'l10', 'l12']", + "152, receptors ['l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10613822", + "TEXT": "Thrombospondin-1 (TSP-1) is a naturally occurring inhibitor of angiogenesis that limits vessel density in normal tissues and curtails tumor growth. Here, we show that the inhibition of angiogenesis in vitro and in vivo and the induction of apoptosis by thrombospondin-1 all required the sequential activation of CD36, p59fyn, caspase-3 like proteases and p38 mitogen-activated protein kinases. We also detected increased endothelial cell apoptosis in situ at the margins of tumors in mice treated with thrombospondin-1. These results indicate that thrombospondin-1, and possibly other broad-spectrum natural inhibitors of angiogenesis, act in vivo by inducing receptor-mediated apoptosis in activated microvascular endothelial cells.", + "TAG_DATA": [ + "28, in {'context': 'B-in vitro'}", + "29, vitro {'context': 'I-in vitro'}", + "31, in {'context': 'B-in vivo'}", + "32, vivo {'context': 'I-in vivo'}", + "35, induction {'effect': 'B-positive'}", + "37, apoptosis {'phenotype': 'B-apoptosis'}", + "59, increased {'effect': 'B-positive'}", + "60, endothelial {'context': 'B-cells'}", + "61, cell {'context': 'I-cells'}", + "62, apoptosis {'phenotype': 'B-apoptosis'}", + "69, tumors {'context': 'B-neoplasm'}", + "71, mice {'context': 'B-organism'}", + "89, in {'context': 'B-in vivo'}", + "92, inducing {'effect': 'B-positive'}", + "94, apoptosis {'phenotype': 'B-apoptosis'}", + "97, microvascular {'context': 'B-cells'}", + "98, endothelial {'context': 'I-cells'}", + "99, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "28, in ['l0']", + "29, vitro ['l0']", + "31, in ['l1', 'l2', 'l3']", + "32, vivo ['l1', 'l4', 'l5']", + "35, induction ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "37, apoptosis ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "59, increased ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "60, endothelial ['l2', 'l4', 'l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "61, cell ['l3', 'l5', 'l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "62, apoptosis ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "69, tumors ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']", + "71, mice ['l27', 'l28', 'l29']", + "89, in ['l30', 'l31', 'l32', 'l33', 'l34']", + "92, inducing ['l30', 'l35', 'l36', 'l37', 'l38']", + "94, apoptosis ['l31', 'l35', 'l39', 'l40', 'l41']", + "97, microvascular ['l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "98, endothelial ['l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "99, cells. ['l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induction", + "increased", + "inducing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction", + "increased", + "inducing" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell", + "microvascular", + "cells." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction", + "increased" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell", + "microvascular", + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "10581086", + "TEXT": "Angiogenesis, the formation of new capillary blood vessels, is essential not only for the growth and metastasis of solid tumors, but also for wound and ulcer healing, because without the restoration of blood flow, oxygen and nutrients cannot be delivered to the healing site. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indomethacin and ibuprofen are the most widely used drugs for pain, arthritis, cardiovascular diseases and, more recently, the prevention of colon cancer and Alzheimer disease. However, NSAIDs produce gastroduodenal ulcers in about 25% of users (often with bleeding and/or perforations) and delay ulcer healing, presumably by blocking prostaglandin synthesis from cyclooxygenase (COX)-1 and COX-2 (ref. 10). The hypothesis that the gastrointestinal side effects of NSAIDs result from inhibition of COX-1, but not COX-2 (ref. 11), prompted the development of NSAIDs that selectively inhibit only COX-2 (such as celecoxib and rofecoxib). Our study demonstrates that both selective and nonselective NSAIDs inhibit angiogenesis through direct effects on endothelial cells. We also show that this action involves inhibition of mitogen-activated protein (MAP) kinase (ERK2) activity, interference with ERK nuclear translocation, is independent of protein kinase C and has prostaglandin-dependent and prostaglandin-independent components. Finally, we show that both COX-1 and COX-2 are important for the regulation of angiogenesis. These findings challenge the premise that selective COX-2 inhibitors will not affect the gastrointestinal tract and ulcer/wound healing.", + "TAG_DATA": [ + "156, endothelial {'context': 'B-cells'}", + "157, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "135, COX-2 ['l0', 'l1']", + "156, endothelial ['l0', 'l2']", + "157, cells. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10581084", + "TEXT": "Transplantation approaches using cellular bridges, fetal central nervous system cells, fibroblasts expressing neurotrophin-3 (ref. 6), hybridoma cells expressing inhibitory protein-blocking antibodies, or olfactory nerves ensheathing glial cells transplanted into the acutely injured spinal cord have produced axonal regrowth or functional benefits. Transplants of rat or cat fetal spinal cord tissue into the chronically injured cord survive and integrate with the host cord, and may be associated with some functional improvements. In addition, rats transplanted with fetal spinal cord cells have shown improvements in some gait parameters, and the delayed transplantation of fetal raphe cells can enhance reflexes. We transplanted neural differentiated mouse embryonic stem cells into a rat spinal cord 9 days after traumatic injury. Histological analysis 2-5 weeks later showed that transplant-derived cells survived and differentiated into astrocytes, oligodendrocytes and neurons, and migrated as far as 8 mm away from the lesion edge. Furthermore, gait analysis demonstrated that transplanted rats showed hindlimb weight support and partial hindlimb coordination not found in 'sham-operated' controls or control rats transplanted with adult mouse neocortical cells.", + "TAG_DATA": [ + "99, neural {'context': 'B-cells'}", + "100, differentiated {'context': 'I-cells'}", + "101, mouse {'context': 'I-cells'}", + "102, embryonic {'context': 'I-cells'}", + "103, stem {'context': 'I-cells'}", + "104, cells {'context': 'I-cells'}", + "107, rat {'context': 'B-tissue/organ'}", + "108, spinal {'context': 'I-tissue/organ'}", + "109, cord {'context': 'I-tissue/organ'}", + "123, cells {'context': 'I-cells'}", + "126, differentiated {'phenotype': 'B-differentiation'}", + "128, astrocytes, {'context': 'B-cells'}", + "129, oligodendrocytes {'context': 'B-cells'}", + "131, neurons, {'context': 'B-cells'}", + "150, rats {'context': 'B-organism'}", + "166, rats {'context': 'B-organism'}", + "169, adult {'context': 'B-cells'}", + "170, mouse {'context': 'I-cells'}", + "171, neocortical {'context': 'I-cells'}", + "172, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "99, neural ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "100, differentiated ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "101, mouse ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "102, embryonic ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "103, stem ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "104, cells ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "107, rat ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "108, spinal ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74']", + "109, cord ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l75', 'l76', 'l77']", + "123, cells ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l78', 'l79', 'l80', 'l81']", + "126, differentiated ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l71', 'l78', 'l82', 'l83', 'l84']", + "128, astrocytes, ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l72', 'l75', 'l79', 'l82', 'l85', 'l86']", + "129, oligodendrocytes ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l73', 'l76', 'l80', 'l83', 'l85', 'l87']", + "131, neurons, ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l74', 'l77', 'l81', 'l84', 'l86', 'l87']", + "150, rats ['l88', 'l89', 'l90', 'l91', 'l92']", + "166, rats ['l88', 'l93', 'l94', 'l95', 'l96']", + "169, adult ['l89', 'l93', 'l97', 'l98', 'l99']", + "170, mouse ['l90', 'l94', 'l97', 'l100', 'l101']", + "171, neocortical ['l91', 'l95', 'l98', 'l100', 'l102']", + "172, cells. ['l92', 'l96', 'l99', 'l101', 'l102']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "neural", + "differentiated", + "mouse", + "embryonic", + "stem", + "cells", + "astrocytes,", + "oligodendrocytes", + "neurons," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiated" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "spinal" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiated" + ] + } + } + ] + }, + { + "PMID": "10581080", + "TEXT": "The acceleration of atherosclerosis by polygenic (essential) hypertension is well-characterized in humans; however, the lack of an animal model that simulates human disease hinders the elucidation of pathogenic mechanisms. We report here a transgenic atherosclerosis-polygenic hypertension model in Dahl salt-sensitive hypertensive rats that overexpress the human cholesteryl ester transfer protein (Tg[hCETP]DS). Male Tg[hCETP]DS rats fed regular rat chow showed age-dependent severe combined hyperlipidemia, atherosclerotic lesions, myocardial infarctions and decreased survival. These findings differ from various mouse atherosclerosis models, demonstrating the necessity of complex disease modeling in different species. The data demonstrate that cholesteryl ester transfer protein can be proatherogenic. The interaction of polygenic hypertension and hyperlipidemia in the pathogenesis of atherosclerosis in Tg[hCETP]DS rats substantiates epidemiological observations in humans.", + "TAG_DATA": [ + "38, Dahl {'context': 'B-organism'}", + "39, salt-sensitive {'context': 'I-organism'}", + "40, hypertensive {'context': 'I-organism'}", + "41, rats {'context': 'I-organism'}", + "43, overexpress {'perturbing_action': 'B-gene gain-of-function'}", + "44, the {'perturbing_action': 'I-gene gain-of-function'}", + "45, human {'perturbing_action': 'I-gene gain-of-function'}", + "46, cholesteryl {'perturbing_action': 'I-gene gain-of-function'}", + "47, ester {'perturbing_action': 'I-gene gain-of-function'}", + "48, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "49, protein {'perturbing_action': 'I-gene gain-of-function'}", + "50, (Tg[hCETP]DS). {'perturbing_action': 'I-gene gain-of-function'}", + "51, Male {'context': 'B-organism'}", + "53, rats {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "38, Dahl ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "39, salt-sensitive ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "40, hypertensive ['l1', 'l10', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "41, rats ['l2', 'l11', 'l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "43, overexpress ['l12', 'l21', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "44, the ['l3', 'l13', 'l22', 'l29', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "45, human ['l4', 'l14', 'l23', 'l30', 'l37', 'l45', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "46, cholesteryl ['l5', 'l15', 'l24', 'l31', 'l38', 'l46', 'l53', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "47, ester ['l6', 'l16', 'l25', 'l32', 'l39', 'l47', 'l54', 'l60', 'l66', 'l67', 'l68', 'l69', 'l70']", + "48, transfer ['l7', 'l17', 'l26', 'l33', 'l40', 'l48', 'l55', 'l61', 'l66', 'l71', 'l72', 'l73', 'l74']", + "49, protein ['l8', 'l18', 'l27', 'l34', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l75', 'l76', 'l77']", + "50, (Tg[hCETP]DS). ['l9', 'l19', 'l28', 'l35', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l78', 'l79']", + "51, Male ['l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l76', 'l78', 'l80']", + "53, rats ['l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l79', 'l80']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Dahl", + "salt-sensitive", + "hypertensive", + "rats", + "Male" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "the", + "human", + "cholesteryl", + "ester", + "transfer", + "protein", + "(Tg[hCETP]DS).", + "overexpress" + ] + } + } + ] + }, + { + "PMID": "10581063", + "TEXT": "Tremendous controversy has surrounded efforts to undertake research on totipotent human stem cells. To date public policy in the United States has attempted to skirt the ethical and social questions raised by this research. Annas et al. argue that research using human embryos as a source of totipotent stem cells can secure broad public support if there is an open and public discussion about the ethical justification for undertaking such research and the assurance of adequate federal regulation and oversight.", + "TAG_DATA": [ + "41, human {'context': 'B-cells'}", + "42, embryos {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "41, human ['l0']", + "42, embryos ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10545997", + "TEXT": "The alloimmune response against fully MHC-mismatched allografts, compared with immune responses to nominal antigens, entails an unusually large clonal size of alloreactive T cells. Thus, induction of peripheral allograft tolerance established in the absence of immune system ablation and reconstitution is a challenging task in transplantation. Here, we determined whether a reduction in the mass of alloreactive T cells due to apoptosis is an essential initial step for induction of stable allograft tolerance with non-lymphoablative therapy. Blocking both CD28-B7 and CD40-CD40 ligand interactions (co-stimulation blockade) inhibited proliferation of alloreactive T cells in vivo while allowing cell cycle-dependent T-cell apoptosis of proliferating T cells, with permanent engraftment of cardiac allografts but not skin allografts. Treatment with rapamycin plus co-stimulation blockade resulted in massive apoptosis of alloreactive T cells and produced stable skin allograft tolerance, a very stringent test of allograft tolerance. In contrast, treatment with cyclosporine A and co-stimulation blockade abolished T-cell proliferation and apoptosis, as well as the induction of stable allograft tolerance. Our data indicate that induction of T-cell apoptosis and peripheral allograft tolerance is prevented by blocking both signal 1 and signal 2 of T-cell activation.", + "TAG_DATA": [ + "85, inhibited {'effect': 'B-negative'}", + "86, proliferation {'phenotype': 'B-proliferation'}", + "88, alloreactive {'context': 'B-cells'}", + "89, T {'context': 'I-cells'}", + "90, cells {'context': 'I-cells'}", + "91, in {'context': 'B-in vivo'}", + "92, vivo {'context': 'I-in vivo'}", + "94, allowing {'effect': 'B-positive'}", + "97, T-cell {'context': 'B-cells'}", + "98, apoptosis {'phenotype': 'B-apoptosis'}", + "100, proliferating {'context': 'B-cells'}", + "101, T {'context': 'I-cells'}", + "102, cells, {'context': 'I-cells'}", + "107, cardiac {'context': 'B-tissue/organ'}", + "108, allografts {'context': 'I-xenograft'}", + "111, skin {'context': 'B-tissue/organ'}", + "112, allografts. {'context': 'I-xenograft'}", + "119, resulted {'effect': 'B-positive'}", + "120, in {'effect': 'I-positive'}", + "122, apoptosis {'phenotype': 'B-apoptosis'}", + "124, alloreactive {'context': 'B-cells'}", + "125, T {'context': 'I-cells'}", + "126, cells {'context': 'I-cells'}", + "149, abolished {'effect': 'B-negative'}", + "150, T-cell {'context': 'B-cells'}", + "151, proliferation {'phenotype': 'B-proliferation'}", + "153, apoptosis, {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "85, inhibited ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "86, proliferation ['l0', 'l8', 'l9', 'l10', 'l11', 'l12']", + "88, alloreactive ['l1', 'l8', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "89, T ['l2', 'l9', 'l13', 'l20', 'l21', 'l22', 'l23']", + "90, cells ['l3', 'l10', 'l14', 'l20', 'l24', 'l25']", + "91, in ['l4', 'l11', 'l15', 'l21', 'l24', 'l26', 'l27', 'l28']", + "92, vivo ['l5', 'l12', 'l16', 'l22', 'l25', 'l26', 'l29']", + "94, allowing ['l17', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "97, T-cell ['l30', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "98, apoptosis ['l31', 'l39', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "100, proliferating ['l32', 'l40', 'l47', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "101, T ['l6', 'l18', 'l27', 'l33', 'l41', 'l48', 'l54', 'l60', 'l61', 'l62', 'l63', 'l64']", + "102, cells, ['l7', 'l19', 'l23', 'l28', 'l29', 'l34', 'l42', 'l49', 'l55', 'l60', 'l65', 'l66', 'l67', 'l68']", + "107, cardiac ['l35', 'l43', 'l50', 'l56', 'l61', 'l65', 'l69', 'l70', 'l71']", + "108, allografts ['l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l69', 'l72', 'l73']", + "111, skin ['l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l70', 'l72', 'l74']", + "112, allografts. ['l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l73', 'l74']", + "119, resulted ['l75', 'l76', 'l77', 'l78', 'l79']", + "120, in ['l75', 'l80', 'l81', 'l82', 'l83']", + "122, apoptosis ['l76', 'l80', 'l84', 'l85', 'l86']", + "124, alloreactive ['l77', 'l81', 'l84', 'l87', 'l88']", + "125, T ['l78', 'l82', 'l85', 'l87', 'l89']", + "126, cells ['l79', 'l83', 'l86', 'l88', 'l89']", + "149, abolished ['l90', 'l91', 'l92']", + "150, T-cell ['l90', 'l93', 'l94']", + "151, proliferation ['l91', 'l93', 'l95']", + "153, apoptosis, ['l92', 'l94', 'l95']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "abolished" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "abolished" + ] + }, + "context": { + "val": "cells", + "words": [ + "alloreactive", + "T", + "cells", + "cells,", + "T-cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "alloreactive", + "T", + "cells", + "T-cell" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "alloreactive", + "T-cell", + "proliferating", + "T", + "cells,", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "allowing", + "resulted", + "in" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "allowing", + "resulted", + "in" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "allowing" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "cardiac", + "skin" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "allowing" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "allografts", + "allografts." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T-cell", + "proliferating", + "T", + "cells,", + "alloreactive", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "cardiac", + "skin" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "allografts", + "allografts." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abolished" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + } + ] + }, + { + "PMID": "10545994", + "TEXT": "Thrombospondin forms a 'molecular bridge' between phagocytic and apoptotic cells through interaction with alphavbeta3/CD36. We report here that engagement of CD47, a newly described thrombospondin receptor, by immobilized monoclonal antibody against CD47 or by thrombospondin induced in all B-cell chronic lymphocytic leukemia clones the cytoplasmic features of apoptosis (cell shrinkage, decrease in mitochondrial transmembrane potential and phosphatidylserine externalization) without the nuclear features (chromatin condensation, appearance of single-stranded DNA, DNA fragmentation and cleavage of poly ADP-ribose polymerase). These cytoplasmic events of apoptosis were not prevented by the addition of caspase inhibitor z-VAD-fmk, or by the presence of survival factors (such as interleukin-4 and gamma interferon) or cell activation. Morphological studies confirmed the integrity of the nucleus and showed swelling of the mitochondria. This caspase-independent death pathway may be relevant to the development of alternate therapeutic strategies in chronic lymphocytic leukemia, which remains an incurable disease.", + "TAG_DATA": [ + "35, induced {'effect': 'B-positive'}", + "38, B-cell {'context': 'B-transformed cells'}", + "39, chronic {'context': 'I-transformed cells'}", + "40, lymphocytic {'context': 'I-transformed cells'}", + "41, leukemia {'context': 'I-transformed cells'}", + "42, clones {'context': 'I-transformed cells'}", + "47, apoptosis {'phenotype': 'B-apoptosis'}", + "80, apoptosis {'phenotype': 'B-apoptosis'}", + "105, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "35, induced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "38, B-cell ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "39, chronic ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "40, lymphocytic ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "41, leukemia ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "42, clones ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "47, apoptosis ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "105, cell ['l21']", + "106, activation. ['l21']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "B-cell", + "chronic", + "lymphocytic", + "leukemia", + "clones" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "B-cell", + "chronic", + "lymphocytic", + "leukemia", + "clones" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "10545993", + "TEXT": "Cytotoxic T-lymphocyte (CTL) responses to human immunodeficiency virus arise early after infection, but ultimately fail to prevent progression to AIDS. Human immunodeficiency virus may evade the CTL response by accumulating amino-acid replacements within CTL epitopes. We studied 10 CTL epitopes during the course of simian immunodeficiency virus disease progression in three related macaques. All 10 of these CTL epitopes accumulated amino-acid replacements and showed evidence of positive selection by the time the macaques died. Many of the amino-acid replacements in these epitopes reduced or eliminated major histocompatibility complex class I binding and/or CTL recognition. These findings strongly support the CTL 'escape' hypothesis.", + "TAG_DATA": [ + "51, related {'context': 'B-organism'}", + "52, macaques. {'context': 'I-organism'}", + "72, macaques {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "51, related ['l0']", + "52, macaques. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10545992", + "TEXT": "Early growth response factor-1 (Egr-1) binds to the promoters of many genes whose products influence cell movement and replication in the artery wall. Here we targeted Egr-1 using a new class of DNA-based enzyme that specifically cleaved Egr-1 mRNA, blocked induction of Egr-1 protein, and inhibited cell proliferation and wound repair in culture. The DNA enzyme also inhibited Egr-1 induction and neointima formation after balloon injury to the rat carotid artery wall. These findings demonstrate the utility of DNA enzymes as biological tools to delineate the specific functions of a given gene, and implicate catalytic nucleic acid molecules composed entirely of DNA as potential therapeutic agents.", + "TAG_DATA": [ + "45, inhibited {'effect': 'B-negative'}", + "46, cell {'context': 'B-cells'}", + "47, proliferation {'phenotype': 'B-proliferation'}", + "52, culture. {'context': 'B-cells'}", + "57, inhibited {'effect': 'B-negative'}", + "61, neointima {'phenotype': 'B-tumourigenesis'}", + "62, formation {'phenotype': 'I-tumourigenesis'}", + "68, rat {'context': 'B-tissue/organ'}", + "69, carotid {'context': 'I-tissue/organ'}", + "70, artery {'context': 'I-tissue/organ'}", + "71, wall. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "45, inhibited ['l0', 'l1', 'l2']", + "46, cell ['l0', 'l3', 'l4']", + "47, proliferation ['l1', 'l3', 'l5']", + "52, culture. ['l2', 'l4', 'l5']", + "57, inhibited ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "61, neointima ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "62, formation ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "68, rat ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "69, carotid ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "70, artery ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "71, wall. ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "culture." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell", + "culture." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neointima", + "formation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "carotid", + "artery", + "wall." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neointima", + "formation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "carotid", + "artery", + "wall." + ] + } + } + ] + }, + { + "PMID": "10545990", + "TEXT": "Dendritic cells, the most potent antigen-presenting cells, need to be activated before they can function to initiate an immune response. We report here that, in the absence of any foreign substances, dendritic cells can be activated by endogenous signals received from cells that are stressed, virally infected or killed necrotically, but not by healthy cells or those dying apoptotically. Injected in vivo with an antigen, the endogenous activating substances can function as natural adjuvants to stimulate a primary immune response, and they may represent the natural initiators of transplant rejection, spontaneous tumor rejection, and some forms of autoimmunity.", + "TAG_DATA": [ + "31, dendritic {'context': 'B-cells'}", + "32, cells {'context': 'I-cells'}", + "54, cells {'context': 'I-cells'}", + "60, in {'context': 'B-in vivo'}", + "61, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "31, dendritic ['l0']", + "32, cells ['l0']", + "60, in ['l1']", + "61, vivo ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10545986", + "TEXT": "Clinical diagnosis of mismatch repair defects has recently been complicated by the discovery of multiple gene alterations that lead to an expanded tumor spectrum. Studies of mismatch repair protein function will improve our understanding of this process and result in better prognostic indicators of mismatch repair-associated tumor development.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10502826", + "TEXT": "Platelet activation is characterized by shape change, induction of fibrinogen receptor expression and release of granular contents, leading to aggregation and plug formation. While this response is essential for hemostasis, it is also important in the pathogenesis of a broad spectrum of diseases, including myocardial infarction, stroke and unstable angina. Adenosine 5'-diphosphate (ADP) induces platelet aggregation, but the mechanism for this has not been established, and the relative contribution of ADP in hemostasis and the development of arterial thrombosis is poorly understood. We show here that the purinoceptor P2Y1 is required for platelet shape change in response to ADP and is also a principal receptor mediating ADP-induced platelet aggregation. Activation of P2Y1 resulted in increased intracellular calcium but no alteration in cyclic adenosine monophosphate (cAMP) levels. P2Y1-deficient platelets partially aggregated at higher ADP concentrations, and the lack of P2Y1 did not alter the ability of ADP to inhibit cAMP, indicating that platelets express at least one additional ADP receptor. In vivo, the lack of P2Y1 expression increased bleeding time and protected from collagen- and ADP-induced thromboembolism. These findings support the hypothesis that the ATP receptor P2Y1 is a principal receptor mediating both physiologic and pathological ADP-induced processes in platelets.", + "TAG_DATA": [ + "126, P2Y1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "127, platelets {'context': 'B-cells'}", + "136, lack {'perturbing_action': 'B-gene loss-of-function'}", + "137, of {'perturbing_action': 'I-gene loss-of-function'}", + "138, P2Y1 {'perturbing_action': 'I-gene loss-of-function'}", + "159, In {'context': 'B-in vivo'}", + "160, vivo, {'context': 'I-in vivo'}", + "162, lack {'perturbing_action': 'B-gene loss-of-function'}", + "163, of {'perturbing_action': 'I-gene loss-of-function'}", + "164, P2Y1 {'perturbing_action': 'I-gene loss-of-function'}", + "165, expression {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "126, P2Y1-deficient ['l0']", + "127, platelets ['l0']", + "136, lack ['l1', 'l2']", + "137, of ['l1', 'l3']", + "138, P2Y1 ['l2', 'l3']", + "159, In ['l4', 'l5', 'l6', 'l7', 'l8']", + "160, vivo, ['l4', 'l9', 'l10', 'l11', 'l12']", + "162, lack ['l5', 'l9', 'l13', 'l14', 'l15']", + "163, of ['l6', 'l10', 'l13', 'l16', 'l17']", + "164, P2Y1 ['l7', 'l11', 'l14', 'l16', 'l18']", + "165, expression ['l8', 'l12', 'l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "P2Y1-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelets" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "P2Y1", + "expression" + ] + } + } + ] + }, + { + "PMID": "10502824", + "TEXT": "Neuropeptide Y (NPY), a 36-amino-acid peptide widely expressed in the brain is involved in many physiological responses, including hypothalamic control of food intake and cardiovascular homeostasis. NPY mediates its effects through binding to the Y1, Y2 and Y5 G-protein-coupled receptors. Little is known of the role of the Y2 receptor in mediating the different NPY effects. We inactivated the Y2 receptor subtype in mice and found that these mice developed increased body weight, food intake and fat deposition. The null mutant mice showed an attenuated response to leptin administration but a normal response to NPY-induced food intake and intact regulation of re-feeding and body weight after starvation. An absence of the Y2 receptor subtype also affected the basal control of heart rate, but did not influence blood pressure. These findings indicate an inhibitory role for the Y2 receptor subtype in the central regulation of body weight and control of food intake.", + "TAG_DATA": [ + "57, inactivated {'perturbing_action': 'B-gene loss-of-function'}", + "58, the {'perturbing_action': 'I-gene loss-of-function'}", + "59, Y2 {'perturbing_action': 'I-gene loss-of-function'}", + "60, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "61, subtype {'perturbing_action': 'I-gene loss-of-function'}", + "63, mice {'context': 'B-organism'}", + "68, mice {'context': 'B-organism'}", + "79, null {'perturbing_action': 'B-gene loss-of-function'}", + "81, mice {'context': 'B-organism'}", + "108, absence {'perturbing_action': 'B-gene loss-of-function'}", + "109, of {'perturbing_action': 'I-gene loss-of-function'}", + "110, the {'perturbing_action': 'I-gene loss-of-function'}", + "111, Y2 {'perturbing_action': 'I-gene loss-of-function'}", + "112, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "113, subtype {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "57, inactivated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "58, the ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "59, Y2 ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "60, receptor ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "61, subtype ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "63, mice ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "68, mice ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "79, null ['l21', 'l22']", + "80, mutant ['l21', 'l23']", + "81, mice ['l22', 'l23']", + "108, absence ['l24', 'l25', 'l26', 'l27', 'l28']", + "109, of ['l24', 'l29', 'l30', 'l31', 'l32']", + "110, the ['l25', 'l29', 'l33', 'l34', 'l35']", + "111, Y2 ['l26', 'l30', 'l33', 'l36', 'l37']", + "112, receptor ['l27', 'l31', 'l34', 'l36', 'l38']", + "113, subtype ['l28', 'l32', 'l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivated", + "the", + "Y2", + "receptor", + "subtype", + "null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "10502823", + "TEXT": "Retinitis pigmentosa is an inherited degenerative disease of photoreceptors leading to blindness. A well-characterized model for this disease is provided by the retinal degeneration mouse, in which the gene for the rod cGMP phosphodiesterase is mutated, as in some affected human families. We report that D-cis-diltiazem, a calcium-channel blocker that also acts at light-sensitive cGMP-gated channels, rescued photoreceptors and preserved visual function in the retinal degeneration mouse. The long record of diltiazem prescription in cardiology should facilitate the design of clinical trials for some forms of retinitis pigmentosa.", + "TAG_DATA": [ + "57, photoreceptors {'context': 'B-cells'}", + "66, mouse. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "57, photoreceptors ['l0']", + "66, mouse. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10502818", + "TEXT": "The mechanisms regulating airway function are complex and still poorly understood. In diseases such as asthma, involvement of immune-dependent mechanisms has been suggested in causing changes in airway responsiveness to bronchoconstrictors. We now demonstrate that gammadelta T cells can regulate airway function in an alphabeta T cell-independent manner, identifying them as important cells in pulmonary homeostasis. This function of gammadelta T cells differs from previously described immune-dependent mechanisms and may reflect their interaction with innate systems of host defense.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10502816", + "TEXT": "Cardiac rupture is a fatal complication of acute myocardial infarction lacking treatment. Here, acute myocardial infarction resulted in rupture in wild-type mice and in mice lacking tissue-type plasminogen activator, urokinase receptor, matrix metalloproteinase stromelysin-1 or metalloelastase. Instead, deficiency of urokinase-type plasminogen activator (u-PA-/-) completely protected against rupture, whereas lack of gelatinase-B partially protected against rupture. However, u-PA-/- mice showed impaired scar formation and infarct revascularization, even after treatment with vascular endothelial growth factor, and died of cardiac failure due to depressed contractility, arrhythmias and ischemia. Temporary administration of PA inhibitor-1 or the matrix metalloproteinase-inhibitor TIMP-1 completely protected wild-type mice against rupture but did not abort infarct healing, thus constituting a new approach to prevent cardiac rupture after acute myocardial infarction.", + "TAG_DATA": [ + "21, mice {'context': 'B-organism'}", + "24, mice {'context': 'B-organism'}", + "25, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "37, deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "38, of {'perturbing_action': 'I-gene loss-of-function'}", + "39, urokinase-type {'perturbing_action': 'I-gene loss-of-function'}", + "40, plasminogen {'perturbing_action': 'I-gene loss-of-function'}", + "41, activator {'perturbing_action': 'I-gene loss-of-function'}", + "42, (u-PA-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "48, lack {'perturbing_action': 'B-gene loss-of-function'}", + "49, of {'perturbing_action': 'I-gene loss-of-function'}", + "50, gelatinase-B {'perturbing_action': 'I-gene loss-of-function'}", + "56, u-PA-/- {'perturbing_action': 'B-gene loss-of-function'}", + "57, mice {'context': 'B-organism'}", + "98, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "24, mice ['l0', 'l1']", + "25, lacking ['l0', 'l2']", + "37, deficiency ['l3', 'l4', 'l5', 'l6', 'l7']", + "38, of ['l3', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "39, urokinase-type ['l4', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "40, plasminogen ['l5', 'l9', 'l14', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "41, activator ['l6', 'l10', 'l15', 'l21', 'l27', 'l28', 'l29', 'l30']", + "42, (u-PA-/-) ['l1', 'l2', 'l7', 'l11', 'l16', 'l22', 'l27']", + "48, lack ['l17', 'l23', 'l31', 'l32', 'l33', 'l34']", + "49, of ['l18', 'l24', 'l28', 'l31', 'l35', 'l36', 'l37']", + "50, gelatinase-B ['l12', 'l19', 'l25', 'l29', 'l32', 'l35', 'l38', 'l39']", + "56, u-PA-/- ['l33', 'l36', 'l38', 'l40']", + "57, mice ['l13', 'l20', 'l26', 'l30', 'l34', 'l37', 'l39', 'l40']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "(u-PA-/-)", + "of", + "urokinase-type", + "plasminogen", + "activator", + "lack", + "gelatinase-B", + "u-PA-/-" + ] + } + } + ] + }, + { + "PMID": "10470089", + "TEXT": "Malignant transformation of human cells requires the accumulation of multiple genetic alterations, such as the activation of oncogenes and loss of function of tumor suppressor genes or those related to genomic instability. Among the genetic alterations most frequently found in human tumors are chromosomal translocations that may result in the expression of chimeric products with transforming capability or are able to change the expression of oncogenes. We show here that the adenovirus early region 1A (E1A) gene can induce a specific human fusion transcript (EWS-FLI1) that is characteristic of Ewing tumors. This fusion transcript was detected by RT-PCR in normal human fibroblasts and keratinocytes after expression of the adenovirus E1A gene, as well as in human cell lines immortalized by adenoviruses. Cloning and sequencing of the RT-PCR product showed fusion points between EWS and FLI1 cDNA identical to those detected in Ewing tumors. In addition, we detected a chimeric protein by western blot analysis and immunoprecipitation and a t(11,22) by fluorescent in situ hybridization. This association between a single viral gene and a specific human fusion transcript indicates a direct link between viral genes and chromosome translocations, one of the hallmarks of many human tumors.", + "TAG_DATA": [ + "100, human {'context': 'I-cells'}", + "101, fibroblasts {'context': 'I-cells'}", + "103, keratinocytes {'context': 'B-cells'}", + "115, human {'context': 'B-cells'}", + "116, cell {'context': 'I-cells'}", + "117, lines {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "100, human ['l0', 'l1']", + "101, fibroblasts ['l0', 'l2']", + "103, keratinocytes ['l1', 'l2']", + "115, human ['l3', 'l4']", + "116, cell ['l3', 'l5']", + "117, lines ['l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10470087", + "TEXT": "Pro-opiomelanocortin (POMC)-derived peptides (the melanocortins adrenocorticotropin, alpha-, beta- and gamma-melanocyte stimulating hormone; and the endogenous opioid beta-endorphin) have a diverse array of biological activities, including roles in pigmentation, adrenocortical function and regulation of energy stores, and in the immune system and the central and peripheral nervous systems. We show here that mice lacking the POMC-derived peptides have obesity, defective adrenal development and altered pigmentation. This phenotype is similar to that of the recently identified human POMC-deficient patients. When treated with a stable alpha-melanocyte-stimulating hormone agonist, mutant mice lost more than 40% of their excess weight after 2 weeks. Our results identify the POMC-null mutant mouse as a model for studying the human POMC-null syndrome, and indicate the therapeutic use of peripheral melanocortin in the treatment of obesity.", + "TAG_DATA": [ + "51, mice {'context': 'B-organism'}", + "52, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "53, the {'perturbing_action': 'I-gene loss-of-function'}", + "54, POMC-derived {'perturbing_action': 'I-gene loss-of-function'}", + "55, peptides {'perturbing_action': 'I-gene loss-of-function'}", + "86, mice {'context': 'B-organism'}", + "102, POMC-null {'perturbing_action': 'B-gene loss-of-function'}", + "103, mutant {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "51, mice ['l0', 'l1', 'l2', 'l3']", + "52, lacking ['l0', 'l4', 'l5', 'l6']", + "53, the ['l1', 'l4', 'l7', 'l8']", + "54, POMC-derived ['l2', 'l5', 'l7', 'l9']", + "55, peptides ['l3', 'l6', 'l8', 'l9']", + "102, POMC-null ['l10']", + "103, mutant ['l10']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "POMC-derived", + "peptides" + ] + } + } + ] + }, + { + "PMID": "10470085", + "TEXT": "Although the inflammatory response is essential for protecting tissues from injury and infection, unrestrained inflammation can cause chronic inflammatory diseases such as arthritis, colitis and asthma. Physiological mechanisms that downregulate inflammation are poorly understood. Potent control might be achieved by regulating early stages in the inflammatory response, such as accumulation of neutrophils at the site of injury, where these cells release chemical mediators that promote inflammatory processes including plasma extravasation, bacteriocide and proteolysis. To access an inflammatory site, neutrophils must first adhere to the vascular endothelium in a process mediated in part by the leukocyte adhesion molecule L-selectin. This adhesion is prevented when L-selectin is shed from the neutrophil membrane. Although shedding of L-selectin is recognized as a potentially important mechanism for regulating neutrophils, its physiological function has not been demonstrated. Shedding of L-selectin may mediate endogenous downregulation of inflammation by limiting neutrophil accumulation at inflammatory sites. Here we show that activation of nociceptive neurons induces shedding of L-selectin from circulating neutrophils in vivo and that this shedding suppresses an ongoing inflammatory response by inhibiting neutrophil accumulation. These findings indicate a previously unknown mechanism for endogenous feedback control of inflammation. Failure of this mechanism could contribute to the etiology of chronic inflammatory disease.", + "TAG_DATA": [ + "153, nociceptive {'context': 'B-cells'}", + "154, neurons {'context': 'I-cells'}", + "162, in {'context': 'B-in vivo'}", + "163, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "153, nociceptive ['l0', 'l1', 'l2']", + "154, neurons ['l0', 'l3', 'l4']", + "162, in ['l1', 'l3', 'l5']", + "163, vivo ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10470081", + "TEXT": "Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that causes life-threatening disease in patients who are immunosuppressed for bone marrow or tissue transplantation or who have AIDS (ref. 1). HCMV establishes lifelong latent infections and, after periodic reactivation from latency, uses a panel of immune evasion proteins to survive and replicate in the face of robust, fully primed host immunity. Monocyte/macrophages are important host cells for HCMV, serving as a latent reservoir and as a means of dissemination throughout the body. Macrophages and other HCMV-permissive cells, such as endothelial and glial cells, can express MHC class II proteins and present antigens to CD4+ T lymphocytes. Here, we show that the HCMV protein US2 causes degradation of two essential proteins in the MHC class II antigen presentation pathway: HLA-DR-alpha and DM-alpha. This was unexpected, as US2 has been shown to cause degradation of MHC class I (refs. 5,6), which has only limited homology with class II proteins. Expression of US2 in cells reduced or abolished their ability to present antigen to CD4+ T lymphocytes. Thus, US2 may allow HCMV-infected macrophages to remain relatively 'invisible' to CD4+ T cells, a property that would be important after virus reactivation.", + "TAG_DATA": [ + "155, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "156, of {'perturbing_action': 'I-gene gain-of-function'}", + "157, US2 {'perturbing_action': 'I-gene gain-of-function'}", + "159, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "155, Expression ['l0', 'l1', 'l2']", + "156, of ['l0', 'l3', 'l4']", + "157, US2 ['l1', 'l3', 'l5']", + "159, cells ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "US2" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "10470080", + "TEXT": "We have designed short peptides composed of two functional domains, one a tumor blood vessel 'homing' motif and the other a programmed cell death-inducing sequence, and synthesized them by simple peptide chemistry. The 'homing' domain was designed to guide the peptide to targeted cells and allow its internalization. The pro-apoptotic domain was designed to be nontoxic outside cells, but toxic when internalized into targeted cells by the disruption of mitochondrial membranes. Although our prototypes contain only 21 and 26 residues, they were selectively toxic to angiogenic endothelial cells and showed anti-cancer activity in mice. This approach may yield new therapeutic agents.", + "TAG_DATA": [ + "57, cells, {'context': 'B-cells'}", + "85, angiogenic {'context': 'B-cells'}", + "86, endothelial {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}", + "93, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "85, angiogenic ['l0', 'l1', 'l2']", + "86, endothelial ['l0', 'l3', 'l4']", + "87, cells ['l1', 'l3', 'l5']", + "93, mice. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10470075", + "TEXT": "Infection of macrophage lineage cells is a feature of primate lentivirus replication, and several properties of primate lentiviruses seem to have evolved to promote the infection of macrophages. Here we demonstrate that the accessory gene product Nef induces the production of two CC-chemokines, macrophage inflammatory proteins 1alpha and 1beta, by HIV-1-infected macrophages. Adenovirus-mediated expression of Nef in primary macrophages was sufficient for chemokine induction. Supernatants from Nef-expressing macrophages induced both the chemotaxis and activation of resting T lymphocytes, permitting productive HIV-1 infection. These results indicate a role for Nef in lymphocyte recruitment and activation at sites of virus replication.", + "TAG_DATA": [ + "51, macrophages. {'context': 'B-cells'}", + "52, Adenovirus-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "53, expression {'perturbing_action': 'I-gene gain-of-function'}", + "54, of {'perturbing_action': 'I-gene gain-of-function'}", + "55, Nef {'perturbing_action': 'I-gene gain-of-function'}", + "57, primary {'context': 'B-cells'}", + "58, macrophages {'context': 'I-cells'}", + "66, Nef-expressing {'context': 'B-cells'}", + "67, macrophages {'context': 'I-cells'}", + "68, induced {'effect': 'B-positive'}", + "71, chemotaxis {'phenotype': 'B-migration'}", + "76, T {'context': 'B-cells'}", + "77, lymphocytes, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "52, Adenovirus-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "53, expression ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "54, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "55, Nef ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "57, primary ['l3', 'l11', 'l18', 'l24', 'l30']", + "58, macrophages ['l4', 'l12', 'l19', 'l25', 'l30', 'l31']", + "66, Nef-expressing ['l32', 'l33', 'l34', 'l35', 'l36']", + "67, macrophages ['l32', 'l37', 'l38', 'l39', 'l40']", + "68, induced ['l5', 'l13', 'l20', 'l26', 'l31', 'l33', 'l37', 'l41', 'l42', 'l43']", + "71, chemotaxis ['l6', 'l14', 'l21', 'l27', 'l34', 'l38', 'l41', 'l44', 'l45']", + "76, T ['l7', 'l15', 'l22', 'l28', 'l35', 'l39', 'l42', 'l44', 'l46']", + "77, lymphocytes, ['l8', 'l16', 'l23', 'l29', 'l36', 'l40', 'l43', 'l45', 'l46']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenovirus-mediated", + "expression", + "of", + "Nef" + ] + }, + "context": { + "val": "cells", + "words": [ + "primary", + "macrophages", + "T", + "lymphocytes," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenovirus-mediated", + "expression", + "of", + "Nef" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenovirus-mediated", + "expression", + "of", + "Nef" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "macrophages", + "Nef-expressing", + "T", + "lymphocytes," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Nef-expressing", + "macrophages", + "T", + "lymphocytes," + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + } + } + ] + }, + { + "PMID": "10426321", + "TEXT": "Azodicarbonamide was recently identified as a new anti-HIV agent that targets the zinc finger domains of the HIV-1 NCp7 nucleocapsid protein. Here, we demonstrate that azodicarbonamide inhibits in a dose-dependent manner the responses of purified human CD4+ T lymphocytes stimulated either by monoclonal antibodies against CD3 and CD28 or by allogeneic dendritic cells. These suppressive effects involve a direct action on the calcium mobilization machinery, as azodicarbonamide strongly inhibited the calcium influx induced either by antibodies against CD3 and CD28 or the chemokine RANTES, as well as by thapsigargin, an activator of depletion-activated calcium channels. In vivo, administration of azodicarbonamide into mice blunted their response to polyclonal T-cell activation induced by the injection of monoclonal antibody against CD3 and resulted in delayed rejection of skin allografts. In addition to its anti-HIV properties, azodicarbonamide is a new immunosuppressive agent that might have therapeutic applications in T cell-mediated inflammatory disorders.", + "TAG_DATA": [ + "34, purified {'context': 'B-cells'}", + "35, human {'context': 'I-cells'}", + "36, CD4+ {'context': 'I-cells'}", + "37, T {'context': 'I-cells'}", + "38, lymphocytes {'context': 'I-cells'}", + "50, allogeneic {'context': 'B-cells'}", + "51, dendritic {'context': 'I-cells'}", + "52, cells. {'context': 'I-cells'}", + "95, In {'context': 'B-in vivo'}", + "96, vivo, {'context': 'I-in vivo'}", + "101, mice {'context': 'B-organism'}", + "107, T-cell {'context': 'I-cells'}", + "124, skin {'context': 'B-xenograft'}", + "125, allografts. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "34, purified ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "35, human ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "36, CD4+ ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "37, T ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "38, lymphocytes ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "50, allogeneic ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "51, dendritic ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "52, cells. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "95, In ['l28', 'l29', 'l30', 'l31', 'l32']", + "96, vivo, ['l28', 'l33', 'l34']", + "101, mice ['l29', 'l33', 'l35', 'l36', 'l37']", + "107, T-cell ['l30', 'l34', 'l35']", + "124, skin ['l31', 'l36', 'l38']", + "125, allografts. ['l32', 'l37', 'l38']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10426319", + "TEXT": "Tumor-associated antigens that can be recognized by the immune system include the MAGE-family, p53, MUC-1, HER2/neu and p21ras. Despite their expression of these distinct antigens, tumor elimination by the immune system is often inefficient. Postulated mechanisms include insufficient expression of co-stimulatory or adhesion molecules by tumor cells, or defective processing and presentation of antigens on their cell surfaces. Tumor cells may also evade immune attack by expressing CD95 (APO-1/Fas) ligand or other molecules that induce apoptosis in activated T cells. Here we describe RCAS1 (receptor-binding cancer antigen expressed on SiSo cells), a membrane molecule expressed on human cancer cells. RCAS1 acts as a ligand for a putative receptor present on various human cell lines and normal peripheral lymphocytes such as T, B and NK cells. The receptor expression was enhanced by activation of the lymphocytes. RCAS1 inhibited the in vitro growth of receptor-expressing cells and induced apoptotic cell death. Given these results, tumor cells may evade immune surveillance by expression of RCAS1, which would suppress clonal expansion and induce apoptosis in RCAS1 receptor-positive immune cells.", + "TAG_DATA": [ + "138, in {'context': 'B-in vitro'}", + "139, vitro {'context': 'I-in vitro'}", + "142, receptor-expressing {'context': 'B-cells'}", + "143, cells {'context': 'I-cells'}", + "145, induced {'effect': 'B-positive'}", + "146, apoptotic {'phenotype': 'B-apoptosis'}", + "147, cell {'phenotype': 'I-apoptosis'}", + "148, death. {'phenotype': 'I-apoptosis'}" + ], + "LINK_DATA": [ + "138, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "139, vitro ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "142, receptor-expressing ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "143, cells ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "145, induced ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "146, apoptotic ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "147, cell ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "148, death. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "receptor-expressing", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "receptor-expressing", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "10426315", + "TEXT": "The central nervous dysfunctions of lethargy, fever and anorexia are manifestations of sepsis that seem to be mediated by increased cytokine production. Here we demonstrate that tumor necrosis factor (TNF)-alpha, an essential mediator of endotoxin-induced sepsis, prevents the proteasome-dependent degradation of RGS7, a regulator of G-protein signaling. The stabilization of RGS7 by TNF-alpha requires activation of the stress-activated protein kinase p38 and the presence of candidate mitogen-activated protein kinase phosphorylation sites. In vivo, RGS7 is rapidly upregulated in mouse brain after exposure to either endotoxin or TNF-alpha, a response that is nearly abrogated in mice lacking TNF receptor 1. Our findings indicate that TNF-mediated upregulation of RGS7 may contribute to sepsis-induced changes in central nervous function.", + "TAG_DATA": [ + "71, In {'context': 'B-in vivo'}", + "72, vivo, {'context': 'I-in vivo'}", + "78, mouse {'context': 'B-tissue/organ'}", + "79, brain {'context': 'I-tissue/organ'}", + "94, mice {'context': 'B-organism'}", + "95, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "96, TNF {'perturbing_action': 'I-gene loss-of-function'}", + "97, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "98, 1. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "71, In ['l0', 'l1', 'l2']", + "72, vivo, ['l0', 'l3', 'l4']", + "78, mouse ['l1', 'l3', 'l5']", + "79, brain ['l2', 'l4', 'l5']", + "94, mice ['l6', 'l7', 'l8', 'l9']", + "95, lacking ['l6', 'l10', 'l11', 'l12']", + "96, TNF ['l7', 'l10', 'l13', 'l14']", + "97, receptor ['l8', 'l11', 'l13', 'l15']", + "98, 1. ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "TNF", + "receptor", + "1." + ] + } + } + ] + }, + { + "PMID": "10426313", + "TEXT": "Intestinal inflammatory diseases are mediated by dysregulated immune responses to undefined luminal antigens. Feeding hen egg-white lysozyme to mice expressing a transgenic T-cell receptor that recognizes hen egg-white lysozyme peptide 46-61 resulted in no intestinal pathology; however, simultaneous administration of cyclooxygenase-2 inhibitors and dietary hen egg-white lysozyme resulted in increased proliferation of lamina propria mononuclear cells and crypt epithelial cells, crypt expansion and villus blunting. Lamina propria mononuclear cells produce high levels of cyclooxygenase-2-dependent arachidonic acid metabolites, which act as immunomodulators in the immune response to dietary antigen. These findings establish that cyclooxygenase-2-dependent arachidonic acid metabolites are essential in the development and maintenance of intestinal immune homeostasis.", + "TAG_DATA": [ + "18, mice {'context': 'B-organism'}", + "19, expressing {'perturbing_action': 'B-other'}", + "20, a {'perturbing_action': 'I-gene gain-of-function'}", + "21, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "22, T-cell {'perturbing_action': 'I-other'}", + "23, receptor {'perturbing_action': 'I-other'}", + "24, that {'perturbing_action': 'I-other'}", + "25, recognizes {'perturbing_action': 'I-other'}", + "30, 46-61 {'perturbing_action': 'I-other'}", + "40, cyclooxygenase-2 {'perturbing_action': 'B-pharmacological inhibition'}", + "41, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "49, increased {'effect': 'B-positive'}", + "50, proliferation {'phenotype': 'B-proliferation'}", + "52, lamina {'context': 'B-cells'}", + "53, propria {'context': 'I-cells'}", + "54, mononuclear {'context': 'I-cells'}", + "55, cells {'context': 'I-cells'}", + "57, crypt {'context': 'B-cells'}", + "58, epithelial {'context': 'I-cells'}", + "59, cells, {'context': 'I-cells'}", + "65, Lamina {'context': 'B-cells'}", + "66, propria {'context': 'B-cells'}", + "67, mononuclear {'context': 'I-cells'}", + "68, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "18, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "19, expressing ['l0', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "20, a ['l1', 'l18', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "21, transgenic ['l2', 'l19', 'l38', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "22, T-cell ['l3', 'l20', 'l39', 'l57', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "23, receptor ['l4', 'l21', 'l40', 'l58', 'l75', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "24, that ['l5', 'l22', 'l41', 'l59', 'l76', 'l92', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "25, recognizes ['l6', 'l23', 'l42', 'l60', 'l77', 'l93', 'l108', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "26, hen ['l7', 'l24', 'l43', 'l61', 'l78', 'l94', 'l109', 'l123', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "27, egg-white ['l8', 'l25', 'l44', 'l62', 'l79', 'l95', 'l110', 'l124', 'l137', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "28, lysozyme ['l9', 'l26', 'l45', 'l63', 'l80', 'l96', 'l111', 'l125', 'l138', 'l150', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "29, peptide ['l10', 'l27', 'l46', 'l64', 'l81', 'l97', 'l112', 'l126', 'l139', 'l151', 'l162', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "30, 46-61 ['l11', 'l28', 'l47', 'l65', 'l82', 'l98', 'l113', 'l127', 'l140', 'l152', 'l163', 'l173', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "40, cyclooxygenase-2 ['l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201']", + "41, inhibitors ['l189', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213']", + "49, increased ['l29', 'l48', 'l66', 'l83', 'l99', 'l114', 'l128', 'l141', 'l153', 'l164', 'l174', 'l190', 'l202', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221']", + "50, proliferation ['l12', 'l30', 'l49', 'l67', 'l84', 'l100', 'l115', 'l129', 'l142', 'l154', 'l165', 'l175', 'l183', 'l191', 'l203', 'l214', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228']", + "52, lamina ['l13', 'l31', 'l50', 'l68', 'l85', 'l101', 'l116', 'l130', 'l143', 'l155', 'l166', 'l176', 'l184', 'l192', 'l204', 'l215', 'l222', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234']", + "53, propria ['l14', 'l32', 'l51', 'l69', 'l86', 'l102', 'l117', 'l131', 'l144', 'l156', 'l167', 'l177', 'l185', 'l193', 'l205', 'l216', 'l223', 'l229', 'l235', 'l236', 'l237', 'l238', 'l239']", + "54, mononuclear ['l15', 'l33', 'l52', 'l70', 'l87', 'l103', 'l118', 'l132', 'l145', 'l157', 'l168', 'l178', 'l186', 'l194', 'l206', 'l217', 'l224', 'l230', 'l235', 'l240', 'l241', 'l242', 'l243']", + "55, cells ['l16', 'l34', 'l53', 'l71', 'l88', 'l104', 'l119', 'l133', 'l146', 'l158', 'l169', 'l179', 'l187', 'l195', 'l207', 'l218', 'l225', 'l231', 'l236', 'l240', 'l244', 'l245', 'l246']", + "57, crypt ['l35', 'l54', 'l72', 'l89', 'l105', 'l120', 'l134', 'l147', 'l159', 'l170', 'l180', 'l196', 'l208', 'l219', 'l226', 'l232', 'l237', 'l241', 'l244', 'l247', 'l248']", + "58, epithelial ['l36', 'l55', 'l73', 'l90', 'l106', 'l121', 'l135', 'l148', 'l160', 'l171', 'l181', 'l197', 'l209', 'l220', 'l227', 'l233', 'l238', 'l242', 'l245', 'l247', 'l249']", + "59, cells, ['l17', 'l37', 'l56', 'l74', 'l91', 'l107', 'l122', 'l136', 'l149', 'l161', 'l172', 'l182', 'l188', 'l198', 'l210', 'l221', 'l228', 'l234', 'l239', 'l243', 'l246', 'l248', 'l249']", + "65, Lamina ['l250', 'l251', 'l252']", + "66, propria ['l199', 'l211', 'l250', 'l253', 'l254']", + "67, mononuclear ['l200', 'l212', 'l251', 'l253', 'l255']", + "68, cells ['l201', 'l213', 'l252', 'l254', 'l255']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "T-cell", + "receptor", + "that", + "recognizes", + "46-61" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "a", + "transgenic" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "T-cell", + "receptor", + "that", + "recognizes" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "T-cell", + "receptor", + "that", + "recognizes", + "46-61" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "T-cell", + "receptor", + "that", + "recognizes", + "46-61" + ] + }, + "context": { + "val": "cells", + "words": [ + "lamina", + "propria", + "mononuclear", + "cells", + "crypt", + "epithelial", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "a", + "transgenic" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "a", + "transgenic" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "a", + "transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "lamina", + "propria", + "mononuclear", + "cells", + "crypt", + "epithelial", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "cyclooxygenase-2", + "inhibitors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "cyclooxygenase-2", + "inhibitors" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "cyclooxygenase-2", + "inhibitors" + ] + }, + "context": { + "val": "cells", + "words": [ + "lamina", + "propria", + "mononuclear", + "cells", + "crypt", + "epithelial", + "cells," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "cells", + "words": [ + "lamina", + "propria", + "mononuclear", + "cells", + "crypt", + "epithelial", + "cells," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "lamina", + "propria", + "mononuclear", + "cells", + "crypt", + "epithelial", + "cells," + ] + } + } + ] + }, + { + "PMID": "10395328", + "TEXT": "The elusive and enigmatic origin of AIDS-associated Kaposi's sarcoma (AIDS-KS) makes it a complex tumor and therefore difficult to treat. Here we demonstrate that AIDS-KS cells express surface interleukin-4 (IL-4) receptors, and that IL-4 toxin (IL-4(38-37)-PE38KDEL) is specifically cytotoxic to these cells. Intratumoral, intraperitoneal and intravenous administration of IL-4 toxin in nude mice with established subcutaneous AIDS-KS tumors caused considerable anti-tumor activity in a dose-dependent manner, with highest dose producing durable complete responses. Metabolic changes, including cachexia and lymphopenia, induced by KS tumors were prevented by IL-4 toxin treatment. This report establishes IL-4(38-37)-PE38KDEL as an experimental therapeutic agent for the treatment of AIDS-KS.", + "TAG_DATA": [ + "51, nude {'context': 'B-organism'}", + "52, mice {'context': 'I-organism'}", + "55, subcutaneous {'context': 'B-neoplasm'}", + "56, AIDS-KS {'context': 'I-neoplasm'}", + "57, tumors {'context': 'I-neoplasm'}", + "81, KS {'context': 'B-neoplasm'}", + "82, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "51, nude ['l0', 'l1', 'l2', 'l3']", + "52, mice ['l0', 'l4', 'l5', 'l6']", + "55, subcutaneous ['l1', 'l4', 'l7', 'l8']", + "56, AIDS-KS ['l2', 'l5', 'l7', 'l9']", + "57, tumors ['l3', 'l6', 'l8', 'l9']", + "81, KS ['l10']", + "82, tumors ['l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10395326", + "TEXT": "The endoglycosidase heparanase is an important in the degradation of the extracellular matrix by invading cells, notably metastatic tumor cells and migrating leukocytes. Here we report the cDNA sequence of the human platelet enzyme, which encodes a unique protein of 543 amino acids, and the identification of highly homologous sequences in activated mouse T cells and in a highly metastatic rat adenocarcinoma. Furthermore, the expression of heparanase mRNA in rat tumor cells correlates with their metastatic potential. Exhaustive studies have shown only one heparanase sequence, consistent with the idea that this enzyme is the dominant endoglucuronidase in mammalian tissues.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10395324", + "TEXT": "Sepsis in humans is a difficult condition to treat and is often associated with a high mortality rate. In this study, we induced sepsis in rats using cecal ligation and puncture (CLP). In rats depleted of the complement factor C3, CLP led to very short survival times (about 4 days). Of the rats that underwent CLP ('CLP rats') that were C3-intact and treated with preimmune IgG, most (92%) were dead by 7 days. Blood neutrophils from these rats contained on their surfaces the powerful complement activation product C5a. This group had high levels of bacteremia, and their blood neutrophils when stimulated in vitro had greatly reduced production of H2O2, which is known to be essential for the bactericidal function of neutrophils. In contrast, when companion CLP rats were treated with IgG antibody against C5a, survival rates were significantly improved, levels of bacteremia were considerably reduced, and the H2O2 response of blood neutrophils was preserved. Bacterial colony-forming units in spleen and liver were very high in CLP rats treated with preimmune IgG and very low in CLP rats treated with IgG antibody against C5a, similar to values obtained in rats that underwent 'sham' operations (without CLP). These data indicate that sepsis causes an excessive production of C5a, which compromises the bactericidal function of neutrophils. Thus, C5a may be a useful target for the treatment of sepsis.", + "TAG_DATA": [ + "25, rats {'context': 'B-organism'}", + "33, rats {'context': 'B-organism'}", + "52, rats {'context': 'B-organism'}", + "101, in {'context': 'B-in vitro'}", + "102, vitro {'context': 'I-in vitro'}", + "126, rats {'context': 'I-organism'}", + "158, spleen {'context': 'B-tissue/organ'}", + "160, liver {'context': 'B-tissue/organ'}", + "166, rats {'context': 'I-organism'}", + "176, rats {'context': 'I-organism'}", + "188, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "25, rats ['l0']", + "33, rats ['l0']", + "52, rats ['l1', 'l2']", + "101, in ['l1', 'l3']", + "102, vitro ['l2', 'l3']", + "126, rats ['l4']", + "158, spleen ['l5', 'l6', 'l7']", + "160, liver ['l5', 'l8', 'l9']", + "166, rats ['l4', 'l6', 'l8', 'l10']", + "176, rats ['l7', 'l9', 'l10', 'l11']", + "188, rats ['l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10371507", + "TEXT": "We identified circulating CD8+ T-cell populations specific for the tumor-associated antigens (TAAs) MART-1 (27-35) or tyrosinase (368-376) in six of eleven patients with metastatic melanoma using peptide/HLA-A*0201 tetramers. These TAA-specific populations were of two phenotypically distinct types: one, typical for memory/effector T cells; the other, a previously undescribed phenotype expressing both naive and effector cell markers. This latter type represented more than 2% of the total CD8+ T cells in one patient, permitting detailed phenotypic and functional analysis. Although these cells have many of the hallmarks of effector T cells, they were functionally unresponsive, unable to directly lyse melanoma target cells or produce cytokines in response to mitogens. In contrast, CD8+ T cells from the same patient were able to lyse EBV-pulsed target cells and showed robust allogeneic responses. Thus, the clonally expanded TAA-specific population seems to have been selectively rendered anergic in vivo. Peptide stimulation of the TAA-specific T-cell populations in other patients failed to induce substantial upregulation of CD69 expression, indicating that these cells may also have functional defects, leading to blunted activation responses. These data demonstrate that systemic TAA-specific T-cell responses can develop de novo in cancer patients, but that antigen-specific unresponsiveness may explain why such cells are unable to control tumor growth.", + "TAG_DATA": [ + "98, melanoma {'context': 'B-neoplasm'}", + "99, target {'context': 'I-transformed cells'}", + "100, cells {'context': 'I-transformed cells'}", + "110, CD8+ {'context': 'B-cells'}", + "111, T {'context': 'I-cells'}", + "112, cells {'context': 'I-cells'}", + "122, target {'context': 'B-cells'}", + "123, cells {'context': 'I-cells'}", + "142, in {'context': 'B-in vivo'}", + "143, vivo. {'context': 'I-in vivo'}", + "148, TAA-specific {'context': 'B-cells'}", + "149, T-cell {'context': 'I-cells'}", + "150, populations {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "98, melanoma ['l0', 'l1']", + "99, target ['l0', 'l2']", + "100, cells ['l1', 'l2']", + "110, CD8+ ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "111, T ['l3', 'l9', 'l10', 'l11']", + "112, cells ['l4', 'l9', 'l12', 'l13']", + "122, target ['l5', 'l10', 'l12', 'l14', 'l15']", + "123, cells ['l6', 'l11', 'l13', 'l14']", + "142, in ['l7', 'l16', 'l17', 'l18', 'l19']", + "143, vivo. ['l8', 'l15', 'l16', 'l20', 'l21', 'l22']", + "148, TAA-specific ['l17', 'l20', 'l23', 'l24']", + "149, T-cell ['l18', 'l21', 'l23', 'l25']", + "150, populations ['l19', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10371506", + "TEXT": "Blockage in myeloid differentiation characterizes acute myeloid leukemia (AML); the stage of the blockage defines distinct AML subtypes (AML1/2 to AML5). Differentiation therapy in AML has recently raised interest because the survival of AML3 patients has been greatly improved using the differentiating agent retinoic acid. However, this molecule is ineffective in other AML subtypes. The CD44 surface antigen, on leukemic blasts from most AML patients, is involved in myeloid differentiation. Here, we report that ligation of CD44 with specific anti-CD44 monoclonal antibodies or with hyaluronan, its natural ligand, can reverse myeloid differentiation blockage in AML1/2 to AML5 subtypes. The differentiation of AML blasts was evidenced by the ability to produce oxidative bursts, the expression of lineage antigens and cytological modifications, all specific to normal differentiated myeloid cells. These results indicate new possibilities for the development of CD44-targeted differentiation therapy in the AML1/2 to AML5 subtypes.", + "TAG_DATA": [ + "74, ligation {'perturbing_action': 'B-other'}", + "75, of {'perturbing_action': 'I-other'}", + "76, CD44 {'perturbing_action': 'I-other'}", + "89, reverse {'effect': 'B-negative'}", + "92, blockage {'effect': 'B-negative'}", + "99, differentiation {'phenotype': 'B-differentiation'}", + "101, AML {'context': 'B-transformed cells'}", + "102, blasts {'context': 'I-transformed cells'}", + "125, myeloid {'context': 'I-cells'}", + "126, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "74, ligation ['l0', 'l1', 'l2', 'l3', 'l4']", + "75, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "76, CD44 ['l1', 'l5', 'l9', 'l10', 'l11']", + "77, with ['l2', 'l6', 'l9', 'l12', 'l13']", + "89, reverse ['l3', 'l7', 'l10', 'l12', 'l14']", + "92, blockage ['l4', 'l8', 'l11', 'l13', 'l14']", + "99, differentiation ['l15', 'l16', 'l17', 'l18', 'l19']", + "101, AML ['l15', 'l20', 'l21', 'l22', 'l23']", + "102, blasts ['l16', 'l20', 'l24', 'l25', 'l26']", + "124, differentiated ['l17', 'l21', 'l24', 'l27', 'l28']", + "125, myeloid ['l18', 'l22', 'l25', 'l27', 'l29']", + "126, cells. ['l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "ligation", + "of", + "CD44" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reverse", + "blockage" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "AML", + "blasts" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "cells." + ] + } + } + ] + }, + { + "PMID": "10371505", + "TEXT": "Resistance to chemotherapy is a principal problem in the treatment of small cell lung cancer (SCLC). We show here that SCLC is surrounded by an extensive stroma of extracellular matrix (ECM) at both primary and metastatic sites. Adhesion of SCLC cells to ECM enhances tumorigenicity and confers resistance to chemotherapeutic agents as a result of beta1 integrin-stimulated tyrosine kinase activation suppressing chemotherapy-induced apoptosis. SCLC may create a specialized microenvironment, and the survival of cells bound to ECM could explain the partial responses and local recurrence of SCLC often seen clinically after chemotherapy. Strategies based on blocking beta1 integrin-mediated survival signals may represent a new therapeutic approach to improve the response to chemotherapy in SCLC.", + "TAG_DATA": [ + "39, SCLC {'context': 'B-transformed cells'}", + "40, cells {'context': 'I-transformed cells'}", + "43, enhances {'effect': 'B-positive'}", + "44, tumorigenicity {'phenotype': 'B-tumourigenesis'}", + "60, suppressing {'effect': 'B-negative'}", + "61, chemotherapy-induced {'effect': 'B-positive'}", + "62, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "39, SCLC ['l0', 'l1', 'l2', 'l3', 'l4']", + "40, cells ['l0', 'l5', 'l6']", + "43, enhances ['l1', 'l5', 'l7']", + "44, tumorigenicity ['l2', 'l6', 'l7']", + "60, suppressing ['l3', 'l8', 'l9']", + "61, chemotherapy-induced ['l8', 'l10']", + "62, apoptosis. ['l4', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "SCLC", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "SCLC", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "SCLC" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressing" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "SCLC" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "chemotherapy-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "10371504", + "TEXT": "Cubilin is the intestinal receptor for the endocytosis of intrinsic factor-vitamin B12. However, several lines of evidence, including a high expression in kidney and yolk sac, indicate it may have additional functions. We isolated apolipoprotein A-I (apoA-I), the main protein of high-density lipoprotein (HDL), using cubilin affinity chromatography. Surface plasmon resonance analysis demonstrated a high-affinity binding of apoA-I and HDL to cubilin, and cubilin-expressing yolk sac cells showed efficient 125I-HDL endocytosis that could be inhibited by IgG antibodies against apoA-I and cubilin. The physiological relevance of the cubilin-apoA-I interaction was further emphasized by urinary apoA-I loss in some known cases of functional cubilin deficiency. Therefore, cubilin is a receptor in epithelial apoA-I/HDL metabolism.", + "TAG_DATA": [ + "64, yolk {'context': 'I-cells'}", + "65, sac {'context': 'I-cells'}", + "66, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "64, yolk ['l0', 'l1']", + "65, sac ['l0', 'l2']", + "66, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10229238", + "TEXT": "The sedative drug thalidomide ([+]-alpha-phthalimidoglutarimide), once abandoned for causing birth defects in humans, has found new therapeutic license in leprosy and other diseases, with renewed teratological consequences. Although the mechanism of teratogenesis and determinants of risk remain unclear, related teratogenic xenobiotics are bioactivated by embryonic prostaglandin H synthase (PHS) to a free-radical intermediates that produce reactive oxygen species (ROS), which cause oxidative damage to DNA and other cellular macromolecules. Similarly, thalidomide is bioactivated by horseradish peroxidase, and oxidizes DNA and glutathione, indicating free radical-mediated oxidative stress. Furthermore, thalidomide teratogenicity in rabbits is reduced by the PHS inhibitor acetylsalicylic acid, indicating PHS-catalyzed bioactivation. Here, we show in rabbits that thalidomide initiates embryonic DNA oxidation and teratogenicity, both of which are abolished by pre-treatment with the free radical spin trapping agent alpha-phenyl-N-t-butylnitrone (PBN). In contrast, in mice, a species resistant to thalidomide teratogenicity, thalidomide does not enhance DNA oxidation, even at a dose 300% higher than that used in rabbits, providing insight into an embryonic determinant of species-dependent susceptibility. In addition to their therapeutic implications, these results constitute direct evidence that the teratogenicity of thalidomide may involve free radical-mediated oxidative damage to embryonic cellular macromolecules.", + "TAG_DATA": [ + "106, rabbits {'context': 'B-organism'}", + "134, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10229236", + "TEXT": "The World Health Organization has recommended repeat mass drug administration as part of their global initiative to eliminate blinding trachoma by the year 2020. The efficacy of repeat treatment will be tested empirically, but the results will not be available for many years, and recommendations for the necessary frequency of treatment are needed immediately. We have developed a mathematical model that uses available epidemiological data from a variety of countries. We recommend, based on our analysis, that in areas where trachoma is moderately prevalent (<35% in children), it should be treated annually, but hyperendemic areas (>50% in children), it should be treated biannually.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10229230", + "TEXT": "Genetic variants of human and simian immunodeficiency virus (HIV and SIV) that evolve during the course of infection and progression to AIDS are phenotypically and antigenically distinct from their progenitor viruses present at early stages of infection. However, it has been unclear how these late variants, which are typically T-cell tropic, cytopathic and resistant to neutralizing antibodies, influence the development of clinical AIDS. To address this, we infected macaques with cloned SIVs representing prototype variants from early-, intermediate- and late-stage infection having biological characteristics typical of viruses found at similar stages of HIV infection in humans. These studies demonstrate that sequential, phenotypic and antigenic variants represent viruses that have become increasingly fit for replication in the host, and our data support the hypothesis that emerging variants have increased pathogenicity and drive disease progression in SIV and HIV infection.", + "TAG_DATA": [ + "68, macaques {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10202939", + "TEXT": "Familial forms of frontotemporal dementias are associated with mutations in the tau gene. A kindred affected by progressive subcortical gliosis (PSG), a rare form of presenile dementia, has genetic linkage to chromosome 17q21-22. This kindred (PSG-1) is included in the 'frontotemporal dementias and Parkinsonism linked to chromosome 17' group along with kindreds affected by apparently different forms of atypical dementias. Some of these kindreds have mutations in the tau gene. We report here that PSG-1 has a tau mutation at position +16 of the intron after exon 10. The mutation destabilizes a predicted stem-loop structure and leads to an over-representation of the soluble four-repeat tau isoforms, which assemble into wide, twisted, ribbon-like filaments and ultimately result in abundant neuronal and glial tau pathology. The mutations associated with PSG and other atypical dementias can be subdivided into three groups according to their tau gene locations and effects on tau. The existence of tau mutations with distinct pathogenetic mechanisms may explain the phenotypic heterogeneity of atypical dementias that previously led to their classification into separate disease entities.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10202938", + "TEXT": "The mammalian brain has a high degree of plasticity, with dentate granule cell neurogenesis and glial proliferation stimulated by an enriched environment combining both complex inanimate and social stimulation. Moreover, rodents exposed to an enriched environment both before and after a cerebral insult show improved cognitive performance. One of the most robust associations of environmental enrichment is improved learning and memory in the Morris water maze, a spatial task that mainly involves the hippocampus. Furthermore, clinical evidence showing an association between higher educational attainment and reduced risk of Alzheimer and Parkinson-related dementia indicates that a stimulating environment has positive effects on cerebral health that may provide some resilience to cerebral insults. Here we show that in addition to its effects on neurogenesis, an enriched environment reduces spontaneous apoptotic cell death in the rat hippocampus by 45%. Moreover, these environmental conditions protect against kainate-induced seizures and excitotoxic injury. The enriched environment induces expression of glial-derived neurotrophic factor and brain-derived neurotrophic factor and increases phosphorylation of the transcription factor cyclic-AMP response element binding protein, indicating that the influence of the environment on spontaneous apoptosis and cerebral resistance to insults may be mediated through transcription factor activation and induction of growth factor expression.", + "TAG_DATA": [ + "125, reduces {'effect': 'B-negative'}", + "127, apoptotic {'phenotype': 'B-apoptosis'}", + "128, cell {'phenotype': 'I-apoptosis'}", + "129, death {'phenotype': 'I-apoptosis'}", + "132, rat {'context': 'B-tissue/organ'}", + "133, hippocampus {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "125, reduces ['l0', 'l1', 'l2', 'l3', 'l4']", + "127, apoptotic ['l0', 'l5', 'l6', 'l7', 'l8']", + "128, cell ['l1', 'l5', 'l9', 'l10', 'l11']", + "129, death ['l2', 'l6', 'l9', 'l12', 'l13']", + "132, rat ['l3', 'l7', 'l10', 'l12', 'l14']", + "133, hippocampus ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "hippocampus" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "hippocampus" + ] + } + } + ] + }, + { + "PMID": "10202936", + "TEXT": "Limb-girdle muscular dystrophies 2C-F represent a family of autosomal recessive diseases caused by defects in sarcoglycan genes. The cardiomyopathic hamster is a naturally occurring model for limb-girdle muscular dystrophy caused by a primary deficiency in delta-sarcoglycan. We show here that acute sarcolemmal disruption occurs in this animal model during forceful muscle contraction. A recombinant adeno-associated virus vector encoding human delta-sarcoglycan conferred efficient and stable genetic reconstitution in the adult cardiomyopathic hamster when injected directly into muscle. A quantitative assay demonstrated that vector-transduced muscle fibers are stably protected from sarcolemmal disruption; there was no associated inflammation or immunologic response to the vector-encoded protein. Efficient gene transduction with rescue of the sarcoglycan complex in muscle fibers of the distal hindlimb was also obtained after infusion of recombinant adeno-associated virus into the femoral artery in conjunction with histamine-induced endothelial permeabilization. This study provides a strong rationale for the development of gene therapy for limb-girdle muscular dystrophy.", + "TAG_DATA": [ + "53, recombinant {'perturbing_action': 'B-gene gain-of-function'}", + "54, adeno-associated {'perturbing_action': 'I-gene gain-of-function'}", + "55, virus {'perturbing_action': 'I-gene gain-of-function'}", + "56, vector {'perturbing_action': 'I-gene gain-of-function'}", + "57, encoding {'perturbing_action': 'I-gene gain-of-function'}", + "58, human {'perturbing_action': 'I-gene gain-of-function'}", + "59, delta-sarcoglycan {'perturbing_action': 'I-gene gain-of-function'}", + "68, adult {'context': 'B-organism'}", + "69, cardiomyopathic {'context': 'I-organism'}", + "70, hamster {'context': 'I-organism'}", + "82, muscle {'context': 'B-cells'}", + "83, fibers {'context': 'I-cells'}", + "112, muscle {'context': 'B-cells'}", + "113, fibers {'context': 'I-cells'}", + "116, distal {'context': 'B-tissue/organ'}", + "117, hindlimb {'context': 'I-tissue/organ'}", + "130, artery {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "53, recombinant ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "54, adeno-associated ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "55, virus ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "56, vector ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "57, encoding ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "58, human ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "59, delta-sarcoglycan ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "68, adult ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57']", + "69, cardiomyopathic ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l58']", + "70, hamster ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l58']", + "82, muscle ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l59']", + "83, fibers ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59']", + "112, muscle ['l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "113, fibers ['l60', 'l66', 'l67', 'l68', 'l69']", + "116, distal ['l61', 'l66', 'l70', 'l71', 'l72', 'l73']", + "117, hindlimb ['l62', 'l67', 'l70', 'l74', 'l75', 'l76']", + "125, adeno-associated ['l63', 'l71', 'l74', 'l77', 'l78']", + "129, femoral ['l64', 'l68', 'l72', 'l75', 'l77', 'l79']", + "130, artery ['l65', 'l69', 'l73', 'l76', 'l78', 'l79']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "recombinant", + "adeno-associated", + "virus", + "vector", + "encoding", + "human", + "delta-sarcoglycan" + ] + }, + "context": { + "val": "organism", + "words": [ + "adult", + "cardiomyopathic", + "hamster" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "recombinant", + "adeno-associated", + "virus", + "vector", + "encoding", + "human", + "delta-sarcoglycan" + ] + }, + "context": { + "val": "cells", + "words": [ + "muscle", + "fibers" + ] + } + } + ] + }, + { + "PMID": "10202933", + "TEXT": "Neonates face a high risk of infection because of the immaturity of their immune systems. Although the transplacental transfer of maternal antibodies to the fetus may convey improved postnatal immunity, this transfer occurs late in gestation and may fail to prevent in utero infection. Both fetal immunization and in utero exposure to antigen can result in a state of immunologic tolerance in the neonate. Tolerance induction of fetal and premature infant lymphocytes has become a paradigm for neonatal responsiveness. However, fetal IgM responses have been demonstrated to maternal immunization with tetanus toxoid and to congenital infections such as rubella, toxoplasma, cytomegalovirus and human immunodeficiency virus. Moreover, 1-week-old infants can respond to standard pediatric vaccination, and neonates immunized with polysaccharide antigens do not develop immunologic tolerance. Here, direct immunization of the baboon fetus with recombinant hepatitis B surface antigen produced a specific fetal IgG antibody response. No specific maternal antibody response was detected, eliminating the possibility of vertical antibody transmission to the fetus. Some infants also responded to later vaccinations with hepatitis B surface antigen, indicating that no immunological tolerance was induced by prior fetal immunization. These results characterize the ability of the fetal immune system to respond to in utero vaccination. We demonstrate that active fetal immunization can serve as a safe and efficient vaccination strategy for the fetus and neonate.", + "TAG_DATA": [ + "130, baboon {'context': 'B-organism'}", + "131, fetus {'context': 'I-organism'}", + "163, infants {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "130, baboon ['l0']", + "131, fetus ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10202931", + "TEXT": "We report here that ultraviolet irradiation substantially reduced the mRNA and protein of the two major nuclear retinoid receptors, RAR-gamma and RXR-alpha, in human skin in vivo. Pre-treatment with retinoic acid mitigated this loss of nuclear retinoid receptors. Ultraviolet irradiation caused a near-total loss of retinoic acid induction of two RAR/RXR target genes, cellular retinoic acid binding protein-II and RA 4-hydroxylase, but did not affect 1,25-dihydroxyvitamin D3 induction of the vitamin D receptor/RXR-regulated gene vitamin D 24-hydroxylase. In effect, ultraviolet irradiation causes a functional vitamin A deficiency that may have deleterious effects on skin function, contributing to skin photo-aging and carcinogenesis.", + "TAG_DATA": [ + "23, human {'context': 'B-tissue/organ'}", + "24, skin {'context': 'I-tissue/organ'}", + "25, in {'context': 'B-in vivo'}", + "26, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "23, human ['l0', 'l1', 'l2']", + "24, skin ['l0', 'l3', 'l4']", + "25, in ['l1', 'l3', 'l5']", + "26, vivo. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10202927", + "TEXT": "Pseudomonas aeruginosa is an opportunistic bacterial pathogen that can cause fatal acute lung infections in critically ill individuals. Damage to the lung epithelium is associated with the expression of toxins that are directly injected into eukaryotic cells through a type Ill-mediated secretion and translocation mechanism. Here we show that the P. aeruginosa homolog of the Yersinia V antigen, PcrV, is involved in the translocation of type III toxins. Vaccination against PcrV ensured the survival of challenged mice and decreased lung inflammation and injury. Antibodies to PcrV inhibited the translocation of type III toxins.", + "TAG_DATA": [ + "76, mice {'context': 'B-organism'}", + "79, lung {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "76, mice ['l0']", + "79, lung ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10086394", + "TEXT": "A rapid decline in T-cell counts and the progression to AIDS is often associated with a switch from CCR5-tropic (R5) HIV-1 to CXCR4-tropic (X4) HIV-1 or R5/X4 HIV-1 variants. Experimental infection with R5 HIV-1 causes less T-cell depletion than infection with X4 or R5/X4 variants in T-cell cultures, in ex vivo infected human lymphoid tissue and in SCID/hu mice, despite similar replication levels. Experimental genetic changes in those sequences in gp120 that transform R5 HIV-1 variants into otherwise isogenic X4 viruses make them highly cytopathic. Thus, it is now believed that R5 variants are less cytopathic for T cells than are X4 variants. However, it is not known why CCR5-mediated HIV-1 infection does not lead to a massive CD4+ T-cell depletion, as occurs in CXCR4-mediated HIV-1 infection. Here we demonstrate that R5 HIV-1 isolates are indeed highly cytopathic, but only for CCR5+/CD4+ T cells. Because these cells constitute only a small fraction of CD4+ T cells, their depletion does not substantially change the total CD4+ T-cell count. These results may explain why the clinical stage of HIV disease correlates with viral tropism.", + "TAG_DATA": [ + "46, T-cell {'context': 'B-cells'}", + "47, cultures, {'context': 'I-cells'}", + "52, human {'context': 'B-tissue/organ'}", + "53, lymphoid {'context': 'I-tissue/organ'}", + "54, tissue {'context': 'I-tissue/organ'}", + "58, mice, {'context': 'B-organism'}", + "141, CCR5+/CD4+ {'context': 'B-cells'}", + "142, T {'context': 'I-cells'}", + "143, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "46, T-cell ['l0', 'l1']", + "47, cultures, ['l0']", + "52, human ['l2', 'l3', 'l4']", + "53, lymphoid ['l2', 'l5', 'l6']", + "54, tissue ['l1', 'l3', 'l5', 'l7']", + "58, mice, ['l4', 'l6', 'l7']", + "141, CCR5+/CD4+ ['l8', 'l9']", + "142, T ['l8', 'l10']", + "143, cells. ['l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10086391", + "TEXT": "Nitric oxide (NO) is an ubiquitous signaling molecule produced from L-arginine by NO synthase (NOS). In the vasculature, NO mediates parasympathetic endothelium-dependent vasodilation. NO may also mediate the parasympathetic control of myocardial function. This is supported by the observations that NOS3, the endothelial constitutive NOS, is expressed in normal cardiac myocytes from rodents and human, and NOS and/or guanylyl cyclase inhibitors antagonize the effect of muscarinic agonists on heart rate, atrio-ventricular conduction, contractility and L-type calcium current. Here we examine the autonomic regulation of the heart in genetically engineered mice deficient in NOS3 (NOS3-KO). We show that the chronotropic and inotropic responses to both beta-adrenergic and muscarinic agonists were unaltered in isolated cardiac tissue preparations from NOS3-KO mice, although these mice have a defective parasympathetic regulation of vascular tone. Similarly, beta-adrenergic stimulation and muscarinic inhibition of the calcium current did not differ in cardiac myocytes from NOS3-KO mice and those from wild-type mice. RT-PCR did not demonstrate upregulation of other NOS isoforms. Similarly, Gi/Go proteins and muscarinic receptor density were unaltered. These data refute the idea that NOS3 is obligatory for the normal autonomic control of cardiac muscle function.", + "TAG_DATA": [ + "87, genetically {'context': 'B-organism'}", + "88, engineered {'context': 'I-organism'}", + "89, mice {'context': 'I-organism'}", + "90, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "91, in {'perturbing_action': 'I-gene loss-of-function'}", + "92, NOS3 {'perturbing_action': 'I-gene loss-of-function'}", + "93, (NOS3-KO). {'perturbing_action': 'I-gene loss-of-function'}", + "112, cardiac {'context': 'B-tissue/organ'}", + "113, tissue {'context': 'I-tissue/organ'}", + "114, preparations {'context': 'I-tissue/organ'}", + "116, NOS3-KO {'perturbing_action': 'B-gene loss-of-function'}", + "117, mice, {'context': 'B-organism'}", + "120, mice {'context': 'B-organism'}", + "143, cardiac {'context': 'B-cells'}", + "144, myocytes {'context': 'I-cells'}", + "146, NOS3-KO {'perturbing_action': 'B-gene loss-of-function'}", + "147, mice {'context': 'B-organism'}", + "152, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "87, genetically ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "88, engineered ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "89, mice ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "90, deficient ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "91, in ['l3', 'l11', 'l18', 'l24', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "92, NOS3 ['l4', 'l12', 'l19', 'l25', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "93, (NOS3-KO). ['l5', 'l13', 'l20', 'l26', 'l32', 'l39', 'l46', 'l47', 'l48']", + "112, cardiac ['l6', 'l14', 'l21', 'l27', 'l33', 'l40', 'l46', 'l49', 'l50', 'l51', 'l52', 'l53']", + "113, tissue ['l7', 'l15', 'l22', 'l28', 'l34', 'l41', 'l47', 'l49', 'l54', 'l55', 'l56', 'l57']", + "114, preparations ['l8', 'l16', 'l23', 'l29', 'l35', 'l42', 'l48', 'l50', 'l54', 'l58', 'l59', 'l60']", + "116, NOS3-KO ['l36', 'l43', 'l51', 'l55', 'l58', 'l61', 'l62', 'l63', 'l64', 'l65']", + "117, mice, ['l30', 'l37', 'l44', 'l52', 'l56', 'l59', 'l61', 'l66']", + "120, mice ['l38', 'l45', 'l53', 'l57', 'l60', 'l62', 'l66', 'l67', 'l68', 'l69']", + "143, cardiac ['l63', 'l67', 'l70', 'l71', 'l72']", + "144, myocytes ['l64', 'l68', 'l70', 'l73', 'l74']", + "146, NOS3-KO ['l71', 'l73', 'l75']", + "147, mice ['l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "genetically", + "engineered", + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "NOS3", + "(NOS3-KO).", + "NOS3-KO" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "NOS3", + "(NOS3-KO).", + "NOS3-KO" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "cardiac", + "tissue", + "preparations" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NOS3-KO" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiac", + "myocytes" + ] + } + } + ] + }, + { + "PMID": "10086385", + "TEXT": "Half of the survivors of bacterial meningitis experience motor deficits, seizures, hearing loss or cognitive impairment, despite adequate bacterial killing by antibiotics. We demonstrate that the broad-spectrum caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl-ketone (z-VAD-fmk) prevented hippocampal neuronal cell death and white blood cell influx into the cerebrospinal fluid compartment in experimental pneumococcal meningitis. Hippocampal neuronal death was due to apoptosis derived from the inflammatory response in the cerebrospinal fluid. Apoptosis was induced in vitro in human neurons by inflamed cerebrospinal fluid and was blocked by z-VAD-fmk. As apoptosis drives neuronal loss in pneumococcal meningitis, caspase inhibitors might provide a new therapeutic option directed specifically at reducing brain damage.", + "TAG_DATA": [ + "31, prevented {'effect': 'B-negative'}", + "32, hippocampal {'context': 'B-cells'}", + "34, cell {'phenotype': 'B-cell death'}", + "35, death {'phenotype': 'I-cell death'}", + "37, white {'context': 'B-cells'}", + "38, blood {'context': 'I-cells'}", + "39, cell {'context': 'I-cells'}", + "56, apoptosis {'phenotype': 'B-apoptosis'}", + "66, Apoptosis {'phenotype': 'B-apoptosis'}", + "68, induced {'effect': 'B-positive'}", + "69, in {'context': 'B-in vitro'}", + "70, vitro {'context': 'I-in vitro'}", + "72, human {'context': 'B-cells'}", + "73, neurons {'context': 'I-cells'}", + "80, blocked {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "31, prevented ['l0', 'l1', 'l2', 'l3', 'l4']", + "32, hippocampal ['l0', 'l5', 'l6', 'l7', 'l8']", + "34, cell ['l1', 'l5', 'l9']", + "35, death ['l2', 'l6', 'l9']", + "37, white ['l3', 'l7', 'l10', 'l11', 'l12', 'l13']", + "38, blood ['l10', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "39, cell ['l4', 'l8', 'l11', 'l14', 'l22', 'l23', 'l24', 'l25', 'l26']", + "56, apoptosis ['l12', 'l15', 'l22', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "66, Apoptosis ['l16', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "68, induced ['l13', 'l17', 'l23', 'l28', 'l33', 'l38', 'l39', 'l40', 'l41']", + "69, in ['l18', 'l29', 'l34', 'l38', 'l42', 'l43', 'l44']", + "70, vitro ['l19', 'l24', 'l30', 'l35', 'l39', 'l42', 'l45', 'l46']", + "72, human ['l20', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l47']", + "73, neurons ['l21', 'l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "cells", + "words": [ + "hippocampal", + "white", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hippocampal" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "white", + "blood", + "cell", + "human", + "neurons" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "Apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "white", + "blood", + "cell", + "human", + "neurons" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "Apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "Apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "10086384", + "TEXT": "A principal cause of blindness is subretinal neovascularization associated with age-related macular degeneration. Excised neovascular membranes from patients with age-related macular degeneration demonstrated a pattern of Fas+ new vessels in the center of the vascular complex, surrounded by FasL+ retinal pigment epithelial cells. In a murine model, Fas (CD95)-deficient (Ipr) and FasL-defective (gld) mice had a significantly increased incidence of neovascularization compared with normal mice. Furthermore, in gld mice there is massive subretinal neovascularization with uncontrolled growth of vessels. We found that cultured choroidal endothelial cells were induced to undergo apoptosis by retinal pigment epithelial cells through a Fas-FasL interaction. In addition, antibody against Fas prevented vascular tube formation of choroidal endothelial cells derived from the eye in a three-dimensional in vitro assay. Thus, FasL expressed on retinal pigment epithelial cells may control the growth and development of new subretinal vessels that can damage vision.", + "TAG_DATA": [ + "45, murine {'context': 'B-organism'}", + "46, model, {'context': 'I-organism'}", + "47, Fas {'perturbing_action': 'B-gene loss-of-function'}", + "48, (CD95)-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "49, (Ipr) {'perturbing_action': 'I-gene loss-of-function'}", + "51, FasL-defective {'perturbing_action': 'B-gene loss-of-function'}", + "52, (gld) {'perturbing_action': 'I-gene loss-of-function'}", + "53, mice {'context': 'B-organism'}", + "67, gld {'perturbing_action': 'B-gene loss-of-function'}", + "68, mice {'context': 'B-organism'}", + "83, choroidal {'context': 'I-cells'}", + "84, endothelial {'context': 'I-cells'}", + "85, cells {'context': 'I-cells'}", + "87, induced {'effect': 'B-positive'}", + "90, apoptosis {'phenotype': 'B-apoptosis'}", + "92, retinal {'context': 'B-cells'}", + "93, pigment {'context': 'I-cells'}", + "94, epithelial {'context': 'I-cells'}", + "95, cells {'context': 'I-cells'}", + "110, choroidal {'context': 'B-cells'}", + "111, endothelial {'context': 'I-cells'}", + "112, cells {'context': 'I-cells'}", + "113, derived {'context': 'I-cells'}", + "114, from {'context': 'I-cells'}", + "115, the {'context': 'I-cells'}", + "116, eye {'context': 'I-tissue/organ'}", + "120, in {'context': 'B-in vitro'}", + "121, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "45, murine ['l0', 'l1', 'l2', 'l3']", + "46, model, ['l0', 'l4', 'l5', 'l6']", + "47, Fas ['l1', 'l4', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "48, (CD95)-deficient ['l7', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "49, (Ipr) ['l2', 'l5', 'l8', 'l17', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "51, FasL-defective ['l9', 'l18', 'l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "52, (gld) ['l10', 'l19', 'l29', 'l35', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "53, mice ['l3', 'l6', 'l11', 'l20', 'l30', 'l36', 'l48']", + "67, gld ['l12', 'l21', 'l31', 'l37', 'l49', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "68, mice ['l13', 'l22', 'l32', 'l38', 'l50', 'l59', 'l65', 'l66']", + "83, choroidal ['l14', 'l23', 'l39', 'l51', 'l60', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "84, endothelial ['l15', 'l24', 'l33', 'l40', 'l52', 'l61', 'l65', 'l67', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "85, cells ['l16', 'l25', 'l34', 'l41', 'l53', 'l62', 'l66', 'l68', 'l76', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "87, induced ['l42', 'l54', 'l69', 'l77', 'l84', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "89, undergo ['l26', 'l43', 'l55', 'l63', 'l70', 'l78', 'l85', 'l91', 'l97', 'l98', 'l99', 'l100', 'l101']", + "90, apoptosis ['l44', 'l56', 'l71', 'l79', 'l86', 'l92', 'l97', 'l102', 'l103', 'l104', 'l105']", + "92, retinal ['l72', 'l80', 'l87', 'l93', 'l98', 'l102', 'l106', 'l107', 'l108']", + "93, pigment ['l45', 'l73', 'l81', 'l88', 'l94', 'l99', 'l103', 'l106', 'l109', 'l110']", + "94, epithelial ['l46', 'l57', 'l74', 'l82', 'l89', 'l95', 'l100', 'l104', 'l107', 'l109', 'l111']", + "95, cells ['l27', 'l47', 'l58', 'l64', 'l75', 'l83', 'l90', 'l96', 'l101', 'l105', 'l108', 'l110', 'l111']", + "110, choroidal ['l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "111, endothelial ['l112', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "112, cells ['l113', 'l120', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "113, derived ['l114', 'l121', 'l127', 'l133', 'l134', 'l135', 'l136', 'l137']", + "114, from ['l115', 'l122', 'l128', 'l133', 'l138', 'l139', 'l140', 'l141']", + "115, the ['l116', 'l123', 'l129', 'l134', 'l138', 'l142', 'l143', 'l144']", + "116, eye ['l117', 'l124', 'l130', 'l135', 'l139', 'l142', 'l145', 'l146']", + "120, in ['l118', 'l125', 'l131', 'l136', 'l140', 'l143', 'l145', 'l147']", + "121, vitro ['l119', 'l126', 'l132', 'l137', 'l141', 'l144', 'l146', 'l147']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "murine", + "model,", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fas", + "(Ipr)", + "(CD95)-deficient", + "FasL-defective", + "(gld)", + "gld" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fas", + "(CD95)-deficient", + "(Ipr)", + "FasL-defective", + "(gld)", + "gld" + ] + }, + "context": { + "val": "cells", + "words": [ + "choroidal", + "endothelial", + "cells", + "pigment", + "epithelial" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FasL-defective", + "(gld)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FasL-defective", + "(gld)" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "choroidal", + "endothelial", + "cells", + "retinal", + "pigment", + "epithelial" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "choroidal", + "endothelial", + "cells", + "retinal", + "pigment", + "epithelial" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "10086383", + "TEXT": "As in the development of many human cancers, in a transgenic mouse model of beta-cell carcinogenesis (Rip1Tag2), expression of neural cell adhesion molecule (NCAM) changes from the 120-kDa isoform in normal tissue to the 140/180-kDa isoforms in tumors. NCAM-deficient RiplTag2 mice, generated by crossing Rip1Tag2 mice with NCAM knockout mice, develop metastases, a tumor stage that is not seen in normal Rip1Tag2 mice. In contrast, overexpression of NCAM 120 in NCAM-deficient Rip1Tag2 mice prevents tumor metastasis. The results indicate that the loss of NCAM-mediated cell adhesion is one rate-limiting step in the actual metastatic dissemination of beta tumor cells.", + "TAG_DATA": [ + "38, NCAM-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "39, RiplTag2 {'perturbing_action': 'B-gene loss-of-function'}", + "40, mice, {'context': 'B-organism'}", + "45, mice {'context': 'I-organism'}", + "47, NCAM {'perturbing_action': 'B-gene loss-of-function'}", + "48, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "49, mice, {'context': 'B-organism'}", + "50, develop {'effect': 'B-positive'}", + "51, metastases, {'phenotype': 'B-metastasis'}", + "62, mice. {'context': 'B-organism'}", + "65, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "66, of {'perturbing_action': 'I-gene gain-of-function'}", + "67, NCAM {'perturbing_action': 'I-gene gain-of-function'}", + "68, 120 {'perturbing_action': 'I-gene gain-of-function'}", + "70, NCAM-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "71, Rip1Tag2 {'perturbing_action': 'B-gene loss-of-function'}", + "72, mice {'context': 'B-organism'}", + "73, prevents {'effect': 'B-negative'}", + "74, tumor {'phenotype': 'B-metastasis'}", + "75, metastasis. {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "38, NCAM-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "39, RiplTag2 ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "40, mice, ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "45, mice ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "47, NCAM ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "48, knockout ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "49, mice, ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "50, develop ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "51, metastases, ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "62, mice. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "65, overexpression ['l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "66, of ['l45', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "67, NCAM ['l46', 'l54', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "68, 120 ['l47', 'l55', 'l62', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "70, NCAM-deficient ['l48', 'l56', 'l63', 'l69', 'l75', 'l76', 'l77', 'l78', 'l79']", + "71, Rip1Tag2 ['l49', 'l57', 'l64', 'l70', 'l75', 'l80', 'l81', 'l82', 'l83']", + "72, mice ['l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l84', 'l85', 'l86']", + "73, prevents ['l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l87', 'l88']", + "74, tumor ['l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l87', 'l89']", + "75, metastasis. ['l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l89']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NCAM-deficient", + "RiplTag2", + "NCAM", + "knockout", + "Rip1Tag2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NCAM-deficient", + "RiplTag2", + "NCAM", + "knockout" + ] + }, + "effect": { + "val": "positive", + "words": [ + "develop" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NCAM-deficient", + "RiplTag2", + "NCAM", + "knockout", + "Rip1Tag2" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases,", + "tumor", + "metastasis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice,", + "mice", + "mice." + ] + }, + "effect": { + "val": "positive", + "words": [ + "develop" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice,", + "mice", + "mice." + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases,", + "tumor", + "metastasis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "develop" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "NCAM", + "120" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "NCAM", + "120" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "NCAM", + "120" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "tumor", + "metastasis." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NCAM-deficient", + "Rip1Tag2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "tumor", + "metastasis." + ] + } + } + ] + }, + { + "PMID": "9930876", + "TEXT": "A PCR-based approach was developed that provides a powerful tool for engineering recombinant molecules without reliance on restriction sites. DNA sequences were first amplified by high-fidelity PCR using Pfu polymerase; they were then used both as 'megaprimers' and templates in subsequent asymmetric long PCR amplifications to form chimeric clones. To demonstrate the technique, we constructed chimeric full-length HIV-1 clones derived from reverse-transcribed plasma viral RNA and proviral LTRs. Biologic characterization of these clones showed that most were infectious in tissue culture and sequence analysis demonstrated an error rate of only one base change in 20 kb of DNA sequence. For PCR-mediated recombination, it is necessary to know the sequence of the 3' and 5' overlapping regions of the desired PCR products. This method may be extended to include construction of chimeras between any DNA fragments lacking sequence homology. Such chimeras may be constructed by introducing overlapping sequences to one of the fragments. To ensure that unwanted mutations have not been introduced into the clones constructed by this method, each clone should be sequenced. Our results demonstrate that by using a high-fidelity polymerase and highly controlled PCR conditions, the PCR-introduced error rate can be greatly minimized. This new procedure may be used to construct infectious chimeras of HIV or SIV for studies of vaccines and pathogenesis. Moreover, the method is designed to exchange viral genes at precise boundaries to study individual gene products from different HIV genomes. It can also be used to construct expression vectors for production of specific proteins or delivery vectors for gene transfer and gene therapy. Finally, the technique described here provides a versatile tool to transfer genes or gene fragments from different sources for genetic investigation and engineering.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9930872", + "TEXT": "Adhesion of tumor cells to host cell layers and subsequent transcellular migration are pivotal steps in cancer invasion and metastasis. The small GTPase Rho controls cell adhesion and motility through reorganization of the actin cytoskeleton and regulation of actomyosin contractility. Cultured rat MM1 hepatoma cells migrate through a mesothelial cell monolayer in vitro in a serum-dependent, Rho-mediated manners. Among several proteins isolated as putative target molecules of Rho, the ROCK (ROK) family of Rho-associated serine-threonine protein kinases are thought to participate in the induction of focal adhesions and stress fibers in cultured cells, and to mediate calcium sensitization of smooth muscle contraction by enhancing phosphorylation of the regulatory light chain of myosin. Transfection of MM1 cells with cDNA encoding a dominant active mutant of ROCK conferred invasive activity independently of serum and Rho. In contrast, expression of a dominant negative, kinase-defective ROCK mutant substantially attenuated the invasive phenotype. A specific ROCK inhibitor (Y-27632) blocked both Rho-mediated activation of actomyosin and invasive activity of these cells. Furthermore, continuous delivery of this inhibitor using osmotic pumps considerably reduced the dissemination of MM1 cells implanted into the peritoneal cavity of syngeneic rats. These results indicate that ROCK plays an essential part in tumor cell invasion, and demonstrate its potential as a therapeutic target for the prevention of cancer invasion and metastasis.", + "TAG_DATA": [ + "112, Transfection {'perturbing_action': 'B-other'}", + "114, MM1 {'context': 'B-cells'}", + "115, cells {'context': 'I-cells'}", + "116, with {'perturbing_action': 'I-other'}", + "117, cDNA {'perturbing_action': 'I-other'}", + "118, encoding {'perturbing_action': 'I-other'}", + "119, a {'perturbing_action': 'I-other'}", + "120, dominant {'perturbing_action': 'I-other'}", + "121, active {'perturbing_action': 'I-other'}", + "122, mutant {'perturbing_action': 'I-other'}", + "123, of {'perturbing_action': 'I-other'}", + "124, ROCK {'perturbing_action': 'I-other'}", + "135, expression {'perturbing_action': 'B-other'}", + "136, of {'perturbing_action': 'I-other'}", + "137, a {'perturbing_action': 'I-other'}", + "138, dominant {'perturbing_action': 'I-other'}", + "139, negative, {'perturbing_action': 'I-other'}", + "140, kinase-defective {'perturbing_action': 'I-other'}", + "141, ROCK {'perturbing_action': 'I-other'}", + "142, mutant {'perturbing_action': 'I-other'}", + "144, attenuated {'effect': 'B-negative'}", + "149, specific {'perturbing_action': 'B-pharmacological inhibition'}", + "150, ROCK {'perturbing_action': 'I-pharmacological inhibition'}", + "151, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "152, (Y-27632) {'perturbing_action': 'I-pharmacological inhibition'}", + "153, blocked {'effect': 'B-negative'}", + "160, invasive {'phenotype': 'B-invasion'}", + "161, activity {'phenotype': 'I-invasion'}", + "164, cells. {'context': 'B-cells'}", + "179, MM1 {'context': 'B-cells'}", + "180, cells {'context': 'I-cells'}", + "187, syngeneic {'context': 'B-organism'}", + "188, rats. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "112, Transfection ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "114, MM1 ['l0', 'l11', 'l12']", + "115, cells ['l1', 'l11', 'l13', 'l14']", + "116, with ['l2', 'l12', 'l13', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "117, cDNA ['l3', 'l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "118, encoding ['l4', 'l16', 'l23', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "119, a ['l5', 'l17', 'l24', 'l36', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "120, dominant ['l6', 'l18', 'l25', 'l37', 'l48', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "121, active ['l7', 'l19', 'l26', 'l38', 'l49', 'l59', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "122, mutant ['l8', 'l20', 'l27', 'l39', 'l50', 'l60', 'l69', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "123, of ['l9', 'l21', 'l28', 'l40', 'l51', 'l61', 'l70', 'l78', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "124, ROCK ['l10', 'l14', 'l22', 'l29', 'l41', 'l52', 'l62', 'l71', 'l79', 'l86', 'l93', 'l94', 'l95', 'l96', 'l97']", + "135, expression ['l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "136, of ['l98', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "137, a ['l99', 'l116', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "138, dominant ['l100', 'l117', 'l135', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "139, negative, ['l101', 'l118', 'l136', 'l153', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185']", + "140, kinase-defective ['l102', 'l119', 'l137', 'l154', 'l170', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200']", + "141, ROCK ['l103', 'l120', 'l138', 'l155', 'l171', 'l186', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212']", + "142, mutant ['l104', 'l121', 'l139', 'l156', 'l172', 'l187', 'l201', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222']", + "144, attenuated ['l30', 'l42', 'l53', 'l63', 'l72', 'l80', 'l87', 'l93', 'l105', 'l122', 'l140', 'l157', 'l173', 'l188', 'l202', 'l213', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228']", + "146, invasive ['l31', 'l43', 'l54', 'l64', 'l73', 'l81', 'l88', 'l94', 'l106', 'l123', 'l141', 'l158', 'l174', 'l189', 'l203', 'l214', 'l223', 'l229', 'l230', 'l231', 'l232']", + "149, specific ['l107', 'l124', 'l142', 'l159', 'l175', 'l190', 'l204', 'l215', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244']", + "150, ROCK ['l108', 'l125', 'l143', 'l160', 'l176', 'l191', 'l205', 'l216', 'l233', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255']", + "151, inhibitor ['l109', 'l126', 'l144', 'l161', 'l177', 'l192', 'l206', 'l217', 'l234', 'l245', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265']", + "152, (Y-27632) ['l110', 'l127', 'l145', 'l162', 'l178', 'l193', 'l207', 'l218', 'l224', 'l235', 'l246', 'l256', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274']", + "153, blocked ['l32', 'l44', 'l55', 'l65', 'l74', 'l82', 'l89', 'l111', 'l128', 'l146', 'l163', 'l179', 'l194', 'l208', 'l219', 'l225', 'l229', 'l236', 'l247', 'l257', 'l266', 'l275', 'l276', 'l277']", + "160, invasive ['l33', 'l45', 'l56', 'l66', 'l75', 'l83', 'l90', 'l95', 'l112', 'l129', 'l147', 'l164', 'l180', 'l195', 'l209', 'l220', 'l226', 'l230', 'l237', 'l248', 'l258', 'l267', 'l275', 'l278', 'l279']", + "161, activity ['l34', 'l46', 'l57', 'l67', 'l76', 'l84', 'l91', 'l96', 'l113', 'l130', 'l148', 'l165', 'l181', 'l196', 'l210', 'l221', 'l227', 'l231', 'l238', 'l249', 'l259', 'l268', 'l276', 'l278', 'l280']", + "164, cells. ['l35', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l97', 'l114', 'l131', 'l149', 'l166', 'l182', 'l197', 'l211', 'l222', 'l228', 'l232', 'l239', 'l250', 'l260', 'l269', 'l277', 'l279', 'l280']", + "179, MM1 ['l240', 'l251', 'l261', 'l270', 'l281', 'l282', 'l283', 'l284']", + "180, cells ['l132', 'l150', 'l167', 'l183', 'l198', 'l241', 'l252', 'l262', 'l271', 'l281', 'l285', 'l286', 'l287']", + "185, cavity ['l115', 'l133', 'l151', 'l168', 'l184', 'l199', 'l212', 'l242', 'l253', 'l263', 'l272', 'l282', 'l285', 'l288', 'l289']", + "187, syngeneic ['l243', 'l254', 'l264', 'l273', 'l283', 'l286', 'l288', 'l290']", + "188, rats. ['l134', 'l152', 'l169', 'l185', 'l200', 'l244', 'l255', 'l265', 'l274', 'l284', 'l287', 'l289', 'l290']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Transfection", + "with", + "ROCK", + "cDNA", + "encoding", + "a", + "dominant", + "active", + "mutant", + "of", + "expression", + "negative,", + "kinase-defective" + ] + }, + "context": { + "val": "cells", + "words": [ + "MM1", + "cells", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "cDNA", + "encoding", + "a", + "dominant", + "active", + "mutant", + "of", + "ROCK", + "expression", + "negative,", + "kinase-defective" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuated", + "blocked" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "cDNA", + "encoding", + "a", + "dominant", + "active", + "mutant", + "of", + "ROCK", + "expression", + "negative,", + "kinase-defective" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasive", + "activity" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "of", + "a", + "dominant", + "negative,", + "kinase-defective" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated", + "blocked" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "(Y-27632)", + "specific", + "ROCK", + "inhibitor" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated", + "blocked" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasive", + "activity" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated", + "blocked" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "ROCK", + "inhibitor", + "(Y-27632)" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasive", + "activity" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "ROCK", + "inhibitor", + "(Y-27632)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells.", + "MM1", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "ROCK", + "inhibitor", + "(Y-27632)" + ] + }, + "context": { + "val": "organism", + "words": [ + "syngeneic", + "rats." + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasive", + "activity" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "9883849", + "TEXT": "Fabry disease is a disorder of glycosphingolipid metabolism caused by deficiency of lysosomal alpha-galactosidase A (alpha-Gal A), resulting in renal failure along with premature myocardial infarction and strokes. No effective treatment of this disorder is available at present. Studies of residual activities of mutant enzymes in many Fabry patients showed that some of them had kinetic properties similar to those for normal alpha-Gal A, but were significantly less stable, especially in conditions of neutral pH (refs. 3-5). The biosynthetic processing was delayed in cultured fibroblasts of a Fabry patient, and the mutant protein formed an aggregate in endoplasmic reticulum, indicating that the enzyme deficiency in some mutants was mainly caused by abortive exit from the endoplasmic reticulum, leading to excessive degradation of the enzyme. We report here that 1-deoxy-galactonojirimycin (DGJ), a potent competitive inhibitor of alpha-Gal A, effectively enhanced alpha-Gal A activity in Fabry lymphoblasts, when administrated at concentrations lower than that usually required for intracellular inhibition of the enzyme. DGJ seemed to accelerate transport and maturation of the mutant enzyme. Oral administration of DGJ to transgenic mice overexpressing a mutant alpha-Gal A substantially elevated the enzyme activity in some organs. We propose a new molecular therapeutic strategy for genetic metabolic diseases of administering competitive inhibitors as 'chemical chaperons' at sub-inhibitory intracellular concentrations.", + "TAG_DATA": [ + "84, fibroblasts {'context': 'I-cells'}", + "143, Fabry {'context': 'B-cells'}", + "144, lymphoblasts, {'context': 'I-cells'}", + "176, transgenic {'context': 'B-organism'}", + "177, mice {'context': 'I-organism'}", + "178, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "179, a {'perturbing_action': 'I-other'}", + "180, mutant {'perturbing_action': 'I-other'}", + "181, alpha-Gal {'perturbing_action': 'I-other'}", + "182, A {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "143, Fabry ['l0']", + "144, lymphoblasts, ['l0']", + "176, transgenic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "177, mice ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "178, overexpressing ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "179, a ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "180, mutant ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "181, alpha-Gal ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "182, A ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "a", + "mutant", + "alpha-Gal", + "A" + ] + } + } + ] + }, + { + "PMID": "9883847", + "TEXT": "Excitotoxicity, a form of neuronal injury in which excessive activation of glutamate receptors results in cellular calcium overload, has been implicated in the pathogenesis of Alzheimer disease (AD), although direct evidence is lacking. Mutations in the presenilin-1 (PS1) gene on chromosome 14 are causally linked to many cases of early-onset inherited AD (refs. 5,6). We generated PS1 mutant mice (PS1M146VKI) that express the PS1 M146V targeted allele at normal physiological levels. Although PS1M146VKI mice have no overt mutant phenotype, they are hypersensitive to seizure-induced synaptic degeneration and necrotic neuronal death in the hippocampus. Cultured hippocampal neurons from PS1M146VKI mice have increased vulnerability to death induced by glutamate, which is correlated with perturbed calcium homeostasis, increased oxidative stress and mitochondrial dysfunction. Agents that suppress calcium influx or release and antioxidants protect neurons against the excitotoxic action of the PS1 mutation. These findings establish a direct link between a genetic defect that causes AD and excitotoxic neuronal degeneration, and indicate new avenues for therapeutic intervention in AD patients.", + "TAG_DATA": [ + "56, PS1 {'perturbing_action': 'B-other'}", + "57, mutant {'perturbing_action': 'I-other'}", + "58, mice {'context': 'B-organism'}", + "59, (PS1M146VKI) {'perturbing_action': 'I-other'}", + "64, M146V {'perturbing_action': 'I-other'}", + "65, targeted {'perturbing_action': 'I-other'}", + "72, PS1M146VKI {'perturbing_action': 'B-other'}", + "73, mice {'context': 'B-organism'}", + "92, hippocampus. {'context': 'B-tissue/organ'}", + "93, Cultured {'context': 'B-cells'}", + "94, hippocampal {'context': 'I-cells'}", + "95, neurons {'context': 'I-cells'}", + "97, PS1M146VKI {'perturbing_action': 'B-other'}", + "98, mice {'context': 'B-organism'}", + "130, neurons {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "56, PS1 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "57, mutant ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "58, mice ['l1', 'l8', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "59, (PS1M146VKI) ['l2', 'l9', 'l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "64, M146V ['l3', 'l10', 'l17', 'l22', 'l27', 'l28', 'l29', 'l30', 'l31']", + "65, targeted ['l4', 'l11', 'l18', 'l23', 'l27', 'l32', 'l33', 'l34', 'l35']", + "66, allele ['l5', 'l12', 'l19', 'l24', 'l28', 'l32', 'l36', 'l37', 'l38']", + "72, PS1M146VKI ['l13', 'l29', 'l33', 'l36', 'l39', 'l40']", + "73, mice ['l6', 'l14', 'l20', 'l25', 'l30', 'l34', 'l37', 'l39', 'l41']", + "92, hippocampus. ['l7', 'l15', 'l21', 'l26', 'l31', 'l35', 'l38', 'l40', 'l41']", + "93, Cultured ['l42', 'l43', 'l44', 'l45']", + "94, hippocampal ['l42', 'l46', 'l47', 'l48']", + "95, neurons ['l43', 'l46', 'l49', 'l50']", + "97, PS1M146VKI ['l44', 'l47', 'l49', 'l51']", + "98, mice ['l45', 'l48', 'l50', 'l51']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "PS1", + "mutant", + "(PS1M146VKI)", + "M146V", + "targeted", + "PS1M146VKI" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "PS1", + "mutant", + "(PS1M146VKI)", + "M146V", + "targeted", + "PS1M146VKI" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Cultured", + "hippocampal", + "neurons" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "PS1M146VKI" + ] + } + } + ] + }, + { + "PMID": "9883844", + "TEXT": "The dynamic basis for T-cell depletion in late-stage HIV-1 disease remains controversial. Using a new, non-radioactive, endogenous labeling technique, we report direct measurements of circulating T-cell kinetics in normal and in HIV-1-infected humans. In healthy, HIV-1-seronegative subjects, CD4+ and CD8+ T cells had half-lives of 87 days and 77 days, respectively, with absolute production rates of 10 CD4+ T cells/microl per day and 6 CD8+ T cells/microl per day. In untreated HIV-1-infected subjects (with a mean CD4 level of 342 cells/microl), the half-life of each subpopulation was less than 1/3 as long as those of healthy, HIV-1-seronegative subjects but was not compensated by an increased absolute production rate of CD4+ T cells. After viral replication was suppressed by highly active antiretroviral therapy for 12 weeks, the production rates of circulating CD4+ and CD8+ T cells were considerably elevated; the kinetic basis of increased CD4 levels was greater production, not a longer half-life, of circulating cells. These direct measurements indicate that CD4+ T-cell lymphopenia is due to both a shortened survival time and a failure to increase the production of circulating CD4+ T cells. Our results focus attention on T-cell production systems in the pathogenesis of HIV-1 disease and the response to antiretroviral therapy.", + "TAG_DATA": [ + "37, CD4+ {'context': 'B-cells'}", + "38, and {'context': 'I-cells'}", + "39, CD8+ {'context': 'I-cells'}", + "40, T {'context': 'I-cells'}", + "41, cells {'context': 'I-cells'}", + "109, CD4+ {'context': 'B-cells'}", + "110, T {'context': 'I-cells'}", + "111, cells. {'context': 'I-cells'}", + "129, circulating {'context': 'B-cells'}", + "130, CD4+ {'context': 'I-cells'}", + "131, and {'context': 'I-cells'}", + "132, CD8+ {'context': 'I-cells'}", + "133, T {'context': 'I-cells'}", + "134, cells {'context': 'I-cells'}", + "153, circulating {'context': 'B-cells'}", + "154, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "37, CD4+ ['l0', 'l1', 'l2', 'l3']", + "38, and ['l0', 'l4', 'l5', 'l6']", + "39, CD8+ ['l1', 'l4', 'l7', 'l8']", + "40, T ['l2', 'l5', 'l7', 'l9']", + "41, cells ['l3', 'l6', 'l8', 'l9']", + "109, CD4+ ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "110, T ['l10', 'l18', 'l19', 'l20']", + "111, cells. ['l11', 'l18', 'l21']", + "129, circulating ['l12', 'l22', 'l23', 'l24', 'l25', 'l26']", + "130, CD4+ ['l13', 'l22', 'l27', 'l28', 'l29', 'l30']", + "131, and ['l14', 'l23', 'l27', 'l31', 'l32', 'l33']", + "132, CD8+ ['l15', 'l24', 'l28', 'l31', 'l34', 'l35']", + "133, T ['l16', 'l19', 'l25', 'l29', 'l32', 'l34', 'l36']", + "134, cells ['l17', 'l20', 'l21', 'l26', 'l30', 'l33', 'l35', 'l36']", + "153, circulating ['l37']", + "154, cells. ['l37']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9883839", + "TEXT": "Autoimmunity to antigens of the central nervous system is usually considered detrimental. T cells specific to a central nervous system self antigen, such as myelin basic protein, can indeed induce experimental autoimmune encephalomyelitis, but such T cells may nevertheless appear in the blood of healthy individuals. We show here that autoimmune T cells specific to myelin basic protein can protect injured central nervous system neurons from secondary degeneration. After a partial crush injury of the optic nerve, rats injected with activated anti-myelin basic protein T cells retained approximately 300% more retinal ganglion cells with functionally intact axons than did rats injected with activated T cells specific for other antigens. Electrophysiological analysis confirmed this finding and suggested that the neuroprotection could result from a transient reduction in energy requirements owing to a transient reduction in nerve activity. These findings indicate that T-cell autoimmunity in the central nervous system, under certain circumstances, can exert a beneficial effect by protecting injured neurons from the spread of damage.", + "TAG_DATA": [ + "61, central {'context': 'B-cells'}", + "62, nervous {'context': 'I-cells'}", + "63, system {'context': 'I-cells'}", + "75, optic {'context': 'B-tissue/organ'}", + "76, nerve, {'context': 'I-tissue/organ'}", + "77, rats {'context': 'B-organism'}", + "90, retinal {'context': 'B-cells'}", + "91, ganglion {'context': 'I-cells'}", + "92, cells {'context': 'I-cells'}", + "99, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "61, central ['l0', 'l1', 'l2', 'l3']", + "62, nervous ['l0', 'l4', 'l5', 'l6']", + "63, system ['l1', 'l4', 'l7', 'l8']", + "75, optic ['l2', 'l5', 'l7', 'l9', 'l10', 'l11', 'l12', 'l13']", + "76, nerve, ['l3', 'l6', 'l8', 'l9', 'l14', 'l15', 'l16', 'l17']", + "77, rats ['l10', 'l14', 'l18', 'l19', 'l20', 'l21']", + "90, retinal ['l11', 'l15', 'l18', 'l22', 'l23', 'l24']", + "91, ganglion ['l12', 'l16', 'l19', 'l22', 'l25', 'l26']", + "92, cells ['l13', 'l17', 'l20', 'l23', 'l25', 'l27']", + "99, rats ['l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9883836", + "TEXT": "At present, treatment of HIV infection uses small inhibitory molecules that target HIV protease; however, the emergence of resistant HIV strains is increasingly problematic. To circumvent this, we report here a new 'Trojan horse' strategy to kill HIV-infected cells by exploiting HIV protease. We engineered a transducing, modified, apoptosis-promoting caspase-3 protein, TAT-Casp3, that substitutes HIV proteolytic cleavage sites for endogenous ones and efficiently transduces about 100% of cells, but remains inactive in uninfected cells. In HIV-infected cells, TAT-Casp3 becomes processed into an active form by HIV protease, resulting in apoptosis of the infected cell. This strategy could also be applied to other pathogens encoding specific proteases, such as hepatitis C virus, cytomegalovirus and malaria.", + "TAG_DATA": [ + "67, cells, {'context': 'B-cells'}", + "73, cells. {'context': 'B-cells'}", + "76, cells, {'context': 'B-cells'}", + "87, resulting {'effect': 'B-positive'}", + "88, in {'effect': 'I-positive'}", + "89, apoptosis {'phenotype': 'B-apoptosis'}", + "93, cell. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "67, cells, ['l0']", + "73, cells. ['l0']", + "76, cells, ['l1', 'l2', 'l3', 'l4']", + "87, resulting ['l1', 'l5', 'l6', 'l7']", + "88, in ['l2', 'l5', 'l8', 'l9']", + "89, apoptosis ['l3', 'l6', 'l8', 'l10']", + "93, cell. ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells,", + "cell." + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells,", + "cell." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "9846586", + "TEXT": "Duchenne muscular dystrophy (DMD) is a lethal, progressive muscle wasting disease caused by a loss of sarcolemmal bound dystrophin, which results in the death of the muscle fiber leading to the gradual depletion of skeletal muscle. The molecular structure of dystrophin is very similar to that of the related protein utrophin. Utrophin is found in all tissues and is confined to the neuromuscular and myotendinous junctions in mature muscle. Sarcolemmal localization of a truncated utrophin transgene in the dystrophin-deficient mdx mouse significantly improves the dystrophic muscle phenotype. Therefore, up-regulation of utrophin by drug therapy is a plausible therapeutic approach in the treatment of DMD. Here we demonstrate that expression of full-length utrophin in mdx mice prevents the development of muscular dystrophy. We assessed muscle morphology, fiber regeneration and mechanical properties (force development and resistance to stretch) of mdx and transgenic mdx skeletal and diaphragm muscle. The utrophin levels required in muscle are significantly less than the normal endogenous utrophin levels seen in lung and kidney, and we provide evidence that the pathology depends on the amount of utrophin expression. These results also have important implications for DMD therapies in which utrophin replacement is achieved by delivery using exogenous vectors.", + "TAG_DATA": [ + "78, dystrophin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "79, mdx {'perturbing_action': 'B-gene loss-of-function', 'context': 'B-organism'}", + "80, mouse {'context': 'I-organism'}", + "108, expression {'perturbing_action': 'B-gene gain-of-function'}", + "109, of {'perturbing_action': 'I-gene gain-of-function'}", + "110, full-length {'perturbing_action': 'I-gene gain-of-function'}", + "111, utrophin {'perturbing_action': 'I-gene gain-of-function'}", + "114, mice {'context': 'B-organism'}", + "123, muscle {'context': 'B-tissue/organ'}", + "137, mdx {'perturbing_action': 'B-gene gain-of-function'}", + "139, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "140, mdx {'perturbing_action': 'I-gene gain-of-function'}", + "141, skeletal {'context': 'B-tissue/organ'}", + "142, and {'context': 'I-tissue/organ'}", + "143, diaphragm {'context': 'I-tissue/organ'}", + "144, muscle. {'context': 'I-tissue/organ'}", + "150, muscle {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "78, dystrophin-deficient ['l0', 'l1']", + "79, mdx ['l0', 'l2']", + "80, mouse ['l1', 'l2']", + "108, expression ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "109, of ['l3', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "110, full-length ['l4', 'l15', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "111, utrophin ['l5', 'l16', 'l26', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "114, mice ['l6', 'l17', 'l27', 'l36', 'l44']", + "123, muscle ['l7', 'l18', 'l28', 'l37', 'l44', 'l45', 'l46', 'l47', 'l48']", + "137, mdx ['l8', 'l19', 'l29', 'l38', 'l45', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "139, transgenic ['l9', 'l20', 'l30', 'l49', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "140, mdx ['l10', 'l21', 'l31', 'l39', 'l50', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "141, skeletal ['l11', 'l22', 'l32', 'l40', 'l46', 'l51', 'l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "142, and ['l12', 'l23', 'l33', 'l41', 'l47', 'l52', 'l57', 'l62', 'l66', 'l70', 'l71', 'l72']", + "143, diaphragm ['l13', 'l24', 'l34', 'l42', 'l53', 'l58', 'l63', 'l67', 'l70', 'l73', 'l74']", + "144, muscle. ['l14', 'l25', 'l35', 'l43', 'l48', 'l54', 'l59', 'l64', 'l68', 'l71', 'l73']", + "150, muscle ['l60', 'l65', 'l69', 'l72', 'l74']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient", + "mdx" + ] + }, + "context": { + "val": "organism", + "words": [ + "mdx", + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "full-length", + "utrophin" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "full-length", + "utrophin", + "mdx", + "transgenic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscle", + "skeletal", + "and", + "diaphragm", + "muscle." + ] + } + } + ] + }, + { + "PMID": "9846583", + "TEXT": "Prion diseases are typically initiated by infection of peripheral sites, as in the case of bovine spongiform encephalopathy, new variant Creutzfeldt-Jakob disease, kuru and most cases of iatrogenic Creutzfeldt-Jakob disease. In mouse scrapie, prion infectivity accumulates in lymphoid organs, and the absence of mature B lymphocytes prevents peripherally administered prions from inducing central nervous system disease. We have now assessed whether expression of the cellular prion protein, PrPc, is required for B lymphocytes to mediate neuroinvasion. We found that repopulation of SCID and Rag-1(-/-) mice with fetal liver cells from either PrP-expressing or PrP-deficient mice and from T-cell deficient mice, but not from B-cell deficient mice, is equally efficient in restoring neuroinvasion after intraperitoneal inoculation of scrapie prions. These results indicate that cells whose maturation depends on B cells or their products, such as follicular dendritic cells, may enhance neuroinvasion. Alternatively, B cells may transport prions to the nervous system by a PrP-independent mechanism.", + "TAG_DATA": [ + "83, Rag-1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "84, mice {'context': 'B-organism'}", + "86, fetal {'context': 'B-cells'}", + "87, liver {'context': 'I-cells'}", + "88, cells {'context': 'I-cells'}", + "93, PrP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "94, mice {'context': 'B-organism'}", + "97, T-cell {'perturbing_action': 'B-gene loss-of-function'}", + "98, deficient {'perturbing_action': 'I-gene loss-of-function'}", + "99, mice, {'context': 'B-organism'}", + "104, deficient {'perturbing_action': 'I-gene loss-of-function'}", + "105, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "83, Rag-1(-/-) ['l0', 'l1', 'l2', 'l3']", + "84, mice ['l0', 'l4', 'l5', 'l6']", + "86, fetal ['l1', 'l4', 'l7', 'l8', 'l9', 'l10']", + "87, liver ['l2', 'l5', 'l7', 'l11', 'l12', 'l13']", + "88, cells ['l3', 'l6', 'l8', 'l11', 'l14', 'l15']", + "93, PrP-deficient ['l9', 'l12', 'l14', 'l16']", + "94, mice ['l10', 'l13', 'l15', 'l16']", + "97, T-cell ['l17', 'l18', 'l19', 'l20', 'l21']", + "98, deficient ['l17', 'l22', 'l23', 'l24', 'l25']", + "99, mice, ['l18', 'l22', 'l26', 'l27', 'l28']", + "103, B-cell ['l19', 'l23', 'l26', 'l29', 'l30']", + "104, deficient ['l20', 'l24', 'l27', 'l29', 'l31']", + "105, mice, ['l21', 'l25', 'l28', 'l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rag-1(-/-)", + "PrP-deficient", + "T-cell", + "deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rag-1(-/-)", + "PrP-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "fetal", + "liver", + "cells" + ] + } + } + ] + }, + { + "PMID": "9809557", + "TEXT": "The genesis of new cells, including neurons, in the adult human brain has not yet been demonstrated. This study was undertaken to investigate whether neurogenesis occurs in the adult human brain, in regions previously identified as neurogenic in adult rodents and monkeys. Human brain tissue was obtained postmortem from patients who had been treated with the thymidine analog, bromodeoxyuridine (BrdU), that labels DNA during the S phase. Using immunofluorescent labeling for BrdU and for one of the neuronal markers, NeuN, calbindin or neuron specific enolase (NSE), we demonstrate that new neurons, as defined by these markers, are generated from dividing progenitor cells in the dentate gyrus of adult humans. Our results further indicate that the human hippocampus retains its ability to generate neurons throughout life.", + "TAG_DATA": [ + "42, Human {'context': 'B-tissue/organ'}", + "43, brain {'context': 'I-tissue/organ'}", + "44, tissue {'context': 'I-tissue/organ'}", + "49, patients {'context': 'B-patient'}", + "104, dentate {'context': 'B-tissue/organ'}", + "105, gyrus {'context': 'I-tissue/organ'}", + "108, humans. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "42, Human ['l0', 'l1', 'l2']", + "43, brain ['l0', 'l3', 'l4']", + "44, tissue ['l1', 'l3', 'l5']", + "49, patients ['l2', 'l4', 'l5']", + "101, cells ['l6', 'l7', 'l8']", + "104, dentate ['l6', 'l9', 'l10']", + "105, gyrus ['l7', 'l9', 'l11']", + "108, humans. ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9809556", + "TEXT": "We used brain imaging to study long-term neurodegenerative and bioadaptive neurochemical changes in a primate model of Parkinson disease. We gradually induced a selective loss of nigrostriatal dopamine neurons, similar to that of Parkinson disease, by creating oxidative stress through infusion of the mitochondrial complex 1 inhibitor MPTP for 14+/-5 months. Repeated evaluations over 3 years by positron emission tomography (PET) demonstrated progressive and persistent loss of neuronal dopamine pre-synaptic re-uptake sites; repeated magnetic resonance spectroscopy (MRS) studies indicated a 23-fold increase in lactate and macromolecules in the striatum region of the brain for up to 10 months after the last administration of MPTP. By 2 years after the MPTP infusions, these MRS striatal lactate and macromolecule values had returned to normal levels. In contrast, there were persistent increases in striatal choline and decreases in N-acetylaspartate. Thus, these combined PET/MRS studies demonstrate patterns of neurochemical changes that are both dynamic and persistent long after selective dopaminergic degeneration.", + "TAG_DATA": [ + "26, nigrostriatal {'context': 'B-cells'}", + "27, dopamine {'context': 'I-cells'}", + "28, neurons, {'context': 'I-cells'}", + "88, striatum {'context': 'B-tissue/organ'}", + "89, region {'context': 'I-tissue/organ'}", + "90, of {'context': 'I-tissue/organ'}", + "92, brain {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "26, nigrostriatal ['l0', 'l1', 'l2', 'l3']", + "27, dopamine ['l0', 'l4', 'l5', 'l6']", + "28, neurons, ['l1', 'l4']", + "88, striatum ['l7', 'l8', 'l9']", + "89, region ['l7', 'l10', 'l11']", + "90, of ['l2', 'l5', 'l8', 'l10', 'l12']", + "92, brain ['l3', 'l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9809554", + "TEXT": "We describe here a method for drug target validation and identification of secondary drug target effects based on genome-wide gene expression patterns. The method is demonstrated by several experiments, including treatment of yeast mutant strains defective in calcineurin, immunophilins or other genes with the immunosuppressants cyclosporin A or FK506. Presence or absence of the characteristic drug 'signature' pattern of altered gene expression in drug-treated cells with a mutation in the gene encoding a putative target established whether that target was required to generate the drug signature. Drug dependent effects were seen in 'targetless' cells, showing that FK506 affects additional pathways independent of calcineurin and the immunophilins. The described method permits the direct confirmation of drug targets and recognition of drug-dependent changes in gene expression that are modulated through pathways distinct from the drug's intended target. Such a method may prove useful in improving the efficiency of drug development programs.", + "TAG_DATA": [ + "32, yeast {'context': 'B-organism'}", + "33, mutant {'context': 'I-organism'}", + "34, strains {'context': 'I-organism'}", + "64, cells {'context': 'B-cells'}", + "93, cells, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "32, yeast ['l0', 'l1', 'l2']", + "33, mutant ['l0', 'l3', 'l4']", + "34, strains ['l1', 'l3', 'l5']", + "64, cells ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9771751", + "TEXT": "Epileptic seizures are a principal brain dysfunction with important public health implications, as they affect 0.8% of humans. Many of these patients (20%) are resistant to treatment with drugs. The ability to anticipate the onset of seizures in such cases would permit clinical interventions. The view of chronic focal epilepsy now is that abnormally discharging neurons act as pacemakers to recruit and entrain other normal neurons by loss of inhibition and synchronization into a critical mass. Thus, preictal changes should be detectable during the stages of recruitment. Traditional signal analyses, such as the count of focal spike density, the frequency coherence or spectral analyses are not reliable predictors. Non-linear indicators may undergo consistent changes around seizure onset. Our objective was to follow the transition into seizure by reconstructing intracranial recordings in implanted patients as trajectories in a phase space and then introduce non-linear indicators to characterize them. These indicators take into account the extended spatio-temporal nature of the epileptic recruitment processes and the corresponding physiological events governed by short-term causalities in the time series. We demonstrate that in most cases (17 of 19), seizure onset could be anticipated well in advance (between 2-6 minutes beforehand), and that all subjects seemed to share a similar 'route' towards seizure.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9771746", + "TEXT": "One of the main impediments to effective gene therapy of blood disorders is the resistance of human hematopoietic stem cells to stable genetic modification. We show here that a small minority of retrovirally transduced stem cells can be selectively enriched in vivo, which might be a way to circumvent this obstacle. We constructed two retroviral vectors containing an antifolate-resistant dihydrofolate reductase cDNA transcriptionally linked to a reporter gene. Mice were transplanted with transduced bone marrow cells and then treated with an antifolate-based regimen that kills unmodified stem cells. Drug treatment significantly increased the percentage of vector-expressing peripheral blood erythrocytes, platelets, granulocytes, and T and B lymphocytes. Secondary transplant experiments demonstrated that selection occurred at the level of hematopoietic stem cells. This system for in vivo stem-cell selection provides a means to increase the number of genetically modified cells after transplant, and may circumvent an substantial obstacle to successful gene therapy for human blood diseases.", + "TAG_DATA": [ + "68, Mice {'context': 'B-organism'}", + "73, bone {'context': 'B-cells'}", + "74, marrow {'context': 'I-cells'}", + "75, cells {'context': 'I-cells'}", + "86, stem {'context': 'B-cells'}", + "87, cells. {'context': 'I-cells'}", + "96, peripheral {'context': 'B-cells'}", + "97, blood {'context': 'I-cells'}", + "98, erythrocytes, {'context': 'I-cells'}", + "99, platelets, {'context': 'I-cells'}", + "100, granulocytes, {'context': 'B-cells'}", + "102, T {'context': 'B-cells'}", + "103, and {'context': 'I-cells'}", + "104, B {'context': 'I-cells'}", + "105, lymphocytes. {'context': 'I-cells'}", + "117, hematopoietic {'context': 'B-cells'}", + "118, stem {'context': 'I-cells'}", + "119, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "68, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "73, bone ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "74, marrow ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "75, cells ['l2', 'l11', 'l19', 'l26', 'l27', 'l28', 'l29']", + "86, stem ['l3', 'l12', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "87, cells. ['l4', 'l13', 'l20', 'l30', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "96, peripheral ['l5', 'l14', 'l21', 'l31', 'l40', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "97, blood ['l6', 'l15', 'l22', 'l26', 'l32', 'l41', 'l49', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "98, erythrocytes, ['l7', 'l16', 'l23', 'l27', 'l33', 'l42', 'l50', 'l57', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "99, platelets, ['l8', 'l17', 'l24', 'l28', 'l34', 'l43', 'l51', 'l58', 'l64', 'l70', 'l71', 'l72', 'l73', 'l74']", + "100, granulocytes, ['l9', 'l18', 'l25', 'l29', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l75', 'l76', 'l77', 'l78']", + "102, T ['l36', 'l45', 'l53', 'l60', 'l66', 'l71', 'l75', 'l79', 'l80', 'l81']", + "103, and ['l37', 'l46', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l82', 'l83']", + "104, B ['l38', 'l47', 'l55', 'l62', 'l68', 'l73', 'l77', 'l80', 'l82', 'l84']", + "105, lymphocytes. ['l39', 'l48', 'l56', 'l63', 'l69', 'l74', 'l78', 'l81', 'l83', 'l84']", + "117, hematopoietic ['l85', 'l86']", + "118, stem ['l85', 'l87']", + "119, cells. ['l86', 'l87']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9734400", + "TEXT": "A high-fat diet increases the risk of colon, breast and prostate cancer. The molecular mechanism by which dietary lipids promote tumorigenesis is unknown. Their effects may be mediated at least in part by the peroxisome proliferator-activated receptors (PPARs). These ligand-activated nuclear receptors modulate gene expression in response to fatty acids, lipid-derived metabolites and antidiabetic drugs. To explore the role of the PPARs in diet-induced carcinogenesis, we treated mice predisposed to intestinal neoplasia with a synthetic PPARgamma ligand. Reflecting the pattern of expression of PPARgamma in the gastrointestinal tract, treated mice developed a considerably greater number of polyps in the colon but not in the small intestine, indicating that PPARgamma activation may provide a molecular link between a high-fat diet and increased risk of colorectal cancer.", + "TAG_DATA": [ + "67, mice {'context': 'B-organism'}", + "68, predisposed {'effect': 'B-positive'}", + "69, to {'effect': 'I-positive'}", + "71, neoplasia {'phenotype': 'I-tumourigenesis'}", + "89, mice {'context': 'B-organism'}", + "99, colon {'context': 'B-tissue/organ'}", + "104, small {'context': 'B-tissue/organ'}", + "105, intestine, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "67, mice ['l0', 'l1', 'l2', 'l3']", + "68, predisposed ['l0', 'l4', 'l5', 'l6']", + "69, to ['l1', 'l4', 'l7', 'l8']", + "70, intestinal ['l2', 'l5', 'l7', 'l9']", + "71, neoplasia ['l3', 'l6', 'l8', 'l9']", + "89, mice ['l10', 'l11', 'l12']", + "99, colon ['l10', 'l13', 'l14']", + "104, small ['l11', 'l13', 'l15']", + "105, intestine, ['l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "predisposed", + "to" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasia" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "predisposed", + "to" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasia" + ] + } + } + ] + }, + { + "PMID": "9734399", + "TEXT": "The development of colorectal cancer, one of the most frequent cancers, is influenced by prostaglandins and fatty acids. Decreased prostaglandin production, seen in mice with mutations in the cyclooxygenase 2 gene or in animals and humans treated with cyclooxygenase inhibitors, prevents or attenuates colon cancer development. There is also a strong correlation between the intake of fatty acids from animal origin and colon cancer. Therefore, the peroxisome proliferator-activated receptor gamma (PPARgamma), a downstream transcriptional mediator for prostaglandins and fatty acids which is highly expressed in the colon may be involved in this process. Activation of PPARgamma by two different synthetic agonists increased the frequency and size of colon tumors in C57BL/6J-APCMin/+ mice, an animal model susceptible to intestinal neoplasia. Tumor frequency was only increased in the colon, and did not change in the small intestine, coinciding with the colon-restricted expression of PPARgamma. Treatment with PPARgamma agonists increased beta-catenin levels both in the colon of C57BL/61-APCMin/+ mice and in HT-29 colon carcinoma cells. Genetic abnormalities in the Wnt/wingless/APC pathway, which enhance the transcriptional activity of the beta-catenin-T-cell factor/lymphoid enhancer factor 1 transcription complex, often underly the development of colon tumors. Our data indicate that PPARgamma activation modifies the development of colon tumors in C57BL/61-APCMin/+ mice.", + "TAG_DATA": [ + "93, Activation {'perturbing_action': 'B-pharmacological augmentation'}", + "94, of {'perturbing_action': 'I-pharmacological augmentation'}", + "95, PPARgamma {'perturbing_action': 'I-pharmacological augmentation'}", + "96, by {'perturbing_action': 'I-pharmacological augmentation'}", + "99, synthetic {'perturbing_action': 'I-pharmacological augmentation'}", + "100, agonists {'perturbing_action': 'I-pharmacological augmentation'}", + "107, colon {'context': 'B-neoplasm'}", + "108, tumors {'context': 'I-neoplasm'}", + "110, C57BL/6J-APCMin/+ {'perturbing_action': 'B-other'}", + "111, mice, {'context': 'B-organism'}", + "119, Tumor {'phenotype': 'B-tumourigenesis'}", + "126, colon, {'context': 'B-tissue/organ'}", + "133, small {'context': 'B-tissue/organ'}", + "134, intestine, {'context': 'I-tissue/organ'}", + "152, colon {'context': 'B-tissue/organ'}", + "154, C57BL/61-APCMin/+ {'perturbing_action': 'B-other'}", + "155, mice {'context': 'B-organism'}", + "158, HT-29 {'context': 'B-transformed cells'}", + "159, colon {'context': 'I-transformed cells'}", + "160, carcinoma {'context': 'I-transformed cells'}", + "161, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "93, Activation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "94, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "95, PPARgamma ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "96, by ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "99, synthetic ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "100, agonists ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "107, colon ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65']", + "108, tumors ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l66', 'l67']", + "110, C57BL/6J-APCMin/+ ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l66', 'l68', 'l69']", + "111, mice, ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l67', 'l68']", + "119, Tumor ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l70', 'l71', 'l72', 'l73']", + "126, colon, ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l69', 'l70', 'l74', 'l75']", + "133, small ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l71', 'l74', 'l76', 'l77', 'l78']", + "134, intestine, ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l72', 'l75', 'l76', 'l79']", + "152, colon ['l73', 'l77', 'l79', 'l80', 'l81', 'l82']", + "154, C57BL/61-APCMin/+ ['l80', 'l83', 'l84', 'l85', 'l86', 'l87']", + "155, mice ['l78', 'l81', 'l83', 'l88', 'l89', 'l90', 'l91']", + "158, HT-29 ['l84', 'l88', 'l92', 'l93', 'l94']", + "159, colon ['l85', 'l89', 'l92', 'l95', 'l96']", + "160, carcinoma ['l86', 'l90', 'l93', 'l95', 'l97']", + "161, cells. ['l82', 'l87', 'l91', 'l94', 'l96', 'l97']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "PPARgamma", + "by", + "synthetic", + "agonists" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "colon", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "PPARgamma", + "by", + "synthetic", + "agonists" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "PPARgamma", + "by", + "synthetic", + "agonists" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "Tumor" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "PPARgamma", + "by", + "synthetic", + "agonists" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "colon,", + "small", + "intestine," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "colon", + "tumors" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "C57BL/6J-APCMin/+" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "C57BL/6J-APCMin/+", + "C57BL/61-APCMin/+" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "C57BL/6J-APCMin/+", + "C57BL/61-APCMin/+" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "colon,", + "colon" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "Tumor" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "colon,", + "small", + "intestine,", + "colon" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "C57BL/61-APCMin/+" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HT-29", + "colon", + "carcinoma", + "cells." + ] + } + } + ] + }, + { + "PMID": "9734397", + "TEXT": "The detection of primitive hematopoietic cells based on repopulation of immune-deficient mice is a powerful tool to characterize the human stem-cell compartment. Here, we identify a newly discovered human repopulating cell, distinct from previously identified repopulating cells, that initiates multilineage hematopoiesis in NOD/SCID mice. We call such cells CD34neg-SCID repopulating cells, or CD34neg-SRC. CD34neg-SRC are restricted to a Lin-CD34-CD38- population without detectable surface markers for multiple lineages and CD38 or those previously associated with stem cells (HLA-DR, Thy-1 and CD34). In contrast to CD34+ subfractions, Lin-CD34-CD38- cells have low clonogenicity in short-and long-term in vitro assays. The number of CD34neg-SRC increased in short-term suspension cultures in conditions that did not maintain SRC derived from CD34+ populations, providing independent biological evidence of their distinctiveness. The identification of this newly discovered cell demonstrates complexity of the organization of the human stem-cell compartment and has important implications for clinical applications involving stem-cell transplantation.", + "TAG_DATA": [ + "104, cultures {'context': 'I-in vitro'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9734396", + "TEXT": "A highly divergent HIV-1 isolate, designated YBF 30, was obtained in 1995 from a 40-year-old Cameroonian woman with AIDS. Depending on the genes studied, phylogenetic analysis showed that YBF30 branched either with SIVcpz-gab or between SIVcpz-gab and HIV-1 group M. The structural genes and tat, vpr, and nef of YBF30 are approximately equidistant from those of HIV-1 group M and SIVcpz-gab. In contrast, vif and rev are closer to HIV-1 group M, and vpu is highly divergent. Using a YBF30 V3 loop peptide enzyme immunoassay, we screened 700 HIV-1-positive sera collected in Cameroon; three reacted strongly with the YBF30 peptides and one was confirmed as being related to YBF30 by genetic analysis of a pol fragment. YBF30 is as distinct from SIVcpz-gab as it is from HIV-1 group M and can thus be considered as the prototype strain of a new human immunodeficiency virus group.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9734395", + "TEXT": "Accelerated atherosclerosis in patients with diabetes is a major cause of their morbidity and mortality, and it is unresponsive to therapy aimed at restoring relative euglycemia. In hyperglycemia, nonenzymatic glycation and oxidation of proteins and lipids results in the accumulation of irreversibly formed advanced glycation endproducts. These advanced glycation endproducts engage their receptor in cells of the blood vessel wall, thereby activating mechanisms linked to the development of vascular lesions. We report here a model of accelerated and advanced atherosclerosis in diabetic mice deficient for apolipoprotein E. Treatment of these mice with the soluble extracellular domain of the receptor for advanced glycation endproducts completely suppressed diabetic atherosclerosis in a glycemia- and lipid-independent manner. These findings indicate interaction between the advanced glycation endproducts and their receptor is involved in the development of accelerated atherosclerosis in diabetes, and identify this receptor as a new therapeutic target in diabetic macrovascular disease.", + "TAG_DATA": [ + "81, diabetic {'context': 'B-organism'}", + "82, mice {'context': 'I-organism'}", + "83, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "84, for {'perturbing_action': 'I-gene loss-of-function'}", + "85, apolipoprotein {'perturbing_action': 'I-gene loss-of-function'}", + "86, E. {'perturbing_action': 'I-gene loss-of-function'}", + "90, mice {'context': 'B-organism'}", + "104, suppressed {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "81, diabetic ['l0', 'l1', 'l2', 'l3', 'l4']", + "82, mice ['l0', 'l5', 'l6', 'l7', 'l8']", + "83, deficient ['l1', 'l5', 'l9', 'l10', 'l11']", + "84, for ['l2', 'l6', 'l9', 'l12', 'l13']", + "85, apolipoprotein ['l3', 'l7', 'l10', 'l12', 'l14']", + "86, E. ['l4', 'l8', 'l11', 'l13', 'l14']", + "90, mice ['l15', 'l16']", + "104, suppressed ['l15', 'l17']", + "106, atherosclerosis ['l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "diabetic", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "apolipoprotein", + "E." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + } + ] + }, + { + "PMID": "9734394", + "TEXT": "Leukemia inhibitory factor is essential for embryo implantation, and a shift from type 1 T-helper to type 2 T-helper response at the fetal-maternal interface may contribute to successful pregnancy. We show that LIF production is associated with type 2 T-helper cells, is upregulated by IL-4 and progesterone and is downregulated by IL-12, IFN-gamma and IFN-alpha. We also show a decreased production of LIF, IL-4 and IL-10 by decidual T cells of women with unexplained recurrent abortions in comparison with that of women with normal gestation. The defective production of LIF and/or type 2 T-helper cytokines may contribute to the development of unexplained recurrent abortions.", + "TAG_DATA": [ + "67, decidual {'context': 'B-cells'}", + "68, T {'context': 'I-cells'}", + "69, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "67, decidual ['l0', 'l1']", + "68, T ['l0', 'l2']", + "69, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9701253", + "TEXT": "Ribozymes, catalytic RNA molecules that cleave a complementary mRNA sequence, have potential as therapeutics for dominantly inherited disease. Twelve percent of American patients with the blinding disease autosomal dominant retinitis pigmentosa (ADRP) carry a substitution of histidine for proline at codon 23 (P23H) in their rhodopsin gene, resulting in photoreceptor cell death from the synthesis of the abnormal gene product. Ribozymes can discriminate and catalyze the in vitro destruction of P23H mutant mRNAs from a transgenic rat model of ADRP. Here, we demonstrate that in vivo expression of either a hammerhead or hairpin ribozyme in this rat model considerably slows the rate of photoreceptor degeneration for at least three months. Catalytically inactive control ribozymes had less effect on the retinal degeneration. Intracellular production of ribozymes in photoreceptors was achieved by transduction with a recombinant adeno-associated virus (rAAV) incorporating a rod opsin promoter. Ribozyme-directed cleavage of mutant mRNAs, therefore, may be an effective therapy for ADRP and also may be applicable to other inherited diseases.", + "TAG_DATA": [ + "84, in {'context': 'B-in vivo'}", + "85, vivo {'context': 'I-in vivo'}", + "96, rat {'context': 'B-organism'}", + "97, model {'context': 'I-organism'}", + "103, photoreceptor {'context': 'B-cells'}", + "126, photoreceptors {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "84, in ['l0', 'l1', 'l2', 'l3']", + "85, vivo ['l0', 'l4', 'l5', 'l6']", + "96, rat ['l1', 'l4', 'l7', 'l8']", + "97, model ['l2', 'l5', 'l7', 'l9']", + "103, photoreceptor ['l3', 'l6', 'l8', 'l9']", + "126, photoreceptors ['l10', 'l11', 'l12']", + "134, adeno-associated ['l10', 'l13', 'l14']", + "135, virus ['l11', 'l13', 'l15']", + "136, (rAAV) ['l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9701251", + "TEXT": "Prostate apoptosis response-4 (Par-4) is a protein containing both a leucine zipper and a death domain that was isolated by differential screening for genes upregulated in prostate cancer cells undergoing apoptosis. Par-4 is expressed in the nervous system, where its function is unknown. In Alzheimer disease (AD), neurons may die by apoptosis, and amyloid beta-protein (A beta) may play a role in this. We report here that Par-4 expression is increased in vulnerable neurons in AD brain and is induced in cultured neurons undergoing apoptosis. Blockade of Par-4 expression or function prevented neuronal apoptosis induced by Ab and trophic factor withdrawal. Par-4 expression was enhanced, and mitochondrial dysfunction and apoptosis exacerbated, in cells expressing presenilin-1 mutations associated with early-onset inherited AD.", + "TAG_DATA": [ + "85, Blockade {'perturbing_action': 'B-rnai/knockdown'}", + "86, of {'perturbing_action': 'I-rnai/knockdown'}", + "87, Par-4 {'perturbing_action': 'I-rnai/knockdown'}", + "88, expression {'perturbing_action': 'I-rnai/knockdown'}", + "91, prevented {'effect': 'B-negative'}", + "92, neuronal {'context': 'B-cells'}", + "93, apoptosis {'phenotype': 'B-apoptosis'}", + "94, induced {'effect': 'B-positive'}", + "109, apoptosis {'phenotype': 'B-apoptosis'}", + "110, exacerbated, {'effect': 'B-positive'}", + "112, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "85, Blockade ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "86, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "87, Par-4 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "88, expression ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "91, prevented ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "92, neuronal ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "93, apoptosis ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "94, induced ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "109, apoptosis ['l28', 'l29']", + "110, exacerbated, ['l28', 'l30']", + "112, cells ['l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Blockade", + "of", + "Par-4", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Blockade", + "of", + "Par-4", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "neuronal" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Blockade", + "of", + "Par-4", + "expression" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Blockade", + "of", + "Par-4", + "expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "cells", + "words": [ + "neuronal" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neuronal", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neuronal", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "exacerbated," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "exacerbated," + ] + } + } + ] + }, + { + "PMID": "9701249", + "TEXT": "More than 40,000 people die annually from rabies worldwide. Most of these fatalities occur in developing countries, where rabies is endemic, public health resources are inadequate and there is limited access to preventive treatment. Because of the high cost of vaccines derived from cell culture, many countries still use vaccines produced in sheep, goat or suckling mouse brain. The stability and low cost for mass production of DNA vaccines would make them ideal for use in developing countries. To investigate the potential of DNA vaccines for rabies immunization in humans, we vaccinated Macaca fascicularis (Cynomolgus) monkeys with DNA encoding the glycoprotein of the challenge virus standard rabies virus, or with a human diploid cell vaccine (HDCV). The monkeys then were challenged with a non-passaged rabies virus. DNA or HDCV vaccination elicited comparable primary and anamnestic neutralizing antibody responses. All ten vaccinated monkeys (DNA or HDCV) survived a rabies virus challenge, whereas monkeys vaccinated with only the DNA vector developed rabies. Furthermore, serum samples from DNA- or HDCV-vaccinated monkeys neutralized a global spectrum of rabies virus variants in vitro. This study shows that DNA immunization elicits protective immunity in nonhuman primates against lethal challenge with a human viral pathogen of the central nervous system. Our findings indicate that DNA vaccines may have a promising future in human rabies immunization.", + "TAG_DATA": [ + "92, Macaca {'context': 'B-organism'}", + "93, fascicularis {'context': 'I-organism'}", + "94, (Cynomolgus) {'context': 'I-organism'}", + "95, monkeys {'context': 'I-organism'}", + "117, monkeys {'context': 'B-organism'}", + "141, monkeys {'context': 'B-organism'}", + "151, monkeys {'context': 'B-organism'}", + "167, monkeys {'context': 'B-organism'}", + "176, in {'context': 'B-in vitro'}", + "177, vitro. {'context': 'I-in vitro'}", + "188, nonhuman {'context': 'B-organism'}", + "189, primates {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "92, Macaca ['l0', 'l1', 'l2']", + "93, fascicularis ['l0', 'l3', 'l4']", + "94, (Cynomolgus) ['l1', 'l3', 'l5']", + "95, monkeys ['l2', 'l4', 'l5']", + "141, monkeys ['l6']", + "151, monkeys ['l6']", + "167, monkeys ['l7', 'l8', 'l9', 'l10']", + "176, in ['l7', 'l11', 'l12', 'l13']", + "177, vitro. ['l8', 'l11', 'l14', 'l15']", + "188, nonhuman ['l9', 'l12', 'l14', 'l16']", + "189, primates ['l10', 'l13', 'l15', 'l16']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9701245", + "TEXT": "The adult heart lacks reserve cardiocytes and cannot regenerate. Therefore, a large acute myocardial infarction often develops into congestive heart failure. To attempt to prevent this progression, we transplanted skeletal myoblasts into cryoinfarcted myocardium of the same rabbits (autologous transfer), monitored cardiac function in vivo for two to six weeks and examined serial sections of the hearts by light and electron microscopy. Islands of different sizes comprising elongated, striated cells that retained characteristics of both skeletal and cardiac cells were found in the cryoinfarct. In rabbits in which myoblasts were incorporated, myocardial performance was improved. The ability to regenerate functioning muscle after autologous myoblast transplantation could have a important effect on patients after acute myocardial infarction.", + "TAG_DATA": [ + "29, skeletal {'context': 'B-cells'}", + "30, myoblasts {'context': 'I-cells'}", + "33, myocardium {'context': 'B-tissue/organ'}", + "37, rabbits {'context': 'B-organism'}", + "43, in {'context': 'B-in vivo'}", + "44, vivo {'context': 'I-in vivo'}", + "75, skeletal {'context': 'B-cells'}", + "76, and {'context': 'I-cells'}", + "77, cardiac {'context': 'I-cells'}", + "78, cells {'context': 'I-cells'}", + "85, rabbits {'context': 'B-organism'}", + "88, myoblasts {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "29, skeletal ['l0', 'l1', 'l2', 'l3', 'l4']", + "30, myoblasts ['l0', 'l5', 'l6', 'l7', 'l8']", + "33, myocardium ['l1', 'l5', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "37, rabbits ['l2', 'l6', 'l9', 'l16', 'l17', 'l18']", + "43, in ['l3', 'l7', 'l10', 'l16', 'l19']", + "44, vivo ['l4', 'l8', 'l11', 'l17', 'l19']", + "75, skeletal ['l12', 'l20', 'l21', 'l22']", + "76, and ['l13', 'l20', 'l23', 'l24']", + "77, cardiac ['l14', 'l21', 'l23', 'l25']", + "78, cells ['l15', 'l18', 'l22', 'l24', 'l25']", + "85, rabbits ['l26']", + "88, myoblasts ['l26']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9662378", + "TEXT": "The p53 tumor suppressor gene, which is induced by DNA damage and/or stress stimuli, causes cells to undergo G1-arrest or apoptotic death; thus it plays an essential role in human carcinogenesis. We have searched for p53-related genes by using degenerate PCR, and have identified two cDNA fragments similar to but distinct from p53: one previously reported, p73, and the other new. We cloned two major splicing variants of the latter gene and named these p51A and p51B (a human homologue of rat Ket). The p51A gene encodes a 448-amino-acid protein with a molecular weight of 50.9 kDa; and p51B, a 641-amino-acid protein with a molecular weight of 71.9 kDa. In contrast with the ubiquitous expression of p53, expression of p51 mRNA was found in a limited number of tissues, including skeletal muscle, placenta, mammary gland, prostate, trachea, thymus, salivary gland, uterus, heart and lung. In p53-deficient cells, p51A induced growth-suppression and apoptosis, and upregulated p21waf-1 through p53 regulatory elements. Mutations in p51 were found in some human epidermal tumors.", + "TAG_DATA": [ + "145, p53-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "146, cells, {'context': 'B-cells'}", + "148, induced {'effect': 'B-positive'}", + "151, apoptosis, {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "145, p53-deficient ['l0', 'l1', 'l2']", + "146, cells, ['l0', 'l3', 'l4']", + "148, induced ['l1', 'l3', 'l5']", + "151, apoptosis, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + } + ] + }, + { + "PMID": "9662377", + "TEXT": "Previously, we cloned a cDNA fragment, TSIP 2 (tumor suppressor inhibited pathway clone 2), that detects by northern blot analysis of M1-LTR6 cells a 3-kb mRNA downregulated during p53-induced apoptosis. Cloning the full-length TSIP 2 cDNA showed that it corresponds to the presenilin 1 (PS1) gene, in which mutations have been reported in early-onset familial Alzheimer's disease. Here we demonstrate that PS1 is downregulated in a series of model systems for p53-dependent and p53-independent apoptosis and tumor suppression. To investigate the biological relevance of this downregulation, we stably transfected U937 cells with antisense PS1 cDNA. The downregulation of PS1 in these U937 transfectants results in reduced growth with an increased fraction of the cells in apoptosis. When injected into mice homozygous for severe combined immunodeficiency disease (scid/scid mice), these cells show a suppression of their malignant phenotype. Our results indicate that PS1, initially identified in a neurodegenerative disease, may also be involved in the regulation of cancer-related pathways.", + "TAG_DATA": [ + "87, stably {'perturbing_action': 'B-gene gain-of-function'}", + "88, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "89, U937 {'context': 'B-cells'}", + "90, cells {'context': 'I-cells'}", + "91, with {'perturbing_action': 'I-gene gain-of-function'}", + "92, antisense {'perturbing_action': 'I-gene gain-of-function'}", + "93, PS1 {'perturbing_action': 'I-gene gain-of-function'}", + "94, cDNA. {'perturbing_action': 'I-gene gain-of-function'}", + "96, downregulation {'perturbing_action': 'B-gene loss-of-function'}", + "97, of {'perturbing_action': 'I-gene loss-of-function'}", + "98, PS1 {'perturbing_action': 'I-rnai/knockdown'}", + "101, U937 {'context': 'B-cells'}", + "102, transfectants {'context': 'I-cells'}", + "109, increased {'effect': 'B-positive'}", + "113, cells {'context': 'B-cells'}", + "115, apoptosis. {'phenotype': 'B-apoptosis'}", + "119, mice {'context': 'B-organism'}", + "120, homozygous {'perturbing_action': 'B-other'}", + "121, for {'perturbing_action': 'I-gene loss-of-function'}", + "122, severe {'perturbing_action': 'I-gene loss-of-function'}", + "123, combined {'perturbing_action': 'I-gene loss-of-function'}", + "124, immunodeficiency {'perturbing_action': 'I-gene loss-of-function'}", + "125, disease {'perturbing_action': 'I-gene loss-of-function'}", + "129, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "87, stably ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "88, transfected ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "89, U937 ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "90, cells ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43']", + "91, with ['l3', 'l16', 'l28', 'l39', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "92, antisense ['l4', 'l17', 'l29', 'l44', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "93, PS1 ['l5', 'l18', 'l30', 'l40', 'l45', 'l55', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "94, cDNA. ['l6', 'l19', 'l31', 'l41', 'l46', 'l56', 'l65', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "96, downregulation ['l47', 'l57', 'l66', 'l74', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "97, of ['l7', 'l20', 'l32', 'l48', 'l58', 'l67', 'l75', 'l82', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "98, PS1 ['l8', 'l21', 'l33', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l95', 'l96', 'l97', 'l98', 'l99']", + "101, U937 ['l9', 'l22', 'l34', 'l50', 'l60', 'l69', 'l77', 'l84', 'l90', 'l95', 'l100', 'l101', 'l102', 'l103']", + "102, transfectants ['l10', 'l23', 'l35', 'l51', 'l61', 'l70', 'l78', 'l85', 'l91', 'l96', 'l100', 'l104', 'l105', 'l106']", + "109, increased ['l11', 'l24', 'l36', 'l42', 'l52', 'l62', 'l71', 'l79', 'l86', 'l92', 'l97', 'l101', 'l104', 'l107', 'l108']", + "113, cells ['l12', 'l25', 'l37', 'l43', 'l53', 'l63', 'l72', 'l80', 'l87', 'l93', 'l98', 'l102', 'l105', 'l107', 'l109']", + "115, apoptosis. ['l13', 'l26', 'l38', 'l54', 'l64', 'l73', 'l81', 'l88', 'l94', 'l99', 'l103', 'l106', 'l108', 'l109']", + "119, mice ['l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "120, homozygous ['l110', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "121, for ['l111', 'l117', 'l123', 'l124', 'l125', 'l126', 'l127']", + "122, severe ['l112', 'l118', 'l123', 'l128', 'l129', 'l130', 'l131']", + "123, combined ['l113', 'l119', 'l124', 'l128', 'l132', 'l133', 'l134']", + "124, immunodeficiency ['l114', 'l120', 'l125', 'l129', 'l132', 'l135', 'l136']", + "125, disease ['l115', 'l121', 'l126', 'l130', 'l133', 'l135', 'l137']", + "129, cells ['l116', 'l122', 'l127', 'l131', 'l134', 'l136', 'l137']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "stably", + "transfected", + "with", + "antisense", + "PS1", + "cDNA." + ] + }, + "context": { + "val": "cells", + "words": [ + "U937", + "cells", + "transfectants" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "stably", + "transfected", + "with", + "antisense", + "PS1", + "cDNA." + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "stably", + "transfected", + "with", + "antisense", + "PS1", + "cDNA." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "U937", + "transfectants", + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "downregulation", + "for", + "severe", + "combined", + "immunodeficiency", + "disease" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "U937", + "transfectants", + "cells" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PS1" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "U937", + "cells", + "transfectants" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "U937", + "transfectants", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "downregulation", + "of" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "downregulation", + "of" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PS1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PS1" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "homozygous" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "for", + "severe", + "combined", + "immunodeficiency", + "disease" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "homozygous" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "9662375", + "TEXT": "The formation of fibrillar deposits of amyloid beta protein (Abeta) in the brain is a pathological hallmark of Alzheimer's disease (AD). A central question is whether Abeta plays a direct role in the neurodegenerative process in AD. The involvement of Abeta in the neurodegenerative process is suggested by the neurotoxicity of the fibrillar form of Abeta in vitro. However, mice transgenic for the Abeta precursor protein that develop amyloid deposits in the brain do not show the degree of neuronal loss or tau phosphorylation found in AD. Here we show that microinjection of plaque-equivalent concentrations of fibrillar, but not soluble, Abeta in the aged rhesus monkey cerebral cortex results in profound neuronal loss, tau phosphorylation and microglial proliferation. Fibrillar Abeta at plaque-equivalent concentrations is not toxic in the young adult rhesus brain. Abeta toxicity in vivo is also highly species-specific; toxicity is greater in aged rhesus monkeys than in aged marmoset monkeys, and is not significant in aged rats. These results suggest that Abeta neurotoxicity in vivo is a pathological response of the aging brain, which is most pronounced in higher order primates. Thus, longevity may contribute to the unique susceptibility of humans to Alzheimer's disease by rendering the brain vulnerable to Abeta neurotoxicity.", + "TAG_DATA": [ + "103, aged {'context': 'B-organism'}", + "104, rhesus {'context': 'I-organism'}", + "105, monkey {'context': 'I-tissue/organ'}", + "106, cerebral {'context': 'I-tissue/organ'}", + "107, cortex {'context': 'I-tissue/organ'}", + "116, microglial {'context': 'B-cells'}", + "117, proliferation. {'phenotype': 'B-proliferation'}", + "128, young {'context': 'B-organism'}", + "129, adult {'context': 'I-organism'}", + "130, rhesus {'context': 'I-tissue/organ'}", + "131, brain. {'context': 'I-tissue/organ'}", + "134, in {'context': 'B-in vivo'}", + "135, vivo {'context': 'I-in vivo'}", + "144, aged {'context': 'B-organism'}", + "145, rhesus {'context': 'I-organism'}", + "146, monkeys {'context': 'I-organism'}", + "149, aged {'context': 'B-organism'}", + "150, marmoset {'context': 'I-organism'}", + "151, monkeys, {'context': 'I-organism'}", + "157, aged {'context': 'B-organism'}", + "158, rats. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "103, aged ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "104, rhesus ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "105, monkey ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "106, cerebral ['l2', 'l7', 'l11', 'l15', 'l16']", + "107, cortex ['l3', 'l8', 'l12', 'l15', 'l17']", + "116, microglial ['l4', 'l9', 'l13', 'l18', 'l19']", + "117, proliferation. ['l5', 'l10', 'l14', 'l16', 'l17', 'l18']", + "128, young ['l20', 'l21', 'l22', 'l23', 'l24']", + "129, adult ['l20', 'l25', 'l26', 'l27']", + "130, rhesus ['l21', 'l25', 'l28', 'l29', 'l30', 'l31']", + "131, brain. ['l19', 'l22', 'l26', 'l28']", + "134, in ['l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "135, vivo ['l32', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "144, aged ['l33', 'l41', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "145, rhesus ['l34', 'l42', 'l49', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "146, monkeys ['l23', 'l27', 'l29', 'l35', 'l43', 'l50', 'l56', 'l62', 'l63', 'l64']", + "149, aged ['l30', 'l36', 'l44', 'l51', 'l57', 'l62', 'l65', 'l66']", + "150, marmoset ['l37', 'l45', 'l52', 'l58', 'l63', 'l65', 'l67', 'l68', 'l69']", + "151, monkeys, ['l24', 'l31', 'l38', 'l46', 'l53', 'l59', 'l64', 'l66', 'l67']", + "157, aged ['l39', 'l47', 'l54', 'l60', 'l68', 'l70']", + "158, rats. ['l40', 'l48', 'l55', 'l61', 'l69', 'l70']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "aged", + "rhesus" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "monkey", + "cerebral", + "cortex" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "microglial" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "9662369", + "TEXT": "Allelic variants for the HIV-1 co-receptors chemokine receptor 5 (CCR5) and CCR2, as well as the ligand for the co-receptor CXCR4, stromal-derived factor (SDF-1), have been associated with a delay in disease progression. We began this study to test whether polymorphisms in the CCR5 regulatory regions influence the course of HIV-1 disease, as well as to examine the role of the previously identified allelic variants in 1,090 HIV-1 infected individuals. Here we describe the evolutionary relationships between the phenotypically important CCR5 alleles, define precisely the CCR5 regulatory sequences that are linked to the CCR5-delta32 and CCR2-641 polymorphisms, and identify genotypes associated with altered rates of HIV-1 disease progression. The disease-retarding effects of the CCR2-641 allele were found in African Americans but not in Caucasians, and the SDF1-3'A/3'A genotype was associated with an accelerated progression to death. In contrast, the CCR5-delta32 allele and a CCR5 promoter mutation with which it is tightly linked were associated with limited disease-retarding effects. Collectively, these findings draw attention to a complex array of genetic determinants in the HIV-host interplay.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9623985", + "TEXT": "Huntington's disease is an autosomal dominant, inherited disorder that results in progressive degeneration of the basal ganglia (especially the neostriatal caudate nucleus and putamen) and other forebrain structures and is associated with a clinical profile of movement, cognitive and psychiatric impairments for which there is at present no effective therapy. Neuropathological, neurochemical and behavioral features of the disease can all be reproduced in experimental animals by local injection of excitotoxic or metabolic toxins into the neostriatum. All these features of the disease can be alleviated, at least in rats, by transplantation of embryonic striatal tissue into the degenerated striatum, which was the basis for commencing the first clinical trials of striatal transplantation in Huntington's patients. However, although rat striatal xenografts may temporarily reduce apomorphine-induced dyskinesias in monkeys, there has been no demonstration that allograft techniques that work well in rats translate effectively to the much larger differentiated striatum of primates. Here we demonstrate good survival, differentiation and integration of striatal allografts in the primate neostriatum, and recovery in a test of skilled motor performance. Long-term graft survival in primates indicates probable success for clinical transplants in Huntington's disease; in addition, our data suggest that graft placement has a direct influence on the pattern and extent of functional recovery.", + "TAG_DATA": [ + "117, rat {'context': 'B-xenograft'}", + "118, striatal {'context': 'I-xenograft'}", + "119, xenografts {'context': 'I-xenograft'}", + "126, monkeys, {'context': 'B-organism'}", + "155, differentiation {'phenotype': 'B-differentiation'}", + "159, striatal {'context': 'B-xenograft'}", + "160, allografts {'context': 'I-xenograft'}", + "163, primate {'context': 'B-tissue/organ'}", + "164, neostriatum, {'context': 'I-tissue/organ'}", + "178, primates {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "93, striatal ['l0']", + "94, tissue ['l0']", + "117, rat ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "118, striatal ['l1', 'l7', 'l8', 'l9', 'l10']", + "119, xenografts ['l2', 'l7', 'l11', 'l12', 'l13']", + "126, monkeys, ['l3', 'l8', 'l11', 'l14']", + "155, differentiation ['l4', 'l9', 'l12', 'l14', 'l15', 'l16', 'l17', 'l18']", + "159, striatal ['l15', 'l19', 'l20', 'l21']", + "160, allografts ['l16', 'l19', 'l22', 'l23']", + "163, primate ['l5', 'l17', 'l20', 'l22', 'l24']", + "164, neostriatum, ['l6', 'l10', 'l13', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "xenograft", + "words": [ + "rat", + "striatal", + "xenografts", + "allografts" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "monkeys," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "primate", + "neostriatum," + ] + } + } + ] + }, + { + "PMID": "9623984", + "TEXT": "Neuropeptide Y (NPY) is a 36-amino-acid neurotransmitter which is widely distributed throughout the central and peripheral nervous system. NPY involvement has been suggested in various physiological responses including cardiovascular homeostasis and the hypothalamic control of food intake. At least six subtypes of NPY receptors have been described. Because of the lack of selective antagonists, the specific role of each receptor subtype has been difficult to establish. Here we describe mice deficient for the expression of the Y1 receptor subtype. Homozygous mutant mice demonstrate a complete absence of blood pressure response to NPY, whereas they retain normal response to other vasoconstrictors. Daily food intake, as well as NPY-stimulated feeding, are only slightly diminished, whereas fast-induced refeeding is markedly reduced. Adult mice lacking the NPY Y1 receptor are characterized by increased body fat with no change in protein content. The higher energetic efficiency of mutant mice might result, in part, from the lower metabolic rate measured during the active period, associated with reduced locomotor activity. These results demonstrate the importance of NPY Y1 receptors in NPY-mediated cardiovascular response and in the regulation of body weight through central control of energy expenditure. In addition, these data are also indicative of a role for the Y1 receptor in the control of food intake.", + "TAG_DATA": [ + "69, mice {'context': 'B-organism'}", + "70, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "71, for {'perturbing_action': 'I-gene loss-of-function'}", + "72, the {'perturbing_action': 'I-gene loss-of-function'}", + "73, expression {'perturbing_action': 'I-gene loss-of-function'}", + "74, of {'perturbing_action': 'I-gene loss-of-function'}", + "75, the {'perturbing_action': 'I-gene loss-of-function'}", + "76, Y1 {'perturbing_action': 'I-gene loss-of-function'}", + "77, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "78, subtype. {'perturbing_action': 'I-gene loss-of-function'}", + "79, Homozygous {'perturbing_action': 'B-other'}", + "81, mice {'context': 'B-organism'}", + "118, Adult {'context': 'B-organism'}", + "119, mice {'context': 'I-organism'}", + "120, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "121, the {'perturbing_action': 'I-gene loss-of-function'}", + "122, NPY {'perturbing_action': 'I-gene loss-of-function'}", + "123, Y1 {'perturbing_action': 'I-gene loss-of-function'}", + "124, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "143, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "69, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "70, deficient ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "71, for ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "72, the ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "73, expression ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "74, of ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "75, the ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "76, Y1 ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "77, receptor ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "78, subtype. ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "79, Homozygous ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "80, mutant ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "81, mice ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "118, Adult ['l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "119, mice ['l78', 'l84', 'l85', 'l86', 'l87', 'l88']", + "120, lacking ['l79', 'l84', 'l89', 'l90', 'l91', 'l92']", + "121, the ['l80', 'l85', 'l89', 'l93', 'l94', 'l95']", + "122, NPY ['l81', 'l86', 'l90', 'l93', 'l96', 'l97']", + "123, Y1 ['l82', 'l87', 'l91', 'l94', 'l96', 'l98']", + "124, receptor ['l83', 'l88', 'l92', 'l95', 'l97', 'l98']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "Adult" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "the", + "expression", + "of", + "Y1", + "receptor", + "subtype.", + "lacking", + "NPY" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Homozygous" + ] + } + } + ] + }, + { + "PMID": "9623983", + "TEXT": "Neuropeptide Y (NPY), a 36-amino-acid neuromodulator abundantly expressed in the brain, has been implicated in the regulation of food intake and body weight. Pharmacological data suggest that NPY's stimulatory effect on appetite is transduced by the G-protein-coupled NPY Y5 receptor (Y5R). We have inactivated the Y5R gene in mice and report that younger Y5R-null mice feed and grow normally; however, they develop mild late-onset obesity characterized by increased body weight, food intake and adiposity. Fasting-induced refeeding is unchanged in younger Y5R-null mice and they exhibit normal sensitivity to leptin. Their response to intracerebroventricular (i.c.v.) administration of NPY and related peptides is either reduced or absent. NPY deficiency attenuates the obesity syndrome of mice deficient for leptin (ob/ob), but these effects are not mediated by NPY signaling through the Y5R because Y5R-null ob/ob mice are equally obese. These results demonstrate that the Y5R contributes to feeding induced by centrally administered NPY and its analogs, but is not a critical physiological feeding receptor in mice.", + "TAG_DATA": [ + "43, inactivated {'perturbing_action': 'B-gene loss-of-function'}", + "44, the {'perturbing_action': 'I-gene loss-of-function'}", + "45, Y5R {'perturbing_action': 'I-gene loss-of-function'}", + "46, gene {'perturbing_action': 'I-gene loss-of-function'}", + "48, mice {'context': 'B-organism'}", + "53, Y5R-null {'perturbing_action': 'B-gene loss-of-function'}", + "54, mice {'context': 'B-organism'}", + "80, Y5R-null {'perturbing_action': 'B-gene loss-of-function'}", + "81, mice {'context': 'B-organism'}", + "105, NPY {'perturbing_action': 'B-gene loss-of-function'}", + "106, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "112, mice {'context': 'B-organism'}", + "113, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "114, for {'perturbing_action': 'I-gene loss-of-function'}", + "115, leptin {'perturbing_action': 'I-gene loss-of-function'}", + "116, (ob/ob), {'perturbing_action': 'I-gene loss-of-function'}", + "130, Y5R-null {'perturbing_action': 'B-gene loss-of-function'}", + "131, ob/ob {'perturbing_action': 'B-gene loss-of-function', 'context': 'B-organism'}", + "132, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "43, inactivated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "44, the ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "45, Y5R ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "46, gene ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "48, mice ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28']", + "53, Y5R-null ['l4', 'l11', 'l17', 'l22', 'l26', 'l29', 'l30']", + "54, mice ['l5', 'l12', 'l18', 'l23', 'l27', 'l29']", + "80, Y5R-null ['l6', 'l13', 'l19', 'l24', 'l31']", + "81, mice ['l7', 'l14', 'l20', 'l25', 'l28', 'l30', 'l31']", + "105, NPY ['l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "106, deficiency ['l32', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "112, mice ['l33', 'l41', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "113, deficient ['l34', 'l42', 'l48', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "114, for ['l35', 'l43', 'l49', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "115, leptin ['l36', 'l44', 'l50', 'l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "116, (ob/ob), ['l37', 'l45', 'l51', 'l57', 'l62', 'l66', 'l70', 'l71', 'l72']", + "130, Y5R-null ['l38', 'l52', 'l58', 'l63', 'l67', 'l70', 'l73', 'l74']", + "131, ob/ob ['l39', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l73', 'l75']", + "132, mice ['l40', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivated", + "the", + "Y5R", + "gene", + "Y5R-null", + "NPY", + "deficiency", + "deficient", + "for", + "leptin", + "(ob/ob),", + "ob/ob" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "ob/ob" + ] + } + } + ] + }, + { + "PMID": "9623979", + "TEXT": "Liver transplantation is the only therapeutic strategy for many inherited and acquired diseases. The formation of reactive oxygen species following ischemia/reperfusion is a cause of hepatocellular injury during transplantation. This report describes the therapeutic application of mitochondrial superoxide dismutase gene transfer to the liver for acute ischemia/reperfusion injury. Recombinant adenoviral expression of mitochondrial superoxide dismutase in mouse liver prior to lobar ischemia/reperfusion significantly reduced acute liver damage and associated redox activation of both NF-kappaB and AP1. These immediate early transcription factors represent common pathways by which cells respond to environmental stress. This work provides the foundation for redox-mediated gene therapies directed at ameliorating ischemia/reperfusion injury and associated acute rejection in orthotopic liver transplantation.", + "TAG_DATA": [ + "48, Recombinant {'perturbing_action': 'B-gene gain-of-function'}", + "49, adenoviral {'perturbing_action': 'I-gene gain-of-function'}", + "50, expression {'perturbing_action': 'I-gene gain-of-function'}", + "51, of {'perturbing_action': 'I-gene gain-of-function'}", + "52, mitochondrial {'perturbing_action': 'I-gene gain-of-function'}", + "53, superoxide {'perturbing_action': 'I-gene gain-of-function'}", + "54, dismutase {'perturbing_action': 'I-gene gain-of-function'}", + "56, mouse {'context': 'B-tissue/organ'}", + "57, liver {'context': 'I-tissue/organ'}", + "65, liver {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "48, Recombinant ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "49, adenoviral ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "50, expression ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "51, of ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "52, mitochondrial ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "53, superoxide ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "54, dismutase ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "56, mouse ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "57, liver ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "65, liver ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Recombinant", + "adenoviral", + "expression", + "of", + "mitochondrial", + "superoxide", + "dismutase" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "liver" + ] + } + } + ] + }, + { + "PMID": "9623977", + "TEXT": "The transfer of apoptosis genes to tumors is one of the most promising strategies for cancer gene therapy. We have shown that massive apoptosis occurs when wild-type p53 expression is induced in glioma cells carrying a p53 gene mutation. However, adenovirus-mediated p53 gene transfer is ineffective in causing apoptosis in glioma cells that retain a wild-type p53 genotype. We evaluated the effect of E2F-1 overexpression on the growth of gliomas in vitro and in vivo. In the in vitro study, the adenovirus-mediated transfer of exogenous E2F-1 protein precipitated generalized apoptosis in gliomas. The treatment with Ad5CMV-E2F-1 of nude mice carrying subcutaneous gliomas arrested tumor growth. Our results indicate that E2F-1 has anti-glioma activity in vitro and in vivo.", + "TAG_DATA": [ + "63, E2F-1 {'perturbing_action': 'B-gene gain-of-function'}", + "64, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "69, gliomas {'context': 'B-neoplasm'}", + "70, in {'context': 'B-in vitro'}", + "71, vitro {'context': 'I-in vitro'}", + "73, in {'context': 'B-in vivo'}", + "74, vivo. {'context': 'I-in vivo'}", + "77, in {'context': 'B-in vitro'}", + "78, vitro {'context': 'I-in vitro'}", + "81, adenovirus-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "82, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "83, of {'perturbing_action': 'I-gene gain-of-function'}", + "84, exogenous {'perturbing_action': 'I-gene gain-of-function'}", + "85, E2F-1 {'perturbing_action': 'I-gene gain-of-function'}", + "86, protein {'perturbing_action': 'I-gene gain-of-function'}", + "87, precipitated {'effect': 'B-positive'}", + "89, apoptosis {'phenotype': 'B-apoptosis'}", + "91, gliomas. {'context': 'B-neoplasm'}", + "97, nude {'context': 'B-organism'}", + "98, mice {'context': 'I-organism'}", + "100, subcutaneous {'context': 'B-neoplasm'}", + "101, gliomas {'context': 'I-neoplasm'}", + "102, arrested {'effect': 'B-negative'}", + "103, tumor {'phenotype': 'B-tumour growth'}", + "104, growth. {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "63, E2F-1 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "64, overexpression ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "69, gliomas ['l1', 'l17', 'l33', 'l34', 'l35', 'l36']", + "70, in ['l2', 'l18', 'l33', 'l37']", + "71, vitro ['l3', 'l19', 'l34', 'l37']", + "73, in ['l4', 'l20', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "74, vivo. ['l5', 'l21', 'l38', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "77, in ['l6', 'l22', 'l39', 'l50', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "78, vitro ['l7', 'l23', 'l35', 'l40', 'l51', 'l61', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "81, adenovirus-mediated ['l8', 'l24', 'l41', 'l52', 'l62', 'l71', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "82, transfer ['l9', 'l25', 'l42', 'l53', 'l63', 'l72', 'l80', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "83, of ['l10', 'l26', 'l43', 'l54', 'l64', 'l73', 'l81', 'l88', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "84, exogenous ['l11', 'l27', 'l44', 'l55', 'l65', 'l74', 'l82', 'l89', 'l95', 'l101', 'l102', 'l103', 'l104', 'l105']", + "85, E2F-1 ['l12', 'l28', 'l45', 'l56', 'l66', 'l75', 'l83', 'l90', 'l96', 'l101', 'l106', 'l107', 'l108', 'l109']", + "86, protein ['l13', 'l29', 'l46', 'l57', 'l67', 'l76', 'l84', 'l91', 'l97', 'l102', 'l106', 'l110', 'l111', 'l112']", + "87, precipitated ['l14', 'l30', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l98', 'l103', 'l107', 'l110', 'l113', 'l114']", + "89, apoptosis ['l15', 'l31', 'l48', 'l59', 'l69', 'l78', 'l86', 'l93', 'l99', 'l104', 'l108', 'l111', 'l113', 'l115']", + "91, gliomas. ['l16', 'l32', 'l36', 'l49', 'l60', 'l70', 'l79', 'l87', 'l94', 'l100', 'l105', 'l109', 'l112', 'l114', 'l115']", + "97, nude ['l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "98, mice ['l116', 'l122', 'l123', 'l124', 'l125', 'l126']", + "100, subcutaneous ['l117', 'l122', 'l127', 'l128', 'l129']", + "101, gliomas ['l118', 'l123', 'l127', 'l130']", + "102, arrested ['l119', 'l124', 'l128', 'l130', 'l131', 'l132']", + "103, tumor ['l120', 'l125', 'l131', 'l133']", + "104, growth. ['l121', 'l126', 'l129', 'l132', 'l133']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "E2F-1", + "overexpression", + "adenovirus-mediated", + "transfer", + "of", + "exogenous", + "protein" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "gliomas", + "gliomas." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "E2F-1", + "overexpression", + "adenovirus-mediated", + "transfer", + "of", + "exogenous", + "protein" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "E2F-1", + "overexpression", + "adenovirus-mediated", + "transfer", + "of", + "exogenous", + "protein" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "E2F-1", + "overexpression", + "adenovirus-mediated", + "transfer", + "of", + "exogenous", + "protein" + ] + }, + "effect": { + "val": "positive", + "words": [ + "precipitated" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "E2F-1", + "overexpression", + "adenovirus-mediated", + "transfer", + "of", + "exogenous", + "protein" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "effect": { + "val": "positive", + "words": [ + "precipitated" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "precipitated" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "precipitated" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "precipitated" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "gliomas." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "gliomas." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "nude", + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrested" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "nude", + "mice" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "subcutaneous", + "gliomas" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrested" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "subcutaneous" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "arrested" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + } + ] + }, + { + "PMID": "9585236", + "TEXT": "Compared with vaccine delivery by injection, oral vaccines offer the hope of more convenient immunization strategies and a more practical means of implementing universal vaccination programs throughout the world. Oral vaccines act by stimulating the immune system at effector sites (lymphoid tissue) located in the gut. Genetic engineering has been used with variable success to design living and non-living systems as a means to deliver antigens to these sites and to stimulate a desired immune response. More recently, plant biotechnology techniques have been used to create plants which contain a gene derived from a human pathogen; the resultant plant tissues will accumulate an antigenic protein encoded by the foreign DNA. In pre-clinical trials, we found that antigenic proteins produced in transgenic plants retained immunogenic properties when purified; if injected into mice the antigen caused production of protein-specific antibodies. Moreover, in some experiments, if the plant tissues were simply fed to mice, a mucosal immune response occurred. The present study was conducted as a proof of principle to determine if humans would also develop a serum and/or mucosal immune response to an antigen delivered in an uncooked foodstuff.", + "TAG_DATA": [ + "130, mice {'context': 'B-organism'}", + "150, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "121, plants ['l0']", + "130, mice ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9585232", + "TEXT": "In situ killing of tumor cells using suicide gene transfer to generate death by a non-apoptotic pathway was associated with high immunogenicity and induction of heat shock protein (hsp) expression. In contrast, a syngeneic colorectal tumor line, CMT93, killed predominantly by apoptosis, showed low levels of hsp expression and less immunogenicity. When apoptosis was inhibited in CMT93 cells by overexpression of bcl-2, hsp was also induced. Furthermore, when cDNA encoding hsp70 was stably transfected into B16 and CMT93 cells, its expression significantly enhanced the immunogenicity of both tumors. Increased levels of hsp, induced by non-apoptotic cell killing, may provide an immunostimulatory signal in vivo which helps break tolerance to tumor antigens. These findings have important implications for the development of novel anti-cancer therapies aimed at promoting patients' immune responses to their own tumors.", + "TAG_DATA": [ + "33, syngeneic {'context': 'B-transformed cells'}", + "34, colorectal {'context': 'I-transformed cells'}", + "35, tumor {'context': 'I-transformed cells'}", + "36, line, {'context': 'I-transformed cells'}", + "37, CMT93, {'context': 'I-transformed cells'}", + "52, apoptosis {'phenotype': 'B-apoptosis'}", + "54, inhibited {'effect': 'B-negative'}", + "56, CMT93 {'context': 'B-cells'}", + "57, cells {'context': 'I-cells'}", + "59, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "60, of {'perturbing_action': 'I-gene gain-of-function'}", + "61, bcl-2, {'perturbing_action': 'I-gene gain-of-function'}", + "68, cDNA {'perturbing_action': 'B-gene gain-of-function'}", + "69, encoding {'perturbing_action': 'I-gene gain-of-function'}", + "70, hsp70 {'perturbing_action': 'I-gene gain-of-function'}", + "72, stably {'perturbing_action': 'B-gene gain-of-function'}", + "73, transfected {'perturbing_action': 'I-gene gain-of-function'}", + "75, B16 {'context': 'B-cells'}", + "76, and {'context': 'I-cells'}", + "77, CMT93 {'context': 'I-cells'}", + "78, cells, {'context': 'I-cells'}", + "87, tumors. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "33, syngeneic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "34, colorectal ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "35, tumor ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23']", + "36, line, ['l2', 'l11', 'l19', 'l24', 'l25']", + "37, CMT93, ['l3', 'l12', 'l20', 'l24', 'l26']", + "52, apoptosis ['l4', 'l13', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "54, inhibited ['l5', 'l14', 'l27', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "56, CMT93 ['l6', 'l15', 'l22', 'l28', 'l37', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "57, cells ['l7', 'l16', 'l23', 'l25', 'l26', 'l29', 'l38', 'l46', 'l54', 'l55', 'l56', 'l57']", + "59, overexpression ['l30', 'l39', 'l47', 'l54', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "60, of ['l8', 'l17', 'l31', 'l40', 'l48', 'l55', 'l58', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "61, bcl-2, ['l9', 'l18', 'l32', 'l41', 'l49', 'l56', 'l59', 'l67', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "68, cDNA ['l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "69, encoding ['l80', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "70, hsp70 ['l60', 'l68', 'l74', 'l81', 'l89', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "72, stably ['l82', 'l90', 'l97', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "73, transfected ['l61', 'l83', 'l91', 'l98', 'l104', 'l110', 'l111', 'l112', 'l113', 'l114']", + "75, B16 ['l33', 'l42', 'l50', 'l62', 'l69', 'l75', 'l84', 'l92', 'l99', 'l105', 'l110', 'l115', 'l116', 'l117', 'l118']", + "76, and ['l34', 'l43', 'l51', 'l63', 'l70', 'l76', 'l85', 'l93', 'l100', 'l106', 'l111', 'l115', 'l119', 'l120', 'l121']", + "77, CMT93 ['l35', 'l44', 'l52', 'l64', 'l71', 'l77', 'l86', 'l94', 'l101', 'l107', 'l112', 'l116', 'l119', 'l122', 'l123']", + "78, cells, ['l36', 'l45', 'l53', 'l57', 'l65', 'l72', 'l78', 'l87', 'l95', 'l102', 'l108', 'l113', 'l117', 'l120', 'l122', 'l124']", + "87, tumors. ['l66', 'l73', 'l79', 'l88', 'l96', 'l103', 'l109', 'l114', 'l118', 'l121', 'l123', 'l124']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "syngeneic", + "colorectal", + "tumor" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "syngeneic", + "colorectal" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "syngeneic", + "colorectal" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "bcl-2," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "CMT93", + "cells", + "B16", + "and", + "cells," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "bcl-2," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "CMT93", + "cells", + "B16", + "and", + "cells," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "bcl-2," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CMT93", + "cells", + "B16", + "and", + "cells," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "bcl-2,", + "cDNA", + "encoding", + "hsp70", + "stably", + "transfected" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "bcl-2,", + "cDNA", + "encoding", + "hsp70", + "stably", + "transfected" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors." + ] + } + } + ] + }, + { + "PMID": "9546791", + "TEXT": "Alzheimer's disease (AD) is characterized by the accumulation of cerebral plaques composed of 40- and 42-amino acid beta-amyloid (Abeta) peptides, and autosomal dominant forms of AD appear to cause disease by promoting brain Abeta accumulation. Recent studies indicate that postmenopausal estrogen replacement therapy may prevent or delay the onset of AD. Here we present evidence that physiological levels of 17beta-estradiol reduce the generation of Abeta by neuroblastoma cells and by primary cultures of rat, mouse and human embryonic cerebrocortical neurons. These results suggest a mechanism by which estrogen replacement therapy can delay or prevent AD.", + "TAG_DATA": [ + "66, neuroblastoma {'context': 'B-transformed cells'}", + "67, cells {'context': 'I-transformed cells'}", + "70, primary {'context': 'B-cells'}", + "71, cultures {'context': 'I-cells'}", + "72, of {'context': 'I-cells'}", + "73, rat, {'context': 'B-cells'}", + "74, mouse {'context': 'I-cells'}", + "75, and {'context': 'I-cells'}", + "76, human {'context': 'I-cells'}", + "77, embryonic {'context': 'I-cells'}", + "78, cerebrocortical {'context': 'I-cells'}", + "79, neurons. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "66, neuroblastoma ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "67, cells ['l0', 'l9', 'l10']", + "70, primary ['l1', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "71, cultures ['l2', 'l9', 'l11', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "72, of ['l3', 'l10', 'l12', 'l20', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "73, rat, ['l4', 'l13', 'l21', 'l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "74, mouse ['l5', 'l14', 'l22', 'l29', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "75, and ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l46', 'l47', 'l48', 'l49']", + "76, human ['l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l50', 'l51', 'l52']", + "77, embryonic ['l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l53', 'l54']", + "78, cerebrocortical ['l7', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l55']", + "79, neurons. ['l8', 'l19', 'l27', 'l34', 'l40', 'l45', 'l49', 'l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9546789", + "TEXT": "At a position equivalent to the gene encoding the saimiri transforming protein (STP) of herpesvirus saimiri (HVS), Kaposi's sarcoma-associated herpesvirus (KSHV) contains a distinct open reading frame called K1. Although KSHV and HVS are related members of the rhadinovirus subgroup of gamma herpesviruses, K1 and STP exhibit no similarity in amino acid sequence or in structural organization. Since STP is required for the oncogenic potential of HVS, we investigated the functional consequence of K1 expression. Expression of the K1 gene in rodent fibroblasts produced morphologic changes and focus formation indicative of transformation. A recombinant herpesvirus in which the STP oncogene of HVS was replaced with K1, immortalized primary T lymphocytes to IL-2 independent growth and induced lymphoma in common marmosets. These results demonstrate the transforming potential of the K1 gene of KSHV.", + "TAG_DATA": [ + "75, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "76, of {'perturbing_action': 'I-gene gain-of-function'}", + "77, the {'perturbing_action': 'I-gene gain-of-function'}", + "78, K1 {'perturbing_action': 'I-gene gain-of-function'}", + "79, gene {'perturbing_action': 'I-gene gain-of-function'}", + "81, rodent {'context': 'B-cells'}", + "82, fibroblasts {'context': 'I-cells'}", + "97, the {'perturbing_action': 'I-other'}", + "98, STP {'perturbing_action': 'I-other'}", + "99, oncogene {'perturbing_action': 'I-other'}", + "100, of {'perturbing_action': 'I-other'}", + "101, HVS {'perturbing_action': 'I-other'}", + "102, was {'perturbing_action': 'I-other'}", + "103, replaced {'perturbing_action': 'I-other'}", + "104, with {'perturbing_action': 'I-other'}", + "105, K1, {'perturbing_action': 'I-other'}", + "107, primary {'context': 'B-cells'}", + "108, T {'context': 'I-cells'}", + "109, lymphocytes {'context': 'I-cells'}", + "115, induced {'effect': 'B-positive'}", + "116, lymphoma {'phenotype': 'B-tumourigenesis'}", + "118, common {'context': 'B-organism'}", + "119, marmosets. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "75, Expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "76, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "77, the ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "78, K1 ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "79, gene ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "81, rodent ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "82, fibroblasts ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "93, recombinant ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "94, herpesvirus ['l21', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "97, the ['l22', 'l38', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "98, STP ['l23', 'l39', 'l54', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "99, oncogene ['l24', 'l40', 'l55', 'l69', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "100, of ['l25', 'l41', 'l56', 'l70', 'l83', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "101, HVS ['l26', 'l42', 'l57', 'l71', 'l84', 'l96', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "102, was ['l27', 'l43', 'l58', 'l72', 'l85', 'l97', 'l108', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "103, replaced ['l28', 'l44', 'l59', 'l73', 'l86', 'l98', 'l109', 'l119', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "104, with ['l29', 'l45', 'l60', 'l74', 'l87', 'l99', 'l110', 'l120', 'l129', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145']", + "105, K1, ['l30', 'l46', 'l61', 'l75', 'l88', 'l100', 'l111', 'l121', 'l130', 'l138', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "107, primary ['l31', 'l47', 'l62', 'l76', 'l89', 'l101', 'l112', 'l122', 'l131', 'l139', 'l146', 'l153', 'l154']", + "108, T ['l32', 'l48', 'l63', 'l77', 'l90', 'l102', 'l113', 'l123', 'l132', 'l140', 'l147', 'l153', 'l155']", + "109, lymphocytes ['l33', 'l49', 'l64', 'l78', 'l91', 'l103', 'l114', 'l124', 'l133', 'l141', 'l148', 'l154', 'l155']", + "115, induced ['l34', 'l50', 'l65', 'l79', 'l92', 'l104', 'l115', 'l125', 'l134', 'l142', 'l149', 'l156', 'l157', 'l158']", + "116, lymphoma ['l35', 'l51', 'l66', 'l80', 'l93', 'l105', 'l116', 'l126', 'l135', 'l143', 'l150', 'l156', 'l159', 'l160']", + "118, common ['l36', 'l52', 'l67', 'l81', 'l94', 'l106', 'l117', 'l127', 'l136', 'l144', 'l151', 'l157', 'l159', 'l161']", + "119, marmosets. ['l37', 'l53', 'l68', 'l82', 'l95', 'l107', 'l118', 'l128', 'l137', 'l145', 'l152', 'l158', 'l160', 'l161']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "the", + "K1", + "gene" + ] + }, + "context": { + "val": "cells", + "words": [ + "rodent", + "fibroblasts" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "the", + "STP", + "oncogene", + "of", + "HVS", + "was", + "replaced", + "with", + "K1," + ] + }, + "context": { + "val": "cells", + "words": [ + "primary", + "T", + "lymphocytes" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "the", + "STP", + "oncogene", + "of", + "HVS", + "was", + "replaced", + "with", + "K1," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "the", + "STP", + "oncogene", + "of", + "HVS", + "was", + "replaced", + "with", + "K1," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "the", + "STP", + "oncogene", + "of", + "HVS", + "was", + "replaced", + "with", + "K1," + ] + }, + "context": { + "val": "organism", + "words": [ + "common", + "marmosets." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "common", + "marmosets." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + }, + "context": { + "val": "organism", + "words": [ + "common", + "marmosets." + ] + } + } + ] + }, + { + "PMID": "9546787", + "TEXT": "The impact of antigenic stimulation on the dynamics of simian immunodeficiency virus (SIV) replication was studied following repeated intravenous BCG inoculation of a SIV infected macaque. At the site of a delayed type hypersensitivity reaction to purified protein derivative of M. tuberculosis, a distinctive SIV variant was noted, probably as a result of the infiltration of activated antigen-specific T cell clones as opposed to infection by blood borne virus in situ. The dynamics of SIV quasispecies in peripheral blood suggests sequential waves of viral replication, illustrating the role of antigenic stimulation as a driving force in viral dissemination and pathogenesis.", + "TAG_DATA": [ + "25, macaque. {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9546786", + "TEXT": "It is generally believed that the vascular endothelium serves as an inflammatory barrier by providing a nonadherent surface to leukocytes. Here, we report that Fas ligand (FasL) is expressed on vascular endothelial cells (ECs) and that it may function to actively inhibit leukocyte extravasation. TNFalpha downregulates FasL expression with an accompanying decrease in EC cytotoxicity toward co-cultured Fas-bearing cells. Local administration of TNFalpha to arteries downregulates endothelial FasL expression and induces mononuclear cell infiltration. Constitutive FasL expression markedly attenuates TNFalpha-induced cell infiltration and adherent mononuclear cells undergo apoptosis under these conditions. These findings suggest that endothelial FasL expression can negatively regulate leukocyte extravasation.", + "TAG_DATA": [ + "53, EC {'context': 'B-cells'}", + "57, Fas-bearing {'context': 'B-cells'}", + "58, cells. {'context': 'I-cells'}", + "64, arteries {'context': 'B-tissue/organ'}", + "71, mononuclear {'context': 'B-cells'}", + "72, cell {'context': 'I-cells'}", + "74, Constitutive {'perturbing_action': 'B-gene gain-of-function'}", + "75, FasL {'perturbing_action': 'I-gene gain-of-function'}", + "76, expression {'perturbing_action': 'I-gene gain-of-function'}", + "80, cell {'context': 'B-cells'}", + "83, adherent {'context': 'B-cells'}", + "84, mononuclear {'context': 'I-cells'}", + "85, cells {'context': 'I-cells'}", + "86, undergo {'effect': 'B-positive'}", + "87, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "53, EC ['l0', 'l1', 'l2']", + "57, Fas-bearing ['l0', 'l3', 'l4', 'l5', 'l6']", + "58, cells. ['l1', 'l3', 'l7', 'l8', 'l9']", + "64, arteries ['l4', 'l7', 'l10', 'l11']", + "71, mononuclear ['l5', 'l8', 'l10', 'l12']", + "72, cell ['l2', 'l6', 'l9', 'l11', 'l12']", + "74, Constitutive ['l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "75, FasL ['l13', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "76, expression ['l14', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "80, cell ['l15', 'l22', 'l28']", + "83, adherent ['l16', 'l23', 'l29', 'l34', 'l35', 'l36', 'l37']", + "84, mononuclear ['l17', 'l24', 'l30', 'l34', 'l38', 'l39', 'l40']", + "85, cells ['l18', 'l25', 'l31', 'l35', 'l38', 'l41', 'l42']", + "86, undergo ['l19', 'l26', 'l32', 'l36', 'l39', 'l41', 'l43']", + "87, apoptosis ['l20', 'l27', 'l33', 'l37', 'l40', 'l42', 'l43']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Constitutive", + "FasL", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "adherent", + "mononuclear", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Constitutive", + "FasL", + "expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "undergo" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Constitutive", + "FasL", + "expression" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "adherent", + "mononuclear", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "undergo" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "adherent", + "mononuclear", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "undergo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "9546785", + "TEXT": "Administration of tumor necrosis factor (TNF) and gamma interferon (IFN-gamma) to melanoma patients causes selective disruption of the tumor vasculature but the mechanism of this disruption is unknown. Here we report that exposure of human endothelial cells to TNF and IFN-gamma results in a reduced activation of integrin alphaVbeta3, an adhesion receptor that plays a key role in tumor angiogenesis, leading to a decreased alphaVbeta3-dependent endothelial cell adhesion and survival. Detachment and apoptosis of angiogenic endothelial cells was demonstrated in vivo in melanoma metastases of patients treated with TNF and IFN-gamma. These results implicate integrin alphaVbeta3 in the anti-vascular activity of TNF and IFN-gamma and demonstrate a new mechanism by which cytokines control cell adhesion.", + "TAG_DATA": [ + "34, human {'context': 'B-cells'}", + "35, endothelial {'context': 'I-cells'}", + "36, cells {'context': 'I-cells'}", + "63, decreased {'effect': 'B-negative'}", + "65, endothelial {'context': 'B-cells'}", + "66, cell {'context': 'I-cells'}", + "67, adhesion {'phenotype': 'B-adhesion'}", + "72, apoptosis {'phenotype': 'B-apoptosis'}", + "74, angiogenic {'context': 'B-cells'}", + "75, endothelial {'context': 'I-cells'}", + "76, cells {'context': 'I-cells'}", + "79, in {'context': 'B-in vivo'}", + "80, vivo {'context': 'I-in vivo'}", + "82, melanoma {'context': 'B-neoplasm'}", + "83, metastases {'context': 'I-neoplasm', 'phenotype': 'I-metastasis'}", + "85, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "34, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "35, endothelial ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "36, cells ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "63, decreased ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "65, endothelial ['l3', 'l8', 'l12', 'l15', 'l18', 'l19', 'l20', 'l21']", + "66, cell ['l4', 'l9', 'l13', 'l16', 'l18', 'l22']", + "67, adhesion ['l5', 'l10', 'l14', 'l17', 'l19', 'l22']", + "72, apoptosis ['l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "74, angiogenic ['l23', 'l30', 'l31', 'l32', 'l33']", + "75, endothelial ['l20', 'l24', 'l30', 'l34', 'l35']", + "76, cells ['l21', 'l25', 'l31', 'l34', 'l36']", + "79, in ['l26', 'l32', 'l37', 'l38', 'l39']", + "80, vivo ['l27', 'l33', 'l35', 'l36', 'l37', 'l40', 'l41']", + "82, melanoma ['l28', 'l38', 'l40', 'l42', 'l43']", + "83, metastases ['l29', 'l39', 'l41', 'l42', 'l44']", + "85, patients ['l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "endothelial", + "cells", + "cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "endothelial", + "cells", + "cell" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "angiogenic", + "endothelial", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "melanoma", + "metastases" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "metastases", + "melanoma" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + }, + "context": { + "val": "patient", + "words": [ + "patients" + ] + } + } + ] + }, + { + "PMID": "9546783", + "TEXT": "Immunization with irradiated sporozoites can protect against malaria infection and intensive efforts are aimed at reproducing this effect with subunit vaccines. A particular sequence of subunit immunization with pre-erythrocytic antigens of Plasmodium berghei, consisting of single dose priming with plasmid DNA followed by a single boost with a recombinant modified vaccinia virus Ankara (MVA) expressing the same antigen, induced unprecedented complete protection against P. berghei sporozoite challenge in two strains of mice. Protection was associated with very high levels of splenic peptide-specific interferon-gamma-secreting CD8+ T cells and was abrogated when the order of immunization was reversed. DNA priming followed by MVA boosting may provide a general immunization regime for induction of high levels of CD8+ T cells.", + "TAG_DATA": [ + "71, mice. {'context': 'B-organism'}", + "83, CD8+ {'context': 'B-cells'}", + "84, T {'context': 'I-cells'}", + "85, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "71, mice. ['l0']", + "83, CD8+ ['l1', 'l2']", + "84, T ['l1', 'l3']", + "85, cells ['l0', 'l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9500612", + "TEXT": "Viral and host factors influence the rate of HIV-1 disease progression. For HIV-1 to fuse, a CD4+ cell must express a co-receptor that the virus can use. The chemokine receptors CCR5 and CXCR4 are used by R5 and X4 viruses, respectively. Most new infections involve transmission of R5 viruses, but variants can arise later that also use CXCR4 (R5-X4 or X4 viruses). This is associated with an increased rate of CD4+ T-cell loss and poor prognosis. The ability of host cells to support HIV-1 entry also influences progression. The absence of CCR5 in approximately 1% of the Caucasian population, due to homozygosity for a 32-nucleotide deletion in the coding region (delta32-CCR5 allele), very strongly protects against HIV-1 transmission. Heterozygosity for the delta32-CCR5 allele delays progression typically by 2 years. A recent study showed that a conservative substitution (V64I) in the coding region of CCR2 also has a significant impact on disease progression, but not on HIV-1 transmission. This was unexpected, since CCR2 is rarely used as a co-receptor in vitro and the V64I change is in a transmembrane region. Because a subsequent study did not confirm this effect on progression to disease, we analyzed CCR2-V64I using subjects in the Chicago MACS. We show that CCR2-V64I is indeed protective against disease progression and go on to show that the CCR2-V64I allele is in complete linkage disequilibrium with a point mutation in the CCR5 regulatory region.", + "TAG_DATA": [ + "89, absence {'perturbing_action': 'B-gene loss-of-function'}", + "90, of {'perturbing_action': 'I-gene loss-of-function'}", + "91, CCR5 {'perturbing_action': 'I-gene loss-of-function'}", + "118, Heterozygosity {'perturbing_action': 'B-other'}", + "119, for {'perturbing_action': 'I-other'}", + "120, the {'perturbing_action': 'I-other'}", + "121, delta32-CCR5 {'perturbing_action': 'I-other'}", + "122, allele {'perturbing_action': 'I-other'}", + "136, substitution {'perturbing_action': 'I-other'}", + "137, (V64I) {'perturbing_action': 'I-other'}", + "138, in {'perturbing_action': 'I-other'}", + "139, the {'perturbing_action': 'I-other'}", + "140, coding {'perturbing_action': 'I-other'}", + "141, region {'perturbing_action': 'I-other'}", + "142, of {'perturbing_action': 'I-other'}", + "143, CCR2 {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "89, absence ['l0', 'l1']", + "90, of ['l0', 'l2']", + "91, CCR5 ['l1', 'l2']", + "118, Heterozygosity ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "119, for ['l3', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "120, the ['l4', 'l15', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "121, delta32-CCR5 ['l5', 'l16', 'l26', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "122, allele ['l6', 'l17', 'l27', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "136, substitution ['l7', 'l18', 'l28', 'l37', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "137, (V64I) ['l8', 'l19', 'l29', 'l38', 'l51', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "138, in ['l9', 'l20', 'l30', 'l39', 'l45', 'l52', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "139, the ['l10', 'l21', 'l31', 'l40', 'l46', 'l53', 'l59', 'l64', 'l69', 'l70', 'l71', 'l72']", + "140, coding ['l11', 'l22', 'l32', 'l41', 'l47', 'l54', 'l60', 'l65', 'l69', 'l73', 'l74', 'l75']", + "141, region ['l12', 'l23', 'l33', 'l42', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l76', 'l77']", + "142, of ['l13', 'l24', 'l34', 'l43', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l78']", + "143, CCR2 ['l14', 'l25', 'l35', 'l44', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l77', 'l78']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9500611", + "TEXT": "Both cellular and humoral immunodeficiency develop in vivo after prolonged infection with HIV-1, but the mechanisms are unclear. Initial infection with HIV-1 is transmitted by macrophage (M)-tropic/non-syncytia-inducing (NSI) viruses, which hyperactivate the immune system, and, in one view, cause immunodeficiency by \"exhaustion\" of lymphoid tissue. An alternative hypothesis is that immunodeficiency is caused by the replacement of M-tropic viruses by T cell (T)-tropic/syncytia-inducing (SI) viruses, which are known to be highly cytopathic in vitro and emerge late in infected individuals around the time of transition to AIDS (refs. 1, 7-9). To test these two possibilities, we have developed an ex vivo model of humoral immunity to recall antigens using human lymphoid tissue. This tissue supports productive infection with both M- and T-tropic HIV-1 isolates when cultured ex vivo. We found that specific immune responses were enhanced by productive infection of the tissue with M-tropic/NSI HIV-1 isolates, but were blocked by T-tropic/SI HIV-1 isolates. The mechanism involves specific irreversible effect on B-cell activity. Our results support the hypothesis that the phenotype switch to T-tropic viruses is a key determinant of acquired humoral immunodeficiency in patients infected with HIV.", + "TAG_DATA": [ + "109, human {'context': 'B-tissue/organ'}", + "110, lymphoid {'context': 'I-tissue/organ'}", + "111, tissue. {'context': 'I-tissue/organ'}", + "141, tissue {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "109, human ['l0', 'l1']", + "110, lymphoid ['l0', 'l2']", + "111, tissue. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9500610", + "TEXT": "Evolutionary patterns of virus replication and distribution in lymphoid tissue during the early phases of HIV infection have not been delineated. Lymph node (LN) biopsies were excised from patients at different times after the estimated time of primary infection. Within 3 months of the acute viral syndrome, HIV was mostly present in individual virus-expressing cells in LNs; trapping of virions in the follicular dendritic cell (FDC) network was minimal or absent, but was the predominant form of HIV detected in LNs of subjects with chronic infection, either recent (4-20 months after primary infection) or long-term (>2-3 years after primary infection). Plasma viremia was significantly higher in patients during the first 3 months than in those recently infected; however, there were no significant differences in the number of virus-expressing cells per square millimeter of LN tissue in these two groups. Numbers of virus-expressing cells in lymphoid tissue were significantly lower in the subjects with long-term infection than in the other two groups. Therefore, during the transition from primary to chronic HIV infection, the level of HIV replication in lymphoid tissue remains elevated despite the fact that viremia is significantly downregulated. These findings have implications for therapeutic strategies in primary HIV infection and in recent seroconvertors.", + "TAG_DATA": [ + "128, cells {'context': 'I-cells'}", + "133, LN {'context': 'B-tissue/organ'}", + "134, tissue {'context': 'I-tissue/organ'}", + "141, virus-expressing {'context': 'B-cells'}", + "142, cells {'context': 'I-cells'}", + "144, lymphoid {'context': 'B-tissue/organ'}", + "145, tissue {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "128, cells ['l0', 'l1']", + "133, LN ['l0', 'l2']", + "134, tissue ['l1', 'l2']", + "141, virus-expressing ['l3', 'l4', 'l5']", + "142, cells ['l3', 'l6', 'l7']", + "144, lymphoid ['l4', 'l6', 'l8']", + "145, tissue ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9500608", + "TEXT": "Medawar and co-workers originally demonstrated that injection of donor bone marrow (DBM) into immuno-incompetent neonatal rodents could induce tolerance to grafts from animals of the same strain as the bone marrow donor. Induction of tolerance in this manner can also be accomplished in mature mice, dogs and monkeys if the resident T-cell populations in the recipient are depleted by a polyclonal antithymocyte globulin or an anti-T cell immunotoxin. The molecular mechanisms by which bone marrow cells mediate the induction of tolerance remain uncertain. Here we examined a well-established adult mouse model of antithymocyte globulin and DBM treatment and show that expression of functional Fas ligand (FasL, also CD95L) on the injected bone marrow cells is required for tolerance induction. The results indicate that a state of microchimerism per se is insufficient for the induction of tolerance in T cell-depleted transplant recipients. Moreover, the results are consistent with the hypothesis that tolerance induced by DBM involves an apoptotic process leading to deletion of graft-reactive cells.", + "TAG_DATA": [ + "43, mature {'context': 'B-organism'}", + "44, mice, {'context': 'I-organism'}", + "51, T-cell {'context': 'I-cells'}", + "88, adult {'context': 'B-organism'}", + "89, mouse {'context': 'I-organism'}", + "90, model {'context': 'I-organism'}", + "111, bone {'context': 'B-cells'}", + "112, marrow {'context': 'I-cells'}", + "113, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "43, mature ['l0', 'l1', 'l2', 'l3', 'l4']", + "44, mice, ['l0', 'l5', 'l6', 'l7', 'l8']", + "51, T-cell ['l1', 'l5', 'l9', 'l10', 'l11', 'l12']", + "88, adult ['l2', 'l6', 'l9', 'l13', 'l14']", + "89, mouse ['l3', 'l7', 'l10', 'l13', 'l15']", + "90, model ['l4', 'l8', 'l11', 'l14', 'l15']", + "111, bone ['l16', 'l17']", + "112, marrow ['l16', 'l18']", + "113, cells ['l12', 'l17', 'l18']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9500607", + "TEXT": "Melanoma is the main cause of death in patients with skin cancer. Cytotoxic T lymphocytes (CTLs) attack melanoma cells in an HLA-restricted and tumor antigen-specific manner. Several melanoma-associated tumor antigens have been identified. These antigens are suitable candidates for a vaccination therapy of melanoma. Dendritic cells (DCs) are antigen-presenting cells (APCs) specialized for the induction of a primary T-cell response. Mouse studies have demonstrated the potent capacity of DCs to induce antitumor immunity. In the present clinical pilot study, DCs were generated in the presence of granulocyte/macrophage-colony stimulating factor (GM-CSF) and interleukin 4 (IL-4) and were pulsed with tumor lysate or a cocktail of peptides known to be recognized by CTLs, depending on the patient's HLA haplotype. Keyhole limpet hemocyanin (KLH) was added as a CD4 helper antigen and immunological tracer molecule. Sixteen patients with advanced melanoma were immunized on an outpatient basis. Vaccination was well tolerated. No physical sign of autoimmunity was detected in any of the patients. DC vaccination induced delayed-type hypersensitivity (DTH) reactivity toward KLH in all patients, as well as a positive DTH reaction to peptide-pulsed DCs in 11 patients. Recruitment of peptide-specific CTLs to the DTH challenge site was also demonstrated. Therefore, antigen-specific immunity was induced during DC vaccination. Objective responses were evident in 5 out of 16 evaluated patients (two complete responses, three partial responses) with regression of metastases in various organs (skin, soft tissue, lung, pancreas) and one additional minor response. These data indicate that vaccination with autologous DCs generated from peripheral blood is a safe and promising approach in the treatment of metastatic melanoma. Further studies are necessary to demonstrate clinical effectiveness and impact on the survival of melanoma patients.", + "TAG_DATA": [ + "79, DCs {'context': 'B-cells'}", + "133, patients {'context': 'B-patient'}", + "134, with {'context': 'I-patient'}", + "135, advanced {'context': 'I-neoplasm'}", + "136, melanoma {'context': 'I-neoplasm'}", + "222, regression {'effect': 'B-negative', 'phenotype': 'B-tumour regression'}", + "224, metastases {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "79, DCs ['l0', 'l1', 'l2']", + "133, patients ['l0', 'l3', 'l4', 'l5']", + "134, with ['l3', 'l6', 'l7']", + "135, advanced ['l1', 'l4', 'l6', 'l8']", + "136, melanoma ['l2', 'l5', 'l7', 'l8']", + "222, regression ['l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "223, of ['l9', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "224, metastases ['l10', 'l18', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "225, in ['l11', 'l19', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "227, organs ['l12', 'l20', 'l27', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "228, (skin, ['l13', 'l21', 'l28', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47']", + "229, soft ['l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l48', 'l49', 'l50']", + "230, tissue, ['l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l51', 'l52']", + "231, lung, ['l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l53']", + "232, pancreas) ['l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l53']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "regression" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "regression" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + } + ] + }, + { + "PMID": "9500604", + "TEXT": "CD8 molecules function as co-receptors on cytotoxic T lymphocytes (CTLs), interacting with a nonpolymorphic region of the major histocompatibility complex (MHC) class I a3 domain on antigen-presenting cells. Analogues were designed from a structural model of the mouse CD8a molecule to identify surfaces involved in CD8 function. Peptides were screened for in vitro biological activity on alloreactive CTLs, and analogue SC4 (p54-59) was found to be inhibitory during both the generation and effector stages. SC4 was also able to significantly prolong skin allograft survival across a MHC class I barrier. Thus, such CD8 analogues may have therapeutic potential as immunoregulators of CTL immune responses.", + "TAG_DATA": [ + "57, CTLs, {'context': 'B-cells'}", + "81, skin {'context': 'B-xenograft'}", + "82, allograft {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "81, skin ['l0']", + "82, allograft ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9500600", + "TEXT": "A chimeric RNA/DNA oligonucleotide was constructed to induce a sequence mutation in the rat factor IX gene, resulting in prolonged coagulation. Oligonucleotides were targeted to hepatocytes in cell culture or in vivo by intravenous injection. Nucleotide conversion was both site-specific and dose-dependent. The mutated gene was associated in vivo with significantly reduced factor IX coagulant activity and a marked prolongation of the activated partial thromboplastin time. The results demonstrate that single base-pair alterations can be introduced in hepatocytes in situ by RNA/DNA oligonucleotides, suggesting a potentially powerful strategy for hepatic gene repair without the use of viral vectors.", + "TAG_DATA": [ + "25, hepatocytes {'context': 'B-cells'}", + "26, in {'context': 'B-cells'}", + "27, cell {'context': 'B-cells'}", + "28, culture {'context': 'I-cells'}", + "30, in {'context': 'B-in vivo'}", + "31, vivo {'context': 'I-in vivo'}", + "47, in {'context': 'B-in vivo'}", + "48, vivo {'context': 'I-in vivo'}", + "77, hepatocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "25, hepatocytes ['l0', 'l1', 'l2', 'l3']", + "26, in ['l0', 'l4', 'l5']", + "27, cell ['l1', 'l4', 'l6']", + "28, culture ['l2', 'l5', 'l6']", + "30, in ['l7']", + "31, vivo ['l3', 'l7']", + "47, in ['l8']", + "48, vivo ['l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9461198", + "TEXT": "Intravenous tissue plasminogen activator (tPA) is used to treat acute stroke because of its thrombolytic activity and its ability to restore circulation to the brain. However, this protease also promotes neurodegeneration after intracerebral injection of excitotoxins such as glutamate, and neuronal damage after a cerebral infarct is thought to be mediated by excitotoxins. To investigate the effects of tPA on cerebral viability during ischemia/reperfusion, we occluded the middle cerebral artery in wild-type and tPA-deficient mice with an intravascular filament. This procedure allowed us to examine the role of tPA in ischemia, independent of its effect as a thrombolytic agent. tPA-deficient mice exhibited approximately 50% smaller cerebral infarcts than wild-type mice. Intravenous injection of tPA into tPA-/- or wild-type mice produced larger infarcts, indicating that tPA can increase stroke-induced injury. Since tPA promotes desirable (thrombolytic) as well as undesirable (neurotoxic) outcomes during stroke, future therapies should be aimed at countering the excitotoxic damage of tPA to afford even better neuroprotection after an acute cerebral infarct.", + "TAG_DATA": [ + "73, tPA-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "74, mice {'context': 'B-organism'}", + "99, tPA-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "100, mice {'context': 'B-organism'}", + "109, mice. {'context': 'B-organism'}", + "115, tPA-/- {'perturbing_action': 'B-gene loss-of-function'}", + "118, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, tPA-deficient ['l0']", + "74, mice ['l0']", + "99, tPA-deficient ['l1', 'l2']", + "100, mice ['l1', 'l3']", + "109, mice. ['l2', 'l3']", + "115, tPA-/- ['l4']", + "118, mice ['l4']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "tPA-deficient", + "tPA-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "9461192", + "TEXT": "Demyelination alone has been considered sufficient for development of neurological deficits following central nervous system (CNS) disease. However, extensive demyelination is not always associated with clinical deficits in patients with multiple sclerosis (MS), the most common primary demyelinating disease in humans. We used the Theiler's murine encephalomyelitis virus model of demyelination to investigate the role of major histocompatibility complex (MHC) class I and class II gene products in the development of functional and neurophysiological deficits following demyelination. We measured spontaneous clinical activity by two independent assays and recorded hind-limb motor-evoked potentials in infected class I-deficient and class II-deficient mice of an identical genetic background as well as in highly susceptible SJL/J mice. The results show that despite a similar distribution and extent of demyelinated lesions in all mice, only class I-deficient mice were functionally normal. We propose that the mechanism by which demyelinated class I-deficient mice maintain neurologic function results from increased sodium channel densities and the relative preservation of axons. These findings are the first to implicate a role for MHC class I in the development of neurological deficits following demyelination.", + "TAG_DATA": [ + "93, class {'perturbing_action': 'B-gene loss-of-function'}", + "94, I-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "96, class {'perturbing_action': 'B-gene loss-of-function'}", + "97, II-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "98, mice {'context': 'B-organism'}", + "110, SJL/J {'context': 'B-organism'}", + "111, mice. {'context': 'I-organism'}", + "127, mice, {'context': 'B-organism'}", + "129, class {'perturbing_action': 'B-gene loss-of-function'}", + "130, I-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "131, mice {'context': 'B-organism'}", + "143, class {'perturbing_action': 'B-gene loss-of-function'}", + "144, I-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "145, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "93, class ['l0', 'l1', 'l2', 'l3']", + "94, I-deficient ['l0', 'l4', 'l5', 'l6']", + "96, class ['l1', 'l4', 'l7', 'l8', 'l9']", + "97, II-deficient ['l2', 'l5', 'l7', 'l10']", + "98, mice ['l3', 'l6', 'l8', 'l10']", + "110, SJL/J ['l11', 'l12']", + "111, mice. ['l9', 'l11']", + "127, mice, ['l12']", + "129, class ['l13', 'l14', 'l15', 'l16', 'l17']", + "130, I-deficient ['l13', 'l18', 'l19', 'l20', 'l21']", + "131, mice ['l14', 'l18', 'l22', 'l23', 'l24']", + "143, class ['l15', 'l19', 'l22', 'l25', 'l26']", + "144, I-deficient ['l16', 'l20', 'l23', 'l25', 'l27']", + "145, mice ['l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "class", + "I-deficient", + "II-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "9427614", + "TEXT": "Genetic causes of Alzheimer's disease (AD) include mutations in the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) genes. The mutant APP(K670N,M671L) transgenic line, Tg2576, shows markedly elevated amyloid beta-protein (A beta) levels at an early age and, by 9-12 months, develops extracellular AD-type A beta deposits in the cortex and hippocampus. Mutant PS1 transgenic mice do not show abnormal pathology, but do display subtly elevated levels of the highly amyloidogenic 42- or 43-amino acid peptide A beta42(43). Here we demonstrate that the doubly transgenic progeny from a cross between line Tg2576 and a mutant PS1M146L transgenic line develop large numbers of fibrillar A beta deposits in cerebral cortex and hippocampus far earlier than their singly transgenic Tg2576 littermates. In the period preceding overt A beta deposition, the doubly transgenic mice show a selective 41% increase in A beta42(43) in their brains. Thus, the development of AD-like pathology is substantially enhanced when a PS1 mutation, which causes a modest increase in A beta42(43), is introduced into Tg2576-derived mice. Remarkably, both doubly and singly transgenic mice showed reduced spontaneous alternation performance in a \"Y\" maze before substantial A beta deposition was apparent. This suggests that some aspects of the behavioral phenotype in these mice may be related to an event that precedes plaque formation.", + "TAG_DATA": [ + "23, mutant {'perturbing_action': 'B-other'}", + "55, Mutant {'perturbing_action': 'B-gene gain-of-function'}", + "56, PS1 {'perturbing_action': 'I-gene gain-of-function'}", + "57, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "58, mice {'context': 'B-organism'}", + "97, mutant {'perturbing_action': 'B-other'}", + "98, PS1M146L {'perturbing_action': 'I-other'}", + "99, transgenic {'perturbing_action': 'I-other'}", + "110, cerebral {'context': 'B-tissue/organ'}", + "111, cortex {'context': 'I-tissue/organ'}", + "113, hippocampus {'context': 'B-tissue/organ'}", + "133, mice {'context': 'B-organism'}", + "156, PS1 {'perturbing_action': 'B-other'}", + "157, mutation, {'perturbing_action': 'I-other'}", + "169, Tg2576-derived {'context': 'B-cells'}", + "170, mice. {'context': 'B-organism'}", + "177, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "23, mutant ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "24, APP(K670N,M671L) ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "25, transgenic ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "55, Mutant ['l2', 'l12', 'l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "56, PS1 ['l3', 'l13', 'l22', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "57, transgenic ['l4', 'l14', 'l23', 'l30', 'l35', 'l40', 'l41']", + "58, mice ['l5', 'l15', 'l24', 'l31', 'l36', 'l40']", + "86, doubly ['l6', 'l16', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "94, Tg2576 ['l7', 'l17', 'l25', 'l42', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "97, mutant ['l43', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "98, PS1M146L ['l44', 'l57', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "99, transgenic ['l45', 'l51', 'l58', 'l64', 'l70', 'l71', 'l72', 'l73', 'l74']", + "100, line ['l46', 'l52', 'l59', 'l65', 'l70', 'l75', 'l76', 'l77', 'l78']", + "110, cerebral ['l8', 'l18', 'l26', 'l32', 'l37', 'l47', 'l53', 'l60', 'l66', 'l71', 'l75', 'l79', 'l80']", + "111, cortex ['l9', 'l19', 'l27', 'l33', 'l38', 'l41', 'l48', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l81']", + "113, hippocampus ['l10', 'l20', 'l28', 'l34', 'l39', 'l49', 'l55', 'l62', 'l68', 'l73', 'l77', 'l80', 'l81']", + "133, mice ['l50', 'l56', 'l63', 'l69', 'l74', 'l78']", + "156, PS1 ['l82', 'l83', 'l84', 'l85']", + "157, mutation, ['l82', 'l86', 'l87', 'l88']", + "169, Tg2576-derived ['l83', 'l86', 'l89', 'l90']", + "170, mice. ['l84', 'l87', 'l89', 'l91']", + "177, mice ['l85', 'l88', 'l90', 'l91']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "PS1M146L", + "transgenic", + "PS1", + "mutation," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "PS1M146L", + "transgenic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "cerebral", + "cortex", + "hippocampus" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Mutant", + "PS1", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Mutant", + "PS1", + "transgenic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "cerebral", + "cortex", + "hippocampus" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "PS1", + "mutation," + ] + }, + "context": { + "val": "cells", + "words": [ + "Tg2576-derived" + ] + } + } + ] + }, + { + "PMID": "9427612", + "TEXT": "In this report we describe a potentially powerful method for vaccinating infants against encapsulated bacterial pathogens such as Haemophilus influenzae, Streptococcus pneumoniae and Neisseria meningitidis. High levels of antibody directed against the polysaccharides of the bacterial capsule are normally protective. Unfortunately, the capsular polysaccharides are T cell-independent antigens (TI); lacking T-cell help, they induce only weak, predominantly IgM antibody responses, with infants responding especially poorly. T-cell help, given to B cells during responses to protein antigens, causes stronger antibody responses and isotype switching to the IgG isotypes. T-cell help is mainly mediated through ligation of the B-cell surface antigen, CD40, by its cognate T-cell ligand, CD154. Here we show that administering anti-CD40 monoclonal antibody to mice, along with pneumococcal polysaccharide, provides a substitute for T-cell help and results in the generation of strong, isotype-switched antibody responses, which are protective. The work points the way toward a possible effective and inexpensive means of protecting susceptible groups against important bacterial pathogens.", + "TAG_DATA": [ + "69, B {'context': 'B-cells'}", + "70, cells {'context': 'B-cells'}", + "115, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "69, B ['l0']", + "70, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9427611", + "TEXT": "Nitric oxide (NO) is well established as a neurotransmitter in the central and peripheral nervous systems. More recently, another gas, carbon monoxide (CO) has also been implicated in neurotransmission. In the nervous system CO is formed by a subtype of heme oxygenase (HO) designated HO2. HO2 is localized to discrete neuronal populations in the brain resembling localizations of soluble guanylyl cyclase, which is activated by CO. CO may also function in the peripheral autonomic nervous system, in conjunction with NO. The majority of ganglia in the myenteric plexus possess both HO2 and neuronal NO synthase (NOS). Defects in myenteric plexus neurotransmission occur both in mice with targeted deletion of genes for HO2 and neuronal NOS. HO2 also occurs in other autonomic ganglia including the petrosal, superior cervical and nodose ganglia. Neuronal NOS is localized to neurons regulating male reproductive behavior, such as penile erection, and NOS inhibitors prevent erection. Because of the other parallels between NO and CO, we speculated that CO may play a role in male reproductive behavior. In the present study we describe HO2 localization in neuronal structures regulating copulatory reflexes. Reflex activity of the bulbospongiosus muscle, which mediates ejaculation and ejaculatory behavior, is markedly diminished in mice with targeted deletion of the gene for HO2 (HO2-).", + "TAG_DATA": [ + "104, mice {'context': 'B-organism'}", + "106, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "107, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "108, of {'perturbing_action': 'I-gene loss-of-function'}", + "109, genes {'perturbing_action': 'I-gene loss-of-function'}", + "110, for {'perturbing_action': 'I-gene loss-of-function'}", + "111, HO2 {'perturbing_action': 'I-gene loss-of-function'}", + "188, bulbospongiosus {'context': 'B-cells'}", + "189, muscle, {'context': 'I-tissue/organ'}", + "200, mice {'context': 'B-organism'}", + "202, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "203, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "204, of {'perturbing_action': 'I-gene loss-of-function'}", + "205, the {'perturbing_action': 'I-gene loss-of-function'}", + "206, gene {'perturbing_action': 'I-gene loss-of-function'}", + "207, for {'perturbing_action': 'I-gene loss-of-function'}", + "208, HO2 {'perturbing_action': 'I-gene loss-of-function'}", + "209, (HO2-). {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "104, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "106, targeted ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "107, deletion ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "108, of ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "109, genes ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "110, for ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "111, HO2 ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "188, bulbospongiosus ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "189, muscle, ['l21', 'l31', 'l32', 'l33', 'l34', 'l35']", + "200, mice ['l22', 'l31', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "202, targeted ['l23', 'l36', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "203, deletion ['l24', 'l37', 'l44', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "204, of ['l25', 'l38', 'l45', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "205, the ['l26', 'l39', 'l46', 'l52', 'l57', 'l62', 'l63', 'l64', 'l65']", + "206, gene ['l27', 'l32', 'l40', 'l47', 'l53', 'l58', 'l62', 'l66', 'l67', 'l68']", + "207, for ['l28', 'l33', 'l41', 'l48', 'l54', 'l59', 'l63', 'l66', 'l69', 'l70']", + "208, HO2 ['l29', 'l34', 'l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l71']", + "209, (HO2-). ['l30', 'l35', 'l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l71']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "deletion", + "of", + "genes", + "for", + "HO2", + "the", + "gene", + "(HO2-)." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "bulbospongiosus" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "deletion", + "of", + "the", + "gene", + "for", + "HO2", + "(HO2-)." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "muscle," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "gene", + "for", + "HO2", + "(HO2-)." + ] + } + } + ] + }, + { + "PMID": "9427609", + "TEXT": "The bicyclam AMD3100 (formula weight 830) blocks HIV-1 entry and membrane fusion via the CXCR4 co-receptor, but not via CCR5. AMD3100 prevents monoclonal antibody 12G5 from binding to CXCR4, but has no effect on binding of monoclonal antibody 2D7 to CCR5. It also inhibits binding of the CXC-chemokine, SDF-1alpha, to CXCR4 and subsequent signal transduction, but does not itself cause signaling and has no effect on RANTES signaling via CCR5. Thus, AMD3100 prevents CXCR4 functioning as both a HIV-1 co-receptor and a CXC-chemokine receptor. Development of small molecule inhibitors of HIV-1 entry is feasible.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9427604", + "TEXT": "Infection by Ebola virus causes rapidly progressive, often fatal, symptoms of fever, hemorrhage and hypotension. Previous attempts to elicit protective immunity for this disease have not met with success. We report here that protection against the lethal effects of Ebola virus can be achieved in an animal model by immunizing with plasmids encoding viral proteins. We analyzed immune responses to the viral nucleoprotein (NP) and the secreted or transmembrane forms of the glycoprotein (sGP or GP) and their ability to protect against infection in a guinea pig infection model analogous to the human disease. Protection was achieved and correlated with antibody titer and antigen-specific T-cell responses to sGP or GP. Immunity to Ebola virus can therefore be developed through genetic vaccination and may facilitate efforts to limit the spread of this disease.", + "TAG_DATA": [ + "46, animal {'context': 'B-organism'}", + "47, model {'context': 'I-organism'}", + "85, guinea {'context': 'B-organism'}", + "86, pig {'context': 'I-organism'}", + "104, T-cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "46, animal ['l0']", + "47, model ['l0']", + "85, guinea ['l1']", + "86, pig ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9427603", + "TEXT": "Apoptosis-inducing Fas ligand (FasL) is a type II membrane protein, predominantly expressed in the activated T cells. FasL is cleaved by a putative metalloproteinase to produce a soluble form. Here, we blocked the shedding of human FasL by deleting its cleavage site. Although human Jurkat cells and mouse primary hepatocytes that express a low level of Fas were resistant to the soluble form of FasL, they were efficiently killed by membrane-bound FasL. Furthermore, soluble FasL inhibited cytotoxicity of the membrane-bound FasL. These results indicate that the membrane-bound form of FasL is the functional form and suggest that shedding of FasL is to prevent the killing of the healthy bystander cells by cytotoxic T cells.", + "TAG_DATA": [ + "43, human {'context': 'B-cells'}", + "44, Jurkat {'context': 'I-cells'}", + "45, cells {'context': 'I-cells'}", + "47, mouse {'context': 'B-cells'}", + "48, primary {'context': 'I-cells'}", + "49, hepatocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "43, human ['l0', 'l1', 'l2', 'l3', 'l4']", + "44, Jurkat ['l0', 'l5', 'l6', 'l7', 'l8']", + "45, cells ['l1', 'l5', 'l9', 'l10', 'l11']", + "47, mouse ['l2', 'l6', 'l9', 'l12', 'l13']", + "48, primary ['l3', 'l7', 'l10', 'l12', 'l14']", + "49, hepatocytes ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9396614", + "TEXT": "Excessive binding of Plasmodium falciparum-infected red blood cells (pRBCs) to the vascular endothelium (cytoadherence) and to uninfected erythrocytes (rosetting) may lead to occlusion of the microvasculature and thereby contribute directly to the acute pathology of severe human malaria. A number of endothelial receptors have been identified as targets for the pRBCs, including CD36, intercellular adhesion molecule-1 (ICAM-1) and chondroitin-4-sulfate (CSA). In vitro, CD36 is the most frequent target of strains from patients with mild as well as severe P. falciparum malaria, but is expressed at low levels on the cerebral microvasculature and therefore seems unlikely to be involved in the evolution of cerebral disease. Strains of P. falciparum that form rosettes are associated both with the occurrence of cerebral malaria and severe anemia. Here we report that malaria-infected RBCs adhere to platelet/endothelial cell adhesion molecule-1 (PECAM-1/CD31) on the vascular endothelium. pRBCs bind to endothelial cells, to PECAM-1/CD31 transfected cells, and directly to recombinant PECAM-1/CD31 absorbed onto plastic. Soluble PECAM-1/CD31 and monoclonal antibodies specific for the amino-terminal segment of PECAM-1/CD31 (domains 1-4) blocked the binding. Interferon-gamma (IFN-gamma)-essential for the development of cerebral malaria in the mouse-was found to augment adhesion of human pRBCs to PECAM-1/CD31 on endothelial cell monolayers. Our results suggest that PECAM-1/CD31 is a virulence-associated endothelial receptor of P. falciparum-infected RBCs.", + "TAG_DATA": [ + "128, RBCs {'context': 'B-cells'}", + "140, pRBCs {'context': 'B-cells'}", + "143, endothelial {'context': 'B-cells'}", + "144, cells, {'context': 'I-cells'}", + "146, PECAM-1/CD31 {'perturbing_action': 'B-gene gain-of-function'}", + "147, transfected {'perturbing_action': 'I-gene gain-of-function'}", + "148, cells, {'context': 'B-cells'}", + "190, human {'context': 'B-cells'}", + "191, pRBCs {'context': 'I-cells'}", + "195, endothelial {'context': 'B-cells'}", + "196, cell {'context': 'I-cells'}", + "197, monolayers. {'context': 'I-organoid'}" + ], + "LINK_DATA": [ + "128, RBCs ['l0', 'l1', 'l2', 'l3']", + "140, pRBCs ['l0', 'l4', 'l5', 'l6', 'l7', 'l8']", + "143, endothelial ['l1', 'l4', 'l9', 'l10', 'l11', 'l12']", + "144, cells, ['l2', 'l5', 'l9', 'l13', 'l14']", + "146, PECAM-1/CD31 ['l6', 'l10', 'l15', 'l16']", + "147, transfected ['l7', 'l11', 'l13', 'l15', 'l17']", + "148, cells, ['l3', 'l8', 'l12', 'l14', 'l16', 'l17']", + "190, human ['l18', 'l19', 'l20', 'l21']", + "191, pRBCs ['l18', 'l22', 'l23', 'l24']", + "195, endothelial ['l19', 'l22', 'l25', 'l26']", + "196, cell ['l20', 'l23', 'l25', 'l27']", + "197, monolayers. ['l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "pRBCs", + "endothelial", + "cells," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PECAM-1/CD31", + "transfected" + ] + } + } + ] + }, + { + "PMID": "9396607", + "TEXT": "Transmission of HIV-1 is predominantly restricted to macrophage (Mphi)-tropic strains. Langerhans cells (LCs) in mucosal epithelium, as well as macrophages located in the submucosal tissues, may be initial targets for HIV-1. This study was designed to determine whether restricted transmission of HIV-1 correlates with expression and function of HIV-1 co-receptors on LCs and macrophages. Using polyclonal rabbit IgGs specific for the HIV co-receptors cytokines CXCR4 and CCR5, we found that freshly isolated epidermal LCs (resembling resident mucosal LCs) expressed CCR5, but not CXCR, on their surfaces. In concordance with surface expression, fresh LCs fused with Mphi-tropic but not with T-tropic HIV-1 envelopes. However, fresh LCs did contain intracellular CXCR4 protein that was transported to the surface during in vitro culture. Macrophages expressed high levels of both co-receptors on their surfaces, but only CCR5 was functional in a fusion assay. These data provide several possible explanations for the selective transmission of Mphi-tropic HIV variants and for the resistance to infection conferred by the CCR5 deletion.", + "TAG_DATA": [ + "72, epidermal {'context': 'B-cells'}", + "73, LCs {'context': 'I-cells'}", + "74, (resembling {'context': 'I-cells'}", + "92, LCs {'context': 'B-cells'}", + "104, LCs {'context': 'B-cells'}", + "117, in {'context': 'B-in vitro'}", + "118, vitro {'context': 'I-in vitro'}", + "120, Macrophages {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "72, epidermal ['l0', 'l1']", + "73, LCs ['l0', 'l2']", + "74, (resembling ['l1', 'l2']", + "92, LCs ['l3', 'l4']", + "104, LCs ['l5', 'l6']", + "117, in ['l3', 'l5', 'l7']", + "118, vitro ['l4', 'l6', 'l7']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9396606", + "TEXT": "We investigated regional therapy of recurrent malignant brain tumors with transferrin-CRM107, a conjugate of human transferrin (Tf) and a genetic mutant of diphtheria toxin (CRM107) that lacks native toxin binding. Physiological barriers to delivering proteins to tumor and surrounding infiltrated brain were circumvented with high-flow interstitial microinfusion. At least a 50% reduction in tumor volume on magnetic resonance imaging (MRI) occurred in 9 of 15 patients who could be evaluated (60%), including two complete responses. Peritumoral toxicity developed 1-4 weeks after treatment in three of three patients at 1.0 microg/ml, but in zero of nine patients treated at lower concentrations. No symptomatic systemic toxicity occurred. Regional perfusion with Tf-CRM107 produces tumor responses without systemic toxicity in patients with malignant brain tumors refractory to conventional therapy. Direct interstitial infusion can be used successfully to distribute a large protein in the tumor and infiltrated brain surrounding the tumor.", + "TAG_DATA": [ + "53, tumor {'context': 'B-neoplasm'}", + "116, patients {'context': 'B-patient'}", + "118, malignant {'context': 'B-neoplasm'}", + "119, brain {'context': 'I-neoplasm'}", + "120, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "116, patients ['l0', 'l1', 'l2']", + "118, malignant ['l0', 'l3', 'l4']", + "119, brain ['l1', 'l3', 'l5']", + "120, tumors ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9359707", + "TEXT": "The nfkb1 and nfkb2 genes encode closely related products regulating immune and inflammatory responses. Their role during development and differentiation remains unclear. The generation of nfkb1 null mice (p50-/-) resulted in altered immune responses, but had no effect on development. Similarly, nfkb2 knockout mice (p52-/-) did not show developmental defects (J.C. et al., manuscript submitted). We have investigated the potential for in vivo compensatory functions of these genes by generating double-knockout mice. The surprising result was that the animals developed osteopetrosis because of a defect in osteoclast differentiation, suggesting redundant functions of NF-kappaB1 and NF-kappaB2 proteins in the development of this cell lineage. The osteopetrotic phenotype was rescued by bone marrow transplantation, indicating that the hematopoietic component was impaired. These results define a new mouse osteopetrotic mutant and implicate NF-kappaB proteins in bone development, raising new directions in the treatment of bone disorders.", + "TAG_DATA": [ + "25, nfkb1 {'perturbing_action': 'B-gene loss-of-function'}", + "26, null {'perturbing_action': 'I-gene loss-of-function'}", + "27, mice {'context': 'B-organism'}", + "28, (p50-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "41, nfkb2 {'perturbing_action': 'B-gene loss-of-function'}", + "42, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "43, mice {'context': 'B-organism'}", + "44, (p52-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "71, mice. {'context': 'B-organism'}", + "78, animals {'context': 'B-organism'}", + "84, defect {'effect': 'B-negative'}", + "87, differentiation, {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "25, nfkb1 ['l0', 'l1', 'l2']", + "26, null ['l0', 'l3', 'l4']", + "27, mice ['l1', 'l3', 'l5']", + "28, (p50-/-) ['l2', 'l4', 'l5']", + "41, nfkb2 ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "42, knockout ['l6', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "43, mice ['l7', 'l14', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "44, (p52-/-) ['l8', 'l15', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "71, mice. ['l9', 'l16', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "78, animals ['l10', 'l17', 'l23', 'l28', 'l32', 'l36', 'l37', 'l38']", + "84, defect ['l11', 'l18', 'l24', 'l29', 'l33', 'l36', 'l39', 'l40']", + "86, osteoclast ['l12', 'l19', 'l25', 'l30', 'l34', 'l37', 'l39', 'l41']", + "87, differentiation, ['l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nfkb1", + "null", + "(p50-/-)", + "nfkb2", + "knockout", + "(p52-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "animals" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nfkb2", + "knockout", + "(p52-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defect" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nfkb2", + "knockout", + "(p52-/-)" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "animals" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defect" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "animals" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "defect" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + } + ] + }, + { + "PMID": "9359705", + "TEXT": "The multidrug resistance-associated protein (MRP) mediates the cellular excretion of many drugs, glutathione S-conjugates (GS-X) of lipophilic xenobiotics and endogenous cysteinyl leukotrienes. Increased MRP levels in tumor cells can cause multidrug resistance (MDR) by decreasing the intracellular drug concentration. The physiological role or roles of MRP remain ill-defined, however. We have generated MRP-deficient mice by using embryonic stem cell technology. Mice homozygous for the mrp mutant allele, mrp-/-, are viable and fertile, but their response to an inflammatory stimulus is impaired. We attribute this defect to a decreased secretion of leukotriene C4 (LTC4) from leukotriene-synthesizing cells. Moreover, the mrp-/- mice are hypersensitive to the anticancer drug etoposide. The phenotype of mrp-/- mice is consistent with a role for MRP as the main LTC4-exporter in leukotriene-synthesizing cells, and as an important drug exporter in drug-sensitive cells. Our results suggest that this ubiquitous GS-X pump is dispensable in mice, making treatment of MDR with MRP-specific reversal agents potentially feasible.", + "TAG_DATA": [ + "52, MRP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "53, mice {'context': 'B-organism'}", + "60, Mice {'context': 'B-organism'}", + "61, homozygous {'perturbing_action': 'B-gene loss-of-function'}", + "62, for {'perturbing_action': 'I-gene loss-of-function'}", + "63, the {'perturbing_action': 'I-gene loss-of-function'}", + "64, mrp {'perturbing_action': 'I-gene loss-of-function'}", + "65, mutant {'perturbing_action': 'I-other'}", + "66, allele, {'perturbing_action': 'I-gene loss-of-function'}", + "67, mrp-/-, {'perturbing_action': 'I-gene loss-of-function'}", + "98, mrp-/- {'perturbing_action': 'B-gene loss-of-function'}", + "99, mice {'context': 'B-organism'}", + "110, mrp-/- {'perturbing_action': 'B-gene loss-of-function'}", + "111, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "52, MRP-deficient ['l0', 'l1', 'l2']", + "53, mice ['l0', 'l3', 'l4']", + "57, stem ['l1', 'l3', 'l5']", + "58, cell ['l2', 'l4', 'l5']", + "60, Mice ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "61, homozygous ['l6', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "62, for ['l7', 'l13', 'l20', 'l21', 'l22', 'l23', 'l24']", + "63, the ['l8', 'l14', 'l20', 'l25', 'l26', 'l27', 'l28']", + "64, mrp ['l9', 'l15', 'l21', 'l25', 'l29', 'l30', 'l31']", + "65, mutant ['l10', 'l16', 'l22', 'l26', 'l29', 'l32', 'l33']", + "66, allele, ['l11', 'l17', 'l23', 'l27', 'l30', 'l32', 'l34']", + "67, mrp-/-, ['l12', 'l18', 'l24', 'l28', 'l31', 'l33', 'l34']", + "98, mrp-/- ['l35']", + "99, mice ['l19', 'l35']", + "110, mrp-/- ['l36']", + "111, mice ['l36']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MRP-deficient", + "homozygous", + "for", + "the", + "mrp", + "allele,", + "mrp-/-,", + "mrp-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "Mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutant" + ] + } + } + ] + }, + { + "PMID": "9359699", + "TEXT": "Human immunodeficiency virus (HIV)-1 infection is associated with the development of aggressive extranodal B-cell non-Hodgkin's lymphomas. Using microvascular endothelial cell (MVEC)-enriched bone marrow stromal cultures, HIV infection of stromal MVECs from lymphoma patients induced the outgrowth of malignant B cells. MVECs were the only HIV-infected cells in the stroma, and purified brain MVECs also induced a phenotype supportive of neoplastic B-cell attachment and proliferation. HIV infection of MVECs stimulated surface expression of CD40 and allowed preferential induction of the vascular cell adhesion molecule VCAM-1 after CD40 triggering. B-lymphoma cells expressed the CD40 ligand (CD40L), and blocking of CD40-CD40L interactions between HIV-infected MVECs and B-lymphoma cells inhibited B-cell attachment and proliferation. These observations suggest that HIV promotes B-lymphoma cell growth through facilitating attachment of lymphoma cells to HIV-infected MVECs and represent a novel mechanism through which viruses may induce malignancies.", + "TAG_DATA": [ + "37, malignant {'context': 'B-transformed cells'}", + "38, B {'context': 'I-transformed cells'}", + "39, cells. {'context': 'I-transformed cells'}", + "63, proliferation. {'phenotype': 'B-proliferation'}", + "67, MVECs {'context': 'B-cells'}", + "87, B-lymphoma {'context': 'B-transformed cells'}", + "88, cells {'context': 'I-transformed cells'}", + "101, MVECs {'context': 'B-cells'}", + "103, B-lymphoma {'context': 'B-transformed cells'}", + "104, cells {'context': 'I-transformed cells'}", + "105, inhibited {'effect': 'B-negative'}", + "106, B-cell {'context': 'B-cells'}", + "109, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "37, malignant ['l0', 'l1', 'l2']", + "38, B ['l0', 'l3', 'l4']", + "39, cells. ['l1', 'l3', 'l5']", + "51, brain ['l6', 'l7', 'l8']", + "52, MVECs ['l6', 'l9', 'l10']", + "63, proliferation. ['l2', 'l4', 'l5', 'l7', 'l9']", + "67, MVECs ['l8', 'l10']", + "87, B-lymphoma ['l11', 'l12', 'l13']", + "88, cells ['l11']", + "101, MVECs ['l14', 'l15', 'l16', 'l17', 'l18']", + "103, B-lymphoma ['l14', 'l19', 'l20', 'l21', 'l22']", + "104, cells ['l12', 'l15', 'l19', 'l23', 'l24', 'l25']", + "105, inhibited ['l16', 'l20', 'l23', 'l26', 'l27']", + "106, B-cell ['l17', 'l21', 'l24', 'l26', 'l28']", + "109, proliferation. ['l13', 'l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "malignant", + "B", + "cells.", + "B-lymphoma", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "MVECs", + "B-cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "MVECs", + "B-cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "B-lymphoma", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "9359698", + "TEXT": "Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States. Five-fluorouracil (5FU) remains the single most effective treatment for advanced disease, despite a response rate of only 20%. Herein, we show that the antioxidants pyrrolidinedithiocarbamate and vitamin E induce apoptosis in CRC cells. This effect is mediated by induction of p21WAF1/CIP1, a powerful inhibitor of the cell cycle, through a mechanism involving C/EBPbeta (a member of the CCAAT/enhancer binding protein family of transcription factors), independent of p53. Antioxidants significantly enhance CRC tumor growth inhibition by cytotoxic chemotherapy in vitro (5FU and doxorubicin) and in vivo (5FU). Thus, chemotherapeutic agents administered in the presence of antioxidants may provide a novel therapy for colorectal cancer.", + "TAG_DATA": [ + "43, induce {'effect': 'B-positive'}", + "44, apoptosis {'phenotype': 'B-apoptosis'}", + "46, CRC {'context': 'B-transformed cells'}", + "47, cells. {'context': 'I-transformed cells'}", + "84, enhance {'effect': 'B-positive'}", + "85, CRC {'context': 'B-neoplasm'}", + "86, tumor {'phenotype': 'B-tumour growth'}", + "87, growth {'phenotype': 'I-tumour growth'}", + "88, inhibition {'effect': 'B-negative'}", + "92, in {'context': 'B-in vitro'}", + "93, vitro {'context': 'I-in vitro'}", + "98, in {'context': 'B-in vivo'}", + "99, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "43, induce ['l0', 'l1', 'l2']", + "44, apoptosis ['l0', 'l3', 'l4']", + "46, CRC ['l1', 'l3', 'l5']", + "47, cells. ['l2', 'l4', 'l5']", + "84, enhance ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "85, CRC ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "86, tumor ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "87, growth ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "88, inhibition ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "92, in ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "93, vitro ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']", + "98, in ['l27']", + "99, vivo ['l27']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "CRC", + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "CRC", + "cells." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhance" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "CRC" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhance" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhance" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "CRC" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "CRC" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "9359697", + "TEXT": "Female sterility resulting from oocyte destruction is an unfortunate, and in many cases inevitable, consequence of chemotherapy. We show that unfertilized mouse oocytes exposed to therapeutic levels of the antitumor drug, doxorubicin (DXR), undergo apoptosis; however, fertilized oocytes do not initiate apoptosis, but enter cell-cycle arrest, when treated with DXR. Apoptosis induced by DXR in oocytes is blocked by sphingosine-1-phosphate, an inhibitor of ceramide-promoted cell death. Oocytes from Bax-deficient, but not p53-null, female mice display complete resistance to DXR-induced apoptosis in vivo and in vitro. Pretreatment of oocytes with a specific peptide inhibitor of caspases also abrogates the apoptotic response to DXR. These findings indicate that oocyte destruction caused by chemotherapy can be prevented by manipulation of apoptosis-associated signaling pathways.", + "TAG_DATA": [ + "20, unfertilized {'context': 'B-cells'}", + "21, mouse {'context': 'I-cells'}", + "22, oocytes {'context': 'I-cells'}", + "33, undergo {'effect': 'B-positive'}", + "34, apoptosis; {'phenotype': 'B-apoptosis'}", + "36, fertilized {'context': 'B-cells'}", + "37, oocytes {'context': 'I-cells'}", + "38, do {'effect': 'B-negative'}", + "39, not {'effect': 'I-no effect'}", + "40, initiate {'effect': 'I-no effect'}", + "41, apoptosis, {'phenotype': 'B-apoptosis'}", + "43, enter {'effect': 'B-positive'}", + "44, cell-cycle {'phenotype': 'B-cell cycle arrest'}", + "45, arrest, {'phenotype': 'I-cell cycle arrest'}", + "50, Apoptosis {'phenotype': 'B-apoptosis'}", + "51, induced {'effect': 'B-positive'}", + "55, oocytes {'context': 'B-cells'}", + "57, blocked {'effect': 'B-negative'}", + "64, cell {'phenotype': 'B-cell death'}", + "65, death. {'phenotype': 'I-cell death'}", + "66, Oocytes {'context': 'B-cells'}", + "68, Bax-deficient, {'perturbing_action': 'B-gene loss-of-function'}", + "71, p53-null, {'perturbing_action': 'B-gene loss-of-function'}", + "72, female {'context': 'B-organism'}", + "73, mice {'context': 'I-organism'}", + "76, resistance {'effect': 'B-negative'}", + "78, DXR-induced {'effect': 'B-positive'}", + "79, apoptosis {'phenotype': 'B-apoptosis'}", + "80, in {'context': 'B-in vivo'}", + "81, vivo {'context': 'I-in vivo'}", + "83, in {'context': 'B-in vitro'}", + "84, vitro. {'context': 'I-in vitro'}", + "87, oocytes {'context': 'B-cells'}", + "96, abrogates {'effect': 'B-negative'}", + "98, apoptotic {'phenotype': 'B-apoptosis'}", + "99, response {'phenotype': 'I-apoptosis'}" + ], + "LINK_DATA": [ + "20, unfertilized ['l0', 'l1', 'l2', 'l3', 'l4']", + "21, mouse ['l0', 'l5', 'l6', 'l7']", + "22, oocytes ['l1', 'l5', 'l8', 'l9']", + "33, undergo ['l2', 'l6', 'l8', 'l10']", + "34, apoptosis; ['l3', 'l7', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "36, fertilized ['l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "37, oocytes ['l18', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "38, do ['l19', 'l41', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "39, not ['l11', 'l20', 'l42', 'l55', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "40, initiate ['l12', 'l21', 'l43', 'l56', 'l67', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "41, apoptosis, ['l13', 'l22', 'l44', 'l57', 'l68', 'l78', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "43, enter ['l23', 'l45', 'l58', 'l69', 'l79', 'l88', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "44, cell-cycle ['l14', 'l24', 'l46', 'l59', 'l70', 'l80', 'l89', 'l97', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "45, arrest, ['l15', 'l25', 'l47', 'l60', 'l71', 'l81', 'l90', 'l98', 'l105', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "50, Apoptosis ['l26', 'l48', 'l61', 'l72', 'l82', 'l91', 'l99', 'l106', 'l112', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "51, induced ['l4', 'l16', 'l27', 'l49', 'l62', 'l73', 'l83', 'l92', 'l100', 'l107', 'l113', 'l118', 'l124', 'l125', 'l126', 'l127']", + "55, oocytes ['l17', 'l28', 'l50', 'l63', 'l74', 'l84', 'l93', 'l101', 'l108', 'l114', 'l119', 'l124', 'l128', 'l129', 'l130']", + "57, blocked ['l29', 'l51', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l115', 'l120', 'l125', 'l128', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "64, cell ['l30', 'l52', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l121', 'l126', 'l129', 'l131', 'l138', 'l139', 'l140', 'l141']", + "65, death. ['l31', 'l53', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l127', 'l130', 'l132', 'l138', 'l142', 'l143', 'l144']", + "66, Oocytes ['l32', 'l133', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "68, Bax-deficient, ['l33', 'l145', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "71, p53-null, ['l146', 'l156', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "72, female ['l34', 'l147', 'l157', 'l166', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "73, mice ['l35', 'l148', 'l158', 'l167', 'l175', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189']", + "76, resistance ['l36', 'l54', 'l123', 'l134', 'l139', 'l142', 'l149', 'l159', 'l168', 'l176', 'l183', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195']", + "78, DXR-induced ['l37', 'l150', 'l160', 'l169', 'l177', 'l184', 'l190', 'l196', 'l197', 'l198', 'l199', 'l200']", + "79, apoptosis ['l38', 'l135', 'l140', 'l143', 'l151', 'l161', 'l170', 'l178', 'l185', 'l191', 'l196', 'l201', 'l202']", + "80, in ['l39', 'l136', 'l152', 'l162', 'l171', 'l179', 'l186', 'l192', 'l197', 'l201', 'l203']", + "81, vivo ['l40', 'l137', 'l141', 'l144', 'l153', 'l163', 'l172', 'l180', 'l187', 'l193', 'l198', 'l202', 'l203']", + "83, in ['l154', 'l164', 'l173', 'l181', 'l188', 'l194', 'l199', 'l204']", + "84, vitro. ['l155', 'l165', 'l174', 'l182', 'l189', 'l195', 'l200', 'l204']", + "87, oocytes ['l205', 'l206', 'l207']", + "96, abrogates ['l205', 'l208', 'l209']", + "98, apoptotic ['l206', 'l208', 'l210']", + "99, response ['l207', 'l209', 'l210']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "unfertilized", + "mouse", + "oocytes", + "fertilized", + "Oocytes" + ] + }, + "effect": { + "val": "positive", + "words": [ + "undergo", + "induced", + "enter", + "DXR-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "unfertilized", + "mouse", + "oocytes", + "fertilized", + "Oocytes" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis;", + "apoptosis,", + "Apoptosis", + "apoptosis", + "apoptotic", + "response" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "undergo", + "induced", + "enter", + "DXR-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis;", + "apoptosis,", + "Apoptosis", + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis;", + "apoptosis,", + "Apoptosis" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "initiate" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "fertilized", + "oocytes", + "Oocytes" + ] + }, + "effect": { + "val": "negative", + "words": [ + "do", + "blocked", + "resistance", + "abrogates" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "fertilized", + "oocytes" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "initiate" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "fertilized", + "oocytes" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "fertilized", + "oocytes" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "fertilized", + "Oocytes" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bax-deficient,", + "p53-null," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "do", + "blocked", + "resistance", + "abrogates" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis,", + "Apoptosis", + "apoptosis", + "apoptotic", + "response" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "do", + "blocked" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "do", + "blocked", + "resistance" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "initiate" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest," + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "initiate" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enter", + "induced" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enter", + "induced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked", + "resistance" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bax-deficient,", + "p53-null," + ] + }, + "context": { + "val": "organism", + "words": [ + "female", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bax-deficient,", + "p53-null," + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bax-deficient,", + "p53-null," + ] + }, + "effect": { + "val": "positive", + "words": [ + "DXR-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bax-deficient,", + "p53-null," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bax-deficient,", + "p53-null," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bax-deficient,", + "p53-null," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "female", + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "female", + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "DXR-induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "female", + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "DXR-induced" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "DXR-induced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "9359696", + "TEXT": "The importance of angiogenesis in malignant tumor growth has been interpreted mainly in terms of oxygen and nutrient supply. Here we demonstrate its fundamental role for tumor invasion of malignant human keratinocytes in surface transplants on nude mice. Distinct patterns of angiogenesis and vascular endothelial growth factor receptor-2 (VEGFR-2) expression allowed us to distinguish between benign and malignant cells. Functional inactivation of VEGF-R2 by a blocking antibody disrupted ongoing angiogenesis and prevented invasion of malignant cells, without reducing tumor cell proliferation. The reversion of a malignant into a benign phenotype by halting angiogenesis demonstrates a significant function of vascular endothelium for tumor invasion.", + "TAG_DATA": [ + "59, Functional {'perturbing_action': 'B-gene loss-of-function'}", + "60, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "61, of {'perturbing_action': 'I-gene loss-of-function'}", + "62, VEGF-R2 {'perturbing_action': 'I-gene loss-of-function'}", + "63, by {'perturbing_action': 'I-gene loss-of-function'}", + "71, prevented {'effect': 'B-negative'}", + "72, invasion {'phenotype': 'B-invasion'}", + "74, malignant {'context': 'B-transformed cells'}", + "75, cells, {'context': 'I-transformed cells'}", + "76, without {'effect': 'B-no effect'}", + "77, reducing {'effect': 'I-no effect'}", + "78, tumor {'context': 'B-transformed cells'}", + "79, cell {'context': 'I-transformed cells'}", + "80, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "59, Functional ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "60, inactivation ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "61, of ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "62, VEGF-R2 ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "63, by ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "71, prevented ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58']", + "72, invasion ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l59', 'l60', 'l61']", + "74, malignant ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l59', 'l62', 'l63', 'l64', 'l65', 'l66']", + "75, cells, ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l60', 'l62']", + "76, without ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l61', 'l63', 'l67', 'l68', 'l69', 'l70']", + "77, reducing ['l9', 'l21', 'l32', 'l42', 'l51', 'l64', 'l67', 'l71', 'l72', 'l73']", + "78, tumor ['l10', 'l22', 'l33', 'l43', 'l52', 'l68', 'l71', 'l74', 'l75']", + "79, cell ['l11', 'l23', 'l34', 'l44', 'l53', 'l65', 'l69', 'l72', 'l74', 'l76']", + "80, proliferation. ['l12', 'l24', 'l35', 'l45', 'l54', 'l66', 'l70', 'l73', 'l75', 'l76']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Functional", + "inactivation", + "of", + "VEGF-R2", + "by" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Functional", + "inactivation", + "of", + "VEGF-R2", + "by" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Functional", + "inactivation", + "of", + "VEGF-R2", + "by" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "malignant", + "cells,", + "tumor", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Functional", + "inactivation", + "of", + "VEGF-R2", + "by" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "without", + "reducing" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Functional", + "inactivation", + "of", + "VEGF-R2", + "by" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "malignant", + "cells," + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "malignant", + "cells," + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "without" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "malignant", + "tumor", + "cell" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "without", + "reducing" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "malignant", + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "without", + "reducing" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "9359694", + "TEXT": "The cellular and molecular mechanisms underlying the effects of aging on human cutaneous wound healing are poorly understood, and the possible role of reproductive hormones in this process has never been investigated. We report that aging in healthy females was associated with a reduced rate of cutaneous wound healing, but an improved quality of scarring both microscopically and macroscopically, and with reduced levels of transforming growth factor-beta1 (TGF-beta1) immunostaining and steady-state mRNA in the wound. These age-related changes were reversed by the systemic administration of hormone replacement therapy (HRT). Moreover, ovariectomized young female rodents exhibited a marked delay in repair of acute incisional wounds, which was reversed by the topical application of estrogen. The cellular mechanism underlying these changes appears to involve an estrogen-induced increase in latent TGF-beta1 secretion by dermal fibroblasts. These results suggest that both the rate and quality of wound healing depend on reproductive hormone levels.", + "TAG_DATA": [ + "91, young {'context': 'B-organism'}", + "92, female {'context': 'I-organism'}", + "93, rodents {'context': 'I-organism'}", + "97, delay {'effect': 'B-negative'}", + "130, dermal {'context': 'B-cells'}", + "131, fibroblasts. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "91, young ['l0', 'l1', 'l2']", + "92, female ['l0', 'l3', 'l4']", + "93, rodents ['l1', 'l3', 'l5']", + "97, delay ['l2', 'l4', 'l5']", + "130, dermal ['l6']", + "131, fibroblasts. ['l6']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "young", + "female", + "rodents" + ] + }, + "effect": { + "val": "negative", + "words": [ + "delay" + ] + } + } + ] + }, + { + "PMID": "9334729", + "TEXT": "Recent data suggest that many tumors, such as malignant gliomas, have disrupted pRB function, either because of RB-1 gene mutations or as a result of mutations affecting upstream regulators of pRB such as cyclin D1 or p16/INK4a/MTS1 (ref. 1-5). Tumor suppression by pRB has been linked to its ability to repress E2F-responsive promoters such as the E2F-1 promoter. Thus, a prediction, which has not yet been demonstrated experimentally in vivo, is that E2F-responsive promoters should be more active in tumor cells relative to normal cells because of an excess of \"free\" E2F and loss of pRB/E2F repressor complexes. We demonstrate that adenoviral vectors that contain transgenes driven by the E2F-1 promoter can mediate tumor-selective gene expression in vivo, allowing for eradication of established gliomas with significantly less normal tissue toxicity than seen with standard adenoviral vectors. Our data indicate that de-repression of the E2F-1 promoter occurs in cancer cells in vivo, a finding that can be exploited to design viral vectors that mediate tumor-selective gene expression.", + "TAG_DATA": [ + "116, in {'context': 'B-in vivo'}", + "117, vivo, {'context': 'I-in vivo'}", + "123, gliomas {'context': 'B-neoplasm'}", + "149, in {'context': 'B-in vivo'}", + "150, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "116, in ['l0', 'l1']", + "117, vivo, ['l0', 'l2']", + "123, gliomas ['l1', 'l2']", + "149, in ['l3']", + "150, vivo, ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9334727", + "TEXT": "The growth and metastatic spread of cancer is directly related to tumor angiogenesis, and the driving factors need to be understood to exploit this process therapeutically. However, tumor cells and their normal stroma express a multitude of candidate angiogenic factors, and very few specific inhibitors have been generated to assess which of these gene products are only innocent bystanders and which contribute significantly to tumor angiogenesis and metastasis. Here we investigated whether the expression in tumors of a secreted fibroblast growth factor (FGF)-binding protein (FGF-BP) that mobilizes and activates locally stored FGFs (ref. 11) can serve as an angiogenic switch molecule. Developmental expression of the retinoid-regulated FGF-BP gene is prominent in the skin and intestine during the perinatal phase and is down-modulated in the adult. The gene is, however, upregulated in carcinogen-induced skin tumors, in squamous cell carcinoma (SCC) and in some colon cancer cell lines and tumor samples. To assess the significance of FGF-BP expression in tumors, we depleted human SCC (ME-180) and colon carcinoma (LS174T) cell lines of their endogenous FGF-BP by targeting with specific ribozymes. We found that the reduction of FGF-BP reduced the release of biologically active basic FGF (bFGF) from cells in culture. Furthermore, the growth and angiogenesis of xenograft tumors in mice was decreased in parallel with the reduction of FGF-BP. This suggests that human tumors can utilize FGF-BP as an angiogenic switch molecule.", + "TAG_DATA": [ + "160, human {'context': 'B-transformed cells'}", + "161, SCC {'context': 'I-transformed cells'}", + "162, (ME-180) {'context': 'I-transformed cells'}", + "163, and {'context': 'I-transformed cells'}", + "164, colon {'context': 'I-transformed cells'}", + "165, carcinoma {'context': 'I-transformed cells'}", + "166, (LS174T) {'context': 'I-transformed cells'}", + "167, cell {'context': 'I-transformed cells'}", + "168, lines {'context': 'I-transformed cells'}", + "195, cells {'context': 'B-cells'}", + "197, culture. {'context': 'I-in vitro'}", + "204, xenograft {'context': 'B-xenograft'}", + "205, tumors {'context': 'I-xenograft'}", + "207, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "160, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "161, SCC ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "162, (ME-180) ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "163, and ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "164, colon ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "165, carcinoma ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "166, (LS174T) ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "167, cell ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "168, lines ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "195, cells ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "197, culture. ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "204, xenograft ['l55', 'l56']", + "205, tumors ['l55', 'l57']", + "207, mice ['l56', 'l57']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9334725", + "TEXT": "Neural tissue transplantation has become an alternative treatment for Parkinson's disease (PD) and other neurodegenerative disorders. The clinical use of neural grafts as a source of dopamine for Parkinson's disease patients, although beneficial, is associated with logistical and ethical issues. Thus, alternative graft sources have been explored including polymer-encapsulated cells and nonneural cells (that is, adrenal chromaffin cells) or genetically modified cells that secrete dopamine and/or trophic factors. Although progress has been made, no current alternative graft source has ideal characteristics for transplantation. Emerging evidence suggests the importance of trophic factors in enhancing survival and regeneration of intrinsic dopaminergic neurons. It would be desirable to transplant cells that are readily available, immunologically accepted by the central nervous system and capable of producing dopamine and/or trophic factors. Sertoli cells have been shown to secrete CD-95 ligand and regulatory proteins, as well as trophic, tropic, and immunosuppressive factors that provide the testis, in part, with its \"immunoprivileged\" status. The present study demonstrated that transplantation of rat testis-derived Sertoli cells into adult rat brains ameliorated behavioral deficits in rats with 6-hydroxydopamine-induced hemiparkinsonism. This was associated with enhanced tyrosine hydroxylase (TH) immunoreactivity in the striatum in the area around the transplanted Sertoli cells. Furthermore, in vitro experiments demonstrated enhanced dopaminergic neuronal survival and outgrowth when embryonic neurons were cultured with medium in which rat Sertoli cells had been grown. Transplantation of Sertoli cells may provide a useful alternative treatment for PD and other neurodegenerative disorders.", + "TAG_DATA": [ + "163, rat {'context': 'B-cells'}", + "164, testis-derived {'context': 'I-cells'}", + "165, Sertoli {'context': 'I-cells'}", + "166, cells {'context': 'I-cells'}", + "168, adult {'context': 'B-tissue/organ'}", + "169, rat {'context': 'I-tissue/organ'}", + "170, brains {'context': 'I-tissue/organ'}", + "175, rats {'context': 'B-organism'}", + "197, Sertoli {'context': 'B-cells'}", + "198, cells. {'context': 'I-cells'}", + "200, in {'context': 'B-in vitro'}", + "201, vitro {'context': 'I-in vitro'}", + "211, embryonic {'context': 'B-cells'}", + "212, neurons {'context': 'I-cells'}", + "219, rat {'context': 'B-cells'}", + "220, Sertoli {'context': 'I-cells'}", + "221, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "163, rat ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "164, testis-derived ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "165, Sertoli ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "166, cells ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "168, adult ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "169, rat ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "170, brains ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "175, rats ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27', 'l28']", + "197, Sertoli ['l29']", + "198, cells. ['l28', 'l29']", + "200, in ['l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "201, vitro ['l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "211, embryonic ['l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "212, neurons ['l32', 'l37', 'l41', 'l45', 'l46', 'l47']", + "219, rat ['l33', 'l38', 'l42', 'l45', 'l48', 'l49']", + "220, Sertoli ['l34', 'l39', 'l43', 'l46', 'l48', 'l50']", + "221, cells ['l35', 'l40', 'l44', 'l47', 'l49', 'l50']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9334722", + "TEXT": "CXC-chemokine receptor (CXCR)-4/fusin, a newly discovered co-receptor for T-cell line (T)-tropic HIV-1 virus, plays a critical role in T-tropic virus fusion and entry into permissive cells. The occurrence of T-tropic HIV viruses is associated with CD4-positive cell decline and progression to AIDS, suggesting that the T-tropic HIV-1 contributes to AIDS pathogenesis. In this study, we used a novel strategy to inactivate CXCR-4 by targeting a modified CXC-chemokine to the endoplasmic reticulum (ER) to block the surface expression of newly synthesized CXCR-4. The genetically modified lymphocytes expressing this intracellular chemokine, termed \"intrakine\", are immune to T-tropic virus infection and appear to retain normal biological features. Thus, this genetic intrakine strategy is uniquely targeted at the conserved cellular receptor for the prevention of HIV-1 entry and may be developed into an effective treatment for HIV-1 infection and AIDS.", + "TAG_DATA": [ + "84, lymphocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9334720", + "TEXT": "GLUT4, the insulin-responsive glucose transporter, plays an important role in postprandial glucose disposal. Altered GLUT4 activity is suggested to be one of the factors responsible for decreased glucose uptake in muscle and adipose tissue in obesity and diabetes. To assess the effect of GLUT4 expression on whole-body glucose homeostasis, we disrupted the murine GLUT4 gene by homologous recombination. Male mice heterozygous for the mutation (GLUT4 +/-) exhibited a decrease in GLUT4 expression in adipose tissue and skeletal muscle. This decrease in GLUT4 expression did not result in obesity but led to increased serum glucose and insulin, reduced muscle glucose uptake, hypertension, and diabetic histopathologies in the heart and liver similar to those of humans with non-insulin-dependent diabetes mellitus (NIDDM). The male GLUT4 +/- mice represent a good model for studying the development of NIDDM without the complications associated with obesity.", + "TAG_DATA": [ + "50, disrupted {'perturbing_action': 'B-gene loss-of-function'}", + "51, the {'perturbing_action': 'I-gene loss-of-function'}", + "52, murine {'perturbing_action': 'I-gene loss-of-function'}", + "53, GLUT4 {'perturbing_action': 'I-gene loss-of-function'}", + "54, gene {'perturbing_action': 'I-gene loss-of-function'}", + "58, Male {'context': 'B-organism'}", + "59, mice {'context': 'I-organism'}", + "60, heterozygous {'perturbing_action': 'B-other'}", + "61, for {'perturbing_action': 'I-other'}", + "62, the {'perturbing_action': 'I-other'}", + "63, mutation {'perturbing_action': 'I-other'}", + "64, (GLUT4 {'perturbing_action': 'I-other'}", + "65, +/-) {'perturbing_action': 'I-other'}", + "73, adipose {'context': 'B-tissue/organ'}", + "74, tissue {'context': 'I-tissue/organ'}", + "76, skeletal {'context': 'B-tissue/organ'}", + "77, muscle. {'context': 'I-tissue/organ'}", + "97, muscle {'context': 'B-tissue/organ'}", + "106, heart {'context': 'B-tissue/organ'}", + "108, liver {'context': 'B-tissue/organ'}", + "120, male {'perturbing_action': 'B-gene loss-of-function'}", + "121, GLUT4 {'perturbing_action': 'B-gene loss-of-function'}", + "122, +/- {'perturbing_action': 'B-gene loss-of-function'}", + "123, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, disrupted ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "51, the ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "52, murine ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "53, GLUT4 ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "54, gene ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "58, Male ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "59, mice ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "60, heterozygous ['l51', 'l61', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "61, for ['l52', 'l62', 'l71', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "62, the ['l53', 'l63', 'l72', 'l81', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "63, mutation ['l54', 'l64', 'l73', 'l82', 'l90', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "64, (GLUT4 ['l6', 'l17', 'l27', 'l36', 'l44', 'l55', 'l65', 'l74', 'l83', 'l91', 'l98', 'l104', 'l105', 'l106', 'l107', 'l108']", + "65, +/-) ['l7', 'l18', 'l28', 'l37', 'l45', 'l56', 'l66', 'l75', 'l84', 'l92', 'l99', 'l104', 'l109', 'l110', 'l111', 'l112']", + "73, adipose ['l8', 'l19', 'l29', 'l38', 'l46', 'l57', 'l67', 'l76', 'l85', 'l93', 'l100', 'l105', 'l109', 'l113', 'l114', 'l115']", + "74, tissue ['l9', 'l20', 'l30', 'l39', 'l47', 'l58', 'l68', 'l77', 'l86', 'l94', 'l101', 'l106', 'l110', 'l113', 'l116', 'l117']", + "76, skeletal ['l10', 'l21', 'l31', 'l40', 'l48', 'l59', 'l69', 'l78', 'l87', 'l95', 'l102', 'l107', 'l111', 'l114', 'l116', 'l118']", + "77, muscle. ['l11', 'l22', 'l32', 'l41', 'l49', 'l60', 'l70', 'l79', 'l88', 'l96', 'l103', 'l108', 'l112', 'l115', 'l117', 'l118']", + "97, muscle ['l80', 'l89', 'l97', 'l119', 'l120']", + "106, heart ['l119', 'l121']", + "108, liver ['l120', 'l121']", + "120, male ['l122', 'l123', 'l124']", + "121, GLUT4 ['l122', 'l125', 'l126']", + "122, +/- ['l123', 'l125', 'l127']", + "123, mice ['l124', 'l126', 'l127']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "disrupted", + "the", + "murine", + "GLUT4", + "gene", + "male", + "+/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "Male", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "disrupted", + "the", + "murine", + "GLUT4", + "gene" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "adipose", + "tissue", + "skeletal", + "muscle." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Male", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous", + "for", + "the", + "mutation", + "(GLUT4", + "+/-)" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous", + "for", + "the", + "mutation", + "(GLUT4", + "+/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "adipose", + "tissue", + "skeletal", + "muscle.", + "muscle" + ] + } + } + ] + }, + { + "PMID": "9288726", + "TEXT": "We show here that transient forebrain ischemia selectively elevates levels of neuronal apoptosis inhibitory protein (NAIP) in rat neurons that are resistant to the injurious effects of this treatment. This observation suggests that increasing NAIP levels may confer protection against ischemic cell death. Consistent with this proposal, we demonstrate that two other treatments that increase neuronal NAIP levels, systemic administration of the bacterial alkaloid K252a and intracerebral injection of an adenovirus vector capable of overexpressing NAIP in vivo, reduce ischemic damage in the rat hippocampus. Taken together, these findings suggest that NAIP may play a key role in conferring resistance to ischemic damage and that treatments that elevate neuronal levels of this antiapoptotic protein may have utility in the treatment of stroke.", + "TAG_DATA": [ + "70, adenovirus {'perturbing_action': 'B-gene gain-of-function'}", + "71, vector {'perturbing_action': 'I-gene gain-of-function'}", + "72, capable {'perturbing_action': 'I-gene gain-of-function'}", + "73, of {'perturbing_action': 'I-gene gain-of-function'}", + "74, overexpressing {'perturbing_action': 'I-gene gain-of-function'}", + "75, NAIP {'perturbing_action': 'I-gene gain-of-function'}", + "76, in {'context': 'B-in vivo'}", + "77, vivo, {'context': 'I-in vivo'}", + "83, rat {'context': 'B-tissue/organ'}", + "84, hippocampus. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "70, adenovirus ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "71, vector ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "72, capable ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "73, of ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "74, overexpressing ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "75, NAIP ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "76, in ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "77, vivo, ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "83, rat ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "84, hippocampus. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "vector", + "capable", + "of", + "overexpressing", + "NAIP" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "vector", + "capable", + "of", + "overexpressing", + "NAIP" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "hippocampus." + ] + } + } + ] + }, + { + "PMID": "9256281", + "TEXT": "The transcriptional factor nuclear factor-kappaB (NFkappaB) plays a pivotal role in the coordinated transactivation of cytokine and adhesion molecule genes that might be involved in myocardial damage after ischemia and reperfusion. Therefore, we hypothesized that synthetic double-stranded DNA with high affinity for NFkappaB could be introduced in vivo as \"decoy\" cis elements to bind the transcriptional factor and to block the activation of genes mediating myocardial infarction, thus providing effective therapy for myocardial infarction. Treatment before and after infarction by transfection of NFkappaB decoy, but not scrambled decoy, oligodeoxynucleotides before coronary artery occlusion or immediately after reperfusion had a significant inhibitory effect on the area of infarction. Here, we report the first successful in vivo transfer of NFkappaB decoy oligodeoxynucleotides to reduce the extent of myocardial infarction following reperfusion, providing a new therapeutic strategy for myocardial infarction.", + "TAG_DATA": [ + "80, transfection {'perturbing_action': 'B-gene gain-of-function'}", + "81, of {'perturbing_action': 'I-gene gain-of-function'}", + "82, NFkappaB {'perturbing_action': 'I-gene gain-of-function'}", + "83, decoy, {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "80, transfection ['l0', 'l1', 'l2']", + "81, of ['l0', 'l3', 'l4']", + "82, NFkappaB ['l1', 'l3', 'l5']", + "83, decoy, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9256277", + "TEXT": "Dengue virus is a human pathogen that has reemerged as an increasingly important public health threat. We found that the cellular receptor utilized by dengue envelope protein to bind to target cells is a highly sulfated type of heparan sulfate. Heparin, highly sulfated heparan sulfate, and the polysulfonate pharmaceutical Suramin effectively prevented dengue virus infection of target cells, indicating that the envelope protein-target cell receptor interaction is a critical determinant of infectivity. The dengue envelope protein sequence includes two putative glycosaminoglycan-binding motifs at the carboxy terminus; the first could be structurally modeled and formed an unusual extended binding surface of basic amino acids. Similar motifs were also identified in the envelope proteins of other flaviviridae. Developing pharmaceuticals that inhibit target cell binding may be an effective strategy for treating flavivirus infections.", + "TAG_DATA": [ + "56, target {'context': 'B-cells'}", + "57, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "56, target ['l0']", + "57, cells, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9212108", + "TEXT": "Donor-specific tolerance induced by bone marrow transplantation (BMT) would allow organ allografting without chronic immunosuppressive therapy. However, the toxicity of conditioning regimens used to achieve marrow engraftment has precluded the clinical use of BMT for tolerance induction. We have developed a BMT strategy that achieves alloengraftment without toxic or myelosuppressive host conditioning. B6 mice received depleting anti-CD4 and anti-CD8 monoclonal antibodies, local thymic irradiation, and a high-dose (174 x 10(6)) of major histocompatibility (MHC)-mismatched B10.A bone marrow cells (BMCs) divided over days 0 through 4. High levels of donor cells were observed among white blood cells (WBCs) of all lineages. Permanent, multilineage mixed chimerism; donor-specific skin-graft tolerance; and in vitro tolerance were observed in most animals. Large numbers of donor class II(high) cells were detected in thymuses of long-term chimeras, and their presence was associated with intrathymic deletion of donor-reactive host thymocytes. The treatment was not associated with significant myelosuppression, toxicity, or graft-versus-host disease (GVHD). Thus, high levels of allogeneic stem-cell engraftment can be achieved without myelosuppressive host conditioning. As stem-cell mobilization and in vitro culture techniques have increased the feasibility of administering high doses of hematopoietic cells to humans, this approach brings hematopoietic cell transplantation closer to clinical use for the induction of central deletional T-cell tolerance.", + "TAG_DATA": [ + "52, B6 {'context': 'B-organism'}", + "53, mice {'context': 'I-organism'}", + "108, in {'context': 'B-in vitro'}", + "109, vitro {'context': 'I-in vitro'}", + "115, animals. {'context': 'B-organism'}", + "126, thymuses {'context': 'B-tissue/organ'}", + "139, donor-reactive {'context': 'B-cells'}", + "140, host {'context': 'I-cells'}", + "141, thymocytes. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "52, B6 ['l0']", + "53, mice ['l0']", + "108, in ['l1', 'l2', 'l3', 'l4', 'l5']", + "109, vitro ['l1', 'l6', 'l7', 'l8', 'l9', 'l10']", + "115, animals. ['l2', 'l6', 'l11']", + "126, thymuses ['l3', 'l7', 'l11', 'l12', 'l13', 'l14']", + "139, donor-reactive ['l8', 'l12', 'l15', 'l16']", + "140, host ['l4', 'l9', 'l13', 'l15', 'l17']", + "141, thymocytes. ['l5', 'l10', 'l14', 'l16', 'l17']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9212103", + "TEXT": "Neuropeptide Y (NPY) is widely distributed in interneurons of the central nervous system (CNS), including the hippocampus and cerebral cortex, in concentrations exceeding those of any other known neuropeptides. Sequence data comparing different species show that NPY is highly conserved. This suggests a critical role in regulation of regional neuronal excitability. Kainic acid, a glutamate agonist at kainic acid receptors, causes severe limbic motor seizures culminating in status epilepticus. We here report that NPY administered into the lateral ventricle is a powerful inhibitor of motor as well as electroencephalographic (EEG) seizures induced by kainic acid. This effect was mediated via receptors with a pharmacological profile similar to the recently cloned rat Y5 receptor. The present study is the first to demonstrate that NPY possesses anticonvulsant activity. This is consistent with the concept that NPY is an endogenous anticonvulsant and suggests that agonists acting at Y5-like receptors may constitute a novel group of drugs in antiepileptic therapy.", + "TAG_DATA": [ + "77, lateral {'context': 'B-tissue/organ'}", + "78, ventricle {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "77, lateral ['l0']", + "78, ventricle ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9212102", + "TEXT": "Mutations in the presenilin 1 (PS1) and presenilin 2 (PS2) genes can cause Alzheimer's disease in affected members of the majority of early-onset familial Alzheimer's disease (FAD) pedigrees. PS1 encodes an ubiquitously expressed, eight transmembrane protein. PS1 is endoproteolytically processed to an amino-terminal derivative (approximately 27-28 kDa) and a carboxy-terminal derivative (approximately 17-18 kDa). These polypeptides accumulate to saturable levels in the brains of transgenic mice, independent of the expression of PS1 holoprotein. We now document that, in the brains of transgenic mice, the absolute amounts of accumulated N- and C-terminal derivatives generated from the FAD-linked PS1 variants in which Glu replaces Ala at codon 246 (A246E) or Leu replaces Met at codon 146 (M146L) accumulate to a significantly higher degree (approximately 40-50%) than the fragments derived from wild-type PS1. Moreover, the FAD-linked deltaE9 PS1 variant, a polypeptide that is not subject to endoproteolytic cleavage in vivo, also accumulates in greater amounts than the fragments generated from wild-type human PS1. Thus, the metabolism of PS1 variants linked to FAD is fundamentally different from that of wild-type PS1 in vivo.", + "TAG_DATA": [ + "79, brains {'context': 'B-tissue/organ'}", + "82, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "79, brains ['l0']", + "82, mice, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9212100", + "TEXT": "A subset of patients with high plasma HDL concentrations have enhanced rather than reduced atherosclerosis. We have developed a new transgenic mouse model overexpressing human lecithin-cholesteryl acyltransferase (LCAT) that has elevated HDL and increased diet-induced atherosclerosis. LCAT transgenic mouse HDLs are abnormal in both composition and function. Liver uptake of [3H]cholesteryl ether incorporated in transgenic mouse HDL was reduced by 41% compared with control HDL, indicating ineffective transport of HDL-cholesterol to the liver and impaired reverse cholesterol transport. Analysis of this LCAT-transgenic mouse model provides in vivo evidence for dysfunctional HDL as a potential mechanism leading to increased atherosclerosis in the presence of high plasma HDL levels.", + "TAG_DATA": [ + "20, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "21, mouse {'context': 'B-organism'}", + "22, model {'context': 'I-organism'}", + "23, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "24, human {'perturbing_action': 'I-gene gain-of-function'}", + "25, lecithin-cholesteryl {'perturbing_action': 'I-gene gain-of-function'}", + "26, acyltransferase {'perturbing_action': 'I-gene gain-of-function'}", + "27, (LCAT) {'perturbing_action': 'I-gene gain-of-function'}", + "36, LCAT {'perturbing_action': 'B-gene gain-of-function'}", + "37, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "38, mouse {'perturbing_action': 'I-gene gain-of-function'}", + "47, Liver {'context': 'B-tissue/organ'}", + "54, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "55, mouse {'context': 'I-organism'}", + "81, LCAT-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "82, mouse {'context': 'B-organism'}", + "83, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "20, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "21, mouse ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "22, model ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "23, overexpressing ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "24, human ['l3', 'l13', 'l22', 'l30', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "25, lecithin-cholesteryl ['l4', 'l14', 'l23', 'l31', 'l39', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "26, acyltransferase ['l5', 'l15', 'l24', 'l32', 'l40', 'l47', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "27, (LCAT) ['l6', 'l16', 'l25', 'l33', 'l41', 'l48', 'l54', 'l60', 'l61', 'l62', 'l63']", + "36, LCAT ['l7', 'l17', 'l26', 'l34', 'l42', 'l49', 'l55', 'l60', 'l64', 'l65', 'l66', 'l67', 'l68']", + "37, transgenic ['l8', 'l18', 'l27', 'l35', 'l43', 'l50', 'l56', 'l61', 'l64', 'l69', 'l70', 'l71', 'l72']", + "38, mouse ['l9', 'l19', 'l28', 'l36', 'l44', 'l51', 'l57', 'l62', 'l65', 'l69', 'l73', 'l74', 'l75']", + "47, Liver ['l10', 'l20', 'l29', 'l37', 'l45', 'l52', 'l58', 'l63', 'l66', 'l70', 'l73', 'l76', 'l77']", + "54, transgenic ['l67', 'l71', 'l74', 'l76', 'l78']", + "55, mouse ['l38', 'l46', 'l53', 'l59', 'l68', 'l72', 'l75', 'l77', 'l78']", + "81, LCAT-transgenic ['l79', 'l80']", + "82, mouse ['l79', 'l81']", + "83, model ['l80', 'l81']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "overexpressing", + "human", + "lecithin-cholesteryl", + "acyltransferase", + "(LCAT)", + "LCAT", + "mouse", + "LCAT-transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "overexpressing", + "human", + "lecithin-cholesteryl", + "acyltransferase", + "(LCAT)", + "LCAT", + "mouse" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "Liver" + ] + } + } + ] + }, + { + "PMID": "9212099", + "TEXT": "Fas ligand is believed to mediate immune privilege in a variety of tissues, including the eye, testis, and a subset of tumors. We tested whether expression of Fas ligand on pancreatic islets either following adenoviral or germline gene transfer could confer immune privilege after transplantation. Islets were infected with an adenoviral vector containing the murine Fas ligand cDNA (AdFasL), and were transplanted into allogenic diabetic hosts. Paradoxically, AdFasL-infected islets underwent accelerated neutrophilic rejection. The rejection was T cell and B cell independent and required Fas protein expression by host cells, but not on islets. Similarly, transgenic mice expressing Fas ligand in pancreatic beta cells developed massive neutrophilic infiltrates and diabetes at a young age. Thus, Fas ligand expression on pancreatic islets results in neutrophilic infiltration and islet destruction. These results have important implications for the development of Fas ligand-based immunotherapies.", + "TAG_DATA": [ + "45, Islets {'context': 'B-cells'}", + "68, islets {'context': 'B-cells'}", + "93, islets. {'context': 'B-cells'}", + "95, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "96, mice {'context': 'I-organism'}", + "97, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "98, Fas {'perturbing_action': 'I-gene gain-of-function'}", + "99, ligand {'perturbing_action': 'I-gene gain-of-function'}", + "101, pancreatic {'context': 'B-cells'}", + "102, beta {'context': 'I-cells'}", + "103, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, Islets ['l0']", + "68, islets ['l0', 'l1']", + "93, islets. ['l1']", + "95, transgenic ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "96, mice ['l2', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "97, expressing ['l3', 'l9', 'l15', 'l16', 'l17', 'l18', 'l19']", + "98, Fas ['l4', 'l10', 'l15', 'l20', 'l21', 'l22', 'l23']", + "99, ligand ['l5', 'l11', 'l16', 'l20', 'l24', 'l25', 'l26']", + "101, pancreatic ['l6', 'l12', 'l17', 'l21', 'l24', 'l27', 'l28']", + "102, beta ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l29']", + "103, cells ['l8', 'l14', 'l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "Fas", + "ligand" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "Fas", + "ligand" + ] + }, + "context": { + "val": "cells", + "words": [ + "pancreatic", + "beta", + "cells" + ] + } + } + ] + }, + { + "PMID": "9212098", + "TEXT": "On the subject of acute myeloid leukemia (AML), there is little consensus about the target cell within the hematopoietic stem cell hierarchy that is susceptible to leukemic transformation, or about the mechanism that underlies the phenotypic, genotypic and clinical heterogeneity. Here we demonstrate that the cell capable of initiating human AML in non-obese diabetic mice with severe combined immunodeficiency disease (NOD/SCID mice) - termed the SCID leukemia-initiating cell, or SL-IC - possesses the differentiative and proliferative capacities and the potential for self-renewal expected of a leukemic stem cell. The SL-ICs from all subtypes of AML analyzed, regardless of the heterogeneity in maturation characteristics of the leukemic blasts, were exclusively CD34++ CD38-, similar to the cell-surface phenotype of normal SCID-repopulating cells, suggesting that normal primitive cells, rather than committed progenitor cells, are the target for leukemic transformation. The SL-ICs were able to differentiate in vivo into leukemic blasts, indicating that the leukemic clone is organized as a hierarchy.", + "TAG_DATA": [ + "45, cell {'context': 'B-cells'}", + "49, human {'context': 'B-neoplasm'}", + "50, AML {'context': 'I-neoplasm'}", + "52, non-obese {'context': 'B-organism'}", + "53, diabetic {'context': 'I-organism'}", + "54, mice {'context': 'I-organism'}", + "79, potential {'effect': 'B-positive'}", + "81, self-renewal {'phenotype': 'B-self-renewal'}", + "141, differentiate {'phenotype': 'B-differentiation'}", + "142, in {'context': 'B-in vivo'}", + "143, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "45, cell ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "48, initiating ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "49, human ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "50, AML ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "52, non-obese ['l3', 'l8', 'l12', 'l15', 'l18', 'l19', 'l20', 'l21']", + "53, diabetic ['l4', 'l9', 'l13', 'l16', 'l18', 'l22', 'l23', 'l24']", + "54, mice ['l5', 'l10', 'l14', 'l17', 'l19', 'l22', 'l25', 'l26']", + "79, potential ['l20', 'l23', 'l25', 'l27', 'l28']", + "81, self-renewal ['l21', 'l24', 'l26', 'l27', 'l29']", + "94, AML ['l28', 'l29']", + "141, differentiate ['l30', 'l31']", + "142, in ['l30', 'l32']", + "143, vivo ['l31', 'l32']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "non-obese", + "diabetic", + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "potential" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "non-obese", + "diabetic", + "mice" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "potential" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "9176498", + "TEXT": "The 4-1BB glycoprotein is a member of the tumor necrosis factor receptor superfamily and binds to a high-affinity ligand (4-1BBL) expressed on several antigen-presenting cells such as macrophages and activated B cells. Expression of 4-1BB is restricted to primed CD4+ and CD8+ T cells, and 4-1BB signaling either by binding to 4-1BBL or by antibody ligation delivers a dual mitogenic signal for T-cell activation and growth. These observations suggest an important role for 4-1BB in the amplification of T cell-mediated immune responses. We now show that administration of anti-4-1BB monoclonal antibodies can eradicate established large tumors in mice, including the poorly immunogenic Ag104A sarcoma and the highly tumorigenic P815 masto cytoma. The immune response induced by anti-4- 1BB monoclonal antibodies is mediated by both CD8+ and CD4+ T cells and is accompanied by a marked augmentation of tumor-selective cytolytic T-cell activity. Our data suggest that a similar approach may be efficacious for immunotherapy of human cancer.", + "TAG_DATA": [ + "95, tumors {'context': 'I-neoplasm'}", + "97, mice, {'context': 'B-organism'}", + "100, poorly {'context': 'B-neoplasm'}", + "101, immunogenic {'context': 'I-neoplasm'}", + "102, Ag104A {'context': 'I-neoplasm'}", + "103, sarcoma {'context': 'I-neoplasm'}", + "109, masto {'context': 'I-neoplasm'}", + "110, cytoma. {'context': 'I-neoplasm'}", + "124, CD8+ {'context': 'B-cells'}", + "125, and {'context': 'I-cells'}", + "126, CD4+ {'context': 'I-cells'}", + "127, T {'context': 'I-cells'}", + "128, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "95, tumors ['l0', 'l1', 'l2', 'l3', 'l4']", + "97, mice, ['l0', 'l5', 'l6', 'l7', 'l8']", + "100, poorly ['l1', 'l5', 'l9', 'l10', 'l11', 'l12', 'l13']", + "101, immunogenic ['l2', 'l6', 'l9', 'l14', 'l15', 'l16']", + "102, Ag104A ['l3', 'l7', 'l10', 'l14', 'l17', 'l18', 'l19']", + "103, sarcoma ['l4', 'l8', 'l11', 'l15', 'l17']", + "108, P815 ['l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "109, masto ['l12', 'l18', 'l20', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "110, cytoma. ['l13', 'l16', 'l19', 'l21', 'l27', 'l33', 'l34', 'l35', 'l36']", + "124, CD8+ ['l22', 'l28', 'l33', 'l37', 'l38', 'l39', 'l40']", + "125, and ['l23', 'l29', 'l34', 'l37', 'l41', 'l42', 'l43']", + "126, CD4+ ['l24', 'l30', 'l38', 'l41', 'l44', 'l45']", + "127, T ['l25', 'l31', 'l35', 'l39', 'l42', 'l44', 'l46']", + "128, cells ['l26', 'l32', 'l36', 'l40', 'l43', 'l45', 'l46']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9176493", + "TEXT": "Interleukin-16 (IL-16) is secreted by activated CD8+ T lymphocytes and acts on CD4+ T lymphocytes, monocytes and eosinophils. Recently, the C-terminal 130-amino acid portion of IL-16 was shown to suppress HIV-1 replication in vitro. To explore the potential of human IL-16 for gene therapy, this portion was transfected into HIV-1-susceptible CD4+ jurkat cells by means of a mammalian expression vector. The stable transfectants synthesized and secreted IL-16 protein. The expression of IL-16 did not alter growth rate and CD4 expression; however, HIV replication was inhibited by as much as 99%. Furthermore, during the initial phase of the infection, equal amounts of HIV-1 proviral DNA were found in cells transfected with IL-16 and with vector alone. In contrast, the 2-kilobase HIV-1 transcripts were markedly reduced and the 4-kb and 9-kb transcripts were undetectable in the cells transfected with IL-16. These findings indicate that IL-16-mediated inhibition of HIV-1 is not at the level of viral entry or reverse transcription, but at messenger RNA expression.", + "TAG_DATA": [ + "50, CD4+ {'context': 'B-cells'}", + "51, jurkat {'context': 'I-cells'}", + "52, cells {'context': 'I-cells'}", + "62, transfectants {'perturbing_action': 'I-gene gain-of-function'}", + "69, expression {'perturbing_action': 'B-gene gain-of-function'}", + "70, of {'perturbing_action': 'I-gene gain-of-function'}", + "71, IL-16 {'perturbing_action': 'I-gene gain-of-function'}", + "107, cells {'context': 'B-cells'}", + "108, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "109, with {'perturbing_action': 'I-gene gain-of-function'}", + "110, IL-16 {'perturbing_action': 'I-gene gain-of-function'}", + "134, cells {'context': 'B-cells'}", + "135, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "136, with {'perturbing_action': 'I-gene gain-of-function'}", + "137, IL-16. {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "50, CD4+ ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "51, jurkat ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "52, cells ['l1', 'l6', 'l11', 'l12']", + "62, transfectants ['l2', 'l7', 'l13', 'l14', 'l15']", + "69, expression ['l3', 'l8', 'l13', 'l16', 'l17']", + "70, of ['l4', 'l9', 'l11', 'l14', 'l16', 'l18']", + "71, IL-16 ['l5', 'l10', 'l12', 'l15', 'l17', 'l18']", + "107, cells ['l19', 'l20', 'l21']", + "108, transfected ['l19', 'l22', 'l23']", + "109, with ['l20', 'l22', 'l24']", + "110, IL-16 ['l21', 'l23', 'l24']", + "134, cells ['l25', 'l26', 'l27']", + "135, transfected ['l25', 'l28', 'l29']", + "136, with ['l26', 'l28', 'l30']", + "137, IL-16. ['l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD4+", + "jurkat", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfectants", + "expression", + "of", + "IL-16", + "transfected", + "with", + "IL-16." + ] + } + } + ] + }, + { + "PMID": "9142122", + "TEXT": "Changes in CD4+ T-cell surface marker phenotype and antigen receptor (TCR) repertoire were examined during the course of HIV infection and following therapy. A preferential decline in naive CD4+ T cells was noted as disease progressed. Following protease inhibitor therapy, naive CD4+ T cells increased only if they were present before initiation of therapy. Disruptions of the CD4+ TCR repertoire were most prevalent in patients with the lowest CD4+ T-cell counts. Antiviral or IL-12 therapy-induced increases in CD4+ T-cell counts led to only minor changes in previously disrupted repertoires. Thus, CD4+ T-cell death mediated by HIV-1 infection may result in a preferential decline in the number of naive CD4+ T cells and disruptions of the CD4+ T-cell repertoire that are not immediately corrected by antiviral or immune-based therapies.", + "TAG_DATA": [ + "27, naive {'context': 'B-cells'}", + "28, CD4+ {'context': 'I-cells'}", + "29, T {'context': 'I-cells'}", + "30, cells {'context': 'I-cells'}", + "40, naive {'context': 'B-cells'}", + "41, CD4+ {'context': 'I-cells'}", + "42, T {'context': 'I-cells'}", + "43, cells {'context': 'I-cells'}", + "64, patients {'context': 'B-patient'}", + "77, CD4+ {'context': 'B-cells'}", + "78, T-cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "27, naive ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "28, CD4+ ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "29, T ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "30, cells ['l2', 'l8', 'l13', 'l18', 'l19', 'l20']", + "40, naive ['l3', 'l9', 'l14', 'l18', 'l21', 'l22', 'l23', 'l24']", + "41, CD4+ ['l4', 'l10', 'l15', 'l21', 'l25', 'l26', 'l27']", + "42, T ['l5', 'l11', 'l16', 'l19', 'l22', 'l25', 'l28', 'l29']", + "43, cells ['l6', 'l12', 'l17', 'l20', 'l23', 'l26', 'l28']", + "64, patients ['l24', 'l27', 'l29']", + "77, CD4+ ['l30', 'l31']", + "78, T-cell ['l30', 'l32']", + "108, CD4+ ['l33']", + "109, T ['l31', 'l32', 'l33']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9095182", + "TEXT": "The effect of nitroglycerin on oxygen (O2) release in the microcirculation was investigated by examining single, unbranched hepatic sinusoids of rats using dual-spot microspectroscopy. Nitroglycerin significantly increased O2 release from erythrocytes flowing in the sinusoids. Differences in O2 saturation of hemoglobin per unit length of the sinusoid were significantly enhanced, while there were no significant changes in erythrocyte velocity, hemoglobin concentration or oxyhemoglobin flow into the sinusoids, or in regional hepatic blood flow measured with a laser tissue blood flow meter. No change was noted for hepatic O2 consumption measured in isolated liver perfused with hemoglobin-free oxygenated buffer. Isosorbide dinitrate showed a similar but slower effect. These findings suggest that nitroglycerin and isosorbide dinitrate enhance O2 release from erythrocytes without significantly increasing tissue blood flow.", + "TAG_DATA": [ + "92, liver {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9095181", + "TEXT": "Antitumor immune responses are mediated primarily by T cells. Downregulation of the major histocompatibility complex (MHC) and the molecules that costimulate the immune response is associated with defective signaling by tumor cells for T-cell activation. In vitro treatment with a combination of cytokines significantly increased the expression of MHC class I and adhesion molecules on tumor cell surfaces. When tumor cells were first incubated with a bispecific monoclonal antibody that binds antigen on tumor cells to CD28 on T cells, the modified tumor cells become immunogenic and are able to stimulate naive T cells, generating tumor-specific cytotoxic T cells in vitro. Immunization with the modified tumor cells elicits an immune response mediated by CD8+ T cells. This response protected against a challenge with parental tumor cells and cured established tumors. The approach was effective in both low immunogenic and nonimmunogenic tumor model systems. Modification of tumor cells with this two-step procedure may provide a strategy for development of tumor vaccines that is effective for cancer immunotherapy.", + "TAG_DATA": [ + "35, In {'context': 'B-in vitro'}", + "36, vitro {'context': 'I-in vitro'}", + "55, tumor {'context': 'B-transformed cells'}", + "59, tumor {'context': 'B-transformed cells'}", + "60, cells {'context': 'I-transformed cells'}", + "82, tumor {'context': 'B-transformed cells'}", + "83, cells {'context': 'I-transformed cells'}", + "91, naive {'context': 'B-cells'}", + "92, T {'context': 'I-cells'}", + "93, cells, {'context': 'I-cells'}", + "99, in {'context': 'B-in vitro'}", + "100, vitro. {'context': 'I-in vitro'}", + "105, tumor {'context': 'B-transformed cells'}", + "106, cells {'context': 'I-transformed cells'}", + "113, CD8+ {'context': 'B-cells'}", + "114, T {'context': 'I-cells'}", + "115, cells. {'context': 'I-cells'}", + "124, tumor {'context': 'B-transformed cells'}", + "125, cells {'context': 'I-transformed cells'}", + "129, tumors. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "35, In ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "36, vitro ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "55, tumor ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "59, tumor ['l2', 'l10', 'l17', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "60, cells ['l3', 'l11', 'l18', 'l26', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "82, tumor ['l4', 'l12', 'l19', 'l27', 'l34', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "83, cells ['l5', 'l13', 'l20', 'l28', 'l35', 'l41', 'l47', 'l48', 'l49', 'l50', 'l51']", + "91, naive ['l6', 'l14', 'l21', 'l29', 'l36', 'l42', 'l47', 'l52', 'l53', 'l54', 'l55']", + "92, T ['l7', 'l15', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l56', 'l57', 'l58']", + "93, cells, ['l8', 'l16', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l59', 'l60']", + "99, in ['l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l59', 'l61']", + "100, vitro. ['l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l58', 'l60', 'l61']", + "105, tumor ['l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "106, cells ['l62', 'l68', 'l69', 'l70', 'l71', 'l72']", + "113, CD8+ ['l63', 'l68', 'l73', 'l74', 'l75', 'l76', 'l77']", + "114, T ['l64', 'l69', 'l73', 'l78', 'l79', 'l80']", + "115, cells. ['l65', 'l70', 'l74', 'l78', 'l81', 'l82']", + "124, tumor ['l66', 'l71', 'l75', 'l79', 'l81', 'l83']", + "125, cells ['l67', 'l72', 'l76', 'l80', 'l82', 'l83']", + "129, tumors. ['l77']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9095180", + "TEXT": "Breast cancers are either primarily resistant to chemotherapy (intrinsic resistance), or respond to chemotherapy but later recur with a multidrug-resistant phenotype because of overexpression of the multidrug transporter P-glycoprotein. The MDR1 gene encoding P-glycoprotein may be transcriptionally regulated by a Y-box transcription factor. We now report that, in multidrug-resistant MCF-7 breast cancer cells, nuclear localization of YB-1 is associated with MDR-1 gene expression. In drug-sensitive MCF-7 cells, however, YB-1 was localized to the cytoplasm. Regulated overexpression of YB-1 in drug-sensitive diploid breast epithelial cells induced MDR-1 gene expression and multidrug resistance. In 27 out of 27 untreated primary breast cancers, YB-1 protein was expressed in the cytoplasm although it was undetectable in normal breast tissue of these patients. In a subgroup of tumors (9/27), however, YB-1 was also localized to the nucleus and, in these cases, high levels of P-glycoprotein were present. These results show that in a subset of untreated primary breast cancers, nuclear localization of YB-1 protein is associated with intrinsic multidrug resistance. Our data show that YB-1 has an important role in controlling MDR1 gene transcription and this finding provides a basis for the analysis of molecular mechanisms responsible for intrinsic multidrug resistance in human breast cancer.", + "TAG_DATA": [ + "74, Regulated {'perturbing_action': 'B-gene gain-of-function'}", + "75, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "76, of {'perturbing_action': 'I-gene gain-of-function'}", + "77, YB-1 {'perturbing_action': 'I-gene gain-of-function'}", + "79, drug-sensitive {'context': 'B-cells'}", + "80, diploid {'context': 'I-cells'}", + "81, breast {'context': 'I-cells'}", + "82, epithelial {'context': 'I-cells'}", + "83, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "74, Regulated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "75, overexpression ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "76, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "77, YB-1 ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "79, drug-sensitive ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "80, diploid ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "81, breast ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "82, epithelial ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "83, cells ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Regulated", + "overexpression", + "of", + "YB-1" + ] + }, + "context": { + "val": "cells", + "words": [ + "drug-sensitive", + "diploid", + "breast", + "epithelial", + "cells" + ] + } + } + ] + }, + { + "PMID": "9095178", + "TEXT": "Chronic systemic delivery of therapeutic proteins, such as inhibitors of angiogenesis, present a number of difficult pharmacological challenges. To overcome these problems for one such protein, we constructed retroviral and adenoviral vectors that express a novel, secretable form of the antiangiogenic protein, platelet factor 4 (sPF4). Vector-mediated sPF4 transduction selectively inhibits endothelial cell proliferation in vitro, and results in hypovascular tumors that grow slowly in vivo. Additionally, tumor-associated angiogenesis is inhibited and animal survival is prolonged, following transduction of established intracerebral gliomas by an sPF4-expressing adenoviral vector. These data support the concept that targeted antiangiogenesis, using virally mediated gene transfer, represents a promising strategy for delivering antiangiogenic therapy.", + "TAG_DATA": [ + "46, Vector-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "47, sPF4 {'perturbing_action': 'I-gene gain-of-function'}", + "48, transduction {'perturbing_action': 'I-gene gain-of-function'}", + "50, inhibits {'effect': 'B-negative'}", + "51, endothelial {'context': 'B-cells'}", + "52, cell {'context': 'I-cells'}", + "53, proliferation {'phenotype': 'B-proliferation'}", + "54, in {'context': 'B-in vitro'}", + "55, vitro, {'context': 'I-in vitro'}", + "60, tumors {'context': 'B-neoplasm'}", + "64, in {'context': 'B-in vivo'}", + "65, vivo. {'context': 'I-in vivo'}", + "72, animal {'context': 'B-organism', 'phenotype': 'B-cell survival'}", + "80, intracerebral {'context': 'B-neoplasm'}", + "81, gliomas {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "46, Vector-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "47, sPF4 ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "48, transduction ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "50, inhibits ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "51, endothelial ['l3', 'l13', 'l22', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "52, cell ['l4', 'l14', 'l23', 'l31', 'l36', 'l41', 'l42', 'l43']", + "53, proliferation ['l5', 'l15', 'l24', 'l32', 'l37', 'l41', 'l44', 'l45']", + "54, in ['l6', 'l16', 'l25', 'l33', 'l38', 'l42', 'l44', 'l46', 'l47']", + "55, vitro, ['l7', 'l17', 'l26', 'l34', 'l39', 'l43', 'l45', 'l46', 'l48']", + "60, tumors ['l8', 'l18', 'l27', 'l35', 'l40', 'l47', 'l48', 'l49', 'l50']", + "64, in ['l9', 'l19', 'l28', 'l49', 'l51']", + "65, vivo. ['l10', 'l20', 'l29', 'l50', 'l51']", + "72, animal ['l52', 'l53', 'l54']", + "80, intracerebral ['l52', 'l55', 'l56', 'l57']", + "81, gliomas ['l53', 'l55', 'l58', 'l59']", + "85, adenoviral ['l56', 'l58', 'l60']", + "86, vector. ['l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Vector-mediated", + "sPF4", + "transduction" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Vector-mediated", + "sPF4", + "transduction" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Vector-mediated", + "sPF4", + "transduction" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Vector-mediated", + "sPF4", + "transduction" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Vector-mediated", + "sPF4", + "transduction" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Vector-mediated", + "sPF4", + "transduction" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animal" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "animal" + ] + } + }, + { + "phenotype": { + "val": "cell survival", + "words": [ + "animal" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "intracerebral", + "gliomas" + ] + } + } + ] + }, + { + "PMID": "9095175", + "TEXT": "We have studied the interactions of phosphodiester and phosphorothioate oligodeoxynucleotides with Mac-1 (CD11b/CD18; alpha M beta 2), a heparin-binding integrin found predominantly on the surface of polymorphonuclear leukocytes (PMNs), macrophages and natural killer cells. Binding of a homopolymer of thymidine occurred on both the alpha M and beta 2 subunits. Soluble fibrinogen, a natural ligand for Mac-1, was an excellent competitor of the binding of a phosphorothioate oligodeoxynucleotide to both TNF-alpha-activated and nonactivated PMNs. Upregulation of cell-surface Mac-1 expression increased cell-surface binding of oligodeoxynucleotides. Binding was inhibited by anti-Mac-1 monoclonal antibodies, and the increase in cell-surface binding was correlated with a three- to fourfold increase in internalization by PMNs. An oligodeoxynucleotide inhibited beta 2-dependent migration through Matrigel, but the production of reactive oxygen species in PMNs adherent to fibrinogen dramatically increased. Thus, our data demonstrate that Mac-1 is a cell-surface receptor for oligodeoxynucleotides that can mediate their internalization and that this binding may have important functional consequences.", + "TAG_DATA": [ + "74, Upregulation {'perturbing_action': 'B-gene gain-of-function'}", + "75, of {'perturbing_action': 'I-gene gain-of-function'}", + "76, cell-surface {'perturbing_action': 'I-gene gain-of-function'}", + "77, Mac-1 {'perturbing_action': 'I-gene gain-of-function'}", + "78, expression {'perturbing_action': 'I-gene gain-of-function'}", + "111, inhibited {'effect': 'B-negative'}", + "114, migration {'phenotype': 'B-migration'}", + "125, PMNs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "74, Upregulation ['l0', 'l1', 'l2', 'l3']", + "75, of ['l0', 'l4', 'l5', 'l6']", + "76, cell-surface ['l1', 'l4', 'l7', 'l8']", + "77, Mac-1 ['l2', 'l5', 'l7', 'l9']", + "78, expression ['l3', 'l6', 'l8', 'l9']", + "111, inhibited ['l10']", + "114, migration ['l10']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + } + ] + }, + { + "PMID": "9055862", + "TEXT": "Mutations in the presenilin genes are associated with early onset familial Alzheimer's disease and lead to increased accumulation of beta A4 peptide, the proteolytic product of the amyloid precursor protein (APP). To test whether presenilins interfere with APP metabolism, presenilin-2 (PS2) was coexpressed with APP in mammalian cells. Analysis of PS2 immunoprecipitates revealed that a fraction of APP was associated with the PS2 immunocomplexes. This non-covalent association was specific for the APP family of proteins and restricted to immature forms, occurring probably during transit through the endoplasmic reticulum. Additionally, coexpression with PS2 resulted in a decrease of APP secretion, suggesting a direct participation of presenilins in the intracellular sorting, trafficking and processing of APP molecules.", + "TAG_DATA": [ + "39, presenilin-2 {'perturbing_action': 'B-gene gain-of-function'}", + "40, (PS2) {'perturbing_action': 'I-gene gain-of-function'}", + "42, coexpressed {'perturbing_action': 'I-gene gain-of-function'}", + "43, with {'perturbing_action': 'I-gene gain-of-function'}", + "44, APP {'perturbing_action': 'I-gene gain-of-function'}", + "46, mammalian {'context': 'B-cells'}", + "47, cells. {'context': 'I-cells'}", + "89, coexpression {'perturbing_action': 'B-gene gain-of-function'}", + "90, with {'perturbing_action': 'I-gene gain-of-function'}", + "91, PS2 {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "39, presenilin-2 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "40, (PS2) ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "42, coexpressed ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "43, with ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "44, APP ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "46, mammalian ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "47, cells. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "89, coexpression ['l21', 'l22']", + "90, with ['l21', 'l23']", + "91, PS2 ['l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "presenilin-2", + "(PS2)", + "coexpressed", + "with", + "APP" + ] + }, + "context": { + "val": "cells", + "words": [ + "mammalian", + "cells." + ] + } + } + ] + }, + { + "PMID": "9055860", + "TEXT": "Migration inhibitory factor (MIF) is known to exert significant pro-inflammatory effects and has the potential to override the anti-inflammatory action of glucocorticoids. In this study we have identified significant quantities of MIF in the alveolar airspaces of patients with acute respiratory distress syndrome (ARDS). We show in alveolar cells from patients with ARDS that MIF augments pro-inflammatory cytokine secretion (TNF alpha and IL-8), anti-MIF significantly attenuates TNF alpha and IL-8 secretion and MIF overrides, in a concentration-related fashion, the anti-inflammatory effects of glucocorticoids. These findings suggest that MIF may act as a mediator sustaining the pulmonary inflammatory response in ARDS and that an anti-MIF strategy may represent a novel therapeutic approach in inflammatory diseases such as ARDS.", + "TAG_DATA": [ + "47, alveolar {'context': 'B-cells'}", + "48, cells {'context': 'I-cells'}", + "49, from {'context': 'I-cells'}", + "50, patients {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "47, alveolar ['l0', 'l1', 'l2']", + "48, cells ['l0', 'l3', 'l4']", + "49, from ['l1', 'l3', 'l5']", + "50, patients ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9055858", + "TEXT": "Although gene transfer with adeno-associated virus (AAV) vectors has typically been low, transduction can be enhanced in the presence of adenovirus gene products through the formation of double stranded, non-integrated AAV genomes. We describe the unexpected finding of high level and stable transgene expression in mice following intramuscular injection of purified recombinant AAV (rAAV). The rAAV genome is efficiently incorporated into nuclei of differentiated muscle fibers where it persists as head-to-tail concatamers. Fluorescent in situ hybridization of muscle tissue suggests single integration sites. Neutralizing antibody against AAV capsid proteins does not prevent readministration of vector. Remarkably, no humoral or cellular immune responses are elicited to the neoantigenic transgene product E. coli beta-galactosidase. The favorable biology of rAAV in muscle-directed gene therapy described in this study expands the potential of this vector for the treatment of inherited and acquired diseases.", + "TAG_DATA": [ + "45, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9055854", + "TEXT": "The possible use of pig organs and tissues as xenografts in humans is actively being considered in biomedical research. We therefore examined whether pig endogenous retrovirus (PERV) genomes can be infectiously transmitted to human cells in culture. Two pig kidney cell lines spontaneously produce C-type retrovirus particles. Cell-free retrovirus produced by the PK-15 kidney cell line (PERV-PK) infected pig, mink and human kidney 293 cell lines and co-cultivation of X-irradiated PK-15 cells with human cells resulted in a broader range of human cell infection, including human diploid fibroblasts and B- and T-cell lines. Kidney, heart and spleen tissue obtained from domestic pigs contained multiple copies of integrated PERV genomes and expressed viral RNA. Upon passage in human cells PERV-PK could rescue a Moloney retroviral vector and acquired resistance to lysis by human complement.", + "TAG_DATA": [ + "54, cell {'context': 'I-cells'}", + "55, line {'context': 'I-cells'}", + "58, pig, {'context': 'B-organism'}", + "59, mink {'context': 'B-organism'}", + "60, and {'context': 'I-cells'}", + "61, human {'context': 'I-cells'}", + "62, kidney {'context': 'I-cells'}", + "63, 293 {'context': 'I-cells'}", + "64, cell {'context': 'I-cells'}", + "65, lines {'context': 'I-cells'}", + "70, PK-15 {'context': 'B-cells'}", + "71, cells {'context': 'I-cells'}", + "73, human {'context': 'B-cells'}", + "74, cells {'context': 'I-cells'}", + "81, human {'context': 'B-cells'}", + "82, cell {'context': 'I-cells'}", + "85, human {'context': 'B-cells'}", + "86, diploid {'context': 'I-cells'}", + "87, fibroblasts {'context': 'I-cells'}", + "89, B- {'context': 'B-cells'}", + "90, and {'context': 'I-cells'}", + "91, T-cell {'context': 'I-cells'}", + "92, lines. {'context': 'I-cells'}", + "93, Kidney, {'context': 'B-tissue/organ'}", + "94, heart {'context': 'I-tissue/organ'}", + "95, and {'context': 'I-tissue/organ'}", + "96, spleen {'context': 'I-tissue/organ'}", + "97, tissue {'context': 'I-tissue/organ'}", + "100, domestic {'context': 'B-organism'}", + "101, pigs {'context': 'I-organism'}", + "116, human {'context': 'B-cells'}", + "117, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "39, kidney ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "40, cell ['l0', 'l9', 'l10', 'l11', 'l12']", + "53, kidney ['l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "54, cell ['l13', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "55, line ['l14', 'l35', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "58, pig, ['l1', 'l15', 'l36', 'l56', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "59, mink ['l2', 'l16', 'l37', 'l57', 'l76', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "60, and ['l3', 'l9', 'l17', 'l38', 'l58', 'l77', 'l94', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "61, human ['l4', 'l18', 'l39', 'l59', 'l78', 'l95', 'l111', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141']", + "62, kidney ['l5', 'l10', 'l19', 'l40', 'l60', 'l79', 'l96', 'l112', 'l127', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "63, 293 ['l6', 'l20', 'l41', 'l61', 'l80', 'l97', 'l113', 'l128', 'l142', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168']", + "64, cell ['l7', 'l11', 'l21', 'l42', 'l62', 'l81', 'l98', 'l114', 'l129', 'l143', 'l156', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179']", + "65, lines ['l8', 'l12', 'l22', 'l43', 'l63', 'l82', 'l99', 'l115', 'l130', 'l144', 'l157', 'l169', 'l180', 'l181', 'l182', 'l183']", + "70, PK-15 ['l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202']", + "71, cells ['l23', 'l44', 'l64', 'l184', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219']", + "73, human ['l24', 'l45', 'l65', 'l83', 'l100', 'l116', 'l131', 'l145', 'l158', 'l170', 'l185', 'l203', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229']", + "74, cells ['l25', 'l46', 'l66', 'l84', 'l101', 'l117', 'l132', 'l146', 'l159', 'l171', 'l180', 'l186', 'l204', 'l220', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238']", + "81, human ['l26', 'l47', 'l67', 'l85', 'l102', 'l118', 'l133', 'l147', 'l160', 'l172', 'l181', 'l187', 'l205', 'l221', 'l230', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246']", + "82, cell ['l27', 'l48', 'l68', 'l86', 'l103', 'l119', 'l134', 'l148', 'l161', 'l173', 'l182', 'l188', 'l206', 'l222', 'l231', 'l239', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253']", + "85, human ['l28', 'l49', 'l69', 'l87', 'l104', 'l120', 'l135', 'l149', 'l162', 'l174', 'l189', 'l207', 'l223', 'l232', 'l240', 'l247', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259']", + "86, diploid ['l29', 'l50', 'l70', 'l88', 'l105', 'l121', 'l136', 'l150', 'l163', 'l175', 'l190', 'l208', 'l224', 'l233', 'l241', 'l248', 'l254', 'l260', 'l261', 'l262', 'l263', 'l264']", + "87, fibroblasts ['l30', 'l51', 'l71', 'l89', 'l106', 'l122', 'l137', 'l151', 'l164', 'l176', 'l183', 'l191', 'l209', 'l225', 'l234', 'l242', 'l249', 'l255', 'l260', 'l265', 'l266', 'l267', 'l268']", + "89, B- ['l31', 'l52', 'l72', 'l90', 'l107', 'l123', 'l138', 'l152', 'l165', 'l177', 'l192', 'l210', 'l226', 'l235', 'l243', 'l250', 'l256', 'l261', 'l265', 'l269', 'l270', 'l271']", + "90, and ['l32', 'l53', 'l73', 'l91', 'l108', 'l124', 'l139', 'l153', 'l166', 'l193', 'l211', 'l227', 'l236', 'l244', 'l251', 'l257', 'l262', 'l266', 'l269', 'l272', 'l273']", + "91, T-cell ['l33', 'l54', 'l74', 'l92', 'l109', 'l125', 'l140', 'l154', 'l167', 'l178', 'l194', 'l212', 'l228', 'l237', 'l245', 'l252', 'l258', 'l263', 'l267', 'l270', 'l272', 'l274']", + "92, lines. ['l34', 'l55', 'l75', 'l93', 'l110', 'l126', 'l141', 'l155', 'l168', 'l179', 'l195', 'l213', 'l229', 'l238', 'l246', 'l253', 'l259', 'l264', 'l268', 'l271', 'l273', 'l274']", + "93, Kidney, ['l196', 'l214', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280']", + "94, heart ['l197', 'l215', 'l275', 'l281', 'l282', 'l283', 'l284', 'l285']", + "95, and ['l198', 'l216', 'l276', 'l281', 'l286', 'l287', 'l288', 'l289']", + "96, spleen ['l199', 'l217', 'l277', 'l282', 'l286', 'l290', 'l291', 'l292']", + "97, tissue ['l200', 'l218', 'l278', 'l283', 'l287', 'l290', 'l293', 'l294']", + "100, domestic ['l201', 'l279', 'l284', 'l288', 'l291', 'l293', 'l295']", + "101, pigs ['l202', 'l219', 'l280', 'l285', 'l289', 'l292', 'l294', 'l295']", + "116, human ['l296']", + "117, cells ['l296']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9018240", + "TEXT": "The HIV-1-specific cytotoxic T lymphocyte (CTL) response is temporally associated with the decline in viremia during primary HIV-1 infection, but definitive evidence that it is of importance in virus containment has been lacking. Here we show that in a patient whose early CTL response was focused on a highly immunodominant epitope in gp 160, there was rapid elimination of the transmitted virus strain and selection for a virus population bearing amino acid changes at a single residue within this epitope, which conferred escape from recognition by epitope-specific CTL. The magnitude (> 100-fold), kinetics (30-72 days from onset of symptoms) and genetic pathways of virus escape from CTL pressure were comparable to virus escape from antiretroviral therapy, indicating the biological significance of the CTL response in vivo. One aim of HIV-1 vaccines should thus be to elicit strong CTL responses against multiple codominant viral epitopes.", + "TAG_DATA": [ + "39, patient {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8986738", + "TEXT": "The search for a suitable and reliable animal model for human AIDS that is easy to use on a large scale continues. Here we describe a new condition in mice that closely resembles human AIDS, namely, chronic lymphoproliferation with dramatic depletion of CD4-positive cells, progressive impairment of the immune responses, and Kaposi's sarcoma-like tumors or terminal B-lymphomas. The AIDS-like disease was primarily induced by mating BALB/c female mice to C57BL/6 males during a 1-year period (7-10 allogeneic pregnancies) followed by immunization with paternal lymphocytes. The disease is sexually and vertically transmissible, transferrable by cell-free plasma and is associated with autoimmune reactions to major histocompatibility complex antigens and CD4 cells. We hope that this becomes a model for studying the mechanisms of AIDS immunopathogenesis and immune-based treatment approaches.", + "TAG_DATA": [ + "65, BALB/c {'context': 'B-organism'}", + "66, female {'context': 'I-organism'}", + "67, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "65, BALB/c ['l0', 'l1']", + "66, female ['l0', 'l2']", + "67, mice ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8986737", + "TEXT": "A major safety concern of using live-attenuated vaccine strategies against AIDS is the potential exposure of neonates or fetuses to vaccine virus from the mother. Here we report that high viral loads and disease were observed in only 2 of 18 neonatal monkeys infected with gene-deleted vaccine strains of simian immunodeficiency virus. Pathogenicity was restricted to neonates born to unvaccinated mothers, that is, lacking maternal immunity, and that received extremely high doses of vaccine virus orally. No in utero transmission of vaccine virus was observed in four neonates born to mothers vaccinated during the second trimester. Our results suggest that the live attenuated vaccine approach should remain a viable option for preventing HIV infection and disease in high-risk human populations.", + "TAG_DATA": [ + "41, neonatal {'context': 'B-organism'}", + "42, monkeys {'context': 'I-organism'}", + "45, gene-deleted {'perturbing_action': 'B-gene loss-of-function'}", + "56, neonates {'context': 'B-organism'}", + "77, in {'context': 'B-in vivo'}", + "78, utero {'context': 'B-in vivo'}", + "87, neonates {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "41, neonatal ['l0']", + "42, monkeys ['l0']", + "45, gene-deleted ['l1']", + "56, neonates ['l1']", + "77, in ['l2', 'l3']", + "78, utero ['l2', 'l4']", + "87, neonates ['l3', 'l4']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "gene-deleted" + ] + }, + "context": { + "val": "organism", + "words": [ + "neonates" + ] + } + } + ] + }, + { + "PMID": "8946842", + "TEXT": "The control of cell proliferation is of central importance to the proper development of a multicellular organism, the homeostatic maintenance of tissues, and the ability of certain cell types to respond appropriately to environmental cues. Disruption of normal cell growth control underlies many pathological conditions, including endothelial proliferative disorders in cardiovascular disease as well as the development of malignant tumors. Particularly critical for the control of cell growth is the pathway involving the G1 cyclin-dependent kinases that regulate the Rb family of proteins, which in turn control E2F transcription factor activity. Because E2F is critical for regulation of cell proliferation, we sought to identify and to develop specific inhibitors of E2F function that might also be useful in the control of cellular proliferation. Moreover, because the control of E2F activity appears to be the end result of G1 regulatory cascades, the ability to inhibit E2F may be particularly effective in impeding a wide variety of proliferative events. We have used in vitro selection to isolate several unique RNA species from high complexity RNA libraries that avidly bind to the E2F family of proteins. These RNAs also inhibit the DNA binding capacity of the E2F proteins. We also show that an E2F RNA ligand can block the induction of S phase in quiescent cells stimulated by serum addition. As such, these data demonstrate the critical role for E2F activity in cell proliferation and suggest that such RNA molecules may be effective as therapeutic entities to control cellular proliferation.", + "TAG_DATA": [ + "160, in {'context': 'B-in vitro'}", + "161, vitro {'context': 'I-in vitro'}", + "204, block {'effect': 'B-negative'}", + "206, induction {'effect': 'B-positive'}", + "208, S {'phenotype': 'I-cell cycle arrest'}", + "209, phase {'phenotype': 'I-cell cycle arrest'}", + "211, quiescent {'context': 'B-cells', 'phenotype': 'B-quiescence'}", + "212, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "160, in ['l0']", + "161, vitro ['l0']", + "204, block ['l1', 'l2', 'l3', 'l4', 'l5']", + "206, induction ['l1', 'l6', 'l7', 'l8', 'l9']", + "208, S ['l2', 'l6', 'l10', 'l11', 'l12']", + "209, phase ['l3', 'l7', 'l10', 'l13', 'l14']", + "211, quiescent ['l4', 'l8', 'l11', 'l13', 'l15']", + "212, cells ['l5', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "block" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "S", + "phase" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "block" + ] + }, + "context": { + "val": "cells", + "words": [ + "quiescent", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "block" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescent" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "quiescent" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescent" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "S", + "phase" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "context": { + "val": "cells", + "words": [ + "quiescent", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescent" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "S", + "phase" + ] + }, + "context": { + "val": "cells", + "words": [ + "quiescent", + "cells" + ] + } + } + ] + }, + { + "PMID": "8946841", + "TEXT": "Pyridostigmine, a carbamate acetylcholinesterase (AChE) inhibitor, is routinely employed in the treatment of the autoimmune disease myasthenia gravis. Pyridostigmine is also recommended by most Western armies for use as pretreatment under threat of chemical warfare, because of its protective effect against organophosphate poisoning. Because of this drug's quaternary ammonium group, which prevents its penetration through the blood-brain barrier, the symptoms associated with its routine use primarily reflect perturbations in peripheral nervous system functions. Unexpectedly, under a similar regimen, pyridostigmine administration during the Persian Gulf War resulted in a greater than threefold increase in the frequency of reported central nervous system symptoms. This increase was not due to enhanced absorption (or decreased elimination) of the drug, because the inhibition efficacy of serum butyryl-cholinesterase was not modified. Because previous animal studies have shown stress-induced disruption of the blood-brain barrier, an alternative possibility was that the stress situation associated with war allowed pyridostigmine penetration into the brain. Here we report that after mice were subjected to a forced swim protocol (shown previously to simulate stress), an increase in blood-brain barrier permeability reduced the pyridostigmine dose required to inhibit mouse brain AChE activity by 50% to less than 1/100th of the usual dose. Under these conditions, peripherally administered pyridostigmine increased the brain levels of c-fos oncogene and AChE mRNAs. Moreover, in vitro exposure to pyridostigmine increased both electrical excitability and c-fos mRNA levels in brain slices, demonstrating that the observed changes could be directly induced by pyridostigmine. These findings suggest that peripherally acting drugs administered under stress may reach the brain and affect centrally controlled functions.", + "TAG_DATA": [ + "159, mice {'context': 'B-organism'}", + "185, mouse {'context': 'B-tissue/organ'}", + "186, brain {'context': 'I-tissue/organ'}", + "216, in {'context': 'B-in vitro'}", + "217, vitro {'context': 'I-in vitro'}", + "230, brain {'context': 'B-tissue/organ'}", + "231, slices, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "159, mice ['l0', 'l1']", + "185, mouse ['l0', 'l2']", + "186, brain ['l1', 'l2']", + "216, in ['l3', 'l4', 'l5']", + "217, vitro ['l3', 'l6', 'l7']", + "230, brain ['l4', 'l6', 'l8']", + "231, slices, ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8946834", + "TEXT": "In nonobese diabetic (NOD) mice, beta-cell reactive T-helper type 1 (Th1) responses develop spontaneously and gradually spread, creating a cascade of responses that ultimately destroys the beta-cells. The diversity of the autoreactive T-cell repertoire creates a major obstacle to the development of therapeutics. We show that even in the presence of established Th1 responses, it is possible to induce autoantigen-specific anti-inflammatory Th2 responses. Immune deviation of T-cell responses to the beta-cell autoantigen glutamate decarboxylase (GAD65), induced an active form of self-tolerance that was associated with an inhibition of disease progression in prediabetic mice and prolonged survival of syngeneic islet grafts in diabetic NOD mice. Thus, modulation of autoantigen-specific Th1/Th2 balances may provide a minimally invasive means of downregulating established pathogenic autoimmune responses.", + "TAG_DATA": [ + "86, inhibition {'effect': 'B-negative'}", + "88, disease {'phenotype': 'B-tumour progression'}", + "89, progression {'phenotype': 'I-tumour progression'}", + "91, prediabetic {'context': 'B-organism'}", + "92, mice {'context': 'I-organism'}", + "97, syngeneic {'context': 'B-xenograft'}", + "98, islet {'context': 'I-xenograft'}", + "99, grafts {'context': 'I-xenograft'}", + "101, diabetic {'context': 'B-organism'}", + "102, NOD {'context': 'I-organism'}", + "103, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "86, inhibition ['l0', 'l1', 'l2', 'l3']", + "88, disease ['l0', 'l4', 'l5', 'l6']", + "89, progression ['l1', 'l4', 'l7', 'l8']", + "91, prediabetic ['l2', 'l5', 'l7', 'l9']", + "92, mice ['l3', 'l6', 'l8', 'l9']", + "97, syngeneic ['l10', 'l11', 'l12', 'l13', 'l14']", + "98, islet ['l10', 'l15', 'l16', 'l17', 'l18']", + "99, grafts ['l11', 'l15', 'l19', 'l20', 'l21']", + "101, diabetic ['l12', 'l16', 'l19', 'l22', 'l23']", + "102, NOD ['l13', 'l17', 'l20', 'l22', 'l24']", + "103, mice. ['l14', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "disease", + "progression" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "prediabetic", + "mice" + ] + } + }, + { + "phenotype": { + "val": "tumour progression", + "words": [ + "disease", + "progression" + ] + }, + "context": { + "val": "organism", + "words": [ + "prediabetic", + "mice" + ] + } + } + ] + }, + { + "PMID": "8946830", + "TEXT": "The Dunning rat prostatic carcinoma is a model system where cell motility closely correlates with the metastatic phenotype. We have identified a novel gene, upregulated in the highly motile and metastatic Dunning cancer cell lines, that represents a new member of the thymosin-beta family, thymosin beta 15. Transfection of antisense thymosin beta 15 constructs into rat prostatic carcinoma cells demonstrates that this molecule positively regulates cell motility, a critical component of the metastatic pathway. Thymosin beta 15 levels are elevated in human prostate cancer and correlate positively with the Gleason tumor grade. Thymosin beta 15 may represent a potential new biochemical marker for human prostate cancer progression.", + "TAG_DATA": [ + "47, Transfection {'perturbing_action': 'B-gene gain-of-function'}", + "48, of {'perturbing_action': 'I-rnai/knockdown'}", + "49, antisense {'perturbing_action': 'I-rnai/knockdown'}", + "50, thymosin {'perturbing_action': 'I-rnai/knockdown'}", + "51, beta {'perturbing_action': 'I-rnai/knockdown'}", + "52, 15 {'perturbing_action': 'I-rnai/knockdown'}", + "53, constructs {'perturbing_action': 'I-rnai/knockdown'}", + "55, rat {'context': 'B-transformed cells'}", + "56, prostatic {'context': 'I-transformed cells'}", + "57, carcinoma {'context': 'I-transformed cells'}", + "58, cells {'context': 'I-transformed cells'}", + "65, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "47, Transfection ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "48, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "49, antisense ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "50, thymosin ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "51, beta ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "52, 15 ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "53, constructs ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "55, rat ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "56, prostatic ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "57, carcinoma ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "58, cells ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "65, cell ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transfection" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "rat", + "prostatic", + "carcinoma", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transfection" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "antisense", + "thymosin", + "beta", + "15", + "constructs" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "rat", + "prostatic", + "carcinoma", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "antisense", + "thymosin", + "beta", + "15", + "constructs" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + } + ] + }, + { + "PMID": "8946829", + "TEXT": "The retinoblastoma gene (RB) is the prototypic tumor suppressor. Studies to date have demonstrated cancer suppression with tumor cells reconstituted with RB ex vivo and implanted into immunodeficient mice, as well as with germline transmission of a human RB transgene into tumor-prone Rb +/- mice. To mimic the therapy of cancer more closely, spontaneous pituitary melanotroph tumors arising in immunocompetent Rb +/- mice were treated with a recombinant adenovirus carrying RB cDNA. Intratumoral RB gene transfer decreased tumor cell proliferation, reestablished innervation by growth-regulatory dopaminergic neurons, inhibited the growth of tumors, and prolonged the life spans of treated animals.", + "TAG_DATA": [ + "42, Rb {'perturbing_action': 'B-gene loss-of-function'}", + "43, +/- {'perturbing_action': 'B-gene loss-of-function'}", + "44, mice. {'context': 'B-organism'}", + "54, pituitary {'context': 'B-neoplasm'}", + "55, melanotroph {'context': 'I-neoplasm', 'phenotype': 'I-tumourigenesis'}", + "56, tumors {'context': 'I-neoplasm'}", + "59, immunocompetent {'context': 'B-organism'}", + "60, Rb {'context': 'I-organism'}", + "61, +/- {'context': 'I-organism'}", + "62, mice {'context': 'I-organism'}", + "68, adenovirus {'perturbing_action': 'I-gene gain-of-function'}", + "69, carrying {'perturbing_action': 'I-gene gain-of-function'}", + "73, RB {'perturbing_action': 'I-gene gain-of-function'}", + "74, gene {'perturbing_action': 'I-gene gain-of-function'}", + "75, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "76, decreased {'effect': 'B-negative'}", + "77, tumor {'context': 'B-transformed cells'}", + "78, cell {'context': 'I-transformed cells'}", + "79, proliferation, {'phenotype': 'B-proliferation'}", + "83, growth-regulatory {'context': 'B-cells'}", + "84, dopaminergic {'context': 'I-cells'}", + "85, neurons, {'context': 'I-cells'}", + "86, inhibited {'effect': 'B-negative'}", + "90, tumors, {'context': 'B-neoplasm'}", + "98, animals. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "42, Rb ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "43, +/- ['l0', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "44, mice. ['l1', 'l18', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "54, pituitary ['l2', 'l19', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "55, melanotroph ['l3', 'l20', 'l34', 'l42', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "56, tumors ['l4', 'l21', 'l35', 'l43', 'l57', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "59, immunocompetent ['l5', 'l22', 'l36', 'l44', 'l58', 'l73', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "60, Rb ['l6', 'l23', 'l37', 'l45', 'l59', 'l74', 'l86', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "61, +/- ['l7', 'l24', 'l38', 'l46', 'l60', 'l75', 'l87', 'l102', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "62, mice ['l8', 'l25', 'l39', 'l47', 'l61', 'l76', 'l88', 'l103', 'l117', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "68, adenovirus ['l62', 'l89', 'l104', 'l118', 'l131', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "69, carrying ['l63', 'l90', 'l105', 'l119', 'l141', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "71, cDNA. ['l91', 'l106', 'l120', 'l142', 'l156', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "73, RB ['l143', 'l157', 'l170', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "74, gene ['l144', 'l158', 'l171', 'l183', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205']", + "75, transfer ['l92', 'l107', 'l121', 'l145', 'l159', 'l172', 'l184', 'l195', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215']", + "76, decreased ['l9', 'l26', 'l48', 'l64', 'l77', 'l93', 'l108', 'l122', 'l132', 'l146', 'l160', 'l173', 'l185', 'l196', 'l206', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223']", + "77, tumor ['l10', 'l27', 'l49', 'l65', 'l78', 'l94', 'l109', 'l123', 'l133', 'l147', 'l161', 'l174', 'l186', 'l197', 'l207', 'l216', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230']", + "78, cell ['l11', 'l28', 'l40', 'l50', 'l66', 'l79', 'l95', 'l110', 'l124', 'l134', 'l148', 'l162', 'l175', 'l187', 'l198', 'l208', 'l217', 'l224', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236']", + "79, proliferation, ['l12', 'l29', 'l41', 'l51', 'l67', 'l80', 'l96', 'l111', 'l125', 'l135', 'l149', 'l163', 'l176', 'l188', 'l199', 'l209', 'l218', 'l225', 'l231', 'l237', 'l238', 'l239', 'l240', 'l241']", + "83, growth-regulatory ['l13', 'l52', 'l68', 'l81', 'l97', 'l112', 'l126', 'l136', 'l150', 'l164', 'l177', 'l189', 'l200', 'l210', 'l219', 'l226', 'l232', 'l237', 'l242', 'l243', 'l244', 'l245', 'l246']", + "84, dopaminergic ['l14', 'l30', 'l53', 'l69', 'l82', 'l98', 'l113', 'l127', 'l137', 'l151', 'l165', 'l178', 'l190', 'l201', 'l211', 'l220', 'l227', 'l233', 'l238', 'l242', 'l247', 'l248', 'l249', 'l250']", + "85, neurons, ['l15', 'l31', 'l54', 'l70', 'l83', 'l99', 'l114', 'l128', 'l138', 'l152', 'l166', 'l179', 'l191', 'l202', 'l212', 'l221', 'l228', 'l234', 'l239', 'l243', 'l247', 'l251', 'l252', 'l253']", + "86, inhibited ['l16', 'l55', 'l71', 'l84', 'l100', 'l115', 'l129', 'l139', 'l153', 'l167', 'l180', 'l192', 'l203', 'l213', 'l222', 'l229', 'l235', 'l240', 'l244', 'l248', 'l251', 'l254', 'l255']", + "90, tumors, ['l17', 'l32', 'l56', 'l72', 'l85', 'l101', 'l116', 'l130', 'l140', 'l154', 'l168', 'l181', 'l193', 'l204', 'l214', 'l223', 'l230', 'l236', 'l241', 'l245', 'l249', 'l252', 'l254']", + "98, animals. ['l155', 'l169', 'l182', 'l194', 'l205', 'l215', 'l246', 'l250', 'l253', 'l255']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rb", + "+/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "immunocompetent", + "Rb", + "+/-", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rb", + "+/-" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "pituitary", + "melanotroph", + "tumors", + "tumors," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rb", + "+/-" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "melanotroph" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "melanotroph", + "pituitary" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "melanotroph" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rb", + "+/-" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased", + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rb", + "+/-" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rb", + "+/-" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rb", + "+/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "growth-regulatory", + "dopaminergic", + "neurons," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice.", + "immunocompetent", + "Rb", + "+/-", + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "melanotroph" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice.", + "immunocompetent", + "Rb", + "+/-", + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "pituitary", + "melanotroph", + "tumors", + "tumors," + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased", + "inhibited" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "pituitary", + "melanotroph", + "tumors", + "tumors," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "melanotroph", + "tumors," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "carrying", + "RB", + "gene", + "transfer" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "melanotroph" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "carrying" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "melanotroph" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased", + "inhibited" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "melanotroph" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "melanotroph" + ] + }, + "context": { + "val": "cells", + "words": [ + "growth-regulatory", + "dopaminergic", + "neurons," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "immunocompetent", + "Rb", + "+/-", + "mice", + "animals." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "carrying", + "transfer", + "RB", + "gene" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "immunocompetent", + "Rb", + "+/-", + "mice", + "animals." + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased", + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "carrying", + "RB", + "gene", + "transfer" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased", + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "carrying", + "RB", + "gene", + "transfer" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "carrying", + "RB", + "gene", + "transfer" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "carrying", + "RB", + "gene", + "transfer" + ] + }, + "context": { + "val": "cells", + "words": [ + "growth-regulatory", + "dopaminergic", + "neurons," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased", + "inhibited" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased", + "inhibited" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased", + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "growth-regulatory", + "dopaminergic", + "neurons," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "context": { + "val": "cells", + "words": [ + "growth-regulatory", + "dopaminergic", + "neurons," + ] + } + } + ] + }, + { + "PMID": "8898753", + "TEXT": "The ability of CD8 T cells derived from human immunodeficiency virus (HIV)-infected patients to produce soluble HIV-suppressive factor(s) (HIV-SF) has been suggested as an important mechanism of control of HIV infection in vivo. The C-C chemokines RANTES, MIP-1 alpha and MIP-1 beta were recently identified as the major components of the HIV-SF produced by both immortalized and primary patient CD8 T cells. Whereas they potently inhibit infection by primary and macrophage-tropic HIV-1 isolates, T-cell line-adapted viral strains tend to be insensitive to their suppressive effects. Consistent with this discrepancy, two distinct chemokine receptors, namely, CXCR4 (ref. 7) and CCR5 (ref. 8), were recently identified as potential co-receptors for T-cell line-adapted and macrophage-tropic HIV-1 isolates, respectively. Here, we demonstrate that the third hypervariable domain of the gp 120 envelope glycoprotein is a critical determinant of the susceptibility of HIV-1 to chemokines. Moreover, we show that RANTES, MIP-1 alpha and MIP-1 beta block the entry of HIV-1 into cells and that their antiviral activity is independent of pertussis toxin-sensitive signal transduction pathways mediated by chemokine receptors. The ability of the chemokines to block the early steps of HIV infection could be exploited to develop novel therapeutic approaches for AIDS.", + "TAG_DATA": [ + "156, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8837612", + "TEXT": "Cocaine abuse is a major medical and public health concern in the United States, with approximately 2.1 million people dependent on cocaine. Pharmacological approaches to the treatment of cocaine addiction have thus far been disappointing, and new therapies are urgently needed. This paper describes an immunological approach to cocaine addiction. Antibody therapy for neutralization of abused drugs has been described previously, including a recent paper demonstrating the induction of anti-cocaine antibodies. However, both the rapidity of entry of cocaine into the brain and the high doses of cocaine frequently encountered have created challenges for an antibody-based therapy. Here we demonstrate that antibodies are efficacious in an animal model of addiction. Intravenous cocaine self-administration in rats was inhibited by passive transfer of an anti-cocaine monoclonal antibody. To actively induce anti-cocaine antibodies, a cocaine vaccine was developed that generated a high-titer, long-lasting antibody response in mice. Immunized mice displayed a significant change in cocaine pharmacokinetics, with decreased levels of cocaine measured in the brain of immunized mice only 30 seconds after intravenous (i.v.) administration of cocaine. These data establish the feasibility of a therapeutic cocaine vaccine for the treatment of cocaine addiction.", + "TAG_DATA": [ + "114, rats {'context': 'B-organism'}", + "116, inhibited {'effect': 'B-negative'}", + "143, mice. {'context': 'B-organism'}", + "145, mice {'context': 'B-organism'}", + "164, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "114, rats ['l0']", + "116, inhibited ['l0']", + "145, mice ['l1']", + "164, mice ['l1']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "rats" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + } + ] + }, + { + "PMID": "8837611", + "TEXT": "Delivery of antigen in a manner that induces effective, antigen-specific immunity is a critical challenge in vaccine design. Optimal antigen presentation is mediated by professional antigen-presenting cells (APCs) capable of taking up, processing and presenting antigen to T cells in the context of costimulatory signals required for T-cell activation. Developing immunization strategies to optimize antigen presentation by dendritic cells, the most potent APCs, is a rational approach to vaccine design. Here we show that cutaneous genetic immunization with naked DNA results in potent, antigen-specific, cytotoxic T lymphocyte-mediated protective tumor immunity. This method of immunization results in the transfection of skin-derived dendritic cells, which localize in the draining lymph nodes. These observations provide a basis for further development of DNA-based vaccines and demonstrate the feasibility of genetically engineering dendritic cells in vivo.", + "TAG_DATA": [ + "99, skin-derived {'context': 'B-cells'}", + "100, dendritic {'context': 'I-cells'}", + "101, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "99, skin-derived ['l0', 'l1', 'l2']", + "100, dendritic ['l0', 'l3', 'l4']", + "101, cells, ['l1', 'l3', 'l5']", + "108, nodes. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8837608", + "TEXT": "It is widely believed that the hepatitis B virus (HBV) is completely cleared by antiviral antibodies and specific cytotoxic T lymphocytes (CTLs) during acute viral hepatitis. We now demonstrate that traces of HBV are often detectable in the blood for many years after clinical recovery from acute hepatitis, despite the presence of serum antibodies and HBV-specific CTLs, which can be present at acute-stage levels. The strength of the CTL response to HBV following clinical recovery correlates with persistence of HBV DNA. It is of particular interest that HBV-specific CTLs from patients studied up to 23 years after clinical and serological recovery expressed activation markers (HLA-DR, CD69) indicating recent contact with antigen. These results suggest that sterilizing immunity to HBV frequently fails to occur after recovery from acute hepatitis and that traces of virus can maintain the CTL response for decades following clinical recovery, apparently creating a negative feedback loop that keeps the virus under control, perhaps for life.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8782465", + "TEXT": "Idiotypic determinants of the immunoglobulin expressed on the surface of B-cell lymphomas are tumor-specific antigens (TSAs), which can be targeted by immunotherapy. Immunization with DNA constructs encoding the idiotype (ld) of a murine B-cell lymphoma induced specific anti-ld antibody responses and protected mice against tumor challenge. Use of DNA encoding an ld/GM-CSF (idiotype/granulocyte-macrophage colony-stimulating factor) fusion protein improved vaccine efficacy, and xenogeneic immunoglobulin constant region determinants were required for immunogenicity. These results indicate that DNA may be a simple and efficacious means of inducing immune responses against a weak, otherwise unrecognized tumor antigen, provided that additional stimuli are included with the DNA.", + "TAG_DATA": [ + "32, murine {'context': 'B-neoplasm'}", + "33, B-cell {'context': 'I-neoplasm'}", + "34, lymphoma {'context': 'I-neoplasm'}", + "42, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "32, murine ['l0', 'l1', 'l2']", + "33, B-cell ['l0', 'l3', 'l4']", + "34, lymphoma ['l1', 'l3', 'l5']", + "42, mice ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8782457", + "TEXT": "Chronic intestinal inflammation induced by 2,4,6,-trinitrobenzene sulfonic acid (TNBS) is characterized by a transmural granulomatous colitis that mimics some characteristics of human Crohn's disease. Here, we show that the transcription factor NF-kappa B p65 was strongly activated in TNBS-induced colitis and in colitis of interleukin-10-deficient mice. Local administration of p65 antisense phosphorothioate oligonucleotides abrogated clinical and histological signs of colitis and was more effective in treating TNBS-induced colitis than single or daily administration of glucocorticoids. The data provide direct evidence for the central importance of p65 in chronic intestinal inflammation and suggest a potential therapeutic utility of p65 antisense oligonucleotides as a novel molecular approach for the treatment of patients with Crohn's disease.", + "TAG_DATA": [ + "44, interleukin-10-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "45, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "44, interleukin-10-deficient ['l0']", + "45, mice. ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interleukin-10-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "8782456", + "TEXT": "Localization of activated natural killer (A-NK) cells in the microvasculature of growing tumors is the result of recognition of the intracellular and vascular cell-adhesion molecules ICAM-1 and VCAM-1 on the tumor endothelium, mediated by lymphocyte function-associated protein LFA-1 and vascular lymphocyte function-associated protein VLA-4. In vitro and in vivo studies of A-NK cell adhesion to endothelial cells showed that vascular endothelial growth factor (VEGF) promotes adhesion, whereas basic fibroblast growth factor (bFGF) inhibits adhesion through the regulation of these molecules on tumor vasculature. Thus, some angiogenic factors may facilitate lymphocyte recognition of angiogenic vessels, whereas others may provide such vessels with a mechanism that protects them from cytotoxic lymphocytes.", + "TAG_DATA": [ + "44, In {'context': 'B-in vitro'}", + "45, vitro {'context': 'I-in vitro'}", + "47, in {'context': 'B-in vivo'}", + "48, vivo {'context': 'I-in vivo'}", + "51, A-NK {'context': 'B-cells'}", + "52, cell {'context': 'I-cells'}", + "55, endothelial {'context': 'B-cells'}", + "56, cells {'context': 'I-cells'}", + "64, promotes {'effect': 'B-positive'}", + "65, adhesion, {'phenotype': 'B-adhesion'}", + "72, inhibits {'effect': 'B-negative'}", + "73, adhesion {'phenotype': 'B-adhesion'}" + ], + "LINK_DATA": [ + "44, In ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "45, vitro ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "47, in ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "48, vivo ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "51, A-NK ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "52, cell ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "55, endothelial ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "56, cells ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "64, promotes ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "65, adhesion, ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "72, inhibits ['l45']", + "73, adhesion ['l45']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "A-NK", + "cell", + "endothelial", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "A-NK", + "cell", + "endothelial", + "cells" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + } + ] + }, + { + "PMID": "8782454", + "TEXT": "We present a system for cancer targeting based on single-chain Fv (scFv) antibodies selected from combinatorial libraries, produced in bacteria and purified by using an engineered tag. Combinatorial libraries of scFv genes contain great diversity, and scFv antibodies with characteristics optimized for a particular task can be selected from them using filamentous bacteriophage. We illustrate the benefits of this system by imaging patients with carcinoembryonic antigen (CEA)-producing cancers using an iodine-123 labeled scFv anti-CEA selected for high affinity. All known tumor deposits were located, and advantages over current imaging technology are illustrated. ScFvs are produced in a cloned form and can be readily engineered to have localizing and therapeutic functions that will be applicable in cancer and other diseases.", + "TAG_DATA": [ + "62, patients {'context': 'B-patient'}", + "64, carcinoembryonic {'context': 'B-neoplasm'}", + "67, cancers {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "62, patients ['l0', 'l1', 'l2', 'l3']", + "64, carcinoembryonic ['l0', 'l4', 'l5', 'l6']", + "65, antigen ['l1', 'l4', 'l7', 'l8']", + "66, (CEA)-producing ['l2', 'l5', 'l7', 'l9']", + "67, cancers ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8705857", + "TEXT": "Safety concerns about introducing genetically engineered cells into the body have prevented their use in medical treatments. To solve this problem, we prepared polymeric membrane artificial cells (semipermeable microcapsules) containing genetically engineered live cells from the bacteria Escherichia coli DH5. When given orally, the cells remain at all times in the microcapsules and are finally excreted in the stool. During their passage through the intestine, small molecules like urea diffuse rapidly into the microcapsules and are acted on by the genetically engineered cells. This lowers the high plasma urea level to normal in uremic rats with induced kidney failure, and has exciting implications for the use of this and many other types of genetically engineered cells in a number of medical applications.", + "TAG_DATA": [ + "32, live {'context': 'I-cells'}", + "33, cells {'context': 'I-cells'}", + "44, cells {'context': 'B-cells'}", + "94, rats {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "24, membrane ['l0', 'l1', 'l2', 'l3', 'l4']", + "25, artificial ['l0', 'l5', 'l6', 'l7', 'l8']", + "26, cells ['l1', 'l5', 'l9', 'l10', 'l11']", + "32, live ['l2', 'l6', 'l9', 'l12', 'l13']", + "33, cells ['l3', 'l7', 'l10', 'l12', 'l14']", + "44, cells ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8705855", + "TEXT": "Alzheimer's disease (AD) is characterized by the presence of numerous neurons with neurofibrillary tangles of paired helical filaments (PHFs). The microtubule-associated protein tau in abnormally hyperphosphorylated form is the major protein subunit of the PHF. We now show that PHF tangles isolated from AD brains are glycosylated, whereas no glycan is detected in normal tau. Deglycosylation of PHF tangles by endoglycosidase F/N-glycosidase F converts them into bundles of straight filaments 2.5 +/- 0.5 nm in diameter, similar to those generated by the interaction of normal tau and abnormally hyperphosphorylated tau (AD P-tau). Deglycosylation plus dephosphorylation, but not deglycosylation alone, of AD P-tau and tau from PHF tangles restores their microtubule polymerization activity. Dephosphorylation of deglycosylated PHF tangles results in increased tau release. Thus, although the abnormal phosphorylation might promote aggregation of tau and inhibition of the assembly of microtubules, glycosylation appears to be responsible for the maintenance of the PHF structure.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8673931", + "TEXT": "The ability to activate biological macromolecules remotely, at specific locations and times, will allow the manipulation of a wide range of cellular activities and give rise to many practical applications. Interest has been shown in the theoretical possibility of accomplishing this by means of photochemical approaches. Photochemical changes of the guest-binding cavity of cyclodextrins has been suggested; however, these changes require organic solvent. What is needed is a widely and readily applicable method allowing activation under physiological conditions. We have developed such a method. This is based on our demonstration that relatively large amounts of the a-methyl substituted 2-nitrobenzyl alcohol, namely, 1-(2-nitrophenyl)ethanol (NPE) can be coupled to proteins using diphosgene. Previous work involved \"caging\" of small molecules such as ATP (ref. 5-9) and blocking amino acids in peptide synthesis with 2-nitrobenzyl compounds. For large molecules, site-specific reversible inactivation of T4-lysozyme has been reported following introduction of an aspartyl beta-nibenzyl ester into its active site by mutagenesis. In contrast, the present simple procedure allows an existing protein to be deactivated and then, when and where required, reactivated by exposure to ultraviolet-A (UV-A) light. We have employed antibodies as models for both receptors and ligands and have successfully modulated: antibody binding sites for antigen; antigen binding sites for antibody, and antibody Fc binding sites for Protein A.", + "TAG_DATA": [ + "139, T4-lysozyme {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8640565", + "TEXT": "Methamphetamine is a drug that is significantly abused worldwide, Although long-lasting depletion of dopamine and other dopamine nerve terminal markers has been reported in striatum of nonhuman primates receiving very high doses of the psychostimulant, no information is available for humans. We found reduced levels of three dopamine nerve terminal markers (dopamine, tyrosine hydroxylase and the dopamine transporter) in post-mortem striatum (nucleus accumbens, caudate, putamen) of chronic methamphetamine users. However, levels of DOPA decarboxylase and the vesicular monoamine transporter, known to be reduced in Parkinson's disease, were normal. This suggests that chronic exposure to methamphetamine does not cause permanent degeneration of striatal dopamine nerve terminals at the doses used by the young subjects in our study. However, the dopamine reduction might explain some of the dysphoric effects of the drug, whereas the decreased dopamine transporter could provide the basis for dose escalation occurring in some methamphetamine users.", + "TAG_DATA": [ + "101, striatal {'context': 'B-cells'}", + "102, dopamine {'context': 'I-cells'}", + "103, nerve {'context': 'I-cells'}", + "104, terminals {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "101, striatal ['l0', 'l1', 'l2']", + "102, dopamine ['l0', 'l3', 'l4']", + "103, nerve ['l1', 'l3', 'l5']", + "104, terminals ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8640562", + "TEXT": "There is now considerable direct evidence that tumor growth is angiogenesis-dependent. The most compelling evidence is based on the discovery of angiostatin, an angiogenesis inhibitor that selectively instructs endothelium to become refractory to angiogenic stimuli. Angiostatin, which specifically inhibits endothelial proliferation, induced dormancy of metastases defined by a balance of apoptosis and proliferation. We now show that systemic administration of human angiostatin potently inhibits the growth of three human and three murine primary carcinomas in mice. An almost complete inhibition of tumor growth was observed without detectable toxicity or resistance. The human carcinomas regressed to microscopic dormant foci in which tumor cell proliferation was balanced by apoptosis in the presence of blocked angiogenesis. This regression of primary tumors without toxicity has not been previously described. This is also the first demonstration of dormancy therapy, a novel anticancer strategy in which malignant tumors are regressed by prolonged blockade of angiogenesis.", + "TAG_DATA": [ + "68, human {'context': 'B-neoplasm'}", + "69, and {'context': 'I-neoplasm'}", + "71, murine {'context': 'I-neoplasm'}", + "72, primary {'context': 'I-neoplasm'}", + "73, carcinomas {'context': 'I-neoplasm'}", + "75, mice. {'context': 'B-organism'}", + "79, inhibition {'effect': 'B-negative'}", + "81, tumor {'phenotype': 'B-tumour growth'}", + "82, growth {'phenotype': 'I-tumour growth'}", + "91, human {'context': 'B-neoplasm'}", + "92, carcinomas {'context': 'I-neoplasm'}", + "100, tumor {'context': 'B-transformed cells'}", + "101, cell {'context': 'I-transformed cells'}", + "102, proliferation {'phenotype': 'B-proliferation'}", + "106, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "68, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "69, and ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "71, murine ['l1', 'l6', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "72, primary ['l2', 'l7', 'l11', 'l17', 'l18']", + "73, carcinomas ['l3', 'l8', 'l12', 'l17', 'l19']", + "75, mice. ['l4', 'l9', 'l13', 'l18', 'l19', 'l20']", + "79, inhibition ['l14', 'l21', 'l22']", + "81, tumor ['l15', 'l21', 'l23']", + "82, growth ['l5', 'l10', 'l16', 'l20', 'l22', 'l23']", + "91, human ['l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "92, carcinomas ['l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "100, tumor ['l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "101, cell ['l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "102, proliferation ['l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "104, balanced ['l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "106, apoptosis ['l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "human", + "and", + "murine" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth", + "tumor" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "murine" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "human", + "carcinomas" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "human", + "carcinomas" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "8640559", + "TEXT": "Microsatellite (MS) mutations can potentially unravel the past of mutator phenotype tumors, with greater genetic diversity expected in older regions. Rapid clonal expansions of xenografts were characterized by relatively homogenous MS alleles, whereas greater diversity was observed in a colorectal cancer with the greatest variation in its adjacent adenoma. A subcutaneous lung cancer metastasis demonstrated diversity consistent with its one-month clinical duration and evidence of active mitosis during dormancy. The genetic legacy inherent to multistep tumorigenesis provides direct estimates of tumor ages, with up to thousands of cell divisions and high death rates necessary to yield the observed diversities. MS molecular tumor clocks have the unique potential to systematically reconstruct the early and occult evolution of individual human mutator phenotype tumors.", + "TAG_DATA": [ + "50, subcutaneous {'context': 'B-neoplasm'}", + "51, lung {'context': 'I-neoplasm'}", + "52, cancer {'context': 'I-neoplasm'}", + "53, metastasis {'context': 'I-neoplasm', 'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "50, subcutaneous ['l0', 'l1', 'l2']", + "51, lung ['l0', 'l3', 'l4']", + "52, cancer ['l1', 'l3', 'l5']", + "53, metastasis ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "subcutaneous", + "lung", + "cancer" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + } + ] + }, + { + "PMID": "8640558", + "TEXT": "Substantial evidence exists supporting a direct role for raf kinases in the development and maintenance of certain human malignancies. Here we test the potential of phosphorothioate antisense oligodeoxynucleotides targeted against human C-raf-1 kinase to specifically inhibit C-raf-1 kinase gene expression and tumor progression in cell culture and in vivo, using human tumor xenograft mouse models. Treatment of human tumor cells with appropriate phosphorothioate antisense oligodeoxynucleotides led to specific inhibition of C-raf kinase gene expression in cell culture and in vivo at well-tolerated doses. Moreover, oligodeoxynucleotide treatment resulted in potent antiproliferative effects in cell culture and potent antitumor effects in vivo against a variety of tumor types that were highly consistent with an antisense mechanism of action for these compounds. These studies strongly suggest that antisense inhibitors targeted against C-raf-1 kinase may be of considerable value as antineoplastic agents that display activity against a wide spectrum of tumor types at well-tolerated doses.", + "TAG_DATA": [ + "44, cell {'context': 'B-cells'}", + "45, culture {'context': 'I-cells'}", + "47, in {'context': 'B-in vivo'}", + "48, vivo, {'context': 'I-in vivo'}", + "50, human {'context': 'B-xenograft'}", + "51, tumor {'context': 'I-xenograft'}", + "52, xenograft {'context': 'I-xenograft'}", + "53, mouse {'context': 'I-xenograft'}", + "54, models. {'context': 'I-xenograft'}", + "57, human {'context': 'B-transformed cells'}", + "58, tumor {'context': 'I-transformed cells'}", + "59, cells {'context': 'I-transformed cells'}", + "75, cell {'context': 'B-cells'}", + "76, culture {'context': 'I-cells'}", + "78, in {'context': 'B-in vivo'}", + "79, vivo {'context': 'I-in vivo'}", + "92, cell {'context': 'B-cells'}", + "93, culture {'context': 'I-cells'}", + "98, in {'context': 'B-in vivo'}", + "99, vivo {'context': 'I-in vivo'}", + "104, tumor {'context': 'B-neoplasm'}", + "105, types {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "44, cell ['l0']", + "45, culture ['l0']", + "47, in ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "48, vivo, ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "50, human ['l2', 'l7', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "51, tumor ['l3', 'l8', 'l12', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "52, xenograft ['l4', 'l9', 'l13', 'l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "53, mouse ['l5', 'l10', 'l14', 'l22', 'l31', 'l38', 'l39', 'l40']", + "54, models. ['l6', 'l11', 'l15', 'l23', 'l32', 'l38', 'l41', 'l42']", + "57, human ['l24', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "58, tumor ['l25', 'l43', 'l49', 'l50', 'l51', 'l52', 'l53']", + "59, cells ['l16', 'l26', 'l33', 'l44', 'l49', 'l54', 'l55', 'l56', 'l57']", + "75, cell ['l17', 'l27', 'l34', 'l39', 'l41', 'l45', 'l50', 'l54', 'l58', 'l59', 'l60']", + "76, culture ['l18', 'l28', 'l35', 'l40', 'l42', 'l46', 'l51', 'l55', 'l58', 'l61', 'l62']", + "78, in ['l19', 'l29', 'l36', 'l47', 'l52', 'l56', 'l59', 'l61', 'l63']", + "79, vivo ['l20', 'l30', 'l37', 'l48', 'l53', 'l57', 'l60', 'l62', 'l63']", + "92, cell ['l64']", + "93, culture ['l64']", + "98, in ['l65', 'l66', 'l67']", + "99, vivo ['l65', 'l68', 'l69']", + "104, tumor ['l66', 'l68', 'l70']", + "105, types ['l67', 'l69', 'l70']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8640557", + "TEXT": "Naturally pyrazinamide (PZA)-resistant Mycobacterium bovis and acquired PZA-resistant M. tuberculosis strains lose pyrazinamidase (PZase). To investigate the molecular mechanism of PZA resistance, we have cloned the gene (pncA) encoding M. tuberculosis PZase. Mutations in pncA were identified in both types of PZA-resistant strains, and transformation of these strains with a functional pncA gene restored PZase activity and PZA susceptibility. These findings, besides providing the basis for understanding how PZA works, should have implications for rapid detection of PZA-resistant clinical isolates of M. tuberculosis and also for rapid differentiation of M. bovis from M. tuberculosis strains.", + "TAG_DATA": [ + "44, transformation {'perturbing_action': 'B-gene gain-of-function', 'phenotype': 'B-transformation'}", + "48, with {'perturbing_action': 'I-gene gain-of-function'}", + "49, a {'perturbing_action': 'I-gene gain-of-function'}", + "50, functional {'perturbing_action': 'I-gene gain-of-function'}", + "51, pncA {'perturbing_action': 'I-gene gain-of-function'}", + "52, gene {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "44, transformation ['l0', 'l1', 'l2', 'l3', 'l4']", + "48, with ['l0', 'l5', 'l6', 'l7', 'l8']", + "49, a ['l1', 'l5', 'l9', 'l10', 'l11']", + "50, functional ['l2', 'l6', 'l9', 'l12', 'l13']", + "51, pncA ['l3', 'l7', 'l10', 'l12', 'l14']", + "52, gene ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transformation" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + } + } + ] + }, + { + "PMID": "8640554", + "TEXT": "In mammalian cells, genetic instructions are usually revised by RNA splicing before they are translated to proteins. Here we demonstrate that a trans-splicing group I ribozyme can be employed to intentionally modify the sequence of targeted transcripts in tissue culture cells. By analyzing the ribozyme reaction products, we demonstrate that targeted trans-splicing can proceed in murine fibroblasts with high fidelity, providing direct evidence that ribozymes function as anticipated in a therapeutically relevant setting. Trans-splicing is not very specific however, and the ribozyme reacted with and tagged a variety of cellular transcripts with its 3' exon sequence. RNA tagging provides a unique approach to study RNA catalysis in mammalian cells. Such analysis should facilitate the logical development of safe, therapeutic ribozymes that can repair mutant RNAs associated with a variety of inherited diseases.", + "TAG_DATA": [ + "55, murine {'context': 'B-cells'}", + "56, fibroblasts {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "55, murine ['l0']", + "56, fibroblasts ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8640544", + "TEXT": "Predictive diagnosis by molecular methods will change the scientific basis of prognostics. At the same time, it will change the ethical dimensions of the relation among patients, their doctors and other providers of care.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8616722", + "TEXT": "The adipocyte hormone, leptin (OB protein), is proposed to be an \"adiposity signal\" that acts in the brain to lower food intake and adiposity. As plasma leptin levels are elevated in most overweight individuals, obesity may be associated with leptin resistance. To investigate the mechanisms underlying brain leptin uptake and to determine whether reduced uptake may contribute to leptin resistance, we measured immunoreactive leptin levels in plasma and cerebrospinal fluid (CSF) of 53 human subjects. Leptin concentrations in CSF were strongly correlated to the plasma level in a nonlinear manner (r = 0.92; p = 0.0001). Like levels in plasma, CSF leptin levels were correlated to body mass index (r = 0.43; p = 0.001), demonstrating that plasma leptin enters human cerebrospinal fluid in proportion to body adiposity. However, the efficiency of this uptake (measured as the CSF:plasma leptin ratio) was lower among those in the highest as compared with the lowest plasma leptin quintile (5.4-fold difference). We hypothesize that a saturable mechanism mediates CSF leptin transport, and that reduced efficiency of brain leptin delivery among obese individuals with high plasma leptin levels results in apparent leptin resistance.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8616717", + "TEXT": "Cytosine arabinoside (ara-C) is a cytidine analog that incorporates into replicating DNA and induces lethal DNA strand breaks. Although ara-C is a potent antitumor agent for hematologic malignancies, it has only minimal activity against most solid tumors. The rate-limiting step in intracellular ara-C activation is phosphorylation of the prodrug by deoxycytidine kinase (dCK). The present results demonstrate that both retroviral and adenoviral vector-mediated transduction of the dCK cDNA results in marked sensitization of glioma cells lines to the cytotoxic effects of ara-C in vitro. We also demonstrate that ara-C treatment of established intradermal and intracerebral gliomas transduced with dCK results in significant antitumor effects in vivo. These data suggest that viral vector transduction of the dCK gene followed by treatment with ara-C represents a new chemosensitization strategy for cancer gene therapy.", + "TAG_DATA": [ + "59, retroviral {'perturbing_action': 'B-gene gain-of-function'}", + "60, and {'perturbing_action': 'I-gene gain-of-function'}", + "61, adenoviral {'perturbing_action': 'B-gene gain-of-function'}", + "62, vector-mediated {'perturbing_action': 'I-gene gain-of-function'}", + "63, transduction {'perturbing_action': 'I-gene gain-of-function'}", + "64, of {'perturbing_action': 'I-gene gain-of-function'}", + "65, the {'perturbing_action': 'I-gene gain-of-function'}", + "66, dCK {'perturbing_action': 'I-gene gain-of-function'}", + "67, cDNA {'perturbing_action': 'I-gene gain-of-function'}", + "73, glioma {'context': 'B-transformed cells'}", + "74, cells {'context': 'I-transformed cells'}", + "75, lines {'context': 'I-transformed cells'}", + "82, in {'context': 'B-in vitro'}", + "83, vitro. {'context': 'I-in vitro'}", + "92, intradermal {'context': 'B-neoplasm'}", + "93, and {'context': 'I-neoplasm'}", + "94, intracerebral {'context': 'B-neoplasm'}", + "95, gliomas {'context': 'I-neoplasm'}", + "96, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "97, with {'perturbing_action': 'I-gene gain-of-function'}", + "98, dCK {'perturbing_action': 'I-gene gain-of-function'}", + "104, in {'context': 'B-in vivo'}", + "105, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "59, retroviral ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "60, and ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "61, adenoviral ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "62, vector-mediated ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "63, transduction ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "64, of ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "65, the ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "66, dCK ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "67, cDNA ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "73, glioma ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "74, cells ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86']", + "75, lines ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l87', 'l88']", + "82, in ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l87', 'l89']", + "83, vitro. ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l86', 'l88', 'l89']", + "92, intradermal ['l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "93, and ['l90', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "94, intracerebral ['l91', 'l98', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "95, gliomas ['l92', 'l99', 'l105', 'l111', 'l112', 'l113', 'l114', 'l115']", + "96, transduced ['l93', 'l100', 'l106', 'l111', 'l116', 'l117', 'l118', 'l119']", + "97, with ['l94', 'l101', 'l107', 'l112', 'l116', 'l120', 'l121', 'l122']", + "98, dCK ['l95', 'l102', 'l108', 'l113', 'l117', 'l120', 'l123', 'l124']", + "104, in ['l96', 'l103', 'l109', 'l114', 'l118', 'l121', 'l123', 'l125']", + "105, vivo. ['l97', 'l104', 'l110', 'l115', 'l119', 'l122', 'l124', 'l125']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "retroviral", + "and", + "adenoviral", + "vector-mediated", + "transduction", + "of", + "the", + "dCK", + "cDNA" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "glioma", + "cells", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "retroviral", + "and", + "adenoviral", + "vector-mediated", + "transduction", + "of", + "the", + "dCK", + "cDNA" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "intradermal", + "and", + "intracerebral", + "gliomas" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "dCK" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "dCK" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "8616716", + "TEXT": "The bcr-abl oncogene, present in 95% of patients with chronic myelogenous leukemia (CML), has been implicated as the cause of this disease. A compound, designed to inhibit the Abl protein tyrosine kinase, was evaluated for its effects on cells containing the Bcr-Abl fusion protein. Cellular proliferation and tumor formation by Bcr-Abl-expressing cells were specifically inhibited by this compound. In colony-forming assays of peripheral blood or bone marrow from patients with CML, there was a 92-98% decrease in the number of bcr-abl colonies formed but no inhibition of normal colony formation. This compound may be useful in the treatment of bcr-abl-positive leukemias.", + "TAG_DATA": [ + "38, cells {'context': 'B-cells'}", + "45, proliferation {'phenotype': 'B-proliferation'}", + "47, tumor {'phenotype': 'B-tumourigenesis'}", + "48, formation {'phenotype': 'I-tumourigenesis'}", + "50, Bcr-Abl-expressing {'context': 'B-cells'}", + "51, cells {'context': 'I-cells'}", + "54, inhibited {'effect': 'B-negative'}", + "75, decrease {'effect': 'B-negative'}", + "85, inhibition {'effect': 'B-negative'}", + "88, colony {'phenotype': 'B-colony formation'}", + "89, formation. {'phenotype': 'I-colony formation'}" + ], + "LINK_DATA": [ + "38, cells ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "44, Cellular ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "45, proliferation ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "47, tumor ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "48, formation ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "50, Bcr-Abl-expressing ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "51, cells ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "54, inhibited ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "75, decrease ['l28']", + "85, inhibition ['l29', 'l30']", + "88, colony ['l29', 'l31']", + "89, formation. ['l28', 'l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells", + "Bcr-Abl-expressing" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "Bcr-Abl-expressing" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "formation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "Bcr-Abl-expressing" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "formation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decrease", + "inhibition" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "formation.", + "colony" + ] + } + } + ] + }, + { + "PMID": "8597962", + "TEXT": "Biological soft tissues are almost transparent to hard X rays and therefore cannot be investigated without enhancement with a contrast medium, such as iodine. On the other hand, phase-contrast X-ray imaging is sensitive to light elements (1-8). This is because the X-ray phase shift cross section is almost thousand times larger than the X-ray absorption cross section for light elements such as hydrogen, carbon, nitrogen and oxygen (4,5). Hence, phase-contrast X-ray imaging is a promising technique for observing the structure inside biological soft tissues without the need for staining and without serious radiation exposure. We have devised a means of observing biological tissues in three dimensions using a novel X-ray computed tomography (CT) by modifying the phase-contrast technique. To generate appropriate CT input data, we used phase-mapping images obtained using an X-ray interferometer (6) and computer analysis of interference patterns (9). Now, we present a three-dimensional observation result of a nonstained sample of a cancerous rabbit liver, using a synchrotron X-ray source. Phase-contrast X-ray CT was able to clearly differentiate the cancer lesion from the normal tissue. Moreover, fine structures corresponding to cancerous degeneration and fibrous tissues were clearly depicted.", + "TAG_DATA": [ + "154, cancerous {'context': 'B-tissue/organ'}", + "155, rabbit {'context': 'I-tissue/organ'}", + "156, liver, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "154, cancerous ['l0', 'l1']", + "155, rabbit ['l0', 'l2']", + "156, liver, ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8597960", + "TEXT": "Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR). A single recessive mutation, the deletion of phenylalanine 508 (deltaF508), causes severe CF and resides on 70% of mutant chromosomes. Severe CF is also caused by premature stop mutations, which are found on 5% of CF chromosomes. Here we report that two common, disease-associated stop mutations can be suppressed by treating cells with low doses of the aminoglycoside antibiotic G-418. Aminoglycoside treatment resulted in the expression of full-length CFTR and restored its cyclic AMP-activated chloride channel activity. Another aminoglycoside, gentamicin, also promoted the expression of full-length CFTR. These results suggest that treatment with aminoglycosides may provide a means of restoring CFTR function in patients with this class of mutation.", + "TAG_DATA": [ + "68, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8597956", + "TEXT": "Eotaxin is an eosinophil-specific chemoattractant that has been recently identified in rodent models of asthma and host response against tumors. To determine whether a similar molecule might play a role in human inflammatory diseases characterized by eosinophilia, we isolated the human eotaxin gene. We demonstrate that human eotaxin is an early response gene of cytokine-stimulated epithelial and endothelial cells, and is induced in peripheral blood eosinophils by interleukin-3. Eotaxin is directly chemotactic for eosinophils, but not mononuclear cells or neutrophils. Eotaxin messenger RNA accumulates markedly in the lesions of patients with inflammatory bowel disease (ulcerative colitis and Crohn's disease), but not in the lesions of patients with diverticulitis. These results now provide a mechanism involving eotaxin to explain the eosinophil infiltration seen in a variety of human disease; as such, an eotaxin antagonist may be a novel therapy for certain human diseases characterized by tissue eosinophilia.", + "TAG_DATA": [ + "55, epithelial {'context': 'B-cells'}", + "56, and {'context': 'I-cells'}", + "57, endothelial {'context': 'I-cells'}", + "58, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "55, epithelial ['l0', 'l1', 'l2']", + "56, and ['l0', 'l3', 'l4']", + "57, endothelial ['l1', 'l3', 'l5']", + "58, cells, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8597951", + "TEXT": "There are currently no effective therapies for progressive fibrotic diseases. Recent evidence has implicated overproduction of transforming growth factor-beta1 (TGF-beta1) as a major cause of tissue fibrosis. Furthermore, this evidence implies that inhibitors of TGF-beta1 may be clinically useful as antifibrotic agents. The proteoglycan decorin is a known inhibitor of TGF-beta1. In a rat model of glomerulonephritis we have shown that fibrosis is mediated by TGF-beta1. We report here that transfer of decorin cDNA into rat skeletal muscle increases the amount of decorin messenger RNA and protein present in skeletal muscle and decorin present in kidney, where it has a marked therapeutic effect on fibrosis induced by glomerulonephritis. Transfected glomerulonephritic rats showed a significant reduction in levels of glomerular TGF-beta1 mRNA and TGF-beta1 protein, extracellular matrix accumulation and proteinuria. These results demonstrate the potential of gene therapy as a novel treatment for fibrotic diseases caused by TGF-beta1.", + "TAG_DATA": [ + "71, of {'perturbing_action': 'I-gene gain-of-function'}", + "72, decorin {'perturbing_action': 'I-gene gain-of-function'}", + "73, cDNA {'perturbing_action': 'I-gene gain-of-function'}", + "75, rat {'context': 'B-tissue/organ'}", + "76, skeletal {'context': 'I-tissue/organ'}", + "77, muscle {'context': 'I-tissue/organ'}", + "90, muscle {'context': 'I-tissue/organ'}", + "110, rats {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "70, transfer ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "71, of ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "72, decorin ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "73, cDNA ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "75, rat ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "76, skeletal ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "77, muscle ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "89, skeletal ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "90, muscle ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "decorin", + "cDNA" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "skeletal", + "muscle" + ] + } + } + ] + }, + { + "PMID": "8612236", + "TEXT": "Kaposi's sarcoma (KS) is the leading neoplasm of AIDS patients, and HIV infection is known to be a major risk factor for its development. However, KS can occur in the absence of HIV infection and the risk of KS development varies widely even among HIV-infected patients, with homosexual men with AIDS being 20 times more likely to develop KS than AIDS-afflicted children or hemophiliacs. These and other data strongly suggest that a sexually transmitted agent or co-factor may be involved in KS pathogenesis. Recently, DNA sequences corresponding to the genome of a novel member of the herpesvirus family have been identified within AIDS-KS biopsies, and several reports indicate that these sequences are also present in all forms of HIV-negative KS. These and other findings suggest this new agent, referred to as KS-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8), as a candidate for the putative etiologic cofactor. However, the role of this agent in KS remains hotly debated. Further progress in understanding its biology has been severely hampered by the lack of a cell culture system for virus growth. Here we report the development of a system for the lytic growth of this virus in a latently infected B cell line and present the first ultrastructural visualization of the virus. This system will facilitate the detailed study of the molecular biology of viral replication, the testing of antiviral drugs and the development of diagnostic tests for viral infection.", + "TAG_DATA": [ + "198, B {'context': 'B-cells'}", + "199, cell {'context': 'I-cells'}", + "200, line {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "198, B ['l0', 'l1']", + "199, cell ['l0', 'l2']", + "200, line ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8612230", + "TEXT": "Overexpression of the normally imprinted fetal insulin-like growth factor II (IGF2) has been implicated in the pathogenesis of the cancer-predisposing Beckwith-Wiedemann syndrome (BWS). We have detected constitutional relaxation of imprinting of IGF2 in four children with somatic overgrowth who do not show diagnostic features of BWS. Three children showed constitutional abnormalities of H19 methylation. All four children showed nephromegaly and two developed Wilms' tumors. Gene methylation is known to be associated with gene silencing, and three children showed constitutional abnormalities of H19 gene methylation. Disruption of H19 methylation, and concomitant relaxation of IGF2 imprinting, provides another mechanism that can increase IGF2 expression in children with overgrowth. The accumulated data on normal and pathologic IGF2 expression are now sufficient to define an entity, \"IGF2 overgrowth disorder,\" of which BWS may be one extreme manifestation. These findings have broad implications for the characterization of idiopathic overgrowth.", + "TAG_DATA": [ + "62, Wilms' {'phenotype': 'B-tumourigenesis'}", + "63, tumors. {'phenotype': 'I-tumourigenesis'}" + ], + "LINK_DATA": [ + "62, Wilms' ['l0']", + "63, tumors. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8612227", + "TEXT": "Catalytically active thrombin, acting locally, is thought to mediate neointima formation after arterial injury. We constructed an adenovirus vector, AdHV-1.2, containing a complementary DNA for the thrombin inhibitor hirudin. AdHV-1.2 directed the synthesis and secretion of biologically active hirudin from vascular cells in vitro. In vivo gene transfer of hirudin into smooth muscle cells of injured rat carotid arteries resulted in peak secretion of at least 34+/-23 pg hirudin per vessel per 24 hours, and resulted in a significant (P<0.05) 35% reduction in neointima formation. Systemic partial thromboplastin times were not affected by local hirudin expression. These results support the hypothesis that local thrombin activity contributes to neointima formation after arterial injury and suggest that local delivery of a highly specific antithrombin may constitute an effective intervention for arterial proliferative disease.", + "TAG_DATA": [ + "40, vascular {'context': 'B-cells'}", + "41, cells {'context': 'I-cells'}", + "42, in {'context': 'B-in vitro'}", + "43, vitro. {'context': 'I-in vitro'}", + "44, In {'context': 'B-in vivo'}", + "45, vivo {'context': 'I-in vivo'}", + "46, gene {'perturbing_action': 'B-gene gain-of-function'}", + "47, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "48, of {'perturbing_action': 'I-gene gain-of-function'}", + "49, hirudin {'perturbing_action': 'I-gene gain-of-function'}", + "51, smooth {'context': 'B-cells'}", + "52, muscle {'context': 'I-cells'}", + "53, cells {'context': 'I-cells'}", + "56, rat {'context': 'B-tissue/organ'}", + "57, carotid {'context': 'I-tissue/organ'}", + "58, arteries {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "40, vascular ['l0', 'l1', 'l2', 'l3', 'l4']", + "41, cells ['l0', 'l5', 'l6']", + "42, in ['l1', 'l5', 'l7', 'l8']", + "43, vitro. ['l2', 'l6', 'l7', 'l9']", + "44, In ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "45, vivo ['l10', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "46, gene ['l11', 'l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "47, transfer ['l12', 'l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "48, of ['l13', 'l23', 'l32', 'l40', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "49, hirudin ['l14', 'l24', 'l33', 'l41', 'l48', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "51, smooth ['l15', 'l25', 'l34', 'l42', 'l49', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "52, muscle ['l16', 'l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "53, cells ['l3', 'l8', 'l9', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l70', 'l71', 'l72']", + "56, rat ['l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l70', 'l73', 'l74']", + "57, carotid ['l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l73', 'l75']", + "58, arteries ['l4', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "gene", + "transfer", + "of", + "hirudin" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "gene", + "transfer", + "of", + "hirudin" + ] + }, + "context": { + "val": "cells", + "words": [ + "smooth", + "muscle", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "gene", + "transfer", + "of", + "hirudin" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "carotid", + "arteries" + ] + } + } + ] + }, + { + "PMID": "8612226", + "TEXT": "Activation of plasminogen (Plg) has been proposed to play a role in proteolytic degradation of extracellular matrices in tissue remodeling events, including wound healing. However, there has been no definitive proof of involvement of Plg in such processes. We now report that healing of skin wounds is severely impaired in mice made deficient in Plg by targeted gene disruption. The results demonstrate that Plg is required for normal repair of skin wounds in mice and support the assumption that it also plays a central role in other disease processes involving extracellular matrix degradation, such as cancer invasion.", + "TAG_DATA": [ + "44, skin {'context': 'B-neoplasm'}", + "50, mice {'context': 'B-organism'}", + "52, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "53, in {'perturbing_action': 'I-gene loss-of-function'}", + "54, Plg {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "44, skin ['l0']", + "45, wounds ['l0']", + "50, mice ['l1', 'l2', 'l3']", + "52, deficient ['l1', 'l4', 'l5']", + "53, in ['l2', 'l4', 'l6']", + "54, Plg ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Plg" + ] + } + } + ] + }, + { + "PMID": "8574966", + "TEXT": "Infections with the malaria parasite Plasmodium falciparum are characterized by sequestration of erythrocytes infected by mature forms of the parasite. Sequestration seems critical for the survival of the parasite, but may lead to excessive binding in the microvasculature and death of the human host. We report here that a novel electrondense fibrillar structure, containing immunoglobulins M or M and G, is found at the surface of infected erythrocytes that adhere to host cells. In cases of cerebral malaria, fibrillar strands are also seen in the microvasculature at autopsy. Our findings may explain the adhesive mechanism by which malaria-infected erythrocytes cause the vascular obstruction seen in complicated malaria infections.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8574963", + "TEXT": "The OX-40 protein was selectively upregulated on encephalitogenic myelin basic protein (MBP)-specific T cells at the site of inflammation during the onset of experimental autoimmune encephalomyelitis (EAE). An OX-40 immunotoxin was used to target and eliminate MBP-specific T cells within the central nervous system without affecting peripheral T cells. When injected in vivo, the OX-40 immunotoxin bound exclusively to myelin-reactive T cells isolated from the CNS, which resulted in amelioration of EAE. Expression of the human OX-40 antigen was also found in peripheral blood of patients with acute graft-versus-host disease and the synovia of patients with rheumatoid arthritis during active disease. The unique expression of the OX-40 molecule may provide a novel therapeutic strategy for eliminating autoreactive CD4+T cells that does not require prior knowledge of the pathogenic autoantigen.", + "TAG_DATA": [ + "46, peripheral {'context': 'B-cells'}", + "47, T {'context': 'I-cells'}", + "48, cells. {'context': 'I-cells'}", + "51, in {'context': 'B-in vivo'}", + "52, vivo, {'context': 'I-in vivo'}", + "59, myelin-reactive {'context': 'B-cells'}", + "60, T {'context': 'I-cells'}", + "61, cells {'context': 'I-cells'}", + "62, isolated {'context': 'I-cells'}", + "63, from {'context': 'I-cells'}", + "64, the {'context': 'I-cells'}", + "65, CNS, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "46, peripheral ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "47, T ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "48, cells. ['l1', 'l6', 'l12', 'l13']", + "51, in ['l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "52, vivo, ['l2', 'l7', 'l14', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "59, myelin-reactive ['l15', 'l22', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "60, T ['l3', 'l8', 'l12', 'l16', 'l23', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "61, cells ['l4', 'l9', 'l13', 'l17', 'l24', 'l30', 'l35', 'l40', 'l41', 'l42', 'l43']", + "62, isolated ['l10', 'l18', 'l25', 'l31', 'l36', 'l40', 'l44', 'l45', 'l46']", + "63, from ['l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l47', 'l48']", + "64, the ['l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l49']", + "65, CNS, ['l5', 'l11', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l49']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8574955", + "TEXT": "The enzyme, telomerase, may be switched on in tumor cells. Inhibitors of this enzyme might constitute a new class of anti-cancer drugs.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8564848", + "TEXT": "Chronic inflammatory diseases place a heavy social and economic burden on the resources of many nations, but the number of safe and effective treatments is limited. To date, the major research effort has concentrated on those mediators responsible for the initiation and maintenance of the pathological process. In contrast, little attention has been focused on endogenous factors responsible for the resolution of the inflammation. Heme oxygenase ((HO); EC 1.14.99.3) is the rate-limiting enzyme in the catabolism of heme to biliverdin (which is converted to bilirubin by biliverdin reductase), free iron and carbon monoxide (CO). Two isoforms of HO have been characterized, the constitutive isoform, HO-2, which is the major isoform present under physiological conditions, and the stress-induced isoform, HO-1, which has also been classified as heat-shock protein 32K (ref. 1). Increases in HO activity have been implicated in tissue protection against oxidative stress. In this communication, we describe the effects of modulating HO during an acute complement-dependent inflammatory response. Elevation of this enzyme resulted in a striking suppression, whereas inhibition of the enzyme led to a potentiation of the inflammatory response. Such novel enzyme modulation has application on the one hand to the treatment of inflammatory diseases and on the other hand to immnosuppressed states in which the impaired ability to mount an adequate inflammatory response may result in death from opportunistic infections.", + "TAG_DATA": [ + "169, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "170, of {'perturbing_action': 'I-pharmacological inhibition'}", + "171, the {'perturbing_action': 'I-pharmacological inhibition'}", + "172, enzyme {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "169, inhibition ['l0', 'l1', 'l2']", + "170, of ['l0', 'l3', 'l4']", + "171, the ['l1', 'l3', 'l5']", + "172, enzyme ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8564845", + "TEXT": "Fetal grafts of normal cerebellar tissue were implanted into the cerebellum of Purkinje cell degeneration mutant mice (pcd/pcd), a model of adult-onset recessively inherited cerebello-olivary atrophy, in an attempt at correcting their cellular and motor impairment. Donor cerebellar cells engrafted in the appropriate sites, as evidenced by the pattern of expression of insulin-like growth factor-I (IGF-I) system genes. Bilateral cerebellar grafts led to an improvement of motor behaviors in balance rod tests and in the open field, providing evidence for functional integration into the atrophic mouse cerebellum and underscoring the potential of neural transplantation for counteracting the human cerebellar ataxias.", + "TAG_DATA": [ + "10, cerebellum {'context': 'B-tissue/organ'}", + "12, Purkinje {'perturbing_action': 'B-other'}", + "14, degeneration {'perturbing_action': 'I-gene loss-of-function'}", + "15, mutant {'perturbing_action': 'I-gene loss-of-function'}", + "16, mice {'context': 'B-organism'}", + "17, (pcd/pcd), {'perturbing_action': 'I-other'}", + "36, Donor {'context': 'B-cells'}", + "37, cerebellar {'context': 'I-cells'}", + "38, cells {'context': 'I-cells'}", + "60, grafts {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "4, cerebellar ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "5, tissue ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "10, cerebellum ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "12, Purkinje ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "13, cell ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "14, degeneration ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "15, mutant ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "16, mice ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "17, (pcd/pcd), ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "36, Donor ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "37, cerebellar ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "38, cells ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "59, cerebellar ['l66']", + "60, grafts ['l66']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "cerebellum" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Purkinje", + "(pcd/pcd)," + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "cerebellum" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "degeneration", + "mutant" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Purkinje", + "(pcd/pcd)," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Purkinje", + "(pcd/pcd)," + ] + }, + "context": { + "val": "cells", + "words": [ + "Donor", + "cerebellar", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "degeneration", + "mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "degeneration", + "mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "Donor", + "cerebellar", + "cells" + ] + } + } + ] + }, + { + "PMID": "8564835", + "TEXT": "Tissue factor is a transmembrane protein that activates the extrinsic coagulation pathway by binding factor VII. Endothelial cells, being in contact with circulating blood, do not normally express tissue factor. Here we provide evidence that oxygen free radicals induce tissue factor messenger RNA transcription and expression of tissue factor procoagulant activity in endothelial cells in culture. Isolated, perfused rabbit hearts exposed to exogenous oxygen free radicals also showed a marked increase in tissue factor activity within the coronary circulation. Furthermore, in ex vivo and in vivo hearts subjected to ischemia and reperfusion, a condition associated with a production of oxygen free radicals in large amounts, a marked increase in tissue factor activity occurred. This phenomenon could be abolished by oxygen radical scavengers. This increase in tissue factor activity during postischemic reperfusion was accompanied by a significant decrease in coronary flow, suggesting that increase in tissue factor activity with the consequent activation of the coagulation cascade might impair coronary flow during reperfusion and possibly contribute to the occurrence of reperfusion injury.", + "TAG_DATA": [ + "52, endothelial {'context': 'B-cells'}", + "53, cells {'context': 'I-cells'}", + "58, rabbit {'context': 'B-tissue/organ'}", + "59, hearts {'context': 'I-tissue/organ'}", + "84, in {'context': 'B-in vivo'}", + "85, vivo {'context': 'I-in vivo'}", + "86, hearts {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "52, endothelial ['l0', 'l1', 'l2']", + "53, cells ['l0', 'l3', 'l4']", + "58, rabbit ['l1', 'l3', 'l5']", + "59, hearts ['l2', 'l4', 'l5']", + "84, in ['l6', 'l7']", + "85, vivo ['l6', 'l8']", + "86, hearts ['l7', 'l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7489415", + "TEXT": "The regulation of body weight and composition involves input from genes and the environment, demonstrated, for example, by the variable susceptibility of inbred strains of mice to obesity when offered a high-fat diet. The identification of the gene responsible for obesity in the ob/ob mouse provides a new approach to defining links between diet and genetics in the regulation of body weight. The ob gene protein product, leptin, is an adipocyte-derived circulating protein. Administration of recombinant leptin reduces food intake and increases energy expenditure in ob/ob mice, suggesting that it signals to the brain the magnitude of fat stores. Information on the regulation of this protein is limited. In several rodent models of obesity including db/db, fa/fa, yellow (Ay/a) VMH-lesioned, and those induced by gold thioglucose, monosodium glutamate, and transgenic ablation of brown adipose tissue, leptin mRNA expression and the level of circulating leptin are increased, suggesting resistance to one or more of its actions. We have assessed the impact of increased dietary fat on circulating leptin levels in normal FVB mice and FVB mice with transgene-induced ablation of brown adipose tissue. We find that high-fat diet evokes a sustained increase in circulating leptin in both normal and transgenic mice, with leptin levels accurately reflecting the amount of body lipid across a broad range of body fat. However, despite increased leptin levels, animals fed a high-fat diet became obese without decreasing their caloric intake, suggesting that a high content of dietary fat changes the 'set point' for body weight, at least in part by limiting the action of leptin.", + "TAG_DATA": [ + "85, ob/ob {'context': 'B-organism'}", + "86, mice, {'context': 'I-organism'}", + "129, transgenic {'perturbing_action': 'B-gene loss-of-function'}", + "130, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "131, of {'perturbing_action': 'I-gene loss-of-function'}", + "132, brown {'perturbing_action': 'I-gene loss-of-function'}", + "133, adipose {'perturbing_action': 'I-gene loss-of-function'}", + "134, tissue, {'perturbing_action': 'I-gene loss-of-function'}", + "170, FVB {'context': 'B-organism'}", + "171, mice {'context': 'I-organism'}", + "173, FVB {'context': 'B-organism'}", + "174, mice {'context': 'I-organism'}", + "176, transgene-induced {'perturbing_action': 'B-gene loss-of-function'}", + "177, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "178, of {'perturbing_action': 'I-gene loss-of-function'}", + "179, brown {'perturbing_action': 'I-gene loss-of-function'}", + "180, adipose {'perturbing_action': 'I-gene loss-of-function'}", + "181, tissue. {'perturbing_action': 'I-gene loss-of-function'}", + "198, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "199, mice, {'context': 'B-organism'}", + "222, animals {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "85, ob/ob ['l0']", + "86, mice, ['l0']", + "129, transgenic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "130, ablation ['l1', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "131, of ['l2', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "132, brown ['l3', 'l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "133, adipose ['l4', 'l12', 'l19', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37']", + "134, tissue, ['l5', 'l13', 'l20', 'l26', 'l33', 'l38', 'l39', 'l40']", + "170, FVB ['l6', 'l14', 'l21', 'l27', 'l34', 'l38', 'l41', 'l42', 'l43']", + "171, mice ['l7', 'l15', 'l22', 'l28', 'l35', 'l39', 'l41']", + "173, FVB ['l8', 'l16', 'l23', 'l29', 'l36', 'l42', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "174, mice ['l44', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "176, transgene-induced ['l45', 'l52', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "177, ablation ['l46', 'l53', 'l59', 'l66', 'l67', 'l68', 'l69', 'l70']", + "178, of ['l30', 'l47', 'l54', 'l60', 'l66', 'l71', 'l72', 'l73', 'l74']", + "179, brown ['l48', 'l55', 'l61', 'l67', 'l71', 'l75', 'l76', 'l77', 'l78']", + "180, adipose ['l31', 'l49', 'l56', 'l62', 'l68', 'l72', 'l75', 'l79', 'l80', 'l81']", + "181, tissue. ['l9', 'l17', 'l24', 'l32', 'l37', 'l40', 'l43', 'l50', 'l57', 'l63', 'l69', 'l73', 'l76', 'l79', 'l82']", + "198, transgenic ['l64', 'l77', 'l80', 'l83']", + "199, mice, ['l51', 'l58', 'l65', 'l70', 'l74', 'l78', 'l81', 'l82', 'l83']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "transgenic", + "ablation", + "of", + "brown", + "adipose", + "tissue,", + "tissue.", + "transgene-induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "FVB", + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "7489411", + "TEXT": "Several missense mutations causing early-onset Alzheimer's disease (AD) have been described in the gene coding for the beta-amyloid precursor protein (beta APP). A double mutation found in a Swedish family is located before the amyloid beta-peptide (A beta) region of beta APP and results in the increased production and secretion of A beta. Here we show that the increased production of A beta results from a cellular mechanism, which differs substantially from that responsible for the production of A beta from wild-type beta APP. In the latter case, A beta generation requires reinternalization and recycling of beta APP. In the case of the Swedish mutation the N-terminal beta-secretase cleavage of A beta occurs in Golgi-derived vesicles, most likely within secretory vesicles. Therefore, this cleavage occurs in the same compartment as the alpha-secretase cleavage, which normally prevents A beta production, explaining the increased A beta generation by a competition between alpha- and beta-secretase.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "7489406", + "TEXT": "The major obstacle to successful discordant xenotransplantation is the phenomenon of hyperacute rejection (HAR). In the pig-to-primate discordant transplant setting, HAR results from the deposition of high-titre anti-alpha-galactosyl antibodies and complement activation leading to endothelial cell destruction and rapid graft failure. To overcome HAR, we developed an enzymatic carbohydrate remodelling strategy designed to replace expression of the Gal alpha-1,3-Gal xenoepitope on the surface of porcine cells with the non-antigenic universal donor human blood group O antigen, the alpha-1,2-fucosyl lactosamine moiety (H-epitope). Xenogenic cells expressing the human alpha-1,2-fucosyltransferase expressed high levels of the H-epitope and significantly reduced Gal alpha-1,3-Gal expression. As a result, these cells were shown to be resistant to human natural antibody binding and complement-mediated cytolysis.", + "TAG_DATA": [ + "64, porcine {'context': 'B-cells'}", + "65, cells {'context': 'I-cells'}", + "81, Xenogenic {'context': 'B-cells'}", + "82, cells {'context': 'I-cells'}", + "103, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "64, porcine ['l0']", + "65, cells ['l0']", + "81, Xenogenic ['l1']", + "82, cells ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7584985", + "TEXT": "We are using the zebrafish, Danio rerio, to identify genes that generate and pattern the vertebrate vasculature. We have isolated a recessive mutation, gridlockm145 (grlm145) in which blood flow to the tail is impeded by a localized vascular defect. Using a novel microangiographic method, we show that the blockade is in the anterior trunk, where the paired lateral dorsal aortae normally merge to form the single midline aorta. Arterial-venous shunts and collateral vessels develop in most mutant embryos, bypassing the lesion and reconstituting caudal blood flow. The grl defect resembles coarctation of the aorta, a human congenital cardiovascular malformation of unknown aetiology, in the location of the lesion and its consequences and in the mutants' dependence on collateral vessels for survival.", + "TAG_DATA": [ + "77, embryos, {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "7584980", + "TEXT": "Internalization of targeted therapeutics is often needed for efficacy, but also alters drug penetration of a tissue. A new model explores the trade-offs of intracellular drug trafficking.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "7584977", + "TEXT": "We now have a number of effective drugs for osteoporosis. However, close inspection of clinical trials results suggests we should aim for even better ones.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "7489381", + "TEXT": "PIP: The syndrome known as AIDS is eventually brought on after initial infection with HIV. Infection with either HIV-1 or HIV-2 will lead to AIDS. However, different strains of HIV-1 have been found to exist, varying between continents. The strains, or clades, vary quite significantly in their surface antigens and genetic sequences. HIV-1 subtype B, the initial causative virus of AIDS in Western industrialized countries, is reproducibly different from subtypes C and E, respectively found in sub-Saharan Africa and northwestern Thailand. Each subtype provokes divergent host immune responses substantial enough to affect the course of vaccine development. There are currently two HIV/AIDS epidemics in Thailand, one spawned from the initial outbreak of HIV-1 subtype B in 1988 among IV drug users in Bangkok, and the other involving subtype E in and around Chiang Mai. Max Essex and his group have reported recent data which suggest that HIV-1 subtype E may be capable of more efficient spread than subtype B during vaginal intercourse. Both subtypes were found to replicate in almost the same manner in cells of lymphoid origin. Subtype E, however, thrives in vitro among Langerhans cells from either vaginal mucosa or penile foreskin, while subtype B replicates only sluggishly at best. Infection of the Langerhans cells could not be blocked by soluble CD4, reflecting a differential preference of subtype E for another, as yet unidentified, receptor. Clade E could be considered the heterosexual AIDS virus. Essex's hypothesis is worthy of pursuit. The same experiments need to be conducted with other clades in the laboratory along with ongoing epidemiologic monitoring of the pandemic to potentially spot newly introduced clades capable of altering transmission patterns. It has also been suggested that mixed infection occurs and that HIV-1 recombinations are possible. Regardless of whether or not Essex's findings eventually prove true, however, the author stresses that HIV-1 of all clades can spread through all sexual routes; it is just a question of variable efficiency. Appropriate efforts and precautions to prevent the spread of HIV must continue.", + "TAG_DATA": [ + "182, in {'context': 'B-in vitro'}", + "183, vitro {'context': 'I-in vitro'}", + "185, Langerhans {'context': 'B-cells'}", + "186, cells {'context': 'I-cells'}", + "189, vaginal {'context': 'B-tissue/organ'}", + "190, mucosa {'context': 'I-tissue/organ'}", + "192, penile {'context': 'B-tissue/organ'}", + "193, foreskin, {'context': 'I-tissue/organ'}", + "205, Langerhans {'context': 'B-cells'}", + "206, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "182, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "183, vitro ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "185, Langerhans ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "186, cells ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "189, vaginal ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "190, mucosa ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "192, penile ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "193, foreskin, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "205, Langerhans ['l28']", + "206, cells ['l28']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7489368", + "TEXT": "Coronary occlusive disease is the leading cause of death in industrial nations and affects one in four adults. Although heart attacks are caused by occlusion of a coronary artery, some patients have occlusions without infarction because they have sufficient collateral vessels providing an alternate pathway for blood supply. Vascular endothelial growth factor (VEGF) is an angiogenic peptide that can stimulate collateral vessel development in the ischaemic myocardium. We used magnetic resonance imaging (MRI) and image processing to identify and quantify non-invasively the benefits related to VEGF infusion on collateral development in the heart. This was accomplished as a placebo-controlled study in the porcine model of chronic ischaemia that most closely mimics the human pathophysiology of progressive coronary occlusion. Image series converted to a space-time map demonstrated that with treatment the ischaemic zone was smaller and the contrast arrival delay was less, which resulted in better ejection fraction and regional wall thickening. These findings demonstrate in a manner applicable to humans, that VEGF improves collateral blood supply, resulting in improved cardiac global and regional function after and in spite of coronary artery occlusion.", + "TAG_DATA": [ + "102, porcine {'context': 'B-organism'}", + "103, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "102, porcine ['l0']", + "103, model ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7489364", + "TEXT": "The earliest event so far known that occurs in the brain affected with Alzheimer's disease (AD) is the deposition and fibril formation of amyloid beta-protein (A beta). A beta is cleaved from a glycosylated membrane protein, called beta-amyloid protein precursor, and normally secreted into the extracellular space. Here we report on the presence of membrane-bound A beta that tightly binds GM1 ganglioside. This suggests that this novel A beta species, rather than secreted A beta, may act as a 'seed' for amyloid and further that intracellular abnormalities in the membrane recycling already exist at the stage of amyloidogenesis.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "7489361", + "TEXT": "As a result of bioassay-guided fractionation, betulinic acid, a pentacyclic triterpene, was identified as a melanoma-specific cytotoxic agent. In follow-up studies conducted with athymic mice carrying human melanomas, tumour growth was completely inhibited without toxicity. As judged by a variety of cellular responses, antitumour activity was mediated by the induction of apoptosis. Betulinic acid is inexpensive and available in abundant supply from common natural sources, notably the bark of white birch trees. The compound is currently undergoing preclinical development for the treatment or prevention of malignant melanoma.", + "TAG_DATA": [ + "23, athymic {'context': 'B-organism'}", + "24, mice {'context': 'I-organism'}", + "26, human {'context': 'B-neoplasm'}", + "27, melanomas, {'context': 'I-neoplasm'}", + "28, tumour {'phenotype': 'B-tumour growth'}", + "29, growth {'phenotype': 'I-tumour growth'}", + "32, inhibited {'effect': 'B-negative'}", + "49, induction {'effect': 'B-positive'}", + "51, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "23, athymic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "24, mice ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "26, human ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "27, melanomas, ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "28, tumour ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "29, growth ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "32, inhibited ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "49, induction ['l21']", + "51, apoptosis. ['l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "athymic", + "mice" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumour", + "growth" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "athymic", + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "human", + "melanomas," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumour", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "human", + "melanomas," + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumour", + "growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "7585224", + "TEXT": "Obesity presents a significant challenge to the general health of affluent nations in terms of the number of people affected, the serious associated maladies and the lack of effective treatments. While common wisdom has held that obesity results from 'gluttony and sloth', a number of studies have indicated physiological causes of underlying the pathogenesis of obesity, with the degree of adiposity having a strong genetic component. Recently, the obese gene in the ob/ob mouse was cloned, along with its human homologue. The specific production of the obese protein by adipose tissue suggested that it may function in a feedback loop from fat tissue to the hypothalamus to control energy intake and/or energy expenditure, and that it may play a role in the pathogenesis of human obesity. In this study we report that obese mRNA expression is elevated in ex vivo omental adipocytes isolated from massively obese humans in the absence of an identifiable mutation. Therefore, we speculate that this increased expression may suggest that the massively obese are insensitive to the putative regulatory function(s) of the obese gene product.", + "TAG_DATA": [ + "72, ob/ob {'context': 'B-organism'}", + "73, mouse {'context': 'I-organism'}", + "140, omental {'context': 'B-cells'}", + "141, adipocytes {'context': 'I-cells'}", + "146, humans {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "72, ob/ob ['l0']", + "73, mouse ['l0']", + "140, omental ['l1', 'l2']", + "141, adipocytes ['l1', 'l3']", + "146, humans ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7585221", + "TEXT": "We have created a double mutant of the herpes simplex virus (HSV) type 1 (termed G207) with favourable properties for treating human malignant brain tumours: replication-competence in glioblastoma cells (and other dividing cells), attenuated neurovirulence, temperature sensitivity, ganciclovir hypersensitivity, and the presence of an easily detectable histochemical marker. G207 has deletions at both gamma 34.5 (RL1) loci and a lacZ gene insertion inactivating the ICP6 gene (UL39). G207 kills human glioma cells in monolayer cultures. In nude mice harbouring subcutaneous or intracerebral U-87MG gliomas, intraneoplastic inoculation with G207 causes decreased tumour growth and/or prolonged survival. G207 is avirulent upon intracerebral inoculation of mice and HSV-sensitive non-human primates. These results suggest that G207 should be considered for clinical evaluation in the treatment of glioblastomas.", + "TAG_DATA": [ + "69, human {'context': 'B-transformed cells'}", + "70, glioma {'context': 'I-transformed cells'}", + "71, cells {'context': 'I-transformed cells'}", + "73, monolayer {'context': 'B-in vitro'}", + "74, cultures. {'context': 'I-in vitro'}", + "76, nude {'context': 'B-organism'}", + "77, mice {'context': 'I-organism'}", + "83, gliomas, {'context': 'B-neoplasm'}", + "89, decreased {'effect': 'B-negative'}", + "90, tumour {'phenotype': 'B-tumour growth'}", + "91, growth {'phenotype': 'I-tumour growth'}", + "102, mice {'context': 'B-organism'}", + "105, non-human {'context': 'B-organism'}", + "106, primates. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "69, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "70, glioma ['l0', 'l6', 'l7', 'l8', 'l9']", + "71, cells ['l1', 'l6', 'l10', 'l11']", + "73, monolayer ['l2', 'l7', 'l10', 'l12', 'l13', 'l14']", + "74, cultures. ['l3', 'l8', 'l11', 'l12']", + "76, nude ['l4', 'l13', 'l15', 'l16']", + "77, mice ['l5', 'l9', 'l14', 'l15', 'l17']", + "83, gliomas, ['l16', 'l17']", + "89, decreased ['l18', 'l19']", + "90, tumour ['l18', 'l20']", + "91, growth ['l19', 'l20']", + "102, mice ['l21', 'l22']", + "105, non-human ['l21', 'l23']", + "106, primates. ['l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumour", + "growth" + ] + } + } + ] + }, + { + "PMID": "7585220", + "TEXT": "Transforming growth factor beta 1 (TGF-beta 1) is a platelet-derived cytokine involved in both normal wound healing and scarring. We show that human platelets contain two pools of latent TGF-beta 1, which constitute more than 95% of the total TGF-beta assayed in whole platelets. During clotting, one pool, the large latent TGF-beta complex consisting of latent TGF-beta binding protein (LTBP), the latency-associated peptide (LAP) and the 25-kD mature TGF-beta 1 dimer is released into the serum. A second pool, which contains LAP but not LTBP, is retained in the clot, but can be released by RGD peptide. When the clot is dissolved by plasmin this bound TGF-beta 1 is gradually activated and released. If similar mechanisms operate in vivo, the clot will act as a slow-release capsule of TGF-beta 1 activity during wound healing.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "7585213", + "TEXT": "Enthusiasm for the use of recombinant adenoviruses in gene therapy has been tempered by the problematic immune responses that develop to the virus and virus-infected cells. Humoral immune responses to the input viral proteins generate neutralizing antibodies that thwart attempts to effectively administer the therapy more than once. Previous studies in murine models of gene therapy for cystic fibrosis (CF) have shown that the formation of adenoviral antibodies of the IgA subtype, a process that is dependent on T helper cells of the TH2 subset, contributes to a block in gene transfer that occurs following a second administration of virus. We show in this report that coadministration of interferon-gamma (IFN-gamma) (or interleukin-12, which activates TH1 cells to secrete IFN-gamma) with the recombinant adenovirus into the airway of C57BL/6 mice diminishes the activation of TH2 cells and formation of neutralizing antibody, allowing for efficient readministration of recombinant virus. This suggests a strategy for gene therapy of CF in which administration of a short-acting immune modulator at the time of gene therapy may be sufficient to overcome the problems of humoral immunity.", + "TAG_DATA": [ + "114, TH1 {'context': 'B-cells'}", + "115, cells {'context': 'I-cells'}", + "127, C57BL/6 {'context': 'B-organism'}", + "128, mice {'context': 'I-organism'}", + "133, TH2 {'context': 'B-cells'}", + "134, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "114, TH1 ['l0', 'l1', 'l2', 'l3', 'l4']", + "115, cells ['l0', 'l5', 'l6', 'l7', 'l8']", + "127, C57BL/6 ['l1', 'l5', 'l9', 'l10', 'l11']", + "128, mice ['l2', 'l6', 'l9', 'l12', 'l13']", + "133, TH2 ['l3', 'l7', 'l10', 'l12', 'l14']", + "134, cells ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7585189", + "TEXT": "The neuropathologic hallmarks of Alzheimer's disease (AD) are extracellular plaques and intracellular neurofibrillary tangles. A constituent of senile plaques in AD is beta-amyloid, a hydrophobic peptide of 39-43 amino acids and a fragment of the amyloid precursor protein (APP). APP can be metabolized by at least two pathways, one of which involves generation of soluble APP by an unidentified enzyme named alpha-secretase. This cleavage generates alpha-secretase-cleaved, soluble APP (alpha-sAPP), which in this investigation was measured by a new assay in cerebrospinal fluid (CSF) from members of a Swedish AD family with a pathogenic mutation at APP670/671 (ref. 2). Family members who carry the mutation and are diagnosed with AD had low levels of alpha-sAPP (160 +/- 48 ng ml-1), with no overlap compared with non-carriers (257 +/- 48 ng ml-1). Carriers of the presymptomatic mutation showed intermediate alpha-sAPP levels. Today there exists no antemortem marker in AD with sufficient sensitivity and specificity, but measurement of alpha-sAPP represents a new and promising diagnostic marker.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "7585187", + "TEXT": "A partial cDNA sequence for the gene linked to the von Hippel-Lindau (VHL) syndrome was reported in 1993. Mutation or loss of both VHL alleles has been documented in sporadic renal cell carcinomas and in the neoplasms that arise in von Hippel-Lindau kindreds. We have determined that the protein product of the VHL gene is an approximately 30 kilodalton cytoplasmic protein. The renal carcinoma cell line 786-O is known to harbour a VHL mutation and, as shown here, fails to produce a wild-type VHL protein. Reintroduction of wild-type, but not mutant, VHL into these cells had no demonstrable effect on their growth in vitro but inhibited their ability to form tumours in nude mice.", + "TAG_DATA": [ + "62, renal {'context': 'B-transformed cells'}", + "63, carcinoma {'context': 'I-transformed cells'}", + "64, cell {'context': 'I-transformed cells'}", + "65, line {'context': 'I-transformed cells'}", + "66, 786-O {'context': 'I-transformed cells'}", + "85, Reintroduction {'perturbing_action': 'B-gene gain-of-function'}", + "86, of {'perturbing_action': 'I-gene gain-of-function'}", + "87, wild-type, {'perturbing_action': 'I-gene gain-of-function'}", + "91, VHL {'perturbing_action': 'I-gene gain-of-function'}", + "94, cells {'context': 'B-cells'}", + "102, in {'context': 'B-in vitro'}", + "103, vitro {'context': 'I-in vitro'}", + "105, inhibited {'effect': 'B-negative'}", + "107, ability {'effect': 'I-negative'}", + "109, form {'phenotype': 'B-tumourigenesis'}", + "110, tumours {'phenotype': 'I-tumourigenesis'}", + "112, nude {'context': 'B-organism'}", + "113, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "62, renal ['l0', 'l1', 'l2', 'l3']", + "63, carcinoma ['l0', 'l4', 'l5', 'l6']", + "64, cell ['l1', 'l4', 'l7', 'l8']", + "65, line ['l2', 'l5', 'l7', 'l9']", + "66, 786-O ['l3', 'l6', 'l8', 'l9']", + "85, Reintroduction ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "86, of ['l10', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "87, wild-type, ['l11', 'l22', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "91, VHL ['l12', 'l23', 'l33', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "94, cells ['l13', 'l24', 'l34', 'l43', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "102, in ['l14', 'l25', 'l35', 'l44', 'l52', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "103, vitro ['l15', 'l26', 'l36', 'l45', 'l53', 'l60', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "105, inhibited ['l16', 'l27', 'l37', 'l46', 'l54', 'l61', 'l67', 'l73', 'l74', 'l75', 'l76', 'l77']", + "107, ability ['l17', 'l28', 'l38', 'l47', 'l55', 'l62', 'l68', 'l73', 'l78', 'l79', 'l80', 'l81']", + "109, form ['l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l69', 'l74', 'l78', 'l82', 'l83', 'l84']", + "110, tumours ['l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l75', 'l79', 'l82', 'l85', 'l86']", + "112, nude ['l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l83', 'l85', 'l87']", + "113, mice. ['l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l86', 'l87']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reintroduction", + "of", + "wild-type,", + "VHL" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reintroduction", + "of", + "wild-type,", + "VHL" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reintroduction", + "of", + "wild-type,", + "VHL" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "ability" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reintroduction", + "of", + "wild-type,", + "VHL" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumours" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reintroduction", + "of", + "wild-type,", + "VHL" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "ability" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumours" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "ability" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumours" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "ability" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumours" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "ability" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumours" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice." + ] + } + } + ] + }, + { + "PMID": "7585182", + "TEXT": "For Ras oncoproteins to transform mammalian cells, they must be post-translationally modified with a farnesyl group in a reaction catalysed by the enzyme farnesyl-protein transferase (FPTase). Inhibitors of FPTase have therefore been proposed as anti-cancer agents. We show that L-744,832, which mimics the CaaX motif to which the farnesyl group is added, is a potent and selective inhibitor of FPTase. In MMTV-v-Ha-ras mice bearing palpable tumours, daily administration of L-744,832 caused tumour regression. Following cessation of treatment, tumours reappeared, the majority of which regressed upon retreatment. No systemic toxicity was found upon necropsy of L-744,832-treated mice. This first demonstration of anti-FPTase-mediated tumour regression suggests that FPTase inhibitors may be safe and effective anti-tumour agents in some cancers.", + "TAG_DATA": [ + "61, MMTV-v-Ha-ras {'perturbing_action': 'B-other'}", + "62, mice {'context': 'B-organism'}", + "64, palpable {'context': 'B-neoplasm'}", + "65, tumours, {'context': 'I-neoplasm'}", + "70, caused {'effect': 'B-positive'}", + "71, tumour {'phenotype': 'B-tumour regression'}", + "72, regression. {'phenotype': 'I-tumour regression'}", + "77, tumours {'phenotype': 'B-tumour regression'}", + "78, reappeared, {'phenotype': 'I-tumour regression'}", + "95, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "61, MMTV-v-Ha-ras ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "62, mice ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "64, palpable ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "65, tumours, ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "70, caused ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "71, tumour ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "72, regression. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "77, tumours ['l21']", + "78, reappeared, ['l21']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "MMTV-v-Ha-ras" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "MMTV-v-Ha-ras" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "palpable", + "tumours," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "MMTV-v-Ha-ras" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "MMTV-v-Ha-ras" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumour", + "regression." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumour", + "regression." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "palpable", + "tumours," + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "palpable", + "tumours," + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumour", + "regression." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumour", + "regression." + ] + } + } + ] + }, + { + "PMID": "7585153", + "TEXT": "Paired helical filament (PHF) tau is the principal component of neurofibrillary tangles, a characteristic feature of the neurodegenerative pathology in Alzheimer's disease (AD). Post-translational modification of tau, especially phosphorylation, has been considered a major factor in aggregation and diminished microtubule interactions of PHF-tau. Recently, it has been recognized that PHF-tau is also subject to non-enzymatic glycation, with formation of advanced glycation end products (AGEs). We now show that as a consequence of glycation, PHF-tau from AD and AGE-tau generate oxygen free radicals, thereby activating transcription via nuclear factor-kappa B, increasing amyloid beta-protein precursor and release of approximately 4 kD amyloid beta-peptides. These data provide insight into how PHF-tau disturbs neuronal function, and add to a growing body of evidence that oxidant stress contributes to the pathogenesis of AD.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "7585150", + "TEXT": "We and others have postulated that a constant number of T lymphocytes is normally maintained without regard to CD4+ or CD8+ phenotype ('blind' T-cell homeostasis). Here we confirm essentially constant T-cell levels (despite marked decline in CD4+ T cells and increase in CD8+ T cells) in homosexual men with incident human immunodeficiency virus, type 1 (HIV-1), infection who remained free of acquired immunodeficiency syndrome (AIDS) for up to eight years after seroconversion. In contrast, seroconverters who developed AIDS exhibited rapidly declining T cells (both CD4+ and CD8+) for approximately two years before AIDS, independent of the time between seroconversion and AIDS, suggesting that homeostasis failure is an important landmark in HIV disease progression. Given the high rate of T-cell turnover in HIV-1 infection, blind T-cell homeostasis may contribute to HIV pathogenesis through a CD8+ T lymphocytosis that interferes with regeneration of lost CD4+ T cells.", + "TAG_DATA": [ + "81, T {'context': 'B-cells'}", + "82, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "81, T ['l0']", + "82, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7585147", + "TEXT": "Evidence from animal experiments shows that the brain stem is involved in the pathophysiology of migraine. To investigate human migraine, we used positron emission tomography to examine the changes in regional cerebral blood flow as an index of neuronal activity in the human brain during spontaneous migraine attacks. During the attacks, increased blood flow was found in the cerebral hemispheres in cingulate, auditory and visual association cortices and in the brain stem. However, only the brain stem activation persisted after the injection of sumatriptan had induced complete relief from headache and phono- and photophobia. These findings support the idea that the pathogenesis of migraine is related to an imbalance in activity between brain stem nuclei regulating antinociception and vascular control.", + "TAG_DATA": [ + "59, hemispheres {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "59, hemispheres ['l0']", + "70, brain ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7585143", + "TEXT": "To investigate how overexpression of MAD, an antagonist of MYC oncogenes influences the malignant phenotype of human cancer cells, an adenovirus vector system was used to transfer the human MAD gene (AdMAD) into human astrocytoma cells. Decreased growth potential of AdMAD-infected cells was evidenced by a decrease in [3H]thymidine incorporation, an increase in cell doubling time and alteration of cell-cycle distribution. Diminished malignant potential of AdMAD-infected cells was manifested by their loss of anchorage-independent growth in soft agar and by their inability, in general, to induce tumorigenesis in a xenograft animal model. These studies indicate that adenovirus constructs encoding MAD dramatically inhibit the proliferation and tumorigenicity of human astrocytoma cells and support the use of MAD for gene therapy of human tumours.", + "TAG_DATA": [ + "33, human {'context': 'B-transformed cells'}", + "34, astrocytoma {'context': 'I-transformed cells'}", + "35, cells. {'context': 'I-transformed cells'}", + "41, cells {'context': 'B-cells'}", + "53, cell {'context': 'B-cells'}", + "66, cells {'context': 'B-cells'}", + "71, loss {'effect': 'B-negative'}", + "81, inability, {'effect': 'B-negative'}", + "84, to {'effect': 'I-no effect'}", + "85, induce {'effect': 'B-positive'}", + "86, tumorigenesis {'phenotype': 'B-tumourigenesis'}", + "89, xenograft {'context': 'B-xenograft'}", + "90, animal {'context': 'I-xenograft'}", + "91, model. {'context': 'I-xenograft'}", + "101, inhibit {'effect': 'B-negative'}", + "103, proliferation {'phenotype': 'B-proliferation'}", + "105, tumorigenicity {'phenotype': 'B-tumourigenesis'}", + "107, human {'context': 'B-transformed cells'}", + "108, astrocytoma {'context': 'I-transformed cells'}", + "109, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "33, human ['l0', 'l1', 'l2', 'l3']", + "34, astrocytoma ['l0', 'l4', 'l5', 'l6']", + "35, cells. ['l1', 'l4', 'l7']", + "41, cells ['l2', 'l5', 'l7', 'l8']", + "53, cell ['l3', 'l6', 'l8']", + "66, cells ['l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "71, loss ['l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "81, inability, ['l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "84, to ['l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "85, induce ['l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "86, tumorigenesis ['l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "89, xenograft ['l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "90, animal ['l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "91, model. ['l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "101, inhibit ['l45', 'l46', 'l47', 'l48', 'l49']", + "103, proliferation ['l45', 'l50', 'l51', 'l52', 'l53']", + "105, tumorigenicity ['l46', 'l50', 'l54', 'l55', 'l56']", + "107, human ['l47', 'l51', 'l54', 'l57', 'l58']", + "108, astrocytoma ['l48', 'l52', 'l55', 'l57', 'l59']", + "109, cells ['l49', 'l53', 'l56', 'l58', 'l59']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss", + "inability," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "to" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "loss", + "inability,", + "inhibit" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis", + "tumorigenicity" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "loss", + "inability," + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "animal", + "model." + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "to" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "to" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "animal", + "model." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "animal", + "model." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "animal", + "model." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "astrocytoma", + "cells" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "astrocytoma", + "cells" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "astrocytoma", + "cells" + ] + } + } + ] + }, + { + "PMID": "7585127", + "TEXT": "Vaccination with plasmid DNA expression vectors encoding foreign proteins elicits antibodies and cell-mediated immunity and protects against disease in animal models. We report a comparison of DNA vaccines, using contemporary human strains of virus, and clinically licensed (inactivated virus or subvirion) vaccines in preclinical animal models, to better predict their efficacy in humans. Influenza DNA vaccines elicited antibodies in both non-human primates and ferrets and protected ferrets against challenge with an antigenically distinct epidemic human influenza virus more effectively than the contemporary clinically licensed vaccine. These studies demonstrate that DNA vaccines may be more effective, particularly against different strains of virus, than inactivated virus or subvirion vaccines.", + "TAG_DATA": [ + "60, non-human {'context': 'B-organism'}", + "61, primates {'context': 'I-organism'}", + "63, ferrets {'context': 'B-organism'}", + "66, ferrets {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "60, non-human ['l0', 'l1']", + "61, primates ['l0', 'l2']", + "63, ferrets ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7585126", + "TEXT": "Multidrug-resistant cancer cells frequently overexpress the 110-kD LRP protein (originally named Lung Resistance-related Protein). LRP overexpression has been found to predict a poor response to chemotherapy in acute myeloid leukaemia and ovarian carcinoma. We describe the cloning and chromosome localization of the gene coding for this novel protein. The deduced LRP amino acid sequence shows 87.7% identity with the 104-kD rat major vault protein. Vaults are multi-subunit structures that may be involved in nucleo-cytoplasmic transport. The LRP gene is located on chromosome 16, close to the genes coding for multidrug resistance-associated protein and protein kinase C-beta, and may mediate drug resistance, perhaps via a transport process.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "7585125", + "TEXT": "For several human tumour types, allelic loss data suggest that one or more tumour suppressor genes reside telomeric to the p53 gene at chromosome 17p13.1. In the present study we have used a new strategy, involving molecular analysis of a DNA site hypermethylated in tumour DNA, to identify a candidate gene in this region (17p13.3). Our approach has led to identification of HIC-1 (hypermethylated in cancer), a new zinc-finger transcription factor gene which is ubiquitously expressed in normal tissues, but underexpressed in different tumour cells where it is hypermethylated. Multiple characteristics of this gene, including the presence of a p53 binding site in the 5' flanking region, activation of the gene by expression of a wild-type p53 gene and suppression of G418 selectability of cultured brain, breast and colon cancer cells following insertion of the gene, make HIC-1 gene a strong candidate for a tumour suppressor gene in region 17p13.3.", + "TAG_DATA": [ + "125, brain, {'context': 'I-cells'}", + "126, breast {'context': 'I-transformed cells'}", + "127, and {'context': 'I-transformed cells'}", + "128, colon {'context': 'I-transformed cells'}", + "129, cancer {'context': 'I-transformed cells'}", + "130, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "124, cultured ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "125, brain, ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "126, breast ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "127, and ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "128, colon ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "129, cancer ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "130, cells ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "135, gene, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7585124", + "TEXT": "Two viruses, GB virus A (GBV-A) and GB virus B (GBV-B), were recently identified in the GB hepatitis agent. Human sera containing antibodies that recognize GBV-A and/or GBV-B recombinant proteins were subjected to polymerase chain reaction studies with degenerate oligonucleotides capable of amplifying a segment of the putative helicase genes from GBV-A, GBV-B or hepatitis C virus. Novel sequences related to members of the Flaviviridae were identified in sera from 12 individuals including 4 individuals with hepatitis. The limited nucleotide sequence identity between GBV-A, GBV-B and HCV sequences suggests that a novel virus, tentatively named GB virus C, may be responsible for some cases of non-A, non-B, non-C, non-D, non-E hepatitis.", + "TAG_DATA": [ + "19, Human {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "7585123", + "TEXT": "A ubiquitous cell adhesion receptor, CD44, preferentially binds hyaluronan, a polysaccharide macromolecule that is present in most extracellular matrices. Hyaluronan molecules have large hydrodynamic volumes that entrap substantial amounts of water and can therefore control tissue hydration (swelling). CD44 is overexpressed by synovial cells and leukocytes, and hyaluronan is overproduced in the rheumatoid synovium and in other inflammatory sites. Nevertheless, the role of the CD44-hyaluronan interaction during inflammation is unclear. Our evidence shows that the CD44 receptor plays a critical role in governing the migration of inflammatory leukocytes into the extravascular compartment of the synovium in murine arthritis. An anti-CD44 antibody induces a rapid loss of CD44 from both leukocytes and synovial cells and displays an inhibitory effect on cell-extracellular matrix interactions in the synovium. As a result, the administration of such an antibody abrogates tissue swelling and leukocyte infiltration, two major components of inflammation.", + "TAG_DATA": [ + "109, leukocytes {'context': 'B-cells'}", + "111, synovial {'context': 'B-cells'}", + "112, cells {'context': 'I-cells'}", + "124, synovium. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "109, leukocytes ['l0', 'l1', 'l2']", + "111, synovial ['l0', 'l3', 'l4']", + "112, cells ['l1', 'l3', 'l5']", + "124, synovium. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7585122", + "TEXT": "Despite the prevalence of gamma delta T cells in mucosae that are typically colonized by Candida albicans, little is known of the possible role of these cells in resistance to candidiasis. A sharp increase in the number of gamma delta T cells and macrophages following intraperitoneal inoculation of mice with C. albicans led us to examine the role of these cells in the immune response to C. albicans. We show that the gamma delta T cells enhance macrophage nitric oxide (NO) production and anti-candida activity, in vitro. We also propose that the gamma delta T cells regulate macrophage function during candidiasis in vivo as well, because depletion of these cells abrogated inducible NO synthase expression in mucosae and enhanced murine susceptibility to candidiasis.", + "TAG_DATA": [ + "43, macrophages {'context': 'B-cells'}", + "48, mice {'context': 'B-organism'}", + "72, gamma {'context': 'B-cells'}", + "73, delta {'context': 'B-cells'}", + "74, T {'context': 'I-cells'}", + "75, cells {'context': 'I-cells'}", + "85, in {'context': 'B-in vitro'}", + "86, vitro. {'context': 'I-in vitro'}", + "101, in {'context': 'B-in vivo'}", + "102, vivo {'context': 'I-in vivo'}", + "109, cells {'context': 'B-cells'}", + "116, mucosae {'context': 'B-tissue/organ'}", + "119, murine {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "43, macrophages ['l0', 'l1', 'l2', 'l3']", + "48, mice ['l0']", + "72, gamma ['l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "73, delta ['l4', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "74, T ['l5', 'l11', 'l17', 'l18', 'l19', 'l20', 'l21']", + "75, cells ['l1', 'l6', 'l12', 'l17', 'l22', 'l23']", + "85, in ['l2', 'l7', 'l13', 'l18', 'l22', 'l24']", + "86, vitro. ['l3', 'l8', 'l14', 'l19', 'l23', 'l24']", + "101, in ['l9', 'l15', 'l20', 'l25']", + "102, vivo ['l10', 'l16', 'l21', 'l25']", + "109, cells ['l26', 'l27']", + "116, mucosae ['l26', 'l28']", + "119, murine ['l27', 'l28']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7585121", + "TEXT": "High concentrations of nitrite present in saliva (derived from dietary nitrate) may, upon acidification, generate nitrogen oxides in the stomach in sufficient amounts to provide protection from swallowed pathogens. We now show that, in the rat, reduction of nitrate to nitrite is confined to a specialized area on the posterior surface of the tongue, which is heavily colonized by bacteria, and that nitrate reduction is absent in germ-free rats. We also show that in humans increased salivary nitrite production resulting from nitrate intake enhances oral nitric oxide production. We propose that the salivary generation of nitrite is accomplished by a symbiotic relationship involving nitrate-reducing bacteria on the tongue surface, which is designed to provide host defence against microbial pathogens in the mouth and lower gut. These results provide further evidence for beneficial effects of dietary nitrate.", + "TAG_DATA": [ + "74, humans {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "7585095", + "TEXT": "We report the existence of a 'placental clock', which is active from an early stage in human pregnancy and determines the length of gestation and the timing of parturition and delivery. Using a prospective, longitudinal cohort study of 485 pregnant women we have demonstrated that placental secretion of corticotropin-releasing hormone (CRH) is a marker of this process and that measurement of the maternal plasma CRH concentration as early as 16-20 weeks of gestation identifies groups of women who are destined to experience normal term, preterm or post-term delivery. Further, we report that the exponential rise in maternal plasma CRH concentrations with advancing pregnancy is associated with a concomitant fall in concentrations of the specific CRH binding protein in late pregnancy, leading to a rapid increase in circulating levels of bioavailable CRH at a time that coincides with the onset of parturition, suggesting that CRH may act directly as a trigger for parturition in humans.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "7585090", + "TEXT": "Previous work from our laboratory demonstrated that selenium deficiency in the mouse allows a normally benign (amyocarditic) cloned and sequenced Coxackievirus to cause significant heart damage. Furthermore, Coxsackievirus recovered from the hearts of selenium-deficient mice inoculated into selenium-adequate mice still induced significant heart damage, suggesting that the amyocarditic Coxsackievirus had mutated to a virulent phenotype. Here we report that sequence analysis revealed six nucleotide changes between the virulent virus recovered from the selenium-deficient host and the avirulent input virus. These nucleotide changes are consistent with known differences in base composition between virulent and avirulent strains of Coxsackievirus. To the best of our knowledge, this is the first report of a specific nutritional deficiency driving changes in a viral genome, permitting an avirulent virus to acquire virulence due to genetic mutation.", + "TAG_DATA": [ + "31, hearts {'context': 'B-tissue/organ'}", + "33, selenium-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "34, mice {'context': 'B-organism'}", + "38, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "31, hearts ['l0', 'l1']", + "33, selenium-deficient ['l0', 'l2']", + "34, mice ['l1', 'l2', 'l3']", + "38, mice ['l3']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "hearts" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selenium-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selenium-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "7585069", + "TEXT": "Nitric oxide (NO) is present in air derived from the nasal airways. However, the precise origin and physiological role of airway-derived NO are unknown. We report that NO in humans is produced by epithelial cells in the paranasal sinuses and is present in sinus air in very high concentrations, close to the highest permissible atmospheric pollution levels. In immunohistochemical and mRNA in situ hybridization studies we show that an NO synthase most closely resembling the inducible isoform is constitutively expressed apically in sinus epithelium. In contrast, only weak NO synthase activity was found in the epithelium of the nasal cavity. Our findings, together with the well-known bacteriostatic effects of NO, suggest a role for NO in the maintenance of sterility in the human paranasal sinuses.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "7585067", + "TEXT": "Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common human genetic diseases. In addition to polycystic kidneys, the disease can cause cystic changes in liver and other organs, cardiac valvular insufficiency and cerebral arterial aneurysms. Using antibodies raised against the predicted gene product of PKD1, which is mutated in about 85% of ADPKD cases, we show that PKD1 is a 530-kD protein localized to the extracellular matrix of kidney, liver and cerebral blood vessels. We discovered that the PKD1 protein was highly expressed in the mesenchyme of developing kidney and liver, transiently localized in the developing glomerulus and juxtaglomerular apparatus and restricted to perivascular, extraglomerular areas in adult renal cortex. These data suggest that the PKD1 protein plays a role in renal and hepatic morphogenesis.", + "TAG_DATA": [ + "111, renal {'context': 'I-tissue/organ'}", + "112, cortex. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "111, renal ['l0']", + "112, cortex. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7585062", + "TEXT": "An HIV-1-seropositive volunteer was infused with an expanded autologous cytotoxic T lymphocyte (CTL) clone directed against the HIV-1 nef protein. This clone was adoptively transferred to determine whether supplementing CTL activity could reduce viral load or improve clinical course. Unexpectedly, infusion was followed by a decline in circulating CD4+ T cells and a rise in viral load. Some of the HIV isolates obtained from the plasma or CD4+ cells of the patient were lacking the nef epitope. These results suggest that active CTL selection of viral variants could contribute to the pathogenesis of AIDS and that clinical progression can occur despite high levels of circulating HIV-1-specific CTLs.", + "TAG_DATA": [ + "2, volunteer {'context': 'I-organism'}", + "49, T {'context': 'I-cells'}", + "67, CD4+ {'context': 'B-cells'}", + "68, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "2, volunteer ['l0']", + "49, T ['l0']", + "67, CD4+ ['l1']", + "68, cells ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7585045", + "TEXT": "Human autologous tumour-specific cytotoxic T lymphocytes (CTL) were generated from peripheral blood on small formalin-fixed paraffin-embedded sections of a gastric cancer. The CTL killed live target cells at an effector/target ratio of 1 within 24 hours and showed the same target specificity as those induced on live cancer cells. The killing activity of the CTL lasted for more than four months in culture and was inhibited by antibodies against CD8 and MHC-class I. These results suggest that adoptive immunotherapy of tumours will be possible with CTL induced on a stable source of tumour antigen.", + "TAG_DATA": [ + "19, gastric {'context': 'B-neoplasm'}", + "20, cancer. {'context': 'I-neoplasm'}", + "25, target {'context': 'B-transformed cells'}", + "26, cells {'context': 'I-transformed cells'}", + "46, live {'context': 'B-transformed cells'}", + "47, cancer {'context': 'I-transformed cells'}", + "48, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "19, gastric ['l0', 'l1', 'l2']", + "20, cancer. ['l0', 'l3', 'l4']", + "25, target ['l1', 'l3', 'l5']", + "26, cells ['l2', 'l4', 'l5']", + "46, live ['l6', 'l7']", + "47, cancer ['l6', 'l8']", + "48, cells. ['l7', 'l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7585037", + "TEXT": "Hepatitis B virus (HBV) infection is the world's most important chronic virus infection. No safe and effective treatment is available at present, and clinical exploration of promising antiviral agents, such as nucleoside analogues is hampered because of significant side-effects due to their aspecific body distribution. We are exploring the possibility of the selective delivery of antiviral active drugs to liver parenchymal cells, the main site of infection and replication of HBV. Chylomicrons, which transport dietary lipids into the liver via apolipoprotein E-specific receptors, could serve as drug carriers. However, their endogenous nature hampers their application as pharmaceutical drug carriers. We report here that incorporation of a derivative of the nucleoside analogue iododeoxyuridine into recombinant chylomicrons leads to selective targeting to liver parenchymal cells. Potentially effective intracellular drug concentrations of 700 nM can be achieved, and we therefore anticipate that these drug carrier complexes represent a conceptual advance in the development of an effective and safe therapy for hepatitis B.", + "TAG_DATA": [ + "120, liver {'context': 'B-cells'}", + "121, parenchymal {'context': 'I-cells'}", + "122, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "120, liver ['l0', 'l1']", + "121, parenchymal ['l0', 'l2']", + "122, cells. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7584956", + "TEXT": "A major problem in the study of lesions of atherosclerosis is the difficulty of imaging noninvasively the lesions and following their progression in vivo. To address this problem, we have developed advanced magnetic resonance techniques to noninvasively and serially image advanced lesions of atherosclerosis in the rabbit abdominal aorta. Both lumen and wall were imaged with high resolution. Progression of disease, resulting in increase in lesion mass, decrease in arterial lumen, or stenosis, and intralesion complications, can be detected. Images acquired in vivo correlate with the fine structure of the lesions of atherosclerosis, including the fibrous cap, necrotic core, and lesion fissures, as verified by gross examination, dissection microscopy, and histology. The ability to noninvasively identify the features of atherosclerotic plaques, has significant implications for determining risks and benefits associated with different therapeutic approaches.", + "TAG_DATA": [ + "46, rabbit {'context': 'B-tissue/organ'}", + "47, abdominal {'context': 'I-tissue/organ'}", + "48, aorta. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "46, rabbit ['l0', 'l1']", + "47, abdominal ['l0', 'l2']", + "48, aorta. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7584951", + "TEXT": "We report the results of a double-blind, placebo-controlled trial in nine cystic fibrosis (CF) subjects receiving cationic liposome complexed with a complementary DNA encoding the CF transmembrane conductance regulator (CFTR), and six CF subjects receiving only liposome to the nasal epithelium. No adverse clinical effects were seen and nasal biopsies showed no histological or immuno-histological changes. A partial restoration of the deficit between CF and non-CF subjects of 20% was seen for the response to low Cl- perfusion following CFTR cDNA administration. This was maximal around day three and had reverted to pretreatment values by day seven. In some cases the response to low Cl- was within the range for non-CF subjects. Plasmid DNA and transgene-derived RNA were detected in the majority of treated subjects. Although these data are encouraging, it is likely that transfection efficiency and the duration of expression will need to be increased for therapeutic benefit.", + "TAG_DATA": [ + "11, cystic {'context': 'B-organism'}", + "12, fibrosis {'context': 'I-organism'}", + "13, (CF) {'context': 'I-organism'}", + "14, subjects {'context': 'I-organism'}", + "32, CF {'context': 'B-organism'}", + "33, subjects {'context': 'I-organism'}", + "63, CF {'context': 'B-patient'}", + "65, non-CF {'context': 'I-cells'}", + "66, subjects {'context': 'I-organism'}", + "79, CFTR {'perturbing_action': 'B-rnai/knockdown'}", + "80, cDNA {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "11, cystic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "12, fibrosis ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "13, (CF) ['l1', 'l8', 'l15', 'l16', 'l17']", + "14, subjects ['l2', 'l9', 'l15']", + "32, CF ['l3', 'l10', 'l16', 'l18', 'l19', 'l20', 'l21']", + "33, subjects ['l4', 'l11', 'l17', 'l18', 'l22', 'l23', 'l24']", + "63, CF ['l5', 'l12', 'l19', 'l22', 'l25', 'l26', 'l27', 'l28']", + "65, non-CF ['l6', 'l13', 'l20', 'l23', 'l25', 'l29', 'l30', 'l31']", + "66, subjects ['l7', 'l14', 'l21', 'l24', 'l26', 'l29', 'l32', 'l33']", + "79, CFTR ['l27', 'l30', 'l32', 'l34']", + "80, cDNA ['l28', 'l31', 'l33', 'l34']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "patient", + "words": [ + "CF" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "CFTR", + "cDNA" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "non-CF" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "CFTR", + "cDNA" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "subjects" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "CFTR", + "cDNA" + ] + } + } + ] + }, + { + "PMID": "33432173", + "TEXT": "We integrated ubiquity, mass and lifespan of all major cell types to achieve a comprehensive quantitative description of cellular turnover. We found a total cellular mass turnover of 80 ± 20 grams per day, dominated by blood cells and gut epithelial cells. In terms of cell numbers, close to 90% of the (0.33 ± 0.02) × 1012 cells per day turnover was blood cells.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33082575", + "TEXT": "Several coronavirus disease 2019 (COVID-19) vaccines are currently in human trials. In June 2020, we surveyed 13,426 people in 19 countries to determine potential acceptance rates and factors influencing acceptance of a COVID-19 vaccine. Of these, 71.5% of participants reported that they would be very or somewhat likely to take a COVID-19 vaccine, and 48.1% reported that they would accept their employer's recommendation to do so. Differences in acceptance rates ranged from almost 90% (in China) to less than 55% (in Russia). Respondents reporting higher levels of trust in information from government sources were more likely to accept a vaccine and take their employer's advice to do so.", + "TAG_DATA": [ + "17, people {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32807930", + "TEXT": "Use of wearable devices that monitor physical activity is projected to increase more than fivefold per half-decade1. We investigated how device-based physical activity energy expenditure (PAEE) and different intensity profiles were associated with all-cause mortality. We used a network harmonization approach to map dominant-wrist acceleration to PAEE in 96,476 UK Biobank participants (mean age 62 years, 56% female). We also calculated the fraction of PAEE accumulated from moderate-to-vigorous-intensity physical activity (MVPA). Over the median 3.1-year follow-up period (302,526 person-years), 732 deaths were recorded. Higher PAEE was associated with a lower hazard of all-cause mortality for a constant fraction of MVPA (for example, 21% (95% confidence interval 4-35%) lower hazard for 20 versus 15 kJ kg-1 d-1 PAEE with 10% from MVPA). Similarly, a higher MVPA fraction was associated with a lower hazard when PAEE remained constant (for example, 30% (8-47%) lower hazard when 20% versus 10% of a fixed 15 kJ kg-1 d-1 PAEE volume was from MVPA). Our results show that higher volumes of PAEE are associated with reduced mortality rates, and achieving the same volume through higher-intensity activity is associated with greater reductions than through lower-intensity activity. The linkage of device-measured activity to energy expenditure creates a framework for using wearables for personalized prevention.", + "TAG_DATA": [], + "LINK_DATA": [ + "49, UK ['l0']", + "50, Biobank ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31700174", + "TEXT": "Chronic kidney disease is common in the general population and associated with excess cardiovascular disease (CVD), but kidney function does not feature in current CVD risk-prediction models. We tested three formulae for estimated glomerular filtration rate (eGFR) to determine which was the most clinically informative for predicting CVD and mortality. Using data from 440,526 participants from UK Biobank, eGFR was calculated using serum creatinine, cystatin C (eGFRcys) and creatinine-cystatin C. Associations of each eGFR with CVD outcome and mortality were compared using Cox models and adjusting for atherosclerotic risk factors (per relevant risk scores), and the predictive utility was determined by the C-statistic and categorical net reclassification index. We show that eGFRcys is most strongly associated with CVD and mortality, and, along with albuminuria, adds predictive discrimination to current CVD risk scores, whilst traditional creatinine-based measures are weakly associated with risk. Clinicians should consider measuring eGFRcys as part of cardiovascular risk assessment.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "29867230", + "TEXT": "We describe results from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in 305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments. These molecular profiles suggest that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade.", + "TAG_DATA": [ + "23, patients {'context': 'B-patient'}", + "25, treatment-naive {'context': 'B-neoplasm'}", + "26, metastatic {'context': 'I-neoplasm'}", + "27, renal {'context': 'I-neoplasm'}", + "28, cell {'context': 'I-neoplasm'}", + "29, carcinoma. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "23, patients ['l0', 'l1', 'l2', 'l3', 'l4']", + "25, treatment-naive ['l0', 'l5', 'l6', 'l7', 'l8']", + "26, metastatic ['l1', 'l5', 'l9', 'l10', 'l11']", + "27, renal ['l2', 'l6', 'l9', 'l12', 'l13']", + "28, cell ['l3', 'l7', 'l10', 'l12', 'l14']", + "29, carcinoma. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26937618", + "TEXT": "Depression is a common, devastating illness. Current pharmacotherapies help many patients, but high rates of a partial response or no response, and the delayed onset of the effects of antidepressant therapies, leave many patients inadequately treated. However, new insights into the neurobiology of stress and human mood disorders have shed light on mechanisms underlying the vulnerability of individuals to depression and have pointed to novel antidepressants. Environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology, resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function. Although current antidepressants, such as serotonin-reuptake inhibitors, produce subtle changes that take effect in weeks or months, it has recently been shown that treatment with new agents results in an improvement in mood ratings within hours of dosing patients who are resistant to typical antidepressants. Within a similar time scale, these new agents have also been shown to reverse the synaptic deficits caused by stress.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22772566", + "TEXT": "The spondyloarthropathies are a group of rheumatic diseases that are associated with inflammation at anatomically distal sites, particularly the tendon-bone attachments (entheses) and the aortic root. Serum concentrations of interleukin-23 (IL-23) are elevated and polymorphisms in the IL-23 receptor are associated with ankyosing spondylitis, however, it remains unclear whether IL-23 acts locally at the enthesis or distally on circulating cell populations. We show here that IL-23 is essential in enthesitis and acts on previously unidentified IL-23 receptor (IL-23R)(+), RAR-related orphan receptor γt (ROR-γt)(+)CD3(+)CD4(-)CD8(-), stem cell antigen 1 (Sca1)(+) entheseal resident T cells. These cells allow entheses to respond to IL-23 in vitro-in the absence of further cellular recruitment--and to elaborate inflammatory mediators including IL-6, IL-17, IL-22 and chemokine (C-X-C motif) ligand 1 (CXCL1). Notably, the in vivo expression of IL-23 is sufficient to phenocopy the human disease, with the specific and characteristic development of enthesitis and entheseal new bone formation in the initial complete absence of synovitis. As in the human condition, inflammation also develops in vivo at the aortic root and valve, which are structurally similar to entheses. The presence of these entheseal resident cells and their production of IL-22, which activates signal transducer and activator of transcription 3 (STAT3)-dependent osteoblast-mediated bone remodeling, explains why dysregulation of IL-23 results in inflammation at this precise anatomical site.", + "TAG_DATA": [ + "125, in {'context': 'B-in vivo'}", + "126, vivo {'context': 'I-in vivo'}", + "165, in {'context': 'B-in vivo'}", + "166, vivo {'context': 'I-in vivo'}", + "169, aortic {'context': 'B-tissue/organ'}", + "170, root {'context': 'I-tissue/organ'}", + "172, valve, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "125, in ['l0']", + "126, vivo ['l0']", + "165, in ['l1', 'l2', 'l3', 'l4']", + "166, vivo ['l1', 'l5', 'l6', 'l7']", + "169, aortic ['l2', 'l5', 'l8', 'l9']", + "170, root ['l3', 'l6', 'l8', 'l10']", + "172, valve, ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22561821", + "TEXT": "Mechanisms triggering methicillin-resistant Staphylococcus aureus (MRSA) epidemics are poorly understood. A recent study provides new evidence that horizontal gene transfer may be the culprit for the emergence of new resistant and virulent MRSA clones.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20948530", + "TEXT": "The incidence of chronic pain is estimated to be 20-25% worldwide. Few patients with chronic pain obtain complete relief from the drugs that are currently available, and more than half report inadequate relief. Underlying the challenge of developing better drugs to manage chronic pain is incomplete understanding of the heterogeneity of mechanisms that contribute to the transition from acute tissue insult to chronic pain and to pain conditions for which the underlying pathology is not apparent. An intact central nervous system (CNS) is required for the conscious perception of pain, and changes in the CNS are clearly evident in chronic pain states. However, the blockage of nociceptive input into the CNS can effectively relieve or markedly attenuate discomfort and pain, revealing the importance of ongoing peripheral input to the maintenance of chronic pain. Accordingly, we focus here on nociceptors: their excitability, their heterogeneity and their role in initiating and maintaining pain.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19029983", + "TEXT": "Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening adverse drug reactions characterized by massive epidermal necrosis, in which the specific danger signals involved remain unclear. Here we show that blister cells from skin lesions of SJS-TEN primarily consist of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, and both blister fluids and cells were cytotoxic. Gene expression profiling identified granulysin as the most highly expressed cytotoxic molecule, confirmed by quantitative PCR and immunohistochemistry. Granulysin concentrations in the blister fluids were two to four orders of magnitude higher than perforin, granzyme B or soluble Fas ligand concentrations, and depleting granulysin reduced the cytotoxicity. Granulysin in the blister fluids was a 15-kDa secretory form, and injection of it into mouse skin resulted in features mimicking SJS-TEN. Our findings demonstrate that secretory granulysin is a key molecule responsible for the disseminated keratinocyte death in SJS-TEN and highlight a mechanism for CTL- or NK cell--mediated cytotoxicity that does not require direct cellular contact.", + "TAG_DATA": [ + "55, cells {'context': 'B-cells'}", + "100, depleting {'perturbing_action': 'B-gene loss-of-function'}", + "101, granulysin {'perturbing_action': 'I-gene loss-of-function'}", + "120, mouse {'context': 'B-tissue/organ'}", + "121, skin {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "100, depleting ['l0']", + "101, granulysin ['l0']", + "120, mouse ['l1']", + "121, skin ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18836458", + "TEXT": "Pauci-immune focal necrotizing glomerulonephritis (FNGN) is a severe inflammatory disease associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA). Here we characterize autoantibodies to lysosomal membrane protein-2 (LAMP-2) and show that they are a new ANCA subtype present in almost all individuals with FNGN. Consequently, its prevalence is nearly twice that of the classical ANCAs that recognize myeloperoxidase or proteinase-3. Furthermore, antibodies to LAMP-2 cause pauci-immune FNGN when injected into rats, and a monoclonal antibody to human LAMP-2 (H4B4) induces apoptosis of human microvascular endothelium in vitro. The autoantibodies in individuals with pauci-immune FNGN commonly recognize a human LAMP-2 epitope (designated P(41-49)) with 100% homology to the bacterial adhesin FimH, with which they cross-react. Rats immunized with FimH develop pauci-immune FNGN and also develop antibodies to rat and human LAMP-2. Finally, we show that infections with fimbriated pathogens are common before the onset of FNGN. Thus, FimH-triggered autoimmunity to LAMP-2 provides a previously undescribed clinically relevant molecular mechanism for the development of pauci-immune FNGN.", + "TAG_DATA": [ + "69, rats, {'context': 'B-organism'}", + "72, monoclonal {'perturbing_action': 'B-other'}", + "74, to {'perturbing_action': 'I-rnai/knockdown'}", + "75, human {'perturbing_action': 'I-other'}", + "76, LAMP-2 {'perturbing_action': 'I-other'}", + "77, (H4B4) {'perturbing_action': 'I-rnai/knockdown'}", + "78, induces {'effect': 'B-positive'}", + "79, apoptosis {'phenotype': 'B-apoptosis'}", + "81, human {'context': 'B-cells'}", + "82, microvascular {'context': 'I-cells'}", + "83, endothelium {'context': 'I-cells'}", + "84, in {'context': 'B-in vitro'}", + "85, vitro. {'context': 'I-in vitro'}", + "113, Rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "72, monoclonal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "73, antibody ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "74, to ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "75, human ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "76, LAMP-2 ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "77, (H4B4) ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "78, induces ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "79, apoptosis ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "81, human ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "82, microvascular ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "83, endothelium ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "84, in ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "85, vitro. ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "monoclonal", + "human", + "LAMP-2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "monoclonal", + "human", + "LAMP-2" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "monoclonal", + "human", + "LAMP-2" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "microvascular", + "endothelium" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "monoclonal", + "human", + "LAMP-2" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "to", + "(H4B4)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "to", + "(H4B4)" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "to", + "(H4B4)" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "microvascular", + "endothelium" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "to", + "(H4B4)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "microvascular", + "endothelium" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "microvascular", + "endothelium" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "16155579", + "TEXT": "Obesity-related disorders are associated with the development of ischemic heart disease. Adiponectin is a circulating adipose-derived cytokine that is downregulated in obese individuals and after myocardial infarction. Here, we examine the role of adiponectin in myocardial remodeling in response to acute injury. Ischemia-reperfusion in adiponectin-deficient (APN-KO) mice resulted in increased myocardial infarct size, myocardial apoptosis and tumor necrosis factor (TNF)-alpha expression compared with wild-type mice. Administration of adiponectin diminished infarct size, apoptosis and TNF-alpha production in both APN-KO and wild-type mice. In cultured cardiac cells, adiponectin inhibited apoptosis and TNF-alpha production. Dominant negative AMP-activated protein kinase (AMPK) reversed the inhibitory effects of adiponectin on apoptosis but had no effect on the suppressive effect of adiponectin on TNF-alpha production. Adiponectin induced cyclooxygenase (COX)-2-dependent synthesis of prostaglandin E(2) in cardiac cells, and COX-2 inhibition reversed the inhibitory effects of adiponectin on TNF-alpha production and infarct size. These data suggest that adiponectin protects the heart from ischemia-reperfusion injury through both AMPK- and COX-2-dependent mechanisms.", + "TAG_DATA": [ + "44, adiponectin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "45, (APN-KO) {'perturbing_action': 'I-gene loss-of-function'}", + "46, mice {'context': 'B-organism'}", + "54, apoptosis {'phenotype': 'B-apoptosis'}", + "64, mice. {'context': 'B-organism'}", + "71, apoptosis {'phenotype': 'B-apoptosis'}", + "77, APN-KO {'perturbing_action': 'B-gene loss-of-function'}", + "80, mice. {'context': 'B-organism'}", + "82, cultured {'context': 'B-cells'}", + "83, cardiac {'context': 'I-cells'}", + "84, cells, {'context': 'I-cells'}", + "86, inhibited {'effect': 'B-negative'}", + "87, apoptosis {'phenotype': 'B-apoptosis'}", + "91, Dominant {'perturbing_action': 'B-rnai/knockdown'}", + "99, inhibitory {'effect': 'B-negative'}", + "104, apoptosis {'phenotype': 'B-apoptosis'}", + "127, cardiac {'context': 'B-cells'}", + "128, cells, {'context': 'I-cells'}", + "130, COX-2 {'perturbing_action': 'B-pharmacological inhibition'}", + "131, inhibition {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "44, adiponectin-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "45, (APN-KO) ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "46, mice ['l1', 'l6', 'l11', 'l12', 'l13']", + "53, myocardial ['l2', 'l7', 'l11', 'l14', 'l15']", + "54, apoptosis ['l3', 'l8', 'l12', 'l14', 'l16']", + "64, mice. ['l4', 'l9', 'l13', 'l15', 'l16']", + "71, apoptosis ['l5', 'l10']", + "77, APN-KO ['l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "80, mice. ['l17', 'l23']", + "82, cultured ['l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "83, cardiac ['l19', 'l24', 'l29', 'l30', 'l31', 'l32', 'l33']", + "84, cells, ['l20', 'l23', 'l25', 'l29', 'l34', 'l35', 'l36']", + "86, inhibited ['l21', 'l26', 'l30', 'l34', 'l37', 'l38', 'l39']", + "87, apoptosis ['l22', 'l27', 'l31', 'l35', 'l37', 'l40']", + "91, Dominant ['l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "92, negative ['l41', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "93, AMP-activated ['l42', 'l50', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "94, protein ['l43', 'l51', 'l58', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "95, kinase ['l44', 'l52', 'l59', 'l65', 'l71', 'l72', 'l73', 'l74', 'l75']", + "96, (AMPK) ['l45', 'l53', 'l60', 'l66', 'l71', 'l76', 'l77', 'l78', 'l79']", + "99, inhibitory ['l32', 'l38', 'l46', 'l54', 'l61', 'l67', 'l72', 'l76', 'l80', 'l81', 'l82']", + "104, apoptosis ['l28', 'l33', 'l36', 'l39', 'l40', 'l47', 'l55', 'l62', 'l68', 'l73', 'l77', 'l80', 'l83']", + "127, cardiac ['l48', 'l56', 'l63', 'l69', 'l74', 'l78', 'l81', 'l84']", + "128, cells, ['l49', 'l57', 'l64', 'l70', 'l75', 'l79', 'l82', 'l83', 'l84']", + "130, COX-2 ['l85']", + "131, inhibition ['l85']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adiponectin-deficient", + "(APN-KO)", + "APN-KO" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adiponectin-deficient", + "(APN-KO)", + "APN-KO" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "APN-KO" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "cardiac", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "APN-KO" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "cardiac", + "cells," + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "inhibitory" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "cardiac", + "cells," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "inhibitory" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Dominant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibitory" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Dominant" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Dominant" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiac", + "cells," + ] + } + } + ] + }, + { + "PMID": "14625544", + "TEXT": "Genetic susceptibility and autoimmunity triggered by microbial infections are factors implicated in the pathogenesis of dilated cardiomyopathy, the most common cause of heart failure in young patients. Here we show that dendritic cells (DCs) loaded with a heart-specific self peptide induce CD4+ T-cell-mediated myocarditis in nontransgenic mice. Toll-like receptor (TLR) stimulation, in concert with CD40 triggering of self peptide-loaded dendritic cells, was shown to be required for disease induction. After resolution of acute myocarditis, DC-immunized mice developed heart failure, and TLR stimulation of these mice resulted in relapse of inflammatory infiltrates. Injection of damaged, syngeneic cardiomyocytes also induced myocarditis in mice if TLRs were activated in vivo. DC-induced myocarditis provides a unifying theory as to how tissue damage and activation of TLRs during infection can induce autoimmunity, relapses and cardiomyopathy.", + "TAG_DATA": [ + "45, nontransgenic {'context': 'B-organism'}", + "46, mice. {'context': 'I-organism'}", + "75, mice {'context': 'B-organism'}", + "84, mice {'context': 'B-organism'}", + "94, syngeneic {'context': 'I-cells'}", + "95, cardiomyocytes {'context': 'I-cells'}", + "100, mice {'context': 'B-organism'}", + "105, in {'context': 'B-in vivo'}", + "106, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "45, nontransgenic ['l0']", + "46, mice. ['l0']", + "75, mice ['l1']", + "84, mice ['l1']", + "94, syngeneic ['l2', 'l3']", + "95, cardiomyocytes ['l2', 'l4']", + "100, mice ['l3', 'l4']", + "105, in ['l5']", + "106, vivo. ['l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12925847", + "TEXT": "In the 1960s, a formalin-inactivated measles vaccine (FIMV) predisposed recipients to atypical measles, an immune complex-mediated disease. To identify characteristics of the immune priming that leads to atypical measles, responses of monkeys to FIMV were compared with responses to live attenuated virus (LAV) and hemagglutinin (H-DNA) vaccines that do not prime for atypical measles. Antibodies induced by FIMV were transient and avidity did not mature. Antibodies induced by LAV and H-DNA vaccines were sustained and avidity matured over time. After challenge with measles virus, FIMV and H-DNA recipients developed high titers of complement-fixing antibodies. In FIMV recipients, the antibodies were of low avidity, whereas in H-DNA vaccine recipients, the antibodies were of high avidity. Neutralizing capacity in B958 cells correlated with avidity. Only FIMV recipients had immune complex deposition. Failure of FIMV to induce affinity maturation results in anamnestic production of nonprotective, complement-fixing antibodies, immune complex deposition and atypical measles.", + "TAG_DATA": [ + "31, monkeys {'context': 'B-organism'}", + "117, B958 {'context': 'B-cells'}", + "118, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "117, B958 ['l0']", + "118, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32929266", + "TEXT": "In a human menstrual cycle the endometrium undergoes remodeling, shedding and regeneration, all of which are driven by substantial gene expression changes in the underlying cellular hierarchy. Despite its importance in human fertility and regenerative biology, our understanding of this unique type of tissue homeostasis remains rudimentary. We characterized the transcriptomic transformation of human endometrium at single-cell resolution across the menstrual cycle, resolving cellular heterogeneity in multiple dimensions. We profiled the behavior of seven endometrial cell types, including a previously uncharacterized ciliated cell type, during four major phases of endometrial transformation, and found characteristic signatures for each cell type and phase. We discovered that the human window of implantation opens with an abrupt and discontinuous transcriptomic activation in the epithelia, accompanied with a widespread decidualization feature in the stromal fibroblasts. Our study provides a high-resolution molecular and cellular characterization of human endometrial transformation across the menstrual cycle, providing insights into this essential physiological process.", + "TAG_DATA": [ + "119, epithelia, {'context': 'B-cells'}", + "128, stromal {'context': 'B-cells'}", + "129, fibroblasts. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "128, stromal ['l0']", + "129, fibroblasts. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32929265", + "TEXT": "The therapeutic potential of donor-derived mesenchymal stromal cells (MSCs) has been investigated in diverse diseases1, including steroid-resistant acute graft versus host disease (SR-aGvHD)2. However, conventional manufacturing approaches are hampered by challenges with scalability and interdonor variability, and clinical trials have shown inconsistent outcomes3,4. Induced pluripotent stem cells (iPSCs) have the potential to overcome these challenges, due to their capacity for multilineage differentiation and indefinite proliferation5,6. Nonetheless, human clinical trials of iPSC-derived cells have not previously been completed. CYP-001 (iPSC-derived MSCs) is produced using an optimized, good manufacturing practice (GMP)-compliant manufacturing process. We conducted a phase 1, open-label clinical trial (no. NCT02923375) in subjects with SR-aGvHD. Sixteen subjects were screened and sequentially assigned to cohort A or cohort B (n = 8 per group). One subject in cohort B withdrew before receiving CYP-001 and was excluded from analysis. All other subjects received intravenous infusions of CYP-001 on days 0 and 7, at a dose level of either 1 × 106 cells per kg body weight, to a maximum of 1 × 108 cells per infusion (cohort A), or 2 × 106 cells per kg body weight, to a maximum dose of 2 × 108 cells per infusion (cohort B). The primary objective was to assess the safety and tolerability of CYP-001, while the secondary objectives were to evaluate efficacy based on the proportion of participants who showed a complete response (CR), overall response (OR) and overall survival (OS) by days 28/100. CYP-001 was safe and well tolerated. No serious adverse events were assessed as related to CYP-001. OR, CR and OS rates by day 100 were 86.7, 53.3 and 86.7%, respectively. The therapeutic application of iPSC-derived MSCs may now be explored in diverse inflammatory and immune-mediated diseases.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32908272", + "TEXT": "Many widely used health algorithms have been shown to encode and reinforce racial health inequities, prioritizing the needs of white patients over those of patients of color. Because automated systems are becoming so crucial to access to health, researchers in the field of artificial intelligence must become actively anti-racist. Here we list some concrete steps to enable anti-racist practices in medical research and practice.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32868878", + "TEXT": "An effective strategy to cure HIV will likely require a potent and sustained antiviral T cell response. Here we explored the utility of chimeric antigen receptor (CAR) T cells, expressing the CD4 ectodomain to confer specificity for the HIV envelope, to mitigate HIV-induced pathogenesis in bone marrow, liver, thymus (BLT) humanized mice. CAR T cells expressing the 4-1BB/CD3-ζ endodomain were insufficient to prevent viral rebound and CD4+ T cell loss after the discontinuation of antiretroviral therapy. Through iterative improvements to the CAR T cell product, we developed Dual-CAR T cells that simultaneously expressed both 4-1BB/CD3-ζ and CD28/CD3-ζ endodomains. Dual-CAR T cells exhibited expansion kinetics that exceeded 4-1BB-, CD28- and third-generation costimulated CAR T cells, elicited effector functions equivalent to CD28-costimulated CAR T cells and prevented HIV-induced CD4+ T cell loss despite persistent viremia. Moreover, when Dual-CAR T cells were protected from HIV infection through expression of the C34-CXCR4 fusion inhibitor, these cells significantly reduced acute-phase viremia, as well as accelerated HIV suppression in the presence of antiretroviral therapy and reduced tissue viral burden. Collectively, these studies demonstrate the enhanced therapeutic potency of a novel Dual-CAR T cell product with the potential to effectively treat HIV infection.", + "TAG_DATA": [ + "51, mice. {'context': 'B-organism'}", + "53, T {'context': 'I-cells'}", + "54, cells {'context': 'I-cells'}", + "66, CD4+ {'context': 'B-cells'}", + "67, T {'context': 'I-cells'}", + "68, cell {'context': 'I-cells'}", + "88, T {'context': 'I-cells'}", + "89, cells {'context': 'I-cells'}", + "99, T {'context': 'I-cells'}", + "100, cells {'context': 'I-cells'}", + "120, CAR {'context': 'B-cells'}", + "121, T {'context': 'I-cells'}", + "122, cells {'context': 'I-cells'}", + "126, CD4+ {'context': 'B-cells'}", + "127, T {'context': 'I-cells'}", + "128, cell {'context': 'I-cells'}", + "135, Dual-CAR {'context': 'B-cells'}", + "136, T {'context': 'I-cells'}", + "137, cells {'context': 'I-cells'}", + "151, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "47, liver, ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "48, thymus ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "49, (BLT) ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "50, humanized ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34']", + "51, mice. ['l3', 'l13', 'l22', 'l30', 'l35', 'l36', 'l37']", + "53, T ['l4', 'l14', 'l23', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "54, cells ['l5', 'l15', 'l24', 'l31', 'l38', 'l44', 'l45', 'l46', 'l47', 'l48']", + "66, CD4+ ['l6', 'l16', 'l25', 'l32', 'l35', 'l39', 'l44', 'l49', 'l50']", + "67, T ['l7', 'l17', 'l26', 'l33', 'l36', 'l40', 'l45', 'l49', 'l51']", + "68, cell ['l8', 'l18', 'l27', 'l34', 'l37', 'l41', 'l46', 'l50', 'l51']", + "88, T ['l9', 'l19', 'l28', 'l42', 'l47', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "89, cells ['l10', 'l20', 'l29', 'l43', 'l48', 'l52', 'l58', 'l59', 'l60', 'l61']", + "99, T ['l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "100, cells ['l62', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "120, CAR ['l63', 'l69', 'l75', 'l76', 'l77', 'l78', 'l79']", + "121, T ['l53', 'l64', 'l70', 'l75', 'l80', 'l81', 'l82', 'l83']", + "122, cells ['l54', 'l58', 'l65', 'l71', 'l76', 'l80', 'l84', 'l85', 'l86']", + "126, CD4+ ['l55', 'l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l87', 'l88']", + "127, T ['l56', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l87', 'l89']", + "128, cell ['l57', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l89']", + "135, Dual-CAR ['l90', 'l91', 'l92']", + "136, T ['l90', 'l93', 'l94']", + "137, cells ['l91', 'l93', 'l95']", + "151, cells ['l92', 'l94', 'l95']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32839624", + "TEXT": "Several studies have revealed that the hyper-inflammatory response induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major cause of disease severity and death. However, predictive biomarkers of pathogenic inflammation to help guide targetable immune pathways are critically lacking. We implemented a rapid multiplex cytokine assay to measure serum interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α and IL-1β in hospitalized patients with coronavirus disease 2019 (COVID-19) upon admission to the Mount Sinai Health System in New York. Patients (n = 1,484) were followed up to 41 d after admission (median, 8 d), and clinical information, laboratory test results and patient outcomes were collected. We found that high serum IL-6, IL-8 and TNF-α levels at the time of hospitalization were strong and independent predictors of patient survival (P < 0.0001, P = 0.0205 and P = 0.0140, respectively). Notably, when adjusting for disease severity, common laboratory inflammation markers, hypoxia and other vitals, demographics, and a range of comorbidities, IL-6 and TNF-α serum levels remained independent and significant predictors of disease severity and death. These findings were validated in a second cohort of patients (n = 231). We propose that serum IL-6 and TNF-α levels should be considered in the management and treatment of patients with COVID-19 to stratify prospective clinical trials, guide resource allocation and inform therapeutic options.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32839619", + "TEXT": "Differences in cardiac and aortic structure and function are associated with cardiovascular diseases and a wide range of other types of disease. Here we analyzed cardiovascular magnetic resonance images from a population-based study, the UK Biobank, using an automated machine-learning-based analysis pipeline. We report a comprehensive range of structural and functional phenotypes for the heart and aorta across 26,893 participants, and explore how these phenotypes vary according to sex, age and major cardiovascular risk factors. We extended this analysis with a phenome-wide association study, in which we tested for correlations of a wide range of non-imaging phenotypes of the participants with imaging phenotypes. We further explored the associations of imaging phenotypes with early-life factors, mental health and cognitive function using both observational analysis and Mendelian randomization. Our study illustrates how population-based cardiac and aortic imaging phenotypes can be used to better define cardiovascular disease risks as well as heart-brain health interactions, highlighting new opportunities for studying disease mechanisms and developing image-based biomarkers.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32807934", + "TEXT": "Improved understanding and management of COVID-19, a potentially life-threatening disease, could greatly reduce the threat posed by its etiologic agent, SARS-CoV-2. Toward this end, we have identified a core peripheral blood immune signature across 63 hospital-treated patients with COVID-19 who were otherwise highly heterogeneous. The signature includes discrete changes in B and myelomonocytic cell composition, profoundly altered T cell phenotypes, selective cytokine/chemokine upregulation and SARS-CoV-2-specific antibodies. Some signature traits identify links with other settings of immunoprotection and immunopathology; others, including basophil and plasmacytoid dendritic cell depletion, correlate strongly with disease severity; while a third set of traits, including a triad of IP-10, interleukin-10 and interleukin-6, anticipate subsequent clinical progression. Hence, contingent upon independent validation in other COVID-19 cohorts, individual traits within this signature may collectively and individually guide treatment options; offer insights into COVID-19 pathogenesis; and aid early, risk-based patient stratification that is particularly beneficial in phasic diseases such as COVID-19.", + "TAG_DATA": [ + "57, T {'context': 'B-cells'}", + "58, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "57, T ['l0']", + "58, cell ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32770167", + "TEXT": "The burden of malaria is heavily concentrated in sub-Saharan Africa (SSA) where cases and deaths associated with COVID-19 are rising1. In response, countries are implementing societal measures aimed at curtailing transmission of SARS-CoV-22,3. Despite these measures, the COVID-19 epidemic could still result in millions of deaths as local health facilities become overwhelmed4. Advances in malaria control this century have been largely due to distribution of long-lasting insecticidal nets (LLINs)5, with many SSA countries having planned campaigns for 2020. In the present study, we use COVID-19 and malaria transmission models to estimate the impact of disruption of malaria prevention activities and other core health services under four different COVID-19 epidemic scenarios. If activities are halted, the malaria burden in 2020 could be more than double that of 2019. In Nigeria alone, reducing case management for 6 months and delaying LLIN campaigns could result in 81,000 (44,000-119,000) additional deaths. Mitigating these negative impacts is achievable, and LLIN distributions in particular should be prioritized alongside access to antimalarial treatments to prevent substantial malaria epidemics.", + "TAG_DATA": [ + "128, Nigeria {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "128, Nigeria ['l0']", + "132, management ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32641783", + "TEXT": "Population-based data on COVID-19 are urgently needed. We report on three rounds of probability sample household surveys in the state of Rio Grande do Sul (Brazil), carried out in nine large municipalities using the Wondfo lateral flow point-of-care test for immunoglobulin M and G antibodies against SARS-CoV-2 (https://en.wondfo.com.cn/product/wondfo-sars-cov-2-antibody-test-lateral-flow-method-2/). Before survey use, the assay underwent four validation studies with pooled estimates of sensitivity (84.8%; 95% confidence interval (CI) = 81.4-87.8%) and specificity (99.0%; 95% CI = 97.8-99.7%). We calculated that the seroprevalence was 0.048% (2/4,151; 95% CI = 0.006-0.174) on 11-13 April (round 1), 0.135% (6/4,460; 95% CI = 0.049-0.293%) on 25-27 April (round 2) and 0.222% (10/4,500; 95% CI = 0.107-0.408) on 9-11 May (round 3), with a significant upward trend over the course of the surveys. Of 37 family members of positive individuals, 17 (35%) were also positive. The epidemic is at an early stage in the state, and there is high compliance with social distancing, unlike in other parts of Brazil. Periodic survey rounds will continue to monitor trends until at least the end of September, and our population-based data will inform decisions on preventive policies and health system preparedness at the state level.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32601338", + "TEXT": "A burgeoning epidemic of drug-resistant tuberculosis (TB) threatens to derail global control efforts. Although the mechanisms remain poorly clarified, drug-resistant strains are widely believed to be less infectious than drug-susceptible strains. Consequently, we hypothesized that lower proportions of patients with drug-resistant TB would have culturable Mycobacterium tuberculosis from respirable, cough-generated aerosols compared to patients with drug-susceptible TB, and that multiple factors, including mycobacterial genomic variation, would predict culturable cough aerosol production. We enumerated the colony forming units in aerosols (≤10 µm) from 452 patients with TB (227 with drug resistance), compared clinical characteristics, and performed mycobacterial whole-genome sequencing, dormancy phenotyping and drug-susceptibility analyses on M. tuberculosis from sputum. After considering treatment duration, we found that almost half of the patients with drug-resistant TB were cough aerosol culture-positive. Surprisingly, neither mycobacterial genomic variants, lineage, nor dormancy status predicted cough aerosol culture positivity. However, mycobacterial sputum bacillary load and clinical characteristics, including a lower symptom score and stronger cough, were strongly predictive, thereby supporting targeted transmission-limiting interventions. Effective treatment largely abrogated cough aerosol culture positivity; however, this was not always rapid. These data question current paradigms, inform public health strategies and suggest the need to redirect TB transmission-associated research efforts toward host-pathogen interactions.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32601337", + "TEXT": "Acute myeloid leukemia (AML) is driven by leukemia stem cells (LSCs) that resist conventional chemotherapy and are the major cause of relapse1,2. Hypomethylating agents (HMAs) are the standard of care in the treatment of older or unfit patients with AML, but responses are modest and not durable3-5. Here we demonstrate that LSCs upregulate the tumor necrosis factor family ligand CD70 in response to HMA treatment resulting in increased CD70/CD27 signaling. Blocking CD70/CD27 signaling and targeting CD70-expressing LSCs with cusatuzumab, a human αCD70 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity activity, eliminated LSCs in vitro and in xenotransplantation experiments. Based on these preclinical results, we performed a phase 1/2 trial in previously untreated older patients with AML with a single dose of cusatuzumab monotherapy followed by a combination therapy with the HMA azacitidine ( NCT03030612 ). We report results from the phase 1 dose escalation part of the clinical trial. Hematological responses in the 12 patients enrolled included 8 complete remission, 2 complete remission with incomplete blood count recovery and 2 partial remission with 4 patients achieving minimal residual disease negativity by flow cytometry at <10-3. Median time to response was 3.3 months. Median progression-free survival was not reached yet at the time of the data cutoff. No dose-limiting toxicities were reported and the maximum tolerated dose of cusatuzumab was not reached. Importantly, cusatuzumab treatment substantially reduced LSCs and triggered gene signatures related to myeloid differentiation and apoptosis.", + "TAG_DATA": [ + "75, CD70-expressing {'context': 'B-transformed cells'}", + "76, LSCs {'context': 'I-transformed cells'}", + "91, LSCs {'context': 'B-transformed cells'}", + "92, in {'context': 'B-in vitro'}", + "93, vitro {'context': 'I-in vitro'}", + "96, xenotransplantation {'context': 'B-xenograft'}", + "112, older {'context': 'B-patient'}", + "113, patients {'context': 'I-patient'}", + "114, with {'context': 'I-patient'}", + "115, AML {'context': 'I-patient'}", + "226, LSCs {'context': 'B-transformed cells'}" + ], + "LINK_DATA": [ + "75, CD70-expressing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "76, LSCs ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "91, LSCs ['l1', 'l9', 'l17', 'l18']", + "92, in ['l2', 'l10', 'l17', 'l19']", + "93, vitro ['l3', 'l11', 'l18', 'l19']", + "96, xenotransplantation ['l4', 'l12', 'l20', 'l21']", + "112, older ['l5', 'l13', 'l20', 'l22', 'l23', 'l24']", + "113, patients ['l6', 'l14', 'l21', 'l22', 'l25', 'l26']", + "114, with ['l7', 'l15', 'l23', 'l25', 'l27']", + "115, AML ['l8', 'l16', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32601335", + "TEXT": "Immune-regulatory mechanisms of drug-free remission in rheumatoid arthritis (RA) are unknown. We hypothesized that synovial tissue macrophages (STM), which persist in remission, contribute to joint homeostasis. We used single-cell transcriptomics to profile 32,000 STMs and identified phenotypic changes in patients with early/active RA, treatment-refractory/active RA and RA in sustained remission. Each clinical state was characterized by different frequencies of nine discrete phenotypic clusters within four distinct STM subpopulations with diverse homeostatic, regulatory and inflammatory functions. This cellular atlas, combined with deep-phenotypic, spatial and functional analyses of synovial biopsy fluorescent activated cell sorted STMs, revealed two STM subpopulations (MerTKposTREM2high and MerTKposLYVE1pos) with unique remission transcriptomic signatures enriched in negative regulators of inflammation. These STMs were potent producers of inflammation-resolving lipid mediators and induced the repair response of synovial fibroblasts in vitro. A low proportion of MerTKpos STMs in remission was associated with increased risk of disease flare after treatment cessation. Therapeutic modulation of MerTKpos STM subpopulations could therefore be a potential treatment strategy for RA.", + "TAG_DATA": [ + "125, synovial {'context': 'B-cells'}", + "126, fibroblasts {'context': 'I-cells'}", + "127, in {'context': 'B-in vitro'}", + "128, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "125, synovial ['l0', 'l1', 'l2']", + "126, fibroblasts ['l0', 'l3', 'l4']", + "127, in ['l1', 'l3', 'l5']", + "128, vitro. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32572265", + "TEXT": "Definitive diagnosis of intracranial tumors relies on tissue specimens obtained by invasive surgery. Noninvasive diagnostic approaches provide an opportunity to avoid surgery and mitigate unnecessary risk to patients. In the present study, we show that DNA-methylation profiles from plasma reveal highly specific signatures to detect and accurately discriminate common primary intracranial tumors that share cell-of-origin lineages and can be challenging to distinguish using standard-of-care imaging.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32546824", + "TEXT": "The COVID-19 pandemic has shown a markedly low proportion of cases among children1-4. Age disparities in observed cases could be explained by children having lower susceptibility to infection, lower propensity to show clinical symptoms or both. We evaluate these possibilities by fitting an age-structured mathematical model to epidemic data from China, Italy, Japan, Singapore, Canada and South Korea. We estimate that susceptibility to infection in individuals under 20 years of age is approximately half that of adults aged over 20 years, and that clinical symptoms manifest in 21% (95% credible interval: 12-31%) of infections in 10- to 19-year-olds, rising to 69% (57-82%) of infections in people aged over 70 years. Accordingly, we find that interventions aimed at children might have a relatively small impact on reducing SARS-CoV-2 transmission, particularly if the transmissibility of subclinical infections is low. Our age-specific clinical fraction and susceptibility estimates have implications for the expected global burden of COVID-19, as a result of demographic differences across settings. In countries with younger population structures-such as many low-income countries-the expected per capita incidence of clinical cases would be lower than in countries with older population structures, although it is likely that comorbidities in low-income countries will also influence disease severity. Without effective control measures, regions with relatively older populations could see disproportionally more cases of COVID-19, particularly in the later stages of an unmitigated epidemic.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32514174", + "TEXT": "There is an urgent need to better understand the pathophysiology of Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, which has infected more than three million people worldwide1. Approximately 20% of patients with COVID-19 develop severe disease and 5% of patients require intensive care2. Severe disease has been associated with changes in peripheral immune activity, including increased levels of pro-inflammatory cytokines3,4 that may be produced by a subset of inflammatory monocytes5,6, lymphopenia7,8 and T cell exhaustion9,10. To elucidate pathways in peripheral immune cells that might lead to immunopathology or protective immunity in severe COVID-19, we applied single-cell RNA sequencing (scRNA-seq) to profile peripheral blood mononuclear cells (PBMCs) from seven patients hospitalized for COVID-19, four of whom had acute respiratory distress syndrome, and six healthy controls. We identify reconfiguration of peripheral immune cell phenotype in COVID-19, including a heterogeneous interferon-stimulated gene signature, HLA class II downregulation and a developing neutrophil population that appears closely related to plasmablasts appearing in patients with acute respiratory failure requiring mechanical ventilation. Importantly, we found that peripheral monocytes and lymphocytes do not express substantial amounts of pro-inflammatory cytokines. Collectively, we provide a cell atlas of the peripheral immune response to severe COVID-19.", + "TAG_DATA": [ + "104, peripheral {'context': 'B-cells'}", + "105, blood {'context': 'I-cells'}", + "106, mononuclear {'context': 'I-cells'}", + "107, cells {'context': 'I-cells'}", + "108, (PBMCs) {'context': 'I-cells'}", + "172, peripheral {'context': 'B-cells'}", + "173, monocytes {'context': 'I-cells'}", + "175, lymphocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "104, peripheral ['l0', 'l1', 'l2', 'l3']", + "105, blood ['l0', 'l4', 'l5', 'l6']", + "106, mononuclear ['l1', 'l4', 'l7', 'l8']", + "107, cells ['l2', 'l5', 'l7', 'l9']", + "108, (PBMCs) ['l3', 'l6', 'l8', 'l9']", + "172, peripheral ['l10', 'l11']", + "173, monocytes ['l10', 'l12']", + "175, lymphocytes ['l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32483361", + "TEXT": "The mucosal epithelium is a common target of damage by chronic bacterial infections and the accompanying toxins, and most cancers originate from this tissue. We investigated whether colibactin, a potent genotoxin1 associated with certain strains of Escherichia coli2, creates a specific DNA-damage signature in infected human colorectal cells. Notably, the genomic contexts of colibactin-induced DNA double-strand breaks were enriched for an AT-rich hexameric sequence motif, associated with distinct DNA-shape characteristics. A survey of somatic mutations at colibactin target sites of several thousand cancer genomes revealed notable enrichment of this motif in colorectal cancers. Moreover, the exact double-strand-break loci corresponded with mutational hot spots in cancer genomes, reminiscent of a trinucleotide signature previously identified in healthy colorectal epithelial cells3. The present study provides evidence for the etiological role of colibactin in human cancer.", + "TAG_DATA": [ + "45, human {'context': 'B-cells'}", + "46, colorectal {'context': 'I-cells'}", + "47, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, human ['l0', 'l1']", + "46, colorectal ['l0', 'l2']", + "47, cells. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32483358", + "TEXT": "Neutralizing antibodies to adeno-associated virus (AAV) vectors are highly prevalent in humans1,2, and block liver transduction3-5 and vector readministration6; thus, they represent a major limitation to in vivo gene therapy. Strategies aimed at overcoming anti-AAV antibodies are being studied7, which often involve immunosuppression and are not efficient in removing pre-existing antibodies. Imlifidase (IdeS) is an endopeptidase able to degrade circulating IgG that is currently being tested in transplant patients8. Here, we studied if IdeS could eliminate anti-AAV antibodies in the context of gene therapy. We showed efficient cleavage of pooled human IgG (intravenous Ig) in vitro upon endopeptidase treatment. In mice passively immunized with intravenous Ig, IdeS administration decreased anti-AAV antibodies and enabled efficient liver gene transfer. The approach was scaled up to nonhuman primates, a natural host for wild-type AAV. IdeS treatment before AAV vector infusion was safe and resulted in enhanced liver transduction, even in the setting of vector readministration. Finally, IdeS reduced anti-AAV antibody levels from human plasma samples in vitro, including plasma from prospective gene therapy trial participants. These results provide a potential solution to overcome pre-existing antibodies to AAV-based gene therapy.", + "TAG_DATA": [ + "94, in {'context': 'B-in vitro'}", + "95, vitro {'context': 'I-in vitro'}", + "100, mice {'context': 'B-organism'}", + "114, liver {'context': 'B-tissue/organ'}", + "123, nonhuman {'context': 'B-organism'}", + "124, primates, {'context': 'I-organism'}", + "143, liver {'context': 'B-tissue/organ'}", + "162, in {'context': 'B-in vitro'}", + "163, vitro, {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "94, in ['l0']", + "95, vitro ['l0']", + "100, mice ['l1']", + "114, liver ['l1']", + "123, nonhuman ['l2', 'l3']", + "124, primates, ['l2', 'l4']", + "143, liver ['l3', 'l4']", + "162, in ['l5']", + "163, vitro, ['l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32472114", + "TEXT": "PD-1 blockade has transformed the management of advanced clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of the PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors from patients with advanced ccRCC enrolled in prospective clinical trials of treatment with PD-1 blockade by whole-exome and RNA sequencing, integrated with immunofluorescence analysis, to uncover the immunogenomic determinants of the therapeutic response. Although conventional genomic markers (such as tumor mutation burden and neoantigen load) and the degree of CD8+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations associated with response or resistance to PD-1 blockade. These advanced ccRCC tumors were highly CD8+ T cell infiltrated, with only 27% having a non-infiltrated phenotype. Our analysis revealed that infiltrated tumors are depleted of favorable PBRM1 mutations and enriched for unfavorable chromosomal losses of 9p21.3, as compared with non-infiltrated tumors, demonstrating how the potential interplay of immunophenotypes with somatic alterations impacts therapeutic efficacy.", + "TAG_DATA": [ + "30, tumors {'context': 'B-neoplasm'}", + "32, patients {'context': 'I-patient'}", + "33, with {'context': 'I-neoplasm'}", + "34, advanced {'context': 'I-neoplasm'}", + "35, ccRCC {'context': 'I-neoplasm'}", + "103, advanced {'context': 'B-neoplasm'}", + "104, ccRCC {'context': 'I-neoplasm'}", + "105, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "30, tumors ['l0', 'l1', 'l2', 'l3']", + "32, patients ['l0', 'l4', 'l5', 'l6']", + "33, with ['l1', 'l4', 'l7', 'l8']", + "34, advanced ['l2', 'l5', 'l7', 'l9']", + "35, ccRCC ['l3', 'l6', 'l8', 'l9']", + "103, advanced ['l10', 'l11']", + "104, ccRCC ['l10', 'l12']", + "105, tumors ['l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32461698", + "TEXT": "Remarkable progress in molecular analyses has improved our understanding of the evolution of cancer cells toward immune escape1-5. However, the spatial configurations of immune and stromal cells, which may shed light on the evolution of immune escape across tumor geographical locations, remain unaddressed. We integrated multiregion exome and RNA-sequencing (RNA-seq) data with spatial histology mapped by deep learning in 100 patients with non-small cell lung cancer from the TRACERx cohort6. Cancer subclones derived from immune cold regions were more closely related in mutation space, diversifying more recently than subclones from immune hot regions. In TRACERx and in an independent multisample cohort of 970 patients with lung adenocarcinoma, tumors with more than one immune cold region had a higher risk of relapse, independently of tumor size, stage and number of samples per patient. In lung adenocarcinoma, but not lung squamous cell carcinoma, geometrical irregularity and complexity of the cancer-stromal cell interface significantly increased in tumor regions without disruption of antigen presentation. Decreased lymphocyte accumulation in adjacent stroma was observed in tumors with low clonal neoantigen burden. Collectively, immune geospatial variability elucidates tumor ecological constraints that may shape the emergence of immune-evading subclones and aggressive clinical phenotypes.", + "TAG_DATA": [ + "60, patients {'context': 'B-patient'}", + "61, with {'context': 'I-patient'}", + "62, non-small {'context': 'I-patient'}", + "63, cell {'context': 'I-neoplasm'}", + "64, lung {'context': 'I-neoplasm'}", + "65, cancer {'context': 'I-neoplasm'}", + "105, lung {'context': 'B-neoplasm'}", + "106, adenocarcinoma, {'context': 'I-neoplasm'}", + "107, tumors {'context': 'B-neoplasm'}", + "133, lung {'context': 'B-neoplasm'}", + "134, adenocarcinoma, {'context': 'I-neoplasm'}", + "169, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "60, patients ['l0', 'l1', 'l2', 'l3', 'l4']", + "61, with ['l0', 'l5', 'l6', 'l7', 'l8']", + "62, non-small ['l1', 'l5', 'l9', 'l10', 'l11']", + "63, cell ['l2', 'l6', 'l9', 'l12', 'l13']", + "64, lung ['l3', 'l7', 'l10', 'l12', 'l14']", + "65, cancer ['l4', 'l8', 'l11', 'l13', 'l14']", + "105, lung ['l15', 'l16']", + "106, adenocarcinoma, ['l15', 'l17']", + "107, tumors ['l16', 'l17']", + "133, lung ['l18', 'l19', 'l20', 'l21', 'l22']", + "134, adenocarcinoma, ['l18', 'l23', 'l24', 'l25', 'l26']", + "137, lung ['l19', 'l23', 'l27', 'l28', 'l29']", + "138, squamous ['l20', 'l24', 'l27', 'l30', 'l31']", + "139, cell ['l21', 'l25', 'l28', 'l30', 'l32']", + "140, carcinoma, ['l22', 'l26', 'l29', 'l31', 'l32']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32461697", + "TEXT": "Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson's disease3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns5-8, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)9, 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2. Experimental validation of three variants, combined with previous work10, confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.", + "TAG_DATA": [ + "161, heterozygous {'perturbing_action': 'B-other'}", + "162, pLoF {'perturbing_action': 'I-other'}", + "163, variants {'perturbing_action': 'I-other'}", + "164, in {'perturbing_action': 'I-other'}", + "165, LRRK2 {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "161, heterozygous ['l0', 'l1', 'l2', 'l3']", + "162, pLoF ['l0', 'l4', 'l5', 'l6']", + "163, variants ['l1', 'l4', 'l7', 'l8']", + "164, in ['l2', 'l5', 'l7', 'l9']", + "165, LRRK2 ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32451497", + "TEXT": "Common germline variants of the APOE gene are major risk modifiers of neurodegenerative and atherosclerotic diseases1-3, but their effect on cancer outcome is poorly defined. Here we report that, in a reversal of their effect on Alzheimer's disease, the APOE4 and APOE2 variants confer favorable and poor outcomes in melanoma, respectively. Mice expressing the human APOE4 allele exhibited reduced melanoma progression and metastasis relative to APOE2 mice. APOE4 mice exhibited enhanced anti-tumor immune activation relative to APOE2 mice, and T cell depletion experiments showed that the effect of APOE genotype on melanoma progression was mediated by altered anti-tumor immunity. Consistently, patients with melanoma carrying the APOE4 variant experienced improved survival in comparison to carriers of APOE2. Notably, APOE4 mice also showed improved outcomes under PD1 immune checkpoint blockade relative to APOE2 mice, and patients carrying APOE4 experienced improved anti-PD1 immunotherapy survival after progression on frontline regimens. Finally, enhancing APOE expression via pharmacologic activation of liver X receptors, previously shown to boost anti-tumor immunity4, exhibited therapeutic efficacy in APOE4 mice but not in APOE2 mice. These findings demonstrate that pre-existing hereditary genetics can impact progression and survival outcomes of a future malignancy and warrant prospective investigation of APOE genotype as a biomarker for melanoma outcome and therapeutic response.", + "TAG_DATA": [ + "51, Mice {'context': 'B-organism'}", + "52, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "53, the {'perturbing_action': 'I-gene gain-of-function'}", + "54, human {'perturbing_action': 'I-gene gain-of-function'}", + "55, APOE4 {'perturbing_action': 'I-other'}", + "56, allele {'perturbing_action': 'I-gene gain-of-function'}", + "58, reduced {'effect': 'B-negative'}", + "59, melanoma {'context': 'B-neoplasm'}", + "62, metastasis {'phenotype': 'B-metastasis'}", + "68, mice {'context': 'B-organism'}", + "91, melanoma {'context': 'B-neoplasm'}", + "100, patients {'context': 'B-patient'}", + "102, melanoma {'context': 'B-neoplasm'}", + "105, APOE4 {'perturbing_action': 'I-other'}", + "106, variant {'perturbing_action': 'I-other'}", + "118, mice {'context': 'B-organism'}", + "133, patients {'context': 'B-patient'}", + "147, enhancing {'perturbing_action': 'B-gene gain-of-function'}", + "148, APOE {'perturbing_action': 'I-gene gain-of-function'}", + "149, expression {'perturbing_action': 'I-gene gain-of-function'}", + "168, mice {'context': 'B-organism'}", + "173, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "51, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "52, expressing ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "53, the ['l1', 'l8', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "54, human ['l2', 'l9', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "55, APOE4 ['l3', 'l10', 'l18', 'l25', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "56, allele ['l4', 'l11', 'l19', 'l26', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "58, reduced ['l5', 'l12', 'l20', 'l27', 'l33', 'l38', 'l43', 'l44']", + "59, melanoma ['l6', 'l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l45']", + "62, metastasis ['l7', 'l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l45']", + "68, mice ['l15', 'l23', 'l30', 'l36', 'l41', 'l46']", + "91, melanoma ['l16', 'l24', 'l31', 'l37', 'l42', 'l46']", + "100, patients ['l47', 'l48', 'l49']", + "102, melanoma ['l47', 'l50', 'l51']", + "105, APOE4 ['l48', 'l50', 'l52']", + "106, variant ['l49', 'l51', 'l52']", + "147, enhancing ['l53', 'l54', 'l55', 'l56']", + "148, APOE ['l53', 'l57', 'l58', 'l59']", + "149, expression ['l54', 'l57', 'l60', 'l61']", + "168, mice ['l55', 'l58', 'l60', 'l62']", + "173, mice. ['l56', 'l59', 'l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice", + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "the", + "human", + "allele", + "enhancing", + "APOE", + "expression" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "APOE4" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "the", + "human", + "allele" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "the", + "human", + "allele" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "melanoma" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "the", + "human", + "allele" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "APOE4" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "APOE4", + "variant" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "melanoma" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "APOE4" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "melanoma" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "melanoma" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "APOE4", + "variant" + ] + } + } + ] + }, + { + "PMID": "32451496", + "TEXT": "The circumsporozoite protein of the human malaria parasite Plasmodium falciparum (PfCSP) is the main target of antibodies that prevent the infection and disease, as shown in animal models. However, the limited efficacy of the PfCSP-based vaccine RTS,S calls for a better understanding of the mechanisms driving the development of the most potent human PfCSP antibodies and identification of their target epitopes. By characterizing 200 human monoclonal PfCSP antibodies induced by sporozoite immunization, we establish that the most potent antibodies bind around a conserved (N/D)PNANPN(V/A) core. High antibody affinity to the core correlates with protection from parasitemia in mice and evolves around the recognition of NANP motifs. The data suggest that the rational design of a next-generation PfCSP vaccine that elicits high-affinity antibody responses against the core epitope will promote the induction of protective humoral immune responses.", + "TAG_DATA": [ + "97, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32405060", + "TEXT": "Single-cell genomics is essential to chart tumor ecosystems. Although single-cell RNA-Seq (scRNA-Seq) profiles RNA from cells dissociated from fresh tumors, single-nucleus RNA-Seq (snRNA-Seq) is needed to profile frozen or hard-to-dissociate tumors. Each requires customization to different tissue and tumor types, posing a barrier to adoption. Here, we have developed a systematic toolbox for profiling fresh and frozen clinical tumor samples using scRNA-Seq and snRNA-Seq, respectively. We analyzed 216,490 cells and nuclei from 40 samples across 23 specimens spanning eight tumor types of varying tissue and sample characteristics. We evaluated protocols by cell and nucleus quality, recovery rate and cellular composition. scRNA-Seq and snRNA-Seq from matched samples recovered the same cell types, but at different proportions. Our work provides guidance for studies in a broad range of tumors, including criteria for testing and selecting methods from the toolbox for other tumors, thus paving the way for charting tumor atlases.", + "TAG_DATA": [ + "109, cell {'context': 'B-cells'}", + "110, types, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "109, cell ['l0']", + "110, types, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32398875", + "TEXT": "Respiratory immune characteristics associated with Coronavirus Disease 2019 (COVID-19) severity are currently unclear. We characterized bronchoalveolar lavage fluid immune cells from patients with varying severity of COVID-19 and from healthy people by using single-cell RNA sequencing. Proinflammatory monocyte-derived macrophages were abundant in the bronchoalveolar lavage fluid from patients with severe COVID-9. Moderate cases were characterized by the presence of highly clonally expanded CD8+ T cells. This atlas of the bronchoalveolar immune microenvironment suggests potential mechanisms underlying pathogenesis and recovery in COVID-19.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32371934", + "TEXT": "We identified seasonal human coronaviruses, influenza viruses and rhinoviruses in exhaled breath and coughs of children and adults with acute respiratory illness. Surgical face masks significantly reduced detection of influenza virus RNA in respiratory droplets and coronavirus RNA in aerosols, with a trend toward reduced detection of coronavirus RNA in respiratory droplets. Our results indicate that surgical face masks could prevent transmission of human coronaviruses and influenza viruses from symptomatic individuals.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32367060", + "TEXT": "The ongoing substance misuse epidemic in the United States is complex and dynamic and should be approached as such in the development and evaluation of policy1. Drug overdose deaths (largely attributable to opioid misuse) in the United States have grown exponentially for almost four decades, but the mechanisms of this growth are poorly understood2. From analysis of 661,565 overdose deaths from 1999 to 2017, we show that the age-specific drug overdose mortality curve for each birth-year cohort rises and falls according to a Gaussian-shaped curve. The ascending portion of each successive birth-year cohort mortality curve is accelerated compared with that of all preceding birth-year cohorts. This acceleration can be attributed to either of two distinct processes: a stable peak age, with an increasing amplitude of mortality rate curves from one birth-year cohort to the next; or a youthward shift in the peak age of the mortality rate curves. The overdose epidemic emerged and increased in amplitude among the 1945-1964 cohort (Baby Boomers), shifted youthward among the 1965-1980 cohort (Generation X), and then resumed the pattern of increasing amplitude in the 1981-1990 Millennials. These shifting age and generational patterns are likely to be driven by socioeconomic factors and drug availability, the understanding of which is important for the development of effective overdose prevention measures.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32327758", + "TEXT": "We investigated SARS-CoV-2 potential tropism by surveying expression of viral entry-associated genes in single-cell RNA-sequencing data from multiple tissues from healthy human donors. We co-detected these transcripts in specific respiratory, corneal and intestinal epithelial cells, potentially explaining the high efficiency of SARS-CoV-2 transmission. These genes are co-expressed in nasal epithelial cells with genes involved in innate immunity, highlighting the cells' potential role in initial viral infection, spread and clearance. The study offers a useful resource for further lines of inquiry with valuable clinical samples from COVID-19 patients and we provide our data in a comprehensive, open and user-friendly fashion at www.covid19cellatlas.org.", + "TAG_DATA": [ + "29, respiratory, {'context': 'B-cells'}", + "30, corneal {'context': 'I-cells'}", + "31, and {'context': 'I-cells'}", + "32, intestinal {'context': 'I-cells'}", + "33, epithelial {'context': 'I-cells'}", + "34, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "29, respiratory, ['l0', 'l1', 'l2', 'l3', 'l4']", + "30, corneal ['l0', 'l5', 'l6', 'l7', 'l8']", + "31, and ['l1', 'l5', 'l9', 'l10', 'l11']", + "32, intestinal ['l2', 'l6', 'l9', 'l12', 'l13']", + "33, epithelial ['l3', 'l7', 'l10', 'l12', 'l14']", + "34, cells, ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32322102", + "TEXT": "In Italy, 128,948 confirmed cases and 15,887 deaths of people who tested positive for SARS-CoV-2 were registered as of 5 April 2020. Ending the global SARS-CoV-2 pandemic requires implementation of multiple population-wide strategies, including social distancing, testing and contact tracing. We propose a new model that predicts the course of the epidemic to help plan an effective control strategy. The model considers eight stages of infection: susceptible (S), infected (I), diagnosed (D), ailing (A), recognized (R), threatened (T), healed (H) and extinct (E), collectively termed SIDARTHE. Our SIDARTHE model discriminates between infected individuals depending on whether they have been diagnosed and on the severity of their symptoms. The distinction between diagnosed and non-diagnosed individuals is important because the former are typically isolated and hence less likely to spread the infection. This delineation also helps to explain misperceptions of the case fatality rate and of the epidemic spread. We compare simulation results with real data on the COVID-19 epidemic in Italy, and we model possible scenarios of implementation of countermeasures. Our results demonstrate that restrictive social-distancing measures will need to be combined with widespread testing and contact tracing to end the ongoing COVID-19 pandemic.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32284619", + "TEXT": "Large-scale collection of data could help curb the COVID-19 pandemic, but it should not neglect privacy and public trust. Best practices should be identified to maintain responsible data-collection and data-processing standards at a global scale.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32235930", + "TEXT": "Direct evidence in humans for the impact of the microbiome on nutrient absorption is lacking. We conducted an extended inpatient study using two interventions that we hypothesized would alter the gut microbiome and nutrient absorption. In each, stool calorie loss, a direct proxy of nutrient absorption, was measured. The first phase was a randomized cross-over dietary intervention in which all participants underwent in random order 3 d of over- and underfeeding. The second was a randomized, double-blind, placebo-controlled pharmacologic intervention using oral vancomycin or matching placebo (NCT02037295). Twenty-seven volunteers (17 men and 10 women, age 35.1 ± 7.3, BMI 32.3 ± 8.0), who were healthy other than having impaired glucose tolerance and obesity, were enrolled and 25 completed the entire trial. The primary endpoints were the effects of dietary and pharmacological intervention on stool calorie loss. We hypothesized that stool calories expressed as percentage of caloric intake would increase with underfeeding compared with overfeeding and increase during oral vancomycin treatment. Both primary endpoints were met. Greater stool calorie loss was observed during underfeeding relative to overfeeding and during vancomycin treatment compared with placebo. Key secondary endpoints were to evaluate the changes in gut microbial community structure as evidenced by amplicon sequencing and metagenomics. We observed only a modest perturbation of gut microbial community structure with under- versus overfeeding but a more widespread change in community structure with reduced diversity with oral vancomycin. Increase in Akkermansia muciniphila was common to both interventions that resulted in greater stool calorie loss. These results indicate that nutrient absorption is sensitive to environmental perturbations and support the translational relevance of preclinical models demonstrating a possible causal role for the gut microbiome in dietary energy harvest.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32231295", + "TEXT": "The National Institute of Mental Health (NIMH) 'fast-fail' approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia with a POM study determining whether robust target engagement favorably impacts the brain circuitry hypothesized to mediate clinical effects. Here we report the results from a multicenter, 8-week, double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder (selective KOR antagonist (JNJ-67953964, 10 mg; n = 45) and placebo (n = 44)). JNJ-67953964 significantly increased functional magnetic resonance imaging (fMRI) ventral striatum activation during reward anticipation (primary outcome) as compared to placebo (baseline-adjusted mean: JNJ-67953964, 0.72 (s.d. = 0.67); placebo, 0.33 (s.d. = 0.68); F(1,86) = 5.58, P < 0.01; effect size = 0.58 (95% confidence interval, 0.13-0.99)). JNJ-67953964, generally well tolerated, was not associated with any serious adverse events. This study supports proceeding with assessment of the clinical impact of target engagement and serves as a model for implementing the 'fast-fail' approach.", + "TAG_DATA": [ + "78, patients {'context': 'B-patient'}", + "88, KOR {'perturbing_action': 'I-pharmacological inhibition'}", + "89, antagonist {'perturbing_action': 'I-pharmacological inhibition'}", + "90, (JNJ-67953964, {'perturbing_action': 'I-pharmacological inhibition'}", + "91, 10 mg; {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "78, patients ['l0', 'l1', 'l2', 'l3']", + "88, KOR ['l0', 'l4', 'l5', 'l6']", + "89, antagonist ['l1', 'l4', 'l7', 'l8']", + "90, (JNJ-67953964, ['l2', 'l5', 'l7', 'l9']", + "91, 10 mg; ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "KOR", + "antagonist", + "(JNJ-67953964,", + "10 mg;" + ] + } + } + ] + }, + { + "PMID": "32161412", + "TEXT": "Development of tau-based therapies for Alzheimer's disease requires an understanding of the timing of disease-related changes in tau. We quantified the phosphorylation state at multiple sites of the tau protein in cerebrospinal fluid markers across four decades of disease progression in dominantly inherited Alzheimer's disease. We identified a pattern of tau staging where site-specific phosphorylation changes occur at different periods of disease progression and follow distinct trajectories over time. These tau phosphorylation state changes are uniquely associated with structural, metabolic, neurodegenerative and clinical markers of disease, and some (p-tau217 and p-tau181) begin with the initial increases in aggregate amyloid-β as early as two decades before the development of aggregated tau pathology. Others (p-tau205 and t-tau) increase with atrophy and hypometabolism closer to symptom onset. These findings provide insights into the pathways linking tau, amyloid-β and neurodegeneration, and may facilitate clinical trials of tau-based treatments.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32161403", + "TEXT": "The diagnosis of lymphomas and leukemias requires hematopathologists to integrate microscopically visible cellular morphology with antibody-identified cell surface molecule expression. To merge these into one high-throughput, highly multiplexed, single-cell assay, we quantify cell morphological features by their underlying, antibody-measurable molecular components, which empowers mass cytometers to 'see' like pathologists. When applied to 71 diverse clinical samples, single-cell morphometric profiling reveals robust and distinct patterns of 'morphometric' markers for each major cell type. Individually, lamin B1 highlights acute leukemias, lamin A/C helps distinguish normal from neoplastic mature T cells, and VAMP-7 recapitulates light-cytometric side scatter. Combined with machine learning, morphometric markers form intuitive visualizations of normal and neoplastic cellular distribution and differentiation. When recalibrated for myelomonocytic blast enumeration, this approach is superior to flow cytometry and comparable to expert microscopy, bypassing years of specialized training. The contextualization of traditional surface markers on independent morphometric frameworks permits more sensitive and automated diagnosis of complex hematopoietic diseases.", + "TAG_DATA": [ + "86, T {'context': 'I-cells'}", + "87, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "86, T ['l0']", + "87, cells, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32161402", + "TEXT": "Private industry is increasingly soliciting hospitals to sell or share health data and biospecimens, but current laws offer more disclosure and consent protections for research participants than for patients receiving clinical care. Hospitals can offer more protections than required by law, however, and should move toward greater transparency with their patients about the research use of clinical health data and biospecimens to respect patients and avoid distrust.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32108160", + "TEXT": "In late December 2019, a cluster of patients with ‘atypical pneumonia’ of unknown etiology was reported in Wuhan, China. A novel human coronavirus, now provisionally called ‘SARS-CoV-2’, was identified as the cause of this disease, now named ‘COVID-19’.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32094925", + "TEXT": "Retinal gene therapy has shown great promise in treating retinitis pigmentosa (RP), a primary photoreceptor degeneration that leads to severe sight loss in young people. In the present study, we report the first-in-human phase 1/2, dose-escalation clinical trial for X-linked RP caused by mutations in the RP GTPase regulator (RPGR) gene in 18 patients over up to 6 months of follow-up (https://clinicaltrials.gov/: NCT03116113). The primary outcome of the study was safety, and secondary outcomes included visual acuity, microperimetry and central retinal thickness. Apart from steroid-responsive subretinal inflammation in patients at the higher doses, there were no notable safety concerns after subretinal delivery of an adeno-associated viral vector encoding codon-optimized human RPGR (AAV8-coRPGR), meeting the pre-specified primary endpoint. Visual field improvements beginning at 1 month and maintained to the last point of follow-up were observed in six patients.", + "TAG_DATA": [ + "43, mutations {'perturbing_action': 'B-other'}", + "44, in {'perturbing_action': 'I-other'}", + "45, the {'perturbing_action': 'I-other'}", + "46, RP {'perturbing_action': 'I-other'}", + "47, GTPase {'perturbing_action': 'I-other'}", + "48, regulator {'perturbing_action': 'I-other'}", + "49, (RPGR) {'perturbing_action': 'I-other'}", + "50, gene {'perturbing_action': 'I-other'}", + "53, patients {'context': 'B-patient'}", + "87, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "39, X-linked ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "43, mutations ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "44, in ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "45, the ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "46, RP ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "47, GTPase ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "48, regulator ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "49, (RPGR) ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "50, gene ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "53, patients ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutations", + "in", + "the", + "RP", + "GTPase", + "regulator", + "(RPGR)", + "gene" + ] + }, + "context": { + "val": "patient", + "words": [ + "patients" + ] + } + } + ] + }, + { + "PMID": "32094924", + "TEXT": "Transmembrane protein 30A (TMEM30A) maintains the asymmetric distribution of phosphatidylserine, an integral component of the cell membrane and 'eat-me' signal recognized by macrophages. Integrative genomic and transcriptomic analysis of diffuse large B-cell lymphoma (DLBCL) from the British Columbia population-based registry uncovered recurrent biallelic TMEM30A loss-of-function mutations, which were associated with a favorable outcome and uniquely observed in DLBCL. Using TMEM30A-knockout systems, increased accumulation of chemotherapy drugs was observed in TMEM30A-knockout cell lines and TMEM30A-mutated primary cells, explaining the improved treatment outcome. Furthermore, we found increased tumor-associated macrophages and an enhanced effect of anti-CD47 blockade limiting tumor growth in TMEM30A-knockout models. By contrast, we show that TMEM30A loss-of-function increases B-cell signaling following antigen stimulation-a mechanism conferring selective advantage during B-cell lymphoma development. Our data highlight a multifaceted role for TMEM30A in B-cell lymphomagenesis, and characterize intrinsic and extrinsic vulnerabilities of cancer cells that can be therapeutically exploited.", + "TAG_DATA": [ + "59, TMEM30A-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "69, TMEM30A-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "70, cell {'context': 'B-cells'}", + "71, lines {'context': 'I-cells'}", + "73, TMEM30A-mutated {'perturbing_action': 'B-other'}", + "74, primary {'context': 'B-cells'}", + "75, cells, {'context': 'I-cells'}", + "85, tumor-associated {'context': 'B-cells'}", + "86, macrophages {'context': 'I-cells'}", + "94, limiting {'effect': 'B-negative'}", + "95, tumor {'phenotype': 'B-tumour growth'}", + "96, growth {'phenotype': 'I-tumour growth'}", + "98, TMEM30A-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "99, models. {'context': 'B-neoplasm'}", + "105, TMEM30A {'perturbing_action': 'B-gene loss-of-function'}", + "106, loss-of-function {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "59, TMEM30A-knockout ['l0', 'l1', 'l2', 'l3', 'l4']", + "69, TMEM30A-knockout ['l0', 'l5', 'l6', 'l7', 'l8']", + "70, cell ['l1', 'l5', 'l9']", + "71, lines ['l2', 'l6', 'l9']", + "73, TMEM30A-mutated ['l10', 'l11', 'l12']", + "74, primary ['l3', 'l7', 'l10', 'l13']", + "75, cells, ['l4', 'l8', 'l11', 'l13']", + "85, tumor-associated ['l14', 'l15', 'l16', 'l17', 'l18']", + "86, macrophages ['l12', 'l14', 'l19', 'l20', 'l21']", + "94, limiting ['l15', 'l19', 'l22', 'l23', 'l24', 'l25']", + "95, tumor ['l16', 'l20', 'l22', 'l26', 'l27', 'l28']", + "96, growth ['l17', 'l21', 'l23', 'l26', 'l29', 'l30']", + "98, TMEM30A-knockout ['l24', 'l27', 'l29', 'l31']", + "99, models. ['l18', 'l25', 'l28', 'l30', 'l31']", + "105, TMEM30A ['l32']", + "106, loss-of-function ['l32']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TMEM30A-knockout" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "lines", + "primary", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "TMEM30A-mutated" + ] + }, + "context": { + "val": "cells", + "words": [ + "primary", + "cells,", + "macrophages" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "tumor-associated", + "macrophages" + ] + }, + "effect": { + "val": "negative", + "words": [ + "limiting" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "tumor-associated", + "macrophages" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limiting" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limiting" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TMEM30A-knockout" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limiting" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TMEM30A-knockout" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TMEM30A-knockout" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models." + ] + } + } + ] + }, + { + "PMID": "32066976", + "TEXT": "Tuberculosis (TB) is the leading cause of death from a single infectious agent, requiring at least 6 months of multidrug treatment to achieve cure1. However, the lack of reliable data on antimicrobial pharmacokinetics (PK) at infection sites hinders efforts to optimize antimicrobial dosing and shorten TB treatments2. In this study, we applied a new tool to perform unbiased, noninvasive and multicompartment measurements of antimicrobial concentration-time profiles in humans3. Newly identified patients with rifampin-susceptible pulmonary TB were enrolled in a first-in-human study4 using dynamic [11C]rifampin (administered as a microdose) positron emission tomography (PET) and computed tomography (CT). [11C]rifampin PET-CT was safe and demonstrated spatially compartmentalized rifampin exposures in pathologically distinct TB lesions within the same patients, with low cavity wall rifampin exposures. Repeat PET-CT measurements demonstrated independent temporal evolution of rifampin exposure trajectories in different lesions within the same patients. Similar findings were recapitulated by PET-CT in experimentally infected rabbits with cavitary TB and confirmed using postmortem mass spectrometry. Integrated modeling of the PET-captured concentration-time profiles in hollow-fiber bacterial kill curve experiments provided estimates on the rifampin dosing required to achieve cure in 4 months. These data, capturing the spatial and temporal heterogeneity of intralesional drug PK, have major implications for antimicrobial drug development.", + "TAG_DATA": [ + "70, patients {'context': 'B-patient'}", + "148, rabbits {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32066974", + "TEXT": "Dysregulation of the immune response to bacterial infection can lead to sepsis, a condition with high mortality. Multiple whole-blood gene-expression studies have defined sepsis-associated molecular signatures, but have not resolved changes in transcriptional states of specific cell types. Here, we used single-cell RNA-sequencing to profile the blood of people with sepsis (n = 29) across three clinical cohorts with corresponding controls (n = 36). We profiled total peripheral blood mononuclear cells (PBMCs, 106,545 cells) and dendritic cells (19,806 cells) across all subjects and, on the basis of clustering of their gene-expression profiles, defined 16 immune-cell states. We identified a unique CD14+ monocyte state that is expanded in people with sepsis and validated its power in distinguishing these individuals from controls using public transcriptomic data from subjects with different disease etiologies and from multiple geographic locations (18 cohorts, n = 1,467 subjects). We identified a panel of surface markers for isolation and quantification of the monocyte state and characterized its epigenomic and functional phenotypes, and propose a model for its induction from human bone marrow. This study demonstrates the utility of single-cell genomics in discovering disease-associated cytologic signatures and provides insight into the cellular basis of immune dysregulation in bacterial sepsis.", + "TAG_DATA": [ + "71, dendritic {'context': 'B-cells'}", + "72, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "71, dendritic ['l0']", + "72, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32042192", + "TEXT": "Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22-1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33-1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76-0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses.", + "TAG_DATA": [ + "122, men {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31988463", + "TEXT": "Chronic granulomatous disease (CGD) is a rare inherited disorder of phagocytic cells1,2. We report the initial results of nine severely affected X-linked CGD (X-CGD) patients who received ex vivo autologous CD34+ hematopoietic stem and progenitor cell-based lentiviral gene therapy following myeloablative conditioning in first-in-human studies (trial registry nos. NCT02234934 and NCT01855685). The primary objectives were to assess the safety and evaluate the efficacy and stability of biochemical and functional reconstitution in the progeny of engrafted cells at 12 months. The secondary objectives included the evaluation of augmented immunity against bacterial and fungal infection, as well as assessment of hematopoietic stem cell transduction and engraftment. Two enrolled patients died within 3 months of treatment from pre-existing comorbidities. At 12 months, six of the seven surviving patients demonstrated stable vector copy numbers (0.4-1.8 copies per neutrophil) and the persistence of 16-46% oxidase-positive neutrophils. There was no molecular evidence of either clonal dysregulation or transgene silencing. Surviving patients have had no new CGD-related infections, and six have been able to discontinue CGD-related antibiotic prophylaxis. The primary objective was met in six of the nine patients at 12 months follow-up, suggesting that autologous gene therapy is a promising approach for CGD patients.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31959989", + "TEXT": "Most infants with cystic fibrosis (CF) have pancreatic exocrine insufficiency that results in nutrient malabsorption and requires oral pancreatic enzyme replacement. Newborn screening for CF has enabled earlier diagnosis, nutritional intervention and enzyme replacement for these infants, allowing most infants with CF to achieve their weight goals by 12 months of age1. Nevertheless, most infants with CF continue to have poor linear growth during their first year of life1. Although this early linear growth failure is associated with worse long-term respiratory function and survival2,3, the determinants of body length in infants with CF have not been defined. Several characteristics of the CF gastrointestinal (GI) tract, including inflammation, maldigestion and malabsorption, may promote intestinal dysbiosis4,5. As GI microbiome activities are known to affect endocrine functions6,7, the intestinal microbiome of infants with CF may also impact growth. We identified an early, progressive fecal dysbiosis that distinguished infants with CF and low length from infants with CF and normal length. This dysbiosis included altered abundances of taxa that perform functions that are important for GI health, nutrient harvest and growth hormone signaling, including decreased abundance of Bacteroidetes and increased abundance of Proteobacteria. Thus, the GI microbiota represent a potential therapeutic target for the correction of low linear growth in infants with CF.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31932806", + "TEXT": "The molecular changes that occur with aging are not well understood1-4. Here, we performed longitudinal and deep multiomics profiling of 106 healthy individuals from 29 to 75 years of age and examined how different types of 'omic' measurements, including transcripts, proteins, metabolites, cytokines, microbes and clinical laboratory values, correlate with age. We identified both known and new markers that associated with age, as well as distinct molecular patterns of aging in insulin-resistant as compared to insulin-sensitive individuals. In a longitudinal setting, we identified personal aging markers whose levels changed over a short time frame of 2-3 years. Further, we defined different types of aging patterns in different individuals, termed 'ageotypes', on the basis of the types of molecular pathways that changed over time in a given individual. Ageotypes may provide a molecular assessment of personal aging, reflective of personal lifestyle and medical history, that may ultimately be useful in monitoring and intervening in the aging process.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31932801", + "TEXT": "Methods for identifying patients at high risk for osteoporotic fractures, including dual-energy X-ray absorptiometry (DXA)1,2 and risk predictors like the Fracture Risk Assessment Tool (FRAX)3-6, are underutilized. We assessed the feasibility of automatic, opportunistic fracture risk evaluation based on routine abdomen or chest computed tomography (CT) scans. A CT-based predictor was created using three automatically generated bone imaging biomarkers (vertebral compression fractures (VCFs), simulated DXA T-scores and lumbar trabecular density) and CT metadata of age and sex. A cohort of 48,227 individuals (51.8% women) aged 50-90 with available CTs before 2012 (index date) were assessed for 5-year fracture risk using FRAX with no bone mineral density (BMD) input (FRAXnb) and the CT-based predictor. Predictions were compared to outcomes of major osteoporotic fractures and hip fractures during 2012-2017 (follow-up period). Compared with FRAXnb, the major osteoporotic fracture CT-based predictor presented better receiver operating characteristic area under curve (AUC), sensitivity and positive predictive value (PPV) (+1.9%, +2.4% and +0.7%, respectively). The AUC, sensitivity and PPV measures of the hip fracture CT-based predictor were noninferior to FRAXnb at a noninferiority margin of 1%. When FRAXnb inputs are not available, the initial evaluation of fracture risk can be done completely automatically based on a single abdomen or chest CT, which is often available for screening candidates7,8.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31932796", + "TEXT": "Discovery of genotype-phenotype relationships remains a major challenge in clinical medicine. Here, we combined three sources of phenotypic data to uncover a new mechanism for rare and common diseases resulting from collagen secretion deficits. Using a zebrafish genetic screen, we identified the ric1 gene as being essential for skeletal biology. Using a gene-based phenome-wide association study (PheWAS) in the EHR-linked BioVU biobank, we show that reduced genetically determined expression of RIC1 is associated with musculoskeletal and dental conditions. Whole-exome sequencing identified individuals homozygous-by-descent for a rare variant in RIC1 and, through a guided clinical re-evaluation, it was discovered that they share signs with the BioVU-associated phenome. We named this new Mendelian syndrome CATIFA (cleft lip, cataract, tooth abnormality, intellectual disability, facial dysmorphism, attention-deficit hyperactivity disorder) and revealed further disease mechanisms. This gene-based, PheWAS-guided approach can accelerate the discovery of clinically relevant disease phenome and associated biological mechanisms.", + "TAG_DATA": [ + "36, zebrafish {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31873309", + "TEXT": "Immune checkpoint therapy with anti-CTLA-4 and anti-PD-1/PD-L1 has revolutionized the treatment of many solid tumors. However, the clinical efficacy of immune checkpoint therapy is limited to a subset of patients with specific tumor types1,2. Multiple clinical trials with combinatorial immune checkpoint strategies are ongoing; however, the mechanistic rationale for tumor-specific targeting of immune checkpoints is elusive. To garner an insight into tumor-specific immunomodulatory targets, we analyzed 94 patients representing five different cancer types, including those that respond relatively well to immune checkpoint therapy and those that do not, such as glioblastoma multiforme, prostate cancer and colorectal cancer. Through mass cytometry and single-cell RNA sequencing, we identified a unique population of CD73hi macrophages in glioblastoma multiforme that persists after anti-PD-1 treatment. To test if targeting CD73 would be important for a successful combination strategy in glioblastoma multiforme, we performed reverse translational studies using CD73-/- mice. We found that the absence of CD73 improved survival in a murine model of glioblastoma multiforme treated with anti-CTLA-4 and anti-PD-1. Our data identified CD73 as a specific immunotherapeutic target to improve antitumor immune responses to immune checkpoint therapy in glioblastoma multiforme and demonstrate that comprehensive human and reverse translational studies can be used for rational design of combinatorial immune checkpoint strategies.", + "TAG_DATA": [ + "142, CD73-/- {'perturbing_action': 'B-gene loss-of-function'}", + "143, mice. {'context': 'B-organism'}", + "148, absence {'perturbing_action': 'B-gene loss-of-function'}", + "149, of {'perturbing_action': 'I-gene loss-of-function'}", + "150, CD73 {'perturbing_action': 'I-gene loss-of-function'}", + "155, murine {'context': 'B-organism'}", + "156, model {'context': 'I-neoplasm'}", + "157, of {'context': 'I-neoplasm'}", + "158, glioblastoma {'context': 'I-neoplasm'}", + "159, multiforme {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "142, CD73-/- ['l0']", + "143, mice. ['l0']", + "148, absence ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "149, of ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "150, CD73 ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "155, murine ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "156, model ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "157, of ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "158, glioblastoma ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "159, multiforme ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD73-/-", + "absence", + "of", + "CD73" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "murine" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "CD73" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "model", + "of", + "glioblastoma", + "multiforme" + ] + } + } + ] + }, + { + "PMID": "31806903", + "TEXT": "Aging is a predominant risk factor for several chronic diseases that limit healthspan1. Mechanisms of aging are thus increasingly recognized as potential therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues2-10, which supports a hypothesis that age-related molecular changes in blood could provide new insights into age-related disease biology. We measured 2,925 plasma proteins from 4,263 young adults to nonagenarians (18-95 years old) and developed a new bioinformatics approach that uncovered marked non-linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh and eighth decades of life reflected distinct biological pathways and revealed differential associations with the genome and proteome of age-related diseases and phenotypic traits. This new approach to the study of aging led to the identification of unexpected signatures and pathways that might offer potential targets for age-related diseases.", + "TAG_DATA": [ + "62, young {'context': 'B-cells'}", + "63, adults {'context': 'I-organism'}", + "65, nonagenarians {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "62, young ['l0', 'l1']", + "63, adults ['l0', 'l2']", + "65, nonagenarians ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31806889", + "TEXT": "To celebrate the end of our 25th anniversary year, we asked thought leaders and experts in the field to answer one question: What will shape the next 25 years of medical research?", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31792462", + "TEXT": "Proteins are effector molecules that mediate the functions of genes1,2 and modulate comorbidities3-10, behaviors and drug treatments11. They represent an enormous potential resource for personalized, systemic and data-driven diagnosis, prevention, monitoring and treatment. However, the concept of using plasma proteins for individualized health assessment across many health conditions simultaneously has not been tested. Here, we show that plasma protein expression patterns strongly encode for multiple different health states, future disease risks and lifestyle behaviors. We developed and validated protein-phenotype models for 11 different health indicators: liver fat, kidney filtration, percentage body fat, visceral fat mass, lean body mass, cardiopulmonary fitness, physical activity, alcohol consumption, cigarette smoking, diabetes risk and primary cardiovascular event risk. The analyses were prospectively planned, documented and executed at scale on archived samples and clinical data, with a total of ~85 million protein measurements in 16,894 participants. Our proof-of-concept study demonstrates that protein expression patterns reliably encode for many different health issues, and that large-scale protein scanning12-16 coupled with machine learning is viable for the development and future simultaneous delivery of multiple measures of health. We anticipate that, with further validation and the addition of more protein-phenotype models, this approach could enable a single-source, individualized so-called liquid health check.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31768066", + "TEXT": "Accurate identification of tumor-derived somatic variants in plasma circulating cell-free DNA (cfDNA) requires understanding of the various biological compartments contributing to the cfDNA pool. We sought to define the technical feasibility of a high-intensity sequencing assay of cfDNA and matched white blood cell DNA covering a large genomic region (508 genes; 2 megabases; >60,000× raw depth) in a prospective study of 124 patients with metastatic cancer, with contemporaneous matched tumor tissue biopsies, and 47 controls without cancer. The assay displayed high sensitivity and specificity, allowing for de novo detection of tumor-derived mutations and inference of tumor mutational burden, microsatellite instability, mutational signatures and sources of somatic mutations identified in cfDNA. The vast majority of cfDNA mutations (81.6% in controls and 53.2% in patients with cancer) had features consistent with clonal hematopoiesis. This cfDNA sequencing approach revealed that clonal hematopoiesis constitutes a pervasive biological phenomenon, emphasizing the importance of matched cfDNA-white blood cell sequencing for accurate variant interpretation.", + "TAG_DATA": [ + "61, patients {'context': 'B-patient'}", + "62, with {'context': 'I-patient'}", + "63, metastatic {'context': 'I-neoplasm'}", + "64, cancer, {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "61, patients ['l0', 'l1', 'l2']", + "62, with ['l0', 'l3', 'l4']", + "63, metastatic ['l1', 'l3', 'l5']", + "64, cancer, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31700169", + "TEXT": "The physiology of weight regain still baffles scientists, but surprising insights have emerged.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31636453", + "TEXT": "Since 2012, the United States of America has experienced a biennial spike in pediatric acute flaccid myelitis (AFM)1-6. Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF)2. CSF from children with AFM (n = 42) and other pediatric neurologic disease controls (n = 58) were investigated for intrathecal antiviral antibodies, using a phage display library expressing 481,966 overlapping peptides derived from all known vertebrate and arboviruses (VirScan). Metagenomic next-generation sequencing (mNGS) of AFM CSF RNA (n = 20 cases) was also performed, both unbiased sequencing and with targeted enrichment for EVs. Using VirScan, the viral family significantly enriched by the CSF of AFM cases relative to controls was Picornaviridae, with the most enriched Picornaviridae peptides belonging to the genus Enterovirus (n = 29/42 cases versus 4/58 controls). EV VP1 ELISA confirmed this finding (n = 22/26 cases versus 7/50 controls). mNGS did not detect additional EV RNA. Despite rare detection of EV RNA, pan-viral serology frequently identified high levels of CSF EV-specific antibodies in AFM compared with controls, providing further evidence for a causal role of non-polio EVs in AFM.", + "TAG_DATA": [ + "40, children {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31591606", + "TEXT": "Somatic mutations together with immunoediting drive extensive heterogeneity within non-small-cell lung cancer (NSCLC). Herein we examine heterogeneity of the T cell antigen receptor (TCR) repertoire. The number of TCR sequences selectively expanded in tumors varies within and between tumors and correlates with the number of nonsynonymous mutations. Expanded TCRs can be subdivided into TCRs found in all tumor regions (ubiquitous) and those present in a subset of regions (regional). The number of ubiquitous and regional TCRs correlates with the number of ubiquitous and regional nonsynonymous mutations, respectively. Expanded TCRs form part of clusters of TCRs of similar sequence, suggestive of a spatially constrained antigen-driven process. CD8+ tumor-infiltrating lymphocytes harboring ubiquitous TCRs display a dysfunctional tissue-resident phenotype. Ubiquitous TCRs are preferentially detected in the blood at the time of tumor resection as compared to routine follow-up. These findings highlight a noninvasive method to identify and track relevant tumor-reactive TCRs for use in adoptive T cell immunotherapy.", + "TAG_DATA": [ + "105, CD8+ {'context': 'B-cells'}", + "106, tumor-infiltrating {'context': 'I-cells'}", + "107, lymphocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "105, CD8+ ['l0', 'l1']", + "106, tumor-infiltrating ['l0', 'l2']", + "107, lymphocytes ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31591602", + "TEXT": "An aim of molecular biomarkers is to stratify patients with cancer into disease subtypes predictive of outcome, improving diagnostic precision beyond clinical descriptors such as tumor stage1. Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types2-6. Here, we analyze multi-region whole-exome and RNA sequencing data for 156 tumor regions from 48 patients enrolled in the TRACERx study to explore and control for RNA-ITH in non-small cell lung cancer. We find that chromosomal instability is a major driver of RNA-ITH, and existing prognostic gene expression signatures are vulnerable to tumor sampling bias. To address this, we identify genes expressed homogeneously within individual tumors that encode expression modules of cancer cell proliferation and are often driven by DNA copy-number gains selected early in tumor evolution. Clonal transcriptomic biomarkers overcome tumor sampling bias, associate with survival independent of clinicopathological risk factors, and may provide a general strategy to refine biomarker design across cancer types.", + "TAG_DATA": [ + "71, non-small {'context': 'B-neoplasm'}", + "72, cell {'context': 'I-neoplasm'}", + "73, lung {'context': 'I-neoplasm'}", + "74, cancer. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "71, non-small ['l0', 'l1', 'l2']", + "72, cell ['l0', 'l3', 'l4']", + "73, lung ['l1', 'l3', 'l5']", + "74, cancer. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31591593", + "TEXT": "Therapies to reduce liver fibrosis and stimulate organ regeneration are urgently needed. We conducted a first-in-human, phase 1 dose-escalation trial of autologous macrophage therapy in nine adults with cirrhosis and a Model for End-Stage Liver Disease (MELD) score of 10-16 (ISRCTN 10368050). Groups of three participants received a single peripheral infusion of 107, 108 or up to 109 cells. Leukapheresis and macrophage infusion were well tolerated with no transfusion reactions, dose-limiting toxicities or macrophage activation syndrome. All participants were alive and transplant-free at one year, with only one clinical event recorded, the occurrence of minimal ascites. The primary outcomes of safety and feasibility were met. This study informs and provides a rationale for efficacy studies in cirrhosis and other fibrotic diseases.", + "TAG_DATA": [ + "26, adults {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31406351", + "TEXT": "The microscopic assessment of tissue samples is instrumental for the diagnosis and staging of cancer, and thus guides therapy. However, these assessments demonstrate considerable variability and many regions of the world lack access to trained pathologists. Though artificial intelligence (AI) promises to improve the access and quality of healthcare, the costs of image digitization in pathology and difficulties in deploying AI solutions remain as barriers to real-world use. Here we propose a cost-effective solution: the augmented reality microscope (ARM). The ARM overlays AI-based information onto the current view of the sample in real time, enabling seamless integration of AI into routine workflows. We demonstrate the utility of ARM in the detection of metastatic breast cancer and the identification of prostate cancer, with latency compatible with real-time use. We anticipate that the ARM will remove barriers towards the use of AI designed to improve the accuracy and efficiency of cancer diagnosis.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31359002", + "TEXT": "Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of patients with cancer1. However, whether the T cell response to checkpoint blockade relies on reinvigoration of pre-existing tumor-infiltrating lymphocytes or on recruitment of novel T cells remains unclear2-4. Here we performed paired single-cell RNA and T cell receptor sequencing on 79,046 cells from site-matched tumors from patients with basal or squamous cell carcinoma before and after anti-PD-1 therapy. Tracking T cell receptor clones and transcriptional phenotypes revealed coupling of tumor recognition, clonal expansion and T cell dysfunction marked by clonal expansion of CD8+CD39+ T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, the expansion of T cell clones did not derive from pre-existing tumor-infiltrating T lymphocytes; instead, the expanded clones consisted of novel clonotypes that had not previously been observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8+ T cells and evident in patients with basal or squamous cell carcinoma. These results demonstrate that pre-existing tumor-specific T cells may have limited reinvigoration capacity, and that the T cell response to checkpoint blockade derives from a distinct repertoire of T cell clones that may have just recently entered the tumor.", + "TAG_DATA": [ + "56, cells {'context': 'B-cells'}", + "58, site-matched {'context': 'B-neoplasm'}", + "59, tumors {'context': 'I-neoplasm'}", + "61, patients {'context': 'B-patient'}", + "62, with {'context': 'I-patient'}", + "63, basal {'context': 'B-neoplasm'}", + "64, or {'context': 'I-neoplasm'}", + "65, squamous {'context': 'I-neoplasm'}", + "66, cell {'context': 'I-neoplasm'}", + "67, carcinoma {'context': 'I-neoplasm'}", + "97, CD8+CD39+ {'context': 'B-cells'}", + "98, T {'context': 'I-cells'}", + "99, cells, {'context': 'I-cells'}", + "114, T {'context': 'B-cells'}", + "115, cell {'context': 'B-cells'}", + "146, T {'context': 'B-cells'}", + "147, cells {'context': 'B-cells'}", + "153, CD8+ {'context': 'B-cells'}", + "154, T {'context': 'I-cells'}", + "155, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "56, cells ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "58, site-matched ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "59, tumors ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "61, patients ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "62, with ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "63, basal ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "64, or ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "65, squamous ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43', 'l44']", + "66, cell ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l45', 'l46']", + "67, carcinoma ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "97, CD8+CD39+ ['l47', 'l48']", + "98, T ['l47', 'l49']", + "99, cells, ['l44', 'l46', 'l48', 'l49']", + "114, T ['l50']", + "115, cell ['l50']", + "146, T ['l51', 'l52', 'l53', 'l54']", + "147, cells ['l51', 'l55', 'l56', 'l57']", + "153, CD8+ ['l52', 'l55', 'l58', 'l59']", + "154, T ['l53', 'l56', 'l58', 'l60']", + "155, cells ['l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31359001", + "TEXT": "In response to various stimuli, vascular smooth muscle cells (SMCs) can de-differentiate, proliferate and migrate in a process known as phenotypic modulation. However, the phenotype of modulated SMCs in vivo during atherosclerosis and the influence of this process on coronary artery disease (CAD) risk have not been clearly established. Using single-cell RNA sequencing, we comprehensively characterized the transcriptomic phenotype of modulated SMCs in vivo in atherosclerotic lesions of both mouse and human arteries and found that these cells transform into unique fibroblast-like cells, termed 'fibromyocytes', rather than into a classical macrophage phenotype. SMC-specific knockout of TCF21-a causal CAD gene-markedly inhibited SMC phenotypic modulation in mice, leading to the presence of fewer fibromyocytes within lesions as well as within the protective fibrous cap of the lesions. Moreover, TCF21 expression was strongly associated with SMC phenotypic modulation in diseased human coronary arteries, and higher levels of TCF21 expression were associated with decreased CAD risk in human CAD-relevant tissues. These results establish a protective role for both TCF21 and SMC phenotypic modulation in this disease.", + "TAG_DATA": [ + "61, SMCs {'context': 'B-cells'}", + "62, in {'context': 'B-in vivo'}", + "63, vivo {'context': 'I-in vivo'}", + "69, mouse {'context': 'B-tissue/organ'}", + "70, and {'context': 'I-tissue/organ'}", + "71, human {'context': 'I-tissue/organ'}", + "72, arteries {'context': 'I-tissue/organ'}", + "92, SMC-specific {'perturbing_action': 'B-gene loss-of-function'}", + "93, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "94, of {'perturbing_action': 'I-gene loss-of-function'}", + "95, TCF21-a {'perturbing_action': 'I-gene loss-of-function'}", + "100, SMC {'context': 'B-cells'}", + "104, mice, {'context': 'B-organism'}", + "111, fibromyocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "61, SMCs ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "62, in ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "63, vivo ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "69, mouse ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "70, and ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "71, human ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "72, arteries ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "92, SMC-specific ['l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "93, knockout ['l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "94, of ['l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "95, TCF21-a ['l23', 'l28', 'l32', 'l36', 'l37', 'l38']", + "100, SMC ['l24', 'l29', 'l33', 'l36', 'l39', 'l40']", + "104, mice, ['l25', 'l30', 'l34', 'l37', 'l39', 'l41']", + "111, fibromyocytes ['l26', 'l31', 'l35', 'l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SMC-specific", + "knockout", + "of", + "TCF21-a" + ] + }, + "context": { + "val": "cells", + "words": [ + "SMC", + "fibromyocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SMC-specific", + "knockout", + "of", + "TCF21-a" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "31285633", + "TEXT": "The ability to safely control transgene expression with simple synthetic gene switches is critical for effective gene- and cell-based therapies. In the present study, the signaling pathway controlled by human transient receptor potential (TRP) melastatin 8 (hTRPM8), a TRP channel family member1, is harnessed to control transgene expression. Human TRPM8 signaling is stimulated by menthol, an innocuous, natural, cooling compound, or by exposure to a cool environment (15-18 °C). By functionally linking hTRPM8-induced signaling to a synthetic promoter containing elements that bind nuclear factor of activated T cells, a synthetic gene circuit was designed that can be adjusted by exposure to either a cool environment or menthol. It was shown that this gene switch is functional in various cell types and human primary cells, as well as in mice implanted with engineered cells. In response to transdermal delivery of menthol, microencapsulated cell implants harboring this gene circuit, coupled to expression of either of two therapeutic proteins, insulin or a modified, activin type IIB, receptor ligand trap protein (mActRIIBECD-hFc), could alleviate hyperglycemia in alloxan-treated mice (a model of type 1 diabetes) or reverse muscle atrophy in dexamethasone-treated mice (a model of muscle wasting), respectively. This fully human-derived orthogonal transgene switch should be amenable to a wide range of clinical applications.", + "TAG_DATA": [ + "117, cell {'context': 'B-cells'}", + "118, types {'context': 'I-cells'}", + "120, human {'context': 'B-cells'}", + "121, primary {'context': 'I-cells'}", + "122, cells, {'context': 'I-cells'}", + "127, mice {'context': 'B-organism'}", + "172, mice {'context': 'B-organism'}", + "173, (a {'context': 'B-organism'}", + "180, reverse {'effect': 'B-negative'}", + "185, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "117, cell ['l0', 'l1', 'l2', 'l3']", + "118, types ['l0', 'l4', 'l5', 'l6']", + "120, human ['l1', 'l4', 'l7', 'l8']", + "121, primary ['l2', 'l5', 'l7', 'l9']", + "122, cells, ['l3', 'l6', 'l8', 'l9']", + "172, mice ['l10']", + "173, (a ['l10']", + "180, reverse ['l11', 'l12']", + "181, muscle ['l11', 'l13']", + "185, mice ['l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "reverse" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "31270506", + "TEXT": "Salmonella Typhi is a human host-restricted pathogen that is responsible for typhoid fever in approximately 10.9 million people annually1. The typhoid toxin is postulated to have a central role in disease pathogenesis, the establishment of chronic infection and human host restriction2-6. However, its precise role in typhoid disease in humans is not fully defined. We studied the role of typhoid toxin in acute infection using a randomized, double-blind S. Typhi human challenge model7. Forty healthy volunteers were randomized (1:1) to oral challenge with 104 colony-forming units of wild-type or an isogenic typhoid toxin deletion mutant (TN) of S. Typhi. We observed no significant difference in the rate of typhoid infection (fever ≥38 °C for ≥12 h and/or S. Typhi bacteremia) between participants challenged with wild-type or TN S. Typhi (15 out of 21 (71%) versus 15 out of 19 (79%); P = 0.58). The duration of bacteremia was significantly longer in participants challenged with the TN strain compared with wild-type (47.6 hours (28.9-97.0) versus 30.3(3.6-49.4); P ≤ 0.001). The clinical syndrome was otherwise indistinguishable between wild-type and TN groups. These data suggest that the typhoid toxin is not required for infection and the development of early typhoid fever symptoms within the context of a human challenge model. Further clinical data are required to assess the role of typhoid toxin in severe disease or the establishment of bacterial carriage.", + "TAG_DATA": [ + "75, volunteers {'context': 'I-organism'}", + "90, isogenic {'perturbing_action': 'B-gene loss-of-function'}", + "91, typhoid {'perturbing_action': 'I-gene loss-of-function'}", + "92, toxin {'perturbing_action': 'I-gene loss-of-function'}", + "93, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "94, mutant {'perturbing_action': 'I-gene loss-of-function'}", + "95, (TN) {'perturbing_action': 'I-gene loss-of-function'}", + "96, of {'perturbing_action': 'I-gene loss-of-function'}", + "97, S. {'perturbing_action': 'I-gene loss-of-function'}", + "98, Typhi. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "75, volunteers ['l0', 'l1']", + "90, isogenic ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "91, typhoid ['l2', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "92, toxin ['l3', 'l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "93, deletion ['l4', 'l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "94, mutant ['l5', 'l12', 'l18', 'l23', 'l28', 'l29', 'l30', 'l31']", + "95, (TN) ['l6', 'l13', 'l19', 'l24', 'l28', 'l32', 'l33', 'l34']", + "96, of ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l35', 'l36']", + "97, S. ['l0', 'l8', 'l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l37']", + "98, Typhi. ['l1', 'l9', 'l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "volunteers" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "S.", + "Typhi." + ] + } + } + ] + }, + { + "PMID": "31270504", + "TEXT": "Synthetic biology is driving a new era of medicine through the genetic programming of living cells1,2. This transformative approach allows for the creation of engineered systems that intelligently sense and respond to diverse environments, ultimately adding specificity and efficacy that extends beyond the capabilities of molecular-based therapeutics3-6. One particular area of focus has been the engineering of bacteria as therapeutic delivery systems to selectively release therapeutic payloads in vivo7-11. Here we engineered a non-pathogenic Escherichia coli strain to specifically lyse within the tumor microenvironment and release an encoded nanobody antagonist of CD47 (CD47nb)12, an anti-phagocytic receptor that is commonly overexpressed in several human cancer types13,14. We show that delivery of CD47nb by tumor-colonizing bacteria increases activation of tumor-infiltrating T cells, stimulates rapid tumor regression, prevents metastasis and leads to long-term survival in a syngeneic tumor model in mice. Moreover, we report that local injection of CD47nb-expressing bacteria stimulates systemic tumor-antigen-specific immune responses that reduce the growth of untreated tumors, providing proof-of-concept for an abscopal effect induced by an engineered bacterial immunotherapy. Thus, engineered bacteria may be used for safe and local delivery of immunotherapeutic payloads leading to systemic antitumor immunity.", + "TAG_DATA": [ + "73, non-pathogenic {'context': 'B-cells'}", + "119, cells, {'context': 'I-cells'}", + "120, stimulates {'effect': 'B-positive'}", + "122, tumor {'phenotype': 'B-tumour regression'}", + "123, regression, {'phenotype': 'I-tumour regression'}", + "124, prevents {'effect': 'B-negative'}", + "125, metastasis {'phenotype': 'B-metastasis'}", + "133, syngeneic {'context': 'B-neoplasm'}", + "134, tumor {'context': 'I-neoplasm'}", + "135, model {'context': 'I-neoplasm'}", + "137, mice. {'context': 'B-organism'}", + "158, tumors, {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "73, non-pathogenic ['l0', 'l1', 'l2', 'l3', 'l4']", + "119, cells, ['l0', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "120, stimulates ['l1', 'l5', 'l13', 'l14', 'l15', 'l16']", + "122, tumor ['l2', 'l6', 'l13', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "123, regression, ['l3', 'l7', 'l14', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "124, prevents ['l4', 'l8', 'l15', 'l18', 'l23', 'l28', 'l29', 'l30']", + "125, metastasis ['l9', 'l16', 'l19', 'l24', 'l28', 'l31', 'l32', 'l33', 'l34']", + "133, syngeneic ['l31', 'l35', 'l36', 'l37']", + "134, tumor ['l10', 'l20', 'l25', 'l29', 'l32', 'l35', 'l38', 'l39']", + "135, model ['l11', 'l21', 'l26', 'l30', 'l33', 'l36', 'l38', 'l40']", + "137, mice. ['l12', 'l22', 'l27', 'l34', 'l37', 'l39', 'l40']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "non-pathogenic", + "cells," + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "non-pathogenic", + "cells," + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "non-pathogenic", + "cells," + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression," + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor", + "model" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor", + "model" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "syngeneic", + "tumor", + "model" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "31270503", + "TEXT": "Since most dominant human mutations are single nucleotide substitutions1,2, we explored gene editing strategies to disrupt dominant mutations efficiently and selectively without affecting wild-type alleles. However, single nucleotide discrimination can be difficult to achieve3 because commonly used endonucleases, such as Streptococcus pyogenes Cas9 (SpCas9), can tolerate up to seven mismatches between guide RNA (gRNA) and target DNA. Furthermore, the protospacer-adjacent motif (PAM) in some Cas9 enzymes can tolerate mismatches with the target DNA3,4. To circumvent these limitations, we screened 14 Cas9/gRNA combinations for specific and efficient disruption of a nucleotide substitution that causes the dominant progressive hearing loss, DFNA36. As a model for DFNA36, we used Beethoven mice5, which harbor a point mutation in Tmc1, a gene required for hearing that encodes a pore-forming subunit of mechanosensory transduction channels in inner-ear hair cells6. We identified a PAM variant of Staphylococcus aureus Cas9 (SaCas9-KKH) that selectively and efficiently disrupted the mutant allele, but not the wild-type Tmc1/TMC1 allele, in Beethoven mice and in a DFNA36 human cell line. Adeno-associated virus (AAV)-mediated SaCas9-KKH delivery prevented deafness in Beethoven mice up to one year post injection. Analysis of current ClinVar entries revealed that ~21% of dominant human mutations could be targeted using a similar approach.", + "TAG_DATA": [ + "107, mice5, {'context': 'B-organism'}", + "110, a {'perturbing_action': 'I-other'}", + "111, point {'perturbing_action': 'I-other'}", + "112, mutation {'perturbing_action': 'I-other'}", + "113, in {'perturbing_action': 'I-other'}", + "114, Tmc1, {'perturbing_action': 'I-other'}", + "159, mice {'context': 'B-organism'}", + "164, human {'context': 'I-cells'}", + "165, cell {'context': 'I-cells'}", + "166, line. {'context': 'I-cells'}", + "167, Adeno-associated {'perturbing_action': 'B-gene gain-of-function'}", + "168, virus {'perturbing_action': 'I-gene gain-of-function'}", + "169, (AAV)-mediated {'perturbing_action': 'I-gene gain-of-function'}", + "176, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "107, mice5, ['l0', 'l1', 'l2', 'l3', 'l4']", + "110, a ['l0', 'l5', 'l6', 'l7', 'l8', 'l9']", + "111, point ['l1', 'l5', 'l10', 'l11', 'l12', 'l13']", + "112, mutation ['l2', 'l6', 'l10', 'l14', 'l15', 'l16']", + "113, in ['l3', 'l7', 'l11', 'l14', 'l17', 'l18']", + "114, Tmc1, ['l4', 'l8', 'l12', 'l15', 'l17', 'l19']", + "159, mice ['l9', 'l13', 'l16', 'l18', 'l19']", + "164, human ['l20', 'l21']", + "165, cell ['l20', 'l22']", + "166, line. ['l21', 'l22']", + "167, Adeno-associated ['l23', 'l24', 'l25']", + "168, virus ['l23', 'l26', 'l27']", + "169, (AAV)-mediated ['l24', 'l26', 'l28']", + "176, mice ['l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice5,", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "a", + "point", + "mutation", + "in", + "Tmc1," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adeno-associated", + "virus", + "(AAV)-mediated" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "31263286", + "TEXT": "Most pancreatic neuroendocrine tumors (PNETs) do not produce excess hormones and are therefore considered 'non-functional'1-3. As clinical behaviors vary widely and distant metastases are eventually lethal2,4, biological classifications might guide treatment. Using enhancer maps to infer gene regulatory programs, we find that non-functional PNETs fall into two major subtypes, with epigenomes and transcriptomes that partially resemble islet α- and β-cells. Transcription factors ARX and PDX1 specify these normal cells, respectively5,6, and 84% of 142 non-functional PNETs expressed one or the other factor, occasionally both. Among 103 cases, distant relapses occurred almost exclusively in patients with ARX+PDX1- tumors and, within this subtype, in cases with alternative lengthening of telomeres. These markedly different outcomes belied similar clinical presentations and histology and, in one cohort, occurred irrespective of MEN1 mutation. This robust molecular stratification provides insight into cell lineage correlates of non-functional PNETs, accurately predicts disease course and can inform postoperative clinical decisions.", + "TAG_DATA": [], + "LINK_DATA": [ + "95, ARX+PDX1- ['l0']", + "96, tumors ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31263284", + "TEXT": "Metabolic syndrome is characterized by a constellation of comorbidities that predispose individuals to an increased risk of developing cardiovascular pathologies as well as type 2 diabetes mellitus1. The gut microbiota is a new key contributor involved in the onset of obesity-related disorders2. In humans, studies have provided evidence for a negative correlation between Akkermansia muciniphila abundance and overweight, obesity, untreated type 2 diabetes mellitus or hypertension3-8. Since the administration of A. muciniphila has never been investigated in humans, we conducted a randomized, double-blind, placebo-controlled pilot study in overweight/obese insulin-resistant volunteers; 40 were enrolled and 32 completed the trial. The primary end points were safety, tolerability and metabolic parameters (that is, insulin resistance, circulating lipids, visceral adiposity and body mass). Secondary outcomes were gut barrier function (that is, plasma lipopolysaccharides) and gut microbiota composition. In this single-center study, we demonstrated that daily oral supplementation of 1010 A. muciniphila bacteria either live or pasteurized for three months was safe and well tolerated. Compared to placebo, pasteurized A. muciniphila improved insulin sensitivity (+28.62 ± 7.02%, P = 0.002), and reduced insulinemia (-34.08 ± 7.12%, P = 0.006) and plasma total cholesterol (-8.68 ± 2.38%, P = 0.02). Pasteurized A. muciniphila supplementation slightly decreased body weight (-2.27 ± 0.92 kg, P = 0.091) compared to the placebo group, and fat mass (-1.37 ± 0.82 kg, P = 0.092) and hip circumference (-2.63 ± 1.14 cm, P = 0.091) compared to baseline. After three months of supplementation, A. muciniphila reduced the levels of the relevant blood markers for liver dysfunction and inflammation while the overall gut microbiome structure was unaffected. In conclusion, this proof-of-concept study (clinical trial no. NCT02637115 ) shows that the intervention", + "TAG_DATA": [ + "87, overweight/obese {'context': 'B-organism'}", + "88, insulin-resistant {'context': 'I-organism'}", + "89, volunteers; {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "87, overweight/obese ['l0', 'l1']", + "88, insulin-resistant ['l0', 'l2']", + "89, volunteers; ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31235963", + "TEXT": "Relapse after allogeneic hematopoietic cell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) entering HCT with poor-risk features1-3. When HCT does produce prolonged relapse-free survival, it commonly reflects graft-versus-leukemia effects mediated by donor T cells reactive with antigens on leukemic cells4. As graft T cells have not been selected for leukemia specificity and frequently recognize proteins expressed by many normal host tissues, graft-versus-leukemia effects are often accompanied by morbidity and mortality from graft-versus-host disease5. Thus, AML relapse risk might be more effectively reduced with T cells expressing receptors (TCRs) that target selected AML antigens6. We therefore isolated a high-affinity Wilms' Tumor Antigen 1-specific TCR (TCRC4) from HLA-A2+ normal donor repertoires, inserted TCRC4 into Epstein-Bar virus-specific donor CD8+ T cells (TTCR-C4) to minimize graft-versus-host disease risk and enhance transferred T cell survival7,8, and infused these cells prophylactically post-HCT into 12 patients ( NCT01640301 ). Relapse-free survival was 100% at a median of 44 months following infusion, while a concurrent comparative group of 88 patients with similar risk AML had 54% relapse-free survival (P = 0.002). TTCR-C4 maintained TCRC4 expression, persisted long-term and were polyfunctional. This strategy appears promising for preventing AML recurrence in individuals at increased risk of post-HCT relapse.", + "TAG_DATA": [ + "120, Epstein-Bar {'context': 'B-cells'}", + "122, donor {'context': 'I-cells'}", + "123, CD8+ {'context': 'I-cells'}", + "124, T {'context': 'I-cells'}", + "125, cells {'context': 'I-cells'}", + "135, T {'context': 'B-cells'}", + "136, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "120, Epstein-Bar ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "121, virus-specific ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "122, donor ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "123, CD8+ ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "124, T ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "125, cells ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "135, T ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "136, cell ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31209335", + "TEXT": "Neonates are protected from colonizing bacteria by antibodies secreted into maternal milk. Necrotizing enterocolitis (NEC) is a disease of neonatal preterm infants with high morbidity and mortality that is associated with intestinal inflammation driven by the microbiota1-3. The incidence of NEC is substantially lower in infants fed with maternal milk, although the mechanisms that underlie this benefit are not clear4-6. Here we show that maternal immunoglobulin A (IgA) is an important factor for protection against NEC. Analysis of IgA binding to fecal bacteria from preterm infants indicated that maternal milk was the predominant source of IgA in the first month of life and that a relative decrease in IgA-bound bacteria is associated with the development of NEC. Sequencing of IgA-bound and unbound bacteria revealed that before the onset of disease, NEC was associated with increasing domination by Enterobacteriaceae in the IgA-unbound fraction of the microbiota. Furthermore, we confirmed that IgA is critical for preventing NEC in a mouse model, in which pups that are reared by IgA-deficient mothers are susceptible to disease despite exposure to maternal milk. Our findings show that maternal IgA shapes the host-microbiota relationship of preterm neonates and that IgA in maternal milk is a critical and necessary factor for the prevention of NEC.", + "TAG_DATA": [ + "157, mouse {'context': 'B-organism'}", + "158, model, {'context': 'I-organism'}", + "161, pups {'context': 'B-organism'}", + "166, IgA-deficient {'perturbing_action': 'B-gene loss-of-function'}" + ], + "LINK_DATA": [ + "157, mouse ['l0', 'l1', 'l2']", + "158, model, ['l0']", + "161, pups ['l1', 'l3']", + "166, IgA-deficient ['l2', 'l3']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "pups" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IgA-deficient" + ] + } + } + ] + }, + { + "PMID": "31171876", + "TEXT": "Melanoma treatment has progressed in the past decade with the development and approval of immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand (PD-L1) and cytotoxic T lymphocyte-associated antigen 4, as well as small molecule inhibitors of BRAF and/or MEK for the subgroup of patients with BRAFV600 mutations1-9. BRAF/MEK-targeted therapies have effects on the tumor microenvironment that support their combination with PD-1/PD-L1 inhibitors10-20. This phase Ib study (ClinicalTrials.gov, number NCT01656642 ) evaluated the safety and anti-tumor activity of combining atezolizumab (anti-PD-L1) with vemurafenib (BRAF inhibitor), or cobimetinib (MEK inhibitor) + vemurafenib, in patients with BRAFV600-mutated metastatic melanoma. Triple combination therapy with atezolizumab + cobimetinib + vemurafenib, after a 28-d run-in period with cobimetinib + vemurafenib, had substantial but manageable toxicity. Exploratory biomarker data show that the cobimetinib + vemurafenib run-in was associated with an increase in proliferating CD4+ T-helper cells but not with an increase in T-regulatory cells, as observed in the vemurafenib-only run-in period. The confirmed objective response rate was 71.8% (95% confidence interval 55.1-85.0). The estimated median duration of response was 17.4 months (95% confidence interval 10.6-25.3) with ongoing response in 39.3% of patients after 29.9 months of follow-up. Further investigation in a phase III trial is underway.", + "TAG_DATA": [ + "89, (MEK {'perturbing_action': 'I-pharmacological inhibition'}", + "90, inhibitor) + vemurafenib, {'perturbing_action': 'I-pharmacological inhibition'}", + "92, patients {'context': 'B-patient'}", + "95, metastatic {'context': 'B-neoplasm'}", + "96, melanoma. {'context': 'I-neoplasm'}", + "130, CD4+ {'context': 'I-cells'}", + "131, T-helper {'context': 'I-cells'}", + "132, cells {'context': 'I-cells'}", + "139, T-regulatory {'context': 'B-cells'}", + "140, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "86, inhibitor), ['l0', 'l1', 'l2', 'l3', 'l4']", + "89, (MEK ['l0', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "90, inhibitor) + vemurafenib, ['l1', 'l5', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "92, patients ['l2', 'l6', 'l14', 'l21', 'l22']", + "95, metastatic ['l3', 'l7', 'l15', 'l21', 'l23']", + "96, melanoma. ['l4', 'l8', 'l16', 'l22', 'l23']", + "127, increase ['l9', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28']", + "130, CD4+ ['l10', 'l18', 'l24', 'l29', 'l30', 'l31', 'l32']", + "131, T-helper ['l11', 'l19', 'l25', 'l29', 'l33', 'l34', 'l35']", + "132, cells ['l12', 'l20', 'l26', 'l30', 'l33', 'l36', 'l37']", + "139, T-regulatory ['l27', 'l31', 'l34', 'l36', 'l38']", + "140, cells, ['l13', 'l28', 'l32', 'l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "(MEK", + "inhibitor) + vemurafenib," + ] + }, + "context": { + "val": "patient", + "words": [ + "patients" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "(MEK", + "inhibitor) + vemurafenib," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "metastatic", + "melanoma." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "(MEK", + "inhibitor) + vemurafenib," + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "T-helper", + "cells", + "cells," + ] + } + } + ] + }, + { + "PMID": "31160820", + "TEXT": "It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene1. The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches2-5. For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases6-8. This includes muscle biopsies from patients with undiagnosed rare muscle disorders6,9, and cultured fibroblasts from patients with mitochondrial disorders7. However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31142850", + "TEXT": "The microbiome of the female reproductive tract has implications for women's reproductive health. We examined the vaginal microbiome in two cohorts of women who experienced normal term births: a cross-sectionally sampled cohort of 613 pregnant and 1,969 non-pregnant women, focusing on 300 pregnant and 300 non-pregnant women of African, Hispanic or European ancestry case-matched for race, gestational age and household income; and a longitudinally sampled cohort of 90 pregnant women of African or non-African ancestry. In these women, the vaginal microbiome shifted during pregnancy toward Lactobacillus-dominated profiles at the expense of taxa often associated with vaginal dysbiosis. The shifts occurred early in pregnancy, followed predictable patterns, were associated with simplification of the metabolic capacity of the microbiome and were significant only in women of African or Hispanic ancestry. Both genomic and environmental factors are likely contributors to these trends, with socioeconomic status as a likely environmental influence.", + "TAG_DATA": [ + "42, pregnant {'context': 'B-cells'}", + "43, and {'context': 'I-organism'}", + "45, non-pregnant {'context': 'I-cells'}", + "46, women {'context': 'I-organism'}", + "68, pregnant {'context': 'B-cells'}", + "69, women {'context': 'I-organism'}", + "122, women {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "42, pregnant ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "43, and ['l0', 'l8', 'l9', 'l10', 'l11', 'l12']", + "44, 300 ['l1', 'l8', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "45, non-pregnant ['l2', 'l9', 'l13', 'l20', 'l21', 'l22', 'l23']", + "46, women ['l3', 'l10', 'l14', 'l20', 'l24', 'l25']", + "49, Hispanic ['l4', 'l11', 'l15', 'l21', 'l24', 'l26', 'l27', 'l28']", + "51, European ['l5', 'l12', 'l16', 'l22', 'l25', 'l26']", + "68, pregnant ['l29', 'l30', 'l31']", + "69, women ['l6', 'l17', 'l23', 'l27', 'l29', 'l32', 'l33']", + "72, or ['l7', 'l18', 'l28', 'l30', 'l32', 'l34']", + "73, non-African ['l19', 'l31', 'l33', 'l34']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31036879", + "TEXT": "Modulating T cell homeostatic mechanisms with checkpoint blockade can efficiently promote endogenous anti-tumor T cell responses1-11. However, many patients still do not benefit from checkpoint blockade12, highlighting the need for targeting of alternative immune pathways13. Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) is an attractive target for immunotherapy, owing to its capacity to promote effector T cell (Teff) functions14,15 and hamper regulatory T cell (Treg) suppression16-20. On the basis of the potent preclinical anti-tumor activity of agonist anti-GITR antibodies, reported by us and others16,21,22, we initiated the first in-human phase 1 trial of GITR agonism with the anti-GITR antibody TRX518 ( NCT01239134 ). Here, we report the safety profile and immune effects of TRX518 monotherapy in patients with advanced cancer and provide mechanistic preclinical evidence to rationally combine GITR agonism with checkpoint blockade in future clinical trials. We demonstrate that TRX518 reduces circulating and intratumoral Treg cells to similar extents, providing an easily assessable biomarker of anti-GITR activity. Despite Treg reductions and increased Teff:Treg ratios, substantial clinical responses were not seen. Similarly, in mice with advanced tumors, GITR agonism was not sufficient to activate cytolytic T cells due to persistent exhaustion. We demonstrate that T cell reinvigoration with PD-1 blockade can overcome resistance of advanced tumors to anti-GITR monotherapy. These findings led us to start investigating TRX518 with PD-1 pathway blockade in patients with advanced refractory tumors ( NCT02628574 ).", + "TAG_DATA": [ + "119, cancer {'context': 'I-neoplasm'}", + "173, mice {'context': 'B-organism'}", + "175, advanced {'context': 'I-neoplasm'}", + "176, tumors, {'context': 'I-neoplasm'}", + "178, agonism {'perturbing_action': 'I-pharmacological augmentation'}", + "204, advanced {'context': 'B-neoplasm'}", + "205, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "173, mice ['l0', 'l1', 'l2']", + "175, advanced ['l0', 'l3', 'l4']", + "176, tumors, ['l1', 'l3', 'l5']", + "178, agonism ['l2', 'l4', 'l5', 'l6', 'l7']", + "204, advanced ['l6', 'l8']", + "205, tumors ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "agonism" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "advanced", + "tumors,", + "tumors" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "agonism" + ] + } + } + ] + }, + { + "PMID": "31011205", + "TEXT": "Precision medicine focuses on DNA abnormalities, but not all tumors have tractable genomic alterations. The WINTHER trial ( NCT01856296 ) navigated patients to therapy on the basis of fresh biopsy-derived DNA sequencing (arm A; 236 gene panel) or RNA expression (arm B; comparing tumor to normal). The clinical management committee (investigators from five countries) recommended therapies, prioritizing genomic matches; physicians determined the therapy given. Matching scores were calculated post-hoc for each patient, according to drugs received: for DNA, the number of alterations matched divided by the total alteration number; for RNA, expression-matched drug ranks. Overall, 303 patients consented; 107 (35%; 69 in arm A and 38 in arm B) were evaluable for therapy. The median number of previous therapies was three. The most common diagnoses were colon, head and neck, and lung cancers. Among the 107 patients, the rate of stable disease ≥6 months and partial or complete response was 26.2% (arm A: 23.2%; arm B: 31.6% (P = 0.37)). The patient proportion with WINTHER versus previous therapy progression-free survival ratio of >1.5 was 22.4%, which did not meet the pre-specified primary end point. Fewer previous therapies, better performance status and higher matching score correlated with longer progression-free survival (all P < 0.05, multivariate). Our study shows that genomic and transcriptomic profiling are both useful for improving therapy recommendations and patient outcome, and expands personalized cancer treatment.", + "TAG_DATA": [], + "LINK_DATA": [ + "127, head ['l0', 'l1', 'l2', 'l3']", + "128, and ['l0', 'l4', 'l5', 'l6']", + "129, neck, ['l1', 'l4', 'l7', 'l8']", + "131, lung ['l2', 'l5', 'l7', 'l9']", + "132, cancers. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31011203", + "TEXT": "Chronic inflammation is postulated to be involved in the development of end-stage renal disease in diabetes, but which specific circulating inflammatory proteins contribute to this risk remain unknown. To study this, we examined 194 circulating inflammatory proteins in subjects from three independent cohorts with type 1 and type 2 diabetes. In each cohort, we identified an extremely robust kidney risk inflammatory signature (KRIS), consisting of 17 proteins enriched in tumor necrosis factor-receptor superfamily members, that was associated with a 10-year risk of end-stage renal disease. All these proteins had a systemic, non-kidney source. Our prospective study findings provide strong evidence that KRIS proteins contribute to the inflammatory process underlying end-stage renal disease development in both types of diabetes. These proteins point to new therapeutic targets and new prognostic tests to identify subjects at risk of end-stage renal disease, as well as biomarkers to measure responses to treatment of diabetic kidney disease.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30936548", + "TEXT": "Several studies have investigated links between the gut microbiome and colorectal cancer (CRC), but questions remain about the replicability of biomarkers across cohorts and populations. We performed a meta-analysis of five publicly available datasets and two new cohorts and validated the findings on two additional cohorts, considering in total 969 fecal metagenomes. Unlike microbiome shifts associated with gastrointestinal syndromes, the gut microbiome in CRC showed reproducibly higher richness than controls (P < 0.01), partially due to expansions of species typically derived from the oral cavity. Meta-analysis of the microbiome functional potential identified gluconeogenesis and the putrefaction and fermentation pathways as being associated with CRC, whereas the stachyose and starch degradation pathways were associated with controls. Predictive microbiome signatures for CRC trained on multiple datasets showed consistently high accuracy in datasets not considered for model training and independent validation cohorts (average area under the curve, 0.84). Pooled analysis of raw metagenomes showed that the choline trimethylamine-lyase gene was overabundant in CRC (P = 0.001), identifying a relationship between microbiome choline metabolism and CRC. The combined analysis of heterogeneous CRC cohorts thus identified reproducible microbiome biomarkers and accurate disease-predictive models that can form the basis for clinical prognostic tests and hypothesis-driven mechanistic studies.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30936544", + "TEXT": "Epithelial barrier loss is a driver of intestinal and systemic diseases. Myosin light chain kinase (MLCK) is a key effector of barrier dysfunction and a potential therapeutic target, but enzymatic inhibition has unacceptable toxicity. Here, we show that a unique domain within the MLCK splice variant MLCK1 directs perijunctional actomyosin ring (PAMR) recruitment. Using the domain structure and multiple screens, we identify a domain-binding small molecule (divertin) that blocks MLCK1 recruitment without inhibiting enzymatic function. Divertin blocks acute, tumor necrosis factor (TNF)-induced MLCK1 recruitment as well as downstream myosin light chain (MLC) phosphorylation, barrier loss, and diarrhea in vitro and in vivo. Divertin corrects barrier dysfunction and prevents disease development and progression in experimental inflammatory bowel disease. Beyond applications of divertin in gastrointestinal disease, this general approach to enzymatic inhibition by preventing access to specific subcellular sites provides a new paradigm for safely and precisely targeting individual properties of enzymes with multiple functions.", + "TAG_DATA": [ + "97, in {'context': 'B-in vitro'}", + "98, vitro {'context': 'I-in vitro'}", + "100, in {'context': 'B-in vivo'}", + "101, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "97, in ['l0', 'l1']", + "98, vitro ['l0', 'l2']", + "100, in ['l3']", + "101, vivo. ['l1', 'l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30918364", + "TEXT": "In the version of this article initially published, the label over the bottom schematic in Fig. 1a was \"pH > 5.0\"; it should have been \"pH < 5.0\". Further, the original article misspelt the surname of Katrin P. Guillen as \"Gullien\". These errors have been corrected in the print, PDF and HTML versions of the article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30886409", + "TEXT": "All circulating immunoglobulin G (IgG) antibodies in human newborns are of maternal origin1 and transferred across the placenta to provide passive immunity until newborn IgG production takes over 15 weeks after birth2. However, maternal IgG can also negatively interfere with newborn vaccine responses3. The concentration of IgG increases sharply during the third trimester of gestation and children delivered extremely preterm are believed to largely lack this passive immunity1,2,4. Antibodies to individual viruses have been reported5-12, but the global repertoire of maternal IgG, its variation in children, and the epitopes targeted are poorly understood. Here, we assess antibodies against 93,904 epitopes from 206 viruses in 32 preterm and 46 term mother-child dyads. We find that extremely preterm children receive comparable repertoires of IgG as term children, albeit at lower absolute concentrations and consequent shorter half-life. Neutralization of the clinically important respiratory syncytial virus (RS-virus) was also comparable until three months of age. These findings have implications for understanding infectious disease susceptibility, vaccine development, and vaccine scheduling in newborn children.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30842671", + "TEXT": "Transcriptional signatures and immune cell infiltrates associated with immune activation distinguish patients with glioblastoma who initially respond to immune checkpoint blockade from those who do not.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30833749", + "TEXT": "Celastrol, a pentacyclic triterpene, is the most potent antiobesity agent that has been reported thus far1. The mechanism of celastrol's leptin-sensitizing and antiobesity effects has not yet been elucidated. In this study, we identified interleukin-1 receptor 1 (IL1R1) as a mediator of celastrol's action by using temporally resolved analysis of the hypothalamic transcriptome in celastrol-treated DIO, lean, and db/db mice. We demonstrate that IL1R1-deficient mice are completely resistant to the effects of celastrol in leptin sensitization and treatment of obesity, diabetes, and nonalcoholic steatohepatitis. Thus, we conclude that IL1R1 is a gatekeeper for celastrol's metabolic actions.", + "TAG_DATA": [ + "58, db/db {'context': 'B-organism'}", + "59, mice. {'context': 'I-organism'}", + "63, IL1R1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "64, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "58, db/db ['l0', 'l1']", + "59, mice. ['l0']", + "63, IL1R1-deficient ['l1', 'l2']", + "64, mice ['l2']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "db/db", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IL1R1-deficient" + ] + } + } + ] + }, + { + "PMID": "30833747", + "TEXT": "Spitzoid melanoma is a specific morphologic variant of melanoma that most commonly affects children and adolescents, and ranges on the spectrum of malignancy from low grade to overtly malignant. These tumors are generally driven by fusions of ALK, RET, NTRK1/3, MET, ROS1 and BRAF1,2. However, in approximately 50% of cases no genetic driver has been established2. Clinical whole-genome and transcriptome sequencing (RNA-Seq) of a spitzoid tumor from an adolescent revealed a novel gene fusion of MAP3K8, encoding a serine-threonine kinase that activates MEK3,4. The patient, who had exhausted all other therapeutic options, was treated with a MEK inhibitor and underwent a transient clinical response. We subsequently analyzed spitzoid tumors from 49 patients by RNA-Seq and found in-frame fusions or C-terminal truncations of MAP3K8 in 33% of cases. The fusion transcripts and truncated genes all contained MAP3K8 exons 1-8 but lacked the autoinhibitory final exon. Data mining of RNA-Seq from the Cancer Genome Atlas (TCGA) uncovered analogous MAP3K8 rearrangements in 1.5% of adult melanomas. Thus, MAP3K8 rearrangements-uncovered by comprehensive clinical sequencing of a single case-are the most common genetic event in spitzoid melanoma, are present in adult melanomas and could be amenable to MEK inhibition.", + "TAG_DATA": [ + "96, MEK {'perturbing_action': 'B-pharmacological inhibition'}", + "97, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "107, spitzoid {'context': 'B-neoplasm'}", + "108, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "64, spitzoid ['l0']", + "65, tumor ['l0']", + "96, MEK ['l1', 'l2', 'l3']", + "97, inhibitor ['l1', 'l4', 'l5']", + "107, spitzoid ['l2', 'l4', 'l6']", + "108, tumors ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "MEK", + "inhibitor" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "spitzoid", + "tumors" + ] + } + } + ] + }, + { + "PMID": "30804514", + "TEXT": "MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Heterozygous loss-of-function point mutations of miRNA genes are associated with several human congenital disorders1-5, but neomorphic (gain-of-new-function) mutations in miRNAs due to nucleotide substitutions have not been reported. Here we describe a neomorphic seed region mutation in the chondrocyte-specific, super-enhancer-associated MIR140 gene encoding microRNA-140 (miR-140) in a novel autosomal dominant human skeletal dysplasia. Mice with the corresponding single nucleotide substitution show skeletal abnormalities similar to those of the patients but distinct from those of miR-140-null mice6. This mutant miRNA gene yields abundant mutant miR-140-5p expression without miRNA-processing defects. In chondrocytes, the mutation causes widespread derepression of wild-type miR-140-5p targets and repression of mutant miR-140-5p targets, indicating that the mutation produces both loss-of-function and gain-of-function effects. Furthermore, the mutant miR-140-5p seed competes with the conserved RNA-binding protein Ybx1 for overlapping binding sites. This finding may explain the potent target repression and robust in vivo effect by this mutant miRNA even in the absence of evolutionary selection of miRNA-target RNA interactions, which contributes to the strong regulatory effects of conserved miRNAs7,8. Our study presents the first case of a pathogenic gain-of-function miRNA mutation and provides molecular insight into neomorphic actions of emerging and/or mutant miRNAs.", + "TAG_DATA": [ + "61, Mice {'context': 'B-organism'}", + "82, miR-140-null {'perturbing_action': 'B-gene loss-of-function'}", + "97, chondrocytes, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "61, Mice ['l0']", + "82, miR-140-null ['l0']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "miR-140-null" + ] + } + } + ] + }, + { + "PMID": "30787481", + "TEXT": "In the version of this article originally published, some cases that were presented in Fig. 3 should have been underlined but were not. The appropriate cases have now been underlined. The error has been corrected in the print, PDF and HTML versions of the article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30778239", + "TEXT": "CRISPR/Cas9-based therapies hold considerable promise for the treatment of genetic diseases. Among these, Hutchinson-Gilford progeria syndrome, caused by a point mutation in the LMNA gene, stands out as a potential candidate. Here, we explore the efficacy of a CRISPR/Cas9-based approach that reverts several alterations in Hutchinson-Gilford progeria syndrome cells and mice by introducing frameshift mutations in the LMNA gene.", + "TAG_DATA": [ + "45, Hutchinson-Gilford {'context': 'B-transformed cells'}", + "46, progeria {'context': 'I-transformed cells'}", + "47, syndrome {'context': 'I-transformed cells'}", + "48, cells {'context': 'I-transformed cells'}", + "50, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "45, Hutchinson-Gilford ['l0', 'l1', 'l2', 'l3']", + "46, progeria ['l0', 'l4', 'l5']", + "47, syndrome ['l1', 'l4', 'l6']", + "48, cells ['l2', 'l5', 'l6']", + "50, mice ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30778238", + "TEXT": "Duchenne muscular dystrophy (DMD) is a monogenic disorder and a candidate for therapeutic genome editing. There have been several recent reports of genome editing in preclinical models of Duchenne muscular dystrophy1-6, however, the long-term persistence and safety of these genome editing approaches have not been addressed. Here we show that genome editing and dystrophin protein restoration is sustained in the mdx mouse model of Duchenne muscular dystrophy for 1 year after a single intravenous administration of an adeno-associated virus that encodes CRISPR (AAV-CRISPR). We also show that AAV-CRISPR is immunogenic when administered to adult mice7; however, humoral and cellular immune responses can be avoided by treating neonatal mice. Additionally, we describe unintended genome and transcript alterations induced by AAV-CRISPR that should be considered for the development of AAV-CRISPR as a therapeutic approach. This study shows the potential of AAV-CRISPR for permanent genome corrections and highlights aspects of host response and alternative genome editing outcomes that require further study.", + "TAG_DATA": [ + "60, mdx {'context': 'B-organism'}", + "61, mouse {'context': 'I-organism'}", + "62, model {'context': 'I-organism'}", + "63, of {'context': 'I-organism'}", + "64, Duchenne {'context': 'I-organism'}", + "66, dystrophy {'context': 'I-organism'}", + "92, adult {'context': 'B-organism'}", + "93, mice7; {'context': 'I-organism'}", + "105, neonatal {'context': 'B-organism'}", + "106, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "60, mdx ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "61, mouse ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "62, model ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "63, of ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "64, Duchenne ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "65, muscular ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "66, dystrophy ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "92, adult ['l21']", + "93, mice7; ['l21']", + "105, neonatal ['l22']", + "106, mice. ['l22']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30742120", + "TEXT": "Glioblastoma is the most common primary central nervous system malignancy and has a poor prognosis. Standard first-line treatment, which includes surgery followed by adjuvant radio-chemotherapy, produces only modest benefits to survival1,2. Here, to explore the feasibility, safety and immunobiological effects of PD-1 blockade in patients undergoing surgery for glioblastoma, we conducted a single-arm phase II clinical trial (NCT02550249) in which we tested a presurgical dose of nivolumab followed by postsurgical nivolumab until disease progression or unacceptable toxicity in 30 patients (27 salvage surgeries for recurrent cases and 3 cases of primary surgery for newly diagnosed patients). Availability of tumor tissue pre- and post-nivolumab dosing and from additional patients who did not receive nivolumab allowed the evaluation of changes in the tumor immune microenvironment using multiple molecular and cellular analyses. Neoadjuvant nivolumab resulted in enhanced expression of chemokine transcripts, higher immune cell infiltration and augmented TCR clonal diversity among tumor-infiltrating T lymphocytes, supporting a local immunomodulatory effect of treatment. Although no obvious clinical benefit was substantiated following salvage surgery, two of the three patients treated with nivolumab before and after primary surgery remain alive 33 and 28 months later.", + "TAG_DATA": [ + "119, tumor {'context': 'B-neoplasm'}", + "148, T {'context': 'I-cells'}", + "149, lymphocytes, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "119, tumor ['l0', 'l1']", + "148, T ['l0', 'l2']", + "149, lymphocytes, ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30733621", + "TEXT": "In the version of this article originally published, the VPC and VCS flux data shown in Fig. 6e,f were inadvertently duplicated from Fig. 5j,k. The correct data are now shown in Fig. 6e,f. In these corrected data, VPC flux in response to chronic oral metformin treatment was still significantly decreased (Fig. 6e), and there was still no impact of metformin on VCS flux (Fig. 6f). Therefore, the text describing these data remains the same and this correction does not change the conclusion of this study.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30692695", + "TEXT": "The CRISPR-Cas9 system is a powerful tool for genome editing, which allows the precise modification of specific DNA sequences. Many efforts are underway to use the CRISPR-Cas9 system to therapeutically correct human genetic diseases1-6. The most widely used orthologs of Cas9 are derived from Staphylococcus aureus and Streptococcus pyogenes5,7. Given that these two bacterial species infect the human population at high frequencies8,9, we hypothesized that humans may harbor preexisting adaptive immune responses to the Cas9 orthologs derived from these bacterial species, SaCas9 (S. aureus) and SpCas9 (S. pyogenes). By probing human serum for the presence of anti-Cas9 antibodies using an enzyme-linked immunosorbent assay, we detected antibodies against both SaCas9 and SpCas9 in 78% and 58% of donors, respectively. We also found anti-SaCas9 T cells in 78% and anti-SpCas9 T cells in 67% of donors, which demonstrates a high prevalence of antigen-specific T cells against both orthologs. We confirmed that these T cells were Cas9-specific by demonstrating a Cas9-specific cytokine response following isolation, expansion, and antigen restimulation. Together, these data demonstrate that there are preexisting humoral and cell-mediated adaptive immune responses to Cas9 in humans, a finding that should be taken into account as the CRISPR-Cas9 system moves toward clinical trials.", + "TAG_DATA": [ + "150, T {'context': 'B-cells'}", + "151, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "150, T ['l0']", + "151, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30679787", + "TEXT": "In the version of this article originally published, the x axis labels in Fig. 1a were incorrect. The labels originally were 'Specificity,' but should have been '1 - Specificity.' Also, the x axis label in Fig. 2b was incorrect. It was originally 'DNN predicted label,' but should have been 'Average cardiologist label.' The errors have been corrected in the PDF and HTML versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30664785", + "TEXT": "Leber congenital amaurosis type 10 is a severe retinal dystrophy caused by mutations in the CEP290 gene1,2. We developed EDIT-101, a candidate genome-editing therapeutic, to remove the aberrant splice donor created by the IVS26 mutation in the CEP290 gene and restore normal CEP290 expression. Key to this therapeutic, we identified a pair of Staphylococcus aureus Cas9 guide RNAs that were highly active and specific to the human CEP290 target sequence. In vitro experiments in human cells and retinal explants demonstrated the molecular mechanism of action and nuclease specificity. Subretinal delivery of EDIT-101 in humanized CEP290 mice showed rapid and sustained CEP290 gene editing. A comparable surrogate non-human primate (NHP) vector also achieved productive editing of the NHP CEP290 gene at levels that met the target therapeutic threshold, and demonstrated the ability of CRISPR/Cas9 to edit somatic primate cells in vivo. These results support further development of EDIT-101 for LCA10 and additional CRISPR-based medicines for other inherited retinal disorders.", + "TAG_DATA": [ + "70, In {'context': 'B-in vitro'}", + "71, vitro {'context': 'I-in vitro'}", + "74, human {'context': 'B-cells'}", + "75, cells {'context': 'I-cells'}", + "77, retinal {'context': 'B-tissue/organ'}", + "78, explants {'context': 'I-tissue/organ'}", + "93, humanized {'context': 'B-organism'}", + "94, CEP290 {'context': 'I-organism'}", + "95, mice {'context': 'I-organism'}", + "107, primate {'context': 'I-organism'}", + "108, (NHP) {'context': 'I-organism'}", + "135, somatic {'context': 'B-cells'}", + "136, primate {'context': 'B-organism'}", + "137, cells {'context': 'I-cells'}", + "138, in {'context': 'B-in vivo'}", + "139, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "70, In ['l0', 'l1', 'l2', 'l3', 'l4']", + "71, vitro ['l0', 'l5', 'l6', 'l7', 'l8']", + "74, human ['l1', 'l5', 'l9', 'l10', 'l11']", + "75, cells ['l2', 'l6', 'l9', 'l12', 'l13']", + "77, retinal ['l3', 'l7', 'l10', 'l12', 'l14']", + "78, explants ['l4', 'l8', 'l11', 'l13', 'l14']", + "93, humanized ['l15', 'l16']", + "94, CEP290 ['l15', 'l17']", + "95, mice ['l16', 'l17']", + "107, primate ['l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "108, (NHP) ['l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "135, somatic ['l19', 'l24', 'l29', 'l30', 'l31', 'l32']", + "136, primate ['l20', 'l25', 'l29', 'l33', 'l34', 'l35']", + "137, cells ['l21', 'l26', 'l30', 'l33', 'l36', 'l37']", + "138, in ['l22', 'l27', 'l31', 'l34', 'l36', 'l38']", + "139, vivo. ['l23', 'l28', 'l32', 'l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30664784", + "TEXT": "Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30664782", + "TEXT": "Tuberculosis (TB) remains the deadliest infectious disease1, and the widely used Bacillus Calmette-Guérin (BCG) vaccine fails to curb the epidemic. An improved vaccination strategy could provide a cost-effective intervention to break the transmission cycle and prevent antimicrobial resistance2,3. Limited knowledge of the host responses critically involved in protective immunity hampers the development of improved TB vaccination regimens. Therefore, assessment of new strategies in preclinical models to select the best candidate vaccines before clinical vaccine testing remains indispensable. We have previously established in rhesus macaques (Macaca mulatta) that pulmonary mucosal BCG delivery reduces TB disease where standard intradermal injection fails4,5. Here, we show that pulmonary BCG prevents infection by using a repeated limiting-dose Mycobacterium tuberculosis challenge model and identify polyfunctional T-helper type 17 (TH17) cells, interleukin-10 and immunoglobulin A as correlates of local protective immunity. These findings warrant further research into mucosal immunization strategies and their translation to clinical application to more effectively prevent the spread of TB.", + "TAG_DATA": [ + "82, rhesus {'context': 'B-organism'}", + "83, macaques {'context': 'I-organism'}", + "84, (Macaca {'context': 'I-organism'}", + "85, mulatta) {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "82, rhesus ['l0', 'l1', 'l2']", + "83, macaques ['l0', 'l3', 'l4']", + "84, (Macaca ['l1', 'l3', 'l5']", + "85, mulatta) ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30617320", + "TEXT": "Computerized electrocardiogram (ECG) interpretation plays a critical role in the clinical ECG workflow1. Widely available digital ECG data and the algorithmic paradigm of deep learning2 present an opportunity to substantially improve the accuracy and scalability of automated ECG analysis. However, a comprehensive evaluation of an end-to-end deep learning approach for ECG analysis across a wide variety of diagnostic classes has not been previously reported. Here, we develop a deep neural network (DNN) to classify 12 rhythm classes using 91,232 single-lead ECGs from 53,549 patients who used a single-lead ambulatory ECG monitoring device. When validated against an independent test dataset annotated by a consensus committee of board-certified practicing cardiologists, the DNN achieved an average area under the receiver operating characteristic curve (ROC) of 0.97. The average F1 score, which is the harmonic mean of the positive predictive value and sensitivity, for the DNN (0.837) exceeded that of average cardiologists (0.780). With specificity fixed at the average specificity achieved by cardiologists, the sensitivity of the DNN exceeded the average cardiologist sensitivity for all rhythm classes. These findings demonstrate that an end-to-end deep learning approach can classify a broad range of distinct arrhythmias from single-lead ECGs with high diagnostic performance similar to that of cardiologists. If confirmed in clinical settings, this approach could reduce the rate of misdiagnosed computerized ECG interpretations and improve the efficiency of expert human ECG interpretation by accurately triaging or prioritizing the most urgent conditions.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30617317", + "TEXT": "Diagnostic procedures, therapeutic recommendations, and medical risk stratifications are based on dedicated, strictly controlled clinical trials. However, a plethora of real-world medical data exists, whereupon the increase in data volume comes at the expense of completeness, uniformity, and control. Here, a case-by-case comparison shows that the predictive power of our real world data-based model for diabetes-related chronic kidney disease outperforms published algorithms, which were derived from clinical study data.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30559422", + "TEXT": "Interferons (IFNs) are cytokines that play a critical role in limiting infectious and malignant diseases 1-4 . Emerging data suggest that the strength and duration of IFN signaling can differentially impact cancer therapies, including immune checkpoint blockade 5-7 . Here, we characterize the output of IFN signaling, specifically IFN-stimulated gene (ISG) signatures, in primary tumors from The Cancer Genome Atlas. While immune infiltration correlates with the ISG signature in some primary tumors, the existence of ISG signature-positive tumors without evident infiltration of IFN-producing immune cells suggests that cancer cells per se can be a source of IFN production. Consistent with this hypothesis, analysis of patient-derived tumor xenografts propagated in immune-deficient mice shows evidence of ISG-positive tumors that correlates with expression of human type I and III IFNs derived from the cancer cells. Mechanistic studies using cell line models from the Cancer Cell Line Encyclopedia that harbor ISG signatures demonstrate that this is a by-product of a STING-dependent pathway resulting in chronic tumor-derived IFN production. This imposes a transcriptional state on the tumor, poising it to respond to the aberrant accumulation of double-stranded RNA (dsRNA) due to increased sensor levels (MDA5, RIG-I and PKR). By interrogating our functional short-hairpin RNA screen dataset across 398 cancer cell lines, we show that this ISG transcriptional state creates a novel genetic vulnerability. ISG signature-positive cancer cells are sensitive to the loss of ADAR, a dsRNA-editing enzyme that is also an ISG. A genome-wide CRISPR genetic suppressor screen reveals that the entire type I IFN pathway and the dsRNA-activated kinase, PKR, are required for the lethality induced by ADAR depletion. Therefore, tumor-derived IFN resulting in chronic signaling creates a cellular state primed to respond to dsRNA accumulation, rendering ISG-positive tumors susceptible to ADAR loss.", + "TAG_DATA": [ + "104, patient-derived {'context': 'B-xenograft'}", + "105, tumor {'context': 'I-xenograft'}", + "106, xenografts {'context': 'I-xenograft'}", + "109, immune-deficient {'perturbing_action': 'B-gene loss-of-function', 'context': 'B-organism'}", + "110, mice {'context': 'I-organism'}", + "203, cancer {'context': 'B-transformed cells'}", + "204, cell {'context': 'I-transformed cells'}", + "205, lines, {'context': 'I-transformed cells'}", + "218, ISG {'context': 'B-transformed cells'}", + "220, cancer {'context': 'I-transformed cells'}", + "221, cells {'context': 'I-transformed cells'}", + "264, depletion. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "104, patient-derived ['l0', 'l1', 'l2', 'l3']", + "105, tumor ['l0', 'l4', 'l5', 'l6']", + "106, xenografts ['l1', 'l4', 'l7', 'l8']", + "109, immune-deficient ['l2', 'l5', 'l7', 'l9']", + "110, mice ['l3', 'l6', 'l8', 'l9']", + "203, cancer ['l10', 'l11', 'l12', 'l13', 'l14']", + "204, cell ['l10', 'l15', 'l16', 'l17', 'l18']", + "205, lines, ['l11', 'l15', 'l19', 'l20', 'l21']", + "218, ISG ['l12', 'l16', 'l19', 'l22', 'l23', 'l24']", + "220, cancer ['l13', 'l17', 'l20', 'l22', 'l25']", + "221, cells ['l14', 'l18', 'l21', 'l23', 'l25']", + "264, depletion. ['l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "xenograft", + "words": [ + "patient-derived", + "tumor", + "xenografts" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immune-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immune-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "immune-deficient" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "ISG" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion." + ] + } + } + ] + }, + { + "PMID": "30559420", + "TEXT": "Photoreceptor ciliopathies constitute the most common molecular mechanism of the childhood blindness Leber congenital amaurosis. Ten patients with Leber congenital amaurosis carrying the c.2991+1655A>G allele in the ciliopathy gene centrosomal protein 290 (CEP290) were treated (ClinicalTrials.gov no. NCT03140969 ) with intravitreal injections of an antisense oligonucleotide to restore correct splicing. There were no serious adverse events, and vision improved at 3 months. The visual acuity of one exceptional responder improved from light perception to 20/400.", + "TAG_DATA": [ + "16, patients {'context': 'B-patient'}", + "22, the {'perturbing_action': 'I-other'}", + "23, c.2991+1655A>G {'perturbing_action': 'I-other'}", + "24, allele {'perturbing_action': 'I-other'}", + "25, in {'perturbing_action': 'I-other'}", + "26, the {'perturbing_action': 'I-other'}", + "27, ciliopathy {'perturbing_action': 'I-other'}", + "28, gene {'perturbing_action': 'I-other'}", + "29, centrosomal {'perturbing_action': 'I-other'}", + "30, protein {'perturbing_action': 'I-other'}", + "31, 290 {'perturbing_action': 'I-other'}", + "32, (CEP290) {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "16, patients ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "22, the ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "23, c.2991+1655A>G ['l1', 'l6', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "24, allele ['l2', 'l7', 'l16', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "25, in ['l3', 'l8', 'l17', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "26, the ['l4', 'l9', 'l18', 'l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "27, ciliopathy ['l10', 'l19', 'l27', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "28, gene ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "29, centrosomal ['l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57']", + "30, protein ['l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l58', 'l59']", + "31, 290 ['l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58', 'l60']", + "32, (CEP290) ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "the", + "c.2991+1655A>G", + "allele", + "in", + "(CEP290)" + ] + } + } + ] + }, + { + "PMID": "30397358", + "TEXT": "Epigenomics regulates gene expression and is as important as genomics in precision personal health, as it is heavily influenced by environment and lifestyle. We profiled whole-genome DNA methylation and the corresponding transcriptome of peripheral blood mononuclear cells collected from a human volunteer over a period of 36 months, generating 28 methylome and 57 transcriptome datasets. We found that DNA methylomic changes are associated with infrequent glucose level alteration, whereas the transcriptome underwent dynamic changes during events such as viral infections. Most DNA meta-methylome changes occurred 80-90 days before clinically detectable glucose elevation. Analysis of the deep personal methylome dataset revealed an unprecedented number of allelic differentially methylated regions that remain stable longitudinally and are preferentially associated with allele-specific gene regulation. Our results revealed that changes in different types of 'omics' data associate with different physiological aspects of this individual: DNA methylation with chronic conditions and transcriptome with acute events.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30397357", + "TEXT": "Human microbiome studies have revealed the intricate interplay of host immunity and bacterial communities to achieve homeostatic balance. Healthy skin microbial communities are dominated by bacteria with low viral representation1-3, mainly bacteriophage. Specific eukaryotic viruses have been implicated in both common and rare skin diseases, but cataloging skin viral communities has been limited. Alterations in host immunity provide an opportunity to expand our understanding of microbial-host interactions. Primary immunodeficient patients manifest with various viral, bacterial, fungal, and parasitic infections, including skin infections4. Dedicator of cytokinesis 8 (DOCK8) deficiency is a rare primary human immunodeficiency characterized by recurrent cutaneous and systemic infections, as well as atopy and cancer susceptibility5. DOCK8, encoding a guanine nucleotide exchange factor highly expressed in lymphocytes, regulates actin cytoskeleton, which is critical for migration through collagen-dense tissues such as skin6. Analyzing deep metagenomic sequencing data from DOCK8-deficient skin samples demonstrated a notable increase in eukaryotic viral representation and diversity compared with healthy volunteers. De novo assembly approaches identified hundreds of novel human papillomavirus genomes, illuminating microbial dark matter. Expansion of the skin virome in DOCK8-deficient patients underscores the importance of immune surveillance in controlling eukaryotic viral colonization and infection.", + "TAG_DATA": [ + "139, DOCK8-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "140, skin {'context': 'B-tissue/organ'}", + "141, samples {'context': 'I-patient'}", + "177, DOCK8-deficient {'perturbing_action': 'B-gene loss-of-function'}" + ], + "LINK_DATA": [ + "139, DOCK8-deficient ['l0', 'l1']", + "140, skin ['l0', 'l2']", + "141, samples ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "DOCK8-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skin" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "DOCK8-deficient" + ] + }, + "context": { + "val": "patient", + "words": [ + "samples" + ] + } + } + ] + }, + { + "PMID": "30349087", + "TEXT": "Identifying immunodominant T cell epitopes remains a significant challenge in the context of infectious disease, autoimmunity, and immuno-oncology. To address the challenge of antigen discovery, we developed a quantitative proteomic approach that enabled unbiased identification of major histocompatibility complex class II (MHCII)-associated peptide epitopes and biochemical features of antigenicity. On the basis of these data, we trained a deep neural network model for genome-scale predictions of immunodominant MHCII-restricted epitopes. We named this model bacteria originated T cell antigen (BOTA) predictor. In validation studies, BOTA accurately predicted novel CD4 T cell epitopes derived from the model pathogen Listeria monocytogenes and the commensal microorganism Muribaculum intestinale. To conclusively define immunodominant T cell epitopes predicted by BOTA, we developed a high-throughput approach to screen DNA-encoded peptide-MHCII libraries for functional recognition by T cell receptors identified from single-cell RNA sequencing. Collectively, these studies provide a framework for defining the immunodominance landscape across a broad range of immune pathologies.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30349086", + "TEXT": "Brain tumors are the leading cause of cancer-related death in children. Genomic studies have provided insights into molecular subgroups and oncogenic drivers of pediatric brain tumors that may lead to novel therapeutic strategies. To evaluate new treatments, better preclinical models adequately reflecting the biological heterogeneity are needed. Through the Children's Oncology Group ACNS02B3 study, we have generated and comprehensively characterized 30 patient-derived orthotopic xenograft models and seven cell lines representing 14 molecular subgroups of pediatric brain tumors. Patient-derived orthotopic xenograft models were found to be representative of the human tumors they were derived from in terms of histology, immunohistochemistry, gene expression, DNA methylation, copy number, and mutational profiles. In vivo drug sensitivity of targeted therapeutics was associated with distinct molecular tumor subgroups and specific genetic alterations. These models and their molecular characterization provide an unprecedented resource for the cancer community to study key oncogenic drivers and to evaluate novel treatment strategies.", + "TAG_DATA": [ + "61, patient-derived {'context': 'B-xenograft'}", + "62, orthotopic {'context': 'I-xenograft'}", + "63, xenograft {'context': 'I-xenograft'}", + "64, models {'context': 'I-xenograft'}", + "67, cell {'context': 'B-cells'}", + "68, lines {'context': 'I-cells'}", + "77, Patient-derived {'context': 'B-xenograft'}", + "78, orthotopic {'context': 'I-xenograft'}", + "79, xenograft {'context': 'I-xenograft'}", + "80, models {'context': 'I-xenograft'}", + "108, In {'context': 'B-in vivo'}", + "109, vivo {'context': 'B-in vivo'}" + ], + "LINK_DATA": [ + "61, patient-derived ['l0', 'l1', 'l2', 'l3']", + "62, orthotopic ['l0', 'l4', 'l5', 'l6', 'l7']", + "63, xenograft ['l1', 'l4', 'l8', 'l9']", + "64, models ['l2', 'l5', 'l8']", + "67, cell ['l6', 'l10', 'l11', 'l12', 'l13']", + "68, lines ['l3', 'l7', 'l9', 'l10', 'l14']", + "77, Patient-derived ['l15', 'l16', 'l17']", + "78, orthotopic ['l11', 'l15', 'l18', 'l19']", + "79, xenograft ['l12', 'l16', 'l18', 'l20']", + "80, models ['l13', 'l14', 'l17', 'l19', 'l20']", + "108, In ['l21']", + "109, vivo ['l21']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30333558", + "TEXT": "In the version of this article originally published, there was an error in the URL linked to by an accession code in the data availability section of the methods. The erroneous URL was: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE100351 . The correct URL is: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE115821 . The error has been corrected in the HTML and PDF versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30297910", + "TEXT": "Peripheral nerve injuries represent a significant problem in public health, constituting 2-5% of all trauma cases1. For severe nerve injuries, even advanced forms of clinical intervention often lead to incomplete and unsatisfactory motor and/or sensory function2. Numerous studies report the potential of pharmacological approaches (for example, growth factors, immunosuppressants) to accelerate and enhance nerve regeneration in rodent models3-10. Unfortunately, few have had a positive impact in clinical practice. Direct intraoperative electrical stimulation of injured nerve tissue proximal to the site of repair has been demonstrated to enhance and accelerate functional recovery11,12, suggesting a novel nonpharmacological, bioelectric form of therapy that could complement existing surgical approaches. A significant limitation of this technique is that existing protocols are constrained to intraoperative use and limited therapeutic benefits13. Herein we introduce (i) a platform for wireless, programmable electrical peripheral nerve stimulation, built with a collection of circuit elements and substrates that are entirely bioresorbable and biocompatible, and (ii) the first reported demonstration of enhanced neuroregeneration and functional recovery in rodent models as a result of multiple episodes of electrical stimulation of injured nervous tissue.", + "TAG_DATA": [ + "165, rodent {'context': 'B-organism'}", + "166, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "165, rodent ['l0']", + "166, models ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30297908", + "TEXT": "Available corrector drugs are unable to effectively rescue the folding defects of CFTR-ΔF508 (or CFTR-F508del), the most common disease-causing mutation of the cystic fibrosis transmembrane conductance regulator, a plasma membrane (PM) anion channel, and thus to substantially ameliorate clinical phenotypes of cystic fibrosis (CF). To overcome the corrector efficacy ceiling, here we show that compounds targeting distinct structural defects of CFTR can synergistically rescue mutant expression and function at the PM. High-throughput cell-based screens and mechanistic analysis identified three small-molecule series that target defects at nucleotide-binding domain (NBD1), NBD2 and their membrane-spanning domain (MSD) interfaces. Although individually these compounds marginally improve ΔF508-CFTR folding efficiency, function and stability, their combinations lead to ~50-100% of wild-type-level correction in immortalized and primary human airway epithelia and in mouse nasal epithelia. Likewise, corrector combinations were effective against rare missense mutations in various CFTR domains, probably acting via structural allostery, suggesting a mechanistic framework for their broad application.", + "TAG_DATA": [ + "116, immortalized {'context': 'B-cells'}", + "117, and {'context': 'I-tissue/organ'}", + "118, primary {'context': 'I-tissue/organ'}", + "119, human {'context': 'I-tissue/organ'}", + "120, airway {'context': 'I-tissue/organ'}", + "121, epithelia {'context': 'I-tissue/organ'}", + "124, mouse {'context': 'B-tissue/organ'}", + "125, nasal {'context': 'I-tissue/organ'}", + "126, epithelia. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "116, immortalized ['l0', 'l1', 'l2', 'l3', 'l4']", + "117, and ['l0', 'l5', 'l6', 'l7', 'l8']", + "118, primary ['l1', 'l5', 'l9', 'l10', 'l11']", + "119, human ['l2', 'l6', 'l9', 'l12', 'l13']", + "120, airway ['l3', 'l7', 'l10', 'l12', 'l14']", + "121, epithelia ['l4', 'l8', 'l11', 'l13', 'l14']", + "124, mouse ['l15', 'l16']", + "125, nasal ['l15', 'l17']", + "126, epithelia. ['l16', 'l17']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30291359", + "TEXT": "In the version of this article originally published, there was an error in Fig. 2n. The top line of the HR comparison chart originally was Atezo + bev vs sun. It should have been Atezo + bev vs atezo. The error has been corrected in the HTML and PDF versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30258217", + "TEXT": "Monotherapy of HIV-1 infection with single antiretroviral agents is ineffective because error-prone HIV-1 replication leads to the production of drug-resistant viral variants1,2. Combinations of drugs can establish long-term control, however, antiretroviral therapy (ART) requires daily dosing, can cause side effects and does not eradicate the infection3,4. Although anti-HIV-1 antibodies constitute a potential alternative to ART5,6, treatment of viremic individuals with a single antibody also results in emergence of resistant viral variants7-9. Moreover, combinations of first-generation anti-HIV-1 broadly neutralizing antibodies (bNAbs) had little measurable effect on the infection10-12. Here we report on a phase 1b clinical trial ( NCT02825797 ) in which two potent bNAbs, 3BNC11713 and 10-107414, were administered in combination to seven HIV-1 viremic individuals. Infusions of 30 mg kg-1 of each of the antibodies were well-tolerated. In the four individuals with dual antibody-sensitive viruses, immunotherapy resulted in an average reduction in HIV-1 viral load of 2.05 log10 copies per ml that remained significantly reduced for three months following the first of up to three infusions. In addition, none of these individuals developed resistance to both antibodies. Larger studies will be necessary to confirm the efficacy of antibody combinations in reducing HIV-1 viremia and limiting the emergence of resistant viral variants.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30250144", + "TEXT": "In the version of this article originally published, in the sentence \"Applying the same approach to obesity (Fig. 2b), MetS (Fig. 2c) and fatty liver (Fig. 2d) yielded similar results,\" two figure panels were cited incorrectly. The data for obesity are in Fig. 2c, and the data for MetS are in Fig. 2b. The sentence has been updated with the correct citations in the print, PDF and HTML versions of the article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30250140", + "TEXT": "Spinal sensorimotor networks that are functionally disconnected from the brain because of spinal cord injury (SCI) can be facilitated via epidural electrical stimulation (EES) to restore robust, coordinated motor activity in humans with paralysis1-3. Previously, we reported a clinical case of complete sensorimotor paralysis of the lower extremities in which EES restored the ability to stand and the ability to control step-like activity while side-lying or suspended vertically in a body-weight support system (BWS)4. Since then, dynamic task-specific training in the presence of EES, termed multimodal rehabilitation (MMR), was performed for 43 weeks and resulted in bilateral stepping on a treadmill, independent from trainer assistance or BWS. Additionally, MMR enabled independent stepping over ground while using a front-wheeled walker with trainer assistance at the hips to maintain balance. Furthermore, MMR engaged sensorimotor networks to achieve dynamic performance of standing and stepping. To our knowledge, this is the first report of independent stepping enabled by task-specific training in the presence of EES by a human with complete loss of lower extremity sensorimotor function due to SCI.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30224757", + "TEXT": "Visual inspection of histopathology slides is one of the main methods used by pathologists to assess the stage, type and subtype of lung tumors. Adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) are the most prevalent subtypes of lung cancer, and their distinction requires visual inspection by an experienced pathologist. In this study, we trained a deep convolutional neural network (inception v3) on whole-slide images obtained from The Cancer Genome Atlas to accurately and automatically classify them into LUAD, LUSC or normal lung tissue. The performance of our method is comparable to that of pathologists, with an average area under the curve (AUC) of 0.97. Our model was validated on independent datasets of frozen tissues, formalin-fixed paraffin-embedded tissues and biopsies. Furthermore, we trained the network to predict the ten most commonly mutated genes in LUAD. We found that six of them-STK11, EGFR, FAT1, SETBP1, KRAS and TP53-can be predicted from pathology images, with AUCs from 0.733 to 0.856 as measured on a held-out population. These findings suggest that deep-learning models can assist pathologists in the detection of cancer subtype or gene mutations. Our approach can be applied to any cancer type, and the code is available at https://github.com/ncoudray/DeepPATH .", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30177821", + "TEXT": "Antibodies are the primary correlate of protection for most licensed vaccines; however, their mechanisms of protection may vary, ranging from physical blockade to clearance via the recruitment of innate immunity. Here, we uncover striking functional diversity in vaccine-induced antibodies that is driven by immunization site and is associated with reduced risk of SIV infection in nonhuman primates. While equivalent levels of protection were observed following intramuscular (IM) and aerosol (AE) immunization with an otherwise identical DNA prime-Ad5 boost regimen, reduced risk of infection was associated with IgG-driven antibody-dependent monocyte-mediated phagocytosis in the IM vaccinees, but with vaccine-elicited IgA-driven neutrophil-mediated phagocytosis in AE-immunized animals. Thus, although route-independent correlates indicate a critical role for phagocytic Fc-effector activity in protection from SIV, the site of immunization may drive this Fc activity via distinct innate effector cells and antibody isotypes. Moreover, the same correlates predicted protection from SHIV infection in a second nonhuman primate vaccine trial using a disparate IM canarypox prime-protein boost strategy, analogous to that used in the first moderately protective human HIV vaccine trial. These data identify orthogonal functional humoral mechanisms, initiated by distinct vaccination routes and immunization strategies, pointing to multiple, potentially complementary correlates of immunity that may support the rational design of a protective vaccine against HIV.", + "TAG_DATA": [ + "102, animals. {'context': 'B-organism'}", + "149, primate {'context': 'I-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30127395", + "TEXT": "Nicotinamide adenine dinucleotide (NAD+) extends longevity in experimental organisms, raising interest in its impact on human health. De novo NAD+ biosynthesis from tryptophan is evolutionarily conserved yet considered supplanted among higher species by biosynthesis from nicotinamide (NAM). Here we show that a bottleneck enzyme in de novo biosynthesis, quinolinate phosphoribosyltransferase (QPRT), defends renal NAD+ and mediates resistance to acute kidney injury (AKI). Following murine AKI, renal NAD+ fell, quinolinate rose, and QPRT declined. QPRT+/- mice exhibited higher quinolinate, lower NAD+, and higher AKI susceptibility. Metabolomics suggested an elevated urinary quinolinate/tryptophan ratio (uQ/T) as an indicator of reduced QPRT. Elevated uQ/T predicted AKI and other adverse outcomes in critically ill patients. A phase 1 placebo-controlled study of oral NAM demonstrated a dose-related increase in circulating NAD+ metabolites. NAM was well tolerated and was associated with less AKI. Therefore, impaired NAD+ biosynthesis may be a feature of high-risk hospitalizations for which NAD+ augmentation could be beneficial.", + "TAG_DATA": [ + "73, QPRT+/- {'perturbing_action': 'B-gene loss-of-function'}", + "74, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, QPRT+/- ['l0']", + "74, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "QPRT+/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "30127394", + "TEXT": "Immune checkpoint blockade (ICB) therapy provides remarkable clinical gains and has been very successful in treatment of melanoma. However, only a subset of patients with advanced tumors currently benefit from ICB therapies, which at times incur considerable side effects and costs. Constructing predictors of patient response has remained a serious challenge because of the complexity of the immune response and the shortage of large cohorts of ICB-treated patients that include both 'omics' and response data. Here we build immuno-predictive score (IMPRES), a predictor of ICB response in melanoma which encompasses 15 pairwise transcriptomics relations between immune checkpoint genes. It is based on two key conjectures: (i) immune mechanisms underlying spontaneous regression in neuroblastoma can predict melanoma response to ICB, and (ii) key immune interactions can be captured via specific pairwise relations of the expression of immune checkpoint genes. IMPRES is validated on nine published datasets1-6 and on a newly generated dataset with 31 patients treated with anti-PD-1 and 10 with anti-CTLA-4, spanning 297 samples in total. It achieves an overall accuracy of AUC = 0.83, outperforming existing predictors and capturing almost all true responders while misclassifying less than half of the nonresponders. Future studies are warranted to determine the value of the approach presented here in other cancer types.", + "TAG_DATA": [ + "153, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30127392", + "TEXT": "Amyotrophic lateral sclerosis (ALS) is a heterogeneous motor neuron disease for which no effective treatment is available, despite decades of research into SOD1-mutant familial ALS (FALS). The majority of ALS patients have no familial history, making the modeling of sporadic ALS (SALS) essential to the development of ALS therapeutics. However, as mutations underlying ALS pathogenesis have not yet been identified, it remains difficult to establish useful models of SALS. Using induced pluripotent stem cell (iPSC) technology to generate stem and differentiated cells retaining the patients' full genetic information, we have established a large number of in vitro cellular models of SALS. These models showed phenotypic differences in their pattern of neuronal degeneration, types of abnormal protein aggregates, cell death mechanisms, and onset and progression of these phenotypes in vitro among cases. We therefore developed a system for case clustering capable of subdividing these heterogeneous SALS models by their in vitro characteristics. We further evaluated multiple-phenotype rescue of these subclassified SALS models using agents selected from non-SOD1 FALS models, and identified ropinirole as a potential therapeutic candidate. Integration of the datasets acquired in this study permitted the visualization of molecular pathologies shared across a wide range of SALS models.", + "TAG_DATA": [ + "70, induced {'context': 'B-cells'}", + "71, pluripotent {'context': 'I-cells'}", + "72, stem {'context': 'I-cells'}", + "73, cell {'context': 'I-cells'}", + "74, (iPSC) {'context': 'I-cells'}", + "78, stem {'context': 'B-cells'}", + "79, and {'context': 'I-cells'}", + "80, differentiated {'context': 'I-cells'}", + "81, cells {'context': 'I-cells'}", + "95, in {'context': 'B-in vitro'}", + "96, vitro {'context': 'I-in vitro'}", + "127, in {'context': 'B-in vitro'}", + "128, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "70, induced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "71, pluripotent ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "72, stem ['l1', 'l12', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "73, cell ['l2', 'l13', 'l24', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "74, (iPSC) ['l3', 'l14', 'l25', 'l33', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "75, technology ['l4', 'l15', 'l26', 'l34', 'l41', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "78, stem ['l5', 'l16', 'l27', 'l35', 'l42', 'l48', 'l54', 'l55', 'l56', 'l57', 'l58']", + "79, and ['l6', 'l17', 'l28', 'l36', 'l43', 'l49', 'l54', 'l59', 'l60', 'l61', 'l62']", + "80, differentiated ['l7', 'l18', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l63', 'l64', 'l65']", + "81, cells ['l8', 'l19', 'l30', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l66', 'l67']", + "95, in ['l9', 'l20', 'l31', 'l39', 'l46', 'l52', 'l57', 'l61', 'l64', 'l66', 'l68']", + "96, vitro ['l10', 'l21', 'l32', 'l40', 'l47', 'l53', 'l58', 'l62', 'l65', 'l67', 'l68']", + "127, in ['l22', 'l69']", + "128, vitro ['l11', 'l23', 'l69']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30127391", + "TEXT": "Tuberous sclerosis complex (TSC) is a multisystem developmental disorder caused by mutations in the TSC1 or TSC2 genes, whose protein products are negative regulators of mechanistic target of rapamycin complex 1 signaling. Hallmark pathologies of TSC are cortical tubers-regions of dysmorphic, disorganized neurons and glia in the cortex that are linked to epileptogenesis. To determine the developmental origin of tuber cells, we established human cellular models of TSC by CRISPR-Cas9-mediated gene editing of TSC1 or TSC2 in human pluripotent stem cells (hPSCs). Using heterozygous TSC2 hPSCs with a conditional mutation in the functional allele, we show that mosaic biallelic inactivation during neural progenitor expansion is necessary for the formation of dysplastic cells and increased glia production in three-dimensional cortical spheroids. Our findings provide support for the second-hit model of cortical tuber formation and suggest that variable developmental timing of somatic mutations could contribute to the heterogeneity in the neurological presentation of TSC.", + "TAG_DATA": [ + "69, CRISPR-Cas9-mediated {'perturbing_action': 'B-gene loss-of-function'}", + "70, gene {'perturbing_action': 'I-gene loss-of-function'}", + "71, editing {'perturbing_action': 'I-gene loss-of-function'}", + "72, of {'perturbing_action': 'I-gene loss-of-function'}", + "73, TSC1 {'perturbing_action': 'I-gene loss-of-function'}", + "74, or {'perturbing_action': 'I-gene loss-of-function'}", + "75, TSC2 {'perturbing_action': 'I-gene loss-of-function'}", + "77, human {'context': 'B-cells'}", + "78, pluripotent {'context': 'I-cells'}", + "79, stem {'context': 'I-cells'}", + "80, cells {'context': 'I-cells'}", + "81, (hPSCs). {'context': 'I-cells'}", + "83, heterozygous {'perturbing_action': 'B-other'}", + "84, TSC2 {'perturbing_action': 'I-gene loss-of-function'}", + "85, hPSCs {'context': 'I-cells'}", + "88, conditional {'perturbing_action': 'B-other'}", + "89, mutation {'perturbing_action': 'I-other'}", + "90, in {'perturbing_action': 'I-other'}", + "91, the {'perturbing_action': 'I-other'}", + "92, functional {'perturbing_action': 'I-other'}", + "93, allele, {'perturbing_action': 'I-other'}", + "114, glia {'context': 'B-cells'}", + "117, three-dimensional {'context': 'B-organoid'}", + "118, cortical {'context': 'I-organoid'}", + "119, spheroids. {'context': 'I-organoid'}" + ], + "LINK_DATA": [ + "69, CRISPR-Cas9-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "70, gene ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "71, editing ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "72, of ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "73, TSC1 ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "74, or ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "75, TSC2 ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "77, human ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "78, pluripotent ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "79, stem ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "80, cells ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "81, (hPSCs). ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "83, heterozygous ['l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "84, TSC2 ['l66', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "85, hPSCs ['l67', 'l78', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "88, conditional ['l68', 'l79', 'l87', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "89, mutation ['l69', 'l80', 'l88', 'l97', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "90, in ['l70', 'l81', 'l89', 'l98', 'l106', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "91, the ['l71', 'l82', 'l90', 'l99', 'l107', 'l114', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "92, functional ['l72', 'l83', 'l91', 'l100', 'l108', 'l115', 'l121', 'l127', 'l128', 'l129', 'l130', 'l131']", + "93, allele, ['l73', 'l84', 'l92', 'l101', 'l109', 'l116', 'l122', 'l127', 'l132', 'l133', 'l134', 'l135']", + "114, glia ['l74', 'l85', 'l93', 'l102', 'l110', 'l117', 'l123', 'l128', 'l132', 'l136', 'l137', 'l138']", + "117, three-dimensional ['l75', 'l94', 'l103', 'l111', 'l118', 'l124', 'l129', 'l133', 'l136', 'l139', 'l140']", + "118, cortical ['l76', 'l95', 'l104', 'l112', 'l119', 'l125', 'l130', 'l134', 'l137', 'l139', 'l141']", + "119, spheroids. ['l77', 'l86', 'l96', 'l105', 'l113', 'l120', 'l126', 'l131', 'l135', 'l138', 'l140', 'l141']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CRISPR-Cas9-mediated", + "gene", + "editing", + "of", + "TSC1", + "or", + "TSC2" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "pluripotent", + "stem", + "cells", + "(hPSCs).", + "hPSCs", + "glia" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous", + "conditional", + "mutation", + "in", + "the", + "functional", + "allele," + ] + }, + "context": { + "val": "cells", + "words": [ + "hPSCs", + "glia" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous", + "conditional", + "mutation", + "in", + "the", + "functional", + "allele," + ] + }, + "context": { + "val": "organoid", + "words": [ + "three-dimensional", + "cortical", + "spheroids." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TSC2" + ] + }, + "context": { + "val": "organoid", + "words": [ + "spheroids." + ] + } + } + ] + }, + { + "PMID": "30104766", + "TEXT": "T cell dysfunction contributes to tumor immune escape in patients with cancer and is particularly severe amidst glioblastoma (GBM). Among other defects, T cell lymphopenia is characteristic, yet often attributed to treatment. We reveal that even treatment-naïve subjects and mice with GBM can harbor AIDS-level CD4 counts, as well as contracted, T cell-deficient lymphoid organs. Missing naïve T cells are instead found sequestered in large numbers in the bone marrow. This phenomenon characterizes not only GBM but a variety of other cancers, although only when tumors are introduced into the intracranial compartment. T cell sequestration is accompanied by tumor-imposed loss of S1P1 from the T cell surface and is reversible upon precluding S1P1 internalization. In murine models of GBM, hindering S1P1 internalization and reversing sequestration licenses T cell-activating therapies that were previously ineffective. Sequestration of T cells in bone marrow is therefore a tumor-adaptive mode of T cell dysfunction, whose reversal may constitute a promising immunotherapeutic adjunct.", + "TAG_DATA": [ + "39, mice {'context': 'B-organism'}", + "41, GBM {'context': 'B-neoplasm'}", + "115, murine {'context': 'B-neoplasm'}", + "116, models {'context': 'I-neoplasm'}", + "117, of {'context': 'I-neoplasm'}", + "118, GBM, {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "39, mice ['l0', 'l1', 'l2']", + "41, GBM ['l0', 'l3', 'l4']", + "53, lymphoid ['l1', 'l3', 'l5']", + "54, organs. ['l2', 'l4', 'l5']", + "115, murine ['l6', 'l7', 'l8']", + "116, models ['l6', 'l9', 'l10']", + "117, of ['l7', 'l9', 'l11']", + "118, GBM, ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30093730", + "TEXT": "In the Supplementary Information originally published with this article, a lane was missing in the β-actin blot in Supplementary Fig. 2. The lane has been added. The error has been corrected in the Supplementary Information associated with this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30038220", + "TEXT": "Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy.", + "TAG_DATA": [ + "147, cell {'context': 'B-cells'}", + "148, lines {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "147, cell ['l0']", + "148, lines ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30013199", + "TEXT": "For inherited genetic diseases, fetal gene therapy offers the potential of prophylaxis against early, irreversible and lethal pathological change. To explore this, we studied neuronopathic Gaucher disease (nGD), caused by mutations in GBA. In adult patients, the milder form presents with hepatomegaly, splenomegaly and occasional lung and bone disease; this is managed, symptomatically, by enzyme replacement therapy. The acute childhood lethal form of nGD is untreatable since enzyme cannot cross the blood-brain barrier. Patients with nGD exhibit signs consistent with hindbrain neurodegeneration, including neck hyperextension, strabismus and, often, fatal apnea1. We selected a mouse model of nGD carrying a loxP-flanked neomycin disruption of Gba plus Cre recombinase regulated by the keratinocyte-specific K14 promoter. Exclusive skin expression of Gba prevents fatal neonatal dehydration. Instead, mice develop fatal neurodegeneration within 15 days2. Using this model, fetal intracranial injection of adeno-associated virus (AAV) vector reconstituted neuronal glucocerebrosidase expression. Mice lived for up to at least 18 weeks, were fertile and fully mobile. Neurodegeneration was abolished and neuroinflammation ameliorated. Neonatal intervention also rescued mice but less effectively. As the next step to clinical translation, we also demonstrated the feasibility of ultrasound-guided global AAV gene transfer to fetal macaque brains.", + "TAG_DATA": [ + "93, mouse {'context': 'B-organism'}", + "94, model {'context': 'I-organism'}", + "113, Exclusive {'perturbing_action': 'B-gene gain-of-function'}", + "114, skin {'perturbing_action': 'I-gene gain-of-function'}", + "115, expression {'perturbing_action': 'I-gene gain-of-function'}", + "116, of {'perturbing_action': 'I-gene gain-of-function'}", + "117, Gba {'perturbing_action': 'I-gene gain-of-function'}", + "123, mice {'context': 'B-organism'}", + "144, Mice {'context': 'B-organism'}", + "168, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "93, mouse ['l0', 'l1', 'l2']", + "94, model ['l0', 'l3', 'l4', 'l5']", + "113, Exclusive ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "114, skin ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "115, expression ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "116, of ['l3', 'l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "117, Gba ['l1', 'l4', 'l9', 'l14', 'l18', 'l21', 'l24']", + "123, mice ['l2', 'l5', 'l10', 'l15', 'l19', 'l22', 'l24']", + "144, Mice ['l11', 'l16', 'l20', 'l23']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "mice", + "Mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Gba", + "of", + "Exclusive", + "skin", + "expression" + ] + } + } + ] + }, + { + "PMID": "30013197", + "TEXT": "Clinical studies support the efficacy of programmed cell death 1 (PD-1) targeted therapy in a subset of patients with metastatic gastric cancer (mGC). With the goal of identifying determinants of response, we performed molecular characterization of tissues and circulating tumor DNA (ctDNA) from 61 patients with mGC who were treated with pembrolizumab as salvage treatment in a prospective phase 2 clinical trial. In patients with microsatellite instability-high and Epstein-Barr virus-positive tumors, which are mutually exclusive, dramatic responses to pembrolizumab were observed (overall response rate (ORR) 85.7% in microsatellite instability-high mGC and ORR 100% in Epstein-Barr virus-positive mGC). For the 55 patients for whom programmed death-ligand 1 (PD-L1) combined positive score positivity was available (combined positive score cut-off value ≥1%), ORR was significantly higher in PD-L1(+) gastric cancer when compared to PD-L1(-) tumors (50.0% versus 0.0%, P value <0.001). Changes in ctDNA levels at six weeks post-treatment predicted response and progression-free survival, and decreased ctDNA was associated with improved outcomes. Our findings provide insight into the molecular features associated with response to pembrolizumab in patients with mGC and provide biomarkers potentially relevant for the selection of patients who may derive greater benefit from PD-1 inhibition.", + "TAG_DATA": [ + "46, mGC {'context': 'B-neoplasm'}", + "63, patients {'context': 'B-patient'}", + "100, patients {'context': 'B-patient'}", + "124, PD-L1(+) {'context': 'B-neoplasm'}", + "125, gastric {'context': 'B-neoplasm'}", + "126, cancer {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "46, mGC ['l0']", + "63, patients ['l0']", + "100, patients ['l1', 'l2', 'l3']", + "124, PD-L1(+) ['l1', 'l4', 'l5']", + "125, gastric ['l2', 'l4', 'l6']", + "126, cancer ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30013196", + "TEXT": "In the version of this article initially published, the line graph showing TNF-α levels in Fig. 2d was inadvertently duplicated. A graph of IL-6 levels should be shown in place of the duplication.These results were also incorrectly described in the main text, which originally stated: \"At an early time point of infection (6 h), RTX-treated mice showed higher induction of total inflammatory-protein levels in the bronchoalveolar lavage fluid (BALF) (Fig. 2c), as well as levels of the cytokines TNF-α and IL-6, and the chemokine CXCL-1 (Fig. 2d)\". This should instead read: \"At an early time point of infection (6 h), RTX-treated mice showed higher induction of total inflammatory-protein levels in the bronchoalveolar lavage fluid (BALF) (Fig. 2c), as well as levels of the cytokine TNF-α and the chemokine CXCL-1 (Fig. 2d)\".In the supplementary information initially posted online, incorrect bar graphs were presented in Supplementary Fig. 1b (VG, TRPV1+ data, top panel) and Supplementary Fig. 4b (DRG, CGRP+ data, middle panel).", + "TAG_DATA": [ + "55, mice {'context': 'B-organism'}", + "101, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "29988143", + "TEXT": "The pattern of somatic mutations observed at diagnosis of acute myeloid leukemia (AML) has been well-characterized. However, the premalignant mutational landscape of AML and its impact on risk and time to diagnosis is unknown. Here we identified 212 women from the Women's Health Initiative who were healthy at study baseline, but eventually developed AML during follow-up (median time: 9.6 years). Deep sequencing was performed on peripheral blood DNA of these cases and compared to age-matched controls that did not develop AML. We discovered that mutations in IDH1, IDH2, TP53, DNMT3A, TET2 and spliceosome genes significantly increased the odds of developing AML. All subjects with TP53 mutations (n = 21 out of 21 patients) and IDH1 and IDH2 (n = 15 out of 15 patients) mutations eventually developed AML in our study. The presence of detectable mutations years before diagnosis suggests that there is a period of latency that precedes AML during which early detection, monitoring and interventional studies should be considered.", + "TAG_DATA": [ + "38, women {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "29988141", + "TEXT": "In the past decade, many challenges faced by women seeking to advance their scientific careers have been identified. Although new policies encouraging equal opportunities in academic research are closing the gap, multipronged measures are needed in order to achieve long-lasting changes that make science gender-blind.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "29988130", + "TEXT": "Physical function declines in old age, portending disability, increased health expenditures, and mortality. Cellular senescence, leading to tissue dysfunction, may contribute to these consequences of aging, but whether senescence can directly drive age-related pathology and be therapeutically targeted is still unclear. Here we demonstrate that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues. Transplanting even fewer senescent cells had the same effect in older recipients and was accompanied by reduced survival, indicating the potency of senescent cells in shortening health- and lifespan. The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells, decreased the number of naturally occurring senescent cells and their secretion of frailty-related proinflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell-transplanted young mice and naturally aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%. Our study provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, while senolytics can enhance remaining health- and lifespan in old mice.", + "TAG_DATA": [ + "51, cells {'context': 'I-cells'}", + "53, young {'context': 'B-organism'}", + "54, mice {'context': 'I-organism'}", + "75, senescent {'context': 'B-cells'}", + "76, cells {'context': 'I-cells'}", + "120, senescent {'context': 'B-cells', 'phenotype': 'B-senescence'}", + "121, cells {'context': 'I-cells'}", + "130, explants {'context': 'B-tissue/organ'}", + "131, of {'context': 'I-tissue/organ'}", + "132, human {'context': 'I-tissue/organ'}", + "133, adipose {'context': 'I-tissue/organ'}", + "134, tissue. {'context': 'I-tissue/organ'}", + "143, senescent {'context': 'B-cells'}", + "144, cell-transplanted {'context': 'I-cells'}", + "145, young {'context': 'B-organism'}", + "146, mice {'context': 'I-organism'}", + "148, naturally {'context': 'B-organism'}", + "149, aged {'context': 'I-organism'}", + "150, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "51, cells ['l0', 'l1', 'l2', 'l3']", + "53, young ['l0', 'l4', 'l5']", + "54, mice ['l1', 'l4', 'l6']", + "75, senescent ['l2', 'l7', 'l8', 'l9', 'l10']", + "76, cells ['l3', 'l5', 'l6', 'l7']", + "120, senescent ['l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "121, cells ['l8', 'l11', 'l17', 'l18', 'l19', 'l20', 'l21']", + "130, explants ['l12', 'l17', 'l22', 'l23', 'l24', 'l25']", + "131, of ['l9', 'l13', 'l18', 'l22', 'l26', 'l27', 'l28']", + "132, human ['l14', 'l19', 'l23', 'l26', 'l29', 'l30']", + "133, adipose ['l15', 'l20', 'l24', 'l27', 'l29', 'l31']", + "134, tissue. ['l10', 'l16', 'l21', 'l25', 'l28', 'l30', 'l31']", + "143, senescent ['l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "144, cell-transplanted ['l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "145, young ['l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "146, mice ['l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "148, naturally ['l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "149, aged ['l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "150, mice ['l37', 'l42', 'l46', 'l49', 'l51', 'l52']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "senescent" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescent" + ] + } + }, + { + "phenotype": { + "val": "senescence", + "words": [ + "senescent" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "explants", + "of", + "human", + "adipose", + "tissue." + ] + } + } + ] + }, + { + "PMID": "29988129", + "TEXT": "Cancer cells are embedded in the tumor microenvironment (TME), a complex ecosystem of stromal cells. Here, we present a 52,698-cell catalog of the TME transcriptome in human lung tumors at single-cell resolution, validated in independent samples where 40,250 additional cells were sequenced. By comparing with matching non-malignant lung samples, we reveal a highly complex TME that profoundly molds stromal cells. We identify 52 stromal cell subtypes, including novel subpopulations in cell types hitherto considered to be homogeneous, as well as transcription factors underlying their heterogeneity. For instance, we discover fibroblasts expressing different collagen sets, endothelial cells downregulating immune cell homing and genes coregulated with established immune checkpoint transcripts and correlating with T-cell activity. By assessing marker genes for these cell subtypes in bulk RNA-sequencing data from 1,572 patients, we illustrate how these correlate with survival, while immunohistochemistry for selected markers validates them as separate cellular entities in an independent series of lung tumors. Hence, in providing a comprehensive catalog of stromal cells types and by characterizing their phenotype and co-optive behavior, this resource provides deeper insights into lung cancer biology that will be helpful in advancing lung cancer diagnosis and therapy.", + "TAG_DATA": [ + "89, fibroblasts {'context': 'B-cells'}", + "94, endothelial {'context': 'B-cells'}", + "95, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "89, fibroblasts ['l0', 'l1']", + "94, endothelial ['l0', 'l2']", + "95, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29988126", + "TEXT": "Idiopathic pulmonary fibrosis is characterized by excessive deposition of collagen in the lung, leading to chronically impaired gas exchange and death1-3. Oxidative stress is believed to be critical in this disease pathogenesis4-6, although the exact mechanisms remain enigmatic. Protein S-glutathionylation (PSSG) is a post-translational modification of proteins that can be reversed by glutaredoxin-1 (GLRX)7. It remains unknown whether GLRX and PSSG play a role in lung fibrosis. Here, we explored the impact of GLRX and PSSG status on the pathogenesis of pulmonary fibrosis, using lung tissues from subjects with idiopathic pulmonary fibrosis, transgenic mouse models and direct administration of recombinant Glrx to airways of mice with existing fibrosis. We demonstrate that GLRX enzymatic activity was strongly decreased in fibrotic lungs, in accordance with increases in PSSG. Mice lacking Glrx were far more susceptible to bleomycin- or adenovirus encoding active transforming growth factor beta-1 (AdTGFB1)-induced pulmonary fibrosis, whereas transgenic overexpression of Glrx in the lung epithelium attenuated fibrosis. We furthermore show that endogenous GLRX was inactivated through an oxidative mechanism and that direct administration of the Glrx protein into airways augmented Glrx activity and reversed increases in collagen in mice with TGFB1- or bleomycin-induced fibrosis, even when administered to fibrotic, aged animals. Collectively, these findings suggest the therapeutic potential of exogenous GLRX in treating lung fibrosis.", + "TAG_DATA": [ + "93, mouse {'context': 'I-organism'}", + "94, models {'context': 'I-organism'}", + "104, mice {'context': 'B-organism'}", + "126, Mice {'context': 'B-organism'}", + "127, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "128, Glrx {'perturbing_action': 'I-gene loss-of-function'}", + "136, adenovirus {'perturbing_action': 'B-gene gain-of-function'}", + "137, encoding {'perturbing_action': 'I-gene gain-of-function'}", + "138, active {'perturbing_action': 'I-gene gain-of-function'}", + "139, transforming {'perturbing_action': 'I-gene gain-of-function'}", + "140, growth {'perturbing_action': 'I-gene gain-of-function'}", + "141, factor {'perturbing_action': 'I-gene gain-of-function'}", + "142, beta-1 {'perturbing_action': 'I-gene gain-of-function'}", + "143, (AdTGFB1)-induced {'perturbing_action': 'I-gene gain-of-function'}", + "147, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "148, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "149, of {'perturbing_action': 'I-gene gain-of-function'}", + "150, Glrx {'perturbing_action': 'I-gene gain-of-function'}", + "151, in {'perturbing_action': 'I-gene gain-of-function'}", + "152, the {'perturbing_action': 'I-gene gain-of-function'}", + "153, lung {'perturbing_action': 'I-gene loss-of-function', 'context': 'B-tissue/organ'}", + "154, epithelium {'context': 'I-tissue/organ'}", + "188, mice {'context': 'B-organism'}", + "199, aged {'context': 'I-organism'}", + "200, animals. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "93, mouse ['l0', 'l1']", + "94, models ['l0', 'l2']", + "104, mice ['l3', 'l4', 'l5', 'l6']", + "119, lungs, ['l1', 'l2', 'l3']", + "126, Mice ['l4', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "127, lacking ['l5', 'l7', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "128, Glrx ['l6', 'l8', 'l17', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "136, adenovirus ['l9', 'l18', 'l26', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "137, encoding ['l10', 'l19', 'l27', 'l34', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "138, active ['l11', 'l20', 'l28', 'l35', 'l42', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "139, transforming ['l12', 'l21', 'l29', 'l36', 'l43', 'l55', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "140, growth ['l13', 'l22', 'l30', 'l37', 'l44', 'l56', 'l66', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "141, factor ['l14', 'l23', 'l31', 'l38', 'l45', 'l57', 'l67', 'l76', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "142, beta-1 ['l15', 'l24', 'l32', 'l39', 'l46', 'l58', 'l68', 'l77', 'l85', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "143, (AdTGFB1)-induced ['l16', 'l25', 'l33', 'l40', 'l47', 'l59', 'l69', 'l78', 'l86', 'l93', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "147, transgenic ['l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "148, overexpression ['l48', 'l106', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "149, of ['l49', 'l60', 'l70', 'l79', 'l87', 'l94', 'l100', 'l107', 'l114', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "150, Glrx ['l50', 'l61', 'l71', 'l80', 'l88', 'l95', 'l101', 'l108', 'l115', 'l121', 'l127', 'l128', 'l129', 'l130', 'l131']", + "151, in ['l51', 'l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l109', 'l116', 'l122', 'l127', 'l132', 'l133', 'l134', 'l135']", + "152, the ['l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l110', 'l117', 'l123', 'l128', 'l132', 'l136', 'l137', 'l138']", + "153, lung ['l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l111', 'l118', 'l124', 'l129', 'l133', 'l136', 'l139', 'l140']", + "154, epithelium ['l41', 'l54', 'l65', 'l75', 'l84', 'l92', 'l99', 'l105', 'l112', 'l119', 'l125', 'l130', 'l134', 'l137', 'l139']", + "188, mice ['l113', 'l120', 'l126', 'l131', 'l135', 'l138', 'l140']", + "199, aged ['l141']", + "200, animals. ['l141']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "Glrx", + "lung" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice", + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "encoding", + "active", + "transforming", + "growth", + "factor", + "beta-1", + "(AdTGFB1)-induced", + "transgenic", + "overexpression", + "of", + "Glrx", + "in", + "the" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "encoding", + "active", + "transforming", + "growth", + "factor", + "beta-1", + "(AdTGFB1)-induced", + "transgenic", + "overexpression", + "of", + "Glrx", + "in", + "the" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "epithelium", + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lung" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + } + ] + }, + { + "PMID": "29988123", + "TEXT": "Despite the introduction of more than one dozen new antiepileptic drugs in the past 20 years, approximately one-third of people who develop epilepsy continue to have seizures on mono- or polytherapy1. Viral-vector-mediated gene transfer offers the opportunity to design a rational treatment that builds on mechanistic understanding of seizure generation and that can be targeted to specific neuronal populations in epileptogenic foci2. Several such strategies have shown encouraging results in different animal models, although clinical translation is limited by possible effects on circuits underlying cognitive, mnemonic, sensory or motor function. Here, we describe an autoregulatory antiepileptic gene therapy, which relies on neuronal inhibition in response to elevations in extracellular glutamate. It is effective in a rodent model of focal epilepsy and is well tolerated, thus lowering the barrier to clinical translation.", + "TAG_DATA": [ + "115, rodent {'context': 'B-organism'}", + "116, model {'context': 'I-neoplasm'}", + "117, of {'context': 'I-neoplasm'}", + "118, focal {'context': 'I-neoplasm'}", + "119, epilepsy {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "115, rodent ['l0', 'l1', 'l2', 'l3']", + "116, model ['l0', 'l4', 'l5', 'l6']", + "117, of ['l1', 'l4', 'l7', 'l8']", + "118, focal ['l2', 'l5', 'l7', 'l9']", + "119, epilepsy ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29955182", + "TEXT": "In the version of this article originally published, an asterisk was omitted from Fig. 1a. The asterisk has been added to the figure. Additionally, a \"NOTCH2\" label was erroneously included in Fig. 4a. The label has been removed. The errors have been corrected in the PDF and HTML versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "29955181", + "TEXT": "In the version of this article originally published, some text above the \"Tri-nucleotide sequence motifs\" label in Fig. 2a appeared incorrectly. The text was garbled and should have appeared as nucleotide codes.Additionally, the labels on the bars in Fig. 2c were not italicized in the original publication. These are gene symbols, and they should have been italicized.The colored labels above the graphs in Fig. 4b were also erroneously not italicized. These labels represent gene names and loci, and they should have been italicized.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "29942091", + "TEXT": "The major genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is a C9orf72 G4C2 repeat expansion1,2. Proposed mechanisms by which the expansion causes c9FTD/ALS include toxicity from repeat-containing RNA and from dipeptide repeat proteins translated from these transcripts. To investigate the contribution of poly(GR) dipeptide repeat proteins to c9FTD/ALS pathogenesis in a mammalian in vivo model, we generated mice that expressed GFP-(GR)100 in the brain. GFP-(GR)100 mice developed age-dependent neurodegeneration, brain atrophy, and motor and memory deficits through the accumulation of diffuse, cytoplasmic poly(GR). Poly(GR) co-localized with ribosomal subunits and the translation initiation factor eIF3η in GFP-(GR)100 mice and, of importance, in c9FTD/ALS patients. Combined with the differential expression of ribosome-associated genes in GFP-(GR)100 mice, these findings demonstrate poly(GR)-mediated ribosomal distress. Indeed, poly(GR) inhibited canonical and non-canonical protein translation in HEK293T cells, and also induced the formation of stress granules and delayed their disassembly. These data suggest that poly(GR) contributes to c9FTD/ALS by impairing protein translation and stress granule dynamics, consequently causing chronic cellular stress and preventing cells from mounting an effective stress response. Decreasing poly(GR) and/or interrupting interactions between poly(GR) and ribosomal and stress granule-associated proteins may thus represent potential therapeutic strategies to restore homeostasis.", + "TAG_DATA": [ + "61, mice {'context': 'B-organism'}", + "69, mice {'context': 'B-organism'}", + "133, HEK293T {'context': 'B-cells'}", + "134, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "61, mice ['l0']", + "69, mice ['l0']", + "133, HEK293T ['l1']", + "134, cells, ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29942088", + "TEXT": "Interleukin-2 (IL-2) has been shown to suppress immune pathologies by preferentially expanding regulatory T cells (Tregs). However, this therapy has been limited by off-target complications due to pathogenic cell expansion. Recent efforts have been focused on developing a more selective IL-2. It is well documented that certain anti-mouse IL-2 antibodies induce conformational changes that result in selective targeting of Tregs. We report the generation of a fully human anti-IL-2 antibody, F5111.2, that stabilizes IL-2 in a conformation that results in the preferential STAT5 phosphorylation of Tregs in vitro and selective expansion of Tregs in vivo. When complexed with human IL-2, F5111.2 induced remission of type 1 diabetes in the NOD mouse model, reduced disease severity in a model of experimental autoimmune encephalomyelitis and protected mice against xenogeneic graft-versus-host disease. These results suggest that IL-2-F5111.2 may provide an immunotherapy to treat autoimmune diseases and graft-versus-host disease.", + "TAG_DATA": [ + "93, in {'context': 'B-in vivo'}", + "94, vivo. {'context': 'I-in vivo'}", + "109, NOD {'context': 'B-organism'}", + "110, mouse {'context': 'I-organism'}", + "111, model, {'context': 'I-organism'}", + "124, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "93, in ['l0']", + "94, vivo. ['l0']", + "109, NOD ['l1', 'l2']", + "110, mouse ['l1', 'l3']", + "111, model, ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29934536", + "TEXT": "In the version of this article originally published, a URL provided in the Methods section was incorrect. The URL had a solidus at the end but should have appeared as http://www.nature.com/authors/policies/image.html. The error has been corrected in the PDF and HTML versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "29915259", + "TEXT": "Recent work has highlighted the importance of transient low-frequency oscillatory (LFO; <4 Hz) activity in the healthy primary motor cortex during skilled upper-limb tasks. These brief bouts of oscillatory activity may establish the timing or sequencing of motor actions. Here, we show that LFOs track motor recovery post-stroke and can be a physiological target for neuromodulation. In rodents, we found that reach-related LFOs, as measured in both the local field potential and the related spiking activity, were diminished after stroke and that spontaneous recovery was closely correlated with their restoration in the perilesional cortex. Sensorimotor LFOs were also diminished in a human subject with chronic disability after stroke in contrast to two non-stroke subjects who demonstrated robust LFOs. Therapeutic delivery of electrical stimulation time-locked to the expected onset of LFOs was found to significantly improve skilled reaching in stroke animals. Together, our results suggest that restoration or modulation of cortical oscillatory dynamics is important for the recovery of upper-limb function and that they may serve as a novel target for clinical neuromodulation.", + "TAG_DATA": [ + "56, rodents, {'context': 'B-organism'}", + "100, human {'context': 'B-organism'}", + "101, subject {'context': 'I-organism'}", + "138, animals. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "100, human ['l0']", + "101, subject ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29895835", + "TEXT": "In the version of this article initially published, the \"[13C2]α-ketoglutarate\" label on Fig. 1g is incorrect. It should be \"[13C5]α-ketoglutarate\". Additionally, in Fig. 3b, the \"AAV-GFP\" group is missing a notation for significance, and in Fig. 3c, the \"AAV-GLS2-sh\" group is missing a notation for significance. There should be a double asterisk notating significance in both panels. Finally, in the Fig. 4g legend, \"[13C6]UDP-glucose\" should be \"[13C3]UDP-glucose\", and in the Fig. 4h legend, \"[13C6]hexose\" should be \"[13C3]hexose\". The errors have been corrected in the HTML and PDF versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "29808007", + "TEXT": "In the clinic, chimeric antigen receptor-modified T (CAR T) cell therapy is frequently associated with life-threatening cytokine-release syndrome (CRS) and neurotoxicity. Understanding the nature of these pathologies and developing treatments for them are hampered by the lack of appropriate animal models. Herein, we describe a mouse model recapitulating key features of CRS and neurotoxicity. In humanized mice with high leukemia burden, CAR T cell-mediated clearance of cancer triggered high fever and elevated IL-6 levels, which are hallmarks of CRS. Human monocytes were the major source of IL-1 and IL-6 during CRS. Accordingly, the syndrome was prevented by monocyte depletion or by blocking IL-6 receptor with tocilizumab. Nonetheless, tocilizumab failed to protect mice from delayed lethal neurotoxicity, characterized by meningeal inflammation. Instead, the IL-1 receptor antagonist anakinra abolished both CRS and neurotoxicity, resulting in substantially extended leukemia-free survival. These findings offer a therapeutic strategy to tackle neurotoxicity and open new avenues to safer CAR T cell therapies.", + "TAG_DATA": [ + "55, humanized {'context': 'B-organism'}", + "56, mice {'context': 'I-organism'}", + "79, Human {'context': 'B-cells'}", + "80, monocytes {'context': 'I-cells'}", + "101, blocking {'perturbing_action': 'B-pharmacological inhibition'}", + "102, IL-6 {'perturbing_action': 'I-pharmacological inhibition'}", + "103, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "104, with {'perturbing_action': 'I-pharmacological inhibition'}", + "105, tocilizumab. {'perturbing_action': 'I-pharmacological inhibition'}", + "111, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "55, humanized ['l0', 'l1', 'l2']", + "56, mice ['l0', 'l3', 'l4']", + "79, Human ['l1', 'l3', 'l5', 'l6']", + "80, monocytes ['l2', 'l4', 'l5', 'l7']", + "101, blocking ['l8', 'l9', 'l10', 'l11', 'l12']", + "102, IL-6 ['l8', 'l13', 'l14', 'l15', 'l16']", + "103, receptor ['l9', 'l13', 'l17', 'l18', 'l19']", + "104, with ['l10', 'l14', 'l17', 'l20', 'l21']", + "105, tocilizumab. ['l6', 'l7', 'l11', 'l15', 'l18', 'l20']", + "111, mice ['l12', 'l16', 'l19', 'l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Human", + "monocytes" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "tocilizumab." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blocking", + "IL-6", + "receptor", + "with" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "29785028", + "TEXT": "Chronic lymphocytic leukemia (CLL) is a frequent hematological neoplasm in which underlying epigenetic alterations are only partially understood. Here, we analyze the reference epigenome of seven primary CLLs and the regulatory chromatin landscape of 107 primary cases in the context of normal B cell differentiation. We identify that the CLL chromatin landscape is largely influenced by distinct dynamics during normal B cell maturation. Beyond this, we define extensive catalogues of regulatory elements de novo reprogrammed in CLL as a whole and in its major clinico-biological subtypes classified by IGHV somatic hypermutation levels. We uncover that IGHV-unmutated CLLs harbor more active and open chromatin than IGHV-mutated cases. Furthermore, we show that de novo active regions in CLL are enriched for NFAT, FOX and TCF/LEF transcription factor family binding sites. Although most genetic alterations are not associated with consistent epigenetic profiles, CLLs with MYD88 mutations and trisomy 12 show distinct chromatin configurations. Furthermore, we observe that non-coding mutations in IGHV-mutated CLLs are enriched in H3K27ac-associated regulatory elements outside accessible chromatin. Overall, this study provides an integrative portrait of the CLL epigenome, identifies extensive networks of altered regulatory elements and sheds light on the relationship between the genetic and epigenetic architecture of the disease.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "29785026", + "TEXT": "The lysine methyltransferase KMT2C (also known as MLL3), a subunit of the COMPASS complex, implements monomethylation of Lys4 on histone H3 (H3K4) at gene enhancers. KMT2C (hereafter referred to as MLL3) frequently incurs point mutations across a range of human tumor types, but precisely how these lesions alter MLL3 function and contribute to oncogenesis is unclear. Here we report a cancer mutational hotspot in MLL3 within the region encoding its plant homeodomain (PHD) repeats and demonstrate that this domain mediates association of MLL3 with the histone H2A deubiquitinase and tumor suppressor BAP1. Cancer-associated mutations in the sequence encoding the MLL3 PHD repeats disrupt the interaction between MLL3 and BAP1 and correlate with poor patient survival. Cancer cells that had PHD-associated MLL3 mutations or lacked BAP1 showed reduced recruitment of MLL3 and the H3K27 demethylase KDM6A (also known as UTX) to gene enhancers. As a result, inhibition of the H3K27 methyltransferase activity of the Polycomb repressive complex 2 (PRC2) in tumor cells harboring BAP1 or MLL3 mutations restored normal gene expression patterns and impaired cell proliferation in vivo. This study provides mechanistic insight into the oncogenic effects of PHD-associated mutations in MLL3 and suggests that restoration of a balanced state of Polycomb-COMPASS activity may have therapeutic efficacy in tumors that bear mutations in the genes encoding these epigenetic factors.", + "TAG_DATA": [ + "115, Cancer {'context': 'B-transformed cells'}", + "116, cells {'context': 'I-transformed cells'}", + "119, PHD-associated {'perturbing_action': 'B-other'}", + "120, MLL3 {'perturbing_action': 'I-other'}", + "121, mutations {'perturbing_action': 'I-other'}", + "123, lacked {'perturbing_action': 'B-gene loss-of-function'}", + "124, BAP1 {'perturbing_action': 'I-gene loss-of-function'}", + "159, tumor {'context': 'B-transformed cells'}", + "160, cells {'context': 'I-transformed cells'}", + "162, BAP1 {'perturbing_action': 'B-other'}", + "163, or {'perturbing_action': 'I-other'}", + "164, MLL3 {'perturbing_action': 'I-other'}", + "165, mutations {'perturbing_action': 'I-other'}", + "172, impaired {'effect': 'B-negative'}", + "173, cell {'context': 'B-cells'}", + "174, proliferation {'phenotype': 'B-proliferation'}", + "175, in {'context': 'B-in vivo'}", + "176, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "115, Cancer ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "116, cells ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "119, PHD-associated ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "120, MLL3 ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "121, mutations ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "123, lacked ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "124, BAP1 ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "159, tumor ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "160, cells ['l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "162, BAP1 ['l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "163, or ['l23', 'l32', 'l40', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "164, MLL3 ['l24', 'l33', 'l41', 'l48', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "165, mutations ['l25', 'l34', 'l42', 'l49', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "172, impaired ['l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "173, cell ['l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l70', 'l71', 'l72']", + "174, proliferation ['l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l70', 'l73', 'l74']", + "175, in ['l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l73', 'l75']", + "176, vivo. ['l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "Cancer", + "cells", + "tumor" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "PHD-associated", + "MLL3", + "mutations", + "BAP1", + "or" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "Cancer", + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacked", + "BAP1" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BAP1", + "or", + "MLL3", + "mutations" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BAP1", + "or", + "MLL3", + "mutations" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BAP1", + "or", + "MLL3", + "mutations" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BAP1", + "or", + "MLL3", + "mutations" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "29713087", + "TEXT": "Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogeneous disease that is further classified into transcriptionally defined activated B cell (ABC) and germinal center B cell (GCB) subtypes. We carried out a comprehensive genetic analysis of 304 primary DLBCLs and identified low-frequency alterations, captured recurrent mutations, somatic copy number alterations, and structural variants, and defined coordinate signatures in patients with available outcome data. We integrated these genetic drivers using consensus clustering and identified five robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; two distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2A loss, and associated genomic instability. The genetic features of the newly characterized subsets, their mutational signatures, and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, our results provide a roadmap for an actionable DLBCL classification.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "29686424", + "TEXT": "Although most activating mutations of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancers (NSCLCs) are sensitive to available EGFR tyrosine kinase inhibitors (TKIs), a subset with alterations in exon 20 of EGFR and HER2 are intrinsically resistant and lack an effective therapy. We used in silico, in vitro, and in vivo testing to model structural alterations induced by exon 20 mutations and to identify effective inhibitors. 3D modeling indicated alterations restricted the size of the drug-binding pocket, limiting the binding of large, rigid inhibitors. We found that poziotinib, owing to its small size and flexibility, can circumvent these steric changes and is a potent inhibitor of the most common EGFR and HER2 exon 20 mutants. Poziotinib demonstrated greater activity than approved EGFR TKIs in vitro and in patient-derived xenograft models of EGFR or HER2 exon 20 mutant NSCLC and in genetically engineered mouse models of NSCLC. In a phase 2 trial, the first 11 patients with NSCLC with EGFR exon 20 mutations receiving poziotinib had a confirmed objective response rate of 64%. These data identify poziotinib as a potent, clinically active inhibitor of EGFR and HER2 exon 20 mutations and illuminate the molecular features of TKIs that may circumvent steric changes induced by these mutations.", + "TAG_DATA": [ + "50, in {'context': 'B-in vivo'}", + "51, vivo {'context': 'B-in vivo'}", + "124, in {'context': 'B-in vitro'}", + "125, vitro {'context': 'I-in vitro'}", + "128, patient-derived {'context': 'B-xenograft'}", + "129, xenograft {'context': 'I-xenograft'}", + "130, models {'context': 'I-xenograft'}", + "132, EGFR {'context': 'I-xenograft'}", + "133, or {'perturbing_action': 'I-other'}", + "134, HER2 {'perturbing_action': 'I-other'}", + "135, exon {'perturbing_action': 'I-other'}", + "136, 20 {'perturbing_action': 'I-other'}", + "137, mutant {'perturbing_action': 'I-other'}", + "138, NSCLC {'context': 'B-neoplasm'}", + "141, genetically {'context': 'B-organism'}", + "142, engineered {'context': 'I-xenograft'}", + "143, mouse {'context': 'I-neoplasm'}", + "144, models {'context': 'I-neoplasm'}", + "145, of {'context': 'I-neoplasm'}", + "146, NSCLC. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "50, in ['l0']", + "51, vivo ['l0']", + "124, in ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "125, vitro ['l1', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "128, patient-derived ['l2', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "129, xenograft ['l3', 'l13', 'l22', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "130, models ['l4', 'l14', 'l23', 'l33', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "132, EGFR ['l5', 'l15', 'l24', 'l34', 'l41', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "133, or ['l6', 'l16', 'l25', 'l35', 'l42', 'l48', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "134, HER2 ['l7', 'l17', 'l26', 'l36', 'l43', 'l49', 'l59', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "135, exon ['l8', 'l18', 'l27', 'l37', 'l44', 'l50', 'l60', 'l69', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "136, 20 ['l9', 'l19', 'l28', 'l38', 'l45', 'l51', 'l61', 'l70', 'l79', 'l87', 'l88', 'l89', 'l90']", + "137, mutant ['l10', 'l20', 'l29', 'l39', 'l46', 'l52', 'l62', 'l71', 'l80', 'l87', 'l91', 'l92', 'l93']", + "138, NSCLC ['l11', 'l21', 'l30', 'l40', 'l47', 'l53', 'l63', 'l72', 'l81', 'l88', 'l91']", + "141, genetically ['l54', 'l64', 'l73', 'l82', 'l94', 'l95', 'l96', 'l97', 'l98']", + "142, engineered ['l55', 'l65', 'l74', 'l83', 'l94', 'l99', 'l100', 'l101', 'l102']", + "143, mouse ['l75', 'l95', 'l99', 'l103', 'l104', 'l105']", + "144, models ['l56', 'l66', 'l76', 'l84', 'l96', 'l100', 'l103', 'l106', 'l107']", + "145, of ['l31', 'l57', 'l67', 'l77', 'l85', 'l89', 'l92', 'l97', 'l101', 'l104', 'l106', 'l108']", + "146, NSCLC. ['l32', 'l58', 'l68', 'l78', 'l86', 'l90', 'l93', 'l98', 'l102', 'l105', 'l107', 'l108']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "or", + "HER2", + "exon", + "20", + "mutant" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "patient-derived", + "xenograft", + "models", + "EGFR", + "engineered" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "or", + "HER2", + "exon", + "20", + "mutant" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "or", + "HER2", + "exon", + "20", + "mutant" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "NSCLC", + "models", + "of", + "NSCLC.", + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "or", + "HER2", + "exon" + ] + }, + "context": { + "val": "organism", + "words": [ + "genetically" + ] + } + } + ] + }, + { + "PMID": "29632371", + "TEXT": "Efforts to develop drugs for Alzheimer's disease (AD) have shown promise in animal studies, only to fail in human trials, suggesting a pressing need to study AD in human model systems. Using human neurons derived from induced pluripotent stem cells that expressed apolipoprotein E4 (ApoE4), a variant of the APOE gene product and the major genetic risk factor for AD, we demonstrated that ApoE4-expressing neurons had higher levels of tau phosphorylation, unrelated to their increased production of amyloid-β (Aβ) peptides, and that they displayed GABAergic neuron degeneration. ApoE4 increased Aβ production in human, but not in mouse, neurons. Converting ApoE4 to ApoE3 by gene editing rescued these phenotypes, indicating the specific effects of ApoE4. Neurons that lacked APOE behaved similarly to those expressing ApoE3, and the introduction of ApoE4 expression recapitulated the pathological phenotypes, suggesting a gain of toxic effects from ApoE4. Treatment of ApoE4-expressing neurons with a small-molecule structure corrector ameliorated the detrimental effects, thus showing that correcting the pathogenic conformation of ApoE4 is a viable therapeutic approach for ApoE4-related AD.", + "TAG_DATA": [ + "32, human {'context': 'B-cells'}", + "33, neurons {'context': 'I-cells'}", + "34, derived {'context': 'I-cells'}", + "35, from {'context': 'I-cells'}", + "36, induced {'context': 'I-cells'}", + "37, pluripotent {'context': 'I-cells'}", + "38, stem {'context': 'I-cells'}", + "39, cells {'context': 'I-cells'}", + "64, neurons {'context': 'I-cells'}", + "92, human, {'context': 'B-cells'}", + "96, mouse, {'context': 'B-cells'}", + "97, neurons. {'context': 'I-cells'}", + "98, Converting {'perturbing_action': 'B-other'}", + "99, ApoE4 {'perturbing_action': 'I-other'}", + "100, to {'perturbing_action': 'I-other'}", + "101, ApoE3 {'perturbing_action': 'I-other'}", + "102, by {'perturbing_action': 'I-other'}", + "103, gene {'perturbing_action': 'I-other'}", + "104, editing {'perturbing_action': 'I-other'}", + "114, Neurons {'context': 'B-cells'}", + "128, ApoE4 {'perturbing_action': 'I-gene gain-of-function'}", + "129, expression {'perturbing_action': 'I-gene gain-of-function'}", + "144, ApoE4-expressing {'context': 'B-cells'}", + "145, neurons {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "32, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "33, neurons ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "34, derived ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "35, from ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "36, induced ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "37, pluripotent ['l4', 'l13', 'l21', 'l28', 'l34', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "38, stem ['l5', 'l14', 'l22', 'l29', 'l35', 'l41', 'l47', 'l48', 'l49', 'l50', 'l51']", + "39, cells ['l6', 'l15', 'l23', 'l30', 'l36', 'l42', 'l47', 'l52', 'l53', 'l54']", + "64, neurons ['l7', 'l16', 'l24', 'l31', 'l37', 'l43', 'l48', 'l52']", + "92, human, ['l8', 'l17', 'l25', 'l32', 'l38', 'l44', 'l49', 'l53', 'l55', 'l56']", + "96, mouse, ['l39', 'l45', 'l50', 'l55', 'l57']", + "97, neurons. ['l9', 'l18', 'l26', 'l33', 'l40', 'l46', 'l51', 'l54', 'l56', 'l57']", + "98, Converting ['l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "99, ApoE4 ['l58', 'l65', 'l66', 'l67', 'l68', 'l69']", + "100, to ['l59', 'l65', 'l70', 'l71', 'l72', 'l73']", + "101, ApoE3 ['l60', 'l66', 'l70', 'l74', 'l75', 'l76']", + "102, by ['l61', 'l67', 'l71', 'l74', 'l77', 'l78']", + "103, gene ['l62', 'l68', 'l72', 'l75', 'l77', 'l79']", + "104, editing ['l63', 'l69', 'l73', 'l76', 'l78', 'l79']", + "114, Neurons ['l64', 'l80', 'l81']", + "128, ApoE4 ['l80', 'l82']", + "129, expression ['l81', 'l82']", + "144, ApoE4-expressing ['l83']", + "145, neurons ['l83']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Converting" + ] + }, + "context": { + "val": "cells", + "words": [ + "Neurons" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Neurons" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ApoE4", + "expression" + ] + } + } + ] + }, + { + "PMID": "29554084", + "TEXT": "Immunization with attenuated Plasmodium falciparum sporozoites (PfSPZs) has been shown to be protective against malaria, but the features of the antibody response induced by this treatment remain unclear. To investigate this response in detail, we isolated IgM and IgG monoclonal antibodies from Tanzanian volunteers who were immunized with repeated injection of Sanaria PfSPZ Vaccine and who were found to be protected from controlled human malaria infection with infectious homologous PfSPZs. All isolated IgG monoclonal antibodies bound to P. falciparum circumsporozoite protein (PfCSP) and recognized distinct epitopes in its N terminus, NANP-repeat region, and C terminus. Strikingly, the most effective antibodies, as determined in a humanized mouse model, bound not only to the repeat region, but also to a minimal peptide at the PfCSP N-terminal junction that is not in the RTS,S vaccine. These dual-specific antibodies were isolated from different donors and were encoded by VH3-30 or VH3-33 alleles that encode tryptophan or arginine at position 52. Using structural and mutational data, we describe the elements required for germline recognition and affinity maturation. Our study provides potent neutralizing antibodies and relevant information for lineage-targeted vaccine design and immunization strategies.", + "TAG_DATA": [ + "42, Tanzanian {'context': 'B-organism'}", + "43, volunteers {'context': 'I-organism'}", + "104, humanized {'context': 'B-organism'}", + "105, mouse {'context': 'I-organism'}", + "106, model, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "42, Tanzanian ['l0']", + "43, volunteers ['l0']", + "104, humanized ['l1', 'l2']", + "105, mouse ['l1', 'l3']", + "106, model, ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29529016", + "TEXT": "Memories become less precise and generalized over time as memory traces reorganize in hippocampal-cortical networks. Increased time-dependent loss of memory precision is characterized by an overgeneralization of fear in individuals with post-traumatic stress disorder (PTSD) or age-related cognitive impairments. In the hippocampal dentate gyrus (DG), memories are thought to be encoded by so-called 'engram-bearing' dentate granule cells (eDGCs). Here we show, using rodents, that contextual fear conditioning increases connectivity between eDGCs and inhibitory interneurons (INs) in the downstream hippocampal CA3 region. We identify actin-binding LIM protein 3 (ABLIM3) as a mossy-fiber-terminal-localized cytoskeletal factor whose levels decrease after learning. Downregulation of ABLIM3 expression in DGCs was sufficient to increase connectivity with CA3 stratum lucidum INs (SLINs), promote parvalbumin (PV)-expressing SLIN activation, enhance feedforward inhibition onto CA3 and maintain a fear memory engram in the DG over time. Furthermore, downregulation of ABLIM3 expression in DGCs conferred conditioned context-specific reactivation of memory traces in hippocampal-cortical and amygdalar networks and decreased fear memory generalization at remote (i.e., distal) time points. Consistent with the observation of age-related hyperactivity of CA3, learning failed to increase DGC-SLIN connectivity in 17-month-old mice, whereas downregulation of ABLIM3 expression was sufficient to restore DGC-SLIN connectivity, increase PV+ SLIN activation and improve the precision of remote memories. These studies exemplify a connectivity-based strategy that targets a molecular brake of feedforward inhibition in DG-CA3 and may be harnessed to decrease time-dependent memory generalization in individuals with PTSD and improve memory precision in aging individuals.", + "TAG_DATA": [ + "62, rodents, {'context': 'B-organism'}", + "98, Downregulation {'perturbing_action': 'B-gene loss-of-function'}", + "99, of {'perturbing_action': 'I-gene loss-of-function'}", + "100, ABLIM3 {'perturbing_action': 'I-gene loss-of-function'}", + "101, expression {'perturbing_action': 'I-gene loss-of-function'}", + "103, DGCs {'context': 'B-cells'}", + "137, downregulation {'perturbing_action': 'B-gene loss-of-function'}", + "138, of {'perturbing_action': 'I-gene loss-of-function'}", + "139, ABLIM3 {'perturbing_action': 'I-gene loss-of-function'}", + "140, expression {'perturbing_action': 'I-gene loss-of-function'}", + "142, DGCs {'context': 'B-cells'}", + "151, hippocampal-cortical {'context': 'B-tissue/organ'}", + "152, and {'context': 'I-tissue/organ'}", + "153, amygdalar {'context': 'I-tissue/organ'}", + "154, networks {'context': 'I-tissue/organ'}", + "183, mice, {'context': 'B-organism'}", + "185, downregulation {'perturbing_action': 'B-gene loss-of-function'}", + "186, of {'perturbing_action': 'I-gene loss-of-function'}", + "187, ABLIM3 {'perturbing_action': 'I-gene loss-of-function'}", + "188, expression {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "62, rodents, ['l0', 'l1', 'l2', 'l3', 'l4']", + "98, Downregulation ['l0', 'l5', 'l6', 'l7', 'l8']", + "99, of ['l1', 'l5', 'l9', 'l10', 'l11']", + "100, ABLIM3 ['l2', 'l6', 'l9', 'l12', 'l13']", + "101, expression ['l3', 'l7', 'l10', 'l12', 'l14']", + "103, DGCs ['l4', 'l8', 'l11', 'l13', 'l14']", + "137, downregulation ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "138, of ['l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "139, ABLIM3 ['l16', 'l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "140, expression ['l17', 'l24', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "142, DGCs ['l18', 'l25', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "151, hippocampal-cortical ['l19', 'l26', 'l32', 'l37', 'l41', 'l45', 'l46', 'l47']", + "152, and ['l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l48', 'l49']", + "153, amygdalar ['l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l50']", + "154, networks ['l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l50']", + "185, downregulation ['l51', 'l52', 'l53']", + "186, of ['l51', 'l54', 'l55']", + "187, ABLIM3 ['l52', 'l54', 'l56']", + "188, expression ['l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "rodents," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Downregulation", + "of", + "ABLIM3", + "expression" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Downregulation", + "of", + "ABLIM3", + "expression", + "downregulation" + ] + }, + "context": { + "val": "cells", + "words": [ + "DGCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "downregulation", + "of", + "ABLIM3", + "expression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hippocampal-cortical", + "and", + "amygdalar", + "networks" + ] + } + } + ] + }, + { + "PMID": "29505034", + "TEXT": "Leukemia stem cells (LSCs) in individuals with chronic myelogenous leukemia (CML) (hereafter referred to as CML LSCs) are responsible for initiating and maintaining clonal hematopoiesis. These cells persist in the bone marrow (BM) despite effective inhibition of BCR-ABL kinase activity by tyrosine kinase inhibitors (TKIs). Here we show that although the microRNA (miRNA) miR-126 supported the quiescence, self-renewal and engraftment capacity of CML LSCs, miR-126 levels were lower in CML LSCs than in long-term hematopoietic stem cells (LT-HSCs) from healthy individuals. Downregulation of miR-126 levels in CML LSCs was due to phosphorylation of Sprouty-related EVH1-domain-containing 1 (SPRED1) by BCR-ABL, which led to inhibition of the RAN-exportin-5-RCC1 complex that mediates miRNA maturation. Endothelial cells (ECs) in the BM supply miR-126 to CML LSCs to support quiescence and leukemia growth, as shown using mouse models of CML in which Mir126a (encoding miR-126) was conditionally knocked out in ECs and/or LSCs. Inhibition of BCR-ABL by TKI treatment caused an undesired increase in endogenous miR-126 levels, which enhanced LSC quiescence and persistence. Mir126a knockout in LSCs and/or ECs, or treatment with a miR-126 inhibitor that targets miR-126 expression in both LSCs and ECs, enhanced the in vivo anti-leukemic effects of TKI treatment and strongly diminished LSC leukemia-initiating capacity, providing a new strategy for the elimination of LSCs in individuals with CML.", + "TAG_DATA": [ + "111, Endothelial {'context': 'B-cells'}", + "112, cells {'context': 'I-cells'}", + "113, (ECs) {'context': 'I-cells'}", + "120, CML {'context': 'B-transformed cells'}", + "121, LSCs {'context': 'I-transformed cells'}", + "123, support {'effect': 'B-positive'}", + "124, quiescence {'phenotype': 'B-quiescence'}", + "126, leukemia {'context': 'B-neoplasm'}", + "131, mouse {'context': 'B-neoplasm'}", + "132, models {'context': 'I-neoplasm'}", + "133, of {'context': 'I-neoplasm'}", + "134, CML {'context': 'I-neoplasm'}", + "137, Mir126a {'perturbing_action': 'B-rnai/knockdown'}", + "138, (encoding {'perturbing_action': 'I-rnai/knockdown'}", + "139, miR-126) {'perturbing_action': 'I-rnai/knockdown'}", + "140, was {'perturbing_action': 'I-gene loss-of-function'}", + "141, conditionally {'perturbing_action': 'B-gene loss-of-function'}", + "142, knocked {'perturbing_action': 'I-gene loss-of-function'}", + "143, out {'perturbing_action': 'I-gene loss-of-function'}", + "145, ECs {'context': 'B-cells'}", + "147, LSCs. {'context': 'B-transformed cells'}", + "148, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "149, of {'perturbing_action': 'I-pharmacological inhibition'}", + "150, BCR-ABL {'perturbing_action': 'I-pharmacological inhibition'}", + "163, enhanced {'effect': 'B-positive'}", + "164, LSC {'context': 'B-transformed cells'}", + "165, quiescence {'phenotype': 'B-quiescence'}", + "168, Mir126a {'perturbing_action': 'B-gene loss-of-function'}", + "169, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "171, LSCs {'context': 'B-transformed cells'}", + "173, ECs, {'context': 'B-transformed cells'}", + "178, miR-126 {'perturbing_action': 'B-pharmacological inhibition'}", + "179, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "111, Endothelial ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "112, cells ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "113, (ECs) ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "120, CML ['l2', 'l21', 'l39', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "121, LSCs ['l3', 'l22', 'l40', 'l57', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "123, support ['l4', 'l23', 'l41', 'l58', 'l73', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "124, quiescence ['l5', 'l24', 'l42', 'l59', 'l74', 'l88', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "126, leukemia ['l6', 'l25', 'l43', 'l60', 'l75', 'l89', 'l101', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "131, mouse ['l7', 'l26', 'l44', 'l61', 'l76', 'l90', 'l102', 'l114', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "132, models ['l8', 'l27', 'l45', 'l62', 'l77', 'l91', 'l103', 'l115', 'l126', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "133, of ['l9', 'l28', 'l46', 'l63', 'l78', 'l92', 'l104', 'l116', 'l127', 'l138', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158']", + "134, CML ['l10', 'l29', 'l47', 'l64', 'l79', 'l93', 'l105', 'l117', 'l128', 'l139', 'l149', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "137, Mir126a ['l11', 'l30', 'l48', 'l65', 'l80', 'l94', 'l106', 'l118', 'l129', 'l140', 'l150', 'l159', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "138, (encoding ['l12', 'l31', 'l49', 'l66', 'l81', 'l95', 'l107', 'l119', 'l130', 'l141', 'l151', 'l160', 'l168', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "139, miR-126) ['l13', 'l32', 'l50', 'l67', 'l82', 'l96', 'l108', 'l120', 'l131', 'l142', 'l152', 'l161', 'l169', 'l179', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197']", + "140, was ['l14', 'l33', 'l51', 'l68', 'l83', 'l97', 'l109', 'l121', 'l132', 'l143', 'l153', 'l162', 'l170', 'l180', 'l189', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "141, conditionally ['l15', 'l34', 'l52', 'l133', 'l144', 'l154', 'l163', 'l171', 'l181', 'l190', 'l198', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211']", + "142, knocked ['l16', 'l35', 'l53', 'l69', 'l84', 'l110', 'l122', 'l134', 'l145', 'l155', 'l164', 'l172', 'l182', 'l191', 'l199', 'l205', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217']", + "143, out ['l17', 'l36', 'l54', 'l70', 'l85', 'l98', 'l111', 'l123', 'l135', 'l146', 'l156', 'l165', 'l173', 'l183', 'l192', 'l200', 'l206', 'l212', 'l218', 'l219', 'l220']", + "145, ECs ['l18', 'l37', 'l55', 'l71', 'l86', 'l99', 'l112', 'l124', 'l136', 'l147', 'l157', 'l166', 'l174', 'l184', 'l193', 'l201', 'l207', 'l213', 'l218', 'l221']", + "147, LSCs. ['l19', 'l38', 'l56', 'l72', 'l87', 'l100', 'l113', 'l125', 'l137', 'l148', 'l158', 'l167', 'l175', 'l185', 'l194', 'l202', 'l208', 'l214', 'l219', 'l221']", + "148, Inhibition ['l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230']", + "149, of ['l222', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238']", + "150, BCR-ABL ['l223', 'l231', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245']", + "163, enhanced ['l176', 'l186', 'l195', 'l203', 'l209', 'l215', 'l220', 'l224', 'l232', 'l239', 'l246', 'l247', 'l248']", + "164, LSC ['l177', 'l187', 'l196', 'l210', 'l216', 'l225', 'l233', 'l240', 'l246', 'l249', 'l250']", + "165, quiescence ['l178', 'l188', 'l197', 'l204', 'l211', 'l217', 'l226', 'l234', 'l241', 'l247', 'l249', 'l251']", + "168, Mir126a ['l227', 'l235', 'l242', 'l252', 'l253', 'l254', 'l255', 'l256']", + "169, knockout ['l228', 'l236', 'l243', 'l252', 'l257', 'l258']", + "171, LSCs ['l229', 'l237', 'l244', 'l253', 'l257', 'l259']", + "173, ECs, ['l230', 'l238', 'l245', 'l248', 'l250', 'l251', 'l254', 'l258', 'l259']", + "178, miR-126 ['l255', 'l260']", + "179, inhibitor ['l256', 'l260']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Endothelial", + "cells", + "(ECs)", + "ECs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "support" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Endothelial", + "cells", + "(ECs)", + "ECs" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Endothelial", + "cells", + "(ECs)", + "ECs" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Mir126a", + "(encoding", + "miR-126)" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Endothelial", + "cells", + "(ECs)", + "ECs" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "was", + "conditionally", + "knocked", + "out" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CML", + "LSCs", + "LSCs.", + "LSC", + "ECs," + ] + }, + "effect": { + "val": "positive", + "words": [ + "support", + "enhanced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CML", + "LSCs", + "LSCs.", + "LSC", + "ECs," + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CML", + "LSCs", + "LSCs.", + "LSC" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Mir126a", + "(encoding", + "miR-126)" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CML", + "LSCs", + "LSCs.", + "LSC", + "ECs," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "was", + "knocked", + "out", + "conditionally", + "Mir126a", + "knockout" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "support", + "enhanced" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "support" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia", + "mouse", + "models", + "of", + "CML" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "support", + "enhanced" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Mir126a", + "(encoding", + "miR-126)" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "support", + "enhanced" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "was", + "out", + "conditionally", + "knocked" + ] + } + }, + { + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia", + "mouse", + "models", + "of", + "CML" + ] + } + }, + { + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Mir126a", + "(encoding", + "miR-126)" + ] + } + }, + { + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "was", + "knocked", + "out", + "conditionally" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "leukemia", + "mouse", + "models", + "of", + "CML" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Mir126a", + "(encoding", + "miR-126)" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "leukemia", + "mouse", + "models", + "of", + "CML" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "was", + "knocked", + "out", + "conditionally" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "BCR-ABL" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "BCR-ABL" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "LSC", + "LSCs", + "ECs," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "BCR-ABL" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + } + } + ] + }, + { + "PMID": "29505031", + "TEXT": "Lung-innervating nociceptor sensory neurons detect noxious or harmful stimuli and consequently protect organisms by mediating coughing, pain, and bronchoconstriction. However, the role of sensory neurons in pulmonary host defense is unclear. Here, we found that TRPV1+ nociceptors suppressed protective immunity against lethal Staphylococcus aureus pneumonia. Targeted TRPV1+-neuron ablation increased survival, cytokine induction, and lung bacterial clearance. Nociceptors suppressed the recruitment and surveillance of neutrophils, and altered lung γδ T cell numbers, which are necessary for immunity. Vagal ganglia TRPV1+ afferents mediated immunosuppression through release of the neuropeptide calcitonin gene-related peptide (CGRP). Targeting neuroimmunological signaling may be an effective approach to treat lung infections and bacterial pneumonia.", + "TAG_DATA": [ + "45, Targeted {'perturbing_action': 'B-gene loss-of-function'}", + "46, TRPV1+-neuron {'perturbing_action': 'I-gene loss-of-function'}", + "47, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "53, lung {'context': 'B-tissue/organ'}", + "66, lung {'context': 'B-tissue/organ'}", + "67, γδ {'context': 'B-cells'}", + "68, T {'context': 'I-cells'}", + "69, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, Targeted ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "46, TRPV1+-neuron ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "47, ablation ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "53, lung ['l2', 'l8', 'l13']", + "66, lung ['l3', 'l9', 'l14', 'l18', 'l19', 'l20']", + "67, γδ ['l4', 'l10', 'l15', 'l18', 'l21', 'l22']", + "68, T ['l5', 'l11', 'l16', 'l19', 'l21', 'l23']", + "69, cell ['l6', 'l12', 'l17', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Targeted", + "TRPV1+-neuron", + "ablation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Targeted", + "TRPV1+-neuron", + "ablation" + ] + }, + "context": { + "val": "cells", + "words": [ + "γδ", + "T", + "cell" + ] + } + } + ] + }, + { + "PMID": "29480895", + "TEXT": "Several clinical trials have demonstrated that antiretroviral (ARV) drugs taken as pre-exposure prophylaxis (PrEP) can prevent HIV infection, with the magnitude of protection ranging from -49 to 86% (refs. ). Although these divergent outcomes are thought to be due primarily to differences in product adherence, biological factors likely contribute. Despite selective recruitment of higher-risk participants for prevention trials, HIV risk is heterogeneous even within higher-risk groups. To determine whether this heterogeneity could influence patient outcomes following PrEP, we undertook a post hoc prospective analysis of results from the CAPRISA 004 trial for 1% tenofovir gel (n = 774 patients), one of the first trials to demonstrate protection against HIV infection. Concentrations of nine proinflammatory cytokines were measured in cervicovaginal lavages at >2,000 visits, and a graduated cytokine score was used to define genital inflammation. In women without genital inflammation, tenofovir was 57% protective against HIV (95% confidence interval (CI): 7-80%) but was 3% protective (95% CI: -104-54%) if genital inflammation was present. Among women who highly adhered to the gel, tenofovir protection was 75% (95% CI: 25-92%) in women without inflammation compared to -10% (95% CI: -184-57%) in women with inflammation. Immunological predictors of HIV risk may modify the effectiveness of tools for HIV prevention; reducing genital inflammation in women may augment HIV prevention efforts.", + "TAG_DATA": [ + "135, women {'context': 'B-patient'}", + "163, women {'context': 'B-patient'}", + "178, women {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "163, women ['l0']", + "178, women ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29457796", + "TEXT": "Genomic analyses of cancer have identified recurrent point mutations in the RNA splicing factor-encoding genes SF3B1, U2AF1, and SRSF2 that confer an alteration of function. Cancer cells bearing these mutations are preferentially dependent on wild-type (WT) spliceosome function, but clinically relevant means to therapeutically target the spliceosome do not currently exist. Here we describe an orally available modulator of the SF3b complex, H3B-8800, which potently and preferentially kills spliceosome-mutant epithelial and hematologic tumor cells. These killing effects of H3B-8800 are due to its direct interaction with the SF3b complex, as evidenced by loss of H3B-8800 activity in drug-resistant cells bearing mutations in genes encoding SF3b components. Although H3B-8800 modulates WT and mutant spliceosome activity, the preferential killing of spliceosome-mutant cells is due to retention of short, GC-rich introns, which are enriched for genes encoding spliceosome components. These data demonstrate the therapeutic potential of splicing modulation in spliceosome-mutant cancers.", + "TAG_DATA": [ + "69, epithelial {'context': 'B-transformed cells'}", + "70, and {'context': 'I-transformed cells'}", + "71, hematologic {'context': 'I-transformed cells'}", + "72, tumor {'context': 'I-transformed cells'}", + "73, cells. {'context': 'I-transformed cells'}", + "97, drug-resistant {'context': 'B-cells'}", + "98, cells {'context': 'I-cells'}", + "119, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "69, epithelial ['l0', 'l1', 'l2', 'l3']", + "70, and ['l0', 'l4', 'l5', 'l6']", + "71, hematologic ['l1', 'l4', 'l7', 'l8']", + "72, tumor ['l2', 'l5', 'l7', 'l9']", + "73, cells. ['l3', 'l6', 'l8', 'l9']", + "97, drug-resistant ['l10']", + "98, cells ['l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29431743", + "TEXT": "Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD+ leukemia cells. This synergized with the allogeneic CD8+ T cell response, leading to long-term survival in six mouse models of FLT3-ITD+ AML. Sorafenib-related IL-15 production caused an increase in CD8+CD107a+IFN-γ+ T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD+ AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8+ T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.", + "TAG_DATA": [ + "49, FLT3-ITD+ {'context': 'B-transformed cells'}", + "50, leukemia {'context': 'I-transformed cells'}", + "51, cells. {'context': 'I-transformed cells'}", + "67, mouse {'context': 'B-neoplasm'}", + "68, models {'context': 'I-neoplasm'}", + "69, of {'context': 'I-neoplasm'}", + "70, FLT3-ITD+ {'context': 'I-neoplasm'}", + "71, AML. {'context': 'I-neoplasm'}", + "96, leukemia {'context': 'B-neoplasm'}", + "125, IRF7 {'perturbing_action': 'B-rnai/knockdown'}", + "126, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "128, ATF4 {'perturbing_action': 'B-gene gain-of-function'}", + "129, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "131, leukemia {'context': 'B-transformed cells'}", + "132, cells {'context': 'I-transformed cells'}", + "137, in {'context': 'B-in vitro'}", + "138, vitro. {'context': 'I-in vitro'}", + "139, Human {'context': 'B-transformed cells'}", + "140, FLT3-ITD+ {'context': 'I-transformed cells'}", + "141, AML {'context': 'I-transformed cells'}", + "142, cells {'context': 'I-transformed cells'}", + "173, CD8+ {'context': 'B-cells'}", + "174, T {'context': 'I-cells'}", + "175, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "49, FLT3-ITD+ ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "50, leukemia ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "51, cells. ['l1', 'l7', 'l13', 'l14']", + "67, mouse ['l2', 'l8', 'l15', 'l16', 'l17', 'l18']", + "68, models ['l3', 'l9', 'l13', 'l15', 'l19', 'l20', 'l21']", + "69, of ['l4', 'l10', 'l14', 'l16', 'l19', 'l22', 'l23', 'l24']", + "70, FLT3-ITD+ ['l5', 'l11', 'l17', 'l20', 'l22', 'l25', 'l26']", + "71, AML. ['l6', 'l12', 'l18', 'l21', 'l23', 'l25', 'l27']", + "96, leukemia ['l24', 'l26', 'l27']", + "125, IRF7 ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "126, knockdown ['l28', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "128, ATF4 ['l29', 'l37', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "129, overexpression ['l30', 'l38', 'l43', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "131, leukemia ['l31', 'l39', 'l44', 'l52', 'l60', 'l61', 'l62']", + "132, cells ['l32', 'l40', 'l45', 'l53', 'l60', 'l63', 'l64']", + "137, in ['l33', 'l41', 'l46', 'l54', 'l61', 'l63', 'l65']", + "138, vitro. ['l34', 'l42', 'l47', 'l55', 'l62', 'l64', 'l65']", + "139, Human ['l48', 'l56', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "140, FLT3-ITD+ ['l49', 'l57', 'l66', 'l72', 'l73', 'l74', 'l75', 'l76']", + "141, AML ['l35', 'l50', 'l58', 'l67', 'l72', 'l77', 'l78', 'l79']", + "142, cells ['l36', 'l51', 'l59', 'l68', 'l73', 'l77', 'l80', 'l81']", + "173, CD8+ ['l69', 'l74', 'l82', 'l83']", + "174, T ['l70', 'l75', 'l78', 'l80', 'l82', 'l84']", + "175, cells ['l71', 'l76', 'l79', 'l81', 'l83', 'l84']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "IRF7", + "knockdown" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "leukemia", + "cells", + "AML" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "IRF7", + "knockdown" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ATF4", + "overexpression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "leukemia", + "cells", + "Human", + "FLT3-ITD+", + "AML" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ATF4", + "overexpression" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "29334375", + "TEXT": "The ubiquitin-proteasome system (UPS) comprises a network of enzymes that is responsible for maintaining cellular protein homeostasis. The therapeutic potential of this pathway has been validated by the clinical successes of a number of UPS modulators, including proteasome inhibitors and immunomodulatory imide drugs (IMiDs). Here we identified TAK-243 (formerly known as MLN7243) as a potent, mechanism-based small-molecule inhibitor of the ubiquitin activating enzyme (UAE), the primary mammalian E1 enzyme that regulates the ubiquitin conjugation cascade. TAK-243 treatment caused depletion of cellular ubiquitin conjugates, resulting in disruption of signaling events, induction of proteotoxic stress, and impairment of cell cycle progression and DNA damage repair pathways. TAK-243 treatment caused death of cancer cells and, in primary human xenograft studies, demonstrated antitumor activity at tolerated doses. Due to its specificity and potency, TAK-243 allows for interrogation of ubiquitin biology and for assessment of UAE inhibition as a new approach for cancer treatment.", + "TAG_DATA": [ + "109, cancer {'context': 'B-transformed cells'}", + "110, cells {'context': 'I-transformed cells'}", + "113, primary {'context': 'B-xenograft'}", + "114, human {'context': 'I-xenograft'}", + "115, xenograft {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "109, cancer ['l0']", + "110, cells ['l0']", + "113, primary ['l1', 'l2']", + "114, human ['l1', 'l3']", + "115, xenograft ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29334372", + "TEXT": "The unique metabolic demands of cancer cells underscore potentially fruitful opportunities for drug discovery in the era of precision medicine. However, therapeutic targeting of cancer metabolism has led to surprisingly few new drugs to date. The neutral amino acid glutamine serves as a key intermediate in numerous metabolic processes leveraged by cancer cells, including biosynthesis, cell signaling, and oxidative protection. Herein we report the preclinical development of V-9302, a competitive small molecule antagonist of transmembrane glutamine flux that selectively and potently targets the amino acid transporter ASCT2. Pharmacological blockade of ASCT2 with V-9302 resulted in attenuated cancer cell growth and proliferation, increased cell death, and increased oxidative stress, which collectively contributed to antitumor responses in vitro and in vivo. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of glutamine transport in oncology, representing a new class of targeted therapy and laying a framework for paradigm-shifting therapies targeting cancer cell metabolism.", + "TAG_DATA": [ + "87, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "88, blockade {'perturbing_action': 'I-pharmacological inhibition'}", + "89, of {'perturbing_action': 'I-pharmacological inhibition'}", + "90, ASCT2 {'perturbing_action': 'I-pharmacological inhibition'}", + "91, with {'perturbing_action': 'I-pharmacological inhibition'}", + "92, V-9302 {'perturbing_action': 'I-pharmacological inhibition'}", + "95, attenuated {'effect': 'B-negative'}", + "96, cancer {'context': 'B-neoplasm'}", + "97, cell {'phenotype': 'B-cell growth'}", + "98, growth {'phenotype': 'I-cell growth'}", + "100, proliferation, {'phenotype': 'B-proliferation'}", + "101, increased {'effect': 'B-positive'}", + "102, cell {'phenotype': 'B-cell death'}", + "103, death, {'phenotype': 'I-cell death'}", + "114, in {'context': 'B-in vitro'}", + "115, vitro {'context': 'I-in vitro'}", + "117, in {'context': 'B-in vivo'}", + "118, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "87, Pharmacological ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "88, blockade ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "89, of ['l1', 'l16', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "90, ASCT2 ['l2', 'l17', 'l31', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "91, with ['l3', 'l18', 'l32', 'l44', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "92, V-9302 ['l4', 'l19', 'l33', 'l45', 'l56', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "95, attenuated ['l5', 'l20', 'l34', 'l46', 'l57', 'l67', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "96, cancer ['l6', 'l21', 'l35', 'l47', 'l58', 'l68', 'l77', 'l84', 'l85', 'l86']", + "97, cell ['l7', 'l22', 'l36', 'l48', 'l59', 'l69', 'l78', 'l84', 'l87', 'l88']", + "98, growth ['l8', 'l23', 'l37', 'l49', 'l60', 'l70', 'l79', 'l85', 'l87', 'l89']", + "100, proliferation, ['l9', 'l24', 'l38', 'l50', 'l61', 'l71', 'l80', 'l86', 'l88', 'l89']", + "101, increased ['l10', 'l25', 'l39', 'l51', 'l62', 'l72', 'l81', 'l90', 'l91']", + "102, cell ['l11', 'l26', 'l40', 'l52', 'l63', 'l73', 'l82', 'l90', 'l92']", + "103, death, ['l12', 'l27', 'l41', 'l53', 'l64', 'l74', 'l83', 'l91', 'l92']", + "114, in ['l13', 'l28', 'l42', 'l54', 'l65', 'l75', 'l93']", + "115, vitro ['l14', 'l29', 'l43', 'l55', 'l66', 'l76', 'l93']", + "117, in ['l94']", + "118, vivo. ['l15', 'l30', 'l94']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "ASCT2", + "with", + "V-9302" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "ASCT2", + "with", + "V-9302" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "cancer" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "ASCT2", + "with", + "V-9302" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "ASCT2", + "with", + "V-9302" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "ASCT2", + "with", + "V-9302" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "ASCT2", + "with", + "V-9302" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "ASCT2", + "with", + "V-9302" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "cancer" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "cancer" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "cancer" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + } + ] + }, + { + "PMID": "29309059", + "TEXT": "Immune-checkpoint blockade has revolutionized cancer therapy. In particular, inhibition of programmed cell death protein 1 (PD-1) has been found to be effective for the treatment of metastatic melanoma and other cancers. Despite a dramatic increase in progression-free survival, a large proportion of patients do not show durable responses. Therefore, predictive biomarkers of a clinical response are urgently needed. Here we used high-dimensional single-cell mass cytometry and a bioinformatics pipeline for the in-depth characterization of the immune cell subsets in the peripheral blood of patients with stage IV melanoma before and after 12 weeks of anti-PD-1 immunotherapy. During therapy, we observed a clear response to immunotherapy in the T cell compartment. However, before commencing therapy, a strong predictor of progression-free and overall survival in response to anti-PD-1 immunotherapy was the frequency of CD14+CD16-HLA-DRhi monocytes. We confirmed this by conventional flow cytometry in an independent, blinded validation cohort, and we propose that the frequency of monocytes in PBMCs may serve in clinical decision support.", + "TAG_DATA": [ + "83, patients {'context': 'B-patient'}", + "84, with {'context': 'I-patient'}", + "85, stage {'context': 'B-neoplasm'}", + "86, IV {'context': 'I-neoplasm'}", + "87, melanoma {'context': 'I-neoplasm'}", + "107, T {'context': 'B-cells'}", + "108, cell {'context': 'B-cells'}", + "109, compartment. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "83, patients ['l0', 'l1', 'l2', 'l3']", + "84, with ['l0', 'l4', 'l5', 'l6']", + "85, stage ['l1', 'l4', 'l7', 'l8']", + "86, IV ['l2', 'l5', 'l7', 'l9']", + "87, melanoma ['l3', 'l6', 'l8', 'l9']", + "107, T ['l10', 'l11']", + "108, cell ['l10', 'l12']", + "109, compartment. ['l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29291352", + "TEXT": "Hemophagocytic syndrome (HPS) is a fatal hyperinflammatory disease with a poorly understood mechanism that occurs most frequently in extranodal natural killer/T cell lymphoma (ENKTL). Through exome sequencing of ENKTL tumor-normal samples, we have identified a hotspot mutation (c.419T>C) in the evolutionarily conserved signaling intermediate in Toll pathway (ECSIT) gene, encoding a V140A variant of ECSIT. ECSIT-V140A activated NF-κB more potently than the wild-type protein owing to its increased affinity for the S100A8 and S100A9 heterodimer, which promotes NADPH oxidase activity. ECSIT-T419C knock-in mice showed higher peritoneal NADPH oxidase activity than mice with wild-type ECSIT in response to LPS. ECSIT-T419C-transfected ENKTL cell lines produced tumor necrosis factor (TNF)-α and interferon (IFN)-γ, which induced macrophage activation and massive cytokine secretion in cell culture and mouse xenografts. In individuals with ENKTL, ECSIT-V140A was associated with activation of NF-κB, higher HPS incidence, and poor prognosis. The immunosuppressive drug thalidomide prevented NF-κB from binding to the promoters of its target genes (including TNF and IFNG), and combination treatment with thalidomide and dexamethasone extended survival of mice engrafted with ECSIT-T419C-transfected ENKTL cells. We added thalidomide to the conventional dexamethasone-containing therapy regimen for two patients with HPS who expressed ECSIT-V140A, and we observed reversal of their HPS and disease-free survival for longer than 3 years. These findings provide mechanistic insights and a potential therapeutic strategy for ENKTL-associated HPS.", + "TAG_DATA": [ + "80, ECSIT-T419C {'perturbing_action': 'B-rnai/knockdown'}", + "81, knock-in {'perturbing_action': 'I-rnai/knockdown'}", + "82, mice {'context': 'B-organism'}", + "90, mice {'context': 'B-organism'}", + "98, ECSIT-T419C-transfected {'perturbing_action': 'B-gene gain-of-function'}", + "99, ENKTL {'context': 'B-transformed cells'}", + "100, cell {'context': 'I-transformed cells'}", + "101, lines {'context': 'I-transformed cells'}", + "112, macrophage {'context': 'B-cells'}", + "119, cell {'context': 'B-cells'}", + "120, culture {'context': 'I-in vitro'}", + "122, mouse {'context': 'B-xenograft'}", + "123, xenografts. {'context': 'I-xenograft'}", + "170, mice {'context': 'B-xenograft'}", + "171, engrafted {'context': 'I-xenograft'}", + "172, with {'context': 'I-xenograft'}", + "173, ECSIT-T419C-transfected {'perturbing_action': 'B-gene gain-of-function'}", + "174, ENKTL {'context': 'B-transformed cells'}", + "175, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "80, ECSIT-T419C ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "81, knock-in ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "82, mice ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "90, mice ['l2', 'l13', 'l23', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "98, ECSIT-T419C-transfected ['l3', 'l14', 'l32', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "99, ENKTL ['l4', 'l15', 'l24', 'l33', 'l41', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "100, cell ['l5', 'l16', 'l25', 'l34', 'l42', 'l49', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "101, lines ['l6', 'l17', 'l26', 'l35', 'l43', 'l50', 'l56', 'l62', 'l63', 'l64', 'l65', 'l66']", + "112, macrophage ['l7', 'l18', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l67', 'l68', 'l69', 'l70']", + "119, cell ['l8', 'l19', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l71', 'l72']", + "120, culture ['l9', 'l20', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71']", + "122, mouse ['l10', 'l21', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l73']", + "123, xenografts. ['l11', 'l22', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l72', 'l73']", + "170, mice ['l74', 'l75', 'l76', 'l77', 'l78']", + "171, engrafted ['l74', 'l79', 'l80', 'l81', 'l82']", + "172, with ['l75', 'l79', 'l83', 'l84', 'l85']", + "173, ECSIT-T419C-transfected ['l76', 'l80', 'l83', 'l86', 'l87']", + "174, ENKTL ['l77', 'l81', 'l84', 'l86', 'l88']", + "175, cells. ['l78', 'l82', 'l85', 'l87', 'l88']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "ECSIT-T419C", + "knock-in" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "ECSIT-T419C", + "knock-in" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ENKTL", + "cell", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "ECSIT-T419C", + "knock-in" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophage", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "ECSIT-T419C", + "knock-in" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "ECSIT-T419C", + "knock-in" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "mouse", + "xenografts." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ECSIT-T419C-transfected" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ECSIT-T419C-transfected" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ENKTL", + "cell", + "lines", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ECSIT-T419C-transfected" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophage", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ECSIT-T419C-transfected" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ECSIT-T419C-transfected" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "mouse", + "xenografts.", + "mice", + "engrafted", + "with" + ] + } + } + ] + }, + { + "PMID": "29291351", + "TEXT": "Nonalcoholic steatohepatitis (NASH) is a common clinical condition that can lead to advanced liver diseases. Lack of effective pharmacotherapies for NASH is largely attributable to an incomplete understanding of its pathogenesis. The deubiquitinase cylindromatosis (CYLD) plays key roles in inflammation and cancer. Here we identified CYLD as a suppressor of NASH in mice and in monkeys. CYLD is progressively degraded upon interaction with the E3 ligase TRIM47 in proportion to NASH severity. We observed that overexpression of Cyld in hepatocytes concomitantly inhibits lipid accumulation, insulin resistance, inflammation and fibrosis in mice with NASH induced in an experimental setting. Mechanistically, CYLD interacts directly with the kinase TAK1 and removes its K63-linked polyubiquitin chain, which blocks downstream activation of the JNK-p38 cascades. Notably, reconstitution of hepatic CYLD expression effectively reverses disease progression in mice with dietary or genetically induced NASH and in high-fat diet-fed monkeys predisposed to metabolic syndrome. Collectively, our findings demonstrate that CYLD mitigates NASH severity and identify the CYLD-TAK1 axis as a promising therapeutic target for management of the disease.", + "TAG_DATA": [ + "75, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "76, of {'perturbing_action': 'I-gene gain-of-function'}", + "77, Cyld {'perturbing_action': 'I-gene gain-of-function'}", + "79, hepatocytes {'context': 'B-cells'}", + "90, mice {'context': 'B-organism'}", + "121, reconstitution {'perturbing_action': 'B-gene gain-of-function'}", + "122, of {'perturbing_action': 'I-gene gain-of-function'}", + "123, hepatic {'perturbing_action': 'I-gene gain-of-function'}", + "124, CYLD {'perturbing_action': 'I-gene gain-of-function'}", + "125, expression {'perturbing_action': 'I-gene gain-of-function'}", + "131, mice {'context': 'B-organism'}", + "142, monkeys {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "75, overexpression ['l0', 'l1', 'l2', 'l3']", + "76, of ['l0', 'l4', 'l5', 'l6']", + "77, Cyld ['l1', 'l4', 'l7', 'l8']", + "79, hepatocytes ['l2', 'l5', 'l7', 'l9']", + "90, mice ['l3', 'l6', 'l8', 'l9']", + "121, reconstitution ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "122, of ['l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "123, hepatic ['l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "124, CYLD ['l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "125, expression ['l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "131, mice ['l14', 'l19', 'l23', 'l26', 'l28']", + "142, monkeys ['l15', 'l20', 'l24', 'l27', 'l29']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Cyld" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Cyld", + "reconstitution", + "hepatic", + "CYLD", + "expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "monkeys" + ] + } + } + ] + }, + { + "PMID": "29227475", + "TEXT": "Hepatic ischemia-reperfusion (IR) injury is a common clinical issue lacking effective therapy and validated pharmacological targets. Here, using integrative 'omics' analysis, we identified an arachidonate 12-lipoxygenase (ALOX12)-12-hydroxyeicosatetraenoic acid (12-HETE)-G-protein-coupled receptor 31 (GPR31) signaling axis as a key determinant of the hepatic IR process. We found that ALOX12 was markedly upregulated in hepatocytes during ischemia to promote 12-HETE accumulation and that 12-HETE then directly binds to GPR31, triggering an inflammatory response that exacerbates liver damage. Notably, blocking 12-HETE production inhibits IR-induced liver dysfunction, inflammation and cell death in mice and pigs. Furthermore, we established a nonhuman primate hepatic IR model that closely recapitulates clinical liver dysfunction following liver resection. Most strikingly, blocking 12-HETE accumulation effectively attenuated all pathologies of hepatic IR in this model. Collectively, this study has revealed previously uncharacterized metabolic reprogramming involving an ALOX12-12-HETE-GPR31 axis that functionally determines hepatic IR procession. We have also provided proof of concept that blocking 12-HETE production is a promising strategy for preventing and treating IR-induced liver damage.", + "TAG_DATA": [ + "78, inhibits {'effect': 'B-negative'}", + "80, liver {'context': 'B-tissue/organ'}", + "84, cell {'phenotype': 'B-cell death'}", + "85, death {'phenotype': 'I-cell death'}", + "87, mice {'context': 'B-organism'}", + "89, pigs. {'context': 'B-organism'}", + "94, nonhuman {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "78, inhibits ['l0', 'l1', 'l2', 'l3', 'l4']", + "80, liver ['l0', 'l5', 'l6', 'l7', 'l8']", + "84, cell ['l1', 'l5', 'l9', 'l10', 'l11']", + "85, death ['l2', 'l6', 'l9', 'l12', 'l13']", + "87, mice ['l3', 'l7', 'l10', 'l12', 'l14']", + "89, pigs. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "pigs." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "pigs." + ] + } + } + ] + }, + { + "PMID": "29176737", + "TEXT": "Geographic atrophy is a blinding form of age-related macular degeneration characterized by retinal pigmented epithelium (RPE) death; the RPE also exhibits DICER1 deficiency, resultant accumulation of endogenous Alu-retroelement RNA, and NLRP3-inflammasome activation. How the inflammasome is activated in this untreatable disease is largely unknown. Here we demonstrate that RPE degeneration in human-cell-culture and mouse models is driven by a noncanonical-inflammasome pathway that activates caspase-4 (caspase-11 in mice) and caspase-1, and requires cyclic GMP-AMP synthase (cGAS)-dependent interferon-β production and gasdermin D-dependent interleukin-18 secretion. Decreased DICER1 levels or Alu-RNA accumulation triggers cytosolic escape of mitochondrial DNA, which engages cGAS. Moreover, caspase-4, gasdermin D, interferon-β, and cGAS levels were elevated in the RPE in human eyes with geographic atrophy. Collectively, these data highlight an unexpected role of cGAS in responding to mobile-element transcripts, reveal cGAS-driven interferon signaling as a conduit for mitochondrial-damage-induced inflammasome activation, expand the immune-sensing repertoire of cGAS and caspase-4 to noninfectious human disease, and identify new potential targets for treatment of a major cause of blindness.", + "TAG_DATA": [ + "51, human-cell-culture {'context': 'B-cells'}", + "53, mouse {'context': 'B-organism'}", + "54, models {'context': 'I-organism'}", + "111, human {'context': 'B-patient'}", + "112, eyes {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "51, human-cell-culture ['l0', 'l1']", + "53, mouse ['l0', 'l2']", + "54, models ['l1', 'l2']", + "111, human ['l3']", + "112, eyes ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29155425", + "TEXT": "Endothelial cells are a critical component of the bone marrow (BM) stromal network, which maintains and regulates hematopoietic cells. Vascular regeneration precedes, and is necessary for, successful hematopoietic stem cell (HSC) transplantation, the only cure for most hematopoietic diseases. Recent data suggest that mature hematopoietic cells regulate BM stromal-cell function. Whether a similar cross-talk regulates the BM vasculature is not known. Here we found that donor hematopoietic cells act on sinusoidal endothelial cells and induce host blood vessel and hematopoietic regeneration after BM transplantation in mice. Adoptive transfer of BM, but not peripheral, granulocytes prevented the death of mice transplanted with limited numbers of HSCs and accelerated recovery of host vessels and hematopoietic cells. Moreover, selective granulocyte ablation in vivo impaired vascular and hematopoietic regeneration after BM transplantation. Gene expression analyses indicated that granulocytes are the main source of the cytokine TNFα, whereas its receptor TNFR1 is selectively upregulated in regenerating blood vessels. In adoptive transfer experiments, wild type, but not Tnfa-/-, granulocytes induced vascular recovery, and wild-type granulocyte transfer did not prevent death or promote vascular regeneration in Tnfr1-/-; Tnfr2-/- mice. Thus, by delivering TNFα to endothelial cells, granulocytes promote blood vessel growth and hematopoietic regeneration. Manipulation of the cross-talk between granulocytes and endothelial cells may lead to new therapeutic approaches to improve blood vessel regeneration and increase survival and hematopoietic recovery after HSC transplantation.", + "TAG_DATA": [ + "85, mice. {'context': 'B-organism'}", + "92, peripheral, {'context': 'B-cells'}", + "93, granulocytes {'context': 'I-cells'}", + "98, mice {'context': 'B-organism'}", + "104, HSCs {'context': 'B-cells'}", + "112, hematopoietic {'context': 'B-cells'}", + "113, cells. {'context': 'I-cells'}", + "115, selective {'perturbing_action': 'B-gene loss-of-function'}", + "116, granulocyte {'perturbing_action': 'I-gene loss-of-function'}", + "117, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "118, in {'context': 'B-in vivo'}", + "119, vivo {'context': 'I-in vivo'}", + "161, Tnfa-/-, {'perturbing_action': 'B-gene loss-of-function'}", + "162, granulocytes {'context': 'B-cells'}", + "168, granulocyte {'context': 'B-cells'}", + "179, Tnfr1-/-; {'perturbing_action': 'B-gene loss-of-function'}", + "180, Tnfr2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "181, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "92, peripheral, ['l0', 'l1', 'l2', 'l3', 'l4']", + "93, granulocytes ['l0', 'l5', 'l6', 'l7', 'l8']", + "98, mice ['l1', 'l5', 'l9', 'l10', 'l11']", + "104, HSCs ['l2', 'l6', 'l9', 'l12', 'l13']", + "112, hematopoietic ['l3', 'l7', 'l10', 'l12', 'l14']", + "113, cells. ['l4', 'l8', 'l11', 'l13', 'l14']", + "115, selective ['l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "116, granulocyte ['l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "117, ablation ['l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "118, in ['l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "119, vivo ['l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "161, Tnfa-/-, ['l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "162, granulocytes ['l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "168, granulocyte ['l36', 'l37', 'l38']", + "179, Tnfr1-/-; ['l36', 'l39', 'l40']", + "180, Tnfr2-/- ['l37', 'l39', 'l41']", + "181, mice. ['l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "granulocyte", + "ablation", + "Tnfa-/-," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "granulocyte", + "ablation", + "Tnfa-/-,", + "Tnfr1-/-;", + "Tnfr2-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "granulocytes", + "granulocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tnfr1-/-;", + "Tnfr2-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "29131159", + "TEXT": "The Cre-loxP recombination system is the most widely used technology for in vivo tracing of stem or progenitor cell lineages. The precision of this genetic system largely depends on the specificity of Cre recombinase expression in targeted stem or progenitor cells. However, Cre expression in nontargeted cell types can complicate the interpretation of lineage-tracing studies and has caused controversy in many previous studies. Here we describe a new genetic lineage tracing system that incorporates the Dre-rox recombination system to enhance the precision of conventional Cre-loxP-mediated lineage tracing. The Dre-rox system permits rigorous control of Cre-loxP recombination in lineage tracing, effectively circumventing potential uncertainty of the cell-type specificity of Cre expression. Using this new system we investigated two topics of recent debates-the contribution of c-Kit+ cardiac stem cells to cardiomyocytes in the heart and the contribution of Sox9+ hepatic progenitor cells to hepatocytes in the liver. By overcoming the technical hurdle of nonspecific Cre-loxP-mediated recombination, this new technology provides more precise analysis of cell lineage and fate decisions and facilitates the in vivo study of stem and progenitor cell plasticity in disease and regeneration.", + "TAG_DATA": [ + "141, hepatocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "29106401", + "TEXT": "Interferon regulatory factor 3 (IRF3) and type I interferons (IFNs) protect against infections and cancer, but excessive IRF3 activation and type I IFN production cause autoinflammatory conditions such as Aicardi-Goutières syndrome and STING-associated vasculopathy of infancy (SAVI). Myocardial infarction (MI) elicits inflammation, but the dominant molecular drivers of MI-associated inflammation remain unclear. Here we show that ischemic cell death and uptake of cell debris by macrophages in the heart fuel a fatal response to MI by activating IRF3 and type I IFN production. In mice, single-cell RNA-seq analysis of 4,215 leukocytes isolated from infarcted and non-infarcted hearts showed that MI provokes activation of an IRF3-interferon axis in a distinct population of interferon-inducible cells (IFNICs) that were classified as cardiac macrophages. Mice genetically deficient in cyclic GMP-AMP synthase (cGAS), its adaptor STING, IRF3, or the type I IFN receptor IFNAR exhibited impaired interferon-stimulated gene (ISG) expression and, in the case of mice deficient in IRF3 or IFNAR, improved survival after MI as compared to controls. Interruption of IRF3-dependent signaling resulted in decreased cardiac expression of inflammatory cytokines and chemokines and decreased inflammatory cell infiltration of the heart, as well as in attenuated ventricular dilation and improved cardiac function. Similarly, treatment of mice with an IFNAR-neutralizing antibody after MI ablated the interferon response and improved left ventricular dysfunction and survival. These results identify IRF3 and the type I IFN response as a potential therapeutic target for post-MI cardioprotection.", + "TAG_DATA": [ + "84, mice, {'context': 'B-organism'}", + "96, hearts {'context': 'I-tissue/organ'}", + "120, Mice {'context': 'B-organism'}", + "150, mice {'context': 'B-organism'}", + "151, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "152, in {'perturbing_action': 'I-gene loss-of-function'}", + "153, IRF3 {'perturbing_action': 'I-gene loss-of-function'}", + "154, or {'perturbing_action': 'I-gene loss-of-function'}", + "155, IFNAR, {'perturbing_action': 'I-gene loss-of-function'}", + "200, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "84, mice, ['l0']", + "96, hearts ['l0']", + "120, Mice ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "150, mice ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "151, deficient ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "152, in ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "153, IRF3 ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "154, or ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "155, IFNAR, ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "IRF3", + "or", + "IFNAR," + ] + } + } + ] + }, + { + "PMID": "29106398", + "TEXT": "Asprosin is a recently discovered fasting-induced hormone that promotes hepatic glucose production. Here we demonstrate that asprosin in the circulation crosses the blood-brain barrier and directly activates orexigenic AgRP+ neurons via a cAMP-dependent pathway. This signaling results in inhibition of downstream anorexigenic proopiomelanocortin (POMC)-positive neurons in a GABA-dependent manner, which then leads to appetite stimulation and a drive to accumulate adiposity and body weight. In humans, a genetic deficiency in asprosin causes a syndrome characterized by low appetite and extreme leanness; this is phenocopied by mice carrying similar mutations and can be fully rescued by asprosin. Furthermore, we found that obese humans and mice had pathologically elevated concentrations of circulating asprosin, and neutralization of asprosin in the blood with a monoclonal antibody reduced appetite and body weight in obese mice, in addition to improving their glycemic profile. Thus, in addition to performing a glucogenic function, asprosin is a centrally acting orexigenic hormone that is a potential therapeutic target in the treatment of both obesity and diabetes.", + "TAG_DATA": [ + "67, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "68, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "69, in {'perturbing_action': 'I-gene loss-of-function'}", + "70, asprosin {'perturbing_action': 'I-gene loss-of-function'}", + "85, mice {'context': 'B-organism'}", + "128, obese {'context': 'B-organism'}", + "129, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "67, genetic ['l0', 'l1', 'l2', 'l3']", + "68, deficiency ['l0', 'l4', 'l5', 'l6']", + "69, in ['l1', 'l4', 'l7', 'l8']", + "70, asprosin ['l2', 'l5', 'l7', 'l9']", + "85, mice ['l3', 'l6', 'l8', 'l9']", + "128, obese ['l10']", + "129, mice, ['l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deficiency", + "in", + "asprosin" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "29058717", + "TEXT": "Maladaptive wound healing responses to chronic tissue injury result in organ fibrosis. Fibrosis, which entails excessive extracellular matrix (ECM) deposition and tissue remodeling by activated myofibroblasts, leads to loss of proper tissue architecture and organ function; however, the molecular mediators of myofibroblast activation have yet to be fully identified. Here we identify soluble ephrin-B2 (sEphrin-B2) as a new profibrotic mediator in lung and skin fibrosis. We provide molecular, functional and translational evidence that the ectodomain of membrane-bound ephrin-B2 is shed from fibroblasts into the alveolar airspace after lung injury. Shedding of sEphrin-B2 promotes fibroblast chemotaxis and activation via EphB3 and/or EphB4 receptor signaling. We found that mice lacking ephrin-B2 in fibroblasts are protected from skin and lung fibrosis and that a disintegrin and metalloproteinase 10 (ADAM10) is the major ephrin-B2 sheddase in fibroblasts. ADAM10 expression is increased by transforming growth factor (TGF)-β1, and ADAM10-mediated sEphrin-B2 generation is required for TGF-β1-induced myofibroblast activation. Pharmacological inhibition of ADAM10 reduces sEphrin-B2 levels in bronchoalveolar lavage and prevents lung fibrosis in mice. Consistent with the mouse data, ADAM10-sEphrin-B2 signaling is upregulated in fibroblasts from human subjects with idiopathic pulmonary fibrosis. These results uncover a new molecular mechanism of tissue fibrogenesis and identify sEphrin-B2, its receptors EphB3 and EphB4 and ADAM10 as potential therapeutic targets in the treatment of fibrotic diseases.", + "TAG_DATA": [ + "92, promotes {'effect': 'B-positive'}", + "93, fibroblast {'context': 'B-cells'}", + "94, chemotaxis {'phenotype': 'B-migration'}", + "106, mice {'context': 'B-organism'}", + "107, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "108, ephrin-B2 {'perturbing_action': 'I-gene loss-of-function'}", + "110, fibroblasts {'context': 'B-cells'}", + "150, myofibroblast {'context': 'B-cells'}", + "152, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "153, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "154, of {'perturbing_action': 'I-pharmacological inhibition'}", + "155, ADAM10 {'perturbing_action': 'I-pharmacological inhibition'}", + "164, lung {'context': 'B-tissue/organ'}", + "167, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "92, promotes ['l0', 'l1', 'l2', 'l3']", + "93, fibroblast ['l0', 'l4', 'l5', 'l6']", + "94, chemotaxis ['l1', 'l4', 'l7', 'l8']", + "106, mice ['l2', 'l5', 'l7', 'l9', 'l10', 'l11']", + "107, lacking ['l9', 'l12', 'l13']", + "108, ephrin-B2 ['l10', 'l12', 'l14']", + "110, fibroblasts ['l3', 'l6', 'l8', 'l11', 'l13', 'l14']", + "152, Pharmacological ['l15', 'l16', 'l17', 'l18', 'l19']", + "153, inhibition ['l15', 'l20', 'l21', 'l22', 'l23']", + "154, of ['l16', 'l20', 'l24', 'l25', 'l26']", + "155, ADAM10 ['l17', 'l21', 'l24', 'l27', 'l28']", + "164, lung ['l18', 'l22', 'l25', 'l27', 'l29']", + "167, mice. ['l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "cells", + "words": [ + "fibroblast", + "fibroblasts" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "fibroblast", + "fibroblasts" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "ephrin-B2" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "ephrin-B2" + ] + }, + "context": { + "val": "cells", + "words": [ + "fibroblasts" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "ADAM10" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "ADAM10" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "29035364", + "TEXT": "The cellular mechanism(s) linking macrophages to norepinephrine (NE)-mediated regulation of thermogenesis have been a topic of debate. Here we identify sympathetic neuron-associated macrophages (SAMs) as a population of cells that mediate clearance of NE via expression of solute carrier family 6 member 2 (SLC6A2), an NE transporter, and monoamine oxidase A (MAOA), a degradation enzyme. Optogenetic activation of the sympathetic nervous system (SNS) upregulates NE uptake by SAMs and shifts the SAM profile to a more proinflammatory state. NE uptake by SAMs is prevented by genetic deletion of Slc6a2 or inhibition of the encoded transporter. We also observed an increased proportion of SAMs in the SNS of two mouse models of obesity. Genetic ablation of Slc6a2 in SAMs increases brown adipose tissue (BAT) content, causes browning of white fat, increases thermogenesis, and leads to substantial and sustained weight loss in obese mice. We further show that this pathway is conserved, as human sympathetic ganglia also contain SAMs expressing the analogous molecular machinery for NE clearance, which thus constitutes a potential target for obesity treatment.", + "TAG_DATA": [ + "85, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "86, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "87, of {'perturbing_action': 'I-gene loss-of-function'}", + "88, Slc6a2 {'perturbing_action': 'I-gene loss-of-function'}", + "112, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "113, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "114, of {'perturbing_action': 'I-gene loss-of-function'}", + "115, Slc6a2 {'perturbing_action': 'I-gene loss-of-function'}", + "117, SAMs {'context': 'B-cells'}", + "140, obese {'context': 'B-organism'}", + "141, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "85, genetic ['l0', 'l1', 'l2']", + "86, deletion ['l0', 'l3', 'l4']", + "87, of ['l1', 'l3', 'l5']", + "88, Slc6a2 ['l2', 'l4', 'l5']", + "112, Genetic ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "113, ablation ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "114, of ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "115, Slc6a2 ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "117, SAMs ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "140, obese ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "141, mice. ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "ablation", + "of", + "Slc6a2" + ] + }, + "context": { + "val": "cells", + "words": [ + "SAMs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "ablation", + "of", + "Slc6a2" + ] + }, + "context": { + "val": "organism", + "words": [ + "obese", + "mice." + ] + } + } + ] + }, + { + "PMID": "28920960", + "TEXT": "Targeting EGFR is a validated approach in the treatment of squamous-cell cancers (SCCs), although there are no established biomarkers for predicting response. We have identified a synonymous mutation in EGFR, c.2361G>A (encoding p.Gln787Gln), in two patients with head and neck SCC (HNSCC) who were exceptional responders to gefitinib, and we showed in patient-derived cultures that the A/A genotype was associated with greater sensitivity to tyrosine kinase inhibitors (TKIs) as compared to the G/A and G/G genotypes. Remarkably, single-copy G>A nucleotide editing in isogenic models conferred a 70-fold increase in sensitivity due to decreased stability of the EGFR-AS1 long noncoding RNA (lncRNA). In the appropriate context, sensitivity could be recapitulated through EGFR-AS1 knockdown in vitro and in vivo, whereas overexpression was sufficient to induce resistance to TKIs. Reduced EGFR-AS1 levels shifted splicing toward EGFR isoform D, leading to ligand-mediated pathway activation. In co-clinical trials involving patients and patient-derived xenograft (PDX) models, tumor shrinkage was most pronounced in the context of the A/A genotype for EGFR-Q787Q, low expression of EGFR-AS1 and high expression of EGFR isoform D. Our study reveals how a 'silent' mutation influences the levels of a lncRNA, resulting in noncanonical EGFR addiction, and delineates a new predictive biomarker suite for response to EGFR TKIs.", + "TAG_DATA": [ + "52, patient-derived {'context': 'B-cells'}", + "53, cultures {'context': 'I-cells'}", + "110, EGFR-AS1 {'perturbing_action': 'B-rnai/knockdown'}", + "111, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "112, in {'context': 'B-in vitro'}", + "113, vitro {'context': 'I-in vitro'}", + "115, in {'context': 'B-in vivo'}", + "116, vivo, {'context': 'I-in vivo'}", + "146, patient-derived {'context': 'B-xenograft'}", + "147, xenograft {'context': 'I-xenograft'}", + "148, (PDX) {'context': 'I-xenograft'}", + "149, models, {'context': 'I-xenograft'}", + "150, tumor {'phenotype': 'B-tumour regression'}", + "151, shrinkage {'phenotype': 'I-tumour regression'}" + ], + "LINK_DATA": [ + "38, and ['l0', 'l1', 'l2', 'l3']", + "39, neck ['l0', 'l4', 'l5', 'l6']", + "40, SCC ['l1', 'l4', 'l7', 'l8']", + "52, patient-derived ['l2', 'l5', 'l7', 'l9']", + "53, cultures ['l3', 'l6', 'l8', 'l9']", + "110, EGFR-AS1 ['l10', 'l11', 'l12', 'l13', 'l14']", + "111, knockdown ['l10', 'l15', 'l16', 'l17', 'l18']", + "112, in ['l11', 'l15', 'l19', 'l20', 'l21']", + "113, vitro ['l12', 'l16', 'l19', 'l22', 'l23']", + "115, in ['l13', 'l17', 'l20', 'l22', 'l24']", + "116, vivo, ['l14', 'l18', 'l21', 'l23', 'l24']", + "146, patient-derived ['l25', 'l26', 'l27', 'l28', 'l29']", + "147, xenograft ['l25', 'l30', 'l31', 'l32', 'l33']", + "148, (PDX) ['l26', 'l30', 'l34', 'l35', 'l36']", + "149, models, ['l27', 'l31', 'l34', 'l37', 'l38']", + "150, tumor ['l28', 'l32', 'l35', 'l37', 'l39']", + "151, shrinkage ['l29', 'l33', 'l36', 'l38', 'l39']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "EGFR-AS1", + "knockdown" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "EGFR-AS1", + "knockdown" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "patient-derived", + "xenograft", + "(PDX)", + "models," + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "shrinkage" + ] + } + } + ] + }, + { + "PMID": "28892064", + "TEXT": "Embryonal tumors with multilayered rosettes (ETMRs) have recently been described as a new entity of rare pediatric brain tumors with a fatal outcome. We show here that ETMRs are characterized by a parallel activation of Shh and Wnt signaling. Co-activation of these pathways in mouse neural precursors is sufficient to induce ETMR-like tumors in vivo that resemble their human counterparts on the basis of histology and global gene-expression analyses, and that point to apical radial glia cells as the possible tumor cell of origin. Overexpression of LIN28A, which is a hallmark of human ETMRs, augments Sonic-hedgehog (Shh) and Wnt signaling in these precursor cells through the downregulation of let7-miRNA, and LIN28A/let7a interaction with the Shh pathway was detected at the level of Gli mRNA. Finally, human ETMR cells that were transplanted into immunocompromised host mice were responsive to the SHH inhibitor arsenic trioxide (ATO). Our work provides a novel mouse model in which to study this tumor type, demonstrates the driving role of Wnt and Shh activation in the growth of ETMRs and proposes downstream inhibition of Shh signaling as a therapeutic option for patients with ETMRs.", + "TAG_DATA": [ + "44, mouse {'context': 'B-cells'}", + "45, neural {'context': 'I-cells'}", + "46, precursors {'context': 'I-cells'}", + "51, ETMR-like {'phenotype': 'B-tumourigenesis'}", + "52, tumors {'phenotype': 'I-tumourigenesis'}", + "53, in {'context': 'B-in vivo'}", + "54, vivo {'context': 'I-in vivo'}", + "84, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "85, of {'perturbing_action': 'I-gene gain-of-function'}", + "86, LIN28A, {'perturbing_action': 'I-gene gain-of-function'}", + "102, precursor {'context': 'B-cells'}", + "103, cells {'context': 'I-cells'}", + "125, human {'context': 'B-transformed cells'}", + "126, ETMR {'context': 'I-transformed cells'}", + "127, cells {'context': 'I-transformed cells'}", + "133, host {'context': 'I-organism'}", + "134, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "44, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "45, neural ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "46, precursors ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "51, ETMR-like ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "52, tumors ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37']", + "53, in ['l4', 'l13', 'l21', 'l28', 'l34', 'l38', 'l39', 'l40', 'l41', 'l42']", + "54, vivo ['l5', 'l14', 'l22', 'l29', 'l35', 'l38', 'l43', 'l44']", + "84, Overexpression ['l45', 'l46', 'l47', 'l48']", + "85, of ['l6', 'l15', 'l23', 'l30', 'l39', 'l45', 'l49', 'l50', 'l51']", + "86, LIN28A, ['l7', 'l16', 'l24', 'l31', 'l40', 'l46', 'l49', 'l52', 'l53']", + "102, precursor ['l8', 'l17', 'l25', 'l32', 'l36', 'l41', 'l43', 'l47', 'l50', 'l52', 'l54']", + "103, cells ['l9', 'l18', 'l26', 'l33', 'l37', 'l42', 'l44', 'l48', 'l51', 'l53', 'l54']", + "125, human ['l55', 'l56', 'l57', 'l58']", + "126, ETMR ['l55', 'l59', 'l60', 'l61']", + "127, cells ['l56', 'l59', 'l62', 'l63']", + "133, host ['l57', 'l60', 'l62', 'l64']", + "134, mice ['l58', 'l61', 'l63', 'l64']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "mouse", + "neural", + "precursors", + "precursor", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "ETMR-like", + "tumors" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "neural", + "precursors", + "precursor", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "LIN28A,", + "Overexpression" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "ETMR-like", + "tumors" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "ETMR-like" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "LIN28A," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "LIN28A," + ] + } + } + ] + }, + { + "PMID": "28886002", + "TEXT": "A recent study reveals sexually dimorphic disease-associated gene-expression modules and hub genes in postmortem brains from female and male individuals with depression. These modules are conserved in mouse models of depression.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28846099", + "TEXT": "Growth differentiation factor 15 (GDF15; also known as MIC-1) is a divergent member of the TGF-β superfamily and is associated with body-weight regulation in humans and rodents. However, the cognate receptor of GDF15 is unknown. Here we show that GDF15 binds specifically to GDNF family receptor α-like (GFRAL) with high affinity, and that GFRAL requires association with the coreceptor RET to elicit intracellular signaling in response to GDF15 stimulation. We also found that GDF15-mediated reductions in food intake and body weight of mice with obesity were abolished in GFRAL-knockout mice. We further found that GFRAL expression was limited to hindbrain neurons and not present in peripheral tissues, which suggests that GDF15-GFRAL-mediated regulation of food intake is by a central mechanism. Lastly, given that GDF15 did not increase energy expenditure in treated mice with obesity, the anti-obesity actions of the cytokine are likely driven primarily by a reduction in food intake.", + "TAG_DATA": [ + "82, mice {'context': 'B-organism'}", + "88, GFRAL-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "89, mice. {'context': 'B-organism'}", + "131, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "88, GFRAL-knockout ['l0']", + "89, mice. ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "GFRAL-knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "28846098", + "TEXT": "Growth/differentiation factor 15 (GDF15), also known as MIC-1, is a distant member of the transforming growth factor-β (TGF-β) superfamily and has been implicated in various biological functions, including cancer cachexia, renal and heart failure, atherosclerosis and metabolism. A connection between GDF15 and body-weight regulation was initially suggested on the basis of an observation that increasing GDF15 levels in serum correlated with weight loss in individuals with advanced prostate cancer. In animal models, overexpression of GDF15 leads to a lean phenotype, hypophagia and other improvements in metabolic parameters, suggesting that recombinant GDF15 protein could potentially be used in the treatment of obesity and type 2 diabetes. However, the signaling and mechanism of action of GDF15 are poorly understood owing to the absence of a clearly identified cognate receptor. Here we report that GDNF-family receptor α-like (GFRAL), an orphan member of the GFR-α family, is a high-affinity receptor for GDF15. GFRAL binds to GDF15 in vitro and is required for the metabolic actions of GDF15 with respect to body weight and food intake in vivo in mice. Gfral-/- mice were refractory to the effects of recombinant human GDF15 on body-weight, food-intake and glucose parameters. Blocking the interaction between GDF15 and GFRAL with a monoclonal antibody prevented the metabolic effects of GDF15 in rats. Gfral mRNA is highly expressed in the area postrema of mouse, rat and monkey, in accordance with previous reports implicating this region of the brain in the metabolic actions of GDF15 (refs. 4,5,6). Together, our data demonstrate that GFRAL is a receptor for GDF15 that mediates the metabolic effects of GDF15.", + "TAG_DATA": [ + "70, animal {'context': 'B-organism'}", + "71, models, {'context': 'I-organism'}", + "72, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "73, of {'perturbing_action': 'I-gene gain-of-function'}", + "74, GDF15 {'perturbing_action': 'I-gene gain-of-function'}", + "172, vivo {'context': 'I-in vivo'}", + "174, mice. {'context': 'B-organism'}", + "175, Gfral-/- {'perturbing_action': 'B-gene loss-of-function'}", + "176, mice {'context': 'B-organism'}", + "210, rats. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "70, animal ['l0', 'l1', 'l2', 'l3']", + "71, models, ['l0', 'l4', 'l5', 'l6']", + "72, overexpression ['l1', 'l4', 'l7', 'l8', 'l9', 'l10']", + "73, of ['l2', 'l5', 'l7', 'l11', 'l12', 'l13']", + "74, GDF15 ['l3', 'l6', 'l8', 'l11', 'l14', 'l15']", + "172, vivo ['l9', 'l12', 'l14', 'l16']", + "174, mice. ['l10', 'l13', 'l15', 'l16']", + "175, Gfral-/- ['l17']", + "176, mice ['l17']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "animal", + "models,", + "mice." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "GDF15" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "GDF15" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gfral-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "28846097", + "TEXT": "Growth differentiation factor 15 (GDF15), a distant member of the transforming growth factor (TGF)-β family, is a secreted protein that circulates as a 25-kDa dimer. In humans, elevated GDF15 correlates with weight loss, and the administration of GDF15 to mice with obesity reduces body weight, at least in part, by decreasing food intake. The mechanisms through which GDF15 reduces body weight remain poorly understood, because the cognate receptor for GDF15 is unknown. Here we show that recombinant GDF15 induces weight loss in mice fed a high-fat diet and in nonhuman primates with spontaneous obesity. Furthermore, we find that GDF15 binds with high affinity to GDNF family receptor α-like (GFRAL), a distant relative of receptors for a distinct class of the TGF-β superfamily ligands. Gfral is expressed in neurons of the area postrema and nucleus of the solitary tract in mice and humans, and genetic deletion of the receptor abrogates the ability of GDF15 to decrease food intake and body weight in mice. In addition, diet-induced obesity and insulin resistance are exacerbated in GFRAL-deficient mice, suggesting a homeostatic role for this receptor in metabolism. Finally, we demonstrate that GDF15-induced cell signaling requires the interaction of GFRAL with the coreceptor RET. Our data identify GFRAL as a new regulator of body weight and as the bona fide receptor mediating the metabolic effects of GDF15, enabling a more comprehensive assessment of GDF15 as a potential pharmacotherapy for the treatment of obesity.", + "TAG_DATA": [ + "82, mice {'context': 'B-organism'}", + "89, nonhuman {'context': 'B-organism'}", + "90, primates {'context': 'I-organism'}", + "143, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "144, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "145, of {'perturbing_action': 'I-gene loss-of-function'}", + "146, the {'perturbing_action': 'I-gene loss-of-function'}", + "147, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "161, mice. {'context': 'B-organism'}", + "172, GFRAL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "173, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "89, nonhuman ['l0']", + "90, primates ['l0']", + "143, genetic ['l1', 'l2', 'l3', 'l4', 'l5']", + "144, deletion ['l1', 'l6', 'l7', 'l8', 'l9']", + "145, of ['l2', 'l6', 'l10', 'l11', 'l12']", + "146, the ['l3', 'l7', 'l10', 'l13', 'l14']", + "147, receptor ['l4', 'l8', 'l11', 'l13', 'l15']", + "161, mice. ['l5', 'l9', 'l12', 'l14', 'l15']", + "172, GFRAL-deficient ['l16']", + "173, mice, ['l16']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "the", + "receptor", + "GFRAL-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice," + ] + } + } + ] + }, + { + "PMID": "28805821", + "TEXT": "It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer-associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are preferentially degraded by endometrial cancer-associated SPOP mutants. The resulting reduction of BET protein levels sensitized cancer cells to BET inhibitors. Conversely, prostate cancer-specific SPOP mutations resulted in impaired degradation of BETs, promoting their resistance to pharmacologic inhibition. These results uncover an oncogenomics paradox, whereby mutations mapping to the same domain evoke opposing drug susceptibilities. Specifically, we provide a molecular rationale for the use of BET inhibitors to treat patients with endometrial but not prostate cancer who harbor SPOP mutations.", + "TAG_DATA": [ + "93, cancer {'context': 'B-transformed cells'}", + "94, cells {'context': 'I-transformed cells'}", + "99, prostate {'perturbing_action': 'B-other'}", + "100, cancer-specific {'perturbing_action': 'I-other'}", + "101, SPOP {'perturbing_action': 'I-other'}", + "102, mutations {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "93, cancer ['l0']", + "94, cells ['l0']", + "99, prostate ['l1', 'l2', 'l3']", + "100, cancer-specific ['l1', 'l4', 'l5']", + "101, SPOP ['l2', 'l4', 'l6']", + "102, mutations ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28805820", + "TEXT": "The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer. Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer; they are therefore being pursued as attractive therapeutic targets for selective inhibition in patients with cancer. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed and have shown promising outcomes in early clinical trials. Although resistance to BET inhibitors has been documented in preclinical models, the molecular mechanisms underlying acquired resistance are largely unknown. Here we report that cullin-3SPOP earmarks BET proteins, including BRD2, BRD3 and BRD4, for ubiquitination-mediated degradation. Pathologically, prostate cancer-associated SPOP mutants fail to interact with and promote the degradation of BET proteins, leading to their elevated abundance in SPOP-mutant prostate cancer. As a result, prostate cancer cell lines and organoids derived from individuals harboring SPOP mutations are more resistant to BET-inhibitor-induced cell growth arrest and apoptosis. Therefore, our results elucidate the tumor-suppressor role of SPOP in prostate cancer in which it acts as a negative regulator of BET protein stability and also provide a molecular mechanism for resistance to BET inhibitors in individuals with prostate cancer bearing SPOP mutations.", + "TAG_DATA": [ + "193, prostate {'context': 'B-neoplasm'}", + "198, prostate {'context': 'B-transformed cells'}", + "199, cancer {'context': 'I-transformed cells'}", + "200, cell {'context': 'I-transformed cells'}", + "201, lines {'context': 'I-transformed cells'}", + "203, organoids {'context': 'B-organoid'}", + "208, SPOP {'perturbing_action': 'B-other'}", + "209, mutations {'perturbing_action': 'I-other'}", + "211, more {'effect': 'B-negative'}", + "212, resistant {'effect': 'B-negative'}", + "214, BET-inhibitor-induced {'perturbing_action': 'B-pharmacological inhibition'}", + "215, cell {'phenotype': 'B-cell growth'}", + "216, growth {'phenotype': 'I-cell growth'}", + "217, arrest {'effect': 'B-negative', 'phenotype': 'I-cell cycle arrest'}", + "219, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "198, prostate ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "199, cancer ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "200, cell ['l1', 'l13', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "201, lines ['l2', 'l14', 'l24', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "203, organoids ['l3', 'l15', 'l25', 'l34', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "208, SPOP ['l4', 'l43', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "209, mutations ['l5', 'l16', 'l26', 'l35', 'l44', 'l52', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "211, more ['l6', 'l17', 'l27', 'l36', 'l45', 'l53', 'l60', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "212, resistant ['l7', 'l18', 'l28', 'l37', 'l46', 'l54', 'l61', 'l67', 'l73', 'l74', 'l75', 'l76', 'l77']", + "214, BET-inhibitor-induced ['l8', 'l19', 'l29', 'l38', 'l47', 'l55', 'l62', 'l68', 'l73', 'l78', 'l79', 'l80', 'l81']", + "215, cell ['l9', 'l20', 'l30', 'l39', 'l48', 'l56', 'l63', 'l69', 'l74', 'l78', 'l82', 'l83', 'l84']", + "216, growth ['l10', 'l21', 'l31', 'l40', 'l49', 'l57', 'l64', 'l70', 'l75', 'l79', 'l82', 'l85', 'l86']", + "217, arrest ['l11', 'l22', 'l32', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l83', 'l85', 'l87']", + "219, apoptosis. ['l12', 'l23', 'l33', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l86', 'l87']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cell", + "lines" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "SPOP", + "mutations" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cell", + "lines" + ] + }, + "effect": { + "val": "negative", + "words": [ + "more", + "resistant", + "arrest" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cell", + "lines" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BET-inhibitor-induced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cell", + "lines" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cell", + "lines" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "arrest", + "more", + "resistant" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cell", + "lines" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "organoids" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "SPOP", + "mutations" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "organoids" + ] + }, + "effect": { + "val": "negative", + "words": [ + "more", + "resistant", + "arrest" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "organoids" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BET-inhibitor-induced" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "organoids" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "organoids" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "organoids" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "SPOP", + "mutations" + ] + }, + "effect": { + "val": "negative", + "words": [ + "more", + "resistant", + "arrest" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "SPOP", + "mutations" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "SPOP", + "mutations" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "SPOP", + "mutations" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "more", + "resistant", + "arrest" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BET-inhibitor-induced" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "more", + "resistant", + "arrest" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "more", + "resistant", + "arrest" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BET-inhibitor-induced" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BET-inhibitor-induced" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BET-inhibitor-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "28714991", + "TEXT": "Inflammatory diseases such as arthritis are chronic conditions that fail to resolve spontaneously. While the cytokine and cellular pathways triggering arthritis are well defined, those responsible for the resolution of inflammation are incompletely characterized. Here we identified interleukin (IL)-9-producing type 2 innate lymphoid cells (ILC2s) as the mediators of a molecular and cellular pathway that orchestrates the resolution of chronic inflammation. In mice, the absence of IL-9 impaired ILC2 proliferation and activation of regulatory T (Treg) cells, and resulted in chronic arthritis with excessive cartilage destruction and bone loss. In contrast, treatment with IL-9 promoted ILC2-dependent Treg activation and effectively induced resolution of inflammation and protection of bone. Patients with rheumatoid arthritis in remission exhibited high numbers of IL-9+ ILC2s in joints and the circulation. Hence, fostering IL-9-mediated ILC2 activation may offer a novel therapeutic approach inducing resolution of inflammation rather than suppression of inflammatory responses.", + "TAG_DATA": [ + "62, mice, {'context': 'B-organism'}", + "64, absence {'perturbing_action': 'B-gene loss-of-function'}", + "65, of {'perturbing_action': 'I-gene loss-of-function'}", + "66, IL-9 {'perturbing_action': 'I-gene loss-of-function'}", + "67, impaired {'effect': 'B-negative'}", + "68, ILC2 {'context': 'B-cells'}", + "69, proliferation {'phenotype': 'B-proliferation'}", + "73, regulatory {'context': 'B-cells'}", + "74, T {'context': 'I-cells'}", + "75, (Treg) {'context': 'I-cells'}", + "76, cells, {'context': 'I-cells'}", + "96, Treg {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "62, mice, ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "64, absence ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "65, of ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "66, IL-9 ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "67, impaired ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "68, ILC2 ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "69, proliferation ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "73, regulatory ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "74, T ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "75, (Treg) ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "76, cells, ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "IL-9" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "IL-9" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "IL-9" + ] + }, + "context": { + "val": "cells", + "words": [ + "ILC2", + "regulatory", + "T", + "(Treg)", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "IL-9" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "cells", + "words": [ + "ILC2", + "regulatory", + "T", + "(Treg)", + "cells," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "ILC2", + "regulatory", + "T", + "(Treg)", + "cells," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "28650456", + "TEXT": "Soluble urokinase plasminogen activator receptor (suPAR) independently predicts chronic kidney disease (CKD) incidence and progression. Apolipoprotein L1 (APOL1) gene variants G1 and G2, but not the reference allele (G0), are associated with an increased risk of CKD in individuals of recent African ancestry. Here we show in two large, unrelated cohorts that decline in kidney function associated with APOL1 risk variants was dependent on plasma suPAR levels: APOL1-related risk was attenuated in patients with lower suPAR, and strengthened in those with higher suPAR levels. Mechanistically, surface plasmon resonance studies identified high-affinity interactions between suPAR, APOL1 and αvβ3 integrin, whereby APOL1 protein variants G1 and G2 exhibited higher affinity for suPAR-activated avb3 integrin than APOL1 G0. APOL1 G1 or G2 augments αvβ3 integrin activation and causes proteinuria in mice in a suPAR-dependent manner. The synergy of circulating factor suPAR and APOL1 G1 or G2 on αvβ3 integrin activation is a mechanism for CKD.", + "TAG_DATA": [ + "127, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28628112", + "TEXT": "Emerging evidence has linked the gut microbiome to human obesity. We performed a metagenome-wide association study and serum metabolomics profiling in a cohort of lean and obese, young, Chinese individuals. We identified obesity-associated gut microbial species linked to changes in circulating metabolites. The abundance of Bacteroides thetaiotaomicron, a glutamate-fermenting commensal, was markedly decreased in obese individuals and was inversely correlated with serum glutamate concentration. Consistently, gavage with B. thetaiotaomicron reduced plasma glutamate concentration and alleviated diet-induced body-weight gain and adiposity in mice. Furthermore, weight-loss intervention by bariatric surgery partially reversed obesity-associated microbial and metabolic alterations in obese individuals, including the decreased abundance of B. thetaiotaomicron and the elevated serum glutamate concentration. Our findings identify previously unknown links between intestinal microbiota alterations, circulating amino acids and obesity, suggesting that it may be possible to intervene in obesity by targeting the gut microbiota.", + "TAG_DATA": [ + "81, mice. {'context': 'B-organism'}", + "97, individuals, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "96, obese ['l0']", + "97, individuals, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28604702", + "TEXT": "The extracellular matrix (ECM) is a master regulator of cellular phenotype and behavior. It has a crucial role in both normal tissue homeostasis and disease pathology. Here we present a fast and efficient approach to enhance the study of ECM composition and structure. Termed in situ decellularization of tissues (ISDoT), it allows whole organs to be decellularized, leaving native ECM architecture intact. These three-dimensional decellularized tissues can be studied using high-resolution fluorescence and second harmonic imaging, and can be used for quantitative proteomic interrogation of the ECM. Our method is superior to other methods tested in its ability to preserve the structural integrity of the ECM, facilitate high-resolution imaging and quantitatively detect ECM proteins. In particular, we performed high-resolution sub-micron imaging of matrix topography in normal tissue and over the course of primary tumor development and progression to metastasis in mice, providing the first detailed imaging of the metastatic niche. These data show that cancer-driven ECM remodeling is organ specific, and that it is accompanied by comprehensive changes in ECM composition and topological structure. We also describe differing patterns of basement-membrane organization surrounding different types of blood vessels in healthy and diseased tissues. The ISDoT procedure allows for the study of native ECM structure under normal and pathological conditions in unprecedented detail.", + "TAG_DATA": [ + "132, primary {'context': 'B-neoplasm'}", + "133, tumor {'context': 'I-neoplasm'}", + "134, development {'phenotype': 'I-tumourigenesis'}", + "138, metastasis {'phenotype': 'B-metastasis'}", + "140, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "132, primary ['l0', 'l1', 'l2', 'l3', 'l4']", + "133, tumor ['l0', 'l5', 'l6', 'l7', 'l8']", + "134, development ['l1', 'l5', 'l9', 'l10', 'l11']", + "136, progression ['l2', 'l6', 'l9', 'l12', 'l13']", + "138, metastasis ['l3', 'l7', 'l10', 'l12', 'l14']", + "140, mice, ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "primary", + "tumor" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "primary", + "tumor" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "28586335", + "TEXT": "Neuroendocrine (NE) cancers are a diverse group of neoplasms typically diagnosed and treated on the basis of their site of origin. This Perspective focuses on advances in our understanding of the tumorigenesis and treatment of poorly differentiated neuroendocrine tumors. Recent evidence from sequencing indicates that, although neuroendocrine tumors can arise de novo, they can also develop as a result of lineage plasticity in response to pressure from targeted therapies. We discuss the shared genomic alterations of these tumors independently of their site of origin, and we explore potential therapeutic strategies on the basis of recent biological findings.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28504725", + "TEXT": "Fragile X syndrome (FXS) is the leading monogenic cause of autism spectrum disorders (ASD). Trinucleotide repeat expansions in FMR1 abolish FMRP expression, leading to hyperactivation of ERK and mTOR signaling upstream of mRNA translation. Here we show that metformin, the most widely used drug for type 2 diabetes, rescues core phenotypes in Fmr1-/y mice and selectively normalizes ERK signaling, eIF4E phosphorylation and the expression of MMP-9. Thus, metformin is a potential FXS therapeutic.", + "TAG_DATA": [ + "52, Fmr1-/y {'perturbing_action': 'B-gene loss-of-function'}", + "53, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "52, Fmr1-/y ['l0']", + "53, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fmr1-/y" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "28459438", + "TEXT": "Blood vessels in the central nervous system (CNS) are controlled by neuronal activity. For example, widespread vessel constriction (vessel tone) is induced by brainstem neurons that release the monoamines serotonin and noradrenaline, and local vessel dilation is induced by glutamatergic neuron activity. Here we examined how vessel tone adapts to the loss of neuron-derived monoamines after spinal cord injury (SCI) in rats. We find that, months after the imposition of SCI, the spinal cord below the site of injury is in a chronic state of hypoxia owing to paradoxical excess activity of monoamine receptors (5-HT1) on pericytes, despite the absence of monoamines. This monoamine-receptor activity causes pericytes to locally constrict capillaries, which reduces blood flow to ischemic levels. Receptor activation in the absence of monoamines results from the production of trace amines (such as tryptamine) by pericytes that ectopically express the enzyme aromatic L-amino acid decarboxylase (AADC), which synthesizes trace amines directly from dietary amino acids (such as tryptophan). Inhibition of monoamine receptors or of AADC, or even an increase in inhaled oxygen, produces substantial relief from hypoxia and improves motoneuron and locomotor function after SCI.", + "TAG_DATA": [ + "72, spinal {'context': 'B-tissue/organ'}", + "73, cord {'context': 'I-tissue/organ'}", + "106, pericytes {'context': 'B-cells'}", + "136, pericytes {'context': 'B-cells'}", + "138, ectopically {'perturbing_action': 'B-gene gain-of-function'}", + "139, express {'perturbing_action': 'I-gene gain-of-function'}", + "140, the {'perturbing_action': 'I-gene gain-of-function'}", + "141, enzyme {'perturbing_action': 'I-gene gain-of-function'}", + "142, aromatic {'perturbing_action': 'I-gene gain-of-function'}", + "143, L-amino {'perturbing_action': 'I-gene gain-of-function'}", + "144, acid {'perturbing_action': 'I-gene gain-of-function'}", + "145, decarboxylase {'perturbing_action': 'I-gene gain-of-function'}", + "146, (AADC), {'perturbing_action': 'I-gene gain-of-function'}", + "180, motoneuron {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "72, spinal ['l0', 'l1']", + "73, cord ['l0', 'l2']", + "106, pericytes ['l1', 'l2']", + "136, pericytes ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "138, ectopically ['l3', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "139, express ['l4', 'l14', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "140, the ['l5', 'l15', 'l24', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "141, enzyme ['l6', 'l16', 'l25', 'l33', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "142, aromatic ['l7', 'l17', 'l26', 'l34', 'l41', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "143, L-amino ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l54', 'l55', 'l56', 'l57', 'l58']", + "144, acid ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l59', 'l60', 'l61', 'l62']", + "145, decarboxylase ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l63', 'l64', 'l65']", + "146, (AADC), ['l11', 'l21', 'l30', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l66', 'l67']", + "162, receptors ['l12', 'l22', 'l31', 'l39', 'l46', 'l52', 'l57', 'l61', 'l64', 'l66', 'l68']", + "180, motoneuron ['l13', 'l23', 'l32', 'l40', 'l47', 'l53', 'l58', 'l62', 'l65', 'l67', 'l68']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "pericytes", + "motoneuron" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopically", + "express", + "the", + "enzyme", + "aromatic", + "L-amino", + "acid", + "decarboxylase", + "(AADC)," + ] + } + } + ] + }, + { + "PMID": "28414328", + "TEXT": "Splenic marginal zone B (MZB) cells, positioned at the interface between circulating blood and lymphoid tissue, detect and respond to blood-borne antigens. Here we show that MZB cells in mice activate a homeostatic program in response to a high-cholesterol diet (HCD) and regulate both the differentiation and accumulation of T follicular helper (TFH) cells. Feeding mice an HCD resulted in upregulated MZB cell surface expression of the immunoregulatory ligand PDL1 in an ATF3-dependent manner and increased the interaction between MZB cells and pre-TFH cells, leading to PDL1-mediated suppression of TFH cell motility, alteration of TFH cell differentiation, reduced TFH abundance and suppression of the proatherogenic TFH response. Our findings reveal a previously unsuspected role for MZB cells in controlling the TFH-germinal center response to a cholesterol-rich diet and uncover a PDL1-dependent mechanism through which MZB cells use their innate immune properties to limit an exaggerated adaptive immune response.", + "TAG_DATA": [ + "55, mice {'context': 'B-organism'}", + "82, pre-TFH {'context': 'B-cells'}", + "83, cells, {'context': 'I-cells'}", + "87, suppression {'effect': 'B-negative'}", + "89, TFH {'context': 'B-cells'}", + "90, cell {'context': 'I-cells'}", + "91, motility, {'phenotype': 'B-migration'}", + "92, alteration {'effect': 'B-regulates'}", + "94, TFH {'context': 'B-cells'}", + "95, cell {'context': 'I-cells'}", + "96, differentiation, {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "55, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "82, pre-TFH ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "83, cells, ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "87, suppression ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "89, TFH ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38']", + "90, cell ['l4', 'l13', 'l21', 'l28', 'l34', 'l39', 'l40', 'l41']", + "91, motility, ['l5', 'l14', 'l22', 'l29', 'l35', 'l39', 'l42', 'l43']", + "92, alteration ['l6', 'l15', 'l23', 'l30', 'l36', 'l44', 'l45', 'l46']", + "94, TFH ['l7', 'l16', 'l24', 'l31', 'l44', 'l47', 'l48']", + "95, cell ['l8', 'l17', 'l25', 'l32', 'l37', 'l40', 'l42', 'l45', 'l47', 'l49']", + "96, differentiation, ['l9', 'l18', 'l26', 'l33', 'l38', 'l41', 'l43', 'l46', 'l48', 'l49']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppression" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "motility," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "alteration" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pre-TFH", + "cells,", + "TFH", + "cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppression" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pre-TFH", + "cells,", + "TFH", + "cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "motility," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pre-TFH", + "cells,", + "TFH", + "cell" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "alteration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pre-TFH", + "cells,", + "TFH", + "cell" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppression" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "motility," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppression" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "alteration" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + } + ] + }, + { + "PMID": "28346411", + "TEXT": "Brown adipose tissue (BAT) and beige adipose tissue combust fuels for heat production in adult humans, and so constitute an appealing target for the treatment of metabolic disorders such as obesity, diabetes and hyperlipidemia. Cold exposure can enhance energy expenditure by activating BAT, and it has been shown to improve nutrient metabolism. These therapies, however, are time consuming and uncomfortable, demonstrating the need for pharmacological interventions. Recently, lipids have been identified that are released from tissues and act locally or systemically to promote insulin sensitivity and glucose tolerance; as a class, these lipids are referred to as 'lipokines'. Because BAT is a specialized metabolic tissue that takes up and burns lipids and is linked to systemic metabolic homeostasis, we hypothesized that there might be thermogenic lipokines that activate BAT in response to cold. Here we show that the lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) is a stimulator of BAT activity, and that its levels are negatively correlated with body-mass index and insulin sensitivity. Using a global lipidomic analysis, we found that 12,13-diHOME was increased in the circulation of humans and mice exposed to cold. Furthermore, we found that the enzymes that produce 12,13-diHOME were uniquely induced in BAT by cold stimulation. The injection of 12,13-diHOME acutely activated BAT fuel uptake and enhanced cold tolerance, which resulted in decreased levels of serum triglycerides. Mechanistically, 12,13-diHOME increased fatty acid (FA) uptake into brown adipocytes by promoting the translocation of the FA transporters FATP1 and CD36 to the cell membrane. These data suggest that 12,13-diHOME, or a functional analog, could be developed as a treatment for metabolic disorders.", + "TAG_DATA": [ + "205, BAT {'context': 'B-cells'}", + "228, brown {'context': 'B-cells'}", + "229, adipocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "228, brown ['l0']", + "229, adipocytes ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28170383", + "TEXT": "Biomarkers have transformed modern medicine but remain largely elusive in psychiatry, partly because there is a weak correspondence between diagnostic labels and their neurobiological substrates. Like other neuropsychiatric disorders, depression is not a unitary disease, but rather a heterogeneous syndrome that encompasses varied, co-occurring symptoms and divergent responses to treatment. By using functional magnetic resonance imaging (fMRI) in a large multisite sample (n = 1,188), we show here that patients with depression can be subdivided into four neurophysiological subtypes (‘biotypes’) defined by distinct patterns of dysfunctional connectivity in limbic and frontostriatal networks. Clustering patients on this basis enabled the development of diagnostic classifiers (biomarkers) with high (82–93%) sensitivity and specificity for depression subtypes in multisite validation (n = 711) and out-of-sample replication (n = 477) data sets. These biotypes cannot be differentiated solely on the basis of clinical features, but they are associated with differing clinical-symptom profiles. They also predict responsiveness to transcranial magnetic stimulation therapy (n = 154). Our results define novel subtypes of depression that transcend current diagnostic boundaries and may be useful for identifying the individuals who are most likely to benefit from targeted neurostimulation therapies.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28165481", + "TEXT": "Hepatitis B virus (HBV)-specific CD8 T cells are functionally exhausted in chronic hepatitis B infection, and this condition can be corrected only partially through the modulation of inhibitory pathways, which suggests that a more complex molecular interplay underlies T cell exhaustion. To gain broader insight into this process and identify additional targets for the restoration of T cell function, we compared the transcriptome profiles of HBV-specific CD8 T cells from patients with acute and chronic disease with those of HBV-specific CD8 T cells from patients able to resolve HBV infection spontaneously and influenza (FLU)-specific CD8 T cells from healthy participants. The results indicate that exhausted HBV-specific CD8 T cells are markedly impaired at multiple levels and show substantial downregulation of various cellular processes centered on extensive mitochondrial alterations. A notable improvement of mitochondrial and antiviral CD8 functions was elicited by mitochondrion-targeted antioxidants, which suggests a central role for reactive oxygen species (ROS) in T cell exhaustion. Thus, mitochondria represent promising targets for novel reconstitution therapies to treat chronic hepatitis B infection.", + "TAG_DATA": [ + "65, HBV-specific {'context': 'B-cells'}", + "66, CD8 {'context': 'I-cells'}", + "67, T {'context': 'I-cells'}", + "68, cells {'context': 'I-cells'}", + "79, HBV-specific {'context': 'B-cells'}", + "80, CD8 {'context': 'I-cells'}", + "81, T {'context': 'I-cells'}", + "82, cells {'context': 'I-cells'}", + "84, patients {'context': 'B-patient'}", + "94, CD8 {'context': 'I-cells'}", + "95, T {'context': 'I-cells'}", + "96, cells {'context': 'I-cells'}", + "105, HBV-specific {'context': 'B-cells'}", + "106, CD8 {'context': 'I-cells'}", + "107, T {'context': 'I-cells'}", + "108, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "65, HBV-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "66, CD8 ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "67, T ['l1', 'l6', 'l11', 'l12']", + "68, cells ['l2', 'l7', 'l11', 'l13']", + "79, HBV-specific ['l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "80, CD8 ['l3', 'l8', 'l14', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "81, T ['l4', 'l9', 'l15', 'l22', 'l28', 'l29', 'l30', 'l31']", + "82, cells ['l5', 'l10', 'l12', 'l13', 'l16', 'l23', 'l28', 'l32', 'l33', 'l34']", + "84, patients ['l17', 'l24', 'l29', 'l32', 'l35', 'l36', 'l37', 'l38', 'l39']", + "94, CD8 ['l18', 'l35', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "95, T ['l19', 'l25', 'l30', 'l33', 'l36', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "96, cells ['l20', 'l26', 'l31', 'l34', 'l37', 'l41', 'l46', 'l51', 'l52', 'l53']", + "105, HBV-specific ['l42', 'l47', 'l54', 'l55', 'l56']", + "106, CD8 ['l43', 'l48', 'l51', 'l54', 'l57', 'l58']", + "107, T ['l38', 'l44', 'l49', 'l52', 'l55', 'l57', 'l59']", + "108, cells ['l21', 'l27', 'l39', 'l45', 'l50', 'l53', 'l56', 'l58', 'l59']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28112736", + "TEXT": "Human microbial communities are characterized by their taxonomic, metagenomic and metabolic diversity, which varies by distinct body sites and influences human physiology. However, when and how microbial communities within each body niche acquire unique taxonomical and functional signatures in early life remains underexplored. We thus sought to determine the taxonomic composition and potential metabolic function of the neonatal and early infant microbiota across multiple body sites and assess the effect of the mode of delivery and its potential confounders or modifiers. A cohort of pregnant women in their early third trimester (n = 81) were prospectively enrolled for longitudinal sampling through 6 weeks after delivery, and a second matched cross-sectional cohort (n = 81) was additionally recruited for sampling once at the time of delivery. Samples across multiple body sites, including stool, oral gingiva, nares, skin and vagina were collected for each maternal-infant dyad. Whole-genome shotgun sequencing and sequencing analysis of the gene encoding the 16S rRNA were performed to interrogate the composition and function of the neonatal and maternal microbiota. We found that the neonatal microbiota and its associated functional pathways were relatively homogeneous across all body sites at delivery, with the notable exception of the neonatal meconium. However, by 6 weeks after delivery, the infant microbiota structure and function had substantially expanded and diversified, with the body site serving as the primary determinant of the composition of the bacterial community and its functional capacity. Although minor variations in the neonatal (immediately at birth) microbiota community structure were associated with the cesarean mode of delivery in some body sites (oral gingiva, nares and skin; R2 = 0.038), this was not true for neonatal stool (meconium; Mann-Whitney P > 0.05), and there was no observable difference in community function regardless of delivery mode. For infants at 6 weeks of age, the microbiota structure and function had expanded and diversified with demonstrable body site specificity (P < 0.001, R2 = 0.189) but without discernable differences in community structure or function between infants delivered vaginally or by cesarean surgery (P = 0.057, R2 = 0.007). We conclude that", + "TAG_DATA": [ + "84, pregnant {'context': 'B-cells'}", + "85, women {'context': 'I-organism'}", + "294, infants {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "84, pregnant ['l0']", + "85, women ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28092666", + "TEXT": "Opioid pain medications have detrimental side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). Tolerance and OIH counteract opioid analgesia and drive dose escalation. The cell types and receptors on which opioids act to initiate these maladaptive processes remain disputed, which has prevented the development of therapies to maximize and sustain opioid analgesic efficacy. We found that μ opioid receptors (MORs) expressed by primary afferent nociceptors initiate tolerance and OIH development. RNA sequencing and histological analysis revealed that MORs are expressed by nociceptors, but not by spinal microglia. Deletion of MORs specifically in nociceptors eliminated morphine tolerance, OIH and pronociceptive synaptic long-term potentiation without altering antinociception. Furthermore, we found that co-administration of methylnaltrexone bromide, a peripherally restricted MOR antagonist, was sufficient to abrogate morphine tolerance and OIH without diminishing antinociception in perioperative and chronic pain models. Collectively, our data support the idea that opioid agonists can be combined with peripheral MOR antagonists to limit analgesic tolerance and OIH.", + "TAG_DATA": [ + "88, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "89, of {'perturbing_action': 'I-gene loss-of-function'}", + "90, MORs {'perturbing_action': 'I-gene loss-of-function'}", + "91, specifically {'perturbing_action': 'I-gene loss-of-function'}", + "93, nociceptors {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "88, Deletion ['l0', 'l1', 'l2', 'l3']", + "89, of ['l0', 'l4', 'l5', 'l6']", + "90, MORs ['l1', 'l4', 'l7', 'l8']", + "91, specifically ['l2', 'l5', 'l7', 'l9']", + "93, nociceptors ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "MORs", + "specifically" + ] + }, + "context": { + "val": "cells", + "words": [ + "nociceptors" + ] + } + } + ] + }, + { + "PMID": "28092665", + "TEXT": "Monoclonal antibody 10-1074 targets the V3 glycan supersite on the HIV-1 envelope (Env) protein. It is among the most potent anti-HIV-1 neutralizing antibodies isolated so far. Here we report on its safety and activity in 33 individuals who received a single intravenous infusion of the antibody. 10-1074 was well tolerated and had a half-life of 24.0 d in participants without HIV-1 infection and 12.8 d in individuals with HIV-1 infection. Thirteen individuals with viremia received the highest dose of 30 mg/kg 10-1074. Eleven of these participants were 10-1074-sensitive and showed a rapid decline in viremia by a mean of 1.52 log10 copies/ml. Virologic analysis revealed the emergence of multiple independent 10-1074-resistant viruses in the first weeks after infusion. Emerging escape variants were generally resistant to the related V3-specific antibody PGT121, but remained sensitive to antibodies targeting nonoverlapping epitopes, such as the anti-CD4-binding-site antibodies 3BNC117 and VRC01. The results demonstrate the safety and activity of 10-1074 in humans and support the idea that antibodies targeting the V3 glycan supersite might be useful for the treatment and prevention of HIV-1 infection.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28067901", + "TEXT": "The cytostatic deoxycytidine analog cytarabine (ara-C) is the most active agent available against acute myelogenous leukemia (AML). Together with anthracyclines, ara-C forms the backbone of AML treatment for children and adults. In AML, both the cytotoxicity of ara-C in vitro and the clinical response to ara-C therapy are correlated with the ability of AML blasts to accumulate the active metabolite ara-C triphosphate (ara-CTP), which causes DNA damage through perturbation of DNA synthesis. Differences in expression levels of known transporters or metabolic enzymes relevant to ara-C only partially account for patient-specific differential ara-CTP accumulation in AML blasts and response to ara-C treatment. Here we demonstrate that the deoxynucleoside triphosphate (dNTP) triphosphohydrolase SAM domain and HD domain 1 (SAMHD1) promotes the detoxification of intracellular ara-CTP pools. Recombinant SAMHD1 exhibited ara-CTPase activity in vitro, and cells in which SAMHD1 expression was transiently reduced by treatment with the simian immunodeficiency virus (SIV) protein Vpx were dramatically more sensitive to ara-C-induced cytotoxicity. CRISPR-Cas9-mediated disruption of the gene encoding SAMHD1 sensitized cells to ara-C, and this sensitivity could be abrogated by ectopic expression of wild-type (WT), but not dNTPase-deficient, SAMHD1. Mouse models of AML lacking SAMHD1 were hypersensitive to ara-C, and treatment ex vivo with Vpx sensitized primary patient-derived AML blasts to ara-C. Finally, we identified SAMHD1 as a risk factor in cohorts of both pediatric and adult patients with de novo AML who received ara-C treatment. Thus, SAMHD1 expression levels dictate patient sensitivity to ara-C, providing proof-of-concept that the targeting of SAMHD1 by Vpx could be an attractive therapeutic", + "TAG_DATA": [ + "129, in {'context': 'B-in vitro'}", + "130, vitro, {'context': 'I-in vitro'}", + "132, cells {'context': 'B-cells'}", + "157, CRISPR-Cas9-mediated {'perturbing_action': 'B-gene loss-of-function'}", + "158, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "159, of {'perturbing_action': 'I-gene loss-of-function'}", + "160, the {'perturbing_action': 'I-gene loss-of-function'}", + "161, gene {'perturbing_action': 'I-gene loss-of-function'}", + "162, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "163, SAMHD1 {'perturbing_action': 'I-gene loss-of-function'}", + "165, cells {'context': 'B-cells'}", + "175, ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "176, expression {'perturbing_action': 'I-gene gain-of-function'}", + "177, of {'perturbing_action': 'I-gene gain-of-function'}", + "178, wild-type {'perturbing_action': 'I-gene gain-of-function'}", + "179, (WT), {'perturbing_action': 'I-gene gain-of-function'}", + "183, SAMHD1. {'perturbing_action': 'I-gene loss-of-function'}", + "184, Mouse {'context': 'B-organism'}", + "185, models {'context': 'I-neoplasm'}", + "186, of {'context': 'I-neoplasm'}", + "187, AML {'context': 'I-neoplasm'}", + "188, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "189, SAMHD1 {'perturbing_action': 'I-gene loss-of-function'}", + "201, primary {'context': 'B-transformed cells'}", + "202, patient-derived {'context': 'I-transformed cells'}", + "203, AML {'context': 'I-transformed cells'}", + "204, blasts {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "129, in ['l0', 'l1']", + "130, vitro, ['l0', 'l2']", + "132, cells ['l1', 'l2']", + "157, CRISPR-Cas9-mediated ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "158, disruption ['l3', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "159, of ['l4', 'l15', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "160, the ['l5', 'l16', 'l25', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "161, gene ['l6', 'l17', 'l26', 'l34', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "162, encoding ['l7', 'l18', 'l27', 'l35', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "163, SAMHD1 ['l8', 'l19', 'l28', 'l36', 'l44', 'l51', 'l58']", + "165, cells ['l9', 'l20', 'l29', 'l37', 'l45', 'l52', 'l58']", + "175, ectopic ['l10', 'l21', 'l30', 'l38', 'l46', 'l53', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "176, expression ['l11', 'l22', 'l31', 'l39', 'l47', 'l54', 'l59', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "177, of ['l12', 'l23', 'l32', 'l40', 'l48', 'l55', 'l60', 'l71', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "178, wild-type ['l61', 'l72', 'l84', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "179, (WT), ['l13', 'l41', 'l49', 'l56', 'l62', 'l73', 'l85', 'l96', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "183, SAMHD1. ['l14', 'l24', 'l33', 'l42', 'l50', 'l57', 'l63', 'l74', 'l86', 'l97', 'l108', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "184, Mouse ['l64', 'l75', 'l87', 'l98', 'l109', 'l119', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "185, models ['l65', 'l76', 'l88', 'l99', 'l110', 'l120', 'l129', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145']", + "186, of ['l66', 'l77', 'l89', 'l100', 'l111', 'l121', 'l130', 'l138', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "187, AML ['l67', 'l78', 'l90', 'l101', 'l112', 'l122', 'l131', 'l139', 'l146', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158']", + "188, lacking ['l68', 'l79', 'l91', 'l102', 'l113', 'l123', 'l132', 'l140', 'l147', 'l153', 'l159', 'l160', 'l161', 'l162', 'l163']", + "189, SAMHD1 ['l69', 'l80', 'l92', 'l103', 'l114', 'l124', 'l133', 'l141', 'l148', 'l154', 'l159', 'l164', 'l165', 'l166', 'l167']", + "201, primary ['l104', 'l115', 'l125', 'l134', 'l142', 'l149', 'l155', 'l160', 'l164', 'l168', 'l169', 'l170']", + "202, patient-derived ['l81', 'l93', 'l105', 'l116', 'l126', 'l135', 'l143', 'l150', 'l156', 'l161', 'l165', 'l168', 'l171', 'l172']", + "203, AML ['l82', 'l94', 'l106', 'l117', 'l127', 'l136', 'l144', 'l151', 'l157', 'l162', 'l166', 'l169', 'l171', 'l173']", + "204, blasts ['l70', 'l83', 'l95', 'l107', 'l118', 'l128', 'l137', 'l145', 'l152', 'l158', 'l163', 'l167', 'l170', 'l172', 'l173']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CRISPR-Cas9-mediated", + "disruption", + "of", + "the", + "gene", + "encoding", + "SAMHD1" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "expression", + "of", + "wild-type", + "(WT)," + ] + }, + "context": { + "val": "organism", + "words": [ + "Mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "expression", + "of", + "wild-type", + "(WT)," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models", + "of", + "AML" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "expression", + "of", + "wild-type", + "(WT)," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "blasts", + "patient-derived", + "AML", + "primary" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SAMHD1.", + "lacking", + "SAMHD1" + ] + }, + "context": { + "val": "organism", + "words": [ + "Mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SAMHD1.", + "lacking", + "SAMHD1" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models", + "of", + "AML" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SAMHD1.", + "lacking", + "SAMHD1" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "patient-derived", + "AML", + "blasts" + ] + } + } + ] + }, + { + "PMID": "28024084", + "TEXT": "Prader-Willi syndrome (PWS) is an imprinting disorder caused by a deficiency of paternally expressed gene(s) in the 15q11-q13 chromosomal region. The regulation of imprinted gene expression in this region is coordinated by an imprinting center (PWS-IC). In individuals with PWS, genes responsible for PWS on the maternal chromosome are present, but repressed epigenetically, which provides an opportunity for the use of epigenetic therapy to restore expression from the maternal copies of PWS-associated genes. Through a high-content screen (HCS) of >9,000 small molecules, we discovered that UNC0638 and UNC0642-two selective inhibitors of euchromatic histone lysine N-methyltransferase-2 (EHMT2, also known as G9a)-activated the maternal (m) copy of candidate genes underlying PWS, including the SnoRNA cluster SNORD116, in cells from humans with PWS and also from a mouse model of PWS carrying a paternal (p) deletion from small nuclear ribonucleoprotein N (Snrpn (S)) to ubiquitin protein ligase E3A (Ube3a (U)) (mouse model referred to hereafter as m+/pΔS-U). Both UNC0642 and UNC0638 caused a selective reduction of the dimethylation of histone H3 lysine 9 (H3K9me2) at PWS-IC, without changing DNA methylation, when analyzed by bisulfite genomic sequencing. This indicates that histone modification is essential for the imprinting of candidate genes underlying PWS. UNC0642 displayed therapeutic effects in the PWS mouse model by improving the survival and the growth of m+/pΔS-U newborn pups. This study provides the first proof of principle for an epigenetics-based therapy for PWS.", + "TAG_DATA": [ + "115, cells {'context': 'B-cells'}", + "124, mouse {'context': 'B-organism'}", + "125, model {'context': 'I-organism'}", + "126, of {'context': 'I-organism'}", + "127, PWS {'context': 'I-organism'}", + "130, paternal {'perturbing_action': 'B-gene loss-of-function'}", + "132, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "204, PWS {'context': 'B-organism'}", + "205, mouse {'context': 'I-organism'}", + "206, model {'context': 'I-organism'}", + "216, newborn {'context': 'B-organism'}", + "217, pups. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "124, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "125, model ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "126, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "127, PWS ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "130, paternal ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "131, (p) ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "132, deletion ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "140, to ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "144, E3A ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "204, PWS ['l36', 'l37', 'l38', 'l39']", + "205, mouse ['l36', 'l40', 'l41', 'l42']", + "206, model ['l37', 'l40', 'l43', 'l44']", + "216, newborn ['l38', 'l41', 'l43', 'l45']", + "217, pups. ['l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "PWS" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "paternal", + "deletion" + ] + } + } + ] + }, + { + "PMID": "27941793", + "TEXT": "New therapeutic approaches are needed to treat leukemia effectively. Dietary restriction regimens, including fasting, have been considered for the prevention and treatment of certain solid tumor types. However, whether and how dietary restriction affects hematopoietic malignancies is unknown. Here we report that fasting alone robustly inhibits the initiation and reverses the leukemic progression of both B cell and T cell acute lymphoblastic leukemia (B-ALL and T-ALL, respectively), but not acute myeloid leukemia (AML), in mouse models of these tumors. Mechanistically, we found that attenuated leptin-receptor (LEPR) expression is essential for the development and maintenance of ALL, and that fasting inhibits ALL development by upregulation of LEPR and its downstream signaling through the protein PR/SET domain 1 (PRDM1). The expression of LEPR signaling-related genes correlated with the prognosis of pediatric patients with pre-B-ALL, and fasting effectively inhibited B-ALL growth in a human xenograft model. Our results indicate that the effects of fasting on tumor growth are cancer-type dependent, and they suggest new avenues for the development of treatment strategies for leukemia.", + "TAG_DATA": [ + "45, inhibits {'effect': 'B-negative'}", + "49, reverses {'effect': 'B-negative'}", + "51, leukemic {'context': 'B-neoplasm', 'phenotype': 'B-autophagy'}", + "52, progression {'phenotype': 'I-tumour progression'}", + "55, B {'context': 'B-neoplasm'}", + "56, cell {'context': 'I-neoplasm'}", + "57, and {'context': 'I-neoplasm'}", + "58, T {'context': 'I-neoplasm'}", + "59, cell {'context': 'I-neoplasm'}", + "60, acute {'context': 'I-neoplasm'}", + "61, lymphoblastic {'context': 'I-neoplasm'}", + "62, leukemia {'context': 'I-neoplasm'}", + "63, (B-ALL {'context': 'I-neoplasm'}", + "65, T-ALL, {'context': 'I-transformed cells'}", + "69, acute {'context': 'B-neoplasm'}", + "70, myeloid {'context': 'I-neoplasm'}", + "71, leukemia {'context': 'I-neoplasm'}", + "72, (AML), {'context': 'I-neoplasm'}", + "74, mouse {'context': 'B-organism'}", + "75, models {'context': 'I-neoplasm'}", + "76, of {'context': 'I-neoplasm'}", + "77, these {'context': 'I-neoplasm'}", + "78, tumors. {'context': 'I-neoplasm'}", + "99, inhibits {'effect': 'B-negative'}", + "100, ALL {'context': 'B-neoplasm'}", + "136, B-ALL {'context': 'B-neoplasm'}", + "140, human {'context': 'B-xenograft'}", + "141, xenograft {'context': 'I-xenograft'}", + "142, model. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "45, inhibits ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "49, reverses ['l0', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "51, leukemic ['l1', 'l22', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "52, progression ['l2', 'l23', 'l42', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "55, B ['l3', 'l24', 'l43', 'l62', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "56, cell ['l4', 'l25', 'l44', 'l63', 'l77', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "57, and ['l5', 'l26', 'l45', 'l64', 'l78', 'l95', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127']", + "58, T ['l6', 'l27', 'l46', 'l65', 'l79', 'l96', 'l112', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "59, cell ['l7', 'l28', 'l47', 'l66', 'l80', 'l97', 'l113', 'l128', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156']", + "60, acute ['l8', 'l29', 'l48', 'l67', 'l81', 'l98', 'l114', 'l129', 'l143', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "61, lymphoblastic ['l9', 'l30', 'l49', 'l68', 'l82', 'l99', 'l115', 'l130', 'l144', 'l157', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181']", + "62, leukemia ['l10', 'l31', 'l50', 'l69', 'l83', 'l100', 'l116', 'l131', 'l145', 'l158', 'l170', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192']", + "63, (B-ALL ['l11', 'l32', 'l51', 'l70', 'l84', 'l101', 'l117', 'l132', 'l146', 'l159', 'l171', 'l182', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202']", + "65, T-ALL, ['l12', 'l33', 'l52', 'l71', 'l85', 'l102', 'l118', 'l133', 'l147', 'l160', 'l172', 'l183', 'l193', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211']", + "69, acute ['l13', 'l34', 'l53', 'l86', 'l103', 'l119', 'l134', 'l148', 'l161', 'l173', 'l184', 'l194', 'l203', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219']", + "70, myeloid ['l14', 'l54', 'l87', 'l104', 'l120', 'l135', 'l149', 'l162', 'l174', 'l185', 'l195', 'l204', 'l212', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226']", + "71, leukemia ['l15', 'l35', 'l55', 'l88', 'l105', 'l121', 'l136', 'l150', 'l163', 'l175', 'l186', 'l196', 'l205', 'l213', 'l220', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232']", + "72, (AML), ['l16', 'l36', 'l56', 'l89', 'l106', 'l122', 'l137', 'l151', 'l164', 'l176', 'l187', 'l197', 'l206', 'l214', 'l221', 'l227', 'l233', 'l234', 'l235', 'l236', 'l237']", + "74, mouse ['l17', 'l37', 'l57', 'l72', 'l90', 'l107', 'l123', 'l138', 'l152', 'l165', 'l177', 'l188', 'l198', 'l207', 'l215', 'l222', 'l228', 'l233', 'l238', 'l239', 'l240', 'l241']", + "75, models ['l18', 'l38', 'l58', 'l73', 'l91', 'l108', 'l124', 'l139', 'l153', 'l166', 'l178', 'l189', 'l199', 'l208', 'l216', 'l223', 'l229', 'l234', 'l238', 'l242', 'l243', 'l244']", + "76, of ['l19', 'l39', 'l59', 'l74', 'l92', 'l109', 'l125', 'l140', 'l154', 'l167', 'l179', 'l190', 'l200', 'l209', 'l217', 'l224', 'l230', 'l235', 'l239', 'l242', 'l245', 'l246']", + "77, these ['l20', 'l40', 'l60', 'l75', 'l93', 'l110', 'l126', 'l141', 'l155', 'l168', 'l180', 'l191', 'l201', 'l210', 'l218', 'l225', 'l231', 'l236', 'l240', 'l243', 'l245', 'l247']", + "78, tumors. ['l21', 'l41', 'l61', 'l76', 'l94', 'l111', 'l127', 'l142', 'l156', 'l169', 'l181', 'l192', 'l202', 'l211', 'l219', 'l226', 'l232', 'l237', 'l241', 'l244', 'l246', 'l247']", + "99, inhibits ['l248']", + "100, ALL ['l248']", + "136, B-ALL ['l249', 'l250', 'l251']", + "140, human ['l249', 'l252', 'l253']", + "141, xenograft ['l250', 'l252', 'l254']", + "142, model. ['l251', 'l253', 'l254']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "reverses" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemic", + "B", + "cell", + "and", + "T", + "acute", + "lymphoblastic", + "leukemia", + "(B-ALL", + "myeloid", + "(AML),", + "models", + "of", + "these", + "tumors.", + "ALL" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "reverses" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "leukemic" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "leukemic" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "leukemic" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "reverses" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "progression" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "reverses" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "T-ALL," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "reverses" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "leukemic", + "B", + "cell", + "and", + "T", + "acute", + "lymphoblastic", + "leukemia", + "(B-ALL", + "models", + "of", + "these", + "tumors." + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "progression" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "leukemic" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "T-ALL," + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "leukemic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "phenotype": { + "val": "tumour progression", + "words": [ + "progression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "T-ALL," + ] + } + }, + { + "phenotype": { + "val": "tumour progression", + "words": [ + "progression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + } + ] + }, + { + "PMID": "27941791", + "TEXT": "Excess levels of protein in urine (proteinuria) is a hallmark of kidney disease that typically occurs in conjunction with diabetes, hypertension, gene mutations, toxins or infections but may also be of unknown cause (idiopathic). Systemic soluble urokinase plasminogen activator receptor (suPAR) is a circulating factor implicated in the onset and progression of chronic kidney disease (CKD), such as focal segmental glomerulosclerosis (FSGS). The cellular source(s) of elevated suPAR associated with future and progressing kidney disease is unclear, but is likely extra-renal, as the pathological uPAR is circulating and FSGS can recur even after a damaged kidney is replaced with a healthy donor organ. Here we report that bone marrow (BM) Gr-1lo immature myeloid cells are responsible for the elevated, pathological levels of suPAR, as evidenced by BM chimera and BM ablation and cell transfer studies. A marked increase of Gr-1lo myeloid cells was commonly found in the BM of proteinuric animals having high suPAR, and these cells efficiently transmit proteinuria when transferred to healthy mice. In accordance with the results seen in suPAR-associated proteinuric animal models, in which kidney damage is caused not by local podocyte-selective injury but more likely by systemic insults, a humanized xenograft model of FSGS resulted in an expansion of Gr-1lo cells in the BM, leading to high plasma suPAR and proteinuric kidney disease. Together, these results identify suPAR as a functional connection between the BM and the kidney, and they implicate BM immature myeloid cells as a key contributor to glomerular dysfunction.", + "TAG_DATA": [ + "112, myeloid {'context': 'I-cells'}", + "164, mice. {'context': 'B-organism'}", + "194, humanized {'context': 'B-xenograft'}", + "195, xenograft {'context': 'I-xenograft'}", + "196, model {'context': 'I-xenograft'}", + "198, FSGS {'context': 'I-xenograft'}", + "205, cells {'context': 'I-cells'}", + "208, BM, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "112, myeloid ['l0']", + "164, mice. ['l0']", + "194, humanized ['l1', 'l2', 'l3', 'l4', 'l5']", + "195, xenograft ['l1', 'l6', 'l7', 'l8', 'l9']", + "196, model ['l2', 'l6', 'l10', 'l11', 'l12']", + "198, FSGS ['l3', 'l7', 'l10', 'l13', 'l14']", + "205, cells ['l4', 'l8', 'l11', 'l13', 'l15']", + "208, BM, ['l5', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27918563", + "TEXT": "The role of osteolineage cells in regulating hematopoietic stem cell (HSC) regeneration following myelosuppression is not well understood. Here we show that deletion of the pro-apoptotic genes Bak and Bax in osterix (Osx, also known as Sp7 transcription factor 7)-expressing cells in mice promotes HSC regeneration and hematopoietic radioprotection following total body irradiation. These mice showed increased bone marrow (BM) levels of the protein dickkopf-1 (Dkk1), which was produced in Osx-expressing BM cells. Treatment of irradiated HSCs with Dkk1 in vitro increased the recovery of both long-term repopulating HSCs and progenitor cells, and systemic administration of Dkk1 to irradiated mice increased hematopoietic recovery and improved survival. Conversely, inducible deletion of one allele of Dkk1 in Osx-expressing cells in adult mice inhibited the recovery of BM stem and progenitor cells and of complete blood counts following irradiation. Dkk1 promoted hematopoietic regeneration via both direct effects on HSCs, in which treatment with Dkk1 decreased the levels of mitochondrial reactive oxygen species and suppressed senescence, and indirect effects on BM endothelial cells, in which treatment with Dkk1 induced epidermal growth factor (EGF) secretion. Accordingly, blockade of the EGF receptor partially abrogated Dkk1-mediated hematopoietic recovery. These data identify Dkk1 as a regulator of hematopoietic regeneration and demonstrate paracrine cross-talk between BM osteolineage cells and endothelial cells in regulating hematopoietic reconstitution following injury.", + "TAG_DATA": [ + "22, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "23, of {'perturbing_action': 'I-gene loss-of-function'}", + "24, the {'perturbing_action': 'I-gene loss-of-function'}", + "25, pro-apoptotic {'perturbing_action': 'I-gene loss-of-function'}", + "26, genes {'perturbing_action': 'I-gene loss-of-function'}", + "27, Bak {'perturbing_action': 'I-gene loss-of-function'}", + "28, and {'perturbing_action': 'I-gene loss-of-function'}", + "29, Bax {'perturbing_action': 'I-gene loss-of-function'}", + "30, in {'perturbing_action': 'I-gene loss-of-function'}", + "31, osterix {'perturbing_action': 'I-gene loss-of-function'}", + "32, (Osx, {'perturbing_action': 'I-gene loss-of-function'}", + "36, Sp7 {'perturbing_action': 'I-gene loss-of-function'}", + "37, transcription {'perturbing_action': 'I-gene loss-of-function'}", + "38, factor {'perturbing_action': 'I-gene loss-of-function'}", + "39, 7)-expressing {'perturbing_action': 'I-gene loss-of-function'}", + "40, cells {'perturbing_action': 'I-gene loss-of-function'}", + "42, mice {'context': 'B-organism'}", + "54, mice {'context': 'B-organism'}", + "76, HSCs {'context': 'B-cells'}", + "79, in {'context': 'B-in vitro'}", + "80, vitro {'context': 'I-in vitro'}", + "88, HSCs {'context': 'I-cells'}", + "90, progenitor {'context': 'B-cells'}", + "91, cells, {'context': 'I-cells'}", + "99, mice {'context': 'B-organism'}", + "107, inducible {'perturbing_action': 'B-gene loss-of-function'}", + "108, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "109, of {'perturbing_action': 'I-gene loss-of-function'}", + "110, one {'perturbing_action': 'I-gene loss-of-function'}", + "111, allele {'perturbing_action': 'I-gene loss-of-function'}", + "112, of {'perturbing_action': 'I-gene loss-of-function'}", + "113, Dkk1 {'perturbing_action': 'I-gene loss-of-function'}", + "115, Osx-expressing {'context': 'B-cells'}", + "116, cells {'context': 'I-cells'}", + "118, adult {'context': 'B-organism'}", + "119, mice {'context': 'I-organism'}", + "124, BM {'context': 'B-cells'}", + "125, stem {'context': 'I-cells'}", + "126, and {'context': 'I-cells'}", + "127, progenitor {'context': 'I-cells'}", + "128, cells {'context': 'I-cells'}", + "145, HSCs, {'context': 'B-cells'}", + "160, suppressed {'effect': 'B-negative'}", + "161, senescence, {'phenotype': 'B-senescence'}", + "166, BM {'context': 'B-cells'}", + "167, endothelial {'context': 'I-cells'}", + "168, cells, {'context': 'I-cells'}", + "181, blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "182, of {'perturbing_action': 'I-pharmacological inhibition'}", + "183, the {'perturbing_action': 'I-pharmacological inhibition'}", + "184, EGF {'perturbing_action': 'I-pharmacological inhibition'}", + "185, receptor {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "22, deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "23, of ['l0', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "24, the ['l1', 'l25', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "25, pro-apoptotic ['l2', 'l26', 'l49', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "26, genes ['l3', 'l27', 'l50', 'l72', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "27, Bak ['l4', 'l28', 'l51', 'l73', 'l94', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "28, and ['l5', 'l29', 'l52', 'l74', 'l95', 'l115', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "29, Bax ['l6', 'l30', 'l53', 'l75', 'l96', 'l116', 'l135', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171']", + "30, in ['l7', 'l31', 'l54', 'l76', 'l97', 'l117', 'l136', 'l154', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "31, osterix ['l8', 'l32', 'l55', 'l77', 'l98', 'l118', 'l137', 'l155', 'l172', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "32, (Osx, ['l9', 'l33', 'l56', 'l78', 'l99', 'l119', 'l138', 'l156', 'l173', 'l189', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219']", + "33, also ['l10', 'l34', 'l57', 'l79', 'l100', 'l120', 'l139', 'l157', 'l174', 'l190', 'l205', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234']", + "36, Sp7 ['l11', 'l35', 'l58', 'l80', 'l101', 'l121', 'l140', 'l158', 'l175', 'l191', 'l206', 'l220', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248']", + "37, transcription ['l12', 'l36', 'l59', 'l81', 'l102', 'l122', 'l141', 'l159', 'l176', 'l192', 'l207', 'l221', 'l235', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261']", + "38, factor ['l13', 'l37', 'l60', 'l82', 'l103', 'l123', 'l142', 'l160', 'l177', 'l193', 'l208', 'l222', 'l236', 'l249', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273']", + "39, 7)-expressing ['l14', 'l38', 'l61', 'l83', 'l104', 'l124', 'l143', 'l161', 'l178', 'l194', 'l209', 'l223', 'l237', 'l250', 'l262', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284']", + "40, cells ['l15', 'l39', 'l62', 'l84', 'l105', 'l125', 'l144', 'l162', 'l179', 'l195', 'l210', 'l224', 'l238', 'l251', 'l263', 'l274', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292']", + "42, mice ['l16', 'l40', 'l63', 'l85', 'l106', 'l126', 'l145', 'l163', 'l180', 'l196', 'l211', 'l225', 'l239', 'l252', 'l264', 'l275', 'l285', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298']", + "54, mice ['l17', 'l41', 'l64', 'l86', 'l107', 'l127', 'l146', 'l164', 'l181', 'l197', 'l212', 'l226', 'l240', 'l253', 'l265', 'l276', 'l286', 'l293', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304']", + "76, HSCs ['l18', 'l42', 'l65', 'l87', 'l108', 'l128', 'l147', 'l165', 'l182', 'l198', 'l213', 'l227', 'l241', 'l254', 'l266', 'l277', 'l287', 'l294', 'l299', 'l305', 'l306', 'l307', 'l308', 'l309']", + "79, in ['l19', 'l43', 'l66', 'l88', 'l109', 'l129', 'l148', 'l166', 'l183', 'l199', 'l214', 'l228', 'l242', 'l255', 'l267', 'l278', 'l288', 'l295', 'l300', 'l305', 'l310', 'l311', 'l312', 'l313']", + "80, vitro ['l20', 'l44', 'l67', 'l89', 'l110', 'l130', 'l149', 'l167', 'l184', 'l200', 'l215', 'l229', 'l243', 'l256', 'l268', 'l279', 'l289', 'l296', 'l301', 'l306', 'l310', 'l314', 'l315', 'l316']", + "88, HSCs ['l21', 'l45', 'l68', 'l90', 'l111', 'l131', 'l150', 'l168', 'l185', 'l201', 'l216', 'l230', 'l244', 'l257', 'l269', 'l280', 'l290', 'l297', 'l302', 'l307', 'l311', 'l314', 'l317', 'l318']", + "90, progenitor ['l22', 'l46', 'l69', 'l91', 'l112', 'l132', 'l151', 'l169', 'l186', 'l202', 'l217', 'l231', 'l245', 'l258', 'l270', 'l281', 'l291', 'l303', 'l308', 'l312', 'l315', 'l317', 'l319']", + "91, cells, ['l23', 'l47', 'l70', 'l92', 'l113', 'l133', 'l152', 'l170', 'l187', 'l203', 'l218', 'l232', 'l246', 'l259', 'l271', 'l282', 'l292', 'l298', 'l304', 'l309', 'l313', 'l316', 'l318', 'l319']", + "99, mice ['l24', 'l48', 'l71', 'l93', 'l114', 'l134', 'l153', 'l171', 'l188', 'l204', 'l219', 'l233', 'l247', 'l260', 'l272', 'l283']", + "107, inducible ['l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327', 'l328', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340']", + "108, deletion ['l320', 'l341', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348', 'l349', 'l350', 'l351', 'l352', 'l353', 'l354', 'l355', 'l356', 'l357', 'l358', 'l359', 'l360']", + "109, of ['l321', 'l341', 'l361', 'l362', 'l363', 'l364', 'l365', 'l366', 'l367', 'l368', 'l369', 'l370', 'l371', 'l372', 'l373', 'l374', 'l375', 'l376', 'l377', 'l378', 'l379']", + "110, one ['l322', 'l342', 'l361', 'l380', 'l381', 'l382', 'l383', 'l384', 'l385', 'l386', 'l387', 'l388', 'l389', 'l390', 'l391', 'l392', 'l393', 'l394', 'l395', 'l396', 'l397']", + "111, allele ['l323', 'l343', 'l362', 'l380', 'l398', 'l399', 'l400', 'l401', 'l402', 'l403', 'l404', 'l405', 'l406', 'l407', 'l408', 'l409', 'l410', 'l411', 'l412', 'l413', 'l414']", + "112, of ['l324', 'l344', 'l363', 'l381', 'l398', 'l415', 'l416', 'l417', 'l418', 'l419', 'l420', 'l421', 'l422', 'l423', 'l424', 'l425', 'l426', 'l427', 'l428', 'l429', 'l430']", + "113, Dkk1 ['l325', 'l345', 'l364', 'l382', 'l399', 'l415', 'l431', 'l432', 'l433', 'l434', 'l435', 'l436', 'l437', 'l438', 'l439', 'l440', 'l441', 'l442', 'l443', 'l444', 'l445']", + "115, Osx-expressing ['l326', 'l346', 'l365', 'l383', 'l400', 'l416', 'l431', 'l446', 'l447', 'l448', 'l449', 'l450', 'l451', 'l452', 'l453', 'l454', 'l455', 'l456', 'l457']", + "116, cells ['l327', 'l347', 'l366', 'l384', 'l401', 'l417', 'l432', 'l446', 'l458', 'l459', 'l460', 'l461', 'l462', 'l463', 'l464', 'l465', 'l466', 'l467', 'l468']", + "118, adult ['l328', 'l348', 'l367', 'l385', 'l402', 'l418', 'l433', 'l447', 'l458', 'l469', 'l470', 'l471', 'l472', 'l473', 'l474', 'l475', 'l476', 'l477', 'l478']", + "119, mice ['l329', 'l349', 'l368', 'l386', 'l403', 'l419', 'l434', 'l448', 'l459', 'l469', 'l479', 'l480', 'l481', 'l482', 'l483', 'l484', 'l485', 'l486']", + "124, BM ['l330', 'l350', 'l369', 'l387', 'l404', 'l420', 'l435', 'l449', 'l460', 'l470', 'l479', 'l487', 'l488', 'l489', 'l490', 'l491', 'l492', 'l493']", + "125, stem ['l331', 'l351', 'l370', 'l388', 'l405', 'l421', 'l436', 'l450', 'l461', 'l471', 'l480', 'l487', 'l494', 'l495', 'l496', 'l497', 'l498', 'l499']", + "126, and ['l332', 'l352', 'l371', 'l389', 'l406', 'l422', 'l437', 'l451', 'l462', 'l472', 'l481', 'l488', 'l494', 'l500', 'l501', 'l502', 'l503']", + "127, progenitor ['l333', 'l353', 'l372', 'l390', 'l407', 'l423', 'l438', 'l452', 'l463', 'l473', 'l482', 'l489', 'l495', 'l500', 'l504', 'l505', 'l506', 'l507']", + "128, cells ['l234', 'l248', 'l261', 'l273', 'l284', 'l334', 'l354', 'l373', 'l391', 'l408', 'l424', 'l439', 'l453', 'l464', 'l474', 'l483', 'l490', 'l496', 'l501', 'l504']", + "145, HSCs, ['l335', 'l355', 'l374', 'l392', 'l409', 'l425', 'l440', 'l454', 'l465', 'l475', 'l484', 'l491', 'l497', 'l502', 'l505', 'l508', 'l509', 'l510', 'l511', 'l512']", + "160, suppressed ['l336', 'l356', 'l375', 'l393', 'l410', 'l426', 'l441', 'l455', 'l466', 'l476', 'l485', 'l492', 'l498', 'l503', 'l506', 'l508', 'l513', 'l514', 'l515']", + "161, senescence, ['l337', 'l357', 'l376', 'l394', 'l411', 'l427', 'l442', 'l456', 'l467', 'l477', 'l486', 'l493', 'l499', 'l507', 'l509', 'l513', 'l516', 'l517', 'l518']", + "166, BM ['l338', 'l358', 'l377', 'l395', 'l412', 'l428', 'l443', 'l510', 'l516', 'l519', 'l520']", + "167, endothelial ['l339', 'l359', 'l378', 'l396', 'l413', 'l429', 'l444', 'l511', 'l514', 'l517', 'l519', 'l521']", + "168, cells, ['l340', 'l360', 'l379', 'l397', 'l414', 'l430', 'l445', 'l457', 'l468', 'l478', 'l512', 'l515', 'l518', 'l520', 'l521']", + "181, blockade ['l522', 'l523', 'l524', 'l525']", + "182, of ['l522', 'l526', 'l527', 'l528']", + "183, the ['l523', 'l526', 'l529', 'l530']", + "184, EGF ['l524', 'l527', 'l529', 'l531']", + "185, receptor ['l525', 'l528', 'l530', 'l531']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "pro-apoptotic", + "genes", + "Bak", + "and", + "Bax", + "in", + "osterix", + "(Osx,", + "Sp7", + "transcription", + "factor", + "7)-expressing", + "cells", + "inducible", + "one", + "allele", + "Dkk1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "adult" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "pro-apoptotic", + "genes", + "Bak", + "and", + "Bax", + "in", + "osterix", + "(Osx,", + "Sp7", + "transcription", + "factor", + "7)-expressing", + "cells", + "inducible", + "one", + "allele", + "Dkk1" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSCs", + "progenitor", + "cells,", + "cells", + "Osx-expressing", + "BM", + "stem", + "and", + "HSCs,", + "endothelial" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "pro-apoptotic", + "genes", + "Bak", + "and", + "Bax", + "in", + "osterix", + "(Osx,", + "Sp7", + "transcription", + "factor", + "7)-expressing", + "cells" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inducible", + "deletion", + "of", + "one", + "allele", + "Dkk1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inducible", + "deletion", + "of", + "one", + "allele", + "Dkk1" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Osx-expressing", + "cells", + "BM", + "stem", + "and", + "progenitor", + "HSCs,", + "endothelial", + "cells," + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Osx-expressing", + "cells", + "BM", + "stem", + "progenitor", + "HSCs,", + "endothelial", + "cells," + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "adult", + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "adult", + "mice" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence," + ] + } + } + ] + }, + { + "PMID": "27869803", + "TEXT": "Forward genetic screens with CRISPR-Cas9 genome editing enable high-resolution detection of genetic vulnerabilities in cancer cells. We conducted genome-wide CRISPR-Cas9 screens in RNF43-mutant pancreatic ductal adenocarcinoma (PDAC) cells, which rely on Wnt signaling for proliferation. Through these screens, we discovered a unique requirement for a Wnt signaling circuit: engaging FZD5, one of the ten Frizzled receptors encoded in the human genome. Our results uncover an underappreciated level of context-dependent specificity at the Wnt receptor level. We further derived a panel of recombinant antibodies that reports the expression of nine FZD proteins and confirms that FZD5 functional specificity cannot be explained by protein expression patterns. Additionally, antibodies that specifically bind FZD5 and FZD8 robustly inhibited the growth of RNF43-mutant PDAC cells grown in vitro and as xenografts in vivo, providing orthogonal support for the functional specificity observed genetically. Proliferation of a patient-derived PDAC cell line harboring an RNF43 variant was also selectively inhibited by the FZD5 antibodies, further demonstrating their use as a potential targeted therapy. Tumor organoid cultures from colorectal carcinoma patients that carried RNF43 mutations were also sensitive to the FZD5 antibodies, highlighting the potential generalizability of these findings beyond PDAC. Our results show that CRIPSR-based genetic screens can be leveraged to identify and validate cell surface targets for antibody development and therapy.", + "TAG_DATA": [ + "117, RNF43-mutant {'perturbing_action': 'B-other'}", + "118, PDAC {'context': 'B-transformed cells'}", + "119, cells {'context': 'I-transformed cells'}", + "121, in {'context': 'B-in vitro'}", + "122, vitro {'context': 'I-in vitro'}", + "125, xenografts {'context': 'B-xenograft'}", + "126, in {'context': 'B-in vivo'}", + "127, vivo, {'context': 'I-in vivo'}", + "137, Proliferation {'phenotype': 'B-proliferation'}", + "140, patient-derived {'context': 'B-transformed cells'}", + "141, PDAC {'context': 'I-transformed cells'}", + "142, cell {'context': 'I-transformed cells'}", + "143, line {'context': 'I-transformed cells'}", + "146, RNF43 {'perturbing_action': 'I-other'}", + "147, variant {'perturbing_action': 'I-other'}", + "151, inhibited {'effect': 'B-negative'}", + "165, Tumor {'context': 'B-organoid'}", + "166, organoid {'context': 'I-organoid'}", + "167, cultures {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "117, RNF43-mutant ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "118, PDAC ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "119, cells ['l1', 'l7', 'l13', 'l14']", + "121, in ['l2', 'l8', 'l13', 'l15', 'l16']", + "122, vitro ['l3', 'l9', 'l14', 'l15']", + "125, xenografts ['l4', 'l10', 'l17', 'l18']", + "126, in ['l5', 'l11', 'l17', 'l19']", + "127, vivo, ['l6', 'l12', 'l16', 'l18', 'l19']", + "137, Proliferation ['l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "140, patient-derived ['l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "141, PDAC ['l21', 'l29', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "142, cell ['l22', 'l30', 'l36', 'l42', 'l43', 'l44', 'l45']", + "143, line ['l23', 'l31', 'l37', 'l42', 'l46', 'l47', 'l48']", + "146, RNF43 ['l24', 'l32', 'l38', 'l43', 'l46', 'l49', 'l50', 'l51']", + "147, variant ['l25', 'l33', 'l39', 'l44', 'l47', 'l49', 'l52', 'l53']", + "151, inhibited ['l26', 'l34', 'l40', 'l45', 'l48', 'l50', 'l52', 'l54']", + "165, Tumor ['l55', 'l56']", + "166, organoid ['l27', 'l55', 'l57']", + "167, cultures ['l28', 'l35', 'l41', 'l51', 'l53', 'l54', 'l56', 'l57']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "RNF43-mutant", + "RNF43", + "variant" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "PDAC", + "cells", + "patient-derived", + "cell", + "line" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "RNF43-mutant" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "RNF43-mutant", + "RNF43", + "variant" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenografts", + "cultures" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "RNF43-mutant" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "Proliferation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "patient-derived", + "PDAC", + "cell", + "line" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "Proliferation" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "RNF43", + "variant" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "Proliferation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "Proliferation" + ] + }, + "context": { + "val": "organoid", + "words": [ + "organoid" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "Proliferation" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "cultures" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "patient-derived", + "PDAC", + "cell", + "line" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "RNF43", + "variant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "cultures" + ] + } + } + ] + }, + { + "PMID": "27869802", + "TEXT": "In most patients with small-cell lung cancer (SCLC)-a metastatic, aggressive disease-the condition is initially chemosensitive but then relapses with acquired chemoresistance. In a minority of patients, however, relapse occurs within 3 months of initial treatment; in these cases, disease is defined as chemorefractory. The molecular mechanisms that differentiate chemosensitive from chemorefractory disease are currently unknown. To identify genetic features that distinguish chemosensitive from chemorefractory disease, we examined copy-number aberrations (CNAs) in circulating tumor cells (CTCs) from pretreatment SCLC blood samples. After analysis of 88 CTCs isolated from 13 patients (training set), we generated a CNA-based classifier that we validated in 18 additional patients (testing set, 112 CTC samples) and in six SCLC patient-derived CTC explant tumors. The classifier correctly assigned 83.3% of the cases as chemorefractory or chemosensitive. Furthermore, a significant difference was observed in progression-free survival (PFS) (Kaplan-Meier P value = 0.0166) between patients designated as chemorefractory or chemosensitive by using the baseline CNA classifier. Notably, CTC CNA profiles obtained at relapse from five patients with initially chemosensitive disease did not switch to a chemorefractory CNA profile, which suggests that the genetic basis for initial chemoresistance differs from that underlying acquired chemoresistance.", + "TAG_DATA": [ + "111, SCLC {'context': 'B-neoplasm'}", + "112, patient-derived {'context': 'I-neoplasm'}", + "113, CTC {'context': 'I-neoplasm'}", + "114, explant {'context': 'I-neoplasm'}", + "115, tumors. {'context': 'I-neoplasm'}", + "144, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "111, SCLC ['l0', 'l1', 'l2', 'l3']", + "112, patient-derived ['l0', 'l4', 'l5', 'l6', 'l7']", + "113, CTC ['l1', 'l4', 'l8', 'l9']", + "114, explant ['l2', 'l5', 'l8', 'l10']", + "115, tumors. ['l3', 'l6', 'l9', 'l10']", + "144, patients ['l7']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27841876", + "TEXT": "Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease.", + "TAG_DATA": [ + "40, old {'context': 'B-organism'}", + "41, mice. {'context': 'I-organism'}", + "44, enhanced {'effect': 'B-positive'}", + "46, autophagy, {'phenotype': 'B-autophagy'}", + "47, mitophagy {'phenotype': 'B-mitophagy'}", + "59, cardiomyocytes {'context': 'B-cells'}", + "60, in {'context': 'B-in vivo'}", + "61, vivo, {'context': 'I-in vivo'}", + "78, mice {'context': 'B-organism'}", + "86, cardiomyocytes. {'context': 'B-cells'}", + "88, Dahl {'context': 'B-organism'}", + "89, salt-sensitive {'context': 'I-organism'}", + "90, rats {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "40, old ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "41, mice. ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "44, enhanced ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "46, autophagy, ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "47, mitophagy ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "59, cardiomyocytes ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "60, in ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "61, vivo, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "78, mice ['l28', 'l29']", + "86, cardiomyocytes. ['l28', 'l30']", + "88, Dahl ['l31', 'l32']", + "89, salt-sensitive ['l31', 'l33']", + "90, rats ['l29', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "old", + "mice." + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "old", + "mice." + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "old", + "mice." + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "mitophagy" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "mitophagy" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "phenotype": { + "val": "mitophagy", + "words": [ + "mitophagy" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes" + ] + } + }, + { + "phenotype": { + "val": "mitophagy", + "words": [ + "mitophagy" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + } + ] + }, + { + "PMID": "27783067", + "TEXT": "There is a growing understanding that pathological genetic variation and environmental insults during sensitive periods in brain development have long-term consequences on brain function, which range from learning disabilities to complex psychiatric disorders such as schizophrenia. Furthermore, recent experiments in animal models suggest that therapeutic interventions during sensitive periods, typically before the onset of clear neurological and behavioral symptoms, might prevent or ameliorate the development of specific pathologies. These studies suggest that understanding the dynamic nature of the pathophysiological mechanisms underlying psychiatric disorders is crucial for the development of effective therapies. In this Perspective, I explore the emerging concept of developmental windows in psychiatric disorders, their relevance for understanding disease progression and their potential for the design of new therapies. The limitations and caveats of early interventions in psychiatric disorders are also discussed in this context.", + "TAG_DATA": [ + "40, animal {'context': 'B-organism'}", + "41, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "40, animal ['l0']", + "41, models ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27783064", + "TEXT": "Recent genomic studies have revealed the highly polygenic nature of psychiatric disorders, including schizophrenia, bipolar disorder and major depressive disorder. Many of the individual genetic associations are shared across multiple disorders in a way that points to extensive biological pleiotropy and further challenges the biological validity of existing diagnostic approaches. Here we argue that the existence of risk alleles specific to a single diagnostic category is unlikely. We also highlight some of the important clinical repercussions of pleiotropy.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27775705", + "TEXT": "Triple-negative breast cancer (TNBC), in which cells lack expression of the estrogen receptor (ER), the progesterone receptor (PR) and the ERBB2 (also known as HER2) receptor, is the breast cancer subtype with the poorest outcome. No targeted therapy is available against this subtype of cancer owing to a lack of validated molecular targets. We previously reported that signaling involving MYC-an essential, pleiotropic transcription factor that regulates the expression of hundreds of genes-is disproportionally higher in triple-negative (TN) tumors than in receptor-positive (RP) tumors. Direct inhibition of the oncogenic transcriptional activity of MYC has been challenging to achieve. Here, by conducting a shRNA screen targeting the kinome, we identified PIM1, a non-essential serine-threonine kinase, in a synthetic lethal interaction with MYC. PIM1 expression was higher in TN tumors than in RP tumors and was associated with poor prognosis in patients with hormone- and HER2-negative tumors. Small-molecule PIM kinase inhibitors halted the growth of human TN tumors with elevated MYC expression in patient-derived tumor xenograft (PDX) and MYC-driven transgenic mouse models of breast cancer by inhibiting the oncogenic transcriptional activity of MYC and restoring the function of the endogenous cell cycle inhibitor, p27. Our findings warrant clinical evaluation of PIM kinase inhibitors in patients with TN tumors that have elevated MYC expression.", + "TAG_DATA": [ + "144, Small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "145, PIM {'perturbing_action': 'I-pharmacological inhibition'}", + "146, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "147, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "152, human {'context': 'B-neoplasm'}", + "153, TN {'context': 'I-neoplasm'}", + "154, tumors {'context': 'I-neoplasm'}", + "160, patient-derived {'context': 'B-xenograft'}", + "161, tumor {'context': 'I-xenograft'}", + "162, xenograft {'context': 'I-xenograft'}", + "163, (PDX) {'context': 'I-xenograft'}", + "167, mouse {'context': 'I-neoplasm'}", + "168, models {'context': 'I-neoplasm'}", + "169, of {'context': 'I-neoplasm'}", + "170, breast {'context': 'I-neoplasm'}", + "171, cancer {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "144, Small-molecule ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "145, PIM ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "146, kinase ['l1', 'l16', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "147, inhibitors ['l2', 'l17', 'l31', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "152, human ['l3', 'l18', 'l32', 'l45', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "153, TN ['l4', 'l19', 'l33', 'l46', 'l58', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "154, tumors ['l5', 'l20', 'l34', 'l47', 'l59', 'l67', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "160, patient-derived ['l6', 'l21', 'l35', 'l48', 'l60', 'l68', 'l76', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "161, tumor ['l7', 'l22', 'l36', 'l49', 'l61', 'l69', 'l77', 'l84', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "162, xenograft ['l8', 'l23', 'l37', 'l50', 'l62', 'l70', 'l78', 'l85', 'l93', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "163, (PDX) ['l9', 'l24', 'l38', 'l51', 'l63', 'l71', 'l79', 'l86', 'l94', 'l101', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "166, transgenic ['l10', 'l25', 'l39', 'l52', 'l87', 'l95', 'l102', 'l108', 'l114', 'l115', 'l116', 'l117', 'l118']", + "167, mouse ['l11', 'l26', 'l40', 'l53', 'l88', 'l96', 'l103', 'l109', 'l114', 'l119', 'l120', 'l121', 'l122']", + "168, models ['l12', 'l27', 'l41', 'l54', 'l64', 'l72', 'l80', 'l89', 'l97', 'l104', 'l110', 'l115', 'l119', 'l123', 'l124', 'l125']", + "169, of ['l13', 'l28', 'l42', 'l55', 'l65', 'l73', 'l81', 'l90', 'l98', 'l105', 'l111', 'l116', 'l120', 'l123', 'l126', 'l127']", + "170, breast ['l14', 'l29', 'l43', 'l56', 'l74', 'l82', 'l91', 'l99', 'l106', 'l112', 'l117', 'l121', 'l124', 'l126', 'l128']", + "171, cancer ['l15', 'l30', 'l44', 'l57', 'l66', 'l75', 'l83', 'l92', 'l100', 'l107', 'l113', 'l118', 'l122', 'l125', 'l127', 'l128']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Small-molecule", + "PIM", + "kinase", + "inhibitors" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "TN", + "tumors", + "mouse", + "models", + "of", + "breast", + "cancer" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Small-molecule", + "PIM", + "kinase", + "inhibitors" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "patient-derived", + "tumor", + "xenograft", + "(PDX)" + ] + } + } + ] + }, + { + "PMID": "27748747", + "TEXT": "The efficacy of angiogenesis inhibitors in cancer is limited by resistance mechanisms that are poorly understood. Notably, instead of through the induction of angiogenesis, tumor vascularization can occur through the nonangiogenic mechanism of vessel co-option. Here we show that vessel co-option is associated with a poor response to the anti-angiogenic agent bevacizumab in patients with colorectal cancer liver metastases. Moreover, we find that vessel co-option is also prevalent in human breast cancer liver metastases, a setting in which results with anti-angiogenic therapy have been disappointing. In preclinical mechanistic studies, we found that cancer cell motility mediated by the actin-related protein 2/3 complex (Arp2/3) is required for vessel co-option in liver metastases in vivo and that, in this setting, combined inhibition of angiogenesis and vessel co-option is more effective than the inhibition of angiogenesis alone. Vessel co-option is therefore a clinically relevant mechanism of resistance to anti-angiogenic therapy and combined inhibition of angiogenesis and vessel co-option might be a warranted therapeutic strategy.", + "TAG_DATA": [ + "92, cancer {'context': 'B-transformed cells'}", + "93, cell {'context': 'I-transformed cells'}", + "109, liver {'phenotype': 'B-metastasis'}", + "110, metastases {'context': 'I-neoplasm', 'phenotype': 'I-metastasis'}", + "111, in {'context': 'B-in vivo'}", + "112, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "92, cancer ['l0', 'l1', 'l2', 'l3', 'l4']", + "93, cell ['l0', 'l5', 'l6', 'l7', 'l8']", + "109, liver ['l1', 'l5', 'l9', 'l10', 'l11']", + "110, metastases ['l2', 'l6', 'l9', 'l12', 'l13']", + "111, in ['l3', 'l7', 'l10', 'l12', 'l14']", + "112, vivo ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cell" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "liver", + "metastases" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "metastases" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases", + "liver" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "liver", + "metastases" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "27723722", + "TEXT": "In Alzheimer's disease (AD) and other tauopathies, the tau protein forms fibrils, which are believed to be neurotoxic. However, fibrillar tau has been dissociated from neuron death and network dysfunction, suggesting the involvement of nonfibrillar species. Here we describe a novel pathological process in which caspase-2 cleavage of tau at Asp314 impairs cognitive and synaptic function in animal and cellular models of tauopathies by promoting the missorting of tau to dendritic spines. The truncation product, Δtau314, resists fibrillation and is present at higher levels in brains from cognitively impaired mice and humans with AD. The expression of tau mutants that resisted caspase-2 cleavage prevented tau from infiltrating spines, dislocating glutamate receptors and impairing synaptic function in cultured neurons, and it prevented memory deficits and neurodegeneration in mice. Decreasing the levels of caspase-2 restored long-term memory in mice that had existing deficits. Our results suggest an overall treatment strategy for re-establishing synaptic function and restoring memory in patients with AD by preventing tau from accumulating in dendritic spines.", + "TAG_DATA": [ + "95, expression {'perturbing_action': 'B-other'}", + "96, of {'perturbing_action': 'I-other'}", + "97, tau {'perturbing_action': 'I-other'}", + "98, mutants {'perturbing_action': 'I-other'}", + "116, cultured {'context': 'B-cells'}", + "117, neurons, {'context': 'I-cells'}", + "126, mice. {'context': 'B-organism'}", + "127, Decreasing {'perturbing_action': 'B-gene loss-of-function'}", + "128, the {'perturbing_action': 'I-rnai/knockdown'}", + "129, levels {'perturbing_action': 'I-rnai/knockdown'}", + "130, of {'perturbing_action': 'I-rnai/knockdown'}", + "131, caspase-2 {'perturbing_action': 'I-rnai/knockdown'}", + "136, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "95, expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "96, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "97, tau ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "98, mutants ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "116, cultured ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "117, neurons, ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "126, mice. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "127, Decreasing ['l21', 'l22', 'l23', 'l24', 'l25']", + "128, the ['l21', 'l26', 'l27', 'l28', 'l29']", + "129, levels ['l22', 'l26', 'l30', 'l31', 'l32']", + "130, of ['l23', 'l27', 'l30', 'l33', 'l34']", + "131, caspase-2 ['l24', 'l28', 'l31', 'l33', 'l35']", + "136, mice ['l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "tau", + "mutants" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "neurons," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "tau", + "mutants" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Decreasing" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "the", + "levels", + "of", + "caspase-2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "27694932", + "TEXT": "Successful recovery from lung injury requires the repair and regeneration of alveolar epithelial cells to restore the integrity of gas-exchanging regions within the lung and preserve organ function. Improper regeneration of the alveolar epithelium is often associated with severe pulmonary fibrosis, the latter of which involves the recruitment and activation of fibroblasts, as well as matrix accumulation. Type 2 alveolar epithelial cells (AEC2s) are stem cells in the adult lung that contribute to the lung repair process. The mechanisms that regulate AEC2 renewal are incompletely understood. We provide evidence that expression of the innate immune receptor Toll-like receptor 4 (TLR4) and the extracellular matrix glycosaminoglycan hyaluronan (HA) on AEC2s are important for AEC2 renewal, repair of lung injury and limiting the extent of fibrosis. Either deletion of TLR4 or HA synthase 2 in surfactant-protein-C-positive AEC2s leads to impaired renewal capacity, severe fibrosis and mortality. Furthermore, AEC2s from patients with severe pulmonary fibrosis have reduced cell surface HA and impaired renewal capacity, suggesting that HA and TLR4 are key contributors to lung stem cell renewal and that severe pulmonary fibrosis is the result of distal epithelial stem cell failure.", + "TAG_DATA": [ + "125, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "126, of {'perturbing_action': 'I-gene loss-of-function'}", + "127, TLR4 {'perturbing_action': 'I-gene loss-of-function'}", + "128, or {'perturbing_action': 'I-gene loss-of-function'}", + "133, surfactant-protein-C-positive {'context': 'B-cells'}", + "134, AEC2s {'context': 'I-cells'}", + "137, impaired {'effect': 'B-negative'}", + "138, renewal {'phenotype': 'B-self-renewal'}", + "145, AEC2s {'context': 'B-cells'}", + "158, impaired {'effect': 'B-negative'}", + "159, renewal {'phenotype': 'B-self-renewal'}" + ], + "LINK_DATA": [ + "125, deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "126, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "127, TLR4 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "128, or ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "133, surfactant-protein-C-positive ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "134, AEC2s ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "137, impaired ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "138, renewal ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "145, AEC2s ['l28', 'l29']", + "158, impaired ['l28', 'l30']", + "159, renewal ['l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "TLR4", + "or" + ] + }, + "context": { + "val": "cells", + "words": [ + "surfactant-protein-C-positive", + "AEC2s" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "TLR4", + "or" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "TLR4", + "or" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "renewal" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "surfactant-protein-C-positive", + "AEC2s" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "surfactant-protein-C-positive", + "AEC2s" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "renewal" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "renewal" + ] + } + } + ] + }, + { + "PMID": "27668937", + "TEXT": "Microglia, the only lifelong resident immune cells of the central nervous system (CNS), are highly specialized macrophages that have been recognized to have a crucial role in neurodegenerative diseases such as Alzheimer's, Parkinson's and adrenoleukodystrophy (ALD). However, in contrast to other cell types of the human CNS, bona fide microglia have not yet been derived from cultured human pluripotent stem cells. Here we establish a robust and efficient protocol for the rapid production of microglia-like cells from human (h) embryonic stem (ES) and induced pluripotent stem (iPS) cells that uses defined serum-free culture conditions. These in vitro pluripotent stem cell-derived microglia-like cells (termed pMGLs) faithfully recapitulate the expected ontogeny and characteristics of their in vivo counterparts, and they resemble primary fetal human and mouse microglia. We generated these cells from multiple disease-specific cell lines and find that pMGLs derived from an hES model of Rett syndrome are smaller than their isogenic controls. We further describe a platform to study the integration and live behavior of pMGLs in organotypic 3D cultures. This modular differentiation system allows for the study of microglia in highly defined conditions as they mature in response to developmentally relevant cues, and it provides a framework in which to study the long-term interactions of microglia residing in a tissue-like environment.", + "TAG_DATA": [ + "77, human {'context': 'B-cells'}", + "78, (h) {'context': 'I-cells'}", + "79, embryonic {'context': 'I-cells'}", + "80, stem {'context': 'I-cells'}", + "81, (ES) {'context': 'I-cells'}", + "83, induced {'context': 'B-cells'}", + "84, pluripotent {'context': 'I-cells'}", + "85, stem {'context': 'I-cells'}", + "86, (iPS) {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}", + "95, in {'context': 'B-in vitro'}", + "96, vitro {'context': 'I-in vitro'}", + "97, pluripotent {'context': 'I-cells'}", + "98, stem {'context': 'I-cells'}", + "99, cell-derived {'context': 'I-cells'}", + "100, microglia-like {'context': 'I-cells'}", + "101, cells {'context': 'I-cells'}", + "132, cell {'context': 'B-cells'}", + "133, lines {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "77, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "78, (h) ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "79, embryonic ['l1', 'l11', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "80, stem ['l2', 'l12', 'l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "81, (ES) ['l3', 'l13', 'l21', 'l29', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "83, induced ['l4', 'l14', 'l22', 'l30', 'l37', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "84, pluripotent ['l5', 'l15', 'l23', 'l31', 'l38', 'l44', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "85, stem ['l6', 'l16', 'l24', 'l32', 'l39', 'l45', 'l55', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "86, (iPS) ['l7', 'l17', 'l25', 'l33', 'l40', 'l46', 'l56', 'l65', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "87, cells ['l8', 'l18', 'l26', 'l34', 'l41', 'l47', 'l57', 'l66', 'l74', 'l82']", + "95, in ['l48', 'l58', 'l67', 'l75', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "96, vitro ['l49', 'l59', 'l68', 'l76', 'l83', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "97, pluripotent ['l50', 'l60', 'l69', 'l77', 'l84', 'l90', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "98, stem ['l51', 'l61', 'l70', 'l78', 'l85', 'l91', 'l97', 'l103', 'l104', 'l105', 'l106']", + "99, cell-derived ['l52', 'l62', 'l71', 'l79', 'l86', 'l92', 'l98', 'l103', 'l107', 'l108', 'l109']", + "100, microglia-like ['l9', 'l27', 'l35', 'l42', 'l53', 'l63', 'l72', 'l80', 'l87', 'l93', 'l99', 'l104', 'l107', 'l110', 'l111']", + "101, cells ['l10', 'l19', 'l28', 'l36', 'l43', 'l54', 'l64', 'l73', 'l81', 'l82', 'l88', 'l94', 'l100', 'l105', 'l108', 'l110']", + "132, cell ['l95', 'l101', 'l112']", + "133, lines ['l89', 'l96', 'l102', 'l106', 'l109', 'l111', 'l112']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27618649", + "TEXT": "The MYCN proto-oncogene is amplified in a number of advanced-stage human tumors, such as neuroblastomas. Similar to other members of the MYC family of oncoproteins, MYCN (also known as N-Myc) is a transcription factor, and its stability and activity are tightly controlled by ubiquitination-dependent proteasome degradation. Although numerous studies have demonstrated that N-Myc is a driver of neuroblastoma tumorigenesis, therapies that directly suppress N-Myc activity in human tumors are limited. Here we have identified ubiquitin-specific protease 7 (USP7; also known as HAUSP) as a regulator of N-Myc function in neuroblastoma. HAUSP interacts with N-Myc, and HAUSP expression induces deubiquitination and subsequent stabilization of N-Myc. Conversely, RNA interference (RNAi)-mediated knockdown of USP7 in neuroblastoma cancer cell lines, or genetic ablation of Usp7 in the mouse brain, destabilizes N-Myc, which leads to inhibition of N-Myc function. Notably, HAUSP is more abundant in patients with neuroblastoma who have poorer prognosis, and HAUSP expression substantially correlates with N-Myc transcriptional activity. Furthermore, small-molecule inhibitors of HAUSP's deubiquitinase activity markedly suppress the growth of MYCN-amplified human neuroblastoma cell lines in xenograft mouse models. Taken together, our findings demonstrate a crucial role of HAUSP in regulating N-Myc function in vivo and suggest that HAUSP inhibition is a potential therapy for MYCN-amplified tumors.", + "TAG_DATA": [ + "105, RNA {'perturbing_action': 'B-rnai/knockdown'}", + "106, interference {'perturbing_action': 'B-rnai/knockdown'}", + "107, (RNAi)-mediated {'perturbing_action': 'I-rnai/knockdown'}", + "108, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "109, of {'perturbing_action': 'I-rnai/knockdown'}", + "110, USP7 {'perturbing_action': 'I-rnai/knockdown'}", + "112, neuroblastoma {'context': 'B-transformed cells'}", + "113, cancer {'context': 'I-transformed cells'}", + "114, cell {'context': 'I-transformed cells'}", + "115, lines, {'context': 'I-transformed cells'}", + "117, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "118, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "119, of {'perturbing_action': 'I-gene loss-of-function'}", + "120, Usp7 {'perturbing_action': 'I-gene loss-of-function'}", + "123, mouse {'context': 'B-tissue/organ'}", + "124, brain, {'context': 'I-tissue/organ'}", + "169, human {'context': 'I-transformed cells'}", + "170, neuroblastoma {'context': 'I-transformed cells'}", + "171, cell {'context': 'I-transformed cells'}", + "172, lines {'context': 'I-transformed cells'}", + "174, xenograft {'context': 'B-xenograft'}", + "175, mouse {'context': 'I-xenograft'}", + "176, models. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "105, RNA ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "106, interference ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "107, (RNAi)-mediated ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "108, knockdown ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "109, of ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "110, USP7 ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "112, neuroblastoma ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "113, cancer ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "114, cell ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "115, lines, ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "117, genetic ['l45', 'l46', 'l47', 'l48', 'l49']", + "118, ablation ['l45', 'l50', 'l51', 'l52', 'l53']", + "119, of ['l46', 'l50', 'l54', 'l55', 'l56']", + "120, Usp7 ['l47', 'l51', 'l54', 'l57', 'l58']", + "123, mouse ['l48', 'l52', 'l55', 'l57', 'l59']", + "124, brain, ['l49', 'l53', 'l56', 'l58', 'l59']", + "168, MYCN-amplified ['l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "169, human ['l60', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "170, neuroblastoma ['l61', 'l67', 'l73', 'l74', 'l75', 'l76', 'l77']", + "171, cell ['l62', 'l68', 'l73', 'l78', 'l79', 'l80', 'l81']", + "172, lines ['l63', 'l69', 'l74', 'l78', 'l82', 'l83', 'l84']", + "174, xenograft ['l64', 'l70', 'l75', 'l79', 'l82', 'l85', 'l86']", + "175, mouse ['l65', 'l71', 'l76', 'l80', 'l83', 'l85', 'l87']", + "176, models. ['l66', 'l72', 'l77', 'l81', 'l84', 'l86', 'l87']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "RNA", + "interference", + "(RNAi)-mediated", + "knockdown", + "of", + "USP7" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "neuroblastoma", + "cancer", + "cell", + "lines," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "Usp7" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "brain," + ] + } + } + ] + }, + { + "PMID": "27548576", + "TEXT": "Activated protein C (APC) is a blood protease with anticoagulant activity and cell-signaling activities mediated by the activation of protease-activated receptor 1 (F2R, also known as PAR1) and F2RL1 (also known as PAR3) via noncanonical cleavage. Recombinant variants of APC, such as the 3K3A-APC (Lys191-193Ala) mutant in which three Lys residues (KKK191-193) were replaced with alanine, and/or its other mutants with reduced (>90%) anticoagulant activity, engineered to reduce APC-associated bleeding risk while retaining normal cell-signaling activity, have shown benefits in preclinical models of ischemic stroke, brain trauma, multiple sclerosis, amyotrophic lateral sclerosis, sepsis, ischemic and reperfusion injury of heart, kidney and liver, pulmonary, kidney and gastrointestinal inflammation, diabetes and lethal body radiation. On the basis of proof-of-concept studies and an excellent safety profile in humans, 3K3A-APC has advanced to clinical trials as a neuroprotectant in ischemic stroke. Recently, 3K3A-APC has been shown to stimulate neuronal production by human neural stem and progenitor cells (NSCs) in vitro via a PAR1-PAR3-sphingosine-1-phosphate-receptor 1-Akt pathway, which suggests the potential for APC-based treatment as a strategy for structural repair in the human central nervous (CNS) system. Here we report that late postischemic treatment of mice with 3K3A-APC stimulates neuronal production by transplanted human NSCs, promotes circuit restoration and improves functional recovery. Thus, 3K3A-APC-potentiated neuronal recruitment from engrafted NSCs might offer a new approach to the treatment of stroke and related neurological disorders.", + "TAG_DATA": [ + "147, human {'context': 'B-cells'}", + "148, neural {'context': 'I-cells'}", + "149, stem {'context': 'I-cells'}", + "150, and {'context': 'I-cells'}", + "151, progenitor {'context': 'I-cells'}", + "152, cells {'context': 'I-cells'}", + "153, (NSCs) {'context': 'I-cells'}", + "154, in {'context': 'B-in vitro'}", + "155, vitro {'context': 'I-in vitro'}", + "189, mice {'context': 'B-organism'}", + "197, human {'context': 'B-cells'}", + "198, NSCs, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "147, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "148, neural ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "149, stem ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "150, and ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "151, progenitor ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "152, cells ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "153, (NSCs) ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "154, in ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "155, vitro ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "189, mice ['l36', 'l37']", + "197, human ['l36', 'l38']", + "198, NSCs, ['l37', 'l38']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27525524", + "TEXT": "Disorders resulting from mutations in the hemoglobin subunit beta gene (HBB; which encodes β-globin), mainly sickle cell disease (SCD) and β-thalassemia, become symptomatic postnatally as fetal γ-globin expression from two paralogous genes, hemoglobin subunit gamma 1 (HBG1) and HBG2, decreases and adult β-globin expression increases, thereby shifting red blood cell (RBC) hemoglobin from the fetal (referred to as HbF or α2γ2) to adult (referred to as HbA or α2β2) form. These disorders are alleviated when postnatal expression of fetal γ-globin is maintained. For example, in hereditary persistence of fetal hemoglobin (HPFH), a benign genetic condition, mutations attenuate γ-globin-to-β-globin switching, causing high-level HbF expression throughout life. Co-inheritance of HPFH with β-thalassemia- or SCD-associated gene mutations alleviates their clinical manifestations. Here we performed CRISPR-Cas9-mediated genome editing of human blood progenitors to mutate a 13-nt sequence that is present in the promoters of the HBG1 and HBG2 genes, thereby recapitulating a naturally occurring HPFH-associated mutation. Edited progenitors produced RBCs with increased HbF levels that were sufficient to inhibit the pathological hypoxia-induced RBC morphology found in SCD. Our findings identify a potential DNA target for genome-editing-mediated therapy of β-hemoglobinopathies.", + "TAG_DATA": [ + "125, human {'context': 'B-cells'}", + "126, blood {'context': 'I-cells'}", + "127, progenitors {'context': 'I-cells'}", + "153, progenitors {'context': 'B-cells'}", + "155, RBCs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "125, human ['l0', 'l1']", + "126, blood ['l0', 'l2']", + "127, progenitors ['l1', 'l2']", + "153, progenitors ['l3']", + "155, RBCs ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27500725", + "TEXT": "Systemic lupus erythematosus (SLE) is a potentially life-threatening autoimmune disease characterized by altered balance of activity between effector and regulatory CD4(+) T cells. The homeostasis of CD4(+) T cell subsets is regulated by interleukin (IL)-2, and reduced production of IL-2 by T cells is observed in individuals with SLE. Here we report that treatment with low-dose recombinant human IL-2 selectively modulated the abundance of regulatory T (Treg) cells, follicular helper T (TFH) cells and IL-17-producing helper T (TH17) cells, but not TH1 or TH2 cells, accompanied by marked reductions of disease activity in patients with SLE.", + "TAG_DATA": [ + "64, regulatory {'context': 'B-cells'}", + "65, T {'context': 'I-cells'}", + "66, (Treg) {'context': 'I-cells'}", + "67, cells, {'context': 'I-cells'}", + "68, follicular {'context': 'B-cells'}", + "69, helper {'context': 'I-cells'}", + "70, T {'context': 'I-cells'}", + "71, (TFH) {'context': 'I-cells'}", + "72, cells {'context': 'I-cells'}", + "75, helper {'context': 'B-cells'}", + "76, T {'context': 'I-cells'}", + "77, (TH17) {'context': 'I-cells'}", + "78, cells, {'context': 'I-cells'}", + "81, TH1 {'context': 'B-cells'}", + "83, TH2 {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "64, regulatory ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "65, T ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "66, (Treg) ['l1', 'l10', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "67, cells, ['l2', 'l11', 'l20', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "68, follicular ['l3', 'l12', 'l21', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "69, helper ['l4', 'l13', 'l22', 'l28', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "70, T ['l5', 'l14', 'l23', 'l29', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "71, (TFH) ['l6', 'l15', 'l24', 'l30', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "72, cells ['l7', 'l16', 'l25', 'l31', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66']", + "75, helper ['l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "76, T ['l17', 'l38', 'l46', 'l53', 'l59', 'l64', 'l67', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "77, (TH17) ['l8', 'l18', 'l39', 'l47', 'l54', 'l60', 'l65', 'l68', 'l74', 'l80', 'l81', 'l82', 'l83', 'l84']", + "78, cells, ['l9', 'l19', 'l26', 'l32', 'l40', 'l48', 'l55', 'l61', 'l66', 'l69', 'l75', 'l80', 'l85', 'l86', 'l87', 'l88']", + "81, TH1 ['l70', 'l76', 'l81', 'l85', 'l89', 'l90', 'l91']", + "82, or ['l71', 'l77', 'l82', 'l86', 'l89', 'l92', 'l93']", + "83, TH2 ['l72', 'l78', 'l83', 'l87', 'l90', 'l92', 'l94']", + "84, cells, ['l41', 'l49', 'l56', 'l62', 'l73', 'l79', 'l84', 'l88', 'l91', 'l93', 'l94']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27479085", + "TEXT": "The increasing global prevalence of obesity and its associated disorders points to an urgent need for the development of novel and effective therapeutic strategies that induce healthy weight loss. Obesity is characterized by hyperleptinemia and central leptin resistance. In an attempt to identify compounds that could reverse leptin resistance and thus promote weight loss, we analyzed a library of small molecules that have mRNA expression profiles similar to that of celastrol, a naturally occurring compound that we previously identified as a leptin sensitizer. Through this process, we identified another naturally occurring compound, withaferin A, that also acts as a leptin sensitizer. We found that withaferin-A treatment of mice with diet-induced obesity (DIO) resulted in a 20-25% reduction of body weight, while also decreasing obesity-associated abnormalities, including hepatic steatosis. Withaferin-A treatment marginally affected the body weight of ob/ob and db/db mice, both of which are deficient in leptin signaling. In addition, withaferin A, unlike celastrol, has beneficial effects on glucose metabolism that occur independently of its leptin-sensitizing effect. Our results show that the metabolic abnormalities of DIO can be mitigated by sensitizing animals to endogenous leptin, and they indicate that withaferin A is a potential leptin sensitizer with additional antidiabetic actions.", + "TAG_DATA": [ + "107, mice {'context': 'B-organism'}", + "136, ob/ob {'context': 'B-organism'}", + "138, db/db {'context': 'B-organism'}", + "139, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "136, ob/ob ['l0', 'l1']", + "138, db/db ['l0', 'l2']", + "139, mice, ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27479084", + "TEXT": "Mechanisms by which regulatory T (Treg) cells fail to control inflammation in asthma remain poorly understood. We show that a severe asthma-associated polymorphism in the gene encoding the interleukin (IL)-4 receptor alpha chain (Il4ra(R576)) promotes conversion of induced Treg (iTreg) cells toward a T helper 17 (TH17) cell fate. This skewing is mediated by the recruitment by IL-4Rα(R576) of the growth-factor-receptor-bound protein 2 (GRB2) adaptor protein, which drives IL-17 expression by activating a pathway that involves extracellular-signal-regulated kinase, IL-6 and the transcription factor STAT3. Treg cell-specific deletion of genes that regulate TH17 cell differentiation, including Il6ra and RAR-related orphan receptor gamma (Rorc), but not of Il4 or Il13, prevented exacerbated airway inflammation in mice expressing Il4ra(R576) (hereafter referred to as Il4ra(R576) mice). Furthermore, treatment of Il4ra(R576) mice with a neutralizing IL-6-specific antibody prevented iTreg cell reprogramming into TH17-like cells and protected against severe airway inflammation. These findings identify a previously unknown mechanism for the development of mixed TH2-TH17 cell inflammation in genetically prone individuals and point to interventions that stabilize iTreg cells as potentially effective therapeutic strategies.", + "TAG_DATA": [ + "84, Treg {'perturbing_action': 'B-gene loss-of-function'}", + "85, cell-specific {'perturbing_action': 'I-gene loss-of-function'}", + "86, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "87, of {'perturbing_action': 'I-gene loss-of-function'}", + "113, mice {'context': 'B-organism'}", + "125, Il4ra(R576) {'perturbing_action': 'B-other'}", + "126, mice {'context': 'B-organism'}", + "133, iTreg {'context': 'B-cells'}", + "137, TH17-like {'context': 'B-cells'}", + "138, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "84, Treg ['l0', 'l1', 'l2', 'l3']", + "85, cell-specific ['l0', 'l4', 'l5', 'l6']", + "86, deletion ['l1', 'l4', 'l7', 'l8']", + "87, of ['l2', 'l5', 'l7', 'l9']", + "113, mice ['l3', 'l6', 'l8', 'l9']", + "125, Il4ra(R576) ['l10', 'l11', 'l12', 'l13', 'l14']", + "126, mice ['l10', 'l15', 'l16', 'l17', 'l18']", + "133, iTreg ['l11', 'l15', 'l19', 'l20', 'l21']", + "134, cell ['l12', 'l16', 'l19', 'l22', 'l23']", + "137, TH17-like ['l13', 'l17', 'l20', 'l22', 'l24']", + "138, cells ['l14', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Treg", + "cell-specific", + "deletion", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Il4ra(R576)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Il4ra(R576)" + ] + }, + "context": { + "val": "cells", + "words": [ + "iTreg", + "TH17-like", + "cells" + ] + } + } + ] + }, + { + "PMID": "27428901", + "TEXT": "Fungal infections claim an estimated 1.5 million lives each year. Mechanisms that protect from fungal infections are still elusive. Recognition of fungal pathogens relies on C-type lectin receptors (CLRs) and their downstream signaling kinase SYK. Here we report that the E3 ubiquitin ligase CBLB controls proximal CLR signaling in macrophages and dendritic cells. We show that CBLB associates with SYK and ubiquitinates SYK, dectin-1, and dectin-2 after fungal recognition. Functionally, CBLB deficiency results in increased inflammasome activation, enhanced reactive oxygen species production, and increased fungal killing. Genetic deletion of Cblb protects mice from morbidity caused by cutaneous infection and markedly improves survival after a lethal systemic infection with Candida albicans. On the basis of these findings, we engineered a cell-permeable CBLB inhibitory peptide that protects mice from lethal C. albicans infections. We thus describe a key role for Cblb in the regulation of innate antifungal immunity and establish a novel paradigm for the treatment of fungal sepsis.", + "TAG_DATA": [ + "70, CBLB {'perturbing_action': 'B-gene loss-of-function'}", + "71, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "86, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "87, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "88, of {'perturbing_action': 'I-gene loss-of-function'}", + "89, Cblb {'perturbing_action': 'I-gene loss-of-function'}", + "91, mice {'context': 'B-organism'}", + "125, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "70, CBLB ['l0']", + "71, deficiency ['l0']", + "86, Genetic ['l1', 'l2', 'l3', 'l4']", + "87, deletion ['l1', 'l5', 'l6', 'l7']", + "88, of ['l2', 'l5', 'l8', 'l9']", + "89, Cblb ['l3', 'l6', 'l8', 'l10']", + "91, mice ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "deletion", + "of", + "Cblb" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "27428900", + "TEXT": "Iron is an essential component of the erythrocyte protein hemoglobin and is crucial to oxygen transport in vertebrates. In the steady state, erythrocyte production is in equilibrium with erythrocyte removal. In various pathophysiological conditions, however, erythrocyte life span is compromised severely, which threatens the organism with anemia and iron toxicity. Here we identify an on-demand mechanism that clears erythrocytes and recycles iron. We show that monocytes that express high levels of lymphocyte antigen 6 complex, locus C1 (LY6C1, also known as Ly-6C) ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate into ferroportin 1 (FPN1, encoded by SLC40A1)-expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1(+)Tim-4(neg) macrophages are transient, reside alongside embryonically derived T cell immunoglobulin and mucin domain containing 4 (Timd4, also known as Tim-4)(high) Kupffer cells (KCs), and depend on the growth factor Csf1 and the transcription factor Nrf2 (encoded by Nfe2l2). The spleen, likewise, recruits iron-loaded Ly-6C(high) monocytes, but these do not differentiate into iron-recycling macrophages, owing to the suppressive action of Csf2. The accumulation of a transient macrophage population in the liver also occurs in mouse models of hemolytic anemia, anemia of inflammation, and sickle cell disease. Inhibition of monocyte recruitment to the liver during stressed erythrocyte delivery leads to kidney and liver damage. These observations identify the liver as the primary organ that supports rapid erythrocyte removal and iron recycling, and uncover a mechanism by which the body adapts to fluctuations in erythrocyte integrity.", + "TAG_DATA": [ + "152, spleen, {'context': 'B-tissue/organ'}", + "182, liver {'context': 'B-tissue/organ'}", + "186, mouse {'context': 'B-organism'}", + "187, models {'context': 'I-organism'}", + "211, kidney {'context': 'B-tissue/organ'}", + "213, liver {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "152, spleen, ['l0', 'l1', 'l2']", + "182, liver ['l0', 'l3', 'l4']", + "186, mouse ['l1', 'l3', 'l5']", + "187, models ['l2', 'l4', 'l5']", + "211, kidney ['l6']", + "213, liver ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27400265", + "TEXT": "The biological effects of urolithins remain poorly characterized, despite wide-spread human exposure via the dietary consumption of their metabolic precursors, the ellagitannins, which are found in the pomegranate fruit, as well as in nuts and berries. We identified urolithin A (UA) as a first-in-class natural compound that induces mitophagy both in vitro and in vivo following oral consumption. In C. elegans, UA prevented the accumulation of dysfunctional mitochondria with age and extended lifespan. Likewise, UA prolonged normal activity during aging in C. elegans, including mobility and pharyngeal pumping, while maintaining mitochondrial respiratory capacity. These effects translated to rodents, where UA improved exercise capacity in two different mouse models of age-related decline of muscle function, as well as in young rats. Our findings highlight the health benefits of urolithin A and its potential application in strategies to improve mitochondrial and muscle function.", + "TAG_DATA": [ + "47, induces {'effect': 'B-positive'}", + "48, mitophagy {'phenotype': 'B-mitophagy'}", + "50, in {'context': 'B-in vitro'}", + "51, vitro {'context': 'I-in vitro'}", + "53, in {'context': 'B-in vivo'}", + "54, vivo {'context': 'I-in vivo'}", + "59, C. {'context': 'B-organism'}", + "60, elegans, {'context': 'I-organism'}", + "81, C. {'context': 'B-organism'}", + "82, elegans, {'context': 'B-organism'}", + "97, rodents, {'context': 'B-organism'}", + "106, mouse {'context': 'B-organism'}", + "107, models {'context': 'I-organism'}", + "118, young {'context': 'B-organism'}", + "119, rats. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "47, induces ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "48, mitophagy ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "50, in ['l1', 'l7', 'l13', 'l14', 'l15']", + "51, vitro ['l2', 'l8', 'l13', 'l16', 'l17']", + "53, in ['l3', 'l9', 'l18', 'l19', 'l20']", + "54, vivo ['l4', 'l10', 'l18', 'l21', 'l22']", + "59, C. ['l5', 'l11', 'l14', 'l16', 'l19', 'l21', 'l23']", + "60, elegans, ['l6', 'l12', 'l15', 'l17', 'l20', 'l22', 'l23']", + "81, C. ['l24']", + "82, elegans, ['l24']", + "97, rodents, ['l25', 'l26']", + "106, mouse ['l25', 'l27', 'l28', 'l29']", + "107, models ['l26', 'l27', 'l30', 'l31']", + "118, young ['l28', 'l30', 'l32']", + "119, rats. ['l29', 'l31', 'l32']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "mitophagy" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "organism", + "words": [ + "C.", + "elegans," + ] + } + }, + { + "phenotype": { + "val": "mitophagy", + "words": [ + "mitophagy" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "mitophagy", + "words": [ + "mitophagy" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "mitophagy", + "words": [ + "mitophagy" + ] + }, + "context": { + "val": "organism", + "words": [ + "C.", + "elegans," + ] + } + } + ] + }, + { + "PMID": "27376575", + "TEXT": "Interactions between stem cells and their microenvironment, or niche, are essential for stem cell maintenance and function. Our knowledge of the niche for the skeletal muscle stem cell, i.e., the satellite cell (SC), is incomplete. Here we show that β1-integrin is an essential niche molecule that maintains SC homeostasis, and sustains the expansion and self-renewal of this stem cell pool during regeneration. We further show that β1-integrin cooperates with fibroblast growth factor 2 (Fgf2), a potent growth factor for SCs, to synergistically activate their common downstream effectors, the mitogen-activated protein (MAP) kinase Erk and protein kinase B (Akt). Notably, SCs in aged mice show altered β1-integrin activity and insensitivity to Fgf2. Augmenting β1-integrin activity with a monoclonal antibody restores Fgf2 sensitivity and improves regeneration after experimentally induced muscle injury. The same treatment also enhances regeneration and function of dystrophic muscles in mdx mice, a model for Duchenne muscular dystrophy. Therefore, β1-integrin senses the SC niche to maintain responsiveness to Fgf2, and this integrin represents a potential therapeutic target for pathological conditions of the muscle in which the stem cell niche is compromised.", + "TAG_DATA": [ + "99, SCs {'context': 'B-cells'}", + "101, aged {'context': 'B-organism'}", + "102, mice {'context': 'I-organism'}", + "127, muscle {'context': 'B-tissue/organ'}", + "138, dystrophic {'context': 'B-tissue/organ'}", + "139, muscles {'context': 'I-tissue/organ'}", + "141, mdx {'perturbing_action': 'B-other', 'context': 'B-organism'}", + "142, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "99, SCs ['l0', 'l1']", + "101, aged ['l0', 'l2']", + "102, mice ['l1', 'l2']", + "138, dystrophic ['l3', 'l4', 'l5']", + "139, muscles ['l3', 'l6', 'l7']", + "141, mdx ['l4', 'l6', 'l8']", + "142, mice, ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "dystrophic", + "muscles" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mdx" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mdx" + ] + }, + "context": { + "val": "organism", + "words": [ + "mdx" + ] + } + } + ] + }, + { + "PMID": "27376574", + "TEXT": "Little is known about the inter-individual variation of cytokine responses to different pathogens in healthy individuals. To systematically describe cytokine responses elicited by distinct pathogens and to determine the effect of genetic variation on cytokine production, we profiled cytokines produced by peripheral blood mononuclear cells from 197 individuals of European origin from the 200 Functional Genomics (200FG) cohort in the Human Functional Genomics Project (http://www.humanfunctionalgenomics.org), obtained over three different years. We compared bacteria- and fungi-induced cytokine profiles and found that most cytokine responses were organized around a physiological response to specific pathogens, rather than around a particular immune pathway or cytokine. We then correlated genome-wide single-nucleotide polymorphism (SNP) genotypes with cytokine abundance and identified six cytokine quantitative trait loci (QTLs). Among them, a cytokine QTL at the NAA35-GOLM1 locus markedly modulated interleukin (IL)-6 production in response to multiple pathogens and was associated with susceptibility to candidemia. Furthermore, the cytokine QTLs that we identified were enriched among SNPs previously associated with infectious diseases and heart diseases. These data reveal and begin to explain the variability in cytokine production by human immune cells in response to pathogens.", + "TAG_DATA": [ + "41, peripheral {'context': 'B-cells'}", + "42, blood {'context': 'I-cells'}", + "43, mononuclear {'context': 'I-cells'}", + "44, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "41, peripheral ['l0', 'l1', 'l2', 'l3', 'l4']", + "42, blood ['l0', 'l5', 'l6', 'l7', 'l8']", + "43, mononuclear ['l1', 'l5', 'l9', 'l10', 'l11']", + "44, cells ['l2', 'l6', 'l9', 'l12', 'l13']", + "47, individuals ['l3', 'l7', 'l10', 'l12', 'l14']", + "50, origin ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27322743", + "TEXT": "Individuals who have mutations in the breast-cancer-susceptibility gene BRCA1 (hereafter referred to as BRCA1-mutation carriers) frequently undergo prophylactic mastectomy to minimize their risk of breast cancer. The identification of an effective prevention therapy therefore remains a 'holy grail' for the field. Precancerous BRCA1(mut/+) tissue harbors an aberrant population of luminal progenitor cells, and deregulated progesterone signaling has been implicated in BRCA1-associated oncogenesis. Coupled with the findings that tumor necrosis factor superfamily member 11 (TNFSF11; also known as RANKL) is a key paracrine effector of progesterone signaling and that RANKL and its receptor TNFRSF11A (also known as RANK) contribute to mammary tumorigenesis, we investigated a role for this pathway in the pre-neoplastic phase of BRCA1-mutation carriers. We identified two subsets of luminal progenitors (RANK(+) and RANK(-)) in histologically normal tissue of BRCA1-mutation carriers and showed that RANK(+) cells are highly proliferative, have grossly aberrant DNA repair and bear a molecular signature similar to that of basal-like breast cancer. These data suggest that RANK(+) and not RANK(-) progenitors are a key target population in these women. Inhibition of RANKL signaling by treatment with denosumab in three-dimensional breast organoids derived from pre-neoplastic BRCA1(mut/+) tissue attenuated progesterone-induced proliferation. Notably, proliferation was markedly reduced in breast biopsies from BRCA1-mutation carriers who were treated with denosumab. Furthermore, inhibition of RANKL in a Brca1-deficient mouse model substantially curtailed mammary tumorigenesis. Taken together, these findings identify a targetable pathway in a putative cell-of-origin population in BRCA1-mutation carriers and implicate RANKL blockade as a promising strategy in the prevention of breast cancer.", + "TAG_DATA": [ + "183, three-dimensional {'context': 'B-organoid'}", + "184, breast {'context': 'I-organoid'}", + "185, organoids {'context': 'I-organoid'}", + "188, pre-neoplastic {'context': 'B-cells'}", + "189, BRCA1(mut/+) {'context': 'I-tissue/organ'}", + "190, tissue {'context': 'I-tissue/organ'}", + "191, attenuated {'effect': 'B-negative'}", + "192, progesterone-induced {'effect': 'B-positive'}", + "193, proliferation. {'phenotype': 'B-proliferation'}", + "195, proliferation {'phenotype': 'B-proliferation'}", + "198, reduced {'effect': 'B-negative'}", + "200, breast {'context': 'B-transformed cells'}", + "201, biopsies {'context': 'I-patient'}", + "211, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "212, of {'perturbing_action': 'I-pharmacological inhibition'}", + "213, RANKL {'perturbing_action': 'I-pharmacological inhibition'}", + "216, Brca1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "217, mouse {'context': 'B-organism'}", + "218, model {'context': 'I-organism'}", + "220, curtailed {'effect': 'B-negative'}", + "221, mammary {'context': 'B-tissue/organ'}", + "222, tumorigenesis. {'phenotype': 'B-tumourigenesis'}" + ], + "LINK_DATA": [ + "183, three-dimensional ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "184, breast ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "185, organoids ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "188, pre-neoplastic ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "189, BRCA1(mut/+) ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "190, tissue ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54']", + "191, attenuated ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l55', 'l56', 'l57', 'l58']", + "192, progesterone-induced ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l55', 'l59', 'l60', 'l61']", + "193, proliferation. ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l56', 'l59']", + "195, proliferation ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l57', 'l60', 'l62', 'l63', 'l64']", + "198, reduced ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l58', 'l61', 'l62', 'l65', 'l66']", + "200, breast ['l10', 'l21', 'l31', 'l40', 'l48', 'l63', 'l65', 'l67']", + "201, biopsies ['l11', 'l22', 'l32', 'l41', 'l49', 'l64', 'l66', 'l67']", + "211, inhibition ['l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "212, of ['l68', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "213, RANKL ['l69', 'l76', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "216, Brca1-deficient ['l70', 'l77', 'l83', 'l89', 'l90', 'l91', 'l92', 'l93']", + "217, mouse ['l71', 'l78', 'l84', 'l89', 'l94', 'l95', 'l96', 'l97']", + "218, model ['l72', 'l79', 'l85', 'l90', 'l94', 'l98', 'l99', 'l100']", + "220, curtailed ['l73', 'l80', 'l86', 'l91', 'l95', 'l98', 'l101', 'l102']", + "221, mammary ['l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l101', 'l103']", + "222, tumorigenesis. ['l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l103']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organoid", + "words": [ + "three-dimensional", + "breast", + "organoids" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuated", + "reduced" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "three-dimensional", + "breast", + "organoids" + ] + }, + "effect": { + "val": "positive", + "words": [ + "progesterone-induced" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "three-dimensional", + "breast", + "organoids" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation.", + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pre-neoplastic" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuated", + "reduced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pre-neoplastic" + ] + }, + "effect": { + "val": "positive", + "words": [ + "progesterone-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pre-neoplastic" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation.", + "proliferation" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "BRCA1(mut/+)", + "tissue", + "mammary" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuated", + "reduced", + "curtailed" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "BRCA1(mut/+)", + "tissue" + ] + }, + "effect": { + "val": "positive", + "words": [ + "progesterone-induced" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "BRCA1(mut/+)", + "tissue" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation.", + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated", + "reduced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation.", + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "progesterone-induced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation.", + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "breast" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "patient", + "words": [ + "biopsies" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "breast" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "patient", + "words": [ + "biopsies" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "RANKL" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "RANKL" + ] + }, + "effect": { + "val": "negative", + "words": [ + "curtailed" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "RANKL" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mammary" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "RANKL" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Brca1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Brca1-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "curtailed" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Brca1-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mammary" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Brca1-deficient" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "effect": { + "val": "negative", + "words": [ + "curtailed" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "curtailed" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mammary" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + } + ] + }, + { + "PMID": "27270589", + "TEXT": "Humans with obesity differ in their susceptibility to developing insulin resistance and type 2 diabetes (T2D). This variation may relate to the extent of adipose tissue (AT) inflammation that develops as their obesity progresses. The state of macrophage activation has a central role in determining the degree of AT inflammation and thus its dysfunction, and these states are driven by epigenomic alterations linked to gene expression. The underlying mechanisms that regulate these alterations, however, are poorly defined. Here we demonstrate that a co-repressor complex containing G protein pathway suppressor 2 (GPS2) crucially controls the macrophage epigenome during activation by metabolic stress. The study of AT from humans with and without obesity revealed correlations between reduced GPS2 expression in macrophages, elevated systemic and AT inflammation, and diabetic status. The causality of this relationship was confirmed by using macrophage-specific Gps2-knockout (KO) mice, in which inappropriate co-repressor complex function caused enhancer activation, pro-inflammatory gene expression and hypersensitivity toward metabolic-stress signals. By contrast, transplantation of GPS2-overexpressing bone marrow into two mouse models of obesity (ob/ob and diet-induced obesity) reduced inflammation and improved insulin sensitivity. Thus, our data reveal a potentially reversible disease mechanism that links co-repressor-dependent epigenomic alterations in macrophages to AT inflammation and the development of T2D.", + "TAG_DATA": [ + "136, macrophage-specific {'perturbing_action': 'B-gene loss-of-function'}", + "137, Gps2-knockout {'perturbing_action': 'I-gene loss-of-function'}", + "138, (KO) {'perturbing_action': 'I-gene loss-of-function'}", + "139, mice, {'context': 'B-organism'}", + "161, GPS2-overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "162, bone {'context': 'B-tissue/organ'}", + "163, marrow {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "136, macrophage-specific ['l0', 'l1', 'l2']", + "137, Gps2-knockout ['l0', 'l3', 'l4']", + "138, (KO) ['l1', 'l3', 'l5']", + "139, mice, ['l2', 'l4', 'l5']", + "161, GPS2-overexpressing ['l6', 'l7']", + "162, bone ['l6', 'l8']", + "163, marrow ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "macrophage-specific", + "Gps2-knockout", + "(KO)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GPS2-overexpressing" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "bone", + "marrow" + ] + } + } + ] + }, + { + "PMID": "27213817", + "TEXT": "Xenotransplantation models represent powerful tools for the investigation of healthy and malignant human hematopoiesis. However, current models do not fully mimic the components of the human bone marrow (BM) microenvironment, and they enable only limited engraftment of samples from some human malignancies. Here we show that a xenotransplantation model bearing subcutaneous humanized ossicles with an accessible BM microenvironment, formed by in situ differentiation of human BM-derived mesenchymal stromal cells, enables the robust engraftment of healthy human hematopoietic stem and progenitor cells, as well as primary acute myeloid leukemia (AML) samples, at levels much greater than those in unmanipulated mice. Direct intraossicle transplantation accelerated engraftment and resulted in the detection of substantially higher leukemia-initiating cell (LIC) frequencies. We also observed robust engraftment of acute promyelocytic leukemia (APL) and myelofibrosis (MF) samples, and identified LICs in these malignancies. This humanized ossicle xenotransplantation approach provides a system for modeling a wide variety of human hematological diseases.", + "TAG_DATA": [ + "74, healthy {'context': 'B-transformed cells'}", + "75, human {'context': 'I-cells'}", + "76, hematopoietic {'context': 'I-cells'}", + "77, stem {'context': 'I-cells'}", + "78, and {'context': 'I-cells'}", + "79, progenitor {'context': 'I-cells'}", + "80, cells, {'context': 'I-cells'}", + "84, primary {'context': 'B-transformed cells'}", + "85, acute {'context': 'I-transformed cells'}", + "86, myeloid {'context': 'I-transformed cells'}", + "87, leukemia {'context': 'I-transformed cells'}", + "88, (AML) {'context': 'I-transformed cells'}", + "89, samples, {'context': 'I-transformed cells'}", + "98, mice. {'context': 'B-organism'}", + "122, acute {'context': 'B-transformed cells'}", + "123, promyelocytic {'context': 'I-transformed cells'}", + "124, leukemia {'context': 'I-transformed cells'}", + "125, (APL) {'context': 'I-transformed cells'}", + "129, samples, {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "74, healthy ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "75, human ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "76, hematopoietic ['l1', 'l12', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "77, stem ['l2', 'l13', 'l24', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "78, and ['l3', 'l14', 'l25', 'l35', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "79, progenitor ['l4', 'l15', 'l26', 'l36', 'l45', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "80, cells, ['l5', 'l16', 'l27', 'l37', 'l46', 'l54', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "84, primary ['l6', 'l17', 'l28', 'l38', 'l47', 'l55', 'l62', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "85, acute ['l7', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l68', 'l74', 'l75', 'l76', 'l77', 'l78']", + "86, myeloid ['l8', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l69', 'l74', 'l79', 'l80', 'l81', 'l82']", + "87, leukemia ['l9', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l70', 'l75', 'l79', 'l83', 'l84', 'l85']", + "88, (AML) ['l10', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l71', 'l76', 'l80', 'l83', 'l86', 'l87']", + "89, samples, ['l11', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l72', 'l77', 'l81', 'l84', 'l86', 'l88']", + "98, mice. ['l23', 'l34', 'l44', 'l53', 'l61', 'l73', 'l78', 'l82', 'l85', 'l87', 'l88']", + "122, acute ['l89', 'l90', 'l91', 'l92', 'l93']", + "123, promyelocytic ['l89', 'l94', 'l95', 'l96', 'l97']", + "124, leukemia ['l90', 'l94', 'l98', 'l99', 'l100']", + "125, (APL) ['l91', 'l95', 'l98', 'l101', 'l102']", + "126, and ['l92', 'l96', 'l99', 'l101', 'l103']", + "129, samples, ['l93', 'l97', 'l100', 'l102', 'l103']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27213815", + "TEXT": "MYC oncoproteins are involved in the genesis and maintenance of the majority of human tumors but are considered undruggable. By using a direct in vivo shRNA screen, we show that liver cancer cells that have mutations in the gene encoding the tumor suppressor protein p53 (Trp53 in mice and TP53 in humans) and that are driven by the oncoprotein NRAS become addicted to MYC stabilization via a mechanism mediated by aurora kinase A (AURKA). This MYC stabilization enables the tumor cells to overcome a latent G2/M cell cycle arrest that is mediated by AURKA and the tumor suppressor protein p19(ARF). MYC directly binds to AURKA, and inhibition of this protein-protein interaction by conformation-changing AURKA inhibitors results in subsequent MYC degradation and cell death. These conformation-changing AURKA inhibitors, with one of them currently being tested in early clinical trials, suppressed tumor growth and prolonged survival in mice bearing Trp53-deficient, NRAS-driven MYC-expressing hepatocellular carcinomas (HCCs). TP53-mutated human HCCs revealed increased AURKA expression and a positive correlation between AURKA and MYC expression. In xenograft models, mice bearing TP53-mutated or TP53-deleted human HCCs were hypersensitive to treatment with conformation-changing AURKA inhibitors, thus suggesting a therapeutic strategy for this subgroup of human HCCs.", + "TAG_DATA": [ + "30, liver {'context': 'B-transformed cells'}", + "31, cancer {'context': 'I-transformed cells'}", + "32, cells {'context': 'I-transformed cells'}", + "79, tumor {'context': 'B-transformed cells'}", + "80, cells {'context': 'I-transformed cells'}", + "85, G2/M {'phenotype': 'I-cell cycle arrest'}", + "86, cell {'phenotype': 'I-cell cycle arrest'}", + "87, cycle {'phenotype': 'I-cell cycle arrest'}", + "88, arrest {'phenotype': 'I-cell cycle arrest'}", + "112, conformation-changing {'perturbing_action': 'B-pharmacological inhibition'}", + "113, AURKA {'perturbing_action': 'B-pharmacological inhibition'}", + "114, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "115, results {'effect': 'B-positive'}", + "116, in {'effect': 'I-positive'}", + "121, cell {'phenotype': 'B-cell death'}", + "122, death. {'phenotype': 'I-cell death'}", + "124, conformation-changing {'perturbing_action': 'B-pharmacological inhibition'}", + "125, AURKA {'perturbing_action': 'I-pharmacological inhibition'}", + "126, inhibitors, {'perturbing_action': 'I-pharmacological inhibition'}", + "138, suppressed {'effect': 'B-negative'}", + "139, tumor {'phenotype': 'B-tumour growth'}", + "140, growth {'phenotype': 'I-tumour growth'}", + "145, mice {'context': 'B-organism'}", + "147, Trp53-deficient, {'perturbing_action': 'B-gene loss-of-function'}", + "149, MYC-expressing {'context': 'I-neoplasm'}", + "150, hepatocellular {'context': 'I-neoplasm'}", + "151, carcinomas {'context': 'I-neoplasm'}", + "152, (HCCs). {'context': 'I-neoplasm'}", + "155, HCCs {'context': 'I-neoplasm'}", + "170, xenograft {'context': 'B-xenograft'}", + "171, models, {'context': 'I-xenograft'}", + "172, mice {'context': 'B-organism'}", + "174, TP53-mutated {'perturbing_action': 'B-other'}", + "176, TP53-deleted {'perturbing_action': 'B-gene loss-of-function'}", + "177, human {'context': 'B-neoplasm'}", + "178, HCCs {'context': 'I-neoplasm'}", + "184, conformation-changing {'perturbing_action': 'B-pharmacological inhibition'}", + "185, AURKA {'perturbing_action': 'I-pharmacological inhibition'}", + "186, inhibitors, {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "30, liver ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "31, cancer ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "32, cells ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "79, tumor ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "80, cells ['l3', 'l10', 'l16', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32']", + "85, G2/M ['l4', 'l11', 'l17', 'l22', 'l28', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "86, cell ['l5', 'l12', 'l18', 'l23', 'l29', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "87, cycle ['l6', 'l13', 'l19', 'l24', 'l30', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "88, arrest ['l7', 'l14', 'l20', 'l25', 'l31', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "112, conformation-changing ['l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "113, AURKA ['l55', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "114, inhibitors ['l56', 'l75', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "115, results ['l36', 'l42', 'l47', 'l51', 'l57', 'l76', 'l94', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "116, in ['l37', 'l43', 'l48', 'l52', 'l58', 'l77', 'l95', 'l112', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "121, cell ['l26', 'l38', 'l44', 'l49', 'l53', 'l59', 'l78', 'l96', 'l113', 'l125', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145']", + "122, death. ['l27', 'l32', 'l39', 'l45', 'l50', 'l54', 'l60', 'l79', 'l97', 'l114', 'l126', 'l137', 'l146', 'l147', 'l148', 'l149', 'l150']", + "124, conformation-changing ['l61', 'l80', 'l98', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163']", + "125, AURKA ['l62', 'l81', 'l99', 'l151', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175']", + "126, inhibitors, ['l63', 'l82', 'l100', 'l152', 'l164', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186']", + "138, suppressed ['l64', 'l83', 'l101', 'l115', 'l127', 'l138', 'l146', 'l153', 'l165', 'l176', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195']", + "139, tumor ['l65', 'l84', 'l102', 'l116', 'l128', 'l139', 'l147', 'l154', 'l166', 'l177', 'l187', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203']", + "140, growth ['l66', 'l85', 'l103', 'l117', 'l129', 'l140', 'l148', 'l155', 'l167', 'l178', 'l188', 'l196', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210']", + "145, mice ['l67', 'l86', 'l104', 'l118', 'l130', 'l141', 'l156', 'l168', 'l179', 'l189', 'l197', 'l204', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217']", + "147, Trp53-deficient, ['l68', 'l87', 'l105', 'l119', 'l131', 'l157', 'l169', 'l180', 'l190', 'l198', 'l205', 'l211', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223']", + "148, NRAS-driven ['l69', 'l88', 'l106', 'l120', 'l132', 'l158', 'l170', 'l181', 'l191', 'l199', 'l206', 'l212', 'l218', 'l224', 'l225', 'l226', 'l227', 'l228']", + "149, MYC-expressing ['l70', 'l89', 'l107', 'l121', 'l133', 'l142', 'l159', 'l171', 'l182', 'l192', 'l200', 'l207', 'l213', 'l219', 'l224', 'l229', 'l230', 'l231', 'l232']", + "150, hepatocellular ['l71', 'l90', 'l108', 'l122', 'l134', 'l143', 'l160', 'l172', 'l183', 'l193', 'l201', 'l208', 'l214', 'l220', 'l225', 'l229', 'l233', 'l234', 'l235']", + "151, carcinomas ['l72', 'l91', 'l109', 'l123', 'l135', 'l144', 'l149', 'l161', 'l173', 'l184', 'l194', 'l202', 'l209', 'l215', 'l221', 'l226', 'l230', 'l233', 'l236', 'l237']", + "152, (HCCs). ['l73', 'l92', 'l110', 'l124', 'l136', 'l145', 'l150', 'l162', 'l174', 'l185', 'l195', 'l203', 'l210', 'l216', 'l222', 'l227', 'l231', 'l234', 'l236', 'l238']", + "155, HCCs ['l74', 'l93', 'l111', 'l163', 'l175', 'l186', 'l217', 'l223', 'l228', 'l232', 'l235', 'l237', 'l238']", + "170, xenograft ['l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247']", + "171, models, ['l239', 'l248', 'l249', 'l250', 'l251', 'l252']", + "172, mice ['l240', 'l248', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259']", + "174, TP53-mutated ['l241', 'l249', 'l253', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265']", + "176, TP53-deleted ['l242', 'l250', 'l254', 'l260', 'l266', 'l267', 'l268', 'l269', 'l270']", + "177, human ['l243', 'l251', 'l255', 'l261', 'l266', 'l271', 'l272', 'l273', 'l274']", + "178, HCCs ['l244', 'l252', 'l256', 'l262', 'l267', 'l271', 'l275', 'l276', 'l277']", + "184, conformation-changing ['l245', 'l257', 'l263', 'l268', 'l272', 'l275', 'l278', 'l279']", + "185, AURKA ['l246', 'l258', 'l264', 'l269', 'l273', 'l276', 'l278', 'l280']", + "186, inhibitors, ['l247', 'l259', 'l265', 'l270', 'l274', 'l277', 'l279', 'l280']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "liver", + "cancer", + "cells", + "tumor" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G2/M", + "cell", + "cycle", + "arrest" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G2/M", + "cell", + "cycle", + "arrest" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "conformation-changing", + "AURKA", + "inhibitors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "conformation-changing", + "AURKA", + "inhibitors" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "conformation-changing", + "AURKA", + "inhibitors", + "inhibitors," + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "conformation-changing", + "AURKA", + "inhibitors", + "inhibitors," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "conformation-changing", + "AURKA", + "inhibitors", + "inhibitors," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "conformation-changing", + "AURKA", + "inhibitors", + "inhibitors," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "MYC-expressing", + "hepatocellular", + "carcinomas", + "(HCCs).", + "HCCs", + "human" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trp53-deficient," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "MYC-expressing", + "hepatocellular", + "carcinomas", + "(HCCs)." + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "MYC-expressing", + "hepatocellular", + "carcinomas", + "(HCCs)." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trp53-deficient," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "MYC-expressing", + "hepatocellular", + "carcinomas", + "(HCCs)." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trp53-deficient," + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "MYC-expressing", + "hepatocellular", + "carcinomas", + "(HCCs)." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trp53-deficient,", + "TP53-deleted" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trp53-deficient,", + "TP53-deleted" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "MYC-expressing", + "hepatocellular", + "carcinomas", + "(HCCs).", + "HCCs", + "human" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "models," + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "TP53-mutated" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "models," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TP53-deleted" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenograft" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "conformation-changing", + "AURKA", + "inhibitors," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "TP53-mutated" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "TP53-mutated" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "HCCs" + ] + } + } + ] + }, + { + "PMID": "27158904", + "TEXT": "Complex interactions between the host and the gut microbiota govern intestinal homeostasis but remain poorly understood. Here we reveal a relationship between gut microbiota and caspase recruitment domain family member 9 (CARD9), a susceptibility gene for inflammatory bowel disease (IBD) that functions in the immune response against microorganisms. CARD9 promotes recovery from colitis by promoting interleukin (IL)-22 production, and Card9(-/-) mice are more susceptible to colitis. The microbiota is altered in Card9(-/-) mice, and transfer of the microbiota from Card9(-/-) to wild-type, germ-free recipients increases their susceptibility to colitis. The microbiota from Card9(-/-) mice fails to metabolize tryptophan into metabolites that act as aryl hydrocarbon receptor (AHR) ligands. Intestinal inflammation is attenuated after inoculation of mice with three Lactobacillus strains capable of metabolizing tryptophan or by treatment with an AHR agonist. Reduced production of AHR ligands is also observed in the microbiota from individuals with IBD, particularly in those with CARD9 risk alleles associated with IBD. Our findings reveal that host genes affect the composition and function of the gut microbiota, altering the production of microbial metabolites and intestinal inflammation.", + "TAG_DATA": [ + "59, Card9(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "60, mice {'context': 'B-organism'}", + "71, Card9(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "72, mice, {'context': 'B-organism'}", + "79, Card9(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "92, Card9(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "93, mice {'context': 'B-organism'}", + "115, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "59, Card9(-/-) ['l0', 'l1', 'l2']", + "60, mice ['l0', 'l3', 'l4']", + "71, Card9(-/-) ['l1', 'l3', 'l5', 'l6']", + "72, mice, ['l2', 'l4', 'l5']", + "79, Card9(-/-) ['l6']", + "92, Card9(-/-) ['l7', 'l8']", + "93, mice ['l7', 'l9']", + "115, mice ['l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Card9(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + } + ] + }, + { + "PMID": "27111280", + "TEXT": "CD4(+) T cells that express the forkhead box P3 (FOXP3) transcription factor function as regulatory T (Treg) cells and hinder effective immune responses against cancer cells. Abundant Treg cell infiltration into tumors is associated with poor clinical outcomes in various types of cancers. However, the role of Treg cells is controversial in colorectal cancers (CRCs), in which FOXP3(+) T cell infiltration indicated better prognosis in some studies. Here we show that CRCs, which are commonly infiltrated by suppression-competent FOXP3(hi) Treg cells, can be classified into two types by the degree of additional infiltration of FOXP3(lo) nonsuppressive T cells. The latter, which are distinguished from FOXP3(+) Treg cells by non-expression of the naive T cell marker CD45RA and instability of FOXP3, secreted inflammatory cytokines. Indeed, CRCs with abundant infiltration of FOXP3(lo) T cells showed significantly better prognosis than those with predominantly FOXP3(hi) Treg cell infiltration. Development of such inflammatory FOXP3(lo) non-Treg cells may depend on secretion of interleukin (IL)-12 and transforming growth factor (TGF)-β by tissues and their presence was correlated with tumor invasion by intestinal bacteria, especially Fusobacterium nucleatum. Thus, functionally distinct subpopulations of tumor-infiltrating FOXP3(+) T cells contribute in opposing ways to determining CRC prognosis. Depletion of FOXP3(hi) Treg cells from tumor tissues, which would augment antitumor immunity, could thus be used as an effective treatment strategy for CRCs and other cancers, whereas strategies that locally increase the population of FOXP3(lo) non-Treg cells could be used to suppress or prevent tumor formation.", + "TAG_DATA": [ + "241, tumor {'phenotype': 'B-tumourigenesis'}", + "242, formation. {'phenotype': 'I-tumourigenesis'}" + ], + "LINK_DATA": [ + "241, tumor ['l0']", + "242, formation. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27089515", + "TEXT": "Bacteroides fragilis is the leading cause of anaerobic bacteremia and sepsis. Enterotoxigenic strains that produce B. fragilis toxin (BFT, fragilysin) contribute to colitis and intestinal malignancy, yet are also isolated in bloodstream infection. It is not known whether these strains harbor unique genetic determinants that confer virulence in extra-intestinal disease. We demonstrate that BFT contributes to sepsis in mice, and we identify a B. fragilis protease called fragipain (Fpn) that is required for the endogenous activation of BFT through the removal of its auto-inhibitory prodomain. Structural analysis of Fpn reveals a His-Cys catalytic dyad that is characteristic of C11-family cysteine proteases that are conserved in multiple pathogenic Bacteroides spp. and Clostridium spp. Fpn-deficient, enterotoxigenic B. fragilis has an attenuated ability to induce sepsis in mice; however, Fpn is dispensable in B. fragilis colitis, wherein host proteases mediate BFT activation. Our findings define a role for B. fragilis enterotoxin and its activating protease in the pathogenesis of bloodstream infection, which indicates a greater complexity of cellular targeting and activity of BFT than previously recognized. The expression of fpn by both toxigenic and nontoxigenic strains suggests that this protease may contribute to anaerobic sepsis in ways that extend beyond its role in toxin activation. It could thus potentially serve as a target for disease modification.", + "TAG_DATA": [ + "112, Fpn-deficient, {'perturbing_action': 'B-gene loss-of-function'}", + "124, mice; {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "112, Fpn-deficient, ['l0']", + "124, mice; ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fpn-deficient," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice;" + ] + } + } + ] + }, + { + "PMID": "27043494", + "TEXT": "Inflammation-associated pathways are active in intestinal epithelial cells (IECs) and contribute to the pathogenesis of colorectal cancer (CRC). Calcineurin, a phosphatase required for the activation of the nuclear factor of activated T cells (NFAT) family of transcription factors, shows increased expression in CRC. We therefore investigated the role of calcineurin in intestinal tumor development. We demonstrate that calcineurin and NFAT factors are constitutively expressed by primary IECs and selectively activated in intestinal tumors as a result of impaired stratification of the tumor-associated microbiota and toll-like receptor signaling. Epithelial calcineurin supports the survival and proliferation of cancer stem cells in an NFAT-dependent manner and promotes the development of intestinal tumors in mice. Moreover, somatic mutations that have been identified in human CRC are associated with constitutive activation of calcineurin, whereas nuclear translocation of NFAT is associated with increased death from CRC. These findings highlight an epithelial cell-intrinsic pathway that integrates signals derived from the commensal microbiota to promote intestinal tumor development.", + "TAG_DATA": [ + "89, supports {'effect': 'B-positive'}", + "93, proliferation {'phenotype': 'B-proliferation'}", + "95, cancer {'context': 'B-transformed cells'}", + "96, stem {'context': 'I-transformed cells'}", + "97, cells {'context': 'I-transformed cells'}", + "103, promotes {'effect': 'B-positive'}", + "105, development {'phenotype': 'I-tumourigenesis'}", + "107, intestinal {'phenotype': 'B-tumourigenesis'}", + "108, tumors {'phenotype': 'I-tumourigenesis'}", + "110, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "89, supports ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "93, proliferation ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "95, cancer ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "96, stem ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "97, cells ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33']", + "103, promotes ['l4', 'l12', 'l19', 'l25', 'l30', 'l34', 'l35', 'l36', 'l37']", + "105, development ['l5', 'l13', 'l20', 'l26', 'l31', 'l34', 'l38', 'l39', 'l40']", + "107, intestinal ['l6', 'l14', 'l21', 'l27', 'l35', 'l38', 'l41', 'l42']", + "108, tumors ['l7', 'l15', 'l22', 'l28', 'l32', 'l36', 'l39', 'l41', 'l43']", + "110, mice. ['l8', 'l16', 'l23', 'l29', 'l33', 'l37', 'l40', 'l42', 'l43']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "supports", + "promotes" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "supports", + "promotes" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "stem", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "supports", + "promotes" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development", + "intestinal", + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "supports", + "promotes" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "stem", + "cells" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "stem", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development", + "intestinal", + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development", + "intestinal", + "tumors" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "27019329", + "TEXT": "The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC). However, the determinants of AR overexpression in CRPC are poorly defined. Here we show that retinoic acid receptor-related orphan receptor γ (ROR-γ) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors. ROR-γ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an AR-ROR response element (RORE) to stimulate AR gene transcription. ROR-γ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-γ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR target gene network. Finally, ROR-γ antagonists suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPC tumors to enzalutamide, without overt toxicity, in mice. Taken together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa.", + "TAG_DATA": [ + "81, ROR-γ {'perturbing_action': 'B-pharmacological inhibition'}", + "82, antagonists {'perturbing_action': 'I-pharmacological inhibition'}", + "94, prostate {'context': 'B-transformed cells'}", + "95, cancer {'context': 'I-transformed cells'}", + "96, (PCa) {'context': 'I-transformed cells'}", + "97, cell {'context': 'I-transformed cells'}", + "98, lines {'context': 'I-transformed cells'}", + "100, tumors. {'context': 'B-neoplasm'}", + "101, ROR-γ {'perturbing_action': 'B-pharmacological inhibition'}", + "102, antagonists {'perturbing_action': 'I-pharmacological inhibition'}", + "120, ROR-γ {'perturbing_action': 'B-pharmacological inhibition'}", + "121, antagonists {'perturbing_action': 'I-pharmacological inhibition'}", + "122, suppressed {'effect': 'B-negative'}", + "123, tumor {'phenotype': 'B-tumour growth'}", + "124, growth {'phenotype': 'I-tumour growth'}", + "131, xenograft {'context': 'I-xenograft'}", + "132, PCa {'context': 'I-neoplasm'}", + "133, models, {'context': 'I-neoplasm'}", + "138, CRPC {'context': 'B-neoplasm'}", + "139, tumors {'context': 'I-neoplasm'}", + "146, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "81, ROR-γ ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "82, antagonists ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "94, prostate ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "95, cancer ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "96, (PCa) ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "97, cell ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "98, lines ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "100, tumors. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "101, ROR-γ ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "102, antagonists ['l28', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "120, ROR-γ ['l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "121, antagonists ['l29', 'l36', 'l43', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "122, suppressed ['l30', 'l37', 'l44', 'l53', 'l62', 'l63', 'l64', 'l65', 'l66']", + "123, tumor ['l31', 'l38', 'l45', 'l54', 'l62', 'l67', 'l68', 'l69', 'l70']", + "124, growth ['l32', 'l39', 'l46', 'l55', 'l63', 'l67', 'l71', 'l72', 'l73']", + "131, xenograft ['l33', 'l40', 'l47', 'l56', 'l64', 'l68', 'l71', 'l74', 'l75', 'l76']", + "132, PCa ['l34', 'l41', 'l48', 'l57', 'l65', 'l69', 'l72', 'l74', 'l77']", + "133, models, ['l35', 'l42', 'l49', 'l58', 'l66', 'l70', 'l73', 'l75', 'l77']", + "138, CRPC ['l50', 'l59', 'l78', 'l79']", + "139, tumors ['l51', 'l60', 'l76', 'l78', 'l80']", + "146, mice. ['l52', 'l61', 'l79', 'l80']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ROR-γ", + "antagonists" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "(PCa)", + "cell", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ROR-γ", + "antagonists" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors.", + "PCa", + "models,", + "CRPC", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ROR-γ", + "antagonists" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ROR-γ", + "antagonists" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ROR-γ", + "antagonists" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ROR-γ", + "antagonists" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "PCa", + "models," + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "PCa", + "models," + ] + } + } + ] + }, + { + "PMID": "26950361", + "TEXT": "Epidemiological and experimental data implicate branched-chain amino acids (BCAAs) in the development of insulin resistance, but the mechanisms that underlie this link remain unclear. Insulin resistance in skeletal muscle stems from the excess accumulation of lipid species, a process that requires blood-borne lipids to initially traverse the blood vessel wall. How this trans-endothelial transport occurs and how it is regulated are not well understood. Here we leveraged PPARGC1a (also known as PGC-1α; encoded by Ppargc1a), a transcriptional coactivator that regulates broad programs of fatty acid consumption, to identify 3-hydroxyisobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, as a new paracrine regulator of trans-endothelial fatty acid transport. We found that 3-HIB is secreted from muscle cells, activates endothelial fatty acid transport, stimulates muscle fatty acid uptake in vivo and promotes lipid accumulation in muscle, leading to insulin resistance in mice. Conversely, inhibiting the synthesis of 3-HIB in muscle cells blocks the ability of PGC-1α to promote endothelial fatty acid uptake. 3-HIB levels are elevated in muscle from db/db mice with diabetes and from human subjects with diabetes, as compared to those without diabetes. These data unveil a mechanism in which the metabolite 3-HIB, by regulating the trans-endothelial flux of fatty acids, links the regulation of fatty acid flux to BCAA catabolism, providing a mechanistic explanation for how increased BCAA catabolic flux can cause diabetes.", + "TAG_DATA": [ + "122, muscle {'context': 'B-tissue/organ'}", + "126, in {'context': 'B-in vivo'}", + "127, vivo {'context': 'I-in vivo'}", + "133, muscle, {'context': 'B-tissue/organ'}", + "139, mice. {'context': 'B-organism'}", + "147, muscle {'context': 'B-cells'}", + "148, cells {'context': 'I-cells'}", + "167, db/db {'context': 'B-organism'}", + "168, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "122, muscle ['l0', 'l1', 'l2', 'l3']", + "126, in ['l0', 'l4', 'l5', 'l6']", + "127, vivo ['l1', 'l4', 'l7', 'l8']", + "133, muscle, ['l2', 'l5', 'l7', 'l9']", + "139, mice. ['l3', 'l6', 'l8', 'l9']", + "147, muscle ['l10', 'l11']", + "148, cells ['l10']", + "167, db/db ['l12']", + "168, mice ['l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26950360", + "TEXT": "Expression of the oncogenic transcription factor MYC is disproportionately elevated in triple-negative breast cancer (TNBC), as compared to estrogen receptor-, progesterone receptor- or human epidermal growth factor 2 receptor-positive (RP) breast cancer. We and others have shown that MYC alters metabolism during tumorigenesis. However, the role of MYC in TNBC metabolism remains mostly unexplored. We hypothesized that MYC-dependent metabolic dysregulation is essential for the growth of MYC-overexpressing TNBC cells and may identify new therapeutic targets for this clinically challenging subset of breast cancer. Using a targeted metabolomics approach, we identified fatty acid oxidation (FAO) intermediates as being dramatically upregulated in a MYC-driven model of TNBC. We also identified a lipid metabolism gene signature in patients with TNBC that were identified from The Cancer Genome Atlas database and from multiple other clinical data sets, implicating FAO as a dysregulated pathway that is critical for TNBC cell metabolism. We found that pharmacologic inhibition of FAO catastrophically decreased energy metabolism in MYC-overexpressing TNBC cells and blocked tumor growth in a MYC-driven transgenic TNBC model and in a MYC-overexpressing TNBC patient-derived xenograft. These findings demonstrate that MYC-overexpressing TNBC shows an increased bioenergetic reliance on FAO and identify the inhibition of FAO as a potential therapeutic strategy for this subset of breast cancer.", + "TAG_DATA": [ + "149, pharmacologic {'perturbing_action': 'B-pharmacological inhibition'}", + "150, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "151, of {'perturbing_action': 'I-pharmacological inhibition'}", + "152, FAO {'perturbing_action': 'I-pharmacological inhibition'}", + "158, MYC-overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "159, TNBC {'context': 'B-transformed cells'}", + "160, cells {'context': 'I-transformed cells'}", + "162, blocked {'effect': 'B-negative'}", + "163, tumor {'phenotype': 'B-tumour growth'}", + "164, growth {'phenotype': 'I-tumour growth'}", + "168, transgenic {'context': 'I-xenograft'}", + "169, TNBC {'context': 'I-neoplasm'}", + "170, model {'context': 'I-neoplasm'}", + "174, MYC-overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "175, TNBC {'context': 'B-xenograft'}", + "176, patient-derived {'context': 'I-xenograft'}", + "177, xenograft. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "149, pharmacologic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "150, inhibition ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "151, of ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "152, FAO ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "158, MYC-overexpressing ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44']", + "159, TNBC ['l4', 'l15', 'l25', 'l34', 'l42', 'l45']", + "160, cells ['l5', 'l16', 'l26', 'l35', 'l43', 'l45']", + "162, blocked ['l6', 'l17', 'l27', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50']", + "163, tumor ['l7', 'l18', 'l28', 'l37', 'l46', 'l51', 'l52', 'l53', 'l54']", + "164, growth ['l8', 'l19', 'l29', 'l38', 'l47', 'l51', 'l55', 'l56', 'l57']", + "168, transgenic ['l9', 'l20', 'l30', 'l39', 'l48', 'l52', 'l55', 'l58', 'l59']", + "169, TNBC ['l10', 'l21', 'l31', 'l40', 'l49', 'l53', 'l56', 'l58', 'l60']", + "170, model ['l11', 'l22', 'l32', 'l41', 'l44', 'l50', 'l54', 'l57', 'l59', 'l60']", + "174, MYC-overexpressing ['l61', 'l62', 'l63']", + "175, TNBC ['l61', 'l64', 'l65']", + "176, patient-derived ['l62', 'l64', 'l66']", + "177, xenograft. ['l63', 'l65', 'l66']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "FAO" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "FAO" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "FAO" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "FAO" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "FAO" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "TNBC", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "MYC-overexpressing" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "MYC-overexpressing" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "model" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "transgenic" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "TNBC", + "model" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "transgenic" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "TNBC", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "MYC-overexpressing" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "TNBC", + "patient-derived", + "xenograft." + ] + } + } + ] + }, + { + "PMID": "26878232", + "TEXT": "Impaired erythropoiesis in the deletion 5q (del(5q)) subtype of myelodysplastic syndrome (MDS) has been linked to heterozygous deletion of RPS14, which encodes the ribosomal protein small subunit 14. We generated mice with conditional inactivation of Rps14 and demonstrated an erythroid differentiation defect that is dependent on the tumor suppressor protein p53 (encoded by Trp53 in mice) and is characterized by apoptosis at the transition from polychromatic to orthochromatic erythroblasts. This defect resulted in age-dependent progressive anemia, megakaryocyte dysplasia and loss of hematopoietic stem cell (HSC) quiescence. As assessed by quantitative proteomics, mutant erythroblasts expressed higher levels of proteins involved in innate immune signaling, notably the heterodimeric S100 calcium-binding proteins S100a8 and S100a9. S100a8--whose expression was increased in mutant erythroblasts, monocytes and macrophages--is functionally involved in the erythroid defect caused by the Rps14 deletion, as addition of recombinant S100a8 was sufficient to induce a differentiation defect in wild-type erythroid cells, and genetic inactivation of S100a8 expression rescued the erythroid differentiation defect of Rps14-haploinsufficient HSCs. Our data link Rps14 haploinsufficiency in del(5q) MDS to activation of the innate immune system and induction of S100A8-S100A9 expression, leading to a p53-dependent erythroid differentiation defect.", + "TAG_DATA": [ + "30, mice {'context': 'B-organism'}", + "32, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "33, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "34, of {'perturbing_action': 'I-gene loss-of-function'}", + "35, Rps14 {'perturbing_action': 'I-gene loss-of-function'}", + "79, loss {'effect': 'B-negative'}", + "81, hematopoietic {'context': 'B-cells'}", + "82, stem {'context': 'I-cells'}", + "83, cell {'context': 'I-cells'}", + "84, (HSC) {'context': 'I-cells'}", + "85, quiescence. {'phenotype': 'B-quiescence'}", + "92, erythroblasts {'context': 'B-cells'}", + "131, Rps14 {'perturbing_action': 'B-gene loss-of-function'}", + "132, deletion, {'perturbing_action': 'I-gene loss-of-function'}", + "141, induce {'effect': 'B-positive'}", + "143, differentiation {'phenotype': 'B-differentiation'}", + "144, defect {'effect': 'B-negative', 'phenotype': 'I-differentiation'}", + "147, erythroid {'context': 'B-cells'}", + "148, cells, {'context': 'I-cells'}", + "150, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "151, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "152, of {'perturbing_action': 'I-gene loss-of-function'}", + "153, S100a8 {'perturbing_action': 'I-gene loss-of-function'}", + "154, expression {'perturbing_action': 'I-gene loss-of-function'}", + "155, rescued {'effect': 'B-rescues'}", + "158, differentiation {'phenotype': 'I-differentiation'}", + "159, defect {'effect': 'B-negative'}", + "161, Rps14-haploinsufficient {'perturbing_action': 'B-gene loss-of-function'}", + "162, HSCs. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "30, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "32, conditional ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "33, inactivation ['l1', 'l10', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "34, of ['l2', 'l11', 'l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "35, Rps14 ['l3', 'l12', 'l21', 'l29', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "79, loss ['l4', 'l13', 'l22', 'l30', 'l37', 'l44', 'l45', 'l46', 'l47', 'l48']", + "81, hematopoietic ['l5', 'l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "82, stem ['l6', 'l15', 'l24', 'l32', 'l39', 'l45', 'l49', 'l56', 'l57', 'l58', 'l59', 'l60']", + "83, cell ['l7', 'l16', 'l25', 'l33', 'l40', 'l46', 'l50', 'l56', 'l61', 'l62', 'l63', 'l64']", + "84, (HSC) ['l8', 'l17', 'l26', 'l34', 'l41', 'l47', 'l51', 'l57', 'l61', 'l65', 'l66', 'l67']", + "85, quiescence. ['l9', 'l18', 'l27', 'l35', 'l42', 'l48', 'l52', 'l58', 'l62', 'l65', 'l68']", + "92, erythroblasts ['l19', 'l28', 'l36', 'l43', 'l53', 'l59', 'l63', 'l66', 'l68', 'l69', 'l70', 'l71']", + "131, Rps14 ['l54', 'l69', 'l72', 'l73', 'l74', 'l75', 'l76']", + "132, deletion, ['l55', 'l60', 'l64', 'l67', 'l70', 'l72', 'l77']", + "141, induce ['l73', 'l78', 'l79', 'l80', 'l81']", + "143, differentiation ['l74', 'l78', 'l82', 'l83', 'l84']", + "144, defect ['l75', 'l79', 'l82', 'l85', 'l86']", + "147, erythroid ['l80', 'l83', 'l85', 'l87']", + "148, cells, ['l71', 'l76', 'l77', 'l81', 'l84', 'l86', 'l87']", + "150, genetic ['l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "151, inactivation ['l88', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "152, of ['l89', 'l97', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "153, S100a8 ['l90', 'l98', 'l105', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "154, expression ['l91', 'l99', 'l106', 'l112', 'l118', 'l119', 'l120', 'l121', 'l122']", + "155, rescued ['l92', 'l100', 'l107', 'l113', 'l118', 'l123', 'l124', 'l125', 'l126']", + "158, differentiation ['l93', 'l101', 'l108', 'l114', 'l119', 'l123', 'l127', 'l128', 'l129']", + "159, defect ['l94', 'l102', 'l109', 'l115', 'l120', 'l124', 'l127', 'l130', 'l131']", + "161, Rps14-haploinsufficient ['l95', 'l103', 'l110', 'l116', 'l121', 'l125', 'l128', 'l130', 'l132']", + "162, HSCs. ['l96', 'l104', 'l111', 'l117', 'l122', 'l126', 'l129', 'l131', 'l132']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "inactivation", + "of", + "Rps14" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "inactivation", + "of", + "Rps14", + "genetic", + "S100a8", + "expression", + "Rps14-haploinsufficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss", + "defect" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "inactivation", + "of", + "Rps14", + "deletion,", + "genetic", + "S100a8", + "expression", + "Rps14-haploinsufficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cell", + "(HSC)", + "erythroblasts", + "cells,", + "HSCs." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "inactivation", + "of", + "Rps14" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "loss", + "defect" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cell", + "(HSC)", + "erythroid", + "cells,", + "HSCs." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "loss" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cell", + "(HSC)", + "erythroblasts" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rps14" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rps14", + "genetic", + "inactivation", + "of", + "S100a8", + "expression", + "Rps14-haploinsufficient" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "defect" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "defect" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "defect", + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "defect" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "erythroid", + "cells," + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "defect" + ] + }, + "context": { + "val": "cells", + "words": [ + "erythroid", + "cells,", + "HSCs." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inactivation", + "of", + "S100a8", + "expression", + "Rps14-haploinsufficient" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSCs." + ] + } + } + ] + }, + { + "PMID": "26855148", + "TEXT": "An increasingly recognized resistance mechanism to androgen receptor (AR)-directed therapy in prostate cancer involves epithelial plasticity, in which tumor cells demonstrate low to absent AR expression and often have neuroendocrine features. The etiology and molecular basis for this 'alternative' treatment-resistant cell state remain incompletely understood. Here, by analyzing whole-exome sequencing data of metastatic biopsies from patients, we observed substantial genomic overlap between castration-resistant tumors that were histologically characterized as prostate adenocarcinomas (CRPC-Adeno) and neuroendocrine prostate cancer (CRPC-NE); analysis of biopsy samples from the same individuals over time points to a model most consistent with divergent clonal evolution. Genome-wide DNA methylation analysis revealed marked epigenetic differences between CRPC-NE tumors and CRPC-Adeno, and also designated samples of CRPC-Adeno with clinical features of AR independence as CRPC-NE, suggesting that epigenetic modifiers may play a role in the induction and/or maintenance of this treatment-resistant state. This study supports the emergence of an alternative, 'AR-indifferent' cell state through divergent clonal evolution as a mechanism of treatment resistance in advanced prostate cancer.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "26845399", + "TEXT": "In December, the US government approved a $2 billion increase in the budget of the US National Institutes of Health (NIH) for the 2016 fiscal year. With that increase comes relief, optimism and the pressure to spend wisely.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "26779813", + "TEXT": "Systemic immune suppression may curtail the ability to mount the protective, cell-mediated immune responses that are needed for brain repair. By using mouse models of Alzheimer's disease (AD), we show that immune checkpoint blockade directed against the programmed death-1 (PD-1) pathway evokes an interferon (IFN)-γ-dependent systemic immune response, which is followed by the recruitment of monocyte-derived macrophages to the brain. When induced in mice with established pathology, this immunological response leads to clearance of cerebral amyloid-β (Aβ) plaques and improved cognitive performance. Repeated treatment sessions were required to maintain a long-lasting beneficial effect on disease pathology. These findings suggest that immune checkpoints may be targeted therapeutically in AD.", + "TAG_DATA": [ + "23, models {'context': 'I-organism'}", + "63, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "26752518", + "TEXT": "Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death. Acute mortality from AP-MODS exceeds 20% (ref. 3), and the lifespans of those who survive the initial episode are typically shorter than those of the general population. There are no specific therapies available to protect individuals from AP-MODS. Here we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism, is central to the pathogenesis of AP-MODS. We created a mouse strain that is deficient for Kmo (encoding KMO) and that has a robust biochemical phenotype that protects against extrapancreatic tissue injury to the lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of the oxazolidinone GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in the levels of kynurenine pathway metabolites in vivo, and it afforded therapeutic protection against MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS, and they open up a new area for drug discovery in critical illness.", + "TAG_DATA": [ + "93, mouse {'context': 'B-organism'}", + "94, strain {'context': 'I-organism'}", + "97, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "98, for {'perturbing_action': 'I-gene loss-of-function'}", + "99, Kmo {'perturbing_action': 'I-gene loss-of-function'}", + "100, (encoding {'perturbing_action': 'I-gene loss-of-function'}", + "101, KMO) {'perturbing_action': 'I-gene loss-of-function'}", + "184, in {'context': 'B-in vivo'}", + "185, vivo, {'context': 'I-in vivo'}", + "195, rat {'context': 'B-organism'}", + "196, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "93, mouse ['l0', 'l1', 'l2', 'l3', 'l4']", + "94, strain ['l0', 'l5', 'l6', 'l7', 'l8']", + "97, deficient ['l1', 'l5', 'l9', 'l10', 'l11', 'l12']", + "98, for ['l2', 'l6', 'l9', 'l13', 'l14', 'l15']", + "99, Kmo ['l3', 'l7', 'l10', 'l13', 'l16', 'l17']", + "100, (encoding ['l4', 'l8', 'l11', 'l14', 'l16', 'l18']", + "101, KMO) ['l12', 'l15', 'l17', 'l18']", + "184, in ['l19']", + "185, vivo, ['l19']", + "195, rat ['l20']", + "196, model ['l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "strain" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "Kmo", + "(encoding" + ] + } + } + ] + }, + { + "PMID": "26735408", + "TEXT": "Adoptive transfer of receptor-engineered T cells has produced impressive results in treating patients with B cell leukemias and lymphomas. This success has captured public imagination and driven academic and industrial researchers to develop similar 'off-the-shelf' receptors targeting shared antigens on epithelial cancers, the leading cause of cancer-related deaths. However, the successful treatment of large numbers of people with solid cancers using this strategy is unlikely to be straightforward. Receptor-engineered T cells have the potential to cause lethal toxicity from on-target recognition of normal tissues, and there is a paucity of truly tumor-specific antigens shared across tumor types. Here we offer our perspective on how expanding the use of genetically redirected T cells to treat the majority of patients with solid cancers will require major technical, manufacturing and regulatory innovations centered around the development of autologous gene therapies targeting private somatic mutations.", + "TAG_DATA": [ + "69, T {'context': 'B-cells'}", + "70, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "69, T ['l0']", + "70, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26692334", + "TEXT": "The ubiquitin proteasome system (UPS) degrades misfolded proteins including those implicated in neurodegenerative diseases. We investigated the effects of tau accumulation on proteasome function in a mouse model of tauopathy and in a cross to a UPS reporter mouse (line Ub-G76V-GFP). Accumulation of insoluble tau was associated with a decrease in the peptidase activity of brain 26S proteasomes, higher levels of ubiquitinated proteins and undegraded Ub-G76V-GFP. 26S proteasomes from mice with tauopathy were physically associated with tau and were less active in hydrolyzing ubiquitinated proteins, small peptides and ATP. 26S proteasomes from normal mice incubated with recombinant oligomers or fibrils also showed lower hydrolyzing capacity in the same assays, implicating tau as a proteotoxin. Administration of an agent that activates cAMP-protein kinase A (PKA) signaling led to attenuation of proteasome dysfunction, probably through proteasome subunit phosphorylation. In vivo, this led to lower levels of aggregated tau and improvements in cognitive performance.", + "TAG_DATA": [ + "93, mice {'context': 'B-organism'}", + "136, In {'context': 'B-in vivo'}", + "137, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "136, In ['l0']", + "137, vivo, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26692333", + "TEXT": "AIRAPL (arsenite-inducible RNA-associated protein-like) is an evolutionarily conserved regulator of cellular proteostasis linked to longevity in nematodes, but its biological function in mammals is unknown. We show herein that AIRAPL-deficient mice develop a fully-penetrant myeloproliferative neoplastic process. Proteomic analysis of AIRAPL-deficient mice revealed that this protein exerts its antineoplastic function through the regulation of the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. We demonstrate that AIRAPL interacts with newly synthesized insulin-related growth factor-1 receptor (IGF1R) polypeptides, promoting their ubiquitination and proteasome-mediated degradation. Accordingly, genetic and pharmacological IGF1R inhibitory strategies prevent the hematological disease found in AIRAPL-deficient mice as well as that in mice carrying the Jak2(V617F) mutation, thereby demonstrating the causal involvement of this pathway in the pathogenesis of myeloproliferative neoplasms. Consistent with its proposed role as a tumor suppressor of myeloid transformation, AIRAPL expression is widely abrogated in human myeloproliferative disorders. Collectively, these findings support the oncogenic relevance of proteostasis deregulation in hematopoietic cells, and they unveil novel therapeutic targets for these frequent hematological neoplasias.", + "TAG_DATA": [ + "29, AIRAPL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "30, mice {'context': 'B-organism'}", + "40, AIRAPL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "41, mice {'context': 'B-organism'}", + "86, IGF1R {'perturbing_action': 'I-pharmacological inhibition'}", + "87, inhibitory {'perturbing_action': 'I-pharmacological inhibition'}", + "95, AIRAPL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "96, mice {'context': 'B-organism'}", + "102, mice {'context': 'B-organism'}", + "104, the {'perturbing_action': 'I-other'}", + "105, Jak2(V617F) {'perturbing_action': 'B-other'}", + "106, mutation, {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "29, AIRAPL-deficient ['l0', 'l1', 'l2']", + "30, mice ['l0', 'l3', 'l4']", + "40, AIRAPL-deficient ['l1', 'l3', 'l5']", + "41, mice ['l2', 'l4', 'l5']", + "86, IGF1R ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "87, inhibitory ['l6', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "88, strategies ['l7', 'l14', 'l21', 'l22', 'l23', 'l24', 'l25']", + "95, AIRAPL-deficient ['l8', 'l15', 'l21', 'l26']", + "96, mice ['l9', 'l16', 'l22', 'l26']", + "102, mice ['l10', 'l17', 'l23', 'l27', 'l28', 'l29']", + "104, the ['l11', 'l18', 'l27', 'l30', 'l31']", + "105, Jak2(V617F) ['l12', 'l19', 'l24', 'l28', 'l30', 'l32']", + "106, mutation, ['l13', 'l20', 'l25', 'l29', 'l31', 'l32']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "AIRAPL-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "IGF1R", + "inhibitory" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "the", + "Jak2(V617F)", + "mutation," + ] + } + } + ] + }, + { + "PMID": "26569380", + "TEXT": "Brown adipose tissue (BAT) promotes a lean and healthy phenotype and improves insulin sensitivity. In response to cold or exercise, brown fat cells also emerge in the white adipose tissue (WAT; also known as beige cells), a process known as browning. Here we show that the development of functional beige fat in the inguinal subcutaneous adipose tissue (ingSAT) and perigonadal visceral adipose tissue (pgVAT) is promoted by the depletion of microbiota either by means of antibiotic treatment or in germ-free mice. This leads to improved glucose tolerance and insulin sensitivity and decreased white fat and adipocyte size in lean mice, obese leptin-deficient (ob/ob) mice and high-fat diet (HFD)-fed mice. Such metabolic improvements are mediated by eosinophil infiltration, enhanced type 2 cytokine signaling and M2 macrophage polarization in the subcutaneous white fat depots of microbiota-depleted animals. The metabolic phenotype and the browning of the subcutaneous fat are impaired by the suppression of type 2 cytokine signaling, and they are reversed by recolonization of the antibiotic-treated or germ-free mice with microbes. These results provide insight into the microbiota-fat signaling axis and beige-fat development in health and metabolic disease.", + "TAG_DATA": [ + "80, mice. {'context': 'I-organism'}", + "98, lean {'context': 'B-organism'}", + "99, mice, {'context': 'I-organism'}", + "100, obese {'perturbing_action': 'B-gene loss-of-function'}", + "101, leptin-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "102, (ob/ob) {'perturbing_action': 'I-gene loss-of-function'}", + "103, mice {'context': 'I-organism'}", + "108, mice. {'context': 'B-organism'}", + "134, animals. {'context': 'B-organism'}", + "166, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "80, mice. ['l0', 'l1']", + "98, lean ['l0', 'l2']", + "99, mice, ['l1', 'l2']", + "100, obese ['l3', 'l4', 'l5', 'l6', 'l7']", + "101, leptin-deficient ['l3', 'l8', 'l9', 'l10', 'l11', 'l12']", + "102, (ob/ob) ['l4', 'l8', 'l13', 'l14', 'l15', 'l16']", + "103, mice ['l5', 'l9', 'l13', 'l17', 'l18']", + "108, mice. ['l10', 'l14', 'l19', 'l20', 'l21']", + "129, white ['l6', 'l11', 'l15', 'l17', 'l19', 'l22', 'l23']", + "130, fat ['l7', 'l12', 'l16', 'l18', 'l20', 'l22', 'l24']", + "134, animals. ['l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "obese", + "leptin-deficient", + "(ob/ob)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "26540384", + "TEXT": "Cancer cachexia leads to involuntary weight loss resulting from the atrophy of skeletal muscle and adipose tissues. Now, in metastatic mouse models of cancer, investigators reveal a cross talk pathway between bone and muscle that provides a new understanding of wasting in advanced cancers.", + "TAG_DATA": [ + "19, metastatic {'context': 'B-neoplasm'}", + "20, mouse {'context': 'I-neoplasm'}", + "21, models {'context': 'I-neoplasm'}", + "22, of {'context': 'I-neoplasm'}", + "23, cancer, {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "19, metastatic ['l0', 'l1', 'l2', 'l3']", + "20, mouse ['l0', 'l4', 'l5', 'l6']", + "21, models ['l1', 'l4', 'l7', 'l8']", + "22, of ['l2', 'l5', 'l7', 'l9']", + "23, cancer, ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26523969", + "TEXT": "Human tumors show a high level of genetic heterogeneity, but the processes that influence the timing and route of metastatic dissemination of the subclones are unknown. Here we have used whole-exome sequencing of 103 matched benign, malignant and metastatic skin tumors from genetically heterogeneous mice to demonstrate that most metastases disseminate synchronously from the primary tumor, supporting parallel rather than linear evolution as the predominant model of metastasis. Shared mutations between primary carcinomas and their matched metastases have the distinct A-to-T signature of the initiating carcinogen dimethylbenzanthracene, but non-shared mutations are primarily G-to-T, a signature associated with oxidative stress. The existence of carcinomas that either did or did not metastasize in the same host animal suggests that there are tumor-intrinsic factors that influence metastatic seeding. We also demonstrate the importance of germline polymorphisms in determining allele-specific mutations, and we identify somatic genetic alterations that are specifically related to initiation of carcinogenesis by Hras or Kras mutations. Mouse tumors that mimic the genetic heterogeneity of human cancers can aid our understanding of the clonal evolution of metastasis and provide a realistic model for the testing of novel therapies.", + "TAG_DATA": [ + "35, benign, {'context': 'B-neoplasm'}", + "36, malignant {'context': 'I-neoplasm'}", + "37, and {'context': 'I-neoplasm'}", + "38, metastatic {'context': 'I-neoplasm'}", + "39, skin {'context': 'I-neoplasm'}", + "40, tumors {'context': 'I-neoplasm'}", + "102, carcinomas {'context': 'B-neoplasm'}", + "105, did {'effect': 'B-negative'}", + "107, did {'effect': 'B-negative'}", + "108, not {'effect': 'B-no effect'}", + "109, metastasize {'phenotype': 'B-metastasis'}", + "113, host {'context': 'B-organism'}", + "114, animal {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "35, benign, ['l0', 'l1', 'l2', 'l3', 'l4']", + "36, malignant ['l0', 'l5', 'l6', 'l7', 'l8']", + "37, and ['l1', 'l5', 'l9', 'l10', 'l11']", + "38, metastatic ['l2', 'l6', 'l9', 'l12', 'l13']", + "39, skin ['l3', 'l7', 'l10', 'l12', 'l14']", + "40, tumors ['l4', 'l8', 'l11', 'l13', 'l14']", + "102, carcinomas ['l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "105, did ['l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "107, did ['l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "108, not ['l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "109, metastasize ['l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "113, host ['l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "114, animal ['l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "carcinomas" + ] + }, + "effect": { + "val": "negative", + "words": [ + "did" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "carcinomas" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "carcinomas" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasize" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "did" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasize" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "did" + ] + }, + "context": { + "val": "organism", + "words": [ + "host", + "animal" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasize" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not" + ] + }, + "context": { + "val": "organism", + "words": [ + "host", + "animal" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasize" + ] + }, + "context": { + "val": "organism", + "words": [ + "host", + "animal" + ] + } + } + ] + }, + { + "PMID": "26479923", + "TEXT": "Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient responses for patient-selection strategies. We established ∼1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 × 1 × 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. In addition, our results suggest that PCTs may represent a more accurate approach than cell line models for assessing the clinical potential of some therapeutic modalities. We therefore propose that this experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses.", + "TAG_DATA": [ + "46, in {'context': 'B-in vivo'}", + "47, vivo {'context': 'B-in vivo'}" + ], + "LINK_DATA": [ + "46, in ['l0']", + "47, vivo ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26457759", + "TEXT": "Colorectal cancer (CRC) is a frequently lethal disease with heterogeneous outcomes and drug responses. To resolve inconsistencies among the reported gene expression-based CRC classifications and facilitate clinical translation, we formed an international consortium dedicated to large-scale data sharing and analytics across expert groups. We show marked interconnectivity between six independent classification systems coalescing into four consensus molecular subtypes (CMSs) with distinguishing features: CMS1 (microsatellite instability immune, 14%), hypermutated, microsatellite unstable and strong immune activation; CMS2 (canonical, 37%), epithelial, marked WNT and MYC signaling activation; CMS3 (metabolic, 13%), epithelial and evident metabolic dysregulation; and CMS4 (mesenchymal, 23%), prominent transforming growth factor-β activation, stromal invasion and angiogenesis. Samples with mixed features (13%) possibly represent a transition phenotype or intratumoral heterogeneity. We consider the CMS groups the most robust classification system currently available for CRC-with clear biological interpretability-and the basis for future clinical stratification and subtype-based targeted interventions.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "26457758", + "TEXT": "Cancer-associated muscle weakness is a poorly understood phenomenon, and there is no effective treatment. Here we find that seven different mouse models of human osteolytic bone metastases-representing breast, lung and prostate cancers, as well as multiple myeloma-exhibited impaired muscle function, implicating a role for the tumor-bone microenvironment in cancer-associated muscle weakness. We found that transforming growth factor (TGF)-β, released from the bone surface as a result of metastasis-induced bone destruction, upregulated NADPH oxidase 4 (Nox4), resulting in elevated oxidization of skeletal muscle proteins, including the ryanodine receptor and calcium (Ca(2+)) release channel (RyR1). The oxidized RyR1 channels leaked Ca(2+), resulting in lower intracellular signaling, which is required for proper muscle contraction. We found that inhibiting RyR1 leakage, TGF-β signaling, TGF-β release from bone or Nox4 activity improved muscle function in mice with MDA-MB-231 bone metastases. Humans with breast- or lung cancer-associated bone metastases also had oxidized skeletal muscle RyR1 that is not seen in normal muscle. Similarly, skeletal muscle weakness, increased Nox4 binding to RyR1 and oxidation of RyR1 were present in a mouse model of Camurati-Engelmann disease, a nonmalignant metabolic bone disorder associated with increased TGF-β activity. Thus, pathological TGF-β release from bone contributes to muscle weakness by decreasing Ca(2+)-induced muscle force production.", + "TAG_DATA": [ + "127, muscle {'context': 'B-tissue/organ'}", + "130, mice {'context': 'B-organism'}", + "133, bone {'phenotype': 'I-metastasis'}", + "134, metastases. {'phenotype': 'I-metastasis'}", + "135, Humans {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "127, muscle ['l0']", + "130, mice ['l0', 'l1', 'l2', 'l3']", + "132, MDA-MB-231 ['l1', 'l4', 'l5']", + "133, bone ['l2', 'l4', 'l6']", + "134, metastases. ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "bone", + "metastases." + ] + } + } + ] + }, + { + "PMID": "26457756", + "TEXT": "The elicitation of broadly neutralizing antibodies (bNAbs) is likely to be essential for a preventative HIV-1 vaccine, but this has not yet been achieved by immunization. In contrast, some HIV-1-infected individuals naturally mount bNAb responses during chronic infection, suggesting that years of maturation may be required for neutralization breadth. Recent studies have shown that viral diversification precedes the emergence of bNAbs, but the significance of this observation is unknown. Here we delineate the key viral events that drove neutralization breadth within the CAP256-VRC26 family of 33 monoclonal antibodies (mAbs) isolated from a superinfected individual. First, we identified minority viral variants, termed bNAb-initiating envelopes, that were distinct from both of the transmitted/founder (T/F) viruses and that efficiently engaged the bNAb precursor. Second, deep sequencing revealed a pool of diverse epitope variants (immunotypes) that were preferentially neutralized by broader members of the antibody lineage. In contrast, a 'dead-end' antibody sublineage unable to neutralize these immunotypes showed limited evolution and failed to develop breadth. Thus, early viral escape at key antibody-virus contact sites selects for antibody sublineages that can tolerate these changes, thereby providing a mechanism for the generation of neutralization breadth within a developing antibody lineage.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "26343801", + "TEXT": "Modest transcriptional changes caused by genetic or epigenetic mechanisms are frequent in human cancer. Although loss or near-complete loss of the hematopoietic transcription factor PU.1 induces acute myeloid leukemia (AML) in mice, a similar degree of PU.1 impairment is exceedingly rare in human AML; yet, moderate PU.1 inhibition is common in AML patients. We assessed functional consequences of modest reductions in PU.1 expression on leukemia development in mice harboring DNA lesions resembling those acquired during human stem cell aging. Heterozygous deletion of an enhancer of PU.1, which resulted in a 35% reduction of PU.1 expression, was sufficient to induce myeloid-biased preleukemic stem cells and their subsequent transformation to AML in a DNA mismatch repair-deficient background. AML progression was mediated by inhibition of expression of a PU.1-cooperating transcription factor, Irf8. Notably, we found marked molecular similarities between the disease in these mice and human myelodysplastic syndrome and AML. This study demonstrates that minimal reduction of a key lineage-specific transcription factor, which commonly occurs in human disease, is sufficient to initiate cancer development, and it provides mechanistic insight into the formation and progression of preleukemic stem cells in AML.", + "TAG_DATA": [ + "67, mice {'context': 'B-organism'}", + "79, Heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "80, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "81, of {'perturbing_action': 'I-gene loss-of-function'}", + "82, an {'perturbing_action': 'I-gene loss-of-function'}", + "83, enhancer {'perturbing_action': 'I-gene loss-of-function'}", + "84, of {'perturbing_action': 'I-gene loss-of-function'}", + "85, PU.1, {'perturbing_action': 'I-gene loss-of-function'}", + "98, induce {'effect': 'B-positive'}", + "100, preleukemic {'context': 'B-cells'}", + "101, stem {'context': 'I-cells'}", + "102, cells {'context': 'I-cells'}", + "106, transformation {'phenotype': 'B-transformation'}", + "107, to {'phenotype': 'B-transformation'}", + "108, AML {'phenotype': 'B-transformation'}" + ], + "LINK_DATA": [ + "79, Heterozygous ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "80, deletion ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "81, of ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "82, an ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "83, enhancer ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "84, of ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "85, PU.1, ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "98, induce ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "100, preleukemic ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "101, stem ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "102, cells ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "106, transformation ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "107, to ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "108, AML ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Heterozygous", + "deletion", + "of", + "an", + "enhancer", + "PU.1," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Heterozygous", + "deletion", + "of", + "an", + "enhancer", + "PU.1," + ] + }, + "context": { + "val": "cells", + "words": [ + "preleukemic", + "stem", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Heterozygous", + "deletion", + "of", + "an", + "enhancer", + "PU.1," + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation", + "to", + "AML" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "preleukemic", + "stem", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation", + "to", + "AML" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "preleukemic", + "stem", + "cells" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation", + "to", + "AML" + ] + } + } + ] + }, + { + "PMID": "26343800", + "TEXT": "Finding new treatment-shortening antibiotics to improve cure rates and curb the alarming emergence of drug resistance is the major objective of tuberculosis (TB) drug development. Using a matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging suite in a biosafety containment facility, we show that the key sterilizing drugs rifampicin and pyrazinamide efficiently penetrate the sites of TB infection in lung lesions. Rifampicin even accumulates in necrotic caseum, a critical lesion site where persisting tubercle bacilli reside. In contrast, moxifloxacin, which is active in vitro against a subpopulation of Mycobacterium tuberculosis that persists in specific niches under drug pressure and has achieved treatment shortening in mice, does not diffuse well in caseum, concordant with its failure to shorten therapy in recent clinical trials. We suggest that such differential spatial distribution and kinetics of accumulation in lesions may create temporal and spatial windows of monotherapy in specific niches, allowing the gradual development of multidrug-resistant TB. We propose an alternative working model to prioritize new antibiotic regimens based on quantitative and spatial distribution of TB drugs in the major lesion types found in human lungs. The finding that lesion penetration may contribute to treatment outcome has wide implications for TB.", + "TAG_DATA": [ + "81, in {'context': 'B-in vitro'}", + "82, vitro {'context': 'I-in vitro'}", + "103, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "81, in ['l0', 'l1', 'l2']", + "82, vitro ['l0', 'l3', 'l4']", + "88, tuberculosis ['l1', 'l3', 'l5']", + "103, mice, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26280121", + "TEXT": "Tumor necrosis factor-α (TNF-α), one of the major stress-induced proinflammatory cytokines, is upregulated in the heart after tissue injury, and its sustained expression can contribute to the development of heart failure. Whether TNF-α also exerts cytoprotective effects in heart failure is not known. Here we provide evidence for a cardioprotective function of TNF-α in a genetic heart failure model, desmin-deficient mice. The cardioprotective effects of TNF-α are a consequence of nuclear factor-κB (NF-κB)-mediated ectopic expression in cardiomyocytes of keratin 8 (K8) and keratin 18 (K18), two epithelial-specific intermediate filament proteins. In cardiomyocytes, K8 and K18 (K8/K18) formed an alternative cytoskeletal network that localized mainly at intercalated discs (IDs) and conferred cardioprotection by maintaining normal ID structure and mitochondrial integrity and function. Ectopic induction of K8/K18 expression in cardiomyocytes also occurred in other genetic and experimental models of heart failure. Loss of the K8/K18 network resulted in a maladaptive cardiac phenotype following transverse aortic constriction. In human failing myocardium, where TNF-α expression is upregulated, K8/K18 were also ectopically expressed and localized primarily at IDs, which did not contain detectable amounts of desmin. Thus, TNF-α- and NF-κB-mediated formation of an alternative, stress-induced intermediate filament cytoskeleton has cardioprotective function in mice and potentially in humans.", + "TAG_DATA": [ + "59, desmin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "60, mice. {'context': 'B-organism'}", + "91, cardiomyocytes, {'context': 'B-cells'}", + "121, Ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "122, induction {'perturbing_action': 'I-gene gain-of-function'}", + "123, of {'perturbing_action': 'I-gene gain-of-function'}", + "124, K8/K18 {'perturbing_action': 'I-gene gain-of-function'}", + "125, expression {'perturbing_action': 'I-gene gain-of-function'}", + "127, cardiomyocytes {'context': 'B-cells'}", + "139, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "140, of {'perturbing_action': 'I-gene loss-of-function'}", + "141, the {'perturbing_action': 'I-gene loss-of-function'}", + "142, K8/K18 {'perturbing_action': 'I-gene loss-of-function'}", + "143, network {'perturbing_action': 'I-gene loss-of-function'}", + "155, human {'context': 'B-tissue/organ'}", + "156, failing {'context': 'I-tissue/organ'}", + "157, myocardium, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "59, desmin-deficient ['l0', 'l1', 'l2']", + "60, mice. ['l0', 'l3']", + "91, cardiomyocytes, ['l1', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "121, Ectopic ['l4', 'l10', 'l11', 'l12', 'l13', 'l14']", + "122, induction ['l5', 'l10', 'l15', 'l16', 'l17', 'l18']", + "123, of ['l6', 'l11', 'l15', 'l19', 'l20', 'l21']", + "124, K8/K18 ['l7', 'l12', 'l16', 'l19', 'l22', 'l23']", + "125, expression ['l8', 'l13', 'l17', 'l20', 'l22', 'l24']", + "127, cardiomyocytes ['l2', 'l9', 'l14', 'l18', 'l21', 'l23', 'l24']", + "139, Loss ['l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "140, of ['l25', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "141, the ['l26', 'l31', 'l37', 'l38', 'l39', 'l40', 'l41']", + "142, K8/K18 ['l27', 'l32', 'l37', 'l42', 'l43', 'l44', 'l45']", + "143, network ['l28', 'l33', 'l38', 'l42']", + "155, human ['l34', 'l39', 'l43', 'l46', 'l47']", + "156, failing ['l29', 'l35', 'l40', 'l44', 'l46', 'l48']", + "157, myocardium, ['l30', 'l36', 'l41', 'l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "desmin-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "desmin-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes,", + "cardiomyocytes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cardiomyocytes,", + "cardiomyocytes" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "induction", + "of", + "K8/K18", + "expression" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Loss", + "of", + "the", + "K8/K18" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "failing", + "myocardium,", + "human" + ] + } + } + ] + }, + { + "PMID": "26280120", + "TEXT": "The intestine is densely populated by anaerobic commensal bacteria. These microorganisms shape immune system development, but understanding of host-commensal interactions is hampered by a lack of tools for studying the anaerobic intestinal environment. We applied metabolic oligosaccharide engineering and bioorthogonal click chemistry to label various commensal anaerobes, including Bacteroides fragilis, a common and immunologically important commensal. We studied the dissemination of B. fragilis after acute peritonitis and characterized the interactions of the intact microbe and its polysaccharide components in myeloid and B cell lineages. We were able to assess the distribution and colonization of labeled B. fragilis along the intestine, as well as niche competition after coadministration of multiple species of the microbiota. We also fluorescently labeled nine additional commensals (eight anaerobic and one microaerophilic) from three phyla common in the gut--Bacteroidetes, Firmicutes and Proteobacteria--as well as one aerobic pathogen (Staphylococcus aureus). This strategy permits visualization of the anaerobic microbial niche by various methods, including intravital two-photon microscopy and non-invasive whole-body imaging, and can be used to study microbial colonization and host-microbe interactions in real time.", + "TAG_DATA": [ + "99, intestine, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "26248264", + "TEXT": "A new study shows that astrocytes are involved in the development of chronic itch in a mouse model. This dependent on upregulation of lipocalin 2 (LCN2) by the transcription factor STAT-3 and astrogliosis.", + "TAG_DATA": [ + "16, mouse {'context': 'B-organism'}", + "17, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "16, mouse ['l0']", + "17, model. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26236992", + "TEXT": "Myostatin (also known as growth and differentiation factor 8) is a secreted member of the transforming growth factor-β (TGF-β) family that is mainly expressed in skeletal muscle, which is also its primary target tissue. Deletion of the myostatin gene (Mstn) in mice leads to muscle hypertrophy, and animal studies support the concept that myostatin is a negative regulator of muscle growth and regeneration. However, myostatin deficiency also increases bone formation, mainly through loading-associated effects on bone. Here we report a previously unknown direct role for myostatin in osteoclastogenesis and in the progressive loss of articular bone in rheumatoid arthritis (RA). We demonstrate that myostatin is highly expressed in the synovial tissues of RA subjects and of human tumor necrosis factor (TNF)-α transgenic (hTNFtg) mice, a model for human RA. Myostatin strongly accelerates receptor activator of nuclear factor κB ligand (RANKL)-mediated osteoclast formation in vitro through transcription factor SMAD2-dependent regulation of nuclear factor of activated T-cells (NFATC1). Myostatin deficiency or antibody-mediated inhibition leads to an amelioration of arthritis severity in hTNFtg mice, chiefly reflected by less bone destruction. Consistent with these effects in hTNFtg mice, the lack of myostatin leads to increased grip strength and less bone erosion in the K/BxN serum-induced arthritis model in mice. The results strongly suggest that myostatin is a potent therapeutic target for interfering with osteoclast formation and joint destruction in RA.", + "TAG_DATA": [ + "116, human {'perturbing_action': 'B-gene gain-of-function'}", + "117, tumor {'perturbing_action': 'I-gene gain-of-function'}", + "118, necrosis {'perturbing_action': 'I-gene gain-of-function'}", + "119, factor {'perturbing_action': 'I-gene gain-of-function'}", + "121, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "122, (hTNFtg) {'perturbing_action': 'I-gene gain-of-function'}", + "123, mice, {'context': 'B-organism'}", + "142, in {'context': 'B-in vitro'}", + "143, vitro {'context': 'I-in vitro'}", + "156, Myostatin {'perturbing_action': 'B-gene loss-of-function'}", + "157, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "169, hTNFtg {'perturbing_action': 'B-other'}", + "170, mice, {'context': 'B-organism'}", + "182, hTNFtg {'perturbing_action': 'B-other'}", + "183, mice, {'context': 'B-organism'}", + "185, lack {'perturbing_action': 'B-gene loss-of-function'}", + "186, of {'perturbing_action': 'I-gene loss-of-function'}", + "187, myostatin {'perturbing_action': 'I-gene loss-of-function'}", + "204, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "116, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "117, tumor ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "118, necrosis ['l1', 'l10', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "119, factor ['l2', 'l11', 'l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "121, transgenic ['l3', 'l12', 'l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "122, (hTNFtg) ['l4', 'l13', 'l23', 'l32', 'l40', 'l47', 'l48', 'l49']", + "123, mice, ['l5', 'l14', 'l24', 'l33', 'l41', 'l47', 'l50', 'l51']", + "142, in ['l6', 'l15', 'l25', 'l34', 'l42', 'l48', 'l50', 'l52']", + "143, vitro ['l7', 'l16', 'l26', 'l35', 'l43', 'l49', 'l51', 'l52']", + "156, Myostatin ['l17', 'l27', 'l36', 'l53', 'l54', 'l55']", + "157, deficiency ['l18', 'l28', 'l37', 'l44', 'l53', 'l56', 'l57']", + "169, hTNFtg ['l8', 'l19', 'l29', 'l38', 'l45', 'l54', 'l56', 'l58']", + "170, mice, ['l9', 'l20', 'l30', 'l39', 'l46', 'l55', 'l57', 'l58']", + "182, hTNFtg ['l59']", + "183, mice, ['l59']", + "185, lack ['l60', 'l61', 'l62']", + "186, of ['l60', 'l63', 'l64']", + "187, myostatin ['l61', 'l63', 'l65']", + "204, mice. ['l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "human", + "tumor", + "necrosis", + "factor", + "transgenic", + "(hTNFtg)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "human", + "tumor", + "necrosis", + "factor", + "transgenic", + "(hTNFtg)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Myostatin", + "deficiency", + "lack", + "of", + "myostatin" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "hTNFtg" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "26236990", + "TEXT": "Endogenous mechanisms leading to host protection and resolution of infections without immunosuppression are of wide interest. Here we elucidate the structures of four new host-protective molecules produced in neutrophil-endothelial cocultures and present in human and mouse tissues after sterile inflammation or infection. The bioactive molecules contain conjugated triene and diene double bonds, carry an alcohol at C13 and are derived from n-3 docosapentaenoic acid (DPA, C22:5). These compounds, termed 13-series resolvins (RvTs), demonstrated potent protective actions increasing mice survival during Escherichia coli infections. RvTs also regulated human and mouse phagocyte responses stimulating bacterial phagocytosis and regulating inflammasome components. Their biosynthesis during neutrophil-endothelial cell interactions was initiated by endothelial cyclooxygenase-2 (COX-2), increased by atorvastatin via S-nitrosylation of COX-2 and reduced by COX-2 inhibitors. The actions of atorvastatin and RvTs were additive in E. coli infections in mice, where they accelerated resolution of inflammation and increased survival >60%. Taken together, these results document host-protective molecules in bacterial infections, namely RvTs, derived from n-3 DPA via transcellular biosynthesis and increased by atorvastatin. These molecules regulate key innate protective responses in the resolution of infectious inflammation.", + "TAG_DATA": [ + "77, mice {'context': 'B-organism'}", + "120, COX-2 {'perturbing_action': 'B-pharmacological inhibition'}", + "121, inhibitors. {'perturbing_action': 'I-pharmacological inhibition'}", + "135, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "120, COX-2 ['l0', 'l1']", + "121, inhibitors. ['l0']", + "135, mice, ['l1']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "COX-2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "26214837", + "TEXT": "Inflammation is a pathological hallmark of Alzheimer's disease, and innate immune cells have been shown to contribute to disease pathogenesis. In two transgenic models of Alzheimer's disease (5xFAD and 3xTg-AD mice), neutrophils extravasated and were present in areas with amyloid-β (Aβ) deposits, where they released neutrophil extracellular traps (NETs) and IL-17. Aβ42 peptide triggered the LFA-1 integrin high-affinity state and rapid neutrophil adhesion to integrin ligands. In vivo, LFA-1 integrin controlled neutrophil extravasation into the CNS and intraparenchymal motility. In transgenic Alzheimer's disease models, neutrophil depletion or inhibition of neutrophil trafficking via LFA-1 blockade reduced Alzheimer's disease-like neuropathology and improved memory in mice already showing cognitive dysfunction. Temporary depletion of neutrophils for 1 month at early stages of disease led to sustained improvements in memory. Transgenic Alzheimer's disease model mice lacking LFA-1 were protected from cognitive decline and had reduced gliosis. In humans with Alzheimer's disease, neutrophils adhered to and spread inside brain venules and were present in the parenchyma, along with NETs. Our results demonstrate that neutrophils contribute to Alzheimer's disease pathogenesis and cognitive impairment and suggest that the inhibition of neutrophil trafficking may be beneficial in Alzheimer's disease.", + "TAG_DATA": [ + "66, In {'context': 'B-in vivo'}", + "67, vivo, {'context': 'I-in vivo'}", + "80, transgenic {'context': 'B-organism'}", + "102, mice {'context': 'B-organism'}", + "125, Transgenic {'context': 'B-organism'}", + "126, Alzheimer's {'context': 'I-organism'}", + "127, disease {'context': 'I-organism'}", + "128, model {'context': 'I-organism'}", + "129, mice {'context': 'I-organism'}", + "130, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "131, LFA-1 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "66, In ['l0', 'l1', 'l2', 'l3', 'l4']", + "67, vivo, ['l0', 'l5', 'l6', 'l7', 'l8']", + "80, transgenic ['l1', 'l5', 'l9', 'l10', 'l11', 'l12']", + "81, Alzheimer's ['l2', 'l6', 'l9', 'l13', 'l14', 'l15']", + "82, disease ['l3', 'l7', 'l10', 'l13', 'l16', 'l17']", + "83, models, ['l4', 'l8', 'l11', 'l14', 'l16', 'l18']", + "102, mice ['l12', 'l15', 'l17', 'l18']", + "125, Transgenic ['l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "126, Alzheimer's ['l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "127, disease ['l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "128, model ['l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "129, mice ['l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "130, lacking ['l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "131, LFA-1 ['l24', 'l29', 'l33', 'l36', 'l38', 'l39']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Transgenic", + "Alzheimer's", + "disease", + "model", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "LFA-1" + ] + } + } + ] + }, + { + "PMID": "26168295", + "TEXT": "Colon cancer prevention currently relies on colonoscopy using white light to detect and remove polyps, but small and flat polyps are difficult to detect and frequently missed when using this technique. Fluorescence colonoscopy combined with a fluorescent probe specific for a polyp biomarker may improve polyp detection. Here we describe GE-137, a water-soluble probe consisting of a 26-amino acid cyclic peptide that binds the human tyrosine kinase c-Met conjugated to a fluorescent cyanine dye. Intravenous administration of GE-137 leads to its accumulation specifically in c-Met-expressing tumors in mice, and it is safe and well tolerated in humans. Fluorescence colonoscopy in patients receiving intravenous GE-137 enabled visualization of all neoplastic polyps that were visible with white light (38), as well as an additional nine polyps that were not visible with white light. This first-in-human pilot study shows that molecular imaging using an intravenous fluorescent agent specific for c-Met is feasible and safe, and that it may enable the detection of polyps missed by other techniques.", + "TAG_DATA": [ + "84, c-Met-expressing {'context': 'B-neoplasm'}", + "85, tumors {'context': 'I-neoplasm'}", + "87, mice, {'context': 'B-organism'}", + "100, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "84, c-Met-expressing ['l0', 'l1']", + "85, tumors ['l0', 'l2']", + "87, mice, ['l1', 'l2']", + "100, patients ['l3', 'l4']", + "108, neoplastic ['l3', 'l5']", + "109, polyps ['l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26099046", + "TEXT": "Interleukin-18 (IL18) participates in atherogenesis through several putative mechanisms. Interruption of IL18 action reduces atherosclerosis in mice. Here, we show that absence of the IL18 receptor (IL18r) does not affect atherosclerosis in apolipoprotein E-deficient (Apoe(-/-)) mice, nor does it affect IL18 cell surface binding to or signaling in endothelial cells. As identified initially by co-immunoprecipitation with IL18, we found that IL18 interacts with the Na-Cl co-transporter (NCC; also known as SLC12A3), a 12-transmembrane-domain ion transporter protein preferentially expressed in the kidney. NCC is expressed in atherosclerotic lesions, where it colocalizes with IL18r. In Apoe(-/-) mice, combined deficiency of IL18r and NCC, but not single deficiency of either protein, protects mice from atherosclerosis. Peritoneal macrophages from Apoe(-/-) mice or from Apoe(-/-) mice lacking IL18r or NCC show IL18 binding and induction of cell signaling and cytokine and chemokine expression, but macrophages from Apoe(-/-) mice with combined deficiency of IL18r and NCC have a blunted response. An interaction between NCC and IL18r on macrophages was detected by co-immunoprecipitation. IL18 binds to the cell surface of NCC-transfected COS-7 cells, which do not express IL18r, and induces cell signaling and cytokine expression. This study identifies NCC as an IL18-binding protein that collaborates with IL18r in cell signaling, inflammatory molecule expression, and experimental atherogenesis.", + "TAG_DATA": [ + "21, absence {'perturbing_action': 'B-gene loss-of-function'}", + "22, of {'perturbing_action': 'I-gene loss-of-function'}", + "23, the {'perturbing_action': 'I-gene loss-of-function'}", + "25, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "26, (IL18r) {'perturbing_action': 'I-gene loss-of-function'}", + "32, apolipoprotein {'perturbing_action': 'B-gene loss-of-function'}", + "33, E-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "34, (Apoe(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "35, mice, {'context': 'B-organism'}", + "93, Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "94, mice, {'context': 'B-organism'}", + "95, combined {'perturbing_action': 'B-gene loss-of-function'}", + "96, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "97, of {'perturbing_action': 'I-gene loss-of-function'}", + "98, IL18r {'perturbing_action': 'I-gene loss-of-function'}", + "99, and {'perturbing_action': 'I-gene loss-of-function'}", + "100, NCC, {'perturbing_action': 'I-gene loss-of-function'}", + "109, mice {'context': 'B-organism'}", + "112, Peritoneal {'context': 'B-cells'}", + "113, macrophages {'context': 'I-cells'}", + "115, Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "116, mice {'context': 'B-organism'}", + "119, Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "120, mice {'context': 'B-organism'}", + "121, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "122, IL18r {'perturbing_action': 'I-gene loss-of-function'}", + "123, or {'perturbing_action': 'I-gene loss-of-function'}", + "124, NCC {'perturbing_action': 'I-gene loss-of-function'}", + "139, macrophages {'context': 'B-cells'}", + "141, Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "142, mice {'context': 'B-organism'}", + "144, combined {'perturbing_action': 'B-gene loss-of-function'}", + "145, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "146, of {'perturbing_action': 'I-gene loss-of-function'}", + "147, IL18r {'perturbing_action': 'I-gene loss-of-function'}", + "148, and {'perturbing_action': 'I-gene loss-of-function'}", + "149, NCC {'perturbing_action': 'I-gene loss-of-function'}", + "161, macrophages {'context': 'B-cells'}", + "173, NCC-transfected {'perturbing_action': 'B-gene gain-of-function'}", + "174, COS-7 {'context': 'B-cells'}", + "175, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "21, absence ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "22, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "23, the ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "25, receptor ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "26, (IL18r) ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "32, apolipoprotein ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "33, E-deficient ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "34, (Apoe(-/-)) ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "35, mice, ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56']", + "93, Apoe(-/-) ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "94, mice, ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l60', 'l71', 'l72', 'l73']", + "95, combined ['l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "96, deficiency ['l61', 'l74', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "97, of ['l62', 'l75', 'l90', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "98, IL18r ['l63', 'l71', 'l76', 'l91', 'l105', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "99, and ['l64', 'l77', 'l92', 'l106', 'l119', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "100, NCC, ['l65', 'l72', 'l78', 'l93', 'l107', 'l120', 'l132', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "109, mice ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l66', 'l73', 'l79', 'l94', 'l108', 'l121', 'l133', 'l144', 'l155', 'l156', 'l157', 'l158']", + "112, Peritoneal ['l67', 'l80', 'l95', 'l109', 'l122', 'l134', 'l145', 'l155', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "113, macrophages ['l68', 'l81', 'l96', 'l110', 'l123', 'l135', 'l146', 'l156', 'l159', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175']", + "115, Apoe(-/-) ['l69', 'l82', 'l97', 'l111', 'l124', 'l136', 'l147', 'l157', 'l160', 'l168', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "116, mice ['l70', 'l83', 'l98', 'l112', 'l125', 'l137', 'l148', 'l158', 'l161', 'l169', 'l176', 'l183', 'l184', 'l185']", + "119, Apoe(-/-) ['l84', 'l99', 'l113', 'l126', 'l138', 'l149', 'l162', 'l170', 'l177', 'l186', 'l187', 'l188', 'l189', 'l190']", + "120, mice ['l85', 'l100', 'l114', 'l127', 'l139', 'l150', 'l163', 'l171', 'l178', 'l186', 'l191', 'l192', 'l193', 'l194']", + "121, lacking ['l86', 'l101', 'l115', 'l128', 'l140', 'l151', 'l164', 'l172', 'l179', 'l187', 'l191', 'l195', 'l196', 'l197']", + "122, IL18r ['l87', 'l102', 'l116', 'l129', 'l141', 'l152', 'l165', 'l173', 'l180', 'l183', 'l188', 'l192', 'l195', 'l198', 'l199']", + "123, or ['l88', 'l103', 'l117', 'l130', 'l142', 'l153', 'l166', 'l174', 'l181', 'l184', 'l189', 'l193', 'l196', 'l198', 'l200']", + "124, NCC ['l89', 'l104', 'l118', 'l131', 'l143', 'l154', 'l167', 'l175', 'l182', 'l185', 'l190', 'l194', 'l197', 'l199', 'l200']", + "139, macrophages ['l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208']", + "141, Apoe(-/-) ['l201', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217']", + "142, mice ['l202', 'l209', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224']", + "144, combined ['l203', 'l210', 'l218', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233']", + "145, deficiency ['l204', 'l211', 'l219', 'l225', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239']", + "146, of ['l205', 'l212', 'l220', 'l226', 'l234', 'l240', 'l241', 'l242', 'l243', 'l244']", + "147, IL18r ['l206', 'l213', 'l221', 'l227', 'l235', 'l240', 'l245', 'l246']", + "148, and ['l207', 'l214', 'l222', 'l228', 'l236', 'l241', 'l245', 'l247']", + "149, NCC ['l208', 'l215', 'l223', 'l229', 'l237', 'l242', 'l246', 'l247']", + "161, macrophages ['l216', 'l224', 'l230', 'l238', 'l243', 'l248', 'l249', 'l250']", + "173, NCC-transfected ['l231', 'l248', 'l251', 'l252']", + "174, COS-7 ['l232', 'l249', 'l251', 'l253']", + "175, cells, ['l217', 'l233', 'l239', 'l244', 'l250', 'l252', 'l253']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "the", + "receptor", + "(IL18r)", + "apolipoprotein", + "E-deficient", + "(Apoe(-/-))", + "Apoe(-/-)", + "IL18r", + "NCC,", + "combined", + "deficiency", + "and", + "or", + "NCC", + "lacking" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apoe(-/-)", + "combined", + "deficiency", + "of", + "IL18r", + "and", + "NCC,", + "lacking", + "or", + "NCC" + ] + }, + "context": { + "val": "cells", + "words": [ + "Peritoneal", + "macrophages", + "cells,", + "COS-7" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "macrophages", + "COS-7", + "cells," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "NCC-transfected" + ] + } + } + ] + }, + { + "PMID": "26053625", + "TEXT": "Candida albicans colonization is required for invasive disease. Unlike humans, adult mice with mature intact gut microbiota are resistant to C. albicans gastrointestinal (GI) colonization, but the factors that promote C. albicans colonization resistance are unknown. Here we demonstrate that commensal anaerobic bacteria-specifically clostridial Firmicutes (clusters IV and XIVa) and Bacteroidetes-are critical for maintaining C. albicans colonization resistance in mice. Using Bacteroides thetaiotamicron as a model organism, we find that hypoxia-inducible factor-1α (HIF-1α), a transcription factor important for activating innate immune effectors, and the antimicrobial peptide LL-37 (CRAMP in mice) are key determinants of C. albicans colonization resistance. Although antibiotic treatment enables C. albicans colonization, pharmacologic activation of colonic Hif1a induces CRAMP expression and results in a significant reduction of C. albicans GI colonization and a 50% decrease in mortality from invasive disease. In the setting of antibiotics, Hif1a and Camp (which encodes CRAMP) are required for B. thetaiotamicron-induced protection against C. albicans colonization of the gut. Thus, modulating C. albicans GI colonization by activation of gut mucosal immune effectors may represent a novel therapeutic approach for preventing invasive fungal disease in humans.", + "TAG_DATA": [ + "105, pharmacologic {'perturbing_action': 'B-pharmacological augmentation'}", + "106, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "107, of {'perturbing_action': 'I-pharmacological augmentation'}", + "108, colonic {'perturbing_action': 'I-pharmacological augmentation'}", + "109, Hif1a {'perturbing_action': 'I-pharmacological augmentation'}" + ], + "LINK_DATA": [ + "105, pharmacologic ['l0', 'l1', 'l2', 'l3']", + "106, activation ['l0', 'l4', 'l5', 'l6']", + "107, of ['l1', 'l4', 'l7', 'l8']", + "108, colonic ['l2', 'l5', 'l7', 'l9']", + "109, Hif1a ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26030178", + "TEXT": "Metastasis is responsible for most cancer-related deaths, and, among common tumor types, melanoma is one with great potential to metastasize. Here we study the contribution of epigenetic changes to the dissemination process by analyzing the changes that occur at the DNA methylation level between primary cancer cells and metastases. We found a hypomethylation event that reactivates a cryptic transcript of the Rab GTPase activating protein TBC1D16 (TBC1D16-47 kDa; referred to hereafter as TBC1D16-47KD) to be a characteristic feature of the metastatic cascade. This short isoform of TBC1D16 exacerbates melanoma growth and metastasis both in vitro and in vivo. By combining immunoprecipitation and mass spectrometry, we identified RAB5C as a new TBC1D16 target and showed that it regulates EGFR in melanoma cells. We also found that epigenetic reactivation of TBC1D16-47KD is associated with poor clinical outcome in melanoma, while conferring greater sensitivity to BRAF and MEK inhibitors.", + "TAG_DATA": [ + "87, exacerbates {'effect': 'B-positive'}", + "88, melanoma {'context': 'B-neoplasm'}", + "91, metastasis {'phenotype': 'B-metastasis'}", + "93, in {'context': 'B-in vitro'}", + "94, vitro {'context': 'I-in vitro'}", + "96, in {'context': 'B-in vivo'}", + "97, vivo. {'context': 'I-in vivo'}", + "119, melanoma {'context': 'B-transformed cells'}", + "120, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "87, exacerbates ['l0', 'l1', 'l2', 'l3', 'l4']", + "88, melanoma ['l0', 'l5', 'l6', 'l7']", + "91, metastasis ['l1', 'l5', 'l8', 'l9']", + "93, in ['l2', 'l6', 'l8', 'l10']", + "94, vitro ['l3', 'l7', 'l9', 'l10']", + "96, in ['l11']", + "97, vivo. ['l4', 'l11']", + "119, melanoma ['l12']", + "120, cells. ['l12']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "exacerbates" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "melanoma" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "exacerbates" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "exacerbates" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "exacerbates" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "melanoma" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "25962120", + "TEXT": "Relapse is the leading cause of mortality in children with acute lymphoblastic leukemia (ALL). Among chemotherapeutics, thiopurines are key drugs in ALL combination therapy. Using whole-exome sequencing, we identified relapse-specific mutations in the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1), which encodes a rate-limiting purine biosynthesis enzyme, in 24/358 (6.7%) relapsed childhood B cell ALL (B-ALL) cases. All individuals who harbored PRPS1 mutations relapsed early during treatment, and mutated ALL clones expanded exponentially before clinical relapse. Our functional analyses of PRPS1 mutants uncovered a new chemotherapy-resistance mechanism involving reduced feedback inhibition of de novo purine biosynthesis and competitive inhibition of thiopurine activation. Notably, the de novo purine synthesis inhibitor lometrexol effectively abrogated PRPS1 mutant-driven drug resistance. These results highlight the importance of constitutive activation of the de novo purine synthesis pathway in thiopurine resistance, and they offer therapeutic strategies for the treatment of relapsed and thiopurine-resistant ALL.", + "TAG_DATA": [ + "68, ALL {'context': 'B-transformed cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25951526", + "TEXT": "A new study reveals that B cells restrict the transendothelial migration of T cells in physiological inflammation in response to adiponectin, but that this mechanism is compromised in autoimmunity and is hence a novel avenue for therapy development.", + "TAG_DATA": [ + "12, T {'context': 'B-cells'}", + "13, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "12, T ['l0']", + "13, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25939064", + "TEXT": "Accumulation of visceral adipose tissue correlates with elevated inflammation and increased risk of metabolic diseases. However, little is known about the molecular mechanisms that control its pathological expansion. Transcription factor interferon regulatory factor 5 (IRF5) has been implicated in polarizing macrophages towards an inflammatory phenotype. Here we demonstrate that mice lacking Irf5, when placed on a high-fat diet, show no difference in the growth of their epididymal white adipose tissue (epiWAT) but they show expansion of their subcutaneous white adipose tissue, as compared to wild-type (WT) mice on the same diet. EpiWAT from Irf5-deficient mice is marked by accumulation of alternatively activated macrophages, higher collagen deposition that restricts adipocyte size, and enhanced insulin sensitivity compared to epiWAT from WT mice. In obese individuals, IRF5 expression is negatively associated with insulin sensitivity and collagen deposition in visceral adipose tissue. Genome-wide analysis of gene expression in adipose tissue macrophages highlights the transforming growth factor β1 (TGFB1) gene itself as a direct target of IRF5-mediated inhibition. This study uncovers a new function for IRF5 in controlling the relative mass of different adipose tissue depots and thus insulin sensitivity in obesity, and it suggests that inhibition of IRF5 may promote a healthy metabolic state during this condition.", + "TAG_DATA": [ + "49, mice {'context': 'B-organism'}", + "50, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "51, Irf5, {'perturbing_action': 'I-gene loss-of-function'}", + "93, Irf5-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "94, mice {'context': 'B-organism'}", + "102, macrophages, {'context': 'B-cells'}", + "108, adipocyte {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "49, mice ['l0', 'l1']", + "50, lacking ['l0', 'l2']", + "51, Irf5, ['l1', 'l2']", + "93, Irf5-deficient ['l3', 'l4', 'l5']", + "94, mice ['l3', 'l6', 'l7']", + "102, macrophages, ['l4', 'l6', 'l8']", + "108, adipocyte ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "Irf5,", + "Irf5-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Irf5-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages,", + "adipocyte" + ] + } + } + ] + }, + { + "PMID": "25915831", + "TEXT": "Neuropathic pain is a major, intractable clinical problem and its pathophysiology is not well understood. Although recent gene expression profiling studies have enabled the identification of novel targets for pain therapy, classical study designs provide unclear results owing to the differential expression of hundreds of genes across sham and nerve-injured groups, which can be difficult to validate, particularly with respect to the specificity of pain modulation. To circumvent this, we used two outbred lines of rats, which are genetically similar except for being genetically segregated as a result of selective breeding for differences in neuropathic pain hypersensitivity. SerpinA3N, a serine protease inhibitor, was upregulated in the dorsal root ganglia (DRG) after nerve injury, which was further validated for its mouse homolog. Mice lacking SerpinA3N developed more neuropathic mechanical allodynia than wild-type (WT) mice, and exogenous delivery of SerpinA3N attenuated mechanical allodynia in WT mice. T lymphocytes infiltrate the DRG after nerve injury and release leukocyte elastase (LE), which was inhibited by SerpinA3N derived from DRG neurons. Genetic loss of LE or exogenous application of a LE inhibitor (Sivelastat) in WT mice attenuated neuropathic mechanical allodynia. Overall, we reveal a novel and clinically relevant role for a member of the serpin superfamily and a leukocyte elastase and crosstalk between neurons and T cells in the modulation of neuropathic pain.", + "TAG_DATA": [ + "72, outbred {'context': 'B-organism'}", + "73, lines {'context': 'I-organism'}", + "75, rats, {'context': 'I-organism'}", + "121, Mice {'context': 'B-organism'}", + "122, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "123, SerpinA3N {'perturbing_action': 'I-gene loss-of-function'}", + "132, mice, {'context': 'B-organism'}", + "143, mice. {'context': 'B-organism'}", + "144, T {'context': 'B-cells'}", + "145, lymphocytes {'context': 'I-cells'}", + "164, DRG {'context': 'B-cells'}", + "165, neurons. {'context': 'I-cells'}", + "166, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "167, loss {'perturbing_action': 'I-gene loss-of-function'}", + "168, of {'perturbing_action': 'I-gene loss-of-function'}", + "169, LE {'perturbing_action': 'I-gene loss-of-function'}", + "175, LE {'perturbing_action': 'B-pharmacological inhibition'}", + "176, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "177, (Sivelastat) {'perturbing_action': 'I-pharmacological inhibition'}", + "180, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "72, outbred ['l0', 'l1', 'l2', 'l3', 'l4']", + "73, lines ['l0', 'l5', 'l6', 'l7']", + "75, rats, ['l1', 'l5', 'l8', 'l9', 'l10']", + "121, Mice ['l2', 'l8', 'l11', 'l12', 'l13']", + "122, lacking ['l3', 'l6', 'l9', 'l11', 'l14', 'l15']", + "123, SerpinA3N ['l4', 'l7', 'l10', 'l12', 'l14', 'l16']", + "132, mice, ['l13', 'l15', 'l16', 'l17']", + "143, mice. ['l18', 'l19', 'l20', 'l21']", + "144, T ['l18', 'l22', 'l23', 'l24']", + "145, lymphocytes ['l17', 'l19', 'l22', 'l25', 'l26']", + "164, DRG ['l20', 'l23', 'l25', 'l27']", + "165, neurons. ['l21', 'l24', 'l26', 'l27']", + "166, Genetic ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "167, loss ['l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "168, of ['l29', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "169, LE ['l30', 'l36', 'l41', 'l46', 'l47', 'l48', 'l49']", + "175, LE ['l31', 'l37', 'l42', 'l46', 'l50', 'l51', 'l52']", + "176, inhibitor ['l32', 'l38', 'l43', 'l47', 'l50', 'l53', 'l54']", + "177, (Sivelastat) ['l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l55']", + "180, mice ['l34', 'l40', 'l45', 'l49', 'l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "outbred", + "lines", + "rats,", + "Mice", + "mice,", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "SerpinA3N", + "Genetic", + "loss", + "of", + "LE" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "LE", + "inhibitor", + "(Sivelastat)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "25849135", + "TEXT": "A common key regulator of oncogenic signaling pathways in multiple tumor types is the unique isomerase Pin1. However, available Pin1 inhibitors lack the required specificity and potency for inhibiting Pin1 function in vivo. By using mechanism-based screening, here we find that all-trans retinoic acid (ATRA)--a therapy for acute promyelocytic leukemia (APL) that is considered the first example of targeted therapy in cancer, but whose drug target remains elusive--inhibits and degrades active Pin1 selectively in cancer cells by directly binding to the substrate phosphate- and proline-binding pockets in the Pin1 active site. ATRA-induced Pin1 ablation degrades the protein encoded by the fusion oncogene PML-RARA and treats APL in APL cell and animal models as well as in human patients. ATRA-induced Pin1 ablation also potently inhibits triple-negative breast cancer cell growth in human cells and in animal models by acting on many Pin1 substrate oncogenes and tumor suppressors. Thus, ATRA simultaneously blocks multiple Pin1-regulated cancer-driving pathways, an attractive property for treating aggressive and drug-resistant tumors.", + "TAG_DATA": [ + "74, cancer {'context': 'B-transformed cells'}", + "75, cells {'context': 'I-transformed cells'}", + "91, ATRA-induced {'perturbing_action': 'B-gene loss-of-function'}", + "92, Pin1 {'perturbing_action': 'B-gene loss-of-function'}", + "93, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "107, APL {'context': 'B-transformed cells'}", + "108, cell {'context': 'I-transformed cells'}", + "110, animal {'context': 'B-organism'}", + "111, models {'context': 'I-transformed cells'}", + "118, ATRA-induced {'perturbing_action': 'B-gene loss-of-function'}", + "119, Pin1 {'perturbing_action': 'B-gene loss-of-function'}", + "120, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "123, inhibits {'effect': 'B-negative'}", + "124, triple-negative {'context': 'B-neoplasm'}", + "125, breast {'context': 'I-neoplasm'}", + "126, cancer {'context': 'I-neoplasm'}", + "127, cell {'phenotype': 'B-cell growth'}", + "128, growth {'phenotype': 'I-cell growth'}", + "130, human {'context': 'B-cells'}", + "131, cells {'context': 'I-cells'}", + "134, animal {'context': 'B-organism'}", + "135, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "74, cancer ['l0', 'l1', 'l2']", + "75, cells ['l0', 'l3', 'l4']", + "91, ATRA-induced ['l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "92, Pin1 ['l5', 'l11', 'l12', 'l13', 'l14', 'l15']", + "93, ablation ['l6', 'l11', 'l16', 'l17', 'l18', 'l19']", + "107, APL ['l7', 'l12', 'l16', 'l20', 'l21', 'l22']", + "108, cell ['l1', 'l3', 'l8', 'l13', 'l17', 'l20', 'l23', 'l24']", + "110, animal ['l9', 'l14', 'l18', 'l21', 'l23', 'l25']", + "111, models ['l2', 'l4', 'l10', 'l15', 'l19', 'l22', 'l24', 'l25']", + "118, ATRA-induced ['l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "119, Pin1 ['l26', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "120, ablation ['l27', 'l38', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "123, inhibits ['l28', 'l39', 'l49', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "124, triple-negative ['l29', 'l40', 'l50', 'l59', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "125, breast ['l30', 'l41', 'l51', 'l60', 'l68', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "126, cancer ['l31', 'l42', 'l52', 'l61', 'l69', 'l76', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "127, cell ['l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l83', 'l89', 'l90', 'l91', 'l92', 'l93']", + "128, growth ['l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l89', 'l94', 'l95', 'l96', 'l97']", + "130, human ['l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l94', 'l98', 'l99', 'l100']", + "131, cells ['l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l98', 'l101', 'l102']", + "134, animal ['l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l101', 'l103']", + "135, models ['l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l103']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ATRA-induced", + "Pin1", + "ablation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "APL", + "cell", + "models" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ATRA-induced", + "Pin1", + "ablation" + ] + }, + "context": { + "val": "organism", + "words": [ + "animal", + "models" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ATRA-induced", + "Pin1", + "ablation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ATRA-induced", + "Pin1", + "ablation" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "triple-negative", + "breast", + "cancer" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ATRA-induced", + "Pin1", + "ablation" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ATRA-induced", + "Pin1", + "ablation" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "triple-negative", + "breast", + "cancer" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "organism", + "words": [ + "animal", + "models" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "triple-negative", + "breast", + "cancer" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "cells" + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "animal", + "models" + ] + } + } + ] + }, + { + "PMID": "25822366", + "TEXT": "Rearrangements of MLL (encoding lysine-specific methyltransferase 2A and officially known as KMT2A; herein referred to as MLL to denote the gene associated with mixed-lineage leukemia) generate MLL fusion proteins that bind DNA and drive leukemogenic gene expression. This gene expression program is dependent on the disruptor of telomeric silencing 1-like histone 3 lysine 79 (H3K79) methyltransferase DOT1L, and small-molecule DOT1L inhibitors show promise as therapeutics for these leukemias. However, the mechanisms underlying this dependency are unclear. We conducted a genome-scale RNAi screen and found that the histone deacetylase SIRT1 is required for the establishment of a heterochromatin-like state around MLL fusion target genes after DOT1L inhibition. DOT1L inhibits chromatin localization of a repressive complex composed of SIRT1 and the H3K9 methyltransferase SUV39H1, thereby maintaining an open chromatin state with elevated H3K9 acetylation and minimal H3K9 methylation at MLL fusion target genes. Furthermore, the combination of SIRT1 activators and DOT1L inhibitors shows enhanced antiproliferative activity against MLL-rearranged leukemia cells. These results indicate that the dynamic interplay between chromatin regulators controlling the activation and repression of gene expression could provide novel opportunities for combination therapy.", + "TAG_DATA": [ + "104, DOT1L {'perturbing_action': 'B-pharmacological inhibition'}", + "105, inhibition. {'perturbing_action': 'I-pharmacological inhibition'}", + "148, DOT1L {'perturbing_action': 'B-pharmacological inhibition'}", + "149, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "156, leukemia {'context': 'I-transformed cells'}", + "157, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "104, DOT1L ['l0']", + "105, inhibition. ['l0']", + "148, DOT1L ['l1', 'l2', 'l3']", + "149, inhibitors ['l1', 'l4', 'l5']", + "156, leukemia ['l2', 'l4', 'l6']", + "157, cells. ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "DOT1L", + "inhibitors" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "leukemia", + "cells." + ] + } + } + ] + }, + { + "PMID": "25799227", + "TEXT": "Focal cortical dysplasia type II (FCDII) is a sporadic developmental malformation of the cerebral cortex characterized by dysmorphic neurons, dyslamination and medically refractory epilepsy. It has been hypothesized that FCD is caused by somatic mutations in affected regions. Here, we used deep whole-exome sequencing (read depth, 412-668×) validated by site-specific amplicon sequencing (100-347,499×) in paired brain-blood DNA from four subjects with FCDII and uncovered a de novo brain somatic mutation, mechanistic target of rapamycin (MTOR) c.7280T>C (p.Leu2427Pro) in two subjects. Deep sequencing of the MTOR gene in an additional 73 subjects with FCDII using hybrid capture and PCR amplicon sequencing identified eight different somatic missense mutations found in multiple brain tissue samples of ten subjects. The identified mutations accounted for 15.6% of all subjects with FCDII studied (12 of 77). The identified mutations induced the hyperactivation of mTOR kinase. Focal cortical expression of mutant MTOR by in utero electroporation in mice was sufficient to disrupt neuronal migration and cause spontaneous seizures and cytomegalic neurons. Inhibition of mTOR with rapamycin suppressed cytomegalic neurons and epileptic seizures. This study provides, to our knowledge, the first evidence that brain somatic activating mutations in MTOR cause FCD and identifies mTOR as a treatment target for intractable epilepsy in FCD.", + "TAG_DATA": [ + "139, Focal {'perturbing_action': 'B-gene gain-of-function'}", + "140, cortical {'perturbing_action': 'I-gene gain-of-function'}", + "141, expression {'perturbing_action': 'I-other'}", + "142, of {'perturbing_action': 'I-other'}", + "143, mutant {'perturbing_action': 'I-other'}", + "144, MTOR {'perturbing_action': 'I-other'}", + "150, mice {'context': 'B-organism'}", + "154, disrupt {'effect': 'B-negative'}", + "156, migration {'phenotype': 'B-migration'}", + "163, neurons. {'context': 'I-cells'}", + "164, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "165, of {'perturbing_action': 'I-pharmacological inhibition'}", + "166, mTOR {'perturbing_action': 'I-pharmacological inhibition'}", + "167, with {'perturbing_action': 'I-pharmacological inhibition'}", + "168, rapamycin {'perturbing_action': 'I-pharmacological inhibition'}", + "170, cytomegalic {'context': 'B-cells'}", + "171, neurons {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "139, Focal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "140, cortical ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "141, expression ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "142, of ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "143, mutant ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "144, MTOR ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "145, by ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "150, mice ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66']", + "154, disrupt ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l68', 'l69']", + "156, migration ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l67', 'l70']", + "163, neurons. ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l68', 'l70', 'l71']", + "164, Inhibition ['l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "165, of ['l72', 'l78', 'l79', 'l80', 'l81', 'l82']", + "166, mTOR ['l73', 'l78', 'l83', 'l84', 'l85', 'l86']", + "167, with ['l74', 'l79', 'l83', 'l87', 'l88', 'l89']", + "168, rapamycin ['l75', 'l80', 'l84', 'l87', 'l90', 'l91']", + "170, cytomegalic ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l76', 'l81', 'l85', 'l88', 'l90', 'l92']", + "171, neurons ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l66', 'l69', 'l71', 'l77', 'l82', 'l86', 'l89', 'l91', 'l92']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Focal", + "cortical" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Focal", + "cortical" + ] + }, + "effect": { + "val": "negative", + "words": [ + "disrupt" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Focal", + "cortical" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Focal", + "cortical" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons.", + "cytomegalic", + "neurons" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "mutant", + "MTOR" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "mutant", + "MTOR" + ] + }, + "effect": { + "val": "negative", + "words": [ + "disrupt" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "mutant", + "MTOR" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "mutant", + "MTOR" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons.", + "cytomegalic", + "neurons" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "disrupt" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "disrupt" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "disrupt" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons.", + "neurons" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "mTOR", + "with", + "rapamycin" + ] + }, + "context": { + "val": "cells", + "words": [ + "cytomegalic", + "neurons" + ] + } + } + ] + }, + { + "PMID": "25799226", + "TEXT": "Cigarette smoking promotes body weight reduction in humans while paradoxically also promoting insulin resistance (IR) and hyperinsulinemia. However, the mechanisms behind these effects are unclear. Here we show that nicotine, a major constituent of cigarette smoke, selectively activates AMP-activated protein kinase α2 (AMPKα2) in adipocytes, which in turn phosphorylates MAP kinase phosphatase-1 (MKP1) at serine 334, initiating its proteasome-dependent degradation. The nicotine-dependent reduction of MKP1 induces the aberrant activation of both p38 mitogen-activated protein kinase and c-Jun N-terminal kinase, leading to increased phosphorylation of insulin receptor substrate 1 (IRS1) at serine 307. Phosphorylation of IRS1 leads to its degradation, protein kinase B inhibition, and the loss of insulin-mediated inhibition of lipolysis. Consequently, nicotine increases lipolysis, which results in body weight reduction, but this increase also elevates the levels of circulating free fatty acids and thus causes IR in insulin-sensitive tissues. These results establish AMPKα2 as an essential mediator of nicotine-induced whole-body IR in spite of reductions in adiposity.", + "TAG_DATA": [ + "44, adipocytes, {'context': 'B-cells'}", + "139, tissues. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "138, insulin-sensitive ['l0']", + "139, tissues. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25730264", + "TEXT": "Detection of cyclic-di-adenosine monophosphate (c-di-AMP), a bacterial second messenger, by the host cytoplasmic surveillance pathway (CSP) is known to elicit type I interferon (IFN) responses, which are crucial to antimicrobial defense. However, the mechanisms and role of c-di-AMP signaling in Mycobacterium tuberculosis virulence remain unclear. Here we show that resistance to tuberculosis requires CSP-mediated detection of c-di-AMP produced by M. tuberculosis and that levels of c-di-AMP modulate the fate of infection. We found that a di-adenylate cyclase (disA or dacA)-overexpressing M. tuberculosis strain that secretes excess c-di-AMP activates the interferon regulatory factor (IRF) pathway with enhanced levels of IFN-β, elicits increased macrophage autophagy, and exhibits substantial virulence attenuation in mice. We show that c-di-AMP-mediated IFN-β induction during M. tuberculosis infection requires stimulator of interferon genes (STING)-signaling. We observed that c-di-AMP induction of IFN-β is independent of the cytosolic nucleic acid receptor cyclic GMP-AMP (cGAMP) synthase (cGAS), but cGAS nevertheless contributes substantially to the overall IFN-β response to M. tuberculosis infection. In sum, our results reveal c-di-AMP to be a key mycobacterial pathogen-associated molecular pattern (PAMP) driving host type I IFN responses and autophagy. These findings suggest that modulating the levels of this small molecule may lead to novel immunotherapeutic strategies against tuberculosis.", + "TAG_DATA": [ + "75, di-adenylate {'perturbing_action': 'B-gene gain-of-function'}", + "77, (disA {'perturbing_action': 'I-gene gain-of-function'}", + "78, or {'perturbing_action': 'I-gene gain-of-function'}", + "79, dacA)-overexpressing {'perturbing_action': 'I-gene gain-of-function'}", + "80, M. {'context': 'B-transformed cells'}", + "81, tuberculosis {'perturbing_action': 'I-other', 'context': 'I-transformed cells'}", + "82, strain {'perturbing_action': 'I-other', 'context': 'I-transformed cells'}", + "99, elicits {'effect': 'B-positive'}", + "100, increased {'effect': 'B-positive'}", + "101, macrophage {'context': 'B-cells'}", + "102, autophagy, {'phenotype': 'B-autophagy'}", + "109, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "75, di-adenylate ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "77, (disA ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "78, or ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "79, dacA)-overexpressing ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "80, M. ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "81, tuberculosis ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "82, strain ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "99, elicits ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58']", + "100, increased ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l60']", + "101, macrophage ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l59', 'l61']", + "102, autophagy, ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l60', 'l61']", + "109, mice. ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "di-adenylate", + "(disA", + "or", + "dacA)-overexpressing" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "M.", + "tuberculosis", + "strain" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "tuberculosis", + "strain" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tuberculosis", + "strain", + "M." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "di-adenylate", + "(disA", + "or", + "dacA)-overexpressing" + ] + }, + "effect": { + "val": "positive", + "words": [ + "elicits", + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "di-adenylate", + "(disA", + "or", + "dacA)-overexpressing" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophage" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "di-adenylate", + "(disA", + "or", + "dacA)-overexpressing" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "di-adenylate", + "(disA", + "or", + "dacA)-overexpressing" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "M.", + "tuberculosis", + "strain" + ] + }, + "effect": { + "val": "positive", + "words": [ + "elicits", + "increased" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "M.", + "tuberculosis", + "strain" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "tuberculosis", + "strain" + ] + }, + "effect": { + "val": "positive", + "words": [ + "elicits", + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "tuberculosis", + "strain" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophage" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "tuberculosis", + "strain" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "tuberculosis", + "strain" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "elicits", + "increased" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophage" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "elicits", + "increased" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "macrophage" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + } + } + ] + }, + { + "PMID": "25686106", + "TEXT": "The ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (AcAc) support mammalian survival during states of energy deficit by serving as alternative sources of ATP. BHB levels are elevated by starvation, caloric restriction, high-intensity exercise, or the low-carbohydrate ketogenic diet. Prolonged fasting reduces inflammation; however, the impact that ketones and other alternative metabolic fuels produced during energy deficits have on the innate immune response is unknown. We report that BHB, but neither AcAc nor the structurally related short-chain fatty acids butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to urate crystals, ATP and lipotoxic fatty acids. BHB did not inhibit caspase-1 activation in response to pathogens that activate the NLR family, CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome and did not affect non-canonical caspase-11, inflammasome activation. Mechanistically, BHB inhibits the NLRP3 inflammasome by preventing K(+) efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 are not dependent on chirality or starvation-regulated mechanisms like AMP-activated protein kinase (AMPK), reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocks the NLRP3 inflammasome without undergoing oxidation in the TCA cycle, and independently of uncoupling protein-2 (UCP2), sirtuin-2 (SIRT2), the G protein-coupled receptor GPR109A or hydrocaboxylic acid receptor 2 (HCAR2). BHB reduces NLRP3 inflammasome-mediated interleukin (IL)-1β and IL-18 production in human monocytes. In vivo, BHB or a ketogenic diet attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases such as Muckle-Wells syndrome, familial cold", + "TAG_DATA": [ + "218, human {'context': 'B-cells'}", + "219, monocytes. {'context': 'I-cells'}", + "220, In {'context': 'B-in vivo'}", + "221, vivo, {'context': 'I-in vivo'}", + "234, mouse {'context': 'B-organism'}", + "235, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "218, human ['l0']", + "219, monocytes. ['l0']", + "220, In ['l1', 'l2', 'l3']", + "221, vivo, ['l1', 'l4', 'l5']", + "234, mouse ['l2', 'l4', 'l6']", + "235, models ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25621899", + "TEXT": "Autism spectrum disorder (ASD) is genetically heterogeneous, with evidence for hundreds of susceptibility loci. Previous microarray and exome-sequencing studies have examined portions of the genome in simplex families (parents and one ASD-affected child) having presumed sporadic forms of the disorder. We used whole-genome sequencing (WGS) of 85 quartet families (parents and two ASD-affected siblings), consisting of 170 individuals with ASD, to generate a comprehensive data resource encompassing all classes of genetic variation (including noncoding variants) and accompanying phenotypes, in apparently familial forms of ASD. By examining de novo and rare inherited single-nucleotide and structural variations in genes previously reported to be associated with ASD or other neurodevelopmental disorders, we found that some (69.4%) of the affected siblings carried different ASD-relevant mutations. These siblings with discordant mutations tended to demonstrate more clinical variability than those who shared a risk variant. Our study emphasizes that substantial genetic heterogeneity exists in ASD, necessitating the use of WGS to delineate all genic and non-genic susceptibility variants in research and in clinical diagnostics.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25599132", + "TEXT": "Chronic-phase HIV and simian immunodeficiency virus (SIV) replication is reduced by as much as 10,000-fold in elite controllers (ECs) compared with typical progressors (TPs), but sufficient viral replication persists in EC tissues to allow viral sequence evolution and induce excess immune activation. Here we show that productive SIV infection in rhesus monkey ECs, but not TPs, is markedly restricted to CD4(+) follicular helper T (TFH) cells, suggesting that these EC monkeys' highly effective SIV-specific CD8(+) T cells can effectively clear productive SIV infection from extrafollicular sites, but their relative exclusion from B cell follicles prevents their elimination of productively infected TFH cells. CD8(+) lymphocyte depletion in EC monkeys resulted in a dramatic re-distribution of productive SIV infection to non-TFH cells, with restriction of productive infection to TFH cells resuming upon CD8(+) T cell recovery. Thus, B cell follicles constitute 'sanctuaries' for persistent SIV replication in the presence of potent anti-viral CD8(+) T cell responses, potentially complicating efforts to cure HIV infection with therapeutic vaccination or T cell immunotherapy.", + "TAG_DATA": [ + "103, lymphocyte {'context': 'I-cells'}", + "106, EC {'context': 'B-organism'}", + "107, monkeys {'context': 'I-organism'}", + "118, non-TFH {'context': 'B-cells'}", + "119, cells, {'context': 'I-cells'}", + "126, TFH {'context': 'B-cells'}", + "127, cells {'context': 'I-cells'}", + "130, CD8(+) {'context': 'B-cells'}", + "131, T {'context': 'I-cells'}", + "132, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "103, lymphocyte ['l0', 'l1', 'l2', 'l3', 'l4']", + "106, EC ['l0', 'l5', 'l6', 'l7', 'l8']", + "107, monkeys ['l1', 'l5', 'l9', 'l10']", + "118, non-TFH ['l2', 'l6', 'l9', 'l11', 'l12']", + "119, cells, ['l3', 'l7', 'l10', 'l11']", + "126, TFH ['l13', 'l14', 'l15', 'l16']", + "127, cells ['l4', 'l8', 'l12', 'l13', 'l17', 'l18', 'l19']", + "130, CD8(+) ['l14', 'l17', 'l20', 'l21']", + "131, T ['l15', 'l18', 'l20', 'l22']", + "132, cell ['l16', 'l19', 'l21', 'l22']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25581519", + "TEXT": "Type 2 diabetes is a major health problem worldwide, and one of its key features is the inability of elevated glucose to stimulate the release of sufficient amounts of insulin from pancreatic beta cells to maintain normal blood glucose levels. New therapeutic strategies to improve beta cell function are therefore believed to be beneficial. Here we demonstrate that the short-chain fatty acid receptors FFA2 (encoded by FFAR2) and FFA3 (encoded by FFAR3) are expressed in mouse and human pancreatic beta cells and mediate an inhibition of insulin secretion by coupling to Gi-type G proteins. We also provide evidence that mice with dietary-induced obesity and type 2 diabetes, as compared to non-obese control mice, have increased local formation by pancreatic islets of acetate, an endogenous agonist of FFA2 and FFA3, as well as increased systemic levels. This elevation may contribute to the insufficient capacity of beta cells to respond to hyperglycemia in obese states. Indeed, we found that genetic deletion of both receptors, either on the whole-body level or specifically in pancreatic beta cells, leads to greater insulin secretion and a profound improvement of glucose tolerance when mice are on a high-fat diet compared to controls. On the other hand, deletion of Ffar2 and Ffar3 in intestinal cells did not alter glucose tolerance in diabetic animals, suggesting these receptors act in a cell-autonomous manner in beta cells to regulate insulin secretion. In summary, under diabetic conditions elevated acetate acts on FFA2 and FFA3 to inhibit proper glucose-stimulated insulin secretion, and we expect antagonists of FFA2 and FFA3 to improve insulin secretion in type 2 diabetes.", + "TAG_DATA": [ + "99, mice {'context': 'B-organism'}", + "157, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "158, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "159, of {'perturbing_action': 'I-gene loss-of-function'}", + "160, both {'perturbing_action': 'I-gene loss-of-function'}", + "161, receptors, {'perturbing_action': 'I-gene loss-of-function'}", + "170, pancreatic {'context': 'B-cells'}", + "171, beta {'context': 'I-cells'}", + "172, cells, {'context': 'I-cells'}", + "186, mice {'context': 'B-organism'}", + "199, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "200, of {'perturbing_action': 'I-gene loss-of-function'}", + "201, Ffar2 {'perturbing_action': 'I-gene loss-of-function'}", + "202, and {'perturbing_action': 'I-gene loss-of-function'}", + "203, Ffar3 {'perturbing_action': 'I-gene loss-of-function'}", + "205, intestinal {'context': 'B-cells'}", + "206, cells {'context': 'I-cells'}", + "213, diabetic {'context': 'B-organism'}", + "214, animals, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "157, genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "158, deletion ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "159, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "160, both ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "161, receptors, ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "170, pancreatic ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "171, beta ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "172, cells, ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "186, mice ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "199, deletion ['l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "200, of ['l36', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "201, Ffar2 ['l37', 'l44', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "202, and ['l38', 'l45', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "203, Ffar3 ['l39', 'l46', 'l52', 'l57', 'l62', 'l63', 'l64', 'l65']", + "205, intestinal ['l40', 'l47', 'l53', 'l58', 'l62', 'l66', 'l67', 'l68']", + "206, cells ['l41', 'l48', 'l54', 'l59', 'l63', 'l66', 'l69', 'l70']", + "213, diabetic ['l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l71']", + "214, animals, ['l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l71']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "both", + "receptors,", + "Ffar2", + "and", + "Ffar3" + ] + }, + "context": { + "val": "cells", + "words": [ + "pancreatic", + "beta", + "cells,", + "intestinal", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "both", + "receptors,", + "Ffar2", + "and", + "Ffar3" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "diabetic", + "animals," + ] + } + } + ] + }, + { + "PMID": "25581517", + "TEXT": "Mesenchymal responses are an essential aspect of tissue repair. Failure to terminate this repair process correctly, however, results in fibrosis and organ dysfunction. Therapies that block fibrosis and restore tissue homeostasis are not yet available for clinical use. Here we characterize the nuclear receptor NR4A1 as an endogenous inhibitor of transforming growth factor-β (TGF-β) signaling and as a potential target for anti-fibrotic therapies. NR4A1 recruits a repressor complex comprising SP1, SIN3A, CoREST, LSD1, and HDAC1 to TGF-β target genes, thereby limiting pro-fibrotic TGF-β effects. Even though temporary upregulation of TGF-β in physiologic wound healing induces NR4A1 expression and thereby creates a negative feedback loop, the persistent activation of TGF-β signaling in fibrotic diseases uses AKT- and HDAC-dependent mechanisms to inhibit NR4A1 expression and activation. Small-molecule NR4A1 agonists can overcome this lack of active NR4A1 and inhibit experimentally-induced skin, lung, liver, and kidney fibrosis in mice. Our data demonstrate a regulatory role of NR4A1 in TGF-β signaling and fibrosis, providing the first proof of concept for targeting NR4A1 in fibrotic diseases.", + "TAG_DATA": [ + "124, Small-molecule {'perturbing_action': 'B-pharmacological augmentation'}", + "125, NR4A1 {'perturbing_action': 'I-pharmacological augmentation'}", + "126, agonists {'perturbing_action': 'I-pharmacological augmentation'}", + "137, skin, {'context': 'B-tissue/organ'}", + "138, lung, {'context': 'I-tissue/organ'}", + "139, liver, {'context': 'I-tissue/organ'}", + "140, and {'context': 'I-tissue/organ'}", + "141, kidney {'context': 'I-tissue/organ'}", + "144, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "124, Small-molecule ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "125, NR4A1 ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "126, agonists ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "137, skin, ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "138, lung, ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "139, liver, ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "140, and ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "141, kidney ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "144, mice. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Small-molecule", + "NR4A1", + "agonists" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skin,", + "lung,", + "liver,", + "and", + "kidney" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Small-molecule", + "NR4A1", + "agonists" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "25559344", + "TEXT": "The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver. However, unlike systemic agonism, we find that Fex reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue (WAT). These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome.", + "TAG_DATA": [ + "50, gut-restricted {'perturbing_action': 'B-pharmacological augmentation'}", + "51, FXR {'perturbing_action': 'I-pharmacological augmentation'}", + "52, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "53, fexaramine {'perturbing_action': 'I-pharmacological augmentation'}", + "54, (Fex) {'perturbing_action': 'I-pharmacological augmentation'}", + "79, liver. {'context': 'B-tissue/organ'}", + "104, white {'context': 'B-tissue/organ'}", + "105, adipose {'context': 'I-tissue/organ'}", + "106, tissue {'context': 'I-tissue/organ'}", + "107, (WAT). {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "50, gut-restricted ['l0', 'l1', 'l2', 'l3', 'l4']", + "51, FXR ['l0', 'l5', 'l6', 'l7', 'l8']", + "52, agonist ['l1', 'l5', 'l9', 'l10', 'l11']", + "53, fexaramine ['l2', 'l6', 'l9', 'l12', 'l13']", + "54, (Fex) ['l3', 'l7', 'l10', 'l12', 'l14']", + "79, liver. ['l4', 'l8', 'l11', 'l13', 'l14']", + "104, white ['l15', 'l16', 'l17']", + "105, adipose ['l15', 'l18', 'l19']", + "106, tissue ['l16', 'l18', 'l20']", + "107, (WAT). ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "gut-restricted", + "FXR", + "agonist", + "fexaramine", + "(Fex)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver." + ] + } + } + ] + }, + { + "PMID": "25485912", + "TEXT": "The hepatic Ashwell-Morell receptor (AMR) can bind and remove desialylated platelets. Here we demonstrate that platelets become desialylated as they circulate and age in blood. Binding of desialylated platelets to the AMR induces hepatic expression of thrombopoietin (TPO) mRNA and protein, thereby regulating platelet production. Endocytic AMR controls TPO expression through Janus kinase 2 (JAK2) and the acute phase response signal transducer and activator of transcription 3 (STAT3) in vivo and in vitro. Recognition of this newly identified physiological feedback mechanism illuminates the pathophysiology of platelet diseases, such as essential thrombocythemia and immune thrombocytopenia, and contributes to an understanding of the mechanisms of thrombocytopenia observed with JAK1/2 inhibition.", + "TAG_DATA": [ + "68, in {'context': 'B-in vivo'}", + "69, vivo {'context': 'I-in vivo'}", + "71, in {'context': 'B-in vitro'}", + "72, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "68, in ['l0', 'l1', 'l2']", + "69, vivo ['l0', 'l3', 'l4']", + "71, in ['l1', 'l3', 'l5']", + "72, vitro. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25473917", + "TEXT": "Frontotemporal dementia (FTD) is a neurodegenerative disease that causes social dysfunction and other symptoms. A new study suggests that social dysfunction in FTD is due to decreased microRNA-124 expression and resulting changes in glutamate receptor composition in the prefrontal cortex.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25473916", + "TEXT": "Diffuse intrinsic pontine glioma is a uniformly lethal malignant tumor of infancy with no effective therapies. A new study reveals that inhibition of JMJD3 has robust antitumor activity in diffuse intrinsic pontine glioma xenografts.", + "TAG_DATA": [ + "21, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "22, of {'perturbing_action': 'I-pharmacological inhibition'}", + "23, JMJD3 {'perturbing_action': 'I-pharmacological inhibition'}", + "29, diffuse {'context': 'B-xenograft'}", + "30, intrinsic {'context': 'I-xenograft'}", + "31, pontine {'context': 'I-xenograft'}", + "32, glioma {'context': 'I-xenograft'}", + "33, xenografts. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "21, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "22, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "23, JMJD3 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "29, diffuse ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "30, intrinsic ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "31, pontine ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "32, glioma ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "33, xenografts. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "JMJD3" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "diffuse", + "intrinsic", + "pontine", + "glioma", + "xenografts." + ] + } + } + ] + }, + { + "PMID": "25419706", + "TEXT": "We have identified a rare coding mutation, T835M (rs137875858), in the UNC5C netrin receptor gene that segregated with disease in an autosomal dominant pattern in two families enriched for late-onset Alzheimer's disease and that was associated with disease across four large case-control cohorts (odds ratio = 2.15, Pmeta = 0.0095). T835M alters a conserved residue in the hinge region of UNC5C, and in vitro studies demonstrate that this mutation leads to increased cell death in human HEK293T cells and in rodent neurons. Furthermore, neurons expressing T835M UNC5C are more susceptible to cell death from multiple neurotoxic stimuli, including β-amyloid (Aβ), glutamate and staurosporine. On the basis of these data and the enriched hippocampal expression of UNC5C in the adult nervous system, we propose that one possible mechanism in which T835M UNC5C contributes to the risk of Alzheimer's disease is by increasing susceptibility to neuronal cell death, particularly in vulnerable regions of the Alzheimer's disease brain.", + "TAG_DATA": [ + "62, in {'context': 'B-in vitro'}", + "63, vitro {'context': 'I-in vitro'}", + "69, leads {'effect': 'B-positive'}", + "70, to {'effect': 'I-positive'}", + "71, increased {'effect': 'B-positive'}", + "72, cell {'phenotype': 'B-cell death'}", + "73, death {'phenotype': 'I-cell death'}", + "75, human {'context': 'B-cells'}", + "76, HEK293T {'context': 'I-cells'}", + "77, cells {'context': 'I-cells'}", + "80, rodent {'context': 'B-cells'}", + "81, neurons. {'context': 'I-cells'}", + "83, neurons {'context': 'B-cells'}", + "88, more {'effect': 'B-positive'}", + "89, susceptible {'effect': 'I-positive'}", + "90, to {'effect': 'I-positive'}", + "91, cell {'phenotype': 'B-cell death'}", + "92, death {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "62, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "63, vitro ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "69, leads ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "70, to ['l2', 'l12', 'l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "71, increased ['l3', 'l13', 'l22', 'l29', 'l36', 'l37', 'l38', 'l39', 'l40']", + "72, cell ['l4', 'l14', 'l23', 'l30', 'l36', 'l41', 'l42', 'l43', 'l44']", + "73, death ['l5', 'l15', 'l24', 'l31', 'l37', 'l41', 'l45', 'l46', 'l47']", + "75, human ['l6', 'l16', 'l25', 'l32', 'l38', 'l42', 'l45', 'l48', 'l49', 'l50']", + "76, HEK293T ['l7', 'l17', 'l26', 'l33', 'l39', 'l43', 'l46', 'l48', 'l51', 'l52', 'l53']", + "77, cells ['l8', 'l18', 'l27', 'l34', 'l40', 'l44', 'l47', 'l49', 'l51']", + "80, rodent ['l9', 'l19', 'l52', 'l54']", + "81, neurons. ['l10', 'l20', 'l28', 'l35', 'l50', 'l53', 'l54']", + "83, neurons ['l55', 'l56', 'l57', 'l58', 'l59']", + "88, more ['l55', 'l60', 'l61', 'l62', 'l63']", + "89, susceptible ['l56', 'l60', 'l64', 'l65', 'l66']", + "90, to ['l57', 'l61', 'l64', 'l67', 'l68']", + "91, cell ['l58', 'l62', 'l65', 'l67', 'l69']", + "92, death ['l59', 'l63', 'l66', 'l68', 'l69']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "leads", + "to", + "increased" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "leads", + "to", + "increased", + "more", + "susceptible" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "leads", + "to", + "increased", + "more", + "susceptible" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "HEK293T", + "cells", + "neurons.", + "neurons" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "HEK293T", + "cells", + "neurons" + ] + } + } + ] + }, + { + "PMID": "25419705", + "TEXT": "Renal fibrosis is the histological manifestation of a progressive, usually irreversible process causing chronic and end-stage kidney disease. We performed genome-wide transcriptome studies of a large cohort (n = 95) of normal and fibrotic human kidney tubule samples followed by systems and network analyses and identified inflammation and metabolism as the top dysregulated pathways in the diseased kidneys. In particular, we found that humans and mouse models with tubulointerstitial fibrosis had lower expression of key enzymes and regulators of fatty acid oxidation (FAO) and higher intracellular lipid deposition compared to controls. In vitro experiments indicated that inhibition of FAO in tubule epithelial cells caused ATP depletion, cell death, dedifferentiation and intracellular lipid deposition, phenotypes observed in fibrosis. In contrast, restoring fatty acid metabolism by genetic or pharmacological methods protected mice from tubulointerstitial fibrosis. Our results raise the possibility that correcting the metabolic defect in FAO may be useful for preventing and treating chronic kidney disease.", + "TAG_DATA": [ + "91, In {'context': 'B-in vitro'}", + "92, vitro {'context': 'I-in vitro'}", + "96, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "97, of {'perturbing_action': 'I-pharmacological inhibition'}", + "98, FAO {'perturbing_action': 'I-pharmacological inhibition'}", + "100, tubule {'context': 'B-cells'}", + "101, epithelial {'context': 'I-cells'}", + "102, cells {'context': 'I-cells'}", + "103, caused {'effect': 'B-positive'}", + "106, cell {'phenotype': 'B-cell death'}", + "107, death, {'phenotype': 'I-cell death'}", + "108, dedifferentiation {'phenotype': 'B-differentiation'}", + "129, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "91, In ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "92, vitro ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "96, inhibition ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "97, of ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "98, FAO ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "100, tubule ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "101, epithelial ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "102, cells ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "103, caused ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "106, cell ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "107, death, ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "108, dedifferentiation ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "FAO" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "dedifferentiation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "FAO" + ] + }, + "context": { + "val": "cells", + "words": [ + "tubule", + "epithelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "FAO" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "FAO" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "FAO" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "dedifferentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "tubule", + "epithelial", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "tubule", + "epithelial", + "cells" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "tubule", + "epithelial", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "dedifferentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "dedifferentiation" + ] + } + } + ] + }, + { + "PMID": "25401693", + "TEXT": "Pediatric brainstem gliomas often harbor oncogenic K27M mutation of histone H3.3. Here we show that GSKJ4 pharmacologic inhibition of K27 demethylase JMJD3 increases cellular H3K27 methylation in K27M tumor cells and demonstrate potent antitumor activity both in vitro against K27M cells and in vivo against K27M xenografts. Our results demonstrate that increasing H3K27 methylation by inhibiting K27 demethylase is a valid therapeutic strategy for treating K27M-expressing brainstem glioma.", + "TAG_DATA": [ + "15, GSKJ4 {'perturbing_action': 'B-pharmacological inhibition'}", + "16, pharmacologic {'perturbing_action': 'I-pharmacological inhibition'}", + "17, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "18, of {'perturbing_action': 'I-pharmacological inhibition'}", + "19, K27 {'perturbing_action': 'I-pharmacological inhibition'}", + "20, demethylase {'perturbing_action': 'I-pharmacological inhibition'}", + "21, JMJD3 {'perturbing_action': 'I-pharmacological inhibition'}", + "27, K27M {'context': 'B-transformed cells'}", + "28, tumor {'context': 'I-transformed cells'}", + "29, cells {'context': 'I-transformed cells'}", + "36, in {'context': 'B-in vitro'}", + "37, vitro {'context': 'I-in vitro'}", + "39, K27M {'context': 'B-transformed cells'}", + "40, cells {'context': 'I-transformed cells'}", + "42, in {'context': 'B-in vivo'}", + "43, vivo {'context': 'I-in vivo'}", + "45, K27M {'context': 'B-xenograft'}", + "46, xenografts. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "15, GSKJ4 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "16, pharmacologic ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "17, inhibition ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "18, of ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "19, K27 ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "20, demethylase ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "21, JMJD3 ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "27, K27M ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71']", + "28, tumor ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l72']", + "29, cells ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l72']", + "36, in ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l73', 'l74', 'l75']", + "37, vitro ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l76', 'l77']", + "39, K27M ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l76', 'l78', 'l79']", + "40, cells ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l77', 'l78']", + "42, in ['l80', 'l81', 'l82']", + "43, vivo ['l79', 'l80', 'l83', 'l84']", + "45, K27M ['l81', 'l83', 'l85']", + "46, xenografts. ['l82', 'l84', 'l85']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "GSKJ4", + "pharmacologic", + "inhibition", + "of", + "K27", + "demethylase", + "JMJD3" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "K27M", + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "GSKJ4", + "pharmacologic", + "inhibition", + "of", + "K27", + "demethylase", + "JMJD3" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "25401691", + "TEXT": "Brown fat activates uncoupled respiration in response to cold temperature and contributes to systemic metabolic homeostasis. To date, the metabolic action of brown fat has been primarily attributed to its role in fuel oxidation and uncoupling protein 1 (UCP1)-mediated thermogenesis. Whether brown fat engages other tissues through secreted factors remains largely unexplored. Here we show that neuregulin 4 (Nrg4), a member of the epidermal growth factor (EGF) family of extracellular ligands, is highly expressed in adipose tissues, enriched in brown fat and markedly increased during brown adipocyte differentiation. Adipose tissue Nrg4 expression was reduced in rodent and human obesity. Gain- and loss-of-function studies in mice demonstrated that Nrg4 protects against diet-induced insulin resistance and hepatic steatosis through attenuating hepatic lipogenic signaling. Mechanistically, Nrg4 activates ErbB3 and ErbB4 signaling in hepatocytes and negatively regulates de novo lipogenesis mediated by LXR and SREBP1c in a cell-autonomous manner. These results establish Nrg4 as a brown fat-enriched endocrine factor with therapeutic potential for the treatment of obesity-associated disorders, including type 2 diabetes and nonalcoholic fatty liver disease (NAFLD).", + "TAG_DATA": [ + "104, mice {'context': 'B-organism'}", + "129, hepatocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25362255", + "TEXT": "Increasing evidence points to a role for the immune system in the regulation of metabolism. Two new studies in mice indicate treatment with interleukin-22 restores mucosal immunity in diabetes and alleviates metabolic disease, resulting in improved glycemic control.", + "TAG_DATA": [ + "19, mice {'context': 'B-organism'}", + "28, diabetes {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "19, mice ['l0']", + "28, diabetes ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25362254", + "TEXT": "Peripheral artery disease (PAD) generates tissue ischemia through arterial occlusions and insufficient collateral vessel formation. Vascular insufficiency in PAD occurs despite higher circulating levels of vascular endothelial growth factor A (VEGF-A), a key regulator of angiogenesis. Here we show that clinical PAD is associated with elevated levels of an antiangiogenic VEGF-A splice isoform (VEGF-A165b) and a corresponding reduction in levels of the proangiogenic VEGF-A165a splice isoform. In mice, VEGF-A165b expression was upregulated by conditions associated with impaired limb revascularization, including leptin deficiency, diet-induced obesity, genetic ablation of the secreted frizzled-related protein 5 (Sfrp5) adipokine and transgenic overexpression of Wnt5a in myeloid cells. In a mouse model of PAD, delivery of VEGF-A165b inhibited revascularization of ischemic hind limbs, whereas treatment with an isoform-specific neutralizing antibody reversed impaired revascularization caused by metabolic dysfunction or perturbations in the Wnt5a-Sfrp5 regulatory system. These results indicate that inflammation-driven expression of the antiangiogenic VEGF-A isoform can contribute to impaired collateralization in ischemic cardiovascular disease.", + "TAG_DATA": [ + "67, mice, {'context': 'B-organism'}", + "84, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "85, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "86, of {'perturbing_action': 'I-gene loss-of-function'}", + "87, the {'perturbing_action': 'I-gene loss-of-function'}", + "88, secreted {'perturbing_action': 'I-gene loss-of-function'}", + "89, frizzled-related {'perturbing_action': 'I-gene loss-of-function'}", + "90, protein {'perturbing_action': 'I-gene loss-of-function'}", + "91, 5 {'perturbing_action': 'I-gene loss-of-function'}", + "92, (Sfrp5) {'perturbing_action': 'I-gene loss-of-function'}", + "93, adipokine {'perturbing_action': 'I-gene loss-of-function'}", + "95, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "96, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "97, of {'perturbing_action': 'I-gene gain-of-function'}", + "98, Wnt5a {'perturbing_action': 'I-gene gain-of-function'}", + "100, myeloid {'context': 'B-cells'}", + "101, cells. {'context': 'I-cells'}", + "104, mouse {'context': 'B-organism'}", + "105, model {'context': 'I-organism'}", + "115, hind {'context': 'B-tissue/organ'}", + "116, limbs, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "84, genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "85, ablation ['l0', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "86, of ['l1', 'l18', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "87, the ['l2', 'l19', 'l35', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "88, secreted ['l3', 'l20', 'l36', 'l52', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "89, frizzled-related ['l4', 'l21', 'l37', 'l53', 'l68', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "90, protein ['l5', 'l22', 'l38', 'l54', 'l69', 'l83', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "91, 5 ['l6', 'l23', 'l39', 'l55', 'l70', 'l84', 'l97', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "92, (Sfrp5) ['l7', 'l24', 'l40', 'l56', 'l71', 'l85', 'l98', 'l110', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "93, adipokine ['l8', 'l25', 'l41', 'l57', 'l72', 'l86', 'l99', 'l111', 'l122', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "95, transgenic ['l9', 'l26', 'l42', 'l58', 'l73', 'l87', 'l100', 'l112', 'l123', 'l133', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151']", + "96, overexpression ['l10', 'l27', 'l43', 'l59', 'l74', 'l88', 'l101', 'l113', 'l124', 'l134', 'l143', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159']", + "97, of ['l11', 'l28', 'l44', 'l60', 'l75', 'l89', 'l102', 'l114', 'l125', 'l135', 'l144', 'l152', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166']", + "98, Wnt5a ['l12', 'l29', 'l45', 'l61', 'l76', 'l90', 'l103', 'l115', 'l126', 'l136', 'l145', 'l153', 'l160', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "100, myeloid ['l13', 'l30', 'l46', 'l62', 'l77', 'l91', 'l104', 'l116', 'l127', 'l137', 'l146', 'l154', 'l161', 'l167', 'l173', 'l174', 'l175', 'l176']", + "101, cells. ['l14', 'l31', 'l47', 'l63', 'l78', 'l92', 'l105', 'l117', 'l128', 'l138', 'l147', 'l155', 'l162', 'l168', 'l173', 'l177', 'l178']", + "104, mouse ['l15', 'l32', 'l48', 'l64', 'l79', 'l93', 'l106', 'l118', 'l129', 'l139', 'l148', 'l156', 'l163', 'l169', 'l174', 'l177', 'l179', 'l180', 'l181']", + "105, model ['l16', 'l33', 'l49', 'l65', 'l80', 'l94', 'l107', 'l119', 'l130', 'l140', 'l149', 'l157', 'l164', 'l170', 'l175', 'l178', 'l179', 'l182', 'l183']", + "115, hind ['l50', 'l66', 'l81', 'l95', 'l108', 'l120', 'l131', 'l141', 'l150', 'l158', 'l165', 'l171', 'l180', 'l182', 'l184']", + "116, limbs, ['l17', 'l34', 'l51', 'l67', 'l82', 'l96', 'l109', 'l121', 'l132', 'l142', 'l151', 'l159', 'l166', 'l172', 'l176', 'l181', 'l183', 'l184']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "the", + "secreted", + "frizzled-related", + "protein", + "5", + "(Sfrp5)", + "adipokine" + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "the", + "secreted", + "frizzled-related", + "protein", + "5", + "(Sfrp5)", + "adipokine" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "the", + "secreted", + "frizzled-related", + "protein", + "5", + "(Sfrp5)", + "adipokine" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "limbs,", + "hind" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "overexpression", + "of", + "Wnt5a" + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "overexpression", + "of", + "Wnt5a" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "overexpression", + "of", + "Wnt5a" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hind", + "limbs," + ] + } + } + ] + }, + { + "PMID": "25362253", + "TEXT": "In type 2 diabetes, hyperglycemia is present when an increased demand for insulin, typically due to insulin resistance, is not met as a result of progressive pancreatic beta cell dysfunction. This defect in beta cell activity is typically characterized by impaired insulin biosynthesis and secretion, usually accompanied by oxidative and endoplasmic reticulum (ER) stress. We demonstrate that multiple inflammatory cytokines elevated in diabetic pancreatic islets induce beta cell oxidative and ER stress, with interleukin-23 (IL-23), IL-24 and IL-33 being the most potent. Conversely, we show that islet-endogenous and exogenous IL-22, by regulating oxidative stress pathways, suppresses oxidative and ER stress caused by cytokines or glucolipotoxicity in mouse and human beta cells. In obese mice, antibody neutralization of IL-23 or IL-24 partially reduced beta cell ER stress and improved glucose tolerance, whereas IL-22 administration modulated oxidative stress regulatory genes in islets, suppressed ER stress and inflammation, promoted secretion of high-quality efficacious insulin and fully restored glucose homeostasis followed by restitution of insulin sensitivity. Thus, therapeutic manipulation of immune regulators of beta cell stress reverses the hyperglycemia central to diabetes pathology.", + "TAG_DATA": [ + "106, mouse {'context': 'B-cells'}", + "107, and {'context': 'I-cells'}", + "108, human {'context': 'I-cells'}", + "109, beta {'context': 'I-cells'}", + "110, cells. {'context': 'I-cells'}", + "112, obese {'context': 'B-organism'}", + "113, mice, {'context': 'I-organism'}", + "114, antibody {'perturbing_action': 'B-rnai/knockdown'}", + "122, beta {'context': 'B-cells'}", + "123, cell {'context': 'I-cells'}", + "139, islets, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "106, mouse ['l0', 'l1', 'l2', 'l3']", + "107, and ['l0', 'l4', 'l5', 'l6']", + "108, human ['l1', 'l4', 'l7', 'l8']", + "109, beta ['l2', 'l5', 'l7', 'l9']", + "110, cells. ['l3', 'l6', 'l8', 'l9']", + "112, obese ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "113, mice, ['l10', 'l16', 'l17']", + "114, antibody ['l11', 'l18', 'l19', 'l20', 'l21', 'l22']", + "115, neutralization ['l12', 'l18', 'l23', 'l24', 'l25', 'l26']", + "116, of ['l13', 'l19', 'l23', 'l27', 'l28', 'l29']", + "122, beta ['l14', 'l16', 'l20', 'l24', 'l27', 'l30']", + "123, cell ['l15', 'l17', 'l21', 'l25', 'l28', 'l30']", + "139, islets, ['l22', 'l26', 'l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "obese" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antibody" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antibody" + ] + }, + "context": { + "val": "cells", + "words": [ + "beta", + "cell", + "islets," + ] + } + } + ] + }, + { + "PMID": "25344740", + "TEXT": "Pulmonary hypertension (PH) is characterized by increased proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs). Forkhead box O (FoxO) transcription factors are key regulators of cellular proliferation. Here we show that in pulmonary vessels and PASMCs of human and experimental PH lungs, FoxO1 expression is downregulated and FoxO1 is inactivated via phosphorylation and nuclear exclusion. These findings could be reproduced using ex vivo exposure of PASMCs to growth factors and inflammatory cytokines. Pharmacological inhibition and genetic ablation of FoxO1 in smooth muscle cells reproduced PH features in vitro and in vivo. Either pharmacological reconstitution of FoxO1 activity using intravenous or inhaled paclitaxel, or reconstitution of the transcriptional activity of FoxO1 by gene therapy, restored the physiologically quiescent PASMC phenotype in vitro, linked to changes in cell cycle control and bone morphogenic protein receptor type 2 (BMPR2) signaling, and reversed vascular remodeling and right-heart hypertrophy in vivo. Thus, PASMC FoxO1 is a critical integrator of multiple signaling pathways driving PH, and reconstitution of FoxO1 activity offers a potential therapeutic option for PH.", + "TAG_DATA": [ + "68, PASMCs {'context': 'B-cells'}", + "78, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "79, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "80, of {'perturbing_action': 'I-gene loss-of-function'}", + "81, FoxO1 {'perturbing_action': 'I-gene loss-of-function'}", + "83, smooth {'context': 'B-cells'}", + "84, muscle {'context': 'I-cells'}", + "85, cells {'context': 'I-cells'}", + "89, in {'context': 'B-in vitro'}", + "90, vitro {'context': 'I-in vitro'}", + "92, in {'context': 'B-in vivo'}", + "93, vivo. {'context': 'I-in vivo'}", + "95, pharmacological {'perturbing_action': 'B-gene gain-of-function'}", + "96, reconstitution {'perturbing_action': 'I-gene loss-of-function'}", + "97, of {'perturbing_action': 'I-gene gain-of-function'}", + "98, FoxO1 {'perturbing_action': 'I-gene gain-of-function'}", + "99, activity {'perturbing_action': 'I-gene gain-of-function'}", + "100, using {'perturbing_action': 'I-gene loss-of-function'}", + "111, of {'perturbing_action': 'I-gene gain-of-function'}", + "112, FoxO1 {'perturbing_action': 'I-gene gain-of-function'}", + "120, PASMC {'context': 'B-cells'}", + "122, in {'context': 'B-in vitro'}", + "123, vitro, {'context': 'I-in vitro'}", + "147, in {'context': 'B-in vivo'}", + "148, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "68, PASMCs ['l0', 'l1']", + "78, genetic ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "79, ablation ['l2', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "80, of ['l3', 'l14', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "81, FoxO1 ['l4', 'l15', 'l25', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "83, smooth ['l5', 'l16', 'l26', 'l35', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "84, muscle ['l0', 'l6', 'l17', 'l27', 'l36', 'l43', 'l49', 'l50', 'l51', 'l52']", + "85, cells ['l1', 'l7', 'l18', 'l28', 'l37', 'l44', 'l49', 'l53', 'l54']", + "89, in ['l8', 'l19', 'l29', 'l38', 'l45', 'l50', 'l53', 'l55']", + "90, vitro ['l9', 'l20', 'l30', 'l39', 'l46', 'l51', 'l54', 'l55']", + "92, in ['l10', 'l21', 'l31', 'l40', 'l47', 'l56']", + "93, vivo. ['l11', 'l22', 'l32', 'l41', 'l48', 'l52', 'l56']", + "95, pharmacological ['l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "96, reconstitution ['l57', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "97, of ['l58', 'l68', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "98, FoxO1 ['l59', 'l69', 'l77', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "99, activity ['l60', 'l70', 'l78', 'l85', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "100, using ['l61', 'l71', 'l79', 'l86', 'l92', 'l98', 'l99', 'l100', 'l101', 'l102']", + "101, intravenous ['l12', 'l23', 'l33', 'l42', 'l62', 'l72', 'l80', 'l87', 'l93', 'l98', 'l103', 'l104', 'l105', 'l106']", + "103, inhaled ['l13', 'l24', 'l34', 'l63', 'l73', 'l81', 'l88', 'l94', 'l99', 'l103', 'l107', 'l108', 'l109']", + "109, transcriptional ['l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "110, activity ['l110', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "111, of ['l111', 'l118', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "112, FoxO1 ['l112', 'l119', 'l125', 'l131', 'l132', 'l133', 'l134', 'l135']", + "120, PASMC ['l64', 'l74', 'l82', 'l89', 'l95', 'l100', 'l104', 'l107', 'l113', 'l120', 'l126', 'l131', 'l136', 'l137', 'l138', 'l139']", + "122, in ['l65', 'l75', 'l83', 'l90', 'l96', 'l101', 'l105', 'l108', 'l114', 'l121', 'l127', 'l132', 'l136', 'l140', 'l141', 'l142']", + "123, vitro, ['l66', 'l76', 'l84', 'l91', 'l97', 'l102', 'l106', 'l109', 'l115', 'l122', 'l128', 'l133', 'l137', 'l140', 'l143']", + "147, in ['l116', 'l123', 'l129', 'l134', 'l138', 'l141', 'l144']", + "148, vivo. ['l67', 'l117', 'l124', 'l130', 'l135', 'l139', 'l142', 'l143', 'l144']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "FoxO1", + "reconstitution", + "using" + ] + }, + "context": { + "val": "cells", + "words": [ + "smooth", + "muscle", + "cells", + "PASMC" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "FoxO1", + "reconstitution", + "using" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro", + "vitro," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "FoxO1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "pharmacological", + "of", + "FoxO1", + "activity" + ] + }, + "context": { + "val": "cells", + "words": [ + "PASMC" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "pharmacological", + "of", + "FoxO1", + "activity" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "pharmacological", + "of", + "FoxO1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo.", + "in" + ] + } + } + ] + }, + { + "PMID": "25329329", + "TEXT": "The protein cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of immune responses, and its loss causes fatal autoimmunity in mice. We studied a large family in which five individuals presented with a complex, autosomal dominant immune dysregulation syndrome characterized by hypogammaglobulinemia, recurrent infections and multiple autoimmune clinical features. We identified a heterozygous nonsense mutation in exon 1 of CTLA4. Screening of 71 unrelated patients with comparable clinical phenotypes identified five additional families (nine individuals) with previously undescribed splice site and missense mutations in CTLA4. Clinical penetrance was incomplete (eight adults of a total of 19 genetically proven CTLA4 mutation carriers were considered unaffected). However, CTLA-4 protein expression was decreased in regulatory T cells (Treg cells) in both patients and carriers with CTLA4 mutations. Whereas Treg cells were generally present at elevated numbers in these individuals, their suppressive function, CTLA-4 ligand binding and transendocytosis of CD80 were impaired. Mutations in CTLA4 were also associated with decreased circulating B cell numbers. Taken together, mutations in CTLA4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding result in disrupted T and B cell homeostasis and a complex immune dysregulation syndrome.", + "TAG_DATA": [ + "113, regulatory {'context': 'B-cells'}", + "114, T {'context': 'I-cells'}", + "115, cells {'context': 'I-cells'}", + "117, cells) {'context': 'I-cells'}", + "124, CTLA4 {'perturbing_action': 'B-other'}", + "125, mutations. {'perturbing_action': 'I-other'}", + "127, Treg {'context': 'B-cells'}", + "128, cells {'context': 'I-cells'}", + "159, B {'context': 'B-cells'}", + "160, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "113, regulatory ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "114, T ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "115, cells ['l1', 'l7', 'l13', 'l14', 'l15']", + "116, (Treg ['l2', 'l8', 'l13', 'l16', 'l17']", + "117, cells) ['l3', 'l9', 'l14', 'l16']", + "124, CTLA4 ['l4', 'l10', 'l18', 'l19', 'l20']", + "125, mutations. ['l5', 'l11', 'l15', 'l17', 'l18', 'l21', 'l22']", + "127, Treg ['l19', 'l21', 'l23']", + "128, cells ['l6', 'l12', 'l20', 'l22', 'l23']", + "159, B ['l24']", + "160, cell ['l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "regulatory", + "T", + "cells", + "Treg" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "CTLA4", + "mutations." + ] + } + } + ] + }, + { + "PMID": "25216639", + "TEXT": "Neurons have an important role in retinal vascular development. Here we show that the G protein-coupled receptor (GPCR) coagulation factor II receptor-like 1 (F2rl1, previously known as Par2) is abundant in retinal ganglion cells and is associated with new blood vessel formation during retinal development and in ischemic retinopathy. After stimulation, F2rl1 in retinal ganglion cells translocates from the plasma membrane to the cell nucleus using a microtubule-dependent shuttle that requires sorting nexin 11 (Snx11). At the nucleus, F2rl1 facilitates recruitment of the transcription factor Sp1 to trigger Vegfa expression and, in turn, neovascularization. In contrast, classical plasma membrane activation of F2rl1 leads to the expression of distinct genes, including Ang1, that are involved in vessel maturation. Mutant versions of F2rl1 that prevent nuclear relocalization but not plasma membrane activation interfere with Vegfa but not Ang1 expression. Complementary angiogenic factors are therefore regulated by the subcellular localization of a receptor (F2rl1) that governs angiogenesis. These findings may have implications for the selectivity of drug actions based on the subcellular distribution of their targets.", + "TAG_DATA": [ + "53, retinal {'context': 'B-cells'}", + "54, ganglion {'context': 'I-cells'}", + "55, cells {'context': 'I-cells'}", + "117, Mutant {'perturbing_action': 'B-other'}", + "118, versions {'perturbing_action': 'I-other'}", + "119, of {'perturbing_action': 'I-other'}", + "120, F2rl1 {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "53, retinal ['l0', 'l1']", + "54, ganglion ['l0', 'l2']", + "55, cells ['l1', 'l2']", + "117, Mutant ['l3', 'l4', 'l5']", + "118, versions ['l3', 'l6', 'l7']", + "119, of ['l4', 'l6', 'l8']", + "120, F2rl1 ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25216637", + "TEXT": "The integrity of the plasma membrane is maintained through an active repair process, especially in skeletal and cardiac muscle cells, in which contraction-induced mechanical damage frequently occurs in vivo. Muscular dystrophies (MDs) are a group of muscle diseases characterized by skeletal muscle wasting and weakness. An important cause of these group of diseases is defective repair of sarcolemmal injuries, which normally requires Ca(2+) sensor proteins and Ca(2+)-dependent delivery of intracellular vesicles to the sites of injury. MCOLN1 (also known as TRPML1, ML1) is an endosomal and lysosomal Ca(2+) channel whose human mutations cause mucolipidosis IV (ML4), a neurodegenerative disease with motor disabilities. Here we report that ML1-null mice develop a primary, early-onset MD independent of neural degeneration. Although the dystrophin-glycoprotein complex and the known membrane repair proteins are expressed normally, membrane resealing was defective in ML1-null muscle fibers and also upon acute and pharmacological inhibition of ML1 channel activity or vesicular Ca(2+) release. Injury facilitated the trafficking and exocytosis of vesicles by upmodulating ML1 channel activity. In the dystrophic mdx mouse model, overexpression of ML1 decreased muscle pathology. Collectively, our data have identified an intracellular Ca(2+) channel that regulates membrane repair in skeletal muscle via Ca(2+)-dependent vesicle exocytosis.", + "TAG_DATA": [ + "106, ML1-null {'perturbing_action': 'B-gene loss-of-function'}", + "107, mice {'context': 'B-organism'}", + "135, ML1-null {'perturbing_action': 'B-gene loss-of-function'}", + "136, muscle {'context': 'B-cells'}", + "137, fibers {'context': 'I-cells'}", + "143, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "144, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "145, of {'perturbing_action': 'I-pharmacological inhibition'}", + "146, ML1 {'perturbing_action': 'I-pharmacological inhibition'}", + "147, channel {'perturbing_action': 'I-pharmacological inhibition'}", + "148, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "168, dystrophic {'context': 'B-organism'}", + "169, mdx {'context': 'I-organism'}", + "170, mouse {'context': 'I-organism'}", + "171, model, {'context': 'I-organism'}", + "172, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "173, of {'perturbing_action': 'I-gene gain-of-function'}", + "174, ML1 {'perturbing_action': 'I-gene gain-of-function'}", + "176, muscle {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "106, ML1-null ['l0', 'l1', 'l2', 'l3']", + "107, mice ['l0', 'l4', 'l5', 'l6']", + "135, ML1-null ['l1', 'l4', 'l7', 'l8', 'l9', 'l10', 'l11']", + "136, muscle ['l2', 'l5', 'l7', 'l12']", + "137, fibers ['l3', 'l6', 'l8', 'l12']", + "143, pharmacological ['l13', 'l14', 'l15', 'l16', 'l17']", + "144, inhibition ['l13', 'l18', 'l19', 'l20', 'l21']", + "145, of ['l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "146, ML1 ['l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "147, channel ['l16', 'l20', 'l23', 'l25', 'l27']", + "148, activity ['l11', 'l17', 'l21', 'l24', 'l26', 'l27']", + "168, dystrophic ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "169, mdx ['l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "170, mouse ['l29', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "171, model, ['l30', 'l36', 'l41', 'l46', 'l47', 'l48']", + "172, overexpression ['l31', 'l37', 'l42', 'l49', 'l50', 'l51']", + "173, of ['l32', 'l38', 'l43', 'l46', 'l49', 'l52', 'l53']", + "174, ML1 ['l33', 'l39', 'l44', 'l47', 'l50', 'l52', 'l54']", + "176, muscle ['l34', 'l40', 'l45', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ML1-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ML1-null" + ] + }, + "context": { + "val": "cells", + "words": [ + "muscle", + "fibers" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "dystrophic", + "mdx", + "mouse", + "model," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "ML1" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "ML1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscle" + ] + } + } + ] + }, + { + "PMID": "25198048", + "TEXT": "Alopecia areata is an immune-mediated, nonscarring form of hair loss. A new study using human clinical samples and a mouse model demonstrates that CD8αβ⁺NKG2D⁺ T effector memory cells mediate alopecia areata in part through Janus kinase (JAK) signaling and that alopecia areata might be treated with JAK inhibitors.", + "TAG_DATA": [ + "19, mouse {'context': 'B-organism'}", + "20, model {'context': 'I-organism'}", + "25, effector {'context': 'I-cells'}", + "26, memory {'context': 'I-cells'}", + "27, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "19, mouse ['l0', 'l1', 'l2', 'l3']", + "20, model ['l0', 'l4', 'l5', 'l6']", + "25, effector ['l1', 'l4', 'l7', 'l8']", + "26, memory ['l2', 'l5', 'l7', 'l9']", + "27, cells ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25194572", + "TEXT": "The progressive loss of muscle regenerative capacity with age or disease results in part from a decline in the number and function of satellite cells, the direct cellular contributors to muscle repair. However, little is known about the molecular effectors underlying satellite cell impairment and depletion. Elevated levels of inflammatory cytokines, including interleukin-6 (IL-6), are associated with both age-related and muscle-wasting conditions. The levels of STAT3, a downstream effector of IL-6, are also elevated with muscle wasting, and STAT3 has been implicated in the regulation of self-renewal and stem cell fate in several tissues. Here we show that IL-6-activated Stat3 signaling regulates satellite cell behavior, promoting myogenic lineage progression through myogenic differentiation 1 (Myod1) regulation. Conditional ablation of Stat3 in Pax7-expressing satellite cells resulted in their increased expansion during regeneration, but compromised myogenic differentiation prevented the contribution of these cells to regenerating myofibers. In contrast, transient Stat3 inhibition promoted satellite cell expansion and enhanced tissue repair in both aged and dystrophic muscle. The effects of STAT3 inhibition on cell fate and proliferation were conserved in human myoblasts. The results of this study indicate that pharmacological manipulation of STAT3 activity can be used to counteract the functional exhaustion of satellite cells in pathological conditions, thereby maintaining the endogenous regenerative response and ameliorating muscle-wasting diseases.", + "TAG_DATA": [ + "115, Conditional {'perturbing_action': 'B-gene loss-of-function'}", + "116, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "117, of {'perturbing_action': 'I-gene loss-of-function'}", + "118, Stat3 {'perturbing_action': 'I-gene loss-of-function'}", + "120, Pax7-expressing {'context': 'B-cells'}", + "121, satellite {'context': 'I-cells'}", + "122, cells {'context': 'I-cells'}", + "131, compromised {'effect': 'B-negative'}", + "132, myogenic {'phenotype': 'B-differentiation'}", + "133, differentiation {'phenotype': 'I-differentiation'}", + "139, cells {'context': 'B-cells'}", + "145, transient {'perturbing_action': 'B-pharmacological inhibition'}", + "146, Stat3 {'perturbing_action': 'I-pharmacological inhibition'}", + "147, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "149, satellite {'context': 'B-cells'}", + "150, cell {'context': 'I-cells'}", + "158, aged {'context': 'B-tissue/organ'}", + "160, dystrophic {'context': 'B-tissue/organ'}", + "161, muscle. {'context': 'I-tissue/organ'}", + "165, STAT3 {'perturbing_action': 'B-pharmacological inhibition'}", + "166, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "171, proliferation {'phenotype': 'B-proliferation'}", + "175, human {'context': 'B-cells'}", + "176, myoblasts. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "115, Conditional ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "116, ablation ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "117, of ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "118, Stat3 ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "120, Pax7-expressing ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "121, satellite ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47']", + "122, cells ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l48']", + "131, compromised ['l6', 'l16', 'l25', 'l33', 'l40', 'l49', 'l50', 'l51', 'l52']", + "132, myogenic ['l7', 'l17', 'l26', 'l34', 'l41', 'l49', 'l53', 'l54', 'l55']", + "133, differentiation ['l8', 'l18', 'l27', 'l35', 'l42', 'l46', 'l50', 'l53', 'l56', 'l57']", + "139, cells ['l9', 'l19', 'l28', 'l36', 'l43', 'l47', 'l48', 'l51', 'l54', 'l56', 'l58']", + "142, myofibers. ['l10', 'l20', 'l29', 'l37', 'l44', 'l52', 'l55', 'l57', 'l58']", + "145, transient ['l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "146, Stat3 ['l59', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "147, inhibition ['l60', 'l71', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "149, satellite ['l61', 'l72', 'l81', 'l88', 'l89', 'l90', 'l91']", + "150, cell ['l62', 'l73', 'l82', 'l88', 'l92', 'l93', 'l94']", + "158, aged ['l63', 'l74', 'l83', 'l89', 'l92', 'l95', 'l96']", + "160, dystrophic ['l64', 'l75', 'l84', 'l90', 'l93', 'l95', 'l97']", + "161, muscle. ['l65', 'l76', 'l85', 'l91', 'l94', 'l96', 'l97']", + "165, STAT3 ['l66', 'l98', 'l99', 'l100', 'l101']", + "166, inhibition ['l67', 'l77', 'l98', 'l102', 'l103', 'l104']", + "171, proliferation ['l68', 'l78', 'l99', 'l102', 'l105', 'l106']", + "175, human ['l69', 'l79', 'l86', 'l100', 'l103', 'l105', 'l107']", + "176, myoblasts. ['l70', 'l80', 'l87', 'l101', 'l104', 'l106', 'l107']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "ablation", + "of", + "Stat3" + ] + }, + "context": { + "val": "cells", + "words": [ + "Pax7-expressing", + "satellite", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "ablation", + "of", + "Stat3" + ] + }, + "effect": { + "val": "negative", + "words": [ + "compromised" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "ablation", + "of", + "Stat3" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "myogenic", + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Pax7-expressing", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "compromised" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Pax7-expressing", + "satellite", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "myogenic", + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "compromised" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "myogenic", + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "transient", + "Stat3", + "inhibition", + "STAT3" + ] + }, + "context": { + "val": "cells", + "words": [ + "satellite", + "cell", + "human", + "myoblasts." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "transient", + "Stat3", + "inhibition" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "aged", + "dystrophic", + "muscle." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "transient", + "Stat3", + "STAT3", + "inhibition" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "myoblasts." + ] + } + } + ] + }, + { + "PMID": "25194570", + "TEXT": "Efforts to identify and annotate cancer driver genetic lesions have been focused primarily on the analysis of protein-coding genes; however, most genetic abnormalities found in human cancer are located in intergenic regions. Here we identify a new long range-acting MYC enhancer controlled by NOTCH1 that is targeted by recurrent chromosomal duplications in human T cell acute lymphoblastic leukemia (T-ALL). This highly conserved regulatory element, hereby named N-Me for NOTCH MYC enhancer, is located within a broad super-enhancer region +1.47 Mb from the MYC transcription initiating site, interacts with the MYC proximal promoter and induces orientation-independent MYC expression in reporter assays. Moreover, analysis of N-Me knockout mice demonstrates a selective and essential role of this regulatory element during thymocyte development and in NOTCH1-induced T-ALL. Together these results identify N-Me as a long-range oncogenic enhancer implicated directly in the pathogenesis of human leukemia and highlight the importance of the NOTCH1-MYC regulatory axis in T cell transformation and as a therapeutic target in T-ALL.", + "TAG_DATA": [ + "103, N-Me {'perturbing_action': 'B-gene loss-of-function'}", + "104, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "105, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "103, N-Me ['l0', 'l1']", + "104, knockout ['l0', 'l2']", + "105, mice ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "N-Me", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "25173427", + "TEXT": "Crizotinib, a selective tyrosine kinase inhibitor (TKI), shows marked activity in patients whose lung cancers harbor fusions in the gene encoding anaplastic lymphoma receptor tyrosine kinase (ALK), but its efficacy is limited by variable primary responses and acquired resistance. In work arising from the clinical observation of a patient with ALK fusion-positive lung cancer who had an exceptional response to an insulin-like growth factor 1 receptor (IGF-1R)-specific antibody, we define a therapeutic synergism between ALK and IGF-1R inhibitors. Similar to IGF-1R, ALK fusion proteins bind to the adaptor insulin receptor substrate 1 (IRS-1), and IRS-1 knockdown enhances the antitumor effects of ALK inhibitors. In models of ALK TKI resistance, the IGF-1R pathway is activated, and combined ALK and IGF-1R inhibition improves therapeutic efficacy. Consistent with this finding, the levels of IGF-1R and IRS-1 are increased in biopsy samples from patients progressing on crizotinib monotherapy. Collectively these data support a role for the IGF-1R-IRS-1 pathway in both ALK TKI-sensitive and ALK TKI-resistant states and provide a biological rationale for further clinical development of dual ALK and IGF-1R inhibitors.", + "TAG_DATA": [ + "94, IRS-1 {'perturbing_action': 'B-rnai/knockdown'}", + "95, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "101, ALK {'perturbing_action': 'B-pharmacological inhibition'}", + "102, inhibitors. {'perturbing_action': 'I-pharmacological inhibition'}", + "116, ALK {'perturbing_action': 'B-pharmacological inhibition'}", + "117, and {'perturbing_action': 'I-pharmacological inhibition'}", + "118, IGF-1R {'perturbing_action': 'I-pharmacological inhibition'}", + "119, inhibition {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "94, IRS-1 ['l0', 'l1', 'l2']", + "95, knockdown ['l0', 'l3', 'l4']", + "101, ALK ['l1', 'l3', 'l5']", + "102, inhibitors. ['l2', 'l4', 'l5']", + "116, ALK ['l6', 'l7', 'l8']", + "117, and ['l6', 'l9', 'l10']", + "118, IGF-1R ['l7', 'l9', 'l11']", + "119, inhibition ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25129481", + "TEXT": "Alopecia areata (AA) is a common autoimmune disease resulting from damage of the hair follicle by T cells. The immune pathways required for autoreactive T cell activation in AA are not defined limiting clinical development of rational targeted therapies. Genome-wide association studies (GWAS) implicated ligands for the NKG2D receptor (product of the KLRK1 gene) in disease pathogenesis. Here, we show that cytotoxic CD8(+)NKG2D(+) T cells are both necessary and sufficient for the induction of AA in mouse models of disease. Global transcriptional profiling of mouse and human AA skin revealed gene expression signatures indicative of cytotoxic T cell infiltration, an interferon-γ (IFN-γ) response and upregulation of several γ-chain (γc) cytokines known to promote the activation and survival of IFN-γ-producing CD8(+)NKG2D(+) effector T cells. Therapeutically, antibody-mediated blockade of IFN-γ, interleukin-2 (IL-2) or interleukin-15 receptor β (IL-15Rβ) prevented disease development, reducing the accumulation of CD8(+)NKG2D(+) T cells in the skin and the dermal IFN response in a mouse model of AA. Systemically administered pharmacological inhibitors of Janus kinase (JAK) family protein tyrosine kinases, downstream effectors of the IFN-γ and γc cytokine receptors, eliminated the IFN signature and prevented the development of AA, while topical administration promoted hair regrowth and reversed established disease. Notably, three patients treated with oral ruxolitinib, an inhibitor of JAK1 and JAK2, achieved near-complete hair regrowth within 5 months of treatment, suggesting the potential clinical utility of JAK inhibition in human AA.", + "TAG_DATA": [ + "142, CD8(+)NKG2D(+) {'context': 'B-cells'}", + "143, T {'context': 'I-cells'}", + "144, cells {'context': 'I-cells'}", + "155, mouse {'context': 'B-organism'}", + "156, model {'context': 'I-organism'}", + "207, an {'perturbing_action': 'I-pharmacological inhibition'}", + "208, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "209, of {'perturbing_action': 'I-pharmacological inhibition'}", + "210, JAK1 {'perturbing_action': 'I-pharmacological inhibition'}", + "211, and {'perturbing_action': 'I-pharmacological inhibition'}", + "212, JAK2, {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "142, CD8(+)NKG2D(+) ['l0', 'l1', 'l2', 'l3']", + "143, T ['l0', 'l4', 'l5', 'l6']", + "144, cells ['l1', 'l4', 'l7', 'l8']", + "155, mouse ['l2', 'l5', 'l7', 'l9']", + "156, model ['l3', 'l6', 'l8', 'l9']", + "207, an ['l10', 'l11', 'l12', 'l13', 'l14']", + "208, inhibitor ['l10', 'l15', 'l16', 'l17', 'l18']", + "209, of ['l11', 'l15', 'l19', 'l20', 'l21']", + "210, JAK1 ['l12', 'l16', 'l19', 'l22', 'l23']", + "211, and ['l13', 'l17', 'l20', 'l22', 'l24']", + "212, JAK2, ['l14', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25108526", + "TEXT": "Aging-related bone loss and osteoporosis affect millions of people worldwide. Chronic inflammation associated with aging promotes bone resorption and impairs bone formation. Here we show that Wnt4 attenuates bone loss in osteoporosis and skeletal aging mouse models by inhibiting nuclear factor-κB (NF-κB) via noncanonical Wnt signaling. Transgenic mice expressing Wnt4 from osteoblasts were significantly protected from bone loss and chronic inflammation induced by ovariectomy, tumor necrosis factor or natural aging. In addition to promoting bone formation, Wnt4 inhibited osteoclast formation and bone resorption. Mechanistically, Wnt4 inhibited NF-κB activation mediated by transforming growth factor-β-activated kinase-1 (Tak1) in macrophages and osteoclast precursors independently of β-catenin. Moreover, recombinant Wnt4 alleviated bone loss and inflammation by inhibiting NF-κB in vivo in mouse models of bone disease. Given its dual role in promoting bone formation and inhibiting bone resorption, our results suggest that Wnt4 signaling could be an attractive therapeutic target for treating osteoporosis and preventing skeletal aging.", + "TAG_DATA": [ + "35, mouse {'context': 'B-organism'}", + "36, models {'context': 'I-organism'}", + "46, Transgenic {'perturbing_action': 'B-gene gain-of-function', 'context': 'B-organism'}", + "47, mice {'context': 'I-organism'}", + "48, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "49, Wnt4 {'perturbing_action': 'I-gene gain-of-function'}", + "50, from {'perturbing_action': 'I-gene gain-of-function'}", + "51, osteoblasts {'perturbing_action': 'I-gene gain-of-function', 'context': 'B-cells'}", + "96, macrophages {'context': 'B-cells'}", + "98, osteoclast {'context': 'B-cells'}", + "114, in {'context': 'B-in vivo'}", + "115, vivo {'context': 'I-in vivo'}", + "117, mouse {'context': 'B-organism'}", + "118, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "35, mouse ['l0', 'l1']", + "36, models ['l0', 'l2']", + "46, Transgenic ['l3', 'l4', 'l5', 'l6', 'l7']", + "47, mice ['l3', 'l8', 'l9', 'l10', 'l11']", + "48, expressing ['l4', 'l8', 'l12', 'l13', 'l14']", + "49, Wnt4 ['l5', 'l9', 'l12', 'l15', 'l16']", + "50, from ['l6', 'l10', 'l13', 'l15', 'l17']", + "51, osteoblasts ['l1', 'l2', 'l7', 'l11', 'l14', 'l16', 'l17']", + "96, macrophages ['l18']", + "98, osteoclast ['l18']", + "114, in ['l19', 'l20', 'l21']", + "115, vivo ['l19', 'l22', 'l23']", + "117, mouse ['l20', 'l22', 'l24']", + "118, models ['l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "Transgenic", + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "osteoblasts", + "Transgenic", + "expressing", + "Wnt4", + "from" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "osteoblasts", + "Transgenic", + "expressing", + "Wnt4", + "from" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoblasts" + ] + } + } + ] + }, + { + "PMID": "25100527", + "TEXT": "The scientific community is currently witnessing substantial strides in understanding stem cell biology in humans; however, major disappointments in translating this knowledge into medical therapies are flooding the field as well. Despite these setbacks, investigators are determined to better understand the caveats of regeneration, so that major pathways of repair and regrowth can be exploited in treating aged and diseased tissues. Last year, in an effort to contribute to this burgeoning field, Nature Medicine, in collaboration with the Volkswagen Foundation, organized a meeting with a panel of experts in regenerative medicine to identify the most pressing challenges, as well as the crucial strategies and stem cell concepts that can best help advance the translational regenerative field. Here some experts who participated in the meeting provide an outlook at some of those key issues and concepts.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25038825", + "TEXT": "Type 1 diabetes (T1D) is an autoimmune disease, whereas type 2 diabetes (T2D) results from insulin resistance and beta cell dysfunction. Previously, the onset of these two separate diseases was easily distinguished, with children being most at risk for T1D and T2D occurring in overweight adults. However, the dramatic rise in obesity, coupled with the notable increase in T1D, has created a large overlap in these previously discrete patient populations. Delayed diagnosis of T1D can result in severe illness or death, and rapid diagnosis of T1D is critical for the efficacy of emerging therapies. However, attempts to apply next-generation platforms have been unsuccessful for detecting diabetes biomarkers. Here we describe the development of a plasmonic gold chip for near-infrared fluorescence-enhanced (NIR-FE) detection of islet cell-targeting autoantibodies. We demonstrate that this platform has high sensitivity and specificity for the diagnosis of T1D and can be used to discover previously unknown biomarkers of T1D.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24997609", + "TEXT": "Individuals with neurofibromatosis type-1 (NF1) can manifest focal skeletal dysplasias that remain extremely difficult to treat. NF1 is caused by mutations in the NF1 gene, which encodes the RAS GTPase-activating protein neurofibromin. We report here that ablation of Nf1 in bone-forming cells leads to supraphysiologic accumulation of pyrophosphate (PPi), a strong inhibitor of hydroxyapatite formation, and that a chronic extracellular signal-regulated kinase (ERK)-dependent increase in expression of genes promoting PPi synthesis and extracellular transport, namely Enpp1 and Ank, causes this phenotype. Nf1 ablation also prevents bone morphogenic protein-2-induced osteoprogenitor differentiation and, consequently, expression of alkaline phosphatase and PPi breakdown, further contributing to PPi accumulation. The short stature and impaired bone mineralization and strength in mice lacking Nf1 in osteochondroprogenitors or osteoblasts can be corrected by asfotase-α enzyme therapy aimed at reducing PPi concentration. These results establish neurofibromin as an essential regulator of bone mineralization. They also suggest that altered PPi homeostasis contributes to the skeletal dysplasias associated with NF1 and that some of the NF1 skeletal conditions could be prevented pharmacologically.", + "TAG_DATA": [ + "36, ablation {'perturbing_action': 'B-gene loss-of-function'}", + "37, of {'perturbing_action': 'I-gene loss-of-function'}", + "38, Nf1 {'perturbing_action': 'I-gene loss-of-function'}", + "40, bone-forming {'context': 'B-cells'}", + "41, cells {'context': 'I-cells'}", + "81, Nf1 {'perturbing_action': 'B-gene loss-of-function'}", + "82, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "84, prevents {'effect': 'B-negative'}", + "87, protein-2-induced {'effect': 'B-positive'}", + "88, osteoprogenitor {'context': 'B-cells', 'phenotype': 'B-differentiation'}", + "89, differentiation {'phenotype': 'B-differentiation'}", + "114, mice {'context': 'B-organism'}", + "115, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "116, Nf1 {'perturbing_action': 'I-gene loss-of-function'}", + "118, osteochondroprogenitors {'context': 'B-cells'}", + "120, osteoblasts {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "36, ablation ['l0', 'l1', 'l2', 'l3']", + "37, of ['l0', 'l4', 'l5', 'l6']", + "38, Nf1 ['l1', 'l4', 'l7', 'l8']", + "40, bone-forming ['l2', 'l5', 'l7', 'l9']", + "41, cells ['l3', 'l6', 'l8', 'l9']", + "81, Nf1 ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "82, ablation ['l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "84, prevents ['l11', 'l16', 'l21', 'l22', 'l23']", + "87, protein-2-induced ['l12', 'l17', 'l21', 'l24', 'l25']", + "88, osteoprogenitor ['l13', 'l18', 'l22', 'l24', 'l26']", + "89, differentiation ['l14', 'l19', 'l23', 'l25', 'l26']", + "114, mice ['l27', 'l28', 'l29', 'l30']", + "115, lacking ['l27', 'l31', 'l32', 'l33']", + "116, Nf1 ['l28', 'l31', 'l34', 'l35']", + "118, osteochondroprogenitors ['l15', 'l20', 'l29', 'l32', 'l34', 'l36']", + "120, osteoblasts ['l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablation", + "of", + "Nf1", + "lacking" + ] + }, + "context": { + "val": "cells", + "words": [ + "bone-forming", + "cells", + "osteoprogenitor", + "osteochondroprogenitors", + "osteoblasts" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nf1", + "ablation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nf1", + "ablation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "protein-2-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nf1", + "ablation" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "osteoprogenitor", + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoprogenitor" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "osteoprogenitor" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoprogenitor" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "osteoprogenitor", + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "protein-2-induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoprogenitor" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "protein-2-induced" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "osteoprogenitor", + "differentiation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "Nf1" + ] + } + } + ] + }, + { + "PMID": "24952648", + "TEXT": "Ribosomal protein haploinsufficiency occurs in diverse human diseases including Diamond-Blackfan anemia (DBA), congenital asplenia and T cell leukemia. Yet, how mutations in genes encoding ubiquitously expressed proteins such as these result in cell-type- and tissue-specific defects remains unknown. Here, we identify mutations in GATA1, encoding the critical hematopoietic transcription factor GATA-binding protein-1, that reduce levels of full-length GATA1 protein and cause DBA in rare instances. We show that ribosomal protein haploinsufficiency, the more common cause of DBA, can lead to decreased GATA1 mRNA translation, possibly resulting from a higher threshold for initiation of translation of this mRNA in comparison with other mRNAs. In primary hematopoietic cells from patients with mutations in RPS19, encoding ribosomal protein S19, the amplitude of a transcriptional signature of GATA1 target genes was globally and specifically reduced, indicating that the activity, but not the mRNA level, of GATA1 is decreased in patients with DBA associated with mutations affecting ribosomal proteins. Moreover, the defective hematopoiesis observed in patients with DBA associated with ribosomal protein haploinsufficiency could be partially overcome by increasing GATA1 protein levels. Our results provide a paradigm by which selective defects in translation due to mutations affecting ubiquitous ribosomal proteins can result in human disease.", + "TAG_DATA": [ + "103, primary {'context': 'B-cells'}", + "104, hematopoietic {'context': 'I-cells'}", + "105, cells {'context': 'I-cells'}", + "107, patients {'context': 'B-patient'}", + "109, mutations {'perturbing_action': 'B-other'}", + "110, in {'perturbing_action': 'I-other'}", + "111, RPS19, {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "103, primary ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "104, hematopoietic ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "105, cells ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "107, patients ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "109, mutations ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "110, in ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "111, RPS19, ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "primary", + "hematopoietic", + "cells" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutations", + "in", + "RPS19," + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutations", + "in", + "RPS19," + ] + } + } + ] + }, + { + "PMID": "24952646", + "TEXT": "Exposure to psychosocial stress is a risk factor for many diseases, including atherosclerosis. Although incompletely understood, interaction between the psyche and the immune system provides one potential mechanism linking stress and disease inception and progression. Known cross-talk between the brain and immune system includes the hypothalamic-pituitary-adrenal axis, which centrally drives glucocorticoid production in the adrenal cortex, and the sympathetic-adrenal-medullary axis, which controls stress-induced catecholamine release in support of the fight-or-flight reflex. It remains unknown, however, whether chronic stress changes hematopoietic stem cell activity. Here we show that stress increases proliferation of these most primitive hematopoietic progenitors, giving rise to higher levels of disease-promoting inflammatory leukocytes. We found that chronic stress induced monocytosis and neutrophilia in humans. While investigating the source of leukocytosis in mice, we discovered that stress activates upstream hematopoietic stem cells. Under conditions of chronic variable stress in mice, sympathetic nerve fibers released surplus noradrenaline, which signaled bone marrow niche cells to decrease CXCL12 levels through the β3-adrenergic receptor. Consequently, hematopoietic stem cell proliferation was elevated, leading to an increased output of neutrophils and inflammatory monocytes. When atherosclerosis-prone Apoe(-/-) mice were subjected to chronic stress, accelerated hematopoiesis promoted plaque features associated with vulnerable lesions that cause myocardial infarction and stroke in humans.", + "TAG_DATA": [ + "88, increases {'effect': 'B-positive'}", + "89, proliferation {'phenotype': 'B-proliferation'}", + "140, mice, {'context': 'B-organism'}", + "141, sympathetic {'context': 'B-cells'}", + "142, nerve {'context': 'I-cells'}", + "143, fibers {'context': 'I-cells'}", + "162, hematopoietic {'context': 'B-cells'}", + "163, stem {'context': 'I-cells'}", + "164, cell {'context': 'I-cells'}", + "165, proliferation {'phenotype': 'B-proliferation'}", + "167, elevated, {'effect': 'B-positive'}", + "179, atherosclerosis-prone {'perturbing_action': 'B-gene loss-of-function'}", + "180, Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "181, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "88, increases ['l0']", + "89, proliferation ['l0']", + "140, mice, ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "141, sympathetic ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "142, nerve ['l2', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "143, fibers ['l3', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "162, hematopoietic ['l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "163, stem ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "164, cell ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "165, proliferation ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "167, elevated, ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "179, atherosclerosis-prone ['l36', 'l37']", + "180, Apoe(-/-) ['l36', 'l38']", + "181, mice ['l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "increases", + "elevated," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "positive", + "words": [ + "elevated," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "sympathetic", + "nerve", + "fibers", + "hematopoietic", + "stem", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "sympathetic", + "nerve", + "fibers", + "hematopoietic", + "stem", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "elevated," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "atherosclerosis-prone", + "Apoe(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "24908571", + "TEXT": "Major depressive disorder (MDD) is a prevalent mood disorder that is associated with differential prefrontal brain expression patterns. Treatment of MDD includes a variety of biopsychosocial approaches. In medical practice, antidepressant drugs are the most common treatment for depressive episodes, and they are among the most prescribed medications in North America. Although antidepressants are clearly effective, particularly for moderate to severe depressive episodes, there is variability in how individuals respond to antidepressant treatment. Failure to respond has individual, economic and social consequences for patients and their families. Several lines of evidence demonstrate that genes are regulated through the activity of microRNAs (miRNAs), which act as fine-tuners and on-off switches of gene expression. Here we report on complementary studies using postmortem human brain samples, cellular assays and samples from clinical trials of patients with depression and show that miR-1202, a miRNA specific to primates and enriched in the human brain, is differentially expressed in individuals with depression. Additionally, miR-1202 regulates expression of the gene encoding metabotropic glutamate receptor-4 (GRM4) and predicts antidepressant response at baseline. These results suggest that miR-1202 is associated with the pathophysiology of depression and is a potential target for new antidepressant treatments.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24880616", + "TEXT": "Despite the fact that genitourinary defects are among the most common birth defects in newborns, little is known about their etiology. Here we analyzed children born with congenital genitourinary tract masculinization disorders by array-comparative genomic hybridization, which revealed in 1.35% of cases the presence of de novo copy number gains at Xq28 encompassing the VAMP7 gene, which encodes a vesicle-trafficking protein that is part of the SNARE complex. Transgenic mice carrying a bacterial artificial chromosome encoding human VAMP7 mimicked the defective urogenital traits observed in boys with masculinization disorders such as cryptorchidism, urethral defects and hypospadias. Transgenic mice also exhibited reduced penile length, focal spermatogenic anomalies, diminished sperm motility and subfertility. VAMP7 colocalized with estrogen receptor α (ESR1) in the presence of its cognate ligand, 17β-estradiol. Elevated levels of VAMP7 markedly intensified ESR1-potentiated transcriptional activity by increasing ESR1 protein cellular content upon ligand stimulation and upregulated the expression of estrogen-responsive genes including ATF3, CYR61 and CTGF, all of which have been implicated in human hypospadias. Hence, increased gene dosage of VAMP7, and thus higher expression levels of its protein product, enhances estrogen receptor action in male genitourinary tissues, affects the virilization of the reproductive tract and results in genitourinary birth defects in humans.", + "TAG_DATA": [ + "68, Transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "69, mice {'context': 'I-organism'}", + "70, carrying {'perturbing_action': 'B-gene gain-of-function'}", + "71, a {'perturbing_action': 'I-gene gain-of-function'}", + "72, bacterial {'perturbing_action': 'I-gene gain-of-function'}", + "73, artificial {'perturbing_action': 'I-gene gain-of-function'}", + "74, chromosome {'perturbing_action': 'I-gene gain-of-function'}", + "75, encoding {'perturbing_action': 'I-gene gain-of-function'}", + "76, human {'perturbing_action': 'I-gene gain-of-function'}", + "77, VAMP7 {'perturbing_action': 'I-gene gain-of-function'}", + "96, Transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "97, mice {'context': 'B-organism'}", + "106, diminished {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "68, Transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "69, mice ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "70, carrying ['l1', 'l9', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "71, a ['l2', 'l10', 'l15', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "72, bacterial ['l3', 'l16', 'l24', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "73, artificial ['l4', 'l17', 'l25', 'l34', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "74, chromosome ['l5', 'l11', 'l18', 'l26', 'l35', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "75, encoding ['l6', 'l12', 'l19', 'l27', 'l36', 'l44', 'l51', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "76, human ['l7', 'l13', 'l20', 'l28', 'l37', 'l45', 'l52', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "77, VAMP7 ['l8', 'l14', 'l21', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l69', 'l70']", + "96, Transgenic ['l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l71', 'l72', 'l73']", + "97, mice ['l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l71', 'l74', 'l75']", + "106, diminished ['l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l69', 'l72', 'l74', 'l76']", + "107, sperm ['l23', 'l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l70', 'l73', 'l75', 'l76']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgenic", + "carrying", + "a", + "chromosome", + "encoding", + "human", + "VAMP7", + "bacterial", + "artificial" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "carrying", + "a", + "bacterial", + "artificial", + "chromosome", + "encoding", + "human", + "VAMP7", + "Transgenic" + ] + }, + "effect": { + "val": "negative", + "words": [ + "diminished" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "diminished" + ] + } + } + ] + }, + { + "PMID": "24880614", + "TEXT": "Neisseria meningitidis is a cause of meningitis epidemics worldwide and of rapidly progressing fatal septic shock. A crucial step in the pathogenesis of invasive meningococcal infections is the adhesion of bloodborne meningococci to both peripheral and brain endothelia, leading to major vascular dysfunction. Initial adhesion of pathogenic strains to endothelial cells relies on meningococcal type IV pili, but the endothelial receptor for bacterial adhesion remains unknown. Here, we report that the immunoglobulin superfamily member CD147 (also called extracellular matrix metalloproteinase inducer (EMMPRIN) or Basigin) is a critical host receptor for the meningococcal pilus components PilE and PilV. Interfering with this interaction potently inhibited the primary attachment of meningococci to human endothelial cells in vitro and prevented colonization of vessels in human brain tissue explants ex vivo and in humanized mice in vivo. These findings establish the molecular events by which meningococci target human endothelia, and they open new perspectives for treatment and prevention of meningococcus-induced vascular dysfunctions.", + "TAG_DATA": [ + "109, human {'context': 'B-cells'}", + "110, endothelial {'context': 'I-cells'}", + "111, cells {'context': 'I-cells'}", + "112, in {'context': 'B-in vitro'}", + "113, vitro {'context': 'I-in vitro'}", + "118, vessels {'context': 'B-tissue/organ'}", + "120, human {'context': 'B-tissue/organ'}", + "121, brain {'context': 'I-tissue/organ'}", + "122, tissue {'context': 'I-tissue/organ'}", + "128, humanized {'context': 'B-organism'}", + "129, mice {'context': 'I-organism'}", + "130, in {'context': 'B-in vivo'}", + "131, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "109, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "110, endothelial ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "111, cells ['l1', 'l6', 'l11', 'l12']", + "112, in ['l2', 'l7', 'l11', 'l13']", + "113, vitro ['l3', 'l8', 'l12', 'l13']", + "118, vessels ['l14', 'l15', 'l16']", + "120, human ['l14', 'l17', 'l18']", + "121, brain ['l4', 'l9', 'l15', 'l17', 'l19']", + "122, tissue ['l5', 'l10', 'l16', 'l18', 'l19']", + "128, humanized ['l20', 'l21', 'l22']", + "129, mice ['l20', 'l23', 'l24']", + "130, in ['l21', 'l23', 'l25']", + "131, vivo. ['l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24813250", + "TEXT": "We previously demonstrated that low biosynthesis of ω-3 fatty acid-derived proresolution mediators, termed protectins, is associated with an impaired global resolution capacity, inflammation and insulin resistance in obese high-fat diet-fed mice. These findings prompted a more direct study of the therapeutic potential of protectins for the treatment of metabolic disorders. Herein we show that protectin DX (PDX) exerts an unanticipated glucoregulatory activity that is distinct from its anti-inflammatory actions. We found that PDX selectively stimulated the release of the prototypic myokine interleukin-6 (IL-6) from skeletal muscle and thereby initiated a myokine-liver signaling axis, which blunted hepatic glucose production via signal transducer and activator of transcription 3 (STAT3)-mediated transcriptional suppression of the gluconeogenic program. These effects of PDX were abrogated in Il6-null mice. PDX also activated AMP-activated protein kinase (AMPK); however, it did so in an IL-6-independent manner. Notably, we demonstrated that administration of PDX to obese diabetic db/db mice raises skeletal muscle IL-6 levels and substantially improves their insulin sensitivity without any impact on adipose tissue inflammation. Our findings thus support the development of PDX-based selective muscle IL-6 secretagogues as a new class of therapy for the treatment of insulin resistance and type 2 diabetes.", + "TAG_DATA": [ + "84, skeletal {'context': 'B-tissue/organ'}", + "85, muscle {'context': 'I-tissue/organ'}", + "120, Il6-null {'perturbing_action': 'B-gene loss-of-function'}", + "121, mice. {'context': 'B-organism'}", + "145, obese {'context': 'B-organism'}", + "146, diabetic {'context': 'I-organism'}", + "147, db/db {'context': 'I-organism'}", + "148, mice {'context': 'I-organism'}", + "150, skeletal {'context': 'B-tissue/organ'}", + "151, muscle {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "84, skeletal ['l0']", + "85, muscle ['l0']", + "120, Il6-null ['l1']", + "121, mice. ['l1']", + "145, obese ['l2', 'l3', 'l4', 'l5', 'l6']", + "146, diabetic ['l2', 'l7', 'l8', 'l9', 'l10']", + "147, db/db ['l3', 'l7', 'l11', 'l12', 'l13']", + "148, mice ['l4', 'l8', 'l11', 'l14', 'l15']", + "150, skeletal ['l5', 'l9', 'l12', 'l14', 'l16']", + "151, muscle ['l6', 'l10', 'l13', 'l15', 'l16']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Il6-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "24813249", + "TEXT": "Epidemiological data point toward a critical period in early life during which environmental cues can set an individual on a trajectory toward respiratory health or disease. The neonatal immune system matures during this period, although little is known about the signals that lead to its maturation. Here we report that the formation of the lung microbiota is a key parameter in this process. Immediately following birth, neonatal mice were prone to develop exaggerated airway eosinophilia, release type 2 helper T cell cytokines and exhibit airway hyper-responsiveness following exposure to house dust mite allergens, even though their lungs harbored high numbers of natural CD4(+)Foxp3(+)CD25(+)Helios(+) regulatory T (Treg) cells. During the first 2 weeks after birth, the bacterial load in the lungs increased, and representation of the bacterial phyla shifts from a predominance of Gammaproteobacteria and Firmicutes towards Bacteroidetes. The changes in the microbiota were associated with decreased aeroallergen responsiveness and the emergence of a Helios(-) Treg cell subset that required interaction with programmed death ligand 1 (PD-L1) for development. Absence of microbial colonization(10) or blockade of PD-L1 during the first 2 weeks postpartum maintained exaggerated responsiveness to allergens through to adulthood. Adoptive transfer of Treg cells from adult mice to neonates before aeroallergen exposure ameliorated disease. Thus, formation of the airway microbiota induces regulatory cells early in life, which, when dysregulated, can lead to sustained susceptibility to allergic airway inflammation in adulthood.", + "TAG_DATA": [ + "66, neonatal {'context': 'B-organism'}", + "67, mice {'context': 'I-organism'}", + "96, lungs {'context': 'B-tissue/organ'}", + "119, lungs {'context': 'B-tissue/organ'}", + "153, Helios(-) {'context': 'B-cells'}", + "154, Treg {'context': 'I-cells'}", + "155, cell {'context': 'I-cells'}", + "156, subset {'context': 'I-cells'}", + "173, blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "174, of {'perturbing_action': 'I-pharmacological inhibition'}", + "175, PD-L1 {'perturbing_action': 'I-pharmacological inhibition'}", + "193, Treg {'context': 'B-cells'}", + "194, cells {'context': 'I-cells'}", + "196, adult {'context': 'B-organism'}", + "197, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "66, neonatal ['l0', 'l1']", + "67, mice ['l0', 'l2']", + "96, lungs ['l1', 'l2', 'l3']", + "119, lungs ['l3', 'l4']", + "153, Helios(-) ['l5', 'l6', 'l7']", + "154, Treg ['l5', 'l8', 'l9']", + "155, cell ['l4', 'l6', 'l8', 'l10']", + "156, subset ['l7', 'l9', 'l10']", + "173, blockade ['l11', 'l12', 'l13']", + "174, of ['l11', 'l14', 'l15']", + "175, PD-L1 ['l12', 'l14', 'l16']", + "193, Treg ['l17', 'l18', 'l19']", + "194, cells ['l13', 'l15', 'l16', 'l17', 'l20', 'l21']", + "196, adult ['l18', 'l20', 'l22']", + "197, mice ['l19', 'l21', 'l22']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "PD-L1" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "24804743", + "TEXT": "Last month, Genentech launched an unusual five-year research pact. The San Francisco subsidiary of the drug giant Roche partnered with Cambridge, Massachusetts-based PatientsLikeMe to mine the online patient network's database of real-world experiences. In exchange for an undisclosed fee, Genentech now has access to nearly all of the information collected by PatientsLikeMe, which currently includes more than 250,000 members with 2,000 different conditions. The hope is that studying the network will help Genentech learn how to stratify patient populations more precisely and measure drug effectiveness better, among other things.At the helm of PatientsLikeMe is Jamie Heywood, a mechanical engineer by training who devised the idea for the platform ten years ago when he noticed some striking similarities between the information asked of online dating websites and clinical trial portals. With his brother Benjamin and friend Jeff Cole, Heywood founded PatientsLikeMe later that same year. Nicholette Zeliadt spoke to Heywood about where the crowdsourcing site stands a decade on from its inception and what this new partnership with Genentech will mean for open-participation research.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24784232", + "TEXT": "Interferon-α (IFN-α) is essential for antiviral immunity, but in the absence of matrix metalloproteinase-12 (MMP-12) or IκBα (encoded by NFKBIA) we show that IFN-α is retained in the cytosol of virus-infected cells and is not secreted. Our findings suggest that activated IκBα mediates the export of IFN-α from virus-infected cells and that the inability of cells in Mmp12(-/-) but not wild-type mice to express IκBα and thus export IFN-α makes coxsackievirus type B3 infection lethal and renders respiratory syncytial virus more pathogenic. We show here that after macrophage secretion, MMP-12 is transported into virus-infected cells. In HeLa cells MMP-12 is also translocated to the nucleus, where it binds to the NFKBIA promoter, driving transcription. We also identified dual-regulated substrates that are repressed both by MMP-12 binding to the substrate's gene exons and by MMP-12-mediated cleavage of the substrate protein itself. Whereas intracellular MMP-12 mediates NFKBIA transcription, leading to IFN-α secretion and host protection, extracellular MMP-12 cleaves off the IFN-α receptor 2 binding site of systemic IFN-α, preventing an unchecked immune response. Consistent with an unexpected role for MMP-12 in clearing systemic IFN-α, treatment of coxsackievirus type B3-infected wild-type mice with a membrane-impermeable MMP-12 inhibitor elevates systemic IFN-α levels and reduces viral replication in pancreas while sparing intracellular MMP-12. These findings suggest that inhibiting extracellular MMP-12 could be a new avenue for the development of antiviral treatments.", + "TAG_DATA": [ + "55, cells {'context': 'B-cells'}", + "57, Mmp12(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "61, mice {'context': 'B-organism'}", + "188, mice {'context': 'B-organism'}", + "191, membrane-impermeable {'perturbing_action': 'B-pharmacological inhibition'}", + "192, MMP-12 {'perturbing_action': 'I-pharmacological inhibition'}", + "193, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "203, pancreas {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "55, cells ['l0', 'l1', 'l2']", + "57, Mmp12(-/-) ['l0', 'l3', 'l4']", + "61, mice ['l1', 'l3', 'l5']", + "97, cells ['l2', 'l4', 'l5']", + "188, mice ['l6', 'l7', 'l8', 'l9']", + "191, membrane-impermeable ['l6', 'l10', 'l11', 'l12']", + "192, MMP-12 ['l7', 'l10', 'l13', 'l14']", + "193, inhibitor ['l8', 'l11', 'l13', 'l15']", + "203, pancreas ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mmp12(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mmp12(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "membrane-impermeable", + "MMP-12", + "inhibitor" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "membrane-impermeable", + "MMP-12", + "inhibitor" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "pancreas" + ] + } + } + ] + }, + { + "PMID": "24747746", + "TEXT": "Inflammation has a critical role in the development of insulin resistance. Recent evidence points to a contribution by the central nervous system in the modulation of peripheral inflammation through the anti-inflammatory reflex. However, the importance of this phenomenon remains elusive in type 2 diabetes pathogenesis. Here we show that rat insulin-2 promoter (Rip)-mediated deletion of Pten, a gene encoding a negative regulator of PI3K signaling, led to activation of the cholinergic anti-inflammatory pathway that is mediated by M2 activated macrophages in peripheral tissues. As such, Rip-cre(+) Pten(flox/flox) mice showed lower systemic inflammation and greater insulin sensitivity under basal conditions compared to littermate controls, which were abolished when the mice were treated with an acetylcholine receptor antagonist or when macrophages were depleted. After feeding with a high-fat diet, the Pten-deleted mice remained markedly insulin sensitive, which correlated with massive subcutaneous fat expansion. They also exhibited more adipogenesis with M2 macrophage infiltration, both of which were abolished after disruption of the anti-inflammatory efferent pathway by left vagotomy. In summary, we show that Pten expression in Rip(+) neurons has a critical role in diabetes pathogenesis through mediating the anti-inflammatory reflex.", + "TAG_DATA": [ + "49, rat {'perturbing_action': 'B-gene loss-of-function'}", + "50, insulin-2 {'perturbing_action': 'I-gene loss-of-function'}", + "51, promoter {'perturbing_action': 'I-gene loss-of-function'}", + "52, (Rip)-mediated {'perturbing_action': 'I-gene loss-of-function'}", + "53, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "54, of {'perturbing_action': 'I-gene loss-of-function'}", + "55, Pten, {'perturbing_action': 'I-gene loss-of-function'}", + "85, Rip-cre(+) {'perturbing_action': 'B-gene loss-of-function'}", + "86, Pten(flox/flox) {'perturbing_action': 'I-gene loss-of-function'}", + "87, mice {'context': 'B-organism'}", + "108, mice {'context': 'B-organism'}", + "118, macrophages {'context': 'B-cells'}", + "128, Pten-deleted {'perturbing_action': 'B-gene loss-of-function'}", + "129, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "49, rat ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "50, insulin-2 ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "51, promoter ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "52, (Rip)-mediated ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "53, deletion ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "54, of ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "55, Pten, ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "85, Rip-cre(+) ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "86, Pten(flox/flox) ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "87, mice ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "108, mice ['l45']", + "118, macrophages ['l45']", + "128, Pten-deleted ['l46']", + "129, mice ['l46']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "rat", + "insulin-2", + "promoter", + "(Rip)-mediated", + "deletion", + "of", + "Pten,", + "Rip-cre(+)", + "Pten(flox/flox)", + "Pten-deleted" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "24747745", + "TEXT": "Vaccination has been the most widely used strategy to protect against viral infections for centuries. However, the molecular mechanisms governing the long-term persistence of immunological memory in response to vaccines remain unclear. Here we show that autophagy has a critical role in the maintenance of memory B cells that protect against influenza virus infection. Memory B cells displayed elevated levels of basal autophagy with increased expression of genes that regulate autophagy initiation or autophagosome maturation. Mice with B cell-specific deletion of Atg7 (B/Atg7(-/-) mice) showed normal primary antibody responses after immunization against influenza but failed to generate protective secondary antibody responses when challenged with influenza viruses, resulting in high viral loads, widespread lung destruction and increased fatality. Our results suggest that autophagy is essential for the survival of virus-specific memory B cells in mice and the maintenance of protective antibody responses required to combat infections.", + "TAG_DATA": [ + "54, Memory {'context': 'B-cells'}", + "55, B {'context': 'I-cells'}", + "56, cells {'context': 'I-cells'}", + "62, autophagy {'phenotype': 'B-autophagy'}", + "75, Mice {'context': 'B-organism'}", + "77, B {'perturbing_action': 'B-gene loss-of-function'}", + "78, cell-specific {'perturbing_action': 'I-gene loss-of-function'}", + "79, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "80, of {'perturbing_action': 'I-gene loss-of-function'}", + "81, Atg7 {'perturbing_action': 'I-gene loss-of-function'}", + "82, (B/Atg7(-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "83, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "112, lung {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "54, Memory ['l0', 'l1', 'l2']", + "55, B ['l0', 'l3', 'l4']", + "56, cells ['l1', 'l3', 'l5']", + "62, autophagy ['l2', 'l4', 'l5']", + "75, Mice ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "77, B ['l6', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "78, cell-specific ['l7', 'l14', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "79, deletion ['l8', 'l15', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "80, of ['l9', 'l16', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "81, Atg7 ['l10', 'l17', 'l23', 'l28', 'l32', 'l36', 'l37', 'l38']", + "82, (B/Atg7(-/-) ['l11', 'l18', 'l24', 'l29', 'l33', 'l36', 'l39', 'l40']", + "83, mice) ['l12', 'l19', 'l25', 'l30', 'l34', 'l37', 'l39', 'l41']", + "112, lung ['l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Memory", + "B", + "cells" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "B", + "cell-specific", + "deletion", + "of", + "Atg7", + "(B/Atg7(-/-)", + "mice)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "B", + "cell-specific", + "deletion", + "of", + "Atg7", + "(B/Atg7(-/-)", + "mice)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + } + ] + }, + { + "PMID": "24743305", + "TEXT": "Interleukin-10 (IL-10)-producing regulatory B (Breg) cells suppress autoimmune disease, and increased numbers of Breg cells prevent host defense to infection and promote tumor growth and metastasis by converting resting CD4(+) T cells to regulatory T (Treg) cells. The mechanisms mediating the induction and development of Breg cells remain unclear. Here we show that IL-35 induces Breg cells and promotes their conversion to a Breg subset that produces IL-35 as well as IL-10. Treatment of mice with IL-35 conferred protection from experimental autoimmune uveitis (EAU), and mice lacking IL-35 (p35 knockout (KO) mice) or defective in IL-35 signaling (IL-12Rβ2 KO mice) produced less Breg cells endogenously or after treatment with IL-35 and developed severe uveitis. Adoptive transfer of Breg cells induced by recombinant IL-35 suppressed EAU when transferred to mice with established disease, inhibiting pathogenic T helper type 17 (TH17) and TH1 cells while promoting Treg cell expansion. In B cells, IL-35 activates STAT1 and STAT3 through the IL-35 receptor comprising the IL-12Rβ2 and IL-27Rα subunits. As IL-35 also induced the conversion of human B cells into Breg cells, these findings suggest that IL-35 may be used to induce autologous Breg and IL-35(+) Breg cells and treat autoimmune and inflammatory disease.", + "TAG_DATA": [ + "74, mice {'context': 'B-organism'}", + "85, mice {'context': 'B-organism'}", + "86, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "87, IL-35 {'perturbing_action': 'I-gene loss-of-function'}", + "88, (p35 {'perturbing_action': 'I-gene loss-of-function'}", + "89, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "90, (KO) {'perturbing_action': 'I-gene loss-of-function'}", + "91, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "97, (IL-12Rβ2 {'perturbing_action': 'I-gene loss-of-function'}", + "98, KO {'perturbing_action': 'I-gene loss-of-function'}", + "99, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "102, Breg {'context': 'B-cells'}", + "103, cells {'context': 'I-cells'}", + "117, Breg {'context': 'B-cells'}", + "118, cells {'context': 'I-cells'}", + "128, mice {'context': 'B-organism'}", + "135, helper {'context': 'I-cells'}", + "136, type {'context': 'I-cells'}", + "139, and {'context': 'I-cells'}", + "140, TH1 {'context': 'I-cells'}", + "141, cells {'context': 'I-cells'}", + "144, Treg {'context': 'B-cells'}", + "145, cell {'context': 'I-cells'}", + "148, B {'context': 'B-cells'}", + "149, cells, {'context': 'I-cells'}", + "172, human {'context': 'B-cells'}", + "173, B {'context': 'I-cells'}", + "174, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "85, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "86, lacking ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "87, IL-35 ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "88, (p35 ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "89, knockout ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "90, (KO) ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "91, mice) ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "97, (IL-12Rβ2 ['l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "98, KO ['l35', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "99, mice) ['l36', 'l47', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "102, Breg ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l37', 'l48', 'l58', 'l68']", + "103, cells ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l38', 'l49', 'l59', 'l68']", + "117, Breg ['l39', 'l50', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "118, cells ['l40', 'l51', 'l61', 'l69', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "128, mice ['l41', 'l52', 'l62', 'l70', 'l79', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "135, helper ['l42', 'l53', 'l63', 'l71', 'l80', 'l86', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "136, type ['l43', 'l54', 'l64', 'l72', 'l81', 'l87', 'l94', 'l100', 'l101', 'l102', 'l103', 'l104']", + "139, and ['l44', 'l55', 'l65', 'l73', 'l82', 'l88', 'l95', 'l100', 'l105', 'l106', 'l107']", + "140, TH1 ['l45', 'l56', 'l66', 'l74', 'l83', 'l89', 'l96', 'l101', 'l105', 'l108', 'l109', 'l110', 'l111']", + "141, cells ['l46', 'l57', 'l67', 'l75', 'l84', 'l90', 'l97', 'l102', 'l106', 'l108', 'l112']", + "144, Treg ['l76', 'l91', 'l109', 'l113', 'l114', 'l115']", + "145, cell ['l77', 'l85', 'l92', 'l98', 'l103', 'l107', 'l110', 'l112', 'l113', 'l116', 'l117']", + "148, B ['l114', 'l116', 'l118', 'l119', 'l120', 'l121']", + "149, cells, ['l78', 'l93', 'l99', 'l104', 'l111', 'l115', 'l117', 'l118', 'l122', 'l123']", + "172, human ['l119', 'l124', 'l125']", + "173, B ['l120', 'l122', 'l124', 'l126']", + "174, cells ['l121', 'l123', 'l125', 'l126']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "IL-35", + "(p35", + "knockout", + "(KO)", + "mice)", + "(IL-12Rβ2", + "KO" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "IL-35", + "(p35", + "knockout", + "(KO)", + "mice)", + "(IL-12Rβ2", + "KO" + ] + }, + "context": { + "val": "cells", + "words": [ + "Breg", + "cells", + "helper", + "type", + "and", + "TH1" + ] + } + } + ] + }, + { + "PMID": "24728410", + "TEXT": "Liver disease is one of the leading causes of death worldwide. Patients with cirrhosis display an increased predisposition to and mortality from infection due to multimodal defects in the innate immune system; however, the causative mechanism has remained elusive. We present evidence that the cyclooxygenase (COX)-derived eicosanoid prostaglandin E2 (PGE2) drives cirrhosis-associated immunosuppression. We observed elevated circulating concentrations (more than seven times as high as in healthy volunteers) of PGE2 in patients with acute decompensation of cirrhosis. Plasma from these and patients with end-stage liver disease (ESLD) suppressed macrophage proinflammatory cytokine secretion and bacterial killing in vitro in a PGE2-dependent manner via the prostanoid type E receptor-2 (EP2), effects not seen with plasma from patients with stable cirrhosis (Child-Pugh score grade A). Albumin, which reduces PGE2 bioavailability, was decreased in the serum of patients with acute decompensation or ESLD (<30 mg/dl) and appears to have a role in modulating PGE2-mediated immune dysfunction. In vivo administration of human albumin solution to these patients significantly improved the plasma-induced impairment of macrophage proinflammatory cytokine production in vitro. Two mouse models of liver injury (bile duct ligation and carbon tetrachloride) also exhibited elevated PGE2, reduced circulating albumin concentrations and EP2-mediated immunosuppression. Treatment with COX inhibitors or albumin restored immune competence and survival following infection with group B Streptococcus. Taken together, human albumin solution infusions may be used to reduce circulating PGE2 levels, attenuating immune suppression and reducing the risk of infection in patients with acutely decompensated cirrhosis or ESLD.", + "TAG_DATA": [ + "95, in {'context': 'B-in vitro'}", + "96, vitro {'context': 'I-in vitro'}", + "152, In {'context': 'B-in vivo'}", + "153, vivo {'context': 'I-in vivo'}", + "168, macrophage {'context': 'B-cells'}", + "172, in {'context': 'B-in vitro'}", + "173, vitro. {'context': 'I-in vitro'}", + "175, mouse {'context': 'B-organism'}", + "176, models {'context': 'I-organism'}", + "178, liver {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "95, in ['l0']", + "96, vitro ['l0']", + "152, In ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "153, vivo ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "168, macrophage ['l2', 'l7', 'l12', 'l13']", + "172, in ['l3', 'l8', 'l12', 'l14']", + "173, vitro. ['l4', 'l9', 'l13', 'l14']", + "175, mouse ['l15', 'l16']", + "176, models ['l5', 'l10', 'l15', 'l17']", + "178, liver ['l6', 'l11', 'l16', 'l17']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24710377", + "TEXT": "Certain biological features are inherent traits of cancer, yet some of them still hold mysteries for researchers and clinicians. The heterogeneity of a tumor mass is an old concept that has lately become both a puzzling factor and a feature that should be harnessed to better understand tumor vulnerabilities. Improved scientific approaches to further determine and uncover the meaning of these heterogeneous features are still needed to translate findings into ways to develop therapies, identify drug response biomarkers and stratify patients. In Bedside to Bench, Maria Kleppe and Ross L. Levine look at recent clinical cancer trials that have advanced the field and discuss main questions regarding the role of tumor heterogeneity in predicting therapeutic response and tumor progression. In addition, they raise awareness of the relevance of the interactions among different tumor entities and their contribution to the malignancy of the whole tumor. In Bench to Bedside, Kornelia Polyak peruses studies that uncover specific mutations conferring endocrine drug resistance in breast tumors and that add to our knowledge of the evolution and architecture of tumors, and she discusses how this can be used to implement drug regimens.", + "TAG_DATA": [ + "161, breast {'context': 'B-neoplasm'}", + "162, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "161, breast ['l0']", + "162, tumors ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24658075", + "TEXT": "In response to microbial infection, expression of the defensin-like peptide hepcidin (encoded by Hamp) is induced in hepatocytes to decrease iron release from macrophages. To elucidate the mechanism by which Salmonella enterica var. Typhimurium (S. typhimurium), an intramacrophage bacterium, alters host iron metabolism for its own survival, we examined the role of nuclear receptor family members belonging to the NR3B subfamily in mouse hepatocytes. Here, we report that estrogen-related receptor γ (ERRγ, encoded by Esrrg) modulates the intramacrophage proliferation of S. typhimurium by altering host iron homeostasis, and we demonstrate an antimicrobial effect of an ERRγ inverse agonist. Hepatic ERRγ expression was induced by S. typhimurium-stimulated interleukin-6 signaling, resulting in an induction of hepcidin and eventual hypoferremia in mice. Conversely, ablation of ERRγ mRNA expression in liver attenuated the S. typhimurium-mediated induction of hepcidin and normalized the hypoferremia caused by S. typhimurium infection. An inverse agonist of ERRγ ameliorated S. typhimurium-mediated hypoferremia through reduction of ERRγ-mediated hepcidin mRNA expression and exerted a potent antimicrobial effect on the S. typhimurium infection, thereby improving host survival. Taken together, these findings suggest an alternative approach to control multidrug-resistant intracellular bacteria by modulating host iron homeostasis.", + "TAG_DATA": [ + "118, mice. {'context': 'B-organism'}", + "120, ablation {'perturbing_action': 'B-gene loss-of-function'}", + "121, of {'perturbing_action': 'I-gene loss-of-function'}", + "122, ERRγ {'perturbing_action': 'I-gene loss-of-function'}", + "123, mRNA {'perturbing_action': 'I-gene loss-of-function'}", + "124, expression {'perturbing_action': 'I-gene loss-of-function'}", + "126, liver {'context': 'B-tissue/organ'}", + "144, inverse {'perturbing_action': 'B-pharmacological augmentation'}", + "145, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "146, of {'perturbing_action': 'I-pharmacological augmentation'}", + "147, ERRγ {'perturbing_action': 'I-pharmacological augmentation'}" + ], + "LINK_DATA": [ + "120, ablation ['l0', 'l1', 'l2', 'l3', 'l4']", + "121, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "122, ERRγ ['l1', 'l5', 'l9', 'l10', 'l11']", + "123, mRNA ['l2', 'l6', 'l9', 'l12', 'l13']", + "124, expression ['l3', 'l7', 'l10', 'l12', 'l14']", + "126, liver ['l4', 'l8', 'l11', 'l13', 'l14']", + "144, inverse ['l15', 'l16', 'l17']", + "145, agonist ['l15', 'l18', 'l19']", + "146, of ['l16', 'l18', 'l20']", + "147, ERRγ ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablation", + "of", + "ERRγ", + "mRNA", + "expression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "24562382", + "TEXT": "As antibodies to tumor necrosis factor (TNF) suppress immune responses in Crohn's disease by binding to membrane-bound TNF (mTNF), we created a fluorescent antibody for molecular mTNF imaging in this disease. Topical antibody administration in 25 patients with Crohn's disease led to detection of intestinal mTNF(+) immune cells during confocal laser endomicroscopy. Patients with high numbers of mTNF(+) cells showed significantly higher short-term response rates (92%) at week 12 upon subsequent anti-TNF therapy as compared to patients with low amounts of mTNF(+) cells (15%). This clinical response in the former patients was sustained over a follow-up period of 1 year and was associated with mucosal healing observed in follow-up endoscopy. These data indicate that molecular imaging with fluorescent antibodies has the potential to predict therapeutic responses to biological treatment and can be used for personalized medicine in Crohn's disease and autoimmune or inflammatory disorders.", + "TAG_DATA": [ + "36, patients {'context': 'B-patient'}", + "37, with {'context': 'I-patient'}", + "38, Crohn's {'context': 'I-patient'}", + "39, disease {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "36, patients ['l0', 'l1', 'l2']", + "37, with ['l0', 'l3', 'l4']", + "38, Crohn's ['l1', 'l3', 'l5']", + "39, disease ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24562381", + "TEXT": "Previous anti-inflammatory strategies against sepsis, a leading cause of death in hospitals, had limited efficacy in clinical trials, in part because they targeted single cytokines and the experimental models failed to mimic clinical settings. Neuronal networks represent physiological mechanisms, selected by evolution to control inflammation, that can be exploited for the treatment of inflammatory and infectious disorders. Here, we report that sciatic nerve activation with electroacupuncture controls systemic inflammation and rescues mice from polymicrobial peritonitis. Electroacupuncture at the sciatic nerve controls systemic inflammation by inducing vagal activation of aromatic L-amino acid decarboxylase, leading to the production of dopamine in the adrenal medulla. Experimental models with adrenolectomized mice mimic clinical adrenal insufficiency, increase the susceptibility to sepsis and prevent the anti-inflammatory effects of electroacupuncture. Dopamine inhibits cytokine production via dopamine type 1 (D1) receptors. D1 receptor agonists suppress systemic inflammation and rescue mice with adrenal insufficiency from polymicrobial peritonitis. Our results suggest a new anti-inflammatory mechanism mediated by the sciatic and vagus nerves that modulates the production of catecholamines in the adrenal glands. From a pharmacological perspective, the effects of selective dopamine agonists mimic the anti-inflammatory effects of electroacupuncture and can provide therapeutic advantages to control inflammation in infectious and inflammatory disorders.", + "TAG_DATA": [ + "71, mice {'context': 'B-organism'}", + "106, mice {'context': 'B-organism'}", + "135, agonists {'perturbing_action': 'I-pharmacological augmentation'}", + "141, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "135, agonists ['l0']", + "141, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "agonists" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "24509527", + "TEXT": "Malaria relapses, resulting from the activation of quiescent hepatic hypnozoites of Plasmodium vivax and Plasmodium ovale, hinder global efforts to control and eliminate malaria. As primaquine, the only drug capable of eliminating hypnozoites, is unsuitable for mass administration, an alternative drug is needed urgently. Currently, analyses of hypnozoites, including screening of compounds that would eliminate them, can only be made using common macaque models, principally Macaca rhesus and Macaca fascicularis, experimentally infected with the relapsing Plasmodium cynomolgi. Here, we present a protocol for long-term in vitro cultivation of P. cynomolgi-infected M. fascicularis primary hepatocytes during which hypnozoites persist and activate to resume normal development. In a proof-of-concept experiment, we obtained evidence that exposure to an inhibitor of histone modification enzymes implicated in epigenetic control of gene expression induces an accelerated rate of hypnozoite activation. The protocol presented may further enable investigations of hypnozoite biology and the search for compounds that kill hypnozoites or disrupt their quiescence.", + "TAG_DATA": [ + "84, in {'context': 'B-in vitro'}", + "85, vitro {'context': 'I-in vitro'}", + "90, M. {'context': 'B-cells'}", + "91, fascicularis {'context': 'I-cells'}", + "92, primary {'context': 'I-cells'}", + "93, hepatocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "84, in ['l0', 'l1', 'l2', 'l3', 'l4']", + "85, vitro ['l0', 'l5', 'l6', 'l7', 'l8']", + "90, M. ['l1', 'l5', 'l9', 'l10', 'l11']", + "91, fascicularis ['l2', 'l6', 'l9', 'l12', 'l13']", + "92, primary ['l3', 'l7', 'l10', 'l12', 'l14']", + "93, hepatocytes ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24504404", + "TEXT": "The growing relevance of the gut microbiota to various human diseases may also directly impinge on the efficacy of chemotherapeutics. A recent study shows that subcutaneous tumors fail to respond to immunotherapy and platinum chemotherapy after antibiotic treatment, whereas another study reports that the effect of cyclophosphamide on the antitumor immune response relies on the presence of a ‘healthy’ gut microbiota. The mechanisms mediating the role of the microbiota in the immune system during chemotherapy seem to involve the innate and adaptive immune arms. The unexpected influence of commensal intestinal bacteria in the outcome of cancer treatment and the function of anticancer immunity poses new questions from a preclinical and clinical standpoint in the cancer field.", + "TAG_DATA": [ + "25, subcutaneous {'context': 'B-neoplasm'}", + "26, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "25, subcutaneous ['l0']", + "26, tumors ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24412926", + "TEXT": "Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML)-retinoic acid receptor-α (PML-RARA) fusion protein, which interferes with nuclear receptor signaling and PML nuclear body (NB) assembly. APL is the only malignancy definitively cured by targeted therapies: retinoic acid (RA) and/or arsenic trioxide, which both trigger PML-RARA degradation through nonoverlapping pathways. Yet, the cellular and molecular determinants of treatment efficacy remain disputed. We demonstrate that a functional Pml-transformation-related protein 53 (Trp53) axis is required to eradicate leukemia-initiating cells in a mouse model of APL. Upon RA-induced PML-RARA degradation, normal Pml elicits NB reformation and induces a Trp53 response exhibiting features of senescence but not apoptosis, ultimately abrogating APL-initiating activity. Apart from triggering PML-RARA degradation, arsenic trioxide also targets normal PML to enhance NB reformation, which may explain its clinical potency, alone or with RA. This Pml-Trp53 checkpoint initiated by therapy-triggered NB restoration is specific for PML-RARA-driven APL, but not the RA-resistant promyelocytic leukemia zinc finger (PLZF)-RARA variant. Yet, as NB biogenesis is druggable, it could be therapeutically exploited in non-APL malignancies.", + "TAG_DATA": [ + "81, mouse {'context': 'B-organism'}", + "82, model {'context': 'I-neoplasm'}", + "83, of {'context': 'I-neoplasm'}", + "84, APL. {'context': 'I-neoplasm'}", + "102, senescence {'phenotype': 'B-senescence'}", + "105, apoptosis, {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "81, mouse ['l0', 'l1', 'l2']", + "82, model ['l0', 'l3', 'l4']", + "83, of ['l1', 'l3', 'l5']", + "84, APL. ['l2', 'l4', 'l5']", + "102, senescence ['l6']", + "105, apoptosis, ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24412925", + "TEXT": "Cellular HIV-1 reservoirs that persist despite antiretroviral treatment are incompletely defined. We show that during suppressive antiretroviral therapy, CD4(+) T memory stem cells (TSCM cells) harbor high per-cell levels of HIV-1 DNA and make increasing contributions to the total viral CD4(+) T cell reservoir over time. Moreover, we conducted phylogenetic studies that suggested long-term persistence of viral quasispecies in CD4(+) TSCM cells. Thus, HIV-1 may exploit the stem cell characteristics of cellular immune memory to promote long-term viral persistence.", + "TAG_DATA": [ + "59, CD4(+) {'context': 'B-cells'}", + "60, TSCM {'context': 'I-cells'}", + "61, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "59, CD4(+) ['l0', 'l1']", + "60, TSCM ['l0', 'l2']", + "61, cells. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24336247", + "TEXT": "Hypercholesterolemia, typically due to excessive cholesterol uptake, is a major risk factor for cardiovascular disease, which is responsible for ∼50% of all deaths in developed societies. Although it has been shown that intestinal cholesterol absorption is mediated by vesicular endocytosis of the Niemann-Pick C1-like 1 (NPC1L1) protein, the mechanism of sterol-stimulated NPC1L1 internalization is still mysterious. Here, we identified an endocytic peptide signal, YVNXXF (where X stands for any amino acid), in the cytoplasmic C-terminal tail of NPC1L1. Cholesterol binding on the N-terminal domain of NPC1L1 released the YVNXXF-containing region of NPC1L1 from association with the plasma membrane and enabled Numb binding. We also found that Numb, a clathrin adaptor, specifically recognized this motif and recruited clathrin for internalization. Disrupting the NPC1L1-Numb interaction decreased cholesterol uptake. Ablation of Numb in mouse intestine significantly reduced dietary cholesterol absorption and plasma cholesterol level. Together, these data show that Numb is a pivotal protein for intestinal cholesterol absorption and may provide a therapeutic target for hypercholesterolemia.", + "TAG_DATA": [ + "126, Ablation {'perturbing_action': 'B-gene loss-of-function'}", + "127, of {'perturbing_action': 'I-gene loss-of-function'}", + "128, Numb {'perturbing_action': 'I-gene loss-of-function'}", + "130, mouse {'context': 'B-tissue/organ'}", + "131, intestine {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "126, Ablation ['l0', 'l1', 'l2', 'l3']", + "127, of ['l0', 'l4', 'l5', 'l6']", + "128, Numb ['l1', 'l4', 'l7', 'l8']", + "130, mouse ['l2', 'l5', 'l7', 'l9']", + "131, intestine ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "Numb" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "intestine" + ] + } + } + ] + }, + { + "PMID": "24317120", + "TEXT": "Despite the central role of the liver in the regulation of glucose and lipid metabolism, there are currently no methods to directly assess hepatic oxidative metabolism in humans in vivo. By using a new (13)C-labeling strategy in combination with (13)C magnetic resonance spectroscopy, we show that rates of mitochondrial oxidation and anaplerosis in human liver can be directly determined noninvasively. Using this approach, we found the mean rates of hepatic tricarboxylic acid (TCA) cycle flux (VTCA) and anaplerotic flux (VANA) to be 0.43 ± 0.04 μmol g(-1) min(-1) and 0.60 ± 0.11 μmol g(-1) min(-1), respectively, in twelve healthy, lean individuals. We also found the VANA/VTCA ratio to be 1.39 ± 0.22, which is severalfold lower than recently published estimates using an indirect approach. This method will be useful for understanding the pathogenesis of nonalcoholic fatty liver disease and type 2 diabetes, as well as for assessing the effectiveness of new therapies targeting these pathways in humans.", + "TAG_DATA": [ + "54, liver {'context': 'I-tissue/organ'}", + "99, lean {'context': 'I-organism'}", + "100, individuals. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "53, human ['l0']", + "54, liver ['l0']", + "99, lean ['l1']", + "100, individuals. ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24317118", + "TEXT": "Human CD4(+)CD25(high)CD127(-)FoxP3(+) regulatory T (Treg) cells suppress immune responses in vitro and in vivo. Reduced suppressive function and/or number of peripheral Treg cells has been previously reported in autoimmune disorders. Treg cells represent the most actively replicating compartment within the CD4(+) cells in vivo, but they are hyporesponsive to classical T cell receptor (TCR) stimulation in vitro, a condition that is secondary to their overactive metabolic state. Here we report that proliferation of Treg cells after TCR stimulation is impaired in subjects with relapsing-remitting multiple sclerosis (RRMS) because of altered interleukin-2 (IL-2) secretion and IL-2 receptor (IL-2R)-signal transducer and activator of transcription 5 (STAT5) signaling. This is associated with decreased expression of the forkhead box P3 (FoxP3) 44- and 47-kDa splicing forms, overactivation of S6 ribosomal protein (a downstream target of the mammalian target of rapamycin, mTOR) and altered activity of the cyclin-dependent kinase inhibitor p27 (p27(kip1)) and extracellular signal-related kinases 1 and 2 (ERK1/2). The impaired capacity of Treg cells to proliferate in RRMS correlates with the clinical state of the subject, where increasing disease severity is associated with a decline in Treg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of Treg cells in autoimmune disease.", + "TAG_DATA": [ + "71, proliferation {'phenotype': 'B-proliferation'}", + "73, Treg {'context': 'B-cells'}", + "74, cells {'context': 'I-cells'}", + "79, impaired {'effect': 'B-negative'}", + "156, impaired {'effect': 'B-negative'}", + "157, capacity {'effect': 'I-negative'}", + "159, Treg {'context': 'B-cells'}", + "160, cells {'context': 'I-cells'}", + "162, proliferate {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "71, proliferation ['l0', 'l1', 'l2']", + "73, Treg ['l0', 'l3', 'l4']", + "74, cells ['l1', 'l3', 'l5']", + "79, impaired ['l2', 'l4', 'l5']", + "156, impaired ['l6', 'l7', 'l8', 'l9']", + "157, capacity ['l6', 'l10', 'l11', 'l12']", + "159, Treg ['l7', 'l10', 'l13', 'l14']", + "160, cells ['l8', 'l11', 'l13', 'l15']", + "162, proliferate ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation", + "proliferate" + ] + }, + "context": { + "val": "cells", + "words": [ + "Treg", + "cells" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation", + "proliferate" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired", + "capacity" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Treg", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired", + "capacity" + ] + } + } + ] + }, + { + "PMID": "24309642", + "TEXT": "Japan boasts the second-largest pharmaceutical industry in the world. With its rich background in medical research, the country has turned its attention to diseases of the developing world with this year's launch of the Global Health Innovative Technology (GHIT) Fund--a new public-private partnership between five Japanese pharmaceutical companies, two government ministries and the Bill & Melinda Gates Foundation. In November, the Tokyo-based fund announced its first round of awards totaling $5.7 million. The six grants will go to partnerships aimed at developing new drugs and vaccines to fight malaria, tuberculosis and Chagas disease, a neglected disease endemic to Latin America. Leading the new $120 million, five-year initiative is BT Slingsby, a US-born scholar of the Japanese healthcare industry who most recently served as director of global partner solutions at Eisai, a Tokyo-based drugmaker. On a recent trip to New York, Slingsby, who serves as GHIT's executive director and CEO, met with Cassandra Willyard to discuss the new fund and how Japan can help drive development of medicines and vaccines for diseases of the developing world.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24240185", + "TEXT": "Tumor recurrence represents a major clinical challenge. Our data show that emergent recurrent tumors acquire a phenotype radically different from that of their originating primary tumors. This phenotype allows them to evade a host-derived innate immune response elicited by the progression from minimal residual disease (MRD) to actively growing recurrence. Screening for this innate response predicted accurately in which mice recurrence would occur. Premature induction of recurrence resensitized MRD to the primary therapy, suggesting a possible paradigm shift for clinical treatment of dormant disease in which the current expectant approach is replaced with active attempts to uncover MRD before evolution of the escape phenotype is complete. By combining screening with second-line treatments targeting innate insensitivity, up to 100% of mice that would have otherwise relapsed were cured. These data may open new avenues for early detection and appropriately timed, highly targeted treatment of tumor recurrence irrespective of tumor type or frontline treatment.", + "TAG_DATA": [ + "119, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24185694", + "TEXT": "Here, we describe a quantitative neuroimaging method to estimate the macromolecular tissue volume (MTV), a fundamental measure of brain anatomy. By making measurements over a range of field strengths and scan parameters, we tested the key assumptions and the robustness of the method. The measurements confirm that a consistent quantitative estimate of MTV can be obtained across a range of scanners. MTV estimates are sufficiently precise to enable a comparison between data obtained from an individual subject with control population data. We describe two applications. First, we show that MTV estimates can be combined with T1 and diffusion measurements to augment our understanding of the tissue properties. Second, we show that MTV provides a sensitive measure of disease status in individual patients with multiple sclerosis. The MTV maps are obtained using short clinically appropriate scans that can reveal how tissue changes influence behavior and cognition.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24162815", + "TEXT": "We identified new gene fusions in patients with lung cancer harboring the kinase domain of the NTRK1 gene that encodes the high-affinity nerve growth factor receptor (TRKA protein). Both the MPRIP-NTRK1 and CD74-NTRK1 fusions lead to constitutive TRKA kinase activity and are oncogenic. Treatment of cells expressing NTRK1 fusions with inhibitors of TRKA kinase activity inhibited autophosphorylation of TRKA and cell growth. Tumor samples from 3 of 91 patients with lung cancer (3.3%) without known oncogenic alterations assayed by next-generation sequencing or fluorescence in situ hybridization demonstrated evidence of NTRK1 gene fusions.", + "TAG_DATA": [ + "45, cells {'context': 'B-cells'}", + "55, inhibited {'effect': 'B-negative'}", + "60, cell {'phenotype': 'B-cell growth'}", + "61, growth. {'phenotype': 'I-cell growth'}" + ], + "LINK_DATA": [ + "45, cells ['l0', 'l1', 'l2']", + "55, inhibited ['l0', 'l3', 'l4']", + "60, cell ['l1', 'l3', 'l5']", + "61, growth. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth." + ] + } + } + ] + }, + { + "PMID": "24100977", + "TEXT": "Glioblastoma multiforme (GBM) is the most common type of aggressive malignant brain cancer. The current lack of successful therapeutics means that this disease has a dismal prognosis. However, a new study in mice offers hope for patients with GBM by demonstrating the efficacy of a novel drug that targets GBM-associated macrophages (pages 1264–1272).", + "TAG_DATA": [ + "32, mice {'context': 'B-organism'}", + "49, GBM-associated {'context': 'B-cells'}", + "50, macrophages {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "49, GBM-associated ['l0']", + "50, macrophages ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24097189", + "TEXT": "A systemic inflammatory response is observed in patients undergoing hemorrhagic shock and sepsis. Here we report increased levels of cold-inducible RNA-binding protein (CIRP) in the blood of individuals admitted to the surgical intensive care unit with hemorrhagic shock. In animal models of hemorrhage and sepsis, CIRP is upregulated in the heart and liver and released into the circulation. In macrophages under hypoxic stress, CIRP translocates from the nucleus to the cytosol and is released. Recombinant CIRP stimulates the release of tumor necrosis factor-α (TNF-α) and HMGB1 from macrophages and induces inflammatory responses and causes tissue injury when injected in vivo. Hemorrhage-induced TNF-α and HMGB1 release and lethality were reduced in CIRP-deficient mice. Blockade of CIRP using antisera to CIRP attenuated inflammatory cytokine release and mortality after hemorrhage and sepsis. The activity of extracellular CIRP is mediated through the Toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex. Surface plasmon resonance analysis indicated that CIRP binds to the TLR4-MD2 complex, as well as to TLR4 and MD2 individually. In particular, human CIRP amino acid residues 106-125 bind to MD2 with high affinity. Thus, CIRP is a damage-associated molecular pattern molecule that promotes inflammatory responses in shock and sepsis.", + "TAG_DATA": [ + "87, macrophages {'context': 'B-cells'}", + "98, in {'context': 'B-in vivo'}", + "99, vivo. {'context': 'I-in vivo'}", + "110, CIRP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "111, mice. {'context': 'B-organism'}", + "112, Blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "113, of {'perturbing_action': 'I-pharmacological inhibition'}", + "114, CIRP {'perturbing_action': 'I-pharmacological inhibition'}", + "115, using {'perturbing_action': 'I-pharmacological inhibition'}", + "116, antisera {'perturbing_action': 'I-pharmacological inhibition'}", + "117, to {'perturbing_action': 'I-pharmacological inhibition'}", + "118, CIRP {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "87, macrophages ['l0', 'l1']", + "98, in ['l0', 'l2']", + "99, vivo. ['l1', 'l2']", + "110, CIRP-deficient ['l3']", + "111, mice. ['l3']", + "112, Blockade ['l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "113, of ['l4', 'l10', 'l11', 'l12', 'l13', 'l14']", + "114, CIRP ['l5', 'l10', 'l15', 'l16', 'l17', 'l18']", + "115, using ['l6', 'l11', 'l15', 'l19', 'l20', 'l21']", + "116, antisera ['l7', 'l12', 'l16', 'l19', 'l22', 'l23']", + "117, to ['l8', 'l13', 'l17', 'l20', 'l22', 'l24']", + "118, CIRP ['l9', 'l14', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CIRP-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "24056773", + "TEXT": "Glioblastoma multiforme (GBM) comprises several molecular subtypes, including proneural GBM. Most therapeutic approaches targeting glioma cells have failed. An alternative strategy is to target cells in the glioma microenvironment, such as tumor-associated macrophages and microglia (TAMs). Macrophages depend on colony stimulating factor-1 (CSF-1) for differentiation and survival. We used an inhibitor of the CSF-1 receptor (CSF-1R) to target TAMs in a mouse proneural GBM model, which significantly increased survival and regressed established tumors. CSF-1R blockade additionally slowed intracranial growth of patient-derived glioma xenografts. Surprisingly, TAMs were not depleted in treated mice. Instead, glioma-secreted factors, including granulocyte-macrophage CSF (GM-CSF) and interferon-γ (IFN-γ), facilitated TAM survival in the context of CSF-1R inhibition. Expression of alternatively activated M2 markers decreased in surviving TAMs, which is consistent with impaired tumor-promoting functions. These gene signatures were associated with enhanced survival in patients with proneural GBM. Our results identify TAMs as a promising therapeutic target for proneural gliomas and establish the translational potential of CSF-1R inhibition for GBM.", + "TAG_DATA": [ + "50, inhibitor {'perturbing_action': 'B-pharmacological inhibition'}", + "51, of {'perturbing_action': 'I-pharmacological inhibition'}", + "52, the {'perturbing_action': 'I-pharmacological inhibition'}", + "53, CSF-1 {'perturbing_action': 'I-pharmacological inhibition'}", + "54, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "55, (CSF-1R) {'perturbing_action': 'I-pharmacological inhibition'}", + "61, mouse {'context': 'B-neoplasm'}", + "62, proneural {'context': 'I-neoplasm'}", + "63, GBM {'context': 'I-neoplasm'}", + "64, model, {'context': 'I-neoplasm'}", + "72, tumors. {'context': 'B-neoplasm'}", + "80, patient-derived {'context': 'B-xenograft'}", + "81, glioma {'context': 'I-xenograft'}", + "82, xenografts. {'context': 'I-xenograft'}", + "84, TAMs {'context': 'B-cells'}", + "90, mice. {'context': 'B-organism'}", + "102, TAM {'context': 'B-cells'}", + "108, CSF-1R {'perturbing_action': 'B-pharmacological inhibition'}", + "109, inhibition. {'perturbing_action': 'I-pharmacological inhibition'}", + "119, TAMs, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "50, inhibitor ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "51, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "52, the ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "53, CSF-1 ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "54, receptor ['l3', 'l15', 'l26', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "55, (CSF-1R) ['l4', 'l16', 'l27', 'l37', 'l45', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "61, mouse ['l5', 'l17', 'l28', 'l38', 'l46', 'l53', 'l60', 'l61', 'l62', 'l63', 'l64']", + "62, proneural ['l6', 'l18', 'l29', 'l39', 'l47', 'l54', 'l60', 'l65', 'l66', 'l67', 'l68']", + "63, GBM ['l7', 'l19', 'l30', 'l40', 'l48', 'l55', 'l61', 'l65', 'l69', 'l70', 'l71']", + "64, model, ['l8', 'l20', 'l31', 'l41', 'l49', 'l56', 'l62', 'l66', 'l69', 'l72', 'l73']", + "70, regressed ['l9', 'l21', 'l32', 'l42', 'l50', 'l57', 'l63', 'l67', 'l70', 'l72', 'l74']", + "72, tumors. ['l10', 'l22', 'l33', 'l43', 'l51', 'l58', 'l64', 'l68', 'l71', 'l73', 'l74']", + "80, patient-derived ['l75', 'l76']", + "81, glioma ['l11', 'l23', 'l34', 'l44', 'l52', 'l59', 'l75', 'l77']", + "82, xenografts. ['l12', 'l24', 'l35', 'l76', 'l77']", + "84, TAMs ['l78']", + "90, mice. ['l78']", + "102, TAM ['l79', 'l80']", + "108, CSF-1R ['l79', 'l81']", + "109, inhibition. ['l80', 'l81']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitor", + "of", + "the", + "CSF-1", + "receptor", + "(CSF-1R)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "proneural", + "GBM", + "model,", + "tumors." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitor", + "of", + "the", + "CSF-1", + "receptor", + "(CSF-1R)" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "glioma", + "xenografts." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "TAM" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CSF-1R", + "inhibition." + ] + } + } + ] + }, + { + "PMID": "24037094", + "TEXT": "Insulin initiates diverse hepatic metabolic responses, including gluconeogenic suppression and induction of glycogen synthesis and lipogenesis. The liver possesses a rich sinusoidal capillary network with a higher degree of hypoxia and lower gluconeogenesis in the perivenous zone as compared to the rest of the organ. Here, we show that diverse vascular endothelial growth factor (VEGF) inhibitors improved glucose tolerance in nondiabetic C57BL/6 and diabetic db/db mice, potentiating hepatic insulin signaling with lower gluconeogenic gene expression, higher glycogen storage and suppressed hepatic glucose production. VEGF inhibition induced hepatic hypoxia through sinusoidal vascular regression and sensitized liver insulin signaling through hypoxia-inducible factor-2α (Hif-2α, encoded by Epas1) stabilization. Notably, liver-specific constitutive activation of HIF-2α, but not HIF-1α, was sufficient to augment hepatic insulin signaling through direct and indirect induction of insulin receptor substrate-2 (Irs2), an essential insulin receptor adaptor protein. Further, liver Irs2 was both necessary and sufficient to mediate Hif-2α and Vegf inhibition effects on glucose tolerance and hepatic insulin signaling. These results demonstrate an unsuspected intersection between Hif-2α-mediated hypoxic signaling and hepatic insulin action through Irs2 induction, which can be co-opted by Vegf inhibitors to modulate glucose metabolism. These studies also indicate distinct roles in hepatic metabolism for Hif-1α, which promotes glycolysis, and Hif-2α, which suppresses gluconeogenesis, and suggest new treatment approaches for type 2 diabetes mellitus.", + "TAG_DATA": [ + "50, vascular {'perturbing_action': 'B-pharmacological inhibition'}", + "51, endothelial {'perturbing_action': 'I-pharmacological inhibition'}", + "52, growth {'perturbing_action': 'I-pharmacological inhibition'}", + "53, factor {'perturbing_action': 'I-pharmacological inhibition'}", + "54, (VEGF) {'perturbing_action': 'I-pharmacological inhibition'}", + "55, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "60, nondiabetic {'context': 'B-organism'}", + "61, C57BL/6 {'context': 'I-organism'}", + "63, diabetic {'context': 'B-organism'}", + "64, db/db {'context': 'I-organism'}", + "65, mice, {'context': 'I-organism'}", + "94, liver {'context': 'B-tissue/organ'}", + "106, liver-specific {'perturbing_action': 'B-gene gain-of-function'}", + "107, constitutive {'perturbing_action': 'I-gene gain-of-function'}", + "108, activation {'perturbing_action': 'I-gene gain-of-function'}", + "109, of {'perturbing_action': 'I-gene gain-of-function'}", + "110, HIF-2α, {'perturbing_action': 'I-gene gain-of-function'}", + "138, liver {'context': 'B-tissue/organ'}", + "149, Vegf {'perturbing_action': 'B-pharmacological inhibition'}", + "150, inhibition {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "50, vascular ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "51, endothelial ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "52, growth ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "53, factor ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "54, (VEGF) ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "55, inhibitors ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "60, nondiabetic ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "61, C57BL/6 ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "63, diabetic ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "64, db/db ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "65, mice, ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "106, liver-specific ['l55', 'l56', 'l57', 'l58']", + "107, constitutive ['l55', 'l59', 'l60', 'l61']", + "108, activation ['l56', 'l59', 'l62', 'l63']", + "109, of ['l57', 'l60', 'l62', 'l64']", + "110, HIF-2α, ['l58', 'l61', 'l63', 'l64']", + "138, liver ['l65', 'l66']", + "149, Vegf ['l65', 'l67']", + "150, inhibition ['l66', 'l67']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "vascular", + "endothelial", + "growth", + "factor", + "(VEGF)", + "inhibitors" + ] + }, + "context": { + "val": "organism", + "words": [ + "nondiabetic", + "C57BL/6", + "diabetic", + "db/db", + "mice," + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Vegf", + "inhibition" + ] + } + } + ] + }, + { + "PMID": "24037093", + "TEXT": "Signaling initiated by hypoxia and insulin powerfully alters cellular metabolism. The protein stability of hypoxia-inducible factor-1 alpha (Hif-1α) and Hif-2α is regulated by three prolyl hydroxylase domain-containing protein isoforms (Phd1, Phd2 and Phd3). Insulin receptor substrate-2 (Irs2) is a critical mediator of the anabolic effects of insulin, and its decreased expression contributes to the pathophysiology of insulin resistance and diabetes. Although Hif regulates many metabolic pathways, it is unknown whether the Phd proteins regulate glucose and lipid metabolism in the liver. Here, we show that acute deletion of hepatic Phd3, also known as Egln3, improves insulin sensitivity and ameliorates diabetes by specifically stabilizing Hif-2α, which then increases Irs2 transcription and insulin-stimulated Akt activation. Hif-2α and Irs2 are both necessary for the improved insulin sensitivity, as knockdown of either molecule abrogates the beneficial effects of Phd3 knockout on glucose tolerance and insulin-stimulated Akt phosphorylation. Augmenting levels of Hif-2α through various combinations of Phd gene knockouts did not further improve hepatic metabolism and only added toxicity. Thus, isoform-specific inhibition of Phd3 could be exploited to treat type 2 diabetes without the toxicity that could occur with chronic inhibition of multiple Phd isoforms.", + "TAG_DATA": [ + "86, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "87, of {'perturbing_action': 'I-gene loss-of-function'}", + "88, hepatic {'perturbing_action': 'I-gene loss-of-function'}", + "89, Phd3, {'perturbing_action': 'I-gene loss-of-function'}", + "90, also {'perturbing_action': 'I-gene loss-of-function'}", + "91, known {'perturbing_action': 'I-gene loss-of-function'}", + "92, as {'perturbing_action': 'I-gene loss-of-function'}", + "93, Egln3, {'perturbing_action': 'I-gene loss-of-function'}", + "125, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "126, of {'perturbing_action': 'I-rnai/knockdown'}", + "127, either {'perturbing_action': 'I-rnai/knockdown'}", + "128, molecule {'perturbing_action': 'I-rnai/knockdown'}", + "134, Phd3 {'perturbing_action': 'B-gene loss-of-function'}", + "135, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "151, Phd {'perturbing_action': 'B-gene loss-of-function'}", + "152, gene {'perturbing_action': 'I-gene loss-of-function'}", + "153, knockouts {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "86, deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "87, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "88, hepatic ['l1', 'l7', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "89, Phd3, ['l2', 'l8', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "90, also ['l3', 'l9', 'l15', 'l20', 'l25', 'l26', 'l27', 'l28', 'l29']", + "91, known ['l4', 'l10', 'l16', 'l21', 'l25', 'l30', 'l31', 'l32', 'l33']", + "92, as ['l5', 'l11', 'l17', 'l22', 'l26', 'l30', 'l34', 'l35', 'l36']", + "93, Egln3, ['l6', 'l12', 'l18', 'l23', 'l27', 'l31', 'l34', 'l37', 'l38']", + "125, knockdown ['l39', 'l40', 'l41', 'l42', 'l43']", + "126, of ['l39', 'l44', 'l45', 'l46', 'l47']", + "127, either ['l40', 'l44', 'l48', 'l49', 'l50']", + "128, molecule ['l28', 'l32', 'l35', 'l37', 'l41', 'l45', 'l48', 'l51', 'l52']", + "134, Phd3 ['l42', 'l46', 'l49', 'l51', 'l53']", + "135, knockout ['l13', 'l19', 'l24', 'l29', 'l33', 'l36', 'l38', 'l43', 'l47', 'l50', 'l52', 'l53']", + "151, Phd ['l54', 'l55']", + "152, gene ['l54', 'l56']", + "153, knockouts ['l55', 'l56']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24013743", + "TEXT": "TACE-mediated proteolysis is a key event interfering with both Alzheimer's and prion diseases. A new study shows that phosphoinositide-dependent kinase-1 (PDK1) is activated by cellular prion protein, which alters membrane-associated TACE levels, thereby influencing both Alzheimer's and prion pathologies.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24013741", + "TEXT": "There is no rulebook for how to be a scientist–advocate, but that shouldn’t stop researchers from engaging with the broader community. In fact, it’s an essential part of being a good steward of your science.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24013740", + "TEXT": "It begins as a slowly expanding spot of light or similar visual disturbance, often accompanied by phantom noises and other sensory distortions. People who experience such 'auras' know all too well that these early warning signs will culminate in a head-splitting migraine, yet scientists have little idea what causes the debilitating deluge of symptoms. Elie Dolgin talks to neurologists hoping to change that - by triggering auras in the laboratory in order to study them.", + "TAG_DATA": [ + "58, neurologists {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24013701", + "TEXT": "In the era of personalized medicine, there is an urgent need for in vivo techniques able to sensitively detect and quantify molecular activities. Sensitive imaging of gamma rays is widely used; however, radioactive decay is a physical constant, and its signal is independent of biological interactions. Here, we introduce a framework of previously uncharacterized targeted and activatable probes that are excited by a nuclear decay-derived signal to identify and measure molecular signatures of disease. We accomplished this by using Cerenkov luminescence, the light produced by β-particle-emitting radionuclides such as clinical positron emission tomography (PET) tracers. Disease markers were detected using nanoparticles to produce secondary Cerenkov-induced fluorescence. This approach reduces background signal compared to conventional fluorescence imaging. In addition to tumor identification from a conventional PET scan, we demonstrate the medical utility of our approach by quantitatively determining prognostically relevant enzymatic activity. This technique can be applied to monitor other markers and represents a shift toward activatable nuclear medicine agents.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23955714", + "TEXT": "α-secretase-mediated cleavage of amyloid precursor protein (APP) precludes formation of neurotoxic amyloid-β (Aβ) peptides, and α-cleavage of cellular prion protein (PrP(C)) prevents its conversion into misfolded, pathogenic prions (PrP(Sc)). The mechanisms leading to decreased α-secretase activity in Alzheimer's and prion disease remain unclear. Here, we find that tumor necrosis factor-α-converting enzyme (TACE)-mediated α-secretase activity is impaired at the surface of neurons infected with PrP(Sc) or isolated from APP-transgenic mice with amyloid pathology. 3-phosphoinositide-dependent kinase-1 (PDK1) activity is increased in neurons infected with prions or affected by Aβ deposition and in the brains of individuals with Alzheimer's disease. PDK1 induces phosphorylation and caveolin-1-mediated internalization of TACE. This dysregulation of TACE increases PrP(Sc) and Aβ accumulation and reduces shedding of TNF-α receptor type 1 (TNFR1). Inhibition of PDK1 promotes localization of TACE to the plasma membrane, restores TACE-dependent α-secretase activity and cleavage of APP, PrP(C) and TNFR1, and attenuates PrP(Sc)- and Aβ-induced neurotoxicity. In mice, inhibition or siRNA-mediated silencing of PDK1 extends survival and reduces motor impairment following PrP(Sc) infection and in APP-transgenic mice reduces Alzheimer's disease-like pathology and memory impairment.", + "TAG_DATA": [ + "60, neurons {'context': 'B-cells'}", + "67, APP-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "68, mice {'context': 'B-organism'}", + "79, neurons {'context': 'B-cells'}", + "123, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "124, of {'perturbing_action': 'I-pharmacological inhibition'}", + "125, PDK1 {'perturbing_action': 'I-pharmacological inhibition'}", + "152, mice, {'context': 'B-organism'}", + "155, siRNA-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "156, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "157, of {'perturbing_action': 'I-rnai/knockdown'}", + "158, PDK1 {'perturbing_action': 'I-rnai/knockdown'}", + "170, APP-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "171, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "60, neurons ['l0', 'l1', 'l2']", + "67, APP-transgenic ['l0', 'l3', 'l4']", + "68, mice ['l1', 'l3', 'l5']", + "79, neurons ['l2', 'l4', 'l5']", + "123, Inhibition ['l6', 'l7', 'l8']", + "124, of ['l6', 'l9', 'l10']", + "125, PDK1 ['l7', 'l9', 'l11']", + "152, mice, ['l8', 'l10', 'l11', 'l12', 'l13']", + "155, siRNA-mediated ['l14', 'l15', 'l16', 'l17', 'l18']", + "156, silencing ['l14', 'l19', 'l20', 'l21', 'l22']", + "157, of ['l15', 'l19', 'l23', 'l24', 'l25']", + "158, PDK1 ['l12', 'l16', 'l20', 'l23', 'l26', 'l27']", + "170, APP-transgenic ['l17', 'l21', 'l24', 'l26', 'l28']", + "171, mice ['l13', 'l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "neurons" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "APP-transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "APP-transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "PDK1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PDK1", + "siRNA-mediated", + "silencing", + "of" + ] + } + } + ] + }, + { + "PMID": "23955713", + "TEXT": "Measurement of vessel caliber by magnetic resonance imaging (MRI) is a valuable technique for in vivo monitoring of hemodynamic status and vascular development, especially in the brain. Here, we introduce a new paradigm in MRI termed vessel architectural imaging (VAI) that exploits an overlooked temporal shift in the magnetic resonance signal, forming the basis for vessel caliber estimation, and show how this phenomenon can reveal new information on vessel type and function not assessed by any other noninvasive imaging technique. We also show how this biomarker can provide new biological insights into the treatment of patients with cancer. As an example, we demonstrate using VAI that anti-angiogenic therapy can improve microcirculation and oxygen saturation and reduce vessel calibers in patients with recurrent glioblastomas and, more crucially, that patients with these responses have prolonged survival. Thus, VAI has the potential to identify patients who would benefit from therapies.", + "TAG_DATA": [ + "119, patients {'context': 'B-patient'}", + "121, recurrent {'context': 'B-neoplasm'}", + "122, glioblastomas {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "119, patients ['l0', 'l1']", + "121, recurrent ['l0', 'l2']", + "122, glioblastomas ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23955712", + "TEXT": "Type 2 diabetes mellitus (T2DM) progresses from compensated insulin resistance to beta cell failure resulting in uncompensated hyperglycemia, a process replicated in the Zucker diabetic fatty (ZDF) rat. The Nlrp3 inflammasome has been implicated in obesity-induced insulin resistance and beta cell failure. Endocannabinoids contribute to insulin resistance through activation of peripheral CB1 receptors (CB₁Rs) and also promote beta cell failure. Here we show that beta cell failure in adult ZDF rats is not associated with CB₁R signaling in beta cells, but rather in M1 macrophages infiltrating into pancreatic islets, and that this leads to activation of the Nlrp3-ASC inflammasome in the macrophages. These effects are replicated in vitro by incubating wild-type human or rodent macrophages, but not macrophages from CB₁R-deficient (Cnr1(-/-)) or Nlrp3(-/-) mice, with the endocannabinoid anandamide. Peripheral CB₁R blockade, in vivo depletion of macrophages or macrophage-specific knockdown of CB₁R reverses or prevents these changes and restores normoglycemia and glucose-induced insulin secretion. These findings implicate endocannabinoids and inflammasome activation in beta cell failure and identify macrophage-expressed CB₁R as a therapeutic target in T2DM.", + "TAG_DATA": [ + "106, in {'context': 'B-in vitro'}", + "107, vitro {'context': 'I-in vitro'}", + "111, human {'context': 'B-cells'}", + "112, or {'context': 'I-cells'}", + "113, rodent {'context': 'I-cells'}", + "114, macrophages, {'context': 'I-cells'}", + "117, macrophages {'context': 'B-cells'}", + "119, CB₁R-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "120, (Cnr1(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "122, Nlrp3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "123, mice, {'context': 'B-organism'}", + "131, in {'context': 'B-in vivo'}", + "132, vivo {'context': 'I-in vivo'}", + "135, macrophages {'context': 'B-cells'}", + "137, macrophage-specific {'perturbing_action': 'B-rnai/knockdown'}", + "138, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "139, of {'perturbing_action': 'I-rnai/knockdown'}", + "140, CB₁R {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "106, in ['l0', 'l1', 'l2', 'l3', 'l4']", + "107, vitro ['l0', 'l5', 'l6', 'l7', 'l8']", + "111, human ['l1', 'l5', 'l9', 'l10', 'l11', 'l12']", + "112, or ['l2', 'l6', 'l9', 'l13', 'l14', 'l15']", + "113, rodent ['l3', 'l7', 'l10', 'l13', 'l16', 'l17', 'l18']", + "114, macrophages, ['l4', 'l8', 'l11', 'l14', 'l16', 'l19', 'l20']", + "117, macrophages ['l12', 'l15', 'l17', 'l19', 'l21', 'l22', 'l23', 'l24']", + "119, CB₁R-deficient ['l21', 'l25', 'l26', 'l27']", + "120, (Cnr1(-/-)) ['l18', 'l20', 'l22', 'l25', 'l28', 'l29']", + "122, Nlrp3(-/-) ['l23', 'l26', 'l28', 'l30', 'l31']", + "123, mice, ['l24', 'l27', 'l29', 'l30']", + "131, in ['l32', 'l33', 'l34']", + "132, vivo ['l32', 'l35', 'l36', 'l37']", + "135, macrophages ['l31', 'l33', 'l35']", + "137, macrophage-specific ['l38', 'l39', 'l40']", + "138, knockdown ['l38', 'l41', 'l42']", + "139, of ['l36', 'l39', 'l41', 'l43']", + "140, CB₁R ['l34', 'l37', 'l40', 'l42', 'l43']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "rodent", + "macrophages,", + "macrophages" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "(Cnr1(-/-))", + "CB₁R-deficient", + "Nlrp3(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CB₁R-deficient", + "(Cnr1(-/-))", + "Nlrp3(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "CB₁R", + "of" + ] + } + } + ] + }, + { + "PMID": "23933983", + "TEXT": "Preventing reproduction during nutritional deprivation is an adaptive process that is conserved and essential for the survival of species. In mammals, the mechanisms that inhibit fertility during starvation are complex and incompletely understood. Here we show that exposure of female mice to fibroblast growth factor 21 (FGF21), a fasting-induced hepatokine, mimics infertility secondary to starvation. Mechanistically, FGF21 acts on the suprachiasmatic nucleus (SCN) in the hypothalamus to suppress the vasopressin-kisspeptin signaling cascade, thereby inhibiting the proestrus surge in luteinizing hormone. Mice lacking the FGF21 co-receptor, β-Klotho, in the SCN are refractory to the inhibitory effect of FGF21 on female fertility. Thus, FGF21 defines an important liver-neuroendocrine axis that modulates female reproduction in response to nutritional challenge.", + "TAG_DATA": [ + "39, female {'context': 'B-organism'}", + "40, mice {'context': 'I-organism'}", + "80, Mice {'context': 'B-organism'}", + "81, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "82, the {'perturbing_action': 'I-gene loss-of-function'}", + "83, FGF21 {'perturbing_action': 'I-gene loss-of-function'}", + "84, co-receptor, {'perturbing_action': 'I-gene loss-of-function'}", + "85, β-Klotho, {'perturbing_action': 'I-gene loss-of-function'}", + "86, in {'perturbing_action': 'I-gene loss-of-function'}", + "87, the {'perturbing_action': 'I-gene loss-of-function'}", + "88, SCN {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "39, female ['l0']", + "40, mice ['l0']", + "80, Mice ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "81, lacking ['l1', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "82, the ['l2', 'l9', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "83, FGF21 ['l3', 'l10', 'l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "84, co-receptor, ['l4', 'l11', 'l17', 'l22', 'l27', 'l28', 'l29', 'l30']", + "85, β-Klotho, ['l5', 'l12', 'l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "86, in ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "87, the ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "88, SCN ['l8', 'l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "FGF21", + "co-receptor,", + "β-Klotho,", + "in", + "SCN" + ] + } + } + ] + }, + { + "PMID": "23913123", + "TEXT": "New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis, several of which are currently in clinical trials. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis.", + "TAG_DATA": [ + "150, MDR {'context': 'B-transformed cells'}", + "151, and {'context': 'I-transformed cells'}", + "152, XDR {'context': 'I-transformed cells'}", + "153, M. {'context': 'I-transformed cells'}", + "154, tuberculosis {'context': 'I-transformed cells'}", + "155, clinical {'context': 'I-transformed cells'}", + "156, isolates {'context': 'I-transformed cells'}", + "171, mouse {'context': 'B-organism'}", + "172, model {'context': 'I-neoplasm'}", + "173, of {'context': 'I-neoplasm'}", + "174, tuberculosis {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "150, MDR ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "151, and ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "152, XDR ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "153, M. ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "154, tuberculosis ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "155, clinical ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "156, isolates ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "171, mouse ['l21', 'l22', 'l23']", + "172, model ['l21', 'l24', 'l25']", + "173, of ['l22', 'l24', 'l26']", + "174, tuberculosis ['l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23836200", + "TEXT": "The ability to patent human genes has been costly to researchers and patients, and has restricted competition in the biotech marketplace. The recent US Supreme Court decision making isolated human genes unpatentable will bring freedom of choice to the patient, and level the playing field for research and development.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23817023", + "TEXT": "Successful pregnancy requires coordination of an array of signals and factors from multiple tissues. One such element, liver receptor homolog-1 (Lrh-1), is an orphan nuclear receptor that regulates metabolism and hormone synthesis. It is strongly expressed in granulosa cells of ovarian follicles and in the corpus luteum of rodents and humans. Germline ablation of Nr5a2 (also called Lrh-1), the gene coding for Lrh-1, in mice is embryonically lethal at gastrulation. Depletion of Lrh-1 in the ovarian follicle shows that it regulates genes required for both steroid synthesis and ovulation. To study the effects of Lrh-1 on mouse gestation, we genetically disrupted its expression in the corpus luteum, resulting in luteal insufficiency. Hormone replacement permitted embryo implantation but was followed by gestational failure with impaired endometrial decidualization, compromised placental formation, fetal growth retardation and fetal death. Lrh-1 is also expressed in the mouse and human endometrium, and in a primary culture of human endometrial stromal cells, reduction of NR5A2 transcript abundance by RNA interference abrogated decidualization. These findings show that Lrh-1 is necessary for maintenance of the corpus luteum, for promotion of decidualization and for formation of the placenta. It therefore has multiple, indispensible roles in establishing and sustaining pregnancy.", + "TAG_DATA": [ + "51, Germline {'perturbing_action': 'B-gene loss-of-function'}", + "52, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "53, of {'perturbing_action': 'I-gene loss-of-function'}", + "54, Nr5a2 {'perturbing_action': 'I-gene loss-of-function'}", + "55, (also {'perturbing_action': 'I-gene loss-of-function'}", + "56, called {'perturbing_action': 'I-gene loss-of-function'}", + "57, Lrh-1), {'perturbing_action': 'I-gene loss-of-function'}", + "70, Depletion {'perturbing_action': 'B-gene loss-of-function'}", + "71, of {'perturbing_action': 'I-gene loss-of-function'}", + "72, Lrh-1 {'perturbing_action': 'I-gene loss-of-function'}", + "73, in {'perturbing_action': 'I-gene loss-of-function'}", + "100, disrupted {'perturbing_action': 'I-gene loss-of-function'}", + "102, expression {'perturbing_action': 'I-gene loss-of-function'}", + "103, in {'perturbing_action': 'I-gene loss-of-function'}", + "105, corpus {'context': 'B-tissue/organ'}", + "106, luteum, {'context': 'I-tissue/organ'}", + "113, permitted {'effect': 'B-positive'}", + "114, embryo {'context': 'B-organism'}", + "115, implantation {'phenotype': 'B-self-renewal'}", + "148, primary {'context': 'B-cells'}", + "149, culture {'context': 'I-cells'}", + "150, of {'context': 'I-cells'}", + "151, human {'context': 'I-cells'}", + "152, endometrial {'context': 'I-cells'}", + "153, stromal {'context': 'I-cells'}", + "154, cells, {'context': 'I-cells'}", + "155, reduction {'perturbing_action': 'B-rnai/knockdown'}", + "156, of {'perturbing_action': 'I-rnai/knockdown'}", + "157, NR5A2 {'perturbing_action': 'I-rnai/knockdown'}", + "158, transcript {'perturbing_action': 'I-rnai/knockdown'}", + "159, abundance {'perturbing_action': 'I-rnai/knockdown'}", + "161, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "162, interference {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "51, Germline ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "52, ablation ['l0', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "53, of ['l1', 'l19', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "54, Nr5a2 ['l2', 'l20', 'l36', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "55, (also ['l3', 'l21', 'l37', 'l52', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "56, called ['l4', 'l22', 'l38', 'l53', 'l68', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "57, Lrh-1), ['l5', 'l23', 'l39', 'l54', 'l69', 'l83', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "70, Depletion ['l6', 'l24', 'l40', 'l55', 'l70', 'l84', 'l98', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "71, of ['l7', 'l25', 'l41', 'l56', 'l71', 'l85', 'l99', 'l111', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "72, Lrh-1 ['l8', 'l26', 'l42', 'l57', 'l72', 'l86', 'l100', 'l112', 'l122', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "73, in ['l9', 'l27', 'l43', 'l58', 'l73', 'l87', 'l101', 'l113', 'l123', 'l131', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145']", + "100, disrupted ['l10', 'l28', 'l44', 'l59', 'l74', 'l88', 'l102', 'l114', 'l124', 'l132', 'l139', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151']", + "101, its ['l11', 'l29', 'l45', 'l60', 'l75', 'l89', 'l103', 'l115', 'l125', 'l133', 'l140', 'l146', 'l152', 'l153', 'l154', 'l155', 'l156']", + "102, expression ['l12', 'l30', 'l46', 'l61', 'l76', 'l90', 'l104', 'l116', 'l126', 'l134', 'l141', 'l147', 'l152', 'l157', 'l158', 'l159', 'l160']", + "103, in ['l13', 'l31', 'l47', 'l62', 'l77', 'l91', 'l105', 'l117', 'l127', 'l135', 'l142', 'l148', 'l153', 'l157', 'l161', 'l162', 'l163', 'l164', 'l165']", + "104, the ['l14', 'l32', 'l48', 'l63', 'l78', 'l92', 'l106', 'l118', 'l128', 'l136', 'l143', 'l149', 'l154', 'l158', 'l161', 'l166', 'l167', 'l168', 'l169']", + "105, corpus ['l15', 'l33', 'l49', 'l64', 'l79', 'l93', 'l107', 'l119', 'l129', 'l137', 'l144', 'l150', 'l155', 'l159', 'l162', 'l166', 'l170', 'l171', 'l172']", + "106, luteum, ['l16', 'l34', 'l50', 'l65', 'l80', 'l94', 'l108', 'l120', 'l130', 'l138', 'l145', 'l151', 'l156', 'l160', 'l163', 'l167', 'l170', 'l173', 'l174']", + "113, permitted ['l95', 'l175', 'l176']", + "114, embryo ['l17', 'l66', 'l81', 'l96', 'l109', 'l164', 'l168', 'l171', 'l173', 'l175', 'l177']", + "115, implantation ['l18', 'l35', 'l51', 'l67', 'l82', 'l97', 'l110', 'l121', 'l165', 'l169', 'l172', 'l174', 'l176', 'l177']", + "148, primary ['l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185']", + "149, culture ['l178', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191']", + "150, of ['l179', 'l186', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198']", + "151, human ['l180', 'l187', 'l192', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208']", + "152, endometrial ['l181', 'l188', 'l193', 'l199', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216']", + "153, stromal ['l182', 'l189', 'l194', 'l200', 'l209', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222']", + "154, cells, ['l183', 'l190', 'l195', 'l201', 'l210', 'l217', 'l223', 'l224']", + "155, reduction ['l202', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230']", + "156, of ['l203', 'l211', 'l225', 'l231', 'l232', 'l233', 'l234', 'l235']", + "157, NR5A2 ['l184', 'l191', 'l196', 'l204', 'l212', 'l218', 'l223', 'l226', 'l231', 'l236', 'l237', 'l238', 'l239']", + "158, transcript ['l205', 'l213', 'l219', 'l227', 'l232', 'l236', 'l240', 'l241', 'l242']", + "159, abundance ['l206', 'l214', 'l220', 'l228', 'l233', 'l237', 'l240', 'l243', 'l244']", + "161, RNA ['l197', 'l207', 'l215', 'l221', 'l229', 'l234', 'l238', 'l241', 'l243', 'l245']", + "162, interference ['l185', 'l198', 'l208', 'l216', 'l222', 'l224', 'l230', 'l235', 'l239', 'l242', 'l244', 'l245']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Germline", + "ablation", + "of", + "Nr5a2", + "(also", + "called", + "Lrh-1),", + "Depletion", + "Lrh-1", + "in", + "disrupted", + "expression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "corpus", + "luteum," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Germline", + "Nr5a2", + "(also", + "called", + "Lrh-1),", + "in" + ] + }, + "context": { + "val": "organism", + "words": [ + "embryo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Germline", + "ablation", + "of", + "Nr5a2", + "(also", + "called", + "Lrh-1),", + "Depletion", + "in" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "implantation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "called" + ] + }, + "effect": { + "val": "positive", + "words": [ + "permitted" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "corpus", + "luteum," + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "implantation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "permitted" + ] + }, + "context": { + "val": "organism", + "words": [ + "embryo" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "permitted" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "implantation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "embryo" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "implantation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "primary", + "culture", + "of", + "human", + "endometrial", + "stromal", + "cells," + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "NR5A2", + "interference", + "RNA", + "reduction", + "of", + "transcript", + "abundance" + ] + } + } + ] + }, + { + "PMID": "23817021", + "TEXT": "Studies of ETS-mediated prostate oncogenesis have been hampered by a lack of suitable experimental systems. Here we describe a new conditional mouse model that shows robust, homogenous ERG expression throughout the prostate. When combined with homozygous Pten loss, the mice developed accelerated, highly penetrant invasive prostate cancer. In mouse prostate tissue, ERG markedly increased androgen receptor (AR) binding. Robust ERG-mediated transcriptional changes, observed only in the setting of Pten loss, included the restoration of AR transcriptional output and upregulation of genes involved in cell death, migration, inflammation and angiogenesis. Similarly, ETS variant 1 (ETV1) positively regulated the AR cistrome and transcriptional output in ETV1-translocated, PTEN-deficient human prostate cancer cells. In two large clinical cohorts, expression of ERG and ETV1 correlated with higher AR transcriptional output in PTEN-deficient prostate cancer specimens. We propose that ETS factors cause prostate-specific transformation by altering the AR cistrome, priming the prostate epithelium to respond to aberrant upstream signals such as PTEN loss.", + "TAG_DATA": [ + "35, homozygous {'perturbing_action': 'B-gene loss-of-function'}", + "36, Pten {'perturbing_action': 'I-gene loss-of-function'}", + "37, loss, {'perturbing_action': 'I-gene loss-of-function'}", + "39, mice {'context': 'B-organism'}", + "44, invasive {'phenotype': 'B-tumourigenesis'}", + "45, prostate {'phenotype': 'I-tumourigenesis'}", + "46, cancer. {'phenotype': 'I-tumourigenesis'}", + "48, mouse {'context': 'B-tissue/organ'}", + "49, prostate {'context': 'I-tissue/organ'}", + "50, tissue, {'context': 'I-tissue/organ'}", + "68, Pten {'perturbing_action': 'B-gene loss-of-function'}", + "69, loss, {'perturbing_action': 'I-gene loss-of-function'}", + "104, PTEN-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "105, human {'context': 'B-transformed cells'}", + "106, prostate {'context': 'I-transformed cells'}", + "107, cancer {'context': 'I-transformed cells'}", + "108, cells. {'context': 'I-transformed cells'}", + "126, PTEN-deficient {'perturbing_action': 'B-gene loss-of-function'}" + ], + "LINK_DATA": [ + "35, homozygous ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "36, Pten ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "37, loss, ['l1', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "39, mice ['l2', 'l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "44, invasive ['l3', 'l14', 'l23', 'l31', 'l37', 'l38', 'l39', 'l40', 'l41']", + "45, prostate ['l4', 'l15', 'l24', 'l32', 'l37', 'l42', 'l43', 'l44', 'l45']", + "46, cancer. ['l5', 'l16', 'l25', 'l33', 'l38', 'l42', 'l46']", + "48, mouse ['l6', 'l17', 'l26', 'l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "49, prostate ['l7', 'l18', 'l27', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51', 'l52']", + "50, tissue, ['l8', 'l19', 'l28', 'l36', 'l41', 'l45', 'l46', 'l48', 'l50', 'l53']", + "68, Pten ['l9', 'l20', 'l29', 'l51', 'l54', 'l55', 'l56', 'l57', 'l58']", + "69, loss, ['l10', 'l21', 'l30', 'l49', 'l52', 'l53', 'l54', 'l59']", + "104, PTEN-deficient ['l60', 'l61', 'l62', 'l63']", + "105, human ['l55', 'l60', 'l64', 'l65', 'l66']", + "106, prostate ['l56', 'l61', 'l64', 'l67', 'l68']", + "107, cancer ['l57', 'l62', 'l65', 'l67', 'l69']", + "108, cells. ['l11', 'l58', 'l59', 'l63', 'l66', 'l68', 'l69']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "homozygous", + "Pten", + "loss," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "homozygous", + "Pten", + "loss," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "invasive", + "prostate", + "cancer." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "homozygous", + "Pten", + "loss," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "prostate", + "tissue," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "homozygous", + "Pten", + "loss,", + "PTEN-deficient" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells.", + "human", + "prostate", + "cancer" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "invasive", + "prostate", + "cancer." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "invasive", + "prostate", + "cancer." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "prostate", + "tissue," + ] + } + } + ] + }, + { + "PMID": "23793098", + "TEXT": "The contribution of HLA class II-restricted CD4(+) T cell responses to HIV immune control is poorly defined. Here, we delineated previously uncharacterized peptide-DRB1 restrictions in functional assays and analyzed the host genetic effects of HLA-DRB1 alleles on HIV viremia in a large cohort of HIV controllers and progressors. We found distinct stratifications in the effect of HLA-DRB1 alleles on HIV viremia, with HLA-DRB1*15:02 significantly associated with low viremia and HLA-DRB1*03:01 significantly associated with high viremia. Notably, a subgroup of HLA-DRB1 variants linked with low viremia showed the ability to promiscuously present a larger breadth of peptides with lower functional avidity when compared to HLA-DRB1 variants linked with high viremia. Our data provide systematic evidence that HLA-DRB1 variant expression has a considerable impact on the control of HIV replication, an effect that seems to be mediated primarily by the protein specificity of CD4(+) T cell responses to HIV Gag and Nef.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23770692", + "TEXT": "Major depression is a highly prevalent severe mood disorder that is treated with antidepressants. The molecular targets of antidepressants require definition. We investigated the role of the acid sphingomyelinase (Asm)-ceramide system as a target for antidepressants. Therapeutic concentrations of the antidepressants amitriptyline and fluoxetine reduced Asm activity and ceramide concentrations in the hippocampus, increased neuronal proliferation, maturation and survival and improved behavior in mouse models of stress-induced depression. Genetic Asm deficiency abrogated these effects. Mice overexpressing Asm, heterozygous for acid ceramidase, treated with blockers of ceramide metabolism or directly injected with C16 ceramide in the hippocampus had higher ceramide concentrations and lower rates of neuronal proliferation, maturation and survival compared with controls and showed depression-like behavior even in the absence of stress. The decrease of ceramide abundance achieved by antidepressant-mediated inhibition of Asm normalized these effects. Lowering ceramide abundance may thus be a central goal for the future development of antidepressants.", + "TAG_DATA": [ + "53, increased {'effect': 'B-positive'}", + "55, proliferation, {'phenotype': 'B-proliferation'}", + "63, mouse {'context': 'B-organism'}", + "64, models {'context': 'I-organism'}", + "68, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "69, Asm {'perturbing_action': 'I-gene loss-of-function'}", + "70, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "74, Mice {'context': 'B-organism'}", + "75, overexpressing {'perturbing_action': 'I-gene gain-of-function'}", + "76, Asm, {'perturbing_action': 'I-gene gain-of-function'}", + "95, hippocampus {'context': 'B-tissue/organ'}", + "101, lower {'effect': 'B-negative'}", + "105, proliferation, {'phenotype': 'B-proliferation'}", + "129, antidepressant-mediated {'perturbing_action': 'B-pharmacological inhibition'}", + "130, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "131, of {'perturbing_action': 'I-pharmacological inhibition'}", + "132, Asm {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "52, hippocampus, ['l0', 'l1', 'l2', 'l3']", + "53, increased ['l0', 'l4', 'l5']", + "55, proliferation, ['l1', 'l4', 'l6', 'l7']", + "63, mouse ['l2', 'l6', 'l8']", + "64, models ['l3', 'l5', 'l7', 'l8']", + "68, Genetic ['l9', 'l10', 'l11', 'l12']", + "69, Asm ['l9', 'l13', 'l14']", + "70, deficiency ['l10', 'l13', 'l15']", + "74, Mice ['l16', 'l17', 'l18', 'l19', 'l20']", + "75, overexpressing ['l16', 'l21', 'l22', 'l23', 'l24']", + "76, Asm, ['l17', 'l21', 'l25', 'l26', 'l27']", + "95, hippocampus ['l18', 'l22', 'l25', 'l28', 'l29']", + "101, lower ['l11', 'l19', 'l23', 'l26', 'l28', 'l30']", + "105, proliferation, ['l12', 'l14', 'l15', 'l20', 'l24', 'l27', 'l29', 'l30']", + "129, antidepressant-mediated ['l31', 'l32', 'l33']", + "130, inhibition ['l31', 'l34', 'l35']", + "131, of ['l32', 'l34', 'l36']", + "132, Asm ['l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "organism", + "words": [ + "models" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "Mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "Asm", + "deficiency" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "Asm," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "Asm," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "Asm," + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "Asm," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "lower" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + } + ] + }, + { + "PMID": "23749232", + "TEXT": "During wound healing, stem cells provide functional mature cells to meet acute demands for tissue regeneration. Simultaneously, the tissue must maintain a pool of stem cells to sustain its future regeneration capability. However, how these requirements are balanced in response to injury is unknown. Here we demonstrate that after wounding or ultraviolet type B irradiation, melanocyte stem cells (McSCs) in the hair follicle exit the stem cell niche before their initial cell division, potentially depleting the pool of these cells. We also found that McSCs migrate to the epidermis in a melanocortin 1 receptor (Mc1r)-dependent manner and differentiate into functional epidermal melanocytes, providing a pigmented protective barrier against ultraviolet irradiation over the damaged skin. These findings provide an example in which stem cell differentiation due to injury takes precedence over stem cell maintenance and show the potential for developing therapies for skin pigmentation disorders by manipulating McSCs.", + "TAG_DATA": [ + "55, melanocyte {'context': 'B-cells'}", + "97, differentiate {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "55, melanocyte ['l0']", + "62, follicle ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23749230", + "TEXT": "Parasites of the Leishmania genus are the causative agents of leishmaniasis in humans, a disease that affects more than 12 million people worldwide. These parasites replicate intracellularly in macrophages, and the primary mechanisms underlying host resistance involve the production of nitric oxide (NO). In this study we show that the Nlrp3 inflammasome is activated in response to Leishmania infection and is important for the restriction of parasite replication both in macrophages and in vivo as demonstrated through the infection of inflammasome-deficient mice with Leishmania amazonensis, Leishmania braziliensis and Leishmania infantum chagasi. Inflammasome-driven interleukin-1β (IL-1β) production facilitated host resistance to infection, as signaling through IL-1 receptor (IL-1R) and MyD88 was necessary and sufficient to trigger inducible nitric oxide synthase (NOS2)-mediated production of NO. In this manuscript we identify a major signaling platform for host resistance to Leishmania spp. infection and describe the molecular mechanisms underlying Leishmania-induced NO production.", + "TAG_DATA": [ + "80, inflammasome-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "81, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "80, inflammasome-deficient ['l0']", + "81, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inflammasome-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23744139", + "TEXT": "Almost 50 years ago, the World Medical Association adopted the Declaration of Helsinki as an ethical guide for research involving human subjects. There are now proposed revisions under consideration that will provide additional protection for study participants as well as increased clarity regarding the responsibilities of those conducting the research. Making these changes is important in a complex environment where what is ethical is not always self-evident.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23744137", + "TEXT": "When letters containing anthrax spores were mailed to several US senators and media offices in September 2001, just one week after the 9/11 attacks, bioterrorism catapulted to the national stage. Political leaders and public health officials, desperate for guidance on this once-theoretical scenario, turned to experts including Tom Inglesby, then deputy director of the Johns Hopkins Center for Civilian Biodefense Strategies, a bioterrorism research and analysis think tank in Baltimore. In the years that followed, Inglesby and his colleagues ran exercises to simulate bioterror incidents, established a peer-reviewed journal on biodefense and advised government agencies on how to reduce the public health impact of biological threats.Today, he continues his work with the think tank, which moved to the University of Pittsburgh Medical Center (UPMC) in 2003 (although it stayed headquartered in Baltimore) and which was recently renamed the UPMC Center for Health Security. As director and chief executive officer for the past four years, Inglesby has expanded the center's focus toward preventing public health crises arising from infectious diseases, pandemics and major natural disasters, in addition to biological, chemical and nuclear accidents or threats. Inglesby spoke with Kevin Jiang about how responses to bioterrorism, pandemics and natural disasters aren't all that different.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23744133", + "TEXT": "A recent plea by oncologists condemning inflated prices for some cancer drugs has ignited a debate on this topic between clinicians and pharmaceutical companies and highlights the need for a broader assessment of drug valuation.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23727931", + "TEXT": "We recently established conditions allowing for long-term expansion of epithelial organoids from intestine, recapitulating essential features of the in vivo tissue architecture. Here we apply this technology to study primary intestinal organoids of people suffering from cystic fibrosis, a disease caused by mutations in CFTR, encoding cystic fibrosis transmembrane conductance regulator. Forskolin induces rapid swelling of organoids derived from healthy controls or wild-type mice, but this effect is strongly reduced in organoids of subjects with cystic fibrosis or in mice carrying the Cftr F508del mutation and is absent in Cftr-deficient organoids. This pattern is phenocopied by CFTR-specific inhibitors. Forskolin-induced swelling of in vitro-expanded human control and cystic fibrosis organoids corresponds quantitatively with forskolin-induced anion currents in freshly excised ex vivo rectal biopsies. Function of the CFTR F508del mutant protein is restored by incubation at low temperature, as well as by CFTR-restoring compounds. This relatively simple and robust assay will facilitate diagnosis, functional studies, drug development and personalized medicine approaches in cystic fibrosis.", + "TAG_DATA": [ + "56, organoids {'context': 'B-organoid'}", + "63, mice, {'context': 'B-organism'}", + "71, organoids {'context': 'B-organoid'}", + "79, mice {'context': 'B-organism'}", + "81, the {'perturbing_action': 'I-other'}", + "82, Cftr {'perturbing_action': 'I-other'}", + "83, F508del {'perturbing_action': 'I-other'}", + "84, mutation {'perturbing_action': 'I-other'}", + "89, Cftr-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "90, organoids. {'context': 'B-organoid'}", + "96, CFTR-specific {'perturbing_action': 'B-pharmacological inhibition'}", + "97, inhibitors. {'perturbing_action': 'I-pharmacological inhibition'}", + "101, in {'context': 'B-in vitro'}", + "102, vitro-expanded {'context': 'I-in vitro'}", + "103, human {'context': 'B-organoid'}", + "104, control {'context': 'I-organoid'}", + "105, and {'context': 'I-organoid'}", + "106, cystic {'context': 'B-organoid'}", + "107, fibrosis {'context': 'I-organoid'}", + "108, organoids {'context': 'I-organoid'}", + "125, CFTR {'perturbing_action': 'B-other'}", + "126, F508del {'perturbing_action': 'I-other'}", + "127, mutant {'perturbing_action': 'I-other'}", + "128, protein {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "56, organoids ['l0', 'l1']", + "63, mice, ['l0', 'l2']", + "71, organoids ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "79, mice ['l3', 'l8', 'l9', 'l10', 'l11', 'l12']", + "81, the ['l4', 'l8', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "82, Cftr ['l5', 'l9', 'l13', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "83, F508del ['l6', 'l10', 'l14', 'l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "84, mutation ['l7', 'l11', 'l15', 'l21', 'l26', 'l31', 'l32']", + "89, Cftr-deficient ['l16', 'l22', 'l27', 'l31', 'l33', 'l34', 'l35']", + "90, organoids. ['l12', 'l17', 'l23', 'l28', 'l32', 'l33', 'l36', 'l37']", + "96, CFTR-specific ['l18', 'l24', 'l29', 'l34', 'l36', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "97, inhibitors. ['l19', 'l25', 'l30', 'l35', 'l37', 'l38', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "101, in ['l39', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "102, vitro-expanded ['l40', 'l47', 'l54', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "103, human ['l41', 'l48', 'l55', 'l63', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "104, control ['l42', 'l49', 'l56', 'l64', 'l71', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "105, and ['l43', 'l50', 'l57', 'l65', 'l72', 'l78', 'l84', 'l85', 'l86', 'l87', 'l88']", + "106, cystic ['l44', 'l51', 'l58', 'l66', 'l73', 'l79', 'l84', 'l89', 'l90', 'l91', 'l92']", + "107, fibrosis ['l45', 'l52', 'l59', 'l67', 'l74', 'l80', 'l85', 'l89', 'l93', 'l94', 'l95']", + "108, organoids ['l46', 'l53', 'l60', 'l68', 'l75', 'l81', 'l86', 'l90', 'l93', 'l96', 'l97']", + "120, rectal ['l61', 'l69', 'l76', 'l82', 'l87', 'l91', 'l94', 'l96', 'l98']", + "121, biopsies. ['l62', 'l70', 'l77', 'l83', 'l88', 'l92', 'l95', 'l97', 'l98']", + "125, CFTR ['l99', 'l100', 'l101']", + "126, F508del ['l99', 'l102', 'l103']", + "127, mutant ['l100', 'l102', 'l104']", + "128, protein ['l101', 'l103', 'l104']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organoid", + "words": [ + "organoids", + "organoids." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "the", + "Cftr", + "F508del", + "mutation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "the", + "Cftr", + "F508del", + "mutation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cftr-deficient" + ] + }, + "context": { + "val": "organoid", + "words": [ + "organoids." + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "organoids.", + "human", + "control", + "and", + "cystic", + "fibrosis", + "organoids" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CFTR-specific", + "inhibitors." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CFTR-specific", + "inhibitors." + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro-expanded" + ] + } + } + ] + }, + { + "PMID": "23708290", + "TEXT": "Oxidative damage from elevated production of reactive oxygen species (ROS) contributes to ischemia-reperfusion injury in myocardial infarction and stroke. The mechanism by which the increase in ROS occurs is not known, and it is unclear how this increase can be prevented. A wide variety of nitric oxide donors and S-nitrosating agents protect the ischemic myocardium from infarction, but the responsible mechanisms are unclear. Here we used a mitochondria-selective S-nitrosating agent, MitoSNO, to determine how mitochondrial S-nitrosation at the reperfusion phase of myocardial infarction is cardioprotective in vivo in mice. We found that protection is due to the S-nitrosation of mitochondrial complex I, which is the entry point for electrons from NADH into the respiratory chain. Reversible S-nitrosation of complex I slows the reactivation of mitochondria during the crucial first minutes of the reperfusion of ischemic tissue, thereby decreasing ROS production, oxidative damage and tissue necrosis. Inhibition of complex I is afforded by the selective S-nitrosation of Cys39 on the ND3 subunit, which becomes susceptible to modification only after ischemia. Our results identify rapid complex I reactivation as a central pathological feature of ischemia-reperfusion injury and show that preventing this reactivation by modification of a cysteine switch is a robust cardioprotective mechanism and hence a rational therapeutic strategy.", + "TAG_DATA": [ + "85, in {'context': 'B-in vivo'}", + "86, vivo {'context': 'I-in vivo'}", + "88, mice. {'context': 'B-organism'}", + "137, decreasing {'effect': 'B-negative'}", + "144, necrosis. {'phenotype': 'B-necrosis'}" + ], + "LINK_DATA": [ + "85, in ['l0', 'l1']", + "86, vivo ['l0', 'l2']", + "88, mice. ['l1', 'l2']", + "137, decreasing ['l3', 'l4']", + "143, tissue ['l3', 'l5']", + "144, necrosis. ['l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "decreasing" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis." + ] + } + } + ] + }, + { + "PMID": "23685841", + "TEXT": "Innate sensing mechanisms trigger a variety of humoral and cellular events that are essential to adaptive immune responses. Here we describe an innate sensing pathway triggered by Plasmodium infection that regulates dendritic cell homeostasis and adaptive immunity through Flt3 ligand (Flt3l) release. Plasmodium-induced Flt3l release in mice requires Toll-like receptor (TLR) activation and type I interferon (IFN) production. We found that type I IFN supports the upregulation of xanthine dehydrogenase, which metabolizes the xanthine accumulating in infected erythrocytes to uric acid. Uric acid crystals trigger mast cells to release soluble Flt3l from a pre-synthesized membrane-associated precursor. During infection, Flt3l preferentially stimulates expansion of the CD8-α(+) dendritic cell subset or its BDCA3(+) human dendritic cell equivalent and has a substantial impact on the magnitude of T cell activation, mostly in the CD8(+) compartment. Our findings highlight a new mechanism that regulates dendritic cell homeostasis and T cell responses to infection.", + "TAG_DATA": [ + "46, mice {'context': 'B-organism'}", + "85, mast {'context': 'B-cells'}", + "86, cells {'context': 'I-cells'}", + "104, CD8-α(+) {'context': 'B-cells'}", + "105, dendritic {'context': 'I-cells'}", + "106, cell {'context': 'I-cells'}", + "107, subset {'context': 'I-cells'}", + "110, BDCA3(+) {'context': 'B-cells'}", + "111, human {'context': 'I-cells'}", + "112, dendritic {'context': 'I-cells'}", + "113, cell {'context': 'I-cells'}", + "124, T {'context': 'B-cells'}", + "125, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "85, mast ['l0', 'l1', 'l2', 'l3']", + "86, cells ['l0', 'l4', 'l5', 'l6']", + "104, CD8-α(+) ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "105, dendritic ['l1', 'l4', 'l7', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "106, cell ['l2', 'l5', 'l8', 'l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "107, subset ['l3', 'l6', 'l9', 'l16', 'l22', 'l28', 'l29', 'l30', 'l31', 'l32']", + "110, BDCA3(+) ['l10', 'l17', 'l23', 'l28', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "111, human ['l11', 'l18', 'l24', 'l29', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "112, dendritic ['l12', 'l19', 'l25', 'l30', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47']", + "113, cell ['l13', 'l20', 'l26', 'l31', 'l35', 'l40', 'l44', 'l48', 'l49', 'l50']", + "114, equivalent ['l14', 'l21', 'l27', 'l32', 'l36', 'l41', 'l45', 'l48', 'l51', 'l52']", + "124, T ['l37', 'l42', 'l46', 'l49', 'l51', 'l53']", + "125, cell ['l38', 'l43', 'l47', 'l50', 'l52', 'l53']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23624600", + "TEXT": "Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) that is initiated when self-reactive T cells enter the brain and become locally activated after encountering their specific nervous antigens. When and where the disease-relevant antigen encounters occur is unclear. Here we combined fluorescently labeled nuclear factor of activated T cells (NFAT) with histone protein H2B to create a broadly applicable molecular sensor for intravital imaging of T cell activation. In experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis, we report that effector T cells entering the CNS become activated after short contacts with leptomeningeal phagocytes. During established disease, the activation process is extended to the depth of the CNS parenchyma, where the cells form contacts with microglia and recruited phagocytes. We show that it is the activation processes during the preclinical phase rather than during established disease that are essential for the intensity and duration of the disease bout.", + "TAG_DATA": [ + "85, effector {'context': 'B-cells'}", + "86, T {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}", + "113, parenchyma, {'context': 'I-tissue/organ'}", + "116, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "85, effector ['l0', 'l1']", + "86, T ['l0', 'l2']", + "87, cells ['l1', 'l2']", + "112, CNS ['l3', 'l4']", + "113, parenchyma, ['l3', 'l5']", + "116, cells ['l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23624599", + "TEXT": "CD4(+) type 1 T regulatory (Tr1) cells are induced in the periphery and have a pivotal role in promoting and maintaining tolerance. The absence of surface markers that uniquely identify Tr1 cells has limited their study and clinical applications. By gene expression profiling of human Tr1 cell clones, we identified the surface markers CD49b and lymphocyte activation gene 3 (LAG-3) as being stably and selectively coexpressed on mouse and human Tr1 cells. We showed the specificity of these markers in mouse models of intestinal inflammation and helminth infection and in the peripheral blood of healthy volunteers. The coexpression of CD49b and LAG-3 enables the isolation of highly suppressive human Tr1 cells from in vitro anergized cultures and allows the tracking of Tr1 cells in the peripheral blood of subjects who developed tolerance after allogeneic hematopoietic stem cell transplantation. The use of these markers makes it feasible to track Tr1 cells in vivo and purify Tr1 cells for cell therapy to induce or restore tolerance in subjects with immune-mediated diseases.", + "TAG_DATA": [ + "80, mouse {'context': 'B-organism'}", + "81, models {'context': 'I-organism'}", + "91, peripheral {'context': 'B-cells'}", + "92, blood {'context': 'I-tissue/organ'}", + "97, coexpression {'perturbing_action': 'B-gene gain-of-function'}", + "98, of {'perturbing_action': 'I-gene gain-of-function'}", + "99, CD49b {'perturbing_action': 'I-gene gain-of-function'}", + "100, and {'perturbing_action': 'I-gene gain-of-function'}", + "101, LAG-3 {'perturbing_action': 'I-gene gain-of-function'}", + "108, human {'context': 'B-cells'}", + "109, Tr1 {'context': 'I-cells'}", + "110, cells {'context': 'I-cells'}", + "112, in {'context': 'B-in vitro'}", + "113, vitro {'context': 'I-in vitro'}", + "121, Tr1 {'context': 'B-cells'}", + "122, cells {'context': 'I-cells'}", + "125, peripheral {'context': 'B-cells'}", + "126, blood {'context': 'I-cells'}", + "134, hematopoietic {'context': 'I-cells'}", + "135, stem {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "80, mouse ['l0', 'l1', 'l2']", + "81, models ['l0', 'l3', 'l4']", + "91, peripheral ['l1', 'l3', 'l5']", + "92, blood ['l2', 'l4', 'l5']", + "97, coexpression ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "98, of ['l6', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "99, CD49b ['l7', 'l24', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "100, and ['l8', 'l25', 'l41', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "101, LAG-3 ['l9', 'l26', 'l42', 'l56', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "108, human ['l10', 'l27', 'l43', 'l57', 'l68', 'l78', 'l79', 'l80', 'l81', 'l82']", + "109, Tr1 ['l11', 'l28', 'l44', 'l58', 'l69', 'l78', 'l83', 'l84', 'l85', 'l86']", + "110, cells ['l12', 'l29', 'l45', 'l59', 'l70', 'l79', 'l83', 'l87', 'l88', 'l89']", + "112, in ['l13', 'l30', 'l46', 'l60', 'l71', 'l80', 'l84', 'l87', 'l90', 'l91']", + "113, vitro ['l14', 'l31', 'l47', 'l61', 'l72', 'l81', 'l85', 'l88', 'l90', 'l92']", + "115, cultures ['l15', 'l32', 'l48', 'l62', 'l73', 'l82', 'l86', 'l89', 'l91', 'l92']", + "121, Tr1 ['l16', 'l33', 'l49', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "122, cells ['l17', 'l34', 'l50', 'l63', 'l74', 'l93', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "125, peripheral ['l18', 'l35', 'l51', 'l64', 'l75', 'l94', 'l100', 'l106', 'l107', 'l108', 'l109', 'l110']", + "126, blood ['l19', 'l36', 'l52', 'l65', 'l76', 'l95', 'l101', 'l106', 'l111', 'l112', 'l113', 'l114']", + "133, allogeneic ['l20', 'l37', 'l96', 'l102', 'l107', 'l111', 'l115', 'l116', 'l117']", + "134, hematopoietic ['l21', 'l38', 'l53', 'l97', 'l103', 'l108', 'l112', 'l115', 'l118', 'l119']", + "135, stem ['l22', 'l39', 'l54', 'l66', 'l98', 'l104', 'l109', 'l113', 'l116', 'l118', 'l120']", + "136, cell ['l23', 'l40', 'l55', 'l67', 'l77', 'l99', 'l105', 'l110', 'l114', 'l117', 'l119', 'l120']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "coexpression", + "of", + "CD49b", + "and", + "LAG-3" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "Tr1", + "cells", + "peripheral", + "blood", + "hematopoietic", + "stem" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "coexpression", + "of", + "CD49b", + "and", + "LAG-3" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "23584091", + "TEXT": "Approximately 100,000 individuals in the United States currently await kidney transplantation, and 400,000 individuals live with end-stage kidney disease requiring hemodialysis. The creation of a transplantable graft to permanently replace kidney function would address donor organ shortage and the morbidity associated with immunosuppression. Such a bioengineered graft must have the kidney's architecture and function and permit perfusion, filtration, secretion, absorption and drainage of urine. We decellularized rat, porcine and human kidneys by detergent perfusion, yielding acellular scaffolds with vascular, cortical and medullary architecture, a collecting system and ureters. To regenerate functional tissue, we seeded rat kidney scaffolds with epithelial and endothelial cells and perfused these cell-seeded constructs in a whole-organ bioreactor. The resulting grafts produced rudimentary urine in vitro when perfused through their intrinsic vascular bed. When transplanted in an orthotopic position in rat, the grafts were perfused by the recipient's circulation and produced urine through the ureteral conduit in vivo.", + "TAG_DATA": [ + "66, rat, {'context': 'B-tissue/organ'}", + "67, porcine {'context': 'I-tissue/organ'}", + "68, and {'context': 'I-tissue/organ'}", + "69, human {'context': 'I-tissue/organ'}", + "70, kidneys {'context': 'I-tissue/organ'}", + "94, rat {'context': 'B-tissue/organ'}", + "95, kidney {'context': 'I-tissue/organ'}", + "96, scaffolds {'context': 'I-organoid'}", + "98, epithelial {'context': 'B-cells'}", + "99, and {'context': 'I-cells'}", + "100, endothelial {'context': 'I-cells'}", + "101, cells {'context': 'I-cells'}", + "117, in {'context': 'B-in vitro'}", + "118, vitro {'context': 'I-in vitro'}", + "133, rat, {'context': 'B-organism'}", + "147, ureteral {'context': 'B-tissue/organ'}", + "148, conduit {'context': 'I-tissue/organ'}", + "149, in {'context': 'B-in vivo'}", + "150, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "66, rat, ['l0', 'l1', 'l2', 'l3']", + "67, porcine ['l0', 'l4', 'l5', 'l6']", + "68, and ['l1', 'l4', 'l7', 'l8']", + "69, human ['l2', 'l5', 'l7', 'l9']", + "70, kidneys ['l3', 'l6', 'l8', 'l9']", + "94, rat ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "95, kidney ['l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "96, scaffolds ['l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "98, epithelial ['l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "99, and ['l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "100, endothelial ['l14', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "101, cells ['l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "117, in ['l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "118, vitro ['l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']", + "133, rat, ['l46', 'l47', 'l48', 'l49']", + "147, ureteral ['l46', 'l50', 'l51', 'l52']", + "148, conduit ['l47', 'l50', 'l53', 'l54']", + "149, in ['l48', 'l51', 'l53', 'l55']", + "150, vivo. ['l49', 'l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23584090", + "TEXT": "Colon cancer is a clinically diverse disease. This heterogeneity makes it difficult to determine which patients will benefit most from adjuvant therapy and impedes the development of new targeted agents. More insight into the biological diversity of colon cancers, especially in relation to clinical features, is therefore needed. We demonstrate, using an unsupervised classification strategy involving over 1,100 individuals with colon cancer, that three main molecularly distinct subtypes can be recognized. Two subtypes have been previously identified and are well characterized (chromosomal-instable and microsatellite-instable cancers). The third subtype is largely microsatellite stable and contains relatively more CpG island methylator phenotype-positive carcinomas but cannot be identified on the basis of characteristic mutations. We provide evidence that this subtype relates to sessile-serrated adenomas, which show highly similar gene expression profiles, including upregulation of genes involved in matrix remodeling and epithelial-mesenchymal transition. The identification of this subtype is crucial, as it has a very unfavorable prognosis and, moreover, is refractory to epidermal growth factor receptor-targeted therapy.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23542787", + "TEXT": "Fragile X syndrome (FXS), the most common monogenic cause of inherited intellectual disability and autism, is caused by the silencing of the FMR1 gene, leading to the loss of fragile X mental retardation protein (FMRP), a synaptically expressed RNA-binding protein regulating translation. The Fmr1 knockout model recapitulates the main traits of the disease. Uncontrolled activity of metabotropic glutamate receptor 5 (mGluR5) and mammalian target of rapamycin (mTOR) signaling seem crucial in the pathology of this disease. The endocannabinoid system (ECS) is a key modulator of synaptic plasticity, cognitive performance, anxiety, nociception and seizure susceptibility, all of which are affected in FXS. The cannabinoid receptors CB1 (CB1R) and CB2 (CB2R) are activated by phospholipid-derived endocannabinoids, and CB1R-driven long-term regulation of synaptic strength, as a consequence of mGluR5 activation, is altered in several brain areas of Fmr1 knockout mice. We found that CB1R blockade in male Fmr1 knockout (Fmr1(-/y)) mice through pharmacological and genetic approaches normalized cognitive impairment, nociceptive desensitization, susceptibility to audiogenic seizures, overactivated mTOR signaling and altered spine morphology, whereas pharmacological blockade of CB2R normalized anxiolytic-like behavior. Some of these traits were also reversed by pharmacological inhibition of mTOR or mGluR5. Thus, blockade of ECS is a potential therapeutic approach to normalize specific alterations in FXS.", + "TAG_DATA": [ + "134, Fmr1 {'perturbing_action': 'B-gene loss-of-function'}", + "135, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "140, CB1R {'perturbing_action': 'B-pharmacological inhibition'}", + "141, blockade {'perturbing_action': 'I-gene loss-of-function'}", + "144, Fmr1 {'perturbing_action': 'B-gene loss-of-function'}", + "145, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "146, (Fmr1(-/y)) {'perturbing_action': 'I-gene loss-of-function'}", + "147, mice {'context': 'B-organism'}", + "170, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "171, blockade {'perturbing_action': 'I-pharmacological inhibition'}", + "172, of {'perturbing_action': 'I-pharmacological inhibition'}", + "173, CB2R {'perturbing_action': 'I-pharmacological inhibition'}", + "185, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "186, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "187, of {'perturbing_action': 'I-pharmacological inhibition'}", + "188, mTOR {'perturbing_action': 'I-pharmacological inhibition'}", + "189, or {'perturbing_action': 'I-pharmacological inhibition'}", + "190, mGluR5. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "134, Fmr1 ['l0', 'l1', 'l2']", + "135, knockout ['l0', 'l3', 'l4']", + "140, CB1R ['l1', 'l3', 'l5', 'l6', 'l7', 'l8', 'l9']", + "141, blockade ['l2', 'l4', 'l5', 'l10', 'l11', 'l12', 'l13']", + "144, Fmr1 ['l6', 'l10', 'l14', 'l15', 'l16', 'l17']", + "145, knockout ['l7', 'l11', 'l14', 'l18', 'l19', 'l20']", + "146, (Fmr1(-/y)) ['l8', 'l12', 'l15', 'l18', 'l21', 'l22']", + "147, mice ['l9', 'l13', 'l16', 'l19', 'l21', 'l23']", + "167, spine ['l17', 'l20', 'l22', 'l23']", + "170, pharmacological ['l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "171, blockade ['l24', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "172, of ['l25', 'l33', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "173, CB2R ['l26', 'l34', 'l41', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "185, pharmacological ['l27', 'l35', 'l42', 'l48', 'l54', 'l55', 'l56', 'l57', 'l58']", + "186, inhibition ['l28', 'l36', 'l43', 'l49', 'l54', 'l59', 'l60', 'l61', 'l62']", + "187, of ['l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l63', 'l64', 'l65']", + "188, mTOR ['l30', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l66', 'l67']", + "189, or ['l31', 'l39', 'l46', 'l52', 'l57', 'l61', 'l64', 'l66', 'l68']", + "190, mGluR5. ['l32', 'l40', 'l47', 'l53', 'l58', 'l62', 'l65', 'l67', 'l68']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CB1R" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "blockade", + "Fmr1", + "knockout", + "(Fmr1(-/y))" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23524343", + "TEXT": "Sorting nexin 27 (SNX27), a brain-enriched PDZ domain protein, regulates endocytic sorting and trafficking. Here we show that Snx27(-/-) mice have severe neuronal deficits in the hippocampus and cortex. Although Snx27(+/-) mice have grossly normal neuroanatomy, we found defects in synaptic function, learning and memory and a reduction in the amounts of ionotropic glutamate receptors (NMDA and AMPA receptors) in these mice. SNX27 interacts with these receptors through its PDZ domain, regulating their recycling to the plasma membrane. We demonstrate a concomitant reduced expression of SNX27 and CCAAT/enhancer binding protein β (C/EBPβ) in Down's syndrome brains and identify C/EBPβ as a transcription factor for SNX27. Down's syndrome causes overexpression of miR-155, a chromosome 21-encoded microRNA that negatively regulates C/EBPβ, thereby reducing SNX27 expression and resulting in synaptic dysfunction. Upregulating SNX27 in the hippocampus of Down's syndrome mice rescues synaptic and cognitive deficits. Our identification of the role of SNX27 in synaptic function establishes a new molecular mechanism of Down's syndrome pathogenesis.", + "TAG_DATA": [ + "18, Snx27(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "19, mice {'context': 'B-organism'}", + "30, Snx27(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "31, mice {'context': 'B-organism'}", + "128, Upregulating {'perturbing_action': 'B-gene gain-of-function'}", + "129, SNX27 {'perturbing_action': 'I-gene gain-of-function'}", + "132, hippocampus {'context': 'B-tissue/organ'}", + "134, Down's {'context': 'B-organism'}", + "135, syndrome {'context': 'B-organism'}", + "136, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "18, Snx27(-/-) ['l0', 'l1']", + "19, mice ['l0']", + "30, Snx27(+/-) ['l2']", + "31, mice ['l1', 'l2']", + "128, Upregulating ['l3', 'l4', 'l5', 'l6', 'l7']", + "129, SNX27 ['l3', 'l8', 'l9', 'l10', 'l11']", + "132, hippocampus ['l4', 'l8', 'l12', 'l13', 'l14']", + "134, Down's ['l5', 'l9', 'l12', 'l15', 'l16']", + "135, syndrome ['l6', 'l10', 'l13', 'l15', 'l17']", + "136, mice ['l7', 'l11', 'l14', 'l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Snx27(-/-)", + "Snx27(+/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Upregulating", + "SNX27" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Upregulating", + "SNX27" + ] + }, + "context": { + "val": "organism", + "words": [ + "Down's", + "syndrome", + "mice" + ] + } + } + ] + }, + { + "PMID": "23502961", + "TEXT": "Regulation of erythropoiesis is achieved by the integration of distinct signals. Among them, macrophages are emerging as erythropoietin-complementary regulators of erythroid development, particularly under stress conditions. We investigated the contribution of macrophages to physiological and pathological conditions of enhanced erythropoiesis. We used mouse models of induced anemia, polycythemia vera and β-thalassemia in which macrophages were chemically depleted. Our data indicate that macrophages contribute decisively to recovery from induced anemia, as well as the pathological progression of polycythemia vera and β-thalassemia, by modulating erythroid proliferation and differentiation. We validated these observations in primary human cultures, showing a direct impact of macrophages on the proliferation and enucleation of erythroblasts from healthy individuals and patients with polycythemia vera or β-thalassemia. The contribution of macrophages to stress and pathological erythropoiesis, which we have termed stress erythropoiesis macrophage-supporting activity, may have therapeutic implications.", + "TAG_DATA": [ + "42, mouse {'context': 'B-organism'}", + "43, models {'context': 'I-organism'}", + "53, macrophages {'context': 'B-cells'}", + "81, modulating {'effect': 'B-regulates'}", + "83, proliferation {'phenotype': 'B-proliferation'}", + "91, primary {'context': 'B-cells'}", + "92, human {'context': 'I-cells'}", + "93, cultures, {'context': 'I-cells'}", + "102, proliferation {'phenotype': 'B-proliferation'}", + "106, erythroblasts {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "42, mouse ['l0', 'l1']", + "43, models ['l0', 'l2']", + "53, macrophages ['l3', 'l4']", + "81, modulating ['l3', 'l5']", + "83, proliferation ['l1', 'l2', 'l4', 'l5']", + "91, primary ['l6', 'l7', 'l8']", + "92, human ['l6', 'l9', 'l10']", + "93, cultures, ['l7', 'l9']", + "102, proliferation ['l8', 'l10', 'l11']", + "106, erythroblasts ['l11']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "macrophages" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "modulating" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "macrophages", + "primary", + "human", + "erythroblasts" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "modulating" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "23467247", + "TEXT": "Herpes simplex virus-2 (HSV-2) is periodically shed throughout the human genital tract. Although a high viral load correlates with the development of genital ulcers, shedding also commonly occurs even when ulcers are absent, allowing for silent transmission during coitus and contributing to high seroprevalence of HSV-2 worldwide. Frequent viral reactivation occurs within ganglia despite diverse and complementary host and viral mechanisms that predispose toward latency, suggesting that viral replication may be constantly occurring in a small minority of neurons at these sites. Within genital mucosa, the in vivo expansion and clearance rates of HSV-2 are extremely rapid. Resident dendritic cells and memory HSV-2 specific T cells persist at prior sites of genital tract reactivation and, in conjunction with prompt innate recognition of infected cells, lead to rapid containment of infected cells. The fact that immune responses usually control viral replication in genital skin before lesions develop provides hope that enhancing such responses could lead to effective vaccines and immunotherapies.", + "TAG_DATA": [ + "86, in {'context': 'B-in vivo'}", + "87, vivo {'context': 'I-in vivo'}", + "97, Resident {'context': 'B-cells'}", + "98, dendritic {'context': 'I-cells'}", + "99, cells {'context': 'I-cells'}", + "101, memory {'context': 'B-cells'}", + "102, HSV-2 {'context': 'I-cells'}", + "103, specific {'context': 'I-cells'}", + "104, T {'context': 'I-cells'}", + "105, cells {'context': 'I-cells'}", + "130, cells. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "86, in ['l0', 'l1']", + "87, vivo ['l0', 'l2']", + "97, Resident ['l3', 'l4', 'l5', 'l6', 'l7']", + "98, dendritic ['l3', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "99, cells ['l1', 'l2', 'l4', 'l8', 'l14', 'l15', 'l16']", + "101, memory ['l9', 'l17', 'l18', 'l19', 'l20', 'l21']", + "102, HSV-2 ['l10', 'l17', 'l22', 'l23', 'l24', 'l25']", + "103, specific ['l5', 'l11', 'l14', 'l18', 'l22', 'l26', 'l27']", + "104, T ['l6', 'l12', 'l15', 'l19', 'l23', 'l26', 'l28', 'l29']", + "105, cells ['l7', 'l13', 'l16', 'l20', 'l24', 'l27', 'l28']", + "130, cells. ['l21', 'l25', 'l29']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23435171", + "TEXT": "Previous attempts to identify neuroprotective targets by studying the ischemic cascade and devising ways to suppress it have failed to translate to efficacious therapies for acute ischemic stroke. We hypothesized that studying the molecular determinants of endogenous neuroprotection in two well-established paradigms, the resistance of CA3 hippocampal neurons to global ischemia and the tolerance conferred by ischemic preconditioning (IPC), would reveal new neuroprotective targets. We found that the product of the tuberous sclerosis complex 1 gene (TSC1), hamartin, is selectively induced by ischemia in hippocampal CA3 neurons. In CA1 neurons, hamartin was unaffected by ischemia but was upregulated by IPC preceding ischemia, which protects the otherwise vulnerable CA1 cells. Suppression of hamartin expression with TSC1 shRNA viral vectors both in vitro and in vivo increased the vulnerability of neurons to cell death following oxygen glucose deprivation (OGD) and ischemia. In vivo, suppression of TSC1 expression increased locomotor activity and decreased habituation in a hippocampal-dependent task. Overexpression of hamartin increased resistance to OGD by inducing productive autophagy through an mTORC1-dependent mechanism.", + "TAG_DATA": [ + "88, CA1 {'context': 'B-cells'}", + "89, neurons, {'context': 'I-cells'}", + "107, CA1 {'context': 'B-cells'}", + "109, Suppression {'perturbing_action': 'B-rnai/knockdown'}", + "110, of {'perturbing_action': 'I-rnai/knockdown'}", + "111, hamartin {'perturbing_action': 'I-rnai/knockdown'}", + "112, expression {'perturbing_action': 'I-rnai/knockdown'}", + "113, with {'perturbing_action': 'I-rnai/knockdown'}", + "114, TSC1 {'perturbing_action': 'I-rnai/knockdown'}", + "115, shRNA {'perturbing_action': 'I-rnai/knockdown'}", + "116, viral {'perturbing_action': 'I-rnai/knockdown'}", + "117, vectors {'perturbing_action': 'I-rnai/knockdown'}", + "119, in {'context': 'B-in vitro'}", + "120, vitro {'context': 'I-in vitro'}", + "122, in {'context': 'B-in vivo'}", + "123, vivo {'context': 'I-in vivo'}", + "124, increased {'effect': 'B-positive'}", + "128, neurons {'context': 'B-cells'}", + "130, cell {'phenotype': 'B-cell death'}", + "131, death {'phenotype': 'I-cell death'}", + "139, In {'context': 'B-in vivo'}", + "140, vivo, {'context': 'I-in vivo'}", + "141, suppression {'perturbing_action': 'B-rnai/knockdown'}", + "142, of {'perturbing_action': 'I-rnai/knockdown'}", + "143, TSC1 {'perturbing_action': 'I-rnai/knockdown'}", + "144, expression {'perturbing_action': 'I-rnai/knockdown'}", + "155, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "156, of {'perturbing_action': 'I-gene gain-of-function'}", + "157, hamartin {'perturbing_action': 'I-gene gain-of-function'}", + "163, inducing {'effect': 'B-positive'}", + "165, autophagy {'phenotype': 'B-autophagy'}" + ], + "LINK_DATA": [ + "88, CA1 ['l0', 'l1']", + "89, neurons, ['l0', 'l2']", + "107, CA1 ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "109, Suppression ['l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "110, of ['l12', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "111, hamartin ['l13', 'l32', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "112, expression ['l14', 'l33', 'l50', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "113, with ['l15', 'l34', 'l51', 'l65', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "114, TSC1 ['l16', 'l35', 'l52', 'l66', 'l79', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "115, shRNA ['l17', 'l36', 'l53', 'l67', 'l80', 'l93', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "116, viral ['l18', 'l37', 'l54', 'l68', 'l81', 'l94', 'l108', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "117, vectors ['l19', 'l38', 'l55', 'l69', 'l82', 'l95', 'l109', 'l123', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "119, in ['l3', 'l20', 'l39', 'l56', 'l70', 'l83', 'l96', 'l110', 'l124', 'l136', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "120, vitro ['l4', 'l21', 'l40', 'l57', 'l71', 'l84', 'l97', 'l111', 'l125', 'l137', 'l148', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162']", + "122, in ['l5', 'l22', 'l41', 'l58', 'l72', 'l85', 'l98', 'l112', 'l126', 'l138', 'l149', 'l156', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168']", + "123, vivo ['l6', 'l23', 'l42', 'l59', 'l73', 'l86', 'l99', 'l113', 'l127', 'l139', 'l150', 'l157', 'l163', 'l169', 'l170', 'l171', 'l172', 'l173']", + "124, increased ['l7', 'l24', 'l43', 'l60', 'l74', 'l87', 'l100', 'l114', 'l128', 'l140', 'l151', 'l158', 'l164', 'l169', 'l174', 'l175', 'l176', 'l177']", + "126, vulnerability ['l8', 'l25', 'l44', 'l61', 'l75', 'l88', 'l101', 'l115', 'l129', 'l141', 'l152', 'l159', 'l165', 'l170', 'l174', 'l178', 'l179', 'l180']", + "128, neurons ['l9', 'l26', 'l45', 'l62', 'l76', 'l89', 'l102', 'l116', 'l130', 'l142', 'l153', 'l160', 'l166', 'l171', 'l175', 'l178', 'l181', 'l182']", + "130, cell ['l10', 'l27', 'l46', 'l63', 'l77', 'l90', 'l103', 'l117', 'l131', 'l143', 'l154', 'l161', 'l167', 'l172', 'l176', 'l179', 'l181', 'l183']", + "131, death ['l11', 'l28', 'l47', 'l64', 'l78', 'l91', 'l104', 'l118', 'l132', 'l144', 'l155', 'l162', 'l168', 'l173', 'l177', 'l180', 'l182', 'l183']", + "139, In ['l29', 'l48', 'l92', 'l105', 'l119', 'l133', 'l145', 'l184', 'l185', 'l186', 'l187', 'l188']", + "140, vivo, ['l30', 'l49', 'l106', 'l120', 'l134', 'l146', 'l184', 'l189', 'l190', 'l191', 'l192']", + "141, suppression ['l185', 'l189', 'l193', 'l194', 'l195']", + "142, of ['l186', 'l190', 'l193', 'l196', 'l197']", + "143, TSC1 ['l121', 'l187', 'l191', 'l194', 'l196', 'l198']", + "144, expression ['l31', 'l107', 'l122', 'l135', 'l147', 'l188', 'l192', 'l195', 'l197', 'l198']", + "155, Overexpression ['l199', 'l200', 'l201', 'l202']", + "156, of ['l199', 'l203', 'l204', 'l205']", + "157, hamartin ['l200', 'l203', 'l206', 'l207']", + "163, inducing ['l201', 'l204', 'l206', 'l208']", + "165, autophagy ['l202', 'l205', 'l207', 'l208']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CA1", + "neurons" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CA1", + "neurons" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Suppression", + "of", + "hamartin", + "expression", + "with", + "TSC1", + "shRNA", + "viral", + "vectors" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Suppression", + "of", + "hamartin", + "expression", + "with", + "TSC1", + "shRNA", + "viral", + "vectors", + "suppression" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "In", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Suppression", + "of", + "hamartin", + "expression", + "with", + "TSC1", + "shRNA", + "viral", + "vectors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Suppression", + "of", + "hamartin", + "expression", + "with", + "TSC1", + "shRNA", + "viral", + "vectors" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Suppression", + "of", + "hamartin", + "expression", + "with", + "TSC1", + "shRNA", + "viral", + "vectors" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "hamartin" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "hamartin" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + } + ] + }, + { + "PMID": "23416703", + "TEXT": "Depression induces structural and functional synaptic plasticity in brain reward circuits, although the mechanisms promoting these changes and their relevance to behavioral outcomes are unknown. Transcriptional profiling of the nucleus accumbens (NAc) for Rho GTPase-related genes, which are known regulators of synaptic structure, revealed a sustained reduction in RAS-related C3 botulinum toxin substrate 1 (Rac1) expression after chronic social defeat stress. This was associated with a repressive chromatin state surrounding the proximal promoter of Rac1. Inhibition of class 1 histone deacetylases (HDACs) with MS-275 rescued both the decrease in Rac1 transcription after social defeat stress and depression-related behavior, such as social avoidance. We found a similar repressive chromatin state surrounding the RAC1 promoter in the NAc of subjects with depression, which corresponded with reduced RAC1 transcription. Viral-mediated reduction of Rac1 expression or inhibition of Rac1 activity in the NAc increases social defeat-induced social avoidance and anhedonia in mice. Chronic social defeat stress induces the formation of stubby excitatory spines through a Rac1-dependent mechanism involving the redistribution of synaptic cofilin, an actin-severing protein downstream of Rac1. Overexpression of constitutively active Rac1 in the NAc of mice after chronic social defeat stress reverses depression-related behaviors and prunes stubby spines. Taken together, our data identify epigenetic regulation of RAC1 in the NAc as a disease mechanism in depression and reveal a functional role for Rac1 in rodents in regulating stress-related behaviors.", + "TAG_DATA": [ + "126, Viral-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "127, reduction {'perturbing_action': 'I-rnai/knockdown'}", + "128, of {'perturbing_action': 'I-rnai/knockdown'}", + "129, Rac1 {'perturbing_action': 'I-rnai/knockdown'}", + "130, expression {'perturbing_action': 'I-rnai/knockdown'}", + "132, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "133, of {'perturbing_action': 'I-pharmacological inhibition'}", + "134, Rac1 {'perturbing_action': 'I-pharmacological inhibition'}", + "135, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "136, in {'perturbing_action': 'I-pharmacological inhibition'}", + "137, the {'perturbing_action': 'I-pharmacological inhibition'}", + "138, NAc {'perturbing_action': 'I-pharmacological inhibition'}", + "147, mice. {'context': 'B-organism'}", + "175, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "176, of {'perturbing_action': 'I-gene gain-of-function'}", + "177, constitutively {'perturbing_action': 'I-gene gain-of-function'}", + "178, active {'perturbing_action': 'I-gene gain-of-function'}", + "179, Rac1 {'perturbing_action': 'I-gene gain-of-function'}", + "182, NAc {'context': 'B-tissue/organ'}", + "184, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "126, Viral-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "127, reduction ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "128, of ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "129, Rac1 ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "130, expression ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "132, inhibition ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "133, of ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "134, Rac1 ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l58', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "135, activity ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l59', 'l65', 'l71', 'l72', 'l73', 'l74']", + "136, in ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l60', 'l66', 'l71', 'l75', 'l76', 'l77']", + "137, the ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l61', 'l67', 'l72', 'l75', 'l78', 'l79']", + "138, NAc ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l62', 'l68', 'l73', 'l76', 'l78', 'l80']", + "147, mice. ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l63', 'l69', 'l74', 'l77', 'l79', 'l80']", + "175, Overexpression ['l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "176, of ['l81', 'l87', 'l88', 'l89', 'l90', 'l91']", + "177, constitutively ['l82', 'l87', 'l92', 'l93', 'l94', 'l95']", + "178, active ['l83', 'l88', 'l92', 'l96', 'l97', 'l98']", + "179, Rac1 ['l84', 'l89', 'l93', 'l96', 'l99', 'l100']", + "182, NAc ['l57', 'l64', 'l70', 'l85', 'l90', 'l94', 'l97', 'l99', 'l101']", + "184, mice ['l86', 'l91', 'l95', 'l98', 'l100', 'l101']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Viral-mediated", + "reduction", + "of", + "Rac1", + "expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "Rac1", + "activity", + "in", + "the", + "NAc" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "Rac1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "NAc" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "constitutively", + "active", + "Rac1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "NAc" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "constitutively", + "active", + "Rac1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23416702", + "TEXT": "Enhanced fetal γ-globin synthesis alleviates symptoms of β-globinopathies such as sickle cell disease and β-thalassemia, but current γ-globin-inducing drugs offer limited beneficial effects. We show here that lysine-specific demethylase 1 (LSD1) inhibition by RNAi in human erythroid cells or by the monoamine oxidase inhibitor tranylcypromine in human erythroid cells or β-type globin-transgenic mice enhances γ-globin expression. LSD1 is thus a promising therapeutic target for γ-globin induction, and tranylcypromine may serve as a lead compound for the development of a new γ-globin inducer.", + "TAG_DATA": [ + "27, lysine-specific {'perturbing_action': 'B-pharmacological inhibition'}", + "28, demethylase {'perturbing_action': 'I-pharmacological inhibition'}", + "29, 1 {'perturbing_action': 'I-pharmacological inhibition'}", + "30, (LSD1) {'perturbing_action': 'I-pharmacological inhibition'}", + "31, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "32, by {'perturbing_action': 'I-rnai/knockdown'}", + "33, RNAi {'perturbing_action': 'I-rnai/knockdown'}", + "35, human {'context': 'B-cells'}", + "36, erythroid {'context': 'I-cells'}", + "37, cells {'context': 'I-cells'}", + "46, human {'context': 'B-cells'}", + "47, erythroid {'context': 'I-cells'}", + "48, cells {'context': 'I-cells'}", + "50, β-type {'perturbing_action': 'B-gene gain-of-function'}", + "51, globin-transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "52, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "27, lysine-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "28, demethylase ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "29, 1 ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "30, (LSD1) ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "31, inhibition ['l3', 'l15', 'l26', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "32, by ['l4', 'l16', 'l27', 'l37', 'l45', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "33, RNAi ['l5', 'l17', 'l28', 'l38', 'l46', 'l53', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "35, human ['l6', 'l18', 'l29', 'l39', 'l47', 'l54', 'l60', 'l66', 'l67', 'l68', 'l69', 'l70']", + "36, erythroid ['l7', 'l19', 'l30', 'l40', 'l48', 'l55', 'l61', 'l66', 'l71', 'l72', 'l73', 'l74']", + "37, cells ['l8', 'l20', 'l31', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l75']", + "46, human ['l9', 'l21', 'l32', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l76', 'l77', 'l78', 'l79', 'l80']", + "47, erythroid ['l10', 'l22', 'l33', 'l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l76', 'l81', 'l82', 'l83', 'l84']", + "48, cells ['l11', 'l23', 'l34', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l75', 'l77', 'l81', 'l85', 'l86', 'l87']", + "50, β-type ['l78', 'l82', 'l85', 'l88', 'l89']", + "51, globin-transgenic ['l12', 'l24', 'l35', 'l79', 'l83', 'l86', 'l88', 'l90']", + "52, mice ['l80', 'l84', 'l87', 'l89', 'l90']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "lysine-specific", + "demethylase", + "1", + "(LSD1)", + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "erythroid", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "by", + "RNAi" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "erythroid", + "cells" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "erythroid", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "β-type", + "globin-transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "β-type", + "globin-transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23396208", + "TEXT": "Regulatory T (Treg) cells suppress autoimmune disease, and impaired Treg cell function is associated with rheumatoid arthritis. Here we demonstrate that forkhead box P3 (FOXP3) transcriptional activity and, consequently, Treg cell suppressive function are regulated by phosphorylation at Ser418 in the C-terminal DNA-binding domain. In rheumatoid arthritis-derived Treg cells, the Ser418 site was specifically dephosphorylated by protein phosphatase 1 (PP1), whose expression and enzymatic activity were induced in the inflamed synovium by tumor necrosis factor α (TNF-α), leading to impaired Treg cell function. Moreover, TNF-α-induced Treg cell dysfunction correlated with increased numbers of interleukin-17 (IL-17)(+) and interferon-γ (IFN-γ)(+)CD4(+) T cells within the inflamed synovium in rheumatoid arthritis. Treatment with a TNF-α-specific antibody restored Treg cell function in subjects with rheumatoid arthritis, which was associated with decreased PP1 expression and increased FOXP3 phosphorylation in Treg cells. Thus, TNF-α controls the balance between Treg cells and pathogenic TH17 and TH1 cells in the synovium of individuals with rheumatoid arthritis through FOXP3 dephosphorylation.", + "TAG_DATA": [ + "47, Treg {'context': 'B-cells'}", + "48, cells, {'context': 'I-cells'}", + "80, Treg {'context': 'B-cells'}", + "81, cell {'context': 'I-cells'}", + "113, Treg {'context': 'B-cells'}", + "114, cell {'context': 'I-cells'}", + "117, subjects {'context': 'B-patient'}", + "133, Treg {'context': 'B-cells'}", + "134, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "47, Treg ['l0', 'l1', 'l2']", + "48, cells, ['l0', 'l3', 'l4']", + "80, Treg ['l1', 'l3', 'l5']", + "81, cell ['l2', 'l4', 'l5']", + "113, Treg ['l6', 'l7', 'l8', 'l9']", + "114, cell ['l6', 'l10', 'l11']", + "117, subjects ['l7', 'l10', 'l12', 'l13']", + "133, Treg ['l8', 'l12', 'l14']", + "134, cells. ['l9', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23389615", + "TEXT": "The past decade witnessed unprecedented efforts to control malaria, including renewed political and financial commitment and increased availability of both old and new strategies and tools. However, malaria still represents a major health burden, particularly in Africa. Important challenges such as the fragility of many health systems, the rise of insecticide and drug resistance, and particularly the expected decline both in funding and in the coverage of key interventions if they are not replaced as needed, urgently need to be addressed. Further research and development is also becoming increasingly crucial. Among other needs, common methodologies for estimating and tracking the malaria burden, new strategies to measure transmission, better understanding of immunity, and increased knowledge of the mechanisms and effects of resistance to drugs and insecticides stand out. The ongoing efforts in research and development for new antimalarial drugs, more sensitive point-of-care rapid diagnostic tests and new insecticides need further innovation and substantial strengthening. Clearly, efforts should focus not only on Plasmodium falciparum but also and increasingly on Plasmodium vivax, the neglected human malaria parasite. Addressing these challenges in a comprehensive and timely way will allow us to sustain the gains made so far and make further progress in control and progressive elimination.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23353556", + "TEXT": "The functional contribution of myofibroblasts in fibrosis is not well understood. Using a new genetic mouse model to track and isolate myofibroblasts, we performed gene expression profiling followed by biological validation to identify HE4 (encoding human epididymis protein 4, also known as WAP 4-disulfide core domain-2 or Wfdc2) as the most upregulated gene in fibrosis-associated myofibroblasts. The HE4 gene encodes for a putative serine protease inhibitor that is upregulated in human and mouse fibrotic kidneys and is elevated in the serum of patients with kidney fibrosis. HE4 suppresses the activity of multiple proteases, including serine proteases and matrix metalloproteinases, and specifically inhibits their capacity to degrade type I collagen. In particular, we identified two serine proteases, Prss35 and Prss23, as HE4 targets with functional relevance in kidney fibrosis. Administration of HE4-neutralizing antibodies accelerated collagen I degradation and inhibited fibrosis in three different mouse models of renal disease. Collectively these studies suggest that HE4 is a potential biomarker of renal fibrosis and a new therapeutic target.", + "TAG_DATA": [ + "142, mouse {'context': 'B-organism'}", + "143, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "142, mouse ['l0', 'l1', 'l2', 'l3']", + "143, models ['l0', 'l4', 'l5', 'l6']", + "144, of ['l1', 'l4', 'l7', 'l8']", + "145, renal ['l2', 'l5', 'l7', 'l9']", + "146, disease. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23314056", + "TEXT": "Here we introduce tethered capsule endomicroscopy, which involves swallowing an optomechanically engineered pill that captures cross-sectional microscopic images of the gut wall at 30 μm (lateral) × 7 μm (axial) resolution as it travels through the digestive tract. Results in human subjects show that this technique rapidly provides three-dimensional, microstructural images of the upper gastrointestinal tract in a simple and painless procedure, opening up new opportunities for screening for internal diseases.", + "TAG_DATA": [ + "40, human {'context': 'B-organism'}", + "41, subjects {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "40, human ['l0']", + "41, subjects ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23295999", + "TEXT": "India has become a hotbed of clinical trials, but recent reports of safety lapses have prompted calls for better regulation in this area. Currently, trial requirements can be relaxed if doing so is in the 'public interest', but a clearer definition of what this means is needed before this provision should be used.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23178247", + "TEXT": "The pathology of Alzheimer's disease has an inflammatory component that is characterized by upregulation of proinflammatory cytokines, particularly in response to amyloid-β (Aβ). Using the APPPS1 Alzheimer's disease mouse model, we found increased production of the common interleukin-12 (IL-12) and IL-23 subunit p40 by microglia. Genetic ablation of the IL-12/IL-23 signaling molecules p40, p35 or p19, in which deficiency of p40 or its receptor complex had the strongest effect, resulted in decreased cerebral amyloid load. Although deletion of IL-12/IL-23 signaling from the radiation-resistant glial compartment of the brain was most efficient in mitigating cerebral amyloidosis, peripheral administration of a neutralizing p40-specific antibody likewise resulted in a reduction of cerebral amyloid load in APPPS1 mice. Furthermore, intracerebroventricular delivery of antibodies to p40 significantly reduced the concentration of soluble Aβ species and reversed cognitive deficits in aged APPPS1 mice. The concentration of p40 was also increased in the cerebrospinal fluid of subjects with Alzheimer's disease, which suggests that inhibition of the IL-12/IL-23 pathway may attenuate Alzheimer's disease pathology and cognitive deficits.", + "TAG_DATA": [ + "44, microglia. {'context': 'B-cells'}", + "45, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "46, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "47, of {'perturbing_action': 'I-gene loss-of-function'}", + "48, the {'perturbing_action': 'I-gene loss-of-function'}", + "49, IL-12/IL-23 {'perturbing_action': 'I-gene loss-of-function'}", + "50, signaling {'perturbing_action': 'I-gene loss-of-function'}", + "51, molecules {'perturbing_action': 'I-gene loss-of-function'}", + "52, p40, {'perturbing_action': 'I-gene loss-of-function'}", + "53, p35 {'perturbing_action': 'I-gene loss-of-function'}", + "54, or {'perturbing_action': 'I-gene loss-of-function'}", + "55, p19, {'perturbing_action': 'I-gene loss-of-function'}", + "58, deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "59, of {'perturbing_action': 'I-gene loss-of-function'}", + "60, p40 {'perturbing_action': 'I-gene loss-of-function'}", + "61, or {'perturbing_action': 'I-gene loss-of-function'}", + "62, its {'perturbing_action': 'I-gene loss-of-function'}", + "63, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "64, complex {'perturbing_action': 'I-gene loss-of-function'}", + "81, the {'perturbing_action': 'I-gene loss-of-function'}", + "82, radiation-resistant {'context': 'B-cells'}", + "83, glial {'context': 'I-cells'}", + "84, compartment {'context': 'I-cells'}", + "85, of {'context': 'I-cells'}", + "112, APPPS1 {'context': 'B-organism'}", + "113, mice. {'context': 'I-organism'}", + "134, aged {'context': 'B-organism'}", + "135, APPPS1 {'context': 'I-organism'}", + "136, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "45, Genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "46, ablation ['l0', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "47, of ['l1', 'l24', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "48, the ['l2', 'l25', 'l48', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "49, IL-12/IL-23 ['l3', 'l26', 'l49', 'l71', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "50, signaling ['l4', 'l27', 'l50', 'l72', 'l93', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "51, molecules ['l5', 'l28', 'l51', 'l73', 'l94', 'l114', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "52, p40, ['l6', 'l29', 'l52', 'l74', 'l95', 'l115', 'l134', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170']", + "53, p35 ['l7', 'l30', 'l53', 'l75', 'l96', 'l116', 'l135', 'l153', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "54, or ['l8', 'l31', 'l54', 'l76', 'l97', 'l117', 'l136', 'l154', 'l171', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203']", + "55, p19, ['l9', 'l32', 'l55', 'l77', 'l98', 'l118', 'l137', 'l155', 'l172', 'l188', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218']", + "58, deficiency ['l10', 'l33', 'l56', 'l78', 'l99', 'l119', 'l138', 'l156', 'l173', 'l189', 'l204', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233']", + "59, of ['l11', 'l34', 'l57', 'l79', 'l100', 'l120', 'l139', 'l157', 'l174', 'l190', 'l205', 'l219', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247']", + "60, p40 ['l12', 'l35', 'l58', 'l80', 'l101', 'l121', 'l140', 'l158', 'l175', 'l191', 'l206', 'l220', 'l234', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261']", + "61, or ['l13', 'l36', 'l59', 'l81', 'l102', 'l122', 'l141', 'l159', 'l176', 'l192', 'l207', 'l221', 'l235', 'l248', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274']", + "62, its ['l14', 'l37', 'l60', 'l82', 'l103', 'l123', 'l142', 'l160', 'l177', 'l193', 'l208', 'l222', 'l236', 'l249', 'l262', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286']", + "63, receptor ['l15', 'l38', 'l61', 'l83', 'l104', 'l124', 'l143', 'l161', 'l178', 'l194', 'l209', 'l223', 'l237', 'l250', 'l263', 'l275', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297']", + "64, complex ['l16', 'l39', 'l62', 'l84', 'l105', 'l125', 'l144', 'l162', 'l179', 'l195', 'l210', 'l224', 'l238', 'l251', 'l264', 'l276', 'l287', 'l298', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304', 'l305', 'l306']", + "80, from ['l40', 'l63', 'l85', 'l106', 'l126', 'l145', 'l163', 'l180', 'l196', 'l211', 'l225', 'l239', 'l252', 'l265', 'l277', 'l288', 'l298', 'l307', 'l308', 'l309', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315']", + "81, the ['l17', 'l41', 'l64', 'l86', 'l107', 'l127', 'l146', 'l164', 'l181', 'l197', 'l212', 'l226', 'l240', 'l253', 'l266', 'l278', 'l289', 'l299', 'l307', 'l316', 'l317', 'l318', 'l319', 'l320', 'l321', 'l322', 'l323']", + "82, radiation-resistant ['l18', 'l42', 'l65', 'l87', 'l108', 'l128', 'l147', 'l165', 'l182', 'l198', 'l213', 'l227', 'l241', 'l254', 'l267', 'l279', 'l290', 'l300', 'l308', 'l316', 'l324', 'l325', 'l326', 'l327', 'l328', 'l329', 'l330']", + "83, glial ['l19', 'l43', 'l66', 'l88', 'l109', 'l129', 'l148', 'l166', 'l183', 'l199', 'l214', 'l228', 'l242', 'l255', 'l268', 'l280', 'l291', 'l301', 'l309', 'l317', 'l324', 'l331', 'l332', 'l333', 'l334', 'l335', 'l336']", + "84, compartment ['l20', 'l44', 'l67', 'l89', 'l110', 'l130', 'l149', 'l167', 'l184', 'l200', 'l215', 'l229', 'l243', 'l256', 'l269', 'l281', 'l292', 'l302', 'l310', 'l318', 'l325', 'l331', 'l337', 'l338', 'l339', 'l340', 'l341']", + "85, of ['l21', 'l45', 'l68', 'l90', 'l111', 'l131', 'l150', 'l168', 'l185', 'l201', 'l216', 'l230', 'l244', 'l257', 'l270', 'l282', 'l293', 'l303', 'l311', 'l319', 'l326', 'l332', 'l337', 'l342', 'l343', 'l344', 'l345']", + "86, the ['l22', 'l46', 'l69', 'l91', 'l112', 'l132', 'l151', 'l169', 'l186', 'l202', 'l217', 'l231', 'l245', 'l258', 'l271', 'l283', 'l294', 'l304', 'l312', 'l320', 'l327', 'l333', 'l338', 'l342', 'l346', 'l347', 'l348']", + "87, brain ['l23', 'l47', 'l70', 'l92', 'l113', 'l133', 'l152', 'l170', 'l187', 'l203', 'l218', 'l232', 'l246', 'l259', 'l272', 'l284', 'l295', 'l305', 'l313', 'l321', 'l328', 'l334', 'l339', 'l343', 'l346', 'l349', 'l350']", + "112, APPPS1 ['l260', 'l273', 'l285', 'l296', 'l314', 'l322', 'l329', 'l335', 'l340', 'l344', 'l347', 'l349', 'l351']", + "113, mice. ['l233', 'l247', 'l261', 'l274', 'l286', 'l297', 'l306', 'l315', 'l323', 'l330', 'l336', 'l341', 'l345', 'l348', 'l350', 'l351']", + "134, aged ['l352', 'l353']", + "135, APPPS1 ['l352', 'l354']", + "136, mice. ['l353', 'l354']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "ablation", + "of", + "the", + "IL-12/IL-23", + "signaling", + "molecules", + "p40,", + "p35", + "or", + "p19,", + "deficiency", + "p40", + "its", + "receptor", + "complex" + ] + }, + "context": { + "val": "cells", + "words": [ + "radiation-resistant", + "glial", + "compartment", + "of" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "of", + "p40", + "or", + "its", + "receptor", + "complex", + "the" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "APPPS1" + ] + } + } + ] + }, + { + "PMID": "23135510", + "TEXT": "A new study provides mechanistic insights into how live attenuated simian immunodeficiency virus (SIV) vaccines (LAVs) can protect monkeys from infection with pathogenic SIV. The authors show that replicating LAVs stimulate a protective immune response from a safe haven in the germinal centers of lymph nodes (pages 1673-1681).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23135508", + "TEXT": "A long-standing question in the HIV field is why HIV-1 fails to replicate in resting CD4(+) T cells. A new study shows that host deoxynucleoside triphosphate triphosphohydrolase (dNTPase) sterile α motif and histidine/aspartic domain-containing protein 1 (SAMHD1), previously shown to block HIV infection in myeloid cells, also restricts HIV replication in resting CD4(+) T cells by hydrolyzing dNTPs, which are needed for reverse transcription of the virus (pages 1682-1687).", + "TAG_DATA": [ + "52, CD4(+) {'context': 'B-cells'}", + "53, T {'context': 'I-cells'}", + "54, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "52, CD4(+) ['l0', 'l1']", + "53, T ['l0', 'l2']", + "54, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23135505", + "TEXT": "Clinical trials typically address more than one question. But in attempting to protect against misleading results that are due to chance when multiple interrelated tests are run simultaneously, researchers sometimes apply overly strict statistical devices that mask true effects. They should give more consideration to choosing the type of statistical analysis that fits best.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23086476", + "TEXT": "The microenvironment, or niche, surrounding a stem cell largely governs its cellular fate. Two anatomical niches for hematopoietic stem cells (HSCs) have been reported in the bone marrow, but a distinct function for each of these niches remains unclear. Here we report a new role for the adhesion molecule E-selectin expressed exclusively by bone marrow endothelial cells in the vascular HSC niche. HSC quiescence was enhanced and self-renewal potential was increased in E-selectin knockout (Sele(-/-)) mice or after administration of an E-selectin antagonist, demonstrating that E-selectin promotes HSC proliferation and is a crucial component of the vascular niche. These effects are not mediated by canonical E-selectin ligands. Deletion or blockade of E-selectin enhances HSC survival threefold to sixfold after treatment of mice with chemotherapeutic agents or irradiation and accelerates blood neutrophil recovery. As bone marrow suppression is a severe side effect of high-dose chemotherapy, transient blockade of E-selectin is potentially a promising treatment for the protection of HSCs during chemotherapy or irradiation.", + "TAG_DATA": [ + "62, HSC {'context': 'B-transformed cells'}", + "63, quiescence {'phenotype': 'B-quiescence'}", + "65, enhanced {'effect': 'B-positive'}", + "67, self-renewal {'phenotype': 'B-self-renewal'}", + "68, potential {'phenotype': 'I-colony formation'}", + "70, increased {'effect': 'B-positive'}", + "72, E-selectin {'perturbing_action': 'B-gene loss-of-function'}", + "73, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "74, (Sele(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "75, mice {'context': 'B-organism'}", + "81, E-selectin {'perturbing_action': 'B-pharmacological inhibition'}", + "82, antagonist, {'perturbing_action': 'I-pharmacological inhibition'}", + "86, promotes {'effect': 'B-positive'}", + "88, proliferation {'phenotype': 'B-proliferation'}", + "109, blockade {'perturbing_action': 'B-gene loss-of-function'}", + "110, of {'perturbing_action': 'I-gene loss-of-function'}", + "111, E-selectin {'perturbing_action': 'I-gene loss-of-function'}", + "113, HSC {'context': 'B-transformed cells'}", + "121, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "62, HSC ['l0', 'l1']", + "63, quiescence ['l0', 'l2']", + "65, enhanced ['l1', 'l2']", + "67, self-renewal ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "68, potential ['l3', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "70, increased ['l4', 'l11', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "72, E-selectin ['l5', 'l12', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "73, knockout ['l6', 'l13', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32', 'l33']", + "74, (Sele(-/-)) ['l7', 'l14', 'l20', 'l25', 'l29', 'l34', 'l35', 'l36', 'l37', 'l38']", + "75, mice ['l8', 'l15', 'l21', 'l26', 'l30', 'l34', 'l39', 'l40']", + "81, E-selectin ['l35', 'l41', 'l42', 'l43']", + "82, antagonist, ['l31', 'l36', 'l41', 'l44', 'l45']", + "86, promotes ['l9', 'l16', 'l22', 'l27', 'l32', 'l37', 'l39', 'l42', 'l44', 'l46']", + "88, proliferation ['l10', 'l17', 'l23', 'l28', 'l33', 'l38', 'l40', 'l43', 'l45', 'l46']", + "109, blockade ['l47', 'l48', 'l49', 'l50']", + "110, of ['l47', 'l51', 'l52', 'l53']", + "111, E-selectin ['l48', 'l51', 'l54', 'l55']", + "113, HSC ['l49', 'l52', 'l54', 'l56']", + "121, mice ['l50', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "promotes" + ] + } + }, + { + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "E-selectin", + "knockout", + "(Sele(-/-))" + ] + } + }, + { + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "potential" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "promotes" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "potential" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "E-selectin", + "knockout", + "(Sele(-/-))" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "potential" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased", + "promotes" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "E-selectin", + "knockout", + "(Sele(-/-))" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased", + "promotes" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased", + "promotes" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "E-selectin", + "knockout", + "(Sele(-/-))", + "blockade", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "E-selectin", + "knockout", + "(Sele(-/-))" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "E-selectin", + "antagonist," + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "E-selectin", + "antagonist," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "blockade", + "of", + "E-selectin" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + } + } + ] + }, + { + "PMID": "23086475", + "TEXT": "Neutralizing antibodies are likely to play a crucial part in a preventative HIV-1 vaccine. Although efforts to elicit broadly cross-neutralizing (BCN) antibodies by vaccination have been unsuccessful, a minority of individuals naturally develop these antibodies after many years of infection. How such antibodies arise, and the role of viral evolution in shaping these responses, is unknown. Here we show, in two HIV-1-infected individuals who developed BCN antibodies targeting the glycan at Asn332 on the gp120 envelope, that this glycan was absent on the initial infecting virus. However, this BCN epitope evolved within 6 months, through immune escape from earlier strain-specific antibodies that resulted in a shift of a glycan to position 332. Both viruses that lacked the glycan at amino acid 332 were resistant to the Asn332-dependent BCN monoclonal antibody PGT128 (ref. 8), whereas escaped variants that acquired this glycan were sensitive. Analysis of large sequence and neutralization data sets showed the 332 glycan to be significantly under-represented in transmitted subtype C viruses compared to chronic viruses, with the absence of this glycan corresponding with resistance to PGT128. These findings highlight the dynamic interplay between early antibodies and viral escape in driving the evolution of conserved BCN antibody epitopes.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23023500", + "TEXT": "The ability of the human immune system to respond to vaccination declines with age. We identified an age-associated defect in T cell receptor (TCR)-induced extracellular signal-regulated kinase (ERK) phosphorylation in naive CD4(+) T cells, whereas other signals, such as ζ chain-associated protein kinase 70 (ZAP70) and phospholipase C-γ1 phosphorylation, were not impaired. The defective ERK signaling was caused by the dual specific phosphatase 6 (DUSP6), whose protein expression increased with age due to a decline in repression by miR-181a. Reconstitution of miR-181a lowered DUSP6 expression in naive CD4(+) T cells in elderly individuals. DUSP6 repression using miR-181a or specific siRNA and DUSP6 inhibition by the allosteric inhibitor (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one improved CD4(+) T cell responses, as seen by increased expression of activation markers, improved proliferation and supported preferential T helper type 1 cell differentiation. DUSP6 is a potential intervention target for restoring T cell responses in the elderly, which may augment the effectiveness of vaccination.", + "TAG_DATA": [ + "86, naive {'context': 'B-cells'}", + "87, CD4(+) {'context': 'I-cells'}", + "88, T {'context': 'I-cells'}", + "89, cells {'context': 'I-cells'}", + "93, DUSP6 {'perturbing_action': 'B-rnai/knockdown'}", + "94, repression {'perturbing_action': 'I-rnai/knockdown'}", + "95, using {'perturbing_action': 'I-rnai/knockdown'}", + "96, miR-181a {'perturbing_action': 'I-rnai/knockdown'}", + "98, specific {'perturbing_action': 'B-rnai/knockdown'}", + "99, siRNA {'perturbing_action': 'I-rnai/knockdown'}", + "101, DUSP6 {'perturbing_action': 'B-pharmacological inhibition'}", + "102, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "103, by {'perturbing_action': 'I-pharmacological inhibition'}", + "104, the {'perturbing_action': 'I-pharmacological inhibition'}", + "105, allosteric {'perturbing_action': 'I-pharmacological inhibition'}", + "106, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "107, (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one {'perturbing_action': 'I-pharmacological inhibition'}", + "109, CD4(+) {'context': 'B-cells'}", + "110, T {'context': 'I-cells'}", + "111, cell {'context': 'I-cells'}", + "121, improved {'effect': 'B-positive'}", + "122, proliferation {'phenotype': 'B-proliferation'}", + "124, supported {'effect': 'B-positive'}", + "126, T {'context': 'B-cells'}", + "127, helper {'context': 'I-cells'}", + "128, type {'context': 'I-cells'}", + "129, 1 {'context': 'I-cells'}", + "130, cell {'context': 'I-cells'}", + "131, differentiation. {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "86, naive ['l0', 'l1', 'l2']", + "87, CD4(+) ['l0', 'l3', 'l4']", + "88, T ['l1', 'l3', 'l5']", + "89, cells ['l2', 'l4', 'l5']", + "93, DUSP6 ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "94, repression ['l6', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "95, using ['l7', 'l28', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "96, miR-181a ['l8', 'l29', 'l48', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "98, specific ['l9', 'l30', 'l49', 'l64', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "99, siRNA ['l10', 'l31', 'l50', 'l65', 'l82', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "101, DUSP6 ['l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "102, inhibition ['l115', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "103, by ['l11', 'l116', 'l133', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "104, the ['l12', 'l32', 'l66', 'l83', 'l99', 'l117', 'l134', 'l150', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180']", + "105, allosteric ['l13', 'l33', 'l67', 'l84', 'l100', 'l118', 'l135', 'l151', 'l166', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "106, inhibitor ['l14', 'l34', 'l51', 'l68', 'l85', 'l101', 'l119', 'l136', 'l152', 'l167', 'l181', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207']", + "107, (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one ['l15', 'l35', 'l52', 'l69', 'l86', 'l102', 'l120', 'l137', 'l153', 'l168', 'l182', 'l195', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219']", + "109, CD4(+) ['l16', 'l36', 'l53', 'l70', 'l87', 'l103', 'l121', 'l138', 'l154', 'l169', 'l183', 'l196', 'l208', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230']", + "110, T ['l17', 'l37', 'l54', 'l71', 'l88', 'l104', 'l122', 'l139', 'l155', 'l170', 'l184', 'l197', 'l209', 'l220', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240']", + "111, cell ['l18', 'l38', 'l55', 'l72', 'l89', 'l105', 'l123', 'l140', 'l156', 'l171', 'l185', 'l198', 'l210', 'l221', 'l231', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247']", + "121, improved ['l19', 'l39', 'l56', 'l73', 'l90', 'l106', 'l124', 'l141', 'l157', 'l172', 'l186', 'l199', 'l211', 'l222', 'l232', 'l241', 'l248', 'l249']", + "122, proliferation ['l20', 'l40', 'l57', 'l74', 'l91', 'l107', 'l125', 'l142', 'l158', 'l173', 'l187', 'l200', 'l212', 'l223', 'l233', 'l242', 'l248', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256']", + "124, supported ['l21', 'l41', 'l58', 'l75', 'l92', 'l108', 'l126', 'l143', 'l159', 'l174', 'l188', 'l201', 'l213', 'l224', 'l234', 'l243', 'l250', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262']", + "126, T ['l22', 'l42', 'l76', 'l93', 'l109', 'l127', 'l144', 'l160', 'l175', 'l189', 'l202', 'l214', 'l225', 'l235', 'l251', 'l257', 'l263', 'l264', 'l265', 'l266', 'l267']", + "127, helper ['l23', 'l43', 'l59', 'l77', 'l94', 'l110', 'l128', 'l145', 'l161', 'l176', 'l190', 'l203', 'l215', 'l226', 'l236', 'l252', 'l258', 'l263', 'l268', 'l269', 'l270', 'l271']", + "128, type ['l24', 'l44', 'l60', 'l78', 'l95', 'l111', 'l129', 'l146', 'l162', 'l177', 'l191', 'l204', 'l216', 'l227', 'l237', 'l244', 'l253', 'l259', 'l264', 'l268', 'l272', 'l273', 'l274']", + "129, 1 ['l25', 'l45', 'l61', 'l79', 'l96', 'l112', 'l130', 'l147', 'l163', 'l178', 'l192', 'l205', 'l217', 'l228', 'l238', 'l245', 'l254', 'l260', 'l265', 'l269', 'l272', 'l275', 'l276']", + "130, cell ['l26', 'l46', 'l62', 'l80', 'l97', 'l113', 'l131', 'l148', 'l164', 'l179', 'l193', 'l206', 'l218', 'l229', 'l239', 'l246', 'l255', 'l261', 'l266', 'l270', 'l273', 'l275', 'l277']", + "131, differentiation. 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Here we used mesoporous-silica-coated upconversion fluorescent nanoparticles (UCNs) as a nanotransducer to convert deeply penetrating near-infrared light to visible wavelengths and a carrier of photosensitizers. We also used the multicolor-emission capability of the UCNs at a single excitation wavelength for simultaneous activation of two photosensitizers for enhanced PDT. We showed a greater PDT efficacy with the dual-photosensitizer approach compared to approaches using a single photosensitizer, as determined by enhanced generation of singlet oxygen and reduced cell viability. In vivo studies also showed tumor growth inhibition in PDT-treated mice by direct injection of UCNs into melanoma tumors or intravenous injection of UCNs conjugated with a tumor-targeting agent into tumor-bearing mice. As the first demonstration, to the best of our knowledge, of the photosensitizer-loaded UCN as an in vivo-targeted PDT agent, this finding may serve as a platform for future noninvasive deep-cancer therapy.", + "TAG_DATA": [ + "91, reduced {'effect': 'B-negative'}", + "92, cell {'phenotype': 'B-cell survival'}", + "93, viability. {'phenotype': 'I-cell survival'}", + "94, In {'context': 'B-in vivo'}", + "95, vivo {'context': 'I-in vivo'}", + "99, tumor {'phenotype': 'B-tumour growth'}", + "100, growth {'phenotype': 'I-tumour growth'}", + "101, inhibition {'effect': 'B-negative'}", + "104, mice {'context': 'B-organism'}", + "111, melanoma {'context': 'B-neoplasm'}", + "112, tumors {'context': 'I-neoplasm'}", + "124, tumor-bearing {'context': 'B-organism'}", + "125, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "91, reduced ['l0', 'l1']", + "92, cell ['l0', 'l2']", + "93, viability. ['l1', 'l2']", + "94, In ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "95, vivo ['l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "99, tumor ['l4', 'l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "100, growth ['l5', 'l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "101, inhibition ['l6', 'l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "104, mice ['l7', 'l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "111, melanoma ['l8', 'l14', 'l19', 'l23', 'l26', 'l28', 'l30']", + "112, tumors ['l9', 'l15', 'l20', 'l24', 'l27', 'l29', 'l30']", + "124, tumor-bearing ['l31']", + "125, mice. ['l31']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "viability." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "melanoma", + "tumors" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "melanoma", + "tumors" + ] + } + } + ] + }, + { + "PMID": "22961148", + "TEXT": "By 2014, the UK will be changing the way it regulates the price it pays for medicines. Currently the country's National Health Service (NHS) uses the Pharmaceutical Price Regulation Scheme (PPRS), which controls the maximum profit a drug manufacturer can make on the basis of capital investments the manufacturer has made. A review of this system, carried out by the UK Office of Fair Trading in 2007, recommended that, instead, medicines should be priced according to the therapeutic benefits they offer to patients-an idea known as value-based pricing (VBP) that has similarities to systems already used in smaller countries such as Australia and Canada. This pricing scheme has been embraced by the UK government, and negotiations on how the system will work are due to begin this month. A British switch to VBP could have ripple effects throughout the global pharmaceutical industry. Even though the UK's share of the world drug market is relatively small-just 3%-drug prices in the country are important because a quarter of national governments reference British values to determine their own sticker prices. One of the most influential thinkers on the UK's proposed system is health economist Mark Sculpher, director of the Programme on Economic Evaluation and Health Technology Assessment at the University of York. As a regular advisor to the UK National Institute for Health and Clinical Excellence (NICE) and former chair of a task force on methods guidance for economic evaluation at the agency, Sculpher has had an instrumental role in guiding value-based decision-making in the country's healthcare system. Kate Ravilious met with Sculpher at his office in York to discuss the value of VBP.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22941276", + "TEXT": "We investigated whether ancestral liver damage leads to heritable reprogramming of hepatic wound healing in male rats. We found that a history of liver damage corresponds with transmission of an epigenetic suppressive adaptation of the fibrogenic component of wound healing to the male F1 and F2 generations. Underlying this adaptation was less generation of liver myofibroblasts, higher hepatic expression of the antifibrogenic factor peroxisome proliferator-activated receptor γ (PPAR-γ) and lower expression of the profibrogenic factor transforming growth factor β1 (TGF-β1) compared to rats without this adaptation. Remodeling of DNA methylation and histone acetylation underpinned these alterations in gene expression. Sperm from rats with liver fibrosis were enriched for the histone variant H2A.Z and trimethylation of histone H3 at Lys27 (H3K27me3) at PPAR-γ chromatin. These modifications to the sperm chromatin were transmittable by adaptive serum transfer from fibrotic rats to naive rats and similar modifications were induced in mesenchymal stem cells exposed to conditioned media from cultured rat or human myofibroblasts. Thus, it is probable that a myofibroblast-secreted soluble factor stimulates heritable epigenetic signatures in sperm so that the resulting offspring better adapt to future fibrogenic hepatic insults. Adding possible relevance to humans, we found that people with mild liver fibrosis have hypomethylation of the PPARG promoter compared to others with severe fibrosis.", + "TAG_DATA": [ + "54, liver {'context': 'B-cells'}", + "55, myofibroblasts, {'context': 'I-cells'}", + "82, rats {'context': 'B-organism'}", + "147, mesenchymal {'context': 'B-cells'}", + "148, stem {'context': 'I-cells'}", + "149, cells {'context': 'I-cells'}", + "156, rat {'context': 'I-cells'}", + "157, or {'context': 'I-cells'}", + "158, human {'context': 'I-cells'}", + "159, myofibroblasts. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "54, liver ['l0']", + "55, myofibroblasts, ['l0']", + "147, mesenchymal ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "148, stem ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "149, cells ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "156, rat ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "157, or ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "158, human ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "159, myofibroblasts. ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22941275", + "TEXT": "Cilia are evolutionarily conserved microtubule-based organelles that are crucial for diverse biological functions, including motility, cell signaling and sensory perception. In humans, alterations in the formation and function of cilia manifest clinically as ciliopathies, a growing class of pleiotropic genetic disorders. Despite the substantial progress that has been made in identifying genes that cause ciliopathies, therapies for these disorders are not yet available to patients. Although mice with a hypomorphic mutation in the intraflagellar transport protein IFT88 (Ift88Tg737Rpw mice, also known as ORPK mice)5 have been well studied, the relevance of IFT88 mutations to human pathology is unknown. We show that a mutation in IFT88 causes a hitherto unknown human ciliopathy. In vivo complementation assays in zebrafish and mIMCD3 cells show the pathogenicity of this newly discovered allele. We further show that ORPK mice are functionally anosmic as a result of the loss of cilia on their olfactory sensory neurons (OSNs). Notably, adenoviral-mediated expression of IFT88 in mature, fully differentiated OSNs of ORPK mice is sufficient to restore ciliary structures and rescue olfactory function. These studies are the first to use in vivo therapeutic treatment to reestablish cilia in a mammalian ciliopathy. More broadly, our studies indicate that gene therapy is a viable option for cellular and functional rescue of the complex ciliary organelle in established differentiated cells.", + "TAG_DATA": [ + "111, In {'context': 'B-in vivo'}", + "112, vivo {'context': 'I-in vivo'}", + "116, zebrafish {'context': 'B-organism'}", + "118, mIMCD3 {'context': 'B-cells'}", + "119, cells {'context': 'I-cells'}", + "133, mice {'context': 'B-organism'}", + "147, olfactory {'context': 'B-cells'}", + "148, sensory {'context': 'I-cells'}", + "149, neurons {'context': 'I-cells'}", + "150, (OSNs). {'context': 'I-cells'}", + "152, adenoviral-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "153, expression {'perturbing_action': 'I-gene gain-of-function'}", + "154, of {'perturbing_action': 'I-gene gain-of-function'}", + "155, IFT88 {'perturbing_action': 'I-gene gain-of-function'}", + "157, mature, {'context': 'B-cells'}", + "158, fully {'context': 'I-cells'}", + "159, differentiated {'context': 'I-cells'}", + "160, OSNs {'context': 'I-cells'}", + "162, ORPK {'perturbing_action': 'B-other', 'context': 'B-organism'}", + "163, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "111, In ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "112, vivo ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "116, zebrafish ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "118, mIMCD3 ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "119, cells ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "133, mice ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "147, olfactory ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "148, sensory ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "149, neurons ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "150, (OSNs). ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "152, adenoviral-mediated ['l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "153, expression ['l45', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "154, of ['l46', 'l54', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "155, IFT88 ['l47', 'l55', 'l62', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "157, mature, ['l48', 'l56', 'l63', 'l69', 'l75', 'l76', 'l77', 'l78', 'l79']", + "158, fully ['l49', 'l57', 'l64', 'l70', 'l75', 'l80', 'l81', 'l82', 'l83']", + "159, differentiated ['l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l84', 'l85', 'l86']", + "160, OSNs ['l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l87', 'l88']", + "162, ORPK ['l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l87', 'l89']", + "163, mice ['l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l89']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral-mediated", + "expression", + "of", + "IFT88" + ] + }, + "context": { + "val": "cells", + "words": [ + "mature,", + "fully", + "differentiated", + "OSNs" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral-mediated", + "expression", + "of", + "IFT88" + ] + }, + "context": { + "val": "organism", + "words": [ + "ORPK", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "ORPK" + ] + }, + "context": { + "val": "organism", + "words": [ + "ORPK" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mature,", + "fully", + "differentiated", + "OSNs" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "ORPK" + ] + } + } + ] + }, + { + "PMID": "22922410", + "TEXT": "Neutrophil extracellular traps (NETs) are released as neutrophils die in vitro in a process requiring hours, leaving a temporal gap that invasive microbes may exploit. Neutrophils capable of migration and phagocytosis while undergoing NETosis have not been documented. During Gram-positive skin infections, we directly visualized live polymorphonuclear cells (PMNs) in vivo rapidly releasing NETs, which prevented systemic bacterial dissemination. NETosis occurred during crawling, thereby casting large areas of NETs. NET-releasing PMNs developed diffuse decondensed nuclei, ultimately becoming devoid of DNA. Cells with abnormal nuclei showed unusual crawling behavior highlighted by erratic pseudopods and hyperpolarization consistent with the nucleus being a fulcrum for crawling. A requirement for both Toll-like receptor 2 and complement-mediated opsonization tightly regulated NET release. Additionally, live human PMNs injected into mouse skin developed decondensed nuclei and formed NETS in vivo, and intact anuclear neutrophils were abundant in Gram-positive human abscesses. Therefore early in infection NETosis involves neutrophils that do not undergo lysis and retain the ability to multitask.", + "TAG_DATA": [ + "49, in {'context': 'B-in vivo'}", + "50, vivo {'context': 'I-in vivo'}", + "70, PMNs {'context': 'B-cells'}", + "80, Cells {'context': 'B-cells'}", + "118, live {'context': 'B-cells'}", + "119, human {'context': 'I-cells'}", + "120, PMNs {'context': 'I-cells'}", + "123, mouse {'context': 'B-tissue/organ'}", + "124, skin {'context': 'I-tissue/organ'}", + "131, in {'context': 'B-in vivo'}", + "132, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "49, in ['l0', 'l1']", + "50, vivo ['l0', 'l2']", + "70, PMNs ['l1', 'l2']", + "118, live ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "119, human ['l3', 'l9', 'l10', 'l11', 'l12', 'l13']", + "120, PMNs ['l4', 'l9', 'l14', 'l15', 'l16', 'l17']", + "123, mouse ['l5', 'l10', 'l14', 'l18', 'l19', 'l20']", + "124, skin ['l6', 'l11', 'l15', 'l18', 'l21', 'l22']", + "131, in ['l7', 'l12', 'l16', 'l19', 'l21', 'l23']", + "132, vivo, ['l8', 'l13', 'l17', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22902875", + "TEXT": "We developed a new, silicon-based peptide array for a broad range of biological applications, including potential development as a real-time point-of-care platform. We used photolithography on silicon wafers to synthesize microarrays (Intel arrays) that contained every possible overlapping peptide within a linear protein sequence covering the N-terminal tail of human histone H2B. These arrays also included peptides with acetylated and methylated lysine residues, reflecting post-translational modifications of H2B. We defined minimum binding epitopes for commercial antibodies recognizing the modified and unmodified H2B peptides. We further found that this platform is suitable for the highly sensitive characterization of methyltransferases and kinase substrates. The Intel arrays also revealed specific H2B epitopes that are recognized by autoantibodies in individuals with systemic lupus erythematosus who have elevated disease severity. By combining emerging nonfluorescence-based detection methods with an underlying integrated circuit, we are now poised to create a truly transformative proteomics platform with applications in bioscience, drug development and clinical diagnostics.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22869182", + "TEXT": "There is currently much interest in dissecting the mechanisms of tumor immunity. A new study shows that a subset of CD4+ T cells that produce the cytokine interleukin-9 (IL-9) mediate inhibition of melanoma growth in mice and that analogous IL-9-producing T cells are present in human skin (pages 1248–1253). Could such cells be manipulated to develop new therapeutic strategies for melanoma?", + "TAG_DATA": [ + "30, inhibition {'effect': 'B-negative'}", + "32, melanoma {'context': 'B-neoplasm'}", + "33, growth {'phenotype': 'I-tumour growth'}", + "35, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "30, inhibition ['l0', 'l1', 'l2']", + "32, melanoma ['l0', 'l3', 'l4']", + "33, growth ['l1', 'l3', 'l5']", + "35, mice ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "melanoma" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "melanoma" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "22842477", + "TEXT": "Toll-like receptor 4 (TLR4) has a key role in innate immunity by activating an inflammatory signaling pathway. Free fatty acids (FFAs) stimulate adipose tissue inflammation through the TLR4 pathway, resulting in insulin resistance. However, current evidence suggests that FFAs do not directly bind to TLR4, but an endogenous ligand for TLR4 remains to be identified. Here we show that fetuin-A (FetA) could be this endogenous ligand and that it has a crucial role in regulating insulin sensitivity via Tlr4 signaling in mice. FetA (officially known as Ahsg) knockdown in mice with insulin resistance caused by a high-fat diet (HFD) resulted in downregulation of Tlr4-mediated inflammatory signaling in adipose tissue, whereas selective administration of FetA induced inflammatory signaling and insulin resistance. FFA-induced proinflammatory cytokine expression in adipocytes occurred only in the presence of both FetA and Tlr4; removing either of them prevented FFA-induced insulin resistance. We further found that FetA, through its terminal galactoside moiety, directly binds the residues of Leu100-Gly123 and Thr493-Thr516 in Tlr4. FFAs did not produce insulin resistance in adipocytes with mutated Tlr4 or galactoside-cleaved FetA. Taken together, our results suggest that FetA fulfills the requirement of an endogenous ligand for TLR4 through which lipids induce insulin resistance. This may position FetA as a new therapeutic target for managing insulin resistance and type 2 diabetes.", + "TAG_DATA": [ + "82, FetA {'perturbing_action': 'B-rnai/knockdown'}", + "83, (officially {'perturbing_action': 'I-rnai/knockdown'}", + "84, known {'perturbing_action': 'I-rnai/knockdown'}", + "85, as {'perturbing_action': 'I-rnai/knockdown'}", + "86, Ahsg) {'perturbing_action': 'I-rnai/knockdown'}", + "87, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "89, mice {'context': 'B-organism'}", + "107, adipose {'context': 'B-tissue/organ'}", + "108, tissue, {'context': 'I-tissue/organ'}", + "125, adipocytes {'context': 'B-cells'}", + "171, adipocytes {'context': 'B-cells'}", + "173, mutated {'perturbing_action': 'B-other'}", + "174, Tlr4 {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "82, FetA ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "83, (officially ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "84, known ['l1', 'l8', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "85, as ['l2', 'l9', 'l16', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "86, Ahsg) ['l3', 'l10', 'l17', 'l23', 'l29', 'l30', 'l31', 'l32']", + "87, knockdown ['l4', 'l11', 'l18', 'l24', 'l29', 'l33', 'l34', 'l35']", + "89, mice ['l5', 'l12', 'l19', 'l25', 'l30', 'l33', 'l36', 'l37']", + "107, adipose ['l6', 'l13', 'l20', 'l26', 'l31', 'l34', 'l36', 'l38']", + "108, tissue, ['l7', 'l14', 'l21', 'l27', 'l32', 'l35', 'l37', 'l38']", + "125, adipocytes ['l15', 'l22', 'l28']", + "171, adipocytes ['l39', 'l40']", + "173, mutated ['l39', 'l41']", + "174, Tlr4 ['l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "FetA", + "(officially", + "known", + "as", + "Ahsg)", + "knockdown" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "FetA", + "(officially", + "known", + "as", + "Ahsg)", + "knockdown" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "adipose", + "tissue," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "(officially", + "known", + "as" + ] + }, + "context": { + "val": "cells", + "words": [ + "adipocytes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "adipocytes" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "Tlr4" + ] + } + } + ] + }, + { + "PMID": "22772463", + "TEXT": "Exposure to ultraviolet B (UVB) radiation from the sun can result in sunburn, premature aging and carcinogenesis, but the mechanism responsible for acute inflammation of the skin is not well understood. Here we show that RNA is released from keratinocytes after UVB exposure and that this stimulates production of the inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) from nonirradiated keratinocytes and peripheral blood mononuclear cells (PBMCs). Whole-transcriptome sequencing revealed that UVB irradiation of keratinocytes induced alterations in the double-stranded domains of some noncoding RNAs. We found that this UVB-damaged RNA was sufficient to induce cytokine production from nonirradiated cells, as UVB irradiation of a purified noncoding RNA (U1 RNA) reproduced the same response as the one we observed to UVB-damaged keratinocytes. The responses to both UVB-damaged self-RNAs and UVB-damaged keratinocytes were dependent on Toll-like receptor 3 (TLR3) and Toll-like receptor adaptor molecule 1 (TRIF). In response to UVB exposure, Tlr3(-/-) mice did not upregulate TNF-α in the skin. Moreover, TLR3 was also necessary for UVB-radiation-induced immune suppression. These findings establish that UVB damage is detected by TLR3 and that self-RNA is a damage-associated molecular pattern that serves as an endogenous signal of solar injury.", + "TAG_DATA": [ + "76, keratinocytes {'context': 'B-cells'}", + "101, cells, {'context': 'I-cells'}", + "123, keratinocytes. {'context': 'B-cells'}", + "132, keratinocytes {'context': 'B-cells'}", + "152, Tlr3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "153, mice {'context': 'B-organism'}", + "160, skin. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "76, keratinocytes ['l0']", + "101, cells, ['l0']", + "123, keratinocytes. ['l1']", + "132, keratinocytes ['l1', 'l2']", + "152, Tlr3(-/-) ['l3', 'l4']", + "153, mice ['l3', 'l5']", + "160, skin. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tlr3(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tlr3(-/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skin." + ] + } + } + ] + }, + { + "PMID": "22729285", + "TEXT": "Host remodeling is important for the success of medical implants, including vascular substitutes. Synthetic and tissue-engineered grafts have yet to show clinical effectiveness in arteries smaller than 5 mm in diameter. We designed cell-free biodegradable elastomeric grafts that degrade rapidly to yield neoarteries nearly free of foreign materials 3 months after interposition grafting in rat abdominal aorta. This design focuses on enabling rapid host remodeling. Three months after implantation, the neoarteries resembled native arteries in the following aspects: regular, strong and synchronous pulsation; a confluent endothelium and contractile smooth muscle layers; expression of elastin, collagen and glycosaminoglycan; and tough and compliant mechanical properties. Therefore, future studies employing large animal models more representative of human vascular regeneration are warranted before clinical translation. This cell-free approach represents a philosophical shift from the prevailing focus on cells in vascular tissue engineering and may have an impact on regenerative medicine in general.", + "TAG_DATA": [ + "54, rat {'context': 'B-tissue/organ'}", + "55, abdominal {'context': 'I-tissue/organ'}", + "56, aorta. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "54, rat ['l0', 'l1']", + "55, abdominal ['l0', 'l2']", + "56, aorta. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22706386", + "TEXT": "Duplication of PLP1 (proteolipid protein gene 1) and the subsequent overexpression of the myelin protein PLP (also known as DM20) in oligodendrocytes is the most frequent cause of Pelizaeus-Merzbacher disease (PMD), a fatal leukodystrophy without therapeutic options. PLP binds cholesterol and is contained within membrane lipid raft microdomains. Cholesterol availability is the rate-limiting factor of central nervous system myelin synthesis. Transgenic mice with extra copies of the Plp1 gene are accurate models of PMD. Dysmyelination followed by demyelination, secondary inflammation and axon damage contribute to the severe motor impairment in these mice. The finding that in Plp1-transgenic oligodendrocytes, PLP and cholesterol accumulate in late endosomes and lysosomes (endo/lysosomes), prompted us to further investigate the role of cholesterol in PMD. Here we show that cholesterol itself promotes normal PLP trafficking and that dietary cholesterol influences PMD pathology. In a preclinical trial, PMD mice were fed a cholesterol-enriched diet. This restored oligodendrocyte numbers and ameliorated intracellular PLP accumulation. Moreover, myelin content increased, inflammation and gliosis were reduced and motor defects improved. Even after onset of clinical symptoms, cholesterol treatment prevented disease progression. Dietary cholesterol did not reduce Plp1 overexpression but facilitated incorporation of PLP into myelin membranes. These findings may have implications for therapeutic interventions in patients with PMD.", + "TAG_DATA": [ + "96, Plp1-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "97, oligodendrocytes, {'context': 'B-cells'}", + "140, PMD {'context': 'B-organism'}", + "141, mice {'context': 'I-organism'}", + "149, oligodendrocyte {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "96, Plp1-transgenic ['l0', 'l1']", + "97, oligodendrocytes, ['l0']", + "140, PMD ['l2', 'l3']", + "141, mice ['l2', 'l4']", + "149, oligodendrocyte ['l1', 'l3', 'l4']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Plp1-transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "oligodendrocytes,", + "oligodendrocyte" + ] + } + } + ] + }, + { + "PMID": "22673995", + "TEXT": "Bariatric surgery to treat obesity can also be effective against type 2 diabetes, but it is unclear how such surgical procedures improve glucose metabolism. A new study in rats suggests that nutrient sensing in the jejunum contributes to the antidiabetic effects of duodenal-jejeunal bypass (pages 950–955).", + "TAG_DATA": [ + "28, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22673989", + "TEXT": "In the run-up to his reelection, Russian president Vladimir Putin outlined 28 tasks to be undertaken by his administration, including one that commanded the development of weapons based on “genetic principles.” Political pressure must be applied by governments and professional societies to ensure that there is not a modern reincarnation of the Soviet biological warfare program.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22581286", + "TEXT": "Despite the clear major contribution of hyperlipidemia to the prevalence of cardiovascular disease in the developed world, the direct effects of lipoproteins on endothelial cells have remained obscure and are under debate. Here we report a previously uncharacterized mechanism of vessel growth modulation by lipoprotein availability. Using a genetic screen for vascular defects in zebrafish, we initially identified a mutation, stalactite (stl), in the gene encoding microsomal triglyceride transfer protein (mtp), which is involved in the biosynthesis of apolipoprotein B (ApoB)-containing lipoproteins. By manipulating lipoprotein concentrations in zebrafish, we found that ApoB negatively regulates angiogenesis and that it is the ApoB protein particle, rather than lipid moieties within ApoB-containing lipoproteins, that is primarily responsible for this effect. Mechanistically, we identified downregulation of vascular endothelial growth factor receptor 1 (VEGFR1), which acts as a decoy receptor for VEGF, as a key mediator of the endothelial response to lipoproteins, and we observed VEGFR1 downregulation in hyperlipidemic mice. These findings may open new avenues for the treatment of lipoprotein-related vascular disorders.", + "TAG_DATA": [ + "54, zebrafish, {'context': 'B-organism'}", + "87, zebrafish, {'context': 'B-organism'}", + "154, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "54, zebrafish, ['l0']", + "87, zebrafish, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22581285", + "TEXT": "This study establishes a mechanism for metabolic hyperalgesia based on the glycolytic metabolite methylglyoxal. We found that concentrations of plasma methylglyoxal above 600 nM discriminate between diabetes-affected individuals with pain and those without pain. Methylglyoxal depolarizes sensory neurons and induces post-translational modifications of the voltage-gated sodium channel Na(v)1.8, which are associated with increased electrical excitability and facilitated firing of nociceptive neurons, whereas it promotes the slow inactivation of Na(v)1.7. In mice, treatment with methylglyoxal reduces nerve conduction velocity, facilitates neurosecretion of calcitonin gene-related peptide, increases cyclooxygenase-2 (COX-2) expression and evokes thermal and mechanical hyperalgesia. This hyperalgesia is reflected by increased blood flow in brain regions that are involved in pain processing. We also found similar changes in streptozotocin-induced and genetic mouse models of diabetes but not in Na(v)1.8 knockout (Scn10(-/-)) mice. Several strategies that include a methylglyoxal scavenger are effective in reducing methylglyoxal- and diabetes-induced hyperalgesia. This previously undescribed concept of metabolically driven hyperalgesia provides a new basis for the design of therapeutic interventions for painful diabetic neuropathy.", + "TAG_DATA": [ + "70, mice, {'context': 'B-organism'}", + "120, mouse {'context': 'B-organism'}", + "121, models {'context': 'I-organism'}", + "127, Na(v)1.8 {'perturbing_action': 'B-gene loss-of-function'}", + "128, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "129, (Scn10(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "130, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "120, mouse ['l0', 'l1', 'l2', 'l3']", + "121, models ['l0', 'l4', 'l5']", + "127, Na(v)1.8 ['l1', 'l4', 'l6', 'l7', 'l8']", + "128, knockout ['l2', 'l5', 'l6', 'l9', 'l10']", + "129, (Scn10(-/-)) ['l3', 'l7', 'l9', 'l11']", + "130, mice. ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Na(v)1.8", + "knockout", + "(Scn10(-/-))" + ] + } + } + ] + }, + { + "PMID": "22561824", + "TEXT": "Losing weight can pose a challenge, but how to avoid putting those pounds back on can be a real struggle. A major health problem for obese people is that diseases linked to obesity, such as type 2 diabetes and cardiovascular disease, put their lives at risk, even in young individuals. Although bariatric surgery-a surgical method to reduce or modify the gastrointestinal tract-was originally envisioned for the most severe cases of obesity, evidence suggests that the benefit of this procedure may not be limited to the staggering weight loss it causes. Endogenous factors released from the gut, and modified after surgery, may explain why bariatric surgery can be beneficial for obesity-related diseases and why operated individuals successfully maintain the weight loss. In 'Bedside to Bench,' Rachel Larder and Stephen O'Rahilly peruse a human study with dieters who regained weight despite a successful diet. Appetite-regulating hormones in the gut may be responsible for this relapse in the long term. In 'Bench to Bedside,' Keval Chandarana and Rachel Batterham examine how two different methods of bariatric surgery highlight the relevance of gut-derived hormones not only in inducing sustained weight loss but also in improving glucose homeostasis. These insights may open new avenues to bypass the surgery and obtain the same results with targeted drugs.", + "TAG_DATA": [ + "131, human {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22561823", + "TEXT": "Losing weight can pose a challenge, but how to avoid putting those pounds back on can be a real struggle. A major health problem for obese people is that diseases linked to obesity, such as type 2 diabetes and cardiovascular disease, put their lives at risk, even in young individuals. Although bariatric surgery-a surgical method to reduce or modify the gastrointestinal tract-was originally envisioned for the most severe cases of obesity, evidence suggests that the benefit of this procedure may not be limited to the staggering weight loss it causes. Endogenous factors released from the gut, and modified after surgery, may explain why bariatric surgery can be beneficial for obesity-related diseases and why operated individuals successfully maintain the weight loss. In 'Bedside to Bench,' Rachel Larder and Stephen O'Rahilly peruse a human study with dieters who regained weight despite a successful diet. Appetite-regulating hormones in the gut may be responsible for this relapse in the long term. In 'Bench to Bedside,' Keval Chandarana and Rachel Batterham examine how two different methods of bariatric surgery highlight the relevance of gut-derived hormones not only in inducing sustained weight loss but also in improving glucose homeostasis. These insights may open new avenues to bypass the surgery and obtain the same results with targeted drugs.", + "TAG_DATA": [ + "131, human {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22561818", + "TEXT": "Clinicians note that bariatric operations can dramatically resolve type 2 diabetes, often before and out of proportion to postoperative weight loss. Now two randomized controlled trials formally show superior results from surgical compared with medical diabetes care, including among only mildly obese patients. The concept of 'metabolic surgery' to treat diabetes has taken a big step forward.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22561687", + "TEXT": "T cell immunity can potentially eradicate malignant cells and lead to clinical remission in a minority of patients with cancer. In the majority of these individuals, however, there is a failure of the specific T cell receptor (TCR)–mediated immune recognition and activation process. Here we describe the engineering and characterization of new reagents termed immune-mobilizing monoclonal TCRs against cancer (ImmTACs). Four such ImmTACs, each comprising a distinct tumor-associated epitope-specific monoclonal TCR with picomolar affinity fused to a humanized cluster of differentiation 3 (CD3)-specific single-chain antibody fragment (scFv), effectively redirected T cells to kill cancer cells expressing extremely low surface epitope densities. Furthermore, these reagents potently suppressed tumor growth in vivo. Thus, ImmTACs overcome immune tolerance to cancer and represent a new approach to tumor immunotherapy.", + "TAG_DATA": [ + "89, T {'context': 'B-cells'}", + "90, cells {'context': 'B-cells'}", + "93, cancer {'context': 'B-transformed cells'}", + "94, cells {'context': 'I-transformed cells'}", + "105, suppressed {'effect': 'B-negative'}", + "106, tumor {'phenotype': 'B-tumour growth'}", + "107, growth {'phenotype': 'I-tumour growth'}", + "108, in {'context': 'B-in vivo'}", + "109, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "89, T ['l0', 'l1', 'l2']", + "90, cells ['l0', 'l3', 'l4']", + "93, cancer ['l1', 'l3', 'l5']", + "94, cells ['l2', 'l4', 'l5']", + "105, suppressed ['l6', 'l7', 'l8', 'l9']", + "106, tumor ['l6', 'l10', 'l11', 'l12']", + "107, growth ['l7', 'l10', 'l13', 'l14']", + "108, in ['l8', 'l11', 'l13', 'l15']", + "109, vivo. ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "22522562", + "TEXT": "The mammalian intestine harbors a complex microbial community that provides numerous benefits to its host. However, the microbiota can also include potentially virulent species, termed pathobiont, which can cause disease when intestinal homeostasis is disrupted. The molecular mechanisms by which pathobionts cause disease remain poorly understood. Here we describe a sepsis-like disease that occurs upon gut injury in antibiotic-treated mice. Sepsis was associated with the systemic spread of a specific multidrug-resistant Escherichia coli pathobiont that expanded markedly in the microbiota of antibiotic-treated mice. Rapid sepsis-like death required a component of the innate immune system, the Naip5-Nlrc4 inflammasome. In accordance with Koch's postulates, we found the E. coli pathobiont was sufficient to activate Naip5-Nlrc4 and cause disease when injected intravenously into unmanipulated mice. These findings reveal how sepsis-like disease can result from recognition of pathobionts by the innate immune system.", + "TAG_DATA": [ + "59, mice. {'context': 'B-organism'}", + "82, mice. {'context': 'B-organism'}", + "121, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22484809", + "TEXT": "Cytotoxic CD8(+) T cells recognize the antigenic peptides presented by class I major histocompatibility complex (MHC) molecules. These T cells have key roles in infectious diseases, autoimmunity and tumor immunology, but there is currently no unbiased method for the reliable identification of their target antigens. This is because of the low affinities of antigen-specific T cell receptors (TCR) to their target MHC-peptide complexes, the polyspecificity of these TCRs and the requirement that these TCRs recognize protein antigens that have been processed by antigen-presenting cells (APCs). Here we describe a technology for the unbiased identification of the antigenic peptides presented by MHC class I molecules. The technology uses plasmid-encoded combinatorial peptide libraries and a single-cell detection system. We validated this approach using a well-characterized influenza-virus–specific TCR, MHC and peptide combination. Single APCs carrying antigenic peptides can be detected among several million APCs that carry irrelevant peptides. The identified peptide sequences showed a converging pattern of mimotopes that revealed the parent influenza antigen. This technique should be generally applicable to the identification of disease-relevant T cell antigens.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22447075", + "TEXT": "Chronic pain is highly variable between individuals, as is the response to analgesics. Although much of the variability in chronic pain and analgesic response is heritable, an understanding of the genetic determinants underlying this variability is rudimentary. Here we show that variation within the coding sequence of the gene encoding the P2X7 receptor (P2X7R) affects chronic pain sensitivity in both mice and humans. P2X7Rs, which are members of the family of ionotropic ATP-gated receptors, have two distinct modes of function: they can function through their intrinsic cationic channel or by forming nonselective pores that are permeable to molecules with a mass of up to 900 Da. Using genome-wide linkage analyses, we discovered an association between nerve-injury-induced pain behavior (mechanical allodynia) and the P451L mutation of the mouse P2rx7 gene, such that mice in which P2X7Rs have impaired pore formation as a result of this mutation showed less allodynia than mice with the pore-forming P2rx7 allele. Administration of a peptide corresponding to the P2X7R C-terminal domain, which blocked pore formation but not cation channel activity, selectively reduced nerve injury and inflammatory allodynia only in mice with the pore-forming P2rx7 allele. Moreover, in two independent human chronic pain cohorts, a cohort with pain after mastectomy and a cohort with osteoarthritis, we observed a genetic association between lower pain intensity and the hypofunctional His270 (rs7958311) allele of P2RX7. Our findings suggest that selectively targeting P2X7R pore formation may be a new strategy for individualizing the treatment of chronic pain.", + "TAG_DATA": [ + "122, P451L {'perturbing_action': 'B-other'}", + "123, mutation {'perturbing_action': 'I-other'}", + "124, of {'perturbing_action': 'I-other'}", + "125, the {'perturbing_action': 'I-other'}", + "126, mouse {'perturbing_action': 'I-other'}", + "127, P2rx7 {'perturbing_action': 'I-other'}", + "128, gene, {'perturbing_action': 'I-other'}", + "131, mice {'context': 'B-organism'}", + "149, mice {'context': 'B-organism'}", + "183, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "122, P451L ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "123, mutation ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "124, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "125, the ['l2', 'l9', 'l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "126, mouse ['l3', 'l10', 'l16', 'l22', 'l28', 'l29', 'l30', 'l31']", + "127, P2rx7 ['l4', 'l11', 'l17', 'l23', 'l28', 'l32', 'l33', 'l34']", + "128, gene, ['l5', 'l12', 'l18', 'l24', 'l29', 'l32', 'l35']", + "131, mice ['l6', 'l13', 'l19', 'l25', 'l30', 'l33', 'l35', 'l36', 'l37', 'l38']", + "149, mice ['l7', 'l14', 'l20', 'l26', 'l31', 'l34', 'l36', 'l39', 'l40']", + "153, P2rx7 ['l37', 'l39', 'l41']", + "154, allele. ['l21', 'l27', 'l38', 'l40', 'l41']", + "183, mice ['l42', 'l43']", + "187, P2rx7 ['l42', 'l44']", + "188, allele. ['l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "P451L", + "mutation", + "of", + "the", + "mouse", + "P2rx7", + "gene," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "22388089", + "TEXT": "During chronic injury a population of bipotent hepatic progenitor cells (HPCs) become activated to regenerate both cholangiocytes and hepatocytes. Here we show in human diseased liver and mouse models of the ductular reaction that Notch and Wnt signaling direct specification of HPCs via their interactions with activated myofibroblasts or macrophages. In particular, we found that during biliary regeneration, expression of Jagged 1 (a Notch ligand) by myofibroblasts promoted Notch signaling in HPCs and thus their biliary specification to cholangiocytes. Alternatively, during hepatocyte regeneration, macrophage engulfment of hepatocyte debris induced Wnt3a expression. This resulted in canonical Wnt signaling in nearby HPCs, thus maintaining expression of Numb (a cell fate determinant) within these cells and the promotion of their specification to hepatocytes. By these two pathways adult parenchymal regeneration during chronic liver injury is promoted.", + "TAG_DATA": [ + "66, myofibroblasts {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22366950", + "TEXT": "CD4-unhelped CD8(+) T cells are functionally defective T cells primed in the absence of CD4(+) T cell help. Given the co-stimulatory role of natural-killer group 2, member D protein (NKG2D) on CD8(+) T cells, we investigated its ability to rescue these immunologically impotent cells. We demonstrate that augmented co-stimulation through NKG2D during priming paradoxically rescues memory, but not effector, CD8(+) T cell responses. NKG2D-mediated rescue is characterized by reversal of elevated transcription factor T-box expressed in T cells (T-bet) expression and recovery of interleukin-2 and interferon-γ production and cytolytic responses. Rescue is abrogated in CD8(+) T cells lacking NKG2D. Augmented co-stimulation through NKG2D confers a high rate of survival to mice lacking CD4(+) T cells in a CD4-dependent influenza model and rescues HIV-specific CD8(+) T cell responses from CD4-deficient HIV-positive donors. These findings demonstrate that augmented co-stimulation through NKG2D is effective in rescuing CD4-unhelped CD8(+) T cells from their pathophysiological fate and may provide therapeutic benefits.", + "TAG_DATA": [ + "58, effector, {'context': 'B-cells'}", + "59, CD8(+) {'context': 'B-cells'}", + "60, T {'context': 'I-cells'}", + "61, cell {'context': 'I-cells'}", + "94, CD8(+) {'context': 'B-cells'}", + "95, T {'context': 'I-cells'}", + "96, cells {'context': 'I-cells'}", + "97, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "98, NKG2D. {'perturbing_action': 'I-gene loss-of-function'}", + "110, mice {'context': 'B-organism'}", + "112, CD4(+) {'context': 'B-cells'}", + "113, T {'context': 'I-cells'}", + "114, cells {'context': 'I-cells'}", + "123, CD8(+) {'context': 'B-cells'}", + "124, T {'context': 'I-cells'}", + "125, cell {'context': 'I-cells'}", + "128, CD4-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "129, HIV-positive {'context': 'B-organism'}", + "130, donors. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "58, effector, ['l0', 'l1', 'l2']", + "59, CD8(+) ['l0', 'l3', 'l4']", + "60, T ['l1', 'l3', 'l5']", + "61, cell ['l2', 'l4', 'l5']", + "94, CD8(+) ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "95, T ['l6', 'l14', 'l15', 'l16', 'l17', 'l18']", + "96, cells ['l7', 'l14', 'l19', 'l20', 'l21', 'l22']", + "97, lacking ['l8', 'l15', 'l19', 'l23', 'l24', 'l25', 'l26', 'l27']", + "98, NKG2D. ['l9', 'l16', 'l20', 'l23', 'l28', 'l29', 'l30', 'l31']", + "110, mice ['l10', 'l24', 'l28', 'l32', 'l33', 'l34', 'l35', 'l36']", + "112, CD4(+) ['l11', 'l25', 'l29', 'l32', 'l37', 'l38', 'l39', 'l40']", + "113, T ['l12', 'l17', 'l21', 'l26', 'l30', 'l33', 'l37', 'l41']", + "114, cells ['l13', 'l18', 'l22', 'l27', 'l31', 'l34', 'l38', 'l41']", + "123, CD8(+) ['l42', 'l43', 'l44', 'l45', 'l46']", + "124, T ['l35', 'l39', 'l42', 'l47', 'l48', 'l49', 'l50']", + "125, cell ['l36', 'l40', 'l43', 'l47', 'l51', 'l52', 'l53']", + "128, CD4-deficient ['l44', 'l48', 'l51', 'l54', 'l55']", + "129, HIV-positive ['l45', 'l49', 'l52', 'l54', 'l56']", + "130, donors. ['l46', 'l50', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "T", + "cells", + "CD4(+)", + "cell" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "NKG2D.", + "CD4-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "NKG2D.", + "CD4-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "HIV-positive", + "donors." + ] + } + } + ] + }, + { + "PMID": "22344298", + "TEXT": "In advanced cancer, including glioblastoma, the transforming growth factor β (TGF-β) pathway acts as an oncogenic factor and is considered to be a therapeutic target. Using a functional RNAi screen, we identified the deubiquitinating enzyme ubiquitin-specific peptidase 15 (USP15) as a key component of the TGF-β signaling pathway. USP15 binds to the SMAD7-SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) complex and deubiquitinates and stabilizes type I TGF-β receptor (TβR-I), leading to an enhanced TGF-β signal. High expression of USP15 correlates with high TGF-β activity, and the USP15 gene is found amplified in glioblastoma, breast and ovarian cancer. USP15 amplification confers poor prognosis in individuals with glioblastoma. Downregulation or inhibition of USP15 in a patient-derived orthotopic mouse model of glioblastoma decreases TGF-β activity. Moreover, depletion of USP15 decreases the oncogenic capacity of patient-derived glioma-initiating cells due to the repression of TGF-β signaling. Our results show that USP15 regulates the TGF-β pathway and is a key factor in glioblastoma pathogenesis.", + "TAG_DATA": [ + "109, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "110, of {'perturbing_action': 'I-pharmacological inhibition'}", + "111, USP15 {'perturbing_action': 'I-pharmacological inhibition'}", + "114, patient-derived {'context': 'B-organism'}", + "115, orthotopic {'context': 'I-neoplasm'}", + "116, mouse {'context': 'I-neoplasm'}", + "117, model {'context': 'I-neoplasm'}", + "118, of {'context': 'I-neoplasm'}", + "119, glioblastoma {'context': 'I-neoplasm'}", + "124, depletion {'perturbing_action': 'B-gene loss-of-function'}", + "125, of {'perturbing_action': 'I-gene loss-of-function'}", + "126, USP15 {'perturbing_action': 'I-gene loss-of-function'}", + "127, decreases {'effect': 'B-negative'}", + "129, oncogenic {'phenotype': 'B-tumourigenesis'}", + "130, capacity {'phenotype': 'I-tumour initiation'}", + "132, patient-derived {'context': 'B-cells'}", + "133, glioma-initiating {'context': 'I-cells'}", + "134, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "109, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "110, of ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "111, USP15 ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "114, patient-derived ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "115, orthotopic ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "116, mouse ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "117, model ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "118, of ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "119, glioblastoma ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "124, depletion ['l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "125, of ['l36', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "126, USP15 ['l37', 'l44', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "127, decreases ['l38', 'l45', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "129, oncogenic ['l39', 'l46', 'l52', 'l57', 'l62', 'l63', 'l64', 'l65']", + "130, capacity ['l40', 'l47', 'l53', 'l58', 'l62', 'l66', 'l67', 'l68']", + "132, patient-derived ['l41', 'l48', 'l54', 'l59', 'l63', 'l66', 'l69', 'l70']", + "133, glioma-initiating ['l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l71']", + "134, cells ['l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l71']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "USP15" + ] + }, + "context": { + "val": "organism", + "words": [ + "patient-derived" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "USP15" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "orthotopic", + "mouse", + "model", + "of", + "glioblastoma" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "USP15" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreases" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "USP15" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "oncogenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "USP15" + ] + }, + "phenotype": { + "val": "tumour initiation", + "words": [ + "capacity" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "USP15" + ] + }, + "context": { + "val": "cells", + "words": [ + "patient-derived", + "glioma-initiating", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreases" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "oncogenic" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreases" + ] + }, + "phenotype": { + "val": "tumour initiation", + "words": [ + "capacity" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreases" + ] + }, + "context": { + "val": "cells", + "words": [ + "patient-derived", + "glioma-initiating", + "cells" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "oncogenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "patient-derived", + "glioma-initiating", + "cells" + ] + } + }, + { + "phenotype": { + "val": "tumour initiation", + "words": [ + "capacity" + ] + }, + "context": { + "val": "cells", + "words": [ + "patient-derived", + "glioma-initiating", + "cells" + ] + } + } + ] + }, + { + "PMID": "22344295", + "TEXT": "Considerable data support the idea that forkhead box O1 (Foxo1) drives the liver transcriptional program during fasting and is then inhibited by thymoma viral proto-oncogene 1 (Akt) after feeding. Here we show that mice with hepatic deletion of Akt1 and Akt2 were glucose intolerant, insulin resistant and defective in their transcriptional response to feeding in the liver. These defects were normalized with concomitant liver-specific deletion of Foxo1. Notably, in the absence of both Akt and Foxo1, mice adapted appropriately to both the fasted and fed state, and insulin suppressed hepatic glucose production normally. A gene expression analysis revealed that deletion of Akt in liver led to the constitutive activation of Foxo1-dependent gene expression, but again, concomitant ablation of Foxo1 restored postprandial regulation, preventing the inhibition of the metabolic response to nutrient intake caused by deletion of Akt. These results are inconsistent with the canonical model of hepatic metabolism in which Akt is an obligate intermediate for proper insulin signaling. Rather, they show that a major role of hepatic Akt is to restrain the activity of Foxo1 and that in the absence of Foxo1, Akt is largely dispensable for insulin- and nutrient-mediated hepatic metabolic regulation in vivo.", + "TAG_DATA": [ + "33, mice {'context': 'B-organism'}", + "35, hepatic {'perturbing_action': 'B-gene loss-of-function'}", + "36, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "37, of {'perturbing_action': 'I-gene loss-of-function'}", + "38, Akt1 {'perturbing_action': 'I-gene loss-of-function'}", + "39, and {'perturbing_action': 'I-gene loss-of-function'}", + "40, Akt2 {'perturbing_action': 'I-gene loss-of-function'}", + "56, liver. {'context': 'B-tissue/organ'}", + "62, concomitant {'perturbing_action': 'B-gene loss-of-function'}", + "63, liver-specific {'perturbing_action': 'B-gene loss-of-function'}", + "64, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "65, of {'perturbing_action': 'I-gene loss-of-function'}", + "66, Foxo1. {'perturbing_action': 'I-gene loss-of-function'}", + "70, absence {'perturbing_action': 'B-gene loss-of-function'}", + "71, of {'perturbing_action': 'I-gene loss-of-function'}", + "72, both {'perturbing_action': 'I-gene loss-of-function'}", + "73, Akt {'perturbing_action': 'I-gene loss-of-function'}", + "74, and {'perturbing_action': 'I-gene loss-of-function'}", + "75, Foxo1, {'perturbing_action': 'I-gene loss-of-function'}", + "76, mice {'context': 'B-organism'}", + "99, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "100, of {'perturbing_action': 'I-gene loss-of-function'}", + "101, Akt {'perturbing_action': 'I-gene loss-of-function'}", + "103, liver {'context': 'B-tissue/organ'}", + "116, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "117, of {'perturbing_action': 'I-gene loss-of-function'}", + "118, Foxo1 {'perturbing_action': 'I-gene loss-of-function'}", + "134, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "135, of {'perturbing_action': 'I-gene loss-of-function'}", + "136, Akt. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "33, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "35, hepatic ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "36, deletion ['l1', 'l7', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "37, of ['l2', 'l8', 'l18', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "38, Akt1 ['l3', 'l9', 'l19', 'l32', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "39, and ['l4', 'l10', 'l20', 'l33', 'l47', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "40, Akt2 ['l5', 'l11', 'l21', 'l34', 'l48', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67']", + "56, liver. ['l6', 'l12', 'l22', 'l35', 'l49', 'l56', 'l63']", + "62, concomitant ['l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "63, liver-specific ['l13', 'l23', 'l36', 'l50', 'l57', 'l64', 'l68', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "64, deletion ['l14', 'l24', 'l37', 'l51', 'l58', 'l69', 'l83', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "65, of ['l15', 'l25', 'l38', 'l52', 'l59', 'l65', 'l70', 'l84', 'l96', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "66, Foxo1. ['l16', 'l26', 'l39', 'l53', 'l60', 'l66', 'l71', 'l85', 'l97', 'l109', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "70, absence ['l27', 'l40', 'l72', 'l86', 'l98', 'l110', 'l120', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139']", + "71, of ['l41', 'l73', 'l87', 'l99', 'l111', 'l121', 'l130', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "72, both ['l42', 'l74', 'l88', 'l100', 'l112', 'l122', 'l131', 'l140', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156']", + "73, Akt ['l28', 'l43', 'l75', 'l89', 'l101', 'l113', 'l123', 'l132', 'l141', 'l149', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163']", + "74, and ['l29', 'l44', 'l76', 'l90', 'l102', 'l114', 'l124', 'l133', 'l142', 'l150', 'l157', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "75, Foxo1, ['l30', 'l45', 'l61', 'l77', 'l91', 'l103', 'l115', 'l125', 'l134', 'l143', 'l151', 'l158', 'l164', 'l170', 'l171', 'l172', 'l173', 'l174']", + "76, mice ['l17', 'l31', 'l46', 'l54', 'l62', 'l67', 'l78', 'l92', 'l104', 'l116', 'l126', 'l135', 'l144', 'l152', 'l159', 'l165', 'l170']", + "99, deletion ['l79', 'l105', 'l136', 'l145', 'l153', 'l160', 'l166', 'l171', 'l175', 'l176', 'l177']", + "100, of ['l80', 'l93', 'l106', 'l117', 'l127', 'l137', 'l146', 'l154', 'l161', 'l167', 'l172', 'l175', 'l178', 'l179']", + "101, Akt ['l81', 'l94', 'l107', 'l118', 'l128', 'l138', 'l147', 'l155', 'l162', 'l168', 'l173', 'l176', 'l178', 'l180']", + "103, liver ['l82', 'l95', 'l108', 'l119', 'l129', 'l139', 'l148', 'l156', 'l163', 'l169', 'l174', 'l177', 'l179', 'l180']", + "116, ablation ['l181', 'l182', 'l183', 'l184', 'l185']", + "117, of ['l181', 'l186', 'l187', 'l188', 'l189']", + "118, Foxo1 ['l182', 'l186', 'l190', 'l191', 'l192']", + "134, deletion ['l183', 'l187', 'l190', 'l193', 'l194']", + "135, of ['l184', 'l188', 'l191', 'l193', 'l195']", + "136, Akt. ['l185', 'l189', 'l192', 'l194', 'l195']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "hepatic", + "deletion", + "of", + "Akt1", + "and", + "Akt2", + "concomitant", + "liver-specific", + "Foxo1.", + "absence", + "both", + "Akt", + "Foxo1," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "hepatic", + "deletion", + "of", + "Akt1", + "and", + "Akt2", + "concomitant", + "liver-specific", + "Foxo1.", + "absence", + "both", + "Akt", + "Foxo1," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver.", + "liver" + ] + } + } + ] + }, + { + "PMID": "22286307", + "TEXT": "Protective immunity against influenza virus infection is mediated by neutralizing antibodies, but the precise role of T cells in human influenza immunity is uncertain. We conducted influenza infection studies in healthy volunteers with no detectable antibodies to the challenge viruses H3N2 or H1N1. We mapped T cell responses to influenza before and during infection. We found a large increase in influenza-specific T cell responses by day 7, when virus was completely cleared from nasal samples and serum antibodies were still undetectable. Preexisting CD4+, but not CD8+, T cells responding to influenza internal proteins were associated with lower virus shedding and less severe illness. These CD4+ cells also responded to pandemic H1N1 (A/CA/07/2009) peptides and showed evidence of cytotoxic activity. These cells are an important statistical correlate of homotypic and heterotypic response and may limit severity of influenza infection by new strains in the absence of specific antibody responses. Our results provide information that may aid the design of future vaccines against emerging influenza strains.", + "TAG_DATA": [ + "31, volunteers {'context': 'I-organism'}", + "61, T {'context': 'B-cells'}", + "62, cell {'context': 'B-cells'}", + "87, cells {'context': 'I-cells'}", + "104, CD4+ {'context': 'B-cells'}", + "105, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "31, volunteers ['l0', 'l1']", + "61, T ['l0', 'l2']", + "62, cell ['l1', 'l2']", + "104, CD4+ ['l3']", + "105, cells ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22245781", + "TEXT": "Barrett's esophagus is an example of a pre-invasive state, for which current endoscopic surveillance methods to detect dysplasia are time consuming and inadequate. The prognosis of cancer arising in Barrett's esophagus is improved by early detection at the stage of mucosal carcinoma or high-grade dysplasia. Molecular imaging methods could revolutionize the detection of dysplasia, provided they permit a wide field of view and highlight abnormalities in real time. We show here that cell-surface glycans are altered in the progression from Barrett's esophagus to adenocarcinoma and lead to specific changes in lectin binding patterns. We chose wheat germ agglutinin as a candidate lectin with clinical potential. The binding of wheat germ agglutinin to human tissue was determined to be specific, and we validated this specific binding by successful endoscopic visualization of high-grade dysplastic lesions, which were not detectable by conventional endoscopy, with a high signal-to-background ratio of over 5.", + "TAG_DATA": [ + "112, human {'context': 'B-tissue/organ'}", + "113, tissue {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "112, human ['l0']", + "113, tissue ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22245779", + "TEXT": "Helminths induce potent T helper 2 (TH2)-type immune responses that can mediate worm expulsion, but the role of this response in controlling the acute tissue damage caused by migrating multicellular parasites through vital tissues remains uncertain. We used a helminth infection model in which parasitic nematode larvae migrate transiently through the lung, resulting in hemorrhage and inflammation. We found that IL-17 initially contributed to inflammation and lung damage, whereas subsequent IL-4 receptor (IL-4R) signaling reduced elevations in IL-17 mRNA levels, enhanced the expression of insulin-like growth factor 1 (IGF-1) and IL-10 and stimulated the development of M2 macrophages, all of which contributed to the rapid resolution of tissue damage. These studies indicate an essential role for TH2-type immune responses in mediating acute wound healing during helminth infection.", + "TAG_DATA": [ + "66, lung {'context': 'B-tissue/organ'}", + "96, M2 {'context': 'B-cells'}", + "97, macrophages, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "96, M2 ['l0']", + "97, macrophages, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22231558", + "TEXT": "In addition to allelic mutations, cancers are known to harbor alterations in their chromatin landscape. Here we show that genomic ablation of Smad ubiquitin regulatory factor 2 (Smurf2), a HECT-domain E3 ubiquitin ligase, results in dysregulation of both the DNA damage response and genomic stability, culminating in increased susceptibility to various types of cancers in aged mice. We show that Smurf2 regulates the monoubiquitination of histone H2B as well as the trimethylation of histone H3 at Lys4 and Lys79 by targeting ring finger protein 20 (RNF20) for proteasomal degradation in both mouse and human cells. We also show that Smurf2 and RNF20 are colocalized at the γ-H2AX foci of double-stranded DNA breaks in the nucleus. Thus, Smurf2 has a tumor suppression function that normally maintains genomic stability by controlling the epigenetic landscape of histone modifications through RNF20.", + "TAG_DATA": [ + "19, genomic {'perturbing_action': 'B-gene loss-of-function'}", + "20, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "21, of {'perturbing_action': 'I-gene loss-of-function'}", + "22, Smad {'perturbing_action': 'I-gene loss-of-function'}", + "23, ubiquitin {'perturbing_action': 'I-gene loss-of-function'}", + "24, regulatory {'perturbing_action': 'I-gene loss-of-function'}", + "25, factor {'perturbing_action': 'I-gene loss-of-function'}", + "26, 2 {'perturbing_action': 'I-gene loss-of-function'}", + "27, (Smurf2), {'perturbing_action': 'I-gene loss-of-function'}", + "53, cancers {'context': 'B-neoplasm'}", + "55, aged {'context': 'B-organism'}", + "56, mice. {'context': 'I-organism'}", + "91, mouse {'context': 'B-cells'}", + "92, and {'context': 'I-cells'}", + "93, human {'context': 'I-cells'}", + "94, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "19, genomic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "20, ablation ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "21, of ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "22, Smad ['l2', 'l16', 'l29', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "23, ubiquitin ['l3', 'l17', 'l30', 'l42', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "24, regulatory ['l4', 'l18', 'l31', 'l43', 'l54', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "25, factor ['l5', 'l19', 'l32', 'l44', 'l55', 'l65', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "26, 2 ['l6', 'l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "27, (Smurf2), ['l7', 'l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l84', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "53, cancers ['l8', 'l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l99', 'l100']", + "55, aged ['l9', 'l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l86', 'l93', 'l99', 'l101']", + "56, mice. ['l10', 'l24', 'l37', 'l49', 'l60', 'l70', 'l79', 'l87', 'l94', 'l100', 'l101']", + "91, mouse ['l11', 'l25', 'l38', 'l50', 'l61', 'l71', 'l80', 'l88', 'l95', 'l102', 'l103', 'l104']", + "92, and ['l12', 'l26', 'l39', 'l51', 'l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l105', 'l106']", + "93, human ['l13', 'l27', 'l40', 'l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l105', 'l107']", + "94, cells. ['l14', 'l28', 'l41', 'l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l106', 'l107']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genomic", + "ablation", + "of", + "Smad", + "ubiquitin", + "regulatory", + "factor", + "2", + "(Smurf2)," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "cancers" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genomic", + "ablation", + "of", + "Smad", + "ubiquitin", + "regulatory", + "factor", + "2", + "(Smurf2)," + ] + }, + "context": { + "val": "organism", + "words": [ + "aged", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genomic", + "ablation", + "of", + "Smad", + "ubiquitin", + "regulatory", + "factor", + "2", + "(Smurf2)," + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "and", + "human", + "cells." + ] + } + } + ] + }, + { + "PMID": "22231557", + "TEXT": "Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. With ∼170 million individuals infected and current interferon-based treatment having toxic side effects and marginal efficacy, more effective antivirals are crucially needed. Although HCV protease inhibitors were just approved by the US Food and Drug Administration (FDA), optimal HCV therapy, analogous to HIV therapy, will probably require a combination of antivirals targeting multiple aspects of the viral lifecycle. Viral entry represents a potential multifaceted target for antiviral intervention; however, to date, FDA-approved inhibitors of HCV cell entry are unavailable. Here we show that the cellular Niemann-Pick C1-like 1 (NPC1L1) cholesterol uptake receptor is an HCV entry factor amendable to therapeutic intervention. Specifically, NPC1L1 expression is necessary for HCV infection, as silencing or antibody-mediated blocking of NPC1L1 impairs cell culture-derived HCV (HCVcc) infection initiation. In addition, the clinically available FDA-approved NPC1L1 antagonist ezetimibe potently blocks HCV uptake in vitro via a virion cholesterol-dependent step before virion-cell membrane fusion. Moreover, ezetimibe inhibits infection by all major HCV genotypes in vitro and in vivo delays the establishment of HCV genotype 1b infection in mice with human liver grafts. Thus, we have not only identified NPC1L1 as an HCV cell entry factor but also discovered a new antiviral target and potential therapeutic agent.", + "TAG_DATA": [ + "124, antibody-mediated {'perturbing_action': 'B-pharmacological inhibition'}", + "125, blocking {'perturbing_action': 'I-pharmacological inhibition'}", + "126, of {'perturbing_action': 'I-pharmacological inhibition'}", + "127, NPC1L1 {'perturbing_action': 'I-pharmacological inhibition'}", + "129, cell {'context': 'B-cells'}", + "130, culture-derived {'context': 'I-cells'}", + "141, NPC1L1 {'perturbing_action': 'I-pharmacological inhibition'}", + "142, antagonist {'perturbing_action': 'I-pharmacological inhibition'}", + "148, in {'context': 'B-in vitro'}", + "149, vitro {'context': 'I-in vitro'}", + "168, in {'context': 'B-in vitro'}", + "169, vitro {'context': 'I-in vitro'}", + "171, in {'context': 'B-in vivo'}", + "172, vivo {'context': 'I-in vivo'}", + "182, mice {'context': 'B-organism'}", + "184, human {'context': 'B-xenograft'}", + "185, liver {'context': 'I-xenograft'}", + "186, grafts. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "124, antibody-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "125, blocking ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "126, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "127, NPC1L1 ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "129, cell ['l3', 'l11', 'l18', 'l24', 'l30']", + "130, culture-derived ['l4', 'l12', 'l19', 'l25', 'l30']", + "141, NPC1L1 ['l5', 'l13', 'l20', 'l26', 'l31', 'l32', 'l33', 'l34', 'l35']", + "142, antagonist ['l6', 'l14', 'l21', 'l27', 'l31', 'l36', 'l37', 'l38', 'l39']", + "148, in ['l7', 'l15', 'l22', 'l28', 'l32', 'l36', 'l40', 'l41']", + "149, vitro ['l8', 'l16', 'l23', 'l29', 'l33', 'l37', 'l40', 'l42']", + "168, in ['l34', 'l38', 'l41', 'l42', 'l43']", + "169, vitro ['l35', 'l39', 'l43']", + "171, in ['l44', 'l45', 'l46', 'l47', 'l48']", + "172, vivo ['l44', 'l49', 'l50', 'l51', 'l52']", + "182, mice ['l45', 'l49', 'l53', 'l54', 'l55']", + "184, human ['l46', 'l50', 'l53', 'l56', 'l57']", + "185, liver ['l47', 'l51', 'l54', 'l56', 'l58']", + "186, grafts. ['l48', 'l52', 'l55', 'l57', 'l58']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antibody-mediated", + "blocking", + "of", + "NPC1L1" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "culture-derived" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antibody-mediated", + "blocking", + "of", + "NPC1L1", + "antagonist" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "22231556", + "TEXT": "Mice with a knock-in mutation (Y524S) in the type I ryanodine receptor (Ryr1), a mutation analogous to the Y522S mutation that is associated with malignant hyperthermia in humans, die when exposed to short periods of temperature elevation (≥37 °C). We show here that treatment with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) prevents this heat-induced sudden death in this mouse model. The protection by AICAR is independent of AMP-activated protein kinase (AMPK) activation and results from a newly identified action of the compound on mutant Ryr1 to reduce Ca(2+) leak from the sarcoplasmic reticulum to the sarcoplasm. AICAR thus prevents Ca(2+)-dependent increases in the amount of both reactive oxygen species (ROS) and reactive nitrogen species (RNS) that act to further increase resting Ca(2+) concentrations. If unchecked, the temperature-driven increases in resting Ca(2+) concentrations and the amounts of ROS and RNS create an amplifying cycle that ultimately triggers sustained muscle contractions, rhabdomyolysis and death. Although antioxidants are effective in reducing this cycle in vitro, only AICAR prevents heat-induced death in vivo. Our findings suggest that AICAR is probably effective in prophylactic treatment of humans with enhanced susceptibility to exercise- and/or heat-induced sudden death associated with RYR1 mutations.", + "TAG_DATA": [ + "55, mouse {'context': 'B-organism'}", + "56, model. {'context': 'I-organism'}", + "157, in {'context': 'B-in vitro'}", + "158, vitro, {'context': 'I-in vitro'}", + "164, in {'context': 'B-in vivo'}", + "165, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "55, mouse ['l0']", + "56, model. ['l0']", + "157, in ['l1']", + "158, vitro, ['l1']", + "164, in ['l2']", + "165, vivo. ['l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22198278", + "TEXT": "Endogenous tissue inhibitors of metalloproteinases (TIMPs) have key roles in regulating physiological and pathological cellular processes. Imitating the inhibitory molecular mechanisms of TIMPs while increasing selectivity has been a challenging but desired approach for antibody-based therapy. TIMPs use hybrid protein-protein interactions to form an energetic bond with the catalytic metal ion, as well as with enzyme surface residues. We used an innovative immunization strategy that exploits aspects of molecular mimicry to produce inhibitory antibodies that show TIMP-like binding mechanisms toward the activated forms of gelatinases (matrix metalloproteinases 2 and 9). Specifically, we immunized mice with a synthetic molecule that mimics the conserved structure of the metalloenzyme catalytic zinc-histidine complex residing within the enzyme active site. This immunization procedure yielded selective function-blocking monoclonal antibodies directed against the catalytic zinc-protein complex and enzyme surface conformational epitopes of endogenous gelatinases. The therapeutic potential of these antibodies has been demonstrated with relevant mouse models of inflammatory bowel disease. Here we propose a general experimental strategy for generating inhibitory antibodies that effectively target the in vivo activity of dysregulated metalloproteinases by mimicking the mechanism employed by TIMPs.", + "TAG_DATA": [ + "93, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22198277", + "TEXT": "Studying regeneration in the central nervous system (CNS) is hampered by current histological and imaging techniques because they provide only partial information about axonal and glial reactions. Here we developed a tetrahydrofuran-based clearing procedure that renders fixed and unsectioned adult CNS tissue transparent and fully penetrable for optical imaging. In large spinal cord segments, we imaged fluorescently labeled cells by 'ultramicroscopy' and two-photon microscopy without the need for histological sectioning. We found that more than a year after injury growth-competent axons regenerated abundantly through the injury site. A few growth-incompetent axons could also regenerate when they bypassed the lesion. Moreover, we accurately determined quantitative changes of glial cells after spinal cord injury. Thus, clearing CNS tissue enables an unambiguous evaluation of axon regeneration and glial reactions. Our clearing procedure also renders other organs transparent, which makes this approach useful for a large number of preclinical paradigms.", + "TAG_DATA": [ + "51, spinal {'context': 'B-tissue/organ'}", + "52, cord {'context': 'I-tissue/organ'}", + "53, segments, {'context': 'I-tissue/organ'}", + "80, axons {'context': 'B-cells'}", + "90, axons {'context': 'I-cells'}", + "106, glial {'context': 'B-cells'}", + "107, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "51, spinal ['l0', 'l1']", + "52, cord ['l0', 'l2']", + "53, segments, ['l1', 'l2']", + "106, glial ['l3']", + "107, cells ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22179317", + "TEXT": "Sepsis, sepsis-induced hyperinflammation and subsequent sepsis-associated immunosuppression (SAIS) are important causes of death. Here we show in humans that the loss of the major reactive oxygen species (ROS) scavenger, glutathione (GSH), during SAIS directly correlates with an increase in the expression of activating transcription factor 3 (ATF3). In endotoxin-stimulated monocytes, ROS stress strongly superinduced NF-E2-related factor 2 (NRF2)-dependent ATF3. In vivo, this ROS-mediated superinduction of ATF3 protected against endotoxic shock by inhibiting innate cytokines, as Atf3(-/-) mice remained susceptible to endotoxic shock even under conditions of ROS stress. Although it protected against endotoxic shock, this ROS-mediated superinduction of ATF3 caused high susceptibility to bacterial and fungal infections through the suppression of interleukin 6 (IL-6). As a result, Atf3(-/-) mice were protected against bacterial and fungal infections, even under conditions of ROS stress, whereas Atf3(-/-)Il6(-/-) mice were highly susceptible to these infections. Moreover, in a model of SAIS, secondary infections caused considerably less mortality in Atf3(-/-) mice than in wild-type mice, indicating that ROS-induced ATF3 crucially determines susceptibility to secondary infections during SAIS.", + "TAG_DATA": [ + "49, monocytes, {'context': 'B-cells'}", + "59, In {'context': 'B-in vivo'}", + "60, vivo, {'context': 'I-in vivo'}", + "75, Atf3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "76, mice {'context': 'B-organism'}", + "117, Atf3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "118, mice {'context': 'B-organism'}", + "133, Atf3(-/-)Il6(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "134, mice {'context': 'B-organism'}", + "154, Atf3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "155, mice {'context': 'B-organism'}", + "159, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "49, monocytes, ['l0', 'l1']", + "59, In ['l0', 'l2']", + "60, vivo, ['l1', 'l2']", + "75, Atf3(-/-) ['l3']", + "76, mice ['l3']", + "117, Atf3(-/-) ['l4']", + "118, mice ['l4']", + "133, Atf3(-/-)Il6(-/-) ['l5']", + "134, mice ['l5']", + "154, Atf3(-/-) ['l6', 'l7']", + "155, mice ['l6', 'l8']", + "159, mice, ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atf3(-/-)", + "Atf3(-/-)Il6(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + } + ] + }, + { + "PMID": "22157680", + "TEXT": "Congenital disorder of glycosylation-Ia (CDG-Ia, also known as PMM2-CDG) is caused by mutations in the gene that encodes phosphomannomutase 2 (PMM2, EC 5.4.2.8) leading to a multisystemic disease with severe psychomotor and mental retardation. In a hypomorphic Pmm2 mouse model, we were able to overcome embryonic lethality by feeding mannose to pregnant dams. The results underline the essential role of glycosylation in embryonic development and may open new treatment options for this disease.", + "TAG_DATA": [ + "36, hypomorphic {'perturbing_action': 'B-other'}", + "37, Pmm2 {'perturbing_action': 'I-other'}", + "38, mouse {'context': 'I-organism'}", + "39, model, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "36, hypomorphic ['l0', 'l1', 'l2']", + "37, Pmm2 ['l0', 'l3', 'l4']", + "38, mouse ['l1', 'l3', 'l5']", + "39, model, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "hypomorphic", + "Pmm2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model," + ] + } + } + ] + }, + { + "PMID": "22138751", + "TEXT": "Mechanisms of epithelial cell renewal remain poorly understood in the mammalian kidney, particularly in the glomerulus, a site of cellular damage in chronic kidney disease. Within the glomerulus, podocytes--differentiated epithelial cells crucial for filtration--are thought to lack substantial capacity for regeneration. Here we show that podocytes rapidly lose differentiation markers and enter the cell cycle in adult mice in which the telomerase protein component TERT is conditionally expressed. Transgenic TERT expression in mice induces marked upregulation of Wnt signaling and disrupts glomerular structure, resulting in a collapsing glomerulopathy resembling those in human disease, including HIV-associated nephropathy (HIVAN). Human and mouse HIVAN kidneys show increased expression of TERT and activation of Wnt signaling, indicating that these are general features of collapsing glomerulopathies. Silencing transgenic TERT expression or inhibiting Wnt signaling through systemic expression of the Wnt inhibitor Dkk1 in either TERT transgenic mice or in a mouse model of HIVAN results in marked normalization of podocytes, including rapid cell-cycle exit, re-expression of differentiation markers and improved filtration barrier function. These data reveal an unexpected capacity of podocytes to reversibly enter the cell cycle, suggest that podocyte renewal may contribute to glomerular homeostasis and implicate the telomerase and Wnt-β-catenin pathways in podocyte proliferation and disease.", + "TAG_DATA": [ + "56, adult {'context': 'B-organism'}", + "57, mice {'context': 'I-organism'}", + "68, Transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "69, TERT {'perturbing_action': 'I-gene gain-of-function'}", + "70, expression {'perturbing_action': 'I-gene gain-of-function'}", + "72, mice {'context': 'B-organism'}", + "121, Silencing {'perturbing_action': 'B-rnai/knockdown'}", + "122, transgenic {'perturbing_action': 'I-rnai/knockdown'}", + "123, TERT {'perturbing_action': 'I-rnai/knockdown'}", + "124, expression {'perturbing_action': 'I-rnai/knockdown'}", + "139, TERT {'perturbing_action': 'B-gene gain-of-function'}", + "140, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "141, mice {'context': 'B-organism'}", + "145, mouse {'context': 'B-organism'}", + "146, model {'context': 'I-organism'}", + "154, podocytes, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "56, adult ['l0', 'l1', 'l2', 'l3', 'l4']", + "57, mice ['l0', 'l5', 'l6', 'l7', 'l8']", + "68, Transgenic ['l1', 'l5', 'l9', 'l10', 'l11', 'l12']", + "69, TERT ['l2', 'l6', 'l9', 'l13', 'l14', 'l15']", + "70, expression ['l3', 'l7', 'l10', 'l13', 'l16', 'l17']", + "72, mice ['l4', 'l8', 'l11', 'l14', 'l16']", + "101, kidneys ['l12', 'l15', 'l17']", + "121, Silencing ['l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "122, transgenic ['l18', 'l26', 'l27', 'l28', 'l29', 'l30']", + "123, TERT ['l19', 'l26', 'l31', 'l32', 'l33', 'l34']", + "124, expression ['l20', 'l27', 'l31']", + "139, TERT ['l21', 'l35', 'l36', 'l37', 'l38', 'l39']", + "140, transgenic ['l22', 'l28', 'l32', 'l35', 'l40', 'l41', 'l42', 'l43']", + "141, mice ['l23', 'l29', 'l33', 'l36', 'l40', 'l44', 'l45', 'l46']", + "145, mouse ['l37', 'l41', 'l44', 'l47', 'l48']", + "146, model ['l24', 'l38', 'l42', 'l45', 'l47', 'l49']", + "154, podocytes, ['l25', 'l30', 'l34', 'l39', 'l43', 'l46', 'l48', 'l49']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "adult", + "mice", + "mouse", + "model" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgenic", + "TERT", + "expression", + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "transgenic", + "TERT" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "transgenic", + "TERT" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocytes," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "TERT", + "transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocytes," + ] + } + } + ] + }, + { + "PMID": "22101765", + "TEXT": "Although there is evidence that redox regulation has an essential role in malignancies, its impact on tumor prognosis remains unclear. Here we show crosstalk between oxidative stress and the miR-200 family of microRNAs that affects tumorigenesis and chemosensitivity. miR-141 and miR-200a target p38α and modulate the oxidative stress response. Enhanced expression of these microRNAs mimics p38α deficiency and increases tumor growth in mouse models, but it also improves the response to chemotherapeutic agents. High-grade human ovarian adenocarcinomas that accumulate miR-200a have low concentrations of p38α and an associated oxidative stress signature. The miR200a-dependent stress signature correlates with improved survival of patients in response to treatment. Therefore, the role of miR-200a in stress could be a predictive marker for clinical outcome in ovarian cancer. In addition, although oxidative stress promotes tumor growth, it also sensitizes tumors to treatment, which could account for the limited success of antioxidants in clinical trials.", + "TAG_DATA": [ + "49, Enhanced {'perturbing_action': 'B-gene gain-of-function'}", + "50, expression {'perturbing_action': 'I-gene gain-of-function'}", + "51, of {'perturbing_action': 'I-gene gain-of-function'}", + "52, these {'perturbing_action': 'I-gene gain-of-function'}", + "53, microRNAs {'perturbing_action': 'I-gene gain-of-function'}", + "58, increases {'effect': 'B-positive'}", + "59, tumor {'phenotype': 'B-tumour growth'}", + "60, growth {'phenotype': 'I-tumour growth'}", + "62, mouse {'context': 'B-organism'}", + "63, models, {'context': 'I-organism'}", + "74, human {'context': 'I-neoplasm'}", + "75, ovarian {'context': 'I-neoplasm'}", + "76, adenocarcinomas {'context': 'I-neoplasm'}", + "128, promotes {'effect': 'B-positive'}", + "129, tumor {'phenotype': 'B-tumour growth'}", + "130, growth, {'phenotype': 'I-tumour growth'}", + "134, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "49, Enhanced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "50, expression ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "51, of ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "52, these ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "53, microRNAs ['l3', 'l14', 'l24', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "58, increases ['l4', 'l15', 'l25', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47']", + "59, tumor ['l5', 'l16', 'l26', 'l35', 'l40', 'l44', 'l48', 'l49', 'l50']", + "60, growth ['l6', 'l17', 'l27', 'l36', 'l41', 'l45', 'l48', 'l51', 'l52']", + "62, mouse ['l7', 'l18', 'l28', 'l37', 'l42', 'l46', 'l49', 'l51', 'l53']", + "63, models, ['l8', 'l19', 'l29', 'l38', 'l43', 'l47', 'l50', 'l52', 'l53']", + "74, human ['l9', 'l20', 'l30', 'l54', 'l55']", + "75, ovarian ['l10', 'l21', 'l31', 'l54', 'l56']", + "76, adenocarcinomas ['l11', 'l22', 'l32', 'l55', 'l56']", + "128, promotes ['l57', 'l58', 'l59']", + "129, tumor ['l57', 'l60', 'l61']", + "130, growth, ['l58', 'l60', 'l62']", + "134, tumors ['l59', 'l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enhanced", + "expression", + "of", + "these", + "microRNAs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increases" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enhanced", + "expression", + "of", + "these", + "microRNAs" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enhanced", + "expression", + "of", + "these", + "microRNAs" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enhanced", + "expression", + "of" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "ovarian", + "adenocarcinomas" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases", + "promotes" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth", + "growth," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models," + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + } + ] + }, + { + "PMID": "22081024", + "TEXT": "RAF kinases regulate cell proliferation and survival and can be dysregulated in tumors. The role of RAF in cell proliferation has been linked to its ability to activate mitogen-activated protein kinase kinase 1 (MEK) and mitogen-activated protein kinase 1 (ERK). Here we identify a MEK-independent role for RAF in tumor growth. Specifically, in mitotic cells, CRAF becomes phosphorylated on Ser338 and localizes to the mitotic spindle of proliferating tumor cells in vitro as well as in murine tumor models and in biopsies from individuals with cancer. Treatment of tumors with allosteric inhibitors, but not ATP-competitive RAF inhibitors, prevents CRAF phosphorylation on Ser338 and localization to the mitotic spindle and causes cell-cycle arrest at prometaphase. Furthermore, we identify phospho-Ser338 CRAF as a potential biomarker for tumor progression and a surrogate marker for allosteric RAF blockade. Mechanistically, CRAF, but not BRAF, associates with Aurora kinase A (Aurora-A) and Polo-like kinase 1 (Plk1) at the centrosomes and spindle poles during G2/M. Indeed, allosteric or genetic inhibition of phospho-Ser338 CRAF impairs Plk1 activation and accumulation at the kinetochores, causing prometaphase arrest, whereas a phospho-mimetic Ser338D CRAF mutant potentiates Plk1 activation, mitosis and tumor progression in mice. These findings show a previously undefined role for RAF in tumor progression beyond the RAF-MEK-ERK paradigm, opening new avenues for targeting RAF in cancer.", + "TAG_DATA": [ + "88, tumors {'context': 'B-neoplasm'}", + "109, causes {'effect': 'B-positive'}", + "110, cell-cycle {'phenotype': 'B-cell cycle arrest'}", + "111, arrest {'phenotype': 'I-cell cycle arrest'}", + "161, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "162, inhibition {'perturbing_action': 'I-gene loss-of-function'}", + "163, of {'perturbing_action': 'I-gene loss-of-function'}", + "164, phospho-Ser338 {'perturbing_action': 'I-gene loss-of-function'}", + "165, CRAF {'perturbing_action': 'I-gene loss-of-function'}", + "174, causing {'effect': 'B-positive'}", + "175, prometaphase {'phenotype': 'B-cell cycle arrest'}", + "176, arrest, {'phenotype': 'I-cell cycle arrest'}", + "179, phospho-mimetic {'perturbing_action': 'B-other'}", + "180, Ser338D {'perturbing_action': 'I-other'}", + "181, CRAF {'perturbing_action': 'I-other'}", + "182, mutant {'perturbing_action': 'I-other'}", + "188, tumor {'phenotype': 'B-tumour progression'}", + "189, progression {'phenotype': 'I-tumour progression'}", + "191, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "88, tumors ['l0', 'l1', 'l2']", + "109, causes ['l0', 'l3', 'l4']", + "110, cell-cycle ['l1', 'l3', 'l5']", + "111, arrest ['l2', 'l4', 'l5']", + "161, genetic ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "162, inhibition ['l6', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "163, of ['l7', 'l14', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "164, phospho-Ser338 ['l8', 'l15', 'l23', 'l31', 'l32', 'l33', 'l34', 'l35']", + "165, CRAF ['l9', 'l16', 'l24', 'l31', 'l36', 'l37', 'l38']", + "174, causing ['l10', 'l17', 'l25', 'l32', 'l36', 'l39', 'l40']", + "175, prometaphase ['l11', 'l18', 'l26', 'l33', 'l37', 'l39', 'l41']", + "176, arrest, ['l12', 'l19', 'l27', 'l34', 'l38', 'l40', 'l41']", + "179, phospho-mimetic ['l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "180, Ser338D ['l42', 'l48', 'l49', 'l50', 'l51', 'l52']", + "181, CRAF ['l43', 'l48', 'l53', 'l54', 'l55', 'l56']", + "182, mutant ['l44', 'l49', 'l53', 'l57', 'l58', 'l59']", + "188, tumor ['l20', 'l28', 'l45', 'l50', 'l54', 'l57', 'l60', 'l61']", + "189, progression ['l13', 'l21', 'l29', 'l35', 'l46', 'l51', 'l55', 'l58', 'l60', 'l62']", + "191, mice. ['l22', 'l30', 'l47', 'l52', 'l56', 'l59', 'l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "causes" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes", + "causing" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest", + "prometaphase", + "arrest," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inhibition", + "of", + "phospho-Ser338", + "CRAF" + ] + }, + "effect": { + "val": "positive", + "words": [ + "causing" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inhibition", + "of", + "phospho-Ser338", + "CRAF" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "prometaphase", + "arrest," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inhibition", + "of", + "phospho-Ser338" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "progression", + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inhibition", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "phospho-mimetic", + "Ser338D", + "CRAF", + "mutant" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "phospho-mimetic", + "Ser338D", + "CRAF", + "mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "22037646", + "TEXT": "Intra-abdominal tumors, such as ovarian cancer, have a clear predilection for metastasis to the omentum, an organ primarily composed of adipocytes. Currently, it is unclear why tumor cells preferentially home to and proliferate in the omentum, yet omental metastases typically represent the largest tumor in the abdominal cavities of women with ovarian cancer. We show here that primary human omental adipocytes promote homing, migration and invasion of ovarian cancer cells, and that adipokines including interleukin-8 (IL-8) mediate these activities. Adipocyte-ovarian cancer cell coculture led to the direct transfer of lipids from adipocytes to ovarian cancer cells and promoted in vitro and in vivo tumor growth. Furthermore, coculture induced lipolysis in adipocytes and β-oxidation in cancer cells, suggesting adipocytes act as an energy source for the cancer cells. A protein array identified upregulation of fatty acid-binding protein 4 (FABP4, also known as aP2) in omental metastases as compared to primary ovarian tumors, and FABP4 expression was detected in ovarian cancer cells at the adipocyte-tumor cell interface. FABP4 deficiency substantially impaired metastatic tumor growth in mice, indicating that FABP4 has a key role in ovarian cancer metastasis. These data indicate adipocytes provide fatty acids for rapid tumor growth, identifying lipid metabolism and transport as new targets for the treatment of cancers where adipocytes are a major component of the microenvironment.", + "TAG_DATA": [ + "65, invasion {'phenotype': 'B-invasion'}", + "67, ovarian {'context': 'B-transformed cells'}", + "68, cancer {'context': 'I-transformed cells'}", + "69, cells, {'context': 'I-transformed cells'}", + "80, cancer {'context': 'I-transformed cells'}", + "93, ovarian {'context': 'B-transformed cells'}", + "94, cancer {'context': 'I-transformed cells'}", + "95, cells {'context': 'I-transformed cells'}", + "97, promoted {'effect': 'B-positive'}", + "98, in {'context': 'B-in vitro'}", + "99, vitro {'context': 'I-in vitro'}", + "101, in {'context': 'B-in vivo'}", + "102, vivo {'context': 'I-in vivo'}", + "103, tumor {'phenotype': 'B-tumour growth'}", + "104, growth. {'phenotype': 'I-tumour growth'}", + "114, cancer {'context': 'B-transformed cells'}", + "115, cells, {'context': 'I-transformed cells'}", + "165, FABP4 {'perturbing_action': 'B-gene loss-of-function'}", + "166, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "168, impaired {'effect': 'B-negative'}", + "169, metastatic {'phenotype': 'B-metastasis'}", + "170, tumor {'phenotype': 'I-tumour growth'}", + "171, growth {'phenotype': 'I-tumour growth'}", + "173, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "65, invasion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "67, ovarian ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "68, cancer ['l1', 'l9', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "69, cells, ['l2', 'l10', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "80, cancer ['l3', 'l11', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "93, ovarian ['l4', 'l12', 'l20', 'l26', 'l31', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "94, cancer ['l5', 'l13', 'l21', 'l27', 'l32', 'l41', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "95, cells ['l6', 'l14', 'l22', 'l28', 'l33', 'l42', 'l49', 'l55', 'l56', 'l57', 'l58']", + "97, promoted ['l7', 'l15', 'l23', 'l29', 'l34', 'l43', 'l50', 'l55', 'l59', 'l60', 'l61', 'l62']", + "98, in ['l35', 'l44', 'l51', 'l59', 'l63', 'l64', 'l65', 'l66']", + "99, vitro ['l36', 'l45', 'l52', 'l56', 'l60', 'l63', 'l67', 'l68', 'l69']", + "101, in ['l37', 'l70', 'l71', 'l72']", + "102, vivo ['l38', 'l46', 'l64', 'l67', 'l70', 'l73', 'l74']", + "103, tumor ['l16', 'l39', 'l47', 'l53', 'l57', 'l61', 'l65', 'l68', 'l71', 'l73', 'l75']", + "104, growth. ['l8', 'l17', 'l24', 'l30', 'l40', 'l48', 'l54', 'l58', 'l62', 'l66', 'l69', 'l72', 'l74', 'l75']", + "114, cancer ['l76']", + "115, cells, ['l76']", + "165, FABP4 ['l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "166, deficiency ['l77', 'l83', 'l84', 'l85', 'l86', 'l87']", + "168, impaired ['l78', 'l83', 'l88', 'l89', 'l90', 'l91']", + "169, metastatic ['l79', 'l84', 'l88', 'l92', 'l93', 'l94']", + "170, tumor ['l80', 'l85', 'l89', 'l92', 'l95', 'l96']", + "171, growth ['l81', 'l86', 'l90', 'l93', 'l95', 'l97']", + "173, mice, ['l82', 'l87', 'l91', 'l94', 'l96', 'l97']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "cancer", + "cells,", + "cells" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "cancer", + "cells,", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "cancer", + "cells,", + "cells" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FABP4", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FABP4", + "deficiency" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FABP4", + "deficiency" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FABP4", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "22019888", + "TEXT": "Most of the currently available drugs for osteoporosis inhibit osteoclastic bone resorption; only a few drugs promote osteoblastic bone formation. It is thus becoming increasingly necessary to identify the factors that regulate bone formation. We found that osteoclasts express semaphorin 4D (Sema4D), previously shown to be an axon guidance molecule, which potently inhibits bone formation. The binding of Sema4D to its receptor Plexin-B1 on osteoblasts resulted in the activation of the small GTPase RhoA, which inhibits bone formation by suppressing insulin-like growth factor-1 (IGF-1) signaling and by modulating osteoblast motility. Sema4d-/- mice, Plxnb1-/- mice and mice expressing a dominant-negative RhoA specifically in osteoblasts showed an osteosclerotic phenotype due to augmented bone formation. Notably, Sema4D-specific antibody treatment markedly prevented bone loss in a model of postmenopausal osteoporosis. Thus, Sema4D has emerged as a new therapeutic target for the discovery and development of bone-increasing drugs.", + "TAG_DATA": [ + "64, osteoblasts {'context': 'B-cells'}", + "88, osteoblast {'context': 'B-cells'}", + "90, Sema4d-/- {'perturbing_action': 'B-gene loss-of-function'}", + "91, mice, {'context': 'B-organism'}", + "92, Plxnb1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "93, mice {'context': 'B-organism'}", + "95, mice {'context': 'B-organism'}", + "97, a {'perturbing_action': 'I-other'}", + "98, dominant-negative {'perturbing_action': 'I-other'}", + "99, RhoA {'perturbing_action': 'I-other'}", + "102, osteoblasts {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "64, osteoblasts ['l0', 'l1']", + "88, osteoblast ['l0', 'l2']", + "90, Sema4d-/- ['l1', 'l2', 'l3', 'l4', 'l5']", + "91, mice, ['l3']", + "92, Plxnb1-/- ['l4', 'l6', 'l7']", + "93, mice ['l5', 'l6']", + "95, mice ['l8', 'l9', 'l10', 'l11']", + "97, a ['l8', 'l12', 'l13', 'l14']", + "98, dominant-negative ['l9', 'l12', 'l15', 'l16']", + "99, RhoA ['l10', 'l13', 'l15', 'l17']", + "102, osteoblasts ['l7', 'l11', 'l14', 'l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "osteoblasts", + "osteoblast" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sema4d-/-", + "Plxnb1-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sema4d-/-", + "Plxnb1-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "a", + "dominant-negative", + "RhoA" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "a", + "dominant-negative", + "RhoA" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoblasts" + ] + } + } + ] + }, + { + "PMID": "22019886", + "TEXT": "Anemia because of insufficient production of and/or response to erythropoietin (Epo) is a major complication of chronic kidney disease and cancer. The mechanisms modulating the sensitivity of erythroblasts to Epo remain poorly understood. We show that, when cultured with Epo at suboptimal concentrations, the growth and clonogenic potential of erythroblasts was rescued by transferrin receptor 1 (TfR1)-bound polymeric IgA1 (pIgA1). Under homeostatic conditions, erythroblast numbers were increased in mice expressing human IgA1 compared to control mice. Hypoxic stress of these mice led to increased amounts of pIgA1 and erythroblast expansion. Expression of human IgA1 or treatment of wild-type mice with the TfR1 ligands pIgA1 or iron-loaded transferrin (Fe-Tf) accelerated recovery from acute anemia. TfR1 engagement by either pIgA1 or Fe-Tf increased cell sensitivity to Epo by inducing activation of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways. These cellular responses were mediated through the TfR1-internalization motif, YXXΦ. Our results show that pIgA1 and TfR1 are positive regulators of erythropoiesis in both physiological and pathological situations. Targeting this pathway may provide alternate approaches to the treatment of ineffective erythropoiesis and anemia.", + "TAG_DATA": [ + "46, clonogenic {'phenotype': 'B-colony formation'}", + "47, potential {'phenotype': 'I-colony formation'}", + "49, erythroblasts {'context': 'B-cells'}", + "51, rescued {'effect': 'B-rescues'}", + "63, erythroblast {'context': 'B-cells'}", + "68, mice {'context': 'B-organism'}", + "69, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "70, human {'perturbing_action': 'I-gene gain-of-function'}", + "71, IgA1 {'perturbing_action': 'I-gene gain-of-function'}", + "80, mice {'context': 'B-organism'}", + "88, erythroblast {'context': 'B-cells'}", + "90, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "91, of {'perturbing_action': 'I-gene gain-of-function'}", + "92, human {'perturbing_action': 'I-gene gain-of-function'}", + "93, IgA1 {'perturbing_action': 'I-gene gain-of-function'}", + "98, mice {'context': 'B-organism'}", + "121, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "46, clonogenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "47, potential ['l0', 'l7', 'l8', 'l9', 'l10']", + "49, erythroblasts ['l1', 'l7', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "51, rescued ['l2', 'l8', 'l11', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "63, erythroblast ['l3', 'l9', 'l12', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "68, mice ['l4', 'l10', 'l13', 'l18', 'l23', 'l28', 'l29', 'l30', 'l31', 'l32']", + "69, expressing ['l14', 'l19', 'l24', 'l28', 'l33', 'l34', 'l35', 'l36']", + "70, human ['l20', 'l25', 'l29', 'l33', 'l37', 'l38', 'l39']", + "71, IgA1 ['l5', 'l15', 'l21', 'l26', 'l30', 'l34', 'l37', 'l40', 'l41']", + "80, mice ['l6', 'l16', 'l22', 'l27', 'l31', 'l35', 'l38', 'l40', 'l42']", + "88, erythroblast ['l32', 'l36', 'l39', 'l41', 'l42']", + "90, Expression ['l43', 'l44', 'l45']", + "91, of ['l43', 'l46', 'l47']", + "92, human ['l44', 'l46', 'l48']", + "93, IgA1 ['l45', 'l47', 'l48']", + "98, mice ['l49']", + "121, cell ['l49']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenic", + "potential" + ] + }, + "context": { + "val": "cells", + "words": [ + "erythroblasts", + "erythroblast" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenic", + "potential" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenic", + "potential" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenic" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "IgA1" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "erythroblasts", + "erythroblast" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "erythroblasts", + "erythroblast" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "IgA1", + "human" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "human", + "IgA1" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "human", + "IgA1" + ] + } + } + ] + }, + { + "PMID": "22019885", + "TEXT": "Tissue factor, the initiator of the coagulation cascade, mediates coagulation factor VIIa-dependent activation of protease-activated receptor 2 (PAR2). Here we delineate a role for this signaling pathway in obesity and its complications. Mice lacking PAR2 (F2rl1) or the cytoplasmic domain of tissue factor were protected from weight gain and insulin resistance induced by a high-fat diet. In hematopoietic cells, genetic ablation of tissue factor-PAR2 signaling reduced adipose tissue macrophage inflammation, and specific pharmacological inhibition of macrophage tissue factor signaling rapidly ameliorated insulin resistance. In contrast, nonhematopoietic cell tissue factor-VIIa-PAR2 signaling specifically promoted obesity. Mechanistically, adipocyte tissue factor cytoplasmic domain-dependent VIIa signaling suppressed Akt phosphorylation with concordant adverse transcriptional changes of key regulators of obesity and metabolism. Pharmacological blockade of adipocyte tissue factor in vivo reversed these effects of tissue factor-VIIa signaling and rapidly increased energy expenditure. Thus, inhibition of tissue factor signaling is a potential therapeutic avenue for improving impaired metabolism and insulin resistance in obesity.", + "TAG_DATA": [ + "32, Mice {'context': 'B-organism'}", + "33, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "34, PAR2 {'perturbing_action': 'I-gene loss-of-function'}", + "35, (F2rl1) {'perturbing_action': 'I-gene loss-of-function'}", + "36, or {'perturbing_action': 'I-gene loss-of-function'}", + "37, the {'perturbing_action': 'I-gene loss-of-function'}", + "38, cytoplasmic {'perturbing_action': 'I-gene loss-of-function'}", + "39, domain {'perturbing_action': 'I-gene loss-of-function'}", + "40, of {'perturbing_action': 'I-gene loss-of-function'}", + "41, tissue {'perturbing_action': 'I-gene loss-of-function'}", + "42, factor {'perturbing_action': 'I-gene loss-of-function'}", + "57, hematopoietic {'context': 'B-cells'}", + "58, cells, {'context': 'I-cells'}", + "59, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "60, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "61, of {'perturbing_action': 'I-gene loss-of-function'}", + "62, tissue {'perturbing_action': 'I-gene loss-of-function'}", + "63, factor-PAR2 {'perturbing_action': 'I-gene loss-of-function'}", + "64, signaling {'perturbing_action': 'I-gene loss-of-function'}", + "66, adipose {'context': 'B-cells'}", + "67, tissue {'context': 'I-cells'}", + "68, macrophage {'context': 'I-cells'}", + "71, specific {'perturbing_action': 'B-pharmacological inhibition'}", + "72, pharmacological {'perturbing_action': 'I-pharmacological inhibition'}", + "73, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "74, of {'perturbing_action': 'I-pharmacological inhibition'}", + "75, macrophage {'perturbing_action': 'I-pharmacological inhibition'}", + "76, tissue {'perturbing_action': 'I-pharmacological inhibition'}", + "77, factor {'perturbing_action': 'I-pharmacological inhibition'}", + "78, signaling {'perturbing_action': 'I-pharmacological inhibition'}", + "85, nonhematopoietic {'context': 'B-cells'}", + "86, cell {'context': 'I-cells'}", + "116, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "117, blockade {'perturbing_action': 'I-pharmacological inhibition'}", + "118, of {'perturbing_action': 'I-pharmacological inhibition'}", + "119, adipocyte {'perturbing_action': 'I-pharmacological inhibition'}", + "120, tissue {'perturbing_action': 'I-pharmacological inhibition'}", + "121, factor {'perturbing_action': 'I-pharmacological inhibition'}", + "122, in {'context': 'B-in vivo'}", + "123, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "32, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "33, lacking ['l0', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "34, PAR2 ['l1', 'l23', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "35, (F2rl1) ['l2', 'l24', 'l51', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "36, or ['l3', 'l25', 'l52', 'l78', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "37, the ['l26', 'l53', 'l79', 'l104', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "38, cytoplasmic ['l27', 'l54', 'l80', 'l105', 'l129', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175']", + "39, domain ['l28', 'l55', 'l81', 'l106', 'l130', 'l153', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197']", + "40, of ['l4', 'l29', 'l56', 'l82', 'l107', 'l131', 'l154', 'l176', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218']", + "41, tissue ['l5', 'l30', 'l57', 'l83', 'l108', 'l132', 'l155', 'l177', 'l198', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238']", + "42, factor ['l6', 'l31', 'l58', 'l84', 'l109', 'l133', 'l156', 'l178', 'l199', 'l219', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256']", + "57, hematopoietic ['l7', 'l32', 'l59', 'l85', 'l110', 'l134', 'l157', 'l179', 'l200', 'l220', 'l239', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269']", + "58, cells, ['l8', 'l33', 'l60', 'l86', 'l111', 'l135', 'l158', 'l180', 'l201', 'l221', 'l240', 'l257', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278']", + "59, genetic ['l9', 'l34', 'l61', 'l87', 'l112', 'l136', 'l159', 'l181', 'l202', 'l222', 'l241', 'l258', 'l270', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290']", + "60, ablation ['l10', 'l35', 'l62', 'l88', 'l113', 'l137', 'l160', 'l182', 'l203', 'l223', 'l242', 'l259', 'l271', 'l279', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302', 'l303']", + "61, of ['l11', 'l36', 'l63', 'l89', 'l114', 'l138', 'l161', 'l183', 'l204', 'l224', 'l243', 'l260', 'l272', 'l280', 'l291', 'l304', 'l305', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315', 'l316']", + "62, tissue ['l12', 'l37', 'l64', 'l90', 'l115', 'l139', 'l162', 'l184', 'l205', 'l225', 'l244', 'l261', 'l273', 'l281', 'l292', 'l304', 'l317', 'l318', 'l319', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327', 'l328']", + "63, factor-PAR2 ['l13', 'l38', 'l65', 'l91', 'l116', 'l140', 'l163', 'l185', 'l206', 'l226', 'l245', 'l262', 'l274', 'l282', 'l293', 'l305', 'l317', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340']", + "64, signaling ['l14', 'l39', 'l66', 'l92', 'l117', 'l141', 'l164', 'l186', 'l207', 'l227', 'l246', 'l263', 'l275', 'l283', 'l294', 'l306', 'l318', 'l329', 'l341', 'l342', 'l343', 'l344', 'l345', 'l346']", + "66, adipose ['l15', 'l40', 'l67', 'l93', 'l118', 'l142', 'l165', 'l187', 'l208', 'l228', 'l247', 'l264', 'l276', 'l284', 'l295', 'l307', 'l319', 'l330', 'l341', 'l347', 'l348', 'l349']", + "67, tissue ['l16', 'l41', 'l68', 'l94', 'l119', 'l143', 'l166', 'l188', 'l209', 'l229', 'l248', 'l265', 'l277', 'l285', 'l296', 'l308', 'l320', 'l331', 'l342', 'l347', 'l350']", + "68, macrophage ['l17', 'l42', 'l69', 'l95', 'l120', 'l144', 'l167', 'l189', 'l210', 'l230', 'l249', 'l266', 'l278', 'l286', 'l297', 'l309', 'l321', 'l332', 'l343', 'l348', 'l350']", + "71, specific ['l43', 'l70', 'l96', 'l121', 'l145', 'l168', 'l190', 'l211', 'l231', 'l250', 'l298', 'l310', 'l322', 'l333', 'l351', 'l352', 'l353', 'l354', 'l355', 'l356', 'l357']", + "72, pharmacological ['l44', 'l71', 'l97', 'l122', 'l146', 'l169', 'l191', 'l212', 'l232', 'l334', 'l351', 'l358', 'l359', 'l360', 'l361', 'l362', 'l363']", + "73, inhibition ['l45', 'l72', 'l98', 'l123', 'l147', 'l170', 'l192', 'l213', 'l233', 'l251', 'l311', 'l323', 'l335', 'l352', 'l358', 'l364', 'l365', 'l366', 'l367', 'l368']", + "74, of ['l18', 'l46', 'l73', 'l99', 'l124', 'l148', 'l171', 'l193', 'l214', 'l234', 'l252', 'l299', 'l312', 'l324', 'l336', 'l353', 'l359', 'l364', 'l369', 'l370', 'l371', 'l372']", + "75, macrophage ['l19', 'l47', 'l74', 'l100', 'l125', 'l149', 'l172', 'l194', 'l215', 'l235', 'l253', 'l287', 'l300', 'l313', 'l325', 'l337', 'l354', 'l360', 'l365', 'l369', 'l373', 'l374', 'l375']", + "76, tissue ['l20', 'l48', 'l75', 'l101', 'l126', 'l150', 'l173', 'l195', 'l216', 'l236', 'l254', 'l267', 'l288', 'l301', 'l314', 'l326', 'l338', 'l344', 'l355', 'l361', 'l366', 'l370', 'l373', 'l376', 'l377']", + "77, factor ['l21', 'l49', 'l76', 'l102', 'l127', 'l151', 'l174', 'l196', 'l217', 'l237', 'l255', 'l268', 'l289', 'l302', 'l315', 'l327', 'l339', 'l345', 'l356', 'l362', 'l367', 'l371', 'l374', 'l376', 'l378']", + "78, signaling ['l22', 'l50', 'l77', 'l103', 'l128', 'l152', 'l175', 'l197', 'l218', 'l238', 'l256', 'l269', 'l290', 'l303', 'l316', 'l328', 'l340', 'l346', 'l349', 'l357', 'l363', 'l368', 'l372', 'l375', 'l377', 'l378']", + "85, nonhematopoietic ['l379']", + "86, cell ['l379']", + "116, Pharmacological ['l380', 'l381', 'l382', 'l383', 'l384', 'l385', 'l386']", + "117, blockade ['l380', 'l387', 'l388', 'l389', 'l390', 'l391', 'l392']", + "118, of ['l381', 'l387', 'l393', 'l394', 'l395', 'l396', 'l397']", + "119, adipocyte ['l382', 'l388', 'l393', 'l398', 'l399', 'l400', 'l401']", + "120, tissue ['l383', 'l389', 'l394', 'l398', 'l402', 'l403', 'l404']", + "121, factor ['l384', 'l390', 'l395', 'l399', 'l402', 'l405', 'l406']", + "122, in ['l385', 'l391', 'l396', 'l400', 'l403', 'l405', 'l407']", + "123, vivo ['l386', 'l392', 'l397', 'l401', 'l404', 'l406', 'l407']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "PAR2", + "(F2rl1)", + "or", + "of", + "tissue", + "factor", + "genetic", + "ablation", + "factor-PAR2", + "signaling" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "of", + "macrophage", + "tissue", + "factor", + "signaling" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "PAR2", + "(F2rl1)", + "or", + "the", + "cytoplasmic", + "domain", + "of", + "tissue", + "factor", + "genetic", + "ablation", + "factor-PAR2", + "signaling" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "cells,", + "adipose", + "tissue", + "macrophage" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "adipose" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "tissue", + "factor", + "signaling" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "adipocyte", + "tissue", + "factor" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "21963515", + "TEXT": "Calcineurin inhibitors (CNIs) are immunosuppressive drugs that are used widely to prevent rejection of transplanted organs and to treat autoimmune disease. Hypertension and renal tubule dysfunction, including hyperkalemia, hypercalciuria and acidosis, often complicate their use. These side effects resemble familial hyperkalemic hypertension, a genetic disease characterized by overactivity of the renal sodium chloride cotransporter (NCC) and caused by mutations in genes encoding WNK kinases. We hypothesized that CNIs induce hypertension by stimulating NCC. In wild-type mice, the CNI tacrolimus caused salt-sensitive hypertension and increased the abundance of phosphorylated NCC and the NCC-regulatory kinases WNK3, WNK4 and SPAK. We demonstrated the functional importance of NCC in this response by showing that tacrolimus did not affect blood pressure in NCC-knockout mice, whereas the hypertensive response to tacrolimus was exaggerated in mice overexpressing NCC. Moreover, hydrochlorothiazide, an NCC-blocking drug, reversed tacrolimus-induced hypertension. These observations were extended to humans by showing that kidney transplant recipients treated with tacrolimus had a greater fractional chloride excretion in response to bendroflumethiazide, another NCC-blocking drug, than individuals not treated with tacrolimus; renal NCC abundance was also greater. Together, these findings indicate that tacrolimus-induced chronic hypertension is mediated largely by NCC activation, and suggest that inexpensive and well-tolerated thiazide diuretics may be especially effective in preventing the complications of CNI treatment.", + "TAG_DATA": [ + "75, mice, {'context': 'B-organism'}", + "117, NCC-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "118, mice, {'context': 'B-organism'}", + "128, mice {'context': 'B-organism'}", + "129, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "130, NCC. {'perturbing_action': 'I-gene gain-of-function'}", + "148, kidney {'context': 'B-xenograft'}", + "149, transplant {'context': 'I-xenograft'}", + "150, recipients {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "75, mice, ['l0']", + "117, NCC-knockout ['l0', 'l1']", + "118, mice, ['l1']", + "128, mice ['l2', 'l3']", + "129, overexpressing ['l2', 'l4']", + "130, NCC. ['l3', 'l4']", + "148, kidney ['l5', 'l6']", + "149, transplant ['l5', 'l7']", + "150, recipients ['l6', 'l7']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NCC-knockout" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "NCC." + ] + } + } + ] + }, + { + "PMID": "21963514", + "TEXT": "Placebo analgesia is mediated by both opioid and nonopioid mechanisms, but so far nothing is known about the nonopioid component. Here we show that the specific CB1 cannabinoid receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (rimonabant or SR141716) blocks nonopioid placebo analgesic responses but has no effect on opioid placebo responses. These findings suggest that the endocannabinoid system has a pivotal role in placebo analgesia in some circumstances when the opioid system is not involved.", + "TAG_DATA": [ + "41, no {'effect': 'B-no effect'}" + ], + "LINK_DATA": [ + "26, CB1 ['l0', 'l1', 'l2', 'l3']", + "27, cannabinoid ['l0', 'l4', 'l5', 'l6']", + "28, receptor ['l1', 'l4', 'l7', 'l8']", + "29, antagonist ['l2', 'l5', 'l7', 'l9']", + "41, no ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21926977", + "TEXT": "Immunological memory is thought to depend on a stem cell-like, self-renewing population of lymphocytes capable of differentiating into effector cells in response to antigen re-exposure. Here we describe a long-lived human memory T cell population that has an enhanced capacity for self-renewal and a multipotent ability to derive central memory, effector memory and effector T cells. These cells, specific to multiple viral and self-tumor antigens, were found within a CD45RO(-), CCR7(+), CD45RA(+), CD62L(+), CD27(+), CD28(+) and IL-7Rα(+) T cell compartment characteristic of naive T cells. However, they expressed large amounts of CD95, IL-2Rβ, CXCR3, and LFA-1, and showed numerous functional attributes distinctive of memory cells. Compared with known memory populations, these lymphocytes had increased proliferative capacity and more efficiently reconstituted immunodeficient hosts, and they mediated superior antitumor responses in a humanized mouse model. The identification of a human stem cell-like memory T cell population is of direct relevance to the design of vaccines and T cell therapies.", + "TAG_DATA": [ + "111, lymphocytes {'context': 'B-cells'}", + "113, increased {'effect': 'B-positive'}", + "114, proliferative {'phenotype': 'B-proliferation'}", + "115, capacity {'phenotype': 'I-proliferation'}", + "130, humanized {'context': 'B-organism'}", + "131, mouse {'context': 'I-organism'}", + "132, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "111, lymphocytes ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "113, increased ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "114, proliferative ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "115, capacity ['l2', 'l7', 'l11', 'l15']", + "130, humanized ['l3', 'l8', 'l12', 'l16', 'l17']", + "131, mouse ['l4', 'l9', 'l13', 'l16', 'l18']", + "132, model. ['l5', 'l10', 'l14', 'l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "lymphocytes" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "lymphocytes" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "capacity" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "capacity" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "organism", + "words": [ + "humanized", + "mouse", + "model." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "capacity" + ] + }, + "context": { + "val": "organism", + "words": [ + "humanized", + "mouse", + "model." + ] + } + } + ] + }, + { + "PMID": "21909105", + "TEXT": "Osteocytes embedded in bone have been postulated to orchestrate bone homeostasis by regulating both bone-forming osteoblasts and bone-resorbing osteoclasts. We find here that purified osteocytes express a much higher amount of receptor activator of nuclear factor-κB ligand (RANKL) and have a greater capacity to support osteoclastogenesis in vitro than osteoblasts and bone marrow stromal cells. Furthermore, the severe osteopetrotic phenotype that we observe in mice lacking RANKL specifically in osteocytes indicates that osteocytes are the major source of RANKL in bone remodeling in vivo.", + "TAG_DATA": [ + "46, in {'context': 'B-in vitro'}", + "47, vitro {'context': 'I-in vitro'}", + "49, osteoblasts {'context': 'B-cells'}", + "51, bone {'context': 'B-cells'}", + "52, marrow {'context': 'I-cells'}", + "53, stromal {'context': 'I-cells'}", + "54, cells. {'context': 'I-cells'}", + "64, mice {'context': 'B-organism'}", + "65, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "66, RANKL {'perturbing_action': 'I-gene loss-of-function'}", + "67, specifically {'perturbing_action': 'I-gene loss-of-function'}", + "68, in {'perturbing_action': 'I-gene loss-of-function'}", + "69, osteocytes {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "46, in ['l0', 'l1', 'l2']", + "47, vitro ['l0', 'l3', 'l4']", + "49, osteoblasts ['l1', 'l3', 'l5', 'l6', 'l7', 'l8']", + "51, bone ['l5', 'l9', 'l10', 'l11']", + "52, marrow ['l6', 'l9', 'l12', 'l13']", + "53, stromal ['l7', 'l10', 'l12', 'l14']", + "54, cells. ['l2', 'l4', 'l8', 'l11', 'l13', 'l14']", + "64, mice ['l15', 'l16', 'l17', 'l18', 'l19']", + "65, lacking ['l15', 'l20', 'l21', 'l22', 'l23']", + "66, RANKL ['l16', 'l20', 'l24', 'l25', 'l26']", + "67, specifically ['l17', 'l21', 'l24', 'l27', 'l28']", + "68, in ['l18', 'l22', 'l25', 'l27', 'l29']", + "69, osteocytes ['l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "RANKL", + "specifically", + "in", + "osteocytes" + ] + } + } + ] + }, + { + "PMID": "21900936", + "TEXT": "Alzheimer's disease constitutes a personal and societal tragedy of immense proportions. Since 1960, research in laboratories and clinics worldwide has elucidated many features of this insidious and ultimately fatal syndrome, and this progress has led to initial human trials of potentially disease-modifying agents. However, some of these agents have already failed. Gnawing controversies and important gaps in our knowledge seem to cast additional doubt on the ability of the field to move forward effectively. Here I discuss some of these looming concerns and offer possible explanations for the major trial failures that suggest they are not predictive of the future. Rigorous preclinical validation of mechanism-based therapeutic agents followed by meticulously designed trials that focus on the cardinal cognitive symptoms and their associated biomarkers in the mild or presymptomatic phases of Alzheimer's disease are likely to lead to success, perhaps in the not-too-distant future.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21892181", + "TEXT": "Here we describe the isolation of stem cells of the human colonic epithelium. Differential cell surface abundance of ephrin type-B receptor 2 (EPHB2) allows the purification of different cell types from human colon mucosa biopsies. The highest EPHB2 surface levels correspond to epithelial colonic cells with the longest telomeres and elevated expression of intestinal stem cell (ISC) marker genes. Moreover, using culturing conditions that recreate the ISC niche, a substantial proportion of EPHB2-high cells can be expanded in vitro as an undifferentiated and multipotent population.", + "TAG_DATA": [ + "73, cells {'context': 'B-cells'}", + "77, in {'context': 'B-in vitro'}", + "78, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "73, cells ['l0', 'l1']", + "77, in ['l0', 'l2']", + "78, vitro ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21873988", + "TEXT": "Xenograft studies indicate that some solid tumors and leukemias are organized as cellular hierarchies sustained by cancer stem cells (CSCs). Despite the promise of the CSC model, its relevance in humans remains uncertain. Here we show that acute myeloid leukemia (AML) follows a CSC model on the basis of sorting multiple populations from each of 16 primary human AML samples and identifying which contain leukemia stem cells (LSCs) using a sensitive xenograft assay. Analysis of gene expression from all functionally validated populations yielded an LSC-specific signature. Similarly, a hematopoietic stem cell (HSC) gene signature was established. Bioinformatic analysis identified a core transcriptional program shared by LSCs and HSCs, revealing the molecular machinery underlying 'stemness' properties. Both stem cell programs were highly significant independent predictors of patient survival and were found in existing prognostic signatures. Thus, determinants of stemness influence the clinical outcome of AML, establishing that LSCs are clinically relevant and not artifacts of xenotransplantation.", + "TAG_DATA": [ + "57, human {'context': 'I-transformed cells'}", + "58, AML {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "57, human ['l0']", + "58, AML ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21857653", + "TEXT": "The global prevalence of severe Clostridium difficile infection highlights the profound clinical significance of clostridial glucosylating toxins. Virulence is dependent on the autoactivation of a toxin cysteine protease, which is promoted by the allosteric cofactor inositol hexakisphosphate (InsP(6)). Host mechanisms that protect against such exotoxins are poorly understood. It is increasingly appreciated that the pleiotropic functions attributed to nitric oxide (NO), including host immunity, are in large part mediated by S-nitrosylation of proteins. Here we show that C. difficile toxins are S-nitrosylated by the infected host and that S-nitrosylation attenuates virulence by inhibiting toxin self-cleavage and cell entry. Notably, InsP(6)- and inositol pyrophosphate (InsP(7))-induced conformational changes in the toxin enabled host S-nitrosothiols to transnitrosylate the toxin catalytic cysteine, which forms part of a structurally conserved nitrosylation motif. Moreover, treatment with exogenous InsP(6) enhanced the therapeutic actions of oral S-nitrosothiols in mouse models of C. difficile infection. Allostery in bacterial proteins has thus been successfully exploited in the evolutionary development of nitrosothiol-based innate immunity and may provide an avenue to new therapeutic approaches.", + "TAG_DATA": [ + "89, attenuates {'effect': 'B-negative'}", + "92, inhibiting {'effect': 'B-negative'}", + "96, cell {'context': 'B-cells', 'phenotype': 'B-cell growth'}", + "97, entry. {'phenotype': 'B-mitophagy'}", + "140, mouse {'context': 'B-organism'}", + "141, models {'context': 'I-organism'}", + "142, of {'context': 'I-organism'}", + "143, C. {'context': 'I-organism'}", + "144, difficile {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "89, attenuates ['l0', 'l1', 'l2']", + "92, inhibiting ['l0', 'l3', 'l4']", + "96, cell ['l1', 'l3', 'l5']", + "97, entry. ['l2', 'l4', 'l5']", + "140, mouse ['l6', 'l7', 'l8', 'l9']", + "141, models ['l6', 'l10', 'l11', 'l12']", + "142, of ['l7', 'l10', 'l13', 'l14']", + "143, C. ['l8', 'l11', 'l13', 'l15']", + "144, difficile ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "attenuates", + "inhibiting" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuates", + "inhibiting" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuates", + "inhibiting" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "entry." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "entry." + ] + } + } + ] + }, + { + "PMID": "21841783", + "TEXT": "A connection between diet, obesity and diabetes exists in multiple species and is the basis of an escalating human health problem. The factors responsible provoke both insulin resistance and pancreatic beta cell dysfunction but remain to be fully identified. We report a combination of molecular events in human and mouse pancreatic beta cells, induced by elevated levels of free fatty acids or by administration of a high-fat diet with associated obesity, that comprise a pathogenic pathway to diabetes. Elevated concentrations of free fatty acids caused nuclear exclusion and reduced expression of the transcription factors FOXA2 and HNF1A in beta cells. This resulted in a deficit of GnT-4a glycosyltransferase expression in beta cells that produced signs of metabolic disease, including hyperglycemia, impaired glucose tolerance, hyperinsulinemia, hepatic steatosis and diminished insulin action in muscle and adipose tissues. Protection from disease was conferred by enforced beta cell-specific GnT-4a protein glycosylation and involved the maintenance of glucose transporter expression and the preservation of glucose transport. We observed that this pathogenic process was active in human islet cells obtained from donors with type 2 diabetes; thus, illuminating a pathway to disease implicated in the diet- and obesity-associated component of type 2 diabetes mellitus.", + "TAG_DATA": [ + "47, human {'context': 'B-cells'}", + "48, and {'context': 'I-cells'}", + "49, mouse {'context': 'I-cells'}", + "50, pancreatic {'context': 'I-cells'}", + "51, beta {'context': 'I-cells'}", + "52, cells, {'context': 'I-cells'}", + "98, beta {'context': 'B-cells'}", + "99, cells. {'context': 'I-cells'}", + "110, beta {'context': 'B-cells'}", + "111, cells {'context': 'I-cells'}", + "131, muscle {'context': 'B-tissue/organ'}", + "133, adipose {'context': 'B-tissue/organ'}", + "134, tissues. {'context': 'I-tissue/organ'}", + "170, human {'context': 'B-cells'}", + "171, islet {'context': 'I-cells'}", + "172, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "47, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "48, and ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "49, mouse ['l1', 'l7', 'l14', 'l15', 'l16', 'l17', 'l18']", + "50, pancreatic ['l2', 'l8', 'l14', 'l19', 'l20', 'l21', 'l22']", + "51, beta ['l3', 'l9', 'l15', 'l19', 'l23', 'l24', 'l25']", + "52, cells, ['l4', 'l10', 'l16', 'l20', 'l23', 'l26', 'l27']", + "98, beta ['l5', 'l11', 'l17', 'l21', 'l24', 'l26', 'l28', 'l29', 'l30']", + "99, cells. ['l6', 'l12', 'l18', 'l22', 'l25', 'l27', 'l28', 'l31']", + "110, beta ['l29', 'l32', 'l33', 'l34', 'l35']", + "111, cells ['l13', 'l30', 'l31', 'l32', 'l36', 'l37']", + "131, muscle ['l33', 'l36', 'l38', 'l39']", + "133, adipose ['l34', 'l38', 'l40']", + "134, tissues. ['l35', 'l37', 'l39', 'l40']", + "170, human ['l41', 'l42']", + "171, islet ['l41', 'l43']", + "172, cells ['l42', 'l43']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21822286", + "TEXT": "Although the role of miR-200s in regulating E-cadherin expression and epithelial-to-mesenchymal transition is well established, their influence on metastatic colonization remains controversial. Here we have used clinical and experimental models of breast cancer metastasis to discover a pro-metastatic role of miR-200s that goes beyond their regulation of E-cadherin and epithelial phenotype. Overexpression of miR-200s is associated with increased risk of metastasis in breast cancer and promotes metastatic colonization in mouse models, phenotypes that cannot be recapitulated by E-cadherin expression alone. Genomic and proteomic analyses revealed global shifts in gene expression upon miR-200 overexpression toward that of highly metastatic cells. miR-200s promote metastatic colonization partly through direct targeting of Sec23a, which mediates secretion of metastasis-suppressive proteins, including Igfbp4 and Tinagl1, as validated by functional and clinical correlation studies. Overall, these findings suggest a pleiotropic role of miR-200s in promoting metastatic colonization by influencing E-cadherin-dependent epithelial traits and Sec23a-mediated tumor cell secretome.", + "TAG_DATA": [ + "51, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "52, of {'perturbing_action': 'I-gene gain-of-function'}", + "53, miR-200s {'perturbing_action': 'I-gene gain-of-function'}", + "65, promotes {'effect': 'B-positive'}", + "66, metastatic {'phenotype': 'B-metastasis'}", + "67, colonization {'phenotype': 'I-metastasis'}", + "69, mouse {'context': 'B-organism'}", + "70, models, {'context': 'I-organism'}", + "91, miR-200 {'perturbing_action': 'B-gene gain-of-function'}", + "92, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "100, promote {'effect': 'B-positive'}", + "101, metastatic {'phenotype': 'B-metastasis'}", + "102, colonization {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "51, Overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "52, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "53, miR-200s ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "65, promotes ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "66, metastatic ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "67, colonization ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "69, mouse ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "70, models, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "91, miR-200 ['l28']", + "92, overexpression ['l28']", + "100, promote ['l29', 'l30']", + "101, metastatic ['l29', 'l31']", + "102, colonization ['l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "miR-200s" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "miR-200s" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "colonization" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "miR-200s" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes", + "promote" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "colonization" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models," + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "colonization" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models," + ] + } + } + ] + }, + { + "PMID": "21804540", + "TEXT": "Transcription factor FoxO1 promotes hepatic glucose production. Genetic inhibition of FoxO1 function prevents diabetes in experimental animal models, providing impetus to identify pharmacological approaches to modulate this function. Altered Notch signaling is evident in tumorigenesis, and Notch antagonists are in clinical testing for application in cancer. Here we report that FoxO1 and Notch coordinately regulate hepatic glucose metabolism. Combined haploinsufficiency of FoxO1 and Notch1 markedly raises insulin sensitivity in diet-induced insulin resistance, as does liver-specific knockout of the Notch transcriptional effector Rbp-Jκ. Conversely, Notch1 gain-of-function promotes insulin resistance in a FoxO1-dependent manner and induces glucose-6-phosphatase expression. Pharmacological blockade of Notch signaling with γ-secretase inhibitors raises insulin sensitivity after in vivo administration in lean mice and in obese, insulin-resistant mice. The data identify a heretofore unknown metabolic function of Notch and suggest that Notch inhibition is beneficial in diabetes treatment, in part by helping to offset excessive FoxO1-driven hepatic glucose production.", + "TAG_DATA": [ + "58, Combined {'perturbing_action': 'B-gene loss-of-function'}", + "59, haploinsufficiency {'perturbing_action': 'I-gene loss-of-function'}", + "60, of {'perturbing_action': 'I-gene loss-of-function'}", + "61, FoxO1 {'perturbing_action': 'I-gene loss-of-function'}", + "62, and {'perturbing_action': 'I-gene loss-of-function'}", + "63, Notch1 {'perturbing_action': 'I-gene loss-of-function'}", + "74, liver-specific {'perturbing_action': 'B-gene loss-of-function'}", + "75, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "76, of {'perturbing_action': 'I-gene loss-of-function'}", + "77, the {'perturbing_action': 'I-gene loss-of-function'}", + "78, Notch {'perturbing_action': 'I-gene loss-of-function'}", + "79, transcriptional {'perturbing_action': 'I-gene loss-of-function'}", + "80, effector {'perturbing_action': 'I-gene loss-of-function'}", + "81, Rbp-Jκ. {'perturbing_action': 'I-gene loss-of-function'}", + "83, Notch1 {'perturbing_action': 'B-gene gain-of-function'}", + "84, gain-of-function {'perturbing_action': 'I-gene gain-of-function'}", + "108, in {'context': 'B-in vivo'}", + "109, vivo {'context': 'I-in vivo'}", + "112, lean {'context': 'B-organism'}", + "113, mice {'context': 'I-organism'}", + "116, obese, {'context': 'B-organism'}", + "117, insulin-resistant {'context': 'I-organism'}", + "118, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "58, Combined ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "59, haploinsufficiency ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "60, of ['l1', 'l11', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "61, FoxO1 ['l2', 'l12', 'l23', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "62, and ['l3', 'l13', 'l24', 'l34', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "63, Notch1 ['l4', 'l14', 'l25', 'l35', 'l43', 'l52']", + "74, liver-specific ['l5', 'l15', 'l26', 'l36', 'l44', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "75, knockout ['l6', 'l16', 'l27', 'l37', 'l45', 'l53', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "76, of ['l17', 'l28', 'l38', 'l46', 'l54', 'l61', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "77, the ['l7', 'l18', 'l29', 'l39', 'l47', 'l55', 'l62', 'l69', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "78, Notch ['l8', 'l19', 'l30', 'l40', 'l48', 'l56', 'l63', 'l70', 'l76', 'l82', 'l83', 'l84', 'l85', 'l86']", + "79, transcriptional ['l20', 'l31', 'l49', 'l57', 'l64', 'l71', 'l77', 'l82', 'l87', 'l88', 'l89', 'l90']", + "80, effector ['l9', 'l21', 'l32', 'l41', 'l50', 'l58', 'l65', 'l72', 'l78', 'l83', 'l87', 'l91', 'l92', 'l93']", + "81, Rbp-Jκ. ['l10', 'l22', 'l33', 'l42', 'l51', 'l52', 'l59', 'l66', 'l73', 'l79', 'l84', 'l88', 'l91', 'l94']", + "83, Notch1 ['l60', 'l67', 'l74', 'l80', 'l85', 'l89', 'l92', 'l94', 'l95']", + "84, gain-of-function ['l68', 'l75', 'l81', 'l86', 'l90', 'l93', 'l95']", + "108, in ['l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "109, vivo ['l96', 'l102', 'l103', 'l104', 'l105', 'l106']", + "112, lean ['l97', 'l102', 'l107', 'l108', 'l109', 'l110']", + "113, mice ['l98', 'l103', 'l107', 'l111', 'l112', 'l113']", + "116, obese, ['l99', 'l104', 'l108', 'l111', 'l114', 'l115']", + "117, insulin-resistant ['l100', 'l105', 'l109', 'l112', 'l114', 'l116']", + "118, mice. ['l101', 'l106', 'l110', 'l113', 'l115', 'l116']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21785431", + "TEXT": "Survivors of pediatric Hodgkin's lymphoma are at risk for radiation therapy-induced second malignant neoplasms (SMNs). We identified two variants at chromosome 6q21 associated with SMNs in survivors of Hodgkin's lymphoma treated with radiation therapy as children but not as adults. The variants comprise a risk locus associated with decreased basal expression of PRDM1 (encoding PR domain containing 1, with ZNF domain) and impaired induction of the PRDM1 protein after radiation exposure. These data suggest a new gene-exposure interaction that may implicate PRDM1 in the etiology of radiation therapy-induced SMNs.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21738155", + "TEXT": "A new combinatorial approach harnesses the power of immuno- and virotherapy in a vesicular stomatitis virus (VSV) vector carrying a cDNA library that expresses normal human prostate antigens, thus providing proof of principle that this vaccine can induce prostate tumor rejection in mice (pages 854–859). This strategy might bypass many of the issues associated with conventional cancer immuno- or virotherapy.", + "TAG_DATA": [ + "37, induce {'effect': 'B-positive'}", + "38, prostate {'context': 'B-neoplasm'}", + "39, tumor {'phenotype': 'B-tumour regression'}", + "40, rejection {'phenotype': 'I-tumour regression'}", + "42, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "37, induce ['l0', 'l1', 'l2', 'l3']", + "38, prostate ['l0', 'l4', 'l5', 'l6']", + "39, tumor ['l1', 'l4', 'l7', 'l8']", + "40, rejection ['l2', 'l5', 'l7', 'l9']", + "42, mice ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "prostate" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "rejection" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "prostate" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "rejection" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "rejection" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "21725296", + "TEXT": "In cancer treatment, apoptosis is a well-recognized cell death mechanism through which cytotoxic agents kill tumor cells. Here we report that dying tumor cells use the apoptotic process to generate potent growth-stimulating signals to stimulate the repopulation of tumors undergoing radiotherapy. Furthermore, activated caspase 3, a key executioner in apoptosis, is involved in the growth stimulation. One downstream effector that caspase 3 regulates is prostaglandin E(2) (PGE(2)), which can potently stimulate growth of surviving tumor cells. Deficiency of caspase 3 either in tumor cells or in tumor stroma caused substantial tumor sensitivity to radiotherapy in xenograft or mouse tumors. In human subjects with cancer, higher amounts of activated caspase 3 in tumor tissues are correlated with markedly increased rate of recurrence and death. We propose the existence of a cell death-induced tumor repopulation pathway in which caspase 3 has a major role.", + "TAG_DATA": [ + "74, tumor {'context': 'B-transformed cells'}", + "75, cells. {'context': 'I-transformed cells'}", + "76, Deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "77, of {'perturbing_action': 'I-gene loss-of-function'}", + "78, caspase {'perturbing_action': 'I-gene loss-of-function'}", + "79, 3 {'perturbing_action': 'I-gene loss-of-function'}", + "82, tumor {'context': 'B-transformed cells'}", + "83, cells {'context': 'I-transformed cells'}", + "86, tumor {'context': 'B-neoplasm'}", + "90, tumor {'context': 'B-neoplasm'}", + "95, xenograft {'context': 'B-xenograft'}", + "97, mouse {'context': 'B-neoplasm'}", + "98, tumors. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "74, tumor ['l0']", + "75, cells. ['l0']", + "76, Deficiency ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "77, of ['l1', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "78, caspase ['l2', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "79, 3 ['l3', 'l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "80, either ['l4', 'l14', 'l23', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "82, tumor ['l5', 'l15', 'l24', 'l32', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "83, cells ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l52', 'l53', 'l54', 'l55']", + "86, tumor ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l56', 'l57', 'l58', 'l59']", + "90, tumor ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l52', 'l56', 'l60', 'l61', 'l62']", + "95, xenograft ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l53', 'l57', 'l60', 'l63', 'l64']", + "97, mouse ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l54', 'l58', 'l61', 'l63', 'l65']", + "98, tumors. ['l11', 'l21', 'l30', 'l38', 'l45', 'l51', 'l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deficiency", + "of", + "caspase", + "3" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deficiency", + "of", + "caspase", + "3" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor", + "mouse", + "tumors." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deficiency", + "of", + "caspase", + "3" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft" + ] + } + } + ] + }, + { + "PMID": "21706030", + "TEXT": "Cells that are deficient in homologous recombination, such as those that lack functional breast cancer-associated 1 (BRCA1) or BRCA2, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, BRCA-deficient tumors represent only a small fraction of adult cancers, which might restrict the therapeutic utility of PARP inhibitor monotherapy. Cyclin-dependent kinase 1 (Cdk1) phosphorylates BRCA1, and this is essential for efficient formation of BRCA1 foci. Here we show that depletion or inhibition of Cdk1 compromises the ability of cells to repair DNA by homologous recombination. Combined inhibition of Cdk1 and PARP in BRCA-wild-type cancer cells resulted in reduced colony formation, delayed growth of human tumor xenografts and tumor regression with prolonged survival in a mouse model of lung adenocarcinoma. Inhibition of Cdk1 did not sensitize nontransformed cells or tissues to inhibition of PARP. Because reduced Cdk1 activity impaired BRCA1 function and consequently, repair by homologous recombination, inhibition of Cdk1 represents a plausible strategy for expanding the utility of PARP inhibitors to BRCA-proficient cancers.", + "TAG_DATA": [ + "70, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "71, of {'perturbing_action': 'I-pharmacological inhibition'}", + "72, Cdk1 {'perturbing_action': 'I-pharmacological inhibition'}", + "77, cells {'context': 'B-cells'}", + "84, Combined {'perturbing_action': 'B-pharmacological inhibition'}", + "85, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "86, of {'perturbing_action': 'I-pharmacological inhibition'}", + "87, Cdk1 {'perturbing_action': 'I-pharmacological inhibition'}", + "88, and {'perturbing_action': 'I-pharmacological inhibition'}", + "89, PARP {'perturbing_action': 'I-pharmacological inhibition'}", + "91, BRCA-wild-type {'context': 'B-transformed cells'}", + "92, cancer {'context': 'B-transformed cells'}", + "93, cells {'context': 'I-transformed cells'}", + "96, reduced {'effect': 'B-negative'}", + "97, colony {'phenotype': 'B-colony formation'}", + "98, formation, {'phenotype': 'I-colony formation'}", + "102, human {'context': 'B-xenograft'}", + "103, tumor {'context': 'I-xenograft'}", + "104, xenografts {'context': 'I-xenograft'}", + "106, tumor {'phenotype': 'B-tumour regression'}", + "107, regression {'phenotype': 'I-tumour regression'}", + "113, mouse {'context': 'B-neoplasm'}", + "114, model {'context': 'I-neoplasm'}", + "115, of {'context': 'I-neoplasm'}", + "116, lung {'context': 'I-neoplasm'}", + "117, adenocarcinoma. {'context': 'I-neoplasm'}", + "118, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "119, of {'perturbing_action': 'I-pharmacological inhibition'}", + "120, Cdk1 {'perturbing_action': 'I-pharmacological inhibition'}", + "124, nontransformed {'context': 'B-cells'}", + "125, cells {'context': 'I-cells'}", + "129, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "130, of {'perturbing_action': 'I-pharmacological inhibition'}", + "131, PARP. {'perturbing_action': 'I-pharmacological inhibition'}", + "133, reduced {'perturbing_action': 'B-other'}", + "134, Cdk1 {'perturbing_action': 'I-rnai/knockdown'}", + "135, activity {'perturbing_action': 'I-rnai/knockdown'}", + "145, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "146, of {'perturbing_action': 'I-pharmacological inhibition'}", + "147, Cdk1 {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "70, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "71, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "72, Cdk1 ['l1', 'l11', 'l19', 'l20', 'l21', 'l22']", + "77, cells ['l2', 'l12', 'l19']", + "84, Combined ['l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "85, inhibition ['l23', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "86, of ['l3', 'l24', 'l44', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "87, Cdk1 ['l25', 'l45', 'l64', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "88, and ['l4', 'l26', 'l46', 'l65', 'l83', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "89, PARP ['l27', 'l47', 'l66', 'l84', 'l101', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "91, BRCA-wild-type ['l5', 'l13', 'l28', 'l48', 'l67', 'l85', 'l102', 'l118', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145']", + "92, cancer ['l6', 'l14', 'l20', 'l29', 'l49', 'l68', 'l86', 'l103', 'l119', 'l134', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "93, cells ['l7', 'l15', 'l21', 'l30', 'l50', 'l69', 'l87', 'l104', 'l120', 'l135', 'l146', 'l153', 'l154', 'l155', 'l156']", + "96, reduced ['l8', 'l16', 'l31', 'l51', 'l70', 'l88', 'l105', 'l121', 'l136', 'l147', 'l153', 'l157', 'l158', 'l159', 'l160']", + "97, colony ['l9', 'l17', 'l32', 'l52', 'l71', 'l89', 'l106', 'l122', 'l137', 'l148', 'l154', 'l157', 'l161', 'l162']", + "98, formation, ['l10', 'l18', 'l22', 'l33', 'l53', 'l72', 'l90', 'l107', 'l123', 'l138', 'l149', 'l155', 'l158', 'l161']", + "102, human ['l34', 'l54', 'l73', 'l91', 'l108', 'l124', 'l139', 'l150', 'l159', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170']", + "103, tumor ['l35', 'l55', 'l74', 'l92', 'l109', 'l125', 'l140', 'l151', 'l163', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "104, xenografts ['l36', 'l56', 'l75', 'l93', 'l110', 'l126', 'l141', 'l152', 'l156', 'l160', 'l162', 'l164', 'l171', 'l179', 'l180', 'l181', 'l182', 'l183']", + "106, tumor ['l37', 'l57', 'l76', 'l94', 'l111', 'l127', 'l142', 'l165', 'l172', 'l179', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189']", + "107, regression ['l38', 'l58', 'l77', 'l95', 'l112', 'l128', 'l143', 'l166', 'l173', 'l180', 'l184', 'l190', 'l191', 'l192', 'l193', 'l194']", + "113, mouse ['l39', 'l59', 'l78', 'l96', 'l113', 'l129', 'l174', 'l185', 'l190', 'l195', 'l196', 'l197', 'l198']", + "114, model ['l40', 'l60', 'l79', 'l97', 'l114', 'l130', 'l144', 'l167', 'l175', 'l181', 'l186', 'l191', 'l195', 'l199', 'l200', 'l201']", + "115, of ['l41', 'l61', 'l80', 'l98', 'l115', 'l131', 'l145', 'l168', 'l176', 'l182', 'l187', 'l192', 'l196', 'l199', 'l202', 'l203']", + "116, lung ['l42', 'l62', 'l81', 'l99', 'l116', 'l132', 'l169', 'l177', 'l188', 'l193', 'l197', 'l200', 'l202', 'l204']", + "117, adenocarcinoma. ['l43', 'l63', 'l82', 'l100', 'l117', 'l133', 'l170', 'l178', 'l183', 'l189', 'l194', 'l198', 'l201', 'l203', 'l204']", + "118, Inhibition ['l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218']", + "119, of ['l205', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231']", + "120, Cdk1 ['l206', 'l219', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243']", + "124, nontransformed ['l207', 'l220', 'l232', 'l244', 'l245', 'l246', 'l247', 'l248']", + "125, cells ['l208', 'l221', 'l233', 'l244', 'l249', 'l250', 'l251', 'l252']", + "127, tissues ['l209', 'l222', 'l234', 'l245', 'l249', 'l253', 'l254', 'l255']", + "129, inhibition ['l210', 'l223', 'l235', 'l246', 'l250', 'l253', 'l256', 'l257', 'l258', 'l259', 'l260']", + "130, of ['l211', 'l224', 'l236', 'l247', 'l251', 'l254', 'l256', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266']", + "131, PARP. ['l212', 'l225', 'l237', 'l248', 'l252', 'l255', 'l257', 'l261', 'l267']", + "133, reduced ['l213', 'l226', 'l238', 'l258', 'l262', 'l268', 'l269', 'l270', 'l271', 'l272']", + "134, Cdk1 ['l214', 'l227', 'l239', 'l259', 'l263', 'l268', 'l273', 'l274', 'l275', 'l276']", + "135, activity ['l215', 'l228', 'l240', 'l260', 'l264', 'l267', 'l269', 'l273', 'l277', 'l278', 'l279']", + "145, inhibition ['l216', 'l229', 'l241', 'l265', 'l270', 'l274', 'l277', 'l280', 'l281']", + "146, of ['l217', 'l230', 'l242', 'l266', 'l271', 'l275', 'l278', 'l280', 'l282']", + "147, Cdk1 ['l218', 'l231', 'l243', 'l272', 'l276', 'l279', 'l281', 'l282']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "Cdk1", + "Inhibition", + "PARP." + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "nontransformed" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "Cdk1", + "Combined", + "and", + "PARP" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "BRCA-wild-type", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "Combined", + "Cdk1", + "and", + "PARP" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "Cdk1", + "Combined", + "and", + "PARP" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "colony", + "formation," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Combined", + "inhibition", + "of", + "Cdk1", + "and", + "PARP" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "human", + "tumor", + "xenografts" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Combined", + "inhibition", + "of", + "Cdk1", + "and", + "PARP" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Combined", + "inhibition", + "of", + "Cdk1", + "and", + "PARP" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "lung", + "adenocarcinoma." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "BRCA-wild-type", + "cancer", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "BRCA-wild-type", + "cancer", + "cells" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "colony", + "formation," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "BRCA-wild-type" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "colony", + "formation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "human", + "xenografts" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "colony" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenografts" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "human", + "tumor", + "xenografts" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "lung", + "adenocarcinoma." + ] + } + } + ] + }, + { + "PMID": "21706029", + "TEXT": "We report that breast cancer cells that infiltrate the lungs support their own metastasis-initiating ability by expressing tenascin C (TNC). We find that the expression of TNC, an extracellular matrix protein of stem cell niches, is associated with the aggressiveness of pulmonary metastasis. Cancer cell-derived TNC promotes the survival and outgrowth of pulmonary micrometastases. TNC enhances the expression of stem cell signaling components, musashi homolog 1 (MSI1) and leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5). MSI1 is a positive regulator of NOTCH signaling, whereas LGR5 is a target gene of the WNT pathway. TNC modulation of stem cell signaling occurs without affecting the expression of transcriptional enforcers of the stem cell phenotype and pluripotency, namely nanog homeobox (NANOG), POU class 5 homeobox 1 (POU5F1), also known as OCT4, and SRY-box 2 (SOX2). TNC protects MSI1-dependent NOTCH signaling from inhibition by signal transducer and activator of transcription 5 (STAT5), and selectively enhances the expression of LGR5 as a WNT target gene. Cancer cell-derived TNC remains essential for metastasis outgrowth until the tumor stroma takes over as a source of TNC. These findings link TNC to pathways that support the fitness of metastasis-initiating breast cancer cells and highlight the relevance of TNC as an extracellular matrix component of the metastatic niche.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21602800", + "TEXT": "Cellular immunity has an inherent high level of functional heterogeneity. Capturing the full spectrum of these functions requires analysis of large numbers of effector molecules from single cells. We report a microfluidic platform designed for highly multiplexed (more than ten proteins), reliable, sample-efficient (∼1 × 10(4) cells) and quantitative measurements of secreted proteins from single cells. We validated the platform by assessment of multiple inflammatory cytokines from lipopolysaccharide (LPS)-stimulated human macrophages and comparison to standard immunotechnologies. We applied the platform toward the ex vivo quantification of T cell polyfunctional diversity via the simultaneous measurement of a dozen effector molecules secreted from tumor antigen-specific cytotoxic T lymphocytes (CTLs) that were actively responding to tumor and compared against a cohort of healthy donor controls. We observed profound, yet focused, functional heterogeneity in active tumor antigen-specific CTLs, with the major functional phenotypes quantitatively identified. The platform represents a new and informative tool for immune monitoring and clinical assessment.", + "TAG_DATA": [ + "69, human {'context': 'B-cells'}", + "70, macrophages {'context': 'I-cells'}", + "104, T {'context': 'I-cells'}", + "105, lymphocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "69, human ['l0']", + "70, macrophages ['l0']", + "103, cytotoxic ['l1', 'l2', 'l3']", + "104, T ['l1', 'l4', 'l5']", + "105, lymphocytes ['l2', 'l4', 'l6']", + "106, (CTLs) ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21572428", + "TEXT": "Endocrine resistance is a major obstacle to hormonal therapy for breast cancers. Although reduced expression of estrogen receptor-α (ER-α) is a known contributing factor to endocrine resistance, the mechanism of ER-α downregulation in endocrine resistance is still not fully understood. Here we report that CUE domain-containing protein-2 (CUEDC2), a ubiquitin-binding motif-containing protein, is a key factor in endocrine resistance in breast cancer. We show that CUEDC2 modulates ER-α protein stability through the ubiquitin-proteasome pathway. Through the study of specimens from a large cohort of subjects with breast cancer, we found a strong inverse correlation between CUEDC2 and ER-α protein expression. Notably, subjects with tumors that highly expressed CUEDC2 had poor responsiveness to tamoxifen treatment and high potential for relapse. We further show that ectopic CUEDC2 expression impaired the responsiveness of breast cancer cells to tamoxifen. Therefore, our findings suggest that CUEDC2 is a crucial determinant of resistance to endocrine therapies in breast cancer.", + "TAG_DATA": [ + "123, ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "124, CUEDC2 {'perturbing_action': 'I-gene gain-of-function'}", + "125, expression {'perturbing_action': 'I-gene gain-of-function'}", + "130, breast {'context': 'B-transformed cells'}", + "131, cancer {'context': 'I-transformed cells'}", + "132, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "123, ectopic ['l0', 'l1', 'l2', 'l3', 'l4']", + "124, CUEDC2 ['l0', 'l5', 'l6', 'l7', 'l8']", + "125, expression ['l1', 'l5', 'l9', 'l10', 'l11']", + "130, breast ['l2', 'l6', 'l9', 'l12', 'l13']", + "131, cancer ['l3', 'l7', 'l10', 'l12', 'l14']", + "132, cells ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "CUEDC2", + "expression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "breast", + "cancer", + "cells" + ] + } + } + ] + }, + { + "PMID": "21532596", + "TEXT": "In adipose tissue, muscle, liver and macrophages, signaling by the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ) is a determinant of insulin sensitivity and this receptor mediates the insulin-sensitizing effects of thiazolidinediones (TZDs). As PPAR-γ is also expressed in neurons, we generated mice with neuron-specific Pparg knockout (Pparg brain knockout (BKO)) to determine whether neuronal PPAR-γ signaling contributes to either weight gain or insulin sensitivity. During high-fat diet (HFD) feeding, food intake was reduced and energy expenditure increased in Pparg-BKO mice compared to Pparg(f/f) mice, resulting in reduced weight gain. Pparg-BKO mice also responded better to leptin administration than Pparg(f/f) mice. When treated with the TZD rosiglitazone, Pparg-BKO mice were resistant to rosiglitazone-induced hyperphagia and weight gain and, relative to rosiglitazone-treated Pparg(f/f) mice, experienced only a marginal improvement in glucose metabolism. Hyperinsulinemic euglycemic clamp studies showed that the increase in hepatic insulin sensitivity induced by rosiglitazone treatment during HFD feeding was completely abolished in Pparg-BKO mice, an effect associated with the failure of rosiglitazone to improve liver insulin receptor signal transduction. We conclude that excess weight gain induced by HFD feeding depends in part on the effect of neuronal PPAR-γ signaling to limit thermogenesis and increase food intake. Neuronal PPAR-γ signaling is also required for the hepatic insulin sensitizing effects of TZDs.", + "TAG_DATA": [ + "41, mice {'context': 'B-organism'}", + "43, neuron-specific {'perturbing_action': 'B-gene loss-of-function'}", + "44, Pparg {'perturbing_action': 'I-gene loss-of-function'}", + "45, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "46, (Pparg {'perturbing_action': 'I-gene loss-of-function'}", + "47, brain {'perturbing_action': 'I-gene loss-of-function'}", + "48, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "49, (BKO)) {'perturbing_action': 'I-gene loss-of-function'}", + "78, Pparg-BKO {'perturbing_action': 'B-gene loss-of-function'}", + "79, mice {'context': 'B-organism'}", + "82, Pparg(f/f) {'perturbing_action': 'B-other'}", + "89, Pparg-BKO {'perturbing_action': 'B-gene loss-of-function'}", + "90, mice {'context': 'B-organism'}", + "98, Pparg(f/f) {'perturbing_action': 'B-other'}", + "99, mice. {'context': 'B-organism'}", + "106, Pparg-BKO {'perturbing_action': 'B-gene loss-of-function'}", + "107, mice {'context': 'B-organism'}", + "120, Pparg(f/f) {'perturbing_action': 'B-other'}", + "121, mice, {'context': 'B-organism'}", + "153, Pparg-BKO {'perturbing_action': 'B-gene loss-of-function'}", + "154, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "41, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "43, neuron-specific ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "44, Pparg ['l1', 'l10', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "45, knockout ['l2', 'l11', 'l20', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "46, (Pparg ['l3', 'l12', 'l21', 'l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "47, brain ['l4', 'l13', 'l22', 'l29', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "48, knockout ['l5', 'l14', 'l23', 'l30', 'l36', 'l41', 'l46', 'l47', 'l48', 'l49']", + "49, (BKO)) ['l6', 'l15', 'l24', 'l31', 'l37', 'l42', 'l46', 'l50', 'l51', 'l52']", + "78, Pparg-BKO ['l7', 'l16', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l53', 'l54']", + "79, mice ['l8', 'l17', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53']", + "82, Pparg(f/f) ['l9', 'l18', 'l27', 'l34', 'l40', 'l45', 'l49', 'l52', 'l54', 'l55']", + "89, Pparg-BKO ['l56', 'l57', 'l58', 'l59']", + "90, mice ['l19', 'l55', 'l56', 'l60']", + "98, Pparg(f/f) ['l57', 'l61', 'l62']", + "99, mice. ['l58', 'l60', 'l61']", + "106, Pparg-BKO ['l63', 'l64', 'l65']", + "107, mice ['l59', 'l62', 'l63', 'l66', 'l67']", + "120, Pparg(f/f) ['l64', 'l66', 'l68']", + "121, mice, ['l65', 'l67', 'l68']", + "153, Pparg-BKO ['l69']", + "154, mice, ['l69']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "neuron-specific", + "Pparg", + "knockout", + "(Pparg", + "brain", + "(BKO))", + "Pparg-BKO" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "mice," + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Pparg(f/f)" + ] + } + } + ] + }, + { + "PMID": "21516088", + "TEXT": "Deficiency in fragile X mental retardation protein (FMRP) results in fragile X syndrome (FXS), an inherited form of intellectual disability. Despite extensive research, it is unclear how FMRP deficiency contributes to the cognitive deficits in FXS. Fmrp-null mice show reduced adult hippocampal neurogenesis. As Fmrp is also enriched in mature neurons, we investigated the function of Fmrp expression in neural stem and progenitor cells (aNSCs) and its role in adult neurogenesis. Here we show that ablation of Fmrp in aNSCs by inducible gene recombination leads to reduced hippocampal neurogenesis in vitro and in vivo, as well as markedly impairing hippocampus-dependent learning in mice. Conversely, restoration of Fmrp expression specifically in aNSCs rescues these learning deficits in Fmrp-deficient mice. These data suggest that defective adult neurogenesis may contribute to the learning impairment seen in FXS, and these learning deficits can be rectified by delayed restoration of Fmrp specifically in aNSCs.", + "TAG_DATA": [ + "36, Fmrp-null {'perturbing_action': 'B-gene loss-of-function'}", + "75, ablation {'perturbing_action': 'B-gene loss-of-function'}", + "76, of {'perturbing_action': 'I-gene loss-of-function'}", + "77, Fmrp {'perturbing_action': 'I-gene loss-of-function'}", + "79, aNSCs {'context': 'B-cells'}", + "80, by {'perturbing_action': 'I-gene loss-of-function'}", + "81, inducible {'perturbing_action': 'I-gene loss-of-function'}", + "82, gene {'perturbing_action': 'I-gene loss-of-function'}", + "83, recombination {'perturbing_action': 'I-gene loss-of-function'}", + "89, in {'context': 'B-in vitro'}", + "90, vitro {'context': 'I-in vitro'}", + "92, in {'context': 'B-in vivo'}", + "93, vivo, {'context': 'I-in vivo'}", + "102, mice. {'context': 'B-organism'}", + "104, restoration {'perturbing_action': 'B-gene gain-of-function'}", + "105, of {'perturbing_action': 'I-gene gain-of-function'}", + "106, Fmrp {'perturbing_action': 'I-gene gain-of-function'}", + "107, expression {'perturbing_action': 'I-gene gain-of-function'}", + "108, specifically {'perturbing_action': 'I-gene gain-of-function'}", + "110, aNSCs {'context': 'B-cells'}", + "116, Fmrp-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "117, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "36, Fmrp-null ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "75, ablation ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "76, of ['l6', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "77, Fmrp ['l0', 'l7', 'l18', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "79, aNSCs ['l1', 'l8', 'l19', 'l29', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "80, by ['l2', 'l9', 'l20', 'l30', 'l39', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "81, inducible ['l10', 'l21', 'l31', 'l40', 'l48', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "82, gene ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "83, recombination ['l12', 'l23', 'l33', 'l42', 'l50', 'l57', 'l63', 'l69', 'l70', 'l71', 'l72', 'l73']", + "89, in ['l3', 'l13', 'l24', 'l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l74', 'l75']", + "90, vitro ['l4', 'l14', 'l25', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l76']", + "92, in ['l15', 'l26', 'l36', 'l45', 'l53', 'l60', 'l66', 'l71', 'l77', 'l78']", + "93, vivo, ['l5', 'l16', 'l27', 'l37', 'l46', 'l54', 'l61', 'l67', 'l72', 'l75', 'l76', 'l77', 'l79']", + "102, mice. ['l17', 'l28', 'l38', 'l47', 'l55', 'l62', 'l68', 'l73', 'l78', 'l79']", + "104, restoration ['l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "105, of ['l80', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "106, Fmrp ['l81', 'l87', 'l93', 'l94', 'l95', 'l96', 'l97']", + "107, expression ['l82', 'l88', 'l93', 'l98', 'l99', 'l100', 'l101']", + "108, specifically ['l83', 'l89', 'l94', 'l98', 'l102', 'l103', 'l104']", + "110, aNSCs ['l84', 'l90', 'l95', 'l99', 'l102', 'l105', 'l106']", + "116, Fmrp-deficient ['l85', 'l91', 'l96', 'l100', 'l103', 'l105', 'l107']", + "117, mice. ['l86', 'l92', 'l97', 'l101', 'l104', 'l106', 'l107']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fmrp-null", + "ablation", + "of", + "Fmrp", + "by", + "inducible", + "gene", + "recombination", + "Fmrp-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "aNSCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fmrp-null", + "ablation", + "of", + "Fmrp", + "by", + "inducible", + "gene", + "recombination" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fmrp-null", + "ablation", + "of", + "Fmrp", + "by", + "inducible", + "gene", + "recombination" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo,", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablation", + "of", + "Fmrp", + "by", + "inducible", + "gene", + "recombination", + "Fmrp-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "restoration", + "of", + "Fmrp", + "expression", + "specifically" + ] + }, + "context": { + "val": "cells", + "words": [ + "aNSCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "restoration", + "of", + "Fmrp", + "expression", + "specifically" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "21516086", + "TEXT": "Inflammatory cell recruitment after myocardial infarction needs to be tightly controlled to permit infarct healing while avoiding fatal complications such as cardiac rupture. Growth differentiation factor-15 (GDF-15), a transforming growth factor-β (TGF-β)-related cytokine, is induced in the infarcted heart of mice and humans. We show that coronary artery ligation in Gdf15-deficient mice led to enhanced recruitment of polymorphonuclear leukocytes (PMNs) into the infarcted myocardium and an increased incidence of cardiac rupture. Conversely, infusion of recombinant GDF-15 repressed PMN recruitment after myocardial infarction. In vitro, GDF-15 inhibited PMN adhesion, arrest under flow and transendothelial migration. Mechanistically, GDF-15 counteracted chemokine-triggered conformational activation and clustering of β(2) integrins on PMNs by activating the small GTPase Cdc42 and inhibiting activation of the small GTPase Rap1. Intravital microscopy in vivo in Gdf15-deficient mice showed that Gdf-15 is required to prevent excessive chemokine-activated leukocyte arrest on the endothelium. Genetic ablation of β(2) integrins in myeloid cells rescued the mortality of Gdf15-deficient mice after myocardial infarction. To our knowledge, GDF-15 is the first cytokine identified as an inhibitor of PMN recruitment by direct interference with chemokine signaling and integrin activation. Loss of this anti-inflammatory mechanism leads to fatal cardiac rupture after myocardial infarction.", + "TAG_DATA": [ + "50, Gdf15-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "51, mice {'context': 'B-organism'}", + "77, PMN {'context': 'B-cells'}", + "82, In {'context': 'B-in vitro'}", + "83, vitro, {'context': 'I-in vitro'}", + "85, inhibited {'effect': 'B-negative'}", + "86, PMN {'context': 'B-cells'}", + "87, adhesion, {'phenotype': 'B-adhesion'}", + "123, in {'context': 'B-in vivo'}", + "124, vivo {'context': 'I-in vivo'}", + "126, Gdf15-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "127, mice {'context': 'B-organism'}", + "137, leukocyte {'context': 'B-cells'}", + "142, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "143, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "144, of {'perturbing_action': 'I-gene loss-of-function'}", + "145, β(2) {'perturbing_action': 'I-gene loss-of-function'}", + "146, integrins {'perturbing_action': 'I-gene loss-of-function'}", + "148, myeloid {'context': 'B-cells'}", + "149, cells {'context': 'I-cells'}", + "154, Gdf15-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "155, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, Gdf15-deficient ['l0', 'l1']", + "51, mice ['l0', 'l2']", + "77, PMN ['l1', 'l2']", + "82, In ['l3', 'l4', 'l5', 'l6']", + "83, vitro, ['l3', 'l7', 'l8', 'l9']", + "85, inhibited ['l4', 'l7', 'l10', 'l11', 'l12']", + "86, PMN ['l5', 'l8', 'l10', 'l13']", + "87, adhesion, ['l6', 'l9', 'l11', 'l13']", + "123, in ['l14', 'l15', 'l16', 'l17']", + "124, vivo ['l14', 'l18', 'l19', 'l20']", + "126, Gdf15-deficient ['l15', 'l18', 'l21', 'l22', 'l23']", + "127, mice ['l16', 'l19', 'l21', 'l24']", + "137, leukocyte ['l12', 'l17', 'l20', 'l22', 'l24']", + "142, Genetic ['l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "143, ablation ['l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "144, of ['l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "145, β(2) ['l27', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "146, integrins ['l28', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "148, myeloid ['l29', 'l36', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57']", + "149, cells ['l23', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l58', 'l59']", + "154, Gdf15-deficient ['l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58', 'l60']", + "155, mice ['l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gdf15-deficient", + "Genetic", + "ablation", + "of", + "β(2)", + "integrins" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gdf15-deficient", + "Genetic", + "ablation", + "of", + "β(2)", + "integrins" + ] + }, + "context": { + "val": "cells", + "words": [ + "PMN", + "leukocyte", + "cells", + "myeloid" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "PMN", + "leukocyte" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "PMN" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gdf15-deficient" + ] + } + } + ] + }, + { + "PMID": "21499269", + "TEXT": "Chronic inflammation characterized by T cell and macrophage infiltration of visceral adipose tissue (VAT) is a hallmark of obesity-associated insulin resistance and glucose intolerance. Here we show a fundamental pathogenic role for B cells in the development of these metabolic abnormalities. B cells accumulate in VAT in diet-induced obese (DIO) mice, and DIO mice lacking B cells are protected from disease despite weight gain. B cell effects on glucose metabolism are mechanistically linked to the activation of proinflammatory macrophages and T cells and to the production of pathogenic IgG antibodies. Treatment with a B cell-depleting CD20 antibody attenuates disease, whereas transfer of IgG from DIO mice rapidly induces insulin resistance and glucose intolerance. Moreover, insulin resistance in obese humans is associated with a unique profile of IgG autoantibodies. These results establish the importance of B cells and adaptive immunity in insulin resistance and suggest new diagnostic and therapeutic modalities for managing the disease.", + "TAG_DATA": [ + "50, mice, {'context': 'B-organism'}", + "53, mice {'context': 'I-organism'}", + "54, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "55, B {'context': 'B-cells'}", + "56, cells {'context': 'I-cells'}", + "93, B {'perturbing_action': 'B-gene loss-of-function'}", + "94, cell-depleting {'perturbing_action': 'I-gene loss-of-function'}", + "95, CD20 {'perturbing_action': 'I-gene loss-of-function'}", + "96, antibody {'perturbing_action': 'I-gene loss-of-function'}", + "105, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "53, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "54, lacking ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "55, B ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "56, cells ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "93, B ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "94, cell-depleting ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "95, CD20 ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "96, antibody ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "B", + "cell-depleting", + "CD20", + "antibody" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "B", + "cell-depleting", + "CD20", + "antibody" + ] + }, + "context": { + "val": "cells", + "words": [ + "B", + "cells" + ] + } + } + ] + }, + { + "PMID": "21475222", + "TEXT": "On 13 June, donors to the GAVI Alliance will gather in London to affirm their commitment to fund immunizations in the developing world. At the meeting, participants will address the estimated $3.7 billion financing gap needed over the next four years to scale up childhood vaccination efforts to meet the demand forecasts for those countries that receive assistance from the Geneva-based organization. But attendees of the pledging conference will also be discussing something not on the formal agenda: the announcement last month that Seth Berkley, who founded and heads the International AIDS Vaccine Initiative (IAVI), will take over the helm of the alliance in August. Berkley will lead a unique chapter in GAVI's development as the organization narrows in on the looming deadline set by Millennium Development Goal 4, which aims to reduce child mortality by two thirds by 2015. Yet, in a sense, these efforts will be a continuation of the work Berkley has fostered at IAVI since he formally launched the New York-based nonprofit in 1996. Berkley, an epidemiologist who previously held jobs with the Rockefeller Foundation, the Carter Center and the US Centers for Disease Control and Prevention, has witnessed ups and downs in the vaccination field, from the disappointing STEP trial in 2007 to the more recent good news from the 2009 Thai study, which reported as much as 31% protection against HIV. Roxanne Khamsi spoke with Berkley about what he has learned in his quest for a preventative shot against AIDS.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21460849", + "TEXT": "Heterotopic ossification consists of ectopic bone formation within soft tissues after surgery or trauma. It can have debilitating consequences, but there is no definitive cure. Here we show that heterotopic ossification was essentially prevented in mice receiving a nuclear retinoic acid receptor-γ (RAR-γ) agonist. Side effects were minimal, and there was no significant rebound effect. To uncover the mechanisms of these responses, we treated mouse mesenchymal stem cells with an RAR-γ agonist and transplanted them into nude mice. Whereas control cells formed ectopic bone masses, cells that had been pretreated with the RAR-γ agonist did not, suggesting that they had lost their skeletogenic potential. The cells became unresponsive to rBMP-2 treatment in vitro and showed decreases in phosphorylation of Smad1, Smad5 and Smad8 and in overall levels of Smad proteins. In addition, an RAR-γ agonist blocked heterotopic ossification in transgenic mice expressing activin receptor-like kinase-2 (ALK2) Q207D, a constitutively active form of the receptor that is related to ALK2 R206H found in individuals with fibrodysplasia ossificans progressiva. The data indicate that RAR-γ agonists are potent inhibitors of heterotopic ossification in mouse models and, thus, may also be effective against injury-induced and congenital heterotopic ossification in humans.", + "TAG_DATA": [ + "35, mice {'context': 'B-organism'}", + "64, mouse {'context': 'B-cells'}", + "65, mesenchymal {'context': 'I-cells'}", + "66, stem {'context': 'I-cells'}", + "67, cells {'context': 'I-cells'}", + "71, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "76, nude {'context': 'B-organism'}", + "77, mice. {'context': 'I-organism'}", + "80, cells {'context': 'B-cells'}", + "85, cells {'context': 'B-cells'}", + "105, cells {'context': 'B-cells'}", + "111, in {'context': 'B-in vitro'}", + "112, vitro {'context': 'I-in vitro'}", + "133, RAR-γ {'perturbing_action': 'B-pharmacological augmentation'}", + "134, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "139, transgenic {'context': 'B-organism'}", + "140, mice {'context': 'I-organism'}", + "141, expressing {'perturbing_action': 'B-other'}", + "142, activin {'perturbing_action': 'I-other'}", + "143, receptor-like {'perturbing_action': 'I-other'}", + "144, kinase-2 {'perturbing_action': 'I-other'}", + "145, (ALK2) {'perturbing_action': 'I-other'}", + "146, Q207D, {'perturbing_action': 'I-other'}", + "147, a {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "35, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "64, mouse ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "65, mesenchymal ['l1', 'l8', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "66, stem ['l2', 'l9', 'l16', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "67, cells ['l3', 'l10', 'l17', 'l23', 'l29', 'l30', 'l31', 'l32', 'l33']", + "70, RAR-γ ['l4', 'l11', 'l18', 'l24', 'l29', 'l34', 'l35', 'l36', 'l37']", + "71, agonist ['l5', 'l12', 'l19', 'l25', 'l30', 'l34', 'l38', 'l39', 'l40']", + "76, nude ['l6', 'l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l41']", + "77, mice. ['l7', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l41']", + "80, cells ['l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42']", + "85, cells ['l42', 'l43', 'l44']", + "105, cells ['l43', 'l45', 'l46']", + "111, in ['l45', 'l47']", + "112, vitro ['l44', 'l46', 'l47']", + "133, RAR-γ ['l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "134, agonist ['l48', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "139, transgenic ['l49', 'l58', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "140, mice ['l50', 'l59', 'l67', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "141, expressing ['l51', 'l60', 'l68', 'l75', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "142, activin ['l52', 'l61', 'l69', 'l76', 'l82', 'l88', 'l89', 'l90', 'l91', 'l92']", + "143, receptor-like ['l53', 'l62', 'l70', 'l77', 'l83', 'l88', 'l93', 'l94', 'l95', 'l96']", + "144, kinase-2 ['l54', 'l63', 'l71', 'l78', 'l84', 'l89', 'l93', 'l97', 'l98', 'l99']", + "145, (ALK2) ['l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l94', 'l97', 'l100', 'l101']", + "146, Q207D, ['l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l98', 'l100', 'l102']", + "147, a ['l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l101', 'l102']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "nude", + "mice.", + "transgenic" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "agonist", + "RAR-γ" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "mesenchymal", + "stem", + "cells" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "agonist" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "activin", + "receptor-like", + "kinase-2", + "(ALK2)", + "Q207D,", + "a" + ] + } + } + ] + }, + { + "PMID": "21460848", + "TEXT": "Pancreatic ductal adenocarcinoma (PDA) is a lethal disease. Overall survival is typically 6 months from diagnosis. Numerous phase 3 trials of agents effective in other malignancies have failed to benefit unselected PDA populations, although patients do occasionally respond. Studies in other solid tumors have shown that heterogeneity in response is determined, in part, by molecular differences between tumors. Furthermore, treatment outcomes are improved by targeting drugs to tumor subtypes in which they are selectively effective, with breast and lung cancers providing recent examples. Identification of PDA molecular subtypes has been frustrated by a paucity of tumor specimens available for study. We have overcome this problem by combined analysis of transcriptional profiles of primary PDA samples from several studies, along with human and mouse PDA cell lines. We define three PDA subtypes: classical, quasimesenchymal and exocrine-like, and we present evidence for clinical outcome and therapeutic response differences between them. We further define gene signatures for these subtypes that may have utility in stratifying patients for treatment and present preclinical model systems that may be used to identify new subtype specific therapies.", + "TAG_DATA": [ + "113, PDA {'context': 'I-transformed cells'}", + "120, human {'context': 'B-transformed cells'}", + "121, and {'context': 'I-transformed cells'}", + "122, mouse {'context': 'I-transformed cells'}", + "123, PDA {'context': 'I-transformed cells'}", + "124, cell {'context': 'I-transformed cells'}", + "125, lines. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "113, PDA ['l0']", + "120, human ['l1', 'l2', 'l3', 'l4', 'l5']", + "121, and ['l1', 'l6', 'l7', 'l8', 'l9']", + "122, mouse ['l2', 'l6', 'l10', 'l11', 'l12']", + "123, PDA ['l3', 'l7', 'l10', 'l13', 'l14']", + "124, cell ['l4', 'l8', 'l11', 'l13', 'l15']", + "125, lines. ['l0', 'l5', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21423183", + "TEXT": "Emerging technologies allow the high-throughput profiling of metabolic status from a blood specimen (metabolomics). We investigated whether metabolite profiles could predict the development of diabetes. Among 2,422 normoglycemic individuals followed for 12 years, 201 developed diabetes. Amino acids, amines and other polar metabolites were profiled in baseline specimens by liquid chromatography-tandem mass spectrometry (LC-MS). Cases and controls were matched for age, body mass index and fasting glucose. Five branched-chain and aromatic amino acids had highly significant associations with future diabetes: isoleucine, leucine, valine, tyrosine and phenylalanine. A combination of three amino acids predicted future diabetes (with a more than fivefold higher risk for individuals in top quartile). The results were replicated in an independent, prospective cohort. These findings underscore the potential key role of amino acid metabolism early in the pathogenesis of diabetes and suggest that amino acid profiles could aid in diabetes risk assessment.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21399646", + "TEXT": "As an approved vaccine adjuvant for use in humans, alum has vast health implications, but, as it is a crystal, questions remain regarding its mechanism. Furthermore, little is known about the target cells, receptors, and signaling pathways engaged by alum. Here we report that, independent of inflammasome and membrane proteins, alum binds dendritic cell (DC) plasma membrane lipids with substantial force. Subsequent lipid sorting activates an abortive phagocytic response that leads to antigen uptake. Such activated DCs, without further association with alum, show high affinity and stable binding with CD4(+) T cells via the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1). We propose that alum triggers DC responses by altering membrane lipid structures. This study therefore suggests an unexpected mechanism for how this crystalline structure interacts with the immune system and how the DC plasma membrane may behave as a general sensor for solid structures.", + "TAG_DATA": [ + "52, dendritic {'context': 'B-cells'}", + "53, cell {'context': 'I-cells'}", + "54, (DC) {'context': 'I-cells'}", + "76, DCs, {'context': 'B-cells'}", + "89, CD4(+) {'context': 'B-cells'}", + "90, T {'context': 'I-cells'}", + "91, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "52, dendritic ['l0', 'l1', 'l2']", + "53, cell ['l0', 'l3', 'l4']", + "54, (DC) ['l1', 'l3', 'l5']", + "76, DCs, ['l2', 'l4', 'l5', 'l6', 'l7', 'l8']", + "89, CD4(+) ['l6', 'l9', 'l10']", + "90, T ['l7', 'l9', 'l11']", + "91, cells ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21386834", + "TEXT": "The gradual shift from cytotoxic drugs to highly selective, targeted therapeutic agents for cancer requires a parallel effort to characterize cancers at the molecular level to guide the choice of therapy for the individual patient. Here we review the genomic technologies that can be used to develop these drug response indicators, or biomarkers. We also discuss hurdles in their development and the implementation of biomarkers in clinical practice.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21383744", + "TEXT": "Recent advances in genome technologies and the ensuing outpouring of genomic information related to cancer have accelerated the convergence of discovery science and clinical medicine. Successful examples of translating cancer genomics into therapeutics and diagnostics reinforce its potential to make possible personalized cancer medicine. However, the bottlenecks along the path of converting a genome discovery into a tangible clinical endpoint are numerous and formidable. In this Perspective, we emphasize the importance of establishing the biological relevance of a cancer genomic discovery in realizing its clinical potential and discuss some of the major obstacles to moving from the bench to the bedside.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21383740", + "TEXT": "Neuroblastoma is a fatal childhood cancer, but lack of knowledge about the underlying causative genes has hampered the development of effective therapies. The identification of anaplastic lymphoma kinase (ALK) mutations as drivers of neuroblastoma has indicated that targeted therapy with ALK inhibitors might be a valuable strategy in the fight against this lethal cancer.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21336283", + "TEXT": "Atherosclerosis and its consequences remain the main cause of mortality in industrialized and developing nations. Plaque burden and progression have been shown to be independent predictors for future cardiac events by intravascular ultrasound. Routine prospective imaging is hampered by the invasive nature of intravascular ultrasound. A noninvasive technique would therefore be more suitable for screening of atherosclerosis in large populations. Here we introduce an elastin-specific magnetic resonance contrast agent (ESMA) for noninvasive quantification of plaque burden in a mouse model of atherosclerosis. The strong signal provided by ESMA allows for imaging with high spatial resolution, resulting in accurate assessment of plaque burden. Additionally, plaque characterization by quantifying intraplaque elastin content using signal intensity measurements is possible. Changes in elastin content and the high abundance of elastin during plaque development, in combination with the imaging properties of ESMA, provide potential for noninvasive assessment of plaque burden by molecular magnetic resonance imaging (MRI).", + "TAG_DATA": [ + "78, mouse {'context': 'B-organism'}", + "79, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "78, mouse ['l0']", + "79, model ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21297610", + "TEXT": "Cystic fibrosis can manifest in many organs, but infection and inflammation of the airways cause the most severe morbidity and mortality. Early studies suggested that increased epithelial Na+ reabsorption may be a key initiating event in cystic fibrosis lung disease. However, the importance of Na+ hyperabsorption and the consequent depletion of pericellular airway liquid in cystic fibrosis lung disease has been called into question by a recent study by Jeng-Haur Chen et al.. Newborn pigs lacking cystic fibrosis transmembrane conductance regulator (CFTR−/− pigs) developed lung pathology reminiscent of human cystic fibrosis. Although epithelia from these pigs had reduced Cl− and HCO3− transport, there were no alterations in Na+ or liquid absorption, suggesting that defective anion transport is responsible for cystic fibrosis lung disease. Here three experts comment on how these findings might affect our understanding of cystic fibrosis lung pathogenesis and strategies for cystic fibrosis therapy.", + "TAG_DATA": [ + "73, Newborn {'context': 'B-organism'}", + "74, pigs {'context': 'I-organism'}", + "75, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "76, cystic {'perturbing_action': 'I-gene loss-of-function'}", + "77, fibrosis {'perturbing_action': 'I-gene loss-of-function'}", + "78, transmembrane {'perturbing_action': 'I-gene loss-of-function'}", + "79, conductance {'perturbing_action': 'I-gene loss-of-function'}", + "80, regulator {'perturbing_action': 'I-gene loss-of-function'}", + "81, (CFTR−/− {'perturbing_action': 'I-gene loss-of-function'}", + "82, pigs) {'perturbing_action': 'I-gene loss-of-function'}", + "95, pigs {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, Newborn ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "74, pigs ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "75, lacking ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "76, cystic ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "77, fibrosis ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "78, transmembrane ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "79, conductance ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "80, regulator ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "81, (CFTR−/− ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "82, pigs) ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60']", + "92, epithelia ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63']", + "95, pigs ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l63']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Newborn", + "pigs" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "cystic", + "fibrosis", + "transmembrane", + "conductance", + "regulator", + "(CFTR−/−", + "pigs)" + ] + } + } + ] + }, + { + "PMID": "21240262", + "TEXT": "Cancer stem cells (CSCs), or tumor-initiating cells, are involved in tumor progression and metastasis. MicroRNAs (miRNAs) regulate both normal stem cells and CSCs, and dysregulation of miRNAs has been implicated in tumorigenesis. CSCs in many tumors--including cancers of the breast, pancreas, head and neck, colon, small intestine, liver, stomach, bladder and ovary--have been identified using the adhesion molecule CD44, either individually or in combination with other marker(s). Prostate CSCs with enhanced clonogenic and tumor-initiating and metastatic capacities are enriched in the CD44(+) cell population, but whether miRNAs regulate CD44(+) prostate cancer cells and prostate cancer metastasis remains unclear. Here we show, through expression analysis, that miR-34a, a p53 target, was underexpressed in CD44(+) prostate cancer cells purified from xenograft and primary tumors. Enforced expression of miR-34a in bulk or purified CD44(+) prostate cancer cells inhibited clonogenic expansion, tumor regeneration, and metastasis. In contrast, expression of miR-34a antagomirs in CD44(-) prostate cancer cells promoted tumor development and metastasis. Systemically delivered miR-34a inhibited prostate cancer metastasis and extended survival of tumor-bearing mice. We identified and validated CD44 as a direct and functional target of miR-34a and found that CD44 knockdown phenocopied miR-34a overexpression in inhibiting prostate cancer regeneration and metastasis. Our study shows that miR-34a is a key negative regulator of CD44(+) prostate cancer cells and establishes a strong rationale for developing miR-34a as a novel therapeutic agent against prostate CSCs.", + "TAG_DATA": [ + "112, CD44(+) {'context': 'B-transformed cells'}", + "122, Enforced {'perturbing_action': 'B-gene gain-of-function'}", + "123, expression {'perturbing_action': 'I-gene gain-of-function'}", + "124, of {'perturbing_action': 'I-gene gain-of-function'}", + "125, miR-34a {'perturbing_action': 'I-gene gain-of-function'}", + "130, CD44(+) {'context': 'B-transformed cells'}", + "131, prostate {'context': 'I-transformed cells'}", + "132, cancer {'context': 'I-transformed cells'}", + "133, cells {'context': 'I-transformed cells'}", + "134, inhibited {'effect': 'B-negative'}", + "135, clonogenic {'phenotype': 'B-colony formation'}", + "136, expansion, {'phenotype': 'I-colony formation'}", + "137, tumor {'phenotype': 'B-tumour progression'}", + "138, regeneration, {'phenotype': 'I-tumour progression'}", + "140, metastasis. {'phenotype': 'B-metastasis'}", + "143, expression {'perturbing_action': 'B-rnai/knockdown'}", + "144, of {'perturbing_action': 'I-rnai/knockdown'}", + "145, miR-34a {'perturbing_action': 'I-rnai/knockdown'}", + "146, antagomirs {'perturbing_action': 'I-rnai/knockdown'}", + "148, CD44(-) {'context': 'B-transformed cells'}", + "149, prostate {'context': 'I-transformed cells'}", + "150, cancer {'context': 'I-transformed cells'}", + "151, cells {'context': 'I-transformed cells'}", + "152, promoted {'effect': 'B-positive'}", + "153, tumor {'phenotype': 'B-tumourigenesis'}", + "154, development {'phenotype': 'I-tumourigenesis'}", + "156, metastasis. {'phenotype': 'B-metastasis'}", + "157, Systemically {'perturbing_action': 'B-gene gain-of-function'}", + "158, delivered {'perturbing_action': 'I-gene gain-of-function'}", + "159, miR-34a {'perturbing_action': 'I-gene gain-of-function'}", + "160, inhibited {'effect': 'B-negative'}", + "161, prostate {'context': 'B-neoplasm'}", + "162, cancer {'context': 'I-neoplasm'}", + "163, metastasis {'phenotype': 'B-metastasis'}", + "168, tumor-bearing {'context': 'B-organism'}", + "169, mice. {'context': 'I-organism'}", + "186, CD44 {'perturbing_action': 'B-rnai/knockdown'}", + "187, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "189, miR-34a {'perturbing_action': 'B-gene gain-of-function'}", + "190, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "192, inhibiting {'effect': 'B-negative'}", + "193, prostate {'context': 'B-neoplasm'}", + "194, cancer {'context': 'I-neoplasm'}", + "197, metastasis. {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "112, CD44(+) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "113, prostate ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "114, cancer ['l1', 'l15', 'l26', 'l27', 'l28', 'l29']", + "122, Enforced ['l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "123, expression ['l2', 'l30', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "124, of ['l3', 'l16', 'l31', 'l48', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "125, miR-34a ['l4', 'l17', 'l32', 'l49', 'l63', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "130, CD44(+) ['l5', 'l18', 'l33', 'l50', 'l64', 'l77', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "131, prostate ['l6', 'l19', 'l26', 'l34', 'l51', 'l65', 'l78', 'l89', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "132, cancer ['l7', 'l20', 'l27', 'l35', 'l52', 'l66', 'l79', 'l90', 'l100', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "133, cells ['l8', 'l21', 'l28', 'l36', 'l53', 'l67', 'l80', 'l91', 'l101', 'l108', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "134, inhibited ['l9', 'l22', 'l37', 'l54', 'l68', 'l81', 'l92', 'l102', 'l109', 'l115', 'l121', 'l122', 'l123', 'l124', 'l125']", + "135, clonogenic ['l10', 'l23', 'l38', 'l55', 'l69', 'l82', 'l93', 'l103', 'l110', 'l116', 'l121', 'l126', 'l127', 'l128', 'l129']", + "136, expansion, ['l11', 'l24', 'l29', 'l39', 'l56', 'l70', 'l83', 'l94', 'l104', 'l111', 'l117', 'l122', 'l126', 'l130', 'l131', 'l132']", + "137, tumor ['l12', 'l40', 'l57', 'l71', 'l84', 'l95', 'l105', 'l112', 'l118', 'l123', 'l127', 'l130', 'l133', 'l134']", + "138, regeneration, ['l13', 'l25', 'l41', 'l58', 'l72', 'l85', 'l96', 'l106', 'l113', 'l119', 'l124', 'l128', 'l131', 'l133', 'l135']", + "140, metastasis. ['l14', 'l42', 'l59', 'l73', 'l86', 'l97', 'l107', 'l114', 'l120', 'l125', 'l129', 'l132', 'l134', 'l135']", + "143, expression ['l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146']", + "144, of ['l136', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "145, miR-34a ['l137', 'l147', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166']", + "146, antagomirs ['l138', 'l148', 'l158', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175']", + "148, CD44(-) ['l139', 'l149', 'l159', 'l167', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "149, prostate ['l140', 'l150', 'l160', 'l168', 'l176', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "150, cancer ['l43', 'l60', 'l74', 'l141', 'l151', 'l161', 'l169', 'l177', 'l183', 'l189', 'l190', 'l191', 'l192', 'l193']", + "151, cells ['l44', 'l61', 'l75', 'l87', 'l98', 'l142', 'l152', 'l162', 'l170', 'l178', 'l184', 'l189', 'l194', 'l195', 'l196', 'l197']", + "152, promoted ['l45', 'l143', 'l153', 'l163', 'l171', 'l179', 'l185', 'l190', 'l194', 'l198', 'l199', 'l200']", + "153, tumor ['l46', 'l144', 'l154', 'l164', 'l172', 'l180', 'l186', 'l191', 'l195', 'l198', 'l201', 'l202']", + "154, development ['l47', 'l62', 'l76', 'l88', 'l99', 'l145', 'l155', 'l165', 'l173', 'l181', 'l187', 'l192', 'l196', 'l199', 'l201', 'l203']", + "156, metastasis. ['l146', 'l156', 'l166', 'l174', 'l182', 'l188', 'l193', 'l197', 'l200', 'l202', 'l203']", + "157, Systemically ['l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219']", + "158, delivered ['l204', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234']", + "159, miR-34a ['l205', 'l220', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248']", + "160, inhibited ['l206', 'l221', 'l235', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257']", + "161, prostate ['l207', 'l222', 'l236', 'l249', 'l258', 'l259', 'l260', 'l261', 'l262']", + "162, cancer ['l157', 'l175', 'l208', 'l223', 'l237', 'l250', 'l258', 'l263', 'l264', 'l265']", + "163, metastasis ['l209', 'l224', 'l238', 'l251', 'l259', 'l263', 'l266', 'l267']", + "168, tumor-bearing ['l210', 'l225', 'l239', 'l252', 'l260', 'l264', 'l266', 'l268', 'l269', 'l270', 'l271', 'l272']", + "169, mice. ['l211', 'l226', 'l240', 'l253', 'l261', 'l265', 'l267', 'l268', 'l273', 'l274', 'l275', 'l276']", + "186, CD44 ['l212', 'l227', 'l241', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283']", + "187, knockdown ['l213', 'l228', 'l242', 'l277', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289']", + "189, miR-34a ['l214', 'l229', 'l243', 'l278', 'l284', 'l290', 'l291', 'l292', 'l293', 'l294']", + "190, overexpression ['l215', 'l230', 'l244', 'l279', 'l285', 'l290', 'l295', 'l296', 'l297', 'l298']", + "192, inhibiting ['l216', 'l231', 'l245', 'l254', 'l269', 'l273', 'l280', 'l286', 'l291', 'l295', 'l299', 'l300', 'l301']", + "193, prostate ['l217', 'l232', 'l246', 'l255', 'l270', 'l274', 'l281', 'l287', 'l292', 'l296', 'l299', 'l302', 'l303']", + "194, cancer ['l218', 'l233', 'l247', 'l256', 'l262', 'l271', 'l275', 'l282', 'l288', 'l293', 'l297', 'l300', 'l302', 'l304']", + "197, metastasis. ['l219', 'l234', 'l248', 'l257', 'l272', 'l276', 'l283', 'l289', 'l294', 'l298', 'l301', 'l303', 'l304']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "CD44(+)", + "prostate", + "cancer", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "miR-34a", + "Enforced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CD44(+)", + "prostate", + "cancer", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CD44(+)", + "prostate", + "cancer", + "cells" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenic", + "expansion," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CD44(+)", + "prostate", + "cancer", + "cells" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "regeneration," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CD44(+)", + "prostate", + "cancer", + "cells", + "CD44(-)" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced", + "expression", + "of", + "miR-34a", + "Systemically", + "delivered", + "overexpression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "inhibiting" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced", + "expression", + "of", + "miR-34a" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenic", + "expansion," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced", + "expression", + "of", + "miR-34a" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "regeneration," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced", + "expression", + "of", + "miR-34a", + "Systemically", + "delivered", + "overexpression" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis.", + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced", + "expression", + "of", + "miR-34a" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CD44(+)", + "CD44(-)", + "prostate", + "cancer", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development", + "tumor" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenic", + "expansion," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "regeneration," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "inhibiting" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis.", + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "miR-34a", + "antagomirs" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "CD44(-)", + "prostate", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "miR-34a", + "antagomirs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "miR-34a", + "antagomirs" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "miR-34a", + "antagomirs", + "CD44", + "knockdown" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "antagomirs", + "CD44", + "knockdown" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "cancer", + "prostate" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CD44(-)", + "prostate", + "cancer", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Systemically", + "delivered", + "miR-34a", + "overexpression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "prostate", + "cancer" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Systemically", + "delivered", + "miR-34a" + ] + }, + "context": { + "val": "organism", + "words": [ + "tumor-bearing", + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "inhibiting" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "prostate", + "cancer" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "inhibiting" + ] + }, + "context": { + "val": "organism", + "words": [ + "tumor-bearing", + "mice." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "prostate", + "cancer" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "metastasis." + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "metastasis." + ] + }, + "context": { + "val": "organism", + "words": [ + "tumor-bearing", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "CD44", + "knockdown" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibiting" + ] + } + } + ] + }, + { + "PMID": "21217695", + "TEXT": "The emergence of chronic inflammation during obesity in the absence of overt infection or well-defined autoimmune processes is a puzzling phenomenon. The Nod-like receptor (NLR) family of innate immune cell sensors, such as the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (Nlrp3, but also known as Nalp3 or cryopyrin) inflammasome are implicated in recognizing certain nonmicrobial originated 'danger signals' leading to caspase-1 activation and subsequent interleukin-1β (IL-1β) and IL-18 secretion. We show that calorie restriction and exercise-mediated weight loss in obese individuals with type 2 diabetes is associated with a reduction in adipose tissue expression of Nlrp3 as well as with decreased inflammation and improved insulin sensitivity. We further found that the Nlrp3 inflammasome senses lipotoxicity-associated increases in intracellular ceramide to induce caspase-1 cleavage in macrophages and adipose tissue. Ablation of Nlrp3 in mice prevents obesity-induced inflammasome activation in fat depots and liver as well as enhances insulin signaling. Furthermore, elimination of Nlrp3 in obese mice reduces IL-18 and adipose tissue interferon-γ (IFN-γ) expression, increases naive T cell numbers and reduces effector T cell numbers in adipose tissue. Collectively, these data establish that the Nlrp3 inflammasome senses obesity-associated danger signals and contributes to obesity-induced inflammation and insulin resistance.", + "TAG_DATA": [ + "128, Ablation {'perturbing_action': 'B-gene loss-of-function'}", + "129, of {'perturbing_action': 'I-gene loss-of-function'}", + "130, Nlrp3 {'perturbing_action': 'I-gene loss-of-function'}", + "132, mice {'context': 'B-organism'}", + "141, liver {'context': 'B-tissue/organ'}", + "149, elimination {'perturbing_action': 'B-gene loss-of-function'}", + "150, of {'perturbing_action': 'I-gene loss-of-function'}", + "151, Nlrp3 {'perturbing_action': 'I-gene loss-of-function'}", + "153, obese {'context': 'B-organism'}", + "154, mice {'context': 'I-organism'}", + "164, naive {'context': 'B-cells'}", + "165, T {'context': 'I-cells'}", + "166, cell {'context': 'I-cells'}", + "170, effector {'context': 'B-cells'}", + "171, T {'context': 'I-cells'}", + "172, cell {'context': 'I-cells'}", + "175, adipose {'context': 'B-tissue/organ'}", + "176, tissue. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "128, Ablation ['l0', 'l1', 'l2', 'l3']", + "129, of ['l0', 'l4', 'l5', 'l6']", + "130, Nlrp3 ['l1', 'l4', 'l7', 'l8']", + "132, mice ['l2', 'l5', 'l7', 'l9']", + "141, liver ['l3', 'l6', 'l8', 'l9']", + "149, elimination ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "150, of ['l10', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "151, Nlrp3 ['l11', 'l22', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "153, obese ['l12', 'l23', 'l33', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "154, mice ['l13', 'l24', 'l34', 'l43', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "164, naive ['l14', 'l25', 'l35', 'l44', 'l52', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "165, T ['l15', 'l26', 'l36', 'l45', 'l53', 'l60', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "166, cell ['l16', 'l27', 'l37', 'l46', 'l54', 'l61', 'l67', 'l73', 'l74', 'l75', 'l76']", + "170, effector ['l17', 'l28', 'l38', 'l47', 'l55', 'l62', 'l68', 'l77', 'l78', 'l79', 'l80']", + "171, T ['l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l69', 'l73', 'l77', 'l81', 'l82', 'l83']", + "172, cell ['l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l74', 'l78', 'l81', 'l84', 'l85']", + "175, adipose ['l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l75', 'l79', 'l82', 'l84', 'l86']", + "176, tissue. ['l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l76', 'l80', 'l83', 'l85', 'l86']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "Nlrp3", + "elimination" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "obese" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "Nlrp3", + "elimination" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver", + "adipose", + "tissue." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "elimination", + "of", + "Nlrp3" + ] + }, + "context": { + "val": "cells", + "words": [ + "naive", + "T", + "cell", + "effector" + ] + } + } + ] + }, + { + "PMID": "21186369", + "TEXT": "The adipocyte-derived secretory factor adiponectin promotes insulin sensitivity, decreases inflammation and promotes cell survival. No unifying mechanism has yet explained how adiponectin can exert such a variety of beneficial systemic effects. Here, we show that adiponectin potently stimulates a ceramidase activity associated with its two receptors, AdipoR1 and AdipoR2, and enhances ceramide catabolism and formation of its antiapoptotic metabolite--sphingosine-1-phosphate (S1P)--independently of AMP-dependent kinase (AMPK). Using models of inducible apoptosis in pancreatic beta cells and cardiomyocytes, we show that transgenic overproduction of adiponectin decreases caspase-8-mediated death, whereas genetic ablation of adiponectin enhances apoptosis in vivo through a sphingolipid-mediated pathway. Ceramidase activity is impaired in cells lacking both adiponectin receptor isoforms, leading to elevated ceramide levels and enhanced susceptibility to palmitate-induced cell death. Combined, our observations suggest a unifying mechanism of action for the beneficial systemic effects exerted by adiponectin, with sphingolipid metabolism as its core upstream signaling component.", + "TAG_DATA": [ + "67, inducible {'effect': 'B-positive'}", + "68, apoptosis {'phenotype': 'B-apoptosis'}", + "70, pancreatic {'context': 'B-cells'}", + "71, beta {'context': 'I-cells'}", + "72, cells {'context': 'I-cells'}", + "74, cardiomyocytes, {'context': 'B-cells'}", + "78, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "79, overproduction {'perturbing_action': 'I-gene gain-of-function'}", + "80, of {'perturbing_action': 'I-gene gain-of-function'}", + "81, adiponectin {'perturbing_action': 'I-gene gain-of-function'}", + "86, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "87, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "88, of {'perturbing_action': 'I-gene loss-of-function'}", + "89, adiponectin {'perturbing_action': 'I-gene loss-of-function'}", + "90, enhances {'effect': 'B-positive'}", + "91, apoptosis {'phenotype': 'B-apoptosis'}", + "92, in {'context': 'B-in vivo'}", + "93, vivo {'context': 'I-in vivo'}", + "103, cells {'context': 'B-cells'}", + "104, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "105, both {'perturbing_action': 'I-gene loss-of-function'}", + "106, adiponectin {'perturbing_action': 'I-gene loss-of-function'}", + "107, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "108, isoforms, {'perturbing_action': 'I-gene loss-of-function'}", + "115, enhanced {'effect': 'B-positive'}", + "116, susceptibility {'effect': 'I-positive'}", + "118, palmitate-induced {'effect': 'B-positive'}", + "119, cell {'phenotype': 'B-cell death'}", + "120, death. {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "67, inducible ['l0', 'l1', 'l2', 'l3', 'l4']", + "68, apoptosis ['l0', 'l5', 'l6', 'l7', 'l8']", + "70, pancreatic ['l1', 'l5', 'l9', 'l10', 'l11']", + "71, beta ['l2', 'l6', 'l9', 'l12', 'l13']", + "72, cells ['l3', 'l7', 'l10', 'l12', 'l14']", + "74, cardiomyocytes, ['l4', 'l8', 'l11', 'l13', 'l14', 'l15', 'l16']", + "78, transgenic ['l17', 'l18', 'l19']", + "79, overproduction ['l17', 'l20', 'l21']", + "80, of ['l15', 'l18', 'l20', 'l22']", + "81, adiponectin ['l16', 'l19', 'l21', 'l22']", + "86, genetic ['l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "87, ablation ['l23', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "88, of ['l24', 'l39', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "89, adiponectin ['l25', 'l40', 'l55', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "90, enhances ['l26', 'l41', 'l56', 'l70', 'l79', 'l80', 'l81']", + "91, apoptosis ['l27', 'l42', 'l57', 'l71', 'l79', 'l82', 'l83']", + "92, in ['l28', 'l43', 'l58', 'l72', 'l80', 'l82', 'l84']", + "93, vivo ['l29', 'l44', 'l59', 'l73', 'l81', 'l83', 'l84']", + "103, cells ['l30', 'l45', 'l60', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "104, lacking ['l85', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "105, both ['l46', 'l61', 'l86', 'l95', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "106, adiponectin ['l31', 'l47', 'l62', 'l87', 'l96', 'l104', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "107, receptor ['l32', 'l48', 'l63', 'l88', 'l97', 'l105', 'l112', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "108, isoforms, ['l33', 'l49', 'l64', 'l89', 'l98', 'l106', 'l113', 'l119', 'l125', 'l126', 'l127', 'l128', 'l129']", + "115, enhanced ['l34', 'l50', 'l65', 'l74', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l130', 'l131', 'l132', 'l133']", + "116, susceptibility ['l35', 'l51', 'l66', 'l75', 'l91', 'l100', 'l108', 'l115', 'l121', 'l126', 'l130', 'l134', 'l135', 'l136']", + "118, palmitate-induced ['l36', 'l52', 'l67', 'l76', 'l92', 'l101', 'l109', 'l116', 'l122', 'l127', 'l131', 'l134', 'l137', 'l138']", + "119, cell ['l37', 'l53', 'l68', 'l77', 'l93', 'l102', 'l110', 'l117', 'l123', 'l128', 'l132', 'l135', 'l137', 'l139']", + "120, death. ['l38', 'l54', 'l69', 'l78', 'l94', 'l103', 'l111', 'l118', 'l124', 'l129', 'l133', 'l136', 'l138', 'l139']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "inducible", + "enhances" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducible", + "enhanced", + "susceptibility", + "palmitate-induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "pancreatic", + "beta", + "cells", + "cardiomyocytes," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "pancreatic", + "beta", + "cells", + "cardiomyocytes," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cardiomyocytes," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "adiponectin" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "adiponectin", + "lacking", + "both", + "receptor", + "isoforms," + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances", + "enhanced", + "susceptibility", + "palmitate-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "adiponectin" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "adiponectin" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "lacking", + "both", + "adiponectin", + "receptor", + "isoforms," + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "adiponectin", + "lacking", + "both", + "receptor", + "isoforms," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced", + "susceptibility", + "palmitate-induced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "21170048", + "TEXT": "It remains difficult to distinguish tumor recurrence from radiation necrosis after brain tumor therapy. Here we show that these lesions can be distinguished using the amide proton transfer (APT) magnetic resonance imaging (MRI) signals of endogenous cellular proteins and peptides as an imaging biomarker. When comparing two models of orthotopic glioma (SF188/V+ glioma and 9L gliosarcoma) with a model of radiation necrosis in rats, we could clearly differentiate viable glioma (hyperintense) from radiation necrosis (hypointense to isointense) by APT MRI. When we irradiated rats with U87MG gliomas, the APT signals in the irradiated tumors had decreased substantially by 3 d and 6 d after radiation. The amide protons that can be detected by APT provide a unique and noninvasive MRI biomarker for distinguishing viable malignancy from radiation necrosis and predicting tumor response to therapy.", + "TAG_DATA": [ + "61, necrosis {'phenotype': 'B-necrosis'}", + "63, rats, {'context': 'B-organism'}", + "83, rats {'context': 'B-organism'}", + "85, U87MG {'context': 'B-neoplasm'}", + "86, gliomas, {'context': 'I-neoplasm'}", + "93, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "50, glioma ['l0', 'l1']", + "61, necrosis ['l0', 'l2']", + "63, rats, ['l1', 'l2']", + "83, rats ['l3', 'l4', 'l5']", + "85, U87MG ['l3', 'l6', 'l7']", + "86, gliomas, ['l4', 'l6', 'l8']", + "93, tumors ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats," + ] + } + } + ] + }, + { + "PMID": "21170046", + "TEXT": "Hypoxia can act as an initial trigger to induce erythrocyte sickling and eventual end organ damage in sickle cell disease (SCD). Many factors and metabolites are altered in response to hypoxia and may contribute to the pathogenesis of the disease. Using metabolomic profiling, we found that the steady-state concentration of adenosine in the blood was elevated in a transgenic mouse model of SCD. Adenosine concentrations were similarly elevated in the blood of humans with SCD. Increased adenosine levels promoted sickling, hemolysis and damage to multiple tissues in SCD transgenic mice and promoted sickling of human erythrocytes. Using biochemical, genetic and pharmacological approaches, we showed that adenosine A(2B) receptor (A(2B)R)-mediated induction of 2,3-diphosphoglycerate, an erythrocyte-specific metabolite that decreases the oxygen binding affinity of hemoglobin, underlies the induction of erythrocyte sickling by excess adenosine both in cultured human red blood cells and in SCD transgenic mice. Thus, excessive adenosine signaling through the A(2B)R has a pathological role in SCD. These findings may provide new therapeutic possibilities for this disease.", + "TAG_DATA": [ + "87, SCD {'perturbing_action': 'B-gene gain-of-function'}", + "88, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "89, mice {'context': 'I-organism'}", + "94, human {'context': 'B-cells'}", + "95, erythrocytes. {'context': 'I-cells'}", + "135, human {'context': 'I-cells'}", + "136, red {'context': 'I-cells'}", + "137, blood {'context': 'I-cells'}", + "138, cells {'context': 'I-cells'}", + "141, SCD {'perturbing_action': 'B-gene gain-of-function'}", + "142, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "143, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "87, SCD ['l0', 'l1']", + "88, transgenic ['l0', 'l2']", + "89, mice ['l1', 'l2']", + "94, human ['l3']", + "95, erythrocytes. ['l3']", + "135, human ['l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "136, red ['l4', 'l10', 'l11', 'l12', 'l13', 'l14']", + "137, blood ['l5', 'l10', 'l15', 'l16', 'l17', 'l18']", + "138, cells ['l6', 'l11', 'l15']", + "141, SCD ['l7', 'l12', 'l16', 'l19', 'l20']", + "142, transgenic ['l8', 'l13', 'l17', 'l19', 'l21']", + "143, mice. ['l9', 'l14', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "SCD", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "red", + "blood" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "SCD", + "transgenic" + ] + } + } + ] + }, + { + "PMID": "21151137", + "TEXT": "We have identified desmoglein-2 (DSG-2) as the primary high-affinity receptor used by adenoviruses Ad3, Ad7, Ad11 and Ad14. These serotypes represent key human pathogens causing respiratory and urinary tract infections. In epithelial cells, adenovirus binding of DSG-2 triggers events reminiscent of epithelial-to-mesenchymal transition, leading to transient opening of intercellular junctions. This opening improves access to receptors, for example, CD46 and Her2/neu, that are trapped in intercellular junctions. In addition to complete virions, dodecahedral particles (PtDds), formed by excess amounts of viral capsid proteins, penton base and fiber during viral replication, can trigger DSG-2-mediated opening of intercellular junctions as shown by studies with recombinant Ad3 PtDds. Our findings shed light on adenovirus biology and pathogenesis and may have implications for cancer therapy.", + "TAG_DATA": [ + "31, epithelial {'context': 'B-cells'}", + "32, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "31, epithelial ['l0']", + "32, cells, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21113155", + "TEXT": "Localized abdominal surgery can lead to disruption of motility in the entire gastrointestinal tract (postoperative ileus). Intestinal macrophages produce mediators that paralyze myocytes, but it is unclear how the macrophages are activated, especially those in unmanipulated intestinal areas. Here we show that intestinal surgery activates intestinal CD103(+)CD11b(+) dendritic cells (DCs) to produce interleukin-12 (IL-12). This promotes interferon-γ (IFN-γ) secretion by CCR9(+) memory T helper type 1 (T(H)1) cells which activates the macrophages. IL-12 also caused some T(H)1 cells to migrate from surgically manipulated sites through the bloodstream to unmanipulated intestinal areas where they induced ileus. Preventing T cell migration with the drug FTY720 or inhibition of IL-12, T-bet (T(H)1-specific T box transcription factor) or IFN-γ prevented postoperative ileus. CCR9(+) T(H)1 memory cells were detected in the venous blood of subjects 1 h after abdominal surgery. These findings indicate that postoperative ileus is a T(H)1 immune-mediated disease and identify potential targets for disease monitoring and therapy.", + "TAG_DATA": [ + "71, macrophages. {'context': 'B-cells'}", + "76, T(H)1 {'context': 'B-cells'}", + "77, cells {'context': 'I-cells'}", + "96, T {'context': 'B-cells'}", + "97, cell {'context': 'I-cells'}", + "98, migration {'phenotype': 'B-migration'}", + "104, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "105, of {'perturbing_action': 'I-pharmacological inhibition'}", + "106, IL-12, {'perturbing_action': 'I-pharmacological inhibition'}", + "107, T-bet {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "71, macrophages. ['l0', 'l1']", + "76, T(H)1 ['l0', 'l2']", + "77, cells ['l1', 'l2']", + "96, T ['l3', 'l4']", + "97, cell ['l3', 'l5']", + "98, migration ['l4', 'l5']", + "104, inhibition ['l6', 'l7', 'l8']", + "105, of ['l6', 'l9', 'l10']", + "106, IL-12, ['l7', 'l9', 'l11']", + "107, T-bet ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + } + ] + }, + { + "PMID": "21102460", + "TEXT": "Mesenchymal stem cells can give rise to several cell types, but varying results depending on isolation methods and tissue source have led to controversies about their usefulness in clinical medicine. Here we show that vascular endothelial cells can transform into multipotent stem-like cells by an activin-like kinase-2 (ALK2) receptor-dependent mechanism. In lesions from individuals with fibrodysplasia ossificans progressiva (FOP), a disease in which heterotopic ossification occurs as a result of activating ALK2 mutations, or from transgenic mice expressing constitutively active ALK2, chondrocytes and osteoblasts expressed endothelial markers. Lineage tracing of heterotopic ossification in mice using a Tie2-Cre construct also suggested an endothelial origin of these cell types. Expression of constitutively active ALK2 in endothelial cells caused endothelial-to-mesenchymal transition and acquisition of a stem cell-like phenotype. Similar results were obtained by treatment of untransfected endothelial cells with the ligands transforming growth factor-β2 (TGF-β2) or bone morphogenetic protein-4 (BMP4) in an ALK2-dependent manner. These stem-like cells could be triggered to differentiate into osteoblasts, chondrocytes or adipocytes. We suggest that conversion of endothelial cells to stem-like cells may provide a new approach to tissue engineering.", + "TAG_DATA": [ + "75, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "76, mice {'context': 'I-organism'}", + "77, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "78, constitutively {'perturbing_action': 'I-gene gain-of-function'}", + "79, active {'perturbing_action': 'I-gene gain-of-function'}", + "80, ALK2, {'perturbing_action': 'I-gene gain-of-function'}", + "93, mice {'context': 'B-organism'}", + "107, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "108, of {'perturbing_action': 'I-gene gain-of-function'}", + "109, constitutively {'perturbing_action': 'I-gene gain-of-function'}", + "110, active {'perturbing_action': 'I-gene gain-of-function'}", + "111, ALK2 {'perturbing_action': 'I-gene gain-of-function'}", + "113, endothelial {'context': 'B-cells'}", + "114, cells {'context': 'I-cells'}", + "115, caused {'effect': 'B-positive'}", + "116, endothelial-to-mesenchymal {'phenotype': 'B-epithelial-mesenchymal transition'}", + "117, transition {'phenotype': 'I-epithelial-mesenchymal transition'}", + "133, endothelial {'context': 'B-cells'}", + "134, cells {'context': 'I-cells'}", + "152, stem-like {'context': 'B-cells'}", + "153, cells {'context': 'I-cells'}", + "156, triggered {'effect': 'B-positive'}", + "158, differentiate {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "75, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "76, mice ['l0', 'l6', 'l7', 'l8', 'l9']", + "77, expressing ['l1', 'l6', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "78, constitutively ['l2', 'l7', 'l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "79, active ['l3', 'l8', 'l11', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29']", + "80, ALK2, ['l4', 'l9', 'l12', 'l18', 'l25', 'l30', 'l31']", + "93, mice ['l5', 'l13', 'l19', 'l26', 'l30', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "96, Tie2-Cre ['l14', 'l20', 'l27', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "107, Expression ['l38', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "108, of ['l39', 'l48', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "109, constitutively ['l40', 'l49', 'l59', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "110, active ['l41', 'l50', 'l60', 'l69', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "111, ALK2 ['l42', 'l51', 'l61', 'l70', 'l78', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "113, endothelial ['l33', 'l43', 'l52', 'l62', 'l71', 'l79', 'l85', 'l91', 'l92', 'l93', 'l94']", + "114, cells ['l21', 'l34', 'l44', 'l53', 'l63', 'l72', 'l80', 'l86', 'l91', 'l95', 'l96', 'l97']", + "115, caused ['l15', 'l22', 'l28', 'l35', 'l45', 'l54', 'l64', 'l73', 'l81', 'l87', 'l92', 'l95', 'l98', 'l99']", + "116, endothelial-to-mesenchymal ['l23', 'l36', 'l46', 'l55', 'l65', 'l74', 'l82', 'l88', 'l93', 'l96', 'l98', 'l100']", + "117, transition ['l16', 'l24', 'l29', 'l31', 'l37', 'l47', 'l56', 'l66', 'l75', 'l83', 'l89', 'l94', 'l97', 'l99', 'l100']", + "133, endothelial ['l57', 'l67', 'l76', 'l101', 'l102']", + "134, cells ['l58', 'l68', 'l77', 'l84', 'l90', 'l101']", + "152, stem-like ['l103', 'l104', 'l105']", + "153, cells ['l102', 'l103', 'l106', 'l107']", + "156, triggered ['l104', 'l106', 'l108']", + "158, differentiate ['l105', 'l107', 'l108']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "constitutively", + "active", + "ALK2," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "constitutively", + "active", + "Expression", + "of", + "ALK2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "constitutively", + "active", + "ALK2,", + "Expression", + "of", + "ALK2" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "transition", + "endothelial-to-mesenchymal" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutively", + "Expression", + "of", + "active", + "ALK2" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "endothelial" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "endothelial-to-mesenchymal", + "transition" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells", + "stem-like" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused", + "triggered" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "endothelial-to-mesenchymal", + "transition" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "endothelial-to-mesenchymal", + "transition" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "stem-like", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggered" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate" + ] + } + } + ] + }, + { + "PMID": "21102458", + "TEXT": "Danger signals released upon cell damage can cause excessive immune-mediated tissue destruction such as that found in acute graft-versus-host disease (GVHD), allograft rejection and systemic inflammatory response syndrome. Given that ATP is found in small concentrations in the extracellular space under physiological conditions, and its receptor P2X(7)R is expressed on several immune cell types, ATP could function as a danger signal when released from dying cells. We observed increased ATP concentrations in the peritoneal fluid after total body irradiation, and during the development of GVHD in mice and in humans. Stimulation of antigen-presenting cells (APCs) with ATP led to increased expression of CD80 and CD86 in vitro and in vivo and actuated a cascade of proinflammatory events, including signal transducer and activator of transcription-1 (STAT1) phosphorylation, interferon-γ (IFN-γ) production and donor T cell expansion, whereas regulatory T cell numbers were reduced. P2X(7)R expression increased when GVHD evolved, rendering APCs more responsive to the detrimental effects of ATP, thereby providing positive feedback signals. ATP neutralization, early P2X(7)R blockade or genetic deficiency of P2X(7)R during GVHD development improved survival without immune paralysis. These data have major implications for transplantation medicine, as pharmacological interference with danger signals that act via P2X(7)R could lead to the development of tolerance without the need for intensive immunosuppression.", + "TAG_DATA": [ + "92, antigen-presenting {'context': 'B-cells'}", + "93, cells {'context': 'I-cells'}", + "94, (APCs) {'context': 'I-cells'}", + "105, in {'context': 'B-in vitro'}", + "106, vitro {'context': 'I-in vitro'}", + "108, in {'context': 'B-in vivo'}", + "109, vivo {'context': 'I-in vivo'}", + "130, donor {'context': 'B-cells'}", + "131, T {'context': 'I-cells'}", + "132, cell {'context': 'I-cells'}", + "135, regulatory {'context': 'B-cells'}", + "136, T {'context': 'I-cells'}", + "137, cell {'context': 'I-cells'}", + "148, APCs {'context': 'B-cells'}", + "168, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "169, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "170, of {'perturbing_action': 'I-gene loss-of-function'}", + "171, P2X(7)R {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "92, antigen-presenting ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "93, cells ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "94, (APCs) ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "105, in ['l2', 'l13', 'l23', 'l32', 'l33', 'l34']", + "106, vitro ['l3', 'l14', 'l24', 'l32', 'l35', 'l36', 'l37']", + "108, in ['l4', 'l15', 'l25', 'l38', 'l39', 'l40', 'l41', 'l42']", + "109, vivo ['l5', 'l16', 'l26', 'l33', 'l35', 'l38', 'l43', 'l44', 'l45', 'l46']", + "130, donor ['l6', 'l17', 'l27', 'l39', 'l43', 'l47', 'l48', 'l49', 'l50', 'l51']", + "131, T ['l7', 'l18', 'l28', 'l36', 'l40', 'l44', 'l47', 'l52', 'l53', 'l54', 'l55']", + "132, cell ['l8', 'l19', 'l29', 'l34', 'l37', 'l41', 'l45', 'l48', 'l52', 'l56', 'l57', 'l58']", + "135, regulatory ['l9', 'l20', 'l49', 'l53', 'l56', 'l59', 'l60']", + "136, T ['l10', 'l21', 'l30', 'l50', 'l54', 'l57', 'l59', 'l61']", + "137, cell ['l11', 'l22', 'l31', 'l42', 'l46', 'l51', 'l55', 'l58', 'l60', 'l61']", + "168, genetic ['l62', 'l63', 'l64']", + "169, deficiency ['l62', 'l65', 'l66']", + "170, of ['l63', 'l65', 'l67']", + "171, P2X(7)R ['l64', 'l66', 'l67']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21052079", + "TEXT": "Neurodegenerative diseases are the sixth leading cause of death in the US. The market for disease-modifying drugs is enormous, but no drug exists. Academic scientists are increasingly pursuing the discovery and development of therapeutics. Their progress could potentially reduce the risk of failure sufficiently to warrant greater industry investment and movement of leads into clinical trials. Here we consider the many obstacles to the development of therapeutics for neurodegenerative disease within academia, with a special focus on organizational issues.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21052075", + "TEXT": "Age-related neurodegenerative diseases are largely limited to humans and rarely occur spontaneously in animals. Genetically engineered mouse models recapitulate aspects of the corresponding human diseases and are instrumental in studying disease mechanisms and testing therapeutic strategies. If considered within the range of their validity, mouse models have been predictive of clinical outcome. Translational failure is less the result of the incomplete nature of the models than of inadequate preclinical studies and misinterpretation of the models. This commentary summarizes current models and highlights key questions we should be asking about animal models, as well as questions that cannot be answered with the current models.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21052074", + "TEXT": "Divergent disease triggers in neurodegeneration may induce convergent endogenous pathways in neuronal, glial and vascular elements as the central nervous system (CNS) attempts to compensate, remodel and recover. Dissecting these multicellular mechanisms and the integrative responses in cerebral blood flow and metabolism may allow us to understand the balance between injury and repair, validate new targets and define therapeutic time windows for neurodegeneration.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20953200", + "TEXT": "The lifetime prevalence (∼16%) and the economic burden ($100 billion annually) associated with major depressive disorder (MDD) make it one of the most common and debilitating neurobiological illnesses. To date, the exact cellular and molecular mechanisms underlying the pathophysiology of MDD have not been identified. Here we use whole-genome expression profiling of postmortem tissue and show significantly increased expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1, encoded by DUSP1, but hereafter called MKP-1) in the hippocampal subfields of subjects with MDD compared to matched controls. MKP-1, also known as dual-specificity phosphatase-1 (DUSP1), is a member of a family of proteins that dephosphorylate both threonine and tyrosine residues and thereby serves as a key negative regulator of the MAPK cascade, a major signaling pathway involved in neuronal plasticity, function and survival. We tested the role of altered MKP-1 expression in rat and mouse models of depression and found that increased hippocampal MKP-1 expression, as a result of stress or viral-mediated gene transfer, causes depressive behaviors. Conversely, chronic antidepressant treatment normalizes stress-induced MKP-1 expression and behavior, and mice lacking MKP-1 are resilient to stress. These postmortem and preclinical studies identify MKP-1 as a key factor in MDD pathophysiology and as a new target for therapeutic interventions.", + "TAG_DATA": [ + "175, mice {'context': 'B-organism'}", + "176, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "177, MKP-1 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "175, mice ['l0', 'l1']", + "176, lacking ['l0', 'l2']", + "177, MKP-1 ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "MKP-1" + ] + } + } + ] + }, + { + "PMID": "20935628", + "TEXT": "Hepatitis C virus (HCV) infection is closely tied to the lipid metabolism of liver cells. Here we identify the triglyceride-synthesizing enzyme diacylglycerol acyltransferase-1 (DGAT1) as a key host factor for HCV infection. DGAT1 interacts with the viral nucleocapsid core and is required for the trafficking of core to lipid droplets. Inhibition of DGAT1 activity or RNAi-mediated knockdown of DGAT1 severely impairs infectious virion production, implicating DGAT1 as a new target for antiviral therapy.", + "TAG_DATA": [ + "50, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "51, of {'perturbing_action': 'I-pharmacological inhibition'}", + "52, DGAT1 {'perturbing_action': 'I-pharmacological inhibition'}", + "53, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "55, RNAi-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "56, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "57, of {'perturbing_action': 'I-rnai/knockdown'}", + "58, DGAT1 {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "50, Inhibition ['l0', 'l1', 'l2', 'l3']", + "51, of ['l0', 'l4', 'l5']", + "52, DGAT1 ['l1', 'l4', 'l6']", + "53, activity ['l2', 'l5', 'l6']", + "55, RNAi-mediated ['l7', 'l8', 'l9']", + "56, knockdown ['l7', 'l10', 'l11']", + "57, of ['l8', 'l10', 'l12']", + "58, DGAT1 ['l3', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20930745", + "TEXT": "Bacterial pneumonia can be a life-threatening disease that causes lung injury. A new study shows that accumulation of a phospholipid in the lung fluid in mice and humans worsens gas exchange during the microbial infection (pages 1120–1127). Clearance of this lipid may improve lung function during infection.", + "TAG_DATA": [ + "25, mice {'context': 'B-organism'}", + "27, humans {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "25, mice ['l0']", + "27, humans ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20890292", + "TEXT": "Maternal HIV-1-specific antibodies are efficiently transferred to newborns, but their role in disease control is unknown. We administered neutralizing IgG, including the human neutralizing monoclonal IgG1b12, at levels insufficient to block infection, to six newborn macaques before oral challenge with simian-HIV strain SF162P3 (SHIV(SF162P3)). All of the macaques rapidly developed neutralizing antibodies and had significantly reduced plasma viremia for six months. These studies support the use of neutralizing antibodies in enhancing B cell responses and viral control in perinatal settings.", + "TAG_DATA": [ + "34, newborn {'context': 'B-organism'}", + "35, macaques {'context': 'I-organism'}", + "47, macaques {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "34, newborn ['l0']", + "35, macaques ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20871611", + "TEXT": "Migraine with aura is a common, debilitating, recurrent headache disorder associated with transient and reversible focal neurological symptoms. A role has been suggested for the two-pore domain (K2P) potassium channel, TWIK-related spinal cord potassium channel (TRESK, encoded by KCNK18), in pain pathways and general anaesthesia. We therefore examined whether TRESK is involved in migraine by screening the KCNK18 gene in subjects diagnosed with migraine. Here we report a frameshift mutation, F139WfsX24, which segregates perfectly with typical migraine with aura in a large pedigree. We also identified prominent TRESK expression in migraine-salient areas such as the trigeminal ganglion. Functional characterization of this mutation demonstrates that it causes a complete loss of TRESK function and that the mutant subunit suppresses wild-type channel function through a dominant-negative effect, thus explaining the dominant penetrance of this allele. These results therefore support a role for TRESK in the pathogenesis of typical migraine with aura and further support the role of this channel as a potential therapeutic target.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20871609", + "TEXT": "Inactivation of the p53 tumor suppressor pathway allows cell survival in times of stress and occurs in many human cancers; however, normal embryonic stem cells and some cancers such as neuroblastoma maintain wild-type human TP53 and mouse Trp53 (referred to collectively as p53 herein). Here we describe a miRNA, miR-380-5p, that represses p53 expression via a conserved sequence in the p53 3' untranslated region (UTR). miR-380-5p is highly expressed in mouse embryonic stem cells and neuroblastomas, and high expression correlates with poor outcome in neuroblastomas with neuroblastoma derived v-myc myelocytomatosis viral-related oncogene (MYCN) amplification. miR-380 overexpression cooperates with activated HRAS oncoprotein to transform primary cells, block oncogene-induced senescence and form tumors in mice. Conversely, inhibition of endogenous miR-380-5p in embryonic stem or neuroblastoma cells results in induction of p53, and extensive apoptotic cell death. In vivo delivery of a miR-380-5p antagonist decreases tumor size in an orthotopic mouse model of neuroblastoma. We demonstrate a new mechanism of p53 regulation in cancer and stem cells and uncover a potential therapeutic target for neuroblastoma.", + "TAG_DATA": [ + "94, miR-380 {'perturbing_action': 'B-gene gain-of-function'}", + "95, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "103, primary {'context': 'B-cells'}", + "104, cells, {'context': 'I-cells'}", + "105, block {'effect': 'B-negative'}", + "106, oncogene-induced {'effect': 'B-positive'}", + "107, senescence {'phenotype': 'B-senescence'}", + "109, form {'phenotype': 'B-tumourigenesis'}", + "110, tumors {'phenotype': 'B-tumourigenesis'}", + "112, mice. {'context': 'B-organism'}", + "114, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "115, of {'perturbing_action': 'I-pharmacological inhibition'}", + "116, endogenous {'perturbing_action': 'I-pharmacological inhibition'}", + "117, miR-380-5p {'perturbing_action': 'I-pharmacological inhibition'}", + "119, embryonic {'context': 'B-transformed cells'}", + "120, stem {'context': 'I-transformed cells'}", + "121, or {'context': 'I-transformed cells'}", + "122, neuroblastoma {'context': 'I-transformed cells'}", + "123, cells {'context': 'I-transformed cells'}", + "131, apoptotic {'phenotype': 'B-apoptosis'}", + "132, cell {'phenotype': 'I-apoptosis'}", + "133, death. {'phenotype': 'I-apoptosis'}", + "134, In {'context': 'B-in vivo'}", + "135, vivo {'context': 'I-in vivo'}", + "141, decreases {'effect': 'B-negative'}", + "142, tumor {'phenotype': 'B-tumourigenesis'}", + "143, size {'phenotype': 'I-tumourigenesis'}", + "146, orthotopic {'context': 'B-neoplasm'}", + "147, mouse {'context': 'I-neoplasm'}", + "148, model {'context': 'I-neoplasm'}", + "149, of {'context': 'I-neoplasm'}", + "150, neuroblastoma. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "94, miR-380 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "95, overexpression ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "103, primary ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "104, cells, ['l2', 'l12', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32']", + "105, block ['l3', 'l13', 'l22', 'l28', 'l33', 'l34', 'l35', 'l36', 'l37']", + "106, oncogene-induced ['l4', 'l14', 'l23', 'l33', 'l38', 'l39', 'l40', 'l41', 'l42']", + "107, senescence ['l5', 'l15', 'l24', 'l29', 'l34', 'l38', 'l43', 'l44', 'l45']", + "109, form ['l6', 'l16', 'l25', 'l30', 'l35', 'l39', 'l43', 'l46', 'l47']", + "110, tumors ['l7', 'l17', 'l26', 'l31', 'l36', 'l40', 'l44', 'l46', 'l48']", + "112, mice. ['l8', 'l18', 'l27', 'l32', 'l37', 'l41', 'l45', 'l47', 'l48']", + "114, inhibition ['l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "115, of ['l49', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "116, endogenous ['l50', 'l61', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "117, miR-380-5p ['l51', 'l62', 'l74', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "119, embryonic ['l52', 'l63', 'l75', 'l83', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "120, stem ['l9', 'l19', 'l53', 'l64', 'l76', 'l84', 'l91', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "121, or ['l54', 'l65', 'l77', 'l85', 'l92', 'l98', 'l104', 'l105', 'l106', 'l107', 'l108']", + "122, neuroblastoma ['l55', 'l66', 'l78', 'l86', 'l93', 'l99', 'l104', 'l109', 'l110', 'l111', 'l112']", + "123, cells ['l10', 'l20', 'l42', 'l56', 'l67', 'l79', 'l87', 'l94', 'l100', 'l105', 'l109', 'l113', 'l114', 'l115']", + "131, apoptotic ['l57', 'l68', 'l80', 'l88', 'l95', 'l101', 'l106', 'l110', 'l113', 'l116', 'l117']", + "132, cell ['l58', 'l69', 'l81', 'l89', 'l96', 'l102', 'l107', 'l111', 'l114', 'l116', 'l118']", + "133, death. ['l59', 'l70', 'l82', 'l90', 'l97', 'l103', 'l108', 'l112', 'l115', 'l117', 'l118']", + "134, In ['l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127']", + "135, vivo ['l119', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "141, decreases ['l120', 'l128', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "142, tumor ['l121', 'l129', 'l136', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "143, size ['l60', 'l71', 'l122', 'l130', 'l137', 'l143', 'l149', 'l150', 'l151', 'l152', 'l153']", + "146, orthotopic ['l123', 'l131', 'l138', 'l144', 'l149', 'l154', 'l155', 'l156', 'l157']", + "147, mouse ['l124', 'l132', 'l139', 'l145', 'l150', 'l154', 'l158', 'l159', 'l160']", + "148, model ['l125', 'l133', 'l140', 'l146', 'l151', 'l155', 'l158', 'l161', 'l162']", + "149, of ['l72', 'l126', 'l134', 'l141', 'l147', 'l152', 'l156', 'l159', 'l161', 'l163']", + "150, neuroblastoma. ['l73', 'l127', 'l135', 'l142', 'l148', 'l153', 'l157', 'l160', 'l162', 'l163']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "miR-380", + "overexpression" + ] + }, + "context": { + "val": "cells", + "words": [ + "primary", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "miR-380", + "overexpression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "block" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "miR-380", + "overexpression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "oncogene-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "miR-380", + "overexpression" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "miR-380", + "overexpression" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "miR-380", + "overexpression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "miR-380", + "overexpression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "stem", + "cells" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "primary", + "cells," + ] + }, + "effect": { + "val": "negative", + "words": [ + "block" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "primary" + ] + }, + "effect": { + "val": "positive", + "words": [ + "oncogene-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "primary", + "cells," + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "primary", + "cells," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumors" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "block" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "block", + "decreases" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumors", + "tumor", + "size" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "block" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "oncogene-induced" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "oncogene-induced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "oncogene-induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "oncogene-induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells" + ] + } + }, + { + "phenotype": { + "val": "senescence", + "words": [ + "senescence" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumors" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "endogenous", + "miR-380-5p" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "embryonic", + "stem", + "or", + "neuroblastoma", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "endogenous", + "miR-380-5p" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "size" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "of" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "of", + "neuroblastoma." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "embryonic", + "stem", + "or", + "neuroblastoma", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreases" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "size" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreases" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "orthotopic", + "mouse", + "model", + "of", + "neuroblastoma." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "size" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "orthotopic", + "mouse", + "model", + "of", + "neuroblastoma." + ] + } + } + ] + }, + { + "PMID": "20852622", + "TEXT": "Pneumonia remains the leading cause of death from infection in the US, yet fundamentally new conceptual models underlying its pathogenesis have not emerged. We show that humans and mice with bacterial pneumonia have markedly elevated amounts of cardiolipin, a rare, mitochondrial-specific phospholipid, in lung fluid and find that it potently disrupts surfactant function. Intratracheal cardiolipin administration in mice recapitulates the clinical phenotype of pneumonia, including impaired lung mechanics, modulation of cell survival and cytokine networks and lung consolidation. We have identified and characterized the activity of a unique cardiolipin transporter, the P-type ATPase transmembrane lipid pump Atp8b1, a mutant version of which is associated with severe pneumonia in humans and mice. Atp8b1 bound and internalized cardiolipin from extracellular fluid via a basic residue-enriched motif. Administration of a peptide encompassing the cardiolipin binding motif or Atp8b1 gene transfer in mice lessened bacteria-induced lung injury and improved survival. The results unveil a new paradigm whereby Atp8b1 is a cardiolipin importer whose capacity to remove cardiolipin from lung fluid is exceeded during inflammation or when Atp8b1 is defective. This discovery opens the door for new therapeutic strategies directed at modulating the abundance or molecular interactions of cardiolipin in pneumonia.", + "TAG_DATA": [ + "57, mice {'context': 'B-organism'}", + "134, Atp8b1 {'perturbing_action': 'B-gene gain-of-function'}", + "135, gene {'perturbing_action': 'I-gene gain-of-function'}", + "136, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "138, mice {'context': 'B-organism'}", + "141, lung {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "134, Atp8b1 ['l0', 'l1', 'l2', 'l3']", + "135, gene ['l0', 'l4', 'l5', 'l6']", + "136, transfer ['l1', 'l4', 'l7', 'l8']", + "138, mice ['l2', 'l5', 'l7', 'l9']", + "141, lung ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Atp8b1", + "gene", + "transfer" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Atp8b1", + "gene", + "transfer" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + } + ] + }, + { + "PMID": "20729866", + "TEXT": "Currently, no vaccines or therapeutics are licensed to counter Ebola or Marburg viruses, highly pathogenic filoviruses that are causative agents of viral hemorrhagic fever. Here we show that administration of positively charged phosphorodiamidate morpholino oligomers (PMOplus), delivered by various dosing strategies initiated 30-60 min after infection, protects>60% of rhesus monkeys against lethal Zaire Ebola virus (ZEBOV) and 100% of cynomolgus monkeys against Lake Victoria Marburg virus (MARV) infection. PMOplus may be useful for treating these and other highly pathogenic viruses in humans.", + "TAG_DATA": [ + "48, rhesus {'context': 'B-organism'}", + "49, monkeys {'context': 'I-organism'}", + "59, cynomolgus {'context': 'B-organism'}", + "60, monkeys {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "48, rhesus ['l0']", + "49, monkeys ['l0']", + "59, cynomolgus ['l1']", + "60, monkeys ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20711198", + "TEXT": "A major limitation of cell therapies is the rapid decline in viability and function of the transplanted cells. Here we describe a strategy to enhance cell therapy via the conjugation of adjuvant drug-loaded nanoparticles to the surfaces of therapeutic cells. With this method of providing sustained pseudoautocrine stimulation to donor cells, we elicited marked enhancements in tumor elimination in a model of adoptive T cell therapy for cancer. We also increased the in vivo repopulation rate of hematopoietic stem cell grafts with very low doses of adjuvant drugs that were ineffective when given systemically. This approach is a simple and generalizable strategy to augment cytoreagents while minimizing the systemic side effects of adjuvant drugs. In addition, these results suggest therapeutic cells are promising vectors for actively targeted drug delivery.", + "TAG_DATA": [ + "54, enhancements {'effect': 'B-positive'}", + "56, tumor {'phenotype': 'B-tumour regression'}", + "57, elimination {'phenotype': 'I-tumour regression'}", + "67, cancer. {'context': 'B-neoplasm'}", + "70, increased {'effect': 'B-positive'}", + "72, in {'context': 'B-in vivo'}", + "73, vivo {'context': 'B-in vivo'}", + "77, hematopoietic {'context': 'B-xenograft'}", + "78, stem {'context': 'I-xenograft'}", + "79, cell {'context': 'I-xenograft'}", + "80, grafts {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "54, enhancements ['l0', 'l1', 'l2']", + "56, tumor ['l0', 'l3', 'l4']", + "57, elimination ['l1', 'l3', 'l5']", + "67, cancer. ['l2', 'l4', 'l5']", + "70, increased ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "72, in ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "73, vivo ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "77, hematopoietic ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "78, stem ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "79, cell ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "80, grafts ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "enhancements" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "elimination" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhancements" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "cancer." + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "elimination" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "cancer." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "hematopoietic", + "stem", + "cell", + "grafts" + ] + } + } + ] + }, + { + "PMID": "20689547", + "TEXT": "Elevated amounts of glutamate, which acts as a neurotransmitter but is also a neurotoxin, are a hallmark of the autoimmune neurological disease multiple sclerosis and may contribute to its pathology. The discovery that a receptor for glutamate can inhibit the development of autoimmunity and protect from neuroinflammation in a mouse model of multiple sclerosis suggests that glutamate may also have a protective role and that its receptor may represent a therapeutic target (pages 897–902).", + "TAG_DATA": [ + "49, mouse {'context': 'B-organism'}", + "50, model {'context': 'I-organism'}", + "51, of {'context': 'I-organism'}", + "52, multiple {'context': 'I-organism'}", + "53, sclerosis {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "49, mouse ['l0', 'l1', 'l2', 'l3']", + "50, model ['l0', 'l4', 'l5', 'l6']", + "51, of ['l1', 'l4', 'l7', 'l8']", + "52, multiple ['l2', 'l5', 'l7', 'l9']", + "53, sclerosis ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20628374", + "TEXT": "About 2,000 patients now await a donor lung in the United States. Worldwide, 50 million individuals are living with end-stage lung disease. Creation of a bioartificial lung requires engineering of viable lung architecture enabling ventilation, perfusion and gas exchange. We decellularized lungs by detergent perfusion and yielded scaffolds with acellular vasculature, airways and alveoli. To regenerate gas exchange tissue, we seeded scaffolds with epithelial and endothelial cells. To establish function, we perfused and ventilated cell-seeded constructs in a bioreactor simulating the physiologic environment of developing lung. By day 5, constructs could be perfused with blood and ventilated using physiologic pressures, and they generated gas exchange comparable to that of isolated native lungs. To show in vivo function, we transplanted regenerated lungs into orthotopic position. After transplantation, constructs were perfused by the recipient's circulation and ventilated by means of the recipient's airway and respiratory muscles, and they provided gas exchange in vivo for up to 6 h after extubation.", + "TAG_DATA": [ + "63, epithelial {'context': 'B-cells'}", + "64, and {'context': 'I-cells'}", + "65, endothelial {'context': 'I-cells'}", + "66, cells. {'context': 'I-cells'}", + "74, cell-seeded {'context': 'B-cells'}", + "75, constructs {'context': 'B-organoid'}", + "114, in {'context': 'B-in vivo'}", + "115, vivo {'context': 'I-in vivo'}", + "119, regenerated {'context': 'B-tissue/organ'}", + "120, lungs {'context': 'B-tissue/organ'}", + "149, in {'context': 'B-in vivo'}", + "150, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "63, epithelial ['l0', 'l1', 'l2', 'l3', 'l4']", + "64, and ['l0', 'l5', 'l6', 'l7', 'l8']", + "65, endothelial ['l1', 'l5', 'l9', 'l10', 'l11']", + "66, cells. ['l2', 'l6', 'l9', 'l12', 'l13']", + "74, cell-seeded ['l3', 'l7', 'l10', 'l12', 'l14']", + "75, constructs ['l4', 'l8', 'l11', 'l13', 'l14']", + "114, in ['l15', 'l16', 'l17', 'l18']", + "115, vivo ['l15', 'l19', 'l20', 'l21']", + "119, regenerated ['l22', 'l23', 'l24']", + "120, lungs ['l16', 'l19', 'l22', 'l25', 'l26']", + "149, in ['l17', 'l20', 'l23', 'l25', 'l27']", + "150, vivo ['l18', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20613753", + "TEXT": "A popular—and controversial—theory is that tumors are initiated and maintained by a fixed population of stem cell–like tumor cells. Research on human cells and mice adds a twist to this theory, suggesting that such stem cell–like cells might be more plastic than previously thought. Alexander Roesch et al. find that a group of cells, which divide slowly, can sustain melanoma growth and self-renew—hallmarks of cancer stem cells. However, the cells can switch phenotype through epigenetic changes mediated by JARID1B, a histone modifier, suggesting a plastic process. They found that human cells expressing JAR1D1B could initiate and sustain melanoma growth when implanted into mice, whereas JARD1B-negative cells could only initiate tumors. JARD1B-negative cells, however, could switch on JARD1B to support tumor growth. Might cancer stem cells be ‘moving’ targets? What, then, are the therapeutic implications?", + "TAG_DATA": [ + "89, human {'context': 'B-cells'}", + "90, cells {'context': 'I-cells'}", + "91, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "92, JAR1D1B {'perturbing_action': 'I-gene gain-of-function'}", + "94, initiate {'effect': 'B-positive'}", + "97, melanoma {'context': 'B-neoplasm'}", + "102, mice, {'context': 'B-organism'}", + "104, JARD1B-negative {'perturbing_action': 'B-gene loss-of-function', 'context': 'B-cells'}", + "105, cells {'context': 'I-cells'}", + "108, initiate {'effect': 'B-positive'}", + "109, tumors. {'phenotype': 'B-tumourigenesis'}", + "110, JARD1B-negative {'context': 'B-cells'}", + "111, cells, {'context': 'I-cells'}", + "118, support {'effect': 'B-positive'}", + "119, tumor {'phenotype': 'B-tumour growth'}", + "120, growth. {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "89, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "90, cells ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "91, expressing ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "92, JAR1D1B ['l2', 'l7', 'l11', 'l15', 'l16', 'l17', 'l18']", + "94, initiate ['l3', 'l8', 'l12', 'l15', 'l19', 'l20']", + "97, melanoma ['l4', 'l9', 'l13', 'l16', 'l19', 'l21']", + "102, mice, ['l5', 'l10', 'l14', 'l17', 'l20', 'l21']", + "104, JARD1B-negative ['l22', 'l23', 'l24']", + "105, cells ['l18', 'l22', 'l25', 'l26']", + "108, initiate ['l23', 'l25', 'l27']", + "109, tumors. ['l24', 'l26', 'l27']", + "110, JARD1B-negative ['l28', 'l29', 'l30', 'l31']", + "111, cells, ['l28', 'l32', 'l33', 'l34']", + "118, support ['l29', 'l32', 'l35', 'l36']", + "119, tumor ['l30', 'l33', 'l35', 'l37']", + "120, growth. ['l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "JAR1D1B" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "cells", + "JARD1B-negative", + "cells," + ] + }, + "effect": { + "val": "positive", + "words": [ + "initiate", + "support" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "JAR1D1B" + ] + }, + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "JAR1D1B" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "melanoma" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "JAR1D1B" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "melanoma" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "JARD1B-negative" + ] + }, + "context": { + "val": "cells", + "words": [ + "JARD1B-negative" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "JARD1B-negative" + ] + }, + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "JARD1B-negative" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "JARD1B-negative", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "JARD1B-negative", + "cells," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "support" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + } + ] + }, + { + "PMID": "20601951", + "TEXT": "Candida albicans is a major fungal pathogen that causes serious systemic and mucosal infections in immunocompromised individuals. In yeast, histone H3 Lys56 acetylation (H3K56ac) is an abundant modification regulated by enzymes that have fungal-specific properties, making them appealing targets for antifungal therapy. Here we demonstrate that H3K56ac in C. albicans is regulated by the RTT109 and HST3 genes, which respectively encode the H3K56 acetyltransferase (Rtt109p) and deacetylase (Hst3p). We show that reduced levels of H3K56ac sensitize C. albicans to genotoxic and antifungal agents. Inhibition of Hst3p activity by conditional gene repression or nicotinamide treatment results in a loss of cell viability associated with abnormal filamentous growth, histone degradation and gross aberrations in DNA staining. We show that genetic or pharmacological alterations in H3K56ac levels reduce virulence in a mouse model of C. albicans infection. Our results demonstrate that modulation of H3K56ac is a unique strategy for treatment of C. albicans and, possibly, other fungal infections.", + "TAG_DATA": [ + "76, C. {'context': 'B-organism'}", + "77, albicans {'context': 'I-organism'}", + "83, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "84, of {'perturbing_action': 'I-other'}", + "85, Hst3p {'perturbing_action': 'I-other'}", + "86, activity {'perturbing_action': 'I-other'}", + "87, by {'perturbing_action': 'I-other'}", + "88, conditional {'perturbing_action': 'I-other'}", + "89, gene {'perturbing_action': 'I-other'}", + "90, repression {'perturbing_action': 'I-other'}", + "97, loss {'effect': 'B-negative'}", + "99, cell {'phenotype': 'B-cell survival'}", + "100, viability {'phenotype': 'I-cell survival'}", + "124, reduce {'effect': 'B-negative'}", + "128, mouse {'context': 'B-organism'}", + "129, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "76, C. ['l0', 'l1', 'l2', 'l3']", + "77, albicans ['l0', 'l4', 'l5', 'l6']", + "83, Inhibition ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "84, of ['l7', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "85, Hst3p ['l8', 'l17', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "86, activity ['l9', 'l18', 'l26', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "87, by ['l10', 'l19', 'l27', 'l34', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "88, conditional ['l11', 'l20', 'l28', 'l35', 'l41', 'l47', 'l48', 'l49', 'l50', 'l51']", + "89, gene ['l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l52', 'l53', 'l54', 'l55']", + "90, repression ['l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l56', 'l57', 'l58']", + "97, loss ['l1', 'l4', 'l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l59', 'l60']", + "99, cell ['l2', 'l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l59', 'l61']", + "100, viability ['l3', 'l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l58', 'l60', 'l61']", + "124, reduce ['l62', 'l63']", + "128, mouse ['l62', 'l64']", + "129, model ['l63', 'l64']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "C.", + "albicans", + "mouse", + "model" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss", + "reduce" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "C.", + "albicans" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "viability" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "viability" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "of", + "Hst3p", + "activity", + "by", + "conditional", + "gene", + "repression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "of", + "Hst3p", + "activity", + "by", + "conditional", + "gene", + "repression" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "viability" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "loss" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "viability" + ] + } + } + ] + }, + { + "PMID": "20562878", + "TEXT": "Polycystic kidney disease (PKD) represents a family of genetic disorders characterized by renal cystic growth and progression to kidney failure. No treatment is currently available for people with PKD, although possible therapeutic interventions are emerging. Despite genetic and clinical heterogeneity, PKDs have in common defects of cystic epithelia, including increased proliferation, apoptosis and activation of growth regulatory pathways. Sphingolipids and glycosphingolipids are emerging as major regulators of these cellular processes. We sought to evaluate the therapeutic potential for glycosphingolipid modulation as a new approach to treat PKD. Here we demonstrate that kidney glucosylceramide (GlcCer) and ganglioside GM3 levels are higher in human and mouse PKD tissue as compared to normal tissue, regardless of the causative mutation. Blockade of GlcCer accumulation with the GlcCer synthase inhibitor Genz-123346 effectively inhibits cystogenesis in mouse models orthologous to human autosomal dominant PKD (Pkd1 conditional knockout mice) and nephronophthisis (jck and pcy mice). Molecular analysis in vitro and in vivo indicates that Genz-123346 acts through inhibition of the two key pathways dysregulated in PKD: Akt protein kinase-mammalian target of rapamycin signaling and cell cycle machinery. Taken together, our data suggest that inhibition of GlcCer synthesis represents a new and effective treatment option for PKD.", + "TAG_DATA": [ + "130, mouse {'context': 'B-organism'}", + "131, models {'context': 'I-organism'}", + "133, to {'perturbing_action': 'I-other'}", + "134, human {'perturbing_action': 'I-other'}", + "135, autosomal {'perturbing_action': 'I-other'}", + "136, dominant {'perturbing_action': 'I-other'}", + "137, PKD {'perturbing_action': 'I-gene loss-of-function'}", + "139, conditional {'perturbing_action': 'I-gene loss-of-function'}", + "140, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "141, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "154, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "130, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "131, models ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "132, orthologous ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "133, to ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "134, human ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "135, autosomal ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "136, dominant ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "137, PKD ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "139, conditional ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "140, knockout ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "141, mice) ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "to", + "human", + "autosomal", + "dominant" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PKD", + "conditional", + "knockout", + "mice)" + ] + } + } + ] + }, + { + "PMID": "20526313", + "TEXT": "Basophils have recently been identified as antigen-presenting cells that are required for optimal antibody responses. New findings now show that activation of these cells can amplify autoimmune responses in systemic lupus erythematosus (SLE).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20526349", + "TEXT": "Although recurrent gene fusions involving erythroblastosis virus E26 transformation-specific (ETS) family transcription factors are common in prostate cancer, their products are considered 'undruggable' by conventional approaches. Recently, rare targetable gene fusions involving the anaplastic lymphoma receptor tyrosine kinase (ALK) gene, have been identified in 1-5% of lung cancers, suggesting that similar rare gene fusions may occur in other common epithelial cancers, including prostate cancer. Here we used paired-end transcriptome sequencing to screen ETS rearrangement-negative prostate cancers for targetable gene fusions and identified the SLC45A3-BRAF (solute carrier family 45, member 3-v-raf murine sarcoma viral oncogene homolog B1) and ESRP1-RAF1 (epithelial splicing regulatory protein-1-v-raf-1 murine leukemia viral oncogene homolog-1) gene fusions. Expression of SLC45A3-BRAF or ESRP1-RAF1 in prostate cells induced a neoplastic phenotype that was sensitive to RAF and mitogen-activated protein kinase kinase (MAP2K1) inhibitors. Screening a large cohort of patients, we found that, although rare, recurrent rearrangements in the RAF pathway tend to occur in advanced prostate cancers, gastric cancers and melanoma. Taken together, our results emphasize the key role of RAF family gene rearrangements in cancer, suggest that RAF and MEK inhibitors may be useful in a subset of gene fusion-harboring solid tumors and demonstrate that sequencing of tumor transcriptomes and genomes may lead to the identification of rare targetable fusions across cancer types.", + "TAG_DATA": [ + "109, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "110, of {'perturbing_action': 'I-gene gain-of-function'}", + "111, SLC45A3-BRAF {'perturbing_action': 'I-gene gain-of-function'}", + "112, or {'perturbing_action': 'I-gene gain-of-function'}", + "113, ESRP1-RAF1 {'perturbing_action': 'I-gene gain-of-function'}", + "115, prostate {'context': 'B-transformed cells'}", + "116, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "109, Expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "110, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "111, SLC45A3-BRAF ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "112, or ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "113, ESRP1-RAF1 ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "115, prostate ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "116, cells ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "SLC45A3-BRAF", + "or", + "ESRP1-RAF1" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cells" + ] + } + } + ] + }, + { + "PMID": "20526348", + "TEXT": "Using ultrasound-guided in utero infections of fluorescently traceable lentiviruses carrying RNAi or Cre recombinase into mouse embryos, we have demonstrated noninvasive, highly efficient selective transduction of surface epithelium, in which progenitors stably incorporate and propagate the desired genetic alterations. We achieved epidermal-specific infection using small generic promoters of existing lentiviral short hairpin RNA libraries, thus enabling rapid assessment of gene function as well as complex genetic interactions in skin morphogenesis and disease in vivo. We adapted this technology to devise a new quantitative method for ascertaining whether a gene confers a growth advantage or disadvantage in skin tumorigenesis. Using alpha1-catenin as a model, we uncover new insights into its role as a widely expressed tumor suppressor and reveal physiological interactions between Ctnna1 and the Hras1-Mapk3 and Trp53 gene pathways in regulating skin cell proliferation and apoptosis. Our study illustrates the strategy and its broad applicability for investigations of tissue morphogenesis, lineage specification and cancers.", + "TAG_DATA": [ + "15, mouse {'context': 'B-organism'}", + "16, embryos, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "15, mouse ['l0', 'l1']", + "16, embryos, ['l0', 'l2']", + "97, tumorigenesis. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20512127", + "TEXT": "In systemic lupus erythematosus (SLE), self-reactive antibodies can target the kidney (lupus nephritis), leading to functional failure and possible mortality. We report that activation of basophils by autoreactive IgE causes their homing to lymph nodes, promoting T helper type 2 (T(H)2) cell differentiation and enhancing the production of self-reactive antibodies that cause lupus-like nephritis in mice lacking the Src family protein tyrosine kinase Lyn (Lyn(-/-) mice). Individuals with SLE also have elevated serum IgE, self-reactive IgEs and activated basophils that express CD62 ligand (CD62L) and the major histocompatibility complex (MHC) class II molecule human leukocyte antigen-DR (HLA-DR), parameters that are associated with increased disease activity and active lupus nephritis. Basophils were also present in the lymph nodes and spleen of subjects with SLE. Thus, in Lyn(-/-) mice, basophils and IgE autoantibodies amplify autoantibody production that leads to lupus nephritis, and in individuals with SLE IgE autoantibodies and activated basophils are factors associated with disease activity and nephritis.", + "TAG_DATA": [ + "35, promoting {'effect': 'B-positive'}", + "55, mice {'context': 'B-organism'}", + "56, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "57, the {'perturbing_action': 'I-gene loss-of-function'}", + "58, Src {'perturbing_action': 'I-gene loss-of-function'}", + "59, family {'perturbing_action': 'I-gene loss-of-function'}", + "60, protein {'perturbing_action': 'I-gene loss-of-function'}", + "61, tyrosine {'perturbing_action': 'I-gene loss-of-function'}", + "62, kinase {'perturbing_action': 'I-gene loss-of-function'}", + "63, Lyn {'perturbing_action': 'I-gene loss-of-function'}", + "64, (Lyn(-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "65, mice). {'perturbing_action': 'I-gene loss-of-function'}", + "125, Lyn(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "126, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "35, promoting ['l0', 'l1']", + "55, mice ['l0', 'l2', 'l3']", + "56, lacking ['l2', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "57, the ['l4', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "58, Src ['l5', 'l13', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "59, family ['l6', 'l14', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "60, protein ['l7', 'l15', 'l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "61, tyrosine ['l8', 'l16', 'l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "62, kinase ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "63, Lyn ['l10', 'l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "64, (Lyn(-/-) ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "65, mice). ['l1', 'l3', 'l12', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l48']", + "125, Lyn(-/-) ['l49']", + "126, mice, ['l49']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "mice)." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "mice).", + "Lyn(-/-)" + ] + } + } + ] + }, + { + "PMID": "20512124", + "TEXT": "Although vaccination is most effective when used to prevent disease, cancer vaccine development has focused predominantly on providing therapy against established growing tumors. The difficulty in developing prophylactic cancer vaccines is primarily due to the fact that tumor antigens are variations of self proteins and would probably mediate profound autoimmune complications if used in a preventive vaccine setting. Here we use several mouse breast cancer models to define a prototypic strategy for prophylactic cancer vaccination. We selected alpha-lactalbumin as our target vaccine autoantigen because it is a breast-specific differentiation protein expressed in high amounts in the majority of human breast carcinomas and in mammary epithelial cells only during lactation. We found that immunoreactivity against alpha-lactalbumin provides substantial protection and therapy against growth of autochthonous tumors in transgenic mouse models of breast cancer and against 4T1 transplantable breast tumors in BALB/c mice. Because alpha-lactalbumin is conditionally expressed only during lactation, vaccination-induced prophylaxis occurs without any detectable inflammation in normal nonlactating breast tissue. Thus, alpha-lactalbumin vaccination may provide safe and effective protection against the development of breast cancer for women in their post-child-bearing, premenopausal years, when lactation is readily avoidable and risk for developing breast cancer is high.", + "TAG_DATA": [ + "123, autochthonous {'context': 'B-neoplasm', 'phenotype': 'I-tumour regression'}", + "124, tumors {'context': 'I-neoplasm'}", + "126, transgenic {'context': 'B-organism'}", + "127, mouse {'context': 'I-organism'}", + "128, models {'context': 'I-organism'}", + "129, of {'context': 'I-neoplasm'}", + "130, breast {'context': 'I-neoplasm'}", + "131, cancer {'context': 'I-neoplasm'}", + "135, transplantable {'phenotype': 'I-tumour regression'}", + "136, breast {'context': 'I-neoplasm'}", + "137, tumors {'context': 'I-neoplasm'}", + "139, BALB/c {'context': 'B-organism'}", + "140, mice. {'context': 'I-organism'}", + "158, nonlactating {'context': 'B-tissue/organ'}", + "159, breast {'context': 'I-tissue/organ'}", + "160, tissue. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "63, breast ['l0']", + "64, cancer ['l0']", + "123, autochthonous ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "124, tumors ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "126, transgenic ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "127, mouse ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "128, models ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "129, of ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "130, breast ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "131, cancer ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']", + "134, 4T1 ['l29', 'l30', 'l31', 'l32', 'l33']", + "135, transplantable ['l29', 'l34', 'l35', 'l36', 'l37']", + "136, breast ['l30', 'l34', 'l38', 'l39', 'l40']", + "137, tumors ['l31', 'l35', 'l38', 'l41', 'l42']", + "139, BALB/c ['l32', 'l36', 'l39', 'l41', 'l43']", + "140, mice. ['l33', 'l37', 'l40', 'l42', 'l43']", + "158, nonlactating ['l44', 'l45']", + "159, breast ['l44', 'l46']", + "160, tissue. ['l45', 'l46']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "autochthonous", + "breast", + "tumors" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "autochthonous", + "transplantable" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "autochthonous", + "transplantable" + ] + }, + "context": { + "val": "organism", + "words": [ + "transgenic", + "mouse", + "models", + "BALB/c", + "mice." + ] + } + } + ] + }, + { + "PMID": "20473308", + "TEXT": "Mechanisms linking innate immunity and autoimmune responses are poorly understood. Myeloid-related protein-8 (Mrp8) and Mrp14 are damage-associated molecular pattern molecules (DAMPs) highly upregulated in various autoimmune disorders. We show in a mouse autoimmune model that local Mrp8 and Mrp14 production is essential for the induction of autoreactive CD8+ T cells and the development of systemic autoimmunity. This effect is mediated via Toll-like receptor 4 (TLR4) signaling leading to increased interleukin-17 (IL-17) expression. Notably, expression of Mrp8 and Mrp14 was upregulated in cutaneous lupus erythematosus, and stimulation of CD8+ T cells from individuals with lupus erythematosus with MRP proteins resulted in an upregulation of IL-17, suggesting a key role for MRP8 and MRP14 for the development of autoreactive lymphocytes during human autoimmunity as well. These results demonstrate a link between local expression of DAMP molecules and the development of systemic autoimmunity.", + "TAG_DATA": [ + "87, CD8+ {'context': 'B-cells'}", + "88, T {'context': 'I-cells'}", + "89, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "87, CD8+ ['l0', 'l1']", + "88, T ['l0', 'l2']", + "89, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20376051", + "TEXT": "In type 2 diabetes and obesity, the homeostatic control of glucose and energy balance is impaired, leading to hyperglycemia and hyperphagia. Recent studies indicate that nutrient-sensing mechanisms in the body activate negative-feedback systems to regulate energy and glucose homeostasis through a neuronal network. Direct metabolic signaling within the intestine activates gut-brain and gut-brain-liver axes to regulate energy and glucose homeostasis, respectively. In parallel, direct metabolism of nutrients within the hypothalamus regulates food intake and blood glucose levels. These findings highlight the importance of the central nervous system in mediating the ability of nutrient sensing to maintain homeostasis. Futhermore, they provide a physiological and neuronal framework by which enhancing or restoring nutrient sensing in the intestine and the brain could normalize energy and glucose homeostasis in diabetes and obesity.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20348922", + "TEXT": "Brain inflammation is a major factor in epilepsy, but the impact of specific inflammatory mediators on neuronal excitability is incompletely understood. Using models of acute and chronic seizures in C57BL/6 mice, we discovered a proconvulsant pathway involving high-mobility group box-1 (HMGB1) release from neurons and glia and its interaction with Toll-like receptor 4 (TLR4), a key receptor of innate immunity. Antagonists of HMGB1 and TLR4 retard seizure precipitation and decrease acute and chronic seizure recurrence. TLR4-defective C3H/HeJ mice are resistant to kainate-induced seizures. The proconvulsant effects of HMGB1, like those of interleukin-1beta (IL-1beta), are partly mediated by ifenprodil-sensitive N-methyl-d-aspartate (NMDA) receptors. Increased expression of HMGB1 and TLR4 in human epileptogenic tissue, like that observed in the mouse model of chronic seizures, suggests a role for the HMGB1-TLR4 axis in human epilepsy. Thus, HMGB1-TLR4 signaling may contribute to generating and perpetuating seizures in humans and might be targeted to attain anticonvulsant effects in epilepsies that are currently resistant to drugs.", + "TAG_DATA": [ + "29, C57BL/6 {'context': 'B-organism'}", + "30, mice, {'context': 'I-organism'}", + "60, Antagonists {'perturbing_action': 'B-pharmacological inhibition'}", + "61, of {'perturbing_action': 'I-pharmacological inhibition'}", + "62, HMGB1 {'perturbing_action': 'I-pharmacological inhibition'}", + "63, and {'perturbing_action': 'I-pharmacological inhibition'}", + "64, TLR4 {'perturbing_action': 'I-pharmacological inhibition'}", + "75, TLR4-defective {'perturbing_action': 'B-other'}", + "76, C3H/HeJ {'context': 'B-organism'}", + "77, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "29, C57BL/6 ['l0', 'l1', 'l2', 'l3']", + "30, mice, ['l0', 'l4']", + "60, Antagonists ['l5', 'l6', 'l7', 'l8']", + "61, of ['l5', 'l9', 'l10', 'l11']", + "62, HMGB1 ['l1', 'l6', 'l9', 'l12', 'l13']", + "63, and ['l2', 'l7', 'l10', 'l12', 'l14']", + "64, TLR4 ['l3', 'l4', 'l8', 'l11', 'l13', 'l14']", + "75, TLR4-defective ['l15', 'l16']", + "76, C3H/HeJ ['l15', 'l17']", + "77, mice ['l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "C57BL/6", + "mice," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "HMGB1", + "and", + "TLR4" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "TLR4-defective" + ] + }, + "context": { + "val": "organism", + "words": [ + "C3H/HeJ", + "mice" + ] + } + } + ] + }, + { + "PMID": "20305661", + "TEXT": "The peptidoglycan layer is a vital component of the bacterial cell wall. The existing paradigm describes the peptidoglycan network as a static structure that is cross-linked predominantly by 4-->3 transpeptide linkages. However, the nonclassical 3-->3 linkages predominate the transpeptide networking of the peptidoglycan layer of nonreplicating Mycobacterium tuberculosis. The molecular basis of these linkages and their role in the physiology of the peptidoglycan layer, virulence and susceptibility of M. tuberculosis to drugs remain undefined. Here we identify MT2594 as an L,D-transpeptidase that generates 3-->3 linkages in M. tuberculosis. We show that the loss of this protein leads to altered colony morphology, loss of virulence and increased susceptibility to amoxicillin-clavulanate during the chronic phase of infection. This suggests that 3-->3 cross-linking is vital to the physiology of the peptidoglycan layer. Although a functional homolog exists, expression of ldtMt2 is dominant throughout the growth phases of M. tuberculosis. 4-->3 transpeptide linkages are targeted by one of the most widely used classes of antibacterial drugs in human clinical use today, beta-lactams. Recently, meropenem-clavulanate was shown to be effective against drug-resistant M. tuberculosis. Our study suggests that a combination of L,D-transpeptidase and beta-lactamase inhibitors could effectively target persisting bacilli during the chronic phase of tuberculosis.", + "TAG_DATA": [ + "92, loss {'perturbing_action': 'B-gene loss-of-function'}", + "93, of {'perturbing_action': 'I-gene loss-of-function'}", + "94, this {'perturbing_action': 'I-gene loss-of-function'}", + "95, protein {'perturbing_action': 'I-gene loss-of-function'}", + "99, colony {'phenotype': 'B-colony formation'}", + "100, morphology, {'phenotype': 'I-colony formation'}", + "101, loss {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "92, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "93, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "94, this ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "95, protein ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "98, altered ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "99, colony ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "100, morphology, ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "101, loss ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "this", + "protein" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "colony", + "morphology," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "this", + "protein" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "colony", + "morphology," + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + } + ] + }, + { + "PMID": "20228816", + "TEXT": "Conventional anticancer drug screening is typically performed in the absence of accessory cells of the tumor microenvironment, which can profoundly alter antitumor drug activity. To address this limitation, we developed the tumor cell-specific in vitro bioluminescence imaging (CS-BLI) assay. Tumor cells (for example, myeloma, leukemia and solid tumors) stably expressing luciferase are cultured with nonmalignant accessory cells (for example, stromal cells) for selective quantification of tumor cell viability, in presence versus absence of stromal cells or drug treatment. CS-BLI is high-throughput scalable and identifies stroma-induced chemoresistance in diverse malignancies, including imatinib resistance in leukemic cells. A stroma-induced signature in tumor cells correlates with adverse clinical prognosis and includes signatures for activated Akt, Ras, NF-kappaB, HIF-1alpha, myc, hTERT and IRF4; for biological aggressiveness; and for self-renewal. Unlike conventional screening, CS-BLI can also identify agents with increased activity against tumor cells interacting with stroma. One such compound, reversine, shows more potent activity in an orthotopic model of diffuse myeloma bone lesions than in conventional subcutaneous xenografts. Use of CS-BLI, therefore, enables refined screening of candidate anticancer agents to enrich preclinical pipelines with potential therapeutics that overcome stroma-mediated drug resistance and can act in a synthetic lethal manner in the context of tumor-stroma interactions.", + "TAG_DATA": [ + "40, cells {'context': 'I-transformed cells'}", + "152, orthotopic {'context': 'B-neoplasm'}", + "153, model {'context': 'I-neoplasm'}", + "154, of {'context': 'I-neoplasm'}", + "155, diffuse {'context': 'I-neoplasm'}", + "156, myeloma {'context': 'I-neoplasm'}", + "157, bone {'context': 'I-neoplasm'}", + "158, lesions {'context': 'I-neoplasm'}", + "162, subcutaneous {'context': 'B-xenograft'}", + "163, xenografts. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "152, orthotopic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "153, model ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "154, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "155, diffuse ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "156, myeloma ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "157, bone ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "158, lesions ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "162, subcutaneous ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "163, xenografts. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20208540", + "TEXT": "Viral replication and microbial translocation from the gut to the blood during HIV infection lead to hyperimmune activation, which contributes to the decline in CD4+ T cell numbers during HIV infection. Programmed death-1 (PD-1) and interleukin-10 (IL-10) are both upregulated during HIV infection. Blocking interactions between PD-1 and programmed death ligand-1 (PD-L1) and between IL-10 and IL-10 receptor (IL-10R) results in viral clearance and improves T cell function in animal models of chronic viral infections. Here we show that high amounts of microbial products and inflammatory cytokines in the plasma of HIV-infected subjects lead to upregulation of PD-1 expression on monocytes that correlates with high plasma concentrations of IL-10. Triggering of PD-1 expressed on monocytes by PD-L1 expressed on various cell types induced IL-10 production and led to reversible CD4+ T cell dysfunction. We describe a new function for PD-1 whereby microbial products inhibit T cell expansion and function by upregulating PD-1 levels and IL-10 production by monocytes after binding of PD-1 by PD-L1.", + "TAG_DATA": [ + "129, CD4+ {'context': 'B-cells'}", + "130, T {'context': 'I-cells'}", + "131, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "129, CD4+ ['l0', 'l1']", + "130, T ['l0', 'l2']", + "131, cell ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20173752", + "TEXT": "The worldwide diversity of HIV-1 presents an unprecedented challenge for vaccine development. Antigens derived from natural HIV-1 sequences have elicited only a limited breadth of cellular immune responses in nonhuman primate studies and clinical trials to date. Polyvalent 'mosaic' antigens, in contrast, are designed to optimize cellular immunologic coverage of global HIV-1 sequence diversity. Here we show that mosaic HIV-1 Gag, Pol and Env antigens expressed by recombinant, replication-incompetent adenovirus serotype 26 vectors markedly augmented both the breadth and depth without compromising the magnitude of antigen-specific T lymphocyte responses as compared with consensus or natural sequence HIV-1 antigens in rhesus monkeys. Polyvalent mosaic antigens therefore represent a promising strategy to expand cellular immunologic vaccine coverage for genetically diverse pathogens such as HIV-1.", + "TAG_DATA": [ + "86, T {'context': 'B-cells'}", + "87, lymphocyte {'context': 'I-cells'}", + "99, rhesus {'context': 'B-organism'}", + "100, monkeys. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "86, T ['l0', 'l1', 'l2']", + "87, lymphocyte ['l0', 'l3', 'l4']", + "99, rhesus ['l1', 'l3', 'l5']", + "100, monkeys. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20154697", + "TEXT": "Metastasis is responsible for the majority of prostate cancer-related deaths; however, little is known about the molecular mechanisms that underlie this process. Here we identify an oncogene-tumor suppressor cascade that promotes prostate cancer growth and metastasis by coordinately activating the small GTPase Ras and nuclear factor-kappaB (NF-kappaB). Specifically, we show that loss of the Ras GTPase-activating protein (RasGAP) gene DAB2IP induces metastatic prostate cancer in an orthotopic mouse tumor model. Notably, DAB2IP functions as a signaling scaffold that coordinately regulates Ras and NF-kappaB through distinct domains to promote tumor growth and metastasis, respectively. DAB2IP is suppressed in human prostate cancer, where its expression inversely correlates with tumor grade and predicts prognosis. Moreover, we report that epigenetic silencing of DAB2IP is a key mechanism by which the polycomb-group protein histone-lysine N-methyltransferase EZH2 activates Ras and NF-kappaB and triggers metastasis. These studies define the mechanism by which two major pathways can be simultaneously activated in metastatic prostate cancer and establish EZH2 as a driver of metastasis.", + "TAG_DATA": [ + "51, loss {'perturbing_action': 'B-gene loss-of-function'}", + "52, of {'perturbing_action': 'I-gene loss-of-function'}", + "53, the {'perturbing_action': 'I-gene loss-of-function'}", + "54, Ras {'perturbing_action': 'I-gene loss-of-function'}", + "55, GTPase-activating {'perturbing_action': 'I-gene loss-of-function'}", + "56, protein {'perturbing_action': 'I-gene loss-of-function'}", + "57, (RasGAP) {'perturbing_action': 'I-gene loss-of-function'}", + "58, gene {'perturbing_action': 'I-gene loss-of-function'}", + "59, DAB2IP {'perturbing_action': 'I-gene loss-of-function'}", + "60, induces {'effect': 'B-positive'}", + "61, metastatic {'phenotype': 'B-tumourigenesis'}", + "62, prostate {'phenotype': 'I-tumourigenesis'}", + "63, cancer {'phenotype': 'I-tumourigenesis'}", + "66, orthotopic {'context': 'B-organism'}", + "67, mouse {'context': 'I-neoplasm'}", + "68, tumor {'context': 'I-neoplasm'}", + "69, model. {'context': 'I-neoplasm'}", + "87, promote {'effect': 'B-positive'}", + "88, tumor {'phenotype': 'B-tumour growth'}", + "89, growth {'phenotype': 'I-tumour growth'}", + "91, metastasis, {'phenotype': 'B-metastasis'}", + "116, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "117, of {'perturbing_action': 'I-rnai/knockdown'}", + "118, DAB2IP {'perturbing_action': 'I-rnai/knockdown'}", + "136, triggers {'effect': 'B-positive'}", + "137, metastasis. {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "51, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "52, of ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "53, the ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "54, Ras ['l2', 'l21', 'l39', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "55, GTPase-activating ['l3', 'l22', 'l40', 'l57', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "56, protein ['l4', 'l23', 'l41', 'l58', 'l74', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "57, (RasGAP) ['l5', 'l24', 'l42', 'l59', 'l75', 'l90', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "58, gene ['l6', 'l25', 'l43', 'l60', 'l76', 'l91', 'l105', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "59, DAB2IP ['l7', 'l26', 'l44', 'l61', 'l77', 'l92', 'l106', 'l119', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "60, induces ['l8', 'l27', 'l45', 'l62', 'l78', 'l93', 'l107', 'l120', 'l132', 'l144', 'l145', 'l146']", + "61, metastatic ['l9', 'l28', 'l46', 'l63', 'l79', 'l94', 'l108', 'l121', 'l133', 'l144', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "62, prostate ['l10', 'l29', 'l47', 'l64', 'l80', 'l95', 'l109', 'l122', 'l134', 'l145', 'l147', 'l153', 'l154']", + "63, cancer ['l11', 'l30', 'l48', 'l65', 'l81', 'l96', 'l110', 'l123', 'l135', 'l146', 'l148', 'l153']", + "66, orthotopic ['l12', 'l31', 'l49', 'l66', 'l82', 'l97', 'l111', 'l124', 'l136', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "67, mouse ['l13', 'l32', 'l50', 'l67', 'l83', 'l98', 'l112', 'l125', 'l137', 'l155', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "68, tumor ['l14', 'l33', 'l51', 'l68', 'l84', 'l99', 'l113', 'l126', 'l138', 'l149', 'l156', 'l162', 'l168', 'l169', 'l170', 'l171', 'l172']", + "69, model. ['l15', 'l34', 'l52', 'l69', 'l85', 'l100', 'l114', 'l127', 'l139', 'l150', 'l154', 'l157', 'l163', 'l168', 'l173', 'l174', 'l175', 'l176']", + "87, promote ['l16', 'l35', 'l53', 'l70', 'l86', 'l101', 'l115', 'l128', 'l140', 'l151', 'l158', 'l164', 'l169', 'l173', 'l177', 'l178', 'l179']", + "88, tumor ['l17', 'l36', 'l54', 'l71', 'l87', 'l102', 'l116', 'l129', 'l141', 'l159', 'l165', 'l170', 'l174', 'l177', 'l180', 'l181']", + "89, growth ['l18', 'l37', 'l55', 'l72', 'l88', 'l103', 'l117', 'l130', 'l142', 'l152', 'l160', 'l166', 'l171', 'l175', 'l178', 'l180', 'l182']", + "91, metastasis, ['l19', 'l38', 'l56', 'l73', 'l89', 'l104', 'l118', 'l131', 'l143', 'l161', 'l167', 'l172', 'l176', 'l179', 'l181', 'l182']", + "116, silencing ['l183', 'l184', 'l185', 'l186']", + "117, of ['l183', 'l187', 'l188', 'l189']", + "118, DAB2IP ['l184', 'l187', 'l190', 'l191']", + "136, triggers ['l185', 'l188', 'l190', 'l192']", + "137, metastasis. ['l186', 'l189', 'l191', 'l192']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Ras", + "GTPase-activating", + "protein", + "(RasGAP)", + "gene", + "DAB2IP" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces", + "promote" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Ras", + "GTPase-activating", + "protein", + "(RasGAP)", + "gene", + "DAB2IP" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "metastatic", + "prostate", + "cancer" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Ras", + "GTPase-activating", + "protein", + "(RasGAP)", + "gene", + "DAB2IP" + ] + }, + "context": { + "val": "organism", + "words": [ + "orthotopic" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Ras", + "GTPase-activating", + "protein", + "(RasGAP)", + "gene", + "DAB2IP" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "tumor", + "model." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Ras", + "GTPase-activating", + "protein", + "(RasGAP)", + "gene", + "DAB2IP" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Ras", + "GTPase-activating", + "protein", + "(RasGAP)", + "gene", + "DAB2IP" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "promote" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "metastatic", + "prostate", + "cancer" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "metastatic", + "prostate" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor", + "model." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "orthotopic" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promote" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "orthotopic" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "orthotopic" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "tumor", + "model." + ] + }, + "effect": { + "val": "positive", + "words": [ + "promote" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "tumor", + "model." + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "tumor", + "model." + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote", + "triggers" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis,", + "metastasis." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "of", + "DAB2IP" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "of", + "DAB2IP" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + } + ] + }, + { + "PMID": "20154695", + "TEXT": "Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (encoded by Cftr) that impair its role as an apical chloride channel that supports bicarbonate transport. Individuals with cystic fibrosis show retained, thickened mucus that plugs airways and obstructs luminal organs as well as numerous other abnormalities that include inflammation of affected organs, alterations in lipid metabolism and insulin resistance. Here we show that colonic epithelial cells and whole lung tissue from Cftr-deficient mice show a defect in peroxisome proliferator-activated receptor-gamma (PPAR-gamma, encoded by Pparg) function that contributes to a pathological program of gene expression. Lipidomic analysis of colonic epithelial cells suggests that this defect results in part from reduced amounts of the endogenous PPAR-gamma ligand 15-keto-prostaglandin E(2) (15-keto-PGE(2)). Treatment of Cftr-deficient mice with the synthetic PPAR-gamma ligand rosiglitazone partially normalizes the altered gene expression pattern associated with Cftr deficiency and reduces disease severity. Rosiglitazone has no effect on chloride secretion in the colon, but it increases expression of the genes encoding carbonic anhydrases 4 and 2 (Car4 and Car2), increases bicarbonate secretion and reduces mucus retention. These studies reveal a reversible defect in PPAR-gamma signaling in Cftr-deficient cells that can be pharmacologically corrected to ameliorate the severity of the cystic fibrosis phenotype in mice.", + "TAG_DATA": [ + "67, colonic {'context': 'B-cells'}", + "68, epithelial {'context': 'I-cells'}", + "69, cells {'context': 'I-cells'}", + "72, lung {'context': 'I-tissue/organ'}", + "73, tissue {'context': 'I-tissue/organ'}", + "75, Cftr-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "76, mice {'context': 'B-organism'}", + "101, colonic {'context': 'B-cells'}", + "102, epithelial {'context': 'I-cells'}", + "103, cells {'context': 'I-cells'}", + "124, Cftr-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "125, mice {'context': 'B-organism'}", + "141, Cftr {'perturbing_action': 'B-gene loss-of-function'}", + "142, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "156, colon, {'context': 'B-tissue/organ'}", + "190, Cftr-deficient {'perturbing_action': 'B-gene loss-of-function'}" + ], + "LINK_DATA": [ + "67, colonic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "68, epithelial ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "69, cells ['l1', 'l7', 'l15', 'l16', 'l17', 'l18', 'l19']", + "72, lung ['l2', 'l8', 'l15', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "73, tissue ['l3', 'l9', 'l16', 'l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "75, Cftr-deficient ['l4', 'l10', 'l17', 'l21', 'l26', 'l31', 'l32', 'l33', 'l34']", + "76, mice ['l5', 'l11', 'l18', 'l22', 'l27', 'l31', 'l35', 'l36']", + "101, colonic ['l12', 'l23', 'l28', 'l32', 'l35', 'l37', 'l38', 'l39']", + "102, epithelial ['l13', 'l24', 'l29', 'l33', 'l37', 'l40', 'l41']", + "103, cells ['l6', 'l14', 'l19', 'l25', 'l30', 'l34', 'l36', 'l38', 'l40', 'l42']", + "124, Cftr-deficient ['l43', 'l44', 'l45', 'l46']", + "125, mice ['l43', 'l47', 'l48', 'l49']", + "141, Cftr ['l44', 'l47', 'l50']", + "142, deficiency ['l39', 'l41', 'l42', 'l45', 'l48', 'l50']", + "156, colon, ['l46', 'l49']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "colonic", + "epithelial", + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cftr-deficient", + "deficiency" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "lung", + "tissue", + "colon," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cftr-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cftr-deficient", + "Cftr", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "20139992", + "TEXT": "Lymphocytic choriomeningitis virus (LCMV) exhibits natural tropism for dendritic cells and represents the prototypic infection that elicits protective CD8(+) T cell (cytotoxic T lymphocyte (CTL)) immunity. Here we have harnessed the immunobiology of this arenavirus for vaccine delivery. By using producer cells constitutively synthesizing the viral glycoprotein (GP), it was possible to replace the gene encoding LCMV GP with vaccine antigens to create replication-defective vaccine vectors. These rLCMV vaccines elicited CTL responses that were equivalent to or greater than those elicited by recombinant adenovirus 5 or recombinant vaccinia virus in their magnitude and cytokine profiles, and they exhibited more effective protection in several models. In contrast to recombinant adenovirus 5, rLCMV failed to elicit vector-specific antibody immunity, which facilitated re-administration of the same vector for booster vaccination. In addition, rLCMV elicited T helper type 1 CD4+ T cell responses and protective neutralizing antibodies to vaccine antigens. These features, together with low seroprevalence in humans, suggest that rLCMV may show utility as a vaccine platform against infectious diseases and cancer.", + "TAG_DATA": [ + "40, producer {'context': 'B-cells'}", + "41, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "40, producer ['l0']", + "41, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20139991", + "TEXT": "Osteoporosis is a disease of low bone mass most often caused by an increase in bone resorption that is not sufficiently compensated for by a corresponding increase in bone formation. As gut-derived serotonin (GDS) inhibits bone formation, we asked whether hampering its biosynthesis could treat osteoporosis through an anabolic mechanism (that is, by increasing bone formation). We synthesized and used LP533401, a small molecule inhibitor of tryptophan hydroxylase-1 (Tph-1), the initial enzyme in GDS biosynthesis. Oral administration of this small molecule once daily for up to six weeks acts prophylactically or therapeutically, in a dose-dependent manner, to treat osteoporosis in ovariectomized rodents because of an isolated increase in bone formation. These results provide a proof of principle that inhibiting GDS biosynthesis could become a new anabolic treatment for osteoporosis.", + "TAG_DATA": [ + "101, rodents {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20111039", + "TEXT": "Chikungunya virus (CHIKV) has infected millions of people in Africa, Europe and Asia since this alphavirus reemerged from Kenya in 2004. The severity of the disease and the spread of this epidemic virus present a serious public health threat in the absence of vaccines or antiviral therapies. Here, we describe a new vaccine that protects against CHIKV infection of nonhuman primates. We show that selective expression of viral structural proteins gives rise to virus-like particles (VLPs) in vitro that resemble replication-competent alphaviruses. Immunization with these VLPs elicited neutralizing antibodies against envelope proteins from alternative CHIKV strains. Monkeys immunized with VLPs produced high-titer neutralizing antibodies that protected against viremia after high-dose challenge. We transferred these antibodies into immunodeficient mice, where they protected against subsequent lethal CHIKV challenge, indicating a humoral mechanism of protection. Immunization with alphavirus VLP vaccines represents a strategy to contain the spread of CHIKV and related pathogenic viruses in humans.", + "TAG_DATA": [ + "76, in {'context': 'B-in vitro'}", + "77, vitro {'context': 'I-in vitro'}", + "96, Monkeys {'context': 'B-organism'}", + "117, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "76, in ['l0']", + "77, vitro ['l0']", + "116, immunodeficient ['l1']", + "117, mice, ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20081864", + "TEXT": "Variola major (smallpox) infection claimed hundreds of millions lives before it was eradicated by a simple vaccination strategy: epicutaneous application of the related orthopoxvirus vaccinia virus (VACV) to superficially injured skin (skin scarification, s.s.). However, the remarkable success of this strategy was attributed to the immunogenicity of VACV rather than to the unique mode of vaccine delivery. We now show that VACV immunization via s.s., but not conventional injection routes, is essential for the generation of superior T cell-mediated immune responses that provide complete protection against subsequent challenges, independent of neutralizing antibodies. Skin-resident effector memory T cells (T(EM) cells) provide complete protection against cutaneous challenge, whereas protection against lethal respiratory challenge requires both respiratory mucosal T(EM) cells and central memory T cells (T(CM) cells). Vaccination with recombinant VACV (rVACV) expressing a tumor antigen was protective against tumor challenge only if delivered via the s.s. route; it was ineffective if delivered by hypodermic injection. The clinically safer nonreplicative modified vaccinia Ankara virus (MVA) also generated far superior protective immunity when delivered via the s.s. route compared to intramuscular (i.m.) injection as used in MVA clinical trials. Thus, delivery of rVACV-based vaccines, including MVA vaccines, through physically disrupted epidermis has clear-cut advantages over conventional vaccination via hypodermic injection.", + "TAG_DATA": [ + "92, Skin-resident {'context': 'B-cells'}", + "93, effector {'context': 'I-cells'}", + "94, memory {'context': 'I-cells'}", + "95, T {'context': 'I-cells'}", + "96, cells {'context': 'I-cells'}", + "97, (T(EM) {'context': 'I-cells'}", + "98, cells) {'context': 'I-cells'}", + "113, respiratory {'context': 'B-cells'}", + "114, mucosal {'context': 'I-cells'}", + "115, T(EM) {'context': 'I-cells'}", + "116, cells {'context': 'I-cells'}", + "118, central {'context': 'B-cells'}", + "119, memory {'context': 'I-cells'}", + "120, T {'context': 'I-cells'}", + "121, cells {'context': 'I-cells'}", + "122, (T(CM) {'context': 'I-cells'}", + "123, cells). {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "92, Skin-resident ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "93, effector ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "94, memory ['l1', 'l10', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "95, T ['l2', 'l11', 'l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "96, cells ['l3', 'l12', 'l21', 'l29', 'l36', 'l37', 'l38']", + "97, (T(EM) ['l4', 'l13', 'l22', 'l30', 'l36', 'l39', 'l40']", + "98, cells) ['l5', 'l14', 'l23', 'l31', 'l37', 'l39']", + "113, respiratory ['l6', 'l15', 'l24', 'l32', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "114, mucosal ['l7', 'l16', 'l25', 'l33', 'l41', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "115, T(EM) ['l8', 'l17', 'l26', 'l34', 'l42', 'l50', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "116, cells ['l9', 'l18', 'l27', 'l35', 'l38', 'l40', 'l43', 'l51', 'l58', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "118, central ['l44', 'l52', 'l59', 'l65', 'l71', 'l72', 'l73', 'l74', 'l75']", + "119, memory ['l45', 'l53', 'l60', 'l66', 'l71', 'l76', 'l77', 'l78', 'l79']", + "120, T ['l46', 'l54', 'l61', 'l67', 'l72', 'l76', 'l80', 'l81', 'l82']", + "121, cells ['l47', 'l55', 'l62', 'l68', 'l73', 'l77', 'l80', 'l83', 'l84']", + "122, (T(CM) ['l48', 'l56', 'l63', 'l69', 'l74', 'l78', 'l81', 'l83', 'l85']", + "123, cells). ['l19', 'l28', 'l49', 'l57', 'l64', 'l70', 'l75', 'l79', 'l82', 'l84', 'l85']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20023636", + "TEXT": "Human T cell leukemia virus type 1 (HTLV-1) is a lymphotropic retrovirus whose cell-to-cell transmission requires cell contacts. HTLV-1-infected T lymphocytes form 'virological synapses', but the mechanism of HTLV-1 transmission remains poorly understood. We show here that HTLV-1-infected T lymphocytes transiently store viral particles as carbohydrate-rich extracellular assemblies that are held together and attached to the cell surface by virally-induced extracellular matrix components, including collagen and agrin, and cellular linker proteins, such as tetherin and galectin-3. Extracellular viral assemblies rapidly adhere to other cells upon cell contact, allowing virus spread and infection of target cells. Their removal strongly reduces the ability of HTLV-1-producing cells to infect target cells. Our findings unveil a novel virus transmission mechanism based on the generation of extracellular viral particle assemblies whose structure, composition and function resemble those of bacterial biofilms. HTLV-1 biofilm-like structures represent a major route for virus transmission from cell to cell.", + "TAG_DATA": [ + "102, HTLV-1-producing {'context': 'B-cells'}", + "103, cells {'context': 'I-cells'}", + "106, target {'context': 'B-cells'}", + "107, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "102, HTLV-1-producing ['l0', 'l1', 'l2']", + "103, cells ['l0', 'l3', 'l4']", + "106, target ['l1', 'l3', 'l5']", + "107, cells. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19966811", + "TEXT": "Hepatocyte nuclear factor-1beta (HNF-1beta) is a transcription factor required for the expression of several renal cystic genes and whose prenatal deletion leads to polycystic kidney disease (PKD). We show here that inactivation of Hnf1b from postnatal day 10 onward does not elicit cystic dilations in tubules after their proliferative morphogenetic elongation is over. Cystogenic resistance is intrinsically linked to the quiescent state of cells. In fact, when Hnf1b deficient quiescent cells are forced to proliferate by an ischemia-reperfusion injury, they give rise to cysts, owing to loss of oriented cell division. Remarkably, in quiescent cells, the transcription of crucial cystogenic target genes is maintained even in the absence of HNF-1beta. However, their expression is lost as soon as cells proliferate and the chromatin of target genes acquires heterochromatin marks. These results unveil a previously undescribed aspect of gene regulation. It is well established that transcription is shut off during the mitotic condensation of chromatin. We propose that transcription factors such as HNF-1beta might be involved in reprogramming gene expression after transcriptional silencing is induced by mitotic chromatin condensation. Notably, HNF-1beta remains associated with the mitotically condensed chromosomal barrels. This association suggests that HNF-1beta is a bookmarking factor that is necessary for reopening the chromatin of target genes after mitotic silencing.", + "TAG_DATA": [ + "31, inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "32, of {'perturbing_action': 'I-gene loss-of-function'}", + "33, Hnf1b {'perturbing_action': 'I-gene loss-of-function'}", + "67, Hnf1b {'perturbing_action': 'B-gene loss-of-function'}", + "68, deficient {'perturbing_action': 'I-gene loss-of-function'}", + "69, quiescent {'context': 'B-cells'}", + "70, cells {'context': 'I-cells'}", + "72, forced {'effect': 'B-positive'}", + "74, proliferate {'phenotype': 'B-proliferation'}", + "86, loss {'effect': 'B-negative'}", + "89, cell {'phenotype': 'B-proliferation'}", + "90, division. {'phenotype': 'I-proliferation'}", + "93, quiescent {'context': 'B-cells'}", + "94, cells, {'context': 'I-cells'}", + "118, cells {'context': 'B-cells'}", + "119, proliferate {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "31, inactivation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "32, of ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "33, Hnf1b ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "67, Hnf1b ['l2', 'l13', 'l23', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "68, deficient ['l3', 'l14', 'l24', 'l32', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "69, quiescent ['l4', 'l15', 'l25', 'l33', 'l41', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "70, cells ['l5', 'l16', 'l26', 'l34', 'l42', 'l49', 'l56', 'l57', 'l58', 'l59', 'l60']", + "72, forced ['l6', 'l17', 'l27', 'l35', 'l43', 'l50', 'l56', 'l61', 'l62', 'l63', 'l64', 'l65']", + "74, proliferate ['l7', 'l18', 'l28', 'l36', 'l44', 'l51', 'l57', 'l61', 'l66', 'l67', 'l68', 'l69']", + "86, loss ['l8', 'l19', 'l29', 'l37', 'l45', 'l52', 'l58', 'l62', 'l66', 'l70', 'l71', 'l72']", + "89, cell ['l9', 'l20', 'l30', 'l38', 'l46', 'l53', 'l59', 'l63', 'l67', 'l70', 'l73', 'l74']", + "90, division. ['l10', 'l21', 'l31', 'l39', 'l47', 'l54', 'l60', 'l64', 'l68', 'l71', 'l73', 'l75']", + "93, quiescent ['l76', 'l77', 'l78']", + "94, cells, ['l11', 'l22', 'l40', 'l48', 'l55', 'l65', 'l69', 'l72', 'l74', 'l75', 'l76', 'l79', 'l80']", + "118, cells ['l77', 'l79', 'l81']", + "119, proliferate ['l78', 'l80', 'l81']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "Hnf1b", + "deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "quiescent", + "cells", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "Hnf1b", + "deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "forced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "Hnf1b", + "deficient" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate", + "cell", + "division." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "Hnf1b", + "deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "quiescent", + "cells", + "cells," + ] + }, + "effect": { + "val": "positive", + "words": [ + "forced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "quiescent", + "cells", + "cells," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate", + "cell", + "division." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "quiescent", + "cells", + "cells," + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "forced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate", + "cell", + "division." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate", + "cell", + "division." + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + } + ] + }, + { + "PMID": "19966782", + "TEXT": "Retroviral vectors have induced subtle clonal skewing in many gene therapy patients and severe clonal proliferation and leukemia in some of them, emphasizing the need for comprehensive integration site analyses to assess the biosafety and genomic pharmacokinetics of vectors and clonal fate of gene-modified cells in vivo. Integration site analyses such as linear amplification-mediated PCR (LAM-PCR) require a restriction digest generating unevenly small fragments of the genome. Here we show that each restriction motif allows for identification of only a fraction of all genomic integrants, hampering the understanding and prediction of biological consequences after vector insertion. We developed a model to define genomic access to the viral integration site that provides optimal restriction motif combinations and minimizes the percentage of nonaccessible insertion loci. We introduce a new nonrestrictive LAM-PCR approach that has superior capabilities for comprehensive unbiased integration site retrieval in preclinical and clinical samples independent of restriction motifs and amplification inefficiency.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19966780", + "TEXT": "Excitotoxic neuronal damage caused by overactivation of N-methyl-D-aspartate glutamate receptors (NMDARs) is thought to be a principal cause of neuronal loss after stroke and brain trauma. Here we report that activation of sterol regulatory element binding protein-1 (SREBP-1) transcription factor in affected neurons is an essential step in NMDAR-mediated excitotoxic neuronal death in both in vitro and in vivo models of stroke. The NMDAR-mediated activation of SREBP-1 is a result of increased insulin-induced gene-1 (Insig-1) degradation, which can be inhibited with an Insig-1-derived interference peptide (Indip) that we have developed. Using a focal ischemia model of stroke, we show that systemic administration of Indip not only prevents SREBP-1 activation but also substantially reduces neuronal damage and improves behavioral outcome. Our study suggests that agents that reduce SREBP-1 activation such as Indip may represent a new class of neuroprotective therapeutics against stroke.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19915593", + "TEXT": "Huntington's disease is caused by an expanded CAG repeat in the gene encoding huntingtin (HTT), resulting in loss of striatal and cortical neurons. Given that the gene product is widely expressed, it remains unclear why neurons are selectively targeted. Here we show the relationship between synaptic and extrasynaptic activity, inclusion formation of mutant huntingtin protein (mtHtt) and neuronal survival. Synaptic N-methyl-D-aspartate-type glutamate receptor (NMDAR) activity induces mtHtt inclusions via a T complex-1 (TCP-1) ring complex (TRiC)-dependent mechanism, rendering neurons more resistant to mtHtt-mediated cell death. In contrast, stimulation of extrasynaptic NMDARs increases the vulnerability of mtHtt-containing neurons to cell death by impairing the neuroprotective cyclic AMP response element-binding protein (CREB)-peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) cascade and increasing the level of the small guanine nucleotide-binding protein Rhes, which is known to sumoylate and disaggregate mtHtt. Treatment of transgenic mice expressing a yeast artificial chromosome containing 128 CAG repeats (YAC128) with low-dose memantine blocks extrasynaptic (but not synaptic) NMDARs and ameliorates neuropathological and behavioral manifestations. By contrast, high-dose memantine, which blocks both extrasynaptic and synaptic NMDAR activity, decreases neuronal inclusions and worsens these outcomes. Our findings offer a rational therapeutic approach for protecting susceptible neurons in Huntington's disease.", + "TAG_DATA": [ + "78, neurons {'context': 'B-cells'}", + "79, more {'effect': 'B-positive'}", + "80, resistant {'effect': 'I-positive'}", + "81, to {'effect': 'I-positive'}", + "83, cell {'phenotype': 'B-cell death'}", + "84, death. {'phenotype': 'I-cell death'}", + "96, neurons {'context': 'B-cells'}", + "98, cell {'phenotype': 'B-cell death'}", + "99, death {'phenotype': 'I-cell death'}", + "136, transgenic {'perturbing_action': 'B-other', 'context': 'B-organism'}", + "137, mice {'context': 'I-organism'}", + "138, expressing {'perturbing_action': 'B-other'}", + "139, a {'perturbing_action': 'I-other'}", + "140, yeast {'perturbing_action': 'I-other'}", + "141, artificial {'perturbing_action': 'I-other'}", + "142, chromosome {'perturbing_action': 'I-other'}", + "143, containing {'perturbing_action': 'I-other'}", + "144, 128 {'perturbing_action': 'I-other'}", + "145, CAG {'perturbing_action': 'I-other'}", + "146, repeats {'perturbing_action': 'I-other'}", + "147, (YAC128) {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "78, neurons ['l0', 'l1', 'l2', 'l3', 'l4']", + "79, more ['l0', 'l5', 'l6', 'l7', 'l8']", + "80, resistant ['l1', 'l5', 'l9', 'l10', 'l11']", + "81, to ['l2', 'l6', 'l9', 'l12', 'l13']", + "83, cell ['l3', 'l7', 'l10', 'l12', 'l14']", + "84, death. ['l4', 'l8', 'l11', 'l13', 'l14']", + "96, neurons ['l15', 'l16']", + "98, cell ['l15', 'l17']", + "99, death ['l16', 'l17']", + "136, transgenic ['l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "137, mice ['l18', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "138, expressing ['l19', 'l29', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "139, a ['l20', 'l30', 'l39', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "140, yeast ['l21', 'l31', 'l40', 'l48', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "141, artificial ['l22', 'l32', 'l41', 'l49', 'l56', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "142, chromosome ['l23', 'l33', 'l42', 'l50', 'l57', 'l63', 'l69', 'l70', 'l71', 'l72', 'l73']", + "143, containing ['l24', 'l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l74', 'l75', 'l76', 'l77']", + "144, 128 ['l25', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l78', 'l79', 'l80']", + "145, CAG ['l26', 'l36', 'l45', 'l53', 'l60', 'l66', 'l71', 'l75', 'l78', 'l81', 'l82']", + "146, repeats ['l27', 'l37', 'l46', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l81', 'l83']", + "147, (YAC128) ['l28', 'l38', 'l47', 'l55', 'l62', 'l68', 'l73', 'l77', 'l80', 'l82', 'l83']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "neurons" + ] + }, + "effect": { + "val": "positive", + "words": [ + "more", + "resistant", + "to" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neurons" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death.", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "more", + "resistant", + "to" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "transgenic", + "expressing", + "a", + "yeast", + "artificial", + "chromosome", + "containing", + "128", + "CAG", + "repeats", + "(YAC128)" + ] + }, + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + } + } + ] + }, + { + "PMID": "19898489", + "TEXT": "5q- syndrome is a subtype of myelodysplastic syndrome characterized by severe anemia and variable neutropenia but normal or high platelet counts with dysplastic megakaryocytes. We examined expression of microRNAs (miRNAs) encoded on chromosome 5q as a possible cause of haploinsufficiency. We show that deletion of chromosome 5q correlates with loss of two miRNAs that are abundant in hematopoietic stem/progenitor cells (HSPCs), miR-145 and miR-146a, and we identify Toll-interleukin-1 receptor domain-containing adaptor protein (TIRAP) and tumor necrosis factor receptor-associated factor-6 (TRAF6) as respective targets of these miRNAs. TIRAP is known to lie upstream of TRAF6 in innate immune signaling. Knockdown of miR-145 and miR-146a together or enforced expression of TRAF6 in mouse HSPCs resulted in thrombocytosis, mild neutropenia and megakaryocytic dysplasia. A subset of mice transplanted with TRAF6-expressing marrow progressed either to marrow failure or acute myeloid leukemia. Thus, inappropriate activation of innate immune signals in HSPCs phenocopies several clinical features of 5q- syndrome.", + "TAG_DATA": [ + "98, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "99, of {'perturbing_action': 'I-rnai/knockdown'}", + "100, miR-145 {'perturbing_action': 'I-rnai/knockdown'}", + "101, and {'perturbing_action': 'I-rnai/knockdown'}", + "102, miR-146a {'perturbing_action': 'I-rnai/knockdown'}", + "105, enforced {'perturbing_action': 'B-gene gain-of-function'}", + "106, expression {'perturbing_action': 'I-gene gain-of-function'}", + "107, of {'perturbing_action': 'I-gene gain-of-function'}", + "108, TRAF6 {'perturbing_action': 'I-gene gain-of-function'}", + "110, mouse {'context': 'B-cells'}", + "111, HSPCs {'context': 'I-cells'}", + "123, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "98, Knockdown ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "99, of ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "100, miR-145 ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "101, and ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "102, miR-146a ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "105, enforced ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "106, expression ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "107, of ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "108, TRAF6 ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "110, mouse ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "111, HSPCs ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "miR-145", + "and", + "miR-146a" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "HSPCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "enforced", + "expression", + "of", + "TRAF6" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "HSPCs" + ] + } + } + ] + }, + { + "PMID": "19820717", + "TEXT": "Advances in biosensor technologies for in vitro diagnostics have the potential to transform the practice of medicine. Despite considerable work in the biosensor field, there is still no general sensing platform that can be ubiquitously applied to detect the constellation of biomolecules in diverse clinical samples (for example, serum, urine, cell lysates or saliva) with high sensitivity and large linear dynamic range. A major limitation confounding other technologies is signal distortion that occurs in various matrices due to heterogeneity in ionic strength, pH, temperature and autofluorescence. Here we present a magnetic nanosensor technology that is matrix insensitive yet still capable of rapid, multiplex protein detection with resolution down to attomolar concentrations and extensive linear dynamic range. The matrix insensitivity of our platform to various media demonstrates that our magnetic nanosensor technology can be directly applied to a variety of settings such as molecular biology, clinical diagnostics and biodefense.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19783995", + "TEXT": "Rapid chilling causes glycoprotein-Ib (GPIb) receptors to cluster on blood platelets. Hepatic macrophage beta(2) integrin binding to beta-N-acetylglucosamine (beta-GlcNAc) residues in the clusters leads to rapid clearance of acutely chilled platelets after transfusion. Although capping the beta-GlcNAc moieties by galactosylation prevents clearance of short-term-cooled platelets, this strategy is ineffective after prolonged refrigeration. We report here that prolonged refrigeration increased the density and concentration of exposed galactose residues on platelets such that hepatocytes, through Ashwell-Morell receptor binding, become increasingly involved in platelet removal. Macrophages rapidly removed a large fraction of transfused platelets independent of their storage conditions. With prolonged platelet chilling, hepatocyte-dependent clearance further diminishes platelet recovery and survival after transfusion. Inhibition of chilled platelet clearance by both beta(2) integrin and Ashwell-Morell receptors may afford a potentially simple method for storing platelets in the cold.", + "TAG_DATA": [ + "68, platelets {'context': 'B-cells'}", + "71, hepatocytes, {'context': 'B-cells'}", + "82, Macrophages {'context': 'B-cells'}", + "90, platelets {'context': 'B-cells'}", + "104, platelet {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "68, platelets ['l0', 'l1']", + "71, hepatocytes, ['l0', 'l2']", + "82, Macrophages ['l3']", + "90, platelets ['l1', 'l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19749771", + "TEXT": "The brain vasculature forms an immense network such that most neural cells are in contact with a microvessel. Here we tested the hypothesis that endothelia lining these vessels can be harnessed to create a cellular reservoir of enzyme replacement therapy to diseased brain. As a model system, we used mice with central nervous system (CNS) deficits due to lysosomal storage disease (LSD mice). The basic premise of this work is that recombinant enzyme expressed in, and secreted from, the vascular endothelia will be endocytosed by underlying neurons and glia, decreasing neuropathology. We screened a phage library in vivo by panning to identify peptides that bound the vascular endothelia in diseased and wild-type mice. Epitopes binding diseased brain were distinct from those panned from normal brain. Moreover, different epitopes were identified in two distinct LSD disease models, implying a unique vascular signature imparted by the disease state. Presentation of these epitopes on the capsid of adeno-associated virus (AAV) expanded the biodistribution of intravenously injected AAV from predominantly liver to include the CNS. Peripheral injection of the epitope-modified AAVs expressing the enzymes lacking in LSD mice reconstituted enzyme activity throughout the brain and improved disease phenotypes in two distinct disease models.", + "TAG_DATA": [ + "96, in {'context': 'B-in vivo'}", + "97, vivo {'context': 'I-in vivo'}", + "112, mice. {'context': 'B-organism'}", + "116, brain {'context': 'B-tissue/organ'}", + "189, brain {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "96, in ['l0', 'l1']", + "97, vivo ['l0', 'l2']", + "112, mice. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19734909", + "TEXT": "Lissencephaly is a devastating neurological disorder caused by defective neuronal migration. LIS1 (official symbol PAFAH1B1, for platelet-activating factor acetylhydrolase, isoform 1b, subunit 1) was identified as the gene mutated in individuals with lissencephaly, and it was found to regulate cytoplasmic dynein function and localization. Here we show that inhibition or knockdown of calpains protects LIS1 from proteolysis, resulting in the augmentation of LIS1 amounts in Lis1(+/-) mouse embryonic fibroblast cells and rescue of the aberrant distribution of cytoplasmic dynein, mitochondria and beta-COP-positive vesicles. We also show that calpain inhibitors improve neuronal migration of Lis1(+/-) cerebellar granular neurons. Intraperitoneal injection of the calpain inhibitor ALLN to pregnant Lis1(+/-) dams rescued apoptotic neuronal cell death and neuronal migration defects in Lis1(+/-) offspring. Furthermore, in utero knockdown of calpain by short hairpin RNA rescued defective cortical layering in Lis1(+/-) mice. Thus, calpain inhibition is a potential therapeutic intervention for lissencephaly.", + "TAG_DATA": [ + "50, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "51, of {'perturbing_action': 'I-rnai/knockdown'}", + "52, calpains {'perturbing_action': 'I-rnai/knockdown'}", + "65, Lis1(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "66, mouse {'context': 'B-cells'}", + "67, embryonic {'context': 'I-cells'}", + "68, fibroblast {'context': 'I-cells'}", + "69, cells {'context': 'I-cells'}", + "87, calpain {'perturbing_action': 'B-pharmacological inhibition'}", + "88, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "89, improve {'effect': 'B-positive'}", + "91, migration {'phenotype': 'B-migration'}", + "93, Lis1(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "94, cerebellar {'context': 'B-cells'}", + "95, granular {'context': 'I-cells'}", + "96, neurons. {'context': 'I-cells'}", + "101, calpain {'perturbing_action': 'I-pharmacological inhibition'}", + "102, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "103, ALLN {'perturbing_action': 'I-pharmacological inhibition'}", + "106, Lis1(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "107, dams {'context': 'I-organism'}", + "108, rescued {'effect': 'B-rescues'}", + "109, apoptotic {'phenotype': 'B-apoptosis'}", + "110, neuronal {'phenotype': 'I-apoptosis'}", + "111, cell {'phenotype': 'I-apoptosis'}", + "112, death {'phenotype': 'I-apoptosis'}", + "118, Lis1(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "119, offspring. {'context': 'B-organism'}", + "121, in {'context': 'B-in vivo'}", + "122, utero {'context': 'I-in vivo'}", + "123, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "124, of {'perturbing_action': 'I-rnai/knockdown'}", + "125, calpain {'perturbing_action': 'I-rnai/knockdown'}", + "126, by {'perturbing_action': 'I-rnai/knockdown'}", + "127, short {'perturbing_action': 'I-rnai/knockdown'}", + "128, hairpin {'perturbing_action': 'I-rnai/knockdown'}", + "129, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "135, Lis1(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "136, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, knockdown ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "51, of ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "52, calpains ['l1', 'l14', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "65, Lis1(+/-) ['l2', 'l15', 'l26', 'l37', 'l38', 'l39', 'l40', 'l41']", + "66, mouse ['l3', 'l16', 'l27', 'l37', 'l42', 'l43', 'l44', 'l45', 'l46']", + "67, embryonic ['l4', 'l17', 'l28', 'l38', 'l42', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "68, fibroblast ['l5', 'l18', 'l29', 'l39', 'l43', 'l47', 'l53', 'l54', 'l55', 'l56', 'l57']", + "69, cells ['l6', 'l19', 'l30', 'l40', 'l44', 'l48', 'l53']", + "87, calpain ['l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "88, inhibitors ['l7', 'l58', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "89, improve ['l8', 'l20', 'l31', 'l49', 'l54', 'l59', 'l75', 'l88', 'l89', 'l90', 'l91', 'l92']", + "91, migration ['l9', 'l21', 'l32', 'l41', 'l45', 'l50', 'l55', 'l60', 'l76', 'l88', 'l93', 'l94', 'l95', 'l96']", + "93, Lis1(+/-) ['l10', 'l22', 'l33', 'l51', 'l56', 'l61', 'l77', 'l89', 'l93', 'l97', 'l98', 'l99', 'l100', 'l101']", + "94, cerebellar ['l11', 'l23', 'l34', 'l62', 'l78', 'l90', 'l94', 'l97', 'l102', 'l103', 'l104', 'l105', 'l106']", + "95, granular ['l12', 'l24', 'l35', 'l63', 'l79', 'l91', 'l95', 'l98', 'l102', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "96, neurons. ['l13', 'l25', 'l36', 'l46', 'l52', 'l57', 'l64', 'l80', 'l92', 'l96', 'l99', 'l103', 'l107', 'l114', 'l115']", + "101, calpain ['l65', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "102, inhibitor ['l66', 'l116', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "103, ALLN ['l67', 'l117', 'l127', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145']", + "106, Lis1(+/-) ['l68', 'l81', 'l108', 'l118', 'l128', 'l137', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "107, dams ['l69', 'l82', 'l119', 'l129', 'l138', 'l146', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160']", + "108, rescued ['l70', 'l83', 'l109', 'l120', 'l130', 'l139', 'l147', 'l154', 'l161', 'l162', 'l163', 'l164', 'l165']", + "109, apoptotic ['l71', 'l84', 'l110', 'l121', 'l131', 'l140', 'l148', 'l155', 'l161', 'l166', 'l167', 'l168', 'l169']", + "110, neuronal ['l72', 'l85', 'l104', 'l111', 'l122', 'l132', 'l141', 'l149', 'l156', 'l162', 'l166', 'l170', 'l171', 'l172']", + "111, cell ['l73', 'l86', 'l100', 'l105', 'l112', 'l114', 'l123', 'l133', 'l142', 'l150', 'l157', 'l163', 'l167', 'l170', 'l173']", + "112, death ['l74', 'l87', 'l101', 'l106', 'l113', 'l115', 'l124', 'l134', 'l143', 'l151', 'l158', 'l164', 'l168', 'l171', 'l173']", + "118, Lis1(+/-) ['l125', 'l135', 'l144', 'l152', 'l159', 'l165', 'l169', 'l172', 'l174']", + "119, offspring. ['l126', 'l136', 'l145', 'l153', 'l160', 'l174']", + "121, in ['l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184']", + "122, utero ['l175', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "123, knockdown ['l176', 'l185', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201']", + "124, of ['l177', 'l186', 'l194', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208']", + "125, calpain ['l178', 'l187', 'l195', 'l202', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214']", + "126, by ['l179', 'l188', 'l196', 'l203', 'l209', 'l215', 'l216', 'l217', 'l218', 'l219']", + "127, short ['l180', 'l189', 'l197', 'l204', 'l210', 'l215', 'l220', 'l221', 'l222', 'l223']", + "128, hairpin ['l181', 'l190', 'l198', 'l205', 'l211', 'l216', 'l220', 'l224', 'l225', 'l226']", + "129, RNA ['l182', 'l191', 'l199', 'l206', 'l212', 'l217', 'l221', 'l224', 'l227', 'l228']", + "135, Lis1(+/-) ['l183', 'l192', 'l200', 'l207', 'l213', 'l218', 'l222', 'l225', 'l227', 'l229']", + "136, mice. ['l184', 'l193', 'l201', 'l208', 'l214', 'l219', 'l223', 'l226', 'l228', 'l229']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "calpains" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "embryonic", + "fibroblast", + "cells", + "cerebellar", + "granular", + "neurons." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "calpains" + ] + }, + "effect": { + "val": "positive", + "words": [ + "improve" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "calpains" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lis1(+/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "embryonic", + "fibroblast", + "cells", + "cerebellar", + "granular", + "neurons." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lis1(+/-)" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "embryonic", + "fibroblast", + "cerebellar", + "granular", + "neurons." + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "embryonic", + "fibroblast", + "cerebellar", + "granular", + "neurons." + ] + }, + "effect": { + "val": "positive", + "words": [ + "improve" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "calpain", + "inhibitors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "improve" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "calpain", + "inhibitors" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "calpain", + "inhibitors" + ] + }, + "context": { + "val": "cells", + "words": [ + "cerebellar", + "granular", + "neurons." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "calpain", + "inhibitors", + "inhibitor", + "ALLN" + ] + }, + "context": { + "val": "organism", + "words": [ + "dams", + "offspring." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "calpain", + "inhibitors", + "inhibitor", + "ALLN" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "calpain", + "inhibitors", + "inhibitor", + "ALLN" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "neuronal", + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "improve" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "improve" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lis1(+/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lis1(+/-)" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "cell", + "death", + "apoptotic", + "neuronal" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cerebellar", + "granular", + "neurons." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "neuronal", + "cell", + "death", + "apoptotic" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "granular" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lis1(+/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "dams", + "offspring.", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lis1(+/-)" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "dams" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "dams" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "neuronal", + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "neuronal", + "cell", + "death" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "utero" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "calpain", + "by", + "short", + "hairpin", + "RNA" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "utero" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lis1(+/-)" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "calpain", + "by", + "short", + "hairpin", + "RNA" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "19701205", + "TEXT": "Primary cilia are present on most mammalian cells and are implicated in transducing Hedgehog (Hh) signals during development; however, the prevalence of cilia on human tumors remains unclear, and the role of cilia in cancer has not been examined. Here we show that human basal cell carcinomas (BCCs) are frequently ciliated, and we test the role of cilia in BCC by conditionally deleting Kif3a (encoding kinesin family member 3A) or Ift88 (encoding intraflagellar transport protein 88), genes required for ciliogenesis, in two Hh pathway-dependent mouse tumor models. Ciliary ablation strongly inhibited BCC-like tumors induced by an activated form of Smoothened. In contrast, removal of cilia accelerated tumors induced by activated Gli2, a transcriptional effector of Hh signaling. These seemingly paradoxical effects are consistent with a dual role for cilia in mediating both the activation and the repression of the Hh signaling pathway. Our findings demonstrate that cilia function as unique signaling organelles that can either mediate or suppress tumorigenesis depending on the nature of the oncogenic initiating event.", + "TAG_DATA": [ + "61, conditionally {'perturbing_action': 'B-gene loss-of-function'}", + "62, deleting {'perturbing_action': 'B-gene loss-of-function'}", + "63, Kif3a {'perturbing_action': 'I-gene loss-of-function'}", + "84, mouse {'context': 'B-neoplasm'}", + "85, tumor {'context': 'I-neoplasm'}", + "86, models. {'context': 'I-neoplasm'}", + "87, Ciliary {'perturbing_action': 'B-gene loss-of-function'}", + "88, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "90, inhibited {'effect': 'B-negative'}", + "91, BCC-like {'context': 'B-neoplasm'}", + "92, tumors {'context': 'I-neoplasm'}", + "105, accelerated {'effect': 'B-positive'}", + "106, tumors {'phenotype': 'B-tumourigenesis'}", + "107, induced {'effect': 'B-positive'}" + ], + "LINK_DATA": [ + "61, conditionally ['l0', 'l1', 'l2', 'l3', 'l4']", + "62, deleting ['l0', 'l5', 'l6', 'l7', 'l8']", + "63, Kif3a ['l1', 'l5', 'l9', 'l10', 'l11', 'l12', 'l13']", + "84, mouse ['l2', 'l6', 'l9', 'l14', 'l15']", + "85, tumor ['l3', 'l7', 'l10', 'l14', 'l16']", + "86, models. ['l4', 'l8', 'l11', 'l15', 'l16']", + "87, Ciliary ['l17', 'l18', 'l19', 'l20']", + "88, ablation ['l17', 'l21', 'l22', 'l23']", + "90, inhibited ['l18', 'l21', 'l24', 'l25']", + "91, BCC-like ['l12', 'l19', 'l22', 'l24', 'l26']", + "92, tumors ['l13', 'l20', 'l23', 'l25', 'l26']", + "105, accelerated ['l27', 'l28']", + "106, tumors ['l27', 'l29']", + "107, induced ['l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditionally", + "deleting", + "Kif3a", + "Ciliary", + "ablation" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "tumor", + "models.", + "BCC-like", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ciliary", + "ablation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "BCC-like", + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "accelerated", + "induced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors" + ] + } + } + ] + }, + { + "PMID": "19684582", + "TEXT": "Aggrecan cleavage by a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 5 (ADAMTS-5) is crucial for the breakdown of cartilage matrix during osteoarthritis, a degenerative joint disease that leads to the progressive destruction of articular structures. The mechanisms of ADAMTS-5 activation and their links to the pathogenesis of osteoarthritis remain poorly understood, but syndecans have been shown to be involved in the activation of ADAMTS-4 (ref. 3). Here we show that syndecan-4 is specifically induced in type X collagen-producing chondrocytes both in human osteoarthritis and in murine models of the disease. The loss of syndecan-4 in genetically modified mice and intra-articular injections of syndecan-4-specific antibodies into wild-type mice protect from proteoglycan loss and thereby prevent osteoarthritic cartilage damage in a surgically induced model of osteoarthritis. The occurrence of less severe osteoarthritis-like cartilage destruction in both syndecan-4-deficient mice and syndecan-4-specific antibody-treated wild-type mice results from a marked decrease in ADAMTS-5 activity. Syndecan-4 controls the activation of ADAMTS-5 through direct interaction with the protease and through regulating mitogen-activated protein kinase (MAPK)-dependent synthesis of matrix metalloproteinase-3 (MMP-3). Our data suggest that strategies aimed at the inhibition of syndecan-4 will be of great value for the treatment of cartilage damage in osteoarthritis.", + "TAG_DATA": [ + "95, loss {'perturbing_action': 'B-gene loss-of-function'}", + "96, of {'perturbing_action': 'I-gene loss-of-function'}", + "97, syndecan-4 {'perturbing_action': 'I-gene loss-of-function'}", + "100, modified {'context': 'I-organism'}", + "101, mice {'context': 'I-organism'}", + "110, mice {'context': 'B-organism'}", + "138, syndecan-4-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "139, mice {'context': 'B-organism'}", + "144, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "95, loss ['l0', 'l1', 'l2', 'l3', 'l4']", + "96, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "97, syndecan-4 ['l1', 'l5', 'l9', 'l10', 'l11', 'l12']", + "99, genetically ['l2', 'l6', 'l9', 'l13', 'l14']", + "100, modified ['l3', 'l7', 'l10', 'l13', 'l15']", + "101, mice ['l4', 'l8', 'l11', 'l14', 'l15']", + "110, mice ['l12']", + "138, syndecan-4-deficient ['l16']", + "139, mice ['l16']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "syndecan-4", + "syndecan-4-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "modified", + "mice" + ] + } + } + ] + }, + { + "PMID": "19648928", + "TEXT": "Basal-like breast cancers arising in women carrying mutations in the BRCA1 gene, encoding the tumor suppressor protein BRCA1, are thought to develop from the mammary stem cell. To explore early cellular changes that occur in BRCA1 mutation carriers, we have prospectively isolated distinct epithelial subpopulations from normal mammary tissue and preneoplastic specimens from individuals heterozygous for a BRCA1 mutation. We describe three epithelial subsets including basal stem/progenitor, luminal progenitor and mature luminal cells. Unexpectedly, we found that breast tissue from BRCA1 mutation carriers harbors an expanded luminal progenitor population that shows factor-independent growth in vitro. Moreover, gene expression profiling revealed that breast tissue heterozygous for a BRCA1 mutation and basal breast tumors were more similar to normal luminal progenitor cells than any other subset, including the stem cell-enriched population. The c-KIT tyrosine kinase receptor (encoded by KIT) emerged as a key marker of luminal progenitor cells and was more highly expressed in BRCA1-associated preneoplastic tissue and tumors. Our findings suggest that an aberrant luminal progenitor population is a target for transformation in BRCA1-associated basal tumors .", + "TAG_DATA": [ + "93, in {'context': 'B-in vitro'}", + "94, vitro. {'context': 'B-in vitro'}", + "101, breast {'context': 'B-neoplasm'}", + "102, tissue {'context': 'I-neoplasm'}", + "103, heterozygous {'perturbing_action': 'B-other'}", + "104, for {'perturbing_action': 'I-other'}", + "105, a {'perturbing_action': 'I-other'}", + "106, BRCA1 {'perturbing_action': 'I-other'}", + "107, mutation {'perturbing_action': 'I-other'}", + "109, basal {'context': 'B-neoplasm'}", + "110, breast {'context': 'I-neoplasm'}", + "111, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "93, in ['l0']", + "94, vitro. ['l0']", + "101, breast ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "102, tissue ['l1', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "103, heterozygous ['l2', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "104, for ['l3', 'l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "105, a ['l4', 'l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "106, BRCA1 ['l5', 'l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "107, mutation ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "109, basal ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "110, breast ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "111, tumors ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "breast", + "tissue", + "basal", + "tumors" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous", + "for", + "a", + "BRCA1", + "mutation" + ] + } + } + ] + }, + { + "PMID": "19620961", + "TEXT": "The immunologic basis for the potential enhanced HIV-1 acquisition in adenovirus serotype 5 (Ad5)-seropositive individuals who received the Merck recombinant Ad5 HIV-1 vaccine in the STEP study remains unclear. Here we show that baseline Ad5-specific neutralizing antibodies are not correlated with Ad5-specific T lymphocyte responses and that Ad5-seropositive subjects do not develop higher vector-specific cellular immune responses as compared with Ad5-seronegative subjects after vaccination. These findings challenge the hypothesis that activated Ad5-specific T lymphocytes were the cause of the potential enhanced HIV-1 susceptibility in the STEP study.", + "TAG_DATA": [ + "47, Ad5-seropositive {'perturbing_action': 'B-other'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19597505", + "TEXT": "Manifestations of viral infections can differ between women and men, and marked sex differences have been described in the course of HIV-1 disease. HIV-1-infected women tend to have lower viral loads early in HIV-1 infection but progress faster to AIDS for a given viral load than men. Here we show substantial sex differences in the response of plasmacytoid dendritic cells (pDCs) to HIV-1. pDCs derived from women produce markedly more interferon-alpha (IFN-alpha) in response to HIV-1-encoded Toll-like receptor 7 (TLR7) ligands than pDCs derived from men, resulting in stronger secondary activation of CD8(+) T cells. In line with these in vitro studies, treatment-naive women chronically infected with HIV-1 had considerably higher levels of CD8(+) T cell activation than men after adjusting for viral load. These data show that sex differences in TLR-mediated activation of pDCs may account for higher immune activation in women compared to men at a given HIV-1 viral load and provide a mechanism by which the same level of viral replication might result in faster HIV-1 disease progression in women compared to men. Modulation of the TLR7 pathway in pDCs may therefore represent a new approach to reduce HIV-1-associated pathology.", + "TAG_DATA": [ + "57, plasmacytoid {'context': 'B-cells'}", + "58, dendritic {'context': 'I-cells'}", + "59, cells {'context': 'I-cells'}", + "60, (pDCs) {'context': 'I-cells'}", + "63, pDCs {'context': 'B-cells'}", + "82, pDCs {'context': 'B-cells'}", + "92, CD8(+) {'context': 'B-cells'}", + "93, T {'context': 'I-cells'}", + "94, cells. {'context': 'I-cells'}", + "103, women {'context': 'I-organism'}", + "113, CD8(+) {'context': 'B-cells'}", + "114, T {'context': 'I-cells'}", + "115, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "57, plasmacytoid ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "58, dendritic ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "59, cells ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "60, (pDCs) ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "63, pDCs ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "82, pDCs ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "92, CD8(+) ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "93, T ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "94, cells. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "103, women ['l36', 'l37', 'l38']", + "113, CD8(+) ['l36', 'l39', 'l40']", + "114, T ['l37', 'l39', 'l41']", + "115, cell ['l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19584866", + "TEXT": "Many sarcomas and leukemias carry nonrandom chromosomal translocations encoding tumor-specific mutant fusion transcription factors that are essential to their molecular pathogenesis. Ewing's sarcoma family tumors (ESFTs) contain a characteristic t(11;22) translocation leading to expression of the oncogenic fusion protein EWS-FLI1. EWS-FLI1 is a disordered protein that precludes standard structure-based small-molecule inhibitor design. EWS-FLI1 binding to RNA helicase A (RHA) is important for its oncogenic function. We therefore used surface plasmon resonance screening to identify compounds that bind EWS-FLI1 and might block its interaction with RHA. YK-4-279, a derivative of the lead compound from the screen, blocks RHA binding to EWS-FLI1, induces apoptosis in ESFT cells and reduces the growth of ESFT orthotopic xenografts. These findings provide proof of principle that inhibiting the interaction of mutant cancer-specific transcription factors with the normal cellular binding partners required for their oncogenic activity provides a promising strategy for the development of uniquely effective, tumor-specific anticancer agents.", + "TAG_DATA": [ + "100, induces {'effect': 'B-positive'}", + "101, apoptosis {'phenotype': 'B-apoptosis'}", + "103, ESFT {'context': 'B-transformed cells'}", + "104, cells {'context': 'I-transformed cells'}", + "110, ESFT {'context': 'B-xenograft'}", + "111, orthotopic {'context': 'I-xenograft'}", + "112, xenografts. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "100, induces ['l0', 'l1', 'l2']", + "101, apoptosis ['l0', 'l3', 'l4']", + "103, ESFT ['l1', 'l3', 'l5']", + "104, cells ['l2', 'l4', 'l5']", + "110, ESFT ['l6', 'l7']", + "111, orthotopic ['l6', 'l8']", + "112, xenografts. ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ESFT", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ESFT", + "cells" + ] + } + } + ] + }, + { + "PMID": "19584865", + "TEXT": "Memory T cells promote allograft rejection particularly in co-stimulation blockade-based immunosuppressive regimens. Here we show that the CD2-specific fusion protein alefacept (lymphocyte function-associated antigen-3-Ig; LFA -3-Ig) selectively eliminates memory T cells and, when combined with a co-stimulation blockade-based regimen using cytotoxic T lymphocyte antigen-4 (CTLA-4)-Ig, a CD80- and CD86-specific fusion protein, prevents renal allograft rejection and alloantibody formation in nonhuman primates. These results support the immediate translation of a regimen for the prevention of allograft rejection without the use of calcineurin inhibitors, steroids or pan-T cell depletion.", + "TAG_DATA": [ + "28, memory {'context': 'B-cells'}", + "29, T {'context': 'I-cells'}", + "30, cells {'context': 'I-cells'}", + "51, prevents {'effect': 'B-negative'}", + "52, renal {'context': 'B-tissue/organ'}", + "59, nonhuman {'context': 'B-organism'}", + "60, primates. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "28, memory ['l0', 'l1', 'l2', 'l3', 'l4']", + "29, T ['l0', 'l5', 'l6', 'l7', 'l8']", + "30, cells ['l1', 'l5', 'l9', 'l10', 'l11']", + "51, prevents ['l2', 'l6', 'l9', 'l12', 'l13', 'l14', 'l15']", + "52, renal ['l3', 'l7', 'l10', 'l12', 'l16', 'l17', 'l18']", + "53, allograft ['l4', 'l8', 'l11', 'l13', 'l16', 'l19', 'l20']", + "59, nonhuman ['l14', 'l17', 'l19', 'l21']", + "60, primates. ['l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "memory", + "T", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "renal" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "context": { + "val": "organism", + "words": [ + "nonhuman", + "primates." + ] + } + } + ] + }, + { + "PMID": "19543284", + "TEXT": "Enterovirus 71 (EV71) is a major causative agent of hand, foot and mouth disease (HFMD), a common febrile disease occurring mainly in young children. Although clinical manifestations of HFMD are usually mild and self limiting, a severe EV71 outbreak can lead to a diverse array of neurological diseases. Identification of the specific cellular receptors is crucial for elucidating the mechanism of early virus-host interactions and the pathogenesis of enteroviruses. Here we identify human P-selectin glycoprotein ligand-1 (PSGL-1; CD162), a sialomucin membrane protein expressed on leukocytes that has a major role in early stages of inflammation, as a functional receptor for EV71 using an expression cloning method by panning. The N-terminal region of PSGL-1 binds specifically to EV71. Stable PSGL-1 expression allowed EV71 entry and replication, and development of cytopathic effects in nonsusceptible mouse L929 cells. Five out of eight EV71 strains bound soluble PSGL-1 and used intact PSGL-1 as the primary receptor for infection of Jurkat T cells. Three other EV71 strains did not use PSGL-1, suggesting the presence of strain-specific replication of EV71 in leukocytes. EV71 replicated in nonleukocyte cell lines in a PSGL-1-independent manner, indicating the presence of alternative receptor(s) for EV71. The identification of PSGL-1 as a receptor for EV71 sheds new light on a role for PSGL-1-positive leukocytes in cell tropism and pathogenesis during the course of HFMD and other EV71-mediated diseases.", + "TAG_DATA": [ + "117, Stable {'perturbing_action': 'B-gene gain-of-function'}", + "118, PSGL-1 {'perturbing_action': 'I-gene gain-of-function'}", + "119, expression {'perturbing_action': 'I-gene gain-of-function'}", + "132, mouse {'context': 'B-cells'}", + "133, L929 {'context': 'I-cells'}", + "134, cells. {'context': 'I-cells'}", + "155, Jurkat {'context': 'B-cells'}", + "156, T {'context': 'I-cells'}", + "157, cells. {'context': 'I-cells'}", + "179, nonleukocyte {'context': 'B-cells'}", + "180, cell {'context': 'I-cells'}", + "181, lines {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "117, Stable ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "118, PSGL-1 ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "119, expression ['l1', 'l7', 'l12', 'l13', 'l14']", + "132, mouse ['l2', 'l8', 'l12', 'l15', 'l16']", + "133, L929 ['l3', 'l9', 'l13', 'l15', 'l17']", + "134, cells. ['l4', 'l10', 'l14', 'l16', 'l17']", + "155, Jurkat ['l18', 'l19']", + "156, T ['l5', 'l18', 'l20']", + "157, cells. ['l6', 'l11', 'l19', 'l20']", + "179, nonleukocyte ['l21', 'l22']", + "180, cell ['l21', 'l23']", + "181, lines ['l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Stable", + "PSGL-1", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "L929", + "cells.", + "T" + ] + } + } + ] + }, + { + "PMID": "19543282", + "TEXT": "Enterovirus 71 (EV71) belongs to human enterovirus species A of the genus Enterovirus within the family Picornaviridae. EV71, together with coxsackievirus A16 (CVA16), are most frequently associated with hand, foot and mouth disease (HFMD). Although HFMD is considered a mild exanthematous infection, infections involving EV71, but not CVA16, can progress to severe neurological disease, including fatal encephalitis, aseptic meningitis and acute flaccid paralysis. In recent years, epidemic and sporadic outbreaks of neurovirulent EV71 infections have been reported in Taiwan, Malaysia, Singapore, Japan and China. Here, we show that human scavenger receptor class B, member 2 (SCARB2, also known as lysosomal integral membrane protein II or CD36b like-2) is a receptor for EV71. EV71 binds soluble SCARB2 or cells expressing SCARB2, and the binding is inhibited by an antibody to SCARB2. Expression of human SCARB2 enables normally unsusceptible cell lines to support EV71 propagation and develop cytopathic effects. EV71 infection is hampered by the antibody to SCARB2 and soluble SCARB2. SCARB2 also supports the infection of the milder pathogen CVA16. The identification of SCARB2 as an EV71 and CVA16 receptor contributes to a better understanding of the pathogenicity of these viruses.", + "TAG_DATA": [ + "117, cells {'context': 'B-cells'}", + "130, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "131, of {'perturbing_action': 'I-gene gain-of-function'}", + "132, human {'perturbing_action': 'I-gene gain-of-function'}", + "133, SCARB2 {'perturbing_action': 'I-gene gain-of-function'}", + "137, cell {'context': 'B-cells'}", + "138, lines {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "130, Expression ['l0', 'l1', 'l2', 'l3', 'l4']", + "131, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "132, human ['l1', 'l5', 'l9', 'l10', 'l11']", + "133, SCARB2 ['l2', 'l6', 'l9', 'l12', 'l13']", + "137, cell ['l3', 'l7', 'l10', 'l12', 'l14']", + "138, lines ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "human", + "SCARB2" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "lines" + ] + } + } + ] + }, + { + "PMID": "19525965", + "TEXT": "Neutralizing antibodies are thought to be crucial for HIV vaccine protection, but studies in animal models suggest that high antibody concentrations are required. This is a major potential hurdle for vaccine design. However, these studies typically apply a large virus inoculum to ensure infection in control animals in single-challenge experiments. In contrast, most human infection via sexual encounter probably involves repeated exposures to much lower doses of virus. Therefore, animal studies may have provided an overestimate of the levels of antibodies required for protection in humans. We investigated whether plasma concentrations of antibody corresponding to relatively modest neutralization titers in vitro could protect macaques from repeated intravaginal exposure to low doses of a simian immunodeficiency virus-HIV chimera (SHIV) that uses the CC chemokine receptor 5 (CCR5) co-receptor. An effector function-deficient variant of the neutralizing antibody was also included. The results show that a substantially larger number of challenges is required to infect macaques treated with neutralizing antibody than control antibody-treated macaques, and support the notion that effector function may contribute to antibody protection. Overall, the results imply that lower amounts of antibody than previously considered protective may provide benefit in the context of typical human exposure to HIV-1.", + "TAG_DATA": [ + "103, macaques {'context': 'B-organism'}", + "128, effector {'perturbing_action': 'B-gene loss-of-function'}", + "129, function-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "152, macaques {'context': 'B-organism'}", + "160, macaques, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "128, effector ['l0', 'l1', 'l2']", + "129, function-deficient ['l0', 'l3', 'l4']", + "152, macaques ['l1', 'l3', 'l5']", + "160, macaques, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "effector", + "function-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "macaques", + "macaques," + ] + } + } + ] + }, + { + "PMID": "19525962", + "TEXT": "Self-renewing cell populations such as hematopoietic stem cells and memory B and T lymphocytes might be regulated by shared signaling pathways. The Wnt-beta-catenin pathway is an evolutionarily conserved pathway that promotes hematopoietic stem cell self-renewal and multipotency by limiting stem cell proliferation and differentiation, but its role in the generation and maintenance of memory T cells is unknown. We found that induction of Wnt-beta-catenin signaling by inhibitors of glycogen sythase kinase-3beta or the Wnt protein family member Wnt3a arrested CD8(+) T cell development into effector cells. By blocking T cell differentiation, Wnt signaling promoted the generation of CD44(low)CD62L(high)Sca-1(high)CD122(high)Bcl-2(high) self-renewing multipotent CD8(+) memory stem cells with proliferative and antitumor capacities exceeding those of central and effector memory T cell subsets. These findings reveal a key role for Wnt signaling in the maintenance of 'stemness' in mature memory CD8(+) T cells and have major implications for the design of new vaccination strategies and adoptive immunotherapies.", + "TAG_DATA": [ + "66, inhibitors {'perturbing_action': 'B-pharmacological inhibition'}", + "67, of {'perturbing_action': 'I-pharmacological inhibition'}", + "68, glycogen {'perturbing_action': 'I-pharmacological inhibition'}", + "69, sythase {'perturbing_action': 'I-pharmacological inhibition'}", + "70, kinase-3beta {'perturbing_action': 'I-pharmacological inhibition'}", + "71, or {'perturbing_action': 'I-pharmacological inhibition'}", + "72, the {'perturbing_action': 'I-pharmacological inhibition'}", + "77, Wnt3a {'perturbing_action': 'I-pharmacological inhibition'}", + "79, CD8(+) {'context': 'B-cells'}", + "80, T {'context': 'I-cells'}", + "81, cell {'context': 'I-cells'}", + "85, cells. {'context': 'I-cells'}", + "87, blocking {'effect': 'B-negative'}", + "88, T {'context': 'B-cells'}", + "89, cell {'context': 'B-cells'}", + "90, differentiation, {'phenotype': 'B-differentiation'}", + "100, CD8(+) {'context': 'B-cells'}", + "101, memory {'context': 'I-cells'}", + "102, stem {'context': 'I-cells'}", + "103, cells {'context': 'I-cells'}", + "112, central {'context': 'B-cells'}", + "113, and {'context': 'I-cells'}", + "114, effector {'context': 'I-cells'}", + "115, memory {'context': 'I-cells'}", + "116, T {'context': 'I-cells'}", + "117, cell {'context': 'I-cells'}", + "118, subsets. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "66, inhibitors ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "67, of ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "68, glycogen ['l1', 'l16', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "69, sythase ['l2', 'l17', 'l31', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "70, kinase-3beta ['l3', 'l18', 'l32', 'l45', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "71, or ['l4', 'l19', 'l33', 'l46', 'l58', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "72, the ['l5', 'l20', 'l34', 'l47', 'l59', 'l70', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "73, Wnt ['l6', 'l21', 'l35', 'l48', 'l60', 'l71', 'l81', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "77, Wnt3a ['l7', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "79, CD8(+) ['l8', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l100', 'l108', 'l109', 'l110']", + "80, T ['l9', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l108', 'l111', 'l112']", + "81, cell ['l10', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l111', 'l113']", + "85, cells. ['l11', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l112', 'l113']", + "87, blocking ['l12', 'l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l114', 'l115', 'l116']", + "88, T ['l13', 'l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l114', 'l117', 'l118']", + "89, cell ['l14', 'l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l115', 'l117', 'l119']", + "90, differentiation, ['l15', 'l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l116', 'l118', 'l119']", + "100, CD8(+) ['l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "101, memory ['l120', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "102, stem ['l121', 'l130', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "103, cells ['l122', 'l131', 'l139']", + "112, central ['l123', 'l132', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150']", + "113, and ['l124', 'l133', 'l140', 'l145', 'l151', 'l152', 'l153', 'l154', 'l155']", + "114, effector ['l125', 'l134', 'l146', 'l151', 'l156', 'l157', 'l158', 'l159']", + "115, memory ['l126', 'l135', 'l141', 'l147', 'l152', 'l156', 'l160', 'l161', 'l162']", + "116, T ['l127', 'l136', 'l142', 'l148', 'l153', 'l157', 'l160', 'l163', 'l164']", + "117, cell ['l128', 'l137', 'l143', 'l149', 'l154', 'l158', 'l161', 'l163', 'l165']", + "118, subsets. ['l129', 'l138', 'l144', 'l150', 'l155', 'l159', 'l162', 'l164', 'l165']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "glycogen", + "sythase", + "kinase-3beta", + "or", + "the", + "Wnt3a" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "T", + "cell", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "glycogen", + "sythase", + "kinase-3beta", + "or", + "the", + "Wnt3a" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocking" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "glycogen", + "sythase", + "kinase-3beta", + "or", + "the", + "Wnt3a" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocking" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocking" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + } + ] + }, + { + "PMID": "19525961", + "TEXT": "The immunoproteasome, a distinct class of proteasome found predominantly in monocytes and lymphocytes, is known to shape the antigenic repertoire presented on class I major histocompatibility complexes (MHC-I). However, a specific role for the immunoproteasome in regulating other facets of immune responses has not been established. We describe here the characterization of PR-957, a selective inhibitor of low-molecular mass polypeptide-7 (LMP7, encoded by Psmb8), the chymotrypsin-like subunit of the immunoproteasome. PR-957 blocked presentation of LMP7-specific, MHC-I-restricted antigens in vitro and in vivo. Selective inhibition of LMP7 by PR-957 blocked production of interleukin-23 (IL-23) by activated monocytes and interferon-gamma and IL-2 by T cells. In mouse models of rheumatoid arthritis, PR-957 treatment reversed signs of disease and resulted in reductions in cellular infiltration, cytokine production and autoantibody levels. These studies reveal a unique role for LMP7 in controlling pathogenic immune responses and provide a therapeutic rationale for targeting LMP7 in autoimmune disorders.", + "TAG_DATA": [ + "77, in {'context': 'B-in vitro'}", + "78, vitro {'context': 'I-in vitro'}", + "80, in {'context': 'B-in vivo'}", + "81, vivo. {'context': 'I-in vivo'}", + "82, Selective {'perturbing_action': 'B-pharmacological inhibition'}", + "83, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "84, of {'perturbing_action': 'I-pharmacological inhibition'}", + "85, LMP7 {'perturbing_action': 'I-pharmacological inhibition'}", + "86, by {'perturbing_action': 'I-pharmacological inhibition'}", + "87, PR-957 {'perturbing_action': 'I-pharmacological inhibition'}", + "95, monocytes {'context': 'B-cells'}", + "101, T {'context': 'B-cells'}", + "102, cells. {'context': 'B-cells'}", + "104, mouse {'context': 'B-organism'}", + "105, models {'context': 'I-organism'}", + "106, of {'context': 'I-organism'}", + "107, rheumatoid {'context': 'I-organism'}", + "108, arthritis, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "77, in ['l0']", + "78, vitro ['l0']", + "80, in ['l1', 'l2', 'l3']", + "81, vivo. ['l1', 'l4', 'l5']", + "82, Selective ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "83, inhibition ['l6', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "84, of ['l7', 'l19', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "85, LMP7 ['l8', 'l20', 'l31', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "86, by ['l9', 'l21', 'l32', 'l42', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "87, PR-957 ['l10', 'l22', 'l33', 'l43', 'l51', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "95, monocytes ['l2', 'l4', 'l11', 'l23', 'l34', 'l44', 'l52', 'l59', 'l66', 'l67']", + "101, T ['l12', 'l24', 'l35', 'l45', 'l53', 'l60', 'l66', 'l68']", + "102, cells. ['l3', 'l5', 'l13', 'l25', 'l36', 'l46', 'l54', 'l61', 'l67', 'l68']", + "104, mouse ['l14', 'l26', 'l37', 'l69', 'l70', 'l71', 'l72']", + "105, models ['l15', 'l27', 'l38', 'l47', 'l55', 'l62', 'l69', 'l73', 'l74', 'l75']", + "106, of ['l16', 'l28', 'l39', 'l48', 'l56', 'l63', 'l70', 'l73', 'l76', 'l77']", + "107, rheumatoid ['l17', 'l29', 'l40', 'l49', 'l57', 'l64', 'l71', 'l74', 'l76', 'l78']", + "108, arthritis, ['l18', 'l30', 'l41', 'l50', 'l58', 'l65', 'l72', 'l75', 'l77', 'l78']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Selective", + "inhibition", + "of", + "LMP7", + "by", + "PR-957" + ] + }, + "context": { + "val": "cells", + "words": [ + "monocytes", + "T", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Selective", + "inhibition", + "of", + "LMP7", + "by", + "PR-957" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "of", + "rheumatoid", + "arthritis," + ] + } + } + ] + }, + { + "PMID": "19465929", + "TEXT": "Platelet aggregation at sites of vascular injury is essential for hemostasis and arterial thrombosis. It has long been assumed that platelet aggregation and thrombus growth are initiated by soluble agonists generated at sites of vascular injury. By using high-resolution intravital imaging techniques and hydrodynamic analyses, we show that platelet aggregation is primarily driven by changes in blood flow parameters (rheology), with soluble agonists having a secondary role, stabilizing formed aggregates. We find that in response to vascular injury, thrombi initially develop through the progressive stabilization of discoid platelet aggregates. Analysis of blood flow dynamics revealed that discoid platelets preferentially adhere in low-shear zones at the downstream face of forming thrombi, with stabilization of aggregates dependent on the dynamic restructuring of membrane tethers. These findings provide insight into the prothrombotic effects of disturbed blood flow parameters and suggest a fundamental reinterpretation of the mechanisms driving platelet aggregation and thrombus growth.", + "TAG_DATA": [ + "96, discoid {'context': 'B-cells'}", + "97, platelets {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "96, discoid ['l0']", + "97, platelets ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19465927", + "TEXT": "Staphylococcal superantigens are pyrogenic exotoxins that cause massive T cell activation leading to toxic shock syndrome and death. Despite the strong adaptive immune response induced by these toxins, infections by superantigen-producing staphylococci are very common clinical events. We hypothesized that this may be partly a result of staphylococcal strains having developed strategies that downregulate the T cell response to these toxins. Here we show that the human interleukin-2 response to staphylococcal superantigens is inhibited by the simultaneous presence of bacteria. Such a downregulatory effect is the result of peptidoglycan-embedded molecules binding to Toll-like receptor 2 and inducing interleukin-10 production and apoptosis of antigen-presenting cells. We corroborated these findings in vivo by showing substantial prevention of mortality after simultaneous administration of staphylococcal enterotoxin B with either heat-killed staphylococci or Staphylococcus aureus peptidoglycan in mouse models of superantigen-induced toxic shock syndrome.", + "TAG_DATA": [ + "96, inducing {'effect': 'B-positive'}", + "100, apoptosis {'phenotype': 'B-apoptosis'}", + "102, antigen-presenting {'context': 'B-cells'}", + "103, cells. {'context': 'I-cells'}", + "108, in {'context': 'B-in vivo'}", + "109, vivo {'context': 'I-in vivo'}", + "132, mouse {'context': 'B-organism'}", + "133, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "96, inducing ['l0', 'l1', 'l2', 'l3']", + "100, apoptosis ['l0', 'l4', 'l5']", + "102, antigen-presenting ['l1', 'l4', 'l6']", + "103, cells. ['l2', 'l5', 'l6']", + "108, in ['l7', 'l8']", + "109, vivo ['l3', 'l7', 'l9']", + "132, mouse ['l10']", + "133, models ['l8', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "cells", + "words": [ + "antigen-presenting", + "cells." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "antigen-presenting", + "cells." + ] + } + } + ] + }, + { + "PMID": "19424201", + "TEXT": "Interleukin-17 (IL-17A) is a pro-inflammatory cytokine that has recently been implicated in pathogenesis of Langerhans Cell Histiocytosis (LCH), a potentially fatal disease characterized by lesions including CD207+ (langerin +) histiocytes. However, in this study we were unable to identify IL-17A gene expression in Langerhans cell lesions, and plasma levels of IL-17A did not correlate with disease activity. Therefore, this study does not support a central role for IL-17A in LCH pathogenesis.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19377486", + "TEXT": "H2A histone family member X (H2AX, encoded by H2AFX) and its C-terminal phosphorylation (gamma-H2AX) participates in the DNA damage response and mediates DNA repair. Hypoxia is a physiological stress that induces a replication-associated DNA damage response. Moreover, hypoxia is the major driving force for neovascularization, as the hypoxia-mediated induction of vascular growth factors triggers endothelial cell proliferation. Here we studied the role of the hypoxia-induced DNA damage response in endothelial cell function and in hypoxia-driven neovascularization in vivo. Hypoxia induced replication-associated generation of gamma-H2AX in endothelial cells in vitro and in mice. Both in cultured cells and in mice, endothelial cell proliferation under hypoxic conditions was reduced by H2AX deficiency. Whereas developmental angiogenesis was not affected in H2afx(-/-) mice, hypoxia-induced neovascularization during pathologic proliferative retinopathy, in response to hind limb ischemia or during tumor angiogenesis was substantially lower in H2afx(-/-) mice. Moreover, endothelial-specific H2afx deletion resulted in reduced hypoxia-driven retina neovascularization and tumor neovascularization. Our findings establish that H2AX, and hence activation of the DNA repair response, is needed for endothelial cells to maintain their proliferation under hypoxic conditions and is crucial for hypoxia-driven neovascularization.", + "TAG_DATA": [ + "85, endothelial {'context': 'B-cells'}", + "86, cells {'context': 'I-cells'}", + "87, in {'context': 'B-in vitro'}", + "88, vitro {'context': 'I-in vitro'}", + "91, mice. {'context': 'B-organism'}", + "94, cultured {'context': 'B-cells'}", + "95, cells {'context': 'I-cells'}", + "98, mice, {'context': 'B-organism'}", + "99, endothelial {'context': 'B-cells'}", + "100, cell {'context': 'I-cells'}", + "101, proliferation {'phenotype': 'B-proliferation'}", + "106, reduced {'effect': 'B-negative'}", + "108, H2AX {'perturbing_action': 'B-gene loss-of-function'}", + "109, deficiency. {'perturbing_action': 'I-gene loss-of-function'}", + "117, H2afx(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "118, mice, {'context': 'B-organism'}", + "139, H2afx(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "140, mice. {'context': 'B-organism'}", + "142, endothelial-specific {'perturbing_action': 'B-gene loss-of-function'}", + "143, H2afx {'perturbing_action': 'I-gene loss-of-function'}", + "144, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "152, tumor {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "85, endothelial ['l0', 'l1', 'l2', 'l3']", + "86, cells ['l0', 'l4', 'l5']", + "87, in ['l1', 'l4', 'l6']", + "88, vitro ['l2', 'l5', 'l6']", + "91, mice. ['l3', 'l7', 'l8']", + "94, cultured ['l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "95, cells ['l7', 'l9', 'l15', 'l16', 'l17', 'l18']", + "98, mice, ['l10', 'l15', 'l19', 'l20', 'l21', 'l22', 'l23']", + "99, endothelial ['l11', 'l16', 'l19', 'l24', 'l25', 'l26', 'l27']", + "100, cell ['l8', 'l12', 'l17', 'l20', 'l24', 'l28', 'l29']", + "101, proliferation ['l13', 'l18', 'l21', 'l25', 'l28', 'l30', 'l31']", + "106, reduced ['l22', 'l26', 'l30', 'l32', 'l33', 'l34', 'l35']", + "108, H2AX ['l32', 'l36', 'l37', 'l38']", + "109, deficiency. ['l14', 'l23', 'l27', 'l29', 'l31', 'l33', 'l36', 'l39', 'l40']", + "117, H2afx(-/-) ['l34', 'l37', 'l39', 'l41', 'l42', 'l43']", + "118, mice, ['l35', 'l38', 'l40', 'l41', 'l44']", + "139, H2afx(-/-) ['l42', 'l44', 'l45']", + "140, mice. ['l43', 'l45']", + "142, endothelial-specific ['l46', 'l47', 'l48', 'l49']", + "143, H2afx ['l46', 'l50', 'l51', 'l52']", + "144, deletion ['l47', 'l50', 'l53', 'l54']", + "149, retina ['l48', 'l51', 'l53', 'l55']", + "152, tumor ['l49', 'l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cultured", + "cells", + "endothelial", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "endothelial", + "cell" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice,", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency.", + "H2AX", + "H2afx(-/-)" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "H2AX", + "deficiency.", + "H2afx(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "endothelial-specific", + "H2afx", + "deletion" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + } + ] + }, + { + "PMID": "19363496", + "TEXT": "Current methods of protein detection are insensitive to detecting subtle changes in oncoprotein activation that underlie key cancer signaling processes. The requirement for large numbers of cells precludes serial tumor sampling for assessing a response to therapeutics. Therefore, we have developed a nanofluidic proteomic immunoassay (NIA) to quantify total and low-abundance protein isoforms in nanoliter volumes. Our method can quantify amounts of MYC oncoprotein and B cell lymphoma protein-2 (BCL2) in Burkitt's and follicular lymphoma; identify changes in activation of extracellular signal-related kinases-1 (ERK1) and ERK2, mitogen-activated kinase-1 (MEK), signal transducer and activator of transcription protein-3 (STAT3) and STAT5, c-Jun N-terminal kinase (JNK) and caspase-3 in imatinib-treated chronic myelogeneous leukemia (CML) cells; measure an unanticipated change in the phosphorylation of an ERK2 isomer in individuals with CML who responded to imatinib; and detect a decrease in STAT3 and STAT5 phosphorylation in individuals with lymphoma who were treated with atorvastatin. Therefore, we have described a new and highly sensitive method for determining oncoprotein expression and phosphorylation in clinical specimens for the development of new therapeutics for cancer.", + "TAG_DATA": [ + "107, chronic {'context': 'B-transformed cells'}", + "108, myelogeneous {'context': 'I-transformed cells'}", + "109, leukemia {'context': 'I-transformed cells'}", + "110, (CML) {'context': 'I-transformed cells'}", + "111, cells; {'context': 'I-transformed cells'}", + "124, individuals {'context': 'B-patient'}", + "125, with {'context': 'I-patient'}", + "126, CML {'context': 'I-patient'}", + "141, individuals {'context': 'B-patient'}", + "142, with {'context': 'I-patient'}", + "143, lymphoma {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "107, chronic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "108, myelogeneous ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "109, leukemia ['l1', 'l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "110, (CML) ['l2', 'l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "111, cells; ['l3', 'l8', 'l13', 'l17']", + "124, individuals ['l4', 'l9', 'l14', 'l18', 'l21', 'l22']", + "125, with ['l5', 'l10', 'l15', 'l19', 'l21', 'l23']", + "126, CML ['l11', 'l16', 'l20', 'l22', 'l23']", + "141, individuals ['l24', 'l25']", + "142, with ['l24', 'l26']", + "143, lymphoma ['l25', 'l26']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19330008", + "TEXT": "Granulocyte colony-stimulating factor (G-CSF) is often used to hasten neutrophil recovery after allogeneic bone marrow transplantation (BMT), but the clinical and immunological consequences evoked remain unclear. We examined the effect of G-CSF administration after transplantation in mouse models and found that exposure to either standard G-CSF or pegylated-G-CSF soon after BMT substantially increased graft-versus-host disease (GVHD). This effect was dependent on total body irradiation (TBI) rendering host dendritic cells (DCs) responsive to G-CSF by upregulating their expression of the G-CSF receptor. Stimulation of host DCs by G-CSF subsequently unleashed a cascade of events characterized by donor natural killer T cell (NKT cell) activation, interferon-gamma secretion and CD40-dependent amplification of donor cytotoxic T lymphocyte function during the effector phase of GVHD. Crucially, the detrimental effects of G-CSF were only present when it was administered after TBI conditioning and at a time when residual host antigen presenting cells were still present, perhaps explaining the conflicting and somewhat controversial clinical studies from the large European and North American BMT registries. These data have major implications for the use of G-CSF in disease states where NKT cell activation may have effects on outcome.", + "TAG_DATA": [ + "36, mouse {'context': 'B-organism'}", + "37, models {'context': 'I-organism'}", + "67, dendritic {'context': 'I-cells'}", + "68, cells {'context': 'I-cells'}", + "69, (DCs) {'context': 'I-cells'}", + "84, DCs {'context': 'B-cells'}", + "96, natural {'context': 'I-cells'}", + "97, killer {'context': 'I-cells'}", + "98, T {'context': 'I-cells'}", + "99, cell {'context': 'I-cells'}", + "100, (NKT {'context': 'I-cells'}", + "101, cell) {'context': 'I-cells'}", + "143, antigen {'context': 'I-cells'}", + "144, presenting {'context': 'I-cells'}", + "145, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "36, mouse ['l0']", + "37, models ['l0']", + "67, dendritic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "68, cells ['l1', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "69, (DCs) ['l2', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "84, DCs ['l3', 'l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "96, natural ['l4', 'l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "97, killer ['l5', 'l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "98, T ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "99, cell ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "100, (NKT ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "101, cell) ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']", + "143, antigen ['l46', 'l47']", + "144, presenting ['l46', 'l48']", + "145, cells ['l47', 'l48']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19330007", + "TEXT": "Barrier epithelial cells and airway dendritic cells (DCs) make up the first line of defense against inhaled substances such as house dust mite (HDM) allergen and endotoxin (lipopolysaccharide, LPS). We hypothesized that these cells need to communicate with each other to cause allergic disease. We show in irradiated chimeric mice that Toll-like receptor 4 (TLR4) expression on radioresistant lung structural cells, but not on DCs, is necessary and sufficient for DC activation in the lung and for priming of effector T helper responses to HDM. TLR4 triggering on structural cells caused production of the innate proallergic cytokines thymic stromal lymphopoietin, granulocyte-macrophage colony-stimulating factor, interleukin-25 and interleukin-33. The absence of TLR4 on structural cells, but not on hematopoietic cells, abolished HDM-driven allergic airway inflammation. Finally, inhalation of a TLR4 antagonist to target exposed epithelial cells suppressed the salient features of asthma, including bronchial hyperreactivity. Our data identify an innate immune function of airway epithelial cells that drives allergic inflammation via activation of mucosal DCs.", + "TAG_DATA": [ + "48, chimeric {'context': 'B-organism'}", + "49, mice {'context': 'I-organism'}", + "88, structural {'context': 'B-cells'}", + "89, cells {'context': 'I-cells'}", + "107, absence {'perturbing_action': 'B-gene loss-of-function'}", + "108, of {'perturbing_action': 'I-gene loss-of-function'}", + "109, TLR4 {'perturbing_action': 'I-gene loss-of-function'}", + "111, structural {'context': 'B-cells'}", + "112, cells, {'context': 'I-cells'}", + "116, hematopoietic {'context': 'B-cells'}", + "117, cells, {'context': 'I-cells'}", + "127, TLR4 {'perturbing_action': 'B-pharmacological inhibition'}", + "128, antagonist {'perturbing_action': 'I-pharmacological inhibition'}", + "132, epithelial {'context': 'B-cells'}", + "133, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "48, chimeric ['l0', 'l1', 'l2']", + "49, mice ['l0', 'l3']", + "88, structural ['l1', 'l4', 'l5', 'l6']", + "89, cells ['l2', 'l3', 'l4']", + "107, absence ['l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "108, of ['l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "109, TLR4 ['l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "111, structural ['l5', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "112, cells, ['l6', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "116, hematopoietic ['l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "117, cells, ['l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "127, TLR4 ['l28', 'l29', 'l30']", + "128, antagonist ['l28', 'l31', 'l32']", + "132, epithelial ['l29', 'l31', 'l33']", + "133, cells ['l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "TLR4" + ] + }, + "context": { + "val": "cells", + "words": [ + "structural", + "cells,", + "hematopoietic" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "TLR4", + "antagonist" + ] + }, + "context": { + "val": "cells", + "words": [ + "epithelial", + "cells" + ] + } + } + ] + }, + { + "PMID": "19305414", + "TEXT": "The myeloperoxidase (MPO) system of activated phagocytes is central to normal host defense mechanisms, and dysregulated MPO contributes to the pathogenesis of inflammatory disease states ranging from atherosclerosis to cancer. Here we show that upon systemic administration, the small molecule luminol enables noninvasive bioluminescence imaging (BLI) of MPO activity in vivo. Luminol-BLI allowed quantitative longitudinal monitoring of MPO activity in animal models of acute dermatitis, mixed allergic contact hypersensitivity, focal arthritis and spontaneous large granular lymphocytic tumors. Bioluminescence colocalized with histological sites of inflammation and was totally abolished in gene-deleted Mpo(-/-) mice, despite massive tissue infiltration of neutrophils and activated eosinophils, indicating that eosinophil peroxidase did not contribute to luminol-BLI in vivo. Thus, luminol-BLI provides a noninvasive, specific and highly sensitive optical readout of phagocyte-mediated MPO activity in vivo and may enable new diagnostic applications in a wide range of acute and chronic inflammatory conditions.", + "TAG_DATA": [ + "89, gene-deleted {'perturbing_action': 'B-gene loss-of-function'}", + "90, Mpo(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "91, mice, {'context': 'B-organism'}", + "100, eosinophils, {'context': 'B-cells'}", + "110, in {'context': 'B-in vivo'}", + "111, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "89, gene-deleted ['l0', 'l1', 'l2']", + "90, Mpo(-/-) ['l0', 'l3', 'l4']", + "91, mice, ['l1', 'l3']", + "100, eosinophils, ['l2', 'l4', 'l5', 'l6']", + "110, in ['l5', 'l7']", + "111, vivo. ['l6', 'l7']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "gene-deleted", + "Mpo(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "gene-deleted", + "Mpo(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "eosinophils," + ] + } + } + ] + }, + { + "PMID": "19305412", + "TEXT": "Selectins and their ligands mediate leukocyte rolling, allowing interactions with chemokines that lead to integrin activation and arrest. Here we show that E-selectin is crucial for generating a secondary wave of activating signals, transduced specifically by E-selectin ligand-1, that induces polarized, activated alpha(M)beta(2) integrin clusters at the leading edge of crawling neutrophils, allowing capture of circulating erythrocytes or platelets. In a humanized mouse model of sickle cell disease, the capture of erythrocytes by alpha(M)beta(2) microdomains leads to acute lethal vascular occlusions. In a model of transfusion-related acute lung injury, polarized neutrophils capture circulating platelets, resulting in the generation of oxidative species that produce vascular damage and lung injury. Inactivation of E-selectin or alpha(M)beta(2) prevents tissue injury in both inflammatory models, suggesting broad implications of this paradigm in thromboinflammatory diseases. These results indicate that endothelial selectins can influence neutrophil behavior beyond its canonical rolling step through delayed, organ-damaging, polarized activation.", + "TAG_DATA": [ + "61, humanized {'context': 'B-organism'}", + "62, mouse {'context': 'I-organism'}", + "63, model {'context': 'I-organism'}", + "64, of {'context': 'I-organism'}", + "87, lung {'context': 'B-tissue/organ'}", + "106, lung {'context': 'B-tissue/organ'}", + "108, Inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "109, of {'perturbing_action': 'I-gene loss-of-function'}", + "110, E-selectin {'perturbing_action': 'I-gene loss-of-function'}", + "111, or {'perturbing_action': 'I-gene loss-of-function'}", + "112, alpha(M)beta(2) {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "61, humanized ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "62, mouse ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "63, model ['l1', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "64, of ['l2', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "65, sickle ['l3', 'l10', 'l15', 'l19', 'l23', 'l24']", + "66, cell ['l4', 'l11', 'l16', 'l20', 'l23', 'l25', 'l26']", + "67, disease, ['l5', 'l12', 'l17', 'l21', 'l24', 'l25']", + "87, lung ['l6', 'l13', 'l18', 'l22', 'l26', 'l27']", + "106, lung ['l7', 'l27']", + "108, Inactivation ['l28', 'l29', 'l30', 'l31']", + "109, of ['l28', 'l32', 'l33', 'l34']", + "110, E-selectin ['l29', 'l32', 'l35', 'l36']", + "111, or ['l30', 'l33', 'l35', 'l37']", + "112, alpha(M)beta(2) ['l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19287392", + "TEXT": "Animals are remarkably efficient in absorbing dietary fat and assimilating this energy-dense nutrient into the white adipose tissue (WAT) for storage. Although this metabolic efficiency may confer an advantage in times of calorie deprivation, it contributes to obesity and associated metabolic disorders when dietary fat is abundant. Here we show that the intestinal lipid synthesis enzyme acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) has a crucial role in the assimilation of dietary fat and the accretion of body fat in mice. Mice lacking MGAT2 have a normal phenotype on a low-fat diet. However, on a high-fat diet, MGAT2-deficient mice are protected against developing obesity, glucose intolerance, hypercholesterolemia and fatty livers. Caloric intake is normal in MGAT2-deficient mice, and dietary fat is absorbed fully. However, entry of dietary fat into the circulation occurs at a reduced rate. This altered kinetics of fat absorption apparently results in more partitioning of dietary fat toward energy dissipation rather than toward storage in the WAT. Thus, our studies identify MGAT2 as a key determinant of energy metabolism in response to dietary fat and suggest that the inhibition of this enzyme may prove to be a useful strategy for treating obesity and other metabolic diseases associated with excessive fat intake.", + "TAG_DATA": [ + "78, Mice {'context': 'B-organism'}", + "79, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "80, MGAT2 {'perturbing_action': 'I-gene loss-of-function'}", + "94, MGAT2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "95, mice {'context': 'B-organism'}", + "112, MGAT2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "113, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "78, Mice ['l0', 'l1']", + "79, lacking ['l0', 'l2']", + "80, MGAT2 ['l1', 'l2']", + "94, MGAT2-deficient ['l3', 'l4', 'l5']", + "95, mice ['l3']", + "112, MGAT2-deficient ['l4', 'l6']", + "113, mice, ['l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice", + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "MGAT2", + "MGAT2-deficient" + ] + } + } + ] + }, + { + "PMID": "19287391", + "TEXT": "Amyloid-beta (Abeta) peptides, found in Alzheimer's disease brain, accumulate rapidly after traumatic brain injury (TBI) in both humans and animals. Here we show that blocking either beta- or gamma-secretase, enzymes required for production of Abeta from amyloid precursor protein (APP), can ameliorate motor and cognitive deficits and reduce cell loss after experimental TBI in mice. Thus, APP secretases are promising targets for treatment of TBI.", + "TAG_DATA": [ + "24, blocking {'perturbing_action': 'B-pharmacological inhibition'}", + "47, reduce {'effect': 'B-negative'}", + "48, cell {'phenotype': 'B-cell death'}", + "49, loss {'phenotype': 'I-cell death'}", + "54, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "24, blocking ['l0', 'l1', 'l2', 'l3']", + "47, reduce ['l0', 'l4', 'l5', 'l6']", + "48, cell ['l1', 'l4', 'l7', 'l8']", + "49, loss ['l2', 'l5', 'l7', 'l9']", + "54, mice. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blocking" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduce" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blocking" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "loss" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blocking" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduce" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "loss" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduce" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "loss" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "19252501", + "TEXT": "Tumor hypoxia is associated with disease progression, resistance to conventional cancer therapies and poor prognosis. Hypoxia, by largely unknown mechanisms, leads to deregulated accumulation of and signaling via receptor tyrosine kinases (RTKs) that are critical for driving oncogenesis. Here, we show that hypoxia or loss of von Hippel-Lindau protein--the principal negative regulator of hypoxia-inducible factor (HIF)--prolongs the activation of epidermal growth factor receptor that is attributable to lengthened receptor half-life and retention in the endocytic pathway. The deceleration in endocytosis is due to the attenuation of Rab5-mediated early endosome fusion via HIF-dependent downregulation of a critical Rab5 effector, rabaptin-5, at the level of transcription. Primary kidney and breast tumors with strong hypoxic signatures show significantly lower expression of rabaptin-5 RNA and protein. These findings reveal a general role of the oxygen-sensing pathway in endocytosis and support a model in which tumor hypoxia or oncogenic activation of HIF prolongs RTK-mediated signaling by delaying endocytosis-mediated deactivation of receptors.", + "TAG_DATA": [ + "44, loss {'perturbing_action': 'B-gene loss-of-function'}", + "45, of {'perturbing_action': 'I-gene loss-of-function'}", + "46, von {'perturbing_action': 'I-gene loss-of-function'}", + "47, Hippel-Lindau {'perturbing_action': 'I-gene loss-of-function'}", + "48, protein--the {'perturbing_action': 'I-gene loss-of-function'}", + "104, Primary {'context': 'B-neoplasm'}", + "105, kidney {'context': 'I-neoplasm'}", + "106, and {'context': 'I-neoplasm'}", + "107, breast {'context': 'I-neoplasm'}", + "108, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "44, loss ['l0', 'l1', 'l2', 'l3']", + "45, of ['l0', 'l4', 'l5', 'l6']", + "46, von ['l1', 'l4', 'l7', 'l8']", + "47, Hippel-Lindau ['l2', 'l5', 'l7', 'l9']", + "48, protein--the ['l3', 'l6', 'l8', 'l9']", + "104, Primary ['l10', 'l11', 'l12', 'l13']", + "105, kidney ['l10', 'l14', 'l15', 'l16']", + "106, and ['l11', 'l14', 'l17', 'l18']", + "107, breast ['l12', 'l15', 'l17', 'l19']", + "108, tumors ['l13', 'l16', 'l18', 'l19']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19234462", + "TEXT": "Activated antigen-specific T cells produce a variety of effector molecules for clearing infection but also contribute to inflammation and tissue injury. Here we report an anti-inflammatory property of antiviral CD8+ and CD4+ effector T cells (T(eff) cells) in the infected periphery during acute virus infection. We find that, during acute influenza infection, interleukin-10 (IL-10) is produced in the infected lungs in large amounts--exclusively by infiltrating virus-specific T(eff) cells, with CD8+ T(eff) cells contributing a larger fraction of the IL-10 produced. These T(eff) cells in the periphery simultaneously produce IL-10 and proinflammatory cytokines and express lineage markers characteristic of conventional T helper type 1 or T cytotoxic type 1 cells. Notably, blocking the action of the T(eff) cell-derived IL-10 results in enhanced pulmonary inflammation and lethal injury. Our results show that antiviral T(eff) cells exert regulatory functions--that is, they fine-tune the extent of lung inflammation and injury associated with influenza infection by producing an anti-inflammatory cytokine. We discuss the potential implications of these findings for infection with highly pathogenic influenza viruses.", + "TAG_DATA": [ + "69, CD8+ {'context': 'B-cells'}", + "70, T(eff) {'context': 'I-cells'}", + "71, cells {'context': 'I-cells'}", + "115, T(eff) {'context': 'B-cells'}", + "116, cell-derived {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "69, CD8+ ['l0', 'l1']", + "70, T(eff) ['l0', 'l2']", + "71, cells ['l1', 'l2']", + "115, T(eff) ['l3']", + "116, cell-derived ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19234460", + "TEXT": "Monogenic deficiency diseases provide unique opportunities to define the contributions of individual molecules to human physiology and to identify pathologies arising from their dysfunction. Here we describe a deficiency disease in two human siblings that presented with severe bleeding, frequent infections and osteopetrosis at an early age. These symptoms are consistent with but more severe than those reported for people with leukocyte adhesion deficiency III (LAD-III). Mechanistically, these symptoms arose from an inability to activate the integrins expressed on hematopoietic cells, including platelets and leukocytes. Immortalized lymphocyte cell lines isolated from the two individuals showed integrin activation defects. Several proteins previously implicated in integrin activation, including Ras-associated protein-1 (RAP1) and calcium and diacylglycerol-regulated guanine nucleotide exchange factor-1 (CALDAG-GEF1), were present and functional in these cell lines. The genetic basis for this disease was traced to a point mutation in the coding region of the KINDLIN3 (official gene symbol FERMT3) gene. When wild-type KINDLIN-3 was expressed in the immortalized lymphocytes, their integrins became responsive to activation signals. These results identify a genetic disease that severely compromises the health of the affected individuals and establish an essential role of KINDLIN-3 in integrin activation in humans. Furthermore, allogeneic bone marrow transplantation was shown to alleviate the symptoms of the disease.", + "TAG_DATA": [ + "86, lymphocyte {'context': 'B-cells'}", + "87, cell {'context': 'I-cells'}", + "88, lines {'context': 'I-cells'}", + "124, cell {'context': 'B-cells'}", + "125, lines. {'context': 'I-cells'}", + "157, immortalized {'context': 'B-cells'}", + "158, lymphocytes, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "86, lymphocyte ['l0', 'l1', 'l2']", + "87, cell ['l0', 'l3']", + "88, lines ['l1', 'l3']", + "124, cell ['l4']", + "125, lines. ['l2', 'l4']", + "157, immortalized ['l5']", + "158, lymphocytes, ['l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19169264", + "TEXT": "The role of transient receptor potential M4 (Trpm4), an unusual member of the Trp family of ion channels, is poorly understood. Using rodent models of spinal cord injury, we studied involvement of Trpm4 in the progressive expansion of secondary hemorrhage associated with capillary fragmentation, the most destructive mechanism of secondary injury in the central nervous system. Trpm4 mRNA and protein were abundantly upregulated in capillaries preceding their fragmentation and formation of petechial hemorrhages. Trpm4 expression in vitro rendered COS-7 cells highly susceptible to oncotic swelling and oncotic death following ATP depletion. After spinal cord injury, in vivo gene suppression in rats treated with Trpm4 antisense or in Trpm4(-/-) mice preserved capillary structural integrity, eliminated secondary hemorrhage, yielded a threefold to fivefold reduction in lesion volume and produced a substantial improvement in neurological function. To our knowledge, this is the first example of a Trp channel that must undergo de novo expression for manifestation of central nervous system pathology.", + "TAG_DATA": [ + "75, in {'context': 'B-in vitro'}", + "76, vitro {'context': 'I-in vitro'}", + "78, COS-7 {'context': 'B-cells'}", + "79, cells {'context': 'I-cells'}", + "95, in {'context': 'B-in vivo'}", + "96, vivo {'context': 'I-in vivo'}", + "97, gene {'perturbing_action': 'B-rnai/knockdown'}", + "98, suppression {'perturbing_action': 'I-rnai/knockdown'}", + "100, rats {'context': 'B-organism'}", + "103, Trpm4 {'perturbing_action': 'B-rnai/knockdown'}", + "104, antisense {'perturbing_action': 'I-rnai/knockdown'}", + "107, Trpm4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "108, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "75, in ['l0', 'l1', 'l2']", + "76, vitro ['l0', 'l3', 'l4']", + "78, COS-7 ['l1', 'l3', 'l5']", + "79, cells ['l2', 'l4', 'l5']", + "95, in ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "96, vivo ['l6', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "97, gene ['l7', 'l12', 'l18', 'l19', 'l20', 'l21']", + "98, suppression ['l8', 'l13', 'l18', 'l22', 'l23', 'l24']", + "100, rats ['l9', 'l14', 'l19', 'l22', 'l25', 'l26']", + "103, Trpm4 ['l10', 'l15', 'l20', 'l23', 'l25', 'l27', 'l28']", + "104, antisense ['l11', 'l16', 'l21', 'l24', 'l26', 'l27']", + "107, Trpm4(-/-) ['l29']", + "108, mice ['l17', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "gene", + "suppression", + "Trpm4", + "antisense" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "gene", + "suppression", + "Trpm4", + "antisense" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trpm4(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "19151729", + "TEXT": "Tumor necrosis factor (TNF) synthesis is known to play a major part in numerous inflammatory disorders, and multiple transcriptional and post-transcriptional regulatory mechanisms have therefore evolved to dampen the production of this key proinflammatory cytokine. The high expression of nicotinamide phosphoribosyltransferase (Nampt), an enzyme involved in the nicotinamide-dependent NAD biosynthetic pathway, in cells of the immune system has led us to examine the potential relationship between NAD metabolism and inflammation. We show here that intracellular NAD concentration promotes TNF synthesis by activated immune cells. Using a positive screen, we have identified Sirt6, a member of the sirtuin family, as the NAD-dependent enzyme able to regulate TNF production by acting at a post-transcriptional step. These studies reveal a previously undescribed relationship between metabolism and the inflammatory response and identify Sirt6 and the nicotinamide-dependent NAD biosynthetic pathway as novel candidates for immunointervention in an inflammatory setting.", + "TAG_DATA": [ + "82, immune {'context': 'B-cells'}", + "83, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "82, immune ['l0']", + "83, cells. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19136964", + "TEXT": "A main function of white adipose tissue is to release fatty acids from stored triacylglycerol for other tissues to use as an energy source. Whereas endocrine regulation of lipolysis has been extensively studied, autocrine and paracrine regulation is not well understood. Here we describe the role of the newly identified major adipocyte phospholipase A(2), AdPLA (encoded by Pla2g16, also called HREV107), in the regulation of lipolysis and adiposity. AdPLA-null mice have a markedly higher rate of lipolysis owing to increased cyclic AMP levels arising from the marked reduction in the amount of adipose prostaglandin E(2) that binds the Galpha(i)-coupled receptor, EP3. AdPLA-null mice have markedly reduced adipose tissue mass and triglyceride content but normal adipogenesis. They also have higher energy expenditure with increased fatty acid oxidation within adipocytes. AdPLA-deficient ob/ob mice remain hyperphagic but lean, with increased energy expenditure, yet have ectopic triglyceride storage and insulin resistance. AdPLA is a major regulator of adipocyte lipolysis and is crucial for the development of obesity.", + "TAG_DATA": [ + "68, AdPLA-null {'perturbing_action': 'B-gene loss-of-function'}", + "69, mice {'context': 'B-organism'}", + "101, AdPLA-null {'perturbing_action': 'B-gene loss-of-function'}", + "102, mice {'context': 'B-organism'}", + "127, adipocytes. {'context': 'B-cells'}", + "128, AdPLA-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "129, ob/ob {'perturbing_action': 'B-gene loss-of-function', 'context': 'B-organism'}", + "130, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "68, AdPLA-null ['l0']", + "69, mice ['l0']", + "101, AdPLA-null ['l1', 'l2']", + "102, mice ['l1']", + "127, adipocytes. ['l2']", + "128, AdPLA-deficient ['l3', 'l4']", + "129, ob/ob ['l3', 'l5']", + "130, mice ['l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "AdPLA-null", + "AdPLA-deficient", + "ob/ob" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "ob/ob" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "AdPLA-null" + ] + }, + "context": { + "val": "cells", + "words": [ + "adipocytes." + ] + } + } + ] + }, + { + "PMID": "19136963", + "TEXT": "Ethylmalonic encephalopathy is an autosomal recessive, invariably fatal disorder characterized by early-onset encephalopathy, microangiopathy, chronic diarrhea, defective cytochrome c oxidase (COX) in muscle and brain, high concentrations of C4 and C5 acylcarnitines in blood and high excretion of ethylmalonic acid in urine. ETHE1, a gene encoding a beta-lactamase-like, iron-coordinating metalloprotein, is mutated in ethylmalonic encephalopathy. In bacteria, ETHE1-like sequences are in the same operon of, or fused with, orthologs of TST, the gene encoding rhodanese, a sulfurtransferase. In eukaryotes, both ETHE1 and rhodanese are located within the mitochondrial matrix. We created a Ethe1(-/-) mouse that showed the cardinal features of ethylmalonic encephalopathy. We found that thiosulfate was excreted in massive amounts in urine of both Ethe1(-/-) mice and humans with ethylmalonic encephalopathy. High thiosulfate and sulfide concentrations were present in Ethe1(-/-) mouse tissues. Sulfide is a powerful inhibitor of COX and short-chain fatty acid oxidation, with vasoactive and vasotoxic effects that explain the microangiopathy in ethylmalonic encephalopathy patients. Sulfide is detoxified by a mitochondrial pathway that includes a sulfur dioxygenase. Sulfur dioxygenase activity was absent in Ethe1(-/-) mice, whereas it was markedly increased by ETHE1 overexpression in HeLa cells and Escherichia coli. Therefore, ETHE1 is a mitochondrial sulfur dioxygenase involved in catabolism of sulfide that accumulates to toxic levels in ethylmalonic encephalopathy.", + "TAG_DATA": [ + "92, Ethe1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "93, mouse {'context': 'B-organism'}", + "115, Ethe1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "116, mice {'context': 'B-organism'}", + "130, Ethe1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "131, mouse {'context': 'B-tissue/organ'}", + "132, tissues. {'context': 'I-tissue/organ'}", + "176, Ethe1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "177, mice, {'context': 'B-organism'}", + "184, ETHE1 {'perturbing_action': 'B-gene gain-of-function'}", + "185, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "187, HeLa {'context': 'B-transformed cells'}", + "188, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "92, Ethe1(-/-) ['l0', 'l1', 'l2']", + "93, mouse ['l0', 'l3', 'l4']", + "115, Ethe1(-/-) ['l1', 'l3', 'l5', 'l6']", + "116, mice ['l2', 'l4', 'l5', 'l7']", + "118, humans ['l6', 'l7']", + "130, Ethe1(-/-) ['l8', 'l9']", + "131, mouse ['l8', 'l10']", + "132, tissues. ['l9', 'l10']", + "176, Ethe1(-/-) ['l11', 'l12', 'l13', 'l14', 'l15']", + "177, mice, ['l11', 'l16', 'l17', 'l18', 'l19']", + "184, ETHE1 ['l12', 'l16', 'l20', 'l21', 'l22']", + "185, overexpression ['l13', 'l17', 'l20', 'l23', 'l24']", + "187, HeLa ['l14', 'l18', 'l21', 'l23', 'l25']", + "188, cells ['l15', 'l19', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ethe1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ethe1(-/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "tissues." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ethe1(-/-)" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HeLa", + "cells" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ETHE1", + "overexpression" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ETHE1", + "overexpression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HeLa", + "cells" + ] + } + } + ] + }, + { + "PMID": "19122658", + "TEXT": "To better understand the relationship between tumor-host interactions and the efficacy of chemotherapy, we have developed an analytical approach to quantify several biological processes observed in gene expression data sets. We tested the approach on tumor biopsies from individuals with estrogen receptor-negative breast cancer treated with chemotherapy. We report that increased stromal gene expression predicts resistance to preoperative chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC) in subjects in the EORTC 10994/BIG 00-01 trial. The predictive value of the stromal signature was successfully validated in two independent cohorts of subjects who received chemotherapy but not in an untreated control group, indicating that the signature is predictive rather than prognostic. The genes in the signature are expressed in reactive stroma, according to reanalysis of data from microdissected breast tumor samples. These findings identify a previously undescribed resistance mechanism to FEC treatment and suggest that antistromal agents may offer new ways to overcome resistance to chemotherapy.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19060905", + "TEXT": "The extracellular-regulated kinases ERK1 and ERK2 (commonly referred to as ERK1/2) have a crucial role in cardiac hypertrophy. ERK1/2 is activated by mitogen-activated protein kinase kinase-1 (MEK1) and MEK2 (commonly referred to as MEK1/2)-dependent phosphorylation in the TEY motif of the activation loop, but how ERK1/2 is targeted toward specific substrates is not well understood. Here we show that autophosphorylation of ERK1/2 on Thr188 directs ERK1/2 to phosphorylate nuclear targets known to cause cardiac hypertrophy. Thr188 autophosphorylation requires the activation and assembly of the entire Raf-MEK-ERK kinase cascade, phosphorylation of the TEY motif, dimerization of ERK1/2 and binding to G protein betagamma subunits released from activated G(q). Thr188 phosphorylation of ERK1/2 was observed in isolated cardiomyocytes induced to undergo hypertrophic growth, in mice upon stimulation of G(q)-coupled receptors or after aortic banding and in failing human hearts. Experiments using transgenic mouse models carrying mutations at the Thr188 phosphorylation site of ERK2 suggested a causal relationship to cardiac hypertrophy. We propose that specific phosphorylation events on ERK1/2 integrate differing upstream signals (Raf1-MEK1/2 or G protein-coupled receptor-G(q)) to induce cardiac hypertrophy.", + "TAG_DATA": [ + "115, cardiomyocytes {'context': 'B-cells'}", + "122, mice {'context': 'B-organism'}", + "134, failing {'context': 'B-tissue/organ'}", + "135, human {'context': 'I-tissue/organ'}", + "136, hearts. {'context': 'I-tissue/organ'}", + "139, transgenic {'context': 'B-organism'}", + "140, mouse {'context': 'I-organism'}", + "141, models {'context': 'I-organism'}", + "143, mutations {'perturbing_action': 'B-other'}", + "144, at {'perturbing_action': 'I-other'}", + "145, the {'perturbing_action': 'I-other'}", + "146, Thr188 {'perturbing_action': 'I-other'}", + "147, phosphorylation {'perturbing_action': 'I-other'}", + "148, site {'perturbing_action': 'I-other'}", + "149, of {'perturbing_action': 'I-other'}", + "150, ERK2 {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "122, mice ['l0', 'l1', 'l2']", + "134, failing ['l0', 'l3', 'l4']", + "135, human ['l1', 'l3', 'l5']", + "136, hearts. ['l2', 'l4', 'l5']", + "139, transgenic ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "140, mouse ['l6', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "141, models ['l7', 'l16', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "143, mutations ['l8', 'l17', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "144, at ['l9', 'l18', 'l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "145, the ['l10', 'l19', 'l27', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "146, Thr188 ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "147, phosphorylation ['l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57']", + "148, site ['l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l58', 'l59']", + "149, of ['l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58', 'l60']", + "150, ERK2 ['l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mouse", + "models" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutations", + "at", + "the", + "Thr188", + "phosphorylation", + "site", + "of", + "ERK2" + ] + } + } + ] + }, + { + "PMID": "19011637", + "TEXT": "Chronic pain hypersensitivity depends on N-methyl-D-aspartate receptors (NMDARs). However, clinical use of NMDAR blockers is limited by side effects resulting from suppression of the physiological functions of these receptors. Here we report a means to suppress pain hypersensitivity without blocking NMDARs, but rather by inhibiting the binding of a key enhancer of NMDAR function, the protein tyrosine kinase Src. We show that a peptide consisting of amino acids 40-49 of Src fused to the protein transduction domain of the HIV Tat protein (Src40-49Tat) prevented pain behaviors induced by intraplantar formalin and reversed pain hypersensitivity produced by intraplantar injection of complete Freund's adjuvant or by peripheral nerve injury. Src40-49Tat had no effect on basal sensory thresholds, acute nociceptive responses or cardiovascular, respiratory, locomotor or cognitive functions. Thus, through targeting of Src-mediated enhancement of NMDARs, inflammatory and neuropathic pain are suppressed without the deleterious consequences of directly blocking NMDARs, an approach that may be of broad relevance to managing chronic pain.", + "TAG_DATA": [ + "65, of {'perturbing_action': 'I-other'}", + "66, amino {'perturbing_action': 'I-other'}", + "68, 40-49 {'perturbing_action': 'I-other'}", + "72, to {'perturbing_action': 'I-other'}", + "74, protein {'perturbing_action': 'I-other'}", + "75, transduction {'perturbing_action': 'I-other'}", + "76, domain {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "64, consisting ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "65, of ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "66, amino ['l1', 'l16', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "67, acids ['l2', 'l17', 'l31', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "68, 40-49 ['l3', 'l18', 'l32', 'l45', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "69, of ['l4', 'l19', 'l33', 'l46', 'l58', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "70, Src ['l5', 'l20', 'l34', 'l47', 'l59', 'l70', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "71, fused ['l6', 'l21', 'l35', 'l48', 'l60', 'l71', 'l81', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "72, to ['l7', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "73, the ['l8', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l100', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "74, protein ['l9', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l108', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "75, transduction ['l10', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l115', 'l121', 'l122', 'l123', 'l124', 'l125']", + "76, domain ['l11', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l121', 'l126', 'l127', 'l128', 'l129']", + "77, of ['l12', 'l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l126', 'l130', 'l131', 'l132']", + "78, the ['l13', 'l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l118', 'l123', 'l127', 'l130', 'l133', 'l134']", + "79, HIV ['l14', 'l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l113', 'l119', 'l124', 'l128', 'l131', 'l133', 'l135']", + "80, Tat ['l15', 'l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l129', 'l132', 'l134', 'l135']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18997777", + "TEXT": "HIV's considerable capacity to vary its HLA-I-restricted peptide antigens allows it to escape from host cytotoxic T lymphocytes (CTLs). Nevertheless, therapeutics able to target HLA-I-associated antigens, with specificity for the spectrum of preferred CTL escape mutants, could prove effective. Here we use phage display to isolate and enhance a T-cell antigen receptor (TCR) originating from a CTL line derived from an infected person and specific for the immunodominant HLA-A(*)02-restricted, HIVgag-specific peptide SLYNTVATL (SL9). High-affinity (K(D) < 400 pM) TCRs were produced that bound with a half-life in excess of 2.5 h, retained specificity, targeted HIV-infected cells and recognized all common escape variants of this epitope. CD8 T cells transduced with this supraphysiologic TCR produced a greater range of soluble factors and more interleukin-2 than those transduced with natural SL9-specific TCR, and they effectively controlled wild-type and mutant strains of HIV at effector-to-target ratios that could be achieved by T-cell therapy.", + "TAG_DATA": [ + "56, CTL {'context': 'B-cells'}", + "57, line {'context': 'I-cells'}", + "94, HIV-infected {'context': 'B-cells'}", + "95, cells {'context': 'I-cells'}", + "105, CD8 {'context': 'B-cells'}", + "106, T {'context': 'I-cells'}", + "107, cells {'context': 'I-cells'}", + "108, transduced {'perturbing_action': 'B-gene gain-of-function'}" + ], + "LINK_DATA": [ + "56, CTL ['l0']", + "57, line ['l0']", + "94, HIV-infected ['l1']", + "95, cells ['l1']", + "105, CD8 ['l2', 'l3', 'l4']", + "106, T ['l2', 'l5', 'l6']", + "107, cells ['l3', 'l5', 'l7']", + "108, transduced ['l4', 'l6', 'l7']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD8", + "T", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced" + ] + } + } + ] + }, + { + "PMID": "18931684", + "TEXT": "Infantile hemangiomas are localized and rapidly growing regions of disorganized angiogenesis. We show that expression of vascular endothelial growth factor receptor-1 (VEGFR1) in hemangioma endothelial cells (hemECs) and hemangioma tissue is markedly reduced compared to controls. Low VEGFR1 expression in hemECs results in VEGF-dependent activation of VEGFR2 and downstream signaling pathways. In hemECs, transcription of the gene encoding VEGFR1 (FLT1) is dependent on nuclear factor of activated T cells (NFAT). Low VEGFR1 expression in hemECs is caused by reduced activity of a pathway involving beta1 integrin, the integrin-like receptor tumor endothelial marker-8 (TEM8), VEGFR2 and NFAT. In a subset of individuals with hemangioma, we found missense mutations in the genes encoding VEGFR2 (KDR) and TEM8 (ANTXR1). These mutations result in increased interactions among VEGFR2, TEM8 and beta1 integrin proteins and in inhibition of integrin activity. Normalization of the constitutive VEGFR2 signaling in hemECs with soluble VEGFR1 or antibodies that neutralize VEGF or stimulate beta1 integrin suggests that local administration of these or similar agents may be effective in hemangioma treatment.", + "TAG_DATA": [ + "142, hemECs {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "18776891", + "TEXT": "We investigated the possibility of using a pharmacologic agent to modulate viral gene expression to target radiotherapy to tumor tissue. In a mouse xenograft model, we had previously shown targeting of [(125)I]2'-fluoro-2'-deoxy-beta-D-5-iodouracil-arabinofuranoside ([(125)I]FIAU) to tumors engineered to express the Epstein-Barr virus thymidine kinase (EBV-TK). Here we extend those results to targeting of a therapeutic radiopharmaceutical [(131)I]FIAU to slow or stop tumor growth or to achieve tumor regression. These outcomes were achieved in xenografts with tumors that constitutively expressed the EBV-TK. With naturally infected EBV tumor cell lines (Burkitt's lymphoma and gastric carcinoma), activation of viral gene expression by pretreatment with bortezomib was required. Marked changes in tumor growth could also be achieved in naturally infected Kaposi's sarcoma herpesvirus tumors after pretreatment with bortezomib. Bortezomib-induced enzyme-targeted radiation therapy illustrates the possibility of pharmacologically modulating tumor gene expression to result in targeted radiotherapy.", + "TAG_DATA": [ + "22, mouse {'context': 'B-xenograft'}", + "23, xenograft {'context': 'I-xenograft'}", + "24, model, {'context': 'I-xenograft'}", + "57, slow {'effect': 'B-negative'}", + "59, stop {'effect': 'B-negative'}", + "60, tumor {'phenotype': 'B-tumour growth'}", + "61, growth {'phenotype': 'I-tumour growth'}", + "64, achieve {'effect': 'B-positive'}", + "65, tumor {'phenotype': 'B-tumour regression'}", + "66, regression. {'phenotype': 'I-tumour regression'}", + "72, xenografts {'context': 'B-xenograft'}", + "74, tumors {'context': 'B-neoplasm'}", + "83, EBV {'context': 'B-transformed cells'}", + "84, tumor {'context': 'I-transformed cells'}", + "85, cell {'context': 'I-transformed cells'}", + "86, lines {'context': 'I-transformed cells'}", + "87, (Burkitt's {'context': 'I-transformed cells'}", + "88, lymphoma {'context': 'I-transformed cells'}", + "89, and {'context': 'I-transformed cells'}", + "90, gastric {'context': 'I-transformed cells'}", + "91, carcinoma), {'context': 'I-transformed cells'}", + "104, changes {'effect': 'B-regulates'}", + "106, tumor {'phenotype': 'B-tumour growth'}", + "107, growth {'phenotype': 'I-tumour growth'}", + "115, Kaposi's {'context': 'B-neoplasm'}", + "116, sarcoma {'context': 'I-neoplasm'}", + "117, herpesvirus {'context': 'I-neoplasm'}", + "118, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "22, mouse ['l0', 'l1', 'l2', 'l3']", + "23, xenograft ['l0', 'l4', 'l5', 'l6']", + "24, model, ['l1', 'l4', 'l7', 'l8']", + "57, slow ['l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "59, stop ['l9', 'l15', 'l16', 'l17', 'l18', 'l19']", + "60, tumor ['l2', 'l5', 'l7', 'l10', 'l15', 'l20', 'l21', 'l22', 'l23']", + "61, growth ['l3', 'l6', 'l8', 'l11', 'l16', 'l20', 'l24', 'l25', 'l26']", + "64, achieve ['l12', 'l17', 'l21', 'l24', 'l27', 'l28']", + "65, tumor ['l13', 'l18', 'l22', 'l25', 'l27', 'l29']", + "66, regression. ['l14', 'l19', 'l23', 'l26', 'l28', 'l29', 'l30']", + "72, xenografts ['l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "74, tumors ['l31', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "83, EBV ['l38', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "84, tumor ['l39', 'l47', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "85, cell ['l40', 'l48', 'l55', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "86, lines ['l32', 'l41', 'l49', 'l56', 'l62', 'l68', 'l69', 'l70', 'l71', 'l72']", + "87, (Burkitt's ['l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l73', 'l74', 'l75', 'l76']", + "88, lymphoma ['l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l77', 'l78', 'l79']", + "89, and ['l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l80', 'l81']", + "90, gastric ['l36', 'l45', 'l53', 'l60', 'l66', 'l71', 'l75', 'l78', 'l80', 'l82']", + "91, carcinoma), ['l37', 'l46', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l81', 'l82']", + "104, changes ['l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "106, tumor ['l83', 'l89', 'l90', 'l91', 'l92', 'l93']", + "107, growth ['l84', 'l89', 'l94', 'l95', 'l96', 'l97']", + "115, Kaposi's ['l85', 'l90', 'l94', 'l98', 'l99', 'l100']", + "116, sarcoma ['l86', 'l91', 'l95', 'l98', 'l101', 'l102']", + "117, herpesvirus ['l87', 'l92', 'l96', 'l99', 'l101', 'l103']", + "118, tumors ['l88', 'l93', 'l97', 'l100', 'l102', 'l103']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "xenograft", + "words": [ + "mouse", + "xenograft", + "model," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "slow", + "stop" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "slow", + "stop" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "effect": { + "val": "positive", + "words": [ + "achieve" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "achieve" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression." + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression." + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenografts" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "changes" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "changes" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "Kaposi's", + "sarcoma", + "herpesvirus", + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "Kaposi's", + "sarcoma", + "herpesvirus", + "tumors" + ] + } + } + ] + }, + { + "PMID": "18758446", + "TEXT": "The adipocyte-derived hormone leptin maintains energy balance by acting on hypothalamic leptin receptors (Leprs) that act on the signal transducer and activator of transcription 3 (Stat3). Although disruption of Lepr-Stat3 signaling promotes obesity in mice, other features of Lepr function, such as fertility, seem normal, pointing to the involvement of additional regulators. Here we show that the cyclic AMP responsive element-binding protein-1 (Creb1)-regulated transcription coactivator-1 (Crtc1) is required for energy balance and reproduction-Crtc1(-/-) mice are hyperphagic, obese and infertile. Hypothalamic Crtc1 was phosphorylated and inactive in leptin-deficient ob/ob mice, while leptin administration increased amounts of dephosphorylated nuclear Crtc1. Dephosphorylated Crtc1 stimulated expression of the Cartpt and Kiss1 genes, which encode hypothalamic neuropeptides that mediate leptin's effects on satiety and fertility. Crtc1 overexpression in hypothalamic cells increased Cartpt and Kiss1 gene expression, whereas Crtc1 depletion decreased it. Indeed, leptin enhanced Crtc1 activity over the Cartpt and Kiss1 promoters in cells overexpressing Lepr, and these effects were disrupted by expression of a dominant-negative Creb1 polypeptide. As leptin administration increased recruitment of hypothalamic Crtc1 to Cartpt and Kiss1 promoters, our results indicate that the Creb1-Crtc1 pathway mediates the central effects of hormones and nutrients on energy balance and fertility.", + "TAG_DATA": [ + "73, mice {'context': 'B-organism'}", + "86, leptin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "87, ob/ob {'perturbing_action': 'B-gene loss-of-function', 'context': 'B-organism'}", + "88, mice, {'context': 'B-organism'}", + "120, Crtc1 {'perturbing_action': 'B-gene gain-of-function'}", + "121, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "123, hypothalamic {'context': 'B-cells'}", + "124, cells {'context': 'I-cells'}", + "132, Crtc1 {'perturbing_action': 'B-gene loss-of-function'}", + "133, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "148, cells {'context': 'B-cells'}", + "149, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "150, Lepr, {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "73, mice ['l0', 'l1', 'l2']", + "86, leptin-deficient ['l0', 'l3', 'l4']", + "87, ob/ob ['l1', 'l3', 'l5', 'l6']", + "88, mice, ['l2', 'l4', 'l5']", + "120, Crtc1 ['l7', 'l8', 'l9']", + "121, overexpression ['l7', 'l10', 'l11']", + "123, hypothalamic ['l8', 'l10', 'l12']", + "124, cells ['l6', 'l9', 'l11', 'l12']", + "132, Crtc1 ['l13']", + "133, depletion ['l13']", + "148, cells ['l14', 'l15']", + "149, overexpressing ['l14', 'l16']", + "150, Lepr, ['l15', 'l16']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "ob/ob", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "leptin-deficient", + "ob/ob" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ob/ob" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Crtc1", + "overexpression", + "overexpressing", + "Lepr," + ] + }, + "context": { + "val": "cells", + "words": [ + "hypothalamic", + "cells" + ] + } + } + ] + }, + { + "PMID": "18670422", + "TEXT": "The measurement of circulating nucleic acids has transformed the management of chronic viral infections such as HIV. The development of analogous markers for individuals with cancer could similarly enhance the management of their disease. DNA containing somatic mutations is highly tumor specific and thus, in theory, can provide optimum markers. However, the number of circulating mutant gene fragments is small compared to the number of normal circulating DNA fragments, making it difficult to detect and quantify them with the sensitivity required for meaningful clinical use. In this study, we applied a highly sensitive approach to quantify circulating tumor DNA (ctDNA) in 162 plasma samples from 18 subjects undergoing multimodality therapy for colorectal cancer. We found that ctDNA measurements could be used to reliably monitor tumor dynamics in subjects with cancer who were undergoing surgery or chemotherapy. We suggest that this personalized genetic approach could be generally applied to individuals with other types of cancer.", + "TAG_DATA": [ + "127, subjects {'context': 'B-patient'}", + "129, cancer {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "127, subjects ['l0']", + "129, cancer ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18587406", + "TEXT": "Several human progerias, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by the accumulation at the nuclear envelope of farnesylated forms of truncated prelamin A, a protein that is also altered during normal aging. Previous studies in cells from individuals with HGPS have shown that farnesyltransferase inhibitors (FTIs) improve nuclear abnormalities associated with prelamin A accumulation, suggesting that these compounds could represent a therapeutic approach for this devastating progeroid syndrome. We show herein that both prelamin A and its truncated form progerin/LADelta50 undergo alternative prenylation by geranylgeranyltransferase in the setting of farnesyltransferase inhibition, which could explain the low efficiency of FTIs in ameliorating the phenotypes of progeroid mouse models. We also show that a combination of statins and aminobisphosphonates efficiently inhibits both farnesylation and geranylgeranylation of progerin and prelamin A and markedly improves the aging-like phenotypes of mice deficient in the metalloproteinase Zmpste24, including growth retardation, loss of weight, lipodystrophy, hair loss and bone defects. Likewise, the longevity of these mice is substantially extended. These findings open a new therapeutic approach for human progeroid syndromes associated with nuclear-envelope abnormalities.", + "TAG_DATA": [ + "136, mice {'context': 'B-organism'}", + "137, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "138, in {'perturbing_action': 'I-gene loss-of-function'}", + "139, the {'perturbing_action': 'I-gene loss-of-function'}", + "140, metalloproteinase {'perturbing_action': 'I-gene loss-of-function'}", + "141, Zmpste24, {'perturbing_action': 'I-gene loss-of-function'}", + "159, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "136, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "137, deficient ['l0', 'l5', 'l6', 'l7', 'l8', 'l9']", + "138, in ['l1', 'l5', 'l10', 'l11', 'l12', 'l13']", + "139, the ['l2', 'l6', 'l10', 'l14', 'l15', 'l16']", + "140, metalloproteinase ['l3', 'l7', 'l11', 'l14', 'l17', 'l18']", + "141, Zmpste24, ['l4', 'l8', 'l12', 'l15', 'l17', 'l19']", + "159, mice ['l9', 'l13', 'l16', 'l18', 'l19']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "the", + "metalloproteinase", + "Zmpste24," + ] + } + } + ] + }, + { + "PMID": "18568035", + "TEXT": "Alzheimer's disease constitutes a rising threat to public health. Despite extensive research in cellular and animal models, identifying the pathogenic agent present in the human brain and showing that it confers key features of Alzheimer's disease has not been achieved. We extracted soluble amyloid-beta protein (Abeta) oligomers directly from the cerebral cortex of subjects with Alzheimer's disease. The oligomers potently inhibited long-term potentiation (LTP), enhanced long-term depression (LTD) and reduced dendritic spine density in normal rodent hippocampus. Soluble Abeta from Alzheimer's disease brain also disrupted the memory of a learned behavior in normal rats. These various effects were specifically attributable to Abeta dimers. Mechanistically, metabotropic glutamate receptors were required for the LTD enhancement, and N-methyl D-aspartate receptors were required for the spine loss. Co-administering antibodies to the Abeta N-terminus prevented the LTP and LTD deficits, whereas antibodies to the midregion or C-terminus were less effective. Insoluble amyloid plaque cores from Alzheimer's disease cortex did not impair LTP unless they were first solubilized to release Abeta dimers, suggesting that plaque cores are largely inactive but sequester Abeta dimers that are synaptotoxic. We conclude that soluble Abeta oligomers extracted from Alzheimer's disease brains potently impair synapse structure and function and that dimers are the smallest synaptotoxic species.", + "TAG_DATA": [ + "75, rodent {'context': 'B-tissue/organ'}", + "76, hippocampus. {'context': 'I-tissue/organ'}", + "93, rats. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "75, rodent ['l0']", + "76, hippocampus. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18552857", + "TEXT": "Highly active antiretroviral therapy (HAART) can control HIV-1 replication, but suboptimal treatment allows for the evolution of resistance and rebound viremia. A comparative measure of antiviral activity under clinically relevant conditions would guide drug development and the selection of regimens that maximally suppress replication. Here we show that current measures of antiviral activity, including IC(50) and inhibitory quotient, neglect a key dimension, the dose-response curve slope. Using infectivity assays with wide dynamic range, we show that this slope has noteworthy effects on antiviral activity. Slope values are class specific for antiviral drugs and define intrinsic limitations on antiviral activity for some classes. Nucleoside reverse transcriptase inhibitors and integrase inhibitors have slopes of approximately 1, characteristic of noncooperative reactions, whereas non-nucleoside reverse transcriptase inhibitors, protease inhibitors and fusion inhibitors unexpectedly show slopes >1. Instantaneous inhibitory potential (IIP), the log reduction in single-round infectivity at clinical drug concentrations, is strongly influenced by slope and varies by >8 logs for anti-HIV drugs. IIP provides a more accurate measure of antiviral activity and in general correlates with clinical outcomes. Only agents with slopes >1 achieve high-level inhibition of single-round infectivity, a finding with profound implications for drug and vaccine development.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "18454156", + "TEXT": "The function of the C5a receptors, C5ar (encoded by C5ar) and C5l2 (encoded by Gpr77), especially of C5l2, which was originally termed a 'default receptor', remains a controversial topic. Here we investigated the role of each receptor in the setting of cecal ligation and puncture-induced sepsis by using antibody-induced blockade of C5a receptors and knockout mice. In 'mid-grade' sepsis (30-40% survival), blockade or absence of either C5ar or C5l2 greatly improved survival and attenuated the buildup of proinflammatory mediators in plasma. In vivo appearance or in vitro release of high mobility group box 1 protein (HMGB1) required C5l2 but not C5ar. In 'high-grade' sepsis (100% lethality), the only protective condition was the combined blockade of C5l2 and C5ar. These data suggest that C5ar and C5l2 contribute synergistically to the harmful consequences in sepsis and that C5l2 is required for the release of HMGB1. Thus, contrary to earlier speculation, C5l2 is a functional receptor rather than merely a default receptor.", + "TAG_DATA": [ + "55, mice. {'context': 'B-organism'}", + "63, absence {'perturbing_action': 'B-gene loss-of-function'}", + "64, of {'perturbing_action': 'I-gene loss-of-function'}", + "65, either {'perturbing_action': 'I-gene loss-of-function'}", + "66, C5ar {'perturbing_action': 'I-gene loss-of-function'}", + "67, or {'perturbing_action': 'I-gene loss-of-function'}", + "68, C5l2 {'perturbing_action': 'I-gene loss-of-function'}", + "81, In {'context': 'B-in vivo'}", + "82, vivo {'context': 'I-in vivo'}", + "85, in {'context': 'B-in vitro'}", + "86, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "55, mice. ['l0', 'l1', 'l2', 'l3']", + "63, absence ['l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "64, of ['l4', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "65, either ['l0', 'l5', 'l13', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "66, C5ar ['l1', 'l6', 'l14', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "67, or ['l2', 'l7', 'l15', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "68, C5l2 ['l3', 'l8', 'l16', 'l23', 'l28', 'l32', 'l36', 'l37', 'l38']", + "81, In ['l9', 'l17', 'l24', 'l29', 'l33', 'l36', 'l39', 'l40', 'l41']", + "82, vivo ['l10', 'l18', 'l25', 'l30', 'l34', 'l37', 'l39', 'l42', 'l43']", + "85, in ['l11', 'l19', 'l40', 'l42', 'l44']", + "86, vitro ['l12', 'l20', 'l26', 'l31', 'l35', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "either", + "C5ar", + "or", + "C5l2" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "either", + "C5ar", + "or", + "C5l2" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "either", + "C5ar", + "or", + "C5l2" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "18408729", + "TEXT": "PCR is widely employed as the initial DNA amplification step for genetic testing. However, a key limitation of PCR-based methods is the inability to selectively amplify low levels of mutations in a wild-type background. As a result, downstream assays are limited in their ability to identify subtle genetic changes that can have a profound impact in clinical decision-making and outcome. Here we describe co-amplification at lower denaturation temperature PCR (COLD-PCR), a novel form of PCR that amplifies minority alleles selectively from mixtures of wild-type and mutation-containing sequences irrespective of the mutation type or position on the sequence. We replaced regular PCR with COLD-PCR before sequencing or genotyping assays to improve mutation detection sensitivity by up to 100-fold and identified new mutations in the genes encoding p53, KRAS and epidermal growth factor in heterogeneous cancer samples that had been missed by the currently used methods. For clinically relevant microdeletions, COLD-PCR enabled exclusive amplification and isolation of the mutants. COLD-PCR will transform the capabilities of PCR-based genetic testing, including applications in cancer, infectious diseases and prenatal identification of fetal alleles in maternal blood.", + "TAG_DATA": [ + "132, heterogeneous {'context': 'B-neoplasm'}", + "133, cancer {'context': 'I-neoplasm'}", + "134, samples {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "132, heterogeneous ['l0', 'l1']", + "133, cancer ['l0', 'l2']", + "134, samples ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18391963", + "TEXT": "Two subjects with Parkinson's disease who had long-term survival of transplanted fetal mesencephalic dopaminergic neurons (11-16 years) developed alpha-synuclein-positive Lewy bodies in grafted neurons. Our observation has key implications for understanding Parkinson's pathogenesis by providing the first evidence, to our knowledge, that the disease can propagate from host to graft cells. However, available data suggest that the majority of grafted cells are functionally unimpaired after a decade, and recipients can still experience long-term symptomatic relief.", + "TAG_DATA": [ + "11, fetal {'context': 'I-cells'}", + "12, mesencephalic {'context': 'I-cells'}", + "13, dopaminergic {'context': 'I-cells'}", + "14, neurons {'context': 'I-cells'}", + "23, neurons. {'context': 'B-cells'}", + "60, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "11, fetal ['l0', 'l1', 'l2', 'l3', 'l4']", + "12, mesencephalic ['l0', 'l5', 'l6', 'l7', 'l8']", + "13, dopaminergic ['l1', 'l5', 'l9', 'l10', 'l11']", + "14, neurons ['l2', 'l6', 'l9', 'l12', 'l13']", + "23, neurons. ['l3', 'l7', 'l10', 'l12']", + "60, cells ['l4', 'l8', 'l11', 'l13']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18391929", + "TEXT": "In 1999, Hussein bin Talal, the king of Jordan, died after a long battle with non-Hodgkin's lymphoma. Since then, his eldest son and successor, King Abdullah II bin Al Hussein, has sought to improve cancer treatment in his country as part of an effort to boost healthcare and technological development. The country's capital, Amman, now boasts a world-class cancer treatment center, which draws patients from throughout the region. To lead that effort, the king tapped Samir Khleif, chief of the cancer vaccine section at the US National Cancer Institute in Bethesda, Maryland. Khleif, who received his medical degree in Jordan, now has an even bigger mandate from the king: to build an internationally renowned institute devoted to cancer research and biotechnology. Construction on The King Hussein Institute for Cancer and Biotechnology is scheduled to begin on the outskirts of Amman this month, with an expected completion in 2010.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "18376407", + "TEXT": "The basis for the extensive variability seen in the reconstitution of CD4(+) T cell counts in HIV-infected individuals receiving highly active antiretroviral therapy (HAART) is not fully known. Here, we show that variations in CCL3L1 gene dose and CCR5 genotype, but not major histocompatibility complex HLA alleles, influence immune reconstitution, especially when HAART is initiated at <350 CD4(+) T cells/mm(3). The CCL3L1-CCR5 genotypes favoring CD4(+) T cell recovery are similar to those that blunted CD4(+) T cell depletion during the time before HAART became available (pre-HAART era), suggesting that a common CCL3L1-CCR5 genetic pathway regulates the balance between pathogenic and reparative processes from early in the disease course. Hence, CCL3L1-CCR5 variations influence HIV pathogenesis even in the presence of HAART and, therefore, may prospectively identify subjects in whom earlier initiation of therapy is more likely to mitigate immunologic failure despite viral suppression by HAART. Furthermore, as reconstitution of CD4(+) cells during HAART is more sensitive to CCL3L1 dose than to CCR5 genotypes, CCL3L1 analogs might be efficacious in supporting immunological reconstitution.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "18345013", + "TEXT": "A combination of targeted probes and new imaging technologies provides a powerful set of tools with the potential to improve the early detection of cancer. To develop a probe for detecting colon cancer, we screened phage display peptide libraries against fresh human colonic adenomas for high-affinity ligands with preferential binding to premalignant tissue. We identified a specific heptapeptide sequence, VRPMPLQ, which we synthesized, conjugated with fluorescein and tested in patients undergoing colonoscopy. We imaged topically administered peptide using a fluorescence confocal microendoscope delivered through the instrument channel of a standard colonoscope. In vivo images were acquired at 12 frames per second with 50-microm working distance and 2.5-microm (transverse) and 20-microm (axial) resolution. The fluorescein-conjugated peptide bound more strongly to dysplastic colonocytes than to adjacent normal cells with 81% sensitivity and 82% specificity. This methodology represents a promising diagnostic imaging approach for the early detection of colorectal cancer and potentially of other epithelial malignancies.", + "TAG_DATA": [ + "91, In {'context': 'B-in vivo'}", + "92, vivo {'context': 'I-in vivo'}", + "119, dysplastic {'context': 'B-transformed cells'}", + "120, colonocytes {'context': 'I-transformed cells'}", + "123, adjacent {'context': 'B-cells'}", + "124, normal {'context': 'I-cells'}", + "125, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "42, colonic ['l0']", + "43, adenomas ['l0']", + "91, In ['l1']", + "92, vivo ['l1']", + "119, dysplastic ['l2', 'l3', 'l4', 'l5']", + "120, colonocytes ['l2', 'l6', 'l7', 'l8']", + "123, adjacent ['l3', 'l6', 'l9', 'l10']", + "124, normal ['l4', 'l7', 'l9', 'l11']", + "125, cells ['l5', 'l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18345012", + "TEXT": "Intestinal adhesions are bands of fibrous tissue that connect the loops of the intestine to each other, to other abdominal organs or to the abdominal wall. Fibrous tissue formation is regulated by the balance between plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (tPA), which reciprocally regulate fibrin deposition. Several components of the inflammatory system, including cytokines, chemokines, cell adhesion molecules and neuropeptide substance P, have been reported to participate in adhesion formation. We have used cecal cauterization to develop a unique experimental mouse model of intestinal adhesion. Mice developed severe intestinal adhesion after this treatment. Adhesion development depended upon the interferon-gamma (IFN-gamma) and signal transducer and activator of transcription-1 (STAT1) system. Natural killer T (NKT) cell-deficient mice developed adhesion poorly, whereas they developed severe adhesion after reconstitution with NKT cells from wild-type mice, suggesting that NKT cell IFN-gamma production is indispensable for adhesion formation. This response does not depend on STAT4, STAT6, interleukin-12 (IL-12), IL-18, tumor necrosis factor-alpha, Toll-like receptor 4 or myeloid differentiation factor-88-mediated signals. Wild-type mice increased the ratio of PAI-1 to tPA after cecal cauterization, whereas Ifng(-/-) or Stat1(-/-) mice did not, suggesting that IFN-gamma has a crucial role in the differential regulation of PAI-1 and tPA. Additionally, hepatocyte growth factor, a potent mitogenic factor for hepatocytes, strongly inhibited intestinal adhesion by diminishing IFN-gamma production, providing a potential new way to prevent postoperative adhesions.", + "TAG_DATA": [ + "90, Mice {'context': 'B-organism'}", + "114, Natural {'perturbing_action': 'B-gene loss-of-function'}", + "115, killer {'perturbing_action': 'I-gene loss-of-function'}", + "116, T {'perturbing_action': 'I-gene loss-of-function'}", + "117, (NKT) {'perturbing_action': 'I-gene loss-of-function'}", + "118, cell-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "119, mice {'context': 'B-organism'}", + "131, NKT {'context': 'B-cells'}", + "132, cells {'context': 'I-cells'}", + "135, mice, {'context': 'B-organism'}", + "170, mice {'context': 'B-organism'}", + "182, Ifng(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "183, or {'perturbing_action': 'I-gene loss-of-function'}", + "184, Stat1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "185, mice {'context': 'B-organism'}", + "214, inhibited {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "114, Natural ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "115, killer ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "116, T ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21']", + "117, (NKT) ['l2', 'l10', 'l17', 'l22', 'l23', 'l24', 'l25']", + "118, cell-deficient ['l3', 'l11', 'l18', 'l22', 'l26', 'l27', 'l28']", + "119, mice ['l4', 'l12', 'l19', 'l23', 'l26', 'l29']", + "121, adhesion ['l5', 'l13', 'l20', 'l24', 'l27', 'l29']", + "127, adhesion ['l6', 'l14', 'l21', 'l25', 'l28', 'l30', 'l31', 'l32']", + "131, NKT ['l30', 'l33', 'l34', 'l35']", + "132, cells ['l7', 'l15', 'l31', 'l33', 'l36', 'l37']", + "135, mice, ['l8', 'l16', 'l32', 'l34', 'l36']", + "170, mice ['l35', 'l37']", + "182, Ifng(-/-) ['l38', 'l39', 'l40', 'l41', 'l42']", + "183, or ['l38', 'l43', 'l44', 'l45', 'l46']", + "184, Stat1(-/-) ['l39', 'l43', 'l47', 'l48', 'l49']", + "185, mice ['l40', 'l44', 'l47', 'l50', 'l51']", + "214, inhibited ['l41', 'l45', 'l48', 'l50', 'l52']", + "215, intestinal ['l42', 'l46', 'l49', 'l51', 'l52']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Natural", + "killer", + "T", + "(NKT)", + "cell-deficient", + "Ifng(-/-)", + "or", + "Stat1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Natural", + "killer" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ifng(-/-)", + "or", + "Stat1(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + } + ] + }, + { + "PMID": "18345010", + "TEXT": "Treatment for schistosomiasis, which is responsible for more than 280,000 deaths annually, depends almost exclusively on praziquantel. Millions of people are treated annually with praziquantel, and drug-resistant parasites thus are likely to evolve. Phosphinic amides and oxadiazole 2-oxides, identified from a quantitative high-throughput screen, were shown to inhibit a parasite enzyme, thioredoxin glutathione reductase (TGR), with activities in the low micromolar to low nanomolar range. Incubation of parasites with these compounds led to rapid inhibition of TGR activity and parasite death. The activity of the oxadiazole 2-oxides was associated with a donation of nitric oxide. Treatment of schistosome-infected mice with 4-phenyl-1,2,5-oxadiazole-3-carbonitrile-2-oxide led to marked reductions in worm burdens from treatments against multiple parasite stages and egg-associated pathologies. The compound was active against the three major schistosome species infecting humans. These protective effects exceed benchmark activity criteria set by the World Health Organization for lead compound development for schistosomiasis.", + "TAG_DATA": [ + "67, parasites {'context': 'B-organism'}", + "98, mice {'context': 'B-organism'}", + "106, worm {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "67, parasites ['l0']", + "79, parasite ['l0']", + "98, mice ['l1']", + "106, worm ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18345009", + "TEXT": "The angiogenic sprout has been compared to the growing axon, and indeed, many proteins direct pathfinding by both structures. The Roundabout (Robo) proteins are guidance receptors with well-established functions in the nervous system; however, their role in the mammalian vasculature remains ill defined. Here we show that an endothelial-specific Robo, Robo4, maintains vascular integrity. Activation of Robo4 by Slit2 inhibits vascular endothelial growth factor (VEGF)-165-induced migration, tube formation and permeability in vitro and VEGF-165-stimulated vascular leak in vivo by blocking Src family kinase activation. In mouse models of retinal and choroidal vascular disease, Slit2 inhibited angiogenesis and vascular leak, whereas deletion of Robo4 enhanced these pathologic processes. Our results define a previously unknown function for Robo receptors in stabilizing the vasculature and suggest that activating Robo4 may have broad therapeutic application in diseases characterized by excessive angiogenesis and/or vascular leak.", + "TAG_DATA": [ + "54, Activation {'perturbing_action': 'B-pharmacological augmentation'}", + "55, of {'perturbing_action': 'I-pharmacological augmentation'}", + "56, Robo4 {'perturbing_action': 'I-pharmacological augmentation'}", + "57, by {'perturbing_action': 'I-pharmacological augmentation'}", + "58, Slit2 {'perturbing_action': 'I-pharmacological augmentation'}", + "59, inhibits {'effect': 'B-negative'}", + "65, migration, {'phenotype': 'B-migration'}", + "66, tube {'phenotype': 'B-colony formation'}", + "67, formation {'phenotype': 'I-colony formation'}", + "70, in {'context': 'B-in vitro'}", + "71, vitro {'context': 'I-in vitro'}", + "76, in {'context': 'B-in vivo'}", + "77, vivo {'context': 'I-in vivo'}", + "85, mouse {'context': 'B-organism'}", + "86, models {'context': 'I-organism'}", + "100, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "101, of {'perturbing_action': 'I-gene loss-of-function'}", + "102, Robo4 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "54, Activation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "55, of ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "56, Robo4 ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "57, by ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "58, Slit2 ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "59, inhibits ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54']", + "65, migration, ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l55', 'l56', 'l57', 'l58']", + "66, tube ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l55', 'l59', 'l60', 'l61']", + "67, formation ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l56', 'l59', 'l62']", + "70, in ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l57', 'l60', 'l62', 'l63']", + "71, vitro ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l58', 'l61', 'l63']", + "76, in ['l10', 'l21', 'l31', 'l40', 'l48', 'l64']", + "77, vivo ['l11', 'l22', 'l32', 'l41', 'l49', 'l64']", + "85, mouse ['l65', 'l66', 'l67', 'l68']", + "86, models ['l65', 'l69', 'l70', 'l71']", + "88, retinal ['l66', 'l69', 'l72', 'l73']", + "89, and ['l67', 'l70', 'l72', 'l74']", + "90, choroidal ['l68', 'l71', 'l73', 'l74']", + "100, deletion ['l75', 'l76']", + "101, of ['l75', 'l77']", + "102, Robo4 ['l76', 'l77']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "Robo4", + "by", + "Slit2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "Robo4", + "by", + "Slit2" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "Robo4", + "by", + "Slit2" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "tube", + "formation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "Robo4", + "by", + "Slit2" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "Robo4", + "by", + "Slit2" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "tube", + "formation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "tube", + "formation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "18278054", + "TEXT": "Multiple sclerosis is an inflammatory, demyelinating disease of the central nervous system (CNS) characterized by a wide range of clinical signs. The location of lesions in the CNS is variable and is a crucial determinant of clinical outcome. Multiple sclerosis is believed to be mediated by myelin-specific T cells, but the mechanisms that determine where T cells initiate inflammation are unknown. Differences in lesion distribution have been linked to the HLA complex, suggesting that T cell specificity influences sites of inflammation. We demonstrate that T cells that are specific for different myelin epitopes generate populations characterized by different T helper type 17 (T(H)17) to T helper type 1 (T(H)1) ratios depending on the functional avidity of interactions between TCR and peptide-MHC complexes. Notably, the T(H)17:T(H)1 ratio of infiltrating T cells determines where inflammation occurs in the CNS. Myelin-specific T cells infiltrate the meninges throughout the CNS, regardless of the T(H)17:T(H)1 ratio. However, T cell infiltration and inflammation in the brain parenchyma occurs only when T(H)17 cells outnumber T(H)1 cells and trigger a disproportionate increase in interleukin-17 expression in the brain. In contrast, T cells showing a wide range of T(H)17:T(H)1 ratios induce spinal cord parenchymal inflammation. These findings reveal critical differences in the regulation of inflammation in the brain and spinal cord.", + "TAG_DATA": [ + "159, brain {'context': 'B-tissue/organ'}", + "160, parenchyma {'context': 'I-tissue/organ'}", + "164, T(H)17 {'context': 'B-cells'}", + "165, cells {'context': 'I-cells'}", + "179, brain. {'context': 'B-tissue/organ'}", + "182, T {'context': 'B-cells'}", + "183, cells {'context': 'I-cells'}", + "192, spinal {'context': 'B-tissue/organ'}", + "193, cord {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "159, brain ['l0', 'l1', 'l2', 'l3']", + "160, parenchyma ['l0', 'l4', 'l5', 'l6']", + "164, T(H)17 ['l1', 'l4', 'l7', 'l8']", + "165, cells ['l2', 'l5', 'l7', 'l9']", + "179, brain. ['l3', 'l6', 'l8', 'l9']", + "182, T ['l10', 'l11', 'l12']", + "183, cells ['l10', 'l13', 'l14']", + "192, spinal ['l11', 'l13', 'l15']", + "193, cord ['l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18278053", + "TEXT": "Integrin-mediated platelet adhesion and aggregation are essential for sealing injured blood vessels and preventing blood loss, and excessive platelet aggregation can initiate arterial thrombosis, causing heart attacks and stroke. To ensure that platelets aggregate only at injury sites, integrins on circulating platelets exist in a low-affinity state and shift to a high-affinity state (in a process known as integrin activation or priming) after contacting a wounded vessel. The shift is mediated through binding of the cytoskeletal protein Talin to the beta subunit cytoplasmic tail. Here we show that platelets lacking the adhesion plaque protein Kindlin-3 cannot activate integrins despite normal Talin expression. As a direct consequence, Kindlin-3 deficiency results in severe bleeding and resistance to arterial thrombosis. Mechanistically, Kindlin-3 can directly bind to regions of beta-integrin tails distinct from those of Talin and trigger integrin activation. We have therefore identified Kindlin-3 as a novel and essential element for platelet integrin activation in hemostasis and thrombosis.", + "TAG_DATA": [ + "88, platelets {'context': 'B-cells'}", + "89, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "90, the {'perturbing_action': 'I-gene loss-of-function'}", + "91, adhesion {'perturbing_action': 'I-gene loss-of-function'}", + "92, plaque {'perturbing_action': 'I-gene loss-of-function'}", + "93, protein {'perturbing_action': 'I-gene loss-of-function'}", + "94, Kindlin-3 {'perturbing_action': 'I-gene loss-of-function'}", + "106, Kindlin-3 {'perturbing_action': 'B-gene loss-of-function'}", + "107, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "113, resistance {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "88, platelets ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "89, lacking ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "90, the ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "91, adhesion ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "92, plaque ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "93, protein ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "94, Kindlin-3 ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "106, Kindlin-3 ['l21', 'l22']", + "107, deficiency ['l21', 'l23']", + "113, resistance ['l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "platelets" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "adhesion", + "plaque", + "protein", + "Kindlin-3" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Kindlin-3", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + } + } + ] + }, + { + "PMID": "18264109", + "TEXT": "Infections by attaching and effacing (A/E) bacterial pathogens, such as Escherichia coli O157:H7, pose a serious threat to public health. Using a mouse A/E pathogen, Citrobacter rodentium, we show that interleukin-22 (IL-22) has a crucial role in the early phase of host defense against C. rodentium. Infection of IL-22 knockout mice results in increased intestinal epithelial damage, systemic bacterial burden and mortality. We also find that IL-23 is required for the early induction of IL-22 during C. rodentium infection, and adaptive immunity is not essential for the protective role of IL-22 in this model. Instead, IL-22 is required for the direct induction of the Reg family of antimicrobial proteins, including RegIIIbeta and RegIIIgamma, in colonic epithelial cells. Exogenous mouse or human RegIIIgamma substantially improves survival of IL-22 knockout mice after C. rodentium infection. Together, our data identify a new innate immune function for IL-22 in regulating early defense mechanisms against A/E bacterial pathogens.", + "TAG_DATA": [ + "48, IL-22 {'perturbing_action': 'B-gene loss-of-function'}", + "49, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "50, mice {'context': 'B-organism'}", + "114, colonic {'context': 'B-cells'}", + "115, epithelial {'context': 'I-cells'}", + "116, cells. {'context': 'I-cells'}", + "118, mouse {'perturbing_action': 'I-gene gain-of-function'}", + "120, human {'perturbing_action': 'I-gene gain-of-function'}", + "126, IL-22 {'perturbing_action': 'B-gene loss-of-function'}", + "127, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "128, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "48, IL-22 ['l0', 'l1']", + "49, knockout ['l0', 'l2']", + "50, mice ['l1', 'l2']", + "114, colonic ['l3', 'l4']", + "115, epithelial ['l3', 'l5']", + "116, cells. ['l4', 'l5']", + "118, mouse ['l6', 'l7', 'l8', 'l9']", + "120, human ['l6', 'l10', 'l11', 'l12']", + "126, IL-22 ['l7', 'l10', 'l13', 'l14']", + "127, knockout ['l8', 'l11', 'l13', 'l15']", + "128, mice ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IL-22", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "mouse", + "human" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "18246077", + "TEXT": "Long-lasting protection against viral infection is best achieved by vaccination with attenuated viruses. Obtaining stably attenuated vaccine strains has traditionally been an empirical process, which greatly restricts the number of effective vaccines for viral diseases. Here we describe a rational approach for engineering stably attenuated viruses that can serve as safe and effective vaccines. Our approach exploits the observation that restricting viral population diversity by increasing replication fidelity greatly reduces viral tissue tropism and pathogenicity. We show that poliovirus variants with reduced genetic diversity elicit a protective immune response in an animal model of infection. Indeed, these novel vaccine candidates are comparable in efficacy to the currently available Sabin type 1 vaccine strain, but have the added advantage of being more stable, as their increased replication fidelity prevents reversion to the pathogenic wild-type phenotype. We propose that restricting viral quasispecies diversity provides a general approach for the rational design of stable, attenuated vaccines for a wide variety of viruses.", + "TAG_DATA": [ + "91, animal {'context': 'B-organism'}", + "92, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "91, animal ['l0']", + "92, model ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18223655", + "TEXT": "The proapoptotic BCL-2 family member BAD resides in a glucokinase-containing complex that regulates glucose-driven mitochondrial respiration. Here, we present genetic evidence of a physiologic role for BAD in glucose-stimulated insulin secretion by beta cells. This novel function of BAD is specifically dependent upon the phosphorylation of its BH3 sequence, previously defined as an essential death domain. We highlight the pharmacologic relevance of phosphorylated BAD BH3 by using cell-permeable, hydrocarbon-stapled BAD BH3 helices that target glucokinase, restore glucose-driven mitochondrial respiration and correct the insulin secretory response in Bad-deficient islets. Our studies uncover an alternative target and function for the BAD BH3 domain and emphasize the therapeutic potential of phosphorylated BAD BH3 mimetics in selectively restoring beta cell function. Furthermore, we show that BAD regulates the physiologic adaptation of beta cell mass during high-fat feeding. Our findings provide genetic proof of the bifunctional activities of BAD in both beta cell survival and insulin secretion.", + "TAG_DATA": [ + "86, Bad-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "87, islets. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "86, Bad-deficient ['l0']", + "87, islets. ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bad-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "islets." + ] + } + } + ] + }, + { + "PMID": "18223654", + "TEXT": "Allergic asthma is a chronic disease characterized by airway obstruction in response to allergen exposure. It results from an inappropriate T helper type 2 response to environmental airborne antigens and affects 300 million individuals. Its prevalence has increased markedly in recent decades, most probably as a result of changes in environmental factors. Exposure to environmental antigens during infancy is crucial to the development of asthma. Epidemiological studies on the relationship between breastfeeding and allergic diseases have reached conflicting results. Here, we have investigated whether the exposure of lactating mice to an airborne allergen affects asthma development in progeny. We found that airborne antigens were efficiently transferred from the mother to the neonate through milk and that tolerance induction did not require the transfer of immunoglobulins. Breastfeeding-induced tolerance relied on the presence of transforming growth factor (TGF)-beta during lactation, was mediated by regulatory CD4+ T lymphocytes and depended on TGF-beta signaling in T cells. In conclusion, breast milk-mediated transfer of an antigen to the neonate resulted in oral tolerance induction leading to antigen-specific protection from allergic airway disease. This study may pave the way for the design of new strategies to prevent the development of allergic diseases.", + "TAG_DATA": [ + "87, lactating {'context': 'B-organism'}", + "88, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "87, lactating ['l0']", + "88, mice ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18157141", + "TEXT": "Conditional targeted cell ablation is a powerful approach for investigating the pathogenesis of human diseases and in vivo cellular functions. Intermedilysin (ILY) is a cytolytic pore-forming toxin secreted by Streptococcus intermedius that lyses human cells exclusively, owing to its receptor specificity for human CD59. We generated two transgenic mouse strains that express human CD59 either on erythrocytes (strain ThCD59(RBC)) or on endothelia (strain ThCD59(END)). Intravenous injection of ILY in ThCD59(RBC) mice induced acute intravascular hemolysis, leading to reduced nitric oxide bioavailability, increased platelet activation and rapid death. In ThCD59(END) mice, ILY induced rapid endothelial damage, leading to acute death and disseminated intravascular coagulation. Additionally, we show that human serum contains ILY-specific neutralizing antibodies not found in any other animal species. Together, these results suggest that this new rapid conditional targeted ILY-mediated cell ablation technique can be used in combination with any available transgenic expression system to study the physiologic role of specific cell populations.", + "TAG_DATA": [ + "47, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "48, mouse {'context': 'I-organism'}", + "49, strains {'context': 'I-organism'}", + "51, express {'perturbing_action': 'I-gene gain-of-function'}", + "52, human {'perturbing_action': 'I-gene gain-of-function'}", + "53, CD59 {'perturbing_action': 'I-gene gain-of-function'}", + "69, ThCD59(RBC) {'perturbing_action': 'B-other'}", + "70, mice {'context': 'B-organism'}", + "82, platelet {'context': 'B-cells'}", + "88, ThCD59(END) {'perturbing_action': 'B-other'}", + "89, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "47, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "48, mouse ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "49, strains ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "51, express ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "52, human ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "53, CD59 ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "69, ThCD59(RBC) ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "70, mice ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "82, platelet ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "88, ThCD59(END) ['l36']", + "89, mice, ['l36']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "express", + "human", + "CD59" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "strains", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "express", + "human", + "CD59" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelet" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "strains", + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "ThCD59(RBC)", + "ThCD59(END)" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "ThCD59(RBC)" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelet" + ] + } + } + ] + }, + { + "PMID": "18059283", + "TEXT": "Exercise has many health benefits, including antidepressant actions in depressed human subjects, but the mechanisms underlying these effects have not been elucidated. We used a custom microarray to identify a previously undescribed profile of exercise-regulated genes in the mouse hippocampus, a brain region implicated in mood and antidepressant response. Pathway analysis of the regulated genes shows that exercise upregulates a neurotrophic factor signaling cascade that has been implicated in the actions of antidepressants. One of the most highly regulated target genes of exercise and of the growth factor pathway is the gene encoding the VGF nerve growth factor, a peptide precursor previously shown to influence synaptic plasticity and metabolism. We show that administration of a synthetic VGF-derived peptide produces a robust antidepressant response in mice and, conversely, that mutation of VGF in mice produces the opposite effects. The results suggest a new role for VGF and identify VGF signaling as a potential therapeutic target for antidepressant drug development.", + "TAG_DATA": [ + "124, mice {'context': 'B-organism'}", + "128, mutation {'perturbing_action': 'B-other'}", + "129, of {'perturbing_action': 'I-other'}", + "130, VGF {'perturbing_action': 'I-other'}", + "132, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "128, mutation ['l0', 'l1', 'l2']", + "129, of ['l0', 'l3', 'l4']", + "130, VGF ['l1', 'l3', 'l5']", + "132, mice ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "of", + "VGF" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "18037896", + "TEXT": "The serine-threonine kinases Pim-1 and Akt regulate cellular proliferation and survival. Although Akt is known to be a crucial signaling protein in the myocardium, the role of Pim-1 has been overlooked. Pim-1 expression in the myocardium of mice decreased during postnatal development, re-emerged after acute pathological injury in mice and was increased in failing hearts of both mice and humans. Cardioprotective stimuli associated with Akt activation induced Pim-1 expression, but compensatory increases in Akt abundance and phosphorylation after pathological injury by infarction or pressure overload did not protect the myocardium in Pim-1-deficient mice. Transgenic expression of Pim-1 in the myocardium protected mice from infarction injury, and Pim-1 expression inhibited cardiomyocyte apoptosis with concomitant increases in Bcl-2 and Bcl-X(L) protein levels, as well as in Bad phosphorylation levels. Relative to nontransgenic controls, calcium dynamics were significantly enhanced in Pim-1-overexpressing transgenic hearts, associated with increased expression of SERCA2a, and were depressed in Pim-1-deficient hearts. Collectively, these data suggest that Pim-1 is a crucial facet of cardioprotection downstream of Akt.", + "TAG_DATA": [ + "89, myocardium {'context': 'B-tissue/organ'}", + "91, Pim-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "92, mice. {'context': 'B-organism'}", + "93, Transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "94, expression {'perturbing_action': 'I-gene gain-of-function'}", + "95, of {'perturbing_action': 'I-gene gain-of-function'}", + "96, Pim-1 {'perturbing_action': 'I-gene gain-of-function'}", + "99, myocardium {'context': 'B-tissue/organ'}", + "101, mice {'context': 'B-organism'}", + "106, Pim-1 {'perturbing_action': 'B-gene gain-of-function'}", + "107, expression {'perturbing_action': 'I-gene gain-of-function'}", + "108, inhibited {'effect': 'B-negative'}", + "109, cardiomyocyte {'context': 'B-cells'}", + "110, apoptosis {'phenotype': 'B-apoptosis'}", + "137, Pim-1-overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "138, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "139, hearts, {'context': 'B-tissue/organ'}", + "150, Pim-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "151, hearts. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "89, myocardium ['l0', 'l1']", + "91, Pim-1-deficient ['l0', 'l2']", + "92, mice. ['l1', 'l2']", + "93, Transgenic ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "94, expression ['l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "95, of ['l4', 'l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "96, Pim-1 ['l5', 'l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "99, myocardium ['l6', 'l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "101, mice ['l7', 'l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "106, Pim-1 ['l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "107, expression ['l30', 'l37', 'l38', 'l39']", + "108, inhibited ['l31', 'l37', 'l40', 'l41']", + "109, cardiomyocyte ['l8', 'l14', 'l19', 'l23', 'l26', 'l28', 'l32', 'l38', 'l40', 'l42']", + "110, apoptosis ['l9', 'l15', 'l20', 'l24', 'l27', 'l29', 'l33', 'l39', 'l41', 'l42']", + "137, Pim-1-overexpressing ['l34', 'l43', 'l44', 'l45', 'l46']", + "138, transgenic ['l35', 'l43', 'l47', 'l48']", + "139, hearts, ['l36', 'l44', 'l47', 'l49']", + "150, Pim-1-deficient ['l45', 'l50']", + "151, hearts. ['l46', 'l48', 'l49', 'l50']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "myocardium", + "hearts." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pim-1-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pim-1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgenic", + "expression", + "of", + "Pim-1", + "Pim-1-overexpressing", + "transgenic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "myocardium", + "hearts,", + "hearts." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgenic", + "expression", + "of", + "Pim-1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgenic", + "expression", + "of", + "Pim-1" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgenic", + "expression", + "of", + "Pim-1" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "myocardium" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Pim-1", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocyte" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cardiomyocyte" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "18026115", + "TEXT": "To reject tumors, T cells must overcome poor tumor immunogenicity and an adverse tumor microenvironment. Providing agonistic costimulatory signals to tumor-infiltrating T cells to augment T cell function remains a challenge for the implementation of safe and effective immunotherapy. We hypothesized that T cells overexpressing selected costimulatory ligands could serve as cellular vehicles mediating powerful, yet constrained, anatomically targeted costimulation. Here, we show that primary human T cells expressing CD80 and 4-1BB ligand (4-1BBL) vigorously respond to tumor cells lacking costimulatory ligands and provoke potent rejection of large, systemic tumors in immunodeficient mice. In addition to showing costimulation of bystander T cells (transcostimulation), we show the effect of CD80 and 4-1BBL binding to their respective receptors in the immunological synapse of isolated single cells (autocostimulation). This new strategy of endowing T cells with constitutively expressed costimulatory ligands could be extended to other ligand-receptor pairs and used to enhance any targeted adoptive transfer therapy.", + "TAG_DATA": [ + "64, primary {'context': 'B-cells'}", + "65, human {'context': 'I-cells'}", + "66, T {'context': 'I-cells'}", + "67, cells {'context': 'I-cells'}", + "77, tumor {'context': 'B-transformed cells'}", + "78, cells {'context': 'I-transformed cells'}", + "88, systemic {'context': 'B-neoplasm'}", + "89, tumors {'context': 'I-neoplasm'}", + "91, immunodeficient {'context': 'B-organism'}", + "92, mice. {'context': 'I-organism'}", + "100, T {'context': 'I-cells'}", + "101, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "64, primary ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "65, human ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "66, T ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "67, cells ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "77, tumor ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "78, cells ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "88, systemic ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "89, tumors ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "91, immunodeficient ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "92, mice. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "100, T ['l45']", + "101, cells ['l45']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18026113", + "TEXT": "A successful pregnancy requires synchronized adaptation of maternal immune-endocrine mechanisms to the fetus. Here we show that galectin-1 (Gal-1), an immunoregulatory glycan-binding protein, has a pivotal role in conferring fetomaternal tolerance. Consistently with a marked decrease in Gal-1 expression during failing pregnancies, Gal-1-deficient (Lgals1-/-) mice showed higher rates of fetal loss compared to wild-type mice in allogeneic matings, whereas fetal survival was unaffected in syngeneic matings. Treatment with recombinant Gal-1 prevented fetal loss and restored tolerance through multiple mechanisms, including the induction of tolerogenic dendritic cells, which in turn promoted the expansion of interleukin-10 (IL-10)-secreting regulatory T cells in vivo. Accordingly, Gal-1's protective effects were abrogated in mice depleted of regulatory T cells or deficient in IL-10. In addition, we provide evidence for synergy between Gal-1 and progesterone in the maintenance of pregnancy. Thus, Gal-1 is a pivotal regulator of fetomaternal tolerance that has potential therapeutic implications in threatened pregnancies.", + "TAG_DATA": [ + "42, Gal-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "43, (Lgals1-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "44, mice {'context': 'B-organism'}", + "54, mice {'context': 'B-organism'}", + "84, dendritic {'context': 'B-cells'}", + "85, cells, {'context': 'I-cells'}", + "95, regulatory {'context': 'B-cells'}", + "96, T {'context': 'I-cells'}", + "97, cells {'context': 'I-cells'}", + "98, in {'context': 'B-in vivo'}", + "99, vivo. {'context': 'I-in vivo'}", + "107, mice {'context': 'B-organism'}", + "110, regulatory {'context': 'B-cells'}", + "111, T {'context': 'I-cells'}", + "112, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "42, Gal-1-deficient ['l0', 'l1', 'l2']", + "43, (Lgals1-/-) ['l0', 'l3', 'l4']", + "44, mice ['l1', 'l3', 'l5']", + "54, mice ['l2', 'l4', 'l5']", + "84, dendritic ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "85, cells, ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "95, regulatory ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "96, T ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "97, cells ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "98, in ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "99, vivo. ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']", + "107, mice ['l27', 'l28', 'l29']", + "110, regulatory ['l27', 'l30', 'l31']", + "111, T ['l28', 'l30', 'l32']", + "112, cells ['l29', 'l31', 'l32']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gal-1-deficient", + "(Lgals1-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "17987005", + "TEXT": "It can take twice as long to get a PhD in biomedical sciences in the US as it does in other countries such as the UK and Australia. Are US PhDs worth more, or are there advantages to a speedier system?", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17982462", + "TEXT": "Anorexia and weight loss are part of the wasting syndrome of late-stage cancer, are a major cause of morbidity and mortality in cancer, and are thought to be cytokine mediated. Macrophage inhibitory cytokine-1 (MIC-1) is produced by many cancers. Examination of sera from individuals with advanced prostate cancer showed a direct relationship between MIC-1 abundance and cancer-associated weight loss. In mice with xenografted prostate tumors, elevated MIC-1 levels were also associated with marked weight, fat and lean tissue loss that was mediated by decreased food intake and was reversed by administration of antibody to MIC-1. Additionally, normal mice given systemic MIC-1 and transgenic mice overexpressing MIC-1 showed hypophagia and reduced body weight. MIC-1 mediates its effects by central mechanisms that implicate the hypothalamic transforming growth factor-beta receptor II, extracellular signal-regulated kinases 1 and 2, signal transducer and activator of transcription-3, neuropeptide Y and pro-opiomelanocortin. Thus, MIC-1 is a newly defined central regulator of appetite and a potential target for the treatment of both cancer anorexia and weight loss, as well as of obesity.", + "TAG_DATA": [ + "60, mice {'context': 'B-organism'}", + "62, xenografted {'context': 'B-xenograft'}", + "63, prostate {'context': 'I-xenograft'}", + "64, tumors, {'context': 'I-xenograft'}", + "97, mice {'context': 'I-organism'}", + "102, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "103, mice {'context': 'I-organism'}", + "104, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "105, MIC-1 {'perturbing_action': 'I-gene gain-of-function'}", + "107, hypophagia {'phenotype': 'B-necrosis'}" + ], + "LINK_DATA": [ + "60, mice ['l0', 'l1', 'l2']", + "62, xenografted ['l0', 'l3', 'l4']", + "63, prostate ['l1', 'l3', 'l5']", + "64, tumors, ['l2', 'l4', 'l5']", + "97, mice ['l6']", + "102, transgenic ['l7', 'l8', 'l9', 'l10']", + "103, mice ['l7', 'l11', 'l12', 'l13']", + "104, overexpressing ['l8', 'l11', 'l14', 'l15']", + "105, MIC-1 ['l9', 'l12', 'l14', 'l16']", + "107, hypophagia ['l6', 'l10', 'l13', 'l15', 'l16']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "hypophagia" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "overexpressing", + "MIC-1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "overexpressing", + "MIC-1" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "hypophagia" + ] + } + } + ] + }, + { + "PMID": "17952091", + "TEXT": "Proteoglycans are a family of extracellular macromolecules comprised of glycosaminoglycan chains of a repeated disaccharide linked to a central core protein. Proteoglycans have critical roles in chondrogenesis and skeletal development. The glycosaminoglycan chains found in cartilage proteoglycans are primarily composed of chondroitin sulfate. The integrity of chondroitin sulfate chains is important to cartilage proteoglycan function; however, chondroitin sulfate metabolism in mammals remains poorly understood. The solute carrier-35 D1 (SLC35D1) gene (SLC35D1) encodes an endoplasmic reticulum nucleotide-sugar transporter (NST) that might transport substrates needed for chondroitin sulfate biosynthesis. Here we created Slc35d1-deficient mice that develop a lethal form of skeletal dysplasia with severe shortening of limbs and facial structures. Epiphyseal cartilage in homozygous mutant mice showed a decreased proliferating zone with round chondrocytes, scarce matrices and reduced proteoglycan aggregates. These mice had short, sparse chondroitin sulfate chains caused by a defect in chondroitin sulfate biosynthesis. We also identified that loss-of-function mutations in human SLC35D1 cause Schneckenbecken dysplasia, a severe skeletal dysplasia. Our findings highlight the crucial role of NSTs in proteoglycan function and cartilage metabolism, thus revealing a new paradigm for skeletal disease and glycobiology.", + "TAG_DATA": [ + "90, Slc35d1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "91, mice {'context': 'B-organism'}", + "113, mice {'context': 'B-organism'}", + "116, decreased {'effect': 'B-negative'}", + "117, proliferating {'phenotype': 'B-proliferation'}", + "118, zone {'phenotype': 'I-proliferation'}", + "129, mice {'context': 'B-organism'}", + "148, loss-of-function {'perturbing_action': 'B-gene loss-of-function'}", + "149, mutations {'perturbing_action': 'I-gene loss-of-function'}", + "150, in {'perturbing_action': 'I-gene loss-of-function'}", + "151, human {'perturbing_action': 'I-gene loss-of-function'}", + "152, SLC35D1 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "90, Slc35d1-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "91, mice ['l0']", + "112, mutant ['l1', 'l6', 'l7', 'l8', 'l9']", + "113, mice ['l2', 'l6', 'l10', 'l11', 'l12']", + "116, decreased ['l3', 'l7', 'l10', 'l13', 'l14']", + "117, proliferating ['l4', 'l8', 'l11', 'l13', 'l15']", + "118, zone ['l5', 'l9', 'l12', 'l14', 'l15']", + "148, loss-of-function ['l16', 'l17', 'l18', 'l19']", + "149, mutations ['l16', 'l20', 'l21', 'l22']", + "150, in ['l17', 'l20', 'l23', 'l24']", + "151, human ['l18', 'l21', 'l23', 'l25']", + "152, SLC35D1 ['l19', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Slc35d1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Slc35d1-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Slc35d1-deficient" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferating", + "zone" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferating", + "zone" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferating", + "zone" + ] + } + } + ] + }, + { + "PMID": "17934471", + "TEXT": "The role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in immune responses mediated by T-helper 2 (T(H)2) lymphocytes is unknown. Here we characterize the development of allergic airway disease in TRAIL-deficient (Tnfsf10(-/-)) mice and in mice exposed to short interfering RNA targeting TRAIL. We show that TRAIL is abundantly expressed in the airway epithelium of allergic mice and that inhibition of signaling impairs production of the chemokine CCL20 and homing of myeloid dendritic cells and T cells expressing CCR6 and CD4 to the airways. Attenuated homing limits T(H)2 cytokine release, inflammation, airway hyperreactivity and expression of the transcriptional activator STAT6. Activation of STAT6 by interleukin-13 restores airway hyperreactivity in Tnfsf10(-/-) mice. Recombinant TRAIL induces pathognomic features of asthma and stimulates the production of CCL20 in primary human bronchial epithelium cells. TRAIL is also increased in sputum of asthmatics. The function of TRAIL in the airway epithelium identifies this molecule as a target for the treatment of asthma.", + "TAG_DATA": [ + "30, TRAIL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "31, (Tnfsf10(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "32, mice {'context': 'B-organism'}", + "35, mice {'context': 'B-organism'}", + "38, short {'perturbing_action': 'B-rnai/knockdown'}", + "39, interfering {'perturbing_action': 'I-rnai/knockdown'}", + "40, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "41, targeting {'perturbing_action': 'I-rnai/knockdown'}", + "42, TRAIL. {'perturbing_action': 'I-rnai/knockdown'}", + "71, myeloid {'context': 'B-cells'}", + "72, dendritic {'context': 'I-cells'}", + "73, cells {'context': 'I-cells'}", + "75, T {'context': 'B-cells'}", + "76, cells {'context': 'B-cells'}", + "109, Tnfsf10(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "110, mice. {'context': 'B-organism'}", + "125, primary {'context': 'B-cells'}", + "126, human {'context': 'I-cells'}", + "127, bronchial {'context': 'I-cells'}", + "128, epithelium {'context': 'I-cells'}", + "129, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "30, TRAIL-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "31, (Tnfsf10(-/-)) ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "32, mice ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "35, mice ['l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "38, short ['l18', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "39, interfering ['l19', 'l28', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "40, RNA ['l20', 'l29', 'l37', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "41, targeting ['l21', 'l30', 'l38', 'l45', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "42, TRAIL. ['l22', 'l31', 'l39', 'l46', 'l52', 'l58', 'l59', 'l60', 'l61', 'l62']", + "71, myeloid ['l2', 'l8', 'l13', 'l23', 'l32', 'l40', 'l47', 'l53', 'l58', 'l63', 'l64', 'l65', 'l66']", + "72, dendritic ['l3', 'l9', 'l14', 'l24', 'l33', 'l41', 'l48', 'l54', 'l59', 'l63', 'l67', 'l68', 'l69']", + "73, cells ['l4', 'l10', 'l15', 'l25', 'l34', 'l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l70', 'l71']", + "75, T ['l5', 'l11', 'l16', 'l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l72']", + "76, cells ['l6', 'l12', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l69', 'l71', 'l72']", + "109, Tnfsf10(-/-) ['l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "110, mice. ['l73', 'l79', 'l80']", + "125, primary ['l74', 'l81', 'l82', 'l83', 'l84']", + "126, human ['l75', 'l81', 'l85', 'l86', 'l87']", + "127, bronchial ['l76', 'l82', 'l85', 'l88', 'l89']", + "128, epithelium ['l77', 'l79', 'l83', 'l86', 'l88', 'l90']", + "129, cells. ['l78', 'l80', 'l84', 'l87', 'l89', 'l90']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TRAIL-deficient", + "(Tnfsf10(-/-))", + "Tnfsf10(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TRAIL-deficient", + "(Tnfsf10(-/-))", + "Tnfsf10(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "dendritic", + "cells", + "T", + "primary", + "human", + "bronchial", + "epithelium", + "cells." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "short", + "interfering", + "RNA", + "targeting", + "TRAIL." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "short", + "interfering", + "RNA", + "targeting", + "TRAIL." + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "dendritic", + "cells", + "T" + ] + } + } + ] + }, + { + "PMID": "17934470", + "TEXT": "Sepsis, a leading cause of death worldwide, involves proinflammatory responses and inefficient bacterial clearance. Phagocytic cells play a crucial part in the prevention of sepsis by clearing bacteria through host innate receptors. Here we show that the FcRgamma adaptor, an immunoreceptor tyrosine-based activation motif (ITAM)-bearing signal transduction subunit of the Fc receptor family, has a deleterious effect on sepsis. FcRgamma(-/-) mice show increased survival during peritonitis, owing to markedly increased E. coli phagocytosis and killing and to lower production of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha. The FcRgamma-associated receptor that inhibits E. coli phagocytosis is FcgammaRIII (also called CD16), and its absence protects mice from sepsis. FcgammaRIII binds E. coli, and this interaction induces FcRgamma phosphorylation, recruitment of the tyrosine phosphatase SHP-1 and phosphatidylinositide-3 kinase (PI3K) dephosphorylation. Decreased PI3K activity inhibits E. coli phagocytosis and increases TNF-alpha production through Toll-like receptor 4. We identified the phagocytic receptor negatively regulated by FcRgamma on macrophages as the class A scavenger receptor MARCO. E. coli-FcgammaRIII interaction induces the recruitment of SHP-1 to MARCO, thereby inhibiting E. coli phagocytosis. Thus, by binding FcgammaRIII, E. coli triggers an inhibitory FcRgamma pathway that both impairs MARCO-mediated bacterial clearance and activates TNF-alpha secretion.", + "TAG_DATA": [ + "59, FcRgamma(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "60, mice {'context': 'B-organism'}", + "91, inhibits {'effect': 'B-negative'}", + "94, phagocytosis {'phenotype': 'B-mitophagy'}", + "104, mice {'context': 'B-organism'}", + "131, inhibits {'effect': 'B-negative'}", + "134, phagocytosis {'phenotype': 'B-mitophagy'}", + "172, inhibiting {'effect': 'B-negative'}", + "175, phagocytosis. {'phenotype': 'B-mitophagy'}" + ], + "LINK_DATA": [ + "59, FcRgamma(-/-) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "60, mice ['l0', 'l6', 'l7', 'l8']", + "91, inhibits ['l1', 'l9', 'l10', 'l11', 'l12']", + "92, E. ['l2', 'l6', 'l9', 'l13', 'l14', 'l15']", + "93, coli ['l3', 'l7', 'l10', 'l13', 'l16', 'l17']", + "94, phagocytosis ['l4', 'l8', 'l11', 'l14', 'l16', 'l18']", + "104, mice ['l5', 'l12', 'l15', 'l17', 'l18']", + "131, inhibits ['l19']", + "134, phagocytosis ['l19']", + "172, inhibiting ['l20', 'l21', 'l22']", + "173, E. ['l20', 'l23', 'l24']", + "174, coli ['l21', 'l23', 'l25']", + "175, phagocytosis. ['l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FcRgamma(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FcRgamma(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FcRgamma(-/-)" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "inhibiting" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis", + "phagocytosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "17828273", + "TEXT": "Post-translational modification and functional impairment of proteins through carbamylation is thought to promote vascular dysfunction during end-stage renal disease. Cyanate, a reactive species in equilibrium with urea, carbamylates protein lysine residues to form epsilon-carbamyllysine (homocitrulline), altering protein structure and function. We now report the discovery of an alternative and quantitatively dominant mechanism for cyanate formation and protein carbamylation at sites of inflammation and atherosclerotic plaque: myeloperoxidase-catalyzed oxidation of thiocyanate, an anion abundant in blood whose levels are elevated in smokers. We also show that myeloperoxidase-catalyzed lipoprotein carbamylation facilitates multiple pro-atherosclerotic activities, including conversion of low-density lipoprotein into a ligand for macrophage scavenger receptor A1 recognition, cholesterol accumulation and foam-cell formation. In two separate clinical studies (combined n = 1,000 subjects), plasma levels of protein-bound homocitrulline independently predicted increased risk of coronary artery disease, future myocardial infarction, stroke and death. We propose that protein carbamylation is a mechanism linking inflammation, smoking, uremia and coronary artery disease pathogenesis.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17767166", + "TEXT": "Schizophrenia is a chronic, complex and heterogeneous mental disorder, with pathological features of disrupted neuronal excitability and plasticity within limbic structures of the brain. These pathological features manifest behaviorally as positive symptoms (including hallucinations, delusions and thought disorder), negative symptoms (such as social withdrawal, apathy and emotional blunting) and other psychopathological symptoms (such as psychomotor retardation, lack of insight, poor attention and impulse control). Altered glutamate neurotransmission has for decades been linked to schizophrenia, but all commonly prescribed antipsychotics act on dopamine receptors. LY404039 is a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors and has shown antipsychotic potential in animal studies. With data from rodents, we provide new evidence that mGlu2/3 receptor agonists work by a distinct mechanism different from that of olanzapine. To clinically test this mechanism, an oral prodrug of LY404039 (LY2140023) was evaluated in schizophrenic patients with olanzapine as an active control in a randomized, three-armed, double-blind, placebo-controlled study. Treatment with LY2140023, like treatment with olanzapine, was safe and well-tolerated; treated patients showed statistically significant improvements in both positive and negative symptoms of schizophrenia compared to placebo (P < 0.001 at week 4). Notably, patients treated with LY2140023 did not differ from placebo-treated patients with respect to prolactin elevation, extrapyramidal symptoms or weight gain. These data suggest that mGlu2/3 receptor agonists have antipsychotic properties and may provide a new alternative for the treatment of schizophrenia.", + "TAG_DATA": [ + "138, schizophrenic {'context': 'B-patient'}", + "139, patients {'context': 'I-patient'}", + "165, patients {'context': 'B-patient'}", + "188, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "138, schizophrenic ['l0']", + "139, patients ['l0']", + "188, patients ['l1']", + "197, patients ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17767165", + "TEXT": "To identify new components that regulate the inflammatory cascade during sepsis, we characterized the functions of myeloid-related protein-8 (Mrp8, S100A8) and myeloid-related protein-14 (Mrp14, S100A9), two abundant cytoplasmic proteins of phagocytes. We now demonstrate that mice lacking Mrp8-Mrp14 complexes are protected from endotoxin-induced lethal shock and Escherichia coli-induced abdominal sepsis. Both proteins are released during activation of phagocytes, and Mrp8-Mrp14 complexes amplify the endotoxin-triggered inflammatory responses of phagocytes. Mrp8 is the active component that induces intracellular translocation of myeloid differentiation primary response protein 88 and activation of interleukin-1 receptor-associated kinase-1 and nuclear factor-kappaB, resulting in elevated expression of tumor necrosis factor-alpha (TNF-alpha). Using phagocytes expressing a nonfunctional Toll-like receptor 4 (TLR4), HEK293 cells transfected with TLR4, CD14 and MD2, and by surface plasmon resonance studies in vitro, we demonstrate that Mrp8 specifically interacts with the TLR4-MD2 complex, thus representing an endogenous ligand of TLR4. Therefore Mrp8-Mrp14 complexes are new inflammatory components that amplify phagocyte activation during sepsis upstream of TNFalpha-dependent effects.", + "TAG_DATA": [ + "35, mice {'context': 'B-organism'}", + "103, phagocytes {'context': 'B-cells'}", + "111, HEK293 {'context': 'B-cells'}", + "112, cells {'context': 'I-cells'}", + "113, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "114, with {'perturbing_action': 'I-gene gain-of-function'}", + "115, TLR4, {'perturbing_action': 'I-gene gain-of-function'}", + "116, CD14 {'perturbing_action': 'I-gene gain-of-function'}", + "117, and {'perturbing_action': 'I-gene gain-of-function'}", + "118, MD2, {'perturbing_action': 'I-gene gain-of-function'}", + "125, in {'context': 'B-in vitro'}", + "126, vitro, {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "103, phagocytes ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "111, HEK293 ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "112, cells ['l1', 'l8', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "113, transfected ['l2', 'l9', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "114, with ['l3', 'l10', 'l18', 'l25', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "115, TLR4, ['l4', 'l11', 'l19', 'l26', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "116, CD14 ['l5', 'l12', 'l20', 'l27', 'l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "117, and ['l6', 'l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "118, MD2, ['l7', 'l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "125, in ['l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "126, vitro, ['l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l52']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "phagocytes", + "HEK293", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "TLR4,", + "CD14", + "and", + "MD2," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "TLR4,", + "CD14", + "and", + "MD2," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + } + ] + }, + { + "PMID": "17704786", + "TEXT": "Conventional cancer treatments rely on radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Here we show that the success of some protocols for anticancer therapy depends on innate and adaptive antitumor immune responses. We describe in both mice and humans a previously unrecognized pathway for the activation of tumor antigen-specific T-cell immunity that involves secretion of the high-mobility-group box 1 (HMGB1) alarmin protein by dying tumor cells and the action of HMGB1 on Toll-like receptor 4 (TLR4) expressed by dendritic cells (DCs). During chemotherapy or radiotherapy, DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. Patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy and chemotherapy than those carrying the normal TLR4 allele. These results delineate a clinically relevant immunoadjuvant pathway triggered by tumor cell death.", + "TAG_DATA": [ + "94, DCs {'context': 'B-cells'}", + "114, Patients {'context': 'B-patient'}", + "115, with {'context': 'I-patient'}", + "116, breast {'context': 'I-neoplasm'}", + "117, cancer {'context': 'I-neoplasm'}", + "121, TLR4 {'perturbing_action': 'B-gene loss-of-function'}", + "122, loss-of-function {'perturbing_action': 'I-gene loss-of-function'}", + "123, allele {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "114, Patients ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "115, with ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "116, breast ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "117, cancer ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "121, TLR4 ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "122, loss-of-function ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "123, allele ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "patient", + "words": [ + "Patients", + "with" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TLR4", + "loss-of-function", + "allele" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "breast", + "cancer" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TLR4", + "loss-of-function", + "allele" + ] + } + } + ] + }, + { + "PMID": "17643110", + "TEXT": "Sepsis remains a global clinical problem. By using the mouse cecal ligation and puncture model of sepsis, here we identify an important aspect of mast cell (MC)-dependent, innate immune defenses against Gram-negative bacteria by demonstrating that MC protease activity is regulated by interleukin-15 (IL-15). Mouse MCs express both constitutive and lipopolysaccharide-inducible IL-15 and store it intracellularly. Deletion of Il15 in mice markedly increases chymase activities, leading to greater MC bactericidal responses, increased processing and activation of neutrophil-recruiting chemokines, and significantly higher survival rates of mice after septic peritonitis. By showing that intracellular IL-15 acts as a specific negative transcriptional regulator of a mouse MC chymase (mast cell protease-2), we provide evidence that defined MC protease activity is transcriptionally regulated by an intracellularly retained cytokine. Our results identify an unexpected breach in MC-dependent innate immune defenses against sepsis and suggest that inhibiting intracellular IL-15 in MCs may improve survival from sepsis.", + "TAG_DATA": [ + "56, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "57, of {'perturbing_action': 'I-gene loss-of-function'}", + "58, Il15 {'perturbing_action': 'I-gene loss-of-function'}", + "60, mice {'context': 'B-organism'}", + "84, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, Deletion ['l0', 'l1', 'l2', 'l3']", + "57, of ['l0', 'l4', 'l5', 'l6']", + "58, Il15 ['l1', 'l4', 'l7', 'l8']", + "60, mice ['l2', 'l5', 'l7']", + "84, mice ['l3', 'l6', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "Il15" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "17632527", + "TEXT": "Interaction of cancer cells with their microenvironment generated by stromal cells is essential for tumor cell survival and influences the localization of tumor growth. Here we demonstrate that hedgehog ligands secreted by bone-marrow, nodal and splenic stromal cells function as survival factors for malignant lymphoma and plasmacytoma cells derived from transgenic Emu-Myc mice or isolated from humans with these malignancies. Hedgehog pathway inhibition in lymphomas induced apoptosis through downregulation of Bcl2, but was independent of p53 or Bmi1 expression. Blockage of hedgehog signaling in vivo inhibited expansion of mouse lymphoma cells in a syngeneic mouse model and reduced tumor mass in mice with fully developed disease. Our data indicate that stromally induced hedgehog signaling may provide an important survival signal for B- and plasma-cell malignancies in vitro and in vivo. Disruption of this interaction by hedgehog pathway inhibition could provide a new strategy in lymphoma and multiple myeloma therapy.", + "TAG_DATA": [ + "64, lymphomas {'context': 'B-neoplasm'}", + "65, induced {'effect': 'B-positive'}", + "66, apoptosis {'phenotype': 'B-apoptosis'}", + "83, in {'context': 'B-in vivo'}", + "84, vivo {'context': 'I-in vivo'}", + "85, inhibited {'effect': 'B-negative'}", + "88, mouse {'context': 'B-transformed cells'}", + "89, lymphoma {'context': 'I-transformed cells'}", + "90, cells {'context': 'I-transformed cells'}", + "93, syngeneic {'context': 'B-organism'}", + "94, mouse {'context': 'I-organism'}", + "95, model {'context': 'I-organism'}", + "97, reduced {'effect': 'B-negative'}", + "98, tumor {'phenotype': 'B-tumourigenesis'}", + "99, mass {'phenotype': 'I-tumourigenesis'}", + "101, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "64, lymphomas ['l0', 'l1']", + "65, induced ['l0', 'l2']", + "66, apoptosis ['l1', 'l2']", + "83, in ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "84, vivo ['l3', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "85, inhibited ['l4', 'l11', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "88, mouse ['l5', 'l12', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "89, lymphoma ['l6', 'l13', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32']", + "90, cells ['l7', 'l14', 'l20', 'l25', 'l29', 'l33', 'l34']", + "93, syngeneic ['l8', 'l15', 'l21', 'l26', 'l30', 'l35', 'l36']", + "94, mouse ['l9', 'l16', 'l22', 'l27', 'l31', 'l33', 'l35', 'l37']", + "95, model ['l10', 'l17', 'l23', 'l28', 'l32', 'l34', 'l36', 'l37']", + "97, reduced ['l38', 'l39', 'l40']", + "98, tumor ['l38', 'l41', 'l42']", + "99, mass ['l39', 'l41', 'l43']", + "101, mice ['l40', 'l42', 'l43']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "lymphomas" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "lymphomas" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "mouse", + "lymphoma", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "reduced" + ] + }, + "context": { + "val": "organism", + "words": [ + "syngeneic", + "mouse", + "model", + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "mass" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "mass" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "17618294", + "TEXT": "The E3 ubiquitin ligase Cblb has a crucial role in the prevention of chronic inflammation and autoimmunity. Here we show that Cblb also has an unexpected function in acute lung inflammation. Cblb attenuates the sequestration of inflammatory cells in the lungs after administration of lipopolysaccharide (LPS). In a model of polymicrobial sepsis in which acute lung inflammation depends on the LPS receptor (Toll-like receptor 4, TLR-4), the loss of Cblb expression accentuates acute lung inflammation and reduces survival. Loss of Cblb significantly increases sepsis-induced release of inflammatory cytokines and chemokines. Cblb controls the association between TLR4 and the intracellular adaptor MyD88. Expression of wild-type Cblb, but not expression of a Cblb mutant that lacks E3 ubiquitin ligase function, prevents the activity of a reporter gene for the transcription factor nuclear factor-kappaB (NF-kappaB) in monocytes that have been challenged with LPS. The downregulation of TLR4 expression on the cell surface of neutrophils is impaired in the absence of Cblb. Our data reveal that Cblb regulates the TLR4-mediated acute inflammatory response that is induced by sepsis.", + "TAG_DATA": [ + "67, loss {'perturbing_action': 'B-gene loss-of-function'}", + "68, of {'perturbing_action': 'I-gene loss-of-function'}", + "69, Cblb {'perturbing_action': 'I-gene loss-of-function'}", + "70, expression {'perturbing_action': 'I-gene loss-of-function'}", + "73, lung {'context': 'B-tissue/organ'}", + "78, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "79, of {'perturbing_action': 'I-gene loss-of-function'}", + "80, Cblb {'perturbing_action': 'I-gene loss-of-function'}", + "101, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "102, of {'perturbing_action': 'I-gene gain-of-function'}", + "103, wild-type {'perturbing_action': 'I-gene gain-of-function'}", + "104, Cblb, {'perturbing_action': 'I-gene gain-of-function'}", + "110, Cblb {'perturbing_action': 'B-other'}", + "111, mutant {'perturbing_action': 'I-other'}", + "133, monocytes {'context': 'B-cells'}", + "155, absence {'perturbing_action': 'B-gene loss-of-function'}", + "156, of {'perturbing_action': 'I-gene loss-of-function'}", + "157, Cblb. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "67, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "68, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "69, Cblb ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "70, expression ['l2', 'l8', 'l13', 'l18']", + "73, lung ['l3', 'l9', 'l14', 'l18']", + "78, Loss ['l4', 'l10', 'l15', 'l19', 'l20']", + "79, of ['l5', 'l11', 'l16', 'l19', 'l21']", + "80, Cblb ['l6', 'l12', 'l17', 'l20', 'l21']", + "101, Expression ['l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "102, of ['l22', 'l28', 'l29', 'l30', 'l31']", + "103, wild-type ['l23', 'l28', 'l32', 'l33', 'l34', 'l35']", + "104, Cblb, ['l24', 'l29', 'l32', 'l36']", + "110, Cblb ['l25', 'l33', 'l37', 'l38', 'l39', 'l40', 'l41']", + "111, mutant ['l26', 'l30', 'l34', 'l37', 'l42', 'l43', 'l44', 'l45']", + "133, monocytes ['l27', 'l31', 'l35', 'l36', 'l38', 'l42']", + "155, absence ['l39', 'l43', 'l46', 'l47']", + "156, of ['l40', 'l44', 'l46', 'l48']", + "157, Cblb. ['l41', 'l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Cblb", + "expression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "wild-type", + "Cblb," + ] + }, + "context": { + "val": "cells", + "words": [ + "monocytes" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Cblb", + "mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "monocytes" + ] + } + } + ] + }, + { + "PMID": "17603493", + "TEXT": "Antigen-specific CD8+ T-cell tolerance, induced by myeloid-derived suppressor cells (MDSCs), is one of the main mechanisms of tumor escape. Using in vivo models, we show here that MDSCs directly disrupt the binding of specific peptide-major histocompatibility complex (pMHC) dimers to CD8-expressing T cells through nitration of tyrosines in a T-cell receptor (TCR)-CD8 complex. This process makes CD8-expressing T cells unable to bind pMHC and to respond to the specific peptide, although they retain their ability to respond to nonspecific stimulation. Nitration of TCR-CD8 is induced by MDSCs through hyperproduction of reactive oxygen species and peroxynitrite during direct cell-cell contact. Molecular modeling suggests specific sites of nitration that might affect the conformational flexibility of TCR-CD8 and its interaction with pMHC. These data identify a previously unknown mechanism of T-cell tolerance in cancer that is also pertinent to many pathological conditions associated with accumulation of MDSCs.", + "TAG_DATA": [ + "40, CD8-expressing {'context': 'B-cells'}", + "41, T {'context': 'I-cells'}", + "42, cells {'context': 'I-cells'}", + "56, CD8-expressing {'context': 'B-cells'}", + "57, T {'context': 'I-cells'}", + "58, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "40, CD8-expressing ['l0', 'l1', 'l2', 'l3', 'l4']", + "41, T ['l0', 'l5', 'l6', 'l7', 'l8']", + "42, cells ['l1', 'l5', 'l9', 'l10', 'l11']", + "56, CD8-expressing ['l2', 'l6', 'l9', 'l12', 'l13']", + "57, T ['l3', 'l7', 'l10', 'l12', 'l14']", + "58, cells ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17589522", + "TEXT": "Many sight-threatening diseases have two critical phases, vessel loss followed by hypoxia-driven destructive neovascularization. These diseases include retinopathy of prematurity and diabetic retinopathy, leading causes of blindness in childhood and middle age affecting over 4 million people in the United States. We studied the influence of omega-3- and omega-6-polyunsaturated fatty acids (PUFAs) on vascular loss, vascular regrowth after injury, and hypoxia-induced pathological neovascularization in a mouse model of oxygen-induced retinopathy. We show that increasing omega-3-PUFA tissue levels by dietary or genetic means decreased the avascular area of the retina by increasing vessel regrowth after injury, thereby reducing the hypoxic stimulus for neovascularization. The bioactive omega-3-PUFA-derived mediators neuroprotectinD1, resolvinD1 and resolvinE1 also potently protected against neovascularization. The protective effect of omega-3-PUFAs and their bioactive metabolites was mediated, in part, through suppression of tumor necrosis factor-alpha. This inflammatory cytokine was found in a subset of microglia that was closely associated with retinal vessels. These findings indicate that increasing the sources of omega-3-PUFA or their bioactive products reduces pathological angiogenesis. Western diets are often deficient in omega-3-PUFA, and premature infants lack the important transfer from the mother to the infant of omega-3-PUFA that normally occurs in the third trimester of pregnancy. Supplementing omega-3-PUFA intake may be of benefit in preventing retinopathy.", + "TAG_DATA": [ + "65, mouse {'context': 'B-organism'}", + "66, model {'context': 'I-organism'}", + "88, retina {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "65, mouse ['l0', 'l1']", + "66, model ['l0', 'l2']", + "88, retina ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17589521", + "TEXT": "Functional deficiency of the FEN1 gene has been suggested to cause genomic instability and cancer predisposition. We have identified a group of FEN1 mutations in human cancer specimens. Most of these mutations abrogated two of three nuclease activities of flap endonuclease 1 (FEN1). To demonstrate the etiological significance of these somatic mutations, we inbred a mouse line harboring the E160D mutation representing mutations identified in human cancers. Selective elimination of nuclease activities led to frequent spontaneous mutations and accumulation of incompletely digested DNA fragments in apoptotic cells. The mutant mice were predisposed to autoimmunity, chronic inflammation and cancers. The mutator phenotype results in the initiation of cancer, whereas chronic inflammation promotes the cancer progression. The current work exemplifies the approach of studying the mechanisms of individual polymorphisms and somatic mutations in cancer development, and may serve as a reference in developing new therapeutic regimens through the suppression of inflammatory responses.", + "TAG_DATA": [ + "55, mouse {'context': 'B-organism'}", + "56, line {'context': 'I-organism'}", + "59, E160D {'perturbing_action': 'B-other'}", + "60, mutation {'perturbing_action': 'I-other'}", + "86, cells. {'context': 'B-cells'}", + "89, mice {'context': 'B-organism'}", + "104, initiation {'effect': 'B-positive'}", + "106, cancer, {'phenotype': 'B-tumourigenesis'}", + "110, promotes {'effect': 'B-positive'}", + "112, cancer {'phenotype': 'B-tumour progression'}", + "113, progression. {'phenotype': 'I-tumour progression'}" + ], + "LINK_DATA": [ + "55, mouse ['l0', 'l1', 'l2', 'l3']", + "56, line ['l0', 'l4', 'l5', 'l6']", + "59, E160D ['l1', 'l4', 'l7', 'l8']", + "60, mutation ['l2', 'l5', 'l7', 'l9']", + "86, cells. ['l3', 'l6', 'l8', 'l9']", + "89, mice ['l10', 'l11']", + "104, initiation ['l10', 'l12']", + "106, cancer, ['l11', 'l12']", + "110, promotes ['l13', 'l14']", + "112, cancer ['l13', 'l15']", + "113, progression. ['l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "line" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "E160D", + "mutation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "E160D", + "mutation" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "initiation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "cancer," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiation" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "cancer," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "cancer", + "progression." + ] + } + } + ] + }, + { + "PMID": "17572687", + "TEXT": "Hepatic tissue engineering using primary hepatocytes has been considered a valuable new therapeutic modality for several classes of liver diseases. Recent progress in the development of clinically feasible liver tissue engineering approaches, however, has been hampered mainly by insufficient cell-to-cell contact of the engrafted hepatocytes. We developed a method to engineer a uniformly continuous sheet of hepatic tissue using isolated primary hepatocytes cultured on temperature-responsive surfaces. Sheets of hepatic tissue transplanted into the subcutaneous space resulted in efficient engraftment to the surrounding cells, with the formation of two-dimensional hepatic tissues that stably persisted for longer than 200 d. The engineered hepatic tissues also showed several characteristics of liver-specific functionality. Additionally, when the hepatic tissue sheets were layered in vivo, three-dimensional miniature liver systems having persistent survivability could be also engineered. This technology for liver tissue engineering is simple, minimally invasive and free of potentially immunogenic biodegradable scaffolds.", + "TAG_DATA": [ + "59, isolated {'context': 'B-cells'}", + "60, primary {'context': 'I-cells'}", + "61, hepatocytes {'context': 'I-cells'}", + "82, cells, {'context': 'B-cells'}", + "100, hepatic {'context': 'B-tissue/organ'}", + "101, tissues {'context': 'I-tissue/organ'}", + "117, in {'context': 'B-in vivo'}", + "118, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "59, isolated ['l0', 'l1', 'l2', 'l3']", + "60, primary ['l0', 'l4', 'l5', 'l6']", + "61, hepatocytes ['l1', 'l4', 'l7', 'l8']", + "69, tissue ['l2', 'l5', 'l7', 'l9']", + "82, cells, ['l3', 'l6', 'l8', 'l9']", + "100, hepatic ['l10']", + "101, tissues ['l10']", + "113, tissue ['l11', 'l12']", + "117, in ['l11', 'l13']", + "118, vivo, ['l12', 'l13']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17572686", + "TEXT": "Dying cells stimulate inflammation, and this response is thought to contribute to the pathogenesis of many diseases. Very little has been known, however, about how cell death triggers inflammation. We found here that the acute neutrophilic inflammatory response to cell injury requires the signaling protein myeloid differentiation primary response gene 88 (Myd88). Analysis of the contribution of Myd88-dependent receptors to this response revealed only a minor reduction in mice doubly deficient in Toll-like receptor 2 (Tlr2) and Tlr4 and normal responses in mice lacking Tlr1, Tlr3, Tlr6, Tlr7, Tlr9, Tlr11 or the interleukin-18 receptor (IL-18R). However, mice lacking IL-1R showed a markedly reduced neutrophilic inflammatory response to dead cells and tissue injury in vivo as well as greatly decreased collateral damage from inflammation. This inflammatory response required IL-1alpha, and IL-1R function was required on non-bone-marrow-derived cells. Notably, the acute monocyte response to cell death, which is thought to be important for tissue repair, was much less dependent on the IL-1R-Myd88 pathway. Also, this pathway was not required for the neutrophil response to a microbial stimulus. These findings suggest that inhibiting the IL-1R-Myd88 pathway in vivo could block the damage from acute inflammation that occurs in response to sterile cell death, and do so in a way that might not compromise tissue repair or host defense against pathogens.", + "TAG_DATA": [ + "68, mice {'context': 'B-organism'}", + "69, doubly {'perturbing_action': 'B-gene loss-of-function'}", + "70, deficient {'perturbing_action': 'I-gene loss-of-function'}", + "71, in {'perturbing_action': 'I-gene loss-of-function'}", + "72, Toll-like {'perturbing_action': 'I-gene loss-of-function'}", + "73, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "74, 2 {'perturbing_action': 'I-gene loss-of-function'}", + "75, (Tlr2) {'perturbing_action': 'I-gene loss-of-function'}", + "76, and {'perturbing_action': 'I-gene loss-of-function'}", + "77, Tlr4 {'perturbing_action': 'I-gene loss-of-function'}", + "82, mice {'context': 'B-organism'}", + "83, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "84, Tlr1, {'perturbing_action': 'I-gene loss-of-function'}", + "85, Tlr3, {'perturbing_action': 'I-gene loss-of-function'}", + "86, Tlr6, {'perturbing_action': 'I-gene loss-of-function'}", + "87, Tlr7, {'perturbing_action': 'I-gene loss-of-function'}", + "88, Tlr9, {'perturbing_action': 'I-gene loss-of-function'}", + "89, Tlr11 {'perturbing_action': 'I-gene loss-of-function'}", + "91, the {'perturbing_action': 'I-gene loss-of-function'}", + "96, mice {'context': 'B-organism'}", + "97, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "98, IL-1R {'perturbing_action': 'I-gene loss-of-function'}", + "107, dead {'context': 'B-cells'}", + "108, cells {'context': 'I-cells'}", + "112, in {'context': 'B-in vivo'}", + "113, vivo {'context': 'I-in vivo'}", + "134, non-bone-marrow-derived {'context': 'B-cells'}", + "135, cells. {'context': 'I-cells'}", + "139, monocyte {'context': 'B-cells'}", + "142, cell {'phenotype': 'B-cell death'}", + "143, death, {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "68, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "69, doubly ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "70, deficient ['l1', 'l9', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "71, in ['l2', 'l10', 'l31', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "72, Toll-like ['l3', 'l11', 'l32', 'l51', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "73, receptor ['l4', 'l12', 'l33', 'l52', 'l71', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "74, 2 ['l5', 'l13', 'l34', 'l53', 'l72', 'l90', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "75, (Tlr2) ['l6', 'l14', 'l35', 'l54', 'l73', 'l91', 'l108', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139']", + "76, and ['l7', 'l15', 'l36', 'l55', 'l74', 'l92', 'l109', 'l125', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "77, Tlr4 ['l8', 'l16', 'l37', 'l56', 'l75', 'l93', 'l110', 'l126', 'l140', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164']", + "82, mice ['l17', 'l38', 'l57', 'l76', 'l94', 'l111', 'l127', 'l141', 'l154', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177']", + "83, lacking ['l18', 'l39', 'l58', 'l77', 'l95', 'l112', 'l128', 'l142', 'l155', 'l165', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189']", + "84, Tlr1, ['l19', 'l40', 'l59', 'l78', 'l96', 'l113', 'l129', 'l143', 'l156', 'l166', 'l178', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200']", + "85, Tlr3, ['l20', 'l41', 'l60', 'l79', 'l97', 'l114', 'l130', 'l144', 'l157', 'l167', 'l179', 'l190', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210']", + "86, Tlr6, ['l21', 'l42', 'l61', 'l80', 'l98', 'l115', 'l131', 'l145', 'l158', 'l168', 'l180', 'l191', 'l201', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219']", + "87, Tlr7, ['l22', 'l43', 'l62', 'l81', 'l99', 'l116', 'l132', 'l146', 'l159', 'l169', 'l181', 'l192', 'l202', 'l211', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227']", + "88, Tlr9, ['l23', 'l44', 'l63', 'l82', 'l100', 'l117', 'l133', 'l147', 'l160', 'l170', 'l182', 'l193', 'l203', 'l212', 'l220', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234']", + "89, Tlr11 ['l24', 'l45', 'l64', 'l83', 'l101', 'l118', 'l134', 'l148', 'l161', 'l171', 'l183', 'l194', 'l204', 'l213', 'l221', 'l228', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240']", + "90, or ['l25', 'l46', 'l65', 'l84', 'l102', 'l119', 'l135', 'l149', 'l172', 'l184', 'l195', 'l205', 'l214', 'l222', 'l229', 'l235', 'l241', 'l242', 'l243', 'l244', 'l245']", + "91, the ['l26', 'l66', 'l85', 'l103', 'l120', 'l173', 'l185', 'l196', 'l206', 'l215', 'l223', 'l230', 'l236', 'l241', 'l246', 'l247', 'l248', 'l249', 'l250']", + "96, mice ['l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261']", + "97, lacking ['l251', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271']", + "98, IL-1R ['l246', 'l252', 'l262', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280']", + "107, dead ['l27', 'l47', 'l67', 'l86', 'l104', 'l121', 'l136', 'l150', 'l174', 'l186', 'l197', 'l207', 'l216', 'l224', 'l231', 'l237', 'l242', 'l247', 'l253', 'l263', 'l272', 'l281', 'l282', 'l283']", + "108, cells ['l28', 'l48', 'l68', 'l87', 'l105', 'l122', 'l137', 'l151', 'l162', 'l175', 'l187', 'l198', 'l208', 'l217', 'l225', 'l232', 'l238', 'l243', 'l248', 'l254', 'l264', 'l273', 'l281', 'l284', 'l285']", + "112, in ['l29', 'l49', 'l69', 'l88', 'l106', 'l123', 'l138', 'l152', 'l163', 'l176', 'l188', 'l199', 'l209', 'l218', 'l226', 'l233', 'l239', 'l244', 'l249', 'l255', 'l265', 'l274', 'l282', 'l284', 'l286']", + "113, vivo ['l30', 'l50', 'l70', 'l89', 'l107', 'l124', 'l139', 'l153', 'l164', 'l177', 'l189', 'l200', 'l210', 'l219', 'l227', 'l234', 'l240', 'l245', 'l250', 'l256', 'l266', 'l275', 'l283', 'l285', 'l286']", + "134, non-bone-marrow-derived ['l257', 'l267', 'l276', 'l287', 'l288', 'l289', 'l290']", + "135, cells. ['l258', 'l268', 'l277', 'l287', 'l291', 'l292', 'l293']", + "139, monocyte ['l259', 'l269', 'l278', 'l288', 'l291', 'l294', 'l295']", + "142, cell ['l260', 'l270', 'l279', 'l289', 'l292', 'l294', 'l296']", + "143, death, ['l261', 'l271', 'l280', 'l290', 'l293', 'l295', 'l296']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "doubly", + "deficient", + "in", + "Toll-like", + "receptor", + "2", + "(Tlr2)", + "and", + "Tlr4", + "lacking", + "Tlr1,", + "Tlr3,", + "Tlr6,", + "Tlr7,", + "Tlr9,", + "Tlr11", + "the", + "IL-1R" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "doubly", + "deficient", + "in", + "Toll-like", + "receptor", + "2", + "(Tlr2)", + "and", + "Tlr4", + "lacking", + "Tlr1,", + "Tlr3,", + "Tlr6,", + "Tlr7,", + "Tlr9,", + "Tlr11", + "the", + "IL-1R" + ] + }, + "context": { + "val": "cells", + "words": [ + "dead", + "cells", + "non-bone-marrow-derived", + "cells.", + "monocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "doubly", + "deficient", + "in", + "Toll-like", + "receptor", + "2", + "(Tlr2)", + "and", + "Tlr4", + "lacking", + "Tlr1,", + "Tlr3,", + "Tlr6,", + "Tlr7,", + "Tlr9,", + "Tlr11", + "the", + "IL-1R" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "IL-1R" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "non-bone-marrow-derived", + "cells.", + "monocyte" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + } + ] + }, + { + "PMID": "17515896", + "TEXT": "Exotoxins of Staphylococcus aureus belong to a family of bacterial proteins that act as superantigens by activating a large subset of the T-cell population, causing massive release of inflammatory cytokines. This cascade can ultimately result in toxic shock syndrome and death. Therapeutics targeting the early stage of the pathogenic process, when the superantigen binds to its receptor, could limit the severity of disease. We engineered picomolar binding affinity agents to neutralize the potent toxin staphylococcal enterotoxin B (SEB). A single immunoglobulin-like domain of the T-cell receptor (variable region, Vbeta) was subjected to multiple rounds of directed evolution using yeast display. Soluble forms of the engineered Vbeta proteins produced in Escherichia coli were effective inhibitors of SEB-mediated T-cell activation and completely neutralized the lethal activity of SEB in animal models. These Vbeta proteins represent an easily produced potential treatment for diseases mediated by bacterial superantigens.", + "TAG_DATA": [ + "116, T-cell {'context': 'B-cells'}", + "127, animal {'context': 'B-organism'}", + "128, models. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "127, animal ['l0']", + "128, models. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17468766", + "TEXT": "Growing evidence indicates that microRNAs (miRNAs or miRs) are involved in basic cell functions and oncogenesis. Here we report that miR-133 has a critical role in determining cardiomyocyte hypertrophy. We observed decreased expression of both miR-133 and miR-1, which belong to the same transcriptional unit, in mouse and human models of cardiac hypertrophy. In vitro overexpression of miR-133 or miR-1 inhibited cardiac hypertrophy. In contrast, suppression of miR-133 by 'decoy' sequences induced hypertrophy, which was more pronounced than that after stimulation with conventional inducers of hypertrophy. In vivo inhibition of miR-133 by a single infusion of an antagomir caused marked and sustained cardiac hypertrophy. We identified specific targets of miR-133: RhoA, a GDP-GTP exchange protein regulating cardiac hypertrophy; Cdc42, a signal transduction kinase implicated in hypertrophy; and Nelf-A/WHSC2, a nuclear factor involved in cardiogenesis. Our data show that miR-133, and possibly miR-1, are key regulators of cardiac hypertrophy, suggesting their therapeutic application in heart disease.", + "TAG_DATA": [ + "53, In {'context': 'B-in vitro'}", + "54, vitro {'context': 'I-in vitro'}", + "55, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "56, of {'perturbing_action': 'I-gene gain-of-function'}", + "57, miR-133 {'perturbing_action': 'I-gene gain-of-function'}", + "58, or {'perturbing_action': 'I-gene gain-of-function'}", + "59, miR-1 {'perturbing_action': 'I-gene gain-of-function'}", + "65, suppression {'perturbing_action': 'B-pharmacological inhibition'}", + "66, of {'perturbing_action': 'I-rnai/knockdown'}", + "67, miR-133 {'perturbing_action': 'I-pharmacological inhibition'}", + "68, by {'perturbing_action': 'I-rnai/knockdown'}", + "69, 'decoy' {'perturbing_action': 'I-rnai/knockdown'}", + "70, sequences {'perturbing_action': 'I-rnai/knockdown'}", + "86, In {'context': 'B-in vivo'}", + "87, vivo {'context': 'I-in vivo'}", + "88, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "89, of {'perturbing_action': 'I-pharmacological inhibition'}", + "90, miR-133 {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "53, In ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "54, vitro ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "55, overexpression ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "56, of ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "57, miR-133 ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "58, or ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "59, miR-1 ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "65, suppression ['l21', 'l22', 'l23', 'l24', 'l25']", + "66, of ['l21', 'l26', 'l27', 'l28', 'l29']", + "67, miR-133 ['l22', 'l26', 'l30', 'l31', 'l32']", + "68, by ['l23', 'l27', 'l30', 'l33', 'l34']", + "69, 'decoy' ['l24', 'l28', 'l31', 'l33', 'l35']", + "70, sequences ['l25', 'l29', 'l32', 'l34', 'l35']", + "86, In ['l36', 'l37', 'l38', 'l39']", + "87, vivo ['l36', 'l40', 'l41', 'l42']", + "88, inhibition ['l37', 'l40', 'l43', 'l44']", + "89, of ['l38', 'l41', 'l43', 'l45']", + "90, miR-133 ['l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "miR-133", + "or", + "miR-1" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "miR-133" + ] + } + } + ] + }, + { + "PMID": "17417651", + "TEXT": "Glucocorticoid-induced tumor necrosis factor receptor (GITR) on T cells and its natural ligand, GITRL, on accessory cells contribute to the control of immune homeostasis. Here we show that reverse signaling through GITRL after engagement by soluble GITR initiates the immunoregulatory pathway of tryptophan catabolism in mouse plasmacytoid dendritic cells, by means of noncanonical NF-kappaB-dependent induction of indoleamine 2,3-dioxygenase (IDO). The synthetic glucocorticoid dexamethasone administered in vivo activated IDO through the symmetric induction of GITR in CD4(+) T cells and GITRL in plasmacytoid dendritic cells. The drug exerted IDO-dependent protection in a model of allergic airway inflammation. Modulation of tryptophan catabolism via the GITR-GITRL coreceptor system might represent an effective therapeutic target in immune regulation. Induction of IDO could be an important mechanism underlying the anti-inflammatory action of corticosteroids.", + "TAG_DATA": [ + "45, mouse {'context': 'B-cells'}", + "46, plasmacytoid {'context': 'I-cells'}", + "47, dendritic {'context': 'I-cells'}", + "48, cells, {'context': 'I-cells'}", + "64, in {'context': 'B-in vivo'}", + "65, vivo {'context': 'I-in vivo'}", + "75, CD4(+) {'context': 'B-cells'}", + "76, T {'context': 'I-cells'}", + "77, cells {'context': 'I-cells'}", + "81, plasmacytoid {'context': 'B-cells'}", + "82, dendritic {'context': 'I-cells'}", + "83, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, mouse ['l0', 'l1', 'l2']", + "46, plasmacytoid ['l0', 'l3', 'l4']", + "47, dendritic ['l1', 'l3', 'l5']", + "48, cells, ['l2', 'l4', 'l5']", + "64, in ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "65, vivo ['l6', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "75, CD4(+) ['l7', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "76, T ['l8', 'l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "77, cells ['l9', 'l15', 'l20', 'l24', 'l28', 'l29', 'l30']", + "81, plasmacytoid ['l10', 'l16', 'l21', 'l25', 'l28', 'l31', 'l32']", + "82, dendritic ['l11', 'l17', 'l22', 'l26', 'l29', 'l31', 'l33']", + "83, cells. ['l12', 'l18', 'l23', 'l27', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17384649", + "TEXT": "Treatment with ex vivo-generated regulatory T cells (T-reg) has been regarded as a potentially attractive therapeutic approach for autoimmune diseases. However, the dynamics and function of T-reg in autoimmunity are not well understood. Thus, we developed Foxp3gfp knock-in (Foxp3gfp.KI) mice and myelin oligodendrocyte glycoprotein (MOG)(35-55)/IA(b) (MHC class II) tetramers to track autoantigen-specific effector T cells (T-eff) and T-reg in vivo during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. MOG tetramer-reactive, Foxp3(+) T-reg expanded in the peripheral lymphoid compartment and readily accumulated in the central nervous system (CNS), but did not prevent the onset of disease. Foxp3(+) T cells isolated from the CNS were effective in suppressing naive MOG-specific T cells, but failed to control CNS-derived encephalitogenic T-eff that secreted interleukin (IL)-6 and tumor necrosis factor (TNF). Our data suggest that in order for CD4(+)Foxp3(+) T-reg to effectively control autoimmune reactions in the target organ, it may also be necessary to control tissue inflammation.", + "TAG_DATA": [ + "36, Foxp3gfp {'perturbing_action': 'B-gene loss-of-function'}", + "37, knock-in {'perturbing_action': 'I-gene loss-of-function'}", + "38, (Foxp3gfp.KI) {'perturbing_action': 'I-gene loss-of-function'}", + "39, mice {'context': 'B-organism'}", + "58, in {'context': 'B-in vivo'}", + "59, vivo {'context': 'I-in vivo'}", + "98, Foxp3(+) {'context': 'B-cells'}", + "99, T {'context': 'I-cells'}", + "100, cells {'context': 'I-cells'}", + "101, isolated {'context': 'I-cells'}", + "102, from {'context': 'I-cells'}", + "103, the {'context': 'I-cells'}", + "104, CNS {'context': 'I-cells'}", + "109, naive {'context': 'B-cells'}", + "110, MOG-specific {'context': 'I-cells'}", + "111, T {'context': 'I-cells'}", + "112, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "36, Foxp3gfp ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "37, knock-in ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "38, (Foxp3gfp.KI) ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "39, mice ['l2', 'l8', 'l13', 'l18', 'l19']", + "58, in ['l3', 'l9', 'l14', 'l18', 'l20']", + "59, vivo ['l4', 'l10', 'l15', 'l19', 'l20']", + "79, lymphoid ['l5', 'l11', 'l16', 'l21']", + "80, compartment ['l6', 'l12', 'l17', 'l21']", + "98, Foxp3(+) ['l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "99, T ['l22', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "100, cells ['l23', 'l32', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "101, isolated ['l24', 'l33', 'l41', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "102, from ['l25', 'l34', 'l42', 'l49', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "103, the ['l26', 'l35', 'l43', 'l50', 'l56', 'l62', 'l63', 'l64', 'l65', 'l66']", + "104, CNS ['l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l67', 'l68', 'l69', 'l70']", + "109, naive ['l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l71', 'l72', 'l73']", + "110, MOG-specific ['l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l74', 'l75']", + "111, T ['l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l74', 'l76']", + "112, cells, ['l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l76']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Foxp3gfp", + "knock-in", + "(Foxp3gfp.KI)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Foxp3gfp", + "knock-in", + "(Foxp3gfp.KI)" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "17351626", + "TEXT": "We describe a new generation of protein-targeted contrast agents for multimodal imaging of the cell-surface receptors for vascular endothelial growth factor (VEGF). These receptors have a key role in angiogenesis and are important targets for drug development. Our probes are based on a single-chain recombinant VEGF expressed with a cysteine-containing tag that allows site-specific labeling with contrast agents for near-infrared fluorescence imaging, single-photon emission computed tomography or positron emission tomography. These probes retain VEGF activities in vitro and undergo selective and highly specific focal uptake into the vasculature of tumors and surrounding host tissue in vivo. The fluorescence contrast agent shows long-term persistence and co-localizes with endothelial cell markers, indicating that internalization is mediated by the receptors. We expect that multimodal imaging of VEGF receptors with these probes will be useful for clinical diagnosis and therapeutic monitoring, and will help to accelerate the development of new angiogenesis-directed drugs and treatments.", + "TAG_DATA": [ + "75, in {'context': 'B-in vitro'}", + "76, vitro {'context': 'I-in vitro'}", + "89, tumors {'context': 'B-neoplasm'}", + "94, in {'context': 'B-in vivo'}", + "95, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "75, in ['l0', 'l1', 'l2', 'l3']", + "76, vitro ['l0', 'l4', 'l5', 'l6']", + "89, tumors ['l1', 'l4', 'l7', 'l8']", + "94, in ['l2', 'l5', 'l7', 'l9']", + "95, vivo. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17351625", + "TEXT": "Intracranial transplantation of neural stem cells (NSCs) delayed disease onset, preserved motor function, reduced pathology and prolonged survival in a mouse model of Sandhoff disease, a lethal gangliosidosis. Although donor-derived neurons were electrophysiologically active within chimeric regions, the small degree of neuronal replacement alone could not account for the improvement. NSCs also increased brain beta-hexosaminidase levels, reduced ganglioside storage and diminished activated microgliosis. Additionally, when oral glycosphingolipid biosynthesis inhibitors (beta-hexosaminidase substrate inhibitors) were combined with NSC transplantation, substantial synergy resulted. Efficacy extended to human NSCs, both to those isolated directly from the central nervous system (CNS) and to those derived secondarily from embryonic stem cells. Appreciating that NSCs exhibit a broad repertoire of potentially therapeutic actions, of which neuronal replacement is but one, may help in formulating rational multimodal strategies for the treatment of neurodegenerative diseases.", + "TAG_DATA": [ + "20, mouse {'context': 'B-organism'}", + "21, model {'context': 'I-organism'}", + "29, donor-derived {'context': 'B-cells'}", + "30, neurons {'context': 'I-cells'}", + "83, human {'context': 'B-cells'}", + "84, NSCs, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "4, stem ['l0', 'l1', 'l2', 'l3', 'l4']", + "5, cells ['l0', 'l5', 'l6', 'l7', 'l8']", + "20, mouse ['l1', 'l5', 'l9', 'l10', 'l11']", + "21, model ['l2', 'l6', 'l9', 'l12', 'l13']", + "29, donor-derived ['l3', 'l7', 'l10', 'l12', 'l14']", + "30, neurons ['l4', 'l8', 'l11', 'l13', 'l14']", + "83, human ['l15']", + "84, NSCs, ['l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17351623", + "TEXT": "Microglia are the principal immune cells of the brain. In Alzheimer disease, these brain mononuclear phagocytes are recruited from the blood and accumulate in senile plaques. However, the role of microglia in Alzheimer disease has not been resolved. Microglia may be neuroprotective by phagocytosing amyloid-beta (Abeta), but their activation and the secretion of neurotoxins may also cause neurodegeneration. Ccr2 is a chemokine receptor expressed on microglia, which mediates the accumulation of mononuclear phagocytes at sites of inflammation. Here we show that Ccr2 deficiency accelerates early disease progression and markedly impairs microglial accumulation in a transgenic mouse model of Alzheimer disease (Tg2576). Alzheimer disease mice deficient in Ccr2 accumulated Abeta earlier and died prematurely, in a manner that correlated with Ccr2 gene dosage, indicating that absence of early microglial accumulation leads to decreased Abeta clearance and increased mortality. Thus, Ccr2-dependent microglial accumulation plays a protective role in the early stages of Alzheimer disease by promoting Abeta clearance.", + "TAG_DATA": [ + "81, Ccr2 {'perturbing_action': 'B-gene loss-of-function'}", + "82, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "94, transgenic {'context': 'B-organism'}", + "95, mouse {'context': 'I-organism'}", + "96, model {'context': 'I-organism'}", + "97, of {'context': 'I-organism'}", + "98, Alzheimer {'context': 'I-organism'}", + "99, disease {'context': 'I-organism'}", + "100, (Tg2576). {'context': 'I-organism'}", + "101, Alzheimer {'context': 'B-organism'}", + "102, disease {'context': 'I-organism'}", + "103, mice {'context': 'I-organism'}", + "104, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "105, in {'perturbing_action': 'I-gene loss-of-function'}", + "106, Ccr2 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "81, Ccr2 ['l0']", + "82, deficiency ['l0']", + "94, transgenic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "95, mouse ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "96, model ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "97, of ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "98, Alzheimer ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "99, disease ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "100, (Tg2576). ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']", + "101, Alzheimer ['l22', 'l23', 'l24', 'l25', 'l26']", + "102, disease ['l22', 'l27', 'l28', 'l29', 'l30']", + "103, mice ['l23', 'l27', 'l31', 'l32', 'l33']", + "104, deficient ['l24', 'l28', 'l31', 'l34', 'l35']", + "105, in ['l25', 'l29', 'l32', 'l34', 'l36']", + "106, Ccr2 ['l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Alzheimer", + "disease", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Ccr2" + ] + } + } + ] + }, + { + "PMID": "17342099", + "TEXT": "To win the fight against bird flu, the World Health Organization must forge partnerships with the governments of developing countries hit hardest by the disease.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17293870", + "TEXT": "Hereditary hemochromatosis and transfusional iron overload are frequent clinical conditions associated with progressive iron accumulation in parenchymal tissues, leading to eventual organ failure. We have discovered a new mechanism to reverse iron overload-pharmacological modulation of the divalent metal transporter-1 (DMT-1). DMT-1 mediates intracellular iron transport during the transferrin cycle and apical iron absorption in the duodenum. Its additional functions in iron handling in the kidney and liver are less well understood. We show that the L-type calcium channel blocker nifedipine increases DMT-1-mediated cellular iron transport 10- to 100-fold at concentrations between 1 and 100 microM. Mechanistically, nifedipine causes this effect by prolonging the iron-transporting activity of DMT-1. We show that nifedipine mobilizes iron from the liver of mice with primary and secondary iron overload and enhances urinary iron excretion. Modulation of DMT-1 function by L-type calcium channel blockers emerges as a new pharmacological therapy for the treatment of iron overload disorders.", + "TAG_DATA": [ + "115, liver {'context': 'B-tissue/organ'}", + "117, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "115, liver ['l0']", + "117, mice ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17268472", + "TEXT": "Adiponectin plays a central role as an antidiabetic and antiatherogenic adipokine. AdipoR1 and AdipoR2 serve as receptors for adiponectin in vitro, and their reduction in obesity seems to be correlated with reduced adiponectin sensitivity. Here we show that adenovirus-mediated expression of AdipoR1 and R2 in the liver of Lepr(-/-) mice increased AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor (PPAR)-alpha signaling pathways, respectively. Activation of AMPK reduced gluconeogenesis, whereas expression of the receptors in both cases increased fatty acid oxidation and lead to an amelioration of diabetes. Alternatively, targeted disruption of AdipoR1 resulted in the abrogation of adiponectin-induced AMPK activation, whereas that of AdipoR2 resulted in decreased activity of PPAR-alpha signaling pathways. Simultaneous disruption of both AdipoR1 and R2 abolished adiponectin binding and actions, resulting in increased tissue triglyceride content, inflammation and oxidative stress, and thus leading to insulin resistance and marked glucose intolerance. Therefore, AdipoR1 and R2 serve as the predominant receptors for adiponectin in vivo and play important roles in the regulation of glucose and lipid metabolism, inflammation and oxidative stress in vivo.", + "TAG_DATA": [ + "38, adenovirus-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "39, expression {'perturbing_action': 'I-gene gain-of-function'}", + "40, of {'perturbing_action': 'I-gene gain-of-function'}", + "41, AdipoR1 {'perturbing_action': 'I-gene gain-of-function'}", + "42, and {'perturbing_action': 'I-gene gain-of-function'}", + "43, R2 {'perturbing_action': 'I-gene gain-of-function'}", + "46, liver {'context': 'B-tissue/organ'}", + "48, Lepr(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "49, mice {'context': 'B-organism'}", + "89, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "90, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "91, of {'perturbing_action': 'I-gene loss-of-function'}", + "92, AdipoR1 {'perturbing_action': 'I-gene loss-of-function'}", + "114, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "115, of {'perturbing_action': 'I-gene loss-of-function'}", + "116, both {'perturbing_action': 'I-gene loss-of-function'}", + "117, AdipoR1 {'perturbing_action': 'I-gene loss-of-function'}", + "118, and {'perturbing_action': 'I-gene loss-of-function'}", + "119, R2 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "38, adenovirus-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "39, expression ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "40, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "41, AdipoR1 ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "42, and ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "43, R2 ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "46, liver ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "48, Lepr(-/-) ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "49, mice ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "89, targeted ['l36', 'l37', 'l38']", + "90, disruption ['l36', 'l39', 'l40']", + "91, of ['l37', 'l39', 'l41']", + "92, AdipoR1 ['l38', 'l40', 'l41']", + "114, disruption ['l42', 'l43', 'l44', 'l45', 'l46']", + "115, of ['l42', 'l47', 'l48', 'l49', 'l50']", + "116, both ['l43', 'l47', 'l51', 'l52', 'l53']", + "117, AdipoR1 ['l44', 'l48', 'l51', 'l54', 'l55']", + "118, and ['l45', 'l49', 'l52', 'l54', 'l56']", + "119, R2 ['l46', 'l50', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus-mediated", + "expression", + "of", + "AdipoR1", + "and", + "R2" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus-mediated", + "expression", + "of", + "AdipoR1", + "and", + "R2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lepr(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lepr(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "17237793", + "TEXT": "Degenerative and inflammatory joint diseases lead to a destruction of the joint architecture. Whereas degenerative osteoarthritis results in the formation of new bone, rheumatoid arthritis leads to bone resorption. The molecular basis of these different patterns of joint disease is unknown. By inhibiting Dickkopf-1 (DKK-1), a regulatory molecule of the Wnt pathway, we were able to reverse the bone-destructive pattern of a mouse model of rheumatoid arthritis to the bone-forming pattern of osteoarthritis. In this way, no overall bone erosion resulted, although bony nodules, so-called osteophytes, did form. We identified tumor necrosis factor-alpha (TNF) as a key inducer of DKK-1 in the mouse inflammatory arthritis model and in human rheumatoid arthritis. These results suggest that the Wnt pathway is a key regulator of joint remodeling.", + "TAG_DATA": [ + "42, inhibiting {'perturbing_action': 'B-pharmacological inhibition'}", + "43, Dickkopf-1 {'perturbing_action': 'I-pharmacological inhibition'}", + "44, (DKK-1), {'perturbing_action': 'I-pharmacological inhibition'}", + "62, mouse {'context': 'B-organism'}", + "63, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "42, inhibiting ['l0', 'l1', 'l2', 'l3']", + "43, Dickkopf-1 ['l0', 'l4', 'l5', 'l6']", + "44, (DKK-1), ['l1', 'l4', 'l7', 'l8']", + "62, mouse ['l2', 'l5', 'l7', 'l9']", + "63, model ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibiting", + "Dickkopf-1", + "(DKK-1)," + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + } + ] + }, + { + "PMID": "17206149", + "TEXT": "Poor human-to-human transmission of influenza A H5N1 virus has been attributed to the paucity of putative sialic acid alpha2-3 virus receptors in the epithelium of the human upper respiratory tract, and thus to the presumed inability of the virus to replicate efficiently at this site. We now demonstrate that ex vivo cultures of human nasopharyngeal, adenoid and tonsillar tissues can be infected with H5N1 viruses in spite of an apparent lack of these receptors.", + "TAG_DATA": [ + "49, ex {'context': 'B-in vitro'}", + "50, vivo {'context': 'I-in vitro'}", + "51, cultures {'context': 'I-in vitro'}", + "53, human {'context': 'B-tissue/organ'}", + "54, nasopharyngeal, {'context': 'I-tissue/organ'}", + "55, adenoid {'context': 'I-tissue/organ'}", + "56, and {'context': 'I-tissue/organ'}", + "57, tonsillar {'context': 'I-tissue/organ'}", + "58, tissues {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "49, ex ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "50, vivo ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "51, cultures ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "53, human ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "54, nasopharyngeal, ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "55, adenoid ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "56, and ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "57, tonsillar ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "58, tissues ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17195838", + "TEXT": "Lysosome-related organelles have versatile functions, including protein and lipid degradation, signal transduction and protein secretion. The molecular elucidation of rare congenital diseases affecting endosomal-lysosomal biogenesis has given insights into physiological functions of the innate and adaptive immune system. Here, we describe a previously unknown human primary immunodeficiency disorder and provide evidence that the endosomal adaptor protein p14, previously characterized as confining mitogen-activated protein kinase (MAPK) signaling to late endosomes, is crucial for the function of neutrophils, B cells, cytotoxic T cells and melanocytes. Combining genetic linkage studies and transcriptional profiling analysis, we identified a homozygous point mutation in the 3' untranslated region (UTR) of p14 (also known as MAPBPIP), resulting in decreased protein expression. In p14-deficient cells, the distribution of late endosomes was severely perturbed, suggesting a previously unknown role for p14 in endosomal biogenesis. These findings have implications for understanding endosomal membrane dynamics, compartmentalization of cell signal cascades, and their role in immunity.", + "TAG_DATA": [ + "95, point {'perturbing_action': 'I-other'}", + "96, mutation {'perturbing_action': 'I-other'}", + "97, in {'perturbing_action': 'I-other'}", + "98, the {'perturbing_action': 'I-other'}", + "99, 3' {'perturbing_action': 'I-other'}", + "100, untranslated {'perturbing_action': 'I-other'}", + "101, region {'perturbing_action': 'I-other'}", + "103, of {'perturbing_action': 'I-other'}", + "104, p14 {'perturbing_action': 'I-other'}", + "105, (also {'perturbing_action': 'I-other'}", + "115, p14-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "116, cells, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "94, homozygous ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "95, point ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "96, mutation ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "97, in ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "98, the ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "99, 3' ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "100, untranslated ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "101, region ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "102, (UTR) ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "103, of ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "104, p14 ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "105, (also ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "115, p14-deficient ['l66']", + "116, cells, ['l66']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p14-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells," + ] + } + } + ] + }, + { + "PMID": "17159988", + "TEXT": "Interstitial loss of all or part of the long arm of chromosome 5, or del(5q), is a frequent clonal chromosomal abnormality in human myelodysplastic syndrome (MDS, a preleukemic disorder) and acute myeloid leukemia (AML), and is thought to contribute to the pathogenesis of these diseases by deleting one or more tumor-suppressor genes. Although a major commonly deleted region (CDR) has been delineated on chromosome band 5q31.1 (refs. 3-7), attempts to identify tumor suppressors within this band have been unsuccessful. We focused our analysis of gene expression on RNA from primitive leukemia-initiating cells, which harbor 5q deletions, and analyzed 12 genes within the CDR that are expressed by normal hematopoietic stem cells. Here we show that the gene encoding alpha-catenin (CTNNA1) is expressed at a much lower level in leukemia-initiating stem cells from individuals with AML or MDS with a 5q deletion than in individuals with MDS or AML lacking a 5q deletion or in normal hematopoietic stem cells. Analysis of HL-60 cells, a myeloid leukemia line with deletion of the 5q31 region, showed that the CTNNA1 promoter of the retained allele is suppressed by both methylation and histone deacetylation. Restoration of CTNNA1 expression in HL-60 cells resulted in reduced proliferation and apoptotic cell death. Thus, loss of expression of the alpha-catenin tumor suppressor in hematopoietic stem cells may provide a growth advantage that contributes to human MDS or AML with del(5q).", + "TAG_DATA": [ + "155, hematopoietic {'context': 'I-cells'}", + "156, stem {'context': 'I-cells'}", + "157, cells. {'context': 'I-cells'}", + "160, HL-60 {'context': 'B-cells'}", + "161, cells, {'context': 'I-cells'}", + "163, myeloid {'context': 'B-transformed cells'}", + "164, leukemia {'context': 'I-transformed cells'}", + "165, line {'context': 'I-transformed cells'}", + "189, Restoration {'perturbing_action': 'B-gene gain-of-function'}", + "190, of {'perturbing_action': 'I-gene gain-of-function'}", + "191, CTNNA1 {'perturbing_action': 'I-gene gain-of-function'}", + "192, expression {'perturbing_action': 'I-gene gain-of-function'}", + "194, HL-60 {'context': 'B-cells'}", + "195, cells {'context': 'I-cells'}", + "198, reduced {'effect': 'B-negative'}", + "199, proliferation {'phenotype': 'B-proliferation'}", + "201, apoptotic {'phenotype': 'B-apoptosis'}", + "202, cell {'phenotype': 'I-apoptosis'}", + "203, death. {'phenotype': 'I-apoptosis'}" + ], + "LINK_DATA": [ + "155, hematopoietic ['l0', 'l1', 'l2', 'l3']", + "156, stem ['l0', 'l4', 'l5']", + "157, cells. ['l1', 'l4']", + "160, HL-60 ['l2', 'l6', 'l7', 'l8', 'l9']", + "161, cells, ['l3', 'l5', 'l6', 'l10', 'l11', 'l12']", + "163, myeloid ['l7', 'l10', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "164, leukemia ['l8', 'l11', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "165, line ['l9', 'l12', 'l14', 'l19', 'l24', 'l25', 'l26']", + "189, Restoration ['l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "190, of ['l27', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "191, CTNNA1 ['l28', 'l37', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "192, expression ['l29', 'l38', 'l46', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "194, HL-60 ['l30', 'l39', 'l47', 'l54', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "195, cells ['l31', 'l40', 'l48', 'l55', 'l61', 'l67', 'l68', 'l69', 'l70', 'l71']", + "198, reduced ['l15', 'l20', 'l24', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l72', 'l73', 'l74', 'l75']", + "199, proliferation ['l16', 'l21', 'l25', 'l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l76', 'l77', 'l78']", + "201, apoptotic ['l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l76', 'l79', 'l80']", + "202, cell ['l17', 'l22', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l79', 'l81']", + "203, death. ['l18', 'l23', 'l26', 'l36', 'l45', 'l53', 'l60', 'l66', 'l71', 'l75', 'l78', 'l80', 'l81']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "myeloid", + "leukemia", + "line" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "myeloid", + "leukemia", + "line" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "myeloid", + "leukemia", + "line" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoration", + "of", + "CTNNA1", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "HL-60", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoration", + "of", + "CTNNA1", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoration", + "of", + "CTNNA1", + "expression" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoration", + "of", + "CTNNA1", + "expression" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HL-60", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HL-60", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HL-60", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "17159985", + "TEXT": "Abdominal pain is common in the general population and, in patients with irritable bowel syndrome, is attributed to visceral hypersensitivity. We found that oral administration of specific Lactobacillus strains induced the expression of mu-opioid and cannabinoid receptors in intestinal epithelial cells, and mediated analgesic functions in the gut-similar to the effects of morphine. These results suggest that the microbiology of the intestinal tract influences our visceral perception, and suggest new approaches for the treatment of abdominal pain and irritable bowel syndrome.", + "TAG_DATA": [ + "38, intestinal {'context': 'B-cells'}", + "39, epithelial {'context': 'I-cells'}", + "40, cells, {'context': 'I-cells'}", + "47, gut-similar {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "38, intestinal ['l0', 'l1', 'l2']", + "39, epithelial ['l0', 'l3', 'l4']", + "40, cells, ['l1', 'l3', 'l5']", + "47, gut-similar ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17143277", + "TEXT": "Islet transplantation is an attractive approach for treating type-1 diabetes, but there is a massive loss of transplanted islets. It is currently only possible to estimate islet mass indirectly, through measurement of circulating C-peptide and insulin levels. This type of estimation, however, is not sufficiently sensitive or reproducible for follow-up of individuals who have undergone islet transplantation. Here we show that islet graft survival could be assessed for 1 month in diabetic NOD mice using 9-(4-[(18)F]-fluoro-3-hydroxymethylbutyl)guanine ([(18)F]FHBG)-positron emission tomography (PET) technology, the PET signal reflecting insulin secretory capacity of transplanted islets. Expression of the gene encoding viral interleukin-10 (vIL-10), was measurable in real time with PET scanning. Additionally, we addressed the clinical potential of this approach by visualizing transplanted islets in the liver, the preferred clinical transplantation site. We conclude that quantitative in vivo PET imaging is a valid method for facilitating the development of protocols for prolonging islet survival, with the potential for tracking human transplants.", + "TAG_DATA": [ + "71, diabetic {'context': 'B-organism'}", + "72, NOD {'context': 'I-organism'}", + "73, mice {'context': 'I-organism'}", + "90, islets. {'context': 'B-cells'}", + "119, islets {'context': 'B-cells'}", + "122, liver, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "71, diabetic ['l0', 'l1', 'l2']", + "72, NOD ['l0', 'l3', 'l4']", + "73, mice ['l1', 'l3', 'l5']", + "90, islets. ['l2', 'l4', 'l5']", + "119, islets ['l6']", + "122, liver, ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17128269", + "TEXT": "Calcium (Ca(2+)) signaling is essential for a variety of cellular responses and higher biological functions. Ca(2+)/calmodulin-dependent kinases (CaMKs) and the phosphatase calcineurin activate distinct downstream pathways that are mediated by the transcription factors cAMP response element (CRE)-binding protein (CREB) and nuclear factor of activated T cells (NFAT), respectively. The importance of the calcineurin-NFAT pathway in bone metabolism has been demonstrated in osteoclasts, osteoblasts and chondrocytes. However, the contribution of the CaMK-CREB pathway is poorly understood, partly because of the difficulty of dissecting the functions of homologous family members. Here we show that the CaMKIV-CREB pathway is crucial for osteoclast differentiation and function. Pharmacological inhibition of CaMKs as well as the genetic ablation of Camk4 reduced CREB phosphorylation and downregulated the expression of c-Fos, which is required for the induction of NFATc1 (the master transcription factor for osteoclastogenesis) that is activated by receptor activator of NF-kappaB ligand (RANKL). Furthermore, CREB together with NFATc1 induced the expression of specific genes expressed by differentiated osteoclasts. Thus, the CaMK-CREB pathway biphasically functions to regulate the transcriptional program of osteoclastic bone resorption, by not only enhancing induction of NFATc1 but also facilitating NFATc1-dependent gene regulation once its expression is induced. This provides a molecular basis for a new therapeutic strategy for bone diseases.", + "TAG_DATA": [ + "102, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "103, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "104, of {'perturbing_action': 'I-pharmacological inhibition'}", + "105, CaMKs {'perturbing_action': 'I-pharmacological inhibition'}", + "110, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "111, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "112, of {'perturbing_action': 'I-gene loss-of-function'}", + "113, Camk4 {'perturbing_action': 'I-gene loss-of-function'}", + "161, osteoclasts. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "102, Pharmacological ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "103, inhibition ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "104, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18']", + "105, CaMKs ['l2', 'l9', 'l15', 'l19', 'l20', 'l21', 'l22', 'l23']", + "110, genetic ['l3', 'l10', 'l19', 'l24', 'l25', 'l26', 'l27']", + "111, ablation ['l4', 'l11', 'l20', 'l24', 'l28', 'l29', 'l30']", + "112, of ['l5', 'l12', 'l16', 'l21', 'l25', 'l28', 'l31', 'l32']", + "113, Camk4 ['l6', 'l13', 'l17', 'l22', 'l26', 'l29', 'l31', 'l33']", + "161, osteoclasts. ['l7', 'l14', 'l18', 'l23', 'l27', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "CaMKs" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclasts." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "Camk4" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclasts." + ] + } + } + ] + }, + { + "PMID": "17115046", + "TEXT": "Chronic activation of the immune system is a hallmark of progressive HIV infection and better predicts disease outcome than plasma viral load, yet its etiology remains obscure. Here we show that circulating microbial products, probably derived from the gastrointestinal tract, are a cause of HIV-related systemic immune activation. Circulating lipopolysaccharide, which we used as an indicator of microbial translocation, was significantly increased in chronically HIV-infected individuals and in simian immunodeficiency virus (SIV)-infected rhesus macaques (P g) at position -270 from the start codon of PIGM, a mannosyltransferase-encoding gene, disrupts binding of the transcription factor Sp1 to its cognate promoter motif. This mutation substantially reduces transcription of PIGM and blocks mannosylation of GPI, leading to partial but severe deficiency of GPI. These findings indicate that biosynthesis of GPI is essential to maintain homeostasis of blood coagulation and neurological function.", + "TAG_DATA": [ + "87, mutation {'perturbing_action': 'I-other'}", + "91, at {'perturbing_action': 'I-other'}", + "92, position {'perturbing_action': 'I-other'}", + "93, -270 {'perturbing_action': 'I-other'}", + "94, from {'perturbing_action': 'I-other'}", + "95, the {'perturbing_action': 'I-other'}", + "96, start {'perturbing_action': 'I-other'}", + "99, PIGM, {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "87, mutation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "88, (c ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "91, at ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "92, position ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "93, -270 ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "94, from ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "95, the ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "96, start ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "97, codon ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "98, of ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "99, PIGM, ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16767098", + "TEXT": "When given orally to a transgenic mouse model of Alzheimer disease, cyclohexanehexol stereoisomers inhibit aggregation of amyloid beta peptide (Abeta) into high-molecular-weight oligomers in the brain and ameliorate several Alzheimer disease-like phenotypes in these mice, including impaired cognition, altered synaptic physiology, cerebral Abeta pathology and accelerated mortality. These therapeutic effects, which occur regardless of whether the compounds are given before or well after the onset of the Alzheimer disease-like phenotype, support the idea that the accumulation of Abeta oligomers has a central role in the pathogenesis of Alzheimer disease.", + "TAG_DATA": [ + "5, transgenic {'context': 'B-organism'}", + "6, mouse {'context': 'I-organism'}", + "7, model {'context': 'I-organism'}", + "8, of {'context': 'I-organism'}", + "9, Alzheimer {'context': 'I-organism'}", + "10, disease, {'context': 'I-organism'}", + "34, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "5, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "6, mouse ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "7, model ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "8, of ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "9, Alzheimer ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "10, disease, ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "34, mice, ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16767097", + "TEXT": "Although much is known about environmental factors that predispose individuals to hypertension and cardiovascular disease, little information is available regarding the genetic and signaling events involved. Indeed, few genes associated with the progression of these pathologies have been discovered despite intensive research in animal models and human populations. Here we identify Vav3, a GDP-GTP exchange factor that stimulates Rho and Rac GTPases, as an essential factor regulating the homeostasis of the cardiovascular system. Vav3-deficient mice exhibited tachycardia, systemic arterial hypertension and extensive cardiovascular remodeling. These mice also showed hyperactivity of sympathetic neurons from the time of birth. The high catecholamine levels associated with this condition led to the activation of the renin-angiotensin system, increased levels of kidney-related hormones and the progressive loss of cardiovascular and renal homeostasis. Pharmacological studies with drugs targeting sympathetic and renin-angiotensin responses confirmed the causative role and hierarchy of these events in the development of the Vav3-null mouse phenotype. These observations uncover the crucial role of Vav3 in the regulation of the sympathetic nervous system (SNS) and cardiovascular physiology, and reveal a signaling pathway that could be involved in the pathophysiology of human disease states involving tachycardia and sympathetic hyperactivity with unknown etiologies.", + "TAG_DATA": [ + "73, Vav3-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "74, mice {'context': 'B-organism'}", + "85, mice {'context': 'B-organism'}", + "150, Vav3-null {'perturbing_action': 'B-gene loss-of-function'}", + "151, mouse {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, Vav3-deficient ['l0']", + "74, mice ['l0']", + "150, Vav3-null ['l1']", + "151, mouse ['l1']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Vav3-deficient", + "Vav3-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mouse" + ] + } + } + ] + }, + { + "PMID": "16732281", + "TEXT": "Here we report the presence of hyperphagia, obesity and insulin resistance in knockout mice deficient in IL-18 or IL-18 receptor, and in mice transgenic for expression of IL-18 binding protein. Obesity of Il18-/- mice resulted from accumulation of fat tissue based on increased food intake. Il18-/- mice also had hyperinsulinemia, consistent with insulin resistance and hyperglycemia. Insulin resistance was secondary to obesity induced by increased food intake and occurred at the liver level as well as at the muscle and fat-tissue level. The molecular mechanisms responsible for the hepatic insulin resistance in the Il18-/- mice involved an enhanced expression of genes associated with gluconeogenesis in the liver of Il18-/- mice, resulting from defective phosphorylation of STAT3. Recombinant IL-18 (rIL-18) administered intracerebrally inhibited food intake. In addition, rIL-18 reversed hyperglycemia in Il18-/- mice through activation of STAT3 phosphorylation. These findings indicate a new role of IL-18 in the homeostasis of energy intake and insulin sensitivity.", + "TAG_DATA": [ + "12, knockout {'context': 'B-organism'}", + "13, mice {'context': 'I-organism'}", + "14, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "15, in {'perturbing_action': 'I-gene loss-of-function'}", + "16, IL-18 {'perturbing_action': 'I-gene loss-of-function'}", + "17, or {'perturbing_action': 'I-gene loss-of-function'}", + "18, IL-18 {'perturbing_action': 'I-gene loss-of-function'}", + "19, receptor, {'perturbing_action': 'I-gene loss-of-function'}", + "22, mice {'context': 'B-organism'}", + "23, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "24, for {'perturbing_action': 'I-gene gain-of-function'}", + "25, expression {'perturbing_action': 'I-gene gain-of-function'}", + "26, of {'perturbing_action': 'I-gene gain-of-function'}", + "27, IL-18 {'perturbing_action': 'I-gene gain-of-function'}", + "28, binding {'perturbing_action': 'I-gene gain-of-function'}", + "29, protein. {'perturbing_action': 'I-gene gain-of-function'}", + "32, Il18-/- {'perturbing_action': 'B-gene loss-of-function'}", + "33, mice {'context': 'B-organism'}", + "45, Il18-/- {'perturbing_action': 'B-gene loss-of-function'}", + "46, mice {'context': 'B-organism'}", + "93, Il18-/- {'perturbing_action': 'B-gene loss-of-function'}", + "94, mice {'context': 'B-organism'}", + "106, liver {'context': 'B-tissue/organ'}", + "108, Il18-/- {'perturbing_action': 'B-gene loss-of-function'}", + "109, mice, {'context': 'B-organism'}", + "130, Il18-/- {'perturbing_action': 'B-gene loss-of-function'}", + "131, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "12, knockout ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "13, mice ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "14, deficient ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "15, in ['l2', 'l11', 'l19', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "16, IL-18 ['l3', 'l12', 'l20', 'l31', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "17, or ['l4', 'l13', 'l21', 'l32', 'l46', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "18, IL-18 ['l5', 'l14', 'l22', 'l33', 'l47', 'l57', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "19, receptor, ['l6', 'l15', 'l23', 'l34', 'l48', 'l58', 'l70', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "22, mice ['l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "23, transgenic ['l91', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "24, for ['l92', 'l107', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "25, expression ['l93', 'l108', 'l122', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "26, of ['l94', 'l109', 'l123', 'l136', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160']", + "27, IL-18 ['l71', 'l95', 'l110', 'l124', 'l137', 'l149', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171']", + "28, binding ['l35', 'l59', 'l72', 'l96', 'l111', 'l125', 'l138', 'l150', 'l161', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181']", + "29, protein. ['l36', 'l60', 'l73', 'l97', 'l112', 'l126', 'l139', 'l151', 'l162', 'l172', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190']", + "32, Il18-/- ['l7', 'l16', 'l24', 'l37', 'l49', 'l61', 'l74', 'l83', 'l98', 'l113', 'l127', 'l140', 'l152', 'l163', 'l173', 'l182', 'l191']", + "33, mice ['l8', 'l17', 'l25', 'l38', 'l50', 'l62', 'l75', 'l84', 'l99', 'l114', 'l128', 'l141', 'l153', 'l164', 'l174', 'l183', 'l191']", + "45, Il18-/- ['l26', 'l39', 'l51', 'l63', 'l76', 'l85', 'l100', 'l115', 'l129', 'l142', 'l154', 'l165', 'l175', 'l184', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197']", + "46, mice ['l27', 'l40', 'l52', 'l64', 'l77', 'l86', 'l101', 'l116', 'l130', 'l143', 'l155', 'l166', 'l176', 'l185', 'l192', 'l198', 'l199', 'l200', 'l201']", + "93, Il18-/- ['l28', 'l41', 'l53', 'l65', 'l78', 'l87', 'l102', 'l117', 'l131', 'l144', 'l156', 'l167', 'l177', 'l186', 'l193', 'l198', 'l202', 'l203', 'l204', 'l205']", + "94, mice ['l9', 'l18', 'l29', 'l42', 'l54', 'l66', 'l79', 'l88', 'l103', 'l118', 'l132', 'l145', 'l157', 'l168', 'l178', 'l187', 'l194', 'l199', 'l202', 'l206', 'l207', 'l208']", + "106, liver ['l30', 'l43', 'l55', 'l67', 'l80', 'l89', 'l104', 'l119', 'l133', 'l146', 'l158', 'l169', 'l179', 'l188', 'l195', 'l200', 'l203', 'l206', 'l209', 'l210']", + "108, Il18-/- ['l44', 'l68', 'l81', 'l105', 'l120', 'l134', 'l147', 'l159', 'l170', 'l180', 'l189', 'l196', 'l204', 'l207', 'l209', 'l211']", + "109, mice, ['l45', 'l56', 'l69', 'l82', 'l90', 'l106', 'l121', 'l135', 'l148', 'l160', 'l171', 'l181', 'l190', 'l197', 'l201', 'l205', 'l208', 'l210', 'l211']", + "130, Il18-/- ['l212']", + "131, mice ['l212']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "knockout", + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "IL-18", + "or", + "receptor,", + "Il18-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "IL-18", + "or", + "receptor,", + "Il18-/-" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "expression", + "of", + "IL-18", + "binding", + "protein." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "expression", + "of", + "IL-18", + "binding", + "protein." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "16732279", + "TEXT": "The lymphatic system has become the subject of great interest in recent years because of its important role in normal and pathological processes. Progress in understanding the origins and early development of this system, however, has been hampered by difficulties in observing lymphatic cells in vivo and in performing defined genetic and experimental manipulation of the lymphatic system in currently available model organisms. Here, we show that the optically clear developing zebrafish provides a useful model for imaging and studying lymphatic development, with a lymphatic system that shares many of the morphological, molecular and functional characteristics of the lymphatic vessels found in other vertebrates. Using two-photon time-lapse imaging of transgenic zebrafish, we trace the migration and lineage of individual cells incorporating into the lymphatic endothelium. Our results show lymphatic endothelial cells of the thoracic duct arise from primitive veins through a novel and unexpected pathway.", + "TAG_DATA": [ + "110, zebrafish, {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16715087", + "TEXT": "Hepatic fibrosis, the common response associated with chronic liver diseases, ultimately leads to cirrhosis, a major public health problem worldwide. We recently showed that activation of hepatic cannabinoid CB2 receptors limits progression of experimental liver fibrosis. We also found that during the course of chronic hepatitis C, daily cannabis use is an independent predictor of fibrosis progression. Overall, these results suggest that endocannabinoids may drive both CB2-mediated antifibrogenic effects and CB2-independent profibrogenic effects. Here we investigated whether activation of cannabinoid CB1 receptors (encoded by Cnr1) promotes progression of fibrosis. CB1 receptors were highly induced in human cirrhotic samples and in liver fibrogenic cells. Treatment with the CB1 receptor antagonist SR141716A decreased the wound-healing response to acute liver injury and inhibited progression of fibrosis in three models of chronic liver injury. We saw similar changes in Cnr1-/- mice as compared to wild-type mice. Genetic or pharmacological inactivation of CB1 receptors decreased fibrogenesis by lowering hepatic transforming growth factor (TGF)-beta1 and reducing accumulation of fibrogenic cells in the liver after apoptosis and growth inhibition of hepatic myofibroblasts. In conclusion, our study shows that CB1 receptor antagonists hold promise for the treatment of liver fibrosis.", + "TAG_DATA": [ + "116, liver {'context': 'B-tissue/organ'}", + "135, Cnr1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "136, mice {'context': 'B-organism'}", + "141, mice. {'context': 'B-organism'}", + "144, pharmacological {'perturbing_action': 'B-gene loss-of-function'}", + "145, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "146, of {'perturbing_action': 'I-gene loss-of-function'}", + "147, CB1 {'perturbing_action': 'I-gene loss-of-function'}", + "148, receptors {'perturbing_action': 'I-gene loss-of-function'}", + "162, fibrogenic {'context': 'B-cells'}", + "163, cells {'context': 'I-cells'}", + "166, liver {'context': 'B-tissue/organ'}", + "168, apoptosis {'phenotype': 'B-apoptosis'}", + "173, hepatic {'context': 'B-cells'}", + "174, myofibroblasts. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "135, Cnr1-/- ['l0', 'l1', 'l2', 'l3', 'l4']", + "136, mice ['l0', 'l5', 'l6', 'l7', 'l8']", + "141, mice. ['l1', 'l5', 'l9', 'l10', 'l11']", + "144, pharmacological ['l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "145, inactivation ['l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "146, of ['l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "147, CB1 ['l14', 'l23', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "148, receptors ['l15', 'l24', 'l32', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "162, fibrogenic ['l2', 'l6', 'l9', 'l16', 'l25', 'l33', 'l40', 'l46', 'l52', 'l53', 'l54', 'l55', 'l56']", + "163, cells ['l3', 'l7', 'l10', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l57', 'l58', 'l59', 'l60']", + "166, liver ['l4', 'l8', 'l11', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l61', 'l62', 'l63']", + "168, apoptosis ['l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l64', 'l65']", + "173, hepatic ['l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l66']", + "174, myofibroblasts. ['l21', 'l30', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l65', 'l66']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cnr1-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cnr1-/-", + "pharmacological", + "inactivation", + "of", + "CB1", + "receptors" + ] + }, + "context": { + "val": "cells", + "words": [ + "fibrogenic", + "cells", + "hepatic", + "myofibroblasts." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cnr1-/-", + "pharmacological", + "inactivation", + "of", + "CB1", + "receptors" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pharmacological", + "inactivation", + "of", + "CB1", + "receptors" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "fibrogenic", + "cells", + "hepatic", + "myofibroblasts." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "16648859", + "TEXT": "The mechanisms through which hematopoietic cytokines accelerate revascularization are unknown. Here, we show that the magnitude of cytokine-mediated release of SDF-1 from platelets and the recruitment of nonendothelial CXCR4+ VEGFR1+ hematopoietic progenitors, 'hemangiocytes,' constitute the major determinant of revascularization. Soluble Kit-ligand (sKitL), thrombopoietin (TPO, encoded by Thpo) and, to a lesser extent, erythropoietin (EPO) and granulocyte-macrophage colony-stimulating factor (GM-CSF) induced the release of SDF-1 from platelets, enhancing neovascularization through mobilization of CXCR4+ VEGFR1+ hemangiocytes. Although revascularization of ischemic hindlimbs was partially diminished in mice deficient in both GM-CSF and G-CSF (Csf2-/- Csf3-/-), profound impairment in neovascularization was detected in sKitL-deficient Mmp9-/- as well as thrombocytopenic Thpo-/- and TPO receptor-deficient (Mpl-/-) mice. SDF-1-mediated mobilization and incorporation of hemangiocytes into ischemic limbs were impaired in Thpo-/-, Mpl-/- and Mmp9-/- mice. Transplantation of CXCR4+ VEGFR1+ hemangiocytes into Mmp9-/- mice restored revascularization, whereas inhibition of CXCR4 abrogated cytokine- and VEGF-A-mediated mobilization of CXCR4+ VEGFR1+ cells and suppressed angiogenesis. In conclusion, hematopoietic cytokines, through graded deployment of SDF-1 from platelets, support mobilization and recruitment of CXCR4+ VEGFR1+ hemangiocytes, whereas VEGFR1 is essential for their angiogenic competency for augmenting revascularization. Delivery of SDF-1", + "TAG_DATA": [ + "78, hindlimbs {'context': 'B-tissue/organ'}", + "83, mice {'context': 'B-organism'}", + "91, Csf3-/-), {'perturbing_action': 'I-gene loss-of-function'}", + "99, sKitL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "100, Mmp9-/- {'perturbing_action': 'I-gene loss-of-function'}", + "104, thrombocytopenic {'perturbing_action': 'B-gene loss-of-function'}", + "105, Thpo-/- {'perturbing_action': 'I-gene loss-of-function'}", + "106, and {'perturbing_action': 'I-gene loss-of-function'}", + "107, TPO {'perturbing_action': 'I-gene loss-of-function'}", + "108, receptor-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "109, (Mpl-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "110, mice. {'context': 'B-organism'}", + "116, hemangiocytes {'context': 'B-cells'}", + "123, Thpo-/-, {'perturbing_action': 'B-gene loss-of-function'}", + "124, Mpl-/- {'perturbing_action': 'I-gene loss-of-function'}", + "126, Mmp9-/- {'perturbing_action': 'B-gene loss-of-function'}", + "127, mice. {'context': 'B-organism'}", + "128, Transplantation {'context': 'B-xenograft'}", + "130, CXCR4+ {'context': 'B-cells'}", + "131, VEGFR1+ {'context': 'I-cells'}", + "132, hemangiocytes {'context': 'I-cells'}", + "134, Mmp9-/- {'perturbing_action': 'B-gene loss-of-function'}", + "135, mice {'context': 'B-organism'}", + "139, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "140, of {'perturbing_action': 'I-pharmacological inhibition'}", + "141, CXCR4 {'perturbing_action': 'I-pharmacological inhibition'}", + "148, CXCR4+ {'context': 'B-cells'}", + "149, VEGFR1+ {'context': 'I-cells'}", + "150, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "78, hindlimbs ['l0', 'l1']", + "83, mice ['l0', 'l2', 'l3', 'l4']", + "84, deficient ['l2', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "91, Csf3-/-), ['l1', 'l3', 'l5', 'l11', 'l12', 'l13', 'l14', 'l15']", + "99, sKitL-deficient ['l6', 'l11', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "100, Mmp9-/- ['l4', 'l7', 'l12', 'l16', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "104, thrombocytopenic ['l8', 'l13', 'l17', 'l24', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "105, Thpo-/- ['l18', 'l25', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "106, and ['l19', 'l26', 'l32', 'l40', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "107, TPO ['l33', 'l41', 'l50', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "108, receptor-deficient ['l34', 'l42', 'l51', 'l59', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "109, (Mpl-/-) ['l20', 'l27', 'l35', 'l43', 'l52', 'l60', 'l67', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "110, mice. ['l9', 'l14', 'l21', 'l28', 'l36', 'l44', 'l53', 'l61', 'l68', 'l74', 'l80', 'l81']", + "116, hemangiocytes ['l10', 'l15', 'l22', 'l29', 'l37', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l82', 'l83']", + "123, Thpo-/-, ['l38', 'l46', 'l55', 'l63', 'l70', 'l76', 'l82', 'l84', 'l85', 'l86']", + "124, Mpl-/- ['l47', 'l56', 'l64', 'l71', 'l77', 'l84', 'l87', 'l88', 'l89', 'l90']", + "126, Mmp9-/- ['l48', 'l57', 'l65', 'l72', 'l78', 'l85', 'l87', 'l91', 'l92']", + "127, mice. ['l23', 'l30', 'l39', 'l49', 'l58', 'l66', 'l73', 'l79', 'l81', 'l83', 'l86', 'l88', 'l91']", + "128, Transplantation ['l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "130, CXCR4+ ['l93', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "131, VEGFR1+ ['l89', 'l94', 'l101', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "132, hemangiocytes ['l90', 'l92', 'l95', 'l102', 'l108', 'l114', 'l115', 'l116', 'l117', 'l118']", + "134, Mmp9-/- ['l96', 'l103', 'l109', 'l114', 'l119', 'l120', 'l121', 'l122']", + "135, mice ['l97', 'l104', 'l110', 'l115', 'l119']", + "139, inhibition ['l123', 'l124', 'l125', 'l126', 'l127']", + "140, of ['l123', 'l128', 'l129', 'l130', 'l131']", + "141, CXCR4 ['l124', 'l128', 'l132', 'l133', 'l134']", + "148, CXCR4+ ['l98', 'l105', 'l111', 'l116', 'l120', 'l125', 'l129', 'l132', 'l135', 'l136']", + "149, VEGFR1+ ['l99', 'l106', 'l112', 'l117', 'l121', 'l126', 'l130', 'l133', 'l135', 'l137']", + "150, cells ['l100', 'l107', 'l113', 'l118', 'l122', 'l127', 'l131', 'l134', 'l136', 'l137']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "hindlimbs" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Csf3-/-)," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Csf3-/-),", + "Mmp9-/-", + "sKitL-deficient", + "thrombocytopenic", + "Thpo-/-", + "and", + "TPO", + "receptor-deficient", + "(Mpl-/-)", + "Thpo-/-,", + "Mpl-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Csf3-/-),", + "sKitL-deficient", + "Mmp9-/-", + "thrombocytopenic", + "Thpo-/-", + "and", + "TPO", + "receptor-deficient", + "(Mpl-/-)", + "Thpo-/-,", + "Mpl-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "hemangiocytes", + "VEGFR1+", + "CXCR4+", + "cells" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "Transplantation" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mmp9-/-" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "CXCR4" + ] + }, + "context": { + "val": "cells", + "words": [ + "CXCR4+", + "VEGFR1+", + "cells" + ] + } + } + ] + }, + { + "PMID": "16633349", + "TEXT": "Discrepancies between resistance in vitro and therapeutic efficacy in vivo are generally attributed to failure of laboratory susceptibility tests to reflect an antibiotic's pharmacokinetic or pharmacodynamic properties. We show here that this phenomenon can result from differential in vitro-in vivo expression of bacterial determinants of antibiotic susceptibility. We found that an in vivo-induced virulence factor, Hpt, also mediates uptake of fosfomycin in Listeria monocytogenes. These bacteria therefore seem resistant to fosfomycin in vitro, although they are in fact susceptible to the antibiotic during infection.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16582918", + "TEXT": "The mechanisms underlying leptin resistance are still being defined. We report here the presence in human blood of several serum leptin-interacting proteins (SLIPs), isolated by leptin-affinity chromatography and identified by mass spectrometry and immunochemical analysis. We confirmed that one of the major SLIPs is C-reactive protein (CRP). In vitro, human CRP directly inhibits the binding of leptin to its receptors and blocks its ability to signal in cultured cells. In vivo, infusion of human CRP into ob/ob mice blocked the effects of leptin upon satiety and weight reduction. In mice that express a transgene encoding human CRP, the actions of human leptin were completely blunted. We also found that physiological concentrations of leptin can stimulate expression of CRP in human primary hepatocytes. Recently, human CRP has been correlated with increased adiposity and plasma leptin. Thus, our results suggest a potential mechanism contributing to leptin resistance, by which circulating CRP binds to leptin and attenuates its physiological functions.", + "TAG_DATA": [ + "47, In {'context': 'B-in vitro'}", + "48, vitro, {'context': 'I-in vitro'}", + "67, cultured {'context': 'B-cells'}", + "68, cells. {'context': 'I-cells'}", + "69, In {'context': 'B-in vivo'}", + "70, vivo, {'context': 'I-in vivo'}", + "76, ob/ob {'context': 'B-organism'}", + "77, mice {'context': 'I-organism'}", + "89, mice {'context': 'B-organism'}", + "91, express {'perturbing_action': 'B-gene gain-of-function'}", + "92, a {'perturbing_action': 'I-gene gain-of-function'}", + "93, transgene {'perturbing_action': 'I-gene gain-of-function'}", + "94, encoding {'perturbing_action': 'I-gene gain-of-function'}", + "95, human {'perturbing_action': 'I-gene gain-of-function'}", + "96, CRP, {'perturbing_action': 'I-gene gain-of-function'}", + "119, human {'context': 'B-cells'}", + "120, primary {'context': 'I-cells'}", + "121, hepatocytes. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "47, In ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "48, vitro, ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "67, cultured ['l1', 'l6', 'l11', 'l12']", + "68, cells. ['l2', 'l7', 'l11']", + "69, In ['l3', 'l8', 'l12', 'l13', 'l14', 'l15']", + "70, vivo, ['l4', 'l9', 'l13', 'l16', 'l17']", + "76, ob/ob ['l14', 'l16', 'l18']", + "77, mice ['l5', 'l10', 'l15', 'l17', 'l18']", + "89, mice ['l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "91, express ['l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "92, a ['l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "93, transgene ['l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "94, encoding ['l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "95, human ['l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "96, CRP, ['l24', 'l29', 'l33', 'l36', 'l38', 'l39']", + "119, human ['l40', 'l41']", + "120, primary ['l40', 'l42']", + "121, hepatocytes. ['l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "express", + "a", + "transgene", + "encoding", + "human", + "CRP," + ] + } + } + ] + }, + { + "PMID": "16491083", + "TEXT": "Cell-based diabetes therapy requires an abundant cell source. Here, we report reversal of diabetes for more than 100 d in cynomolgus macaques after intraportal transplantation of cultured islets from genetically unmodified pigs without Gal-specific antibody manipulation. Immunotherapy with CD25-specific and CD154-specific monoclonal antibodies, FTY720 (or tacrolimus), everolimus and leflunomide suppressed indirect activation of T cells, elicitation of non-Gal pig-specific IgG antibody, intragraft expression of proinflammatory cytokines and invasion of infiltrating mononuclear cells into islets.", + "TAG_DATA": [ + "20, cynomolgus {'context': 'B-organism'}", + "21, macaques {'context': 'I-organism'}", + "27, islets {'context': 'I-cells'}", + "31, pigs {'context': 'I-organism'}", + "53, T {'context': 'B-cells'}", + "54, cells, {'context': 'B-cells'}", + "70, mononuclear {'context': 'I-cells'}", + "71, cells {'context': 'I-cells'}", + "73, islets. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "20, cynomolgus ['l0', 'l1', 'l2']", + "21, macaques ['l0', 'l3']", + "27, islets ['l1', 'l3', 'l4', 'l5', 'l6']", + "31, pigs ['l2', 'l4', 'l7', 'l8']", + "53, T ['l5', 'l7', 'l9', 'l10', 'l11']", + "54, cells, ['l6', 'l8', 'l9', 'l12']", + "67, invasion ['l10', 'l13', 'l14', 'l15']", + "70, mononuclear ['l13', 'l16', 'l17']", + "71, cells ['l11', 'l12', 'l14', 'l16', 'l18']", + "73, islets. ['l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16462802", + "TEXT": "The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the receptor tyrosine kinase Tie-2 (refs. 1,2). Paracrine Ang-1-mediated activation of Tie-2 acts as a regulator of vessel maturation and vascular quiescence. In turn, the antagonistic ligand Ang-2 acts by an autocrine mechanism and is stored in endothelial Weibel-Palade bodies from where it can be rapidly released upon stimulation. The rapid release of Ang-2 implies functions of the angiopoietin-Tie system beyond its established role during vascular morphogenesis as a regulator of rapid vascular responses. Here we show that mice deficient in Ang-2 (encoded by the gene Angpt2) cannot elicit an inflammatory response in thioglycollate-induced or Staphylococcus aureus-induced peritonitis, or in the dorsal skinfold chamber model. Recombinant Ang-2 restores the inflammation defect in Angpt2(-/-) mice. Intravital microscopy showed normal TNF-alpha-induced leukocyte rolling in the vasculature of Angpt2(-/-)mice, but rolling cells did not firmly adhere to activated endothelium. Cellular experiments showed that Ang-2 promotes adhesion by sensitizing endothelial cells toward TNF-alpha and modulating TNF-alpha-induced expression of endothelial cell adhesion molecules. Together, these findings identify Ang-2 as an autocrine regulator of endothelial cell inflammatory responses. Ang-2 thereby acts as a switch of vascular responsiveness exerting a permissive role for the activities of proinflammatory cytokines.", + "TAG_DATA": [ + "89, mice {'context': 'B-organism'}", + "90, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "91, in {'perturbing_action': 'I-gene loss-of-function'}", + "92, Ang-2 {'perturbing_action': 'I-gene loss-of-function'}", + "93, (encoded {'perturbing_action': 'I-gene loss-of-function'}", + "94, by {'perturbing_action': 'I-gene loss-of-function'}", + "95, the {'perturbing_action': 'I-gene loss-of-function'}", + "96, gene {'perturbing_action': 'I-gene loss-of-function'}", + "97, Angpt2) {'perturbing_action': 'I-gene loss-of-function'}", + "112, dorsal {'context': 'B-tissue/organ'}", + "113, skinfold {'context': 'I-tissue/organ'}", + "114, chamber {'context': 'I-tissue/organ'}", + "123, Angpt2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "124, mice. {'context': 'B-organism'}", + "130, leukocyte {'context': 'B-cells'}", + "134, vasculature {'context': 'B-tissue/organ'}", + "136, Angpt2(-/-)mice, {'perturbing_action': 'B-gene loss-of-function'}", + "139, cells {'context': 'B-cells'}", + "152, promotes {'effect': 'B-positive'}", + "153, adhesion {'phenotype': 'B-adhesion'}", + "156, endothelial {'context': 'B-cells'}", + "157, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "89, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "90, deficient ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "91, in ['l1', 'l8', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "92, Ang-2 ['l2', 'l9', 'l19', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "93, (encoded ['l3', 'l10', 'l20', 'l30', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "94, by ['l4', 'l11', 'l21', 'l31', 'l40', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "95, the ['l5', 'l12', 'l22', 'l32', 'l41', 'l49', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "96, gene ['l6', 'l13', 'l23', 'l33', 'l42', 'l50', 'l57', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "97, Angpt2) ['l7', 'l14', 'l24', 'l34', 'l43', 'l51', 'l58', 'l64', 'l70', 'l71', 'l72', 'l73', 'l74']", + "112, dorsal ['l15', 'l25', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l75', 'l76', 'l77', 'l78']", + "113, skinfold ['l16', 'l26', 'l36', 'l45', 'l53', 'l60', 'l66', 'l71', 'l75', 'l79', 'l80', 'l81']", + "114, chamber ['l17', 'l27', 'l37', 'l46', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l82', 'l83']", + "123, Angpt2(-/-) ['l84', 'l85', 'l86', 'l87', 'l88']", + "124, mice. ['l84', 'l89', 'l90', 'l91', 'l92']", + "130, leukocyte ['l18', 'l28', 'l38', 'l47', 'l55', 'l62', 'l68', 'l73', 'l77', 'l80', 'l82', 'l85', 'l89', 'l93']", + "134, vasculature ['l29', 'l39', 'l48', 'l56', 'l63', 'l69', 'l74', 'l78', 'l81', 'l83', 'l86', 'l90', 'l93', 'l94', 'l95']", + "136, Angpt2(-/-)mice, ['l87', 'l91', 'l94', 'l96', 'l97']", + "139, cells ['l88', 'l92', 'l95', 'l96']", + "152, promotes ['l98', 'l99', 'l100']", + "153, adhesion ['l98', 'l101', 'l102']", + "156, endothelial ['l99', 'l101', 'l103']", + "157, cells ['l97', 'l100', 'l102', 'l103']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Ang-2", + "(encoded", + "by", + "the", + "gene", + "Angpt2)", + "Angpt2(-/-)", + "Angpt2(-/-)mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Ang-2", + "(encoded", + "by", + "the", + "gene", + "Angpt2)", + "Angpt2(-/-)", + "Angpt2(-/-)mice," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "dorsal", + "skinfold", + "chamber", + "vasculature" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Ang-2", + "(encoded", + "by", + "the", + "gene", + "Angpt2)", + "Angpt2(-/-)", + "Angpt2(-/-)mice," + ] + }, + "context": { + "val": "cells", + "words": [ + "leukocyte", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + } + }, + { + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + } + } + ] + }, + { + "PMID": "16444265", + "TEXT": "The interferon (IFN)-gamma-induced TRAIL effector mechanism is a vital component of cancer immunosurveillance by natural killer (NK) cells in mice. Here we show that the main source of IFN-gamma is not the conventional NK cell but a subset of B220(+)Ly6C(-) dendritic cells, which are atypical insofar as they express NK cell-surface molecules. Upon contact with a variety of tumor cells that are poorly recognized by NK cells, B220(+)NK1.1(+) dendritic cells secrete high levels of IFN-gamma and mediate TRAIL-dependent lysis of tumor cells. Adoptive transfer of these IFN-producing killer dendritic cells (IKDCs) into tumor-bearing Rag2(-/-)Il2rg(-/-) mice prevented tumor outgrowth, whereas transfer of conventional NK cells did not. In conclusion, we identified IKDCs as pivotal sensors and effectors of the innate antitumor immune response.", + "TAG_DATA": [ + "86, IFN-producing {'context': 'B-cells'}", + "87, killer {'context': 'I-cells'}", + "88, dendritic {'context': 'I-cells'}", + "89, cells {'context': 'I-cells'}", + "90, (IKDCs) {'context': 'I-cells'}", + "92, tumor-bearing {'perturbing_action': 'B-gene loss-of-function'}", + "93, Rag2(-/-)Il2rg(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "94, mice {'context': 'B-organism'}", + "95, prevented {'effect': 'B-negative'}", + "96, tumor {'phenotype': 'B-tumour regression'}", + "97, outgrowth, {'phenotype': 'I-tumour regression'}", + "102, NK {'context': 'I-cells'}", + "103, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "86, IFN-producing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "87, killer ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "88, dendritic ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "89, cells ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "90, (IKDCs) ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "92, tumor-bearing ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "93, Rag2(-/-)Il2rg(-/-) ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "94, mice ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "95, prevented ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "96, tumor ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "97, outgrowth, ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "102, NK ['l55']", + "103, cells ['l55']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "IFN-producing", + "killer", + "dendritic", + "cells", + "(IKDCs)" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "tumor-bearing", + "Rag2(-/-)Il2rg(-/-)" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "IFN-producing", + "killer", + "dendritic", + "cells", + "(IKDCs)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "IFN-producing", + "killer", + "dendritic", + "cells", + "(IKDCs)" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "outgrowth," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "tumor-bearing", + "Rag2(-/-)Il2rg(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "tumor-bearing", + "Rag2(-/-)Il2rg(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "tumor-bearing", + "Rag2(-/-)Il2rg(-/-)" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "outgrowth," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "outgrowth," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "outgrowth," + ] + } + } + ] + }, + { + "PMID": "16444264", + "TEXT": "Little is known about the consequences of immune recognition of mutated gene products, despite their potential relevance to autoimmunity and tumor immunity. To identify mutations that induce immunity, here we have developed a systematic approach in which combinatorial DNA libraries encoding large numbers of random mutations in two syngeneic tyrosinase-related proteins are used to immunize black mice. We show that the libraries of mutated DNA induce autoimmune hypopigmentation and tumor immunity through cross-recognition of nonmutated gene products. Truncations are present in all immunogenic clones and are sufficient to elicit immunity to self, triggering recognition of normally silent epitopes. Immunity is further enhanced by specific amino acid substitutions that promote T helper cell responses. Thus, presentation of a vast repertoire of antigen variants to the immune system can enhance the generation of adaptive immune responses to self.", + "TAG_DATA": [ + "55, black {'context': 'B-organism'}", + "56, mice. {'context': 'I-organism'}", + "69, tumor {'context': 'B-neoplasm'}", + "109, T {'context': 'B-cells'}", + "110, helper {'context': 'I-cells'}", + "111, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "55, black ['l0']", + "56, mice. ['l0']", + "109, T ['l1', 'l2']", + "110, helper ['l1', 'l3']", + "111, cell ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16429146", + "TEXT": "Successful ex vivo expansion of hematopoietic stem cells (HSCs) would greatly benefit the treatment of disease and the understanding of crucial questions of stem cell biology. Here we show, using microarray studies, that the HSC-supportive mouse fetal liver CD3(+) cells specifically express the proteins angiopoietin-like 2 (Angptl2) and angiopoietin-like 3 (Angptl3). We observed a 24- or 30-fold net expansion of long-term HSCs by reconstitution analysis when we cultured highly enriched HSCs for 10 days in the presence of Angptl2 or Angptl3 together with saturating levels of other growth factors. The coiled-coil domain of Angptl2 was capable of stimulating expansion of HSCs. Furthermore, angiopoietin-like 5, angiopoietin-like 7 and microfibril-associated glycoprotein 4 also supported expansion of HSCs in culture.", + "TAG_DATA": [ + "60, long-term {'context': 'B-cells'}", + "61, HSCs {'context': 'I-cells'}", + "70, HSCs {'context': 'B-cells'}", + "100, HSCs. {'context': 'B-cells'}", + "114, HSCs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "60, long-term ['l0']", + "61, HSCs ['l0']", + "100, HSCs. ['l1']", + "114, HSCs ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16341241", + "TEXT": "Recent studies suggest that increased T-cell and autoantibody reactivity to lipids may be present in the autoimmune demyelinating disease multiple sclerosis. To perform large-scale multiplex analysis of antibody responses to lipids in multiple sclerosis, we developed microarrays composed of lipids present in the myelin sheath, including ganglioside, sulfatide, cerebroside, sphingomyelin and total brain lipid fractions. Lipid-array analysis showed lipid-specific antibodies against sulfatide, sphingomyelin and oxidized lipids in cerebrospinal fluid (CSF) derived from individuals with multiple sclerosis. Sulfatide-specific antibodies were also detected in SJL/J mice with acute experimental autoimmune encephalomyelitis (EAE). Immunization of mice with sulfatide plus myelin peptide resulted in a more severe disease course of EAE, and administration of sulfatide-specific antibody exacerbated EAE. Thus, autoimmune responses to sulfatide and other lipids are present in individuals with multiple sclerosis and in EAE, and may contribute to the pathogenesis of autoimmune demyelination.", + "TAG_DATA": [ + "82, SJL/J {'context': 'B-organism'}", + "83, mice {'context': 'I-organism'}", + "92, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "82, SJL/J ['l0']", + "83, mice ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16327800", + "TEXT": "The structure and function of blood vessels adapt to environmental changes such as physical development and exercise. This phenomenon is based on the ability of the endothelial cells to sense and respond to blood flow; however, the underlying mechanisms remain unclear. Here we show that the ATP-gated P2X4 ion channel, expressed on endothelial cells and encoded by P2rx4 in mice, has a key role in the response of endothelial cells to changes in blood flow. P2rx4(-/-) mice do not have normal endothelial cell responses to flow, such as influx of Ca(2+) and subsequent production of the potent vasodilator nitric oxide (NO). Additionally, vessel dilation induced by acute increases in blood flow is markedly suppressed in P2rx4(-/-) mice. Furthermore, P2rx4(-/-) mice have higher blood pressure and excrete smaller amounts of NO products in their urine than do wild-type mice. Moreover, no adaptive vascular remodeling, that is, a decrease in vessel size in response to a chronic decrease in blood flow, was observed in P2rx4(-/-) mice. Thus, endothelial P2X4 channels are crucial to flow-sensitive mechanisms that regulate blood pressure and vascular remodeling.", + "TAG_DATA": [ + "75, P2rx4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "76, mice {'context': 'B-organism'}", + "81, endothelial {'context': 'B-cells'}", + "82, cell {'context': 'I-cells'}", + "115, P2rx4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "116, mice. {'context': 'B-organism'}", + "118, P2rx4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "119, mice {'context': 'B-organism'}", + "137, mice. {'context': 'B-organism'}", + "162, P2rx4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "163, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "75, P2rx4(-/-) ['l0', 'l1', 'l2', 'l3']", + "76, mice ['l0', 'l4', 'l5']", + "81, endothelial ['l1', 'l4', 'l6']", + "82, cell ['l2', 'l5', 'l6']", + "115, P2rx4(-/-) ['l7']", + "116, mice. ['l3', 'l7']", + "118, P2rx4(-/-) ['l8', 'l9']", + "119, mice ['l8', 'l10']", + "137, mice. ['l9', 'l10']", + "162, P2rx4(-/-) ['l11']", + "163, mice. ['l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "P2rx4(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "P2rx4(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + } + } + ] + }, + { + "PMID": "16288283", + "TEXT": "The immune system can act as an extrinsic suppressor of tumors. Therefore, tumor progression depends in part on mechanisms that downmodulate intrinsic immune surveillance. Identifying these inhibitory pathways may provide promising targets to enhance antitumor immunity. Here, we show that Stat3 is constitutively activated in diverse tumor-infiltrating immune cells, and ablating Stat3 in hematopoietic cells triggers an intrinsic immune-surveillance system that inhibits tumor growth and metastasis. We observed a markedly enhanced function of dendritic cells, T cells, natural killer (NK) cells and neutrophils in tumor-bearing mice with Stat3(-/-) hematopoietic cells, and showed that tumor regression requires immune cells. Targeting Stat3 with a small-molecule drug induces T cell- and NK cell-dependent growth inhibition of established tumors otherwise resistant to direct killing by the inhibitor. Our findings show that Stat3 signaling restrains natural tumor immune surveillance and that inhibiting hematopoietic Stat3 in tumor-bearing hosts elicits multicomponent therapeutic antitumor immunity.", + "TAG_DATA": [ + "50, ablating {'perturbing_action': 'B-gene loss-of-function'}", + "51, Stat3 {'perturbing_action': 'I-gene loss-of-function'}", + "53, hematopoietic {'context': 'B-cells'}", + "54, cells {'context': 'I-cells'}", + "61, inhibits {'effect': 'B-negative'}", + "62, tumor {'phenotype': 'B-tumour growth'}", + "63, growth {'phenotype': 'I-tumour growth'}", + "65, metastasis. {'phenotype': 'B-metastasis'}", + "73, dendritic {'context': 'B-cells'}", + "74, cells, {'context': 'I-cells'}", + "84, tumor-bearing {'context': 'B-organism'}", + "85, mice {'context': 'I-organism'}", + "87, Stat3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "88, hematopoietic {'context': 'B-cells'}", + "89, cells, {'context': 'I-cells'}", + "93, tumor {'phenotype': 'B-tumour regression'}", + "94, regression {'phenotype': 'I-tumour regression'}", + "96, immune {'context': 'B-cells'}", + "97, cells. {'context': 'I-cells'}", + "98, Targeting {'perturbing_action': 'B-other'}", + "99, Stat3 {'perturbing_action': 'I-other'}", + "114, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "50, ablating ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "51, Stat3 ['l0', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "53, hematopoietic ['l1', 'l18', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "54, cells ['l2', 'l19', 'l32', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "61, inhibits ['l3', 'l20', 'l33', 'l44', 'l53', 'l54', 'l55', 'l56', 'l57']", + "62, tumor ['l4', 'l21', 'l34', 'l45', 'l53', 'l58', 'l59', 'l60', 'l61']", + "63, growth ['l5', 'l22', 'l35', 'l46', 'l54', 'l58', 'l62', 'l63', 'l64']", + "65, metastasis. ['l6', 'l23', 'l36', 'l47', 'l55', 'l59', 'l62', 'l65', 'l66']", + "73, dendritic ['l7', 'l24', 'l37', 'l48', 'l56', 'l60', 'l63', 'l65', 'l67', 'l68', 'l69', 'l70', 'l71']", + "74, cells, ['l8', 'l25', 'l38', 'l49', 'l57', 'l61', 'l64', 'l66', 'l67', 'l72', 'l73', 'l74']", + "84, tumor-bearing ['l9', 'l26', 'l39', 'l50', 'l68', 'l72', 'l75', 'l76', 'l77', 'l78', 'l79']", + "85, mice ['l10', 'l27', 'l40', 'l51', 'l69', 'l73', 'l75', 'l80', 'l81', 'l82']", + "87, Stat3(-/-) ['l11', 'l28', 'l41', 'l70', 'l76', 'l80', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "88, hematopoietic ['l12', 'l29', 'l42', 'l77', 'l81', 'l83', 'l89', 'l90', 'l91', 'l92', 'l93']", + "89, cells, ['l13', 'l30', 'l43', 'l52', 'l71', 'l74', 'l78', 'l82', 'l84', 'l89', 'l94', 'l95', 'l96', 'l97']", + "93, tumor ['l14', 'l85', 'l90', 'l94', 'l98', 'l99', 'l100']", + "94, regression ['l15', 'l86', 'l91', 'l95', 'l98', 'l101', 'l102']", + "96, immune ['l16', 'l87', 'l92', 'l96', 'l99', 'l101', 'l103']", + "97, cells. ['l17', 'l31', 'l79', 'l88', 'l93', 'l97', 'l100', 'l102', 'l103']", + "98, Targeting ['l104', 'l105', 'l106', 'l107']", + "99, Stat3 ['l104', 'l108', 'l109', 'l110']", + "100, with ['l105', 'l108', 'l111', 'l112']", + "102, small-molecule ['l106', 'l109', 'l111', 'l113']", + "114, tumors ['l107', 'l110', 'l112', 'l113']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablating", + "Stat3", + "Stat3(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "cells", + "dendritic", + "cells,", + "immune", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablating", + "Stat3" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablating", + "Stat3" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablating", + "Stat3" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablating", + "Stat3", + "Stat3(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "tumor-bearing", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablating", + "Stat3(-/-)" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "cells", + "dendritic", + "cells," + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "cells", + "dendritic", + "cells," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "cells", + "dendritic", + "cells," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "cells,", + "immune", + "cells." + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Targeting", + "Stat3" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + } + ] + }, + { + "PMID": "16288281", + "TEXT": "The discovery of long-lived epithelial stem cells in the bulge region of the hair follicle led to the hypothesis that epidermal renewal and epidermal repair after wounding both depend on these cells. To determine whether bulge cells are necessary for epidermal renewal, here we have ablated these cells by targeting them with a suicide gene encoding herpes simplex virus thymidine kinase (HSV-TK) using a Keratin 1-15 (Krt1-15) promoter. We show that ablation leads to complete loss of hair follicles but survival of the epidermis. Through fate-mapping experiments, we find that stem cells in the hair follicle bulge do not normally contribute cells to the epidermis which is organized into epidermal proliferative units, as previously predicted. After epidermal injury, however, cells from the bulge are recruited into the epidermis and migrate in a linear manner toward the center of the wound, ultimately forming a marked radial pattern. Notably, although the bulge-derived cells acquire an epidermal phenotype, most are eliminated from the epidermis over several weeks, indicating that bulge stem cells respond rapidly to epidermal wounding by generating short-lived 'transient amplifying' cells responsible for acute wound repair. Our findings have implications for both gene therapy and developing treatments for wounds because it will be necessary to consider epidermal and hair follicle stem cells as distinct populations.", + "TAG_DATA": [ + "47, cells {'context': 'B-cells'}", + "49, targeting {'perturbing_action': 'B-other'}", + "83, epidermis. {'context': 'B-tissue/organ'}", + "119, cells {'context': 'B-cells'}", + "149, bulge-derived {'context': 'B-cells'}", + "150, cells {'context': 'I-cells'}", + "160, epidermis {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "47, cells ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "49, targeting ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "53, suicide ['l1', 'l13', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "54, gene ['l2', 'l14', 'l27', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "55, encoding ['l3', 'l15', 'l28', 'l40', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "56, herpes ['l4', 'l16', 'l29', 'l41', 'l52', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "57, simplex ['l5', 'l17', 'l30', 'l42', 'l53', 'l63', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "58, virus ['l6', 'l18', 'l31', 'l43', 'l54', 'l64', 'l73', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "59, thymidine ['l7', 'l19', 'l32', 'l44', 'l55', 'l65', 'l74', 'l82', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "60, kinase ['l8', 'l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l83', 'l90', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "61, (HSV-TK) ['l9', 'l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l84', 'l91', 'l97', 'l103', 'l104', 'l105', 'l106', 'l107']", + "62, using ['l10', 'l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l98', 'l103', 'l108', 'l109', 'l110', 'l111']", + "65, 1-15 ['l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l86', 'l93', 'l99', 'l104', 'l108', 'l112', 'l113', 'l114']", + "66, (Krt1-15) ['l24', 'l37', 'l49', 'l60', 'l70', 'l79', 'l87', 'l94', 'l100', 'l105', 'l109', 'l112', 'l115', 'l116']", + "67, promoter. ['l11', 'l25', 'l38', 'l50', 'l61', 'l71', 'l80', 'l88', 'l95', 'l101', 'l106', 'l110', 'l113', 'l115', 'l117']", + "83, epidermis. ['l12', 'l26', 'l39', 'l51', 'l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l107', 'l111', 'l114', 'l116', 'l117']", + "149, bulge-derived ['l118', 'l119']", + "150, cells ['l118']", + "160, epidermis ['l119']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "targeting" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "targeting" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "epidermis." + ] + } + } + ] + }, + { + "PMID": "16286922", + "TEXT": "The rodent corticospinal tract (CST) has been used extensively to investigate regeneration and remodeling of central axons after injury. CST axons are currently visualized after injection of tracer dye, which is invasive, incomplete and prone to variation, and often does not show functionally crucial but numerically minor tract components. Here, we characterize transgenic mice in which CST fibers are specifically and completely labeled by yellow fluorescent protein (YFP). Using these CST-YFP mice, we show that minor CST components are responsible for most monosynaptic contacts onto motoneurons. Lesions of the main dorsal CST lead to extension of new collaterals, some of them originating from large, heavily myelinated axons within the minor dorsolateral and ventral CST components. Some of these new collaterals form additional direct synapses onto motoneurons. We propose that CST-YFP mice will be useful for evaluating strategies designed to maximize such remodeling and to promote regeneration.", + "TAG_DATA": [ + "53, mice {'context': 'I-organism'}", + "90, dorsal {'context': 'I-tissue/organ'}", + "91, CST {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "87, of ['l0', 'l1', 'l2', 'l3']", + "88, the ['l0', 'l4', 'l5', 'l6']", + "89, main ['l1', 'l4', 'l7', 'l8']", + "90, dorsal ['l2', 'l5', 'l7', 'l9']", + "91, CST ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16258537", + "TEXT": "Here we describe molecular imaging of cancer using signal amplification of a radiotracer in situ by pretargeting a multivalent, bispecific antibody to carcinoembryonic antigen (CEA), which subsequently also captures a radioactive hapten-peptide. Human colon cancer xenografts as small as approximately 0.15 g were disclosed in nude mice within 1 h of giving the radiotracer, with tumor/blood ratios increased by >or=40-fold (approximately 10:1 at 1 h, approximately 100:1 at 24 h), compared to a (99m)Tc-labeled CEA-specific F(ab') used clinically for colorectal cancer detection, while also increasing tumor uptake tenfold ( approximately 20% injected dose/g) under optimal conditions. This technology could be adapted to other antibodies and imaging modalities.", + "TAG_DATA": [ + "32, Human {'context': 'B-xenograft'}", + "33, colon {'context': 'I-xenograft'}", + "34, cancer {'context': 'I-xenograft'}", + "35, xenografts {'context': 'I-xenograft'}", + "45, nude {'context': 'B-organism'}", + "46, mice {'context': 'I-organism'}", + "85, tumor {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "32, Human ['l0', 'l1', 'l2', 'l3', 'l4']", + "33, colon ['l0', 'l5', 'l6', 'l7', 'l8']", + "34, cancer ['l1', 'l5', 'l9', 'l10', 'l11']", + "35, xenografts ['l2', 'l6', 'l9', 'l12', 'l13']", + "45, nude ['l3', 'l7', 'l10', 'l12', 'l14']", + "46, mice ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16227990", + "TEXT": "Immunodeficiency is a barrier to successful vaccination in individuals with cancer and chronic infection. We performed a randomized phase 1/2 study in lymphopenic individuals after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for myeloma. Combination immunotherapy consisting of a single early post-transplant infusion of in vivo vaccine-primed and ex vivo costimulated autologous T cells followed by post-transplant booster immunizations improved the severe immunodeficiency associated with high-dose chemotherapy and led to the induction of clinically relevant immunity in adults within a month after transplantation. Immune assays showed accelerated restoration of CD4 T-cell numbers and function. Early T-cell infusions also resulted in significantly improved T-cell proliferation in response to antigens that were not contained in the vaccine, as assessed by responses to staphylococcal enterotoxin B and cytomegalovirus antigens (P < 0.05). In the setting of lymphopenia, combined vaccine therapy and adoptive T-cell transfer fosters the development of enhanced memory T-cell responses.", + "TAG_DATA": [ + "53, T {'context': 'I-cells'}", + "54, cells {'context': 'I-cells'}", + "78, adults {'context': 'B-organism'}", + "90, CD4 {'context': 'B-cells'}", + "91, T-cell {'context': 'I-cells'}", + "102, improved {'effect': 'B-positive'}", + "103, T-cell {'context': 'B-cells'}", + "104, proliferation {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "23, individuals ['l0']", + "53, T ['l1', 'l2', 'l3', 'l4']", + "54, cells ['l1', 'l5', 'l6', 'l7']", + "78, adults ['l0', 'l2', 'l5', 'l8']", + "90, CD4 ['l3', 'l6', 'l9']", + "91, T-cell ['l4', 'l7', 'l8', 'l9']", + "102, improved ['l10', 'l11']", + "103, T-cell ['l10', 'l12']", + "104, proliferation ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "improved" + ] + }, + "context": { + "val": "cells", + "words": [ + "T-cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "improved" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T-cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "16208318", + "TEXT": "Host defense against viruses probably depends on targeted death of infected host cells and then clearance of cellular corpses by macrophages. For this process to be effective, the macrophage must presumably avoid its own virus-induced death. Here we identify one such mechanism. We show that mice lacking the chemokine Ccl5 are immune compromised to the point of delayed viral clearance, excessive airway inflammation and respiratory death after mouse parainfluenza or human influenza virus infection. Virus-inducible levels of Ccl5 are required to prevent apoptosis of virus-infected mouse macrophages in vivo and mouse and human macrophages ex vivo. The protective effect of Ccl5 requires activation of the Ccr5 chemokine receptor and consequent bilateral activation of G(alphai)-PI3K-AKT and G(alphai)-MEK-ERK signaling pathways. The antiapoptotic action of chemokine signaling may therefore allow scavengers to finally stop the host cell-to-cell infectious process.", + "TAG_DATA": [ + "45, mice {'context': 'B-organism'}", + "46, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "47, the {'perturbing_action': 'I-gene loss-of-function'}", + "48, chemokine {'perturbing_action': 'I-gene loss-of-function'}", + "49, Ccl5 {'perturbing_action': 'I-gene loss-of-function'}", + "81, prevent {'effect': 'B-negative'}", + "82, apoptosis {'phenotype': 'B-apoptosis'}", + "85, mouse {'context': 'B-cells'}", + "86, macrophages {'context': 'I-cells'}", + "87, in {'context': 'B-in vivo'}", + "88, vivo {'context': 'I-in vivo'}", + "90, mouse {'context': 'B-cells'}", + "91, and {'context': 'I-cells'}", + "92, human {'context': 'I-cells'}", + "93, macrophages {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "46, lacking ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "47, the ['l1', 'l8', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "48, chemokine ['l2', 'l9', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "49, Ccl5 ['l3', 'l10', 'l18', 'l25', 'l32', 'l33', 'l34', 'l35']", + "81, prevent ['l11', 'l19', 'l26', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "82, apoptosis ['l12', 'l20', 'l27', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49']", + "85, mouse ['l4', 'l13', 'l21', 'l28', 'l32', 'l37', 'l45', 'l50', 'l51', 'l52']", + "86, macrophages ['l5', 'l14', 'l22', 'l29', 'l33', 'l38', 'l46', 'l50', 'l53', 'l54']", + "87, in ['l6', 'l15', 'l23', 'l30', 'l34', 'l39', 'l47', 'l51', 'l53', 'l55']", + "88, vivo ['l7', 'l16', 'l24', 'l31', 'l35', 'l40', 'l48', 'l52', 'l54', 'l55']", + "90, mouse ['l41', 'l49', 'l56', 'l57', 'l58']", + "91, and ['l42', 'l56', 'l59', 'l60']", + "92, human ['l43', 'l57', 'l59', 'l61']", + "93, macrophages ['l44', 'l58', 'l60', 'l61']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "chemokine", + "Ccl5" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "chemokine" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "chemokine" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "chemokine", + "Ccl5" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "macrophages" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "chemokine", + "Ccl5" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "macrophages", + "and", + "human" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "macrophages" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "16200072", + "TEXT": "Mucolipidosis II (ML II) is a fatal lysosomal storage disorder resulting from defects in the multimeric GlcNAc-1-phosphotransferase responsible for the initial step in the generation of the mannose 6-phosphate (M6P) recognition marker. M6P residues on oligosaccharides of newly synthesized lysosomal enzymes are essential for efficient receptor-mediated transport to lysosomes. We used the recombinant GlcNAc-1-phosphotransferase gamma subunit as an affinity matrix to purify an unknown protein identified as the product of GNPTA (encoding GNPTA, previously known as MGC4170). The cDNA encodes a protein of 1,256 amino acids with two putative transmembrane domains and a complex preserved modular structure comprising at least six domains. The N-terminal domain of GNPTA, interrupted by a long insertion, shows similarities to bacterial capsule biosynthesis proteins. We identified seven mutations in GNPTA that lead to premature translational termination in six individuals with ML II. Retroviral transduction of fibroblasts from an individual with ML II resulted in the expression and localization of GNPTA in the Golgi apparatus, accompanied by the correction of hypersecretion of lysosomal enzymes. Our results provide evidence that GNPTA encodes a subunit of GlcNAc-1-phosphotransferase defective in individuals with ML II.", + "TAG_DATA": [ + "140, fibroblasts {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16200071", + "TEXT": "Here we show that a new class of antibiotics-acyldepsipeptides-has antibacterial activity against Gram-positive bacteria in vitro and in several rodent models of bacterial infection. The acyldepsipeptides are active against isolates that are resistant to antibiotics in clinical application, implying a new target, which we identify as ClpP, the core unit of a major bacterial protease complex. ClpP is usually tightly regulated and strictly requires a member of the family of Clp-ATPases and often further accessory proteins for proteolytic activation. Binding of acyldepsipeptides to ClpP eliminates these safeguards. The acyldepsipeptide-activated ClpP core is capable of proteolytic degradation in the absence of the regulatory Clp-ATPases. Such uncontrolled proteolysis leads to inhibition of bacterial cell division and eventually cell death.", + "TAG_DATA": [ + "108, inhibition {'effect': 'B-negative'}", + "111, cell {'phenotype': 'B-proliferation'}", + "112, division {'phenotype': 'I-proliferation'}", + "115, cell {'phenotype': 'B-cell death'}", + "116, death. {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "108, inhibition ['l0', 'l1', 'l2', 'l3']", + "111, cell ['l0', 'l4', 'l5', 'l6']", + "112, division ['l1', 'l4', 'l7', 'l8']", + "115, cell ['l2', 'l5', 'l7', 'l9']", + "116, death. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "16155578", + "TEXT": "Although major histocompatibility complex (MHC) class II-restricted CD4 T cells are well appreciated for their contribution to peripheral tolerance to tissue allografts, little is known regarding MHC class I-dependent reactivity in this process. Here we show a crucial role for host MHC class I-dependent NK cell reactivity for allograft tolerance in mice induced through either costimulation blockade using CD154-specific antibody therapy or by targeting LFA-1 (also known as CD11a). Tolerance induction absolutely required host expression of MHC class I, but was independent of CD8 T cell-dependent immunity. Rather, tolerance required innate immunity involving NK1.1(+) cells, but was independent of CD1d-restricted NKT cells. Therefore, NK cells seem to be generally required for induction of tolerance to islet allografts. Additional studies indicate that CD154-specific antibody-induced allograft tolerance is perforin dependent. Notably, NK cells that are perforin competent are sufficient to restore allograft tolerance in perforin-deficient recipients. Together, these results show an obligatory role for NK cells, through perforin, for induction of tolerance to islet allografts.", + "TAG_DATA": [ + "51, mice {'context': 'B-organism'}", + "63, targeting {'perturbing_action': 'B-other'}", + "64, LFA-1 {'perturbing_action': 'I-other'}", + "65, (also {'perturbing_action': 'I-other'}", + "66, known {'perturbing_action': 'I-other'}", + "67, as {'perturbing_action': 'I-other'}", + "68, CD11a). {'perturbing_action': 'I-other'}", + "129, NK {'context': 'B-cells'}", + "130, cells {'context': 'I-cells'}", + "142, perforin-deficient {'perturbing_action': 'B-gene loss-of-function'}" + ], + "LINK_DATA": [ + "63, targeting ['l0', 'l1', 'l2', 'l3', 'l4']", + "64, LFA-1 ['l0', 'l5', 'l6', 'l7', 'l8']", + "65, (also ['l1', 'l5', 'l9', 'l10', 'l11']", + "66, known ['l2', 'l6', 'l9', 'l12', 'l13']", + "67, as ['l3', 'l7', 'l10', 'l12', 'l14']", + "68, CD11a). ['l4', 'l8', 'l11', 'l13', 'l14']", + "129, NK ['l15', 'l16', 'l17']", + "130, cells ['l15', 'l18', 'l19']", + "142, perforin-deficient ['l16', 'l18', 'l20']", + "143, recipients. ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "NK", + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "perforin-deficient" + ] + } + } + ] + }, + { + "PMID": "16142243", + "TEXT": "Nitric oxide (NO) production by endothelial cell nitric oxide synthase (eNOS) in sinusoidal endothelial cells is reduced in the injured liver and leads to intrahepatic portal hypertension. We sought to understand the mechanism underlying defective eNOS function. Phosphorylation of the serine-threonine kinase Akt, which activates eNOS, was substantially reduced in sinusoidal endothelial cells from injured livers. Overexpression of Akt in vivo restored phosphorylation of Akt and production of NO and reduced portal pressure in portal hypertensive rats. We found that Akt physically interacts with G-protein-coupled receptor kinase-2 (GRK2), and that this interaction inhibits Akt activity. Furthermore, GRK2 expression increased in sinusoidal endothelial cells from portal hypertensive rats and knockdown of GRK2 restored Akt phosphorylation and NO production, and normalized portal pressure. Finally, after liver injury, GRK2-deficient mice developed less severe portal hypertension than control mice. Thus, an important mechanism underlying impaired activity of eNOS in injured sinusoidal endothelial cells is defective phosphorylation of Akt caused by overexpression of GRK2 after injury.", + "TAG_DATA": [ + "50, sinusoidal {'context': 'B-cells'}", + "51, endothelial {'context': 'I-cells'}", + "52, cells {'context': 'I-cells'}", + "55, livers. {'context': 'I-tissue/organ'}", + "56, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "57, of {'perturbing_action': 'I-gene gain-of-function'}", + "58, Akt {'perturbing_action': 'I-gene gain-of-function'}", + "59, in {'context': 'B-in vivo'}", + "60, vivo {'context': 'I-in vivo'}", + "76, rats. {'context': 'B-organism'}", + "100, sinusoidal {'context': 'B-cells'}", + "101, endothelial {'context': 'I-cells'}", + "102, cells {'context': 'I-cells'}", + "108, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "109, of {'perturbing_action': 'I-rnai/knockdown'}", + "110, GRK2 {'perturbing_action': 'I-rnai/knockdown'}", + "125, GRK2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "126, mice {'context': 'B-organism'}", + "134, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, sinusoidal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "51, endothelial ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "52, cells ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "55, livers. ['l2', 'l7', 'l11', 'l15']", + "56, Overexpression ['l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "57, of ['l16', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "58, Akt ['l17', 'l24', 'l31', 'l32', 'l33', 'l34', 'l35']", + "59, in ['l3', 'l8', 'l12', 'l18', 'l25', 'l31', 'l36', 'l37', 'l38']", + "60, vivo ['l4', 'l9', 'l13', 'l15', 'l19', 'l26', 'l32', 'l36', 'l39']", + "76, rats. ['l5', 'l10', 'l14', 'l20', 'l27', 'l33', 'l37', 'l39']", + "100, sinusoidal ['l21', 'l28', 'l40', 'l41']", + "101, endothelial ['l22', 'l29', 'l34', 'l40', 'l42']", + "102, cells ['l23', 'l30', 'l35', 'l38', 'l41', 'l42']", + "108, knockdown ['l43', 'l44']", + "109, of ['l43', 'l45']", + "110, GRK2 ['l44', 'l45']", + "125, GRK2-deficient ['l46', 'l47']", + "126, mice ['l46', 'l48']", + "134, mice. ['l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "Akt" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "Akt" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "Akt" + ] + }, + "context": { + "val": "cells", + "words": [ + "sinusoidal", + "endothelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "GRK2-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "16127437", + "TEXT": "Phosphoinositide 3-kinases (PI3K) have long been considered promising drug targets for the treatment of inflammatory and autoimmune disorders as well as cancer and cardiovascular diseases. But the lack of specificity, isoform selectivity and poor biopharmaceutical profile of PI3K inhibitors have so far hampered rigorous disease-relevant target validation. Here we describe the identification and development of specific, selective and orally active small-molecule inhibitors of PI3Kgamma (encoded by Pik3cg). We show that Pik3cg(-/-) mice are largely protected in mouse models of rheumatoid arthritis; this protection correlates with defective neutrophil migration, further validating PI3Kgamma as a therapeutic target. We also describe that oral treatment with a PI3Kgamma inhibitor suppresses the progression of joint inflammation and damage in two distinct mouse models of rheumatoid arthritis, reproducing the protective effects shown by Pik3cg(-/-) mice. Our results identify selective PI3Kgamma inhibitors as potential therapeutic molecules for the treatment of chronic inflammatory disorders such as rheumatoid arthritis.", + "TAG_DATA": [ + "70, Pik3cg(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "71, mice {'context': 'B-organism'}", + "76, mouse {'context': 'B-organism'}", + "77, models {'context': 'I-organism'}", + "103, PI3Kgamma {'perturbing_action': 'B-pharmacological inhibition'}", + "104, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "116, mouse {'context': 'B-organism'}", + "117, models {'context': 'I-organism'}", + "119, rheumatoid {'context': 'I-organism'}", + "120, arthritis, {'context': 'I-organism'}", + "127, Pik3cg(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "128, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "70, Pik3cg(-/-) ['l0', 'l1', 'l2']", + "71, mice ['l0', 'l3', 'l4']", + "76, mouse ['l1', 'l3', 'l5']", + "77, models ['l2', 'l4', 'l5']", + "103, PI3Kgamma ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "104, inhibitor ['l6', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "116, mouse ['l7', 'l13', 'l19', 'l20', 'l21']", + "117, models ['l8', 'l14', 'l19', 'l22', 'l23']", + "119, rheumatoid ['l9', 'l15', 'l20', 'l22', 'l24']", + "120, arthritis, ['l10', 'l16', 'l21', 'l23', 'l24']", + "127, Pik3cg(-/-) ['l11', 'l17', 'l25']", + "128, mice. ['l12', 'l18', 'l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pik3cg(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "models", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PI3Kgamma", + "inhibitor" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "rheumatoid", + "arthritis,", + "mice." + ] + } + } + ] + }, + { + "PMID": "16127436", + "TEXT": "Prion diseases are caused by an unconventional infectious agent termed prion, composed mainly of the misfolded prion protein (PrP(Sc)). The development of highly sensitive assays for biochemical detection of PrP(Sc) in blood is a top priority for minimizing the spread of the disease. Here we show that the protein misfolding cyclic amplification (PMCA) technology can be automated and optimized for high-efficiency amplification of PrP(Sc). We show that 140 PMCA cycles leads to a 6,600-fold increase in sensitivity over standard detection methods. Two successive rounds of PMCA cycles resulted in a 10 million-fold increase in sensitivity and a capability to detect as little as 8,000 equivalent molecules of PrP(Sc). Notably, serial PMCA enables detection of PrP(Sc) in blood samples of scrapie-afflicted hamsters with 89% sensitivity and 100% specificity. These findings represent the first time that PrP(Sc) has been detected biochemically in blood, offering promise for developing a noninvasive method for early diagnosis of prion diseases.", + "TAG_DATA": [ + "120, hamsters {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16116433", + "TEXT": "Hypersynchronous neuronal firing is a hallmark of epilepsy, but the mechanisms underlying simultaneous activation of multiple neurons remains unknown. Epileptic discharges are in part initiated by a local depolarization shift that drives groups of neurons into synchronous bursting. In an attempt to define the cellular basis for hypersynchronous bursting activity, we studied the occurrence of paroxysmal depolarization shifts after suppressing synaptic activity using tetrodotoxin (TTX) and voltage-gated Ca(2+) channel blockers. Here we report that paroxysmal depolarization shifts can be initiated by release of glutamate from extrasynaptic sources or by photolysis of caged Ca(2+) in astrocytes. Two-photon imaging of live exposed cortex showed that several antiepileptic agents, including valproate, gabapentin and phenytoin, reduced the ability of astrocytes to transmit Ca(2+) signaling. Our results show an unanticipated key role for astrocytes in seizure activity. As such, these findings identify astrocytes as a proximal target for the treatment of epileptic disorders.", + "TAG_DATA": [ + "99, exposed {'context': 'B-tissue/organ'}", + "100, cortex {'context': 'I-tissue/organ'}", + "115, astrocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "99, exposed ['l0']", + "100, cortex ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16086024", + "TEXT": "Approximately 50% of the US population received smallpox vaccinations before routine immunization ceased in 1972 for civilians and in 1990 for military personnel. Several studies have shown long-term immunity after smallpox vaccination, but skepticism remains as to whether this will translate into full protection against the onset of orthopoxvirus-induced disease. The US monkeypox outbreak of 2003 provided the opportunity to examine this issue. Using independent and internally validated diagnostic approaches with >or=95% sensitivity and >or=90% specificity for detecting clinical monkeypox infection, we identified three previously unreported cases of monkeypox in preimmune individuals at 13, 29 and 48 years after smallpox vaccination. These individuals were unaware that they had been infected because they were spared any recognizable disease symptoms. Together, this shows that the US monkeypox outbreak was larger than previously realized and, more importantly, shows that cross-protective antiviral immunity against West African monkeypox can potentially be maintained for decades after smallpox vaccination.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15965483", + "TEXT": "We describe the generation and characterization of the first inducible 'fatless' model system, the FAT-ATTAC mouse (fat apoptosis through targeted activation of caspase 8). This transgenic mouse develops identically to wild-type littermates. Apoptosis of adipocytes can be induced at any developmental stage by administration of a FK1012 analog leading to the dimerization of a membrane-bound, adipocyte-specific caspase 8-FKBP fusion protein. Within 2 weeks of dimerizer administration, FAT-ATTAC mice show near-knockout levels of circulating adipokines and markedly reduced levels of adipose tissue. FAT-ATTAC mice are glucose intolerant, have diminished basal and endotoxin-stimulated systemic inflammation, are less responsive to glucose-stimulated insulin secretion and show increased food intake independent of the effects of leptin. Most importantly, we show that functional adipocytes can be recovered upon cessation of treatment, allowing the study of adipogenesis in vivo, as well as a detailed examination of the importance of the adipocyte in the regulation of multiple physiological functions and pathological states.", + "TAG_DATA": [ + "32, Apoptosis {'phenotype': 'B-apoptosis'}", + "34, adipocytes {'context': 'B-cells'}", + "37, induced {'effect': 'B-positive'}", + "66, FAT-ATTAC {'perturbing_action': 'B-gene loss-of-function'}", + "67, mice {'context': 'B-organism'}", + "81, FAT-ATTAC {'perturbing_action': 'B-gene loss-of-function'}", + "82, mice {'context': 'B-organism'}", + "117, adipocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "32, Apoptosis ['l0', 'l1', 'l2', 'l3']", + "34, adipocytes ['l0', 'l4', 'l5', 'l6']", + "37, induced ['l1', 'l4', 'l7', 'l8']", + "66, FAT-ATTAC ['l2', 'l5', 'l7', 'l9']", + "67, mice ['l3', 'l6', 'l8', 'l9']", + "81, FAT-ATTAC ['l10']", + "82, mice ['l10']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "apoptosis", + "words": [ + "Apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "adipocytes" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "Apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "Apoptosis" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FAT-ATTAC" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "Apoptosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "adipocytes" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "adipocytes" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FAT-ATTAC" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FAT-ATTAC" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FAT-ATTAC" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15951824", + "TEXT": "Efficient boosting of memory T-cell numbers to protective levels generally requires a relatively long interval between immunizations. Decreasing this interval could be crucial in biodefense and cancer immunotherapy, in which rapid protective responses are essential. Here, we show that vaccination with peptide-coated dendritic cells (DCs) generated CD8+ T cells with the phenotype and function of memory cells within 4-6 d. These early memory CD8+ T cells underwent vigorous secondary expansion in response to a variety of booster immunizations, leading to elevated numbers of effector and memory T cells and enhanced protective immunity. Coinjection of CpG oligodeoxynucleotides, potent inducers of inflammation that did not alter the duration of DC antigen display, prevented the rapid generation of memory T cells in wild-type mice but not in mice lacking the interferon (IFN)-gamma receptor. These data show that DC vaccination stimulates a pathway of accelerated generation of memory T cells, and suggest that events of inflammation, including the action of IFN-gamma on the responding T cells, control the rate of development of memory CD8+ T cells.", + "TAG_DATA": [ + "46, CD8+ {'context': 'B-cells'}", + "47, T {'context': 'I-cells'}", + "48, cells {'context': 'I-cells'}", + "55, memory {'context': 'B-cells'}", + "56, cells {'context': 'I-cells'}", + "62, memory {'context': 'B-cells'}", + "63, CD8+ {'context': 'I-cells'}", + "64, T {'context': 'I-cells'}", + "65, cells {'context': 'I-cells'}", + "83, effector {'context': 'B-cells'}", + "84, and {'context': 'I-cells'}", + "85, memory {'context': 'I-cells'}", + "86, T {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}", + "115, memory {'context': 'B-cells'}", + "116, T {'context': 'I-cells'}", + "117, cells {'context': 'I-cells'}", + "120, mice {'context': 'B-organism'}", + "124, mice {'context': 'B-organism'}", + "125, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "126, the {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "46, CD8+ ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "47, T ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "48, cells ['l1', 'l13', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "55, memory ['l2', 'l14', 'l23', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "56, cells ['l3', 'l15', 'l24', 'l32', 'l39', 'l40', 'l41', 'l42']", + "62, memory ['l4', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "63, CD8+ ['l5', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "64, T ['l6', 'l16', 'l25', 'l44', 'l51', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "65, cells ['l7', 'l17', 'l26', 'l33', 'l45', 'l52', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "83, effector ['l8', 'l18', 'l27', 'l34', 'l46', 'l53', 'l59', 'l64', 'l69', 'l70', 'l71', 'l72']", + "84, and ['l9', 'l19', 'l28', 'l35', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l73', 'l74', 'l75']", + "85, memory ['l10', 'l20', 'l29', 'l36', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l76', 'l77']", + "86, T ['l11', 'l21', 'l30', 'l37', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l78']", + "87, cells ['l12', 'l22', 'l31', 'l38', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l77', 'l78']", + "115, memory ['l79', 'l80', 'l81']", + "116, T ['l79', 'l82', 'l83']", + "117, cells ['l80', 'l82', 'l84']", + "120, mice ['l81', 'l83', 'l84']", + "124, mice ['l85', 'l86', 'l87']", + "125, lacking ['l85', 'l88', 'l89']", + "126, the ['l86', 'l88', 'l90']", + "129, receptor. ['l87', 'l89', 'l90']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the" + ] + } + } + ] + }, + { + "PMID": "15937495", + "TEXT": "Vaccines and therapies are urgently needed to address public health needs stemming from emerging pathogens and biological threat agents such as the filoviruses Ebola virus (EBOV) and Marburg virus (MARV). Here, we developed replication-competent vaccines against EBOV and MARV based on attenuated recombinant vesicular stomatitis virus vectors expressing either the EBOV glycoprotein or MARV glycoprotein. A single intramuscular injection of the EBOV or MARV vaccine elicited completely protective immune responses in nonhuman primates against lethal EBOV or MARV challenges. Notably, vaccine vector shedding was not detectable in the monkeys and none of the animals developed fever or other symptoms of illness associated with vaccination. The EBOV vaccine induced humoral and apparent cellular immune responses in all vaccinated monkeys, whereas the MARV vaccine induced a stronger humoral than cellular immune response. No evidence of EBOV or MARV replication was detected in any of the protected animals after challenge. Our data suggest that these vaccine candidates are safe and highly efficacious in a relevant animal model.", + "TAG_DATA": [ + "71, nonhuman {'context': 'B-organism'}", + "72, primates {'context': 'I-organism'}", + "88, monkeys {'context': 'B-organism'}", + "93, animals {'context': 'B-organism'}", + "117, monkeys, {'context': 'B-organism'}", + "144, animals {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "71, nonhuman ['l0']", + "72, primates ['l0']", + "88, monkeys ['l1']", + "93, animals ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15908955", + "TEXT": "Accelerated osteoclastic bone resorption has a central role in the pathogenesis of osteoporosis and other bone diseases. Identifying the molecular pathways that regulate osteoclast activity provides a key to understanding the causes of these diseases and to the development of new treatments. Here we show that mice with inactivation of cannabinoid type 1 (CB1) receptors have increased bone mass and are protected from ovariectomy-induced bone loss. Pharmacological antagonists of CB1 and CB2 receptors prevented ovariectomy-induced bone loss in vivo and caused osteoclast inhibition in vitro by promoting osteoclast apoptosis and inhibiting production of several osteoclast survival factors. These studies show that the CB1 receptor has a role in the regulation of bone mass and ovariectomy-induced bone loss and that CB1- and CB2-selective cannabinoid receptor antagonists are a new class of osteoclast inhibitors that may be of value in the treatment of osteoporosis and other bone diseases.", + "TAG_DATA": [ + "46, mice {'context': 'B-organism'}", + "48, inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "49, of {'perturbing_action': 'I-gene loss-of-function'}", + "50, cannabinoid {'perturbing_action': 'I-gene loss-of-function'}", + "51, type {'perturbing_action': 'I-gene loss-of-function'}", + "52, 1 {'perturbing_action': 'I-gene loss-of-function'}", + "53, (CB1) {'perturbing_action': 'I-gene loss-of-function'}", + "54, receptors {'perturbing_action': 'I-gene loss-of-function'}", + "66, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "67, antagonists {'perturbing_action': 'I-pharmacological inhibition'}", + "68, of {'perturbing_action': 'I-pharmacological inhibition'}", + "69, CB1 {'perturbing_action': 'I-pharmacological inhibition'}", + "70, and {'perturbing_action': 'I-pharmacological inhibition'}", + "71, CB2 {'perturbing_action': 'I-pharmacological inhibition'}", + "72, receptors {'perturbing_action': 'I-pharmacological inhibition'}", + "77, in {'context': 'B-in vivo'}", + "78, vivo {'context': 'I-in vivo'}", + "83, in {'context': 'B-in vitro'}", + "84, vitro {'context': 'I-in vitro'}", + "86, promoting {'effect': 'B-positive'}", + "87, osteoclast {'context': 'B-cells'}", + "88, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "46, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "48, inactivation ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "49, of ['l1', 'l8', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "50, cannabinoid ['l2', 'l9', 'l19', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "51, type ['l3', 'l10', 'l20', 'l31', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "52, 1 ['l4', 'l11', 'l21', 'l32', 'l42', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "53, (CB1) ['l5', 'l12', 'l22', 'l33', 'l43', 'l51', 'l59', 'l60', 'l61', 'l62']", + "54, receptors ['l6', 'l13', 'l23', 'l34', 'l44', 'l52', 'l59', 'l63', 'l64']", + "66, Pharmacological ['l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "67, antagonists ['l65', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "68, of ['l66', 'l78', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "69, CB1 ['l67', 'l79', 'l90', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "70, and ['l68', 'l80', 'l91', 'l101', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "71, CB2 ['l69', 'l81', 'l92', 'l102', 'l111', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127']", + "72, receptors ['l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "77, in ['l14', 'l24', 'l35', 'l45', 'l53', 'l60', 'l63', 'l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l128', 'l135', 'l136', 'l137', 'l138']", + "78, vivo ['l7', 'l15', 'l25', 'l36', 'l46', 'l54', 'l61', 'l64', 'l72', 'l84', 'l95', 'l105', 'l114', 'l122', 'l129', 'l135']", + "83, in ['l16', 'l26', 'l37', 'l47', 'l55', 'l73', 'l85', 'l96', 'l106', 'l115', 'l123', 'l130', 'l136', 'l139', 'l140', 'l141', 'l142']", + "84, vitro ['l27', 'l38', 'l74', 'l86', 'l97', 'l107', 'l116', 'l124', 'l131', 'l139', 'l143', 'l144', 'l145']", + "86, promoting ['l17', 'l28', 'l39', 'l48', 'l56', 'l62', 'l75', 'l87', 'l98', 'l108', 'l117', 'l125', 'l132', 'l137', 'l140', 'l143', 'l146', 'l147']", + "87, osteoclast ['l18', 'l29', 'l40', 'l49', 'l57', 'l76', 'l88', 'l99', 'l109', 'l118', 'l126', 'l133', 'l138', 'l141', 'l144', 'l146', 'l148']", + "88, apoptosis ['l30', 'l41', 'l50', 'l58', 'l77', 'l89', 'l100', 'l110', 'l119', 'l127', 'l134', 'l142', 'l145', 'l147', 'l148']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "cannabinoid", + "type", + "1", + "(CB1)", + "receptors" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "cannabinoid", + "type", + "1", + "(CB1)", + "receptors" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "cannabinoid", + "type", + "1" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "cannabinoid", + "type", + "1", + "(CB1)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "cannabinoid", + "type", + "1" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "cannabinoid", + "type", + "1" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "antagonists", + "of", + "CB1", + "and", + "CB2", + "receptors" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "antagonists", + "of", + "CB1", + "and", + "CB2", + "receptors" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "antagonists", + "of", + "CB1", + "and", + "CB2", + "receptors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "antagonists", + "of", + "CB1", + "and", + "CB2", + "receptors" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "antagonists", + "of", + "CB1", + "and", + "CB2", + "receptors" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "15880118", + "TEXT": "Leprosy enables investigation of mechanisms by which the innate immune system contributes to host defense against infection, because in one form, the disease progresses, and in the other, the infection is limited. We report that Toll-like receptor (TLR) activation of human monocytes induces rapid differentiation into two distinct subsets: DC-SIGN+ CD16+ macrophages and CD1b+ DC-SIGN- dendritic cells. DC-SIGN+ phagocytic macrophages were expanded by TLR-mediated upregulation of interleukin (IL)-15 and IL-15 receptor. CD1b+ dendritic cells were expanded by TLR-mediated upregulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) and its receptor, promoted T cell activation and secreted proinflammatory cytokines. Whereas DC-SIGN+ macrophages were detected in lesions and after TLR activation in all leprosy patients, CD1b+ dendritic cells were not detected in lesions or after TLR activation of peripheral monocytes in individuals with the progressive lepromatous form, except during reversal reactions in which bacilli were cleared by T helper type 1 (TH1) responses. In tuberculoid lepromatous lesions, DC-SIGN+ cells were positive for macrophage markers, but negative for dendritic cell markers. Thus, TLR-induced differentiation of monocytes into either macrophages or dendritic cells seems to crucially influence effective host defenses in human infectious disease.", + "TAG_DATA": [ + "40, human {'context': 'B-cells'}", + "41, monocytes {'context': 'I-cells'}", + "42, induces {'effect': 'B-positive'}", + "57, DC-SIGN+ {'context': 'B-cells'}", + "58, phagocytic {'context': 'I-cells'}", + "59, macrophages {'context': 'I-cells'}", + "71, CD1b+ {'context': 'B-cells'}", + "72, dendritic {'context': 'I-cells'}", + "73, cells {'context': 'I-cells'}", + "88, T {'context': 'B-cells'}", + "89, cell {'context': 'B-cells'}", + "96, DC-SIGN+ {'context': 'B-cells'}", + "97, macrophages {'context': 'I-cells'}", + "110, CD1b+ {'context': 'B-cells'}", + "111, dendritic {'context': 'I-cells'}", + "112, cells {'context': 'I-cells'}", + "123, peripheral {'context': 'B-cells'}", + "124, monocytes {'context': 'I-cells'}", + "126, individuals {'context': 'B-patient'}", + "152, DC-SIGN+ {'context': 'B-cells'}", + "153, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "40, human ['l0', 'l1', 'l2', 'l3', 'l4']", + "41, monocytes ['l0', 'l5', 'l6', 'l7', 'l8']", + "42, induces ['l1', 'l5', 'l9']", + "57, DC-SIGN+ ['l2', 'l6', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "58, phagocytic ['l3', 'l7', 'l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "59, macrophages ['l4', 'l8', 'l9', 'l11', 'l17', 'l23', 'l24', 'l25', 'l26']", + "71, CD1b+ ['l12', 'l18', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "72, dendritic ['l13', 'l19', 'l23', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "73, cells ['l14', 'l20', 'l24', 'l28', 'l33', 'l38', 'l39', 'l40', 'l41']", + "88, T ['l15', 'l21', 'l25', 'l29', 'l34', 'l38', 'l42', 'l43']", + "89, cell ['l16', 'l22', 'l26', 'l30', 'l35', 'l39', 'l42', 'l44']", + "96, DC-SIGN+ ['l31', 'l36', 'l40', 'l45', 'l46']", + "97, macrophages ['l32', 'l37', 'l41', 'l43', 'l44', 'l45', 'l47']", + "110, CD1b+ ['l48', 'l49', 'l50', 'l51', 'l52']", + "111, dendritic ['l48', 'l53', 'l54', 'l55', 'l56']", + "112, cells ['l46', 'l47', 'l49', 'l53', 'l57', 'l58', 'l59']", + "123, peripheral ['l50', 'l54', 'l57', 'l60', 'l61']", + "124, monocytes ['l51', 'l55', 'l58', 'l60', 'l62']", + "126, individuals ['l52', 'l56', 'l59', 'l61', 'l62']", + "152, DC-SIGN+ ['l63']", + "153, cells ['l63']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "monocytes", + "macrophages" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + } + ] + }, + { + "PMID": "15852018", + "TEXT": "Alveolar cell apoptosis is involved in the pathogenesis of emphysema, a prevalent disease primarily caused by cigarette smoking. We report that ceramide, a second messenger lipid, is a crucial mediator of alveolar destruction in emphysema. Inhibition of enzymes controlling de novo ceramide synthesis prevented alveolar cell apoptosis, oxidative stress and emphysema caused by blockade of the vascular endothelial growth factor (VEGF) receptors in both rats and mice. Emphysema was reproduced with intratracheal instillation of ceramide in naive mice. Excessive ceramide triggers a feed-forward mechanism mediated by activation of secretory acid sphingomyelinase, as suggested by experiments with neutralizing ceramide antibody in mice and with acid sphingomyelinase-deficient fibroblasts. Concomitant augmentation of signaling initiated by a prosurvival metabolite, sphingosine-1-phosphate, prevented lung apoptosis, implying that a balance between ceramide and sphingosine-1-phosphate is required for maintenance of alveolar septal integrity. Finally, increased lung ceramides in individuals with smoking-induced emphysema suggests that ceramide upregulation may be a crucial pathogenic element and a promising target in this disease that currently lacks effective therapies.", + "TAG_DATA": [ + "43, prevented {'effect': 'B-negative'}", + "44, alveolar {'context': 'B-cells'}", + "45, cell {'context': 'I-cells'}", + "46, apoptosis, {'phenotype': 'B-apoptosis'}", + "53, blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "54, of {'perturbing_action': 'I-pharmacological inhibition'}", + "55, the {'perturbing_action': 'I-pharmacological inhibition'}", + "56, vascular {'perturbing_action': 'I-pharmacological inhibition'}", + "57, endothelial {'perturbing_action': 'I-pharmacological inhibition'}", + "58, growth {'perturbing_action': 'I-pharmacological inhibition'}", + "59, factor {'perturbing_action': 'I-pharmacological inhibition'}", + "60, (VEGF) {'perturbing_action': 'I-pharmacological inhibition'}", + "61, receptors {'perturbing_action': 'I-pharmacological inhibition'}", + "64, rats {'context': 'B-organism'}", + "66, mice. {'context': 'B-organism'}", + "77, mice. {'context': 'I-organism'}", + "100, mice {'context': 'B-organism'}", + "103, acid {'perturbing_action': 'B-gene loss-of-function'}", + "104, sphingomyelinase-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "105, fibroblasts. {'context': 'B-cells'}", + "116, prevented {'effect': 'B-negative'}", + "117, lung {'context': 'B-tissue/organ'}", + "118, apoptosis, {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "43, prevented ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "44, alveolar ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "45, cell ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "46, apoptosis, ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "53, blockade ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "54, of ['l4', 'l17', 'l29', 'l40', 'l50', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "55, the ['l5', 'l18', 'l30', 'l41', 'l51', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "56, vascular ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "57, endothelial ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "58, growth ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l90', 'l91', 'l92', 'l93', 'l94']", + "59, factor ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l95', 'l96', 'l97', 'l98']", + "60, (VEGF) ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l99', 'l100', 'l101']", + "61, receptors ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l102', 'l103']", + "64, rats ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l104']", + "66, mice. ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l104']", + "103, acid ['l105', 'l106', 'l107', 'l108', 'l109']", + "104, sphingomyelinase-deficient ['l105', 'l110', 'l111', 'l112', 'l113']", + "105, fibroblasts. ['l106', 'l110', 'l114', 'l115', 'l116']", + "116, prevented ['l107', 'l111', 'l114', 'l117', 'l118']", + "117, lung ['l108', 'l112', 'l115', 'l117', 'l119']", + "118, apoptosis, ['l109', 'l113', 'l116', 'l118', 'l119']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "cells", + "words": [ + "alveolar", + "cell", + "fibroblasts." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "the", + "vascular", + "endothelial", + "growth", + "factor", + "(VEGF)", + "receptors" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats", + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "alveolar", + "cell", + "fibroblasts." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "alveolar", + "cell" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "the", + "vascular", + "endothelial", + "growth", + "factor", + "(VEGF)", + "receptors" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "the", + "vascular", + "endothelial", + "growth", + "factor", + "(VEGF)", + "receptors" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + }, + "context": { + "val": "organism", + "words": [ + "rats", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "the", + "vascular", + "endothelial", + "growth", + "factor", + "(VEGF)", + "receptors" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "acid", + "sphingomyelinase-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "fibroblasts." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "acid", + "sphingomyelinase-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "acid", + "sphingomyelinase-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "acid", + "sphingomyelinase-deficient" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + } + ] + }, + { + "PMID": "15834430", + "TEXT": "Systemic inflammation induces various adaptive responses including tachycardia. Although inflammation-associated tachycardia has been thought to result from increased sympathetic discharge caused by inflammatory signals of the immune system, definitive proof has been lacking. Prostanoids, including prostaglandin (PG) D(2), PGE(2), PGF(2alpha), PGI(2) and thromboxane (TX) A(2), exert their actions through specific receptors: DP, EP (EP(1), EP(2), EP(3), EP(4)), FP, IP and TP, respectively. Here we have examined the roles of prostanoids in inflammatory tachycardia using mice that lack each of these receptors individually. The TXA(2) analog I-BOP and PGF(2alpha) each increased the beating rate of the isolated atrium of wild-type mice in vitro through interaction with TP and FP receptors, respectively. The cytokine-induced increase in beating rate was markedly inhibited in atria from mice lacking either TP or FP receptors. The tachycardia induced in wild-type mice by injection of lipopolysaccharide (LPS) was greatly attenuated in TP-deficient or FP-deficient mice and was completely absent in mice lacking both TP and FP. The beta-blocker propranolol did not block the LPS-induced increase in heart rate in wild-type animals. Our results show that inflammatory tachycardia is caused by a direct action on the heart of TXA(2) and PGF(2alpha) formed under systemic inflammatory conditions.", + "TAG_DATA": [ + "95, isolated {'context': 'B-tissue/organ'}", + "96, atrium {'context': 'I-tissue/organ'}", + "98, wild-type {'context': 'B-organism'}", + "99, mice {'context': 'B-organism'}", + "100, in {'context': 'B-in vitro'}", + "101, vitro {'context': 'I-in vitro'}", + "120, atria {'context': 'B-tissue/organ'}", + "122, mice {'context': 'B-organism'}", + "123, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "124, either {'perturbing_action': 'I-gene loss-of-function'}", + "125, TP {'perturbing_action': 'I-gene loss-of-function'}", + "126, or {'perturbing_action': 'I-gene loss-of-function'}", + "127, FP {'perturbing_action': 'I-gene loss-of-function'}", + "128, receptors. {'perturbing_action': 'I-gene loss-of-function'}", + "133, wild-type {'context': 'B-organism'}", + "134, mice {'context': 'B-organism'}", + "144, TP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "146, FP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "147, mice {'context': 'B-organism'}", + "153, mice {'context': 'B-organism'}", + "154, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "155, both {'perturbing_action': 'I-gene loss-of-function'}", + "156, TP {'perturbing_action': 'I-gene loss-of-function'}", + "157, and {'perturbing_action': 'I-gene loss-of-function'}", + "158, FP. {'perturbing_action': 'I-gene loss-of-function'}", + "173, animals. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "95, isolated ['l0', 'l1', 'l2', 'l3', 'l4']", + "96, atrium ['l0', 'l5', 'l6', 'l7', 'l8']", + "98, wild-type ['l1', 'l5', 'l9', 'l10', 'l11']", + "99, mice ['l2', 'l6', 'l9', 'l12', 'l13']", + "100, in ['l3', 'l7', 'l10', 'l12', 'l14']", + "101, vitro ['l4', 'l8', 'l11', 'l13', 'l14']", + "120, atria ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "122, mice ['l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "123, lacking ['l16', 'l23', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "124, either ['l17', 'l24', 'l31', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "125, TP ['l18', 'l25', 'l32', 'l38', 'l44', 'l45', 'l46', 'l47', 'l48']", + "126, or ['l19', 'l26', 'l33', 'l39', 'l44', 'l49', 'l50', 'l51', 'l52']", + "127, FP ['l20', 'l27', 'l34', 'l40', 'l45', 'l49', 'l53', 'l54', 'l55']", + "128, receptors. ['l21', 'l28', 'l35', 'l41', 'l46', 'l50', 'l53', 'l56', 'l57']", + "133, wild-type ['l29', 'l36', 'l42', 'l47', 'l51', 'l54', 'l56', 'l58', 'l59']", + "134, mice ['l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l57', 'l58']", + "144, TP-deficient ['l59', 'l60', 'l61']", + "146, FP-deficient ['l60', 'l62']", + "147, mice ['l61', 'l62']", + "153, mice ['l63', 'l64', 'l65', 'l66', 'l67']", + "154, lacking ['l63', 'l68', 'l69', 'l70', 'l71']", + "155, both ['l64', 'l68', 'l72', 'l73', 'l74']", + "156, TP ['l65', 'l69', 'l72', 'l75', 'l76']", + "157, and ['l66', 'l70', 'l73', 'l75', 'l77']", + "158, FP. ['l67', 'l71', 'l74', 'l76', 'l77']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "atria" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "either", + "TP", + "or", + "FP", + "receptors." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "wild-type" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "either", + "TP", + "or", + "FP", + "receptors.", + "TP-deficient", + "FP-deficient", + "both", + "and", + "FP." + ] + } + } + ] + }, + { + "PMID": "15834429", + "TEXT": "Platelet activation at sites of vascular injury is essential for the arrest of bleeding; however, excessive platelet accumulation at regions of atherosclerotic plaque rupture can result in the development of arterial thrombi, precipitating diseases such as acute myocardial infarction and ischemic stroke. Rheological disturbances (high shear stress) have an important role in promoting arterial thrombosis by enhancing the adhesive and signaling function of platelet integrin alpha(IIb)beta(3) (GPIIb-IIIa). In this study we have defined a key role for the Type Ia phosphoinositide 3-kinase (PI3K) p110beta isoform in regulating the formation and stability of integrin alpha(IIb)beta(3) adhesion bonds, necessary for shear activation of platelets. Isoform-selective PI3K p110beta inhibitors have been developed which prevent formation of stable integrin alpha(IIb)beta(3) adhesion contacts, leading to defective platelet thrombus formation. In vivo, these inhibitors eliminate occlusive thrombus formation but do not prolong bleeding time. These studies define PI3K p110beta as an important new target for antithrombotic therapy.", + "TAG_DATA": [ + "102, Isoform-selective {'perturbing_action': 'B-pharmacological inhibition'}", + "103, PI3K {'perturbing_action': 'I-pharmacological inhibition'}", + "104, p110beta {'perturbing_action': 'I-pharmacological inhibition'}", + "105, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "121, platelet {'context': 'B-cells'}", + "124, In {'context': 'B-in vivo'}", + "125, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "102, Isoform-selective ['l0', 'l1', 'l2', 'l3']", + "103, PI3K ['l0', 'l4', 'l5', 'l6']", + "104, p110beta ['l1', 'l4', 'l7', 'l8']", + "105, inhibitors ['l2', 'l5', 'l7', 'l9']", + "121, platelet ['l3', 'l6', 'l8', 'l9']", + "124, In ['l10']", + "125, vivo, ['l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Isoform-selective", + "PI3K", + "p110beta", + "inhibitors" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelet" + ] + } + } + ] + }, + { + "PMID": "15821749", + "TEXT": "Insulin receptor substrate-1 (IRS-1) and IRS-2 are known to transduce and amplify signals emanating from the insulin receptor. Here we show that Grb2-associated binder 1 (Gab1), despite its structural similarity to IRS proteins, is a negative modulator of hepatic insulin action. Liver-specific Gab1 knockout (LGKO) mice showed enhanced hepatic insulin sensitivity with reduced glycemia and improved glucose tolerance. In LGKO liver, basal and insulin-stimulated tyrosine phosphorylation of IRS-1 and IRS-2 was elevated, accompanied by enhanced Akt/PKB activation. Conversely, Erk activation by insulin was suppressed in LGKO liver, leading to defective IRS-1 Ser612 phosphorylation. Thus, Gab1 acts to attenuate, through promotion of the Erk pathway, insulin-elicited signals flowing through IRS and Akt proteins, which represents a novel balancing mechanism for control of insulin signal strength in the liver.", + "TAG_DATA": [ + "41, Liver-specific {'perturbing_action': 'B-gene loss-of-function'}", + "42, Gab1 {'perturbing_action': 'I-gene loss-of-function'}", + "43, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "44, (LGKO) {'perturbing_action': 'I-gene loss-of-function'}", + "45, mice {'context': 'B-organism'}", + "59, LGKO {'perturbing_action': 'B-gene loss-of-function'}", + "60, liver, {'context': 'B-tissue/organ'}", + "85, LGKO {'perturbing_action': 'B-gene loss-of-function'}", + "86, liver, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "41, Liver-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "42, Gab1 ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "43, knockout ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "44, (LGKO) ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "45, mice ['l3', 'l8', 'l12', 'l15']", + "59, LGKO ['l4', 'l9', 'l13', 'l16', 'l18']", + "60, liver, ['l5', 'l10', 'l14', 'l17', 'l18']", + "85, LGKO ['l19']", + "86, liver, ['l19']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Liver-specific", + "Gab1", + "knockout", + "(LGKO)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Liver-specific", + "Gab1", + "knockout", + "(LGKO)", + "LGKO" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver," + ] + } + } + ] + }, + { + "PMID": "15793583", + "TEXT": "High-density lipoproteins (HDLs) are considered antiatherogenic because they mediate reverse cholesterol transport from the periphery to the liver for excretion and degradation. Here we show that mice deficient in apolipoprotein M (apoM), a component of the HDL particle, accumulated cholesterol in large HDL particles (HDL(1)) while the conversion of HDL to prebeta-HDL was impaired. Accordingly, apoM-deficient mice lacked prebeta-HDL, a subclass of lipid-poor apolipoproteins that serves as a key acceptor of peripheral cellular cholesterol. This deficiency led to a markedly reduced cholesterol efflux from macrophages to apoM-deficient HDL compared to normal HDL in vitro. Overexpression of apoM in Ldlr(-/-) mice protected against atherosclerosis when the mice were challenged with a cholesterol-enriched diet, showing that apoM is important for the formation of prebeta-HDL and cholesterol efflux to HDL, and thereby inhibits formation of atherosclerotic lesions.", + "TAG_DATA": [ + "26, mice {'context': 'B-organism'}", + "27, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "28, in {'perturbing_action': 'I-gene loss-of-function'}", + "29, apolipoprotein {'perturbing_action': 'I-gene loss-of-function'}", + "30, M {'perturbing_action': 'I-gene loss-of-function'}", + "31, (apoM), {'perturbing_action': 'I-gene loss-of-function'}", + "55, apoM-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "56, mice {'context': 'B-organism'}", + "84, macrophages {'context': 'B-cells'}", + "86, apoM-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "92, in {'context': 'B-in vitro'}", + "93, vitro. {'context': 'I-in vitro'}", + "94, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "95, of {'perturbing_action': 'I-gene gain-of-function'}", + "96, apoM {'perturbing_action': 'I-gene gain-of-function'}", + "98, Ldlr(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "99, mice {'context': 'B-organism'}", + "100, protected {'effect': 'B-negative'}", + "101, against {'effect': 'I-negative'}", + "105, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "26, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "27, deficient ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "28, in ['l1', 'l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "29, apolipoprotein ['l2', 'l7', 'l12', 'l17', 'l18', 'l19', 'l20', 'l21']", + "30, M ['l3', 'l8', 'l13', 'l17', 'l22', 'l23', 'l24']", + "31, (apoM), ['l4', 'l9', 'l14', 'l18', 'l22', 'l25', 'l26']", + "55, apoM-deficient ['l27', 'l28', 'l29', 'l30', 'l31']", + "56, mice ['l10', 'l15', 'l19', 'l23', 'l25', 'l27', 'l32', 'l33', 'l34', 'l35']", + "84, macrophages ['l5', 'l11', 'l16', 'l20', 'l24', 'l26', 'l28', 'l32', 'l36', 'l37', 'l38']", + "86, apoM-deficient ['l29', 'l33', 'l36', 'l39', 'l40']", + "92, in ['l30', 'l34', 'l37', 'l39', 'l41']", + "93, vitro. ['l21', 'l31', 'l35', 'l38', 'l40', 'l41']", + "94, Overexpression ['l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "95, of ['l42', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "96, apoM ['l43', 'l49', 'l55', 'l56', 'l57', 'l58', 'l59']", + "98, Ldlr(-/-) ['l44', 'l50', 'l55', 'l60', 'l61', 'l62', 'l63']", + "99, mice ['l45', 'l51', 'l56', 'l60', 'l64', 'l65', 'l66']", + "100, protected ['l46', 'l52', 'l57', 'l61', 'l64', 'l67', 'l68']", + "101, against ['l47', 'l53', 'l58', 'l62', 'l65', 'l67', 'l69']", + "105, mice ['l48', 'l54', 'l59', 'l63', 'l66', 'l68', 'l69']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "apolipoprotein", + "M", + "(apoM),", + "apoM-deficient", + "Ldlr(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "apolipoprotein", + "M", + "(apoM),", + "apoM-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "apolipoprotein", + "apoM-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "vitro.", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "apoM" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "apoM" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protected", + "against" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ldlr(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protected", + "against" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protected", + "against" + ] + } + } + ] + }, + { + "PMID": "15750601", + "TEXT": "Morphogenesis and remodeling of bone involve synthesis of bone matrix by osteoblasts and coordinate resorption of bone by osteoclasts. Defective bone remodeling caused by altered osteoclast activity underlies a multitude of osteopenic disorders. Receptor activator of NF-kappaB (RANK) and its ligand RANKL have been identified as essential factors involved in osteoclast development and bone remodeling, but their mechanism and interacting factors have not been fully characterized. Here we report that the molecular adapter Grb-2-associated binder-2 (Gab2) associates with RANK and mediates RANK-induced activation of NF-kappaB, Akt and Jnk. Inactivation of the gene encoding Gab2 in mice results in osteopetrosis and decreased bone resorption as a result of defective osteoclast differentiation. We also show that Gab2 has a crucial role in the differentiation of human progenitor cells into osteoclasts. We have thus identified a new, key regulatory scaffold molecule, Gab2, that controls select RANK signaling pathways and is essential for osteoclastogenesis and bone homeostasis.", + "TAG_DATA": [ + "88, Inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "89, of {'perturbing_action': 'I-gene loss-of-function'}", + "90, the {'perturbing_action': 'I-gene loss-of-function'}", + "91, gene {'perturbing_action': 'I-gene loss-of-function'}", + "92, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "93, Gab2 {'perturbing_action': 'I-gene loss-of-function'}", + "95, mice {'context': 'B-organism'}", + "107, defective {'effect': 'B-negative'}", + "108, osteoclast {'context': 'B-cells'}", + "109, differentiation. {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "88, Inactivation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "89, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "90, the ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "91, gene ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "92, encoding ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "93, Gab2 ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "95, mice ['l5', 'l13', 'l20', 'l26', 'l31', 'l35']", + "107, defective ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l40']", + "108, osteoclast ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l39', 'l41']", + "109, differentiation. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Inactivation", + "of", + "the", + "gene", + "encoding", + "Gab2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Inactivation", + "of", + "the", + "gene", + "encoding", + "Gab2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Inactivation", + "of", + "the", + "gene", + "encoding", + "Gab2" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Inactivation", + "of", + "the", + "gene", + "encoding", + "Gab2" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "defective" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "defective" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + } + ] + }, + { + "PMID": "15723075", + "TEXT": "Short interfering RNA (siRNA) is used in RNA interference technology to avoid non-target-related induction of type I interferon (IFN) typical for long double-stranded RNA. Here we show that in plasmacytoid dendritic cells (PDC), an immune cell subset specialized in the detection of viral nucleic acids and production of type I IFN, some siRNA sequences, independent of their GU content, are potent stimuli of IFN-alpha production. Localization of the immunostimulatory motif on the sense strand of a potent IFN-alpha-inducing siRNA allowed dissection of immunostimulation and target silencing. Injection into mice of immunostimulatory siRNA, when complexed with cationic liposomes, induced systemic immune responses in the same range as the TLR9 ligand CpG, including IFN-alpha in serum and activation of T cells and dendritic cells in spleen. Immunostimulation by siRNA was absent in TLR7-deficient mice. Thus sequence-specific TLR7-dependent immune recognition in PDC needs to be considered as an additional biological activity of siRNA, which then should be termed immunostimulatory RNA (isRNA).", + "TAG_DATA": [ + "88, mice {'context': 'B-organism'}", + "117, T {'context': 'B-cells'}", + "118, cells {'context': 'B-cells'}", + "120, dendritic {'context': 'B-cells'}", + "121, cells {'context': 'I-cells'}", + "123, spleen. {'context': 'B-tissue/organ'}", + "130, TLR7-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "131, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "88, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "117, T ['l0', 'l5', 'l6', 'l7', 'l8']", + "118, cells ['l1', 'l5', 'l9', 'l10', 'l11']", + "120, dendritic ['l2', 'l6', 'l9', 'l12', 'l13']", + "121, cells ['l3', 'l7', 'l10', 'l12', 'l14']", + "123, spleen. ['l4', 'l8', 'l11', 'l13', 'l14']", + "130, TLR7-deficient ['l15']", + "131, mice. ['l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TLR7-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "15723072", + "TEXT": "Granulocyte colony-stimulating factor (G-CSF) was reported to induce myocardial regeneration by promoting mobilization of bone marrow stem cells to the injured heart after myocardial infarction, but the precise mechanisms of the beneficial effects of G-CSF are not fully understood. Here we show that G-CSF acts directly on cardiomyocytes and promotes their survival after myocardial infarction. G-CSF receptor was expressed on cardiomyocytes and G-CSF activated the Jak/Stat pathway in cardiomyocytes. The G-CSF treatment did not affect initial infarct size at 3 d but improved cardiac function as early as 1 week after myocardial infarction. Moreover, the beneficial effects of G-CSF on cardiac function were reduced by delayed start of the treatment. G-CSF induced antiapoptotic proteins and inhibited apoptotic death of cardiomyocytes in the infarcted hearts. G-CSF also reduced apoptosis of endothelial cells and increased vascularization in the infarcted hearts, further protecting against ischemic injury. All these effects of G-CSF on infarcted hearts were abolished by overexpression of a dominant-negative mutant Stat3 protein in cardiomyocytes. These results suggest that G-CSF promotes survival of cardiac myocytes and prevents left ventricular remodeling after myocardial infarction through the functional communication between cardiomyocytes and noncardiomyocytes.", + "TAG_DATA": [ + "115, inhibited {'effect': 'B-negative'}", + "116, apoptotic {'phenotype': 'B-apoptosis'}", + "117, death {'phenotype': 'I-apoptosis'}", + "119, cardiomyocytes {'context': 'B-cells'}", + "123, hearts. {'context': 'B-tissue/organ'}", + "126, reduced {'effect': 'B-negative'}", + "127, apoptosis {'phenotype': 'B-apoptosis'}", + "129, endothelial {'context': 'B-cells'}", + "130, cells {'context': 'I-cells'}", + "137, hearts, {'context': 'B-tissue/organ'}", + "150, hearts {'context': 'I-tissue/organ'}", + "154, overexpression {'perturbing_action': 'B-other'}", + "155, of {'perturbing_action': 'I-other'}", + "156, a {'perturbing_action': 'I-other'}", + "157, dominant-negative {'perturbing_action': 'I-other'}", + "158, mutant {'perturbing_action': 'I-other'}", + "159, Stat3 {'perturbing_action': 'I-other'}", + "160, protein {'perturbing_action': 'I-other'}", + "162, cardiomyocytes. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "115, inhibited ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "116, apoptotic ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "117, death ['l1', 'l8', 'l14', 'l15', 'l16']", + "119, cardiomyocytes ['l2', 'l9', 'l14', 'l17', 'l18']", + "123, hearts. ['l3', 'l10', 'l15', 'l17', 'l19']", + "126, reduced ['l4', 'l20', 'l21', 'l22', 'l23']", + "127, apoptosis ['l20', 'l24', 'l25', 'l26']", + "129, endothelial ['l5', 'l11', 'l21', 'l24', 'l27', 'l28']", + "130, cells ['l6', 'l12', 'l16', 'l18', 'l19', 'l22', 'l25', 'l27', 'l29']", + "137, hearts, ['l7', 'l13', 'l23', 'l26', 'l28', 'l29']", + "150, hearts ['l30']", + "154, overexpression ['l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "155, of ['l31', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "156, a ['l32', 'l38', 'l44', 'l45', 'l46', 'l47', 'l48']", + "157, dominant-negative ['l33', 'l39', 'l44', 'l49', 'l50', 'l51', 'l52']", + "158, mutant ['l34', 'l40', 'l45', 'l49', 'l53', 'l54', 'l55']", + "159, Stat3 ['l35', 'l41', 'l46', 'l50', 'l53', 'l56', 'l57']", + "160, protein ['l36', 'l42', 'l47', 'l51', 'l54', 'l56', 'l58']", + "162, cardiomyocytes. ['l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l57', 'l58']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "reduced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death", + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "reduced" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes", + "endothelial", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "reduced" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hearts.", + "hearts," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death", + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes", + "endothelial", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death", + "apoptosis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hearts.", + "hearts," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "overexpression", + "of", + "a", + "dominant-negative", + "mutant", + "Stat3", + "protein" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes." + ] + } + } + ] + }, + { + "PMID": "15711562", + "TEXT": "The adaptor molecule SAP is expressed in T lymphocytes and natural killer (NK) cells, where it regulates cytokine production and cytotoxicity. Here, we show that SAP, encoded by the SH2D1A gene locus, also has a crucial role during the development of NKT cells, a lymphocyte subset with immunoregulatory functions in response to infection, cancer and autoimmune disease. Following stimulation with the NKT cell-specific agonist alpha-galactosyl ceramide (alphaGC), Sh2d1a-/- splenocytes did not produce cytokines or activate other lymphoid lineages in an NKT cell-dependent manner. While evaluating the abnormalities in alphaGC-induced immune responses, we observed that Sh2d1a-/- animals lacked NKT cells in the thymus and peripheral organs. The defect in NKT cell ontogeny was hematopoietic cell autonomous and could be rescued by reconstitution of SAP expression within Sh2d1a-/- bone marrow cells. Seventeen individuals with X-linked lymphoproliferative disease (XLP), who harbored germline mutations in SH2D1A, also lacked NKT cells. Furthermore, a female XLP carrier showed completely skewed X chromosome inactivation within NKT cells, but not T or B cells. Thus, SAP is a crucial regulator of NKT cell ontogeny in humans and in mice. The absence of NKT cells may contribute to the phenotypes of SAP deficiency, including abnormal antiviral and antitumor immunity and hypogammaglobulinemia.", + "TAG_DATA": [ + "67, Sh2d1a-/- {'perturbing_action': 'B-gene loss-of-function'}", + "68, splenocytes {'context': 'B-cells'}", + "94, Sh2d1a-/- {'perturbing_action': 'B-gene loss-of-function'}", + "95, animals {'context': 'B-organism'}", + "97, NKT {'context': 'B-cells'}", + "98, cells {'context': 'I-cells'}", + "101, thymus {'context': 'B-tissue/organ'}", + "104, organs. {'context': 'I-tissue/organ'}", + "108, NKT {'context': 'B-cells'}", + "109, cell {'context': 'I-cells'}", + "120, reconstitution {'perturbing_action': 'B-gene gain-of-function'}", + "121, of {'perturbing_action': 'I-gene gain-of-function'}", + "122, SAP {'perturbing_action': 'I-gene gain-of-function'}", + "123, expression {'perturbing_action': 'I-gene gain-of-function'}", + "125, Sh2d1a-/- {'perturbing_action': 'B-gene loss-of-function'}", + "126, bone {'context': 'B-cells'}", + "127, marrow {'context': 'I-cells'}", + "128, cells. {'context': 'I-cells'}", + "144, NKT {'context': 'B-cells'}", + "145, cells. {'context': 'I-cells'}", + "158, NKT {'context': 'B-cells'}", + "159, cells, {'context': 'I-cells'}", + "162, T {'context': 'B-cells'}", + "163, or {'context': 'I-cells'}", + "164, B {'context': 'I-cells'}", + "165, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "67, Sh2d1a-/- ['l0']", + "68, splenocytes ['l0']", + "94, Sh2d1a-/- ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "95, animals ['l1', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "97, NKT ['l2', 'l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "98, cells ['l3', 'l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "101, thymus ['l4', 'l12', 'l18', 'l23', 'l28', 'l29', 'l30', 'l31']", + "103, peripheral ['l5', 'l13', 'l19', 'l24', 'l28', 'l32', 'l33', 'l34']", + "104, organs. ['l6', 'l14', 'l20', 'l25', 'l29', 'l32', 'l35', 'l36']", + "108, NKT ['l7', 'l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "109, cell ['l8', 'l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l37', 'l46', 'l47', 'l48']", + "120, reconstitution ['l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "121, of ['l38', 'l49', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "122, SAP ['l39', 'l50', 'l58', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "123, expression ['l40', 'l51', 'l59', 'l66', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "125, Sh2d1a-/- ['l41', 'l52', 'l60', 'l67', 'l73', 'l79', 'l80', 'l81', 'l82', 'l83']", + "126, bone ['l42', 'l46', 'l53', 'l61', 'l68', 'l74', 'l79', 'l84', 'l85', 'l86', 'l87']", + "127, marrow ['l43', 'l47', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l88', 'l89', 'l90']", + "128, cells. ['l9', 'l44', 'l48', 'l55', 'l63', 'l70', 'l76', 'l81', 'l85', 'l88', 'l91', 'l92']", + "144, NKT ['l56', 'l64', 'l71', 'l77', 'l82', 'l86', 'l89', 'l91', 'l93']", + "145, cells. ['l45', 'l57', 'l65', 'l72', 'l78', 'l83', 'l87', 'l90', 'l92', 'l93']", + "158, NKT ['l94', 'l95', 'l96', 'l97', 'l98']", + "159, cells, ['l94', 'l99', 'l100', 'l101', 'l102']", + "162, T ['l95', 'l99', 'l103', 'l104', 'l105']", + "163, or ['l96', 'l100', 'l103', 'l106', 'l107']", + "164, B ['l97', 'l101', 'l104', 'l106', 'l108']", + "165, cells. ['l98', 'l102', 'l105', 'l107', 'l108']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sh2d1a-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "splenocytes", + "NKT", + "cells", + "cell", + "cells.", + "bone", + "marrow" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sh2d1a-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "animals" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sh2d1a-/-" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "thymus", + "organs." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "NKT", + "bone", + "marrow", + "cells." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "SAP", + "expression", + "reconstitution" + ] + } + } + ] + }, + { + "PMID": "15711557", + "TEXT": "Immune escape is a crucial feature of cancer progression about which little is known. Elevation of the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) in tumor cells can facilitate immune escape. Not known is how IDO becomes elevated or whether IDO inhibitors will be useful for cancer treatment. Here we show that IDO is under genetic control of Bin1, which is attenuated in many human malignancies. Mouse knockout studies indicate that Bin1 loss elevates the STAT1- and NF-kappaB-dependent expression of IDO, driving escape of oncogenically transformed cells from T cell-dependent antitumor immunity. In MMTV-Neu mice, an established breast cancer model, we show that small-molecule inhibitors of IDO cooperate with cytotoxic agents to elicit regression of established tumors refractory to single-agent therapy. Our findings suggest that Bin1 loss promotes immune escape in cancer by deregulating IDO and that IDO inhibitors may improve responses to cancer chemotherapy.", + "TAG_DATA": [ + "64, Mouse {'context': 'B-organism'}", + "69, Bin1 {'perturbing_action': 'B-gene loss-of-function'}", + "70, loss {'perturbing_action': 'I-gene loss-of-function'}", + "84, cells {'context': 'I-transformed cells'}", + "91, MMTV-Neu {'perturbing_action': 'B-other'}", + "92, mice, {'context': 'B-organism'}", + "101, small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "102, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "103, of {'perturbing_action': 'I-pharmacological inhibition'}", + "104, IDO {'perturbing_action': 'I-pharmacological inhibition'}", + "110, elicit {'effect': 'B-positive'}", + "111, regression {'phenotype': 'B-tumour regression'}", + "114, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "64, Mouse ['l0', 'l1', 'l2', 'l3']", + "69, Bin1 ['l0', 'l4', 'l5', 'l6']", + "70, loss ['l1', 'l4', 'l7', 'l8']", + "83, transformed ['l2', 'l5', 'l7', 'l9']", + "84, cells ['l3', 'l6', 'l8', 'l9']", + "91, MMTV-Neu ['l10']", + "92, mice, ['l10']", + "101, small-molecule ['l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "102, inhibitors ['l11', 'l17', 'l18', 'l19', 'l20', 'l21']", + "103, of ['l12', 'l17', 'l22', 'l23', 'l24', 'l25']", + "104, IDO ['l13', 'l18', 'l22', 'l26', 'l27', 'l28']", + "110, elicit ['l14', 'l19', 'l23', 'l26', 'l29', 'l30']", + "111, regression ['l15', 'l20', 'l24', 'l27', 'l29', 'l31']", + "114, tumors ['l16', 'l21', 'l25', 'l28', 'l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mouse" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bin1", + "loss" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bin1", + "loss" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "MMTV-Neu" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "inhibitors", + "of", + "IDO" + ] + }, + "effect": { + "val": "positive", + "words": [ + "elicit" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "inhibitors", + "of", + "IDO" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "inhibitors", + "of", + "IDO" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "elicit" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "elicit" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + } + ] + }, + { + "PMID": "15685173", + "TEXT": "We show that NF-kappaB and transcriptional targets are activated in liver by obesity and high-fat diet (HFD). We have matched this state of chronic, subacute 'inflammation' by low-level activation of NF-kappaB in the liver of transgenic mice, designated LIKK, by selectively expressing constitutively active IKK-b in hepatocytes. These mice exhibit a type 2 diabetes phenotype, characterized by hyperglycemia, profound hepatic insulin resistance, and moderate systemic insulin resistance, including effects in muscle. The hepatic production of proinflammatory cytokines, including IL-6, IL-1beta and TNF-alpha, was increased in LIKK mice to a similar extent as induced by HFD in in wild-type mice. Parallel increases were observed in cytokine signaling in liver and mucscle of LIKK mice. Insulin resistance was improved by systemic neutralization of IL-6 or salicylate inhibition of IKK-beta. Hepatic expression of the IkappaBalpha superrepressor (LISR) reversed the phenotype of both LIKK mice and wild-type mice fed an HFD. These findings indicate that lipid accumulation in the liver leads to subacute hepatic 'inflammation' through NF-kappaB activation and downstream cytokine production. This causes insulin resistance both locally in liver and systemically.", + "TAG_DATA": [ + "40, selectively {'perturbing_action': 'B-gene gain-of-function'}", + "41, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "42, constitutively {'perturbing_action': 'I-gene gain-of-function'}", + "43, active {'perturbing_action': 'I-gene gain-of-function'}", + "44, IKK-b {'perturbing_action': 'I-gene gain-of-function'}", + "45, in {'perturbing_action': 'I-gene gain-of-function'}", + "46, hepatocytes. {'context': 'B-cells'}", + "48, mice {'context': 'B-organism'}", + "85, LIKK {'perturbing_action': 'B-other'}", + "86, mice {'context': 'B-organism'}", + "98, mice. {'context': 'B-organism'}", + "107, liver {'context': 'B-tissue/organ'}", + "109, mucscle {'context': 'I-tissue/organ'}", + "111, LIKK {'perturbing_action': 'B-other'}", + "112, mice. {'context': 'B-organism'}", + "123, salicylate {'perturbing_action': 'B-pharmacological inhibition'}", + "124, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "125, of {'perturbing_action': 'I-pharmacological inhibition'}", + "126, IKK-beta. {'perturbing_action': 'I-pharmacological inhibition'}", + "127, Hepatic {'perturbing_action': 'B-gene gain-of-function'}", + "128, expression {'perturbing_action': 'I-gene gain-of-function'}", + "129, of {'perturbing_action': 'I-gene gain-of-function'}", + "130, the {'perturbing_action': 'I-gene gain-of-function'}", + "131, IkappaBalpha {'perturbing_action': 'I-gene gain-of-function'}", + "132, superrepressor {'perturbing_action': 'I-gene gain-of-function'}", + "133, (LISR) {'perturbing_action': 'I-gene gain-of-function'}", + "139, LIKK {'perturbing_action': 'B-other'}", + "140, mice {'context': 'B-organism'}", + "143, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "40, selectively ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "41, expressing ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "42, constitutively ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "43, active ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "44, IKK-b ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "45, in ['l4', 'l17', 'l29', 'l40', 'l50', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "46, hepatocytes. ['l5', 'l18', 'l30', 'l41', 'l51', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "48, mice ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l77', 'l78']", + "85, LIKK ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l79', 'l80', 'l81']", + "86, mice ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l79']", + "98, mice. ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l80', 'l82', 'l83', 'l84', 'l85']", + "107, liver ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l81', 'l82', 'l86', 'l87', 'l88']", + "109, mucscle ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l83', 'l86', 'l89', 'l90']", + "111, LIKK ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l84', 'l87', 'l89', 'l91']", + "112, mice. ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l85', 'l88', 'l90', 'l91']", + "123, salicylate ['l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "124, inhibition ['l92', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "125, of ['l93', 'l102', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "126, IKK-beta. ['l94', 'l103', 'l113', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "127, Hepatic ['l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "128, expression ['l104', 'l114', 'l130', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146']", + "129, of ['l105', 'l115', 'l131', 'l139', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "130, the ['l95', 'l106', 'l116', 'l123', 'l132', 'l140', 'l147', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159']", + "131, IkappaBalpha ['l96', 'l107', 'l117', 'l124', 'l133', 'l141', 'l148', 'l154', 'l160', 'l161', 'l162', 'l163', 'l164']", + "132, superrepressor ['l97', 'l108', 'l118', 'l125', 'l134', 'l142', 'l149', 'l155', 'l160', 'l165', 'l166', 'l167', 'l168']", + "133, (LISR) ['l98', 'l109', 'l119', 'l126', 'l135', 'l143', 'l150', 'l156', 'l161', 'l165', 'l169', 'l170', 'l171']", + "139, LIKK ['l99', 'l110', 'l120', 'l127', 'l136', 'l144', 'l151', 'l157', 'l162', 'l166', 'l169', 'l172', 'l173']", + "140, mice ['l100', 'l111', 'l121', 'l128', 'l137', 'l145', 'l152', 'l158', 'l163', 'l167', 'l170', 'l172', 'l174']", + "143, mice ['l101', 'l112', 'l122', 'l129', 'l138', 'l146', 'l153', 'l159', 'l164', 'l168', 'l171', 'l173', 'l174']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "selectively", + "expressing", + "constitutively", + "active", + "IKK-b", + "in" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "selectively", + "expressing", + "constitutively", + "active", + "IKK-b", + "in", + "Hepatic", + "expression", + "of", + "the", + "IkappaBalpha", + "superrepressor", + "(LISR)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "selectively", + "expressing", + "constitutively", + "active", + "IKK-b", + "in" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver", + "mucscle" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hepatocytes." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "LIKK" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "LIKK" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "LIKK" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver", + "mucscle" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "salicylate", + "inhibition", + "of", + "IKK-beta." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15685172", + "TEXT": "Human embryonic stem cells (HESC) can potentially generate every body cell type, making them excellent candidates for cell- and tissue-replacement therapies. HESC are typically cultured with animal-derived 'serum replacements' on mouse feeder layers. Both of these are sources of the nonhuman sialic acid Neu5Gc, against which many humans have circulating antibodies. Both HESC and derived embryoid bodies metabolically incorporate substantial amounts of Neu5Gc under standard conditions. Exposure to human sera with antibodies specific for Neu5Gc resulted in binding of immunoglobulin and deposition of complement, which would lead to cell killing in vivo. Levels of Neu5Gc on HESC and embryoid bodies dropped after culture in heat-inactivated anti-Neu5Gc antibody-negative human serum, reducing binding of antibodies and complement from high-titer sera, while allowing maintenance of the undifferentiated state. Complete elimination of Neu5Gc would be likely to require using human serum with human feeder layers, ideally starting with fresh HESC that have never been exposed to animal products.", + "TAG_DATA": [ + "90, in {'context': 'B-in vivo'}", + "91, vivo. {'context': 'I-in vivo'}", + "96, HESC {'context': 'B-cells'}", + "98, embryoid {'context': 'B-cells'}", + "99, bodies {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "90, in ['l0']", + "91, vivo. ['l0']", + "96, HESC ['l1', 'l2']", + "98, embryoid ['l1', 'l3']", + "99, bodies ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15654326", + "TEXT": "Autoimmune diabetes mellitus in humans is characterized by immunological destruction of pancreatic beta islet cells. We investigated the circumstances under which CD8(+) T cells specific for pancreatic beta-islet antigens induce disease in mice expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) as a transgene under the control of the rat insulin promoter. In contrast to infection with LCMV, immunization with LCMV-GP derived peptide did not induce autoimmune diabetes despite large numbers of autoreactive cytotoxic T cells. Only subsequent treatment with Toll-like receptor ligands elicited overt autoimmune disease. This difference was critically regulated by the peripheral target organ itself, which upregulated class I major histocompatibility complex (MHC) in response to systemic Toll-like receptor-triggered interferon-alpha production. These data identify the 'inflammatory status' of the target organ as a separate and limiting factor determining the development of autoimmune disease.", + "TAG_DATA": [ + "32, mice {'context': 'B-organism'}", + "38, glycoprotein {'perturbing_action': 'I-gene gain-of-function'}", + "39, (GP) {'perturbing_action': 'I-gene gain-of-function'}", + "40, as {'perturbing_action': 'I-gene gain-of-function'}", + "41, a {'perturbing_action': 'I-gene gain-of-function'}", + "42, transgene {'perturbing_action': 'I-gene gain-of-function'}", + "43, under {'perturbing_action': 'I-gene gain-of-function'}", + "44, the {'perturbing_action': 'I-gene gain-of-function'}", + "45, control {'perturbing_action': 'I-gene gain-of-function'}", + "46, of {'perturbing_action': 'I-gene gain-of-function'}", + "47, the {'perturbing_action': 'I-gene gain-of-function'}", + "48, rat {'perturbing_action': 'I-gene gain-of-function'}", + "50, promoter. {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "32, mice ['l0', 'l1', 'l2']", + "35, choriomeningitis ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "36, virus ['l3', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "37, (LCMV) ['l0', 'l4', 'l18', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "38, glycoprotein ['l1', 'l5', 'l19', 'l32', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "39, (GP) ['l2', 'l6', 'l20', 'l33', 'l45', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "40, as ['l7', 'l21', 'l34', 'l46', 'l57', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "41, a ['l8', 'l22', 'l35', 'l47', 'l58', 'l68', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "42, transgene ['l9', 'l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "43, under ['l10', 'l24', 'l37', 'l49', 'l60', 'l70', 'l79', 'l87', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "44, the ['l11', 'l25', 'l38', 'l50', 'l61', 'l71', 'l80', 'l88', 'l95', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "45, control ['l12', 'l26', 'l39', 'l51', 'l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l108', 'l109', 'l110', 'l111', 'l112']", + "46, of ['l13', 'l27', 'l40', 'l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l108', 'l113', 'l114', 'l115', 'l116']", + "47, the ['l14', 'l28', 'l41', 'l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l109', 'l113', 'l117', 'l118', 'l119']", + "48, rat ['l15', 'l29', 'l42', 'l54', 'l65', 'l75', 'l84', 'l92', 'l99', 'l105', 'l110', 'l114', 'l117', 'l120', 'l121']", + "49, insulin ['l16', 'l30', 'l43', 'l55', 'l66', 'l76', 'l85', 'l93', 'l100', 'l106', 'l111', 'l115', 'l118', 'l120', 'l122']", + "50, promoter. ['l17', 'l31', 'l44', 'l56', 'l67', 'l77', 'l86', 'l94', 'l101', 'l107', 'l112', 'l116', 'l119', 'l121', 'l122']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "glycoprotein", + "(GP)" + ] + } + } + ] + }, + { + "PMID": "15619632", + "TEXT": "Respiratory syncytial virus (RSV) and parainfluenza virus (PIV) are two respiratory pathogens of paramount medical significance that exert high mortality. At present, there is no reliable vaccine or antiviral drug against either virus. Using an RNA interference (RNAi) approach, we show that individual as well as joint infection by RSV and PIV can be specifically prevented and inhibited by short interfering RNAs (siRNAs), instilled intranasally in the mouse, with or without transfection reagents. The degree of protection matched the antiviral activity of the siRNA in cell culture, allowing an avenue for quick screening of an efficacious siRNA. When targeting both viruses in a joint infection, excess of one siRNA moderated the inhibitory effect of the other, suggesting competition for the RNAi machinery. Our results suggest that, if properly designed, low dosages of inhaled siRNA might offer a fast, potent and easily administrable antiviral regimen against respiratory viral diseases in humans.", + "TAG_DATA": [ + "67, mouse, {'context': 'B-organism'}", + "85, cell {'context': 'B-cells'}", + "86, culture, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "67, mouse, ['l0', 'l1']", + "85, cell ['l0', 'l2']", + "86, culture, ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15619629", + "TEXT": "Molecular profiling of human biopsies and surgical specimens is frequently complicated by their inherent biological heterogeneity and by the need to conserve tissue for clinical diagnosis. We have developed a set of novel 'tissue print' and 'print-phoresis' technologies to facilitate tissue and tumor-marker profiling under these circumstances. Tissue printing transfers cells and extracellular matrix components from a tissue surface onto nitrocellulose membranes, generating a two-dimensional anatomical image on which molecular markers can be visualized by specific protein and RNA- and DNA-detection techniques. Print-phoresis is a complementary new electrophoresis method in which thin strips from the print are subjected to polyacrylamide gel electrophoresis, providing a straightforward interface between the tissue-print image and gel-based proteomic techniques. Here we have utilized these technologies to identify and characterize markers of tumor invasion of the prostate capsule, an event generally not apparent to the naked eye that may result in tumor at the surgical margins ('positive margins'). We have also shown that tissue-print technologies can provide a general platform for the generation of marker maps that can be superimposed directly onto histopathological and radiological images, permitting molecular identification and classification of individual malignant lesions.", + "TAG_DATA": [ + "131, capsule, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15577934", + "TEXT": "Fifty years ago, the age-old scourge of infectious disease was receding in the developed world in response to improved public health measures, while the advent of antibiotics, better vaccines, insecticides and improved surveillance held the promise of eradicating residual problems. By the late twentieth century, however, an increase in the emergence and re-emergence of infectious diseases was evident in many parts of the world. This upturn looms as the fourth major transition in human-microbe relationships since the advent of agriculture around 10,000 years ago. About 30 new diseases have been identified, including Legionnaires' disease, human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), hepatitis C, bovine spongiform encephalopathy (BSE)/variant Creutzfeldt-Jakob disease (vCJD), Nipah virus, several viral hemorrhagic fevers and, most recently, severe acute respiratory syndrome (SARS) and avian influenza. The emergence of these diseases, and resurgence of old ones like tuberculosis and cholera, reflects various changes in human ecology: rural-to-urban migration resulting in high-density peri-urban slums; increasing long-distance mobility and trade; the social disruption of war and conflict; changes in personal behavior; and, increasingly, human-induced global changes, including widespread forest clearance and climate change. Political ignorance, denial and obduracy (as with HIV/AIDS) further compound the risks. The use and misuse of medical technology also pose risks, such as drug-resistant microbes and contaminated equipment or biological medicines. A better understanding of the evolving social dynamics of emerging infectious diseases ought to help us to anticipate and hopefully ameliorate current and future risks.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15577931", + "TEXT": "Much progress has been made in recent years to strengthen local, state, national and international capacities to detect and respond to bioterrorism events and naturally occurring outbreaks of disease. New tools and systems are available to estimate the potential impact of a biological event and predict resource needs for effective response, enable earlier detection of an attack or outbreak, enhance diagnostic capacity and facilitate rapid intervention to mitigate the impact of an event on a community. These advances have required new approaches to preparedness, planning and surveillance, as well as new partnerships and collaborations across a range of disciplines. We examine some of these developments, discuss potential uses and limitations of these approaches, and identify priorities for the future.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15558057", + "TEXT": "Cholesterol gallstone disease is characterized by several events, including cholesterol precipitation in bile, increased bile salt hydrophobicity and gallbladder inflammation. Here, we describe the same phenotype in mice lacking the bile acid receptor, FXR. Furthermore, in susceptible wild-type mice that recapitulate human cholesterol gallstone disease, treatment with a synthetic FXR agonist prevented sequelae of the disease. These effects were mediated by FXR-dependent increases in biliary bile salt and phospholipid concentrations, which restored cholesterol solubility and thereby prevented gallstone formation. Taken together, these results indicate that FXR is a promising therapeutic target for treating or preventing cholesterol gallstone disease.", + "TAG_DATA": [ + "27, mice {'context': 'B-organism'}", + "28, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "29, the {'perturbing_action': 'I-gene loss-of-function'}", + "30, bile {'perturbing_action': 'I-gene loss-of-function'}", + "31, acid {'perturbing_action': 'I-gene loss-of-function'}", + "32, receptor, {'perturbing_action': 'I-gene loss-of-function'}", + "33, FXR. {'perturbing_action': 'I-gene loss-of-function'}", + "38, mice {'context': 'B-organism'}", + "48, synthetic {'perturbing_action': 'B-pharmacological augmentation'}", + "49, FXR {'perturbing_action': 'I-pharmacological augmentation'}", + "50, agonist {'perturbing_action': 'I-pharmacological augmentation'}" + ], + "LINK_DATA": [ + "27, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "28, lacking ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "29, the ['l1', 'l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "30, bile ['l2', 'l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "31, acid ['l3', 'l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "32, receptor, ['l4', 'l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "33, FXR. ['l5', 'l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "38, mice ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']", + "48, synthetic ['l27', 'l28']", + "49, FXR ['l27', 'l29']", + "50, agonist ['l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "bile", + "acid", + "receptor,", + "FXR." + ] + } + } + ] + }, + { + "PMID": "15558056", + "TEXT": "We have developed a multiplexed reverse phase protein (RPP) microarray platform for simultaneous monitoring of site-specific phosphorylation of numerous signaling proteins using nanogram amounts of lysates derived from stimulated living cells. We first show the application of RPP microarrays to the study of signaling kinetics and pathway delineation in Jurkat T lymphocytes. RPP microarrays were used to profile the phosphorylation state of 62 signaling components in Jurkat T cells stimulated through their membrane CD3 and CD28 receptors, identifying a previously unrecognized link between CD3 crosslinking and dephosphorylation of Raf-1 at Ser259. Finally, the potential of this technology to analyze rare primary cell populations is shown in a study of differential STAT protein phosphorylation in interleukin (IL)-2-stimulated CD4(+)CD25(+) regulatory T cells. RPP microarrays, prepared using simple procedures and standard microarray equipment, represent a powerful new tool for the study of signal transduction in both health and disease.", + "TAG_DATA": [ + "66, Jurkat {'context': 'B-cells'}", + "67, T {'context': 'I-cells'}", + "68, cells {'context': 'I-cells'}", + "116, CD4(+)CD25(+) {'context': 'B-cells'}", + "117, regulatory {'context': 'I-cells'}", + "118, T {'context': 'I-cells'}", + "119, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "66, Jurkat ['l0', 'l1']", + "67, T ['l0', 'l2']", + "68, cells ['l1', 'l2']", + "116, CD4(+)CD25(+) ['l3', 'l4', 'l5']", + "117, regulatory ['l3', 'l6', 'l7']", + "118, T ['l4', 'l6', 'l8']", + "119, cells. ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15558055", + "TEXT": "West Nile virus (WNV), a mosquito-borne single-stranded (ss)RNA flavivirus, causes human disease of variable severity. We investigated the involvement of Toll-like receptor (Tlr) 3, which recognizes viral double-stranded (ds)RNA, on WNV infection. Tlr3-deficient (Tlr3(-/-)) mice were more resistant to lethal WNV infection and had impaired cytokine production and enhanced viral load in the periphery, whereas in the brain, viral load, inflammatory responses and neuropathology were reduced compared to wild-type mice. Peripheral WNV infection led to a breakdown of the blood-brain barrier and enhanced brain infection in wild-type but not in Tlr3(-/-) mice, although both groups were equally susceptible upon intracerebroventricular administration of the virus. Tumor necrosis factor-alpha receptor 1 signaling is vital for blood-brain barrier compromise upon Tlr3 stimulation by dsRNA or WNV. Collectively, WNV infection leads to a Tlr3-dependent inflammatory response, which is involved in brain penetration of the virus and neuronal injury.", + "TAG_DATA": [ + "32, Tlr3-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "33, (Tlr3(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "34, mice {'context': 'B-organism'}", + "57, brain, {'context': 'B-tissue/organ'}", + "69, mice. {'context': 'B-organism'}", + "83, brain {'context': 'B-tissue/organ'}", + "90, Tlr3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "91, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "32, Tlr3-deficient ['l0', 'l1', 'l2', 'l3', 'l4']", + "33, (Tlr3(-/-)) ['l0', 'l5', 'l6', 'l7']", + "34, mice ['l1', 'l5', 'l8']", + "57, brain, ['l2', 'l6', 'l8']", + "69, mice. ['l3', 'l7']", + "83, brain ['l4', 'l9']", + "90, Tlr3(-/-) ['l10']", + "91, mice, ['l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tlr3-deficient", + "(Tlr3(-/-))", + "Tlr3(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tlr3-deficient", + "(Tlr3(-/-))" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain,", + "brain" + ] + } + } + ] + }, + { + "PMID": "15516917", + "TEXT": "Over the past decade, microbiology and infectious disease research have undergone the most profound revolution since the times of Pasteur. Genomic sequencing has revealed the much-awaited blueprint of most pathogens. Screening blood for the nucleic acids of infectious agents has blunted the spread of pathogens by transfusion, the field of antiviral therapeutics has exploded and technologies for the development of novel and safer vaccines have become available. The quantum jump in our ability to detect, prevent and treat infectious diseases resulting from improved technologies and genomics was moderated during this period by the greatest emergence of new infectious agents ever recorded and a worrisome increase in resistance to existing therapies. Dozens of new infectious diseases are expected to emerge in the coming decades. Controlling these diseases will require a better understanding of the worldwide threat and economic burden of infectious diseases and a global agenda.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15502845", + "TEXT": "Bioluminescence imaging has previously been used to monitor the formation of grafted tumors in vivo and measure cell number during tumor progression and response to therapy. The development and optimization of successful cancer therapy strategies may well require detailed and specific assessment of biological processes in response to mechanistic intervention. Here, we use bioluminescence imaging to monitor the cell cycle in a genetically engineered, histologically accurate model of glioma in vivo. In these platelet-derived growth factor (PDGF)-driven oligodendrogliomas, G1 cell-cycle arrest is generated by blockade of either the PDGF receptor or mTOR using small-molecule inhibitors.", + "TAG_DATA": [ + "66, model {'context': 'B-neoplasm'}", + "67, of {'context': 'B-neoplasm'}", + "68, glioma {'context': 'B-neoplasm'}", + "69, in {'context': 'B-in vivo'}", + "70, vivo. {'context': 'I-in vivo'}", + "77, oligodendrogliomas, {'context': 'B-neoplasm'}", + "78, G1 {'phenotype': 'B-cell cycle arrest'}", + "79, cell-cycle {'phenotype': 'I-cell cycle arrest'}", + "80, arrest {'phenotype': 'I-cell cycle arrest'}", + "84, blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "85, of {'perturbing_action': 'I-pharmacological inhibition'}", + "86, either {'perturbing_action': 'I-pharmacological inhibition'}", + "87, the {'perturbing_action': 'I-pharmacological inhibition'}", + "88, PDGF {'perturbing_action': 'I-pharmacological inhibition'}", + "89, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "90, or {'perturbing_action': 'I-pharmacological inhibition'}", + "91, mTOR {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "66, model ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "67, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "68, glioma ['l1', 'l7', 'l13', 'l14', 'l15']", + "69, in ['l2', 'l8', 'l13', 'l16', 'l17', 'l18', 'l19']", + "70, vivo. ['l3', 'l9', 'l14', 'l16', 'l20', 'l21', 'l22']", + "77, oligodendrogliomas, ['l4', 'l10', 'l15', 'l17', 'l20', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "78, G1 ['l23', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "79, cell-cycle ['l5', 'l11', 'l18', 'l21', 'l24', 'l34', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "80, arrest ['l6', 'l12', 'l19', 'l22', 'l25', 'l35', 'l44', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "84, blockade ['l26', 'l36', 'l45', 'l53', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "85, of ['l27', 'l37', 'l46', 'l54', 'l61', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "86, either ['l28', 'l38', 'l47', 'l55', 'l62', 'l68', 'l74', 'l75', 'l76', 'l77', 'l78']", + "87, the ['l29', 'l39', 'l48', 'l56', 'l63', 'l69', 'l74', 'l79', 'l80', 'l81', 'l82']", + "88, PDGF ['l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l75', 'l79', 'l83', 'l84', 'l85']", + "89, receptor ['l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l83', 'l86', 'l87']", + "90, or ['l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l86', 'l88']", + "91, mTOR ['l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l87', 'l88']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "model", + "of", + "oligodendrogliomas," + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest", + "G1" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "oligodendrogliomas," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "either", + "the", + "PDGF", + "receptor", + "or", + "mTOR" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G1", + "cell-cycle", + "arrest" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "either", + "the", + "PDGF", + "receptor", + "or", + "mTOR" + ] + } + } + ] + }, + { + "PMID": "15475962", + "TEXT": "Excessive salt intake is a major risk factor for hypertension. Here we identify the role of Na(+)/Ca(2+) exchanger type 1 (NCX1) in salt-sensitive hypertension using SEA0400, a specific inhibitor of Ca(2+) entry through NCX1, and genetically engineered mice. SEA0400 lowers arterial blood pressure in salt-dependent hypertensive rat models, but not in other types of hypertensive rats or in normotensive rats. Infusion of SEA0400 into the femoral artery in salt-dependent hypertensive rats increases arterial blood flow, indicating peripheral vasodilation. SEA0400 reverses ouabain-induced cytosolic Ca(2+) elevation and vasoconstriction in arteries. Furthermore, heterozygous NCX1-deficient mice have low salt sensitivity, whereas transgenic mice that specifically express NCX1.3 in smooth muscle are hypersensitive to salt. SEA0400 lowers the blood pressure in salt-dependent hypertensive mice expressing NCX1.3, but not in SEA0400-insensitive NCX1.3 mutants. These findings indicate that salt-sensitive hypertension is triggered by Ca(2+) entry through NCX1 in arterial smooth muscle and suggest that NCX1 inhibitors might be useful therapeutically.", + "TAG_DATA": [ + "44, salt-dependent {'context': 'B-organism'}", + "46, rat {'context': 'I-organism'}", + "47, models, {'context': 'I-organism'}", + "55, rats {'context': 'I-organism'}", + "58, normotensive {'context': 'B-organism'}", + "59, rats. {'context': 'I-organism'}", + "68, salt-dependent {'context': 'B-organism'}", + "69, hypertensive {'context': 'I-organism'}", + "70, rats {'context': 'I-organism'}", + "87, arteries. {'context': 'B-tissue/organ'}", + "89, heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "90, NCX1-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "91, mice {'context': 'B-organism'}", + "97, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "98, mice {'context': 'I-organism'}", + "116, salt-dependent {'context': 'B-organism'}", + "117, hypertensive {'context': 'I-organism'}", + "118, mice {'context': 'I-organism'}", + "119, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "120, NCX1.3, {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "44, salt-dependent ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "45, hypertensive ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "46, rat ['l1', 'l7', 'l14', 'l15', 'l16', 'l17', 'l18']", + "47, models, ['l2', 'l8', 'l14', 'l19', 'l20']", + "55, rats ['l3', 'l9', 'l15', 'l19', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "58, normotensive ['l21', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "59, rats. ['l4', 'l10', 'l16', 'l22', 'l27', 'l33', 'l34', 'l35', 'l36']", + "66, artery ['l5', 'l11', 'l17', 'l23', 'l28', 'l33', 'l37', 'l38', 'l39', 'l40']", + "68, salt-dependent ['l24', 'l29', 'l34', 'l37', 'l41', 'l42', 'l43']", + "69, hypertensive ['l12', 'l25', 'l30', 'l35', 'l38', 'l41', 'l44', 'l45']", + "70, rats ['l6', 'l13', 'l18', 'l20', 'l26', 'l31', 'l36', 'l39', 'l42', 'l44', 'l46']", + "87, arteries. ['l32', 'l40', 'l43', 'l45', 'l46']", + "89, heterozygous ['l47', 'l48', 'l49']", + "90, NCX1-deficient ['l47', 'l50']", + "91, mice ['l48', 'l50']", + "97, transgenic ['l51', 'l52', 'l53']", + "98, mice ['l49', 'l51']", + "116, salt-dependent ['l54', 'l55', 'l56', 'l57']", + "117, hypertensive ['l52', 'l54', 'l58', 'l59', 'l60']", + "118, mice ['l55', 'l58', 'l61', 'l62']", + "119, expressing ['l53', 'l56', 'l59', 'l61', 'l63']", + "120, NCX1.3, ['l57', 'l60', 'l62', 'l63']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "heterozygous", + "NCX1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "NCX1.3," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "hypertensive", + "salt-dependent" + ] + } + } + ] + }, + { + "PMID": "15467726", + "TEXT": "Autoimmune diseases are often mediated by self-reactive T cells, which must be activated to cause immunopathology. One mechanism, known as molecular mimicry, proposes that self-reactive T cells may be activated by pathogens expressing crossreactive ligands. Here we have developed a model to investigate how the affinity of the T-cell receptor (TCR) for the activating agent influences autoimmunity. Our model shows that an approximately fivefold difference in the TCR affinity for the activating ligand results in a 50% reduction in the incidence of autoimmunity. A reduction in TCR-ligand affinity to approximately 20 times lower than normal does not induce autoimmunity despite the unexpected induction of cytotoxic T lymphocytes (CTLs) and insulitis. Furthermore, in the absence of a key negative regulatory molecule, Cbl-b, 100% of mice develop autoimmunity upon infection with viruses encoding the lower-affinity ligand. Therefore, autoimmune disease is sensitive both to the affinity of the activating ligand and to normal mechanisms that negatively regulate the immune response.", + "TAG_DATA": [ + "113, absence {'perturbing_action': 'B-gene loss-of-function'}", + "123, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "113, absence ['l0']", + "123, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15378056", + "TEXT": "Mathematical models have recently been used to predict the future burden of multidrug-resistant tuberculosis (MDRTB). These models suggest the threat of multidrug resistance to TB control will depend on the relative 'fitness' of MDR strains and imply that if the average fitness of MDR strains is considerably less than that of drug-sensitive strains, the emergence of resistance will not jeopardize the success of tuberculosis control efforts. Multidrug resistance in M. tuberculosis is conferred by the sequential acquisition of a number of different single-locus mutations that have been shown to have heterogeneous phenotypic effects. Here we model the impact of initial fitness estimates on the emergence of MDRTB assuming that the relative fitness of MDR strains is heterogeneous. We find that even when the average relative fitness of MDR strains is low and a well-functioning control program is in place, a small subpopulation of a relatively fit MDR strain may eventually outcompete both the drug-sensitive strains and the less fit MDR strains. These results imply that current epidemiological measures and short-term trends in the burden of MDRTB do not provide evidence that MDRTB strains can be contained in the absence of specific efforts to limit transmission from those with MDR disease.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15378055", + "TEXT": "Exaggerated levels of VEGF (vascular endothelial growth factor) are present in persons with asthma, but the role(s) of VEGF in normal and asthmatic lungs has not been defined. We generated lung-targeted VEGF(165) transgenic mice and evaluated the role of VEGF in T-helper type 2 cell (T(H)2)-mediated inflammation. In these mice, VEGF induced, through IL-13-dependent and -independent pathways, an asthma-like phenotype with inflammation, parenchymal and vascular remodeling, edema, mucus metaplasia, myocyte hyperplasia and airway hyper-responsiveness. VEGF also enhanced respiratory antigen sensitization and T(H)2 inflammation and increased the number of activated DC2 dendritic cells. In antigen-induced inflammation, VEGF was produced by epithelial cells and preferentially by T(H)2 versus T(H)1 cells. In this setting, it had a critical role in T(H)2 inflammation, cytokine production and physiologic dysregulation. Thus, VEGF is a mediator of vascular and extravascular remodeling and inflammation that enhances antigen sensitization and is crucial in adaptive T(H)2 inflammation. VEGF regulation may be therapeutic in asthma and other T(H)2 disorders.", + "TAG_DATA": [ + "30, lung-targeted {'perturbing_action': 'B-gene gain-of-function'}", + "31, VEGF(165) {'perturbing_action': 'I-gene gain-of-function'}", + "32, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "33, mice {'context': 'B-organism'}", + "49, mice, {'context': 'B-organism'}", + "89, DC2 {'context': 'B-cells'}", + "90, dendritic {'context': 'I-cells'}", + "91, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "30, lung-targeted ['l0', 'l1', 'l2', 'l3']", + "31, VEGF(165) ['l0', 'l4', 'l5', 'l6']", + "32, transgenic ['l1', 'l4', 'l7', 'l8']", + "33, mice ['l2', 'l5', 'l7', 'l9']", + "49, mice, ['l3', 'l6', 'l8', 'l9']", + "89, DC2 ['l10', 'l11']", + "90, dendritic ['l10', 'l12']", + "91, cells. ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "lung-targeted", + "VEGF(165)", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + } + ] + }, + { + "PMID": "15378053", + "TEXT": "'Hot zones' are areas that have >5% prevalence (or incidence) of multidrug-resistant tuberculosis (MDRTB). We present a new mathematical model (the amplifier model) that tracks the emergence and evolution of multiple (pre-MDR, MDR and post-MDR) strains of drug-resistant Mycobacterium tuberculosis. We reconstruct possible evolutionary trajectories that generated hot zones over the past three decades, and identify the key causal factors. Results are consistent with recently reported World Health Organization (WHO) data. Our analyses yield three important insights. First, paradoxically we found that areas with programs that successfully reduced wild-type pansensitive strains often evolved into hot zones. Second, some hot zones emerged even when MDR strains were substantially less fit (and thus less transmissible) than wild-type pansensitive strains. Third, levels of MDR are driven by case-finding rates, cure rates and amplification probabilities. To effectively control MDRTB in the hot zones, it is essential that the WHO specify a goal for minimizing the amplification probability.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15361865", + "TEXT": "The blood anion nitrite contributes to hypoxic vasodilation through a heme-based, nitric oxide (NO)-generating reaction with deoxyhemoglobin and potentially other heme proteins. We hypothesized that this biochemical reaction could be harnessed for the treatment of neonatal pulmonary hypertension, an NO-deficient state characterized by pulmonary vasoconstriction, right-to-left shunt pathophysiology and systemic hypoxemia. To test this, we delivered inhaled sodium nitrite by aerosol to newborn lambs with hypoxic and normoxic pulmonary hypertension. Inhaled nitrite elicited a rapid and sustained reduction ( approximately 65%) in hypoxia-induced pulmonary hypertension, with a magnitude approaching that of the effects of 20 p.p.m. NO gas inhalation. This reduction was associated with the immediate appearance of NO in expiratory gas. Pulmonary vasodilation elicited by aerosolized nitrite was deoxyhemoglobin- and pH-dependent and was associated with increased blood levels of iron-nitrosyl-hemoglobin. Notably, from a therapeutic standpoint, short-term delivery of nitrite dissolved in saline through nebulization produced selective, sustained pulmonary vasodilation with no clinically significant increase in blood methemoglobin levels. These data support the concept that nitrite is a vasodilator acting through conversion to NO, a process coupled to hemoglobin deoxygenation and protonation, and evince a new, simple and inexpensive potential therapy for neonatal pulmonary hypertension.", + "TAG_DATA": [ + "62, newborn {'context': 'B-organism'}", + "63, lambs {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "62, newborn ['l0']", + "63, lambs ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15340404", + "TEXT": "Successful translation of modern molecular immunology into effective cancer immunotherapy is threatened by regulatory barriers and challenges to the development of novel agents and combinatorial strategies through effective public-private partnerships. For its promise to be fully realized, both the National Cancer Institute and Food and Drug Administration must take active steps to help academic investigators and companies jointly navigate the pathways from laboratory to clinic.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15334072", + "TEXT": "Metastasis is an impediment to the development of effective cancer therapies. Our understanding of metastasis is limited by our inability to follow this process in vivo. Fluorescence microscopy offers the potential to follow cells at high resolution in living animals. Semiconductor nanocrystals, quantum dots (QDs), offer considerable advantages over organic fluorophores for this purpose. We used QDs and emission spectrum scanning multiphoton microscopy to develop a means to study extravasation in vivo. Although QD labeling shows no deleterious effects on cultured cells, concern over their potential toxicity in vivo has caused resistance toward their application to such studies. To test if effects of QD labeling emerge in vivo, tumor cells labeled with QDs were intravenously injected into mice and followed as they extravasated into lung tissue. The behavior of QD-labeled tumor cells in vivo was indistinguishable from that of unlabeled cells. QDs and spectral imaging allowed the simultaneous identification of five different populations of cells using multiphoton laser excitation. Besides establishing the safety of QDs for in vivo studies, our approach permits the study of multicellular interactions in vivo.", + "TAG_DATA": [ + "106, in {'context': 'B-in vivo'}", + "107, vivo, {'context': 'I-in vivo'}", + "108, tumor {'context': 'B-transformed cells'}", + "109, cells {'context': 'I-transformed cells'}", + "117, mice {'context': 'B-organism'}", + "130, tumor {'context': 'B-transformed cells'}", + "131, cells {'context': 'I-transformed cells'}", + "132, in {'context': 'B-in vivo'}", + "133, vivo {'context': 'I-in vivo'}", + "140, cells. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "106, in ['l0', 'l1', 'l2', 'l3']", + "107, vivo, ['l0', 'l4', 'l5', 'l6']", + "108, tumor ['l1', 'l4', 'l7', 'l8']", + "109, cells ['l2', 'l5', 'l7', 'l9']", + "117, mice ['l3', 'l6', 'l8', 'l9']", + "130, tumor ['l10', 'l11', 'l12', 'l13']", + "131, cells ['l10', 'l14', 'l15', 'l16']", + "132, in ['l11', 'l14', 'l17', 'l18']", + "133, vivo ['l12', 'l15', 'l17', 'l19']", + "140, cells. ['l13', 'l16', 'l18', 'l19']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15322538", + "TEXT": "Several non-hypercalcemic analogs of 1alpha,25-dihydroxyvitamin D3 (1,25(OH)(2)D(3)) show antitumor activity in a subset of cancer patients. High vitamin D receptor (VDR) expression, which is associated with good prognosis but is lost during tumor progression. We show that the SNAIL transcription factor represses VDR gene expression in human colon cancer cells and blocks the antitumor action of EB1089, a 1,25(OH)(2)D(3) analog, in xenografted mice. In human colon cancers, elevated SNAIL expression correlates with downregulation of VDR.", + "TAG_DATA": [ + "46, human {'context': 'B-transformed cells'}", + "47, colon {'context': 'I-transformed cells'}", + "48, cancer {'context': 'I-transformed cells'}", + "49, cells {'context': 'I-transformed cells'}", + "61, xenografted {'context': 'B-xenograft'}", + "62, mice. {'context': 'I-xenograft'}", + "64, human {'context': 'B-neoplasm'}", + "65, colon {'context': 'I-neoplasm'}", + "66, cancers, {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "46, human ['l0', 'l1', 'l2']", + "47, colon ['l0', 'l3', 'l4']", + "48, cancer ['l1', 'l3', 'l5']", + "49, cells ['l2', 'l4', 'l5']", + "61, xenografted ['l6']", + "62, mice. ['l6']", + "64, human ['l7', 'l8']", + "65, colon ['l7', 'l9']", + "66, cancers, ['l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15286785", + "TEXT": "Graft-versus-host disease (GVHD) is a major source of morbidity in allogenic stem cell transplantation. We previously showed that recipient antigen-presenting cells (APCs) are required for CD8-dependent GVHD in a mouse model across only minor histocompatibility antigens (minor H antigens). However, these studies did not address the function of donor-derived APCs after GVHD is initiated. Here we show that GVHD develops in recipients of donor major histocompatibility complex class I-deficient (MHC I(-)) bone marrow. Thus, after initial priming, CD8 cells caused GVHD without a further requirement for hematopoietic APCs, indicating that host APCs are necessary and sufficient for GHVD. Nonetheless, GVHD was less severe in recipients of MHC I(-) bone marrow. Therefore, once initiated, GVHD is intensified by donor-derived cells, most probably donor APCs cross-priming alloreactive CD8 cells. Nevertheless, donor APCs were not required for CD8-mediated graft-versus-leukemia (GVL) against a mouse model of chronic-phase chronic myelogenous leukemia. These studies identify donor APCs as a new target for treating GVHD, which may preserve GVL.", + "TAG_DATA": [ + "63, donor {'perturbing_action': 'B-gene loss-of-function'}", + "64, major {'perturbing_action': 'I-gene loss-of-function'}", + "65, histocompatibility {'perturbing_action': 'I-gene loss-of-function'}", + "66, complex {'perturbing_action': 'I-gene loss-of-function'}", + "67, class {'perturbing_action': 'I-gene loss-of-function'}", + "68, I-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "69, (MHC {'perturbing_action': 'I-gene loss-of-function'}", + "70, I(-)) {'perturbing_action': 'I-gene loss-of-function'}", + "71, bone {'perturbing_action': 'I-gene loss-of-function'}", + "72, marrow. {'perturbing_action': 'I-gene loss-of-function'}", + "77, CD8 {'context': 'B-cells'}", + "78, cells {'context': 'I-cells'}", + "106, MHC {'perturbing_action': 'B-gene loss-of-function'}", + "107, I(-) {'perturbing_action': 'B-gene loss-of-function'}", + "108, bone {'perturbing_action': 'I-gene loss-of-function'}", + "139, mouse {'context': 'B-organism'}", + "140, model {'context': 'I-neoplasm'}", + "141, of {'context': 'I-neoplasm'}", + "142, chronic-phase {'context': 'I-neoplasm'}", + "143, chronic {'context': 'I-neoplasm'}", + "144, myelogenous {'context': 'I-neoplasm'}", + "145, leukemia. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "63, donor ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "64, major ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "65, histocompatibility ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "66, complex ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "67, class ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "68, I-deficient ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "69, (MHC ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "70, I(-)) ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "71, bone ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "72, marrow. ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63']", + "77, CD8 ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l64']", + "78, cells ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l63', 'l64']", + "106, MHC ['l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "107, I(-) ['l65', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "108, bone ['l66', 'l75', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "109, marrow. ['l67', 'l76', 'l83']", + "139, mouse ['l68', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "140, model ['l69', 'l77', 'l84', 'l90', 'l96', 'l97', 'l98', 'l99', 'l100']", + "141, of ['l70', 'l78', 'l85', 'l91', 'l96', 'l101', 'l102', 'l103', 'l104']", + "142, chronic-phase ['l71', 'l79', 'l86', 'l92', 'l97', 'l101', 'l105', 'l106', 'l107']", + "143, chronic ['l72', 'l80', 'l87', 'l93', 'l98', 'l102', 'l105', 'l108', 'l109']", + "144, myelogenous ['l73', 'l81', 'l88', 'l94', 'l99', 'l103', 'l106', 'l108', 'l110']", + "145, leukemia. ['l74', 'l82', 'l89', 'l95', 'l100', 'l104', 'l107', 'l109', 'l110']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "donor", + "major", + "histocompatibility", + "complex", + "class", + "I-deficient", + "(MHC", + "I(-))", + "bone", + "marrow." + ] + }, + "context": { + "val": "cells", + "words": [ + "CD8", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MHC" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MHC", + "I(-)", + "bone" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "model", + "of", + "chronic-phase", + "chronic", + "myelogenous", + "leukemia." + ] + } + } + ] + }, + { + "PMID": "15286768", + "TEXT": "Research groups worldwide are trying to make immunogens intended to elicit neutralizing antibody responses as part of a prophylactic vaccine to counter the spread of HIV-1. The relative merits of different designs can only be gauged properly through comparative studies, and particularly by evaluating human or animal antisera under identical, or comparable, conditions. Hence there is a need for assay standardization and for the creation of a centralized testing facility that could distribute consensus protocols and reagents.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15273746", + "TEXT": "Noonan syndrome is a common human autosomal dominant birth defect, characterized by short stature, facial abnormalities, heart defects and possibly increased risk of leukemia. Mutations of Ptpn11 (also known as Shp2), which encodes the protein-tyrosine phosphatase Shp2, occur in approximately 50% of individuals with Noonan syndrome, but their molecular, cellular and developmental effects, and the relationship between Noonan syndrome and leukemia, are unclear. We generated mice expressing the Noonan syndrome-associated mutant D61G. When homozygous, the D61G mutant is embryonic lethal, whereas heterozygotes have decreased viability. Surviving Ptpn11(D61G/+) embryos ( approximately 50%) have short stature, craniofacial abnormalities similar to those in Noonan syndrome, and myeloproliferative disease. Severely affected Ptpn11(D61G/+) embryos ( approximately 50%) have multiple cardiac defects similar to those in mice lacking the Ras-GAP protein neurofibromin. Their endocardial cushions have increased Erk activation, but Erk hyperactivation is cell and pathway specific. Our results clarify the relationship between Noonan syndrome and leukemia and show that a single Ptpn11 gain-of-function mutation evokes all major features of Noonan syndrome by acting on multiple developmental lineages in a gene dosage-dependent and pathway-selective manner.", + "TAG_DATA": [ + "65, mice {'context': 'B-organism'}", + "68, Noonan {'perturbing_action': 'I-other'}", + "69, syndrome-associated {'perturbing_action': 'I-other'}", + "70, mutant {'perturbing_action': 'I-other'}", + "71, D61G. {'perturbing_action': 'I-other'}", + "75, D61G {'perturbing_action': 'I-other'}", + "76, mutant {'perturbing_action': 'I-other'}", + "86, Ptpn11(D61G/+) {'perturbing_action': 'B-other'}", + "87, embryos {'context': 'I-organism'}", + "107, Ptpn11(D61G/+) {'perturbing_action': 'B-other'}", + "108, embryos {'context': 'I-organism'}", + "120, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "65, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "68, Noonan ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "69, syndrome-associated ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "70, mutant ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "71, D61G. ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "75, D61G ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "76, mutant ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "86, Ptpn11(D61G/+) ['l21', 'l22']", + "87, embryos ['l21']", + "107, Ptpn11(D61G/+) ['l23', 'l24']", + "108, embryos ['l23', 'l25']", + "120, mice ['l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "embryos" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Noonan", + "syndrome-associated", + "mutant", + "D61G.", + "D61G", + "Ptpn11(D61G/+)" + ] + } + } + ] + }, + { + "PMID": "15258577", + "TEXT": "Secondary injury exacerbates the extent of spinal cord insults, yet the mechanistic basis of this phenomenon has largely been unexplored. Here we report that broad regions of the peritraumatic zone are characterized by a sustained process of pathologic, high ATP release. Spinal cord neurons expressed P2X7 purine receptors (P2X7R), and exposure to ATP led to high-frequency spiking, irreversible increases in cytosolic calcium and cell death. To assess the potential effect of P2X7R blockade in ameliorating acute spinal cord injury (SCI), we delivered P2X7R antagonists OxATP or PPADS to rats after acute impact injury. We found that both OxATP and PPADS significantly improved functional recovery and diminished cell death in the peritraumatic zone. These observations demonstrate that SCI is associated with prolonged purinergic receptor activation, which results in excitotoxicity-based neuronal degeneration. P2X7R antagonists inhibit this process, reducing both the histological extent and functional sequelae of acute SCI.", + "TAG_DATA": [ + "63, cell {'phenotype': 'B-cell death'}", + "64, death. {'phenotype': 'I-cell death'}", + "82, P2X7R {'perturbing_action': 'B-pharmacological inhibition'}", + "83, antagonists {'perturbing_action': 'I-pharmacological inhibition'}", + "84, OxATP {'perturbing_action': 'I-pharmacological inhibition'}", + "86, PPADS {'perturbing_action': 'I-pharmacological inhibition'}", + "88, rats {'context': 'B-organism'}", + "105, diminished {'effect': 'B-negative'}", + "106, cell {'phenotype': 'B-cell death'}", + "107, death {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "63, cell ['l0']", + "64, death. ['l0']", + "82, P2X7R ['l1', 'l2', 'l3', 'l4']", + "83, antagonists ['l1', 'l5', 'l6', 'l7']", + "84, OxATP ['l2', 'l5', 'l8', 'l9']", + "86, PPADS ['l3', 'l6', 'l8', 'l10']", + "88, rats ['l4', 'l7', 'l9', 'l10']", + "105, diminished ['l11', 'l12']", + "106, cell ['l11', 'l13']", + "107, death ['l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "P2X7R", + "antagonists", + "OxATP", + "PPADS" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "diminished" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + } + ] + }, + { + "PMID": "15247913", + "TEXT": "Passive serotherapy can confer immediate protection against microbial infection, but methods to rapidly generate human neutralizing monoclonal antibodies are not yet available. We have developed an improved method for Epstein-Barr virus transformation of human B cells. We used this method to analyze the memory repertoire of a patient who recovered from severe acute respiratory syndrome coronavirus (SARS-CoV) infection and to isolate monoclonal antibodies specific for different viral proteins, including 35 antibodies with in vitro neutralizing activity ranging from 10(-8)M to 10(-11)M. One such antibody confers protection in vivo in a mouse model of SARS-CoV infection. These results show that it is possible to interrogate the memory repertoire of immune donors to rapidly and efficiently isolate neutralizing antibodies that have been selected in the course of natural infection.", + "TAG_DATA": [ + "86, in {'context': 'B-in vivo'}", + "87, vivo {'context': 'I-in vivo'}", + "90, mouse {'context': 'B-organism'}", + "91, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "86, in ['l0', 'l1', 'l2']", + "87, vivo ['l0', 'l3', 'l4']", + "90, mouse ['l1', 'l3', 'l5']", + "91, model ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15235599", + "TEXT": "There are no studies so far linking molecular regulation of lymphangiogenesis and induction of adaptive immunity. Here, we show that blockade of vascular endothelial growth factor receptor-3 (VEGFR-3) signaling significantly suppresses corneal antigen-presenting (dendritic) cell trafficking to draining lymph nodes, induction of delayed-type hypersensitivity and rejection of corneal transplants. Regulating the function of VEGFR-3 may therefore be a mechanism for modulating adaptive immunity in the periphery.", + "TAG_DATA": [ + "20, blockade {'perturbing_action': 'B-gene loss-of-function'}", + "21, of {'perturbing_action': 'I-gene loss-of-function'}", + "22, vascular {'perturbing_action': 'I-gene loss-of-function'}", + "23, endothelial {'perturbing_action': 'I-gene loss-of-function'}", + "24, growth {'perturbing_action': 'I-gene loss-of-function'}", + "25, factor {'perturbing_action': 'I-gene loss-of-function'}", + "26, receptor-3 {'perturbing_action': 'I-gene loss-of-function'}", + "27, (VEGFR-3) {'perturbing_action': 'I-gene loss-of-function'}", + "28, signaling {'perturbing_action': 'I-gene loss-of-function'}", + "31, corneal {'context': 'B-cells'}", + "32, antigen-presenting {'context': 'B-cells'}", + "33, (dendritic) {'context': 'I-cells'}", + "34, cell {'context': 'I-cells'}", + "37, draining {'context': 'B-cells'}", + "38, lymph {'context': 'I-cells'}", + "39, nodes, {'context': 'I-cells'}", + "47, corneal {'context': 'B-xenograft'}" + ], + "LINK_DATA": [ + "20, blockade ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "21, of ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "22, vascular ['l1', 'l17', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "23, endothelial ['l2', 'l18', 'l33', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "24, growth ['l3', 'l19', 'l34', 'l48', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "25, factor ['l4', 'l20', 'l35', 'l49', 'l62', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "26, receptor-3 ['l5', 'l21', 'l36', 'l50', 'l63', 'l75', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "27, (VEGFR-3) ['l6', 'l22', 'l37', 'l51', 'l64', 'l76', 'l87', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "28, signaling ['l7', 'l23', 'l38', 'l52', 'l65', 'l77', 'l88', 'l98', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "31, corneal ['l8', 'l24', 'l39', 'l53', 'l66', 'l78', 'l89', 'l99', 'l108', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "32, antigen-presenting ['l9', 'l25', 'l40', 'l54', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "33, (dendritic) ['l10', 'l26', 'l41', 'l55', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l123', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "34, cell ['l11', 'l27', 'l42', 'l56', 'l69', 'l81', 'l92', 'l102', 'l111', 'l119', 'l124', 'l129', 'l135', 'l136', 'l137']", + "37, draining ['l12', 'l28', 'l43', 'l57', 'l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l125', 'l130', 'l135', 'l138', 'l139']", + "38, lymph ['l13', 'l29', 'l44', 'l58', 'l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l126', 'l131', 'l136', 'l138', 'l140']", + "39, nodes, ['l14', 'l30', 'l45', 'l59', 'l72', 'l84', 'l95', 'l105', 'l114', 'l122', 'l127', 'l132', 'l137', 'l139', 'l140']", + "47, corneal ['l15', 'l31', 'l46', 'l60', 'l73', 'l85', 'l96', 'l106', 'l115', 'l133', 'l141']", + "48, transplants. ['l16', 'l32', 'l47', 'l61', 'l74', 'l86', 'l97', 'l107', 'l116', 'l128', 'l134', 'l141']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "blockade", + "of", + "vascular", + "endothelial", + "growth", + "factor", + "receptor-3", + "(VEGFR-3)", + "signaling" + ] + }, + "context": { + "val": "cells", + "words": [ + "corneal", + "antigen-presenting", + "(dendritic)", + "cell", + "draining", + "lymph", + "nodes," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "blockade", + "of", + "vascular", + "endothelial", + "growth", + "factor", + "receptor-3", + "(VEGFR-3)", + "signaling" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "corneal" + ] + } + } + ] + }, + { + "PMID": "15235597", + "TEXT": "The trafficking of circulating stem and progenitor cells to areas of tissue damage is poorly understood. The chemokine stromal cell-derived factor-1 (SDF-1 or CXCL12) mediates homing of stem cells to bone marrow by binding to CXCR4 on circulating cells. SDF-1 and CXCR4 are expressed in complementary patterns during embryonic organogenesis and guide primordial stem cells to sites of rapid vascular expansion. However, the regulation of SDF-1 and its physiological role in peripheral tissue repair remain incompletely understood. Here we show that SDF-1 gene expression is regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1) in endothelial cells, resulting in selective in vivo expression of SDF-1 in ischemic tissue in direct proportion to reduced oxygen tension. HIF-1-induced SDF-1 expression increases the adhesion, migration and homing of circulating CXCR4-positive progenitor cells to ischemic tissue. Blockade of SDF-1 in ischemic tissue or CXCR4 on circulating cells prevents progenitor cell recruitment to sites of injury. Discrete regions of hypoxia in the bone marrow compartment also show increased SDF-1 expression and progenitor cell tropism. These data show that the recruitment of CXCR4-positive progenitor cells to regenerating tissues is mediated by hypoxic gradients via HIF-1-induced expression of SDF-1.", + "TAG_DATA": [ + "99, in {'context': 'B-in vivo'}", + "100, vivo {'context': 'I-in vivo'}", + "117, increases {'effect': 'B-positive'}", + "119, adhesion, {'phenotype': 'B-adhesion'}", + "120, migration {'phenotype': 'B-migration'}", + "124, circulating {'context': 'B-cells'}", + "125, CXCR4-positive {'context': 'I-cells'}", + "126, progenitor {'context': 'I-cells'}", + "127, cells {'context': 'I-cells'}", + "131, Blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "132, of {'perturbing_action': 'I-pharmacological inhibition'}", + "133, SDF-1 {'perturbing_action': 'I-pharmacological inhibition'}", + "140, circulating {'context': 'B-cells'}", + "141, cells {'context': 'I-cells'}", + "143, progenitor {'context': 'B-cells'}", + "144, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "99, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "100, vivo ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "117, increases ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "119, adhesion, ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "120, migration ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "124, circulating ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "125, CXCR4-positive ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "126, progenitor ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "127, cells ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "131, Blockade ['l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "132, of ['l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "133, SDF-1 ['l37', 'l42', 'l47', 'l48', 'l49', 'l50']", + "140, circulating ['l38', 'l43', 'l47', 'l51', 'l52', 'l53']", + "141, cells ['l39', 'l44', 'l48', 'l51', 'l54', 'l55']", + "143, progenitor ['l40', 'l45', 'l49', 'l52', 'l54', 'l56']", + "144, cell ['l41', 'l46', 'l50', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increases" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "context": { + "val": "cells", + "words": [ + "circulating", + "CXCR4-positive", + "progenitor", + "cells" + ] + } + }, + { + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + }, + "context": { + "val": "cells", + "words": [ + "circulating", + "CXCR4-positive", + "progenitor", + "cells" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "cells", + "words": [ + "circulating", + "CXCR4-positive", + "progenitor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "SDF-1" + ] + }, + "context": { + "val": "cells", + "words": [ + "circulating", + "cells", + "progenitor", + "cell" + ] + } + } + ] + }, + { + "PMID": "15208706", + "TEXT": "Niemann-Pick type C (NP-C) disease is a fatal, autosomal recessive, childhood neurodegenerative disease. The NP-C mouse recapitulates the cholesterol and sphingolipid storage, onset of neurological deficits, histopathological lesions, Purkinje cell loss and early death typical of the most severe form of human NP-C. Neurosteroids, steroids made in the brain, affect neuronal growth and differentiation, and modulate neurotransmitter receptors. Disordered cholesterol trafficking might disrupt neurosteroidogenesis, thereby contributing to the NP-C phenotype. Here we show that NP-C mouse brain contains substantially less neurosteroid than wild-type brain and has an age-related decrease in the ability to synthesize 5alpha-dihydroprogesterone and allopregnanolone. Immunohistochemical assessment confirms a decrease in expression of 5alpha-reductase and 3alpha-hydroxysteroid dehydrogenase, especially in cerebellum. Neonatal administration of allopregnanolone delays the onset of neurological symptoms, increases Purkinje and granule cell survival, reduces cortical GM2 and GM3 ganglioside accumulation and doubles the lifespan of NP-C mice. Earlier administration increases effectiveness of treatment. Decreased production of allopregnanolone apparently contributes to the pathology of NP-C; thus, neurosteroid treatment may be useful in ameliorating progression of the disease.", + "TAG_DATA": [ + "75, mouse {'context': 'I-tissue/organ'}", + "123, Purkinje {'context': 'B-cells'}", + "124, and {'context': 'I-cells'}", + "125, granule {'context': 'I-cells'}", + "126, cell {'context': 'I-cells'}", + "127, survival, {'phenotype': 'B-cell survival'}", + "140, NP-C {'context': 'B-organism'}", + "141, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "123, Purkinje ['l0', 'l1', 'l2', 'l3']", + "124, and ['l0', 'l4', 'l5', 'l6']", + "125, granule ['l1', 'l4', 'l7', 'l8']", + "126, cell ['l2', 'l5', 'l7', 'l9']", + "127, survival, ['l3', 'l6', 'l8', 'l9']", + "140, NP-C ['l10']", + "141, mice. ['l10']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Purkinje", + "and", + "granule", + "cell" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "survival," + ] + } + } + ] + }, + { + "PMID": "15195085", + "TEXT": "We have previously shown that apolipoprotein E (Apoe) promotes the formation of amyloid in brain and that astrocyte-specific expression of APOE markedly affects the deposition of amyloid-beta peptides (Abeta) in a mouse model of Alzheimer disease. Given the capacity of astrocytes to degrade Abeta, we investigated the potential role of Apoe in this astrocyte-mediated degradation. In contrast to cultured adult wild-type mouse astrocytes, adult Apoe(-/-) astrocytes do not degrade Abeta present in Abeta plaque-bearing brain sections in vitro. Coincubation with antibodies to either Apoe or Abeta, or with RAP, an antagonist of the low-density lipoprotein receptor family, effectively blocks Abeta degradation by astrocytes. Phase-contrast and confocal microscopy show that Apoe(-/-) astrocytes do not respond to or internalize Abeta deposits to the same extent as do wild-type astrocytes. Thus, Apoe seems to be important in the degradation and clearance of deposited Abeta species by astrocytes, a process that may be impaired in Alzheimer disease.", + "TAG_DATA": [ + "59, adult {'context': 'B-cells'}", + "60, wild-type {'context': 'I-cells'}", + "61, mouse {'context': 'I-cells'}", + "62, astrocytes, {'context': 'I-cells'}", + "63, adult {'context': 'B-cells'}", + "64, Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "65, astrocytes {'context': 'B-cells'}", + "76, in {'context': 'B-in vitro'}", + "77, vitro. {'context': 'I-in vitro'}", + "102, astrocytes. {'context': 'B-cells'}", + "109, Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "110, astrocytes {'context': 'B-cells'}", + "126, astrocytes. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "59, adult ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "60, wild-type ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "61, mouse ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "62, astrocytes, ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "63, adult ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "64, Apoe(-/-) ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "65, astrocytes ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "76, in ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "77, vitro. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "109, Apoe(-/-) ['l36', 'l37']", + "110, astrocytes ['l36', 'l38']", + "126, astrocytes. ['l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "adult", + "wild-type", + "mouse", + "astrocytes,", + "astrocytes", + "astrocytes." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apoe(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apoe(-/-)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "15156201", + "TEXT": "Loss of PTEN function leads to activation of phosphoinositide 3-kinase (PI3K) signaling and Akt. Clinical trials are now testing whether mammalian target of rapamycin (mTOR) inhibition is useful in treating PTEN-null cancers. Here, we report that mTOR inhibition induced apoptosis of epithelial cells and the complete reversal of a neoplastic phenotype in the prostate of mice expressing human AKT1 in the ventral prostate. Induction of cell death required the mitochondrial pathway, as prostate-specific coexpression of BCL2 blocked apoptosis. Thus, there is an mTOR-dependent survival signal required downstream of Akt. Bcl2 expression, however, only partially restored intraluminal cell growth in the setting of mTOR inhibition. Expression profiling showed that Hif-1 alpha targets, including genes encoding most glycolytic enzymes, constituted the dominant transcriptional response to AKT activation and mTOR inhibition. These data suggest that the expansion of AKT-driven prostate epithelial cells requires mTOR-dependent survival signaling and activation of HIF-1 alpha, and that clinical resistance to mTOR inhibitors may emerge through BCL2 expression and/or upregulation of HIF-1 alpha activity.", + "TAG_DATA": [ + "36, mTOR {'perturbing_action': 'B-pharmacological inhibition'}", + "37, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "38, induced {'effect': 'B-positive'}", + "39, apoptosis {'phenotype': 'B-apoptosis'}", + "41, epithelial {'context': 'B-cells'}", + "42, cells {'context': 'I-cells'}", + "49, neoplastic {'phenotype': 'B-tumourigenesis'}", + "50, phenotype {'phenotype': 'I-senescence'}", + "53, prostate {'context': 'B-tissue/organ'}", + "55, mice {'context': 'B-organism'}", + "56, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "57, human {'perturbing_action': 'I-gene gain-of-function'}", + "58, AKT1 {'perturbing_action': 'I-gene gain-of-function'}", + "59, in {'perturbing_action': 'I-gene gain-of-function'}", + "60, the {'perturbing_action': 'I-gene gain-of-function'}", + "61, ventral {'perturbing_action': 'I-gene gain-of-function'}", + "62, prostate. {'perturbing_action': 'I-gene gain-of-function'}", + "63, Induction {'effect': 'B-positive'}", + "65, cell {'phenotype': 'B-cell death'}", + "66, death {'phenotype': 'I-cell death'}", + "72, prostate-specific {'perturbing_action': 'B-gene gain-of-function'}", + "73, coexpression {'perturbing_action': 'I-gene gain-of-function'}", + "74, of {'perturbing_action': 'I-gene gain-of-function'}", + "75, BCL2 {'perturbing_action': 'I-gene gain-of-function'}", + "76, blocked {'effect': 'B-negative'}", + "77, apoptosis. {'phenotype': 'B-apoptosis'}", + "93, partially {'effect': 'B-rescues'}", + "94, restored {'effect': 'I-rescues'}", + "96, cell {'phenotype': 'B-cell growth'}", + "97, growth {'phenotype': 'I-cell growth'}", + "102, mTOR {'perturbing_action': 'B-pharmacological inhibition'}", + "103, inhibition. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "36, mTOR ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "37, inhibition ['l0', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "38, induced ['l1', 'l19', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "39, apoptosis ['l2', 'l20', 'l37', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "41, epithelial ['l3', 'l21', 'l38', 'l43', 'l49', 'l50', 'l51', 'l52']", + "42, cells ['l4', 'l22', 'l39', 'l44', 'l49', 'l53', 'l54']", + "49, neoplastic ['l5', 'l23', 'l40', 'l45', 'l50', 'l53', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "50, phenotype ['l6', 'l24', 'l41', 'l46', 'l51', 'l54', 'l55', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "53, prostate ['l7', 'l25', 'l42', 'l47', 'l52', 'l56', 'l65', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "55, mice ['l8', 'l26', 'l66', 'l75', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "56, expressing ['l9', 'l27', 'l57', 'l67', 'l76', 'l86', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "57, human ['l10', 'l28', 'l77', 'l87', 'l96', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "58, AKT1 ['l11', 'l29', 'l58', 'l68', 'l78', 'l88', 'l97', 'l106', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "59, in ['l12', 'l30', 'l59', 'l69', 'l79', 'l89', 'l98', 'l107', 'l118', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "60, the ['l13', 'l31', 'l48', 'l60', 'l70', 'l80', 'l90', 'l99', 'l108', 'l119', 'l126', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "61, ventral ['l14', 'l32', 'l61', 'l71', 'l81', 'l91', 'l100', 'l109', 'l120', 'l127', 'l133', 'l139', 'l140', 'l141', 'l142']", + "62, prostate. ['l15', 'l33', 'l62', 'l72', 'l82', 'l92', 'l101', 'l110', 'l121', 'l128', 'l134', 'l139', 'l143', 'l144', 'l145']", + "63, Induction ['l16', 'l34', 'l83', 'l93', 'l102', 'l111', 'l122', 'l129', 'l135', 'l140', 'l143', 'l146', 'l147', 'l148']", + "65, cell ['l17', 'l35', 'l63', 'l73', 'l84', 'l94', 'l103', 'l112', 'l123', 'l130', 'l136', 'l141', 'l144', 'l146', 'l149']", + "66, death ['l18', 'l36', 'l64', 'l74', 'l85', 'l95', 'l104', 'l113', 'l124', 'l131', 'l137', 'l142', 'l145', 'l147', 'l149']", + "72, prostate-specific ['l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158']", + "73, coexpression ['l150', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166']", + "74, of ['l114', 'l151', 'l159', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "75, BCL2 ['l115', 'l152', 'l160', 'l167', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179']", + "76, blocked ['l105', 'l116', 'l125', 'l132', 'l138', 'l148', 'l153', 'l161', 'l168', 'l174', 'l180', 'l181', 'l182']", + "77, apoptosis. ['l117', 'l154', 'l162', 'l169', 'l175', 'l180', 'l183', 'l184', 'l185']", + "93, partially ['l155', 'l163', 'l170', 'l176', 'l186', 'l187', 'l188', 'l189', 'l190']", + "94, restored ['l156', 'l164', 'l171', 'l177', 'l183', 'l186', 'l191', 'l192', 'l193', 'l194']", + "96, cell ['l157', 'l165', 'l172', 'l178', 'l181', 'l184', 'l187', 'l191', 'l195', 'l196', 'l197']", + "97, growth ['l158', 'l166', 'l173', 'l179', 'l182', 'l185', 'l188', 'l192', 'l195', 'l198', 'l199']", + "102, mTOR ['l189', 'l193', 'l196', 'l198', 'l200']", + "103, inhibition. ['l190', 'l194', 'l197', 'l199', 'l200']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibition" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "Induction" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibition" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "epithelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibition" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplastic" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibition" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "phenotype" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibition" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "prostate" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibition" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "epithelial", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplastic" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "phenotype" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "Induction" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "prostate" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "epithelial", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "prostate" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "the", + "human", + "prostate-specific", + "coexpression", + "of", + "BCL2" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "epithelial", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplastic" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "epithelial", + "cells" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "phenotype" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplastic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "prostate" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplastic" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "AKT1", + "in", + "the", + "ventral", + "prostate." + ] + } + }, + { + "phenotype": { + "val": "senescence", + "words": [ + "phenotype" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "prostate" + ] + } + }, + { + "phenotype": { + "val": "senescence", + "words": [ + "phenotype" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "senescence", + "words": [ + "phenotype" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "AKT1", + "in", + "the", + "ventral", + "prostate." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "prostate" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "human", + "AKT1", + "in", + "the", + "ventral", + "prostate." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "prostate" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "human", + "AKT1", + "in", + "the", + "ventral", + "prostate." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "Induction" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "human", + "AKT1", + "in", + "the", + "ventral", + "prostate." + ] + }, + "effect": { + "val": "positive", + "words": [ + "Induction" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "human", + "AKT1", + "in", + "the", + "ventral", + "prostate." + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "human", + "AKT1", + "in", + "the", + "prostate-specific", + "coexpression", + "of", + "BCL2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Induction" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "prostate-specific", + "coexpression", + "of", + "BCL2" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "partially", + "restored" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "prostate-specific", + "coexpression", + "of", + "BCL2" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "partially", + "restored" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "partially", + "restored" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibition." + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibition." + ] + } + } + ] + }, + { + "PMID": "15146178", + "TEXT": "Hepatic gluconeogenesis is essential for maintenance of normal blood glucose concentrations and is regulated by opposing stimulatory (cyclic adenosine monophosphate, cAMP) and inhibitory (insulin) signaling pathways. The cAMP signaling pathway leads to phosphorylation of cAMP response element-binding (CREB) protein, resulting in recruitment of the coactivators CREB-binding protein (CBP) and p300 and subsequent activation of gluconeogenesis. Insulin signaling leads to phosphorylation of CBP at serine 436, a residue near its CREB-interacting domain, but it is unknown whether this event modulates cAMP signaling. Here, we show in vitro and in 'knock-in' mice that a mutant CBP (S436A) is aberrantly recruited to CREB protein, resulting in inappropriate activation of gluconeogenesis in the fed state and glucose intolerance resulting from increased hepatic glucose production. We propose that insulin signaling may directly regulate many cAMP signaling pathways at the transcriptional level by controlling CBP recruitment.", + "TAG_DATA": [ + "84, in {'context': 'B-in vitro'}", + "85, vitro {'context': 'I-in vitro'}", + "89, mice {'context': 'B-organism'}", + "92, mutant {'perturbing_action': 'B-other'}", + "93, CBP {'perturbing_action': 'I-other'}", + "94, (S436A) {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "84, in ['l0']", + "85, vitro ['l0']", + "92, mutant ['l1', 'l2']", + "93, CBP ['l1', 'l3']", + "94, (S436A) ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15146177", + "TEXT": "Suramin is a polysulfonated derivative of urea and has been widely used both to treat infections and as a chemotherapeutic drug. Suramin has been shown to inhibit growth factor signaling pathways; however, its effect on apoptosis is unknown. Here we show that suramin inhibits apoptosis induced through death receptors in hepatoma and lymphoma cells. It also inhibits the proapoptotic effect of chemotherapeutic drugs. The antiapoptotic mechanism is specific to cell type and is caused by reduced activation, but not altered composition, of the death-inducing signaling complex (DISC), and by inhibition of the initiator caspases 8, 9 and 10. Suramin also shows similar effects in in vivo models: apoptotic liver damage induced by CD95 stimulation and endotoxic shock mediated by tumor-necrosis factor (TNF) are inhibited in mice, but necrotic liver damage is not inhibited in a rat model of liver transplantation. Thus, the antiapoptotic property of suramin in the liver may be therapeutically exploited.", + "TAG_DATA": [ + "43, inhibits {'effect': 'B-negative'}", + "44, apoptosis {'phenotype': 'B-apoptosis'}", + "50, hepatoma {'context': 'B-transformed cells'}", + "51, and {'context': 'I-transformed cells'}", + "52, lymphoma {'context': 'I-transformed cells'}", + "53, cells. {'context': 'I-transformed cells'}", + "104, in {'context': 'B-in vivo'}", + "105, vivo {'context': 'I-in vivo'}", + "106, models: {'context': 'I-in vivo'}", + "107, apoptotic {'phenotype': 'B-apoptosis'}", + "108, liver {'phenotype': 'I-apoptosis'}", + "123, inhibited {'effect': 'B-negative'}", + "125, mice, {'context': 'B-organism'}", + "128, liver {'phenotype': 'I-necrosis'}", + "135, rat {'context': 'B-xenograft'}", + "136, model {'context': 'I-xenograft'}", + "138, liver {'context': 'I-tissue/organ'}", + "139, transplantation. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "43, inhibits ['l0', 'l1', 'l2', 'l3', 'l4']", + "44, apoptosis ['l0', 'l5', 'l6', 'l7', 'l8']", + "50, hepatoma ['l1', 'l5', 'l9', 'l10', 'l11']", + "51, and ['l2', 'l6', 'l9', 'l12', 'l13']", + "52, lymphoma ['l3', 'l7', 'l10', 'l12', 'l14']", + "53, cells. ['l4', 'l8', 'l11', 'l13', 'l14']", + "104, in ['l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "105, vivo ['l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "106, models: ['l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "107, apoptotic ['l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "108, liver ['l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "123, inhibited ['l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "125, mice, ['l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "127, necrotic ['l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "128, liver ['l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "135, rat ['l37', 'l42', 'l47', 'l48', 'l49', 'l50']", + "136, model ['l38', 'l43', 'l47', 'l51', 'l52', 'l53']", + "137, of ['l39', 'l44', 'l48', 'l51', 'l54', 'l55']", + "138, liver ['l40', 'l45', 'l49', 'l52', 'l54', 'l56']", + "139, transplantation. ['l41', 'l46', 'l50', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "inhibited" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptotic", + "liver" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "hepatoma", + "and", + "lymphoma", + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "hepatoma", + "and", + "lymphoma", + "cells." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "models:" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "liver" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "models:" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "liver" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "liver" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "rat", + "model", + "transplantation." + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "liver" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "15064758", + "TEXT": "Cardiovascular disease is primarily diagnosed using invasive X-ray cineangiography. Here we introduce a new concept in magnetic resonance imaging (MRI) that, for the first time, produces similar images noninvasively and without a contrast agent. Protons in moving blood are 'tagged' every few milliseconds as they travel through an arbitrary region in space. Simultaneous with ongoing tagging of new blood, previously tagged blood is maintained in a state of global coherent free precession (GCFP), which allows acquisition of consecutive movie frames as the heart pushes blood through the vascular bed. Body tissue surrounding the moving blood is never excited and therefore remains invisible. In 18 subjects, pulsating blood could be seen flowing through three-dimensional (3D) space for distances of up to 16 cm outside the stationary excitation region. These data underscore that our approach noninvasively characterizes both anatomy and blood flow in a manner directly analogous to invasive procedures.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15034572", + "TEXT": "Gene replacement or gene reactivation therapies for sickle-cell disease (SCD) typically target the mutant beta(S)-globin subunits of hemoglobin-S (alpha(2)beta(S)(2)) for substitution by nonpathological beta-like globins. Here we show, in vitro and in vivo in a transgenic mouse model of SCD, that the adverse properties of hemoglobin-S can be reversed by exchanging its normal alpha-globin subunits for zeta-globin, an endogenous, developmentally silenced, non-beta-like globin.", + "TAG_DATA": [ + "28, in {'context': 'B-in vitro'}", + "29, vitro {'context': 'I-in vitro'}", + "31, in {'context': 'B-in vivo'}", + "32, vivo {'context': 'I-in vivo'}", + "35, transgenic {'context': 'B-organism'}", + "36, mouse {'context': 'I-organism'}", + "37, model {'context': 'I-organism'}", + "38, of {'context': 'I-organism'}", + "39, SCD, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "28, in ['l0', 'l1', 'l2']", + "29, vitro ['l0', 'l3', 'l4']", + "31, in ['l1', 'l3', 'l5', 'l6', 'l7']", + "32, vivo ['l2', 'l4', 'l5', 'l8', 'l9']", + "35, transgenic ['l10', 'l11', 'l12', 'l13']", + "36, mouse ['l10', 'l14', 'l15', 'l16']", + "37, model ['l11', 'l14', 'l17', 'l18']", + "38, of ['l6', 'l8', 'l12', 'l15', 'l17', 'l19']", + "39, SCD, ['l7', 'l9', 'l13', 'l16', 'l18', 'l19']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15034571", + "TEXT": "Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition in which motoneurons of the spinal cord and motor cortex die, resulting in progressive paralysis. This condition has no cure and results in eventual death, usually within 1-5 years of diagnosis. Although the specific etiology of ALS is unknown, 20% of familial cases of the disease carry mutations in the gene encoding Cu/Zn superoxide dismutase-1 (SOD1). Transgenic mice overexpressing human mutant SOD1 have a phenotype and pathology that are very similar to that seen in human ALS patients. Here we show that treatment with arimoclomol, a coinducer of heat shock proteins (HSPs), significantly delays disease progression in mice expressing a SOD1 mutant in which glycine is substituted with alanine at position 93 (SOD1(G93A)). Arimoclomol-treated SOD1(G93A) mice show marked improvement in hind limb muscle function and motoneuron survival in the later stages of the disease, resulting in a 22% increase in lifespan. Pharmacological activation of the heat shock response may therefore be a successful therapeutic approach to treating ALS, and possibly other neurodegenerative diseases.", + "TAG_DATA": [ + "67, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "68, human {'perturbing_action': 'I-gene gain-of-function'}", + "69, mutant {'perturbing_action': 'I-gene gain-of-function'}", + "70, SOD1 {'perturbing_action': 'I-gene gain-of-function'}", + "106, mice {'context': 'B-organism'}", + "109, SOD1 {'perturbing_action': 'B-other'}", + "110, mutant {'perturbing_action': 'I-other'}", + "111, in {'perturbing_action': 'I-other'}", + "112, which {'perturbing_action': 'I-other'}", + "113, glycine {'perturbing_action': 'I-other'}", + "114, is {'perturbing_action': 'I-other'}", + "115, substituted {'perturbing_action': 'I-other'}", + "117, alanine {'perturbing_action': 'I-other'}", + "118, at {'perturbing_action': 'I-other'}", + "119, position {'perturbing_action': 'I-other'}", + "120, 93 {'perturbing_action': 'I-other'}", + "121, (SOD1(G93A)). {'perturbing_action': 'I-other'}", + "124, mice {'context': 'B-organism'}", + "129, hind {'context': 'B-tissue/organ'}", + "130, limb {'context': 'I-tissue/organ'}", + "131, muscle {'context': 'I-tissue/organ'}", + "134, motoneuron {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "67, overexpressing ['l0', 'l1', 'l2']", + "68, human ['l0', 'l3', 'l4']", + "69, mutant ['l1', 'l3', 'l5']", + "70, SOD1 ['l2', 'l4', 'l5']", + "106, mice ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "109, SOD1 ['l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "110, mutant ['l17', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "111, in ['l6', 'l18', 'l32', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "112, which ['l7', 'l19', 'l33', 'l46', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "113, glycine ['l8', 'l20', 'l34', 'l47', 'l59', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "114, is ['l9', 'l21', 'l35', 'l48', 'l60', 'l71', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "115, substituted ['l10', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "116, with ['l11', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "117, alanine ['l12', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "118, at ['l13', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "119, position ['l14', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l122', 'l123', 'l124', 'l125', 'l126']", + "120, 93 ['l15', 'l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l127', 'l128', 'l129', 'l130']", + "121, (SOD1(G93A)). ['l16', 'l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l118', 'l123', 'l127', 'l131', 'l132', 'l133']", + "124, mice ['l134', 'l135', 'l136', 'l137']", + "129, hind ['l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l113', 'l119', 'l124', 'l128', 'l131', 'l134', 'l138', 'l139', 'l140']", + "130, limb ['l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l129', 'l132', 'l135', 'l138', 'l141']", + "131, muscle ['l31', 'l45', 'l58', 'l70', 'l81', 'l91', 'l100', 'l108', 'l115', 'l121', 'l126', 'l130', 'l133', 'l136', 'l139', 'l141']", + "134, motoneuron ['l137', 'l140']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "in", + "which", + "glycine", + "is", + "substituted", + "alanine", + "at", + "position", + "93", + "(SOD1(G93A))." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "SOD1", + "mutant", + "in", + "which", + "glycine", + "is", + "substituted", + "alanine", + "at", + "position", + "93", + "(SOD1(G93A))." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hind", + "limb", + "muscle" + ] + } + } + ] + }, + { + "PMID": "15034570", + "TEXT": "Although Nogo-A has been identified in the central nervous system as an inhibitor of axonal regeneration, the peripheral roles of Nogo isoforms remain virtually unknown. Here, using a proteomic analysis to identify proteins enriched in caveolae and/or lipid rafts (CEM/LR), we show that Nogo-B is highly expressed in cultured endothelial and smooth muscle cells, as well as in intact blood vessels. The N terminus of Nogo-B promotes the migration of endothelial cells but inhibits the migration of vascular smooth muscle (VSM) cells, processes necessary for vascular remodeling. Vascular injury in Nogo-A/B-deficient mice promotes exaggerated neointimal proliferation, and adenoviral-mediated gene transfer of Nogo-B rescues the abnormal vascular expansion in those knockout mice. Our discovery that Nogo-B is a regulator of vascular homeostasis and remodeling broadens the functional scope of this family of proteins.", + "TAG_DATA": [ + "66, promotes {'effect': 'B-positive'}", + "68, migration {'phenotype': 'B-migration'}", + "70, endothelial {'context': 'B-cells'}", + "71, cells {'context': 'I-cells'}", + "73, inhibits {'effect': 'B-negative'}", + "75, migration {'phenotype': 'B-migration'}", + "77, vascular {'context': 'B-cells'}", + "78, smooth {'context': 'I-cells'}", + "79, muscle {'context': 'I-cells'}", + "80, (VSM) {'context': 'I-cells'}", + "81, cells, {'context': 'I-cells'}", + "90, Nogo-A/B-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "91, mice {'context': 'B-organism'}", + "92, promotes {'effect': 'B-positive'}", + "95, proliferation, {'phenotype': 'B-proliferation'}", + "97, adenoviral-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "98, gene {'perturbing_action': 'I-gene gain-of-function'}", + "99, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "100, of {'perturbing_action': 'I-gene gain-of-function'}", + "101, Nogo-B {'perturbing_action': 'I-gene gain-of-function'}", + "102, rescues {'effect': 'B-rescues'}", + "110, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "66, promotes ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "68, migration ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "70, endothelial ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "71, cells ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "73, inhibits ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "75, migration ['l4', 'l13', 'l21', 'l28', 'l34', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "77, vascular ['l5', 'l14', 'l22', 'l29', 'l35', 'l42', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "78, smooth ['l6', 'l15', 'l23', 'l30', 'l36', 'l43', 'l48', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "79, muscle ['l7', 'l16', 'l24', 'l31', 'l37', 'l44', 'l49', 'l56', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "80, (VSM) ['l8', 'l17', 'l25', 'l32', 'l38', 'l45', 'l50', 'l57', 'l63', 'l69', 'l70', 'l71', 'l72', 'l73']", + "81, cells, ['l9', 'l18', 'l26', 'l33', 'l39', 'l46', 'l51', 'l58', 'l64', 'l69', 'l74']", + "90, Nogo-A/B-deficient ['l52', 'l59', 'l65', 'l70', 'l75', 'l76', 'l77']", + "91, mice ['l40', 'l47', 'l53', 'l60', 'l66', 'l71', 'l74', 'l75', 'l78', 'l79']", + "92, promotes ['l41', 'l54', 'l61', 'l67', 'l72', 'l76', 'l78', 'l80']", + "95, proliferation, ['l55', 'l62', 'l68', 'l73', 'l77', 'l79', 'l80']", + "97, adenoviral-mediated ['l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "98, gene ['l81', 'l87', 'l88', 'l89', 'l90', 'l91']", + "99, transfer ['l82', 'l87', 'l92', 'l93', 'l94', 'l95']", + "100, of ['l83', 'l88', 'l92', 'l96', 'l97', 'l98']", + "101, Nogo-B ['l84', 'l89', 'l93', 'l96', 'l99', 'l100']", + "102, rescues ['l85', 'l90', 'l94', 'l97', 'l99', 'l101']", + "110, mice. ['l86', 'l91', 'l95', 'l98', 'l100', 'l101']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells", + "vascular", + "smooth", + "muscle", + "(VSM)", + "cells," + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells", + "vascular", + "smooth", + "muscle", + "(VSM)", + "cells," + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells", + "vascular", + "smooth", + "muscle", + "(VSM)", + "cells," + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "vascular", + "smooth", + "muscle", + "(VSM)" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nogo-A/B-deficient" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "vascular", + "smooth", + "muscle", + "(VSM)" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nogo-A/B-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nogo-A/B-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nogo-A/B-deficient" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral-mediated", + "gene", + "transfer", + "of", + "Nogo-B" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescues" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral-mediated", + "gene", + "transfer", + "of", + "Nogo-B" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescues" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "15034568", + "TEXT": "Genomic amplification at 20q11-13 is a common event in human cancers. We isolated a germline translocation breakpoint at 20q11 from a bladder cancer patient. We identified CDC91L1, the gene encoding CDC91L1 (also called phosphatidylinositol glycan class U (PIG-U), a transamidase complex unit in the glycosylphosphatidylinositol (GPI) anchoring pathway), as the only gene whose expression was affected by the translocation. CDC91L1 was amplified and overexpressed in about one-third of bladder cancer cell lines and primary tumors, as well as in oncogenic uroepithelial cells transformed with human papillomavirus (HPV) E7. Forced overexpression of CDC91L1 malignantly transformed NIH3T3 cells in vitro and in vivo. Overexpression of CDC91L1 also resulted in upregulation of the urokinase receptor (uPAR), a GPI-anchored protein, and in turn increased STAT-3 phosphorylation in bladder cancer cells. Our findings suggest that CDC91L1 is an oncogene in bladder cancer, and implicate the GPI anchoring system as a potential oncogenic pathway and therapeutic target in human cancers.", + "TAG_DATA": [ + "79, oncogenic {'context': 'B-cells'}", + "80, uroepithelial {'context': 'I-cells'}", + "81, cells {'context': 'I-cells'}", + "82, transformed {'phenotype': 'B-transformation'}", + "88, Forced {'perturbing_action': 'B-gene gain-of-function'}", + "89, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "90, of {'perturbing_action': 'I-gene gain-of-function'}", + "91, CDC91L1 {'perturbing_action': 'I-gene gain-of-function'}", + "93, transformed {'phenotype': 'B-transformation'}", + "94, NIH3T3 {'context': 'B-cells'}", + "95, cells {'context': 'I-cells'}", + "96, in {'context': 'B-in vitro'}", + "97, vitro {'context': 'I-in vitro'}", + "99, in {'context': 'B-in vivo'}", + "100, vivo. {'context': 'I-in vivo'}", + "101, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "102, of {'perturbing_action': 'I-gene gain-of-function'}", + "103, CDC91L1 {'perturbing_action': 'I-gene gain-of-function'}", + "123, bladder {'context': 'B-transformed cells'}", + "124, cancer {'context': 'I-transformed cells'}", + "125, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "79, oncogenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "80, uroepithelial ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "81, cells ['l1', 'l8', 'l15', 'l16', 'l17', 'l18']", + "82, transformed ['l2', 'l9', 'l15', 'l19', 'l20', 'l21', 'l22', 'l23']", + "88, Forced ['l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "89, overexpression ['l24', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "90, of ['l25', 'l34', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "91, CDC91L1 ['l26', 'l35', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "93, transformed ['l3', 'l10', 'l16', 'l19', 'l27', 'l36', 'l44', 'l51', 'l58', 'l59', 'l60', 'l61']", + "94, NIH3T3 ['l4', 'l11', 'l17', 'l20', 'l28', 'l37', 'l45', 'l52', 'l58', 'l62', 'l63', 'l64', 'l65', 'l66']", + "95, cells ['l5', 'l12', 'l18', 'l21', 'l29', 'l38', 'l46', 'l53', 'l59', 'l62', 'l67', 'l68']", + "96, in ['l6', 'l13', 'l22', 'l30', 'l39', 'l47', 'l54', 'l60', 'l63', 'l67', 'l69']", + "97, vitro ['l7', 'l14', 'l23', 'l31', 'l40', 'l48', 'l55', 'l61', 'l64', 'l68', 'l69']", + "99, in ['l32', 'l41', 'l49', 'l56', 'l65', 'l70']", + "100, vivo. ['l33', 'l42', 'l50', 'l57', 'l66', 'l70']", + "101, Overexpression ['l71', 'l72', 'l73', 'l74', 'l75']", + "102, of ['l71', 'l76', 'l77', 'l78', 'l79']", + "103, CDC91L1 ['l72', 'l76', 'l80', 'l81', 'l82']", + "123, bladder ['l73', 'l77', 'l80', 'l83', 'l84']", + "124, cancer ['l74', 'l78', 'l81', 'l83', 'l85']", + "125, cells. ['l75', 'l79', 'l82', 'l84', 'l85']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "oncogenic", + "uroepithelial", + "cells", + "NIH3T3" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformed" + ] + } + }, + { + "phenotype": { + "val": "transformation", + "words": [ + "transformed" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "overexpression", + "of", + "CDC91L1" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformed" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "overexpression", + "of", + "CDC91L1" + ] + }, + "context": { + "val": "cells", + "words": [ + "NIH3T3", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "overexpression", + "of", + "CDC91L1" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "overexpression", + "of", + "CDC91L1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "CDC91L1" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "bladder", + "cancer", + "cells." + ] + } + } + ] + }, + { + "PMID": "15004554", + "TEXT": "The clinical outcome of spinal cord injury (SCI) depends in part on the extent of secondary damage, to which apoptosis contributes. The CD95 and tumor necrosis factor (TNF) ligand/receptor systems play an essential role in various apoptotic mechanisms. To determine the involvement of these ligands in SCI-induced damage, we neutralized the activity of CD95 ligand (CD95L) and/or TNF in spinal cord-injured mice. Therapeutic neutralization of CD95L, but not of TNF, significantly decreased apoptotic cell death after SCI. Mice treated with CD95L-specific antibodies were capable of initiating active hind-limb movements several weeks after injury. The improvement in locomotor performance was mirrored by an increase in regenerating fibers and upregulation of growth-associated protein-43 (GAP-43). Thus, neutralization of CD95L promoted axonal regeneration and functional improvement in injured adult animals. This therapeutic strategy may constitute a potent future treatment for human spinal injury.", + "TAG_DATA": [ + "61, mice. {'context': 'B-organism'}", + "62, Therapeutic {'perturbing_action': 'B-pharmacological inhibition'}", + "63, neutralization {'perturbing_action': 'I-pharmacological inhibition'}", + "64, of {'perturbing_action': 'I-pharmacological inhibition'}", + "65, CD95L, {'perturbing_action': 'I-pharmacological inhibition'}", + "71, decreased {'effect': 'B-negative'}", + "72, apoptotic {'phenotype': 'B-apoptosis'}", + "73, cell {'phenotype': 'I-apoptosis'}", + "74, death {'phenotype': 'I-apoptosis'}", + "77, Mice {'context': 'B-organism'}", + "104, regenerating {'context': 'B-cells'}", + "105, fibers {'context': 'I-cells'}", + "113, neutralization {'perturbing_action': 'B-pharmacological inhibition'}", + "114, of {'perturbing_action': 'I-pharmacological inhibition'}", + "124, adult {'context': 'B-organism'}", + "125, animals. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "61, mice. ['l0', 'l1']", + "62, Therapeutic ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "63, neutralization ['l2', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "64, of ['l3', 'l11', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "65, CD95L, ['l4', 'l12', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "71, decreased ['l5', 'l13', 'l19', 'l24', 'l29', 'l30', 'l31']", + "72, apoptotic ['l6', 'l14', 'l20', 'l25', 'l29', 'l32', 'l33']", + "73, cell ['l0', 'l7', 'l15', 'l21', 'l26', 'l30', 'l32', 'l34']", + "74, death ['l1', 'l8', 'l16', 'l22', 'l27', 'l31', 'l33', 'l34']", + "77, Mice ['l9', 'l35', 'l36']", + "87, hind-limb ['l10', 'l17', 'l23', 'l28', 'l35']", + "104, regenerating ['l37']", + "105, fibers ['l36', 'l37']", + "113, neutralization ['l38', 'l39', 'l40', 'l41']", + "114, of ['l38', 'l42', 'l43', 'l44']", + "115, CD95L ['l39', 'l42', 'l45', 'l46']", + "124, adult ['l40', 'l43', 'l45', 'l47']", + "125, animals. ['l41', 'l44', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Therapeutic", + "neutralization", + "of", + "CD95L," + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Therapeutic", + "neutralization", + "of", + "CD95L," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Therapeutic", + "neutralization", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "Mice", + "adult", + "animals." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death" + ] + } + } + ] + }, + { + "PMID": "14991050", + "TEXT": "Autoimmune T-helper cells drive pathogenic autoantibody production in systemic lupus erythematosus (SLE), but the mechanisms maintaining those T cells are unknown. Autoreactive T cells are normally eliminated by functional inactivation (anergy) and activation-induced cell death (AICD) or apoptosis through death receptor (Fas) signaling. However, mutations in the genes encoding Fas and its ligand (FasL) are rare in classical SLE. By gene microarray profiling, validated by functional and biochemical studies, we establish here that activated T cells of lupus patients resist anergy and apoptosis by markedly upregulating and sustaining cyclooxygenase-2 (COX-2) expression. Inhibition of COX-2 caused apoptosis of the anergy-resistant lupus T cells by augmenting Fas signaling and markedly decreasing the survival molecule c-FLIP (cellular homolog of viral FLICE inhibitory protein). Studies with COX-2 inhibitors and Cox-2-deficient mice confirmed that this COX-2/FLIP antiapoptosis program is used selectively by anergy-resistant lupus T cells, and not by cancer cells or other autoimmune T cells. Notably, the gene encoding COX-2 is located in a lupus-susceptibility region on chromosome 1. We also found that only some COX-2 inhibitors were able to suppress the production of pathogenic autoantibodies to DNA by causing autoimmune T-cell apoptosis, an effect that was independent of prostaglandin E(2) (PGE(2)). These findings could be useful in the design of lupus therapies.", + "TAG_DATA": [ + "82, apoptosis {'phenotype': 'B-apoptosis'}", + "91, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "92, of {'perturbing_action': 'I-pharmacological inhibition'}", + "93, COX-2 {'perturbing_action': 'I-pharmacological inhibition'}", + "94, caused {'effect': 'B-positive'}", + "95, apoptosis {'phenotype': 'B-apoptosis'}", + "98, anergy-resistant {'context': 'B-cells'}", + "99, lupus {'context': 'I-cells'}", + "100, T {'context': 'I-cells'}", + "101, cells {'context': 'I-cells'}", + "122, COX-2 {'perturbing_action': 'B-pharmacological inhibition'}", + "123, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "125, Cox-2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "126, mice {'context': 'B-organism'}", + "145, cells {'context': 'I-transformed cells'}", + "171, COX-2 {'perturbing_action': 'B-pharmacological inhibition'}", + "172, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "185, causing {'effect': 'B-positive'}", + "186, autoimmune {'context': 'B-cells'}", + "187, T-cell {'context': 'I-cells'}", + "188, apoptosis, {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "91, Inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "92, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "93, COX-2 ['l1', 'l11', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "94, caused ['l2', 'l12', 'l20', 'l28', 'l29', 'l30', 'l31', 'l32']", + "95, apoptosis ['l3', 'l13', 'l21', 'l28', 'l33', 'l34', 'l35', 'l36']", + "98, anergy-resistant ['l4', 'l14', 'l22', 'l29', 'l33', 'l37', 'l38', 'l39']", + "99, lupus ['l5', 'l15', 'l23', 'l30', 'l34', 'l37', 'l40', 'l41']", + "100, T ['l6', 'l16', 'l24', 'l31', 'l35', 'l38', 'l40', 'l42']", + "101, cells ['l7', 'l17', 'l25', 'l32', 'l36', 'l39', 'l41', 'l42']", + "122, COX-2 ['l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "123, inhibitors ['l43', 'l49', 'l50', 'l51', 'l52', 'l53']", + "125, Cox-2-deficient ['l44', 'l49', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "126, mice ['l45', 'l50', 'l54', 'l62', 'l63', 'l64']", + "139, T ['l8', 'l18', 'l26', 'l46', 'l51', 'l55', 'l62', 'l65', 'l66']", + "140, cells, ['l9', 'l19', 'l27', 'l47', 'l52', 'l56', 'l63', 'l65', 'l67']", + "145, cells ['l10', 'l48', 'l53', 'l57', 'l64', 'l66', 'l67']", + "171, COX-2 ['l68', 'l69', 'l70', 'l71', 'l72']", + "172, inhibitors ['l68', 'l73', 'l74', 'l75', 'l76']", + "185, causing ['l58', 'l69', 'l73', 'l77', 'l78', 'l79']", + "186, autoimmune ['l59', 'l70', 'l74', 'l77', 'l80', 'l81']", + "187, T-cell ['l60', 'l71', 'l75', 'l78', 'l80', 'l82']", + "188, apoptosis, ['l61', 'l72', 'l76', 'l79', 'l81', 'l82']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "COX-2", + "inhibitors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused", + "causing" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "COX-2", + "inhibitors" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "COX-2", + "inhibitors" + ] + }, + "context": { + "val": "cells", + "words": [ + "anergy-resistant", + "lupus", + "T", + "cells", + "autoimmune", + "T-cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "COX-2", + "inhibitors" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused", + "causing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused", + "causing" + ] + }, + "context": { + "val": "cells", + "words": [ + "anergy-resistant", + "lupus", + "T", + "cells", + "autoimmune", + "T-cell" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis," + ] + }, + "context": { + "val": "cells", + "words": [ + "anergy-resistant", + "lupus", + "T", + "cells", + "autoimmune", + "T-cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "COX-2", + "inhibitors" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cox-2-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cox-2-deficient" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cox-2-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "causing" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cox-2-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "autoimmune", + "T-cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cox-2-deficient" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + } + ] + }, + { + "PMID": "14966519", + "TEXT": "Embryonic development of multilineage hematopoiesis requires the precisely regulated expression of lineage-specific transcription factors, including AML-1 (encoded by Runx1; also known as CBFA-2 or PEBP-2alphaB). In vitro studies and findings in human diseases, including leukemias, myelodysplastic syndromes and familial platelet disorder with predisposition to acute myeloid leukemia (AML), suggest that AML-1 has a pivotal role in adult hematopoiesis. However, this role has not been fully uncovered in vivo because of the embryonic lethality of Runx1 knockout in mice. Here we assess the requirement of AML-1/Runx1 in adult hematopoiesis using an inducible gene-targeting method. In the absence of AML-1, hematopoietic progenitors were fully maintained with normal myeloid cell development. However, AML-1-deficient bone marrow showed inhibition of megakaryocytic maturation, increased hematopoietic progenitor cells and defective T- and B-lymphocyte development. AML-1 is thus required for maturation of megakaryocytes and differentiation of T and B cells, but not for maintenance of hematopoietic stem cells (HSCs) in adult hematopoiesis.", + "TAG_DATA": [ + "95, absence {'perturbing_action': 'B-gene loss-of-function'}", + "96, of {'perturbing_action': 'I-gene loss-of-function'}", + "97, AML-1, {'perturbing_action': 'I-gene loss-of-function'}", + "98, hematopoietic {'context': 'B-cells'}", + "99, progenitors {'context': 'I-cells'}", + "105, myeloid {'context': 'B-cells'}", + "106, cell {'context': 'I-cells'}", + "109, AML-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "110, bone {'context': 'B-tissue/organ'}", + "111, marrow {'context': 'I-tissue/organ'}", + "118, hematopoietic {'context': 'B-cells'}", + "119, progenitor {'context': 'I-cells'}", + "120, cells {'context': 'I-cells'}", + "123, T- {'context': 'B-cells'}", + "124, and {'context': 'I-cells'}", + "125, B-lymphocyte {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "95, absence ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "96, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "97, AML-1, ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "98, hematopoietic ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "99, progenitors ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "105, myeloid ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "106, cell ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "109, AML-1-deficient ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "110, bone ['l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "111, marrow ['l22', 'l29', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "118, hematopoietic ['l23', 'l30', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "119, progenitor ['l24', 'l31', 'l37', 'l42', 'l47', 'l48', 'l49', 'l50']", + "120, cells ['l25', 'l32', 'l38', 'l43', 'l47', 'l51', 'l52', 'l53']", + "123, T- ['l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l54', 'l55']", + "124, and ['l27', 'l34', 'l40', 'l45', 'l49', 'l52', 'l54', 'l56']", + "125, B-lymphocyte ['l28', 'l35', 'l41', 'l46', 'l50', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "AML-1,", + "AML-1-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "progenitors", + "myeloid", + "cell", + "progenitor", + "cells", + "T-", + "and", + "B-lymphocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "AML-1-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "bone", + "marrow" + ] + } + } + ] + }, + { + "PMID": "14770176", + "TEXT": "Calcineurin inhibitors such as cyclosporine A and FK506 have been used for transplant therapy and treatment of autoimmune diseases. However, the inhibition of calcineurin outside the immune system has a number of side effects, including hyperglycemia. In the search for safer drugs, we developed a cell-permeable inhibitor of NFAT (nuclear factor of activated T cells) using the polyarginine peptide delivery system. This peptide provided immunosuppression for fully mismatched islet allografts in mice. In addition, it did not affect insulin secretion, whereas FK506 caused a dose-dependent decrease in insulin secretion. Cell-permeable peptides can thus provide a new strategy for drug development and may eventually be useful clinically.", + "TAG_DATA": [ + "68, islet {'context': 'B-xenograft'}", + "69, allografts {'context': 'I-xenograft'}", + "71, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "68, islet ['l0', 'l1']", + "69, allografts ['l0', 'l2']", + "71, mice. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14745442", + "TEXT": "To study the pathogenesis of fatal cerebral malaria, we conducted autopsies in 31 children with this clinical diagnosis. We found that 23% of the children had actually died from other causes. The remaining patients had parasites sequestered in cerebral capillaries, and 75% of those had additional intra- and perivascular pathology. Retinopathy was the only clinical sign distinguishing malarial from nonmalarial coma. These data have implications for treating malaria patients, designing clinical trials and assessing malaria-specific disease associations.", + "TAG_DATA": [ + "13, children {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "14730359", + "TEXT": "Inhibition of polyglutamine-induced protein aggregation could provide treatment options for polyglutamine diseases such as Huntington disease. Here we showed through in vitro screening studies that various disaccharides can inhibit polyglutamine-mediated protein aggregation. We also found that various disaccharides reduced polyglutamine aggregates and increased survival in a cellular model of Huntington disease. Oral administration of trehalose, the most effective of these disaccharides, decreased polyglutamine aggregates in cerebrum and liver, improved motor dysfunction and extended lifespan in a transgenic mouse model of Huntington disease. We suggest that these beneficial effects are the result of trehalose binding to expanded polyglutamines and stabilizing the partially unfolded polyglutamine-containing protein. Lack of toxicity and high solubility, coupled with efficacy upon oral administration, make trehalose promising as a therapeutic drug or lead compound for the treatment of polyglutamine diseases. The saccharide-polyglutamine interaction identified here thus provides a new therapeutic strategy for polyglutamine diseases.", + "TAG_DATA": [ + "20, in {'context': 'B-in vitro'}", + "21, vitro {'context': 'I-in vitro'}", + "46, cellular {'context': 'B-cells'}", + "47, model {'context': 'I-organism'}", + "65, cerebrum {'context': 'B-tissue/organ'}", + "67, liver, {'context': 'B-tissue/organ'}", + "76, transgenic {'context': 'B-organism'}", + "77, mouse {'context': 'I-organism'}", + "78, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "20, in ['l0', 'l1', 'l2', 'l3', 'l4']", + "21, vitro ['l0', 'l5', 'l6', 'l7', 'l8']", + "46, cellular ['l1', 'l5', 'l9', 'l10', 'l11']", + "47, model ['l2', 'l6', 'l9', 'l12', 'l13']", + "48, of ['l3', 'l7', 'l10', 'l12', 'l14']", + "50, disease. ['l4', 'l8', 'l11', 'l13', 'l14']", + "65, cerebrum ['l15', 'l16', 'l17', 'l18']", + "67, liver, ['l15']", + "76, transgenic ['l19', 'l20', 'l21', 'l22', 'l23']", + "77, mouse ['l19', 'l24', 'l25', 'l26', 'l27']", + "78, model ['l20', 'l24', 'l28', 'l29', 'l30']", + "79, of ['l16', 'l21', 'l25', 'l28', 'l31', 'l32']", + "80, Huntington ['l17', 'l22', 'l26', 'l29', 'l31', 'l33']", + "81, disease. ['l18', 'l23', 'l27', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14716307", + "TEXT": "Mucus hypersecretion is a crucial feature of pulmonary diseases such as asthma, chronic bronchitis and cystic fibrosis. Despite much research, there is still no effective therapy for this condition. Recently, we showed that the myristoylated, alanine-rich C-kinase substrate (MARCKS) protein is required for mucus secretion by human bronchial epithelial cells in culture. Having synthesized a peptide corresponding to the N-terminal domain of MARCKS, we now show that the intratracheal instillation of this peptide blocks mucus hypersecretion in a mouse model of asthma. A missense peptide with the same amino acid composition has no effect. Based on quantitative histochemical analysis of the mouse airways, the peptide seems to act by blocking mucus release from goblet cells, possibly by inhibiting the attachment of MARCKS to membranes of intracellular mucin granules. These results support a pivotal role for MARCKS protein, specifically its N-terminal region, in modulating this secretory process in mammalian airways. Intratracheal administration of this MARCKS-related peptide could therapeutically reduce mucus secretion in the airways of human patients with asthma, chronic bronchitis and cystic fibrosis.", + "TAG_DATA": [ + "46, human {'context': 'B-cells'}", + "47, bronchial {'context': 'I-cells'}", + "48, epithelial {'context': 'I-cells'}", + "49, cells {'context': 'I-cells'}", + "78, mouse {'context': 'B-organism'}", + "79, model {'context': 'I-organism'}", + "80, of {'context': 'I-organism'}", + "81, asthma. {'context': 'I-organism'}", + "113, goblet {'context': 'B-cells'}", + "114, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "46, human ['l0', 'l1', 'l2']", + "47, bronchial ['l0', 'l3', 'l4']", + "48, epithelial ['l1', 'l3', 'l5', 'l6']", + "49, cells ['l2', 'l4', 'l5']", + "78, mouse ['l7', 'l8', 'l9']", + "79, model ['l7', 'l10', 'l11']", + "80, of ['l6', 'l8', 'l10', 'l12']", + "81, asthma. ['l9', 'l11', 'l12']", + "113, goblet ['l13']", + "114, cells, ['l13']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14704791", + "TEXT": "Metastatic cancers, once established, are the primary cause of mortality associated with cancer. Previously, we used a genomic approach to identify metastasis-associated genes in cancer. From this genomic data, we selected ezrin for further study based on its role in physically and functionally connecting the actin cytoskeleton to the cell membrane. In a mouse model of osteosarcoma, a highly metastatic pediatric cancer, we found ezrin to be necessary for metastasis. By imaging metastatic cells in the lungs of mice, we showed that ezrin expression provided an early survival advantage for cancer cells that reached the lung. AKT and MAPK phosphorylation and activity were reduced when ezrin protein was suppressed. Ezrin-mediated early metastatic survival was partially dependent on activation of MAPK, but not AKT. To define the relevance of ezrin in the biology of metastasis, beyond the founding mouse model, we examined ezrin expression in dogs that naturally developed osteosarcoma. High ezrin expression in dog tumors was associated with early development of metastases. Consistent with this data, we found a significant association between high ezrin expression and poor outcome in pediatric osteosarcoma patients.", + "TAG_DATA": [ + "53, mouse {'context': 'B-organism'}", + "54, model {'context': 'I-organism'}", + "55, of {'context': 'I-organism'}", + "56, osteosarcoma, {'context': 'I-organism'}", + "69, metastasis. {'phenotype': 'B-metastasis'}", + "73, cells {'phenotype': 'I-metastasis'}", + "76, lungs {'context': 'B-tissue/organ'}", + "78, mice, {'context': 'B-organism'}", + "90, cancer {'context': 'B-transformed cells'}", + "91, cells {'context': 'I-transformed cells'}", + "111, metastatic {'phenotype': 'B-metastasis'}", + "112, survival {'phenotype': 'I-metastasis'}", + "144, dogs {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "53, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "54, model ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "55, of ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "56, osteosarcoma, ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "69, metastasis. ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42']", + "72, metastatic ['l4', 'l14', 'l23', 'l31', 'l38', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "73, cells ['l5', 'l15', 'l24', 'l32', 'l39', 'l43', 'l49', 'l50', 'l51', 'l52', 'l53']", + "76, lungs ['l6', 'l16', 'l25', 'l33', 'l40', 'l44', 'l49', 'l54', 'l55', 'l56', 'l57']", + "78, mice, ['l7', 'l17', 'l26', 'l34', 'l41', 'l45', 'l50', 'l54', 'l58', 'l59', 'l60']", + "90, cancer ['l8', 'l18', 'l27', 'l35', 'l46', 'l51', 'l55', 'l58', 'l61', 'l62']", + "91, cells ['l9', 'l19', 'l28', 'l36', 'l42', 'l47', 'l52', 'l56', 'l59', 'l61', 'l63']", + "95, lung. ['l10', 'l20', 'l29', 'l37', 'l48', 'l53', 'l57', 'l60', 'l62', 'l63']", + "111, metastatic ['l64', 'l65']", + "112, survival ['l64', 'l66']", + "144, dogs ['l65', 'l66']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "osteosarcoma,", + "mice,", + "dogs" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis.", + "cells", + "metastatic", + "survival" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis.", + "cells" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lungs" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis.", + "cells" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells", + "cancer" + ] + } + } + ] + }, + { + "PMID": "14704789", + "TEXT": "Patients presenting with metastatic rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children, have a very poor clinical prognosis. This is due, in large part, to our rudimentary knowledge of the molecular events that dictate metastatic potential. We used cDNA microarray analysis of RMS cell lines, derived from Ink4a/Arf-deficient mice transgenic for hepatocyte growth factor/scatter factor (HGF/SF), to identify a set of genes whose expression was significantly different between highly and poorly metastatic cells. Subsequent in vivo functional studies revealed that the actin filament-plasma membrane linker ezrin (encoded by Vil2) and the homeodomain-containing transcription factor Six-1 (sine oculis-related homeobox-1 homolog) had essential roles in determining the metastatic fate of RMS cells. VIL2 and SIX1 expression was enhanced in human RMS tissue, significantly correlating with clinical stage. The identification of ezrin and Six-1 as critical regulators of metastasis in RMS provides new mechanistic and therapeutic insights into this pediatric cancer.", + "TAG_DATA": [ + "43, RMS {'context': 'B-transformed cells'}", + "44, cell {'context': 'I-transformed cells'}", + "45, lines, {'context': 'I-transformed cells'}", + "48, Ink4a/Arf-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "49, mice {'context': 'B-organism'}", + "50, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "51, for {'perturbing_action': 'I-gene gain-of-function'}", + "52, hepatocyte {'perturbing_action': 'I-gene gain-of-function'}", + "53, growth {'perturbing_action': 'I-gene gain-of-function'}", + "54, factor/scatter {'perturbing_action': 'I-gene gain-of-function'}", + "55, factor {'perturbing_action': 'I-gene gain-of-function'}", + "56, (HGF/SF), {'perturbing_action': 'I-gene gain-of-function'}", + "75, in {'context': 'B-in vivo'}", + "76, vivo {'context': 'I-in vivo'}", + "109, RMS {'context': 'B-transformed cells'}", + "110, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "43, RMS ['l0', 'l1', 'l2']", + "44, cell ['l0', 'l3', 'l4']", + "45, lines, ['l1', 'l3', 'l5']", + "48, Ink4a/Arf-deficient ['l2', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "49, mice ['l6', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "50, transgenic ['l7', 'l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "51, for ['l8', 'l16', 'l23', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "52, hepatocyte ['l9', 'l17', 'l24', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "53, growth ['l10', 'l18', 'l25', 'l32', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "54, factor/scatter ['l11', 'l19', 'l26', 'l33', 'l40', 'l46', 'l52', 'l53', 'l54', 'l55', 'l56']", + "55, factor ['l12', 'l20', 'l27', 'l34', 'l41', 'l47', 'l52', 'l57', 'l58', 'l59']", + "56, (HGF/SF), ['l13', 'l21', 'l28', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l61', 'l62']", + "75, in ['l29', 'l36', 'l43', 'l49', 'l54', 'l58', 'l60', 'l63', 'l64', 'l65']", + "76, vivo ['l14', 'l22', 'l30', 'l37', 'l44', 'l50', 'l55', 'l59', 'l61', 'l63', 'l66', 'l67']", + "109, RMS ['l64', 'l66', 'l68']", + "110, cells. ['l38', 'l45', 'l51', 'l56', 'l62', 'l65', 'l67', 'l68']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "RMS", + "cell", + "lines," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ink4a/Arf-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ink4a/Arf-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ink4a/Arf-deficient" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "hepatocyte", + "growth", + "factor/scatter", + "factor", + "(HGF/SF)," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "hepatocyte", + "growth", + "factor/scatter", + "factor", + "(HGF/SF)," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "for", + "hepatocyte", + "growth", + "factor/scatter", + "(HGF/SF)," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "14702639", + "TEXT": "Endoplasmic reticulum (ER) stress is caused by the accumulation of unfolded proteins in the ER lumen, and is associated with vascular and neurodegenerative diseases. Although the connection between ER stress and some disease-related proteins has been studied using animal models of these diseases, no in vivo data concerning ER stress are available. Here we report a new method for monitoring ER stress in vivo, based on XBP-1 mRNA splicing by inositol requiring-1 (IRE-1) during ER stress. The stress indicator was constructed by fusing XBP-1 and venus, a variant of green fluorescent protein. During stress, the spliced indicator mRNA is translated into an XBP-1-venus fusion protein, which can be detected by its fluorescence. We used transgenic animals expressing the ER stress indicator to show that it can be used to monitor physiological and pathological ER stress in vivo.", + "TAG_DATA": [ + "114, transgenic {'context': 'B-organism'}", + "115, animals {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "114, transgenic ['l0']", + "115, animals ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14702638", + "TEXT": "Both late-gestation and adult human forebrain contain large numbers of oligodendrocyte progenitor cells (OPCs). These cells may be identified by their A2B5(+)PSA-NCAM(-) phenotype (positive for the early oligodendrocyte marker A2B5 and negative for the polysialylated neural cell adhesion molecule). We used dual-color fluorescence-activated cell sorting (FACS) to extract OPCs from 21- to 23-week-old fetal human forebrain, and A2B5 selection to extract these cells from adult white matter. When xenografted to the forebrains of newborn shiverer mice, fetal OPCs dispersed throughout the white matter and developed into oligodendrocytes and astrocytes. By 12 weeks, the host brains showed extensive myelin production, compaction and axonal myelination. Isolates of OPCs derived from adult human white matter also myelinated shiverer mouse brain, but much more rapidly than their fetal counterparts, achieving widespread and dense myelin basic protein (MBP) expression by 4 weeks after grafting. Adult OPCs generated oligodendrocytes more efficiently than fetal OPCs, and ensheathed more host axons per donor cell than fetal cells. Both fetal and adult OPC phenotypes mediated the extensive and robust myelination of congenitally dysmyelinated host brain, although their differences suggested their use for different disease targets.", + "TAG_DATA": [ + "71, forebrains {'context': 'B-tissue/organ'}", + "73, newborn {'context': 'B-organism'}", + "74, shiverer {'context': 'I-organism'}", + "75, mice, {'context': 'I-organism'}", + "76, fetal {'context': 'B-cells'}", + "77, OPCs {'context': 'I-cells'}", + "88, astrocytes. {'context': 'B-cells'}", + "94, brains {'context': 'B-tissue/organ'}", + "104, of {'context': 'I-cells'}", + "105, OPCs {'context': 'I-cells'}", + "106, derived {'context': 'I-cells'}", + "107, from {'context': 'I-cells'}", + "108, adult {'context': 'I-cells'}", + "109, human {'context': 'I-tissue/organ'}", + "110, white {'context': 'I-tissue/organ'}", + "111, matter {'context': 'I-tissue/organ'}", + "114, shiverer {'context': 'B-tissue/organ'}", + "115, mouse {'context': 'I-tissue/organ'}", + "116, brain, {'context': 'I-tissue/organ'}", + "139, Adult {'context': 'B-cells'}", + "140, OPCs {'context': 'I-cells'}", + "152, axons {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "71, forebrains ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "73, newborn ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "74, shiverer ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "75, mice, ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "76, fetal ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "77, OPCs ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "88, astrocytes. ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "94, brains ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "104, of ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "105, OPCs ['l28', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "106, derived ['l29', 'l38', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "107, from ['l30', 'l39', 'l47', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "108, adult ['l31', 'l40', 'l48', 'l55', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "109, human ['l32', 'l41', 'l49', 'l56', 'l62', 'l68', 'l69', 'l70', 'l71', 'l72']", + "110, white ['l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l73', 'l74', 'l75', 'l76']", + "111, matter ['l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l77', 'l78', 'l79']", + "114, shiverer ['l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l80', 'l81']", + "115, mouse ['l36', 'l45', 'l53', 'l60', 'l66', 'l71', 'l75', 'l78', 'l80', 'l82']", + "116, brain, ['l37', 'l46', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l81', 'l82']", + "139, Adult ['l83', 'l84']", + "140, OPCs ['l83', 'l85']", + "152, axons ['l84', 'l85']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14702636", + "TEXT": "The molecular pathways involved in the differentiation of hematopoietic progenitors are unknown. Here we report that chemokine-mediated interactions of megakaryocyte progenitors with sinusoidal bone marrow endothelial cells (BMECs) promote thrombopoietin (TPO)-independent platelet production. Megakaryocyte-active cytokines, including interleukin-6 (IL-6) and IL-11, did not induce platelet production in thrombocytopenic, TPO-deficient (Thpo(-/-)) or TPO receptor-deficient (Mpl(-/-)) mice. In contrast, megakaryocyte-active chemokines, including stromal-derived factor-1 (SDF-1) and fibroblast growth factor-4 (FGF-4), restored thrombopoiesis in Thpo(-/-) and Mpl(-/-) mice. FGF-4 and SDF-1 enhanced vascular cell adhesion molecule-1 (VCAM-1)- and very late antigen-4 (VLA-4)-mediated localization of CXCR4(+) megakaryocyte progenitors to the vascular niche, promoting survival, maturation and platelet release. Disruption of the vascular niche or interference with megakaryocyte motility inhibited thrombopoiesis under physiological conditions and after myelosuppression. SDF-1 and FGF-4 diminished thrombocytopenia after myelosuppression. These data suggest that TPO supports progenitor cell expansion, whereas chemokine-mediated interaction of progenitors with the bone marrow vascular niche allows the progenitors to relocate to a microenvironment that is permissive and instructive for megakaryocyte maturation and thrombopoiesis. Progenitor-active chemokines offer a new strategy to restore hematopoiesis in a clinical setting.", + "TAG_DATA": [ + "47, TPO-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "48, (Thpo(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "50, TPO {'perturbing_action': 'B-gene loss-of-function'}", + "51, receptor-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "52, (Mpl(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "53, mice. {'context': 'B-organism'}", + "70, Thpo(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "71, and {'perturbing_action': 'I-gene loss-of-function'}", + "72, Mpl(-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "73, mice. {'context': 'B-organism'}", + "111, megakaryocyte {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "47, TPO-deficient ['l0', 'l1']", + "48, (Thpo(-/-)) ['l0', 'l2']", + "50, TPO ['l3', 'l4', 'l5', 'l6']", + "51, receptor-deficient ['l3', 'l7', 'l8', 'l9', 'l10', 'l11']", + "52, (Mpl(-/-)) ['l4', 'l7', 'l12', 'l13', 'l14']", + "53, mice. ['l1', 'l2', 'l5', 'l8', 'l12']", + "70, Thpo(-/-) ['l6', 'l9', 'l13', 'l15', 'l16', 'l17']", + "71, and ['l10', 'l15', 'l18', 'l19']", + "72, Mpl(-/-) ['l16', 'l18', 'l20']", + "73, mice. ['l11', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TPO-deficient", + "(Thpo(-/-))", + "TPO", + "receptor-deficient", + "(Mpl(-/-))", + "Thpo(-/-)", + "and", + "Mpl(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "14702633", + "TEXT": "Current antiestrogen therapy for breast cancer is limited by the mixed estrogenic and antiestrogenic activity of selective estrogen receptor modulators. Here we show that the function of zinc fingers in the estrogen receptor DNA-binding domain (DBD) is susceptible to chemical inhibition by electrophilic disulfide benzamide and benzisothiazolone derivatives, which selectively block binding of the estrogen receptor to its responsive element and subsequent transcription. These compounds also significantly inhibit estrogen-stimulated cell proliferation, markedly reduce tumor mass in nude mice bearing human MCF-7 breast cancer xenografts, and interfere with cell-cycle and apoptosis regulatory gene expression. Functional assays and computational analysis support a molecular mechanism whereby electrophilic agents preferentially disrupt the vulnerable C-terminal zinc finger, thus suppressing estrogen receptor-mediated breast carcinoma progression. Our results provide the proof of principle for a new strategy to inhibit breast cancer at the level of DNA binding, rather than the classical antagonism of estrogen binding.", + "TAG_DATA": [ + "67, inhibit {'effect': 'B-negative'}", + "68, estrogen-stimulated {'effect': 'B-positive'}", + "69, cell {'context': 'B-cells'}", + "70, proliferation, {'phenotype': 'B-proliferation'}", + "72, reduce {'effect': 'B-negative'}", + "73, tumor {'phenotype': 'B-tumourigenesis'}", + "74, mass {'phenotype': 'I-tumourigenesis'}", + "76, nude {'context': 'B-organism'}", + "77, mice {'context': 'I-organism'}", + "79, human {'context': 'B-xenograft'}", + "80, MCF-7 {'context': 'I-xenograft'}", + "81, breast {'context': 'I-xenograft'}", + "82, cancer {'context': 'I-xenograft'}", + "83, xenografts, {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "67, inhibit ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "68, estrogen-stimulated ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "69, cell ['l1', 'l6', 'l11']", + "70, proliferation, ['l2', 'l7', 'l11']", + "72, reduce ['l3', 'l8', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "73, tumor ['l4', 'l9', 'l12', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "74, mass ['l5', 'l10', 'l13', 'l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "76, nude ['l14', 'l22', 'l29', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "77, mice ['l15', 'l23', 'l30', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "79, human ['l16', 'l24', 'l31', 'l37', 'l42', 'l47', 'l48', 'l49', 'l50']", + "80, MCF-7 ['l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l51', 'l52', 'l53']", + "81, breast ['l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l54', 'l55']", + "82, cancer ['l19', 'l27', 'l34', 'l40', 'l45', 'l49', 'l52', 'l54', 'l56']", + "83, xenografts, ['l20', 'l28', 'l35', 'l41', 'l46', 'l50', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit", + "reduce" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "mass" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "estrogen-stimulated" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "estrogen-stimulated" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "estrogen-stimulated" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "mass" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduce" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduce" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "human", + "MCF-7", + "breast", + "cancer", + "xenografts," + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "mass" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "mass" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "human", + "MCF-7", + "breast", + "cancer", + "xenografts," + ] + } + } + ] + }, + { + "PMID": "14702631", + "TEXT": "Infection with malaria parasites frequently induces total immune suppression, which makes it difficult for the host to maintain long-lasting immunity. Here we show that depletion of CD4(+)CD25(+) regulatory T cells (T(reg)) protects mice from death when infected with a lethal strain of Plasmodium yoelii, and that this protection is associated with an increased T-cell responsiveness against parasite-derived antigens. These results suggest that activation of T(reg) cells contributes to immune suppression during malaria infection, and helps malaria parasites to escape from host immune responses.", + "TAG_DATA": [ + "24, depletion {'perturbing_action': 'B-gene loss-of-function'}", + "25, of {'perturbing_action': 'I-gene loss-of-function'}", + "26, CD4(+)CD25(+) {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "27, regulatory {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "28, T {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "29, cells {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "30, (T(reg)) {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "32, mice {'context': 'B-organism'}", + "53, T-cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "24, depletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "25, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "26, CD4(+)CD25(+) ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "27, regulatory ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "28, T ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "29, cells ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "30, (T(reg)) ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "32, mice ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "CD4(+)CD25(+)", + "regulatory", + "T", + "cells", + "(T(reg))" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4(+)CD25(+)", + "regulatory", + "T", + "cells", + "(T(reg))" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "CD4(+)CD25(+)", + "regulatory", + "T", + "cells", + "(T(reg))" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "14625546", + "TEXT": "Recent studies have shown that cells from the bone marrow can give rise to differentiated skeletal muscle fibers. However, the mechanisms and identities of the cell types involved have remained unknown, and the validity of the observation has been questioned. Here, we use transplantation of single CD45+ hematopoietic stem cells (HSCs) to demonstrate that the entire circulating myogenic activity in bone marrow is derived from HSCs and their hematopoietic progeny. We also show that ongoing muscle regeneration and inflammatory cell infiltration are required for HSC-derived contribution, which does not occur through a myogenic stem cell intermediate. Using a lineage tracing strategy, we show that myofibers are derived from mature myeloid cells in response to injury. Our results indicate that circulating myeloid cells, in response to inflammatory cues, migrate to regenerating skeletal muscle and stochastically incorporate into mature myofibers.", + "TAG_DATA": [ + "46, CD45+ {'context': 'B-cells'}", + "47, hematopoietic {'context': 'I-cells'}", + "48, stem {'context': 'I-cells'}", + "49, cells {'context': 'I-cells'}", + "50, (HSCs) {'context': 'I-cells'}", + "104, myofibers {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "46, CD45+ ['l0', 'l1', 'l2', 'l3']", + "47, hematopoietic ['l0', 'l4', 'l5', 'l6']", + "48, stem ['l1', 'l4', 'l7', 'l8']", + "49, cells ['l2', 'l5', 'l7', 'l9']", + "50, (HSCs) ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14595407", + "TEXT": "Nitrite anions comprise the largest vascular storage pool of nitric oxide (NO), provided that physiological mechanisms exist to reduce nitrite to NO. We evaluated the vasodilator properties and mechanisms for bioactivation of nitrite in the human forearm. Nitrite infusions of 36 and 0.36 micromol/min into the forearm brachial artery resulted in supra- and near-physiologic intravascular nitrite concentrations, respectively, and increased forearm blood flow before and during exercise, with or without NO synthase inhibition. Nitrite infusions were associated with rapid formation of erythrocyte iron-nitrosylated hemoglobin and, to a lesser extent, S-nitroso-hemoglobin. NO-modified hemoglobin formation was inversely proportional to oxyhemoglobin saturation. Vasodilation of rat aortic rings and formation of both NO gas and NO-modified hemoglobin resulted from the nitrite reductase activity of deoxyhemoglobin and deoxygenated erythrocytes. This finding links tissue hypoxia, hemoglobin allostery and nitrite bioactivation. These results suggest that nitrite represents a major bioavailable pool of NO, and describe a new physiological function for hemoglobin as a nitrite reductase, potentially contributing to hypoxic vasodilation.", + "TAG_DATA": [ + "46, forearm {'context': 'B-tissue/organ'}", + "47, brachial {'context': 'I-tissue/organ'}", + "48, artery {'context': 'I-tissue/organ'}", + "70, NO {'perturbing_action': 'B-pharmacological inhibition'}", + "71, synthase {'perturbing_action': 'I-pharmacological inhibition'}", + "72, inhibition. {'perturbing_action': 'I-pharmacological inhibition'}", + "101, rat {'context': 'B-tissue/organ'}", + "102, aortic {'context': 'I-tissue/organ'}", + "103, rings {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "46, forearm ['l0', 'l1', 'l2', 'l3', 'l4']", + "47, brachial ['l0', 'l5', 'l6', 'l7', 'l8']", + "48, artery ['l1', 'l5', 'l9']", + "60, forearm ['l2', 'l6', 'l9']", + "70, NO ['l3', 'l7', 'l10', 'l11']", + "71, synthase ['l10', 'l12']", + "72, inhibition. ['l4', 'l8', 'l11', 'l12']", + "101, rat ['l13', 'l14']", + "102, aortic ['l13', 'l15']", + "103, rings ['l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "forearm", + "brachial" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NO", + "inhibition." + ] + } + } + ] + }, + { + "PMID": "14528297", + "TEXT": "We isolated pure, viable populations of tumor-cytolytic T cells directly from patient blood samples using flow cytometric quantification of the surface mobilization of CD107a-an integral membrane protein in cytolytic granules-as a marker for degranulation after tumor stimulation. We show that tumor-cytolytic T cells are indeed elicited in patients after cancer vaccination, and that tumor reactivity is strongly correlated with efficient T-cell recognition of peptide-bearing targets. We combined CD107a mobilization with peptide-major histocompatibility complex (P-MHC) tetramer staining to directly correlate antigen specificity and cytolytic ability on a single-cell level. This showed that tumor-cytolytic T cells with high recognition efficiency represent only a minority of peptide-specific T cells elicited in patients after heteroclitic peptide vaccination. We were also able to expand these cells to high numbers ex vivo while maintaining their cytolytic potential. These techniques will be useful not only for immune monitoring of cancer vaccine trials, but also for adoptive cellular immunotherapy after ex vivo expansion. The ability to rapidly identify and isolate tumor-cytolytic T cells would be very useful in cancer immunotherapy.", + "TAG_DATA": [ + "108, patients {'context': 'B-patient'}", + "120, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "14502281", + "TEXT": "CD8(+) T cells are essential for long-term, vaccine-induced resistance against intracellular pathogens. Here we show that natural antibodies, acting in concert with complement, are endogenous adjuvants for the generation of protective CD8(+) T cells after vaccination against visceral leishmaniasis. IL-4 was crucial for the priming of vaccine-specific CD8(+) T cells, and we defined the primary source of IL-4 as a CD11b(+)CD11c(lo) phagocyte. IL-4 secretion was not observed in antibody-deficient mice and could be reconstituted with serum from normal, but not Btk immune-deficient, mice. Similarly, no IL-4 response or CD8(+) T-cell priming was seen in C1qa(-/-) mice. These results identify a new pathway by which immune complex-mediated complement activation can regulate T-cell-mediated immunity. We propose that this function of natural antibodies could be exploited when developing new vaccines for infectious diseases.", + "TAG_DATA": [ + "47, CD8(+) {'context': 'B-cells'}", + "48, T {'context': 'I-cells'}", + "49, cells, {'context': 'I-cells'}", + "69, mice {'context': 'B-organism'}", + "80, Btk {'perturbing_action': 'B-gene loss-of-function'}", + "81, immune-deficient, {'perturbing_action': 'I-gene loss-of-function'}", + "82, mice. {'context': 'B-organism'}", + "88, CD8(+) {'context': 'B-cells'}", + "89, T-cell {'context': 'I-cells'}", + "94, C1qa(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "95, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "47, CD8(+) ['l0', 'l1', 'l2']", + "48, T ['l0', 'l3', 'l4']", + "49, cells, ['l1', 'l3', 'l5']", + "69, mice ['l2', 'l4', 'l5']", + "80, Btk ['l6', 'l7']", + "81, immune-deficient, ['l6', 'l8']", + "82, mice. ['l7', 'l8']", + "88, CD8(+) ['l9', 'l10', 'l11']", + "89, T-cell ['l9', 'l12', 'l13']", + "94, C1qa(-/-) ['l10', 'l12', 'l14']", + "95, mice. ['l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Btk", + "immune-deficient,", + "C1qa(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "T-cell" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "C1qa(-/-)" + ] + } + } + ] + }, + { + "PMID": "14502277", + "TEXT": "Understanding the process of vector transduction has important implications for the application and optimal use of a vector system for human gene therapy. Recent studies with vectors based on adeno-associated virus type 5 (AAV-5) have shown utility of this vector system in the lung, central nervous system, muscle and eye. To understand the natural tropism of this virus and to identify proteins necessary for AAV-5 transduction, we characterized 43 cell lines as permissive or nonpermissive for AAV-5 transduction and compared the gene expression profiles derived from cDNA microarray analyses of those cell lines. A statistically significant correlation was observed between expression of the platelet-derived growth factor receptor (PDGFR-alpha-polypeptide) and AAV-5 transduction. Subsequent experiments confirmed the role of PDGFR-alpha and PDGFR-beta as receptors for AAV-5. The tropism of AAV-5 in vivo also correlated with the expression pattern of PDGFR-alpha.", + "TAG_DATA": [ + "69, cell {'context': 'B-cells'}", + "70, lines {'context': 'I-cells'}", + "91, cell {'context': 'B-cells'}", + "92, lines. {'context': 'I-cells'}", + "128, in {'context': 'B-in vivo'}", + "129, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "69, cell ['l0']", + "70, lines ['l0']", + "91, cell ['l1']", + "92, lines. ['l1']", + "128, in ['l2']", + "129, vivo ['l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12949501", + "TEXT": "Glucocorticoids, acting through the glucocorticoid receptor, potently modulate immune function and are a mainstay of therapy for treatment of inflammatory conditions, autoimmune diseases, leukemias and lymphomas. Moreover, removal of systemic glucocorticoids, by adrenalectomy in animal models or adrenal insufficiency in humans, has shown that endogenous glucocorticoid production is required for regulation of physiologic immune responses. These effects have been attributed to suppression of cytokines, although the crucial cellular and molecular targets remain unknown. In addition, considerable controversy remains as to whether glucocorticoids are required for thymocyte development. To assess the role of the glucocorticoid receptor in immune system development and function, we generated T-cell-specific glucocorticoid receptor knockout mice. Here we show that the T-cell is a critical cellular target of glucocorticoid receptor signaling, as immune activation in these mice resulted in significant mortality. This lethal activation is rescued by cyclooxygenase-2 (COX-2) inhibition but not steroid administration or cytokine neutralization. These studies indicate that glucocorticoid receptor suppression of COX-2 is crucial for curtailing lethal immune activation, and suggest new therapeutic approaches for regulation of T-cell-mediated inflammatory diseases.", + "TAG_DATA": [ + "103, T-cell-specific {'perturbing_action': 'B-gene loss-of-function'}", + "104, glucocorticoid {'perturbing_action': 'I-gene loss-of-function'}", + "105, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "106, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "107, mice. {'context': 'B-organism'}", + "128, mice {'context': 'B-organism'}", + "139, cyclooxygenase-2 {'perturbing_action': 'B-pharmacological inhibition'}", + "140, (COX-2) {'perturbing_action': 'I-pharmacological inhibition'}", + "141, inhibition {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "103, T-cell-specific ['l0', 'l1', 'l2', 'l3', 'l4']", + "104, glucocorticoid ['l0', 'l5', 'l6', 'l7', 'l8']", + "105, receptor ['l1', 'l5', 'l9', 'l10', 'l11']", + "106, knockout ['l2', 'l6', 'l9', 'l12', 'l13']", + "107, mice. ['l3', 'l7', 'l10', 'l12', 'l14']", + "128, mice ['l4', 'l8', 'l11', 'l13', 'l14']", + "139, cyclooxygenase-2 ['l15', 'l16']", + "140, (COX-2) ['l15', 'l17']", + "141, inhibition ['l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "T-cell-specific", + "glucocorticoid", + "receptor", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + } + ] + }, + { + "PMID": "12910262", + "TEXT": "Transplantation of adult bone marrow-derived mesenchymal stem cells has been proposed as a strategy for cardiac repair following myocardial damage. However, poor cell viability associated with transplantation has limited the reparative capacity of these cells in vivo. In this study, we genetically engineered rat mesenchymal stem cells using ex vivo retroviral transduction to overexpress the prosurvival gene Akt1 (encoding the Akt protein). Transplantation of 5 x 10(6) cells overexpressing Akt into the ischemic rat myocardium inhibited the process of cardiac remodeling by reducing intramyocardial inflammation, collagen deposition and cardiac myocyte hypertrophy, regenerated 80-90% of lost myocardial volume, and completely normalized systolic and diastolic cardiac function. These observed effects were dose (cell number) dependent. Mesenchymal stem cells transduced with Akt1 restored fourfold greater myocardial volume than equal numbers of cells transduced with the reporter gene lacZ. Thus, mesenchymal stem cells genetically enhanced with Akt1 can repair infarcted myocardium, prevent remodeling and nearly normalize cardiac performance.", + "TAG_DATA": [ + "43, rat {'context': 'B-cells'}", + "44, mesenchymal {'context': 'I-cells'}", + "45, stem {'context': 'I-cells'}", + "46, cells {'context': 'I-cells'}", + "53, overexpress {'perturbing_action': 'B-gene gain-of-function'}", + "64, 5 {'perturbing_action': 'B-gene gain-of-function'}", + "65, x {'perturbing_action': 'B-gene gain-of-function'}", + "66, 10(6) {'perturbing_action': 'B-gene gain-of-function'}", + "67, cells {'perturbing_action': 'I-gene gain-of-function'}", + "68, overexpressing {'perturbing_action': 'I-gene gain-of-function'}", + "69, Akt {'perturbing_action': 'I-gene gain-of-function'}", + "73, rat {'context': 'B-tissue/organ'}", + "74, myocardium {'context': 'I-tissue/organ'}", + "88, cardiac {'context': 'B-cells'}", + "89, myocyte {'context': 'I-cells'}", + "113, Mesenchymal {'context': 'B-cells'}", + "114, stem {'context': 'I-cells'}", + "115, cells {'context': 'I-cells'}", + "116, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "117, with {'perturbing_action': 'I-gene gain-of-function'}", + "118, Akt1 {'perturbing_action': 'I-gene gain-of-function'}", + "128, cells {'context': 'B-cells'}", + "129, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "130, with {'perturbing_action': 'I-gene gain-of-function'}", + "131, the {'perturbing_action': 'I-gene gain-of-function'}", + "132, reporter {'perturbing_action': 'I-gene gain-of-function'}", + "133, gene {'perturbing_action': 'I-gene gain-of-function'}", + "134, lacZ. {'perturbing_action': 'I-gene gain-of-function'}", + "136, mesenchymal {'context': 'B-cells'}", + "137, stem {'context': 'I-cells'}", + "138, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "43, rat ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "44, mesenchymal ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "45, stem ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "46, cells ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "53, overexpress ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "64, 5 ['l4', 'l17', 'l29', 'l40', 'l50', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "65, x ['l5', 'l18', 'l30', 'l41', 'l51', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "66, 10(6) ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "67, cells ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "68, overexpressing ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l90', 'l91', 'l92', 'l93', 'l94']", + "69, Akt ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l95', 'l96', 'l97', 'l98']", + "73, rat ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l99', 'l100', 'l101']", + "74, myocardium ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l102', 'l103']", + "88, cardiac ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l104']", + "89, myocyte ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l104']", + "113, Mesenchymal ['l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "114, stem ['l105', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "115, cells ['l106', 'l120', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146']", + "116, transduced ['l107', 'l121', 'l134', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158']", + "117, with ['l108', 'l122', 'l135', 'l147', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "118, Akt1 ['l109', 'l123', 'l136', 'l148', 'l159', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179']", + "128, cells ['l110', 'l124', 'l137', 'l149', 'l160', 'l170', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "129, transduced ['l111', 'l125', 'l138', 'l150', 'l161', 'l171', 'l180', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196']", + "130, with ['l112', 'l126', 'l139', 'l151', 'l162', 'l172', 'l181', 'l189', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203']", + "131, the ['l113', 'l127', 'l140', 'l152', 'l163', 'l173', 'l182', 'l190', 'l197', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209']", + "132, reporter ['l114', 'l128', 'l141', 'l153', 'l164', 'l174', 'l183', 'l191', 'l198', 'l204', 'l210', 'l211', 'l212', 'l213', 'l214']", + "133, gene ['l115', 'l129', 'l142', 'l154', 'l165', 'l175', 'l184', 'l192', 'l199', 'l205', 'l210', 'l215', 'l216', 'l217', 'l218']", + "134, lacZ. ['l116', 'l130', 'l143', 'l155', 'l166', 'l176', 'l185', 'l193', 'l200', 'l206', 'l211', 'l215', 'l219', 'l220', 'l221']", + "136, mesenchymal ['l117', 'l131', 'l144', 'l156', 'l167', 'l177', 'l186', 'l194', 'l201', 'l207', 'l212', 'l216', 'l219', 'l222', 'l223']", + "137, stem ['l118', 'l132', 'l145', 'l157', 'l168', 'l178', 'l187', 'l195', 'l202', 'l208', 'l213', 'l217', 'l220', 'l222', 'l224']", + "138, cells ['l119', 'l133', 'l146', 'l158', 'l169', 'l179', 'l188', 'l196', 'l203', 'l209', 'l214', 'l218', 'l221', 'l223', 'l224']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "rat", + "mesenchymal", + "stem", + "cells", + "cardiac", + "myocyte", + "Mesenchymal" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpress", + "5", + "x", + "10(6)", + "cells", + "overexpressing", + "Akt", + "transduced", + "with", + "Akt1", + "the", + "reporter", + "gene", + "lacZ." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpress", + "5", + "x", + "10(6)", + "cells", + "overexpressing", + "Akt" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "myocardium" + ] + } + } + ] + }, + { + "PMID": "12872166", + "TEXT": "Protective immunity against Mycobacterium tuberculosis involves major histocompatibility complex class I (MHC-I)- and CD1-restricted CD8 T cells, but the mechanisms underlying antigen delivery to antigen-presenting molecules remain enigmatic. Macrophages, the primary host cells for mycobacteria, are CD1-negative. Here we show that M. tuberculosis phagosomes are secluded from the cytosolic MHC-I processing pathway and that mycobacteria-infected cells lose their antigen-presenting capacity. We also show that mycobacteria induce apoptosis in macrophages, causing the release of apoptotic vesicles that carry mycobacterial antigens to uninfected antigen-presenting cells (APCs). Inhibition of apoptosis reduced transfer of antigens to bystander cells and activation of CD8 T cells. Uninfected dendritic cells, which engulfed extracellular vesicles, were indispensable for subsequent cross-presentation of antigens, through MHC-I and CD1b, to T cells from mycobacteria-sensitized donors. This new 'detour' pathway for presentation of antigens from a phagosome-contained pathogen shows the functional significance of infection-induced apoptosis in the activation of CD8 T cells specific for both protein and glycolipid antigens in tuberculosis.", + "TAG_DATA": [ + "65, induce {'effect': 'B-positive'}", + "66, apoptosis {'phenotype': 'B-apoptosis'}", + "68, macrophages, {'context': 'B-cells'}", + "81, antigen-presenting {'context': 'B-cells'}", + "82, cells {'context': 'I-cells'}", + "83, (APCs). {'context': 'I-cells'}", + "84, Inhibition {'effect': 'B-negative'}", + "86, apoptosis {'phenotype': 'B-apoptosis'}", + "92, bystander {'context': 'B-cells'}", + "93, cells {'context': 'I-cells'}", + "97, CD8 {'context': 'B-cells'}", + "98, T {'context': 'I-cells'}", + "99, cells. {'context': 'I-cells'}", + "101, dendritic {'context': 'I-cells'}", + "102, cells, {'context': 'I-cells'}", + "119, T {'context': 'B-cells'}", + "120, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "65, induce ['l0', 'l1', 'l2', 'l3']", + "66, apoptosis ['l0', 'l4', 'l5', 'l6', 'l7']", + "68, macrophages, ['l1', 'l4', 'l8', 'l9', 'l10']", + "81, antigen-presenting ['l5', 'l8', 'l11', 'l12', 'l13', 'l14', 'l15']", + "82, cells ['l2', 'l6', 'l9', 'l11', 'l16', 'l17', 'l18']", + "83, (APCs). ['l3', 'l7', 'l10', 'l12', 'l16', 'l19', 'l20']", + "84, Inhibition ['l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "86, apoptosis ['l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "92, bystander ['l13', 'l17', 'l19', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "93, cells ['l14', 'l18', 'l20', 'l23', 'l28', 'l32', 'l36']", + "97, CD8 ['l24', 'l29', 'l33', 'l37', 'l38']", + "98, T ['l25', 'l30', 'l34', 'l37', 'l39']", + "99, cells. ['l15', 'l26', 'l31', 'l35', 'l36', 'l38', 'l39']", + "101, dendritic ['l40', 'l41', 'l42']", + "102, cells, ['l40', 'l43', 'l44']", + "119, T ['l41', 'l43', 'l45']", + "120, cells ['l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages,", + "cells", + "(APCs)." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages,", + "antigen-presenting", + "cells", + "(APCs).", + "bystander", + "CD8", + "T", + "cells." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "Inhibition" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "Inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "bystander", + "cells", + "CD8", + "T", + "cells." + ] + } + } + ] + }, + { + "PMID": "12872165", + "TEXT": "Current understanding of key transcription factors regulating angiogenesis is limited. Here we show that RNA-cleaving phosphodiester-linked DNA-based enzymes (DNAzymes), targeting a specific motif in the 5' untranslated region of early growth response (Egr-1) mRNA, inhibit Egr-1 protein expression, microvascular endothelial cell replication and migration, and microtubule network formation on basement membrane matrices. Egr-1 DNAzymes blocked angiogenesis in subcutaneous Matrigel plugs in mice, an observation that was independently confirmed by plug analysis in Egr-1-deficient animals, and inhibited MCF-7 human breast carcinoma growth in nude mice. Egr-1 DNAzymes suppressed tumor growth without influencing body weight, wound healing, blood coagulation or other hematological parameters. These agents inhibited endothelial expression of fibroblast growth factor (FGF)-2, a proangiogenic factor downstream of Egr-1, but not that of vascular endothelial growth factor (VEGF). Egr-1 DNAzymes also repressed neovascularization of rat cornea. Thus, microvascular endothelial cell growth, neovascularization, tumor angiogenesis and tumor growth are processes that are critically dependent on Egr-1.", + "TAG_DATA": [ + "43, migration, {'phenotype': 'B-migration'}", + "61, mice, {'context': 'B-organism'}", + "72, Egr-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "73, animals, {'context': 'B-organism'}", + "75, inhibited {'effect': 'B-negative'}", + "76, MCF-7 {'context': 'B-neoplasm'}", + "77, human {'context': 'I-neoplasm'}", + "78, breast {'context': 'I-neoplasm'}", + "79, carcinoma {'context': 'I-neoplasm'}", + "82, nude {'context': 'B-organism'}", + "83, mice. {'context': 'I-organism'}", + "86, suppressed {'effect': 'B-negative'}", + "87, tumor {'phenotype': 'B-tumour growth'}", + "88, growth {'phenotype': 'I-tumour growth'}", + "129, repressed {'effect': 'B-negative'}", + "132, rat {'context': 'B-tissue/organ'}", + "133, cornea. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "72, Egr-1-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "73, animals, ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "75, inhibited ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "76, MCF-7 ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "77, human ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "78, breast ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "79, carcinoma ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "82, nude ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "83, mice. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "86, suppressed ['l36', 'l37']", + "87, tumor ['l36', 'l38']", + "88, growth ['l37', 'l38']", + "129, repressed ['l39', 'l40']", + "132, rat ['l39', 'l41']", + "133, cornea. ['l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Egr-1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "animals,", + "nude", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Egr-1-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Egr-1-deficient" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "MCF-7", + "human", + "breast", + "carcinoma" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animals,", + "nude", + "mice." + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "MCF-7", + "human", + "breast", + "carcinoma" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "repressed" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "cornea." + ] + } + } + ] + }, + { + "PMID": "12847523", + "TEXT": "Conventional gene therapy of hemophilia A relies on the transfer of factor VIII (FVIII; encoded by the F8 gene) cDNA. We carried out spliceosome-mediated RNA trans-splicing (SMaRT) to repair mutant FVIII mRNA. A pre-trans-splicing molecule (PTM) corrected endogenous FVIII mRNA in F8 knockout mice with the hemophilia A phenotype, producing sufficient functional FVIII to correct the hemophilia A phenotype. This is the first description of phenotypic correction of a genetic defect by RNA repair in a knockout animal model. Our results indicate the feasibility of using SMaRT to repair RNA for the treatment of genetic diseases.", + "TAG_DATA": [ + "41, F8 {'perturbing_action': 'B-gene loss-of-function'}", + "42, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "43, mice {'context': 'B-organism'}", + "78, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "41, F8 ['l0', 'l1']", + "42, knockout ['l0', 'l2']", + "43, mice ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "F8", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "12819778", + "TEXT": "Streptococcus pyogenes-induced acute rheumatic fever (ARF) is one of the best examples of postinfectious autoimmunity due to molecular mimicry between host and pathogen. Sydenham chorea is the major neurological manifestation of ARF but its pathogenesis has remained elusive, with no candidate autoantigen or mechanism of pathogenesis described. Chorea monoclonal antibodies showed specificity for mammalian lysoganglioside and N-acetyl-beta-D-glucosamine (GlcNAc), the dominant epitope of the group A streptococcal (GAS) carbohydrate. Chorea antibodies targeted the surface of human neuronal cells, with specific induction of calcium/calmodulin-dependent protein (CaM) kinase II activity by monoclonal antibody 24.3.1 and sera from active chorea. Convalescent sera and sera from other streptococcal diseases in the absence of chorea did not activate the kinase. The new evidence implicates antibody-mediated neuronal cell signaling in the immunopathogenesis of Sydenham chorea and will lead to a better understanding of other antibody-mediated neurological disorders.", + "TAG_DATA": [ + "74, human {'context': 'B-cells'}", + "75, neuronal {'context': 'I-cells'}", + "76, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "74, human ['l0', 'l1']", + "75, neuronal ['l0', 'l2']", + "76, cells, ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12808448", + "TEXT": "Bone morphogenic protein (BMP)-7 is a 35-kDa homodimeric protein and a member of the transforming growth factor (TGF)-beta superfamily. BMP-7 expression is highest in the kidney, and its genetic deletion in mice leads to severe impairment of eye, skeletal and kidney development. Here we report that BMP-7 reverses TGF-beta1-induced epithelial-to-mesenchymal transition (EMT) by reinduction of E-cadherin, a key epithelial cell adhesion molecule. Additionally, we provide molecular evidence for Smad-dependent reversal of TGF-beta1-induced EMT by BMP-7 in renal tubular epithelial cells and mammary ductal epithelial cells. In the kidney, EMT-induced accumulation of myofibroblasts and subsequent tubular atrophy are considered key determinants of renal fibrosis during chronic renal injury. We therefore tested the potential of BMP-7 to reverse TGF-beta1-induced de novo EMT in a mouse model of chronic renal injury. Our results show that systemic administration of recombinant human BMP-7 leads to repair of severely damaged renal tubular epithelial cells, in association with reversal of chronic renal injury. Collectively, these results provide evidence of cross talk between BMP-7 and TGF-beta1 in the regulation of EMT in health and disease.", + "TAG_DATA": [ + "47, reverses {'effect': 'B-negative'}", + "48, TGF-beta1-induced {'effect': 'B-positive'}", + "49, epithelial-to-mesenchymal {'phenotype': 'B-epithelial-mesenchymal transition'}", + "50, transition {'phenotype': 'I-epithelial-mesenchymal transition'}", + "51, (EMT) {'phenotype': 'I-epithelial-mesenchymal transition'}", + "71, TGF-beta1-induced {'effect': 'B-positive'}", + "72, EMT {'phenotype': 'B-epithelial-mesenchymal transition'}", + "76, renal {'context': 'B-cells'}", + "77, tubular {'context': 'I-cells'}", + "78, epithelial {'context': 'I-cells'}", + "79, cells {'context': 'I-cells'}", + "81, mammary {'context': 'B-cells'}", + "82, ductal {'context': 'I-cells'}", + "83, epithelial {'context': 'I-cells'}", + "84, cells. {'context': 'I-cells'}", + "87, kidney, {'context': 'B-tissue/organ'}", + "91, myofibroblasts {'context': 'B-cells'}", + "115, reverse {'effect': 'B-negative'}", + "116, TGF-beta1-induced {'effect': 'B-positive'}", + "119, EMT {'phenotype': 'B-epithelial-mesenchymal transition'}", + "122, mouse {'context': 'B-organism'}", + "123, model {'context': 'I-organism'}", + "144, renal {'context': 'B-cells'}", + "145, tubular {'context': 'I-cells'}", + "146, epithelial {'context': 'I-cells'}", + "147, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "47, reverses ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "48, TGF-beta1-induced ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "49, epithelial-to-mesenchymal ['l1', 'l9', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "50, transition ['l2', 'l10', 'l19', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "51, (EMT) ['l3', 'l11', 'l20', 'l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "71, TGF-beta1-induced ['l12', 'l21', 'l29', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "72, EMT ['l4', 'l13', 'l22', 'l30', 'l36', 'l41', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "76, renal ['l5', 'l14', 'l23', 'l31', 'l37', 'l42', 'l52', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "77, tubular ['l6', 'l15', 'l24', 'l32', 'l38', 'l43', 'l53', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "78, epithelial ['l7', 'l16', 'l25', 'l33', 'l39', 'l44', 'l54', 'l61', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "79, cells ['l8', 'l17', 'l26', 'l34', 'l40', 'l45', 'l55', 'l62', 'l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88']", + "81, mammary ['l46', 'l63', 'l71', 'l78', 'l84', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "82, ductal ['l47', 'l56', 'l64', 'l72', 'l79', 'l85', 'l89', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "83, epithelial ['l48', 'l57', 'l65', 'l73', 'l80', 'l86', 'l90', 'l98', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "84, cells. ['l18', 'l27', 'l49', 'l58', 'l66', 'l74', 'l81', 'l87', 'l91', 'l99', 'l106', 'l113', 'l114', 'l115']", + "87, kidney, ['l50', 'l59', 'l67', 'l75', 'l82', 'l88', 'l92', 'l100', 'l107', 'l113', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "91, myofibroblasts ['l51', 'l68', 'l76', 'l83', 'l93', 'l101', 'l108', 'l114', 'l116', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "115, reverse ['l117', 'l123', 'l129', 'l130', 'l131', 'l132', 'l133']", + "116, TGF-beta1-induced ['l118', 'l124', 'l129', 'l134', 'l135', 'l136', 'l137']", + "118, novo ['l94', 'l102', 'l109', 'l119', 'l125', 'l130', 'l134', 'l138', 'l139', 'l140']", + "119, EMT ['l95', 'l103', 'l110', 'l115', 'l120', 'l126', 'l131', 'l135', 'l138', 'l141', 'l142']", + "122, mouse ['l96', 'l104', 'l111', 'l121', 'l127', 'l132', 'l136', 'l139', 'l141', 'l143']", + "123, model ['l97', 'l105', 'l112', 'l122', 'l128', 'l133', 'l137', 'l140', 'l142', 'l143']", + "144, renal ['l144', 'l145', 'l146']", + "145, tubular ['l144', 'l147', 'l148']", + "146, epithelial ['l145', 'l147', 'l149']", + "147, cells, ['l146', 'l148', 'l149']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "reverses", + "reverse" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "epithelial-to-mesenchymal", + "transition", + "(EMT)", + "EMT" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reverses", + "reverse" + ] + }, + "context": { + "val": "cells", + "words": [ + "renal", + "tubular", + "epithelial", + "cells", + "myofibroblasts" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "TGF-beta1-induced" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "epithelial-to-mesenchymal", + "transition", + "(EMT)", + "EMT" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "TGF-beta1-induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "renal", + "tubular", + "epithelial", + "cells", + "cells.", + "mammary", + "ductal", + "myofibroblasts" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "epithelial-to-mesenchymal", + "transition", + "(EMT)", + "EMT" + ] + }, + "context": { + "val": "cells", + "words": [ + "renal", + "tubular", + "epithelial", + "cells", + "cells.", + "ductal", + "mammary", + "myofibroblasts" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "TGF-beta1-induced" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidney," + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EMT" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidney," + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "kidney," + ] + }, + "effect": { + "val": "negative", + "words": [ + "reverse" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reverse" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "TGF-beta1-induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EMT" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + } + ] + }, + { + "PMID": "12808447", + "TEXT": "Dengue virus presents a growing threat to public health in the developing world. Four major serotypes of dengue virus have been characterized, and epidemiological evidence shows that dengue hemorrhagic fever (DHF), the more serious manifestation of the disease, occurs more frequently upon reinfection with a second serotype. We have studied dengue virus-specific T-cell responses in Thai children. During acute infection, few dengue-responsive CD8+ T cells were recovered; most of those present showed an activated phenotype and were undergoing programmed cell death. Many dengue-specific T cells were of low affinity for the infecting virus and showed higher affinity for other, probably previously encountered strains. Profound T-cell activation and death may contribute to the systemic disturbances leading to DHF, and original antigenic sin in the T-cell responses may suppress or delay viral elimination, leading to higher viral loads and increased immunopathology.", + "TAG_DATA": [ + "62, CD8+ {'context': 'B-cells'}", + "63, T {'context': 'I-cells'}", + "64, cells {'context': 'I-cells'}", + "79, cell {'phenotype': 'B-cell death'}", + "80, death. {'phenotype': 'I-cell death'}", + "82, dengue-specific {'context': 'B-cells'}", + "83, T {'context': 'I-cells'}", + "84, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "62, CD8+ ['l0', 'l1', 'l2', 'l3']", + "63, T ['l0', 'l4', 'l5', 'l6']", + "64, cells ['l1', 'l4', 'l7', 'l8']", + "79, cell ['l2', 'l5', 'l7', 'l9']", + "80, death. ['l3', 'l6', 'l8', 'l9']", + "82, dengue-specific ['l10', 'l11']", + "83, T ['l10', 'l12']", + "84, cells ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD8+", + "T", + "cells" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "12796774", + "TEXT": "A major problem hampering effective stem cell-based therapies is the absence of a clear understanding of the human hematopoietic stem cell (HSC) pool composition. The severe combined immunodeficiency (SCID) repopulating cell (SRC) xenotransplant assay system provides a powerful tool for characterizing the frequency, cell surface markers, cell cycle status, homing and response to cytokine stimulation of human HSCs. Clonal tracking of retrovirally transduced SRCs and transplantation of specific subpopulations revealed SRC classes with distinct repopulation potentials. However, all HSC repopulation assays are based on intravenous injection, a complex process that requires circulation through blood, recognition and extravasation through bone marrow vasculature, and migration to a supportive microenvironment. Thus, some classes of HSCs may remain undetected. By direct intrafemoral injection, we identified rapid SRCs (R-SRCs) within the Lin-CD34+CD38loCD36- subpopulation. R-SRCs rapidly generate high levels of human myeloid and erythroid cells within the injected femur, migrate to the blood and colonize individual bones of non-obese diabetic (NOD)-SCID mice within 2 weeks after transplantation. Lentivector-mediated clonal analysis of individual R-SRCs revealed heterogeneity in their proliferative and migratory properties. The identification of a new HSC class and an effective intrafemoral assay provide the tools required to develop more effective stem cell-based therapies that rely on rapid reconstitution.", + "TAG_DATA": [ + "134, human {'context': 'B-cells'}", + "135, myeloid {'context': 'I-cells'}", + "136, and {'context': 'I-cells'}", + "137, erythroid {'context': 'I-cells'}", + "138, cells {'context': 'I-cells'}", + "142, femur, {'context': 'B-tissue/organ'}", + "152, non-obese {'context': 'B-organism'}", + "153, diabetic {'context': 'I-organism'}", + "154, (NOD)-SCID {'context': 'I-organism'}", + "155, mice {'context': 'I-organism'}", + "173, migratory {'phenotype': 'B-migration'}" + ], + "LINK_DATA": [ + "134, human ['l0', 'l1', 'l2', 'l3', 'l4']", + "135, myeloid ['l0', 'l5', 'l6', 'l7', 'l8']", + "136, and ['l1', 'l5', 'l9', 'l10', 'l11']", + "137, erythroid ['l2', 'l6', 'l9', 'l12', 'l13']", + "138, cells ['l3', 'l7', 'l10', 'l12', 'l14']", + "142, femur, ['l4', 'l8', 'l11', 'l13', 'l14']", + "152, non-obese ['l15', 'l16', 'l17']", + "153, diabetic ['l15', 'l18', 'l19']", + "154, (NOD)-SCID ['l16', 'l18', 'l20']", + "155, mice ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12796773", + "TEXT": "Therapeutic angiogenesis is likely to require the administration of factors that complement each other. Activation of the receptor tyrosine kinase (RTK) Flk1 by vascular endothelial growth factor (VEGF) is crucial, but molecular interactions of other factors with VEGF and Flk1 have been studied to a limited extent. Here we report that placental growth factor (PGF, also known as PlGF) regulates inter- and intramolecular cross talk between the VEGF RTKs Flt1 and Flk1. Activation of Flt1 by PGF resulted in intermolecular transphosphorylation of Flk1, thereby amplifying VEGF-driven angiogenesis through Flk1. Even though VEGF and PGF both bind Flt1, PGF uniquely stimulated the phosphorylation of specific Flt1 tyrosine residues and the expression of distinct downstream target genes. Furthermore, the VEGF/PGF heterodimer activated intramolecular VEGF receptor cross talk through formation of Flk1/Flt1 heterodimers. The inter- and intramolecular VEGF receptor cross talk is likely to have therapeutic implications, as treatment with VEGF/PGF heterodimer or a combination of VEGF plus PGF increased ischemic myocardial angiogenesis in a mouse model that was refractory to VEGF alone.", + "TAG_DATA": [ + "162, mouse {'context': 'B-organism'}", + "163, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "162, mouse ['l0']", + "163, model ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12740571", + "TEXT": "Antigen-specific immune responses in the skin are initiated by antigen uptake into Langerhans cells and the subsequent migration of these cells to draining lymph nodes. Although prostaglandin E2 (PGE2) is produced substantially in skin exposed to antigen, its role remains unclear. Here we show that although Langerhans cells express all four PGE receptor subtypes, their migration to regional lymph nodes was decreased only in EP4-deficient (Ptger4-/-) mice and in wild-type mice treated with an EP4 antagonist. An EP4 agonist promoted the migration of Langerhans cells, increased their expression of costimulatory molecules and enhanced their ability to stimulate T cells in the mixed lymphocyte reaction in vitro. Contact hypersensitivity to antigen was impaired in Ptger4-/- mice and in wild-type mice treated with the EP4 antagonist during sensitization. PGE2-EP4 signaling thus facilitates initiation of skin immune responses by promoting the migration and maturation of Langerhans cells.", + "TAG_DATA": [ + "64, EP4-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "65, (Ptger4-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "66, mice {'context': 'B-organism'}", + "70, mice {'context': 'B-organism'}", + "74, EP4 {'perturbing_action': 'B-pharmacological inhibition'}", + "75, antagonist. {'perturbing_action': 'I-pharmacological augmentation'}", + "77, EP4 {'perturbing_action': 'B-pharmacological augmentation'}", + "78, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "79, promoted {'effect': 'B-positive'}", + "81, migration {'phenotype': 'B-migration'}", + "83, Langerhans {'context': 'B-cells'}", + "84, cells, {'context': 'I-cells'}", + "97, T {'context': 'B-cells'}", + "98, cells {'context': 'B-cells'}", + "104, in {'context': 'B-in vitro'}", + "105, vitro. {'context': 'I-in vitro'}", + "113, Ptger4-/- {'perturbing_action': 'B-gene loss-of-function'}", + "114, mice {'context': 'B-organism'}", + "118, mice {'context': 'B-organism'}", + "122, EP4 {'perturbing_action': 'B-pharmacological inhibition'}", + "123, antagonist {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "64, EP4-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "65, (Ptger4-/-) ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "66, mice ['l1', 'l10', 'l19', 'l20']", + "70, mice ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "74, EP4 ['l21', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "75, antagonist. ['l22', 'l33', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "77, EP4 ['l23', 'l34', 'l44', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "78, agonist ['l24', 'l35', 'l45', 'l54', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "79, promoted ['l2', 'l11', 'l25', 'l36', 'l46', 'l55', 'l63', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "81, migration ['l3', 'l12', 'l26', 'l37', 'l47', 'l56', 'l64', 'l71', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "83, Langerhans ['l4', 'l13', 'l27', 'l38', 'l48', 'l57', 'l65', 'l72', 'l78', 'l84', 'l85', 'l86', 'l87', 'l88']", + "84, cells, ['l5', 'l14', 'l19', 'l28', 'l39', 'l49', 'l58', 'l66', 'l73', 'l79', 'l84', 'l89', 'l90', 'l91', 'l92']", + "97, T ['l6', 'l15', 'l29', 'l40', 'l50', 'l59', 'l67', 'l74', 'l80', 'l85', 'l89', 'l93', 'l94', 'l95']", + "98, cells ['l7', 'l16', 'l20', 'l30', 'l41', 'l51', 'l60', 'l68', 'l75', 'l81', 'l86', 'l90', 'l93', 'l96', 'l97']", + "104, in ['l8', 'l17', 'l31', 'l42', 'l52', 'l61', 'l69', 'l76', 'l82', 'l87', 'l91', 'l94', 'l96', 'l98']", + "105, vitro. ['l9', 'l18', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l83', 'l88', 'l92', 'l95', 'l97', 'l98']", + "113, Ptger4-/- ['l99', 'l100']", + "114, mice ['l99']", + "118, mice ['l100', 'l101', 'l102']", + "122, EP4 ['l101', 'l103']", + "123, antagonist ['l102', 'l103']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EP4-deficient", + "(Ptger4-/-)", + "Ptger4-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EP4-deficient", + "(Ptger4-/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EP4-deficient", + "(Ptger4-/-)" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EP4-deficient", + "(Ptger4-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "Langerhans", + "cells,", + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EP4-deficient", + "(Ptger4-/-)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EP4", + "antagonist" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "antagonist.", + "EP4", + "agonist" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EP4" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EP4" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EP4" + ] + }, + "context": { + "val": "cells", + "words": [ + "Langerhans", + "cells,", + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EP4" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "antagonist.", + "EP4", + "agonist" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "antagonist.", + "EP4", + "agonist" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "antagonist.", + "EP4", + "agonist" + ] + }, + "context": { + "val": "cells", + "words": [ + "Langerhans", + "cells,", + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "antagonist.", + "EP4", + "agonist" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "cells", + "words": [ + "Langerhans", + "cells,", + "T", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "cells", + "words": [ + "Langerhans", + "cells,", + "T", + "cells" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "12724750", + "TEXT": "Forced by scandal to leave Oxford University, infectious disease expert Roy Anderson seemed destined to be persona non grata in the scientific community. Three years later, however, Anderson is back in the thick of things, investigating HIV/AIDS, foot-and-mouth disease and, lately, severe acute respiratory syndrome.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12704383", + "TEXT": "Suppression of dendritic cell function in cancer patients is thought to contribute to the inhibition of immune responses and disease progression. Molecular mechanisms of this suppression remain elusive, however. Here, we show that a fraction of blood monocyte-derived myeloid dendritic cells (MDCs) express B7-H1, a member of the B7 family, on the cell surface. B7-H1 could be further upregulated by tumor environmental factors. Consistent with this finding, virtually all MDCs isolated from the tissues or draining lymph nodes of ovarian carcinomas express B7-H1. Blockade of B7-H1 enhanced MDC-mediated T-cell activation and was accompanied by downregulation of T-cell interleukin (IL)-10 and upregulation of IL-2 and interferon (IFN)-gamma. T cells conditioned with the B7-H1-blocked MDCs had a more potent ability to inhibit autologous human ovarian carcinoma growth in non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice. Therefore, upregulation of B7-H1 on MDCs in the tumor microenvironment downregulates T-cell immunity. Blockade of B7-H1 represents one approach for cancer immunotherapy.", + "TAG_DATA": [ + "83, Blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "84, of {'perturbing_action': 'I-pharmacological inhibition'}", + "85, B7-H1 {'perturbing_action': 'I-pharmacological inhibition'}", + "88, T-cell {'context': 'B-cells'}", + "106, T {'context': 'B-cells'}", + "107, cells {'context': 'I-cells'}", + "111, B7-H1-blocked {'perturbing_action': 'B-pharmacological inhibition'}", + "112, MDCs {'context': 'B-cells'}", + "120, autologous {'context': 'B-neoplasm'}", + "121, human {'context': 'I-neoplasm'}", + "122, ovarian {'context': 'I-neoplasm'}", + "123, carcinoma {'context': 'I-neoplasm'}", + "126, non-obese {'context': 'B-organism'}", + "127, diabetic-severe {'context': 'I-organism'}", + "128, combined {'context': 'I-organism'}", + "129, immunodeficient {'context': 'I-organism'}", + "131, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "83, Blockade ['l0', 'l1', 'l2']", + "84, of ['l0', 'l3', 'l4']", + "85, B7-H1 ['l1', 'l3', 'l5']", + "88, T-cell ['l2', 'l4', 'l5']", + "106, T ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "107, cells ['l6', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "111, B7-H1-blocked ['l7', 'l19', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "112, MDCs ['l8', 'l20', 'l31', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "120, autologous ['l9', 'l21', 'l32', 'l42', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "121, human ['l10', 'l22', 'l33', 'l43', 'l52', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "122, ovarian ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "123, carcinoma ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "126, non-obese ['l13', 'l25', 'l36', 'l46', 'l55', 'l63', 'l70', 'l76', 'l82', 'l83', 'l84', 'l85', 'l86']", + "127, diabetic-severe ['l14', 'l26', 'l37', 'l47', 'l56', 'l64', 'l71', 'l77', 'l82', 'l87', 'l88', 'l89', 'l90']", + "128, combined ['l15', 'l27', 'l38', 'l48', 'l57', 'l65', 'l72', 'l78', 'l83', 'l87', 'l91', 'l92', 'l93']", + "129, immunodeficient ['l16', 'l28', 'l39', 'l49', 'l58', 'l66', 'l73', 'l79', 'l84', 'l88', 'l91', 'l94', 'l95']", + "130, (NOD-SCID) ['l17', 'l29', 'l40', 'l50', 'l59', 'l67', 'l74', 'l80', 'l85', 'l89', 'l92', 'l94', 'l96']", + "131, mice. ['l18', 'l30', 'l41', 'l51', 'l60', 'l68', 'l75', 'l81', 'l86', 'l90', 'l93', 'l95', 'l96']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "B7-H1", + "B7-H1-blocked" + ] + }, + "context": { + "val": "cells", + "words": [ + "T-cell", + "T", + "cells", + "MDCs" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "B7-H1-blocked" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "autologous", + "human", + "ovarian", + "carcinoma" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "B7-H1-blocked" + ] + }, + "context": { + "val": "organism", + "words": [ + "non-obese", + "diabetic-severe", + "combined", + "immunodeficient", + "mice." + ] + } + } + ] + }, + { + "PMID": "12692544", + "TEXT": "The expression and activation of Toll-like receptors (TLRs) was investigated in leprosy, a spectral disease in which clinical manifestations correlate with the type of immune response mounted toward Mycobacterium leprae. TLR2-TLR1 heterodimers mediated cell activation by killed M. leprae, indicating the presence of triacylated lipoproteins. A genome-wide scan of M. leprae detected 31 putative lipoproteins. Synthetic lipopeptides representing the 19-kD and 33-kD lipoproteins activated both monocytes and dendritic cells. Activation was enhanced by type-1 cytokines and inhibited by type-2 cytokines. In addition, interferon (IFN)-gamma and granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced TLR1 expression in monocytes and dendritic cells, respectively, whereas IL-4 downregulated TLR2 expression. TLR2 and TLR1 were more strongly expressed in lesions from the localized tuberculoid form (T-lep) as compared with the disseminated lepromatous form (L-lep) of the disease. These data provide evidence that regulated expression and activation of TLRs at the site of disease contribute to the host defense against microbial pathogens.", + "TAG_DATA": [ + "65, monocytes {'context': 'B-cells'}", + "67, dendritic {'context': 'B-cells'}", + "68, cells. {'context': 'I-cells'}", + "93, monocytes {'context': 'B-cells'}", + "95, dendritic {'context': 'B-cells'}", + "96, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "65, monocytes ['l0', 'l1']", + "67, dendritic ['l0', 'l2']", + "68, cells. ['l1', 'l2']", + "93, monocytes ['l3', 'l4']", + "95, dendritic ['l3', 'l5']", + "96, cells, ['l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12692543", + "TEXT": "Kaposi sarcoma (KS) is a vascular tumor that can develop in recipients of solid tissue transplants as a result of either primary infection or reactivation of a gammaherpesvirus, the KS- associated herpesvirus, also known as human herpesvirus-8 (HHV-8). We studied whether HHV-8 and the elusive KS progenitor cells could be transmitted from the donor through the grafts. We used a variety of molecular, cytogenetic, immunohistochemical and immunofluorescence methods to show that the HHV-8-infected neoplastic cells in post-transplant KS from five of eight renal transplant patients harbored either genetic or antigenic markers of their matched donors. These data suggest the use of donor-derived HHV-8-specific T cells for the control of post-transplant KS.", + "TAG_DATA": [ + "73, neoplastic {'context': 'B-transformed cells'}", + "74, cells {'context': 'I-transformed cells'}", + "82, renal {'context': 'B-patient'}", + "83, transplant {'context': 'I-patient'}", + "84, patients {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "73, neoplastic ['l0', 'l1', 'l2', 'l3']", + "74, cells ['l0', 'l4', 'l5', 'l6']", + "82, renal ['l1', 'l4', 'l7', 'l8']", + "83, transplant ['l2', 'l5', 'l7', 'l9']", + "84, patients ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12669033", + "TEXT": "Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor with restorative effects in a wide variety of rodent and primate models of Parkinson disease, but penetration into brain tissue from either the blood or the cerebro-spinal fluid is limited. Here we delivered GDNF directly into the putamen of five Parkinson patients in a phase 1 safety trial. One catheter needed to be repositioned and there were changes in the magnetic resonance images that disappeared after lowering the concentration of GDNF. After one year, there were no serious clinical side effects, a 39% improvement in the off-medication motor sub-score of the Unified Parkinson's Disease Rating Scale (UPDRS) and a 61% improvement in the activities of daily living sub-score. Medication-induced dyskinesias were reduced by 64% and were not observed off medication during chronic GDNF delivery. Positron emission tomography (PET) scans of [(18)F]dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, suggesting a direct effect of GDNF on dopamine function. This study warrants careful examination of GDNF as a treatment for Parkinson disease.", + "TAG_DATA": [ + "48, putamen {'context': 'B-tissue/organ'}", + "51, Parkinson {'context': 'B-patient'}", + "52, patients {'context': 'I-patient'}", + "149, putamen {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "48, putamen ['l0', 'l1']", + "51, Parkinson ['l0', 'l2']", + "52, patients ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12652295", + "TEXT": "Tissue inhibitor of metalloproteinases-3 (TIMP3) is one of four members of a family of proteins that were originally classified according to their ability to inhibit matrix metalloproteinases (MMP). TIMP3, which encodes a potent angiogenesis inhibitor, is mutated in Sorsby fundus dystrophy, a macular degenerative disease with submacular choroidal neovascularization. In this study we demonstrate the ability of TIMP3 to inhibit vascular endothelial factor (VEGF)-mediated angiogenesis and identify the potential mechanism by which this occurs: TIMP3 blocks the binding of VEGF to VEGF receptor-2 and inhibits downstream signaling and angiogenesis. This property seems to be independent of its MMP-inhibitory activity, indicating a new function for this molecule.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12640448", + "TEXT": "A clinical trial of retroviral-mediated transfer of the adenosine deaminase (ADA) gene into umbilical cord blood CD34(+) cells was started in 1993. ADA-containing peripheral blood mononuclear cells (PBMCs) have persisted in patients from this trial, with T lymphocytes showing the highest prevalence of gene marking. To gain a greater understanding of the nature and number of the transduced cells that were engrafted, we used linear amplification-mediated PCR (LAM-PCR) to identify clonal vector proviral integrants. In one patient, a single vector integrant was predominant in T lymphocytes at a stable level over most of the eight-year time span analyzed and was also detected in some myeloid samples. T-cell clones with the predominant integrant, isolated after eight years, showed multiple patterns of T-cell receptor (TCR) gene rearrangement, indicating that a single pre-thymic stem or progenitor cell served as the source of the majority of the gene-marked cells over an extended period of time. It is important to distinguish the stable pattern of monoclonal gene marking that we observed here from the progressive increase of a T-cell clone with monoclonal gene marking that results from leukemic transformation, as observed in two subjects in a clinical trial of gene therapy for X-linked severe combined immunodeficiency (SCID).", + "TAG_DATA": [ + "84, T {'context': 'B-cells'}", + "85, lymphocytes {'context': 'B-cells'}", + "129, pre-thymic {'context': 'B-cells'}", + "130, stem {'context': 'I-cells'}", + "131, or {'context': 'I-cells'}", + "132, progenitor {'context': 'I-cells'}", + "133, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "84, T ['l0']", + "85, lymphocytes ['l0']", + "129, pre-thymic ['l1', 'l2', 'l3', 'l4']", + "130, stem ['l1', 'l5', 'l6', 'l7']", + "131, or ['l2', 'l5', 'l8', 'l9']", + "132, progenitor ['l3', 'l6', 'l8', 'l10']", + "133, cell ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12627228", + "TEXT": "The spontaneous mouse grey-lethal (gl) mutation is responsible for a coat color defect and for the development of the most severe autosomal recessive form of osteopetrosis. Using a positional cloning approach, we have mapped and isolated the gl locus from a approximately 1.5 cM genetic interval. The gl locus was identified in a bacterial artificial chromosome (BAC) contig by functional genetic complementation in transgenic mice. Genomic sequence analysis revealed that the gl mutation is a deletion resulting in complete loss of function. The unique approximately 3 kb wild-type transcript is expressed primarily in osteoclasts and melanocytes as well as in brain, kidney, thymus and spleen. The gl gene is predicted to encode a 338-amino acid type I transmembrane protein that localizes to the intracellular compartment. Mutation in the human GL gene leads to severe recessive osteopetrosis. Our studies show that mouse Gl protein function is absolutely required for osteoclast and melanocyte maturation and function.", + "TAG_DATA": [ + "64, mice. {'context': 'I-organism'}", + "125, Mutation {'perturbing_action': 'B-other'}", + "126, in {'perturbing_action': 'I-other'}", + "127, the {'perturbing_action': 'I-other'}", + "128, human {'perturbing_action': 'I-other'}", + "129, GL {'perturbing_action': 'I-other'}", + "130, gene {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "63, transgenic ['l0']", + "64, mice. ['l0']", + "125, Mutation ['l1', 'l2', 'l3', 'l4', 'l5']", + "126, in ['l1', 'l6', 'l7', 'l8', 'l9']", + "127, the ['l2', 'l6', 'l10', 'l11', 'l12']", + "128, human ['l3', 'l7', 'l10', 'l13', 'l14']", + "129, GL ['l4', 'l8', 'l11', 'l13', 'l15']", + "130, gene ['l5', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12612547", + "TEXT": "Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by excessive deposition of amyloid-beta (Abeta) peptides in the brain. One of the earliest neuropathological changes in AD is the accumulation of astrocytes at sites of Abeta deposition, but the cause or significance of this cellular response is unclear. Here we show that cultured adult mouse astrocytes migrate in response to monocyte chemoattractant protein-1 (MCP-1), a chemokine present in AD lesions, and cease migration upon interaction with immobilized Abeta(1-42). We also show that astrocytes bind and degrade Abeta(1-42). Astrocytes plated on Abeta-laden brain sections from a mouse model of AD associate with the Abeta deposits and reduce overall Abeta levels in these sections. Our results suggest a novel mechanism for the accumulation of astrocytes around Abeta deposits, indicate a direct role for astrocytes in degradation of Abeta and implicate deficits in astroglial clearance of Abeta in the pathogenesis of AD. Treatments that increase removal of Abeta by astrocytes may therefore be a critical mechanism to reduce the neurodegeneration associated with AD.", + "TAG_DATA": [ + "52, cultured {'context': 'B-cells'}", + "53, adult {'context': 'I-cells'}", + "54, mouse {'context': 'I-cells'}", + "55, astrocytes {'context': 'I-cells'}", + "56, migrate {'phenotype': 'B-migration'}", + "72, migration {'phenotype': 'B-migration'}", + "82, astrocytes {'context': 'B-cells'}", + "87, Astrocytes {'context': 'B-cells'}", + "95, mouse {'context': 'B-organism'}", + "96, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "52, cultured ['l0', 'l1', 'l2', 'l3']", + "53, adult ['l0', 'l4', 'l5', 'l6']", + "54, mouse ['l1', 'l4', 'l7', 'l8']", + "55, astrocytes ['l2', 'l5', 'l7', 'l9']", + "56, migrate ['l3', 'l6', 'l8', 'l9']", + "72, migration ['l10']", + "82, astrocytes ['l10', 'l11']", + "87, Astrocytes ['l11', 'l12', 'l13']", + "95, mouse ['l12', 'l14']", + "96, model ['l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cultured", + "adult", + "mouse", + "astrocytes" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migrate", + "migration" + ] + } + } + ] + }, + { + "PMID": "12563316", + "TEXT": "Activated protein C (APC) is a systemic anti-coagulant and anti-inflammatory factor. It reduces organ damage in animal models of sepsis, ischemic injury and stroke and substantially reduces mortality in patients with severe sepsis. It was not known whether APC acts as a direct cell survival factor or whether its neuroprotective effect is secondary to its anti-coagulant and anti-inflammatory effects. We report that APC directly prevents apoptosis in hypoxic human brain endothelium through transcriptionally dependent inhibition of tumor suppressor protein p53, normalization of the pro-apoptotic Bax/Bcl-2 ratio and reduction of caspase-3 signaling. These mechanisms are distinct from those involving upregulation of the genes encoding the anti-apoptotic Bcl-2 homolog A1 and inhibitor of apoptosis protein-1 (IAP-1) by APC in umbilical vein endothelial cells. Cytoprotection of brain endothelium by APC in vitro required endothelial protein C receptor (EPCR) and protease-activated receptor-1 (PAR-1), as did its in vivo neuroprotective activity in a stroke model of mice with a severe deficiency of EPCR. This is consistent with work showing the direct effects of APC on cultured cells via EPCR and PAR-1 (ref. 9). Moreover, the in vivo neuroprotective effects of low-dose mouse APC seemed to be independent of its anti-coagulant activity. Thus, APC protects the brain from ischemic injury by acting directly on brain cells.", + "TAG_DATA": [ + "64, prevents {'effect': 'B-negative'}", + "65, apoptosis {'phenotype': 'B-apoptosis'}", + "67, hypoxic {'context': 'B-tissue/organ'}", + "68, human {'context': 'I-tissue/organ'}", + "69, brain {'context': 'I-tissue/organ'}", + "70, endothelium {'context': 'I-tissue/organ'}", + "117, umbilical {'context': 'B-cells'}", + "118, vein {'context': 'I-cells'}", + "119, endothelial {'context': 'I-cells'}", + "120, cells. {'context': 'I-cells'}", + "123, brain {'context': 'B-tissue/organ'}", + "124, endothelium {'context': 'I-cells'}", + "127, in {'context': 'B-in vitro'}", + "128, vitro {'context': 'I-in vitro'}", + "142, in {'context': 'B-in vivo'}", + "143, vivo {'context': 'I-in vivo'}", + "151, mice {'context': 'B-organism'}", + "155, deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "180, in {'context': 'B-in vivo'}" + ], + "LINK_DATA": [ + "64, prevents ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "65, apoptosis ['l0', 'l6', 'l7', 'l8', 'l9']", + "67, hypoxic ['l1', 'l6', 'l10', 'l11', 'l12', 'l13']", + "68, human ['l2', 'l7', 'l10', 'l14', 'l15']", + "69, brain ['l3', 'l8', 'l11', 'l14', 'l16']", + "70, endothelium ['l4', 'l9', 'l12', 'l15', 'l16']", + "117, umbilical ['l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "118, vein ['l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "119, endothelial ['l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "120, cells. ['l5', 'l13', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "123, brain ['l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41', 'l42']", + "124, endothelium ['l21', 'l27', 'l32', 'l36', 'l39', 'l43', 'l44']", + "127, in ['l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l45', 'l46']", + "128, vitro ['l23', 'l29', 'l34', 'l38', 'l41', 'l44', 'l45', 'l47']", + "142, in ['l48']", + "143, vivo ['l42', 'l46', 'l47', 'l48']", + "151, mice ['l49']", + "155, deficiency ['l49']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hypoxic", + "human", + "brain", + "endothelium" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hypoxic", + "human", + "brain", + "endothelium" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency" + ] + } + } + ] + }, + { + "PMID": "12539040", + "TEXT": "Hemizygous deletion of chromosome 22q11 (del22q11) causes thymic, parathyroid, craniofacial and life-threatening cardiovascular birth defects in 1 in 4,000 infants. The del22q11 syndrome is likely caused by haploinsufficiency of TBX1, but its variable expressivity indicates the involvement of additional modifiers. Here, we report that absence of the Vegf164 isoform caused birth defects in mice, reminiscent of those found in del22q11 patients. The close correlation of birth and vascular defects indicated that vascular dysgenesis may pathogenetically contribute to the birth defects. Vegf interacted with Tbx1, as Tbx1 expression was reduced in Vegf164-deficient embryos and knocked-down vegf levels enhanced the pharyngeal arch artery defects induced by tbx1 knockdown in zebrafish. Moreover, initial evidence suggested that a VEGF promoter haplotype was associated with an increased risk for cardiovascular birth defects in del22q11 individuals. These genetic data in mouse, fish and human indicate that VEGF is a modifier of cardiovascular birth defects in the del22q11 syndrome.", + "TAG_DATA": [ + "44, absence {'perturbing_action': 'B-gene loss-of-function'}", + "45, of {'perturbing_action': 'I-gene loss-of-function'}", + "46, the {'perturbing_action': 'I-gene loss-of-function'}", + "47, Vegf164 {'perturbing_action': 'I-gene loss-of-function'}", + "48, isoform {'perturbing_action': 'I-gene loss-of-function'}", + "53, mice, {'context': 'B-organism'}", + "90, Vegf164-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "91, embryos {'context': 'B-organism'}", + "93, knocked-down {'perturbing_action': 'B-rnai/knockdown'}", + "94, vegf {'perturbing_action': 'I-rnai/knockdown'}", + "95, levels {'perturbing_action': 'I-rnai/knockdown'}", + "99, arch {'context': 'I-tissue/organ'}", + "104, tbx1 {'perturbing_action': 'B-rnai/knockdown'}", + "105, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "107, zebrafish. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "44, absence ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "45, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "46, the ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "47, Vegf164 ['l2', 'l8', 'l13', 'l18', 'l19', 'l20']", + "48, isoform ['l3', 'l9', 'l14', 'l18', 'l21']", + "53, mice, ['l4', 'l10', 'l15', 'l19', 'l21']", + "90, Vegf164-deficient ['l5', 'l11', 'l16', 'l22', 'l23', 'l24']", + "91, embryos ['l6', 'l12', 'l17', 'l20', 'l22', 'l25']", + "93, knocked-down ['l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "94, vegf ['l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "95, levels ['l27', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "98, pharyngeal ['l23', 'l28', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47']", + "99, arch ['l24', 'l25', 'l29', 'l35', 'l40', 'l44', 'l48', 'l49', 'l50']", + "104, tbx1 ['l30', 'l36', 'l41', 'l45', 'l48', 'l51', 'l52']", + "105, knockdown ['l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l53']", + "107, zebrafish. ['l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l53']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "the", + "Vegf164", + "isoform", + "Vegf164-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "embryos" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Vegf164-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "arch" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knocked-down", + "vegf", + "levels", + "tbx1", + "knockdown" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "arch" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knocked-down", + "vegf", + "levels", + "tbx1", + "knockdown" + ] + }, + "context": { + "val": "organism", + "words": [ + "zebrafish." + ] + } + } + ] + }, + { + "PMID": "12524534", + "TEXT": "Macrophages have important roles in both lipid metabolism and inflammation and are central to the pathogenesis of atherosclerosis. The liver X receptors (LXRs) are established mediators of lipid-inducible gene expression, but their role in inflammation and immunity is unknown. We demonstrate here that LXRs and their ligands are negative regulators of macrophage inflammatory gene expression. Transcriptional profiling of lipopolysaccharide (LPS)-induced macrophages reveals reciprocal LXR-dependent regulation of genes involved in lipid metabolism and the innate immune response. In vitro, LXR ligands inhibit the expression of inflammatory mediators such as inducible nitric oxide synthase, cyclooxygenase (COX)-2 and interleukin-6 (IL-6) in response to bacterial infection or LPS stimulation. In vivo, LXR agonists reduce inflammation in a model of contact dermatitis and inhibit inflammatory gene expression in the aortas of atherosclerotic mice. These findings identify LXRs as lipid-dependent regulators of inflammatory gene expression that may serve to link lipid metabolism and immune functions in macrophages.", + "TAG_DATA": [ + "60, macrophages {'context': 'B-cells'}", + "76, In {'context': 'B-in vitro'}", + "77, vitro, {'context': 'I-in vitro'}", + "105, In {'context': 'B-in vivo'}", + "106, vivo, {'context': 'I-in vivo'}", + "107, LXR {'perturbing_action': 'B-pharmacological augmentation'}", + "108, agonists {'perturbing_action': 'I-pharmacological augmentation'}", + "124, aortas {'context': 'B-tissue/organ'}", + "127, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "60, macrophages ['l0', 'l1']", + "76, In ['l0', 'l2']", + "77, vitro, ['l1', 'l2']", + "105, In ['l3', 'l4', 'l5', 'l6', 'l7']", + "106, vivo, ['l3', 'l8', 'l9', 'l10', 'l11']", + "107, LXR ['l4', 'l8', 'l12', 'l13', 'l14']", + "108, agonists ['l5', 'l9', 'l12', 'l15', 'l16']", + "124, aortas ['l6', 'l10', 'l13', 'l15', 'l17']", + "127, mice. ['l7', 'l11', 'l14', 'l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "LXR", + "agonists" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "LXR", + "agonists" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "aortas" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "LXR", + "agonists" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "12483206", + "TEXT": "Through intracellular receptors, estrogens control growth, differentiation and function of not only reproductive tissues, but also other systems. Estrogen receptors are ligand-dependent transcription factors whose activity is modulated either by estrogens, or by alternative intracellular signaling pathways downstream of growth factors and neurotransmitters. To determine the dynamics of estrogen receptor activity and the dependence of estrogen receptor on 17beta-estradiol in vivo, we generated a transgenic mouse that expresses a luciferase reporter gene under the control of activated estrogen receptors. As expected, luciferase activity, monitored with a cooled charged coupled device camera, paralleled circulating estrogen levels in reproductive tissues and in liver, indicating that the peak transcriptional activity of the estrogen receptor occurred at proestrus. In contrast, in tissues such as bone and brain, the peak activity of estrogen receptors was observed at diestrus. These tissue-specific responses are masked when mice undergo conventional hormone treatment. We also demonstrate that estrogen receptors are active in immature mice before gonadal production of sex hormones as well as in ovariectomized adult mice. These findings emphasize the importance of hormone-independent activation of the estrogen receptor, and have implications for the therapeutic use of estrogens, such as hormone replacement therapy.", + "TAG_DATA": [ + "64, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "65, mouse {'context': 'I-organism'}", + "139, mice {'context': 'B-organism'}", + "153, immature {'context': 'B-organism'}", + "154, mice {'context': 'I-organism'}", + "166, adult {'context': 'B-organism'}", + "167, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "64, transgenic ['l0']", + "65, mouse ['l0']", + "139, mice ['l1', 'l2']", + "153, immature ['l1', 'l3', 'l4', 'l5']", + "154, mice ['l2', 'l3', 'l6', 'l7']", + "166, adult ['l4', 'l6', 'l8']", + "167, mice. ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + } + ] + }, + { + "PMID": "12469115", + "TEXT": "Geographic overlap between malaria and the occurrence of mutant hemoglobin and erythrocyte surface proteins has indicated that polymorphisms in human genes have been selected by severe malaria. Deletion of exon 3 in the glycophorin C gene (called GYPCDeltaex3 here) has been found in Melanesians; this alteration changes the serologic phenotype of the Gerbich (Ge) blood group system, resulting in Ge negativity. The GYPCDeltaex3 allele reaches a high frequency (46.5%) in coastal areas of Papua New Guinea where malaria is hyperendemic. The Plasmodium falciparum erythrocyte-binding antigen 140 (EBA140, also known as BAEBL) binds with high affinity to the surface of human erythrocytes. Here we show that the receptor for EBA140 is glycophorin C (GYPC) and that this interaction mediates a principal P. falciparum invasion pathway into human erythrocytes. EBA140 does not bind to GYPC in Ge-negative erythrocytes, nor can P. falciparum invade such cells using this invasion pathway. This provides compelling evidence that Ge negativity has arisen in Melanesian populations through natural selection by severe malaria.", + "TAG_DATA": [ + "134, Ge-negative {'context': 'B-cells'}", + "135, erythrocytes, {'context': 'I-cells'}", + "142, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "134, Ge-negative ['l0', 'l1']", + "135, erythrocytes, ['l0', 'l2']", + "142, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12447357", + "TEXT": "Although a wide range of risk factors for coronary heart disease have been identified from population studies, these measures, singly or in combination, are insufficiently powerful to provide a reliable, noninvasive diagnosis of the presence of coronary heart disease. Here we show that pattern-recognition techniques applied to proton nuclear magnetic resonance (1H-NMR) spectra of human serum can correctly diagnose not only the presence, but also the severity, of coronary heart disease. Application of supervised partial least squares-discriminant analysis to orthogonal signal-corrected data sets allows >90% of subjects with stenosis of all three major coronary vessels to be distinguished from subjects with angiographically normal coronary arteries, with a specificity of >90%. Our studies show for the first time a technique capable of providing an accurate, noninvasive and rapid diagnosis of coronary heart disease that can be used clinically, either in population screening or to allow effective targeting of treatments such as statins.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12447356", + "TEXT": "Can T cells be directly activated to de novo gene expression by gonadotropin-releasing hormone-II (GnRH-II), a unique 10-amino-acid neuropeptide conserved through 500 million years of evolution? GnRH-II, which has been identified in mammals, shares 70% homology with the mammalian hypothalamic neurohormone GnRH (GnRH-I), the primary regulator of reproduction, but is encoded by a different gene. Although both neuropeptides are produced mainly in brain, their localization and promoter regulation differ, suggestive of distinct functions. Indeed, GnRH-II barely affects reproduction and its role in mammalian physiology is unknown. We find here that human normal and leukemic T cells produce GnRH-II and GnRH-I. Further, exposure of normal or cancerous human or mouse T cells to GnRH-II or GnRH-I triggered de novo gene transcription and cell-surface expression of a 67-kD non-integrin laminin receptor that is involved in cellular adhesion and migration and in tumor invasion and metastasis. GnRH-II or GnRH-I also induced adhesion to laminin and chemotaxis toward SDF-1alpha, and augmented entry in vivo of metastatic T-lymphoma into the spleen and bone marrow. Homing of normal T cells into specific organs was reduced in mice lacking GnRH-I. A specific GnRH-I-receptor antagonist blocked GnRH-I- but not GnRH-II-induced effects, which is suggestive of signaling through distinct receptors. We suggest that GnRH-II and GnRH-I, secreted from nerves or autocrine or paracrine sources, interact directly with T cells and trigger gene transcription, adhesion, chemotaxis and homing to specific organs, which may be of clinical relevance.", + "TAG_DATA": [ + "91, normal {'context': 'I-cells'}", + "92, and {'context': 'I-cells'}", + "93, leukemic {'context': 'I-cells'}", + "94, T {'context': 'I-cells'}", + "95, cells {'context': 'I-cells'}", + "103, normal {'context': 'B-cells'}", + "104, or {'context': 'I-cells'}", + "105, cancerous {'context': 'I-cells'}", + "106, human {'context': 'I-cells'}", + "107, or {'context': 'I-cells'}", + "108, mouse {'context': 'I-cells'}", + "109, T {'context': 'I-cells'}", + "110, cells {'context': 'I-cells'}", + "147, induced {'effect': 'B-positive'}", + "148, adhesion {'phenotype': 'B-adhesion'}", + "152, chemotaxis {'phenotype': 'B-migration'}", + "158, in {'context': 'B-in vivo'}", + "159, vivo {'context': 'I-in vivo'}", + "161, metastatic {'context': 'B-neoplasm'}", + "162, T-lymphoma {'context': 'I-neoplasm'}", + "165, spleen {'context': 'B-tissue/organ'}", + "168, marrow. {'context': 'I-tissue/organ'}", + "171, normal {'context': 'B-cells'}", + "172, T {'context': 'I-cells'}", + "173, cells {'context': 'I-cells'}", + "180, mice {'context': 'B-organism'}", + "184, specific {'perturbing_action': 'B-pharmacological inhibition'}", + "185, GnRH-I-receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "186, antagonist {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "91, normal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "92, and ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "93, leukemic ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "94, T ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "95, cells ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "103, normal ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "104, or ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "105, cancerous ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "106, human ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "107, or ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "108, mouse ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "109, T ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "110, cells ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "147, induced ['l78', 'l79']", + "148, adhesion ['l78', 'l80', 'l81']", + "152, chemotaxis ['l79', 'l80', 'l82', 'l83', 'l84', 'l85', 'l86']", + "158, in ['l82', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "159, vivo ['l83', 'l87', 'l93', 'l94', 'l95', 'l96', 'l97']", + "161, metastatic ['l88', 'l93', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "162, T-lymphoma ['l89', 'l94', 'l98', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "165, spleen ['l84', 'l90', 'l95', 'l99', 'l105', 'l111', 'l112']", + "167, bone ['l85', 'l91', 'l96', 'l100', 'l106', 'l111', 'l113']", + "168, marrow. ['l81', 'l86', 'l92', 'l97', 'l101', 'l107', 'l112', 'l113']", + "171, normal ['l102', 'l108', 'l114', 'l115', 'l116']", + "172, T ['l103', 'l109', 'l114', 'l117', 'l118']", + "173, cells ['l104', 'l110', 'l115', 'l117']", + "180, mice ['l116', 'l118']", + "184, specific ['l119', 'l120']", + "185, GnRH-I-receptor ['l119', 'l121']", + "186, antagonist ['l120', 'l121']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + } + }, + { + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "marrow." + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "spleen", + "marrow." + ] + } + } + ] + }, + { + "PMID": "12436116", + "TEXT": "The role of host genetic factors in conferring predisposition or protection in infectious diseases has become evident. Infection with group A streptococci causes a wide spectrum of disease ranging from pharyngitis to streptococcal toxic shock syndrome. The release of inflammatory cytokines triggered by streptococcal superantigens has a pivotal role in invasive streptococcal disease. However, individuals infected with the same strain can develop very different manifestations. We report here that the immunogenetics of the host influence the outcome of invasive streptococcal infection, and demonstrate the underlying mechanism for these genetic associations. Specific human leukocyte antigen class II haplotypes conferred strong protection from severe systemic disease, whereas others increased the risk of severe disease. Patients with the DRB1*1501/DQB1*0602 haplotype mounted significantly reduced responses and were less likely to develop severe systemic disease (P < 0.0001). We propose that human leukocyte antigen class II allelic variation contributes to differences in severity of invasive streptococcal infections through their ability to regulate cytokine responses triggered by streptococcal superantigens.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12426561", + "TEXT": "Circulating insulin inhibits endogenous glucose production. Here we report that bidirectional changes in hypothalamic insulin signaling affect glucose production. The infusion of either insulin or a small-molecule insulin mimetic in the third cerebral ventricle suppressed glucose production independent of circulating levels of insulin and of other glucoregulatory hormones. Conversely, central antagonism of insulin signaling impaired the ability of circulating insulin to inhibit glucose production. Finally, third-cerebral-ventricle administration of inhibitors of ATP-sensitive potassium channels, but not of antagonists of the central melanocortin receptors, also blunted the effect of hyperinsulinemia on glucose production. These results reveal a new site of action of insulin on glucose production and suggest that hypothalamic insulin resistance can contribute to hyperglycemia in type 2 diabetes mellitus.", + "TAG_DATA": [ + "31, third {'context': 'B-tissue/organ'}", + "32, cerebral {'context': 'I-tissue/organ'}", + "33, ventricle {'context': 'I-tissue/organ'}", + "68, inhibitors {'perturbing_action': 'B-pharmacological inhibition'}", + "69, of {'perturbing_action': 'I-pharmacological inhibition'}", + "70, ATP-sensitive {'perturbing_action': 'I-pharmacological inhibition'}", + "71, potassium {'perturbing_action': 'I-pharmacological inhibition'}", + "72, channels, {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "31, third ['l0', 'l1']", + "32, cerebral ['l0', 'l2']", + "33, ventricle ['l1', 'l2']", + "68, inhibitors ['l3', 'l4', 'l5', 'l6']", + "69, of ['l3', 'l7', 'l8', 'l9']", + "70, ATP-sensitive ['l4', 'l7', 'l10', 'l11']", + "71, potassium ['l5', 'l8', 'l10', 'l12']", + "72, channels, ['l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12415260", + "TEXT": "Levels of insulin-like growth factor I (IGF-I), a neuroprotective hormone, decrease in serum during aging, whereas amyloid-beta (Abeta), which is involved in the pathogenesis of Alzheimer disease, accumulates in the brain. High brain Abeta levels are found at an early age in mutant mice with low circulating IGF-I, and Abeta burden can be reduced in aging rats by increasing serum IGF-I. This opposing relationship between serum IGF-I and brain Abeta levels reflects the ability of IGF-I to induce clearance of brain Abeta, probably by enhancing transport of Abeta carrier proteins such as albumin and transthyretin into the brain. This effect is antagonized by tumor necrosis factor-alpha, a pro-inflammatory cytokine putatively involved in dementia and aging. Because IGF-I treatment of mice overexpressing mutant amyloid markedly reduces their brain Abeta burden, we consider that circulating IGF-I is a physiological regulator of brain amyloid levels with therapeutic potential.", + "TAG_DATA": [ + "119, mice {'context': 'B-organism'}", + "120, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "121, mutant {'perturbing_action': 'I-gene gain-of-function'}", + "122, amyloid {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "119, mice ['l0', 'l1', 'l2', 'l3']", + "120, overexpressing ['l0', 'l4', 'l5', 'l6']", + "121, mutant ['l1', 'l4', 'l7', 'l8']", + "122, amyloid ['l2', 'l5', 'l7', 'l9']", + "126, brain ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "mutant", + "amyloid" + ] + } + } + ] + }, + { + "PMID": "12415259", + "TEXT": "T cell-mediated loss of insulin-secreting beta cells in the islets of Langerhans is the hallmark of type 1 diabetes. The molecular basis for the directed migration of autoreactive T cells leading to insulitis is presently unknown. Here we demonstrate that in response to inflammation, beta cells secrete the chemokines CXC ligand 10 and CXC ligand 9, which specifically attract T-effector cells via the CXC chemokine receptor 3. In mice deficient for this receptor, the onset of type 1 diabetes is substantially delayed. Thus, in the absence of known etiological agents, CXC receptor 3 represents a novel target for therapeutic interference early in type 1 diabetes.", + "TAG_DATA": [ + "44, beta {'context': 'B-cells'}", + "45, cells {'context': 'I-cells'}", + "68, mice {'context': 'B-organism'}", + "69, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "70, for {'perturbing_action': 'I-gene loss-of-function'}", + "71, this {'perturbing_action': 'I-gene loss-of-function'}", + "72, receptor, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "44, beta ['l0']", + "45, cells ['l0']", + "68, mice ['l1', 'l2', 'l3', 'l4']", + "69, deficient ['l1', 'l5', 'l6', 'l7']", + "70, for ['l2', 'l5', 'l8', 'l9']", + "71, this ['l3', 'l6', 'l8', 'l10']", + "72, receptor, ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "this", + "receptor," + ] + } + } + ] + }, + { + "PMID": "12379850", + "TEXT": "Immunization of transgenic mouse models of Alzheimer disease using amyloid-beta peptide (Abeta) reduces both the Alzheimer disease-like neuropathology and the spatial memory impairments of these mice. However, a therapeutic trial of immunization with Abeta42 in humans was discontinued because a few patients developed significant meningo-encephalitic cellular inflammatory reactions. Here we show that beneficial effects in mice arise from antibodies selectively directed against residues 4-10 of Abeta42, and that these antibodies inhibit both Abeta fibrillogenesis and cytotoxicity without eliciting an inflammatory response. These findings provide the basis for improved immunization antigens as well as attempts to design small-molecule mimics as alternative therapies.", + "TAG_DATA": [ + "55, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12379847", + "TEXT": "Adrenocorticotrophic hormone (ACTH)-secreting pituitary tumors are associated with high morbidity due to excess glucocorticoid production. No suitable drug therapies are currently available, and surgical excision is not invariably curative. Here we demonstrate immunoreactive expression of the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) exclusively in normal ACTH-secreting human anterior pituitary cells: PPAR-gamma was abundantly expressed in all of six human ACTH-secreting pituitary tumors studied. PPAR-gamma activators induced G0/G1 cell-cycle arrest and apoptosis and suppressed ACTH secretion in human and murine corticotroph tumor cells. Development of murine corticotroph tumors, generated by subcutaneous injection of ACTH-secreting AtT20 cells, was prevented in four of five mice treated with the thiazolidinedione compound rosiglitazone, and ACTH and corticosterone secretion was suppressed in all treated mice. Based on these findings, thiazolidinediones may be an effective therapy for Cushing disease", + "TAG_DATA": [ + "66, induced {'effect': 'B-positive'}", + "67, G0/G1 {'phenotype': 'B-cell cycle arrest'}", + "68, cell-cycle {'phenotype': 'I-cell cycle arrest'}", + "69, arrest {'phenotype': 'I-cell cycle arrest'}", + "71, apoptosis {'phenotype': 'B-apoptosis'}", + "77, human {'context': 'B-transformed cells'}", + "78, and {'context': 'I-transformed cells'}", + "79, murine {'context': 'I-transformed cells'}", + "80, corticotroph {'context': 'I-transformed cells'}", + "81, tumor {'context': 'I-transformed cells'}", + "82, cells. {'context': 'I-transformed cells'}", + "83, Development {'phenotype': 'B-tumourigenesis'}", + "85, murine {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}", + "86, corticotroph {'context': 'I-neoplasm', 'phenotype': 'I-tumourigenesis'}", + "87, tumors, {'context': 'I-neoplasm', 'phenotype': 'I-tumourigenesis'}", + "94, AtT20 {'context': 'B-cells'}", + "95, cells, {'context': 'I-cells'}", + "97, prevented {'effect': 'B-negative'}", + "102, mice {'context': 'B-organism'}", + "119, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "66, induced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "67, G0/G1 ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "68, cell-cycle ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "69, arrest ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31']", + "71, apoptosis ['l3', 'l12', 'l20', 'l27', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "77, human ['l4', 'l13', 'l21', 'l28', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "78, and ['l5', 'l14', 'l22', 'l29', 'l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "79, murine ['l6', 'l15', 'l23', 'l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "80, corticotroph ['l7', 'l16', 'l24', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "81, tumor ['l8', 'l17', 'l25', 'l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "82, cells. ['l9', 'l18', 'l26', 'l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l52']", + "83, Development ['l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "85, murine ['l53', 'l59', 'l60', 'l61', 'l62', 'l63']", + "86, corticotroph ['l54', 'l59', 'l64', 'l65', 'l66', 'l67']", + "87, tumors, ['l55', 'l60', 'l64', 'l68', 'l69', 'l70']", + "94, AtT20 ['l56', 'l61', 'l65', 'l68', 'l71', 'l72', 'l73']", + "95, cells, ['l57', 'l62', 'l66', 'l69', 'l71', 'l74', 'l75']", + "97, prevented ['l58', 'l63', 'l67', 'l70', 'l72', 'l74', 'l76']", + "102, mice ['l73', 'l75', 'l76']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G0/G1", + "cell-cycle", + "arrest" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "and", + "murine", + "corticotroph", + "tumor", + "cells." + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G0/G1", + "cell-cycle", + "arrest" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "and", + "murine", + "corticotroph", + "tumor", + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "and", + "murine", + "corticotroph", + "tumor", + "cells." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "Development", + "murine", + "corticotroph", + "tumors," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "murine", + "corticotroph", + "tumors," + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "Development", + "murine", + "corticotroph", + "tumors," + ] + }, + "context": { + "val": "cells", + "words": [ + "AtT20", + "cells," + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "Development", + "murine", + "corticotroph", + "tumors," + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "murine", + "corticotroph", + "tumors," + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "AtT20", + "cells," + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "12368906", + "TEXT": "Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, yet molecular events associated with the genesis and progression of this potentially fatal disease are largely unknown. For the molecules and pathways that have been implicated, genetic validation has been impeded by lack of a mouse model of RMS. Here we show that simultaneous loss of Ink4a/Arf function and disruption of c-Met signaling in Ink4a/Arf(-/-) mice transgenic for hepatocyte growth factor/scatter factor (HGF/SF) induces RMS with extremely high penetrance and short latency. In cultured myoblasts, c-Met activation and Ink4a/Arf loss suppress myogenesis in an additive fashion. Our data indicate that human c-MET and INK4a/ARF, situated at the nexus of pathways regulating myogenic growth and differentiation, represent critical targets in RMS pathogenesis. The marked synergism in mice between aberrant c-Met signaling and Ink4a/Arf inactivation, lesions individually implicated in human RMS, suggests a therapeutic combination to combat this devastating childhood cancer.", + "TAG_DATA": [ + "54, loss {'perturbing_action': 'B-gene loss-of-function'}", + "55, of {'perturbing_action': 'I-gene loss-of-function'}", + "56, Ink4a/Arf {'perturbing_action': 'I-gene loss-of-function'}", + "57, function {'perturbing_action': 'I-gene loss-of-function'}", + "64, Ink4a/Arf(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "65, mice {'context': 'B-organism'}", + "66, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "67, for {'perturbing_action': 'I-gene gain-of-function'}", + "68, hepatocyte {'perturbing_action': 'I-gene gain-of-function'}", + "69, growth {'perturbing_action': 'I-gene gain-of-function'}", + "70, factor/scatter {'perturbing_action': 'I-gene gain-of-function'}", + "71, factor {'perturbing_action': 'I-gene gain-of-function'}", + "72, (HGF/SF) {'perturbing_action': 'I-gene gain-of-function'}", + "83, cultured {'context': 'B-cells'}", + "84, myoblasts, {'context': 'I-cells'}", + "88, Ink4a/Arf {'perturbing_action': 'B-gene loss-of-function'}", + "89, loss {'perturbing_action': 'I-gene loss-of-function'}", + "90, suppress {'effect': 'B-negative'}", + "125, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "54, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "55, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "56, Ink4a/Arf ['l1', 'l9', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "57, function ['l2', 'l10', 'l20', 'l30', 'l31', 'l32', 'l33', 'l34']", + "64, Ink4a/Arf(-/-) ['l3', 'l11', 'l21', 'l30', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "65, mice ['l4', 'l12', 'l22', 'l31', 'l35', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "66, transgenic ['l5', 'l13', 'l23', 'l36', 'l45', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "67, for ['l37', 'l46', 'l54', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "68, hepatocyte ['l14', 'l24', 'l38', 'l47', 'l55', 'l64', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "69, growth ['l15', 'l25', 'l39', 'l48', 'l56', 'l65', 'l74', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "70, factor/scatter ['l16', 'l26', 'l40', 'l49', 'l57', 'l66', 'l75', 'l83', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "71, factor ['l6', 'l17', 'l27', 'l32', 'l41', 'l50', 'l58', 'l67', 'l76', 'l84', 'l91', 'l98', 'l99', 'l100', 'l101', 'l102']", + "72, (HGF/SF) ['l7', 'l18', 'l28', 'l33', 'l42', 'l51', 'l59', 'l68', 'l77', 'l85', 'l92', 'l98', 'l103', 'l104', 'l105', 'l106']", + "83, cultured ['l43', 'l52', 'l60', 'l69', 'l78', 'l86', 'l93', 'l99', 'l103', 'l107', 'l108']", + "84, myoblasts, ['l8', 'l19', 'l29', 'l34', 'l44', 'l53', 'l61', 'l70', 'l79', 'l87', 'l94', 'l100', 'l104', 'l107']", + "88, Ink4a/Arf ['l71', 'l80', 'l88', 'l95', 'l109', 'l110']", + "89, loss ['l62', 'l72', 'l81', 'l89', 'l96', 'l101', 'l105', 'l109', 'l111']", + "90, suppress ['l63', 'l73', 'l82', 'l90', 'l97', 'l102', 'l106', 'l108', 'l110', 'l111']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Ink4a/Arf", + "function", + "Ink4a/Arf(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Ink4a/Arf", + "function", + "Ink4a/Arf(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "myoblasts,", + "cultured" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "hepatocyte", + "growth", + "factor/scatter", + "factor", + "(HGF/SF)" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "hepatocyte", + "growth", + "factor/scatter", + "factor", + "(HGF/SF)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "myoblasts," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "hepatocyte", + "growth", + "factor/scatter", + "factor", + "(HGF/SF)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppress" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppress" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ink4a/Arf", + "loss" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppress" + ] + } + } + ] + }, + { + "PMID": "12368904", + "TEXT": "Hypertrophic growth is a risk factor for mortality in heart diseases. Mechanisms are lacking for this global increase in RNA and protein per cell, which underlies hypertrophy. Hypertrophic signals cause phosphorylation of the RNA polymerase II C-terminal domain, required for transcript elongation. RNA polymerase II kinases include cyclin-dependent kinases-7 (Cdk7) and Cdk9, components of two basal transcription factors. We report activation of Cdk7 and -9 in hypertrophy triggered by signaling proteins (Galphaq, calcineurin) or chronic mechanical stress. Only Cdk9 was activated by acute load or, in culture, by endothelin. A preferential role for Cdk9 was shown in RNA polymerase II phosphorylation and growth induced by endothelin, using pharmacological and dominant-negative inhibitors. All four hypertrophic signals dissociated 7SK small nuclear RNA, an endogenous inhibitor, from cyclin T-Cdk9. Cdk9 was limiting for cardiac growth, shown by suppressing its inhibitor (7SK) in culture and preventing downregulation of its activator (cyclin T1) in mouse myocardium.Note: In the AOP version of this article, the numbering of the author affiliations was incorrect. This has now been fixed, and the affiliations appear correctly online and in print.", + "TAG_DATA": [ + "149, mouse {'context': 'B-tissue/organ'}", + "150, myocardium.Note: {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "149, mouse ['l0']", + "150, myocardium.Note: ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12357247", + "TEXT": "During mammalian central nervous system (CNS) development, contact-mediated activation of Notch1 receptors on oligodendrocyte precursors by the ligand Jagged1 induces Hes5, which inhibits maturation of these cells. Here we tested whether the Notch pathway is re-expressed in the adult CNS in multiple sclerosis (MS), an inflammatory demyelinating disease in which remyelination is typically limited. We found that transforming growth factor-beta 1 (TGF-beta 1), a cytokine upregulated in MS, specifically re-induced Jagged1 in primary cultures of human astrocytes. Within and around active MS plaques lacking remyelination, Jagged1 was expressed at high levels by hypertrophic astrocytes, whereas Notch1 and Hes5 localized to cells with an immature oligodendrocyte phenotype, and TGF-beta 1 was associated with perivascular extracellular matrix in the same areas. In contrast, there was negligible Jagged1 expression in remyelinated lesions. Experiments in vitro showed that Jagged1 signaling inhibited process outgrowth from primary human oligodendrocytes. These data are the first to implicate the Notch pathway in the limited remyelination in MS. Thus, Notch may represent a potential target for therapeutic intervention in this disease.", + "TAG_DATA": [ + "72, primary {'context': 'B-cells'}", + "73, cultures {'context': 'I-cells'}", + "75, human {'context': 'B-cells'}", + "76, astrocytes. {'context': 'I-cells'}", + "130, in {'context': 'B-in vitro'}", + "131, vitro {'context': 'I-in vitro'}", + "140, primary {'context': 'B-cells'}", + "141, human {'context': 'I-cells'}", + "142, oligodendrocytes. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "72, primary ['l0', 'l1', 'l2']", + "73, cultures ['l0', 'l3', 'l4']", + "75, human ['l1', 'l3', 'l5']", + "76, astrocytes. ['l2', 'l4', 'l5']", + "130, in ['l6', 'l7', 'l8', 'l9']", + "131, vitro ['l6', 'l10', 'l11', 'l12']", + "140, primary ['l7', 'l10', 'l13', 'l14']", + "141, human ['l8', 'l11', 'l13', 'l15']", + "142, oligodendrocytes. ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12357246", + "TEXT": "Ras acts with other proteins to induce neoplasia. By itself, however, strong Ras signaling can suppress proliferation of normal cells. In primary epidermal cells, we found that oncogenic Ras transiently decreases cyclin-dependent kinase (CDK) 4 expression in association with cell cycle arrest in G1 phase. CDK4 co-expression circumvents Ras growth suppression and induces invasive human neoplasia resembling squamous cell carcinoma. Tumorigenesis is dependent on CDK4 kinase function, with cyclin D1 required but not sufficient for this process. In facilitating escape from G1 growth restraints, Ras and CDK4 alter the composition of cyclin D and cyclin E complexes and promote resistance to growth inhibition by INK4 cyclin-dependent kinase inhibitors. These data identify a new role for oncogenic Ras in CDK4 regulation and highlight the functional importance of CDK4 suppression in preventing uncontrolled growth.", + "TAG_DATA": [ + "21, primary {'context': 'B-cells'}", + "22, epidermal {'context': 'I-cells'}", + "23, cells, {'context': 'I-cells'}", + "39, cell {'phenotype': 'B-cell cycle arrest'}", + "40, cycle {'phenotype': 'I-cell cycle arrest'}", + "41, arrest {'phenotype': 'I-cell cycle arrest'}", + "45, CDK4 {'perturbing_action': 'B-gene gain-of-function'}", + "46, co-expression {'perturbing_action': 'I-gene gain-of-function'}", + "52, induces {'effect': 'B-positive'}", + "54, human {'phenotype': 'B-tumourigenesis'}", + "55, neoplasia {'phenotype': 'I-tumourigenesis'}", + "57, squamous {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}", + "58, cell {'phenotype': 'I-tumourigenesis'}", + "59, carcinoma. {'phenotype': 'I-tumourigenesis'}", + "104, INK4 {'perturbing_action': 'B-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "21, primary ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "22, epidermal ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "23, cells, ['l1', 'l7', 'l13', 'l14', 'l15', 'l16']", + "39, cell ['l2', 'l8', 'l13', 'l17', 'l18', 'l19']", + "40, cycle ['l3', 'l9', 'l14', 'l17', 'l20', 'l21']", + "41, arrest ['l4', 'l10', 'l15', 'l18', 'l20', 'l22']", + "45, CDK4 ['l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "46, co-expression ['l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "52, induces ['l5', 'l11', 'l16', 'l19', 'l21', 'l22', 'l24', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "54, human ['l25', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "55, neoplasia ['l6', 'l12', 'l26', 'l32', 'l37', 'l41', 'l45', 'l46', 'l47']", + "57, squamous ['l27', 'l33', 'l38', 'l42', 'l45', 'l48', 'l49']", + "58, cell ['l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l50']", + "59, carcinoma. ['l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l50']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "primary", + "epidermal", + "cells," + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "primary", + "epidermal", + "cells," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "primary", + "epidermal" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasia" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "CDK4", + "co-expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "CDK4", + "co-expression" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "human", + "neoplasia", + "squamous", + "cell", + "carcinoma." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "CDK4", + "co-expression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "squamous" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "squamous" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "squamous", + "human", + "neoplasia" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "human", + "neoplasia", + "squamous", + "cell", + "carcinoma." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "squamous" + ] + } + } + ] + }, + { + "PMID": "12244305", + "TEXT": "Current gene-transfer technologies display limitations in achieving effective gene delivery. Among these limitations are difficulties in stably integrating large corrective sequences into the genomes of long-lived progenitor-cell populations. Current larger-capacity viral vectors suffer from biosafety concerns, whereas plasmid-based approaches have poor efficiency of stable gene transfer. These barriers hinder genetic correction of many severe inherited human diseases, such as the blistering skin disorder recessive dystrophic epidermolysis bullosa (RDEB), caused by mutations in the large COL7A1 gene. To circumvent these barriers, we used the phi C31 bacteriophage integrase, which stably integrates large DNA sequences containing a specific 285-base-pair attB sequence into genomic 'pseudo-attP sites'. phi C31 integrase-based gene transfer stably integrated the COL7A1 cDNA into genomes of primary epidermal progenitor cells from four unrelated RDEB patients. Skin regenerated using these cells displayed stable correction of hallmark RDEB disease features, including Type VII collagen protein expression, anchoring fibril formation and dermal-epidermal cohesion. These findings establish a practical approach to nonviral genetic correction of severe human genetic disorders requiring stable genomic integration of large DNA sequences.", + "TAG_DATA": [ + "116, primary {'context': 'B-cells'}", + "117, epidermal {'context': 'I-cells'}", + "118, progenitor {'context': 'I-cells'}", + "119, cells {'context': 'I-cells'}", + "125, Skin {'context': 'B-tissue/organ'}", + "129, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "116, primary ['l0', 'l1', 'l2']", + "117, epidermal ['l0', 'l3', 'l4']", + "118, progenitor ['l1', 'l3', 'l5']", + "119, cells ['l2', 'l4', 'l5']", + "125, Skin ['l6']", + "129, cells ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12244303", + "TEXT": "The cyclin-dependent kinase inhibitor p27(kip1) is a putative tumor suppressor for human cancer. The mechanism underlying p27(kip1) deregulation in human cancer is, however, poorly understood. We demonstrate that the serine/threonine kinase Akt regulates cell proliferation in breast cancer cells by preventing p27(kip1)-mediated growth arrest. Threonine 157 (T157), which maps within the nuclear localization signal of p27(kip1), is a predicted Akt-phosphorylation site. Akt-induced T157 phosphorylation causes retention of p27(kip1) in the cytoplasm, precluding p27(kip1)-induced G1 arrest. Conversely, the p27(kip1)-T157A mutant accumulates in cell nuclei and Akt does not affect p27(kip1)-T157A-mediated cell cycle arrest. Lastly, T157-phosphorylated p27(kip1) accumulates in the cytoplasm of primary human breast cancer cells coincident with Akt activation. Thus, cytoplasmic relocalization of p27(kip1), secondary to Akt-mediated phosphorylation, is a novel mechanism whereby the growth inhibitory properties of p27(kip1) are functionally inactivated and the proliferation of breast cancer cells is sustained.", + "TAG_DATA": [ + "40, preventing {'effect': 'B-negative'}", + "43, arrest. {'phenotype': 'I-cell cycle arrest'}", + "71, precluding {'effect': 'B-negative'}", + "73, G1 {'phenotype': 'B-cell cycle arrest'}", + "74, arrest. {'phenotype': 'I-cell cycle arrest'}", + "77, p27(kip1)-T157A {'perturbing_action': 'B-other'}", + "78, mutant {'perturbing_action': 'I-other'}", + "81, cell {'context': 'B-cells'}", + "85, does {'effect': 'B-no effect'}", + "86, not {'effect': 'B-no effect'}", + "87, affect {'effect': 'I-no effect'}", + "89, cell {'phenotype': 'B-cell cycle arrest'}", + "90, cycle {'phenotype': 'I-cell cycle arrest'}", + "91, arrest. {'phenotype': 'I-cell cycle arrest'}", + "100, primary {'context': 'B-transformed cells'}", + "101, human {'context': 'I-transformed cells'}", + "102, breast {'context': 'I-transformed cells'}", + "103, cancer {'context': 'I-transformed cells'}", + "104, cells {'context': 'I-transformed cells'}", + "134, proliferation {'phenotype': 'B-proliferation'}", + "136, breast {'context': 'B-transformed cells'}", + "137, cancer {'context': 'I-transformed cells'}", + "138, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "40, preventing ['l0', 'l1', 'l2', 'l3', 'l4']", + "42, growth ['l0', 'l5', 'l6', 'l7', 'l8']", + "43, arrest. ['l1', 'l5', 'l9', 'l10', 'l11']", + "71, precluding ['l2', 'l6', 'l9', 'l12', 'l13']", + "73, G1 ['l3', 'l7', 'l10', 'l12', 'l14']", + "74, arrest. ['l4', 'l8', 'l11', 'l13', 'l14']", + "77, p27(kip1)-T157A ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "78, mutant ['l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "81, cell ['l16', 'l23', 'l30', 'l31', 'l32', 'l33']", + "85, does ['l17', 'l24', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "86, not ['l18', 'l25', 'l34', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "87, affect ['l19', 'l26', 'l30', 'l35', 'l41', 'l47', 'l48', 'l49', 'l50']", + "89, cell ['l20', 'l27', 'l31', 'l36', 'l42', 'l47', 'l51', 'l52']", + "90, cycle ['l21', 'l28', 'l32', 'l37', 'l43', 'l48', 'l51', 'l53']", + "91, arrest. ['l22', 'l29', 'l33', 'l38', 'l44', 'l49', 'l52', 'l53']", + "100, primary ['l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "101, human ['l54', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "102, breast ['l55', 'l62', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "103, cancer ['l56', 'l63', 'l69', 'l75', 'l76', 'l77', 'l78', 'l79']", + "104, cells ['l57', 'l64', 'l70', 'l75', 'l80', 'l81', 'l82', 'l83']", + "134, proliferation ['l58', 'l65', 'l71', 'l76', 'l80', 'l84', 'l85', 'l86']", + "136, breast ['l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l87', 'l88']", + "137, cancer ['l39', 'l45', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l87', 'l89']", + "138, cells ['l40', 'l46', 'l50', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l89']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "preventing", + "precluding" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest.", + "G1" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "p27(kip1)-T157A", + "mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "p27(kip1)-T157A", + "mutant" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "does", + "not", + "affect" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "p27(kip1)-T157A", + "mutant" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "affect" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest." + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "does", + "not", + "affect" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest." + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "does", + "not", + "affect" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "primary", + "human", + "breast", + "cancer", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "12244301", + "TEXT": "We have shown a novel mechanism of Akt-mediated regulation of the CDK inhibitor p27(kip1). Blockade of HER2/neu in tumor cells inhibits Akt kinase activity and upregulates nuclear levels of the CDK inhibitor (Kip1). Recombinant Akt and Akt precipitated from tumor cells phosphorylated wild-type p27 in vitro. p27 contains an Akt consensus RXRXXT(157)D within its nuclear localization motif. Active (myristoylated) Akt phosphorylated wild-type p27 in vivo but was unable to phosphorylate a T157A-p27 mutant. Wild-type p27 localized in the cytosol and nucleus, whereas T157A-p27 localized exclusively in the nucleus and was resistant to nuclear exclusion by Akt. T157A-p27 was more effective than wild-type p27 in inhibiting cyclin E/CDK2 activity and cell proliferation; these effects were not rescued by active Akt. Expression of Ser(473) phospho Akt in primary human breast cancers statistically correlated with expression of p27 in tumor cytosol. These data indicate that Akt may contribute to tumor-cell proliferation by phosphorylation and cytosolic retention of p27, thus relieving CDK2 from p27-induced inhibition.", + "TAG_DATA": [ + "18, tumor {'context': 'B-transformed cells'}", + "39, tumor {'context': 'B-transformed cells'}", + "40, cells {'context': 'I-transformed cells'}", + "44, in {'context': 'B-in vitro'}", + "45, vitro. {'context': 'I-in vitro'}", + "63, in {'context': 'B-in vivo'}", + "64, vivo {'context': 'I-in vivo'}", + "104, inhibiting {'effect': 'B-negative'}", + "109, cell {'context': 'B-cells'}", + "110, proliferation; {'phenotype': 'B-proliferation'}", + "117, active {'perturbing_action': 'B-gene gain-of-function'}", + "118, Akt. {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "18, tumor ['l0', 'l1', 'l2', 'l3', 'l4']", + "19, cells ['l0', 'l5']", + "39, tumor ['l1', 'l6', 'l7', 'l8', 'l9', 'l10']", + "40, cells ['l2', 'l5', 'l6', 'l11', 'l12', 'l13']", + "44, in ['l7', 'l11', 'l14', 'l15', 'l16']", + "45, vitro. ['l8', 'l14', 'l17', 'l18']", + "63, in ['l3', 'l9', 'l12', 'l15', 'l17', 'l19']", + "64, vivo ['l4', 'l10', 'l13', 'l16', 'l18', 'l19']", + "104, inhibiting ['l20', 'l21']", + "109, cell ['l20', 'l22']", + "110, proliferation; ['l21', 'l22']", + "117, active ['l23']", + "118, Akt. ['l23']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibiting" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibiting" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation;" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation;" + ] + } + } + ] + }, + { + "PMID": "12219086", + "TEXT": "With the advent of HIV and the widespread emergence of drug-resistant strains of Mycobacterium tuberculosis, newer control strategies in the form of a better vaccine could decrease the global incidence of tuberculosis. A desirable trait in an effective live attenuated vaccine strain is an ability to persist within the host in a limited fashion in order to produce important protective antigens in vivo. Attenuated M. tuberculosis vaccine candidates have been constructed by deleting genes required for growth in mice. These candidate vaccines did not elicit adequate protective immunity in animal models, due to their inability to persist sufficiently long within the host tissues. Here we report that an auxotrophic mutant of M. tuberculosis defective in the de novo biosynthesis of pantothenic acid (vitamin B5) is highly attenuated in immunocompromised SCID mice and in immunocompetent BALB/c mice. SCID mice infected with the pantothenate auxotroph survived significantly longer (250 days) than mice infected with either bacille Calmette-Guerin (BCG) vaccine or virulent M. tuberculosis (77 and 35 days, respectively). Subcutaneous immunization with this auxotroph conferred protection in C57BL/6J mice against an aerosol challenge with virulent M. tuberculosis, which was comparable with that afforded by BCG vaccination. Our findings highlight the importance of de novo pantothenate biosynthesis in limiting the intracellular survival and pathogenesis of M. tuberculosis without reducing its immunogenicity in vaccinated mice.", + "TAG_DATA": [ + "108, auxotrophic {'perturbing_action': 'B-other'}", + "109, mutant {'perturbing_action': 'I-other'}", + "110, of {'perturbing_action': 'I-other'}", + "111, M. {'perturbing_action': 'I-other'}", + "112, tuberculosis {'perturbing_action': 'I-other'}", + "130, mice {'context': 'I-organism'}", + "133, immunocompetent {'context': 'B-organism'}", + "134, BALB/c {'context': 'I-organism'}", + "135, mice. {'context': 'I-organism'}", + "136, SCID {'context': 'B-organism'}", + "137, mice {'context': 'I-organism'}", + "149, mice {'context': 'B-organism'}", + "174, C57BL/6J {'context': 'B-organism'}", + "175, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "108, auxotrophic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "109, mutant ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "110, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "111, M. ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "112, tuberculosis ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "130, mice ['l4', 'l12', 'l19', 'l25', 'l30']", + "133, immunocompetent ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l36', 'l37']", + "134, BALB/c ['l6', 'l14', 'l21', 'l27', 'l32', 'l35', 'l38', 'l39', 'l40', 'l41']", + "135, mice. ['l7', 'l15', 'l22', 'l28', 'l33', 'l36', 'l38', 'l42']", + "136, SCID ['l39', 'l43', 'l44']", + "137, mice ['l40', 'l43', 'l45']", + "149, mice ['l8', 'l16', 'l23', 'l29', 'l34', 'l37', 'l41', 'l42', 'l44', 'l45']", + "174, C57BL/6J ['l46']", + "175, mice ['l46']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "auxotrophic", + "mutant", + "of", + "M.", + "tuberculosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "immunocompetent", + "BALB/c", + "mice." + ] + } + } + ] + }, + { + "PMID": "12219085", + "TEXT": "The intracellular signaling mechanisms that specify tissue-specific responses to the interleukin-6 (IL-6) family of cytokines are not well understood. Here, we evaluated the functions of the two major signaling pathways, the signal transducers and activators of transcription 1 and 3 (STAT1/3) and the Src-homology tyrosine phosphatase 2 (SHP2)-Ras-ERK, emanating from the common signal transducer, gp130, in the gastrointestinal tract. Gp130(757F) mice, with a 'knock-in' mutation abrogating SHP2-Ras-ERK signaling, developed gastric adenomas by three months of age. In contrast, mice harboring the reciprocal mutation ablating STAT1/3 signaling (gp130(Delta STAT)), or deficient in IL-6-mediated gp130 signaling (IL-6(-/-) mice), showed impaired colonic mucosal wound healing. These gastrointestinal phenotypes are highly similar to the phenotypes exhibited by mice deficient in trefoil factor 1 (pS2/TFF1) and intestinal trefoil factor (ITF)/TFF3, respectively, and corresponded closely with the capacity of the two pathways to stimulate transcription of the genes encoding pS2/TFF1 and ITF/TFF3. We propose a model whereby mucosal wound healing depends solely on activation of STAT1/3, whereas gastric hyperplasia ensues when the coordinated activation of the STAT1/3 and SHP2-Ras-ERK pathways is disrupted.", + "TAG_DATA": [ + "59, Gp130(757F) {'perturbing_action': 'B-other'}", + "60, mice, {'context': 'B-organism'}", + "63, 'knock-in' {'perturbing_action': 'B-gene loss-of-function'}", + "64, mutation {'perturbing_action': 'I-rnai/knockdown'}", + "65, abrogating {'perturbing_action': 'I-rnai/knockdown'}", + "69, gastric {'phenotype': 'B-tumourigenesis'}", + "70, adenomas {'phenotype': 'I-tumourigenesis'}", + "78, mice {'context': 'B-organism'}", + "81, reciprocal {'perturbing_action': 'I-other'}", + "82, mutation {'perturbing_action': 'I-other'}", + "83, ablating {'perturbing_action': 'I-gene loss-of-function'}", + "84, STAT1/3 {'perturbing_action': 'I-gene loss-of-function'}", + "85, signaling {'perturbing_action': 'I-other'}", + "86, (gp130(Delta {'perturbing_action': 'I-other'}", + "87, STAT)), {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "59, Gp130(757F) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "60, mice, ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "63, 'knock-in' ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "64, mutation ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "65, abrogating ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "69, gastric ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "70, adenomas ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "78, mice ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "81, reciprocal ['l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "82, mutation ['l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "83, ablating ['l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "84, STAT1/3 ['l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "85, signaling ['l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "86, (gp130(Delta ['l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "87, STAT)), ['l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Gp130(757F)", + "reciprocal", + "mutation", + "signaling", + "(gp130(Delta" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Gp130(757F)" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "gastric", + "adenomas" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "'knock-in'", + "ablating", + "STAT1/3", + "STAT))," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "mutation", + "abrogating" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "gastric", + "adenomas" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "'knock-in'" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "gastric", + "adenomas" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "mutation", + "abrogating" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "gastric", + "adenomas" + ] + } + } + ] + }, + { + "PMID": "12185361", + "TEXT": "Angiogenesis is a highly regulated process that results from the sequential actions of naturally occurring stimulators and inhibitors. Here, we show that parathyroid hormone-related peptide, a peptide hormone derived from normal and tumor cells that regulates bone metabolism and vascular tone, is a naturally occurring angiogenesis inhibitor. Parathyroid hormone-related peptide or a ten-amino-acid peptide from its N terminus inhibits endothelial cell migration in vitro and angiogenesis in vivo by activating endothelial cell protein kinase A. Activation of protein kinase A inhibits cell migration and angiogenesis by inhibiting the small GTPase Rac. In contrast, inhibition of protein kinase A reverses the anti-migratory and anti-angiogenic properties of parathyroid hormone-related peptide. These studies show that parathyroid hormone-related peptide is a naturally occurring angiogenesis inhibitor that functions by activation of protein kinase A.", + "TAG_DATA": [ + "58, inhibits {'effect': 'B-negative'}", + "59, endothelial {'context': 'B-cells'}", + "60, cell {'context': 'I-cells'}", + "61, migration {'phenotype': 'B-migration'}", + "62, in {'context': 'B-in vitro'}", + "63, vitro {'context': 'I-in vitro'}", + "66, in {'context': 'B-in vivo'}", + "67, vivo {'context': 'I-in vivo'}", + "70, endothelial {'context': 'B-cells'}", + "71, cell {'context': 'I-cells'}", + "75, Activation {'perturbing_action': 'B-pharmacological augmentation'}", + "76, of {'perturbing_action': 'I-pharmacological augmentation'}", + "77, protein {'perturbing_action': 'I-pharmacological augmentation'}", + "78, kinase {'perturbing_action': 'I-pharmacological augmentation'}", + "79, A {'perturbing_action': 'I-pharmacological augmentation'}", + "80, inhibits {'effect': 'B-negative'}", + "81, cell {'context': 'B-cells'}", + "82, migration {'phenotype': 'B-migration'}", + "93, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "94, of {'perturbing_action': 'I-pharmacological inhibition'}", + "95, protein {'perturbing_action': 'I-pharmacological inhibition'}", + "96, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "97, A {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "58, inhibits ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "59, endothelial ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "60, cell ['l1', 'l7', 'l12', 'l13', 'l14']", + "61, migration ['l2', 'l8', 'l12', 'l15', 'l16']", + "62, in ['l3', 'l9', 'l13', 'l15', 'l17']", + "63, vitro ['l4', 'l10', 'l14', 'l16', 'l17', 'l18']", + "66, in ['l5', 'l19', 'l20', 'l21']", + "67, vivo ['l6', 'l11', 'l18', 'l19', 'l22', 'l23']", + "70, endothelial ['l20', 'l22', 'l24', 'l25', 'l26', 'l27']", + "71, cell ['l21', 'l23', 'l24', 'l28', 'l29', 'l30']", + "75, Activation ['l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "76, of ['l31', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "77, protein ['l32', 'l38', 'l44', 'l45', 'l46', 'l47', 'l48']", + "78, kinase ['l33', 'l39', 'l44', 'l49', 'l50', 'l51', 'l52']", + "79, A ['l34', 'l40', 'l45', 'l49', 'l53', 'l54', 'l55']", + "80, inhibits ['l25', 'l28', 'l35', 'l41', 'l46', 'l50', 'l53', 'l56', 'l57']", + "81, cell ['l26', 'l29', 'l36', 'l42', 'l47', 'l51', 'l54', 'l56', 'l58']", + "82, migration ['l27', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l57', 'l58']", + "93, inhibition ['l59', 'l60', 'l61', 'l62']", + "94, of ['l59', 'l63', 'l64', 'l65']", + "95, protein ['l60', 'l63', 'l66', 'l67']", + "96, kinase ['l61', 'l64', 'l66', 'l68']", + "97, A ['l62', 'l65', 'l67', 'l68']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "protein", + "kinase", + "A" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "protein", + "kinase", + "A" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "protein", + "kinase", + "A" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + } + ] + }, + { + "PMID": "12172542", + "TEXT": "The prevalence of asthma continues to increase and its optimal treatment remains a challenge. Here, we investigated the actions of lipoxin A(4) (LXA(4)) and its leukocyte receptor in pulmonary inflammation using a murine model of asthma. Allergen challenge initiated airway biosynthesis of LXA(4) and increased expression of its receptor. Administration of a stable analog of LXA(4) blocked both airway hyper-responsiveness and pulmonary inflammation, as shown by decreased leukocytes and mediators, including interleukin-5, interleukin-13, eotaxin, prostanoids and cysteinyl leukotrienes. Moreover, transgenic expression of human LXA(4) receptors in murine leukocytes led to significant inhibition of pulmonary inflammation and eicosanoid-initiated eosinophil tissue infiltration. Inhibition of airway hyper-responsiveness and allergic airway inflammation with a stable LXA(4) analog highlights a unique counter-regulatory profile for the LXA(4) system and its leukocyte receptor in airway responses. Moreover, our findings suggest that lipoxin and related pathways offer novel multi-pronged therapeutic approaches for human asthma.", + "TAG_DATA": [ + "79, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "80, expression {'perturbing_action': 'I-gene gain-of-function'}", + "81, of {'perturbing_action': 'I-gene gain-of-function'}", + "82, human {'perturbing_action': 'I-gene gain-of-function'}", + "83, LXA(4) {'perturbing_action': 'I-gene gain-of-function'}", + "84, receptors {'perturbing_action': 'I-gene gain-of-function'}", + "86, murine {'context': 'B-cells'}", + "87, leukocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "79, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "80, expression ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "81, of ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "82, human ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "83, LXA(4) ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "84, receptors ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "86, murine ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "87, leukocytes ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "of", + "human", + "LXA(4)", + "receptors" + ] + }, + "context": { + "val": "cells", + "words": [ + "murine", + "leukocytes" + ] + } + } + ] + }, + { + "PMID": "12118247", + "TEXT": "Melanin concentrating hormone (MCH) is an orexigenic hypothalamic neuropeptide, which plays an important role in the complex regulation of energy balance and body weight. Here we show that SNAP-7941, a selective, high-affinity MCH1 receptor (MCH1-R) antagonist, inhibited food intake stimulated by central administration of MCH, reduced consumption of palatable food, and, after chronic administration to rats with diet-induced obesity, resulted in a marked, sustained decrease in body weight. In addition, after mapping the binding sites for [(3)H]SNAP-7941 in rat brain, we evaluated its effects in a series of behavioral models. SNAP-7941 produced effects similar to clinically used antidepressants and anxiolytics in three animal models of depression/anxiety: the rat forced-swim test, rat social interaction and guinea pig maternal-separation vocalization tests. Given these observations, an MCH1-R antagonist may be useful not only in the management of obesity but also as a treatment for depression and/or anxiety.", + "TAG_DATA": [ + "28, SNAP-7941, {'perturbing_action': 'B-pharmacological inhibition'}", + "29, a {'perturbing_action': 'I-pharmacological inhibition'}", + "30, selective, {'perturbing_action': 'I-pharmacological inhibition'}", + "31, high-affinity {'perturbing_action': 'I-pharmacological inhibition'}", + "32, MCH1 {'perturbing_action': 'I-pharmacological inhibition'}", + "33, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "34, (MCH1-R) {'perturbing_action': 'I-pharmacological inhibition'}", + "35, antagonist, {'perturbing_action': 'I-pharmacological inhibition'}", + "55, rats {'context': 'B-organism'}", + "107, rat {'context': 'B-organism'}", + "110, rat {'context': 'B-organism'}", + "114, guinea {'context': 'B-organism'}", + "115, pig {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "28, SNAP-7941, ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "29, a ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "30, selective, ['l1', 'l7', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "31, high-affinity ['l2', 'l8', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "32, MCH1 ['l3', 'l9', 'l15', 'l20', 'l25', 'l26', 'l27', 'l28']", + "33, receptor ['l4', 'l10', 'l16', 'l21', 'l25', 'l29', 'l30', 'l31']", + "34, (MCH1-R) ['l5', 'l11', 'l17', 'l22', 'l26', 'l29', 'l32', 'l33']", + "35, antagonist, ['l6', 'l12', 'l18', 'l23', 'l27', 'l30', 'l32']", + "55, rats ['l13', 'l19', 'l24', 'l28', 'l31', 'l33']", + "107, rat ['l34']", + "110, rat ['l34']", + "114, guinea ['l35']", + "115, pig ['l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "a", + "selective,", + "high-affinity", + "MCH1", + "receptor", + "(MCH1-R)" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + } + ] + }, + { + "PMID": "12091880", + "TEXT": "The mechanism by which angiogenic factors recruit bone marrow (BM)-derived quiescent endothelial and hematopoietic stem cells (HSCs) is not known. Here, we report that functional vascular endothelial growth factor receptor-1 (VEGFR1) is expressed on human CD34(+) and mouse Lin(-)Sca-1(+)c-Kit(+) BM-repopulating stem cells, conveying signals for recruitment of HSCs and reconstitution of hematopoiesis. Inhibition of VEGFR1, but not VEGFR2, blocked HSC cell cycling, differentiation and hematopoietic recovery after BM suppression, resulting in the demise of the treated mice. Placental growth factor (PlGF), which signals through VEGFR1, restored early and late phases of hematopoiesis following BM suppression. PlGF enhanced early phases of BM recovery directly through rapid chemotaxis of VEGFR1(+) BM-repopulating and progenitor cells. The late phase of hematopoietic recovery was driven by PlGF-induced upregulation of matrix metalloproteinase-9, mediating the release of soluble Kit ligand. Thus, PlGF promotes recruitment of VEGFR1(+) HSCs from a quiescent to a proliferative BM microenvironment, favoring differentiation, mobilization and reconstitution of hematopoiesis.", + "TAG_DATA": [ + "52, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "53, of {'perturbing_action': 'I-pharmacological inhibition'}", + "54, VEGFR1, {'perturbing_action': 'I-pharmacological inhibition'}", + "58, blocked {'effect': 'B-negative'}", + "59, HSC {'context': 'B-transformed cells'}", + "62, differentiation {'phenotype': 'B-differentiation'}", + "76, mice. {'context': 'B-organism'}", + "105, chemotaxis {'phenotype': 'B-migration'}", + "107, VEGFR1(+) {'context': 'B-cells'}", + "108, BM-repopulating {'context': 'I-cells'}", + "109, and {'context': 'I-cells'}", + "110, progenitor {'context': 'I-cells'}", + "111, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "52, Inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "53, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "54, VEGFR1, ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "58, blocked ['l2', 'l7', 'l11', 'l15', 'l16']", + "59, HSC ['l3', 'l8', 'l12', 'l15', 'l17']", + "62, differentiation ['l4', 'l9', 'l13', 'l16', 'l17']", + "76, mice. ['l5', 'l10', 'l14']", + "105, chemotaxis ['l18', 'l19', 'l20', 'l21', 'l22']", + "107, VEGFR1(+) ['l18', 'l23', 'l24', 'l25', 'l26']", + "108, BM-repopulating ['l19', 'l23', 'l27', 'l28', 'l29']", + "109, and ['l20', 'l24', 'l27', 'l30', 'l31']", + "110, progenitor ['l21', 'l25', 'l28', 'l30', 'l32']", + "111, cells. ['l22', 'l26', 'l29', 'l31', 'l32']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "VEGFR1," + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "VEGFR1," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "VEGFR1," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "VEGFR1," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + }, + "context": { + "val": "cells", + "words": [ + "VEGFR1(+)", + "BM-repopulating", + "and", + "progenitor", + "cells." + ] + } + } + ] + }, + { + "PMID": "12091879", + "TEXT": "Asthma is an increasingly common disease that remains poorly understood and difficult to manage. This disease is characterized by airway hyperreactivity (AHR, defined by exaggerated airflow obstruction in response to bronchoconstrictors), mucus overproduction and chronic eosinophilic inflammation. AHR and mucus overproduction are consistently linked to asthma symptoms and morbidity. Asthma is mediated by Th2 lymphocytes, which produce a limited repertoire of cytokines, including interleukin-4 (IL-4), IL-5, IL-9 and IL-13. Although each of these cytokines has been implicated in asthma, IL-13 is now thought to be especially critical. In animal models of allergic asthma, blockade of IL-13 markedly inhibits allergen-induced AHR, mucus production and eosinophilia. Furthermore, IL-13 delivery to the airway causes all of these effects. IL-13 is thus both necessary and sufficient for experimental models of asthma. However, the IL-13-responsive cells causing these effects have not been identified. Here we show that mice lacking signal transducer and activator of transcription 6 (STAT6) were protected from all pulmonary effects of IL-13. Reconstitution of STAT6 only in epithelial cells was sufficient for IL-13-induced AHR and mucus production in the absence of inflammation, fibrosis or other lung pathology. These results demonstrate the importance of direct effects of IL-13 on epithelial cells in causing two central features of asthma.", + "TAG_DATA": [ + "142, mice {'context': 'B-organism'}", + "143, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "144, signal {'perturbing_action': 'I-gene loss-of-function'}", + "145, transducer {'perturbing_action': 'I-gene loss-of-function'}", + "146, and {'perturbing_action': 'I-gene loss-of-function'}", + "147, activator {'perturbing_action': 'I-gene loss-of-function'}", + "148, of {'perturbing_action': 'I-gene loss-of-function'}", + "149, transcription {'perturbing_action': 'I-gene loss-of-function'}", + "150, 6 {'perturbing_action': 'I-gene loss-of-function'}", + "151, (STAT6) {'perturbing_action': 'I-gene loss-of-function'}", + "160, Reconstitution {'perturbing_action': 'B-gene gain-of-function'}", + "161, of {'perturbing_action': 'I-gene loss-of-function'}", + "162, STAT6 {'perturbing_action': 'I-gene loss-of-function'}", + "165, epithelial {'context': 'B-cells'}", + "166, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "142, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "143, lacking ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "144, signal ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "145, transducer ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "146, and ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "147, activator ['l4', 'l12', 'l19', 'l25', 'l30', 'l36', 'l37', 'l38', 'l39']", + "148, of ['l5', 'l13', 'l20', 'l26', 'l31', 'l36', 'l40', 'l41', 'l42']", + "149, transcription ['l6', 'l14', 'l21', 'l27', 'l32', 'l37', 'l40', 'l43', 'l44']", + "150, 6 ['l7', 'l15', 'l22', 'l28', 'l33', 'l38', 'l41', 'l43', 'l45']", + "151, (STAT6) ['l8', 'l16', 'l23', 'l29', 'l34', 'l39', 'l42', 'l44', 'l45']", + "160, Reconstitution ['l46', 'l47', 'l48', 'l49']", + "161, of ['l46', 'l50', 'l51', 'l52']", + "162, STAT6 ['l47', 'l50', 'l53', 'l54']", + "165, epithelial ['l48', 'l51', 'l53', 'l55']", + "166, cells ['l35', 'l49', 'l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "signal", + "transducer", + "and", + "activator", + "of", + "transcription", + "6", + "(STAT6)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "and", + "of", + "STAT6" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "epithelial" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reconstitution" + ] + }, + "context": { + "val": "cells", + "words": [ + "epithelial", + "cells" + ] + } + } + ] + }, + { + "PMID": "12091878", + "TEXT": "The Lyme disease vaccine is based on the outer-surface lipoprotein (OspA) of the pathogen Borrelia burgdorferi, and 95% of vaccine recipients develop substantial titers of antibodies against OspA. Here, we identified seven individuals with very low antibody titers after vaccination (low responders). The macrophages of low responders produced less tumor necrosis factor-alpha and interleukin-6 after OspA stimulation and had lower cell-surface expression of Toll-like receptor (TLR) 1 as compared to normal cells, but normal expression of TLR2. TLRs activate innate responses to pathogens, and TLR2 recognizes lipoproteins and peptidoglycan (PGN). After OspA immunization, mice genetically deficient in either TLR2 (TLR2(-/-)) or TLR1 (TLR1(-/-)) produced low titers of antibodies against OspA. Notably, macrophages from TLR2(-/-) mice were unresponsive to OspA and PGN, whereas those from TLR1(-/-) mice responded normally to PGN but not to OspA. These data indicate that TLR1 and TLR2 are required for lipoprotein recognition and that defects in the TLR1/2 signaling pathway may account for human hyporesponsiveness to OspA vaccination.", + "TAG_DATA": [ + "43, macrophages {'context': 'B-cells'}", + "93, mice {'context': 'B-organism'}", + "95, deficient {'perturbing_action': 'I-gene loss-of-function'}", + "96, in {'perturbing_action': 'I-gene loss-of-function'}", + "97, either {'perturbing_action': 'I-gene loss-of-function'}", + "98, TLR2 {'perturbing_action': 'I-gene loss-of-function'}", + "99, (TLR2(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "100, or {'perturbing_action': 'I-gene loss-of-function'}", + "101, TLR1 {'perturbing_action': 'I-gene loss-of-function'}", + "102, (TLR1(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "111, macrophages {'context': 'B-cells'}", + "113, TLR2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "114, mice {'context': 'B-organism'}", + "124, TLR1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "125, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "93, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "95, deficient ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "96, in ['l1', 'l8', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "97, either ['l2', 'l9', 'l18', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "98, TLR2 ['l3', 'l10', 'l19', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "99, (TLR2(-/-)) ['l4', 'l11', 'l20', 'l27', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "100, or ['l5', 'l12', 'l21', 'l28', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47', 'l48']", + "101, TLR1 ['l6', 'l13', 'l22', 'l29', 'l35', 'l40', 'l44', 'l49', 'l50', 'l51', 'l52']", + "102, (TLR1(-/-)) ['l7', 'l14', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l53', 'l54', 'l55']", + "111, macrophages ['l15', 'l24', 'l31', 'l37', 'l42', 'l46', 'l50', 'l53', 'l56', 'l57', 'l58']", + "113, TLR2(-/-) ['l16', 'l47', 'l51', 'l54', 'l56', 'l59', 'l60', 'l61']", + "114, mice ['l17', 'l25', 'l32', 'l38', 'l43', 'l48', 'l52', 'l55', 'l57', 'l59']", + "124, TLR1(-/-) ['l60', 'l62']", + "125, mice ['l58', 'l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "either", + "TLR2", + "(TLR2(-/-))", + "or", + "TLR1", + "(TLR1(-/-))", + "TLR2(-/-)", + "TLR1(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "either", + "TLR2", + "(TLR2(-/-))", + "or", + "TLR1", + "(TLR1(-/-))", + "TLR2(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages" + ] + } + } + ] + }, + { + "PMID": "12091877", + "TEXT": "The therapeutic potential of placental growth factor (PlGF) and its receptor Flt1 in angiogenesis is poorly understood. Here, we report that PlGF stimulated angiogenesis and collateral growth in ischemic heart and limb with at least a comparable efficiency to vascular endothelial growth factor (VEGF). An antibody against Flt1 suppressed neovascularization in tumors and ischemic retina, and angiogenesis and inflammatory joint destruction in autoimmune arthritis. Anti-Flt1 also reduced atherosclerotic plaque growth and vulnerability, but the atheroprotective effect was not attributable to reduced plaque neovascularization. Inhibition of VEGF receptor Flk1 did not affect arthritis or atherosclerosis, indicating that inhibition of Flk1-driven angiogenesis alone was not sufficient to halt disease progression. The anti-inflammatory effects of anti-Flt1 were attributable to reduced mobilization of bone marrow-derived myeloid progenitors into the peripheral blood; impaired infiltration of Flt1-expressing leukocytes in inflamed tissues; and defective activation of myeloid cells. Thus, PlGF and Flt1 constitute potential candidates for therapeutic modulation of angiogenesis and inflammation.", + "TAG_DATA": [ + "29, heart {'context': 'I-tissue/organ'}", + "31, limb {'context': 'I-tissue/organ'}", + "45, antibody {'perturbing_action': 'B-rnai/knockdown'}", + "46, against {'perturbing_action': 'I-rnai/knockdown'}", + "47, Flt1 {'perturbing_action': 'I-rnai/knockdown'}", + "51, tumors {'context': 'B-neoplasm'}", + "53, ischemic {'context': 'B-tissue/organ'}", + "54, retina, {'context': 'I-tissue/organ'}", + "83, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "84, of {'perturbing_action': 'I-pharmacological inhibition'}", + "85, VEGF {'perturbing_action': 'I-pharmacological inhibition'}", + "86, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "87, Flk1 {'perturbing_action': 'I-pharmacological inhibition'}", + "89, not {'effect': 'I-no effect'}", + "90, affect {'effect': 'I-no effect'}", + "119, bone {'context': 'B-cells'}", + "120, marrow-derived {'context': 'I-cells'}", + "121, myeloid {'context': 'I-cells'}", + "122, progenitors {'context': 'I-cells'}", + "131, leukocytes {'context': 'I-cells'}", + "139, myeloid {'context': 'B-cells'}", + "140, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "29, heart ['l0', 'l1', 'l2', 'l3']", + "31, limb ['l0', 'l4', 'l5', 'l6']", + "45, antibody ['l7', 'l8', 'l9', 'l10', 'l11']", + "46, against ['l7', 'l12', 'l13', 'l14', 'l15']", + "47, Flt1 ['l8', 'l12', 'l16', 'l17', 'l18']", + "51, tumors ['l1', 'l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "53, ischemic ['l2', 'l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "54, retina, ['l3', 'l6', 'l11', 'l15', 'l18', 'l20', 'l21']", + "83, Inhibition ['l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "84, of ['l22', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "85, VEGF ['l23', 'l35', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "86, receptor ['l24', 'l36', 'l46', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "87, Flk1 ['l25', 'l37', 'l47', 'l56', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "89, not ['l26', 'l38', 'l48', 'l57', 'l64', 'l71']", + "90, affect ['l27', 'l39', 'l49', 'l58', 'l65', 'l71']", + "119, bone ['l28', 'l40', 'l50', 'l59', 'l66', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "120, marrow-derived ['l29', 'l41', 'l51', 'l60', 'l67', 'l72', 'l78', 'l79', 'l80', 'l81', 'l82']", + "121, myeloid ['l30', 'l42', 'l52', 'l61', 'l68', 'l73', 'l78', 'l83', 'l84', 'l85', 'l86']", + "122, progenitors ['l31', 'l43', 'l53', 'l62', 'l69', 'l74', 'l79', 'l83', 'l87', 'l88', 'l89']", + "131, leukocytes ['l32', 'l44', 'l54', 'l63', 'l70', 'l75', 'l80', 'l84', 'l87', 'l90', 'l91']", + "139, myeloid ['l33', 'l76', 'l81', 'l85', 'l88', 'l90', 'l92']", + "140, cells. ['l34', 'l45', 'l55', 'l77', 'l82', 'l86', 'l89', 'l91', 'l92']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antibody", + "against", + "Flt1" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antibody", + "against", + "Flt1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "ischemic", + "retina," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "VEGF", + "receptor", + "Flk1" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "affect" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "VEGF", + "receptor", + "Flk1" + ] + }, + "context": { + "val": "cells", + "words": [ + "bone", + "marrow-derived", + "myeloid", + "progenitors", + "leukocytes", + "cells." + ] + } + } + ] + }, + { + "PMID": "12068290", + "TEXT": "Secretion of gastric inhibitory polypeptide (GIP), a duodenal hormone, is primarily induced by absorption of ingested fat. Here we describe a novel pathway of obesity promotion via GIP. Wild-type mice fed a high-fat diet exhibited both hypersecretion of GIP and extreme visceral and subcutaneous fat deposition with insulin resistance. In contrast, mice lacking the GIP receptor (Gipr(-/-)) fed a high-fat diet were clearly protected from both the obesity and the insulin resistance. Moreover, double-homozygous mice (Gipr(-/-), Lep(ob)/Lep(ob)) generated by crossbreeding Gipr(-/-) and obese ob/ob (Lep(ob)/Lep(ob)) mice gained less weight and had lower adiposity than Lep(ob)/Lep(ob) mice. The Gipr(-/-) mice had a lower respiratory quotient and used fat as the preferred energy substrate, and were thus resistant to obesity. Therefore, GIP directly links overnutrition to obesity and it is a potential target for anti-obesity drugs.", + "TAG_DATA": [ + "29, mice {'context': 'B-organism'}", + "51, mice {'context': 'B-organism'}", + "52, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "53, the {'perturbing_action': 'I-gene loss-of-function'}", + "54, GIP {'perturbing_action': 'I-gene loss-of-function'}", + "55, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "56, (Gipr(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "73, double-homozygous {'perturbing_action': 'B-gene loss-of-function'}", + "74, mice {'context': 'B-organism'}", + "75, (Gipr(-/-), {'perturbing_action': 'I-gene loss-of-function'}", + "76, Lep(ob)/Lep(ob)) {'perturbing_action': 'I-gene loss-of-function'}", + "80, Gipr(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "82, obese {'perturbing_action': 'B-other'}", + "83, ob/ob {'perturbing_action': 'B-other'}", + "84, (Lep(ob)/Lep(ob)) {'perturbing_action': 'I-gene loss-of-function'}", + "85, mice {'context': 'B-organism'}", + "94, Lep(ob)/Lep(ob) {'perturbing_action': 'B-gene loss-of-function'}", + "95, mice. {'context': 'B-organism'}", + "97, Gipr(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "98, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "51, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "52, lacking ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "53, the ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "54, GIP ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "55, receptor ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "56, (Gipr(-/-)) ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "73, double-homozygous ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "74, mice ['l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "75, (Gipr(-/-), ['l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "76, Lep(ob)/Lep(ob)) ['l5', 'l10', 'l14', 'l17', 'l19', 'l20', 'l23', 'l32', 'l40']", + "80, Gipr(-/-) ['l24', 'l33', 'l41', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "82, obese ['l25', 'l34', 'l42', 'l48', 'l54', 'l55', 'l56', 'l57', 'l58']", + "83, ob/ob ['l26', 'l35', 'l43', 'l49', 'l54', 'l59', 'l60', 'l61', 'l62']", + "84, (Lep(ob)/Lep(ob)) ['l27', 'l36', 'l44', 'l50', 'l55', 'l59', 'l63', 'l64', 'l65']", + "85, mice ['l28', 'l37', 'l45', 'l51', 'l56', 'l60', 'l63', 'l66', 'l67']", + "94, Lep(ob)/Lep(ob) ['l29', 'l38', 'l46', 'l52', 'l57', 'l61', 'l64', 'l66', 'l68']", + "95, mice. ['l30', 'l39', 'l47', 'l53', 'l58', 'l62', 'l65', 'l67', 'l68']", + "97, Gipr(-/-) ['l69']", + "98, mice ['l69']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "GIP", + "receptor", + "(Gipr(-/-))", + "Lep(ob)/Lep(ob))", + "double-homozygous", + "(Gipr(-/-),", + "Gipr(-/-)", + "(Lep(ob)/Lep(ob))", + "Lep(ob)/Lep(ob)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "obese", + "ob/ob" + ] + } + } + ] + }, + { + "PMID": "12053175", + "TEXT": "Blood vessels of tumors carry specific markers that are usually angiogenesis-related. We previously used phage-displayed peptide libraries in vivo to identify peptides that home to tumors through the circulation and that specifically bind to the endothelia of tumor blood vessels. Here we devised a phage screening procedure that would favor tumor-homing to targets that are accessible to circulating phage, but are not blood vessels. Screening on MDA-MB-435 breast carcinoma xenografts yielded multiple copies of a phage that displays a cyclic 9-amino-acid peptide, LyP-1. Homing and binding to tumor-derived cell suspensions indicated that LyP-1 also recognizes an osteosarcoma xenograft, and spontaneous prostate and breast cancers in transgenic mice, but not two other tumor xenografts. Fluorescein-labeled LyP-1 peptide was detected in tumor structures that were positive for three lymphatic endothelial markers and negative for three blood vessel markers. LyP-1 accumulated in the nuclei of the putative lymphatic cells, and in the nuclei of tumor cells. These results suggest that tumor lymphatics carry specific markers and that it may be possible to specifically target therapies into tumor lymphatics.", + "TAG_DATA": [ + "66, MDA-MB-435 {'context': 'B-xenograft'}", + "67, breast {'context': 'I-xenograft'}", + "68, carcinoma {'context': 'I-xenograft'}", + "69, xenografts {'context': 'I-xenograft'}", + "87, tumor-derived {'context': 'B-cells'}", + "88, cell {'context': 'I-cells'}", + "89, suspensions {'context': 'I-cells'}", + "96, osteosarcoma {'context': 'B-xenograft'}", + "97, xenograft, {'context': 'I-xenograft'}", + "100, prostate {'context': 'B-neoplasm'}", + "101, and {'context': 'I-neoplasm'}", + "102, breast {'context': 'I-neoplasm'}", + "103, cancers {'context': 'I-neoplasm'}", + "105, transgenic {'context': 'B-organism'}", + "106, mice, {'context': 'I-organism'}", + "111, tumor {'context': 'B-xenograft'}", + "112, xenografts. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "66, MDA-MB-435 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "67, breast ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "68, carcinoma ['l1', 'l12', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "69, xenografts ['l2', 'l13', 'l20', 'l27', 'l28', 'l29', 'l30', 'l31']", + "87, tumor-derived ['l3', 'l14', 'l21', 'l27', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "88, cell ['l4', 'l15', 'l22', 'l28', 'l32', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "89, suspensions ['l5', 'l16', 'l23', 'l29', 'l33', 'l40', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "96, osteosarcoma ['l6', 'l17', 'l24', 'l30', 'l34', 'l41', 'l47', 'l53', 'l54', 'l55', 'l56', 'l57']", + "97, xenograft, ['l7', 'l18', 'l25', 'l31', 'l35', 'l42', 'l48', 'l53', 'l58', 'l59', 'l60', 'l61']", + "100, prostate ['l8', 'l36', 'l43', 'l49', 'l54', 'l58', 'l62', 'l63', 'l64', 'l65', 'l66']", + "101, and ['l9', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l67', 'l68', 'l69', 'l70']", + "102, breast ['l10', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l67', 'l71']", + "103, cancers ['l11', 'l19', 'l26', 'l39', 'l46', 'l52', 'l57', 'l61', 'l64', 'l68', 'l71']", + "105, transgenic ['l65', 'l69', 'l72', 'l73', 'l74']", + "106, mice, ['l66', 'l70', 'l72', 'l75', 'l76']", + "111, tumor ['l73', 'l75', 'l77']", + "112, xenografts. ['l74', 'l76', 'l77']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12042811", + "TEXT": "The mechanism by which dopaminergic neurons are selectively lost in Parkinson disease (PD) is unknown. Here we show that accumulation of alpha-synuclein in cultured human dopaminergic neurons results in apoptosis that requires endogenous dopamine production and is mediated by reactive oxygen species. In contrast, alpha-synuclein is not toxic in non-dopaminergic human cortical neurons, but rather exhibits neuroprotective activity. Dopamine-dependent neurotoxicity is mediated by 54 83-kD soluble protein complexes that contain alpha-synuclein and 14-3-3 protein, which are elevated selectively in the substantia nigra in PD. Thus, accumulation of soluble alpha-synuclein protein complexes can render endogenous dopamine toxic, suggesting a potential mechanism for the selectivity of neuronal loss in PD.", + "TAG_DATA": [ + "23, cultured {'context': 'B-cells'}", + "24, human {'context': 'I-cells'}", + "25, dopaminergic {'context': 'I-cells'}", + "26, neurons {'context': 'I-cells'}", + "27, results {'effect': 'B-positive'}", + "28, in {'effect': 'I-positive'}", + "29, apoptosis {'phenotype': 'B-apoptosis'}", + "49, non-dopaminergic {'context': 'B-cells'}", + "50, human {'context': 'I-cells'}", + "51, cortical {'context': 'I-cells'}", + "52, neurons, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "23, cultured ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "24, human ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "25, dopaminergic ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "26, neurons ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "27, results ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "28, in ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "29, apoptosis ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "49, non-dopaminergic ['l28', 'l29', 'l30']", + "50, human ['l28', 'l31', 'l32']", + "51, cortical ['l29', 'l31', 'l33']", + "52, neurons, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cultured", + "human", + "dopaminergic", + "neurons", + "neurons," + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "human", + "dopaminergic", + "neurons", + "neurons," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "12042809", + "TEXT": "CD1d-restricted T cells are implicated as key players in host defense against various microbial infections. However, the mechanisms involved and the role they play, if any, at the mucosal surfaces where pathogenic infections are initiated is unknown. In a murine pneumonia model established by intranasal application of Pseudomonas aeruginosa, CD1d(-/-) mice showed markedly reduced pulmonary eradication of P. aeruginosa compared with wild-type mice; this was associated with significantly lower amounts of macrophage inflammatory protein-2 and reduced numbers of neutrophils within the bronchoalveolar lavage fluid. Corollarily, treatment of mice with alpha-galactosylceramide--a lipid that activates CD1d-restricted T cells--increased the amount of interferon-gamma; this was associated with rapid pulmonary clearance through enhanced phagocytosis of P. aeruginosa by alveolar macrophages. These results reveal a crucial role played by CD1d-restricted T cells in regulating the antimicrobial immune functions of macrophages at the lung mucosal surface.", + "TAG_DATA": [ + "39, murine {'context': 'B-organism'}", + "40, pneumonia {'context': 'I-organism'}", + "41, model {'context': 'I-organism'}", + "49, CD1d(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "50, mice {'context': 'B-organism'}", + "62, mice; {'context': 'B-organism'}", + "87, mice {'context': 'B-organism'}", + "93, CD1d-restricted {'context': 'B-cells'}", + "94, T {'context': 'I-cells'}", + "95, cells--increased {'context': 'I-cells'}", + "108, enhanced {'effect': 'B-positive'}", + "114, alveolar {'context': 'B-cells'}", + "115, macrophages. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "39, murine ['l0', 'l1', 'l2', 'l3']", + "40, pneumonia ['l0', 'l4', 'l5']", + "41, model ['l1', 'l4', 'l6', 'l7']", + "49, CD1d(-/-) ['l2', 'l5', 'l6', 'l8', 'l9']", + "50, mice ['l3', 'l7', 'l8', 'l10']", + "62, mice; ['l9', 'l10']", + "87, mice ['l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "93, CD1d-restricted ['l11', 'l17', 'l18', 'l19', 'l20', 'l21']", + "94, T ['l12', 'l17', 'l22', 'l23', 'l24', 'l25']", + "95, cells--increased ['l13', 'l18', 'l22', 'l26', 'l27', 'l28']", + "108, enhanced ['l14', 'l19', 'l23', 'l26', 'l29', 'l30']", + "114, alveolar ['l15', 'l20', 'l24', 'l27', 'l29', 'l31']", + "115, macrophages. ['l16', 'l21', 'l25', 'l28', 'l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "murine", + "pneumonia", + "model", + "mice", + "mice;" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD1d(-/-)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD1d-restricted", + "T", + "cells--increased", + "alveolar", + "macrophages." + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + } + ] + }, + { + "PMID": "12042808", + "TEXT": "Accumulating evidence suggests that innate immunity interacts with the adaptive immune system to identify potentially harmful antigens and eliminate them from the host. A central facet of innate immunity is complement, which for some time has been recognized as a contributor to inflammation in transplant rejection but without detailed analysis of its role in what is principally a T cell mediated process. Moreover, epithelial and vascular tissues at local sites of inflammation secrete complement components; however, the role of such local synthesis remains unclear. Here we show that the absence of locally synthesized complement component C3 is capable of modulating the rejection of renal allografts in vivo and regulating T-cell responses in vivo and in vitro. The results indicate that improved success in kidney transplantation could come from therapeutic manipulation of innate immunity in concert with T cell directed immunosuppression.", + "TAG_DATA": [ + "89, absence {'perturbing_action': 'B-gene loss-of-function'}", + "90, of {'perturbing_action': 'I-gene loss-of-function'}", + "95, C3 {'perturbing_action': 'I-gene loss-of-function'}", + "103, renal {'context': 'B-xenograft'}", + "104, allografts {'context': 'I-xenograft'}", + "105, in {'context': 'B-in vivo'}", + "106, vivo {'context': 'I-in vivo'}", + "109, T-cell {'context': 'B-cells'}", + "111, in {'context': 'B-in vivo'}", + "112, vivo {'context': 'I-in vivo'}", + "114, in {'context': 'B-in vitro'}", + "115, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "89, absence ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "90, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "95, C3 ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "103, renal ['l2', 'l12', 'l21', 'l30', 'l31', 'l32']", + "104, allografts ['l3', 'l13', 'l22', 'l30', 'l33', 'l34']", + "105, in ['l4', 'l14', 'l23', 'l31', 'l33', 'l35']", + "106, vivo ['l5', 'l15', 'l24', 'l32', 'l34', 'l35']", + "109, T-cell ['l6', 'l16', 'l25', 'l36', 'l37', 'l38', 'l39']", + "111, in ['l7', 'l17', 'l26', 'l36', 'l40', 'l41', 'l42']", + "112, vivo ['l8', 'l18', 'l27', 'l37', 'l40', 'l43']", + "114, in ['l9', 'l19', 'l28', 'l38', 'l41', 'l44']", + "115, vitro. ['l10', 'l20', 'l29', 'l39', 'l42', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "C3" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "renal", + "allografts" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "C3" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "C3" + ] + }, + "context": { + "val": "cells", + "words": [ + "T-cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "C3" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "12042776", + "TEXT": "Interactions of nitric oxide (NO) with hemoglobin (Hb) could regulate the uptake and delivery of oxygen (O(2)) by subserving the classical physiological responses of hypoxic vasodilation and hyperoxic vasconstriction in the human respiratory cycle. Here we show that in in vitro and ex vivo systems as well as healthy adults alternately exposed to hypoxia or hyperoxia (to dilate or constrict pulmonary and systemic arteries in vivo), binding of NO to hemes (FeNO) and thiols (SNO) of Hb varies as a function of HbO(2) saturation (FeO(2)). Moreover, we show that red blood cell (RBC)/SNO-mediated vasodilator activity is inversely proportional to FeO(2) over a wide range, whereas RBC-induced vasoconstriction correlates directly with FeO(2). Thus, native RBCs respond to changes in oxygen tension (pO2) with graded vasodilator and vasoconstrictor activity, which emulates the human physiological response subserving O(2) uptake and delivery. The ability to monitor and manipulate blood levels of NO, in conjunction with O(2) and carbon dioxide, may therefore prove useful in the diagnosis and treatment of many human conditions and in the development of new therapies. Our results also help elucidate the link between RBC dyscrasias and cardiovascular morbidity.", + "TAG_DATA": [ + "39, in {'context': 'B-in vitro'}", + "40, vitro {'context': 'I-in vitro'}", + "48, healthy {'context': 'B-cells'}", + "49, adults {'context': 'I-organism'}", + "60, pulmonary {'context': 'B-tissue/organ'}", + "61, and {'context': 'I-tissue/organ'}", + "62, systemic {'context': 'I-tissue/organ'}", + "64, in {'context': 'B-in vivo'}", + "65, vivo), {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "39, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "40, vitro ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "48, healthy ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "49, adults ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "60, pulmonary ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "61, and ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "62, systemic ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "63, arteries ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "64, in ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "65, vivo), ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11984595", + "TEXT": "Microarray analysis of multiple sclerosis (MS) lesions obtained at autopsy revealed increased transcripts of genes encoding inflammatory cytokines, particularly interleukin-6 and -17, interferon-gamma and associated downstream pathways. Comparison of two poles of MS pathology--acute lesions with inflammation versus 'silent' lesions without inflammation--revealed differentially transcribed genes. Some products of these genes were chosen as targets for therapy of experimental autoimmune encephalomyelitis (EAE) in mice. Granulocyte colony-stimulating factor is upregulated in acute, but not in chronic, MS lesions, and the effect on ameliorating EAE is more pronounced in the acute phase, in contrast to knocking out the immunoglobulin Fc receptor common gamma chain where the effect is greatest on chronic disease. These results in EAE corroborate the microarray studies on MS lesions. Large-scale analysis of transcripts in MS lesions elucidates new aspects of pathology and opens possibilities for therapy.", + "TAG_DATA": [ + "62, mice. {'context': 'B-organism'}", + "92, knocking {'perturbing_action': 'B-gene loss-of-function'}", + "93, out {'perturbing_action': 'I-gene loss-of-function'}", + "94, the {'perturbing_action': 'I-gene loss-of-function'}", + "95, immunoglobulin {'perturbing_action': 'I-gene loss-of-function'}", + "96, Fc {'perturbing_action': 'I-gene loss-of-function'}", + "97, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "98, common {'perturbing_action': 'I-gene loss-of-function'}", + "99, gamma {'perturbing_action': 'I-gene loss-of-function'}", + "100, chain {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "92, knocking ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "93, out ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "94, the ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "95, immunoglobulin ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "96, Fc ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "97, receptor ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "98, common ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "99, gamma ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "100, chain ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11984594", + "TEXT": "Cytotoxic T-lymphocyte (CTL) responses peak coincident with the decline in acute HIV viremia. Despite two reports of CTL-resistant HIV variants emerging during acute infection, the contribution of acute CTL escape to HIV pathogenesis remains unclear. Difficulties inherent in studying acute HIV infection can be overcome by modeling virus-host interactions in SIV-infected rhesus macaques. We sequenced 21 complete simian immunodeficiency virus (SIV)mac239 genomes at four weeks post-infection to determine the extent of acute CTL escape. Here we show that viruses from 19 of 21 macaques escaped from CTLs during acute infection and that these escape-selecting CTLs were responsive to lower concentrations of peptide than other SIV-specific CTLs. Interestingly, CTLs that require low peptide concentrations for stimulation (high 'functional avidity') are particularly effective at controlling other viral infections. Our results suggest that acute viral escape from CTLs is a hallmark of SIV infection and that CTLs with high functional avidity can rapidly select for escape variants.", + "TAG_DATA": [ + "51, rhesus {'context': 'B-organism'}", + "52, macaques. {'context': 'I-organism'}", + "83, macaques {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "51, rhesus ['l0', 'l1']", + "52, macaques. ['l0', 'l2']", + "83, macaques ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11984593", + "TEXT": "The most common mutation in cystic fibrosis, Delta F508, results in a cystic fibrosis transmembrane conductance regulator (CFTR) protein that is retained in the endoplasmic reticulum (ER). Retention is dependent upon chaperone proteins, many of which require Ca(++) for optimal activity. Interfering with chaperone activity by depleting ER Ca(++) stores might allow functional Delta F508-CFTR to reach the cell surface. We exposed several cystic fibrosis cell lines to the ER Ca(++) pump inhibitor thapsigargin and evaluated surface expression of Delta F508-CFTR. Treatment released ER-retained Delta F508-CFTR to the plasma membrane, where it functioned effectively as a Cl(-) channel. Treatment with aerosolized calcium-pump inhibitors reversed the nasal epithelial potential defect observed in a mouse model of Delta F508-CFTR expression. Thus, ER calcium-pump inhibitors represent a potential target for correcting the cystic fibrosis defect.", + "TAG_DATA": [ + "63, cystic {'context': 'B-transformed cells'}", + "64, fibrosis {'context': 'I-transformed cells'}", + "65, cell {'context': 'I-transformed cells'}", + "66, lines {'context': 'I-transformed cells'}", + "112, mouse {'context': 'B-organism'}", + "113, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "63, cystic ['l0', 'l1', 'l2']", + "64, fibrosis ['l0', 'l3', 'l4']", + "65, cell ['l1', 'l3', 'l5']", + "66, lines ['l2', 'l4', 'l5']", + "112, mouse ['l6']", + "113, model ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11984591", + "TEXT": "Corticosteroids have been shown to exert beneficial effects in the treatment of acute myocardial infarction, but the precise mechanisms underlying their protective effects are unknown. Here we show that high-dose corticosteroids exert cardiovascular protection through a novel mechanism involving the rapid, non-transcriptional activation of endothelial nitric oxide synthase (eNOS). Binding of corticosteroids to the glucocorticoid receptor (GR) stimulated phosphatidylinositol 3-kinase and protein kinase Akt, leading to eNOS activation and nitric oxide dependent vasorelaxation. Acute administration of pharmacological concentrations of corticosteroids in mice led to decreased vascular inflammation and reduced myocardial infarct size following ischemia and reperfusion injury. These beneficial effects of corticosteroids were abolished by GR antagonists or eNOS inhibitors in wild-type mice and were completely absent in eNOS-deficient (Nos3(-/-)) mice. The rapid activation of eNOS by the non-nuclear actions of GR, therefore, represents an important cardiovascular protective effect of acute high-dose corticosteroid therapy.", + "TAG_DATA": [ + "81, mice {'context': 'B-organism'}", + "105, GR {'perturbing_action': 'B-pharmacological inhibition'}", + "106, antagonists {'perturbing_action': 'I-pharmacological inhibition'}", + "108, eNOS {'perturbing_action': 'B-pharmacological inhibition'}", + "109, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "112, mice {'context': 'B-organism'}", + "118, eNOS-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "119, (Nos3(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "120, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "105, GR ['l0', 'l1', 'l2', 'l3']", + "106, antagonists ['l0', 'l4', 'l5', 'l6']", + "108, eNOS ['l1', 'l4', 'l7', 'l8', 'l9', 'l10', 'l11']", + "109, inhibitors ['l2', 'l5', 'l7', 'l12', 'l13', 'l14']", + "112, mice ['l3', 'l6', 'l8', 'l12']", + "118, eNOS-deficient ['l9', 'l15', 'l16']", + "119, (Nos3(-/-)) ['l10', 'l13', 'l15', 'l17']", + "120, mice. ['l11', 'l14', 'l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "GR", + "antagonists", + "eNOS", + "inhibitors" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "eNOS-deficient", + "(Nos3(-/-))" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "11927950", + "TEXT": "Skin is an attractive target for delivery of genetic therapies and vaccines. However, new approaches are needed to access this tissue more effectively. Here, we describe a new delivery technology based on arrays of structurally precise, micron-scale silicon projections, which we term microenhancer arrays (MEAs). In a human clinical study, these devices effectively breached the skin barrier, allowing direct access to the epidermis with minimal associated discomfort and skin irritation. In a mouse model, MEA-based delivery enabled topical gene transfer resulting in reporter gene activity up to 2,800-fold above topical controls. MEA-based delivery enabled topical immunization with naked plasmid DNA, inducing stronger and less variable immune responses than via needle-based injections, and reduced the number of immunizations required for full seroconversion. Together, the results provide the first in vivo use of microfabricated devices to breach the skin barrier and deliver vaccines topically, suggesting significant clinical and practical advantages over existing technologies.", + "TAG_DATA": [ + "72, mouse {'context': 'B-organism'}", + "73, model, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "72, mouse ['l0']", + "73, model, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11927946", + "TEXT": "The vast majority of the world population is infected with at least one member of the human herpesvirus family. Herpes simplex virus (HSV) infections are the cause of cold sores and genital herpes as well as life-threatening or sight-impairing disease mainly in immunocompromized patients, pregnant women and newborns. Since the milestone development in the late 1970s of acyclovir (Zovirax), a nucleosidic inhibitor of the herpes DNA polymerase, no new non-nucleosidic anti-herpes drugs have been introduced. Here we report new inhibitors of the HSV helicase-primase with potent in vitro anti-herpes activity, a novel mechanism of action, a low resistance rate and superior efficacy against HSV in animal models. BAY 57-1293 (N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide), a well-tolerated member of this class of compounds, significantly reduces time to healing, prevents rebound of disease after cessation of treatment and, most importantly, reduces frequency and severity of recurrent disease. Thus, this class of drugs has significant potential for the treatment of HSV disease in humans, including those resistant to current medications.", + "TAG_DATA": [ + "106, models. {'context': 'I-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11927941", + "TEXT": "CD39, the endothelial ecto-nucleoside triphosphate diphosphohydrolase (NTPDase), regulates vascular inflammation and thrombosis by hydrolyzing ATP and ADP. Although ecto-NTPDase activities have been used as a marker of epidermal dendritic cells (DCs) known as Langerhans cells, the identity and function of these activities remain unknown. Here we report that Langerhans cells in CD39-/- mice express no detectable ecto-NTPDase activity. Irritant chemicals triggered rapid ATP and ADP release from keratinocytes and caused exacerbated skin inflammation in CD39-/- mice. Paradoxically, T cell-mediated allergic contact hypersensitivity was severely attenuated in CD39-/- mice. As to mechanisms, T cells increased pericellular ATP concentrations upon activation, and CD39-/- DCs showed ATP unresponsiveness (secondary to P2-receptor desensitization) and impaired antigen-presenting capacity. Our results show opposing outcomes of CD39 deficiency in irritant versus allergic contact dermatitis, reflecting its diverse roles in regulating extracellular nucleotide-mediated signaling in inflammatory responses to environmental insults and DC-T cell communication in antigen presentation.", + "TAG_DATA": [ + "48, Langerhans {'context': 'B-cells'}", + "49, cells {'context': 'I-cells'}", + "51, CD39-/- {'perturbing_action': 'B-gene loss-of-function'}", + "52, mice {'context': 'B-organism'}", + "67, keratinocytes {'context': 'B-cells'}", + "71, skin {'context': 'B-tissue/organ'}", + "74, CD39-/- {'perturbing_action': 'B-gene loss-of-function'}", + "75, mice. {'context': 'B-organism'}", + "86, CD39-/- {'perturbing_action': 'B-gene loss-of-function'}", + "87, mice. {'context': 'B-organism'}", + "91, T {'context': 'B-cells'}", + "92, cells {'context': 'B-cells'}", + "100, CD39-/- {'perturbing_action': 'B-gene loss-of-function'}", + "101, DCs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "48, Langerhans ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "49, cells ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "51, CD39-/- ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "52, mice ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "67, keratinocytes ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "71, skin ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "74, CD39-/- ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "75, mice. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "86, CD39-/- ['l28', 'l29', 'l30']", + "87, mice. ['l28', 'l31', 'l32']", + "91, T ['l29', 'l31', 'l33']", + "92, cells ['l30', 'l32', 'l33']", + "100, CD39-/- ['l34']", + "101, DCs ['l34']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Langerhans", + "cells", + "keratinocytes", + "T", + "DCs" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD39-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD39-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD39-/-" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skin" + ] + } + } + ] + }, + { + "PMID": "11875502", + "TEXT": "We constructed miniaturized autoantigen arrays to perform large-scale multiplex characterization of autoantibody responses directed against structurally diverse autoantigens, using submicroliter quantities of clinical samples. Autoantigen microarrays were produced by attaching hundreds of proteins, peptides and other biomolecules to the surface of derivatized glass slides using a robotic arrayer. Arrays were incubated with patient serum, and spectrally resolvable fluorescent labels were used to detect autoantibody binding to specific autoantigens on the array. We describe and characterize arrays containing the major autoantigens in eight distinct human autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis. This represents the first report of application of such technology to multiple human disease sera, and will enable validated detection of antibodies recognizing autoantigens including proteins, peptides, enzyme complexes, ribonucleoprotein complexes, DNA and post-translationally modified antigens. Autoantigen microarrays represent a powerful tool to study the specificity and pathogenesis of autoantibody responses, and to identify and define relevant autoantigens in human autoimmune diseases.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11875500", + "TEXT": "The tumor suppressor p53 inhibits tumor growth primarily through its ability to induce apoptosis. Mutations in p53 occur in at least 50% of human tumors. We hypothesized that reactivation of mutant p53 in such tumors should trigger massive apoptosis and eliminate the tumor cells. To test this, we screened a library of low-molecular-weight compounds in order to identify compounds that can restore wild-type function to mutant p53. We found one compound capable of inducing apoptosis in human tumor cells through restoration of the transcriptional transactivation function to mutant p53. This molecule, named PRIMA-1, restored sequence-specific DNA binding and the active conformation to mutant p53 proteins in vitro and in living cells. PRIMA-1 rescued both DNA contact and structural p53 mutants. In vivo studies in mice revealed an antitumor effect with no apparent toxicity. This molecule may serve as a lead compound for the development of anticancer drugs targeting mutant p53.", + "TAG_DATA": [ + "73, inducing {'effect': 'B-positive'}", + "74, apoptosis {'phenotype': 'B-apoptosis'}", + "76, human {'context': 'B-transformed cells'}", + "77, tumor {'context': 'I-transformed cells'}", + "78, cells {'context': 'I-transformed cells'}", + "105, in {'context': 'B-in vitro'}", + "106, vitro {'context': 'I-in vitro'}", + "109, living {'context': 'B-cells'}", + "110, cells. {'context': 'I-cells'}", + "120, In {'context': 'B-in vivo'}", + "121, vivo {'context': 'I-in vivo'}", + "124, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, inducing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "74, apoptosis ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "76, human ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "77, tumor ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "78, cells ['l3', 'l9', 'l14', 'l18']", + "105, in ['l4', 'l10', 'l15', 'l19', 'l22', 'l23', 'l24']", + "106, vitro ['l5', 'l11', 'l16', 'l20', 'l22', 'l25', 'l26']", + "109, living ['l23', 'l25', 'l27']", + "110, cells. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "120, In ['l28', 'l29']", + "121, vivo ['l28', 'l30']", + "124, mice ['l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "tumor", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "tumor", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "11875499", + "TEXT": "The importance of Bax for induction of tumor apoptosis through death receptors remains unclear. Here we show that Bax can be essential for death receptor--mediated apoptosis in cancer cells. Bax-deficient human colon carcinoma cells were resistant to death-receptor ligands, whereas Bax-expressing sister clones were sensitive. Bax was dispensable for apical death-receptor signaling events including caspase-8 activation, but crucial for mitochondrial changes and downstream caspase activation. Treatment of colon tumor cells deficient in DNA mismatch repair with the death-receptor ligand apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selected in vitro or in vivo for refractory subclones with Bax frameshift mutations including deletions at a novel site. Chemotherapeutic agents upregulated expression of the Apo2L/TRAIL receptor DR5 and the Bax homolog Bak in Baxminus sign/minus sign cells, and restored Apo2L/TRAIL sensitivity in vitro and in vivo. Thus, Bax mutation in mismatch repair--deficient tumors can cause resistance to death receptor--targeted therapy, but pre-exposure to chemotherapy rescues tumor sensitivity.", + "TAG_DATA": [ + "29, Bax-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "30, human {'context': 'B-transformed cells'}", + "31, colon {'context': 'I-transformed cells'}", + "32, carcinoma {'context': 'I-transformed cells'}", + "33, cells {'context': 'I-transformed cells'}", + "40, Bax-expressing {'context': 'B-cells'}", + "41, sister {'context': 'I-cells'}", + "42, clones {'context': 'I-cells'}", + "67, colon {'context': 'B-transformed cells'}", + "68, tumor {'context': 'I-transformed cells'}", + "69, cells {'context': 'I-transformed cells'}", + "88, in {'context': 'B-in vitro'}", + "89, vitro {'context': 'I-in vitro'}", + "91, in {'context': 'B-in vivo'}", + "92, vivo {'context': 'I-in vivo'}", + "124, cells, {'context': 'B-cells'}", + "129, in {'context': 'B-in vitro'}", + "130, vitro {'context': 'I-in vitro'}", + "132, in {'context': 'B-in vivo'}", + "133, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "29, Bax-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "30, human ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "31, colon ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "32, carcinoma ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "33, cells ['l3', 'l9', 'l14', 'l18', 'l22']", + "40, Bax-expressing ['l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "41, sister ['l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "42, clones ['l24', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "67, colon ['l4', 'l10', 'l15', 'l19', 'l25', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "68, tumor ['l5', 'l11', 'l16', 'l20', 'l26', 'l32', 'l37', 'l41', 'l45', 'l46', 'l47']", + "69, cells ['l6', 'l12', 'l17', 'l21', 'l22', 'l27', 'l33', 'l38', 'l42', 'l45', 'l48', 'l49']", + "88, in ['l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l50']", + "89, vitro ['l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l50']", + "91, in ['l51']", + "92, vivo ['l51']", + "124, cells, ['l52', 'l53', 'l54', 'l55']", + "129, in ['l52', 'l56', 'l57', 'l58']", + "130, vitro ['l53', 'l56', 'l59', 'l60']", + "132, in ['l54', 'l57', 'l59', 'l61']", + "133, vivo. ['l55', 'l58', 'l60', 'l61']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bax-deficient" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "colon", + "carcinoma", + "cells", + "tumor" + ] + } + } + ] + }, + { + "PMID": "11875498", + "TEXT": "The concept of stem-cell plasticity received strong support from a recent observation that extensively passaged, clonally derived neural stem cells could contribute to hematopoiesis. We investigated whether hematopoietic potential was a consistent or unusual feature of neural stem cells, and whether it depended on the extent of in vitro passaging before transplantation. Here we transplanted over 128 x 10(6) neurosphere cells into 128 host animals; however, we never observed contribution to hematopoiesis, irrespective of the number of passages and despite the use of an assay that could detect the contribution of a single blood stem cell to hematopoietic repopulation. Although extensively cultured neurosphere cells continued to generate neural progeny, marked changes in their growth properties occurred, including changes in growth-factor dependence, cell-cycle kinetics, cell adhesion and gene expression. Our results exclude hematopoietic competence as a consistent property of intravenously infused neural stem cells. However, the consistent changes that occurred during extended passaging are compatible with genetic or epigenetic alterations and suggest that rare transformation events may account for the neural-to-blood fate switch originally reported.", + "TAG_DATA": [ + "59, neurosphere {'context': 'B-cells'}", + "60, cells {'context': 'I-cells'}", + "64, animals; {'context': 'B-organism'}", + "102, neurosphere {'context': 'B-cells'}", + "103, cells {'context': 'I-cells'}", + "123, cell {'context': 'B-cells'}", + "124, adhesion {'phenotype': 'B-adhesion'}" + ], + "LINK_DATA": [ + "59, neurosphere ['l0', 'l1']", + "60, cells ['l0', 'l2']", + "64, animals; ['l1', 'l2']", + "102, neurosphere ['l3', 'l4', 'l5']", + "103, cells ['l3']", + "123, cell ['l4', 'l6']", + "124, adhesion ['l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "neurosphere", + "cell" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + } + ] + }, + { + "PMID": "11875492", + "TEXT": "Treatment with HIV-1 protease inhibitors (PI) is associated with a reduced incidence or regression of Kaposi sarcoma (KS). Here we show that systemic administration of the PIs indinavir or saquinavir to nude mice blocks the development and induces regression of angioproliferative KS-like lesions promoted by primary human KS cells, basic fibroblast growth factor (bFGF), or bFGF and vascular endothelial growth factor (VEGF) combined. These PIs also block bFGF or VEGF-induced angiogenesis in the chorioallantoic membrane assay with a potency similar to paclitaxel (Taxol). These effects are mediated by the inhibition of endothelial- and KS-cell invasion and of matrix metalloproteinase-2 proteolytic activation by PIs at concentrations present in plasma of treated individuals. As PIs also inhibit the in vivo growth and invasion of an angiogenic tumor-cell line, these data indicate that PIs are potent anti-angiogenic and anti-tumor molecules that might be used in treating non-HIV KS and in other HIV-associated tumors.", + "TAG_DATA": [ + "31, nude {'context': 'B-organism'}", + "32, mice {'context': 'I-organism'}", + "37, induces {'effect': 'B-positive'}", + "38, regression {'phenotype': 'B-tumour regression'}", + "45, primary {'context': 'B-transformed cells'}", + "46, human {'context': 'I-transformed cells'}", + "47, KS {'context': 'I-transformed cells'}", + "48, cells, {'context': 'I-transformed cells'}", + "89, inhibition {'effect': 'B-negative'}", + "91, endothelial- {'context': 'B-cells'}", + "92, and {'context': 'I-cells'}", + "93, KS-cell {'context': 'I-cells'}", + "94, invasion {'phenotype': 'B-invasion'}", + "114, inhibit {'effect': 'B-negative'}", + "116, in {'context': 'B-in vivo'}", + "117, vivo {'context': 'I-in vivo'}", + "120, invasion {'phenotype': 'B-invasion'}", + "123, angiogenic {'context': 'B-transformed cells'}", + "124, tumor-cell {'context': 'I-transformed cells'}", + "125, line, {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "31, nude ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "32, mice ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "37, induces ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "38, regression ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "45, primary ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "46, human ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "47, KS ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "48, cells, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "89, inhibition ['l28', 'l29', 'l30', 'l31']", + "91, endothelial- ['l28', 'l32', 'l33', 'l34']", + "92, and ['l29', 'l32', 'l35', 'l36']", + "93, KS-cell ['l30', 'l33', 'l35', 'l37']", + "94, invasion ['l31', 'l34', 'l36', 'l37']", + "114, inhibit ['l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "116, in ['l38', 'l44', 'l45', 'l46', 'l47', 'l48']", + "117, vivo ['l39', 'l44', 'l49', 'l50', 'l51', 'l52']", + "120, invasion ['l40', 'l45', 'l49', 'l53', 'l54', 'l55']", + "123, angiogenic ['l41', 'l46', 'l50', 'l53', 'l56', 'l57']", + "124, tumor-cell ['l42', 'l47', 'l51', 'l54', 'l56', 'l58']", + "125, line, ['l43', 'l48', 'l52', 'l55', 'l57', 'l58']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "nude", + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "nude", + "mice" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "human", + "KS", + "cells," + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "human", + "KS", + "cells," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial-", + "and", + "KS-cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition", + "inhibit" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial-", + "and", + "KS-cell" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "angiogenic", + "tumor-cell", + "line," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "angiogenic", + "tumor-cell", + "line," + ] + } + } + ] + }, + { + "PMID": "11821901", + "TEXT": "CD4+ T cells are crucial to the development of CD8+ T cell responses against hepatocytes infected with malaria parasites. In the absence of CD4+ T cells, CD8+ T cells initiate a seemingly normal differentiation and proliferation during the first few days after immunization. However, this response fails to develop further and is reduced by more than 90%, compared to that observed in the presence of CD4+ T cells. We report here that interleukin-4 (IL-4) secreted by CD4+ T cells is essential to the full development of this CD8+ T cell response. This is the first demonstration that IL-4 is a mediator of CD4/CD8 cross-talk leading to the development of immunity against an infectious pathogen.", + "TAG_DATA": [ + "26, CD8+ {'context': 'B-cells'}", + "27, T {'context': 'I-cells'}", + "28, cells {'context': 'I-cells'}", + "29, initiate {'effect': 'B-positive'}", + "33, differentiation {'phenotype': 'B-differentiation'}", + "35, proliferation {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "26, CD8+ ['l0', 'l1', 'l2', 'l3', 'l4']", + "27, T ['l0', 'l5', 'l6', 'l7', 'l8']", + "28, cells ['l1', 'l5', 'l9', 'l10', 'l11']", + "29, initiate ['l2', 'l6', 'l9', 'l12', 'l13']", + "33, differentiation ['l3', 'l7', 'l10', 'l12', 'l14']", + "35, proliferation ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD8+", + "T", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD8+", + "T", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD8+", + "T", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "11786911", + "TEXT": "Cisplatin is one of the most widely used agents in the treatment of solid tumors, but its clinical utility is limited by toxicity. The development of less toxic, liposomal formulations of cisplatin has been hampered by the low water solubility and low lipophilicity of cisplatin, resulting in very low encapsulation efficiencies. We describe a novel method allowing the efficient encapsulation of cisplatin in a lipid formulation; it is based on repeated freezing and thawing of a concentrated solution of cisplatin in the presence of negatively charged phospholipids. The method is unique in that it generates nanocapsules, which are small aggregates of cisplatin covered by a single lipid bilayer. The nanocapsules have an unprecedented drug-to-lipid ratio and an in vitro cytotoxicity up to 1000-fold higher than the free drug. Analysis of the mechanism of nanocapsule formation suggests that the method may be generalized to other drugs showing low water solubility and lipophilicity.", + "TAG_DATA": [ + "117, in {'context': 'B-in vitro'}", + "118, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "117, in ['l0', 'l1']", + "118, vitro ['l0', 'l2']", + "119, cytotoxicity ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11689889", + "TEXT": "Myocardial hypertrophy is an adaptational response of the heart to increased work load, but it is also associated with a high risk of cardiac mortality due to its established role in the development of cardiac failure, one of the leading causes of death in developed countries. Multiple growth factors and various downstream signaling pathways involving, for example, ras, gp-130 (ref. 4), JNK/p38 (refs. 5,6) and calcineurin/NFAT/CaM-kinase have been implicated in the hypertrophic response. However, there is evidence that the initial phase in the development of myocardial hypertrophy involves the formation of cardiac para- and/or autocrine factors like endothelin-1, norepinephrine or angiotensin II (refs. 7,8), the receptors of which are coupled to G-proteins of the Gq/11-, G12/13- and Gi/o-families. Cardiomyocyte-specific transgenic overexpression of alpha1-adrenergic or angiotensin (AT1)-receptors as well as of the Gq alpha-subunit, Galphaq, results in myocardial hypertrophy. These data demonstrate that chronic activation of the Gq/G11-family is sufficient to induce myocardial hypertrophy. In order to test whether Gq/G11 mediate the physiological hypertrophy response to pressure overload, we generated a mouse line lacking both Galphaq and Galpha11 in cardiomyocytes. These mice showed no detectable ventricular hypertrophy in response to pressure-overload induced by aortic constriction. The complete lack of a hypertrophic response proves that the Gq/G11-mediated pathway is essential for cardiac hypertrophy induced by pressure overload and makes this signaling process an interesting target for interventions to prevent myocardial hypertrophy.", + "TAG_DATA": [ + "118, Cardiomyocyte-specific {'perturbing_action': 'B-gene gain-of-function'}", + "119, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "120, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "121, of {'perturbing_action': 'I-gene gain-of-function'}", + "122, alpha1-adrenergic {'perturbing_action': 'I-gene gain-of-function'}", + "123, or {'perturbing_action': 'I-gene gain-of-function'}", + "124, angiotensin {'perturbing_action': 'I-gene gain-of-function'}", + "170, mouse {'context': 'B-organism'}", + "171, line {'context': 'I-organism'}", + "172, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "173, both {'perturbing_action': 'I-gene loss-of-function'}", + "174, Galphaq {'perturbing_action': 'I-gene loss-of-function'}", + "175, and {'perturbing_action': 'I-gene loss-of-function'}", + "176, Galpha11 {'perturbing_action': 'I-gene loss-of-function'}", + "178, cardiomyocytes. {'context': 'B-cells'}", + "180, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "118, Cardiomyocyte-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "119, transgenic ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "120, overexpression ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "121, of ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "122, alpha1-adrenergic ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "123, or ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "124, angiotensin ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "170, mouse ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "171, line ['l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "172, lacking ['l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "173, both ['l23', 'l29', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "174, Galphaq ['l24', 'l30', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "175, and ['l25', 'l31', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "176, Galpha11 ['l26', 'l32', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "178, cardiomyocytes. ['l27', 'l33', 'l38', 'l43', 'l47', 'l50', 'l52']", + "180, mice ['l39', 'l44', 'l48', 'l51', 'l53']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "line", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "both", + "Galphaq", + "and", + "Galpha11" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "both", + "Galphaq", + "and", + "Galpha11" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes." + ] + } + } + ] + }, + { + "PMID": "11689886", + "TEXT": "A highly conserved signaling property of Nef proteins encoded by human or simian immunodeficiency virus is the binding and activation of a PAK kinase whose function is unclear. Here we show that Nef-mediated p21-activated kinase (PAK) activation involves phosphatidylinositol 3-kinase, which acts upstream of PAK and is bound and activated by Nef similar to the manner of Polyoma virus middle T antigen. The Nef-associated phosphatidylinositol-3-PAK complex phosphorylated the pro-apoptotic Bad protein without involving the protein kinase B-Akt kinase, which is generally believed to inactivate Bad by serine phosphorylation. Consequently, Nef, but not a Nef mutant incapable of activating PAK, blocked apoptosis in T cells induced by serum starvation or HIV replication. Nef anti-apoptotic effects are likely a crucial mechanism for viral replication in the host and thus in AIDS pathogenesis.", + "TAG_DATA": [ + "99, blocked {'effect': 'B-negative'}", + "100, apoptosis {'phenotype': 'B-apoptosis'}", + "102, T {'context': 'B-cells'}", + "103, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "99, blocked ['l0', 'l1', 'l2']", + "100, apoptosis ['l0', 'l3', 'l4']", + "102, T ['l1', 'l3', 'l5']", + "103, cells ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + } + ] + }, + { + "PMID": "11689885", + "TEXT": "Cyclic ADP-ribose is believed to be an important calcium-mobilizing second messenger in invertebrate, mammalian and plant cells. CD38, the best-characterized mammalian ADP-ribosyl cyclase, is postulated to be an important source of cyclic ADP-ribose in vivo. Using CD38-deficient mice, we demonstrate that the loss of CD38 renders mice susceptible to bacterial infections due to an inability of CD38-deficient neutrophils to directionally migrate to the site of infection. Furthermore, we show that cyclic ADP-ribose can directly induce intracellular Ca++ release in neutrophils and is required for sustained extracellular Ca++ influx in neutrophils that have been stimulated by the bacterial chemoattractant, formyl-methionyl-leucyl-phenylalanine (fMLP). Finally, we demonstrate that neutrophil chemotaxis to fMLP is dependent on Ca++ mobilization mediated by cyclic ADP-ribose. Thus, CD38 controls neutrophil chemotaxis to bacterial chemoattractants through its production of cyclic ADP-ribose, and acts as a critical regulator of inflammation and innate immune responses.", + "TAG_DATA": [ + "36, CD38-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "37, mice, {'context': 'B-organism'}", + "42, loss {'perturbing_action': 'B-gene loss-of-function'}", + "43, of {'perturbing_action': 'I-gene loss-of-function'}", + "44, CD38 {'perturbing_action': 'I-gene loss-of-function'}", + "46, mice {'context': 'B-organism'}", + "56, CD38-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "57, neutrophils {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "36, CD38-deficient ['l0', 'l1', 'l2']", + "37, mice, ['l0', 'l3']", + "42, loss ['l4', 'l5', 'l6', 'l7', 'l8']", + "43, of ['l4', 'l9', 'l10', 'l11', 'l12']", + "44, CD38 ['l1', 'l5', 'l9', 'l13', 'l14']", + "46, mice ['l2', 'l3', 'l6', 'l10', 'l13', 'l15']", + "56, CD38-deficient ['l7', 'l11', 'l16']", + "57, neutrophils ['l8', 'l12', 'l14', 'l15', 'l16']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD38-deficient", + "loss", + "of", + "CD38" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "CD38", + "CD38-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "neutrophils" + ] + } + } + ] + }, + { + "PMID": "11590442", + "TEXT": "Successful adoptive T-cell therapy has been demonstrated in viral disease and selected forms of cancer. However, it is limited by the difficulty to efficiently isolate and amplify autologous tumor-reactive T-cell clones. Tetramers of major histocompatibility complex (MHC) class I and peptide have facilitated the characterization of CD8+ T cells specific for tumor-associated antigens. However, for adoptive T-cell therapy, MHC-tetramers have limitations: they require knowledge of tumor antigens, which is often not available; they select T cells with a single specificity, thereby posing risk for selection of tumor escape variants; they do not select for function, so that T cells may be anergic when isolated from cancer patients; and they do not allow the isolation of CD4+ T cells that can be essential for tumor rejection. Because interferon (IFN)-gamma is essential for tumor rejection, we isolated live T cells based on their IFN-gamma production. IFN-gamma secreted by previously activated T cells is retained on the cell surface, allowing their specific isolation and expansion. We show here that IFN-gamma+ but not IFN-gamma- T cells from tumor-immunized mice are cytolytic and mediate tumor rejection upon adoptive transfer. Importantly, tumor-specific T cells can be enriched from lymphocytes infiltrating human renal cell carcinoma by the IFN-gamma capture assay.", + "TAG_DATA": [ + "136, T {'context': 'B-cells'}", + "137, cells {'context': 'I-cells'}", + "148, T {'context': 'B-cells'}", + "149, cells {'context': 'B-cells'}", + "171, cells {'context': 'B-cells'}", + "174, mice {'context': 'B-organism'}", + "185, tumor-specific {'context': 'B-cells'}", + "186, T {'context': 'I-cells'}", + "187, cells {'context': 'I-cells'}", + "194, human {'context': 'B-neoplasm'}", + "195, renal {'context': 'I-neoplasm'}", + "196, cell {'context': 'I-neoplasm'}", + "197, carcinoma {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "136, T ['l0', 'l1', 'l2']", + "137, cells ['l0', 'l3', 'l4']", + "148, T ['l1', 'l3', 'l5', 'l6', 'l7']", + "149, cells ['l2', 'l4', 'l5', 'l8', 'l9']", + "171, cells ['l6', 'l8', 'l10', 'l11', 'l12', 'l13', 'l14']", + "174, mice ['l7', 'l9', 'l10', 'l15', 'l16', 'l17', 'l18']", + "185, tumor-specific ['l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "186, T ['l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "187, cells ['l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "194, human ['l11', 'l15', 'l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "195, renal ['l12', 'l16', 'l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "196, cell ['l13', 'l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "197, carcinoma ['l14', 'l18', 'l24', 'l29', 'l33', 'l36', 'l38', 'l39']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11590441", + "TEXT": "Ligation of the antigen receptor and costimulatory receptors on the surface of T lymphocytes initiates intracellular signals that regulate cell-cycle progression and cell differentiation. To effectively manipulate the activation of T cells for immunotherapeutic applications, it will be important to understand how these signaling pathways are integrated to control specific gene transcription events. Here we describe a novel transient transfection procedure that efficiently introduces DNA into non-dividing normal human and murine T lymphocytes while maintaining high cell viability. Using this technique, reporter genes can be introduced to characterize intracellular signaling pathways that regulate specific gene transcription events in normal T-lymphocyte populations. We show that the CD28 receptor can be differentially coupled to downstream signaling pathways in different T-lymphocyte populations. In addition, we demonstrate that a gene encoding a tagged constitutively active mitogen-activated kinase kinase-1 protein can be transfected and rapidly expressed to regulate the expression of Bcl-2 in normal thymocytes.", + "TAG_DATA": [ + "67, normal {'context': 'B-cells'}", + "68, human {'context': 'I-cells'}", + "69, and {'context': 'I-cells'}", + "70, murine {'context': 'I-cells'}", + "71, T {'context': 'I-cells'}", + "72, lymphocytes {'context': 'I-cells'}", + "149, thymocytes. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "67, normal ['l0', 'l1', 'l2', 'l3', 'l4']", + "68, human ['l0', 'l5', 'l6', 'l7', 'l8']", + "69, and ['l1', 'l5', 'l9', 'l10', 'l11']", + "70, murine ['l2', 'l6', 'l9', 'l12', 'l13']", + "71, T ['l3', 'l7', 'l10', 'l12', 'l14']", + "72, lymphocytes ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11590433", + "TEXT": "Loss of p53 gene function, which occurs in most colon cancer cells, has been shown to abolish the apoptotic response to 5-fluorouracil (5-FU). To identify genes downstream of p53 that might mediate these effects, we assessed global patterns of gene expression following 5-FU treatment of isogenic cells differing only in their p53 status. The gene encoding mitochondrial ferredoxin reductase (protein, FR; gene, FDXR) was one of the few genes significantly induced by p53 after 5-FU treatment. The FR protein was localized to mitochondria and suppressed the growth of colon cancer cells when over-expressed. Targeted disruption of the FDXR gene in human colon cancer cells showed that it was essential for viability, and partial disruption of the gene resulted in decreased sensitivity to 5-FU-induced apoptosis. These data, coupled with the effects of pharmacologic inhibitors of reactive oxygen species, indicate that FR contributes to p53-mediated apoptosis through the generation of oxidative stress in mitochondria.", + "TAG_DATA": [ + "46, cells {'context': 'B-cells'}", + "88, colon {'context': 'B-transformed cells'}", + "89, cancer {'context': 'I-transformed cells'}", + "90, cells {'context': 'I-transformed cells'}", + "93, Targeted {'perturbing_action': 'B-gene loss-of-function'}", + "94, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "95, of {'perturbing_action': 'I-gene loss-of-function'}", + "96, the {'perturbing_action': 'I-gene loss-of-function'}", + "97, FDXR {'perturbing_action': 'I-gene loss-of-function'}", + "98, gene {'perturbing_action': 'I-gene loss-of-function'}", + "100, human {'context': 'B-transformed cells'}", + "101, colon {'context': 'I-transformed cells'}", + "102, cancer {'context': 'I-transformed cells'}", + "103, cells {'context': 'I-transformed cells'}", + "119, decreased {'effect': 'B-negative'}", + "120, sensitivity {'effect': 'I-negative'}", + "122, 5-FU-induced {'effect': 'B-positive'}", + "123, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "46, cells ['l0', 'l1', 'l2']", + "88, colon ['l0', 'l3', 'l4']", + "89, cancer ['l1', 'l3', 'l5']", + "90, cells ['l2', 'l4', 'l5']", + "93, Targeted ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "94, disruption ['l6', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "95, of ['l7', 'l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "96, the ['l8', 'l16', 'l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "97, FDXR ['l9', 'l17', 'l24', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "98, gene ['l10', 'l18', 'l25', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "100, human ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l45', 'l46', 'l47']", + "101, colon ['l12', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l48', 'l49']", + "102, cancer ['l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l50']", + "103, cells ['l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l50']", + "119, decreased ['l51', 'l52', 'l53']", + "120, sensitivity ['l51', 'l54', 'l55']", + "122, 5-FU-induced ['l52', 'l54', 'l56']", + "123, apoptosis. ['l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Targeted", + "disruption", + "of", + "the", + "FDXR", + "gene" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "colon", + "cancer", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased", + "sensitivity" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "5-FU-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "11533712", + "TEXT": "The population of neurons participating in an epileptiform event varies from moment to moment. Most techniques currently used to localize epileptiform events in vivo have spatial and/or temporal sampling limitations. Here we show in an animal model that optical imaging based on intrinsic signals is an excellent method for in vivo mapping of clinically relevant epileptiform events, such as interictal spikes, ictal onsets, ictal spread and secondary homotopic foci. In addition, a decrease in the optical signal correlates spatially with a decrease in neuronal activity recorded from cortex surrounding an epileptic focus. Optical mapping of epilepsy might be a useful adjunct in the surgical treatment of neocortical epilepsy, which critically depends on the precise localization of intrinsically epileptogenic neurons.", + "TAG_DATA": [ + "35, animal {'context': 'B-organism'}", + "36, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "35, animal ['l0']", + "36, model ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11533707", + "TEXT": "Arterial conduits are increasingly preferred for surgical bypass because of inherent functional properties conferred by arterial endothelial cells, especially nitric oxide production in response to physiologic stimuli. Here we tested whether endothelial progenitor cells (EPCs) can replace arterial endothelial cells and promote patency in tissue-engineered small-diameter blood vessels (4 mm). We isolated EPCs from peripheral blood of sheep, expanded them ex vivo and then seeded them on decellularized porcine iliac vessels. EPC-seeded grafts remained patent for 130 days as a carotid interposition graft in sheep, whereas non-seeded grafts occluded within 15 days. The EPC-explanted grafts exhibited contractile activity and nitric-oxide-mediated vascular relaxation that were similar to native carotid arteries. These results indicate that EPCs can function similarly to arterial endothelial cells and thereby confer longer vascular-graft survival. Due to their unique properties, EPCs might have other general applications for tissue-engineered structures and in treating vascular diseases.", + "TAG_DATA": [ + "52, EPCs {'context': 'B-cells'}", + "54, peripheral {'context': 'I-cells'}", + "55, blood {'context': 'I-cells'}", + "57, sheep, {'context': 'B-organism'}", + "68, porcine {'context': 'B-tissue/organ'}", + "69, iliac {'context': 'I-tissue/organ'}", + "70, vessels. {'context': 'I-tissue/organ'}", + "72, grafts {'context': 'B-tissue/organ'}", + "84, sheep, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "52, EPCs ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "54, peripheral ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "55, blood ['l1', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "57, sheep, ['l2', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "68, porcine ['l3', 'l23', 'l24', 'l25', 'l26']", + "69, iliac ['l4', 'l10', 'l15', 'l19', 'l23', 'l27', 'l28', 'l29']", + "70, vessels. ['l5', 'l11', 'l16', 'l20', 'l24', 'l27', 'l30', 'l31']", + "72, grafts ['l6', 'l12', 'l17', 'l21', 'l25', 'l28', 'l30', 'l32']", + "84, sheep, ['l7', 'l13', 'l18', 'l22', 'l26', 'l29', 'l31', 'l32']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11533705", + "TEXT": "Deletion of amino-acid residues 1505-1507 (KPQ) in the cardiac SCN5A Na(+) channel causes autosomal dominant prolongation of the electrocardiographic QT interval (long-QT syndrome type 3 or LQT3). Excessive prolongation of the action potential at low heart rates predisposes individuals with LQT3 to fatal arrhythmias, typically at rest or during sleep. Here we report that mice heterozygous for a knock-in KPQ-deletion (SCN5A(Delta/+)) show the essential LQT3 features and spontaneously develop life-threatening polymorphous ventricular arrhythmias. Unexpectedly, sudden accelerations in heart rate or premature beats caused lengthening of the action potential with early afterdepolarization and triggered arrhythmias in Scn5a(Delta/+) mice. Adrenergic agonists normalized the response to rate acceleration in vitro and suppressed arrhythmias upon premature stimulation in vivo. These results show the possible risk of sudden heart-rate accelerations. The Scn5a(Delta/+) mouse with its predisposition for pacing-induced arrhythmia might be useful for the development of new treatments for the LQT3 syndrome.", + "TAG_DATA": [ + "54, mice {'context': 'B-organism'}", + "55, heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "56, for {'perturbing_action': 'I-gene loss-of-function'}", + "57, a {'perturbing_action': 'I-gene loss-of-function'}", + "58, knock-in {'perturbing_action': 'B-gene loss-of-function'}", + "59, KPQ-deletion {'perturbing_action': 'I-gene loss-of-function'}", + "60, (SCN5A(Delta/+)) {'perturbing_action': 'I-gene loss-of-function'}", + "95, Scn5a(Delta/+) {'perturbing_action': 'B-other'}", + "96, mice. {'context': 'B-organism'}", + "105, in {'context': 'B-in vitro'}", + "106, vitro {'context': 'I-in vitro'}", + "113, in {'context': 'B-in vivo'}", + "114, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "54, mice ['l0', 'l1']", + "55, heterozygous ['l0', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "56, for ['l2', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "57, a ['l3', 'l9', 'l15', 'l16', 'l17', 'l18', 'l19']", + "58, knock-in ['l4', 'l10', 'l15', 'l20', 'l21', 'l22', 'l23']", + "59, KPQ-deletion ['l5', 'l11', 'l16', 'l20', 'l24', 'l25', 'l26']", + "60, (SCN5A(Delta/+)) ['l1', 'l6', 'l12', 'l17', 'l21', 'l24']", + "95, Scn5a(Delta/+) ['l7', 'l13', 'l18', 'l22', 'l25', 'l27']", + "96, mice. ['l8', 'l14', 'l19', 'l23', 'l26', 'l27']", + "105, in ['l28']", + "106, vitro ['l28']", + "113, in ['l29']", + "114, vivo. ['l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "heterozygous", + "(SCN5A(Delta/+))", + "for", + "a", + "knock-in", + "KPQ-deletion" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Scn5a(Delta/+)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "11533703", + "TEXT": "Glutamate neurotoxicity has been implicated in stroke, head trauma, multiple sclerosis and neurodegenerative diseases. Although recent data show that cultured glioma cells secrete glutamate, the growth potential of brain tumors has not yet been linked to an excitotoxic mechanism. Using bioluminescence detection of glutamate release from freshly prepared brain slices, we show that implanted glioma cells continue to secrete glutamate. Moreover, gliomas with high glutamate release have a distinct growth advantage in host brain that is not present in vitro. Treatment with the NMDA receptor antagonists MK801 or memantine slowed the growth of glutamate-secreting tumors in situ, suggesting that activation of NMDA receptors facilitates tumor expansion. These findings support a new approach for therapy of brain tumors, based upon antagonizing glutamate secretion or its target receptors.", + "TAG_DATA": [ + "54, glioma {'context': 'B-transformed cells'}", + "55, cells {'context': 'I-transformed cells'}", + "93, glutamate-secreting {'context': 'B-neoplasm'}", + "94, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "54, glioma ['l0']", + "55, cells ['l0']", + "93, glutamate-secreting ['l1']", + "94, tumors ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11479626", + "TEXT": "Here we investigated the pathogenesis of deletion mutant mitochondrial (mt)DNA by generating mice with mutant mtDNA carrying a 4696-basepair deletion (DeltamtDNA4696), and by using cytochrome c oxidase (COX) electron micrographs to identify COX activity at the individual mitochondrial level. All mitochondria in tissues with DeltamtDNA4696 showed normal COX activity until DeltamtDNA4696 accumulated predominantly; this prevented mice from expressing disease phenotypes. Moreover, we did not observe coexistence of COX-positive and -negative mitochondria within single cells. These results indicate the occurrence of inter-mitochondrial complementation through exchange of genetic contents between exogenously introduced mitochondria with DeltamtDNA4696 and host mitochondria with normal mtDNA. This complementation shows a mitochondria-specific mechanism for avoiding expression of deletion-mutant mtDNA, and opens the possibility of a gene therapy in which mitochondria possessing full-length DNA are introduced.", + "TAG_DATA": [ + "12, mice {'context': 'B-organism'}", + "55, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11433351", + "TEXT": "Increased secretion and levels of ApoB-containing lipoproteins (BLp) commonly occur in familial hyperlipidemia, obesity and diabetes. The plasma phospholipid-transfer protein (PLTP) is known to mediate transfer of phospholipids between BLp and HDL during their intravascular metabolism. To address a possible role of PLTP in dyslipidemia and atherogenesis, we bred mice deficient in the gene encoding PLTP (PLTP-deficient mice) using different hyperlipidemic mouse strains. In ApoB-transgenic and ApoE-deficient backgrounds, PLTP deficiency resulted in reduced production and levels of BLp and markedly decreased atherosclerosis. BLp secretion was diminished in hepatocytes from ApoB-transgenic PLTP-deficient mice, a defect that was corrected when PLTP was reintroduced in adenovirus. The studies reveal a major, unexpected role of PLTP in regulating the secretion of BLp and identify PLTP as a therapeutic target.", + "TAG_DATA": [ + "49, mice {'context': 'B-organism'}", + "50, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "51, in {'perturbing_action': 'I-gene loss-of-function'}", + "52, the {'perturbing_action': 'I-gene loss-of-function'}", + "53, gene {'perturbing_action': 'I-gene loss-of-function'}", + "54, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "55, PLTP {'perturbing_action': 'I-gene loss-of-function'}", + "56, (PLTP-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "57, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "61, mouse {'context': 'B-organism'}", + "62, strains. {'context': 'I-organism'}", + "64, ApoB-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "66, ApoE-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "68, PLTP {'perturbing_action': 'B-gene loss-of-function'}", + "69, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "80, decreased {'effect': 'B-negative'}", + "87, hepatocytes {'context': 'B-cells'}", + "89, ApoB-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "90, PLTP-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "91, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "49, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "50, deficient ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "51, in ['l1', 'l12', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "52, the ['l2', 'l13', 'l27', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "53, gene ['l3', 'l14', 'l28', 'l41', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "54, encoding ['l4', 'l15', 'l29', 'l42', 'l54', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "55, PLTP ['l5', 'l16', 'l30', 'l43', 'l55', 'l66', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "56, (PLTP-deficient ['l6', 'l17', 'l31', 'l44', 'l56', 'l67', 'l77', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "57, mice) ['l7', 'l18', 'l32', 'l45', 'l57', 'l68', 'l78', 'l87', 'l93', 'l94', 'l95', 'l96']", + "61, mouse ['l8', 'l19', 'l33', 'l46', 'l58', 'l69', 'l79', 'l88', 'l93', 'l97']", + "62, strains. ['l9', 'l20', 'l34', 'l47', 'l59', 'l70', 'l80', 'l89', 'l94', 'l97']", + "64, ApoB-transgenic ['l21', 'l35', 'l48', 'l60', 'l71', 'l81', 'l90', 'l98', 'l99', 'l100', 'l101', 'l102']", + "66, ApoE-deficient ['l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l98', 'l103', 'l104', 'l105', 'l106']", + "68, PLTP ['l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l99', 'l103', 'l107', 'l108', 'l109']", + "69, deficiency ['l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l100', 'l104', 'l107', 'l110', 'l111']", + "80, decreased ['l10', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l91', 'l95', 'l101', 'l105', 'l108', 'l110', 'l112']", + "81, atherosclerosis. ['l11', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l92', 'l96', 'l102', 'l106', 'l109', 'l111', 'l112']", + "87, hepatocytes ['l113', 'l114', 'l115']", + "89, ApoB-transgenic ['l113', 'l116', 'l117']", + "90, PLTP-deficient ['l114', 'l116', 'l118']", + "91, mice, ['l115', 'l117', 'l118']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "strains.", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "the", + "gene", + "encoding", + "PLTP", + "(PLTP-deficient", + "mice)", + "PLTP-deficient" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "the", + "gene", + "encoding", + "PLTP", + "(PLTP-deficient", + "mice)", + "ApoE-deficient", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ApoB-transgenic" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hepatocytes" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ApoB-transgenic" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hepatocytes" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PLTP-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ApoB-transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "11433350", + "TEXT": "Both the risk and the rate of development of atherosclerosis are increased in diabetics, but the mechanisms involved are unknown. Here we report a glucose-mediated increase in CD36 mRNA translation efficiency that results in increased expression of the macrophage scavenger receptor CD36. Expression of CD36 was increased in endarterectomy lesions from patients with a history of hyperglycemia. Macrophages that were differentiated from human peripheral blood monocytes in the presence of high glucose concentrations showed increased expression of cell-surface CD36 secondary to an increase in translational efficiency of CD36 mRNA. We obtained similar data from primary cells isolated from human vascular lesions, and we found that glucose sensitivity is a function of ribosomal reinitiation following translation of an upstream open reading frame (uORF). Increased translation of macrophage CD36 transcript under high glucose conditions provides a mechanism for accelerated atherosclerosis in diabetics.", + "TAG_DATA": [ + "57, Macrophages {'context': 'B-cells'}", + "62, human {'context': 'B-cells'}", + "63, peripheral {'context': 'I-cells'}", + "64, blood {'context': 'I-cells'}", + "65, monocytes {'context': 'I-cells'}", + "95, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "57, Macrophages ['l0', 'l1', 'l2', 'l3', 'l4']", + "62, human ['l0', 'l5', 'l6', 'l7']", + "63, peripheral ['l1', 'l5', 'l8', 'l9']", + "64, blood ['l2', 'l6', 'l8', 'l10']", + "65, monocytes ['l3', 'l7', 'l9', 'l10']", + "95, cells ['l4']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11433345", + "TEXT": "Here we show that apoptotic cells overexpress vinculin and are ingested by dendritic cells, which subsequently cross-prime vinculin-specific cytotoxic T lymphocytes (CTLs). Successful cross-priming requires that the apoptotic cells provide maturation signals to dendritic cells through CD40-CD40 ligand (CD40L) interactions. If apoptotic cells are CD40L-, the help of a third T cell is needed for priming, indicating a regulatory role for apoptotic cells in determining priming or tolerance. Vinculin-specific CTL priming is also related to apoptosis in vivo, given that in HIV-seropositive individuals, the frequency of specific CTLs depends on the proportion of peripheral CD40L+ apoptotic cells.", + "TAG_DATA": [ + "76, in {'context': 'B-in vivo'}", + "77, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "75, apoptosis ['l0', 'l1']", + "76, in ['l0', 'l2']", + "77, vivo, ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11433343", + "TEXT": "Mutations in viral genomes that affect T-cell-receptor recognition by CD8+ cytotoxic T lymphocytes have been shown to allow viral evasion from immune surveillance during persistent viral infections. Although CD4+ T-helper cells are crucially involved in the maintenance of effective cytotoxic T-lymphocyte and neutralizing-antibody responses, their role in viral clearance and therefore in imposing similar selective pressures on the virus is unclear. We show here that transgenic virus-specific CD4+ Tcells, transferred into mice persistently infected with lymphocytic choriomeningitis virus, select for T-helper epitope mutant viruses that are not recognized. Together with the observed antigenic variation of the same T-helper epitope during polyclonal CD4+ T-cell responses in infected pore-forming protein-deficient C57BL/6 mice, this finding indicates that viral escape from CD4+ T lymphocytes is a possible mechanism of virus persistence.", + "TAG_DATA": [ + "65, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "66, virus-specific {'context': 'I-cells'}", + "67, CD4+ {'context': 'I-cells'}", + "68, Tcells, {'context': 'I-cells'}", + "71, mice {'context': 'B-organism'}", + "106, pore-forming {'perturbing_action': 'B-gene loss-of-function'}", + "107, protein-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "108, C57BL/6 {'context': 'B-organism'}", + "109, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "65, transgenic ['l0', 'l1', 'l2', 'l3']", + "66, virus-specific ['l0', 'l4', 'l5', 'l6']", + "67, CD4+ ['l1', 'l4', 'l7', 'l8']", + "68, Tcells, ['l2', 'l5', 'l7', 'l9']", + "71, mice ['l3', 'l6', 'l8', 'l9']", + "106, pore-forming ['l10', 'l11', 'l12']", + "107, protein-deficient ['l10', 'l13', 'l14']", + "108, C57BL/6 ['l11', 'l13', 'l15']", + "109, mice, ['l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "virus-specific", + "CD4+", + "Tcells," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pore-forming", + "protein-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "C57BL/6", + "mice," + ] + } + } + ] + }, + { + "PMID": "11385514", + "TEXT": "A number of different matrix metalloproteinase (MMP) inhibitors have been developed as cytostatic and anti-angiogenic agents and are currently in clinical testing. One major hurdle in assessing the efficacy of such drugs has been the inability to sense or image anti-proteinase activity directly and non-invasively in vivo. We show here that novel, biocompatible near-infrared fluorogenic MMP substrates can be used as activatable reporter probes to sense MMP activity in intact tumors in nude mice. Moreover, we show for the first time that the effect of MMP inhibition can be directly imaged using this approach within hours after initiation of treatment using the potent MMP inhibitor, prinomastat (AG3340). The developed probes, together with novel near-infrared fluorescence imaging technology will enable the detailed analysis of a number of proteinases critical for advancing the therapeutic use of clinical proteinase inhibitors.", + "TAG_DATA": [ + "70, tumors {'context': 'I-neoplasm'}", + "72, nude {'context': 'B-organism'}", + "73, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "70, tumors ['l0', 'l1']", + "72, nude ['l0', 'l2']", + "73, mice. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11385506", + "TEXT": "Heme oxygenase (HO-1, encoded by Hmox1) is an inducible protein activated in systemic inflammatory conditions by oxidant stress. Vascular injury is characterized by a local reparative process with inflammatory components, indicating a potential protective role for HO-1 in arterial wound repair. Here we report that HO-1 directly reduces vasoconstriction and inhibits cell proliferation during vascular injury. Expression of HO-1 in arteries stimulated vascular relaxation, mediated by guanylate cyclase and cGMP, independent of nitric oxide. The unexpected effects of HO-1 on vascular smooth muscle cell growth were mediated by cell-cycle arrest involving p21Cip1. HO-1 reduced the proliferative response to vascular injury in vivo; expression of HO-1 in pig arteries inhibited lesion formation and Hmox1-/- mice produced hyperplastic arteries compared with controls. Induction of the HO-1 pathway moderates the severity of vascular injury by at least two adaptive mechanisms independent of nitric oxide, and is a potential therapeutic target for diseases of the vasculature.", + "TAG_DATA": [ + "50, inhibits {'effect': 'B-negative'}", + "51, cell {'context': 'B-cells'}", + "52, proliferation {'phenotype': 'B-proliferation'}", + "56, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "57, of {'perturbing_action': 'I-gene gain-of-function'}", + "58, HO-1 {'perturbing_action': 'I-gene gain-of-function'}", + "60, arteries {'context': 'B-tissue/organ'}", + "80, vascular {'context': 'B-cells'}", + "81, smooth {'context': 'I-cells'}", + "82, muscle {'context': 'I-cells'}", + "83, cell {'phenotype': 'B-cell growth'}", + "84, growth {'phenotype': 'I-cell growth'}", + "88, cell-cycle {'phenotype': 'B-cell cycle arrest'}", + "89, arrest {'phenotype': 'I-cell cycle arrest'}", + "93, reduced {'effect': 'B-negative'}", + "95, proliferative {'phenotype': 'B-proliferation'}", + "96, response {'phenotype': 'I-proliferation'}", + "100, in {'context': 'B-in vivo'}", + "101, vivo; {'context': 'I-in vivo'}", + "102, expression {'perturbing_action': 'B-gene gain-of-function'}", + "103, of {'perturbing_action': 'I-gene gain-of-function'}", + "104, HO-1 {'perturbing_action': 'I-gene gain-of-function'}", + "106, pig {'context': 'B-tissue/organ'}", + "107, arteries {'context': 'I-tissue/organ'}", + "108, inhibited {'effect': 'B-negative'}", + "112, Hmox1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "113, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, inhibits ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "51, cell ['l0', 'l8', 'l9']", + "52, proliferation ['l1', 'l8', 'l10']", + "56, Expression ['l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "57, of ['l11', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "58, HO-1 ['l12', 'l26', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "60, arteries ['l2', 'l9', 'l10', 'l13', 'l27', 'l40', 'l53', 'l54', 'l55', 'l56', 'l57']", + "80, vascular ['l3', 'l14', 'l28', 'l41', 'l53', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "81, smooth ['l4', 'l15', 'l29', 'l42', 'l54', 'l58', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "82, muscle ['l5', 'l16', 'l30', 'l43', 'l55', 'l59', 'l69', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "83, cell ['l6', 'l17', 'l31', 'l44', 'l56', 'l60', 'l70', 'l79', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "84, growth ['l7', 'l18', 'l32', 'l45', 'l57', 'l61', 'l71', 'l80', 'l88', 'l95', 'l96', 'l97', 'l98', 'l99']", + "88, cell-cycle ['l19', 'l33', 'l46', 'l62', 'l72', 'l81', 'l89', 'l95', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "89, arrest ['l20', 'l34', 'l47', 'l63', 'l73', 'l82', 'l90', 'l96', 'l100', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "93, reduced ['l21', 'l35', 'l48', 'l64', 'l74', 'l83', 'l91', 'l101', 'l108', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "95, proliferative ['l22', 'l36', 'l49', 'l65', 'l75', 'l84', 'l102', 'l109', 'l114', 'l120', 'l121', 'l122', 'l123', 'l124']", + "96, response ['l23', 'l37', 'l50', 'l66', 'l76', 'l85', 'l92', 'l97', 'l103', 'l110', 'l115', 'l120', 'l125', 'l126']", + "100, in ['l24', 'l38', 'l51', 'l67', 'l77', 'l86', 'l93', 'l98', 'l104', 'l111', 'l116', 'l121', 'l125', 'l127']", + "101, vivo; ['l25', 'l39', 'l52', 'l68', 'l78', 'l87', 'l94', 'l99', 'l105', 'l112', 'l117', 'l122', 'l126', 'l127']", + "102, expression ['l128', 'l129', 'l130', 'l131', 'l132']", + "103, of ['l128', 'l133', 'l134', 'l135', 'l136']", + "104, HO-1 ['l129', 'l133', 'l137', 'l138', 'l139']", + "106, pig ['l106', 'l118', 'l123', 'l130', 'l134', 'l137', 'l140', 'l141']", + "107, arteries ['l107', 'l113', 'l119', 'l124', 'l131', 'l135', 'l138', 'l140', 'l142']", + "108, inhibited ['l132', 'l136', 'l139', 'l141', 'l142']", + "112, Hmox1-/- ['l143']", + "113, mice ['l143']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "reduced" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "vascular", + "smooth", + "muscle" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "reduced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation", + "proliferative", + "response" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "reduced", + "inhibited" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "arteries", + "pig" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "reduced" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell", + "vascular", + "smooth", + "muscle" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation", + "proliferative", + "response" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation", + "proliferative" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "arteries", + "pig" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "HO-1", + "expression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "arteries", + "pig" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "HO-1" + ] + }, + "context": { + "val": "cells", + "words": [ + "vascular", + "smooth", + "muscle" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "HO-1" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "HO-1" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "HO-1", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced", + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "HO-1" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "response" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "HO-1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo;" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "arteries" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "vascular", + "smooth", + "muscle" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "vascular", + "smooth", + "muscle" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest" + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo;" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo;" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "pig", + "arteries" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo;" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "response" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo;" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hmox1-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "11385505", + "TEXT": "The beta2 integrin leukocyte function antigen-1 (LFA-1) has an important role in the pathophysiology of inflammatory and autoimmune diseases. Here we report that statin compounds commonly used for the treatment of hypercholesterolemia selectively blocked LFA-1-mediated adhesion and costimulation of lymphocytes. This effect was unrelated to the statins' inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A reductase; instead it occurred via binding to a novel allosteric site within LFA-1. Subsequent optimization of the statins for LFA-1 binding resulted in potent, selective and orally active LFA-1 inhibitors that suppress the inflammatory response in a murine model of peritonitis. Targeting of the statin-binding site of LFA-1 could be used to treat diseases such as psoriasis, rheumatoid arthritis, ischemia/reperfusion injury and transplant rejection.", + "TAG_DATA": [ + "33, blocked {'effect': 'B-negative'}", + "35, adhesion {'phenotype': 'B-adhesion'}", + "39, lymphocytes. {'context': 'B-cells'}", + "79, LFA-1 {'perturbing_action': 'B-pharmacological inhibition'}", + "80, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "88, murine {'context': 'B-organism'}", + "89, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "33, blocked ['l0', 'l1']", + "35, adhesion ['l0', 'l2']", + "39, lymphocytes. ['l1', 'l2']", + "79, LFA-1 ['l3', 'l4', 'l5']", + "80, inhibitors ['l3', 'l6', 'l7']", + "88, murine ['l4', 'l6', 'l8']", + "89, model ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "context": { + "val": "cells", + "words": [ + "lymphocytes." + ] + } + }, + { + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + }, + "context": { + "val": "cells", + "words": [ + "lymphocytes." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "LFA-1", + "inhibitors" + ] + }, + "context": { + "val": "organism", + "words": [ + "murine", + "model" + ] + } + } + ] + }, + { + "PMID": "11329058", + "TEXT": "Angiogenesis has an essential role in many important pathological and physiological settings. It has been shown that vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), a potent cytokine expressed by most malignant tumors, has critical roles in vasculogenesis and both physiological and pathological angiogenesis. We report here that at non-toxic levels, the neurotransmitter dopamine strongly and selectively inhibited the vascular permeabilizing and angiogenic activities of VPF/VEGF. Dopamine acted through D2 dopamine receptors to induce endocytosis of VEGF receptor 2, which is critical for promoting angiogenesis, thereby preventing VPF/VEGF binding, receptor phosphorylation and subsequent signaling steps. The action of dopamine was specific for VPF/VEGF and did not affect other mediators of microvascular permeability or endothelial-cell proliferation or migration. These results reveal a new link between the nervous system and angiogenesis and indicate that dopamine and other D2 receptors, already in clinical use for other purposes, might have value in anti-angiogenesis therapy.", + "TAG_DATA": [ + "104, not {'effect': 'I-no effect'}", + "105, affect {'effect': 'I-no effect'}", + "112, endothelial-cell {'context': 'B-cells'}", + "113, proliferation {'phenotype': 'B-proliferation'}", + "115, migration. {'phenotype': 'B-migration'}" + ], + "LINK_DATA": [ + "104, not ['l0', 'l1', 'l2', 'l3']", + "105, affect ['l0', 'l4', 'l5', 'l6']", + "112, endothelial-cell ['l1', 'l4', 'l7', 'l8']", + "113, proliferation ['l2', 'l5', 'l7', 'l9']", + "115, migration. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "no effect", + "words": [ + "not", + "affect" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial-cell" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "affect" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "affect" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial-cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial-cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + } + ] + }, + { + "PMID": "11283676", + "TEXT": "Neuronal ceroid lipofuscinoses (NCLs) are the most common hereditary neurodegenerative diseases of childhood. The infantile form, INCL, is caused by lysosomal palmitoyl-protein thioesterase (PPT) deficiency, which impairs the cleavage of thioester linkages in palmitoylated proteins, preventing their hydrolysis by lysosomal proteinases. Consequent accumulation of these lipid-modified proteins (constituents of ceroid) in lysosomes leads to INCL. Because thioester linkages are susceptible to nucleophilic attack, drugs with this property may have therapeutic potential for INCL. We report here that two such drugs, phosphocysteamine and N-acetylcysteine, disrupt thioester linkages in a model thioester compound, [14C]palmitoyl approximately CoA. Most importantly, in lymphoblasts derived from INCL patients, phosphocysteamine, a known lysosomotrophic drug, mediates the depletion of lysosomal ceroids, prevents their re-accumulation and inhibits apoptosis. Our results define a novel pharmacological approach to lysosomal ceroid depletion and raise the possibility that nucleophilic drugs such as phosphocysteamine hold therapeutic potential for INCL.", + "TAG_DATA": [ + "97, lymphoblasts {'context': 'B-cells'}", + "117, inhibits {'effect': 'B-negative'}", + "118, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "97, lymphoblasts ['l0']", + "117, inhibits ['l0', 'l1']", + "118, apoptosis. ['l1']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "lymphoblasts" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "11283674", + "TEXT": "Using a novel flow chamber assay system and whole blood, we show that leukocytes from septic individuals have a four-fold elevation of adhesion, but not rolling, on a P-selectin/beta2-integrin substrate. Most leukocytes from septic patients (but not healthy controls) that bound vascular cell adhesion molecule 1 (VCAM-1) were neutrophils. All adhesion was inhibited with an antibody specific for the VCAM-1 ligand alpha4-integrin. The alpha4-integrin was present on neutrophils from septic patients but not on neutrophils from patients with localized bacterial infections. The plasma milieu of septic patients was sufficient to induce neutrophils from healthy subjects to bind VCAM-1 under flow conditions. This is the first description of alpha4-integrin/VCAM-1 pathway of neutrophil recruitment in human disease. This pathway may provide a new therapeutic target to reduce inappropriate neutrophil adhesion without altering the normal yet critical beta2-integrin-mediated adhesive function of neutrophils.", + "TAG_DATA": [ + "52, inhibited {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "31, leukocytes ['l0']", + "50, adhesion ['l0', 'l1']", + "52, inhibited ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11283671", + "TEXT": "The transcription factor CCAAT/enhancer binding protein alpha, or C/EBPalpha, encoded by the CEBPA gene, is crucial for the differentiation of granulocytes. Conditional expression of C/EBPalpha triggers neutrophilic differentiation, and Cebpa knockout mice exhibit an early block in maturation. Dominant-negative mutations of CEBPA have been found in some patients with acute myeloid leukemia (AML), but not in AML with the t(8;21) translocation which gives rise to the fusion gene RUNX1-CBF2T1 (also known as AML1-ETO) encoding the AML1-ETO fusion protein. RUNX1-CBF2T1 positive-AML blasts had eight-fold lower CEBPA RNA levels and undetectable C/EBPalpha protein levels compared with other subgroups of AML patients. Conditional expression of RUNX1-CBF2T1 in U937 cells downregulated CEBPA mRNA, protein and DNA binding activity. AML1-ETO appears to suppress C/EBPalpha expression indirectly by inhibiting positive autoregulation of the CEBPA promoter. Conditional expression of C/EBPalpha in AML1-ETO-positive Kasumi-1 cells results in neutrophilic differentiation. We suggest that restoring C/EBPalpha expression will have therapeutic implications in RUNX1-CBF2T1-positive leukemias.", + "TAG_DATA": [ + "29, Cebpa {'perturbing_action': 'B-gene loss-of-function'}", + "30, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "31, mice {'context': 'B-organism'}", + "99, Conditional {'perturbing_action': 'B-gene gain-of-function'}", + "100, expression {'perturbing_action': 'I-gene gain-of-function'}", + "101, of {'perturbing_action': 'I-gene gain-of-function'}", + "102, RUNX1-CBF2T1 {'perturbing_action': 'I-gene gain-of-function'}", + "104, U937 {'context': 'B-cells'}", + "105, cells {'context': 'I-cells'}", + "129, Conditional {'perturbing_action': 'B-gene gain-of-function'}", + "130, expression {'perturbing_action': 'I-gene gain-of-function'}", + "131, of {'perturbing_action': 'I-gene gain-of-function'}", + "132, C/EBPalpha {'perturbing_action': 'I-gene gain-of-function'}", + "134, AML1-ETO-positive {'perturbing_action': 'B-other'}", + "135, Kasumi-1 {'context': 'I-cells'}", + "136, cells {'context': 'I-cells'}", + "137, results {'effect': 'B-positive'}", + "138, in {'effect': 'I-positive'}", + "140, differentiation. {'phenotype': 'I-differentiation'}" + ], + "LINK_DATA": [ + "29, Cebpa ['l0', 'l1']", + "30, knockout ['l0', 'l2']", + "31, mice ['l1', 'l2']", + "99, Conditional ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "100, expression ['l3', 'l9', 'l10', 'l11', 'l12']", + "101, of ['l4', 'l9', 'l13', 'l14', 'l15']", + "102, RUNX1-CBF2T1 ['l5', 'l10', 'l13', 'l16', 'l17']", + "104, U937 ['l6', 'l11', 'l14', 'l16', 'l18']", + "105, cells ['l7', 'l12', 'l15', 'l17', 'l18']", + "129, Conditional ['l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "130, expression ['l19', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "131, of ['l20', 'l28', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "132, C/EBPalpha ['l21', 'l29', 'l36', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "134, AML1-ETO-positive ['l22', 'l30', 'l37', 'l43', 'l49', 'l50', 'l51', 'l52', 'l53']", + "135, Kasumi-1 ['l23', 'l31', 'l38', 'l44', 'l49', 'l54', 'l55', 'l56', 'l57']", + "136, cells ['l8', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l58', 'l59', 'l60']", + "137, results ['l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l58', 'l61', 'l62']", + "138, in ['l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l61', 'l63']", + "140, differentiation. ['l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l62', 'l63']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cebpa", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Conditional", + "expression", + "of", + "RUNX1-CBF2T1", + "C/EBPalpha" + ] + }, + "context": { + "val": "cells", + "words": [ + "U937", + "cells", + "Kasumi-1" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Conditional", + "expression", + "of", + "C/EBPalpha" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Conditional", + "expression", + "of", + "C/EBPalpha" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "AML1-ETO-positive" + ] + }, + "context": { + "val": "cells", + "words": [ + "Kasumi-1", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "AML1-ETO-positive" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "AML1-ETO-positive" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Kasumi-1", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Kasumi-1", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + } + ] + }, + { + "PMID": "11283669", + "TEXT": "Left ventricular remodeling is a major cause of progressive heart failure and death after myocardial infarction. Although neoangiogenesis within the infarcted tissue is an integral component of the remodeling process, the capillary network is unable to support the greater demands of the hypertrophied myocardium, resulting in progressive loss of viable tissue, infarct extension and fibrous replacement. Here we show that bone marrow from adult humans contains endothelial precursors with phenotypic and functional characteristics of embryonic hemangioblasts, and that these can be used to directly induce new blood vessel formation in the infarct-bed (vasculogenesis) and proliferation of preexisting vasculature (angiogenesis) after experimental myocardial infarction. The neoangiogenesis resulted in decreased apoptosis of hypertrophied myocytes in the peri-infarct region, long-term salvage and survival of viable myocardium, reduction in collagen deposition and sustained improvement in cardiac function. The use of cytokine-mobilized autologous human bone-marrow-derived angioblasts for revascularization of infarcted myocardium (alone or in conjunction with currently used therapies) has the potential to significantly reduce morbidity and mortality associated with left ventricular remodeling.", + "TAG_DATA": [ + "107, decreased {'effect': 'B-negative'}", + "108, apoptosis {'phenotype': 'B-apoptosis'}", + "110, hypertrophied {'context': 'B-cells'}", + "111, myocytes {'context': 'I-cells'}", + "122, myocardium, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "107, decreased ['l0', 'l1', 'l2', 'l3']", + "108, apoptosis ['l0', 'l4', 'l5', 'l6']", + "110, hypertrophied ['l1', 'l4', 'l7', 'l8']", + "111, myocytes ['l2', 'l5', 'l7', 'l9']", + "122, myocardium, ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "context": { + "val": "cells", + "words": [ + "hypertrophied", + "myocytes" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "myocardium," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "hypertrophied", + "myocytes" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "myocardium," + ] + } + } + ] + }, + { + "PMID": "11231638", + "TEXT": "Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the neuromuscular junction. In approximately 80% of patients, auto-antibodies to the muscle nicotinic acetylcholine receptor (AChR) are present. These antibodies cause loss of AChR numbers and function, and lead to failure of neuromuscular transmission with muscle weakness. The pathogenic mechanisms acting in the 20% of patients with generalized MG who are seronegative for AChR-antibodies (AChR-Ab) have not been elucidated, but there is evidence that they also have an antibody-mediated disorder, with the antibodies directed towards another, previously unidentified muscle-surface-membrane target. Here we show that 70% of AChR-Ab-seronegative MG patients, but not AChR-Ab-seropositive MG patients, have serum auto-antibodies against the muscle-specific receptor tyrosine kinase, MuSK. MuSK mediates the agrin-induced clustering of AChRs during synapse formation, and is also expressed at the mature neuromuscular junction. The MuSK antibodies were specific for the extracellular domains of MuSK expressed in transfected COS7 cells and strongly inhibited MuSK function in cultured myotubes. Our results indicate the involvement of MuSK antibodies in the pathogenesis of AChR-Ab-seronegative MG, thus defining two immunologically distinct forms of the disease. Measurement of MuSK antibodies will substantially aid diagnosis and clinical management.", + "TAG_DATA": [ + "146, COS7 {'context': 'B-cells'}", + "147, cells {'context': 'I-cells'}", + "154, cultured {'context': 'B-cells'}", + "155, myotubes. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "146, COS7 ['l0', 'l1', 'l2']", + "147, cells ['l0', 'l3', 'l4']", + "154, cultured ['l1', 'l3', 'l5']", + "155, myotubes. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11231630", + "TEXT": "Oxygen-regulated protein 150 kD (ORP150) is a novel endoplasmic-reticulum-associated chaperone induced by hypoxia/ischemia. Although ORP150 was sparingly upregulated in neurons from human brain undergoing ischemic stress, there was robust induction in astrocytes. Cultured neurons overexpressing ORP150 were resistant to hypoxemic stress, whereas astrocytes with inhibited ORP150 expression were more vulnerable. Mice with targeted neuronal overexpression of ORP150 had smaller strokes compared with controls. Neurons with increased ORP150 demonstrated suppressed caspase-3-like activity and enhanced brain-derived neurotrophic factor (BDNF) under hypoxia signaling. These data indicate that ORP150 is an integral participant in ischemic cytoprotective pathways.", + "TAG_DATA": [ + "32, Cultured {'context': 'B-cells'}", + "33, neurons {'context': 'I-cells'}", + "34, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "35, ORP150 {'perturbing_action': 'I-gene gain-of-function'}", + "42, astrocytes {'context': 'B-cells'}", + "44, inhibited {'perturbing_action': 'B-pharmacological inhibition'}", + "45, ORP150 {'perturbing_action': 'I-rnai/knockdown'}", + "46, expression {'perturbing_action': 'I-rnai/knockdown'}", + "50, Mice {'context': 'B-organism'}", + "52, targeted {'perturbing_action': 'B-gene gain-of-function'}", + "53, neuronal {'perturbing_action': 'I-gene gain-of-function'}", + "54, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "55, of {'perturbing_action': 'I-gene gain-of-function'}", + "56, ORP150 {'perturbing_action': 'I-gene gain-of-function'}", + "63, Neurons {'context': 'B-cells'}", + "65, increased {'perturbing_action': 'B-gene gain-of-function'}" + ], + "LINK_DATA": [ + "32, Cultured ['l0', 'l1', 'l2', 'l3']", + "33, neurons ['l0', 'l4', 'l5', 'l6']", + "34, overexpressing ['l1', 'l4', 'l7', 'l8', 'l9']", + "35, ORP150 ['l2', 'l5', 'l7', 'l10', 'l11']", + "42, astrocytes ['l3', 'l6', 'l8', 'l10', 'l12', 'l13', 'l14']", + "44, inhibited ['l12', 'l15', 'l16', 'l17', 'l18']", + "45, ORP150 ['l13', 'l15', 'l19', 'l20', 'l21']", + "46, expression ['l9', 'l11', 'l14', 'l16', 'l19']", + "50, Mice ['l22', 'l23', 'l24', 'l25', 'l26']", + "52, targeted ['l22', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "53, neuronal ['l23', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "54, overexpression ['l24', 'l28', 'l33', 'l38', 'l39']", + "55, of ['l17', 'l20', 'l25', 'l29', 'l34', 'l38', 'l40']", + "56, ORP150 ['l18', 'l21', 'l26', 'l30', 'l35', 'l39', 'l40']", + "63, Neurons ['l31', 'l36', 'l41']", + "65, increased ['l32', 'l37', 'l41']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Cultured", + "neurons", + "astrocytes", + "Neurons" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "ORP150", + "targeted", + "neuronal", + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "astrocytes" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "astrocytes" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "ORP150", + "expression" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "targeted", + "neuronal", + "overexpression", + "of", + "ORP150" + ] + } + } + ] + }, + { + "PMID": "11231627", + "TEXT": "The initiation of T-cell-mediated antitumor immune responses requires the uptake and processing of tumor antigens by dendritic cells and their presentation on MHC-I molecules. Here we show in a human in vitro model system that exosomes, a population of small membrane vesicles secreted by living tumor cells, contain and transfer tumor antigens to dendritic cells. After mouse tumor exosome uptake, dendritic cells induce potent CD8+ T-cell-dependent antitumor effects on syngeneic and allogeneic established mouse tumors. Therefore, exosomes represent a novel source of tumor-rejection antigens for T-cell cross priming, relevant for immunointerventions.", + "TAG_DATA": [ + "56, mouse {'context': 'B-neoplasm'}", + "60, dendritic {'context': 'B-cells'}", + "61, cells {'context': 'I-cells'}", + "73, mouse {'context': 'B-neoplasm'}", + "74, tumors. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "56, mouse ['l0', 'l1', 'l2', 'l3', 'l4']", + "57, tumor ['l0', 'l5', 'l6', 'l7', 'l8']", + "60, dendritic ['l1', 'l5', 'l9', 'l10', 'l11']", + "61, cells ['l2', 'l6', 'l9', 'l12', 'l13']", + "73, mouse ['l3', 'l7', 'l10', 'l12', 'l14']", + "74, tumors. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11175849", + "TEXT": "Metastasis to local lymph nodes via the lymphatic vessels is a common step in the spread of solid tumors. To investigate the molecular mechanisms underlying the spread of cancer by the lymphatics, we examined the ability of vascular endothelial growth factor (VEGF)-D, a ligand for the lymphatic growth factor receptor VEGFR-3/Flt-4, to induce formation of lymphatics in a mouse tumor model. Staining with markers specific for lymphatic endothelium demonstrated that VEGF-D induced the formation of lymphatics within tumors. Moreover, expression of VEGF-D in tumor cells led to spread of the tumor to lymph nodes, whereas expression of VEGF, an angiogenic growth factor which activates VEGFR-2 but not VEGFR-3, did not. VEGF-D also promoted tumor angiogenesis and growth. Lymphatic spread induced by VEGF-D could be blocked with an antibody specific for VEGF-D. This study demonstrates that lymphatics can be established in solid tumors and implicates VEGF family members in determining the route of metastatic spread.", + "TAG_DATA": [ + "58, mouse {'context': 'B-neoplasm'}", + "59, tumor {'context': 'I-neoplasm'}", + "60, model. {'context': 'I-neoplasm'}", + "77, tumors. {'context': 'B-neoplasm'}", + "79, expression {'perturbing_action': 'B-gene gain-of-function'}", + "80, of {'perturbing_action': 'I-gene gain-of-function'}", + "81, VEGF-D {'perturbing_action': 'I-gene gain-of-function'}", + "83, tumor {'context': 'B-transformed cells'}", + "84, cells {'context': 'I-transformed cells'}", + "90, tumor {'context': 'B-neoplasm'}", + "95, expression {'perturbing_action': 'B-gene gain-of-function'}", + "96, of {'perturbing_action': 'I-gene gain-of-function'}", + "97, VEGF, {'perturbing_action': 'I-gene gain-of-function'}", + "113, tumor {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "58, mouse ['l0', 'l1', 'l2']", + "59, tumor ['l0', 'l3', 'l4']", + "60, model. ['l1', 'l3', 'l5']", + "77, tumors. ['l2', 'l4', 'l5']", + "79, expression ['l6', 'l7', 'l8', 'l9', 'l10']", + "80, of ['l6', 'l11', 'l12', 'l13', 'l14']", + "81, VEGF-D ['l7', 'l11', 'l15', 'l16', 'l17']", + "83, tumor ['l8', 'l12', 'l15', 'l18', 'l19']", + "84, cells ['l9', 'l13', 'l16', 'l18', 'l20']", + "90, tumor ['l10', 'l14', 'l17', 'l19', 'l20']", + "95, expression ['l21', 'l22', 'l23']", + "96, of ['l21', 'l24', 'l25']", + "97, VEGF, ['l22', 'l24', 'l26']", + "113, tumor ['l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "VEGF-D" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "VEGF-D", + "VEGF," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + } + ] + }, + { + "PMID": "11135618", + "TEXT": "HIV-1 use CD4 receptors to infect their primary targets, CD4+ cells, whereas CD8+ cells have a protective role against HIV-1. We recently isolated HIV-1-producing CD8+ clones from two AIDS patients. Here we show that although HIV-1 produced by CD8+ cells maintained the ability to infect CD4+ cells, these viruses were able to infect CD8+ cells independent of CD4. Evidence indicates that these viruses used CD8 as a receptor to infect CD8+ cells. First, expression of CD8 was downmodulated after infection. Second, anti-CD8 antibodies blocked viral entry and replication in CD8+ cells. Finally, resistant cells became susceptible after expression of CD8. Although these viruses used CXCR4 to enter CD4+ cells, it seems that infection of CD8+ cells was independent of CXCR4 or CCR5 co-receptors. Novel changes were observed in envelope sequences of CD8-tropic viruses. These results provide initial evidence that HIV-1 can mutate to infect CD8+ cells using CD8 as a receptor.", + "TAG_DATA": [ + "45, CD4+ {'context': 'B-cells'}", + "46, cells, {'context': 'I-cells'}", + "53, CD8+ {'context': 'B-cells'}", + "54, cells {'context': 'I-cells'}", + "89, CD8+ {'context': 'B-cells'}", + "90, cells. {'context': 'I-cells'}", + "92, resistant {'context': 'B-cells'}", + "93, cells {'context': 'B-cells'}", + "107, CD4+ {'context': 'B-cells'}", + "108, cells, {'context': 'I-cells'}", + "114, CD8+ {'context': 'B-cells'}", + "115, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, CD4+ ['l0', 'l1', 'l2', 'l3', 'l4']", + "46, cells, ['l0', 'l5']", + "53, CD8+ ['l1', 'l6', 'l7', 'l8']", + "54, cells ['l2', 'l6', 'l9', 'l10']", + "89, CD8+ ['l3', 'l7', 'l9', 'l11']", + "90, cells. ['l4', 'l5', 'l8', 'l10', 'l11']", + "92, resistant ['l12']", + "93, cells ['l12']", + "107, CD4+ ['l13', 'l14', 'l15']", + "108, cells, ['l13', 'l16', 'l17']", + "114, CD8+ ['l14', 'l16', 'l18']", + "115, cells ['l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11135625", + "TEXT": "Interleukin (IL)-2 and IL-15 are redundant in stimulating T-cell proliferation in vitro. Their precise role in vivo in governing T-cell expansion and T-cell homeostasis is less clear. Each may have distinct functions and regulate distinct aspects of T-cell activation. The functional receptors for IL-2 and IL-15 consist of a private alpha-chain, which defines the binding specificity for IL-2 or IL-15, and shared IL-2 receptor beta- and gamma-chains. The gamma-chain is also a critical signaling component of IL-4, IL-7 and IL-9 receptors. Thus, the gamma-chain is called the common gamma or gamma-c. As these receptor subunits can be expressed individually or in various combinations resulting in the formation of receptors with different affinities, distinct signaling capabilities or both, we hypothesized that differential expression of IL-2 and IL-15 receptor subunits on cycling T cells in vivo may direct activated T cells to respond to IL-2 or IL-15, thereby regulating the homeostasis of T-cell response in vivo. By observing in vivo T-cell divisions and expression of IL-2 and IL-15 receptor subunits, we demonstrate that IL-15 is a critical growth factor in initiating T cell divisions in vivo, whereas IL-2 limits continued T-cell expansion via downregulation of the gamma-c expression. Decreased gamma-c expression on cycling T cells reduced sustained Bcl-2 expression and rendered cells susceptible to apoptotic cell death. Our study provides data that IL-2 and IL-15 regulate distinct aspects of primary T-cell expansion in vivo.", + "TAG_DATA": [ + "156, in {'context': 'B-in vivo'}", + "157, vivo {'context': 'I-in vivo'}", + "182, in {'context': 'B-in vivo'}", + "183, vivo, {'context': 'I-in vivo'}", + "188, T-cell {'context': 'B-cells'}", + "200, cycling {'context': 'B-cells'}", + "201, T {'context': 'I-cells'}", + "202, cells {'context': 'I-cells'}", + "209, cells {'context': 'B-cells'}", + "210, susceptible {'effect': 'B-negative'}", + "212, apoptotic {'phenotype': 'B-apoptosis'}", + "213, cell {'phenotype': 'I-apoptosis'}", + "214, death. {'phenotype': 'I-apoptosis'}" + ], + "LINK_DATA": [ + "156, in ['l0']", + "157, vivo ['l0']", + "182, in ['l1']", + "183, vivo, ['l1']", + "188, T-cell ['l2']", + "200, cycling ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "201, T ['l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "202, cells ['l2', 'l4', 'l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "209, cells ['l5', 'l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "210, susceptible ['l6', 'l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "212, apoptotic ['l7', 'l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "213, cell ['l8', 'l14', 'l19', 'l23', 'l26', 'l28', 'l30']", + "214, death. ['l9', 'l15', 'l20', 'l24', 'l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cycling", + "T", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "susceptible" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cycling", + "T", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "susceptible" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "11135622", + "TEXT": "Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various tumor cells in vitro, but its physiological role in tumor surveillance remains unknown. Here, we report that TRAIL is constitutively expressed on murine natural killer (NK) cells in the liver and plays a substantial role in suppressing tumor metastasis. Freshly isolated NK cells, but not natural killer T cells or ordinary T cells, from the liver expressed cell surface TRAIL, which was responsible for spontaneous cytotoxicity against TRAIL-sensitive tumor cells in vitro along with perforin and Fas ligand (FasL). Administration of neutralizing monoclonal antibody against TRAIL significantly increased experimental liver metastases of several TRAIL-sensitive tumor cell lines. Such an anti-metastatic effect of TRAIL was not observed in NK cell-depleted mice or interferon-gamma-deficient mice, the latter of which lacked TRAIL on liver NK cells. These findings provide the first evidence for the physiological function of TRAIL as a tumor suppressor.", + "TAG_DATA": [ + "51, NK {'context': 'B-cells'}", + "52, cells, {'context': 'I-cells'}", + "78, tumor {'context': 'I-transformed cells'}", + "79, cells {'context': 'I-transformed cells'}", + "80, in {'context': 'B-in vitro'}", + "81, vitro {'context': 'I-in vitro'}", + "97, increased {'effect': 'B-positive'}", + "99, liver {'phenotype': 'B-metastasis'}", + "100, metastases {'phenotype': 'I-metastasis'}", + "103, TRAIL-sensitive {'context': 'B-transformed cells'}", + "104, tumor {'context': 'I-transformed cells'}", + "105, cell {'context': 'I-transformed cells'}", + "106, lines. {'context': 'I-transformed cells'}", + "119, mice {'context': 'B-organism'}", + "121, interferon-gamma-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "122, mice, {'context': 'B-organism'}", + "130, liver {'context': 'B-cells'}", + "131, NK {'context': 'I-cells'}", + "132, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "51, NK ['l0', 'l1', 'l2', 'l3', 'l4']", + "52, cells, ['l0', 'l5', 'l6', 'l7', 'l8']", + "78, tumor ['l1', 'l5', 'l9', 'l10', 'l11']", + "79, cells ['l2', 'l6', 'l9', 'l12', 'l13']", + "80, in ['l3', 'l7', 'l10', 'l12', 'l14']", + "81, vitro ['l4', 'l8', 'l11', 'l13', 'l14']", + "97, increased ['l15', 'l16', 'l17', 'l18', 'l19']", + "99, liver ['l15', 'l20', 'l21', 'l22', 'l23', 'l24']", + "100, metastases ['l16', 'l20', 'l25', 'l26', 'l27', 'l28']", + "103, TRAIL-sensitive ['l21', 'l25', 'l29', 'l30', 'l31']", + "104, tumor ['l17', 'l22', 'l26', 'l29', 'l32', 'l33']", + "105, cell ['l18', 'l23', 'l27', 'l30', 'l32', 'l34']", + "106, lines. ['l19', 'l24', 'l28', 'l31', 'l33', 'l34']", + "119, mice ['l35', 'l36', 'l37', 'l38', 'l39']", + "121, interferon-gamma-deficient ['l35', 'l40', 'l41', 'l42', 'l43']", + "122, mice, ['l36', 'l40', 'l44', 'l45', 'l46']", + "130, liver ['l37', 'l41', 'l44', 'l47', 'l48']", + "131, NK ['l38', 'l42', 'l45', 'l47', 'l49']", + "132, cells. ['l39', 'l43', 'l46', 'l48', 'l49']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "liver", + "metastases" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell", + "lines." + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "liver", + "metastases" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TRAIL-sensitive", + "tumor", + "cell", + "lines." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interferon-gamma-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interferon-gamma-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "liver", + "NK", + "cells." + ] + } + } + ] + }, + { + "PMID": "11135619", + "TEXT": "We hypothesized that HIV-1-mediated T-cell loss might induce the production of factors that are capable of stimulating lymphocyte development and expansion. Here we perform cross-sectional (n = 168) and longitudinal (n = 11) analyses showing that increased circulating levels of interleukin (IL)-7 are strongly associated with CD4+ T lymphopenia in HIV-1 disease. Using immunohistochemistry with quantitative image analysis, we demonstrate that IL-7 is produced by dendritic-like cells within peripheral lymphoid tissues and that IL-7 production by these cells is greatly increased in lymphocyte-depleted tissues. We propose that IL-7 production increases as part of a homeostatic response to T-cell depletion.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11135607", + "TEXT": "Studies on mice lacking the peroxisome proliferator-activated receptor (PPAR) suggest that PPAR ligands reduce lipid accumulation in foamy macrophages, and may target other receptors. These findings warrant an in-depth investigation into the gene regulatory mechanisms of PPAR ligands, which are currently being developed as drugs to treat atherosclerosis and diabetes.", + "TAG_DATA": [ + "2, mice {'context': 'B-organism'}", + "3, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "4, the {'perturbing_action': 'I-gene loss-of-function'}", + "5, peroxisome {'perturbing_action': 'I-gene loss-of-function'}", + "6, proliferator-activated {'perturbing_action': 'I-gene loss-of-function'}", + "7, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "8, (PPAR) {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "2, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "3, lacking ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "4, the ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "5, peroxisome ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "6, proliferator-activated ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "7, receptor ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "8, (PPAR) ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "peroxisome", + "proliferator-activated", + "receptor", + "(PPAR)" + ] + } + } + ] + }, + { + "PMID": "11100128", + "TEXT": "Transcutaneous immunization, a topical vaccine application, combines the advantages of needle-free delivery while targeting the immunologically rich milieu of the skin. In animal studies, this simple technique induces robust systemic and mucosal antibodies against vaccine antigens. Here, we demonstrate safe application of a patch containing heat-labile enterotoxin (LT, derived from Escherichia coli) to humans, resulting in robust LT-antibody responses. These findings indicate that TCI is feasible for human immunization, and suggest that TCI may enhance efficacy as well as improve vaccine delivery.", + "TAG_DATA": [ + "53, humans, {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11100125", + "TEXT": "Progress toward elucidating the function of alpha1B-adrenergic receptors (alpha1BARs) in the central nervous system has been constrained by a lack of agonists and antagonists with adequate alpha1B-specificity. We have obviated this constraint by generating transgenic mice engineered to overexpress either wild-type or constitutively active alpha1BARs in tissues that normally express the receptor, including the brain. All transgenic lines showed granulovacular neurodegeneration, beginning in alpha1B-expressing domains of the brain and progressing with age to encompass all areas. The degeneration was apoptotic and did not occur in non-transgenic mice. Correspondingly, transgenic mice showed an age-progressive hindlimb disorder that was parkinsonian-like, as demonstrated by rescue of the dysfunction by 3, 4-dihydroxyphenylalanine and considerable dopaminergic-neuronal degeneration in the substantia nigra. Transgenic mice also had a grand mal seizure disorder accompanied by a corresponding dysplasia and neurodegeneration of the cerebral cortex. Both behavioral phenotypes (locomotor impairment and seizure) could be partially rescued with the alpha1AR antagonist terazosin, indicating that alpha1AR signaling participated directly in the pathology. Our results indicate that overstimulation of alpha1BAR leads to apoptotic neurodegeneration with a corresponding multiple system atrophy indicative of Shy-Drager syndrome, a disease whose etiology is unknown.", + "TAG_DATA": [ + "35, mice {'context': 'I-organism'}", + "86, mice. {'context': 'I-organism'}", + "89, mice {'context': 'B-organism'}", + "114, substantia {'context': 'B-tissue/organ'}", + "115, nigra. {'context': 'I-cells'}", + "116, Transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "117, mice {'context': 'I-organism'}", + "134, cerebral {'context': 'B-tissue/organ'}", + "135, cortex. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "35, mice ['l0']", + "86, mice. ['l0']", + "89, mice ['l1', 'l2']", + "114, substantia ['l1', 'l3']", + "115, nigra. ['l2', 'l3']", + "116, Transgenic ['l4', 'l5', 'l6']", + "117, mice ['l4', 'l7', 'l8']", + "134, cerebral ['l5', 'l7', 'l9']", + "135, cortex. ['l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgenic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "cerebral", + "cortex." + ] + } + } + ] + }, + { + "PMID": "11100124", + "TEXT": "Neurological disorders develop in most people infected with human immunodeficiency virus type 1 (HIV-1). However, the underlying mechanisms remain largely unknown. Here we report that binding of HIV-1 transactivator (Tat) protein to low-density lipoprotein receptor-related protein (LRP) promoted efficient uptake of Tat into neurons. LRP-mediated uptake of Tat was followed by translocation to the neuronal nucleus. Furthermore, the binding of Tat to LRP resulted in substantial inhibition of neuronal binding, uptake and degradation of physiological ligands for LRP, including alpha2-macroglobulin, apolipoprotein E4, amyloid precursor protein and amyloid beta-protein. In a model of macaques infected with a chimeric strain of simian-human immunodeficiency virus, increased staining of amyloid precursor protein was associated with Tat expression in the brains of simian-human immunodeficiency virus-infected macaques with encephalitis. These results indicate that HIV-1 Tat may mediate HIV-1-induced neuropathology through a pathway involving disruption of the metabolic balance of LRP ligands and direct activation of neuronal genes.", + "TAG_DATA": [ + "43, neurons. {'context': 'B-cells'}", + "92, macaques {'context': 'B-organism'}", + "115, brains {'context': 'B-tissue/organ'}", + "120, macaques {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "115, brains ['l0']", + "120, macaques ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11100120", + "TEXT": "Activation of the zinc-finger transcription factor early growth response (Egr)-1, initially linked to developmental processes, is shown here to function as a master switch activated by ischemia to trigger expression of pivotal regulators of inflammation, coagulation and vascular hyperpermeability. Chemokine, adhesion receptor, procoagulant and permeability-related genes are coordinately upregulated by rapid ischemia-mediated activation of Egr-1. Deletion of the gene encoding Egr-1 strikingly diminished expression of these mediators of vascular injury in a murine model of lung ischemia/reperfusion, and enhanced animal survival and organ function. Rapid activation of Egr-1 in response to oxygen deprivation primes the vasculature for dysfunction manifest during reperfusion. These studies define a central and unifying role for Egr-1 activation in the pathogenesis of ischemic tissue damage.", + "TAG_DATA": [ + "55, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "56, of {'perturbing_action': 'I-gene loss-of-function'}", + "57, the {'perturbing_action': 'I-gene loss-of-function'}", + "58, gene {'perturbing_action': 'I-gene loss-of-function'}", + "59, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "60, Egr-1 {'perturbing_action': 'I-gene loss-of-function'}", + "72, murine {'context': 'B-organism'}", + "73, model {'context': 'I-organism'}", + "75, lung {'context': 'I-tissue/organ'}", + "95, vasculature {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "55, Deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "56, of ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "57, the ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "58, gene ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "59, encoding ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "60, Egr-1 ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "72, murine ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "73, model ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "75, lung ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "gene", + "encoding", + "Egr-1" + ] + }, + "context": { + "val": "organism", + "words": [ + "murine", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "gene", + "encoding", + "Egr-1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + } + ] + }, + { + "PMID": "11062538", + "TEXT": "In humans, sterile immunity against malaria can be consistently induced through exposure to the bites of thousands of irradiated infected mosquitoes. The same level of protection has yet to be achieved using subunit vaccines. Recent studies have indicated an essential function for intrahepatic parasites, the stage after the mosquito bite, and thus for antigens expressed during this stage. We report here the identification of liver-stage antigen 3, which is expressed both in the mosquito and liver-stage parasites. This Plasmodium falciparum 200-kilodalton protein is highly conserved, and showed promising antigenic and immunogenic properties. In chimpanzees (Pan troglodytes), the primates most closely related to humans and that share a similar susceptibility to P. falciparum liver-stage infection, immunization with LSA-3 induced protection against successive heterologous challenges with large numbers of P. falciparum sporozoites.", + "TAG_DATA": [ + "93, chimpanzees {'context': 'B-organism'}", + "94, (Pan {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "93, chimpanzees ['l0', 'l1']", + "94, (Pan ['l0', 'l2']", + "95, troglodytes), ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11062542", + "TEXT": "Hematopoietic stem cells give rise to progeny that either self-renew in an undifferentiated state or lose self-renewal capabilities and commit to lymphoid or myeloid lineages. Here we evaluated whether hematopoietic stem cell self-renewal is affected by the Notch pathway. Notch signaling controls cell fate choices in both invertebrates and vertebrates by inhibiting certain differentiation pathways, thereby permitting cells to either differentiate along an alternative pathway or to self-renew. Notch receptors are present in hematopoietic precursors and Notch signaling enhances the in vitro generation of human and mouse hematopoietic precursors, determines T- or B-cell lineage specification from a common lymphoid precursor and promotes expansion of CD8(+) cells. Here, we demonstrate that constitutive Notch1 signaling in hematopoietic cells established immortalized, cytokine-dependent cell lines that generated progeny with either lymphoid or myeloid characteristics both in vitro and in vivo. These data support a role for Notch signaling in regulating hematopoietic stem cell self-renewal. Furthermore, the establishment of clonal, pluripotent cell lines provides the opportunity to assess mechanisms regulating stem cell commitment and demonstrates a general method for immortalizing stem cell populations for further analysis.", + "TAG_DATA": [ + "104, CD8(+) {'context': 'B-cells'}", + "110, constitutive {'perturbing_action': 'B-gene gain-of-function'}", + "111, Notch1 {'perturbing_action': 'I-gene gain-of-function'}", + "112, signaling {'perturbing_action': 'I-gene gain-of-function'}", + "114, hematopoietic {'context': 'B-cells'}", + "115, cells {'context': 'I-cells'}", + "119, cell {'context': 'B-cells'}", + "120, lines {'context': 'I-cells'}", + "131, in {'context': 'B-in vitro'}", + "132, vitro {'context': 'I-in vitro'}", + "134, in {'context': 'B-in vivo'}", + "135, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "104, CD8(+) ['l0', 'l1', 'l2', 'l3']", + "110, constitutive ['l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "111, Notch1 ['l0', 'l4', 'l10', 'l11', 'l12', 'l13', 'l14']", + "112, signaling ['l1', 'l5', 'l10', 'l15', 'l16', 'l17', 'l18']", + "114, hematopoietic ['l2', 'l6', 'l11', 'l15', 'l19', 'l20', 'l21']", + "115, cells ['l3', 'l7', 'l12', 'l16', 'l19', 'l22', 'l23']", + "119, cell ['l8', 'l13', 'l17', 'l20', 'l22', 'l24', 'l25']", + "120, lines ['l9', 'l14', 'l18', 'l21', 'l23', 'l24']", + "131, in ['l26', 'l27', 'l28']", + "132, vitro ['l25', 'l26', 'l29', 'l30']", + "134, in ['l27', 'l29', 'l31']", + "135, vivo. ['l28', 'l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "hematopoietic", + "cells", + "cell", + "lines" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Notch1", + "signaling", + "constitutive" + ] + } + } + ] + }, + { + "PMID": "11062535", + "TEXT": "Dysregulation of apoptosis contributes to the pathogenesis of many human diseases. As effectors of the apoptotic machinery, caspases are considered potential therapeutic targets. Using an established in vivo model of Fas-mediated apoptosis, we demonstrate here that elimination of certain caspases was compensated in vivo by the activation of other caspases. Hepatocyte apoptosis and mouse death induced by the Fas agonistic antibody Jo2 required proapoptotic Bcl-2 family member Bid and used a Bid-mediated mitochondrial pathway of caspase activation; deficiency in caspases essential for this pathway, caspase-9 or caspase-3, unexpectedly resulted in rapid activation of alternate caspases after injection of Jo2, and therefore failed to protect mice against Jo2 toxicity. Moreover, both ultraviolet and gamma irradiation, two established inducers of the mitochondrial caspase-activation pathway, also elicited compensatory activation of caspases in cultured caspase-3(-/-) hepatocytes, indicating that the compensatory caspase activation was mediated through the mitochondria. Our findings provide direct experimental evidence for compensatory pathways of caspase activation. This issue should therefore be considered in developing caspase inhibitors for therapeutic applications.", + "TAG_DATA": [ + "42, in {'context': 'B-in vivo'}", + "43, vivo {'context': 'I-in vivo'}", + "50, Hepatocyte {'context': 'B-cells'}", + "51, apoptosis {'phenotype': 'B-apoptosis'}", + "53, mouse {'context': 'B-organism', 'phenotype': 'B-cell death'}", + "54, death {'phenotype': 'I-cell death'}", + "55, induced {'effect': 'B-positive'}", + "104, mice {'context': 'B-organism'}", + "130, caspase-3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "131, hepatocytes, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "42, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "43, vivo ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "50, Hepatocyte ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "51, apoptosis ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "53, mouse ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "54, death ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "55, induced ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "130, caspase-3(-/-) ['l21']", + "131, hepatocytes, ['l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "mouse", + "death" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "mouse" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Hepatocyte" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Hepatocyte" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "mouse", + "death" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Hepatocyte" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "mouse", + "death" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "caspase-3(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes," + ] + } + } + ] + }, + { + "PMID": "11062534", + "TEXT": "Sustained blood cell production requires preservation of a quiescent, multipotential stem cell pool that intermittently gives rise to progenitors with robust proliferative potential. The ability of cells to shift from a highly constrained to a vigorously active proliferative state is critical for maintaining stem cells while providing the responsiveness necessary for host defense. The cyclin-dependent kinase inhibitor (CDKI), p21(cip1/waf1) (p21) dominates stem cell kinetics. Here we report that another CDKI, p27(kip1) (p27), does not affect stem cell number, cell cycling, or self-renewal, but markedly alters progenitor proliferation and pool size. Therefore, distinct CDKIs govern the highly divergent stem and progenitor cell populations. When competitively transplanted, p27-deficient stem cells generate progenitors that eventually dominate blood cell production. Modulating p27 expression in a small number of stem cells may translate into effects on the majority of mature cells, thereby providing a strategy for potentiating the impact of transduced cells in stem cell gene therapy.", + "TAG_DATA": [ + "73, not {'effect': 'I-no effect'}", + "75, stem {'context': 'B-cells'}", + "76, cell {'context': 'I-cells'}", + "81, self-renewal, {'phenotype': 'B-self-renewal'}", + "84, alters {'effect': 'B-regulates'}", + "86, proliferation {'phenotype': 'B-proliferation'}", + "105, p27-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "106, stem {'context': 'B-cells'}", + "107, cells {'context': 'I-cells'}", + "113, blood {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "73, not ['l0', 'l1', 'l2']", + "75, stem ['l0', 'l3', 'l4']", + "76, cell ['l1', 'l3', 'l5']", + "81, self-renewal, ['l2', 'l4', 'l5']", + "84, alters ['l6']", + "86, proliferation ['l6']", + "105, p27-deficient ['l7', 'l8', 'l9']", + "106, stem ['l7', 'l10', 'l11']", + "107, cells ['l8', 'l10', 'l12']", + "113, blood ['l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "no effect", + "words": [ + "not" + ] + }, + "context": { + "val": "cells", + "words": [ + "stem", + "cell" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "stem", + "cell" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal," + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "alters" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p27-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "stem", + "cells", + "blood" + ] + } + } + ] + }, + { + "PMID": "11017150", + "TEXT": "Myelin-specific T lymphocytes are considered essential in the pathogenesis of multiple sclerosis. The myelin basic protein peptide (a.a. 83-99) represents one candidate antigen; therefore, it was chosen to design an altered peptide ligand, CGP77116, for specific immunotherapy of multiple sclerosis. A magnetic resonance imaging-controlled phase II clinical trial with this altered peptide ligand documented that it was poorly tolerated at the dose tested, and the trial had therefore to be halted. Improvement or worsening of clinical or magnetic resonance imaging parameters could not be demonstrated in this small group of individuals because of the short treatment duration. Three patients developed exacerbations of multiple sclerosis, and in two this could be linked to altered peptide ligand treatment by immunological studies demonstrating the encephalitogenic potential of the myelin basic protein peptide (a.a. 83-99) in a subgroup of patients. These data raise important considerations for the use of specific immunotherapies in general.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11017148", + "TEXT": "We have investigated whether dendritic cells genetically modified to express CD40 ligand and pulsed with antigen can trigger B cells to produce antigen-specific antibodies without CD4+ T-cell help. Dendritic cells modified with a recombinant adenovirus vector to express CD40 ligand and pulsed with heat-killed Pseudomonas induced naive B cells to produce antibodies against Pseudomonas in the absence of CD4+ T cells in vitro, initiated Pseudomonas-specific humoral immune responses in vivo in wild-type and CD4-/- mice, and protected immunized wild-type and CD4-/-, but not B-cell -/- mice, from lethal intrapulmonary challenge with Pseudomonas. Thus, genetic modification of dendritic cells with CD40 ligand enables them to present a complex mixture of microbial antigens and establish CD4+ T cell-independent, B cell-mediated protective immunity against a specific microbe.", + "TAG_DATA": [ + "28, Dendritic {'context': 'B-cells'}", + "29, cells {'context': 'I-cells'}", + "46, naive {'context': 'B-cells'}", + "47, B {'context': 'I-cells'}", + "48, cells {'context': 'I-cells'}", + "58, CD4+ {'context': 'B-cells'}", + "59, T {'context': 'I-cells'}", + "60, cells {'context': 'I-cells'}", + "61, in {'context': 'B-in vitro'}", + "62, vitro, {'context': 'I-in vitro'}", + "68, in {'context': 'B-in vivo'}", + "69, vivo {'context': 'I-in vivo'}", + "73, CD4-/- {'perturbing_action': 'B-gene loss-of-function'}", + "74, mice, {'context': 'B-organism'}", + "80, CD4-/-, {'perturbing_action': 'B-gene loss-of-function'}", + "83, B-cell {'perturbing_action': 'B-gene loss-of-function'}", + "84, -/- {'perturbing_action': 'B-gene loss-of-function'}", + "85, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "28, Dendritic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "29, cells ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "46, naive ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "47, B ['l2', 'l14', 'l25', 'l32', 'l33', 'l34', 'l35']", + "48, cells ['l3', 'l15', 'l26', 'l32', 'l36', 'l37', 'l38']", + "58, CD4+ ['l4', 'l16', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "59, T ['l5', 'l17', 'l28', 'l33', 'l36', 'l39', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "60, cells ['l6', 'l18', 'l29', 'l34', 'l37', 'l40', 'l47', 'l53', 'l54', 'l55', 'l56']", + "61, in ['l7', 'l19', 'l30', 'l41', 'l48', 'l53', 'l57', 'l58', 'l59']", + "62, vitro, ['l8', 'l20', 'l31', 'l35', 'l38', 'l42', 'l49', 'l54', 'l57']", + "68, in ['l9', 'l21', 'l43', 'l50', 'l55', 'l58', 'l60', 'l61', 'l62']", + "69, vivo ['l10', 'l22', 'l44', 'l51', 'l56', 'l59', 'l60', 'l63', 'l64']", + "73, CD4-/- ['l11', 'l23', 'l45', 'l61', 'l63', 'l65']", + "74, mice, ['l12', 'l24', 'l46', 'l52', 'l62', 'l64', 'l65']", + "80, CD4-/-, ['l66', 'l67', 'l68']", + "83, B-cell ['l66', 'l69', 'l70']", + "84, -/- ['l67', 'l69', 'l71']", + "85, mice, ['l68', 'l70', 'l71']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Dendritic", + "cells", + "CD4+" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD4-/-" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD4-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD4-/-", + "CD4-/-,", + "B-cell", + "-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "10973324", + "TEXT": "Understanding the basis of chemoresistance is a principal goal of molecular oncology. We have exploited a murine lymphoma model and retroviral gene transfer to rapidly generate a series of spontaneous tumors differing only in a gene of interest, and subsequently studied the impact of the test gene on the treatment sensitivity of tumors at their natural site. We demonstrate that the Bcl-2 oncoprotein produces multi-drug resistance when assessed in primary lymphomas in vivo. In contrast, this effect was dramatically reduced when the primary lymphomas were subjected to long-term culture, and completely missed in the standard clonogenic survival assay. This model highlights the importance of physiological test systems to address the complexity of clinical drug resistance and provides a novel strategy to evaluate compounds targeting specific genetic lesions.", + "TAG_DATA": [ + "69, primary {'context': 'B-neoplasm'}", + "70, lymphomas {'context': 'I-neoplasm'}", + "71, in {'context': 'B-in vivo'}", + "72, vivo. {'context': 'I-in vivo'}", + "82, primary {'context': 'B-neoplasm'}", + "83, lymphomas {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "69, primary ['l0', 'l1', 'l2']", + "70, lymphomas ['l0', 'l3', 'l4']", + "71, in ['l1', 'l3', 'l5']", + "72, vivo. ['l2', 'l4', 'l5']", + "82, primary ['l6']", + "83, lymphomas ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10973316", + "TEXT": "Bone formation by osteoblasts is essential for skeletal growth and remodeling. Fra-1 is a c-Fos-related protein belonging to the AP-1 family of transcription factors. Here we show that transgenic mice overexpressing Fra-1 in various organs develop a progressive increase in bone mass leading to osteosclerosis of the entire skeleton, which is due to a cell-autonomous increase in the number of mature osteoblasts. Moreover, osteoblast differentiation, but not proliferation, was enhanced and osteoclastogenesis was also elevated in vitro. These data indicate that, unlike c-Fos, which causes osteosarcomas, Fra-1 specifically enhances bone formation, which may be exploited to stimulate bone formation in pathological conditions.", + "TAG_DATA": [ + "28, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "29, mice {'context': 'I-organism'}", + "30, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "31, Fra-1 {'perturbing_action': 'I-gene gain-of-function'}", + "48, skeleton, {'context': 'B-tissue/organ'}", + "63, osteoblast {'context': 'B-cells'}", + "64, differentiation, {'phenotype': 'B-differentiation'}", + "67, proliferation, {'phenotype': 'B-proliferation'}", + "69, enhanced {'effect': 'B-positive'}", + "75, in {'context': 'B-in vitro'}", + "76, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "28, transgenic ['l0', 'l1', 'l2', 'l3', 'l4']", + "29, mice ['l0', 'l5', 'l6', 'l7']", + "30, overexpressing ['l1', 'l5', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "31, Fra-1 ['l2', 'l6', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "48, skeleton, ['l3', 'l7', 'l9', 'l14']", + "63, osteoblast ['l10', 'l15', 'l19', 'l20', 'l21']", + "64, differentiation, ['l4', 'l11', 'l16', 'l19', 'l22', 'l23']", + "67, proliferation, ['l12', 'l17', 'l20', 'l22', 'l24']", + "69, enhanced ['l13', 'l18', 'l21', 'l23', 'l24']", + "75, in ['l25']", + "76, vitro. ['l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "overexpressing", + "Fra-1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "overexpressing", + "Fra-1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skeleton," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "overexpressing", + "Fra-1" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "Fra-1" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoblast" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "Fra-1" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "Fra-1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoblast" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoblast" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoblast" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + } + ] + }, + { + "PMID": "10932230", + "TEXT": "One hallmark of Alzheimer disease is the accumulation of amyloid beta-peptide in the brain and its deposition as plaques. Mice transgenic for an amyloid beta precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter (PDAPP mice), which overexpress one of the disease-linked mutant forms of the human amyloid precursor protein, show many of the pathological features of Alzheimer disease, including extensive deposition of extracellular amyloid plaques, astrocytosis and neuritic dystrophy. Active immunization of PDAPP mice with human amyloid beta-peptide reduces plaque burden and its associated pathologies. Several hypotheses have been proposed regarding the mechanism of this response. Here we report that peripheral administration of antibodies against amyloid beta-peptide, was sufficient to reduce amyloid burden. Despite their relatively modest serum levels, the passively administered antibodies were able to enter the central nervous system, decorate plaques and induce clearance of preexisting amyloid. When examined in an ex vivo assay with sections of PDAPP or Alzheimer disease brain tissue, antibodies against amyloid beta-peptide triggered microglial cells to clear plaques through Fc receptor-mediated phagocytosis and subsequent peptide degradation. These results indicate that antibodies can cross the blood-brain barrier to act directly in the central nervous system and should be considered as a therapeutic approach for the treatment of Alzheimer disease and other neurological disorders.", + "TAG_DATA": [ + "19, Mice {'context': 'B-organism'}", + "20, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "21, for {'perturbing_action': 'I-gene gain-of-function'}", + "22, an {'perturbing_action': 'I-gene gain-of-function'}", + "23, amyloid {'perturbing_action': 'I-gene gain-of-function'}", + "24, beta {'perturbing_action': 'I-gene gain-of-function'}", + "25, precursor {'perturbing_action': 'I-gene gain-of-function'}", + "26, protein {'perturbing_action': 'I-gene gain-of-function'}", + "27, (APP) {'perturbing_action': 'I-gene gain-of-function'}", + "28, mini-gene {'perturbing_action': 'I-gene gain-of-function'}", + "29, driven {'perturbing_action': 'I-gene gain-of-function'}", + "30, by {'perturbing_action': 'I-gene gain-of-function'}", + "31, a {'perturbing_action': 'I-gene gain-of-function'}", + "32, platelet-derived {'perturbing_action': 'I-gene gain-of-function'}", + "33, (PD) {'perturbing_action': 'I-gene gain-of-function'}", + "34, growth {'perturbing_action': 'I-gene gain-of-function'}", + "35, factor {'perturbing_action': 'I-gene gain-of-function'}", + "36, promoter {'perturbing_action': 'I-gene gain-of-function'}", + "37, (PDAPP {'perturbing_action': 'I-gene gain-of-function'}", + "38, mice), {'perturbing_action': 'I-gene gain-of-function'}", + "40, overexpress {'perturbing_action': 'I-gene gain-of-function'}", + "41, one {'perturbing_action': 'I-gene gain-of-function'}", + "45, mutant {'perturbing_action': 'I-gene gain-of-function'}", + "46, forms {'perturbing_action': 'I-gene gain-of-function'}", + "47, of {'perturbing_action': 'I-gene gain-of-function'}", + "48, the {'perturbing_action': 'I-gene gain-of-function'}", + "76, PDAPP {'context': 'B-organism'}", + "77, mice {'context': 'I-organism'}", + "164, microglial {'context': 'B-cells'}", + "165, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "19, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "20, transgenic ['l0', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "21, for ['l1', 'l27', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "22, an ['l2', 'l28', 'l53', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "23, amyloid ['l3', 'l29', 'l54', 'l78', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "24, beta ['l4', 'l30', 'l55', 'l79', 'l102', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146']", + "25, precursor ['l5', 'l31', 'l56', 'l80', 'l103', 'l125', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "26, protein ['l6', 'l32', 'l57', 'l81', 'l104', 'l126', 'l147', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "27, (APP) ['l7', 'l33', 'l58', 'l82', 'l105', 'l127', 'l148', 'l168', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206']", + "28, mini-gene ['l8', 'l34', 'l59', 'l83', 'l106', 'l128', 'l149', 'l169', 'l188', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224']", + "29, driven ['l9', 'l35', 'l60', 'l84', 'l107', 'l129', 'l150', 'l170', 'l189', 'l207', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241']", + "30, by ['l10', 'l36', 'l61', 'l85', 'l108', 'l130', 'l151', 'l171', 'l190', 'l208', 'l225', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257']", + "31, a ['l11', 'l37', 'l62', 'l86', 'l109', 'l131', 'l152', 'l172', 'l191', 'l209', 'l226', 'l242', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272']", + "32, platelet-derived ['l12', 'l38', 'l63', 'l87', 'l110', 'l132', 'l153', 'l173', 'l192', 'l210', 'l227', 'l243', 'l258', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286']", + "33, (PD) ['l13', 'l39', 'l64', 'l88', 'l111', 'l133', 'l154', 'l174', 'l193', 'l211', 'l228', 'l244', 'l259', 'l273', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298', 'l299']", + "34, growth ['l14', 'l40', 'l65', 'l89', 'l112', 'l134', 'l155', 'l175', 'l194', 'l212', 'l229', 'l245', 'l260', 'l274', 'l287', 'l300', 'l301', 'l302', 'l303', 'l304', 'l305', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311']", + "35, factor ['l15', 'l41', 'l66', 'l90', 'l113', 'l135', 'l156', 'l176', 'l195', 'l213', 'l230', 'l246', 'l261', 'l275', 'l288', 'l300', 'l312', 'l313', 'l314', 'l315', 'l316', 'l317', 'l318', 'l319', 'l320', 'l321', 'l322']", + "36, promoter ['l16', 'l42', 'l67', 'l91', 'l114', 'l136', 'l157', 'l177', 'l196', 'l214', 'l231', 'l247', 'l262', 'l276', 'l289', 'l301', 'l312', 'l323', 'l324', 'l325', 'l326', 'l327', 'l328', 'l329', 'l330', 'l331', 'l332']", + "37, (PDAPP ['l17', 'l43', 'l68', 'l92', 'l115', 'l137', 'l158', 'l178', 'l197', 'l215', 'l232', 'l248', 'l263', 'l277', 'l290', 'l302', 'l313', 'l323', 'l333', 'l334', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340', 'l341']", + "38, mice), ['l18', 'l44', 'l69', 'l93', 'l116', 'l138', 'l159', 'l179', 'l198', 'l216', 'l233', 'l249', 'l264', 'l278', 'l291', 'l303', 'l314', 'l324', 'l333', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348', 'l349']", + "40, overexpress ['l19', 'l45', 'l70', 'l94', 'l117', 'l139', 'l160', 'l180', 'l199', 'l217', 'l234', 'l250', 'l265', 'l279', 'l292', 'l304', 'l315', 'l325', 'l334', 'l342', 'l350', 'l351', 'l352', 'l353', 'l354', 'l355', 'l356']", + "41, one ['l20', 'l46', 'l71', 'l95', 'l118', 'l140', 'l161', 'l181', 'l200', 'l218', 'l235', 'l251', 'l266', 'l280', 'l293', 'l305', 'l316', 'l326', 'l335', 'l343', 'l350', 'l357', 'l358', 'l359', 'l360', 'l361', 'l362']", + "45, mutant ['l21', 'l47', 'l72', 'l96', 'l119', 'l141', 'l162', 'l182', 'l201', 'l219', 'l236', 'l252', 'l267', 'l281', 'l294', 'l306', 'l317', 'l327', 'l336', 'l344', 'l351', 'l357', 'l363', 'l364', 'l365', 'l366', 'l367']", + "46, forms ['l22', 'l48', 'l73', 'l97', 'l120', 'l142', 'l163', 'l183', 'l202', 'l220', 'l237', 'l253', 'l268', 'l282', 'l295', 'l307', 'l318', 'l328', 'l337', 'l345', 'l352', 'l358', 'l363', 'l368', 'l369', 'l370', 'l371']", + "47, of ['l23', 'l49', 'l74', 'l98', 'l121', 'l143', 'l164', 'l184', 'l203', 'l221', 'l238', 'l254', 'l269', 'l283', 'l296', 'l308', 'l319', 'l329', 'l338', 'l346', 'l353', 'l359', 'l364', 'l368', 'l372', 'l373', 'l374']", + "48, the ['l24', 'l50', 'l75', 'l99', 'l122', 'l144', 'l165', 'l185', 'l204', 'l222', 'l239', 'l255', 'l270', 'l284', 'l297', 'l309', 'l320', 'l330', 'l339', 'l347', 'l354', 'l360', 'l365', 'l369', 'l372', 'l375', 'l376']", + "76, PDAPP ['l25', 'l51', 'l76', 'l100', 'l123', 'l145', 'l166', 'l186', 'l205', 'l223', 'l240', 'l256', 'l271', 'l285', 'l298', 'l310', 'l321', 'l331', 'l340', 'l348', 'l355', 'l361', 'l366', 'l370', 'l373', 'l375', 'l377']", + "77, mice ['l26', 'l52', 'l77', 'l101', 'l124', 'l146', 'l167', 'l187', 'l206', 'l224', 'l241', 'l257', 'l272', 'l286', 'l299', 'l311', 'l322', 'l332', 'l341', 'l349', 'l356', 'l362', 'l367', 'l371', 'l374', 'l376', 'l377']", + "164, microglial ['l378']", + "165, cells ['l378']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice", + "PDAPP", + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "an", + "amyloid", + "beta", + "precursor", + "protein", + "(APP)", + "mini-gene", + "driven", + "by", + "a", + "platelet-derived", + "(PD)", + "growth", + "factor", + "promoter", + "(PDAPP", + "mice),", + "overexpress", + "one", + "mutant", + "forms", + "of", + "the" + ] + } + } + ] + }, + { + "PMID": "10932225", + "TEXT": "Here we defined the main viral determinant of Ebola virus pathogenicity; synthesis of the virion glycoprotein (GP) of Ebola virus Zaire induced cytotoxic effects in human endothelial cells in vitro and in vivo. This effect mapped to a serine-threonine-rich, mucin-like domain of this type I transmembrane glycoprotein, one of seven gene products of the virus. Gene transfer of GP into explanted human or porcine blood vessels caused massive endothelial cell loss within 48 hours that led to a substantial increase in vascular permeability. Deletion of the mucin-like region of GP abolished these effects without affecting protein expression or function. GP derived from the Reston strain of virus, which causes disease in nonhuman primates but not in man, did not disrupt the vasculature of human blood vessels. In contrast, the Zaire GP induced endothelial cell disruption and cytotoxicity in both nonhuman primate and human blood vessels, and the mucin domain was required for this effect. These findings indicate that GP, through its mucin domain, is the viral determinant of Ebola pathogenicity and likely contributes to hemorrhage during infection.", + "TAG_DATA": [ + "25, human {'context': 'B-cells'}", + "26, endothelial {'context': 'I-cells'}", + "27, cells {'context': 'I-cells'}", + "28, in {'context': 'B-in vitro'}", + "29, vitro {'context': 'I-in vitro'}", + "31, in {'context': 'B-in vivo'}", + "32, vivo. {'context': 'I-in vivo'}", + "55, Gene {'perturbing_action': 'B-gene gain-of-function'}", + "56, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "57, of {'perturbing_action': 'I-gene gain-of-function'}", + "58, GP {'perturbing_action': 'I-gene gain-of-function'}", + "61, human {'context': 'B-tissue/organ'}", + "62, or {'context': 'I-tissue/organ'}", + "63, porcine {'context': 'I-tissue/organ'}", + "64, blood {'context': 'I-tissue/organ'}", + "65, vessels {'context': 'I-tissue/organ'}", + "68, endothelial {'context': 'B-cells'}", + "69, cell {'context': 'I-cells'}", + "83, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "84, of {'perturbing_action': 'I-gene loss-of-function'}", + "85, the {'perturbing_action': 'I-gene loss-of-function'}", + "86, mucin-like {'perturbing_action': 'I-gene loss-of-function'}", + "87, region {'perturbing_action': 'I-gene loss-of-function'}", + "88, of {'perturbing_action': 'I-gene loss-of-function'}", + "89, GP {'perturbing_action': 'I-gene loss-of-function'}", + "112, primates {'context': 'I-organism'}", + "123, human {'context': 'B-tissue/organ'}", + "124, blood {'context': 'I-tissue/organ'}", + "125, vessels. {'context': 'I-tissue/organ'}", + "132, endothelial {'context': 'B-cells'}", + "133, cell {'context': 'I-cells'}", + "139, nonhuman {'context': 'B-organism'}", + "140, primate {'context': 'I-organism'}", + "142, human {'context': 'B-tissue/organ'}", + "143, blood {'context': 'I-tissue/organ'}", + "144, vessels, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "25, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "26, endothelial ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "27, cells ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "28, in ['l2', 'l16', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "29, vitro ['l3', 'l17', 'l39', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "31, in ['l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "32, vivo. ['l62', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "55, Gene ['l4', 'l18', 'l29', 'l40', 'l51', 'l63', 'l74', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "56, transfer ['l5', 'l19', 'l41', 'l52', 'l64', 'l75', 'l85', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "57, of ['l6', 'l20', 'l30', 'l42', 'l53', 'l65', 'l76', 'l86', 'l95', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "58, GP ['l7', 'l21', 'l31', 'l43', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "61, human ['l8', 'l22', 'l32', 'l44', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "62, or ['l9', 'l23', 'l33', 'l45', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l113', 'l119', 'l125', 'l126', 'l127', 'l128', 'l129']", + "63, porcine ['l10', 'l24', 'l34', 'l46', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l130', 'l131', 'l132', 'l133']", + "64, blood ['l11', 'l25', 'l35', 'l47', 'l58', 'l70', 'l81', 'l91', 'l100', 'l108', 'l115', 'l121', 'l126', 'l130', 'l134', 'l135', 'l136']", + "65, vessels ['l12', 'l26', 'l36', 'l48', 'l59', 'l71', 'l82', 'l92', 'l101', 'l109', 'l116', 'l122', 'l127', 'l131', 'l134', 'l137', 'l138']", + "68, endothelial ['l13', 'l27', 'l37', 'l49', 'l60', 'l72', 'l83', 'l93', 'l102', 'l110', 'l117', 'l123', 'l128', 'l132', 'l135', 'l137', 'l139']", + "69, cell ['l14', 'l28', 'l38', 'l50', 'l61', 'l73', 'l84', 'l94', 'l103', 'l111', 'l118', 'l124', 'l129', 'l133', 'l136', 'l138', 'l139']", + "83, Deletion ['l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "84, of ['l140', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158']", + "85, the ['l141', 'l150', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166']", + "86, mucin-like ['l142', 'l151', 'l159', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "87, region ['l143', 'l152', 'l160', 'l167', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179']", + "88, of ['l144', 'l153', 'l161', 'l168', 'l174', 'l180', 'l181', 'l182', 'l183', 'l184']", + "89, GP ['l145', 'l154', 'l162', 'l169', 'l175', 'l180', 'l185', 'l186', 'l187', 'l188']", + "112, primates ['l146', 'l155', 'l163', 'l170', 'l176', 'l181', 'l185', 'l189', 'l190', 'l191']", + "123, human ['l147', 'l156', 'l164', 'l171', 'l177', 'l182', 'l186', 'l189', 'l192', 'l193']", + "124, blood ['l148', 'l157', 'l165', 'l172', 'l178', 'l183', 'l187', 'l190', 'l192', 'l194']", + "125, vessels. ['l149', 'l158', 'l166', 'l173', 'l179', 'l184', 'l188', 'l191', 'l193', 'l194']", + "132, endothelial ['l195', 'l196', 'l197', 'l198', 'l199', 'l200']", + "133, cell ['l195', 'l201', 'l202', 'l203', 'l204', 'l205']", + "139, nonhuman ['l196', 'l201', 'l206', 'l207', 'l208', 'l209']", + "140, primate ['l197', 'l202', 'l206', 'l210', 'l211', 'l212']", + "142, human ['l198', 'l203', 'l207', 'l210', 'l213', 'l214']", + "143, blood ['l199', 'l204', 'l208', 'l211', 'l213', 'l215']", + "144, vessels, ['l200', 'l205', 'l209', 'l212', 'l214', 'l215']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "endothelial", + "cells", + "cell" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Gene", + "transfer", + "of", + "GP" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Gene", + "transfer", + "of", + "GP" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Gene", + "transfer", + "of", + "GP" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Gene", + "transfer", + "of", + "GP" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "human", + "or", + "porcine", + "blood", + "vessels" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "mucin-like", + "region", + "GP" + ] + }, + "context": { + "val": "organism", + "words": [ + "primates" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "mucin-like", + "region", + "GP" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "human", + "blood", + "vessels." + ] + } + } + ] + }, + { + "PMID": "10888933", + "TEXT": "Dengue virus (DV), an arthropod-borne flavivirus, causes a febrile illness for which there is no antiviral treatment and no vaccine. Macrophages are important in dengue pathogenesis; however, the initial target cell for DV infection remains unknown. As DV is introduced into human skin by mosquitoes of the genus Aedes, we undertook experiments to determine whether human dendritic cells (DCs) were permissive for the growth of DV. Initial experiments demonstrated that blood-derived DCs were 10-fold more permissive for DV infection than were monocytes or macrophages. We confirmed this with human skin DCs (Langerhans cells and dermal/interstitial DCs). Using cadaveric human skin explants, we exposed skin DCs to DV ex vivo. Of the human leukocyte antigen DR-positive DCs that migrated from the skin, emigrants from both dermis and epidermis, 60-80% expressed DV antigens. These observations were supported by histologic findings from the skin rash of a human subject who received an attenuated tetravalent dengue vaccine. Immunohistochemistry of the skin showed CD1a-positive DCs double-labeled with an antibody against DV envelope glycoprotein. These data demonstrate that human skin DCs are permissive for DV infection, and provide a potential mechanism for the transmission of DV into human skin.", + "TAG_DATA": [ + "70, blood-derived {'context': 'B-cells'}", + "71, DCs {'context': 'I-cells'}", + "88, human {'context': 'B-cells'}", + "89, skin {'context': 'I-cells'}", + "90, DCs {'context': 'I-cells'}", + "97, cadaveric {'context': 'B-tissue/organ'}", + "98, human {'context': 'I-tissue/organ'}", + "99, skin {'context': 'I-tissue/organ'}", + "100, explants, {'context': 'I-tissue/organ'}", + "103, skin {'context': 'B-cells'}", + "104, DCs {'context': 'I-cells'}", + "111, human {'context': 'B-cells'}", + "112, leukocyte {'context': 'I-cells'}", + "113, antigen {'context': 'I-cells'}", + "114, DR-positive {'context': 'I-cells'}", + "115, DCs {'context': 'I-cells'}", + "144, human {'context': 'B-organism'}", + "145, subject {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "70, blood-derived ['l0', 'l1', 'l2', 'l3']", + "71, DCs ['l0', 'l4', 'l5', 'l6']", + "88, human ['l1', 'l4', 'l7', 'l8', 'l9', 'l10', 'l11']", + "89, skin ['l2', 'l5', 'l7', 'l12', 'l13', 'l14', 'l15']", + "90, DCs ['l3', 'l6', 'l8', 'l12', 'l16', 'l17', 'l18']", + "97, cadaveric ['l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "98, human ['l9', 'l13', 'l16', 'l19', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "99, skin ['l10', 'l14', 'l17', 'l20', 'l29', 'l36', 'l37', 'l38', 'l39']", + "100, explants, ['l11', 'l15', 'l18', 'l21', 'l30', 'l36', 'l40', 'l41']", + "103, skin ['l22', 'l31', 'l37', 'l40', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "104, DCs ['l23', 'l32', 'l38', 'l41', 'l42', 'l48', 'l49', 'l50', 'l51', 'l52']", + "111, human ['l24', 'l43', 'l48', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "112, leukocyte ['l25', 'l33', 'l44', 'l49', 'l53', 'l59', 'l60', 'l61', 'l62', 'l63']", + "113, antigen ['l26', 'l34', 'l39', 'l45', 'l50', 'l54', 'l59', 'l64', 'l65', 'l66']", + "114, DR-positive ['l27', 'l46', 'l51', 'l55', 'l60', 'l64', 'l67', 'l68', 'l69']", + "115, DCs ['l28', 'l35', 'l47', 'l52', 'l56', 'l61', 'l65', 'l67', 'l70']", + "144, human ['l57', 'l62', 'l66', 'l68', 'l70', 'l71']", + "145, subject ['l58', 'l63', 'l69', 'l71']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10888926", + "TEXT": "Measles remains a principal cause of worldwide mortality, in part because young infants cannot be immunized effectively. Development of new vaccines has been hindered by previous experience with a formalin-inactivated vaccine that predisposed to a severe form of disease (atypical measles). Here we have developed and tested potential DNA vaccines for immunogenicity, efficacy and safety in a rhesus macaque model of measles. DNA protected from challenge with wild-type measles virus. Protection correlated with levels of neutralizing antibody and not with cytotoxic T lymphocyte activity. There was no evidence in any group, including those receiving hemagglutinin-encoding DNA alone, of 'priming' for atypical measles.", + "TAG_DATA": [ + "57, rhesus {'context': 'B-organism'}", + "58, macaque {'context': 'I-organism'}", + "59, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "57, rhesus ['l0', 'l1']", + "58, macaque ['l0', 'l2']", + "59, model ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10835687", + "TEXT": "New strategies are required to identify the most important targets of protective immunity in complex eukaryotic pathogens. Natural selection maintains allelic variation in some antigens of the malaria parasite Plasmodium falciparum. Analysis of allele frequency distributions could identify the loci under most intense selection. The merozoite surface protein 1 (Msp1) is the most-abundant surface component on the erythrocyte-invading stage of P. falciparum. Immunization with whole Msp1 has protected monkeys completely against homologous and partially against non-homologous parasite strains. The single-copy msp1 gene, of about 5 kilobases, has highly divergent alleles with stable frequencies in endemic populations. To identify the region of msp1 under strongest selection to maintain alleles within populations, we studied multiple intragenic sequence loci in populations in different regions of Africa and Southeast Asia. On both continents, the locus with the lowest inter-population variance in allele frequencies was block 2, indicating selection in this part of the gene. To test the hypothesis of immune selection, we undertook a large prospective longitudinal cohort study. This demonstrated that serum IgG antibodies against each of the two most frequent allelic types of block 2 of the protein were strongly associated with protection from P. falciparum malaria.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10835684", + "TEXT": "The use of agonistic monoclonal antibody against CD40 has emerged as one the most effective ways to boost immune responses against infectious agents or to fight cancer. Here, we report that the same monoclonal antibodies against CD40 (FGK45 and 3/23) previously used to elicit protective immune responses treated the autoimmune inflammatory process of chronic collagen-induced arthritis in DBA/1-TCR-beta transgenic mice, as well as collagen-induced arthritis in DBA/1 mice, both animal models of rheumatoid arthritis. This study indicates that agonistic monoclonal antibody against CD40 can potentially be used to treat chronic autoimmune inflammatory processes.", + "TAG_DATA": [ + "57, DBA/1-TCR-beta {'perturbing_action': 'B-gene gain-of-function'}", + "58, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "59, mice, {'context': 'B-organism'}", + "66, DBA/1 {'context': 'B-organism'}", + "67, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "57, DBA/1-TCR-beta ['l0', 'l1']", + "58, transgenic ['l0', 'l2']", + "59, mice, ['l1', 'l2']", + "66, DBA/1 ['l3']", + "67, mice, ['l3']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "DBA/1-TCR-beta", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "10802716", + "TEXT": "As acute hepatitis C virus (HCV) infection is clinically inapparent in most cases, the immunologic correlates of recovery are not well defined. The cellular immune response is thought to contribute to the elimination of HCV-infected cells and a strong HCV-specific T-helper-cell (Th) response is associated with recovery from acute hepatitis C (ref. 2). However, diagnosis of resolved hepatitis C is based at present on the detection of HCV-specific antibodies and the absence of detectable HCV RNA, and detailed comparison of the humoral and cellular immune response has been hampered by the fact that patient cohorts as well as HCV strains are usually heterogeneous and that clinical data from acute-phase and long-term follow-up after infection generally are not available. We studied a cohort of women accidentally exposed to the same HCV strain of known sequence and found that circulating HCV-specific antibodies were undetectable in many patients 18-20 years after recovery, whereas HCV-specific helper and cytotoxic T-cell responses with an interferon (IFN)-gamma-producing (Tc1) phenotype persisted. The data indicate these HCV-specific CD4 + and CD8+ T cells are biomarkers for a prior HCV exposure and recovery. Because of undetectable antibodies against HCV, the incidence of self-limited HCV infections and recovery may be underestimated in the general population.", + "TAG_DATA": [ + "123, women {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10802714", + "TEXT": "Insulin gene expression is restricted to islet beta cells of the mammalian pancreas through specific control mechanisms mediated in part by specific transcription factors. The protein encoded by the pancreatic and duodenal homeobox gene 1 (PDX-1) is central in regulating pancreatic development and islet cell function. PDX-1 regulates insulin gene expression and is involved in islet cell-specific expression of various genes. Involvement of PDX-1 in islet-cell differentiation and function has been demonstrated mainly by 'loss-of-function' studies. We used a 'gain-of-function' approach to test whether PDX-1 could endow a non-islet tissue with pancreatic beta-cell characteristics in vivo. Recombinant-adenovirus-mediated gene transfer of PDX-1 to the livers of BALB/C and C57BL/6 mice activated expression of the endogenous, otherwise silent, genes for mouse insulin 1 and 2 and prohormone convertase 1/3 (PC 1/3). Expression of PDX-1 resulted in a substantial increase in hepatic immunoreactive insulin content and an increase of 300% in plasma immunoreactive insulin levels, compared with that in mice treated with control adenovirus. Hepatic immunoreactive insulin induced by PDX-1 was processed to mature mouse insulin 1 and 2 and was biologically active; it ameliorated hyperglycemia in diabetic mice treated with streptozotocin. These data indicate the capacity of PDX-1 to reprogram extrapancreatic tissue towards a beta-cell phenotype, may provide a valuable approach for generating 'self' surrogate beta cells, suitable for replacing impaired islet-cell function in diabetics.", + "TAG_DATA": [ + "96, Recombinant-adenovirus-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "97, gene {'perturbing_action': 'I-gene gain-of-function'}", + "98, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "99, of {'perturbing_action': 'I-gene gain-of-function'}", + "100, PDX-1 {'perturbing_action': 'I-gene gain-of-function'}", + "103, livers {'context': 'B-tissue/organ'}", + "105, BALB/C {'context': 'B-organism'}", + "107, C57BL/6 {'context': 'B-organism'}", + "108, mice {'context': 'I-organism'}", + "129, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "130, of {'perturbing_action': 'I-gene gain-of-function'}", + "131, PDX-1 {'perturbing_action': 'I-gene gain-of-function'}", + "156, mice {'context': 'B-organism'}", + "184, diabetic {'context': 'B-organism'}", + "185, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "96, Recombinant-adenovirus-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "97, gene ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "98, transfer ['l1', 'l11', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "99, of ['l2', 'l12', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "100, PDX-1 ['l3', 'l13', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32']", + "103, livers ['l4', 'l14', 'l20', 'l25', 'l29', 'l33', 'l34', 'l35']", + "105, BALB/C ['l5', 'l15', 'l21', 'l26', 'l30', 'l33', 'l36', 'l37']", + "107, C57BL/6 ['l6', 'l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l38', 'l39', 'l40', 'l41', 'l42']", + "108, mice ['l7', 'l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l38']", + "129, Expression ['l8', 'l39', 'l43', 'l44', 'l45']", + "130, of ['l9', 'l40', 'l43', 'l46', 'l47']", + "131, PDX-1 ['l41', 'l44', 'l46', 'l48']", + "156, mice ['l10', 'l42', 'l45', 'l47', 'l48']", + "184, diabetic ['l49']", + "185, mice ['l49']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Recombinant-adenovirus-mediated", + "gene", + "transfer", + "of", + "PDX-1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "livers" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Recombinant-adenovirus-mediated", + "gene", + "transfer", + "of", + "PDX-1", + "Expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "BALB/C", + "C57BL/6", + "mice" + ] + } + } + ] + }, + { + "PMID": "10742156", + "TEXT": "Pathological increases in vascular leakage lead to edema and swelling, causing serious problems in brain tumors, in diabetic retinopathy, after strokes, during sepsis and also in inflammatory conditions such as rheumatoid arthritis and asthma. Although many agents and disease processes increase vascular leakage, no known agent specifically makes vessels resistant to leaking. Vascular endothelial growth factor (VEGF) and the angiopoietins function together during vascular development, with VEGF acting early during vessel formation, and angiopoietin-1 acting later during vessel remodeling, maturation and stabilization. Although VEGF was initially called vascular permeability factor, there has been less focus on its permeability actions and more effort devoted to its involvement in vessel growth and applications in ischemia and cancer. Recent transgenic approaches have confirmed the profound permeability effects of VEGF (refs. 12-14), and have shown that transgenic angiopoietin-1 acts reciprocally as an anti-permeability factor when provided chronically during vessel formation, although it also profoundly affects vascular morphology when thus delivered. To be useful clinically, angiopoietin-1 would have to inhibit leakage when acutely administered to adult vessels, and this action would have to be uncoupled from its profound angiogenic capabilities. Here we show that acute administration of angiopoietin-1 does indeed protect adult vasculature from leaking, countering the potentially lethal actions of VEGF and inflammatory agents.", + "TAG_DATA": [ + "132, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "133, angiopoietin-1 {'perturbing_action': 'I-gene gain-of-function'}", + "196, adult {'context': 'B-tissue/organ'}", + "197, vasculature {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "132, transgenic ['l0']", + "133, angiopoietin-1 ['l0']", + "196, adult ['l1']", + "197, vasculature ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10742153", + "TEXT": "Glioblastomas, the most frequent and malignant of primary brain tumors, have a very poor prognosis. Gene therapy of glioblastomas is limited by the short survival of viral vectors and by their difficulty in reaching glioblastoma cells infiltrating the brain parenchyma. Neural stem/progenitor cells can be engineered to produce therapeutic molecules and have the potential to overcome these limitations because they may travel along the white matter, like neoplastic cells, and engraft stably into the brain. Retrovirus-mediated transfer of the gene for interleukin-4 is an effective treatment for rat brain glioblastomas. Here, we transferred the gene for interleukin-4 into C57BL6J mouse primary neural progenitor cells and injected those cells into established syngeneic brain glioblastomas. This led to the survival of most tumor-bearing mice. We obtained similar results by implanting immortalized neural progenitor cells derived from Sprague-Dawley rats into C6 glioblastomas. We also documented by magnetic resonance imaging the progressive disappearance of large tumors, and detected 5-bromodeoxyuridine-labeled progenitor cells several weeks after the injection. These findings support a new approach for gene therapy of brain tumors, based on the grafting of neural stem cells producing therapeutic molecules.", + "TAG_DATA": [ + "98, C57BL6J {'context': 'B-cells'}", + "99, mouse {'context': 'I-cells'}", + "100, primary {'context': 'I-cells'}", + "101, neural {'context': 'I-cells'}", + "102, progenitor {'context': 'I-cells'}", + "103, cells {'context': 'I-cells'}", + "107, cells {'context': 'B-cells'}", + "110, syngeneic {'context': 'B-neoplasm'}", + "111, brain {'context': 'I-neoplasm'}", + "112, glioblastomas. {'context': 'I-neoplasm'}", + "120, tumor-bearing {'context': 'B-organism'}", + "121, mice. {'context': 'I-organism'}", + "128, immortalized {'context': 'B-cells'}", + "129, neural {'context': 'I-cells'}", + "130, progenitor {'context': 'I-cells'}", + "131, cells {'context': 'I-cells'}", + "132, derived {'context': 'I-cells'}", + "133, from {'context': 'I-cells'}", + "135, rats {'context': 'I-cells'}", + "137, C6 {'context': 'B-neoplasm'}", + "138, glioblastomas. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "98, C57BL6J ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "99, mouse ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "100, primary ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "101, neural ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "102, progenitor ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "103, cells ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42']", + "107, cells ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l43', 'l44', 'l45', 'l46', 'l47']", + "110, syngeneic ['l6', 'l15', 'l23', 'l30', 'l36', 'l43', 'l48', 'l49', 'l50', 'l51']", + "111, brain ['l7', 'l16', 'l24', 'l31', 'l37', 'l41', 'l44', 'l48', 'l52', 'l53', 'l54']", + "112, glioblastomas. ['l8', 'l17', 'l25', 'l32', 'l38', 'l42', 'l45', 'l49', 'l52', 'l55', 'l56']", + "120, tumor-bearing ['l46', 'l50', 'l53', 'l55', 'l57']", + "121, mice. ['l9', 'l18', 'l26', 'l33', 'l39', 'l47', 'l51', 'l54', 'l56', 'l57']", + "128, immortalized ['l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "129, neural ['l58', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "130, progenitor ['l59', 'l66', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "131, cells ['l60', 'l67', 'l73', 'l79', 'l80', 'l81', 'l82', 'l83']", + "132, derived ['l61', 'l68', 'l74', 'l79', 'l84', 'l85', 'l86', 'l87']", + "133, from ['l62', 'l69', 'l75', 'l80', 'l84', 'l88', 'l89', 'l90']", + "135, rats ['l63', 'l70', 'l76', 'l81', 'l85', 'l88', 'l91', 'l92']", + "137, C6 ['l64', 'l71', 'l77', 'l82', 'l86', 'l89', 'l91', 'l93']", + "138, glioblastomas. ['l65', 'l72', 'l78', 'l83', 'l87', 'l90', 'l92', 'l93']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10742152", + "TEXT": "Inhibitory receptors have been proposed to modulate the in vivo cytotoxic response against tumor targets for both spontaneous and antibody-dependent pathways. Using a variety of syngenic and xenograft models, we demonstrate here that the inhibitory FcgammaRIIB molecule is a potent regulator of antibody-dependent cell-mediated cytotoxicity in vivo, modulating the activity of FcgammaRIII on effector cells. Although many mechanisms have been proposed to account for the anti-tumor activities of therapeutic antibodies, including extended half-life, blockade of signaling pathways, activation of apoptosis and effector-cell-mediated cytotoxicity, we show here that engagement of Fcgamma receptors on effector cells is a dominant component of the in vivo activity of antibodies against tumors. Mouse monoclonal antibodies, as well as the humanized, clinically effective therapeutic agents trastuzumab (Herceptin(R)) and rituximab (Rituxan(R)), engaged both activation (FcgammaRIII) and inhibitory (FcgammaRIIB) antibody receptors on myeloid cells, thus modulating their cytotoxic potential. Mice deficient in FcgammaRIIB showed much more antibody-dependent cell-mediated cytotoxicity; in contrast, mice deficient in activating Fc receptors as well as antibodies engineered to disrupt Fc binding to those receptors were unable to arrest tumor growth in vivo. These results demonstrate that Fc-receptor-dependent mechanisms contribute substantially to the action of cytotoxic antibodies against tumors and indicate that an optimal antibody against tumors would bind preferentially to activation Fc receptors and minimally to the inhibitory partner FcgammaRIIB.", + "TAG_DATA": [ + "134, myeloid {'context': 'B-cells'}", + "135, cells, {'context': 'I-cells'}", + "141, Mice {'context': 'B-organism'}", + "142, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "143, in {'perturbing_action': 'I-gene loss-of-function'}", + "144, FcgammaRIIB {'perturbing_action': 'I-gene loss-of-function'}", + "153, mice {'context': 'B-organism'}", + "172, unable {'effect': 'B-no effect'}", + "173, to {'effect': 'I-no effect'}", + "174, arrest {'effect': 'I-negative'}", + "175, tumor {'phenotype': 'B-tumour growth'}", + "176, growth {'phenotype': 'I-tumour growth'}", + "177, in {'context': 'B-in vivo'}", + "178, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "134, myeloid ['l0', 'l1', 'l2', 'l3', 'l4']", + "135, cells, ['l0', 'l5', 'l6', 'l7', 'l8']", + "141, Mice ['l1', 'l5', 'l9', 'l10', 'l11']", + "142, deficient ['l2', 'l6', 'l9', 'l12', 'l13']", + "143, in ['l3', 'l7', 'l10', 'l12', 'l14']", + "144, FcgammaRIIB ['l4', 'l8', 'l11', 'l13', 'l14']", + "153, mice ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "172, unable ['l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "173, to ['l16', 'l22', 'l28', 'l29', 'l30', 'l31', 'l32']", + "174, arrest ['l17', 'l23', 'l28', 'l33', 'l34', 'l35', 'l36']", + "175, tumor ['l18', 'l24', 'l29', 'l33', 'l37', 'l38', 'l39']", + "176, growth ['l19', 'l25', 'l30', 'l34', 'l37', 'l40', 'l41']", + "177, in ['l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l42']", + "178, vivo. ['l21', 'l27', 'l32', 'l36', 'l39', 'l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "myeloid", + "cells," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "FcgammaRIIB" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "FcgammaRIIB" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "unable", + "to" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "unable", + "to" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "unable", + "to" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "arrest" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "arrest" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "10742151", + "TEXT": "Here, we demonstrate a previously unknown function for the 70-kDa heat-shock protein (HSP70) as a cytokine. HSP70 bound with high affinity to the plasma membrane, elicited a rapid intracellular calcium flux, activated nuclear factor (NF)-kappaB and upregulated the expression of pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 in human monocytes. Furthermore, two different signal transduction pathways were activated by exogenous HSP70: one dependent on CD14 and intracellular calcium, which resulted in increased IL-1beta, IL-6 and TNF-alpha; and the other independent of CD14 but dependent on intracellular calcium, which resulted in an increase in TNF-alpha but not IL-1beta or IL-6. These findings indicate that CD14 is a co-receptor for HSP70-mediated signaling in human monocytes and are indicative of an previously unrecognized function for HSP70 as an extracellular protein with regulatory effects on human monocytes, having a dual role as chaperone and cytokine.", + "TAG_DATA": [ + "51, human {'context': 'B-cells'}", + "52, monocytes. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "51, human ['l0']", + "52, monocytes. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10700236", + "TEXT": "Persistence of hepatocytes transplanted into the same or related species has been established. The long-term engraftment of human hepatocytes into rodents would be useful for the study of human viral hepatitis, where it might allow the species, technical and size limitations of the current animal models to be overcome. Although transgenic mice expressing the hepatitis B virus (HBV) genome produce infectious virus in their serum, the viral life cycle is not complete, in that the early stages of viral binding and entry into hepatocytes and production of an episomal transcriptional DNA template do not occur. As for hepatitis delta virus (HDV), another cause of liver disease, no effective therapy exists to eradicate infection, and it remains resistant even to recent regimens that have considerably changed the treatment of HBV (ref. 13). Here, we demonstrate long-term engraftment of primary human hepatocytes transplanted in a matrix under the kidney capsule of mice with administration of an agonistic antibody against c-Met. These mice were susceptible to HBV infection and completion of the viral life cycle. In addition, we demonstrate super-infection of the HBV-infected mice with HDV. Our results describe a new xenotransplant model that allows study of multiple aspects of human hepatitis viral infections, and may enhance studies of human liver diseases.", + "TAG_DATA": [ + "137, primary {'context': 'B-cells'}", + "138, human {'context': 'I-cells'}", + "139, hepatocytes {'context': 'I-cells'}", + "149, mice {'context': 'B-organism'}", + "159, mice {'context': 'B-organism'}", + "180, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "137, primary ['l0', 'l1', 'l2']", + "138, human ['l0', 'l3', 'l4']", + "139, hepatocytes ['l1', 'l3', 'l5']", + "149, mice ['l2', 'l4', 'l5', 'l6']", + "159, mice ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10700232", + "TEXT": "To differentiate into T cells, immature thymocytes must engage, through their antigen-specific T-cell receptor, peptides derived from self proteins presented by cortical epithelial cells in the thymus, a process called positive selection. Despite this requirement for self-recognition during development, mature T cells do not normally show autoreactivity. Mice injected in the thymus with procainamide-hydroxylamine, a metabolite of procainamide, develop autoimmune features resembling drug-induced lupus. Here, we show that when thymocytes undergo positive selection in the presence of procainamide-hydroxylamine, they fail to establish unresponsiveness to low affinity selecting self antigens, resulting in systemic autoimmunity.", + "TAG_DATA": [ + "47, Mice {'context': 'B-organism'}", + "51, thymus {'context': 'B-tissue/organ'}", + "69, thymocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "47, Mice ['l0']", + "51, thymus ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10700228", + "TEXT": "Neurogenesis persists in the adult mammalian hippocampus. To identify and isolate neuronal progenitor cells of the adult human hippocampus, we transfected ventricular zone-free dissociates of surgically-excised dentate gyrus with DNA encoding humanized green fluorescent protein (hGFP), placed under the control of either the nestin enhancer (E/nestin) or the Talpha1 tubulin promoter (P/Talpha1), two regulatory regions that direct transcription in neural progenitor cells. The resultant P/Talpha1:hGFP+ and E/nestin:enhanced (E)GFP+ cells expressed betaIII-tubulin or microtubule-associated protein-2; many incorporated bromodeoxyuridine, indicating their genesis in vitro. Using fluorescence-activated cell sorting, the E/nestin:EGFP+ and P/Talpha1:hGFP+ cells were isolated to near purity, and matured antigenically and physiologically as neurons. Thus, the adult human hippocampus contains mitotically competent neuronal progenitors that can be selectively extracted. The isolation of these cells may provide a cellular substrate for re-populating the damaged or degenerated adult hippocampus.", + "TAG_DATA": [ + "21, ventricular {'context': 'B-tissue/organ'}", + "22, zone-free {'context': 'I-tissue/organ'}", + "23, dissociates {'context': 'I-tissue/organ'}", + "26, dentate {'context': 'B-tissue/organ'}", + "27, gyrus {'context': 'I-tissue/organ'}", + "68, cells {'context': 'B-cells'}", + "90, cells {'context': 'B-cells'}", + "106, human {'context': 'I-tissue/organ'}", + "107, hippocampus {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "21, ventricular ['l0', 'l1', 'l2', 'l3', 'l4']", + "22, zone-free ['l0', 'l5', 'l6', 'l7', 'l8']", + "23, dissociates ['l1', 'l5', 'l9', 'l10', 'l11']", + "26, dentate ['l2', 'l6', 'l9', 'l12', 'l13']", + "27, gyrus ['l3', 'l7', 'l10', 'l12', 'l14']", + "68, cells ['l4', 'l8', 'l11', 'l13', 'l14']", + "90, cells ['l15', 'l16']", + "106, human ['l15', 'l17']", + "107, hippocampus ['l16', 'l17']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10655108", + "TEXT": "Because HER-2/neu overexpression is important in cancer development, we looked for a method of suppressing the cell transformation mediated by HER-2/neu overexpression. We have identified that the DNA-binding protein PEA3, which is encoded by a previously isolated gene of the ets family, specifically targeted a DNA sequence on the HER-2/neu promoter and downregulated the promoter activity. Expression of PEA3 resulted in preferential inhibition of cell growth and tumor development of HER-2/neu-overexpressing cancer cells. This is a new approach to targeting HER-2/neu overexpression and also provides a rationale to the design for repressors of diseases caused by overexpression of pathogenic genes.", + "TAG_DATA": [ + "56, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "57, of {'perturbing_action': 'I-gene gain-of-function'}", + "58, PEA3 {'perturbing_action': 'I-gene gain-of-function'}", + "62, inhibition {'effect': 'B-negative'}", + "64, cell {'phenotype': 'B-cell growth'}", + "65, growth {'phenotype': 'I-cell growth'}", + "67, tumor {'phenotype': 'B-tumourigenesis'}", + "68, development {'phenotype': 'I-tumourigenesis'}", + "70, HER-2/neu-overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "71, cancer {'context': 'B-transformed cells'}", + "72, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "56, Expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "57, of ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "58, PEA3 ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "62, inhibition ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "64, cell ['l3', 'l12', 'l20', 'l27', 'l33', 'l34', 'l35']", + "65, growth ['l4', 'l13', 'l21', 'l28', 'l33', 'l36', 'l37']", + "67, tumor ['l5', 'l14', 'l22', 'l29', 'l34', 'l36', 'l38', 'l39', 'l40', 'l41']", + "68, development ['l6', 'l15', 'l23', 'l30', 'l35', 'l37', 'l38', 'l42', 'l43', 'l44']", + "70, HER-2/neu-overexpressing ['l7', 'l16', 'l24', 'l39', 'l42', 'l45', 'l46']", + "71, cancer ['l8', 'l17', 'l25', 'l31', 'l40', 'l43', 'l45', 'l47']", + "72, cells. ['l9', 'l18', 'l26', 'l32', 'l41', 'l44', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "PEA3" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "PEA3" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "PEA3", + "HER-2/neu-overexpressing" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "PEA3", + "HER-2/neu-overexpressing" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells." + ] + } + } + ] + }, + { + "PMID": "10655107", + "TEXT": "During the development of hypertrophy, cardiac myocytes increase organization of the sarcomere, a highly ordered contractile unit in striated muscle cells. Several hypertrophic agonists, such as angiotensin II, phenylephrine, and endothelin-1, have been shown to promote the sarcomere organization. However, the signaling pathway, which links extracellular stimuli to sarcomere organization, has not been clearly demonstrated. Here, we demonstrate that myosin light chain kinase specifically mediates agonist-induced sarcomere organization during early hypertrophic response. Acute administration of a hypertrophic agonist, phenylephrine, or angiotensin II, causes phosphorylation of myosin light chain 2v both in cultured cardiac myocytes and in the adult heart in vivo. We also show that both sarcomere organization and myosin light chain 2v phosphorylation are dependent on the activation of Ca2+/calmodulin pathway, a known activator of myosin light chain kinase. These results define a new and specific role of myosin light chain kinase in cardiac myocytes, which may provide a rapid adaptive mechanism in response to hypertrophic stimuli.", + "TAG_DATA": [ + "91, cultured {'context': 'B-cells'}", + "92, cardiac {'context': 'I-cells'}", + "93, myocytes {'context': 'I-cells'}", + "97, adult {'context': 'B-tissue/organ'}", + "98, heart {'context': 'I-tissue/organ'}", + "99, in {'context': 'B-in vivo'}", + "100, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "91, cultured ['l0', 'l1']", + "92, cardiac ['l0', 'l2']", + "93, myocytes ['l1', 'l2']", + "97, adult ['l3', 'l4', 'l5']", + "98, heart ['l3', 'l6', 'l7']", + "99, in ['l4', 'l6', 'l8']", + "100, vivo. ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10655106", + "TEXT": "Sickle cell disease is a hereditary disorder characterized by erythrocyte deformity due to hemoglobin polymerization. We assessed in vivo the potential curative threshold of fetal hemoglobin in the SAD transgenic mouse model of sickle cell disease using mating with mice expressing the human fetal Agamma-globin gene. With increasing levels of HbF, AgammaSAD mice showed considerable improvement in all hematologic parameters, morphopathologic features and life span/survival. We established the direct therapeutic effect of fetal hemoglobin on sickle cell disease and demonstrated correction by increasing fetal hemoglobin to about 9-16% in this mouse model. This in vivo study emphasizes the potential of the SAD mouse models for quantitative analysis of gene therapy approaches.", + "TAG_DATA": [ + "39, mice {'context': 'B-organism'}", + "40, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "41, the {'perturbing_action': 'I-gene gain-of-function'}", + "42, human {'perturbing_action': 'I-gene gain-of-function'}", + "43, fetal {'perturbing_action': 'I-gene gain-of-function'}", + "44, Agamma-globin {'perturbing_action': 'I-gene gain-of-function'}", + "45, gene. {'perturbing_action': 'I-gene gain-of-function'}", + "51, AgammaSAD {'perturbing_action': 'B-other'}", + "52, mice {'context': 'B-organism'}", + "90, mouse {'context': 'B-organism'}", + "91, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "39, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "40, expressing ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "41, the ['l1', 'l6', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "42, human ['l2', 'l7', 'l12', 'l18', 'l19', 'l20', 'l21', 'l22']", + "43, fetal ['l3', 'l8', 'l13', 'l18', 'l23', 'l24', 'l25', 'l26']", + "44, Agamma-globin ['l4', 'l9', 'l14', 'l19', 'l23', 'l27', 'l28', 'l29']", + "45, gene. ['l5', 'l10', 'l15', 'l20', 'l24', 'l27']", + "51, AgammaSAD ['l16', 'l21', 'l25', 'l28', 'l30']", + "52, mice ['l11', 'l17', 'l22', 'l26', 'l29', 'l30']", + "90, mouse ['l31']", + "91, model. ['l31']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "the", + "human", + "fetal", + "Agamma-globin", + "gene." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "AgammaSAD" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "10655104", + "TEXT": "Identification of new therapeutic targets for the management of septic shock remains imperative as all investigational therapies, including anti-tumor necrosis factor (TNF) and anti-interleukin (IL)-1 agents, have uniformly failed to lower the mortality of critically ill patients with severe sepsis. We report here that macrophage migration inhibitory factor (MIF) is a critical mediator of septic shock. High concentrations of MIF were detected in the peritoneal exudate fluid and in the systemic circulation of mice with bacterial peritonitis. Experiments performed in TNFalpha knockout mice allowed a direct evaluation of the part played by MIF in sepsis in the absence of this pivotal cytokine of inflammation. Anti-MIF antibody protected TNFalpha knockout from lethal peritonitis induced by cecal ligation and puncture (CLP), providing evidence of an intrinsic contribution of MIF to the pathogenesis of sepsis. Anti-MIF antibody also protected normal mice from lethal peritonitis induced by both CLP and Escherichia coli, even when treatment was started up to 8 hours after CLP. Conversely, co-injection of recombinant MIF and E. coli markedly increased the lethality of peritonitis. Finally, high concentrations of MIF were detected in the plasma of patients with severe sepsis or septic shock. These studies define a critical part for MIF in the pathogenesis of septic shock and identify a new target for therapeutic intervention.", + "TAG_DATA": [ + "73, mice {'context': 'B-organism'}", + "80, TNFalpha {'perturbing_action': 'B-gene loss-of-function'}", + "81, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "82, mice {'context': 'B-organism'}", + "137, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, mice ['l0', 'l1']", + "80, TNFalpha ['l0', 'l2', 'l3']", + "81, knockout ['l2', 'l4']", + "82, mice ['l1', 'l3', 'l4']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TNFalpha", + "knockout" + ] + } + } + ] + }, + { + "PMID": "10655103", + "TEXT": "Cerebral edema contributes significantly to morbidity and death associated with many common neurological disorders. However, current treatment options are limited to hyperosmolar agents and surgical decompression, therapies introduced more than 70 years ago. Here we show that mice deficient in aquaporin-4 (AQP4), a glial membrane water channel, have much better survival than wild-type mice in a model of brain edema caused by acute water intoxication. Brain tissue water content and swelling of pericapillary astrocytic foot processes in AQP4-deficient mice were significantly reduced. In another model of brain edema, focal ischemic stroke produced by middle cerebral artery occlusion, AQP4-deficient mice had improved neurological outcome. Cerebral edema, as measured by percentage of hemispheric enlargement at 24 h, was decreased by 35% in AQP4-deficient mice. These results implicate a key role for AQP4 in modulating brain water transport, and suggest that AQP4 inhibition may provide a new therapeutic option for reducing brain edema in a wide variety of cerebral disorders.", + "TAG_DATA": [ + "37, mice {'context': 'B-organism'}", + "38, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "39, in {'perturbing_action': 'I-gene loss-of-function'}", + "40, aquaporin-4 {'perturbing_action': 'I-gene loss-of-function'}", + "41, (AQP4), {'perturbing_action': 'I-gene loss-of-function'}", + "77, AQP4-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "78, mice {'context': 'B-organism'}", + "97, AQP4-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "98, mice {'context': 'B-organism'}", + "120, AQP4-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "121, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "37, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "38, deficient ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "39, in ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "40, aquaporin-4 ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "41, (AQP4), ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "77, AQP4-deficient ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "78, mice ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "97, AQP4-deficient ['l21']", + "98, mice ['l21']", + "120, AQP4-deficient ['l22']", + "121, mice. ['l22']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "aquaporin-4", + "(AQP4),", + "AQP4-deficient" + ] + } + } + ] + }, + { + "PMID": "10655101", + "TEXT": "Alzheimer amyloid beta-peptide (Abeta) is a physiological peptide constantly anabolized and catabolized under normal conditions. We investigated the mechanism of catabolism by tracing multiple-radiolabeled synthetic peptide injected into rat hippocampus. The Abeta1-42 peptide underwent full degradation through limited proteolysis conducted by neutral endopeptidase (NEP) similar or identical to neprilysin as biochemically analyzed. Consistently, NEP inhibitor infusion resulted in both biochemical and pathological deposition of endogenous Abeta42 in brain. This NEP-catalyzed proteolysis therefore limits the rate of Abeta42 catabolism, up-regulation of which could reduce the risk of developing Alzheimer's disease by preventing Abeta accumulation.", + "TAG_DATA": [ + "53, NEP {'perturbing_action': 'B-pharmacological inhibition'}", + "54, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "67, brain. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "53, NEP ['l0', 'l1']", + "54, inhibitor ['l0', 'l2']", + "67, brain. ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NEP", + "inhibitor" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain." + ] + } + } + ] + }, + { + "PMID": "10655088", + "TEXT": "Infection with some pathogens induces weak functional antibody responses that are non-protective, and there has been some skepticism about a role for antibodies in vaccine design. However, newer data show that antibodies can protect against infection with these pathogens, and new methods to elicit production of functional antibodies should be sought.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10613830", + "TEXT": "Infection with Plasmodium falciparum during pregnancy leads to the accumulation of parasite-infected erythrocytes in the placenta, and is associated with excess perinatal mortality, premature delivery and intrauterine growth retardation in the infant, as well as increased maternal mortality and morbidity. P. falciparum can adhere to specific receptors on host cells, an important virulence factor enabling parasites to accumulate in various organs. We report here that most P. falciparum isolates from infected placentae can bind to hyaluronic acid, a newly discovered receptor for parasite adhesion that is present on the placental lining. In laboratory isolates selected for specific high-level adhesion, binding to hyaluronic acid could be inhibited by dodecamer or larger oligosaccharide fragments or polysaccharides, treatment of immobilized receptor with hyaluronidase, or treatment of infected erythrocytes with trypsin. In vitro flow-based assays demonstrated that high levels of adhesion occurred at low wall shear stress, conditions thought to prevail in the placenta. Our findings indicate that adhesion to hyaluronic acid is involved in mediating placental parasite accumulation, thus changing the present understanding of the mechanisms of placental infection, with implications for the development of therapeutic and preventative interventions.", + "TAG_DATA": [ + "124, erythrocytes {'context': 'B-cells'}", + "127, In {'context': 'B-in vitro'}", + "128, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "124, erythrocytes ['l0', 'l1']", + "127, In ['l0', 'l2']", + "128, vitro ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10613829", + "TEXT": "Replication-competent HIV-1 can be isolated from infected patients despite prolonged plasma virus suppression by anti-retroviral treatment. Recent studies have identified resting, memory CD4+ T lymphocytes as a long-lived latent reservoir of HIV-1 (refs. 4,5). Cross-sectional analyses indicate that the reservoir is rather small, between 103 and 107 cells per patient. In individuals whose plasma viremia levels are well suppressed by anti-retroviral therapy, peripheral blood mononuclear cells containing replication-competent HIV-1 were found to decay with a mean half-life of approximately 6 months, close to the decay characteristics of memory lymphocytes in humans and monkeys. In contrast, little decay was found in a less-selective patient population. We undertook this study to address this apparent discrepancy. Using a quantitative micro-culture assay, we demonstrate here that the latent reservoir decays with a mean half-life of 6.3 months in patients who consistently maintain plasma HIV-1 RNA levels of fewer than 50 copies/ml. Slower decay rates occur in individuals who experience intermittent episodes of plasma viremia. Our findings indicate that the persistence of the latent reservoir of HIV-1 despite prolonged treatment is due not only to its slow intrinsic decay characteristics but also to the inability of current drug regimens to completely block HIV-1 replication.", + "TAG_DATA": [ + "62, peripheral {'context': 'B-cells'}", + "63, blood {'context': 'I-cells'}", + "64, mononuclear {'context': 'I-cells'}", + "65, cells {'context': 'I-cells'}", + "134, patients {'context': 'B-patient'}", + "152, individuals {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "62, peripheral ['l0', 'l1', 'l2']", + "63, blood ['l0', 'l3', 'l4']", + "64, mononuclear ['l1', 'l3', 'l5']", + "65, cells ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10613824", + "TEXT": "Intrathymic expression of tissue-specific self antigens may be involved in immunological tolerance and protection from autoimmune disease. We have analyzed the role of T-cell tolerance to proteolipid protein (PLP), the main protein of the myelin sheath, in susceptibility to experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Intrathymic expression of PLP was largely restricted to the shorter splice variant, DM20. Expression of DM20 by thymic epithelium was sufficient to confer T-cell tolerance to all epitopes of PLP in EAE-resistant C57BL/6 mice. In contrast, the major T-cell epitope in SJL/J mice was only encoded by the central nervous system-specific exon of PLP, but not by thymic DM20. Thus, lack of tolerance to this epitope offers an explanation for the exquisite susceptibility of SJL/J mice to EAE. As PLP expression in the human thymus is also restricted to the DM20 isoform, these findings have implications for selection of the autoimmune T-cell repertoire in multiple sclerosis.", + "TAG_DATA": [ + "62, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "63, of {'perturbing_action': 'I-gene gain-of-function'}", + "64, DM20 {'perturbing_action': 'I-gene gain-of-function'}", + "65, by {'perturbing_action': 'I-gene gain-of-function'}", + "67, epithelium {'context': 'I-tissue/organ'}", + "81, C57BL/6 {'context': 'B-organism'}", + "82, mice. {'context': 'I-organism'}", + "91, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "62, Expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "63, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "64, DM20 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "65, by ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "66, thymic ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "67, epithelium ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "81, C57BL/6 ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "82, mice. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "DM20", + "by" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "epithelium" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "DM20", + "by" + ] + }, + "context": { + "val": "organism", + "words": [ + "C57BL/6", + "mice." + ] + } + } + ] + }, + { + "PMID": "10613821", + "TEXT": "The fusion glycoproteins of human respiratory syncytial virus (RSV) and human parainfluenza virus type-3 (PIV-3) mediate virus entry and syncytium formation. Interaction between the fusion protein of RSV and RhoA, a small GTPase, facilitates virus-induced syncytium formation. We show here a RhoA-derived peptide inhibits RSV and syncytium formation induced by RSV and PIV-3, both in vitro by inhibition of cell-to-cell fusion and in vivo by reduction of peak titer by 2 log10 in RSV-infected mice. These findings indicate that the interaction between these two paramyxovirus fusion proteins and RhoA is an important target for new antiviral strategies.", + "TAG_DATA": [ + "54, in {'context': 'B-in vitro'}", + "55, vitro {'context': 'I-in vitro'}", + "62, in {'context': 'B-in vivo'}", + "63, vivo {'context': 'I-in vivo'}", + "74, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "54, in ['l0', 'l1']", + "55, vitro ['l0', 'l2']", + "62, in ['l3', 'l4']", + "63, vivo ['l1', 'l2', 'l3', 'l5']", + "74, mice. ['l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10581088", + "TEXT": "The worldwide geographic and ethnic clustering of patients with diseases related to human T-cell lymphotropic virus type I (HTLV-I) may be explained by the natural history of HTLV-I infection. The genetic characteristics of indigenous people in the Andes are similar to those of the Japanese, and HTLV-I is generally detected in both groups. To clarify the common origin of HTLV-I in Asia and the Andes, we analyzed HTLV-I provirus DNA from Andean mummies about 1,500 years old. Two of 104 mummy bone marrow specimens yielded a band of human beta-globin gene DNA 110 base pairs in length, and one of these two produced bands of HTLV-I-pX (open reading frame encoding p40x, p27x) and HTLV-I-LTR (long terminal repeat) gene DNA 159 base pairs and 157 base pairs in length, respectively. The nucleotide sequences of ancient HTLV-I-pX and HTLV-I-LTR clones isolated from mummy bone marrow were similar to those in contemporary Andeans and Japanese, although there was microheterogeneity in the sequences of some mummy DNA clones. This result provides evidence that HTLV-I was carried with ancient Mongoloids to the Andes before the Colonial era. Analysis of ancient HTLV-I sequences could be a useful tool for studying the history of human retroviral infection as well as human prehistoric migration.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10581083", + "TEXT": "MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) damages dopaminergic neurons as seen in Parkinson disease. Here we show that after administration of MPTP to mice, there was a robust gliosis in the substantia nigra pars compacta associated with significant upregulation of inducible nitric oxide synthase (iNOS). These changes preceded or paralleled MPTP-induced dopaminergic neurodegeneration. We also show that mutant mice lacking the iNOS gene were significantly more resistant to MPTP than their wild-type littermates. This study demonstrates that iNOS is important in the MPTP neurotoxic process and indicates that inhibitors of iNOS may provide protective benefit in the treatment of Parkinson disease.", + "TAG_DATA": [ + "19, mice, {'context': 'B-organism'}", + "27, substantia {'context': 'B-tissue/organ'}", + "28, nigra {'context': 'I-tissue/organ'}", + "29, pars {'context': 'I-tissue/organ'}", + "30, compacta {'context': 'I-tissue/organ'}", + "54, mice {'context': 'B-organism'}", + "55, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "56, the {'perturbing_action': 'I-gene loss-of-function'}", + "57, iNOS {'perturbing_action': 'I-gene loss-of-function'}", + "58, gene {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "19, mice, ['l0', 'l1']", + "24, gliosis ['l0', 'l2', 'l3', 'l4', 'l5']", + "27, substantia ['l2', 'l6', 'l7', 'l8']", + "28, nigra ['l3', 'l6', 'l9', 'l10']", + "29, pars ['l4', 'l7', 'l9', 'l11']", + "30, compacta ['l1', 'l5', 'l8', 'l10', 'l11']", + "54, mice ['l12', 'l13', 'l14', 'l15']", + "55, lacking ['l12', 'l16', 'l17', 'l18']", + "56, the ['l13', 'l16', 'l19', 'l20']", + "57, iNOS ['l14', 'l17', 'l19', 'l21']", + "58, gene ['l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "iNOS", + "gene" + ] + } + } + ] + }, + { + "PMID": "10581077", + "TEXT": "The B7 family members B7-1 and B7-2 interact with CD28 and constitute an essential T-cell co-stimulatory pathway in the initiation of antigen-specific humoral and cell-mediated immune response. Here, we describe a third member of the B7 family, called B7-H1 that does not bind CD28, cytotoxic T-lymphocyte A4 or ICOS (inducible co-stimulator). Ligation of B7-H1 co-stimulated T-cell responses to polyclonal stimuli and allogeneic antigens, and preferentially stimulated the production of interleukin-10. Interleukin-2, although produced in small amounts, was required for the effect of B7-H1 co-stimulation. Our studies thus define a previously unknown co-stimulatory molecule that may be involved in the negative regulation of cell-mediated immune responses.", + "TAG_DATA": [ + "51, Ligation {'perturbing_action': 'B-pharmacological augmentation'}", + "52, of {'perturbing_action': 'I-pharmacological augmentation'}", + "53, B7-H1 {'perturbing_action': 'I-pharmacological augmentation'}", + "55, T-cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "51, Ligation ['l0', 'l1', 'l2']", + "52, of ['l0', 'l3', 'l4']", + "53, B7-H1 ['l1', 'l3', 'l5']", + "55, T-cell ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Ligation", + "of", + "B7-H1" + ] + }, + "context": { + "val": "cells", + "words": [ + "T-cell" + ] + } + } + ] + }, + { + "PMID": "10545998", + "TEXT": "The mechanisms of allograft tolerance have been classified as deletion, anergy, ignorance and suppression/regulation. Deletion has been implicated in central tolerance, whereas peripheral tolerance has generally been ascribed to clonal anergy and/or active immunoregulatory states. Here, we used two distinct systems to assess the requirement for T-cell deletion in peripheral tolerance induction. In mice transgenic for Bcl-xL, T cells were resistant to passive cell death through cytokine withdrawal, whereas T cells from interleukin-2-deficient mice did not undergo activation-induced cell death. Using either agents that block co-stimulatory pathways or the immunosuppressive drug rapamycin, which we have shown here blocks the proliferative component of interleukin-2 signaling but does not inhibit priming for activation-induced cell death, we found that mice with defective passive or active T-cell apoptotic pathways were resistant to induction of transplantation tolerance. Thus, deletion of activated T cells through activation-induced cell death or growth factor withdrawal seems necessary to achieve peripheral tolerance across major histocompatibility complex barriers.", + "TAG_DATA": [ + "53, mice {'context': 'B-organism'}", + "54, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "55, for {'perturbing_action': 'I-gene gain-of-function'}", + "56, Bcl-xL, {'perturbing_action': 'I-gene gain-of-function'}", + "57, T {'context': 'B-cells'}", + "58, cells {'context': 'I-cells'}", + "60, resistant {'effect': 'B-negative'}", + "63, cell {'phenotype': 'B-cell death'}", + "64, death {'phenotype': 'I-cell death'}", + "69, T {'context': 'B-cells'}", + "70, cells {'context': 'B-cells'}", + "72, interleukin-2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "73, mice {'context': 'B-organism'}", + "74, did {'effect': 'B-negative'}", + "75, not {'effect': 'I-no effect'}", + "76, undergo {'effect': 'I-no effect'}", + "77, activation-induced {'effect': 'B-positive'}", + "78, cell {'phenotype': 'B-cell death'}", + "79, death. {'phenotype': 'I-cell death'}", + "110, activation-induced {'effect': 'B-positive'}", + "111, cell {'phenotype': 'B-cell death'}", + "112, death, {'phenotype': 'I-cell death'}", + "116, mice {'context': 'B-organism'}", + "122, T-cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "53, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "54, transgenic ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "55, for ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "56, Bcl-xL, ['l2', 'l9', 'l15', 'l25', 'l26', 'l27', 'l28', 'l29']", + "57, T ['l3', 'l10', 'l16', 'l25', 'l30', 'l31', 'l32', 'l33']", + "58, cells ['l4', 'l11', 'l17', 'l26', 'l30', 'l34', 'l35', 'l36']", + "60, resistant ['l5', 'l12', 'l18', 'l27', 'l31', 'l34', 'l37', 'l38']", + "63, cell ['l6', 'l13', 'l19', 'l28', 'l32', 'l35', 'l37', 'l39']", + "64, death ['l7', 'l14', 'l20', 'l29', 'l33', 'l36', 'l38', 'l39']", + "69, T ['l21', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "70, cells ['l22', 'l40', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "72, interleukin-2-deficient ['l41', 'l49', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "73, mice ['l42', 'l50', 'l57', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "74, did ['l43', 'l51', 'l58', 'l64', 'l70', 'l71', 'l72', 'l73', 'l74']", + "75, not ['l44', 'l52', 'l59', 'l65', 'l70', 'l75', 'l76', 'l77', 'l78']", + "76, undergo ['l45', 'l53', 'l60', 'l66', 'l71', 'l75', 'l79', 'l80', 'l81']", + "77, activation-induced ['l46', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l82', 'l83']", + "78, cell ['l23', 'l47', 'l55', 'l62', 'l68', 'l73', 'l77', 'l80', 'l82', 'l84']", + "79, death. ['l24', 'l48', 'l56', 'l63', 'l69', 'l74', 'l78', 'l81', 'l83', 'l84']", + "110, activation-induced ['l85', 'l86']", + "111, cell ['l85', 'l87']", + "112, death, ['l86', 'l87']", + "116, mice ['l88']", + "122, T-cell ['l88']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "Bcl-xL," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant", + "did" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "Bcl-xL," + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "Bcl-xL," + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "Bcl-xL," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death", + "death." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant", + "did" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death", + "death." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistant", + "did" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death", + "death." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interleukin-2-deficient" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "undergo" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "activation-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interleukin-2-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interleukin-2-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "did" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interleukin-2-deficient" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "undergo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interleukin-2-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "activation-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interleukin-2-deficient" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "undergo" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "activation-induced" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "undergo" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "activation-induced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death.", + "death," + ] + } + } + ] + }, + { + "PMID": "10545991", + "TEXT": "The long-term consequences of adenovirus-mediated conditional cytotoxic gene therapy for gliomas remain uncharacterized. We report here detection of active brain inflammation 3 months after successful inhibition of syngeneic glioma growth. The inflammatory infiltrate consisted of activated macrophages/microglia and astrocytes, and T lymphocytes positive for leucosyalin, CD3 and CD8, and included secondary demyelination. We detected strong widespread herpes simplex virus 1 thymidine kinase immunoreactivity and vector genomes throughout large areas of the brain. Thus, patient evaluation and the design of clinical trials in ongoing and future gene therapy for brain glioblastoma must address not only tumor-killing efficiency, but also long-term active brain inflammation, loss of myelin fibers and persistent transgene expression.", + "TAG_DATA": [ + "25, inhibition {'effect': 'B-negative'}", + "27, syngeneic {'context': 'B-neoplasm'}", + "28, glioma {'context': 'I-neoplasm'}", + "36, macrophages/microglia {'context': 'B-cells'}", + "38, astrocytes, {'context': 'B-cells'}", + "40, T {'context': 'B-cells'}", + "41, lymphocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "25, inhibition ['l0', 'l1', 'l2', 'l3', 'l4']", + "27, syngeneic ['l0', 'l5', 'l6', 'l7', 'l8']", + "28, glioma ['l1', 'l5', 'l9', 'l10', 'l11']", + "29, growth. ['l2', 'l6', 'l9', 'l12']", + "36, macrophages/microglia ['l3', 'l7', 'l10', 'l13', 'l14', 'l15']", + "38, astrocytes, ['l4', 'l8', 'l11', 'l12', 'l13', 'l16', 'l17']", + "40, T ['l14', 'l16', 'l18']", + "41, lymphocytes ['l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "syngeneic", + "glioma" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages/microglia", + "astrocytes," + ] + } + } + ] + }, + { + "PMID": "10545987", + "TEXT": "Cardiac pressor agents typically reduce the amount of blood pumped with each heartbeat. Cardiovascular hemodynamic principles can show whether such a response is physiologic or maladaptive.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10545984", + "TEXT": "Gene therapy for treatment of glioma often involves delivery of herpes simplex virus-1 thymidine kinase gene. A new study shows that this approach can induce chronic inflammation, and raises important questions about current adenoviral-based clinical trials (pages 1256-1263).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10545982", + "TEXT": "Many studies have been designed to address the role of CTL immune escape in HIV-1 infection, but have not given conclusive answers. Now, an elegant longitudinal analysis clearly demonstrates that progression to disease in SIV-infected macaques is associated with evasion of the CTL response (pages 1270-1276).", + "TAG_DATA": [ + "35, macaques {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10545981", + "TEXT": "Dendritic cells are known to be involved in recognition of foreign antigens and initiation of specific T-cell responses. The 'danger hypothesis' suggests that the immune system can also respond to endogenous signals of distress. New data indicate that dendritic cells are the first to respond to these signals, although the mechanisms involved in their activation are unclear (pages 1249-1255).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10545980", + "TEXT": "Two papers suggest that apoptosis of alloreactive T cells is required for induction of peripheral transplantation tolerance. These findings raise new questions about how lymphocytes reach from beyond the grave to influence the immune response (pages 1298-1302 and 1303-1307).", + "TAG_DATA": [ + "6, alloreactive {'context': 'B-cells'}", + "7, T {'context': 'I-cells'}", + "8, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "6, alloreactive ['l0', 'l1']", + "7, T ['l0', 'l2']", + "8, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10502827", + "TEXT": "Angiogenesis inhibitors produced by a primary tumor can create a systemic anti-angiogenic environment and maintain metastatic tumor cells in a state of dormancy. We show here that the gallbladder microenvironment modulates the production of transforming growth factor (TGF)-beta1, a multifunctional cytokine that functions as an endogenous anti-angiogenic and anti-tumor factor in a cranial window preparation. We found that a wide variety of human gallbladder tumors express TGF-beta1 irrespective of histologic type. We implanted a gel impregnated with basic fibroblast growth factor or Mz-ChA-2 tumor in the cranial windows of mice without tumors or mice with subcutaneous or gallbladder tumors to study angiogenesis and tumor growth at a secondary site. Angiogenesis, leukocyte-endothelial interaction in vessels and tumor growth in the cranial window were substantially inhibited in mice with gallbladder tumors. The concentration of TGF-beta1 in the plasma of mice with gallbladder tumors was 300% higher than that in the plasma of mice without tumors or with subcutaneous tumors. In contrast, there was no difference in the plasma levels of other anti- and pro-angiogenic factors. Treatment with neutralizing antibody against TGF-beta1 reversed both angiogenesis suppression and inhibition of leukocyte rolling induced by gallbladder tumors. TGF-beta1 also inhibited Mz-ChA-2 tumor cell proliferation. Our results indicate that the production of anti-angiogenesis/proliferation factors is regulated by tumor-host interactions.", + "TAG_DATA": [ + "89, mice {'context': 'B-organism'}", + "91, tumors {'context': 'B-neoplasm'}", + "93, mice {'context': 'B-organism'}", + "115, tumor {'phenotype': 'B-tumour growth'}", + "116, growth {'phenotype': 'I-tumour growth'}", + "123, inhibited {'effect': 'B-negative'}", + "125, mice {'context': 'B-organism'}", + "127, gallbladder {'context': 'B-neoplasm'}", + "128, tumors. {'context': 'I-neoplasm'}", + "137, mice {'context': 'B-organism'}", + "139, gallbladder {'context': 'B-neoplasm'}", + "140, tumors {'context': 'I-neoplasm'}", + "150, mice {'context': 'B-organism'}", + "152, tumors {'context': 'B-neoplasm'}", + "186, leukocyte {'context': 'B-cells'}", + "194, inhibited {'effect': 'B-negative'}", + "195, Mz-ChA-2 {'context': 'B-transformed cells'}", + "196, tumor {'context': 'I-transformed cells'}", + "197, cell {'context': 'I-transformed cells'}", + "198, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "89, mice ['l0', 'l1', 'l2', 'l3']", + "91, tumors ['l0', 'l4', 'l5', 'l6']", + "93, mice ['l7', 'l8', 'l9', 'l10', 'l11']", + "115, tumor ['l1', 'l4', 'l7', 'l12', 'l13', 'l14', 'l15']", + "116, growth ['l2', 'l5', 'l8', 'l12', 'l16', 'l17']", + "123, inhibited ['l3', 'l6', 'l9', 'l13', 'l16', 'l18', 'l19', 'l20']", + "125, mice ['l10', 'l14', 'l18', 'l21', 'l22', 'l23']", + "127, gallbladder ['l19', 'l21', 'l24', 'l25', 'l26', 'l27', 'l28']", + "128, tumors. ['l11', 'l15', 'l17', 'l20', 'l22', 'l24', 'l29']", + "137, mice ['l25', 'l30', 'l31', 'l32', 'l33']", + "139, gallbladder ['l26', 'l30', 'l34', 'l35', 'l36']", + "140, tumors ['l23', 'l27', 'l29', 'l31', 'l34', 'l37', 'l38']", + "150, mice ['l32', 'l35', 'l37', 'l39']", + "152, tumors ['l28', 'l33', 'l36', 'l38', 'l39']", + "186, leukocyte ['l40']", + "191, tumors. ['l40']", + "194, inhibited ['l41', 'l42', 'l43', 'l44']", + "195, Mz-ChA-2 ['l41', 'l45', 'l46', 'l47']", + "196, tumor ['l42', 'l45', 'l48', 'l49']", + "197, cell ['l43', 'l46', 'l48', 'l50']", + "198, proliferation. ['l44', 'l47', 'l49', 'l50']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "tumors." + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "gallbladder", + "tumors." + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "Mz-ChA-2", + "tumor", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "Mz-ChA-2", + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "10502825", + "TEXT": "Huntington disease (HD) is a genetically dominant condition caused by expanded CAG repeats coding for glutamine in the HD gene product huntingtin. Although HD symptoms reflect preferential neuronal death in specific brain regions, huntingtin is expressed in almost all tissues, so abnormalities outside the brain might be expected. Although involvement of nuclei and mitochondria in HD pathophysiology has been suggested, specific intracellular defects that might elicit cell death have been unclear. Mitochondria dysfunction is reported in HD brains; mitochondria are organelles that regulates apoptotic cell death. We now report that lymphoblasts derived from HD patients showed increased stress-induced apoptotic cell death associated with caspase-3 activation. When subjected to stress, HD lymphoblasts also manifested a considerable increase in mitochondrial depolarization correlated with increased glutamine repeats.", + "TAG_DATA": [ + "90, lymphoblasts {'context': 'B-cells'}", + "96, increased {'effect': 'B-positive'}", + "97, stress-induced {'effect': 'B-positive'}", + "98, apoptotic {'phenotype': 'B-apoptosis'}", + "99, cell {'phenotype': 'I-apoptosis'}", + "100, death {'phenotype': 'I-apoptosis'}", + "109, HD {'context': 'B-transformed cells'}", + "110, lymphoblasts {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "90, lymphoblasts ['l0', 'l1', 'l2', 'l3', 'l4']", + "96, increased ['l0', 'l5', 'l6', 'l7', 'l8']", + "97, stress-induced ['l1', 'l5', 'l9', 'l10', 'l11']", + "98, apoptotic ['l2', 'l6', 'l9', 'l12', 'l13']", + "99, cell ['l3', 'l7', 'l10', 'l12', 'l14']", + "100, death ['l4', 'l8', 'l11', 'l13', 'l14']", + "109, HD ['l15']", + "110, lymphoblasts ['l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "lymphoblasts" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "stress-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "lymphoblasts" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased", + "stress-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death" + ] + } + } + ] + }, + { + "PMID": "10502819", + "TEXT": "The antigenic variation of influenza virus represents a major health problem. However, the extracellular domain of the minor, virus-coded M2 protein is nearly invariant in all influenza A strains. We genetically fused this M2 domain to the hepatitis B virus core (HBc) protein to create fusion gene coding for M2HBc; this gene was efficiently expressed in Escherichia coli. Intraperitoneal or intranasal administration of purified M2HBc particles to mice provided 90-100% protection against a lethal virus challenge. The protection was mediated by antibodies, as it was transferable by serum. The enhanced immunogenicity of the M2 extracellular domain exposed on HBc particles allows broad-spectrum, long-lasting protection against influenza A infections.", + "TAG_DATA": [ + "67, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10470086", + "TEXT": "Biological circadian clocks oscillate with an approximately 24-hour period, are ubiquitous, and presumably confer a selective advantage by anticipating the transitions between day and night. The circadian rhythms of sleep, melatonin secretion and body core temperature are thought to be generated by the suprachiasmatic nucleus of the hypothalamus, the anatomic locus of the mammalian circadian clock. Autosomal semi-dominant mutations in rodents with fast or slow biological clocks (that is, short or long endogenous period lengths; tau) are associated with phase-advanced or delayed sleep-wake rhythms, respectively. These models predict the existence of familial human circadian rhythm variants but none of the human circadian rhythm disorders are known to have a familial tendency. Although a slight 'morning lark' tendency is common, individuals with a large and disabling sleep phase-advance are rare. This disorder, advanced sleep-phase syndrome, is characterized by very early sleep onset and offset; only two cases are reported in young adults. Here we describe three kindreds with a profound phase advance of the sleep-wake, melatonin and temperature rhythms associated with a very short tau. The trait segregates as an autosomal dominant with high penetrance. These kindreds represent a well-characterized familial circadian rhythm variant in humans and provide a unique opportunity for genetic analysis of human circadian physiology.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10470083", + "TEXT": "Dideoxynucleosides, which are potent inhibitors of HIV reverse transcriptase and other viral DNA polymerases, are a common component of highly active anti-retroviral therapy (HAART) (ref. 1). Six reverse transcriptase inhibitors have been approved for human use: azidothymidine; 2'3'-dideoxycytidine; 2'3'-dideoxyinosine; 2', 3'-didehydro-3'deoxythymidine; 2',3'-dideoxy-3'-thiacytidine; and 4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-++ +metha nol. Although drug-resistant HIV strains resulting from genetic mutation have emerged in patients treated with HAART (ref. 1), some patients show signs of drug resistance in the absence of drug-resistant viruses. In our study of alternative or additional mechanisms of resistance operating during antiviral therapy, overexpression and amplification of the MRP4 gene correlated with ATP-dependent efflux of PMEA (9-(2-phosphonylmethoxyethyl)adenine) and azidothymidine monophosphate from cells and, thus, with resistance to these drugs. Overexpression of MRP4 mRNA and MRP4 protein severely impaired the antiviral efficacy of PMEA, azidothymidine and other nucleoside analogs. Increased resistance to PMEA and amplification of the MRP4 gene correlated with enhanced drug efflux; transfer of chromosome 13 containing the amplified MRP4 gene conferred resistance to PMEA. MRP4 is the first transporter, to our knowledge, directly linked to the efflux of nucleoside monophosphate analogs from mammalian cells.", + "TAG_DATA": [ + "116, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "117, of {'perturbing_action': 'I-gene gain-of-function'}", + "118, MRP4 {'perturbing_action': 'I-gene gain-of-function'}", + "119, mRNA {'perturbing_action': 'I-gene gain-of-function'}", + "120, and {'perturbing_action': 'I-gene gain-of-function'}", + "121, MRP4 {'perturbing_action': 'I-gene gain-of-function'}", + "122, protein {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "116, Overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "117, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "118, MRP4 ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "119, mRNA ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "120, and ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "121, MRP4 ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "122, protein ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10426320", + "TEXT": "Traumatic spinal cord injury often results in complete loss of voluntary motor and sensory function below the site of injury. The long-term neurological deficits after spinal cord trauma may be due in part to widespread apoptosis of neurons and oligodendroglia in regions distant from and relatively unaffected by the initial injury. The caspase family of cysteine proteases regulates the execution of the mammalian apoptotic cell death program. Caspase-3 cleaves several essential downstream substrates involved in the expression of the apoptotic phenotype in vitro, including gelsolin, PAK2, fodrin, nuclear lamins and the inhibitory subunit of DNA fragmentation factor. Caspase-3 activation in vitro can be triggered by upstream events, leading to the release of cytochrome c from the mitochondria and the subsequent transactivation of procaspase-9 by Apaf-1. We report here that these upstream and downstream components of the caspase-3 apoptotic pathway are activated after traumatic spinal cord injury in rats, and occur early in neurons in the injury site and hours to days later in oligodendroglia adjacent to and distant from the injury site. Given these findings, targeting the upstream events of the caspase-3 cascade has therapeutic potential in the treatment of acute traumatic injury to the spinal cord.", + "TAG_DATA": [ + "99, in {'context': 'B-in vitro'}", + "100, vitro {'context': 'I-in vitro'}", + "147, rats, {'context': 'B-organism'}", + "152, neurons {'context': 'B-cells'}", + "163, oligodendroglia {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "99, in ['l0', 'l1']", + "100, vitro ['l0', 'l2']", + "147, rats, ['l1', 'l2', 'l3']", + "152, neurons ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10426314", + "TEXT": "A model for hepatitis B virus-associated chronic liver disease has been made using cloned hepatitis B virus DNA as a transgene in a severe combined immunodeficient host. These mice consistently support virus gene expression and replication. After adoptive transfer of unprimed, syngeneic splenocytes, these mice cleared virus from liver and serum, and developed chronic liver disease. This model will permit identification of the host and virus contributions to chronic liver disease in the absence of tolerance.", + "TAG_DATA": [ + "41, syngeneic {'context': 'B-cells'}", + "42, splenocytes, {'context': 'I-cells'}", + "44, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "41, syngeneic ['l0', 'l1']", + "42, splenocytes, ['l0', 'l2']", + "44, mice ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10395321", + "TEXT": "Definitive cure of an animal model of a human disease by gene transfer into hematopoietic stem cells has not yet been accomplished in the absence of spontaneous in vivo selection for transduced cells. Erythropoietic protoporphyria is a genetic disease in which ferrochelatase is defective. Protoporphyrin accumulates in erythrocytes, leaks into the plasma and results in severe skin photosensitivity. Using a mouse model of erythropoietic protoporphyria, we demonstrate here that ex vivo preselection of hematopoietic stem cells transduced with a polycistronic retrovirus expressing both human ferrochelatase and green fluorescent protein results in complete and long-term correction of skin photosensitivity in all transplanted mice.", + "TAG_DATA": [ + "73, hematopoietic {'context': 'B-cells'}", + "74, stem {'context': 'I-cells'}", + "75, cells {'context': 'I-cells'}", + "76, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "77, with {'perturbing_action': 'I-gene gain-of-function'}", + "78, a {'perturbing_action': 'I-gene gain-of-function'}", + "79, polycistronic {'perturbing_action': 'I-gene gain-of-function'}", + "80, retrovirus {'perturbing_action': 'I-gene gain-of-function'}", + "81, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "82, both {'perturbing_action': 'I-gene gain-of-function'}", + "83, human {'perturbing_action': 'I-gene gain-of-function'}", + "84, ferrochelatase {'perturbing_action': 'I-gene gain-of-function'}", + "85, and {'perturbing_action': 'I-gene gain-of-function'}", + "86, green {'perturbing_action': 'I-gene gain-of-function'}", + "87, fluorescent {'perturbing_action': 'I-gene gain-of-function'}", + "88, protein {'perturbing_action': 'I-gene gain-of-function'}", + "101, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, hematopoietic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "74, stem ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "75, cells ['l1', 'l16', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "76, transduced ['l2', 'l17', 'l31', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "77, with ['l3', 'l18', 'l32', 'l45', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "78, a ['l4', 'l19', 'l33', 'l46', 'l58', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "79, polycistronic ['l5', 'l20', 'l34', 'l47', 'l59', 'l70', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "80, retrovirus ['l6', 'l21', 'l35', 'l48', 'l60', 'l71', 'l81', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "81, expressing ['l7', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "82, both ['l8', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l100', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "83, human ['l9', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l108', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "84, ferrochelatase ['l10', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l115', 'l121', 'l122', 'l123', 'l124', 'l125']", + "85, and ['l11', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l121', 'l126', 'l127', 'l128', 'l129']", + "86, green ['l12', 'l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l126', 'l130', 'l131', 'l132']", + "87, fluorescent ['l13', 'l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l118', 'l123', 'l127', 'l130', 'l133', 'l134']", + "88, protein ['l14', 'l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l113', 'l119', 'l124', 'l128', 'l131', 'l133', 'l135']", + "101, mice. ['l15', 'l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l129', 'l132', 'l134', 'l135']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "a", + "polycistronic", + "retrovirus", + "expressing", + "both", + "human", + "ferrochelatase", + "and", + "green", + "fluorescent", + "protein" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "a", + "polycistronic", + "retrovirus", + "expressing", + "both", + "human", + "ferrochelatase", + "and", + "green", + "fluorescent", + "protein" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "10371500", + "TEXT": "The severe disease atypical measles occurred when individuals immunized with a poorly protective inactivated vaccine contracted measles, and was postulated to be due to a lack of fusion-inhibiting antibodies. Here, rhesus macaques immunized with formalin-inactivated measles vaccine developed transient neutralizing and fusion-inhibiting antibodies, but no cytotoxic T-cell response. Subsequent infection with measles virus caused an atypical rash and pneumonitis, accompanied by immune complex deposition and an increase in eosinophils. Fusion-inhibiting antibody appeared earlier in these monkeys than in non-immunized monkeys. These data indicate that atypical measles results from previous priming for a nonprotective type 2 CD4 T-cell response rather than from lack of functional antibody against the fusion protein.", + "TAG_DATA": [ + "30, rhesus {'context': 'B-organism'}", + "31, macaques {'context': 'I-organism'}", + "75, monkeys {'context': 'B-organism'}", + "79, monkeys. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "30, rhesus ['l0']", + "31, macaques ['l0']", + "75, monkeys ['l1']", + "79, monkeys. ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10371499", + "TEXT": "Hypertrophic chondrocytes in the epiphyseal growth plate express the angiogenic protein vascular endothelial growth factor (VEGF). To determine the role of VEGF in endochondral bone formation, we inactivated this factor through the systemic administration of a soluble receptor chimeric protein (Flt-(1-3)-IgG) to 24-day-old mice. Blood vessel invasion was almost completely suppressed, concomitant with impaired trabecular bone formation and expansion of hypertrophic chondrocyte zone. Recruitment and/or differentiation of chondroclasts, which express gelatinase B/matrix metalloproteinase-9, and resorption of terminal chondrocytes decreased. Although proliferation, differentiation and maturation of chondrocytes were apparently normal, resorption was inhibited. Cessation of the anti-VEGF treatment was followed by capillary invasion, restoration of bone growth, resorption of the hypertrophic cartilage and normalization of the growth plate architecture. These findings indicate that VEGF-mediated capillary invasion is an essential signal that regulates growth plate morphogenesis and triggers cartilage remodeling. Thus, VEGF is an essential coordinator of chondrocyte death, chondroclast function, extracellular matrix remodeling, angiogenesis and bone formation in the growth plate.", + "TAG_DATA": [ + "42, 24-day-old {'context': 'B-organism'}", + "43, mice. {'context': 'I-organism'}", + "80, proliferation, {'phenotype': 'B-proliferation'}", + "81, differentiation {'phenotype': 'B-differentiation'}", + "85, chondrocytes {'context': 'B-cells'}", + "88, normal, {'effect': 'B-no effect'}", + "102, restoration {'effect': 'B-rescues'}", + "104, bone {'phenotype': 'B-tumour growth'}", + "105, growth, {'phenotype': 'I-tumour growth'}", + "115, growth {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "42, 24-day-old ['l0', 'l1']", + "43, mice. ['l0']", + "80, proliferation, ['l2', 'l3', 'l4']", + "81, differentiation ['l2', 'l5', 'l6']", + "85, chondrocytes ['l1', 'l3', 'l5', 'l7']", + "88, normal, ['l4', 'l6', 'l7']", + "102, restoration ['l8', 'l9']", + "104, bone ['l8', 'l10']", + "105, growth, ['l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "context": { + "val": "cells", + "words": [ + "chondrocytes" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "normal," + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "chondrocytes" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "normal," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "chondrocytes" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "normal," + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restoration" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "bone", + "growth," + ] + } + } + ] + }, + { + "PMID": "10229234", + "TEXT": "Familial Alzheimer disease mutations of presenilin 1 (PS-1) enhance the generation of A beta1-42, indicating that PS-1 is involved in amyloidogenesis. However, PS-1 transgenic mice have failed to show amyloid plaques in their brains. Because PS-1 mutations facilitate apoptotic neuronal death in vitro, we did careful quantitative studies in PS-1 transgenic mice and found that neurodegeneration was significantly accelerated in mice older than 13 months (aged mice) with familial Alzheimer disease mutant PS-1, without amyloid plaque formation. However, there were significantly more neurons containing intracellularly deposited A beta42 in aged mutant transgenic mice. Our data indicate that the pathogenic role of the PS-1 mutation is upstream of the amyloid cascade.", + "TAG_DATA": [ + "35, PS-1 {'perturbing_action': 'B-other'}", + "36, mutations {'perturbing_action': 'I-other'}", + "37, facilitate {'effect': 'B-positive'}", + "41, in {'context': 'B-in vitro'}", + "42, vitro, {'context': 'I-in vitro'}", + "49, PS-1 {'perturbing_action': 'B-gene gain-of-function'}", + "50, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "51, mice {'context': 'B-organism'}", + "60, mice {'context': 'B-organism'}", + "66, mice) {'context': 'I-organism'}", + "68, familial {'perturbing_action': 'B-other'}", + "69, Alzheimer {'perturbing_action': 'I-other'}", + "70, disease {'perturbing_action': 'I-other'}", + "71, mutant {'perturbing_action': 'I-other'}", + "72, PS-1, {'perturbing_action': 'I-other'}", + "82, neurons {'context': 'B-cells'}", + "91, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "92, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "35, PS-1 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "36, mutations ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "37, facilitate ['l1', 'l9', 'l15', 'l16', 'l17', 'l18', 'l19']", + "41, in ['l2', 'l10', 'l15', 'l20', 'l21', 'l22', 'l23']", + "42, vitro, ['l3', 'l11', 'l16', 'l20', 'l24', 'l25', 'l26']", + "49, PS-1 ['l4', 'l12', 'l17', 'l21', 'l24', 'l27', 'l28']", + "50, transgenic ['l5', 'l13', 'l18', 'l22', 'l25', 'l27', 'l29']", + "51, mice ['l6', 'l14', 'l19', 'l23', 'l26', 'l28', 'l29']", + "60, mice ['l7', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "66, mice) ['l8', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "68, familial ['l31', 'l36', 'l41', 'l42', 'l43', 'l44', 'l45']", + "69, Alzheimer ['l32', 'l37', 'l41', 'l46', 'l47', 'l48', 'l49']", + "70, disease ['l33', 'l38', 'l42', 'l46', 'l50', 'l51', 'l52']", + "71, mutant ['l34', 'l39', 'l43', 'l47', 'l50', 'l53', 'l54']", + "72, PS-1, ['l35', 'l40', 'l44', 'l48', 'l51', 'l53', 'l55']", + "82, neurons ['l45', 'l49', 'l52', 'l54', 'l55', 'l56', 'l57']", + "91, transgenic ['l56', 'l58']", + "92, mice. ['l57', 'l58']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "PS-1", + "mutations" + ] + }, + "effect": { + "val": "positive", + "words": [ + "facilitate" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "PS-1", + "mutations" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "PS-1", + "mutations", + "familial", + "Alzheimer", + "disease", + "mutant", + "PS-1," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice)" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "facilitate" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "facilitate" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PS-1", + "transgenic" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "facilitate" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PS-1", + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PS-1", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "familial", + "Alzheimer", + "disease", + "mutant", + "PS-1," + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neurons" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + } + } + ] + }, + { + "PMID": "10202937", + "TEXT": "Fludarabine is a nucleoside analog used in the treatment of hematologic malignancies that can induce severe and prolonged immunosuppression. Although it can be incorporated into the DNA of dividing cells, fludarabine is also a potent inhibitor of cells with a low growth fraction, thus it must have other mechanisms of action. STAT1, which is activated in response to many lymphocyte-activating cytokines including the interferons, is essential for cell-mediated immunity, as the absence of this protein is associated with prominent defects in the ability to control viral infections. Here we show that fludarabine, but not the immunosuppressant cyclosporine A, inhibits the cytokine-induced activation of STAT1 and STAT1-dependent gene transcription in normal resting or activated lymphocytes. Fludarabine caused a specific depletion of STAT1 protein (and mRNA) but not of other STATs. This loss of STAT1 was also seen in cells from patients treated with fludarabine in vivo. Brief exposure to fludarabine led to a sustained loss of STAT1, analogous to the prolonged period of immunosuppression induced by exposure to the drug in vivo. Thus, STAT1 may be a useful target in the development of new immunosuppressive and antineoplastic agents.", + "TAG_DATA": [ + "110, resting {'context': 'B-cells'}", + "112, activated {'context': 'B-cells'}", + "113, lymphocytes. {'context': 'B-cells'}", + "137, cells {'context': 'B-cells'}", + "139, patients {'context': 'I-patient'}", + "143, in {'context': 'B-in vivo'}", + "144, vivo. {'context': 'I-in vivo'}", + "169, in {'context': 'B-in vivo'}", + "170, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "110, resting ['l0', 'l1']", + "112, activated ['l0', 'l2']", + "113, lymphocytes. ['l1', 'l2']", + "137, cells ['l3', 'l4', 'l5']", + "139, patients ['l3', 'l6', 'l7']", + "143, in ['l4', 'l6', 'l8']", + "144, vivo. ['l5', 'l7', 'l8']", + "169, in ['l9']", + "170, vivo. ['l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10202930", + "TEXT": "Programmed cell death (apoptosis) seems to be the principal mechanism whereby anti-oncogenic therapies such as chemotherapy and radiation effect their responses. Resistance to apoptosis, therefore, is probably a principal mechanism whereby tumors are able to overcome these cancer therapies. The transcription factor NF-kappaB is activated by chemotherapy and by irradiation in some cancer cell lines. Furthermore, inhibition of NF-kappaB in vitro leads to enhanced apoptosis in response to a variety of different stimuli. We show here that inhibition of NF-kappaB through the adenoviral delivery of a modified form of IkappaBalpha, the inhibitor of NF-kappaB, sensitizes chemoresistant tumors to the apoptotic potential of TNFalpha and of the chemotherapeutic compound CPT-11, resulting in tumor regression. These results demonstrate that the activation of NF-kappaB in response to chemotherapy is a principal mechanism of inducible tumor chemoresistance, and establish the inhibition of NF-kappaB as a new approach to adjuvant therapy in cancer treatment.", + "TAG_DATA": [ + "52, cancer {'context': 'B-transformed cells'}", + "53, cell {'context': 'I-transformed cells'}", + "54, lines. {'context': 'I-transformed cells'}", + "56, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "57, of {'perturbing_action': 'I-pharmacological inhibition'}", + "58, NF-kappaB {'perturbing_action': 'I-pharmacological inhibition'}", + "59, in {'context': 'B-in vitro'}", + "60, vitro {'context': 'I-in vitro'}", + "63, enhanced {'effect': 'B-positive'}", + "64, apoptosis {'phenotype': 'B-apoptosis'}", + "77, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "78, of {'perturbing_action': 'I-pharmacological inhibition'}", + "79, NF-kappaB {'perturbing_action': 'I-pharmacological inhibition'}", + "80, through {'perturbing_action': 'I-other'}", + "82, adenoviral {'perturbing_action': 'B-other'}", + "83, delivery {'perturbing_action': 'I-other'}", + "84, of {'perturbing_action': 'I-other'}", + "85, a {'perturbing_action': 'I-other'}", + "86, modified {'perturbing_action': 'I-other'}", + "87, form {'perturbing_action': 'I-other'}", + "88, of {'perturbing_action': 'I-other'}", + "89, IkappaBalpha, {'perturbing_action': 'I-other'}", + "95, chemoresistant {'context': 'B-neoplasm'}", + "96, tumors {'context': 'I-neoplasm'}", + "99, apoptotic {'phenotype': 'B-apoptosis'}", + "100, potential {'phenotype': 'I-apoptosis'}", + "109, resulting {'effect': 'B-positive'}", + "110, in {'effect': 'I-positive'}", + "111, tumor {'phenotype': 'B-tumour regression'}", + "112, regression. {'phenotype': 'I-tumour regression'}" + ], + "LINK_DATA": [ + "52, cancer ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "53, cell ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "54, lines. ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "56, inhibition ['l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "57, of ['l2', 'l9', 'l15', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "58, NF-kappaB ['l3', 'l10', 'l16', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "59, in ['l4', 'l11', 'l17', 'l23', 'l28', 'l32', 'l36', 'l37', 'l38']", + "60, vitro ['l5', 'l12', 'l18', 'l24', 'l29', 'l33', 'l36', 'l39', 'l40']", + "63, enhanced ['l6', 'l13', 'l19', 'l25', 'l30', 'l34', 'l37', 'l39', 'l41']", + "64, apoptosis ['l7', 'l14', 'l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l41']", + "77, inhibition ['l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "78, of ['l42', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "79, NF-kappaB ['l43', 'l58', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "80, through ['l44', 'l59', 'l73', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "82, adenoviral ['l45', 'l60', 'l74', 'l87', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "83, delivery ['l46', 'l61', 'l75', 'l88', 'l101', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "84, of ['l47', 'l62', 'l76', 'l89', 'l102', 'l114', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "85, a ['l48', 'l63', 'l77', 'l90', 'l103', 'l115', 'l126', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146']", + "86, modified ['l49', 'l64', 'l78', 'l91', 'l104', 'l116', 'l127', 'l137', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "87, form ['l50', 'l65', 'l79', 'l92', 'l105', 'l117', 'l128', 'l138', 'l147', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163']", + "88, of ['l51', 'l66', 'l80', 'l93', 'l106', 'l118', 'l129', 'l139', 'l148', 'l156', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170']", + "89, IkappaBalpha, ['l52', 'l67', 'l81', 'l94', 'l107', 'l119', 'l130', 'l140', 'l149', 'l157', 'l164', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176']", + "95, chemoresistant ['l53', 'l68', 'l82', 'l95', 'l108', 'l120', 'l131', 'l141', 'l150', 'l158', 'l165', 'l171', 'l177', 'l178', 'l179', 'l180', 'l181']", + "96, tumors ['l54', 'l69', 'l83', 'l96', 'l109', 'l121', 'l132', 'l142', 'l151', 'l159', 'l166', 'l172', 'l177', 'l182', 'l183', 'l184']", + "99, apoptotic ['l55', 'l70', 'l84', 'l97', 'l110', 'l122', 'l133', 'l143', 'l152', 'l160', 'l167', 'l173', 'l178', 'l182', 'l185', 'l186', 'l187']", + "100, potential ['l56', 'l71', 'l85', 'l98', 'l111', 'l123', 'l134', 'l144', 'l153', 'l161', 'l168', 'l174', 'l179', 'l183', 'l185', 'l188', 'l189']", + "109, resulting ['l57', 'l72', 'l86', 'l99', 'l112', 'l124', 'l135', 'l145', 'l154', 'l162', 'l169', 'l175', 'l180', 'l184', 'l186', 'l188', 'l190', 'l191', 'l192']", + "110, in ['l100', 'l113', 'l125', 'l136', 'l146', 'l155', 'l163', 'l170', 'l176', 'l181', 'l187', 'l189', 'l190', 'l193', 'l194']", + "111, tumor ['l191', 'l193', 'l195']", + "112, regression. ['l192', 'l194', 'l195']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cell", + "lines." + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "of", + "NF-kappaB" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cell", + "lines." + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cell", + "lines." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "NF-kappaB" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "NF-kappaB" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced", + "resulting" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "NF-kappaB" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptotic", + "potential" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced", + "resulting", + "in" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptotic", + "potential" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "NF-kappaB" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "chemoresistant", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "through", + "adenoviral", + "delivery", + "of", + "a", + "modified", + "form", + "IkappaBalpha," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "chemoresistant", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "through", + "adenoviral", + "delivery", + "of", + "a", + "modified", + "form", + "IkappaBalpha," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "potential" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "through", + "adenoviral", + "delivery", + "of", + "a", + "modified", + "form", + "IkappaBalpha," + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "chemoresistant", + "tumors" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "potential" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "chemoresistant", + "tumors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression." + ] + } + } + ] + }, + { + "PMID": "10202926", + "TEXT": "Food allergy is a common and often fatal disease with no effective treatment. We describe here a new immunoprophylactic strategy using oral allergen-gene immunization to modulate peanut antigen-induced murine anaphylactic responses. Oral administration of DNA nanoparticles synthesized by complexing plasmid DNA with chitosan, a natural biocompatible polysaccharide, resulted in transduced gene expression in the intestinal epithelium. Mice receiving nanoparticles containing a dominant peanut allergen gene (pCMVArah2) produced secretory IgA and serum IgG2a. Compared with non-immunized mice or mice treated with 'naked' DNA, mice immunized with nanoparticles showed a substantial reduction in allergen-induced anaphylaxis associated with reduced levels of IgE, plasma histamine and vascular leakage. These results demonstrate that oral allergen-gene immunization with chitosan-DNA nanoparticles is effective in modulating murine anaphylactic responses, and indicate its prophylactic utility in treating food allergy.", + "TAG_DATA": [ + "54, intestinal {'context': 'B-tissue/organ'}", + "55, epithelium. {'context': 'I-tissue/organ'}", + "56, Mice {'context': 'B-organism'}", + "75, mice {'context': 'B-organism'}", + "77, mice {'context': 'B-organism'}", + "82, mice {'context': 'B-organism'}", + "89, reduction {'effect': 'B-negative'}", + "91, allergen-induced {'effect': 'B-positive'}", + "92, anaphylaxis {'phenotype': 'B-autophagy'}" + ], + "LINK_DATA": [ + "54, intestinal ['l0']", + "55, epithelium. ['l0']", + "77, mice ['l1', 'l2', 'l3', 'l4']", + "82, mice ['l1', 'l5', 'l6', 'l7']", + "89, reduction ['l2', 'l5', 'l8', 'l9']", + "91, allergen-induced ['l3', 'l6', 'l8', 'l10']", + "92, anaphylaxis ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduction" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "allergen-induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "anaphylaxis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduction" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "anaphylaxis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "allergen-induced" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "anaphylaxis" + ] + } + } + ] + }, + { + "PMID": "10086393", + "TEXT": "In areas of stable transmission, clinical immunity to mild malaria is acquired slowly, so it is not usually effective until early adolescence. Life-threatening disease is, however, restricted to a much younger age group, indicating that resistance to the severe clinical consequences of infection is acquired more quickly. Understanding how rapidly immunity develops to severe malaria is essential, as severe malaria should be the primary target of intervention strategies, and predicting the result of interventions that reduce host exposure will require consideration of these dynamics. Severe disease in childhood is less frequent in areas where transmission is the greatest. One explanation for this is that infants experience increased exposure to infection while they are protected from disease, possibly by maternal antibody. They therefore emerge from this period of clinical protection with considerably more immunity than those who experience lower transmission intensities. Here we use this data, assuming a period of clinical protection, to estimate the number of prior infections needed to reduce the risk of severe disease to negligible levels. Contrary to expectations, one or two successful infective bites seem to be all that is necessary across a broad range of transmission intensities.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10086392", + "TEXT": "The tumor suppressor protein p53 is an essential molecule in cell proliferation and programmed cell death (apoptosis), and has been postulated to play a principal part in the development of atherosclerosis. We have examined the effect of p53 inactivation on atherogenesis in apoE-knockout mice, an animal model for atherosclerosis. We found that, compared with p53+/+/apoE-/- mice, p53-/-/apoE-/- mice developed considerably accelerated aortic atherosclerosis in the presence of a similar serum cholesterol in response to a high-fat diet. Furthermore, the atherosclerotic lesions in p53-/-/apoE-/- mice had a significant (approximately 280%) increase in cell proliferation rate and an insignificant (approximately 180%) increase in apoptosis compared with those in p53+/+/apoE-/- mice. Our observations indicate that the role of p53 in atherosclerotic lesion development might be associated with its function in cell replication control, and that p53-independent mechanisms can mediate the apoptotic response in atherosclerosis.", + "TAG_DATA": [ + "42, apoE-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "43, mice, {'context': 'B-organism'}", + "54, p53+/+/apoE-/- {'perturbing_action': 'B-gene loss-of-function'}", + "55, mice, {'context': 'B-organism'}", + "56, p53-/-/apoE-/- {'perturbing_action': 'B-gene loss-of-function'}", + "57, mice {'context': 'B-organism'}", + "61, aortic {'context': 'B-tissue/organ'}", + "82, p53-/-/apoE-/- {'perturbing_action': 'B-gene loss-of-function'}", + "83, mice {'context': 'B-organism'}", + "89, increase {'effect': 'B-positive'}", + "91, cell {'context': 'B-cells'}", + "92, proliferation {'phenotype': 'B-proliferation'}", + "99, increase {'effect': 'B-positive'}", + "101, apoptosis {'phenotype': 'B-apoptosis'}", + "106, p53+/+/apoE-/- {'perturbing_action': 'B-gene loss-of-function'}", + "107, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "42, apoE-knockout ['l0', 'l1']", + "43, mice, ['l0', 'l2']", + "54, p53+/+/apoE-/- ['l3', 'l4', 'l5', 'l6']", + "55, mice, ['l3', 'l7', 'l8', 'l9']", + "56, p53-/-/apoE-/- ['l4', 'l7', 'l10', 'l11']", + "57, mice ['l5', 'l8', 'l10', 'l12']", + "61, aortic ['l1', 'l2', 'l6', 'l9', 'l11', 'l12']", + "82, p53-/-/apoE-/- ['l13', 'l14', 'l15', 'l16', 'l17']", + "83, mice ['l13', 'l18', 'l19', 'l20']", + "89, increase ['l14', 'l18', 'l21', 'l22']", + "91, cell ['l15', 'l19', 'l21', 'l23']", + "92, proliferation ['l16', 'l20', 'l22', 'l23']", + "99, increase ['l17', 'l24', 'l25']", + "101, apoptosis ['l24', 'l26', 'l27']", + "106, p53+/+/apoE-/- ['l26', 'l28']", + "107, mice. ['l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "apoE-knockout", + "p53+/+/apoE-/-", + "p53-/-/apoE-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "apoE-knockout", + "p53+/+/apoE-/-", + "p53-/-/apoE-/-" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "aortic" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-/-/apoE-/-" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increase" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-/-/apoE-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-/-/apoE-/-" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "effect": { + "val": "positive", + "words": [ + "increase" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53+/+/apoE-/-" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "10086382", + "TEXT": "Prostate cancer progresses from a hormone-sensitive, androgen-dependent stage to a hormone-refractory, androgen-independent tumor. The androgen receptor pathway functions in these androgen-independent tumors despite anti-androgen therapy. In our LAPC-4 prostate cancer model, androgen-independent sublines expressed higher levels of the HER-2/neu receptor tyrosine kinase than their androgen-dependent counterparts. Forced overexpression of HER-2/neu in androgen-dependent prostate cancer cells allowed ligand-independent growth. HER-2/neu activated the androgen receptor pathway in the absence of ligand and synergized with low levels of androgen to 'superactivate' the pathway. By modulating the response to low doses of androgen, a tyrosine kinase receptor can restore androgen receptor function to prostate cancer cells, a finding directly related to the clinical progression of prostate cancer.", + "TAG_DATA": [ + "46, Forced {'perturbing_action': 'B-gene gain-of-function'}", + "47, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "48, of {'perturbing_action': 'I-gene gain-of-function'}", + "49, HER-2/neu {'perturbing_action': 'I-gene gain-of-function'}", + "51, androgen-dependent {'context': 'B-transformed cells'}", + "52, prostate {'context': 'I-transformed cells'}", + "53, cancer {'context': 'I-transformed cells'}", + "54, cells {'context': 'I-transformed cells'}", + "99, prostate {'context': 'B-transformed cells'}", + "100, cancer {'context': 'I-transformed cells'}", + "101, cells, {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "46, Forced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "47, overexpression ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "48, of ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "49, HER-2/neu ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "51, androgen-dependent ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "52, prostate ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "53, cancer ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "54, cells ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "99, prostate ['l28', 'l29']", + "100, cancer ['l28', 'l30']", + "101, cells, ['l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "overexpression", + "of", + "HER-2/neu" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "androgen-dependent", + "prostate", + "cancer", + "cells" + ] + } + } + ] + }, + { + "PMID": "10086381", + "TEXT": "Only a small percentage of primary prostate cancers have genetic changes. In contrast, nearly 90% of clinically significant human prostate cancers seems to express high levels of the nuclear phosphoprotein pp32 by in situ hybridization. Because pp32 inhibits oncogene-mediated transformation, we investigated its paradoxical expression in cancer by comparing the sequence and function of pp32 species from paired benign prostate tissue and adjacent prostatic carcinoma from three patients. Here we demonstrate that pp32 is expressed in benign prostatic tissue, but pp32r1 and pp32r2, closely-related genes located on different chromosomes, are expressed in prostate cancer. Although pp32 is a tumor suppressor, pp32r1 and pp32r2 are tumorigenic. Alternative use of the pp32, pp32r1 and pp32r2 genes may modulate the oncogenic potential of human prostate cancer.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9930871", + "TEXT": "Prostaglandins (PGs) are ubiquitous lipid mediators derived from cyclooxygenase metabolism of arachidonic acid that exert a broad range of physiologic activities, including modulation of inflammation, ovulation and arterial blood pressure. PGE2, a chief cyclooxygenase product, modulates blood pressure and fertility, although the specific G protein-coupled receptors mediating these effects remain poorly defined. To evaluate the physiologic role of the PGE2 EP2 receptor subtype, we created mice with targeted disruption of this gene (EP2-/-). EP2-/- mice develop normally but produce small litters and have slightly elevated baseline systolic blood pressure. In EP2-/- mice, the characteristic hypotensive effect of intravenous PGE2 infusion was absent; PGE2 infusion instead produced hypertension. When fed a diet high in salt, the EP2-/- mice developed profound systolic hypertension, whereas wild-type mice showed no change in systolic blood pressure. Analysis of wild-type and EP2-/- mice on day 5 of pregnancy indicated that the reduced litter size of EP2-/- mice is due to a pre-implantation defect. This reduction of implanted embryos could be accounted for by impaired ovulation and dramatic reductions in fertilization observed on day 2 of pregnancy. These data demonstrate that the EP2 receptor mediates arterial dilatation, salt-sensitive hypertension, and also plays an essential part in female fertility.", + "TAG_DATA": [ + "65, mice {'context': 'B-organism'}", + "67, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "68, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "69, of {'perturbing_action': 'I-gene loss-of-function'}", + "70, this {'perturbing_action': 'I-gene loss-of-function'}", + "71, gene {'perturbing_action': 'I-gene loss-of-function'}", + "72, (EP2-/-). {'perturbing_action': 'I-gene loss-of-function'}", + "73, EP2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "74, mice {'context': 'B-organism'}", + "90, EP2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "91, mice, {'context': 'B-organism'}", + "115, EP2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "116, mice {'context': 'B-organism'}", + "123, mice {'context': 'B-organism'}", + "135, EP2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "136, mice {'context': 'B-organism'}", + "149, EP2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "150, mice {'context': 'B-organism'}", + "167, impaired {'effect': 'B-negative'}", + "171, reductions {'effect': 'B-negative'}", + "173, fertilization {'phenotype': 'B-ferroptosis'}" + ], + "LINK_DATA": [ + "65, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "67, targeted ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "68, disruption ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "69, of ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "70, this ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "71, gene ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "72, (EP2-/-). ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "73, EP2-/- ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35', 'l36']", + "74, mice ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "90, EP2-/- ['l37']", + "91, mice, ['l36', 'l37']", + "115, EP2-/- ['l38', 'l39']", + "116, mice ['l38']", + "123, mice ['l39', 'l40', 'l41']", + "135, EP2-/- ['l40', 'l42', 'l43', 'l44', 'l45', 'l46']", + "136, mice ['l41', 'l42', 'l47', 'l48', 'l49']", + "149, EP2-/- ['l43', 'l47', 'l50', 'l51', 'l52', 'l53', 'l54']", + "150, mice ['l44', 'l48', 'l50', 'l55', 'l56']", + "161, embryos ['l45', 'l49', 'l51', 'l55', 'l57', 'l58', 'l59']", + "167, impaired ['l46', 'l52', 'l56', 'l57', 'l60', 'l61']", + "171, reductions ['l53', 'l58', 'l60', 'l62']", + "173, fertilization ['l54', 'l59', 'l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "disruption", + "of", + "this", + "gene", + "(EP2-/-).", + "EP2-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EP2-/-" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired", + "reductions" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EP2-/-" + ] + }, + "phenotype": { + "val": "ferroptosis", + "words": [ + "fertilization" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired", + "reductions" + ] + }, + "phenotype": { + "val": "ferroptosis", + "words": [ + "fertilization" + ] + } + } + ] + }, + { + "PMID": "9930868", + "TEXT": "A substantial risk in using live attenuated, multiply deleted viruses as vaccines against AIDS is their potential to induce AIDS. A mutant of the simian immunodeficiency virus (SIV) with large deletions in nef and vpr and in the negative regulatory element induced AIDS in six of eight infant macaques vaccinated orally or intravenously. Early signs of immune dysfunction were seen in the remaining two offspring. Prolonged follow-up of sixteen vaccinated adult macaques also showed resurgence of chronic viremia in four animals: two of these developed early signs of disease and one died of AIDS. We conclude that this multiply deleted SIV is pathogenic and that human AIDS vaccines built on similar prototypes may cause AIDS.", + "TAG_DATA": [ + "21, mutant {'perturbing_action': 'B-other'}", + "22, of {'perturbing_action': 'I-other'}", + "23, the {'perturbing_action': 'I-other'}", + "24, simian {'perturbing_action': 'I-other'}", + "25, immunodeficiency {'perturbing_action': 'I-other'}", + "26, virus {'perturbing_action': 'I-other'}", + "27, (SIV) {'perturbing_action': 'I-other'}", + "28, with {'perturbing_action': 'I-other'}", + "29, large {'perturbing_action': 'I-other'}", + "30, deletions {'perturbing_action': 'I-other'}", + "31, in {'perturbing_action': 'I-other'}", + "32, nef {'perturbing_action': 'I-gene loss-of-function'}", + "33, and {'perturbing_action': 'I-gene loss-of-function'}", + "34, vpr {'perturbing_action': 'I-gene loss-of-function'}", + "35, and {'perturbing_action': 'I-other'}", + "36, in {'perturbing_action': 'I-other'}", + "37, the {'perturbing_action': 'I-other'}", + "38, negative {'perturbing_action': 'I-other'}", + "39, regulatory {'perturbing_action': 'I-other'}", + "40, element {'perturbing_action': 'I-other'}", + "47, infant {'context': 'B-organism'}", + "48, macaques {'context': 'I-organism'}", + "70, adult {'context': 'B-organism'}", + "71, macaques {'context': 'I-organism'}", + "80, animals: {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "21, mutant ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "22, of ['l0', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "23, the ['l1', 'l21', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "24, simian ['l2', 'l22', 'l41', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "25, immunodeficiency ['l3', 'l23', 'l42', 'l59', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "26, virus ['l4', 'l24', 'l43', 'l60', 'l76', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "27, (SIV) ['l5', 'l25', 'l44', 'l61', 'l77', 'l91', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "28, with ['l6', 'l26', 'l45', 'l62', 'l78', 'l92', 'l105', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "29, large ['l7', 'l27', 'l46', 'l63', 'l79', 'l93', 'l106', 'l117', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "30, deletions ['l8', 'l28', 'l47', 'l64', 'l80', 'l94', 'l107', 'l118', 'l131', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "31, in ['l9', 'l29', 'l48', 'l65', 'l81', 'l95', 'l108', 'l119', 'l132', 'l144', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166']", + "32, nef ['l10', 'l30', 'l49', 'l66', 'l82', 'l96', 'l109', 'l120', 'l133', 'l145', 'l156', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176']", + "33, and ['l11', 'l31', 'l50', 'l67', 'l83', 'l97', 'l110', 'l121', 'l134', 'l146', 'l157', 'l167', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185']", + "34, vpr ['l12', 'l32', 'l51', 'l68', 'l84', 'l98', 'l111', 'l122', 'l135', 'l147', 'l158', 'l168', 'l177', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "35, and ['l13', 'l33', 'l52', 'l69', 'l85', 'l99', 'l112', 'l123', 'l136', 'l148', 'l159', 'l169', 'l178', 'l186', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200']", + "36, in ['l14', 'l34', 'l53', 'l70', 'l86', 'l100', 'l113', 'l124', 'l137', 'l149', 'l160', 'l170', 'l179', 'l187', 'l194', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206']", + "37, the ['l15', 'l35', 'l54', 'l71', 'l87', 'l101', 'l114', 'l125', 'l138', 'l150', 'l161', 'l171', 'l180', 'l188', 'l195', 'l201', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213']", + "38, negative ['l16', 'l36', 'l126', 'l139', 'l151', 'l162', 'l172', 'l181', 'l189', 'l196', 'l202', 'l207', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220']", + "39, regulatory ['l17', 'l37', 'l55', 'l72', 'l127', 'l140', 'l152', 'l163', 'l173', 'l182', 'l190', 'l197', 'l203', 'l208', 'l214', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226']", + "40, element ['l18', 'l38', 'l56', 'l73', 'l88', 'l102', 'l128', 'l141', 'l153', 'l164', 'l174', 'l183', 'l191', 'l198', 'l204', 'l209', 'l215', 'l221', 'l227', 'l228', 'l229', 'l230']", + "47, infant ['l19', 'l39', 'l57', 'l74', 'l89', 'l103', 'l115', 'l129', 'l142', 'l154', 'l165', 'l175', 'l184', 'l192', 'l199', 'l205', 'l210', 'l216', 'l222', 'l227', 'l231']", + "48, macaques ['l20', 'l40', 'l58', 'l75', 'l90', 'l104', 'l116', 'l130', 'l143', 'l155', 'l166', 'l176', 'l185', 'l193', 'l200', 'l206', 'l211', 'l217', 'l223', 'l228', 'l231']", + "70, adult ['l212', 'l218', 'l224', 'l229', 'l232', 'l233']", + "71, macaques ['l213', 'l219', 'l225', 'l230', 'l232', 'l234']", + "80, animals: ['l220', 'l226', 'l233', 'l234']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "of", + "the", + "simian", + "immunodeficiency", + "virus", + "(SIV)", + "with", + "large", + "deletions", + "in", + "and", + "negative", + "regulatory", + "element" + ] + }, + "context": { + "val": "organism", + "words": [ + "infant", + "macaques", + "adult", + "animals:" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nef", + "and", + "vpr" + ] + }, + "context": { + "val": "organism", + "words": [ + "infant", + "macaques" + ] + } + } + ] + }, + { + "PMID": "9930867", + "TEXT": "Infection by live attenuated retroviruses provides excellent protection from challenge with pathogenic viruses in several animal models, but little is known about which immune effectors are necessary for protection. We examined this using adoptive transfer experiments in the Friend virus mouse model. Transfers of immune spleen cells into naive mice conferred complete protection, and transfers of purified lymphocyte subsets demonstrated that this effect required complex immune responses involving CD4+ and CD8+ T cells and also B cells. In addition, passive immunization experiments demonstrated that antibodies alone reduced virus loads but did not prevent infection. These findings may have implications for retroviral vaccine design in general.", + "TAG_DATA": [ + "39, virus {'context': 'I-organism'}", + "40, mouse {'context': 'I-organism'}", + "41, model. {'context': 'I-organism'}", + "44, immune {'context': 'B-cells'}", + "45, spleen {'context': 'I-cells'}", + "46, cells {'context': 'I-cells'}", + "49, mice {'context': 'I-organism'}", + "57, lymphocyte {'context': 'I-cells'}", + "58, subsets {'context': 'I-cells'}", + "75, B {'context': 'B-cells'}", + "76, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "39, virus ['l0', 'l1']", + "40, mouse ['l0', 'l2']", + "41, model. ['l1', 'l2']", + "44, immune ['l3', 'l4', 'l5']", + "45, spleen ['l3', 'l6', 'l7']", + "46, cells ['l4', 'l6', 'l8']", + "49, mice ['l5', 'l7', 'l8']", + "57, lymphocyte ['l9', 'l10', 'l11']", + "58, subsets ['l9', 'l12', 'l13']", + "75, B ['l10', 'l12', 'l14']", + "76, cells. ['l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9930864", + "TEXT": "The molecular mechanisms underlying myelin sheath destruction in multiple sclerosis lesions remain unresolved. With immunogold-labeled peptides of myelin antigens and high-resolution microscopy, techniques that can detect antigen-specific antibodies in situ, we have identified autoantibodies specific for the central nervous system myelin antigen myelin/oligodendrocyte glycoprotein. These autoantibodies were specifically bound to disintegrating myelin around axons in lesions of acute multiple sclerosis and the marmoset model of allergic encephalomyelitis. These findings represent direct evidence that autoantibodies against a specific myelin protein mediate target membrane damage in central nervous system demyelinating disease.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9930863", + "TEXT": "The presenilin proteins are components of high-molecular-weight protein complexes in the endoplasmic reticulum and Golgi apparatus that also contain beta-catenin. We report here that presenilin mutations associated with familial Alzheimer disease (but not the non-pathogenic Glu318Gly polymorphism) alter the intracellular trafficking of beta-catenin after activation of the Wnt/beta-catenin signal transduction pathway. As with their effect on betaAPP processing, the effect of PS1 mutations on trafficking of beta-catenin arises from a dominant 'gain of aberrant function' activity. These results indicate that mistrafficking of selected presenilin ligands is a candidate mechanism for the genesis of Alzheimer disease associated with presenilin mutations, and that dysfunction in the presenilin-beta-catenin protein complexes is central to this process.", + "TAG_DATA": [ + "61, PS1 {'perturbing_action': 'B-other'}", + "62, mutations {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "61, PS1 ['l0']", + "62, mutations ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9883845", + "TEXT": "Fas ligand (FasL) triggers apoptosis during cytotoxicity mediated by cytotoxic T lymphocytes and during immune downregulation. The ability of T cells and natural killer cells to trigger apoptosis through this mechanism is controlled by the cell surface expression of FasL (ref. 2). Because FasL expression is up-regulated on activation, FasL was thought to be delivered directly to the cell surface. Here we show that newly synthesized FasL is stored in specialized secretory lysosomes in both CD4+ and CD8+ T cells and natural killer cells, and that polarized degranulation controls the delivery of FasL to the cell surface. In this way, FasL-mediated apoptosis is finely controlled by receptor-mediated target-cell recognition. The cytoplasmic tail of FasL contains signals that sort FasL to secretory lysosomes in hemopoietic cells. This pathway may provide a general mechanism for controlling the cell surface appearance of proteins involved in immune regulation.", + "TAG_DATA": [ + "100, FasL-mediated {'effect': 'B-regulates'}", + "101, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "100, FasL-mediated ['l0']", + "101, apoptosis ['l0']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "regulates", + "words": [ + "FasL-mediated" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "9883842", + "TEXT": "Adeno-associated virus 2 (AAV)-based vectors have gained attention as a potentially useful alternative to the more commonly used retroviral and adenoviral vectors for human gene therapy. Although AAV uses the ubiquitously expressed cell surface heparan sulfate proteoglycan (HSPG) as a receptor, the transduction efficiency of AAV vectors varies greatly in different cells and tissues in vitro and in vivo. We demonstrate here that cell surface expression of HSPG alone is insufficient for AAV infection, and that AAV also requires human fibroblast growth factor receptor 1 (FGFR1) as a co-receptor for successful viral entry into the host cell. We document that cells that do not express either HSPG or FGFR1 fail to bind AAV and, consequently, are resistant to infection by AAV. These non-permissive cells are successfully transduced by AAV vectors after stable transfections with cDNAs encoding the murine HSPG and the human FGFR1. Furthermore, AAV infection of permissive cells, known to express both FGFR1 and the epidermal growth factor receptor, is abrogated by treatment of cells with basic fibroblast growth factor, but not with epidermal growth factor. The identification of FGFR1 as a co-receptor for AAV should provide new insights not only into its role in the life cycle of AAV, but also in the optimal use of AAV vectors in human gene therapy.", + "TAG_DATA": [ + "100, cells {'context': 'B-cells'}", + "122, non-permissive {'context': 'B-cells'}", + "123, cells {'context': 'I-cells'}", + "131, stable {'perturbing_action': 'B-gene gain-of-function'}", + "132, transfections {'perturbing_action': 'I-gene gain-of-function'}", + "133, with {'perturbing_action': 'I-gene gain-of-function'}", + "134, cDNAs {'perturbing_action': 'I-gene gain-of-function'}", + "135, encoding {'perturbing_action': 'I-gene gain-of-function'}", + "136, the {'perturbing_action': 'I-gene gain-of-function'}", + "137, murine {'perturbing_action': 'I-gene gain-of-function'}", + "138, HSPG {'perturbing_action': 'I-gene gain-of-function'}", + "139, and {'perturbing_action': 'I-gene gain-of-function'}", + "140, the {'perturbing_action': 'I-gene gain-of-function'}", + "141, human {'perturbing_action': 'I-gene gain-of-function'}", + "142, FGFR1. {'perturbing_action': 'I-gene gain-of-function'}", + "147, permissive {'context': 'B-cells'}", + "148, cells, {'context': 'I-cells'}", + "165, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "122, non-permissive ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "123, cells ['l0', 'l10', 'l11', 'l12', 'l13', 'l14']", + "131, stable ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "132, transfections ['l15', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "133, with ['l1', 'l16', 'l28', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "134, cDNAs ['l17', 'l29', 'l40', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "135, encoding ['l2', 'l18', 'l30', 'l41', 'l51', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "136, the ['l3', 'l10', 'l19', 'l31', 'l42', 'l52', 'l61', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "137, murine ['l4', 'l11', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "138, HSPG ['l5', 'l12', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "139, and ['l6', 'l13', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l91', 'l92', 'l93', 'l94', 'l95']", + "140, the ['l7', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l96', 'l97', 'l98', 'l99']", + "141, human ['l8', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l100', 'l101', 'l102']", + "142, FGFR1. ['l9', 'l14', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l103', 'l104']", + "147, permissive ['l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l105', 'l106']", + "148, cells, ['l27', 'l39', 'l50', 'l60', 'l69', 'l77', 'l84', 'l90', 'l95', 'l99', 'l102', 'l104', 'l105', 'l107']", + "165, cells ['l106', 'l107']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "non-permissive", + "cells", + "permissive", + "cells," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "with", + "encoding", + "the", + "murine", + "HSPG", + "and", + "human", + "FGFR1.", + "stable", + "transfections", + "cDNAs" + ] + } + } + ] + }, + { + "PMID": "9883837", + "TEXT": "The persistence of HIV replication in infected individuals may reflect an inadequate host HIV-specific CD8+ cytotoxic T lymphocyte (CTL) response. The functional activity of HIV-specific CTLs and the ability of these effector cells to migrate in vivo to sites of infection was directly assessed by expanding autologous HIV-1 Gag-specific CD8+ CTL clones in vitro and adoptively transferring these CTLs to HIV-infected individuals. The transferred CTLs retained lytic function in vivo, accumulated adjacent to HIV-infected cells in lymph nodes and transiently reduced the levels of circulating productively infected CD4+ T cells. These results provide direct evidence that HIV-specific CTLs target sites of HIV replication and mediate antiviral activity, and indicate that the development of immunotherapeutic approaches to sustain a strong CTL response to HIV may be a useful adjunct to treatment of HIV infection.", + "TAG_DATA": [ + "49, CD8+ {'context': 'B-cells'}", + "50, CTL {'context': 'I-cells'}", + "51, clones {'context': 'I-cells'}", + "52, in {'context': 'B-in vitro'}", + "53, vitro {'context': 'I-in vitro'}", + "68, in {'context': 'B-in vivo'}", + "69, vivo, {'context': 'I-in vivo'}", + "74, cells {'context': 'B-cells'}", + "76, lymph {'context': 'B-tissue/organ'}", + "87, CD4+ {'context': 'B-cells'}", + "88, T {'context': 'I-cells'}", + "89, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "49, CD8+ ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "50, CTL ['l0', 'l7', 'l8', 'l9']", + "51, clones ['l1', 'l7', 'l10', 'l11']", + "52, in ['l2', 'l8', 'l10', 'l12']", + "53, vitro ['l3', 'l9', 'l11', 'l12']", + "68, in ['l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "69, vivo, ['l4', 'l13', 'l20', 'l21', 'l22', 'l23', 'l24']", + "74, cells ['l5', 'l14', 'l20', 'l25', 'l26', 'l27', 'l28', 'l29']", + "76, lymph ['l15', 'l21', 'l25', 'l30', 'l31', 'l32', 'l33']", + "77, nodes ['l6', 'l16', 'l22', 'l26', 'l30', 'l34', 'l35', 'l36']", + "87, CD4+ ['l17', 'l27', 'l31', 'l34', 'l37', 'l38']", + "88, T ['l18', 'l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "89, cells. ['l19', 'l24', 'l29', 'l33', 'l36', 'l38', 'l39']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9846584", + "TEXT": "High serum levels of total and LDL cholesterol are important risk factors in the development of atherosclerotic coronary artery disease. Cholesterol metabolism is affected by nutritional, environmental and genetic factors. Neuropeptide Y (NPY), which is widely expressed in both the central and peripheral nervous systems, has an important role in the hypothalamic regulation of energy balance by stimulating food intake and favoring energy storage through increased lipoprotein lipase activity in white adipose tissue. As a part of ongoing study of the genetic basis of obesity, we screened the NPY gene for sequence variants. We report here the identification of a common Leu(7)-to-Pro(7) polymorphism in the signal peptide of NPY. Presence of this Pro(7) in NPY was associated with higher serum levels of total and LDL cholesterol in obese subjects participating in two independent Finnish and Dutch studies. Furthermore, normal-weight Finns with Pro(7) also had higher serum levels of total and LDL cholesterol than did subjects with Leu(7)/Leu(7), as analyzed in three subsequent determinations at 5-year intervals during a 10-year follow-up period. The NPY polymorphism was not associated with higher cholesterol levels in normal-weight Dutch. Our study provides evidence that NPY is linked to cholesterol metabolism and that the polymorphism producing Pro(7) in NPY is one of the strongest genetic factors identified thus far affecting serum cholesterol, particularly in obese subjects.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9846576", + "TEXT": "We investigated the pathogenesis of chronic allograft rejection in mouse cardiac allografts. Long-term survival occurred after administration of monoclonal antibody to CD4 or CD40-ligand (CD40L) plus donor cells. Both treatments induced permanent graft survival, but, in contrast to transplants in mice treated with CD4 monoclonal antibody, grafts in mice treated with CD40L monoclonal antibody lacked evidence of chronic rejection, including transplant arteriosclerosis. Freedom from chronic rejection in the group treated with CD40L monoclonal antibody correlated with vascular expression of the 'protective' genes heme oxygenase-1 (HO-1), Bcl-xL and A20. Moreover, arteriosclerosis was induced in allografts in immunoglobulin-deficient mice by antibody transfer only when the transfer was done before expression of protective genes. A direct role for protective gene expression in endothelial cells was demonstrated by in vitro experiments in which induction of HO-1 or Bcl-xL suppressed alloantibody-stimulated endothelial activation. Finally, induction of HO-1 in vivo protected allografts against chronic injury. These data show a role for protective genes in the prevention of chronic rejection, and indicate new approaches to protect grafts against development of transplant arteriosclerosis.", + "TAG_DATA": [ + "40, mice {'context': 'B-organism'}", + "46, grafts {'context': 'B-xenograft'}", + "48, mice {'context': 'B-organism'}", + "93, allografts {'context': 'B-xenograft'}", + "95, immunoglobulin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "96, mice {'context': 'B-organism'}", + "124, in {'context': 'B-in vitro'}", + "125, vitro {'context': 'I-in vitro'}", + "129, induction {'perturbing_action': 'B-gene gain-of-function'}", + "130, of {'perturbing_action': 'I-gene gain-of-function'}", + "131, HO-1 {'perturbing_action': 'I-gene gain-of-function'}", + "132, or {'perturbing_action': 'I-gene gain-of-function'}", + "133, Bcl-xL {'perturbing_action': 'I-gene gain-of-function'}", + "139, induction {'perturbing_action': 'B-gene gain-of-function'}", + "140, of {'perturbing_action': 'I-gene gain-of-function'}", + "141, HO-1 {'perturbing_action': 'I-pharmacological augmentation'}", + "142, in {'context': 'B-in vivo'}", + "143, vivo {'context': 'I-in vivo'}", + "145, allografts {'context': 'B-xenograft'}" + ], + "LINK_DATA": [ + "40, mice ['l0', 'l1', 'l2']", + "46, grafts ['l0', 'l3', 'l4', 'l5']", + "48, mice ['l1', 'l3', 'l6', 'l7']", + "93, allografts ['l2', 'l4', 'l6', 'l8', 'l9']", + "95, immunoglobulin-deficient ['l8', 'l10', 'l11']", + "96, mice ['l5', 'l7', 'l9', 'l10']", + "124, in ['l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "125, vitro ['l12', 'l18', 'l19', 'l20', 'l21', 'l22']", + "129, induction ['l13', 'l18', 'l23', 'l24', 'l25', 'l26', 'l27']", + "130, of ['l14', 'l19', 'l23', 'l28', 'l29', 'l30']", + "131, HO-1 ['l15', 'l20', 'l24', 'l28', 'l31', 'l32']", + "132, or ['l16', 'l21', 'l25', 'l29', 'l31', 'l33']", + "133, Bcl-xL ['l17', 'l22', 'l26', 'l30', 'l32', 'l33']", + "139, induction ['l34', 'l35', 'l36', 'l37', 'l38']", + "140, of ['l34', 'l39', 'l40', 'l41', 'l42']", + "141, HO-1 ['l35', 'l39', 'l43', 'l44', 'l45']", + "142, in ['l36', 'l40', 'l43', 'l46', 'l47']", + "143, vivo ['l37', 'l41', 'l44', 'l46', 'l48']", + "145, allografts ['l27', 'l38', 'l42', 'l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "xenograft", + "words": [ + "allografts" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immunoglobulin-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immunoglobulin-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immunoglobulin-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "induction", + "of", + "HO-1", + "or", + "Bcl-xL" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "induction", + "of" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "allografts" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "induction", + "of" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "HO-1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "HO-1" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "allografts" + ] + } + } + ] + }, + { + "PMID": "9846574", + "TEXT": "Fas Ligand (FasL) can induce apoptosis of Fas-bearing cells. It is expressed on the cell surface of many tumor cells, immune-privileged tissues and activated lymphocytes. We report here that FasL can itself transduce signals, leading to cell-cycle arrest and cell death in CD4+ T cells. In vitro, FasL engagement inhibited CD4+ T-cell proliferation, cell-cycle progression, and IL-2 secretion. In vivo, FasL engagement prevented superantigen-mediated CD4+, but not CD8+, T-cell expansion. These findings demonstrate that FasL engagement regulates cell-cycle progression, and show that FasL engagement in vivo has a potent anti-inflammatory effect specific for CD4+ T cells.", + "TAG_DATA": [ + "36, cell-cycle {'phenotype': 'B-cell cycle arrest'}", + "37, arrest {'phenotype': 'I-cell cycle arrest'}", + "39, cell {'phenotype': 'B-cell death'}", + "40, death {'phenotype': 'I-cell death'}", + "42, CD4+ {'context': 'B-cells'}", + "43, T {'context': 'I-cells'}", + "44, cells. {'context': 'I-cells'}", + "45, In {'context': 'B-in vitro'}", + "46, vitro, {'context': 'I-in vitro'}", + "49, inhibited {'effect': 'B-negative'}", + "50, CD4+ {'context': 'B-cells'}", + "51, T-cell {'context': 'I-cells'}", + "52, proliferation, {'phenotype': 'B-proliferation'}", + "58, In {'context': 'B-in vivo'}", + "59, vivo, {'context': 'I-in vivo'}", + "64, CD4+, {'context': 'B-cells'}", + "67, CD8+, {'context': 'B-cells'}", + "68, T-cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "36, cell-cycle ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "37, arrest ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "39, cell ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "40, death ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "42, CD4+ ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "43, T ['l4', 'l12', 'l19', 'l25', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "44, cells. ['l5', 'l13', 'l20', 'l26', 'l31', 'l38', 'l44', 'l45', 'l46']", + "45, In ['l6', 'l14', 'l21', 'l27', 'l32', 'l39', 'l44', 'l47', 'l48', 'l49', 'l50', 'l51']", + "46, vitro, ['l7', 'l15', 'l22', 'l28', 'l33', 'l40', 'l45', 'l47', 'l52', 'l53', 'l54', 'l55']", + "49, inhibited ['l34', 'l48', 'l52', 'l56', 'l57', 'l58']", + "50, CD4+ ['l35', 'l41', 'l49', 'l53', 'l56', 'l59', 'l60']", + "51, T-cell ['l36', 'l42', 'l50', 'l54', 'l57', 'l59', 'l61']", + "52, proliferation, ['l8', 'l16', 'l23', 'l29', 'l37', 'l43', 'l46', 'l51', 'l55', 'l58', 'l60', 'l61']", + "58, In ['l62', 'l63', 'l64', 'l65']", + "59, vivo, ['l62', 'l66', 'l67', 'l68']", + "64, CD4+, ['l63', 'l66', 'l69', 'l70']", + "67, CD8+, ['l64', 'l67', 'l69', 'l71']", + "68, T-cell ['l65', 'l68', 'l70', 'l71']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells." + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells." + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4+", + "T-cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells.", + "T-cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + } + ] + }, + { + "PMID": "9809558", + "TEXT": "Two mutations in the gene encoding alpha-synuclein have been linked to early-onset Parkinson's disease (PD). alpha-Synuclein is a component of Lewy bodies, the fibrous cytoplasmic inclusions characteristic of nigral dopaminergic neurons in the PD brain. This connection between genetics and pathology suggests that the alpha-synuclein mutations may promote PD pathogenesis by accelerating Lewy body formation. To test this, we studied alpha-synuclein folding and aggregation in vitro, in the absence of other Lewy body-associated molecules. We demonstrate here that both mutant forms of alpha-synuclein (A53T and A30P) are, like wild-type alpha-synuclein (WT), disordered in dilute solution. However, at higher concentrations, Lewy body-like fibrils and discrete spherical assemblies are formed; most rapidly by A53T. Thus, mutation-induced acceleration of alpha-synuclein fibril formation may contribute to the early onset of familial PD.", + "TAG_DATA": [ + "64, in {'context': 'B-in vitro'}", + "65, vitro, {'context': 'I-in vitro'}", + "79, mutant {'perturbing_action': 'B-other'}", + "80, forms {'perturbing_action': 'I-other'}", + "81, of {'perturbing_action': 'I-other'}", + "82, alpha-synuclein {'perturbing_action': 'I-other'}", + "83, (A53T {'perturbing_action': 'I-other'}", + "84, and {'perturbing_action': 'I-other'}", + "85, A30P) {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "64, in ['l0']", + "65, vitro, ['l0']", + "79, mutant ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "80, forms ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "81, of ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "82, alpha-synuclein ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "83, (A53T ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "84, and ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "85, A30P) ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9809555", + "TEXT": "T-20, a synthetic peptide corresponding to a region of the transmembrane subunit of the HIV-1 envelope protein, blocks cell fusion and viral entry at concentrations of less than 2 ng/ml in vitro. We administered intravenous T-20 (monotherapy) for 14 days to sixteen HIV-infected adults in four dose groups (3, 10, 30 and 100 mg twice daily). There were significant, dose-related declines in plasma HIV RNA in all subjects who received higher dose levels. All four subjects receiving 100 mg twice daily had a decline in plasma HIV RNA to less than 500 copies/ml, by bDNA assay. A sensitive RT-PCR assay (detection threshold 40 copies/ml) demonstrated that, although undetectable levels were not achieved in the 14-day dosing period, there was a 1.96 log10 median decline in plasma HIV RNA in these subjects. This study provides proof-of-concept that viral entry can be successfully blocked in vivo. Short-term administration of T-20 seems safe and provides potent inhibition of HIV replication comparable to anti-retroviral regimens approved at present.", + "TAG_DATA": [ + "30, in {'context': 'B-in vitro'}", + "42, HIV-infected {'context': 'B-organism'}", + "43, adults {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "30, in ['l0', 'l1']", + "42, HIV-infected ['l0', 'l2']", + "43, adults ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9809547", + "TEXT": "Modifying bacterial virulence genes to probe the nature of host immunity is mostly unexplored. Here we investigate whether host immune responses can be regulated by modification of bacterial virulence genes. In mice, attenuated Salmonella mutant strains with clinical relevance elicited differential host immune responses. Oral administration of a mutant strain with a PhoP-null phenotype promoted potent innate immune responses of macrophages that were sufficient for host defense. In contrast, administration of an Aro- mutant strain elicited stronger specific antibody and T-helper (Th)-cell responses, wherein Th1-type cells were required for clearance. Thus, genetic manipulation of bacteria may be used to broadly alter immune mechanisms that regulate attenuation within the host and to tailor host immunity to specific bacterial pathogens.", + "TAG_DATA": [ + "31, mice, {'context': 'B-organism'}", + "49, strain {'perturbing_action': 'I-other'}", + "52, PhoP-null {'perturbing_action': 'B-gene loss-of-function'}", + "53, phenotype {'perturbing_action': 'I-gene loss-of-function'}", + "60, macrophages {'context': 'B-cells'}", + "72, Aro- {'perturbing_action': 'B-other'}", + "73, mutant {'perturbing_action': 'B-other'}", + "74, strain {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "49, strain ['l0', 'l1', 'l2', 'l3', 'l4']", + "52, PhoP-null ['l0', 'l5', 'l6', 'l7', 'l8', 'l9']", + "53, phenotype ['l1', 'l5', 'l10', 'l11', 'l12', 'l13']", + "60, macrophages ['l2', 'l6', 'l10']", + "72, Aro- ['l7', 'l11', 'l14', 'l15']", + "73, mutant ['l3', 'l8', 'l12', 'l14', 'l16']", + "74, strain ['l4', 'l9', 'l13', 'l15', 'l16']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "strain" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PhoP-null", + "phenotype" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages" + ] + } + } + ] + }, + { + "PMID": "9771755", + "TEXT": "Oxidative modification of low density lipoprotein (LDL) has been implicated in atherogenesis. Evidence consistent with this hypothesis includes the presence of oxidized lipids in atherosclerotic lesions, the newly discovered biological properties conferred on LDL by oxidation and the acceleration of atherogenesis by in vivo delivery of the gene for 15-lipoxygenase, an oxidizing enzyme present in atherosclerotic lesions. However, it is still unknown whether oxidative stress actually coincides with the evolution of the disease or whether it is of functional relevance to atherogenesis in vivo. Isoprostanes are products of arachidonic acid catalyzed by free radicals, which reflect oxidative stress and lipid peroxidation in vivo. Elevation of tissue and urinary isoprostanes is characteristic of human atherosclerosis. Here, deficiency in apolipoprotein E in the mouse (apoE-/-) resulted in atherogenesis and an increase in iPF2alpha-VI, an F2-isoprostane, in urine, plasma and vascular tissue. Supplementation with vitamin E significantly reduced isoprostane generation, but had no effect on plasma cholesterol levels in apoE-/- mice. Aortic lesion areas and iPF2alpha-VI levels in the arterial wall were also reduced significantly by vitamin E. Our results indicate that oxidative stress is increased in the apoE-/- mouse, is of functional importance in the evolution of atherosclerosis and can be suppressed by oral administration of vitamin E.", + "TAG_DATA": [ + "115, deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "116, in {'perturbing_action': 'I-gene loss-of-function'}", + "117, apolipoprotein {'perturbing_action': 'I-gene loss-of-function'}", + "118, E {'perturbing_action': 'I-gene loss-of-function'}", + "121, mouse {'context': 'B-organism'}", + "156, apoE-/- {'perturbing_action': 'B-gene loss-of-function'}", + "157, mice. {'context': 'B-organism'}", + "166, arterial {'context': 'B-tissue/organ'}", + "167, wall {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "115, deficiency ['l0', 'l1', 'l2', 'l3']", + "116, in ['l0', 'l4', 'l5', 'l6']", + "117, apolipoprotein ['l1', 'l4', 'l7', 'l8']", + "118, E ['l2', 'l5', 'l7', 'l9']", + "121, mouse ['l3', 'l6', 'l8', 'l9']", + "156, apoE-/- ['l10']", + "157, mice. ['l10']", + "166, arterial ['l11']", + "167, wall ['l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "in", + "apolipoprotein", + "E", + "apoE-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "mice." + ] + } + } + ] + }, + { + "PMID": "9771750", + "TEXT": "Temporal lobe epilepsy is the most prevalent seizure disorder in adults. Compromised inhibitory neurotransmitter function in the hippocampus contributes to the hyperexcitability generating this condition, but the underlying molecular mechanisms are unknown. Combining patch-clamp recording and single-cell mRNA amplification (aRNA) techniques in single dentate granule cells, we demonstrate that expression of GABA(A) receptor subunit mRNAs is substantially altered in neurons from epileptic rats. These changes in gene expression precede epilepsy onset by weeks and correlate with profound alterations in receptor function, indicating that aberrant GABA(A) receptor expression and function has an essential role in the process of epileptogenesis.", + "TAG_DATA": [ + "43, dentate {'context': 'B-cells'}", + "44, granule {'context': 'I-cells'}", + "45, cells, {'context': 'I-cells'}", + "59, neurons {'context': 'B-cells'}", + "62, rats. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "43, dentate ['l0', 'l1', 'l2', 'l3']", + "44, granule ['l0', 'l4', 'l5', 'l6']", + "45, cells, ['l1', 'l4', 'l7', 'l8']", + "59, neurons ['l2', 'l5', 'l7', 'l9']", + "62, rats. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9771748", + "TEXT": "Brain serotonin and leptin signaling contribute substantially to the regulation of feeding and energy expenditure. Here we show that young adult mice with a targeted mutation of the serotonin 5-HT2C receptor gene consume more food despite normal responses to exogenous leptin administration. Chronic hyperphagia leads to a 'middle-aged'-onset obesity associated with a partial leptin resistance of late onset. In addition, older mice develop insulin resistance and impaired glucose tolerance. Mutant mice also responded more to high-fat feeding, leading to hyperglycemia without hyperlipidemia. These findings demonstrate a dissociation of serotonin and leptin signaling in the regulation of feeding and indicate that a perturbation of brain serotonin systems can predispose to type 2 diabetes.", + "TAG_DATA": [ + "19, young {'context': 'B-organism'}", + "20, adult {'context': 'I-organism'}", + "21, mice {'context': 'I-organism'}", + "24, targeted {'perturbing_action': 'B-other'}", + "25, mutation {'perturbing_action': 'I-other'}", + "26, of {'perturbing_action': 'I-other'}", + "27, the {'perturbing_action': 'I-other'}", + "28, serotonin {'perturbing_action': 'I-other'}", + "29, 5-HT2C {'perturbing_action': 'I-other'}", + "30, receptor {'perturbing_action': 'I-other'}", + "31, gene {'perturbing_action': 'I-other'}", + "60, older {'context': 'B-organism'}", + "61, mice {'context': 'I-organism'}", + "69, Mutant {'perturbing_action': 'B-other'}", + "70, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "19, young ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "20, adult ['l0', 'l9', 'l10', 'l11', 'l12', 'l13']", + "21, mice ['l1', 'l9', 'l14', 'l15']", + "24, targeted ['l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "25, mutation ['l2', 'l16', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "26, of ['l3', 'l17', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "27, the ['l4', 'l10', 'l18', 'l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "28, serotonin ['l5', 'l19', 'l27', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "29, 5-HT2C ['l6', 'l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "30, receptor ['l7', 'l12', 'l14', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57']", + "31, gene ['l8', 'l13', 'l15', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l58']", + "60, older ['l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l59']", + "61, mice ['l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l58', 'l59']", + "69, Mutant ['l60']", + "70, mice ['l60']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "young", + "adult", + "mice", + "older" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "of", + "the", + "serotonin", + "5-HT2C", + "receptor", + "gene", + "targeted", + "Mutant" + ] + } + } + ] + }, + { + "PMID": "9734403", + "TEXT": "The p53 tumor suppressor protein binds to both cellular and viral proteins, which influence its biological activity. One such protein is the large E1b tumor antigen (E1b58kDa) from adenoviruses (Ads), which abrogates the ability of p53 to transactivate various promoters. This inactivation of p53 function is believed to be the mechanism by which E1b58kDa contributes to the cell transformation process. Although the p53-E1b58kDa complex occurs during infection and is conserved among different serotypes, there are limited data demonstrating that it has a role in virus replication. However, loss of p53 expression occurs after adenovirus infection of human cells and an E1b58kDa deletion mutant (Onyx-015, also called dl 1520) selectively replicates in p53-defective cells. These (and other) data indicate a plausible hypothesis is that loss of p53 function may be conducive to efficient adenovirus replication. However, wild-type (wt) Ad5 grows more efficiently in cells expressing a wt p53 protein. These studies indicate that the hypothesis may be an oversimplification. Here, we show that cells expressing wt p53, as well as p53-defective cells, allow adenovirus replication, but only cells expressing wt p53 show evidence of virus-induced cytopathic effect. This correlates with the ability of adenovirus to induce cell death. Our data indicate that p53 plays a necessary part in mediating cellular destruction to allow a productive adenovirus infection. In contrast, p53-deficient cells are less sensitive to the cytolytic effects of adenovirus and as such raise questions about the use of E1b58kDa-deficient adenoviruses in tumor therapy.", + "TAG_DATA": [ + "100, E1b58kDa {'perturbing_action': 'B-gene loss-of-function'}", + "101, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "102, mutant {'perturbing_action': 'I-gene loss-of-function'}", + "103, (Onyx-015, {'perturbing_action': 'I-gene loss-of-function'}", + "104, also {'perturbing_action': 'I-gene loss-of-function'}", + "106, dl {'perturbing_action': 'I-gene loss-of-function'}", + "107, 1520) {'perturbing_action': 'I-gene loss-of-function'}", + "112, cells. {'context': 'B-cells'}", + "142, cells {'context': 'B-cells'}", + "162, cells {'context': 'B-cells'}", + "164, wt {'perturbing_action': 'I-gene gain-of-function'}", + "165, p53, {'perturbing_action': 'I-gene gain-of-function'}", + "170, cells, {'context': 'B-cells'}", + "176, cells {'context': 'B-cells'}", + "178, wt {'perturbing_action': 'I-gene gain-of-function'}", + "179, p53 {'perturbing_action': 'I-gene gain-of-function'}", + "194, induce {'effect': 'B-positive'}", + "195, cell {'phenotype': 'B-cell death'}", + "196, death. {'phenotype': 'I-cell death'}", + "218, p53-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "219, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "100, E1b58kDa ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "101, deletion ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "102, mutant ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "103, (Onyx-015, ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "104, also ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "106, dl ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "107, 1520) ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l56', 'l57', 'l58', 'l59']", + "112, cells. ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l56']", + "142, cells ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l57', 'l60', 'l61', 'l62', 'l63']", + "162, cells ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l58', 'l60', 'l64', 'l65', 'l66']", + "164, wt ['l9', 'l20', 'l30', 'l39', 'l47', 'l61', 'l64', 'l67', 'l68']", + "165, p53, ['l10', 'l21', 'l31', 'l40', 'l48', 'l54', 'l59', 'l62', 'l65', 'l67', 'l69']", + "170, cells, ['l11', 'l22', 'l32', 'l41', 'l49', 'l55', 'l63', 'l66', 'l68', 'l69']", + "176, cells ['l70', 'l71', 'l72', 'l73', 'l74']", + "178, wt ['l70', 'l75', 'l76', 'l77', 'l78', 'l79']", + "179, p53 ['l71', 'l75', 'l80', 'l81', 'l82', 'l83']", + "194, induce ['l72', 'l76', 'l80', 'l84', 'l85']", + "195, cell ['l73', 'l77', 'l81', 'l84', 'l86']", + "196, death. ['l74', 'l78', 'l82', 'l85', 'l86']", + "218, p53-deficient ['l87']", + "219, cells ['l79', 'l83', 'l87']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "E1b58kDa", + "deletion", + "mutant", + "(Onyx-015,", + "also", + "dl", + "1520)", + "p53-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells.", + "cells", + "cells," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "cells," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "wt", + "p53,", + "p53" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "wt", + "p53" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "wt", + "p53" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "9734398", + "TEXT": "PPARgamma is a nuclear receptor that has a dominant regulatory role in differentiation of cells of the adipose lineage, and has recently been shown to be expressed in the colon. We show here that PPARgamma is expressed at high levels in both well- and poorly-differentiated adenocarcinomas, in normal colonic mucosa and in human colon cancer cell lines. Ligand activation of this receptor in colon cancer cells causes a considerable reduction in linear and clonogenic growth, increased expression of carcinoembryonic antigen and the reversal of many gene expression events specifically associated with colon cancer. Transplantable tumors derived from human colon cancer cells show a significant reduction of growth when mice are treated with troglitazone, a PPARgamma ligand. These results indicate that the growth and differentiation of colon cancer cells can be modulated through PPARgamma.", + "TAG_DATA": [ + "57, Ligand {'perturbing_action': 'B-pharmacological augmentation'}", + "58, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "59, of {'perturbing_action': 'I-pharmacological augmentation'}", + "60, this {'perturbing_action': 'I-pharmacological augmentation'}", + "61, receptor {'perturbing_action': 'I-pharmacological augmentation'}", + "63, colon {'context': 'B-transformed cells'}", + "64, cancer {'context': 'I-transformed cells'}", + "65, cells {'context': 'I-transformed cells'}", + "69, reduction {'effect': 'B-negative'}", + "73, clonogenic {'phenotype': 'B-colony formation'}", + "74, growth, {'phenotype': 'I-colony formation'}", + "93, Transplantable {'context': 'B-neoplasm'}", + "94, tumors {'context': 'I-neoplasm'}", + "95, derived {'context': 'I-xenograft'}", + "96, from {'context': 'I-transformed cells'}", + "97, human {'context': 'I-transformed cells'}", + "98, colon {'context': 'I-transformed cells'}", + "99, cancer {'context': 'I-transformed cells'}", + "100, cells {'context': 'I-transformed cells'}", + "108, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "57, Ligand ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "58, activation ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "59, of ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "60, this ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "61, receptor ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "63, colon ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "64, cancer ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "65, cells ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "69, reduction ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "73, clonogenic ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "74, growth, ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "93, Transplantable ['l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "94, tumors ['l55', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "95, derived ['l56', 'l62', 'l68', 'l69', 'l70', 'l71', 'l72']", + "96, from ['l57', 'l63', 'l68', 'l73', 'l74', 'l75', 'l76']", + "97, human ['l58', 'l64', 'l69', 'l73', 'l77', 'l78', 'l79']", + "98, colon ['l59', 'l65', 'l70', 'l74', 'l77', 'l80', 'l81']", + "99, cancer ['l60', 'l66', 'l71', 'l75', 'l78', 'l80', 'l82']", + "100, cells ['l61', 'l67', 'l72', 'l76', 'l79', 'l81', 'l82']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Ligand", + "activation", + "of", + "this", + "receptor" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "colon", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Ligand", + "activation", + "of", + "this", + "receptor" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduction" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Ligand", + "activation", + "of", + "this", + "receptor" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenic", + "growth," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "colon", + "cancer", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduction" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "colon", + "cancer", + "cells" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenic", + "growth," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduction" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenic", + "growth," + ] + } + } + ] + }, + { + "PMID": "9701248", + "TEXT": "B-cell activation depends on the intensity of B-cell receptor cross-linking. Studies of haptenated antigens and vesicular stomatitis virus (VSV) have demonstrated a correlation between antigen repetitiveness and the degree to which B-cell activation is independent of T cells. Here, we compare neutralizing antibody responses to inactivated VSV with those to two inactivated human pathogenic viruses: highly cytopathic poliovirus (PV) and poorly cytopathic measles virus (MV). The rigidly structured PV efficiently induced neutralizing IgM antibodies independent of T cells. In contrast, neutralizing antibodies to the pleomorphic MV were dependent on helper T cells. To test whether this resulted from the differences in virus structure or the capacity of MV to induce cell fusion and/or immunosuppression, we analyzed antibody responses to chimeric MV expressing VSV glycoprotein instead of MV fusion protein and hemagglutinin. IgM antibodies were independent of T cells; in addition, we found IgG responses dependent on T-cell help that were enduring and protective against lethal VSV infection. Because chimeric MV viruses look like MV ultrastructurally, we conclude that not only structural differences in the envelope but also the ability of MV to induce immunosuppression may limit its capacity to directly activate B cells. These findings are relevant for our understanding of B-cell activation by two prototypic human pathogenic viruses and for the design of new recombinant vaccines.", + "TAG_DATA": [ + "76, T {'context': 'B-cells'}", + "77, cells. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "76, T ['l0']", + "77, cells. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9701246", + "TEXT": "Mutations in the low density lipoprotein (LDL) receptor gene cause familial hypercholesterolemia, a human disease characterized by premature atherosclerosis and markedly elevated plasma levels of LDL cholesterol and apolipoprotein (apo) B100. In contrast, mice deficient for the LDL receptor (Ldlr-/-) have only mildly elevated LDL cholesterol levels and little atherosclerosis. This difference results from extensive editing of the hepatic apoB mRNA in the mouse, which limits apoB100 synthesis in favor of apoB48 synthesis. We have generated Ldlr-/- mice that cannot edit the apoB mRNA and therefore synthesize exclusively apoB100. These mice had markedly elevated LDL cholesterol and apoB100 levels and developed extensive atherosclerosis on a chow diet. This authentic model of human familial hypercholesterolemia will provide a new tool for studying atherosclerosis.", + "TAG_DATA": [ + "33, mice {'context': 'B-organism'}", + "34, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "35, for {'perturbing_action': 'I-gene loss-of-function'}", + "36, the {'perturbing_action': 'I-gene loss-of-function'}", + "37, LDL {'perturbing_action': 'I-gene loss-of-function'}", + "38, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "39, (Ldlr-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "76, Ldlr-/- {'perturbing_action': 'B-gene loss-of-function'}", + "77, mice {'context': 'B-organism'}", + "90, mice {'context': 'B-organism'}", + "102, atherosclerosis {'phenotype': 'B-necrosis'}" + ], + "LINK_DATA": [ + "33, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "34, deficient ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "35, for ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "36, the ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "37, LDL ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "38, receptor ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "39, (Ldlr-/-) ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "76, Ldlr-/- ['l21']", + "77, mice ['l21']", + "90, mice ['l22']", + "102, atherosclerosis ['l22']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "the", + "LDL", + "receptor", + "(Ldlr-/-)", + "Ldlr-/-" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "atherosclerosis" + ] + } + } + ] + }, + { + "PMID": "9662381", + "TEXT": "The CD4+ T-cell pool in HIV-infected patients is in a constant state of flux as CD4+ T cells are infected and destroyed by HIV and new cells take their place. To study T-cell survival, we adoptively transferred peripheral blood lymphocytes transduced with the neomycin phosphotransferase gene between syngeneic twin pairs discordant for HIV infection. A stable fraction of marked CD4+ T cells persisted in the circulation for four to eighteen weeks after transfer in all patients. After this time there was a precipitous decline in marked cells in three of the patients. At approximately six months, marked cells were in lymphoid tissues in proportions comparable to those found in peripheral blood. In two patients, the proportion of total signal for the transgene (found by PCR analysis) in the CD4/CD45RA+ T-cell population relative to the CD4/CD45RO+ population increased in the weeks after cell infusion. These findings indicate that genetically-marked CD4+ T cells persist in vivo for weeks to months and that the CD4+ T-cell pool in adults is maintained mostly by the division of mature T cells rather than by differentiation of prethymic stem cells. Thus, after elements of the T-cell repertoire are lost through HIV infection, they may be difficult to replace.", + "TAG_DATA": [ + "37, peripheral {'context': 'B-cells'}", + "38, blood {'context': 'I-cells'}", + "39, lymphocytes {'context': 'I-cells'}", + "40, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "41, with {'perturbing_action': 'I-gene gain-of-function'}", + "42, the {'perturbing_action': 'I-gene gain-of-function'}", + "43, neomycin {'perturbing_action': 'I-gene gain-of-function'}", + "44, phosphotransferase {'perturbing_action': 'I-gene gain-of-function'}", + "45, gene {'perturbing_action': 'I-gene gain-of-function'}", + "59, CD4+ {'context': 'B-cells'}", + "60, T {'context': 'I-cells'}", + "61, cells {'context': 'I-cells'}", + "86, cells {'context': 'B-cells'}", + "128, CD4/CD45RA+ {'context': 'B-cells'}", + "129, T-cell {'context': 'I-cells'}", + "130, population {'context': 'I-cells'}", + "134, CD4/CD45RO+ {'context': 'B-cells'}", + "152, in {'context': 'B-in vivo'}", + "153, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "37, peripheral ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "38, blood ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "39, lymphocytes ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "40, transduced ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "41, with ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "42, the ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "43, neomycin ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "44, phosphotransferase ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "45, gene ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "59, CD4+ ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "60, T ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "61, cells ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "86, cells ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "128, CD4/CD45RA+ ['l78', 'l79', 'l80']", + "129, T-cell ['l78', 'l81', 'l82']", + "130, population ['l79', 'l81', 'l83']", + "134, CD4/CD45RO+ ['l80', 'l82', 'l83', 'l84', 'l85']", + "152, in ['l84', 'l86']", + "153, vivo ['l85', 'l86']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "peripheral", + "blood", + "lymphocytes", + "CD4+", + "T", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "the", + "neomycin", + "phosphotransferase", + "gene" + ] + } + } + ] + }, + { + "PMID": "9662379", + "TEXT": "Many genes and signalling pathways controlling cell proliferation, death and differentiation, as well as genomic integrity, are involved in cancer development. New techniques, such as serial analysis of gene expression and cDNA microarrays, have enabled measurement of the expression of thousands of genes in a single experiment, revealing many new, potentially important cancer genes. These genome screening tools can comprehensively survey one tumor at a time; however, analysis of hundreds of specimens from patients in different stages of disease is needed to establish the diagnostic, prognostic and therapeutic importance of each of the emerging cancer gene candidates. Here we have developed an array-based high-throughput technique that facilitates gene expression and copy number surveys of very large numbers of tumors. As many as 1000 cylindrical tissue biopsies from individual tumors can be distributed in a single tumor tissue microarray. Sections of the microarray provide targets for parallel in situ detection of DNA, RNA and protein targets in each specimen on the array, and consecutive sections allow the rapid analysis of hundreds of molecular markers in the same set of specimens. Our detection of six gene amplifications as well as p53 and estrogen receptor expression in breast cancer demonstrates the power of this technique for defining new subgroups of tumors.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9662376", + "TEXT": "Alzheimer's disease is associated with the intraparenchymal growth of plaque-like amyloid deposits. Amyloid plaques are formed by the progressive deposition and transformation of soluble amyloid beta-protein monomers into insoluble and fibrillar aggregates that contain amyloid beta-protein in a beta-pleated sheet conformation. This process is described as 'seeded polymerization' of the monomers with slow-nucleation and fast-growth kinetics. Soluble amyloid beta-protein monomers are present in the cortical extracellular space and in the cerebrospinal fluid, whereas insoluble aggregates so far can be found only by the examination of brain tissue by biopsy or autopsy. Here we present a biophysical method that uses the principle of seeded polymerization in combination with fluorescence correlation spectroscopy, which allowed us to detect single amyloid beta-peptide aggregates in the cerebrospinal fluid samples from Alzheimer's patients. All of 15 Alzheimer's samples but none of the 19 age-matched control samples produced large peaks with fluorescence correlation spectroscopy indicating the rapid aggregation of the fluorescent labelled synthetic amyloid beta-protein probe onto the amyloid beta-protein 'seeds' present in the cerebrospinal fluid. Our method could enable easy in vivo detection of the cerebral amyloid beta-protein pathology of Alzheimer's disease and might be of potential value to facilitate its routine diagnosis.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9585240", + "TEXT": "Angiogenesis, the formation of new blood vessels, is a requirement for malignant tumor growth and metastasis. In the absence of angiogenesis, local tumor expansion is suppressed at a few millimeters and cells lack routes for distant hematogenous spread. Clinical studies have demonstrated that the degree of angiogenesis is correlated with the malignant potential of several cancers, including breast cancer and malignant melanoma. Moreover, the expression of a specific angiogenesis marker, the endothelial integrin alphaVbeta3, has been shown to correlate with tumor grade. However, studies of tumor angiogenesis such as these have generally relied on invasive procedures, adequate tissue sampling and meticulous estimation of histologic microvessel density. In the present report, we describe a novel approach to detecting angiogenesis in vivo using magnetic resonance imaging (MRI) and a paramagnetic contrast agent targeted to endothelial alphaVbeta3 via the LM609 monoclonal antibody. This approach provided enhanced and detailed imaging of rabbit carcinomas by directly targeting paramagnetic agents to the angiogenic vasculature. In addition, angiogenic 'hot spots' not seen by standard MRI were detected. Our strategy for MR imaging of alphaVbeta3 thus represents a non-invasive means to assess the growth and malignant phenotype of tumors.", + "TAG_DATA": [ + "147, rabbit {'context': 'B-neoplasm'}", + "148, carcinomas {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "147, rabbit ['l0']", + "148, carcinomas ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9585231", + "TEXT": "The cyclin-dependent kinase inhibitor p27Kip1 controls cell proliferation in response to normal mitogenic stimuli. We show here that p27Kip1 also safeguards against excessive cell proliferation in specific pathophysiologic settings. We used experimental glomerulonephritis as a paradigm for immune mediated inflammation and ureteral obstruction as a model for non-immune mediated inflammation. Renal function was substantially decreased in nephritic p27-/- mice compared with control mice, and this was associated with increased glomerular cell proliferation, apoptosis and matrix protein accumulation. Tubular epithelial cell proliferation and apoptosis was also increased in p27-/- mice following ureteral obstruction. p27Kip1 may have a general role in protecting cells and tissues from inflammatory injury.", + "TAG_DATA": [ + "56, nephritic {'perturbing_action': 'B-gene loss-of-function'}", + "57, p27-/- {'perturbing_action': 'B-gene loss-of-function'}", + "58, mice {'context': 'B-organism'}", + "62, mice, {'context': 'B-organism'}", + "68, increased {'effect': 'B-positive'}", + "69, glomerular {'context': 'B-cells'}", + "70, cell {'context': 'I-cells'}", + "71, proliferation, {'phenotype': 'B-proliferation'}", + "72, apoptosis {'phenotype': 'B-apoptosis'}", + "77, Tubular {'context': 'B-cells'}", + "78, epithelial {'context': 'I-cells'}", + "79, cell {'context': 'I-cells'}", + "80, proliferation {'phenotype': 'B-proliferation'}", + "82, apoptosis {'phenotype': 'B-apoptosis'}", + "85, increased {'effect': 'B-positive'}", + "87, p27-/- {'perturbing_action': 'B-gene loss-of-function'}", + "88, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, nephritic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "57, p27-/- ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "58, mice ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "62, mice, ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "68, increased ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "69, glomerular ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "70, cell ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "71, proliferation, ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "72, apoptosis ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "77, Tubular ['l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "78, epithelial ['l36', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "79, cell ['l37', 'l43', 'l49', 'l50', 'l51', 'l52']", + "80, proliferation ['l38', 'l44', 'l49', 'l53', 'l54', 'l55']", + "82, apoptosis ['l39', 'l45', 'l50', 'l53', 'l56', 'l57', 'l58']", + "85, increased ['l40', 'l46', 'l51', 'l54', 'l56', 'l59', 'l60']", + "87, p27-/- ['l41', 'l47', 'l57', 'l59', 'l61']", + "88, mice ['l42', 'l48', 'l52', 'l55', 'l58', 'l60', 'l61']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nephritic", + "p27-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nephritic", + "p27-/-" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nephritic", + "p27-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "glomerular", + "cell", + "Tubular", + "epithelial" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nephritic", + "p27-/-" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nephritic", + "p27-/-" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation,", + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "cells", + "words": [ + "glomerular", + "cell", + "Tubular", + "epithelial" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation,", + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "glomerular", + "cell", + "Tubular", + "epithelial" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation,", + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "glomerular", + "cell", + "Tubular", + "epithelial" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "9546793", + "TEXT": "The central biochemical mechanisms involved in primate parturition are still unclear. Studies in both humans and nonhuman primates such as the baboon and rhesus monkey indicate that many factors play a part in the cascade of interactive positive feedforward loops that progressively promote parturition: changes in maternal endocrinology, a nocturnal switch in myometrial activity from low amplitude, infrequent contractures to high amplitude, high frequency contractions (see Fig. 1), dilation of the cervix and biochemical changes in the fetal membranes that lead to rupture. Here we demonstrate that infusion of the aromatase inhibitor 4-hydroxyandrostenedione (4OHA) inhibits conversion of androgen to estrogen and prevents premature delivery caused by administration of androgen to pregnant rhesus monkeys at 0.8 of pregnancy term. 4OHA also inhibited the androstenedione induced maternal endocrine and fetal membrane biochemical changes, and alteration of myometrial activity patterns. Secondly, peripheral estrogen infusions increased myometrial activity but did not produce preterm delivery or fetal membrane changes. We conclude that paracrine functions of estrogen at its site of production play critical and central roles in delivery in the non-human primate.", + "TAG_DATA": [ + "88, of {'perturbing_action': 'I-pharmacological inhibition'}", + "89, the {'perturbing_action': 'I-pharmacological inhibition'}", + "90, aromatase {'perturbing_action': 'I-pharmacological inhibition'}", + "91, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "92, 4-hydroxyandrostenedione {'perturbing_action': 'I-pharmacological inhibition'}", + "93, (4OHA) {'perturbing_action': 'I-pharmacological inhibition'}", + "111, rhesus {'context': 'B-organism'}", + "112, monkeys {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "88, of ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "89, the ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "90, aromatase ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "91, inhibitor ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "92, 4-hydroxyandrostenedione ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "93, (4OHA) ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "111, rhesus ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "112, monkeys ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "of", + "the", + "aromatase", + "inhibitor", + "4-hydroxyandrostenedione", + "(4OHA)" + ] + }, + "context": { + "val": "organism", + "words": [ + "rhesus", + "monkeys" + ] + } + } + ] + }, + { + "PMID": "9546792", + "TEXT": "We describe a novel variant of Alzheimer's disease (AD) in a Finnish pedigree with 17 affected individuals of both sexes in three generations. The disease is characterized by progressive dementia which is, in most cases, preceded by spastic paraparesis. Neuropathological investigations revealed numerous, distinct, large, round and eosinophilic plaques as well as neurofibrillary tangles and amyloid angiopathy throughout the cerebral cortex. The predominant plaques resembled cotton wool balls and were immunoreactive for Abeta but lacked a congophilic dense core or marked plaque-related neuritic pathology. Molecular genetic analysis revealed that the disease was caused by a deletion of exon 9 (delta9) of the presenilin 1 (PS1) gene from the mRNA: unlike previous examples of the delta9 variant, the deletion was not caused by a splice acceptor site mutation.", + "TAG_DATA": [ + "96, of {'perturbing_action': 'I-gene loss-of-function'}", + "97, exon {'perturbing_action': 'I-gene loss-of-function'}", + "98, 9 {'perturbing_action': 'I-gene loss-of-function'}", + "99, (delta9) {'perturbing_action': 'I-gene loss-of-function'}", + "100, of {'perturbing_action': 'I-gene loss-of-function'}", + "101, the {'perturbing_action': 'I-gene loss-of-function'}", + "102, presenilin {'perturbing_action': 'I-gene loss-of-function'}", + "103, 1 {'perturbing_action': 'I-gene loss-of-function'}", + "104, (PS1) {'perturbing_action': 'I-gene loss-of-function'}", + "105, gene {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "96, of ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "97, exon ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "98, 9 ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "99, (delta9) ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "100, of ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "101, the ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "102, presenilin ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "103, 1 ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "104, (PS1) ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "105, gene ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9500605", + "TEXT": "Successful tumor immunotherapy with peptides requires the induction of cytotoxic T lymphocytes (CTLs) rather than antibodies. Mice immunized with mannan conjugated to MUC1, a peptide found in large amounts in breast cancer, develop CTL responses. In contrast, immunized patients produce high antibodies with poor CTL responses to MUC1. Here, we provide evidence that this \"switch\" in the immune response is due to the fact that antibodies against the Gal alpha(1,3)Gal epitope, which are normally present in humans but not mice, cross-react with MUC1 peptides. In particular, mice that lack the gene for the epitope (and that produce anti-Gal antibodies) (Gal-/- mice) are like humans in their response to MUC1 immunization in that they develop antibody rather than CTL responses. After we exposed macrophages from Gal-/- mice in vitro to MUC1, in the absence of Gal antibody, and adoptively transferred them into the mice, Gal-/- mice produced a predominantly CTL response. The findings are of relevance for immunotherapy studies in humans and emphasize the differences seen in preclinical testing in rodents before clinical trials.", + "TAG_DATA": [ + "122, macrophages {'context': 'B-cells'}", + "124, Gal-/- {'perturbing_action': 'B-gene loss-of-function'}", + "125, mice {'context': 'B-organism'}", + "126, in {'context': 'B-in vitro'}", + "127, vitro {'context': 'I-in vitro'}", + "142, mice, {'context': 'B-organism'}", + "143, Gal-/- {'perturbing_action': 'B-gene loss-of-function'}", + "144, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "122, macrophages ['l0', 'l1', 'l2', 'l3']", + "124, Gal-/- ['l0', 'l4', 'l5', 'l6']", + "125, mice ['l1', 'l4', 'l7', 'l8']", + "126, in ['l2', 'l5', 'l7', 'l9']", + "127, vitro ['l3', 'l6', 'l8', 'l9']", + "142, mice, ['l10', 'l11']", + "143, Gal-/- ['l10', 'l12']", + "144, mice ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "macrophages" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gal-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gal-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gal-/-" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "9500603", + "TEXT": "During early pregnancy, in response to the implanting embryo, the surrounding uterine stroma undergoes a dramatic transformation into a specialized tissue known as the decidua. The decidua encapsulates the developing embryo, facilitating nutrient transfer and limiting trophoblast invasion. Here we show that female mice with a null mutation of the interleukin-11 receptor alpha chain are infertile because of defective decidualization. A temporal analysis revealed IL-11 expression is maximal in the normal pregnant uterus at the time of decidualization, and in situ hybridization studies showed expression of the IL-11 and the IL-11 receptor alpha chain in the developing decidual cells. These observations reveal a previously unrecognized critical role for IL-11 signaling in female reproduction.", + "TAG_DATA": [ + "42, female {'context': 'B-organism'}", + "43, mice {'context': 'I-organism'}", + "46, null {'perturbing_action': 'B-gene loss-of-function'}", + "47, mutation {'perturbing_action': 'I-gene loss-of-function'}", + "48, of {'perturbing_action': 'I-gene loss-of-function'}", + "49, the {'perturbing_action': 'I-gene loss-of-function'}", + "50, interleukin-11 {'perturbing_action': 'I-gene loss-of-function'}", + "51, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "52, alpha {'perturbing_action': 'I-gene loss-of-function'}", + "53, chain {'perturbing_action': 'I-gene loss-of-function'}", + "97, decidual {'context': 'B-cells'}", + "98, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "42, female ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "43, mice ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "46, null ['l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "47, mutation ['l13', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "48, of ['l1', 'l7', 'l14', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "49, the ['l2', 'l8', 'l15', 'l22', 'l28', 'l34', 'l35', 'l36', 'l37']", + "50, interleukin-11 ['l3', 'l9', 'l16', 'l23', 'l29', 'l34', 'l38', 'l39', 'l40']", + "51, receptor ['l4', 'l10', 'l17', 'l24', 'l30', 'l35', 'l38', 'l41', 'l42']", + "52, alpha ['l5', 'l11', 'l18', 'l25', 'l31', 'l36', 'l39', 'l41', 'l43']", + "53, chain ['l6', 'l12', 'l19', 'l26', 'l32', 'l37', 'l40', 'l42', 'l43']", + "97, decidual ['l44']", + "98, cells. ['l20', 'l27', 'l33', 'l44']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "female", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "the", + "interleukin-11", + "receptor", + "alpha", + "chain" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "null", + "mutation", + "of" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "9461197", + "TEXT": "We postulated that activation of a genetic program that tonically inhibits intimal cell death is a necessary condition for the pathogenesis of vascular disease. Studies of vascular lesions in humans and animal models documented increased expression of the anti-apoptotic gene product Bcl-xL within intimal cells. Downregulation of intimal cell bcl-xL expression with the use of antisense oligonucleotides induced apoptosis and acute regression of vascular lesions. These findings indicate that apoptosis regulatory genes such as bcl-xL are critical determinants of intimal lesion formation and that targeted apoptosis may be a novel therapy for intimal vascular disease.", + "TAG_DATA": [ + "45, Downregulation {'perturbing_action': 'B-gene loss-of-function'}", + "46, of {'perturbing_action': 'I-gene loss-of-function'}", + "47, intimal {'perturbing_action': 'I-gene loss-of-function'}", + "48, cell {'perturbing_action': 'I-gene loss-of-function'}", + "49, bcl-xL {'perturbing_action': 'I-gene loss-of-function'}", + "50, expression {'perturbing_action': 'I-rnai/knockdown'}", + "57, induced {'effect': 'B-positive'}", + "58, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "45, Downregulation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "46, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "47, intimal ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "48, cell ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "49, bcl-xL ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "50, expression ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "57, induced ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "58, apoptosis ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Downregulation", + "of", + "intimal", + "cell", + "bcl-xL" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Downregulation", + "of", + "intimal", + "cell", + "bcl-xL" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "9461196", + "TEXT": "The T-cell antigen receptor (TCR) repertoire was studied longitudinally by analyzing the varying lengths of the beta chain CDR3 hypervariable region during the course of HIV-1 infection and following combination antiretroviral therapy. Drastic restrictions in CD8+ T-cell repertoire usage were found at all stages of natural progression and persisted during the first six months of treatment. In contrast, significant CD4+ T-cell repertoire perturbations were not found in early stages of infection but correlated with progression to AIDS. Out of ten patients presenting with pretreatment perturbations, normalization of the CD4+ repertoire was observed in eight good responders, but not in two cases of unsuccessful therapy. These results indicate that, besides CD4+ cell count rise, an efficient control of HIV replication may allow qualitative modifications of the CD4+ repertoire balance.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9461189", + "TEXT": "In order to treat common cancers with immunotherapy, chimeric receptors have been developed that combine the tumor specificity of antibodies with T-cell effector functions. Previously, we demonstrated that T cells transduced with a chimeric receptor gene against human ovarian cancer were able to recognize ovarian cancer cells in vitro and in vivo. We now report that recipients of bone marrow cells transduced with these genes exhibited significant antitumor activity in vivo. Moreover, in vivo depletion of T cells in reconstituted mice did not affect antitumor activity, suggesting that other immune cells expressing the chimeric receptor gene may play an important role in tumor rejection.", + "TAG_DATA": [ + "28, T {'context': 'B-cells'}", + "29, cells {'context': 'B-cells'}", + "30, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "31, with {'perturbing_action': 'I-gene gain-of-function'}", + "32, a {'perturbing_action': 'I-gene gain-of-function'}", + "33, chimeric {'perturbing_action': 'I-gene gain-of-function'}", + "34, receptor {'perturbing_action': 'I-gene gain-of-function'}", + "35, gene {'perturbing_action': 'I-gene gain-of-function'}", + "36, against {'perturbing_action': 'I-rnai/knockdown'}", + "37, human {'context': 'B-neoplasm'}", + "38, ovarian {'context': 'I-transformed cells'}", + "39, cancer {'context': 'I-transformed cells'}", + "44, ovarian {'context': 'B-transformed cells'}", + "45, cancer {'context': 'I-transformed cells'}", + "46, cells {'context': 'I-transformed cells'}", + "47, in {'context': 'B-in vitro'}", + "48, vitro {'context': 'I-in vitro'}", + "50, in {'context': 'B-in vivo'}", + "51, vivo. {'context': 'I-in vivo'}", + "58, bone {'context': 'B-cells'}", + "59, marrow {'context': 'I-cells'}", + "60, cells {'context': 'I-cells'}", + "61, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "62, with {'perturbing_action': 'I-gene gain-of-function'}", + "63, these {'perturbing_action': 'I-gene gain-of-function'}", + "64, genes {'perturbing_action': 'I-gene gain-of-function'}", + "69, in {'context': 'B-in vivo'}", + "70, vivo. {'context': 'I-in vivo'}", + "72, in {'context': 'B-in vivo'}", + "73, vivo {'context': 'I-in vivo'}", + "76, T {'context': 'B-cells'}", + "77, cells {'context': 'B-cells'}", + "80, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "28, T ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "29, cells ['l0', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "30, transduced ['l1', 'l18', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "31, with ['l2', 'l19', 'l35', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "32, a ['l3', 'l20', 'l36', 'l51', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "33, chimeric ['l4', 'l21', 'l37', 'l52', 'l66', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "34, receptor ['l5', 'l22', 'l38', 'l53', 'l67', 'l80', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "35, gene ['l6', 'l23', 'l39', 'l54', 'l68', 'l81', 'l93', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "36, against ['l7', 'l24', 'l40', 'l55', 'l69', 'l82', 'l94', 'l105', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "37, human ['l8', 'l25', 'l41', 'l56', 'l70', 'l83', 'l95', 'l106', 'l116', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "38, ovarian ['l9', 'l26', 'l42', 'l57', 'l71', 'l84', 'l96', 'l107', 'l117', 'l126', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "39, cancer ['l10', 'l27', 'l43', 'l58', 'l72', 'l85', 'l97', 'l108', 'l118', 'l127', 'l135', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "44, ovarian ['l11', 'l28', 'l44', 'l59', 'l73', 'l86', 'l98', 'l109', 'l119', 'l128', 'l136', 'l143', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "45, cancer ['l12', 'l29', 'l45', 'l60', 'l74', 'l87', 'l99', 'l110', 'l120', 'l129', 'l137', 'l144', 'l149', 'l155', 'l156', 'l157', 'l158', 'l159']", + "46, cells ['l13', 'l30', 'l46', 'l61', 'l75', 'l88', 'l100', 'l111', 'l121', 'l130', 'l138', 'l145', 'l150', 'l155', 'l160', 'l161', 'l162']", + "47, in ['l14', 'l31', 'l47', 'l62', 'l76', 'l89', 'l101', 'l112', 'l122', 'l131', 'l139', 'l146', 'l151', 'l156', 'l160', 'l163', 'l164']", + "48, vitro ['l15', 'l32', 'l48', 'l63', 'l77', 'l90', 'l102', 'l113', 'l123', 'l132', 'l140', 'l147', 'l152', 'l157', 'l161', 'l163', 'l165']", + "50, in ['l16', 'l33', 'l49', 'l64', 'l78', 'l91', 'l103', 'l114', 'l124', 'l133', 'l141', 'l153', 'l158', 'l166']", + "51, vivo. ['l17', 'l34', 'l50', 'l65', 'l79', 'l92', 'l104', 'l115', 'l125', 'l134', 'l142', 'l148', 'l154', 'l159', 'l162', 'l164', 'l165', 'l166']", + "58, bone ['l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "59, marrow ['l167', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181']", + "60, cells ['l168', 'l175', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "61, transduced ['l169', 'l176', 'l182', 'l188', 'l189', 'l190', 'l191', 'l192']", + "62, with ['l170', 'l177', 'l183', 'l188', 'l193', 'l194', 'l195', 'l196']", + "63, these ['l171', 'l178', 'l184', 'l189', 'l193', 'l197', 'l198', 'l199']", + "64, genes ['l172', 'l179', 'l185', 'l190', 'l194', 'l197', 'l200', 'l201']", + "69, in ['l173', 'l180', 'l186', 'l191', 'l195', 'l198', 'l200', 'l202']", + "70, vivo. ['l174', 'l181', 'l187', 'l192', 'l196', 'l199', 'l201', 'l202']", + "72, in ['l203', 'l204', 'l205', 'l206']", + "73, vivo ['l203', 'l207', 'l208', 'l209']", + "76, T ['l204', 'l207', 'l210', 'l211']", + "77, cells ['l205', 'l208', 'l210', 'l212']", + "80, mice ['l206', 'l209', 'l211', 'l212']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "bone", + "marrow" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "a", + "chimeric", + "receptor", + "gene", + "these", + "genes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "against" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "a", + "chimeric", + "receptor", + "gene" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "a", + "chimeric", + "receptor", + "gene" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "a", + "chimeric", + "receptor", + "gene" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "a", + "chimeric", + "receptor", + "gene", + "these", + "genes" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "against" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "against" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "against" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "against" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "9427613", + "TEXT": "The glucocorticoid receptor (GR) belongs to a superfamily of ligand-regulated nuclear steroid hormone receptors. The steps in the signal transduction pathway leading to the biological effects of glucocorticoids (GCs) include sequentially binding of the steroid to the GR ligand binding domain (LBD), receptor transformation, nuclear translocation and either positive or negative gene transactivation. Rifampicin (RIF) is a macrocyclic antibiotic used as an antituberculosis agents. As the incidence of tuberculosis has been increasing, in part because of the AIDS epidemic, a growing number of patients are being exposed to the adverse effects of this antibiotic. Indeed, this compound, as are the GCs, is often implicated in noxious drug interactions, because of its strong ability to induce drug-metabolizing enzymes. Moreover, in humans, RIF, as are the GCs, has been described as a potential immunodepressor, associated notably with the reduction of mitogenic responsiveness of human peripheral blood lymphocytes. Here, we report that RIF activates the human glucocorticoid receptor (hGR). Transient expression of wild-type, deleted or mutated GRs; sucrose density gradient sedimentation; and the BIAcore technique strongly suggest that RIF binds to the receptor with the physiological consequence that this antibiotic acts as an immunodepressor. Given the wide use of RIF in the treatment of coinfection of tuberculosis and HIV, this report is highly relevant to current medical practice.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9427606", + "TEXT": "Neutral endopeptidase 24.11 (NEP) is a cell-surface enzyme expressed by prostatic epithelial cells that cleaves and inactivates neuropeptides implicated in the growth of androgen-independent prostate cancer (PC). We report that NEP expression and catalytic activity are lost in vitro in androgen-independent but not androgen-dependent PC cell lines. In vivo, NEP protein expression is commonly decreased in cancer cells of metastatic PC specimens from patients with androgen-independent but not androgen-dependent PC. Overexpression of NEP in androgen-independent PC cells or incubation with recombinant NEP inhibits PC cell growth. Furthermore, in androgen-dependent PC cells, expression of NEP is transcriptionally regulated by androgen and decreases with androgen withdrawal. These data suggest that decreased NEP expression, common in androgen-independent PCs, is facilitated by the elimination of androgens, and that NEP loss plays an important role in the development of androgen-independent PC by allowing PC cells to use mitogenic neuropeptides as an alternate source to androgen in order to stimulate cell proliferation.", + "TAG_DATA": [ + "44, PC {'context': 'I-transformed cells'}", + "45, cell {'context': 'I-transformed cells'}", + "46, lines. {'context': 'I-transformed cells'}", + "70, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "71, of {'perturbing_action': 'I-gene gain-of-function'}", + "72, NEP {'perturbing_action': 'I-gene gain-of-function'}", + "74, androgen-independent {'context': 'B-transformed cells'}", + "75, PC {'context': 'I-transformed cells'}", + "76, cells {'context': 'I-transformed cells'}", + "82, inhibits {'effect': 'B-negative'}", + "83, PC {'context': 'B-neoplasm'}", + "84, cell {'phenotype': 'B-cell growth'}", + "85, growth. {'phenotype': 'I-cell growth'}", + "88, androgen-dependent {'context': 'B-transformed cells'}", + "89, PC {'context': 'I-transformed cells'}", + "90, cells, {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "44, PC ['l0', 'l1']", + "45, cell ['l0', 'l2']", + "46, lines. ['l1', 'l2']", + "70, Overexpression ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "71, of ['l3', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "72, NEP ['l4', 'l12', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "74, androgen-independent ['l5', 'l13', 'l20', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "75, PC ['l6', 'l14', 'l21', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "76, cells ['l7', 'l15', 'l22', 'l28', 'l33', 'l38', 'l39', 'l40', 'l41']", + "82, inhibits ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l42', 'l43', 'l44']", + "83, PC ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l45', 'l46']", + "84, cell ['l10', 'l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l47']", + "85, growth. ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l47']", + "88, androgen-dependent ['l48', 'l49']", + "89, PC ['l48', 'l50']", + "90, cells, ['l49', 'l50']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "NEP" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "androgen-independent", + "PC", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "NEP" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "NEP" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "PC" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "NEP" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "androgen-independent", + "PC", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "androgen-independent", + "PC", + "cells" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "PC" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "PC" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth." + ] + } + } + ] + }, + { + "PMID": "9427605", + "TEXT": "A number of adenocarcinomas abundantly express and secrete underglycosylated MUC1 mucin. Underglycosylation exposes tandem repeat peptide sequences on cancer-associated MUC1 mucin that are normally cryptic. High levels of MUC1 mucin are correlated with a poor prognosis and immunosuppression in adenocarcinoma patients. In this report we show that cancer-associated MUC1 mucin, affinity-purified from ascites fluids of cancer patients, and synthetic tandem repeats of MUC1 mucin core peptide can suppress human T-cell proliferative responses. This MUC1 mucin-induced suppression of T-cell responses can be reversed by the addition of exogenous IL-2 or anti-CD28 monoclonal antibody. These results are consistent with other studies showing that lymphocytes present in the vicinity of tumor cells are anergic and can be reactivated with exogenous interleukin-2. Overcoming MUC1 mucin-induced immunosuppression with IL-2 combined with active specific immunotherapy might be an effective immunotherapeutic strategy against human adenocarcinomas.", + "TAG_DATA": [ + "67, suppress {'effect': 'B-negative'}", + "68, human {'context': 'B-cells'}", + "69, T-cell {'context': 'I-cells'}", + "70, proliferative {'phenotype': 'B-proliferation'}", + "71, responses. {'phenotype': 'I-proliferation'}", + "77, T-cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "67, suppress ['l0', 'l1', 'l2', 'l3']", + "68, human ['l0', 'l4', 'l5', 'l6']", + "69, T-cell ['l1', 'l4', 'l7', 'l8']", + "70, proliferative ['l2', 'l5', 'l7', 'l9']", + "71, responses. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "suppress" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "T-cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppress" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "responses." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "T-cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "responses." + ] + } + } + ] + }, + { + "PMID": "9427593", + "TEXT": "PIP: The Public Citizen's Health Research Group recently called attention to ethical concerns with trials of AZT which are either planned or underway in developing countries. The trials are being conducted to determine the minimum dose of AZT needed to prevent the vertical transmission of HIV from infected mothers to their unborn children. To that end, women who have given their informed consent to enter the trials are randomized into various dosage and placebo arms of the trials. The problem with this standard trial format in this case is that AZT is already proven capable of blocking approximately two thirds of transmissions of HIV to the fetus. The Public Citizen's Health Research Group therefore argues that the trials violate the Helsinki Declaration in that every patient enrolled in a clinical trial should be assured of receiving the best available treatment. Since these study subjects cannot obtain HIV prophylaxis elsewhere, they may enter the trials out of desperation, thereby invalidating their ability to autonomously consent to study participation. The author considers the ideal of informed consent which equates autonomy with competence rather than with freedom, whether freedom equals choice, and freedom, autonomy, and trials in developing countries. AZT vertical transmission trials could be markedly improved by replacing the placebo arm with a contrasting dose cohort.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9396613", + "TEXT": "The ability of adenovirus (Ad) to transfect most cell types efficiently has already resulted in human gene therapy trials involving the systemic administration of adenoviral constructs. However, because of the complexity of brain function and the difficulty in noninvasively monitoring alterations in neuronal gene expression, the potential of Ad gene therapy strategies for treating disorders of the CNS has been difficult to assess. In the present study, we have used an Ad encoding the arginine vasopressin cDNA (AdAVP) in an AVP-deficient animal model of diabetes insipidus (the Brattleboro rat), which allowed us to monitor chronically the success of the gene therapy treatment by noninvasive assays. Injection of AdAVP into the supraoptic nuclei (SON) of the hypothalamus resulted in expression of AVP in magnocellular neurons. This was accompanied by reduced daily water intake and urine volume, as well as increased urine osmolality lasting 4 months. These data show that a single gene defect leading to a neurological disorder can be corrected with an adenovirus-based strategy. This study highlights the potential of using Ad gene therapy for the long-term treatment of disorders of the CNS.", + "TAG_DATA": [ + "80, AVP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "81, animal {'context': 'B-organism'}", + "82, model {'context': 'I-organism'}", + "87, Brattleboro {'context': 'B-organism'}", + "88, rat), {'context': 'I-organism'}", + "110, supraoptic {'context': 'B-tissue/organ'}", + "111, nuclei {'context': 'I-tissue/organ'}", + "112, (SON) {'context': 'I-tissue/organ'}", + "113, of {'context': 'I-tissue/organ'}", + "114, the {'context': 'I-tissue/organ'}", + "115, hypothalamus {'context': 'I-tissue/organ'}", + "122, magnocellular {'context': 'B-cells'}", + "123, neurons. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "80, AVP-deficient ['l0', 'l1', 'l2', 'l3', 'l4']", + "81, animal ['l0', 'l5', 'l6', 'l7', 'l8']", + "82, model ['l1', 'l5', 'l9', 'l10', 'l11']", + "83, of ['l2', 'l6', 'l9', 'l12', 'l13']", + "87, Brattleboro ['l3', 'l7', 'l10', 'l12', 'l14']", + "88, rat), ['l4', 'l8', 'l11', 'l13', 'l14']", + "110, supraoptic ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "111, nuclei ['l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "112, (SON) ['l16', 'l22', 'l28', 'l29', 'l30', 'l31', 'l32']", + "113, of ['l17', 'l23', 'l28', 'l33', 'l34', 'l35', 'l36']", + "114, the ['l18', 'l24', 'l29', 'l33', 'l37', 'l38', 'l39']", + "115, hypothalamus ['l19', 'l25', 'l30', 'l34', 'l37', 'l40', 'l41']", + "122, magnocellular ['l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l42']", + "123, neurons. ['l21', 'l27', 'l32', 'l36', 'l39', 'l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "AVP-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "animal", + "model", + "Brattleboro", + "rat)," + ] + } + } + ] + }, + { + "PMID": "9396612", + "TEXT": "During development, semaphorins (collapsin, fasciclin) mediate repulsive and inhibitory guidance of neurons. Semaphorin III, a secretable member of this family, is expressed by the ventral spinal cord at the time corresponding to projection of sensory afferents from the dorsal root ganglion (DRG) into the spinal cord. The inhibitory effect of E14 ventral cord is active only on nerve growth factor (NGF)-responsive sensory afferents (small-diameter A-delta and C fibers subserving sensations of temperature and pain). Similarly, COS cells secreting recombinant semaphorin III are able to selectively repel DRG afferents whose growth is stimulated by NGF and not NT-3. However, it is not known whether these molecules can exert a functional role in the fully developed adult peripheral nervous system. In this study, we demonstrated that gene gun transfection and production of semaphorin III in corneal epithelial cells in adult rabbits in vivo can cause repulsion of established A-delta and C fiber trigeminal sensory afferents. In addition, it is shown that, following epithelial wounding and denervation, semaphorin III is able to inhibit collateral nerve sprouts from innervating the reepithelialized tissue. These findings are significant in that they provide direct evidence that small-diameter adult sensory neurons retain the ability to respond to semaphorin III. In addition, the corneal gene gun technique may be generally used to study the in vivo effects of neural growth modulators by quantifying the amount of sensory nerve growth.", + "TAG_DATA": [ + "86, DRG {'context': 'B-cells'}", + "87, afferents {'context': 'I-cells'}", + "133, corneal {'context': 'B-cells'}", + "134, epithelial {'context': 'I-cells'}", + "135, cells {'context': 'I-cells'}", + "137, adult {'context': 'B-organism'}", + "138, rabbits {'context': 'I-organism'}", + "139, in {'context': 'B-in vivo'}", + "140, vivo {'context': 'I-in vivo'}", + "146, A-delta {'context': 'B-cells'}", + "147, and {'context': 'I-cells'}", + "148, C {'context': 'I-cells'}", + "149, fiber {'context': 'I-cells'}", + "150, trigeminal {'context': 'I-cells'}", + "151, sensory {'context': 'I-cells'}", + "152, afferents. {'context': 'I-cells'}", + "169, inhibit {'effect': 'B-negative'}", + "170, collateral {'context': 'B-cells'}", + "171, nerve {'context': 'I-cells'}", + "172, sprouts {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "86, DRG ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "87, afferents ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "125, gun ['l1', 'l8', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "126, transfection ['l2', 'l9', 'l17', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "133, corneal ['l10', 'l18', 'l32', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "134, epithelial ['l3', 'l11', 'l19', 'l33', 'l46', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "135, cells ['l4', 'l12', 'l20', 'l34', 'l47', 'l59', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "137, adult ['l5', 'l13', 'l21', 'l35', 'l48', 'l60', 'l71', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "138, rabbits ['l6', 'l14', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "139, in ['l15', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "140, vivo ['l7', 'l16', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "146, A-delta ['l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "147, and ['l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l122', 'l123', 'l124', 'l125', 'l126']", + "148, C ['l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l127', 'l128', 'l129', 'l130']", + "149, fiber ['l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l118', 'l123', 'l127', 'l131', 'l132', 'l133']", + "150, trigeminal ['l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l113', 'l119', 'l124', 'l128', 'l131', 'l134', 'l135']", + "151, sensory ['l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l129', 'l132', 'l134', 'l136']", + "152, afferents. ['l31', 'l45', 'l58', 'l70', 'l81', 'l91', 'l100', 'l108', 'l115', 'l121', 'l126', 'l130', 'l133', 'l135', 'l136']", + "169, inhibit ['l137', 'l138', 'l139']", + "170, collateral ['l137', 'l140', 'l141']", + "171, nerve ['l138', 'l140', 'l142']", + "172, sprouts ['l139', 'l141', 'l142']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "context": { + "val": "cells", + "words": [ + "collateral", + "nerve", + "sprouts" + ] + } + } + ] + }, + { + "PMID": "9396611", + "TEXT": "Viruses have long been suggested to be involved in the etiology of multiple sclerosis (MS). This suggestion is based on (1) epidemiological evidence of childhood exposure to infectious agents and increase in disease exacerbations with viral infection; (2) geographic association of disease susceptibility with evidence of MS clustering; (3) evidence that migration to and from high-risk areas influences the likelihood of developing MS; (4) abnormal immune responses to a variety of viruses; and (5) analogy with animal models and other human diseases in which viruses can cause diseases with long incubation periods, a relapsing-remitting course, and demyelination. Many of these studies involve the demonstration of increased antibody titers to a particular virus, whereas some describe isolation of virus from MS material. However, no virus to date has been definitively associated with this disease. Recently, human herpesvirus 6 (HHV-6), a newly described beta-herpes virus that shares homology with cytomegalovirus (CMV), has been reported to be present in active MS plaques. In order to extend these observations, we have demonstrated increased IgM serum antibody responses to HHV-6 early antigen (p41/38) in patients with relapsing-remitting MS (RRMS), compared with patients with chronic progressive MS (CPMS), patients with other neurologic disease (OND), patients with other autoimmune disease (OID), and normal controls. Given the ubiquitous nature of this virus and the challenging precedent of correlating antiviral antibodies with disease association, these antibody studies have been supported by the detection of HHV-6 DNA from samples of MS serum as a marker of active viral infection.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9359706", + "TEXT": "Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) protein. While 70% of CF chromosomes carry a deletion of the phenylalanine residue 508 (deltaF508) of CFTR, roughly 5% of all CF chromosomes carry a premature stop mutation. We reported that the aminoglycoside antibiotics G-418 and gentamicin can suppress two premature stop mutations [a stop codon in place of glycine residue 542 (G542X) and arginine residue 553 (R553X)] when expressed from a CFTR cDNA in HeLa cells. Suppression resulted in the synthesis of full-length CFTR protein and the appearance of a cAMP-activated anion conductance characteristic of CFTR function. However, it was unclear whether this approach could restore CFTR function in cells expressing mutant forms of CFTR from the nuclear genome. We now report that G-418 and gentamicin are also capable of restoring CFTR expression in a CF bronchial epithelial cell line carrying the CFTR W1282X premature stop mutation (a stop codon in place of tryptophan residue 1282). This conclusion is based on the reappearance of cAMP-activated chloride currents, the restoration of CFTR protein at the apical plasma membrane, and an increase in the abundance of CFTR mRNA levels from the W1282X allele.", + "TAG_DATA": [ + "79, HeLa {'context': 'B-transformed cells'}", + "80, cells. {'context': 'I-transformed cells'}", + "140, CF {'context': 'B-cells'}", + "141, bronchial {'context': 'I-cells'}", + "142, epithelial {'context': 'I-cells'}", + "143, cell {'context': 'I-cells'}", + "144, line {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "79, HeLa ['l0']", + "80, cells. ['l0']", + "140, CF ['l1', 'l2', 'l3', 'l4']", + "141, bronchial ['l1', 'l5', 'l6', 'l7']", + "142, epithelial ['l2', 'l5', 'l8', 'l9']", + "143, cell ['l3', 'l6', 'l8', 'l10']", + "144, line ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9359701", + "TEXT": "Clinical trial results from 11,344 paired urine and serum samples revealed 1,181 HIV-1-positive individuals confirmed by western blot (WB). There were 25 discrepant samples: 10 were urine enzyme immunoassay (EIA) and WB positive, serum non-reactive and serum WB negative or indeterminate, and 15 were serum EIA and WB positive, urine EIA non-reactive or urine WB negative or indeterminate. Serum samples, HIV-1 antibody WB confirmed, revealed a 99.15% sensitivity (1,171 out of 1,181); urine samples, HIV-1 antibody WB confirmed, showed a 98.73% sensitivity (1,166 out of 1,181). This study demonstrated that neither serum nor urine results alone are as sensitive for HIV-1 antibody detection as combined results of both samples.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9359700", + "TEXT": "HIV-specific mucosal and cellular immunity was analyzed in heterosexual couples discordant for HIV status in serum and in HIV-unexposed controls. HIV-specific IgA but not IgG was present in urine and vaginal wash samples from HIV-exposed seronegative individuals (ESN), whereas both IgA and IgG were observed in their HIV-seropositive partners; antibodies were not detected in low-risk controls. Envelope protein (Env) peptide-stimulated interleukin-2 (IL-2) production by peripheral blood mononuclear cells (PBMCs) was detected in 9 out of 16 ESNs, 5 out of 16 HIV-infected patients and 1 out of 50 controls. Env peptide-stimulated PBMCs of ESNs produced more IL-2 and less IL-10 compared with those of HIV-infected individuals; no differences were observed in chemokine production or in CCR5 expression. These data demonstrate that a compartmentalized immune response to pathogens is possible in humans and raise the possibility of protective roles for cell-mediated immunity and mucosal IgA in HIV-seronegative individuals exposed to HIV.", + "TAG_DATA": [ + "64, peripheral {'context': 'B-cells'}", + "65, blood {'context': 'I-cells'}", + "66, mononuclear {'context': 'I-cells'}", + "67, cells {'context': 'I-cells'}", + "68, (PBMCs) {'context': 'I-cells'}", + "91, PBMCs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "64, peripheral ['l0', 'l1', 'l2', 'l3']", + "65, blood ['l0', 'l4', 'l5', 'l6']", + "66, mononuclear ['l1', 'l4', 'l7', 'l8']", + "67, cells ['l2', 'l5', 'l7', 'l9']", + "68, (PBMCs) ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9359695", + "TEXT": "Dystrophin-deficient mice (mdx) expressing a truncated (trc) utrophin transgene show amelioration of the dystrophic phenotype. Here we report a multifunctional study demonstrating that trcutrophin expression leads to major improvements of the mechanical performance of muscle (that is, force development, mechanical resistance to forced lengthenings and maximal spontaneous activity) and of the maintenance of the intracellular calcium homeostasis. These are two essential functions of muscle fibers, known to be impaired in mdx mouse muscles and Duchenne muscular dystrophy (DMD) patients. Our results bring strong support to the hypothesis that muscle wasting in dystrophin-deficient DMD patients could be prevented by upregulation of utrophin.", + "TAG_DATA": [ + "1, mice {'context': 'B-organism'}", + "3, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "4, a {'perturbing_action': 'I-gene gain-of-function'}", + "5, truncated {'perturbing_action': 'I-gene gain-of-function'}", + "6, (trc) {'perturbing_action': 'I-gene gain-of-function'}", + "7, utrophin {'perturbing_action': 'I-gene gain-of-function'}", + "8, transgene {'perturbing_action': 'I-gene gain-of-function'}", + "23, trcutrophin {'perturbing_action': 'B-gene gain-of-function'}", + "24, expression {'perturbing_action': 'I-gene gain-of-function'}", + "34, muscle {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "1, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "3, expressing ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "4, a ['l1', 'l8', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "5, truncated ['l9', 'l16', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "6, (trc) ['l2', 'l10', 'l17', 'l23', 'l29', 'l30', 'l31', 'l32', 'l33']", + "7, utrophin ['l3', 'l11', 'l18', 'l24', 'l29', 'l34', 'l35', 'l36', 'l37']", + "8, transgene ['l4', 'l12', 'l19', 'l25', 'l30', 'l34', 'l38', 'l39', 'l40']", + "23, trcutrophin ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l41', 'l42']", + "24, expression ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l41', 'l43']", + "34, muscle ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l43']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "a", + "(trc)", + "utrophin", + "transgene", + "trcutrophin", + "expression" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "a", + "truncated", + "(trc)", + "utrophin", + "transgene", + "trcutrophin", + "expression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscle" + ] + } + } + ] + }, + { + "PMID": "9334732", + "TEXT": "Entry of human immunodeficiency virus type 1 (HIV-1) into target cells requires both CD4 (ref. 1, 2) and one of a growing number of G-protein-coupled seven-transmembrane receptors. Viruses predominantly use one, or occasionally both, of the major co-receptors CCR5 or CXCR4, although other receptors, including CCR2B and CCR3, function as minor co-receptors. CCR3 appears critical in central nervous system infection. A 32-base pair inactivating deletion in CCR5 (delta 32) common to Northern European populations has been associated with reduced, but not absolute, HIV-1 transmission risk and delayed disease progression. A more commonly distributed transition causing a valine to isoleucine switch in transmembrane domain I of CCR2B (64I) with unknown functional consequences was recently shown to delay disease progression but not reduce infection risk. Although we confirm the lack of association of CCR2B 64I with transmission, we cannot confirm the association with delayed progression. Although subjects with CCR5 delta 32 defects had significantly reduced median viral load at study entry, providing a plausible explanation for the association with delayed progression, this association was not seen with CCR2B 64I. Further studies are needed to define the role of CCR2B64I in HIV pathogenesis.", + "TAG_DATA": [ + "65, in {'perturbing_action': 'I-gene loss-of-function'}", + "66, CCR5 {'perturbing_action': 'I-gene loss-of-function'}", + "146, CCR5 {'perturbing_action': 'B-other'}", + "147, delta {'perturbing_action': 'I-other'}", + "148, 32 {'perturbing_action': 'I-other'}", + "149, defects {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "64, deletion ['l0', 'l1', 'l2']", + "65, in ['l0', 'l3', 'l4']", + "66, CCR5 ['l1', 'l3', 'l5']", + "67, (delta ['l2', 'l4', 'l5']", + "146, CCR5 ['l6', 'l7', 'l8']", + "147, delta ['l6', 'l9', 'l10']", + "148, 32 ['l7', 'l9', 'l11']", + "149, defects ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9334728", + "TEXT": "The decline of growth hormone (GH) and insulin-like growth factor I (IGF-I) production during aging has been likened to the decrease in gonadal steroids in menopause. The repletion of GH/IGF-I levels in aging individuals is suggested to restore the lean tissue anabolism characteristic of youth. In addition to anabolic effects on musculo-skeletal tissues, GH also stimulates mammary glandular growth in some species, although its effects on primate mammary growth remain unclear. Some clinical observations implicate GH in human mammary growth, for example, gynecomastia occurs in some children treated with GH (ref. 6), and tall stature and acromegaly are associated with an increased incidence of breast cancer. To investigate the effects of GH/IGF-I augmentation on mammary tissue in a model relevant to aging humans, we treated aged female rhesus monkeys with GH, IGF-I, GH + IGF-I or saline diluent for 7 weeks. IGF-I treatment was associated with a twofold increase, GH with a three- to fourfold increase, and GH + IGF-I with a four'-to fivefold increase in mammary glandular size and epithelial proliferation index. These mitogenic effects were directly correlated with circulating GH and IGF-I levels, suggesting that either GH or its downstream effector IGF-I stimulates primate mammary epithelial proliferation.", + "TAG_DATA": [ + "125, aged {'context': 'B-organism'}", + "126, female {'context': 'I-organism'}", + "127, rhesus {'context': 'I-organism'}", + "128, monkeys {'context': 'I-organism'}", + "171, proliferation {'phenotype': 'B-proliferation'}", + "194, stimulates {'effect': 'B-positive'}", + "198, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "125, aged ['l0', 'l1', 'l2']", + "126, female ['l0', 'l3', 'l4']", + "127, rhesus ['l1', 'l3', 'l5']", + "128, monkeys ['l2', 'l4', 'l5']", + "194, stimulates ['l6']", + "198, proliferation. ['l6']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "9334726", + "TEXT": "Multiple sclerosis (MS) is a T cell-mediated autoimmune demyelinating disease, which may be initiated by a virus infection. Theiler's murine encephalomyelitis virus (TMEV), a natural mouse pathogen, is a picornavirus that induces a chronic, CD4+ T cell-mediated demyelinating disease with a clinical course and histopathology similar to that of chronic progressive MS (ref. 3). Demyelination in TMEV-infected mice is initiated by a mononuclear inflammatory response mediated by virus-specific CD4+ T cells targeting virus, which chronically persists in the CNS (ref. 4-6). We show that beginning 3-4 weeks after disease onset, T-cell responses to multiple myelin autoepitopes arise in an ordered progression and may play a pathologic role in chronic disease. Kinetic and functional studies show that T-cell responses to the immunodominant myelin proteolipid protein epitope (PLP139-151) did not arise because of cross-reactivity between TMEV and self epitopes (that is, molecular mimicry), but because of de novo priming of self-reactive T cells to sequestered autoantigens released secondary to virus-specific T cell-mediated demyelination (that is, epitope spreading). Epitope spreading is an important alternate mechanism to explain the etiology of virus-induced organ-specific autoimmune diseases.", + "TAG_DATA": [ + "90, T-cell {'context': 'B-cells'}", + "116, T-cell {'context': 'B-cells'}", + "148, self-reactive {'context': 'B-cells'}", + "149, T {'context': 'I-cells'}", + "150, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "116, T-cell ['l0', 'l1']", + "148, self-reactive ['l2', 'l3']", + "149, T ['l0', 'l2', 'l4']", + "150, cells ['l1', 'l3', 'l4']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9334723", + "TEXT": "The HIV-1 accessory gene product Vpr can influence viral pathogenesis by affecting viral replication as well as host cell transcription and proliferation. We have investigated the effects of Vpr on host cell activation and confirm that it influences cellular proliferation. However, we have also found that Vpr modulates T-cell receptor (TCR)-triggered apoptosis in a manner similar to that of glucocorticoids. In the absence of TCR-mediated activation, Vpr induces apoptosis whereas in its presence, Vpr interrupts the expected induction of apoptosis. This regulation of apoptosis is linked to Vpr suppression of NF-kappa B activity via the induction of I kappa B, an inhibitor of NF-kappa B. Further, Vpr suppresses expression of IL-2, IL-10, IL-12, TNF alpha and IL-4, all of which are NF-kappa B-dependent. The effects of Vpr could be reversed by RU486. Our finding that Vpr can regulate NF-kappa B supports the hypothesis that some aspects of viral pathogenesis are the consequence of cell dysregulation by Vpr.", + "TAG_DATA": [ + "47, modulates {'effect': 'B-regulates'}", + "51, apoptosis {'phenotype': 'B-apoptosis'}", + "67, induces {'effect': 'B-positive'}", + "68, apoptosis {'phenotype': 'B-apoptosis'}", + "74, interrupts {'effect': 'B-negative'}", + "77, induction {'effect': 'B-positive'}", + "79, apoptosis. {'phenotype': 'B-apoptosis'}", + "81, regulation {'effect': 'B-regulates'}", + "83, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "47, modulates ['l0', 'l1', 'l2']", + "51, apoptosis ['l0', 'l3', 'l4']", + "67, induces ['l1', 'l3', 'l5']", + "68, apoptosis ['l2', 'l4', 'l5']", + "74, interrupts ['l6', 'l7', 'l8', 'l9']", + "77, induction ['l6', 'l10', 'l11', 'l12']", + "79, apoptosis. ['l7', 'l10', 'l13', 'l14']", + "81, regulation ['l8', 'l11', 'l13', 'l15']", + "83, apoptosis ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "regulates", + "words": [ + "modulates", + "regulation" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces", + "induction" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "interrupts" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis.", + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "9334721", + "TEXT": "Stem cell gene therapy strategies for AIDS require that differentiation-inducing stromal elements of HIV-infected individuals remain functionally intact to support the maturation of exogenous progenitor cells into mature CD4+ cells. To investigate the feasibility of stem cell reconstitution strategies in AIDS, we used the SCID-hu mouse to examine the ability of HIV-infected CD4+ cell-depleted human thymic implants to support renewed thymopoiesis. Here we report that following treatment of these implants with antiretroviral drugs, new thymopoiesis is initiated. This suggests that antiviral therapies might allow de novo production of T lymphocytes and provides support for the concept of therapeutic strategies aimed at reconstitution of the peripheral CD4+ T-cell compartment.", + "TAG_DATA": [ + "44, SCID-hu {'context': 'B-organism'}", + "45, mouse {'context': 'I-organism'}", + "55, thymic {'context': 'I-organoid'}" + ], + "LINK_DATA": [ + "44, SCID-hu ['l0', 'l1', 'l2', 'l3']", + "45, mouse ['l0', 'l4', 'l5', 'l6']", + "53, cell-depleted ['l7', 'l8', 'l9']", + "54, human ['l1', 'l4', 'l7', 'l10', 'l11']", + "55, thymic ['l2', 'l5', 'l8', 'l10', 'l12']", + "56, implants ['l3', 'l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9288731", + "TEXT": "Lead is one of the most toxic and pervasive pollutants in society, and although there has been some lowering of blood lead levels in recent years, the levels continue to be of concern for African Americans, central city residents, residents in the Northeast region of the United States, persons with low income, and those with low educational attainment. Notably, these are the persons and the region where the highest prevalence of dental caries is observed. Information relating lead toxicity to oral health is sparse, but the preponderance of epidemiological data shows a relation between lead in the environment and the prevalence of dental caries. Using our well-defined rat caries model we found that pre- and perinatal exposure to lead results in an almost 40% increase in the prevalence of caries and a decrease in stimulated parotid function of nearly 30%. Levels of lead in milk from lead-treated dams were approximately 10 times as high as the corresponding blood lead levels, suggesting that lead is being concentrated by mammary glands. These findings may help in part to explain the comparatively high levels of dental caries observed in the inner cities of the United States where exposure to lead is common. Environmental sources of lead include drinking water, lead-based paint and, to a lesser extent, automobile and industrial emissions. In humans lead is accumulated and stored in bones (half-life of approximately 62 years), and even maternal exposure to lead decades before pregnancy can subsequently result in exposure of the developing fetus to elevated levels of lead. Moreover, lead concentration in maternal blood has been shown to increase during pregnancy and lactation because of mobilization of stored lead from bone, and typically, lead is found in milk at a higher concentration than the level found in maternal plasma at the same time point.", + "TAG_DATA": [ + "135, parotid {'context': 'B-tissue/organ'}", + "147, dams {'context': 'B-organism'}", + "247, developing {'context': 'B-organism'}", + "248, fetus {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "247, developing ['l0']", + "248, fetus ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9288725", + "TEXT": "The delayed development of recurring seizures is a common consequence of traumatic head injury; the cause of such epilepsy is unknown. We demonstrate here that transection of the mature axons of CA3 pyramidal cells in hippocampal slice cultures leads to the formation by CA3 pyramidal cells of new axon collaterals that are immunoreactive with the growth-associated protein GAP-43. Individual CA3 cell axons had an elevated number of presynaptic boutons 14 days after the lesion, and dual intracellular recordings revealed an increased probability that any two CA3 pyramidal cells were connected by an excitatory synapse. Lesioned cultures were hyperexcitable and synaptic responses often displayed unusual prolonged polysynaptic components. We thus demonstrate that recurrent axon collaterals are newly sprouted by pyramidal cells as a consequence of axonal injury and suggest that this underlies the development of posttraumatic epilepsy.", + "TAG_DATA": [ + "28, mature {'context': 'B-cells'}", + "29, axons {'context': 'I-cells'}", + "30, of {'context': 'I-cells'}", + "31, CA3 {'context': 'B-cells'}", + "32, pyramidal {'context': 'I-cells'}", + "33, cells {'context': 'I-cells'}", + "35, hippocampal {'context': 'B-cells'}", + "36, slice {'context': 'I-cells'}", + "37, cultures {'context': 'I-cells'}", + "43, CA3 {'context': 'B-cells'}", + "44, pyramidal {'context': 'I-cells'}", + "45, cells {'context': 'I-cells'}", + "59, CA3 {'context': 'B-cells'}", + "60, cell {'context': 'I-cells'}", + "61, axons {'context': 'I-cells'}", + "85, CA3 {'context': 'B-cells'}", + "86, pyramidal {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}", + "95, cultures {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "26, of ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "27, the ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "28, mature ['l1', 'l16', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "29, axons ['l2', 'l17', 'l32', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "30, of ['l3', 'l18', 'l33', 'l47', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "31, CA3 ['l4', 'l19', 'l34', 'l48', 'l60', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "32, pyramidal ['l5', 'l20', 'l35', 'l49', 'l61', 'l72', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "33, cells ['l6', 'l21', 'l36', 'l50', 'l62', 'l73', 'l83', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "35, hippocampal ['l7', 'l22', 'l37', 'l51', 'l63', 'l74', 'l84', 'l93', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "36, slice ['l8', 'l23', 'l38', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "37, cultures ['l9', 'l24', 'l39', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "43, CA3 ['l10', 'l25', 'l40', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "44, pyramidal ['l11', 'l26', 'l41', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l118', 'l123', 'l129', 'l130', 'l131', 'l132', 'l133']", + "45, cells ['l12', 'l27', 'l42', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l113', 'l119', 'l124', 'l129', 'l134', 'l135', 'l136']", + "59, CA3 ['l13', 'l28', 'l43', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l130', 'l134', 'l137', 'l138', 'l139', 'l140', 'l141']", + "60, cell ['l14', 'l29', 'l44', 'l58', 'l70', 'l81', 'l91', 'l100', 'l108', 'l115', 'l121', 'l126', 'l131', 'l135', 'l137', 'l142', 'l143', 'l144', 'l145']", + "61, axons ['l15', 'l30', 'l45', 'l59', 'l71', 'l82', 'l92', 'l101', 'l109', 'l116', 'l122', 'l127', 'l132', 'l136', 'l138', 'l142', 'l146', 'l147', 'l148']", + "85, CA3 ['l139', 'l143', 'l146', 'l149', 'l150']", + "86, pyramidal ['l140', 'l144', 'l147', 'l149', 'l151']", + "87, cells ['l31', 'l46', 'l128', 'l133', 'l141', 'l145', 'l148', 'l150', 'l151']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9288723", + "TEXT": "Xenotransplanted adrenocortical tissue of clonal origin was formed in immunodeficient (scid) mice by using techniques of cell transplantation. The experiments reported here used a single clone of bovine adrenocortical cells, but 5 of 20 other randomly selected clones also formed tissue. Most adrenalectomized animals bearing transplanted cells survived indefinitely, demonstrating that the cells restored the animals' capacity to survive in the absence of sodium supplementation. Formation of well-vascularized tissue at the site of transplantation was associated with stable levels of cortisol in the blood, replacing the mouse glucocorticoid (corticosterone). Ultrastructurally, the cultured cells before transplantation had characteristics of rapidly growing cells, but tissue formed in vivo showed features associated with active steroidogenesis. These experiments show that an endocrine tissue can be derived from a single, normal somatic cell.", + "TAG_DATA": [ + "43, animals {'context': 'B-organism'}", + "46, cells {'context': 'B-cells'}", + "52, cells {'context': 'B-cells'}", + "55, animals' {'context': 'B-organism'}", + "92, cells {'context': 'I-cells'}", + "100, cells, {'context': 'B-cells'}", + "104, in {'context': 'B-in vivo'}", + "105, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "43, animals ['l0', 'l1', 'l2']", + "46, cells ['l0', 'l3', 'l4']", + "52, cells ['l1', 'l3', 'l5']", + "55, animals' ['l2', 'l4', 'l5']", + "92, cells ['l6', 'l7']", + "100, cells, ['l6']", + "104, in ['l8']", + "105, vivo ['l7', 'l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9288722", + "TEXT": "Muscle biopsies from six patients with Duchenne muscular dystrophy (DMD) participating in a myoblast transplantation clinical trial were reexamined using a fluorescence in situ hybridization (FISH)-based method. Donor nuclei were detected in all biopsies analyzed, including nine where no donor myoblasts were previously thought to be present. In three patients, more than 10% of the original number of donor cells were calculated as present 6 months after implantation. Half of the detected donor nuclei were fused into host myofibers, and of these, nearly 50% produced dystrophin. These findings demonstrate that although donor myoblasts have persisted after injection, their microenvironment influences whether they fuse and express dystrophin. Our methodology could be used for developing new approaches to improve myoblast transfer efficacy and for the analysis of future gene- and/or cell-based therapies of numerous genetic disorders.", + "TAG_DATA": [ + "59, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9256276", + "TEXT": "The nef gene of simian immunodeficiency virus (SIV) is essential for high viral load and induction of AIDS in rhesus monkeys. A mutant form of the SIVmac239 Nef, which contains changes in a putative SH3-binding domain (amino acids 104 and 107 have been changed from PxxP to AxxA), does not associate with cellular serine/threonine kinases, but is fully active in CD4 downregulation and associates with the cellular tyrosine kinase Src. Infection of two rhesus macaques with SIVmac239 containing the mutant AxxA-Nef caused AIDS and rapid death in both animals. No reversions were observed in the majority of nef sequences analyzed from different time points during infection and from lymphatic tissues at the time of death. Our findings indicate that the putative SH3-ligand domain in SIVmac Nef and the association with cellular serine/threonine kinases are not important for efficient replication and pathogenicity of SIVmac in rhesus macaques.", + "TAG_DATA": [ + "73, rhesus {'context': 'B-organism'}", + "74, macaques {'context': 'I-organism'}", + "77, containing {'perturbing_action': 'I-other'}", + "78, the {'perturbing_action': 'I-other'}", + "79, mutant {'perturbing_action': 'I-other'}", + "80, AxxA-Nef {'perturbing_action': 'I-other'}", + "88, animals. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, rhesus ['l0', 'l1']", + "74, macaques ['l0', 'l2']", + "77, containing ['l3', 'l4', 'l5', 'l6']", + "78, the ['l3', 'l7', 'l8', 'l9']", + "79, mutant ['l4', 'l7', 'l10', 'l11']", + "80, AxxA-Nef ['l5', 'l8', 'l10', 'l12']", + "88, animals. ['l1', 'l2', 'l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "containing", + "the", + "mutant", + "AxxA-Nef" + ] + }, + "context": { + "val": "organism", + "words": [ + "animals." + ] + } + } + ] + }, + { + "PMID": "9212112", + "TEXT": "Cystic fibrosis (CF) is a genetic disease characterized by marked reduction in Cl- conductance across many epithelia. Two kinds of Cl- channels have been associated with CF. One channel, termed the cystic fibrosis transmembrane conductance regulator (CFTR), is directly coded by the CF gene. The other channel is an outwardly rectifying depolarization induced Cl- channel (ORDIC) that is distinguished from other outwardly rectifying chloride channels (ORCCs) because its activity is induced most reliably by patch excision and depolarization. An issue in current CF research is whether ORDIC channels are indirectly activated by CFTR to contribute a significant portion of apical membrane Cl- conductance in airway cells. We now show that ORDIC channels are readily activated in patches excised and depolarized from isolated cells, but are rarer or refractory to activation in patches from the apical membranes of confluent human airway epithelia. These findings have important implications for proposed therapies that would bypass the CFTR conductance by activating ORDIC channels.", + "TAG_DATA": [ + "122, cells, {'context': 'B-cells'}", + "138, human {'context': 'B-tissue/organ'}", + "139, airway {'context': 'I-tissue/organ'}", + "140, epithelia. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "138, human ['l0', 'l1']", + "139, airway ['l0', 'l2']", + "140, epithelia. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9212101", + "TEXT": "Mice were constructed carrying prion protein (PrP) transgenes with individual regions of putative secondary structure deleted. Transgenic mice with amino-terminal regions deleted remained healthy at >400 days of age, whereas those with either of carboxy-terminal alpha-helices deleted spontaneously developed fatal CNS illnesses similar to neuronal storage diseases. Deletion of either C-terminal helix resulted in PrP accumulation within cytoplasmic inclusions in enlarged neurons. Deletion of the penultimate C-terminal helix resulted in proliferation of rough endoplasmic reticulum. Mice with the C-terminal helix deleted were affected with nerve cell loss in the hippocampus and proliferation of smooth endoplasmic reticulum. Whether children with the human counterpart of this malady will be found remains to be determined.", + "TAG_DATA": [ + "17, mice {'context': 'B-organism'}", + "35, alpha-helices {'perturbing_action': 'I-gene loss-of-function'}", + "36, deleted {'perturbing_action': 'I-gene loss-of-function'}", + "47, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "48, of {'perturbing_action': 'I-gene loss-of-function'}", + "49, either {'perturbing_action': 'I-gene loss-of-function'}", + "50, C-terminal {'perturbing_action': 'I-gene loss-of-function'}", + "51, helix {'perturbing_action': 'I-gene loss-of-function'}", + "61, neurons. {'context': 'B-cells'}", + "62, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "63, of {'perturbing_action': 'I-gene loss-of-function'}", + "64, the {'perturbing_action': 'I-gene loss-of-function'}", + "65, penultimate {'perturbing_action': 'I-gene loss-of-function'}", + "66, C-terminal {'perturbing_action': 'I-gene loss-of-function'}", + "67, helix {'perturbing_action': 'I-gene loss-of-function'}", + "68, resulted {'effect': 'B-positive'}", + "69, in {'effect': 'I-positive'}", + "70, proliferation {'phenotype': 'B-proliferation'}", + "75, Mice {'context': 'B-organism'}", + "78, C-terminal {'perturbing_action': 'B-gene loss-of-function'}", + "79, helix {'perturbing_action': 'I-gene loss-of-function'}", + "80, deleted {'perturbing_action': 'I-gene loss-of-function'}", + "84, nerve {'context': 'B-cells'}", + "89, hippocampus {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "17, mice ['l0']", + "35, alpha-helices ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "36, deleted ['l1', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "47, Deletion ['l2', 'l20', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "48, of ['l3', 'l21', 'l36', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "49, either ['l4', 'l22', 'l37', 'l51', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "50, C-terminal ['l5', 'l23', 'l38', 'l52', 'l65', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "51, helix ['l6', 'l24', 'l39', 'l53', 'l66', 'l79', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "61, neurons. ['l0', 'l7', 'l25', 'l40', 'l54', 'l67', 'l80', 'l92']", + "62, Deletion ['l8', 'l26', 'l41', 'l55', 'l68', 'l81', 'l93', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "63, of ['l9', 'l27', 'l42', 'l56', 'l69', 'l82', 'l94', 'l103', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "64, the ['l10', 'l28', 'l43', 'l57', 'l70', 'l83', 'l95', 'l104', 'l114', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "65, penultimate ['l11', 'l29', 'l44', 'l58', 'l71', 'l84', 'l96', 'l105', 'l115', 'l124', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "66, C-terminal ['l12', 'l30', 'l45', 'l59', 'l72', 'l85', 'l97', 'l106', 'l116', 'l125', 'l133', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "67, helix ['l13', 'l31', 'l46', 'l60', 'l73', 'l86', 'l98', 'l107', 'l117', 'l126', 'l134', 'l141', 'l148', 'l149', 'l150', 'l151']", + "68, resulted ['l14', 'l32', 'l47', 'l61', 'l74', 'l87', 'l99', 'l108', 'l118', 'l127', 'l135', 'l142', 'l148', 'l152', 'l153', 'l154']", + "69, in ['l15', 'l33', 'l48', 'l62', 'l75', 'l88', 'l100', 'l109', 'l119', 'l128', 'l136', 'l143', 'l149', 'l152', 'l155', 'l156']", + "70, proliferation ['l16', 'l34', 'l49', 'l63', 'l76', 'l89', 'l101', 'l110', 'l120', 'l129', 'l137', 'l144', 'l150', 'l153', 'l155', 'l157']", + "75, Mice ['l158', 'l159', 'l160', 'l161', 'l162', 'l163']", + "78, C-terminal ['l158', 'l164', 'l165', 'l166', 'l167', 'l168']", + "79, helix ['l159', 'l164', 'l169', 'l170', 'l171', 'l172']", + "80, deleted ['l160', 'l165', 'l169', 'l173', 'l174', 'l175']", + "84, nerve ['l17', 'l77', 'l90', 'l111', 'l121', 'l130', 'l138', 'l145', 'l161', 'l166', 'l170', 'l173', 'l176', 'l177']", + "85, cell ['l18', 'l35', 'l50', 'l64', 'l78', 'l91', 'l102', 'l112', 'l122', 'l131', 'l139', 'l146', 'l151', 'l154', 'l156', 'l157', 'l162', 'l167', 'l171', 'l174', 'l176', 'l178']", + "89, hippocampus ['l19', 'l113', 'l123', 'l132', 'l140', 'l147', 'l163', 'l168', 'l172', 'l175', 'l177', 'l178']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha-helices", + "deleted", + "Deletion", + "of", + "either", + "C-terminal", + "helix", + "the", + "penultimate" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons.", + "nerve" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha-helices", + "deleted", + "Deletion", + "of", + "either", + "C-terminal", + "helix", + "the", + "penultimate" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha-helices", + "deleted", + "Deletion", + "of", + "either", + "C-terminal", + "helix", + "the", + "penultimate" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha-helices", + "Deletion", + "of", + "the", + "penultimate", + "C-terminal", + "helix", + "deleted" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "C-terminal", + "helix", + "deleted" + ] + } + } + ] + }, + { + "PMID": "9176499", + "TEXT": "Lung cancer causes more than 140,000 deaths annually in the United States alone, and the prognosis for non-small cell lung cancer (NSCLC) is particularly poor. Therapies using small molecules that preferentially kill lung tumor cells by inducing cellular suicide (apoptosis) would therefore be highly desirable. Retinoids have shown promise as cancer preventive and cancer therapeutic agents. Retinoid signals are mediated by two classes of nuclear receptors: the retinoic acid receptors (RAR alpha, beta, and gamma) and the retinoid X receptors (RXR alpha, beta and gamma). These receptors usually bind as heterodimers to specific DNA sequences and/or interact with other transcriptional regulators, such as AP-1 (ref. 10) to regulate gene transcription. Synthetic retinoids can be made that activate only specific portions of the complex retinoid response network and activate selective biological programs. To identify retinoids with novel biological activities, we used a high-throughput \"biological activity fingerprint\" screen on a large library of retinoids and retinoid-related molecules (RRMs). We identified new structures that are highly effective against lung cancer cells in vitro, inducing apoptosis. We show here for one of these compounds that it is very effective against a human NSCLC in vivo in an animal model. These new molecules show a distinct pattern of receptor signaling.", + "TAG_DATA": [ + "165, lung {'context': 'B-transformed cells'}", + "166, cancer {'context': 'I-transformed cells'}", + "167, cells {'context': 'I-transformed cells'}", + "168, in {'context': 'B-in vitro'}", + "169, vitro, {'context': 'I-in vitro'}", + "170, inducing {'effect': 'B-positive'}", + "171, apoptosis. {'phenotype': 'B-apoptosis'}", + "187, human {'context': 'B-neoplasm'}", + "188, NSCLC {'context': 'I-neoplasm'}", + "189, in {'context': 'B-in vivo'}", + "190, vivo {'context': 'I-in vivo'}", + "193, animal {'context': 'B-organism'}", + "194, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "165, lung ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "166, cancer ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "167, cells ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "168, in ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "169, vitro, ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "170, inducing ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "171, apoptosis. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "187, human ['l21', 'l22', 'l23', 'l24', 'l25']", + "188, NSCLC ['l21', 'l26', 'l27', 'l28', 'l29']", + "189, in ['l22', 'l26', 'l30', 'l31', 'l32']", + "190, vivo ['l23', 'l27', 'l30', 'l33', 'l34']", + "193, animal ['l24', 'l28', 'l31', 'l33', 'l35']", + "194, model. ['l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "lung", + "cancer", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "lung", + "cancer", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + }, + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "9176492", + "TEXT": "A combination AIDS vaccine approach consisting of priming with adenovirus-HIV-1MN gp160 recombinants followed by boosting with HIV-1SF2 gp120 was evaluated in chimpanzees. Long-lasting protection, requiring only three immunizations, was achieved against a low-dose challenge with the SF2 strain of HIV-1 and a subsequent high-dose SF2 challenge administered 1 year later without an intervening boost. Notably, neutralizing antibody responses against both clinical and laboratory isolates developed in three chimpanzees and persisted until the time of high-dose challenge. The possibility that cytotoxic T-lymphocytes contribute to low-dose protection of a chimpanzee lacking neutralizing antibodies is suggested. Our results validate the live vector priming/subunit booster approach and should stimulate interest in assessing this combination vaccine approach in humans.", + "TAG_DATA": [ + "21, chimpanzees. {'context': 'B-organism'}", + "67, chimpanzees {'context': 'B-organism'}", + "87, chimpanzee {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9142124", + "TEXT": "The atheroprotective effects of estrogen in women are well recognized, but the underlying mechanisms responsible are not well understood. Blood vessel cells express the classic estrogen receptor, ER alpha (ref. 2-6), and are directly affected by estrogen, which inhibits the development of atherosclerotic and injury-induced vascular lesions. We have generated mice in which the ER alpha gene is disrupted and have used a mouse model of carotid arterial injury to compare the effects of estrogen on wild-type and estrogen receptor-deficient mice. Increases in vascular medial area and smooth muscle cell proliferation were quantified following vascular injury in ovariectomized mice treated with vehicle or with physiologic levels of 17 beta-estradiol. Surprisingly, in both wild-type and estrogen receptor-deficient mice, 17 beta-estradiol markedly inhibited to the same degree all measures of vascular injury. These data demonstrate that estrogen inhibits vascular by a novel mechanism that is independent of the classic estrogen receptor, ER alpha.", + "TAG_DATA": [ + "50, mice {'context': 'B-organism'}", + "53, the {'perturbing_action': 'I-gene loss-of-function'}", + "54, ER {'perturbing_action': 'I-gene loss-of-function'}", + "55, alpha {'perturbing_action': 'I-gene loss-of-function'}", + "56, gene {'perturbing_action': 'I-gene loss-of-function'}", + "57, is {'perturbing_action': 'I-gene loss-of-function'}", + "58, disrupted {'perturbing_action': 'I-gene loss-of-function'}", + "63, mouse {'context': 'B-organism'}", + "64, model {'context': 'I-organism'}", + "78, estrogen {'perturbing_action': 'B-gene loss-of-function'}", + "79, receptor-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "80, mice. {'context': 'B-organism'}", + "87, smooth {'context': 'B-cells'}", + "88, muscle {'context': 'I-cells'}", + "89, cell {'context': 'I-cells'}", + "90, proliferation {'phenotype': 'B-proliferation'}", + "98, mice {'context': 'B-organism'}", + "114, estrogen {'perturbing_action': 'B-gene loss-of-function'}", + "115, receptor-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "116, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "53, the ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "54, ER ['l1', 'l16', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "55, alpha ['l2', 'l17', 'l31', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "56, gene ['l3', 'l18', 'l32', 'l45', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "57, is ['l4', 'l19', 'l33', 'l46', 'l58', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "58, disrupted ['l5', 'l20', 'l34', 'l47', 'l59', 'l70', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "63, mouse ['l6', 'l21', 'l35', 'l48', 'l60', 'l71', 'l81', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "64, model ['l7', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l97', 'l98', 'l99', 'l100', 'l101']", + "78, estrogen ['l8', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "79, receptor-deficient ['l9', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l102', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "80, mice. ['l10', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l92', 'l97', 'l103', 'l109', 'l115', 'l116', 'l117', 'l118']", + "87, smooth ['l11', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l93', 'l98', 'l104', 'l110', 'l115', 'l119', 'l120', 'l121', 'l122']", + "88, muscle ['l12', 'l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l94', 'l99', 'l105', 'l111', 'l116', 'l119', 'l123', 'l124', 'l125']", + "89, cell ['l13', 'l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l95', 'l100', 'l106', 'l112', 'l117', 'l120', 'l123', 'l126']", + "90, proliferation ['l14', 'l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l96', 'l101', 'l107', 'l113', 'l118', 'l121', 'l124', 'l126']", + "98, mice ['l15', 'l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l108', 'l114', 'l122', 'l125']", + "114, estrogen ['l127', 'l128']", + "115, receptor-deficient ['l127', 'l129']", + "116, mice, ['l128', 'l129']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "model", + "mice.", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "ER", + "alpha", + "gene", + "is", + "disrupted", + "estrogen", + "receptor-deficient" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "model", + "mice." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "ER", + "alpha", + "gene", + "is", + "disrupted", + "estrogen", + "receptor-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "smooth", + "muscle", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "ER", + "alpha", + "gene", + "is", + "disrupted", + "estrogen", + "receptor-deficient" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "smooth", + "muscle", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "9142123", + "TEXT": "Myocardial infarction results in the formation of granulation tissue in the injured ventricular wall. This tissue contains myofibroblasts in highly organized arrays; their contractile properties may help to prevent the infarct area from dilatation. The mechanisms that control myofibroblast alignment are unknown. We found that myofibroblasts express a homologue of Drosophila tissue polarity gene frizzled (fz2) when migrating into the granulation tissue. The expression is decreased after the cells have aligned. This suggests that fz2 is involved in the spatial control of cardiac wound repair after infarction, possibly through intra- and intercellular transmission of polarity signals as in developing Drosophila. Mutations in the fz2 gene may impair myofibroblast alignment in the infarct area, thereby resulting in ventricular dilatation and aneurism following infarction.", + "TAG_DATA": [ + "45, myofibroblasts {'context': 'B-cells'}", + "68, cells {'context': 'B-cells'}", + "100, Mutations {'perturbing_action': 'B-other'}", + "101, in {'perturbing_action': 'I-other'}", + "102, the {'perturbing_action': 'I-other'}", + "103, fz2 {'perturbing_action': 'I-other'}", + "104, gene {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "100, Mutations ['l0', 'l1', 'l2', 'l3']", + "101, in ['l0', 'l4', 'l5', 'l6']", + "102, the ['l1', 'l4', 'l7', 'l8']", + "103, fz2 ['l2', 'l5', 'l7', 'l9']", + "104, gene ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9142120", + "TEXT": "A characteristic feature of Creutzfeldt-Jakob disease (CJD) is the accumulation in the brain of the amyloid protease-resistant protein PrPres. PrPres derives from a host-encoded, protease-sensitive isoform, PrPsen. Mutations of this protein are linked to familial variants of the disease, and the presence of a methionine or valine residue at the polymorphic position 129 may be critical in sporadic CJD cases. We found that in the brain of patients heterozygous for the mutation in which isoleucine is substituted for valine at codon 210 (Val21Olle), the PrPres is formed by both the wild-type and mutant PrPsen. We also found that in a sporadic CJD patient, who was heterozygous (Met/Val) at position 129, PrPres is also formed by both allotypes. These data associate transmissible spongiform encephalopathies with other amyloidosis, although the nature of the transmissible agent remains unsettled.", + "TAG_DATA": [ + "65, brain {'context': 'B-tissue/organ'}", + "67, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "65, brain ['l0']", + "67, patients ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9142119", + "TEXT": "Solid tumors with areas of low oxygen tension (hypoxia) have a poor prognosis, as cells in this environment often survive radiation and chemotherapy. In this report we describe how this hypoxic environment can be used to activate heterologous gene expression driven by a hypoxia-responsive element (HRE), which interacts with the transcriptional complex hypoxia-inducible factor-1 (HIF-1). Our results demonstrate that the HIF-1/HRE system of gene regulation is active in hypoxic tumor cells and show the potential of exploiting tumor-specific conditions for the targeted expression of diagnostic or therapeutic genes in cancer therapy.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9095177", + "TEXT": "Motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy cause progressive paralysis, often leading to premature death. Neurotrophic factors have been suggested as therapeutic agents for motor neuron diseases, but their clinical use as injected recombinant protein was limited by toxicity and/or poor bioavailability. We demonstrate here that adenovirus-mediated gene transfer of neurotrophin-3 (NT-3) can produce substantial therapeutic effects in the mouse mutant pmn (progressive motor neuronopathy). After intramuscular injection of the NT-3 adenoviral vector, pmn mice showed a 50% increase in life span, reduced loss of motor axons and improved neuromuscular function as assessed by electromyography. These results were further improved by coinjecting an adenoviral vector coding for ciliary neurotrophic factor. Therefore, adenovirus-mediated gene transfer of neurotrophic factors offers new prospects for the treatment of motor neuron diseases.", + "TAG_DATA": [ + "65, mouse {'context': 'B-organism'}", + "80, mice {'context': 'B-organism'}", + "91, motor {'context': 'B-cells'}", + "92, axons {'context': 'I-cells'}", + "109, adenoviral {'perturbing_action': 'B-gene gain-of-function'}", + "110, vector {'perturbing_action': 'I-gene gain-of-function'}", + "111, coding {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "80, mice ['l0', 'l1']", + "91, motor ['l0', 'l2']", + "92, axons ['l1', 'l2']", + "109, adenoviral ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "110, vector ['l3', 'l9', 'l10', 'l11', 'l12', 'l13']", + "111, coding ['l4', 'l9', 'l14', 'l15', 'l16', 'l17']", + "112, for ['l5', 'l10', 'l14', 'l18', 'l19', 'l20']", + "113, ciliary ['l6', 'l11', 'l15', 'l18', 'l21', 'l22']", + "114, neurotrophic ['l7', 'l12', 'l16', 'l19', 'l21', 'l23']", + "115, factor. ['l8', 'l13', 'l17', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9055867", + "TEXT": "The movement disorder in Parkinson's disease results from the selective degeneration of a small group of dopaminergic neurons in the substantia nigra pars compacta region of the brain. A number of exploratory studies using human fetal tissue allografts have suggested that transplantation of dopaminergic neurons may become an effective treatment for patients with Parkinson's disease and the difficulty in obtaining human fetal tissue has generated interest in finding corresponding non-human donor cells. Here we report a post-mortem histological analysis of fetal pig neural cells that were placed unilaterally into the caudate-putamen brain region of a patient suffering from Parkinson's disease. Long-term (over seven months) graft survival was found and the presence of pig dopaminergic neurons and other pig neural and glial cells is documented. Pig neurons extended axons from the graft sites into the host brain. Furthermore, other graft derived cells were observed several millimeters from the implantation sites. Markers for human microglia and T-cells showed only low reactivity in direct proximity to the grafts. This is the first documentation of neural xenograft survival in the human brain and of appropriate growth of non-human dopaminergic neurons for a potential therapeutic response in Parkinson's disease.", + "TAG_DATA": [ + "80, fetal {'context': 'B-cells'}", + "81, pig {'context': 'I-cells'}", + "82, neural {'context': 'I-cells'}", + "83, cells {'context': 'I-cells'}", + "112, pig {'context': 'B-cells'}", + "113, dopaminergic {'context': 'I-cells'}", + "114, neurons {'context': 'I-cells'}", + "117, pig {'context': 'B-cells'}", + "118, neural {'context': 'I-cells'}", + "119, and {'context': 'I-cells'}", + "120, glial {'context': 'I-cells'}", + "121, cells {'context': 'I-cells'}", + "124, Pig {'context': 'B-cells'}", + "125, neurons {'context': 'I-cells'}", + "138, graft {'context': 'B-cells'}", + "139, derived {'context': 'I-cells'}", + "140, cells {'context': 'I-cells'}", + "151, human {'context': 'B-cells'}", + "152, microglia {'context': 'I-cells'}", + "154, T-cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "80, fetal ['l0', 'l1', 'l2', 'l3']", + "81, pig ['l0', 'l4', 'l5', 'l6']", + "82, neural ['l1', 'l4', 'l7', 'l8']", + "83, cells ['l2', 'l5', 'l7', 'l9']", + "91, brain ['l3', 'l6', 'l8', 'l9']", + "112, pig ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "113, dopaminergic ['l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "114, neurons ['l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "117, pig ['l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "118, neural ['l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "119, and ['l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "120, glial ['l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "121, cells ['l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "124, Pig ['l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54', 'l55', 'l56']", + "125, neurons ['l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54', 'l57', 'l58']", + "138, graft ['l59', 'l60', 'l61', 'l62', 'l63']", + "139, derived ['l55', 'l57', 'l59', 'l64', 'l65', 'l66', 'l67']", + "140, cells ['l56', 'l58', 'l60', 'l64', 'l68']", + "151, human ['l61', 'l65', 'l69', 'l70']", + "152, microglia ['l62', 'l66', 'l68', 'l69', 'l71']", + "154, T-cells ['l63', 'l67', 'l70', 'l71']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9055866", + "TEXT": "Apoptotic cell death in the retina was recently demonstrated in animal models of the hereditary human retinal dystrophy known as retinitis pigmentosa. Although recent evidence indicates that the proto-oncogene c-fos is a mediator of apoptosis, its precise role is unclear. In fact, under some conditions, c-fos may even protect against apoptotic cell death. In the retina, c-fos is physiologically expressed in a diurnal manner and is inducible by light. We previously observed a light-elicited, dose-dependent apoptotic response in rat photoreceptors. To determine whether c-fos is involved in the light-induced apoptotic pathway we have used control mice and mice lacking c-fos. We found that following dark adaptation and two hours of light exposure both groups of animals exhibited only a few apoptotic cells. However, at 12 and 24 additional hours after light exposure, apoptosis increased dramatically in controls but was virtually absent in those mice lacking c-fos. Therefore, c-fos is essential for light-induced apoptosis of photoreceptors. Notably, c-fos is continuously upregulated concomitant with apoptotic photoreceptor death in our system and in animal models of retinitis pigmentosa (Agarwal, N. et al., Invest. Ophthalmol. Vis.Sci. Suppl. 36, S638 and Rich, K.A. et al., Invest. Ophthalmol. Vis. Sci. Suppl. 35, 1833). Inhibition of c-fos expression might therefore represent a novel therapeutic strategy to retard the time course of retinal dystrophies and light-induced retinal degeneration.", + "TAG_DATA": [ + "78, rat {'context': 'B-cells'}", + "79, photoreceptors. {'context': 'I-cells'}", + "95, mice {'context': 'B-organism'}", + "97, mice {'context': 'B-organism'}", + "98, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "99, c-fos. {'perturbing_action': 'I-gene loss-of-function'}", + "115, animals {'context': 'B-organism'}", + "120, apoptotic {'phenotype': 'B-apoptosis'}", + "121, cells. {'context': 'B-cells', 'phenotype': 'I-apoptosis'}", + "132, apoptosis {'phenotype': 'B-apoptosis'}", + "133, increased {'effect': 'B-positive'}", + "143, mice {'context': 'B-organism'}", + "144, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "145, c-fos. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "78, rat ['l0', 'l1']", + "79, photoreceptors. ['l0', 'l2']", + "95, mice ['l1', 'l2', 'l3']", + "97, mice ['l3', 'l4', 'l5', 'l6']", + "98, lacking ['l4', 'l7', 'l8', 'l9', 'l10']", + "99, c-fos. ['l5', 'l7', 'l11', 'l12', 'l13']", + "115, animals ['l8', 'l11', 'l14', 'l15']", + "120, apoptotic ['l9', 'l12', 'l14', 'l16']", + "121, cells. ['l6', 'l10', 'l13', 'l15', 'l16']", + "132, apoptosis ['l17', 'l18']", + "133, increased ['l17']", + "143, mice ['l19', 'l20']", + "144, lacking ['l19', 'l21']", + "145, c-fos. ['l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "animals" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "c-fos." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "animals" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "cells.", + "apoptotic" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "cells.", + "apoptotic" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "c-fos." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cells.", + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "c-fos." + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + } + ] + }, + { + "PMID": "9055861", + "TEXT": "Cardiovascular disease, the major cause of death in post-menopausal women, can be reduced by replacement of ovarian steroid hormones. To compare medroxyprogesterone with progesterone as the progestin in hormone replacement therapy from the standpoint of coronary artery vasospasm, we treated ovariectomized rhesus monkeys with physiological levels of estradiol-17 beta in combination with medroxyprogesterone or progesterone for four weeks. Coronary vasospasm in response to pathophysiological stimulation without injury showed that progesterone plus estradiol protected but medroxyprogesterone plus estradiol failed to protect, allowing vasospasm. We conclude that medroxyprogesterone in contrast to progesterone increases the risk of coronary vasospasm.", + "TAG_DATA": [ + "41, rhesus {'context': 'B-organism'}", + "42, monkeys {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "41, rhesus ['l0']", + "42, monkeys ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9055859", + "TEXT": "Repression of cell cycle progression by tumor suppressors might provide a means for tumor therapy. Here we demonstrate that ectopic overexpression of the p16INK4/CDKN2 tumor suppressor from an adenovirus vector in various cell lines results in block of cell division and, subsequently, in a gradual reduction of the levels of the product of retinoblastoma susceptibility gene, pRb. Overexpression of p53 and p16INK4/CDKN2, but not p53 on its own, induces apoptotic death only in tumor cells. Simultaneous adenoviral transfer of p16 and p53 genes leads to inhibition of tumor growth in nude mice. These results suggest that combined delivery of two cooperating genes like p16 and p53 could be the basis for the development of a new strategy for cancer gene therapy.", + "TAG_DATA": [ + "19, ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "20, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "21, of {'perturbing_action': 'I-gene gain-of-function'}", + "22, the {'perturbing_action': 'I-gene gain-of-function'}", + "23, p16INK4/CDKN2 {'perturbing_action': 'I-gene gain-of-function'}", + "24, tumor {'perturbing_action': 'I-gene gain-of-function'}", + "25, suppressor {'perturbing_action': 'I-gene gain-of-function'}", + "26, from {'perturbing_action': 'I-gene gain-of-function'}", + "27, an {'perturbing_action': 'I-gene gain-of-function'}", + "28, adenovirus {'perturbing_action': 'I-gene gain-of-function'}", + "29, vector {'perturbing_action': 'I-gene gain-of-function'}", + "32, cell {'context': 'B-cells'}", + "33, lines {'context': 'I-cells'}", + "36, block {'effect': 'B-negative'}", + "38, cell {'phenotype': 'B-proliferation'}", + "39, division {'phenotype': 'I-proliferation'}", + "57, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "58, of {'perturbing_action': 'I-gene gain-of-function'}", + "59, p53 {'perturbing_action': 'I-gene gain-of-function'}", + "60, and {'perturbing_action': 'I-gene gain-of-function'}", + "61, p16INK4/CDKN2, {'perturbing_action': 'I-gene gain-of-function'}", + "68, induces {'effect': 'B-positive'}", + "69, apoptotic {'phenotype': 'B-apoptosis'}", + "70, death {'phenotype': 'I-apoptosis'}", + "73, tumor {'context': 'B-transformed cells'}", + "74, cells. {'context': 'I-transformed cells'}", + "75, Simultaneous {'perturbing_action': 'B-gene gain-of-function'}", + "76, adenoviral {'perturbing_action': 'I-gene gain-of-function'}", + "77, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "78, of {'perturbing_action': 'I-gene gain-of-function'}", + "79, p16 {'perturbing_action': 'I-gene gain-of-function'}", + "80, and {'perturbing_action': 'I-gene gain-of-function'}", + "81, p53 {'perturbing_action': 'I-gene gain-of-function'}", + "82, genes {'perturbing_action': 'I-gene gain-of-function'}", + "85, inhibition {'effect': 'B-negative'}", + "87, tumor {'phenotype': 'B-tumour growth'}", + "88, growth {'phenotype': 'I-tumour growth'}", + "90, nude {'context': 'B-organism'}", + "91, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "19, ectopic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "20, overexpression ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "21, of ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "22, the ['l2', 'l21', 'l39', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "23, p16INK4/CDKN2 ['l3', 'l22', 'l40', 'l57', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "24, tumor ['l4', 'l23', 'l41', 'l58', 'l74', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "25, suppressor ['l5', 'l24', 'l42', 'l59', 'l75', 'l90', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "26, from ['l6', 'l25', 'l43', 'l60', 'l76', 'l91', 'l105', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "27, an ['l7', 'l26', 'l44', 'l61', 'l77', 'l92', 'l106', 'l119', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "28, adenovirus ['l8', 'l27', 'l45', 'l62', 'l78', 'l93', 'l107', 'l120', 'l132', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "29, vector ['l9', 'l28', 'l46', 'l63', 'l79', 'l94', 'l108', 'l121', 'l133', 'l144', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164']", + "32, cell ['l10', 'l29', 'l47', 'l64', 'l80', 'l95', 'l109', 'l122', 'l134', 'l145', 'l155', 'l165']", + "33, lines ['l11', 'l30', 'l48', 'l65', 'l81', 'l96', 'l110', 'l123', 'l135', 'l146', 'l156', 'l165']", + "36, block ['l12', 'l31', 'l49', 'l66', 'l82', 'l97', 'l111', 'l124', 'l136', 'l147', 'l157', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "38, cell ['l13', 'l32', 'l50', 'l67', 'l83', 'l98', 'l112', 'l125', 'l137', 'l148', 'l158', 'l166', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "39, division ['l14', 'l33', 'l51', 'l68', 'l84', 'l99', 'l113', 'l126', 'l138', 'l149', 'l159', 'l167', 'l173', 'l179', 'l180', 'l181', 'l182', 'l183']", + "57, Overexpression ['l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "58, of ['l184', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202']", + "59, p53 ['l185', 'l194', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209']", + "60, and ['l186', 'l195', 'l203', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216']", + "61, p16INK4/CDKN2, ['l187', 'l196', 'l204', 'l210', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222']", + "68, induces ['l15', 'l34', 'l52', 'l69', 'l85', 'l100', 'l114', 'l127', 'l139', 'l150', 'l160', 'l168', 'l174', 'l179', 'l188', 'l197', 'l205', 'l211', 'l217', 'l223', 'l224', 'l225', 'l226']", + "69, apoptotic ['l16', 'l35', 'l53', 'l70', 'l86', 'l101', 'l115', 'l128', 'l140', 'l151', 'l161', 'l169', 'l175', 'l180', 'l189', 'l198', 'l206', 'l212', 'l218', 'l223', 'l227', 'l228', 'l229']", + "70, death ['l17', 'l36', 'l54', 'l71', 'l87', 'l102', 'l116', 'l129', 'l141', 'l152', 'l162', 'l170', 'l176', 'l181', 'l190', 'l199', 'l207', 'l213', 'l219', 'l224', 'l227', 'l230', 'l231']", + "73, tumor ['l18', 'l37', 'l55', 'l72', 'l88', 'l103', 'l117', 'l130', 'l142', 'l153', 'l163', 'l171', 'l177', 'l182', 'l191', 'l200', 'l208', 'l214', 'l220', 'l225', 'l228', 'l230', 'l232']", + "74, cells. ['l19', 'l38', 'l56', 'l73', 'l89', 'l104', 'l118', 'l131', 'l143', 'l154', 'l164', 'l172', 'l178', 'l183', 'l192', 'l201', 'l209', 'l215', 'l221', 'l226', 'l229', 'l231', 'l232']", + "75, Simultaneous ['l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244']", + "76, adenoviral ['l233', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255']", + "77, transfer ['l234', 'l245', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265']", + "78, of ['l235', 'l246', 'l256', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274']", + "79, p16 ['l236', 'l247', 'l257', 'l266', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282']", + "80, and ['l237', 'l248', 'l258', 'l267', 'l275', 'l283', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289']", + "81, p53 ['l238', 'l249', 'l259', 'l268', 'l276', 'l283', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295']", + "82, genes ['l239', 'l250', 'l260', 'l269', 'l277', 'l284', 'l290', 'l296', 'l297', 'l298', 'l299', 'l300']", + "85, inhibition ['l240', 'l251', 'l261', 'l270', 'l278', 'l285', 'l291', 'l296', 'l301', 'l302', 'l303', 'l304']", + "87, tumor ['l241', 'l252', 'l262', 'l271', 'l279', 'l286', 'l292', 'l297', 'l301', 'l305', 'l306', 'l307']", + "88, growth ['l193', 'l202', 'l216', 'l222', 'l242', 'l253', 'l263', 'l272', 'l280', 'l287', 'l293', 'l298', 'l302', 'l305', 'l308', 'l309']", + "90, nude ['l243', 'l254', 'l264', 'l273', 'l281', 'l288', 'l294', 'l299', 'l303', 'l306', 'l308', 'l310']", + "91, mice. ['l244', 'l255', 'l265', 'l274', 'l282', 'l289', 'l295', 'l300', 'l304', 'l307', 'l309', 'l310']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "the", + "p16INK4/CDKN2", + "tumor", + "suppressor", + "from", + "an", + "adenovirus", + "vector" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "the", + "p16INK4/CDKN2", + "tumor", + "suppressor", + "from", + "an", + "adenovirus", + "vector", + "Simultaneous", + "adenoviral", + "transfer", + "p16", + "and", + "p53", + "genes" + ] + }, + "effect": { + "val": "negative", + "words": [ + "block", + "inhibition" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "the", + "p16INK4/CDKN2", + "tumor", + "suppressor", + "from", + "an", + "adenovirus", + "vector" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "the", + "p16INK4/CDKN2", + "tumor", + "suppressor", + "from", + "an", + "adenovirus", + "vector", + "Overexpression", + "p53", + "and", + "p16INK4/CDKN2," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "the", + "p16INK4/CDKN2", + "tumor", + "suppressor", + "from", + "an", + "adenovirus", + "vector", + "Overexpression", + "p53", + "and", + "p16INK4/CDKN2," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "the", + "p16INK4/CDKN2", + "tumor", + "suppressor", + "from", + "an", + "adenovirus", + "vector", + "Overexpression", + "p53", + "and", + "p16INK4/CDKN2," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "block" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "block" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "block" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "and", + "p16INK4/CDKN2,", + "Simultaneous", + "adenoviral", + "transfer", + "p16", + "p53", + "genes" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth", + "tumor" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Simultaneous", + "adenoviral", + "transfer", + "of", + "p16", + "and", + "p53", + "genes" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice." + ] + } + } + ] + }, + { + "PMID": "9055856", + "TEXT": "Kaposi's sarcoma-associated herpesvirus (KSHV) is a newly discovered herpesvirus etiologically associated with Kaposi's sarcoma (KS) and two lymphoproliferative disorders. We describe a KSHV vbcl-2 gene with homology to the proto-oncogene bcl-2. It is expressed in KS lesions and in cell lines derived from primary effusion lymphomas. Using yeast and human cells we demonstrate the ability of KSHV vBcl-2 protein to suppress Bax toxicity. We show that KSHV vBcl-2 heterodimerizes with human Bcl-2 in a yeast two-hybrid system. These results suggest that KSHV vBcl-2 plays an anti-apoptotic role in virus infected cells.", + "TAG_DATA": [ + "47, yeast {'context': 'B-cells'}", + "49, human {'context': 'B-cells'}", + "50, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "47, yeast ['l0', 'l1']", + "49, human ['l0', 'l2']", + "50, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9018247", + "TEXT": "Leptin, the product of the ob gene, is a hormone, produced by adipose cells, that inhibits food intake and increases energy expenditure in rodents. In humans, plasma leptin concentrations correlate closely with the size of the adipose tissue depot; however, there is considerable variation in plasma leptin concentrations at any given degree of fatness. To investigate whether individuals prone to weight gain are hypoleptinemic, we measured fasting plasma leptin concentrations in two groups of weight-matched nondiabetic Pima Indians followed for approximately 3 years, 19 of whom subsequently gained weight and 17 of whom maintained their weight. After we adjusted for initial percent body fat, mean plasma leptin concentration was lower in those who gained weight than in those whose weight was stable. These data indicate that relatively low plasma leptin concentrations may play a role in the development of obesity in Pima Indians, a population prone to obesity.", + "TAG_DATA": [ + "75, nondiabetic {'context': 'B-organism'}", + "76, Pima {'context': 'I-organism'}", + "77, Indians {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "75, nondiabetic ['l0', 'l1']", + "76, Pima ['l0', 'l2']", + "77, Indians ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9018246", + "TEXT": "Between 1 and 2 million women in the United States have silicone breast implants. Complications include capsular contracture and calcification and possibly connective tissue diseases such as scleroderma and rheumatoid arthritis, a subject of some controversy. In order to accurately assess the role of silicone in any histopathologic change, it is necessary to confirm its presence and to identify other foreign materials in the capsular tissue. Although light microscopy is used to visualize regions of tissue containing foreign inclusions, their chemical identity can only be determined using analytical techniques such as infrared or Raman microscopy. However, these conventional microprobe techniques record spectra only at single points and require an a priori knowledge of the locations of the inclusion to be probed. To significantly extend the capabilities of both infrared spectroscopy and optical microscopy, we have developed a new infrared imaging system that completely integrates these two methods. In this manuscript we highlight the ability of the technique to screen rapidly and to determine accurately the presence, size and chemical composition of silicone gel inclusions in human breast tissue.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9018245", + "TEXT": "The cell-cycle inhibitor p27 is a potential tumor suppressor, but its gene has never been found inactivated in human tumors. Because cell-cycle regulation of p27 cellular abundance occurs at the post-transcriptional level, we analyzed p27 protein expression and degradation in human colorectal carcinomas. Proteasome-mediated degradation activity of p27 was compared with its protein levels in a subset of tumor samples. We found that carcinomas with low or absent p27 protein displayed enhanced proteolytic activity specific for p27, suggesting that low p27 expression can result from increased proteasome-mediated degradation rather than altered gene expression. Patients whose tumors expressed p27 had a median survival of 151 months, whereas patients who lacked p27 (10%) had a median survival of 69 months. By multivariate analysis, p27 was found to be an independent prognostic marker. Lack of p27 was associated with poor prognosis (2.9 risk ratio for death; P = 0.003). The absence of p27 protein expression is thus a powerful negative prognostic marker in colorectal carcinomas, particularly in stage II tumors, and thereby may help in the selection of patients who will benefit from adjuvant therapy. These data suggest that aggressive tumors may result from the selection of a clone or clones that lack p27 due to increased proteasome-mediated degradation.", + "TAG_DATA": [ + "63, carcinomas {'context': 'B-neoplasm'}", + "108, lacked {'perturbing_action': 'B-gene loss-of-function'}", + "109, p27 {'perturbing_action': 'I-gene loss-of-function'}", + "130, Lack {'perturbing_action': 'B-gene loss-of-function'}", + "131, of {'perturbing_action': 'I-gene loss-of-function'}", + "132, p27 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "108, lacked ['l0']", + "109, p27 ['l0']", + "130, Lack ['l1', 'l2']", + "131, of ['l1', 'l3']", + "132, p27 ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9018244", + "TEXT": "Breast cancer is the second leading cause of cancer death in North American women. There is considerable need for reliable prognostic markers to assist clinicians in making management decisions. Although a variety of factors have been tested, only tumor stage, grade, size, hormone receptor status, and S-phase fraction are used on a routine basis. The cell cycle is governed by a family of cyclin-dependent kinases (cdks), which are regulated by associated cyclins and by phosphorylation. p27Kip1, a cyclin-dependent kinase inhibitor, regulates progression from G1 into S phase by binding and inhibiting cyclin/cdks. p27Kip1 protein levels and/or activity are upregulated by growth inhibitory cytokines including transforming growth factor-beta (TGF-beta) and, thus, provide an important link between extracellular regulators and the cell cycle. Loss of p27Kip1, a negative cell-cycle regulator, may contribute to oncogenesis and tumor progression. However, p27Kip1 mutations in human tumors are extremely rare. We have demonstrated by immunohistochemistry that p27Kip1 protein levels are reduced in primary breast cancers and that this is associated with tumor progression in both in situ and invasive lesions. This was confirmed by western analysis, reflected in increased G1/S-phase cyclin-dependent kinase activities and shown to be regulated posttranscriptionally by in situ hybridization. Furthermore, on multivariate analysis, low p27Kip1 is a predictor of reduced disease-free survival. This simple and reliable immunohistochemical assay may become a routine part of breast cancer evaluation and may influence patient management.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9018239", + "TEXT": "Organ xenografts under certain circumstances survive in the presence of anti-graft antibodies and complement, a situation referred to as \"accommodation.\" We find that the endothelial cells (ECs) in hamster hearts that accommodate themselves in rats express genes, such as A20 and bcl-2, that in vitro protect ECs from apoptosis and prevent upregulation in those cells of proinflammatory genes such as cytokines, procoagulant and adhesion molecules. Hearts that are rejected do not express these genes. In addition, vessels of rejected hearts show florid transplant arteriosclerosis whereas those of accommodated hearts do not. Accommodated xenografts have an ongoing T helper cell type 2 (Th2) cytokine immune response, whereas the rejected grafts have a Th1 response. We propose a model for factors that contribute to the survival of xenografts and the avoidance of transplant arteriosclerosis.", + "TAG_DATA": [ + "24, endothelial {'context': 'B-cells'}", + "25, cells {'context': 'I-cells'}", + "26, (ECs) {'context': 'I-cells'}", + "28, hamster {'context': 'B-tissue/organ'}", + "29, hearts {'context': 'I-tissue/organ'}", + "34, rats {'context': 'B-organism'}", + "43, in {'context': 'B-in vitro'}", + "44, vitro {'context': 'I-in vitro'}", + "46, ECs {'context': 'B-cells'}", + "48, apoptosis {'phenotype': 'B-apoptosis'}", + "76, vessels {'context': 'B-tissue/organ'}", + "92, xenografts {'context': 'B-xenograft'}" + ], + "LINK_DATA": [ + "24, endothelial ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "25, cells ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "26, (ECs) ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "28, hamster ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "29, hearts ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "34, rats ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "43, in ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "44, vitro ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "46, ECs ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "48, apoptosis ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells", + "(ECs)", + "ECs" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "hamster", + "hearts" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rats" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "9018238", + "TEXT": "Tumor necrosis factor-alpha occupies a central role in rheumatoid arthritis (RA) pathogenesis. We now report that interleukin-15 (IL-15) can induce TNF-alpha production in RA through activation of synovial T cells. Peripheral blood (PB) T cells activated by IL-15 induced significant TNF-alpha production by macrophages via a cell-contact-dependent mechanism. Freshly isolated RA synovial T cells possessed similar capability, and in vitro, IL-15 was necessary to maintain this activity. IL-15 also induced direct TNF-alpha production by synovial T cells. In contrast, IL-2 induced significantly lower TNF-alpha production in either cell-contact-dependent or direct culture, and IL-8 and MIP-1 alpha were ineffective. Antibodies against CD69, LFA-1 or ICAM-1 significantly inhibited the ability of T cells to activate macrophages by cell contact.", + "TAG_DATA": [ + "30, Peripheral {'context': 'B-cells'}", + "31, blood {'context': 'I-cells'}", + "32, (PB) {'context': 'I-cells'}", + "33, T {'context': 'I-cells'}", + "34, cells {'context': 'I-cells'}", + "43, macrophages {'context': 'B-cells'}", + "50, RA {'context': 'B-cells'}", + "51, synovial {'context': 'I-cells'}", + "52, T {'context': 'I-cells'}", + "53, cells {'context': 'I-cells'}", + "58, in {'context': 'B-in vitro'}", + "59, vitro, {'context': 'I-in vitro'}", + "74, synovial {'context': 'B-cells'}", + "75, T {'context': 'I-cells'}", + "76, cells. {'context': 'I-cells'}", + "109, T {'context': 'B-cells'}", + "110, cells {'context': 'I-cells'}", + "113, macrophages {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "30, Peripheral ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "31, blood ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "32, (PB) ['l1', 'l12', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "33, T ['l2', 'l13', 'l21', 'l29', 'l30', 'l31', 'l32', 'l33']", + "34, cells ['l3', 'l14', 'l22', 'l29', 'l34', 'l35', 'l36']", + "43, macrophages ['l4', 'l15', 'l23', 'l30', 'l34']", + "50, RA ['l5', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "51, synovial ['l6', 'l37', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "52, T ['l7', 'l16', 'l24', 'l38', 'l45', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "53, cells ['l8', 'l17', 'l25', 'l31', 'l39', 'l46', 'l52', 'l58', 'l59', 'l60', 'l61', 'l62']", + "58, in ['l40', 'l47', 'l53', 'l58', 'l63', 'l64', 'l65', 'l66']", + "59, vitro, ['l41', 'l48', 'l54', 'l59', 'l63', 'l67', 'l68', 'l69']", + "74, synovial ['l9', 'l18', 'l26', 'l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l70', 'l71']", + "75, T ['l10', 'l19', 'l27', 'l32', 'l35', 'l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l72']", + "76, cells. ['l11', 'l20', 'l28', 'l33', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l69', 'l71', 'l72']", + "109, T ['l73', 'l74']", + "110, cells ['l73', 'l75']", + "113, macrophages ['l74', 'l75']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9018236", + "TEXT": "The partial pressure of oxygen (pO2) and pH play critical roles in tumor biology and therapy. We report here the first combined, high-resolution (< or = 10 microns) measurements of interstitial pH and pO2 profiles between adjacent vessels in a human tumor xenograft, using fluorescence ratio imaging and phosphorescence quenching microscopy. We found (1) heterogeneity in shapes of pH and pO2 profiles; (2) a discordant relation between local pH profiles and corresponding pO2 profiles, yet a strong correlation between mean pH and pO2 profiles; (3) no correlation between perivascular pH/pO2 and nearest vessel blood flow; and (4) well-perfused tumor vessels that were hypoxic and, consequently, large hypoxic areas in the surrounding interstitium. Such multiparameter measurements of the in vivo microenvironment provide unique insights into biological processes in tumors and their response to treatment.", + "TAG_DATA": [ + "40, human {'context': 'B-xenograft'}", + "41, tumor {'context': 'I-xenograft'}", + "42, xenograft, {'context': 'I-xenograft'}", + "98, tumor {'context': 'B-neoplasm'}", + "99, vessels {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "40, human ['l0', 'l1']", + "41, tumor ['l0', 'l2']", + "42, xenograft, ['l1', 'l2']", + "98, tumor ['l3']", + "99, vessels ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8986747", + "TEXT": "This study describes a novel method of inhibiting T-cell function by the use of peptides rationally designed from the T-cell antigen receptor (TCR) alpha-chain transmembrane sequence involved with TCR receptor assembly. The most effective peptide (core peptide, CP) modulating in vitro and in vivo T-cell function contained nine amino acids two of which, lysine and arginine, were hydrophilic and separated by four hydrophobic amino acids. CP without chemical modification or conjugation was able to enter non-T and T cells. Conjugation of CP at the carboxyl terminus with palmitic acid resulted in a greater inhibition of T-cell interleukin-2 (IL-2) production in vitro than peptide alone. When examined for effects in vivo, CP reduced clinical signs of inflammation in three T cell-mediated disease models including adjuvant-induced arthritis, experimental allergic neuritis, and cyclophosphamide-induced diabetes in NOD/Lt(F) mice. This peptide or its analogues has potential as a therapeutic agent in human inflammatory and autoimmune disorders.", + "TAG_DATA": [ + "39, in {'context': 'B-in vitro'}", + "40, vitro {'context': 'I-in vitro'}", + "42, in {'context': 'B-in vivo'}", + "43, vivo {'context': 'I-in vivo'}", + "44, T-cell {'context': 'B-cells'}", + "75, non-T {'context': 'B-cells'}", + "76, and {'context': 'I-cells'}", + "77, T {'context': 'I-cells'}", + "78, cells. {'context': 'I-cells'}", + "95, T-cell {'context': 'B-cells'}", + "99, in {'context': 'B-in vitro'}", + "100, vitro {'context': 'I-in vitro'}", + "108, in {'context': 'B-in vivo'}", + "109, vivo, {'context': 'I-in vivo'}", + "132, NOD/Lt(F) {'context': 'B-organism'}", + "133, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "39, in ['l0', 'l1', 'l2', 'l3']", + "40, vitro ['l0', 'l4', 'l5', 'l6']", + "42, in ['l1', 'l4', 'l7', 'l8', 'l9', 'l10', 'l11']", + "43, vivo ['l2', 'l5', 'l7', 'l12', 'l13', 'l14', 'l15']", + "44, T-cell ['l3', 'l6', 'l8', 'l12', 'l16', 'l17', 'l18']", + "75, non-T ['l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "76, and ['l9', 'l13', 'l16', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "77, T ['l10', 'l14', 'l17', 'l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "78, cells. ['l11', 'l15', 'l18', 'l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "95, T-cell ['l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "99, in ['l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "100, vitro ['l24', 'l29', 'l33', 'l36', 'l38', 'l39']", + "108, in ['l40', 'l41']", + "109, vivo, ['l40', 'l42', 'l43']", + "132, NOD/Lt(F) ['l42', 'l44']", + "133, mice. ['l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8986746", + "TEXT": "An estimated 300-500 million new infections and 1.5-2.7 million deaths attributed to malaria occur annually in the developing world, and every year tens of millions of travelers from countries where malaria is not transmitted visit countries with malaria. Because the parasites that cause malaria have developed resistance to many antimalarial drugs, new methods for prevention are required. Intraperitoneal injection into mice of one dose of 150 ng (approximately 7.5 micrograms per kg body weight) recombinant mouse interleukin-12 (rmIL-12) 2 days before challenge with Plasmodium yoelii sporozoites protects 100% of mice against malaria. We report that one subcutaneous injection of 10 micrograms/kg recombinant human IL-12 (rhIL-12) 2 days before challenge with P. cynomolgi sporozoites protected seven of seven rhesus monkeys. Protection was associated with marked increases in plasma levels of interferon-gamma (IFN-gamma), and relative increases of lymphoid cell messenger RNA coding for IFN-gamma and several other cytokines. We speculate that rIL-12 protects monkeys through IFN-gamma-dependent elimination of P. cynomolgi-infected hepatocytes. This first report of rIL-12-induced protection of primates against an infectious agent supports assessment of rhIL-12 for immunoprophylaxis of human malaria.", + "TAG_DATA": [ + "60, mice {'context': 'B-organism'}", + "89, mice {'context': 'B-organism'}", + "117, rhesus {'context': 'B-organism'}", + "118, monkeys. {'context': 'I-organism'}", + "151, monkeys {'context': 'B-organism'}", + "158, hepatocytes. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "60, mice ['l0']", + "89, mice ['l0']", + "117, rhesus ['l1']", + "118, monkeys. ['l1']", + "151, monkeys ['l2']", + "158, hepatocytes. ['l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8986743", + "TEXT": "The mechanism by which mutations in the presenilin (PS) genes cause the most aggressive form of early-onset Alzheimer's disease (AD) is unknown, but fibroblasts from mutation carriers secrete increased levels of the amyloidogenic A beta 42 peptide, the main component of AD plaques. We established transfected cell and transgenic mouse models that coexpress human PS and amyloid beta-protein precursor (APP) genes and analyzed quantitatively the effects of PS expression on APP processing. In both models, expression of wild-type PS genes did not alter APP levels, alpha- and beta-secretase activity and A beta production. In the transfected cells, PS1 and PS2 mutations caused a highly significant increase in A beta 42 secretion in all mutant clones. Likewise, mutant but not wildtype PS1 transgenic mice showed significant overproduction of A beta 42 in the brain, and this effect was detectable as early as 2-4 months of age. Different PS mutations had differential effects on A beta generation. The extent of A beta 42 increase did not correlate with presenilin expression levels. Our data demonstrate that the presenilin mutations cause a dominant gain of function and may induce AD by enhancing A beta 42 production, thus promoting cerebral beta-amyloidosis.", + "TAG_DATA": [ + "49, mouse {'context': 'I-organism'}", + "50, models {'context': 'I-organism'}", + "96, cells, {'context': 'B-cells'}", + "97, PS1 {'perturbing_action': 'B-other'}", + "98, and {'perturbing_action': 'I-other'}", + "99, PS2 {'perturbing_action': 'I-other'}", + "100, mutations {'perturbing_action': 'I-other'}", + "120, PS1 {'perturbing_action': 'I-gene gain-of-function'}", + "121, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "122, mice {'context': 'B-organism'}", + "132, brain, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "46, cell ['l0']", + "48, transgenic ['l1', 'l2', 'l3', 'l4', 'l5']", + "49, mouse ['l1', 'l6', 'l7', 'l8']", + "50, models ['l0', 'l2', 'l6']", + "96, cells, ['l3', 'l7', 'l9', 'l10', 'l11', 'l12']", + "97, PS1 ['l9', 'l13', 'l14', 'l15']", + "98, and ['l4', 'l10', 'l13', 'l16', 'l17']", + "99, PS2 ['l11', 'l14', 'l16', 'l18']", + "100, mutations ['l5', 'l8', 'l12', 'l15', 'l17', 'l18']", + "120, PS1 ['l19', 'l20', 'l21']", + "121, transgenic ['l19', 'l22', 'l23']", + "122, mice ['l20', 'l22', 'l24']", + "132, brain, ['l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutations" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells," + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "PS1", + "and", + "PS2", + "mutations" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PS1", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PS1", + "transgenic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain," + ] + } + } + ] + }, + { + "PMID": "8986741", + "TEXT": "There is a lack of effective means of promoting remyelination of the central nervous system (CNS) in humans with chronic demyelinating disease. We have investigated the ability of transplanted glia to myelinate areas of the CNS equivalent to focal demyelinated lesions in multiple sclerosis (MS). In these studies we show that transplantation of oligodendrocytes or their progenitors into the CNS of a neonatal or adult canine myelin mutant results in repair of large areas similar in size to many MS plaques. Progenitor or pre-progenitor cells of the oligodendrocyte lineage have the greatest capacity for myelination following grafting, although cells of neonatal origin may also be used. Such an approach may therefore have therapeutic value in the repair of focal lesions in human myelin disease.", + "TAG_DATA": [ + "53, oligodendrocytes {'context': 'B-cells'}", + "55, their {'context': 'I-cells'}", + "56, progenitors {'context': 'I-cells'}", + "59, CNS {'context': 'B-tissue/organ'}", + "62, neonatal {'context': 'B-organism'}", + "63, or {'context': 'I-cells'}", + "64, adult {'context': 'I-cells'}", + "65, canine {'context': 'I-cells'}", + "66, myelin {'context': 'I-cells'}", + "67, mutant {'context': 'I-cells'}", + "81, Progenitor {'context': 'B-cells'}", + "82, or {'context': 'I-cells'}", + "83, pre-progenitor {'context': 'I-cells'}", + "84, cells {'context': 'I-cells'}", + "85, of {'context': 'I-cells'}", + "86, the {'context': 'I-cells'}", + "87, oligodendrocyte {'context': 'I-cells'}", + "88, lineage {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "53, oligodendrocytes ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "55, their ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "56, progenitors ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "59, CNS ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "62, neonatal ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "63, or ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "64, adult ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "65, canine ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "66, myelin ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "67, mutant ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "81, Progenitor ['l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "82, or ['l45', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "83, pre-progenitor ['l46', 'l52', 'l58', 'l59', 'l60', 'l61', 'l62']", + "84, cells ['l47', 'l53', 'l58', 'l63', 'l64', 'l65', 'l66']", + "85, of ['l48', 'l54', 'l59', 'l63', 'l67', 'l68', 'l69']", + "86, the ['l49', 'l55', 'l60', 'l64', 'l67', 'l70', 'l71']", + "87, oligodendrocyte ['l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l72']", + "88, lineage ['l51', 'l57', 'l62', 'l66', 'l69', 'l71', 'l72']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8986739", + "TEXT": "Contact between various epithelial cell lines and HIV chronically infected mononuclear cell lines results in a massive and rapid budding of HIV virions toward the epithelium followed by their internalization into epithelial endosome-like structures. Here it is shown that as early as 30 minutes after apical contact, primary virus isolates generated from primary peripheral blood leukocytes from HIV-infected patients can cross an epithelial cell line barrier using transcytosis, the characteristic epithelial transcellular vesicular pathway. As the next step in the spread of infection, transcytosed HIV particles can productively infect mononuclear cells located at the basolateral side of the epithelial barrier. These observations suggest an alternative, rapid and efficient mechanism for transmission of HIV across an intact epithelial barrier.", + "TAG_DATA": [ + "10, mononuclear {'context': 'B-cells'}", + "11, cell {'context': 'I-cells'}", + "12, lines {'context': 'I-cells'}", + "62, epithelial {'context': 'B-cells'}", + "63, cell {'context': 'I-cells'}", + "64, line {'context': 'I-cells'}", + "89, mononuclear {'context': 'B-cells'}", + "90, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "5, lines ['l0', 'l1', 'l2', 'l3', 'l4']", + "10, mononuclear ['l5', 'l6', 'l7', 'l8', 'l9']", + "11, cell ['l0', 'l5', 'l10', 'l11', 'l12', 'l13']", + "12, lines ['l1', 'l6', 'l10', 'l14', 'l15', 'l16']", + "62, epithelial ['l2', 'l7', 'l11', 'l14', 'l17', 'l18']", + "63, cell ['l3', 'l8', 'l12', 'l15', 'l17', 'l19']", + "64, line ['l4', 'l9', 'l13', 'l16', 'l18', 'l19']", + "89, mononuclear ['l20']", + "90, cells ['l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8946837", + "TEXT": "Given the plethora of well-documented breast carcinoma-associated antigens in humans including MAGE-1, -2 and -3, mutated p53, p21ras, HER-2/neu and DF3/MUC-1, coupled with evidence that humoral and cytotoxic T-cell responses against these antigens exist, the central dilemma facing tumor immunologists is why the host immune response is so inefficient. One possibility is that tumor cells themselves are either inefficient or ineffective antigen-presenting cells (APCs). The failure of tumor cells to function as APCs may be due to their inability to process and present the antigen, the absence or insufficient numbers of adhesion and costimulatory molecules or, potentially, the secretion of inhibitory cytokines. Therefore, we sought to determine whether human breast cancer cell lines could function as APCs and, if not, to identify mechanism(s) responsible for this defect. Here, we show that human breast cancer cell lines fail to present alloantigen. This defect does not reside in their inherent capacity to present antigen but rather is due to apoptosis of activated T cells induced by exposure to the breast carcinoma-associated mucin antigen, DF3/MUC1. These results support the hypothesis that DF3/MUC1 may contribute to the paucity of clinically significant anticarcinoma-specific immune responses.", + "TAG_DATA": [ + "131, human {'context': 'B-transformed cells'}", + "132, breast {'context': 'I-transformed cells'}", + "133, cancer {'context': 'I-transformed cells'}", + "134, cell {'context': 'I-transformed cells'}", + "135, lines {'context': 'I-transformed cells'}", + "157, apoptosis {'phenotype': 'B-apoptosis'}", + "159, activated {'context': 'B-cells'}", + "160, T {'context': 'B-cells'}", + "161, cells {'context': 'I-cells'}", + "162, induced {'effect': 'B-positive'}" + ], + "LINK_DATA": [ + "131, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "132, breast ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "133, cancer ['l1', 'l7', 'l13', 'l14', 'l15', 'l16']", + "134, cell ['l2', 'l8', 'l13', 'l17', 'l18', 'l19']", + "135, lines ['l3', 'l9', 'l14', 'l17', 'l20', 'l21']", + "157, apoptosis ['l22', 'l23', 'l24', 'l25']", + "159, activated ['l4', 'l10', 'l22', 'l26', 'l27', 'l28']", + "160, T ['l5', 'l11', 'l15', 'l18', 'l20', 'l23', 'l26', 'l29', 'l30']", + "161, cells ['l6', 'l12', 'l16', 'l19', 'l21', 'l24', 'l27', 'l29', 'l31']", + "162, induced ['l25', 'l28', 'l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "activated", + "T", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "activated", + "T", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "8946831", + "TEXT": "The development of stem-cell gene therapy is hindered by the absence of repopulation assays for primitive human hematopoietic cells. Current methods of gene transfer rely on in vitro colony-forming cell (CFC) and long-term culture-initiating cell (LTC-IC) assays, as well as inference from other mammalian species. We have identified a novel human hematopoietic cell, the SCID-repopulating cell (SRC), a cell more primitive than most LTC-ICs and CFCs. The SRC, exclusively present in the CD4+CD8- fraction, is capable of multilineage repopulation of the bone marrow of nonobese diabetic mice with severe combined immunodeficiency disease (NOD/SCID mice). SRCs were rarely transduced with retroviruses, distinguishing them from most CFCs and LTC-ICs. This observation is consistent with the low level of gene marking seen in human gene therapy trials. An SRC assay may aid in the characterization of hematopoiesis, as well as the improvement of transduction methods.", + "TAG_DATA": [ + "84, nonobese {'context': 'B-organism'}", + "85, diabetic {'context': 'I-organism'}", + "86, mice {'context': 'I-organism'}", + "94, SRCs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "82, marrow ['l0', 'l1', 'l2']", + "84, nonobese ['l0', 'l3', 'l4']", + "85, diabetic ['l1', 'l3', 'l5']", + "86, mice ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8898758", + "TEXT": "Lamellar ichthyosis (LI) is a disfiguring skin disease characterized by abnormal epidermal differentiation and defective cutaneous barrier function. LI has been associated with loss of keratinocyte transglutaminase 1 (TGase1), an enzyme believed necessary for normal formation of the cornified epidermal barrier. Using LI as a prototype for therapeutic cutaneous gene delivery, we have used the human skin/immunodeficient mouse xenograft model to correct the molecular, histologic and functional abnormalities of LI patient skin in vivo. We have used TGase1-deficient primary keratinocytes from LI patients combined with high-efficiency transfer of functional TGase1 to regenerate engineered human LI epidermis on immunodeficient mice. Engineered LI epidermis displayed normal TGase1 expression in vivo, unlike unengineered LI epidermis where TGase1 was absent. Epidermal architecture was also normalized by TGase1 restoration, as was expression of the epidermal differentiation marker filaggrin. Engineered LI skin demonstrated restoration of cutaneous barrier function measures to levels seen in epidermis regenerated by keratinocytes from patients with normal skin, indicating functional correction in vivo of the proposed primary pathophysiologic defect in LI. These results confirm a major role for TGase1 in epidermal differentiation and demonstrate a potential future approach to therapeutic gene delivery in human skin.", + "TAG_DATA": [ + "55, human {'context': 'B-xenograft'}", + "56, skin/immunodeficient {'context': 'I-xenograft'}", + "57, mouse {'context': 'I-xenograft'}", + "58, xenograft {'context': 'I-xenograft'}", + "59, model {'context': 'I-xenograft'}", + "72, in {'context': 'B-in vivo'}", + "73, vivo. {'context': 'I-in vivo'}", + "77, TGase1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "78, primary {'context': 'B-cells'}", + "79, keratinocytes {'context': 'I-cells'}", + "93, human {'context': 'B-tissue/organ'}", + "94, LI {'context': 'I-tissue/organ'}", + "95, epidermis {'context': 'I-tissue/organ'}", + "97, immunodeficient {'context': 'B-organism'}", + "98, mice. {'context': 'I-organism'}", + "100, LI {'context': 'I-tissue/organ'}", + "101, epidermis {'context': 'I-tissue/organ'}", + "106, in {'context': 'B-in vivo'}", + "107, vivo, {'context': 'I-in vivo'}", + "110, LI {'context': 'B-tissue/organ'}", + "111, epidermis {'context': 'I-tissue/organ'}", + "134, LI {'context': 'I-tissue/organ'}", + "135, skin {'context': 'I-tissue/organ'}", + "150, keratinocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "55, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "56, skin/immunodeficient ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "57, mouse ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "58, xenograft ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "59, model ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "72, in ['l4', 'l12', 'l19', 'l25', 'l30', 'l35']", + "73, vivo. ['l5', 'l13', 'l20', 'l26', 'l31', 'l35']", + "77, TGase1-deficient ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "78, primary ['l7', 'l15', 'l22', 'l28', 'l33', 'l36', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "79, keratinocytes ['l8', 'l16', 'l23', 'l29', 'l34', 'l37', 'l43', 'l49', 'l50', 'l51', 'l52']", + "93, human ['l38', 'l44', 'l49', 'l53', 'l54', 'l55', 'l56', 'l57']", + "94, LI ['l39', 'l45', 'l50', 'l53', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "95, epidermis ['l40', 'l46', 'l51', 'l54', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "97, immunodeficient ['l41', 'l47', 'l55', 'l59', 'l64', 'l69', 'l70', 'l71', 'l72', 'l73']", + "98, mice. ['l42', 'l48', 'l52', 'l56', 'l60', 'l65', 'l69', 'l74']", + "100, LI ['l61', 'l66', 'l70', 'l75', 'l76', 'l77', 'l78', 'l79']", + "101, epidermis ['l57', 'l62', 'l67', 'l71', 'l74', 'l75', 'l80', 'l81', 'l82', 'l83']", + "106, in ['l72', 'l76', 'l80', 'l84', 'l85', 'l86']", + "107, vivo, ['l63', 'l68', 'l73', 'l77', 'l81', 'l84', 'l87', 'l88']", + "110, LI ['l78', 'l82', 'l85', 'l87', 'l89']", + "111, epidermis ['l79', 'l83', 'l86', 'l88', 'l89']", + "134, LI ['l90', 'l91']", + "135, skin ['l90', 'l92']", + "150, keratinocytes ['l91', 'l92']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "xenograft", + "words": [ + "human", + "skin/immunodeficient", + "mouse", + "xenograft", + "model" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TGase1-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TGase1-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "primary", + "keratinocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TGase1-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "human", + "LI", + "epidermis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TGase1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "immunodeficient", + "mice." + ] + } + } + ] + }, + { + "PMID": "8898748", + "TEXT": "Because no detailed information exists regarding the topographic representation of swallowing musculature on the human cerebral cortex in health or disease, we used transcranial magnetic stimulation to study the cortical topography of human oral, pharyngeal and esophageal musculature in 20 healthy individuals and the topography of pharyngeal musculature in two stroke patients, one with and one without dysphagia. Our results demonstrate that swallowing musculature is discretely and somatotopically represented on the motor and premotor cortex of both hemispheres but displays interhemispheric asymmetry, independent of handedness. Following stroke, dysphagia appeared to be associated with smaller pharyngeal representation on the intact hemisphere, which increases in size with recovery of swallowing.", + "TAG_DATA": [ + "51, patients, {'context': 'I-patient'}", + "99, hemisphere, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8837617", + "TEXT": "Missense mutations in the presenilin 1 (PS1) gene cause the most common form of dominant early-onset familial Alzheimer's disease (FAD) and are associated with increased levels of amyloid beta-peptides (A beta) ending at residue 42 (A beta 42) in plasma and skin fibroblast media of gene carriers. A beta 42 aggregates readily and appears to provide a nidus for the subsequent aggregation of A beta 40 (ref. 4), resulting in the formation of innumerable neuritic plaques. To obtain in vivo information about how PS1 mutations cause AD pathology at such early ages, we characterized the neuropathological phenotype of four PS1-FAD patients from a large Colombian kindred bearing the codon 280 Glu to Ala substitution (Glu280Ala) PS1 mutation. Using antibodies specific to the alternative carboxy-termini of A beta, we detected massive deposition of A beta 42, the earliest and predominant form of plaque A beta to occur in AD (ref. 6-8), in many brain regions. Computer-assisted quantification revealed a significant increase in A beta 42, but not A beta 40, burden in the brains from 4 PS1-FAD patients compared with those from 12 sporadic AD patients. Severe cerebellar pathology included numerous A beta 42-reactive plaques, many bearing dystrophic neurites and reactive glia. Our results in brain tissue are consistent with recent biochemical evidence of increased A beta 42 levels in PS1-FAD patients and strongly suggest that mutant PS1 proteins alter the proteolytic processing of the beta-amyloid precursor protein at the C-terminus of A beta to favor deposition of A beta 42.", + "TAG_DATA": [ + "172, brains {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8837615", + "TEXT": "The induction of tumor cell death by anticancer therapy results from a genetic program of autonomous cell death termed apoptosis. Because the p53 tumor suppressor gene is a critical component for induction of apoptosis in response to DNA damage, its inactivation in cancers may be responsible for their resistance to genotoxic anticancer agents. The cellular response to DNA damage involves a cell-cycle arrest at both the G1/S and G2/M transitions; these checkpoints maintain viability by preventing the replication or segregation of damaged DNA. The arrest at the G1 checkpoint is mediated by p53-dependent induction of p21WAF1/CIP1, whereas the G2 arrest involves inactivation of p34cdc2 kinase. Following DNA damage, p53-deficient cells fail to arrest at G1 and accumulate at the G2/M transition. We demonstrate that abrogation of G2 arrest by caffeine-mediated activation of p34cdc2 kinase results in the selective sensitization of p53-deficient primary and tumor cells to irradiation-induced apoptosis. These data suggest that pharmacologic activation of p34cdc2 kinase may be a useful therapeutic strategy for circumventing the resistance of p53-deficient cancers to genotoxic anticancer agents.", + "TAG_DATA": [ + "108, p53-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "109, cells {'context': 'B-cells'}", + "110, fail {'effect': 'B-negative'}", + "111, to {'effect': 'I-negative', 'phenotype': 'I-cell cycle arrest'}", + "112, arrest {'phenotype': 'I-cell cycle arrest'}", + "113, at {'phenotype': 'I-cell cycle arrest'}", + "114, G1 {'phenotype': 'I-cell cycle arrest'}", + "124, abrogation {'effect': 'B-negative'}", + "126, G2 {'phenotype': 'B-cell cycle arrest'}", + "127, arrest {'phenotype': 'I-cell cycle arrest'}", + "138, sensitization {'effect': 'B-positive'}", + "140, p53-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "141, primary {'context': 'B-transformed cells'}", + "142, and {'context': 'I-transformed cells'}", + "143, tumor {'context': 'I-transformed cells'}", + "144, cells {'context': 'I-transformed cells'}", + "146, irradiation-induced {'effect': 'B-positive'}", + "147, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "108, p53-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "109, cells ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "110, fail ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "111, to ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "112, arrest ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "113, at ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "114, G1 ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "124, abrogation ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "126, G2 ['l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "127, arrest ['l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "138, sensitization ['l23', 'l32', 'l40', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "140, p53-deficient ['l24', 'l33', 'l41', 'l48', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "141, primary ['l25', 'l34', 'l42', 'l49', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "142, and ['l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "143, tumor ['l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l70', 'l71', 'l72']", + "144, cells ['l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l70', 'l73', 'l74']", + "146, irradiation-induced ['l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l73', 'l75']", + "147, apoptosis. ['l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "fail", + "to", + "abrogation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "to", + "arrest", + "at", + "G1", + "G2" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "to", + "fail", + "abrogation" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "to", + "arrest", + "at", + "G1", + "G2" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "fail", + "to" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "to", + "arrest", + "at", + "G1" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "and", + "tumor", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogation" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G2", + "arrest" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitization", + "irradiation-induced" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G2", + "arrest" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "and", + "tumor", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitization", + "irradiation-induced" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitization", + "irradiation-induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "and", + "tumor", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitization", + "irradiation-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "and", + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "primary", + "and", + "tumor", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "8837613", + "TEXT": "Postmenopausal osteoporosis, the most common bone disease in the developed world, is associated with estrogen deficiency. This deficiency induces increased generation and activity of osteoclasts, which perforate bone trabeculae, thus reducing their strength and increasing fracture risk. Estrogen replacement prevents these effects, indicating that estrogen negatively regulates osteoclast formation and function, but how it does this is unclear. Because functional osteoclast life span and thus the amount of bone that osteoclasts resorb could also be enhanced following estrogen deficiency, and since sex steroids regulate apoptosis in other target tissues, we investigated whether estrogen may affect osteoclast function by promoting apoptosis. 17 beta-Estradiol promoted apoptosis of murine osteoclasts in vitro and in vivo by two- to threefold. Tamoxifen, which has estrogenic effects on bone resorption, and transforming growth factor-beta 1 (TGF-beta), whose production by osteoblasts is increased by estrogen, had similar effects in vitro. Anti-TGF-beta antibody inhibited TGF-beta-, estrogen- and tamoxifen-induced osteoclast apoptosis, indicating that TGF-beta might mediate this effect. These findings suggest that estrogen may prevent excessive bone loss before and after the menopause by limiting osteoclast life span through promotion of apoptosis. The development of analogues to promote this mechanism specifically could be a useful and novel therapeutic approach to prevent postmenopausal osteoporosis.", + "TAG_DATA": [ + "102, promoted {'effect': 'B-positive'}", + "103, apoptosis {'phenotype': 'B-apoptosis'}", + "105, murine {'context': 'B-cells'}", + "106, osteoclasts {'context': 'I-cells'}", + "107, in {'context': 'B-in vitro'}", + "108, vitro {'context': 'I-in vitro'}", + "110, in {'context': 'B-in vivo'}", + "111, vivo {'context': 'I-in vivo'}", + "141, in {'context': 'B-in vitro'}", + "142, vitro. {'context': 'I-in vitro'}", + "145, inhibited {'effect': 'B-negative'}", + "150, osteoclast {'context': 'B-cells'}", + "151, apoptosis, {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "102, promoted ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "103, apoptosis ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "105, murine ['l1', 'l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "106, osteoclasts ['l2', 'l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "107, in ['l3', 'l8', 'l13', 'l17', 'l21']", + "108, vitro ['l4', 'l9', 'l14', 'l18', 'l21']", + "110, in ['l10', 'l15', 'l19', 'l22']", + "111, vivo ['l5', 'l11', 'l16', 'l20', 'l22']", + "141, in ['l23']", + "142, vitro. ['l23']", + "145, inhibited ['l24', 'l25']", + "150, osteoclast ['l24', 'l26']", + "151, apoptosis, ['l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "cells", + "words": [ + "murine", + "osteoclasts" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis," + ] + }, + "context": { + "val": "cells", + "words": [ + "murine", + "osteoclasts", + "osteoclast" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + } + ] + }, + { + "PMID": "8837609", + "TEXT": "A T-cell receptor (TCR) peptide vaccine from the V beta 5.2 sequence expressed in multiple sclerosis (MS) plaques and on myelin basic protein (MBP)-specific T cells boosted peptide-reactive T cells in patients with progressive MS. Vaccine responders had a reduced MBP response and remained clinically stable without side effects during one year of therapy, whereas nonresponders had an increased MBP response and progressed clinically. Peptide-specific T helper 2 cells directly inhibited MBP-specific T helper 1 cells in vitro through the release of interleukin-10, implicating a bystander suppression mechanism that holds promise for treatment of MS and other autoimmune diseases.", + "TAG_DATA": [ + "65, T {'context': 'I-cells'}", + "66, helper {'context': 'I-cells'}", + "67, 2 {'context': 'I-cells'}", + "68, cells {'context': 'I-cells'}", + "72, T {'context': 'I-cells'}", + "73, helper {'context': 'I-cells'}", + "74, 1 {'context': 'I-cells'}", + "75, cells {'context': 'I-cells'}", + "76, in {'context': 'B-in vitro'}", + "77, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "65, T ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "66, helper ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "67, 2 ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "68, cells ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "72, T ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "73, helper ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "74, 1 ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "75, cells ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "76, in ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "77, vitro ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8837605", + "TEXT": "Simian immunodeficiency virus (SIV) can cross the intact vaginal epithelium to establish a systemic infection in macaques (mac). Using this SIVmac model, we found that subcutaneous progesterone implants, which could mimic hormonally based contraceptives, thinned the vaginal epithelium and enhanced SIV vaginal transmission 7.7-fold over that observed in macaques treated with placebo implants and exposed to SIV in the follicular phase of the menstrual cycle. Progesterone treatment also increased the number of SIV DNA-positive cells in the vaginal lamina propria as detected by in situ polymerase chain reaction analysis. Moreover, plasma viral RNA was elevated for the first three months in macaques with progesterone implants, and three of the progesterone-treated macaques developed relatively rapid disease courses. This study shows that SIV genital infection and disease course are enhanced by subcutaneous implants containing progesterone when compared with the rate of vaginal transmission in the follicular phase.", + "TAG_DATA": [ + "48, macaques {'context': 'B-organism'}", + "101, macaques {'context': 'B-organism'}", + "110, macaques {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8782464", + "TEXT": "Microsatellite DNA alterations are an integral part of neoplastic progression and are valuable as clonal markers for the detection of human cancers. Moreover, recent evidence suggests that senescent tumor cells may release DNA into the circulation, which is subsequently carried by and therefore enriched in the serum and plasma. We tested 21 patients with primary head and neck squamous cell carcinoma (HNSCC) by polymerase chain reaction (PCR)-based microsatellite analysis of DNA from lymphocytes and paired serum samples. Patients were scored for alterations as defined by the presence of new alleles (shifts) or loss of heterozygosity (LOH) in serum at each of 12 markers and then compared with primary tumor DNA. Six out of 21 patients (29%) were found to have one or more microsatellite alterations in serum precisely matching those in the primary tumors. All six patients had advanced disease (stage III or IV); five of these patients had nodal metastases, three later developed distant metastases, and four died of disease. Microsatellite analysis of serum represents a novel method for the detection of circulating tumor cell DNA. If these results are confirmed in larger studies, microsatellite markers may be useful in assessing tumor burden in cancer patients.", + "TAG_DATA": [ + "54, primary {'context': 'B-neoplasm'}", + "55, head {'context': 'I-neoplasm'}", + "56, and {'context': 'I-neoplasm'}", + "57, neck {'context': 'I-neoplasm'}", + "58, squamous {'context': 'I-neoplasm'}", + "59, cell {'context': 'I-neoplasm'}", + "60, carcinoma {'context': 'I-neoplasm'}", + "61, (HNSCC) {'context': 'I-neoplasm'}", + "149, nodal {'phenotype': 'B-metastasis'}", + "150, metastases, {'phenotype': 'I-metastasis'}", + "154, distant {'phenotype': 'B-metastasis'}", + "155, metastases, {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "54, primary ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "55, head ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "56, and ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "57, neck ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "58, squamous ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "59, cell ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "60, carcinoma ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "61, (HNSCC) ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "149, nodal ['l28', 'l29', 'l30']", + "150, metastases, ['l28', 'l31', 'l32']", + "154, distant ['l29', 'l31', 'l33']", + "155, metastases, ['l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8782458", + "TEXT": "Soluble HLA class I molecules (sHLAs) have been identified in the serum of patients with inflammatory diseases, allografts and autoimmune diseases and in serum of healthy individuals. The biological significance of these molecules, particularly after allogeneic organ transplantation, has been enigmatic. Here we show that primary alloreactive CD8+ T cells interact with sHLA and undergo apoptosis in the absence of a second signal. Ligation of CD28 rescued T cells from death, implying that sHLAs induce apoptosis through selective stimulation of the T-cell receptor. CD95-L was upregulated after cytotoxic T lymphocytes were incubated with sHLAs, and cell death was blocked by a neutralizing anti-CD95-L antibody, suggesting that sHLAs induce endogenous mutual killing of activated T cells. These results provide a molecular basis for the capacity of sHLAs to downregulate T-cell responses, which may be especially relevant to organ transplantation.", + "TAG_DATA": [ + "46, alloreactive {'context': 'I-cells'}", + "47, CD8+ {'context': 'I-cells'}", + "48, T {'context': 'I-cells'}", + "49, cells {'context': 'I-cells'}", + "54, undergo {'effect': 'B-positive'}", + "55, apoptosis {'phenotype': 'B-apoptosis'}", + "63, Ligation {'perturbing_action': 'B-pharmacological augmentation'}", + "64, of {'perturbing_action': 'I-pharmacological augmentation'}", + "65, CD28 {'perturbing_action': 'I-pharmacological augmentation'}", + "67, T {'context': 'B-cells'}", + "68, cells {'context': 'B-cells'}", + "74, induce {'effect': 'B-positive'}", + "75, apoptosis {'phenotype': 'B-apoptosis'}", + "95, cell {'phenotype': 'B-cell death'}", + "96, death {'phenotype': 'I-cell death'}", + "98, blocked {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "46, alloreactive ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "47, CD8+ ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "48, T ['l1', 'l11', 'l21', 'l22', 'l23', 'l24']", + "49, cells ['l2', 'l12', 'l21', 'l25', 'l26', 'l27']", + "54, undergo ['l3', 'l13', 'l22', 'l25', 'l28', 'l29']", + "55, apoptosis ['l4', 'l14', 'l23', 'l26', 'l28', 'l30', 'l31']", + "63, Ligation ['l5', 'l15', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "64, of ['l6', 'l16', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "65, CD28 ['l7', 'l17', 'l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "67, T ['l8', 'l18', 'l30', 'l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "68, cells ['l9', 'l19', 'l24', 'l27', 'l29', 'l31', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "74, induce ['l10', 'l20', 'l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "75, apoptosis ['l37', 'l42', 'l46', 'l49', 'l51', 'l52']", + "95, cell ['l53', 'l54']", + "96, death ['l53', 'l55']", + "98, blocked ['l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "alloreactive", + "CD8+", + "T", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "undergo", + "induce" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "alloreactive", + "CD8+", + "T", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "alloreactive", + "CD8+", + "T", + "cells" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Ligation", + "of", + "CD28" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "undergo", + "induce" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Ligation", + "of", + "CD28" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Ligation", + "of", + "CD28" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + } + ] + }, + { + "PMID": "8782442", + "TEXT": "PIP: The Joint UN Program on AIDS reports that India has more than 3 million adults infected with HIV, more HIV-infected adults than any other country in the world. By the year 2005, India will have more people infected with HIV than does Africa. Having sex with a Bombay housewife today is at least twice as risky as it was to have sex with a prostitute in the city's red light district in 1988. 2-3% of all women in the city are infected with HIV. There is ignorance, apathy, corruption, and lack of commitment at all levels with regard to HIV/AIDS. Accordingly, India's lackluster campaign against AIDS launched 10 years ago has lost momentum just as the epidemic is exploding and at a time when traditional beliefs about cultural barriers and the sexual behavior of Indian males are being called into question. Considerable homosexual behavior occurs in India. However, the most important factor contributing to the spread of HIV throughout India is the virus' spread from urban areas into small villages, often through migrant laborers. Ignorance, illiteracy, and poverty in villages will make AIDS prevention especially difficult. Indian government policy forbidding the distribution of condoms in prisons, needles to injectable-drug users, and free drugs to AIDS patients further contributes to the spread of HIV.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8705867", + "TEXT": "A new imaging technology is under advanced development that has several key advantages over conventional forms of microimaging performed with standard light microscopes, confocal light microscopes, and electron microscopes. The image created by this microscope possesses several unique features: It is intrinsically three-dimensional; it can be formed with very high contrast, a characteristic of the phase-sensitive nature of the recording; the information contained in the image is obtained in a single exposure of the specimen, a feature that eliminates the accumulation of damage to living systems that can occur with techniques utilizing multiple exposures; the method of image construction is fundamentally free from aberration (distortion), thereby obviating the need to employ complex procedures for correction; the exact focal plane of any optical section is digitally determined through computation and is not based on any mechanical adjustments; and the principles of operation, including the computational processes and modalities of image presentation, are uniform over the full range of spectral coverage spanning from the visible (approximately 500 nm) to the X-ray (approximately 0.3 nm) regions. The application of this new technology is expected to open new cost-effective avenues to the understanding, prevention and treatment of broad areas of human disease.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8705865", + "TEXT": "Profoundly deaf people, who gain no benefit from conventional hearing aids, can receive speech cues by direct electrical stimulation of the cochlear nerve. This is achieved by an electronic device, a cochlear implant, which is surgically inserted into the ear. Here we show physiological results from the isolated sciatic nerve of the toad Xenopus laevis, used to predict the response of the human cochlear nerve to vowels coded by a cochlear implant. These results suggest that standard analogue cochlear implants do not evoke the patterns of neural excitation that are normally associated with acoustic stimulation. Adding noise to the stimulus, however, enhanced distinguishing features of the vowel encoded by the fine time structure of neural discharges. On the basis of these results, and those concerning stochastic resonance, we advocate a cochlear implant coding strategy in which noise is deliberately added to cochlear implant signals.", + "TAG_DATA": [ + "48, sciatic {'context': 'B-tissue/organ'}", + "49, nerve {'context': 'I-tissue/organ'}", + "50, of {'context': 'I-cells'}", + "52, toad {'context': 'I-organism'}", + "53, Xenopus {'context': 'I-organism'}", + "54, laevis, {'context': 'I-organism'}", + "62, human {'context': 'B-cells'}", + "63, cochlear {'context': 'I-tissue/organ'}", + "64, nerve {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "48, sciatic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "49, nerve ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "50, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "51, the ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "52, toad ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "53, Xenopus ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "54, laevis, ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "62, human ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "63, cochlear ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "64, nerve ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8705863", + "TEXT": "Striking differences in Kaposi's sarcoma (KS) risk for AIDS patients who acquire HIV via homosexual activity and those whose HIV infections derive from blood product exposure suggest the presence of a sexually transmitted agent other than HIV in the development of KS. Using an immunofluorescence assay, we examined serum samples from 913 patients for the presence of antibody specific for infection by human herpesvirus 8 (HHV8), an agent whose genome is regularly found in KS tissue. The distribution of HHV8 seropositivity conforms to that expected for a sexually transmitted pathogen and tracks closely with the risk for KS development. Our data support the inference that this virus is the etiologic cofactor predicted by the epidemiology of KS.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8705861", + "TEXT": "Primary infection with Epstein-Barr virus often results in the clinical syndrome of acute infectious mononucleosis (glandular fever). This illness is characterized by a striking lymphocytosis, the nature of which has been controversial. We show that large monoclonal or oligoclonal populations of CD8+ T cells account for a significant proportion of the lymphocytosis and provide molecular evidence that these populations have been driven by antigen. The results suggest that the selective and massive expansion of a few dominant clones of CD8+ T cells is an important feature of the primary response to this virus.", + "TAG_DATA": [ + "41, CD8+ {'context': 'B-cells'}", + "42, T {'context': 'I-cells'}", + "43, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "41, CD8+ ['l0', 'l1']", + "42, T ['l0', 'l2']", + "43, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8705860", + "TEXT": "A variable region gene of the T-cell receptor, V beta 8.2, is rearranged, and its product is expressed on pathogenic T cells that induce experimental autoimmune encephalomyelitis (EAE) in H-2u mice after immunization with myelin basic protein (MBP). Vaccination of these mice with naked DNA encoding V beta 8.2 protected mice from EAE. Analysis of T cells reacting to the pathogenic portion of the MBP molecule indicated that in the vaccinated mice there was a reduction in the Th1 cytokines interleukin-2 (IL-2) and interferon-gama. In parallel, there was an elevation in the production of IL-4, a Th2 cytokine associated with suppression of disease. A novel feature of DNA immunization for autoimmune disease, reversal of the autoimmune response from Th1 to Th2, may make this approach attractive for treatment of Th1-mediated diseases like multiple sclerosis, juvenile diabetes and rheumatoid arthritis.", + "TAG_DATA": [ + "29, H-2u {'context': 'B-organism'}", + "30, mice {'context': 'I-organism'}", + "41, mice {'context': 'B-organism'}", + "50, mice {'context': 'B-organism'}", + "55, T {'context': 'B-cells'}", + "56, cells {'context': 'I-cells'}", + "71, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "29, H-2u ['l0']", + "30, mice ['l0']", + "41, mice ['l1', 'l2', 'l3', 'l4']", + "50, mice ['l1', 'l5', 'l6', 'l7']", + "55, T ['l2', 'l5', 'l8', 'l9']", + "56, cells ['l3', 'l6', 'l8', 'l10']", + "71, mice ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8705859", + "TEXT": "Tuberculosis is the most widespread and lethal infectious disease affecting humans. Immunization of mice with plasmid DNA constructs encoding one of the secreted components of Mycobacterium tuberculosis, antigen 85 (Ag85), induced substantial humoral and cell-mediated immune responses and conferred significant protection against challenge with live M. tuberculosis and M. bovis bacille Calmette-Guérin (BCG). These results indicate that immunization with DNA encoding a mycobacterial antigen provides an efficient and simple method for generating protective immunity and that this technique may be useful for defining the protective antigens of M. tuberculosis, leading to the development of a more effective vaccine.", + "TAG_DATA": [ + "13, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8705854", + "TEXT": "To determine whether the presenilin 1 (PS1), presenilin 2 (PS2) and amyloid beta-protein precursor (APP) mutations linked to familial Alzheimer's disease (FAD) increase the extracellular concentration of amyloid beta-protein (A beta) ending at A beta 42(43) in vivo, we performed a blinded comparison of plasma A beta levels in carriers of these mutations and controls. A beta 1-42(43) was elevated in plasma from subjects with FAD-linked PS1 (P < 0.0001), PS2N1411 (P = 0.009), APPK670N,M671L (P < 0.0001), and APPV7171 (one subject) mutations. A beta ending at A beta 42(43) was also significantly elevated in fibroblast media from subjects with PS1 (P < 0.0001) or PS2 (P = 0.03) mutations. These findings indicate that the FAD-linked mutations may all cause Alzhelmer's disease by increasing the extracellular concentration of A beta 42(43), thereby fostering cerebral deposition of this highly amyloidogenic peptide.", + "TAG_DATA": [ + "95, fibroblast {'context': 'B-cells'}", + "96, media {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "95, fibroblast ['l0']", + "96, media ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8673925", + "TEXT": "Brain injury, as occurs in stroke or head trauma, induces a dramatic increase in levels of tumor necrosis factor-alpha (TNF), but its role in brain injury response is unknown. We generated mice genetically deficient in TNF receptors (TNFR-KO) to determine the role of TNF in brain cell injury responses. Damage to neurons caused by focal cerebral ischemia and epileptic seizures was exacerbated in TNFR-KO mice, indicating that TNF serves a neuroprotective function. Oxidative stress was increased and levels of an antioxidant enzyme reduced in brain cells of TNFR-KO mice, indicating that TNF protects neurons by stimulating antioxidant pathways. Injury-induced microglial activation was suppressed in TNFR-KO mice, demonstrating a key role for TNF in injury-induced immune response. Drugs that target TNF signaling pathways may prove beneficial in treating stroke and traumatic brain injury.", + "TAG_DATA": [ + "31, mice {'context': 'B-organism'}", + "33, deficient {'perturbing_action': 'I-gene loss-of-function'}", + "34, in {'perturbing_action': 'I-gene loss-of-function'}", + "35, TNF {'perturbing_action': 'I-gene loss-of-function'}", + "36, receptors {'perturbing_action': 'I-gene loss-of-function'}", + "37, (TNFR-KO) {'perturbing_action': 'I-gene loss-of-function'}", + "51, neurons {'context': 'B-cells'}", + "63, TNFR-KO {'perturbing_action': 'B-gene loss-of-function'}", + "64, mice, {'context': 'B-organism'}", + "84, brain {'context': 'B-cells'}", + "85, cells {'context': 'I-cells'}", + "87, TNFR-KO {'perturbing_action': 'B-gene loss-of-function'}", + "88, mice, {'context': 'B-organism'}", + "93, neurons {'context': 'B-cells'}", + "104, TNFR-KO {'perturbing_action': 'B-gene loss-of-function'}", + "105, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "31, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "32, genetically ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "33, deficient ['l1', 'l7', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "34, in ['l2', 'l8', 'l14', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "35, TNF ['l3', 'l9', 'l15', 'l22', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "36, receptors ['l4', 'l10', 'l16', 'l23', 'l29', 'l35', 'l36', 'l37', 'l38']", + "37, (TNFR-KO) ['l5', 'l11', 'l17', 'l24', 'l30', 'l35', 'l39']", + "51, neurons ['l6', 'l12', 'l18', 'l25', 'l31', 'l36', 'l39', 'l40']", + "63, TNFR-KO ['l19', 'l26', 'l32', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "64, mice, ['l13', 'l20', 'l27', 'l33', 'l37', 'l40', 'l41', 'l47', 'l48', 'l49', 'l50', 'l51']", + "84, brain ['l42', 'l47', 'l52', 'l53', 'l54', 'l55']", + "85, cells ['l21', 'l28', 'l34', 'l38', 'l43', 'l48', 'l52', 'l56', 'l57', 'l58']", + "87, TNFR-KO ['l44', 'l49', 'l53', 'l56', 'l59', 'l60']", + "88, mice, ['l45', 'l50', 'l54', 'l57', 'l59', 'l61']", + "93, neurons ['l46', 'l51', 'l55', 'l58', 'l60', 'l61']", + "104, TNFR-KO ['l62']", + "105, mice, ['l62']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "TNF", + "receptors", + "(TNFR-KO)", + "TNFR-KO" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "TNF", + "receptors", + "(TNFR-KO)", + "TNFR-KO" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons", + "cells", + "brain" + ] + } + } + ] + }, + { + "PMID": "8673924", + "TEXT": "Microtubule-associated protein tau becomes abnormally hyperphosphorylated in Alzheimer's disease (AD) and accumulates as tangles of paired helical filaments in neurons undergoing degeneration. We now show that in solution normal tau associates with the AD hyperphosphorylated tau (AD P-tau) in a nonsaturable fashion, forming large tangles of filaments 3.3 +/- 0.7 nm in diameter. These tangles, which are not detected in identically treated normal tau or AD P-tau alone, are made up of filaments several microns in length and are labeled with tau antibodies. Dephosphorylation with alkaline phosphatase abolishes the ability of AD P-tau to aggregate with normal tau and prevents tangle formation. AD P-tau disassembles microtubules assembled from normal tau and tubulin. These data provide insight into how the hyperphosphorylation of tau might lead to the formation of the neurofibrillary tangles and the degeneration of the affected neurons in AD.", + "TAG_DATA": [ + "99, prevents {'effect': 'B-negative'}", + "101, formation. {'phenotype': 'I-tumourigenesis'}" + ], + "LINK_DATA": [ + "99, prevents ['l0', 'l1']", + "100, tangle ['l0', 'l2']", + "101, formation. ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation." + ] + } + } + ] + }, + { + "PMID": "8673920", + "TEXT": "Naturally occurring mutations in HIV-1-infected patients have important implications for therapy and the outcome of clinical studies. However, little is known about the prevalence of mutations that confer resistance to HIV-1 protease inhibitors in isolates derived from patients naive for such inhibitors. In the first clinical application of high-density oligonucleotide array sequencing, the sequences of 167 viral isolates from 102 patients have been determined. The DNA sequence of USA HIV-1 clade B proteases was found to be extremely variable and 47.5% of the 99 amino acid positions varied. This level of amino acid diversity is greater than that previously known for all worldwide HIV-1 clades combined (40%). Many of the amino acid changes that are known to contribute to drug resistance occurred as natural polymorphisms in isolates from patients who had never received protease inhibitors.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8616721", + "TEXT": "Hematopoietic development is a complex process that involves a large number of growth factors and cytokines. Many cytokines are known to act on more mature, lineage-restricted cells of the hematopoietic system. However, no specific factors have yet been identified that induce the expansion of the most primitive hematopoietic cells without also inducing differentiation. To search for such factors, we isolated novel cell lines from the yolk sac in order to identify genes important in early hematopoietic and endothelial development. This approach led to the discovery of B219, a sequence that is expressed in at least four isoforms in very primitive hematopoietic cell populations and which may represent a novel hemopoietin receptor. The recently published receptor for the obesity (ob) gene product (leptin) is an isoform of B219 with a nearly identical ligand binding domain. B219/obr is expressed in the yolk sac, early fetal liver, enriched hematopoietic stem cells and in a variety of lymphohematopoietic cell lines. B219/obr is also expressed at high levels in adult reproductive organs. B219/obr maps to human chromosome 1p32, a region syntenic with the recently reported location of obr on murine chromosome 4 (ref. 5).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8616715", + "TEXT": "In most mammals, labor is heralded by progesterone withdrawal, which is believed to be related to the activation of multiple pathways leading to parturition. In humans, despite no decrease in placental progesterone production, activation of similar pathways preceding labor suggests the presence of an endogenous antiprogestin, which we reasoned might be cortisol, whose secretion from the fetal adrenal rises markedly at the end of human gestation. We report that in primary cultures of human placenta, cortisol is able to compete with the action of progesterone in the regulation of the corticotropin-releasing hormone (CRH) gene. CRH is a peptide highly expressed in human placenta at the end of gestation, which has been suggested to be involved in regulating the timing of parturition. These findings provide a model for functional progesterone withdrawal at the end of human pregnancy, which may be involved in the initiation of labor.", + "TAG_DATA": [ + "70, primary {'context': 'B-cells'}", + "71, cultures {'context': 'I-cells'}", + "72, of {'context': 'I-cells'}", + "73, human {'context': 'I-tissue/organ'}", + "74, placenta, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "70, primary ['l0', 'l1', 'l2', 'l3']", + "71, cultures ['l0', 'l4', 'l5', 'l6']", + "72, of ['l1', 'l4', 'l7', 'l8']", + "73, human ['l2', 'l5', 'l7', 'l9']", + "74, placenta, ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8616714", + "TEXT": "Adoptive transfer of antigen-specific cytotoxic T lymphocytes (CTLs) offers safe and effective therapy for certain viral infections and could prove useful in the eradication of tumor cells. Whether or not the infused T cells persist for extended periods, retaining their ability to expand in response to antigenic stimulation, is not known. We now report long-term detection of gene-marked Epstein-Barr virus (EBV)-specific CTLs in immunocompromised patients at risk for the development of EBV lymphoproliferative disease. Infusions of CTLs not only restored cellular immune responses against EBV, but also established populations of CTL precursors that could respond to in vivo or ex vivo challenge with the virus for as long as 18 months. Our findings support wider use of antigen-specific CTLs in adoptive immunotherapy.", + "TAG_DATA": [ + "63, immunocompromised {'context': 'B-patient'}", + "64, patients {'context': 'I-patient'}", + "90, CTL {'context': 'B-cells'}", + "91, precursors {'context': 'I-cells'}", + "96, in {'context': 'B-in vivo'}", + "97, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "63, immunocompromised ['l0']", + "64, patients ['l0']", + "90, CTL ['l1', 'l2', 'l3']", + "91, precursors ['l1', 'l4', 'l5']", + "96, in ['l2', 'l4', 'l6']", + "97, vivo ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8616713", + "TEXT": "The use of replication-defective adenoviruses (RDAd) for human gene therapy has been limited by host immune responses that result in transient recombinant gene expression in vivo. It remained unclear whether these immune responses were directed predominantly against viral proteins or, alternatively, against foreign transgene-encoded proteins. In this report, we have compared the stability of recombinant gene expression in adult immunocompetent mice following intramuscular (i.m.) injection with identical RDAd encoding self (murine) or foreign (human) erythropoietin. Our results demonstrate that immune responses direct against foreign transgene-encoded proteins are the major determinants of the stability of gene expression following i.m. injection of RDAd. Moreover, we demonstrate long-term recombinant gene expression in immunocompetent animals following a single i.m. injection of RDAd encoding a self protein. These findings are important for the design of future preclinical and clinical gene therapy trials.", + "TAG_DATA": [ + "58, adult {'context': 'B-organism'}", + "59, immunocompetent {'context': 'I-organism'}", + "60, mice {'context': 'I-organism'}", + "109, immunocompetent {'context': 'B-organism'}", + "110, animals {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "58, adult ['l0', 'l1']", + "59, immunocompetent ['l0', 'l2']", + "60, mice ['l1', 'l2']", + "109, immunocompetent ['l3']", + "110, animals ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8597961", + "TEXT": "An acidic luminal pH (ref. 1-3) is involved in sperm maturation, and in maintaining sperm in an immotile state in the epididymis and vas deferens (2,4-6). Neutralization by prostatic fluid is one of a complex series of events that triggers sperm motility (2,7,8). Failure of the acidification mechanism might, therefore, result in poor sperm maturation, premature motility and infertility. We have shown that a vacuolar (H+)-ATPase is expressed at high levels on the luminal plasma membrane of specialized cells in the epididymis (9), which closely resemble acid-secreting kidney intercalated cells (10,11). We now show that similar cells are also present in the vas deferens, and that a bafilomycin-sensitive proton flux can be detected using a noninvasive proton-selective vibrating probe. Up to 80% of the net proton secretion in the vas deferens is inhibited by bafilomycin, consistent with a major role of a vacuolar-type (H+)-ATPase in this process. This acidification mechanism is a potential target for novel strategies aimed at modulating the acidification capacity of parts of the male reproductive tract and, therefore, in regulating male fertility.", + "TAG_DATA": [ + "129, vas {'context': 'B-tissue/organ'}", + "130, deferens {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "129, vas ['l0']", + "130, deferens ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8597949", + "TEXT": "Major histocompatibility complex (MHC) genes (HLA in humans) regulate the immune response to foreign antigens. Molecular and serologic techniques were used to identify products of HLA class I, class II and transporter (TAP) genes (also part of the MHC) in homosexual seroconverters to human immunodeficiency virus type 1 (HIV-1). Comprehensive statistical analysis produced an HLA profile that predicted time from HIV-1 infection to the onset of AIDS. The profile was developed in a cohort of 139 men and evaluated in a second unrelated cohort of 102 men. In the evaluation cohort, the profile discriminated a sixfold difference between groups with the shortest and longest times to AIDS (P = 0.001). These findings support current theory about control of antigen processing by HLA genes and have implications for immunopathogenesis of HIV-1 and other infections.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8612237", + "TEXT": "At least five adult-onset neurodegenerative diseases, including Huntingtin disease (HD), and dentatorubral-pallidoluysian atrophy (DRPLA) are produced by genes containing a variably increased CAG repeat within the coding region. The size range of the repeats is similar in all diseases; unaffected individuals have fewer than 30 CAG repeats, whereas affected patients usually have more than 40 repeats. The size of the inherited CAG repeat correlates with the severity and age of disease onset. The CAG triplet repeat produces a polyglutamine domain in the expressed proteins. All of these diseases are inherited in a dominant fashion, and a pathologic gain of function in gene carriers has been proposed. We sought to identify proteins in the brain that selectively interact with polyglutamine-domain proteins, hypothesizing that the polyglutamine domain may determine protein-protein interactions.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8612232", + "TEXT": "Although conventional proton magnetic resonance imaging has increased our ability to detect brain tumors, it has not enhanced to nearly the same degree our ability to diagnose tumor type. Proton magnetic resonance spectroscopy is a safe, noninvasive means of performing biochemical analysis in vivo. Using this technique, we characterized and classified tissue from normal brains, as well as tissue from the five most common types of adult supratentorial brain tumors. These six tissue types differed in their pattern across the six metabolites measured. 'Leaving-one-out' linear discriminant analyses based on these resonance profiles correctly classified 104 of 105 spectra, and, whereas conventional preoperative clinical diagnosis misclassified 20 of 91 tumors, the linear discriminant analysis approach missed only 1. Thus, we have found that a pattern-recognition analysis of the biochemical information obtained from proton magnetic resonance spectroscopy can enable accurate, noninvasive diagnosis of the most prevalent types of supratentorial brain tumors.", + "TAG_DATA": [ + "108, tumors, {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8612229", + "TEXT": "Most patients with rheumatoid arthritis express particular HLA-DR alleles. The DRbeta1 chains of these alleles share a highly homologous amino acid motif, in their third hypervariable (HV3) region, and this motif seems to help the development of rheumatoid arthritis via unknown mechanisms. In an attempt to identify a ligand of this motif, we screened bacterial proteins. HV3 peptides from HLA-DRB1 alleles containing a QKRAA or RRRAA motif bound the 70-kD heat shock protein (HSP) from Escherichia coli, dnaK. In lymphoblastoid cells homozygous for these same HLA-DRB1 alleles the constitutive 70-kD HSP, HSP73, that targets selected proteins to lysosomes coprecipitated with HLA-DR. Thus the QKRAA and RRRAA amino acid motifs of HLA-DR mediate binding of HLA-DR to HSP73. This property may influence the intracellular route, processing or peptide associations of the HLA-DRbeta1 chain in these two rheumatoid arthritis-associated alleles.", + "TAG_DATA": [ + "79, lymphoblastoid {'context': 'B-cells'}", + "80, cells {'context': 'I-cells'}", + "81, homozygous {'perturbing_action': 'B-other'}", + "82, for {'perturbing_action': 'I-other'}", + "84, same {'perturbing_action': 'I-other'}", + "85, HLA-DRB1 {'perturbing_action': 'I-other'}", + "86, alleles {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "79, lymphoblastoid ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "80, cells ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "81, homozygous ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "82, for ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "84, same ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "85, HLA-DRB1 ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "86, alleles ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "lymphoblastoid", + "cells" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "homozygous", + "for", + "same", + "HLA-DRB1", + "alleles" + ] + } + } + ] + }, + { + "PMID": "8612228", + "TEXT": "Ideal gene therapy vectors would be delivered intravenously to transfect only specific cells. Existing vectors only transfect cells in vivo in a manner determined by blood flow and the site of introduction. As a general and systematic approach for generating cell-targeting ligands for gene therapy vectors, we have used peptide-presenting phage libraries to select peptides that bind and enter several different cell types. Because of their small size, cell-binding peptides such as these could be incorporated into biological or physical gene therapy vectors. In addition, peptide-presenting phage themselves may also be candidates for gene therapy vectors.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "8574972", + "TEXT": "Retinoic acid (RA) has been shown to be effective in eradicating premalignant lesions and preventing second primary malignancies in patients cured of squamous cell carcinoma of the head and neck (SCCHN) in clinical trials. The basis for this effect is unclear. We have previously demonstrated that messenger RNA from tumor growth factor-alpha (TGF-alpha) and its receptor, the epidermal growth factor (EGFR), is unregulated in tumors and histologically normal mucosal samples from patients with SCCHN compared with control normal mucosa from patients without cancer, implicating this ligand-receptor pair in an autocrine growth pathway early in the molecular pathogenesis of this disease. In this report, we examined the hypothesis that the action of RA on the mucosa of the upper aerodigestive tract is mediated via downregulation of steady-state TGF-alpha and/or EGFR mRNA levels. Following exposure to all-trans-RA, a series of SCCHN cell lines demonstrated a 35.4% reduction in TGF-alpha mRNA expression (P = 0.022) and 58.5% reduction in EGFR mRNA (P = 0.0027). Nuclear run-on analysis indicated that the RA-mediated reduction of TGF-alpha and EGFR steady-state mRNA levels was a result of decreased gene transcription. These results suggest that the clinical effects of RA in SCCHN patients may be due to a downmodulation of TGF-alpha and EGFR mRNA production.", + "TAG_DATA": [ + "138, SCCHN {'context': 'B-transformed cells'}", + "139, cell {'context': 'I-transformed cells'}", + "140, lines {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "138, SCCHN ['l0', 'l1']", + "139, cell ['l0', 'l2']", + "140, lines ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8574967", + "TEXT": "Expression of tissue factor (TF) in the endothelium has been observed only rarely in human disease and has been thought to be elaborated on the surface of vascular endothelial cells (VECs) in vitro as an artifact of tissue culture. Using monoclonal antibodies and a novel probe for functional TF, we have localized TF to the VECs (and tumor cells) within the tumors of seven patients with invasive breast cancer but not in the VECs (or tumor cells) of benign tumors from ten patients with fibrocystic disease of the breast. The potent procoagulant TF was shown to be a marker of the initiation of angiogenesis in human breast cancer. Further evidence that the TF was the demonstration of a similar distribution of cross-linked fibrin only in the VECs of the malignant tumors. We interpret these data as further support for the concept that tumor cells can activate nearby VECs and regulate blood vessel growth in vivo. Large clinical pathologic studies will be necessary to determine whether TF is a useful marker for the \"switch\" to the angiogenic phenotype\" in human breast disease and/or correlates with the thromboembolic complications of breast cancer.", + "TAG_DATA": [ + "73, VECs {'context': 'B-cells'}", + "78, benign {'context': 'B-neoplasm'}", + "79, tumors {'context': 'I-neoplasm'}", + "129, malignant {'context': 'B-neoplasm'}", + "130, tumors. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "73, VECs ['l0', 'l1']", + "78, benign ['l0', 'l2']", + "79, tumors ['l1', 'l2']", + "129, malignant ['l3']", + "130, tumors. ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8574965", + "TEXT": "Recently, cases have been reported in which a mixed chimeric state of blood cells is established after liver transplantation. Because the established chimerism may have aided in the induction of donor-specific tolerance, the mechanism responsible for this chimerism is of clinical importance. To establish this, we examined cells in adult mouse liver and identified the presence of c-kit+ Sca-1+ Lin(lo/-) cells. These cells were capable of forming in vivo as well as in vitro colonies. Furthermore, the cells could reconstitute bone marrow of lethally irradiated recipient mice for at least 12 months. These data obtained from the mouse study strongly suggest that hematopoietic stem cells residing in the donor liver are responsible for mixed chimerism and maintenance of tolerance after liver transplantation.", + "TAG_DATA": [ + "49, adult {'context': 'B-tissue/organ'}", + "50, mouse {'context': 'I-tissue/organ'}", + "51, liver {'context': 'I-tissue/organ'}", + "62, cells {'context': 'B-cells'}", + "66, forming {'phenotype': 'B-colony formation'}", + "67, in {'context': 'B-in vivo'}", + "68, vivo {'context': 'I-in vivo'}", + "72, in {'context': 'B-in vitro'}", + "73, vitro {'context': 'I-in vitro'}", + "74, colonies. {'phenotype': 'I-colony formation'}", + "86, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "49, adult ['l0', 'l1']", + "50, mouse ['l0', 'l2']", + "51, liver ['l1', 'l2']", + "62, cells ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "66, forming ['l3', 'l9', 'l10', 'l11', 'l12', 'l13']", + "67, in ['l4', 'l9', 'l14', 'l15', 'l16', 'l17']", + "68, vivo ['l5', 'l10', 'l14', 'l18', 'l19', 'l20']", + "72, in ['l6', 'l11', 'l15', 'l18', 'l21', 'l22']", + "73, vitro ['l7', 'l12', 'l16', 'l19', 'l21', 'l23']", + "74, colonies. ['l8', 'l13', 'l17', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "forming", + "colonies." + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "forming", + "colonies." + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "forming", + "colonies." + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "8564851", + "TEXT": "Abnormal and excessive accumulation of the amyloid beta-peptide (A beta) in the brain is a major and common characteristic of all Alzheimer's disease (AD) forms irrespective of their genetic background. Insoluble aggregates of A beta are identified as amyloid plaques. These deposits are thought to form when the amount of A beta is increased in the brain parenchyma as a result of either overexpression or altered processing of the amyloid precursor protein (APP). Soluble A beta ending at carboxyl-terminal residue 40 (A beta 40) and, in lesser amount, the form ending at residue 42 (A beta 42), are normal products of the APP metabolism in cell cultures. Increased secretion of soluble A beta 42 has been observed in cells transfected with constructs modeling APP gene mutations of familial forms of AD (refs 4, 5). On the basis of these in vitro data it has been hypothesized that the presence of soluble A beta 42 plays a role in the formation of amyloid plaques. Subjects affected by Down's syndrome (DS) have an increased APP gene dosage and overexpress APP. Apparently because of this overexpression, they almost invariably develop amyloid deposits after the age of 30 years, although they are free of them at earlier ages. Moreover, it has been observed that A beta 42 precedes A beta 40 in the course of amyloid deposition in DS brain. Thus, DS subjects provide the opportunity to investigate in the human brain the metabolic conditions that precede the formation of the amyloid deposits. Here we report that soluble A beta 42 is present in the brains of DS-affected subjects aged from 21 gestational weeks to 61 years but it is undetectable in age-matched controls. It is argued that overexpression of APP leads specifically to A beta 42 increase and that the presence of the soluble A beta 42 is causally related to plaque formation in DS and, likely, in AD brains.", + "TAG_DATA": [ + "118, cells {'context': 'B-cells'}", + "176, overexpress {'perturbing_action': 'B-gene gain-of-function'}", + "177, APP. {'perturbing_action': 'I-gene gain-of-function'}", + "284, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "285, of {'perturbing_action': 'I-gene gain-of-function'}", + "286, APP {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "176, overexpress ['l0']", + "177, APP. ['l0']", + "284, overexpression ['l1', 'l2']", + "285, of ['l1', 'l3']", + "286, APP ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "8564843", + "TEXT": "We studied prion proteins (PrP) in skin and brains of Libyan Jews carrying the E200K mutation who died of familial Creutzfeldt-Jakob disease (CJD). Unexpectedly, studies with brain showed that PrP molecules encoded both by the wild-type (wt) and mutant alleles exhibit altered properties characteristic of the prion protein associated with prion diseases (PrPSc). Using monospecific antisera, we found that wtPrP was insoluble in the brains of three patients who were heterozygous for the E200K mutation, whereas mutant PrP was both insoluble and protease-resistant. Our results argue that both wild-type and mutant PrP undergo conformational changes and are particularly intriguing, because the normal isoform PrPc is soluble in nondenaturing detergents and is readily digested by proteases, whereas PrPSc is insoluble and resistant to proteolytic digestion. Our findings indicate that insoluble wtPrP represents a conformational intermediate, the first to be identified, within a pathway in which PrPc is converted to PrPSc.", + "TAG_DATA": [ + "64, brains {'context': 'B-tissue/organ'}", + "67, patients {'context': 'B-patient'}", + "70, heterozygous {'perturbing_action': 'B-other'}", + "71, for {'perturbing_action': 'I-other'}", + "72, the {'perturbing_action': 'I-other'}", + "73, E200K {'perturbing_action': 'I-other'}", + "74, mutation, {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "64, brains ['l0', 'l1', 'l2', 'l3']", + "67, patients ['l0', 'l4', 'l5', 'l6', 'l7', 'l8']", + "70, heterozygous ['l4', 'l9', 'l10', 'l11', 'l12']", + "71, for ['l5', 'l9', 'l13', 'l14', 'l15']", + "72, the ['l1', 'l6', 'l10', 'l13', 'l16', 'l17']", + "73, E200K ['l2', 'l7', 'l11', 'l14', 'l16', 'l18']", + "74, mutation, ['l3', 'l8', 'l12', 'l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "brains" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "the", + "E200K", + "mutation," + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous", + "for", + "the", + "E200K", + "mutation," + ] + } + } + ] + }, + { + "PMID": "7489407", + "TEXT": "Graft-versus-host disease (GVHD) is uniformly lethal in recipients of HLA-mismatched marrow. In patients with severe combined immunodeficiency disease, this major obstacle can be overcome by rigorous T-cell depletion before transplantation. In leukaemia patients, however, the benefit of preventing GVHD is offset by graft rejection or graft failure. Very recently, this problem was overcome by supplementing T cell-depleted bone marrow transplants with megadoses of peripheral blood stem cells collected by leukapheresis after mobilization of the donor stem cells with granulocyte colony-stimulating factor (G-CSF). In the present study, we further demonstrate in a mouse model (C57BL/6-->C3H/Hej) that escalation of bone marrow doses by four- to fivefold leads to full donor-type chimerism in sublethally irradiated (6.5 Gy) recipients. Thus, the new source of G-CSF mobilized human haematopoietic stem cells may enable extending the use of mismatched bone marrow transplants to patients with non-malignant diseases for whom supralethal conditioning is not a prerequisite.", + "TAG_DATA": [ + "91, mouse {'context': 'B-organism'}", + "92, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "91, mouse ['l0']", + "92, model ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7584997", + "TEXT": "By screening members of Finnish families displaying hereditary nonpolyposis colorectal cancer (HNPCC) for predisposing germline mutations in MSH2 and MLH1, we show that two mutations in MLH1 together account for 63% (19/30) of kindreds meeting international diagnostic criteria. Mutation 1, originally detected as a 165-base pair deletion in MLH1 cDNA comprising exon 16, was shown to consist of a 3.5-kilobase genomic deletion most likely resulting from Alu-mediated recombination. Mutation 2 destroys the splice acceptor site of exon 6. A simple diagnostic test based on polymerase chain reaction was designed for both mutations. Our results show that these two ancestral founding mutations account for a majority of Finnish HNPCC kindreds and represent the first report of Alu-mediated recombination causing a prevalent, dominantly inherited predisposition to cancer.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "7584996", + "TEXT": "In early gestation the internal surface of the lung is structurally simple and an ideal target for somatic gene transfer. The transfer of genes into the growing lung would be particularly useful in the prenatal correction of cystic fibrosis, which has devastating pulmonary complications. In addition, in utero gene therapy has the potential to immunotolerize the individual, and thereby to avoid the immune reactions now seen with the current generation of adenoviral vectors. We injected a replication-defective adenoviral vector containing the lacZ reporter gene (Ad5.CMVlacZ) into the amniotic fluid of rat pups on the 16th day of gestation. At 16 days of gestation, rat lungs are equivalent in maturity to those of a 22-week human fetus as their airways are lined with undifferentiated multipotential stem cells. The pups showed high-level reporter gene expression in their airways a week following birth (13 days following infection). The expression was maintained during a time when the lung volume increased approximately 20-fold, alveolarization occurred, and the epithelial cells differentiated. These data establish gene targeting of undifferentiated fetal cells as an effective means of gene therapy.", + "TAG_DATA": [ + "90, rat {'context': 'B-organism'}", + "91, pups {'context': 'I-organism'}", + "103, rat {'context': 'B-tissue/organ'}", + "104, lungs {'context': 'I-tissue/organ'}", + "127, pups {'context': 'B-organism'}", + "153, lung {'context': 'B-tissue/organ'}", + "162, epithelial {'context': 'B-cells'}", + "163, cells {'context': 'I-cells'}", + "164, differentiated. {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "90, rat ['l0', 'l1', 'l2']", + "91, pups ['l0', 'l3', 'l4']", + "103, rat ['l1', 'l3', 'l5']", + "104, lungs ['l2', 'l4', 'l5']", + "127, pups ['l6', 'l7']", + "153, lung ['l6', 'l8']", + "162, epithelial ['l9', 'l10']", + "163, cells ['l7', 'l8', 'l9', 'l11']", + "164, differentiated. ['l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "epithelial", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiated." + ] + } + } + ] + }, + { + "PMID": "7584995", + "TEXT": "Results from the Diabetes Care and Complications Trial show that tight blood glucose control significantly reduces the long-term complications of diabetes mellitus. In that study, frequent self-testing of glucose and insulin administration resulted in a significant reduction in long-term complications. This protocol, however, also resulted in a threefold increase in the frequency of hypoglycaemic incidents. Currently, self-testing requires a drop of blood for each measurement. The pain and inconvenience of self-testing, along with the fear and danger of hypoglycaemia has led to poor patient acceptance of a tight control regimen, despite the clear long-term advantages. A continuously worn, noninvasive method to periodically measure glucose would provide a convenient and comfortable means of frequent self-testing. A continuously worn device could also alert the user of low glucose levels, thereby reducing the incidence of hypoglycaemia. Guy et al. demonstrated a noninvasive method to transport glucose through the skin using low-level electrical current. To provide a quantitative measurement, the flux of glucose extracted across the skin must correlate with serum glucose in a predictive manner. The results presented here show a quantitative relationship between serum and transdermally extracted glucose in diabetics.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "7489366", + "TEXT": "The molecular recognition theory suggests that binding sites of interacting proteins, for example, peptide hormone and its receptor binding site, were originally encoded by and evolved from complementary strands of genomic DNA. To test this theory, we screened a rat kidney complementary DNA library twice: first with the angiotensin II (AII) followed by the vasopressin (AVP) antisense oligonucleotide probe, expecting to isolate cDNA clones of the respective receptors. Surprisingly, the identical cDNA clone was isolated twice independently. Structural analysis revealed a single receptor polypeptide with seven predicted transmembrane regions, distinct AII and AVP putative binding domains, a Gs protein-activation motif, and an internalization recognition sequence. Functional analysis revealed specific binding to both AII and AVP as well as AII- and AVP-induced coupling to the adenylate cyclase second messenger system. Site-directed mutagenesis of the predicted AII binding domain obliterates AII binding but preserves AVP binding. This corroborates the dual nature of the receptor and provides direct molecular genetic evidence for the molecular recognition theory.", + "TAG_DATA": [ + "39, rat {'context': 'B-tissue/organ'}", + "40, kidney {'context': 'I-tissue/organ'}", + "129, Site-directed {'perturbing_action': 'B-other'}", + "130, mutagenesis {'perturbing_action': 'I-other'}", + "131, of {'perturbing_action': 'I-other'}", + "132, the {'perturbing_action': 'I-other'}", + "133, predicted {'perturbing_action': 'I-other'}", + "134, AII {'perturbing_action': 'I-other'}", + "135, binding {'perturbing_action': 'I-other'}", + "136, domain {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "39, rat ['l0']", + "40, kidney ['l0']", + "129, Site-directed ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "130, mutagenesis ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "131, of ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "132, the ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "133, predicted ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "134, AII ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "135, binding ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "136, domain ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7489362", + "TEXT": "The p21 gene encodes a cyclin-dependent kinase inhibitor that affects cell-cycle progression, but the potential of this gene product to serve as a tumour suppressor in vivo has not been established. In this report, we show that the growth of malignant cells in vitro and in vivo is inhibited by expression of p21. Expression of p21 resulted in an accumulation of cells in G0/G1, altered morphology, and cell differentiation, but apoptosis was not induced. Introduction of p21 with adenoviral vectors into malignant cells completely suppressed their growth in vivo and also reduced the growth of established pre-existing tumours. Gene transfer of p21 may provide a molecular genetic approach to arresting cancer cell growth by committing malignant cells irreversibly to a pathway of terminal differentiation.", + "TAG_DATA": [ + "40, malignant {'context': 'B-transformed cells'}", + "41, cells {'context': 'I-transformed cells'}", + "42, in {'context': 'B-in vitro'}", + "43, vitro {'context': 'I-in vitro'}", + "45, in {'context': 'B-in vivo'}", + "46, vivo {'context': 'I-in vivo'}", + "50, expression {'perturbing_action': 'B-gene gain-of-function'}", + "51, of {'perturbing_action': 'I-gene gain-of-function'}", + "52, p21. {'perturbing_action': 'I-gene gain-of-function'}", + "53, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "54, of {'perturbing_action': 'I-gene gain-of-function'}", + "55, p21 {'perturbing_action': 'I-gene gain-of-function'}", + "61, cells {'context': 'B-cells', 'phenotype': 'I-cell cycle arrest'}", + "63, G0/G1, {'phenotype': 'I-cell cycle arrest'}", + "67, cell {'context': 'B-cells'}", + "68, differentiation, {'phenotype': 'B-differentiation'}", + "70, apoptosis {'phenotype': 'B-apoptosis'}", + "72, not {'effect': 'B-no effect'}", + "73, induced. {'effect': 'B-positive'}", + "74, Introduction {'perturbing_action': 'B-gene gain-of-function'}", + "75, of {'perturbing_action': 'I-gene gain-of-function'}", + "76, p21 {'perturbing_action': 'I-gene gain-of-function'}", + "77, with {'perturbing_action': 'I-gene gain-of-function'}", + "78, adenoviral {'perturbing_action': 'I-gene gain-of-function'}", + "79, vectors {'perturbing_action': 'I-gene gain-of-function'}", + "81, malignant {'context': 'B-transformed cells'}", + "82, cells {'context': 'I-transformed cells'}", + "87, in {'context': 'B-in vivo'}", + "88, vivo {'context': 'I-in vivo'}", + "97, tumours. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "40, malignant ['l0', 'l1', 'l2']", + "41, cells ['l0', 'l3', 'l4']", + "42, in ['l1', 'l3', 'l5']", + "43, vitro ['l2', 'l4', 'l5']", + "45, in ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "46, vivo ['l6', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "50, expression ['l7', 'l20', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "51, of ['l8', 'l21', 'l33', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "52, p21. ['l9', 'l22', 'l34', 'l47', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "53, Expression ['l35', 'l48', 'l60', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "54, of ['l10', 'l23', 'l36', 'l49', 'l61', 'l72', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "55, p21 ['l11', 'l24', 'l37', 'l50', 'l62', 'l73', 'l84', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "56, resulted ['l12', 'l25', 'l38', 'l51', 'l63', 'l74', 'l85', 'l95', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "61, cells ['l13', 'l26', 'l39', 'l52', 'l64', 'l75', 'l86', 'l96', 'l105', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "63, G0/G1, ['l14', 'l27', 'l40', 'l53', 'l65', 'l76', 'l87', 'l97', 'l106', 'l113', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "64, altered ['l15', 'l28', 'l41', 'l54', 'l66', 'l77', 'l88', 'l98', 'l107', 'l114', 'l120', 'l126', 'l127', 'l128', 'l129', 'l130']", + "67, cell ['l16', 'l29', 'l42', 'l55', 'l67', 'l78', 'l89', 'l99', 'l108', 'l115', 'l121', 'l126', 'l131', 'l132', 'l133', 'l134']", + "68, differentiation, ['l17', 'l30', 'l43', 'l56', 'l68', 'l79', 'l90', 'l100', 'l109', 'l116', 'l122', 'l127', 'l131', 'l135', 'l136', 'l137']", + "70, apoptosis ['l44', 'l57', 'l69', 'l80', 'l91', 'l101', 'l110', 'l117', 'l123', 'l128', 'l132', 'l135', 'l138', 'l139']", + "72, not ['l18', 'l31', 'l45', 'l58', 'l70', 'l81', 'l92', 'l102', 'l111', 'l118', 'l124', 'l129', 'l133', 'l136', 'l138', 'l140']", + "73, induced. ['l19', 'l32', 'l46', 'l59', 'l71', 'l82', 'l93', 'l103', 'l112', 'l119', 'l125', 'l130', 'l134', 'l137', 'l139', 'l140']", + "74, Introduction ['l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150']", + "75, of ['l141', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159']", + "76, p21 ['l142', 'l151', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "77, with ['l143', 'l152', 'l160', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "78, adenoviral ['l144', 'l153', 'l161', 'l168', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180']", + "79, vectors ['l145', 'l154', 'l162', 'l169', 'l175', 'l181', 'l182', 'l183', 'l184', 'l185']", + "81, malignant ['l146', 'l155', 'l163', 'l170', 'l176', 'l181', 'l186', 'l187', 'l188', 'l189']", + "82, cells ['l83', 'l94', 'l104', 'l147', 'l156', 'l164', 'l171', 'l177', 'l182', 'l186', 'l190', 'l191']", + "87, in ['l148', 'l157', 'l165', 'l172', 'l178', 'l183', 'l187', 'l190', 'l192', 'l193']", + "88, vivo ['l149', 'l158', 'l166', 'l173', 'l179', 'l184', 'l188', 'l191', 'l192', 'l194']", + "97, tumours. ['l150', 'l159', 'l167', 'l174', 'l180', 'l185', 'l189', 'l193', 'l194']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "p21.", + "p21", + "Introduction", + "with", + "adenoviral", + "vectors" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cells", + "G0/G1," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "cell" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cells", + "G0/G1," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "p21.", + "Expression", + "p21" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "p21.", + "Expression", + "p21" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cells", + "G0/G1," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "p21.", + "Expression", + "p21" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "p21.", + "Expression", + "p21" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "p21.", + "Expression", + "p21" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "p21.", + "Expression", + "p21" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "p21", + "Introduction", + "with", + "adenoviral", + "vectors" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells", + "malignant" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "cell" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "cell" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cells", + "G0/G1," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced." + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cells", + "G0/G1," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Introduction", + "of", + "p21", + "with", + "adenoviral", + "vectors" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumours." + ] + } + } + ] + }, + { + "PMID": "7489359", + "TEXT": "It is unclear whether disseminated tumour cells detected in bone marrow in early stages of solid cancers indicate a subclinical systemic disease component determining the patient's fate or simply represent mainly irrelevant shed cells. Moreover, characteristics differentiating high and low metastatic potential of disseminated tumour cells are not defined. We performed repeated serial bone marrow biopsies during follow-up in operated gastric cancer patients. Most patients with later tumour relapse revealed either an increase or a constantly high number of tumour cells. In contrast, in patients without recurrence, either clearance of tumour cells or negative or low cell counts were seen. Urokinase plasminogen activator (uPA)-receptor expression on disseminated tumour cells was significantly correlated with increasing tumour cell counts and clinical prognosis. These results demonstrate a systemic component in early solid cancer, indicated by early systemically disseminated tumour cells, which may predict individual disease development.", + "TAG_DATA": [ + "60, gastric {'context': 'B-neoplasm'}", + "61, cancer {'context': 'I-neoplasm'}", + "62, patients. {'context': 'I-patient'}", + "64, patients {'context': 'B-patient'}", + "79, tumour {'context': 'B-transformed cells'}", + "84, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "60, gastric ['l0', 'l1', 'l2', 'l3']", + "61, cancer ['l0', 'l4', 'l5', 'l6']", + "62, patients. ['l1', 'l4', 'l7', 'l8']", + "64, patients ['l2', 'l5', 'l7', 'l9']", + "79, tumour ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7489357", + "TEXT": "Retinopathy of prematurity (ROP) is initiated by hyperoxia-induced obliteration of newly formed blood vessels in the retina of the premature newborn. We propose that vessel regression is a consequence of hyperoxia-induced withdrawal of a critical vascular survival factor. We show that regression of retinal capillaries in neonatal rats exposed to high oxygen, is preceded by a shut-off of vascular endothelial growth factor (VEGF) production by nearby neuroglial cells. Vessel regression occurs via selective apoptosis of endothelial cells. Intraocular injection of VEGF at the onset of experimental hyperoxia prevents apoptotic death of endothelial cells and rescues the retinal vasculature. These findings provide evidence for a specific angiogenic factor acting as a vascular survival factor in vivo. The system also provides a paradigm for vascular remodelling as an adaptive response to an increase in oxygen tension and suggests a novel approach to prevention of ROP.", + "TAG_DATA": [ + "46, neonatal {'context': 'B-organism'}", + "47, rats {'context': 'I-organism'}", + "73, apoptosis {'phenotype': 'B-apoptosis'}", + "75, endothelial {'context': 'B-cells'}", + "76, cells. {'context': 'I-cells'}", + "87, prevents {'effect': 'B-negative'}", + "88, apoptotic {'phenotype': 'B-apoptosis'}", + "89, death {'phenotype': 'I-apoptosis'}", + "91, endothelial {'context': 'B-cells'}", + "92, cells {'context': 'I-cells'}", + "96, retinal {'context': 'B-tissue/organ'}", + "97, vasculature. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "46, neonatal ['l0', 'l1', 'l2', 'l3']", + "47, rats ['l0', 'l4', 'l5', 'l6']", + "73, apoptosis ['l1', 'l4', 'l7', 'l8']", + "75, endothelial ['l2', 'l5', 'l7', 'l9']", + "76, cells. ['l3', 'l6', 'l8', 'l9']", + "87, prevents ['l10', 'l11', 'l12', 'l13']", + "88, apoptotic ['l10', 'l14', 'l15', 'l16']", + "89, death ['l11', 'l14', 'l17', 'l18']", + "91, endothelial ['l12', 'l15', 'l17', 'l19']", + "92, cells ['l13', 'l16', 'l18', 'l19']", + "96, retinal ['l20']", + "97, vasculature. ['l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "neonatal", + "rats" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptotic", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells.", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + } + } + ] + }, + { + "PMID": "7489355", + "TEXT": "A colony of 26 chimpanzees given a fruit and vegetable diet of very low Na and high K intake were maintained in long-standing, socially stable small groups for three years. Half of them had salt added progressively to their diet during 20 months. This addition of salt within the human dietetic range caused a highly significant rise in systolic, mean and diastolic blood pressure. The change reversed completely by six months after cessation of salt. The effect of salt differed between chimpanzees, some having a large blood pressure rise and others small or no rise. These results in the species phylogenetically closest to humans bear directly on causation of human hypertension, particularly in relation to migration of preliterate people, with low Na diet, to a Western urban lifestyle with increased salt intake. The hedonic liking for salt and avid ingestion was apt during human prehistory involving hunter-gatherer-scavenger existence in the interior of continents with a scarcity of salt, but is maladaptive in urban technological life with salt cheap and freely available.", + "TAG_DATA": [ + "4, chimpanzees {'context': 'B-organism'}", + "81, chimpanzees, {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "7585225", + "TEXT": "The U.S. Centers for Disease Control and Prevention (CDC) recommends that only heat sterilization be used for all reusable devices entering the oral cavity. However, chemical disinfection is still employed for reprocessing dental devices in many areas of the world. In an analysis of a Florida dental practice responsible for nosocomial human immunodeficiency virus (HIV) transmissions, the possible role of contaminated devices was deemed unlikely in part because they were subjected to high-level disinfection with 2% glutaraldehyde. Disease transmissions have, however, been documented for endoscopes used in diagnostic and surgical procedures even after this treatment. In some dental devices, lubricants mix with potentially infectious patient materials, and organic debris has been observed in endoscopes after cleaning. We have investigated whether lubricants can render high-level chemical disinfection procedures ineffective and have addressed the role that some common devices may play in disease transmission. We report here that HIV in whole-blood samples and Pseudomonas aeruginosa in blood and plasma survived high-level disinfection when entrapped in lubricants used in dental handpieces and endoscopes. We also found that lubricated dental devices used to clean and polish teeth (prophylaxis angles) have the potential to transfer sufficient amounts of blood to infect human lymphocyte cultures with HIV. These results emphasize the need to subject reusable dental devices to a heat-sterilization protocol that penetrates the lubricant.", + "TAG_DATA": [ + "196, human {'context': 'B-cells'}", + "197, lymphocyte {'context': 'I-cells'}", + "198, cultures {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "196, human ['l0', 'l1']", + "197, lymphocyte ['l0', 'l2']", + "198, cultures ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7585223", + "TEXT": "Obesity is accompanied by complications such as hypertension, non-insulin-dependent diabetes mellitus and atherosclerosis, which in turn cause ischaemic heart disease, stroke and premature death. The underlying mechanisms behind imbalance in energy intake and energy expenditure that lead to obesity are still controversial. In most populations, obesity is more common among women than men and is a multifactorial phenotype, which may result from a complex network of genetic and nongenetic factors. The relative importance of genetic factors for obesity is under debate. Genome searches using polymorphic markers in inbred mice with phenotypes that result in extreme obesity and studies of human candidate genes are being performed in an attempt to identify genes that contribute to obesity. There is evidence that body weight is physiologically regulated and it has been postulated that the storage of fat may provide signals to the brain that the body is obese, which in turn may make the subject eat less and burn more fuel. One of the molecules that may be involved in such signalling is the obese (ob) gene product. Mutations in ob result in profound obesity and type II diabetes in mice. The mouse ob gene and its human homologue have been cloned and sequenced. The gene is expressed in adipose tissue and the product has features of a secreted protein. We have investigated human ob expression in subcutaneous and omental adipose tissue obtained from non-obese and massively obese subjects using in situ hybridization histochemistry and report on overexpression in obese people.", + "TAG_DATA": [ + "175, Mutations {'perturbing_action': 'B-other'}", + "176, in {'perturbing_action': 'I-other'}", + "177, ob {'perturbing_action': 'I-other'}", + "187, mice. {'context': 'B-organism'}", + "225, and {'context': 'I-tissue/organ'}", + "226, omental {'context': 'I-tissue/organ'}", + "227, adipose {'context': 'I-tissue/organ'}", + "228, tissue {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "175, Mutations ['l0', 'l1', 'l2', 'l3']", + "176, in ['l0', 'l4', 'l5']", + "177, ob ['l1', 'l4', 'l6']", + "187, mice. ['l2', 'l5', 'l6']", + "224, subcutaneous ['l7', 'l8', 'l9', 'l10', 'l11']", + "225, and ['l7', 'l12', 'l13', 'l14']", + "226, omental ['l8', 'l12', 'l15', 'l16']", + "227, adipose ['l9', 'l13', 'l15', 'l17']", + "228, tissue ['l3', 'l10', 'l14', 'l16', 'l17']", + "246, obese ['l18']", + "247, people. ['l11', 'l18']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Mutations", + "in", + "ob" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Mutations" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tissue" + ] + } + } + ] + }, + { + "PMID": "7585222", + "TEXT": "Prostate cancer is the second most common cause of death from cancer in U.S. men, and advanced, hormone-refractory disease is characterized by painful osteoblastic bone metastases. Endothelin-1, more commonly known as a potent vasoconstrictor, is a normal ejaculate protein that also stimulates osteoblasts. We show here that plasma immunoreactive endothelin concentrations are significantly elevated in men with metastatic prostate cancer and that every human prostate cancer cell line tested produces endothelin-1 messenger RNA and secretes immunoreactive endothelin. Exogenous endothelin-1 is a prostate cancer mitogen in vitro and increases alkaline phosphatase activity in new bone formation, indicating that ectopic endothelin-1 may be a mediator of the osteoblastic response of bone to metastatic prostate cancer.", + "TAG_DATA": [ + "63, human {'context': 'B-transformed cells'}", + "64, prostate {'context': 'I-transformed cells'}", + "65, cancer {'context': 'I-transformed cells'}", + "66, cell {'context': 'I-transformed cells'}", + "67, line {'context': 'I-transformed cells'}", + "84, in {'context': 'B-in vitro'}", + "85, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "63, human ['l0', 'l1', 'l2', 'l3']", + "64, prostate ['l0', 'l4', 'l5', 'l6']", + "65, cancer ['l1', 'l4', 'l7', 'l8']", + "66, cell ['l2', 'l5', 'l7', 'l9']", + "67, line ['l3', 'l6', 'l8', 'l9']", + "84, in ['l10']", + "85, vitro ['l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7585217", + "TEXT": "The aim of this study was to test the ability of a live attenuated human immunodeficiency virus type 2 (HIV-2) vaccine to protect cynomolgus monkeys against superinfection with a pathogenic simian immunodeficiency virus (SIVsm). This report is an update on our previously reported observation period of nine months. The new data here show that three of four monkeys vaccinated with live HIV-2 were protected against immunosuppression and SIV-induced disease during more than five years of follow-up. The quality of the immunity was permissive for infection, but monkeys that survived showed restricted viral replication in peripheral blood and lymph nodes. This study shows that it is possible to induce protection against a pathogenic heterologous primate lentivirus and to prevent disease in vaccinated monkeys even if infection is not prevented. These findings provide evidence that protection against AIDS can be achieved by immunization.", + "TAG_DATA": [ + "23, cynomolgus {'context': 'B-organism'}", + "24, monkeys {'context': 'I-organism'}", + "57, monkeys {'context': 'B-organism'}", + "86, monkeys {'context': 'B-organism'}", + "121, monkeys {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "23, cynomolgus ['l0', 'l1']", + "24, monkeys ['l0']", + "57, monkeys ['l1']", + "86, monkeys ['l2']", + "97, lymph ['l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7585186", + "TEXT": "In developed countries the major tuberculosis epidemics declined long before the disease became curable in the 1940s. We present a theoretical framework for assessing the intrinsic transmission dynamics of tuberculosis. We demonstrate that it takes one to several hundred years for a tuberculosis epidemic to rise, fall and reach a stable endemic level. Our results suggest that some of the decline of tuberculosis is simply due to the natural behaviour of an epidemic. Although other factors must also have contributed to the decline, these causal factors were constrained to operate within the slow response time dictated by the intrinsic dynamics.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "7585184", + "TEXT": "The gaseous free radical nitric oxide (NO.) is an important regulator of a variety of biological functions and also has a role in the pathogenesis of cellular injury. It has been generally accepted that NO. is solely generated in biological tissues by specific nitric oxide synthases, NOSs, which metabolize arginine to citrulline with the formation of NO.. We report that NO. can also be generated in the ischaemic heart by direct reduction of nitrite to NO. under the acidotic and highly reduced conditions that occur. This NO. formation is not blocked by NOS inhibitors, and with long periods of ischaemia progressing to necrosis, this mechanism of NO. formation predominates. We observe that enzyme-independent NO. generation results in myocardial injury with a loss of contractile function. The existence of this enzyme-independent mechanism of NO. formation has important implications in our understanding of the pathogenesis and treatment of tissue injury.", + "TAG_DATA": [ + "102, necrosis, {'phenotype': 'B-necrosis'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "7585155", + "TEXT": "Cystic fibrosis (CF) is a multisystem autosomal recessive disorder caused by mutations of the cystic fibrosis transmembrane regulator (CFTR), a protein that regulates cyclic-AMP-mediated chloride conductance at the apical membrane of secretory epithelia. Mutations in the CFTR gene are common in many populations. In North America, 4-5% of the general population are heterozygous for a CFTR mutation. Although there are over 400 known CFTR mutations, a single mutation, a deletion of the phenylalanine at position 508 (delta F508) in exon 10, accounts for about 70% of all CF chromosomes worldwide. The reasons for the high frequency of the delta F508 CFTR allele--the selective advantage associated with CF heterozygosity--are unknown. Many physiological abnormalities have been observed in CF heterozygotes, although the clinical significance of these observations is unknown. Preliminary unpublished data and anecdotal information from CF families suggested that, remarkably, the delta F508 allele might protect heterozygotes against bronchial asthma prompted us to further investigate this possibility. Here we present evidence that the delta F508 CF allele protects against asthma in childhood and early adult life.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "7585152", + "TEXT": "Loss of heterozygosity on chromosome 9p21 is one of the most frequent genetic alterations identified in human cancer. The rate of point mutations of p16, a candidate suppressor gene of this area, is low in most primary tumours with allelic loss of 9p21. Monosomic cell lines with structurally unaltered p16 show methylation of the 5' CpG island of p16. This distinct methylation pattern was associated with a complete transcriptional block that was reversible upon treatment with 5-deoxyazacytidine. Moreover, de novo methylation of the 5' CpG island of p16 was also found in approximately 20% of different primary neoplasms, but not in normal tissues, potentially representing a common pathway of tumour suppressor gene inactivation in human cancers.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "7585149", + "TEXT": "We have tested a novel strategy of intracellular immunization to block human immunodeficiency virus (HIV) infection. The expression of a specific antibody within a cell was achieved by transduction of genes that encode for immunoglobulin chains with specificity to viral reverse transcriptase. We demonstrated that inhibition of this enzyme makes cells resistant to HIV infection by blocking an early stage of viral replication. If high efficiency transduction with a stable vector into lymphohaematopoietic stem cells or mature lymphocytes can be achieved, gene transfer-mediated intracellular immunization might be a feasible treatment strategy in AIDS.", + "TAG_DATA": [ + "45, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "46, of {'perturbing_action': 'I-pharmacological inhibition'}", + "50, cells {'context': 'B-cells'}", + "72, lymphohaematopoietic {'context': 'B-cells'}", + "73, stem {'context': 'I-cells'}", + "74, cells {'context': 'I-cells'}", + "76, mature {'context': 'B-cells'}", + "77, lymphocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, inhibition ['l0', 'l1', 'l2', 'l3', 'l4']", + "46, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "50, cells ['l1', 'l5']", + "72, lymphohaematopoietic ['l2', 'l6', 'l9', 'l10', 'l11', 'l12']", + "73, stem ['l3', 'l7', 'l9', 'l13', 'l14', 'l15']", + "74, cells ['l4', 'l8', 'l10', 'l13', 'l16', 'l17']", + "76, mature ['l11', 'l14', 'l16', 'l18']", + "77, lymphocytes ['l12', 'l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "lymphohaematopoietic", + "stem" + ] + } + } + ] + }, + { + "PMID": "7585145", + "TEXT": "Cytotoxic T lymphocytes (CTLs) kill neoplastic or virally infected cells after recognizing on their surface antigenic peptides bound to major histocompatibility complex class I molecules. These peptides are derived from antigens that are degraded in the cytosol of the affected cell. Because exogenous proteins cannot enter the cytosol, immunizations with killed pathogens or their proteins do not generally elicit CTLs. However, antigens that are internalized into phagocytic cells can enter the cytosol and be processed for class I presentation. Here we show that immunization with a purified antigen on an avidly phagocytized particle primes CTLs, which in turn protect animals from subsequent challenge with tumours transfected with the antigen gene. Interestingly, these animals also become immune to other antigens expressed by the tumour. This approach could be exploited to develop tumour and viral vaccines.", + "TAG_DATA": [ + "94, CTLs, {'context': 'B-cells'}", + "99, animals {'context': 'B-organism'}", + "104, tumours {'context': 'B-neoplasm'}", + "105, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "106, with {'perturbing_action': 'I-gene gain-of-function'}", + "107, the {'perturbing_action': 'I-gene gain-of-function'}", + "108, antigen {'perturbing_action': 'I-gene gain-of-function'}", + "109, gene. {'perturbing_action': 'I-gene gain-of-function'}", + "112, animals {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "94, CTLs, ['l0']", + "99, animals ['l0', 'l1']", + "104, tumours ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "105, transfected ['l2', 'l7', 'l8', 'l9', 'l10']", + "106, with ['l3', 'l7', 'l11', 'l12', 'l13']", + "107, the ['l4', 'l8', 'l11', 'l14', 'l15', 'l16']", + "108, antigen ['l5', 'l9', 'l12', 'l14', 'l17', 'l18']", + "109, gene. ['l6', 'l10', 'l13', 'l15', 'l17', 'l19']", + "112, animals ['l16', 'l18', 'l19']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "tumours" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "the", + "antigen", + "gene." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "the", + "antigen", + "gene." + ] + }, + "context": { + "val": "organism", + "words": [ + "animals" + ] + } + } + ] + }, + { + "PMID": "7585144", + "TEXT": "Certain strains of transgenic mice that express the rat neu oncogene (neuT) in mammary epithelial cells develop breast tumours at an average of 44 weeks of age. In this study, intraperitoneal injection of a monoclonal anti-receptor antibody specific for the rat neuT oncogene product dramatically affected tumour development in these transgenic mice in a dose-dependent manner. A significant proportion (50%) of mice, when injected with anti-receptor antibodies, did not develop tumours even after 90 weeks of age. The phosphotyrosine levels of the membrane fraction of breast tissues in the anti-receptor antibody-treated mice were almost completely abolished when a higher dose of antibodies was used. This study demonstrates, for the first time, that immunologic manipulation of an oncogene product can effectively prevent the development of tumours in a rodent transgenic model.", + "TAG_DATA": [ + "45, affected {'effect': 'B-regulates'}", + "46, tumour {'phenotype': 'B-tumourigenesis'}", + "47, development {'phenotype': 'I-tumourigenesis'}", + "50, transgenic {'context': 'B-organism'}", + "51, mice {'context': 'I-organism'}", + "61, mice, {'context': 'B-organism'}", + "68, not {'effect': 'I-no effect'}", + "69, develop {'effect': 'I-no effect', 'phenotype': 'B-tumourigenesis'}", + "70, tumours {'phenotype': 'B-tumourigenesis'}", + "91, mice {'context': 'B-organism'}", + "120, prevent {'effect': 'B-negative'}", + "127, rodent {'context': 'B-organism'}", + "129, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "45, affected ['l0', 'l1', 'l2', 'l3']", + "46, tumour ['l0', 'l4', 'l5', 'l6']", + "47, development ['l1', 'l4', 'l7']", + "50, transgenic ['l2', 'l5', 'l8']", + "51, mice ['l3', 'l6', 'l7', 'l8']", + "61, mice, ['l9', 'l10', 'l11', 'l12']", + "68, not ['l9', 'l13', 'l14', 'l15']", + "69, develop ['l10', 'l13', 'l16', 'l17']", + "70, tumours ['l11', 'l14', 'l16', 'l18']", + "91, mice ['l12', 'l15', 'l17', 'l18']", + "120, prevent ['l19', 'l20', 'l21']", + "127, rodent ['l19', 'l22', 'l23']", + "128, transgenic ['l20', 'l22', 'l24']", + "129, model. ['l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "regulates", + "words": [ + "affected" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumour", + "development" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "affected" + ] + }, + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumour", + "development", + "develop", + "tumours" + ] + }, + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice", + "mice," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "develop" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "develop", + "not" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "develop", + "tumours" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "context": { + "val": "organism", + "words": [ + "rodent", + "model." + ] + } + } + ] + }, + { + "PMID": "7585120", + "TEXT": "Proliferation of smooth muscle cells of the arterial wall in response to local injury is an important aetiologic factor of vascular proliferative disorders such as atherosclerosis and restenosis after angioplasty. Ras proteins are key transducers of mitogenic signals from membrane to nucleus in many cell types. We investigated the role of ras proteins in the vascular response to arterial injury by inactivating cellular ras of rats in which the common carotid artery was subjected to balloon injury. DNA vectors expressing ras transdominant negative mutants, which interfere with ras function, reduced neointimal formation after injury. Our results indicate a key role for ras in smooth muscle cell proliferation and show that the local delivery of transdominant negative mutants of ras in vivo might prevent some of the acute vascular injury caused by balloon injury.", + "TAG_DATA": [ + "65, rats {'context': 'B-organism'}", + "69, common {'context': 'B-tissue/organ'}", + "70, carotid {'context': 'I-tissue/organ'}", + "71, artery {'context': 'I-tissue/organ'}", + "77, DNA {'perturbing_action': 'B-rnai/knockdown'}", + "78, vectors {'perturbing_action': 'I-rnai/knockdown'}", + "79, expressing {'perturbing_action': 'I-other'}", + "80, ras {'perturbing_action': 'I-other'}", + "81, transdominant {'perturbing_action': 'I-other'}", + "82, negative {'perturbing_action': 'I-other'}", + "83, mutants, {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "65, rats ['l0', 'l1', 'l2']", + "69, common ['l0', 'l3', 'l4']", + "70, carotid ['l1', 'l3', 'l5']", + "71, artery ['l2', 'l4', 'l5']", + "77, DNA ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "78, vectors ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "79, expressing ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "80, ras ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "81, transdominant ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "82, negative ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "83, mutants, ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7585094", + "TEXT": "To test the hypothesis that induction of endogenous bFGF can lead to angiogenesis in ischaemic skeletal muscle, we studied the expression of bFGF after transposition of a well-vascularized muscle flap onto an ischaemic hindlimb in the rabbit. The results indicated a marked induction of bFGF mRNA throughout the myoblasts of the well-perfused muscle flap but not the myoblasts of the ischaemic muscle. bFGF protein was detected in the muscle flap, particularly in the myoblasts located closest to a newly formed, adjacent interface, and in the interface itself. In contrast, bFGF expression was not induced after transposition of a well-perfused muscle flap onto healthy muscle tissue. These data provide evidence that the juxtaposition of ischaemic skeletal muscle with healthy mesenchymal tissue triggers an increased expression of bFGF in the myoblasts of the well-perfused muscle. This paracrine induction of bFGF, in turn, leads to increased angiogenesis and regeneration of the ischaemic skeletal muscle.", + "TAG_DATA": [ + "36, rabbit. {'context': 'B-organism'}", + "48, myoblasts {'context': 'B-cells'}", + "57, myoblasts {'context': 'B-cells'}", + "73, myoblasts {'context': 'B-cells'}", + "128, myoblasts {'context': 'B-cells'}", + "149, skeletal {'context': 'I-tissue/organ'}", + "150, muscle. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "33, hindlimb ['l0', 'l1', 'l2', 'l3']", + "36, rabbit. ['l0', 'l4', 'l5']", + "48, myoblasts ['l1', 'l4', 'l6']", + "57, myoblasts ['l2', 'l5', 'l6', 'l7']", + "73, myoblasts ['l3', 'l7']", + "128, myoblasts ['l8', 'l9']", + "149, skeletal ['l8', 'l10']", + "150, muscle. ['l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7585093", + "TEXT": "A novel 'multistep molecular mimicry' mechanism for induction of rheumatoid arthritis (RA) by bacterial antigens that activate T lymphocytes previously 'educated' by peptides derived from a class of human histocompatibility antigens is reported here. These antigens have the amino acid sequence QKRAA, which is also present on the Escherichia coli heat-shock protein dnaJ. Synovial fluid cells of early RA patients have strong immune responses to the bacterial antigen, but cells from normal subjects or controls with other autoimmune diseases do not. The activated T cells may cross-react with autologous dnaJ heat-shock proteins that are expressed at synovial sites of inflammation. Our findings may have direct relevance to new strategies for the immune therapy of RA.", + "TAG_DATA": [ + "54, fluid {'context': 'I-cells'}", + "55, cells {'context': 'I-cells'}", + "69, cells {'context': 'B-cells'}", + "83, T {'context': 'B-cells'}", + "84, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "54, fluid ['l0', 'l1']", + "55, cells ['l0', 'l2']", + "69, cells ['l1', 'l2']", + "83, T ['l3']", + "84, cells ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7585071", + "TEXT": "In summary, FMRI is a new technique for discovering the organization and function of the brain. The ability rapidly and non-invasively to image regional cerebral blood flow, blood volume, and blood oxygenation may strengthen diagnoses in neurology, neurosurgery, and trauma medicine. The ability to localize specific functions in an individual's brain will have a large impact on the planning of therapeutic interventions, and in predicting outcomes after disease and injury. Substantial contributions to the diagnosis and treatment of psychiatric disorders are expected based on the ability to image subtle differences in a patient's response to auditory and visual stimuli of different emotional content.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "7585063", + "TEXT": "Various types of alcoholics have been described and heredity has been shown to be involved in some of these types. An important role of the mesolimbic dopamine system has been suggested in the reinforcing effects of alcohol and recent molecular genetic studies are implicating the gene for the D2 dopamine receptor (DRD2) in alcoholism. In a double-blind study, bromocriptine, a DRD2 agonist, or placebo was administered to alcoholics with either the A1 (A1/A1 and A1/A2 genotypes) or only the A2 (A2/A2 genotype) allele of the DRD2 gene. The greatest improvement in craving and anxiety occurred in the bromocriptine-treated A1 alcoholics and attrition was highest in the placebo-treated A1 alcoholics. The feasibility of a pharmacogenetic approach in treating certain types of alcoholics is suggested.", + "TAG_DATA": [ + "58, bromocriptine, {'perturbing_action': 'B-pharmacological augmentation'}", + "59, a {'perturbing_action': 'I-pharmacological augmentation'}", + "60, DRD2 {'perturbing_action': 'I-pharmacological augmentation'}", + "61, agonist, {'perturbing_action': 'I-pharmacological augmentation'}", + "67, alcoholics {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "58, bromocriptine, ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "59, a ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "60, DRD2 ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "61, agonist, ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "67, alcoholics ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "82, allele ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "83, of ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "84, the ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "85, DRD2 ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "86, gene. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "bromocriptine,", + "a", + "DRD2", + "agonist," + ] + }, + "context": { + "val": "cells", + "words": [ + "alcoholics" + ] + } + } + ] + }, + { + "PMID": "7585061", + "TEXT": "Rhesus macaques were immunized with attenuated vaccinia or canarypox human immunodeficiency virus type 1 (HIV-1) recombinants and boosted with HIV-1 protein subunits formulated in alum. Following challenge with HIV-2SBL6669, three out of eight immunized macaques resisted infection for six months and another exhibited significantly delayed infection, whereas all three naive controls became infected. Immunizations elicited both humoral and cellular immune responses; however, no clear correlates of protection were discerned. Although more extensive studies are now called for, this first demonstration of cross-protection between HIV-1 and -2 suggests that viral variability may not be an insurmountable problem in the design of a global AIDS vaccine.", + "TAG_DATA": [ + "1, macaques {'context': 'I-organism'}", + "34, macaques {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "1, macaques ['l0']", + "34, macaques ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7585038", + "TEXT": "A high survival rate of grafted dopamine neurons is crucial for reversing neurological deficits following brain tissue transplantation in Parkinson's disease. For unknown reasons the survival rate of transplanted dopamine neurons is only around 10% in experimental animals. The hypothesis that oxidative stress causes the loss of transplanted neurons was tested by grafting neurons from transgenic mice that overexpress Cu/Zn superoxide dismutase. Compared with the survival of those taken from non-transgenic littermates, the survival was 4 times higher for the transgenic dopamine neurons with a concomitant more extensive functional recovery. The results provide direct support for the free radical hypothesis of dopaminergic neuron death in brain tissue grafting.", + "TAG_DATA": [ + "48, neurons {'context': 'B-cells'}", + "53, neurons {'context': 'B-cells'}", + "56, mice {'context': 'I-organism'}", + "81, dopamine {'context': 'B-cells'}", + "82, neurons {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "48, neurons ['l0']", + "53, neurons ['l0', 'l1']", + "56, mice ['l1', 'l2', 'l3']", + "81, dopamine ['l2', 'l4']", + "82, neurons ['l3', 'l4']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7585011", + "TEXT": "Amyloid is a term for extracellular protein fibril deposits that have characteristic tinctorial and structural properties. Heparan sulphate, or the heparan sulphate proteoglycan perlecan, has been identified in all amyloids and implicated in the earliest stages of inflammation-associated (AA) amyloid induction. Heparan sulphate interacts with the AA amyloid precursor and the beta-peptide of Alzheimer's amyloid, imparting characteristic secondary and tertiary amyloid structural features. These observations suggest that molecules that interfere with this interaction may prevent or arrest amyloidogenesis. We synthesized low-molecular-weight (135-1,000) anionic sulphonate or sulphate compounds. When administered orally, these compounds substantially reduced murine splenic AA amyloid progression. They also interfered with heparan sulphate-stimulated beta-peptide fibril aggregation in vitro.", + "TAG_DATA": [ + "94, murine {'context': 'B-tissue/organ'}", + "95, splenic {'context': 'I-tissue/organ'}", + "108, in {'context': 'B-in vitro'}", + "109, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "94, murine ['l0', 'l1']", + "95, splenic ['l0', 'l2']", + "96, AA ['l1', 'l2']", + "108, in ['l3']", + "109, vitro. ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "7585008", + "TEXT": "Although 13 years have passed since identification of human immunodeficiency virus-1 (HIV-1) as the cause of AIDS, we do not yet know how HIV kills its primary target, the T cell that carries the CD4 antigen. We and others have shown an increase in the percentage of apoptotic cells among circulating CD4+ (and CD8+) T cells of HIV-seropositive individuals and an increase in frequency of apoptosis with disease progression. However, it is not known if this apoptosis occurs in infected or uninfected T cells. We show here, using in situ labelling of lymph nodes from HIV-infected children and SIV-infected macaques, that apoptosis occurs predominantly in bystander cells and not in the productively infected cells themselves. These data have implications for pathogenesis and therapy, namely, arguing that rational drug therapy may involve combination agents targeting viral replication in infected cells and apoptosis of uninfected cells.", + "TAG_DATA": [ + "99, macaques, {'context': 'B-organism'}", + "101, apoptosis {'phenotype': 'B-apoptosis'}", + "106, cells {'context': 'I-cells'}", + "113, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "99, macaques, ['l0', 'l1', 'l2']", + "101, apoptosis ['l0', 'l3', 'l4']", + "106, cells ['l1', 'l3']", + "113, cells ['l2', 'l4']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "macaques," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "7584939", + "TEXT": "Graduate education in the sciences is not doing its job. By preparing students only for academic research, the system neglects the range of opportunities for work in science that young scientists want and society needs.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "33442016", + "TEXT": "COVID-19, caused by SARS-CoV-2 infection, is mild to moderate in the majority of previously healthy individuals, but can cause life-threatening disease or persistent debilitating symptoms in some cases. The most important determinant of disease severity is age, with individuals over 65 years having the greatest risk of requiring intensive care, and men are more susceptible than women. In contrast to other respiratory viral infections, young children seem to be less severely affected. It is now clear that mild to severe acute infection is not the only outcome of COVID-19, and long-lasting symptoms are also possible. In contrast to severe acute COVID-19, such 'long COVID' is seemingly more likely in women than in men. Also, postinfectious hyperinflammatory disease has been described as an additional outcome after SARS-CoV-2 infection. Here I discuss our current understanding of the immunological determinants of COVID-19 disease presentation and severity and relate this to known immune-system differences between young and old people and between men and women, and other factors associated with different disease presentations and severity.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32427924", + "TEXT": "For diagnosis of coronavirus disease 2019 (COVID-19), a SARS-CoV-2 virus-specific reverse transcriptase polymerase chain reaction (RT-PCR) test is routinely used. However, this test can take up to 2 d to complete, serial testing may be required to rule out the possibility of false negative results and there is currently a shortage of RT-PCR test kits, underscoring the urgent need for alternative methods for rapid and accurate diagnosis of patients with COVID-19. Chest computed tomography (CT) is a valuable component in the evaluation of patients with suspected SARS-CoV-2 infection. Nevertheless, CT alone may have limited negative predictive value for ruling out SARS-CoV-2 infection, as some patients may have normal radiological findings at early stages of the disease. In this study, we used artificial intelligence (AI) algorithms to integrate chest CT findings with clinical symptoms, exposure history and laboratory testing to rapidly diagnose patients who are positive for COVID-19. Among a total of 905 patients tested by real-time RT-PCR assay and next-generation sequencing RT-PCR, 419 (46.3%) tested positive for SARS-CoV-2. In a test set of 279 patients, the AI system achieved an area under the curve of 0.92 and had equal sensitivity as compared to a senior thoracic radiologist. The AI system also improved the detection of patients who were positive for COVID-19 via RT-PCR who presented with normal CT scans, correctly identifying 17 of 25 (68%) patients, whereas radiologists classified all of these patients as COVID-19 negative. When CT scans and associated clinical history are available, the proposed AI system can help to rapidly diagnose COVID-19 patients.", + "TAG_DATA": [ + "204, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31171879", + "TEXT": "Oncogene-targeted therapy with B-Raf proto-oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors induces a high initial response rate in patients with BRAFV600-mutated melanoma, with a median duration of response of approximately 1 year1-3. Immunotherapy with antibodies to programmed death 1 (PD-1) produces lower response rates but with long response duration. Preclinical models suggest that combining BRAF and MEK inhibitors with PD-1 blockade therapy improves antitumor activity4-6, which may provide additional treatment options for patients unlikely to have long-lasting responses to either mode of therapy alone. We enrolled 15 patients with BRAFV600-mutated metastatic melanoma in a first-in-human clinical trial of dabrafenib, trametinib and pembrolizumab ( NCT02130466 ). Eleven patients (73%) experienced grade 3/4 treatment-related adverse events, the most common being elevation of liver function tests and pyrexia, most of which resolved with drug interruption or discontinuation of either the anti-PD-1 antibody or the targeted therapy combination. Eleven patients (73%; 95% confidence interval = 45-92%) had an objective response, and six (40%; 95% confidence interval = 16-68%) continued with a response at a median follow-up of 27 months (range = 10.3-38.4+ months) for all patients. This study suggests that this triple-combined therapy may benefit a subset of patients with BRAFV600-mutated metastatic melanoma by increasing the frequency of long-lasting antitumor responses.", + "TAG_DATA": [ + "89, patients {'context': 'B-patient'}", + "92, metastatic {'context': 'B-neoplasm'}", + "93, melanoma {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "89, patients ['l0', 'l1']", + "92, metastatic ['l0', 'l2']", + "93, melanoma ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30291358", + "TEXT": "In the version of this article originally published, there was an error in Fig. 1a. The m.5024C>T mutation, shown as a green T, was displaced by one base. The error has been corrected in the print, HTML and PDF versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16715092", + "TEXT": "Glutamatergic signaling and intracellular calcium mobilization in the spinal cord are crucial for the development of nociceptive plasticity, which is associated with chronic pathological pain. Long-form Homer proteins anchor glutamatergic receptors to sources of calcium influx and release at synapses, which is antagonized by the short, activity-dependent splice variant Homer1a. We show here that Homer1a operates in a negative feedback loop to regulate the excitability of the pain pathway in an activity-dependent manner. Homer1a is rapidly and selectively upregulated in spinal cord neurons after peripheral inflammation in an NMDA receptor-dependent manner. Homer1a strongly attenuates calcium mobilization as well as MAP kinase activation induced by glutamate receptors and reduces synaptic contacts on spinal cord neurons that process pain inputs. Preventing activity-induced upregulation of Homer1a using shRNAs in mice in vivo exacerbates inflammatory pain. Thus, activity-dependent uncoupling of glutamate receptors from intracellular signaling mediators is a novel, endogenous physiological mechanism for counteracting sensitization at the first, crucial synapse in the pain pathway. Furthermore, we observed that targeted gene transfer of Homer1a to specific spinal segments in vivo reduces inflammatory hyperalgesia. Thus, Homer1 function is crucially involved in pain plasticity and constitutes a promising therapeutic target for the treatment of chronic inflammatory pain.", + "TAG_DATA": [ + "111, spinal {'context': 'B-cells'}", + "112, cord {'context': 'I-cells'}", + "113, neurons {'context': 'I-cells'}", + "126, mice {'context': 'B-organism'}", + "127, in {'context': 'B-in vivo'}", + "128, vivo {'context': 'I-in vivo'}", + "164, targeted {'perturbing_action': 'B-gene gain-of-function'}", + "165, gene {'perturbing_action': 'I-gene gain-of-function'}", + "166, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "167, of {'perturbing_action': 'I-gene gain-of-function'}", + "168, Homer1a {'perturbing_action': 'I-gene gain-of-function'}", + "171, spinal {'context': 'B-tissue/organ'}", + "172, segments {'context': 'I-tissue/organ'}", + "173, in {'context': 'B-in vivo'}", + "174, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "111, spinal ['l0', 'l1']", + "112, cord ['l0', 'l2']", + "113, neurons ['l1', 'l2']", + "126, mice ['l3', 'l4']", + "127, in ['l3', 'l5']", + "128, vivo ['l4', 'l5']", + "164, targeted ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "165, gene ['l6', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "166, transfer ['l7', 'l14', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "167, of ['l8', 'l15', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "168, Homer1a ['l9', 'l16', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "171, spinal ['l10', 'l17', 'l23', 'l28', 'l32', 'l36', 'l37', 'l38']", + "172, segments ['l11', 'l18', 'l24', 'l29', 'l33', 'l36', 'l39', 'l40']", + "173, in ['l12', 'l19', 'l25', 'l30', 'l34', 'l37', 'l39', 'l41']", + "174, vivo ['l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "targeted", + "gene", + "transfer", + "of", + "Homer1a" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "spinal", + "segments" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "targeted", + "gene", + "transfer", + "of", + "Homer1a" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "15711558", + "TEXT": "Osteoporosis, a leading cause of morbidity in the elderly, is characterized by progressive loss of bone mass resulting from excess osteoclastic bone resorption relative to osteoblastic bone formation. Here we identify Vav3, a Rho family guanine nucleotide exchange factor, as essential for stimulated osteoclast activation and bone density in vivo. Vav3-deficient osteoclasts show defective actin cytoskeleton organization, polarization, spreading and resorptive activity resulting from impaired signaling downstream of the M-CSF receptor and alpha(v)beta3 integrin. Vav3-deficient mice have increased bone mass and are protected from bone loss induced by systemic bone resorption stimuli such as parathyroid hormone or RANKL. Moreover, we provide genetic and biochemical evidence for the role of Syk tyrosine kinase as a crucial upstream regulator of Vav3 in osteoclasts. Thus, Vav3 is a potential new target for antiosteoporosis therapy.", + "TAG_DATA": [ + "50, Vav3-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "51, osteoclasts {'context': 'B-cells'}", + "74, Vav3-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "75, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, Vav3-deficient ['l0']", + "51, osteoclasts ['l0']", + "74, Vav3-deficient ['l1']", + "75, mice ['l1']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Vav3-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclasts" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Vav3-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "12483208", + "TEXT": "Cytokines can initiate and perpetuate human diseases, and are among the best-validated of therapeutic targets. Cytokines can be blocked by the use of soluble receptors; however, the use of this approach for cytokines such as interleukin (IL)-1, IL-4, IL-6 and IL-13 that use multi-component receptor systems is limited because monomeric soluble receptors generally exhibit low affinity or function as agonists. We describe here a generally applicable method to create very high-affinity blockers called 'cytokine traps' consisting of fusions between the constant region of IgG and the extracellular domains of two distinct cytokine receptor components involved in binding the cytokine. Traps potently block cytokines in vitro and in vivo and represent a substantial advance in creating novel therapeutic candidates for cytokine-driven diseases.", + "TAG_DATA": [ + "103, in {'context': 'B-in vitro'}", + "104, vitro {'context': 'I-in vitro'}", + "106, in {'context': 'B-in vivo'}", + "107, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "103, in ['l0', 'l1', 'l2']", + "104, vitro ['l0', 'l3', 'l4']", + "106, in ['l1', 'l3', 'l5']", + "107, vivo ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11927948", + "TEXT": "Excessive accumulation of smooth-muscle cells (SMCs) has a key role in the pathogenesis of vascular diseases. It has been assumed that SMCs derived from the outer medial layer migrate, proliferate and synthesize extracellular matrix components on the luminal side of the vessel. Although much effort has been devoted to targeting migration and proliferation of medial SMCs, there is no effective therapy that prevents occlusive vascular remodeling. We show here that in models of post-angioplasty restenosis, graft vasculopathy and hyperlipidemia-induced atherosclerosis, bone-marrow cells give rise to most of the SMCs that contribute to arterial remodeling. Notably, purified hematopoietic stem cells differentiate into SMCs in vitro and in vivo. Our findings indicate that somatic stem cells contribute to pathological remodeling of remote organs, and may provide the basis for the development of new therapeutic strategies for vascular diseases through targeting mobilization, homing, differentiation and proliferation of bone marrow-derived vascular progenitor cells.", + "TAG_DATA": [ + "80, bone-marrow {'context': 'B-cells'}", + "81, cells {'context': 'I-cells'}", + "88, SMCs {'context': 'B-cells'}", + "96, hematopoietic {'context': 'I-cells'}", + "97, stem {'context': 'I-cells'}", + "98, cells {'context': 'I-cells'}", + "99, differentiate {'phenotype': 'B-differentiation'}", + "101, SMCs {'context': 'B-cells'}", + "102, in {'context': 'B-in vitro'}", + "103, vitro {'context': 'I-in vitro'}", + "105, in {'context': 'B-in vivo'}", + "106, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "80, bone-marrow ['l0', 'l1']", + "81, cells ['l0', 'l2']", + "88, SMCs ['l1', 'l2']", + "96, hematopoietic ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "97, stem ['l3', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "98, cells ['l4', 'l11', 'l18', 'l19', 'l20', 'l21']", + "99, differentiate ['l5', 'l12', 'l18', 'l22', 'l23', 'l24']", + "101, SMCs ['l6', 'l13', 'l19', 'l22', 'l25', 'l26']", + "102, in ['l7', 'l14', 'l20', 'l23', 'l25', 'l27']", + "103, vitro ['l8', 'l15', 'l21', 'l24', 'l26', 'l27']", + "105, in ['l9', 'l16', 'l28']", + "106, vivo. ['l10', 'l17', 'l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cells", + "SMCs" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "11100118", + "TEXT": "The importance of cholesterol ester synthesis by acyl CoA:cholesterol acyltransferase (ACAT) enzymes in intestinal and hepatic cholesterol metabolism has been unclear. We now demonstrate that ACAT2 is the major ACAT in mouse small intestine and liver, and suggest that ACAT2 deficiency has profound effects on cholesterol metabolism in mice fed a cholesterol-rich diet, including complete resistance to diet-induced hypercholesterolemia and cholesterol gallstone formation. The underlying mechanism involves the lack of cholesterol ester synthesis in the intestine and a resultant reduced capacity to absorb cholesterol. Our results indicate that ACAT2 has an important role in the response to dietary cholesterol, and suggest that ACAT2 inhibition may be a useful strategy for treating hypercholesterolemia or cholesterol gallstones.", + "TAG_DATA": [ + "39, ACAT2 {'perturbing_action': 'B-gene loss-of-function'}", + "40, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "48, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "39, ACAT2 ['l0', 'l1']", + "40, deficiency ['l0', 'l2']", + "48, mice ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ACAT2", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "10932233", + "TEXT": "Infectious diseases are the main cause of neonatal morbidity and mortality in humans. The World Health Organization estimated that in 1995 approximately 8 million infants died within the first year of life from infectious diseases, including 5 million during the first week of life. Some of the salient pathogens involved include herpes simplex virus, human immunodeficiency virus, hepatitis B virus, human cytomegalovirus, group B streptococcus, hemophilus and chlamydia. Infection with these pathogens usually occurs at the end of pregnancy, during birth or by breastfeeding. To reduce the risk of disease transmission, caesarian sections, prophylactic treatment with antibiotics or maternal antiviral therapy during the last trimester are used where available, together with improved neonatal care. None of these approaches, however, completely eliminates the risk of neonatal infection. Therefore, active or passive immunization of the fetus might represent an effective approach to reduce the high risk of neonatal diseases. Here, we demonstrate that a single immunization with a DNA vaccine delivered into the amniotic fluid in the oral cavity induces high serum antibody titers and a cell-mediated immune response, combined with induction of local immunity in the oral cavities of fetal lambs.", + "TAG_DATA": [ + "188, fetal {'context': 'B-organism'}", + "189, lambs. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "188, fetal ['l0']", + "189, lambs. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10742150", + "TEXT": "Infections are thought to be important in the pathogenesis of many heart diseases. Coxsackievirus B3 (CVB3) has been linked to chronic dilated cardiomyopathy, a common cause of progressive heart disease, heart failure and sudden death. We show here that the sarcoma (Src) family kinase Lck (p56lck) is required for efficient CVB3 replication in T-cell lines and for viral replication and persistence in vivo. Whereas infection of wild-type mice with human pathogenic CVB3 caused acute and very severe myocarditis, meningitis, hepatitis, pancreatitis and dilated cardiomyopathy, mice lacking the p56lck gene were completely protected from CVB3-induced acute pathogenicity and chronic heart disease. These data identify a previously unknown function of Src family kinases and indicate that p56lck is the essential host factor that controls the replication and pathogenicity of CVB3.", + "TAG_DATA": [ + "53, T-cell {'context': 'B-cells'}", + "54, lines {'context': 'I-cells'}", + "61, in {'context': 'B-in vivo'}", + "62, vivo. {'context': 'I-in vivo'}", + "67, mice {'context': 'B-organism'}", + "84, mice {'context': 'B-organism'}", + "85, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "86, the {'perturbing_action': 'I-gene loss-of-function'}", + "87, p56lck {'perturbing_action': 'I-gene loss-of-function'}", + "88, gene {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "53, T-cell ['l0', 'l1', 'l2']", + "54, lines ['l0', 'l3', 'l4']", + "61, in ['l1', 'l3', 'l5']", + "62, vivo. ['l2', 'l4', 'l5']", + "84, mice ['l6', 'l7', 'l8', 'l9']", + "85, lacking ['l6', 'l10', 'l11', 'l12']", + "86, the ['l7', 'l10', 'l13', 'l14']", + "87, p56lck ['l8', 'l11', 'l13', 'l15']", + "88, gene ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "p56lck", + "gene" + ] + } + } + ] + }, + { + "PMID": "10470078", + "TEXT": "The molecular mechanism(s) of immunoglobulin A (IgA) nephropathy, the most common primary renal glomerular disease worldwide, is unknown. Its pathologic features include hematuria, high levels of circulating IgA-fibronectin (Fn) complexes, and glomerular deposition of IgA, complement C3, Fn and collagen. We report here that two independent mouse models (gene knockout and antisense transgenic), both manifesting deficiency of an anti-inflammatory protein, uteroglobin (UG), develop almost all of the pathologic features of human IgA nephropathy. We further demonstrate that Fn-UG heteromerization, reported to prevent abnormal glomerular deposition of Fn and collagen, also abrogates both the formation of IgA-Fn complexes and their binding to glomerular cells. Moreover, UG prevents glomerular accumulation of exogenous IgA in UG-null mice. These results define an essential role for UG in preventing mouse IgA nephropathy and warrant further studies to determine if a similar mechanism(s) underlies the human disease.", + "TAG_DATA": [ + "46, mouse {'context': 'B-organism'}", + "47, models {'context': 'I-organism'}", + "49, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "101, glomerular {'context': 'B-cells'}", + "102, cells. {'context': 'I-cells'}", + "112, UG-null {'perturbing_action': 'B-gene loss-of-function'}", + "113, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "46, mouse ['l0', 'l1', 'l2']", + "47, models ['l0', 'l3', 'l4']", + "49, knockout ['l1', 'l3', 'l5', 'l6']", + "101, glomerular ['l5', 'l7']", + "102, cells. ['l2', 'l4', 'l6', 'l7']", + "112, UG-null ['l8']", + "113, mice. ['l8']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout", + "UG-null" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout" + ] + }, + "context": { + "val": "cells", + "words": [ + "glomerular", + "cells." + ] + } + } + ] + }, + { + "PMID": "10395332", + "TEXT": "Fundamental to the concept of idiopathic or primary headache, including migraine, tension-type headache and cluster headache, is the currently accepted view that these conditions are due to abnormal brain function with completely normal brain structure. Cluster headache is one such idiopathic headache with many similarities to migraine, including normal brain structure on magnetic resonance imaging and abnormal function in the hypothalamic grey matter by positron emission tomography. Given the consistency of the positron emission tomography findings with the clinical presentation, we sought to assess whether the brains of such patients were structurally normal. We used voxel-based morphometry, an objective and automated method of analyzing changes in brain structure, to study the structure of the brains of patients with cluster headache. We found a co-localization of structural changes and changes in local brain activity with positron emission tomography in the same area of the brain in the same patients. The results indicate that the current view of the neurobiology of cluster headache requires complete revision and that this periodic headache is associated with a hitherto unrecognized brain abnormality in the hypothalamic region. We believe that voxel-based morphometry has the potential to change in the most fundamental way our concept of primary headache disorders, requiring a radical reappraisal of the tenet of structural normality.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32884153", + "TEXT": "Coronavirus disease 2019 (COVID-19) in humans is often a clinically mild illness, but some individuals develop severe pneumonia, respiratory failure and death1-4. Studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in hamsters5-7 and nonhuman primates8-10 have generally reported mild clinical disease, and preclinical SARS-CoV-2 vaccine studies have demonstrated reduction of viral replication in the upper and lower respiratory tracts in nonhuman primates11-13. Here we show that high-dose intranasal SARS-CoV-2 infection in hamsters results in severe clinical disease, including high levels of virus replication in tissues, extensive pneumonia, weight loss and mortality in a subset of animals. A single immunization with an adenovirus serotype 26 vector-based vaccine expressing a stabilized SARS-CoV-2 spike protein elicited binding and neutralizing antibody responses and protected against SARS-CoV-2-induced weight loss, pneumonia and mortality. These data demonstrate vaccine protection against SARS-CoV-2 clinical disease. This model should prove useful for preclinical studies of SARS-CoV-2 vaccines, therapeutics and pathogenesis.", + "TAG_DATA": [ + "73, hamsters {'context': 'B-organism'}", + "97, animals. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, hamsters ['l0']", + "97, animals. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32807931", + "TEXT": "The global burden of diabetes is rapidly increasing, from 451 million people in 2019 to 693 million by 20451. The insidious onset of type 2 diabetes delays diagnosis and increases morbidity2. Given the multifactorial vascular effects of diabetes, we hypothesized that smartphone-based photoplethysmography could provide a widely accessible digital biomarker for diabetes. Here we developed a deep neural network (DNN) to detect prevalent diabetes using smartphone-based photoplethysmography from an initial cohort of 53,870 individuals (the 'primary cohort'), which we then validated in a separate cohort of 7,806 individuals (the 'contemporary cohort') and a cohort of 181 prospectively enrolled individuals from three clinics (the 'clinic cohort'). The DNN achieved an area under the curve for prevalent diabetes of 0.766 in the primary cohort (95% confidence interval: 0.750-0.782; sensitivity 75%, specificity 65%) and 0.740 in the contemporary cohort (95% confidence interval: 0.723-0.758; sensitivity 81%, specificity 54%). When the output of the DNN, called the DNN score, was included in a regression analysis alongside age, gender, race/ethnicity and body mass index, the area under the curve was 0.830 and the DNN score remained independently predictive of diabetes. The performance of the DNN in the clinic cohort was similar to that in other validation datasets. There was a significant and positive association between the continuous DNN score and hemoglobin A1c (P ≤ 0.001) among those with hemoglobin A1c data. These findings demonstrate that smartphone-based photoplethysmography provides a readily attainable, non-invasive digital biomarker of prevalent diabetes.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32778828", + "TEXT": "Cannabis use in pregnancy has increased1,2, and many women continue to use it throughout pregnancy3. With the legalization of recreational cannabis in many jurisdictions, there is concern about potentially adverse childhood outcomes related to prenatal exposure4. Using the provincial birth registry containing information on cannabis use during pregnancy, we perform a retrospective analysis of all live births in Ontario, Canada, between 1 April 2007 and 31 March 2012. We link pregnancy and birth data to provincial health administrative databases to ascertain child neurodevelopmental outcomes. We use matching techniques to control for confounding and Cox proportional hazards regression models to examine associations between prenatal cannabis use and child neurodevelopment. We find an association between maternal cannabis use in pregnancy and the incidence of autism spectrum disorder in the offspring. The incidence of autism spectrum disorder diagnosis was 4.00 per 1,000 person-years among children with exposure compared to 2.42 among unexposed children, and the fully adjusted hazard ratio was 1.51 (95% confidence interval: 1.17-1.96) in the matched cohort. The incidence of intellectual disability and learning disorders was higher among offspring of mothers who use cannabis in pregnancy, although less statistically robust. We emphasize a cautious interpretation of these findings given the likelihood of residual confounding.", + "TAG_DATA": [ + "138, children {'context': 'B-organism'}", + "146, children, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "138, children ['l0']", + "146, children, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32778826", + "TEXT": "The promise of precision medicine lies in data diversity. More than the sheer size of biomedical data, it is the layering of multiple data modalities, offering complementary perspectives, that is thought to enable the identification of patient subgroups with shared pathophysiology. In the present study, we use autism to test this notion. By combining healthcare claims, electronic health records, familial whole-exome sequences and neurodevelopmental gene expression patterns, we identified a subgroup of patients with dyslipidemia-associated autism.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32778825", + "TEXT": "Public health newborn screening (NBS) programs provide population-scale ascertainment of rare, treatable conditions that require urgent intervention. Tandem mass spectrometry (MS/MS) is currently used to screen newborns for a panel of rare inborn errors of metabolism (IEMs)1-4. The NBSeq project evaluated whole-exome sequencing (WES) as an innovative methodology for NBS. We obtained archived residual dried blood spots and data for nearly all IEM cases from the 4.5 million infants born in California between mid-2005 and 2013 and from some infants who screened positive by MS/MS, but were unaffected upon follow-up testing. WES had an overall sensitivity of 88% and specificity of 98.4%, compared to 99.0% and 99.8%, respectively for MS/MS, although effectiveness varied among individual IEMs. Thus, WES alone was insufficiently sensitive or specific to be a primary screen for most NBS IEMs. However, as a secondary test for infants with abnormal MS/MS screens, WES could reduce false-positive results, facilitate timely case resolution and in some instances even suggest more appropriate or specific diagnosis than that initially obtained. This study represents the largest, to date, sequencing effort of an entire population of IEM-affected cases, allowing unbiased assessment of current capabilities of WES as a tool for population screening.", + "TAG_DATA": [ + "79, infants {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32747830", + "TEXT": "Understanding the pathophysiology of SARS-CoV-2 infection is critical for therapeutic and public health strategies. Viral-host interactions can guide discovery of disease regulators, and protein structure function analysis points to several immune pathways, including complement and coagulation, as targets of coronaviruses. To determine whether conditions associated with dysregulated complement or coagulation systems impact disease, we performed a retrospective observational study and found that history of macular degeneration (a proxy for complement-activation disorders) and history of coagulation disorders (thrombocytopenia, thrombosis and hemorrhage) are risk factors for SARS-CoV-2-associated morbidity and mortality-effects that are independent of age, sex or history of smoking. Transcriptional profiling of nasopharyngeal swabs demonstrated that in addition to type-I interferon and interleukin-6-dependent inflammatory responses, infection results in robust engagement of the complement and coagulation pathways. Finally, in a candidate-driven genetic association study of severe SARS-CoV-2 disease, we identified putative complement and coagulation-associated loci including missense, eQTL and sQTL variants of critical complement and coagulation regulators. In addition to providing evidence that complement function modulates SARS-CoV-2 infection outcome, the data point to putative transcriptional genetic markers of susceptibility. The results highlight the value of using a multimodal analytical approach to reveal determinants and predictors of immunity, susceptibility and clinical outcome associated with infection.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32747828", + "TEXT": "Colonic antigen-experienced lymphocytes such as tissue-resident memory CD8+ T cells can respond rapidly to repeated antigen exposure. However, their cellular phenotypes and the mechanisms by which they drive immune regulation and inflammation remain unclear. Here we compiled an unbiased atlas of human colonic CD8+ T cells in health and ulcerative colitis (UC) using single-cell transcriptomics with T-cell receptor repertoire analysis and mass cytometry. We reveal extensive heterogeneity in CD8+ T-cell composition, including expanded effector and post-effector terminally differentiated CD8+ T cells. While UC-associated CD8+ effector T cells can trigger tissue destruction and produce tumor necrosis factor (TNF)-α, post-effector cells acquire innate signatures to adopt regulatory functions that may mitigate excessive inflammation. Thus, we identify colonic CD8+ T-cell phenotypes in health and UC, define their clonal relationships and characterize terminally differentiated dysfunctional UC CD8+ T cells expressing IL-26, which attenuate acute colitis in a humanized IL-26 transgenic mouse model.", + "TAG_DATA": [ + "94, cells {'context': 'I-cells'}", + "138, humanized {'perturbing_action': 'B-gene gain-of-function'}", + "139, IL-26 {'perturbing_action': 'I-gene gain-of-function'}", + "140, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "141, mouse {'context': 'B-organism'}", + "142, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "138, humanized ['l0', 'l1', 'l2', 'l3']", + "139, IL-26 ['l0', 'l4', 'l5', 'l6']", + "140, transgenic ['l1', 'l4', 'l7', 'l8']", + "141, mouse ['l2', 'l5', 'l7', 'l9']", + "142, model. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "humanized", + "IL-26", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model." + ] + } + } + ] + }, + { + "PMID": "32719489", + "TEXT": "CLN3 Batten disease is an autosomal recessive, neurodegenerative, lysosomal storage disease caused by mutations in CLN3, which encodes a lysosomal membrane protein1-3. There are no disease-modifying treatments for this disease that affects up to 1 in 25,000 births, has an onset of symptoms in early childhood and typically is fatal by 20-30 years of life4-7. Most patients with CLN3 Batten have a deletion encompassing exons 7 and 8 (CLN3∆ex7/8), creating a reading frameshift7,8. Here we demonstrate that mice with this deletion can be effectively treated using an antisense oligonucleotide (ASO) that induces exon skipping to restore the open reading frame. A single treatment of neonatal mice with an exon 5-targeted ASO-induced robust exon skipping for more than a year, improved motor coordination, reduced histopathology in Cln3∆ex7/8 mice and increased survival in a new mouse model of the disease. ASOs also induced exon skipping in cell lines derived from patients with CLN3 Batten disease. Our findings demonstrate the utility of ASO-based reading-frame correction as an approach to treat CLN3 Batten disease and broaden the therapeutic landscape for ASOs in the treatment of other diseases using a similar strategy.", + "TAG_DATA": [ + "77, mice {'context': 'B-organism'}", + "104, neonatal {'context': 'B-organism'}", + "105, mice {'context': 'I-organism'}", + "126, mice {'context': 'B-organism'}", + "133, mouse {'context': 'B-organism'}", + "134, model {'context': 'I-organism'}", + "144, cell {'context': 'B-cells'}", + "145, lines {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "104, neonatal ['l0', 'l1', 'l2', 'l3']", + "105, mice ['l0', 'l4', 'l5', 'l6']", + "126, mice ['l1', 'l4', 'l7']", + "133, mouse ['l2', 'l5', 'l8']", + "134, model ['l3', 'l6', 'l7', 'l8']", + "144, cell ['l9']", + "145, lines ['l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32719484", + "TEXT": "Three inherited autosomal dominant conditions-BRCA-related hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS) and familial hypercholesterolemia (FH)-have been termed the Centers for Disease Control and Prevention Tier 1 (CDCT1) genetic conditions, for which early identification and intervention have a meaningful potential for clinical actionability and a positive impact on public health1. In typical medical practice, genetic testing for these conditions is based on personal or family history, ethnic background or other demographic characteristics2. In this study of a cohort of 26,906 participants in the Healthy Nevada Project (HNP), we first evaluated whether population screening could efficiently identify carriers of these genetic conditions and, second, we evaluated the impact of genetic risk on health outcomes for these participants. We found a 1.33% combined carrier rate for pathogenic and likely pathogenic (P/LP) genetic variants for HBOC, LS and FH. Of these carriers, 21.9% of participants had clinically relevant disease, among whom 70% had been diagnosed with relevant disease before age 65. Moreover, 90% of the risk carriers had not been previously identified, and less than 19.8% of these had documentation in their medical records of inherited genetic disease risk, including family history. In a direct follow-up survey with all carriers, only 25.2% of individuals reported a family history of relevant disease. Our experience with the HNP suggests that genetic screening in patients could identify at-risk carriers, who would not be otherwise identified in routine care.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32678356", + "TEXT": "In late December 2019, a cluster of cases of pneumonia of unknown etiology were reported linked to a market in Wuhan, China1. The causative agent was identified as the species Severe acute respiratory syndrome-related coronavirus and was named SARS-CoV-2 (ref. 2). By 16 April the virus had spread to 185 different countries, infected over 2,000,000 people and resulted in over 130,000 deaths3. In the Netherlands, the first case of SARS-CoV-2 was notified on 27 February. The outbreak started with several different introductory events from Italy, Austria, Germany and France followed by local amplification in, and later also outside, the south of the Netherlands. The combination of near to real-time whole-genome sequence analysis and epidemiology resulted in reliable assessments of the extent of SARS-CoV-2 transmission in the community, facilitating early decision-making to control local transmission of SARS-CoV-2 in the Netherlands. We demonstrate how these data were generated and analyzed, and how SARS-CoV-2 whole-genome sequencing, in combination with epidemiological data, was used to inform public health decision-making in the Netherlands.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32632194", + "TEXT": "Annually, approximately 30 million patients are discharged from the emergency department (ED) after a traumatic event1. These patients are at substantial psychiatric risk, with approximately 10-20% developing one or more disorders, including anxiety, depression or post-traumatic stress disorder (PTSD)2-4. At present, no accurate method exists to predict the development of PTSD symptoms upon ED admission after trauma5. Accurate risk identification at the point of treatment by ED services is necessary to inform the targeted deployment of existing treatment6-9 to mitigate subsequent psychopathology in high-risk populations10,11. This work reports the development and validation of an algorithm for prediction of post-traumatic stress course over 12 months using two independently collected prospective cohorts of trauma survivors from two level 1 emergency trauma centers, which uses routinely collectible data from electronic medical records, along with brief clinical assessments of the patient's immediate stress reaction. Results demonstrate externally validated accuracy to discriminate PTSD risk with high precision. While the predictive algorithm yields useful reproducible results on two independent prospective cohorts of ED patients, future research should extend the generalizability to the broad, clinically heterogeneous ED population under conditions of routine medical care.", + "TAG_DATA": [ + "115, level {'context': 'B-organism'}", + "116, 1 {'context': 'I-cells'}", + "117, emergency {'context': 'I-tissue/organ'}", + "118, trauma {'context': 'I-tissue/organ'}", + "119, centers, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "115, level ['l0', 'l1', 'l2', 'l3']", + "116, 1 ['l0', 'l4', 'l5', 'l6']", + "117, emergency ['l1', 'l4', 'l7', 'l8']", + "118, trauma ['l2', 'l5', 'l7', 'l9']", + "119, centers, ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32632193", + "TEXT": "Modern lifestyles increase the risk of chronic diseases, in part by modifying the microbiome, but the health effects of lifestyles enforced on ethnic minorities are understudied1-3. Lifestyle affects the microbiome early in life, when the microbiome is assembled and the immune system is undergoing maturation4-6. Moreover, the influence of lifestyle has been separated from genetic and geographic factors by studies of genetically similar populations and ethnically distinct groups living in the same geographic location7-11. The lifestyle of Irish Travellers, an ethnically distinct subpopulation, changed with legislation in 2002 that effectively ended nomadism and altered their living conditions. Comparative metagenomics of gut microbiomes shows that Irish Travellers retain a microbiota similar to that of non-industrialized societies. Their microbiota is associated with non-dietary factors and is proportionately linked with risk of microbiome-related metabolic disease. Our findings suggest there are microbiome-related public health implications when ethnic minorities are pressured to change lifestyles.", + "TAG_DATA": [ + "77, Irish {'context': 'B-cells'}", + "78, Travellers, {'context': 'I-cells'}", + "104, Irish {'context': 'B-cells'}", + "105, Travellers {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "77, Irish ['l0', 'l1']", + "78, Travellers, ['l0', 'l2']", + "104, Irish ['l3']", + "105, Travellers ['l1', 'l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32572268", + "TEXT": "Alzheimer's disease (AD) causes unrelenting, progressive cognitive impairments, but its course is heterogeneous, with a broad range of rates of cognitive decline1. The spread of tau aggregates (neurofibrillary tangles) across the cerebral cortex parallels symptom severity2,3. We hypothesized that the kinetics of tau spread may vary if the properties of the propagating tau proteins vary across individuals. We carried out biochemical, biophysical, MS and both cell- and animal-based-bioactivity assays to characterize tau in 32 patients with AD. We found striking patient-to-patient heterogeneity in the hyperphosphorylated species of soluble, oligomeric, seed-competent tau. Tau seeding activity correlates with the aggressiveness of the clinical disease, and some post-translational modification (PTM) sites appear to be associated with both enhanced seeding activity and worse clinical outcomes, whereas others are not. These data suggest that different individuals with 'typical' AD may have distinct biochemical features of tau. These data are consistent with the possibility that individuals with AD, much like people with cancer, may have multiple molecular drivers of an otherwise common phenotype, and emphasize the potential for personalized therapeutic approaches for slowing clinical progression of AD.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32572267", + "TEXT": "The rapid increase in telemedicine coupled with recent advances in diagnostic artificial intelligence (AI) create the imperative to consider the opportunities and risks of inserting AI-based support into new paradigms of care. Here we build on recent achievements in the accuracy of image-based AI for skin cancer diagnosis to address the effects of varied representations of AI-based support across different levels of clinical expertise and multiple clinical workflows. We find that good quality AI-based support of clinical decision-making improves diagnostic accuracy over that of either AI or physicians alone, and that the least experienced clinicians gain the most from AI-based support. We further find that AI-based multiclass probabilities outperformed content-based image retrieval (CBIR) representations of AI in the mobile technology environment, and AI-based support had utility in simulations of second opinions and of telemedicine triage. In addition to demonstrating the potential benefits associated with good quality AI in the hands of non-expert clinicians, we find that faulty AI can mislead the entire spectrum of clinicians, including experts. Lastly, we show that insights derived from AI class-activation maps can inform improvements in human diagnosis. Together, our approach and findings offer a framework for future studies across the spectrum of image-based diagnostics to improve human-computer collaboration in clinical practice.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32572264", + "TEXT": "Malignant abdominal fluid (ascites) frequently develops in women with advanced high-grade serous ovarian cancer (HGSOC) and is associated with drug resistance and a poor prognosis1. To comprehensively characterize the HGSOC ascites ecosystem, we used single-cell RNA sequencing to profile ~11,000 cells from 22 ascites specimens from 11 patients with HGSOC. We found significant inter-patient variability in the composition and functional programs of ascites cells, including immunomodulatory fibroblast sub-populations and dichotomous macrophage populations. We found that the previously described immunoreactive and mesenchymal subtypes of HGSOC, which have prognostic implications, reflect the abundance of immune infiltrates and fibroblasts rather than distinct subsets of malignant cells2. Malignant cell variability was partly explained by heterogeneous copy number alteration patterns or expression of a stemness program. Malignant cells shared expression of inflammatory programs that were largely recapitulated in single-cell RNA sequencing of ~35,000 cells from additionally collected samples, including three ascites, two primary HGSOC tumors and three patient ascites-derived xenograft models. Inhibition of the JAK/STAT pathway, which was expressed in both malignant cells and cancer-associated fibroblasts, had potent anti-tumor activity in primary short-term cultures and patient-derived xenograft models. Our work contributes to resolving the HSGOC landscape3-5 and provides a resource for the development of novel therapeutic approaches.", + "TAG_DATA": [ + "152, patient {'context': 'B-xenograft'}", + "153, ascites-derived {'context': 'I-xenograft'}", + "154, xenograft {'context': 'I-xenograft'}", + "155, models. {'context': 'I-xenograft'}", + "176, primary {'context': 'B-cells'}", + "177, short-term {'context': 'I-cells'}", + "178, cultures {'context': 'I-cells'}", + "180, patient-derived {'context': 'B-xenograft'}", + "181, xenograft {'context': 'I-xenograft'}", + "182, models. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "152, patient ['l0', 'l1', 'l2']", + "153, ascites-derived ['l0', 'l3', 'l4']", + "154, xenograft ['l1', 'l3', 'l5']", + "155, models. ['l2', 'l4', 'l5']", + "176, primary ['l6', 'l7', 'l8', 'l9', 'l10']", + "177, short-term ['l6', 'l11', 'l12', 'l13', 'l14']", + "178, cultures ['l7', 'l11', 'l15', 'l16', 'l17']", + "180, patient-derived ['l8', 'l12', 'l15', 'l18', 'l19']", + "181, xenograft ['l9', 'l13', 'l16', 'l18', 'l20']", + "182, models. ['l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32546823", + "TEXT": "As of 24 April 2020, the SARS-CoV-2 epidemic has resulted in over 830,000 confirmed infections in the United States1. The incidence of COVID-19, the disease associated with this new coronavirus, continues to rise. The epidemic threatens to overwhelm healthcare systems, and identifying those regions where the disease burden is likely to be high relative to the rest of the country is critical for enabling prudent and effective distribution of emergency medical care and public health resources. Globally, the risk of severe outcomes associated with COVID-19 has consistently been observed to increase with age2,3. We used age-specific mortality patterns in tandem with demographic data to map projections of the cumulative case burden of COVID-19 and the subsequent burden on healthcare resources. The analysis was performed at the county level across the United States, assuming a scenario in which 20% of the population of each county acquires infection. We identified counties that will probably be consistently, heavily affected relative to the rest of the country across a range of assumptions about transmission patterns, such as the basic reproductive rate, contact patterns and the efficacy of quarantine. We observed a general pattern that per capita disease burden and relative healthcare system demand may be highest away from major population centers. These findings highlight the importance of ensuring equitable and adequate allocation of medical care and public health resources to communities outside of major urban areas.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32451498", + "TEXT": "The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (TFH) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of TFH cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of TFH cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1+ TFH cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC.", + "TAG_DATA": [ + "69, Suppression {'effect': 'B-negative'}", + "71, IEC {'context': 'B-cells'}", + "72, apoptosis {'phenotype': 'B-apoptosis'}", + "81, mice. {'context': 'B-organism'}", + "106, ileal {'context': 'B-cells'}", + "107, IECs {'context': 'I-cells'}", + "110, TFH {'context': 'I-cells'}", + "111, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "69, Suppression ['l0', 'l1', 'l2']", + "71, IEC ['l0', 'l3', 'l4']", + "72, apoptosis ['l1', 'l3', 'l5']", + "81, mice. ['l2', 'l4', 'l5']", + "106, ileal ['l6', 'l7', 'l8']", + "107, IECs ['l6', 'l9', 'l10']", + "110, TFH ['l7', 'l9', 'l11']", + "111, cells ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "Suppression" + ] + }, + "context": { + "val": "cells", + "words": [ + "IEC" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "Suppression" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "Suppression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "IEC" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "32451495", + "TEXT": "Programmed cell death 1 (PD-1) inhibitors have limited effect in pancreatic ductal adenocarcinoma (PDAC), underscoring the need to co-target alternative pathways. CXC chemokine receptor 4 (CXCR4) blockade promotes T cell tumor infiltration and is synergistic with anti-PD-1 therapy in PDAC mouse models. We conducted a phase IIa, open-label, two-cohort study to assess the safety, efficacy and immunobiological effects of the CXCR4 antagonist BL-8040 (motixafortide) with pembrolizumab and chemotherapy in metastatic PDAC (NCT02826486). The primary outcome was objective response rate (ORR). Secondary outcomes were overall survival (OS), disease control rate (DCR) and safety. In cohort 1, 37 patients with chemotherapy-resistant disease received BL-8040 and pembrolizumab. The DCR was 34.5% in the evaluable population (modified intention to treat, mITT; N = 29), including nine patients (31%) with stable disease and one patient (3.4%) with partial response. Median OS (mOS) was 3.3 months in the ITT population. Notably, in patients receiving study drugs as second-line therapy, the mOS was 7.5 months. BL-8040 increased CD8+ effector T cell tumor infiltration, decreased myeloid-derived suppressor cells (MDSCs) and further decreased circulating regulatory T cells. In cohort 2, 22 patients received BL-8040 and pembrolizumab with chemotherapy, with an ORR, DCR and median duration of response of 32%, 77% and 7.8 months, respectively. These data suggest that combined CXCR4 and PD-1 blockade may expand the benefit of chemotherapy in PDAC and warrants confirmation in subsequent randomized trials.", + "TAG_DATA": [ + "69, metastatic {'context': 'B-neoplasm'}", + "70, PDAC {'context': 'I-neoplasm'}", + "96, patients {'context': 'B-patient'}", + "158, CD8+ {'context': 'B-cells'}", + "159, effector {'context': 'I-cells'}", + "160, T {'context': 'I-cells'}", + "161, cell {'context': 'I-cells'}", + "165, myeloid-derived {'context': 'B-cells'}", + "166, suppressor {'context': 'I-cells'}", + "167, cells {'context': 'I-cells'}", + "168, (MDSCs) {'context': 'I-cells'}", + "172, circulating {'context': 'B-cells'}", + "173, regulatory {'context': 'I-cells'}", + "174, T {'context': 'I-cells'}", + "175, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "69, metastatic ['l0']", + "70, PDAC ['l0']", + "96, patients ['l1']", + "99, disease ['l1']", + "158, CD8+ ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "159, effector ['l2', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "160, T ['l3', 'l13', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "161, cell ['l4', 'l14', 'l23', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "165, myeloid-derived ['l5', 'l15', 'l24', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "166, suppressor ['l6', 'l16', 'l25', 'l33', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "167, cells ['l7', 'l17', 'l26', 'l34', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "168, (MDSCs) ['l8', 'l18', 'l27', 'l35', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "172, circulating ['l9', 'l19', 'l28', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "173, regulatory ['l10', 'l20', 'l29', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "174, T ['l11', 'l21', 'l30', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "175, cells. ['l12', 'l22', 'l31', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32424211", + "TEXT": "Progression to exudative 'wet' age-related macular degeneration (exAMD) is a major cause of visual deterioration. In patients diagnosed with exAMD in one eye, we introduce an artificial intelligence (AI) system to predict progression to exAMD in the second eye. By combining models based on three-dimensional (3D) optical coherence tomography images and corresponding automatic tissue maps, our system predicts conversion to exAMD within a clinically actionable 6-month time window, achieving a per-volumetric-scan sensitivity of 80% at 55% specificity, and 34% sensitivity at 90% specificity. This level of performance corresponds to true positives in 78% and 41% of individual eyes, and false positives in 56% and 17% of individual eyes at the high sensitivity and high specificity points, respectively. Moreover, we show that automatic tissue segmentation can identify anatomical changes before conversion and high-risk subgroups. This AI system overcomes substantial interobserver variability in expert predictions, performing better than five out of six experts, and demonstrates the potential of using AI to predict disease progression.", + "TAG_DATA": [ + "107, eyes {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32405064", + "TEXT": "A major gap in the Plasmodium vivax elimination toolkit is the identification of individuals carrying clinically silent and undetectable liver-stage parasites, called hypnozoites. This study developed a panel of serological exposure markers capable of classifying individuals with recent P. vivax infections who have a high likelihood of harboring hypnozoites. We measured IgG antibody responses to 342 P. vivax proteins in longitudinal clinical cohorts conducted in Thailand and Brazil and identified candidate serological markers of exposure. Candidate markers were validated using samples from year-long observational cohorts conducted in Thailand, Brazil and the Solomon Islands and antibody responses to eight P. vivax proteins classified P. vivax infections in the previous 9 months with 80% sensitivity and specificity. Mathematical models demonstrate that a serological testing and treatment strategy could reduce P. vivax prevalence by 59-69%. These eight antibody responses can serve as a biomarker, identifying individuals who should be targeted with anti-hypnozoite therapy.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32405063", + "TEXT": "Although elevated plasma interleukin-8 (pIL-8) has been associated with poor outcome to immune checkpoint blockade 1, this has not been comprehensively evaluated in large randomized studies. Here we analyzed circulating pIL-8 and IL8 gene expression in peripheral blood mononuclear cells and tumors of patients treated with atezolizumab (anti-PD-L1 monoclonal antibody) from multiple randomized trials representing 1,445 patients with metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma. High levels of IL-8 in plasma, peripheral blood mononuclear cells and tumors were associated with decreased efficacy of atezolizumab in patients with mUC and metastatic renal cell carcinoma, even in tumors that were classically CD8+ T cell inflamed. Low baseline pIL-8 in patients with mUC was associated with increased response to atezolizumab and chemotherapy. Patients with mUC who experienced on-treatment decreases in pIL-8 exhibited improved overall survival when treated with atezolizumab but not with chemotherapy. Single-cell RNA sequencing of the immune compartment showed that IL8 is primarily expressed in circulating and intratumoral myeloid cells and that high IL8 expression is associated with downregulation of the antigen-presentation machinery. Therapies that can reverse the impacts of IL-8-mediated myeloid inflammation will be essential for improving outcomes of patients treated with immune checkpoint inhibitors.", + "TAG_DATA": [ + "63, metastatic {'context': 'B-neoplasm'}", + "89, mUC {'context': 'B-neoplasm'}", + "91, metastatic {'context': 'B-neoplasm'}", + "92, renal {'context': 'I-neoplasm'}", + "93, cell {'context': 'I-neoplasm'}", + "94, carcinoma, {'context': 'I-neoplasm'}", + "97, tumors {'context': 'B-neoplasm'}", + "108, patients {'context': 'B-patient'}", + "110, mUC {'context': 'B-neoplasm'}", + "122, mUC {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "60, carcinoma ['l0', 'l1', 'l2', 'l3', 'l4']", + "63, metastatic ['l0', 'l5', 'l6', 'l7', 'l8']", + "64, renal ['l1', 'l5', 'l9', 'l10', 'l11', 'l12']", + "65, cell ['l2', 'l6', 'l9', 'l13', 'l14', 'l15']", + "66, carcinoma. ['l3', 'l7', 'l10', 'l13', 'l16']", + "89, mUC ['l4', 'l8', 'l11', 'l14', 'l16', 'l17', 'l18', 'l19', 'l20']", + "91, metastatic ['l17', 'l21', 'l22', 'l23', 'l24']", + "92, renal ['l18', 'l21', 'l25', 'l26', 'l27']", + "93, cell ['l19', 'l22', 'l25', 'l28', 'l29']", + "94, carcinoma, ['l12', 'l15', 'l20', 'l23', 'l26', 'l28', 'l30']", + "97, tumors ['l24', 'l27', 'l29', 'l30', 'l31', 'l32']", + "108, patients ['l31', 'l33']", + "110, mUC ['l32', 'l33']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32393804", + "TEXT": "A total of 2,618,862 participants reported their potential symptoms of COVID-19 on a smartphone-based app. Among the 18,401 who had undergone a SARS-CoV-2 test, the proportion of participants who reported loss of smell and taste was higher in those with a positive test result (4,668 of 7,178 individuals; 65.03%) than in those with a negative test result (2,436 of 11,223 participants; 21.71%) (odds ratio = 6.74; 95% confidence interval = 6.31-7.21). A model combining symptoms to predict probable infection was applied to the data from all app users who reported symptoms (805,753) and predicted that 140,312 (17.42%) participants are likely to have COVID-19.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32367062", + "TEXT": "A surge in mental-health problems related to the COVID-19 pandemic is on the horizon. The time to prepare and prevent another health-crisis wave is now.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32313249", + "TEXT": "A double burden of malnutrition occurs when individuals, household members or communities experience both undernutrition and overweight. Here, we show geospatial estimates of overweight and wasting prevalence among children under 5 years of age in 105 low- and middle-income countries (LMICs) from 2000 to 2017 and aggregate these to policy-relevant administrative units. Wasting decreased overall across LMICs between 2000 and 2017, from 8.4% (62.3 (55.1-70.8) million) to 6.4% (58.3 (47.6-70.7) million), but is predicted to remain above the World Health Organization's Global Nutrition Target of <5% in over half of LMICs by 2025. Prevalence of overweight increased from 5.2% (30 (22.8-38.5) million) in 2000 to 6.0% (55.5 (44.8-67.9) million) children aged under 5 years in 2017. Areas most affected by double burden of malnutrition were located in Indonesia, Thailand, southeastern China, Botswana, Cameroon and central Nigeria. Our estimates provide a new perspective to researchers, policy makers and public health agencies in their efforts to address this global childhood syndemic.", + "TAG_DATA": [ + "109, children {'context': 'B-patient'}", + "110, aged {'context': 'I-organism'}", + "111, under {'context': 'I-organism'}", + "112, 5 {'context': 'I-organism'}", + "113, years {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "109, children ['l0', 'l1', 'l2', 'l3']", + "110, aged ['l0', 'l4', 'l5', 'l6']", + "111, under ['l1', 'l4', 'l7', 'l8']", + "112, 5 ['l2', 'l5', 'l7', 'l9']", + "113, years ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32284618", + "TEXT": "The past decade has allowed the development of a multitude of digital tools. Now they can be used to remediate the COVID-19 outbreak.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32284616", + "TEXT": "As of 29 February 2020 there were 79,394 confirmed cases and 2,838 deaths from COVID-19 in mainland China. Of these, 48,557 cases and 2,169 deaths occurred in the epicenter, Wuhan. A key public health priority during the emergence of a novel pathogen is estimating clinical severity, which requires properly adjusting for the case ascertainment rate and the delay between symptoms onset and death. Using public and published information, we estimate that the overall symptomatic case fatality risk (the probability of dying after developing symptoms) of COVID-19 in Wuhan was 1.4% (0.9-2.1%), which is substantially lower than both the corresponding crude or naïve confirmed case fatality risk (2,169/48,557 = 4.5%) and the approximator1 of deaths/deaths + recoveries (2,169/2,169 + 17,572 = 11%) as of 29 February 2020. Compared to those aged 30-59 years, those aged below 30 and above 59 years were 0.6 (0.3-1.1) and 5.1 (4.2-6.1) times more likely to die after developing symptoms. The risk of symptomatic infection increased with age (for example, at ~4% per year among adults aged 30-60 years).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32284611", + "TEXT": "The primary human immunodeficiency virus (HIV) reservoir is composed of resting memory CD4+ T cells, which often express the immune checkpoint receptors programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which limit T cell activation via synergistic mechanisms. Using simian immunodeficiency virus (SIV)-infected, long-term antiretroviral therapy (ART)-treated rhesus macaques, we demonstrate that PD-1, CTLA-4 and dual CTLA-4/PD-1 immune checkpoint blockade using monoclonal antibodies is well tolerated, with evidence of bioactivity in blood and lymph nodes. Dual blockade was remarkably more effective than PD-1 blockade alone in enhancing T cell cycling and differentiation, expanding effector-memory T cells and inducing robust viral reactivation in plasma and peripheral blood mononuclear cells. In lymph nodes, dual CTLA-4/PD-1 blockade, but not PD-1 alone, decreased the total and intact SIV-DNA in CD4+ T cells, and SIV-DNA and SIV-RNA in B cell follicles, a major site of viral persistence during ART. None of the tested interventions enhanced SIV-specific CD8+ T cell responses during ART or viral control after ART interruption. Thus, despite CTLA-4/PD-1 blockade inducing robust latency reversal and reducing total levels of integrated virus, the degree of reservoir clearance was still insufficient to achieve viral control. These results suggest that immune checkpoint blockade regimens targeting PD-1 and/or CTLA-4, if performed in people living with HIV with sustained aviremia, are unlikely to induce HIV remission in the absence of additional interventions.", + "TAG_DATA": [ + "52, rhesus {'context': 'B-organism'}", + "53, macaques, {'context': 'I-organism'}", + "91, enhancing {'effect': 'B-positive'}", + "92, T {'context': 'B-cells'}", + "93, cell {'context': 'B-cells'}", + "96, differentiation, {'phenotype': 'B-differentiation'}", + "98, effector-memory {'context': 'B-cells'}", + "99, T {'context': 'I-cells'}", + "100, cells {'context': 'I-cells'}", + "109, peripheral {'context': 'B-cells'}", + "110, blood {'context': 'I-cells'}", + "111, mononuclear {'context': 'I-cells'}", + "112, cells. {'context': 'I-cells'}", + "114, lymph {'context': 'B-tissue/organ'}", + "115, nodes, {'context': 'I-tissue/organ'}", + "130, CD4+ {'context': 'B-cells'}", + "131, T {'context': 'I-cells'}", + "132, cells, {'context': 'I-cells'}", + "138, B {'context': 'B-cells'}", + "139, cell {'context': 'I-cells'}", + "140, follicles, {'context': 'I-cells'}", + "156, CD8+ {'context': 'B-cells'}", + "157, T {'context': 'I-cells'}", + "158, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "52, rhesus ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "53, macaques, ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "91, enhancing ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "92, T ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "93, cell ['l3', 'l10', 'l16', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "96, differentiation, ['l4', 'l11', 'l17', 'l22', 'l30', 'l36', 'l37', 'l38']", + "98, effector-memory ['l23', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "99, T ['l5', 'l12', 'l18', 'l24', 'l32', 'l36', 'l39', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "100, cells ['l6', 'l13', 'l19', 'l25', 'l33', 'l37', 'l40', 'l53', 'l60', 'l61', 'l62', 'l63']", + "109, peripheral ['l26', 'l41', 'l54', 'l60', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "110, blood ['l27', 'l34', 'l42', 'l55', 'l61', 'l64', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "111, mononuclear ['l28', 'l43', 'l56', 'l62', 'l65', 'l75', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "112, cells. ['l7', 'l14', 'l20', 'l29', 'l35', 'l38', 'l44', 'l57', 'l63', 'l66', 'l76', 'l85', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "114, lymph ['l45', 'l67', 'l77', 'l86', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "115, nodes, ['l46', 'l68', 'l78', 'l87', 'l94', 'l101', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "130, CD4+ ['l47', 'l69', 'l79', 'l88', 'l95', 'l102', 'l108', 'l114', 'l115', 'l116', 'l117', 'l118']", + "131, T ['l48', 'l58', 'l70', 'l80', 'l89', 'l96', 'l103', 'l109', 'l114', 'l119', 'l120', 'l121', 'l122']", + "132, cells, ['l49', 'l59', 'l71', 'l81', 'l90', 'l97', 'l104', 'l110', 'l115', 'l119', 'l123', 'l124', 'l125']", + "138, B ['l50', 'l72', 'l82', 'l91', 'l98', 'l105', 'l111', 'l116', 'l120', 'l123', 'l126', 'l127']", + "139, cell ['l51', 'l73', 'l83', 'l92', 'l99', 'l106', 'l112', 'l117', 'l121', 'l124', 'l126', 'l128']", + "140, follicles, ['l52', 'l74', 'l84', 'l93', 'l100', 'l107', 'l113', 'l118', 'l122', 'l125', 'l127', 'l128']", + "156, CD8+ ['l129', 'l130']", + "157, T ['l129', 'l131']", + "158, cell ['l130', 'l131']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "rhesus", + "macaques," + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhancing" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rhesus", + "macaques," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhancing" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell", + "cells", + "cells." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhancing" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cell", + "cells", + "cells." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + } + ] + }, + { + "PMID": "32284589", + "TEXT": "Among the most urgent public health threats is the worldwide emergence of carbapenem-resistant Enterobacteriaceae1-4, which are resistant to the antibiotic class of 'last resort'. In the United States and Europe, carbapenem-resistant strains of the Klebsiella pneumoniae ST258 (ref. 5) sequence type are dominant, endemic6-8 and associated with high mortality6,9,10. We report the global evolution of pathogenicity in carbapenem-resistant K. pneumoniae, resulting in the repeated convergence of virulence and carbapenem resistance in the United States and Europe, dating back to as early as 2009. We demonstrate that K. pneumoniae can enhance its pathogenicity by adopting two opposing infection programs through easily acquired gain- and loss-of-function mutations. Single-nucleotide polymorphisms in the capsule biosynthesis gene wzc lead to hypercapsule production, which confers phagocytosis resistance, enhanced dissemination and increased mortality in animal models. In contrast, mutations disrupting capsule biosynthesis genes impair capsule production, which enhances epithelial cell invasion, in vitro biofilm formation and persistence in urinary tract infections. These two types of capsule mutants have emerged repeatedly and independently in Europe and the United States, with hypercapsule mutants associated with bloodstream infections and capsule-deficient mutants associated with urinary tract infections. In the latter case, drug-tolerant K. pneumoniae can persist to yield potentially untreatable, persistent infection.", + "TAG_DATA": [ + "107, in {'perturbing_action': 'I-other'}", + "108, the {'perturbing_action': 'I-other'}", + "109, capsule {'perturbing_action': 'I-other'}", + "110, biosynthesis {'perturbing_action': 'I-other'}", + "111, gene {'perturbing_action': 'I-other'}", + "112, wzc {'perturbing_action': 'I-other'}", + "127, animal {'context': 'B-organism'}", + "128, models. {'context': 'I-organism'}", + "131, mutations {'perturbing_action': 'B-other'}", + "132, disrupting {'perturbing_action': 'I-other'}", + "133, capsule {'perturbing_action': 'I-other'}", + "134, biosynthesis {'perturbing_action': 'I-other'}", + "135, genes {'perturbing_action': 'I-other'}", + "140, enhances {'effect': 'B-positive'}", + "141, epithelial {'context': 'B-cells'}", + "142, cell {'context': 'I-cells'}", + "143, invasion, {'phenotype': 'B-invasion'}", + "144, in {'context': 'B-in vitro'}", + "145, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "107, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "108, the ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "109, capsule ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "110, biosynthesis ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "111, gene ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "112, wzc ['l4', 'l17', 'l29', 'l40', 'l50', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "127, animal ['l5', 'l18', 'l30', 'l41', 'l51', 'l60', 'l68', 'l69', 'l70']", + "128, models. ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l68', 'l71']", + "131, mutations ['l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "132, disrupting ['l72', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "133, capsule ['l73', 'l82', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "134, biosynthesis ['l74', 'l83', 'l91', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "135, genes ['l7', 'l20', 'l32', 'l43', 'l53', 'l75', 'l84', 'l92', 'l99', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "140, enhances ['l8', 'l21', 'l33', 'l44', 'l54', 'l62', 'l76', 'l85', 'l93', 'l100', 'l106', 'l112', 'l113', 'l114', 'l115', 'l116']", + "141, epithelial ['l9', 'l22', 'l34', 'l45', 'l55', 'l63', 'l77', 'l86', 'l94', 'l101', 'l107', 'l112', 'l117', 'l118', 'l119', 'l120']", + "142, cell ['l10', 'l23', 'l35', 'l46', 'l56', 'l64', 'l69', 'l71', 'l78', 'l87', 'l95', 'l102', 'l108', 'l113', 'l117', 'l121', 'l122', 'l123']", + "143, invasion, ['l11', 'l24', 'l36', 'l47', 'l57', 'l65', 'l70', 'l79', 'l88', 'l96', 'l103', 'l109', 'l114', 'l118', 'l121', 'l124', 'l125']", + "144, in ['l12', 'l25', 'l37', 'l48', 'l58', 'l66', 'l80', 'l89', 'l97', 'l104', 'l110', 'l115', 'l119', 'l122', 'l124', 'l126']", + "145, vitro ['l13', 'l26', 'l38', 'l49', 'l59', 'l67', 'l81', 'l90', 'l98', 'l105', 'l111', 'l116', 'l120', 'l123', 'l125', 'l126']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "in", + "the", + "capsule", + "biosynthesis", + "gene", + "wzc" + ] + }, + "context": { + "val": "organism", + "words": [ + "animal", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "in", + "the", + "capsule", + "biosynthesis", + "gene", + "wzc", + "mutations", + "disrupting", + "genes" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "in", + "the", + "capsule", + "biosynthesis", + "gene", + "wzc", + "mutations", + "disrupting", + "genes" + ] + }, + "context": { + "val": "cells", + "words": [ + "epithelial", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "in", + "the", + "capsule", + "biosynthesis", + "gene", + "wzc", + "mutations", + "disrupting", + "genes" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "in", + "the", + "capsule", + "biosynthesis", + "gene", + "wzc", + "mutations", + "disrupting", + "genes" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animal" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "context": { + "val": "cells", + "words": [ + "epithelial", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "epithelial", + "cell" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion," + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "32161411", + "TEXT": "Standard clinical care in neonatal and pediatric intensive-care units (NICUs and PICUs, respectively) involves continuous monitoring of vital signs with hard-wired devices that adhere to the skin and, in certain instances, can involve catheter-based pressure sensors inserted into the arteries. These systems entail risks of causing iatrogenic skin injuries, complicating clinical care and impeding skin-to-skin contact between parent and child. Here we present a wireless, non-invasive technology that not only offers measurement equivalency to existing clinical standards for heart rate, respiration rate, temperature and blood oxygenation, but also provides a range of important additional features, as supported by data from pilot clinical studies in both the NICU and PICU. These new modalities include tracking movements and body orientation, quantifying the physiological benefits of skin-to-skin care, capturing acoustic signatures of cardiac activity, recording vocal biomarkers associated with tonality and temporal characteristics of crying and monitoring a reliable surrogate for systolic blood pressure. These platforms have the potential to substantially enhance the quality of neonatal and pediatric critical care.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32152585", + "TEXT": "A compounding factor of the outbreak is the potential for the general public to misunderstand the facts and design conspiracy theories.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32152582", + "TEXT": "Electrocardiogram (ECG) acquisition is increasingly widespread in medical and commercial devices, necessitating the development of automated interpretation strategies. Recently, deep neural networks have been used to automatically analyze ECG tracings and outperform physicians in detecting certain rhythm irregularities1. However, deep learning classifiers are susceptible to adversarial examples, which are created from raw data to fool the classifier such that it assigns the example to the wrong class, but which are undetectable to the human eye2,3. Adversarial examples have also been created for medical-related tasks4,5. However, traditional attack methods to create adversarial examples do not extend directly to ECG signals, as such methods introduce square-wave artefacts that are not physiologically plausible. Here we develop a method to construct smoothed adversarial examples for ECG tracings that are invisible to human expert evaluation and show that a deep learning model for arrhythmia detection from single-lead ECG6 is vulnerable to this type of attack. Moreover, we provide a general technique for collating and perturbing known adversarial examples to create multiple new ones. The susceptibility of deep learning ECG algorithms to adversarial misclassification implies that care should be taken when evaluating these models on ECGs that may have been altered, particularly when incentives for causing misclassification exist.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32123385", + "TEXT": "Plasma phosphorylated tau181 (P-tau181) might be increased in Alzheimer's disease (AD), but its usefulness for differential diagnosis and prognosis is unclear. We studied plasma P-tau181 in three cohorts, with a total of 589 individuals, including cognitively unimpaired participants and patients with mild cognitive impairment (MCI), AD dementia and non-AD neurodegenerative diseases. Plasma P-tau181 was increased in preclinical AD and further increased at the MCI and dementia stages. It correlated with CSF P-tau181 and predicted positive Tau positron emission tomography (PET) scans (area under the curve (AUC) = 0.87-0.91 for different brain regions). Plasma P-tau181 differentiated AD dementia from non-AD neurodegenerative diseases with an accuracy similar to that of Tau PET and CSF P-tau181 (AUC = 0.94-0.98), and detected AD neuropathology in an autopsy-confirmed cohort. High plasma P-tau181 was associated with subsequent development of AD dementia in cognitively unimpaired and MCI subjects. In conclusion, plasma P-tau181 is a noninvasive diagnostic and prognostic biomarker of AD, which may be useful in clinical practice and trials.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32094927", + "TEXT": "Responses to vaccination and to diseases vary widely across individuals, which may be partly due to baseline immune variations. Identifying such baseline predictors of immune responses and their biological basis is of broad interest, given their potential importance for cancer immunotherapy, disease outcomes, vaccination and infection responses. Here we uncover baseline blood transcriptional signatures predictive of antibody responses to both influenza and yellow fever vaccinations in healthy subjects. These same signatures evaluated at clinical quiescence are correlated with disease activity in patients with systemic lupus erythematosus with plasmablast-associated flares. CITE-seq profiling of 82 surface proteins and transcriptomes of 53,201 single cells from healthy high and low influenza vaccination responders revealed that our signatures reflect the extent of activation in a plasmacytoid dendritic cell-type I IFN-T/B lymphocyte network. Our findings raise the prospect that modulating such immune baseline states may improve vaccine responsiveness and mitigate undesirable autoimmune disease activity.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32094926", + "TEXT": "Mucosal immunity develops in the human fetal intestine by 11-14 weeks of gestation, yet whether viable microbes exist in utero and interact with the intestinal immune system is unknown. Bacteria-like morphology was identified in pockets of human fetal meconium at mid-gestation by scanning electron microscopy (n = 4), and a sparse bacterial signal was detected by 16S rRNA sequencing (n = 40 of 50) compared to environmental controls (n = 87). Eighteen taxa were enriched in fetal meconium, with Micrococcaceae (n = 9) and Lactobacillus (n = 6) the most abundant. Fetal intestines dominated by Micrococcaceae exhibited distinct patterns of T cell composition and epithelial transcription. Fetal Micrococcus luteus, isolated only in the presence of monocytes, grew on placental hormones, remained viable within antigen presenting cells, limited inflammation ex vivo and possessed genomic features linked with survival in the fetus. Thus, viable bacteria are highly limited in the fetal intestine at mid-gestation, although strains with immunomodulatory capacity are detected in subsets of specimens.", + "TAG_DATA": [ + "113, antigen {'context': 'B-cells'}", + "114, presenting {'context': 'I-cells'}", + "115, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "113, antigen ['l0', 'l1']", + "114, presenting ['l0', 'l2']", + "115, cells, ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "32015560", + "TEXT": "As the outbreak of a deadly new coronavirus in China and its rapid spread is rattling countries, only the collective international experience and advances derived from past outbreaks can accelerate its control.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "32015556", + "TEXT": "Combination antiretroviral therapy (ART) is highly effective in controlling human immunodeficiency virus (HIV)-1 but requires lifelong medication due to the existence of a latent viral reservoir1,2. Potent broadly neutralizing antibodies (bNAbs) represent a potential alternative or adjuvant to ART. In addition to suppressing viremia, bNAbs may have T cell immunomodulatory effects as seen for other forms of immunotherapy3. However, this has not been established in individuals who are infected with HIV-1. Here, we document increased HIV-1 Gag-specific CD8+ T cell responses in the peripheral blood of all nine study participants who were infected with HIV-1 with suppressed blood viremia, while receiving bNAb therapy during ART interruption4. Increased CD4+ T cell responses were detected in eight individuals. The increased T cell responses were due both to newly detectable reactivity to HIV-1 Gag epitopes and the expansion of pre-existing measurable responses. These data demonstrate that bNAb therapy during ART interruption is associated with enhanced HIV-1-specific T cell responses. Whether these augmented T cell responses can contribute to bNAb-mediated viral control remains to be determined.", + "TAG_DATA": [ + "118, T {'context': 'B-cells'}", + "119, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "118, T ['l0']", + "119, cell ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31988464", + "TEXT": "The strengthening of the Chinese Center for Disease Control and Prevention has been a turning point in outbreak responses in the area. This represents very welcome progress and development for global health security and diplomacy.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31988462", + "TEXT": "Frameshift mutations in the DMD gene, encoding dystrophin, cause Duchenne muscular dystrophy (DMD), leading to terminal muscle and heart failure in patients. Somatic gene editing by sequence-specific nucleases offers new options for restoring the DMD reading frame, resulting in expression of a shortened but largely functional dystrophin protein. Here, we validated this approach in a pig model of DMD lacking exon 52 of DMD (DMDΔ52), as well as in a corresponding patient-derived induced pluripotent stem cell model. In DMDΔ52 pigs1, intramuscular injection of adeno-associated viral vectors of serotype 9 carrying an intein-split Cas9 (ref. 2) and a pair of guide RNAs targeting sequences flanking exon 51 (AAV9-Cas9-gE51) induced expression of a shortened dystrophin (DMDΔ51-52) and improved skeletal muscle function. Moreover, systemic application of AAV9-Cas9-gE51 led to widespread dystrophin expression in muscle, including diaphragm and heart, prolonging survival and reducing arrhythmogenic vulnerability. Similarly, in induced pluripotent stem cell-derived myoblasts and cardiomyocytes of a patient lacking DMDΔ52, AAV6-Cas9-g51-mediated excision of exon 51 restored dystrophin expression and amelioreate skeletal myotube formation as well as abnormal cardiomyocyte Ca2+ handling and arrhythmogenic susceptibility. The ability of Cas9-mediated exon excision to improve DMD pathology in these translational models paves the way for new treatment approaches in patients with this devastating disease.", + "TAG_DATA": [ + "55, pig {'context': 'B-organism'}", + "56, model {'context': 'I-organism'}", + "72, induced {'context': 'I-cells'}", + "73, pluripotent {'context': 'I-cells'}", + "74, stem {'context': 'I-cells'}", + "75, cell {'context': 'I-cells'}", + "76, model. {'context': 'I-cells'}", + "116, skeletal {'context': 'B-tissue/organ'}", + "117, muscle {'context': 'I-tissue/organ'}", + "143, induced {'context': 'B-cells'}", + "144, pluripotent {'context': 'I-cells'}", + "145, stem {'context': 'I-cells'}", + "146, cell-derived {'context': 'I-cells'}", + "147, myoblasts {'context': 'I-cells'}", + "149, cardiomyocytes {'context': 'B-cells'}", + "152, patient {'context': 'B-patient'}", + "153, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "154, DMDΔ52, {'perturbing_action': 'I-gene loss-of-function'}", + "155, AAV6-Cas9-g51-mediated {'perturbing_action': 'B-gene loss-of-function'}", + "156, excision {'perturbing_action': 'I-gene loss-of-function'}", + "157, of {'perturbing_action': 'I-gene loss-of-function'}", + "158, exon {'perturbing_action': 'I-gene loss-of-function'}", + "159, 51 {'perturbing_action': 'I-gene loss-of-function'}", + "164, amelioreate {'effect': 'B-negative'}", + "165, skeletal {'context': 'B-tissue/organ'}", + "166, myotube {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "55, pig ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "56, model ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "71, patient-derived ['l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "72, induced ['l1', 'l8', 'l14', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "73, pluripotent ['l2', 'l15', 'l22', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "74, stem ['l3', 'l9', 'l16', 'l23', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "75, cell ['l4', 'l10', 'l17', 'l24', 'l30', 'l35', 'l40', 'l41', 'l42']", + "76, model. ['l5', 'l11', 'l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l44']", + "116, skeletal ['l6', 'l12', 'l19', 'l26', 'l32', 'l37', 'l41', 'l43', 'l45', 'l46']", + "117, muscle ['l7', 'l13', 'l20', 'l27', 'l33', 'l38', 'l42', 'l44', 'l45']", + "130, muscle, ['l21', 'l28', 'l34', 'l39', 'l46']", + "143, induced ['l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "144, pluripotent ['l47', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "145, stem ['l48', 'l55', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "146, cell-derived ['l49', 'l56', 'l62', 'l68', 'l69', 'l70', 'l71', 'l72']", + "147, myoblasts ['l50', 'l57', 'l63', 'l68', 'l73', 'l74', 'l75', 'l76']", + "149, cardiomyocytes ['l51', 'l58', 'l64', 'l69', 'l73', 'l77', 'l78', 'l79']", + "152, patient ['l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l80', 'l81', 'l82', 'l83', 'l84']", + "153, lacking ['l53', 'l60', 'l66', 'l71', 'l75', 'l78', 'l80', 'l85', 'l86', 'l87', 'l88']", + "154, DMDΔ52, ['l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l81', 'l85', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "155, AAV6-Cas9-g51-mediated ['l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "156, excision ['l95', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "157, of ['l89', 'l96', 'l102', 'l108', 'l109', 'l110', 'l111', 'l112']", + "158, exon ['l90', 'l97', 'l103', 'l108', 'l113', 'l114', 'l115', 'l116']", + "159, 51 ['l91', 'l98', 'l104', 'l109', 'l113', 'l117', 'l118', 'l119']", + "164, amelioreate ['l82', 'l86', 'l92', 'l99', 'l105', 'l110', 'l114', 'l117', 'l120', 'l121']", + "165, skeletal ['l83', 'l87', 'l93', 'l100', 'l106', 'l111', 'l115', 'l118', 'l120', 'l122']", + "166, myotube ['l84', 'l88', 'l94', 'l101', 'l107', 'l112', 'l116', 'l119', 'l121', 'l122']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "induced", + "pluripotent", + "stem", + "cell-derived", + "myoblasts", + "cardiomyocytes", + "myotube" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "DMDΔ52,", + "AAV6-Cas9-g51-mediated", + "excision", + "of", + "exon", + "51" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patient" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "DMDΔ52," + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "amelioreate" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "DMDΔ52,", + "AAV6-Cas9-g51-mediated", + "excision", + "of", + "exon", + "51" + ] + }, + "effect": { + "val": "negative", + "words": [ + "amelioreate" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "DMDΔ52,", + "AAV6-Cas9-g51-mediated", + "excision", + "of", + "exon", + "51" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skeletal" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "amelioreate" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skeletal" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "amelioreate" + ] + }, + "context": { + "val": "cells", + "words": [ + "myotube" + ] + } + } + ] + }, + { + "PMID": "31959990", + "TEXT": "Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) is a potentially fatal multiorgan inflammatory disease associated with herpesvirus reactivation and subsequent onset of autoimmune diseases1-4. Pathophysiology remains elusive and therapeutic options are limited. Cases refractory to corticosteroid therapy pose a clinical challenge1,5 and approximately 30% of patients with DiHS/DRESS develop complications, including infections and inflammatory and autoimmune diseases1,2,5. Progress in single-cell RNA sequencing (scRNA-seq) provides an opportunity to dissect human disease pathophysiology at unprecedented resolutions6, particularly in diseases lacking animal models, such as DiHS/DRESS. We performed scRNA-seq on skin and blood from a patient with refractory DiHS/DRESS, identifying the JAK-STAT signaling pathway as a potential target. We further showed that central memory CD4+ T cells were enriched with DNA from human herpesvirus 6b. Intervention via tofacitinib enabled disease control and tapering of other immunosuppressive agents. Tofacitinib, as well as antiviral agents, suppressed culprit-induced T cell proliferation in vitro, further supporting the roles of the JAK-STAT pathway and herpesviruses in mediating the adverse drug reaction. Thus, scRNA-seq analyses guided successful therapeutic intervention in the patient with refractory DiHS/DRESS. scRNA-seq may improve our understanding of complicated human disease pathophysiology and provide an alternative approach in personalized medicine.", + "TAG_DATA": [ + "112, central {'context': 'B-cells'}", + "113, memory {'context': 'I-cells'}", + "114, CD4+ {'context': 'I-cells'}", + "115, T {'context': 'I-cells'}", + "116, cells {'context': 'I-cells'}", + "143, suppressed {'effect': 'B-negative'}", + "145, T {'context': 'B-cells'}", + "146, cell {'context': 'B-cells'}", + "147, proliferation {'phenotype': 'B-proliferation'}", + "148, in {'context': 'B-in vitro'}", + "149, vitro, {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "112, central ['l0', 'l1', 'l2', 'l3']", + "113, memory ['l0', 'l4', 'l5', 'l6']", + "114, CD4+ ['l1', 'l4', 'l7', 'l8']", + "115, T ['l2', 'l5', 'l7', 'l9']", + "116, cells ['l3', 'l6', 'l8', 'l9']", + "143, suppressed ['l10', 'l11', 'l12', 'l13', 'l14']", + "145, T ['l10', 'l15', 'l16', 'l17', 'l18']", + "146, cell ['l11', 'l15', 'l19', 'l20', 'l21']", + "147, proliferation ['l12', 'l16', 'l19', 'l22', 'l23']", + "148, in ['l13', 'l17', 'l20', 'l22', 'l24']", + "149, vitro, ['l14', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + } + ] + }, + { + "PMID": "31932797", + "TEXT": "Glia have been implicated in Alzheimer's disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscovered Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.", + "TAG_DATA": [ + "112, Astrocyte {'context': 'B-cells'}", + "125, microglia {'context': 'B-cells'}", + "130, TREM2-R47H {'perturbing_action': 'B-other'}", + "132, TREM2-R62H {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "112, Astrocyte ['l0', 'l1', 'l2']", + "125, microglia ['l0', 'l3', 'l4', 'l5']", + "130, TREM2-R47H ['l1', 'l3', 'l6', 'l7']", + "132, TREM2-R62H ['l4', 'l6', 'l8']", + "133, carriers ['l2', 'l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Astrocyte", + "microglia" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "TREM2-R47H", + "TREM2-R62H" + ] + } + } + ] + }, + { + "PMID": "31932788", + "TEXT": "Socioeconomic factors influence brain development and structure, but most studies have overlooked neurotoxic insults that impair development, such as lead exposure. Childhood lead exposure affects cognitive development at the lowest measurable concentrations, but little is known about its impact on brain development during childhood. We examined cross-sectional associations among brain structure, cognition, geocoded measures of the risk of lead exposure and sociodemographic characteristics in 9,712 9- and 10-year-old children. Here we show stronger negative associations of living in high-lead-risk census tracts in children from lower- versus higher-income families. With increasing risk of exposure, children from lower-income families exhibited lower cognitive test scores, smaller cortical volume and smaller cortical surface area. Reducing environmental insults associated with lead-exposure risk might confer greater benefit to children experiencing more environmental adversity, and further understanding of the factors associated with high lead-exposure risk will be critical for improving such outcomes in children.", + "TAG_DATA": [ + "68, children. {'context': 'I-organism'}", + "82, children {'context': 'B-organism'}", + "93, children {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31792461", + "TEXT": "B-cell lymphoma extra large (BCL-XL) is a well-validated cancer target. However, the on-target and dose-limiting thrombocytopenia limits the use of BCL-XL inhibitors, such as ABT263, as safe and effective anticancer agents. To reduce the toxicity of ABT263, we converted it into DT2216, a BCL-XL proteolysis-targeting chimera (PROTAC), that targets BCL-XL to the Von Hippel-Lindau (VHL) E3 ligase for degradation. We found that DT2216 was more potent against various BCL-XL-dependent leukemia and cancer cells but considerably less toxic to platelets than ABT263 in vitro because VHL is poorly expressed in platelets. In vivo, DT2216 effectively inhibits the growth of several xenograft tumors as a single agent or in combination with other chemotherapeutic agents, without causing appreciable thrombocytopenia. These findings demonstrate the potential to use PROTAC technology to reduce on-target drug toxicities and rescue the therapeutic potential of previously undruggable targets. Furthermore, DT2216 may be developed as a safe first-in-class anticancer agent targeting BCL-XL.", + "TAG_DATA": [ + "68, BCL-XL-dependent {'context': 'B-neoplasm'}", + "69, leukemia {'context': 'I-transformed cells'}", + "70, and {'context': 'I-transformed cells'}", + "71, cancer {'context': 'I-transformed cells'}", + "72, cells {'context': 'I-transformed cells'}", + "78, platelets {'context': 'B-cells'}", + "81, in {'context': 'B-in vitro'}", + "82, vitro {'context': 'I-in vitro'}", + "90, In {'context': 'B-in vivo'}", + "91, vivo, {'context': 'I-in vivo'}", + "99, xenograft {'context': 'B-xenograft'}", + "100, tumors {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "68, BCL-XL-dependent ['l0', 'l1', 'l2', 'l3']", + "69, leukemia ['l0', 'l4', 'l5', 'l6']", + "70, and ['l1', 'l4', 'l7', 'l8']", + "71, cancer ['l2', 'l5', 'l7', 'l9']", + "72, cells ['l3', 'l6', 'l8', 'l9']", + "78, platelets ['l10', 'l11']", + "81, in ['l10', 'l12']", + "82, vitro ['l11', 'l12']", + "90, In ['l13', 'l14', 'l15']", + "91, vivo, ['l13', 'l16', 'l17']", + "99, xenograft ['l14', 'l16', 'l18']", + "100, tumors ['l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31792460", + "TEXT": "Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.", + "TAG_DATA": [ + "30, patients {'context': 'B-patient'}", + "31, with {'context': 'I-patient'}", + "32, melanoma {'context': 'B-neoplasm'}", + "45, tumors. {'context': 'B-neoplasm'}", + "95, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "30, patients ['l0', 'l1', 'l2']", + "31, with ['l0', 'l3', 'l4']", + "32, melanoma ['l1', 'l3', 'l5']", + "45, tumors. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31792454", + "TEXT": "Biomarkers for monitoring of disease progression and response to therapy are lacking for muscle diseases such as Duchenne muscular dystrophy. Noninvasive in vivo molecular imaging with multispectral optoacoustic tomography (MSOT) uses pulsed laser light to induce acoustic pressure waves, enabling the visualization of endogenous chromophores. Here we describe an application of MSOT, in which illumination in the near- and extended near-infrared ranges from 680-1,100 nm enables the visualization and quantification of collagen content. We first demonstrated the feasibility of this approach to noninvasive quantification of tissue fibrosis in longitudinal studies in a large-animal Duchenne muscular dystrophy model in pigs, and then applied this approach to pediatric patients. MSOT-derived collagen content measurements in skeletal muscle were highly correlated to the functional status of the patients and provided additional information on molecular features as compared to magnetic resonance imaging. This study highlights the potential of MSOT imaging as a noninvasive, age-independent biomarker for the implementation and monitoring of newly developed therapies in muscular diseases.", + "TAG_DATA": [ + "97, pigs, {'context': 'B-organism'}", + "111, skeletal {'context': 'B-tissue/organ'}", + "112, muscle {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "93, muscular ['l0', 'l1', 'l2']", + "94, dystrophy ['l0', 'l3', 'l4']", + "95, model ['l1', 'l3', 'l5']", + "97, pigs, ['l2', 'l4', 'l5']", + "111, skeletal ['l6']", + "112, muscle ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31700187", + "TEXT": "Millions of people worldwide with incurable end-stage lung disease die because of inadequate treatment options and limited availability of donor organs for lung transplantation1. Current bioengineering strategies to regenerate the lung have not been able to replicate its extraordinary cellular diversity and complex three-dimensional arrangement, which are indispensable for life-sustaining gas exchange2,3. Here we report the successful generation of functional lungs in mice through a conditional blastocyst complementation (CBC) approach that vacates a specific niche in chimeric hosts and allows for initiation of organogenesis by donor mouse pluripotent stem cells (PSCs). We show that wild-type donor PSCs rescued lung formation in genetically defective recipient mouse embryos unable to specify (due to Ctnnb1cnull mutation) or expand (due to Fgfr2cnull mutation) early respiratory endodermal progenitors. Rescued neonates survived into adulthood and had lungs functionally indistinguishable from those of wild-type littermates. Efficient chimera formation and lung complementation required newly developed culture conditions that maintained the developmental potential of the donor PSCs and were associated with global DNA hypomethylation and increased H4 histone acetylation. These results pave the way for the development of new strategies for generating lungs in large animals to enable modeling of human lung disease as well as cell-based therapeutic interventions4-6.", + "TAG_DATA": [ + "62, mice {'context': 'B-organism'}", + "97, rescued {'effect': 'B-rescues'}", + "98, lung {'context': 'B-tissue/organ'}", + "103, recipient {'context': 'B-organism'}", + "104, mouse {'context': 'I-organism'}", + "105, embryos {'context': 'I-organism'}", + "116, to {'perturbing_action': 'I-other'}", + "117, Fgfr2cnull {'perturbing_action': 'I-other'}", + "118, mutation) {'perturbing_action': 'I-other'}", + "124, neonates {'context': 'B-organism'}", + "130, lungs {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "97, rescued ['l0']", + "98, lung ['l0']", + "103, recipient ['l1', 'l2', 'l3', 'l4', 'l5']", + "104, mouse ['l1', 'l6', 'l7', 'l8', 'l9']", + "105, embryos ['l2', 'l6', 'l10', 'l11', 'l12']", + "116, to ['l3', 'l7', 'l10', 'l13', 'l14', 'l15']", + "117, Fgfr2cnull ['l4', 'l8', 'l11', 'l13', 'l16', 'l17']", + "118, mutation) ['l5', 'l9', 'l12', 'l14', 'l16', 'l18']", + "124, neonates ['l15', 'l17', 'l18', 'l19']", + "130, lungs ['l19']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "recipient", + "mouse", + "embryos", + "neonates" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "to", + "Fgfr2cnull", + "mutation)" + ] + } + } + ] + }, + { + "PMID": "31700184", + "TEXT": "A sedentary lifestyle, chronic inflammation and leukocytosis increase atherosclerosis; however, it remains unclear whether regular physical activity influences leukocyte production. Here we show that voluntary running decreases hematopoietic activity in mice. Exercise protects mice and humans with atherosclerosis from chronic leukocytosis but does not compromise emergency hematopoiesis in mice. Mechanistically, exercise diminishes leptin production in adipose tissue, augmenting quiescence-promoting hematopoietic niche factors in leptin-receptor-positive stromal bone marrow cells. Induced deletion of the leptin receptor in Prrx1-creERT2; Leprfl/fl mice reveals that leptin's effect on bone marrow niche cells regulates hematopoietic stem and progenitor cell (HSPC) proliferation and leukocyte production, as well as cardiovascular inflammation and outcomes. Whereas running wheel withdrawal quickly reverses leptin levels, the impact of exercise on leukocyte production and on the HSPC epigenome and transcriptome persists for several weeks. Together, these data show that physical activity alters HSPCs via modulation of their niche, reducing hematopoietic output of inflammatory leukocytes.", + "TAG_DATA": [ + "30, mice. {'context': 'B-organism'}", + "48, mice. {'context': 'B-organism'}", + "55, adipose {'context': 'B-tissue/organ'}", + "56, tissue, {'context': 'I-tissue/organ'}", + "63, leptin-receptor-positive {'context': 'B-cells'}", + "64, stromal {'context': 'I-cells'}", + "65, bone {'context': 'I-cells'}", + "66, marrow {'context': 'I-cells'}", + "67, cells. {'context': 'I-cells'}", + "68, Induced {'perturbing_action': 'B-gene loss-of-function'}", + "69, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "70, of {'perturbing_action': 'I-gene loss-of-function'}", + "71, the {'perturbing_action': 'I-gene loss-of-function'}", + "72, leptin {'perturbing_action': 'I-gene loss-of-function'}", + "73, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "75, Prrx1-creERT2; {'perturbing_action': 'B-gene loss-of-function'}", + "76, Leprfl/fl {'perturbing_action': 'B-gene loss-of-function'}", + "77, mice {'context': 'B-organism'}", + "87, regulates {'effect': 'B-regulates'}", + "88, hematopoietic {'context': 'B-cells'}", + "89, stem {'context': 'I-cells'}", + "90, and {'context': 'I-cells'}", + "91, progenitor {'context': 'I-cells'}", + "92, cell {'context': 'I-cells'}", + "93, (HSPC) {'context': 'I-cells'}", + "94, proliferation {'phenotype': 'B-proliferation'}", + "96, leukocyte {'context': 'B-cells'}", + "118, leukocyte {'context': 'B-cells'}", + "123, HSPC {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "30, mice. ['l0', 'l1', 'l2']", + "48, mice. ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "55, adipose ['l0', 'l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "56, tissue, ['l1', 'l4', 'l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "63, leptin-receptor-positive ['l5', 'l11', 'l16', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "64, stromal ['l6', 'l12', 'l17', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "65, bone ['l7', 'l13', 'l18', 'l22', 'l28', 'l34', 'l35', 'l36', 'l37']", + "66, marrow ['l8', 'l14', 'l19', 'l23', 'l29', 'l34', 'l38', 'l39', 'l40']", + "67, cells. ['l2', 'l9', 'l15', 'l20', 'l24', 'l30', 'l35', 'l38']", + "68, Induced ['l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "69, deletion ['l41', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "70, of ['l42', 'l58', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "71, the ['l43', 'l59', 'l74', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "72, leptin ['l44', 'l60', 'l75', 'l89', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "73, receptor ['l45', 'l61', 'l76', 'l90', 'l103', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127']", + "75, Prrx1-creERT2; ['l46', 'l62', 'l77', 'l91', 'l104', 'l116', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "76, Leprfl/fl ['l47', 'l63', 'l78', 'l92', 'l105', 'l117', 'l128', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "77, mice ['l48', 'l64', 'l79', 'l93', 'l106', 'l118', 'l129', 'l139', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "87, regulates ['l25', 'l31', 'l49', 'l65', 'l80', 'l94', 'l107', 'l119', 'l130', 'l140', 'l149', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "88, hematopoietic ['l50', 'l66', 'l81', 'l95', 'l108', 'l120', 'l131', 'l141', 'l150', 'l158', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "89, stem ['l51', 'l67', 'l82', 'l96', 'l109', 'l121', 'l132', 'l142', 'l151', 'l159', 'l166', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "90, and ['l52', 'l68', 'l83', 'l97', 'l110', 'l122', 'l133', 'l143', 'l152', 'l160', 'l167', 'l173', 'l179', 'l180', 'l181', 'l182', 'l183']", + "91, progenitor ['l53', 'l69', 'l84', 'l98', 'l111', 'l123', 'l134', 'l144', 'l153', 'l161', 'l168', 'l174', 'l179', 'l184', 'l185', 'l186', 'l187']", + "92, cell ['l26', 'l32', 'l36', 'l39', 'l54', 'l70', 'l85', 'l99', 'l112', 'l124', 'l135', 'l145', 'l154', 'l162', 'l169', 'l175', 'l180', 'l184', 'l188', 'l189', 'l190']", + "93, (HSPC) ['l55', 'l71', 'l86', 'l100', 'l113', 'l125', 'l136', 'l146', 'l155', 'l163', 'l170', 'l176', 'l181', 'l185', 'l188', 'l191', 'l192']", + "94, proliferation ['l27', 'l33', 'l37', 'l40', 'l56', 'l72', 'l87', 'l101', 'l114', 'l126', 'l137', 'l147', 'l156', 'l164', 'l171', 'l177', 'l182', 'l186', 'l189', 'l191', 'l193']", + "96, leukocyte ['l57', 'l73', 'l88', 'l102', 'l115', 'l127', 'l138', 'l148', 'l157', 'l165', 'l172', 'l178', 'l183', 'l187', 'l190', 'l192', 'l193']", + "118, leukocyte ['l194']", + "123, HSPC ['l194']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "leptin-receptor-positive", + "stromal", + "hematopoietic", + "stem", + "and", + "progenitor", + "cell", + "(HSPC)", + "leukocyte" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "regulates" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "leptin-receptor-positive", + "stromal", + "bone", + "marrow", + "hematopoietic", + "stem", + "and", + "progenitor", + "cell", + "(HSPC)", + "leukocyte" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Induced", + "deletion", + "of", + "the", + "leptin", + "receptor", + "Prrx1-creERT2;", + "Leprfl/fl" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Induced", + "deletion", + "of", + "the", + "leptin", + "receptor", + "Prrx1-creERT2;", + "Leprfl/fl" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "regulates" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Induced", + "deletion", + "of", + "the", + "leptin", + "receptor", + "Prrx1-creERT2;", + "Leprfl/fl" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "and", + "progenitor", + "cell", + "(HSPC)", + "leukocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Induced", + "deletion", + "of", + "the", + "leptin", + "receptor", + "Prrx1-creERT2;", + "Leprfl/fl" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "regulates" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "regulates" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "31700175", + "TEXT": "Proinflammatory cytokines in the tumor microenvironment can promote tumor growth, yet their value as therapeutic targets remains underexploited. We validated the functional significance of the cardiotrophin-like cytokine factor 1 (CLCF1)-ciliary neurotrophic factor receptor (CNTFR) signaling axis in lung adenocarcinoma (LUAD) and generated a high-affinity soluble receptor (eCNTFR-Fc) that sequesters CLCF1, thereby inhibiting its oncogenic effects. eCNTFR-Fc inhibits tumor growth in multiple xenograft models and in an autochthonous, highly aggressive genetically engineered mouse model of LUAD, driven by activation of oncogenic Kras and loss of Trp53. Abrogation of CLCF1 through eCNTFR-Fc appears most effective in tumors driven by oncogenic KRAS. We observed a correlation between the effectiveness of eCNTFR-Fc and the presence of KRAS mutations that retain the intrinsic capacity to hydrolyze guanosine triphosphate, suggesting that the mechanism of action may be related to altered guanosine triphosphate loading. Overall, we nominate blockade of CLCF1-CNTFR signaling as a novel therapeutic opportunity for LUAD and potentially for other tumor types in which CLCF1 is present in the tumor microenvironment.", + "TAG_DATA": [ + "56, inhibits {'effect': 'B-negative'}", + "57, tumor {'phenotype': 'B-tumour growth'}", + "58, growth {'phenotype': 'I-tumour growth'}", + "61, xenograft {'context': 'B-xenograft'}", + "62, models {'context': 'I-xenograft'}", + "70, engineered {'context': 'I-organism'}", + "71, mouse {'context': 'B-neoplasm'}", + "72, model {'context': 'I-neoplasm'}", + "73, of {'context': 'I-neoplasm'}", + "74, LUAD, {'context': 'I-neoplasm'}", + "82, loss {'perturbing_action': 'B-gene loss-of-function'}", + "83, of {'perturbing_action': 'I-gene loss-of-function'}", + "84, Trp53. {'perturbing_action': 'I-gene loss-of-function'}", + "94, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "56, inhibits ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "57, tumor ['l0', 'l6', 'l7', 'l8']", + "58, growth ['l1', 'l6', 'l9', 'l10']", + "61, xenograft ['l2', 'l7', 'l9', 'l11']", + "62, models ['l3', 'l8', 'l10', 'l11']", + "69, genetically ['l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "70, engineered ['l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "71, mouse ['l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "72, model ['l14', 'l23', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "73, of ['l15', 'l24', 'l32', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "74, LUAD, ['l4', 'l16', 'l25', 'l33', 'l40', 'l46', 'l52', 'l53', 'l54', 'l55', 'l56']", + "77, activation ['l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l57', 'l58', 'l59', 'l60']", + "80, Kras ['l5', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l61', 'l62', 'l63']", + "82, loss ['l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l64', 'l65']", + "83, of ['l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l66']", + "84, Trp53. ['l21', 'l30', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l65', 'l66']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "models" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "LUAD," + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "models" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "engineered" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Trp53." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "LUAD," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Trp53." + ] + } + } + ] + }, + { + "PMID": "31686035", + "TEXT": "Although chromosomal instability (CIN) is a common phenomenon in cleavage-stage embryogenesis following in vitro fertilization (IVF)1-3, its rate in naturally conceived human embryos is unknown. CIN leads to mosaic embryos that contain a combination of genetically normal and abnormal cells, and is significantly higher in in vitro-produced preimplantation embryos as compared to in vivo-conceived preimplantation embryos4. Even though embryos with CIN-derived complex aneuploidies may arrest between the cleavage and blastocyst stages of embryogenesis5,6, a high number of embryos containing abnormal cells can pass this strong selection barrier7,8. However, neither the prevalence nor extent of CIN during prenatal development and at birth, following IVF treatment, is well understood. Here we profiled the genomic landscape of fetal and placental tissues postpartum from both IVF and naturally conceived children, to investigate the prevalence and persistence of large genetic aberrations that probably arose from IVF-related CIN. We demonstrate that CIN is not preserved at later stages of prenatal development, and that de novo numerical aberrations or large structural DNA imbalances occur at similar rates in IVF and naturally conceived live-born neonates. Our findings affirm that human IVF treatment has no detrimental effect on the chromosomal constitution of fetal and placental lineages.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31591603", + "TEXT": "Atherosclerosis is driven by multifaceted contributions of the immune system within the circulation and at vascular focal sites. However, specific characteristics of dysregulated immune cells within atherosclerotic lesions that lead to clinical events such as ischemic stroke or myocardial infarction are poorly understood. Here, using single-cell proteomic and transcriptomic analyses, we uncovered distinct features of both T cells and macrophages in carotid artery plaques of patients with clinically symptomatic disease (recent stroke or transient ischemic attack) compared to asymptomatic disease (no recent stroke). Plaques from symptomatic patients were characterized by a distinct subset of CD4+ T cells and by T cells that were activated and differentiated. Moreover, some T cell subsets in these plaques presented markers of T cell exhaustion. Additionally, macrophages from these plaques contained alternatively activated phenotypes, including subsets associated with plaque vulnerability. In plaques from asymptomatic patients, T cells and macrophages were activated and displayed evidence of interleukin-1β signaling. The identification of specific features of innate and adaptive immune cells in plaques that are associated with cerebrovascular events may enable the design of more precisely tailored cardiovascular immunotherapies.", + "TAG_DATA": [ + "99, T {'context': 'B-cells'}", + "100, cells {'context': 'B-cells'}", + "108, T {'context': 'B-cells'}", + "109, cell {'context': 'B-cells'}", + "121, macrophages {'context': 'B-cells'}", + "140, T {'context': 'B-cells'}", + "141, cells {'context': 'B-cells'}", + "143, macrophages {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "99, T ['l0']", + "100, cells ['l0']", + "108, T ['l1']", + "109, cell ['l1']", + "121, macrophages ['l2']", + "140, T ['l3', 'l4']", + "141, cells ['l2', 'l3', 'l5']", + "143, macrophages ['l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31591594", + "TEXT": "The ability to expand hematopoietic stem and progenitor cells (HSPCs) ex vivo is critical to fully realize the potential of HSPC-based therapies. In particular, the application of clinically effective therapies, such as cord blood transplantation, has been impeded because of limited HSPC availability. Here, using 3D culture of human HSPCs in a degradable zwitterionic hydrogel, we achieved substantial expansion of phenotypically primitive CD34+ cord blood and bone-marrow-derived HSPCs. This culture system led to a 73-fold increase in long-term hematopoietic stem cell (LT-HSC) frequency, as demonstrated by limiting dilution assays, and the expanded HSPCs were capable of hematopoietic reconstitution for at least 24 weeks in immunocompromised mice. Both the zwitterionic characteristics of the hydrogel and the 3D format were important for HSPC self-renewal. Mechanistically, the impact of 3D zwitterionic hydrogel culture on mitigating HSPC differentiation and promoting self-renewal might result from an inhibition of excessive reactive oxygen species (ROS) production via suppression of O2-related metabolism. HSPC expansion using zwitterionic hydrogels has the potential to facilitate the clinical application of hematopoietic-stem-cell therapies.", + "TAG_DATA": [ + "45, 3D {'context': 'B-in vitro'}", + "46, culture {'context': 'I-in vitro'}", + "48, human {'context': 'B-cells'}", + "49, HSPCs {'context': 'I-cells'}", + "62, CD34+ {'context': 'B-cells'}", + "63, cord {'context': 'I-cells'}", + "64, blood {'context': 'I-cells'}", + "66, bone-marrow-derived {'context': 'B-cells'}", + "67, HSPCs. {'context': 'I-cells'}", + "92, HSPCs {'context': 'B-cells'}", + "105, mice. {'context': 'I-organism'}", + "120, HSPC {'context': 'B-cells'}", + "121, self-renewal. {'phenotype': 'B-self-renewal'}", + "132, HSPC {'context': 'B-cells'}", + "135, promoting {'effect': 'B-positive'}", + "136, self-renewal {'phenotype': 'B-self-renewal'}" + ], + "LINK_DATA": [ + "45, 3D ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "46, culture ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "48, human ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "49, HSPCs ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "62, CD34+ ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "63, cord ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "64, blood ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "66, bone-marrow-derived ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "67, HSPCs. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "92, HSPCs ['l36']", + "105, mice. ['l36']", + "120, HSPC ['l37', 'l38', 'l39']", + "121, self-renewal. ['l37']", + "132, HSPC ['l38', 'l40', 'l41']", + "135, promoting ['l39', 'l40', 'l42']", + "136, self-renewal ['l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "HSPC" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal.", + "self-renewal" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSPC" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal" + ] + } + } + ] + }, + { + "PMID": "31591589", + "TEXT": "Malignant mesothelioma (MM) is an aggressive cancer primarily diagnosed on the basis of histological criteria1. The 2015 World Health Organization classification subdivides mesothelioma tumors into three histological types: epithelioid, biphasic and sarcomatoid MM. MM is a highly complex and heterogeneous disease, rendering its diagnosis and histological typing difficult and leading to suboptimal patient care and decisions regarding treatment modalities2. Here we have developed a new approach-based on deep convolutional neural networks-called MesoNet to accurately predict the overall survival of mesothelioma patients from whole-slide digitized images, without any pathologist-provided locally annotated regions. We validated MesoNet on both an internal validation cohort from the French MESOBANK and an independent cohort from The Cancer Genome Atlas (TCGA). We also demonstrated that the model was more accurate in predicting patient survival than using current pathology practices. Furthermore, unlike classical black-box deep learning methods, MesoNet identified regions contributing to patient outcome prediction. Strikingly, we found that these regions are mainly located in the stroma and are histological features associated with inflammation, cellular diversity and vacuolization. These findings suggest that deep learning models can identify new features predictive of patient survival and potentially lead to new biomarker discoveries.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31501611", + "TEXT": "Visceral adipose tissue (VAT)-fat stored around the internal organs-has been suggested as an independent risk factor for cardiovascular and metabolic disease1-3, as well as all-cause, cardiovascular-specific and cancer-specific mortality4,5. Yet, the contribution of genetics to VAT, as well as its disease-related effects, are largely unexplored due to the requirement for advanced imaging technologies to accurately measure VAT. Here, we develop sex-stratified, nonlinear prediction models (coefficient of determination = 0.76; typical 95% confidence interval (CI) = 0.74-0.78) for VAT mass using the UK Biobank cohort. We performed a genome-wide association study for predicted VAT mass and identified 102 novel visceral adiposity loci. Predicted VAT mass was associated with increased risk of hypertension, heart attack/angina, type 2 diabetes and hyperlipidemia, and Mendelian randomization analysis showed visceral fat to be a causal risk factor for all four diseases. In particular, a large difference in causal effect between the sexes was found for type 2 diabetes, with an odds ratio of 7.34 (95% CI = 4.48-12.0) in females and an odds ratio of 2.50 (95% CI = 1.98-3.14) in males. Our findings bolster the role of visceral adiposity as a potentially independent risk factor, in particular for type 2 diabetes in Caucasian females. Independent validation in other cohorts is necessary to determine whether the findings can translate to other ethnicities, or outside the UK.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31477907", + "TEXT": "Our understanding of how the gut microbiome interacts with its human host has been restrained by limited access to longitudinal datasets to examine stability and dynamics, and by having only a few isolates to test mechanistic hypotheses. Here, we present the Broad Institute-OpenBiome Microbiome Library (BIO-ML), a comprehensive collection of 7,758 gut bacterial isolates paired with 3,632 genome sequences and longitudinal multi-omics data. We show that microbial species maintain stable population sizes within and across humans and that commonly used 'omics' survey methods are more reliable when using averages over multiple days of sampling. Variation of gut metabolites within people over time is associated with amino acid levels, and differences across people are associated with differences in bile acids. Finally, we show that genomic diversification can be used to infer eco-evolutionary dynamics and in vivo selection pressures for strains within individuals. The BIO-ML is a unique resource designed to enable hypothesis-driven microbiome research.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31332391", + "TEXT": "Cytokine dysregulation is a central driver of chronic inflammatory diseases such as multiple sclerosis (MS). Here, we sought to determine the characteristic cellular and cytokine polarization profile in patients with relapsing-remitting multiple sclerosis (RRMS) by high-dimensional single-cell mass cytometry (CyTOF). Using a combination of neural network-based representation learning algorithms, we identified an expanded T helper cell subset in patients with MS, characterized by the expression of granulocyte-macrophage colony-stimulating factor and the C-X-C chemokine receptor type 4. This cellular signature, which includes expression of very late antigen 4 in peripheral blood, was also enriched in the central nervous system of patients with relapsing-remitting multiple sclerosis. In independent validation cohorts, we confirmed that this cell population is increased in patients with MS compared with other inflammatory and non-inflammatory conditions. Lastly, we also found the population to be reduced under effective disease-modifying therapy, suggesting that the identified T cell profile represents a specific therapeutic target in MS.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31332389", + "TEXT": "The gut microbiome is emerging as a key regulator of several metabolic, immune and neuroendocrine pathways1,2. Gut microbiome deregulation has been implicated in major conditions such as obesity, type 2 diabetes, cardiovascular disease, non-alcoholic fatty acid liver disease and cancer3-6, but its precise role in aging remains to be elucidated. Here, we find that two different mouse models of progeria are characterized by intestinal dysbiosis with alterations that include an increase in the abundance of Proteobacteria and Cyanobacteria, and a decrease in the abundance of Verrucomicrobia. Consistent with these findings, we found that human progeria patients also display intestinal dysbiosis and that long-lived humans (that is, centenarians) exhibit a substantial increase in Verrucomicrobia and a reduction in Proteobacteria. Fecal microbiota transplantation from wild-type mice enhanced healthspan and lifespan in both progeroid mouse models, and transplantation with the verrucomicrobia Akkermansia muciniphila was sufficient to exert beneficial effects. Moreover, metabolomic analysis of ileal content points to the restoration of secondary bile acids as a possible mechanism for the beneficial effects of reestablishing a healthy microbiome. Our results demonstrate that correction of the accelerated aging-associated intestinal dysbiosis is beneficial, suggesting the existence of a link between aging and the gut microbiota that provides a rationale for microbiome-based interventions against age-related diseases.", + "TAG_DATA": [ + "123, mice {'context': 'B-organism'}", + "130, progeroid {'context': 'B-organism'}", + "131, mouse {'context': 'I-organism'}", + "132, models, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "123, mice ['l0']", + "130, progeroid ['l1', 'l2']", + "131, mouse ['l1', 'l3']", + "132, models, ['l0', 'l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31285631", + "TEXT": "We report neurodevelopmental outcomes in 216 infants followed since the time of PCR-confirmed maternal Zika virus (ZIKV) infection in pregnancy during the Rio de Janeiro epidemic of 2015-2016 (refs. 1,2). Neurodevelopment was assessed by Bayley Scales of Infant and Toddler Development, third edition (Bayley-III; cognitive, language and motor domains) in 146 children and through neurodevelopment questionnaires/neurological examinations in 70 remaining children. Complete eye exams (n = 137) and hearing assessments (n = 114) were also performed. Below-average neurodevelopment and/or abnormal eye or hearing assessments were noted in 31.5% of children between 7 and 32 months of age. Among children assessed by Bayley-III, 12% scored below -2 s.d. (score <70; a score of 100 ± 2 s.d. is the range) in at least one domain; and 28% scored between -1 and -2 s.d. in any domain (scores <85-70). Language function was most affected, with 35% of 146 children below average. Improved neurodevelopmental outcomes were noted in female children, term babies, children with normal eye exams and maternal infection later in pregnancy (P = 0.01). We noted resolution of microcephaly with normal neurodevelopment in two of eight children, development of secondary microcephaly in two other children and autism spectrum disorder in three previously healthy children in the second year of life.", + "TAG_DATA": [ + "140, female {'context': 'B-organism'}", + "141, children, {'context': 'I-organism'}", + "143, babies, {'context': 'I-organism'}", + "144, children {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "140, female ['l0', 'l1', 'l2']", + "141, children, ['l0', 'l3', 'l4']", + "143, babies, ['l1', 'l3', 'l5']", + "144, children ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31263285", + "TEXT": "Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin gene (HTT), which codes for the pathologic mutant HTT (mHTT) protein. Since normal HTT is thought to be important for brain function, we engineered zinc finger protein transcription factors (ZFP-TFs) to target the pathogenic CAG repeat and selectively lower mHTT as a therapeutic strategy. Using patient-derived fibroblasts and neurons, we demonstrate that ZFP-TFs selectively repress >99% of HD-causing alleles over a wide dose range while preserving expression of >86% of normal alleles. Other CAG-containing genes are minimally affected, and virally delivered ZFP-TFs are active and well tolerated in HD neurons beyond 100 days in culture and for at least nine months in the mouse brain. Using three HD mouse models, we demonstrate improvements in a range of molecular, histopathological, electrophysiological and functional endpoints. Our findings support the continued development of an allele-selective ZFP-TF for the treatment of HD.", + "TAG_DATA": [ + "63, patient-derived {'context': 'B-cells'}", + "64, fibroblasts {'context': 'I-cells'}", + "66, neurons, {'context': 'B-cells'}", + "104, HD {'context': 'B-cells'}", + "105, neurons {'context': 'I-cells'}", + "118, mouse {'context': 'B-tissue/organ'}", + "119, brain. {'context': 'I-tissue/organ'}", + "122, HD {'context': 'B-organism'}", + "123, mouse {'context': 'I-organism'}", + "124, models, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "63, patient-derived ['l0', 'l1']", + "64, fibroblasts ['l0', 'l2']", + "66, neurons, ['l1', 'l2']", + "104, HD ['l3', 'l4', 'l5']", + "105, neurons ['l3', 'l6']", + "118, mouse ['l4', 'l7']", + "119, brain. ['l5', 'l6', 'l7']", + "122, HD ['l8', 'l9']", + "123, mouse ['l8', 'l10']", + "124, models, ['l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31263283", + "TEXT": "Clinical studies of Parkinson's disease (PD) using a dopamine cell replacment strategy have been tried for more than 30 years. The outcomes following transplantation of human fetal ventral mesencephalic tissue (hfVM) have been variable, with some patients coming off their anti-PD treatment for many years and others not responding and/or developing significant side effects, including graft-induced dyskinesia. This led to a re-appraisal of the best way to do such trials, which resulted in a new European-Union-funded allograft trial with fetal dopamine cells across several centers in Europe. This new trial, TRANSEURO ( NCT01898390 ), is an open-label study in which some individuals in a large observational cohort of patients with mild PD who were undergoing identical assessments were randomly selected to receive transplants of hfVM. The TRANSEURO trial is currently ongoing as researchers have completed both recruitment into a large multicenter observational study of younger onset early-stage PD and transplantation of hfVM in 11 patients. While completion of TRANSEURO is not expected until 2021, we feel that sharing the rationale for the design of TRANSEURO, along with the lessons we have learned along the way, can help inform researchers and facilitate planning of transplants of dopamine-producing cells derived from human pluripotent stem cells for future clinical trials.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31235962", + "TEXT": "The role of dysbiosis in food allergy (FA) remains unclear. We found that dysbiotic fecal microbiota in FA infants evolved compositionally over time and failed to protect against FA in mice. Infants and mice with FA had decreased IgA and increased IgE binding to fecal bacteria, indicative of a broader breakdown of oral tolerance than hitherto appreciated. Therapy with Clostridiales species impacted by dysbiosis, either as a consortium or as monotherapy with Subdoligranulum variabile, suppressed FA in mice as did a separate immunomodulatory Bacteroidales consortium. Bacteriotherapy induced expression by regulatory T (Treg) cells of the transcription factor ROR-γt in a MyD88-dependent manner, which was deficient in FA infants and mice and ineffectively induced by their microbiota. Deletion of Myd88 or Rorc in Treg cells abrogated protection by bacteriotherapy. Thus, commensals activate a MyD88/ROR-γt pathway in nascent Treg cells to protect against FA, while dysbiosis impairs this regulatory response to promote disease.", + "TAG_DATA": [ + "33, mice {'context': 'B-organism'}", + "77, mice {'context': 'B-organism'}", + "89, regulatory T {'context': 'B-cells'}", + "90, (Treg) {'context': 'I-cells'}", + "91, cells {'context': 'I-cells'}", + "108, mice {'context': 'B-organism'}", + "115, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "116, of {'perturbing_action': 'I-gene loss-of-function'}", + "117, Myd88 {'perturbing_action': 'I-gene loss-of-function'}", + "118, or {'perturbing_action': 'I-gene loss-of-function'}", + "119, Rorc {'perturbing_action': 'I-gene loss-of-function'}", + "121, Treg {'context': 'B-cells'}", + "122, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "89, regulatory T ['l0', 'l1', 'l2']", + "90, (Treg) ['l0', 'l3', 'l4']", + "91, cells ['l1', 'l3', 'l5']", + "108, mice ['l2', 'l4', 'l5']", + "115, Deletion ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "116, of ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "117, Myd88 ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "118, or ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "119, Rorc ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "121, Treg ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "122, cells ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "Myd88", + "or", + "Rorc" + ] + }, + "context": { + "val": "cells", + "words": [ + "Treg", + "cells" + ] + } + } + ] + }, + { + "PMID": "31222179", + "TEXT": "In the version of this article originally published, there was an error in the abstract. The word disease should not have been included in the sentence \"These individuals were highly exposed to Mtb but tested negative disease by IFN-γ release assay and tuberculin skin test, 'resisting' development of classic LTBI\". The sentence should have been \"These individuals were highly exposed to Mtb but tested negative by IFN-γ release assay and tuberculin skin test, 'resisting' development of classic LTBI.\" The error has been corrected in the HTML and PDF versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31209337", + "TEXT": "In the version of this article originally published, there was an error in Fig. 3j. A label on the heatmap read \"TGF-α signaling via NF-κB\". It should have read \"TNF-α signaling via NF-κB\". The error has been corrected in the HTML and PDF versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31209336", + "TEXT": "Human lungs enable efficient gas exchange and form an interface with the environment, which depends on mucosal immunity for protection against infectious agents. Tightly controlled interactions between structural and immune cells are required to maintain lung homeostasis. Here, we use single-cell transcriptomics to chart the cellular landscape of upper and lower airways and lung parenchyma in healthy lungs, and lower airways in asthmatic lungs. We report location-dependent airway epithelial cell states and a novel subset of tissue-resident memory T cells. In the lower airways of patients with asthma, mucous cell hyperplasia is shown to stem from a novel mucous ciliated cell state, as well as goblet cell hyperplasia. We report the presence of pathogenic effector type 2 helper T cells (TH2) in asthmatic lungs and find evidence for type 2 cytokines in maintaining the altered epithelial cell states. Unbiased analysis of cell-cell interactions identifies a shift from airway structural cell communication in healthy lungs to a TH2-dominated interactome in asthmatic lungs.", + "TAG_DATA": [ + "118, T {'context': 'I-cells'}", + "119, cells {'context': 'I-cells'}", + "123, lungs {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "118, T ['l0', 'l1']", + "119, cells ['l0', 'l2']", + "123, lungs ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31160818", + "TEXT": "Influenza viruses remain a severe threat to human health, causing up to 650,000 deaths annually1,2. Seasonal influenza virus vaccines can prevent infection, but are rendered ineffective by antigenic drift. To provide improved protection from infection, novel influenza virus vaccines that target the conserved epitopes of influenza viruses, specifically those in the hemagglutinin stalk and neuraminidase, are currently being developed3. Antibodies against the hemagglutinin stalk confer protection in animal studies4-6. However, no data exist on natural infections in humans, and these antibodies do not show activity in the hemagglutination inhibition assay, the hemagglutination inhibition titer being the current correlate of protection against influenza virus infection7-9. While previous studies have investigated the protective effect of cellular immune responses and neuraminidase-inhibiting antibodies, additional serological correlates of protection from infection could aid the development of broadly protective or universal influenza virus vaccines10-13. To address this gap, we performed a household transmission study to identify alternative correlates of protection from infection and disease in naturally exposed individuals. Using this study, we determined 50% protective titers and levels for hemagglutination inhibition, full-length hemagglutinin, neuraminidase and hemagglutinin stalk-specific antibodies. Further, we found that hemagglutinin stalk antibodies independently correlated with protection from influenza virus infection.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31160815", + "TEXT": "Microsatellite instability determines whether patients with gastrointestinal cancer respond exceptionally well to immunotherapy. However, in clinical practice, not every patient is tested for MSI, because this requires additional genetic or immunohistochemical tests. Here we show that deep residual learning can predict MSI directly from H&E histology, which is ubiquitously available. This approach has the potential to provide immunotherapy to a much broader subset of patients with gastrointestinal cancer.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31110348", + "TEXT": "Exposure to Mycobacterium tuberculosis (Mtb) results in heterogeneous clinical outcomes including primary progressive tuberculosis and latent Mtb infection (LTBI). Mtb infection is identified using the tuberculin skin test and interferon-γ (IFN-γ) release assay IGRA, and a positive result may prompt chemoprophylaxis to prevent progression to tuberculosis. In the present study, we report on a cohort of Ugandan individuals who were household contacts of patients with TB. These individuals were highly exposed to Mtb but tested negative disease by IFN-γ release assay and tuberculin skin test, 'resisting' development of classic LTBI. We show that 'resisters' possess IgM, class-switched IgG antibody responses and non-IFN-γ T cell responses to the Mtb-specific proteins ESAT6 and CFP10, immunologic evidence of exposure to Mtb. Compared to subjects with classic LTBI, 'resisters' display enhanced antibody avidity and distinct Mtb-specific IgG Fc profiles. These data reveal a distinctive adaptive immune profile among Mtb-exposed subjects, supporting an expanded definition of the host response to Mtb exposure, with implications for public health and the design of clinical trials.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31086348", + "TEXT": "An aged circulatory environment can activate microglia, reduce neural precursor cell activity and impair cognition in mice. We hypothesized that brain endothelial cells (BECs) mediate at least some of these effects. We observe that BECs in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of vascular cell adhesion molecule 1 (VCAM1), a protein that facilitates vascular-immune cell interactions. Concomitantly, levels of the shed, soluble form of VCAM1 are prominently increased in the plasma of aged humans and mice, and their plasma is sufficient to increase VCAM1 expression in cultured BECs and the hippocampi of young mice. Systemic administration of anti-VCAM1 antibody or genetic ablation of Vcam1 in BECs counteracts the detrimental effects of plasma from aged individuals on young brains and reverses aging aspects, including microglial reactivity and cognitive deficits, in the brains of aged mice. Together, these findings establish brain endothelial VCAM1 at the blood-brain barrier as a possible target to treat age-related neurodegeneration.", + "TAG_DATA": [ + "37, aged {'context': 'B-tissue/organ'}", + "38, mouse {'context': 'I-tissue/organ'}", + "39, hippocampus {'context': 'I-tissue/organ'}", + "93, BECs {'context': 'B-cells'}", + "96, hippocampi {'context': 'B-tissue/organ'}", + "98, young {'context': 'B-organism'}", + "99, mice. {'context': 'I-organism'}", + "106, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "107, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "108, of {'perturbing_action': 'I-gene loss-of-function'}", + "109, Vcam1 {'perturbing_action': 'I-gene loss-of-function'}", + "111, BECs {'context': 'B-cells'}", + "136, brains {'context': 'B-tissue/organ'}", + "138, aged {'context': 'B-organism'}", + "139, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "37, aged ['l0', 'l1', 'l2']", + "38, mouse ['l0', 'l3', 'l4']", + "39, hippocampus ['l1', 'l3', 'l5']", + "93, BECs ['l2', 'l4', 'l5', 'l6', 'l7', 'l8']", + "96, hippocampi ['l6', 'l9', 'l10']", + "98, young ['l7', 'l9', 'l11']", + "99, mice. ['l8', 'l10', 'l11']", + "106, genetic ['l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "107, ablation ['l12', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "108, of ['l13', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "109, Vcam1 ['l14', 'l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "111, BECs ['l15', 'l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "136, brains ['l16', 'l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "138, aged ['l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "139, mice. ['l18', 'l24', 'l29', 'l33', 'l36', 'l38', 'l39']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "Vcam1" + ] + }, + "context": { + "val": "cells", + "words": [ + "BECs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "Vcam1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brains" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "Vcam1" + ] + }, + "context": { + "val": "organism", + "words": [ + "aged", + "mice." + ] + } + } + ] + }, + { + "PMID": "31086347", + "TEXT": "The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer (TNBC) is low1-5, highlighting a need for strategies that render the tumor microenvironment more sensitive to PD-1 blockade. Preclinical research has suggested immunomodulatory properties for chemotherapy and irradiation6-13. In the first stage of this adaptive, non-comparative phase 2 trial, 67 patients with metastatic TNBC were randomized to nivolumab (1) without induction or with 2-week low-dose induction, or with (2) irradiation (3 × 8 Gy), (3) cyclophosphamide, (4) cisplatin or (5) doxorubicin, all followed by nivolumab. In the overall cohort, the objective response rate (ORR; iRECIST14) was 20%. The majority of responses were observed in the cisplatin (ORR 23%) and doxorubicin (ORR 35%) cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes involved in PD-1-PD-L1 (programmed death ligand 1) and T cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAK-STAT and TNF-α signaling after doxorubicin. Together, the clinical and translational data of this study indicate that short-term doxorubicin and cisplatin may induce a more favorable tumor microenvironment and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types.", + "TAG_DATA": [ + "55, patients {'context': 'B-patient'}", + "57, metastatic {'context': 'I-neoplasm'}", + "58, TNBC {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "55, patients ['l0', 'l1']", + "57, metastatic ['l0', 'l2']", + "58, TNBC ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "31061538", + "TEXT": "Understanding cellular metabolism holds immense potential for developing new classes of therapeutics that target metabolic pathways in cancer. Metabolic pathways are altered in bulk neoplastic cells in comparison to normal tissues. However, carcinoma cells within tumors are heterogeneous, and tumor-initiating cells (TICs) are important therapeutic targets that have remained metabolically uncharacterized. To understand their metabolic alterations, we performed metabolomics and metabolite tracing analyses, which revealed that TICs have highly elevated methionine cycle activity and transmethylation rates that are driven by MAT2A. High methionine cycle activity causes methionine consumption to far outstrip its regeneration, leading to addiction to exogenous methionine. Pharmacological inhibition of the methionine cycle, even transiently, is sufficient to cripple the tumor-initiating capability of these cells. Methionine cycle flux specifically influences the epigenetic state of cancer cells and drives tumor initiation. Methionine cycle enzymes are also enriched in other tumor types, and MAT2A expression impinges upon the sensitivity of certain cancer cells to therapeutic inhibition.", + "TAG_DATA": [ + "110, cripple {'effect': 'B-negative'}", + "112, tumor-initiating {'phenotype': 'B-tumour initiation'}", + "113, capability {'phenotype': 'I-tumour initiation'}", + "116, cells. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "110, cripple ['l0', 'l1', 'l2']", + "112, tumor-initiating ['l0', 'l3', 'l4']", + "113, capability ['l1', 'l3', 'l5']", + "116, cells. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "cripple" + ] + }, + "phenotype": { + "val": "tumour initiation", + "words": [ + "tumor-initiating", + "capability" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "cripple" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "phenotype": { + "val": "tumour initiation", + "words": [ + "tumor-initiating", + "capability" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "31011206", + "TEXT": "Cancer treatments have evolved from indiscriminate cytotoxic agents to selective genome- and immune-targeted drugs that have transformed the outcomes of some malignancies1. Tumor complexity and heterogeneity suggest that the 'precision medicine' paradigm of cancer therapy requires treatment to be personalized to the individual patient2-6. To date, precision oncology trials have been based on molecular matching with predetermined monotherapies7-14. Several of these trials have been hindered by very low matching rates, often in the 5-10% range15, and low response rates. Low matching rates may be due to the use of limited gene panels, restrictive molecular matching algorithms, lack of drug availability, or the deterioration and death of end-stage patients before therapy can be implemented. We hypothesized that personalized treatment with combination therapies would improve outcomes in patients with refractory malignancies. As a first test of this concept, we implemented a cross-institutional prospective study (I-PREDICT, NCT02534675 ) that used tumor DNA sequencing and timely recommendations for individualized treatment with combination therapies. We found that administration of customized multidrug regimens was feasible, with 49% of consented patients receiving personalized treatment. Targeting of a larger fraction of identified molecular alterations, yielding a higher 'matching score', was correlated with significantly improved disease control rates, as well as longer progression-free and overall survival rates, compared to targeting of fewer somatic alterations. Our findings suggest that the current clinical trial paradigm for precision oncology, which pairs one driver mutation with one drug, may be optimized by treating molecularly complex and heterogeneous cancers with combinations of customized agents.", + "TAG_DATA": [ + "173, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "31011202", + "TEXT": "Ovarian cancer (OC) is a heterogeneous disease usually diagnosed at a late stage. Experimental in vitro models that faithfully capture the hallmarks and tumor heterogeneity of OC are limited and hard to establish. We present a protocol that enables efficient derivation and long-term expansion of OC organoids. Utilizing this protocol, we have established 56 organoid lines from 32 patients, representing all main subtypes of OC. OC organoids recapitulate histological and genomic features of the pertinent lesion from which they were derived, illustrating intra- and interpatient heterogeneity, and can be genetically modified. We show that OC organoids can be used for drug-screening assays and capture different tumor subtype responses to the gold standard platinum-based chemotherapy, including acquisition of chemoresistance in recurrent disease. Finally, OC organoids can be xenografted, enabling in vivo drug-sensitivity assays. Taken together, this demonstrates their potential application for research and personalized medicine.", + "TAG_DATA": [ + "54, organoid {'context': 'B-organoid'}", + "55, lines {'context': 'I-organoid'}", + "65, OC {'context': 'B-organoid'}", + "66, organoids {'context': 'I-organoid'}", + "94, OC {'context': 'B-organoid'}", + "95, organoids {'context': 'I-organoid'}", + "122, OC {'context': 'B-organoid'}", + "123, organoids {'context': 'I-organoid'}", + "126, xenografted, {'context': 'B-xenograft'}", + "129, vivo {'context': 'B-in vivo'}" + ], + "LINK_DATA": [ + "54, organoid ['l0']", + "55, lines ['l0']", + "65, OC ['l1']", + "66, organoids ['l1']", + "94, OC ['l2']", + "95, organoids ['l2']", + "122, OC ['l3', 'l4', 'l5']", + "123, organoids ['l3', 'l6', 'l7']", + "126, xenografted, ['l4', 'l6', 'l8']", + "129, vivo ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30962585", + "TEXT": "Indolent non-Hodgkin's lymphomas (iNHLs) are incurable with standard therapy and are poorly responsive to checkpoint blockade. Although lymphoma cells are efficiently killed by primed T cells, in vivo priming of anti-lymphoma T cells has been elusive. Here, we demonstrate that lymphoma cells can directly prime T cells, but in vivo immunity still requires cross-presentation. To address this, we developed an in situ vaccine (ISV), combining Flt3L, radiotherapy, and a TLR3 agonist, which recruited, antigen-loaded and activated intratumoral, cross-presenting dendritic cells (DCs). ISV induced anti-tumor CD8+ T cell responses and systemic (abscopal) cancer remission in patients with advanced stage iNHL in an ongoing trial ( NCT01976585 ). Non-responding patients developed a population of PD1+CD8+ T cells after ISV, and murine tumors became newly responsive to PD1 blockade, prompting a follow-up trial of the combined therapy. Our data substantiate that recruiting and activating intratumoral, cross-priming DCs is achievable and critical to anti-tumor T cell responses and PD1-blockade efficacy.", + "TAG_DATA": [ + "78, dendritic {'context': 'B-cells'}", + "79, cells {'context': 'I-cells'}", + "80, (DCs). {'context': 'I-cells'}", + "94, patients {'context': 'B-patient'}", + "96, advanced {'context': 'B-neoplasm'}", + "97, stage {'context': 'I-neoplasm'}", + "98, iNHL {'context': 'I-neoplasm'}", + "113, T {'context': 'I-cells'}", + "114, cells {'context': 'I-cells'}", + "118, murine {'context': 'B-neoplasm'}", + "119, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "78, dendritic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "79, cells ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "80, (DCs). ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "94, patients ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "96, advanced ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "97, stage ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "98, iNHL ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "113, T ['l21', 'l22', 'l23']", + "114, cells ['l21', 'l24']", + "118, murine ['l22', 'l25']", + "119, tumors ['l23', 'l24', 'l25']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30936549", + "TEXT": "Non-alcoholic fatty liver disease ranges from steatosis to non-alcoholic steatohepatitis (NASH), potentially progressing to cirrhosis and hepatocellular carcinoma (HCC). Here, we show that platelet number, platelet activation and platelet aggregation are increased in NASH but not in steatosis or insulin resistance. Antiplatelet therapy (APT; aspirin/clopidogrel, ticagrelor) but not nonsteroidal anti-inflammatory drug (NSAID) treatment with sulindac prevented NASH and subsequent HCC development. Intravital microscopy showed that liver colonization by platelets depended primarily on Kupffer cells at early and late stages of NASH, involving hyaluronan-CD44 binding. APT reduced intrahepatic platelet accumulation and the frequency of platelet-immune cell interaction, thereby limiting hepatic immune cell trafficking. Consequently, intrahepatic cytokine and chemokine release, macrovesicular steatosis and liver damage were attenuated. Platelet cargo, platelet adhesion and platelet activation but not platelet aggregation were identified as pivotal for NASH and subsequent hepatocarcinogenesis. In particular, platelet-derived GPIbα proved critical for development of NASH and subsequent HCC, independent of its reported cognate ligands vWF, P-selectin or Mac-1, offering a potential target against NASH.", + "TAG_DATA": [ + "65, liver {'context': 'B-tissue/organ'}", + "111, liver {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30936547", + "TEXT": "Association studies have linked microbiome alterations with many human diseases. However, they have not always reported consistent results, thereby necessitating cross-study comparisons. Here, a meta-analysis of eight geographically and technically diverse fecal shotgun metagenomic studies of colorectal cancer (CRC, n = 768), which was controlled for several confounders, identified a core set of 29 species significantly enriched in CRC metagenomes (false discovery rate (FDR) < 1 × 10-5). CRC signatures derived from single studies maintained their accuracy in other studies. By training on multiple studies, we improved detection accuracy and disease specificity for CRC. Functional analysis of CRC metagenomes revealed enriched protein and mucin catabolism genes and depleted carbohydrate degradation genes. Moreover, we inferred elevated production of secondary bile acids from CRC metagenomes, suggesting a metabolic link between cancer-associated gut microbes and a fat- and meat-rich diet. Through extensive validations, this meta-analysis firmly establishes globally generalizable, predictive taxonomic and functional microbiome CRC signatures as a basis for future diagnostics.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30932027", + "TEXT": "In the version of this article initially published, the affiliation of Dr. Sandra Geurts reads \"Sandra Geurts, an epidemiologist at Radbound University in Nijmegen.\" Radbound University is her previous affiliation, and the sentence should have been, \"Sandra Geurts, an epidemiologist at Maastricht University Medical Center+ in the Netherlands.\"", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30911136", + "TEXT": "Combining HLA-DQ-gluten tetramers with mass cytometry and RNA sequencing analysis, we find that gluten-specific CD4+ T cells in the blood and intestines of patients with celiac disease display a surprisingly rare phenotype. Cells with this phenotype are also elevated in patients with systemic sclerosis and systemic lupus erythematosus, suggesting a way to characterize CD4+ T cells specific for disease-driving antigens in multiple autoimmune conditions.", + "TAG_DATA": [ + "14, CD4+ {'context': 'I-cells'}", + "15, T {'context': 'I-cells'}", + "16, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "14, CD4+ ['l0', 'l1']", + "15, T ['l0', 'l2']", + "16, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30858616", + "TEXT": "Malformations of the human cortex represent a major cause of disability1. Mouse models with mutations in known causal genes only partially recapitulate the phenotypes and are therefore not unlimitedly suited for understanding the molecular and cellular mechanisms responsible for these conditions2. Here we study periventricular heterotopia (PH) by analyzing cerebral organoids derived from induced pluripotent stem cells (iPSCs) of patients with mutations in the cadherin receptor-ligand pair DCHS1 and FAT4 or from isogenic knockout (KO) lines1,3. Our results show that human cerebral organoids reproduce the cortical heterotopia associated with PH. Mutations in DCHS1 and FAT4 or knockdown of their expression causes changes in the morphology of neural progenitor cells and result in defective neuronal migration dynamics only in a subset of neurons. Single-cell RNA-sequencing (scRNA-seq) data reveal a subpopulation of mutant neurons with dysregulated genes involved in axon guidance, neuronal migration and patterning. We suggest that defective neural progenitor cell (NPC) morphology and an altered navigation system in a subset of neurons underlie this form of PH.", + "TAG_DATA": [ + "49, cerebral {'context': 'B-organoid'}", + "50, organoids {'context': 'I-organoid'}", + "53, induced {'context': 'B-cells'}", + "54, pluripotent {'context': 'I-cells'}", + "55, stem {'context': 'I-cells'}", + "56, cells {'context': 'I-cells'}", + "57, (iPSCs) {'context': 'I-cells'}", + "59, patients {'context': 'B-patient'}", + "61, mutations {'perturbing_action': 'B-other'}", + "62, in {'perturbing_action': 'I-other'}", + "63, the {'perturbing_action': 'I-other'}", + "64, cadherin {'perturbing_action': 'I-other'}", + "65, receptor-ligand {'perturbing_action': 'I-other'}", + "66, pair {'perturbing_action': 'I-other'}", + "67, DCHS1 {'perturbing_action': 'I-other'}", + "68, and {'perturbing_action': 'I-other'}", + "69, FAT4 {'perturbing_action': 'I-other'}", + "72, isogenic {'perturbing_action': 'B-gene loss-of-function'}", + "73, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "74, (KO) {'perturbing_action': 'I-gene loss-of-function'}", + "75, lines1,3. {'perturbing_action': 'I-gene loss-of-function'}", + "80, human {'context': 'B-organoid'}", + "81, cerebral {'context': 'I-organoid'}", + "82, organoids {'context': 'I-organoid'}", + "90, Mutations {'perturbing_action': 'B-other'}", + "91, in {'perturbing_action': 'I-other'}", + "92, DCHS1 {'perturbing_action': 'I-other'}", + "93, and {'perturbing_action': 'I-other'}", + "94, FAT4 {'perturbing_action': 'I-other'}", + "96, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "97, of {'perturbing_action': 'I-rnai/knockdown'}", + "98, their {'perturbing_action': 'I-rnai/knockdown'}", + "99, expression {'perturbing_action': 'I-rnai/knockdown'}", + "106, neural {'context': 'B-cells'}", + "107, progenitor {'context': 'I-cells'}", + "108, cells {'context': 'I-cells'}", + "112, defective {'effect': 'B-negative'}", + "114, migration {'phenotype': 'B-migration'}", + "121, neurons. {'context': 'B-cells'}", + "131, neurons {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "49, cerebral ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "50, organoids ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "53, induced ['l1', 'l17', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "54, pluripotent ['l2', 'l18', 'l32', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "55, stem ['l3', 'l19', 'l33', 'l51', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "56, cells ['l4', 'l20', 'l34', 'l52', 'l74', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "57, (iPSCs) ['l5', 'l21', 'l35', 'l53', 'l75', 'l90', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "59, patients ['l6', 'l22', 'l36', 'l54', 'l76', 'l91', 'l105', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "61, mutations ['l7', 'l23', 'l37', 'l55', 'l77', 'l92', 'l106', 'l119', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151']", + "62, in ['l8', 'l24', 'l38', 'l56', 'l78', 'l93', 'l107', 'l120', 'l133', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "63, the ['l9', 'l25', 'l39', 'l57', 'l79', 'l94', 'l108', 'l121', 'l134', 'l152', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186']", + "64, cadherin ['l10', 'l26', 'l40', 'l58', 'l80', 'l95', 'l109', 'l122', 'l135', 'l153', 'l170', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203']", + "65, receptor-ligand ['l11', 'l27', 'l41', 'l59', 'l81', 'l96', 'l110', 'l123', 'l136', 'l154', 'l171', 'l187', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219']", + "66, pair ['l12', 'l28', 'l42', 'l60', 'l82', 'l97', 'l111', 'l124', 'l137', 'l155', 'l172', 'l188', 'l204', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233']", + "67, DCHS1 ['l13', 'l29', 'l43', 'l61', 'l83', 'l98', 'l112', 'l125', 'l138', 'l156', 'l173', 'l189', 'l205', 'l220', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246']", + "68, and ['l14', 'l30', 'l44', 'l62', 'l84', 'l99', 'l113', 'l126', 'l139', 'l157', 'l174', 'l190', 'l206', 'l221', 'l234', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258']", + "69, FAT4 ['l15', 'l31', 'l45', 'l63', 'l85', 'l100', 'l114', 'l127', 'l140', 'l158', 'l175', 'l191', 'l207', 'l222', 'l235', 'l247', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268']", + "72, isogenic ['l64', 'l141', 'l159', 'l176', 'l192', 'l208', 'l223', 'l236', 'l248', 'l259', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283']", + "73, knockout ['l65', 'l142', 'l160', 'l177', 'l193', 'l209', 'l224', 'l237', 'l249', 'l260', 'l269', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298']", + "74, (KO) ['l66', 'l143', 'l161', 'l178', 'l194', 'l210', 'l225', 'l238', 'l250', 'l261', 'l270', 'l284', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304', 'l305', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311', 'l312']", + "75, lines1,3. ['l46', 'l67', 'l86', 'l101', 'l115', 'l128', 'l144', 'l162', 'l179', 'l195', 'l211', 'l226', 'l239', 'l251', 'l262', 'l271', 'l285', 'l299', 'l313', 'l314', 'l315', 'l316', 'l317', 'l318', 'l319']", + "80, human ['l47', 'l68', 'l87', 'l102', 'l116', 'l129', 'l145', 'l163', 'l180', 'l196', 'l212', 'l227', 'l240', 'l252', 'l263', 'l272', 'l286', 'l300', 'l313', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325']", + "81, cerebral ['l48', 'l69', 'l88', 'l103', 'l117', 'l130', 'l146', 'l164', 'l181', 'l197', 'l213', 'l228', 'l241', 'l253', 'l264', 'l273', 'l287', 'l301', 'l314', 'l320', 'l326', 'l327', 'l328', 'l329', 'l330', 'l331']", + "82, organoids ['l16', 'l49', 'l70', 'l89', 'l104', 'l118', 'l131', 'l147', 'l165', 'l182', 'l198', 'l214', 'l229', 'l242', 'l254', 'l265', 'l274', 'l288', 'l302', 'l315', 'l321', 'l326', 'l332', 'l333', 'l334', 'l335']", + "90, Mutations ['l336', 'l337', 'l338', 'l339', 'l340', 'l341', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348']", + "91, in ['l289', 'l303', 'l336', 'l349', 'l350', 'l351', 'l352', 'l353', 'l354', 'l355', 'l356', 'l357', 'l358', 'l359', 'l360']", + "92, DCHS1 ['l275', 'l290', 'l304', 'l337', 'l349', 'l361', 'l362', 'l363', 'l364', 'l365', 'l366', 'l367', 'l368']", + "93, and ['l276', 'l291', 'l305', 'l338', 'l350', 'l361', 'l369', 'l370', 'l371', 'l372', 'l373', 'l374', 'l375']", + "94, FAT4 ['l277', 'l292', 'l306', 'l339', 'l351', 'l362', 'l369', 'l376', 'l377', 'l378', 'l379', 'l380', 'l381']", + "96, knockdown ['l382', 'l383', 'l384', 'l385', 'l386', 'l387', 'l388', 'l389', 'l390']", + "97, of ['l340', 'l352', 'l382', 'l391', 'l392', 'l393', 'l394', 'l395', 'l396', 'l397', 'l398']", + "98, their ['l341', 'l353', 'l383', 'l391', 'l399', 'l400', 'l401', 'l402', 'l403', 'l404', 'l405']", + "99, expression ['l342', 'l354', 'l384', 'l392', 'l399', 'l406', 'l407', 'l408', 'l409', 'l410', 'l411']", + "106, neural ['l148', 'l166', 'l183', 'l199', 'l215', 'l230', 'l243', 'l255', 'l278', 'l293', 'l307', 'l316', 'l322', 'l327', 'l332', 'l343', 'l355', 'l363', 'l370', 'l376', 'l385', 'l393', 'l400', 'l406', 'l412', 'l413', 'l414', 'l415', 'l416']", + "107, progenitor ['l71', 'l149', 'l167', 'l184', 'l200', 'l216', 'l231', 'l244', 'l256', 'l266', 'l279', 'l294', 'l308', 'l317', 'l323', 'l328', 'l333', 'l344', 'l356', 'l364', 'l371', 'l377', 'l386', 'l394', 'l401', 'l407', 'l412', 'l417', 'l418', 'l419', 'l420']", + "108, cells ['l50', 'l72', 'l132', 'l150', 'l168', 'l185', 'l201', 'l217', 'l232', 'l245', 'l257', 'l267', 'l280', 'l295', 'l309', 'l318', 'l324', 'l329', 'l334', 'l345', 'l357', 'l365', 'l372', 'l378', 'l387', 'l395', 'l402', 'l408', 'l413', 'l417', 'l421', 'l422', 'l423']", + "112, defective ['l281', 'l296', 'l310', 'l346', 'l358', 'l366', 'l373', 'l379', 'l388', 'l396', 'l403', 'l409', 'l414', 'l418', 'l421', 'l424', 'l425']", + "114, migration ['l73', 'l151', 'l169', 'l186', 'l202', 'l218', 'l233', 'l246', 'l258', 'l268', 'l282', 'l297', 'l311', 'l319', 'l325', 'l330', 'l335', 'l347', 'l359', 'l367', 'l374', 'l380', 'l389', 'l397', 'l404', 'l410', 'l415', 'l419', 'l422', 'l424', 'l426']", + "121, neurons. ['l203', 'l219', 'l283', 'l298', 'l312', 'l331', 'l348', 'l360', 'l368', 'l375', 'l381', 'l390', 'l398', 'l405', 'l411', 'l416', 'l420', 'l423', 'l425', 'l426']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organoid", + "words": [ + "cerebral", + "organoids", + "human" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutations", + "in", + "the", + "cadherin", + "receptor-ligand", + "pair", + "DCHS1", + "and", + "FAT4" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "induced", + "pluripotent", + "stem", + "cells", + "(iPSCs)", + "neural", + "progenitor", + "neurons." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutations", + "in", + "the", + "cadherin", + "receptor-ligand", + "pair", + "DCHS1", + "and", + "FAT4", + "Mutations" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "induced", + "pluripotent", + "stem", + "cells", + "(iPSCs)", + "neural", + "progenitor", + "neurons." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lines1,3.", + "isogenic", + "knockout", + "(KO)" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pluripotent", + "neural", + "progenitor", + "cells", + "neurons." + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutations", + "in", + "the", + "cadherin", + "receptor-ligand", + "pair", + "DCHS1", + "and", + "FAT4" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lines1,3." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutations", + "in", + "the", + "cadherin", + "receptor-ligand", + "pair", + "DCHS1", + "and", + "FAT4", + "Mutations" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "isogenic", + "knockout", + "(KO)", + "lines1,3." + ] + }, + "context": { + "val": "organoid", + "words": [ + "human", + "cerebral", + "organoids" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "isogenic", + "knockout", + "(KO)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "isogenic", + "knockout", + "(KO)", + "lines1,3." + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "human", + "cerebral", + "organoids" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Mutations", + "in", + "DCHS1", + "and", + "FAT4" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "their", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "neural", + "progenitor", + "cells", + "neurons." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "their", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "their", + "expression" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neural", + "progenitor", + "cells", + "neurons." + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "defective" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + } + ] + }, + { + "PMID": "30842675", + "TEXT": "Immune responses generally decline with age. However, the dynamics of this process at the individual level have not been characterized, hindering quantification of an individual's immune age. Here, we use multiple 'omics' technologies to capture population- and individual-level changes in the human immune system of 135 healthy adult individuals of different ages sampled longitudinally over a nine-year period. We observed high inter-individual variability in the rates of change of cellular frequencies that was dictated by their baseline values, allowing identification of steady-state levels toward which a cell subset converged and the ordered convergence of multiple cell subsets toward an older adult homeostasis. These data form a high-dimensional trajectory of immune aging (IMM-AGE) that describes a person's immune status better than chronological age. We show that the IMM-AGE score predicted all-cause mortality beyond well-established risk factors in the Framingham Heart Study, establishing its potential use in clinics for identification of patients at risk.", + "TAG_DATA": [ + "46, healthy {'context': 'B-cells'}", + "47, adult {'context': 'I-organism'}", + "48, individuals {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "46, healthy ['l0', 'l1']", + "47, adult ['l0', 'l2']", + "48, individuals ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30842672", + "TEXT": "Application of immunoprofiling of human peripheral blood samples from an aging cohort identifies changes in the immune system that inform our understanding of age-associated complex diseases.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30833752", + "TEXT": "Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent tumorigenic growth, but the role of KRAS in supporting autophagy has not been established. We show that, to our surprise, suppression of KRAS increased autophagic flux, as did pharmacological inhibition of its effector ERK MAPK. Furthermore, we demonstrate that either KRAS suppression or ERK inhibition decreased both glycolytic and mitochondrial functions. We speculated that ERK inhibition might thus enhance PDAC dependence on autophagy, in part by impairing other KRAS- or ERK-driven metabolic processes. Accordingly, we found that the autophagy inhibitor chloroquine and genetic or pharmacologic inhibition of specific autophagy regulators synergistically enhanced the ability of ERK inhibitors to mediate antitumor activity in KRAS-driven PDAC. We conclude that combinations of pharmacologic inhibitors that concurrently block both ERK MAPK and autophagic processes that are upregulated in response to ERK inhibition may be effective treatments for PDAC.", + "TAG_DATA": [ + "30, suppression {'perturbing_action': 'B-pharmacological inhibition'}", + "31, of {'perturbing_action': 'I-pharmacological inhibition'}", + "32, KRAS {'perturbing_action': 'I-pharmacological inhibition'}", + "33, increased {'effect': 'B-positive'}", + "34, autophagic {'phenotype': 'B-autophagy'}", + "35, flux, {'phenotype': 'I-autophagy'}", + "38, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "39, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "40, of {'perturbing_action': 'I-pharmacological inhibition'}", + "41, its {'perturbing_action': 'I-pharmacological inhibition'}", + "42, effector {'perturbing_action': 'I-pharmacological inhibition'}", + "43, ERK {'perturbing_action': 'I-pharmacological inhibition'}", + "44, MAPK. {'perturbing_action': 'I-pharmacological inhibition'}", + "50, KRAS {'perturbing_action': 'B-pharmacological inhibition'}", + "51, suppression {'perturbing_action': 'I-pharmacological inhibition'}", + "53, ERK {'perturbing_action': 'B-pharmacological inhibition'}", + "54, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "94, pharmacologic {'perturbing_action': 'B-pharmacological inhibition'}", + "95, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "96, of {'perturbing_action': 'I-pharmacological inhibition'}", + "97, specific {'perturbing_action': 'I-pharmacological inhibition'}", + "98, autophagy {'perturbing_action': 'I-pharmacological inhibition'}", + "99, regulators {'perturbing_action': 'I-pharmacological inhibition'}", + "105, ERK {'perturbing_action': 'B-pharmacological inhibition'}", + "106, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "113, PDAC. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "30, suppression ['l0', 'l1', 'l2', 'l3', 'l4']", + "31, of ['l0', 'l5', 'l6', 'l7', 'l8', 'l9']", + "32, KRAS ['l1', 'l5', 'l10', 'l11', 'l12']", + "33, increased ['l2', 'l6', 'l10', 'l13', 'l14']", + "34, autophagic ['l3', 'l7', 'l11', 'l13', 'l15', 'l16']", + "35, flux, ['l4', 'l8', 'l12', 'l14', 'l15']", + "38, pharmacological ['l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "39, inhibition ['l17', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "40, of ['l18', 'l27', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "41, its ['l19', 'l28', 'l36', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "42, effector ['l20', 'l29', 'l37', 'l44', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "43, ERK ['l21', 'l30', 'l38', 'l45', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "44, MAPK. ['l22', 'l31', 'l39', 'l46', 'l52', 'l57', 'l62', 'l63', 'l64', 'l65']", + "50, KRAS ['l23', 'l32', 'l40', 'l47', 'l53', 'l58', 'l62', 'l66', 'l67', 'l68']", + "51, suppression ['l9', 'l16', 'l24', 'l33', 'l41', 'l48', 'l54', 'l59', 'l63', 'l66', 'l69', 'l70']", + "53, ERK ['l25', 'l34', 'l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l71']", + "54, inhibition ['l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l71']", + "94, pharmacologic ['l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "95, inhibition ['l72', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "96, of ['l73', 'l80', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "97, specific ['l74', 'l81', 'l87', 'l93', 'l94', 'l95', 'l96', 'l97']", + "98, autophagy ['l75', 'l82', 'l88', 'l93', 'l98', 'l99', 'l100', 'l101']", + "99, regulators ['l76', 'l83', 'l89', 'l94', 'l98', 'l102', 'l103', 'l104']", + "105, ERK ['l77', 'l84', 'l90', 'l95', 'l99', 'l102', 'l105', 'l106']", + "106, inhibitors ['l78', 'l85', 'l91', 'l96', 'l100', 'l103', 'l105', 'l107']", + "113, PDAC. ['l79', 'l86', 'l92', 'l97', 'l101', 'l104', 'l106', 'l107']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "suppression", + "of", + "KRAS" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "suppression", + "of", + "KRAS" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagic", + "flux," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagic", + "flux," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "specific", + "autophagy", + "regulators", + "ERK", + "inhibitors" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "PDAC." + ] + } + } + ] + }, + { + "PMID": "30804515", + "TEXT": "Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuvant anti-PD-1 therapy in stage III/IV melanoma. We hypothesized that immune reinvigoration in the tumor would be detectable at 3 weeks and that this response would correlate with disease-free survival. We identified a rapid and potent anti-tumor response, with 8 of 27 patients experiencing a complete or major pathological response after a single dose of anti-PD-1, all of whom remain disease free. These rapid pathologic and clinical responses were associated with accumulation of exhausted CD8 T cells in the tumor at 3 weeks, with reinvigoration in the blood observed as early as 1 week. Transcriptional analysis demonstrated a pretreatment immune signature (neoadjuvant response signature) that was associated with clinical benefit. In contrast, patients with disease recurrence displayed mechanisms of resistance including immune suppression, mutational escape, and/or tumor evolution. Neoadjuvant anti-PD-1 treatment is effective in high-risk resectable stage III/IV melanoma. Pathological response and immunological analyses after a single neoadjuvant dose can be used to predict clinical outcome and to dissect underlying mechanisms in checkpoint blockade.", + "TAG_DATA": [ + "112, CD8 {'context': 'B-cells'}", + "113, T {'context': 'I-cells'}", + "114, cells {'context': 'I-cells'}", + "117, tumor {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "112, CD8 ['l0', 'l1', 'l2']", + "113, T ['l0', 'l3', 'l4']", + "114, cells ['l1', 'l3', 'l5']", + "117, tumor ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30778240", + "TEXT": "Hutchinson-Gilford progeria syndrome (HGPS) is a rare lethal genetic disorder characterized by symptoms reminiscent of accelerated aging. The major underlying genetic cause is a substitution mutation in the gene coding for lamin A, causing the production of a toxic isoform called progerin. Here we show that reduction of lamin A/progerin by a single-dose systemic administration of adeno-associated virus-delivered CRISPR-Cas9 components suppresses HGPS in a mouse model.", + "TAG_DATA": [ + "64, mouse {'context': 'B-organism'}", + "65, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "64, mouse ['l0']", + "65, model. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30718908", + "TEXT": "In the version of this article originally published, a sentence was erroneously included in the author contributions, and information regarding second shared authorship was missing from the author contributions. The following should not have been included in the author contributions: \"C.W. and A.J.R.H. supervised the work presented in Figs. 1, 2, 5, 6; P.Z. and C.S. supervised the work presented in Figs. 3, 4.\" Additionally, this sentence should have appeared at the beginning of the author contributions: \"These authors contributed equally: C.W., P.F.Z., C.S., and A.J.R.H.\" The errors have been corrected in the print, PDF and HTML versions of the article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30692699", + "TEXT": "Apolipoprotein-E (ApoE) has been implicated in Alzheimer's disease, atherosclerosis, and other unresolvable inflammatory conditions but a common mechanism of action remains elusive. We found in ApoE-deficient mice that oxidized lipids activated the classical complement cascade (CCC), resulting in leukocyte infiltration of the choroid plexus (ChP). All human ApoE isoforms attenuated CCC activity via high-affinity binding to the activated CCC-initiating C1q protein (KD~140-580 pM) in vitro, and C1q-ApoE complexes emerged as markers for ongoing complement activity of diseased ChPs, Aβ plaques, and atherosclerosis in vivo. C1q-ApoE complexes in human ChPs, Aβ plaques, and arteries correlated with cognitive decline and atherosclerosis, respectively. Treatment with small interfering RNA (siRNA) against C5, which is formed by all complement pathways, attenuated murine ChP inflammation, Aβ-associated microglia accumulation, and atherosclerosis. Thus, ApoE is a direct checkpoint inhibitor of unresolvable inflammation, and reducing C5 attenuates disease burden.", + "TAG_DATA": [ + "25, ApoE-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "26, mice {'context': 'B-organism'}", + "63, in {'context': 'B-in vitro'}", + "64, vitro, {'context': 'I-in vitro'}", + "82, in {'context': 'B-in vivo'}", + "83, vivo. {'context': 'I-in vivo'}", + "102, small {'perturbing_action': 'B-rnai/knockdown'}", + "103, interfering {'perturbing_action': 'I-rnai/knockdown'}", + "104, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "105, (siRNA) {'perturbing_action': 'I-rnai/knockdown'}", + "106, against {'perturbing_action': 'I-rnai/knockdown'}", + "107, C5, {'perturbing_action': 'I-rnai/knockdown'}", + "116, murine {'context': 'B-organism'}", + "119, Aβ-associated {'context': 'B-cells'}", + "120, microglia {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "25, ApoE-deficient ['l0', 'l1', 'l2', 'l3', 'l4']", + "26, mice ['l0', 'l5', 'l6', 'l7']", + "63, in ['l1', 'l5', 'l8', 'l9', 'l10']", + "64, vitro, ['l2', 'l6', 'l8', 'l11', 'l12']", + "82, in ['l3', 'l9', 'l11', 'l13']", + "83, vivo. ['l4', 'l7', 'l10', 'l12', 'l13']", + "102, small ['l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "103, interfering ['l14', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "104, RNA ['l15', 'l22', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "105, (siRNA) ['l16', 'l23', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "106, against ['l17', 'l24', 'l30', 'l35', 'l40', 'l41', 'l42', 'l43']", + "107, C5, ['l18', 'l25', 'l31', 'l36', 'l40', 'l44', 'l45', 'l46']", + "116, murine ['l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l47', 'l48']", + "119, Aβ-associated ['l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l49']", + "120, microglia ['l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l49']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ApoE-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ApoE-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ApoE-deficient" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "small", + "interfering", + "RNA", + "(siRNA)", + "against", + "C5," + ] + }, + "context": { + "val": "organism", + "words": [ + "murine" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "small", + "interfering", + "RNA", + "(siRNA)", + "against", + "C5," + ] + }, + "context": { + "val": "cells", + "words": [ + "Aβ-associated", + "microglia" + ] + } + } + ] + }, + { + "PMID": "30664781", + "TEXT": "ß-thalassemia is caused by ß-globin gene mutations resulting in reduced (β+) or absent (β0) hemoglobin production. Patient life expectancy has recently increased, but the need for chronic transfusions in transfusion-dependent thalassemia (TDT) and iron chelation impairs quality of life1. Allogeneic hematopoietic stem cell (HSC) transplantation represents the curative treatment, with thalassemia-free survival exceeding 80%. However, it is available to a minority of patients and is associated with morbidity, rejection and graft-versus-host disease2. Gene therapy with autologous HSCs modified to express ß-globin represents a potential therapeutic option. We treated three adults and six children with ß0 or severe ß+ mutations in a phase 1/2 trial ( NCT02453477 ) with an intrabone administration of HSCs transduced with the lentiviral vector GLOBE. Rapid hematopoietic recovery with polyclonal multilineage engraftment of vector-marked cells was achieved, with a median of 37.5% (range 12.6-76.4%) in hematopoietic progenitors and a vector copy number per cell (VCN) of 0.58 (range 0.10-1.97) in erythroid precursors at 1 year, in absence of clonal dominance. Transfusion requirement was reduced in the adults. Three out of four evaluable pediatric participants discontinued transfusions after gene therapy and were transfusion independent at the last follow-up. Younger age and persistence of higher VCN in the repopulating hematopoietic cells are associated with better outcome.", + "TAG_DATA": [ + "89, adults {'context': 'B-patient'}", + "92, children {'context': 'I-organism'}", + "112, HSCs {'context': 'B-cells'}", + "113, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "114, with {'perturbing_action': 'I-gene gain-of-function'}", + "115, the {'perturbing_action': 'I-gene gain-of-function'}", + "116, lentiviral {'perturbing_action': 'I-gene gain-of-function'}", + "117, vector {'perturbing_action': 'I-gene gain-of-function'}", + "118, GLOBE. {'perturbing_action': 'I-gene gain-of-function'}", + "128, cells {'context': 'B-cells'}", + "139, hematopoietic {'context': 'B-cells'}", + "140, progenitors {'context': 'I-cells'}", + "154, erythroid {'context': 'B-cells'}", + "155, precursors {'context': 'I-cells'}", + "169, adults. {'context': 'B-patient'}", + "175, pediatric {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "89, adults ['l0']", + "92, children ['l0']", + "112, HSCs ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "113, transduced ['l1', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "114, with ['l2', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "115, the ['l3', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "116, lentiviral ['l4', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "117, vector ['l5', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "118, GLOBE. ['l6', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61']", + "128, cells ['l7', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l63', 'l64', 'l65']", + "139, hematopoietic ['l8', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l62', 'l66', 'l67', 'l68']", + "140, progenitors ['l9', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l63', 'l66', 'l69', 'l70']", + "154, erythroid ['l10', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l64', 'l67', 'l69', 'l71', 'l72']", + "155, precursors ['l11', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l65', 'l68', 'l70', 'l71', 'l73']", + "169, adults. ['l22', 'l32', 'l41', 'l49', 'l56', 'l72', 'l73']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "HSCs", + "cells", + "hematopoietic", + "progenitors", + "erythroid", + "precursors" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "the", + "lentiviral", + "vector", + "GLOBE." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "the", + "lentiviral", + "vector" + ] + }, + "context": { + "val": "patient", + "words": [ + "adults." + ] + } + } + ] + }, + { + "PMID": "30664780", + "TEXT": "The molecular alterations that occur in cells before cancer is manifest are largely uncharted. Lung carcinoma in situ (CIS) lesions are the pre-invasive precursor to squamous cell carcinoma. Although microscopically identical, their future is in equipoise, with half progressing to invasive cancer and half regressing or remaining static. The cellular basis of this clinical observation is unknown. Here, we profile the genomic, transcriptomic, and epigenomic landscape of CIS in a unique patient cohort with longitudinally monitored pre-invasive disease. Predictive modeling identifies which lesions will progress with remarkable accuracy. We identify progression-specific methylation changes on a background of widespread heterogeneity, alongside a strong chromosomal instability signature. We observed mutations and copy number changes characteristic of cancer and chart their emergence, offering a window into early carcinogenesis. We anticipate that this new understanding of cancer precursor biology will improve early detection, reduce overtreatment, and foster preventative therapies targeting early clonal events in lung cancer.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30643288", + "TEXT": "Vascular contributions to cognitive impairment are increasingly recognized1-5 as shown by neuropathological6,7, neuroimaging4,8-11, and cerebrospinal fluid biomarker4,12 studies. Moreover, small vessel disease of the brain has been estimated to contribute to approximately 50% of all dementias worldwide, including those caused by Alzheimer's disease (AD)3,4,13. Vascular changes in AD have been typically attributed to the vasoactive and/or vasculotoxic effects of amyloid-β (Aβ)3,11,14, and more recently tau15. Animal studies suggest that Aβ and tau lead to blood vessel abnormalities and blood-brain barrier (BBB) breakdown14-16. Although neurovascular dysfunction3,11 and BBB breakdown develop early in AD1,4,5,8-10,12,13, how they relate to changes in the AD classical biomarkers Aβ and tau, which also develop before dementia17, remains unknown. To address this question, we studied brain capillary damage using a novel cerebrospinal fluid biomarker of BBB-associated capillary mural cell pericyte, soluble platelet-derived growth factor receptor-β8,18, and regional BBB permeability using dynamic contrast-enhanced magnetic resonance imaging8-10. Our data show that individuals with early cognitive dysfunction develop brain capillary damage and BBB breakdown in the hippocampus irrespective of Alzheimer's Aβ and/or tau biomarker changes, suggesting that BBB breakdown is an early biomarker of human cognitive dysfunction independent of Aβ and tau.", + "TAG_DATA": [ + "166, hippocampus {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30617318", + "TEXT": "Asymptomatic left ventricular dysfunction (ALVD) is present in 3-6% of the general population, is associated with reduced quality of life and longevity, and is treatable when found1-4. An inexpensive, noninvasive screening tool for ALVD in the doctor's office is not available. We tested the hypothesis that application of artificial intelligence (AI) to the electrocardiogram (ECG), a routine method of measuring the heart's electrical activity, could identify ALVD. Using paired 12-lead ECG and echocardiogram data, including the left ventricular ejection fraction (a measure of contractile function), from 44,959 patients at the Mayo Clinic, we trained a convolutional neural network to identify patients with ventricular dysfunction, defined as ejection fraction ≤35%, using the ECG data alone. When tested on an independent set of 52,870 patients, the network model yielded values for the area under the curve, sensitivity, specificity, and accuracy of 0.93, 86.3%, 85.7%, and 85.7%, respectively. In patients without ventricular dysfunction, those with a positive AI screen were at 4 times the risk (hazard ratio, 4.1; 95% confidence interval, 3.3 to 5.0) of developing future ventricular dysfunction compared with those with a negative screen. Application of AI to the ECG-a ubiquitous, low-cost test-permits the ECG to serve as a powerful screening tool in asymptomatic individuals to identify ALVD.", + "TAG_DATA": [ + "146, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30559419", + "TEXT": "Activating BRAF mutants and fusions signal as RAS-independent constitutively active dimers with the exception of BRAF V600 mutant alleles which can function as active monomers1. Current RAF inhibitors are monomer selective, they potently inhibit BRAF V600 monomers but their inhibition of RAF dimers is limited by induction of negative cooperativity when bound to one site in the dimer1-3. Moreover, acquired resistance to these drugs is usually due to molecular lesions that cause V600 mutants to dimerize4-8. We show here that PLX8394, a new RAF inhibitor9, inhibits ERK signaling by specifically disrupting BRAF-containing dimers, including BRAF homodimers and BRAF-CRAF heterodimers, but not CRAF homodimers or ARAF-containing dimers. Differences in the amino acid residues in the amino (N)-terminal portion of the kinase domain of RAF isoforms are responsible for this differential vulnerability. As a BRAF-specific dimer breaker, PLX8394 selectively inhibits ERK signaling in tumors driven by dimeric BRAF mutants, including BRAF fusions and splice variants as well as BRAF V600 monomers, but spares RAF function in normal cells in which CRAF homodimers can drive signaling. Our work suggests that drugs with these properties will be safe and useful for treating tumors driven by activating BRAF mutants or fusions.", + "TAG_DATA": [ + "80, PLX8394, {'perturbing_action': 'B-pharmacological inhibition'}", + "141, tumors {'context': 'B-neoplasm'}", + "164, normal {'context': 'B-cells'}", + "165, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "164, normal ['l0']", + "165, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30552419", + "TEXT": "In the version of this article originally published, data were incorrectly ascribed to monoclonal antibody CIS34 because of a labeling error. The data were generated with monoclonal antibody CIS04. Full details can be found in the correction notice.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30523324", + "TEXT": "Scientific common sense and social justice dictate that the safety and efficacy of new therapies must be tested in the patient populations in need of treatment. Yet a recent study found that African Americans have been dramatically underrepresented in US clinical trials for cancer drugs. Efforts to increase the participation of minorities in clinical trials must become a priority for all drug developers.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30510255", + "TEXT": "Myelodysplastic syndromes (MDS) frequently progress to acute myeloid leukemia (AML); however, the cells leading to malignant transformation have not been directly elucidated. As progression of MDS to AML in humans provides a biological system to determine the cellular origins and mechanisms of neoplastic transformation, we studied highly fractionated stem cell populations in longitudinal samples of patients with MDS who progressed to AML. Targeted deep sequencing combined with single-cell sequencing of sorted cell populations revealed that stem cells at the MDS stage, including immunophenotypically and functionally defined pre-MDS stem cells (pre-MDS-SC), had a significantly higher subclonal complexity compared to blast cells and contained a large number of aging-related variants. Single-cell targeted resequencing of highly fractionated stem cells revealed a pattern of nonlinear, parallel clonal evolution, with distinct subclones within pre-MDS-SC and MDS-SC contributing to generation of MDS blasts or progression to AML, respectively. Furthermore, phenotypically aberrant stem cell clones expanded during transformation and stem cell subclones that were not detectable in MDS blasts became dominant upon AML progression. These results reveal a crucial role of diverse stem cell compartments during MDS progression to AML and have implications for current bulk cell-focused precision oncology approaches, both in MDS and possibly other cancers that evolve from premalignant conditions, that may miss pre-existing rare aberrant stem cells that drive disease progression and leukemic transformation.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30510251", + "TEXT": "In T lymphocytes, the Wiskott-Aldrich Syndrome protein (WASP) and WASP-interacting-protein (WIP) regulate T cell antigen receptor (TCR) signaling, but their role in lymphoma is largely unknown. Here we show that the expression of WASP and WIP is frequently low or absent in anaplastic large cell lymphoma (ALCL) compared to other T cell lymphomas. In anaplastic lymphoma kinase-positive (ALK+) ALCL, WASP and WIP expression is regulated by ALK oncogenic activity via its downstream mediators STAT3 and C/EBP-β. ALK+ lymphomas were accelerated in WASP- and WIP-deficient mice. In the absence of WASP, active GTP-bound CDC42 was increased and the genetic deletion of one CDC42 allele was sufficient to impair lymphoma growth. WASP-deficient lymphoma showed increased mitogen-activated protein kinase (MAPK) pathway activation that could be exploited as a therapeutic vulnerability. Our findings demonstrate that WASP and WIP are tumor suppressors in T cell lymphoma and suggest that MAP-kinase kinase (MEK) inhibitors combined with ALK inhibitors could achieve a more potent therapeutic effect in ALK+ ALCL.", + "TAG_DATA": [ + "81, WASP- {'perturbing_action': 'B-gene loss-of-function'}", + "82, and {'perturbing_action': 'B-gene loss-of-function'}", + "83, WIP-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "84, mice. {'context': 'B-organism'}", + "87, absence {'perturbing_action': 'B-gene loss-of-function'}", + "88, of {'perturbing_action': 'I-gene loss-of-function'}", + "89, WASP, {'perturbing_action': 'I-gene loss-of-function'}", + "97, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "98, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "99, of {'perturbing_action': 'I-gene loss-of-function'}", + "100, one {'perturbing_action': 'I-gene loss-of-function'}", + "101, CDC42 {'perturbing_action': 'I-gene loss-of-function'}", + "102, allele {'perturbing_action': 'I-gene loss-of-function'}", + "106, impair {'effect': 'B-negative'}", + "107, lymphoma {'context': 'B-neoplasm'}", + "109, WASP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "110, lymphoma {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "81, WASP- ['l0', 'l1', 'l2']", + "82, and ['l0', 'l3', 'l4']", + "83, WIP-deficient ['l1', 'l3', 'l5']", + "84, mice. ['l2', 'l4', 'l5']", + "87, absence ['l6', 'l7', 'l8', 'l9']", + "88, of ['l6', 'l10', 'l11', 'l12']", + "89, WASP, ['l7', 'l10', 'l13', 'l14']", + "97, genetic ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "98, deletion ['l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "99, of ['l16', 'l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "100, one ['l17', 'l24', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "101, CDC42 ['l18', 'l25', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "102, allele ['l19', 'l26', 'l32', 'l37', 'l41', 'l45', 'l46']", + "106, impair ['l8', 'l11', 'l13', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47']", + "107, lymphoma ['l9', 'l12', 'l14', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l47']", + "109, WASP-deficient ['l48']", + "110, lymphoma ['l22', 'l29', 'l35', 'l40', 'l44', 'l48']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "WASP-", + "and", + "WIP-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "WASP,", + "genetic", + "deletion", + "one", + "CDC42", + "allele" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impair" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "WASP,", + "genetic", + "deletion", + "one", + "CDC42", + "allele", + "WASP-deficient" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lymphoma" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impair" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lymphoma" + ] + } + } + ] + }, + { + "PMID": "30478424", + "TEXT": "Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance.", + "TAG_DATA": [ + "40, epidermal {'perturbing_action': 'B-other'}", + "41, growth {'perturbing_action': 'B-other'}", + "42, factor {'perturbing_action': 'I-other'}", + "43, receptor {'perturbing_action': 'I-other'}", + "44, (EGFR)-mutant {'perturbing_action': 'I-other'}", + "45, lung {'context': 'B-transformed cells'}", + "46, adenocarcinoma {'context': 'I-transformed cells'}", + "47, cells, {'context': 'I-transformed cells'}", + "83, EGFR {'perturbing_action': 'B-pharmacological inhibition'}", + "84, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "87, mitigates {'effect': 'B-negative'}", + "88, drug-induced {'effect': 'B-positive'}", + "89, apoptosis. {'phenotype': 'B-apoptosis'}", + "90, Aurora {'perturbing_action': 'B-pharmacological inhibition'}", + "91, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "92, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "108, preclinical {'context': 'B-organism'}", + "109, models. {'context': 'I-organism'}", + "121, in {'context': 'B-in vitro'}", + "122, vitro, {'context': 'I-in vitro'}", + "123, in {'context': 'B-in vivo'}", + "124, vivo {'context': 'I-in vivo'}", + "130, EGFR-mutant {'perturbing_action': 'B-other'}", + "131, lung {'context': 'B-neoplasm'}", + "132, adenocarcinoma. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "40, epidermal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "41, growth ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "42, factor ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "43, receptor ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "44, (EGFR)-mutant ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "45, lung ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "46, adenocarcinoma ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "47, cells, ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "83, EGFR ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "84, inhibition ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "87, mitigates ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "88, drug-induced ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "89, apoptosis. ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "90, Aurora ['l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "91, kinase ['l78', 'l84', 'l85', 'l86', 'l87', 'l88']", + "92, inhibitors ['l79', 'l84', 'l89', 'l90', 'l91', 'l92']", + "108, preclinical ['l80', 'l85', 'l89', 'l93']", + "109, models. ['l81', 'l86', 'l90', 'l93']", + "121, in ['l82', 'l87', 'l91', 'l94', 'l95', 'l96']", + "122, vitro, ['l83', 'l88', 'l92', 'l94', 'l97', 'l98']", + "123, in ['l95', 'l97', 'l99', 'l100', 'l101', 'l102']", + "124, vivo ['l96', 'l98', 'l99', 'l103', 'l104', 'l105']", + "130, EGFR-mutant ['l100', 'l103', 'l106', 'l107']", + "131, lung ['l101', 'l104', 'l106', 'l108']", + "132, adenocarcinoma. ['l102', 'l105', 'l107', 'l108']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "epidermal", + "growth", + "factor", + "receptor", + "(EGFR)-mutant" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "lung", + "adenocarcinoma", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "epidermal", + "growth", + "factor", + "receptor", + "(EGFR)-mutant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "mitigates" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "epidermal", + "growth", + "factor", + "receptor", + "(EGFR)-mutant" + ] + }, + "effect": { + "val": "positive", + "words": [ + "drug-induced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "epidermal", + "growth", + "factor", + "receptor", + "(EGFR)-mutant" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "lung", + "adenocarcinoma", + "cells," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EGFR", + "inhibition" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "lung", + "adenocarcinoma", + "cells," + ] + }, + "effect": { + "val": "negative", + "words": [ + "mitigates" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "lung", + "adenocarcinoma", + "cells," + ] + }, + "effect": { + "val": "positive", + "words": [ + "drug-induced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "lung", + "adenocarcinoma", + "cells," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EGFR", + "inhibition" + ] + }, + "effect": { + "val": "negative", + "words": [ + "mitigates" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EGFR", + "inhibition" + ] + }, + "effect": { + "val": "positive", + "words": [ + "drug-induced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EGFR", + "inhibition" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "mitigates" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "drug-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Aurora", + "kinase", + "inhibitors" + ] + }, + "context": { + "val": "organism", + "words": [ + "preclinical", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Aurora", + "kinase", + "inhibitors" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "EGFR-mutant" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "EGFR-mutant" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lung", + "adenocarcinoma." + ] + } + } + ] + }, + { + "PMID": "30478423", + "TEXT": "Programmed cell death protein-1/ligand-1 (PD-1/PD-L1) blockade is effective in a subset of patients with several tumor types, but predicting patient benefit using approved diagnostics is inexact, as some patients with PD-L1-negative tumors also show clinical benefit1,2. Moreover, all biopsy-based tests are subject to the errors and limitations of invasive tissue collection3-11. Preclinical studies of positron-emission tomography (PET) imaging with antibodies to PD-L1 suggested that this imaging method might be an approach to selecting patients12,13. Such a technique, however, requires substantial clinical development and validation. Here we present the initial results from a first-in-human study to assess the feasibility of imaging with zirconium-89-labeled atezolizumab (anti-PD-L1), including biodistribution, and secondly test its potential to predict response to PD-L1 blockade (ClinicalTrials.gov identifiers NCT02453984 and NCT02478099). We imaged 22 patients across three tumor types before the start of atezolizumab therapy. The PET signal, a function of tracer exposure and target expression, was high in lymphoid tissues and at sites of inflammation. In tumors, uptake was generally high but heterogeneous, varying within and among lesions, patients, and tumor types. Intriguingly, clinical responses in our patients were better correlated with pretreatment PET signal than with immunohistochemistry- or RNA-sequencing-based predictive biomarkers, encouraging further development of molecular PET imaging for assessment of PD-L1 status and clinical response prediction.", + "TAG_DATA": [ + "158, tumors, {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30478421", + "TEXT": "Treatment of prostate cancer (PC) by androgen suppression promotes the emergence of aggressive variants that are androgen receptor (AR) independent. Here we identify the transcription factor ONECUT2 (OC2) as a master regulator of AR networks in metastatic castration-resistant prostate cancer (mCRPC). OC2 acts as a survival factor in mCRPC models, suppresses the AR transcriptional program by direct regulation of AR target genes and the AR licensing factor FOXA1, and activates genes associated with neural differentiation and progression to lethal disease. OC2 appears active in a substantial subset of human prostate adenocarcinoma and neuroendocrine tumors. Inhibition of OC2 by a newly identified small molecule suppresses metastasis in mice. These findings suggest that OC2 displaces AR-dependent growth and survival mechanisms in many cases where AR remains expressed, but where its activity is bypassed. OC2 is also a potential drug target in the metastatic phase of aggressive PC.", + "TAG_DATA": [ + "94, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "95, of {'perturbing_action': 'I-pharmacological inhibition'}", + "96, OC2 {'perturbing_action': 'I-pharmacological inhibition'}", + "97, by {'perturbing_action': 'I-pharmacological inhibition'}", + "98, a {'perturbing_action': 'I-pharmacological inhibition'}", + "99, newly {'perturbing_action': 'I-pharmacological inhibition'}", + "100, identified {'perturbing_action': 'I-pharmacological inhibition'}", + "101, small {'perturbing_action': 'I-pharmacological inhibition'}", + "102, molecule {'perturbing_action': 'I-pharmacological inhibition'}", + "103, suppresses {'effect': 'B-negative'}", + "104, metastasis {'phenotype': 'B-metastasis'}", + "106, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "94, Inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "95, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "96, OC2 ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "97, by ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "98, a ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "99, newly ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "100, identified ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "101, small ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "102, molecule ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "103, suppresses ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "104, metastasis ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "106, mice. ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "OC2", + "by", + "a", + "newly", + "identified", + "small", + "molecule" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "OC2", + "by", + "a", + "newly", + "identified", + "small", + "molecule" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "OC2", + "by", + "a", + "newly", + "identified", + "small", + "molecule" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "30429542", + "TEXT": "The version of this article originally published was not open access. This article should have been open access. The error has been fixed, and the article is now open access.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30420755", + "TEXT": "Multiple sclerosis (MS) is characterized by an immune system attack targeting myelin, which is produced by oligodendrocytes (OLs). We performed single-cell transcriptomic analysis of OL lineage cells from the spinal cord of mice induced with experimental autoimmune encephalomyelitis (EAE), which mimics several aspects of MS. We found unique OLs and OL precursor cells (OPCs) in EAE and uncovered several genes specifically alternatively spliced in these cells. Surprisingly, EAE-specific OL lineage populations expressed genes involved in antigen processing and presentation via major histocompatibility complex class I and II (MHC-I and -II), and in immunoprotection, suggesting alternative functions of these cells in a disease context. Importantly, we found that disease-specific oligodendroglia are also present in human MS brains and that a substantial number of genes known to be susceptibility genes for MS, so far mainly associated with immune cells, are expressed in the OL lineage cells. Finally, we demonstrate that OPCs can phagocytose and that MHC-II-expressing OPCs can activate memory and effector CD4-positive T cells. Our results suggest that OLs and OPCs are not passive targets but instead active immunomodulators in MS. The disease-specific OL lineage cells, for which we identify several biomarkers, may represent novel direct targets for immunomodulatory therapeutic approaches in MS.", + "TAG_DATA": [ + "29, spinal {'context': 'B-tissue/organ'}", + "30, cord {'context': 'I-tissue/organ'}", + "32, mice {'context': 'B-organism'}", + "154, OPCs {'context': 'I-cells'}", + "157, memory {'context': 'B-cells'}", + "158, and {'context': 'I-cells'}", + "159, effector {'context': 'I-cells'}", + "160, CD4-positive {'context': 'I-cells'}", + "161, T {'context': 'I-cells'}", + "162, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "29, spinal ['l0', 'l1']", + "30, cord ['l0', 'l2']", + "32, mice ['l1', 'l2']", + "154, OPCs ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "157, memory ['l3', 'l9', 'l10', 'l11', 'l12', 'l13']", + "158, and ['l4', 'l9', 'l14', 'l15', 'l16', 'l17']", + "159, effector ['l5', 'l10', 'l14', 'l18', 'l19', 'l20']", + "160, CD4-positive ['l6', 'l11', 'l15', 'l18', 'l21', 'l22']", + "161, T ['l7', 'l12', 'l16', 'l19', 'l21', 'l23']", + "162, cells. ['l8', 'l13', 'l17', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30349085", + "TEXT": "Sepsis is the third leading cause of death worldwide and the main cause of mortality in hospitals1-3, but the best treatment strategy remains uncertain. In particular, evidence suggests that current practices in the administration of intravenous fluids and vasopressors are suboptimal and likely induce harm in a proportion of patients1,4-6. To tackle this sequential decision-making problem, we developed a reinforcement learning agent, the Artificial Intelligence (AI) Clinician, which extracted implicit knowledge from an amount of patient data that exceeds by many-fold the life-time experience of human clinicians and learned optimal treatment by analyzing a myriad of (mostly suboptimal) treatment decisions. We demonstrate that the value of the AI Clinician's selected treatment is on average reliably higher than human clinicians. In a large validation cohort independent of the training data, mortality was lowest in patients for whom clinicians' actual doses matched the AI decisions. Our model provides individualized and clinically interpretable treatment decisions for sepsis that could improve patient outcomes.", + "TAG_DATA": [ + "133, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30323331", + "TEXT": "A comprehensive evaluation of every patient with a bloodstream infection includes an attempt to identify the infectious source. Pathogens can originate from various places, such as the gut microbiota, skin and the external environment. Identifying the definitive origin of an infection would enable precise interventions focused on management of the source1,2. Unfortunately, hospital infection control practices are often informed by assumptions about the source of various specific pathogens; if these assumptions are incorrect, they lead to interventions that do not decrease pathogen exposure3. Here, we develop and apply a streamlined bioinformatic tool, named StrainSifter, to match bloodstream pathogens precisely to a candidate source. We then leverage this approach to interrogate the gut microbiota as a potential reservoir of bloodstream pathogens in a cohort of hematopoietic cell transplantation recipients. We find that patients with Escherichia coli and Klebsiella pneumoniae bloodstream infections have concomitant gut colonization with these organisms, suggesting that the gut may be a source of these infections. We also find cases where typically nonenteric pathogens, such as Pseudomonas aeruginosa and Staphylococcus epidermidis, are found in the gut microbiota, thereby challenging the existing informal dogma of these infections originating from environmental or skin sources. Thus, we present an approach to distinguish the source of various bloodstream infections, which may facilitate more accurate tracking and prevention of hospital-acquired infections.", + "TAG_DATA": [ + "124, hematopoietic {'context': 'B-xenograft'}", + "125, cell {'context': 'I-xenograft'}", + "126, transplantation {'context': 'I-xenograft'}", + "127, recipients. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "124, hematopoietic ['l0', 'l1', 'l2']", + "125, cell ['l0', 'l3', 'l4']", + "126, transplantation ['l1', 'l3', 'l5']", + "127, recipients. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30297911", + "TEXT": "Adjuvant ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) both improve relapse-free survival of stage III melanoma patients1,2. In stage IV disease, the combination of ipilimumab + nivolumab is superior to ipilimumab alone and also appears to be more effective than nivolumab monotherapy3. Preclinical work suggests that neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy4. To address this question and to test feasibility, 20 patients with palpable stage III melanoma were 1:1 randomized to receive ipilimumab 3 mg kg-1 and nivolumab 1 mg kg-1, as either four courses after surgery (adjuvant arm) or two courses before surgery and two courses postsurgery (neoadjuvant arm). Neoadjuvant therapy was feasible, with all patients undergoing surgery at the preplanned time point. However in both arms, 9/10 patients experienced one or more grade 3/4 adverse events. Pathological responses were achieved in 7/9 (78%) patients treated in the neoadjuvant arm. None of these patients have relapsed so far (median follow-up, 25.6 months). We found that neoadjuvant ipilimumab + nivolumab expand more tumor-resident T cell clones than adjuvant application. While neoadjuvant therapy appears promising, with the current regimen it induced high toxicity rates; therefore, it needs further investigation to preserve efficacy but reduce toxicity.", + "TAG_DATA": [ + "62, patients {'context': 'B-patient'}", + "64, palpable {'context': 'B-neoplasm'}", + "65, stage {'context': 'I-neoplasm'}", + "66, III {'context': 'I-neoplasm'}", + "67, melanoma {'context': 'I-neoplasm'}", + "156, tumor-resident {'context': 'B-cells'}", + "157, T {'context': 'I-cells'}", + "158, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "62, patients ['l0', 'l1', 'l2', 'l3']", + "64, palpable ['l0', 'l4', 'l5', 'l6']", + "65, stage ['l1', 'l4', 'l7', 'l8']", + "66, III ['l2', 'l5', 'l7', 'l9']", + "67, melanoma ['l3', 'l6', 'l8', 'l9']", + "156, tumor-resident ['l10', 'l11']", + "157, T ['l10', 'l12']", + "158, cell ['l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30297895", + "TEXT": "Retinal gene therapy is increasingly recognized as a novel molecular intervention that has huge potential in treating common causes of blindness, the majority of which have a genetic aetiology1-5. Choroideremia is a chronic X-linked retinal degeneration that was first described in 18726. It leads to progressive blindness due to deficiency of Rab-escort protein 1 (REP1). We designed an adeno-associated viral vector to express REP1 and assessed it in a gene therapy clinical trial by subretinal injection in 14 patients with choroideremia. The primary endpoint was vision change in treated eyes 2 years after surgery compared to unoperated fellow eyes. Despite complications in two patients, visual acuity improved in the 14 treated eyes over controls (median 4.5 letter gain, versus 1.5 letter loss, P = 0.04), with 6 treated eyes gaining more than one line of vision (>5 letters). The results suggest that retinal gene therapy can sustain and improve visual acuity in a cohort of predominantly late-stage choroideremia patients in whom rapid visual acuity loss would ordinarily be predicted.", + "TAG_DATA": [ + "89, eyes {'context': 'B-tissue/organ'}", + "111, eyes {'context': 'B-tissue/organ'}", + "126, eyes {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30275570", + "TEXT": "Hematopoietic stem and progenitor cells (HSPC) are endowed with the role of generating and maintaining lifelong the extremely diverse pool of blood cells1. Clinically, transplantation of human HSPC from an allogeneic healthy donor or infusion of autologous gene-corrected HSPC can effectively replenish defective blood cell production caused by congenital or acquired disorders2-9. However, due to methodological and ethical constraints that have limited the study of human HSPC primarily to in vitro assays10 or xenotransplantation models11,12, the in vivo activity of HSPC has to date remained relatively unexplored in humans13-16. Here we report a comprehensive study of the frequencies, dynamics and output of seven HSPC subtypes in humans that was performed by tracking 148,093 individual clones in six patients treated with lentiviral gene therapy using autologous HSPC transplantation and followed for up to 5 years. We discovered that primitive multipotent progenitor and hematopoietic stem cell (HSC) populations have distinct roles during the initial reconstitution after transplant, compared with subsequent steady-state phases. Furthermore, we showed that a fraction of in vitro-activated HSC are resilient and undergo a defined delayed activation period upon transplant. Finally, our data support the concept that early lymphoid-biased progenitors might be capable of long-term survival, such that they can be maintained independently of their continuous production from HSC. Overall, this study provides comprehensive data on HSPC dynamics after autologous transplantation and gene therapy in humans.", + "TAG_DATA": [ + "117, patients {'context': 'B-patient'}", + "125, HSPC {'context': 'I-cells'}", + "167, in {'context': 'B-in vitro'}", + "168, vitro-activated {'context': 'I-in vitro'}", + "169, HSC {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "117, patients ['l0']", + "125, HSPC ['l0']", + "167, in ['l1', 'l2']", + "168, vitro-activated ['l1', 'l3']", + "169, HSC ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30250142", + "TEXT": "Mutations of the mitochondrial genome (mtDNA) underlie a substantial portion of mitochondrial disease burden. These disorders are currently incurable and effectively untreatable, with heterogeneous penetrance, presentation and prognosis. To address the lack of effective treatment for these disorders, we exploited a recently developed mouse model that recapitulates common molecular features of heteroplasmic mtDNA disease in cardiac tissue: the m.5024C>T tRNAAla mouse. Through application of a programmable nuclease therapy approach, using systemically administered, mitochondrially targeted zinc-finger nucleases (mtZFN) delivered by adeno-associated virus, we induced specific elimination of mutant mtDNA across the heart, coupled to a reversion of molecular and biochemical phenotypes. These findings constitute proof of principle that mtDNA heteroplasmy correction using programmable nucleases could provide a therapeutic route for heteroplasmic mitochondrial diseases of diverse genetic origin.", + "TAG_DATA": [ + "43, mouse {'context': 'B-organism'}", + "44, model {'context': 'I-organism'}", + "60, mouse. {'context': 'B-organism'}", + "90, heart, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "43, mouse ['l0', 'l1']", + "44, model ['l0', 'l2']", + "60, mouse. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30224758", + "TEXT": "Cancer cells rely on dysregulated gene expression. This establishes specific transcriptional addictions that may be therapeutically exploited. Yet, the mechanisms that are ultimately responsible for these addictions are poorly understood. Here, we investigated the transcriptional dependencies of transformed cells to the transcription factors YAP and TAZ. YAP/TAZ physically engage the general coactivator bromodomain-containing protein 4 (BRD4), dictating the genome-wide association of BRD4 to chromatin. YAP/TAZ flag a large set of enhancers with super-enhancer-like functional properties. YAP/TAZ-bound enhancers mediate the recruitment of BRD4 and RNA polymerase II at YAP/TAZ-regulated promoters, boosting the expression of a host of growth-regulating genes. Treatment with small-molecule inhibitors of BRD4 blunts YAP/TAZ pro-tumorigenic activity in several cell or tissue contexts, causes the regression of pre-established, YAP/TAZ-addicted neoplastic lesions and reverts drug resistance. This work sheds light on essential mediators, mechanisms and genome-wide regulatory elements that are responsible for transcriptional addiction in cancer and lays the groundwork for a rational use of BET inhibitors according to YAP/TAZ biology.", + "TAG_DATA": [ + "100, small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "101, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "102, of {'perturbing_action': 'I-pharmacological inhibition'}", + "103, BRD4 {'perturbing_action': 'I-pharmacological inhibition'}", + "112, tissue {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "100, small-molecule ['l0', 'l1', 'l2', 'l3']", + "101, inhibitors ['l0', 'l4', 'l5', 'l6']", + "102, of ['l1', 'l4', 'l7', 'l8']", + "103, BRD4 ['l2', 'l5', 'l7', 'l9']", + "112, tissue ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "inhibitors", + "of", + "BRD4" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tissue" + ] + } + } + ] + }, + { + "PMID": "30150716", + "TEXT": "Dysbiosis, departure of the gut microbiome from a healthy state, has been suggested to be a powerful biomarker of disease incidence and progression1-3. Diagnostic applications have been proposed for inflammatory bowel disease diagnosis and prognosis4, colorectal cancer prescreening5 and therapeutic choices in melanoma6. Noninvasive sampling could facilitate large-scale public health applications, including early diagnosis and risk assessment in metabolic7 and cardiovascular diseases8. To understand the generalizability of microbiota-based diagnostic models of metabolic disease, we characterized the gut microbiota of 7,009 individuals from 14 districts within 1 province in China. Among phenotypes, host location showed the strongest associations with microbiota variations. Microbiota-based metabolic disease models developed in one location failed when used elsewhere, suggesting that such models cannot be extrapolated. Interpolated models performed much better, especially in diseases with obvious microbiota-related characteristics. Interpolation efficiency decreased as geographic scale increased, indicating a need to build localized baseline and disease models to predict metabolic risks.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30135555", + "TEXT": "In the version of this article originally published, the institution in affiliation 10 was missing. Affiliation 10 was originally listed as Department of Surgery, Royal Melbourne Hospital and Royal Womens' Hospital, Melbourne, Victoria, Australia. It should have been Department of Surgery, Royal Melbourne Hospital and Royal Womens' Hospital, University of Melbourne, Melbourne, Victoria, Australia. The error has been corrected in the HTML and PDF versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30104768", + "TEXT": "The volume and complexity of diagnostic imaging is increasing at a pace faster than the availability of human expertise to interpret it. Artificial intelligence has shown great promise in classifying two-dimensional photographs of some common diseases and typically relies on databases of millions of annotated images. Until now, the challenge of reaching the performance of expert clinicians in a real-world clinical pathway with three-dimensional diagnostic scans has remained unsolved. Here, we apply a novel deep learning architecture to a clinically heterogeneous set of three-dimensional optical coherence tomography scans from patients referred to a major eye hospital. We demonstrate performance in making a referral recommendation that reaches or exceeds that of experts on a range of sight-threatening retinal diseases after training on only 14,884 scans. Moreover, we demonstrate that the tissue segmentations produced by our architecture act as a device-independent representation; referral accuracy is maintained when using tissue segmentations from a different type of device. Our work removes previous barriers to wider clinical use without prohibitive training data requirements across multiple pathologies in a real-world setting.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30104767", + "TEXT": "Rapid diagnosis and treatment of acute neurological illnesses such as stroke, hemorrhage, and hydrocephalus are critical to achieving positive outcomes and preserving neurologic function-'time is brain'1-5. Although these disorders are often recognizable by their symptoms, the critical means of their diagnosis is rapid imaging6-10. Computer-aided surveillance of acute neurologic events in cranial imaging has the potential to triage radiology workflow, thus decreasing time to treatment and improving outcomes. Substantial clinical work has focused on computer-assisted diagnosis (CAD), whereas technical work in volumetric image analysis has focused primarily on segmentation. 3D convolutional neural networks (3D-CNNs) have primarily been used for supervised classification on 3D modeling and light detection and ranging (LiDAR) data11-15. Here, we demonstrate a 3D-CNN architecture that performs weakly supervised classification to screen head CT images for acute neurologic events. Features were automatically learned from a clinical radiology dataset comprising 37,236 head CTs and were annotated with a semisupervised natural-language processing (NLP) framework16. We demonstrate the effectiveness of our approach to triage radiology workflow and accelerate the time to diagnosis from minutes to seconds through a randomized, double-blinded, prospective trial in a simulated clinical environment.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30093731", + "TEXT": "In the version of this article originally published, the received date was missing. It should have been listed as 2 January 2018. The error has been corrected in the HTML and PDF versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30087435", + "TEXT": "In the version of this article originally published, the months on the axis labeled projected month of conception in Fig. 1a were out of order. April and March should have been the first and last months listed, respectively. The error has been corrected in the print, PDF and HTML versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "30082858", + "TEXT": "Prophylactic vaccination of rhesus macaques with rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens (RhCMV/SIV) elicits immune responses that stringently control highly pathogenic SIV infection, with subsequent apparent clearance of the infection, in ~50% of vaccinees. In contrast, here, we show that therapeutic RhCMV/SIV vaccination of rhesus macaques previously infected with SIV and given continuous combination antiretroviral therapy (cART) beginning 4-9 d post-SIV infection does not mediate measurable SIV reservoir clearance during over 600 d of follow-up on cART relative to RhCMV/control vaccination. However, none of the six animals started on cART on day four or five, across both RhCMV/SIV- and RhCMV/control-vaccinated groups, those rhesus macaques with SIV reservoirs most closely resembling those of prophylactically RhCMV/SIV-vaccinated and protected animals early in their course, showed post-cART viral rebound with up to nine months of follow-up. Moreover, at necropsy, these rhesus macaques showed little to no evidence of replication-competent SIV. These results suggest that the early SIV reservoir is limited in durability and that effective blockade of viral replication and spread in this critical time window by either pharmacologic or immunologic suppression may result in reduction, and potentially loss, of rebound-competent virus over a period of ~two years.", + "TAG_DATA": [ + "48, rhesus {'context': 'B-organism'}", + "49, macaques {'context': 'I-organism'}", + "104, rhesus {'context': 'B-organism'}", + "105, macaques {'context': 'I-organism'}", + "118, animals {'context': 'B-organism'}", + "137, rhesus {'context': 'B-organism'}", + "138, macaques {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "48, rhesus ['l0']", + "49, macaques ['l0']", + "104, rhesus ['l1', 'l2']", + "105, macaques ['l1', 'l3']", + "118, animals ['l2', 'l3']", + "137, rhesus ['l4']", + "138, macaques ['l4']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30061698", + "TEXT": "Sarcopenia, the degenerative loss of skeletal muscle mass, quality and strength, lacks early diagnostic tools and new therapeutic strategies to prevent the frailty-to-disability transition often responsible for the medical institutionalization of elderly individuals. Herein we report that production of the endogenous peptide apelin, induced by muscle contraction, is reduced in an age-dependent manner in humans and rodents and is positively associated with the beneficial effects of exercise in older persons. Mice deficient in either apelin or its receptor (APLNR) presented dramatic alterations in muscle function with increasing age. Various strategies that restored apelin signaling during aging further demonstrated that this peptide considerably enhanced muscle function by triggering mitochondriogenesis, autophagy and anti-inflammatory pathways in myofibers as well as enhancing the regenerative capacity by targeting muscle stem cells. Taken together, these findings revealed positive regulatory feedback between physical activity, apelin and muscle function and identified apelin both as a tool for diagnosis of early sarcopenia and as the target of an innovative pharmacological strategy to prevent age-associated muscle weakness and restore physical autonomy.", + "TAG_DATA": [ + "70, Mice {'context': 'B-organism'}", + "71, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "72, in {'perturbing_action': 'I-gene loss-of-function'}", + "73, either {'perturbing_action': 'I-gene loss-of-function'}", + "74, apelin {'perturbing_action': 'I-gene loss-of-function'}", + "75, or {'perturbing_action': 'I-gene loss-of-function'}", + "76, its {'perturbing_action': 'I-gene loss-of-function'}", + "77, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "78, (APLNR) {'perturbing_action': 'I-gene loss-of-function'}", + "83, muscle {'context': 'B-tissue/organ'}", + "103, muscle {'context': 'B-tissue/organ'}", + "106, triggering {'effect': 'B-positive'}", + "108, autophagy {'phenotype': 'B-autophagy'}", + "113, myofibers {'context': 'B-cells'}", + "123, muscle {'context': 'B-cells'}", + "124, stem {'context': 'I-cells'}", + "125, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "70, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "71, deficient ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "72, in ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "73, either ['l2', 'l14', 'l25', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "74, apelin ['l3', 'l15', 'l26', 'l37', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "75, or ['l4', 'l16', 'l27', 'l38', 'l48', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "76, its ['l5', 'l17', 'l28', 'l39', 'l49', 'l58', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "77, receptor ['l6', 'l18', 'l29', 'l40', 'l50', 'l59', 'l68', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "78, (APLNR) ['l7', 'l19', 'l30', 'l41', 'l51', 'l60', 'l69', 'l77', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "83, muscle ['l8', 'l20', 'l31', 'l42', 'l52', 'l61', 'l70', 'l78', 'l85']", + "103, muscle ['l9', 'l21', 'l32', 'l43', 'l53', 'l62', 'l71', 'l79', 'l86', 'l92', 'l93', 'l94']", + "106, triggering ['l10', 'l22', 'l33', 'l44', 'l54', 'l63', 'l72', 'l80', 'l87', 'l92', 'l95', 'l96']", + "108, autophagy ['l11', 'l23', 'l34', 'l45', 'l55', 'l64', 'l73', 'l81', 'l88', 'l93', 'l95', 'l97']", + "113, myofibers ['l12', 'l24', 'l35', 'l46', 'l56', 'l65', 'l74', 'l82', 'l89', 'l94', 'l96', 'l97']", + "123, muscle ['l98', 'l99']", + "124, stem ['l66', 'l75', 'l83', 'l90', 'l98', 'l100']", + "125, cells. ['l36', 'l47', 'l57', 'l67', 'l76', 'l84', 'l91', 'l99', 'l100']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "either", + "apelin", + "or", + "its", + "receptor", + "(APLNR)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "either", + "apelin", + "or", + "its", + "receptor", + "(APLNR)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscle" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "either", + "apelin", + "or", + "its", + "receptor", + "(APLNR)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "either", + "apelin", + "or", + "its", + "receptor", + "(APLNR)" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "either", + "apelin", + "or", + "its", + "receptor", + "(APLNR)" + ] + }, + "context": { + "val": "cells", + "words": [ + "myofibers", + "cells.", + "stem" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "muscle" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "muscle" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + }, + "context": { + "val": "cells", + "words": [ + "myofibers" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + }, + "context": { + "val": "cells", + "words": [ + "myofibers" + ] + } + } + ] + }, + { + "PMID": "30061696", + "TEXT": "Intestinal microbial dysbiosis has been described in individuals with an HIV-1 infection and may underlie persistent inflammation in chronic infection, thereby contributing to disease progression. Herein, we induced an HIV-1-like intestinal dysbiosis in rhesus macaques (Macaca mulatta) with vancomycin treatment and assessed the contribution of dysbiosis to SIV disease progression. Dysbiotic and control animals had similar disease progression, indicating that intestinal microbial dysbiosis similar to that observed in individuals with HIV is not sufficient to accelerate untreated lentiviral disease progression.", + "TAG_DATA": [ + "33, rhesus {'context': 'B-organism'}", + "34, macaques {'context': 'I-organism'}", + "35, (Macaca {'context': 'I-organism'}", + "36, mulatta) {'context': 'I-organism'}", + "53, animals {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "33, rhesus ['l0', 'l1', 'l2']", + "34, macaques ['l0', 'l3', 'l4']", + "35, (Macaca ['l1', 'l3', 'l5']", + "36, mulatta) ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "30038216", + "TEXT": "The degree of intrinsic and interpatient phenotypic heterogeneity and its role in tumor evolution is poorly understood. Phenotypic drifts can be transmitted via inheritable transcriptional programs. Cell-type specific transcription is maintained through the activation of epigenetically defined regulatory regions including promoters and enhancers. Here we have annotated the epigenome of 47 primary and metastatic estrogen-receptor (ERα)-positive breast cancer clinical specimens and inferred phenotypic heterogeneity from the regulatory landscape, identifying key regulatory elements commonly shared across patients. Shared regions contain a unique set of regulatory information including the motif for transcription factor YY1. We identify YY1 as a critical determinant of ERα transcriptional activity promoting tumor growth in most luminal patients. YY1 also contributes to the expression of genes mediating resistance to endocrine treatment. Finally, we used H3K27ac levels at active enhancer elements as a surrogate of intra-tumor phenotypic heterogeneity to track the expansion and contraction of phenotypic subpopulations throughout breast cancer progression. By tracking the clonality of SLC9A3R1-positive cells, a bona fide YY1-ERα-regulated gene, we show that endocrine therapies select for phenotypic clones under-represented at diagnosis. Collectively, our data show that epigenetic mechanisms significantly contribute to phenotypic heterogeneity and evolution in systemically treated breast cancer patients.", + "TAG_DATA": [ + "158, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "29988128", + "TEXT": "Itch and pain are refractory symptoms of many ocular conditions. Ocular itch is generated mainly in the conjunctiva and is absent from the cornea. In contrast, most ocular pain arises from the cornea. However, the underlying mechanisms remain unknown. Using genetic axonal tracing approaches, we discover distinct sensory innervation patterns between the conjunctiva and cornea. Further genetic and functional analyses in rodent models show that a subset of conjunctival-selective sensory fibers marked by MrgprA3 expression, rather than corneal sensory fibers, mediates ocular itch. Importantly, the actions of both histamine and nonhistamine pruritogens converge onto this unique subset of conjunctiva sensory fibers and enable them to play a key role in mediating itch associated with allergic conjunctivitis. This is distinct from skin itch, in which discrete populations of sensory neurons cooperate to carry itch. Finally, we provide proof of concept that selective silencing of conjunctiva itch-sensing fibers by pruritogen-mediated entry of sodium channel blocker QX-314 is a feasible therapeutic strategy to treat ocular itch in mice. Itch-sensing fibers also innervate the human conjunctiva and allow pharmacological silencing using QX-314. Our results cast new light on the neural mechanisms of ocular itch and open a new avenue for developing therapeutic strategies.", + "TAG_DATA": [ + "61, rodent {'context': 'B-organism'}", + "62, models {'context': 'I-organism'}", + "141, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "143, conjunctiva {'context': 'B-cells'}", + "145, fibers {'context': 'I-cells'}", + "164, mice. {'context': 'B-organism'}", + "165, Itch-sensing {'context': 'B-cells'}", + "170, human {'context': 'B-tissue/organ'}", + "171, conjunctiva {'context': 'I-tissue/organ'}", + "174, pharmacological {'perturbing_action': 'B-rnai/knockdown'}", + "175, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "176, using {'perturbing_action': 'I-rnai/knockdown'}", + "177, QX-314. {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "61, rodent ['l0']", + "62, models ['l0']", + "141, silencing ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "143, conjunctiva ['l1', 'l9', 'l10', 'l11']", + "144, itch-sensing ['l2', 'l9', 'l12', 'l13']", + "145, fibers ['l3', 'l10', 'l12', 'l14']", + "164, mice. ['l4', 'l11', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "165, Itch-sensing ['l5', 'l15', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "166, fibers ['l6', 'l16', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "170, human ['l7', 'l17', 'l20', 'l26', 'l32', 'l33', 'l34', 'l35', 'l36']", + "171, conjunctiva ['l8', 'l18', 'l21', 'l27', 'l32', 'l37', 'l38', 'l39', 'l40']", + "174, pharmacological ['l22', 'l28', 'l33', 'l37', 'l41', 'l42', 'l43']", + "175, silencing ['l23', 'l29', 'l34', 'l38', 'l41', 'l44', 'l45']", + "176, using ['l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l46']", + "177, QX-314. ['l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l46']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "pharmacological", + "using", + "QX-314." + ] + }, + "context": { + "val": "cells", + "words": [ + "conjunctiva", + "fibers", + "Itch-sensing" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "pharmacological", + "using", + "QX-314." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "human", + "conjunctiva" + ] + } + } + ] + }, + { + "PMID": "29988127", + "TEXT": "Recent research has focused on environmental effects that control tissue functionality and systemic metabolism. However, whether such stimuli affect human thermogenesis and body mass index (BMI) has not been explored. Here we show retrospectively that the presence of brown adipose tissue (BAT) and the season of conception are linked to BMI in humans. In mice, we demonstrate that cold exposure (CE) of males, but not females, before mating results in improved systemic metabolism and protection from diet-induced obesity of the male offspring. Integrated analyses of the DNA methylome and RNA sequencing of the sperm from male mice revealed several clusters of co-regulated differentially methylated regions (DMRs) and differentially expressed genes (DEGs), suggesting that the improved metabolic health of the offspring was due to enhanced BAT formation and increased neurogenesis. The conclusions are supported by cell-autonomous studies in the offspring that demonstrate an enhanced capacity to form mature active brown adipocytes, improved neuronal density and more norepinephrine release in BAT in response to cold stimulation. Taken together, our results indicate that in humans and in mice, seasonal or experimental CE induces an epigenetic programming of the sperm such that the offspring harbor hyperactive BAT and an improved adaptation to overnutrition and hypothermia.", + "TAG_DATA": [ + "54, mice, {'context': 'B-organism'}", + "62, males, {'context': 'B-organism'}", + "80, male {'context': 'B-organism'}", + "81, offspring. {'context': 'I-organism'}", + "95, male {'context': 'B-organism'}", + "96, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "54, mice, ['l0', 'l1', 'l2']", + "62, males, ['l0', 'l3', 'l4']", + "80, male ['l1', 'l3', 'l5', 'l6', 'l7']", + "81, offspring. ['l2', 'l4', 'l5', 'l8']", + "95, male ['l6', 'l9']", + "96, mice ['l7', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29988124", + "TEXT": "The oncometabolite (R)-2-hydroxyglutarate (R-2-HG) produced by isocitrate dehydrogenase (IDH) mutations promotes gliomagenesis via DNA and histone methylation. Here, we identify an additional activity of R-2-HG: tumor cell-derived R-2-HG is taken up by T cells where it induces a perturbation of nuclear factor of activated T cells transcriptional activity and polyamine biosynthesis, resulting in suppression of T cell activity. IDH1-mutant gliomas display reduced T cell abundance and altered calcium signaling. Antitumor immunity to experimental syngeneic IDH1-mutant tumors induced by IDH1-specific vaccine or checkpoint inhibition is improved by inhibition of the neomorphic enzymatic function of mutant IDH1. These data attribute a novel, non-tumor cell-autonomous role to an oncometabolite in shaping the tumor immune microenvironment.", + "TAG_DATA": [ + "55, T {'context': 'B-cells'}", + "56, cell {'context': 'B-cells'}", + "58, IDH1-mutant {'perturbing_action': 'B-other'}", + "59, gliomas {'context': 'B-neoplasm'}", + "62, T {'context': 'B-cells'}", + "63, cell {'context': 'B-cells'}", + "73, syngeneic {'perturbing_action': 'B-other'}", + "74, IDH1-mutant {'perturbing_action': 'B-other'}", + "75, tumors {'context': 'B-neoplasm'}", + "93, mutant {'perturbing_action': 'B-other'}", + "94, IDH1. {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "55, T ['l0']", + "56, cell ['l0']", + "58, IDH1-mutant ['l1', 'l2', 'l3']", + "59, gliomas ['l1', 'l4', 'l5']", + "62, T ['l2', 'l4', 'l6']", + "63, cell ['l3', 'l5', 'l6']", + "73, syngeneic ['l7', 'l8']", + "74, IDH1-mutant ['l7', 'l9']", + "75, tumors ['l8', 'l9']", + "93, mutant ['l10']", + "94, IDH1. ['l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "IDH1-mutant", + "syngeneic" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "gliomas", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "IDH1-mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + } + ] + }, + { + "PMID": "29985486", + "TEXT": "In the version of this article originally published, there was an error in the sentence \"That quest, which started in the 1980s, continues through until today: For a paper published online in 2017, a group of researchers based at Brazil's Federal University of Rio Grande do Sul tested Sprague Dawley rats on either a high-fat diet, a cafeteria diet or what they called a 'Western diet', formulated to match up more closely with eating patterns in developed nations (it had 42.5% of its calories from fat and added salt and carbohydrates).\" Wistar rats were used in the experiment, not Sprague Dawley rats. Also, in ref. 7, the first author's last name was listed as Bortoloin. The correct spelling is Bortolin. The errors have been corrected in the HTML and PDF versions of this article.", + "TAG_DATA": [ + "48, Sprague {'context': 'B-organism'}", + "49, Dawley {'context': 'B-organism'}", + "50, rats {'context': 'I-organism'}", + "91, Wistar {'context': 'B-organism'}", + "92, rats {'context': 'I-organism'}", + "99, Sprague {'context': 'B-organism'}", + "100, Dawley {'context': 'B-organism'}", + "101, rats. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "48, Sprague ['l0', 'l1']", + "49, Dawley ['l0', 'l2']", + "50, rats ['l1', 'l2']", + "91, Wistar ['l3', 'l4', 'l5', 'l6']", + "92, rats ['l3', 'l7', 'l8', 'l9']", + "99, Sprague ['l4', 'l7', 'l10', 'l11']", + "100, Dawley ['l5', 'l8', 'l10', 'l12']", + "101, rats. ['l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29967351", + "TEXT": "Fibrosis is a pathological result of a dysfunctional repair response to tissue injury and occurs in a number of organs, including the lungs1. Cellular metabolism regulates tissue repair and remodelling responses to injury2-4. AMPK is a critical sensor of cellular bioenergetics and controls the switch from anabolic to catabolic metabolism5. However, the role of AMPK in fibrosis is not well understood. Here, we demonstrate that in humans with idiopathic pulmonary fibrosis (IPF) and in an experimental mouse model of lung fibrosis, AMPK activity is lower in fibrotic regions associated with metabolically active and apoptosis-resistant myofibroblasts. Pharmacological activation of AMPK in myofibroblasts from lungs of humans with IPF display lower fibrotic activity, along with enhanced mitochondrial biogenesis and normalization of sensitivity to apoptosis. In a bleomycin model of lung fibrosis in mice, metformin therapeutically accelerates the resolution of well-established fibrosis in an AMPK-dependent manner. These studies implicate deficient AMPK activation in non-resolving, pathologic fibrotic processes, and support a role for metformin (or other AMPK activators) to reverse established fibrosis by facilitating deactivation and apoptosis of myofibroblasts.", + "TAG_DATA": [ + "95, Pharmacological {'perturbing_action': 'B-pharmacological augmentation'}", + "96, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "97, of {'perturbing_action': 'I-pharmacological augmentation'}", + "98, AMPK {'perturbing_action': 'I-pharmacological augmentation'}", + "100, myofibroblasts {'context': 'B-cells'}", + "121, apoptosis. {'phenotype': 'B-apoptosis'}", + "130, mice, {'context': 'B-organism'}", + "169, facilitating {'effect': 'B-positive'}", + "174, myofibroblasts. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "95, Pharmacological ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "96, activation ['l0', 'l6', 'l7', 'l8', 'l9']", + "97, of ['l1', 'l6', 'l10', 'l11', 'l12']", + "98, AMPK ['l2', 'l7', 'l10', 'l13', 'l14']", + "100, myofibroblasts ['l3', 'l8', 'l11', 'l13', 'l15']", + "121, apoptosis. ['l4', 'l9', 'l12', 'l14', 'l15']", + "130, mice, ['l5']", + "169, facilitating ['l16', 'l17']", + "172, apoptosis ['l16', 'l18']", + "174, myofibroblasts. ['l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Pharmacological", + "activation", + "of", + "AMPK" + ] + }, + "context": { + "val": "cells", + "words": [ + "myofibroblasts" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Pharmacological", + "activation", + "of", + "AMPK" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Pharmacological" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "myofibroblasts" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "facilitating" + ] + }, + "context": { + "val": "cells", + "words": [ + "myofibroblasts." + ] + } + } + ] + }, + { + "PMID": "29967348", + "TEXT": "Zika virus (ZIKV) infection is associated with congenital defects and pregnancy loss. Here, we found that 26% of nonhuman primates infected with Asian/American ZIKV in early gestation experienced fetal demise later in pregnancy despite showing few clinical signs of infection. Pregnancy loss due to asymptomatic ZIKV infection may therefore be a common but under-recognized adverse outcome related to maternal ZIKV infection.", + "TAG_DATA": [ + "18, nonhuman {'context': 'B-organism'}", + "19, primates {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "18, nonhuman ['l0']", + "19, primates ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29942094", + "TEXT": "Cancer immunotherapies have shown sustained clinical responses in treating non-small-cell lung cancer1-3, but efficacy varies and depends in part on the amount and properties of tumor infiltrating lymphocytes4-6. To depict the baseline landscape of the composition, lineage and functional states of tumor infiltrating lymphocytes, here we performed deep single-cell RNA sequencing for 12,346 T cells from 14 treatment-naïve non-small-cell lung cancer patients. Combined expression and T cell antigen receptor based lineage tracking revealed a significant proportion of inter-tissue effector T cells with a highly migratory nature. As well as tumor-infiltrating CD8+ T cells undergoing exhaustion, we observed two clusters of cells exhibiting states preceding exhaustion, and a high ratio of \"pre-exhausted\" to exhausted T cells was associated with better prognosis of lung adenocarcinoma. Additionally, we observed further heterogeneity within the tumor regulatory T cells (Tregs), characterized by the bimodal distribution of TNFRSF9, an activation marker for antigen-specific Tregs. The gene signature of those activated tumor Tregs, which included IL1R2, correlated with poor prognosis in lung adenocarcinoma. Our study provides a new approach for patient stratification and will help further understand the functional states and dynamics of T cells in lung cancer.", + "TAG_DATA": [ + "53, cells {'context': 'I-cells'}", + "57, non-small-cell {'context': 'B-neoplasm'}", + "58, lung {'context': 'I-neoplasm'}", + "59, cancer {'context': 'I-neoplasm'}", + "60, patients. {'context': 'I-patient'}", + "89, CD8+ {'context': 'B-cells'}", + "90, T {'context': 'I-cells'}", + "91, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "53, cells ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "57, non-small-cell ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "58, lung ['l1', 'l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "59, cancer ['l2', 'l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "60, patients. ['l3', 'l8', 'l13', 'l17', 'l21', 'l22']", + "89, CD8+ ['l9', 'l14', 'l18', 'l23', 'l24']", + "90, T ['l4', 'l10', 'l15', 'l19', 'l21', 'l23', 'l25']", + "91, cells ['l5', 'l11', 'l16', 'l20', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29942089", + "TEXT": "The association between altered gut microbiota, intestinal permeability, inflammation and cardiometabolic diseases is becoming increasingly clear but remains poorly understood1,2. Indoleamine 2,3-dioxygenase is an enzyme induced in many types of immune cells, including macrophages in response to inflammatory stimuli, and catalyzes the degradation of tryptophan along the kynurenine pathway. Indoleamine 2,3-dioxygenase activity is better known for its suppression of effector T cell immunity and its activation of regulatory T cells3,4. However, high indoleamine 2,3-dioxygenase activity predicts worse cardiovascular outcome5-9 and may promote atherosclerosis and vascular inflammation6, suggesting a more complex role in chronic inflammatory settings. Indoleamine 2,3-dioxygenase activity is also increased in obesity10-13, yet its role in metabolic disease is still unexplored. Here, we show that obesity is associated with an increase of intestinal indoleamine 2,3-dioxygenase activity, which shifts tryptophan metabolism from indole derivative and interleukin-22 production toward kynurenine production. Indoleamine 2,3-dioxygenase deletion or inhibition improves insulin sensitivity, preserves the gut mucosal barrier, decreases endotoxemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. These beneficial effects are due to rewiring of tryptophan metabolism toward a microbiota-dependent production of interleukin-22 and are abrogated after treatment with a neutralizing anti-interleukin-22 antibody. In summary, we identify an unexpected function of indoleamine 2,3-dioxygenase in the fine tuning of intestinal tryptophan metabolism with major consequences on microbiota-dependent control of metabolic disease, which suggests indoleamine 2,3-dioxygenase as a potential therapeutic target.", + "TAG_DATA": [ + "140, Indoleamine {'perturbing_action': 'B-gene loss-of-function'}", + "141, 2,3-dioxygenase {'perturbing_action': 'I-gene loss-of-function'}", + "142, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "163, liver {'context': 'B-tissue/organ'}", + "165, adipose {'context': 'I-tissue/organ'}", + "166, tissues. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "140, Indoleamine ['l0', 'l1', 'l2', 'l3', 'l4']", + "141, 2,3-dioxygenase ['l0', 'l5', 'l6', 'l7', 'l8']", + "142, deletion ['l1', 'l5', 'l9', 'l10', 'l11']", + "163, liver ['l2', 'l6', 'l9', 'l12', 'l13']", + "165, adipose ['l3', 'l7', 'l10', 'l12', 'l14']", + "166, tissues. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Indoleamine", + "2,3-dioxygenase", + "deletion" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver", + "adipose", + "tissues." + ] + } + } + ] + }, + { + "PMID": "29934535", + "TEXT": "In the version of this article originally published, the amino acid sequence for Tα1 described in the Online Methods is incorrect. The sequence is described as \"Ac-SDAAVDTSSEITTJDLKEKKEVVEEAEN-OH\". It should be \"Ac-SDAAVDTSSEITTKDLKEKKEVVEEAEN-OH\". The error has been corrected in the HTML and PDF versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "29921958", + "TEXT": "In the version of this article originally published, the names of three authors were incorrect. The authors were listed as \"Coral Fustero-Torres\", \"Elena Pineiro\" and \"Melchor Sánchez-Martínez\". Their respective names are \"Coral Fustero-Torre\", \"Elena Piñeiro-Yáñez\" and \"Melchor Sanchez-Martinez\". The errors have been corrected in the print, HTML and PDF versions of this article.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "29892068", + "TEXT": "Detyrosinated microtubules provide mechanical resistance that can impede the motion of contracting cardiomyocytes. However, the functional effects of microtubule detyrosination in heart failure or in human hearts have not previously been studied. Here, we utilize mass spectrometry and single-myocyte mechanical assays to characterize changes to the cardiomyocyte cytoskeleton and their functional consequences in human heart failure. Proteomic analysis of left ventricle tissue reveals a consistent upregulation and stabilization of intermediate filaments and microtubules in failing human hearts. As revealed by super-resolution imaging, failing cardiomyocytes are characterized by a dense, heavily detyrosinated microtubule network, which is associated with increased myocyte stiffness and impaired contractility. Pharmacological suppression of detyrosinated microtubules lowers the viscoelasticity of failing myocytes and restores 40-50% of lost contractile function; reduction of microtubule detyrosination using a genetic approach also softens cardiomyocytes and improves contractile kinetics. Together, these data demonstrate that a modified cytoskeletal network impedes contractile function in cardiomyocytes from failing human hearts and that targeting detyrosinated microtubules could represent a new inotropic strategy for improving cardiac function.", + "TAG_DATA": [ + "112, failing {'context': 'B-cells'}", + "113, myocytes {'context': 'B-cells'}", + "131, cardiomyocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "112, failing ['l0']", + "113, myocytes ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29892067", + "TEXT": "Here, we report that genome editing by CRISPR-Cas9 induces a p53-mediated DNA damage response and cell cycle arrest in immortalized human retinal pigment epithelial cells, leading to a selection against cells with a functional p53 pathway. Inhibition of p53 prevents the damage response and increases the rate of homologous recombination from a donor template. These results suggest that p53 inhibition may improve the efficiency of genome editing of untransformed cells and that p53 function should be monitored when developing cell-based therapies utilizing CRISPR-Cas9.", + "TAG_DATA": [ + "8, induces {'effect': 'B-positive'}", + "15, cell {'phenotype': 'B-cell cycle arrest'}", + "16, cycle {'phenotype': 'I-cell cycle arrest'}", + "17, arrest {'phenotype': 'I-cell cycle arrest'}", + "19, immortalized {'context': 'B-cells'}", + "20, human {'context': 'I-cells'}", + "21, retinal {'context': 'I-cells'}", + "22, pigment {'context': 'I-cells'}", + "23, epithelial {'context': 'I-cells'}", + "24, cells, {'context': 'I-cells'}", + "30, cells {'context': 'B-cells'}", + "36, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "37, of {'perturbing_action': 'I-pharmacological inhibition'}", + "38, p53 {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "8, induces ['l0', 'l1', 'l2']", + "15, cell ['l0', 'l3', 'l4', 'l5']", + "16, cycle ['l1', 'l3', 'l6', 'l7']", + "17, arrest ['l2', 'l4', 'l6']", + "19, immortalized ['l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "20, human ['l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "21, retinal ['l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "22, pigment ['l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "23, epithelial ['l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "24, cells, ['l5', 'l7', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "30, cells ['l13', 'l18', 'l22', 'l25', 'l27', 'l28']", + "36, Inhibition ['l29', 'l30']", + "37, of ['l29', 'l31']", + "38, p53 ['l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells," + ] + } + } + ] + }, + { + "PMID": "29875463", + "TEXT": "Patients with metastatic cancer experience a severe loss of skeletal muscle mass and function known as cachexia. Cachexia is associated with poor prognosis and accelerated death in patients with cancer, yet its underlying mechanisms remain poorly understood. Here, we identify the metal-ion transporter ZRT- and IRT-like protein 14 (ZIP14) as a critical mediator of cancer-induced cachexia. ZIP14 is upregulated in cachectic muscles of mice and in patients with metastatic cancer and can be induced by TNF-α and TGF-β cytokines. Strikingly, germline ablation or muscle-specific depletion of Zip14 markedly reduces muscle atrophy in metastatic cancer models. We find that ZIP14-mediated zinc uptake in muscle progenitor cells represses the expression of MyoD and Mef2c and blocks muscle-cell differentiation. Importantly, ZIP14-mediated zinc accumulation in differentiated muscle cells induces myosin heavy chain loss. These results highlight a previously unrecognized role for altered zinc homeostasis in metastatic cancer-induced muscle wasting and implicate ZIP14 as a therapeutic target for its treatment.", + "TAG_DATA": [ + "83, muscle-specific {'perturbing_action': 'B-gene loss-of-function'}", + "84, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "85, of {'perturbing_action': 'I-gene loss-of-function'}", + "86, Zip14 {'perturbing_action': 'I-gene loss-of-function'}", + "92, metastatic {'context': 'B-neoplasm'}", + "93, cancer {'context': 'I-neoplasm'}", + "94, models. {'context': 'I-neoplasm'}", + "102, muscle {'context': 'B-cells'}", + "103, progenitor {'context': 'I-cells'}", + "104, cells {'context': 'I-cells'}", + "113, blocks {'effect': 'B-negative'}", + "114, muscle-cell {'context': 'B-cells'}", + "115, differentiation. {'phenotype': 'B-differentiation'}", + "121, differentiated {'context': 'B-cells'}", + "122, muscle {'context': 'I-cells'}", + "123, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "83, muscle-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "84, depletion ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "85, of ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "86, Zip14 ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "92, metastatic ['l3', 'l14', 'l24', 'l33', 'l42', 'l43']", + "93, cancer ['l4', 'l15', 'l25', 'l34', 'l42', 'l44']", + "94, models. ['l5', 'l16', 'l26', 'l35', 'l43', 'l44']", + "102, muscle ['l6', 'l17', 'l27', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49']", + "103, progenitor ['l7', 'l18', 'l28', 'l37', 'l45', 'l50', 'l51', 'l52', 'l53']", + "104, cells ['l8', 'l19', 'l29', 'l38', 'l46', 'l50', 'l54', 'l55', 'l56']", + "113, blocks ['l9', 'l20', 'l30', 'l39', 'l47', 'l51', 'l54', 'l57', 'l58']", + "114, muscle-cell ['l10', 'l21', 'l31', 'l40', 'l48', 'l52', 'l55', 'l57', 'l59']", + "115, differentiation. ['l11', 'l22', 'l32', 'l41', 'l49', 'l53', 'l56', 'l58', 'l59']", + "121, differentiated ['l60', 'l61']", + "122, muscle ['l60', 'l62']", + "123, cells ['l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "muscle-specific", + "depletion", + "of", + "Zip14" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "metastatic", + "cancer", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "muscle-specific", + "depletion", + "of", + "Zip14" + ] + }, + "context": { + "val": "cells", + "words": [ + "muscle", + "progenitor", + "cells", + "muscle-cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "muscle-specific", + "depletion", + "of", + "Zip14" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "muscle-specific", + "depletion", + "of", + "Zip14" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "muscle", + "progenitor", + "cells", + "muscle-cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "muscle", + "progenitor", + "cells", + "muscle-cell" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + } + ] + }, + { + "PMID": "29867228", + "TEXT": "Strategies to treat Zika virus (ZIKV) infection in dengue virus (DENV)-endemic areas are urgently needed. Here we show that a DENV-specific antibody against the E-dimer epitope (EDE) potently cross-neutralizes ZIKV and provides robust therapeutic efficacy as well as prophylactic efficacy against ZIKV in rhesus monkeys. Viral escape was not detected, suggesting a relatively high bar to escape. These data demonstrate the potential for antibody-based therapy and prevention of ZIKV.", + "TAG_DATA": [ + "43, rhesus {'context': 'B-organism'}", + "44, monkeys. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "43, rhesus ['l0']", + "44, monkeys. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29808005", + "TEXT": "Chimeric antigen receptor (CAR) therapy targeting CD19 is an effective treatment for refractory B cell malignancies, especially acute lymphoblastic leukemia (ALL) 1 . Although a majority of patients will achieve a complete response following a single infusion of CD19-targeted CAR-modified T cells (CD19 CAR T cells)2-4, the broad applicability of this treatment is hampered by severe cytokine release syndrome (CRS), which is characterized by fever, hypotension and respiratory insufficiency associated with elevated serum cytokines, including interleukin-6 (IL-6)2,5. CRS usually occurs within days of T cell infusion at the peak of CAR T cell expansion. In ALL, it is most frequent and more severe in patients with high tumor burden2-4. CRS may respond to IL-6 receptor blockade but can require further treatment with high dose corticosteroids to curb potentially lethal severity2-9. Improved therapeutic and preventive treatments require a better understanding of CRS physiopathology, which has so far remained elusive. Here we report a murine model of CRS that develops within 2-3 d of CAR T cell infusion and that is potentially lethal and responsive to IL-6 receptor blockade. We show that its severity is mediated not by CAR T cell-derived cytokines, but by IL-6, IL-1 and nitric oxide (NO) produced by recipient macrophages, which enables new therapeutic interventions.", + "TAG_DATA": [ + "152, murine {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "29785024", + "TEXT": "Recent studies have identified a specialized subset of CD31hiendomucinhi (CD31hiEMCNhi) vascular endothelium that positively regulates bone formation. However, it remains unclear how CD31hiEMCNhi endothelium levels are coupled to anabolic bone formation. Mice with an osteoblast-specific deletion of Shn3, which have markedly elevated bone formation, demonstrated an increase in CD31hiEMCNhi endothelium. Transcriptomic analysis identified SLIT3 as an osteoblast-derived, SHN3-regulated proangiogenic factor. Genetic deletion of Slit3 reduced skeletal CD31hiEMCNhi endothelium, resulted in low bone mass because of impaired bone formation and partially reversed the high bone mass phenotype of Shn3-/- mice. This coupling between osteoblasts and CD31hiEMCNhi endothelium is essential for bone healing, as shown by defective fracture repair in SLIT3-mutant mice and enhanced fracture repair in SHN3-mutant mice. Finally, administration of recombinant SLIT3 both enhanced bone fracture healing and counteracted bone loss in a mouse model of postmenopausal osteoporosis. Thus, drugs that target the SLIT3 pathway may represent a new approach for vascular-targeted osteoanabolic therapy to treat bone loss.", + "TAG_DATA": [ + "31, Mice {'context': 'B-organism'}", + "34, osteoblast-specific {'perturbing_action': 'B-gene loss-of-function'}", + "35, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "36, of {'perturbing_action': 'I-gene loss-of-function'}", + "37, Shn3, {'perturbing_action': 'I-gene loss-of-function'}", + "60, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "61, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "62, of {'perturbing_action': 'I-gene loss-of-function'}", + "63, Slit3 {'perturbing_action': 'I-gene loss-of-function'}", + "87, Shn3-/- {'perturbing_action': 'B-gene loss-of-function'}", + "88, mice. {'context': 'B-organism'}", + "108, SLIT3-mutant {'perturbing_action': 'B-other'}", + "109, mice {'context': 'B-organism'}", + "115, SHN3-mutant {'perturbing_action': 'B-other'}", + "116, mice. {'context': 'B-organism'}", + "133, mouse {'context': 'B-organism'}", + "134, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "31, Mice ['l0', 'l1', 'l2', 'l3']", + "34, osteoblast-specific ['l0', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "35, deletion ['l1', 'l4', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "36, of ['l2', 'l5', 'l11', 'l17', 'l18', 'l19', 'l20', 'l21']", + "37, Shn3, ['l3', 'l6', 'l12', 'l17', 'l22', 'l23']", + "60, Genetic ['l7', 'l13', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "61, deletion ['l8', 'l14', 'l19', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "62, of ['l9', 'l15', 'l20', 'l22', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "63, Slit3 ['l10', 'l16', 'l21', 'l23', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "87, Shn3-/- ['l27', 'l32', 'l36', 'l39', 'l42', 'l43', 'l44', 'l45']", + "88, mice. ['l28', 'l33', 'l37', 'l40', 'l42', 'l46', 'l47']", + "108, SLIT3-mutant ['l43', 'l46', 'l48', 'l49', 'l50']", + "109, mice ['l29', 'l34', 'l38', 'l41', 'l44', 'l47', 'l48', 'l51']", + "115, SHN3-mutant ['l49', 'l52']", + "116, mice. ['l45', 'l50', 'l51', 'l52']", + "133, mouse ['l53']", + "134, model ['l53']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice", + "mice.", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "osteoblast-specific", + "deletion", + "of", + "Shn3,", + "Genetic", + "Slit3", + "Shn3-/-" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "SLIT3-mutant", + "SHN3-mutant" + ] + } + } + ] + }, + { + "PMID": "29785023", + "TEXT": "Qualitative differences in the innate and adaptive responses elicited by different HIV vaccine candidates have not been thoroughly investigated. We tested the ability of the Aventis Pasteur live recombinant canarypox vector (ALVAC)-SIV, DNA-SIV and Ad26-SIV vaccine prime modalities together with two ALVAC-SIV + gp120 protein boosts to reduce the risk of SIVmac251 acquisition in rhesus macaques. We found that the DNA and ALVAC prime regimens were effective, but the Ad26 prime was not. The activation of hypoxia and the inflammasome in CD14+CD16- monocytes, gut-homing CCR5-negative CD4+ T helper 2 (TH2) cells and antibodies to variable region 2 correlated with a decreased risk of SIVmac251 acquisition. By contrast, signal transducer and activator of transcription 3 activation in CD16+ monocytes was associated with an increased risk of virus acquisition. The Ad26 prime regimen induced the accumulation of CX3CR1+CD163+ macrophages in lymph nodes and of long-lasting CD4+ TH17 cells in the gut and lungs. Our data indicate that the selective engagement of monocyte subsets following a vaccine prime influences long-term immunity, uncovering an unexpected association of CD14+ innate monocytes with a reduced risk of SIVmac251 acquisition.", + "TAG_DATA": [ + "52, rhesus {'context': 'B-organism'}", + "53, macaques. {'context': 'I-organism'}", + "79, CD14+CD16- {'context': 'B-cells'}", + "80, monocytes, {'context': 'I-cells'}", + "83, CD4+ {'context': 'I-cells'}", + "84, T {'context': 'I-cells'}", + "85, helper {'context': 'I-cells'}", + "86, 2 {'context': 'I-cells'}", + "87, (TH2) {'context': 'I-cells'}", + "88, cells {'context': 'I-cells'}", + "114, CD16+ {'context': 'B-cells'}", + "115, monocytes {'context': 'I-cells'}", + "133, CX3CR1+CD163+ {'context': 'B-cells'}", + "134, macrophages {'context': 'I-cells'}", + "136, lymph {'context': 'B-tissue/organ'}", + "137, nodes {'context': 'I-tissue/organ'}", + "141, CD4+ {'context': 'B-cells'}", + "142, TH17 {'context': 'I-cells'}", + "143, cells {'context': 'I-cells'}", + "146, gut {'context': 'B-tissue/organ'}", + "148, lungs. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "52, rhesus ['l0', 'l1']", + "53, macaques. ['l0', 'l2']", + "79, CD14+CD16- ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "80, monocytes, ['l1', 'l2', 'l3', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "83, CD4+ ['l4', 'l12', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "84, T ['l5', 'l13', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "85, helper ['l6', 'l14', 'l20', 'l26', 'l32', 'l33', 'l34', 'l35', 'l36']", + "86, 2 ['l7', 'l15', 'l21', 'l27', 'l32', 'l37', 'l38', 'l39', 'l40']", + "87, (TH2) ['l8', 'l16', 'l22', 'l28', 'l33', 'l37', 'l41', 'l42', 'l43']", + "88, cells ['l9', 'l17', 'l23', 'l29', 'l34', 'l38', 'l41', 'l44', 'l45']", + "114, CD16+ ['l10', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l46']", + "115, monocytes ['l11', 'l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l46']", + "133, CX3CR1+CD163+ ['l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "134, macrophages ['l47', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "136, lymph ['l48', 'l55', 'l62', 'l63', 'l64', 'l65', 'l66']", + "137, nodes ['l49', 'l56', 'l62']", + "141, CD4+ ['l50', 'l57', 'l67', 'l68', 'l69', 'l70']", + "142, TH17 ['l51', 'l58', 'l63', 'l67', 'l71', 'l72', 'l73']", + "143, cells ['l52', 'l59', 'l64', 'l68', 'l71', 'l74', 'l75']", + "146, gut ['l53', 'l60', 'l65', 'l69', 'l72', 'l74', 'l76']", + "148, lungs. ['l54', 'l61', 'l66', 'l70', 'l73', 'l75', 'l76']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29760445", + "TEXT": "Polycystic ovary syndrome (PCOS) is the main cause of female infertility worldwide and corresponds with a high degree of comorbidities and economic burden. How PCOS is passed on from one generation to the next is not clear, but it may be a developmental condition. Most women with PCOS exhibit higher levels of circulating luteinizing hormone, suggestive of heightened gonadotropin-releasing hormone (GnRH) release, and anti-Müllerian hormone (AMH) as compared to healthy women. Excess AMH in utero may affect the development of the female fetus. However, as AMH levels drop during pregnancy in women with normal fertility, it was unclear whether their levels were also elevated in pregnant women with PCOS. Here we measured AMH in a cohort of pregnant women with PCOS and control pregnant women and found that AMH is significantly more elevated in the former group versus the latter. To determine whether the elevation of AMH during pregnancy in women with PCOS is a bystander effect or a driver of the condition in the offspring, we modeled our clinical findings by treating pregnant mice with AMH and followed the neuroendocrine phenotype of their female progeny postnatally. This treatment resulted in maternal neuroendocrine-driven testosterone excess and diminished placental metabolism of testosterone to estradiol, resulting in a masculinization of the exposed female fetus and a PCOS-like reproductive and neuroendocrine phenotype in adulthood. We found that the affected females had persistently hyperactivated GnRH neurons and that GnRH antagonist treatment in the adult female offspring restored their neuroendocrine phenotype to a normal state. These findings highlight a critical role for excess prenatal AMH exposure and subsequent aberrant GnRH receptor signaling in the neuroendocrine dysfunctions of PCOS, while offering a new potential therapeutic avenue to treat the condition during adulthood.", + "TAG_DATA": [ + "172, pregnant {'context': 'B-organism'}", + "173, mice {'context': 'I-organism'}", + "209, female {'context': 'B-organism'}", + "210, fetus {'context': 'I-organism'}", + "225, females {'context': 'B-organism'}", + "230, neurons {'context': 'I-cells'}", + "238, adult {'context': 'B-organism'}", + "239, female {'context': 'I-organism'}", + "240, offspring {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "172, pregnant ['l0', 'l1', 'l2', 'l3']", + "173, mice ['l0', 'l4', 'l5']", + "184, progeny ['l1', 'l4', 'l6', 'l7']", + "209, female ['l2', 'l6', 'l8']", + "210, fetus ['l3', 'l5', 'l7', 'l8']", + "225, females ['l9']", + "230, neurons ['l9']", + "238, adult ['l10', 'l11']", + "239, female ['l10', 'l12']", + "240, offspring ['l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29736027", + "TEXT": "Depression, a devastating psychiatric disorder, is a leading cause of disability worldwide. Current antidepressants address specific symptoms of the disease, but there is vast room for improvement 1 . In this respect, new compounds that act beyond classical antidepressants to target signal transduction pathways governing synaptic plasticity and cellular resilience are highly warranted2-4. The extracellular signal-regulated kinase (ERK) pathway is implicated in mood regulation5-7, but its pleiotropic functions and lack of target specificity prohibit optimal drug development. Here, we identified the transcription factor ELK-1, an ERK downstream partner 8 , as a specific signaling module in the pathophysiology and treatment of depression that can be targeted independently of ERK. ELK1 mRNA was upregulated in postmortem hippocampal tissues from depressed suicides; in blood samples from depressed individuals, failure to reduce ELK1 expression was associated with resistance to treatment. In mice, hippocampal ELK-1 overexpression per se produced depressive behaviors; conversely, the selective inhibition of ELK-1 activation prevented depression-like molecular, plasticity and behavioral states induced by stress. Our work stresses the importance of target selectivity for a successful approach for signal-transduction-based antidepressants, singles out ELK-1 as a depression-relevant transducer downstream of ERK and brings proof-of-concept evidence for the druggability of ELK-1.", + "TAG_DATA": [ + "138, mice, {'context': 'B-organism'}", + "139, hippocampal {'perturbing_action': 'B-gene gain-of-function'}", + "140, ELK-1 {'perturbing_action': 'I-gene gain-of-function'}", + "141, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "149, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "150, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "151, of {'perturbing_action': 'I-pharmacological inhibition'}", + "152, ELK-1 {'perturbing_action': 'I-pharmacological inhibition'}", + "153, activation {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "138, mice, ['l0', 'l1', 'l2']", + "139, hippocampal ['l0', 'l3', 'l4']", + "140, ELK-1 ['l1', 'l3', 'l5']", + "141, overexpression ['l2', 'l4', 'l5']", + "149, selective ['l6', 'l7', 'l8', 'l9']", + "150, inhibition ['l6', 'l10', 'l11', 'l12']", + "151, of ['l7', 'l10', 'l13', 'l14']", + "152, ELK-1 ['l8', 'l11', 'l13', 'l15']", + "153, activation ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hippocampal", + "ELK-1", + "overexpression" + ] + } + } + ] + }, + { + "PMID": "29686426", + "TEXT": "T cells create vast amounts of diversity in the genes that encode their T cell receptors (TCRs), which enables individual clones to recognize specific peptide-major histocompatibility complex (MHC) ligands. Here we combined sequencing of the TCR-encoding genes with assay for transposase-accessible chromatin with sequencing (ATAC-seq) analysis at the single-cell level to provide information on the TCR specificity and epigenomic state of individual T cells. By using this approach, termed transcript-indexed ATAC-seq (T-ATAC-seq), we identified epigenomic signatures in immortalized leukemic T cells, primary human T cells from healthy volunteers and primary leukemic T cells from patient samples. In peripheral blood CD4+ T cells from healthy individuals, we identified cis and trans regulators of naive and memory T cell states and found substantial heterogeneity in surface-marker-defined T cell populations. In patients with a leukemic form of cutaneous T cell lymphoma, T-ATAC-seq enabled identification of leukemic and nonleukemic regulatory pathways in T cells from the same individual by allowing separation of the signals that arose from the malignant clone from the background T cell noise. Thus, T-ATAC-seq is a new tool that enables analysis of epigenomic landscapes in clonal T cells and should be valuable for studies of T cell malignancy, immunity and immunotherapy.", + "TAG_DATA": [ + "78, leukemic {'context': 'I-cells'}", + "79, T {'context': 'I-cells'}", + "80, cells, {'context': 'I-cells'}", + "81, primary {'context': 'B-cells'}", + "82, human {'context': 'I-cells'}", + "83, T {'context': 'I-cells'}", + "84, cells {'context': 'I-cells'}", + "87, volunteers {'context': 'I-cells'}", + "89, primary {'context': 'B-transformed cells'}", + "90, leukemic {'context': 'I-transformed cells'}", + "91, T {'context': 'I-transformed cells'}", + "92, cells {'context': 'I-cells'}", + "97, peripheral {'context': 'B-cells'}", + "98, blood {'context': 'I-cells'}", + "99, CD4+ {'context': 'I-cells'}", + "100, T {'context': 'I-cells'}", + "101, cells {'context': 'I-cells'}", + "104, individuals, {'context': 'I-cells'}", + "124, T {'context': 'B-cells'}", + "128, patients {'context': 'B-patient'}", + "147, T {'context': 'B-cells'}", + "148, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "78, leukemic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "79, T ['l0', 'l6']", + "80, cells, ['l1', 'l6']", + "81, primary ['l2', 'l7', 'l8', 'l9', 'l10']", + "82, human ['l3', 'l7', 'l11', 'l12', 'l13', 'l14']", + "83, T ['l8', 'l11', 'l15', 'l16', 'l17', 'l18']", + "84, cells ['l4', 'l9', 'l12', 'l15', 'l19']", + "87, volunteers ['l5', 'l10', 'l13', 'l16', 'l19']", + "89, primary ['l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "90, leukemic ['l20', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "91, T ['l17', 'l21', 'l30', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "92, cells ['l14', 'l18', 'l22', 'l31', 'l39', 'l47', 'l48', 'l49', 'l50', 'l51']", + "97, peripheral ['l23', 'l32', 'l40', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "98, blood ['l24', 'l33', 'l41', 'l47', 'l52', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "99, CD4+ ['l25', 'l34', 'l42', 'l53', 'l61', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "100, T ['l26', 'l35', 'l43', 'l48', 'l54', 'l62', 'l68', 'l76', 'l77', 'l78']", + "101, cells ['l27', 'l36', 'l44', 'l49', 'l55', 'l63', 'l69', 'l76', 'l79', 'l80']", + "104, individuals, ['l28', 'l37', 'l45', 'l50', 'l56', 'l64', 'l70', 'l77', 'l79', 'l81']", + "124, T ['l29', 'l38', 'l46', 'l51', 'l57', 'l65', 'l71', 'l78', 'l80', 'l81', 'l82', 'l83', 'l84']", + "128, patients ['l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "132, form ['l72', 'l85', 'l91', 'l92', 'l93', 'l94', 'l95']", + "134, T ['l58', 'l73', 'l82', 'l86', 'l91', 'l96', 'l97', 'l98', 'l99']", + "135, cell ['l59', 'l66', 'l74', 'l83', 'l87', 'l92', 'l96', 'l100', 'l101', 'l102']", + "136, lymphoma, ['l60', 'l67', 'l75', 'l84', 'l88', 'l93', 'l97', 'l100', 'l103', 'l104']", + "147, T ['l89', 'l94', 'l98', 'l101', 'l103', 'l105']", + "148, cells ['l90', 'l95', 'l99', 'l102', 'l104', 'l105']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29686423", + "TEXT": "Despite suppressive combination antiretroviral therapy (ART), latent HIV-1 proviruses persist in patients. This latent reservoir is established within 48-72 h after infection, has a long half-life1,2, enables viral rebound when ART is interrupted, and is the major barrier to a cure for HIV-1 3 . Latent cells are exceedingly rare in blood (∼1 per 1 × 106 CD4+ T cells) and are typically enumerated by indirect means, such as viral outgrowth assays4,5. We report a new strategy to purify and characterize single reactivated latent cells from HIV-1-infected individuals on suppressive ART. Surface expression of viral envelope protein was used to enrich reactivated latent T cells producing HIV RNA, and single-cell analysis was performed to identify intact virus. Reactivated latent cells produce full-length viruses that are identical to those found in viral outgrowth cultures and represent clones of in vivo expanded T cells, as determined by their T cell receptor sequence. Gene-expression analysis revealed that these cells share a transcriptional profile that includes expression of genes implicated in silencing the virus. We conclude that reactivated latent T cells isolated from blood can share a gene-expression program that allows for cell division without activation of the cell death pathways that are normally triggered by HIV-1 replication.", + "TAG_DATA": [ + "99, latent {'context': 'B-cells'}", + "100, T {'context': 'I-cells'}", + "101, cells {'context': 'I-cells'}", + "115, latent {'context': 'B-cells'}", + "116, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "99, latent ['l0', 'l1']", + "100, T ['l0', 'l2']", + "101, cells ['l1', 'l2']", + "115, latent ['l3']", + "116, cells ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29662202", + "TEXT": "Major depressive disorder (MDD) is considered a 'circuitopathy', and brain stimulation therapies hold promise for ameliorating MDD symptoms, including hippocampal dysfunction. It is unknown whether stimulation of upstream hippocampal circuitry, such as the entorhinal cortex (Ent), is antidepressive, although Ent stimulation improves learning and memory in mice and humans. Here we show that molecular targeting (Ent-specific knockdown of a psychosocial stress-induced protein) and chemogenetic stimulation of Ent neurons induce antidepressive-like effects in mice. Mechanistically, we show that Ent-stimulation-induced antidepressive-like behavior relies on the generation of new hippocampal neurons. Thus, controlled stimulation of Ent hippocampal afferents is antidepressive via increased hippocampal neurogenesis. These findings emphasize the power and potential of Ent glutamatergic afferent stimulation-previously well-known for its ability to influence learning and memory-for MDD treatment.", + "TAG_DATA": [ + "56, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "57, of {'perturbing_action': 'I-rnai/knockdown'}", + "58, a {'perturbing_action': 'I-rnai/knockdown'}", + "59, psychosocial {'perturbing_action': 'I-rnai/knockdown'}", + "60, stress-induced {'perturbing_action': 'I-rnai/knockdown'}", + "61, protein) {'perturbing_action': 'I-rnai/knockdown'}", + "66, Ent {'context': 'B-cells'}", + "67, neurons {'context': 'I-cells'}", + "72, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, knockdown ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "57, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "58, a ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "59, psychosocial ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "60, stress-induced ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "61, protein) ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "66, Ent ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "67, neurons ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "72, mice. ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "87, neurons. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "a", + "psychosocial", + "stress-induced", + "protein)" + ] + }, + "context": { + "val": "cells", + "words": [ + "Ent", + "neurons" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "a", + "psychosocial", + "stress-induced", + "protein)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "29662200", + "TEXT": "Sphingosine-1-phosphate (S1P) signaling influences bone metabolism, but its therapeutic potential in bone disorders has remained unexplored. We show that raising S1P levels in adult mice through conditionally deleting or pharmacologically inhibiting S1P lyase, the sole enzyme responsible for irreversibly degrading S1P, markedly increased bone formation, mass and strength and substantially decreased white adipose tissue. S1P signaling through S1P2 potently stimulated osteoblastogenesis at the expense of adipogenesis by inversely regulating osterix and PPAR-γ, and it simultaneously inhibited osteoclastogenesis by inducing osteoprotegerin through newly discovered p38-GSK3β-β-catenin and WNT5A-LRP5 pathways. Accordingly, S1P2-deficient mice were osteopenic and obese. In ovariectomy-induced osteopenia, S1P lyase inhibition was as effective as intermittent parathyroid hormone (iPTH) treatment in increasing bone mass and was superior to iPTH in enhancing bone strength. Furthermore, lyase inhibition in mice successfully corrected severe genetic osteoporosis caused by osteoprotegerin deficiency. Human data from 4,091 participants of the SHIP-Trend population-based study revealed a positive association between serum levels of S1P and bone formation markers, but not resorption markers. Furthermore, serum S1P levels were positively associated with serum calcium , negatively with PTH , and curvilinearly with body mass index. Bone stiffness, as determined through quantitative ultrasound, was inversely related to levels of both S1P and the bone formation marker PINP, suggesting that S1P stimulates osteoanabolic activity to counteract decreasing bone quality. S1P-based drugs should be considered as a promising therapeutic avenue for the treatment of osteoporotic diseases.", + "TAG_DATA": [ + "23, adult {'context': 'B-organism'}", + "24, mice {'context': 'I-organism'}", + "52, adipose {'context': 'I-tissue/organ'}", + "53, tissue. {'context': 'I-tissue/organ'}", + "86, S1P2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "87, mice {'context': 'B-organism'}", + "124, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "23, adult ['l0', 'l1', 'l2', 'l3']", + "24, mice ['l0', 'l4', 'l5', 'l6']", + "51, white ['l1', 'l4', 'l7', 'l8']", + "52, adipose ['l2', 'l5', 'l7', 'l9']", + "53, tissue. ['l3', 'l6', 'l8', 'l9']", + "86, S1P2-deficient ['l10']", + "87, mice ['l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "S1P2-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "29578539", + "TEXT": "Glucagon levels increase under homeostatic, fasting conditions, promoting the release of glucose from the liver by accelerating the breakdown of glycogen (also known as glycogenolysis). Glucagon also enhances gluconeogenic flux, including from an increase in the hepatic consumption of amino acids. In type 2 diabetes, dysregulated glucagon signaling contributes to the elevated hepatic glucose output and fasting hyperglycemia that occur in this condition. Yet, the mechanism by which glucagon stimulates gluconeogenesis remains incompletely understood. Contrary to the prevailing belief that glucagon acts primarily on cytoplasmic and nuclear targets, we find glucagon-dependent stimulation of mitochondrial anaplerotic flux from glutamine that increases the contribution of this amino acid to the carbons of glucose generated during gluconeogenesis. This enhanced glucose production is dependent on protein kinase A (PKA) and is associated with glucagon-stimulated calcium release from the endoplasmic reticulum, activation of mitochondrial α-ketoglutarate dehydrogenase, and increased glutaminolysis. Mice with reduced levels of hepatic glutaminase 2 (GLS2), the enzyme that catalyzes the first step in glutamine metabolism, show lower glucagon-stimulated glutamine-to-glucose flux in vivo, and GLS2 knockout results in higher fasting plasma glucagon and glutamine levels with lower fasting blood glucose levels in insulin-resistant conditions. As found in genome-wide association studies (GWAS), human genetic variation in the region of GLS2 is associated with higher fasting plasma glucose; here we show in human cryopreserved primary hepatocytes in vitro that these natural gain-of-function missense mutations in GLS2 result in higher glutaminolysis and glucose production. These data emphasize the importance of gluconeogenesis from glutamine, particularly in pathological states of increased glucagon signaling, while suggesting a possible new therapeutic avenue to treat hyperglycemia.", + "TAG_DATA": [ + "144, Mice {'context': 'B-organism'}", + "168, in {'context': 'B-in vivo'}", + "169, vivo, {'context': 'I-in vivo'}", + "171, GLS2 {'perturbing_action': 'B-gene loss-of-function'}", + "172, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "217, human {'context': 'B-cells'}", + "218, cryopreserved {'context': 'I-cells'}", + "219, primary {'context': 'I-cells'}", + "220, hepatocytes {'context': 'I-cells'}", + "221, in {'context': 'B-in vitro'}", + "222, vitro {'context': 'I-in vitro'}", + "228, mutations {'perturbing_action': 'I-gene loss-of-function'}", + "229, in {'perturbing_action': 'I-rnai/knockdown'}", + "230, GLS2 {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "144, Mice ['l0', 'l1']", + "168, in ['l0', 'l2']", + "169, vivo, ['l1', 'l2']", + "171, GLS2 ['l3']", + "172, knockout ['l3']", + "217, human ['l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "218, cryopreserved ['l4', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "219, primary ['l5', 'l13', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "220, hepatocytes ['l6', 'l14', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "221, in ['l7', 'l15', 'l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "222, vitro ['l8', 'l16', 'l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "227, missense ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "228, mutations ['l10', 'l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "229, in ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "230, GLS2 ['l12', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "cryopreserved", + "primary", + "hepatocytes" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "mutations" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "cryopreserved", + "primary", + "hepatocytes" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "in", + "GLS2" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "mutations" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "in", + "GLS2" + ] + } + } + ] + }, + { + "PMID": "29529015", + "TEXT": "Breast tumors of the basal-like, hormone receptor-negative subtype remain an unmet clinical challenge, as there is high rate of recurrence and poor survival in patients following treatment. Coevolution of the malignant mammary epithelium and its underlying stroma instigates cancer-associated fibroblasts (CAFs) to support most, if not all, hallmarks of cancer progression. Here we delineate a previously unappreciated role for CAFs as determinants of the molecular subtype of breast cancer. We identified paracrine crosstalk between cancer cells expressing platelet-derived growth factor (PDGF)-CC and CAFs expressing the cognate receptors in human basal-like mammary carcinomas. Genetic or pharmacological intervention of PDGF-CC activity in mouse models of cancer resulted in conversion of basal-like breast cancers into a hormone receptor-positive state that enhanced sensitivity to endocrine therapy in previously resistant tumors. We conclude that specification of breast cancer to the basal-like subtype is under microenvironmental control and is therapeutically actionable.", + "TAG_DATA": [ + "98, activity {'perturbing_action': 'I-pharmacological augmentation'}", + "100, mouse {'context': 'B-neoplasm'}", + "101, models {'context': 'I-neoplasm'}", + "102, of {'context': 'I-neoplasm'}", + "103, cancer {'context': 'I-neoplasm'}", + "108, basal-like {'context': 'B-neoplasm'}", + "109, breast {'context': 'I-neoplasm'}", + "110, cancers {'context': 'I-neoplasm'}", + "125, tumors. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "95, intervention ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "97, PDGF-CC ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "98, activity ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "100, mouse ['l2', 'l11', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "101, models ['l3', 'l12', 'l20', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "102, of ['l4', 'l13', 'l21', 'l27', 'l33', 'l39', 'l40', 'l41', 'l42']", + "103, cancer ['l5', 'l14', 'l22', 'l28', 'l34', 'l39', 'l43', 'l44', 'l45']", + "108, basal-like ['l6', 'l15', 'l23', 'l29', 'l35', 'l40', 'l43', 'l46', 'l47', 'l48']", + "109, breast ['l7', 'l16', 'l24', 'l30', 'l36', 'l41', 'l44', 'l46', 'l49', 'l50']", + "110, cancers ['l8', 'l17', 'l25', 'l31', 'l37', 'l42', 'l45', 'l47', 'l49', 'l51']", + "125, tumors. ['l9', 'l18', 'l32', 'l38', 'l48', 'l50', 'l51']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activity" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "models", + "of", + "cancer", + "basal-like", + "breast", + "cancers" + ] + } + } + ] + }, + { + "PMID": "29509754", + "TEXT": "In a nonhuman primate model of Zika virus infection, structural and cellular pathology deficits that could have a long-lasting impact on neural development and neurocognitive function are detected in offspring of infected mothers.", + "TAG_DATA": [ + "2, nonhuman {'context': 'B-organism'}", + "3, primate {'context': 'I-organism'}", + "4, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "2, nonhuman ['l0', 'l1']", + "3, primate ['l0', 'l2']", + "4, model ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29509750", + "TEXT": "Studies in metastatic melanoma, non-small-cell lung carcinoma and renal cell carcinoma indicate certain bacteria within the gut microbiota enhance clinical responses to checkpoint blockade.", + "TAG_DATA": [ + "2, metastatic {'context': 'B-neoplasm'}", + "3, melanoma, {'context': 'I-neoplasm'}", + "4, non-small-cell {'context': 'B-neoplasm'}", + "5, lung {'context': 'I-neoplasm'}", + "6, carcinoma {'context': 'I-neoplasm'}", + "8, renal {'context': 'B-neoplasm'}", + "9, cell {'context': 'I-neoplasm'}", + "10, carcinoma {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "2, metastatic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "3, melanoma, ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "4, non-small-cell ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "5, lung ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "6, carcinoma ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "8, renal ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "9, cell ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "10, carcinoma ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29505032", + "TEXT": "Insight into the cancer cell populations that are responsible for relapsed disease is needed to improve outcomes. Here we report a single-cell-based study of B cell precursor acute lymphoblastic leukemia at diagnosis that reveals hidden developmentally dependent cell signaling states that are uniquely associated with relapse. By using mass cytometry we simultaneously quantified 35 proteins involved in B cell development in 60 primary diagnostic samples. Each leukemia cell was then matched to its nearest healthy B cell population by a developmental classifier that operated at the single-cell level. Machine learning identified six features of expanded leukemic populations that were sufficient to predict patient relapse at diagnosis. These features implicated the pro-BII subpopulation of B cells with activated mTOR signaling, and the pre-BI subpopulation of B cells with activated and unresponsive pre-B cell receptor signaling, to be associated with relapse. This model, termed 'developmentally dependent predictor of relapse' (DDPR), significantly improves currently established risk stratification methods. DDPR features exist at diagnosis and persist at relapse. By leveraging a data-driven approach, we demonstrate the predictive value of single-cell 'omics' for patient stratification in a translational setting and provide a framework for its application to human cancer.", + "TAG_DATA": [ + "66, leukemia {'context': 'B-transformed cells'}", + "67, cell {'context': 'I-transformed cells'}", + "74, healthy {'context': 'B-cells'}", + "75, B {'context': 'I-cells'}", + "76, cell {'context': 'I-cells'}", + "77, population {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "66, leukemia ['l0', 'l1', 'l2', 'l3', 'l4']", + "67, cell ['l0', 'l5', 'l6', 'l7', 'l8']", + "74, healthy ['l1', 'l5', 'l9', 'l10', 'l11']", + "75, B ['l2', 'l6', 'l9', 'l12', 'l13']", + "76, cell ['l3', 'l7', 'l10', 'l12', 'l14']", + "77, population ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29431744", + "TEXT": "Deficits in Schwann cell-mediated remyelination impair functional restoration after nerve damage, contributing to peripheral neuropathies. The mechanisms mediating block of remyelination remain elusive. Here, through small-molecule screening focusing on epigenetic modulators, we identified histone deacetylase 3 (HDAC3; a histone-modifying enzyme) as a potent inhibitor of peripheral myelinogenesis. Inhibition of HDAC3 enhanced myelin growth and regeneration and improved functional recovery after peripheral nerve injury in mice. HDAC3 antagonizes the myelinogenic neuregulin-PI3K-AKT signaling axis. Moreover, genome-wide profiling analyses revealed that HDAC3 represses promyelinating programs through epigenetic silencing while coordinating with p300 histone acetyltransferase to activate myelination-inhibitory programs that include the HIPPO signaling effector TEAD4 to inhibit myelin growth. Schwann cell-specific deletion of either Hdac3 or Tead4 in mice resulted in an elevation of myelin thickness in sciatic nerves. Thus, our findings identify the HDAC3-TEAD4 network as a dual-function switch of cell-intrinsic inhibitory machinery that counters myelinogenic signals and maintains peripheral myelin homeostasis, highlighting the therapeutic potential of transient HDAC3 inhibition for improving peripheral myelin repair.", + "TAG_DATA": [ + "47, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "48, of {'perturbing_action': 'I-pharmacological inhibition'}", + "49, HDAC3 {'perturbing_action': 'I-pharmacological inhibition'}", + "64, mice. {'context': 'B-organism'}", + "106, Schwann {'perturbing_action': 'B-gene loss-of-function'}", + "107, cell-specific {'perturbing_action': 'I-gene loss-of-function'}", + "108, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "109, of {'perturbing_action': 'I-gene loss-of-function'}", + "110, either {'perturbing_action': 'I-gene loss-of-function'}", + "111, Hdac3 {'perturbing_action': 'I-gene loss-of-function'}", + "112, or {'perturbing_action': 'I-gene loss-of-function'}", + "113, Tead4 {'perturbing_action': 'I-gene loss-of-function'}", + "115, mice {'context': 'B-organism'}", + "124, sciatic {'context': 'B-tissue/organ'}", + "125, nerves. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "47, Inhibition ['l0', 'l1', 'l2']", + "48, of ['l0', 'l3', 'l4']", + "49, HDAC3 ['l1', 'l3', 'l5']", + "64, mice. ['l2', 'l4', 'l5']", + "106, Schwann ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "107, cell-specific ['l6', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "108, deletion ['l7', 'l16', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "109, of ['l8', 'l17', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "110, either ['l9', 'l18', 'l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "111, Hdac3 ['l10', 'l19', 'l27', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "112, or ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "113, Tead4 ['l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57']", + "115, mice ['l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l58', 'l59']", + "124, sciatic ['l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58', 'l60']", + "125, nerves. ['l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "HDAC3" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Schwann", + "cell-specific", + "deletion", + "of", + "either", + "Hdac3", + "or", + "Tead4" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Schwann", + "cell-specific", + "deletion", + "of", + "either", + "Hdac3", + "or", + "Tead4" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "sciatic", + "nerves." + ] + } + } + ] + }, + { + "PMID": "29400713", + "TEXT": "Adipocytes possess remarkable adaptive capacity to respond to nutrient excess, fasting or cold exposure, and they are thus an important cell type for the maintenance of proper metabolic health. Although the endoplasmic reticulum (ER) is a critical organelle for cellular homeostasis, the mechanisms that mediate adaptation of the ER to metabolic challenges in adipocytes are unclear. Here we show that brown adipose tissue (BAT) thermogenic function requires an adaptive increase in proteasomal activity to secure cellular protein quality control, and we identify the ER-localized transcription factor nuclear factor erythroid 2-like 1 (Nfe2l1, also known as Nrf1) as a critical driver of this process. We show that cold adaptation induces Nrf1 in BAT to increase proteasomal activity and that this is crucial for maintaining ER homeostasis and cellular integrity, specifically when the cells are in a state of high thermogenic activity. In mice, under thermogenic conditions, brown-adipocyte-specific deletion of Nfe2l1 (Nrf1) resulted in ER stress, tissue inflammation, markedly diminished mitochondrial function and whitening of the BAT. In mouse models of both genetic and dietary obesity, stimulation of proteasomal activity by exogenously expressing Nrf1 or by treatment with the proteasome activator PA28α in BAT resulted in improved insulin sensitivity. In conclusion, Nrf1 emerges as a novel guardian of brown adipocyte function, providing increased proteometabolic quality control for adapting to cold or to obesity.", + "TAG_DATA": [ + "141, mice, {'context': 'B-organism'}", + "145, brown-adipocyte-specific {'perturbing_action': 'B-gene loss-of-function'}", + "146, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "147, of {'perturbing_action': 'I-gene loss-of-function'}", + "148, Nfe2l1 {'perturbing_action': 'I-gene loss-of-function'}", + "149, (Nrf1) {'perturbing_action': 'I-gene loss-of-function'}", + "166, mouse {'context': 'B-organism'}", + "167, models {'context': 'I-organism'}", + "179, exogenously {'perturbing_action': 'B-gene gain-of-function'}", + "180, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "181, Nrf1 {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "141, mice, ['l0', 'l1', 'l2', 'l3', 'l4']", + "145, brown-adipocyte-specific ['l0', 'l5', 'l6', 'l7', 'l8']", + "146, deletion ['l1', 'l5', 'l9', 'l10', 'l11']", + "147, of ['l2', 'l6', 'l9', 'l12', 'l13']", + "148, Nfe2l1 ['l3', 'l7', 'l10', 'l12', 'l14']", + "149, (Nrf1) ['l4', 'l8', 'l11', 'l13', 'l14']", + "166, mouse ['l15', 'l16', 'l17', 'l18']", + "167, models ['l15', 'l19', 'l20', 'l21']", + "179, exogenously ['l16', 'l19', 'l22', 'l23']", + "180, expressing ['l17', 'l20', 'l22', 'l24']", + "181, Nrf1 ['l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "brown-adipocyte-specific", + "deletion", + "of", + "Nfe2l1", + "(Nrf1)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "exogenously", + "expressing", + "Nrf1" + ] + } + } + ] + }, + { + "PMID": "29400711", + "TEXT": "Diffuse white-matter disease associated with small-vessel disease and dementia is prevalent in the elderly. The biological mechanisms, however, remain elusive. Using pericyte-deficient mice, magnetic resonance imaging, viral-based tract-tracing, and behavior and tissue analysis, we found that pericyte degeneration disrupted white-matter microcirculation, resulting in an accumulation of toxic blood-derived fibrin(ogen) deposits and blood-flow reductions, which triggered a loss of myelin, axons and oligodendrocytes. This disrupted brain circuits, leading to white-matter functional deficits before neuronal loss occurs. Fibrinogen and fibrin fibrils initiated autophagy-dependent cell death in oligodendrocyte and pericyte cultures, whereas pharmacological and genetic manipulations of systemic fibrinogen levels in pericyte-deficient, but not control mice, influenced the degree of white-matter fibrin(ogen) deposition, pericyte degeneration, vascular pathology and white-matter changes. Thus, our data indicate that pericytes control white-matter structure and function, which has implications for the pathogenesis and treatment of human white-matter disease associated with small-vessel disease.", + "TAG_DATA": [ + "21, pericyte-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "22, mice, {'context': 'B-organism'}", + "79, initiated {'effect': 'B-positive'}", + "81, cell {'phenotype': 'B-cell death'}", + "82, death {'phenotype': 'I-cell death'}", + "84, oligodendrocyte {'context': 'B-cells'}", + "85, and {'context': 'I-cells'}", + "86, pericyte {'context': 'I-cells'}", + "87, cultures, {'context': 'I-cells'}", + "98, pericyte-deficient, {'perturbing_action': 'B-gene loss-of-function'}", + "102, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "21, pericyte-deficient ['l0']", + "22, mice, ['l0']", + "79, initiated ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "81, cell ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "82, death ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "84, oligodendrocyte ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "85, and ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "86, pericyte ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "87, cultures, ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']", + "98, pericyte-deficient, ['l22']", + "102, mice, ['l22']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pericyte-deficient", + "pericyte-deficient," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiated" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiated" + ] + }, + "context": { + "val": "cells", + "words": [ + "oligodendrocyte", + "and", + "pericyte", + "cultures," + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "oligodendrocyte", + "and", + "pericyte", + "cultures," + ] + } + } + ] + }, + { + "PMID": "29400709", + "TEXT": "Zika virus (ZIKV) is a flavivirus with teratogenic effects on fetal brain, but the spectrum of ZIKV-induced brain injury is unknown, particularly when ultrasound imaging is normal. In a pregnant pigtail macaque (Macaca nemestrina) model of ZIKV infection, we demonstrate that ZIKV-induced injury to fetal brain is substantial, even in the absence of microcephaly, and may be challenging to detect in a clinical setting. A common and subtle injury pattern was identified, including (i) periventricular T2-hyperintense foci and loss of fetal noncortical brain volume, (ii) injury to the ependymal epithelium with underlying gliosis and (iii) loss of late fetal neuronal progenitor cells in the subventricular zone (temporal cortex) and subgranular zone (dentate gyrus, hippocampus) with dysmorphic granule neuron patterning. Attenuation of fetal neurogenic output demonstrates potentially considerable teratogenic effects of congenital ZIKV infection even without microcephaly. Our findings suggest that all children exposed to ZIKV in utero should receive long-term monitoring for neurocognitive deficits, regardless of head size at birth.", + "TAG_DATA": [ + "29, pregnant {'context': 'B-organism'}", + "30, pigtail {'context': 'I-organism'}", + "31, macaque {'context': 'I-organism'}", + "32, (Macaca {'context': 'I-organism'}", + "33, nemestrina) {'context': 'I-organism'}", + "34, model {'context': 'I-organism'}", + "44, fetal {'context': 'B-tissue/organ'}", + "45, brain {'context': 'I-tissue/organ'}", + "88, ependymal {'context': 'B-cells'}", + "89, epithelium {'context': 'I-tissue/organ'}", + "97, late {'context': 'B-cells'}", + "98, fetal {'context': 'I-cells'}", + "99, neuronal {'context': 'I-cells'}", + "100, progenitor {'context': 'I-cells'}", + "101, cells {'context': 'I-cells'}", + "105, zone {'context': 'I-cells'}", + "106, (temporal {'context': 'I-cells'}", + "107, cortex) {'context': 'I-cells'}", + "112, gyrus, {'context': 'I-cells'}", + "113, hippocampus) {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "29, pregnant ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "30, pigtail ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "31, macaque ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "32, (Macaca ['l2', 'l10', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "33, nemestrina) ['l3', 'l11', 'l18', 'l23', 'l29', 'l30', 'l31', 'l32', 'l33']", + "34, model ['l4', 'l12', 'l19', 'l24', 'l29', 'l34', 'l35']", + "44, fetal ['l5', 'l13', 'l20', 'l25', 'l30', 'l34', 'l36']", + "45, brain ['l6', 'l14', 'l21', 'l26', 'l31', 'l35', 'l36']", + "88, ependymal ['l7', 'l15', 'l27', 'l32', 'l37', 'l38']", + "89, epithelium ['l8', 'l16', 'l22', 'l28', 'l33', 'l37', 'l39']", + "97, late ['l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "98, fetal ['l40', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "99, neuronal ['l41', 'l50', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "100, progenitor ['l42', 'l51', 'l59', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "101, cells ['l38', 'l39', 'l43', 'l52', 'l60', 'l67', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "104, subventricular ['l44', 'l53', 'l61', 'l68', 'l74', 'l80', 'l81', 'l82', 'l83', 'l84']", + "105, zone ['l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l85', 'l86', 'l87', 'l88']", + "106, (temporal ['l46', 'l55', 'l63', 'l70', 'l76', 'l81', 'l85', 'l89', 'l90', 'l91']", + "107, cortex) ['l47', 'l56', 'l64', 'l71', 'l77', 'l82', 'l86', 'l89', 'l92', 'l93']", + "112, gyrus, ['l48', 'l57', 'l65', 'l72', 'l78', 'l83', 'l87', 'l90', 'l92', 'l94']", + "113, hippocampus) ['l49', 'l58', 'l66', 'l73', 'l79', 'l84', 'l88', 'l91', 'l93', 'l94']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29334374", + "TEXT": "Myeloid-derived suppressor cells (MDSCs) are pathologically activated and relatively immature myeloid cells that have been implicated in the immunological regulation of many pathologic conditions. Phenotypically and morphologically, MDSCs are similar to neutrophils (PMN-MDSCs) and monocytes (M-MDSCs). However, they have potent suppressive activity and distinct gene expression profiles and biochemical characteristics. No or very few MDSCs are observed in steady-state physiological conditions. Therefore, until recently, accumulation of MDSCs was considered a consequence of pathological processes or pregnancy. Here, we report that MDSCs with a potent ability to suppress T cells are present during the first weeks of life in mice and humans. MDSC suppressive activity was triggered by lactoferrin and mediated by nitric oxide, PGE2, and S100A9 and S100A8 proteins. MDSCs from newborns had a transcriptome similar to that of tumor MDSCs, but with strong upregulation of an antimicrobial gene network, and had potent antibacterial activity. MDSCs played a critical role in control of experimental necrotizing enterocolitis (NEC) in newborn mice. MDSCs in infants with very low weight, who are prone to NEC, had lower MDSC levels and suppressive activity than did infants with normal weight. Thus, the transitory presence of MDSCs may be critical for regulation of inflammation in newborns.", + "TAG_DATA": [ + "158, newborn {'context': 'B-organism'}", + "159, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "158, newborn ['l0']", + "159, mice. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29309056", + "TEXT": "There is a substantial unmet clinical need for new strategies to protect the hematopoietic stem cell (HSC) pool and regenerate hematopoiesis after radiation injury from either cancer therapy or accidental exposure. Increasing evidence suggests that sex hormones, beyond their role in promoting sexual dimorphism, regulate HSC self-renewal, differentiation, and proliferation. We and others have previously reported that sex-steroid ablation promotes bone marrow (BM) lymphopoiesis and HSC recovery in aged and immunodepleted mice. Here we found that a luteinizing hormone (LH)-releasing hormone antagonist (LHRH-Ant), currently in wide clinical use for sex-steroid inhibition, promoted hematopoietic recovery and mouse survival when administered 24 h after an otherwise-lethal dose of total-body irradiation (L-TBI). Unexpectedly, this protective effect was independent of sex steroids and instead relied on suppression of LH levels. Human and mouse long-term self-renewing HSCs (LT-HSCs) expressed high levels of the LH/choriogonadotropin receptor (LHCGR) and expanded ex vivo when stimulated with LH. In contrast, the suppression of LH after L-TBI inhibited entry of HSCs into the cell cycle, thus promoting HSC quiescence and protecting the cells from exhaustion. These findings reveal a role of LH in regulating HSC function and offer a new therapeutic approach for hematopoietic regeneration after hematopoietic injury.", + "TAG_DATA": [ + "68, aged {'context': 'B-organism'}", + "71, mice. {'context': 'B-organism'}", + "77, luteinizing {'perturbing_action': 'B-pharmacological inhibition'}", + "78, hormone {'perturbing_action': 'I-pharmacological inhibition'}", + "79, (LH)-releasing {'perturbing_action': 'I-pharmacological inhibition'}", + "80, hormone {'perturbing_action': 'I-pharmacological inhibition'}", + "81, antagonist {'perturbing_action': 'I-pharmacological inhibition'}", + "82, (LHRH-Ant), {'perturbing_action': 'I-pharmacological inhibition'}", + "95, mouse {'context': 'B-organism'}", + "126, Human {'context': 'B-cells'}", + "127, and {'context': 'I-cells'}", + "128, mouse {'context': 'I-cells'}", + "129, long-term {'context': 'I-cells'}", + "130, self-renewing {'context': 'I-cells'}", + "131, HSCs {'context': 'I-cells'}", + "132, (LT-HSCs) {'context': 'I-cells'}", + "160, HSCs {'context': 'B-cells'}", + "166, promoting {'effect': 'B-positive'}", + "167, HSC {'context': 'B-cells'}", + "168, quiescence {'phenotype': 'B-quiescence'}", + "172, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "68, aged ['l0']", + "71, mice. ['l0']", + "77, luteinizing ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "78, hormone ['l1', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "79, (LH)-releasing ['l2', 'l14', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "80, hormone ['l3', 'l15', 'l26', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "81, antagonist ['l4', 'l16', 'l27', 'l37', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "82, (LHRH-Ant), ['l5', 'l17', 'l28', 'l38', 'l47', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "95, mouse ['l6', 'l18', 'l29', 'l39', 'l48', 'l56']", + "126, Human ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "127, and ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l64', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "128, mouse ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l65', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "129, long-term ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l66', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "130, self-renewing ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l67', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "131, HSCs ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l68', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "132, (LT-HSCs) ['l13', 'l25', 'l36', 'l46', 'l55', 'l63', 'l69', 'l74', 'l79', 'l83', 'l86', 'l88']", + "160, HSCs ['l75', 'l80', 'l84', 'l87', 'l89', 'l90', 'l91', 'l92', 'l93']", + "166, promoting ['l90', 'l94', 'l95', 'l96']", + "167, HSC ['l91', 'l94', 'l97', 'l98']", + "168, quiescence ['l92', 'l95', 'l97', 'l99']", + "172, cells ['l93', 'l96', 'l98', 'l99']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "luteinizing", + "hormone", + "(LH)-releasing", + "antagonist", + "(LHRH-Ant)," + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "luteinizing", + "hormone", + "(LH)-releasing", + "antagonist", + "(LHRH-Ant)," + ] + }, + "context": { + "val": "cells", + "words": [ + "Human", + "and", + "mouse", + "long-term", + "self-renewing", + "HSCs", + "(LT-HSCs)" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSCs", + "HSC", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSCs", + "HSC", + "cells" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + } + } + ] + }, + { + "PMID": "29227476", + "TEXT": "We present the molecular landscape of pediatric acute myeloid leukemia (AML) and characterize nearly 1,000 participants in Children's Oncology Group (COG) AML trials. The COG-National Cancer Institute (NCI) TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA and microRNA sequencing and CpG methylation profiling. Validated DNA variants corresponded to diverse, infrequent mutations, with fewer than 40 genes mutated in >2% of cases. In contrast, somatic structural variants, including new gene fusions and focal deletions of MBNL1, ZEB2 and ELF1, were disproportionately prevalent in young individuals as compared to adults. Conversely, mutations in DNMT3A and TP53, which were common in adults, were conspicuously absent from virtually all pediatric cases. New mutations in GATA2, FLT3 and CBL and recurrent mutations in MYC-ITD, NRAS, KRAS and WT1 were frequent in pediatric AML. Deletions, mutations and promoter DNA hypermethylation convergently impacted Wnt signaling, Polycomb repression, innate immune cell interactions and a cluster of zinc finger-encoding genes associated with KMT2A rearrangements. These results highlight the need for and facilitate the development of age-tailored targeted therapies for the treatment of pediatric AML.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "29227474", + "TEXT": "The stress-responsive epigenetic repressor histone deacetylase 4 (HDAC4) regulates cardiac gene expression. Here we show that the levels of an N-terminal proteolytically derived fragment of HDAC4, termed HDAC4-NT, are lower in failing mouse hearts than in healthy control hearts. Virus-mediated transfer of the portion of the Hdac4 gene encoding HDAC4-NT into the mouse myocardium protected the heart from remodeling and failure; this was associated with decreased expression of Nr4a1, which encodes a nuclear orphan receptor, and decreased NR4A1-dependent activation of the hexosamine biosynthetic pathway (HBP). Conversely, exercise enhanced HDAC4-NT levels, and mice with a cardiomyocyte-specific deletion of Hdac4 show reduced exercise capacity, which was characterized by cardiac fatigue and increased expression of Nr4a1. Mechanistically, we found that NR4A1 negatively regulated contractile function in a manner that depended on the HBP and the calcium sensor STIM1. Our work describes a new regulatory axis in which epigenetic regulation of a metabolic pathway affects calcium handling. Activation of this axis during intermittent physiological stress promotes cardiac function, whereas its impairment in sustained pathological cardiac stress leads to heart failure.", + "TAG_DATA": [ + "56, heart {'context': 'B-tissue/organ'}", + "91, mice {'context': 'B-organism'}", + "94, cardiomyocyte-specific {'perturbing_action': 'B-gene loss-of-function'}", + "95, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "96, of {'perturbing_action': 'I-gene loss-of-function'}", + "97, Hdac4 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "91, mice ['l0', 'l1', 'l2', 'l3']", + "94, cardiomyocyte-specific ['l0', 'l4', 'l5', 'l6']", + "95, deletion ['l1', 'l4', 'l7', 'l8']", + "96, of ['l2', 'l5', 'l7', 'l9']", + "97, Hdac4 ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cardiomyocyte-specific", + "deletion", + "of", + "Hdac4" + ] + } + } + ] + }, + { + "PMID": "29155426", + "TEXT": "Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent effects in relapsed and/or refractory pre-B cell acute lymphoblastic leukemia (B-ALL), but antigen loss is a frequent cause of resistance to CD19-targeted immunotherapy. CD22 is also expressed in most cases of B-ALL and is usually retained following CD19 loss. We report results from a phase 1 trial testing a new CD22-targeted CAR (CD22-CAR) in 21 children and adults, including 17 who were previously treated with CD19-directed immunotherapy. Dose-dependent antileukemic activity was observed, with complete remission obtained in 73% (11/15) of patients receiving ≥1 × 106 CD22-CAR T cells per kg body weight, including 5 of 5 patients with CD19dim or CD19- B-ALL. Median remission duration was 6 months. Relapses were associated with diminished CD22 site density that likely permitted CD22+ cell escape from killing by CD22-CAR T cells. These results are the first to establish the clinical activity of a CD22-CAR in B-ALL, including leukemia resistant to anti-CD19 immunotherapy, demonstrating potency against B-ALL comparable to that of CD19-CAR at biologically active doses. Our results also highlight the critical role played by antigen density in regulating CAR function.", + "TAG_DATA": [ + "65, children {'context': 'B-organism'}", + "66, and {'context': 'I-organism'}", + "67, adults, {'context': 'I-organism'}", + "129, CD22+ {'context': 'B-cells'}", + "130, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "65, children ['l0', 'l1']", + "66, and ['l0', 'l2']", + "67, adults, ['l1', 'l2']", + "129, CD22+ ['l3']", + "130, cell ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29131160", + "TEXT": "Human liver cancer research currently lacks in vitro models that can faithfully recapitulate the pathophysiology of the original tumor. We recently described a novel, near-physiological organoid culture system, wherein primary human healthy liver cells form long-term expanding organoids that retain liver tissue function and genetic stability. Here we extend this culture system to the propagation of primary liver cancer (PLC) organoids from three of the most common PLC subtypes: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and combined HCC/CC (CHC) tumors. PLC-derived organoid cultures preserve the histological architecture, gene expression and genomic landscape of the original tumor, allowing for discrimination between different tumor tissues and subtypes, even after long-term expansion in culture in the same medium conditions. Xenograft studies demonstrate that the tumorogenic potential, histological features and metastatic properties of PLC-derived organoids are preserved in vivo. PLC-derived organoids are amenable for biomarker identification and drug-screening testing and led to the identification of the ERK inhibitor SCH772984 as a potential therapeutic agent for primary liver cancer. We thus demonstrate the wide-ranging biomedical utilities of PLC-derived organoid models in furthering the understanding of liver cancer biology and in developing personalized-medicine approaches for the disease.", + "TAG_DATA": [ + "79, PLC-derived {'context': 'B-organoid'}", + "80, organoid {'context': 'I-organoid'}", + "81, cultures {'context': 'I-organoid'}", + "115, Xenograft {'context': 'B-xenograft'}", + "120, tumorogenic {'phenotype': 'B-tumourigenesis'}", + "121, potential, {'phenotype': 'I-tumour initiation'}", + "125, metastatic {'phenotype': 'B-metastasis'}", + "126, properties {'phenotype': 'I-metastasis'}", + "128, PLC-derived {'context': 'B-organoid'}", + "129, organoids {'context': 'I-organoid'}", + "131, preserved {'effect': 'B-no effect'}", + "132, in {'context': 'B-in vivo'}", + "133, vivo. {'context': 'I-in vivo'}", + "134, PLC-derived {'context': 'B-organoid'}", + "135, organoids {'context': 'I-organoid'}" + ], + "LINK_DATA": [ + "79, PLC-derived ['l0', 'l1']", + "80, organoid ['l0', 'l2']", + "81, cultures ['l1', 'l2']", + "115, Xenograft ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "120, tumorogenic ['l3', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "121, potential, ['l4', 'l12', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "125, metastatic ['l5', 'l13', 'l20', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "126, properties ['l6', 'l14', 'l21', 'l27', 'l35', 'l36', 'l37', 'l38', 'l39']", + "128, PLC-derived ['l7', 'l15', 'l22', 'l28', 'l35', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "129, organoids ['l8', 'l16', 'l23', 'l29', 'l36', 'l40', 'l46', 'l47', 'l48', 'l49']", + "131, preserved ['l9', 'l17', 'l24', 'l30', 'l37', 'l41', 'l46', 'l50', 'l51']", + "132, in ['l10', 'l18', 'l25', 'l31', 'l38', 'l42', 'l47', 'l50', 'l52', 'l53']", + "133, vivo. ['l11', 'l19', 'l26', 'l32', 'l39', 'l43', 'l48', 'l51', 'l52', 'l54']", + "134, PLC-derived ['l33', 'l44', 'l55']", + "135, organoids ['l34', 'l45', 'l49', 'l53', 'l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "xenograft", + "words": [ + "Xenograft" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorogenic" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "Xenograft" + ] + }, + "phenotype": { + "val": "tumour initiation", + "words": [ + "potential," + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "Xenograft" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "properties" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "Xenograft" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "preserved" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorogenic" + ] + }, + "context": { + "val": "organoid", + "words": [ + "PLC-derived", + "organoids" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorogenic" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "preserved" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorogenic" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "tumour initiation", + "words": [ + "potential," + ] + }, + "context": { + "val": "organoid", + "words": [ + "PLC-derived", + "organoids" + ] + } + }, + { + "phenotype": { + "val": "tumour initiation", + "words": [ + "potential," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "preserved" + ] + } + }, + { + "phenotype": { + "val": "tumour initiation", + "words": [ + "potential," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "properties" + ] + }, + "context": { + "val": "organoid", + "words": [ + "PLC-derived", + "organoids" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "properties" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "preserved" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "properties" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "PLC-derived", + "organoids" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "preserved" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "preserved" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "29131158", + "TEXT": "Uncoupling protein 1 (UCP1) plays a central role in nonshivering thermogenesis in brown fat; however, its role in beige fat remains unclear. Here we report a robust UCP1-independent thermogenic mechanism in beige fat that involves enhanced ATP-dependent Ca2+ cycling by sarco/endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) and ryanodine receptor 2 (RyR2). Inhibition of SERCA2b impairs UCP1-independent beige fat thermogenesis in humans and mice as well as in pigs, a species that lacks a functional UCP1 protein. Conversely, enhanced Ca2+ cycling by activation of α1- and/or β3-adrenergic receptors or the SERCA2b-RyR2 pathway stimulates UCP1-independent thermogenesis in beige adipocytes. In the absence of UCP1, beige fat dynamically expends glucose through enhanced glycolysis, tricarboxylic acid metabolism and pyruvate dehydrogenase activity for ATP-dependent thermogenesis through the SERCA2b pathway; beige fat thereby functions as a 'glucose sink' and improves glucose tolerance independently of body weight loss. Our study uncovers a noncanonical thermogenic mechanism through which beige fat controls whole-body energy homeostasis via Ca2+ cycling.", + "TAG_DATA": [ + "50, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "51, of {'perturbing_action': 'I-pharmacological inhibition'}", + "52, SERCA2b {'perturbing_action': 'I-pharmacological inhibition'}", + "56, fat {'context': 'I-tissue/organ'}", + "59, humans {'context': 'B-organism'}", + "61, mice {'context': 'B-organism'}", + "66, pigs, {'context': 'B-organism'}", + "94, beige {'context': 'B-cells'}", + "95, adipocytes. {'context': 'I-cells'}", + "98, absence {'perturbing_action': 'B-gene loss-of-function'}", + "99, of {'perturbing_action': 'I-gene loss-of-function'}", + "100, UCP1, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "50, Inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "51, of ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "52, SERCA2b ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "55, beige ['l2', 'l9', 'l15', 'l21', 'l22', 'l23']", + "56, fat ['l3', 'l10', 'l16', 'l21', 'l24', 'l25']", + "59, humans ['l4', 'l11', 'l17', 'l22', 'l24', 'l26']", + "61, mice ['l5', 'l12', 'l18', 'l23', 'l25', 'l26']", + "66, pigs, ['l6', 'l13', 'l19', 'l27']", + "94, beige ['l28']", + "95, adipocytes. ['l7', 'l14', 'l20', 'l27', 'l28']", + "98, absence ['l29', 'l30']", + "99, of ['l29', 'l31']", + "100, UCP1, ['l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "SERCA2b" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "fat" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "SERCA2b" + ] + }, + "context": { + "val": "organism", + "words": [ + "humans", + "mice", + "pigs," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "SERCA2b" + ] + }, + "context": { + "val": "cells", + "words": [ + "adipocytes." + ] + } + } + ] + }, + { + "PMID": "29117171", + "TEXT": "Genetic association studies of the human genome often omit the X chromosome because of the unique analytical challenges it presents. A concerted effort to undo this exclusion could offer medically relevant insights into basic biology that might otherwise be missed.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "29106400", + "TEXT": "Cancer-specific cell-surface antigens are ideal targets for monoclonal antibody (mAb)-based immunotherapy but are likely to have previously been identified in transcriptome or proteome analyses. Here, we show that the active conformer of an integrin can serve as a specific therapeutic target for multiple myeloma (MM). We screened >10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb specifically recognizing a subset of integrin β7 molecules. The MMG49 epitope, in the N-terminal region of the β7 chain, is predicted to be inaccessible in the resting integrin conformer but exposed in the active conformation. Elevated expression and constitutive activation of integrin β7 conferred high MMG49 reactivity on MM cells, whereas MMG49 binding was scarcely detectable in other cell types including normal integrin β7+ lymphocytes. T cells transduced with MMG49-derived chimeric antigen receptor (CAR) exerted anti-MM effects without damaging normal hematopoietic cells. Thus, MMG49 CAR T cell therapy is promising for MM, and a receptor protein with a rare but physiologically relevant conformation can serve as a cancer immunotherapy target.", + "TAG_DATA": [ + "96, constitutive {'perturbing_action': 'B-gene gain-of-function'}", + "97, activation {'perturbing_action': 'I-gene gain-of-function'}", + "98, of {'perturbing_action': 'I-gene gain-of-function'}", + "99, integrin {'perturbing_action': 'I-gene gain-of-function'}", + "100, β7 {'perturbing_action': 'I-gene gain-of-function'}", + "106, MM {'context': 'B-transformed cells'}", + "107, cells, {'context': 'I-transformed cells'}", + "116, cell {'context': 'B-cells'}", + "117, types {'context': 'I-cells'}", + "123, T {'context': 'B-cells'}", + "124, cells {'context': 'B-cells'}", + "125, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "126, with {'perturbing_action': 'I-gene gain-of-function'}", + "127, MMG49-derived {'perturbing_action': 'I-gene gain-of-function'}", + "128, chimeric {'perturbing_action': 'I-gene gain-of-function'}", + "129, antigen {'perturbing_action': 'I-gene gain-of-function'}", + "130, receptor {'perturbing_action': 'I-gene gain-of-function'}", + "131, (CAR) {'perturbing_action': 'I-gene gain-of-function'}", + "138, hematopoietic {'context': 'I-cells'}", + "139, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "96, constitutive ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "97, activation ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "98, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "99, integrin ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "100, β7 ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "106, MM ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "107, cells, ['l5', 'l12', 'l18', 'l23', 'l27', 'l30']", + "116, cell ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33']", + "117, types ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l33']", + "123, T ['l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "124, cells ['l34', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "125, transduced ['l35', 'l44', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "126, with ['l36', 'l45', 'l53', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "127, MMG49-derived ['l37', 'l46', 'l54', 'l61', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "128, chimeric ['l38', 'l47', 'l55', 'l62', 'l68', 'l74', 'l75', 'l76', 'l77', 'l78']", + "129, antigen ['l39', 'l48', 'l56', 'l63', 'l69', 'l74', 'l79', 'l80', 'l81', 'l82']", + "130, receptor ['l40', 'l49', 'l57', 'l64', 'l70', 'l75', 'l79', 'l83', 'l84', 'l85']", + "131, (CAR) ['l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l83', 'l86', 'l87']", + "138, hematopoietic ['l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l86', 'l88']", + "139, cells. ['l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l87', 'l88']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutive", + "activation", + "of", + "integrin", + "β7" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MM", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutive", + "activation", + "of", + "integrin", + "β7", + "transduced", + "with", + "MMG49-derived", + "chimeric", + "antigen", + "receptor", + "(CAR)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "types", + "T", + "cells", + "hematopoietic", + "cells." + ] + } + } + ] + }, + { + "PMID": "29106399", + "TEXT": "Over 40% of microRNAs (miRNAs) are located in introns of protein-coding genes, and many of these intronic miRNAs are co-regulated with their host genes. In such cases of co-regulation, the products of host genes and their intronic miRNAs can cooperate to coordinately regulate biologically important pathways. Therefore, we screened intronic miRNAs dysregulated in the livers of mouse models of obesity to identify previously uncharacterized protein-coding host genes that may contribute to the pathogenesis of obesity-associated insulin resistance and type 2 diabetes mellitus. Our approach revealed that expression of both the gene encoding ectodysplasin A (Eda), the causal gene in X-linked hypohidrotic ectodermal dysplasia (XLHED), and its intronic miRNA, miR-676, was increased in the livers of obese mice. Moreover, hepatic EDA expression is increased in obese human subjects and reduced upon weight loss, and its hepatic expression correlates with systemic insulin resistance. We also found that reducing miR-676 expression in db/db mice increases the expression of proteins involved in fatty acid oxidation and reduces the expression of inflammatory signaling components in the liver. Further, we found that Eda expression in mouse liver is controlled via PPARγ and RXR-α, increases in circulation under conditions of obesity, and promotes JNK activation and inhibitory serine phosphorylation of IRS1 in skeletal muscle. In accordance with these findings, gain- and loss-of-function approaches reveal that liver-derived EDA regulates systemic glucose metabolism, suggesting that EDA is a hepatokine that can contribute to impaired skeletal muscle insulin sensitivity in obesity.", + "TAG_DATA": [ + "115, obese {'context': 'B-organism'}", + "116, mice. {'context': 'I-organism'}", + "145, reducing {'perturbing_action': 'B-gene loss-of-function'}", + "146, miR-676 {'perturbing_action': 'I-rnai/knockdown'}", + "147, expression {'perturbing_action': 'I-rnai/knockdown'}", + "149, db/db {'context': 'B-organism'}", + "150, mice {'context': 'I-organism'}", + "180, liver {'context': 'I-tissue/organ'}", + "205, skeletal {'context': 'B-tissue/organ'}", + "206, muscle. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "115, obese ['l0']", + "116, mice. ['l0']", + "145, reducing ['l1', 'l2', 'l3', 'l4']", + "146, miR-676 ['l1', 'l5', 'l6', 'l7']", + "147, expression ['l2', 'l5', 'l8', 'l9']", + "149, db/db ['l3', 'l6', 'l8', 'l10']", + "150, mice ['l4', 'l7', 'l9', 'l10']", + "179, mouse ['l11', 'l12', 'l13']", + "180, liver ['l11', 'l14', 'l15']", + "205, skeletal ['l12', 'l14', 'l16']", + "206, muscle. ['l13', 'l15', 'l16']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "reducing" + ] + }, + "context": { + "val": "organism", + "words": [ + "db/db", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "miR-676", + "expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "db/db", + "mice" + ] + } + } + ] + }, + { + "PMID": "29035371", + "TEXT": "De novo and acquired resistance, which are largely attributed to genetic alterations, are barriers to effective anti-epidermal-growth-factor-receptor (EGFR) therapy. To generate cetuximab-resistant cells, we exposed cetuximab-sensitive colorectal cancer cells to cetuximab in three-dimensional culture. Using whole-exome sequencing and transcriptional profiling, we found that the long non-coding RNA MIR100HG and two embedded microRNAs, miR-100 and miR-125b, were overexpressed in the absence of known genetic events linked to cetuximab resistance. MIR100HG, miR-100 and miR-125b overexpression was also observed in cetuximab-resistant colorectal cancer and head and neck squamous cell cancer cell lines and in tumors from colorectal cancer patients that progressed on cetuximab. miR-100 and miR-125b coordinately repressed five Wnt/β-catenin negative regulators, resulting in increased Wnt signaling, and Wnt inhibition in cetuximab-resistant cells restored cetuximab responsiveness. Our results describe a double-negative feedback loop between MIR100HG and the transcription factor GATA6, whereby GATA6 represses MIR100HG, but this repression is relieved by miR-125b targeting of GATA6. These findings identify a clinically actionable, epigenetic cause of cetuximab resistance.", + "TAG_DATA": [ + "25, cetuximab-sensitive {'context': 'B-transformed cells'}", + "26, colorectal {'context': 'I-transformed cells'}", + "27, cancer {'context': 'I-transformed cells'}", + "28, cells {'context': 'I-transformed cells'}", + "32, three-dimensional {'context': 'B-in vitro'}", + "33, culture. {'context': 'I-in vitro'}", + "77, cetuximab-resistant {'context': 'B-transformed cells'}", + "78, colorectal {'context': 'I-transformed cells'}", + "79, cancer {'context': 'I-transformed cells'}", + "81, head {'context': 'B-transformed cells'}", + "82, and {'context': 'I-transformed cells'}", + "83, neck {'context': 'I-transformed cells'}", + "84, squamous {'context': 'I-transformed cells'}", + "85, cell {'context': 'I-transformed cells'}", + "86, cancer {'context': 'I-transformed cells'}", + "87, cell {'context': 'I-transformed cells'}", + "88, lines {'context': 'I-transformed cells'}", + "91, tumors {'context': 'B-neoplasm'}", + "93, colorectal {'context': 'B-neoplasm'}", + "94, cancer {'context': 'I-neoplasm'}", + "95, patients {'context': 'I-transformed cells'}", + "118, cetuximab-resistant {'context': 'B-cells'}", + "119, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "25, cetuximab-sensitive ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "26, colorectal ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "27, cancer ['l1', 'l6', 'l11', 'l12', 'l13']", + "28, cells ['l2', 'l7', 'l11', 'l14', 'l15']", + "32, three-dimensional ['l3', 'l8', 'l12', 'l14', 'l16', 'l17', 'l18']", + "33, culture. ['l4', 'l9', 'l13', 'l15', 'l16', 'l19']", + "77, cetuximab-resistant ['l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "78, colorectal ['l20', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "79, cancer ['l21', 'l30', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "81, head ['l22', 'l31', 'l39', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "82, and ['l23', 'l32', 'l40', 'l47', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "83, neck ['l24', 'l33', 'l41', 'l48', 'l58', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "84, squamous ['l25', 'l34', 'l42', 'l49', 'l59', 'l68', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "85, cell ['l26', 'l35', 'l43', 'l50', 'l60', 'l69', 'l77', 'l85', 'l86', 'l87', 'l88', 'l89']", + "86, cancer ['l27', 'l36', 'l44', 'l51', 'l61', 'l70', 'l78', 'l85', 'l90', 'l91']", + "87, cell ['l17', 'l28', 'l37', 'l45', 'l52', 'l62', 'l71', 'l79', 'l86', 'l90', 'l92']", + "88, lines ['l5', 'l10', 'l18', 'l19', 'l29', 'l38', 'l46', 'l53', 'l63', 'l72', 'l80', 'l87', 'l91', 'l92']", + "91, tumors ['l54', 'l64', 'l73', 'l81', 'l93', 'l94', 'l95']", + "93, colorectal ['l55', 'l65', 'l74', 'l82', 'l93', 'l96', 'l97']", + "94, cancer ['l56', 'l66', 'l75', 'l83', 'l88', 'l94', 'l96', 'l98']", + "95, patients ['l57', 'l67', 'l76', 'l84', 'l89', 'l95', 'l97', 'l98']", + "118, cetuximab-resistant ['l99']", + "119, cells ['l99']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "29035369", + "TEXT": "The calcium-binding protein calbindin-D28k is critical for hippocampal function and cognition, but its expression is markedly decreased in various neurological disorders associated with epileptiform activity and seizures. In Alzheimer's disease (AD) and epilepsy, both of which are accompanied by recurrent seizures, the severity of cognitive deficits reflects the degree of calbindin reduction in the hippocampal dentate gyrus (DG). However, despite the importance of calbindin in both neuronal physiology and pathology, the regulatory mechanisms that control its expression in the hippocampus are poorly understood. Here we report an epigenetic mechanism through which seizures chronically suppress hippocampal calbindin expression and impair cognition. We demonstrate that ΔFosB, a highly stable transcription factor, is induced in the hippocampus in mouse models of AD and seizures, in which it binds and triggers histone deacetylation at the promoter of the calbindin gene (Calb1) and downregulates Calb1 transcription. Notably, increasing DG calbindin levels, either by direct virus-mediated expression or inhibition of ΔFosB signaling, improves spatial memory in a mouse model of AD. Moreover, levels of ΔFosB and calbindin expression are inversely related in the DG of individuals with temporal lobe epilepsy (TLE) or AD and correlate with performance on the Mini-Mental State Examination (MMSE). We propose that chronic suppression of calbindin by ΔFosB is one mechanism through which intermittent seizures drive persistent cognitive deficits in conditions accompanied by recurrent seizures.", + "TAG_DATA": [ + "156, improves {'effect': 'B-positive'}", + "161, mouse {'context': 'B-organism'}", + "162, model {'context': 'I-organism'}", + "164, AD. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "156, improves ['l0', 'l1', 'l2', 'l3']", + "161, mouse ['l0', 'l4', 'l5', 'l6']", + "162, model ['l1', 'l4', 'l7', 'l8']", + "163, of ['l2', 'l5', 'l7', 'l9']", + "164, AD. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "improves" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "AD." + ] + } + } + ] + }, + { + "PMID": "29035367", + "TEXT": "Glioblastomas are lethal cancers defined by angiogenesis and pseudopalisading necrosis. Here, we demonstrate that these histological features are associated with distinct transcriptional programs, with vascular regions showing a proneural profile, and hypoxic regions showing a mesenchymal pattern. As these regions harbor glioma stem cells (GSCs), we investigated the epigenetic regulation of these two niches. Proneural, perivascular GSCs activated EZH2, whereas mesenchymal GSCs in hypoxic regions expressed BMI1 protein, which promoted cellular survival under stress due to downregulation of the E3 ligase RNF144A. Using both genetic and pharmacologic inhibition, we found that proneural GSCs are preferentially sensitive to EZH2 disruption, whereas mesenchymal GSCs are more sensitive to BMI1 inhibition. Given that glioblastomas contain both proneural and mesenchymal GSCs, combined EZH2 and BMI1 targeting proved more effective than either agent alone both in culture and in vivo, suggesting that strategies that simultaneously target multiple epigenetic regulators within glioblastomas may be effective in overcoming therapy resistance caused by intratumoral heterogeneity.", + "TAG_DATA": [ + "91, proneural {'context': 'B-transformed cells'}", + "92, GSCs {'context': 'I-transformed cells'}", + "100, mesenchymal {'context': 'B-transformed cells'}", + "101, GSCs {'context': 'I-transformed cells'}", + "106, BMI1 {'perturbing_action': 'B-pharmacological inhibition'}", + "107, inhibition. {'perturbing_action': 'I-pharmacological inhibition'}", + "131, culture {'context': 'I-in vitro'}", + "133, in {'context': 'B-in vivo'}", + "134, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "91, proneural ['l0', 'l1']", + "92, GSCs ['l0', 'l2']", + "100, mesenchymal ['l3', 'l4', 'l5', 'l6', 'l7']", + "101, GSCs ['l1', 'l2', 'l3', 'l8', 'l9', 'l10']", + "106, BMI1 ['l4', 'l8', 'l11', 'l12', 'l13', 'l14']", + "107, inhibition. ['l5', 'l9', 'l11', 'l15', 'l16', 'l17']", + "131, culture ['l6', 'l10', 'l12', 'l15', 'l18', 'l19']", + "133, in ['l7', 'l13', 'l16', 'l18', 'l20']", + "134, vivo, ['l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "mesenchymal", + "GSCs" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BMI1", + "inhibition." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BMI1", + "inhibition." + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BMI1", + "inhibition." + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + } + ] + }, + { + "PMID": "29035366", + "TEXT": "Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies.", + "TAG_DATA": [ + "27, induces {'effect': 'B-positive'}", + "30, cell {'phenotype': 'B-cell death'}", + "31, death, {'phenotype': 'I-cell death'}", + "41, patient-derived {'context': 'B-transformed cells'}", + "42, glioblastoma {'context': 'I-transformed cells'}", + "43, (GBM) {'context': 'I-transformed cells'}", + "44, cells. {'context': 'I-transformed cells'}", + "58, triggering {'effect': 'B-positive'}", + "60, apoptosis. {'phenotype': 'B-apoptosis'}", + "71, stabilization {'perturbing_action': 'I-other'}", + "72, of {'perturbing_action': 'I-other'}", + "73, p53 {'perturbing_action': 'I-other'}", + "85, orthotopic {'context': 'B-xenograft'}", + "86, glioblastoma {'context': 'I-xenograft'}", + "87, xenograft {'context': 'I-xenograft'}", + "88, models. {'context': 'I-xenograft'}", + "132, in {'context': 'B-in vivo'}", + "133, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "27, induces ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "30, cell ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "31, death, ['l1', 'l7', 'l12', 'l13', 'l14', 'l15']", + "41, patient-derived ['l2', 'l8', 'l12', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "42, glioblastoma ['l3', 'l9', 'l13', 'l16', 'l22', 'l23', 'l24', 'l25']", + "43, (GBM) ['l4', 'l10', 'l14', 'l17', 'l22', 'l26', 'l27', 'l28']", + "44, cells. ['l5', 'l11', 'l15', 'l18', 'l23', 'l26', 'l29', 'l30']", + "58, triggering ['l19', 'l24', 'l27', 'l29', 'l31']", + "60, apoptosis. ['l6', 'l20', 'l25', 'l28', 'l30', 'l31']", + "71, stabilization ['l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "72, of ['l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "73, p53 ['l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "85, orthotopic ['l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "86, glioblastoma ['l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "87, xenograft ['l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "88, models. ['l21', 'l37', 'l42', 'l46', 'l49', 'l51', 'l52']", + "132, in ['l53']", + "133, vivo. ['l53']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "triggering" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "patient-derived", + "glioblastoma", + "(GBM)", + "cells." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "triggering" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "patient-derived", + "glioblastoma", + "(GBM)", + "cells." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "patient-derived", + "glioblastoma", + "(GBM)", + "cells." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "stabilization", + "of", + "p53" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "orthotopic", + "glioblastoma", + "xenograft", + "models." + ] + } + } + ] + }, + { + "PMID": "28920959", + "TEXT": "Treatment of chronic myeloid leukemia (CML) with imatinib mesylate and other second- and/or third-generation c-Abl-specific tyrosine kinase inhibitors (TKIs) has substantially extended patient survival. However, TKIs primarily target differentiated cells and do not eliminate leukemic stem cells (LSCs). Therefore, targeting minimal residual disease to prevent acquired resistance and/or disease relapse requires identification of new LSC-selective target(s) that can be exploited therapeutically. Considering that malignant transformation involves cellular metabolic changes, which may in turn render the transformed cells susceptible to specific assaults in a selective manner, we searched for such vulnerabilities in CML LSCs. We performed metabolic analyses on both stem cell-enriched (CD34+ and CD34+CD38-) and differentiated (CD34-) cells derived from individuals with CML, and we compared the signature of these cells with that of their normal counterparts. Through combination of stable isotope-assisted metabolomics with functional assays, we demonstrate that primitive CML cells rely on upregulated oxidative metabolism for their survival. We also show that combination treatment with imatinib and tigecycline, an antibiotic that inhibits mitochondrial protein translation, selectively eradicates CML LSCs both in vitro and in a xenotransplantation model of human CML. Our findings provide a strong rationale for investigation of the use of TKIs in combination with tigecycline to treat patients with CML with minimal residual disease.", + "TAG_DATA": [ + "105, differentiated {'context': 'B-cells'}", + "107, cells {'context': 'I-cells'}", + "140, CML {'context': 'I-transformed cells'}", + "141, cells {'context': 'I-transformed cells'}", + "169, CML {'context': 'B-transformed cells'}", + "170, LSCs {'context': 'I-transformed cells'}", + "172, in {'context': 'B-in vitro'}", + "173, vitro {'context': 'I-in vitro'}", + "177, xenotransplantation {'context': 'B-xenograft'}", + "178, model {'context': 'I-xenograft'}", + "179, of {'context': 'I-xenograft'}", + "180, human {'context': 'I-xenograft'}", + "181, CML. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "105, differentiated ['l0', 'l1', 'l2', 'l3']", + "106, (CD34-) ['l0', 'l4', 'l5', 'l6']", + "107, cells ['l1', 'l4']", + "140, CML ['l2', 'l5', 'l7']", + "141, cells ['l3', 'l6', 'l7']", + "169, CML ['l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "170, LSCs ['l8', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "172, in ['l9', 'l16', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "173, vitro ['l10', 'l17', 'l23', 'l29', 'l30', 'l31', 'l32', 'l33']", + "177, xenotransplantation ['l11', 'l18', 'l24', 'l29', 'l34', 'l35', 'l36', 'l37']", + "178, model ['l12', 'l19', 'l25', 'l30', 'l34', 'l38', 'l39', 'l40']", + "179, of ['l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l41', 'l42']", + "180, human ['l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l41', 'l43']", + "181, CML. ['l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l43']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28920958", + "TEXT": "N6-methyladenosine (m6A) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the m6A modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the m6A-forming enzyme METTL3 in human hematopoietic stem/progenitor cells (HSPCs) promotes cell differentiation, coupled with reduced cell proliferation. Conversely, overexpression of wild-type METTL3, but not of a catalytically inactive form of METTL3, inhibits cell differentiation and increases cell growth. METTL3 mRNA and protein are expressed more abundantly in acute myeloid leukemia (AML) cells than in healthy HSPCs or other types of tumor cells. Furthermore, METTL3 depletion in human myeloid leukemia cell lines induces cell differentiation and apoptosis and delays leukemia progression in recipient mice in vivo. Single-nucleotide-resolution mapping of m6A coupled with ribosome profiling reveals that m6A promotes the translation of c-MYC, BCL2 and PTEN mRNAs in the human acute myeloid leukemia MOLM-13 cell line. Moreover, loss of METTL3 leads to increased levels of phosphorylated AKT, which contributes to the differentiation-promoting effects of METTL3 depletion. Overall, these results provide a rationale for the therapeutic targeting of METTL3 in myeloid leukemia.", + "TAG_DATA": [ + "42, shRNA-mediated {'perturbing_action': 'B-gene loss-of-function'}", + "43, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "44, of {'perturbing_action': 'I-gene loss-of-function'}", + "45, the {'perturbing_action': 'I-gene loss-of-function'}", + "46, m6A-forming {'perturbing_action': 'I-gene loss-of-function'}", + "47, enzyme {'perturbing_action': 'I-gene loss-of-function'}", + "48, METTL3 {'perturbing_action': 'I-gene loss-of-function'}", + "50, human {'context': 'B-cells'}", + "51, hematopoietic {'context': 'I-cells'}", + "52, stem/progenitor {'context': 'I-cells'}", + "53, cells {'context': 'I-cells'}", + "54, (HSPCs) {'context': 'I-cells'}", + "55, promotes {'effect': 'B-positive'}", + "56, cell {'context': 'B-cells'}", + "57, differentiation, {'phenotype': 'B-differentiation'}", + "60, reduced {'effect': 'B-negative'}", + "61, cell {'context': 'B-cells'}", + "62, proliferation. {'phenotype': 'B-proliferation'}", + "64, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "65, of {'perturbing_action': 'I-gene gain-of-function'}", + "66, wild-type {'perturbing_action': 'I-gene gain-of-function'}", + "67, METTL3, {'perturbing_action': 'I-gene gain-of-function'}", + "77, inhibits {'effect': 'B-negative'}", + "78, cell {'context': 'B-cells'}", + "79, differentiation {'phenotype': 'B-differentiation'}", + "81, increases {'effect': 'B-positive'}", + "82, cell {'phenotype': 'B-cell growth'}", + "83, growth. {'phenotype': 'I-cell growth'}", + "100, healthy {'context': 'B-cells'}", + "101, HSPCs {'context': 'I-cells'}", + "109, METTL3 {'perturbing_action': 'B-gene loss-of-function'}", + "110, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "112, human {'context': 'B-transformed cells'}", + "113, myeloid {'context': 'I-transformed cells'}", + "114, leukemia {'context': 'I-transformed cells'}", + "115, cell {'context': 'I-transformed cells'}", + "116, lines {'context': 'I-transformed cells'}", + "117, induces {'effect': 'B-positive'}", + "118, cell {'context': 'B-cells'}", + "119, differentiation {'phenotype': 'B-differentiation'}", + "121, apoptosis {'phenotype': 'B-apoptosis'}", + "123, delays {'effect': 'B-negative'}", + "124, leukemia {'context': 'B-neoplasm'}", + "128, mice {'context': 'B-organism'}", + "129, in {'context': 'B-in vivo'}", + "130, vivo. {'context': 'I-in vivo'}", + "153, human {'context': 'B-transformed cells'}", + "154, acute {'context': 'I-transformed cells'}", + "155, myeloid {'context': 'I-transformed cells'}", + "156, leukemia {'context': 'I-transformed cells'}", + "157, MOLM-13 {'context': 'I-transformed cells'}", + "158, cell {'context': 'I-transformed cells'}", + "159, line. {'context': 'I-transformed cells'}", + "161, loss {'perturbing_action': 'B-gene loss-of-function'}", + "162, of {'perturbing_action': 'I-gene loss-of-function'}", + "163, METTL3 {'perturbing_action': 'I-gene loss-of-function'}", + "178, METTL3 {'perturbing_action': 'B-gene loss-of-function'}", + "179, depletion. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "42, shRNA-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "43, depletion ['l0', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "44, of ['l1', 'l23', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "45, the ['l2', 'l24', 'l45', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "46, m6A-forming ['l3', 'l25', 'l46', 'l66', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "47, enzyme ['l4', 'l26', 'l47', 'l67', 'l86', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "48, METTL3 ['l5', 'l27', 'l48', 'l68', 'l87', 'l105', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139']", + "50, human ['l6', 'l28', 'l49', 'l69', 'l88', 'l106', 'l123', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150']", + "51, hematopoietic ['l7', 'l29', 'l50', 'l70', 'l89', 'l107', 'l124', 'l140', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "52, stem/progenitor ['l8', 'l30', 'l51', 'l71', 'l90', 'l108', 'l125', 'l141', 'l151', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "53, cells ['l9', 'l31', 'l52', 'l72', 'l91', 'l109', 'l126', 'l142', 'l152', 'l162', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180']", + "54, (HSPCs) ['l10', 'l32', 'l53', 'l73', 'l92', 'l110', 'l127', 'l143', 'l153', 'l163', 'l173', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "55, promotes ['l11', 'l33', 'l54', 'l74', 'l93', 'l111', 'l128', 'l144', 'l154', 'l164', 'l174', 'l181', 'l188', 'l189', 'l190', 'l191', 'l192']", + "56, cell ['l12', 'l34', 'l55', 'l75', 'l94', 'l112', 'l129', 'l145', 'l155', 'l165', 'l175', 'l182', 'l188', 'l193', 'l194', 'l195', 'l196']", + "57, differentiation, ['l13', 'l35', 'l56', 'l76', 'l95', 'l113', 'l130', 'l146', 'l156', 'l166', 'l176', 'l183', 'l189', 'l193', 'l197', 'l198', 'l199']", + "60, reduced ['l14', 'l36', 'l57', 'l77', 'l96', 'l114', 'l131', 'l147', 'l157', 'l167', 'l177', 'l184', 'l190', 'l194', 'l197', 'l200', 'l201']", + "61, cell ['l15', 'l37', 'l58', 'l78', 'l97', 'l115', 'l132', 'l148', 'l158', 'l168', 'l178', 'l185', 'l191', 'l195', 'l198', 'l200', 'l202']", + "62, proliferation. ['l16', 'l38', 'l59', 'l79', 'l98', 'l116', 'l133', 'l149', 'l159', 'l169', 'l179', 'l186', 'l192', 'l196', 'l199', 'l201', 'l202']", + "64, overexpression ['l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229']", + "65, of ['l203', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255']", + "66, wild-type ['l204', 'l230', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280']", + "67, METTL3, ['l205', 'l231', 'l256', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302']", + "77, inhibits ['l17', 'l39', 'l60', 'l80', 'l99', 'l117', 'l134', 'l206', 'l232', 'l257', 'l281', 'l303', 'l304', 'l305', 'l306', 'l307', 'l308', 'l309', 'l310']", + "78, cell ['l18', 'l40', 'l61', 'l81', 'l100', 'l118', 'l135', 'l160', 'l170', 'l207', 'l233', 'l258', 'l282', 'l303', 'l311', 'l312', 'l313', 'l314']", + "79, differentiation ['l19', 'l41', 'l62', 'l82', 'l101', 'l119', 'l136', 'l150', 'l161', 'l171', 'l180', 'l187', 'l208', 'l234', 'l259', 'l283', 'l304', 'l311', 'l315', 'l316', 'l317']", + "81, increases ['l20', 'l42', 'l63', 'l83', 'l102', 'l120', 'l137', 'l209', 'l235', 'l260', 'l284', 'l305', 'l312', 'l315', 'l318', 'l319', 'l320']", + "82, cell ['l21', 'l43', 'l64', 'l84', 'l103', 'l121', 'l138', 'l210', 'l236', 'l261', 'l285', 'l306', 'l313', 'l316', 'l318', 'l321', 'l322', 'l323', 'l324']", + "83, growth. ['l22', 'l44', 'l65', 'l85', 'l104', 'l122', 'l139', 'l172', 'l211', 'l237', 'l262', 'l286', 'l307', 'l314', 'l317', 'l319', 'l321']", + "100, healthy ['l212', 'l238', 'l263', 'l287', 'l308', 'l322', 'l325', 'l326', 'l327', 'l328', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334', 'l335', 'l336']", + "101, HSPCs ['l213', 'l239', 'l264', 'l288', 'l309', 'l320', 'l323', 'l325', 'l337', 'l338', 'l339', 'l340', 'l341', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347']", + "109, METTL3 ['l214', 'l240', 'l265', 'l289', 'l348', 'l349', 'l350', 'l351', 'l352', 'l353', 'l354', 'l355', 'l356', 'l357', 'l358', 'l359', 'l360', 'l361', 'l362', 'l363', 'l364', 'l365', 'l366', 'l367', 'l368']", + "110, depletion ['l215', 'l241', 'l266', 'l290', 'l326', 'l337', 'l348', 'l369', 'l370', 'l371', 'l372', 'l373', 'l374', 'l375', 'l376', 'l377', 'l378', 'l379', 'l380', 'l381', 'l382']", + "112, human ['l216', 'l242', 'l267', 'l291', 'l327', 'l338', 'l349', 'l369', 'l383', 'l384', 'l385', 'l386', 'l387', 'l388', 'l389', 'l390', 'l391', 'l392', 'l393', 'l394', 'l395']", + "113, myeloid ['l217', 'l243', 'l268', 'l292', 'l328', 'l339', 'l350', 'l370', 'l383', 'l396', 'l397', 'l398', 'l399', 'l400', 'l401', 'l402', 'l403', 'l404', 'l405', 'l406', 'l407']", + "114, leukemia ['l218', 'l244', 'l269', 'l293', 'l329', 'l340', 'l351', 'l371', 'l384', 'l396', 'l408', 'l409', 'l410', 'l411', 'l412', 'l413', 'l414', 'l415', 'l416', 'l417', 'l418']", + "115, cell ['l219', 'l245', 'l270', 'l294', 'l330', 'l341', 'l352', 'l372', 'l385', 'l397', 'l408', 'l419', 'l420', 'l421', 'l422', 'l423', 'l424', 'l425', 'l426', 'l427']", + "116, lines ['l220', 'l246', 'l271', 'l295', 'l310', 'l324', 'l331', 'l342', 'l353', 'l373', 'l386', 'l398', 'l409', 'l419', 'l428', 'l429', 'l430', 'l431', 'l432', 'l433', 'l434']", + "117, induces ['l221', 'l247', 'l272', 'l296', 'l332', 'l343', 'l354', 'l374', 'l387', 'l399', 'l410', 'l420', 'l428', 'l435', 'l436', 'l437', 'l438', 'l439']", + "118, cell ['l222', 'l248', 'l273', 'l297', 'l333', 'l344', 'l355', 'l375', 'l388', 'l400', 'l411', 'l421', 'l429', 'l435', 'l440', 'l441', 'l442', 'l443', 'l444']", + "119, differentiation ['l223', 'l249', 'l274', 'l298', 'l334', 'l345', 'l356', 'l376', 'l389', 'l401', 'l412', 'l422', 'l430', 'l436', 'l440', 'l445', 'l446', 'l447', 'l448']", + "121, apoptosis ['l224', 'l250', 'l275', 'l299', 'l335', 'l346', 'l357', 'l377', 'l390', 'l402', 'l413', 'l423', 'l431', 'l437', 'l441', 'l445', 'l449', 'l450', 'l451', 'l452', 'l453']", + "123, delays ['l225', 'l251', 'l276', 'l300', 'l336', 'l347', 'l358', 'l378', 'l391', 'l403', 'l414', 'l424', 'l432', 'l438', 'l442', 'l446', 'l449', 'l454', 'l455']", + "124, leukemia ['l226', 'l252', 'l277', 'l301', 'l359', 'l379', 'l392', 'l404', 'l415', 'l425', 'l433', 'l439', 'l443', 'l447', 'l450', 'l454', 'l456', 'l457', 'l458']", + "128, mice ['l227', 'l253', 'l278', 'l302', 'l360', 'l380', 'l393', 'l405', 'l416', 'l426', 'l434', 'l444', 'l448', 'l451', 'l455', 'l456', 'l459', 'l460']", + "129, in ['l228', 'l254', 'l279', 'l361', 'l381', 'l394', 'l406', 'l417', 'l452', 'l457', 'l459', 'l461', 'l462', 'l463', 'l464', 'l465', 'l466', 'l467', 'l468']", + "130, vivo. ['l229', 'l255', 'l280', 'l362', 'l382', 'l395', 'l407', 'l418', 'l427', 'l453', 'l458', 'l460', 'l461', 'l469', 'l470', 'l471', 'l472', 'l473', 'l474', 'l475']", + "153, human ['l462', 'l469', 'l476', 'l477', 'l478', 'l479', 'l480', 'l481']", + "154, acute ['l363', 'l463', 'l470', 'l476', 'l482', 'l483', 'l484', 'l485', 'l486']", + "155, myeloid ['l364', 'l464', 'l471', 'l477', 'l482', 'l487', 'l488', 'l489', 'l490']", + "156, leukemia ['l365', 'l465', 'l472', 'l478', 'l483', 'l487', 'l491', 'l492', 'l493']", + "157, MOLM-13 ['l366', 'l466', 'l473', 'l479', 'l484', 'l488', 'l491', 'l494', 'l495']", + "158, cell ['l367', 'l467', 'l474', 'l480', 'l485', 'l489', 'l492', 'l494', 'l496']", + "159, line. ['l368', 'l468', 'l475', 'l481', 'l486', 'l490', 'l493', 'l495', 'l496']", + "161, loss ['l497', 'l498', 'l499', 'l500']", + "162, of ['l497', 'l501', 'l502', 'l503']", + "163, METTL3 ['l498', 'l501', 'l504', 'l505']", + "178, METTL3 ['l499', 'l502', 'l504', 'l506']", + "179, depletion. ['l500', 'l503', 'l505', 'l506']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "shRNA-mediated", + "depletion", + "of", + "the", + "m6A-forming", + "enzyme", + "METTL3" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "hematopoietic", + "stem/progenitor", + "cells", + "(HSPCs)", + "cell", + "healthy", + "HSPCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "shRNA-mediated", + "depletion", + "of", + "the", + "m6A-forming", + "enzyme", + "METTL3" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes", + "increases", + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "shRNA-mediated", + "depletion", + "of", + "the", + "m6A-forming", + "enzyme", + "METTL3" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation,", + "differentiation" + ] + } + }, + { + "perturbing_action": { 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+ "METTL3", + "depletion" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "myeloid", + "leukemia", + "cell", + "lines", + "acute", + "MOLM-13", + "line." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "METTL3", + "depletion" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "METTL3", + "depletion" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "METTL3", + "depletion" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "METTL3", + "depletion" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "myeloid", + "leukemia", + "cell", + "lines" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "myeloid", + "leukemia", + "cell", + "lines" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "myeloid", + "leukemia", + "cell", + "lines" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "negative", + "words": [ + "delays" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "delays" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "delays" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "28920956", + "TEXT": "Mutations in MECP2 cause Rett syndrome (RTT), an X-linked neurological disorder characterized by regressive loss of neurodevelopmental milestones and acquired psychomotor deficits. However, the cellular heterogeneity of the brain impedes an understanding of how MECP2 mutations contribute to RTT. Here we developed a Cre-inducible method for cell-type-specific biotin tagging of MeCP2 in mice. Combining this approach with an allelic series of knock-in mice carrying frequent RTT-associated mutations (encoding T158M and R106W) enabled the selective profiling of RTT-associated nuclear transcriptomes in excitatory and inhibitory cortical neurons. We found that most gene-expression changes were largely specific to each RTT-associated mutation and cell type. Lowly expressed cell-type-enriched genes were preferentially disrupted by MeCP2 mutations, with upregulated and downregulated genes reflecting distinct functional categories. Subcellular RNA analysis in MeCP2-mutant neurons further revealed reductions in the nascent transcription of long genes and uncovered widespread post-transcriptional compensation at the cellular level. Finally, we overcame X-linked cellular mosaicism in female RTT models and identified distinct gene-expression changes between neighboring wild-type and mutant neurons, providing contextual insights into RTT etiology that support personalized therapeutic interventions.", + "TAG_DATA": [ + "52, mice. {'context': 'B-organism'}", + "62, mice {'context': 'B-organism'}", + "65, RTT-associated {'perturbing_action': 'I-other'}", + "66, mutations {'perturbing_action': 'I-other'}", + "80, excitatory {'context': 'B-cells'}", + "81, and {'context': 'I-cells'}", + "82, inhibitory {'context': 'I-cells'}", + "83, cortical {'context': 'I-cells'}", + "84, neurons. {'context': 'I-cells'}", + "109, MeCP2 {'perturbing_action': 'B-other'}", + "110, mutations, {'perturbing_action': 'I-other'}", + "124, MeCP2-mutant {'perturbing_action': 'B-other'}", + "125, neurons {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "52, mice. ['l0', 'l1', 'l2', 'l3', 'l4']", + "62, mice ['l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "65, RTT-associated ['l5', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "66, mutations ['l6', 'l14', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "67, (encoding ['l7', 'l15', 'l22', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "68, T158M ['l8', 'l16', 'l23', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "80, excitatory ['l0', 'l9', 'l17', 'l24', 'l30', 'l35', 'l40', 'l41', 'l42', 'l43']", + "81, and ['l1', 'l10', 'l18', 'l25', 'l31', 'l36', 'l40', 'l44', 'l45', 'l46']", + "82, inhibitory ['l2', 'l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l47', 'l48']", + "83, cortical ['l3', 'l12', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l49']", + "84, neurons. ['l4', 'l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l49']", + "109, MeCP2 ['l50', 'l51']", + "110, mutations, ['l50', 'l52']", + "124, MeCP2-mutant ['l53']", + "125, neurons ['l51', 'l52', 'l53']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "RTT-associated", + "mutations" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "RTT-associated", + "mutations", + "MeCP2", + "mutations,", + "MeCP2-mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "excitatory", + "and", + "inhibitory", + "cortical", + "neurons.", + "neurons" + ] + } + } + ] + }, + { + "PMID": "28869611", + "TEXT": "There are no approved treatments for Lassa fever, which is endemic to the same regions of West Africa that were recently devastated by Ebola. Here we show that a combination of human monoclonal antibodies that cross-react with the glycoproteins of all four clades of Lassa virus is able to rescue 100% of cynomolgus macaques when treatment is initiated at advanced stages of disease, including up to 8 d after challenge.", + "TAG_DATA": [ + "52, cynomolgus {'context': 'B-organism'}", + "53, macaques {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "52, cynomolgus ['l0']", + "53, macaques ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28825716", + "TEXT": "Aging is associated with increased cellular senescence, which is hypothesized to drive the eventual development of multiple comorbidities. Here we investigate a role for senescent cells in age-related bone loss through multiple approaches. In particular, we used either genetic (i.e., the INK-ATTAC 'suicide' transgene encoding an inducible caspase 8 expressed specifically in senescent cells) or pharmacological (i.e., 'senolytic' compounds) means to eliminate senescent cells. We also inhibited the production of the proinflammatory secretome of senescent cells using a JAK inhibitor (JAKi). In aged (20- to 22-month-old) mice with established bone loss, activation of the INK-ATTAC caspase 8 in senescent cells or treatment with senolytics or the JAKi for 2-4 months resulted in higher bone mass and strength and better bone microarchitecture than in vehicle-treated mice. The beneficial effects of targeting senescent cells were due to lower bone resorption with either maintained (trabecular) or higher (cortical) bone formation as compared to vehicle-treated mice. In vitro studies demonstrated that senescent-cell conditioned medium impaired osteoblast mineralization and enhanced osteoclast-progenitor survival, leading to increased osteoclastogenesis. Collectively, these data establish a causal role for senescent cells in bone loss with aging, and demonstrate that targeting these cells has both anti-resorptive and anabolic effects on bone. Given that eliminating senescent cells and/or inhibiting their proinflammatory secretome also improves cardiovascular function, enhances insulin sensitivity, and reduces frailty, targeting this fundamental mechanism to prevent age-related bone loss suggests a novel treatment strategy not only for osteoporosis, but also for multiple age-related comorbidities.", + "TAG_DATA": [ + "74, senescent {'context': 'B-cells'}", + "75, cells {'context': 'I-cells'}", + "78, JAK {'perturbing_action': 'B-pharmacological inhibition'}", + "79, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "80, (JAKi). {'perturbing_action': 'I-pharmacological inhibition'}", + "82, aged {'context': 'B-organism'}", + "83, (20- {'context': 'I-organism'}", + "86, mice {'context': 'I-organism'}", + "91, activation {'perturbing_action': 'B-pharmacological augmentation'}", + "92, of {'perturbing_action': 'I-pharmacological augmentation'}", + "93, the {'perturbing_action': 'I-pharmacological augmentation'}", + "94, INK-ATTAC {'perturbing_action': 'I-pharmacological augmentation'}", + "95, caspase {'perturbing_action': 'I-pharmacological augmentation'}", + "96, 8 {'perturbing_action': 'I-pharmacological augmentation'}", + "98, senescent {'context': 'B-cells'}", + "99, cells {'context': 'I-cells'}", + "124, mice. {'context': 'B-organism'}", + "130, senescent {'context': 'B-cells'}", + "131, cells {'context': 'I-cells'}", + "151, mice. {'context': 'B-organism'}", + "152, In {'context': 'B-in vitro'}", + "153, vitro {'context': 'I-in vitro'}", + "161, osteoblast {'context': 'B-cells'}", + "165, osteoclast-progenitor {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "74, senescent ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "75, cells ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "78, JAK ['l1', 'l17', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "79, inhibitor ['l2', 'l18', 'l31', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "80, (JAKi). ['l3', 'l19', 'l32', 'l47', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "82, aged ['l4', 'l20', 'l33', 'l48', 'l61', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "83, (20- ['l5', 'l21', 'l34', 'l49', 'l62', 'l74', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "84, to ['l6', 'l22', 'l35', 'l50', 'l63', 'l75', 'l84', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "85, 22-month-old) ['l7', 'l23', 'l36', 'l51', 'l64', 'l76', 'l85', 'l91', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "86, mice ['l8', 'l24', 'l37', 'l52', 'l65', 'l77', 'l86', 'l92', 'l99', 'l106', 'l107']", + "91, activation ['l9', 'l25', 'l38', 'l53', 'l66', 'l78', 'l93', 'l100', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "92, of ['l10', 'l26', 'l39', 'l54', 'l67', 'l79', 'l94', 'l101', 'l108', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "93, the ['l11', 'l40', 'l55', 'l68', 'l109', 'l117', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "94, INK-ATTAC ['l12', 'l41', 'l56', 'l69', 'l110', 'l118', 'l125', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "95, caspase ['l13', 'l27', 'l42', 'l57', 'l70', 'l80', 'l87', 'l95', 'l102', 'l111', 'l119', 'l126', 'l133', 'l141', 'l142', 'l143', 'l144', 'l145']", + "96, 8 ['l14', 'l28', 'l43', 'l58', 'l71', 'l81', 'l88', 'l96', 'l103', 'l112', 'l120', 'l127', 'l134', 'l141', 'l146', 'l147', 'l148', 'l149']", + "98, senescent ['l15', 'l29', 'l44', 'l59', 'l72', 'l82', 'l89', 'l97', 'l104', 'l106', 'l113', 'l121', 'l128', 'l135', 'l142', 'l146', 'l150', 'l151']", + "99, cells ['l16', 'l30', 'l45', 'l60', 'l73', 'l83', 'l90', 'l98', 'l105', 'l107', 'l114', 'l122', 'l129', 'l136', 'l143', 'l147', 'l150']", + "124, mice. ['l115', 'l123', 'l130', 'l137', 'l144', 'l148', 'l152', 'l153', 'l154']", + "130, senescent ['l131', 'l138', 'l152', 'l155', 'l156', 'l157']", + "131, cells ['l46', 'l116', 'l124', 'l132', 'l139', 'l145', 'l149', 'l151', 'l153', 'l155', 'l158']", + "151, mice. ['l140', 'l154', 'l156', 'l158', 'l159']", + "152, In ['l160', 'l161', 'l162']", + "153, vitro ['l160', 'l163', 'l164']", + "161, osteoblast ['l157', 'l159', 'l161', 'l163', 'l165']", + "165, osteoclast-progenitor ['l162', 'l164', 'l165']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "senescent", + "cells" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "JAK", + "inhibitor", + "(JAKi)." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "senescent", + "cells" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "of", + "the", + "INK-ATTAC", + "caspase", + "8" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "JAK", + "inhibitor", + "(JAKi)." + ] + }, + "context": { + "val": "organism", + "words": [ + "aged", + "(20-", + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "aged", + "(20-", + "mice." + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "of", + "caspase", + "8", + "the", + "INK-ATTAC" + ] + } + } + ] + }, + { + "PMID": "28777788", + "TEXT": "Clear links between human genes and influenza disease susceptibility are scarce. A recent study uncovered a gene variant coupled to severe influenza and showed how it hampers expression of an antiviral gene key to immune cell survival.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28759053", + "TEXT": "Much attention has been focused on the role of the bacterial microbiome in human health, but the virome is understudied. Although previously investigated in individuals with inflammatory bowel diseases or solid-organ transplants, virome dynamics in allogeneic hematopoietic stem cell transplantation (HSCT) and enteric graft-versus-host disease (GVHD) remain unexplored. Here we characterize the longitudinal gut virome in 44 recipients of HSCT using metagenomics. A viral 'bloom' was identified, and significant increases were demonstrated in the overall proportion of vertebrate viral sequences following transplantation (P = 0.02). Increases in both the rates of detection (P < 0.0001) and number of sequences (P = 0.047) of persistent DNA viruses (anelloviruses, herpesviruses, papillomaviruses and polyomaviruses) over time were observed in individuals with enteric GVHD relative to those without, a finding accompanied by a reduced phage richness (P = 0.01). Picobirnaviruses were detected in 18 individuals (40.9%), more frequently before or within a week after transplant than at later time points (P = 0.008). In a time-dependent Cox proportional-hazards model, picobirnaviruses were predictive of the occurrence of severe enteric GVHD (hazard ratio, 2.66; 95% confidence interval (CI) = 1.46-4.86; P = 0.001), and correlated with higher fecal levels of two GVHD severity markers, calprotectin and α1-antitrypsin. These results reveal a progressive expansion of vertebrate viral infections over time following HSCT, and they suggest an unexpected association of picobirnaviruses with early post-transplant GVHD.", + "TAG_DATA": [ + "116, individuals {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28714989", + "TEXT": "Splice-site defects account for about 10% of pathogenic mutations that cause Mendelian diseases. Prevalence is higher in neuromuscular disorders (NMDs), owing to the unusually large size and multi-exonic nature of genes encoding muscle structural proteins. Therapeutic genome editing to correct disease-causing splice-site mutations has been accomplished only through the homology-directed repair pathway, which is extremely inefficient in postmitotic tissues such as skeletal muscle. Here we describe a strategy using nonhomologous end-joining (NHEJ) to correct a pathogenic splice-site mutation. As a proof of principle, we focus on congenital muscular dystrophy type 1A (MDC1A), which is characterized by severe muscle wasting and paralysis. Specifically, we correct a splice-site mutation that causes the exclusion of exon 2 from Lama2 mRNA and the truncation of Lama2 protein in the dy2J/dy2J mouse model of MDC1A. Through systemic delivery of adeno-associated virus (AAV) carrying clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 genome-editing components, we simultaneously excise an intronic region containing the mutation and create a functional donor splice site through NHEJ. This strategy leads to the inclusion of exon 2 in the Lama2 transcript and restoration of full-length Lama2 protein. Treated dy2J/dy2J mice display substantial improvement in muscle histopathology and function without signs of paralysis.", + "TAG_DATA": [ + "125, dy2J/dy2J {'perturbing_action': 'B-other'}", + "126, mouse {'context': 'B-organism'}", + "127, model {'context': 'I-organism'}", + "128, of {'context': 'I-organism'}", + "129, MDC1A. {'context': 'I-organism'}", + "185, dy2J/dy2J {'perturbing_action': 'B-other', 'context': 'B-organism'}", + "186, mice {'context': 'I-organism'}", + "191, muscle {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "125, dy2J/dy2J ['l0', 'l1', 'l2', 'l3']", + "126, mouse ['l0', 'l4', 'l5', 'l6']", + "127, model ['l1', 'l4', 'l7', 'l8']", + "128, of ['l2', 'l5', 'l7', 'l9']", + "129, MDC1A. ['l3', 'l6', 'l8', 'l9']", + "185, dy2J/dy2J ['l10', 'l11']", + "186, mice ['l10', 'l12']", + "191, muscle ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "dy2J/dy2J" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "MDC1A.", + "dy2J/dy2J" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "dy2J/dy2J" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscle" + ] + } + } + ] + }, + { + "PMID": "28714988", + "TEXT": "Previous studies have reported associations of IFITM3 SNP rs12252 with severe influenza, but evidence of association and the mechanism by which risk is conferred remain controversial. We prioritized SNPs in IFITM3 on the basis of putative biological function and identified rs34481144 in the 5' UTR. We found evidence of a new association of rs34481144 with severe influenza in three influenza-infected cohorts characterized by different levels of influenza illness severity. We determined a role for rs34481144 as an expression quantitative trait locus (eQTL) for IFITM3, with the risk allele associated with lower mRNA expression. The risk allele was found to have decreased IRF3 binding and increased CTCF binding in promoter-binding assays, and risk allele carriage diminished transcriptional correlations among IFITM3-neighboring genes, indicative of CTCF boundary activity. Furthermore, the risk allele disrupts a CpG site that undergoes differential methylation in CD8+ T cell subsets. Carriers of the risk allele had reduced numbers of CD8+ T cells in their airways during natural influenza infection, consistent with IFITM3 promoting accumulation of CD8+ T cells in airways and indicating that a critical function for IFITM3 may be to promote immune cell persistence at mucosal sites.Our study identifies a new regulator of IFITM3 expression that associates with CD8+ T cell levels in the airways and a spectrum of clinical outcomes.", + "TAG_DATA": [ + "138, CD8+ {'context': 'B-cells'}", + "139, T {'context': 'I-cells'}", + "140, cell {'context': 'I-cells'}", + "142, Carriers {'perturbing_action': 'B-other'}", + "143, of {'perturbing_action': 'I-other'}", + "144, the {'perturbing_action': 'I-other'}", + "145, risk {'perturbing_action': 'I-other'}", + "146, allele {'perturbing_action': 'I-other'}", + "151, CD8+ {'context': 'B-cells'}", + "152, T {'context': 'I-cells'}", + "153, cells {'context': 'I-cells'}", + "156, airways {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "138, CD8+ ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "139, T ['l0', 'l8', 'l9', 'l10', 'l11', 'l12']", + "140, cell ['l1', 'l8', 'l13', 'l14', 'l15', 'l16']", + "142, Carriers ['l2', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "143, of ['l17', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "144, the ['l18', 'l25', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "145, risk ['l19', 'l26', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "146, allele ['l3', 'l20', 'l27', 'l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "151, CD8+ ['l4', 'l9', 'l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "152, T ['l5', 'l10', 'l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "153, cells ['l6', 'l11', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "156, airways ['l7', 'l12', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l52']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD8+", + "T", + "cells" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Carriers", + "allele", + "of", + "the", + "risk" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Carriers", + "of", + "the", + "risk", + "allele" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "airways" + ] + } + } + ] + }, + { + "PMID": "28628111", + "TEXT": "Central nervous system (CNS) injury transforms naive astrocytes into reactive astrocytes, which eventually become scar-forming astrocytes that can impair axonal regeneration and functional recovery. This sequential phenotypic change, known as reactive astrogliosis, has long been considered unidirectional and irreversible. However, we report here that reactive astrocytes isolated from injured spinal cord reverted in retrograde to naive astrocytes when transplanted into a naive spinal cord, whereas they formed astrocytic scars when transplanted into injured spinal cord, indicating the environment-dependent plasticity of reactive astrogliosis. We also found that type I collagen was highly expressed in the spinal cord during the scar-forming phase and induced astrocytic scar formation via the integrin-N-cadherin pathway. In a mouse model of spinal cord injury, pharmacological blockade of reactive astrocyte-type I collagen interaction prevented astrocytic scar formation, thereby leading to improved axonal regrowth and better functional outcomes. Our findings reveal environmental cues regulating astrocytic fate decisions, thereby providing a potential therapeutic target for CNS injury.", + "TAG_DATA": [ + "44, reactive {'context': 'B-cells'}", + "45, astrocytes {'context': 'I-cells'}", + "46, isolated {'context': 'I-cells'}", + "56, astrocytes {'context': 'B-cells'}", + "62, spinal {'context': 'I-tissue/organ'}", + "63, cord, {'context': 'I-tissue/organ'}", + "73, spinal {'context': 'B-tissue/organ'}", + "74, cord, {'context': 'I-tissue/organ'}", + "111, mouse {'context': 'B-organism'}", + "112, model {'context': 'I-organism'}", + "115, cord {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "44, reactive ['l0', 'l1', 'l2', 'l3', 'l4']", + "45, astrocytes ['l0', 'l5', 'l6', 'l7', 'l8']", + "46, isolated ['l1', 'l5', 'l9', 'l10', 'l11']", + "56, astrocytes ['l2', 'l6', 'l9', 'l12', 'l13']", + "62, spinal ['l3', 'l7', 'l10', 'l12', 'l14', 'l15']", + "63, cord, ['l4', 'l8', 'l11', 'l13', 'l14']", + "73, spinal ['l16']", + "74, cord, ['l15', 'l16']", + "111, mouse ['l17', 'l18', 'l19']", + "112, model ['l17', 'l20', 'l21']", + "114, spinal ['l18', 'l20', 'l22']", + "115, cord ['l19', 'l21', 'l22']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28628110", + "TEXT": "With the goal of modeling human disease of the large intestine, we sought to develop an effective protocol for deriving colonic organoids (COs) from differentiated human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs). Extensive gene and immunohistochemical profiling confirmed that the derived COs represent colon rather than small intestine, containing stem cells, transit-amplifying cells, and the expected spectrum of differentiated cells, including goblet and endocrine cells. We applied this strategy to iPSCs derived from patients with familial adenomatous polyposis (FAP-iPSCs) harboring germline mutations in the WNT-signaling-pathway-regulator gene encoding APC, and we generated COs that exhibit enhanced WNT activity and increased epithelial cell proliferation, which we used as a platform for drug testing. Two potential compounds, XAV939 and rapamycin, decreased proliferation in FAP-COs, but also affected cell proliferation in wild-type COs, which thus limits their therapeutic application. By contrast, we found that geneticin, a ribosome-binding antibiotic with translational 'read-through' activity, efficiently targeted abnormal WNT activity and restored normal proliferation specifically in APC-mutant FAP-COs. These studies provide an efficient strategy for deriving human COs, which can be used in disease modeling and drug discovery for colorectal disease.", + "TAG_DATA": [ + "102, increased {'effect': 'B-positive'}", + "103, epithelial {'context': 'B-cells'}", + "104, cell {'context': 'I-cells'}", + "105, proliferation, {'phenotype': 'B-proliferation'}", + "121, decreased {'effect': 'B-negative'}", + "122, proliferation {'phenotype': 'B-proliferation'}", + "124, FAP-COs, {'context': 'B-cells'}", + "127, affected {'effect': 'B-regulates'}", + "128, cell {'context': 'B-cells'}", + "129, proliferation {'phenotype': 'B-proliferation'}", + "158, restored {'effect': 'B-rescues'}", + "160, proliferation {'phenotype': 'B-proliferation'}", + "163, APC-mutant {'perturbing_action': 'B-other'}" + ], + "LINK_DATA": [ + "102, increased ['l0', 'l1', 'l2']", + "103, epithelial ['l0', 'l3', 'l4']", + "104, cell ['l1', 'l3', 'l5']", + "105, proliferation, ['l2', 'l4', 'l5']", + "121, decreased ['l6', 'l7', 'l8', 'l9', 'l10']", + "122, proliferation ['l6', 'l11', 'l12', 'l13', 'l14']", + "124, FAP-COs, ['l7', 'l11', 'l15', 'l16', 'l17']", + "127, affected ['l8', 'l12', 'l15', 'l18', 'l19']", + "128, cell ['l9', 'l13', 'l16', 'l18', 'l20']", + "129, proliferation ['l10', 'l14', 'l17', 'l19', 'l20']", + "158, restored ['l21', 'l22']", + "160, proliferation ['l21', 'l23']", + "163, APC-mutant ['l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "cells", + "words": [ + "epithelial", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "epithelial", + "cell", + "FAP-COs," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation,", + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "context": { + "val": "cells", + "words": [ + "FAP-COs,", + "cell" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "affected" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "FAP-COs,", + "cell" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "affected" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "APC-mutant" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "APC-mutant" + ] + } + } + ] + }, + { + "PMID": "28604704", + "TEXT": "Nonalcoholic fatty liver disease (NAFLD), a common prelude to cirrhosis and hepatocellular carcinoma, is the most common chronic liver disease worldwide. Defining the molecular mechanisms underlying the pathogenesis of NAFLD has been hampered by a lack of animal models that closely recapitulate the severe end of the disease spectrum in humans, including bridging hepatic fibrosis. Here we demonstrate that a novel experimental model employing thermoneutral housing, as opposed to standard housing, resulted in lower stress-driven production of corticosterone, augmented mouse proinflammatory immune responses and markedly exacerbated high-fat diet (HFD)-induced NAFLD pathogenesis. Disease exacerbation at thermoneutrality was conserved across multiple mouse strains and was associated with augmented intestinal permeability, an altered microbiome and activation of inflammatory pathways that are associated with the disease in humans. Depletion of Gram-negative microbiota, hematopoietic cell deletion of Toll-like receptor 4 (TLR4) and inactivation of the IL-17 axis resulted in altered immune responsiveness and protection from thermoneutral-housing-driven NAFLD amplification. Finally, female mice, typically resistant to HFD-induced obesity and NAFLD, develop full disease characteristics at thermoneutrality. Thus, thermoneutral housing provides a sex-independent model of exacerbated NAFLD in mice and represents a novel approach for interrogation of the cellular and molecular mechanisms underlying disease pathogenesis.", + "TAG_DATA": [ + "99, mouse {'context': 'B-organism'}", + "100, strains {'context': 'I-organism'}", + "128, hematopoietic {'context': 'B-cells'}", + "129, cell {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "130, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "131, of {'perturbing_action': 'I-gene loss-of-function'}", + "132, Toll-like {'perturbing_action': 'I-gene loss-of-function'}", + "133, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "134, 4 {'perturbing_action': 'I-gene loss-of-function'}", + "135, (TLR4) {'perturbing_action': 'I-gene loss-of-function'}", + "154, female {'context': 'B-organism'}", + "155, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "99, mouse ['l0']", + "100, strains ['l0']", + "128, hematopoietic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "129, cell ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "130, deletion ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "131, of ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "132, Toll-like ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "133, receptor ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "134, 4 ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "135, (TLR4) ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']", + "154, female ['l29']", + "155, mice, ['l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "cell" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cell", + "deletion", + "of", + "Toll-like", + "receptor", + "4", + "(TLR4)" + ] + } + } + ] + }, + { + "PMID": "28604703", + "TEXT": "Adaptive thermogenesis is an energy-demanding process that is mediated by cold-activated beige and brown adipocytes, and it entails increased uptake of carbohydrates, as well as lipoprotein-derived triglycerides and cholesterol, into these thermogenic cells. Here we report that cold exposure in mice triggers a metabolic program that orchestrates lipoprotein processing in brown adipose tissue (BAT) and hepatic conversion of cholesterol to bile acids via the alternative synthesis pathway. This process is dependent on hepatic induction of cytochrome P450, family 7, subfamily b, polypeptide 1 (CYP7B1) and results in increased plasma levels, as well as fecal excretion, of bile acids that is accompanied by distinct changes in gut microbiota and increased heat production. Genetic and pharmacological interventions that targeted the synthesis and biliary excretion of bile acids prevented the rise in fecal bile acid excretion, changed the bacterial composition of the gut and modulated thermogenic responses. These results identify bile acids as important metabolic effectors under conditions of sustained BAT activation and highlight the relevance of cholesterol metabolism by the host for diet-induced changes of the gut microbiota and energy metabolism.", + "TAG_DATA": [ + "40, mice {'context': 'B-organism'}", + "139, gut {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28553932", + "TEXT": "Clear cell renal cell carcinomas (ccRCCs) frequently exhibit inactivation of the von Hippel-Lindau tumor-suppressor gene, VHL, and often harbor multiple copy-number alterations in genes that regulate cell cycle progression. We show here that modeling these genetic alterations by combined deletion of Vhl, Trp53 and Rb1 specifically in renal epithelial cells in mice caused ccRCC. These tumors arose from proximal tubule epithelial cells and shared molecular markers and mRNA expression profiles with human ccRCC. Exome sequencing revealed that mouse and human ccRCCs exhibit recurrent mutations in genes associated with the primary cilium, uncovering a mutational convergence on this organelle and implicating a subset of ccRCCs as genetic ciliopathies. Different mouse tumors responded differently to standard therapies for advanced human ccRCC, mimicking the range of clinical behaviors in the human disease. Inhibition of hypoxia-inducible factor (HIF)-α transcription factors with acriflavine as third-line therapy had therapeutic effects in some tumors, providing preclinical evidence for further investigation of HIF-α inhibition as a ccRCC treatment. This autochthonous mouse ccRCC model represents a tool to investigate the biology of ccRCC and to identify new treatment strategies.", + "TAG_DATA": [ + "39, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "40, of {'perturbing_action': 'I-gene loss-of-function'}", + "41, Vhl, {'perturbing_action': 'I-gene loss-of-function'}", + "42, Trp53 {'perturbing_action': 'I-gene loss-of-function'}", + "43, and {'perturbing_action': 'I-gene loss-of-function'}", + "44, Rb1 {'perturbing_action': 'I-gene loss-of-function'}", + "47, renal {'context': 'B-cells'}", + "48, epithelial {'context': 'I-cells'}", + "49, cells {'context': 'I-cells'}", + "51, mice {'context': 'B-organism'}", + "108, mouse {'context': 'B-neoplasm'}", + "109, tumors {'context': 'I-neoplasm'}", + "146, tumors, {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "39, deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "40, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "41, Vhl, ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "42, Trp53 ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "43, and ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "44, Rb1 ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "47, renal ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "48, epithelial ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "49, cells ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "51, mice ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "108, mouse ['l45']", + "109, tumors ['l45']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Vhl,", + "Trp53", + "and", + "Rb1" + ] + }, + "context": { + "val": "cells", + "words": [ + "renal", + "epithelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Vhl,", + "Trp53", + "and", + "Rb1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "28530702", + "TEXT": "Metformin is widely used in the treatment of type 2 diabetes (T2D), but its mechanism of action is poorly defined. Recent evidence implicates the gut microbiota as a site of metformin action. In a double-blind study, we randomized individuals with treatment-naive T2D to placebo or metformin for 4 months and showed that metformin had strong effects on the gut microbiome. These results were verified in a subset of the placebo group that switched to metformin 6 months after the start of the trial. Transfer of fecal samples (obtained before and 4 months after treatment) from metformin-treated donors to germ-free mice showed that glucose tolerance was improved in mice that received metformin-altered microbiota. By directly investigating metformin-microbiota interactions in a gut simulator, we showed that metformin affected pathways with common biological functions in species from two different phyla, and many of the metformin-regulated genes in these species encoded metalloproteins or metal transporters. Our findings provide support for the notion that altered gut microbiota mediates some of metformin's antidiabetic effects.", + "TAG_DATA": [ + "99, mice {'context': 'I-organism'}", + "107, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28481357", + "TEXT": "Non-alcoholic steatohepatitis (NASH) is an increasingly prevalent liver pathology that can progress from non-alcoholic fatty liver disease (NAFLD), and it is a leading cause of cirrhosis and hepatocellular carcinoma. There is currently no pharmacological therapy for NASH. Defective lysosome-mediated protein degradation is a key process that underlies steatohepatitis and a well-recognized drug target in a variety of diseases; however, whether it can serve as a therapeutic target for NAFLD and NASH remains unknown. Here we report that transmembrane BAX inhibitor motif-containing 1 (TMBIM1) is an effective suppressor of steatohepatitis and a previously unknown regulator of the multivesicular body (MVB)-lysosomal pathway. Tmbim1 expression in hepatocytes substantially inhibited high-fat diet-induced insulin resistance, hepatic steatosis and inflammation in mice. Mechanistically, Tmbim1 promoted the lysosomal degradation of toll-like receptor 4 by cooperating with the ESCRT endosomal sorting complex to facilitate MVB formation, and the ubiquitination of Tmbim1 by the E3 ubiquitin ligase Nedd4l was required for this process. We also found that overexpression of Tmbim1 in the liver effectively inhibited a severe form of NAFLD in mice and NASH progression in monkeys. Taken together, these findings could lead to the development of promising strategies to treat NASH by targeting MVB regulators to properly orchestrate the lysosome-mediated protein degradation of key mediators of the disease.", + "TAG_DATA": [ + "100, Tmbim1 {'perturbing_action': 'B-gene gain-of-function'}", + "101, expression {'perturbing_action': 'I-gene gain-of-function'}", + "103, hepatocytes {'context': 'B-cells'}", + "115, mice. {'context': 'B-organism'}", + "158, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "159, of {'perturbing_action': 'I-gene gain-of-function'}", + "160, Tmbim1 {'perturbing_action': 'I-gene gain-of-function'}", + "163, liver {'context': 'B-tissue/organ'}", + "172, mice {'context': 'B-organism'}", + "177, monkeys. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "100, Tmbim1 ['l0', 'l1', 'l2']", + "101, expression ['l0', 'l3', 'l4']", + "103, hepatocytes ['l1', 'l3', 'l5']", + "115, mice. ['l2', 'l4', 'l5']", + "158, overexpression ['l6', 'l7', 'l8', 'l9', 'l10']", + "159, of ['l6', 'l11', 'l12', 'l13', 'l14']", + "160, Tmbim1 ['l7', 'l11', 'l15', 'l16', 'l17']", + "163, liver ['l8', 'l12', 'l15', 'l18', 'l19']", + "172, mice ['l9', 'l13', 'l16', 'l18']", + "177, monkeys. ['l10', 'l14', 'l17', 'l19']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Tmbim1", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Tmbim1", + "expression", + "overexpression", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice", + "monkeys." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Tmbim1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "28475571", + "TEXT": "The emergence of immuno-oncology as the first broadly successful strategy for metastatic cancer will require clinicians to integrate this new pillar of medicine with chemotherapy, radiation, and targeted small-molecule compounds. Of equal importance is gaining an understanding of the limitations and toxicities of immunotherapy. Immunotherapy was initially perceived to be a relatively less toxic approach to cancer treatment than other available therapies-and surely it is, when compared to those. However, as the use of immunotherapy becomes more common, especially as first- and second-line treatments, immunotoxicity and autoimmunity are emerging as the Achilles' heel of immunotherapy. In this Perspective, we discuss evidence that the occurrence of immunotoxicity bodes well for the patient, and describe mechanisms that might be related to the induction of autoimmunity. We then explore approaches to limit immunotoxicity, and discuss the future directions of research and reporting that are needed to diminish it.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28475567", + "TEXT": "A new study identifies oncostatin M (OSM) as a potential biomarker and therapeutic target for anti-tumor necrosis factor (TNF)-refractory inflammatory bowel disease (IBD), and pinpoints mucosal stromal cells as key players in OSM-mediated inflammation.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28459436", + "TEXT": "We directly assessed mesial temporal activity using intracranial foramen ovale electrodes in two patients with Alzheimer's disease (AD) without a history or EEG evidence of seizures. We detected clinically silent hippocampal seizures and epileptiform spikes during sleep, a period when these abnormalities were most likely to interfere with memory consolidation. The findings in these index cases support a model in which early development of occult hippocampal hyperexcitability may contribute to the pathogenesis of AD.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28436958", + "TEXT": "Senescent cells (SnCs) accumulate in many vertebrate tissues with age and contribute to age-related pathologies, presumably through their secretion of factors contributing to the senescence-associated secretory phenotype (SASP). Removal of SnCs delays several pathologies and increases healthy lifespan. Aging and trauma are risk factors for the development of osteoarthritis (OA), a chronic disease characterized by degeneration of articular cartilage leading to pain and physical disability. Senescent chondrocytes are found in cartilage tissue isolated from patients undergoing joint replacement surgery, yet their role in disease pathogenesis is unknown. To test the idea that SnCs might play a causative role in OA, we used the p16-3MR transgenic mouse, which harbors a p16INK4a (Cdkn2a) promoter driving the expression of a fusion protein containing synthetic Renilla luciferase and monomeric red fluorescent protein domains, as well as a truncated form of herpes simplex virus 1 thymidine kinase (HSV-TK). This mouse strain allowed us to selectively follow and remove SnCs after anterior cruciate ligament transection (ACLT). We found that SnCs accumulated in the articular cartilage and synovium after ACLT, and selective elimination of these cells attenuated the development of post-traumatic OA, reduced pain and increased cartilage development. Intra-articular injection of a senolytic molecule that selectively killed SnCs validated these results in transgenic, non-transgenic and aged mice. Selective removal of the SnCs from in vitro cultures of chondrocytes isolated from patients with OA undergoing total knee replacement decreased expression of senescent and inflammatory markers while also increasing expression of cartilage tissue extracellular matrix proteins. Collectively, these findings support the use of SnCs as a therapeutic target for treating degenerative joint disease.", + "TAG_DATA": [ + "103, p16-3MR {'context': 'B-organism'}", + "104, transgenic {'context': 'I-organism'}", + "105, mouse, {'context': 'I-organism'}", + "108, a {'perturbing_action': 'I-gene gain-of-function'}", + "109, p16INK4a {'perturbing_action': 'I-other'}", + "110, (Cdkn2a) {'perturbing_action': 'I-other'}", + "111, promoter {'perturbing_action': 'I-other'}", + "144, mouse {'context': 'B-organism'}", + "145, strain {'context': 'I-organism'}", + "178, cells {'context': 'B-cells'}", + "200, SnCs {'context': 'B-cells'}", + "208, aged {'context': 'B-organism'}", + "209, mice. {'context': 'I-organism'}", + "216, in {'context': 'B-in vitro'}", + "217, vitro {'context': 'I-in vitro'}", + "218, cultures {'context': 'I-in vitro'}", + "220, chondrocytes {'context': 'B-cells'}", + "221, isolated {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "103, p16-3MR ['l0', 'l1']", + "104, transgenic ['l0', 'l2']", + "105, mouse, ['l1', 'l2']", + "108, a ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "109, p16INK4a ['l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "110, (Cdkn2a) ['l4', 'l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "111, promoter ['l5', 'l11', 'l16', 'l21', 'l22', 'l23']", + "112, driving ['l6', 'l12', 'l17', 'l21', 'l24', 'l25']", + "144, mouse ['l7', 'l13', 'l18', 'l22', 'l24', 'l26']", + "145, strain ['l8', 'l14', 'l19', 'l23', 'l25', 'l26']", + "178, cells ['l9', 'l15', 'l20']", + "200, SnCs ['l27', 'l28', 'l29']", + "208, aged ['l27', 'l30']", + "209, mice. ['l28', 'l30']", + "216, in ['l31', 'l32', 'l33', 'l34']", + "217, vitro ['l31', 'l35', 'l36', 'l37']", + "218, cultures ['l32', 'l35', 'l38', 'l39']", + "220, chondrocytes ['l33', 'l36', 'l38', 'l40']", + "221, isolated ['l29', 'l34', 'l37', 'l39', 'l40']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "a" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "strain" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "a" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "p16INK4a", + "(Cdkn2a)", + "promoter" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "strain" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "p16INK4a", + "(Cdkn2a)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "28394331", + "TEXT": "The progression of pancreatic oncogenesis requires immune-suppressive inflammation in cooperation with oncogenic mutations. However, the drivers of intratumoral immune tolerance are uncertain. Dectin 1 is an innate immune receptor crucial for anti-fungal immunity, but its role in sterile inflammation and oncogenesis has not been well defined. Furthermore, non-pathogen-derived ligands for dectin 1 have not been characterized. We found that dectin 1 is highly expressed on macrophages in pancreatic ductal adenocarcinoma (PDA). Dectin 1 ligation accelerated the progression of PDA in mice, whereas deletion of Clec7a-the gene encoding dectin 1-or blockade of dectin 1 downstream signaling was protective. We found that dectin 1 can ligate the lectin galectin 9 in mouse and human PDA, which results in tolerogenic macrophage programming and adaptive immune suppression. Upon disruption of the dectin 1-galectin 9 axis, CD4+ and CD8+ T cells, which are dispensable for PDA progression in hosts with an intact signaling axis, become reprogrammed into indispensable mediators of anti-tumor immunity. These data suggest that targeting dectin 1 signaling is an attractive strategy for developing an immunotherapy for PDA.", + "TAG_DATA": [ + "78, PDA {'context': 'B-neoplasm'}", + "80, mice, {'context': 'B-organism'}", + "82, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "83, of {'perturbing_action': 'I-gene loss-of-function'}", + "84, Clec7a-the {'perturbing_action': 'I-gene loss-of-function'}", + "85, gene {'perturbing_action': 'I-gene loss-of-function'}", + "86, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "87, dectin {'perturbing_action': 'I-gene loss-of-function'}", + "88, 1-or {'perturbing_action': 'I-gene loss-of-function'}", + "131, CD4+ {'context': 'B-cells'}", + "132, and {'context': 'I-cells'}", + "133, CD8+ {'context': 'I-cells'}", + "134, T {'context': 'I-cells'}", + "135, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "82, deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "83, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "84, Clec7a-the ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "85, gene ['l2', 'l8', 'l13', 'l18', 'l19', 'l20']", + "86, encoding ['l3', 'l9', 'l14', 'l18', 'l21', 'l22', 'l23']", + "87, dectin ['l4', 'l10', 'l15', 'l19', 'l21', 'l24']", + "88, 1-or ['l5', 'l11', 'l16', 'l20', 'l22', 'l24']", + "109, mouse ['l6', 'l12', 'l17', 'l23', 'l25', 'l26']", + "131, CD4+ ['l27', 'l28', 'l29', 'l30']", + "132, and ['l27', 'l31', 'l32', 'l33']", + "133, CD8+ ['l28', 'l31', 'l34', 'l35']", + "134, T ['l25', 'l29', 'l32', 'l34', 'l36']", + "135, cells, ['l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28394328", + "TEXT": "Zika virus (ZIKV) infection of pregnant women can cause a wide range of congenital abnormalities, including microcephaly, in the infant, a condition now collectively known as congenital ZIKV syndrome. A vaccine to prevent or significantly attenuate viremia in pregnant women who are residents of or travelers to epidemic or endemic regions is needed to avert congenital ZIKV syndrome, and might also help to suppress epidemic transmission. Here we report on a live-attenuated vaccine candidate that contains a 10-nucleotide deletion in the 3' untranslated region of the ZIKV genome (10-del ZIKV). The 10-del ZIKV is highly attenuated, immunogenic, and protective in type 1 interferon receptor-deficient A129 mice. Crucially, a single dose of 10-del ZIKV induced sterilizing immunity with a saturated neutralizing antibody titer, which no longer increased after challenge with an epidemic ZIKV, and completely prevented viremia. The immunized mice also developed a robust T cell response. Intracranial inoculation of 1-d-old immunocompetent CD-1 mice with 1 × 104 infectious focus units (IFU) of 10-del ZIKV caused no mortality, whereas infections with 10 IFU of wild-type ZIKV were lethal. Mechanistically, the attenuated virulence of 10-del ZIKV may be due to decreased viral RNA synthesis and increased sensitivity to type-1-interferon inhibition. The attenuated 10-del ZIKV was incapable of infecting mosquitoes after oral feeding of spiked-blood meals, representing an additional safety feature. Collectively, the safety and efficacy results suggest that further development of this promising, live-attenuated ZIKV vaccine candidate is warranted.", + "TAG_DATA": [ + "100, type {'perturbing_action': 'B-gene loss-of-function'}", + "101, 1 {'perturbing_action': 'B-gene loss-of-function'}", + "102, interferon {'perturbing_action': 'I-gene loss-of-function'}", + "103, receptor-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "104, A129 {'context': 'B-organism'}", + "105, mice. {'context': 'I-organism'}", + "138, mice {'context': 'B-organism'}", + "143, T {'context': 'B-cells'}", + "144, cell {'context': 'B-cells'}", + "150, immunocompetent {'context': 'B-organism'}", + "151, CD-1 {'context': 'I-organism'}", + "152, mice {'context': 'I-organism'}", + "206, mosquitoes {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "100, type ['l0', 'l1', 'l2', 'l3', 'l4']", + "101, 1 ['l0', 'l5', 'l6', 'l7', 'l8']", + "102, interferon ['l1', 'l5', 'l9', 'l10', 'l11']", + "103, receptor-deficient ['l2', 'l6', 'l9', 'l12', 'l13']", + "104, A129 ['l3', 'l7', 'l10', 'l12', 'l14']", + "105, mice. ['l4', 'l8', 'l11', 'l13', 'l14']", + "138, mice ['l15', 'l16']", + "143, T ['l15', 'l17', 'l18', 'l19']", + "144, cell ['l16', 'l17', 'l20']", + "150, immunocompetent ['l21', 'l22']", + "151, CD-1 ['l18', 'l21', 'l23']", + "152, mice ['l19', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "type", + "1", + "interferon", + "receptor-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "A129", + "mice." + ] + } + } + ] + }, + { + "PMID": "28368383", + "TEXT": "Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex chronic inflammatory conditions of the gastrointestinal tract that are driven by perturbed cytokine pathways. Anti-tumor necrosis factor-α (TNF) antibodies are mainstay therapies for IBD. However, up to 40% of patients are nonresponsive to anti-TNF agents, which makes the identification of alternative therapeutic targets a priority. Here we show that, relative to healthy controls, inflamed intestinal tissues from patients with IBD express high amounts of the cytokine oncostatin M (OSM) and its receptor (OSMR), which correlate closely with histopathological disease severity. The OSMR is expressed in nonhematopoietic, nonepithelial intestinal stromal cells, which respond to OSM by producing various proinflammatory molecules, including interleukin (IL)-6, the leukocyte adhesion factor ICAM1, and chemokines that attract neutrophils, monocytes, and T cells. In an animal model of anti-TNF-resistant intestinal inflammation, genetic deletion or pharmacological blockade of OSM significantly attenuates colitis. Furthermore, according to an analysis of more than 200 patients with IBD, including two cohorts from phase 3 clinical trials of infliximab and golimumab, high pretreatment expression of OSM is strongly associated with failure of anti-TNF therapy. OSM is thus a potential biomarker and therapeutic target for IBD, and has particular relevance for anti-TNF-resistant patients.", + "TAG_DATA": [ + "132, animal {'context': 'B-organism'}", + "133, model {'context': 'I-organism'}", + "141, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "142, blockade {'perturbing_action': 'I-gene loss-of-function'}", + "143, of {'perturbing_action': 'I-gene loss-of-function'}", + "144, OSM {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "132, animal ['l0']", + "133, model ['l0']", + "141, pharmacological ['l1', 'l2', 'l3']", + "142, blockade ['l1', 'l4', 'l5']", + "143, of ['l2', 'l4', 'l6']", + "144, OSM ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28263311", + "TEXT": "Cisplatin and its platinum analogs, carboplatin and oxaliplatin, are some of the most widely used cancer chemotherapeutics. Although cisplatin and carboplatin are used primarily in germ cell, breast and lung malignancies, oxaliplatin is instead used almost exclusively to treat colorectal and other gastrointestinal cancers. Here we utilize a unique, multi-platform genetic approach to study the mechanism of action of these clinically established platinum anti-cancer agents, as well as more recently developed cisplatin analogs. We show that oxaliplatin, unlike cisplatin and carboplatin, does not kill cells through the DNA-damage response. Rather, oxaliplatin kills cells by inducing ribosome biogenesis stress. This difference in drug mechanism explains the distinct clinical implementation of oxaliplatin relative to cisplatin, and it might enable mechanistically informed selection of distinct platinum drugs for distinct malignancies. These data highlight the functional diversity of core components of front-line cancer therapy and the potential benefits of applying a mechanism-based rationale to the use of our current arsenal of anti-cancer drugs.", + "TAG_DATA": [ + "84, cells {'context': 'B-cells'}", + "92, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28263310", + "TEXT": "Exercise has numerous health-promoting effects in humans; however, individual responsiveness to exercise with regard to endurance or metabolic health differs markedly. This 'exercise resistance' is considered to be congenital, with no evident acquired causative factors. Here we show that the anti-oxidative hepatokine selenoprotein P (SeP) causes exercise resistance through its muscle receptor low-density lipoprotein receptor-related protein 1 (LRP1). SeP-deficient mice showed a 'super-endurance' phenotype after exercise training, as well as enhanced reactive oxygen species (ROS) production, AMP-activated protein kinase (AMPK) phosphorylation and peroxisome proliferative activated receptor γ coactivator (Ppargc)-1α (also known as PGC-1α; encoded by Ppargc1a) expression in skeletal muscle. Supplementation with the anti-oxidant N-acetylcysteine (NAC) reduced ROS production and the endurance capacity in SeP-deficient mice. SeP treatment impaired hydrogen-peroxide-induced adaptations through LRP1 in cultured myotubes and suppressed exercise-induced AMPK phosphorylation and Ppargc1a gene expression in mouse skeletal muscle-effects which were blunted in mice with a muscle-specific LRP1 deficiency. Furthermore, we found that increased amounts of circulating SeP predicted the ineffectiveness of training on endurance capacity in humans. Our study suggests that inhibitors of the SeP-LRP1 axis may function as exercise-enhancing drugs to treat diseases associated with a sedentary lifestyle.", + "TAG_DATA": [ + "58, SeP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "59, mice {'context': 'B-organism'}", + "114, SeP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "115, mice. {'context': 'B-organism'}", + "124, cultured {'context': 'B-cells'}", + "125, myotubes {'context': 'I-cells'}", + "136, mouse {'context': 'B-tissue/organ'}", + "137, skeletal {'context': 'I-tissue/organ'}", + "138, muscle-effects {'context': 'I-tissue/organ'}", + "143, mice {'context': 'B-organism'}", + "146, muscle-specific {'perturbing_action': 'B-gene loss-of-function'}", + "147, LRP1 {'perturbing_action': 'I-gene loss-of-function'}", + "148, deficiency. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "58, SeP-deficient ['l0']", + "59, mice ['l0']", + "114, SeP-deficient ['l1', 'l2', 'l3']", + "115, mice. ['l1']", + "124, cultured ['l2', 'l4']", + "125, myotubes ['l3', 'l4']", + "136, mouse ['l5', 'l6']", + "137, skeletal ['l5', 'l7']", + "138, muscle-effects ['l6', 'l7']", + "143, mice ['l8', 'l9', 'l10']", + "146, muscle-specific ['l8', 'l11', 'l12']", + "147, LRP1 ['l9', 'l11', 'l13']", + "148, deficiency. ['l10', 'l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SeP-deficient", + "muscle-specific", + "LRP1", + "deficiency." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SeP-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "myotubes" + ] + } + } + ] + }, + { + "PMID": "28263308", + "TEXT": "Identification of epitopes that are recognized by diabetogenic T cells and cause selective beta cell destruction in type 1 diabetes (T1D) has focused on peptides originating from native beta cell proteins. Translational errors represent a major potential source of antigenic peptides to which central immune tolerance is lacking. Here, we describe an alternative open reading frame within human insulin mRNA encoding a highly immunogenic polypeptide that is targeted by T cells in T1D patients. We show that cytotoxic T cells directed against the N-terminal peptide of this nonconventional product are present in the circulation of individuals diagnosed with T1D, and we provide direct evidence that such CD8+ T cells are capable of killing human beta cells and thereby may be diabetogenic. This study reveals a new source of nonconventional polypeptides that act as self-epitopes in clinical autoimmune disease.", + "TAG_DATA": [ + "113, human {'context': 'B-cells'}", + "114, beta {'context': 'I-cells'}", + "115, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "113, human ['l0', 'l1']", + "114, beta ['l0', 'l2']", + "115, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28191887", + "TEXT": "Expression of the MECOM (also known as EVI1) proto-oncogene is deregulated by chromosomal translocations in some cases of acute myeloid leukemia (AML) and is associated with poor clinical outcome. Here, through transcriptomic and metabolomic profiling of hematopoietic cells, we reveal that EVI1 overexpression alters cellular metabolism. A screen using pooled short hairpin RNAs (shRNAs) identified the ATP-buffering, mitochondrial creatine kinase CKMT1 as necessary for survival of EVI1-expressing cells in subjects with EVI1-positive AML. EVI1 promotes CKMT1 expression by repressing the myeloid differentiation regulator RUNX1. Suppression of arginine-creatine metabolism by CKMT1-directed shRNAs or by the small molecule cyclocreatine selectively decreased the viability, promoted the cell cycle arrest and apoptosis of human EVI1-positive cell lines, and prolonged survival in both orthotopic xenograft models and mouse models of primary AML. CKMT1 inhibition altered mitochondrial respiration and ATP production, an effect that was abrogated by phosphocreatine-mediated reactivation of the arginine-creatine pathway. Targeting CKMT1 is thus a promising therapeutic strategy for this EVI1-driven AML subtype that is highly resistant to current treatment regimens.", + "TAG_DATA": [ + "89, CKMT1-directed {'perturbing_action': 'B-rnai/knockdown'}", + "90, shRNAs {'perturbing_action': 'I-rnai/knockdown'}", + "101, promoted {'effect': 'B-positive'}", + "103, cell {'phenotype': 'B-cell cycle arrest'}", + "104, cycle {'phenotype': 'I-cell cycle arrest'}", + "105, arrest {'phenotype': 'I-cell cycle arrest'}", + "107, apoptosis {'phenotype': 'B-apoptosis'}", + "109, human {'context': 'B-cells'}", + "110, EVI1-positive {'context': 'I-cells'}", + "111, cell {'context': 'I-cells'}", + "112, lines, {'context': 'I-cells'}", + "118, orthotopic {'context': 'B-xenograft'}", + "119, xenograft {'context': 'I-xenograft'}", + "120, models {'context': 'I-xenograft'}", + "122, mouse {'context': 'B-neoplasm'}", + "123, models {'context': 'I-neoplasm'}", + "124, of {'context': 'I-neoplasm'}", + "125, primary {'context': 'I-neoplasm'}", + "126, AML. {'context': 'I-neoplasm'}", + "127, CKMT1 {'perturbing_action': 'B-pharmacological inhibition'}", + "128, inhibition {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "89, CKMT1-directed ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "90, shRNAs ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "101, promoted ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "103, cell ['l2', 'l14', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "104, cycle ['l3', 'l15', 'l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "105, arrest ['l4', 'l16', 'l27', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "107, apoptosis ['l5', 'l17', 'l28', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "109, human ['l6', 'l18', 'l29', 'l36', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57', 'l58', 'l59']", + "110, EVI1-positive ['l7', 'l19', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l60', 'l61', 'l62', 'l63', 'l64']", + "111, cell ['l8', 'l20', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l60', 'l65']", + "112, lines, ['l9', 'l21', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l61', 'l65']", + "118, orthotopic ['l10', 'l22', 'l62', 'l66', 'l67']", + "119, xenograft ['l11', 'l23', 'l58', 'l63', 'l66', 'l68']", + "120, models ['l12', 'l24', 'l59', 'l64', 'l67', 'l68']", + "122, mouse ['l69', 'l70', 'l71', 'l72', 'l73']", + "123, models ['l69', 'l74', 'l75', 'l76']", + "124, of ['l70', 'l74', 'l77', 'l78']", + "125, primary ['l71', 'l75', 'l77', 'l79', 'l80']", + "126, AML. ['l72', 'l76', 'l78', 'l79']", + "127, CKMT1 ['l81']", + "128, inhibition ['l73', 'l80', 'l81']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "CKMT1-directed", + "shRNAs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "CKMT1-directed", + "shRNAs" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "CKMT1-directed", + "shRNAs" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "CKMT1-directed", + "shRNAs" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "EVI1-positive", + "cell", + "lines," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "CKMT1-directed", + "shRNAs" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "orthotopic", + "xenograft", + "models" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "EVI1-positive", + "cell", + "lines," + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "EVI1-positive", + "cell", + "lines," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "EVI1-positive", + "cell", + "lines," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "primary" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition" + ] + } + } + ] + }, + { + "PMID": "28165479", + "TEXT": "A substantial proportion of tumors consist of genotypically distinct subpopulations of cancer cells. This intratumor genetic heterogeneity poses a substantial challenge for the implementation of precision medicine. Single-cell genomics constitutes a powerful approach to resolve complex mixtures of cancer cells by tracing cell lineages and discovering cryptic genetic variations that would otherwise be obscured in tumor bulk analyses. Because of the chemical alterations that result from formalin fixation, single-cell genomic approaches have largely remained limited to fresh or rapidly frozen specimens. Here we describe the development and validation of a robust and accurate methodology to perform whole-genome copy-number profiling of single nuclei obtained from formalin-fixed paraffin-embedded clinical tumor samples. We applied the single-cell sequencing approach described here to study the progression from in situ to invasive breast cancer, which revealed that ductal carcinomas in situ show intratumor genetic heterogeneity at diagnosis and that these lesions may progress to invasive breast cancer through a variety of evolutionary processes.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28165478", + "TEXT": "Antitumor T cells are subject to multiple mechanisms of negative regulation. Recent findings that innate lymphoid cells (ILCs) regulate adaptive T cell responses led us to examine the regulatory potential of ILCs in the context of cancer. We identified a unique ILC population that inhibits tumor-infiltrating lymphocytes (TILs) from high-grade serous tumors, defined their suppressive capacity in vitro, and performed a comprehensive analysis of their phenotype. Notably, the presence of this CD56+CD3- population in TIL cultures was associated with reduced T cell numbers, and further functional studies demonstrated that this population suppressed TIL expansion and altered TIL cytokine production. Transcriptome analysis and phenotypic characterization determined that regulatory CD56+CD3- cells exhibit low cytotoxic activity, produce IL-22, and have an expression profile that overlaps with those of natural killer (NK) cells and other ILCs. NKp46 was highly expressed by these cells, and addition of anti-NKp46 antibodies to TIL cultures abrogated the ability of these regulatory ILCs to suppress T cell expansion. Notably, the presence of these regulatory ILCs in TIL cultures corresponded with a striking reduction in the time to disease recurrence. These studies demonstrate that a previously uncharacterized ILC population regulates the activity and expansion of tumor-associated T cells.", + "TAG_DATA": [ + "80, T {'context': 'B-cells'}", + "81, cell {'context': 'B-cells'}", + "92, TIL {'context': 'B-cells'}", + "107, CD56+CD3- {'context': 'I-cells'}", + "108, cells {'context': 'I-cells'}", + "145, TIL {'context': 'B-cells'}", + "146, cultures {'context': 'I-cells'}", + "156, T {'context': 'B-cells'}", + "157, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "56, in ['l0', 'l1']", + "80, T ['l0', 'l2']", + "81, cell ['l1', 'l2']", + "107, CD56+CD3- ['l3', 'l4', 'l5', 'l6', 'l7']", + "108, cells ['l3']", + "145, TIL ['l4', 'l8', 'l9', 'l10']", + "146, cultures ['l5', 'l8', 'l11', 'l12']", + "156, T ['l6', 'l9', 'l11', 'l13']", + "157, cell ['l7', 'l10', 'l12', 'l13']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "28134928", + "TEXT": "Opiates are essential for treating pain, but termination of opiate therapy can cause a debilitating withdrawal syndrome in chronic users. To alleviate or avoid the aversive symptoms of withdrawal, many of these individuals continue to use opiates. Withdrawal is therefore a key determinant of opiate use in dependent individuals, yet its underlying mechanisms are poorly understood and effective therapies are lacking. Here, we identify the pannexin-1 (Panx1) channel as a therapeutic target in opiate withdrawal. We show that withdrawal from morphine induces long-term synaptic facilitation in lamina I and II neurons within the rodent spinal dorsal horn, a principal site of action for opiate analgesia. Genetic ablation of Panx1 in microglia abolished the spinal synaptic facilitation and ameliorated the sequelae of morphine withdrawal. Panx1 is unique in its permeability to molecules up to 1 kDa in size and its release of ATP. We show that Panx1 activation drives ATP release from microglia during morphine withdrawal and that degrading endogenous spinal ATP by administering apyrase produces a reduction in withdrawal behaviors. Conversely, we found that pharmacological inhibition of ATP breakdown exacerbates withdrawal. Treatment with a Panx1-blocking peptide (10panx) or the clinically used broad-spectrum Panx1 blockers, mefloquine or probenecid, suppressed ATP release and reduced withdrawal severity. Our results demonstrate that Panx1-mediated ATP release from microglia is required for morphine withdrawal in rodents and that blocking Panx1 alleviates the severity of withdrawal without affecting opiate analgesia.", + "TAG_DATA": [ + "86, lamina {'context': 'B-cells'}", + "87, I {'context': 'I-cells'}", + "88, and {'context': 'I-cells'}", + "89, II {'context': 'I-cells'}", + "90, neurons {'context': 'I-cells'}", + "93, rodent {'context': 'B-tissue/organ'}", + "94, spinal {'context': 'I-tissue/organ'}", + "95, dorsal {'context': 'I-tissue/organ'}", + "96, horn, {'context': 'I-tissue/organ'}", + "105, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "106, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "107, of {'perturbing_action': 'I-gene loss-of-function'}", + "108, Panx1 {'perturbing_action': 'I-gene loss-of-function'}", + "110, microglia {'context': 'B-cells'}", + "192, Panx1 {'perturbing_action': 'I-pharmacological inhibition'}", + "193, blockers, {'perturbing_action': 'I-pharmacological inhibition'}", + "222, blocking {'perturbing_action': 'B-pharmacological inhibition'}", + "223, Panx1 {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "86, lamina ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "87, I ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "88, and ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "89, II ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "90, neurons ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "93, rodent ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "94, spinal ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "95, dorsal ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "96, horn, ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "105, Genetic ['l36', 'l37', 'l38', 'l39']", + "106, ablation ['l36', 'l40', 'l41', 'l42']", + "107, of ['l37', 'l40', 'l43', 'l44']", + "108, Panx1 ['l38', 'l41', 'l43', 'l45']", + "110, microglia ['l39', 'l42', 'l44', 'l45']", + "191, broad-spectrum ['l46', 'l47', 'l48', 'l49']", + "192, Panx1 ['l46', 'l50', 'l51', 'l52']", + "193, blockers, ['l47', 'l50', 'l53', 'l54']", + "222, blocking ['l48', 'l51', 'l53', 'l55']", + "223, Panx1 ['l49', 'l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "ablation", + "of", + "Panx1" + ] + }, + "context": { + "val": "cells", + "words": [ + "microglia" + ] + } + } + ] + }, + { + "PMID": "28134927", + "TEXT": "Two new studies show that mechanisms mediating the opioid side effects of tolerance, hyperalgesia and physical dependence are mediated spinally and can be dissociated from analgesia. These side effects can be selectively targeted by clinically available drugs without affecting their pain-relieving effects.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28092664", + "TEXT": "Low-grade, chronic inflammation has been associated with many diseases of aging, but the mechanisms responsible for producing this inflammation remain unclear. Inflammasomes can drive chronic inflammation in the context of an infectious disease or cellular stress, and they trigger the maturation of interleukin-1β (IL-1β). Here we find that the expression of specific inflammasome gene modules stratifies older individuals into two extremes: those with constitutive expression of IL-1β, nucleotide metabolism dysfunction, elevated oxidative stress, high rates of hypertension and arterial stiffness; and those without constitutive expression of IL-1β, who lack these characteristics. Adenine and N4-acetylcytidine, nucleotide-derived metabolites that are detectable in the blood of the former group, prime and activate the NLRC4 inflammasome, induce the production of IL-1β, activate platelets and neutrophils and elevate blood pressure in mice. In individuals over 85 years of age, the elevated expression of inflammasome gene modules was associated with all-cause mortality. Thus, targeting inflammasome components may ameliorate chronic inflammation and various other age-associated conditions.", + "TAG_DATA": [ + "126, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "28067900", + "TEXT": "Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. However, graft-versus-host disease (GVHD) and relapse after allo-HSCT remain major impediments to the success of allo-HSCT. Chimeric antigen receptors (CARs) direct tumor cell recognition of adoptively transferred T cells. CD19 is an attractive CAR target, which is expressed in most B cell malignancies, as well as in healthy B cells. Clinical trials using autologous CD19-targeted T cells have shown remarkable promise in various B cell malignancies. However, the use of allogeneic CAR T cells poses a concern in that it may increase risk of the occurrence of GVHD, although this has not been reported in selected patients infused with donor-derived CD19 CAR T cells after allo-HSCT. To understand the mechanism whereby allogeneic CD19 CAR T cells may mediate anti-lymphoma activity without causing a significant increase in the incidence of GVHD, we studied donor-derived CD19 CAR T cells in allo-HSCT and lymphoma models in mice. We demonstrate that alloreactive T cells expressing CD28-costimulated CD19 CARs experience enhanced stimulation, resulting in the progressive loss of both their effector function and proliferative potential, clonal deletion, and significantly decreased occurrence of GVHD. Concurrently, the other CAR T cells that were present in bulk donor T cell populations retained their anti-lymphoma activity in accordance with the requirement that both the T cell receptor (TCR) and CAR be engaged to accelerate T cell exhaustion. In contrast, first-generation and 4-1BB-costimulated CAR T cells increased the occurrence of GVHD. These findings could explain the reduced risk of GVHD occurring with cumulative TCR and CAR signaling.", + "TAG_DATA": [ + "157, mice. {'context': 'B-organism'}", + "161, alloreactive {'context': 'B-cells'}", + "162, T {'context': 'I-cells'}", + "163, cells {'context': 'I-cells'}", + "182, proliferative {'phenotype': 'B-proliferation'}", + "183, potential, {'phenotype': 'I-proliferation'}" + ], + "LINK_DATA": [ + "157, mice. ['l0', 'l1', 'l2']", + "161, alloreactive ['l3', 'l4', 'l5', 'l6']", + "162, T ['l3', 'l7', 'l8', 'l9']", + "163, cells ['l0', 'l4', 'l7', 'l10', 'l11']", + "182, proliferative ['l1', 'l5', 'l8', 'l10', 'l12']", + "183, potential, ['l2', 'l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "potential," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "alloreactive", + "T", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "potential," + ] + } + } + ] + }, + { + "PMID": "27991917", + "TEXT": "Traditionally, vaccine development involves tradeoffs between immunogenicity and safety. Live-attenuated vaccines typically offer rapid and durable immunity but have reduced safety when compared to inactivated vaccines. In contrast, the inability of inactivated vaccines to replicate enhances safety at the expense of immunogenicity, often necessitating multiple doses and boosters. To overcome these tradeoffs, we developed the insect-specific alphavirus, Eilat virus (EILV), as a vaccine platform. To address the chikungunya fever (CHIKF) pandemic, we used an EILV cDNA clone to design a chimeric virus containing the chikungunya virus (CHIKV) structural proteins. The recombinant EILV/CHIKV was structurally identical at 10 Å to wild-type CHIKV, as determined by single-particle cryo-electron microscopy, and it mimicked the early stages of CHIKV replication in vertebrate cells from attachment and entry to viral RNA delivery. Yet the recombinant virus remained completely defective for productive replication, providing a high degree of safety. A single dose of EILV/CHIKV produced in mosquito cells elicited rapid (within 4 d) and long-lasting (>290 d) neutralizing antibodies that provided complete protection in two different mouse models. In nonhuman primates, EILV/CHIKV elicited rapid and robust immunity that protected against viremia and telemetrically monitored fever. Our EILV platform represents the first structurally native application of an insect-specific virus in preclinical vaccine development and highlights the potential application of such viruses in vaccinology.", + "TAG_DATA": [ + "150, mosquito {'context': 'B-cells'}", + "151, cells {'context': 'I-cells'}", + "170, mouse {'context': 'B-organism'}", + "171, models. {'context': 'I-organism'}", + "173, nonhuman {'context': 'B-organism'}", + "174, primates, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "150, mosquito ['l0', 'l1', 'l2']", + "151, cells ['l0', 'l3', 'l4']", + "170, mouse ['l1', 'l3', 'l5']", + "171, models. ['l2', 'l4', 'l5']", + "173, nonhuman ['l6']", + "174, primates, ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27941792", + "TEXT": "In acute myeloid leukemia (AML), therapy resistance frequently occurs, leading to high mortality among patients. However, the mechanisms that render leukemic cells drug resistant remain largely undefined. Here, we identified loss of the histone methyltransferase EZH2 and subsequent reduction of histone H3K27 trimethylation as a novel pathway of acquired resistance to tyrosine kinase inhibitors (TKIs) and cytotoxic drugs in AML. Low EZH2 protein levels correlated with poor prognosis in AML patients. Suppression of EZH2 protein expression induced chemoresistance of AML cell lines and primary cells in vitro and in vivo. Low EZH2 levels resulted in derepression of HOX genes, and knockdown of HOXB7 and HOXA9 in the resistant cells was sufficient to improve sensitivity to TKIs and cytotoxic drugs. The endogenous loss of EZH2 expression in resistant cells and primary blasts from a subset of relapsed AML patients resulted from enhanced CDK1-dependent phosphorylation of EZH2 at Thr487. This interaction was stabilized by heat shock protein 90 (HSP90) and followed by proteasomal degradation of EZH2 in drug-resistant cells. Accordingly, inhibitors of HSP90, CDK1 and the proteasome prevented EZH2 degradation, decreased HOX gene expression and restored drug sensitivity. Finally, patients with reduced EZH2 levels at progression to standard therapy responded to the combination of bortezomib and cytarabine, concomitant with the re-establishment of EZH2 expression and blast clearance. These data suggest restoration of EZH2 protein as a viable approach to overcome treatment resistance in this AML patient population.", + "TAG_DATA": [ + "71, Suppression {'perturbing_action': 'B-rnai/knockdown'}", + "72, of {'perturbing_action': 'I-rnai/knockdown'}", + "73, EZH2 {'perturbing_action': 'I-rnai/knockdown'}", + "74, protein {'perturbing_action': 'I-rnai/knockdown'}", + "75, expression {'perturbing_action': 'I-rnai/knockdown'}", + "79, AML {'context': 'B-transformed cells'}", + "80, cell {'context': 'I-transformed cells'}", + "81, lines {'context': 'I-transformed cells'}", + "83, primary {'context': 'B-cells'}", + "84, cells {'context': 'I-cells'}", + "85, in {'context': 'B-in vitro'}", + "86, vitro {'context': 'I-in vitro'}", + "88, in {'context': 'B-in vivo'}", + "89, vivo. {'context': 'I-in vivo'}", + "100, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "101, of {'perturbing_action': 'I-rnai/knockdown'}", + "102, HOXB7 {'perturbing_action': 'I-rnai/knockdown'}", + "103, and {'perturbing_action': 'I-rnai/knockdown'}", + "104, HOXA9 {'perturbing_action': 'I-rnai/knockdown'}", + "107, resistant {'context': 'B-cells'}", + "108, cells {'context': 'I-cells'}", + "121, loss {'perturbing_action': 'I-gene loss-of-function'}", + "122, of {'perturbing_action': 'I-gene loss-of-function'}", + "123, EZH2 {'perturbing_action': 'I-gene loss-of-function'}", + "124, expression {'perturbing_action': 'I-gene loss-of-function'}", + "126, resistant {'context': 'B-cells'}", + "127, cells {'context': 'I-cells'}", + "129, primary {'context': 'B-transformed cells'}", + "130, blasts {'context': 'I-transformed cells'}", + "165, drug-resistant {'context': 'B-cells'}", + "166, cells. {'context': 'I-cells'}", + "168, inhibitors {'perturbing_action': 'B-pharmacological inhibition'}", + "169, of {'perturbing_action': 'I-pharmacological inhibition'}", + "170, HSP90, {'perturbing_action': 'I-pharmacological inhibition'}", + "171, CDK1 {'perturbing_action': 'I-pharmacological inhibition'}", + "172, and {'perturbing_action': 'I-pharmacological inhibition'}", + "173, the {'perturbing_action': 'I-pharmacological inhibition'}", + "174, proteasome {'perturbing_action': 'I-pharmacological inhibition'}", + "187, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "71, Suppression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "72, of ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "73, EZH2 ['l1', 'l14', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "74, protein ['l2', 'l15', 'l26', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "75, expression ['l3', 'l16', 'l27', 'l37', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "79, AML ['l4', 'l17', 'l28', 'l38', 'l47', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "80, cell ['l5', 'l18', 'l29', 'l39', 'l48', 'l56', 'l62', 'l63', 'l64', 'l65']", + "81, lines ['l6', 'l19', 'l30', 'l40', 'l49', 'l57', 'l62', 'l66', 'l67']", + "83, primary ['l7', 'l20', 'l31', 'l41', 'l50', 'l58', 'l63', 'l66', 'l68', 'l69', 'l70']", + "84, cells ['l8', 'l21', 'l32', 'l42', 'l51', 'l59', 'l64', 'l67', 'l68', 'l71']", + "85, in ['l9', 'l22', 'l33', 'l43', 'l52', 'l60', 'l69', 'l72']", + "86, vitro ['l10', 'l23', 'l34', 'l44', 'l53', 'l61', 'l65', 'l70', 'l71', 'l72']", + "88, in ['l11', 'l24', 'l35', 'l45', 'l54', 'l73']", + "89, vivo. ['l12', 'l25', 'l36', 'l46', 'l55', 'l73']", + "100, knockdown ['l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "101, of ['l74', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "102, HOXB7 ['l75', 'l90', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "103, and ['l76', 'l91', 'l105', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "104, HOXA9 ['l77', 'l92', 'l106', 'l119', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "107, resistant ['l78', 'l93', 'l107', 'l120', 'l132', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "108, cells ['l13', 'l79', 'l94', 'l108', 'l121', 'l133', 'l144', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159']", + "121, loss ['l80', 'l95', 'l109', 'l122', 'l134', 'l145', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168']", + "122, of ['l81', 'l96', 'l110', 'l123', 'l135', 'l146', 'l154', 'l160', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176']", + "123, EZH2 ['l82', 'l97', 'l111', 'l124', 'l136', 'l147', 'l155', 'l161', 'l169', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183']", + "124, expression ['l83', 'l98', 'l112', 'l125', 'l137', 'l148', 'l156', 'l162', 'l170', 'l177', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189']", + "126, resistant ['l84', 'l99', 'l113', 'l126', 'l138', 'l149', 'l157', 'l163', 'l171', 'l178', 'l184', 'l190', 'l191', 'l192', 'l193', 'l194']", + "127, cells ['l85', 'l100', 'l114', 'l127', 'l139', 'l150', 'l158', 'l164', 'l172', 'l179', 'l185', 'l190', 'l195', 'l196', 'l197', 'l198']", + "129, primary ['l86', 'l101', 'l115', 'l128', 'l140', 'l151', 'l165', 'l173', 'l180', 'l186', 'l191', 'l195', 'l199', 'l200', 'l201']", + "130, blasts ['l87', 'l102', 'l116', 'l129', 'l141', 'l152', 'l159', 'l166', 'l174', 'l181', 'l187', 'l192', 'l196', 'l199', 'l202', 'l203']", + "165, drug-resistant ['l88', 'l103', 'l117', 'l130', 'l142', 'l167', 'l175', 'l182', 'l188', 'l193', 'l197', 'l200', 'l202', 'l204']", + "166, cells. ['l89', 'l104', 'l118', 'l131', 'l143', 'l153', 'l168', 'l176', 'l183', 'l189', 'l194', 'l198', 'l201', 'l203', 'l204']", + "168, inhibitors ['l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211']", + "169, of ['l205', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217']", + "170, HSP90, ['l206', 'l212', 'l218', 'l219', 'l220', 'l221', 'l222']", + "171, CDK1 ['l207', 'l213', 'l218', 'l223', 'l224', 'l225', 'l226']", + "172, and ['l208', 'l214', 'l219', 'l223', 'l227', 'l228', 'l229']", + "173, the ['l209', 'l215', 'l220', 'l224', 'l227', 'l230', 'l231']", + "174, proteasome ['l210', 'l216', 'l221', 'l225', 'l228', 'l230', 'l232']", + "187, patients ['l211', 'l217', 'l222', 'l226', 'l229', 'l231', 'l232']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Suppression", + "of", + "EZH2", + "protein", + "expression", + "knockdown", + "HOXB7", + "and", + "HOXA9" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "AML", + "cell", + "lines", + "primary", + "blasts" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Suppression", + "of", + "EZH2", + "protein", + "expression", + "knockdown", + "HOXB7", + "and", + "HOXA9" + ] + }, + "context": { + "val": "cells", + "words": [ + "primary", + "cells", + "resistant", + "drug-resistant", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Suppression", + "of", + "EZH2", + "protein", + "expression" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Suppression", + "of", + "EZH2", + "protein", + "expression" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "resistant", + "cells", + "drug-resistant", + "cells." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "EZH2", + "expression" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "EZH2", + "expression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "blasts" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "HSP90,", + "CDK1", + "and", + "the", + "proteasome" + ] + }, + "context": { + "val": "patient", + "words": [ + "patients" + ] + } + } + ] + }, + { + "PMID": "27923032", + "TEXT": "A recent study shows that spermidine has beneficial effects on health and lifespan in mice, and that these effects are the result of improved cardiovascular function. Similar effects of spermidine on humans are supported by epidemiological studies.", + "TAG_DATA": [ + "14, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27923030", + "TEXT": "Together with recent advances in the processing and culture of human tissue, bioengineering, xenotransplantation and genome editing, Induced pluripotent stem cells (iPSCs) present a range of new opportunities for the study of human cancer. Here we discuss the main advantages and limitations of iPSC modeling, and how the method intersects with other patient-derived models of cancer, such as organoids, organs-on-chips and patient-derived xenografts (PDXs). We highlight the opportunities that iPSC models can provide beyond those offered by existing systems and animal models and present current challenges and crucial areas for future improvements toward wider adoption of this technology.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27869805", + "TEXT": "The enteric nervous system (ENS) of the gastrointestinal tract controls many diverse functions, including motility and epithelial permeability. Perturbations in ENS development or function are common, yet there is no human model for studying ENS-intestinal biology and disease. We used a tissue-engineering approach with embryonic and induced pluripotent stem cells (PSCs) to generate human intestinal tissue containing a functional ENS. We recapitulated normal intestinal ENS development by combining human-PSC-derived neural crest cells (NCCs) and developing human intestinal organoids (HIOs). NCCs recombined with HIOs in vitro migrated into the mesenchyme, differentiated into neurons and glial cells and showed neuronal activity, as measured by rhythmic waves of calcium transients. ENS-containing HIOs grown in vivo formed neuroglial structures similar to a myenteric and submucosal plexus, had functional interstitial cells of Cajal and had an electromechanical coupling that regulated waves of propagating contraction. Finally, we used this system to investigate the cellular and molecular basis for Hirschsprung's disease caused by a mutation in the gene PHOX2B. This is, to the best of our knowledge, the first demonstration of human-PSC-derived intestinal tissue with a functional ENS and how this system can be used to study motility disorders of the human gastrointestinal tract.", + "TAG_DATA": [ + "75, human {'context': 'B-organoid'}", + "76, intestinal {'context': 'I-organoid'}", + "77, organoids {'context': 'I-organoid'}", + "78, (HIOs). {'context': 'I-organoid'}", + "79, NCCs {'context': 'B-cells'}", + "83, in {'context': 'B-in vitro'}", + "84, vitro {'context': 'I-in vitro'}", + "88, mesenchyme, {'context': 'B-tissue/organ'}", + "89, differentiated {'phenotype': 'B-differentiation'}", + "91, neurons {'context': 'B-cells', 'phenotype': 'B-differentiation'}", + "93, glial {'context': 'B-cells'}", + "94, cells {'context': 'I-cells'}", + "110, in {'context': 'B-in vivo'}", + "111, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "75, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "76, intestinal ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "77, organoids ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "78, (HIOs). ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "79, NCCs ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "83, in ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "84, vitro ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "88, mesenchyme, ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "89, differentiated ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "91, neurons ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "93, glial ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "94, cells ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "110, in ['l66']", + "111, vivo ['l66']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organoid", + "words": [ + "human", + "intestinal", + "organoids", + "(HIOs)." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiated", + "neurons" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neurons", + "NCCs", + "glial", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "neurons", + "differentiated" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiated", + "neurons" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mesenchyme," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiated", + "neurons" + ] + } + } + ] + }, + { + "PMID": "27869804", + "TEXT": "Cancer cells experience higher oxidative stress from reactive oxygen species (ROS) than do non-malignant cells because of genetic alterations and abnormal growth; as a result, maintenance of the antioxidant glutathione (GSH) is essential for their survival and proliferation. Under conditions of elevated ROS, endogenous L-cysteine (L-Cys) production is insufficient for GSH synthesis. This necessitates uptake of L-Cys that is predominantly in its disulfide form, L-cystine (CSSC), via the xCT(-) transporter. We show that administration of an engineered and pharmacologically optimized human cyst(e)inase enzyme mediates sustained depletion of the extracellular L-Cys and CSSC pool in mice and non-human primates. Treatment with this enzyme selectively causes cell cycle arrest and death in cancer cells due to depletion of intracellular GSH and ensuing elevated ROS; yet this treatment results in no apparent toxicities in mice even after months of continuous treatment. Cyst(e)inase suppressed the growth of prostate carcinoma allografts, reduced tumor growth in both prostate and breast cancer xenografts and doubled the median survival time of TCL1-Tg:p53-/- mice, which develop disease resembling human chronic lymphocytic leukemia. It was observed that enzyme-mediated depletion of the serum L-Cys and CSSC pool suppresses the growth of multiple tumors, yet is very well tolerated for prolonged periods, suggesting that cyst(e)inase represents a safe and effective therapeutic modality for inactivating antioxidant cellular responses in a wide range of malignancies.", + "TAG_DATA": [ + "94, mice {'context': 'B-organism'}", + "96, non-human {'context': 'B-organism'}", + "97, primates. {'context': 'I-organism'}", + "103, causes {'effect': 'B-positive'}", + "104, cell {'phenotype': 'B-cell cycle arrest'}", + "105, cycle {'phenotype': 'I-cell cycle arrest'}", + "106, arrest {'phenotype': 'I-cell cycle arrest'}", + "110, cancer {'context': 'B-transformed cells'}", + "111, cells {'context': 'I-transformed cells'}", + "131, mice {'context': 'B-organism'}", + "143, prostate {'context': 'B-xenograft'}", + "144, carcinoma {'context': 'I-xenograft'}", + "145, allografts, {'context': 'I-xenograft'}", + "146, reduced {'effect': 'B-negative'}", + "147, tumor {'phenotype': 'B-tumour growth'}", + "148, growth {'phenotype': 'I-tumour growth'}", + "151, prostate {'context': 'B-xenograft'}", + "152, and {'context': 'I-xenograft'}", + "153, breast {'context': 'I-xenograft'}", + "154, cancer {'context': 'I-xenograft'}", + "155, xenografts {'context': 'I-xenograft'}", + "163, TCL1-Tg:p53-/- {'perturbing_action': 'B-gene loss-of-function'}", + "164, mice, {'context': 'B-organism'}", + "186, suppresses {'effect': 'B-negative'}", + "191, tumors, {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "94, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "96, non-human ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "97, primates. ['l1', 'l6', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "103, causes ['l7', 'l14', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "104, cell ['l2', 'l8', 'l15', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "105, cycle ['l3', 'l9', 'l16', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "106, arrest ['l4', 'l10', 'l17', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "110, cancer ['l11', 'l18', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "111, cells ['l5', 'l12', 'l19', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58']", + "131, mice ['l13', 'l20', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l60', 'l61']", + "143, prostate ['l27', 'l35', 'l42', 'l48', 'l53', 'l59', 'l62', 'l63', 'l64', 'l65', 'l66']", + "144, carcinoma ['l28', 'l36', 'l43', 'l49', 'l54', 'l57', 'l60', 'l62', 'l67', 'l68', 'l69', 'l70']", + "145, allografts, ['l29', 'l37', 'l44', 'l50', 'l55', 'l58', 'l61', 'l63', 'l67', 'l71', 'l72']", + "146, reduced ['l64', 'l68', 'l71', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "147, tumor ['l65', 'l69', 'l73', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "148, growth ['l66', 'l70', 'l72', 'l74', 'l80', 'l86', 'l87', 'l88', 'l89', 'l90']", + "151, prostate ['l75', 'l81', 'l86', 'l91', 'l92', 'l93', 'l94']", + "152, and ['l76', 'l82', 'l87', 'l91', 'l95', 'l96', 'l97']", + "153, breast ['l77', 'l83', 'l88', 'l92', 'l95', 'l98', 'l99']", + "154, cancer ['l78', 'l84', 'l89', 'l93', 'l96', 'l98', 'l100']", + "155, xenografts ['l79', 'l85', 'l90', 'l94', 'l97', 'l99', 'l100']", + "163, TCL1-Tg:p53-/- ['l101']", + "164, mice, ['l101']", + "186, suppresses ['l102']", + "191, tumors, ['l102']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "non-human", + "primates." + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "non-human", + "primates.", + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "causes" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "prostate", + "carcinoma", + "allografts," + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "prostate", + "carcinoma", + "allografts," + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "prostate", + "carcinoma", + "allografts,", + "and", + "breast", + "cancer", + "xenografts" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "prostate", + "carcinoma", + "allografts,", + "and", + "breast", + "cancer", + "xenografts" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TCL1-Tg:p53-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors," + ] + } + } + ] + }, + { + "PMID": "27841872", + "TEXT": "The cellular inhibitors of apoptosis (cIAP) 1 and 2 are amplified in about 3% of cancers and have been identified in multiple malignancies as being potential therapeutic targets as a result of their role in the evasion of apoptosis. Consequently, small-molecule IAP antagonists, such as LCL161, have entered clinical trials for their ability to induce tumor necrosis factor (TNF)-mediated apoptosis of cancer cells. However, cIAP1 and cIAP2 are recurrently homozygously deleted in multiple myeloma (MM), resulting in constitutive activation of the noncanonical nuclear factor (NF)-κB pathway. To our surprise, we observed robust in vivo anti-myeloma activity of LCL161 in a transgenic myeloma mouse model and in patients with relapsed-refractory MM, where the addition of cyclophosphamide resulted in a median progression-free-survival of 10 months. This effect was not a result of direct induction of tumor cell death, but rather of upregulation of tumor-cell-autonomous type I interferon (IFN) signaling and a strong inflammatory response that resulted in the activation of macrophages and dendritic cells, leading to phagocytosis of tumor cells. Treatment of a MM mouse model with LCL161 established long-term anti-tumor protection and induced regression in a fraction of the mice. Notably, combination of LCL161 with the immune-checkpoint inhibitor anti-PD1 was curative in all of the treated mice.", + "TAG_DATA": [ + "100, transgenic {'context': 'B-organism'}", + "101, myeloma {'context': 'I-organism'}", + "102, mouse {'context': 'I-organism'}", + "103, model {'context': 'I-organism'}", + "106, patients {'context': 'B-patient'}", + "109, MM, {'context': 'B-neoplasm'}", + "131, induction {'effect': 'B-positive'}", + "133, tumor {'context': 'B-neoplasm'}", + "134, cell {'phenotype': 'B-cell death'}", + "135, death, {'phenotype': 'I-cell death'}", + "158, macrophages {'context': 'B-cells'}", + "160, dendritic {'context': 'B-cells'}", + "161, cells, {'context': 'I-cells'}", + "166, tumor {'context': 'B-transformed cells'}", + "167, cells. {'context': 'I-transformed cells'}", + "171, MM {'context': 'B-organism'}", + "172, mouse {'context': 'I-organism'}", + "173, model {'context': 'I-organism'}", + "181, induced {'effect': 'B-positive'}", + "182, regression {'phenotype': 'B-tumour regression'}", + "188, mice. {'context': 'B-organism'}", + "205, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "100, transgenic ['l0', 'l1', 'l2']", + "101, myeloma ['l0', 'l3', 'l4']", + "102, mouse ['l1', 'l3', 'l5']", + "103, model ['l2', 'l4', 'l5']", + "106, patients ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "109, MM, ['l6', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "131, induction ['l7', 'l16', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "133, tumor ['l8', 'l17', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "134, cell ['l9', 'l18', 'l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "135, death, ['l10', 'l19', 'l27', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "158, macrophages ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "160, dendritic ['l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57']", + "161, cells, ['l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l58', 'l59']", + "166, tumor ['l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58', 'l60']", + "167, cells. ['l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l59', 'l60']", + "171, MM ['l61', 'l62', 'l63', 'l64', 'l65']", + "172, mouse ['l61', 'l66', 'l67', 'l68', 'l69']", + "173, model ['l62', 'l66', 'l70', 'l71', 'l72']", + "181, induced ['l63', 'l67', 'l70', 'l73', 'l74']", + "182, regression ['l64', 'l68', 'l71', 'l73', 'l75']", + "188, mice. ['l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "MM,", + "tumor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "MM,", + "tumor" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages", + "dendritic", + "cells," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages", + "dendritic", + "cells," + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "MM", + "mouse", + "model", + "mice." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "MM", + "mouse", + "model", + "mice." + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + } + ] + }, + { + "PMID": "27820604", + "TEXT": "For broad protection against infection by viruses such as influenza or HIV, vaccines should elicit antibodies that bind conserved viral epitopes, such as the receptor-binding site (RBS). RBS-directed antibodies have been described for both HIV and influenza virus, and the design of immunogens to elicit them is a goal of vaccine research in both fields. Residues in the RBS of influenza virus hemagglutinin (HA) determine a preference for the avian or human receptor, α-2,3-linked sialic acid and α-2,6-linked sialic acid, respectively. Transmission of an avian-origin virus between humans generally requires one or more mutations in the sequences encoding the influenza virus RBS to change the preferred receptor from avian to human, but passage of a human-derived vaccine candidate in chicken eggs can select for reversion to avian receptor preference. For example, the X-181 strain of the 2009 new pandemic H1N1 influenza virus, derived from the A/California/07/2009 isolate and used in essentially all vaccines since 2009, has arginine at position 226, a residue known to confer preference for an α-2,3 linkage in H1 subtype viruses; the wild-type A/California/07/2009 isolate, like most circulating human H1N1 viruses, has glutamine at position 226. We describe, from three different individuals, RBS-directed antibodies that recognize the avian-adapted H1 strain in current influenza vaccines but not the circulating new pandemic 2009 virus; Arg226 in the vaccine-strain RBS accounts for the restriction. The polyclonal sera of the three donors also reflect this preference. Therefore, when vaccines produced from strains that are never passaged in avian cells become widely available, they may prove more capable of eliciting RBS-directed, broadly neutralizing antibodies than those produced from egg-adapted viruses, extending the established benefits of current seasonal influenza immunizations.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27820603", + "TEXT": "Pharmacological manipulation of specific neural circuits to optimize therapeutic index is an unrealized goal in neurology and psychiatry. AMPA receptors are important for excitatory synaptic transmission, and their antagonists are antiepileptic. Although efficacious, AMPA-receptor antagonists, including perampanel (Fycompa), the only approved antagonist for epilepsy, induce dizziness and motor impairment. We hypothesized that blockade of forebrain AMPA receptors without blocking cerebellar AMPA receptors would be antiepileptic and devoid of motor impairment. Taking advantage of an AMPA receptor auxiliary protein, TARP γ-8, which is selectively expressed in the forebrain and modulates the pharmacological properties of AMPA receptors, we discovered that LY3130481 selectively antagonized recombinant and native AMPA receptors containing γ-8, but not γ-2 (cerebellum) or other TARP members. Two amino acid residues unique to γ-8 determined this selectivity. We also observed antagonism of AMPA receptors expressed in hippocampal, but not cerebellar, tissue from an patient with epilepsy. Corresponding to this selective activity, LY3130481 prevented multiple seizure types in rats and mice and without motor side effects. These findings demonstrate the first rationally discovered molecule targeting specific neural circuitries for therapeutic advantage.", + "TAG_DATA": [ + "151, prevented {'effect': 'B-negative'}", + "156, rats {'context': 'B-organism'}", + "158, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "151, prevented ['l0', 'l1', 'l2']", + "154, types ['l0', 'l3', 'l4']", + "156, rats ['l1', 'l3', 'l5']", + "158, mice ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats", + "mice" + ] + } + } + ] + }, + { + "PMID": "27783066", + "TEXT": "The field of medicine is moving toward the use of biomarkers for the optimization of individualized care. This is a particular challenge for the field of psychiatry, in which diagnosis is based on a descriptive collection of behaviors without the availability of any objective test to stratify patients. Neuroimaging techniques such as molecular imaging with positron-emission tomography (PET) or structural and functional magnetic resonance imaging (MRI) provide an opportunity to bring psychiatry from an era of subjective descriptive classification into objective and tangible brain-based measures. Here we provide steps toward the development of robust, reliable and valid biomarkers. The success of such development is crucial because it will enable the field of psychiatry to move forward into the era of modern medicine.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27783065", + "TEXT": "Neuropsychiatric disorders such as autism spectrum disorder (ASD), schizophrenia (SCZ) and bipolar disorder (BPD) are of great societal and medical importance, but the complexity of these diseases and the challenges of modeling the development and function of the human brain have made these disorders difficult to study experimentally. The recent development of 3D brain organoids derived from human pluripotent stem cells offers a promising approach for investigating the phenotypic underpinnings of these highly polygenic disorders and for understanding the contribution of individual risk variants and complex genetic background to human pathology. Here we discuss the advantages, limitations and future applications of human brain organoids as in vitro models of neuropsychiatric disease.", + "TAG_DATA": [ + "53, brain {'context': 'I-organoid'}", + "57, human {'context': 'B-cells'}", + "58, pluripotent {'context': 'I-cells'}", + "59, stem {'context': 'I-cells'}", + "60, cells {'context': 'I-cells'}", + "102, brain {'context': 'I-organoid'}", + "103, organoids {'context': 'I-organoid'}" + ], + "LINK_DATA": [ + "53, brain ['l0', 'l1', 'l2', 'l3', 'l4']", + "54, organoids ['l0', 'l5', 'l6', 'l7', 'l8']", + "57, human ['l1', 'l5', 'l9', 'l10', 'l11', 'l12', 'l13']", + "58, pluripotent ['l2', 'l6', 'l9', 'l14', 'l15', 'l16', 'l17']", + "59, stem ['l3', 'l7', 'l10', 'l14', 'l18', 'l19', 'l20']", + "60, cells ['l4', 'l8', 'l11', 'l15', 'l18', 'l21', 'l22']", + "102, brain ['l12', 'l16', 'l19', 'l21', 'l23']", + "103, organoids ['l13', 'l17', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27775704", + "TEXT": "Triple-negative breast cancers (TNBCs) have poor prognosis and lack targeted therapies. Here we identified increased copy number and expression of the PIM1 proto-oncogene in genomic data sets of patients with TNBC. TNBC cells, but not nonmalignant mammary epithelial cells, were dependent on PIM1 for proliferation and protection from apoptosis. PIM1 knockdown reduced expression of the anti-apoptotic factor BCL2, and dynamic BH3 profiling of apoptotic priming revealed that PIM1 prevents mitochondrial-mediated apoptosis in TNBC cell lines. In TNBC tumors and their cellular models, PIM1 expression was associated with several transcriptional signatures involving the transcription factor MYC, and PIM1 depletion in TNBC cell lines decreased, in a MYC-dependent manner, cell population growth and expression of the MYC target gene MCL1. Treatment with the pan-PIM kinase inhibitor AZD1208 impaired the growth of both cell line and patient-derived xenografts and sensitized them to standard-of-care chemotherapy. This work identifies PIM1 as a malignant-cell-selective target in TNBC and the potential use of PIM1 inhibitors for sensitizing TNBC to chemotherapy-induced apoptotic cell death.", + "TAG_DATA": [ + "49, PIM1 {'perturbing_action': 'B-rnai/knockdown'}", + "50, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "68, prevents {'effect': 'B-negative'}", + "70, apoptosis {'phenotype': 'B-apoptosis'}", + "72, TNBC {'context': 'B-transformed cells'}", + "73, cell {'context': 'I-transformed cells'}", + "74, lines. {'context': 'I-transformed cells'}", + "96, PIM1 {'perturbing_action': 'B-gene loss-of-function'}", + "97, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "99, TNBC {'context': 'B-transformed cells'}", + "100, cell {'context': 'I-transformed cells'}", + "101, lines {'context': 'I-transformed cells'}", + "102, decreased, {'effect': 'B-negative'}", + "107, cell {'context': 'B-cells'}", + "108, population {'phenotype': 'I-cell growth'}", + "109, growth {'phenotype': 'I-cell growth'}", + "130, cell {'context': 'B-cells'}", + "131, line {'context': 'I-cells'}", + "133, patient-derived {'context': 'B-xenograft'}", + "134, xenografts {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "49, PIM1 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "50, knockdown ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "68, prevents ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "70, apoptosis ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "72, TNBC ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "73, cell ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "74, lines. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "96, PIM1 ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "97, depletion ['l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "99, TNBC ['l22', 'l31', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "100, cell ['l23', 'l32', 'l38', 'l44', 'l45', 'l46', 'l47', 'l48']", + "101, lines ['l24', 'l33', 'l39', 'l44', 'l49', 'l50', 'l51', 'l52']", + "102, decreased, ['l25', 'l34', 'l40', 'l45', 'l49', 'l53', 'l54', 'l55']", + "107, cell ['l26', 'l35', 'l41', 'l46', 'l50', 'l53', 'l56', 'l57']", + "108, population ['l27', 'l36', 'l42', 'l47', 'l51', 'l54', 'l56', 'l58']", + "109, growth ['l28', 'l37', 'l43', 'l48', 'l52', 'l55', 'l57', 'l58']", + "130, cell ['l29', 'l59', 'l60', 'l61']", + "131, line ['l30', 'l59', 'l62', 'l63']", + "133, patient-derived ['l60', 'l62', 'l64']", + "134, xenografts ['l61', 'l63', 'l64']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PIM1", + "knockdown" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PIM1", + "knockdown" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PIM1", + "knockdown" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cell", + "lines." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents", + "decreased," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cell", + "lines.", + "lines" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cell", + "lines." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PIM1", + "depletion" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cell", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PIM1", + "depletion" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PIM1", + "depletion" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "line" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PIM1", + "depletion" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "population", + "growth" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cell", + "lines" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "population", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased," + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased," + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "population", + "growth" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "population", + "growth" + ] + } + } + ] + }, + { + "PMID": "27748748", + "TEXT": "Pediatric glioblastoma is one of the most common and most deadly brain tumors in childhood. Using an integrative genetic analysis of 53 pediatric glioblastomas and five in vitro model systems, we identified previously unidentified gene fusions involving the MET oncogene in ∼10% of cases. These MET fusions activated mitogen-activated protein kinase (MAPK) signaling and, in cooperation with lesions compromising cell cycle regulation, induced aggressive glial tumors in vivo. MET inhibitors suppressed MET tumor growth in xenograft models. Finally, we treated a pediatric patient bearing a MET-fusion-expressing glioblastoma with the targeted inhibitor crizotinib. This therapy led to substantial tumor shrinkage and associated relief of symptoms, but new treatment-resistant lesions appeared, indicating that combination therapies are likely necessary to achieve a durable clinical response.", + "TAG_DATA": [ + "64, glial {'context': 'B-neoplasm'}", + "65, tumors {'context': 'I-neoplasm'}", + "66, in {'context': 'B-in vivo'}", + "67, vivo. {'context': 'I-in vivo'}", + "70, suppressed {'effect': 'B-negative'}", + "72, tumor {'phenotype': 'B-tumour growth'}", + "73, growth {'phenotype': 'I-tumour growth'}", + "75, xenograft {'context': 'B-xenograft'}", + "76, models. {'context': 'I-xenograft'}", + "81, pediatric {'context': 'B-patient'}", + "82, patient {'context': 'I-patient'}", + "86, glioblastoma {'context': 'I-neoplasm'}", + "94, led {'effect': 'B-positive'}", + "95, to {'effect': 'I-positive'}", + "97, tumor {'phenotype': 'B-tumour regression'}", + "98, shrinkage {'phenotype': 'I-tumour regression'}" + ], + "LINK_DATA": [ + "64, glial ['l0', 'l1', 'l2']", + "65, tumors ['l0', 'l3', 'l4']", + "66, in ['l1', 'l3', 'l5']", + "67, vivo. ['l2', 'l4', 'l5']", + "70, suppressed ['l6', 'l7', 'l8', 'l9']", + "72, tumor ['l6', 'l10', 'l11', 'l12']", + "73, growth ['l7', 'l10', 'l13', 'l14']", + "75, xenograft ['l8', 'l11', 'l13', 'l15']", + "76, models. ['l9', 'l12', 'l14', 'l15']", + "81, pediatric ['l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "82, patient ['l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "86, glioblastoma ['l17', 'l22', 'l27', 'l28', 'l29', 'l30']", + "94, led ['l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "95, to ['l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "97, tumor ['l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "98, shrinkage ['l21', 'l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "models." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "models." + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "pediatric", + "patient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "pediatric", + "patient" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "shrinkage" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "glioblastoma" + ] + }, + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "glioblastoma" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "shrinkage" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "shrinkage" + ] + } + } + ] + }, + { + "PMID": "27723723", + "TEXT": "Most human cancers, including myeloma, are preceded by a precursor state. There is an unmet need for in vivo models to study the interaction of human preneoplastic cells in the bone marrow microenvironment with non-malignant cells. Here, we genetically humanized mice to permit the growth of primary human preneoplastic and malignant plasma cells together with non-malignant cells in vivo. Growth was largely restricted to the bone marrow, mirroring the pattern in patients with myeloma. Xenografts captured the genomic complexity of parental tumors and revealed additional somatic changes. Moreover, xenografts from patients with preneoplastic gammopathy showed progressive growth, suggesting that the clinical stability of these lesions may in part be due to growth controls extrinsic to tumor cells. These data demonstrate a new approach to investigate the entire spectrum of human plasma cell neoplasia and illustrate the utility of humanized models for understanding the functional diversity of human tumors.", + "TAG_DATA": [ + "46, primary {'context': 'B-transformed cells'}", + "47, human {'context': 'I-transformed cells'}", + "48, preneoplastic {'context': 'I-transformed cells'}", + "49, and {'context': 'I-transformed cells'}", + "50, malignant {'context': 'I-transformed cells'}", + "51, plasma {'context': 'I-transformed cells'}", + "52, cells {'context': 'I-transformed cells'}", + "55, non-malignant {'context': 'B-cells'}", + "56, cells {'context': 'I-cells'}", + "57, in {'context': 'B-in vivo'}", + "58, vivo. {'context': 'I-in vivo'}", + "74, Xenografts {'context': 'B-xenograft'}", + "88, xenografts {'context': 'B-xenograft'}" + ], + "LINK_DATA": [ + "46, primary ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "47, human ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "48, preneoplastic ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "49, and ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "50, malignant ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "51, plasma ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "52, cells ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "55, non-malignant ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "56, cells ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "57, in ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "58, vivo. ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27694934", + "TEXT": "Bacterial infection is highly prevalent in patients who have had a stroke. Despite the potential contribution of micro-aspiration in post-stroke pneumonia, we found that the majority of the microorganisms detected in the patients who developed infections after having a stroke were common commensal bacteria that normally reside in the intestinal tracts. In a mouse model of ischemic stroke, post-stroke infection was only observed in mice that were born and raised in specific-pathogen-free facilities; this was not seen in mice that were born and raised in germ-free facilities. Using high-throughput 16S rRNA gene amplicon sequencing and bioinformatics analyses, we provide evidence demonstrating that the source of the bacteria forming the microbial community in the lungs of post-stroke mice was indeed the host small intestine. Additionally, stroke-induced gut barrier permeability and dysfunction preceded the dissemination of orally inoculated bacteria to peripheral tissues. This study identifies a novel pathway in which stroke promotes the translocation and dissemination of selective strains of bacteria that originated from the host gut microbiota.", + "TAG_DATA": [ + "53, mouse {'context': 'B-organism'}", + "54, model {'context': 'I-organism'}", + "64, mice {'context': 'B-organism'}", + "78, mice {'context': 'B-organism'}", + "113, lungs {'context': 'B-tissue/organ'}", + "116, mice {'context': 'B-organism'}", + "139, tissues. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "53, mouse ['l0', 'l1']", + "54, model ['l0', 'l2']", + "64, mice ['l1', 'l2']", + "78, mice ['l3', 'l4']", + "113, lungs ['l3', 'l5']", + "116, mice ['l4', 'l5']", + "138, peripheral ['l6']", + "139, tissues. ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27618652", + "TEXT": "Gut microbiota bacterial depletions and altered metabolic activity at 3 months are implicated in childhood atopy and asthma. We hypothesized that compositionally distinct human neonatal gut microbiota (NGM) exist, and are differentially related to relative risk (RR) of childhood atopy and asthma. Using stool samples (n = 298; aged 1-11 months) from a US birth cohort and 16S rRNA sequencing, neonates (median age, 35 d) were divisible into three microbiota composition states (NGM1-3). Each incurred a substantially different RR for multisensitized atopy at age 2 years and doctor-diagnosed asthma at age 4 years. The highest risk group, labeled NGM3, showed lower relative abundance of certain bacteria (for example, Bifidobacterium, Akkermansia and Faecalibacterium), higher relative abundance of particular fungi (Candida and Rhodotorula) and a distinct fecal metabolome enriched for pro-inflammatory metabolites. Ex vivo culture of human adult peripheral T cells with sterile fecal water from NGM3 subjects increased the proportion of CD4+ cells producing interleukin (IL)-4 and reduced the relative abundance of CD4+CD25+FOXP3+ cells. 12,13-DiHOME, enriched in NGM3 versus lower-risk NGM states, recapitulated the effect of NGM3 fecal water on relative CD4+CD25+FOXP3+ cell abundance. These findings suggest that neonatal gut microbiome dysbiosis might promote CD4+ T cell dysfunction associated with childhood atopy.", + "TAG_DATA": [ + "134, human {'context': 'B-cells'}", + "135, adult {'context': 'I-cells'}", + "136, peripheral {'context': 'I-cells'}", + "137, T {'context': 'I-cells'}", + "138, cells {'context': 'I-cells'}", + "150, CD4+ {'context': 'B-cells'}", + "151, cells {'context': 'I-cells'}", + "161, CD4+CD25+FOXP3+ {'context': 'B-cells'}", + "162, cells. {'context': 'I-cells'}", + "180, CD4+CD25+FOXP3+ {'context': 'B-cells'}", + "181, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "134, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "135, adult ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "136, peripheral ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "137, T ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "138, cells ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "150, CD4+ ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "151, cells ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "161, CD4+CD25+FOXP3+ ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "162, cells. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "180, CD4+CD25+FOXP3+ ['l36']", + "181, cell ['l36']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27618650", + "TEXT": "Epigenetic reprogramming is a critical process of pathological gene induction during cardiac hypertrophy and remodeling, but the underlying regulatory mechanisms remain to be elucidated. Here we identified a heart-enriched long noncoding (lnc)RNA, named cardiac-hypertrophy-associated epigenetic regulator (Chaer), which is necessary for the development of cardiac hypertrophy. Mechanistically, Chaer directly interacts with the catalytic subunit of polycomb repressor complex 2 (PRC2). This interaction, which is mediated by a 66-mer motif in Chaer, interferes with PRC2 targeting to genomic loci, thereby inhibiting histone H3 lysine 27 methylation at the promoter regions of genes involved in cardiac hypertrophy. The interaction between Chaer and PRC2 is transiently induced after hormone or stress stimulation in a process involving mammalian target of rapamycin complex 1, and this interaction is a prerequisite for epigenetic reprogramming and induction of genes involved in hypertrophy. Inhibition of Chaer expression in the heart before, but not after, the onset of pressure overload substantially attenuates cardiac hypertrophy and dysfunction. Our study reveals that stress-induced pathological gene activation in the heart requires a previously uncharacterized lncRNA-dependent epigenetic checkpoint.", + "TAG_DATA": [ + "135, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "136, of {'perturbing_action': 'I-pharmacological inhibition'}", + "137, Chaer {'perturbing_action': 'I-pharmacological inhibition'}", + "138, expression {'perturbing_action': 'I-pharmacological inhibition'}", + "141, heart {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "135, Inhibition ['l0', 'l1', 'l2', 'l3']", + "136, of ['l0', 'l4', 'l5', 'l6']", + "137, Chaer ['l1', 'l4', 'l7', 'l8']", + "138, expression ['l2', 'l5', 'l7', 'l9']", + "141, heart ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "Chaer", + "expression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "heart" + ] + } + } + ] + }, + { + "PMID": "27595325", + "TEXT": "Adenosine-to-inosine (A-to-I) RNA editing, which is catalyzed by a family of adenosine deaminase acting on RNA (ADAR) enzymes, is important in the epitranscriptomic regulation of RNA metabolism. However, the role of A-to-I RNA editing in vascular disease is unknown. Here we show that cathepsin S mRNA (CTSS), which encodes a cysteine protease associated with angiogenesis and atherosclerosis, is highly edited in human endothelial cells. The 3' untranslated region (3' UTR) of the CTSS transcript contains two inverted repeats, the AluJo and AluSx+ regions, which form a long stem-loop structure that is recognized by ADAR1 as a substrate for editing. RNA editing enables the recruitment of the stabilizing RNA-binding protein human antigen R (HuR; encoded by ELAVL1) to the 3' UTR of the CTSS transcript, thereby controlling CTSS mRNA stability and expression. In endothelial cells, ADAR1 overexpression or treatment of cells with hypoxia or with the inflammatory cytokines interferon-γ and tumor-necrosis-factor-α induces CTSS RNA editing and consequently increases cathepsin S expression. ADAR1 levels and the extent of CTSS RNA editing are associated with changes in cathepsin S levels in patients with atherosclerotic vascular diseases, including subclinical atherosclerosis, coronary artery disease, aortic aneurysms and advanced carotid atherosclerotic disease. These results reveal a previously unrecognized role of RNA editing in gene expression in human atherosclerotic vascular diseases.", + "TAG_DATA": [ + "132, endothelial {'context': 'B-cells'}", + "133, cells, {'context': 'I-cells'}", + "134, ADAR1 {'perturbing_action': 'B-gene gain-of-function'}", + "135, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "139, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "132, endothelial ['l0', 'l1', 'l2']", + "133, cells, ['l0', 'l3', 'l4']", + "134, ADAR1 ['l1', 'l3', 'l5', 'l6']", + "135, overexpression ['l2', 'l4', 'l5', 'l7']", + "139, cells ['l6', 'l7']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells,", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ADAR1", + "overexpression" + ] + } + } + ] + }, + { + "PMID": "27571348", + "TEXT": "Cachexia represents a fatal energy-wasting syndrome in a large number of patients with cancer that mostly results in a pathological loss of skeletal muscle and adipose tissue. Here we show that tumor cell exposure and tumor growth in mice triggered a futile energy-wasting cycle in cultured white adipocytes and white adipose tissue (WAT), respectively. Although uncoupling protein 1 (Ucp1)-dependent thermogenesis was dispensable for tumor-induced body wasting, WAT from cachectic mice and tumor-cell-supernatant-treated adipocytes were consistently characterized by the simultaneous induction of both lipolytic and lipogenic pathways. Paradoxically, this was accompanied by an inactivated AMP-activated protein kinase (Ampk), which is normally activated in peripheral tissues during states of low cellular energy. Ampk inactivation correlated with its degradation and with upregulation of the Ampk-interacting protein Cidea. Therefore, we developed an Ampk-stabilizing peptide, ACIP, which was able to ameliorate WAT wasting in vitro and in vivo by shielding the Cidea-targeted interaction surface on Ampk. Thus, our data establish the Ucp1-independent remodeling of adipocyte lipid homeostasis as a key event in tumor-induced WAT wasting, and we propose the ACIP-dependent preservation of Ampk integrity in the WAT as a concept in future therapies for cachexia.", + "TAG_DATA": [ + "35, tumor {'phenotype': 'B-tumour growth'}", + "36, growth {'phenotype': 'I-tumour growth'}", + "38, mice {'context': 'B-organism'}", + "45, cultured {'context': 'B-cells'}", + "46, white {'context': 'I-cells'}", + "47, adipocytes {'context': 'I-cells'}", + "49, white {'context': 'B-tissue/organ'}", + "50, adipose {'context': 'I-tissue/organ'}", + "51, tissue {'context': 'I-tissue/organ'}", + "52, (WAT), {'context': 'I-cells'}", + "72, adipocytes {'context': 'B-cells'}", + "138, in {'context': 'B-in vitro'}", + "139, vitro {'context': 'I-in vitro'}", + "141, in {'context': 'B-in vivo'}", + "142, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "35, tumor ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "36, growth ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "38, mice ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21']", + "45, cultured ['l2', 'l10', 'l17', 'l22', 'l23', 'l24', 'l25']", + "46, white ['l3', 'l11', 'l18', 'l22', 'l26', 'l27', 'l28']", + "47, adipocytes ['l4', 'l12', 'l19', 'l23', 'l26', 'l29', 'l30']", + "49, white ['l5', 'l13', 'l31', 'l32', 'l33', 'l34']", + "50, adipose ['l6', 'l14', 'l31', 'l35', 'l36', 'l37']", + "51, tissue ['l7', 'l15', 'l20', 'l24', 'l27', 'l29', 'l32', 'l35', 'l38', 'l39']", + "52, (WAT), ['l8', 'l16', 'l21', 'l25', 'l28', 'l30', 'l33', 'l36', 'l38']", + "72, adipocytes ['l34', 'l37', 'l39']", + "138, in ['l40']", + "139, vitro ['l40']", + "141, in ['l41']", + "142, vivo ['l41']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "white", + "adipocytes", + "(WAT)," + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "white", + "adipose", + "tissue" + ] + } + } + ] + }, + { + "PMID": "27500726", + "TEXT": "The protein kinase B-Raf proto-oncogene, serine/threonine kinase (BRAF) is an oncogenic driver and therapeutic target in melanoma. Inhibitors of BRAF (BRAFi) have shown high response rates and extended survival in patients with melanoma who bear tumors that express mutations encoding BRAF proteins mutant at Val600, but a vast majority of these patients develop drug resistance. Here we show that loss of stromal antigen 2 (STAG2) or STAG3, which encode subunits of the cohesin complex, in melanoma cells results in resistance to BRAFi. We identified loss-of-function mutations in STAG2, as well as decreased expression of STAG2 or STAG3 proteins in several tumor samples from patients with acquired resistance to BRAFi and in BRAFi-resistant melanoma cell lines. Knockdown of STAG2 or STAG3 expression decreased sensitivity of BRAF(Val600Glu)-mutant melanoma cells and xenograft tumors to BRAFi. Loss of STAG2 inhibited CCCTC-binding-factor-mediated expression of dual specificity phosphatase 6 (DUSP6), leading to reactivation of mitogen-activated protein kinase (MAPK) signaling (via the MAPKs ERK1 and ERK2; hereafter referred to as ERK). Our studies unveil a previously unknown genetic mechanism of BRAFi resistance and provide new insights into the tumor suppressor function of STAG2 and STAG3.", + "TAG_DATA": [ + "75, melanoma {'context': 'B-transformed cells'}", + "76, cells {'context': 'I-transformed cells'}", + "112, melanoma {'context': 'B-transformed cells'}", + "113, cell {'context': 'I-transformed cells'}", + "114, lines. {'context': 'I-transformed cells'}", + "115, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "116, of {'perturbing_action': 'I-rnai/knockdown'}", + "117, STAG2 {'perturbing_action': 'I-rnai/knockdown'}", + "118, or {'perturbing_action': 'I-rnai/knockdown'}", + "119, STAG3 {'perturbing_action': 'I-rnai/knockdown'}", + "120, expression {'perturbing_action': 'I-rnai/knockdown'}", + "124, BRAF(Val600Glu)-mutant {'perturbing_action': 'B-other'}", + "125, melanoma {'context': 'B-transformed cells'}", + "126, cells {'context': 'I-transformed cells'}", + "128, xenograft {'context': 'B-xenograft'}", + "129, tumors {'context': 'I-xenograft'}", + "132, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "133, of {'perturbing_action': 'I-gene loss-of-function'}", + "134, STAG2 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "75, melanoma ['l0']", + "76, cells ['l0']", + "112, melanoma ['l1', 'l2']", + "113, cell ['l1', 'l3']", + "114, lines. ['l2', 'l3']", + "115, Knockdown ['l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "116, of ['l4', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "117, STAG2 ['l5', 'l14', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "118, or ['l6', 'l15', 'l23', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "119, STAG3 ['l7', 'l16', 'l24', 'l31', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "120, expression ['l8', 'l17', 'l25', 'l32', 'l38', 'l44', 'l45', 'l46', 'l47', 'l48']", + "124, BRAF(Val600Glu)-mutant ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l49', 'l50', 'l51', 'l52']", + "125, melanoma ['l10', 'l19', 'l27', 'l34', 'l40', 'l45', 'l49', 'l53', 'l54', 'l55']", + "126, cells ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l50', 'l53', 'l56']", + "128, xenograft ['l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l54', 'l57']", + "129, tumors ['l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l56', 'l57']", + "132, Loss ['l58', 'l59']", + "133, of ['l58', 'l60']", + "134, STAG2 ['l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "STAG2", + "or", + "STAG3", + "expression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "STAG2", + "or", + "STAG3", + "expression" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BRAF(Val600Glu)-mutant" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BRAF(Val600Glu)-mutant" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "tumors" + ] + } + } + ] + }, + { + "PMID": "27500724", + "TEXT": "Although antiretroviral therapy (ART) suppresses viral replication to clinically undetectable levels, human immunodeficiency virus type 1 (HIV-1) persists in CD4(+) T cells in a latent form that is not targeted by the immune system or by ART. This latent reservoir is a major barrier to curing individuals of HIV-1 infection. Many individuals initiate ART during chronic infection, and in this setting, most proviruses are defective. However, the dynamics of the accumulation and the persistence of defective proviruses during acute HIV-1 infection are largely unknown. Here we show that defective proviruses accumulate rapidly within the first few weeks of infection to make up over 93% of all proviruses, regardless of how early ART is initiated. By using an unbiased method to amplify near-full-length proviral genomes from HIV-1-infected adults treated at different stages of infection, we demonstrate that early initiation of ART limits the size of the reservoir but does not profoundly affect the proviral landscape. This analysis allows us to revise our understanding of the composition of proviral populations and estimate the true reservoir size in individuals who were treated early versus late in infection. Additionally, we demonstrate that common assays for measuring the reservoir do not correlate with reservoir size, as determined by the number of genetically intact proviruses. These findings reveal hurdles that must be overcome to successfully analyze future HIV-1 cure strategies.", + "TAG_DATA": [ + "125, HIV-1-infected {'context': 'B-patient'}", + "126, adults {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "125, HIV-1-infected ['l0']", + "126, adults ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27428899", + "TEXT": "Disseminated candidiasis has become one of the leading causes of hospital-acquired blood stream infections with high mobility and mortality. However, the molecular basis of host defense against disseminated candidiasis remains elusive, and treatment options are limited. Here we report that the E3 ubiquitin ligase CBLB directs polyubiquitination of dectin-1 and dectin-2, two key pattern-recognition receptors for sensing Candida albicans, and their downstream kinase SYK, thus inhibiting dectin-1- and dectin-2-mediated innate immune responses. CBLB deficiency or inactivation protects mice from systemic infection with a lethal dose of C. albicans, and deficiency of dectin-1, dectin-2, or both in Cblb(-/-) mice abrogates this protection. Notably, silencing the Cblb gene in vivo protects mice from lethal systemic C. albicans infection. Our data reveal that CBLB is crucial for homeostatic control of innate immune responses mediated by dectin-1 and dectin-2. Our data also indicate that CBLB represents a potential therapeutic target for protection from disseminated candidiasis.", + "TAG_DATA": [ + "72, CBLB {'perturbing_action': 'B-gene loss-of-function'}", + "73, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "77, mice {'context': 'B-organism'}", + "89, deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "90, of {'perturbing_action': 'I-gene loss-of-function'}", + "91, dectin-1, {'perturbing_action': 'I-gene loss-of-function'}", + "92, dectin-2, {'perturbing_action': 'I-gene loss-of-function'}", + "96, Cblb(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "97, mice {'context': 'B-organism'}", + "102, silencing {'perturbing_action': 'B-rnai/knockdown'}", + "103, the {'perturbing_action': 'I-rnai/knockdown'}", + "104, Cblb {'perturbing_action': 'I-rnai/knockdown'}", + "105, gene {'perturbing_action': 'I-rnai/knockdown'}", + "106, in {'context': 'B-in vivo'}", + "107, vivo {'context': 'I-in vivo'}", + "109, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "72, CBLB ['l0', 'l1']", + "73, deficiency ['l0', 'l2']", + "77, mice ['l1', 'l2']", + "89, deficiency ['l3', 'l4', 'l5', 'l6', 'l7']", + "90, of ['l3', 'l8', 'l9', 'l10', 'l11']", + "91, dectin-1, ['l4', 'l8', 'l12', 'l13', 'l14']", + "92, dectin-2, ['l5', 'l9', 'l12', 'l15', 'l16']", + "96, Cblb(-/-) ['l6', 'l10', 'l13', 'l15', 'l17']", + "97, mice ['l7', 'l11', 'l14', 'l16', 'l17']", + "102, silencing ['l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "103, the ['l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "104, Cblb ['l19', 'l24', 'l29', 'l30', 'l31', 'l32']", + "105, gene ['l20', 'l25', 'l29', 'l33', 'l34', 'l35']", + "106, in ['l21', 'l26', 'l30', 'l33', 'l36', 'l37']", + "107, vivo ['l22', 'l27', 'l31', 'l34', 'l36', 'l38']", + "109, mice ['l23', 'l28', 'l32', 'l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CBLB", + "deficiency", + "of", + "dectin-1,", + "dectin-2,", + "Cblb(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "the", + "Cblb", + "gene" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "the", + "Cblb", + "gene" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "27213816", + "TEXT": "Type 2 diabetes (T2D) is among the most common and costly disorders worldwide. The goal of current medical management for T2D is to transiently ameliorate hyperglycemia through daily dosing of one or more antidiabetic drugs. Hypoglycemia and weight gain are common side effects of therapy, and sustained disease remission is not obtainable with nonsurgical approaches. On the basis of the potent glucose-lowering response elicited by activation of brain fibroblast growth factor (FGF) receptors, we explored the antidiabetic efficacy of centrally administered FGF1, which, unlike other FGF peptides, activates all FGF receptor subtypes. We report that a single intracerebroventricular injection of FGF1 at a dose one-tenth of that needed for antidiabetic efficacy following peripheral injection induces sustained diabetes remission in both mouse and rat models of T2D. This antidiabetic effect is not secondary to weight loss, does not increase the risk of hypoglycemia, and involves a novel and incompletely understood mechanism for increasing glucose clearance from the bloodstream. We conclude that the brain has an inherent potential to induce diabetes remission and that brain FGF receptors are potential pharmacological targets for achieving this goal.", + "TAG_DATA": [ + "120, mouse {'context': 'B-organism'}", + "121, and {'context': 'I-organism'}", + "122, rat {'context': 'I-organism'}", + "123, models {'context': 'I-organism'}", + "124, of {'context': 'I-organism'}", + "125, T2D. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "120, mouse ['l0', 'l1', 'l2', 'l3', 'l4']", + "121, and ['l0', 'l5', 'l6', 'l7', 'l8']", + "122, rat ['l1', 'l5', 'l9', 'l10', 'l11']", + "123, models ['l2', 'l6', 'l9', 'l12', 'l13']", + "124, of ['l3', 'l7', 'l10', 'l12', 'l14']", + "125, T2D. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27158907", + "TEXT": "An attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) vaccine, PfSPZ Vaccine, is highly protective against controlled human malaria infection (CHMI) 3 weeks after immunization, but the durability of protection is unknown. We assessed how vaccine dosage, regimen, and route of administration affected durable protection in malaria-naive adults. After four intravenous immunizations with 2.7 × 10(5) PfSPZ, 6/11 (55%) vaccinated subjects remained without parasitemia following CHMI 21 weeks after immunization. Five non-parasitemic subjects from this dosage group underwent repeat CHMI at 59 weeks, and none developed parasitemia. Although Pf-specific serum antibody levels correlated with protection up to 21-25 weeks after immunization, antibody levels waned substantially by 59 weeks. Pf-specific T cell responses also declined in blood by 59 weeks. To determine whether T cell responses in blood reflected responses in liver, we vaccinated nonhuman primates with PfSPZ Vaccine. Pf-specific interferon-γ-producing CD8 T cells were present at ∼100-fold higher frequencies in liver than in blood. Our findings suggest that PfSPZ Vaccine conferred durable protection to malaria through long-lived tissue-resident T cells and that administration of higher doses may further enhance protection.", + "TAG_DATA": [ + "107, T {'context': 'I-cells'}", + "108, cell {'context': 'I-cells'}", + "131, nonhuman {'context': 'B-organism'}", + "132, primates {'context': 'I-organism'}", + "138, CD8 {'context': 'B-cells'}", + "139, T {'context': 'I-cells'}", + "140, cells {'context': 'I-cells'}", + "148, liver {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "107, T ['l0']", + "108, cell ['l0']", + "131, nonhuman ['l1', 'l2', 'l3', 'l4', 'l5']", + "132, primates ['l1', 'l6', 'l7', 'l8', 'l9']", + "138, CD8 ['l2', 'l6', 'l10', 'l11', 'l12']", + "139, T ['l3', 'l7', 'l10', 'l13', 'l14']", + "140, cells ['l4', 'l8', 'l11', 'l13', 'l15']", + "148, liver ['l5', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "27149220", + "TEXT": "Molecular targeted therapy has the potential to dramatically improve survival in patients with cancer. However, complete and durable responses to targeted therapy are rare in individuals with advanced-stage solid cancers. Even the most effective targeted therapies generally do not induce a complete tumor response, resulting in residual disease and tumor progression that limits patient survival. We discuss the emerging need to more fully understand the molecular basis of residual disease as a prelude to designing therapeutic strategies to minimize or eliminate residual disease so that we can move from temporary to chronic control of disease, or a cure, for patients with advanced-stage solid cancers. Ultimately, we propose a shift from the current reactive paradigm of analyzing and treating acquired drug resistance to a pre-emptive paradigm of defining the mechanisms that result in residual disease, to target and limit this disease reservoir.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27149219", + "TEXT": "Rapid and affordable tumor molecular profiling has led to an explosion of clinical and genomic data poised to enhance the diagnosis, prognostication and treatment of cancer. A critical point has now been reached at which the analysis and storage of annotated clinical and genomic information in unconnected silos will stall the advancement of precision cancer care. Information systems must be harmonized to overcome the multiple technical and logistical barriers to data sharing. Against this backdrop, the Global Alliance for Genomic Health (GA4GH) was established in 2013 to create a common framework that enables responsible, voluntary and secure sharing of clinical and genomic data. This Perspective from the GA4GH Clinical Working Group Cancer Task Team highlights the data-aggregation challenges faced by the field, suggests potential collaborative solutions and describes how GA4GH can catalyze a harmonized data-sharing culture.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "27135740", + "TEXT": "Mutations in genes encoding splicing factors (which we refer to as spliceosomal genes) are commonly found in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). These mutations recurrently affect specific amino acid residues, leading to perturbed normal splice site and exon recognition. Spliceosomal gene mutations are always heterozygous and rarely occur together with one another, suggesting that cells may tolerate only a partial deviation from normal splicing activity. To test this hypothesis, we engineered mice to express a mutated allele of serine/arginine-rich splicing factor 2 (Srsf2(P95H))-which commonly occurs in individuals with MDS and AML-in an inducible, hemizygous manner in hematopoietic cells. These mice rapidly succumbed to fatal bone marrow failure, demonstrating that Srsf2-mutated cells depend on the wild-type Srsf2 allele for survival. In the context of leukemia, treatment with the spliceosome inhibitor E7107 (refs. 7,8) resulted in substantial reductions in leukemic burden, specifically in isogenic mouse leukemias and patient-derived xenograft AMLs carrying spliceosomal mutations. Whereas E7107 treatment of mice resulted in widespread intron retention and cassette exon skipping in leukemic cells regardless of Srsf2 genotype, the magnitude of splicing inhibition following E7107 treatment was greater in Srsf2-mutated than in Srsf2-wild-type leukemia, consistent with the differential effect of E7107 on survival. Collectively, these data provide genetic and pharmacologic evidence that leukemias with spliceosomal gene mutations are preferentially susceptible to additional splicing perturbations in vivo as compared to leukemias without such mutations. Modulation of spliceosome function may thus provide a new therapeutic avenue in genetically defined subsets of individuals with MDS or AML.", + "TAG_DATA": [ + "76, mice {'context': 'B-organism'}", + "78, express {'perturbing_action': 'B-other'}", + "79, a {'perturbing_action': 'I-other'}", + "80, mutated {'perturbing_action': 'B-other'}", + "81, allele {'perturbing_action': 'I-other'}", + "82, of {'perturbing_action': 'I-other'}", + "83, serine/arginine-rich {'perturbing_action': 'I-other'}", + "84, splicing {'perturbing_action': 'I-other'}", + "85, factor {'perturbing_action': 'I-other'}", + "86, 2 {'perturbing_action': 'I-other'}", + "87, (Srsf2(P95H))-which {'perturbing_action': 'I-other'}", + "101, hematopoietic {'context': 'B-cells'}", + "102, cells. {'context': 'I-cells'}", + "104, mice {'context': 'B-organism'}", + "114, Srsf2-mutated {'perturbing_action': 'B-other'}", + "115, cells {'context': 'B-cells'}", + "147, mouse {'context': 'B-neoplasm'}", + "148, leukemias {'context': 'I-neoplasm'}", + "150, patient-derived {'context': 'B-xenograft'}", + "151, xenograft {'context': 'I-xenograft'}", + "152, AMLs {'context': 'I-xenograft'}", + "160, mice {'context': 'B-organism'}", + "171, leukemic {'context': 'B-transformed cells'}", + "172, cells {'context': 'I-transformed cells'}", + "188, Srsf2-mutated {'perturbing_action': 'B-other'}", + "192, leukemia, {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "76, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "78, express ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "79, a ['l1', 'l14', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "80, mutated ['l2', 'l15', 'l30', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "81, allele ['l3', 'l16', 'l31', 'l45', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "82, of ['l4', 'l17', 'l32', 'l46', 'l59', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "83, serine/arginine-rich ['l5', 'l18', 'l33', 'l47', 'l60', 'l72', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "84, splicing ['l6', 'l19', 'l34', 'l48', 'l61', 'l73', 'l84', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "85, factor ['l7', 'l20', 'l35', 'l49', 'l62', 'l74', 'l85', 'l96', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "86, 2 ['l8', 'l21', 'l36', 'l50', 'l63', 'l75', 'l86', 'l97', 'l107', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "87, (Srsf2(P95H))-which ['l9', 'l22', 'l37', 'l51', 'l64', 'l76', 'l87', 'l98', 'l108', 'l116', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "101, hematopoietic ['l10', 'l23', 'l38', 'l52', 'l65', 'l77', 'l88', 'l99', 'l109', 'l117', 'l124', 'l131', 'l132', 'l133']", + "102, cells. ['l11', 'l24', 'l39', 'l53', 'l66', 'l78', 'l89', 'l100', 'l110', 'l118', 'l125', 'l131', 'l134', 'l135']", + "104, mice ['l12', 'l25', 'l40', 'l54', 'l67', 'l79', 'l90', 'l101', 'l111', 'l119', 'l126', 'l132', 'l134', 'l136', 'l137', 'l138']", + "114, Srsf2-mutated ['l26', 'l41', 'l55', 'l68', 'l80', 'l91', 'l102', 'l112', 'l120', 'l127', 'l136', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "115, cells ['l13', 'l27', 'l42', 'l56', 'l69', 'l81', 'l92', 'l103', 'l113', 'l121', 'l128', 'l133', 'l135', 'l137', 'l139', 'l145', 'l146']", + "147, mouse ['l28', 'l43', 'l57', 'l70', 'l82', 'l93', 'l104', 'l114', 'l122', 'l129', 'l140', 'l145', 'l147', 'l148']", + "148, leukemias ['l29', 'l44', 'l58', 'l71', 'l83', 'l94', 'l105', 'l115', 'l123', 'l130', 'l138', 'l141', 'l146', 'l147', 'l149', 'l150', 'l151']", + "150, patient-derived ['l142', 'l149', 'l152', 'l153']", + "151, xenograft ['l143', 'l150', 'l152', 'l154']", + "152, AMLs ['l95', 'l106', 'l144', 'l148', 'l151', 'l153', 'l154']", + "160, mice ['l155', 'l156']", + "171, leukemic ['l155', 'l157']", + "172, cells ['l156', 'l157']", + "188, Srsf2-mutated ['l158']", + "192, leukemia, ['l158']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "express", + "a", + "mutated", + "allele", + "of", + "serine/arginine-rich", + "splicing", + "factor", + "2", + "(Srsf2(P95H))-which", + "Srsf2-mutated" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "express", + "a", + "mutated", + "allele", + "of", + "serine/arginine-rich", + "splicing", + "factor", + "2", + "(Srsf2(P95H))-which", + "Srsf2-mutated" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "cells.", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "express", + "a", + "mutated", + "allele", + "of", + "serine/arginine-rich", + "splicing", + "factor", + "2", + "(Srsf2(P95H))-which", + "Srsf2-mutated" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "leukemias", + "leukemia," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "serine/arginine-rich", + "splicing", + "Srsf2-mutated" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "AMLs", + "patient-derived", + "xenograft" + ] + } + } + ] + }, + { + "PMID": "27043495", + "TEXT": "Granulomas are the pathological hallmark of tuberculosis (TB). However, their function and mechanisms of formation remain poorly understood. To understand the role of granulomas in TB, we analyzed the proteomes of granulomas from subjects with tuberculosis in an unbiased manner. Using laser-capture microdissection, mass spectrometry and confocal microscopy, we generated detailed molecular maps of human granulomas. We found that the centers of granulomas have a pro-inflammatory environment that is characterized by the presence of antimicrobial peptides, reactive oxygen species and pro-inflammatory eicosanoids. Conversely, the tissue surrounding the caseum has a comparatively anti-inflammatory signature. These findings are consistent across a set of six human subjects and in rabbits. Although the balance between systemic pro- and anti-inflammatory signals is crucial to TB disease outcome, here we find that these signals are physically segregated within each granuloma. From the protein and lipid snapshots of human and rabbit lesions analyzed here, we hypothesize that the pathologic response to TB is shaped by the precise anatomical localization of these inflammatory pathways during the development of the granuloma.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "26998835", + "TEXT": "Smith-Lemli-Opitz syndrome (SLOS) is a malformation disorder caused by mutations in DHCR7, which impair the reduction of 7-dehydrocholesterol (7DHC) to cholesterol. SLOS results in cognitive impairment, behavioral abnormalities and nervous system defects, though neither affected cell types nor impaired signaling pathways are fully understood. Whether 7DHC accumulation or cholesterol loss is primarily responsible for disease pathogenesis is also unclear. Using induced pluripotent stem cells (iPSCs) from subjects with SLOS, we identified cellular defects that lead to precocious neuronal specification within SLOS derived neural progenitors. We also demonstrated that 7DHC accumulation, not cholesterol deficiency, is critical for SLOS-associated defects. We further identified downregulation of Wnt/β-catenin signaling as a key initiator of aberrant SLOS iPSC differentiation through the direct inhibitory effects of 7DHC on the formation of an active Wnt receptor complex. Activation of canonical Wnt signaling prevented the neural phenotypes observed in SLOS iPSCs, suggesting that Wnt signaling may be a promising therapeutic target for SLOS.", + "TAG_DATA": [ + "60, induced {'context': 'B-cells'}", + "61, pluripotent {'context': 'I-cells'}", + "62, stem {'context': 'I-cells'}", + "63, cells {'context': 'I-cells'}", + "64, (iPSCs) {'context': 'I-cells'}", + "113, differentiation {'phenotype': 'B-differentiation'}", + "141, SLOS {'context': 'B-cells'}", + "142, iPSCs, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "60, induced ['l0', 'l1', 'l2', 'l3']", + "61, pluripotent ['l0', 'l4', 'l5', 'l6']", + "62, stem ['l1', 'l4', 'l7', 'l8']", + "63, cells ['l2', 'l5', 'l7', 'l9']", + "64, (iPSCs) ['l3', 'l6', 'l8', 'l9']", + "112, iPSC ['l10']", + "113, differentiation ['l10']", + "141, SLOS ['l11']", + "142, iPSCs, ['l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26998834", + "TEXT": "Prevention of mother-to-child transmission (MTCT) of HIV remains a major objective where antenatal care is not readily accessible. We tested HIV-1-specific human neutralizing monoclonal antibodies (NmAbs) as a post-exposure therapy in an infant macaque model for intrapartum MTCT. One-month-old rhesus macaques were inoculated orally with the simian-human immunodeficiency virus SHIVSF162P3. On days 1, 4, 7 and 10 after virus exposure, we injected animals subcutaneously with NmAbs and quantified systemic distribution of NmAbs in multiple tissues within 24 h after antibody administration. Replicating virus was found in multiple tissues by day 1 in animals that were not treated. All NmAb-treated macaques were free of virus in blood and tissues at 6 months after exposure. We detected no anti-SHIV T cell responses in blood or tissues at necropsy, and no virus emerged after CD8(+) T cell depletion. These results suggest that early passive immunotherapy can eliminate early viral foci and thereby prevent the establishment of viral reservoirs.", + "TAG_DATA": [ + "38, One-month-old {'context': 'B-organism'}", + "39, rhesus {'context': 'I-organism'}", + "40, macaques {'context': 'I-organism'}", + "62, animals {'context': 'B-organism'}", + "92, animals {'context': 'B-organism'}", + "99, macaques {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "38, One-month-old ['l0', 'l1', 'l2']", + "39, rhesus ['l0', 'l3', 'l4']", + "40, macaques ['l1', 'l3', 'l5']", + "62, animals ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26974309", + "TEXT": "Upregulation of the persistent sodium current (I(NaP)) in motoneurons contributes to the development of spasticity after spinal cord injury (SCI). We investigated the mechanisms that regulate I(NaP) and observed elevated expression of voltage-gated sodium (Nav) 1.6 channels in spinal lumbar motoneurons of adult rats with SCI. Furthermore, immunoblots revealed a proteolysis of Nav channels, and biochemical assays identified calpain as the main proteolytic factor. Calpain-dependent cleavage of Nav channels after neonatal SCI was associated with an upregulation of I(NaP) in motoneurons. Similarly, the calpain-dependent cleavage of Nav1.6 channels expressed in human embryonic kidney (HEK) 293 cells caused the upregulation of I(NaP). The pharmacological inhibition of calpain activity by MDL28170 reduced the cleavage of Nav channels, I(NaP) in motoneurons and spasticity in rats with SCI. Similarly, the blockade of I(NaP) by riluzole alleviated spasticity. This study demonstrates that Nav channel expression in lumbar motoneurons is altered after SCI, and it shows a tight relationship between the calpain-dependent proteolysis of Nav1.6 channels, the upregulation of I(NaP) and spasticity.", + "TAG_DATA": [ + "90, human {'context': 'B-cells'}", + "91, embryonic {'context': 'I-cells'}", + "92, kidney {'context': 'I-cells'}", + "93, (HEK) {'context': 'I-cells'}", + "94, 293 {'context': 'I-cells'}", + "95, cells {'context': 'I-cells'}", + "102, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "103, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "104, of {'perturbing_action': 'I-pharmacological inhibition'}", + "105, calpain {'perturbing_action': 'I-pharmacological inhibition'}", + "106, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "107, by {'perturbing_action': 'I-pharmacological inhibition'}", + "108, MDL28170 {'perturbing_action': 'I-pharmacological inhibition'}", + "117, motoneurons {'context': 'B-cells'}", + "121, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "90, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "91, embryonic ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "92, kidney ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "93, (HEK) ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "94, 293 ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "95, cells ['l4', 'l12', 'l19', 'l25', 'l30', 'l35']", + "102, pharmacological ['l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "103, inhibition ['l36', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "104, of ['l37', 'l44', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "105, calpain ['l38', 'l45', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "106, activity ['l39', 'l46', 'l52', 'l57', 'l62', 'l63', 'l64', 'l65']", + "107, by ['l5', 'l13', 'l20', 'l26', 'l31', 'l40', 'l47', 'l53', 'l58', 'l62', 'l66', 'l67', 'l68']", + "108, MDL28170 ['l6', 'l14', 'l21', 'l27', 'l32', 'l41', 'l48', 'l54', 'l59', 'l63', 'l66', 'l69', 'l70']", + "117, motoneurons ['l7', 'l15', 'l22', 'l28', 'l33', 'l35', 'l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l71']", + "121, rats ['l8', 'l16', 'l23', 'l29', 'l34', 'l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l71']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "embryonic", + "kidney", + "(HEK)", + "293", + "motoneurons" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "by", + "MDL28170", + "pharmacological", + "inhibition", + "of", + "calpain", + "activity" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "calpain", + "activity", + "by", + "MDL28170" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + } + ] + }, + { + "PMID": "26950362", + "TEXT": "Cellular senescence is thought to contribute to age-associated deterioration of tissue physiology. The senescence effector p16(Ink4a) is expressed in pancreatic beta cells during aging and limits their proliferative potential; however, its effects on beta cell function are poorly characterized. We found that beta cell-specific activation of p16(Ink4a) in transgenic mice enhances glucose-stimulated insulin secretion (GSIS). In mice with diabetes, this leads to improved glucose homeostasis, providing an unexpected functional benefit. Expression of p16(Ink4a) in beta cells induces hallmarks of senescence--including cell enlargement, and greater glucose uptake and mitochondrial activity--which promote increased insulin secretion. GSIS increases during the normal aging of mice and is driven by elevated p16(Ink4a) activity. We found that islets from human adults contain p16(Ink4a)-expressing senescent beta cells and that senescence induced by p16(Ink4a) in a human beta cell line increases insulin secretion in a manner dependent, in part, on the activity of the mechanistic target of rapamycin (mTOR) and the peroxisome proliferator-activated receptor (PPAR)-γ proteins. Our findings reveal a novel role for p16(Ink4a) and cellular senescence in promoting insulin secretion by beta cells and in regulating normal functional tissue maturation with age.", + "TAG_DATA": [ + "42, beta {'perturbing_action': 'B-pharmacological augmentation'}", + "43, cell-specific {'perturbing_action': 'I-pharmacological augmentation'}", + "44, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "45, of {'perturbing_action': 'I-pharmacological augmentation'}", + "46, p16(Ink4a) {'perturbing_action': 'I-pharmacological augmentation'}", + "48, transgenic {'perturbing_action': 'B-gene gain-of-function', 'context': 'B-organism'}", + "49, mice {'context': 'I-organism'}", + "56, mice {'context': 'B-organism'}", + "70, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "71, of {'perturbing_action': 'I-gene gain-of-function'}", + "72, p16(Ink4a) {'perturbing_action': 'I-gene gain-of-function'}", + "74, beta {'context': 'B-cells'}", + "75, cells {'context': 'I-cells'}", + "76, induces {'effect': 'B-positive'}", + "79, senescence--including {'phenotype': 'B-senescence'}", + "100, mice {'context': 'B-organism'}", + "111, islets {'context': 'B-cells'}", + "122, senescence {'phenotype': 'B-senescence'}", + "123, induced {'effect': 'B-positive'}", + "128, human {'context': 'B-cells'}", + "129, beta {'context': 'I-cells'}", + "130, cell {'context': 'I-cells'}", + "131, line {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "42, beta ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "43, cell-specific ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "44, activation ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "45, of ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "46, p16(Ink4a) ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "48, transgenic ['l4', 'l17', 'l29', 'l40', 'l50', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "49, mice ['l5', 'l18', 'l30', 'l41', 'l51', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73']", + "56, mice ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l74', 'l75', 'l76', 'l77']", + "70, Expression ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "71, of ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l78', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "72, p16(Ink4a) ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l79', 'l85', 'l91', 'l92', 'l93', 'l94', 'l95']", + "74, beta ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l70', 'l74', 'l80', 'l86', 'l91', 'l96', 'l97', 'l98']", + "75, cells ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l71', 'l75', 'l81', 'l87', 'l92', 'l96', 'l99', 'l100']", + "76, induces ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l72', 'l76', 'l82', 'l88', 'l93', 'l97', 'l99', 'l101']", + "79, senescence--including ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l73', 'l77', 'l83', 'l89', 'l94', 'l98', 'l100', 'l101']", + "100, mice ['l84', 'l90', 'l95']", + "122, senescence ['l102', 'l103', 'l104', 'l105', 'l106']", + "123, induced ['l102', 'l107', 'l108', 'l109', 'l110']", + "128, human ['l103', 'l107', 'l111', 'l112', 'l113']", + "129, beta ['l104', 'l108', 'l111', 'l114', 'l115']", + "130, cell ['l105', 'l109', 'l112', 'l114', 'l116']", + "131, line ['l106', 'l110', 'l113', 'l115', 'l116']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "beta", + "cell-specific", + "activation", + "of", + "p16(Ink4a)" + ] + }, + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "Expression", + "of", + "p16(Ink4a)" + ] + }, + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "beta", + "cell-specific", + "activation", + "of", + "p16(Ink4a)" + ] + }, + "context": { + "val": "cells", + "words": [ + "beta", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "beta", + "cell-specific", + "activation", + "of", + "p16(Ink4a)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "beta", + "cell-specific", + "activation", + "of", + "p16(Ink4a)" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence--including" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "Expression", + "of", + "p16(Ink4a)" + ] + }, + "context": { + "val": "cells", + "words": [ + "beta", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "Expression", + "of", + "p16(Ink4a)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "Expression", + "of", + "p16(Ink4a)" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence--including" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence--including" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "beta", + "cells", + "human", + "cell", + "line" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces", + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "beta", + "cells", + "human", + "cell", + "line" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence--including", + "senescence" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "induced" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence--including", + "senescence" + ] + } + } + ] + }, + { + "PMID": "26779811", + "TEXT": "Neutrophil extracellular traps (NETs) are implicated in autoimmunity, but how they are generated and their roles in sterile inflammation remain unclear. Ribonucleoprotein immune complexes (RNP ICs), inducers of NETosis, require mitochondrial reactive oxygen species (ROS) for maximal NET stimulation. After RNP IC stimulation of neutrophils, mitochondria become hypopolarized and translocate to the cell surface. Extracellular release of oxidized mitochondrial DNA is proinflammatory in vitro, and when this DNA is injected into mice, it stimulates type I interferon (IFN) signaling through a pathway dependent on the DNA sensor STING. Mitochondrial ROS are also necessary for spontaneous NETosis of low-density granulocytes from individuals with systemic lupus erythematosus. This was also observed in individuals with chronic granulomatous disease, who lack NADPH oxidase activity but still develop autoimmunity and type I IFN signatures. Mitochondrial ROS inhibition in vivo reduces disease severity and type I IFN responses in a mouse model of lupus. Together, these findings highlight a role for mitochondria in the generation not only of NETs but also of pro-inflammatory oxidized mitochondrial DNA in autoimmune diseases.", + "TAG_DATA": [ + "132, in {'context': 'B-in vivo'}", + "133, vivo {'context': 'I-in vivo'}", + "144, mouse {'context': 'B-organism'}", + "145, model {'context': 'I-organism'}", + "146, of {'context': 'I-organism'}", + "147, lupus. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "131, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "132, in ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "133, vivo ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "144, mouse ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "145, model ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "146, of ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "147, lupus. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26752517", + "TEXT": "Protozoan infections are a serious global health problem. Natural killer (NK) cells and cytolytic T lymphocytes (CTLs) eliminate pathogen-infected cells by releasing cytolytic granule contents--granzyme (Gzm) proteases and the pore-forming perforin (PFN)--into the infected cell. However, these cytotoxic molecules do not kill intracellular parasites. CD8(+) CTLs protect against parasite infections in mice primarily by secreting interferon (IFN)-γ. However, human, but not rodent, cytotoxic granules contain the antimicrobial peptide granulysin (GNLY), which selectively destroys cholesterol-poor microbial membranes, and GNLY, PFN and Gzms rapidly kill intracellular bacteria. Here we show that GNLY delivers Gzms into three protozoan parasites (Trypanosoma cruzi, Toxoplasma gondii and Leishmania major), in which the Gzms generate superoxide and inactivate oxidative defense enzymes to kill the parasite. PFN delivers GNLY and Gzms into infected cells, and GNLY then delivers Gzms to the intracellular parasites. Killer cell-mediated parasite death, which we term 'microbe-programmed cell death' or 'microptosis', is caspase independent but resembles mammalian apoptosis, causing mitochondrial swelling, transmembrane potential dissipation, membrane blebbing, phosphatidylserine exposure, DNA damage and chromatin condensation. GNLY-transgenic mice are protected against infection by T. cruzi and T. gondii, and survive infections that are lethal to wild-type mice. Thus, GNLY-, PFN- and Gzm-mediated elimination of intracellular protozoan parasites is an unappreciated immune defense mechanism.", + "TAG_DATA": [ + "125, cells, {'context': 'B-cells'}", + "169, GNLY-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "170, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "169, GNLY-transgenic ['l0']", + "170, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GNLY-transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "26642438", + "TEXT": "Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, which encodes a polyglutamine tract in the HTT protein. We found that peroxisome proliferator-activated receptor delta (PPAR-δ) interacts with HTT and that mutant HTT represses PPAR-δ-mediated transactivation. Increased PPAR-δ transactivation ameliorated mitochondrial dysfunction and improved cell survival of neurons from mouse models of HD. Expression of dominant-negative PPAR-δ in the central nervous system of mice was sufficient to induce motor dysfunction, neurodegeneration, mitochondrial abnormalities and transcriptional alterations that recapitulated HD-like phenotypes. Expression of dominant-negative PPAR-δ specifically in the striatum of medium spiny neurons in mice yielded HD-like motor phenotypes, accompanied by striatal neuron loss. In mouse models of HD, pharmacologic activation of PPAR-δ using the agonist KD3010 improved motor function, reduced neurodegeneration and increased survival. PPAR-δ activation also reduced HTT-induced neurotoxicity in vitro and in medium spiny-like neurons generated from stem cells derived from individuals with HD, indicating that PPAR-δ activation may be beneficial in HD and related disorders.", + "TAG_DATA": [ + "54, improved {'effect': 'B-positive'}", + "55, cell {'phenotype': 'B-cell survival'}", + "56, survival {'phenotype': 'I-cell survival'}", + "58, neurons {'context': 'B-cells'}", + "64, Expression {'perturbing_action': 'B-other'}", + "65, of {'perturbing_action': 'I-other'}", + "66, dominant-negative {'perturbing_action': 'I-other'}", + "67, PPAR-δ {'perturbing_action': 'I-other'}", + "68, in {'perturbing_action': 'I-other'}", + "69, the {'perturbing_action': 'I-other'}", + "70, central {'perturbing_action': 'I-other'}", + "71, nervous {'perturbing_action': 'I-other', 'context': 'I-tissue/organ'}", + "72, system {'perturbing_action': 'I-other', 'context': 'I-tissue/organ'}", + "74, mice {'context': 'B-organism'}", + "91, Expression {'perturbing_action': 'B-other'}", + "92, of {'perturbing_action': 'I-other'}", + "93, dominant-negative {'perturbing_action': 'I-other'}", + "94, PPAR-δ {'perturbing_action': 'I-other'}", + "95, specifically {'perturbing_action': 'I-other'}", + "96, in {'perturbing_action': 'I-other'}", + "97, the {'perturbing_action': 'I-other'}", + "98, striatum {'perturbing_action': 'I-other'}", + "99, of {'perturbing_action': 'I-other'}", + "100, medium {'context': 'B-cells'}", + "101, spiny {'context': 'I-cells'}", + "102, neurons {'context': 'I-cells'}", + "104, mice {'context': 'B-organism'}", + "111, striatal {'context': 'B-cells'}", + "112, neuron {'context': 'I-cells'}", + "115, mouse {'context': 'B-organism'}", + "116, models {'context': 'I-organism'}", + "119, pharmacologic {'perturbing_action': 'B-pharmacological augmentation'}", + "120, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "121, of {'perturbing_action': 'I-pharmacological augmentation'}", + "122, PPAR-δ {'perturbing_action': 'I-pharmacological augmentation'}", + "123, using {'perturbing_action': 'I-pharmacological augmentation'}", + "124, the {'perturbing_action': 'I-pharmacological augmentation'}", + "125, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "126, KD3010 {'perturbing_action': 'I-pharmacological augmentation'}", + "135, PPAR-δ {'perturbing_action': 'B-pharmacological augmentation'}", + "136, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "141, in {'context': 'B-in vitro'}", + "142, vitro {'context': 'I-in vitro'}", + "145, medium {'context': 'B-cells'}", + "146, spiny-like {'context': 'I-cells'}", + "147, neurons {'context': 'I-cells'}", + "148, generated {'context': 'I-cells'}", + "149, from {'context': 'I-cells'}", + "150, stem {'context': 'I-cells'}", + "151, cells {'context': 'I-cells'}", + "152, derived {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "54, improved ['l0', 'l1', 'l2', 'l3']", + "55, cell ['l0', 'l4', 'l5', 'l6']", + "56, survival ['l1', 'l4', 'l7', 'l8']", + "58, neurons ['l2', 'l5', 'l7', 'l9']", + "61, models ['l3', 'l6', 'l8', 'l9']", + "64, Expression ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "65, of ['l10', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "66, dominant-negative ['l11', 'l26', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "67, PPAR-δ ['l12', 'l27', 'l43', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "68, in ['l13', 'l28', 'l44', 'l59', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "69, the ['l14', 'l29', 'l45', 'l60', 'l76', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "70, central ['l15', 'l30', 'l46', 'l61', 'l77', 'l88', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "71, nervous ['l16', 'l31', 'l47', 'l62', 'l78', 'l89', 'l98', 'l104', 'l105', 'l106', 'l107', 'l108']", + "72, system ['l17', 'l32', 'l48', 'l63', 'l79', 'l90', 'l99', 'l104', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "74, mice ['l18', 'l33', 'l49', 'l64', 'l80', 'l91', 'l100', 'l105', 'l109']", + "91, Expression ['l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "92, of ['l115', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "93, dominant-negative ['l116', 'l130', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156']", + "94, PPAR-δ ['l117', 'l131', 'l144', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168']", + "95, specifically ['l65', 'l118', 'l132', 'l145', 'l157', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "96, in ['l66', 'l119', 'l133', 'l146', 'l158', 'l169', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "97, the ['l34', 'l50', 'l67', 'l120', 'l134', 'l147', 'l159', 'l170', 'l179', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195']", + "98, striatum ['l35', 'l51', 'l68', 'l121', 'l135', 'l148', 'l160', 'l171', 'l180', 'l188', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202']", + "99, of ['l19', 'l36', 'l52', 'l69', 'l81', 'l92', 'l110', 'l122', 'l136', 'l149', 'l161', 'l172', 'l181', 'l189', 'l196', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208']", + "100, medium ['l20', 'l37', 'l53', 'l70', 'l82', 'l93', 'l111', 'l123', 'l137', 'l150', 'l162', 'l173', 'l182', 'l190', 'l197', 'l203', 'l209', 'l210', 'l211', 'l212', 'l213']", + "101, spiny ['l21', 'l38', 'l54', 'l71', 'l83', 'l94', 'l101', 'l106', 'l112', 'l124', 'l138', 'l151', 'l163', 'l174', 'l183', 'l191', 'l198', 'l204', 'l209', 'l214', 'l215', 'l216', 'l217']", + "102, neurons ['l22', 'l39', 'l55', 'l72', 'l84', 'l95', 'l102', 'l107', 'l113', 'l125', 'l139', 'l152', 'l164', 'l175', 'l184', 'l192', 'l199', 'l205', 'l210', 'l214', 'l218', 'l219', 'l220']", + "104, mice ['l23', 'l40', 'l56', 'l73', 'l85', 'l126', 'l140', 'l153', 'l165', 'l176', 'l185', 'l193', 'l200', 'l206', 'l211', 'l215', 'l218', 'l221', 'l222']", + "111, striatal ['l24', 'l41', 'l57', 'l74', 'l86', 'l96', 'l127', 'l141', 'l154', 'l166', 'l177', 'l186', 'l194', 'l201', 'l207', 'l212', 'l216', 'l219', 'l221', 'l223']", + "112, neuron ['l25', 'l42', 'l58', 'l75', 'l87', 'l97', 'l103', 'l108', 'l114', 'l128', 'l142', 'l155', 'l167', 'l178', 'l187', 'l195', 'l202', 'l208', 'l213', 'l217', 'l220', 'l222', 'l223']", + "115, mouse ['l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232']", + "116, models ['l129', 'l143', 'l156', 'l168', 'l224', 'l233', 'l234', 'l235', 'l236']", + "119, pharmacologic ['l225', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255']", + "120, activation ['l226', 'l237', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273']", + "121, of ['l227', 'l233', 'l238', 'l256', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290']", + "122, PPAR-δ ['l228', 'l234', 'l239', 'l257', 'l274', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304', 'l305']", + "123, using ['l229', 'l240', 'l258', 'l275', 'l291', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315', 'l316', 'l317', 'l318', 'l319', 'l320']", + "124, the ['l230', 'l235', 'l241', 'l259', 'l276', 'l292', 'l306', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327', 'l328', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334']", + "125, agonist ['l231', 'l242', 'l260', 'l277', 'l293', 'l307', 'l321', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340', 'l341', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347']", + "126, KD3010 ['l232', 'l236', 'l243', 'l261', 'l278', 'l294', 'l308', 'l322', 'l335', 'l348', 'l349', 'l350', 'l351', 'l352', 'l353', 'l354', 'l355', 'l356', 'l357', 'l358']", + "135, PPAR-δ ['l244', 'l262', 'l279', 'l309', 'l323', 'l336', 'l359', 'l360', 'l361', 'l362', 'l363', 'l364', 'l365', 'l366', 'l367', 'l368', 'l369']", + "136, activation ['l245', 'l263', 'l280', 'l295', 'l310', 'l324', 'l337', 'l348', 'l359', 'l370', 'l371', 'l372', 'l373', 'l374', 'l375', 'l376', 'l377', 'l378', 'l379']", + "141, in ['l246', 'l264', 'l281', 'l296', 'l311', 'l325', 'l338', 'l349', 'l360', 'l370', 'l380', 'l381', 'l382', 'l383', 'l384', 'l385', 'l386', 'l387', 'l388']", + "142, vitro ['l247', 'l265', 'l282', 'l297', 'l312', 'l326', 'l339', 'l350', 'l361', 'l371', 'l380', 'l389', 'l390', 'l391', 'l392', 'l393', 'l394', 'l395', 'l396']", + "145, medium ['l248', 'l266', 'l283', 'l298', 'l313', 'l327', 'l340', 'l351', 'l362', 'l372', 'l381', 'l389', 'l397', 'l398', 'l399', 'l400', 'l401', 'l402', 'l403']", + "146, spiny-like ['l249', 'l267', 'l284', 'l299', 'l314', 'l328', 'l341', 'l352', 'l363', 'l373', 'l382', 'l390', 'l397', 'l404', 'l405', 'l406', 'l407', 'l408', 'l409']", + "147, neurons ['l250', 'l268', 'l285', 'l300', 'l315', 'l329', 'l342', 'l353', 'l364', 'l374', 'l383', 'l391', 'l398', 'l404', 'l410', 'l411', 'l412', 'l413', 'l414']", + "148, generated ['l251', 'l269', 'l286', 'l301', 'l316', 'l330', 'l343', 'l354', 'l365', 'l375', 'l384', 'l392', 'l399', 'l405', 'l410', 'l415', 'l416', 'l417', 'l418']", + "149, from ['l252', 'l270', 'l287', 'l302', 'l317', 'l331', 'l344', 'l355', 'l366', 'l376', 'l385', 'l393', 'l400', 'l406', 'l411', 'l415', 'l419', 'l420', 'l421']", + "150, stem ['l253', 'l271', 'l288', 'l303', 'l318', 'l332', 'l345', 'l356', 'l367', 'l377', 'l386', 'l394', 'l401', 'l407', 'l412', 'l416', 'l419', 'l422', 'l423']", + "151, cells ['l254', 'l272', 'l289', 'l304', 'l319', 'l333', 'l346', 'l357', 'l368', 'l378', 'l387', 'l395', 'l402', 'l408', 'l413', 'l417', 'l420', 'l422', 'l424']", + "152, derived ['l255', 'l273', 'l290', 'l305', 'l320', 'l334', 'l347', 'l358', 'l369', 'l379', 'l388', 'l396', 'l403', 'l409', 'l414', 'l418', 'l421', 'l423', 'l424']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "improved" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "survival" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "improved" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons" + ] + } + }, + { + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "survival" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Expression", + "of", + "dominant-negative", + "PPAR-δ", + "in", + "the", + "central", + "nervous", + "system" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "nervous", + "system" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Expression", + "of", + "dominant-negative", + "PPAR-δ", + "in", + "the", + "central", + "nervous", + "system", + "specifically", + "striatum" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "models" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Expression", + "of", + "dominant-negative", + "PPAR-δ", + "in", + "the", + "central", + "nervous", + "system", + "specifically", + "striatum" + ] + }, + "context": { + "val": "cells", + "words": [ + "medium", + "spiny", + "neurons", + "striatal", + "neuron" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "pharmacologic", + "activation", + "of", + "PPAR-δ", + "using", + "the", + "agonist", + "KD3010" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "pharmacologic", + "activation", + "of", + "PPAR-δ", + "using", + "the", + "agonist", + "KD3010" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "pharmacologic", + "activation", + "of", + "PPAR-δ", + "using", + "the", + "agonist", + "KD3010" + ] + }, + "context": { + "val": "cells", + "words": [ + "medium", + "spiny-like", + "neurons", + "generated", + "from", + "stem", + "cells", + "derived" + ] + } + } + ] + }, + { + "PMID": "26642437", + "TEXT": "The glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor transduce nutrient-stimulated signals to control beta cell function. Although the GLP-1 receptor (GLP-1R) is a validated drug target for diabetes, the importance of the GIP receptor (GIPR) for the function of beta cells remains uncertain. We demonstrate that mice with selective ablation of GIPR in beta cells (MIP-Cre:Gipr(Flox/Flox); Gipr(-/-βCell)) exhibit lower levels of meal-stimulated insulin secretion, decreased expansion of adipose tissue mass and preservation of insulin sensitivity when compared to MIP-Cre controls. Beta cells from Gipr(-/-βCell) mice display greater sensitivity to apoptosis and markedly lower islet expression of T cell-specific transcription factor-1 (TCF1, encoded by Tcf7), a protein not previously characterized in beta cells. GIP, but not GLP-1, promotes beta cell Tcf7 expression via a cyclic adenosine monophosphate (cAMP)-independent and extracellular signal-regulated kinase (ERK)-dependent pathway. Tcf7 (in mice) or TCF7 (in humans) levels are lower in islets taken from diabetic mice and in humans with type 2 diabetes; knockdown of TCF7 in human and mouse islets impairs the cytoprotective responsiveness to GIP and enhances the magnitude of apoptotic injury, whereas restoring TCF1 levels in beta cells from Gipr(-/-βCell) mice lowers the number of apoptotic cells compared to that seen in MIP-Cre controls. Tcf7(-/-) mice show impaired insulin secretion, deterioration of glucose tolerance with either aging and/or high-fat feeding and increased sensitivity to beta cell injury relative to wild-type (WT) controls. Hence the GIPR-TCF1 axis represents a potential therapeutic target for preserving both the function and survival of vulnerable, diabetic beta cells.", + "TAG_DATA": [ + "50, mice {'context': 'B-organism'}", + "52, selective {'perturbing_action': 'B-gene loss-of-function'}", + "53, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "54, of {'perturbing_action': 'I-gene loss-of-function'}", + "55, GIPR {'perturbing_action': 'I-gene loss-of-function'}", + "56, in {'perturbing_action': 'I-gene loss-of-function'}", + "57, beta {'perturbing_action': 'I-gene loss-of-function'}", + "58, cells {'perturbing_action': 'I-gene loss-of-function'}", + "59, (MIP-Cre:Gipr(Flox/Flox); {'perturbing_action': 'I-gene loss-of-function'}", + "60, Gipr(-/-βCell)) {'perturbing_action': 'I-gene loss-of-function'}", + "84, Beta {'context': 'B-cells'}", + "85, cells {'context': 'I-cells'}", + "87, Gipr(-/-βCell) {'perturbing_action': 'B-gene loss-of-function'}", + "88, mice {'context': 'B-organism'}", + "90, greater {'effect': 'B-positive'}", + "91, sensitivity {'effect': 'I-positive'}", + "93, apoptosis {'phenotype': 'B-apoptosis'}", + "160, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "161, of {'perturbing_action': 'I-rnai/knockdown'}", + "162, TCF7 {'perturbing_action': 'I-rnai/knockdown'}", + "164, human {'context': 'B-cells'}", + "165, and {'context': 'I-cells'}", + "166, mouse {'context': 'I-cells'}", + "167, islets {'context': 'I-cells'}", + "186, beta {'context': 'B-cells'}", + "187, cells {'context': 'I-cells'}", + "189, Gipr(-/-βCell) {'perturbing_action': 'B-gene loss-of-function'}", + "190, mice {'context': 'B-organism'}", + "196, cells {'phenotype': 'I-apoptosis'}", + "204, Tcf7(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "205, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "52, selective ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "53, ablation ['l1', 'l9', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "54, of ['l2', 'l10', 'l24', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "55, GIPR ['l3', 'l11', 'l25', 'l38', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "56, in ['l4', 'l12', 'l26', 'l39', 'l51', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "57, beta ['l5', 'l13', 'l27', 'l40', 'l52', 'l63', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "58, cells ['l6', 'l14', 'l28', 'l41', 'l53', 'l64', 'l74', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "59, (MIP-Cre:Gipr(Flox/Flox); ['l7', 'l15', 'l29', 'l42', 'l54', 'l65', 'l75', 'l82', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "60, Gipr(-/-βCell)) ['l8', 'l16', 'l30', 'l43', 'l55', 'l66', 'l76', 'l83', 'l89', 'l97', 'l98', 'l99', 'l100', 'l101']", + "84, Beta ['l17', 'l31', 'l44', 'l56', 'l67', 'l77', 'l84', 'l90', 'l97', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "85, cells ['l18', 'l32', 'l45', 'l57', 'l68', 'l78', 'l85', 'l91', 'l98', 'l102', 'l112', 'l113', 'l114', 'l115', 'l116']", + "87, Gipr(-/-βCell) ['l19', 'l33', 'l46', 'l58', 'l69', 'l92', 'l103', 'l112', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "88, mice ['l20', 'l34', 'l47', 'l59', 'l70', 'l79', 'l86', 'l93', 'l99', 'l104', 'l113', 'l117', 'l125', 'l126', 'l127']", + "90, greater ['l21', 'l35', 'l48', 'l60', 'l71', 'l80', 'l87', 'l94', 'l100', 'l105', 'l114', 'l118', 'l125', 'l128', 'l129']", + "91, sensitivity ['l22', 'l36', 'l49', 'l61', 'l72', 'l81', 'l88', 'l95', 'l101', 'l106', 'l115', 'l119', 'l126', 'l128', 'l130']", + "93, apoptosis ['l23', 'l37', 'l50', 'l62', 'l73', 'l96', 'l107', 'l116', 'l120', 'l127', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "160, knockdown ['l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141']", + "161, of ['l135', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "162, TCF7 ['l136', 'l142', 'l148', 'l149', 'l150', 'l151', 'l152']", + "164, human ['l108', 'l121', 'l131', 'l137', 'l143', 'l148', 'l153', 'l154', 'l155']", + "165, and ['l109', 'l122', 'l132', 'l138', 'l144', 'l149', 'l153', 'l156', 'l157']", + "166, mouse ['l110', 'l123', 'l133', 'l139', 'l145', 'l150', 'l154', 'l156', 'l158']", + "167, islets ['l111', 'l124', 'l134', 'l140', 'l146', 'l151', 'l155', 'l157', 'l158', 'l159']", + "186, beta ['l160', 'l161', 'l162', 'l163']", + "187, cells ['l160', 'l164', 'l165', 'l166']", + "189, Gipr(-/-βCell) ['l161', 'l164', 'l167', 'l168', 'l169']", + "190, mice ['l162', 'l165', 'l167', 'l170']", + "196, cells ['l141', 'l147', 'l152', 'l159', 'l163', 'l166', 'l168', 'l170']", + "204, Tcf7(-/-) ['l171']", + "205, mice ['l169', 'l171']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "ablation", + "of", + "GIPR", + "in", + "beta", + "cells", + "(MIP-Cre:Gipr(Flox/Flox);", + "Gipr(-/-βCell))", + "Gipr(-/-βCell)", + "Tcf7(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "ablation", + "of", + "GIPR", + "in", + "beta", + "cells", + "(MIP-Cre:Gipr(Flox/Flox);", + "Gipr(-/-βCell))", + "Gipr(-/-βCell)" + ] + }, + "context": { + "val": "cells", + "words": [ + "Beta", + "cells", + "human", + "and", + "mouse", + "islets", + "beta" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "ablation", + "of", + "GIPR", + "in", + "beta", + "cells", + "(MIP-Cre:Gipr(Flox/Flox);", + "Gipr(-/-βCell))", + "Gipr(-/-βCell)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "greater", + "sensitivity" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "ablation", + "of", + "GIPR", + "in", + "(MIP-Cre:Gipr(Flox/Flox);", + "Gipr(-/-βCell)" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "cells" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Beta", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "greater", + "sensitivity" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Beta", + "cells", + "human", + "and", + "mouse", + "islets", + "beta" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "cells" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "greater", + "sensitivity" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "greater", + "sensitivity" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "TCF7" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "and", + "mouse", + "islets" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "TCF7" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "26594844", + "TEXT": "The nervous system is vulnerable to perturbations during specific developmental periods. Insults during such susceptible time windows can have long-term consequences, including the development of neurological diseases such as epilepsy. Here we report that a pharmacological intervention timed during a vulnerable neonatal period of cortical development prevents pathology in a genetic epilepsy model. By using mice with dysfunctional Kv7 voltage-gated K(+) channels, which are mutated in human neonatal epilepsy syndromes, we demonstrate the safety and efficacy of the sodium-potassium-chloride cotransporter NKCC1 antagonist bumetanide, which was administered during the first two postnatal weeks. In Kv7 current-deficient mice, which normally display epilepsy, hyperactivity and stereotypies as adults, transient bumetanide treatment normalized neonatal in vivo cortical network and hippocampal neuronal activity, prevented structural damage in the hippocampus and restored wild-type adult behavioral phenotypes. Furthermore, bumetanide treatment did not adversely affect control mice. These results suggest that in individuals with disease susceptibility, timing prophylactically safe interventions to specific windows during development may prevent or arrest disease progression.", + "TAG_DATA": [ + "55, mice {'context': 'B-organism'}", + "93, Kv7 {'perturbing_action': 'B-gene loss-of-function'}", + "94, current-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "95, mice, {'context': 'B-organism'}", + "110, in {'context': 'B-in vivo'}", + "111, vivo {'context': 'I-in vivo'}", + "115, hippocampal {'context': 'B-cells'}", + "123, hippocampus {'context': 'B-tissue/organ'}", + "138, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "93, Kv7 ['l0', 'l1', 'l2', 'l3', 'l4']", + "94, current-deficient ['l0', 'l5', 'l6', 'l7', 'l8']", + "95, mice, ['l1', 'l5', 'l9', 'l10']", + "110, in ['l2', 'l6', 'l11', 'l12']", + "111, vivo ['l3', 'l7', 'l9', 'l11', 'l13']", + "115, hippocampal ['l4', 'l8', 'l10', 'l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Kv7", + "current-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Kv7", + "current-deficient" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Kv7", + "current-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "hippocampal" + ] + } + } + ] + }, + { + "PMID": "26594843", + "TEXT": "Acute myeloid leukemia (AML) is mostly driven by oncogenic transcription factors, which have been classically viewed as intractable targets using small-molecule inhibitor approaches. Here we demonstrate that AML driven by repressive transcription factors, including AML1-ETO (encoded by the fusion oncogene RUNX1-RUNX1T1) and PML-RARα fusion oncoproteins (encoded by PML-RARA) are extremely sensitive to poly (ADP-ribose) polymerase (PARP) inhibition, in part owing to their suppressed expression of key homologous recombination (HR)-associated genes and their compromised DNA-damage response (DDR). In contrast, leukemia driven by mixed-lineage leukemia (MLL, encoded by KMT2A) fusions with dominant transactivation ability is proficient in DDR and insensitive to PARP inhibition. Intriguingly, genetic or pharmacological inhibition of an MLL downstream target, HOXA9, which activates expression of various HR-associated genes, impairs DDR and sensitizes MLL leukemia to PARP inhibitors (PARPis). Conversely, HOXA9 overexpression confers PARPi resistance to AML1-ETO and PML-RARα transformed cells. Together, these studies describe a potential utility of PARPi-induced synthetic lethality for leukemia treatment and reveal a novel molecular mechanism governing PARPi sensitivity in AML.", + "TAG_DATA": [ + "104, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "105, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "106, of {'perturbing_action': 'I-pharmacological inhibition'}", + "107, an {'perturbing_action': 'I-pharmacological inhibition'}", + "108, MLL {'perturbing_action': 'I-pharmacological inhibition'}", + "109, downstream {'perturbing_action': 'I-pharmacological inhibition'}", + "110, target, {'perturbing_action': 'I-pharmacological inhibition'}", + "111, HOXA9, {'perturbing_action': 'I-pharmacological inhibition'}", + "123, MLL {'context': 'B-neoplasm'}", + "124, leukemia {'context': 'I-neoplasm'}", + "130, HOXA9 {'perturbing_action': 'B-gene gain-of-function'}", + "131, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "139, transformed {'phenotype': 'B-transformation'}", + "140, cells. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "104, pharmacological ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "105, inhibition ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "106, of ['l1', 'l11', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "107, an ['l2', 'l12', 'l19', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "108, MLL ['l3', 'l13', 'l20', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "109, downstream ['l4', 'l14', 'l21', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "110, target, ['l5', 'l15', 'l22', 'l30', 'l35', 'l39', 'l45', 'l46', 'l47']", + "111, HOXA9, ['l6', 'l16', 'l23', 'l31', 'l36', 'l40', 'l45', 'l48', 'l49']", + "123, MLL ['l7', 'l17', 'l24', 'l32', 'l37', 'l41', 'l46', 'l48', 'l50']", + "124, leukemia ['l8', 'l18', 'l25', 'l33', 'l38', 'l42', 'l47', 'l49', 'l50']", + "130, HOXA9 ['l51', 'l52', 'l53', 'l54']", + "131, overexpression ['l51', 'l55', 'l56', 'l57']", + "138, PML-RARα ['l52', 'l55', 'l58', 'l59']", + "139, transformed ['l9', 'l26', 'l43', 'l53', 'l56', 'l58', 'l60']", + "140, cells. ['l10', 'l27', 'l44', 'l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "an", + "MLL", + "downstream", + "target,", + "HOXA9," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "MLL", + "leukemia" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "of", + "downstream" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformed" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "of", + "downstream" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "HOXA9", + "overexpression" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformed" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "HOXA9", + "overexpression" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "phenotype": { + "val": "transformation", + "words": [ + "transformed" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "26569382", + "TEXT": "Primary myelofibrosis (PMF) is characterized by bone marrow fibrosis, myeloproliferation, extramedullary hematopoiesis, splenomegaly and leukemic progression. Moreover, the bone marrow and spleens of individuals with PMF contain large numbers of atypical megakaryocytes that are postulated to contribute to fibrosis through the release of cytokines, including transforming growth factor (TGF)-β. Although the Janus kinase inhibitor ruxolitinib provides symptomatic relief, it does not reduce the mutant allele burden or substantially reverse fibrosis. Here we show through pharmacologic and genetic studies that aurora kinase A (AURKA) represents a new therapeutic target in PMF. Treatment with MLN8237, a selective AURKA inhibitor, promoted polyploidization and differentiation of megakaryocytes with PMF-associated mutations and had potent antifibrotic and antitumor activity in vivo in mouse models of PMF. Moreover, heterozygous deletion of Aurka was sufficient to ameliorate fibrosis and other PMF features in vivo. Our data suggest that megakaryocytes drive fibrosis in PMF and that targeting them with AURKA inhibitors has the potential to provide therapeutic benefit.", + "TAG_DATA": [ + "92, MLN8237, {'perturbing_action': 'B-pharmacological inhibition'}", + "93, a {'perturbing_action': 'I-pharmacological inhibition'}", + "94, selective {'perturbing_action': 'I-pharmacological inhibition'}", + "95, AURKA {'perturbing_action': 'I-pharmacological inhibition'}", + "96, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "97, promoted {'effect': 'B-positive'}", + "100, differentiation {'phenotype': 'B-differentiation'}", + "102, megakaryocytes {'context': 'B-cells'}", + "113, in {'context': 'B-in vivo'}", + "114, vivo {'context': 'I-in vivo'}", + "116, mouse {'context': 'B-organism'}", + "117, models {'context': 'I-organism'}", + "118, of {'context': 'I-organism'}", + "119, PMF. {'context': 'I-organism'}", + "121, heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "122, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "123, of {'perturbing_action': 'I-gene loss-of-function'}", + "124, Aurka {'perturbing_action': 'I-gene loss-of-function'}", + "134, in {'context': 'B-in vivo'}", + "135, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "92, MLN8237, ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "93, a ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "94, selective ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "95, AURKA ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "96, inhibitor, ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "97, promoted ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "100, differentiation ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "102, megakaryocytes ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "113, in ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "114, vivo ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "116, mouse ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "117, models ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "118, of ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "119, PMF. ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']", + "121, heterozygous ['l91', 'l92', 'l93', 'l94', 'l95']", + "122, deletion ['l91', 'l96', 'l97', 'l98', 'l99']", + "123, of ['l92', 'l96', 'l100', 'l101', 'l102']", + "124, Aurka ['l93', 'l97', 'l100', 'l103', 'l104']", + "134, in ['l94', 'l98', 'l101', 'l103', 'l105']", + "135, vivo. ['l95', 'l99', 'l102', 'l104', 'l105']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "MLN8237,", + "a", + "selective", + "AURKA", + "inhibitor," + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "MLN8237,", + "a", + "selective", + "AURKA", + "inhibitor," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "MLN8237,", + "a", + "selective", + "AURKA", + "inhibitor," + ] + }, + "context": { + "val": "cells", + "words": [ + "megakaryocytes" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "MLN8237,", + "a", + "selective", + "AURKA", + "inhibitor," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "MLN8237,", + "a", + "selective", + "AURKA", + "inhibitor," + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "of", + "PMF." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "cells", + "words": [ + "megakaryocytes" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "of", + "PMF." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "megakaryocytes" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "of", + "PMF." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "heterozygous", + "deletion", + "of", + "Aurka" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "26552009", + "TEXT": "Human cancer genome sequencing has recently revealed that genes that encode subunits of SWI/SNF chromatin remodeling complexes are frequently mutated across a wide variety of cancers, and several subunits of the complex have been shown to have bona fide tumor suppressor activity. However, whether mutations in SWI/SNF subunits result in shared dependencies is unknown. Here we show that EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), is essential in all tested cancer cell lines and xenografts harboring mutations of the SWI/SNF subunits ARID1A, PBRM1, and SMARCA4, which are several of the most frequently mutated SWI/SNF subunits in human cancer, but that co-occurrence of a Ras pathway mutation is correlated with abrogation of this dependence. Notably, we demonstrate that SWI/SNF-mutant cancer cells are primarily dependent on a non-catalytic role of EZH2 in the stabilization of the PRC2 complex, and that they are only partially dependent on EZH2 histone methyltransferase activity. These results not only reveal a shared dependency of cancers with genetic alterations in SWI/SNF subunits, but also suggest that EZH2 enzymatic inhibitors now in clinical development may not fully suppress the oncogenic activity of EZH2.", + "TAG_DATA": [ + "74, cancer {'context': 'B-transformed cells'}", + "75, cell {'context': 'I-transformed cells'}", + "76, lines {'context': 'I-transformed cells'}", + "78, xenografts {'context': 'B-xenograft'}", + "122, cancer {'context': 'B-transformed cells'}", + "123, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "74, cancer ['l0', 'l1']", + "75, cell ['l0', 'l2']", + "76, lines ['l1', 'l2']", + "122, cancer ['l3']", + "123, cells ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26540383", + "TEXT": "Neutralization breadth is thought to be an important feature of an effective vaccine against HIV-1. A study in one individual has now identified the specific viral variant that engaged the necessary antibody precursor, as well as the viral immunotypes that drove neutralization breadth, improving understanding of how to mimic this process with a vaccine.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "26479922", + "TEXT": "The skin harbors a variety of resident leukocyte subsets that must be tightly regulated to maintain immune homeostasis. Hair follicles are unique structures in the skin that contribute to skin dendritic cell homeostasis through chemokine production. We demonstrate that CD4(+) and CD8(+) skin-resident memory T cells (TRM cells), which are responsible for long-term skin immunity, reside predominantly within the hair follicle epithelium of the unperturbed epidermis. TRM cell tropism for the epidermis and follicles is herein termed epidermotropism. Hair follicle expression of IL-15 was required for CD8(+) TRM cells, and IL-7 for CD8(+) and CD4(+) TRM cells, to exert epidermotropism. A lack of either cytokine in the skin led to impaired hapten-induced contact hypersensitivity responses. In a model of cutaneous T cell lymphoma, epidermotropic CD4(+) TRM lymphoma cell localization depended on the presence of hair follicle-derived IL-7. These findings implicate hair follicle-derived cytokines as regulators of malignant and non-malignant TRM cell tissue residence, and they suggest that the cytokines may be targeted therapeutically in inflammatory skin diseases and lymphoma.", + "TAG_DATA": [ + "92, CD8(+) {'context': 'B-cells'}", + "93, and {'context': 'I-cells'}", + "94, CD4(+) {'context': 'I-cells'}", + "95, TRM {'context': 'I-cells'}", + "96, cells, {'context': 'I-cells'}", + "125, TRM {'context': 'I-transformed cells'}", + "126, lymphoma {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "92, CD8(+) ['l0', 'l1', 'l2', 'l3']", + "93, and ['l0', 'l4', 'l5', 'l6']", + "94, CD4(+) ['l1', 'l4', 'l7', 'l8']", + "95, TRM ['l2', 'l5', 'l7', 'l9']", + "96, cells, ['l3', 'l6', 'l8', 'l9']", + "124, CD4(+) ['l10', 'l11']", + "125, TRM ['l10', 'l12']", + "126, lymphoma ['l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26479921", + "TEXT": "Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive neoplasm characterized by a marked fibro-inflammatory microenvironment, the presence of which can promote both cancer induction and growth. Therefore, selective manipulation of local cytokines is an attractive, although unrealized, therapeutic approach. T cells possess a unique mechanism of p38 mitogen-activated protein kinase (MAPK) activation downstream of T cell receptor (TCR) engagement through the phosphorylation of Tyr323 (pY323). This alternative p38 activation pathway is required for pro-inflammatory cytokine production. Here we show in human PDAC that a high percentage of infiltrating pY323(+) T cells was associated with large numbers of tumor necrosis factor (TNF)-α- and interleukin (IL)-17-producing CD4(+) tumor-infiltrating lymphocytes (TILs) and aggressive disease. The growth of mouse pancreatic tumors was inhibited by genetic ablation of the alternative p38 pathway, and transfer of wild-type CD4(+) T cells, but not those lacking the alternative pathway, enhanced tumor growth in T cell-deficient mice. Notably, a plasma membrane-permeable peptide derived from GADD45-α, the naturally occurring inhibitor of p38 pY323(+) (ref. 7), reduced CD4(+) TIL production of TNF-α, IL-17A, IL-10 and secondary cytokines, halted growth of implanted tumors and inhibited progression of spontaneous KRAS-driven adenocarcinoma in mice. Thus, TCR-mediated activation of CD4(+) TILs results in alternative p38 activation and production of protumorigenic factors and can be targeted for therapeutic benefit.", + "TAG_DATA": [ + "114, mouse {'context': 'B-neoplasm'}", + "115, pancreatic {'context': 'I-neoplasm'}", + "116, tumors {'context': 'I-neoplasm'}", + "120, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "121, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "122, of {'perturbing_action': 'I-gene loss-of-function'}", + "123, the {'perturbing_action': 'I-gene loss-of-function'}", + "124, alternative {'perturbing_action': 'I-gene loss-of-function'}", + "125, p38 {'perturbing_action': 'I-gene loss-of-function'}", + "126, pathway, {'perturbing_action': 'I-gene loss-of-function'}", + "131, CD4(+) {'context': 'B-cells'}", + "132, T {'context': 'I-cells'}", + "133, cells, {'context': 'I-cells'}", + "141, enhanced {'effect': 'B-positive'}", + "142, tumor {'phenotype': 'B-tumour growth'}", + "143, growth {'phenotype': 'I-tumour growth'}", + "145, T {'perturbing_action': 'B-gene loss-of-function'}", + "146, cell-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "147, mice. {'context': 'B-organism'}", + "166, CD4(+) {'context': 'B-cells'}", + "167, TIL {'context': 'I-cells'}", + "180, tumors {'context': 'I-xenograft'}", + "186, KRAS-driven {'perturbing_action': 'B-other', 'context': 'B-neoplasm'}", + "187, adenocarcinoma {'context': 'I-neoplasm'}", + "189, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "114, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "115, pancreatic ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "116, tumors ['l1', 'l9', 'l17']", + "120, genetic ['l2', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "121, ablation ['l3', 'l11', 'l18', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "122, of ['l4', 'l12', 'l19', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "123, the ['l5', 'l13', 'l20', 'l27', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "124, alternative ['l6', 'l14', 'l21', 'l28', 'l34', 'l40', 'l47', 'l48', 'l49', 'l50']", + "125, p38 ['l7', 'l15', 'l22', 'l29', 'l35', 'l41', 'l47', 'l51', 'l52', 'l53', 'l54']", + "126, pathway, ['l8', 'l16', 'l17', 'l23', 'l30', 'l36', 'l42', 'l48', 'l51', 'l55']", + "131, CD4(+) ['l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "132, T ['l56', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "133, cells, ['l57', 'l65', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "141, enhanced ['l37', 'l43', 'l52', 'l58', 'l66', 'l73', 'l79', 'l80', 'l81', 'l82', 'l83']", + "142, tumor ['l24', 'l31', 'l38', 'l44', 'l49', 'l53', 'l59', 'l67', 'l74', 'l79', 'l84', 'l85', 'l86', 'l87']", + "143, growth ['l25', 'l32', 'l39', 'l45', 'l50', 'l54', 'l55', 'l60', 'l68', 'l75', 'l80', 'l84', 'l88', 'l89', 'l90']", + "145, T ['l61', 'l69', 'l76', 'l81', 'l85', 'l88', 'l91', 'l92']", + "146, cell-deficient ['l46', 'l62', 'l70', 'l77', 'l82', 'l86', 'l89', 'l91', 'l93']", + "147, mice. ['l63', 'l71', 'l78', 'l83', 'l87', 'l90', 'l92', 'l93']", + "166, CD4(+) ['l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "167, TIL ['l94', 'l100', 'l101', 'l102', 'l103', 'l104']", + "179, implanted ['l95', 'l100', 'l105', 'l106']", + "180, tumors ['l64', 'l72', 'l96', 'l101', 'l105']", + "186, KRAS-driven ['l97', 'l102', 'l107', 'l108']", + "187, adenocarcinoma ['l98', 'l103', 'l106', 'l107', 'l109']", + "189, mice. ['l99', 'l104', 'l108', 'l109']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "pancreatic", + "tumors" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "the", + "alternative", + "p38", + "pathway," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "the", + "alternative", + "p38", + "pathway,", + "T", + "cell-deficient" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "the", + "p38", + "T", + "cell-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cells," + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cells," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cells," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "T", + "cell-deficient" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "T", + "cell-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "TIL" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "KRAS-driven" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "KRAS-driven" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "KRAS-driven" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "KRAS-driven" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "26437366", + "TEXT": "The tumor suppressors BAP1 and ASXL1 interact to form a polycomb deubiquitinase complex that removes monoubiquitin from histone H2A lysine 119 (H2AK119Ub). However, BAP1 and ASXL1 are mutated in distinct cancer types, consistent with independent roles in regulating epigenetic state and malignant transformation. Here we demonstrate that Bap1 loss in mice results in increased trimethylated histone H3 lysine 27 (H3K27me3), elevated enhancer of zeste 2 polycomb repressive complex 2 subunit (Ezh2) expression, and enhanced repression of polycomb repressive complex 2 (PRC2) targets. These findings contrast with the reduction in H3K27me3 levels seen with Asxl1 loss. Conditional deletion of Bap1 and Ezh2 in vivo abrogates the myeloid progenitor expansion induced by Bap1 loss alone. Loss of BAP1 results in a marked decrease in H4K20 monomethylation (H4K20me1). Consistent with a role for H4K20me1 in the transcriptional regulation of EZH2, expression of SETD8-the H4K20me1 methyltransferase-reduces EZH2 expression and abrogates the proliferation of BAP1-mutant cells. Furthermore, mesothelioma cells that lack BAP1 are sensitive to EZH2 pharmacologic inhibition, suggesting a novel therapeutic approach for BAP1-mutant malignancies.", + "TAG_DATA": [ + "47, Bap1 {'perturbing_action': 'B-gene loss-of-function'}", + "48, loss {'perturbing_action': 'I-gene loss-of-function'}", + "50, mice {'context': 'B-organism'}", + "93, Asxl1 {'perturbing_action': 'B-gene loss-of-function'}", + "94, loss. {'perturbing_action': 'I-gene loss-of-function'}", + "95, Conditional {'perturbing_action': 'B-gene loss-of-function'}", + "96, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "97, of {'perturbing_action': 'I-gene loss-of-function'}", + "98, Bap1 {'perturbing_action': 'I-gene loss-of-function'}", + "99, and {'perturbing_action': 'I-gene loss-of-function'}", + "100, Ezh2 {'perturbing_action': 'I-gene loss-of-function'}", + "101, in {'context': 'B-in vivo'}", + "102, vivo {'context': 'I-in vivo'}", + "105, myeloid {'context': 'B-cells'}", + "106, progenitor {'context': 'I-cells'}", + "110, Bap1 {'perturbing_action': 'B-gene loss-of-function'}", + "111, loss {'perturbing_action': 'I-gene loss-of-function'}", + "113, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "114, of {'perturbing_action': 'I-gene loss-of-function'}", + "115, BAP1 {'perturbing_action': 'I-gene loss-of-function'}", + "145, abrogates {'effect': 'B-negative'}", + "147, proliferation {'phenotype': 'B-proliferation'}", + "149, BAP1-mutant {'perturbing_action': 'B-other'}", + "150, cells. {'context': 'B-cells'}", + "152, mesothelioma {'context': 'B-transformed cells'}", + "153, cells {'context': 'I-transformed cells'}", + "155, lack {'perturbing_action': 'B-gene loss-of-function'}", + "156, BAP1 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "47, Bap1 ['l0', 'l1', 'l2', 'l3']", + "48, loss ['l0', 'l4', 'l5', 'l6']", + "50, mice ['l1', 'l4']", + "93, Asxl1 ['l2', 'l5', 'l7']", + "94, loss. ['l3', 'l6', 'l7']", + "95, Conditional ['l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "96, deletion ['l8', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "97, of ['l9', 'l22', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "98, Bap1 ['l10', 'l23', 'l38', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "99, and ['l11', 'l24', 'l39', 'l48', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "100, Ezh2 ['l12', 'l25', 'l40', 'l49', 'l56', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "101, in ['l13', 'l26', 'l41', 'l50', 'l57', 'l63', 'l69', 'l70', 'l71', 'l72', 'l73']", + "102, vivo ['l14', 'l27', 'l42', 'l51', 'l58', 'l64', 'l69', 'l74', 'l75', 'l76', 'l77']", + "105, myeloid ['l15', 'l28', 'l43', 'l52', 'l59', 'l65', 'l70', 'l74', 'l78', 'l79', 'l80']", + "106, progenitor ['l16', 'l29', 'l44', 'l53', 'l60', 'l66', 'l71', 'l75', 'l78', 'l81', 'l82']", + "110, Bap1 ['l17', 'l30', 'l45', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l81', 'l83']", + "111, loss ['l18', 'l31', 'l46', 'l55', 'l62', 'l68', 'l73', 'l77', 'l80', 'l82', 'l83']", + "113, Loss ['l19', 'l32', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "114, of ['l33', 'l84', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "115, BAP1 ['l20', 'l34', 'l85', 'l90', 'l96', 'l97', 'l98', 'l99']", + "145, abrogates ['l21', 'l35', 'l47', 'l86', 'l91', 'l96', 'l100', 'l101', 'l102']", + "147, proliferation ['l36', 'l87', 'l92', 'l97', 'l100', 'l103', 'l104']", + "149, BAP1-mutant ['l88', 'l93', 'l98', 'l101', 'l103', 'l105']", + "150, cells. ['l37', 'l89', 'l94', 'l99', 'l102', 'l104', 'l105']", + "152, mesothelioma ['l106', 'l107', 'l108']", + "153, cells ['l95', 'l106', 'l109', 'l110']", + "155, lack ['l107', 'l109', 'l111']", + "156, BAP1 ['l108', 'l110', 'l111']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bap1", + "loss" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "deletion", + "of", + "Bap1", + "and", + "Ezh2", + "loss" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "deletion", + "of", + "Bap1", + "and", + "Ezh2", + "loss", + "Loss", + "BAP1" + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "progenitor", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "deletion", + "of", + "Loss", + "BAP1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "Loss", + "of", + "BAP1" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "lack", + "BAP1" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells", + "mesothelioma" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "BAP1-mutant" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "BAP1-mutant" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BAP1-mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "26437365", + "TEXT": "The hepatic low-density lipoprotein receptor (LDLR) pathway is essential for clearing circulating LDL cholesterol (LDL-C). Whereas the transcriptional regulation of LDLR is well characterized, the post-transcriptional mechanisms that govern LDLR expression are just beginning to emerge. Here we develop a high-throughput genome-wide screening assay to systematically identify microRNAs (miRNAs) that regulate LDLR activity in human hepatic cells. From this screen we identified and characterized miR-148a as a negative regulator of LDLR expression and activity and defined a sterol regulatory element-binding protein 1 (SREBP1)-mediated pathway through which miR-148a regulates LDL-C uptake. In mice, inhibition of miR-148a increased hepatic LDLR expression and decreased plasma LDL-C. Moreover, we found that miR-148a regulates hepatic expression of ATP-binding cassette, subfamily A, member 1 (ABCA1) and circulating high-density lipoprotein cholesterol (HDL-C) levels in vivo. These studies uncover a role for miR-148a as a key regulator of hepatic LDL-C clearance through direct modulation of LDLR expression and demonstrate the therapeutic potential of inhibiting miR-148a to ameliorate an elevated LDL-C/HDL-C ratio, a prominent risk factor for cardiovascular disease.", + "TAG_DATA": [ + "91, mice, {'context': 'B-organism'}", + "92, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "93, of {'perturbing_action': 'I-pharmacological inhibition'}", + "94, miR-148a {'perturbing_action': 'I-pharmacological inhibition'}", + "126, in {'context': 'B-in vivo'}", + "127, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "92, inhibition ['l0', 'l1']", + "93, of ['l0', 'l2']", + "94, miR-148a ['l1', 'l2']", + "126, in ['l3']", + "127, vivo. ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26398868", + "TEXT": "The vast majority of disease-associated single-nucleotide polymorphisms (SNPs) mapped by genome-wide association studies (GWASs) are located in the non-protein-coding genome, but establishing the functional and mechanistic roles of these sequence variants has proven challenging. Here we describe a general pipeline in which candidate functional SNPs are first evaluated by fine mapping, epigenomic profiling, and epigenome editing, and then interrogated for causal function by using genome editing to create isogenic cell lines followed by phenotypic characterization. To validate this approach, we analyzed the 6q22.1 prostate cancer risk locus and identified rs339331 as the top-scoring SNP. Epigenome editing confirmed that the rs339331 region possessed regulatory potential. By using transcription activator-like effector nuclease (TALEN)-mediated genome editing, we created a panel of isogenic 22Rv1 prostate cancer cell lines representing all three genotypes (TT, TC, CC) at rs339331. Introduction of the 'T' risk allele increased transcription of the regulatory factor 6 (RFX6) gene, increased homeobox B13 (HOXB13) binding at the rs339331 region, and increased deposition of the enhancer-associated H3K4me2 histone mark at the rs339331 region compared to lines homozygous for the 'C' protective allele. The cell lines also differed in cellular morphology and adhesion, and pathway analysis of differentially expressed genes suggested an influence of androgens. In summary, we have developed and validated a widely accessible approach that can be used to establish functional causality for noncoding sequence variants identified by GWASs.", + "TAG_DATA": [ + "120, prostate {'context': 'B-transformed cells'}", + "121, cancer {'context': 'I-transformed cells'}", + "122, cell {'context': 'I-transformed cells'}", + "123, lines {'context': 'I-transformed cells'}", + "180, cell {'context': 'B-cells'}", + "181, lines {'context': 'I-cells'}", + "188, adhesion, {'phenotype': 'B-adhesion'}" + ], + "LINK_DATA": [ + "120, prostate ['l0', 'l1', 'l2']", + "121, cancer ['l0', 'l3', 'l4']", + "122, cell ['l1', 'l3', 'l5']", + "123, lines ['l2', 'l4', 'l5']", + "180, cell ['l6', 'l7']", + "181, lines ['l6', 'l8']", + "188, adhesion, ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cell", + "lines" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + } + ] + }, + { + "PMID": "26390244", + "TEXT": "Activating mutations in NOTCH1 are common in T cell acute lymphoblastic leukemia (T-ALL). Here we identify glutaminolysis as a critical pathway for leukemia cell growth downstream of NOTCH1 and a key determinant of the response to anti-NOTCH1 therapies in vivo. Mechanistically, inhibition of NOTCH1 signaling in T-ALL induces a metabolic shutdown, with prominent inhibition of glutaminolysis and triggers autophagy as a salvage pathway supporting leukemia cell metabolism. Consequently, inhibition of glutaminolysis and inhibition of autophagy strongly and synergistically enhance the antileukemic effects of anti-NOTCH1 therapy in mice harboring T-ALL. Moreover, we demonstrate that Pten loss upregulates glycolysis and consequently rescues leukemic cell metabolism, thereby abrogating the antileukemic effects of NOTCH1 inhibition. Overall, these results identify glutaminolysis as a major node in cancer metabolism controlled by NOTCH1 and as therapeutic target for the treatment of T-ALL.", + "TAG_DATA": [ + "46, T-ALL {'context': 'B-neoplasm'}", + "57, triggers {'effect': 'B-positive'}", + "58, autophagy {'phenotype': 'B-autophagy'}", + "64, leukemia {'context': 'B-transformed cells'}", + "72, inhibition {'effect': 'B-negative'}", + "86, mice {'context': 'B-organism'}", + "88, T-ALL. {'context': 'B-neoplasm'}", + "93, Pten {'perturbing_action': 'B-gene loss-of-function'}", + "94, loss {'perturbing_action': 'I-gene loss-of-function'}", + "100, leukemic {'context': 'B-cells'}", + "101, cell {'context': 'I-cells'}", + "109, NOTCH1 {'perturbing_action': 'B-pharmacological inhibition'}", + "110, inhibition. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "46, T-ALL ['l0', 'l1', 'l2']", + "57, triggers ['l0', 'l3', 'l4']", + "58, autophagy ['l1', 'l3', 'l5']", + "64, leukemia ['l2', 'l4', 'l5']", + "72, inhibition ['l6', 'l7']", + "86, mice ['l6', 'l8']", + "88, T-ALL. ['l7', 'l8']", + "93, Pten ['l9', 'l10', 'l11', 'l12', 'l13']", + "94, loss ['l9', 'l14', 'l15', 'l16', 'l17']", + "100, leukemic ['l10', 'l14', 'l18', 'l19', 'l20']", + "101, cell ['l11', 'l15', 'l18', 'l21', 'l22']", + "109, NOTCH1 ['l12', 'l16', 'l19', 'l21', 'l23']", + "110, inhibition. ['l13', 'l17', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "T-ALL" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "T-ALL" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "leukemia" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "leukemia" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "T-ALL." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pten", + "loss" + ] + }, + "context": { + "val": "cells", + "words": [ + "leukemic", + "cell" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "leukemic", + "cell" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NOTCH1", + "inhibition." + ] + } + } + ] + }, + { + "PMID": "26366712", + "TEXT": "Mutations in the gene encoding the KMT2D (or MLL2) methyltransferase are highly recurrent and occur early during tumorigenesis in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). However, the functional consequences of these mutations and their role in lymphomagenesis are unknown. Here we show that FL- and DLBCL-associated KMT2D mutations impair KMT2D enzymatic activity, leading to diminished global H3K4 methylation in germinal-center (GC) B cells and DLBCL cells. Conditional deletion of Kmt2d early during B cell development, but not after initiation of the GC reaction, results in an increase in GC B cells and enhances B cell proliferation in mice. Moreover, genetic ablation of Kmt2d in mice overexpressing Bcl2 increases the incidence of GC-derived lymphomas resembling human tumors. These findings suggest that KMT2D acts as a tumor suppressor gene whose early loss facilitates lymphomagenesis by remodeling the epigenetic landscape of the cancer precursor cells. Eradication of KMT2D-deficient cells may thus represent a rational therapeutic approach for targeting early tumorigenic events.", + "TAG_DATA": [ + "66, cells {'context': 'I-cells'}", + "68, DLBCL {'context': 'B-transformed cells'}", + "69, cells. {'context': 'I-transformed cells'}", + "70, Conditional {'perturbing_action': 'B-gene loss-of-function'}", + "71, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "72, of {'perturbing_action': 'I-gene loss-of-function'}", + "73, Kmt2d {'perturbing_action': 'I-gene loss-of-function'}", + "92, GC {'context': 'B-transformed cells'}", + "93, B {'context': 'I-transformed cells'}", + "94, cells {'context': 'I-transformed cells'}", + "96, enhances {'effect': 'B-positive'}", + "97, B {'context': 'B-cells'}", + "98, cell {'context': 'I-cells'}", + "99, proliferation {'phenotype': 'B-proliferation'}", + "101, mice. {'context': 'B-organism'}", + "103, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "104, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "105, of {'perturbing_action': 'I-gene loss-of-function'}", + "106, Kmt2d {'perturbing_action': 'I-gene loss-of-function'}", + "108, mice {'context': 'B-organism'}", + "109, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "110, Bcl2 {'perturbing_action': 'I-gene gain-of-function'}", + "115, GC-derived {'context': 'B-neoplasm'}", + "116, lymphomas {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "65, B ['l0', 'l1', 'l2']", + "66, cells ['l0', 'l3', 'l4']", + "68, DLBCL ['l1', 'l3', 'l5']", + "69, cells. ['l2', 'l4', 'l5']", + "70, Conditional ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "71, deletion ['l6', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "72, of ['l7', 'l17', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "73, Kmt2d ['l8', 'l18', 'l27', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "92, GC ['l9', 'l19', 'l28', 'l36', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "93, B ['l10', 'l20', 'l29', 'l37', 'l44', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "94, cells ['l11', 'l21', 'l30', 'l38', 'l45', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "96, enhances ['l12', 'l22', 'l31', 'l39', 'l46', 'l52', 'l57', 'l62', 'l63', 'l64', 'l65']", + "97, B ['l13', 'l23', 'l32', 'l40', 'l47', 'l53', 'l58', 'l62', 'l66', 'l67', 'l68']", + "98, cell ['l14', 'l24', 'l33', 'l41', 'l48', 'l54', 'l59', 'l63', 'l66', 'l69', 'l70']", + "99, proliferation ['l15', 'l25', 'l34', 'l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l71']", + "101, mice. ['l16', 'l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l71']", + "103, genetic ['l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "104, ablation ['l72', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "105, of ['l73', 'l80', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "106, Kmt2d ['l74', 'l81', 'l87', 'l93', 'l94', 'l95', 'l96', 'l97']", + "108, mice ['l75', 'l82', 'l88', 'l93', 'l98', 'l99', 'l100', 'l101']", + "109, overexpressing ['l76', 'l83', 'l89', 'l94', 'l98', 'l102', 'l103', 'l104']", + "110, Bcl2 ['l77', 'l84', 'l90', 'l95', 'l99', 'l102', 'l105', 'l106']", + "115, GC-derived ['l78', 'l85', 'l91', 'l96', 'l100', 'l103', 'l105', 'l107']", + "116, lymphomas ['l79', 'l86', 'l92', 'l97', 'l101', 'l104', 'l106', 'l107']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "deletion", + "of", + "Kmt2d" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "GC", + "B", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "deletion", + "of", + "Kmt2d" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "deletion", + "of", + "Kmt2d" + ] + }, + "context": { + "val": "cells", + "words": [ + "B", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "deletion", + "of", + "Kmt2d" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "deletion", + "of", + "Kmt2d", + "genetic", + "ablation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "GC", + "B", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "GC", + "B", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "context": { + "val": "cells", + "words": [ + "B", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "B", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "Kmt2d" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "GC-derived", + "lymphomas" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "Bcl2" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "Bcl2" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "GC-derived", + "lymphomas" + ] + } + } + ] + }, + { + "PMID": "26366710", + "TEXT": "The gene encoding the lysine-specific histone methyltransferase KMT2D has emerged as one of the most frequently mutated genes in follicular lymphoma and diffuse large B cell lymphoma; however, the biological consequences of KMT2D mutations on lymphoma development are not known. Here we show that KMT2D functions as a bona fide tumor suppressor and that its genetic ablation in B cells promotes lymphoma development in mice. KMT2D deficiency also delays germinal center involution and impedes B cell differentiation and class switch recombination. Integrative genomic analyses indicate that KMT2D affects methylation of lysine 4 on histone H3 (H3K4) and expression of a set of genes, including those in the CD40, JAK-STAT, Toll-like receptor and B cell receptor signaling pathways. Notably, other KMT2D target genes include frequently mutated tumor suppressor genes such as TNFAIP3, SOCS3 and TNFRSF14. Therefore, KMT2D mutations may promote malignant outgrowth by perturbing the expression of tumor suppressor genes that control B cell-activating pathways.", + "TAG_DATA": [ + "55, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "56, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "58, B {'context': 'B-cells'}", + "59, cells {'context': 'I-cells'}", + "60, promotes {'effect': 'B-positive'}", + "61, lymphoma {'phenotype': 'B-tumourigenesis'}", + "62, development {'phenotype': 'I-tumourigenesis'}", + "64, mice. {'context': 'B-organism'}", + "65, KMT2D {'perturbing_action': 'B-gene loss-of-function'}", + "66, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "73, impedes {'effect': 'B-negative'}", + "74, B {'context': 'B-cells'}", + "75, cell {'context': 'I-cells'}", + "76, differentiation {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "55, genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "56, ablation ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "58, B ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19']", + "59, cells ['l2', 'l9', 'l15', 'l20', 'l21', 'l22', 'l23']", + "60, promotes ['l3', 'l10', 'l16', 'l20', 'l24', 'l25', 'l26']", + "61, lymphoma ['l4', 'l11', 'l17', 'l21', 'l24', 'l27', 'l28']", + "62, development ['l5', 'l12', 'l18', 'l22', 'l25', 'l27', 'l29']", + "64, mice. ['l6', 'l13', 'l19', 'l23', 'l26', 'l28', 'l29']", + "65, KMT2D ['l30', 'l31', 'l32', 'l33', 'l34']", + "66, deficiency ['l30', 'l35', 'l36', 'l37', 'l38']", + "73, impedes ['l31', 'l35', 'l39', 'l40', 'l41']", + "74, B ['l32', 'l36', 'l39', 'l42', 'l43']", + "75, cell ['l7', 'l14', 'l33', 'l37', 'l40', 'l42', 'l44']", + "76, differentiation ['l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "KMT2D", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "B", + "cells", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma", + "development" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "B", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "B", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma", + "development" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma", + "development" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma", + "development" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "KMT2D", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impedes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "KMT2D", + "deficiency" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impedes" + ] + }, + "context": { + "val": "cells", + "words": [ + "B", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impedes" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "B", + "cell" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "26322580", + "TEXT": "Given the variation in the HIV-1 viral load (VL) set point across subjects, as opposed to a fairly stable VL over time within an infected individual, it is important to identify the characteristics of the host and virus that affect VL set point. Although recently infected individuals with multiple phylogenetically linked HIV-1 founder variants represent a minority of HIV-1 infections, we found--n two different cohorts--hat more diverse HIV-1 populations in early infection were associated with significantly higher VL 1 year after HIV-1 diagnosis.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "26301691", + "TEXT": "The antibody response to influenza is primarily focused on the head region of the hemagglutinin (HA) glycoprotein, which in turn undergoes antigenic drift, thus necessitating annual updates of influenza vaccines. In contrast, the immunogenically subdominant stem region of HA is highly conserved and recognized by antibodies capable of binding multiple HA subtypes. Here we report the structure-based development of an H1 HA stem-only immunogen that confers heterosubtypic protection in mice and ferrets. Six iterative cycles of structure-based design (Gen1-Gen6) yielded successive H1 HA stabilized-stem (HA-SS) immunogens that lack the immunodominant head domain. Antigenic characterization, determination of two HA-SS crystal structures in complex with stem-specific monoclonal antibodies and cryo-electron microscopy analysis of HA-SS on ferritin nanoparticles (H1-SS-np) confirmed the preservation of key structural elements. Vaccination of mice and ferrets with H1-SS-np elicited broadly cross-reactive antibodies that completely protected mice and partially protected ferrets against lethal heterosubtypic H5N1 influenza virus challenge despite the absence of detectable H5N1 neutralizing activity in vitro. Passive transfer of immunoglobulin from H1-SS-np-immunized mice to naive mice conferred protection against H5N1 challenge, indicating that vaccine-elicited HA stem-specific antibodies can protect against diverse group 1 influenza strains.", + "TAG_DATA": [ + "69, mice {'context': 'B-organism'}", + "125, mice {'context': 'B-organism'}", + "127, ferrets {'context': 'B-organism'}", + "137, mice {'context': 'B-organism'}", + "141, ferrets {'context': 'B-organism'}", + "157, in {'context': 'B-in vitro'}", + "158, vitro. {'context': 'I-in vitro'}", + "165, mice {'context': 'B-organism'}", + "168, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "125, mice ['l0', 'l1', 'l2']", + "127, ferrets ['l0', 'l3', 'l4']", + "137, mice ['l1', 'l3', 'l5']", + "141, ferrets ['l2', 'l4', 'l5', 'l6', 'l7']", + "157, in ['l6', 'l8']", + "158, vitro. ['l7', 'l8']", + "165, mice ['l9']", + "168, mice ['l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26301688", + "TEXT": "Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ(2) meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico-replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG. The pAID-associated single-nucleotide polymorphisms (SNPs) were functionally enriched for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants. We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "26236989", + "TEXT": "Progressive kidney fibrosis contributes greatly to end-stage renal failure, and no specific treatment is available to preserve organ function. During renal fibrosis, myofibroblasts accumulate in the interstitium of the kidney, leading to massive deposition of extracellular matrix and organ dysfunction. The origin of myofibroblasts is manifold, but the contribution of an epithelial-to-mesenchymal transition (EMT) undergone by renal epithelial cells during kidney fibrosis is still debated. We show that the reactivation of Snai1 (encoding snail family zinc finger 1, known as Snail1) in mouse renal epithelial cells is required for the development of fibrosis in the kidney. Damage-mediated Snail1 reactivation induces a partial EMT in tubular epithelial cells that, without directly contributing to the myofibroblast population, relays signals to the interstitium to promote myofibroblast differentiation and fibrogenesis and to sustain inflammation. We also show that Snail1-induced fibrosis can be reversed in vivo and that obstructive nephropathy can be therapeutically ameliorated in mice by targeting Snail1 expression. These results reconcile conflicting data on the role of the EMT in renal fibrosis and provide avenues for the design of novel anti-fibrotic therapies.", + "TAG_DATA": [ + "82, mouse {'context': 'B-cells'}", + "83, renal {'context': 'I-cells'}", + "84, epithelial {'context': 'I-cells'}", + "85, cells {'context': 'I-cells'}", + "99, induces {'effect': 'B-positive'}", + "102, EMT {'phenotype': 'B-epithelial-mesenchymal transition'}", + "104, tubular {'context': 'B-cells'}", + "105, epithelial {'context': 'I-cells'}", + "106, cells {'context': 'I-cells'}", + "139, in {'context': 'B-in vivo'}", + "140, vivo {'context': 'I-in vivo'}", + "150, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "82, mouse ['l0', 'l1', 'l2']", + "83, renal ['l0', 'l3', 'l4']", + "84, epithelial ['l1', 'l3', 'l5']", + "85, cells ['l2', 'l4', 'l5']", + "99, induces ['l6', 'l7', 'l8', 'l9']", + "102, EMT ['l6', 'l10', 'l11', 'l12']", + "104, tubular ['l7', 'l10', 'l13', 'l14']", + "105, epithelial ['l8', 'l11', 'l13', 'l15']", + "106, cells ['l9', 'l12', 'l14', 'l15']", + "139, in ['l16']", + "140, vivo ['l16']", + "150, mice ['l17']", + "152, targeting ['l17']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EMT" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "cells", + "words": [ + "tubular", + "epithelial", + "cells" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EMT" + ] + }, + "context": { + "val": "cells", + "words": [ + "tubular", + "epithelial", + "cells" + ] + } + } + ] + }, + { + "PMID": "26193342", + "TEXT": "Molecular profiles of tumors and tumor-associated cells hold great promise as biomarkers of clinical outcomes. However, existing data sets are fragmented and difficult to analyze systematically. Here we present a pan-cancer resource and meta-analysis of expression signatures from ∼18,000 human tumors with overall survival outcomes across 39 malignancies. By using this resource, we identified a forkhead box MI (FOXM1) regulatory network as a major predictor of adverse outcomes, and we found that expression of favorably prognostic genes, including KLRB1 (encoding CD161), largely reflect tumor-associated leukocytes. By applying CIBERSORT, a computational approach for inferring leukocyte representation in bulk tumor transcriptomes, we identified complex associations between 22 distinct leukocyte subsets and cancer survival. For example, tumor-associated neutrophil and plasma cell signatures emerged as significant but opposite predictors of survival for diverse solid tumors, including breast and lung adenocarcinomas. This resource and associated analytical tools (http://precog.stanford.edu) may help delineate prognostic genes and leukocyte subsets within and across cancers, shed light on the impact of tumor heterogeneity on cancer outcomes, and facilitate the discovery of biomarkers and therapeutic targets.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "26193341", + "TEXT": "Chronic itch is an intractable symptom of inflammatory skin diseases, such as atopic and contact dermatitis. Recent studies have revealed neuronal pathways selective for itch, but the mechanisms by which itch turns into a pathological chronic state are poorly understood. Using mouse models of atopic and contact dermatitis, we demonstrate a long-term reactive state of astrocytes in the dorsal horn of the spinal segments that corresponds to lesioned, itchy skin. We found that reactive astrogliosis depended on the activation of signal transducer and activator of transcription 3 (STAT3). Conditional disruption of astrocytic STAT3 suppressed chronic itch, and pharmacological inhibition of spinal STAT3 ameliorated the fully developed chronic itch. Mice with atopic dermatitis exhibited an increase in scratching elicited by intrathecal administration of the itch-inducer gastrin-releasing peptide (GRP), and this enhancement was normalized by suppressing STAT3-mediated reactive astrogliosis. Moreover, we identified lipocalin-2 (LCN2) as an astrocytic STAT3-dependent upregulated factor that was crucial for chronic itch, and we demonstrated that intrathecal administration of LCN2 to normal mice increased spinal GRP-evoked scratching. Our findings indicate that STAT3-dependent reactive astrocytes act as critical amplifiers of itching through a mechanism involving the enhancement of spinal itch signals by LCN2, thereby providing a previously unrecognized target for treating chronic itch.", + "TAG_DATA": [ + "88, Conditional {'perturbing_action': 'B-gene loss-of-function'}", + "89, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "90, of {'perturbing_action': 'I-gene loss-of-function'}", + "91, astrocytic {'perturbing_action': 'I-gene loss-of-function'}", + "92, STAT3 {'perturbing_action': 'I-gene loss-of-function'}", + "97, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "98, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "99, of {'perturbing_action': 'I-pharmacological inhibition'}", + "100, spinal {'perturbing_action': 'I-pharmacological inhibition'}", + "101, STAT3 {'perturbing_action': 'I-pharmacological inhibition'}", + "108, Mice {'context': 'B-organism'}", + "164, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "88, Conditional ['l0', 'l1', 'l2', 'l3']", + "89, disruption ['l0', 'l4', 'l5', 'l6']", + "90, of ['l1', 'l4', 'l7', 'l8']", + "91, astrocytic ['l2', 'l5', 'l7', 'l9']", + "92, STAT3 ['l3', 'l6', 'l8', 'l9']", + "97, pharmacological ['l10', 'l11', 'l12', 'l13', 'l14']", + "98, inhibition ['l10', 'l15', 'l16', 'l17', 'l18']", + "99, of ['l11', 'l15', 'l19', 'l20', 'l21']", + "100, spinal ['l12', 'l16', 'l19', 'l22', 'l23']", + "101, STAT3 ['l13', 'l17', 'l20', 'l22', 'l24']", + "108, Mice ['l14', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "spinal", + "STAT3" + ] + }, + "context": { + "val": "organism", + "words": [ + "Mice" + ] + } + } + ] + }, + { + "PMID": "26168294", + "TEXT": "Repair of injured lungs represents a longstanding therapeutic challenge. We show that human and mouse embryonic lung tissue from the canalicular stage of development (20-22 weeks of gestation for humans, and embryonic day 15-16 (E15-E16) for mouse) are enriched with progenitors residing in distinct niches. On the basis of the marked analogy to progenitor niches in bone marrow (BM), we attempted strategies similar to BM transplantation, employing sublethal radiation to vacate lung progenitor niches and to reduce stem cell competition. Intravenous infusion of a single cell suspension of canalicular lung tissue from GFP-marked mice or human fetal donors into naphthalene-injured and irradiated syngeneic or SCID mice, respectively, induced marked long-term lung chimerism. Donor type structures or 'patches' contained epithelial, mesenchymal and endothelial cells. Transplantation of differentially labeled E16 mouse lung cells indicated that these patches were probably of clonal origin from the donor. Recipients of the single cell suspension transplant exhibited marked improvement in lung compliance and tissue damping reflecting the energy dissipation in the lung tissues. Our study provides proof of concept for lung reconstitution by canalicular-stage human lung cells after preconditioning of the pulmonary niche.", + "TAG_DATA": [ + "93, mice {'context': 'B-organism'}", + "95, human {'context': 'B-cells'}", + "96, fetal {'context': 'I-cells'}", + "97, donors {'context': 'I-organism'}", + "105, mice, {'context': 'I-organism'}", + "110, lung {'context': 'B-tissue/organ'}", + "118, epithelial, {'context': 'B-cells'}", + "119, mesenchymal {'context': 'I-cells'}", + "120, and {'context': 'I-cells'}", + "121, endothelial {'context': 'I-cells'}", + "122, cells. {'context': 'I-cells'}", + "127, E16 {'context': 'B-cells'}", + "128, mouse {'context': 'I-cells'}", + "129, lung {'context': 'I-cells'}", + "130, cells {'context': 'I-cells'}", + "154, lung {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "93, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "95, human ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "96, fetal ['l1', 'l8', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "97, donors ['l2', 'l9', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "105, mice, ['l3', 'l10', 'l18', 'l25', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "110, lung ['l4', 'l11', 'l19', 'l26', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "118, epithelial, ['l12', 'l20', 'l27', 'l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "119, mesenchymal ['l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "120, and ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "121, endothelial ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "122, cells. ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l52']", + "127, E16 ['l53', 'l54', 'l55', 'l56']", + "128, mouse ['l53', 'l57', 'l58', 'l59']", + "129, lung ['l54', 'l57', 'l60', 'l61']", + "130, cells ['l55', 'l58', 'l60', 'l62']", + "154, lung ['l56', 'l59', 'l61', 'l62']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26168293", + "TEXT": "Nicotinamide N-methyltransferase (Nnmt) methylates nicotinamide, a form of vitamin B3, to produce N(1)-methylnicotinamide (MNAM). Nnmt has emerged as a metabolic regulator in adipocytes, but its role in the liver, the tissue with the strongest Nnmt expression, is not known. In spite of its overall high expression, here we find that hepatic expression of Nnmt is highly variable and correlates with multiple metabolic parameters in mice and humans. Further, we find that suppression of hepatic Nnmt expression in vivo alters glucose and cholesterol metabolism and that the metabolic effects of Nnmt in the liver are mediated by its product MNAM. Supplementation of high-fat diet with MNAM decreases serum and liver cholesterol and liver triglycerides levels in mice. Mechanistically, increasing Nnmt expression or MNAM levels stabilizes sirtuin 1 protein, an effect that is required for their metabolic benefits. In summary, we describe here a novel regulatory pathway for vitamin B3 that could provide a new opportunity for metabolic disease therapy.", + "TAG_DATA": [ + "71, suppression {'perturbing_action': 'B-other'}", + "72, of {'perturbing_action': 'I-other'}", + "73, hepatic {'perturbing_action': 'I-other'}", + "74, Nnmt {'perturbing_action': 'I-other'}", + "75, expression {'perturbing_action': 'I-other'}", + "76, in {'context': 'B-in vivo'}", + "77, vivo {'context': 'I-in vivo'}", + "92, liver {'context': 'B-tissue/organ'}", + "115, mice. {'context': 'B-organism'}", + "117, increasing {'perturbing_action': 'B-gene gain-of-function'}", + "118, Nnmt {'perturbing_action': 'I-gene gain-of-function'}", + "119, expression {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "71, suppression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "72, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "73, hepatic ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "74, Nnmt ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "75, expression ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "76, in ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "77, vivo ['l5', 'l11', 'l16', 'l20', 'l23', 'l25']", + "92, liver ['l6', 'l12', 'l17', 'l21', 'l24', 'l26']", + "117, increasing ['l27', 'l28']", + "118, Nnmt ['l27', 'l29']", + "119, expression ['l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "suppression", + "of", + "hepatic", + "Nnmt", + "expression" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "suppression", + "of", + "hepatic", + "Nnmt", + "expression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "26107252", + "TEXT": "The inflammasome activates caspase-1 and the release of interleukin-1β (IL-1β) and IL-18, and several inflammasomes protect against intestinal inflammation and colitis-associated colon cancer (CAC) in animal models. The absent in melanoma 2 (AIM2) inflammasome is activated by double-stranded DNA, and AIM2 expression is reduced in several types of cancer, but the mechanism by which AIM2 restricts tumor growth remains unclear. We found that Aim2-deficient mice had greater tumor load than Asc-deficient mice in the azoxymethane/dextran sodium sulfate (AOM/DSS) model of colorectal cancer. Tumor burden was also higher in Aim2(-/-)/Apc(Min/+) than in APC(Min/+) mice. The effects of AIM2 on CAC were independent of inflammasome activation and IL-1β and were primarily mediated by a non-bone marrow source of AIM2. In resting cells, AIM2 physically interacted with and limited activation of DNA-dependent protein kinase (DNA-PK), a PI3K-related family member that promotes Akt phosphorylation, whereas loss of AIM2 promoted DNA-PK-mediated Akt activation. AIM2 reduced Akt activation and tumor burden in colorectal cancer models, while an Akt inhibitor reduced tumor load in Aim2(-/-) mice. These findings suggest that Akt inhibitors could be used to treat AIM2-deficient human cancers.", + "TAG_DATA": [ + "63, Aim2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "64, mice {'context': 'B-organism'}", + "66, greater {'effect': 'B-positive'}", + "67, tumor {'phenotype': 'B-tumourigenesis'}", + "68, load {'phenotype': 'I-tumourigenesis'}", + "70, Asc-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "71, mice {'context': 'B-organism'}", + "79, of {'context': 'B-neoplasm'}", + "80, colorectal {'context': 'B-neoplasm'}", + "81, cancer. {'context': 'I-neoplasm'}", + "82, Tumor {'phenotype': 'B-tumourigenesis'}", + "83, burden {'phenotype': 'I-tumourigenesis'}", + "86, higher {'effect': 'B-positive'}", + "88, Aim2(-/-)/Apc(Min/+) {'perturbing_action': 'B-gene loss-of-function'}", + "92, mice. {'context': 'B-organism'}", + "118, resting {'context': 'B-cells'}", + "119, cells, {'context': 'I-cells'}", + "141, loss {'perturbing_action': 'B-gene loss-of-function'}", + "142, of {'perturbing_action': 'I-gene loss-of-function'}", + "143, AIM2 {'perturbing_action': 'I-gene loss-of-function'}", + "153, tumor {'phenotype': 'B-tumourigenesis'}", + "154, burden {'phenotype': 'I-tumourigenesis'}", + "156, colorectal {'context': 'B-neoplasm'}", + "157, cancer {'context': 'I-neoplasm'}", + "158, models, {'context': 'I-neoplasm'}", + "161, Akt {'perturbing_action': 'B-pharmacological inhibition'}", + "162, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "163, reduced {'effect': 'B-negative'}", + "164, tumor {'phenotype': 'B-tumourigenesis'}", + "165, load {'phenotype': 'I-tumourigenesis'}", + "167, Aim2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "168, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "63, Aim2-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "64, mice ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "66, greater ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "67, tumor ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "68, load ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33']", + "70, Asc-deficient ['l4', 'l12', 'l19', 'l25', 'l30', 'l34', 'l35', 'l36', 'l37']", + "71, mice ['l5', 'l13', 'l20', 'l26', 'l31', 'l34', 'l38', 'l39', 'l40']", + "79, of ['l6', 'l14', 'l21', 'l27', 'l32', 'l35', 'l38', 'l41', 'l42']", + "80, colorectal ['l7', 'l15', 'l22', 'l28', 'l36', 'l39', 'l41', 'l43']", + "81, cancer. ['l8', 'l16', 'l23', 'l29', 'l33', 'l37', 'l40', 'l42', 'l43']", + "82, Tumor ['l44', 'l45', 'l46', 'l47', 'l48']", + "83, burden ['l44', 'l49', 'l50', 'l51']", + "86, higher ['l45', 'l49', 'l52', 'l53']", + "88, Aim2(-/-)/Apc(Min/+) ['l46', 'l50', 'l52', 'l54', 'l55', 'l56', 'l57', 'l58']", + "92, mice. ['l54', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "118, resting ['l47', 'l55', 'l59', 'l65', 'l66', 'l67', 'l68', 'l69']", + "119, cells, ['l48', 'l51', 'l53', 'l56', 'l60', 'l65', 'l70', 'l71', 'l72']", + "141, loss ['l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "142, of ['l73', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "143, AIM2 ['l74', 'l80', 'l86', 'l87', 'l88', 'l89', 'l90']", + "153, tumor ['l75', 'l81', 'l86', 'l91', 'l92', 'l93', 'l94']", + "154, burden ['l61', 'l66', 'l70', 'l76', 'l82', 'l87', 'l91', 'l95', 'l96', 'l97']", + "156, colorectal ['l62', 'l67', 'l77', 'l83', 'l88', 'l92', 'l95', 'l98', 'l99']", + "157, cancer ['l57', 'l63', 'l68', 'l71', 'l78', 'l84', 'l89', 'l93', 'l96', 'l98', 'l100']", + "158, models, ['l58', 'l64', 'l69', 'l72', 'l79', 'l85', 'l90', 'l94', 'l97', 'l99', 'l100']", + "161, Akt ['l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "162, inhibitor ['l101', 'l107', 'l108', 'l109', 'l110', 'l111']", + "163, reduced ['l102', 'l107', 'l112', 'l113', 'l114', 'l115']", + "164, tumor ['l103', 'l108', 'l112', 'l116', 'l117', 'l118']", + "165, load ['l104', 'l109', 'l113', 'l116', 'l119', 'l120']", + "167, Aim2(-/-) ['l105', 'l110', 'l114', 'l117', 'l119', 'l121']", + "168, mice. ['l106', 'l111', 'l115', 'l118', 'l120', 'l121']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Aim2-deficient", + "Asc-deficient", + "Aim2(-/-)/Apc(Min/+)", + "Aim2(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Aim2-deficient", + "Asc-deficient", + "Aim2(-/-)/Apc(Min/+)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "greater", + "higher" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Aim2-deficient", + "Asc-deficient", + "Aim2(-/-)/Apc(Min/+)", + "loss", + "of", + "AIM2", + "Aim2(-/-)" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "load", + "Tumor", + "burden" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Aim2-deficient", + "Asc-deficient", + "Aim2(-/-)/Apc(Min/+)", + "loss", + "of", + "AIM2" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "of", + "colorectal", + "cancer.", + "cancer", + "models," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "greater" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "load", + "burden" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "greater", + "higher" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "load", + "Tumor", + "burden" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "greater" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "of", + "colorectal", + "cancer." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "load", + "burden" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "of", + "colorectal", + "cancer.", + "cancer", + "models," + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "Tumor", + "burden" + ] + }, + "context": { + "val": "cells", + "words": [ + "resting", + "cells," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "higher" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Aim2(-/-)/Apc(Min/+)" + ] + }, + "context": { + "val": "cells", + "words": [ + "resting", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Akt", + "inhibitor" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Akt", + "inhibitor" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "load" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Akt", + "inhibitor" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "load" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Aim2(-/-)" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "26099045", + "TEXT": "The sequencing of cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient's tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole-genome and targeted sequencing to multiple samples from each of 50 patients' tumors (303 samples in total). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and late in others. In 13 out of 50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resistance to chemotherapy and the acquisition of invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer.", + "TAG_DATA": [ + "131, potential, {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "126, acquisition ['l0']", + "131, potential, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "26076037", + "TEXT": "Wound healing is impaired in diabetes, resulting in significant morbidity and mortality. Neutrophils are the main leukocytes involved in the early phase of healing. As part of their anti-microbial defense, neutrophils form extracellular traps (NETs) by releasing decondensed chromatin lined with cytotoxic proteins. NETs, however, can also induce tissue damage. Here we show that neutrophils isolated from type 1 and type 2 diabetic humans and mice were primed to produce NETs (a process termed NETosis). Expression of peptidylarginine deiminase 4 (PAD4, encoded by Padi4 in mice), an enzyme important in chromatin decondensation, was elevated in neutrophils from individuals with diabetes. When subjected to excisional skin wounds, wild-type (WT) mice produced large quantities of NETs in wounds, but this was not observed in Padi4(-/-) mice. In diabetic mice, higher levels of citrullinated histone H3 (H3Cit, a NET marker) were found in their wounds than in normoglycemic mice and healing was delayed. Wound healing was accelerated in Padi4(-/-) mice as compared to WT mice, and it was not compromised by diabetes. DNase 1, which disrupts NETs, accelerated wound healing in diabetic and normoglycemic WT mice. Thus, NETs impair wound healing, particularly in diabetes, in which neutrophils are more susceptible to NETosis. Inhibiting NETosis or cleaving NETs may improve wound healing and reduce NET-driven chronic inflammation in diabetes.", + "TAG_DATA": [ + "65, mice {'context': 'B-organism'}", + "108, mice {'context': 'B-organism'}", + "122, Padi4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "123, mice. {'context': 'B-organism'}", + "125, diabetic {'context': 'B-organism'}", + "126, mice, {'context': 'I-organism'}", + "145, mice {'context': 'I-organism'}", + "155, Padi4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "156, mice {'context': 'B-organism'}", + "182, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "108, mice ['l0', 'l1', 'l2']", + "122, Padi4(-/-) ['l3', 'l4', 'l5', 'l6']", + "123, mice. ['l0', 'l3', 'l7', 'l8', 'l9']", + "125, diabetic ['l4', 'l7', 'l10', 'l11']", + "126, mice, ['l1', 'l5', 'l8', 'l10', 'l12']", + "145, mice ['l2', 'l6', 'l9', 'l11', 'l12']", + "153, accelerated ['l13', 'l14']", + "155, Padi4(-/-) ['l13', 'l15']", + "156, mice ['l14', 'l15']", + "174, accelerated ['l16']", + "182, mice. ['l16']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Padi4(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "diabetic", + "mice,", + "mice" + ] + } + } + ] + }, + { + "PMID": "26076036", + "TEXT": "Targeting brown adipose tissue (BAT) content or activity has therapeutic potential for treating obesity and the metabolic syndrome by increasing energy expenditure. However, both inter- and intra-individual differences contribute to heterogeneity in human BAT and potentially to differential thermogenic capacity in human populations. Here we generated clones of brown and white preadipocytes from human neck fat and characterized their adipogenic and thermogenic differentiation. We combined an uncoupling protein 1 (UCP1) reporter system and expression profiling to define novel sets of gene signatures in human preadipocytes that could predict the thermogenic potential of the cells once they were maturated. Knocking out the positive UCP1 regulators, PREX1 and EDNRB, in brown preadipocytes using CRISPR-Cas9 markedly abolished the high level of UCP1 in brown adipocytes differentiated from the preadipocytes. Finally, we were able to prospectively isolate adipose progenitors with great thermogenic potential using the cell surface marker CD29. These data provide new insights into the cellular heterogeneity in human fat and offer potential biomarkers for identifying thermogenically competent preadipocytes.", + "TAG_DATA": [ + "83, human {'context': 'B-cells'}", + "84, preadipocytes {'context': 'I-cells'}", + "98, Knocking {'perturbing_action': 'B-gene loss-of-function'}", + "99, out {'perturbing_action': 'I-gene loss-of-function'}", + "100, the {'perturbing_action': 'I-gene loss-of-function'}", + "101, positive {'perturbing_action': 'I-gene loss-of-function'}", + "102, UCP1 {'perturbing_action': 'I-gene loss-of-function'}", + "103, regulators, {'perturbing_action': 'I-gene loss-of-function'}", + "104, PREX1 {'perturbing_action': 'I-gene loss-of-function'}", + "105, and {'perturbing_action': 'I-gene loss-of-function'}", + "106, EDNRB, {'perturbing_action': 'I-gene loss-of-function'}", + "108, brown {'context': 'B-cells'}", + "109, preadipocytes {'context': 'I-cells'}", + "110, using {'perturbing_action': 'I-gene loss-of-function'}", + "111, CRISPR-Cas9 {'perturbing_action': 'I-gene loss-of-function'}", + "120, brown {'context': 'B-cells'}", + "121, adipocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "83, human ['l0']", + "84, preadipocytes ['l0']", + "98, Knocking ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "99, out ['l1', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "100, the ['l2', 'l15', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "101, positive ['l3', 'l16', 'l28', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "102, UCP1 ['l4', 'l17', 'l29', 'l40', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "103, regulators, ['l5', 'l18', 'l30', 'l41', 'l51', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "104, PREX1 ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "105, and ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "106, EDNRB, ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "108, brown ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l91', 'l92', 'l93']", + "109, preadipocytes ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l94', 'l95']", + "110, using ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l94', 'l96']", + "111, CRISPR-Cas9 ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l95', 'l96', 'l97', 'l98']", + "120, brown ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l97', 'l99']", + "121, adipocytes ['l14', 'l27', 'l39', 'l50', 'l60', 'l69', 'l77', 'l84', 'l90', 'l98', 'l99']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Knocking", + "out", + "the", + "positive", + "UCP1", + "regulators,", + "PREX1", + "and", + "EDNRB,", + "using", + "CRISPR-Cas9" + ] + }, + "context": { + "val": "cells", + "words": [ + "brown", + "preadipocytes", + "adipocytes" + ] + } + } + ] + }, + { + "PMID": "26076035", + "TEXT": "The peptide hormone urocortin3 (Ucn3) is abundantly expressed by mature beta cells, yet its physiological role is unknown. Here we demonstrate that Ucn3 is stored and co-released with insulin and potentiates glucose-stimulated somatostatin secretion via cognate receptors on delta cells. Further, we found that islets lacking endogenous Ucn3 have fewer delta cells, reduced somatostatin content, impaired somatostatin secretion, and exaggerated insulin release, and that these defects are rectified by treatment with synthetic Ucn3 in vitro. Our observations indicate that the paracrine actions of Ucn3 activate a negative feedback loop that promotes somatostatin release to ensure the timely reduction of insulin secretion upon normalization of plasma glucose. Moreover, Ucn3 is markedly depleted from beta cells in mouse and macaque models of diabetes and in human diabetic islets. This suggests that Ucn3 is a key contributor to stable glycemic control, whose reduction during diabetes aggravates glycemic volatility and contributes to the pathophysiology of this disease.", + "TAG_DATA": [ + "44, islets {'context': 'B-cells'}", + "45, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "46, endogenous {'perturbing_action': 'I-gene loss-of-function'}", + "47, Ucn3 {'perturbing_action': 'I-gene loss-of-function'}", + "50, delta {'context': 'B-cells'}", + "51, cells, {'context': 'I-cells'}", + "73, in {'context': 'B-in vitro'}", + "74, vitro. {'context': 'I-in vitro'}", + "112, beta {'context': 'B-cells'}", + "113, cells {'context': 'I-cells'}", + "115, mouse {'context': 'B-organism'}", + "117, macaque {'context': 'I-organism'}", + "123, human {'context': 'B-cells'}", + "124, diabetic {'context': 'I-cells'}", + "125, islets. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "44, islets ['l0', 'l1', 'l2', 'l3', 'l4']", + "45, lacking ['l0', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "46, endogenous ['l1', 'l5', 'l11', 'l12', 'l13', 'l14', 'l15']", + "47, Ucn3 ['l2', 'l6', 'l11', 'l16', 'l17', 'l18', 'l19']", + "50, delta ['l3', 'l7', 'l12', 'l16', 'l20', 'l21']", + "51, cells, ['l4', 'l8', 'l13', 'l17', 'l20']", + "73, in ['l9', 'l14', 'l18', 'l22']", + "74, vitro. ['l10', 'l15', 'l19', 'l21', 'l22']", + "112, beta ['l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "113, cells ['l23', 'l29', 'l30', 'l31', 'l32', 'l33']", + "115, mouse ['l24', 'l29', 'l34']", + "117, macaque ['l25', 'l30', 'l34']", + "123, human ['l26', 'l31', 'l35', 'l36']", + "124, diabetic ['l27', 'l32', 'l35', 'l37']", + "125, islets. ['l28', 'l33', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "islets", + "delta", + "cells," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "endogenous", + "Ucn3" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "endogenous", + "Ucn3" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "26005855", + "TEXT": "Our understanding of the pathways that regulate lymphocyte metabolism, as well as the effects of metabolism and its products on the immune response, is still limited. We report that a metabolic program controlled by the transcription factors hypoxia inducible factor-1α (HIF1-α) and aryl hydrocarbon receptor (AHR) supports the differentiation of type 1 regulatory T cell (Tr1) cells. HIF1-α controls the early metabolic reprograming of Tr1 cells. At later time points, AHR promotes HIF1-α degradation and takes control of Tr1 cell metabolism. Extracellular ATP (eATP) and hypoxia, linked to inflammation, trigger AHR inactivation by HIF1-α and inhibit Tr1 cell differentiation. Conversely, CD39 promotes Tr1 cell differentiation by depleting eATP. CD39 also contributes to Tr1 suppressive activity by generating adenosine in cooperation with CD73 expressed by responder T cells and antigen-presenting cells. These results suggest that HIF1-α and AHR integrate immunological, metabolic and environmental signals to regulate the immune response.", + "TAG_DATA": [ + "95, inhibit {'effect': 'B-negative'}", + "96, Tr1 {'context': 'B-cells'}", + "97, cell {'context': 'I-cells'}", + "98, differentiation. {'phenotype': 'B-differentiation'}", + "101, promotes {'effect': 'B-positive'}", + "102, Tr1 {'context': 'B-cells'}", + "103, cell {'context': 'I-cells'}", + "104, differentiation {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "95, inhibit ['l0', 'l1', 'l2']", + "96, Tr1 ['l0', 'l3', 'l4']", + "97, cell ['l1', 'l3', 'l5']", + "98, differentiation. ['l2', 'l4', 'l5']", + "101, promotes ['l6', 'l7', 'l8']", + "102, Tr1 ['l6', 'l9', 'l10']", + "103, cell ['l7', 'l9', 'l11']", + "104, differentiation ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "context": { + "val": "cells", + "words": [ + "Tr1", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Tr1", + "cell" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation.", + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "cells", + "words": [ + "Tr1", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "25962123", + "TEXT": "Infection with hepatitis B virus (HBV) results in disparate degrees of tissue injury: the virus can either replicate without pathological consequences or trigger immune-mediated necroinflammatory liver damage. We investigated the potential for myeloid-derived suppressor cells (MDSCs) to suppress T cell-mediated immunopathology in this setting. Granulocytic MDSCs (gMDSCs) expanded transiently in acute resolving HBV, decreasing in frequency prior to peak hepatic injury. In persistent infection, arginase-expressing gMDSCs (and circulating arginase) increased most in disease phases characterized by HBV replication without immunopathology, whilst L-arginine decreased. gMDSCs expressed liver-homing chemokine receptors and accumulated in the liver, their expansion supported by hepatic stellate cells. We provide in vitro and ex vivo evidence that gMDSCs potently inhibited T cells in a partially arginase-dependent manner. L-arginine-deprived T cells upregulated system L amino acid transporters to increase uptake of essential nutrients and attempt metabolic reprogramming. These data demonstrate the capacity of expanded arginase-expressing gMDSCs to regulate liver immunopathology in HBV infection.", + "TAG_DATA": [ + "65, gMDSCs {'context': 'I-cells'}", + "97, hepatic {'context': 'B-cells'}", + "98, stellate {'context': 'I-cells'}", + "99, cells. {'context': 'I-cells'}", + "102, in {'context': 'B-in vitro'}", + "103, vitro {'context': 'I-in vitro'}", + "112, T {'context': 'B-cells'}", + "113, cells {'context': 'B-cells'}", + "120, T {'context': 'B-cells'}", + "121, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "65, gMDSCs ['l0']", + "97, hepatic ['l1', 'l2', 'l3', 'l4', 'l5']", + "98, stellate ['l1', 'l6', 'l7', 'l8', 'l9']", + "99, cells. ['l0', 'l2', 'l6', 'l10', 'l11']", + "102, in ['l3', 'l7', 'l10', 'l12', 'l13', 'l14']", + "103, vitro ['l4', 'l8', 'l11', 'l12', 'l15', 'l16']", + "112, T ['l13', 'l15', 'l17']", + "113, cells ['l5', 'l9', 'l14', 'l16', 'l17']", + "120, T ['l18']", + "121, cells ['l18']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25951530", + "TEXT": "Much has been written about the advantages and disadvantages of various oncology model systems, with the overall finding that these models lack the predictive power required to translate preclinical efficacy into clinical activity. Despite assertions that some preclinical model systems are superior to others, no single model can suffice to inform preclinical target validation and molecule selection. This perspective provides a balanced albeit critical view of these claims of superiority and outlines a framework for the proper use of existing preclinical models for drug testing and discovery. We also highlight gaps in oncology mouse models and discuss general and pervasive model-independent shortcomings in preclinical oncology work, and we propose ways to address these issues.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25939063", + "TEXT": "Chimeric antigen receptors (CARs) targeting CD19 have mediated dramatic antitumor responses in hematologic malignancies, but tumor regression has rarely occurred using CARs targeting other antigens. It remains unknown whether the impressive effects of CD19 CARs relate to greater susceptibility of hematologic malignancies to CAR therapies, or superior functionality of the CD19 CAR itself. We show that tonic CAR CD3-ζ phosphorylation, triggered by antigen-independent clustering of CAR single-chain variable fragments, can induce early exhaustion of CAR T cells that limits antitumor efficacy. Such activation is present to varying degrees in all CARs studied, except the highly effective CD19 CAR. We further determine that CD28 costimulation augments, whereas 4-1BB costimulation reduces, exhaustion induced by persistent CAR signaling. Our results provide biological explanations for the antitumor effects of CD19 CARs and for the observations that CD19 CAR T cells incorporating the 4-1BB costimulatory domain are more persistent than those incorporating CD28 in clinical trials.", + "TAG_DATA": [ + "75, T {'context': 'B-cells'}", + "76, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "75, T ['l0']", + "76, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25894826", + "TEXT": "Ocular neovascular diseases are a leading cause of blindness. Vascular endothelial growth factor (VEGF) blockade improves vision, but not all individuals respond to anti-VEGF treatment, making additional means to prevent neovascularization necessary. Slit-family proteins (Slits) are ligands of Roundabout (Robo) receptors that repel developing axons in the nervous system. Robo1 expression is altered in ocular neovascular diseases, and previous in vitro studies have reported both pro- and anti-angiogenic effects of Slits. However, genetic evidence supporting a role for Slits in ocular neovascularization is lacking. Here we generated conditional knockout mice deficient in various Slit and Robo proteins and found that Slit2 potently and selectively promoted angiogenesis via Robo1 and Robo2 in mouse postnatal retina and in a model of ocular neovascular disease. Mechanistically, Slit2 acting through Robo1 and Robo2 promoted the migration of endothelial cells. These receptors are required for both Slit2- and VEGF-induced Rac1 activation and lamellipodia formation. Thus, Slit2 blockade could potentially be used therapeutically to inhibit angiogenesis in individuals with ocular neovascular disease.", + "TAG_DATA": [ + "87, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "88, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "89, mice {'context': 'B-organism'}", + "111, mouse {'context': 'B-tissue/organ'}", + "112, postnatal {'context': 'I-tissue/organ'}", + "113, retina {'context': 'I-tissue/organ'}", + "129, promoted {'effect': 'B-positive'}", + "131, migration {'phenotype': 'B-migration'}", + "133, endothelial {'context': 'B-cells'}", + "134, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "87, conditional ['l0', 'l1', 'l2']", + "88, knockout ['l0', 'l3', 'l4']", + "89, mice ['l1', 'l3', 'l5']", + "111, mouse ['l6', 'l7']", + "112, postnatal ['l6', 'l8']", + "113, retina ['l2', 'l4', 'l5', 'l7', 'l8']", + "129, promoted ['l9', 'l10', 'l11']", + "131, migration ['l9', 'l12', 'l13']", + "133, endothelial ['l10', 'l12', 'l14']", + "134, cells. ['l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "knockout" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "retina" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells." + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells." + ] + } + } + ] + }, + { + "PMID": "25894825", + "TEXT": "Tumors are complex ecosystems composed of networks of interacting 'normal' and malignant cells. It is well recognized that cytokine-mediated cross-talk between normal stromal cells, including cancer-associated fibroblasts (CAFs), vascular endothelial cells, immune cells, and cancer cells, influences all aspects of tumor biology. Here we demonstrate that the cross-talk between CAFs and cancer cells leads to enhanced growth of oncolytic virus (OV)-based therapeutics. Transforming growth factor-β (TGF-β) produced by tumor cells reprogrammed CAFs, dampened their steady-state level of antiviral transcripts and rendered them sensitive to virus infection. In turn, CAFs produced high levels of fibroblast growth factor 2 (FGF2), initiating a signaling cascade in cancer cells that reduced retinoic acid-inducible gene I (RIG-I) expression and impeded the ability of malignant cells to detect and respond to virus. In xenografts derived from individuals with pancreatic cancer, the expression of FGF2 correlated with the susceptibility of the cancer cells to OV infection, and local application of FGF2 to resistant tumor samples sensitized them to virotherapy both in vitro and in vivo. An OV engineered to express FGF2 was safe in tumor-bearing mice, showed improved therapeutic efficacy compared to parental virus and merits consideration for clinical testing.", + "TAG_DATA": [ + "103, cancer {'context': 'B-transformed cells'}", + "104, cells {'context': 'I-transformed cells'}", + "118, malignant {'context': 'B-transformed cells'}", + "119, cells {'context': 'I-transformed cells'}", + "127, xenografts {'context': 'B-xenograft'}", + "128, derived {'context': 'I-xenograft'}", + "129, from {'context': 'I-xenograft'}", + "130, individuals {'context': 'I-xenograft'}", + "131, with {'context': 'I-xenograft'}", + "132, pancreatic {'context': 'I-xenograft'}", + "133, cancer, {'context': 'I-xenograft'}", + "144, cancer {'context': 'B-transformed cells'}", + "145, cells {'context': 'I-transformed cells'}", + "156, tumor {'context': 'B-transformed cells'}", + "163, in {'context': 'B-in vitro'}", + "164, vitro {'context': 'I-in vitro'}", + "166, in {'context': 'B-in vivo'}", + "167, vivo. {'context': 'I-in vivo'}", + "170, engineered {'perturbing_action': 'I-gene gain-of-function'}", + "171, to {'perturbing_action': 'I-gene gain-of-function'}", + "172, express {'perturbing_action': 'I-gene gain-of-function'}", + "173, FGF2 {'perturbing_action': 'I-gene gain-of-function'}", + "177, tumor-bearing {'context': 'B-organism'}", + "178, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "103, cancer ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "104, cells ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "118, malignant ['l1', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "119, cells ['l2', 'l13', 'l22', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "127, xenografts ['l3', 'l14', 'l23', 'l32', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "128, derived ['l4', 'l15', 'l24', 'l33', 'l39', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "129, from ['l5', 'l16', 'l25', 'l34', 'l40', 'l47', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "130, individuals ['l6', 'l17', 'l26', 'l35', 'l41', 'l48', 'l54', 'l60', 'l61', 'l62', 'l63', 'l64']", + "131, with ['l7', 'l18', 'l27', 'l36', 'l42', 'l49', 'l55', 'l60', 'l65', 'l66', 'l67', 'l68']", + "132, pancreatic ['l8', 'l19', 'l28', 'l37', 'l43', 'l50', 'l56', 'l61', 'l65', 'l69', 'l70', 'l71']", + "133, cancer, ['l9', 'l20', 'l29', 'l38', 'l44', 'l51', 'l57', 'l62', 'l66', 'l69', 'l72', 'l73']", + "144, cancer ['l10', 'l30', 'l45', 'l52', 'l58', 'l63', 'l67', 'l70', 'l72', 'l74']", + "145, cells ['l11', 'l21', 'l31', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l73', 'l74']", + "156, tumor ['l75', 'l76', 'l77', 'l78']", + "163, in ['l75', 'l79', 'l80', 'l81']", + "164, vitro ['l76', 'l79', 'l82', 'l83']", + "166, in ['l77', 'l80', 'l82', 'l84']", + "167, vivo. ['l78', 'l81', 'l83', 'l84']", + "170, engineered ['l85', 'l86', 'l87', 'l88', 'l89']", + "171, to ['l85', 'l90', 'l91', 'l92', 'l93']", + "172, express ['l86', 'l90', 'l94', 'l95', 'l96']", + "173, FGF2 ['l87', 'l91', 'l94', 'l97', 'l98']", + "177, tumor-bearing ['l88', 'l92', 'l95', 'l97', 'l99']", + "178, mice, ['l89', 'l93', 'l96', 'l98', 'l99']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "engineered", + "to", + "express", + "FGF2" + ] + }, + "context": { + "val": "organism", + "words": [ + "tumor-bearing", + "mice," + ] + } + } + ] + }, + { + "PMID": "25849132", + "TEXT": "Hemophilia A and B are inherited bleeding disorders characterized by deficiencies in procoagulant factor VIII (FVIII) or factor IX (FIX), respectively. There remains a substantial unmet medical need in hemophilia, especially in patients with inhibitory antibodies against replacement factor therapy, for novel and improved therapeutic agents that can be used prophylactically to provide effective hemostasis. Guided by reports suggesting that co-inheritance of prothrombotic mutations may ameliorate the clinical phenotype in hemophilia, we developed an RNA interference (RNAi) therapeutic (ALN-AT3) targeting antithrombin (AT) as a means to promote hemostasis in hemophilia. When administered subcutaneously, ALN-AT3 showed potent, dose-dependent, and durable reduction of AT levels in wild-type mice, mice with hemophilia A, and nonhuman primates (NHPs). In NHPs, a 50% reduction in AT levels was achieved with weekly dosing at approximately 0.125 mg/kg, and a near-complete reduction in AT levels was achieved with weekly dosing at 1.5 mg/kg. Treatment with ALN-AT3 promoted hemostasis in mouse models of hemophilia and led to improved thrombin generation in an NHP model of hemophilia A with anti-factor VIII inhibitors. This investigational compound is currently in phase 1 clinical testing in subjects with hemophilia A or B.", + "TAG_DATA": [ + "77, therapeutic {'perturbing_action': 'I-rnai/knockdown'}", + "105, mice, {'context': 'B-organism'}", + "106, mice {'context': 'B-organism'}", + "111, nonhuman {'context': 'B-organism'}", + "112, primates {'context': 'I-organism'}", + "113, (NHPs). {'context': 'I-organism'}", + "115, NHPs, {'context': 'B-organism'}", + "152, mouse {'context': 'B-organism'}", + "153, models {'context': 'I-organism'}", + "154, of {'context': 'I-organism'}", + "155, hemophilia {'context': 'I-organism'}", + "164, NHP {'context': 'B-organism'}", + "165, model {'context': 'I-organism'}", + "167, hemophilia {'context': 'I-organism'}", + "168, A {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "77, therapeutic ['l0', 'l1', 'l2', 'l3']", + "105, mice, ['l0', 'l4', 'l5', 'l6', 'l7']", + "106, mice ['l1', 'l4', 'l8', 'l9', 'l10', 'l11']", + "111, nonhuman ['l5', 'l8', 'l12', 'l13', 'l14']", + "112, primates ['l2', 'l6', 'l9', 'l12', 'l15', 'l16']", + "113, (NHPs). ['l3', 'l7', 'l10', 'l13', 'l15', 'l17']", + "115, NHPs, ['l11', 'l14', 'l16', 'l17']", + "152, mouse ['l18', 'l19', 'l20', 'l21', 'l22']", + "153, models ['l18', 'l23', 'l24', 'l25']", + "154, of ['l19', 'l23', 'l26']", + "155, hemophilia ['l20', 'l24', 'l26', 'l27', 'l28', 'l29', 'l30']", + "164, NHP ['l31', 'l32', 'l33', 'l34']", + "165, model ['l27', 'l31', 'l35', 'l36', 'l37']", + "166, of ['l21', 'l28', 'l32', 'l35', 'l38', 'l39']", + "167, hemophilia ['l29', 'l33', 'l36', 'l38', 'l40']", + "168, A ['l22', 'l25', 'l30', 'l34', 'l37', 'l39', 'l40']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "therapeutic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice", + "primates", + "(NHPs)." + ] + } + } + ] + }, + { + "PMID": "25849130", + "TEXT": "Resistance to cancer therapies presents a significant clinical challenge. Recent studies have revealed intratumoral heterogeneity as a source of therapeutic resistance. However, it is unclear whether resistance is driven predominantly by pre-existing or de novo alterations, in part because of the resolution limits of next-generation sequencing. To address this, we developed a high-complexity barcode library, ClonTracer, which enables the high-resolution tracking of more than 1 million cancer cells under drug treatment. In two clinically relevant models, ClonTracer studies showed that the majority of resistant clones were part of small, pre-existing subpopulations that selectively escaped under therapeutic challenge. Moreover, the ClonTracer approach enabled quantitative assessment of the ability of combination treatments to suppress resistant clones. These findings suggest that resistant clones are present before treatment, which would make up-front therapeutic combinations that target non-overlapping resistance a preferred approach. Thus, ClonTracer barcoding may be a valuable tool for optimizing therapeutic regimens with the goal of curative combination therapies for cancer.", + "TAG_DATA": [ + "66, cancer {'context': 'B-transformed cells'}", + "67, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "66, cancer ['l0']", + "67, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25822367", + "TEXT": "Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Although prior work has focused on targeting AR directly, co-activators of AR signaling, which may represent new therapeutic targets, are relatively underexplored. Here we demonstrate that the mixed-lineage leukemia protein (MLL) complex, a well-known driver of MLL fusion-positive leukemia, acts as a co-activator of AR signaling. AR directly interacts with the MLL complex via the menin-MLL subunit. Menin expression is higher in CRPC than in both hormone-naive prostate cancer and benign prostate tissue, and high menin expression correlates with poor overall survival of individuals diagnosed with prostate cancer. Treatment with a small-molecule inhibitor of menin-MLL interaction blocks AR signaling and inhibits the growth of castration-resistant tumors in vivo in mice. Taken together, this work identifies the MLL complex as a crucial co-activator of AR and a potential therapeutic target in advanced prostate cancer.", + "TAG_DATA": [ + "123, castration-resistant {'context': 'B-neoplasm'}", + "124, tumors {'context': 'I-neoplasm'}", + "125, in {'context': 'B-in vivo'}", + "126, vivo {'context': 'I-in vivo'}", + "128, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "123, castration-resistant ['l0', 'l1', 'l2', 'l3']", + "124, tumors ['l0', 'l4', 'l5', 'l6']", + "125, in ['l1', 'l4', 'l7', 'l8']", + "126, vivo ['l2', 'l5', 'l7', 'l9']", + "128, mice. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25774850", + "TEXT": "In the nervous system, NMDA receptors (NMDARs) participate in neurotransmission and modulate the viability of neurons. In contrast, little is known about the role of NMDARs in pancreatic islets and the insulin-secreting beta cells whose functional impairment contributes to diabetes mellitus. Here we found that inhibition of NMDARs in mouse and human islets enhanced their glucose-stimulated insulin secretion (GSIS) and survival of islet cells. Further, NMDAR inhibition prolonged the amount of time that glucose-stimulated beta cells spent in a depolarized state with high cytosolic Ca(2+) concentrations. We also noticed that, in vivo, the NMDAR antagonist dextromethorphan (DXM) enhanced glucose tolerance in mice, and that in vitro dextrorphan, the main metabolite of DXM, amplified the stimulatory effect of exendin-4 on GSIS. In a mouse model of type 2 diabetes mellitus (T2DM), long-term treatment with DXM improved islet insulin content, islet cell mass and blood glucose control. Further, in a small clinical trial we found that individuals with T2DM treated with DXM showed enhanced serum insulin concentrations and glucose tolerance. Our data highlight the possibility that antagonists of NMDARs may provide a useful adjunct treatment for diabetes.", + "TAG_DATA": [ + "45, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "46, of {'perturbing_action': 'I-pharmacological inhibition'}", + "47, NMDARs {'perturbing_action': 'I-pharmacological inhibition'}", + "49, mouse {'context': 'B-cells'}", + "50, and {'context': 'I-cells'}", + "51, human {'context': 'I-cells'}", + "52, islets {'context': 'I-cells'}", + "62, islet {'context': 'B-cells'}", + "63, cells. {'context': 'I-cells'}", + "65, NMDAR {'perturbing_action': 'B-pharmacological inhibition'}", + "66, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "74, beta {'context': 'B-cells'}", + "75, cells {'context': 'I-cells'}", + "90, in {'context': 'B-in vivo'}", + "91, vivo, {'context': 'I-in vivo'}", + "101, mice, {'context': 'B-organism'}", + "104, in {'context': 'B-in vitro'}", + "105, vitro {'context': 'I-in vitro'}", + "122, mouse {'context': 'B-organism'}", + "123, model {'context': 'I-organism'}", + "138, islet {'context': 'B-cells'}", + "139, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "46, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "47, NMDARs ['l1', 'l11', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "49, mouse ['l2', 'l12', 'l22', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "50, and ['l3', 'l13', 'l23', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "51, human ['l4', 'l14', 'l24', 'l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "52, islets ['l5', 'l15', 'l25', 'l34', 'l39', 'l43', 'l47', 'l48']", + "62, islet ['l6', 'l16', 'l26', 'l35', 'l40', 'l44', 'l47', 'l49', 'l50', 'l51']", + "63, cells. ['l7', 'l17', 'l27', 'l36', 'l41', 'l45', 'l48', 'l49']", + "65, NMDAR ['l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "66, inhibition ['l52', 'l58', 'l59', 'l60', 'l61', 'l62']", + "74, beta ['l8', 'l18', 'l28', 'l50', 'l53', 'l58', 'l63', 'l64', 'l65', 'l66']", + "75, cells ['l9', 'l19', 'l29', 'l37', 'l42', 'l46', 'l51', 'l54', 'l59', 'l63', 'l67', 'l68', 'l69']", + "90, in ['l55', 'l60', 'l64', 'l67', 'l70', 'l71']", + "91, vivo, ['l20', 'l30', 'l56', 'l61', 'l65', 'l68', 'l70', 'l72']", + "101, mice, ['l10', 'l21', 'l31', 'l57', 'l62', 'l66', 'l69', 'l71', 'l72']", + "104, in ['l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "105, vitro ['l73', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "122, mouse ['l74', 'l80', 'l86', 'l87', 'l88', 'l89', 'l90']", + "123, model ['l75', 'l81', 'l86', 'l91', 'l92', 'l93', 'l94']", + "125, type ['l76', 'l82', 'l87', 'l91', 'l95', 'l96', 'l97']", + "126, 2 ['l77', 'l83', 'l88', 'l92', 'l95', 'l98', 'l99']", + "138, islet ['l78', 'l84', 'l89', 'l93', 'l96', 'l98', 'l100']", + "139, cell ['l79', 'l85', 'l90', 'l94', 'l97', 'l99', 'l100']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "NMDARs", + "NMDAR" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "and", + "human", + "islets", + "islet", + "cells.", + "beta", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "NMDARs", + "NMDAR" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "of", + "NMDARs", + "NMDAR", + "inhibition" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo,", + "in" + ] + } + } + ] + }, + { + "PMID": "25774849", + "TEXT": "Down syndrome (DS) is the most frequent genetic cause of intellectual disability, and altered GABAergic transmission through Cl(-)-permeable GABAA receptors (GABAARs) contributes considerably to learning and memory deficits in DS mouse models. However, the efficacy of GABAergic transmission has never been directly assessed in DS. Here GABAAR signaling was found to be excitatory rather than inhibitory, and the reversal potential for GABAAR-driven Cl(-) currents (ECl) was shifted toward more positive potentials in the hippocampi of adult DS mice. Accordingly, hippocampal expression of the cation Cl(-) cotransporter NKCC1 was increased in both trisomic mice and individuals with DS. Notably, NKCC1 inhibition by the FDA-approved drug bumetanide restored ECl, synaptic plasticity and hippocampus-dependent memory in adult DS mice. Our findings demonstrate that GABA is excitatory in adult DS mice and identify a new therapeutic approach for the potential rescue of cognitive disabilities in individuals with DS.", + "TAG_DATA": [ + "76, DS {'context': 'I-organism'}", + "77, mice. {'context': 'I-organism'}", + "98, NKCC1 {'perturbing_action': 'B-pharmacological inhibition'}", + "99, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "100, by {'perturbing_action': 'I-pharmacological inhibition'}", + "101, the {'perturbing_action': 'I-pharmacological inhibition'}", + "102, FDA-approved {'perturbing_action': 'I-pharmacological inhibition'}", + "103, drug {'perturbing_action': 'I-pharmacological inhibition'}", + "104, bumetanide {'perturbing_action': 'I-pharmacological inhibition'}", + "113, adult {'context': 'B-organism'}", + "114, DS {'context': 'I-organism'}", + "115, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "76, DS ['l0']", + "77, mice. ['l0']", + "98, NKCC1 ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "99, inhibition ['l1', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "100, by ['l2', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "101, the ['l3', 'l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "102, FDA-approved ['l4', 'l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "103, drug ['l5', 'l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "104, bumetanide ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "113, adult ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "114, DS ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "115, mice. ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NKCC1", + "inhibition", + "by", + "the", + "FDA-approved", + "drug", + "bumetanide" + ] + }, + "context": { + "val": "organism", + "words": [ + "adult", + "DS", + "mice." + ] + } + } + ] + }, + { + "PMID": "25774848", + "TEXT": "Brown adipose tissue (BAT) acts in mammals as a natural defense system against hypothermia, and its activation to a state of increased energy expenditure is believed to protect against the development of obesity. Even though the existence of BAT in adult humans has been widely appreciated, its cellular origin and molecular identity remain elusive largely because of high cellular heterogeneity within various adipose tissue depots. To understand the nature of adult human brown adipocytes at single cell resolution, we isolated clonally derived adipocytes from stromal vascular fractions of adult human BAT from two individuals and globally analyzed their molecular signatures. We used RNA sequencing followed by unbiased genome-wide expression analyses and found that a population of uncoupling protein 1 (UCP1)-positive human adipocytes possessed molecular signatures resembling those of a recruitable form of thermogenic adipocytes (that is, beige adipocytes). In addition, we identified molecular markers that were highly enriched in UCP1-positive human adipocytes, a set that included potassium channel K3 (KCNK3) and mitochondrial tumor suppressor 1 (MTUS1). Further, we functionally characterized these two markers using a loss-of-function approach and found that KCNK3 and MTUS1 were required for beige adipocyte differentiation and thermogenic function. The results of this study present new opportunities for human BAT research, such as facilitating cell-based disease modeling and unbiased screens for thermogenic regulators.", + "TAG_DATA": [ + "88, adult {'context': 'B-tissue/organ'}", + "89, human {'context': 'I-tissue/organ'}", + "90, BAT {'context': 'I-tissue/organ'}", + "121, adipocytes {'context': 'I-cells'}", + "188, differentiation {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "88, adult ['l0', 'l1']", + "89, human ['l0', 'l2']", + "90, BAT ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25742453", + "TEXT": "Osteoclasts are required for bone resorption. A new study in mice indicates that osteoclast differentiation is stabilized by DNA methylation at Irf8 (encoding interferon regulatory factor 8) mediated by DNA methyltransferase 3a (Dnmt3a), which suppresses Irf8 gene expression. The activity of Dnmt3 in osteoclasts requires elevated oxidative metabolism.", + "TAG_DATA": [ + "10, mice {'context': 'B-organism'}", + "43, osteoclasts {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "10, mice ['l0']", + "43, osteoclasts ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25730263", + "TEXT": "Clinical specimens are each inherently unique, limited and nonrenewable. Small samples such as tissue biopsies are often completely consumed after a limited number of analyses. Here we present a method that enables fast and reproducible conversion of a small amount of tissue (approximating the quantity obtained by a biopsy) into a single, permanent digital file representing the mass spectrometry (MS)-measurable proteome of the sample. The method combines pressure cycling technology (PCT) and sequential window acquisition of all theoretical fragment ion spectra (SWATH)-MS. The resulting proteome maps can be analyzed, re-analyzed, compared and mined in silico to detect and quantify specific proteins across multiple samples. We used this method to process and convert 18 biopsy samples from nine patients with renal cell carcinoma into SWATH-MS fragment ion maps. From these proteome maps we detected and quantified more than 2,000 proteins with a high degree of reproducibility across all samples. The measured proteins clearly distinguished tumorous kidney tissues from healthy tissues and differentiated distinct histomorphological kidney cancer subtypes.", + "TAG_DATA": [ + "117, patients {'context': 'B-patient'}", + "118, with {'context': 'I-patient'}", + "119, renal {'context': 'B-neoplasm'}", + "120, cell {'context': 'I-neoplasm'}", + "121, carcinoma {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "117, patients ['l0', 'l1', 'l2', 'l3']", + "118, with ['l0', 'l4', 'l5', 'l6']", + "119, renal ['l1', 'l4', 'l7', 'l8']", + "120, cell ['l2', 'l5', 'l7', 'l9']", + "121, carcinoma ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25706875", + "TEXT": "Human colorectal tumors bear recurrent mutations in genes encoding proteins operative in the WNT, MAPK, TGF-β, TP53 and PI3K pathways. Although these pathways influence intestinal stem cell niche signaling, the extent to which mutations in these pathways contribute to human colorectal carcinogenesis remains unclear. Here we use the CRISPR-Cas9 genome-editing system to introduce multiple such mutations into organoids derived from normal human intestinal epithelium. By modulating the culture conditions to mimic that of the intestinal niche, we selected isogenic organoids harboring mutations in the tumor suppressor genes APC, SMAD4 and TP53, and in the oncogenes KRAS and/or PIK3CA. Organoids engineered to express all five mutations grew independently of niche factors in vitro, and they formed tumors after implantation under the kidney subcapsule in mice. Although they formed micrometastases containing dormant tumor-initiating cells after injection into the spleen of mice, they failed to colonize in the liver. In contrast, engineered organoids derived from chromosome-instable human adenomas formed macrometastatic colonies. These results suggest that 'driver' pathway mutations enable stem cell maintenance in the hostile tumor microenvironment, but that additional molecular lesions are required for invasive behavior.", + "TAG_DATA": [ + "79, organoids {'context': 'B-organoid'}", + "98, Organoids {'context': 'B-organoid'}", + "110, in {'context': 'B-in vitro'}", + "111, vitro, {'context': 'I-in vitro'}", + "115, tumors {'phenotype': 'B-tumourigenesis'}", + "120, kidney {'context': 'B-tissue/organ'}", + "121, subcapsule {'context': 'I-tissue/organ'}", + "123, mice. {'context': 'B-organism'}", + "131, cells {'context': 'I-cells'}", + "136, spleen {'context': 'B-tissue/organ'}", + "138, mice, {'context': 'B-organism'}", + "145, liver. {'context': 'B-tissue/organ'}", + "149, organoids {'context': 'B-organoid'}", + "153, human {'context': 'B-neoplasm'}", + "154, adenomas {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "98, Organoids ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "110, in ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "111, vitro, ['l1', 'l7', 'l12', 'l13', 'l14', 'l15']", + "115, tumors ['l2', 'l8', 'l12', 'l16', 'l17', 'l18']", + "120, kidney ['l3', 'l9', 'l13', 'l16', 'l19', 'l20', 'l21']", + "121, subcapsule ['l4', 'l10', 'l14', 'l17', 'l19', 'l22', 'l23']", + "123, mice. ['l5', 'l11', 'l15', 'l18', 'l20', 'l22']", + "130, tumor-initiating ['l24', 'l25', 'l26', 'l27']", + "131, cells ['l6', 'l21', 'l23', 'l24', 'l28', 'l29', 'l30']", + "136, spleen ['l25', 'l28', 'l31', 'l32']", + "138, mice, ['l26', 'l29', 'l31', 'l33']", + "145, liver. ['l27', 'l30', 'l32', 'l33']", + "149, organoids ['l34', 'l35']", + "153, human ['l34', 'l36']", + "154, adenomas ['l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organoid", + "words": [ + "Organoids" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidney", + "subcapsule" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "25706874", + "TEXT": "Insulin resistance results from several pathophysiologic mechanisms, including chronic tissue inflammation and defective insulin signaling. We found that liver, muscle and adipose tissue exhibit higher levels of the chemotactic eicosanoid LTB4 in obese high-fat diet (HFD)-fed mice. Inhibition of the LTB4 receptor Ltb4r1, through either genetic or pharmacologic loss of function, led to an anti-inflammatory phenotype with protection from insulin resistance and hepatic steatosis. In vitro treatment with LTB4 directly enhanced macrophage chemotaxis, stimulated inflammatory pathways, reduced insulin-stimulated glucose uptake in L6 myocytes, and impaired insulin-mediated suppression of hepatic glucose output in primary mouse hepatocytes. This was accompanied by lower insulin-stimulated Akt phosphorylation and higher Irs-1/2 serine phosphorylation, and all of these events were dependent on Gαi and Jnk1, two downstream mediators of Ltb4r1 signaling. These observations elucidate a novel role of the LTB4-Ltb4r1 signaling pathway in hepatocyte and myocyte insulin resistance, and they show that in vivo inhibition of Ltb4r1 leads to robust insulin-sensitizing effects.", + "TAG_DATA": [ + "37, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "38, of {'perturbing_action': 'I-pharmacological inhibition'}", + "39, the {'perturbing_action': 'I-pharmacological inhibition'}", + "40, LTB4 {'perturbing_action': 'I-pharmacological inhibition'}", + "41, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "42, Ltb4r1, {'perturbing_action': 'I-pharmacological inhibition'}", + "47, pharmacologic {'perturbing_action': 'B-gene loss-of-function'}", + "48, loss {'perturbing_action': 'I-gene loss-of-function'}", + "49, of {'perturbing_action': 'I-gene loss-of-function'}", + "50, function, {'perturbing_action': 'I-gene loss-of-function'}", + "64, In {'context': 'B-in vitro'}", + "65, vitro {'context': 'I-in vitro'}", + "70, enhanced {'effect': 'B-positive'}", + "71, macrophage {'context': 'B-cells'}", + "72, chemotaxis, {'phenotype': 'B-migration'}", + "81, L6 {'context': 'B-cells'}", + "82, myocytes, {'context': 'I-cells'}", + "92, primary {'context': 'B-cells'}", + "93, mouse {'context': 'I-cells'}", + "94, hepatocytes. {'context': 'I-cells'}", + "146, in {'context': 'B-in vivo'}", + "147, vivo {'context': 'I-in vivo'}", + "148, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "149, of {'perturbing_action': 'I-pharmacological inhibition'}", + "150, Ltb4r1 {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "37, Inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "38, of ['l0', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "39, the ['l1', 'l19', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "40, LTB4 ['l2', 'l20', 'l37', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "41, receptor ['l3', 'l21', 'l38', 'l54', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "42, Ltb4r1, ['l4', 'l22', 'l39', 'l55', 'l70', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "47, pharmacologic ['l5', 'l23', 'l40', 'l56', 'l71', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "48, loss ['l6', 'l24', 'l41', 'l57', 'l72', 'l85', 'l97', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "49, of ['l7', 'l25', 'l42', 'l58', 'l73', 'l86', 'l98', 'l110', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "50, function, ['l8', 'l26', 'l43', 'l59', 'l74', 'l87', 'l99', 'l111', 'l122', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "64, In ['l9', 'l27', 'l44', 'l60', 'l75', 'l88', 'l100', 'l112', 'l123', 'l133', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151']", + "65, vitro ['l10', 'l28', 'l45', 'l61', 'l76', 'l89', 'l101', 'l113', 'l124', 'l134', 'l143', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159']", + "70, enhanced ['l11', 'l29', 'l46', 'l62', 'l77', 'l90', 'l102', 'l114', 'l125', 'l135', 'l144', 'l152', 'l160', 'l161', 'l162', 'l163']", + "71, macrophage ['l12', 'l30', 'l47', 'l63', 'l78', 'l91', 'l103', 'l115', 'l126', 'l136', 'l145', 'l153', 'l160', 'l164', 'l165', 'l166']", + "72, chemotaxis, ['l13', 'l31', 'l48', 'l64', 'l79', 'l92', 'l104', 'l116', 'l127', 'l137', 'l146', 'l154', 'l161', 'l164', 'l167', 'l168']", + "81, L6 ['l14', 'l32', 'l49', 'l65', 'l80', 'l93', 'l105', 'l117', 'l128', 'l138', 'l147', 'l155', 'l162', 'l165', 'l167', 'l169']", + "82, myocytes, ['l15', 'l33', 'l50', 'l66', 'l81', 'l94', 'l106', 'l118', 'l129', 'l139', 'l148', 'l156', 'l163', 'l166', 'l168', 'l169']", + "92, primary ['l16', 'l34', 'l51', 'l67', 'l82', 'l95', 'l107', 'l119', 'l130', 'l140', 'l149', 'l157', 'l170', 'l171']", + "93, mouse ['l17', 'l35', 'l52', 'l68', 'l83', 'l108', 'l120', 'l131', 'l141', 'l150', 'l158', 'l170', 'l172']", + "94, hepatocytes. ['l18', 'l36', 'l53', 'l69', 'l84', 'l96', 'l109', 'l121', 'l132', 'l142', 'l151', 'l159', 'l171', 'l172']", + "146, in ['l173', 'l174', 'l175', 'l176']", + "147, vivo ['l173', 'l177', 'l178', 'l179']", + "148, inhibition ['l174', 'l177', 'l180', 'l181']", + "149, of ['l175', 'l178', 'l180', 'l182']", + "150, Ltb4r1 ['l176', 'l179', 'l181', 'l182']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "the", + "LTB4", + "receptor", + "Ltb4r1," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "the", + "LTB4", + "receptor", + "Ltb4r1," + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "the", + "LTB4", + "receptor", + "Ltb4r1," + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophage", + "L6", + "myocytes,", + "primary", + "mouse", + "hepatocytes." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "the", + "LTB4", + "receptor", + "Ltb4r1," + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pharmacologic", + "loss", + "of", + "function," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pharmacologic", + "loss", + "of", + "function," + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pharmacologic", + "loss", + "of", + "function," + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophage", + "L6", + "myocytes,", + "primary", + "mouse", + "hepatocytes." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pharmacologic", + "loss", + "of", + "function," + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis," + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophage", + "L6", + "myocytes," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "macrophage", + "L6", + "myocytes," + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "Ltb4r1" + ] + } + } + ] + }, + { + "PMID": "25665180", + "TEXT": "One function of the glucocorticoid receptor (GR) in corticotroph cells is to suppress the transcription of the gene encoding proopiomelanocortin (POMC), the precursor of the stress hormone adrenocorticotropin (ACTH). Cushing disease is a neuroendocrine condition caused by partially glucocorticoid-resistant corticotroph adenomas that excessively secrete ACTH, which leads to hypercortisolism. Mutations that impair GR function explain glucocorticoid resistance only in sporadic cases. However, the proper folding of GR depends on direct interactions with the chaperone heat shock protein 90 (HSP90, refs. 7,8). We show here that corticotroph adenomas overexpress HSP90 compared to the normal pituitary. N- and C-terminal HSP90 inhibitors act at different steps of the HSP90 catalytic cycle to regulate corticotroph cell proliferation and GR transcriptional activity. C-terminal inhibitors cause the release of mature GR from HSP90, which promotes its exit from the chaperone cycle and potentiates its transcriptional activity in a corticotroph cell line and in primary cultures of human corticotroph adenomas. In an allograft mouse model, the C-terminal HSP90 inhibitor silibinin showed anti-tumorigenic effects, partially reverted hormonal alterations, and alleviated symptoms of Cushing disease. These results suggest that the pathogenesis of Cushing disease caused by overexpression of heat shock proteins and consequently misregulated GR sensitivity may be overcome pharmacologically with an appropriate HSP90 inhibitor.", + "TAG_DATA": [ + "97, HSP90 {'perturbing_action': 'I-pharmacological inhibition'}", + "110, corticotroph {'context': 'B-cells'}", + "111, cell {'context': 'I-cells'}", + "142, corticotroph {'context': 'B-cells'}", + "143, cell {'context': 'I-cells'}", + "144, line {'context': 'I-cells'}", + "147, primary {'context': 'B-cells'}", + "148, cultures {'context': 'I-cells'}", + "150, human {'context': 'B-neoplasm'}", + "151, corticotroph {'context': 'I-neoplasm'}", + "152, adenomas. {'context': 'I-neoplasm'}", + "155, allograft {'context': 'B-organism'}", + "156, mouse {'context': 'I-organism'}", + "157, model, {'context': 'I-organism'}", + "159, C-terminal {'perturbing_action': 'B-pharmacological inhibition'}", + "160, HSP90 {'perturbing_action': 'I-pharmacological inhibition'}", + "161, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "162, silibinin {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "97, HSP90 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "98, inhibitors ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "110, corticotroph ['l1', 'l11', 'l21', 'l22', 'l23', 'l24']", + "111, cell ['l2', 'l12', 'l21', 'l25', 'l26']", + "142, corticotroph ['l3', 'l13', 'l22', 'l27', 'l28', 'l29', 'l30', 'l31']", + "143, cell ['l4', 'l14', 'l23', 'l25', 'l27', 'l32']", + "144, line ['l5', 'l15', 'l24', 'l26', 'l28', 'l32']", + "147, primary ['l6', 'l16', 'l29', 'l33', 'l34', 'l35', 'l36']", + "148, cultures ['l7', 'l17', 'l30', 'l33', 'l37', 'l38', 'l39']", + "150, human ['l8', 'l18', 'l34', 'l37', 'l40', 'l41']", + "151, corticotroph ['l9', 'l19', 'l35', 'l38', 'l40', 'l42']", + "152, adenomas. ['l10', 'l20', 'l31', 'l36', 'l39', 'l41', 'l42']", + "155, allograft ['l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "156, mouse ['l43', 'l49', 'l50', 'l51', 'l52']", + "157, model, ['l44', 'l49', 'l53']", + "159, C-terminal ['l45', 'l54', 'l55', 'l56']", + "160, HSP90 ['l46', 'l50', 'l54', 'l57', 'l58']", + "161, inhibitor ['l47', 'l51', 'l55', 'l57', 'l59']", + "162, silibinin ['l48', 'l52', 'l53', 'l56', 'l58', 'l59']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "HSP90" + ] + }, + "context": { + "val": "cells", + "words": [ + "corticotroph", + "cell", + "line", + "primary", + "cultures" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "HSP90" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "corticotroph", + "adenomas." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "allograft", + "mouse", + "model," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "C-terminal", + "HSP90", + "inhibitor", + "silibinin" + ] + } + } + ] + }, + { + "PMID": "25665179", + "TEXT": "Currently, major concerns about the safety and efficacy of RNA interference (RNAi)-based bone anabolic strategies still exist because of the lack of direct osteoblast-specific delivery systems for osteogenic siRNAs. Here we screened the aptamer CH6 by cell-SELEX, specifically targeting both rat and human osteoblasts, and then we developed CH6 aptamer-functionalized lipid nanoparticles (LNPs) encapsulating osteogenic pleckstrin homology domain-containing family O member 1 (Plekho1) siRNA (CH6-LNPs-siRNA). Our results showed that CH6 facilitated in vitro osteoblast-selective uptake of Plekho1 siRNA, mainly via macropinocytosis, and boosted in vivo osteoblast-specific Plekho1 gene silencing, which promoted bone formation, improved bone microarchitecture, increased bone mass and enhanced mechanical properties in both osteopenic and healthy rodents. These results indicate that osteoblast-specific aptamer-functionalized LNPs could act as a new RNAi-based bone anabolic strategy, advancing the targeted delivery selectivity of osteogenic siRNAs from the tissue level to the cellular level.", + "TAG_DATA": [ + "40, rat {'context': 'B-cells'}", + "41, and {'context': 'I-cells'}", + "42, human {'context': 'I-cells'}", + "43, osteoblasts, {'context': 'I-cells'}", + "71, in {'context': 'B-in vitro'}", + "72, vitro {'context': 'I-in vitro'}", + "76, Plekho1 {'perturbing_action': 'B-rnai/knockdown'}", + "77, siRNA, {'perturbing_action': 'I-rnai/knockdown'}", + "82, boosted {'effect': 'B-positive'}", + "83, in {'context': 'B-in vivo'}", + "84, vivo {'context': 'I-in vivo'}", + "85, osteoblast-specific {'perturbing_action': 'B-rnai/knockdown'}", + "86, Plekho1 {'perturbing_action': 'I-rnai/knockdown'}", + "87, gene {'perturbing_action': 'I-rnai/knockdown'}", + "88, silencing, {'perturbing_action': 'I-rnai/knockdown'}", + "90, promoted {'effect': 'B-positive'}", + "91, bone {'phenotype': 'B-colony formation'}", + "92, formation, {'phenotype': 'I-tumourigenesis'}", + "107, healthy {'context': 'I-organism'}", + "108, rodents. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "40, rat ['l0', 'l1', 'l2']", + "41, and ['l0', 'l3', 'l4']", + "42, human ['l1', 'l3', 'l5']", + "43, osteoblasts, ['l2', 'l4', 'l5']", + "71, in ['l6', 'l7', 'l8']", + "72, vitro ['l6', 'l9', 'l10']", + "76, Plekho1 ['l7', 'l9', 'l11', 'l12', 'l13']", + "77, siRNA, ['l8', 'l10', 'l11', 'l14']", + "82, boosted ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "83, in ['l15', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "84, vivo ['l16', 'l24', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "85, osteoblast-specific ['l17', 'l25', 'l34', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "86, Plekho1 ['l18', 'l26', 'l35', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "87, gene ['l19', 'l27', 'l36', 'l44', 'l51', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "88, silencing, ['l20', 'l28', 'l37', 'l45', 'l52', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "90, promoted ['l21', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l69', 'l70', 'l71']", + "91, bone ['l12', 'l22', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72']", + "92, formation, ['l13', 'l14', 'l23', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l72']", + "107, healthy ['l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l73']", + "108, rodents. ['l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l73']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Plekho1", + "siRNA," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Plekho1", + "osteoblast-specific", + "gene", + "silencing," + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "bone" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Plekho1", + "siRNA,", + "osteoblast-specific", + "gene", + "silencing," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "boosted", + "promoted" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "boosted", + "promoted" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "osteoblast-specific", + "Plekho1", + "gene", + "silencing," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "boosted", + "promoted" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "bone" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "boosted", + "promoted" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "osteoblast-specific", + "Plekho1", + "gene", + "silencing," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "bone" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "osteoblast-specific", + "Plekho1", + "gene", + "silencing," + ] + }, + "context": { + "val": "organism", + "words": [ + "healthy", + "rodents." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "organism", + "words": [ + "healthy" + ] + } + } + ] + }, + { + "PMID": "25559343", + "TEXT": "The typical method for creating targeted contrast agents requires covalent conjugation of separate targeting and fluorophore domains. In this study, we demonstrate that it is possible to create near-infrared (NIR) fluorophores with different tissue specificities driven by their inherent chemical structures. Thus, a single compact molecule performs both targeting and imaging. We use this strategy to solve a major problem in head and neck surgery: the identification and preservation of parathyroid and thyroid glands. We synthesized 700-nm and 800-nm halogenated fluorophores that show high uptake into these glands after a single intravenous (IV) injection of 0.06 mg kg(-1) in a pig. By using a dual-channel NIR imaging system, we observed-in real time and with high sensitivity-the unambiguous distinction of parathyroid and thyroid glands simultaneously in the context of blood and surrounding soft tissue. This novel technology lays a foundation for performing head and neck surgery with increased precision and efficiency along with potentially lower morbidity, and it provides a general strategy for developing targeted NIR fluorophores.", + "TAG_DATA": [ + "100, pig. {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25501906", + "TEXT": "Means for temporally regulating gene expression and cellular activity are invaluable for elucidating underlying physiological processes and would have therapeutic implications. Here we report the development of a genetically encoded system for remote regulation of gene expression by low-frequency radio waves (RFs) or a magnetic field. Iron oxide nanoparticles are synthesized intracellularly as a GFP-tagged ferritin heavy and light chain fusion. The ferritin nanoparticles associate with a camelid anti-GFP-transient receptor potential vanilloid 1 fusion protein, αGFP-TRPV1, and can transduce noninvasive RF or magnetic fields into channel activation, also showing that TRPV1 can transduce a mechanical stimulus. This, in turn, initiates calcium-dependent transgene expression. In mice with stem cell or viral expression of these genetically encoded components, remote stimulation of insulin transgene expression with RF or a magnet lowers blood glucose. This robust, repeatable method for remote regulation in vivo may ultimately have applications in basic science, technology and therapeutics.", + "TAG_DATA": [ + "104, mice {'context': 'B-organism'}", + "107, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "104, mice ['l0']", + "107, cell ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25501905", + "TEXT": "CD4+ T cells differentiate into memory T cells that protect the host from subsequent infection. In contrast, autoreactive memory CD4+ T cells harm the body by persisting in the tissues. The underlying pathways controlling the maintenance of memory CD4+ T cells remain undefined. We show here that memory CD4+ T cell survival is impaired in the absence of the Notch signaling protein known as recombination signal binding protein for immunoglobulin κ J region (Rbpj). Treatment of mice with a Notch inhibitor reduced memory CD4+ T cell numbers and prevented the recurrent induction of experimental autoimmune encephalomyelitis. Rbpj-deficient CD4+ memory T cells exhibit reduced glucose uptake due to impaired AKT phosphorylation, resulting in low Glut1 expression. Treating mice with pyruvic acid, which bypasses glucose uptake and supplies the metabolite downstream of glucose uptake, inhibited the decrease of autoimmune memory CD4+ T cells in the absence of Notch signaling, suggesting memory CD4+ T cell survival relies on glucose metabolism. Together, these data define a central role for Notch signaling in maintaining memory CD4+ T cells through the regulation of glucose uptake.", + "TAG_DATA": [ + "76, mice {'context': 'B-organism'}", + "79, Notch {'perturbing_action': 'B-pharmacological inhibition'}", + "80, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "82, memory {'context': 'B-cells'}", + "83, CD4+ {'context': 'I-cells'}", + "84, T {'context': 'I-cells'}", + "85, cell {'context': 'I-cells'}", + "96, Rbpj-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "97, CD4+ {'context': 'B-cells'}", + "98, memory {'context': 'I-cells'}", + "99, T {'context': 'I-cells'}", + "100, cells {'context': 'I-cells'}", + "116, mice {'context': 'B-organism'}", + "136, autoimmune {'context': 'B-cells'}", + "137, memory {'context': 'I-cells'}", + "138, CD4+ {'context': 'I-cells'}", + "139, T {'context': 'I-cells'}", + "140, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "76, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "79, Notch ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "80, inhibitor ['l1', 'l8', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "82, memory ['l2', 'l9', 'l16', 'l23', 'l24', 'l25']", + "83, CD4+ ['l3', 'l10', 'l17', 'l23', 'l26', 'l27']", + "84, T ['l4', 'l11', 'l18', 'l24', 'l26', 'l28']", + "85, cell ['l5', 'l12', 'l19', 'l25', 'l27', 'l28']", + "96, Rbpj-deficient ['l29', 'l30', 'l31', 'l32']", + "97, CD4+ ['l29', 'l33', 'l34', 'l35']", + "98, memory ['l13', 'l20', 'l30', 'l33', 'l36', 'l37']", + "99, T ['l6', 'l14', 'l21', 'l31', 'l34', 'l36', 'l38']", + "100, cells ['l7', 'l15', 'l22', 'l32', 'l35', 'l37', 'l38']", + "116, mice ['l39', 'l40', 'l41', 'l42', 'l43']", + "136, autoimmune ['l39', 'l44', 'l45', 'l46', 'l47']", + "137, memory ['l40', 'l44', 'l48', 'l49', 'l50']", + "138, CD4+ ['l41', 'l45', 'l48', 'l51', 'l52']", + "139, T ['l42', 'l46', 'l49', 'l51', 'l53']", + "140, cells ['l43', 'l47', 'l50', 'l52', 'l53']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Notch", + "inhibitor" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Notch", + "inhibitor" + ] + }, + "context": { + "val": "cells", + "words": [ + "memory", + "CD4+", + "T", + "cell", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rbpj-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "memory", + "T", + "cells" + ] + } + } + ] + }, + { + "PMID": "25485911", + "TEXT": "Mitochondrial uncoupling protein 1 (UCP1) is enriched within interscapular brown adipose tissue (iBAT) and beige (also known as brite) adipose tissue, but its thermogenic potential is reduced with obesity and type 2 diabetes for reasons that are not understood. Serotonin (5-hydroxytryptamine, 5-HT) is a highly conserved biogenic amine that resides in non-neuronal and neuronal tissues that are specifically regulated via tryptophan hydroxylase 1 (Tph1) and Tph2, respectively. Recent findings suggest that increased peripheral serotonin and polymorphisms in TPH1 are associated with obesity; however, whether this is directly related to reduced BAT thermogenesis and obesity is not known. We find that Tph1-deficient mice fed a high-fat diet (HFD) are protected from obesity, insulin resistance and nonalcoholic fatty liver disease (NAFLD) while exhibiting greater energy expenditure by BAT. Small-molecule chemical inhibition of Tph1 in HFD-fed mice mimics the benefits ascribed to Tph1 genetic deletion, effects that depend on UCP1-mediated thermogenesis. The inhibitory effects of serotonin on energy expenditure are cell autonomous, as serotonin blunts β-adrenergic induction of the thermogenic program in brown and beige adipocytes in vitro. As obesity increases peripheral serotonin, the inhibition of serotonin signaling or its synthesis in adipose tissue may be an effective treatment for obesity and its comorbidities.", + "TAG_DATA": [ + "100, Tph1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "101, mice {'context': 'B-organism'}", + "126, Small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "127, chemical {'perturbing_action': 'I-pharmacological inhibition'}", + "128, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "129, of {'perturbing_action': 'I-pharmacological inhibition'}", + "130, Tph1 {'perturbing_action': 'I-pharmacological inhibition'}", + "133, mice {'context': 'B-organism'}", + "139, Tph1 {'perturbing_action': 'B-gene loss-of-function'}", + "140, genetic {'perturbing_action': 'I-gene loss-of-function'}", + "141, deletion, {'perturbing_action': 'I-gene loss-of-function'}", + "169, brown {'context': 'B-cells'}", + "170, and {'context': 'I-cells'}", + "171, beige {'context': 'I-cells'}", + "172, adipocytes {'context': 'I-cells'}", + "173, in {'context': 'B-in vitro'}", + "174, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "100, Tph1-deficient ['l0']", + "101, mice ['l0']", + "126, Small-molecule ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "127, chemical ['l1', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "128, inhibition ['l2', 'l15', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "129, of ['l3', 'l16', 'l28', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "130, Tph1 ['l4', 'l17', 'l29', 'l40', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "133, mice ['l5', 'l18', 'l30', 'l41', 'l50', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "139, Tph1 ['l6', 'l19', 'l31', 'l42', 'l51', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "140, genetic ['l7', 'l20', 'l32', 'l43', 'l52', 'l59', 'l64', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "141, deletion, ['l8', 'l21', 'l33', 'l44', 'l53', 'l60', 'l65', 'l72', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "169, brown ['l9', 'l22', 'l34', 'l45', 'l54', 'l61', 'l66', 'l73', 'l79', 'l85', 'l86', 'l87', 'l88', 'l89']", + "170, and ['l10', 'l23', 'l35', 'l46', 'l55', 'l62', 'l67', 'l74', 'l80', 'l85', 'l90', 'l91', 'l92', 'l93']", + "171, beige ['l11', 'l24', 'l36', 'l47', 'l56', 'l68', 'l75', 'l81', 'l86', 'l90', 'l94', 'l95', 'l96']", + "172, adipocytes ['l12', 'l25', 'l37', 'l48', 'l57', 'l63', 'l69', 'l76', 'l82', 'l87', 'l91', 'l94', 'l97', 'l98']", + "173, in ['l13', 'l26', 'l38', 'l49', 'l70', 'l77', 'l83', 'l88', 'l92', 'l95', 'l97', 'l99']", + "174, vitro. ['l14', 'l27', 'l39', 'l71', 'l78', 'l84', 'l89', 'l93', 'l96', 'l98', 'l99']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tph1-deficient", + "Tph1", + "genetic", + "deletion," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Small-molecule", + "chemical", + "inhibition", + "of", + "Tph1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Small-molecule", + "chemical", + "inhibition", + "of", + "Tph1" + ] + }, + "context": { + "val": "cells", + "words": [ + "brown", + "and", + "beige", + "adipocytes" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Small-molecule", + "chemical", + "inhibition", + "of" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tph1", + "genetic", + "deletion," + ] + }, + "context": { + "val": "cells", + "words": [ + "brown", + "and", + "beige", + "adipocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tph1", + "genetic", + "deletion," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "25485909", + "TEXT": "We report the discovery of a new monomeric peptide that reduces body weight and diabetic complications in rodent models of obesity by acting as an agonist at three key metabolically-related peptide hormone receptors: glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors. This triple agonist demonstrates supraphysiological potency and equally aligned constituent activities at each receptor, all without cross-reactivity at other related receptors. Such balanced unimolecular triple agonism proved superior to any existing dual coagonists and best-in-class monoagonists to reduce body weight, enhance glycemic control and reverse hepatic steatosis in relevant rodent models. Various loss-of-function models, including genetic knockout, pharmacological blockade and selective chemical knockout, confirmed contributions of each constituent activity in vivo. We demonstrate that these individual constituent activities harmonize to govern the overall metabolic efficacy, which predominantly results from synergistic glucagon action to increase energy expenditure, GLP-1 action to reduce caloric intake and improve glucose control, and GIP action to potentiate the incretin effect and buffer against the diabetogenic effect of inherent glucagon activity. These preclinical studies suggest that, so far, this unimolecular, polypharmaceutical strategy has potential to be the most effective pharmacological approach to reversing obesity and related metabolic disorders.", + "TAG_DATA": [ + "92, rodent {'context': 'B-organism'}", + "93, models. {'context': 'I-organism'}", + "112, in {'context': 'B-in vivo'}", + "113, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "92, rodent ['l0']", + "93, models. ['l0']", + "112, in ['l1']", + "113, vivo. ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25485908", + "TEXT": "Epilepsy is one of the most common and intractable brain disorders. Mutations in the human gene LGI1, encoding a neuronal secreted protein, cause autosomal dominant lateral temporal lobe epilepsy (ADLTE). However, the pathogenic mechanisms of LGI1 mutations remain unclear. We classified 22 reported LGI1 missense mutations as either secretion defective or secretion competent, and we generated and analyzed two mouse models of ADLTE encoding mutant proteins representative of the two groups. The secretion-defective LGI1(E383A) protein was recognized by the ER quality-control machinery and prematurely degraded, whereas the secretable LGI1(S473L) protein abnormally dimerized and was selectively defective in binding to one of its receptors, ADAM22. Both mutations caused a loss of function, compromising intracellular trafficking or ligand activity of LGI1 and converging on reduced synaptic LGI1-ADAM22 interaction. A chemical corrector, 4-phenylbutyrate (4PBA), restored LGI1(E383A) folding and binding to ADAM22 and ameliorated the increased seizure susceptibility of the LGI1(E383A) model mice. This study establishes LGI1-related epilepsy as a conformational disease and suggests new therapeutic options for human epilepsy.", + "TAG_DATA": [ + "146, LGI1(E383A) {'perturbing_action': 'B-other'}", + "147, model {'perturbing_action': 'I-other'}", + "148, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "146, LGI1(E383A) ['l0', 'l1']", + "147, model ['l0', 'l2']", + "148, mice. ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "LGI1(E383A)", + "model" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "25473919", + "TEXT": "Cardiac regeneration is a rapidly evolving and controversial field of research. The identification some 12 years ago of progenitor cells that reside within the heart spurred enthusiasm for cell-based regenerative therapies. However, recent evidence has called into question both the presence of a biologically important stem cell population in the heart and the ability of exogenously derived cells to promote regeneration through direct formation of new cardiomyocytes. Here, we discuss recent developments that suggest an emerging consensus on the ability of different cell types to regenerate the adult mammalian heart.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25473918", + "TEXT": "Vascular endothelial growth factor A (VEGF-A) is a potent proangiogenic cytokine elevated in patients with peripheral artery disease (PAD). A new study links impaired vascular regrowth in PAD to increased expression of an antiangiogenic splice variant of VEGF-A.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25473913", + "TEXT": "This year's newsworthy drugs made major strides against infectious diseases, cancer and more. Some others received attention for controversies they stemmed or stomped. Here is a look at the therapies that leapt forward, some that are in limbo, and others that fell by the wayside.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25419710", + "TEXT": "Proper function of the endoplasmic reticulum (ER) and mitochondria is crucial for cellular homeostasis, and dysfunction at either site has been linked to pathophysiological states, including metabolic diseases. Although the ER and mitochondria play distinct cellular roles, these organelles also form physical interactions with each other at sites defined as mitochondria-associated ER membranes (MAMs), which are essential for calcium, lipid and metabolite exchange. Here we show that in the liver, obesity leads to a marked reorganization of MAMs resulting in mitochondrial calcium overload, compromised mitochondrial oxidative capacity and augmented oxidative stress. Experimental induction of ER-mitochondria interactions results in oxidative stress and impaired metabolic homeostasis, whereas downregulation of PACS-2 or IP3R1, proteins important for ER-mitochondria tethering or calcium transport, respectively, improves mitochondrial oxidative capacity and glucose metabolism in obese animals. These findings establish excessive ER-mitochondrial coupling as an essential component of organelle dysfunction in obesity that may contribute to the development of metabolic pathologies such as insulin resistance and diabetes.", + "TAG_DATA": [ + "69, liver, {'context': 'B-tissue/organ'}", + "105, downregulation {'perturbing_action': 'B-gene loss-of-function'}", + "106, of {'perturbing_action': 'I-gene loss-of-function'}", + "107, PACS-2 {'perturbing_action': 'I-gene loss-of-function'}", + "108, or {'perturbing_action': 'I-gene loss-of-function'}", + "109, IP3R1, {'perturbing_action': 'I-gene loss-of-function'}", + "127, obese {'context': 'B-organism'}", + "128, animals. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "105, downregulation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "106, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "107, PACS-2 ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "108, or ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "109, IP3R1, ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "127, obese ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "128, animals. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "downregulation", + "of", + "PACS-2", + "or", + "IP3R1," + ] + }, + "context": { + "val": "organism", + "words": [ + "obese", + "animals." + ] + } + } + ] + }, + { + "PMID": "25401692", + "TEXT": "Neurodegenerative diseases, such as frontotemporal dementia (FTD), are often associated with behavioral deficits, but the underlying anatomical and molecular causes remain poorly understood. Here we show that forebrain-specific expression of FTD-associated mutant CHMP2B in mice causes several age-dependent neurodegenerative phenotypes, including social behavioral impairments. The social deficits were accompanied by a change in AMPA receptor (AMPAR) composition, leading to an imbalance between Ca(2+)-permeable and Ca(2+)-impermeable AMPARs. Expression of most AMPAR subunits was regulated by the brain-enriched microRNA miR-124, whose abundance was markedly decreased in the superficial layers of the cerebral cortex of mice expressing the mutant CHMP2B. We found similar changes in miR-124 and AMPAR levels in the frontal cortex and induced pluripotent stem cell-derived neurons from subjects with behavioral variant FTD. Moreover, ectopic miR-124 expression in the medial prefrontal cortex of mutant mice decreased AMPAR levels and partially rescued behavioral deficits. Knockdown of the AMPAR subunit Gria2 also alleviated social impairments. Our results identify a previously undescribed mechanism involving miR-124 and AMPARs in regulating social behavior in FTD and suggest a potential therapeutic avenue.", + "TAG_DATA": [ + "27, forebrain-specific {'perturbing_action': 'B-other'}", + "28, expression {'perturbing_action': 'I-other'}", + "29, of {'perturbing_action': 'I-other'}", + "30, FTD-associated {'perturbing_action': 'I-other'}", + "31, mutant {'perturbing_action': 'I-other'}", + "32, CHMP2B {'perturbing_action': 'I-other'}", + "92, mice {'context': 'B-organism'}", + "95, mutant {'perturbing_action': 'B-other'}", + "96, CHMP2B. {'perturbing_action': 'I-other'}", + "112, pluripotent {'context': 'B-cells'}", + "113, stem {'context': 'I-cells'}", + "114, cell-derived {'context': 'I-cells'}", + "115, neurons {'context': 'I-cells'}", + "123, ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "124, miR-124 {'perturbing_action': 'I-gene gain-of-function'}", + "125, expression {'perturbing_action': 'I-gene gain-of-function'}", + "128, medial {'context': 'B-tissue/organ'}", + "129, prefrontal {'context': 'I-tissue/organ'}", + "130, cortex {'context': 'I-tissue/organ'}", + "133, mice {'context': 'B-organism'}", + "142, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "143, of {'perturbing_action': 'I-rnai/knockdown'}", + "144, the {'perturbing_action': 'I-rnai/knockdown'}", + "145, AMPAR {'perturbing_action': 'I-rnai/knockdown'}", + "146, subunit {'perturbing_action': 'I-rnai/knockdown'}", + "147, Gria2 {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "27, forebrain-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "28, expression ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "29, of ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "30, FTD-associated ['l2', 'l8', 'l13', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "31, mutant ['l3', 'l9', 'l14', 'l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "32, CHMP2B ['l4', 'l10', 'l15', 'l21', 'l26', 'l31', 'l32']", + "92, mice ['l5', 'l11', 'l16', 'l22', 'l27', 'l31', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "95, mutant ['l33', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "96, CHMP2B. ['l34', 'l39', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "112, pluripotent ['l35', 'l40', 'l49', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "113, stem ['l17', 'l23', 'l28', 'l36', 'l41', 'l50', 'l56', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "114, cell-derived ['l18', 'l24', 'l29', 'l37', 'l42', 'l51', 'l57', 'l66', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "115, neurons ['l6', 'l12', 'l19', 'l25', 'l30', 'l32', 'l38', 'l43', 'l52', 'l58', 'l67', 'l73', 'l79', 'l80', 'l81']", + "123, ectopic ['l44', 'l53', 'l59', 'l68', 'l74', 'l79', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "124, miR-124 ['l45', 'l54', 'l60', 'l69', 'l75', 'l80', 'l82', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "125, expression ['l46', 'l55', 'l61', 'l70', 'l76', 'l81', 'l83', 'l89', 'l95', 'l96', 'l97', 'l98', 'l99']", + "127, the ['l62', 'l84', 'l90', 'l95', 'l100', 'l101', 'l102', 'l103']", + "128, medial ['l63', 'l85', 'l91', 'l96', 'l100', 'l104', 'l105', 'l106']", + "129, prefrontal ['l47', 'l64', 'l71', 'l77', 'l86', 'l92', 'l97', 'l101', 'l104', 'l107', 'l108']", + "130, cortex ['l48', 'l65', 'l72', 'l78', 'l87', 'l93', 'l98', 'l102', 'l105', 'l107', 'l109']", + "133, mice ['l88', 'l94', 'l99', 'l103', 'l106', 'l108', 'l109']", + "142, Knockdown ['l110', 'l111', 'l112', 'l113', 'l114']", + "143, of ['l110', 'l115', 'l116', 'l117', 'l118']", + "144, the ['l111', 'l115', 'l119', 'l120', 'l121']", + "145, AMPAR ['l112', 'l116', 'l119', 'l122', 'l123']", + "146, subunit ['l113', 'l117', 'l120', 'l122', 'l124']", + "147, Gria2 ['l114', 'l118', 'l121', 'l123', 'l124']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "forebrain-specific", + "expression", + "of", + "FTD-associated", + "mutant", + "CHMP2B", + "CHMP2B." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "forebrain-specific", + "expression", + "of", + "FTD-associated", + "mutant", + "CHMP2B", + "CHMP2B." + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons", + "stem", + "cell-derived", + "pluripotent" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "prefrontal", + "cortex" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pluripotent", + "stem", + "cell-derived", + "neurons" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "miR-124", + "expression" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "miR-124", + "expression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "medial", + "prefrontal", + "cortex" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "miR-124", + "expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "25384087", + "TEXT": "The dynamics of β-amyloid deposition and related second-order physiological effects, such as regional cerebral blood flow (rCBF), are key factors for a deeper understanding of Alzheimer's disease (AD). We present longitudinal in vivo data on the dynamics of β-amyloid deposition and the decline of rCBF in two different amyloid precursor protein (APP) transgenic mouse models of AD. Using a multiparametric positron emission tomography and magnetic resonance imaging approach, we demonstrate that in the presence of cerebral β-amyloid angiopathy (CAA), β-amyloid deposition is accompanied by a decline of rCBF. Loss of perfusion correlates with the growth of β-amyloid plaque burden but is not related to the number of CAA-induced microhemorrhages. However, in a mouse model of parenchymal β-amyloidosis and negligible CAA, rCBF is unchanged. Because synaptically driven spontaneous network activity is similar in both transgenic mouse strains, we conclude that the disease-related decline of rCBF is caused by CAA.", + "TAG_DATA": [ + "48, amyloid {'perturbing_action': 'B-gene gain-of-function'}", + "49, precursor {'perturbing_action': 'I-gene gain-of-function'}", + "50, protein {'perturbing_action': 'I-gene gain-of-function'}", + "51, (APP) {'perturbing_action': 'I-gene gain-of-function'}", + "52, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "53, mouse {'context': 'B-organism'}", + "54, models {'context': 'I-organism'}", + "55, of {'context': 'I-organism'}", + "56, AD. {'context': 'I-organism'}", + "112, mouse {'context': 'B-organism'}", + "113, model {'context': 'I-organism'}", + "133, transgenic {'context': 'B-organism'}", + "134, mouse {'context': 'I-organism'}", + "135, strains, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "48, amyloid ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "49, precursor ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "50, protein ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "51, (APP) ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "52, transgenic ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "53, mouse ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "54, models ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "55, of ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "56, AD. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "112, mouse ['l36']", + "113, model ['l36']", + "133, transgenic ['l37', 'l38']", + "134, mouse ['l37', 'l39']", + "135, strains, ['l38', 'l39']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "amyloid", + "precursor", + "protein", + "(APP)", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "of", + "AD." + ] + } + } + ] + }, + { + "PMID": "25344738", + "TEXT": "Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell-mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN-α and IFN-β receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release of chemokine (C-X-C motif) ligand 10 (CXCL10). Tumors lacking Tlr3 or Ifnar failed to respond to chemotherapy unless type I IFN or Cxcl10, respectively, was artificially supplied. Moreover, a type I IFN-related signature predicted clinical responses to anthracycline-based chemotherapy in several independent cohorts of patients with breast carcinoma characterized by poor prognosis. Our data suggest that anthracycline-mediated immune responses mimic those induced by viral pathogens. We surmise that such 'viral mimicry' constitutes a hallmark of successful chemotherapy.", + "TAG_DATA": [ + "36, malignant {'context': 'B-transformed cells'}", + "81, Tumors {'context': 'B-neoplasm'}", + "82, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "83, Tlr3 {'perturbing_action': 'I-gene loss-of-function'}", + "84, or {'perturbing_action': 'I-gene loss-of-function'}", + "85, Ifnar {'perturbing_action': 'I-gene loss-of-function'}", + "86, failed {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "81, Tumors ['l0', 'l1', 'l2', 'l3', 'l4']", + "82, lacking ['l0', 'l5', 'l6', 'l7', 'l8']", + "83, Tlr3 ['l1', 'l5', 'l9', 'l10', 'l11']", + "84, or ['l2', 'l6', 'l9', 'l12', 'l13']", + "85, Ifnar ['l3', 'l7', 'l10', 'l12', 'l14']", + "86, failed ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "Tumors" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "Tlr3", + "or", + "Ifnar" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "Tumors" + ] + }, + "effect": { + "val": "negative", + "words": [ + "failed" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "Tlr3", + "or", + "Ifnar" + ] + }, + "effect": { + "val": "negative", + "words": [ + "failed" + ] + } + } + ] + }, + { + "PMID": "25326802", + "TEXT": "In the bone marrow, hematopoietic stem cells (HSCs) lodge in specialized microenvironments that tightly control the proliferative state of HSCs to adapt to the varying needs for replenishment of blood cells while also preventing HSC exhaustion. All putative niche cells suggested thus far have a nonhematopoietic origin. Thus, it remains unclear how feedback from mature cells is conveyed to HSCs to adjust their proliferation. Here we show that megakaryocytes (MKs) can directly regulate HSC pool size in mice. Three-dimensional whole-mount imaging revealed that endogenous HSCs are frequently located adjacent to MKs in a nonrandom fashion. Selective in vivo depletion of MKs resulted in specific loss of HSC quiescence and led to a marked expansion of functional HSCs. Gene expression analyses revealed that MKs are the source of chemokine C-X-C motif ligand 4 (CXCL4, also named platelet factor 4 or PF4) in the bone marrow, and we found that CXCL4 regulates HSC cell cycle activity. CXCL4 injection into mice resulted in a reduced number of HSCs because of their increased quiescence. By contrast, Cxcl4(-/-) mice exhibited an increased number of HSCs and increased HSC proliferation. Combined use of whole-mount imaging and computational modeling was highly suggestive of a megakaryocytic niche capable of independently influencing HSC maintenance by regulating quiescence. These results indicate that a terminally differentiated cell type derived from HSCs contributes to the HSC niche, directly regulating HSC behavior.", + "TAG_DATA": [ + "96, in {'context': 'B-in vivo'}", + "97, vivo {'context': 'I-in vivo'}", + "98, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "99, of {'perturbing_action': 'I-gene loss-of-function'}", + "100, MKs {'perturbing_action': 'I-gene loss-of-function'}", + "104, loss {'effect': 'B-negative'}", + "106, HSC {'context': 'B-cells'}", + "107, quiescence {'phenotype': 'B-quiescence'}", + "116, HSCs. {'context': 'B-cells'}", + "157, mice {'context': 'B-organism'}", + "164, HSCs {'context': 'B-cells'}", + "168, increased {'effect': 'B-positive'}", + "169, quiescence. {'phenotype': 'B-quiescence'}", + "172, Cxcl4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "173, mice {'context': 'B-organism'}", + "179, HSCs {'context': 'B-cells'}", + "181, increased {'effect': 'B-positive'}", + "182, HSC {'context': 'B-cells'}", + "183, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "96, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "97, vivo ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "98, depletion ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "99, of ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "100, MKs ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "104, loss ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "106, HSC ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "107, quiescence ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "116, HSCs. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35', 'l36', 'l37', 'l38']", + "157, mice ['l39', 'l40', 'l41']", + "164, HSCs ['l36', 'l39', 'l42', 'l43']", + "168, increased ['l37', 'l40', 'l42', 'l44']", + "169, quiescence. ['l38', 'l41', 'l43', 'l44']", + "172, Cxcl4(-/-) ['l45', 'l46', 'l47', 'l48', 'l49']", + "173, mice ['l45', 'l50', 'l51', 'l52', 'l53']", + "179, HSCs ['l46', 'l50']", + "181, increased ['l47', 'l51', 'l54', 'l55']", + "182, HSC ['l48', 'l52', 'l54', 'l56']", + "183, proliferation. ['l49', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "MKs" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "MKs" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "MKs", + "Cxcl4(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC", + "HSCs.", + "HSCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "MKs" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "loss" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC", + "HSCs." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "loss" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSC", + "HSCs.", + "HSCs" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence", + "quiescence." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSCs.", + "HSCs", + "HSC" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cxcl4(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cxcl4(-/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cxcl4(-/-)" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSC" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "25326801", + "TEXT": "Regulatory B cells (Breg cells) differentiate in response to inflammation and subsequently restrain excessive immune responses via the release of interleukin-10 (IL-10). However, the precise inflammatory signals governing their differentiation remain to be elucidated. Here we show that the gut microbiota promotes the differentiation of Breg cells in the spleen as well as in the mesenteric lymph nodes. Perturbation of the gut microbiome imposed either by antibiotic treatment or by changes in the sterility of housing conditions reduces the number and function of Breg cells. Following the induction of arthritis, IL-1β and IL-6 are produced only in conventionally housed mice and both cytokines directly promote Breg cell differentiation and IL-10 production. Mice lacking IL-6 receptor (IL-6R) or IL-1 receptor 1 (IL-1R1) specifically on B cells have a reduced number of IL-10-producing B cells and develop exacerbated arthritis compared to control animals. Thus, in response to inflammatory signals induced by both the gut flora and arthritis, Breg cells increase in number and restrain excessive inflammation.", + "TAG_DATA": [ + "45, Breg {'context': 'B-cells'}", + "46, cells {'context': 'I-cells'}", + "49, spleen {'context': 'B-tissue/organ'}", + "55, mesenteric {'context': 'B-tissue/organ'}", + "56, lymph {'context': 'I-tissue/organ'}", + "57, nodes. {'context': 'I-tissue/organ'}", + "83, Breg {'context': 'B-cells'}", + "84, cells. {'context': 'I-cells'}", + "104, promote {'effect': 'B-positive'}", + "105, Breg {'context': 'B-cells'}", + "106, cell {'context': 'I-cells'}", + "107, differentiation {'phenotype': 'B-differentiation'}", + "111, Mice {'context': 'B-organism'}", + "112, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "113, IL-6 {'perturbing_action': 'I-gene loss-of-function'}", + "114, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "115, (IL-6R) {'perturbing_action': 'I-gene loss-of-function'}", + "116, or {'perturbing_action': 'I-gene loss-of-function'}", + "117, IL-1 {'perturbing_action': 'I-gene loss-of-function'}", + "118, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "119, 1 {'perturbing_action': 'I-gene loss-of-function'}", + "120, (IL-1R1) {'perturbing_action': 'I-gene loss-of-function'}", + "121, specifically {'perturbing_action': 'I-gene loss-of-function'}", + "122, on {'perturbing_action': 'I-gene loss-of-function'}", + "123, B {'context': 'B-cells'}", + "124, cells {'context': 'I-cells'}", + "131, B {'context': 'B-cells'}", + "132, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, Breg ['l0', 'l1', 'l2', 'l3', 'l4']", + "46, cells ['l0', 'l5', 'l6', 'l7', 'l8']", + "49, spleen ['l1', 'l5', 'l9', 'l10', 'l11', 'l12']", + "55, mesenteric ['l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "56, lymph ['l9', 'l13', 'l19', 'l20', 'l21']", + "57, nodes. ['l2', 'l6', 'l10', 'l14', 'l19', 'l22', 'l23']", + "83, Breg ['l3', 'l7', 'l11', 'l15', 'l20', 'l22', 'l24']", + "84, cells. ['l4', 'l8', 'l12', 'l16', 'l21', 'l23', 'l24']", + "104, promote ['l25', 'l26', 'l27']", + "105, Breg ['l25', 'l28', 'l29']", + "106, cell ['l17', 'l26', 'l28', 'l30']", + "107, differentiation ['l18', 'l27', 'l29', 'l30']", + "111, Mice ['l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "112, lacking ['l31', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "113, IL-6 ['l32', 'l46', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "114, receptor ['l33', 'l47', 'l60', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "115, (IL-6R) ['l34', 'l48', 'l61', 'l73', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "116, or ['l35', 'l49', 'l62', 'l74', 'l85', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "117, IL-1 ['l36', 'l50', 'l63', 'l75', 'l86', 'l96', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "118, receptor ['l37', 'l51', 'l64', 'l76', 'l87', 'l97', 'l106', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "119, 1 ['l38', 'l52', 'l65', 'l77', 'l88', 'l98', 'l107', 'l115', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "120, (IL-1R1) ['l39', 'l53', 'l66', 'l78', 'l89', 'l99', 'l108', 'l116', 'l123', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "121, specifically ['l40', 'l54', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l124', 'l130', 'l136', 'l137', 'l138', 'l139', 'l140']", + "122, on ['l41', 'l55', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l125', 'l131', 'l136', 'l141', 'l142', 'l143', 'l144']", + "123, B ['l42', 'l56', 'l69', 'l81', 'l92', 'l102', 'l111', 'l119', 'l126', 'l132', 'l137', 'l141', 'l145', 'l146', 'l147']", + "124, cells ['l43', 'l57', 'l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l127', 'l133', 'l138', 'l142', 'l145', 'l148', 'l149']", + "131, B ['l44', 'l58', 'l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l128', 'l134', 'l139', 'l143', 'l146', 'l148', 'l150']", + "132, cells ['l45', 'l59', 'l72', 'l84', 'l95', 'l105', 'l114', 'l122', 'l129', 'l135', 'l140', 'l144', 'l147', 'l149', 'l150']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "mesenteric" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote" + ] + }, + "context": { + "val": "cells", + "words": [ + "Breg", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Breg", + "cell" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "IL-6", + "receptor", + "(IL-6R)", + "or", + "IL-1", + "1", + "(IL-1R1)", + "specifically", + "on" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "IL-6", + "receptor", + "(IL-6R)", + "or", + "IL-1", + "1", + "(IL-1R1)", + "specifically", + "on" + ] + }, + "context": { + "val": "cells", + "words": [ + "B", + "cells" + ] + } + } + ] + }, + { + "PMID": "25282359", + "TEXT": "Interleukin-17 (IL-17)-secreting T cells of the T helper 17 (TH17) lineage play a pathogenic role in multiple inflammatory and autoimmune conditions and thus represent a highly attractive target for therapeutic intervention. We report that inhibition of acetyl-CoA carboxylase 1 (ACC1) restrains the formation of human and mouse TH17 cells and promotes the development of anti-inflammatory Foxp3(+) regulatory T (Treg) cells. We show that TH17 cells, but not Treg cells, depend on ACC1-mediated de novo fatty acid synthesis and the underlying glycolytic-lipogenic metabolic pathway for their development. Although TH17 cells use this pathway to produce phospholipids for cellular membranes, Treg cells readily take up exogenous fatty acids for this purpose. Notably, pharmacologic inhibition or T cell-specific deletion of ACC1 not only blocks de novo fatty acid synthesis but also interferes with the metabolic flux of glucose-derived carbon via glycolysis and the tricarboxylic acid cycle. In vivo, treatment with the ACC-specific inhibitor soraphen A or T cell-specific deletion of ACC1 in mice attenuates TH17 cell-mediated autoimmune disease. Our results indicate fundamental differences between TH17 cells and Treg cells regarding their dependency on ACC1-mediated de novo fatty acid synthesis, which might be exploited as a new strategy for metabolic immune modulation of TH17 cell-mediated inflammatory diseases.", + "TAG_DATA": [ + "34, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "35, of {'perturbing_action': 'I-pharmacological inhibition'}", + "36, acetyl-CoA {'perturbing_action': 'I-pharmacological inhibition'}", + "37, carboxylase {'perturbing_action': 'I-pharmacological inhibition'}", + "38, 1 {'perturbing_action': 'I-pharmacological inhibition'}", + "39, (ACC1) {'perturbing_action': 'I-pharmacological inhibition'}", + "44, human {'context': 'B-cells'}", + "45, and {'context': 'I-cells'}", + "46, mouse {'context': 'I-cells'}", + "47, TH17 {'context': 'I-cells'}", + "48, cells {'context': 'I-cells'}", + "98, Treg {'context': 'B-cells'}", + "99, cells {'context': 'I-cells'}", + "113, T {'perturbing_action': 'B-gene loss-of-function'}", + "114, cell-specific {'perturbing_action': 'I-gene loss-of-function'}", + "115, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "116, of {'perturbing_action': 'I-gene loss-of-function'}", + "117, ACC1 {'perturbing_action': 'I-gene loss-of-function'}", + "143, In {'context': 'B-in vivo'}", + "144, vivo, {'context': 'I-in vivo'}", + "153, T {'perturbing_action': 'B-gene loss-of-function'}", + "154, cell-specific {'perturbing_action': 'B-gene loss-of-function'}", + "155, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "156, of {'perturbing_action': 'I-gene loss-of-function'}", + "157, ACC1 {'perturbing_action': 'I-gene loss-of-function'}", + "159, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "34, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "35, of ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "36, acetyl-CoA ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "37, carboxylase ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "38, 1 ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "39, (ACC1) ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "44, human ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60']", + "45, and ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l61', 'l62', 'l63']", + "46, mouse ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l61', 'l64', 'l65']", + "47, TH17 ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l62', 'l64', 'l66']", + "48, cells ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l63', 'l65', 'l66']", + "98, Treg ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l67', 'l68', 'l69']", + "99, cells ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l67']", + "113, T ['l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "114, cell-specific ['l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "115, deletion ['l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "116, of ['l68', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "117, ACC1 ['l69', 'l73', 'l78', 'l82', 'l85']", + "143, In ['l74', 'l79', 'l83', 'l86', 'l88']", + "144, vivo, ['l75', 'l80', 'l84', 'l87', 'l88']", + "153, T ['l89', 'l90', 'l91', 'l92', 'l93']", + "154, cell-specific ['l89', 'l94', 'l95', 'l96', 'l97']", + "155, deletion ['l90', 'l94', 'l98', 'l99', 'l100']", + "156, of ['l91', 'l95', 'l98', 'l101', 'l102']", + "157, ACC1 ['l92', 'l96', 'l99', 'l101', 'l103']", + "159, mice ['l93', 'l97', 'l100', 'l102', 'l103']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "acetyl-CoA", + "carboxylase", + "1", + "(ACC1)" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "and", + "mouse", + "TH17", + "cells", + "Treg" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Treg" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "ACC1" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "T", + "cell-specific", + "deletion", + "of" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "T", + "cell-specific", + "deletion", + "of", + "ACC1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "25282358", + "TEXT": "Osteogenesis during bone modeling and remodeling is coupled with angiogenesis. A recent study showed that a specific vessel subtype, strongly positive for CD31 and endomucin (CD31(hi)Emcn(hi)), couples angiogenesis and osteogenesis. Here, we found that platelet-derived growth factor-BB (PDGF-BB) secreted by preosteoclasts induces CD31(hi)Emcn(hi) vessel formation during bone modeling and remodeling. Mice with depletion of PDGF-BB in the tartrate-resistant acid phosphatase-positive cell lineage show significantly lower trabecular and cortical bone mass, serum and bone marrow PDGF-BB concentrations, and fewer CD31(hi)Emcn(hi) vessels compared to wild-type mice. In the ovariectomy (OVX)-induced osteoporotic mouse model, serum and bone marrow levels of PDGF-BB and numbers of CD31(hi)Emcn(hi) vessels are significantly lower compared to sham-operated controls. Treatment with exogenous PDGF-BB or inhibition of cathepsin K to increase the number of preosteoclasts, and thus the endogenous levels of PDGF-BB, increases CD31(hi)Emcn(hi) vessel number and stimulates bone formation in OVX mice. Thus, pharmacotherapies that increase PDGF-BB secretion from preosteoclasts offer a new therapeutic target for treating osteoporosis by promoting angiogenesis and thus bone formation.", + "TAG_DATA": [ + "50, Mice {'context': 'B-organism'}", + "52, depletion {'perturbing_action': 'B-gene loss-of-function'}", + "53, of {'perturbing_action': 'I-gene loss-of-function'}", + "54, PDGF-BB {'perturbing_action': 'I-gene loss-of-function'}", + "55, in {'perturbing_action': 'I-gene loss-of-function'}", + "56, the {'perturbing_action': 'I-gene loss-of-function'}", + "57, tartrate-resistant {'perturbing_action': 'I-gene loss-of-function'}", + "58, acid {'perturbing_action': 'I-gene loss-of-function'}", + "59, phosphatase-positive {'perturbing_action': 'I-gene loss-of-function'}", + "60, cell {'perturbing_action': 'I-gene loss-of-function'}", + "61, lineage {'perturbing_action': 'I-gene loss-of-function'}", + "89, mouse {'context': 'B-organism'}", + "90, model, {'context': 'I-organism'}", + "115, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "116, of {'perturbing_action': 'I-pharmacological inhibition'}", + "117, cathepsin {'perturbing_action': 'I-pharmacological inhibition'}", + "118, K {'perturbing_action': 'I-pharmacological inhibition'}", + "124, preosteoclasts, {'context': 'B-cells'}", + "137, stimulates {'effect': 'B-positive'}", + "138, bone {'phenotype': 'B-autophagy'}", + "139, formation {'phenotype': 'I-tumourigenesis'}", + "142, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "52, depletion ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "53, of ['l1', 'l10', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "54, PDGF-BB ['l2', 'l11', 'l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "55, in ['l3', 'l12', 'l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "56, the ['l4', 'l13', 'l23', 'l32', 'l40', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "57, tartrate-resistant ['l5', 'l14', 'l24', 'l33', 'l41', 'l48', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "58, acid ['l6', 'l15', 'l25', 'l34', 'l42', 'l49', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "59, phosphatase-positive ['l7', 'l16', 'l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "60, cell ['l8', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l70', 'l71', 'l72']", + "61, lineage ['l9', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l70', 'l73', 'l74']", + "89, mouse ['l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l73', 'l75']", + "90, model, ['l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l74', 'l75']", + "115, inhibition ['l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "116, of ['l76', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "117, cathepsin ['l77', 'l84', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "118, K ['l78', 'l85', 'l91', 'l97', 'l98', 'l99', 'l100', 'l101']", + "124, preosteoclasts, ['l79', 'l86', 'l92', 'l97', 'l102', 'l103', 'l104', 'l105']", + "137, stimulates ['l80', 'l87', 'l93', 'l98', 'l102', 'l106', 'l107', 'l108']", + "138, bone ['l81', 'l88', 'l94', 'l99', 'l103', 'l106', 'l109', 'l110']", + "139, formation ['l82', 'l89', 'l95', 'l100', 'l104', 'l107', 'l109', 'l111']", + "142, mice. ['l83', 'l90', 'l96', 'l101', 'l105', 'l108', 'l110', 'l111']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice", + "mouse", + "model," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "PDGF-BB", + "in", + "the", + "tartrate-resistant", + "acid", + "phosphatase-positive", + "cell", + "lineage" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "cathepsin", + "K" + ] + }, + "context": { + "val": "cells", + "words": [ + "preosteoclasts," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "cathepsin", + "K" + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "cathepsin", + "K" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "bone" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "cathepsin", + "K" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "cathepsin", + "K" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "preosteoclasts," + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "preosteoclasts," + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "bone" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "preosteoclasts," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "bone" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "bone" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "25242415", + "TEXT": "In spite of their precipitous encounter with the environment, newborn infants cannot readily mount T helper type 1 (TH1) cell antibacterial and antiviral responses. Instead, they show skewing toward TH2 responses, which, together with immunoregulatory functions, are thought to limit the potential for inflammatory damage, while simultaneously permitting intestinal colonization by commensals. However, these collective capabilities account for relatively few T cells. Here we demonstrate that a major T cell effector function in human newborns is interleukin-8 (CXCL8) production, which has the potential to activate antimicrobial neutrophils and γδ T cells. CXCL8 production was provoked by antigen receptor engagement of T cells that are distinct from those few cells producing TH1, TH2 and TH17 cytokines, was co-stimulated by Toll-like receptor signaling, and was readily apparent in preterm babies, particularly those experiencing neonatal infections and severe pathology. By contrast, CXCL8-producing T cells were rare in adults, and no equivalent function was evident in neonatal mice. CXCL8 production counters the widely held view that T lymphocytes in very early life are intrinsically anti-inflammatory, with implications for immune monitoring, immune interventions (including vaccination) and immunopathologies. It also emphasizes qualitative distinctions between infants' and adults' immune systems.", + "TAG_DATA": [ + "100, T {'context': 'B-cells'}", + "101, cells {'context': 'B-cells'}", + "139, T {'context': 'B-cells'}", + "140, cells {'context': 'I-cells'}", + "152, neonatal {'context': 'B-organism'}", + "153, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "100, T ['l0']", + "101, cells ['l0']", + "139, T ['l1']", + "140, cells ['l1']", + "152, neonatal ['l2']", + "153, mice. ['l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25198047", + "TEXT": "Mutations in the DMD gene, encoding dystrophin, cause the most common forms of muscular dystrophy. A new study shows that forcing translation of DMD from an internal ribosome entry site can alleviate Duchenne muscular dystrophy symptoms in a mouse model.", + "TAG_DATA": [ + "38, mouse {'context': 'B-organism'}", + "39, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "38, mouse ['l0']", + "39, model. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25198036", + "TEXT": "The size, speed and potential reach of the 2014 Ebola virus outbreak in West Africa presents a wake-up call to the research and pharmaceutical communities - and to federal governments - of the continuing need to invest resources in the study and cure of emerging infectious diseases.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25194571", + "TEXT": "Ebolavirus disease causes high mortality, and the current outbreak has spread unabated through West Africa. Human adenovirus type 5 vectors (rAd5) encoding ebolavirus glycoprotein (GP) generate protective immunity against acute lethal Zaire ebolavirus (EBOV) challenge in macaques, but fail to protect animals immune to Ad5, suggesting natural Ad5 exposure may limit vaccine efficacy in humans. Here we show that a chimpanzee-derived replication-defective adenovirus (ChAd) vaccine also rapidly induced uniform protection against acute lethal EBOV challenge in macaques. Because protection waned over several months, we boosted ChAd3 with modified vaccinia Ankara (MVA) and generated, for the first time, durable protection against lethal EBOV challenge.", + "TAG_DATA": [ + "76, macaques. {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25173428", + "TEXT": "We report a new technique for sensitive, quantitative and rapid detection of Plasmodium spp.-infected red blood cells (RBCs) by means of magnetic resonance relaxometry (MRR). During the intraerythrocytic cycle, malaria parasites metabolize large amounts of cellular hemoglobin and convert it into hemozoin crystallites. We exploit the relatively large paramagnetic susceptibility of these hemozoin particles, which induce substantial changes in the transverse relaxation rate of proton nuclear magnetic resonance of RBCs, to infer the 'parasite load' in blood. Using an inexpensive benchtop 0.5-Tesla MRR system, we show that with minimal sample preparatory steps and without any chemical or immunolabeling, a parasitemia level of fewer than ten parasites per microliter in a volume below 10 μl of whole blood is detected in a few minutes. We demonstrate this method both for cultured Plasmodium falciparum parasites and in vivo with Plasmodium berghei-infected mice.", + "TAG_DATA": [ + "130, Plasmodium {'context': 'I-organism'}", + "131, falciparum {'context': 'I-organism'}", + "132, parasites {'context': 'I-organism'}", + "134, in {'context': 'B-in vivo'}", + "135, vivo {'context': 'I-in vivo'}", + "139, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "130, Plasmodium ['l0', 'l1', 'l2', 'l3', 'l4']", + "131, falciparum ['l0', 'l5', 'l6']", + "132, parasites ['l1', 'l5', 'l7']", + "134, in ['l2', 'l8', 'l9']", + "135, vivo ['l3', 'l8', 'l10']", + "139, mice. ['l4', 'l6', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25150498", + "TEXT": "Duplication of the gene encoding the peripheral myelin protein of 22 kDa (PMP22) underlies the most common inherited neuropathy, Charcot-Marie-Tooth 1A (CMT1A), a disease without a known cure. Although demyelination represents a characteristic feature, the clinical phenotype of CMT1A is determined by the degree of axonal loss, and patients suffer from progressive muscle weakness and impaired sensation. CMT1A disease manifests within the first two decades of life, and walking disabilities, foot deformities and electrophysiological abnormalities are already present in childhood. Here, we show in Pmp22-transgenic rodent models of CMT1A that Schwann cells acquire a persistent differentiation defect during early postnatal development, caused by imbalanced activity of the PI3K-Akt and the Mek-Erk signaling pathways. We demonstrate that enhanced PI3K-Akt signaling by axonally overexpressed neuregulin-1 (NRG1) type I drives diseased Schwann cells toward differentiation and preserves peripheral nerve axons. Notably, in a preclinical experimental therapy using a CMT1A rat model, when treatment is restricted to early postnatal development, soluble NRG1 effectively overcomes impaired peripheral nerve development and restores axon survival into adulthood. Our findings suggest a model in which Schwann cell differentiation within a limited time window is crucial for the long-term maintenance of axonal support.", + "TAG_DATA": [ + "84, Pmp22-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "85, rodent {'context': 'B-organism'}", + "86, models {'context': 'I-organism'}", + "87, of {'context': 'I-organism'}", + "88, CMT1A {'context': 'I-organism'}", + "90, Schwann {'context': 'B-cells'}", + "91, cells {'context': 'I-cells'}", + "92, acquire {'effect': 'B-positive'}", + "95, differentiation {'phenotype': 'B-differentiation'}", + "96, defect {'effect': 'B-negative', 'phenotype': 'I-differentiation'}", + "120, axonally {'perturbing_action': 'B-gene gain-of-function'}", + "121, overexpressed {'perturbing_action': 'I-gene gain-of-function'}", + "122, neuregulin-1 {'perturbing_action': 'I-gene gain-of-function'}", + "123, (NRG1) {'perturbing_action': 'I-gene gain-of-function'}", + "124, type {'perturbing_action': 'I-gene gain-of-function'}", + "125, I {'perturbing_action': 'I-gene gain-of-function'}", + "128, Schwann {'context': 'B-cells'}", + "129, cells {'context': 'I-cells'}", + "131, differentiation {'phenotype': 'B-differentiation'}", + "134, peripheral {'context': 'B-cells'}", + "135, nerve {'context': 'I-cells'}", + "136, axons. {'context': 'I-cells'}", + "145, CMT1A {'context': 'B-organism'}", + "146, rat {'context': 'I-organism'}", + "147, model, {'context': 'I-organism'}", + "161, peripheral {'context': 'B-tissue/organ'}", + "162, nerve {'context': 'I-tissue/organ'}", + "166, axon {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "84, Pmp22-transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "85, rodent ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "86, models ['l1', 'l12', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "87, of ['l2', 'l13', 'l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "88, CMT1A ['l3', 'l14', 'l22', 'l29', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "90, Schwann ['l4', 'l15', 'l23', 'l30', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "91, cells ['l5', 'l16', 'l24', 'l31', 'l37', 'l42', 'l49', 'l50', 'l51', 'l52']", + "92, acquire ['l6', 'l17', 'l25', 'l32', 'l38', 'l43', 'l49', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "95, differentiation ['l7', 'l18', 'l26', 'l33', 'l39', 'l44', 'l50', 'l53', 'l59', 'l60', 'l61', 'l62', 'l63']", + "96, defect ['l8', 'l19', 'l27', 'l34', 'l40', 'l45', 'l51', 'l54', 'l59', 'l64', 'l65', 'l66', 'l67']", + "120, axonally ['l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "121, overexpressed ['l68', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "122, neuregulin-1 ['l69', 'l80', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "123, (NRG1) ['l70', 'l81', 'l91', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "124, type ['l71', 'l82', 'l92', 'l101', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "125, I ['l72', 'l83', 'l93', 'l102', 'l110', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "126, drives ['l55', 'l60', 'l64', 'l73', 'l84', 'l94', 'l103', 'l111', 'l118', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "128, Schwann ['l9', 'l46', 'l56', 'l61', 'l65', 'l74', 'l85', 'l95', 'l104', 'l112', 'l119', 'l125', 'l131', 'l132', 'l133', 'l134', 'l135']", + "129, cells ['l10', 'l20', 'l28', 'l35', 'l41', 'l47', 'l52', 'l57', 'l62', 'l66', 'l75', 'l86', 'l96', 'l105', 'l113', 'l120', 'l126', 'l131', 'l136', 'l137', 'l138', 'l139']", + "131, differentiation ['l11', 'l48', 'l58', 'l63', 'l67', 'l76', 'l87', 'l97', 'l106', 'l114', 'l121', 'l127', 'l132', 'l136', 'l140', 'l141', 'l142']", + "134, peripheral ['l77', 'l88', 'l98', 'l107', 'l115', 'l122', 'l128', 'l133', 'l137', 'l140', 'l143', 'l144']", + "135, nerve ['l78', 'l89', 'l99', 'l108', 'l116', 'l123', 'l129', 'l134', 'l138', 'l141', 'l143', 'l145']", + "136, axons. ['l79', 'l90', 'l100', 'l109', 'l117', 'l124', 'l130', 'l135', 'l139', 'l142', 'l144', 'l145']", + "145, CMT1A ['l146', 'l147', 'l148', 'l149', 'l150']", + "146, rat ['l146', 'l151', 'l152', 'l153', 'l154']", + "147, model, ['l147', 'l151', 'l155', 'l156', 'l157']", + "161, peripheral ['l148', 'l152', 'l155', 'l158', 'l159']", + "162, nerve ['l149', 'l153', 'l156', 'l158', 'l160']", + "166, axon ['l150', 'l154', 'l157', 'l159', 'l160']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Pmp22-transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "rodent", + "models", + "of", + "CMT1A" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Pmp22-transgenic", + "axonally", + "overexpressed", + "neuregulin-1", + "(NRG1)", + "type", + "I" + ] + }, + "context": { + "val": "cells", + "words": [ + "Schwann", + "cells", + "peripheral", + "nerve", + "axons." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Pmp22-transgenic" + ] + }, + "effect": { + "val": "positive", + "words": [ + "acquire" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Pmp22-transgenic", + "axonally", + "overexpressed", + "neuregulin-1", + "(NRG1)", + "type", + "I" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "defect" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Pmp22-transgenic" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defect" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "defect" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "defect", + "differentiation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rodent", + "models", + "of", + "CMT1A" + ] + }, + "effect": { + "val": "positive", + "words": [ + "acquire" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rodent", + "models", + "of", + "CMT1A" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "defect" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rodent", + "models", + "of", + "CMT1A" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defect" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Schwann", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "acquire" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Schwann", + "cells", + "peripheral", + "nerve", + "axons." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "defect" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Schwann", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defect" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "acquire" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "defect" + ] + } + } + ] + }, + { + "PMID": "25150497", + "TEXT": "Glaucoma is the second most common cause of blindness in the world. It is a multifactorial disease with several risk factors, of which intraocular pressure (IOP) is a primary contributing factor. IOP measurements are used for glaucoma diagnosis and patient monitoring. IOP has wide diurnal fluctuation and is dependent on body posture, so the occasional measurements done by the eye care expert in the clinic can be misleading. Here we show that microfluidic principles can be used to develop an implantable sensor that has a limit of detection of 1 mm Hg, high sensitivity and excellent reproducibility. This device has a simple optical interface that enables IOP to be read with a smartphone camera. This sensor, with its ease of fabrication and simple design, as well as its allowance for IOP home monitoring, offers a promising approach for better care of patients with glaucoma.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25150496", + "TEXT": "Medulloblastoma, the most common malignant childhood brain tumor, exhibits distinct molecular subtypes and cellular origins. Genetic alterations driving medulloblastoma initiation and progression remain poorly understood. Herein, we identify GNAS, encoding the G protein Gαs, as a potent tumor suppressor gene that, when expressed at low levels, defines a subset of aggressive Sonic hedgehog (SHH)-driven human medulloblastomas. Ablation of the single Gnas gene in anatomically distinct progenitors in mice is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. Gαs is highly enriched at the primary cilium of granule neuron precursors and suppresses Shh signaling by regulating both the cAMP-dependent pathway and ciliary trafficking of Hedgehog pathway components. Elevation in levels of a Gαs effector, cAMP, effectively inhibits tumor cell proliferation and progression in Gnas-ablated mice. Thus, our gain- and loss-of-function studies identify a previously unrecognized tumor suppressor function for Gαs that can be found consistently across Shh-group medulloblastomas of disparate cellular and anatomical origins, highlighting G protein modulation as a potential therapeutic avenue.", + "TAG_DATA": [ + "56, Ablation {'perturbing_action': 'B-gene loss-of-function'}", + "57, of {'perturbing_action': 'I-gene loss-of-function'}", + "58, the {'perturbing_action': 'I-gene loss-of-function'}", + "59, single {'perturbing_action': 'I-gene loss-of-function'}", + "60, Gnas {'perturbing_action': 'I-gene loss-of-function'}", + "61, gene {'perturbing_action': 'I-gene loss-of-function'}", + "67, mice {'context': 'B-organism'}", + "71, induce {'effect': 'B-positive'}", + "73, medulloblastomas, {'phenotype': 'I-tumourigenesis'}", + "117, inhibits {'effect': 'B-negative'}", + "118, tumor {'context': 'B-transformed cells'}", + "119, cell {'context': 'I-transformed cells'}", + "120, proliferation {'phenotype': 'B-proliferation'}", + "124, Gnas-ablated {'perturbing_action': 'B-gene loss-of-function'}", + "125, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, Ablation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "57, of ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "58, the ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "59, single ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "60, Gnas ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "61, gene ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "67, mice ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "71, induce ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "73, medulloblastomas, ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "117, inhibits ['l36', 'l37', 'l38', 'l39', 'l40']", + "118, tumor ['l36', 'l41', 'l42', 'l43', 'l44']", + "119, cell ['l37', 'l41', 'l45', 'l46', 'l47']", + "120, proliferation ['l38', 'l42', 'l45', 'l48', 'l49']", + "124, Gnas-ablated ['l39', 'l43', 'l46', 'l48', 'l50']", + "125, mice. ['l40', 'l44', 'l47', 'l49', 'l50']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "the", + "single", + "Gnas", + "gene", + "Gnas-ablated" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "the", + "single", + "Gnas", + "gene" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "the", + "single", + "Gnas", + "gene" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "medulloblastomas," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "medulloblastomas," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "medulloblastomas," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gnas-ablated" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gnas-ablated" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gnas-ablated" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "25129480", + "TEXT": "Technologies are needed to map and image biological barriers in vivo that limit solid tumor delivery and, ultimately, the effectiveness of imaging and therapeutic agents. Here we integrate proteomic and imaging analyses of caveolae at the blood-tumor interface to discover an active transendothelial portal to infiltrate tumors. A post-translationally modified form of annexin A1 (AnnA1) is selectively concentrated in human and rodent tumor caveolae. To follow trafficking, we generated a specific AnnA1 antibody that targets caveolae in the tumor endothelium. Intravital microscopy of caveolae-immunotargeted fluorophores even at low intravenous doses showed rapid and robust pumping across the endothelium to enter mammary, prostate and lung tumors. Within 1 h, the fluorescence signal concentrated throughout tumors to exceed the peak levels in blood. This transvascular pumping required the expression of caveolin 1 and annexin A1. Tumor uptake with other antibodies were >100-fold less. This proteomic imaging strategy reveals a unique target, antibody and caveolae pumping system for solid tumor penetration.", + "TAG_DATA": [ + "100, mammary, {'context': 'B-neoplasm'}", + "101, prostate {'context': 'I-neoplasm'}", + "102, and {'context': 'I-neoplasm'}", + "103, lung {'context': 'I-neoplasm'}", + "104, tumors. {'context': 'I-neoplasm'}", + "113, tumors {'context': 'B-neoplasm'}", + "133, Tumor {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "100, mammary, ['l0', 'l1', 'l2', 'l3']", + "101, prostate ['l0', 'l4', 'l5', 'l6']", + "102, and ['l1', 'l4', 'l7', 'l8']", + "103, lung ['l2', 'l5', 'l7', 'l9']", + "104, tumors. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25129479", + "TEXT": "Anxiety disorders are highly prevalent psychiatric diseases. There is need for a deeper understanding of anxiety control mechanisms in the mammalian brain and for development of new anxiolytic agents. Here we report that the coupling between neuronal nitric oxide synthase (nNOS) and its carboxy-terminal PDZ ligand (CAPON) can serve as a target for developing new anxiolytic agents. Augmenting nNOS-CAPON interaction in the hippocampus of mice by overexpressing full-length CAPON gave rise to anxiogenic-like behaviors, whereas dissociating CAPON from nNOS by overexpressing CAPON-125C or CAPON-20C (the C-terminal 125 or 20 amino acids of CAPON) or delivering Tat-CAPON-12C (a peptide comprising Tat and the 12 C-terminal amino acids of CAPON) in the hippocampus of mice produced anxiolytic-like effects. Mice subjected to chronic mild stress (CMS) displayed a substantial increase in nNOS-CAPON coupling in the hippocampus and a consequent anxiogenic-like phenotype. Disrupting nNOS-CAPON coupling reversed the CMS-induced anxiogenic-like behaviors. Moreover, small-molecule blockers of nNOS-CAPON binding rapidly produced anxiolytic-like effects. Dexamethasone-induced ras protein 1 (Dexras1)-extracellular signal-regulated kinase (ERK) signaling was involved in the behavioral effects of nNOS-CAPON association. Thus, nNOS-CAPON association contributes to the modulation of anxiety-related behaviors via regulating Dexras1-ERK signaling and can serve as a target for developing potential anxiolytics.", + "TAG_DATA": [ + "62, hippocampus {'context': 'B-tissue/organ'}", + "64, mice {'context': 'B-organism'}", + "66, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "67, full-length {'perturbing_action': 'I-gene gain-of-function'}", + "68, CAPON {'perturbing_action': 'I-gene gain-of-function'}", + "80, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "81, CAPON-125C {'perturbing_action': 'I-gene gain-of-function'}", + "82, or {'perturbing_action': 'I-gene gain-of-function'}", + "83, CAPON-20C {'perturbing_action': 'I-gene gain-of-function'}", + "84, (the {'perturbing_action': 'I-gene gain-of-function'}", + "110, hippocampus {'context': 'B-tissue/organ'}", + "112, mice {'context': 'B-organism'}", + "116, Mice {'context': 'B-organism'}", + "132, hippocampus {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "62, hippocampus ['l0', 'l1', 'l2', 'l3']", + "64, mice ['l0', 'l4', 'l5', 'l6']", + "66, overexpressing ['l1', 'l4', 'l7', 'l8']", + "67, full-length ['l2', 'l5', 'l7', 'l9']", + "68, CAPON ['l3', 'l6', 'l8', 'l9']", + "80, overexpressing ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "81, CAPON-125C ['l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "82, or ['l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "83, CAPON-20C ['l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "84, (the ['l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "110, hippocampus ['l14', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "112, mice ['l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "116, Mice ['l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "132, hippocampus ['l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "full-length", + "CAPON", + "CAPON-125C", + "or", + "CAPON-20C", + "(the" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "Mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "full-length", + "CAPON", + "CAPON-125C", + "or", + "CAPON-20C", + "(the" + ] + } + } + ] + }, + { + "PMID": "25108527", + "TEXT": "The hormone erythropoietin (EPO), which is synthesized in the kidney or liver of adult mammals, controls erythrocyte production and is regulated by the stress-responsive transcription factor hypoxia-inducible factor-2 (HIF-2). We previously reported that the lysine acetyltransferase CREB-binding protein (CBP) is required for HIF-2α acetylation and efficient HIF-2-dependent EPO induction during hypoxia. We now show that these processes require acetate-dependent acetyl CoA synthetase 2 (ACSS2). In human Hep3B hepatoma cells and in EPO-generating organs of hypoxic or acutely anemic mice, acetate levels rise and ACSS2 is required for HIF-2α acetylation, CBP-HIF-2α complex formation, CBP-HIF-2α recruitment to the EPO enhancer and efficient induction of EPO gene expression. In acutely anemic mice, acetate supplementation augments stress erythropoiesis in an ACSS2-dependent manner. Moreover, in acquired and inherited chronic anemia mouse models, acetate supplementation increases EPO expression and the resting hematocrit. Thus, a mammalian stress-responsive acetate switch controls HIF-2 signaling and EPO induction during pathophysiological states marked by tissue hypoxia.", + "TAG_DATA": [ + "65, human {'context': 'B-transformed cells'}", + "66, Hep3B {'context': 'I-transformed cells'}", + "67, hepatoma {'context': 'I-transformed cells'}", + "68, cells {'context': 'I-transformed cells'}", + "78, mice, {'context': 'B-organism'}", + "108, mice, {'context': 'B-organism'}", + "125, mouse {'context': 'B-organism'}", + "126, models, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "65, human ['l0', 'l1', 'l2', 'l3']", + "66, Hep3B ['l0', 'l4', 'l5', 'l6']", + "67, hepatoma ['l1', 'l4', 'l7', 'l8']", + "68, cells ['l2', 'l5', 'l7', 'l9']", + "78, mice, ['l3', 'l6', 'l8', 'l9']", + "125, mouse ['l10']", + "126, models, ['l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25100522", + "TEXT": "Inhibiting Notch signaling induces adipose browning, improves systemic glucose tolerance and insulin sensitivity, and suppresses weight gain in mice.", + "TAG_DATA": [ + "18, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25100520", + "TEXT": "Restriction factors are host cell proteins that inhibit retroviral infection. A new study using mutants of human HIV-1 restriction factor SAMHD1 suggests that it inhibits infection through degradation of viral RNA rather than through its dNTPase activity as previously suggested.", + "TAG_DATA": [ + "14, mutants {'perturbing_action': 'B-other'}", + "15, of {'perturbing_action': 'I-other'}", + "16, human {'perturbing_action': 'I-other'}", + "17, HIV-1 {'perturbing_action': 'I-other'}", + "18, restriction {'perturbing_action': 'I-other'}", + "19, factor {'perturbing_action': 'I-other'}", + "20, SAMHD1 {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "14, mutants ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "15, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "16, human ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "17, HIV-1 ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "18, restriction ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "19, factor ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "20, SAMHD1 ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "25100518", + "TEXT": "The pharmaceutical industry has recently taken steps to make clinical trial data more accessible. But for there to be meaningful transparency, governments—not drug companies—should set the terms of disclosure.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25100512", + "TEXT": "Regenerative medicine may enable replacement of damaged or diseased tissues. But its clinical success will require deeper understanding of the basic biology of the stem cell niche and coordination between stem cell biologists and those in other fields.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "25038828", + "TEXT": "An imbalance of tau isoforms containing either three or four microtubule-binding repeats causes frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) in families with intronic mutations in the MAPT gene. Here we report equivalent imbalances at the mRNA and protein levels and increased total tau levels in the brains of subjects with Huntington's disease (HD) together with rod-like tau deposits along neuronal nuclei. These tau nuclear rods show an ordered filamentous ultrastructure and can be found filling the neuronal nuclear indentations previously reported in HD brains. Finally, alterations in serine/arginine-rich splicing factor-6 coincide with tau missplicing, and a role of tau in HD pathogenesis is evidenced by the attenuation of motor abnormalities of mutant HTT transgenic mice in tau knockout backgrounds.", + "TAG_DATA": [ + "114, mutant {'perturbing_action': 'B-gene gain-of-function'}", + "115, HTT {'perturbing_action': 'I-gene gain-of-function'}", + "116, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "117, mice {'context': 'B-organism'}", + "119, tau {'perturbing_action': 'B-gene loss-of-function'}", + "120, knockout {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "114, mutant ['l0', 'l1', 'l2', 'l3', 'l4']", + "115, HTT ['l0', 'l5', 'l6', 'l7', 'l8']", + "116, transgenic ['l1', 'l5', 'l9', 'l10', 'l11']", + "117, mice ['l2', 'l6', 'l9', 'l12', 'l13']", + "119, tau ['l3', 'l7', 'l10', 'l12', 'l14']", + "120, knockout ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "mutant", + "HTT", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "tau", + "knockout" + ] + } + } + ] + }, + { + "PMID": "25038827", + "TEXT": "The HIV-1 restriction factor SAM domain- and HD domain-containing protein 1 (SAMHD1) is proposed to inhibit HIV-1 replication by depleting the intracellular dNTP pool. However, phosphorylation of SAMHD1 regulates its ability to restrict HIV-1 without decreasing cellular dNTP levels, which is not consistent with a role for SAMHD1 dNTPase activity in HIV-1 restriction. Here, we show that SAMHD1 possesses RNase activity and that the RNase but not the dNTPase function is essential for HIV-1 restriction. By enzymatically characterizing Aicardi-Goutières syndrome (AGS)-associated SAMHD1 mutations and mutations in the allosteric dGTP-binding site of SAMHD1 for defects in RNase or dNTPase activity, we identify SAMHD1 point mutants that cause loss of one or both functions. The RNase-positive and dNTPase-negative SAMHD1D137N mutant is able to restrict HIV-1 infection, whereas the RNase-negative and dNTPase-positive SAMHD1Q548A mutant is defective for HIV-1 restriction. SAMHD1 associates with HIV-1 RNA and degrades it during the early phases of cell infection. SAMHD1 silencing in macrophages and CD4(+) T cells from healthy donors increases HIV-1 RNA stability, rendering the cells permissive for HIV-1 infection. Furthermore, phosphorylation of SAMHD1 at T592 negatively regulates its RNase activity in cells and impedes HIV-1 restriction. Our results reveal that the RNase activity of SAMHD1 is responsible for preventing HIV-1 infection by directly degrading the HIV-1 RNA.", + "TAG_DATA": [ + "113, RNase-positive {'perturbing_action': 'B-other'}", + "114, and {'perturbing_action': 'I-other'}", + "115, dNTPase-negative {'perturbing_action': 'I-other'}", + "116, SAMHD1D137N {'perturbing_action': 'I-other'}", + "117, mutant {'perturbing_action': 'I-other'}", + "126, RNase-negative {'perturbing_action': 'B-other'}", + "127, and {'perturbing_action': 'I-other'}", + "128, dNTPase-positive {'perturbing_action': 'I-other'}", + "129, SAMHD1Q548A {'perturbing_action': 'I-other'}", + "130, mutant {'perturbing_action': 'I-other'}", + "151, SAMHD1 {'perturbing_action': 'B-rnai/knockdown'}", + "152, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "154, macrophages {'context': 'B-cells'}", + "156, CD4(+) {'context': 'B-cells'}", + "157, T {'context': 'I-cells'}", + "158, cells {'context': 'I-cells'}", + "168, cells {'context': 'B-cells'}", + "185, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "113, RNase-positive ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "114, and ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "115, dNTPase-negative ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "116, SAMHD1D137N ['l2', 'l8', 'l13', 'l20', 'l21']", + "117, mutant ['l3', 'l9', 'l14', 'l20']", + "126, RNase-negative ['l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "127, and ['l22', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "128, dNTPase-positive ['l23', 'l33', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "129, SAMHD1Q548A ['l15', 'l24', 'l34', 'l43', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "130, mutant ['l4', 'l10', 'l16', 'l21', 'l25', 'l35', 'l44', 'l52', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "151, SAMHD1 ['l26', 'l36', 'l45', 'l53', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "152, silencing ['l27', 'l37', 'l46', 'l54', 'l60', 'l66', 'l73', 'l74', 'l75', 'l76', 'l77']", + "154, macrophages ['l5', 'l11', 'l17', 'l28', 'l38', 'l47', 'l55', 'l61', 'l67', 'l73', 'l78', 'l79', 'l80', 'l81']", + "156, CD4(+) ['l29', 'l39', 'l48', 'l56', 'l62', 'l68', 'l74', 'l78', 'l82', 'l83', 'l84']", + "157, T ['l18', 'l30', 'l40', 'l49', 'l57', 'l63', 'l69', 'l75', 'l79', 'l82', 'l85', 'l86']", + "158, cells ['l6', 'l12', 'l19', 'l31', 'l41', 'l50', 'l58', 'l64', 'l70', 'l76', 'l80', 'l83', 'l85', 'l87']", + "168, cells ['l32', 'l42', 'l51', 'l59', 'l65', 'l71', 'l77', 'l81', 'l84', 'l86', 'l87']", + "185, cells ['l72']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "RNase-positive", + "and", + "dNTPase-negative", + "RNase-negative", + "dNTPase-positive", + "SAMHD1Q548A", + "mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages", + "cells", + "T", + "CD4(+)" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "SAMHD1", + "silencing" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages", + "CD4(+)", + "T", + "cells" + ] + } + } + ] + }, + { + "PMID": "24929950", + "TEXT": "The N-terminal fragment of prolactin (16K PRL) inhibits tumor growth by impairing angiogenesis, but the underlying mechanisms are unknown. Here, we found that 16K PRL binds the fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1), which is known to contextually promote tumor angiogenesis and growth. Loss of PAI-1 abrogated the antitumoral and antiangiogenic effects of 16K PRL. PAI-1 bound the ternary complex PAI-1-urokinase-type plasminogen activator (uPA)-uPA receptor (uPAR), thereby exerting antiangiogenic effects. By inhibiting the antifibrinolytic activity of PAI-1, 16K PRL also protected mice against thromboembolism and promoted arterial clot lysis. Thus, by signaling through the PAI-1-uPA-uPAR complex, 16K PRL impairs tumor vascularization and growth and, by inhibiting the antifibrinolytic activity of PAI-1, promotes thrombolysis.", + "TAG_DATA": [ + "43, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "44, of {'perturbing_action': 'I-gene loss-of-function'}", + "45, PAI-1 {'perturbing_action': 'I-gene loss-of-function'}", + "81, mice {'context': 'B-organism'}", + "99, tumor {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "43, Loss ['l0', 'l1']", + "44, of ['l0', 'l2']", + "45, PAI-1 ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24901564", + "TEXT": "A new study in infants shows that broadly neutralizing antibodies (bNAbs) against HIV can be found early in life, demonstrating for the first time that these antibodies can be induced by the infant immune system.", + "TAG_DATA": [ + "4, infants {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24901558", + "TEXT": "The mentorship of early-career scientists is necessary to their individual career success and the future of the biomedical research enterprise as a whole. Recently launched NIH programs and tools aim to facilitate this important type of training.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24859529", + "TEXT": "Eliciting protective neutralizing antibodies (NAbs) against HIV-1 is daunting because of the extensive genetic and antigenic diversity of HIV-1. Moreover, broad and potent responses are uncommon even during persistent infection, with only a subset of adults developing broadly neutralizing antibodies (bNAbs) that recognize viral variants from different HIV-1 clades. It is not known whether bNAbs can also arise in HIV-1-infected infants, who typically progress to disease faster than adults, presumably in part due to an immature immune system. Here, we show that bNAbs develop at least as commonly in infants as in adults. Cross-clade NAb responses were detected in 20/28 infected infants, in some cases within 1 year of infection. Among infants with breadth of responses within the top quartile, neutralization of tier 2 or 3 variants from multiple clades was detected at 20 months after infection. These findings suggest that, even in early life, there is sufficient B cell functionality to mount bNAbs against HIV-1. Additionally, the relatively early appearance of bNAbs in infants may provide a unique setting for understanding the pathways of B cell maturation leading to bNAbs.", + "TAG_DATA": [ + "111, infants {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24859528", + "TEXT": "The application of primary organoid cultures containing epithelial and mesenchymal elements to cancer modeling holds promise for combining the accurate multilineage differentiation and physiology of in vivo systems with the facile in vitro manipulation of transformed cell lines. Here we used a single air-liquid interface culture method without modification to engineer oncogenic mutations into primary epithelial and mesenchymal organoids from mouse colon, stomach and pancreas. Pancreatic and gastric organoids exhibited dysplasia as a result of expression of Kras carrying the G12D mutation (Kras(G12D)), p53 loss or both and readily generated adenocarcinoma after in vivo transplantation. In contrast, primary colon organoids required combinatorial Apc, p53, Kras(G12D) and Smad4 mutations for progressive transformation to invasive adenocarcinoma-like histology in vitro and tumorigenicity in vivo, recapitulating multi-hit models of colorectal cancer (CRC), as compared to the more promiscuous transformation of small intestinal organoids. Colon organoid culture functionally validated the microRNA miR-483 as a dominant driver oncogene at the IGF2 (insulin-like growth factor-2) 11p15.5 CRC amplicon, inducing dysplasia in vitro and tumorigenicity in vivo. These studies demonstrate the general utility of a highly tractable primary organoid system for cancer modeling and driver oncogene validation in diverse gastrointestinal tissues.", + "TAG_DATA": [ + "58, organoids {'context': 'I-organoid'}", + "60, mouse {'context': 'B-tissue/organ'}", + "61, colon, {'context': 'I-tissue/organ'}", + "62, stomach {'context': 'I-tissue/organ'}", + "64, pancreas. {'context': 'I-tissue/organ'}", + "65, Pancreatic {'context': 'B-organoid'}", + "66, and {'context': 'I-organoid'}", + "67, gastric {'context': 'I-organoid'}", + "68, organoids {'context': 'I-organoid'}", + "90, adenocarcinoma {'phenotype': 'B-tumourigenesis'}", + "92, in {'context': 'B-in vivo'}", + "93, vivo {'context': 'I-in vivo'}", + "97, primary {'context': 'B-organoid'}", + "98, colon {'context': 'I-organoid'}", + "99, organoids {'context': 'I-organoid'}", + "110, transformation {'phenotype': 'B-transformation'}", + "115, in {'context': 'B-in vitro'}", + "116, vitro {'context': 'I-in vitro'}", + "118, tumorigenicity {'phenotype': 'B-tumourigenesis'}", + "119, in {'context': 'B-in vivo'}", + "120, vivo, {'context': 'I-in vivo'}", + "136, small {'context': 'B-organoid'}", + "137, intestinal {'context': 'I-organoid'}", + "138, organoids. {'context': 'I-organoid'}", + "139, Colon {'context': 'B-organoid'}", + "140, organoid {'context': 'I-organoid'}", + "161, inducing {'effect': 'B-positive'}", + "163, in {'context': 'B-in vitro'}", + "164, vitro {'context': 'I-in vitro'}", + "166, tumorigenicity {'phenotype': 'B-tumourigenesis'}", + "167, in {'context': 'B-in vivo'}", + "168, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "55, epithelial ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "56, and ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "57, mesenchymal ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "58, organoids ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "60, mouse ['l3', 'l16', 'l28', 'l39', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "61, colon, ['l4', 'l17', 'l29', 'l40', 'l49', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "62, stomach ['l5', 'l18', 'l30', 'l41', 'l50', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "64, pancreas. ['l6', 'l19', 'l31', 'l42', 'l51', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71', 'l72']", + "65, Pancreatic ['l7', 'l20', 'l32', 'l43', 'l52', 'l59', 'l64', 'l68', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "66, and ['l8', 'l21', 'l33', 'l44', 'l53', 'l60', 'l65', 'l69', 'l73', 'l79', 'l80', 'l81', 'l82']", + "67, gastric ['l9', 'l22', 'l34', 'l45', 'l54', 'l61', 'l66', 'l70', 'l74', 'l79', 'l83', 'l84', 'l85']", + "68, organoids ['l10', 'l23', 'l35', 'l46', 'l55', 'l62', 'l67', 'l71', 'l75', 'l80', 'l83', 'l86', 'l87']", + "89, generated ['l11', 'l24', 'l36', 'l47', 'l76', 'l81', 'l84', 'l86', 'l88', 'l89', 'l90']", + "90, adenocarcinoma ['l12', 'l25', 'l37', 'l48', 'l56', 'l72', 'l77', 'l82', 'l85', 'l87', 'l88', 'l91', 'l92']", + "92, in ['l89', 'l91', 'l93']", + "93, vivo ['l13', 'l26', 'l38', 'l78', 'l90', 'l92', 'l93']", + "97, primary ['l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "98, colon ['l94', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "99, organoids ['l95', 'l102', 'l109', 'l110', 'l111', 'l112', 'l113']", + "110, transformation ['l96', 'l103', 'l109', 'l114', 'l115', 'l116']", + "115, in ['l97', 'l104', 'l110', 'l114', 'l117', 'l118', 'l119']", + "116, vitro ['l98', 'l105', 'l111', 'l115', 'l117', 'l120']", + "118, tumorigenicity ['l99', 'l106', 'l112', 'l118', 'l121', 'l122']", + "119, in ['l100', 'l107', 'l121', 'l123']", + "120, vivo, ['l101', 'l108', 'l113', 'l116', 'l119', 'l120', 'l122', 'l123']", + "136, small ['l124', 'l125', 'l126', 'l127']", + "137, intestinal ['l124', 'l128', 'l129', 'l130']", + "138, organoids. ['l125', 'l128', 'l131']", + "139, Colon ['l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "140, organoid ['l132', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "161, inducing ['l133', 'l139', 'l145', 'l146', 'l147', 'l148', 'l149']", + "163, in ['l126', 'l129', 'l131', 'l134', 'l140', 'l145', 'l150', 'l151', 'l152', 'l153']", + "164, vitro ['l127', 'l130', 'l135', 'l141', 'l146', 'l150', 'l154', 'l155', 'l156']", + "166, tumorigenicity ['l136', 'l142', 'l147', 'l151', 'l154', 'l157', 'l158']", + "167, in ['l137', 'l143', 'l148', 'l152', 'l155', 'l157', 'l159']", + "168, vivo. ['l138', 'l144', 'l149', 'l153', 'l156', 'l158', 'l159']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organoid", + "words": [ + "organoids", + "Pancreatic", + "and", + "gastric", + "primary", + "colon", + "Colon", + "organoid" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "adenocarcinoma", + "tumorigenicity" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "pancreas." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "adenocarcinoma" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "adenocarcinoma", + "tumorigenicity" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "vivo,", + "vivo." + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "primary", + "colon", + "organoids" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + } + }, + { + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo," + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "Colon", + "organoid" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "24836575", + "TEXT": "Acute graft-versus-host disease (GVHD) considerably limits wider usage of allogeneic hematopoietic cell transplantation (allo-HCT). Antigen-presenting cells and T cells are populations customarily associated with GVHD pathogenesis. Of note, neutrophils are the largest human white blood cell population. The cells cleave chemokines and produce reactive oxygen species, thereby promoting T cell activation. Therefore, during an allogeneic immune response, neutrophils could amplify tissue damage caused by conditioning regimens. We analyzed neutrophil infiltration of the mouse ileum after allo-HCT by in vivo myeloperoxidase imaging and found that infiltration levels were dependent on the local microbial flora and were not detectable under germ-free conditions. Physical or genetic depletion of neutrophils reduced GVHD-related mortality. The contribution of neutrophils to GVHD severity required reactive oxygen species (ROS) because selective Cybb (encoding cytochrome b-245, beta polypeptide, also known as NOX2) deficiency in neutrophils impairing ROS production led to lower levels of tissue damage, GVHD-related mortality and effector phenotype T cells. Enhanced survival of Bcl-xL transgenic neutrophils increased GVHD severity. In contrast, when we transferred neutrophils lacking Toll-like receptor-2 (TLR2), TLR3, TLR4, TLR7 and TLR9, which are normally less strongly activated by translocating bacteria, into wild-type C57BL/6 mice, GVHD severity was reduced. In humans, severity of intestinal GVHD strongly correlated with levels of neutrophils present in GVHD lesions. This study describes a new potential role for neutrophils in the pathogenesis of GVHD in both mice and humans.", + "TAG_DATA": [ + "72, mouse {'context': 'B-tissue/organ'}", + "73, ileum {'context': 'I-tissue/organ'}", + "122, selective {'perturbing_action': 'B-gene loss-of-function'}", + "123, Cybb {'perturbing_action': 'B-gene loss-of-function'}", + "132, NOX2) {'perturbing_action': 'I-gene loss-of-function'}", + "133, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "151, T {'context': 'I-cells'}", + "152, cells. {'context': 'I-cells'}", + "156, Bcl-xL {'perturbing_action': 'B-gene gain-of-function'}", + "157, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "188, C57BL/6 {'context': 'B-organism'}", + "189, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "72, mouse ['l0']", + "73, ileum ['l0']", + "122, selective ['l1', 'l2', 'l3', 'l4', 'l5']", + "123, Cybb ['l1', 'l6', 'l7', 'l8', 'l9']", + "132, NOX2) ['l2', 'l6', 'l10', 'l11', 'l12']", + "133, deficiency ['l3', 'l7', 'l10', 'l13', 'l14']", + "151, T ['l4', 'l8', 'l11', 'l13', 'l15']", + "152, cells. ['l5', 'l9', 'l12', 'l14', 'l15']", + "156, Bcl-xL ['l16']", + "157, transgenic ['l16']", + "188, C57BL/6 ['l17']", + "189, mice, ['l17']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "Cybb", + "NOX2)", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells." + ] + } + } + ] + }, + { + "PMID": "24784230", + "TEXT": "Huntington's disease (HD) is a fatal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion leading to an elongated polyglutamine stretch in huntingtin. Mutant huntingtin (mHTT) is ubiquitously expressed in all cells but elicits selective cortical and striatal neurodegeneration in HD. The mechanistic basis for such selective neuronal vulnerability remains unclear. A necessary step toward resolving this enigma is to define the cell types in which mHTT expression is causally linked to the disease pathogenesis. Using a conditional transgenic mouse model of HD, in which the mice express full-length human mHTT from a bacterial artificial chromosome transgene (BACHD), we genetically reduced mHTT expression in neuronal populations in the striatum, cortex or both. We show that reduction of cortical mHTT expression in BACHD mice partially improves motor and psychiatric-like behavioral deficits but does not improve neurodegeneration, whereas reduction of mHTT expression in both neuronal populations consistently ameliorates all behavioral deficits and selective brain atrophy in this HD model. Furthermore, whereas reduction of mHTT expression in cortical or striatal neurons partially ameliorates corticostriatal synaptic deficits, further restoration of striatal synaptic function can be achieved by reduction of mHTT expression in both neuronal cell types. Our study demonstrates distinct but interacting roles of cortical and striatal mHTT in HD pathogenesis and suggests that optimal HD therapeutics may require targeting mHTT in both cortical and striatal neurons.", + "TAG_DATA": [ + "78, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "79, transgenic {'perturbing_action': 'I-gene loss-of-function'}", + "80, mouse {'context': 'I-organism'}", + "81, model {'context': 'I-organism'}", + "87, mice {'context': 'B-organism'}", + "94, bacterial {'perturbing_action': 'I-gene loss-of-function'}", + "95, artificial {'perturbing_action': 'I-gene loss-of-function'}", + "96, chromosome {'perturbing_action': 'I-gene loss-of-function'}", + "97, transgene {'perturbing_action': 'I-gene loss-of-function'}", + "98, (BACHD), {'perturbing_action': 'I-gene loss-of-function'}", + "101, reduced {'perturbing_action': 'I-gene loss-of-function'}", + "102, mHTT {'perturbing_action': 'I-rnai/knockdown'}", + "105, neuronal {'context': 'B-cells'}", + "106, populations {'context': 'I-cells'}", + "107, in {'context': 'I-cells'}", + "108, the {'context': 'I-cells'}", + "109, striatum, {'context': 'I-cells'}", + "110, cortex {'context': 'I-cells'}", + "116, reduction {'perturbing_action': 'B-other'}", + "117, of {'perturbing_action': 'I-rnai/knockdown'}", + "118, cortical {'perturbing_action': 'I-rnai/knockdown'}", + "119, mHTT {'perturbing_action': 'I-rnai/knockdown'}", + "120, expression {'perturbing_action': 'I-rnai/knockdown'}", + "123, mice {'context': 'B-organism'}", + "137, reduction {'perturbing_action': 'B-other'}", + "138, of {'perturbing_action': 'I-other'}", + "139, mHTT {'perturbing_action': 'I-other'}", + "140, expression {'perturbing_action': 'I-rnai/knockdown'}", + "143, neuronal {'context': 'B-cells'}", + "144, populations {'context': 'I-cells'}", + "160, reduction {'perturbing_action': 'B-gene loss-of-function'}", + "161, of {'perturbing_action': 'I-rnai/knockdown'}", + "162, mHTT {'perturbing_action': 'I-rnai/knockdown'}", + "163, expression {'perturbing_action': 'I-rnai/knockdown'}", + "165, cortical {'context': 'B-cells'}", + "166, or {'context': 'I-cells'}", + "167, striatal {'context': 'I-cells'}", + "168, neurons {'context': 'I-cells'}", + "184, reduction {'perturbing_action': 'B-gene loss-of-function'}", + "185, of {'perturbing_action': 'I-rnai/knockdown'}", + "186, mHTT {'perturbing_action': 'I-rnai/knockdown'}", + "187, expression {'perturbing_action': 'I-rnai/knockdown'}", + "190, neuronal {'context': 'B-cells'}", + "191, cell {'context': 'I-cells'}", + "192, types. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "78, conditional ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "79, transgenic ['l0', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "80, mouse ['l1', 'l24', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "81, model ['l2', 'l25', 'l42', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "82, of ['l3', 'l26', 'l43', 'l59', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "83, HD, ['l4', 'l27', 'l44', 'l60', 'l75', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "87, mice ['l5', 'l28', 'l45', 'l61', 'l76', 'l89', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "90, human ['l6', 'l29', 'l46', 'l62', 'l77', 'l90', 'l100', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "91, mHTT ['l7', 'l30', 'l47', 'l63', 'l78', 'l91', 'l101', 'l121', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "92, from ['l8', 'l31', 'l48', 'l64', 'l79', 'l92', 'l102', 'l122', 'l144', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186']", + "93, a ['l9', 'l32', 'l49', 'l65', 'l103', 'l123', 'l145', 'l166', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206']", + "94, bacterial ['l10', 'l104', 'l124', 'l146', 'l167', 'l187', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225']", + "95, artificial ['l11', 'l105', 'l125', 'l147', 'l168', 'l188', 'l207', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243']", + "96, chromosome ['l12', 'l33', 'l50', 'l66', 'l80', 'l106', 'l126', 'l148', 'l169', 'l189', 'l208', 'l226', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260']", + "97, transgene ['l13', 'l34', 'l51', 'l67', 'l81', 'l107', 'l127', 'l149', 'l170', 'l190', 'l209', 'l227', 'l244', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276']", + "98, (BACHD), ['l14', 'l35', 'l52', 'l68', 'l82', 'l93', 'l108', 'l128', 'l150', 'l171', 'l191', 'l210', 'l228', 'l245', 'l261', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291']", + "101, reduced ['l15', 'l36', 'l53', 'l69', 'l83', 'l94', 'l109', 'l129', 'l151', 'l172', 'l192', 'l211', 'l229', 'l246', 'l262', 'l277', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304', 'l305']", + "102, mHTT ['l16', 'l110', 'l130', 'l152', 'l173', 'l193', 'l212', 'l230', 'l247', 'l263', 'l278', 'l292', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315', 'l316', 'l317', 'l318']", + "103, expression ['l17', 'l111', 'l131', 'l153', 'l174', 'l194', 'l213', 'l231', 'l248', 'l264', 'l279', 'l293', 'l306', 'l319', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327', 'l328', 'l329', 'l330']", + "105, neuronal ['l18', 'l112', 'l132', 'l154', 'l175', 'l195', 'l214', 'l232', 'l249', 'l265', 'l280', 'l294', 'l307', 'l319', 'l331', 'l332', 'l333', 'l334', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340', 'l341']", + "106, populations ['l19', 'l37', 'l54', 'l70', 'l84', 'l95', 'l113', 'l133', 'l155', 'l176', 'l196', 'l215', 'l233', 'l250', 'l266', 'l281', 'l295', 'l308', 'l320', 'l331', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348', 'l349', 'l350', 'l351']", + "107, in ['l20', 'l38', 'l55', 'l71', 'l85', 'l96', 'l114', 'l134', 'l156', 'l177', 'l197', 'l216', 'l234', 'l251', 'l267', 'l282', 'l296', 'l309', 'l321', 'l332', 'l342', 'l352', 'l353', 'l354', 'l355', 'l356', 'l357', 'l358', 'l359', 'l360']", + "108, the ['l21', 'l39', 'l56', 'l72', 'l86', 'l97', 'l115', 'l135', 'l157', 'l178', 'l198', 'l217', 'l235', 'l252', 'l268', 'l283', 'l297', 'l310', 'l322', 'l333', 'l343', 'l352', 'l361', 'l362', 'l363', 'l364', 'l365', 'l366', 'l367', 'l368']", + "109, striatum, ['l22', 'l40', 'l57', 'l73', 'l87', 'l98', 'l116', 'l136', 'l158', 'l179', 'l199', 'l218', 'l236', 'l253', 'l269', 'l284', 'l298', 'l311', 'l323', 'l334', 'l344', 'l353', 'l361', 'l369', 'l370', 'l371', 'l372', 'l373', 'l374', 'l375']", + "110, cortex ['l23', 'l41', 'l58', 'l74', 'l88', 'l99', 'l117', 'l137', 'l159', 'l180', 'l200', 'l219', 'l237', 'l254', 'l270', 'l285', 'l299', 'l312', 'l324', 'l335', 'l345', 'l354', 'l362', 'l369', 'l376', 'l377']", + "116, reduction ['l138', 'l160', 'l181', 'l201', 'l220', 'l238', 'l255', 'l271', 'l286', 'l300', 'l313', 'l325', 'l336', 'l346', 'l355', 'l363', 'l370', 'l378', 'l379', 'l380', 'l381', 'l382']", + "117, of ['l118', 'l139', 'l161', 'l182', 'l202', 'l221', 'l239', 'l256', 'l272', 'l287', 'l301', 'l314', 'l326', 'l337', 'l347', 'l356', 'l364', 'l371', 'l376', 'l378', 'l383', 'l384', 'l385', 'l386']", + "118, cortical ['l119', 'l140', 'l162', 'l183', 'l203', 'l222', 'l240', 'l257', 'l273', 'l288', 'l302', 'l315', 'l327', 'l338', 'l348', 'l357', 'l365', 'l372', 'l379', 'l383', 'l387', 'l388', 'l389']", + "119, mHTT ['l141', 'l163', 'l184', 'l204', 'l223', 'l241', 'l258', 'l274', 'l289', 'l303', 'l316', 'l328', 'l339', 'l349', 'l358', 'l366', 'l373', 'l380', 'l384', 'l387', 'l390', 'l391']", + "120, expression ['l142', 'l164', 'l185', 'l205', 'l224', 'l242', 'l259', 'l275', 'l290', 'l304', 'l317', 'l329', 'l340', 'l350', 'l359', 'l367', 'l374', 'l381', 'l385', 'l388', 'l390', 'l392']", + "123, mice ['l120', 'l143', 'l165', 'l186', 'l206', 'l225', 'l243', 'l260', 'l276', 'l291', 'l305', 'l318', 'l330', 'l341', 'l351', 'l360', 'l368', 'l375', 'l377', 'l382', 'l386', 'l389', 'l391', 'l392']", + "137, reduction ['l393', 'l394', 'l395', 'l396', 'l397', 'l398', 'l399', 'l400', 'l401']", + "138, of ['l393', 'l402', 'l403', 'l404', 'l405', 'l406', 'l407']", + "139, mHTT ['l394', 'l402', 'l408', 'l409', 'l410', 'l411']", + "140, expression ['l395', 'l403', 'l408', 'l412', 'l413', 'l414']", + "142, both ['l396', 'l404', 'l409', 'l412', 'l415', 'l416']", + "143, neuronal ['l397', 'l405', 'l410', 'l413', 'l415', 'l417']", + "144, populations ['l398', 'l406', 'l411', 'l414', 'l416', 'l417']", + "160, reduction ['l418', 'l419', 'l420', 'l421', 'l422', 'l423', 'l424']", + "161, of ['l418', 'l425', 'l426', 'l427', 'l428', 'l429', 'l430']", + "162, mHTT ['l419', 'l425', 'l431', 'l432', 'l433', 'l434', 'l435']", + "163, expression ['l420', 'l426', 'l431', 'l436', 'l437', 'l438', 'l439']", + "165, cortical ['l399', 'l421', 'l427', 'l432', 'l436', 'l440', 'l441', 'l442']", + "166, or ['l422', 'l428', 'l433', 'l437', 'l440', 'l443', 'l444']", + "167, striatal ['l400', 'l423', 'l429', 'l434', 'l438', 'l441', 'l443', 'l445']", + "168, neurons ['l401', 'l407', 'l424', 'l430', 'l435', 'l439', 'l442', 'l444', 'l445']", + "184, reduction ['l446', 'l447', 'l448', 'l449', 'l450', 'l451']", + "185, of ['l446', 'l452', 'l453', 'l454', 'l455', 'l456']", + "186, mHTT ['l447', 'l452', 'l457', 'l458', 'l459', 'l460']", + "187, expression ['l448', 'l453', 'l457', 'l461', 'l462', 'l463']", + "190, neuronal ['l449', 'l454', 'l458', 'l461', 'l464', 'l465']", + "191, cell ['l450', 'l455', 'l459', 'l462', 'l464', 'l466']", + "192, types. ['l451', 'l456', 'l460', 'l463', 'l465', 'l466']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "transgenic", + "chromosome", + "transgene", + "(BACHD),", + "reduced", + "bacterial", + "artificial" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "transgenic", + "bacterial", + "artificial", + "chromosome", + "transgene", + "(BACHD),", + "reduced", + "reduction" + ] + }, + "context": { + "val": "cells", + "words": [ + "neuronal", + "populations", + "in", + "the", + "striatum,", + "cortex", + "cortical", + "or", + "striatal", + "neurons", + "cell", + "types." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "mHTT", + "of", + "cortical", + "expression" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "mHTT", + "of", + "cortical", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "neuronal", + "populations", + "in", + "the", + "striatum,", + "cortex", + "cortical", + "or", + "striatal", + "neurons", + "cell", + "types." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neuronal", + "populations", + "in", + "the", + "striatum,", + "cortical", + "striatal", + "neurons" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "reduction", + "of", + "mHTT" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "reduction" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "24747744", + "TEXT": "Neonatal colonization by microbes, which begins immediately after birth, is influenced by gestational age and the mother's microbiota and is modified by exposure to antibiotics. In neonates, prolonged duration of antibiotic therapy is associated with increased risk of late-onset sepsis (LOS), a disorder controlled by neutrophils. A role for the microbiota in regulating neutrophil development and susceptibility to sepsis in the neonate remains unclear. We exposed pregnant mouse dams to antibiotics in drinking water to limit transfer of maternal microbes to the neonates. Antibiotic exposure of dams decreased the total number and composition of microbes in the intestine of the neonates. This was associated with decreased numbers of circulating and bone marrow neutrophils and granulocyte/macrophage-restricted progenitor cells in the bone marrow of antibiotic-treated and germ-free neonates. Antibiotic exposure of dams reduced the number of interleukin-17 (IL-17)-producing cells in the intestine and production of granulocyte colony-stimulating factor (G-CSF). Granulocytopenia was associated with impaired host defense and increased susceptibility to Escherichia coli K1 and Klebsiella pneumoniae sepsis in antibiotic-treated neonates, which could be partially reversed by administration of G-CSF. Transfer of a normal microbiota into antibiotic-treated neonates induced IL-17 production by group 3 innate lymphoid cells (ILCs) in the intestine, increasing plasma G-CSF levels and neutrophil numbers in a Toll-like receptor 4 (TLR4)- and myeloid differentiation factor 88 (MyD88)-dependent manner and restored IL-17-dependent resistance to sepsis. Specific depletion of ILCs prevented IL-17- and G-CSF-dependent granulocytosis and resistance to sepsis. These data support a role for the intestinal microbiota in regulation of granulocytosis, neutrophil homeostasis and host resistance to sepsis in neonates.", + "TAG_DATA": [ + "66, pregnant {'context': 'B-organism'}", + "67, mouse {'context': 'I-organism'}", + "68, dams {'context': 'I-organism'}", + "97, intestine {'context': 'B-tissue/organ'}", + "100, neonates. {'context': 'B-organism'}", + "114, granulocyte/macrophage-restricted {'context': 'B-cells'}", + "115, progenitor {'context': 'I-cells'}", + "116, cells {'context': 'I-cells'}", + "119, bone {'context': 'B-cells'}", + "120, marrow {'context': 'I-cells'}", + "125, neonates. {'context': 'I-organism'}", + "139, intestine {'context': 'B-tissue/organ'}", + "167, neonates, {'context': 'B-organism'}", + "184, neonates {'context': 'B-organism'}", + "189, group {'context': 'B-cells'}", + "190, 3 {'context': 'I-cells'}", + "191, innate {'context': 'I-cells'}", + "192, lymphoid {'context': 'I-cells'}", + "193, cells {'context': 'I-cells'}", + "194, (ILCs) {'context': 'I-cells'}", + "197, intestine, {'context': 'B-tissue/organ'}", + "227, ILCs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "66, pregnant ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "67, mouse ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "68, dams ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "97, intestine ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31']", + "100, neonates. ['l3', 'l12', 'l20', 'l27', 'l32', 'l33', 'l34', 'l35']", + "114, granulocyte/macrophage-restricted ['l4', 'l13', 'l21', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "115, progenitor ['l5', 'l14', 'l22', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "116, cells ['l6', 'l15', 'l23', 'l28', 'l32', 'l37', 'l42', 'l47', 'l48', 'l49', 'l50']", + "119, bone ['l7', 'l16', 'l24', 'l29', 'l33', 'l38', 'l43', 'l47', 'l51', 'l52']", + "120, marrow ['l8', 'l17', 'l25', 'l30', 'l34', 'l39', 'l44', 'l48', 'l51', 'l53']", + "125, neonates. ['l9', 'l18', 'l26', 'l31', 'l35', 'l40', 'l45', 'l49', 'l52', 'l53', 'l54']", + "139, intestine ['l41', 'l46', 'l50', 'l54', 'l55']", + "167, neonates, ['l55', 'l56', 'l57']", + "184, neonates ['l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "189, group ['l58', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "190, 3 ['l59', 'l65', 'l71', 'l72', 'l73', 'l74', 'l75']", + "191, innate ['l60', 'l66', 'l71', 'l76', 'l77', 'l78', 'l79']", + "192, lymphoid ['l61', 'l67', 'l72', 'l76', 'l80', 'l81', 'l82']", + "193, cells ['l56', 'l62', 'l68', 'l73', 'l77', 'l80', 'l83', 'l84']", + "194, (ILCs) ['l57', 'l63', 'l69', 'l74', 'l78', 'l81', 'l83', 'l85']", + "197, intestine, ['l64', 'l70', 'l75', 'l79', 'l82', 'l84', 'l85']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24710367", + "TEXT": "For more than four decades, the US Institute of Medicine (IOM) has operated as an independent nonprofit organization with a mission of providing guiding documents on matters of health and biomedical research, many of which are commissioned by the government. The IOM--part of the 151-year-old National Academy of Sciences--issues reports on a wide range of topics, from salt consumption to clinical trial data sharing, and convenes workshops at its headquarters in Washington, DC.The institute counts almost 2,000 experts among its members, including Victor Dzau. On 1 July, Dzau will replace health policy expert Harvey Fineberg as president of the IOM for a six-year term. A cardiologist and researcher by training, Dzau currently serves as chancellor for health affairs at Duke University in Durham, North Carolina. During his time at Duke, he has broadened the reach of the institution by helping to launch the Duke-National University of Singapore Graduate Medical School, the Duke Global Health Institute and the International Partnership for Innovative Healthcare Delivery. Roxanne Khamsi spoke with Dzau about his vision for the IOM. The conversation has been edited for clarity.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24658077", + "TEXT": "The pathophysiology of ineffective erythropoiesis in β-thalassemia is poorly understood. We report that RAP-011, an activin receptor IIA (ActRIIA) ligand trap, improved ineffective erythropoiesis, corrected anemia and limited iron overload in a mouse model of β-thalassemia intermedia. Expression of growth differentiation factor 11 (GDF11), an ActRIIA ligand, was increased in splenic erythroblasts from thalassemic mice and in erythroblasts and sera from subjects with β-thalassemia. Inactivation of GDF11 decreased oxidative stress and the amount of α-globin membrane precipitates, resulting in increased terminal erythroid differentiation. Abnormal GDF11 expression was dependent on reactive oxygen species, suggesting the existence of an autocrine amplification loop in β-thalassemia. GDF11 inactivation also corrected the abnormal ratio of immature/mature erythroblasts by inducing apoptosis of immature erythroblasts through the Fas-Fas ligand pathway. Taken together, these observations suggest that ActRIIA ligand traps may have therapeutic relevance in β-thalassemia by suppressing the deleterious effects of GDF11, a cytokine which blocks terminal erythroid maturation through an autocrine amplification loop involving oxidative stress and α-globin precipitation.", + "TAG_DATA": [ + "32, mouse {'context': 'B-organism'}", + "33, model {'context': 'I-organism'}", + "34, of {'context': 'I-organism'}", + "35, β-thalassemia {'context': 'I-organism'}", + "36, intermedia. {'context': 'I-organism'}", + "50, splenic {'context': 'B-cells'}", + "51, erythroblasts {'context': 'I-cells'}", + "57, erythroblasts {'context': 'B-cells'}", + "64, Inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "65, of {'perturbing_action': 'I-gene loss-of-function'}", + "66, GDF11 {'perturbing_action': 'I-gene loss-of-function'}", + "79, increased {'effect': 'B-positive'}", + "80, terminal {'phenotype': 'B-differentiation'}", + "81, erythroid {'phenotype': 'I-differentiation'}", + "82, differentiation. {'phenotype': 'I-differentiation'}", + "102, GDF11 {'perturbing_action': 'B-gene loss-of-function'}", + "103, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "110, immature/mature {'context': 'B-cells'}", + "111, erythroblasts {'context': 'I-cells'}", + "113, inducing {'effect': 'B-positive'}", + "114, apoptosis {'phenotype': 'B-apoptosis'}", + "116, immature {'context': 'B-cells'}", + "117, erythroblasts {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "32, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "33, model ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "34, of ['l1', 'l9', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "35, β-thalassemia ['l2', 'l10', 'l18', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "36, intermedia. ['l3', 'l11', 'l19', 'l27', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "50, splenic ['l4', 'l12', 'l20', 'l28', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "51, erythroblasts ['l5', 'l13', 'l21', 'l29', 'l37', 'l42', 'l47', 'l48', 'l49']", + "57, erythroblasts ['l22', 'l30', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "64, Inactivation ['l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "65, of ['l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "66, GDF11 ['l31', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "79, increased ['l6', 'l14', 'l23', 'l32', 'l38', 'l43', 'l47', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "80, terminal ['l7', 'l15', 'l24', 'l33', 'l39', 'l44', 'l48', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "81, erythroid ['l16', 'l25', 'l34', 'l40', 'l45', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "82, differentiation. ['l8', 'l17', 'l26', 'l35', 'l41', 'l46', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "102, GDF11 ['l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "103, inactivation ['l78', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "110, immature/mature ['l79', 'l85', 'l91']", + "111, erythroblasts ['l80', 'l86', 'l91']", + "113, inducing ['l81', 'l87', 'l92', 'l93', 'l94']", + "114, apoptosis ['l82', 'l88', 'l92', 'l95', 'l96']", + "116, immature ['l83', 'l89', 'l93', 'l95', 'l97']", + "117, erythroblasts ['l84', 'l90', 'l94', 'l96', 'l97']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "β-thalassemia", + "intermedia." + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "β-thalassemia", + "intermedia." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "terminal", + "differentiation.", + "erythroid" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "β-thalassemia" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "GDF11" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "splenic", + "erythroblasts", + "immature" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "inducing" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "splenic", + "erythroblasts" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "terminal", + "erythroid", + "differentiation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "erythroblasts", + "immature/mature", + "immature" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Inactivation", + "of", + "GDF11", + "inactivation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Inactivation", + "of", + "GDF11", + "inactivation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "inducing" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Inactivation", + "of", + "GDF11" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "terminal", + "erythroid", + "differentiation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "terminal", + "erythroid", + "differentiation." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "GDF11", + "inactivation" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "immature", + "erythroblasts" + ] + } + } + ] + }, + { + "PMID": "24658076", + "TEXT": "HIV-1 persists in a latent reservoir despite antiretroviral therapy (ART). This reservoir is the major barrier to HIV-1 eradication. Current approaches to purging the latent reservoir involve pharmacologic induction of HIV-1 transcription and subsequent killing of infected cells by cytolytic T lymphocytes (CTLs) or viral cytopathic effects. Agents that reverse latency without activating T cells have been identified using in vitro models of latency. However, their effects on latently infected cells from infected individuals remain largely unknown. Using a new ex vivo assay, we demonstrate that none of the latency-reversing agents (LRAs) tested induced outgrowth of HIV-1 from the latent reservoir of patients on ART. Using a quantitative reverse transcription PCR assay specific for all HIV-1 mRNAs, we demonstrate that LRAs that do not cause T cell activation do not induce substantial increases in intracellular HIV-1 mRNA in patient cells; only the protein kinase C agonist bryostatin-1 caused significant increases. These findings demonstrate that current in vitro models do not fully recapitulate mechanisms governing HIV-1 latency in vivo. Further, our data indicate that non-activating LRAs are unlikely to drive the elimination of the latent reservoir in vivo when administered individually.", + "TAG_DATA": [ + "125, T {'context': 'B-cells'}", + "126, cell {'context': 'I-cells'}", + "138, patient {'context': 'B-cells'}", + "139, cells; {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "125, T ['l0', 'l1', 'l2']", + "126, cell ['l0', 'l3', 'l4']", + "138, patient ['l1', 'l3', 'l5']", + "139, cells; ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24633304", + "TEXT": "Tissue mechanics regulate development and homeostasis and are consistently modified in tumor progression. Nevertheless, the fundamental molecular mechanisms through which altered mechanics regulate tissue behavior and the clinical relevance of these changes remain unclear. We demonstrate that increased matrix stiffness modulates microRNA expression to drive tumor progression through integrin activation of β-catenin and MYC. Specifically, in human and mouse tissue, increased matrix stiffness induced miR-18a to reduce levels of the tumor suppressor phosphatase and tensin homolog (PTEN), both directly and indirectly by decreasing levels of homeobox A9 (HOXA9). Clinically, extracellular matrix stiffness correlated directly and significantly with miR-18a expression in human breast tumor biopsies. miR-18a expression was highest in basal-like breast cancers in which PTEN and HOXA9 levels were lowest, and high miR-18a expression predicted poor prognosis in patients with luminal breast cancers. Our findings identify a mechanically regulated microRNA circuit that can promote malignancy and suggest potential prognostic roles for HOXA9 and miR-18a levels in stratifying patients with luminal breast cancers.", + "TAG_DATA": [ + "56, human {'context': 'B-tissue/organ'}", + "57, and {'context': 'I-tissue/organ'}", + "58, mouse {'context': 'I-tissue/organ'}", + "59, tissue, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "56, human ['l0', 'l1', 'l2']", + "57, and ['l0', 'l3', 'l4']", + "58, mouse ['l1', 'l3', 'l5']", + "59, tissue, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24531379", + "TEXT": "Skeletal muscle aging results in a gradual loss of skeletal muscle mass, skeletal muscle function and regenerative capacity, which can lead to sarcopenia and increased mortality. Although the mechanisms underlying sarcopenia remain unclear, the skeletal muscle stem cell, or satellite cell, is required for muscle regeneration. Therefore, identification of signaling pathways affecting satellite cell function during aging may provide insights into therapeutic targets for combating sarcopenia. Here, we show that a cell-autonomous loss in self-renewal occurs via alterations in fibroblast growth factor receptor-1, p38α and p38β mitogen-activated protein kinase signaling in satellite cells from aged mice. We further demonstrate that pharmacological manipulation of these pathways can ameliorate age-associated self-renewal defects. Thus, our data highlight an age-associated deregulation of a satellite cell homeostatic network and reveal potential therapeutic opportunities for the treatment of progressive muscle wasting.", + "TAG_DATA": [ + "72, loss {'effect': 'B-negative'}", + "74, self-renewal {'phenotype': 'B-self-renewal'}", + "91, satellite {'context': 'B-cells'}", + "92, cells {'context': 'I-cells'}", + "94, aged {'context': 'B-organism'}", + "95, mice. {'context': 'I-organism'}", + "106, ameliorate {'effect': 'B-negative'}", + "108, self-renewal {'phenotype': 'B-self-renewal'}", + "109, defects. {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "72, loss ['l0', 'l1', 'l2', 'l3', 'l4']", + "74, self-renewal ['l0', 'l5', 'l6', 'l7', 'l8']", + "91, satellite ['l1', 'l5', 'l9', 'l10', 'l11']", + "92, cells ['l2', 'l6', 'l9', 'l12', 'l13']", + "94, aged ['l3', 'l7', 'l10', 'l12', 'l14']", + "95, mice. ['l4', 'l8', 'l11', 'l13', 'l14']", + "106, ameliorate ['l15', 'l16']", + "108, self-renewal ['l15', 'l17']", + "109, defects. ['l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "loss", + "ameliorate", + "defects." + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "loss" + ] + }, + "context": { + "val": "cells", + "words": [ + "satellite", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "loss" + ] + }, + "context": { + "val": "organism", + "words": [ + "aged", + "mice." + ] + } + }, + { + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal" + ] + }, + "context": { + "val": "cells", + "words": [ + "satellite", + "cells" + ] + } + }, + { + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal" + ] + }, + "context": { + "val": "organism", + "words": [ + "aged", + "mice." + ] + } + } + ] + }, + { + "PMID": "24531378", + "TEXT": "The elderly often suffer from progressive muscle weakness and regenerative failure. We demonstrate that muscle regeneration is impaired with aging owing in part to a cell-autonomous functional decline in skeletal muscle stem cells (MuSCs). Two-thirds of MuSCs from aged mice are intrinsically defective relative to MuSCs from young mice, with reduced capacity to repair myofibers and repopulate the stem cell reservoir in vivo following transplantation. This deficiency is correlated with a higher incidence of cells that express senescence markers and is due to elevated activity of the p38α and p38β mitogen-activated kinase pathway. We show that these limitations cannot be overcome by transplantation into the microenvironment of young recipient muscles. In contrast, subjecting the MuSC population from aged mice to transient inhibition of p38α and p38β in conjunction with culture on soft hydrogel substrates rapidly expands the residual functional MuSC population from aged mice, rejuvenating its potential for regeneration and serial transplantation as well as strengthening of damaged muscles of aged mice. These findings reveal a synergy between biophysical and biochemical cues that provides a paradigm for a localized autologous muscle stem cell therapy for the elderly.", + "TAG_DATA": [ + "61, in {'context': 'B-in vivo'}", + "62, vivo {'context': 'I-in vivo'}", + "114, MuSC {'context': 'B-cells'}", + "115, population {'context': 'I-cells'}", + "117, aged {'context': 'B-organism'}", + "118, mice {'context': 'I-organism'}", + "139, MuSC {'context': 'B-cells'}", + "142, aged {'context': 'B-organism'}", + "143, mice, {'context': 'I-organism'}", + "158, muscles {'context': 'B-tissue/organ'}", + "160, aged {'context': 'B-organism'}", + "161, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "61, in ['l0']", + "62, vivo ['l0']", + "114, MuSC ['l1', 'l2', 'l3']", + "115, population ['l1', 'l4', 'l5']", + "117, aged ['l2', 'l4', 'l6']", + "118, mice ['l3', 'l5', 'l6']", + "139, MuSC ['l7', 'l8', 'l9', 'l10', 'l11']", + "142, aged ['l7', 'l12', 'l13', 'l14', 'l15']", + "143, mice, ['l8', 'l12', 'l16', 'l17', 'l18']", + "158, muscles ['l9', 'l13', 'l16', 'l19', 'l20']", + "160, aged ['l10', 'l14', 'l17', 'l19', 'l21']", + "161, mice. ['l11', 'l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24504397", + "TEXT": "Jeremy Farrar is no stranger to running a charitable organization. In 2011, the clinician-scientist and avid cricket player launched the Farrar Foundation, which spends around £9,000 ($15,000) per year supporting medical and sporting activities in Southeast Asia. As director of the Oxford University Clinical Research Unit, based in Ho Chi Minh City, Vietnam, Farrar wanted to give something back to the people he had worked with in region. Now, he is taking his research and philanthropic agendas to a global level. On 1 October, Farrar took the helm of the Wellcome Trust, the second largest nongovernmental funder of biomedical research in the world.It's a natural fit for the Wellcome Trust and Farrar alike-Farrar has leadership experience in the global health arena and the Trust has supported much of his research into dengue, typhoid and other tropical diseases. But the Wellcome Trust, with its £16 billion endowment, is far more than just an enabler of biomedical research. It is also a key player in wider science policy debates, driving forward agendas such as open access while also maintaining active programs of public engagement. Farrar sat down with Daniel Cressey at the Wellcome headquarters in London to discuss his Trust issues.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24487434", + "TEXT": "Loss of function of the tumor suppressor gene PRDM1 (also known as BLIMP1) or deregulated expression of the oncogene BCL6 occurs in a large proportion of diffuse large B cell lymphoma (DLBCL) cases. However, targeted mutation of either gene in mice leads to only slow and infrequent development of malignant lymphoma, and despite frequent mutation of BCL6 in activated B cells of healthy individuals, lymphoma development is rare. Here we show that T cells prevent the development of overt lymphoma in mice caused by Blimp1 deficiency or overexpression of Bcl6 in the B cell lineage. Impairment of T cell control results in rapid development of DLBCL-like disease, which can be eradicated by polyclonal CD8(+) T cells in a T cell receptor-, CD28- and Fas ligand-dependent manner. Thus, malignant transformation of mature B cells requires mutations that impair intrinsic differentiation processes and permit escape from T cell-mediated tumor surveillance.", + "TAG_DATA": [ + "72, T {'context': 'B-cells'}", + "73, cells {'context': 'B-cells'}", + "74, prevent {'effect': 'B-negative'}", + "79, lymphoma {'phenotype': 'B-tumourigenesis'}", + "81, mice {'context': 'B-organism'}", + "84, Blimp1 {'perturbing_action': 'B-gene loss-of-function'}", + "85, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "87, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "88, of {'perturbing_action': 'I-gene gain-of-function'}", + "89, Bcl6 {'perturbing_action': 'I-gene gain-of-function'}", + "91, the {'perturbing_action': 'I-gene gain-of-function'}", + "92, B {'context': 'B-cells'}", + "93, cell {'context': 'I-cells'}", + "94, lineage. {'context': 'I-cells'}", + "113, CD8(+) {'context': 'B-cells'}", + "114, T {'context': 'I-cells'}", + "115, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "72, T ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "73, cells ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "74, prevent ['l1', 'l11', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "76, development ['l2', 'l12', 'l20', 'l32', 'l33', 'l34', 'l35', 'l36']", + "79, lymphoma ['l3', 'l13', 'l21', 'l32', 'l37', 'l38', 'l39', 'l40']", + "81, mice ['l4', 'l14', 'l22', 'l33', 'l37', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "84, Blimp1 ['l5', 'l15', 'l23', 'l34', 'l38', 'l41', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "85, deficiency ['l6', 'l16', 'l24', 'l35', 'l39', 'l42', 'l48', 'l56', 'l57', 'l58', 'l59']", + "87, overexpression ['l25', 'l49', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "88, of ['l26', 'l43', 'l50', 'l60', 'l66', 'l67', 'l68', 'l69', 'l70']", + "89, Bcl6 ['l27', 'l51', 'l61', 'l66', 'l71', 'l72', 'l73', 'l74']", + "91, the ['l7', 'l28', 'l44', 'l52', 'l56', 'l62', 'l67', 'l71', 'l75', 'l76', 'l77']", + "92, B ['l8', 'l17', 'l29', 'l45', 'l53', 'l57', 'l63', 'l68', 'l72', 'l75', 'l78', 'l79']", + "93, cell ['l9', 'l18', 'l30', 'l36', 'l40', 'l46', 'l54', 'l58', 'l64', 'l69', 'l73', 'l76', 'l78', 'l80']", + "94, lineage. ['l10', 'l19', 'l31', 'l47', 'l55', 'l59', 'l65', 'l70', 'l74', 'l77', 'l79', 'l80']", + "113, CD8(+) ['l81', 'l82']", + "114, T ['l81', 'l83']", + "115, cells ['l82', 'l83']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "B", + "cell", + "lineage." + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "cell" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "B", + "cell", + "lineage." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Blimp1", + "deficiency" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "B", + "cell", + "lineage." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "the", + "overexpression", + "of", + "Bcl6" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Blimp1", + "deficiency" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Bcl6", + "the" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Blimp1", + "deficiency" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Blimp1", + "deficiency" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "the" + ] + } + } + ] + }, + { + "PMID": "24464187", + "TEXT": "Recent studies have indicated that high-density lipoproteins (HDLs) and their major structural protein, apolipoprotein A1 (apoA1), recovered from human atheroma are dysfunctional and are extensively oxidized by myeloperoxidase (MPO). In vitro oxidation of either apoA1 or HDL particles by MPO impairs their cholesterol acceptor function. Here, using phage display affinity maturation, we developed a high-affinity monoclonal antibody that specifically recognizes both apoA1 and HDL that have been modified by the MPO-H2O2-Cl(-) system. An oxindolyl alanine (2-OH-Trp) moiety at Trp72 of apoA1 is the immunogenic epitope. Mutagenesis studies confirmed a critical role for apoA1 Trp72 in MPO-mediated inhibition of the ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol acceptor activity of apoA1 in vitro and in vivo. ApoA1 containing a 2-OH-Trp72 group (oxTrp72-apoA1) is in low abundance within the circulation but accounts for 20% of the apoA1 in atherosclerosis-laden arteries. OxTrp72-apoA1 recovered from human atheroma or plasma is lipid poor, virtually devoid of cholesterol acceptor activity and demonstrated both a potent proinflammatory activity on endothelial cells and an impaired HDL biogenesis activity in vivo. Elevated oxTrp72-apoA1 levels in subjects presenting to a cardiology clinic (n = 627) were associated with increased cardiovascular disease risk. Circulating oxTrp72-apoA1 levels may serve as a way to monitor a proatherogenic process in the artery wall.", + "TAG_DATA": [ + "109, in {'context': 'B-in vitro'}", + "110, vitro {'context': 'I-in vitro'}", + "112, in {'context': 'B-in vivo'}", + "113, vivo. {'context': 'I-in vivo'}", + "161, endothelial {'context': 'B-cells'}", + "162, cells {'context': 'I-cells'}", + "169, in {'context': 'B-in vivo'}", + "170, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "109, in ['l0', 'l1', 'l2']", + "110, vitro ['l0', 'l3', 'l4']", + "112, in ['l1', 'l3', 'l5']", + "113, vivo. ['l2', 'l4', 'l5']", + "161, endothelial ['l6', 'l7', 'l8']", + "162, cells ['l6', 'l9', 'l10']", + "169, in ['l7', 'l9', 'l11']", + "170, vivo. ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24464186", + "TEXT": "Although the classical antibiotic spectinomycin is a potent bacterial protein synthesis inhibitor, poor antimycobacterial activity limits its clinical application for treating tuberculosis. Using structure-based design, we generated a new semisynthetic series of spectinomycin analogs with selective ribosomal inhibition and excellent narrow-spectrum antitubercular activity. In multiple murine infection models, these spectinamides were well tolerated, significantly reduced lung mycobacterial burden and increased survival. In vitro studies demonstrated a lack of cross resistance with existing tuberculosis therapeutics, activity against multidrug-resistant (MDR) and extensively drug-resistant tuberculosis and an excellent pharmacological profile. Key to their potent antitubercular properties was their structural modification to evade the Rv1258c efflux pump, which is upregulated in MDR strains and is implicated in macrophage-induced drug tolerance. The antitubercular efficacy of spectinamides demonstrates that synthetic modifications to classical antibiotics can overcome the challenge of intrinsic efflux pump-mediated resistance and expands opportunities for target-based tuberculosis drug discovery.", + "TAG_DATA": [ + "45, murine {'context': 'B-organism'}", + "46, infection {'context': 'I-organism'}", + "47, models, {'context': 'I-organism'}", + "55, lung {'context': 'B-tissue/organ'}", + "61, In {'context': 'B-in vitro'}", + "62, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "45, murine ['l0', 'l1', 'l2']", + "46, infection ['l0', 'l3', 'l4']", + "47, models, ['l1', 'l3', 'l5']", + "55, lung ['l2', 'l4', 'l5']", + "61, In ['l6']", + "62, vitro ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24441829", + "TEXT": "Fatty acids are integral mediators of energy storage, membrane formation and cell signaling. The pathways that orchestrate uptake of fatty acids remain incompletely understood. Expression of the integrin ligand Mfge8 is increased in human obesity and in mice on a high-fat diet, but its role in obesity is unknown. We show here that Mfge8 promotes the absorption of dietary triglycerides and the cellular uptake of fatty acid and that Mfge8-deficient (Mfge8(-/-)) mice are protected from diet-induced obesity, steatohepatitis and insulin resistance. Mechanistically, we found that Mfge8 coordinates fatty acid uptake through αvβ3 integrin- and αvβ5 integrin-dependent phosphorylation of Akt by phosphatidylinositide-3 kinase and mTOR complex 2, leading to translocation of Cd36 and Fatp1 from cytoplasmic vesicles to the cell surface. Collectively, our results imply a role for Mfge8 in regulating the absorption and storage of dietary fats, as well as in the development of obesity and its complications.", + "TAG_DATA": [ + "69, Mfge8-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "70, (Mfge8(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "71, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "69, Mfge8-deficient ['l0', 'l1']", + "70, (Mfge8(-/-)) ['l0', 'l2']", + "71, mice ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mfge8-deficient", + "(Mfge8(-/-))" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "24390308", + "TEXT": "Metabolites from intestinal microbiota are key determinants of host-microbe mutualism and, consequently, the health or disease of the intestinal tract. However, whether such host-microbe crosstalk influences inflammation in peripheral tissues, such as the lung, is poorly understood. We found that dietary fermentable fiber content changed the composition of the gut and lung microbiota, in particular by altering the ratio of Firmicutes to Bacteroidetes. The gut microbiota metabolized the fiber, consequently increasing the concentration of circulating short-chain fatty acids (SCFAs). Mice fed a high-fiber diet had increased circulating levels of SCFAs and were protected against allergic inflammation in the lung, whereas a low-fiber diet decreased levels of SCFAs and increased allergic airway disease. Treatment of mice with the SCFA propionate led to alterations in bone marrow hematopoiesis that were characterized by enhanced generation of macrophage and dendritic cell (DC) precursors and subsequent seeding of the lungs by DCs with high phagocytic capacity but an impaired ability to promote T helper type 2 (TH2) cell effector function. The effects of propionate on allergic inflammation were dependent on G protein-coupled receptor 41 (GPR41, also called free fatty acid receptor 3 or FFAR3), but not GPR43 (also called free fatty acid receptor 2 or FFAR2). Our results show that dietary fermentable fiber and SCFAs can shape the immunological environment in the lung and influence the severity of allergic inflammation.", + "TAG_DATA": [ + "79, Mice {'context': 'B-organism'}", + "98, lung, {'context': 'B-tissue/organ'}", + "114, mice {'context': 'B-organism'}", + "123, bone {'context': 'B-cells'}", + "124, marrow {'context': 'I-cells'}", + "133, macrophage {'context': 'B-cells'}", + "136, cell {'context': 'I-cells'}", + "144, lungs {'context': 'B-tissue/organ'}", + "146, DCs {'context': 'B-cells'}", + "157, T {'context': 'B-cells'}", + "158, helper {'context': 'I-cells'}", + "159, type {'context': 'I-cells'}", + "160, 2 {'context': 'I-cells'}", + "161, (TH2) {'context': 'I-cells'}", + "162, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "79, Mice ['l0']", + "98, lung, ['l0']", + "114, mice ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "123, bone ['l1', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "124, marrow ['l2', 'l14', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "133, macrophage ['l3', 'l15', 'l25', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "135, dendritic ['l4', 'l16', 'l26', 'l34', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "136, cell ['l5', 'l17', 'l27', 'l35', 'l41', 'l47', 'l48', 'l49', 'l50']", + "144, lungs ['l6', 'l18', 'l28', 'l36', 'l42', 'l47', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "146, DCs ['l7', 'l19', 'l29', 'l37', 'l43', 'l48', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "157, T ['l8', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "158, helper ['l9', 'l20', 'l30', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "159, type ['l10', 'l21', 'l31', 'l38', 'l44', 'l49', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "160, 2 ['l11', 'l22', 'l32', 'l39', 'l45', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "161, (TH2) ['l12', 'l23', 'l33', 'l40', 'l46', 'l50', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "162, cell ['l13', 'l24', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24362934", + "TEXT": "Autoimmune diseases often result from an imbalance between regulatory T (Treg) cells and interleukin-17 (IL-17)-producing T helper (TH17) cells; the origin of the latter cells remains largely unknown. Foxp3 is indispensable for the suppressive function of Treg cells, but the stability of Foxp3 has been under debate. Here we show that TH17 cells originating from Foxp3(+) T cells have a key role in the pathogenesis of autoimmune arthritis. Under arthritic conditions, CD25(lo)Foxp3(+)CD4(+) T cells lose Foxp3 expression (herein called exFoxp3 cells) and undergo transdifferentiation into TH17 cells. Fate mapping analysis showed that IL-17-expressing exFoxp3 T (exFoxp3 TH17) cells accumulated in inflamed joints. The conversion of Foxp3(+)CD4(+) T cells to TH17 cells was mediated by synovial fibroblast-derived IL-6. These exFoxp3 TH17 cells were more potent osteoclastogenic T cells than were naive CD4(+) T cell-derived TH17 cells. Notably, exFoxp3 TH17 cells were characterized by the expression of Sox4, chemokine (C-C motif) receptor 6 (CCR6), chemokine (C-C motif) ligand 20 (CCL20), IL-23 receptor (IL-23R) and receptor activator of NF-κB ligand (RANKL, also called TNFSF11). Adoptive transfer of autoreactive, antigen-experienced CD25(lo)Foxp3(+)CD4(+) T cells into mice followed by secondary immunization with collagen accelerated the onset and increased the severity of arthritis and was associated with the loss of Foxp3 expression in the majority of transferred T cells. We observed IL-17(+)Foxp3(+) T cells in the synovium of subjects with active rheumatoid arthritis (RA), which suggests that plastic Foxp3(+) T cells contribute to the pathogenesis of RA.", + "TAG_DATA": [ + "105, Foxp3(+)CD4(+) {'context': 'B-cells'}", + "106, T {'context': 'I-cells'}", + "107, cells {'context': 'I-cells'}", + "119, TH17 {'context': 'I-cells'}", + "120, cells {'context': 'I-cells'}", + "129, naive {'context': 'B-cells'}", + "130, CD4(+) {'context': 'I-cells'}", + "131, T {'context': 'I-cells'}", + "132, cell-derived {'context': 'I-cells'}", + "133, TH17 {'context': 'I-cells'}", + "134, cells. {'context': 'I-cells'}", + "180, mice {'context': 'B-organism'}", + "210, T {'context': 'B-cells'}", + "211, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "105, Foxp3(+)CD4(+) ['l0', 'l1', 'l2', 'l3']", + "106, T ['l0', 'l4', 'l5', 'l6']", + "107, cells ['l1', 'l4', 'l7']", + "119, TH17 ['l2', 'l5', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "120, cells ['l3', 'l6', 'l7', 'l8']", + "129, naive ['l9', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "130, CD4(+) ['l10', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "131, T ['l11', 'l16', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "132, cell-derived ['l12', 'l17', 'l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "133, TH17 ['l13', 'l18', 'l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "134, cells. ['l14', 'l19', 'l24', 'l30', 'l35', 'l39']", + "177, T ['l25', 'l31', 'l36', 'l40', 'l43', 'l44']", + "178, cells ['l20', 'l26', 'l32', 'l37', 'l41', 'l43', 'l45']", + "180, mice ['l27', 'l33', 'l38', 'l42', 'l44', 'l45']", + "210, T ['l46']", + "211, cells. ['l46']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24292392", + "TEXT": "Tumor recurrence following treatment remains a major clinical challenge. Evidence from xenograft models and human trials indicates selective enrichment of cancer-initiating cells (CICs) in tumors that survive therapy. Together with recent reports showing that CIC gene signatures influence patient survival, these studies predict that targeting self-renewal, the key 'stemness' property unique to CICs, may represent a new paradigm in cancer therapy. Here we demonstrate that tumor formation and, more specifically, human colorectal CIC function are dependent on the canonical self-renewal regulator BMI-1. Downregulation of BMI-1 inhibits the ability of colorectal CICs to self-renew, resulting in the abrogation of their tumorigenic potential. Treatment of primary colorectal cancer xenografts with a small-molecule BMI-1 inhibitor resulted in colorectal CIC loss with long-term and irreversible impairment of tumor growth. Targeting the BMI-1-related self-renewal machinery provides the basis for a new therapeutic approach in the treatment of colorectal cancer.", + "TAG_DATA": [ + "82, Downregulation {'perturbing_action': 'B-gene loss-of-function'}", + "83, of {'perturbing_action': 'I-gene loss-of-function'}", + "84, BMI-1 {'perturbing_action': 'I-gene loss-of-function'}", + "85, inhibits {'effect': 'B-negative'}", + "87, ability {'effect': 'I-negative'}", + "89, colorectal {'context': 'B-cells'}", + "90, CICs {'context': 'I-cells'}", + "92, self-renew, {'phenotype': 'B-self-renewal'}", + "96, abrogation {'effect': 'B-negative'}", + "99, tumorigenic {'phenotype': 'B-tumourigenesis'}", + "100, potential. {'phenotype': 'I-tumour initiation'}", + "103, primary {'context': 'B-xenograft'}", + "104, colorectal {'context': 'I-xenograft'}", + "105, cancer {'context': 'I-xenograft'}", + "106, xenografts {'context': 'I-xenograft'}", + "109, small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "110, BMI-1 {'perturbing_action': 'I-pharmacological inhibition'}", + "111, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "114, colorectal {'context': 'B-cells'}", + "115, CIC {'context': 'I-cells'}", + "121, impairment {'effect': 'B-negative'}", + "123, tumor {'phenotype': 'B-tumour growth'}", + "124, growth. {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "82, Downregulation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "83, of ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "84, BMI-1 ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "85, inhibits ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "87, ability ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "89, colorectal ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "90, CICs ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "92, self-renew, ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "96, abrogation ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "99, tumorigenic ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "100, potential. ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "103, primary ['l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "104, colorectal ['l55', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "105, cancer ['l56', 'l66', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "106, xenografts ['l57', 'l67', 'l76', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "109, small-molecule ['l58', 'l68', 'l77', 'l85', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "110, BMI-1 ['l59', 'l69', 'l78', 'l86', 'l93', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "111, inhibitor ['l60', 'l70', 'l79', 'l87', 'l94', 'l100', 'l106', 'l107', 'l108', 'l109', 'l110']", + "114, colorectal ['l61', 'l71', 'l80', 'l88', 'l95', 'l101', 'l106', 'l111', 'l112', 'l113', 'l114']", + "115, CIC ['l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l107', 'l111', 'l115', 'l116', 'l117']", + "121, impairment ['l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l108', 'l112', 'l115', 'l118', 'l119']", + "123, tumor ['l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l109', 'l113', 'l116', 'l118', 'l120']", + "124, growth. ['l65', 'l75', 'l84', 'l92', 'l99', 'l105', 'l110', 'l114', 'l117', 'l119', 'l120']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Downregulation", + "of", + "BMI-1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits", + "ability", + "abrogation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Downregulation", + "of", + "BMI-1" + ] + }, + "context": { + "val": "cells", + "words": [ + "colorectal", + "CICs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Downregulation", + "of", + "BMI-1" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renew," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Downregulation", + "of", + "BMI-1" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Downregulation", + "of", + "BMI-1" + ] + }, + "phenotype": { + "val": "tumour initiation", + "words": [ + "potential." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "ability", + "abrogation", + "impairment" + ] + }, + "context": { + "val": "cells", + "words": [ + "colorectal", + "CICs", + "CIC" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "ability", + "abrogation" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renew," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "ability", + "abrogation" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenic" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "ability", + "abrogation" + ] + }, + "phenotype": { + "val": "tumour initiation", + "words": [ + "potential." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "colorectal", + "CICs" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renew," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "colorectal", + "CICs" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenic" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "colorectal", + "CICs" + ] + }, + "phenotype": { + "val": "tumour initiation", + "words": [ + "potential." + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "primary", + "colorectal", + "cancer", + "xenografts" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "BMI-1", + "inhibitor" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "primary", + "colorectal", + "cancer", + "xenografts" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impairment" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "primary", + "colorectal", + "cancer", + "xenografts" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "BMI-1", + "inhibitor" + ] + }, + "context": { + "val": "cells", + "words": [ + "colorectal", + "CIC" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "BMI-1", + "inhibitor" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impairment" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "BMI-1", + "inhibitor" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "colorectal", + "CIC" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impairment" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + } + ] + }, + { + "PMID": "24270546", + "TEXT": "Hepatitis C virus (HCV) is endemic in many countries due to its high propensity for establishing persistence. The presence of HCV-specific T cells in subjects repeatedly exposed to HCV who test negative for HCV RNA and antibodies and who do not have any history of HCV infection has been interpreted as T cell-mediated protection. Here, we show in nonhuman primates that repeated exposure to human plasma with trace amounts of HCV induced HCV-specific T cells without seroconversion and systemic viremia but did not protect upon subsequent HCV challenge. Rather, HCV-specific recall and de novo T cell responses, as well as intrahepatic T cell recruitment and interferon-γ (IFN-γ) production, were suppressed upon HCV challenge, concomitant with quantitative and qualitative changes in regulatory T cells (T(reg) cells) that occurred after subinfectious HCV exposure and increased after HCV challenge. In vitro T(reg) cell depletion restored HCV-specific T cell responses. Thus, T cells primed by trace amounts of HCV do not generate effective recall responses upon subsequent HCV infection. Subinfectious HCV exposure predisposes to T(reg) cell expansion, which suppresses effector T cells during subsequent infection. Strategies to reverse this exposure-induced immune suppression should be examined to aid in the development of T cell-based vaccines against HCV and other endemic pathogens.", + "TAG_DATA": [ + "58, nonhuman {'context': 'B-organism'}", + "59, primates {'context': 'I-organism'}", + "73, T {'context': 'B-cells'}", + "74, cells {'context': 'I-cells'}", + "94, T {'context': 'B-cells'}", + "95, cell {'context': 'B-cells'}", + "120, regulatory {'context': 'B-cells'}", + "121, T {'context': 'I-cells'}", + "122, cells {'context': 'I-cells'}", + "136, In {'context': 'B-in vitro'}", + "137, vitro {'context': 'I-in vitro'}", + "138, T(reg) {'context': 'B-cells'}", + "139, cell {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "140, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "143, T {'context': 'B-cells'}", + "144, cell {'context': 'B-cells'}", + "147, T {'context': 'B-cells'}", + "148, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "58, nonhuman ['l0', 'l1', 'l2', 'l3', 'l4']", + "59, primates ['l0', 'l5', 'l6', 'l7', 'l8']", + "73, T ['l1', 'l5', 'l9']", + "74, cells ['l2', 'l6', 'l9']", + "94, T ['l3', 'l7', 'l10']", + "95, cell ['l4', 'l8', 'l10']", + "120, regulatory ['l11', 'l12']", + "121, T ['l11', 'l13']", + "122, cells ['l12', 'l13']", + "136, In ['l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "137, vitro ['l14', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "138, T(reg) ['l15', 'l22', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "139, cell ['l16', 'l23', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "140, depletion ['l17', 'l24', 'l30', 'l35', 'l40', 'l41', 'l42', 'l43']", + "143, T ['l18', 'l25', 'l31', 'l36', 'l40', 'l44', 'l45', 'l46']", + "144, cell ['l19', 'l26', 'l32', 'l37', 'l41', 'l44']", + "147, T ['l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47']", + "148, cells ['l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cell", + "depletion" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cell", + "depletion" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "T(reg)", + "T", + "cells" + ] + } + } + ] + }, + { + "PMID": "24270545", + "TEXT": "Activation of self-reactive T cells and their trafficking to target tissues leads to autoimmune organ destruction. Mice lacking the co-inhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) develop fatal autoimmunity characterized by lymphocytic infiltration into nonlymphoid tissues. Here, we demonstrate that the CD28 co-stimulatory pathway regulates the trafficking of self-reactive Ctla4(-/-) T cells to tissues. Concurrent ablation of the CD28-activated Tec family kinase ITK does not block spontaneous T cell activation but instead causes self-reactive Ctla4(-/-) T cells to accumulate in secondary lymphoid organs. Despite excessive spontaneous T cell activation and proliferation in lymphoid organs, Itk(-/-); Ctla4(-/-) mice are otherwise healthy, mount antiviral immune responses and exhibit a long lifespan. We propose that ITK specifically licenses autoreactive T cells to enter tissues to mount destructive immune responses. Notably, ITK inhibitors mimic the null mutant phenotype and also prevent pancreatic islet infiltration by diabetogenic T cells in mouse models of type 1 diabetes, highlighting their potential utility for the treatment of human autoimmune disorders.", + "TAG_DATA": [ + "55, ablation {'perturbing_action': 'B-gene loss-of-function'}", + "56, of {'perturbing_action': 'I-gene loss-of-function'}", + "57, the {'perturbing_action': 'I-gene loss-of-function'}", + "58, CD28-activated {'perturbing_action': 'I-gene loss-of-function'}", + "59, Tec {'perturbing_action': 'I-gene loss-of-function'}", + "60, family {'perturbing_action': 'I-gene loss-of-function'}", + "61, kinase {'perturbing_action': 'I-gene loss-of-function'}", + "62, ITK {'perturbing_action': 'I-gene loss-of-function'}", + "67, T {'context': 'B-cells'}", + "68, cell {'context': 'B-cells'}", + "74, Ctla4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "75, T {'context': 'B-cells'}", + "76, cells {'context': 'B-cells'}", + "80, secondary {'context': 'B-tissue/organ'}", + "81, lymphoid {'context': 'I-tissue/organ'}", + "82, organs. {'context': 'I-tissue/organ'}", + "86, T {'context': 'B-cells'}", + "87, cell {'context': 'B-cells'}", + "90, proliferation {'phenotype': 'B-proliferation'}", + "92, lymphoid {'context': 'B-tissue/organ'}", + "93, organs, {'context': 'I-tissue/organ'}", + "94, Itk(-/-); {'perturbing_action': 'B-gene loss-of-function'}", + "95, Ctla4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "96, mice {'context': 'B-organism'}", + "127, ITK {'perturbing_action': 'B-pharmacological inhibition'}", + "128, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "137, pancreatic {'context': 'B-cells'}", + "141, diabetogenic {'context': 'B-cells'}", + "142, T {'context': 'I-cells'}", + "143, cells {'context': 'I-cells'}", + "145, mouse {'context': 'B-organism'}", + "146, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "55, ablation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "56, of ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "57, the ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "58, CD28-activated ['l2', 'l21', 'l39', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "59, Tec ['l3', 'l22', 'l40', 'l57', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "60, family ['l4', 'l23', 'l41', 'l58', 'l74', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "61, kinase ['l5', 'l24', 'l42', 'l59', 'l75', 'l90', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "62, ITK ['l6', 'l25', 'l43', 'l60', 'l76', 'l91', 'l105', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "67, T ['l7', 'l26', 'l44', 'l61', 'l77', 'l92', 'l106', 'l119', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "68, cell ['l8', 'l27', 'l45', 'l62', 'l78', 'l93', 'l107', 'l120', 'l132', 'l138', 'l139', 'l140', 'l141', 'l142']", + "74, Ctla4(-/-) ['l9', 'l28', 'l46', 'l63', 'l79', 'l94', 'l108', 'l121', 'l143', 'l144', 'l145', 'l146', 'l147']", + "75, T ['l10', 'l29', 'l47', 'l64', 'l80', 'l95', 'l109', 'l122', 'l133', 'l138', 'l143', 'l148', 'l149', 'l150', 'l151']", + "76, cells ['l11', 'l30', 'l48', 'l65', 'l81', 'l96', 'l110', 'l123', 'l134', 'l139', 'l144', 'l148', 'l152', 'l153', 'l154']", + "80, secondary ['l12', 'l31', 'l49', 'l66', 'l82', 'l97', 'l111', 'l124', 'l135', 'l140', 'l145', 'l149', 'l152', 'l155', 'l156']", + "81, lymphoid ['l13', 'l32', 'l50', 'l67', 'l83', 'l98', 'l112', 'l125', 'l136', 'l141', 'l146', 'l150', 'l153', 'l155', 'l157']", + "82, organs. ['l14', 'l33', 'l51', 'l68', 'l84', 'l99', 'l113', 'l126', 'l137', 'l142', 'l147', 'l151', 'l154', 'l156', 'l157']", + "86, T ['l15', 'l34', 'l52', 'l69', 'l85', 'l100', 'l114', 'l127', 'l158', 'l159', 'l160', 'l161']", + "87, cell ['l16', 'l35', 'l53', 'l70', 'l86', 'l101', 'l115', 'l128', 'l158', 'l162', 'l163', 'l164']", + "90, proliferation ['l17', 'l36', 'l54', 'l71', 'l87', 'l102', 'l116', 'l129', 'l159', 'l162', 'l165', 'l166']", + "92, lymphoid ['l18', 'l37', 'l55', 'l72', 'l88', 'l103', 'l117', 'l130', 'l160', 'l163', 'l165', 'l167']", + "93, organs, ['l19', 'l38', 'l56', 'l73', 'l89', 'l104', 'l118', 'l131', 'l161', 'l164', 'l166', 'l167']", + "94, Itk(-/-); ['l168', 'l169']", + "95, Ctla4(-/-) ['l168', 'l170', 'l171', 'l172', 'l173']", + "96, mice ['l169', 'l170']", + "127, ITK ['l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181']", + "128, inhibitors ['l174', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "137, pancreatic ['l175', 'l182', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "138, islet ['l176', 'l183', 'l189', 'l195', 'l196', 'l197', 'l198', 'l199']", + "141, diabetogenic ['l177', 'l184', 'l190', 'l195', 'l200', 'l201', 'l202', 'l203']", + "142, T ['l171', 'l178', 'l185', 'l191', 'l196', 'l200', 'l204', 'l205', 'l206']", + "143, cells ['l172', 'l179', 'l186', 'l192', 'l197', 'l201', 'l204', 'l207', 'l208']", + "145, mouse ['l180', 'l187', 'l193', 'l198', 'l202', 'l205', 'l207', 'l209']", + "146, models ['l173', 'l181', 'l188', 'l194', 'l199', 'l203', 'l206', 'l208', 'l209']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablation", + "of", + "the", + "CD28-activated", + "Tec", + "family", + "kinase", + "ITK", + "Ctla4(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablation", + "of", + "the", + "CD28-activated", + "Tec", + "family", + "kinase", + "ITK", + "Ctla4(-/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "secondary", + "lymphoid", + "organs.", + "organs," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablation", + "of", + "the", + "CD28-activated", + "Tec", + "family", + "kinase", + "ITK" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lymphoid", + "organs," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Itk(-/-);", + "Ctla4(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "models" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ITK", + "inhibitors" + ] + }, + "context": { + "val": "cells", + "words": [ + "pancreatic", + "diabetogenic", + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ITK", + "inhibitors" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + } + } + ] + }, + { + "PMID": "24240184", + "TEXT": "Ammonia is a ubiquitous waste product of protein metabolism that can accumulate in numerous metabolic disorders, causing neurological dysfunction ranging from cognitive impairment to tremor, ataxia, seizures, coma and death. The brain is especially vulnerable to ammonia as it readily crosses the blood-brain barrier in its gaseous form, NH3, and rapidly saturates its principal removal pathway located in astrocytes. Thus, we wanted to determine how astrocytes contribute to the initial deterioration of neurological functions characteristic of hyperammonemia in vivo. Using a combination of two-photon imaging and electrophysiology in awake head-restrained mice, we show that ammonia rapidly compromises astrocyte potassium buffering, increasing extracellular potassium concentration and overactivating the Na(+)-K(+)-2Cl(-) cotransporter isoform 1 (NKCC1) in neurons. The consequent depolarization of the neuronal GABA reversal potential (EGABA) selectively impairs cortical inhibitory networks. Genetic deletion of NKCC1 or inhibition of it with the clinically used diuretic bumetanide potently suppresses ammonia-induced neurological dysfunction. We did not observe astrocyte swelling or brain edema in the acute phase, calling into question current concepts regarding the neurotoxic effects of ammonia. Instead, our findings identify failure of potassium buffering in astrocytes as a crucial mechanism in ammonia neurotoxicity and demonstrate the therapeutic potential of blocking this pathway by inhibiting NKCC1.", + "TAG_DATA": [ + "89, head-restrained {'context': 'B-organism'}", + "90, mice, {'context': 'I-organism'}", + "97, astrocyte {'context': 'B-cells'}", + "113, neurons. {'context': 'B-cells'}", + "129, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "130, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "131, of {'perturbing_action': 'I-gene loss-of-function'}", + "132, NKCC1 {'perturbing_action': 'I-gene loss-of-function'}", + "152, astrocyte {'context': 'B-cells'}", + "155, brain {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "89, head-restrained ['l0', 'l1', 'l2']", + "90, mice, ['l0', 'l3', 'l4']", + "97, astrocyte ['l1', 'l3', 'l5']", + "113, neurons. ['l2', 'l4', 'l5']", + "129, Genetic ['l6', 'l7', 'l8']", + "130, deletion ['l6', 'l9', 'l10']", + "131, of ['l7', 'l9', 'l11']", + "132, NKCC1 ['l8', 'l10', 'l11']", + "152, astrocyte ['l12']", + "155, brain ['l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24216752", + "TEXT": "Racial differences in the pathophysiology of atherothrombosis are poorly understood. We explored the function and transcriptome of platelets in healthy black (n = 70) and white (n = 84) subjects. Platelet aggregation and calcium mobilization induced by the PAR4 thrombin receptor were significantly greater in black subjects. Numerous differentially expressed RNAs were associated with both race and PAR4 reactivity, including PCTP (encoding phosphatidylcholine transfer protein), and platelets from black subjects expressed higher levels of PC-TP protein. PC-TP inhibition or depletion blocked PAR4- but not PAR1-mediated activation of platelets and megakaryocytic cell lines. miR-376c levels were differentially expressed by race and PAR4 reactivity and were inversely correlated with PCTP mRNA levels, PC-TP protein levels and PAR4 reactivity. miR-376c regulated the expression of PC-TP in human megakaryocytes. A disproportionately high number of microRNAs that were differentially expressed by race and PAR4 reactivity, including miR-376c, are encoded in the DLK1-DIO3 locus and were expressed at lower levels in platelets from black subjects. These results suggest that PC-TP contributes to the racial difference in PAR4-mediated platelet activation, indicate a genomic contribution to platelet function that differs by race and emphasize a need to consider the effects of race when developing anti-thrombotic drugs.", + "TAG_DATA": [ + "87, platelets {'context': 'B-cells'}", + "89, megakaryocytic {'context': 'B-cells'}", + "90, cell {'context': 'I-cells'}", + "91, lines. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "87, platelets ['l0', 'l1', 'l2']", + "89, megakaryocytic ['l0', 'l3', 'l4']", + "90, cell ['l1', 'l3', 'l5']", + "91, lines. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24185692", + "TEXT": "The obesity epidemic has led to an increased incidence of nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. AMP-activated protein kinase (Ampk) regulates energy homeostasis and is activated by cellular stress, hormones and the widely prescribed type 2 diabetes drug metformin. Ampk phosphorylates mouse acetyl-CoA carboxylase 1 (Acc1; refs. 3,4) at Ser79 and Acc2 at Ser212, inhibiting the conversion of acetyl-CoA to malonyl-CoA. The latter metabolite is a precursor in fatty acid synthesis and an allosteric inhibitor of fatty acid transport into mitochondria for oxidation. To test the physiological impact of these phosphorylation events, we generated mice with alanine knock-in mutations in both Acc1 (at Ser79) and Acc2 (at Ser212) (Acc double knock-in, AccDKI). Compared to wild-type mice, these mice have elevated lipogenesis and lower fatty acid oxidation, which contribute to the progression of insulin resistance, glucose intolerance and NAFLD, but not obesity. Notably, AccDKI mice made obese by high-fat feeding are refractory to the lipid-lowering and insulin-sensitizing effects of metformin. These findings establish that inhibitory phosphorylation of Acc by Ampk is essential for the control of lipid metabolism and, in the setting of obesity, for metformin-induced improvements in insulin action.", + "TAG_DATA": [ + "97, mice {'context': 'B-organism'}", + "99, alanine {'perturbing_action': 'B-other'}", + "100, knock-in {'perturbing_action': 'I-gene loss-of-function'}", + "101, mutations {'perturbing_action': 'I-gene loss-of-function'}", + "102, in {'perturbing_action': 'I-gene loss-of-function'}", + "103, both {'perturbing_action': 'I-rnai/knockdown'}", + "104, Acc1 {'perturbing_action': 'I-rnai/knockdown'}", + "105, (at {'perturbing_action': 'I-rnai/knockdown'}", + "106, Ser79) {'perturbing_action': 'I-rnai/knockdown'}", + "107, and {'perturbing_action': 'I-gene loss-of-function'}", + "108, Acc2 {'perturbing_action': 'I-rnai/knockdown'}", + "109, (at {'perturbing_action': 'I-rnai/knockdown'}", + "110, Ser212) {'perturbing_action': 'I-gene loss-of-function'}", + "111, (Acc {'perturbing_action': 'I-gene loss-of-function'}", + "112, double {'perturbing_action': 'I-gene loss-of-function'}", + "113, knock-in, {'perturbing_action': 'I-gene loss-of-function'}", + "114, AccDKI). {'perturbing_action': 'I-gene loss-of-function'}", + "120, mice {'context': 'B-organism'}", + "145, AccDKI {'perturbing_action': 'B-other'}", + "146, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "97, mice ['l0']", + "99, alanine ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "100, knock-in ['l1', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "101, mutations ['l2', 'l17', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "102, in ['l3', 'l18', 'l32', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "103, both ['l4', 'l19', 'l33', 'l46', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "104, Acc1 ['l5', 'l20', 'l34', 'l47', 'l59', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "105, (at ['l6', 'l21', 'l35', 'l48', 'l60', 'l71', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "106, Ser79) ['l7', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "107, and ['l8', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "108, Acc2 ['l9', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "109, (at ['l10', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "110, Ser212) ['l11', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l122', 'l123', 'l124', 'l125', 'l126']", + "111, (Acc ['l12', 'l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l127', 'l128', 'l129', 'l130']", + "112, double ['l13', 'l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l118', 'l123', 'l127', 'l131', 'l132', 'l133']", + "113, knock-in, ['l14', 'l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l113', 'l119', 'l124', 'l128', 'l131', 'l134', 'l135']", + "114, AccDKI). ['l15', 'l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l129', 'l132', 'l134', 'l136']", + "120, mice ['l0', 'l16', 'l31', 'l45', 'l58', 'l70', 'l81', 'l91', 'l100', 'l108', 'l115', 'l121', 'l126', 'l130', 'l133', 'l135', 'l136']", + "145, AccDKI ['l137']", + "146, mice ['l137']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "alanine", + "AccDKI" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knock-in", + "mutations", + "in", + "and", + "Ser212)", + "(Acc", + "double", + "knock-in,", + "AccDKI)." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "both", + "Acc1", + "(at", + "Ser79)", + "Acc2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "24162813", + "TEXT": "Like their normal hematopoietic stem cell counterparts, leukemia stem cells (LSCs) in chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) are presumed to reside in specific niches in the bone marrow microenvironment (BMM) and may be the cause of relapse following chemotherapy. Targeting the niche is a new strategy to eliminate persistent and drug-resistant LSCs. CD44 (refs. 3,4) and interleukin-6 (ref. 5) have been implicated previously in the LSC niche. Transforming growth factor-β1 (TGF-β1) is released during bone remodeling and plays a part in maintenance of CML LSCs, but a role for TGF-β1 from the BMM has not been defined. Here, we show that alteration of the BMM by osteoblastic cell-specific activation of the parathyroid hormone (PTH) receptor attenuates BCR-ABL1 oncogene-induced CML-like myeloproliferative neoplasia (MPN) but enhances MLL-AF9 oncogene-induced AML in mouse transplantation models, possibly through opposing effects of increased TGF-β1 on the respective LSCs. PTH treatment caused a 15-fold decrease in LSCs in wild-type mice with CML-like MPN and reduced engraftment of immune-deficient mice with primary human CML cells. These results demonstrate that LSC niches in CML and AML are distinct and suggest that modulation of the BMM by PTH may be a feasible strategy to reduce LSCs, a prerequisite for the cure of CML.", + "TAG_DATA": [ + "110, osteoblastic {'perturbing_action': 'B-pharmacological augmentation'}", + "111, cell-specific {'perturbing_action': 'I-pharmacological augmentation'}", + "112, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "113, of {'perturbing_action': 'I-pharmacological augmentation'}", + "114, the {'perturbing_action': 'I-pharmacological augmentation'}", + "115, parathyroid {'perturbing_action': 'I-pharmacological augmentation'}", + "116, hormone {'perturbing_action': 'I-pharmacological augmentation'}", + "117, (PTH) {'perturbing_action': 'I-pharmacological augmentation'}", + "118, receptor {'perturbing_action': 'I-pharmacological augmentation'}", + "127, enhances {'effect': 'B-positive'}", + "130, AML {'phenotype': 'B-differentiation'}", + "132, mouse {'context': 'B-organism'}", + "133, transplantation {'context': 'I-organism'}", + "134, models, {'context': 'I-xenograft'}", + "156, mice {'context': 'B-organism'}", + "164, immune-deficient {'perturbing_action': 'B-gene loss-of-function', 'context': 'B-organism'}", + "165, mice {'context': 'I-organism'}", + "167, primary {'context': 'B-transformed cells'}", + "168, human {'context': 'I-transformed cells'}", + "169, CML {'context': 'I-transformed cells'}", + "170, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "110, osteoblastic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "111, cell-specific ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "112, activation ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "113, of ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "114, the ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "115, parathyroid ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "116, hormone ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "117, (PTH) ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "118, receptor ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "127, enhances ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "130, AML ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "132, mouse ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "133, transplantation ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "134, models, ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']", + "164, immune-deficient ['l91', 'l92', 'l93', 'l94', 'l95']", + "165, mice ['l91', 'l96', 'l97', 'l98', 'l99']", + "167, primary ['l92', 'l96', 'l100', 'l101', 'l102']", + "168, human ['l93', 'l97', 'l100', 'l103', 'l104']", + "169, CML ['l94', 'l98', 'l101', 'l103', 'l105']", + "170, cells. ['l95', 'l99', 'l102', 'l104', 'l105']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "osteoblastic", + "cell-specific", + "activation", + "of", + "the", + "parathyroid", + "hormone", + "(PTH)", + "receptor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "osteoblastic", + "cell-specific", + "activation", + "of", + "the", + "parathyroid", + "hormone", + "(PTH)", + "receptor" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "AML" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "osteoblastic", + "cell-specific", + "activation", + "of", + "the", + "parathyroid", + "hormone", + "(PTH)", + "receptor" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "transplantation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "osteoblastic", + "cell-specific", + "activation", + "of", + "the", + "parathyroid", + "hormone", + "(PTH)", + "receptor" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "models," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "AML" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "transplantation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "models," + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "AML" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "transplantation" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "AML" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "models," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immune-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "immune-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immune-deficient" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "human", + "CML", + "cells." + ] + } + } + ] + }, + { + "PMID": "24141422", + "TEXT": "Fragile X syndrome (FXS), the most common cause of inherited mental retardation and autism, is caused by transcriptional silencing of FMR1, which encodes the translational repressor fragile X mental retardation protein (FMRP). FMRP and cytoplasmic polyadenylation element-binding protein (CPEB), an activator of translation, are present in neuronal dendrites, are predicted to bind many of the same mRNAs and may mediate a translational homeostasis that, when imbalanced, results in FXS. Consistent with this possibility, Fmr1(-/y); Cpeb1(-/-) double-knockout mice displayed amelioration of biochemical, morphological, electrophysiological and behavioral phenotypes associated with FXS. Acute depletion of CPEB1 in the hippocampus of adult Fmr1(-/y) mice rescued working memory deficits, demonstrating reversal of this FXS phenotype. Finally, we find that FMRP and CPEB1 balance translation at the level of polypeptide elongation. Our results suggest that disruption of translational homeostasis is causal for FXS and that the maintenance of this homeostasis by FMRP and CPEB1 is necessary for normal neurologic function.", + "TAG_DATA": [ + "73, Fmr1(-/y); {'perturbing_action': 'B-gene loss-of-function'}", + "74, Cpeb1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "75, double-knockout {'perturbing_action': 'I-gene loss-of-function'}", + "76, mice {'context': 'B-organism'}", + "89, Acute {'perturbing_action': 'B-gene loss-of-function'}", + "90, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "91, of {'perturbing_action': 'I-gene loss-of-function'}", + "92, CPEB1 {'perturbing_action': 'I-gene loss-of-function'}", + "95, hippocampus {'context': 'B-tissue/organ'}", + "98, Fmr1(-/y) {'perturbing_action': 'B-gene loss-of-function'}", + "99, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, Fmr1(-/y); ['l0', 'l1', 'l2']", + "74, Cpeb1(-/-) ['l0', 'l3', 'l4']", + "75, double-knockout ['l1', 'l3', 'l5']", + "76, mice ['l2', 'l4', 'l5']", + "89, Acute ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "90, depletion ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "91, of ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "92, CPEB1 ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "95, hippocampus ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "98, Fmr1(-/y) ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "99, mice ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fmr1(-/y);", + "Cpeb1(-/-)", + "double-knockout", + "Acute", + "depletion", + "of", + "CPEB1", + "Fmr1(-/y)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Acute", + "depletion", + "of", + "CPEB1", + "Fmr1(-/y)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus" + ] + } + } + ] + }, + { + "PMID": "24121928", + "TEXT": "The transfer of T cell receptor (TCR) genes into patient T cells is a promising approach for the treatment of both viral infections and cancer. Although efficient methods exist to identify antibodies for the treatment of these diseases, comparable strategies to identify TCRs have been lacking. We have developed a high-throughput DNA-based strategy to identify TCR sequences by the capture and sequencing of genomic DNA fragments encoding the TCR genes. We establish the value of this approach by assembling a large library of cancer germline tumor antigen-reactive TCRs. Furthermore, by exploiting the quantitative nature of TCR gene capture, we show the feasibility of identifying antigen-specific TCRs in oligoclonal T cell populations from either human material or TCR-humanized mice. Finally, we demonstrate the ability to identify tumor-reactive TCRs within intratumoral T cell subsets without knowledge of antigen specificities, which may be the first step toward the development of autologous TCR gene therapy to target patient-specific neoantigens in human cancer.", + "TAG_DATA": [ + "117, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24121927", + "TEXT": "Antigen-specific T cell therapy, or T cell receptor (TCR) gene therapy, is a promising immunotherapy for infectious diseases and cancers. However, a suitable rapid and direct screening system for antigen-specific TCRs is not available. Here, we report an efficient cloning and functional evaluation system to determine the antigen specificity of TCR cDNAs derived from single antigen-specific human T cells within 10 d. Using this system, we cloned and analyzed 380 Epstein-Barr virus-specific TCRs from ten healthy donors with latent Epstein-Barr virus infection and assessed the activity of cytotoxic T lymphocytes (CTLs) carrying these TCRs against antigenic peptide-bearing target cells. We also used this system to clone tumor antigen-specific TCRs from peptide-vaccinated patients with cancer. We obtained 210 tumor-associated antigen-specific TCRs and demonstrated the cytotoxic activity of CTLs carrying these TCRs against peptide-bearing cells. This system may provide a fast and powerful approach for TCR gene therapy for infectious diseases and cancers.", + "TAG_DATA": [ + "113, cancer. {'context': 'B-neoplasm'}", + "131, peptide-bearing {'context': 'B-cells'}", + "132, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "131, peptide-bearing ['l0']", + "132, cells. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24100997", + "TEXT": "Bill and Melinda Gates have led a profound transformation in the way we view the world's most pressing health concerns, looking for effective ways to improve the lives of millions of people. Claire Pomeroy, president of the Albert and Mary Lasker Foundation, spoke with them about their current concerns and plans to advance their agenda.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24100979", + "TEXT": "Aspergillus fumigatus is a fungus that is associated with a severe form of asthma, although the precise immunological basis for this disease is unclear. A new study in mice shows that natural killer T (NKT) cells are crucial for progression of A. fumigatus–induced asthma and also identifies a glycolipid antigen from this fungus that seems to drive this NKT cell–mediated inflammatory response (pages 1297–1304).", + "TAG_DATA": [ + "28, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "24097188", + "TEXT": "The K(+)-Cl(-) cotransporter KCC2 is responsible for maintaining low Cl(-) concentration in neurons of the central nervous system (CNS), which is essential for postsynaptic inhibition through GABA(A) and glycine receptors. Although no CNS disorders have been associated with KCC2 mutations, loss of activity of this transporter has emerged as a key mechanism underlying several neurological and psychiatric disorders, including epilepsy, motor spasticity, stress, anxiety, schizophrenia, morphine-induced hyperalgesia and chronic pain. Recent reports indicate that enhancing KCC2 activity may be the favored therapeutic strategy to restore inhibition and normal function in pathological conditions involving impaired Cl(-) transport. We designed an assay for high-throughput screening that led to the identification of KCC2 activators that reduce intracellular chloride concentration ([Cl(-)]i). Optimization of a first-in-class arylmethylidine family of compounds resulted in a KCC2-selective analog (CLP257) that lowers [Cl(-)]i. CLP257 restored impaired Cl(-) transport in neurons with diminished KCC2 activity. The compound rescued KCC2 plasma membrane expression, renormalized stimulus-evoked responses in spinal nociceptive pathways sensitized after nerve injury and alleviated hypersensitivity in a rat model of neuropathic pain. Oral efficacy for analgesia equivalent to that of pregabalin but without motor impairment was achievable with a CLP257 prodrug. These results validate KCC2 as a druggable target for CNS diseases.", + "TAG_DATA": [ + "140, neurons {'context': 'B-cells'}", + "156, spinal {'context': 'B-cells'}", + "157, nociceptive {'context': 'I-cells'}", + "158, pathways {'context': 'I-cells'}", + "168, rat {'context': 'B-organism'}", + "169, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "140, neurons ['l0']", + "156, spinal ['l1', 'l2', 'l3', 'l4', 'l5']", + "157, nociceptive ['l1', 'l6', 'l7', 'l8', 'l9']", + "158, pathways ['l0', 'l2', 'l6', 'l10', 'l11', 'l12']", + "168, rat ['l3', 'l7', 'l10', 'l13', 'l14']", + "169, model ['l4', 'l8', 'l11', 'l13', 'l15']", + "171, neuropathic ['l5', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24076665", + "TEXT": "In glioblastoma, phosphatidylinositol 3-kinase (PI3K) signaling is frequently activated by loss of the tumor suppressor phosphatase and tensin homolog (PTEN). However, it is not known whether inhibiting PI3K represents a selective and effective approach for treatment. We interrogated large databases and found that sonic hedgehog (SHH) signaling is activated in PTEN-deficient glioblastoma. We demonstrate that the SHH and PI3K pathways synergize to promote tumor growth and viability in human PTEN-deficient glioblastomas. A combination of PI3K and SHH signaling inhibitors not only suppressed the activation of both pathways but also abrogated S6 kinase (S6K) signaling. Accordingly, targeting both pathways simultaneously resulted in mitotic catastrophe and tumor apoptosis and markedly reduced the growth of PTEN-deficient glioblastomas in vitro and in vivo. The drugs tested here appear to be safe in humans; therefore, this combination may provide a new targeted treatment for glioblastoma.", + "TAG_DATA": [ + "50, PTEN-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "62, promote {'effect': 'B-positive'}", + "63, tumor {'phenotype': 'B-tumour growth'}", + "64, growth {'phenotype': 'I-tumour growth'}", + "68, human {'perturbing_action': 'B-gene loss-of-function'}", + "69, PTEN-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "70, glioblastomas. {'context': 'I-neoplasm'}", + "99, resulted {'effect': 'B-positive'}", + "100, in {'effect': 'I-positive'}", + "104, tumor {'context': 'B-neoplasm'}", + "105, apoptosis {'phenotype': 'B-apoptosis'}", + "112, PTEN-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "113, glioblastomas {'context': 'B-neoplasm'}", + "114, in {'context': 'B-in vitro'}", + "115, vitro {'context': 'I-in vitro'}", + "117, in {'context': 'B-in vivo'}", + "118, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "50, PTEN-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "62, promote ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "63, tumor ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "64, growth ['l2', 'l7', 'l11', 'l15', 'l16']", + "68, human ['l3', 'l8', 'l12', 'l15', 'l17', 'l18']", + "69, PTEN-deficient ['l4', 'l9', 'l13', 'l17', 'l19']", + "70, glioblastomas. ['l5', 'l10', 'l14', 'l16', 'l18', 'l19']", + "99, resulted ['l20', 'l21', 'l22']", + "100, in ['l20', 'l23', 'l24']", + "104, tumor ['l21', 'l23', 'l25']", + "105, apoptosis ['l22', 'l24', 'l25']", + "112, PTEN-deficient ['l26', 'l27', 'l28', 'l29', 'l30']", + "113, glioblastomas ['l26', 'l31', 'l32', 'l33', 'l34']", + "114, in ['l27', 'l31', 'l35', 'l36', 'l37']", + "115, vitro ['l28', 'l32', 'l35', 'l38', 'l39']", + "117, in ['l29', 'l33', 'l36', 'l38', 'l40']", + "118, vivo. ['l30', 'l34', 'l37', 'l39', 'l40']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PTEN-deficient", + "human" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promote" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PTEN-deficient", + "human" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PTEN-deficient", + "human" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "glioblastomas.", + "glioblastomas" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote", + "resulted", + "in" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "glioblastomas.", + "tumor" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "glioblastomas." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PTEN-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PTEN-deficient" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "24056772", + "TEXT": "Endothelial secretion of von Willebrand factor (VWF) from intracellular organelles known as Weibel-Palade bodies (WPBs) is required for platelet adhesion to the injured vessel wall. Here we demonstrate that WPBs are often found near or within autophagosomes and that endothelial autophagosomes contain abundant VWF protein. Pharmacological inhibitors of autophagy or knockdown of the essential autophagy genes Atg5 or Atg7 inhibits the in vitro secretion of VWF. Furthermore, although mice with endothelial-specific deletion of Atg7 have normal vessel architecture and capillary density, they exhibit impaired epinephrine-stimulated VWF release, reduced levels of high-molecular weight VWF multimers and a corresponding prolongation of bleeding times. Endothelial-specific deletion of Atg5 or pharmacological inhibition of autophagic flux results in a similar in vivo alteration of hemostasis. Thus, autophagy regulates endothelial VWF secretion, and transient pharmacological inhibition of autophagic flux may be a useful strategy to prevent thrombotic events.", + "TAG_DATA": [ + "50, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "51, of {'perturbing_action': 'I-rnai/knockdown'}", + "52, the {'perturbing_action': 'I-rnai/knockdown'}", + "53, essential {'perturbing_action': 'I-rnai/knockdown'}", + "54, autophagy {'perturbing_action': 'I-rnai/knockdown'}", + "55, genes {'perturbing_action': 'I-rnai/knockdown'}", + "56, Atg5 {'perturbing_action': 'I-rnai/knockdown'}", + "57, or {'perturbing_action': 'I-rnai/knockdown'}", + "58, Atg7 {'perturbing_action': 'I-rnai/knockdown'}", + "61, in {'context': 'B-in vitro'}", + "62, vitro {'context': 'I-in vitro'}", + "68, mice {'context': 'B-organism'}", + "70, endothelial-specific {'perturbing_action': 'B-gene loss-of-function'}", + "71, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "72, of {'perturbing_action': 'I-gene loss-of-function'}", + "73, Atg7 {'perturbing_action': 'I-gene loss-of-function'}", + "101, Endothelial-specific {'perturbing_action': 'B-gene loss-of-function'}", + "102, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "103, of {'perturbing_action': 'I-gene loss-of-function'}", + "104, Atg5 {'perturbing_action': 'I-gene loss-of-function'}", + "115, in {'context': 'B-in vivo'}", + "116, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "50, knockdown ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "51, of ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "52, the ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "53, essential ['l2', 'l16', 'l29', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "54, autophagy ['l3', 'l17', 'l30', 'l42', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "55, genes ['l4', 'l18', 'l31', 'l43', 'l54', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "56, Atg5 ['l5', 'l19', 'l32', 'l44', 'l55', 'l65', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "57, or ['l6', 'l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "58, Atg7 ['l7', 'l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l84', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "61, in ['l8', 'l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l99']", + "62, vitro ['l9', 'l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l86', 'l93', 'l99']", + "68, mice ['l10', 'l24', 'l37', 'l49', 'l60', 'l70', 'l79', 'l87', 'l94', 'l100', 'l101', 'l102', 'l103']", + "70, endothelial-specific ['l11', 'l25', 'l38', 'l50', 'l61', 'l71', 'l80', 'l88', 'l95', 'l100', 'l104', 'l105', 'l106']", + "71, deletion ['l12', 'l26', 'l39', 'l51', 'l62', 'l72', 'l81', 'l89', 'l96', 'l101', 'l104', 'l107', 'l108']", + "72, of ['l13', 'l27', 'l40', 'l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l102', 'l105', 'l107', 'l109']", + "73, Atg7 ['l14', 'l28', 'l41', 'l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l103', 'l106', 'l108', 'l109']", + "101, Endothelial-specific ['l110', 'l111', 'l112', 'l113', 'l114']", + "102, deletion ['l110', 'l115', 'l116', 'l117', 'l118']", + "103, of ['l111', 'l115', 'l119', 'l120', 'l121']", + "104, Atg5 ['l112', 'l116', 'l119', 'l122', 'l123']", + "115, in ['l113', 'l117', 'l120', 'l122', 'l124']", + "116, vivo ['l114', 'l118', 'l121', 'l123', 'l124']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "the", + "essential", + "autophagy", + "genes", + "Atg5", + "or", + "Atg7" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "the", + "essential", + "autophagy", + "genes", + "Atg5", + "or", + "Atg7" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "endothelial-specific", + "deletion", + "of", + "Atg7" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Endothelial-specific", + "deletion", + "of", + "Atg5" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "24056771", + "TEXT": "The role of T cells in mediating heterosubtypic protection against natural influenza illness in humans is uncertain. The 2009 H1N1 pandemic (pH1N1) provided a unique natural experiment to determine whether crossreactive cellular immunity limits symptomatic illness in antibody-naive individuals. We followed 342 healthy adults through the UK pandemic waves and correlated the responses of pre-existing T cells to the pH1N1 virus and conserved core protein epitopes with clinical outcomes after incident pH1N1 infection. Higher frequencies of pre-existing T cells to conserved CD8 epitopes were found in individuals who developed less severe illness, with total symptom score having the strongest inverse correlation with the frequency of interferon-γ (IFN-γ)(+) interleukin-2 (IL-2)(-) CD8(+) T cells (r = -0.6, P = 0.004). Within this functional CD8(+)IFN-γ(+)IL-2(-) population, cells with the CD45RA(+) chemokine (C-C) receptor 7 (CCR7)(-) phenotype inversely correlated with symptom score and had lung-homing and cytotoxic potential. In the absence of crossreactive neutralizing antibodies, CD8(+) T cells specific to conserved viral epitopes correlated with crossprotection against symptomatic influenza. This protective immune correlate could guide universal influenza vaccine development.", + "TAG_DATA": [ + "42, healthy {'context': 'B-organism'}", + "43, adults {'context': 'I-organism'}", + "109, CD8(+) {'context': 'B-cells'}", + "110, T {'context': 'I-cells'}", + "111, cells {'context': 'I-cells'}", + "123, cells {'context': 'B-cells'}", + "151, CD8(+) {'context': 'B-cells'}", + "152, T {'context': 'I-cells'}", + "153, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "42, healthy ['l0']", + "43, adults ['l0']", + "109, CD8(+) ['l1', 'l2']", + "110, T ['l1', 'l3']", + "111, cells ['l2', 'l3']", + "151, CD8(+) ['l4', 'l5']", + "152, T ['l4', 'l6']", + "153, cells ['l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "24037091", + "TEXT": "Acute myocardial infarction is a severe ischemic disease responsible for heart failure and sudden death. Here, we show that after acute myocardial infarction in mice, mature B lymphocytes selectively produce Ccl7 and induce Ly6C(hi) monocyte mobilization and recruitment to the heart, leading to enhanced tissue injury and deterioration of myocardial function. Genetic (Baff receptor deficiency) or antibody-mediated (CD20- or Baff-specific antibody) depletion of mature B lymphocytes impeded Ccl7 production and monocyte mobilization, limited myocardial injury and improved heart function. These effects were recapitulated in mice with B cell-selective Ccl7 deficiency. We also show that high circulating concentrations of CCL7 and BAFF in patients with acute myocardial infarction predict increased risk of death or recurrent myocardial infarction. This work identifies a crucial interaction between mature B lymphocytes and monocytes after acute myocardial ischemia and identifies new therapeutic targets for acute myocardial infarction.", + "TAG_DATA": [ + "52, (Baff {'perturbing_action': 'I-gene loss-of-function'}", + "53, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "54, deficiency) {'perturbing_action': 'I-gene loss-of-function'}", + "63, mature {'context': 'B-cells'}", + "64, B {'context': 'I-cells'}", + "65, lymphocytes {'context': 'I-cells'}", + "70, monocyte {'context': 'B-cells'}", + "77, heart {'context': 'B-tissue/organ'}", + "84, mice {'context': 'B-organism'}", + "86, B {'perturbing_action': 'B-gene loss-of-function'}", + "87, cell-selective {'perturbing_action': 'I-gene loss-of-function'}", + "88, Ccl7 {'perturbing_action': 'I-gene loss-of-function'}", + "89, deficiency. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "52, (Baff ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "53, receptor ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "54, deficiency) ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "63, mature ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "64, B ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "65, lymphocytes ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "70, monocyte ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "77, heart ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "84, mice ['l28', 'l29', 'l30', 'l31']", + "86, B ['l28', 'l32', 'l33', 'l34']", + "87, cell-selective ['l29', 'l32', 'l35', 'l36']", + "88, Ccl7 ['l30', 'l33', 'l35', 'l37']", + "89, deficiency. ['l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "(Baff", + "receptor", + "deficiency)" + ] + }, + "context": { + "val": "cells", + "words": [ + "mature", + "B", + "lymphocytes", + "monocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "(Baff", + "receptor", + "deficiency)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "heart" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "B", + "cell-selective", + "Ccl7", + "deficiency." + ] + } + } + ] + }, + { + "PMID": "24013756", + "TEXT": "Promising advances in cancer therapy stemming from an increasing understanding of the molecular and genetic underpinnings of the tumorigenic process have been fueled by a strong, determined scientific community, influential patient advocacy groups and committed funding bodies. Despite these efforts, the development of effective drugs to prevent systemic dissemination of cancer cells or to eliminate overt metastasis in secondary organs remains a challenge to both researchers and physicians. In an attempt to tackle the most relevant and timely translational issues, a meeting held in 2012 as a result of a successful partnership between the Volkswagen Foundation and Nature Medicine brought together a group of metastasis research experts to identify the most important hurdles and help create a framework for potential clinical and translational strategies.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23852341", + "TEXT": "The B cell-specific transcription factor BACH2 is required for affinity maturation of B cells. Here we show that Bach2-mediated activation of p53 is required for stringent elimination of pre-B cells that failed to productively rearrange immunoglobulin VH-DJH gene segments. After productive VH-DJH gene rearrangement, pre-B cell receptor signaling ends BACH2-mediated negative selection through B cell lymphoma 6 (BCL6)-mediated repression of p53. In patients with pre-B acute lymphoblastic leukemia, the BACH2-mediated checkpoint control is compromised by deletions, rare somatic mutations and loss of its upstream activator, PAX5. Low levels of BACH2 expression in these patients represent a strong independent predictor of poor clinical outcome. In this study, we demonstrate that Bach2(+/+) pre-B cells resist leukemic transformation by Myc through Bach2-dependent upregulation of p53 and do not initiate fatal leukemia in transplant-recipient mice. Chromatin immunoprecipitation sequencing and gene expression analyses carried out by us revealed that BACH2 competes with BCL6 for promoter binding and reverses BCL6-mediated repression of p53 and other cell cycle checkpoint-control genes. These findings identify BACH2 as a crucial mediator of negative selection at the pre-B cell receptor checkpoint and a safeguard against leukemogenesis.", + "TAG_DATA": [ + "109, Bach2(+/+) {'perturbing_action': 'B-gene loss-of-function'}", + "110, pre-B {'context': 'B-cells'}", + "111, cells {'context': 'I-cells'}", + "112, resist {'effect': 'B-negative'}", + "113, leukemic {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}", + "114, transformation {'phenotype': 'B-transformation'}", + "124, not {'effect': 'I-no effect'}", + "125, initiate {'effect': 'I-no effect'}", + "127, leukemia {'phenotype': 'B-tumourigenesis'}", + "130, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "109, Bach2(+/+) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "110, pre-B ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "111, cells ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "112, resist ['l2', 'l10', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "113, leukemic ['l3', 'l11', 'l18', 'l23', 'l29', 'l30', 'l31', 'l32', 'l33']", + "114, transformation ['l4', 'l12', 'l19', 'l24', 'l29', 'l34', 'l35', 'l36']", + "124, not ['l5', 'l13', 'l20', 'l25', 'l30', 'l34', 'l37', 'l38', 'l39']", + "125, initiate ['l6', 'l14', 'l21', 'l26', 'l31', 'l35', 'l37', 'l40', 'l41']", + "127, leukemia ['l7', 'l15', 'l22', 'l27', 'l32', 'l36', 'l38', 'l40', 'l42']", + "130, mice. ['l8', 'l16', 'l28', 'l33', 'l39', 'l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bach2(+/+)" + ] + }, + "context": { + "val": "cells", + "words": [ + "pre-B", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bach2(+/+)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resist" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bach2(+/+)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemic" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bach2(+/+)" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemic", + "leukemia" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "leukemic" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemic" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bach2(+/+)" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bach2(+/+)" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "initiate" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bach2(+/+)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pre-B", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resist" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pre-B", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemic", + "leukemia" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pre-B", + "cells" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pre-B", + "cells" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "initiate" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resist" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemic" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resist" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemic", + "leukemia" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resist" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resist" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "leukemic" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "leukemic" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "initiate" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemic", + "leukemia" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "initiate" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemic", + "leukemia" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "initiate" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "initiate" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "23817022", + "TEXT": "Myofibroblasts are associated with organ fibrosis, but their precise origin and functional role remain unknown. We used multiple genetically engineered mice to track, fate map and ablate cells to determine the source and function of myofibroblasts in kidney fibrosis. Through this comprehensive analysis, we identified that the total pool of myofibroblasts is split, with 50% arising from local resident fibroblasts through proliferation. The nonproliferating myofibroblasts derive through differentiation from bone marrow (35%), the endothelial-to-mesenchymal transition program (10%) and the epithelial-to-mesenchymal transition program (5%). Specific deletion of Tgfbr2 in α-smooth muscle actin (αSMA)(+) cells revealed the importance of this pathway in the recruitment of myofibroblasts through differentiation. Using genetic mouse models and a fate-mapping strategy, we determined that vascular pericytes probably do not contribute to the emergence of myofibroblasts or fibrosis. Our data suggest that targeting diverse pathways is required to substantially inhibit the composite accumulation of myofibroblasts in kidney fibrosis.", + "TAG_DATA": [ + "63, nonproliferating {'context': 'B-cells'}", + "64, myofibroblasts {'context': 'I-cells'}", + "84, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "85, of {'perturbing_action': 'I-gene loss-of-function'}", + "86, Tgfbr2 {'perturbing_action': 'I-gene loss-of-function'}", + "88, α-smooth {'context': 'B-cells'}", + "89, muscle {'context': 'I-cells'}", + "90, actin {'context': 'I-cells'}", + "91, (αSMA)(+) {'context': 'I-cells'}", + "92, cells {'context': 'I-cells'}", + "107, genetic {'context': 'B-organism'}", + "108, mouse {'context': 'I-organism'}", + "109, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "63, nonproliferating ['l0']", + "64, myofibroblasts ['l0']", + "84, deletion ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "85, of ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "86, Tgfbr2 ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "88, α-smooth ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "89, muscle ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "90, actin ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "91, (αSMA)(+) ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "92, cells ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']", + "107, genetic ['l29', 'l30']", + "108, mouse ['l29', 'l31']", + "109, models ['l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Tgfbr2" + ] + }, + "context": { + "val": "cells", + "words": [ + "α-smooth", + "muscle", + "actin", + "(αSMA)(+)", + "cells" + ] + } + } + ] + }, + { + "PMID": "23727932", + "TEXT": "Understanding molecular mechanisms for regeneration of hair follicles provides new opportunities for developing treatments for hair loss and other skin disorders. Here we show that fibroblast growth factor 9 (Fgf9), initially secreted by γδ T cells, modulates hair follicle regeneration after wounding the skin of adult mice. Reducing Fgf9 expression decreases this wound-induced hair neogenesis (WIHN). Conversely, overexpression of Fgf9 results in a two- to threefold increase in the number of neogenic hair follicles. We found that Fgf9 from γδ T cells triggers Wnt expression and subsequent Wnt activation in wound fibroblasts. Through a unique feedback mechanism, activated fibroblasts then express Fgf9, thus amplifying Wnt activity throughout the wound dermis during a crucial phase of skin regeneration. Notably, humans lack a robust population of resident dermal γδ T cells, potentially explaining their inability to regenerate hair after wounding. These findings highlight the essential relationship between the immune system and tissue regeneration. The importance of Fgf9 in hair follicle regeneration suggests that it could be used therapeutically in humans.", + "TAG_DATA": [ + "45, adult {'context': 'B-organism'}", + "46, mice. {'context': 'I-organism'}", + "47, Reducing {'perturbing_action': 'B-gene loss-of-function'}", + "48, Fgf9 {'perturbing_action': 'I-gene loss-of-function'}", + "49, expression {'perturbing_action': 'I-gene loss-of-function'}", + "57, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "58, of {'perturbing_action': 'I-gene gain-of-function'}", + "59, Fgf9 {'perturbing_action': 'I-gene gain-of-function'}", + "79, γδ {'context': 'B-cells'}", + "80, T {'context': 'I-cells'}", + "81, cells {'context': 'I-cells'}", + "90, wound {'context': 'B-cells'}", + "91, fibroblasts. {'context': 'I-cells'}", + "98, fibroblasts {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "45, adult ['l0']", + "46, mice. ['l0']", + "47, Reducing ['l1', 'l2', 'l3']", + "48, Fgf9 ['l1', 'l4', 'l5']", + "49, expression ['l2', 'l4']", + "57, overexpression ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "58, of ['l6', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "59, Fgf9 ['l7', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "79, γδ ['l8', 'l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "80, T ['l9', 'l15', 'l20', 'l24', 'l28', 'l29', 'l30']", + "81, cells ['l3', 'l5', 'l10', 'l16', 'l21', 'l25', 'l28', 'l31', 'l32']", + "90, wound ['l11', 'l17', 'l22', 'l26', 'l29', 'l31', 'l33']", + "91, fibroblasts. ['l12', 'l18', 'l23', 'l27', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Reducing", + "Fgf9" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Fgf9" + ] + }, + "context": { + "val": "cells", + "words": [ + "γδ", + "T", + "cells", + "wound", + "fibroblasts." + ] + } + } + ] + }, + { + "PMID": "23685840", + "TEXT": "Osteoarthritis is a highly prevalent and debilitating joint disorder. There is no effective medical therapy for the condition because of limited understanding of its pathogenesis. We show that transforming growth factor β1 (TGF-β1) is activated in subchondral bone in response to altered mechanical loading in an anterior cruciate ligament transection (ACLT) mouse model of osteoarthritis. TGF-β1 concentrations are also high in subchondral bone from humans with osteoarthritis. High concentrations of TGF-β1 induced formation of nestin-positive mesenchymal stem cell (MSC) clusters, leading to formation of marrow osteoid islets accompanied by high levels of angiogenesis. We found that transgenic expression of active TGF-β1 in osteoblastic cells induced osteoarthritis, whereas inhibition of TGF-β activity in subchondral bone attenuated the degeneration of articular cartilage. In particular, knockout of the TGF-β type II receptor (TβRII) in nestin-positive MSCs led to less development of osteoarthritis relative to wild-type mice after ACLT. Thus, high concentrations of active TGF-β1 in subchondral bone seem to initiate the pathological changes of osteoarthritis, and inhibition of this process could be a potential therapeutic approach to treating this disease.", + "TAG_DATA": [ + "96, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "97, expression {'perturbing_action': 'I-gene gain-of-function'}", + "98, of {'perturbing_action': 'I-gene gain-of-function'}", + "99, active {'perturbing_action': 'I-gene gain-of-function'}", + "100, TGF-β1 {'perturbing_action': 'I-gene gain-of-function'}", + "102, osteoblastic {'context': 'B-cells'}", + "103, cells {'context': 'I-cells'}", + "112, subchondral {'context': 'B-tissue/organ'}", + "113, bone {'context': 'I-tissue/organ'}", + "122, knockout {'perturbing_action': 'B-gene loss-of-function'}", + "123, of {'perturbing_action': 'I-gene loss-of-function'}", + "124, the {'perturbing_action': 'I-gene loss-of-function'}", + "125, TGF-β {'perturbing_action': 'I-gene loss-of-function'}", + "126, type {'perturbing_action': 'I-gene loss-of-function'}", + "127, II {'perturbing_action': 'I-gene loss-of-function'}", + "128, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "129, (TβRII) {'perturbing_action': 'I-gene loss-of-function'}", + "131, nestin-positive {'context': 'B-cells'}", + "132, MSCs {'context': 'I-cells'}", + "142, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "96, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "97, expression ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "98, of ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "99, active ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "100, TGF-β1 ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "102, osteoblastic ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "103, cells ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "112, subchondral ['l21', 'l22']", + "113, bone ['l21']", + "122, knockout ['l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "123, of ['l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "124, the ['l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "125, TGF-β ['l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "126, type ['l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "127, II ['l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "128, receptor ['l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "129, (TβRII) ['l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "131, nestin-positive ['l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "132, MSCs ['l22', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "142, mice ['l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "of", + "active", + "TGF-β1" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoblastic", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout", + "of", + "the", + "TGF-β", + "type", + "II", + "receptor", + "(TβRII)" + ] + }, + "context": { + "val": "cells", + "words": [ + "nestin-positive", + "MSCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout", + "of", + "the", + "TGF-β", + "type", + "II", + "receptor", + "(TβRII)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23652105", + "TEXT": "A study now links platelet generation and cholesterol metabolism, providing new understanding of the mechanisms involved in thrombocytosis and atherogenesis. The authors show that the cholesterol transporter ABCG4 is highly expressed in bone marrow megakaryocyte progenitors, and in its absence, these cells have defective cholesterol efflux and increased proliferation, leading to increased megakaryocyte production, thrombocytosis and accelerated atherogenesis in atherosclerosis-prone mice (pages 586–594).", + "TAG_DATA": [ + "41, cells {'context': 'B-cells'}", + "47, increased {'effect': 'B-positive'}", + "48, proliferation, {'phenotype': 'B-proliferation'}", + "52, megakaryocyte {'context': 'B-cells'}", + "60, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "41, cells ['l0', 'l1', 'l2', 'l3']", + "47, increased ['l0', 'l4', 'l5', 'l6']", + "48, proliferation, ['l1', 'l4', 'l7', 'l8']", + "52, megakaryocyte ['l2', 'l5', 'l7', 'l9']", + "60, mice ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells", + "megakaryocyte" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "megakaryocyte" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23652096", + "TEXT": "Malnutrition affects more than 2 billion people worldwide today, making them more prone to disease and cognitive development problems and more likely to die young. To address this massive health threat, the New York Academy of Sciences created the Sackler Institute for Nutrition Science in 2011. At its helm is Mandana Arabi, a physician-scientist born in Iran who previously worked as a nutrition scientist for UNICEF, the United Nations agency devoted to helping children, where she traveled the world developing large-scale programs to address infant and child malnutrition. Arabi may now be more rooted to her office in lower Manhattan, but she has certainly kept things moving at the newly established institute. This past December, she hosted a two-day conference, attended by World Health Organization (WHO) officials and many global experts, dedicated to creating a forward-looking research agenda for nutrition science. And last month the institute awarded its first research grants to investigate the intersection of nutrition and disease prevention. Arabi spoke with Alisa Opar about how the Sackler Institute hopes to put nutrition research on the scientific map.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23563705", + "TEXT": "Intestinal microbiota metabolism of choline and phosphatidylcholine produces trimethylamine (TMA), which is further metabolized to a proatherogenic species, trimethylamine-N-oxide (TMAO). We demonstrate here that metabolism by intestinal microbiota of dietary L-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosis in mice. Omnivorous human subjects produced more TMAO than did vegans or vegetarians following ingestion of L-carnitine through a microbiota-dependent mechanism. The presence of specific bacterial taxa in human feces was associated with both plasma TMAO concentration and dietary status. Plasma L-carnitine levels in subjects undergoing cardiac evaluation (n = 2,595) predicted increased risks for both prevalent cardiovascular disease (CVD) and incident major adverse cardiac events (myocardial infarction, stroke or death), but only among subjects with concurrently high TMAO levels. Chronic dietary L-carnitine supplementation in mice altered cecal microbial composition, markedly enhanced synthesis of TMA and TMAO, and increased atherosclerosis, but this did not occur if intestinal microbiota was concurrently suppressed. In mice with an intact intestinal microbiota, dietary supplementation with TMAO or either carnitine or choline reduced in vivo reverse cholesterol transport. Intestinal microbiota may thus contribute to the well-established link between high levels of red meat consumption and CVD risk.", + "TAG_DATA": [ + "44, mice. {'context': 'B-organism'}", + "128, mice {'context': 'B-organism'}", + "141, increased {'effect': 'B-positive'}", + "142, atherosclerosis, {'phenotype': 'B-autophagy'}", + "155, mice {'context': 'B-organism'}", + "171, in {'context': 'B-in vivo'}", + "172, vivo {'context': 'B-in vivo'}" + ], + "LINK_DATA": [ + "44, mice. ['l0', 'l1']", + "46, human ['l0', 'l2']", + "47, subjects ['l1', 'l2']", + "128, mice ['l3', 'l4']", + "141, increased ['l3', 'l5']", + "142, atherosclerosis, ['l4', 'l5']", + "155, mice ['l6', 'l7', 'l8', 'l9']", + "159, intestinal ['l6', 'l10', 'l11', 'l12']", + "160, microbiota, ['l7', 'l10', 'l13', 'l14']", + "171, in ['l8', 'l11', 'l13', 'l15']", + "172, vivo ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "atherosclerosis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "atherosclerosis," + ] + } + } + ] + }, + { + "PMID": "23558614", + "TEXT": "It was a single tweet. In February, after US President Barack Obama made a subtle nod to a new neuroscience project in his annual State of the Union address, Francis Collins, director of the country's National Institutes of Health (NIH), posted on the @NIHDirector Twitter feed: \"Obama mentions the #NIH Brain Activity Map in #SOTU.\" Instantly, scientists were buzzing with rumors that the Brain Activity Map could be the next moon shot, with a budget and timeline similar to the Human Genome Project. The brain map began as a brief white paper and has grown into a large--and still largely undefined--collaboration of several government agencies, nonprofit foundations and private companies. As the stakeholders describe in a commentary published last month (339, 1284-1285, 2013), the goal of the initiative is to understand how thousands of neurons work in concert to control behavior and trigger disease. Miyoung Chun, vice president for science programs at The Kavli Foundation in Oxnard, California, has been developing the project since the beginning and is the self-described \"glue\" between its many diverse stakeholders. Chun spoke with Virginia Hughes about the evolution of the project and what it might mean for biomedicine.", + "TAG_DATA": [], + "LINK_DATA": [ + "156, Oxnard, ['l0']", + "157, California, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23524344", + "TEXT": "Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by bilateral renal cyst formation. Recent identification of signaling cascades deregulated in ADPKD has led to the initiation of several clinical trials, but an approved therapy is still lacking. Using a metabolomic approach, we identify a pathogenic pathway in this disease that can be safely targeted for therapy. We show that mutation of PKD1 results in enhanced glycolysis in cells in a mouse model of PKD and in kidneys from humans with ADPKD. Glucose deprivation resulted in lower proliferation and higher apoptotic rates in PKD1-mutant cells than in nondeprived cells. Notably, two distinct PKD mouse models treated with 2-deoxyglucose (2DG), to inhibit glycolysis, had lower kidney weight, volume, cystic index and proliferation rates as compared to nontreated mice. These metabolic alterations depend on the extracellular signal-related kinase (ERK) pathway acting in a dual manner by inhibiting the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) axis on the one hand while activating the mTOR complex 1 (mTORC1)-glycolytic cascade on the other. Enhanced metabolic rates further inhibit AMPK. Forced activation of AMPK acts in a negative feedback loop, restoring normal ERK activity. Taken together, these data indicate that defective glucose metabolism is intimately involved in the pathobiology of ADPKD. Our findings provide a strong rationale for a new therapeutic strategy using existing drugs, either individually or in combination.", + "TAG_DATA": [ + "63, mutation {'perturbing_action': 'B-other'}", + "64, of {'perturbing_action': 'I-other'}", + "65, PKD1 {'perturbing_action': 'I-other'}", + "71, cells {'context': 'B-cells'}", + "74, mouse {'context': 'B-organism'}", + "75, model {'context': 'I-organism'}", + "76, of {'context': 'I-organism'}", + "77, PKD {'context': 'I-organism'}", + "80, kidneys {'context': 'B-tissue/organ'}", + "82, humans {'context': 'B-patient'}", + "89, lower {'effect': 'B-negative'}", + "90, proliferation {'phenotype': 'B-proliferation'}", + "92, higher {'effect': 'B-positive'}", + "93, apoptotic {'phenotype': 'B-apoptosis'}", + "94, rates {'phenotype': 'I-apoptosis'}", + "96, PKD1-mutant {'perturbing_action': 'B-other'}", + "97, cells {'context': 'B-cells'}", + "101, cells. {'context': 'B-cells'}", + "105, PKD {'context': 'B-organism'}", + "106, mouse {'context': 'I-organism'}", + "107, models {'context': 'I-organism'}", + "116, lower {'effect': 'B-negative'}", + "117, kidney {'context': 'B-tissue/organ'}", + "123, proliferation {'phenotype': 'B-proliferation'}", + "129, mice. {'context': 'B-organism'}", + "178, Forced {'perturbing_action': 'B-gene gain-of-function'}", + "179, activation {'perturbing_action': 'I-gene gain-of-function'}", + "180, of {'perturbing_action': 'I-gene gain-of-function'}", + "181, AMPK {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "63, mutation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "64, of ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "65, PKD1 ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "71, cells ['l2', 'l16', 'l29', 'l42', 'l43', 'l44', 'l45']", + "74, mouse ['l3', 'l17', 'l30', 'l42', 'l46', 'l47', 'l48', 'l49']", + "75, model ['l4', 'l18', 'l31', 'l43', 'l46', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "76, of ['l5', 'l19', 'l32', 'l44', 'l47', 'l50', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "77, PKD ['l6', 'l20', 'l33', 'l45', 'l48', 'l51', 'l56', 'l62', 'l63', 'l64']", + "80, kidneys ['l7', 'l21', 'l34', 'l57', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "82, humans ['l8', 'l22', 'l35', 'l65', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "89, lower ['l9', 'l23', 'l36', 'l52', 'l58', 'l66', 'l72', 'l80', 'l81', 'l82', 'l83', 'l84']", + "90, proliferation ['l10', 'l24', 'l37', 'l49', 'l53', 'l59', 'l62', 'l67', 'l73', 'l80', 'l85', 'l86', 'l87']", + "92, higher ['l11', 'l25', 'l38', 'l54', 'l60', 'l63', 'l68', 'l74', 'l81', 'l85', 'l88', 'l89', 'l90']", + "93, apoptotic ['l12', 'l26', 'l39', 'l69', 'l75', 'l82', 'l86', 'l88', 'l91', 'l92', 'l93']", + "94, rates ['l13', 'l27', 'l40', 'l55', 'l61', 'l64', 'l70', 'l76', 'l83', 'l87', 'l89', 'l91']", + "96, PKD1-mutant ['l77', 'l94', 'l95']", + "97, cells ['l14', 'l28', 'l41', 'l71', 'l78', 'l84', 'l90', 'l92', 'l94', 'l96']", + "101, cells. ['l79', 'l93', 'l95', 'l96']", + "105, PKD ['l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "106, mouse ['l97', 'l103', 'l104', 'l105', 'l106', 'l107']", + "107, models ['l98', 'l103', 'l108', 'l109', 'l110', 'l111']", + "116, lower ['l99', 'l104', 'l108', 'l112', 'l113', 'l114']", + "117, kidney ['l100', 'l105', 'l109', 'l112', 'l115', 'l116']", + "123, proliferation ['l101', 'l106', 'l110', 'l113', 'l115', 'l117']", + "129, mice. ['l102', 'l107', 'l111', 'l114', 'l116', 'l117']", + "178, Forced ['l118', 'l119', 'l120']", + "179, activation ['l118', 'l121', 'l122']", + "180, of ['l119', 'l121', 'l123']", + "181, AMPK ['l120', 'l122', 'l123']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "of", + "PKD1", + "PKD1-mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "of", + "PKD1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "PKD" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "of", + "PKD1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidneys" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "of", + "PKD1", + "PKD1-mutant" + ] + }, + "context": { + "val": "patient", + "words": [ + "humans" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "of", + "PKD1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "of", + "PKD1" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "of", + "PKD1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "higher" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "of", + "PKD1" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "rates" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "PKD", + "models", + "mice." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "model", + "of", + "PKD", + "mouse", + "models", + "mice." + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "model", + "of", + "PKD" + ] + }, + "effect": { + "val": "positive", + "words": [ + "higher" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "model", + "of", + "PKD" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "rates" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "kidneys", + "kidney" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "kidneys", + "kidney" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "kidneys" + ] + }, + "effect": { + "val": "positive", + "words": [ + "higher" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "kidneys" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "rates" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "humans" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "humans" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "humans" + ] + }, + "effect": { + "val": "positive", + "words": [ + "higher" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "humans" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "rates" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "lower" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "lower" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "rates" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "lower" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "higher" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "higher" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "rates" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "higher" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "cells." + ] + } + } + ] + }, + { + "PMID": "23455711", + "TEXT": "A previous study reported the use of luminol for the detection of myeloperoxidase (MPO) activity using optical imaging in infiltrating neutrophils under inflammatory disease conditions. The detection is based on a photon-emitting reaction between luminol and an MPO metabolite. Because of tissue absorption and scattering, however, luminol-emitted blue light can be efficiently detected from superficial inflammatory foci only. In this study we report a chemiluminescence resonance energy transfer (CRET) methodology in which luminol-generated blue light excites nanoparticles to emit light in the near-infrared spectral range, resulting in remarkable improvement of MPO detectability in vivo. CRET caused a 37-fold increase in luminescence emission over luminol alone in detecting MPO activity in lung tissues after lipopolysaccharide challenge. We demonstrated a dependence of the chemiluminescent signal on MPO activity using MPO-deficient mice. In addition, co-administration of 4-aminobenzoic acid hydrazide (4-ABAH), an irreversible inhibitor of MPO, significantly attenuated luminescent emission from inflamed lungs. Inhibition of nitric oxide synthase with a nonspecific inhibitor, L-NAME, had no effect on luminol-mediated chemiluminescence production. Pretreatment of mice with MLN120B, a selective inhibitor of IKK-2, resulted in suppression of neutrophil infiltration to the lung tissues and reduction of MPO activity. We also demonstrated that CRET can effectively detect MPO activity at deep tissue tumor foci due to tumor development-associated neutrophil infiltration. We developed a sensitive MPO detection methodology that provides a means for visualizing and quantifying oxidative stress in deep tissue. This method is amenable to rapid evaluation of anti-inflammatory agents in animal models.", + "TAG_DATA": [ + "92, in {'context': 'B-in vivo'}", + "93, vivo. {'context': 'I-in vivo'}", + "110, lung {'context': 'B-tissue/organ'}", + "111, tissues {'context': 'I-tissue/organ'}", + "127, MPO-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "128, mice. {'context': 'B-organism'}", + "148, lungs. {'context': 'B-tissue/organ'}", + "149, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "168, mice {'context': 'B-organism'}", + "171, a {'perturbing_action': 'I-pharmacological inhibition'}", + "172, selective {'perturbing_action': 'I-pharmacological inhibition'}", + "173, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "174, of {'perturbing_action': 'I-pharmacological inhibition'}", + "175, IKK-2, {'perturbing_action': 'I-pharmacological inhibition'}", + "184, lung {'context': 'B-tissue/organ'}", + "185, tissues {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "92, in ['l0', 'l1', 'l2']", + "93, vivo. ['l0', 'l3', 'l4']", + "110, lung ['l1', 'l3', 'l5']", + "111, tissues ['l2', 'l4', 'l5']", + "127, MPO-deficient ['l6', 'l7']", + "128, mice. ['l6']", + "148, lungs. ['l7']", + "149, Inhibition ['l8', 'l9']", + "168, mice ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "171, a ['l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "172, selective ['l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "173, inhibitor ['l12', 'l18', 'l23', 'l28', 'l29', 'l30', 'l31']", + "174, of ['l13', 'l19', 'l24', 'l28', 'l32', 'l33', 'l34']", + "175, IKK-2, ['l14', 'l20', 'l25', 'l29', 'l32', 'l35', 'l36']", + "184, lung ['l8', 'l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l37']", + "185, tissues ['l9', 'l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MPO-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MPO-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lungs." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "a", + "selective", + "inhibitor", + "of", + "IKK-2," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung", + "tissues" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "a", + "selective", + "inhibitor", + "of", + "IKK-2," + ] + } + } + ] + }, + { + "PMID": "23396209", + "TEXT": "Widespread antibiotic resistance among important bacterial pathogens such as Staphylococcus aureus calls for alternative routes of drug development. Interfering with crucial virulence determinants is considered a promising new approach to control bacterial infection. Phenol-soluble modulins (PSMs) are peptide toxins with multiple key roles in pathogenesis and have a major impact on the ability of highly virulent S. aureus to cause disease. However, targeting PSMs for therapeutic intervention is hampered by their multitude and diversity. Here we report that an ATP-binding cassette transporter with previously unknown function is responsible for the export of all PSMs, thus representing a single target for complete obstruction of PSM production. The transporter had a strong effect on virulence phenotypes, such as neutrophil lysis, and the extent of its effect on the development of S. aureus infection was similar to that of the sum of all PSMs. Notably, the transporter was essential for bacterial growth. Furthermore, it contributed to producer immunity toward secreted PSMs and defense against PSM-mediated bacterial interference. Our study reveals a noncanonical, dedicated secretion mechanism for an important class of toxins and identifies this mechanism as a comprehensive potential target for the development of drugs to efficiently inhibit the growth and virulence of pathogenic staphylococci.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23396207", + "TEXT": "EF-hand proteins are ubiquitous in cell signaling. Parvalbumin (Parv), the archetypal EF-hand protein, is a high-affinity Ca(2+) buffer in many biological systems. Given the centrality of Ca(2+) signaling in health and disease, EF-hand motifs designed to have new biological activities may have widespread utility. Here, an EF-hand motif substitution that had been presumed to destroy EF-hand function, that of glutamine for glutamate at position 12 of the second cation binding loop domain of Parv (ParvE101Q), markedly inverted relative cation affinities: Mg(2+) affinity increased, whereas Ca(2+) affinity decreased, forming a new ultra-delayed Ca(2+) buffer with favorable properties for promoting cardiac relaxation. In therapeutic testing, expression of ParvE101Q fully reversed the severe myocyte intrinsic contractile defect inherent to expression of native Parv and corrected abnormal myocardial relaxation in diastolic dysfunction disease models in vitro and in vivo. Strategic design of new EF-hand motif domains to modulate intracellular Ca(2+) signaling could benefit many biological systems with abnormal Ca(2+) handling, including the diseased heart.", + "TAG_DATA": [ + "103, expression {'perturbing_action': 'B-other'}", + "104, of {'perturbing_action': 'I-other'}", + "105, ParvE101Q {'perturbing_action': 'I-other'}", + "130, in {'context': 'B-in vitro'}", + "131, vitro {'context': 'I-in vitro'}", + "133, in {'context': 'B-in vivo'}", + "134, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "103, expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "104, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "105, ParvE101Q ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "130, in ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "131, vitro ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "133, in ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "134, vivo. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "ParvE101Q" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "ParvE101Q" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "23396206", + "TEXT": "Oncolytic viruses and active immunotherapeutics have complementary mechanisms of action (MOA) that are both self amplifying in tumors, yet the impact of dose on subject outcome is unclear. JX-594 (Pexa-Vec) is an oncolytic and immunotherapeutic vaccinia virus. To determine the optimal JX-594 dose in subjects with advanced hepatocellular carcinoma (HCC), we conducted a randomized phase 2 dose-finding trial (n=30). Radiologists infused low- or high-dose JX-594 into liver tumors (days 1, 15 and 29); infusions resulted in acute detectable intravascular JX-594 genomes. Objective intrahepatic Modified Response Evaluation Criteria in Solid Tumors (mRECIST) (15%) and Choi (62%) response rates and intrahepatic disease control (50%) were equivalent in injected and distant noninjected tumors at both doses. JX-594 replication and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression preceded the induction of anticancer immunity. In contrast to tumor response rate and immune endpoints, subject survival duration was significantly related to dose (median survival of 14.1 months compared to 6.7 months on the high and low dose, respectively; hazard ratio 0.39; P=0.020). JX-594 demonstrated oncolytic and immunotherapy MOA, tumor responses and dose-related survival in individuals with HCC.", + "TAG_DATA": [ + "66, liver {'context': 'B-neoplasm'}", + "67, tumors {'context': 'I-neoplasm'}", + "109, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "66, liver ['l0']", + "67, tumors ['l0']", + "108, noninjected ['l1']", + "109, tumors ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23377281", + "TEXT": "Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric patients and over 50% of adult patients with ALL do not achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy the most substantial challenge in the treatment of this disease. Using whole-exome sequencing, we identify mutations in the cytosolic 5'-nucleotidase II gene (NT5C2), which encodes a 5'-nucleotidase enzyme that is responsible for the inactivation of nucleoside-analog chemotherapy drugs, in 20/103 (19%) relapse T cell ALLs and 1/35 (3%) relapse B-precursor ALLs. NT5C2 mutant proteins show increased nucleotidase activity in vitro and conferred resistance to chemotherapy with 6-mercaptopurine and 6-thioguanine when expressed in ALL lymphoblasts. These results support a prominent role for activating mutations in NT5C2 and increased nucleoside-analog metabolism in disease progression and chemotherapy resistance in ALL.", + "TAG_DATA": [ + "93, cell {'context': 'I-neoplasm'}", + "100, ALLs. {'context': 'I-neoplasm'}", + "108, in {'context': 'B-in vitro'}", + "109, vitro {'context': 'I-in vitro'}", + "122, ALL {'context': 'B-cells'}", + "123, lymphoblasts. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "92, T ['l0', 'l1']", + "93, cell ['l0', 'l2']", + "94, ALLs ['l1', 'l2']", + "99, B-precursor ['l3', 'l4', 'l5']", + "100, ALLs. ['l3', 'l6', 'l7']", + "102, mutant ['l8', 'l9', 'l10', 'l11']", + "108, in ['l4', 'l6', 'l8', 'l12']", + "109, vitro ['l5', 'l7', 'l9', 'l12']", + "122, ALL ['l10', 'l13']", + "123, lymphoblasts. ['l11', 'l13']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23334847", + "TEXT": "Allergic airway inflammation is associated with activation of innate immune pathways by allergens. Acute exacerbations of asthma are commonly associated with rhinovirus infection. Here we show that, after exposure to house dust mite (HDM) or rhinovirus infection, the E3 ubiquitin ligase midline 1 (MID1) is upregulated in mouse bronchial epithelium. HDM regulates MID1 expression in a Toll-like receptor 4 (TLR4)- and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-dependent manner. MID1 decreases protein phosphatase 2A (PP2A) activity through association with its catalytic subunit PP2Ac. siRNA-mediated knockdown of MID1 or pharmacological activation of PP2A using a nonphosphorylatable FTY720 analog in mice exposed to HDM reduces airway hyperreactivity and inflammation, including the expression of interleukin-25 (IL-25), IL-33 and CCL20, IL-5 and IL-13 release, nuclear factor (NF)κB activity, p38 mitogen-activated protein kinase (MAPK) phosphorylation, accumulation of eosinophils, T lymphocytes and myeloid dendritic cells, and the number of mucus-producing cells. MID1 inhibition also limited rhinovirus-induced exacerbation of allergic airway disease. We found that MID1 was upregulated in primary human bronchial epithelial cells upon HDM or rhinovirus exposure, and this correlated with TRAIL and CCL20 expression. Together, these findings identify a key role of MID1 in allergic airway inflammation and links innate immune pathway activation to the development and exacerbation of asthma.", + "TAG_DATA": [ + "82, siRNA-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "83, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "84, of {'perturbing_action': 'I-rnai/knockdown'}", + "85, MID1 {'perturbing_action': 'I-rnai/knockdown'}", + "87, pharmacological {'perturbing_action': 'B-pharmacological augmentation'}", + "88, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "89, of {'perturbing_action': 'I-pharmacological augmentation'}", + "90, PP2A {'perturbing_action': 'I-pharmacological augmentation'}", + "91, using {'perturbing_action': 'I-pharmacological augmentation'}", + "92, a {'perturbing_action': 'I-pharmacological augmentation'}", + "94, FTY720 {'perturbing_action': 'I-pharmacological augmentation'}", + "97, mice {'context': 'B-organism'}", + "135, myeloid {'context': 'B-cells'}", + "136, dendritic {'context': 'I-cells'}", + "137, cells, {'context': 'I-cells'}", + "144, MID1 {'perturbing_action': 'B-pharmacological inhibition'}", + "145, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "161, primary {'context': 'B-cells'}", + "162, human {'context': 'I-cells'}", + "163, bronchial {'context': 'I-cells'}", + "164, epithelial {'context': 'I-cells'}", + "165, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "82, siRNA-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "83, knockdown ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "84, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "85, MID1 ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "87, pharmacological ['l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "88, activation ['l26', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "89, of ['l27', 'l39', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "90, PP2A ['l28', 'l40', 'l51', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "91, using ['l29', 'l41', 'l52', 'l62', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "92, a ['l30', 'l42', 'l53', 'l63', 'l72', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "93, nonphosphorylatable ['l31', 'l43', 'l54', 'l64', 'l73', 'l81', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "94, FTY720 ['l32', 'l44', 'l55', 'l65', 'l74', 'l82', 'l89', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "95, analog ['l33', 'l45', 'l56', 'l66', 'l75', 'l83', 'l90', 'l96', 'l102', 'l103', 'l104', 'l105', 'l106']", + "97, mice ['l3', 'l10', 'l16', 'l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l84', 'l91', 'l97', 'l102', 'l107', 'l108', 'l109', 'l110']", + "135, myeloid ['l4', 'l11', 'l17', 'l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l98', 'l103', 'l107', 'l111', 'l112', 'l113']", + "136, dendritic ['l5', 'l12', 'l18', 'l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l86', 'l93', 'l99', 'l104', 'l108', 'l111', 'l114', 'l115']", + "137, cells, ['l6', 'l13', 'l19', 'l24', 'l37', 'l49', 'l60', 'l70', 'l79', 'l87', 'l94', 'l100', 'l105', 'l109', 'l112', 'l114', 'l116']", + "143, cells. ['l7', 'l14', 'l20', 'l25', 'l38', 'l50', 'l61', 'l71', 'l80', 'l88', 'l95', 'l101', 'l106', 'l110', 'l113', 'l115', 'l116']", + "144, MID1 ['l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "145, inhibition ['l117', 'l123', 'l124', 'l125', 'l126', 'l127']", + "161, primary ['l118', 'l123', 'l128', 'l129', 'l130', 'l131']", + "162, human ['l119', 'l124', 'l128', 'l132', 'l133', 'l134']", + "163, bronchial ['l120', 'l125', 'l129', 'l132', 'l135', 'l136']", + "164, epithelial ['l121', 'l126', 'l130', 'l133', 'l135', 'l137']", + "165, cells ['l122', 'l127', 'l131', 'l134', 'l136', 'l137']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA-mediated", + "knockdown", + "of", + "MID1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA-mediated", + "knockdown", + "of", + "MID1" + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "dendritic", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "pharmacological", + "activation", + "of", + "PP2A", + "using", + "a", + "FTY720" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "pharmacological", + "activation", + "of", + "PP2A", + "using", + "a", + "FTY720" + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "dendritic", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "MID1", + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "primary", + "human", + "bronchial", + "epithelial", + "cells" + ] + } + } + ] + }, + { + "PMID": "23314058", + "TEXT": "Two-photon phosphorescence lifetime microscopy (2PLM) has been used recently for depth measurements of oxygen partial pressure (PO(2)) in the rodent brain. In capillaries of olfactory bulb glomeruli, 2PLM has also allowed simultaneous measurements of PO(2) and blood flow and revealed the presence of erythrocyte-associated transients (EATs), which are PO(2) gradients that are associated with individual erythrocytes. We investigated the extent to which EAT properties in capillaries report local neuronal activity. We find that at rest, PO(2) at EAT peaks overestimates the mean PO(2) by 35 mm Hg. PO(2) between two EAT peaks is at equilibrium with, and thus reports, PO(2) in the neuropil. During odor stimulation, there is a small PO(2) decrease before functional hyperemia, showing that the initial dip in PO(2) is present at the level of capillaries. We conclude that imaging oxygen dynamics in capillaries provides a unique and noninvasive approach to map neuronal activity.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23296014", + "TEXT": "Distinct roadblocks prevent translating basic findings in viral pathogenesis into therapies and implementing potential solutions in the clinic. An ongoing partnership between the Volkswagen Foundation and Nature Medicine resulted in an interactive meeting in 2012, as part of the \"Herrenhausen Symposia\" series. Current challenges for various fields of viral research were recognized and discussed with a goal in mind--to identify solutions and propose an agenda to address the translational barriers. Here, some of the researchers who participated at the meeting provide a concise outlook at the most pressing unmet research and clinical needs, identifying these key obstacles is a necessary step towards the prevention and cure of human viral diseases.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23296003", + "TEXT": "The anticancer efficacy of conventional chemotherapies seems to be due, in part, to augmentation of the host immune reactivity. However, a new study reveals that two common chemotherapeutic agents, gemcitabine and 5-fluorouracil, can also activate immune regulatory cells, which stimulates the emergence of protumorigenic cytokines via inflammasome pathways, limiting the antitumor efficacy of the drugs (pages 57–64).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "23291629", + "TEXT": "Obesity develops as a result of altered energy homeostasis favoring fat storage. Here we describe a new transcription co-regulator for adiposity and energy metabolism, SERTA domain containing 2 (TRIP-Br2, also called SERTAD2). TRIP-Br2-null mice are resistant to obesity and obesity-related insulin resistance. Adipocytes of these knockout mice showed greater stimulated lipolysis secondary to enhanced expression of hormone sensitive lipase (HSL) and β3-adrenergic (Adrb3) receptors. The knockout mice also have higher energy expenditure because of increased adipocyte thermogenesis and oxidative metabolism caused by upregulating key enzymes in their respective processes. Our data show that a cell-cycle transcriptional co-regulator, TRIP-Br2, modulates fat storage through simultaneous regulation of lipolysis, thermogenesis and oxidative metabolism. These data, together with the observation that TRIP-Br2 expression is selectively elevated in visceral fat in obese humans, suggests that this transcriptional co-regulator is a new therapeutic target for counteracting the development of obesity, insulin resistance and hyperlipidemia.", + "TAG_DATA": [ + "32, TRIP-Br2-null {'perturbing_action': 'B-gene loss-of-function'}", + "33, mice {'context': 'B-organism'}", + "42, Adipocytes {'context': 'B-cells'}", + "46, mice {'context': 'B-organism'}", + "66, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "32, TRIP-Br2-null ['l0', 'l1', 'l2', 'l3']", + "33, mice ['l0', 'l4', 'l5']", + "42, Adipocytes ['l1', 'l4', 'l6']", + "46, mice ['l2', 'l5', 'l6']", + "66, mice ['l3']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TRIP-Br2-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TRIP-Br2-null" + ] + }, + "context": { + "val": "cells", + "words": [ + "Adipocytes" + ] + } + } + ] + }, + { + "PMID": "23263626", + "TEXT": "Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling associated with obliteration of pulmonary arterioles and formation of plexiform lesions composed of hyperproliferative endothelial and vascular smooth-muscle cells. Here we describe a microRNA (miRNA)-dependent association between apelin (APLN) and fibroblast growth factor 2 (FGF2) signaling in pulmonary artery endothelial cells (PAECs). APLN deficiency in these cells led to increased expression of FGF2 and its receptor FGFR1 as a consequence of decreased expression of miR-424 and miR-503, which directly target FGF2 and FGFR1. miR-424 and miR-503 were downregulated in PAH, exerted antiproliferative effects in PAECs and inhibited the capacity of PAEC-conditioned medium to induce the proliferation of pulmonary artery smooth-muscle cells. Reconstitution of miR-424 and miR-503 in vivo ameliorated pulmonary hypertension in experimental models. These studies identify an APLN-dependent miRNA-FGF signaling axis needed for the maintenance of pulmonary vascular homeostasis.", + "TAG_DATA": [ + "51, APLN {'perturbing_action': 'B-gene loss-of-function'}", + "52, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "55, cells {'context': 'B-cells'}", + "93, PAECs {'context': 'B-cells'}", + "95, inhibited {'effect': 'B-negative'}", + "102, induce {'effect': 'B-positive'}", + "104, proliferation {'phenotype': 'B-proliferation'}", + "106, pulmonary {'context': 'B-cells'}", + "107, artery {'context': 'I-cells'}", + "108, smooth-muscle {'context': 'I-cells'}", + "109, cells. {'context': 'I-cells'}", + "110, Reconstitution {'perturbing_action': 'B-gene gain-of-function'}", + "111, of {'perturbing_action': 'I-gene gain-of-function'}", + "112, miR-424 {'perturbing_action': 'I-gene gain-of-function'}", + "113, and {'perturbing_action': 'I-gene gain-of-function'}", + "114, miR-503 {'perturbing_action': 'I-gene gain-of-function'}", + "115, in {'context': 'B-in vivo'}", + "116, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "51, APLN ['l0', 'l1']", + "52, deficiency ['l0', 'l2']", + "55, cells ['l1', 'l2']", + "93, PAECs ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "95, inhibited ['l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "102, induce ['l4', 'l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "104, proliferation ['l5', 'l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "106, pulmonary ['l6', 'l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "107, artery ['l7', 'l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "108, smooth-muscle ['l8', 'l14', 'l19', 'l23', 'l26', 'l28', 'l30']", + "109, cells. ['l9', 'l15', 'l20', 'l24', 'l27', 'l29', 'l30']", + "110, Reconstitution ['l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "111, of ['l31', 'l37', 'l38', 'l39', 'l40', 'l41']", + "112, miR-424 ['l32', 'l37', 'l42', 'l43', 'l44', 'l45']", + "113, and ['l33', 'l38', 'l42', 'l46', 'l47', 'l48']", + "114, miR-503 ['l34', 'l39', 'l43', 'l46', 'l49', 'l50']", + "115, in ['l35', 'l40', 'l44', 'l47', 'l49', 'l51']", + "116, vivo ['l36', 'l41', 'l45', 'l48', 'l50', 'l51']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "APLN", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "PAECs", + "pulmonary", + "artery", + "smooth-muscle", + "cells." + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "PAECs", + "pulmonary", + "artery", + "smooth-muscle", + "cells." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "PAECs", + "pulmonary", + "artery", + "smooth-muscle", + "cells." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reconstitution", + "of", + "miR-424", + "and", + "miR-503" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "23242473", + "TEXT": "Type 1 diabetes develops over many years and is characterized ultimately by the destruction of insulin-producing pancreatic beta cells by autoreactive T cells. Nonetheless, the role of innate cells in the initiation of this disease remains poorly understood. Here, we show that in young female nonobese diabetic mice, physiological beta cell death induces the recruitment and activation of B-1a cells, neutrophils and plasmacytoid dendritic cells (pDCs) to the pancreas. Activated B-1a cells secrete IgGs specific for double-stranded DNA. IgGs activate neutrophils to release DNA-binding cathelicidin-related antimicrobial peptide (CRAMP), which binds self DNA. Then, self DNA, DNA-specific IgG and CRAMP peptide activate pDCs through the Toll-like receptor 9-myeloid differentiation factor 88 pathway, leading to interferon-α production in pancreatic islets. We further demonstrate through the use of depleting treatments that B-1a cells, neutrophils and IFN-α-producing pDCs are required for the initiation of the diabetogenic T cell response and type 1 diabetes development. These findings reveal that an innate immune cell crosstalk takes place in the pancreas of young NOD mice and leads to the initiation of T1D.", + "TAG_DATA": [ + "43, young {'context': 'B-organism'}", + "44, female {'context': 'I-organism'}", + "45, nonobese {'context': 'I-organism'}", + "46, diabetic {'context': 'I-organism'}", + "47, mice, {'context': 'I-organism'}", + "58, B-1a {'context': 'B-cells'}", + "59, cells, {'context': 'I-cells'}", + "62, plasmacytoid {'context': 'B-cells'}", + "63, dendritic {'context': 'I-cells'}", + "64, cells {'context': 'I-cells'}", + "65, (pDCs) {'context': 'I-cells'}", + "70, B-1a {'context': 'B-cells'}", + "71, cells {'context': 'I-cells'}", + "101, pDCs {'context': 'B-cells'}", + "116, pancreatic {'context': 'B-cells'}", + "117, islets. {'context': 'I-cells'}", + "128, B-1a {'context': 'B-cells'}", + "129, cells, {'context': 'I-cells'}", + "165, young {'context': 'B-organism'}", + "166, NOD {'context': 'I-organism'}", + "167, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "43, young ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "44, female ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "45, nonobese ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "46, diabetic ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "47, mice, ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "58, B-1a ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "59, cells, ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "62, plasmacytoid ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "63, dendritic ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "64, cells ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l69', 'l75', 'l76', 'l77']", + "65, (pDCs) ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l70', 'l75', 'l78', 'l79']", + "70, B-1a ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l71', 'l76', 'l78', 'l80', 'l81', 'l82']", + "71, cells ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l72', 'l77', 'l79', 'l80', 'l83', 'l84']", + "101, pDCs ['l85', 'l86']", + "116, pancreatic ['l73', 'l81', 'l83', 'l85', 'l87']", + "117, islets. ['l68', 'l74', 'l82', 'l84', 'l86', 'l87']", + "128, B-1a ['l88', 'l89', 'l90', 'l91']", + "129, cells, ['l88']", + "165, young ['l89', 'l92', 'l93']", + "166, NOD ['l90', 'l92', 'l94']", + "167, mice ['l91', 'l93', 'l94']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23223005", + "TEXT": "Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response that is specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that loss of Polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) activates HIF-driven chemokine (C-X-C motif) receptor 4 (CXCR4) expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven cytohesin 1 interacting protein (CYTIP) expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway.", + "TAG_DATA": [ + "82, VHL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "83, ccRCC {'context': 'B-transformed cells'}", + "84, cells, {'context': 'I-transformed cells'}", + "133, support {'effect': 'B-regulates'}", + "135, chemotactic {'phenotype': 'B-migration'}", + "136, cell {'phenotype': 'B-migration'}", + "137, invasion, {'phenotype': 'B-invasion'}", + "153, cancer {'context': 'B-transformed cells'}", + "154, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "82, VHL-deficient ['l0', 'l1', 'l2', 'l3']", + "83, ccRCC ['l0', 'l4']", + "84, cells, ['l1', 'l4']", + "133, support ['l5', 'l6', 'l7']", + "135, chemotactic ['l5', 'l8', 'l9']", + "136, cell ['l2', 'l6', 'l8', 'l10']", + "137, invasion, ['l3', 'l7', 'l9', 'l10']", + "153, cancer ['l11']", + "154, cells ['l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "VHL-deficient" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ccRCC", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "VHL-deficient" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "VHL-deficient" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion," + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "support" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotactic", + "cell" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "support" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion," + ] + } + } + ] + }, + { + "PMID": "23223004", + "TEXT": "Emerging evidence indicates that microRNAs (miRNAs) have important roles in regulating osteogenic differentiation and bone formation. Thus far, no study has established the pathophysiological role for miRNAs identified in human osteoporotic bone specimens. Here we found that elevated miR-214 levels correlated with a lower degree of bone formation in bone specimens from aged patients with fractures. We also found that osteoblast-specific manipulation of miR-214 levels by miR-214 antagomir treatment in miR-214 transgenic, ovariectomized, or hindlimb-unloaded mice revealed an inhibitory role of miR-214 in regulating bone formation. Further, in vitro osteoblast activity and matrix mineralization were promoted by antagomir-214 and decreased by agomir-214, and miR-214 directly targeted ATF4 to inhibit osteoblast activity. These data suggest that miR-214 has a crucial role in suppressing bone formation and that miR-214 inhibition in osteoblasts may be a potential anabolic strategy for ameliorating osteoporosis.", + "TAG_DATA": [ + "66, miR-214 {'perturbing_action': 'B-rnai/knockdown'}", + "67, antagomir {'perturbing_action': 'I-rnai/knockdown'}", + "68, treatment {'perturbing_action': 'I-rnai/knockdown'}", + "70, miR-214 {'perturbing_action': 'B-gene gain-of-function'}", + "71, transgenic, {'perturbing_action': 'I-gene gain-of-function'}", + "75, mice {'context': 'B-organism'}", + "87, in {'context': 'B-in vitro'}", + "88, vitro {'context': 'I-in vitro'}", + "89, osteoblast {'context': 'B-cells'}", + "109, osteoblast {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "66, miR-214 ['l0', 'l1', 'l2', 'l3', 'l4']", + "67, antagomir ['l0', 'l5', 'l6', 'l7', 'l8', 'l9']", + "68, treatment ['l1', 'l5', 'l10', 'l11']", + "70, miR-214 ['l2', 'l6', 'l10', 'l12', 'l13', 'l14', 'l15']", + "71, transgenic, ['l3', 'l7', 'l11', 'l12', 'l16', 'l17', 'l18', 'l19']", + "75, mice ['l8', 'l13', 'l16', 'l20', 'l21', 'l22']", + "87, in ['l17', 'l20', 'l23', 'l24']", + "88, vitro ['l14', 'l18', 'l21', 'l23', 'l25']", + "89, osteoblast ['l4', 'l9', 'l15', 'l19', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "miR-214", + "antagomir" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoblast" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antagomir" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "miR-214", + "transgenic," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "miR-214", + "transgenic," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "vitro", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "miR-214", + "transgenic," + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoblast" + ] + } + } + ] + }, + { + "PMID": "23160237", + "TEXT": "Hydrocephalus is a common neurological disorder that leads to expansion of the cerebral ventricles and is associated with a high rate of morbidity and mortality. Most neonatal cases are of unknown etiology and are likely to have complex inheritance involving multiple genes and environmental factors. Identifying molecular mechanisms for neonatal hydrocephalus and developing noninvasive treatment modalities are high priorities. Here we use a hydrocephalic mouse model of the human ciliopathy Bardet-Biedl Syndrome (BBS) and identify a role for neural progenitors in the pathogenesis of neonatal hydrocephalus. We found that hydrocephalus in this mouse model is caused by aberrant platelet-derived growth factor receptor α (PDGFR-α) signaling, resulting in increased apoptosis and impaired proliferation of chondroitin sulfate proteoglycan 4 (also known as neuron-glial antigen 2 or NG2)(+)PDGFR-α(+) neural progenitors. Targeting this pathway with lithium treatment rescued NG2(+)PDGFR-α(+) progenitor cell proliferation in BBS mutant mice, reducing their ventricular volume. Our findings demonstrate that neural progenitors are crucial in the pathogenesis of neonatal hydrocephalus, and we identify new therapeutic targets for this common neurological disorder.", + "TAG_DATA": [ + "92, mouse {'context': 'B-organism'}", + "93, model {'context': 'I-organism'}", + "107, increased {'effect': 'B-positive'}", + "108, apoptosis {'phenotype': 'B-apoptosis'}", + "110, impaired {'effect': 'B-negative'}", + "111, proliferation {'phenotype': 'B-proliferation'}", + "133, rescued {'effect': 'B-rescues'}", + "134, NG2(+)PDGFR-α(+) {'context': 'B-cells'}", + "135, progenitor {'context': 'I-cells'}", + "136, cell {'context': 'I-cells'}", + "137, proliferation {'phenotype': 'B-proliferation'}", + "139, BBS {'perturbing_action': 'B-other'}", + "140, mutant {'perturbing_action': 'I-other'}", + "141, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "92, mouse ['l0', 'l1', 'l2', 'l3', 'l4']", + "93, model ['l0', 'l5', 'l6', 'l7', 'l8']", + "107, increased ['l1', 'l5', 'l9', 'l10', 'l11']", + "108, apoptosis ['l2', 'l6', 'l9', 'l12', 'l13']", + "110, impaired ['l3', 'l7', 'l10', 'l12', 'l14']", + "111, proliferation ['l4', 'l8', 'l11', 'l13', 'l14']", + "133, rescued ['l15', 'l16', 'l17', 'l18']", + "134, NG2(+)PDGFR-α(+) ['l15', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "135, progenitor ['l16', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "136, cell ['l17', 'l20', 'l25', 'l30', 'l31', 'l32']", + "137, proliferation ['l18', 'l21', 'l26', 'l30', 'l33']", + "139, BBS ['l22', 'l27', 'l34', 'l35']", + "140, mutant ['l23', 'l28', 'l31', 'l34', 'l36']", + "141, mice, ['l24', 'l29', 'l32', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "mice," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "context": { + "val": "cells", + "words": [ + "NG2(+)PDGFR-α(+)", + "progenitor", + "cell" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "NG2(+)PDGFR-α(+)", + "progenitor", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "NG2(+)PDGFR-α(+)", + "progenitor", + "cell" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "BBS", + "mutant" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BBS", + "mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "23160236", + "TEXT": "In vivo real-time epifluorescence imaging of mouse hind limb vasculatures in the second near-infrared region (NIR-II) is performed using single-walled carbon nanotubes as fluorophores. Both high spatial (∼30 μm) and temporal (<200 ms per frame) resolution for small-vessel imaging are achieved at 1-3 mm deep in the hind limb owing to the beneficial NIR-II optical window that affords deep anatomical penetration and low scattering. This spatial resolution is unattainable by traditional NIR imaging (NIR-I) or microscopic computed tomography, and the temporal resolution far exceeds scanning microscopic imaging techniques. Arterial and venous vessels are unambiguously differentiated using a dynamic contrast-enhanced NIR-II imaging technique on the basis of their distinct hemodynamics. Further, the deep tissue penetration and high spatial and temporal resolution of NIR-II imaging allow for precise quantifications of blood velocity in both normal and ischemic femoral arteries, which are beyond the capabilities of ultrasonography at lower blood velocities.", + "TAG_DATA": [ + "135, femoral {'context': 'B-tissue/organ'}", + "136, arteries, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "135, femoral ['l0']", + "136, arteries, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23142822", + "TEXT": "Hematopoietic stem cell (HSC) self renewal and lineage commitment depend on complex interactions with the microenvironment. The ability to maintain or expand HSCs for clinical applications or basic research has been substantially limited because these interactions are not well defined. Recent evidence suggests that HSCs reside in a low-perfusion, reduced-nutrient niche and that nutrient-sensing pathways contribute to HSC homeostasis. Here we report that suppression of the mTOR pathway, an established nutrient sensor, combined with activation of canonical Wnt-β-catenin signaling, allows for the ex vivo maintenance of human and mouse long-term HSCs under cytokine-free conditions. We also show that the combination of two clinically approved medications that together activate Wnt-β-catenin and inhibit mTOR signaling increases the number (but not the proportion) of long-term HSCs in vivo.", + "TAG_DATA": [ + "86, human {'context': 'B-cells'}", + "87, and {'context': 'I-cells'}", + "88, mouse {'context': 'I-cells'}", + "89, long-term {'context': 'I-cells'}", + "90, HSCs {'context': 'I-cells'}", + "121, long-term {'context': 'B-cells'}", + "122, HSCs {'context': 'I-cells'}", + "123, in {'context': 'B-in vivo'}", + "124, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "86, human ['l0', 'l1', 'l2', 'l3']", + "87, and ['l0', 'l4', 'l5', 'l6']", + "88, mouse ['l1', 'l4', 'l7', 'l8']", + "89, long-term ['l2', 'l5', 'l7', 'l9']", + "90, HSCs ['l3', 'l6', 'l8', 'l9']", + "121, long-term ['l10', 'l11', 'l12']", + "122, HSCs ['l10', 'l13', 'l14']", + "123, in ['l11', 'l13', 'l15']", + "124, vivo. ['l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23135512", + "TEXT": "The sirtuins (SIRTs) have gained preeminence for their roles in the response to caloric restriction and the regulation of aging and lifespan. A new study now identifies gene promoters that bind the transcription factor AP1 as targets for silencing by SIRT6, providing possible links between SIRT6 deficiency and dysregulation of insulin-like growth factor signaling, hypertrophic cardiomyopathy and heart failure (pages 1643-1650).", + "TAG_DATA": [ + "45, SIRT6 {'perturbing_action': 'B-gene loss-of-function'}", + "46, deficiency {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "45, SIRT6 ['l0']", + "46, deficiency ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23135507", + "TEXT": "Angiogenesis is a key feature of central nervous system injury. A neovessel-derived signal mediated by prostacyclin triggers axonal sprouting and functional recovery in a mouse model of inflammatory spinal cord injury (pages 1658-1664). Are such angiocrine signals relevant to neurovascular remodeling and recovery in other neurological contexts?", + "TAG_DATA": [ + "24, mouse {'context': 'B-organism'}", + "25, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "24, mouse ['l0', 'l1']", + "25, model ['l0', 'l2']", + "29, cord ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23104132", + "TEXT": "Doxorubicin is believed to cause dose-dependent cardiotoxicity through redox cycling and the generation of reactive oxygen species (ROS). Here we show that cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks and transcriptome changes that are responsible for defective mitochondrial biogenesis and ROS formation. Furthermore, cardiomyocyte-specific deletion of Top2b protects mice from the development of doxorubicin-induced progressive heart failure, suggesting that doxorubicin-induced cardiotoxicity is mediated by topoisomerase-IIβ in cardiomyocytes.", + "TAG_DATA": [ + "22, cardiomyocyte-specific {'perturbing_action': 'B-gene loss-of-function'}", + "23, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "24, of {'perturbing_action': 'I-gene loss-of-function'}", + "25, Top2b {'perturbing_action': 'I-gene loss-of-function'}", + "26, (encoding {'perturbing_action': 'I-gene loss-of-function'}", + "27, topoisomerase-IIβ) {'perturbing_action': 'I-gene loss-of-function'}", + "29, cardiomyocytes {'context': 'B-cells'}", + "49, cardiomyocyte-specific {'perturbing_action': 'B-gene loss-of-function'}", + "50, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "51, of {'perturbing_action': 'I-gene loss-of-function'}", + "52, Top2b {'perturbing_action': 'I-gene loss-of-function'}", + "54, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "22, cardiomyocyte-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "23, deletion ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "24, of ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "25, Top2b ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "26, (encoding ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "27, topoisomerase-IIβ) ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "29, cardiomyocytes ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "49, cardiomyocyte-specific ['l21', 'l22', 'l23', 'l24']", + "50, deletion ['l21', 'l25', 'l26', 'l27']", + "51, of ['l22', 'l25', 'l28', 'l29']", + "52, Top2b ['l23', 'l26', 'l28', 'l30']", + "54, mice ['l24', 'l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cardiomyocyte-specific", + "deletion", + "of", + "Top2b", + "(encoding", + "topoisomerase-IIβ)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cardiomyocyte-specific", + "deletion", + "of", + "Top2b" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23086478", + "TEXT": "Reactive oxygen species (ROS), a byproduct of cellular metabolism, damage intracellular macromolecules and, when present in excess, can promote normal hematopoietic stem cell differentiation and exhaustion. However, mechanisms that regulate the amount of ROS in leukemia-initiating cells (LICs) and the biological role of ROS in these cells are largely unknown. We show here that the ROS(low) subset of CD44(+) cells in T cell acute lymphoblastic leukemia (T-ALL), a malignancy of immature T cell progenitors, is highly enriched in the most aggressive LICs and that ROS accumulation is restrained by downregulation of protein kinase C θ (PKC-θ). Notably, primary mouse T-ALLs lacking PKC-θ show improved LIC activity, whereas enforced PKC-θ expression in both mouse and human primary T-ALLs compromised LIC activity. We also show that PKC-θ is regulated by a new pathway in which NOTCH1 induces runt-related transcription factor 3 (RUNX3), RUNX3 represses RUNX1 and RUNX1 induces PKC-θ. NOTCH1, which is frequently activated by mutation in T-ALL and required for LIC activity in both mouse and human models, thus acts to repress PKC-θ. These results reveal key functional roles for PKC-θ and ROS in T-ALL and suggest that aggressive biological behavior in vivo could be limited by therapeutic strategies that promote PKC-θ expression or activity, or the accumulation of ROS.", + "TAG_DATA": [ + "97, primary {'context': 'B-neoplasm'}", + "98, mouse {'context': 'I-neoplasm'}", + "99, T-ALLs {'context': 'I-neoplasm'}", + "100, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "101, PKC-θ {'perturbing_action': 'I-gene loss-of-function'}", + "107, enforced {'perturbing_action': 'B-gene gain-of-function'}", + "108, PKC-θ {'perturbing_action': 'I-gene gain-of-function'}", + "109, expression {'perturbing_action': 'I-gene gain-of-function'}", + "112, mouse {'context': 'B-neoplasm'}", + "113, and {'context': 'I-neoplasm'}", + "114, human {'context': 'I-neoplasm'}", + "115, primary {'context': 'I-neoplasm'}", + "116, T-ALLs {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "97, primary ['l0', 'l1', 'l2', 'l3']", + "98, mouse ['l0', 'l4', 'l5', 'l6']", + "99, T-ALLs ['l1', 'l4', 'l7', 'l8']", + "100, lacking ['l2', 'l5', 'l7', 'l9']", + "101, PKC-θ ['l3', 'l6', 'l8', 'l9']", + "107, enforced ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "108, PKC-θ ['l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "109, expression ['l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "112, mouse ['l12', 'l18', 'l23', 'l28', 'l29', 'l30', 'l31']", + "113, and ['l13', 'l19', 'l24', 'l28', 'l32', 'l33', 'l34']", + "114, human ['l14', 'l20', 'l25', 'l29', 'l32', 'l35', 'l36']", + "115, primary ['l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l37']", + "116, T-ALLs ['l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "primary", + "mouse", + "T-ALLs" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "PKC-θ" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "enforced", + "PKC-θ", + "expression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "and", + "human", + "primary", + "T-ALLs" + ] + } + } + ] + }, + { + "PMID": "23086477", + "TEXT": "Abnormal activation of insulin-like growth factor (IGF)-Akt signaling is implicated in the development of various diseases, including heart failure. However, the molecular mechanisms that regulate activation of this signaling pathway are not completely understood. Here we show that sirtuin 6 (SIRT6), a nuclear histone deacetylase, functions at the level of chromatin to directly attenuate IGF-Akt signaling. SIRT6-deficient mice developed cardiac hypertrophy and heart failure, whereas SIRT6 transgenic mice were protected from hypertrophic stimuli, indicating that SIRT6 acts as a negative regulator of cardiac hypertrophy. SIRT6-deficient mouse hearts showed hyperactivation of IGF signaling-related genes and their downstream targets. Mechanistically, SIRT6 binds to and suppresses the promoter of IGF signaling-related genes by interacting with c-Jun and deacetylating histone 3 at Lys9 (H3K9). We also found reduced SIRT6 expression in human failing hearts. These findings disclose a new link between SIRT6 and IGF-Akt signaling and implicate SIRT6 in the development of cardiac hypertrophy and failure.", + "TAG_DATA": [ + "56, SIRT6-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "57, mice {'context': 'B-organism'}", + "65, SIRT6 {'perturbing_action': 'B-gene gain-of-function'}", + "66, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "67, mice {'context': 'B-organism'}", + "84, SIRT6-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "85, mouse {'context': 'B-tissue/organ'}", + "86, hearts {'context': 'I-tissue/organ'}", + "128, failing {'context': 'I-tissue/organ'}", + "129, hearts. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "56, SIRT6-deficient ['l0']", + "57, mice ['l0']", + "65, SIRT6 ['l1', 'l2', 'l3']", + "66, transgenic ['l1', 'l4', 'l5']", + "67, mice ['l2', 'l4']", + "84, SIRT6-deficient ['l6', 'l7']", + "85, mouse ['l6', 'l8']", + "86, hearts ['l3', 'l5', 'l7', 'l8']", + "127, human ['l9', 'l10']", + "128, failing ['l9', 'l11']", + "129, hearts. ['l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SIRT6-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "SIRT6", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "SIRT6", + "transgenic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hearts" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SIRT6-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "hearts" + ] + } + } + ] + }, + { + "PMID": "23064463", + "TEXT": "Allergic asthma is a complex disease characterized by eosinophilic pulmonary inflammation, mucus production and reversible airway obstruction. Exposure to indoor allergens is a risk factor for asthma, but this disease is also associated with high household levels of total and particularly Gram-negative bacteria. The ability of bacterial products to act as adjuvants suggests they might promote asthma by priming allergic sensitization to inhaled allergens. In support of this idea, house dust extracts (HDEs) can activate antigen-presenting dendritic cells (DCs) in vitro and promote allergic sensitization to inhaled innocuous proteins in vivo. It is unknown which microbial products provide most of the adjuvant activity in HDEs. A screen for adjuvant activity of microbial products revealed that the bacterial protein flagellin (FLA) stimulated strong allergic airway responses to an innocuous inhaled protein, ovalbumin (OVA). Moreover, Toll-like receptor 5 (TLR5), the mammalian receptor for FLA, was required for priming strong allergic responses to natural indoor allergens present in HDEs. In addition, individuals with asthma have higher serum levels of FLA-specific antibodies as compared to nonasthmatic individuals. Together, these findings suggest that household FLA promotes the development of allergic asthma by TLR5-dependent priming of allergic responses to indoor allergens.", + "TAG_DATA": [ + "75, antigen-presenting {'context': 'B-cells'}", + "76, dendritic {'context': 'I-cells'}", + "77, cells {'context': 'I-cells'}", + "78, (DCs) {'context': 'I-cells'}", + "79, in {'context': 'B-in vitro'}", + "80, vitro {'context': 'I-in vitro'}", + "89, in {'context': 'B-in vivo'}" + ], + "LINK_DATA": [ + "75, antigen-presenting ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "76, dendritic ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "77, cells ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "78, (DCs) ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "79, in ['l3', 'l8', 'l12', 'l15', 'l18']", + "80, vitro ['l4', 'l9', 'l13', 'l16', 'l18']", + "89, in ['l5', 'l10', 'l14', 'l17']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23042237", + "TEXT": "Chronic obstructive pulmonary disease (COPD) is increasingly being recognized as a highly heterogeneous disorder, composed of varying pathobiology. Accurate detection of COPD subtypes by image biomarkers is urgently needed to enable individualized treatment, thus improving patient outcome. We adapted the parametric response map (PRM), a voxel-wise image analysis technique, for assessing COPD phenotype. We analyzed whole-lung computed tomography (CT) scans acquired at inspiration and expiration of 194 individuals with COPD from the COPDGene study. PRM identified the extent of functional small airways disease (fSAD) and emphysema as well as provided CT-based evidence that supports the concept that fSAD precedes emphysema with increasing COPD severity. PRM is a versatile imaging biomarker capable of diagnosing disease extent and phenotype while providing detailed spatial information of disease distribution and location. PRM's ability to differentiate between specific COPD phenotypes will allow for more accurate diagnosis of individual patients, complementing standard clinical techniques.", + "TAG_DATA": [ + "67, individuals {'context': 'B-patient'}", + "69, COPD {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "67, individuals ['l0']", + "69, COPD ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23042236", + "TEXT": "Angiogenesis is a prominent feature of central nervous system (CNS) disease and has roles in both the continued promotion of inflammation and the subsequent repair processes. Here we report that prostacyclin (or prostaglandin I(2) (PGI(2))) derived from new vessels promotes axonal remodeling of injured neuronal networks after CNS inflammation. In a localized model of experimental autoimmune encephalomyelitis (EAE), new vessels formed around the inflammatory lesion, followed by sprouting of adjacent corticospinal tract (CST) fibers. These sprouting fibers formed a compensatory motor circuit, leading to recovery of motor function. Capillary endothelial cell-derived prostacyclin bound to its receptor, the type I prostaglandin receptor (IP receptor), on CST neurons, promoting sprouting of CST fibers and contributing to the repair process. Inhibition of prostacyclin receptor signaling impaired motor recovery, whereas the IP receptor agonist iloprost promoted axonal remodeling and motor recovery after the induction of EAE. These findings reveal an important function of angiogenesis in neuronal rewiring and suggest that prostacyclin is a promising molecule for enhancing functional recovery from CNS disease.", + "TAG_DATA": [ + "104, CST {'context': 'B-cells'}", + "105, neurons, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "104, CST ['l0']", + "105, neurons, ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "23001181", + "TEXT": "A noninvasive technology that quantitatively measures the activity of oncogenic signaling pathways could have a broad impact on cancer diagnosis and treatment with targeted therapies. Here we describe the development of (89)Zr-desferrioxamine-labeled transferrin ((89)Zr-transferrin), a new positron emission tomography (PET) radiotracer that binds the transferrin receptor 1 (TFRC, CD71) with high avidity. The use of (89)Zr-transferrin produces high-contrast PET images that quantitatively reflect treatment-induced changes in MYC-regulated TFRC expression in a MYC-driven prostate cancer xenograft model. Moreover, (89)Zr-transferrin imaging can detect the in situ development of prostate cancer in a transgenic MYC prostate cancer model, as well as in prostatic intraepithelial neoplasia (PIN) before histological or anatomic evidence of invasive cancer. These preclinical data establish (89)Zr-transferrin as a sensitive tool for noninvasive measurement of oncogene-driven TFRC expression in prostate and potentially other cancers, with prospective near-term clinical application.", + "TAG_DATA": [ + "71, MYC-driven {'context': 'B-xenograft'}", + "72, prostate {'context': 'I-xenograft'}", + "73, cancer {'context': 'I-xenograft'}", + "74, xenograft {'context': 'I-xenograft'}", + "75, model. {'context': 'I-xenograft'}", + "86, prostate {'context': 'B-neoplasm'}", + "87, cancer {'context': 'I-neoplasm'}", + "90, transgenic {'perturbing_action': 'B-other'}", + "92, prostate {'context': 'I-transformed cells'}", + "93, cancer {'context': 'I-neoplasm'}", + "94, model, {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "71, MYC-driven ['l0', 'l1', 'l2', 'l3']", + "72, prostate ['l0', 'l4', 'l5', 'l6']", + "73, cancer ['l1', 'l4', 'l7', 'l8']", + "74, xenograft ['l2', 'l5', 'l7', 'l9']", + "75, model. ['l3', 'l6', 'l8', 'l9']", + "86, prostate ['l10']", + "87, cancer ['l10']", + "90, transgenic ['l11', 'l12', 'l13', 'l14']", + "91, MYC ['l11', 'l15', 'l16', 'l17']", + "92, prostate ['l12', 'l15', 'l18', 'l19']", + "93, cancer ['l13', 'l16', 'l18', 'l20']", + "94, model, ['l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "cancer", + "model," + ] + } + } + ] + }, + { + "PMID": "22983396", + "TEXT": "The discovery of potent inhibitors of the BRAF proto-oncogene has revolutionized therapy for melanoma harboring mutations in BRAF, yet NRAS-mutant melanoma remains without an effective therapy. Because direct pharmacological inhibition of the RAS proto-oncogene has thus far been unsuccessful, we explored systems biology approaches to identify synergistic drug combination(s) that can mimic RAS inhibition. Here, leveraging an inducible mouse model of NRAS-mutant melanoma, we show that pharmacological inhibition of mitogen-activated protein kinase kinase (MEK) activates apoptosis but not cell-cycle arrest, which is in contrast to complete genetic neuroblastoma RAS homolog (NRAS) extinction, which triggers both of these effects. Network modeling pinpointed cyclin-dependent kinase 4 (CDK4) as a key driver of this differential phenotype. Accordingly, combined pharmacological inhibition of MEK and CDK4 in vivo led to substantial synergy in therapeutic efficacy. We suggest a gradient model of oncogenic NRAS signaling in which the output is gated, resulting in the decoupling of discrete downstream biological phenotypes as a result of incomplete inhibition. Such a gated signaling model offers a new framework to identify nonobvious coextinction target(s) for combined pharmacological inhibition in NRAS-mutant melanomas.", + "TAG_DATA": [ + "57, inducible {'context': 'B-organism'}", + "58, mouse {'context': 'I-organism'}", + "59, model {'context': 'I-neoplasm'}", + "60, of {'context': 'I-neoplasm'}", + "61, NRAS-mutant {'context': 'I-organism'}", + "62, melanoma, {'context': 'I-neoplasm'}", + "66, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "67, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "68, of {'perturbing_action': 'I-pharmacological inhibition'}", + "69, mitogen-activated {'perturbing_action': 'I-pharmacological inhibition'}", + "70, protein {'perturbing_action': 'I-pharmacological inhibition'}", + "71, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "72, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "73, (MEK) {'perturbing_action': 'I-pharmacological inhibition'}", + "74, activates {'effect': 'B-positive'}", + "75, apoptosis {'phenotype': 'B-apoptosis'}", + "78, cell-cycle {'phenotype': 'B-cell cycle arrest'}", + "79, arrest, {'phenotype': 'I-cell cycle arrest'}", + "114, combined {'perturbing_action': 'B-pharmacological inhibition'}", + "115, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "116, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "117, of {'perturbing_action': 'I-pharmacological inhibition'}", + "118, MEK {'perturbing_action': 'I-pharmacological inhibition'}", + "119, and {'perturbing_action': 'I-pharmacological inhibition'}", + "120, CDK4 {'perturbing_action': 'I-pharmacological inhibition'}", + "121, in {'context': 'B-in vivo'}", + "122, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "57, inducible ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "58, mouse ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "59, model ['l1', 'l15', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "60, of ['l2', 'l16', 'l25', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "61, NRAS-mutant ['l3', 'l17', 'l26', 'l34', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "62, melanoma, ['l4', 'l18', 'l27', 'l35', 'l41', 'l53', 'l54', 'l55', 'l56']", + "66, pharmacological ['l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "67, inhibition ['l5', 'l42', 'l57', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "68, of ['l6', 'l43', 'l58', 'l68', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "69, mitogen-activated ['l7', 'l44', 'l59', 'l69', 'l78', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "70, protein ['l45', 'l60', 'l70', 'l79', 'l87', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "71, kinase ['l8', 'l46', 'l61', 'l71', 'l80', 'l88', 'l95', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "72, kinase ['l9', 'l19', 'l28', 'l47', 'l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l108', 'l109', 'l110', 'l111', 'l112']", + "73, (MEK) ['l10', 'l20', 'l29', 'l36', 'l48', 'l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l108', 'l113', 'l114', 'l115', 'l116']", + "74, activates ['l11', 'l21', 'l30', 'l37', 'l49', 'l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l109', 'l113', 'l117', 'l118', 'l119']", + "75, apoptosis ['l12', 'l22', 'l31', 'l38', 'l50', 'l54', 'l65', 'l75', 'l84', 'l92', 'l99', 'l105', 'l110', 'l114', 'l117', 'l120', 'l121']", + "78, cell-cycle ['l13', 'l23', 'l32', 'l39', 'l51', 'l55', 'l66', 'l76', 'l85', 'l93', 'l100', 'l106', 'l111', 'l115', 'l118', 'l120', 'l122']", + "79, arrest, ['l14', 'l24', 'l33', 'l40', 'l52', 'l56', 'l67', 'l77', 'l86', 'l94', 'l101', 'l107', 'l112', 'l116', 'l119', 'l121', 'l122']", + "114, combined ['l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "115, pharmacological ['l123', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "116, inhibition ['l124', 'l131', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "117, of ['l125', 'l132', 'l138', 'l144', 'l145', 'l146', 'l147', 'l148']", + "118, MEK ['l126', 'l133', 'l139', 'l144', 'l149', 'l150', 'l151', 'l152']", + "119, and ['l127', 'l134', 'l140', 'l145', 'l149', 'l153', 'l154', 'l155']", + "120, CDK4 ['l128', 'l135', 'l141', 'l146', 'l150', 'l153', 'l156', 'l157']", + "121, in ['l129', 'l136', 'l142', 'l147', 'l151', 'l154', 'l156', 'l158']", + "122, vivo ['l130', 'l137', 'l143', 'l148', 'l152', 'l155', 'l157', 'l158']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "inducible", + "mouse", + "NRAS-mutant" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "mitogen-activated", + "kinase", + "(MEK)", + "protein" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "inducible", + "mouse", + "NRAS-mutant" + ] + }, + "effect": { + "val": "positive", + "words": [ + "activates" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "inducible", + "mouse", + "NRAS-mutant" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "inducible", + "mouse", + "NRAS-mutant" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "model", + "of" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "kinase", + "(MEK)" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "model", + "of", + "melanoma," + ] + }, + "effect": { + "val": "positive", + "words": [ + "activates" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "model", + "of", + "melanoma," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "model", + "of", + "melanoma," + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "mitogen-activated", + "protein", + "kinase", + "(MEK)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "activates" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "mitogen-activated", + "protein", + "kinase", + "(MEK)" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "mitogen-activated", + "protein", + "kinase", + "(MEK)" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "activates" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "activates" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "combined", + "pharmacological", + "inhibition", + "of", + "MEK", + "and", + "CDK4" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "22961109", + "TEXT": "We examined mouse models with altered adipocyte expression of mitoNEET, a protein residing in the mitochondrial outer membrane, to probe its impact on mitochondrial function and subsequent cellular responses. We found that overexpression of mitoNEET enhances lipid uptake and storage, leading to an expansion of the mass of adipose tissue. Despite the resulting massive obesity, benign aspects of adipose tissue expansion prevail, and insulin sensitivity is preserved. Mechanistically, we also found that mitoNEET inhibits mitochondrial iron transport into the matrix and, because iron is a rate-limiting component for electron transport, lowers the rate of β-oxidation. This effect is associated with a lower mitochondrial membrane potential and lower levels of reactive oxygen species-induced damage, along with increased production of adiponectin. Conversely, a reduction in mitoNEET expression enhances mitochondrial respiratory capacity through enhanced iron content in the matrix, ultimately corresponding to less weight gain on a high-fat diet. However, this reduction in mitoNEET expression also causes heightened oxidative stress and glucose intolerance. Thus, manipulation of mitochondrial function by varying mitoNEET expression markedly affects the dynamics of cellular and whole-body lipid homeostasis.", + "TAG_DATA": [ + "32, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "33, of {'perturbing_action': 'I-gene gain-of-function'}", + "34, mitoNEET {'perturbing_action': 'I-gene gain-of-function'}", + "121, reduction {'perturbing_action': 'B-gene loss-of-function'}", + "122, in {'perturbing_action': 'I-gene loss-of-function'}", + "123, mitoNEET {'perturbing_action': 'I-gene loss-of-function'}", + "124, expression {'perturbing_action': 'I-gene loss-of-function'}", + "148, reduction {'perturbing_action': 'B-gene loss-of-function'}", + "149, in {'perturbing_action': 'I-gene loss-of-function'}", + "150, mitoNEET {'perturbing_action': 'I-gene loss-of-function'}", + "151, expression {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "32, overexpression ['l0', 'l1']", + "33, of ['l0', 'l2']", + "34, mitoNEET ['l1', 'l2']", + "121, reduction ['l3', 'l4', 'l5', 'l6']", + "122, in ['l3', 'l7', 'l8']", + "123, mitoNEET ['l4', 'l7', 'l9']", + "124, expression ['l5', 'l8', 'l9']", + "148, reduction ['l10', 'l11', 'l12']", + "149, in ['l10', 'l13', 'l14']", + "150, mitoNEET ['l11', 'l13', 'l15']", + "151, expression ['l6', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22961106", + "TEXT": "The role of skeletal muscle in nonshivering thermogenesis (NST) is not well understood. Here we show that sarcolipin (Sln), a newly identified regulator of the sarco/endoplasmic reticulum Ca(2+)-ATPase (Serca) pump, is necessary for muscle-based thermogenesis. When challenged to acute cold (4 °C), Sln(-/-) mice were not able to maintain their core body temperature (37 °C) and developed hypothermia. Surgical ablation of brown adipose tissue and functional knockdown of Ucp1 allowed us to highlight the role of muscle in NST. Overexpression of Sln in the Sln-null background fully restored muscle-based thermogenesis, suggesting that Sln is the basis for Serca-mediated heat production. We show that ryanodine receptor 1 (Ryr1)-mediated Ca(2+) leak is an important mechanism for Serca-activated heat generation. Here we present data to suggest that Sln can continue to interact with Serca in the presence of Ca(2+), which can promote uncoupling of the Serca pump and cause futile cycling. We further show that loss of Sln predisposes mice to diet-induced obesity, which suggests that Sln-mediated NST is recruited during metabolic overload. These data collectively suggest that SLN is an important mediator of muscle thermogenesis and whole-body energy metabolism.", + "TAG_DATA": [ + "42, Sln(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "43, mice {'context': 'B-organism'}", + "58, Surgical {'perturbing_action': 'B-gene loss-of-function'}", + "59, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "60, of {'perturbing_action': 'I-gene loss-of-function'}", + "61, brown {'perturbing_action': 'I-gene loss-of-function'}", + "62, adipose {'perturbing_action': 'I-gene loss-of-function'}", + "63, tissue {'perturbing_action': 'I-gene loss-of-function'}", + "65, functional {'perturbing_action': 'B-rnai/knockdown'}", + "66, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "67, of {'perturbing_action': 'I-rnai/knockdown'}", + "68, Ucp1 {'perturbing_action': 'I-rnai/knockdown'}", + "79, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "80, of {'perturbing_action': 'I-gene gain-of-function'}", + "81, Sln {'perturbing_action': 'I-gene gain-of-function'}", + "84, Sln-null {'perturbing_action': 'B-gene loss-of-function'}", + "152, loss {'perturbing_action': 'B-gene loss-of-function'}", + "153, of {'perturbing_action': 'I-gene loss-of-function'}", + "154, Sln {'perturbing_action': 'I-gene loss-of-function'}", + "156, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "42, Sln(-/-) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "43, mice ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "58, Surgical ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "59, ablation ['l2', 'l8', 'l13', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "60, of ['l3', 'l9', 'l14', 'l20', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "61, brown ['l4', 'l10', 'l15', 'l21', 'l26', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "62, adipose ['l5', 'l11', 'l16', 'l22', 'l27', 'l34', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "63, tissue ['l6', 'l12', 'l17', 'l23', 'l28', 'l35', 'l41', 'l47', 'l48']", + "65, functional ['l29', 'l36', 'l42', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "66, knockdown ['l30', 'l37', 'l43', 'l49', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "67, of ['l18', 'l24', 'l31', 'l38', 'l44', 'l47', 'l50', 'l56', 'l62', 'l63', 'l64', 'l65', 'l66']", + "68, Ucp1 ['l19', 'l25', 'l32', 'l39', 'l45', 'l48', 'l51', 'l57', 'l62', 'l67', 'l68', 'l69', 'l70']", + "79, Overexpression ['l52', 'l58', 'l63', 'l67', 'l71', 'l72', 'l73']", + "80, of ['l53', 'l59', 'l64', 'l68', 'l71', 'l74', 'l75']", + "81, Sln ['l54', 'l60', 'l65', 'l69', 'l72', 'l74', 'l76']", + "84, Sln-null ['l33', 'l40', 'l46', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l76']", + "152, loss ['l77', 'l78', 'l79']", + "153, of ['l77', 'l80', 'l81']", + "154, Sln ['l78', 'l80', 'l82']", + "156, mice ['l79', 'l81', 'l82']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sln(-/-)", + "Surgical", + "ablation", + "of", + "brown", + "adipose", + "tissue", + "loss", + "Sln" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "22941277", + "TEXT": "Despite the high inhibition of viral replication achieved by current anti-HIV drugs, many patients fail treatment, often with emergence of drug-resistant virus. Clinical observations show that the relationship between adherence and likelihood of resistance differs dramatically among drug classes. We developed a mathematical model that explains these observations and predicts treatment outcomes. Our model incorporates drug properties, fitness differences between susceptible and resistant strains, mutations and adherence. We show that antiviral activity falls quickly for drugs with sharp dose-response curves and short half-lives, such as boosted protease inhibitors, limiting the time during which resistance can be selected for. We find that poor adherence to such drugs causes treatment failure via growth of susceptible virus, explaining puzzling clinical observations. Furthermore, our model predicts that certain single-pill combination therapies can prevent resistance regardless of patient adherence. Our approach represents a first step for simulating clinical trials of untested anti-HIV regimens and may help in the selection of new drug regimens for investigation.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22922409", + "TEXT": "Complement is an ancient danger-sensing system that contributes to host defense, immune surveillance and homeostasis. C5a and its G protein–coupled receptor mediate many of the proinflammatory properties of complement. Despite the key role of C5a in allergic asthma, autoimmune arthritis, sepsis and cancer, knowledge about its regulation is limited. Here we demonstrate that IgG1 immune complexes (ICs), the inhibitory IgG receptor FcγRIIB and the C-type lectin–like receptor dectin-1 suppress C5a receptor (C5aR) functions. IgG1 ICs promote the association of FcγRIIB with dectin-1, resulting in phosphorylation of Src homology 2 domain–containing inositol phosphatase (SHIP) downstream of FcγRIIB and spleen tyrosine kinase downstream of dectin-1. This pathway blocks C5aR-mediated ERK1/2 phosphorylation, C5a effector functions in vitro and C5a-dependent inflammatory responses in vivo, including peritonitis and skin blisters in experimental epidermolysis bullosa acquisita. Notably, high galactosylation of IgG N-glycans is crucial for this inhibitory property of IgG1 ICs, as it promotes the association between FcγRIIB and dectin-1. Thus, galactosylated IgG1 and FcγRIIB exert anti-inflammatory properties beyond their impact on activating FcγRs.", + "TAG_DATA": [ + "112, in {'context': 'B-in vitro'}", + "113, vitro {'context': 'I-in vitro'}", + "118, in {'context': 'B-in vivo'}", + "119, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "112, in ['l0', 'l1', 'l2']", + "113, vitro ['l0', 'l3', 'l4']", + "118, in ['l1', 'l3', 'l5']", + "119, vivo, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22902876", + "TEXT": "Stem-cell function is an exquisitely regulated process. Thus far, the contribution of metabolic cues to stem-cell function has not been well understood. Here we identify a previously unknown promyelocytic leukemia (PML)–peroxisome proliferator-activated receptor δ (PPAR-δ)–fatty-acid oxidation (FAO) pathway for the maintenance of hematopoietic stem cells (HSCs). We have found that loss of PPAR-δ or inhibition of mitochondrial FAO induces loss of HSC maintenance, whereas treatment with PPAR-δ agonists improved HSC maintenance. PML exerts its essential role in HSC maintenance through regulation of PPAR signaling and FAO. Mechanistically, the PML–PPAR-δ–FAO pathway controls the asymmetric division of HSCs. Deletion of Ppard or Pml as well as inhibition of FAO results in the symmetric commitment of HSC daughter cells, whereas PPAR-δ activation increased asymmetric cell division. Thus, our findings identify a metabolic switch for the control of HSC cell fate with potential therapeutic implications.", + "TAG_DATA": [ + "50, loss {'perturbing_action': 'B-gene loss-of-function'}", + "51, of {'perturbing_action': 'I-gene loss-of-function'}", + "52, PPAR-δ {'perturbing_action': 'I-gene loss-of-function'}", + "54, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "55, of {'perturbing_action': 'I-pharmacological inhibition'}", + "56, mitochondrial {'perturbing_action': 'I-pharmacological inhibition'}", + "57, FAO {'perturbing_action': 'I-pharmacological inhibition'}", + "61, HSC {'context': 'B-transformed cells'}", + "66, PPAR-δ {'perturbing_action': 'B-pharmacological augmentation'}", + "67, agonists {'perturbing_action': 'I-pharmacological augmentation'}", + "69, HSC {'context': 'B-transformed cells'}", + "96, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "97, of {'perturbing_action': 'I-gene loss-of-function'}", + "98, Ppard {'perturbing_action': 'I-gene loss-of-function'}", + "99, or {'perturbing_action': 'I-gene loss-of-function'}", + "100, Pml {'perturbing_action': 'I-gene loss-of-function'}", + "104, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "106, FAO {'perturbing_action': 'I-pharmacological inhibition'}", + "113, HSC {'context': 'B-transformed cells'}", + "114, daughter {'context': 'I-cells'}", + "115, cells, {'context': 'I-cells'}", + "118, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "119, increased {'effect': 'B-positive'}", + "121, cell {'phenotype': 'B-proliferation'}", + "122, division. {'phenotype': 'I-proliferation'}" + ], + "LINK_DATA": [ + "50, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "51, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "52, PPAR-δ ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "54, inhibition ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21', 'l22']", + "55, of ['l3', 'l9', 'l14', 'l18', 'l23', 'l24', 'l25', 'l26']", + "56, mitochondrial ['l4', 'l10', 'l15', 'l19', 'l23', 'l27', 'l28', 'l29']", + "57, FAO ['l5', 'l11', 'l16', 'l20', 'l24', 'l27', 'l30', 'l31']", + "61, HSC ['l6', 'l12', 'l17', 'l21', 'l25', 'l28', 'l30']", + "66, PPAR-δ ['l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "67, agonists ['l32', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "69, HSC ['l22', 'l26', 'l29', 'l31', 'l33', 'l43']", + "96, Deletion ['l34', 'l44', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "97, of ['l35', 'l45', 'l53', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "98, Ppard ['l36', 'l46', 'l54', 'l65', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "99, or ['l37', 'l47', 'l55', 'l66', 'l76', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "100, Pml ['l38', 'l48', 'l56', 'l67', 'l77', 'l85', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "104, inhibition ['l57', 'l68', 'l78', 'l86', 'l93', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "106, FAO ['l39', 'l49', 'l58', 'l69', 'l79', 'l87', 'l94', 'l100', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "113, HSC ['l40', 'l50', 'l59', 'l70', 'l80', 'l88', 'l95', 'l101', 'l108', 'l114', 'l115']", + "114, daughter ['l41', 'l51', 'l60', 'l71', 'l81', 'l89', 'l96', 'l102', 'l109', 'l114', 'l116']", + "115, cells, ['l42', 'l52', 'l61', 'l72', 'l82', 'l90', 'l97', 'l103', 'l110', 'l115', 'l116']", + "118, activation ['l104', 'l117', 'l118', 'l119']", + "119, increased ['l62', 'l73', 'l105', 'l111', 'l117', 'l120', 'l121']", + "121, cell ['l63', 'l74', 'l83', 'l91', 'l98', 'l106', 'l112', 'l118', 'l120', 'l122']", + "122, division. ['l64', 'l75', 'l84', 'l92', 'l99', 'l107', 'l113', 'l119', 'l121', 'l122']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "PPAR-δ", + "Deletion", + "Ppard", + "or", + "Pml" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "mitochondrial", + "FAO" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "PPAR-δ", + "agonists" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "PPAR-δ", + "agonists" + ] + }, + "context": { + "val": "cells", + "words": [ + "daughter", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "Ppard", + "or", + "Pml" + ] + }, + "context": { + "val": "cells", + "words": [ + "daughter", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "Ppard", + "or", + "Pml" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "FAO" + ] + }, + "context": { + "val": "cells", + "words": [ + "daughter", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "FAO" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "FAO" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division." + ] + } + } + ] + }, + { + "PMID": "22863785", + "TEXT": "T cell immunoglobulin and mucin domain–containing 3 (Tim-3) is an inhibitory receptor that is expressed on exhausted T cells during infection with HIV-1 and hepatitis C virus. By contrast, Tim-3 expression and function are defective in multiple human autoimmune diseases. However, the molecular mechanisms modulating Tim-3 function are not well understood. Here we show that human leukocyte antigen B (HLA-B)-associated transcript 3 (Bat3) binds to, and represses the function of, Tim-3. Bat3 protects T helper type 1 (TH1) cells from galectin-9–mediated cell death and promotes both proliferation and proinflammatory cytokine production. Bat3-deficient T cells have elevated expression of exhaustion-associated molecules such as Tim-3, Lag3, Prdm1 and Pbx3, and Bat3 knockdown in myelin-antigen–specific CD4+ T cells markedly inhibits the development of experimental autoimmune encephalomyelitis while promoting the expansion of a dysfunctional Tim-3hi, interferon-γ (IFN-γ)loCD4+ cell population. Furthermore, expression of Bat3 is reduced in exhausted Tim-3+ T cells from mouse tumors and HIV-1–infected individuals. These data indicate that Bat3 acts as an inhibitor of Tim-3–dependent exhaustion and cell death. Bat3 may thus represent a viable therapeutic target in autoimmune disorders, chronic infections and cancers.", + "TAG_DATA": [ + "73, T {'context': 'B-cells'}", + "74, helper {'context': 'I-cells'}", + "75, type {'context': 'I-cells'}", + "76, 1 {'context': 'I-cells'}", + "77, (TH1) {'context': 'I-cells'}", + "78, cells {'context': 'I-cells'}", + "81, cell {'phenotype': 'B-cell death'}", + "82, death {'phenotype': 'I-cell death'}", + "84, promotes {'effect': 'B-positive'}", + "86, proliferation {'phenotype': 'B-proliferation'}", + "91, Bat3-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "92, T {'context': 'B-cells'}", + "93, cells {'context': 'I-cells'}", + "108, Bat3 {'perturbing_action': 'B-rnai/knockdown'}", + "109, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "111, myelin-antigen–specific {'context': 'B-cells'}", + "112, CD4+ {'context': 'I-cells'}", + "113, T {'context': 'I-cells'}", + "114, cells {'context': 'I-cells'}", + "133, cell {'context': 'I-cells'}", + "134, population. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "73, T ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "74, helper ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "75, type ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "76, 1 ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "77, (TH1) ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "78, cells ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "81, cell ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "82, death ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "84, promotes ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "86, proliferation ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "91, Bat3-deficient ['l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "92, T ['l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "93, cells ['l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "108, Bat3 ['l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "109, knockdown ['l60', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "111, myelin-antigen–specific ['l47', 'l52', 'l56', 'l61', 'l67', 'l73', 'l74', 'l75', 'l76', 'l77']", + "112, CD4+ ['l48', 'l53', 'l57', 'l62', 'l68', 'l73', 'l78', 'l79', 'l80', 'l81']", + "113, T ['l49', 'l54', 'l58', 'l63', 'l69', 'l74', 'l78', 'l82']", + "114, cells ['l50', 'l55', 'l59', 'l64', 'l70', 'l75', 'l79', 'l82']", + "133, cell ['l65', 'l71', 'l76', 'l80', 'l83']", + "134, population. ['l66', 'l72', 'l77', 'l81', 'l83']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "helper", + "type", + "1", + "(TH1)", + "cells" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "helper", + "type", + "1", + "(TH1)", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "helper", + "type", + "1", + "(TH1)", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bat3-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "myelin-antigen–specific", + "CD4+" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Bat3", + "knockdown" + ] + }, + "context": { + "val": "cells", + "words": [ + "myelin-antigen–specific", + "CD4+", + "T", + "cells", + "cell", + "population." + ] + } + } + ] + }, + { + "PMID": "22842476", + "TEXT": "Profibrotic cells that develop upon injury generate permanent scar tissue and impair organ recovery, though their origin and fate are unclear. Here we show that transient expression of ADAM12 (a disintegrin and metalloprotease 12) identifies a distinct proinflammatory subset of platelet-derived growth factor receptor-α-positive stromal cells that are activated upon acute injury in the muscle and dermis. By inducible genetic fate mapping, we demonstrate in vivo that injury-induced ADAM12(+) cells are specific progenitors of a major fraction of collagen-overproducing cells generated during scarring, which are progressively eliminated during healing. Genetic ablation of ADAM12(+) cells, or knockdown of ADAM12, is sufficient to limit generation of profibrotic cells and interstitial collagen accumulation. ADAM12(+) cells induced upon injury are developmentally distinct from muscle and skin lineage cells and are derived from fetal ADAM12(+) cells programmed during vascular wall development. Thus, our data identify injury-activated profibrotic progenitors residing in the perivascular space that can be targeted through ADAM12 to limit tissue scarring.", + "TAG_DATA": [ + "64, in {'context': 'B-in vivo'}", + "65, vivo {'context': 'I-in vivo'}", + "89, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "90, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "92, ADAM12(+) {'context': 'B-cells'}", + "93, cells, {'context': 'I-cells'}", + "95, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "96, of {'perturbing_action': 'I-rnai/knockdown'}", + "97, ADAM12, {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "64, in ['l0']", + "65, vivo ['l0']", + "89, Genetic ['l1', 'l2', 'l3']", + "90, ablation ['l1', 'l4', 'l5']", + "92, ADAM12(+) ['l2', 'l4', 'l6']", + "93, cells, ['l3', 'l5', 'l6']", + "95, knockdown ['l7', 'l8']", + "96, of ['l7', 'l9']", + "97, ADAM12, ['l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "ablation" + ] + }, + "context": { + "val": "cells", + "words": [ + "ADAM12(+)", + "cells," + ] + } + } + ] + }, + { + "PMID": "22820645", + "TEXT": "Primary astrocytomas of grade 3 or 4 according to the classification system of the World Health Organization (high-grade astrocytomas or HGAs) are preponderant among adults and are almost invariably fatal despite the use of multimodal therapy. Here we show that the juvenile brain has an endogenous defense mechanism against HGAs. Neural precursor cells (NPCs) migrate to HGAs, reduce glioma expansion and prolong survival time by releasing endovanilloids that activate the vanilloid receptor (transient receptor potential vanilloid subfamily member-1 or TRPV1) on HGA cells. TRPV1 is highly expressed in tumor and weakly expressed in tumor-free brain. TRPV1 stimulation triggers tumor cell death through the branch of the endoplasmic reticulum stress pathway that is controlled by activating transcription factor-3 (ATF3). The antitumorigenic response of NPCs is lost with aging. NPC-mediated tumor suppression can be mimicked in the adult brain by systemic administration of the synthetic vanilloid arvanil, suggesting that TRPV1 agonists have potential as new HGA therapeutics.", + "TAG_DATA": [ + "50, Neural {'context': 'B-cells'}", + "51, precursor {'context': 'I-cells'}", + "52, cells {'context': 'I-cells'}", + "58, glioma {'context': 'B-neoplasm'}", + "81, HGA {'context': 'B-transformed cells'}", + "82, cells. {'context': 'I-transformed cells'}", + "97, triggers {'effect': 'B-positive'}", + "98, tumor {'context': 'B-neoplasm'}", + "99, cell {'phenotype': 'B-cell death'}", + "100, death {'phenotype': 'I-cell death'}", + "122, NPCs {'context': 'B-cells'}", + "135, adult {'context': 'B-tissue/organ'}", + "136, brain {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "50, Neural ['l0', 'l1', 'l2', 'l3', 'l4']", + "51, precursor ['l0', 'l5', 'l6', 'l7', 'l8']", + "52, cells ['l1', 'l5', 'l9', 'l10', 'l11']", + "58, glioma ['l2', 'l6', 'l9', 'l12']", + "81, HGA ['l3', 'l7', 'l10', 'l13']", + "82, cells. ['l4', 'l8', 'l11', 'l12', 'l13']", + "97, triggers ['l14', 'l15', 'l16']", + "98, tumor ['l14', 'l17', 'l18']", + "99, cell ['l15', 'l17', 'l19']", + "100, death ['l16', 'l18', 'l19']", + "122, NPCs ['l20', 'l21']", + "135, adult ['l20', 'l22']", + "136, brain ['l21', 'l22']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + } + ] + }, + { + "PMID": "22820643", + "TEXT": "The inactivation of the p53 tumor suppressor pathway, which often occurs through mutations in TP53 (encoding tumor protein 53) is a common step in human cancer. However, in melanoma-a highly chemotherapy-resistant disease-TP53 mutations are rare, raising the possibility that this cancer uses alternative ways to overcome p53-mediated tumor suppression. Here we show that Mdm4 p53 binding protein homolog (MDM4), a negative regulator of p53, is upregulated in a substantial proportion (∼65%) of stage I-IV human melanomas and that melanocyte-specific Mdm4 overexpression enhanced tumorigenesis in a mouse model of melanoma induced by the oncogene Nras. MDM4 promotes the survival of human metastatic melanoma by antagonizing p53 proapoptotic function. Notably, inhibition of the MDM4-p53 interaction restored p53 function in melanoma cells, resulting in increased sensitivity to cytotoxic chemotherapy and to inhibitors of the BRAF (V600E) oncogene. Our results identify MDM4 as a key determinant of impaired p53 function in human melanoma and designate MDM4 as a promising target for antimelanoma combination therapy.", + "TAG_DATA": [ + "78, melanocyte-specific {'perturbing_action': 'B-gene gain-of-function'}", + "79, Mdm4 {'perturbing_action': 'I-gene gain-of-function'}", + "80, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "81, enhanced {'effect': 'B-positive'}", + "82, tumorigenesis {'phenotype': 'B-tumourigenesis'}", + "85, mouse {'context': 'B-neoplasm'}", + "86, model {'context': 'I-neoplasm'}", + "87, of {'context': 'I-neoplasm'}", + "88, melanoma {'context': 'I-neoplasm'}", + "89, induced {'effect': 'B-positive'}", + "99, human {'context': 'B-neoplasm'}", + "100, metastatic {'context': 'I-neoplasm'}", + "101, melanoma {'context': 'I-neoplasm'}", + "117, melanoma {'context': 'B-transformed cells'}", + "118, cells, {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "78, melanocyte-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "79, Mdm4 ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "80, overexpression ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "81, enhanced ['l2', 'l10', 'l17', 'l24']", + "82, tumorigenesis ['l3', 'l11', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "85, mouse ['l4', 'l12', 'l19', 'l25', 'l30', 'l31', 'l32', 'l33']", + "86, model ['l5', 'l13', 'l20', 'l26', 'l30', 'l34', 'l35', 'l36', 'l37']", + "87, of ['l6', 'l14', 'l21', 'l27', 'l31', 'l34', 'l38', 'l39', 'l40']", + "88, melanoma ['l7', 'l15', 'l22', 'l28', 'l32', 'l35', 'l38', 'l41', 'l42', 'l43', 'l44']", + "89, induced ['l8', 'l16', 'l23', 'l29', 'l33', 'l36', 'l39', 'l41', 'l45', 'l46', 'l47']", + "99, human ['l42', 'l45', 'l48', 'l49']", + "100, metastatic ['l43', 'l46', 'l48', 'l50']", + "101, melanoma ['l37', 'l40', 'l44', 'l47', 'l49', 'l50']", + "117, melanoma ['l51']", + "118, cells, ['l51']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "melanocyte-specific", + "Mdm4", + "overexpression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced", + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "melanocyte-specific", + "Mdm4", + "overexpression" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "melanocyte-specific", + "Mdm4", + "overexpression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "melanoma" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced", + "induced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "melanoma" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "melanoma", + "human", + "metastatic" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "22820642", + "TEXT": "Breast cancer metastasis is a key determinant of long-term patient survival. By comparing the transcriptomes of primary and metastatic tumor cells in a mouse model of spontaneous bone metastasis, we found that a substantial number of genes suppressed in bone metastases are targets of the interferon regulatory factor Irf7. Restoration of Irf7 in tumor cells or administration of interferon led to reduced bone metastases and prolonged survival time. In mice deficient in the interferon (IFN) receptor or in natural killer (NK) and CD8(+) T cell responses, metastasis was accelerated, indicating that Irf7-driven suppression of metastasis was reliant on IFN signaling to host immune cells. We confirmed the clinical relevance of these findings in over 800 patients in which high expression of Irf7-regulated genes in primary tumors was associated with prolonged bone metastasis-free survival. This gene signature may identify patients that could benefit from IFN-based therapies. Thus, we have identified an innate immune pathway intrinsic to breast cancer cells, the suppression of which restricts immunosurveillance to enable metastasis.", + "TAG_DATA": [ + "23, mouse {'context': 'B-organism'}", + "24, model {'context': 'I-organism'}", + "49, Restoration {'perturbing_action': 'B-gene gain-of-function'}", + "50, of {'perturbing_action': 'I-gene gain-of-function'}", + "51, Irf7 {'perturbing_action': 'I-gene gain-of-function'}", + "53, tumor {'context': 'B-transformed cells'}", + "54, cells {'context': 'I-transformed cells'}", + "61, reduced {'effect': 'B-negative'}", + "62, bone {'phenotype': 'B-metastasis'}", + "63, metastases {'phenotype': 'I-metastasis'}", + "69, mice {'context': 'B-organism'}", + "70, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "71, in {'perturbing_action': 'I-gene loss-of-function'}", + "72, the {'perturbing_action': 'I-gene loss-of-function'}", + "86, metastasis {'phenotype': 'B-metastasis'}", + "88, accelerated, {'effect': 'B-positive'}" + ], + "LINK_DATA": [ + "23, mouse ['l0', 'l1', 'l2', 'l3']", + "24, model ['l0', 'l4', 'l5', 'l6']", + "49, Restoration ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "50, of ['l7', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "51, Irf7 ['l8', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "53, tumor ['l9', 'l15', 'l20', 'l25', 'l26', 'l27', 'l28']", + "54, cells ['l10', 'l16', 'l21', 'l25', 'l29', 'l30', 'l31']", + "61, reduced ['l1', 'l4', 'l11', 'l17', 'l22', 'l26', 'l29', 'l32', 'l33']", + "62, bone ['l2', 'l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l32', 'l34']", + "63, metastases ['l3', 'l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l34']", + "69, mice ['l35', 'l36', 'l37', 'l38', 'l39']", + "70, deficient ['l35', 'l40', 'l41', 'l42', 'l43']", + "71, in ['l36', 'l40', 'l44', 'l45', 'l46']", + "72, the ['l37', 'l41', 'l44', 'l47', 'l48']", + "86, metastasis ['l38', 'l42', 'l45', 'l47', 'l49']", + "88, accelerated, ['l39', 'l43', 'l46', 'l48', 'l49']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "mice" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "bone", + "metastases", + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoration", + "of", + "Irf7" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoration", + "of", + "Irf7" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoration", + "of", + "Irf7" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "bone", + "metastases" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "bone", + "metastases" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "bone", + "metastases" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "the" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerated," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "the" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "the" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerated," + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerated," + ] + } + } + ] + }, + { + "PMID": "22797810", + "TEXT": "Temporal lobe epilepsy (TLE) is accompanied by an abnormal location of granule cells in the dentate gyrus. Using a rat model of complex febrile seizures, which are thought to be a precipitating insult of TLE later in life, we report that aberrant migration of neonatal-generated granule cells results in granule cell ectopia that persists into adulthood. Febrile seizures induced an upregulation of GABA(A) receptors (GABA(A)-Rs) in neonatally generated granule cells, and hyperactivation of excitatory GABA(A)-Rs caused a reversal in the direction of granule cell migration. This abnormal migration was prevented by RNAi-mediated knockdown of the Na(+)K(+)2Cl(-) co-transporter (NKCC1), which regulates the excitatory action of GABA. NKCC1 inhibition with bumetanide after febrile seizures rescued the granule cell ectopia, susceptibility to limbic seizures and development of epilepsy. Thus, this work identifies a previously unknown pathogenic role of excitatory GABA(A)-R signaling and highlights NKCC1 as a potential therapeutic target for preventing granule cell ectopia and the development of epilepsy after febrile seizures.", + "TAG_DATA": [ + "44, neonatal-generated {'context': 'B-cells'}", + "45, granule {'context': 'I-cells'}", + "46, cells {'context': 'I-cells'}", + "66, neonatally {'context': 'B-cells'}", + "67, generated {'context': 'B-cells'}", + "68, granule {'context': 'I-cells'}", + "69, cells, {'context': 'I-cells'}", + "82, granule {'context': 'B-cells'}", + "83, cell {'context': 'I-cells'}", + "84, migration. {'phenotype': 'B-migration'}", + "87, migration {'phenotype': 'B-migration'}", + "91, RNAi-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "92, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "93, of {'perturbing_action': 'I-rnai/knockdown'}", + "94, the {'perturbing_action': 'I-rnai/knockdown'}", + "95, Na(+)K(+)2Cl(-) {'perturbing_action': 'I-rnai/knockdown'}", + "96, co-transporter {'perturbing_action': 'I-rnai/knockdown'}", + "97, (NKCC1), {'perturbing_action': 'I-rnai/knockdown'}", + "105, NKCC1 {'perturbing_action': 'B-pharmacological inhibition'}", + "106, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "107, with {'perturbing_action': 'I-pharmacological inhibition'}", + "108, bumetanide {'perturbing_action': 'I-pharmacological inhibition'}", + "112, rescued {'effect': 'B-rescues'}", + "114, granule {'context': 'B-cells'}", + "115, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "44, neonatal-generated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "45, granule ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "46, cells ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "66, neonatally ['l2', 'l10', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "67, generated ['l3', 'l11', 'l18', 'l23', 'l30', 'l31', 'l32', 'l33', 'l34']", + "68, granule ['l4', 'l12', 'l19', 'l24', 'l30', 'l35', 'l36', 'l37', 'l38']", + "69, cells, ['l5', 'l13', 'l20', 'l25', 'l31', 'l35', 'l39', 'l40', 'l41']", + "82, granule ['l6', 'l14', 'l26', 'l32', 'l36', 'l39', 'l42', 'l43', 'l44']", + "83, cell ['l7', 'l15', 'l21', 'l27', 'l33', 'l37', 'l40', 'l42', 'l45']", + "84, migration. ['l8', 'l16', 'l22', 'l28', 'l34', 'l38', 'l41', 'l43', 'l45']", + "87, migration ['l29', 'l44']", + "91, RNAi-mediated ['l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "92, knockdown ['l46', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "93, of ['l47', 'l53', 'l59', 'l60', 'l61', 'l62', 'l63']", + "94, the ['l48', 'l54', 'l59', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "95, Na(+)K(+)2Cl(-) ['l49', 'l55', 'l60', 'l64', 'l70', 'l71', 'l72', 'l73', 'l74']", + "96, co-transporter ['l50', 'l56', 'l61', 'l65', 'l70', 'l75', 'l76', 'l77', 'l78']", + "97, (NKCC1), ['l51', 'l57', 'l62', 'l66', 'l71', 'l75', 'l79', 'l80']", + "105, NKCC1 ['l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "106, inhibition ['l81', 'l87', 'l88', 'l89', 'l90', 'l91']", + "107, with ['l82', 'l87', 'l92', 'l93', 'l94', 'l95']", + "108, bumetanide ['l83', 'l88', 'l92', 'l96', 'l97', 'l98']", + "112, rescued ['l67', 'l72', 'l76', 'l84', 'l89', 'l93', 'l96', 'l99', 'l100']", + "114, granule ['l68', 'l73', 'l77', 'l79', 'l85', 'l90', 'l94', 'l97', 'l99', 'l101']", + "115, cell ['l52', 'l58', 'l63', 'l69', 'l74', 'l78', 'l80', 'l86', 'l91', 'l95', 'l98', 'l100', 'l101']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "neonatal-generated", + "granule", + "cells", + "neonatally", + "generated", + "cells,", + "cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration.", + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "RNAi-mediated", + "knockdown", + "of", + "the", + "Na(+)K(+)2Cl(-)", + "co-transporter", + "(NKCC1)," + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "granule" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "the", + "Na(+)K(+)2Cl(-)", + "co-transporter" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NKCC1", + "inhibition", + "with", + "bumetanide" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NKCC1", + "inhibition", + "with", + "bumetanide" + ] + }, + "context": { + "val": "cells", + "words": [ + "granule", + "cell" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "context": { + "val": "cells", + "words": [ + "granule", + "cell" + ] + } + } + ] + }, + { + "PMID": "22772552", + "TEXT": "Endometriosis is an estrogen-dependent disease. The biologically active estrogen, estradiol, aggravates the pathological processes (e.g., inflammation and growth) and the symptoms (e.g., pain) associated with endometriosis. Abundant quantities of estradiol are available for endometriotic tissue via several mechanisms including local aromatase expression. The question remains, then, what mediates estradiol action. Because estrogen receptor (ER)β levels in endometriosis are >100 times higher than those in endometrial tissue, this review focuses on this nuclear receptor. Deficient methylation of the ERβ promoter results in pathological overexpression of ERβ in endometriotic stromal cells. High levels of ERβ suppress ERα expression. A severely high ERβ-to-ERα ratio in endometriotic stromal cells is associated with suppressed progesterone receptor and increased cyclo-oxygenase-2 levels contributing to progesterone resistance and inflammation. ERβ-selective estradiol antagonists may serve as novel therapeutics of endometriosis in the future.", + "TAG_DATA": [ + "86, endometriotic {'context': 'B-cells'}", + "87, stromal {'context': 'I-cells'}", + "88, cells. {'context': 'I-cells'}", + "102, endometriotic {'context': 'B-cells'}", + "103, stromal {'context': 'I-cells'}", + "104, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "86, endometriotic ['l0', 'l1']", + "87, stromal ['l0', 'l2']", + "88, cells. ['l1', 'l2']", + "102, endometriotic ['l3', 'l4']", + "103, stromal ['l3', 'l5']", + "104, cells ['l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22772464", + "TEXT": "Interleukin-9 (IL-9) is a T cell cytokine that acts through a γC-family receptor on target cells and is associated with inflammation and allergy. We determined that T cells from mice deficient in the T helper type 17 (T(H)17) pathway genes encoding retinoid-related orphan receptor γ (ROR-γ) and IL-23 receptor (IL-23R) produced abundant IL-9, and we found substantial growth inhibition of B16F10 melanoma in these mice. IL-9-blocking antibodies reversed this tumor growth inhibition and enhanced tumor growth in wild-type (WT) mice. Il9r(-/-) mice showed accelerated tumor growth, and administration of recombinant IL-9 (rIL-9) to tumor-bearing WT and Rag1(-/-) mice inhibited melanoma as well as lung carcinoma growth. Adoptive transfer of tumor-antigen-specific T(H)9 cells into both WT and Rag1(-/-) mice suppressed melanoma growth; this effect was abrogated by treatment with neutralizing antibodies to IL-9. Exogenous rIL-9 inhibited tumor growth in Rag1(-/-) mice but not in mast-cell-deficient mice, suggesting that the targets of IL-9 in this setting include mast cells but not T or B cells. In addition, we found higher numbers of T(H)9 cells in normal human skin and blood compared to metastatic lesions of subjects with progressive stage IV melanoma. These results suggest a role for IL-9 in tumor immunity and offer insight into potential therapeutic strategies.", + "TAG_DATA": [ + "26, T {'context': 'B-cells'}", + "27, cells {'context': 'B-cells'}", + "29, mice {'context': 'B-organism'}", + "60, B16F10 {'context': 'B-neoplasm'}", + "61, melanoma {'context': 'I-neoplasm'}", + "64, mice. {'context': 'B-organism'}", + "67, reversed {'effect': 'B-rescues'}", + "69, tumor {'phenotype': 'B-tumour growth'}", + "70, growth {'phenotype': 'I-tumour growth'}", + "71, inhibition {'effect': 'B-negative'}", + "73, enhanced {'effect': 'B-positive'}", + "74, tumor {'phenotype': 'B-tumour growth'}", + "75, growth {'phenotype': 'I-tumour growth'}", + "79, mice. {'context': 'B-organism'}", + "80, Il9r(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "81, mice {'context': 'B-organism'}", + "83, accelerated {'effect': 'B-positive'}", + "84, tumor {'phenotype': 'B-tumour growth'}", + "85, growth, {'phenotype': 'I-tumour growth'}", + "94, WT {'context': 'I-organism'}", + "96, Rag1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "97, mice {'context': 'B-organism'}", + "98, inhibited {'effect': 'B-negative'}", + "99, melanoma {'context': 'B-neoplasm'}", + "103, lung {'context': 'B-neoplasm'}", + "104, carcinoma {'context': 'I-neoplasm'}", + "110, T(H)9 {'context': 'I-cells'}", + "111, cells {'context': 'I-cells'}", + "116, Rag1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "117, mice {'context': 'B-organism'}", + "118, suppressed {'effect': 'B-negative'}", + "119, melanoma {'context': 'B-neoplasm'}", + "134, inhibited {'effect': 'B-negative'}", + "135, tumor {'phenotype': 'B-tumour growth'}", + "136, growth {'phenotype': 'I-tumour growth'}", + "138, Rag1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "139, mice {'context': 'B-organism'}", + "143, mast-cell-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "144, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "26, T ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "27, cells ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "29, mice ['l1', 'l12', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "60, B16F10 ['l2', 'l13', 'l24', 'l35', 'l36', 'l37', 'l38', 'l39']", + "61, melanoma ['l3', 'l14', 'l25', 'l35', 'l40']", + "64, mice. ['l4', 'l15', 'l26', 'l36', 'l40', 'l41', 'l42']", + "67, reversed ['l5', 'l16', 'l27', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "69, tumor ['l6', 'l17', 'l28', 'l37', 'l41', 'l43', 'l50', 'l51', 'l52']", + "70, growth ['l7', 'l18', 'l29', 'l38', 'l42', 'l44', 'l50', 'l53', 'l54', 'l55']", + "71, inhibition ['l8', 'l19', 'l30', 'l39', 'l45', 'l51', 'l53', 'l56', 'l57']", + "73, enhanced ['l9', 'l20', 'l31', 'l46', 'l58', 'l59', 'l60']", + "74, tumor ['l10', 'l21', 'l32', 'l47', 'l54', 'l56', 'l58', 'l61']", + "75, growth ['l11', 'l22', 'l33', 'l48', 'l52', 'l55', 'l57', 'l59', 'l61']", + "79, mice. ['l23', 'l34', 'l49', 'l60']", + "80, Il9r(-/-) ['l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "81, mice ['l62', 'l73', 'l74', 'l75', 'l76']", + "83, accelerated ['l63', 'l73', 'l77', 'l78']", + "84, tumor ['l64', 'l74', 'l77', 'l79']", + "85, growth, ['l65', 'l75', 'l78', 'l79']", + "93, tumor-bearing ['l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "94, WT ['l66', 'l80', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "96, Rag1(-/-) ['l67', 'l81', 'l87', 'l93', 'l94', 'l95', 'l96', 'l97']", + "97, mice ['l68', 'l82', 'l88', 'l93', 'l98', 'l99', 'l100', 'l101']", + "98, inhibited ['l69', 'l83', 'l89', 'l94', 'l98', 'l102', 'l103', 'l104']", + "99, melanoma ['l70', 'l76', 'l84', 'l90', 'l95', 'l99', 'l102', 'l105', 'l106']", + "103, lung ['l71', 'l85', 'l91', 'l96', 'l100', 'l103', 'l105', 'l107']", + "104, carcinoma ['l72', 'l86', 'l92', 'l97', 'l101', 'l104', 'l106', 'l107']", + "110, T(H)9 ['l108', 'l109', 'l110', 'l111', 'l112']", + "111, cells ['l108', 'l113', 'l114', 'l115', 'l116']", + "116, Rag1(-/-) ['l109', 'l113', 'l117', 'l118', 'l119']", + "117, mice ['l110', 'l114', 'l117', 'l120', 'l121']", + "118, suppressed ['l111', 'l115', 'l118', 'l120', 'l122']", + "119, melanoma ['l112', 'l116', 'l119', 'l121', 'l122']", + "134, inhibited ['l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "135, tumor ['l123', 'l129', 'l130', 'l131', 'l132', 'l133']", + "136, growth ['l124', 'l129', 'l134', 'l135', 'l136', 'l137']", + "138, Rag1(-/-) ['l125', 'l130', 'l134', 'l138', 'l139', 'l140']", + "139, mice ['l126', 'l131', 'l135', 'l138', 'l141', 'l142']", + "143, mast-cell-deficient ['l127', 'l132', 'l136', 'l139', 'l141', 'l143']", + "144, mice, ['l128', 'l133', 'l137', 'l140', 'l142', 'l143']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "reversed" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "T(H)9" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition", + "suppressed" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "effect": { + "val": "rescues", + "words": [ + "reversed" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "mice," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth", + "growth," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "WT", + "mice," + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition", + "inhibited", + "suppressed" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced", + "accelerated" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "B16F10" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "B16F10", + "melanoma", + "lung", + "carcinoma" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition", + "inhibited", + "suppressed" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "reversed" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition", + "inhibited" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced", + "accelerated" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth", + "growth," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Il9r(-/-)", + "Rag1(-/-)", + "mast-cell-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "WT", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Il9r(-/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerated" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Il9r(-/-)", + "Rag1(-/-)", + "mast-cell-deficient" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth,", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Il9r(-/-)", + "Rag1(-/-)", + "mast-cell-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Il9r(-/-)", + "Rag1(-/-)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "melanoma", + "lung", + "carcinoma" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T(H)9", + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rag1(-/-)" + ] + } + } + ] + }, + { + "PMID": "22729284", + "TEXT": "Embryo implantation remains a poorly understood process. We demonstrate here that activation of the epithelial Na⁺ channel (ENaC) in mouse endometrial epithelial cells by an embryo-released serine protease, trypsin, triggers Ca²⁺ influx that leads to prostaglandin E₂ (PGE₂) release, phosphorylation of the transcription factor CREB and upregulation of cyclooxygenase 2, the enzyme required for prostaglandin production and implantation. We detected maximum ENaC activation, as indicated by ENaC cleavage, at the time of implantation in mice. Blocking or knocking down uterine ENaC in mice resulted in implantation failure. Furthermore, we found that uterine ENaC expression before in vitro fertilization (IVF) treatment is markedly lower in women with implantation failure as compared to those with successful pregnancy. These results indicate a previously undefined role of ENaC in regulating the PGE₂ production and release required for embryo implantation, defects that may be a cause of miscarriage and low success rates in IVF.", + "TAG_DATA": [ + "19, mouse {'context': 'B-cells'}", + "20, endometrial {'context': 'I-cells'}", + "21, epithelial {'context': 'I-cells'}", + "22, cells {'context': 'I-cells'}", + "74, mice. {'context': 'B-organism'}", + "77, knocking {'perturbing_action': 'B-rnai/knockdown'}", + "78, down {'perturbing_action': 'I-rnai/knockdown'}", + "79, uterine {'perturbing_action': 'I-rnai/knockdown'}", + "80, ENaC {'perturbing_action': 'I-rnai/knockdown'}", + "82, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "19, mouse ['l0', 'l1', 'l2', 'l3']", + "20, endometrial ['l0', 'l4', 'l5', 'l6']", + "21, epithelial ['l1', 'l4', 'l7', 'l8']", + "22, cells ['l2', 'l5', 'l7', 'l9']", + "74, mice. ['l3', 'l6', 'l8', 'l9']", + "77, knocking ['l10', 'l11', 'l12', 'l13', 'l14']", + "78, down ['l10', 'l15', 'l16', 'l17', 'l18']", + "79, uterine ['l11', 'l15', 'l19', 'l20', 'l21']", + "80, ENaC ['l12', 'l16', 'l19', 'l22', 'l23']", + "82, mice ['l13', 'l17', 'l20', 'l22', 'l24']", + "85, implantation ['l14', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knocking", + "down", + "uterine", + "ENaC" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "22729283", + "TEXT": "Insulin-like growth factor 1 (IGF-1), the most abundant growth factor in the bone matrix, maintains bone mass in adulthood. We now report that IGF-1 released from the bone matrix during bone remodeling stimulates osteoblastic differentiation of recruited mesenchymal stem cells (MSCs) by activation of mammalian target of rapamycin (mTOR), thus maintaining proper bone microarchitecture and mass. Mice with knockout of the IGF-1 receptor (Igf1r) in their pre-osteoblastic cells showed lower bone mass and mineral deposition rates than wild-type mice. Further, MSCs from Igf1rflox/flox mice with Igf1r deleted by a Cre adenovirus in vitro, although recruited to the bone surface after implantation, were unable to differentiate into osteoblasts. We also found that the concentrations of IGF-1 in the bone matrix and marrow of aged rats were lower than in those of young rats and directly correlated with the age-related decrease in bone mass. Likewise, in age-related osteoporosis in humans, we found that bone marrow IGF-1 concentrations were 40% lower in individuals with osteoporosis than in individuals without osteoporosis. Notably, injection of IGF-1 plus IGF binding protein 3 (IGFBP3), but not injection of IGF-1 alone, increased the concentration of IGF-1 in the bone matrix and stimulated new bone formation in aged rats. Together, these results provide mechanistic insight into how IGF-1 maintains adult bone mass, while also providing a further rationale for its therapeutic targeting to treat age-related osteoporosis.", + "TAG_DATA": [ + "56, Mice {'context': 'B-organism'}", + "58, knockout {'perturbing_action': 'B-gene loss-of-function'}", + "59, of {'perturbing_action': 'I-gene loss-of-function'}", + "60, the {'perturbing_action': 'I-gene loss-of-function'}", + "61, IGF-1 {'perturbing_action': 'I-gene loss-of-function'}", + "62, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "63, (Igf1r) {'perturbing_action': 'I-gene loss-of-function'}", + "66, pre-osteoblastic {'context': 'B-cells'}", + "67, cells {'context': 'I-cells'}", + "78, mice. {'context': 'B-organism'}", + "80, MSCs {'context': 'B-cells'}", + "82, Igf1rflox/flox {'perturbing_action': 'B-gene loss-of-function'}", + "83, mice {'context': 'B-organism'}", + "85, Igf1r {'perturbing_action': 'B-gene loss-of-function'}", + "86, deleted {'perturbing_action': 'I-gene loss-of-function'}", + "87, by {'perturbing_action': 'I-gene loss-of-function'}", + "88, a {'perturbing_action': 'I-gene loss-of-function'}", + "89, Cre {'perturbing_action': 'I-gene loss-of-function'}", + "90, adenovirus {'perturbing_action': 'I-gene loss-of-function'}", + "91, in {'context': 'B-in vitro'}", + "92, vitro, {'context': 'I-in vitro'}", + "102, unable {'effect': 'B-negative'}", + "104, differentiate {'phenotype': 'B-differentiation'}", + "106, osteoblasts. {'phenotype': 'B-differentiation'}", + "122, aged {'context': 'B-organism'}", + "123, rats {'context': 'I-organism'}", + "193, stimulated {'effect': 'B-positive'}", + "198, aged {'context': 'B-organism'}", + "199, rats. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "56, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "58, knockout ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "59, of ['l1', 'l9', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "60, the ['l2', 'l10', 'l18', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "61, IGF-1 ['l3', 'l11', 'l19', 'l29', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "62, receptor ['l4', 'l12', 'l20', 'l30', 'l40', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "63, (Igf1r) ['l5', 'l13', 'l21', 'l31', 'l41', 'l50', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "66, pre-osteoblastic ['l6', 'l14', 'l22', 'l32', 'l42', 'l51', 'l59', 'l66', 'l67']", + "67, cells ['l7', 'l15', 'l23', 'l33', 'l43', 'l52', 'l60', 'l66', 'l68']", + "78, mice. ['l8', 'l16', 'l24', 'l34', 'l44', 'l53', 'l61', 'l67', 'l68']", + "80, MSCs ['l17', 'l25', 'l35', 'l45', 'l54', 'l62', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "82, Igf1rflox/flox ['l26', 'l36', 'l46', 'l55', 'l63', 'l69', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "83, mice ['l70', 'l83', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "85, Igf1r ['l84', 'l98', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "86, deleted ['l85', 'l99', 'l112', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "87, by ['l71', 'l86', 'l100', 'l113', 'l125', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "88, a ['l72', 'l87', 'l101', 'l114', 'l126', 'l137', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "89, Cre ['l73', 'l88', 'l102', 'l115', 'l127', 'l138', 'l148', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166']", + "90, adenovirus ['l74', 'l89', 'l103', 'l116', 'l128', 'l139', 'l149', 'l158', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "91, in ['l75', 'l90', 'l104', 'l117', 'l129', 'l140', 'l150', 'l159', 'l167', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181']", + "92, vitro, ['l37', 'l47', 'l56', 'l76', 'l91', 'l105', 'l118', 'l130', 'l141', 'l151', 'l160', 'l168', 'l175', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "102, unable ['l77', 'l92', 'l106', 'l119', 'l131', 'l142', 'l152', 'l161', 'l169', 'l176', 'l182', 'l188', 'l189', 'l190', 'l191', 'l192']", + "103, to ['l78', 'l93', 'l107', 'l120', 'l132', 'l143', 'l153', 'l162', 'l170', 'l177', 'l183', 'l188', 'l193', 'l194', 'l195', 'l196']", + "104, differentiate ['l79', 'l94', 'l108', 'l121', 'l133', 'l144', 'l154', 'l163', 'l171', 'l178', 'l184', 'l189', 'l193', 'l197', 'l198', 'l199']", + "106, osteoblasts. ['l80', 'l95', 'l109', 'l122', 'l134', 'l145', 'l155', 'l164', 'l172', 'l179', 'l185', 'l190', 'l194', 'l197', 'l200', 'l201']", + "122, aged ['l27', 'l38', 'l48', 'l57', 'l64', 'l81', 'l96', 'l110', 'l123', 'l135', 'l146', 'l156', 'l165', 'l173', 'l180', 'l186', 'l191', 'l195', 'l198', 'l200', 'l202']", + "123, rats ['l28', 'l39', 'l49', 'l58', 'l65', 'l82', 'l97', 'l111', 'l124', 'l136', 'l147', 'l157', 'l166', 'l174', 'l181', 'l187', 'l192', 'l196', 'l199', 'l201', 'l202']", + "193, stimulated ['l203', 'l204']", + "198, aged ['l203', 'l205']", + "199, rats. ['l204', 'l205']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice", + "mice.", + "aged", + "rats", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout", + "of", + "the", + "IGF-1", + "receptor", + "(Igf1r)", + "Igf1rflox/flox", + "Igf1r", + "deleted", + "by", + "a", + "Cre", + "adenovirus" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout", + "of", + "the", + "IGF-1", + "receptor", + "(Igf1r)", + "Igf1rflox/flox", + "by", + "a", + "Cre", + "adenovirus" + ] + }, + "context": { + "val": "cells", + "words": [ + "pre-osteoblastic", + "cells", + "MSCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "IGF-1", + "receptor", + "Igf1rflox/flox", + "Igf1r", + "deleted", + "by", + "a", + "Cre", + "adenovirus" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "vitro,", + "in" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "MSCs" + ] + }, + "effect": { + "val": "negative", + "words": [ + "unable" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "MSCs" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate", + "osteoblasts." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Igf1rflox/flox", + "Igf1r", + "deleted", + "by", + "a", + "Cre", + "adenovirus" + ] + }, + "effect": { + "val": "negative", + "words": [ + "unable" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Igf1rflox/flox", + "Igf1r", + "deleted", + "by", + "a", + "Cre", + "adenovirus" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate", + "osteoblasts." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "aged", + "rats" + ] + }, + "effect": { + "val": "negative", + "words": [ + "unable" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "aged", + "rats" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate", + "osteoblasts." + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + }, + "effect": { + "val": "negative", + "words": [ + "unable" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate", + "osteoblasts." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "unable" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate", + "osteoblasts." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + }, + "context": { + "val": "organism", + "words": [ + "aged", + "rats." + ] + } + } + ] + }, + { + "PMID": "22673994", + "TEXT": "How blood-borne inflammatory cells cause tissue damage in the brain after ischemic stroke remains elusive. Peroxiredoxins, cytosolic antioxidant proteins vital for redox balance, are released extracellularly from ischemic cells, acting as potent ‘danger signals’ that activate macrophages and lead to a harmful cytokine response, a new study shows. The findings unveil a new culprit in the delayed phase of ischemic injury and suggest new therapeutic approaches (pages 911–917).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22673987", + "TEXT": "On 17 May, Human Genome Sciences (HGS) formally rejected a $2.6 billion unsolicited takeover offer by GlaxoSmithKline. The Maryland-based biotech firm had long partnered with the UK drug giant to develop drugs including Benlysta (belimumab), HGS's first drug on the market and the first new medicine approved to fight lupus in 50 years. But, at $13 a share, GSK's bid was deemed \"inadequate\" by the HGS board. Recent history in the biotech sector shows how high the stakes are in such negotiations. Since last November, six biopharma buyouts have exceeded $1 billion each, with Gilead Sciences' purchase last year of the hepatitis C specialist Pharmasset topping the charts at a whopping $11.2 billion, the highest ever paid for a clinical-stage biotech and an 89% premium to its share price at the time. More recently, in April AstraZeneca paid $1.3 billion for Ardea Biosciences, a company with cancer and gout drugs in the pipeline but nothing on the market.One person watching the upward clime of such deals is biopharma analyst Joseph Schwartz, a managing director at Leerink Swann in Boston. Mark Ratner sought out Schwartz, who was named the top stock picker for pharmaceuticals in the last year's FT/StarMine Analyst Awards, for his views on what's behind the recent buyout spending.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22660635", + "TEXT": "Inflammatory cytokines such as interleukin-17 (IL-17) promote inflammatory autoimmune diseases. Although several microRNAs (miRNAs) have been shown to regulate autoimmune pathogenesis by affecting lymphocyte development and function, the role of miRNAs in resident cells present in inflammatory lesions remains unclear. Here we show that miR-23b is downregulated in inflammatory lesions of humans with lupus or rheumatoid arthritis, as well as in the mouse models of lupus, rheumatoid arthritis or multiple sclerosis. IL-17 downregulates miR-23b expression in human fibroblast-like synoviocytes, mouse primary kidney cells and astrocytes and is essential for the downregulation of miR-23b during autoimmune pathogenesis. In turn, miR-23b suppresses IL-17-, tumor necrosis factor α (TNF-α)- or IL-1β-induced NF-κB activation and inflammatory cytokine expression by targeting TGF-β-activated kinase 1/MAP3K7 binding protein 2 (TAB2), TAB3 and inhibitor of nuclear factor κ-B kinase subunit α (IKK-α) and, consequently, represses autoimmune inflammation. Thus, IL-17 contributes to autoimmune pathogenesis by suppressing miR-23b expression in radio-resident cells and promoting proinflammatory cytokine expression.", + "TAG_DATA": [ + "76, human {'context': 'B-cells'}", + "77, fibroblast-like {'context': 'I-cells'}", + "78, synoviocytes, {'context': 'I-cells'}", + "79, mouse {'context': 'B-cells'}", + "80, primary {'context': 'I-cells'}", + "81, kidney {'context': 'I-cells'}", + "82, cells {'context': 'I-cells'}", + "84, astrocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "76, human ['l0', 'l1', 'l2', 'l3']", + "77, fibroblast-like ['l0', 'l4', 'l5', 'l6', 'l7']", + "78, synoviocytes, ['l1', 'l4', 'l8']", + "79, mouse ['l9', 'l10', 'l11', 'l12']", + "80, primary ['l5', 'l9', 'l13', 'l14', 'l15']", + "81, kidney ['l2', 'l6', 'l10', 'l13', 'l16', 'l17']", + "82, cells ['l3', 'l7', 'l8', 'l11', 'l14', 'l16', 'l18']", + "84, astrocytes ['l12', 'l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22635005", + "TEXT": "Tumor-derived exosomes are emerging mediators of tumorigenesis. We explored the function of melanoma-derived exosomes in the formation of primary tumors and metastases in mice and human subjects. Exosomes from highly metastatic melanomas increased the metastatic behavior of primary tumors by permanently 'educating' bone marrow progenitors through the receptor tyrosine kinase MET. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites and reprogrammed bone marrow progenitors toward a pro-vasculogenic phenotype that was positive for c-Kit, the receptor tyrosine kinase Tie2 and Met. Reducing Met expression in exosomes diminished the pro-metastatic behavior of bone marrow cells. Notably, MET expression was elevated in circulating CD45(-)C-KIT(low/+)TIE2(+) bone marrow progenitors from individuals with metastatic melanoma. RAB1A, RAB5B, RAB7 and RAB27A, regulators of membrane trafficking and exosome formation, were highly expressed in melanoma cells. Rab27A RNA interference decreased exosome production, preventing bone marrow education and reducing, tumor growth and metastasis. In addition, we identified an exosome-specific melanoma signature with prognostic and therapeutic potential comprised of TYRP2, VLA-4, HSP70, an HSP90 isoform and the MET oncoprotein. Our data show that exosome production, transfer and education of bone marrow cells supports tumor growth and metastasis, has prognostic value and offers promise for new therapeutic directions in the metastatic process.", + "TAG_DATA": [ + "62, bone {'context': 'B-cells'}", + "63, marrow {'context': 'I-cells'}", + "64, progenitors {'context': 'I-cells'}", + "91, bone {'context': 'B-cells'}", + "92, marrow {'context': 'I-cells'}", + "93, cells. {'context': 'I-cells'}", + "128, Rab27A {'perturbing_action': 'B-rnai/knockdown'}", + "129, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "130, interference {'perturbing_action': 'I-rnai/knockdown'}", + "139, reducing, {'effect': 'B-negative'}", + "140, tumor {'phenotype': 'B-tumour growth'}", + "141, growth {'phenotype': 'I-tumour growth'}", + "143, metastasis. {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "62, bone ['l0', 'l1', 'l2', 'l3', 'l4']", + "63, marrow ['l0', 'l5', 'l6', 'l7', 'l8']", + "64, progenitors ['l1', 'l5', 'l9', 'l10', 'l11']", + "91, bone ['l2', 'l6', 'l9', 'l12', 'l13']", + "92, marrow ['l3', 'l7', 'l10', 'l12', 'l14']", + "93, cells. ['l4', 'l8', 'l11', 'l13', 'l14']", + "128, Rab27A ['l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "129, RNA ['l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "130, interference ['l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "139, reducing, ['l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "140, tumor ['l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "141, growth ['l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "143, metastasis. ['l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Rab27A", + "RNA", + "interference" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reducing," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Rab27A", + "RNA", + "interference" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Rab27A", + "RNA", + "interference" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reducing," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reducing," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + } + ] + }, + { + "PMID": "22561820", + "TEXT": "Alternative splicing ensures the expression of functionally diverse proteins from individual genes; however, aberrant mRNA splicing is associated with various conditions, including heart disease. A recent study provides new mechanistic insights into heart failure by showing that a human cardiomyopathy-linked mutation in a cardiac splice factor affects post-transcriptional regulation, causing the expression of anomalous isoforms of a whole network of cardiac proteins (pages 766-773).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22561817", + "TEXT": "The normally harmless behavior of bacteria in the intestinal tract is maintained by community structure and the integrity of host defenses. When either or both of these are compromised, a few disgruntled outcasts can cause a riot, taking down the whole neighborhood (pages 799-806).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22561816", + "TEXT": "A new study using a mouse model of lung diseases is the first demonstration in vivo that bone marrow–derived stromal cells can repair tissue injury through the transfer of mitochondria (pages 759-765). This suggests that rescue of injured cells through mitochondrial transfer may be an important process in many diseases.", + "TAG_DATA": [ + "5, mouse {'context': 'B-organism'}", + "6, model {'context': 'I-organism'}", + "7, of {'context': 'I-organism'}", + "8, lung {'context': 'I-organism'}", + "14, in {'context': 'B-in vivo'}", + "15, vivo {'context': 'I-in vivo'}", + "17, bone {'context': 'B-cells'}", + "18, marrow–derived {'context': 'I-cells'}", + "19, stromal {'context': 'I-cells'}", + "20, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "5, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "6, model ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "7, of ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "8, lung ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "9, diseases ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "14, in ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "15, vivo ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "17, bone ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "18, marrow–derived ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "19, stromal ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "20, cells ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22561812", + "TEXT": "The World Health Organization (WHO) is facing an unprecedented crisis that threatens its position as the premier international health agency. To ensure its leading role, it must rethink its internal governance and revamp its financing mechanisms.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22561688", + "TEXT": "Smoking is the only modifiable risk factor that is associated with the development, expansion and rupture of abdominal aortic aneurysm (AAA). However, the causative link between cigarette smoke and AAA is unknown. Here we report a causative link between smoking and AAA in vivo. Acute infusion of angiotensin II (AngII) or nicotine, a major component of cigarette smoke, markedly increased the incidence of AAA in apolipoprotein E (apoE) knockout (Apoe(-/-)) mice and in mice deficient in both apoE and the AMP-activated kinase α1 subunit (AMPK-α1) (Apoe(-/-); Prkaa1(-/-) mice). In contrast, genetic deletion of AMPK-α2 (Apoe(-/-); Prkaa2(-/-) mice) ablated nicotine- or AngII-triggered AAA in vivo. Mechanistically, we found that both nicotine and AngII activated AMPK-α2 in cultured vascular smooth muscle cells (VSMCs), resulting in the phosphorylation of activator protein 2α (AP-2α) and consequent matrix metallopeptidase 2 (MMP2) gene expression. We conclude that smoking (through nicotine) instigates AAA through AMPK-α2–mediated AP-2α–dependent MMP2 expression in VSMCs.", + "TAG_DATA": [ + "63, AAA {'context': 'B-neoplasm'}", + "65, apolipoprotein {'perturbing_action': 'B-gene loss-of-function'}", + "66, E {'perturbing_action': 'I-gene loss-of-function'}", + "67, (apoE) {'perturbing_action': 'I-gene loss-of-function'}", + "68, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "69, (Apoe(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "70, mice {'context': 'B-organism'}", + "73, mice {'context': 'B-organism'}", + "74, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "75, in {'perturbing_action': 'I-gene loss-of-function'}", + "76, both {'perturbing_action': 'I-gene loss-of-function'}", + "77, apoE {'perturbing_action': 'I-gene loss-of-function'}", + "78, and {'perturbing_action': 'I-gene loss-of-function'}", + "79, the {'perturbing_action': 'I-gene loss-of-function'}", + "80, AMP-activated {'perturbing_action': 'I-gene loss-of-function'}", + "81, kinase {'perturbing_action': 'I-gene loss-of-function'}", + "82, α1 {'perturbing_action': 'I-gene loss-of-function'}", + "83, subunit {'perturbing_action': 'I-gene loss-of-function'}", + "84, (AMPK-α1) {'perturbing_action': 'I-gene loss-of-function'}", + "85, (Apoe(-/-); {'perturbing_action': 'I-gene loss-of-function'}", + "86, Prkaa1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "87, mice). {'context': 'B-organism'}", + "90, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "91, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "92, of {'perturbing_action': 'I-gene loss-of-function'}", + "93, AMPK-α2 {'perturbing_action': 'I-gene loss-of-function'}", + "94, (Apoe(-/-); {'perturbing_action': 'I-gene loss-of-function'}", + "95, Prkaa2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "96, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "101, AAA {'context': 'B-neoplasm'}", + "102, in {'context': 'B-in vivo'}", + "103, vivo. {'context': 'I-in vivo'}", + "116, vascular {'context': 'B-cells'}", + "117, smooth {'context': 'I-cells'}", + "118, muscle {'context': 'I-cells'}", + "119, cells {'context': 'I-cells'}", + "120, (VSMCs), {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "63, AAA ['l0', 'l1', 'l2']", + "65, apolipoprotein ['l3', 'l4', 'l5', 'l6', 'l7']", + "66, E ['l3', 'l8', 'l9', 'l10', 'l11']", + "67, (apoE) ['l4', 'l8', 'l12', 'l13', 'l14']", + "68, knockout ['l0', 'l5', 'l9', 'l12', 'l15', 'l16']", + "69, (Apoe(-/-)) ['l1', 'l6', 'l10', 'l13', 'l15', 'l17']", + "70, mice ['l2', 'l7', 'l11', 'l14', 'l16', 'l17']", + "73, mice ['l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "74, deficient ['l18', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "75, in ['l19', 'l32', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "76, both ['l20', 'l33', 'l46', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "77, apoE ['l21', 'l34', 'l47', 'l65', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "78, and ['l22', 'l35', 'l48', 'l66', 'l81', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "79, the ['l23', 'l36', 'l49', 'l67', 'l82', 'l93', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "80, AMP-activated ['l24', 'l37', 'l50', 'l68', 'l83', 'l94', 'l108', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "81, kinase ['l25', 'l38', 'l51', 'l69', 'l84', 'l95', 'l109', 'l123', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "82, α1 ['l26', 'l39', 'l52', 'l70', 'l85', 'l96', 'l110', 'l124', 'l137', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "83, subunit ['l27', 'l40', 'l53', 'l71', 'l86', 'l97', 'l111', 'l125', 'l138', 'l150', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "84, (AMPK-α1) ['l28', 'l41', 'l54', 'l72', 'l87', 'l98', 'l112', 'l126', 'l139', 'l151', 'l162', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "85, (Apoe(-/-); ['l29', 'l42', 'l55', 'l73', 'l88', 'l99', 'l113', 'l127', 'l140', 'l152', 'l163', 'l173', 'l183', 'l184', 'l185']", + "86, Prkaa1(-/-) ['l30', 'l43', 'l56', 'l74', 'l89', 'l100', 'l114', 'l128', 'l141', 'l153', 'l164', 'l174', 'l183', 'l186', 'l187', 'l188']", + "87, mice). ['l31', 'l44', 'l57', 'l75', 'l90', 'l101', 'l115', 'l129', 'l142', 'l154', 'l165', 'l175', 'l184', 'l186']", + "90, genetic ['l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202']", + "91, deletion ['l189', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215']", + "92, of ['l190', 'l203', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227']", + "93, AMPK-α2 ['l191', 'l204', 'l216', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238']", + "94, (Apoe(-/-); ['l192', 'l205', 'l217', 'l228', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248']", + "95, Prkaa2(-/-) ['l193', 'l206', 'l218', 'l229', 'l239', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257']", + "96, mice) ['l194', 'l207', 'l219', 'l230', 'l240', 'l249', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265']", + "101, AAA ['l58', 'l76', 'l102', 'l116', 'l130', 'l143', 'l155', 'l166', 'l176', 'l195', 'l208', 'l220', 'l231', 'l241', 'l250', 'l258', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272']", + "102, in ['l196', 'l209', 'l221', 'l232', 'l242', 'l251', 'l259', 'l266', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278']", + "103, vivo. ['l59', 'l103', 'l117', 'l131', 'l144', 'l156', 'l167', 'l177', 'l197', 'l210', 'l222', 'l233', 'l243', 'l252', 'l260', 'l267', 'l273', 'l279', 'l280', 'l281', 'l282', 'l283']", + "116, vascular ['l60', 'l118', 'l132', 'l145', 'l157', 'l168', 'l178', 'l198', 'l211', 'l223', 'l234', 'l244', 'l253', 'l261', 'l268', 'l274', 'l279', 'l284', 'l285', 'l286', 'l287']", + "117, smooth ['l61', 'l77', 'l104', 'l119', 'l133', 'l146', 'l158', 'l169', 'l179', 'l199', 'l212', 'l224', 'l235', 'l245', 'l254', 'l262', 'l269', 'l275', 'l280', 'l284', 'l288', 'l289', 'l290']", + "118, muscle ['l62', 'l78', 'l91', 'l105', 'l120', 'l134', 'l147', 'l159', 'l170', 'l180', 'l187', 'l200', 'l213', 'l225', 'l236', 'l246', 'l255', 'l263', 'l270', 'l276', 'l281', 'l285', 'l288', 'l291', 'l292']", + "119, cells ['l45', 'l63', 'l79', 'l92', 'l106', 'l121', 'l135', 'l148', 'l160', 'l171', 'l181', 'l185', 'l188', 'l201', 'l214', 'l226', 'l237', 'l247', 'l256', 'l264', 'l271', 'l277', 'l282', 'l286', 'l289', 'l291', 'l293']", + "120, (VSMCs), ['l64', 'l80', 'l107', 'l122', 'l136', 'l149', 'l161', 'l172', 'l182', 'l202', 'l215', 'l227', 'l238', 'l248', 'l257', 'l265', 'l272', 'l278', 'l283', 'l287', 'l290', 'l292', 'l293']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "AAA" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout", + "(Apoe(-/-))", + "in", + "both", + "and", + "the", + "AMP-activated", + "kinase", + "α1", + "subunit", + "(AMPK-α1)", + "genetic", + "deletion", + "of", + "AMPK-α2", + "(Apoe(-/-);", + "Prkaa2(-/-)", + "mice)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "apolipoprotein", + "E", + "(apoE)", + "knockout", + "(Apoe(-/-))", + "deficient", + "in", + "both", + "apoE", + "and", + "the", + "AMP-activated", + "kinase", + "α1", + "subunit", + "(AMPK-α1)", + "(Apoe(-/-);", + "Prkaa1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice)." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "both", + "apoE", + "and", + "the", + "AMP-activated", + "kinase", + "α1", + "subunit", + "(AMPK-α1)", + "(Apoe(-/-);", + "Prkaa1(-/-)", + "genetic", + "deletion", + "of", + "AMPK-α2", + "Prkaa2(-/-)", + "mice)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "vascular", + "smooth", + "muscle", + "(VSMCs)," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "in", + "and", + "the", + "AMP-activated", + "kinase", + "α1", + "subunit", + "(AMPK-α1)", + "genetic", + "deletion", + "of", + "AMPK-α2", + "(Apoe(-/-);", + "Prkaa2(-/-)", + "mice)" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo.", + "in" + ] + } + } + ] + }, + { + "PMID": "22543263", + "TEXT": "Interleukin-25 (IL-25) is a cytokine associated with allergy and asthma that functions to promote type 2 immune responses at mucosal epithelial surfaces and serves to protect against helminth parasitic infections in the intestinal tract. This study identifies the IL-25 receptor, IL-17RB, as a key mediator of both innate and adaptive pulmonary type 2 immune responses. Allergen exposure upregulated IL-25 and induced type 2 cytokine production in a previously undescribed granulocytic population, termed type 2 myeloid (T2M) cells. Il17rb(-/-) mice showed reduced lung pathology after chronic allergen exposure and decreased type 2 cytokine production in T2M cells and CD4(+) T lymphocytes. Airway instillation of IL-25 induced IL-4 and IL-13 production in T2M cells, demonstrating their importance in eliciting T cell-independent inflammation. The adoptive transfer of T2M cells reconstituted IL-25-mediated responses in Il17rb(-/-) mice. High-dose dexamethasone treatment did not reduce the IL-25-induced T2M pulmonary response. Finally, a similar IL-4- and IL-13-producing granulocytic population was identified in peripheral blood of human subjects with asthma. These data establish IL-25 and its receptor IL-17RB as targets for innate and adaptive immune responses in chronic allergic airway disease and identify T2M cells as a new steroid-resistant cell population.", + "TAG_DATA": [ + "77, Il17rb(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "78, mice {'context': 'B-organism'}", + "81, lung {'context': 'B-tissue/organ'}", + "94, T2M {'context': 'B-cells'}", + "95, cells {'context': 'I-cells'}", + "97, CD4(+) {'context': 'B-cells'}", + "98, T {'context': 'I-cells'}", + "99, lymphocytes. {'context': 'I-cells'}", + "110, T2M {'context': 'B-cells'}", + "111, cells, {'context': 'I-cells'}", + "124, T2M {'context': 'B-cells'}", + "125, cells {'context': 'I-cells'}", + "130, Il17rb(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "131, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "77, Il17rb(-/-) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "78, mice ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "81, lung ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21']", + "94, T2M ['l2', 'l10', 'l17', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "95, cells ['l3', 'l11', 'l18', 'l22', 'l28', 'l29', 'l30']", + "97, CD4(+) ['l4', 'l12', 'l23', 'l31', 'l32', 'l33', 'l34']", + "98, T ['l5', 'l13', 'l19', 'l24', 'l28', 'l31', 'l35', 'l36', 'l37']", + "99, lymphocytes. ['l6', 'l14', 'l20', 'l25', 'l29', 'l32', 'l35', 'l38', 'l39']", + "110, T2M ['l7', 'l15', 'l26', 'l33', 'l36', 'l38', 'l40', 'l41']", + "111, cells, ['l8', 'l16', 'l21', 'l27', 'l30', 'l34', 'l37', 'l39', 'l40']", + "124, T2M ['l42', 'l43', 'l44']", + "125, cells ['l41', 'l42', 'l45']", + "130, Il17rb(-/-) ['l43', 'l45', 'l46']", + "131, mice. ['l44', 'l46']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Il17rb(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Il17rb(-/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Il17rb(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "T2M", + "cells", + "CD4(+)", + "T", + "lymphocytes.", + "cells," + ] + } + } + ] + }, + { + "PMID": "22466705", + "TEXT": "The transfer of high-avidity T cell receptor (TCR) genes isolated from rare tumor-specific lymphocytes into polyclonal T cells is an attractive cancer immunotherapy strategy. However, TCR gene transfer results in competition for surface expression and inappropriate pairing between the exogenous and endogenous TCR chains, resulting in suboptimal activity and potentially harmful unpredicted antigen specificities of the resultant TCRs. We designed zinc-finger nucleases (ZFNs) that promoted the disruption of endogenous TCR β- and α-chain genes. Lymphocytes treated with ZFNs lacked surface expression of CD3-TCR and expanded with the addition of interleukin-7 (IL-7) and IL-15. After lentiviral transfer of a TCR specific for the Wilms tumor 1 (WT1) antigen, these TCR-edited cells expressed the new TCR at high levels, were easily expanded to near purity and were superior at specific antigen recognition compared to donor-matched, unedited TCR-transferred cells. In contrast to unedited TCR-transferred cells, the TCR-edited lymphocytes did not mediate off-target reactivity while maintaining their anti-tumor activity in vivo, thus showing that complete editing of T cell specificity generates tumor-specific lymphocytes with improved biosafety profiles.", + "TAG_DATA": [ + "74, Lymphocytes {'context': 'B-cells'}", + "94, lentiviral {'perturbing_action': 'B-gene gain-of-function'}", + "95, transfer {'perturbing_action': 'I-other'}", + "96, of {'perturbing_action': 'I-other'}", + "97, a {'perturbing_action': 'I-other'}", + "98, TCR {'perturbing_action': 'I-other'}", + "99, specific {'perturbing_action': 'I-other'}", + "100, for {'perturbing_action': 'I-other'}", + "101, the {'perturbing_action': 'I-other'}", + "102, Wilms {'perturbing_action': 'I-other'}", + "103, tumor {'perturbing_action': 'I-other'}", + "104, 1 {'perturbing_action': 'I-other'}", + "105, (WT1) {'perturbing_action': 'I-other'}", + "106, antigen, {'perturbing_action': 'I-other'}", + "109, cells {'context': 'B-cells'}", + "144, lymphocytes {'context': 'B-cells'}", + "155, in {'context': 'B-in vivo'}", + "156, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "94, lentiviral ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "95, transfer ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "96, of ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "97, a ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "98, TCR ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "99, specific ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "100, for ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "101, the ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "102, Wilms ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "103, tumor ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "104, 1 ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "105, (WT1) ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "106, antigen, ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "109, cells ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']", + "144, lymphocytes ['l91', 'l92']", + "155, in ['l91', 'l93']", + "156, vivo, ['l92', 'l93']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "lentiviral" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "transfer", + "of", + "a", + "TCR", + "specific", + "for", + "the", + "Wilms", + "tumor", + "1", + "(WT1)", + "antigen," + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "22426421", + "TEXT": "Tyrosine kinase inhibitors (TKIs) elicit high response rates among individuals with kinase-driven malignancies, including chronic myeloid leukemia (CML) and epidermal growth factor receptor-mutated non-small-cell lung cancer (EGFR NSCLC). However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual's response to TKIs. Using paired-end DNA sequencing, we discovered a common intronic deletion polymorphism in the gene encoding BCL2-like 11 (BIM). BIM is a pro-apoptotic member of the B-cell CLL/lymphoma 2 (BCL2) family of proteins, and its upregulation is required for TKIs to induce apoptosis in kinase-driven cancers. The polymorphism switched BIM splicing from exon 4 to exon 3, which resulted in expression of BIM isoforms lacking the pro-apoptotic BCL2-homology domain 3 (BH3). The polymorphism was sufficient to confer intrinsic TKI resistance in CML and EGFR NSCLC cell lines, but this resistance could be overcome with BH3-mimetic drugs. Notably, individuals with CML and EGFR NSCLC harboring the polymorphism experienced significantly inferior responses to TKIs than did individuals without the polymorphism (P = 0.02 for CML and P = 0.027 for EGFR NSCLC). Our results offer an explanation for the heterogeneity of TKI responses across individuals and suggest the possibility of personalizing therapy with BH3 mimetics to overcome BIM-polymorphism-associated TKI resistance.", + "TAG_DATA": [ + "130, CML {'context': 'B-transformed cells'}", + "131, and {'context': 'I-transformed cells'}", + "132, EGFR {'context': 'I-transformed cells'}", + "133, NSCLC {'context': 'I-transformed cells'}", + "134, cell {'context': 'I-transformed cells'}", + "135, lines, {'context': 'I-transformed cells'}", + "146, individuals {'context': 'B-patient'}", + "148, CML {'context': 'B-transformed cells'}", + "150, EGFR {'context': 'I-transformed cells'}", + "151, NSCLC {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "130, CML ['l0', 'l1', 'l2', 'l3', 'l4']", + "131, and ['l0', 'l5', 'l6', 'l7', 'l8']", + "132, EGFR ['l1', 'l5', 'l9', 'l10', 'l11']", + "133, NSCLC ['l2', 'l6', 'l9', 'l12', 'l13']", + "134, cell ['l3', 'l7', 'l10', 'l12', 'l14']", + "135, lines, ['l4', 'l8', 'l11', 'l13', 'l14']", + "146, individuals ['l15', 'l16', 'l17', 'l18']", + "148, CML ['l15', 'l19', 'l20', 'l21']", + "149, and ['l16', 'l19', 'l22', 'l23']", + "150, EGFR ['l17', 'l20', 'l22', 'l24']", + "151, NSCLC ['l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22406745", + "TEXT": "Adult stem-cell therapy holds promise for the treatment of gastrointestinal diseases. Here we describe methods for long-term expansion of colonic stem cells positive for leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5(+) cells) in culture. To test the transplantability of these cells, we reintroduced cultured GFP(+) colon organoids into superficially damaged mouse colon. The transplanted donor cells readily integrated into the mouse colon, covering the area that lacked epithelium as a result of the introduced damage in recipient mice. At 4 weeks after transplantation, the donor-derived cells constituted a single-layered epithelium, which formed self-renewing crypts that were functionally and histologically normal. Moreover, we observed long-term (>6 months) engraftment with transplantation of organoids derived from a single Lgr5(+) colon stem cell after extensive in vitro expansion. These data show the feasibility of colon stem-cell therapy based on the in vitro expansion of a single adult colonic stem cell.", + "TAG_DATA": [ + "44, cultured {'context': 'B-organoid'}", + "45, GFP(+) {'context': 'B-organoid'}", + "46, colon {'context': 'I-organoid'}", + "47, organoids {'context': 'I-organoid'}", + "51, mouse {'context': 'B-tissue/organ'}", + "52, colon. {'context': 'I-tissue/organ'}", + "55, donor {'context': 'B-cells'}", + "56, cells {'context': 'I-cells'}", + "61, mouse {'context': 'B-tissue/organ'}", + "62, colon, {'context': 'I-tissue/organ'}", + "77, recipient {'context': 'B-organism'}", + "78, mice. {'context': 'I-organism'}", + "85, donor-derived {'context': 'B-cells'}", + "86, cells {'context': 'I-cells'}", + "111, organoids {'context': 'B-organoid'}", + "116, Lgr5(+) {'context': 'B-cells'}", + "117, colon {'context': 'I-cells'}", + "118, stem {'context': 'I-cells'}", + "119, cell {'context': 'I-cells'}", + "122, in {'context': 'B-in vitro'}", + "123, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "44, cultured ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "45, GFP(+) ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "46, colon ['l1', 'l10', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "47, organoids ['l2', 'l11', 'l20', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "51, mouse ['l3', 'l12', 'l21', 'l27', 'l34', 'l35', 'l36', 'l37']", + "52, colon. ['l4', 'l13', 'l22', 'l28', 'l34', 'l38', 'l39']", + "55, donor ['l14', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "56, cells ['l5', 'l15', 'l23', 'l29', 'l35', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "61, mouse ['l6', 'l16', 'l24', 'l30', 'l36', 'l38', 'l41', 'l46', 'l51', 'l52', 'l53']", + "62, colon, ['l7', 'l17', 'l25', 'l31', 'l37', 'l39', 'l42', 'l47', 'l51', 'l54', 'l55']", + "77, recipient ['l8', 'l18', 'l32', 'l43', 'l48', 'l52', 'l54', 'l56', 'l57']", + "78, mice. ['l9', 'l19', 'l26', 'l33', 'l44', 'l49', 'l53', 'l55', 'l56']", + "85, donor-derived ['l58']", + "86, cells ['l45', 'l50', 'l57', 'l58']", + "111, organoids ['l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "116, Lgr5(+) ['l59', 'l65', 'l66', 'l67', 'l68', 'l69']", + "117, colon ['l60', 'l65', 'l70', 'l71', 'l72', 'l73']", + "118, stem ['l61', 'l66', 'l70', 'l74', 'l75', 'l76']", + "119, cell ['l62', 'l67', 'l71', 'l74', 'l77', 'l78']", + "122, in ['l63', 'l68', 'l72', 'l75', 'l77', 'l79']", + "123, vitro ['l64', 'l69', 'l73', 'l76', 'l78', 'l79']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22395698", + "TEXT": "The kinase AKT has been regarded as an obligate intermediate in the insulin signaling pathway that suppresses glucose production by inhibiting the transcription factor forkhead box O1 (FoxO1) after meals. A new study shows that, without AKT-FoxO1 signaling, insulin still contributes to postprandial responses, revealing an AKT-independent pathway for insulin action that might be exploited to treat metabolic disease (pages 388–395).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22388091", + "TEXT": "Emerging evidence suggests that the T helper 17 (T(H)17) subset of αβ T cells contributes to the development of allergic asthma. In this study, we found that mice lacking the αvβ8 integrin on dendritic cells did not generate T(H)17 cells in the lung and were protected from airway hyper-responsiveness in response to house dust mite and ovalbumin sensitization and challenge. Because loss of T(H)17 cells inhibited airway narrowing without any obvious effects on airway inflammation or epithelial morphology, we examined the direct effects of T(H)17 cytokines on mouse and human airway smooth muscle function. Interleukin-17A (IL-17A), but not IL-17F or IL-22, enhanced contractile force generation of airway smooth muscle through an IL-17 receptor A (IL-17RA)-IL-17RC, nuclear factor κ light-chain enhancer of activated B cells (NF-κB)-ras homolog gene family, member A (RhoA)-Rho-associated coiled-coil containing protein kinase 2 (ROCK2) signaling cascade. Mice lacking integrin αvβ8 on dendritic cells showed impaired activation of this pathway after ovalbumin sensitization and challenge, and the diminished contraction of the tracheal rings in these mice was reversed by IL-17A. These data indicate that the IL-17A produced by T(H)17 cells contributes to allergen-induced airway hyper-responsiveness through direct effects on airway smooth muscle.", + "TAG_DATA": [ + "27, mice {'context': 'B-organism'}", + "28, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "29, the {'perturbing_action': 'I-gene loss-of-function'}", + "30, αvβ8 {'perturbing_action': 'I-gene loss-of-function'}", + "31, integrin {'perturbing_action': 'I-gene loss-of-function'}", + "32, on {'perturbing_action': 'I-gene loss-of-function'}", + "33, dendritic {'perturbing_action': 'I-gene loss-of-function'}", + "34, cells {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "42, lung {'context': 'B-tissue/organ'}", + "61, loss {'perturbing_action': 'B-gene loss-of-function'}", + "62, of {'perturbing_action': 'I-gene loss-of-function'}", + "63, T(H)17 {'perturbing_action': 'I-gene loss-of-function'}", + "64, cells {'perturbing_action': 'I-gene loss-of-function'}", + "106, airway {'context': 'B-tissue/organ'}", + "107, smooth {'context': 'I-tissue/organ'}", + "108, muscle {'context': 'I-tissue/organ'}", + "139, Mice {'context': 'B-organism'}", + "140, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "141, integrin {'perturbing_action': 'I-gene loss-of-function'}", + "142, αvβ8 {'perturbing_action': 'I-gene loss-of-function'}", + "143, on {'perturbing_action': 'I-gene loss-of-function'}", + "144, dendritic {'context': 'B-cells'}", + "145, cells {'context': 'I-cells'}", + "163, tracheal {'context': 'B-tissue/organ'}", + "164, rings {'context': 'I-tissue/organ'}", + "167, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "27, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "28, lacking ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "29, the ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "30, αvβ8 ['l2', 'l13', 'l23', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "31, integrin ['l3', 'l14', 'l24', 'l36', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "32, on ['l4', 'l15', 'l25', 'l37', 'l48', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "33, dendritic ['l5', 'l16', 'l26', 'l38', 'l49', 'l59', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "34, cells ['l6', 'l17', 'l27', 'l39', 'l50', 'l60', 'l68', 'l75', 'l76', 'l77', 'l78', 'l79']", + "42, lung ['l7', 'l18', 'l28', 'l40', 'l51', 'l61', 'l69', 'l75']", + "61, loss ['l8', 'l19', 'l29', 'l41', 'l52', 'l62', 'l70', 'l76', 'l80', 'l81', 'l82', 'l83', 'l84']", + "62, of ['l9', 'l20', 'l30', 'l42', 'l53', 'l63', 'l71', 'l77', 'l80', 'l85', 'l86', 'l87', 'l88', 'l89']", + "63, T(H)17 ['l10', 'l21', 'l31', 'l43', 'l54', 'l64', 'l72', 'l78', 'l81', 'l85', 'l90', 'l91', 'l92', 'l93']", + "64, cells ['l11', 'l22', 'l32', 'l44', 'l55', 'l65', 'l73', 'l79', 'l82', 'l86', 'l90']", + "106, airway ['l33', 'l45', 'l56', 'l87', 'l91', 'l94', 'l95']", + "107, smooth ['l34', 'l46', 'l57', 'l66', 'l83', 'l88', 'l92', 'l94', 'l96']", + "108, muscle ['l35', 'l47', 'l58', 'l67', 'l74', 'l84', 'l89', 'l93', 'l95', 'l96']", + "139, Mice ['l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "140, lacking ['l97', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "141, integrin ['l98', 'l104', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "142, αvβ8 ['l99', 'l105', 'l112', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "143, on ['l100', 'l106', 'l113', 'l119', 'l125', 'l126', 'l127']", + "144, dendritic ['l101', 'l107', 'l114', 'l120', 'l125', 'l128', 'l129']", + "145, cells ['l102', 'l108', 'l115', 'l121', 'l126', 'l128']", + "163, tracheal ['l109', 'l116', 'l122', 'l130', 'l131']", + "164, rings ['l103', 'l110', 'l117', 'l123', 'l127', 'l129', 'l130', 'l132']", + "167, mice ['l111', 'l118', 'l124', 'l131', 'l132']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "αvβ8", + "integrin", + "on", + "dendritic", + "cells", + "loss", + "of", + "T(H)17" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cells", + "lacking", + "the", + "αvβ8", + "integrin", + "on", + "dendritic" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "dendritic" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "αvβ8", + "integrin", + "on", + "dendritic", + "cells", + "loss", + "of", + "T(H)17" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung", + "airway", + "smooth", + "muscle", + "tracheal", + "rings" + ] + } + } + ] + }, + { + "PMID": "22388088", + "TEXT": "New cancer therapies are likely to arise from an in-depth understanding of the signaling networks influencing tumor initiation, progression and metastasis. We show a fundamental role for Src-homology 2 domain-containing phosphatase 2 (SHP2) in these processes in human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancers. Knockdown of SHP2 eradicated breast tumor-initiating cells in xenograft models, and SHP2 depletion also prevented invasion in three-dimensional cultures and in a transductal invasion assay in vivo. Notably, SHP2 knockdown in established breast tumors blocked their growth and reduced metastasis. Mechanistically, SHP2 activated stemness-associated transcription factors, including v-myc myelocytomatosis viral oncogene homolog (c-Myc) and zinc finger E-box binding homeobox 1 (ZEB1), which resulted in the repression of let-7 microRNA and the expression of a set of 'SHP2 signature' genes. We found these genes to be simultaneously activated in a large subset of human primary breast tumors that are associated with invasive behavior and poor prognosis. These results provide new insights into the signaling cascades influencing tumor-initiating cells as well as a rationale for targeting SHP2 in breast cancer.", + "TAG_DATA": [ + "48, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "49, of {'perturbing_action': 'I-rnai/knockdown'}", + "50, SHP2 {'perturbing_action': 'I-rnai/knockdown'}", + "52, breast {'context': 'B-transformed cells'}", + "53, tumor-initiating {'context': 'I-transformed cells'}", + "54, cells {'context': 'I-transformed cells'}", + "56, xenograft {'context': 'B-xenograft'}", + "57, models, {'context': 'I-xenograft'}", + "59, SHP2 {'perturbing_action': 'B-gene loss-of-function'}", + "60, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "62, prevented {'effect': 'B-negative'}", + "63, invasion {'phenotype': 'B-invasion'}", + "65, three-dimensional {'context': 'B-in vitro'}", + "66, cultures {'context': 'I-in vitro'}", + "73, in {'context': 'B-in vivo'}", + "74, vivo. {'context': 'I-in vivo'}", + "76, SHP2 {'perturbing_action': 'B-rnai/knockdown'}", + "77, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "80, breast {'context': 'B-neoplasm'}", + "81, tumors {'context': 'I-neoplasm'}", + "86, reduced {'effect': 'B-negative'}", + "87, metastasis. {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "48, Knockdown ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "49, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "50, SHP2 ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "52, breast ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40']", + "53, tumor-initiating ['l3', 'l15', 'l26', 'l36', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "54, cells ['l4', 'l16', 'l27', 'l37', 'l41', 'l47', 'l48', 'l49']", + "56, xenograft ['l5', 'l17', 'l28', 'l38', 'l42', 'l47', 'l50', 'l51', 'l52', 'l53', 'l54']", + "57, models, ['l6', 'l18', 'l29', 'l39', 'l43', 'l48', 'l50', 'l55', 'l56']", + "59, SHP2 ['l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "60, depletion ['l57', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "62, prevented ['l7', 'l19', 'l30', 'l51', 'l58', 'l66', 'l75', 'l76', 'l77', 'l78', 'l79']", + "63, invasion ['l8', 'l20', 'l31', 'l44', 'l52', 'l55', 'l59', 'l67', 'l75', 'l80', 'l81']", + "65, three-dimensional ['l9', 'l21', 'l32', 'l45', 'l53', 'l60', 'l68', 'l76', 'l80', 'l82', 'l83', 'l84']", + "66, cultures ['l10', 'l22', 'l33', 'l40', 'l46', 'l49', 'l54', 'l56', 'l61', 'l69', 'l77', 'l81', 'l82']", + "73, in ['l11', 'l23', 'l34', 'l62', 'l70', 'l78', 'l83', 'l85']", + "74, vivo. ['l12', 'l24', 'l35', 'l63', 'l71', 'l79', 'l84', 'l85']", + "76, SHP2 ['l86', 'l87', 'l88', 'l89', 'l90']", + "77, knockdown ['l86', 'l91', 'l92', 'l93', 'l94']", + "80, breast ['l64', 'l72', 'l87', 'l91', 'l95', 'l96', 'l97']", + "81, tumors ['l65', 'l73', 'l88', 'l92', 'l95', 'l98', 'l99']", + "86, reduced ['l74', 'l89', 'l93', 'l96', 'l98', 'l100']", + "87, metastasis. ['l90', 'l94', 'l97', 'l99', 'l100']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "SHP2" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "breast", + "tumor-initiating", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "SHP2" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "models," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "SHP2", + "knockdown" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented", + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "SHP2" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "SHP2" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "three-dimensional", + "cultures" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "SHP2" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor-initiating" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenograft" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "models," + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHP2", + "depletion" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented", + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHP2", + "depletion" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHP2", + "depletion" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "three-dimensional", + "cultures" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHP2", + "depletion" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHP2", + "depletion" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "breast", + "tumors" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "three-dimensional", + "cultures" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "three-dimensional", + "cultures" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "SHP2", + "knockdown" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "breast", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "SHP2", + "knockdown" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "breast", + "tumors" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "breast", + "tumors" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + } + ] + }, + { + "PMID": "22366948", + "TEXT": "Germline stem cells that produce oocytes in vitro and fertilization-competent eggs in vivo have been identified in and isolated from adult mouse ovaries. Here we describe and validate a fluorescence-activated cell sorting-based protocol that can be used with adult mouse ovaries and human ovarian cortical tissue to purify rare mitotically active cells that have a gene expression profile that is consistent with primitive germ cells. Once established in vitro, these cells can be expanded for months and can spontaneously generate 35- to 50-μm oocytes, as determined by morphology, gene expression and haploid (1n) status. Injection of the human germline cells, engineered to stably express GFP, into human ovarian cortical biopsies leads to formation of follicles containing GFP-positive oocytes 1-2 weeks after xenotransplantation into immunodeficient female mice. Thus, ovaries of reproductive-age women, similar to adult mice, possess rare mitotically active germ cells that can be propagated in vitro as well as generate oocytes in vitro and in vivo.", + "TAG_DATA": [ + "97, human {'context': 'B-cells'}", + "98, germline {'context': 'I-cells'}", + "99, cells, {'context': 'I-cells'}", + "101, to {'perturbing_action': 'B-gene gain-of-function'}", + "102, stably {'perturbing_action': 'B-gene gain-of-function'}", + "103, express {'perturbing_action': 'I-gene gain-of-function'}", + "104, GFP, {'perturbing_action': 'I-gene gain-of-function'}", + "106, human {'context': 'B-tissue/organ'}", + "107, ovarian {'context': 'I-patient'}", + "108, cortical {'context': 'I-patient'}", + "109, biopsies {'context': 'I-patient'}", + "121, xenotransplantation {'context': 'B-xenograft'}", + "123, immunodeficient {'context': 'B-organism'}", + "124, female {'context': 'I-organism'}", + "125, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "97, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "98, germline ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "99, cells, ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "100, engineered ['l2', 'l16', 'l29', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "101, to ['l3', 'l17', 'l30', 'l41', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "102, stably ['l4', 'l18', 'l31', 'l42', 'l53', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "103, express ['l5', 'l19', 'l32', 'l43', 'l54', 'l64', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "104, GFP, ['l6', 'l20', 'l33', 'l44', 'l55', 'l65', 'l74', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "106, human ['l7', 'l21', 'l34', 'l45', 'l56', 'l66', 'l75', 'l83', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "107, ovarian ['l8', 'l22', 'l35', 'l46', 'l57', 'l67', 'l76', 'l84', 'l91', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "108, cortical ['l9', 'l23', 'l36', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l98', 'l104', 'l105', 'l106', 'l107', 'l108']", + "109, biopsies ['l10', 'l24', 'l37', 'l48', 'l59', 'l69', 'l78', 'l86', 'l93', 'l99', 'l104', 'l109', 'l110', 'l111', 'l112']", + "121, xenotransplantation ['l11', 'l25', 'l49', 'l60', 'l70', 'l79', 'l87', 'l94', 'l100', 'l105', 'l109', 'l113', 'l114', 'l115']", + "123, immunodeficient ['l12', 'l26', 'l38', 'l50', 'l61', 'l71', 'l80', 'l88', 'l95', 'l101', 'l106', 'l110', 'l113', 'l116', 'l117']", + "124, female ['l13', 'l27', 'l39', 'l51', 'l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l107', 'l111', 'l114', 'l116', 'l118']", + "125, mice. ['l14', 'l28', 'l40', 'l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l108', 'l112', 'l115', 'l117', 'l118']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "germline", + "cells," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "to", + "stably", + "express", + "GFP," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "to", + "stably", + "express", + "GFP," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "human" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "to", + "stably", + "express", + "GFP," + ] + }, + "context": { + "val": "patient", + "words": [ + "ovarian", + "cortical", + "biopsies" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "to", + "stably", + "express", + "GFP," + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenotransplantation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "to", + "stably", + "express", + "GFP," + ] + }, + "context": { + "val": "organism", + "words": [ + "immunodeficient", + "female", + "mice." + ] + } + } + ] + }, + { + "PMID": "22344299", + "TEXT": "The signaling molecule Wnt regulates bone homeostasis through β-catenin-dependent canonical and β-catenin-independent noncanonical pathways. Impairment of canonical Wnt signaling causes bone loss in arthritis and osteoporosis; however, it is unclear how noncanonical Wnt signaling regulates bone resorption. Wnt5a activates noncanonical Wnt signaling through receptor tyrosine kinase-like orphan receptor (Ror) proteins. We showed that Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhanced osteoclastogenesis. Osteoblast-lineage cells expressed Wnt5a, whereas osteoclast precursors expressed Ror2. Mice deficient in either Wnt5a or Ror2, and those with either osteoclast precursor-specific Ror2 deficiency or osteoblast-lineage cell-specific Wnt5a deficiency showed impaired osteoclastogenesis. Wnt5a-Ror2 signals enhanced receptor activator of nuclear factor-κB (RANK) expression in osteoclast precursors by activating JNK and recruiting c-Jun on the promoter of the gene encoding RANK, thereby enhancing RANK ligand (RANKL)-induced osteoclastogenesis. A soluble form of Ror2 acted as a decoy receptor of Wnt5a and abrogated bone destruction in mouse arthritis models. Our results suggest that the Wnt5a-Ror2 pathway is crucial for osteoclastogenesis in physiological and pathological environments and represents a therapeutic target for bone diseases, including arthritis.", + "TAG_DATA": [ + "72, Mice {'context': 'B-organism'}", + "73, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "74, in {'perturbing_action': 'I-gene loss-of-function'}", + "75, either {'perturbing_action': 'I-gene loss-of-function'}", + "76, Wnt5a {'perturbing_action': 'I-gene loss-of-function'}", + "77, or {'perturbing_action': 'I-gene loss-of-function'}", + "78, Ror2, {'perturbing_action': 'I-gene loss-of-function'}", + "83, osteoclast {'perturbing_action': 'B-gene loss-of-function'}", + "84, precursor-specific {'perturbing_action': 'I-gene loss-of-function'}", + "85, Ror2 {'perturbing_action': 'I-gene loss-of-function'}", + "86, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "88, osteoblast-lineage {'perturbing_action': 'B-gene loss-of-function'}", + "89, cell-specific {'perturbing_action': 'I-gene loss-of-function'}", + "90, Wnt5a {'perturbing_action': 'I-gene loss-of-function'}", + "91, deficiency {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "72, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "73, deficient ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "74, in ['l1', 'l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "75, either ['l2', 'l7', 'l12', 'l17', 'l18', 'l19']", + "76, Wnt5a ['l3', 'l8', 'l13', 'l17', 'l20', 'l21', 'l22']", + "77, or ['l4', 'l9', 'l14', 'l18', 'l20', 'l23']", + "78, Ror2, ['l5', 'l10', 'l15', 'l19', 'l21', 'l23', 'l24', 'l25', 'l26']", + "83, osteoclast ['l24', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "84, precursor-specific ['l11', 'l16', 'l22', 'l25', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "85, Ror2 ['l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "86, deficiency ['l26', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "88, osteoblast-lineage ['l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "89, cell-specific ['l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "90, Wnt5a ['l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "91, deficiency ['l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "either", + "Wnt5a", + "or", + "Ror2," + ] + } + } + ] + }, + { + "PMID": "22344296", + "TEXT": "Highly active antiretroviral therapy (HAART) has dramatically decreased mortality from HIV-1 infection and is a major achievement of modern medicine. However, there is no fundamental theory of HAART. Elegant models describe the dynamics of viral replication, but a metric for the antiviral activity of drug combinations relative to a target value needed for control of replication is lacking. Treatment guidelines are based on empirical results of clinical trials in which other factors such as regimen tolerability also affect outcome. Why only certain drug combinations control viral replication remains unclear. Here we quantify the intrinsic antiviral activity of antiretroviral drug combinations. We show that most single antiretroviral drugs show previously unappreciated complex nonlinear pharmacodynamics that determine their inhibitory potential at clinical concentrations. We demonstrate that neither of the major theories for drug combinations accurately predicts the combined effects of multiple antiretrovirals. However, the combined effects can be understood with a new approach that considers the degree of independence of drug effects. This analysis allows a direct comparison of the inhibitory potential of different drug combinations under clinical concentrations, reconciles the results of clinical trials, defines a target level of inhibition associated with treatment success and provides a rational basis for treatment simplification and optimization.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22310693", + "TEXT": "Pathogens exhibit remarkable abilities to flout therapeutic intervention. This outcome is driven by evolution, either as a direct response to intervention (e.g. the evolution of antibiotic resistance), or through long-term coevolution generating host or parasite traits that interact with therapy in undesirable or unpredicted ways. To make progress, the concepts and techniques of evolutionary biology must be deeply integrated with traditional approaches to immunology and pathogen biology. An interdisciplinary approach can inform control strategies, or even patient treatment, positioning us to meet the current and future challenges of controlling infectious diseases.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22286308", + "TEXT": "The microtubule-associated protein tau has risk alleles for both Alzheimer's disease and Parkinson's disease and mutations that cause brain degenerative diseases termed tauopathies. Aggregated tau forms neurofibrillary tangles in these pathologies, but little is certain about the function of tau or its mode of involvement in pathogenesis. Neuronal iron accumulation has been observed pathologically in the cortex in Alzheimer's disease, the substantia nigra (SN) in Parkinson's disease and various brain regions in the tauopathies. Here we report that tau-knockout mice develop age-dependent brain atrophy, iron accumulation and SN neuronal loss, with concomitant cognitive deficits and parkinsonism. These changes are prevented by oral treatment with a moderate iron chelator, clioquinol. Amyloid precursor protein (APP) ferroxidase activity couples with surface ferroportin to export iron, but its activity is inhibited in Alzheimer's disease, thereby causing neuronal iron accumulation. In primary neuronal culture, we found loss of tau also causes iron retention, by decreasing surface trafficking of APP. Soluble tau levels fall in affected brain regions in Alzheimer's disease and tauopathies, and we found a similar decrease of soluble tau in the SN in both Parkinson's disease and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. These data suggest that the loss of soluble tau could contribute to toxic neuronal iron accumulation in Alzheimer's disease, Parkinson's disease and tauopathies, and that it can be rescued pharmacologically.", + "TAG_DATA": [ + "78, tau-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "79, mice {'context': 'B-organism'}", + "136, primary {'context': 'B-cells'}", + "137, neuronal {'context': 'I-cells'}", + "138, culture, {'context': 'I-cells'}", + "141, loss {'perturbing_action': 'B-gene loss-of-function'}", + "142, of {'perturbing_action': 'I-gene loss-of-function'}", + "143, tau {'perturbing_action': 'I-gene loss-of-function'}", + "187, mouse {'context': 'B-organism'}", + "188, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "78, tau-knockout ['l0']", + "79, mice ['l0']", + "136, primary ['l1', 'l2', 'l3', 'l4', 'l5']", + "137, neuronal ['l1', 'l6', 'l7', 'l8', 'l9']", + "138, culture, ['l2', 'l6', 'l10', 'l11', 'l12']", + "141, loss ['l3', 'l7', 'l10', 'l13', 'l14']", + "142, of ['l4', 'l8', 'l11', 'l13', 'l15']", + "143, tau ['l5', 'l9', 'l12', 'l14', 'l15']", + "187, mouse ['l16']", + "188, model. ['l16']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "tau-knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "primary", + "neuronal", + "culture," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "tau" + ] + } + } + ] + }, + { + "PMID": "22286305", + "TEXT": "Leprosy provides a model to investigate mechanisms of immune regulation in humans, given that the disease forms a spectrum of clinical presentations that correlate with host immune responses. Here we identified 13 miRNAs that were differentially expressed in the lesions of subjects with progressive lepromatous (L-lep) versus the self-limited tuberculoid (T-lep) disease. Bioinformatic analysis revealed a significant enrichment of L-lep-specific miRNAs that preferentially target key immune genes downregulated in L-lep versus T-lep lesions. The most differentially expressed miRNA in L-lep lesions, hsa-mir-21, was upregulated in Mycobacterium leprae-infected monocytes. By directly downregulating Toll-like receptor 2/1 heterodimer (TLR2/1)-induced CYP27B1 and IL1B expression as well as indirectly upregulating interleukin-10 (IL-10), hsa-mir-21 inhibited expression of the genes encoding two vitamin D-dependent antimicrobial peptides, CAMP and DEFB4A. Conversely, knockdown of hsa-mir-21 in M. leprae-infected monocytes enhanced expression of CAMP and DEFB4A and restored TLR2/1-mediated antimicrobial activity against M. leprae. Therefore, the ability of M. leprae to upregulate hsa-mir-21 targets multiple genes associated with the immunologically localized disease form, providing an effective mechanism to escape from the vitamin D-dependent antimicrobial pathway.", + "TAG_DATA": [ + "123, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "124, of {'perturbing_action': 'I-rnai/knockdown'}", + "125, hsa-mir-21 {'perturbing_action': 'I-rnai/knockdown'}", + "129, monocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "123, knockdown ['l0', 'l1', 'l2']", + "124, of ['l0', 'l3', 'l4']", + "125, hsa-mir-21 ['l1', 'l3', 'l5']", + "129, monocytes ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "hsa-mir-21" + ] + }, + "context": { + "val": "cells", + "words": [ + "monocytes" + ] + } + } + ] + }, + { + "PMID": "22270723", + "TEXT": "Although aberrant DNA methylation is considered to be one of the key ways by which tumor-suppressor and DNA-repair genes are silenced during tumor initiation and progression, the mechanisms underlying DNA methylation alterations in cancer remain unclear. Here we show that prostaglandin E(2) (PGE(2)) silences certain tumor-suppressor and DNA-repair genes through DNA methylation to promote tumor growth. These findings uncover a previously unrecognized role for PGE(2) in the promotion of tumor progression.", + "TAG_DATA": [ + "53, promote {'effect': 'B-positive'}", + "54, tumor {'phenotype': 'B-tumour growth'}", + "55, growth. {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "53, promote ['l0', 'l1']", + "54, tumor ['l0', 'l2']", + "55, growth. ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promote" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + } + ] + }, + { + "PMID": "22270722", + "TEXT": "Glutamate, a major neurotransmitter in the brain, shows a pH- and concentration-dependent chemical exchange saturation transfer effect (GluCEST) between its amine group and bulk water, with potential for in vivo imaging by nuclear magnetic resonance. GluCEST asymmetry is observed ∼3 p.p.m. downfield from bulk water. Middle cerebral artery occlusion in the rat brain resulted in an ∼100% elevation of GluCEST in the ipsilateral side compared with the contralateral side, predominantly owing to pH changes. In a rat brain tumor model with blood-brain barrier disruption, intravenous glutamate injection resulted in a clear elevation of GluCEST and a similar increase in the proton magnetic resonance spectroscopy signal of glutamate. GluCEST maps from healthy human brain were also obtained. These results demonstrate the feasibility of using GluCEST for mapping relative changes in glutamate concentration, as well as pH, in vivo. Contributions from other brain metabolites to the GluCEST effect are also discussed.", + "TAG_DATA": [ + "51, rat {'context': 'B-tissue/organ'}", + "52, brain {'context': 'I-tissue/organ'}", + "76, rat {'context': 'B-neoplasm'}", + "77, brain {'context': 'I-neoplasm'}", + "78, tumor {'context': 'I-neoplasm'}", + "79, model {'context': 'I-neoplasm'}", + "110, healthy {'context': 'B-tissue/organ'}", + "111, human {'context': 'I-tissue/organ'}", + "112, brain {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "51, rat ['l0']", + "52, brain ['l0']", + "76, rat ['l1', 'l2', 'l3']", + "77, brain ['l1', 'l4', 'l5']", + "78, tumor ['l2', 'l4', 'l6']", + "79, model ['l3', 'l5', 'l6']", + "110, healthy ['l7', 'l8']", + "111, human ['l7', 'l9']", + "112, brain ['l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "22245780", + "TEXT": "Adequate lipid secretion by mammary glands during lactation is essential for the survival of mammalian offspring. However, the mechanism governing this process is poorly understood. Here we show that Cidea is expressed at high levels in lactating mammary glands and its deficiency leads to premature pup death as a result of severely reduced milk lipids. Furthermore, the expression of xanthine oxidoreductase (XOR), an essential factor for milk lipid secretion, is markedly lower in Cidea-deficient mammary glands. Conversely, ectopic Cidea expression induces the expression of XOR and enhances lipid secretion in vivo. Unexpectedly, as Cidea has heretofore been thought of as a cytoplasmic protein, we detected it in the nucleus and found it to physically interact with transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) in mammary epithelial cells. We also observed that Cidea induces XOR expression by promoting the association of C/EBPβ onto, and the dissociation of HDAC1 from, the promoter of the Xdh gene encoding XOR. Finally, we found that Fsp27, another CIDE family protein, is detected in the nucleus and interacts with C/EBPβ to regulate expression of a subset of C/EBPβ downstream genes in adipocytes. Thus, Cidea acts as a previously unknown transcriptional coactivator of C/EBPβ in mammary glands to control lipid secretion and pup survival.", + "TAG_DATA": [ + "73, Cidea-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "77, ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "78, Cidea {'perturbing_action': 'I-gene gain-of-function'}", + "79, expression {'perturbing_action': 'I-gene gain-of-function'}", + "89, in {'context': 'B-in vivo'}", + "90, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "73, Cidea-deficient ['l0', 'l1']", + "77, ectopic ['l2', 'l3', 'l4', 'l5']", + "78, Cidea ['l2', 'l6', 'l7', 'l8']", + "79, expression ['l3', 'l6', 'l9', 'l10']", + "89, in ['l0', 'l4', 'l7', 'l9', 'l11']", + "90, vivo. ['l1', 'l5', 'l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cidea-deficient" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "Cidea", + "expression" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "22227670", + "TEXT": "Autoimmune diseases have a complex etiology and despite great progress having been made in our comprehension of these disorders, there has been limited success in the development of approved medications based on these insights. Development of drugs and strategies for application in translational research and medicine are hampered by an inadequate molecular definition of the human autoimmune phenotype and the organizational models that are necessary to clarify this definition.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22227662", + "TEXT": "Collapsing glomerulopathy, the classic kidney lesion in HIV-associated nephropathy, is characterized by the closure of glomerular capillary loops and epithelial cell proliferation. A new study shows that upregulation of TERT, the reverse transcriptase component of telomerase, in podocytes, the key filtration cells in the kidney, plays a major part in the development of this condition by activating Wnt signaling (pages 111–119).", + "TAG_DATA": [ + "37, podocytes, {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "22157679", + "TEXT": "Screening for genes that reprogram cancer cells for the tumor reversion switch identified TCTP (encoding translationally controlled tumor protein) as a crucial regulator of apoptosis. Here we report a negative feedback loop between P53 and TCTP. TCTP promotes P53 degradation by competing with NUMB for binding to P53-MDM2-containing complexes. TCTP inhibits MDM2 auto-ubiquitination and promotes MDM2-mediated ubiquitination and degradation of P53. Notably, Tctp haploinsufficient mice are sensitized to P53-dependent apoptosis. In addition, P53 directly represses TCTP transcription. In 508 breast cancers, high-TCTP status associates with poorly differentiated, aggressive G3-grade tumors, predicting poor prognosis (P < 0.0005). Tctp knockdown in primary mammary tumor cells from ErbB2 transgenic mice results in increased P53 expression and a decreased number of stem-like cancer cells. The pharmacological compounds sertraline and thioridazine increase the amount of P53 by neutralizing TCTP's action on the MDM2-P53 axis. This study links TCTP and P53 in a previously unidentified regulatory circuitry that may underlie the relevance of TCTP in cancer.", + "TAG_DATA": [ + "62, Tctp {'perturbing_action': 'B-gene loss-of-function'}", + "63, haploinsufficient {'perturbing_action': 'I-gene loss-of-function'}", + "64, mice {'context': 'B-organism'}", + "66, sensitized {'effect': 'B-positive'}", + "69, apoptosis. {'phenotype': 'B-apoptosis'}", + "96, Tctp {'perturbing_action': 'B-rnai/knockdown'}", + "97, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "99, primary {'context': 'B-transformed cells'}", + "100, mammary {'context': 'I-transformed cells'}", + "101, tumor {'context': 'I-transformed cells'}", + "102, cells {'context': 'I-transformed cells'}", + "104, ErbB2 {'perturbing_action': 'B-gene gain-of-function'}", + "105, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "106, mice {'context': 'B-organism'}", + "117, stem-like {'context': 'B-transformed cells'}", + "118, cancer {'context': 'I-transformed cells'}", + "119, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "62, Tctp ['l0', 'l1', 'l2', 'l3']", + "63, haploinsufficient ['l0', 'l4', 'l5', 'l6']", + "64, mice ['l1', 'l4', 'l7', 'l8']", + "66, sensitized ['l2', 'l5', 'l7', 'l9']", + "69, apoptosis. ['l3', 'l6', 'l8', 'l9']", + "96, Tctp ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "97, knockdown ['l10', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "99, primary ['l11', 'l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "100, mammary ['l12', 'l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "101, tumor ['l13', 'l23', 'l32', 'l40', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "102, cells ['l14', 'l24', 'l33', 'l41', 'l47', 'l53', 'l54', 'l55', 'l56']", + "104, ErbB2 ['l15', 'l25', 'l34', 'l42', 'l48', 'l53', 'l57', 'l58', 'l59', 'l60', 'l61']", + "105, transgenic ['l16', 'l26', 'l35', 'l43', 'l49', 'l54', 'l57', 'l62', 'l63', 'l64', 'l65']", + "106, mice ['l17', 'l27', 'l36', 'l44', 'l50', 'l55', 'l58', 'l62', 'l66', 'l67', 'l68']", + "117, stem-like ['l18', 'l28', 'l37', 'l59', 'l63', 'l66', 'l69', 'l70']", + "118, cancer ['l19', 'l29', 'l38', 'l45', 'l51', 'l60', 'l64', 'l67', 'l69', 'l71']", + "119, cells. ['l20', 'l30', 'l39', 'l46', 'l52', 'l56', 'l61', 'l65', 'l68', 'l70', 'l71']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tctp", + "haploinsufficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tctp", + "haploinsufficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tctp", + "haploinsufficient" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Tctp", + "knockdown" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "mammary", + "tumor", + "cells", + "stem-like", + "cancer", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Tctp", + "knockdown" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "primary", + "mammary", + "tumor", + "cells", + "stem-like", + "cancer", + "cells." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ErbB2", + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ErbB2", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "22138754", + "TEXT": "The platelet-derived growth factor (PDGF) signaling system contributes to tumor angiogenesis and vascular remodeling. Here we show in mouse tumor models that PDGF-BB induces erythropoietin (EPO) mRNA and protein expression by targeting stromal and perivascular cells that express PDGF receptor-β (PDGFR-β). Tumor-derived PDGF-BB promoted tumor growth, angiogenesis and extramedullary hematopoiesis at least in part through modulation of EPO expression. Moreover, adenoviral delivery of PDGF-BB to tumor-free mice increased both EPO production and erythropoiesis, as well as protecting from irradiation-induced anemia. At the molecular level, we show that the PDGF-BB-PDGFR-bβ signaling system activates the EPO promoter, acting in part through transcriptional regulation by the transcription factor Atf3, possibly through its association with two additional transcription factors, c-Jun and Sp1. Our findings suggest that PDGF-BB-induced EPO promotes tumor growth through two mechanisms: first, paracrine stimulation of tumor angiogenesis by direct induction of endothelial cell proliferation, migration, sprouting and tube formation, and second, endocrine stimulation of extramedullary hematopoiesis leading to increased oxygen perfusion and protection against tumor-associated anemia.", + "TAG_DATA": [ + "18, mouse {'context': 'B-neoplasm'}", + "19, tumor {'context': 'I-neoplasm'}", + "20, models {'context': 'I-neoplasm'}", + "32, stromal {'context': 'B-cells'}", + "33, and {'context': 'I-cells'}", + "34, perivascular {'context': 'I-cells'}", + "35, cells {'context': 'I-cells'}", + "43, promoted {'effect': 'B-positive'}", + "44, tumor {'phenotype': 'B-tumour growth'}", + "45, growth, {'phenotype': 'I-tumour growth'}", + "60, adenoviral {'perturbing_action': 'B-gene gain-of-function'}", + "61, delivery {'perturbing_action': 'I-gene gain-of-function'}", + "62, of {'perturbing_action': 'I-gene gain-of-function'}", + "63, PDGF-BB {'perturbing_action': 'I-gene gain-of-function'}", + "65, tumor-free {'context': 'B-organism'}", + "66, mice {'context': 'I-organism'}", + "124, promotes {'effect': 'B-positive'}", + "125, tumor {'phenotype': 'B-tumour growth'}", + "126, growth {'phenotype': 'I-tumour growth'}", + "138, induction {'effect': 'B-positive'}", + "140, endothelial {'context': 'B-cells'}", + "141, cell {'context': 'I-cells'}", + "142, proliferation, {'phenotype': 'B-proliferation'}", + "143, migration, {'phenotype': 'B-migration'}", + "146, tube {'phenotype': 'B-tumourigenesis'}", + "147, formation, {'phenotype': 'I-tumourigenesis'}" + ], + "LINK_DATA": [ + "18, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "19, tumor ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "20, models ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "32, stromal ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "33, and ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "34, perivascular ['l4', 'l12', 'l19', 'l25', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "35, cells ['l5', 'l13', 'l20', 'l26', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "43, promoted ['l6', 'l14', 'l21', 'l27', 'l32', 'l37', 'l41', 'l45', 'l46']", + "44, tumor ['l7', 'l15', 'l22', 'l28', 'l33', 'l38', 'l42', 'l45', 'l47']", + "45, growth, ['l8', 'l16', 'l23', 'l29', 'l34', 'l39', 'l43', 'l46', 'l47']", + "60, adenoviral ['l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "61, delivery ['l48', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "62, of ['l49', 'l60', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "63, PDGF-BB ['l50', 'l61', 'l70', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "65, tumor-free ['l51', 'l62', 'l71', 'l79', 'l87']", + "66, mice ['l35', 'l40', 'l44', 'l52', 'l63', 'l72', 'l80', 'l87']", + "124, promotes ['l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "125, tumor ['l88', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "126, growth ['l89', 'l97', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "138, induction ['l53', 'l90', 'l98', 'l105', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "140, endothelial ['l54', 'l64', 'l73', 'l81', 'l91', 'l99', 'l106', 'l112', 'l118', 'l119', 'l120', 'l121', 'l122']", + "141, cell ['l55', 'l65', 'l74', 'l82', 'l92', 'l100', 'l107', 'l113', 'l118', 'l123', 'l124', 'l125', 'l126']", + "142, proliferation, ['l56', 'l66', 'l75', 'l83', 'l93', 'l101', 'l108', 'l114', 'l119', 'l123', 'l127', 'l128', 'l129']", + "143, migration, ['l57', 'l67', 'l76', 'l84', 'l94', 'l102', 'l109', 'l115', 'l120', 'l124', 'l127', 'l130', 'l131']", + "146, tube ['l58', 'l68', 'l77', 'l85', 'l95', 'l103', 'l110', 'l116', 'l121', 'l125', 'l128', 'l130', 'l132']", + "147, formation, ['l59', 'l69', 'l78', 'l86', 'l96', 'l104', 'l111', 'l117', 'l122', 'l126', 'l129', 'l131', 'l132']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "tumor", + "models" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "tumor", + "models" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "stromal", + "and", + "perivascular", + "cells", + "endothelial", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted", + "promotes", + "induction" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "stromal", + "and", + "perivascular", + "cells", + "endothelial", + "cell" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth,", + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted", + "promotes", + "induction" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth,", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral", + "delivery", + "of", + "PDGF-BB" + ] + }, + "context": { + "val": "organism", + "words": [ + "tumor-free", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral", + "delivery", + "of", + "PDGF-BB" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral", + "delivery", + "of", + "PDGF-BB" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral", + "delivery", + "of", + "PDGF-BB" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral", + "delivery", + "of", + "PDGF-BB" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tube", + "formation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes", + "induction" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes", + "induction" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes", + "induction" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tube", + "formation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tube", + "formation," + ] + } + } + ] + }, + { + "PMID": "22101768", + "TEXT": "Using a systems biology approach, we discovered and dissected a three-way interaction between the immune system, the intestinal epithelium and the microbiota. We found that, in the absence of B cells, or of IgA, and in the presence of the microbiota, the intestinal epithelium launches its own protective mechanisms, upregulating interferon-inducible immune response pathways and simultaneously repressing Gata4-related metabolic functions. This shift in intestinal function leads to lipid malabsorption and decreased deposition of body fat. Network analysis revealed the presence of two interconnected epithelial-cell gene networks, one governing lipid metabolism and another regulating immunity, that were inversely expressed. Gene expression patterns in gut biopsies from individuals with common variable immunodeficiency or with HIV infection and intestinal malabsorption were very similar to those of the B cell-deficient mice, providing a possible explanation for a longstanding enigmatic association between immunodeficiency and defective lipid absorption in humans.", + "TAG_DATA": [ + "124, B {'perturbing_action': 'B-gene loss-of-function'}", + "125, cell-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "126, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "124, B ['l0', 'l1']", + "125, cell-deficient ['l0', 'l2']", + "126, mice, ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "B", + "cell-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "22081021", + "TEXT": "Nitric oxide (NO) is crucial in diverse physiological and pathological processes. We show that a hypomorphic mouse model of argininosuccinate lyase (encoded by Asl) deficiency has a distinct phenotype of multiorgan dysfunction and NO deficiency. Loss of Asl in both humans and mice leads to reduced NO synthesis, owing to both decreased endogenous arginine synthesis and an impaired ability to use extracellular arginine for NO production. Administration of nitrite, which can be converted into NO in vivo, rescued the manifestations of NO deficiency in hypomorphic Asl mice, and a nitric oxide synthase (NOS)-independent NO donor restored NO-dependent vascular reactivity in humans with ASL deficiency. Mechanistic studies showed that ASL has a structural function in addition to its catalytic activity, by which it contributes to the formation of a multiprotein complex required for NO production. Our data demonstrate a previously unappreciated role for ASL in NOS function and NO homeostasis. Hence, ASL may serve as a target for manipulating NO production in experimental models, as well as for the treatment of NO-related diseases.", + "TAG_DATA": [ + "16, mouse {'context': 'I-organism'}", + "17, model {'context': 'I-organism'}", + "35, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "36, of {'perturbing_action': 'I-gene loss-of-function'}", + "37, Asl {'perturbing_action': 'I-gene loss-of-function'}", + "40, humans {'context': 'B-organism'}", + "42, mice {'context': 'B-organism'}", + "84, hypomorphic {'perturbing_action': 'B-gene loss-of-function'}", + "86, mice, {'context': 'B-organism'}", + "100, humans {'context': 'B-patient'}", + "102, ASL {'perturbing_action': 'B-gene loss-of-function'}", + "103, deficiency. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "16, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "17, model ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "35, Loss ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "36, of ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "37, Asl ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "40, humans ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "42, mice ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "84, hypomorphic ['l21']", + "86, mice, ['l21']", + "100, humans ['l22', 'l23']", + "102, ASL ['l22', 'l24']", + "103, deficiency. ['l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "humans", + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Loss", + "of", + "Asl", + "hypomorphic" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "humans" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ASL", + "deficiency." + ] + } + } + ] + }, + { + "PMID": "22057348", + "TEXT": "Three major modes of cancer therapy (surgery, radiation and chemotherapy) are the mainstay of modern oncologic therapy. To minimize the side effects of these therapies, molecular-targeted cancer therapies, including armed antibody therapy, have been developed with limited success. In this study, we have developed a new type of molecular-targeted cancer therapy, photoimmunotherapy (PIT), that uses a target-specific photosensitizer based on a near-infrared (NIR) phthalocyanine dye, IR700, conjugated to monoclonal antibodies (mAbs) targeting epidermal growth factor receptors. Cell death was induced immediately after irradiating mAb-IR700-bound target cells with NIR light. We observed in vivo tumor shrinkage after irradiation with NIR light in target cells expressing the epidermal growth factor receptor. The mAb-IR700 conjugates were most effective when bound to the cell membrane and produced no phototoxicity when not bound, suggesting a different mechanism for PIT as compared to conventional photodynamic therapies. Target-selective PIT enables treatment of cancer based on mAb binding to the cell membrane.", + "TAG_DATA": [ + "76, Cell {'phenotype': 'B-cell death'}", + "77, death {'phenotype': 'I-cell death'}", + "79, induced {'effect': 'B-positive'}", + "84, target {'context': 'B-cells'}", + "85, cells {'context': 'I-cells'}", + "91, in {'context': 'B-in vivo'}", + "92, vivo {'context': 'I-in vivo'}", + "93, tumor {'phenotype': 'B-tumour regression'}", + "94, shrinkage {'phenotype': 'I-tumour regression'}", + "101, target {'context': 'B-cells'}", + "102, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "76, Cell ['l0', 'l1', 'l2', 'l3']", + "77, death ['l0', 'l4', 'l5', 'l6']", + "79, induced ['l1', 'l4', 'l7', 'l8']", + "84, target ['l2', 'l5', 'l7', 'l9']", + "85, cells ['l3', 'l6', 'l8', 'l9']", + "91, in ['l10', 'l11', 'l12', 'l13', 'l14']", + "92, vivo ['l10', 'l15', 'l16', 'l17', 'l18']", + "93, tumor ['l11', 'l15', 'l19', 'l20', 'l21']", + "94, shrinkage ['l12', 'l16', 'l19', 'l22', 'l23']", + "101, target ['l13', 'l17', 'l20', 'l22', 'l24']", + "102, cells ['l14', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "cell death", + "words": [ + "Cell", + "death" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "Cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "target", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "target", + "cells" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "shrinkage" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "shrinkage" + ] + }, + "context": { + "val": "cells", + "words": [ + "target", + "cells" + ] + } + } + ] + }, + { + "PMID": "22057346", + "TEXT": "Osteoarthritis, characterized by the breakdown of articular cartilage in synovial joints, has long been viewed as the result of 'wear and tear'. Although low-grade inflammation is detected in osteoarthritis, its role is unclear. Here we identify a central role for the inflammatory complement system in the pathogenesis of osteoarthritis. Through proteomic and transcriptomic analyses of synovial fluids and membranes from individuals with osteoarthritis, we find that expression and activation of complement is abnormally high in human osteoarthritic joints. Using mice genetically deficient in complement component 5 (C5), C6 or the complement regulatory protein CD59a, we show that complement, specifically, the membrane attack complex (MAC)-mediated arm of complement, is crucial to the development of arthritis in three different mouse models of osteoarthritis. Pharmacological modulation of complement in wild-type mice confirmed the results obtained with genetically deficient mice. Expression of inflammatory and degradative molecules was lower in chondrocytes from destabilized joints from C5-deficient mice than C5-sufficient mice, and MAC induced production of these molecules in cultured chondrocytes. Further, MAC colocalized with matrix metalloprotease 13 (MMP13) and with activated extracellular signal-regulated kinase (ERK) around chondrocytes in human osteoarthritic cartilage. Our findings indicate that dysregulation of complement in synovial joints has a key role in the pathogenesis of osteoarthritis.", + "TAG_DATA": [ + "79, mice {'context': 'B-organism'}", + "80, genetically {'perturbing_action': 'B-gene loss-of-function'}", + "81, deficient {'perturbing_action': 'I-gene loss-of-function'}", + "82, in {'perturbing_action': 'I-gene loss-of-function'}", + "83, complement {'perturbing_action': 'I-gene loss-of-function'}", + "84, component {'perturbing_action': 'I-gene loss-of-function'}", + "85, 5 {'perturbing_action': 'I-gene loss-of-function'}", + "86, (C5), {'perturbing_action': 'I-gene loss-of-function'}", + "87, C6 {'perturbing_action': 'I-gene loss-of-function'}", + "88, or {'perturbing_action': 'I-gene loss-of-function'}", + "89, the {'perturbing_action': 'I-gene loss-of-function'}", + "127, mice {'context': 'B-organism'}", + "135, mice. {'context': 'B-organism'}", + "145, chondrocytes {'context': 'B-cells'}", + "150, C5-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "151, mice {'context': 'B-organism'}", + "164, chondrocytes. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "79, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "80, genetically ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "81, deficient ['l1', 'l9', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "82, in ['l2', 'l10', 'l18', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "83, complement ['l3', 'l11', 'l19', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "84, component ['l4', 'l12', 'l20', 'l27', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "85, 5 ['l5', 'l13', 'l21', 'l28', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47']", + "86, (C5), ['l6', 'l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l48', 'l49', 'l50']", + "87, C6 ['l7', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l51', 'l52']", + "88, or ['l8', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l53']", + "89, the ['l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l53', 'l54']", + "127, mice ['l55', 'l56', 'l57', 'l58', 'l59']", + "135, mice. ['l55', 'l60', 'l61', 'l62', 'l63']", + "145, chondrocytes ['l54', 'l56', 'l60', 'l64', 'l65', 'l66']", + "150, C5-deficient ['l57', 'l61', 'l64', 'l67', 'l68']", + "151, mice ['l58', 'l62', 'l65', 'l67', 'l69']", + "164, chondrocytes. ['l59', 'l63', 'l66', 'l68', 'l69']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetically", + "deficient", + "in", + "complement", + "component", + "5", + "(C5),", + "C6", + "or", + "C5-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "C5-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "chondrocytes", + "chondrocytes." + ] + } + } + ] + }, + { + "PMID": "22001907", + "TEXT": "Spinocerebellar ataxia type 1 (SCA1) is an adult-onset, dominantly inherited neurodegenerative disease caused by expansion of a glutamine repeat tract in ataxin-1 (ATXN1). Although the precise function of ATXN1 remains elusive, it seems to be involved in transcriptional repression. We find that mutant ATXN1 represses transcription of the neurotrophic and angiogenic factor vascular endothelial growth factor (VEGF). Genetic overexpression or pharmacologic infusion of recombinant VEGF mitigates SCA1 pathogenesis, suggesting a new therapeutic strategy for this disease.", + "TAG_DATA": [ + "42, mutant {'perturbing_action': 'B-other'}", + "43, ATXN1 {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "42, mutant ['l0']", + "43, ATXN1 ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21988971", + "TEXT": "In October 2005, Mahendra Rao shocked the scientific community when he quit his job as head of the US National Institute on Aging's stem cell section and announced plans to go into industry. Rao felt that a ban at the time on federal funding for most human embryonic stem cell research hampered researchers in his division and prohibited him from doing the job he was hired to do. So he joined the research-tool giant Invitrogen (which later became Life Technologies) as vice president of regenerative medicine at the company's Maryland facility. Six years on, times have changed in the field of stem cell biology: rules governing taxpayer-backed research involving embryonic stem (ES) cells have been relaxed in the US, and induced pluripotent stem (iPS) cells have come into the fray. Prompted by those changes, Rao opted to return to the US National Institutes of Health (NIH) in August to head the new Intramural Center for Regenerative Medicine. The $52 million center was launched in early 2010 by the agency to develop new therapies using stem cell approaches. With a heightened focus at the NIH on translational medicine, Elie Dolgin spoke to Rao to find out how he plans to turn stem cell discoveries into cell-based therapies.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21926978", + "TEXT": "Staphylococcus aureus is a major cause of human disease, responsible for half a million infections and approximately 20,000 deaths per year in the United States alone. This pathogen secretes α-hemolysin, a pore-forming cytotoxin that contributes to the pathogenesis of pneumonia. α-hemolysin injures epithelial cells in vitro by interacting with its receptor, the zinc-dependent metalloprotease ADAM10 (ref. 6). We show here that mice harboring a conditional disruption of the Adam10 gene in lung epithelium are resistant to lethal pneumonia. Investigation of the molecular mechanism of toxin-receptor function revealed that α-hemolysin upregulates ADAM10 metalloprotease activity in alveolar epithelial cells, resulting in cleavage of the adherens junction protein E-cadherin. Cleavage is associated with disruption of epithelial barrier function, contributing to the pathogenesis of lethal acute lung injury. A metalloprotease inhibitor of ADAM10 prevents E-cadherin cleavage in response to Hla; similarly, toxin-dependent E-cadherin proteolysis and barrier disruption is attenuated in ADAM10-knockout mice. Together, these data attest to the function of ADAM10 as the cellular receptor for α-hemolysin. The observation that α-hemolysin can usurp the metalloprotease activity of its receptor reveals a previously unknown mechanism of pore-forming cytotoxin action in which pathologic insults are not solely the result of irreversible membrane injury and defines ADAM10 inhibition as a strategy to attenuate α-hemolysin-induced disease.", + "TAG_DATA": [ + "61, mice {'context': 'B-organism'}", + "64, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "65, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "66, of {'perturbing_action': 'I-gene loss-of-function'}", + "67, the {'perturbing_action': 'I-gene loss-of-function'}", + "68, Adam10 {'perturbing_action': 'I-gene loss-of-function'}", + "69, gene {'perturbing_action': 'I-gene loss-of-function'}", + "71, lung {'context': 'B-tissue/organ'}", + "72, epithelium {'context': 'I-tissue/organ'}", + "94, alveolar {'context': 'B-cells'}", + "95, epithelial {'context': 'I-cells'}", + "96, cells, {'context': 'I-cells'}", + "125, metalloprotease {'perturbing_action': 'B-pharmacological inhibition'}", + "126, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "127, of {'perturbing_action': 'I-pharmacological inhibition'}", + "128, ADAM10 {'perturbing_action': 'I-pharmacological inhibition'}", + "146, ADAM10-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "147, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "61, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "64, conditional ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "65, disruption ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "66, of ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "67, the ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "68, Adam10 ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "69, gene ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "71, lung ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "72, epithelium ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "94, alveolar ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "95, epithelial ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "96, cells, ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "125, metalloprotease ['l66', 'l67', 'l68']", + "126, inhibitor ['l66', 'l69', 'l70']", + "127, of ['l67', 'l69', 'l71']", + "128, ADAM10 ['l68', 'l70', 'l71']", + "146, ADAM10-knockout ['l72']", + "147, mice. ['l72']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "disruption", + "of", + "the", + "Adam10", + "gene", + "ADAM10-knockout" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "disruption", + "of", + "the", + "Adam10", + "gene" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung", + "epithelium" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "disruption", + "of", + "the", + "Adam10", + "gene" + ] + }, + "context": { + "val": "cells", + "words": [ + "alveolar", + "epithelial", + "cells," + ] + } + } + ] + }, + { + "PMID": "21873989", + "TEXT": "Imatinib mesylate targets mutated KIT oncoproteins in gastrointestinal stromal tumor (GIST) and produces a clinical response in 80% of patients. The mechanism is believed to depend predominantly on the inhibition of KIT-driven signals for tumor-cell survival and proliferation. Using a mouse model of spontaneous GIST, we found that the immune system contributes substantially to the antitumor effects of imatinib. Imatinib therapy activated CD8(+) T cells and induced regulatory T cell (T(reg) cell) apoptosis within the tumor by reducing tumor-cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido). Concurrent immunotherapy augmented the efficacy of imatinib in mouse GIST. In freshly obtained human GIST specimens, the T cell profile correlated with imatinib sensitivity and IDO expression. Thus, T cells are crucial to the antitumor effects of imatinib in GIST, and concomitant immunotherapy may further improve outcomes in human cancers treated with targeted agents.", + "TAG_DATA": [ + "40, mouse {'context': 'B-organism'}", + "41, model {'context': 'I-organism'}", + "62, CD8(+) {'context': 'B-cells'}", + "63, T {'context': 'I-cells'}", + "64, cells {'context': 'I-cells'}", + "66, induced {'effect': 'B-positive'}", + "67, regulatory {'context': 'B-cells'}", + "68, T {'context': 'I-cells'}", + "69, cell {'context': 'I-cells'}", + "70, (T(reg) {'context': 'I-cells'}", + "71, cell) {'context': 'I-cells'}", + "72, apoptosis {'phenotype': 'B-apoptosis'}", + "75, tumor {'context': 'B-neoplasm'}", + "78, tumor-cell {'context': 'B-cells'}", + "95, mouse {'context': 'B-neoplasm'}", + "96, GIST. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "40, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "41, model ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "62, CD8(+) ['l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "63, T ['l1', 'l6', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "64, cells ['l2', 'l7', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "66, induced ['l3', 'l8', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "67, regulatory ['l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "68, T ['l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "69, cell ['l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "70, (T(reg) ['l9', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "71, cell) ['l4', 'l10', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "72, apoptosis ['l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "75, tumor ['l5', 'l11', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "78, tumor-cell ['l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "95, mouse ['l78']", + "96, GIST. ['l78']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "T", + "cells", + "regulatory", + "cell", + "(T(reg)", + "cell)", + "tumor-cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "T", + "cells", + "regulatory", + "cell", + "(T(reg)", + "cell)", + "tumor-cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + } + ] + }, + { + "PMID": "21873987", + "TEXT": "Previous studies have proposed roles for hypothalamic reactive oxygen species (ROS) in the modulation of circuit activity of the melanocortin system. Here we show that suppression of ROS diminishes pro-opiomelanocortin (POMC) cell activation and promotes the activity of neuropeptide Y (NPY)- and agouti-related peptide (AgRP)-co-producing (NPY/AgRP) neurons and feeding, whereas ROS-activates POMC neurons and reduces feeding. The levels of ROS in POMC neurons were positively correlated with those of leptin in lean and ob/ob mice, a relationship that was diminished in diet-induced obese (DIO) mice. High-fat feeding resulted in proliferation of peroxisomes and elevated peroxisome proliferator-activated receptor γ (PPAR-γ) mRNA levels within the hypothalamus. The proliferation of peroxisomes in POMC neurons induced by the PPAR-γ agonist rosiglitazone decreased ROS levels and increased food intake in lean mice on high-fat diet. Conversely, the suppression of peroxisome proliferation by the PPAR antagonist GW9662 increased ROS concentrations and c-fos expression in POMC neurons. Also, it reversed high-fat feeding-triggered elevated NPY/AgRP and low POMC neuronal firing, and resulted in decreased feeding of DIO mice. Finally, central administration of ROS alone increased c-fos and phosphorylated signal transducer and activator of transcription 3 (pStat3) expression in POMC neurons and reduced feeding of DIO mice. These observations unmask a previously unknown hypothalamic cellular process associated with peroxisomes and ROS in the central regulation of energy metabolism in states of leptin resistance.", + "TAG_DATA": [ + "89, proliferation {'phenotype': 'B-proliferation'}", + "105, proliferation {'phenotype': 'B-proliferation'}", + "107, peroxisomes {'context': 'B-cells'}", + "109, POMC {'context': 'B-cells'}", + "110, neurons {'context': 'I-cells'}", + "111, induced {'effect': 'B-positive'}", + "115, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "116, rosiglitazone {'perturbing_action': 'I-pharmacological augmentation'}", + "125, lean {'context': 'B-organism'}", + "126, mice {'context': 'I-organism'}", + "132, suppression {'effect': 'B-negative'}", + "135, proliferation {'phenotype': 'B-proliferation'}", + "148, POMC {'context': 'B-cells'}", + "149, neurons. {'context': 'I-cells'}", + "159, POMC {'context': 'B-cells'}", + "160, neuronal {'context': 'I-cells'}", + "169, mice. {'context': 'I-organism'}", + "190, POMC {'context': 'B-cells'}", + "191, neurons {'context': 'I-cells'}", + "197, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "89, proliferation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "105, proliferation ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "107, peroxisomes ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "109, POMC ['l2', 'l11', 'l19', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "110, neurons ['l3', 'l12', 'l20', 'l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "111, induced ['l4', 'l13', 'l21', 'l29', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "114, PPAR-γ ['l5', 'l14', 'l22', 'l30', 'l36', 'l41', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "115, agonist ['l6', 'l15', 'l23', 'l31', 'l37', 'l42', 'l46', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "116, rosiglitazone ['l7', 'l16', 'l24', 'l32', 'l38', 'l43', 'l47', 'l53', 'l59', 'l60', 'l61', 'l62']", + "125, lean ['l8', 'l17', 'l25', 'l33', 'l39', 'l44', 'l48', 'l54', 'l59', 'l63']", + "126, mice ['l9', 'l18', 'l26', 'l34', 'l40', 'l45', 'l49', 'l55', 'l60', 'l63']", + "132, suppression ['l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "135, proliferation ['l50', 'l56', 'l64', 'l70', 'l71']", + "148, POMC ['l51', 'l57', 'l61', 'l65', 'l70', 'l72']", + "149, neurons. ['l27', 'l52', 'l58', 'l62', 'l66', 'l71', 'l72']", + "159, POMC ['l67', 'l73', 'l74']", + "160, neuronal ['l68', 'l73', 'l75']", + "169, mice. ['l69', 'l74', 'l75']", + "190, POMC ['l76', 'l77']", + "191, neurons ['l76', 'l78']", + "197, mice. ['l77', 'l78']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "peroxisomes", + "POMC", + "neurons", + "neurons." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "agonist", + "rosiglitazone" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "organism", + "words": [ + "lean", + "mice" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "peroxisomes", + "POMC", + "neurons" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "peroxisomes", + "POMC", + "neurons", + "neurons." + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "agonist", + "rosiglitazone" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "agonist", + "rosiglitazone" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "lean", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "agonist", + "rosiglitazone" + ] + }, + "context": { + "val": "organism", + "words": [ + "lean", + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppression" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppression" + ] + }, + "context": { + "val": "cells", + "words": [ + "POMC", + "neurons.", + "neuronal" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "21857654", + "TEXT": "Vaccine-induced immunity to Ebola virus infection in nonhuman primates (NHPs) is marked by potent antigen-specific cellular and humoral immune responses; however, the immune mechanism of protection remains unknown. Here we define the immune basis of protection conferred by a highly protective recombinant adenovirus virus serotype 5 (rAd5) encoding Ebola virus glycoprotein (GP) in NHPs. Passive transfer of high-titer polyclonal antibodies from vaccinated Ebola virus-immune cynomolgus macaques to naive macaques failed to confer protection against disease, suggesting a limited role of humoral immunity. In contrast, depletion of CD3(+) T cells in vivo after vaccination and immediately before challenge eliminated immunity in two vaccinated macaques, indicating a crucial requirement for T cells in this setting. The protective effect was mediated largely by CD8(+) cells, as depletion of CD8(+) cells in vivo using the cM-T807 monoclonal antibody (mAb), which does not affect CD4(+) T cell or humoral immune responses, abrogated protection in four out of five subjects. These findings indicate that CD8(+) cells have a major role in rAd5-GP-induced immune protection against Ebola virus infection in NHPs. Understanding the immunologic mechanism of Ebola virus protection will facilitate the development of vaccines for Ebola and related hemorrhagic fever viruses in humans.", + "TAG_DATA": [ + "64, cynomolgus {'context': 'B-organism'}", + "65, macaques {'context': 'I-organism'}", + "68, macaques {'context': 'I-organism'}", + "86, CD3(+) {'context': 'B-cells'}", + "87, T {'context': 'I-cells'}", + "88, cells {'context': 'I-cells'}", + "89, in {'context': 'B-in vivo'}", + "90, vivo {'context': 'I-in vivo'}", + "102, macaques, {'context': 'B-organism'}", + "125, CD8(+) {'context': 'B-cells'}", + "126, cells {'context': 'I-cells'}", + "127, in {'context': 'B-in vivo'}", + "128, vivo {'context': 'I-in vivo'}", + "140, T {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "64, cynomolgus ['l0', 'l1']", + "65, macaques ['l0', 'l2']", + "68, macaques ['l1', 'l2']", + "86, CD3(+) ['l3', 'l4', 'l5', 'l6', 'l7']", + "87, T ['l3', 'l8', 'l9', 'l10', 'l11']", + "88, cells ['l4', 'l8', 'l12', 'l13', 'l14']", + "89, in ['l5', 'l9', 'l12', 'l15', 'l16']", + "90, vivo ['l6', 'l10', 'l13', 'l15', 'l17']", + "102, macaques, ['l7', 'l11', 'l14', 'l16', 'l17']", + "125, CD8(+) ['l18', 'l19', 'l20', 'l21']", + "126, cells ['l18', 'l22', 'l23', 'l24']", + "127, in ['l19', 'l22', 'l25', 'l26']", + "128, vivo ['l20', 'l23', 'l25', 'l27']", + "140, T ['l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21841784", + "TEXT": "Human respiratory syncytial virus (RSV) causes a large burden of disease worldwide. There is no effective vaccine or therapy, and the use of passive immunoprophylaxis with RSV-specific antibodies is limited to high-risk patients. The cellular receptor (or receptors) required for viral entry and replication has yet to be described; its identification will improve understanding of the pathogenesis of infection and provide a target for the development of novel antiviral interventions. Here we show that RSV interacts with host-cell nucleolin via the viral fusion envelope glycoprotein and binds specifically to nucleolin at the apical cell surface in vitro. We observed decreased RSV infection in vitro in neutralization experiments using nucleolin-specific antibodies before viral inoculation, in competition experiments in which virus was incubated with soluble nucleolin before inoculation of cells, and upon RNA interference (RNAi) to silence cellular nucleolin expression. Transfection of nonpermissive Spodoptera frugiperda Sf9 insect cells with human nucleolin conferred susceptibility to RSV infection. RNAi-mediated knockdown of lung nucleolin was associated with a significant reduction in RSV infection in mice (P = 0.0004), confirming that nucleolin is a functional RSV receptor in vivo.", + "TAG_DATA": [ + "102, in {'context': 'B-in vitro'}", + "103, vitro {'context': 'I-in vitro'}", + "127, cells, {'context': 'B-cells'}", + "130, RNA {'perturbing_action': 'B-rnai/knockdown'}", + "131, interference {'perturbing_action': 'I-rnai/knockdown'}", + "132, (RNAi) {'perturbing_action': 'I-rnai/knockdown'}", + "133, to {'perturbing_action': 'I-rnai/knockdown'}", + "134, silence {'perturbing_action': 'I-rnai/knockdown'}", + "135, cellular {'perturbing_action': 'I-rnai/knockdown'}", + "136, nucleolin {'perturbing_action': 'I-rnai/knockdown'}", + "137, expression. {'perturbing_action': 'I-rnai/knockdown'}", + "138, Transfection {'perturbing_action': 'B-gene gain-of-function'}", + "140, nonpermissive {'context': 'B-cells'}", + "141, Spodoptera {'context': 'B-organism'}", + "142, frugiperda {'context': 'I-organism'}", + "143, Sf9 {'context': 'I-cells'}", + "144, insect {'context': 'I-cells'}", + "145, cells {'context': 'I-cells'}", + "146, with {'perturbing_action': 'I-gene gain-of-function'}", + "147, human {'perturbing_action': 'I-gene gain-of-function'}", + "148, nucleolin {'perturbing_action': 'I-gene gain-of-function'}", + "154, RNAi-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "155, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "156, of {'perturbing_action': 'I-rnai/knockdown'}", + "157, lung {'perturbing_action': 'I-rnai/knockdown'}", + "158, nucleolin {'perturbing_action': 'I-rnai/knockdown'}", + "169, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "102, in ['l0']", + "103, vitro ['l0']", + "127, cells, ['l1', 'l2', 'l3']", + "130, RNA ['l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "131, interference ['l4', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "132, (RNAi) ['l1', 'l5', 'l21', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "133, to ['l6', 'l22', 'l37', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "134, silence ['l7', 'l23', 'l38', 'l52', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "135, cellular ['l8', 'l24', 'l39', 'l53', 'l66', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "136, nucleolin ['l2', 'l9', 'l25', 'l40', 'l54', 'l67', 'l79', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "137, expression. ['l3', 'l10', 'l26', 'l41', 'l55', 'l68', 'l80', 'l91', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "138, Transfection ['l11', 'l27', 'l42', 'l56', 'l69', 'l81', 'l92', 'l102', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "140, nonpermissive ['l12', 'l28', 'l43', 'l57', 'l70', 'l82', 'l93', 'l103', 'l112', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "141, Spodoptera ['l13', 'l29', 'l44', 'l58', 'l71', 'l83', 'l94', 'l104', 'l113', 'l122', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "142, frugiperda ['l14', 'l30', 'l45', 'l59', 'l72', 'l84', 'l95', 'l105', 'l114', 'l123', 'l131', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145']", + "143, Sf9 ['l15', 'l31', 'l46', 'l60', 'l73', 'l85', 'l96', 'l106', 'l115', 'l124', 'l132', 'l139', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151']", + "144, insect ['l16', 'l32', 'l47', 'l61', 'l74', 'l86', 'l97', 'l107', 'l116', 'l125', 'l133', 'l140', 'l146', 'l152', 'l153', 'l154', 'l155']", + "145, cells ['l17', 'l33', 'l48', 'l62', 'l75', 'l87', 'l98', 'l108', 'l117', 'l126', 'l134', 'l141', 'l147', 'l152', 'l156', 'l157', 'l158']", + "146, with ['l18', 'l34', 'l49', 'l63', 'l76', 'l88', 'l99', 'l109', 'l118', 'l127', 'l135', 'l142', 'l148', 'l153', 'l156', 'l159', 'l160']", + "147, human ['l19', 'l35', 'l50', 'l64', 'l77', 'l89', 'l100', 'l110', 'l119', 'l128', 'l136', 'l143', 'l149', 'l154', 'l157', 'l159', 'l161']", + "148, nucleolin ['l20', 'l36', 'l51', 'l65', 'l78', 'l90', 'l101', 'l111', 'l120', 'l129', 'l137', 'l144', 'l150', 'l155', 'l158', 'l160', 'l161']", + "154, RNAi-mediated ['l162', 'l163', 'l164', 'l165', 'l166']", + "155, knockdown ['l162', 'l167', 'l168', 'l169', 'l170']", + "156, of ['l163', 'l167', 'l171', 'l172', 'l173']", + "157, lung ['l164', 'l168', 'l171', 'l174', 'l175']", + "158, nucleolin ['l165', 'l169', 'l172', 'l174', 'l176']", + "169, mice ['l121', 'l130', 'l138', 'l145', 'l151', 'l166', 'l170', 'l173', 'l175', 'l176']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells,", + "nonpermissive", + "Sf9", + "insect", + "cells" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "(RNAi)", + "nucleolin", + "expression.", + "RNA", + "interference", + "to", + "silence", + "cellular" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "RNA", + "interference", + "(RNAi)", + "to", + "silence", + "cellular", + "nucleolin", + "expression.", + "RNAi-mediated", + "knockdown", + "of", + "lung" + ] + }, + "context": { + "val": "organism", + "words": [ + "Spodoptera", + "frugiperda", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transfection", + "with", + "human", + "nucleolin" + ] + }, + "context": { + "val": "cells", + "words": [ + "nonpermissive", + "Sf9", + "insect", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transfection", + "with", + "human", + "nucleolin" + ] + }, + "context": { + "val": "organism", + "words": [ + "Spodoptera", + "frugiperda", + "mice" + ] + } + } + ] + }, + { + "PMID": "21822287", + "TEXT": "PIK3CA gain-of-function mutations are a common oncogenic event in human malignancy, making phosphatidylinositol 3-kinase (PI3K) a target for cancer therapy. Despite the promise of targeted therapy, resistance often develops, leading to treatment failure. To elucidate mechanisms of resistance to PI3K-targeted therapy, we constructed a mouse model of breast cancer conditionally expressing human PIK3CA(H1047R). Notably, most PIK3CA(H1047R)-driven mammary tumors recurred after PIK3CA(H1047R) inactivation. Genomic analyses of recurrent tumors revealed multiple lesions, including focal amplification of Met or Myc (also known as c-Met and c-Myc, respectively). Whereas Met amplification led to tumor survival dependent on activation of endogenous PI3K, tumors with Myc amplification became independent of the PI3K pathway. Functional analyses showed that Myc contributed to oncogene independence and resistance to PI3K inhibition. Notably, PIK3CA mutations and c-MYC elevation co-occur in a substantial fraction of human breast tumors. Together, these data suggest that c-MYC elevation represents a potential mechanism by which tumors develop resistance to current PI3K-targeted therapies.", + "TAG_DATA": [ + "44, mouse {'context': 'B-organism'}", + "45, model {'context': 'I-organism'}", + "46, of {'context': 'I-neoplasm'}", + "47, breast {'context': 'I-neoplasm'}", + "48, cancer {'context': 'I-neoplasm'}", + "49, conditionally {'perturbing_action': 'B-gene gain-of-function'}", + "50, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "51, human {'perturbing_action': 'I-gene gain-of-function'}", + "52, PIK3CA(H1047R). {'perturbing_action': 'I-gene gain-of-function'}", + "56, mammary {'context': 'B-neoplasm'}", + "57, tumors {'context': 'I-neoplasm'}", + "60, PIK3CA(H1047R) {'perturbing_action': 'B-gene loss-of-function'}", + "61, inactivation. {'perturbing_action': 'I-gene loss-of-function'}", + "88, to {'effect': 'I-positive'}", + "89, tumor {'phenotype': 'B-tumour progression'}", + "90, survival {'phenotype': 'I-cell survival'}", + "97, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "44, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "45, model ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "46, of ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "47, breast ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "48, cancer ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "49, conditionally ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "50, expressing ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "51, human ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l47', 'l53', 'l54', 'l55', 'l56', 'l57']", + "52, PIK3CA(H1047R). ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l48', 'l53', 'l58', 'l59', 'l60', 'l61']", + "56, mammary ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l49', 'l54', 'l58', 'l62', 'l63']", + "57, tumors ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l50', 'l55', 'l59', 'l62']", + "60, PIK3CA(H1047R) ['l45', 'l51', 'l56', 'l60', 'l64']", + "61, inactivation. ['l46', 'l52', 'l57', 'l61', 'l63', 'l64']", + "87, led ['l65', 'l66', 'l67']", + "88, to ['l65', 'l68', 'l69']", + "89, tumor ['l66', 'l68', 'l70', 'l71']", + "90, survival ['l67', 'l69', 'l70']", + "97, tumors ['l71']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "conditionally", + "expressing", + "human", + "PIK3CA(H1047R)." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "of", + "breast", + "cancer", + "mammary", + "tumors" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "conditionally", + "expressing", + "human", + "PIK3CA(H1047R)." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mammary" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "to" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "to" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "survival" + ] + } + }, + { + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + } + ] + }, + { + "PMID": "21738143", + "TEXT": "Russian medicine is-at long last-undergoing a renaissance. The country's rocky economic ride following the collapse of the Soviet Union disrupted its research rubric and impoverished its healthcare system. Now, however, the nation's leadership is spearheading various initiatives to reverse the situation. One of them, the US-Russian Scientific Forum, established two years ago by a bilateral presidential commission, hopes to bring improvements by facilitating public-private research in biomedicine and innovative drugs. The Forum, which on the Russian side is represented by the country's Ministry of Health and Social Development and the Russian Academy of Sciences, among others, held its inaugural planning meeting in late April in Moscow. Valery Danilenko, who is helping to spearhead the effort and also leads the biotechnology division at the Vavilov Institute of General Genetics in Moscow, told Nature Medicine about the meeting and Russia's hopes for the Forum. The interview was conducted in Russian and translated by the interviewer, Gary Peach.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21725297", + "TEXT": "Survival and differentiation of oligodendrocytes are important for the myelination of central nervous system (CNS) axons during development and crucial for myelin repair in CNS demyelinating diseases such as multiple sclerosis. Here we show that death receptor 6 (DR6) is a negative regulator of oligodendrocyte maturation. DR6 is expressed strongly in immature oligodendrocytes and weakly in mature myelin basic protein (MBP)-positive oligodendrocytes. Overexpression of DR6 in oligodendrocytes leads to caspase 3 (casp3) activation and cell death. Attenuation of DR6 function leads to enhanced oligodendrocyte maturation, myelination and downregulation of casp3. Treatment with a DR6 antagonist antibody promotes remyelination in both lysolecithin-induced demyelination and experimental autoimmune encephalomyelitis (EAE) models. Consistent with the DR6 antagoinst antibody studies, DR6-null mice show enhanced remyelination in both demyelination models. These studies reveal a pivotal role for DR6 signaling in immature oligodendrocyte maturation and myelination that may provide new therapeutic avenues for the treatment of demyelination disorders such as multiple sclerosis.", + "TAG_DATA": [ + "62, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "63, of {'perturbing_action': 'I-gene gain-of-function'}", + "64, DR6 {'perturbing_action': 'I-gene gain-of-function'}", + "66, oligodendrocytes {'context': 'B-cells'}", + "67, leads {'effect': 'B-positive'}", + "68, to {'effect': 'I-positive'}", + "74, cell {'phenotype': 'B-cell death'}", + "75, death. {'phenotype': 'I-cell death'}", + "76, Attenuation {'perturbing_action': 'B-other'}", + "77, of {'perturbing_action': 'I-other'}", + "78, DR6 {'perturbing_action': 'I-other'}", + "79, function {'perturbing_action': 'I-other'}", + "83, oligodendrocyte {'context': 'B-cells'}", + "93, DR6 {'perturbing_action': 'B-pharmacological inhibition'}", + "94, antagonist {'perturbing_action': 'I-rnai/knockdown'}", + "95, antibody {'perturbing_action': 'I-rnai/knockdown'}", + "115, DR6-null {'perturbing_action': 'B-gene loss-of-function'}", + "116, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "62, Overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "63, of ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "64, DR6 ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "66, oligodendrocytes ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "67, leads ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "68, to ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "74, cell ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "75, death. ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "76, Attenuation ['l36', 'l37', 'l38', 'l39']", + "77, of ['l36', 'l40', 'l41', 'l42']", + "78, DR6 ['l37', 'l40', 'l43', 'l44']", + "79, function ['l38', 'l41', 'l43', 'l45']", + "83, oligodendrocyte ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35', 'l39', 'l42', 'l44', 'l45']", + "93, DR6 ['l46', 'l47']", + "94, antagonist ['l46', 'l48']", + "95, antibody ['l47', 'l48']", + "115, DR6-null ['l49']", + "116, mice ['l49']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "DR6" + ] + }, + "context": { + "val": "cells", + "words": [ + "oligodendrocytes", + "oligodendrocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "DR6" + ] + }, + "effect": { + "val": "positive", + "words": [ + "leads", + "to" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "DR6" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "oligodendrocytes", + "oligodendrocyte" + ] + }, + "effect": { + "val": "positive", + "words": [ + "leads", + "to" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "oligodendrocytes", + "oligodendrocyte" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "leads", + "to" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Attenuation", + "of", + "DR6", + "function" + ] + }, + "context": { + "val": "cells", + "words": [ + "oligodendrocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "DR6-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "21706027", + "TEXT": "Snake venom toxins first transit the lymphatic system before entering the bloodstream. Ointment containing a nitric oxide donor, which impedes the intrinsic lymphatic pump, prolonged lymph transit time in rats and humans and also increased rat survival time after injection of venom. This pharmacological approach should give snakebite victims more time to obtain medical care and antivenom treatment.", + "TAG_DATA": [ + "29, rats {'context': 'B-organism'}", + "31, humans {'context': 'B-organism'}", + "35, rat {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "29, rats ['l0']", + "31, humans ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21685898", + "TEXT": "Effective cancer immunotherapy requires the release of a broad spectrum of tumor antigens in the context of potent immune activation. We show here that a cDNA library of normal tissue, expressed from a highly immunogenic viral platform, cures established tumors of the same histological type from which the cDNA library was derived. Immune escape occurred with suboptimal vaccination, but tumor cells that escaped the immune pressure were readily treated by second-line virus-based immunotherapy. This approach has several major advantages. Use of the cDNA library leads to presentation of a broad repertoire of (undefined) tumor-associated antigens, which reduces emergence of treatment-resistant variants and also permits rational, combined-modality approaches in the clinic. Finally, the viral vectors can be delivered systemically, without the need for tumor targeting, and are amenable to clinical-grade production. Therefore, virus-expressed cDNA libraries represent a novel paradigm for cancer treatment addressing many of the key issues that have undermined the efficacy of immuno- and virotherapy to date.", + "TAG_DATA": [ + "39, tumors {'context': 'B-neoplasm'}", + "59, tumor {'context': 'B-transformed cells'}", + "60, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "59, tumor ['l0']", + "60, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21685896", + "TEXT": "Acetylcholine is a neurotransmitter that has a major role in the function of the insulin-secreting pancreatic beta cell. Parasympathetic innervation of the endocrine pancreas, the islets of Langerhans, has been shown to provide cholinergic input to the beta cell in several species, but the role of autonomic innervation in human beta cell function is at present unclear. Here we show that, in contrast to the case in mouse islets, cholinergic innervation of human islets is sparse. Instead, we find that the alpha cells of human islets provide paracrine cholinergic input to surrounding endocrine cells. Human alpha cells express the vesicular acetylcholine transporter and release acetylcholine when stimulated with kainate or a lowering in glucose concentration. Acetylcholine secretion by alpha cells in turn sensitizes the beta cell response to increases in glucose concentration. Our results demonstrate that in human islets acetylcholine is a paracrine signal that primes the beta cell to respond optimally to subsequent increases in glucose concentration. Cholinergic signaling within islets represents a potential therapeutic target in diabetes, highlighting the relevance of this advance to future drug development.", + "TAG_DATA": [ + "94, Human {'context': 'B-cells'}", + "95, alpha {'context': 'I-cells'}", + "96, cells {'context': 'I-cells'}", + "118, alpha {'context': 'B-cells'}", + "119, cells {'context': 'I-cells'}", + "124, beta {'context': 'B-cells'}", + "125, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "94, Human ['l0', 'l1', 'l2']", + "95, alpha ['l0', 'l3', 'l4']", + "96, cells ['l1', 'l3']", + "118, alpha ['l5', 'l6', 'l7']", + "119, cells ['l2', 'l4', 'l5', 'l8', 'l9']", + "124, beta ['l6', 'l8', 'l10']", + "125, cell ['l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21666695", + "TEXT": "Interleukin 17 (IL-17) is a central cytokine implicated in inflammation and antimicrobial defense. After infection, both innate and adaptive IL-17 responses have been reported, but the type of cells involved in innate IL-17 induction, as well as their contribution to in vivo responses, are poorly understood. Here we found that Citrobacter and Salmonella infection triggered early IL-17 production, which was crucial for host defense and was mediated by CD4(+) T helper cells. Enteric innate T helper type 17 (iT(H)17) responses occurred principally in the cecum, were dependent on the Nod-like receptors Nod1 and Nod2, required IL-6 induction and were associated with a decrease in mucosal CD103(+) dendritic cells. Moreover, imprinting by the intestinal microbiota was fully required for the generation of iT(H)17 responses. Together, these results identify the Nod-iT(H)17 axis as a central element in controlling enteric pathogens, which may implicate Nod-driven iT(H)17 responses in the development of inflammatory bowel diseases.", + "TAG_DATA": [ + "104, mucosal {'context': 'B-cells'}", + "105, CD103(+) {'context': 'B-cells'}", + "106, dendritic {'context': 'I-cells'}", + "107, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "104, mucosal ['l0', 'l1', 'l2']", + "105, CD103(+) ['l0', 'l3', 'l4']", + "106, dendritic ['l1', 'l3', 'l5']", + "107, cells. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21666694", + "TEXT": "Here we report that the transcription factor cyclic AMP-responsive element-binding protein H (CREB-H, encoded by CREB3L3) is required for the maintenance of normal plasma triglyceride concentrations. CREB-H-deficient mice showed hypertriglyceridemia secondary to inefficient triglyceride clearance catalyzed by lipoprotein lipase (Lpl), partly due to defective expression of the Lpl coactivators Apoc2, Apoa4 and Apoa5 (encoding apolipoproteins C2, A4 and A5, respectively) and concurrent augmentation of the Lpl inhibitor Apoc3. We identified multiple nonsynonymous mutations in CREB3L3 that produced hypomorphic or nonfunctional CREB-H protein in humans with extreme hypertriglyceridemia, implying a crucial role for CREB-H in human triglyceride metabolism.", + "TAG_DATA": [ + "26, CREB-H-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "27, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "26, CREB-H-deficient ['l0']", + "27, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CREB-H-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "21642979", + "TEXT": "The use of N-type voltage-gated calcium channel (CaV2.2) blockers to treat pain is limited by many physiological side effects. Here we report that inflammatory and neuropathic hypersensitivity can be suppressed by inhibiting the binding of collapsin response mediator protein 2 (CRMP-2) to CaV2.2 and thereby reducing channel function. A peptide of CRMP-2 fused to the HIV transactivator of transcription (TAT) protein (TAT-CBD3) decreased neuropeptide release from sensory neurons and excitatory synaptic transmission in dorsal horn neurons, reduced meningeal blood flow, reduced nocifensive behavior induced by formalin injection or corneal capsaicin application and reversed neuropathic hypersensitivity produced by an antiretroviral drug. TAT-CBD3 was mildly anxiolytic without affecting memory retrieval, sensorimotor function or depression. At doses tenfold higher than that required to reduce hypersensitivity in vivo, TAT-CBD3 caused a transient episode of tail kinking and body contortion. By preventing CRMP-2-mediated enhancement of CaV2.2 function, TAT-CBD3 alleviated inflammatory and neuropathic hypersensitivity, an approach that may prove useful in managing chronic pain.", + "TAG_DATA": [ + "66, sensory {'context': 'B-cells'}", + "67, neurons {'context': 'I-cells'}", + "73, dorsal {'context': 'B-cells'}", + "74, horn {'context': 'I-cells'}", + "75, neurons, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "50, of ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "52, fused ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "53, to ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "55, HIV ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "56, transactivator ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "60, protein ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "66, sensory ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "67, neurons ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "73, dorsal ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "74, horn ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "75, neurons, ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21642977", + "TEXT": "Uncovering principles that regulate energy metabolism in the brain requires mapping of partial pressure of oxygen (PO(2)) and blood flow with high spatial and temporal resolution. Using two-photon phosphorescence lifetime microscopy (2PLM) and the oxygen probe PtP-C343, we show that PO(2) can be accurately measured in the brain at depths up to 300 μm with micron-scale resolution. In addition, 2PLM allowed simultaneous measurements of blood flow and of PO(2) in capillaries with less than one-second temporal resolution. Using this approach, we detected erythrocyte-associated transients (EATs) in oxygen in the rat olfactory bulb and showed the existence of diffusion-based arterio-venous shunts. Sensory stimulation evoked functional hyperemia, accompanied by an increase in PO(2) in capillaries and by a biphasic PO(2) response in the neuropil, consisting of an 'initial dip' and a rebound. 2PLM of PO(2) opens new avenues for studies of brain metabolism and blood flow regulation.", + "TAG_DATA": [ + "89, rat {'context': 'B-tissue/organ'}", + "90, olfactory {'context': 'I-tissue/organ'}", + "91, bulb {'context': 'I-tissue/organ'}", + "121, neuropil, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "89, rat ['l0', 'l1']", + "90, olfactory ['l0', 'l2']", + "91, bulb ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21623382", + "TEXT": "The ciliopathy Joubert syndrome is marked by cerebellar vermis hypoplasia, a phenotype for which the pathogenic mechanism is unclear. To investigate Joubert syndrome pathogenesis, we have examined mice with mutated Ahi1, the first identified Joubert syndrome-associated gene. These mice show cerebellar hypoplasia with a vermis-midline fusion defect early in development. This defect is concomitant with expansion of the roof plate and is also evident in a mouse mutant for another Joubert syndrome-associated gene, Cep290. Furthermore, fetal magnetic resonance imaging (MRI) of human subjects with Joubert syndrome reveals a similar midline cleft, suggesting parallel pathogenic mechanisms. Previous evidence has suggested a role for Jouberin (Jbn), the protein encoded by Ahi1, in canonical Wnt signaling. Consistent with this, we found decreased Wnt reporter activity at the site of hemisphere fusion in the developing cerebellum of Ahi1-mutant mice. This decrease was accompanied by reduced proliferation at the site of fusion. Finally, treatment with lithium, a Wnt pathway agonist, partially rescued this phenotype. Our findings implicate a defect in Wnt signaling in the cerebellar midline phenotype seen in Joubert syndrome that can be overcome with Wnt stimulation.", + "TAG_DATA": [ + "27, mice {'context': 'B-organism'}", + "29, mutated {'perturbing_action': 'B-other'}", + "30, Ahi1, {'perturbing_action': 'I-other'}", + "38, mice {'context': 'B-organism'}", + "66, mouse {'perturbing_action': 'B-other'}", + "67, mutant {'perturbing_action': 'I-other'}", + "131, cerebellum {'context': 'I-tissue/organ'}", + "133, Ahi1-mutant {'perturbing_action': 'B-other'}", + "134, mice. {'context': 'B-organism'}", + "140, reduced {'effect': 'B-negative'}", + "141, proliferation {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "27, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "29, mutated ['l0', 'l5', 'l6', 'l7', 'l8']", + "30, Ahi1, ['l1', 'l5', 'l9', 'l10', 'l11']", + "38, mice ['l2', 'l6', 'l9', 'l12', 'l13']", + "66, mouse ['l3', 'l7', 'l10', 'l12', 'l14']", + "67, mutant ['l4', 'l8', 'l11', 'l13', 'l14']", + "131, cerebellum ['l15', 'l16', 'l17', 'l18']", + "133, Ahi1-mutant ['l15', 'l19', 'l20', 'l21']", + "134, mice. ['l16', 'l19', 'l22', 'l23']", + "140, reduced ['l17', 'l20', 'l22', 'l24']", + "141, proliferation ['l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "Ahi1,", + "mouse", + "mutant", + "Ahi1-mutant" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "cerebellum" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Ahi1-mutant" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "cerebellum" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "cerebellum" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Ahi1-mutant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Ahi1-mutant" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "21602804", + "TEXT": "Therapies targeting estrogen receptor α (ERα, encoded by ESR1) have transformed the treatment of breast cancer. However, large numbers of women relapse, highlighting the need for the discovery of new regulatory targets modulating ERα pathways. An siRNA screen identified kinases whose silencing alters the estrogen response including those previously implicated in regulating ERα activity (such as mitogen-activated protein kinase and AKT). Among the most potent regulators was lemur tyrosine kinase-3 (LMTK3), for which a role has not previously been assigned. In contrast to other modulators of ERα activity, LMTK3 seems to have been subject to Darwinian positive selection, a noteworthy result given the unique susceptibility of humans to ERα+ breast cancer. LMTK3 acts by decreasing the activity of protein kinase C (PKC) and the phosphorylation of AKT (Ser473), thereby increasing binding of forkhead box O3 (FOXO3) to the ESR1 promoter. LMTK3 phosphorylated ERα, protecting it from proteasomal degradation in vitro. Silencing of LMTK3 reduced tumor volume in an orthotopic mouse model and abrogated proliferation of ERα+ but not ERα- cells, indicative of its role in ERα activity. In human cancers, LMTK3 abundance and intronic polymorphisms were significantly associated with disease-free and overall survival and predicted response to endocrine therapies. These findings yield insights into the natural history of breast cancer in humans and reveal LMTK3 as a new therapeutic target.", + "TAG_DATA": [ + "150, Silencing {'perturbing_action': 'B-rnai/knockdown'}", + "151, of {'perturbing_action': 'I-rnai/knockdown'}", + "152, LMTK3 {'perturbing_action': 'I-rnai/knockdown'}", + "153, reduced {'effect': 'B-negative'}", + "154, tumor {'phenotype': 'B-tumourigenesis'}", + "155, volume {'phenotype': 'I-tumourigenesis'}", + "158, orthotopic {'context': 'B-organism'}", + "159, mouse {'context': 'I-organism'}", + "160, model {'context': 'I-organism'}", + "162, abrogated {'effect': 'B-negative'}", + "163, proliferation {'phenotype': 'B-proliferation'}", + "165, ERα+ {'context': 'B-cells'}", + "168, ERα- {'context': 'B-cells'}", + "169, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "150, Silencing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "151, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "152, LMTK3 ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "153, reduced ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40']", + "154, tumor ['l3', 'l15', 'l26', 'l36', 'l41', 'l42', 'l43', 'l44']", + "155, volume ['l4', 'l16', 'l27', 'l37', 'l41', 'l45', 'l46', 'l47']", + "158, orthotopic ['l5', 'l17', 'l28', 'l38', 'l42', 'l45', 'l48', 'l49']", + "159, mouse ['l6', 'l18', 'l29', 'l39', 'l43', 'l46', 'l48', 'l50']", + "160, model ['l7', 'l19', 'l30', 'l40', 'l44', 'l47', 'l49', 'l50']", + "162, abrogated ['l8', 'l20', 'l31', 'l51', 'l52', 'l53', 'l54']", + "163, proliferation ['l9', 'l21', 'l32', 'l51', 'l55', 'l56', 'l57']", + "165, ERα+ ['l10', 'l22', 'l33', 'l52', 'l55', 'l58', 'l59']", + "168, ERα- ['l11', 'l23', 'l34', 'l53', 'l56', 'l58', 'l60']", + "169, cells, ['l12', 'l24', 'l35', 'l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "LMTK3" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced", + "abrogated" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "LMTK3" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "volume" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "LMTK3" + ] + }, + "context": { + "val": "organism", + "words": [ + "orthotopic", + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "LMTK3" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "LMTK3" + ] + }, + "context": { + "val": "cells", + "words": [ + "ERα+", + "ERα-", + "cells," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "volume" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "organism", + "words": [ + "orthotopic", + "mouse", + "model" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "volume" + ] + }, + "context": { + "val": "organism", + "words": [ + "orthotopic", + "mouse", + "model" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogated" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogated" + ] + }, + "context": { + "val": "cells", + "words": [ + "ERα+", + "ERα-", + "cells," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "ERα+", + "ERα-", + "cells," + ] + } + } + ] + }, + { + "PMID": "21602801", + "TEXT": "Mammalian peptidoglycan recognition proteins (PGRPs), similar to antimicrobial lectins, bind the bacterial cell wall and kill bacteria through an unknown mechanism. We show that PGRPs enter the Gram-positive cell wall at the site of daughter cell separation during cell division. In Bacillus subtilis, PGRPs activate the CssR-CssS two-component system that detects and disposes of misfolded proteins that are usually exported out of bacterial cells. This activation results in membrane depolarization, cessation of intracellular peptidoglycan, protein, RNA and DNA synthesis, and production of hydroxyl radicals, which are responsible for bacterial death. PGRPs also bind the outer membrane of Escherichia coli and activate the functionally homologous CpxA-CpxR two-component system, which kills the bacteria. We exclude other potential bactericidal mechanisms, including inhibition of extracellular peptidoglycan synthesis, hydrolysis of peptidoglycan and membrane permeabilization. Thus, we reveal a previously unknown mechanism by which innate immunity proteins that bind the cell wall or outer membrane exploit the bacterial stress defense response to kill bacteria.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21532597", + "TEXT": "Although previous studies have described CD25 expression and production of interleukin-2 (IL-2) by mature dendritic cells (mDCs), it remains unclear how these molecules participate in the activation of T cells. In search of the mechanisms by which daclizumab, a humanized monoclonal antibody against CD25, inhibits brain inflammation in multiple sclerosis, we observed that although the drug has limited effects on polyclonal T cell activation, it potently inhibits activation of antigen-specific T cells by mDCs. We show that mDCs (and antigen-experienced T cells) secrete IL-2 toward the mDC-T cell interface in an antigen-specific manner, and mDCs 'lend' their CD25 to primed T cells in trans to facilitate early high-affinity IL-2 signaling, which is crucial for subsequent T cell expansion and development of antigen-specific effectors. Our data reveal a previously unknown mechanism for the IL-2 receptor system in DC-mediated activation of T cells.", + "TAG_DATA": [ + "61, T {'context': 'I-cells'}", + "62, cell {'context': 'I-cells'}", + "69, antigen-specific {'context': 'B-cells'}", + "70, T {'context': 'I-cells'}", + "71, cells {'context': 'I-cells'}", + "73, mDCs. {'context': 'B-cells'}", + "77, mDCs {'context': 'B-cells'}", + "100, T {'context': 'B-cells'}", + "101, cells {'context': 'B-cells'}", + "115, T {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "61, T ['l0', 'l1', 'l2', 'l3', 'l4']", + "62, cell ['l0', 'l5', 'l6', 'l7', 'l8']", + "69, antigen-specific ['l1', 'l5', 'l9', 'l10', 'l11', 'l12']", + "70, T ['l2', 'l6', 'l9', 'l13', 'l14', 'l15']", + "71, cells ['l3', 'l7', 'l10', 'l13', 'l16', 'l17']", + "73, mDCs. ['l4', 'l8', 'l11', 'l14', 'l16', 'l18']", + "77, mDCs ['l12', 'l15', 'l17', 'l18']", + "100, T ['l19', 'l20']", + "101, cells ['l19', 'l21']", + "115, T ['l20', 'l21']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21499267", + "TEXT": "Individuals with chronic asthma show a progressive decline in lung function that is thought to be due to structural remodeling of the airways characterized by subepithelial fibrosis and smooth muscle hyperplasia. Here we show that the tumor necrosis factor (TNF) family member LIGHT is expressed on lung inflammatory cells after allergen exposure. Pharmacological inhibition of LIGHT using a fusion protein between the IgG Fc domain and lymphotoxin β receptor (LTβR) reduces lung fibrosis, smooth muscle hyperplasia and airway hyperresponsiveness in mouse models of chronic asthma, despite having little effect on airway eosinophilia. LIGHT-deficient mice also show a similar impairment in fibrosis and smooth muscle accumulation. Blockade of LIGHT suppresses expression of lung transforming growth factor-β (TGF-β) and interleukin-13 (IL-13), cytokines implicated in remodeling in humans, whereas exogenous administration of LIGHT to the airways induces fibrosis and smooth muscle hyperplasia, Thus, LIGHT may be targeted to prevent asthma-related airway remodeling.", + "TAG_DATA": [ + "52, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "53, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "54, of {'perturbing_action': 'I-pharmacological inhibition'}", + "55, LIGHT {'perturbing_action': 'I-pharmacological inhibition'}", + "56, using {'perturbing_action': 'I-pharmacological inhibition'}", + "57, a {'perturbing_action': 'I-pharmacological inhibition'}", + "58, fusion {'perturbing_action': 'I-pharmacological inhibition'}", + "59, protein {'perturbing_action': 'I-pharmacological inhibition'}", + "60, between {'perturbing_action': 'I-pharmacological inhibition'}", + "61, the {'perturbing_action': 'I-pharmacological inhibition'}", + "62, IgG {'perturbing_action': 'I-pharmacological inhibition'}", + "63, Fc {'perturbing_action': 'I-pharmacological inhibition'}", + "64, domain {'perturbing_action': 'I-pharmacological inhibition'}", + "65, and {'perturbing_action': 'I-pharmacological inhibition'}", + "66, lymphotoxin {'perturbing_action': 'I-pharmacological inhibition'}", + "67, β {'perturbing_action': 'I-pharmacological inhibition'}", + "68, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "71, lung {'context': 'B-tissue/organ'}", + "80, mouse {'context': 'B-organism'}", + "81, models {'context': 'I-organism'}", + "92, LIGHT-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "93, mice {'context': 'B-organism'}", + "105, Blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "106, of {'perturbing_action': 'I-pharmacological inhibition'}", + "107, LIGHT {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "52, Pharmacological ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "53, inhibition ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "54, of ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "55, LIGHT ['l2', 'l21', 'l39', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "56, using ['l3', 'l22', 'l40', 'l57', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "57, a ['l4', 'l23', 'l41', 'l58', 'l74', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "58, fusion ['l5', 'l24', 'l42', 'l59', 'l75', 'l90', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "59, protein ['l6', 'l25', 'l43', 'l60', 'l76', 'l91', 'l105', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "60, between ['l7', 'l26', 'l44', 'l61', 'l77', 'l92', 'l106', 'l120', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "61, the ['l8', 'l27', 'l45', 'l62', 'l78', 'l93', 'l107', 'l121', 'l134', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160']", + "62, IgG ['l9', 'l28', 'l46', 'l63', 'l79', 'l94', 'l108', 'l122', 'l135', 'l148', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "63, Fc ['l10', 'l29', 'l47', 'l64', 'l80', 'l95', 'l109', 'l123', 'l136', 'l149', 'l161', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183']", + "64, domain ['l11', 'l30', 'l48', 'l65', 'l81', 'l96', 'l110', 'l124', 'l137', 'l150', 'l162', 'l173', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "65, and ['l12', 'l31', 'l49', 'l66', 'l82', 'l97', 'l111', 'l125', 'l138', 'l151', 'l163', 'l174', 'l184', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202']", + "66, lymphotoxin ['l13', 'l32', 'l50', 'l67', 'l83', 'l98', 'l112', 'l126', 'l139', 'l152', 'l164', 'l175', 'l185', 'l194', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210']", + "67, β ['l14', 'l33', 'l51', 'l68', 'l84', 'l99', 'l113', 'l127', 'l140', 'l153', 'l165', 'l176', 'l186', 'l195', 'l203', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217']", + "68, receptor ['l15', 'l34', 'l52', 'l69', 'l85', 'l100', 'l114', 'l128', 'l141', 'l154', 'l166', 'l177', 'l187', 'l196', 'l204', 'l211', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223']", + "69, (LTβR) ['l16', 'l35', 'l53', 'l70', 'l86', 'l101', 'l115', 'l129', 'l142', 'l155', 'l167', 'l178', 'l188', 'l197', 'l205', 'l212', 'l218', 'l224', 'l225', 'l226', 'l227']", + "71, lung ['l17', 'l36', 'l54', 'l71', 'l87', 'l102', 'l116', 'l130', 'l143', 'l156', 'l168', 'l179', 'l189', 'l198', 'l206', 'l213', 'l219', 'l224', 'l228', 'l229']", + "80, mouse ['l18', 'l37', 'l55', 'l72', 'l88', 'l103', 'l117', 'l131', 'l144', 'l157', 'l169', 'l180', 'l190', 'l199', 'l207', 'l214', 'l220', 'l225', 'l228', 'l230']", + "81, models ['l19', 'l38', 'l56', 'l73', 'l89', 'l104', 'l118', 'l132', 'l145', 'l158', 'l170', 'l181', 'l191', 'l200', 'l208', 'l215', 'l221', 'l226', 'l229', 'l230']", + "92, LIGHT-deficient ['l146', 'l159', 'l171', 'l182', 'l192', 'l201', 'l209', 'l216', 'l222', 'l231']", + "93, mice ['l119', 'l133', 'l147', 'l160', 'l172', 'l183', 'l193', 'l202', 'l210', 'l217', 'l223', 'l227', 'l231']", + "105, Blockade ['l232', 'l233', 'l234']", + "106, of ['l232', 'l235', 'l236']", + "107, LIGHT ['l233', 'l235', 'l237']", + "132, airways ['l234', 'l236', 'l237']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "LIGHT", + "using", + "a", + "fusion", + "protein", + "between", + "the", + "IgG", + "Fc", + "domain", + "and", + "lymphotoxin", + "β", + "receptor" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "LIGHT", + "using", + "a", + "fusion", + "protein", + "between", + "the", + "IgG", + "Fc", + "domain", + "and", + "lymphotoxin", + "β", + "receptor" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "LIGHT-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "21399647", + "TEXT": "Trastuzumab is a successful rationally designed ERBB2-targeted therapy. However, about half of individuals with ERBB2-overexpressing breast cancer do not respond to trastuzumab-based therapies, owing to various resistance mechanisms. Clinically applicable regimens for overcoming trastuzumab resistance of different mechanisms are not yet available. We show that the nonreceptor tyrosine kinase c-SRC (SRC) is a key modulator of trastuzumab response and a common node downstream of multiple trastuzumab resistance pathways. We find that SRC is activated in both acquired and de novo trastuzumab-resistant cells and uncover a novel mechanism of SRC regulation involving dephosphorylation by PTEN. Increased SRC activation conferred considerable trastuzumab resistance in breast cancer cells and correlated with trastuzumab resistance in patients. Targeting SRC in combination with trastuzumab sensitized multiple lines of trastuzumab-resistant cells to trastuzumab and eliminated trastuzumab-resistant tumors in vivo, suggesting the potential clinical application of this strategy to overcome trastuzumab resistance.", + "TAG_DATA": [ + "102, breast {'context': 'B-transformed cells'}", + "103, cancer {'context': 'I-transformed cells'}", + "104, cells {'context': 'I-transformed cells'}", + "112, Targeting {'perturbing_action': 'B-other'}", + "113, SRC {'perturbing_action': 'I-other'}", + "122, trastuzumab-resistant {'context': 'B-transformed cells'}", + "123, cells {'context': 'I-cells'}", + "128, trastuzumab-resistant {'context': 'B-neoplasm'}", + "129, tumors {'context': 'I-neoplasm'}", + "130, in {'context': 'B-in vivo'}", + "131, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "102, breast ['l0', 'l1']", + "103, cancer ['l0', 'l2']", + "104, cells ['l1', 'l2']", + "112, Targeting ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "113, SRC ['l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "122, trastuzumab-resistant ['l4', 'l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "123, cells ['l5', 'l11', 'l16']", + "128, trastuzumab-resistant ['l6', 'l12', 'l17', 'l21', 'l22', 'l23']", + "129, tumors ['l7', 'l13', 'l18', 'l21', 'l24', 'l25']", + "130, in ['l8', 'l14', 'l19', 'l22', 'l24', 'l26']", + "131, vivo, ['l9', 'l15', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Targeting", + "SRC" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "trastuzumab-resistant" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Targeting", + "SRC" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Targeting", + "SRC" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "trastuzumab-resistant", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Targeting", + "SRC" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + } + ] + }, + { + "PMID": "21258337", + "TEXT": "Brown adipose tissue (BAT) burns fatty acids for heat production to defend the body against cold and has recently been shown to be present in humans. Triglyceride-rich lipoproteins (TRLs) transport lipids in the bloodstream, where the fatty acid moieties are liberated by the action of lipoprotein lipase (LPL). Peripheral organs such as muscle and adipose tissue take up the fatty acids, whereas the remaining cholesterol-rich remnant particles are cleared by the liver. Elevated plasma triglyceride concentrations and prolonged circulation of cholesterol-rich remnants, especially in diabetic dyslipidemia, are risk factors for cardiovascular disease. However, the precise biological role of BAT for TRL clearance remains unclear. Here we show that increased BAT activity induced by short-term cold exposure controls TRL metabolism in mice. Cold exposure drastically accelerated plasma clearance of triglycerides as a result of increased uptake into BAT, a process crucially dependent on local LPL activity and transmembrane receptor CD36. In pathophysiological settings, cold exposure corrected hyperlipidemia and improved deleterious effects of insulin resistance. In conclusion, BAT activity controls vascular lipoprotein homeostasis by inducing a metabolic program that boosts TRL turnover and channels lipids into BAT. Activation of BAT might be a therapeutic approach to reduce elevated triglyceride concentrations and combat obesity in humans.", + "TAG_DATA": [ + "120, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21240263", + "TEXT": "The combination of intravital microscopy and animal models of disease has propelled studies of disease mechanisms and treatments. However, many disorders afflict tissues inaccessible to light microscopy in live subjects. Here we introduce cellular-level time-lapse imaging deep within the live mammalian brain by one- and two-photon fluorescence microendoscopy over multiple weeks. Bilateral imaging sites allowed longitudinal comparisons within individual subjects, including of normal and diseased tissues. Using this approach, we tracked CA1 hippocampal pyramidal neuron dendrites in adult mice, revealing these dendrites' extreme stability and rare examples of their structural alterations. To illustrate disease studies, we tracked deep lying gliomas by observing tumor growth, visualizing three-dimensional vasculature structure and determining microcirculatory speeds. Average erythrocyte speeds in gliomas declined markedly as the disease advanced, notwithstanding significant increases in capillary diameters. Time-lapse microendoscopy will be applicable to studies of numerous disorders, including neurovascular, neurological, cancerous and trauma-induced conditions.", + "TAG_DATA": [ + "71, CA1 {'context': 'B-cells'}", + "72, hippocampal {'context': 'I-cells'}", + "73, pyramidal {'context': 'I-cells'}", + "74, neuron {'context': 'I-cells'}", + "75, dendrites {'context': 'I-cells'}", + "77, adult {'context': 'B-organism'}", + "78, mice, {'context': 'I-organism'}", + "99, gliomas {'context': 'B-neoplasm'}", + "102, tumor {'phenotype': 'B-tumour growth'}", + "103, growth, {'phenotype': 'I-tumour growth'}", + "116, gliomas {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "71, CA1 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "72, hippocampal ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "73, pyramidal ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "74, neuron ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "75, dendrites ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "77, adult ['l4', 'l10', 'l15', 'l19', 'l22', 'l25']", + "78, mice, ['l5', 'l11', 'l16', 'l20', 'l23', 'l25']", + "99, gliomas ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "102, tumor ['l26', 'l28']", + "103, growth, ['l27', 'l28']", + "113, erythrocyte ['l29']", + "116, gliomas ['l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "gliomas" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth," + ] + } + } + ] + }, + { + "PMID": "21170045", + "TEXT": "Histidine decarboxylase (HDC), the unique enzyme responsible for histamine generation, is highly expressed in myeloid cells, but its function in these cells is poorly understood. Here we show that Hdc-knockout mice show a high rate of colon and skin carcinogenesis. Using Hdc-EGFP bacterial artificial chromosome (BAC) transgenic mice in which EGFP expression is controlled by the Hdc promoter, we show that Hdc is expressed primarily in CD11b(+)Ly6G(+) immature myeloid cells (IMCs) that are recruited early on in chemical carcinogenesis. Transplant of Hdc-deficient bone marrow to wild-type recipients results in increased CD11b(+)Ly6G(+) cell mobilization and reproduces the cancer susceptibility phenotype of Hdc-knockout mice. In addition, Hdc-deficient IMCs promote the growth of tumor allografts, whereas mouse CT26 colon cancer cells downregulate Hdc expression through promoter hypermethylation and inhibit myeloid cell maturation. Exogenous histamine induces the differentiation of IMCs and suppresses their ability to support the growth of tumor allografts. These data indicate key roles for Hdc and histamine in myeloid cell differentiation and CD11b(+)Ly6G(+) IMCs in early cancer development.", + "TAG_DATA": [ + "29, Hdc-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "41, Hdc-EGFP {'perturbing_action': 'B-gene gain-of-function'}", + "42, bacterial {'perturbing_action': 'I-gene gain-of-function'}", + "43, artificial {'perturbing_action': 'I-gene gain-of-function'}", + "44, chromosome {'perturbing_action': 'I-gene gain-of-function'}", + "46, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "47, mice {'context': 'B-organism'}", + "81, Hdc-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "82, bone {'context': 'B-tissue/organ'}", + "83, marrow {'context': 'I-tissue/organ'}", + "90, CD11b(+)Ly6G(+) {'context': 'B-cells'}", + "100, Hdc-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "101, mice. {'context': 'B-organism'}", + "104, Hdc-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "105, IMCs {'context': 'B-cells'}", + "110, tumor {'context': 'B-xenograft'}", + "111, allografts, {'context': 'I-xenograft'}", + "113, mouse {'context': 'B-transformed cells'}", + "114, CT26 {'context': 'I-transformed cells'}", + "115, colon {'context': 'I-transformed cells'}", + "116, cancer {'context': 'I-transformed cells'}", + "117, cells {'context': 'I-transformed cells'}", + "126, myeloid {'context': 'B-cells'}", + "127, cell {'context': 'I-cells'}", + "131, induces {'effect': 'B-positive'}", + "133, differentiation {'phenotype': 'B-differentiation'}", + "135, IMCs {'context': 'B-cells'}", + "145, tumor {'context': 'B-xenograft'}", + "146, allografts. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "29, Hdc-knockout ['l0', 'l1', 'l2']", + "41, Hdc-EGFP ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "42, bacterial ['l3', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "43, artificial ['l4', 'l13', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "44, chromosome ['l0', 'l5', 'l14', 'l22', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "45, (BAC) ['l6', 'l15', 'l23', 'l30', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "46, transgenic ['l1', 'l7', 'l16', 'l24', 'l31', 'l37', 'l43', 'l44', 'l45', 'l46']", + "47, mice ['l2', 'l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l48', 'l49']", + "81, Hdc-deficient ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l47', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "82, bone ['l10', 'l19', 'l27', 'l34', 'l40', 'l45', 'l48', 'l50', 'l56', 'l57', 'l58', 'l59', 'l60']", + "83, marrow ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l49', 'l51', 'l56', 'l61', 'l62']", + "90, CD11b(+)Ly6G(+) ['l12', 'l21', 'l29', 'l36', 'l42', 'l52', 'l57', 'l61', 'l63', 'l64', 'l65', 'l66']", + "100, Hdc-knockout ['l53', 'l58', 'l63', 'l67', 'l68', 'l69', 'l70', 'l71']", + "101, mice. ['l54', 'l59', 'l62', 'l64', 'l67', 'l72']", + "104, Hdc-deficient ['l68', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "105, IMCs ['l69', 'l73', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "110, tumor ['l65', 'l70', 'l74', 'l83', 'l92', 'l93', 'l94', 'l95', 'l96']", + "111, allografts, ['l55', 'l60', 'l66', 'l71', 'l72', 'l75', 'l84', 'l92', 'l97', 'l98', 'l99']", + "113, mouse ['l76', 'l85', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "114, CT26 ['l77', 'l86', 'l100', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "115, colon ['l78', 'l87', 'l93', 'l101', 'l111', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "116, cancer ['l79', 'l88', 'l94', 'l97', 'l102', 'l112', 'l121', 'l127', 'l128', 'l129', 'l130', 'l131']", + "117, cells ['l80', 'l89', 'l95', 'l98', 'l103', 'l113', 'l122', 'l127', 'l132', 'l133', 'l134', 'l135']", + "126, myeloid ['l81', 'l90', 'l104', 'l114', 'l123', 'l128', 'l132', 'l136', 'l137', 'l138', 'l139', 'l140']", + "127, cell ['l82', 'l91', 'l96', 'l99', 'l105', 'l115', 'l124', 'l129', 'l133', 'l136', 'l141', 'l142']", + "131, induces ['l106', 'l116', 'l143', 'l144', 'l145', 'l146']", + "133, differentiation ['l107', 'l117', 'l137', 'l143', 'l147', 'l148', 'l149']", + "135, IMCs ['l108', 'l118', 'l138', 'l144', 'l147', 'l150', 'l151']", + "145, tumor ['l109', 'l119', 'l125', 'l130', 'l134', 'l139', 'l141', 'l145', 'l148', 'l150', 'l152']", + "146, allografts. ['l110', 'l120', 'l126', 'l131', 'l135', 'l140', 'l142', 'l146', 'l149', 'l151', 'l152']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hdc-knockout", + "Hdc-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Hdc-EGFP", + "bacterial", + "artificial", + "chromosome", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Hdc-EGFP", + "bacterial", + "artificial", + "chromosome", + "transgenic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "bone", + "marrow" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Hdc-EGFP", + "bacterial", + "artificial", + "chromosome" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD11b(+)Ly6G(+)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hdc-deficient", + "Hdc-knockout" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "bone", + "marrow" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hdc-deficient", + "Hdc-knockout" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD11b(+)Ly6G(+)", + "IMCs", + "myeloid", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hdc-deficient", + "Hdc-knockout" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "allografts,", + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hdc-deficient" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "mouse", + "CT26", + "colon", + "cancer", + "cells" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "mouse", + "CT26" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "mouse", + "CT26" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "myeloid", + "IMCs" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "cells", + "words": [ + "IMCs" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "tumor", + "allografts." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "tumor", + "allografts." + ] + } + } + ] + }, + { + "PMID": "21151140", + "TEXT": "Molecular-genetic imaging is advancing from a valuable preclinical tool to a guide for patient management. The strategy involves pairing an imaging reporter gene with a complementary imaging agent in a system that can be used to measure gene expression or protein interaction or track gene-tagged cells in vivo. Tissue-specific promoters can be used to delineate gene expression in certain tissues, particularly when coupled with an appropriate amplification mechanism. Here we show that the progression elevated gene-3 (PEG-3) promoter, derived from a rodent gene mediating tumor progression and metastatic phenotypes, can be used to drive imaging reporters selectively to enable detection of micrometastatic disease in mouse models of human melanoma and breast cancer using bioluminescence and radionuclide-based molecular imaging techniques. Because of its strong promoter activity, tumor specificity and capacity for clinical translation, PEG-3 promoter-driven gene expression may represent a practical, new system for facilitating cancer imaging and therapy.", + "TAG_DATA": [ + "104, mouse {'context': 'B-neoplasm'}", + "105, models {'context': 'I-neoplasm'}", + "106, of {'context': 'I-neoplasm'}", + "107, human {'context': 'I-neoplasm'}", + "108, melanoma {'context': 'I-neoplasm'}", + "109, and {'context': 'I-neoplasm'}", + "110, breast {'context': 'I-neoplasm'}", + "111, cancer {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "104, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "105, models ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "106, of ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "107, human ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "108, melanoma ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "109, and ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "110, breast ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "111, cancer ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21151139", + "TEXT": "Adenovirus type 37 (Ad37) is a leading cause of epidemic keratoconjunctivitis (EKC), a severe and highly contagious ocular disease. Whereas most other adenoviruses infect cells by engaging CD46 or the coxsackie and adenovirus receptor (CAR), Ad37 binds previously unknown sialic acid-containing cell surface molecules. By glycan array screening, we show here that the receptor-recognizing knob domain of the Ad37 fiber protein specifically binds a branched hexasaccharide that is present in the GD1a ganglioside and that features two terminal sialic acids. Soluble GD1a glycan and GD1a-binding antibodies efficiently prevented Ad37 virions from binding and infecting corneal cells. Unexpectedly, the receptor is constituted by one or more glycoproteins containing the GD1a glycan motif rather than the ganglioside itself, as shown by binding, infection and flow cytometry experiments. Molecular modeling, nuclear magnetic resonance and X-ray crystallography reveal that the two terminal sialic acids dock into two of three previously established sialic acid-binding sites in the trimeric Ad37 knob. Surface plasmon resonance analysis shows that the knob-GD1a glycan interaction has high affinity. Our findings therefore form a basis for the design and development of sialic acid-containing antiviral drugs for topical treatment of EKC.", + "TAG_DATA": [ + "94, corneal {'context': 'B-cells'}", + "95, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "94, corneal ['l0']", + "95, cells. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21131958", + "TEXT": "Pandemic influenza viruses often cause severe disease in middle-aged adults without preexisting comorbidities. The mechanism of illness associated with severe disease in this age group is not well understood. Here we find preexisting serum antibodies that cross-react with, but do not protect against, 2009 H1N1 influenza virus in middle-aged adults. Nonprotective antibody is associated with immune complex-mediated disease after infection. We detected high titers of serum antibody of low avidity for H1-2009 antigen, and low-avidity pulmonary immune complexes against the same protein, in severely ill individuals. Moreover, C4d deposition--a marker of complement activation mediated by immune complexes--was present in lung sections of fatal cases. Archived lung sections from middle-aged adults with confirmed fatal influenza 1957 H2N2 infection revealed a similar mechanism of illness. These observations provide a previously unknown biological mechanism for the unusual age distribution of severe cases during influenza pandemics.", + "TAG_DATA": [ + "108, middle-aged {'context': 'B-organism'}", + "109, adults {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "108, middle-aged ['l0']", + "109, adults ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21113156", + "TEXT": "We report that coupling between dopamine D1 and D2 receptors was markedly increased in postmortem brain of subjects suffering from major depression. Biochemical analyses revealed that D1 and D2 receptors form heterodimers via a direct protein-protein interaction. Administration of an interfering peptide that disrupts the D1-D2 receptor complex substantially reduced immobility in the forced swim test (FST) without affecting locomotor activity, and decreased escape failures in learned helplessness tests in rats.", + "TAG_DATA": [ + "70, rats. {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21102461", + "TEXT": "Stroke is a major public health problem leading to high rates of death and disability in adults. Excessive stimulation of N-methyl-D-aspartate receptors (NMDARs) and the resulting neuronal nitric oxide synthase (nNOS) activation are crucial for neuronal injury after stroke insult. However, directly inhibiting NMDARs or nNOS can cause severe side effects because they have key physiological functions in the CNS. Here we show that cerebral ischemia induces the interaction of nNOS with postsynaptic density protein-95 (PSD-95). Disrupting nNOS-PSD-95 interaction via overexpressing the N-terminal amino acid residues 1-133 of nNOS (nNOS-N(1-133)) prevented glutamate-induced excitotoxicity and cerebral ischemic damage. Given the mechanism of nNOS-PSD-95 interaction, we developed a series of compounds and discovered a small-molecular inhibitor of the nNOS-PSD-95 interaction, ZL006. This drug blocked the ischemia-induced nNOS-PSD-95 association selectively, had potent neuroprotective activity in vitro and ameliorated focal cerebral ischemic damage in mice and rats subjected to middle cerebral artery occlusion (MCAO) and reperfusion. Moreover, it readily crossed the blood-brain barrier, did not inhibit NMDAR function, catalytic activity of nNOS or spatial memory, and had no effect on aggressive behaviors. Thus, this new drug may serve as a treatment for stroke, perhaps without major side effects.", + "TAG_DATA": [ + "80, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "81, the {'perturbing_action': 'I-gene gain-of-function'}", + "82, N-terminal {'perturbing_action': 'I-gene gain-of-function'}", + "83, amino {'perturbing_action': 'I-gene gain-of-function'}", + "84, acid {'perturbing_action': 'I-gene gain-of-function'}", + "85, residues {'perturbing_action': 'I-gene gain-of-function'}", + "86, 1-133 {'perturbing_action': 'I-gene gain-of-function'}", + "87, of {'perturbing_action': 'I-gene gain-of-function'}", + "88, nNOS {'perturbing_action': 'I-gene gain-of-function'}", + "89, (nNOS-N(1-133)) {'perturbing_action': 'I-gene gain-of-function'}", + "131, in {'context': 'B-in vitro'}", + "132, vitro {'context': 'I-in vitro'}", + "140, mice {'context': 'B-organism'}", + "142, rats {'context': 'B-organism'}", + "173, no {'effect': 'B-no effect'}", + "174, effect {'effect': 'I-no effect'}" + ], + "LINK_DATA": [ + "80, overexpressing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "81, the ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "82, N-terminal ['l1', 'l12', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "83, amino ['l2', 'l13', 'l24', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "84, acid ['l3', 'l14', 'l25', 'l35', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "85, residues ['l4', 'l15', 'l26', 'l36', 'l45', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "86, 1-133 ['l5', 'l16', 'l27', 'l37', 'l46', 'l54', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "87, of ['l6', 'l17', 'l28', 'l38', 'l47', 'l55', 'l62', 'l69', 'l70', 'l71', 'l72', 'l73']", + "88, nNOS ['l7', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l69', 'l74', 'l75', 'l76', 'l77']", + "89, (nNOS-N(1-133)) ['l8', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l74', 'l78', 'l79', 'l80']", + "131, in ['l9', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l75', 'l78', 'l81', 'l82', 'l83']", + "132, vitro ['l10', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l76', 'l79', 'l81', 'l84', 'l85']", + "140, mice ['l11', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l77', 'l80', 'l82', 'l84', 'l86']", + "142, rats ['l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l83', 'l85', 'l86']", + "173, no ['l87']", + "174, effect ['l87']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "the", + "N-terminal", + "amino", + "acid", + "residues", + "1-133", + "of", + "nNOS", + "(nNOS-N(1-133))" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "the", + "N-terminal", + "amino", + "acid", + "residues", + "1-133", + "of", + "nNOS", + "(nNOS-N(1-133))" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "rats" + ] + } + } + ] + }, + { + "PMID": "21102459", + "TEXT": "Refined cancer models are required if researchers are to assess the burgeoning number of potential targets for cancer therapeutics in a clinically relevant context that allows a fast turnaround. Here we use tumor-associated genetic pathways to transform primary human epithelial cells from the epidermis, oropharynx, esophagus and cervix into genetically defined tumors in a human three-dimensional (3D) tissue environment that incorporates cell-populated stroma and intact basement membrane. These engineered organotypic tissues recapitulated natural features of tumor progression, including epithelial invasion through basement membrane, a complex process that is necessary for biological malignancy in 90% of human cancers. Invasion was rapid and was potentiated by stromal cells. Oncogenic signals in 3D tissue, but not 2D culture, resembled gene expression profiles from spontaneous human cancers. We screened 3D organotypic neoplasia with well-characterized signaling pathway inhibitors to distill a clinically faithful cancer gene signature. Multitissue 3D human tissue cancer models may provide an efficient and relevant complement to current approaches to characterizing cancer progression.", + "TAG_DATA": [ + "37, primary {'context': 'B-cells'}", + "38, human {'context': 'I-cells'}", + "39, epithelial {'context': 'I-cells'}", + "40, cells {'context': 'I-cells'}", + "97, Invasion {'phenotype': 'B-invasion'}", + "102, potentiated {'effect': 'B-positive'}", + "104, stromal {'context': 'B-cells'}", + "105, cells. {'context': 'I-cells'}", + "109, 3D {'context': 'B-tissue/organ'}", + "110, tissue, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "37, primary ['l0', 'l1', 'l2', 'l3']", + "38, human ['l0', 'l4', 'l5', 'l6']", + "39, epithelial ['l1', 'l4', 'l7', 'l8']", + "40, cells ['l2', 'l5', 'l7', 'l9']", + "41, from ['l3', 'l6', 'l8', 'l9']", + "97, Invasion ['l10', 'l11', 'l12']", + "102, potentiated ['l10', 'l13', 'l14']", + "104, stromal ['l11', 'l13', 'l15']", + "105, cells. ['l12', 'l14', 'l15']", + "109, 3D ['l16']", + "110, tissue, ['l16']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "invasion", + "words": [ + "Invasion" + ] + }, + "effect": { + "val": "positive", + "words": [ + "potentiated" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "Invasion" + ] + }, + "context": { + "val": "cells", + "words": [ + "stromal", + "cells." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "potentiated" + ] + }, + "context": { + "val": "cells", + "words": [ + "stromal", + "cells." + ] + } + } + ] + }, + { + "PMID": "21076395", + "TEXT": "Aberrant activation of the Hedgehog (Hh) pathway can drive tumorigenesis. To investigate the mechanism by which glioma-associated oncogene family zinc finger-1 (GLI1), a crucial effector of Hh signaling, regulates Hh pathway activation, we searched for GLI1-interacting proteins. We report that the chromatin remodeling protein SNF5 (encoded by SMARCB1, hereafter called SNF5), which is inactivated in human malignant rhabdoid tumors (MRTs), interacts with GLI1. We show that Snf5 localizes to Gli1-regulated promoters and that loss of Snf5 leads to activation of the Hh-Gli pathway. Conversely, re-expression of SNF5 in MRT cells represses GLI1. Consistent with this, we show the presence of a Hh-Gli-activated gene expression profile in primary MRTs and show that GLI1 drives the growth of SNF5-deficient MRT cells in vitro and in vivo. Therefore, our studies reveal that SNF5 is a key mediator of Hh signaling and that aberrant activation of GLI1 is a previously undescribed targetable mechanism contributing to the growth of MRT cells.", + "TAG_DATA": [ + "73, loss {'perturbing_action': 'B-gene loss-of-function'}", + "74, of {'perturbing_action': 'I-gene loss-of-function'}", + "75, Snf5 {'perturbing_action': 'I-gene loss-of-function'}", + "84, re-expression {'perturbing_action': 'B-gene gain-of-function'}", + "85, of {'perturbing_action': 'I-gene gain-of-function'}", + "86, SNF5 {'perturbing_action': 'I-gene gain-of-function'}", + "88, MRT {'context': 'B-cells'}", + "89, cells {'context': 'I-cells'}", + "116, SNF5-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "117, MRT {'context': 'B-cells'}", + "118, cells {'context': 'I-cells'}", + "119, in {'context': 'B-in vitro'}", + "120, vitro {'context': 'I-in vitro'}", + "122, in {'context': 'B-in vivo'}", + "123, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "73, loss ['l0', 'l1']", + "74, of ['l0', 'l2']", + "75, Snf5 ['l1', 'l2']", + "84, re-expression ['l3', 'l4', 'l5', 'l6']", + "85, of ['l3', 'l7', 'l8', 'l9']", + "86, SNF5 ['l4', 'l7', 'l10', 'l11']", + "88, MRT ['l5', 'l8', 'l10', 'l12']", + "89, cells ['l6', 'l9', 'l11', 'l12']", + "116, SNF5-deficient ['l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "117, MRT ['l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "118, cells ['l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "119, in ['l15', 'l20', 'l24', 'l28', 'l29', 'l30']", + "120, vitro ['l16', 'l21', 'l25', 'l28', 'l31', 'l32']", + "122, in ['l17', 'l22', 'l26', 'l29', 'l31', 'l33']", + "123, vivo. ['l18', 'l23', 'l27', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "re-expression", + "of", + "SNF5" + ] + }, + "context": { + "val": "cells", + "words": [ + "MRT", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SNF5-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "MRT", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SNF5-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SNF5-deficient" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "21076393", + "TEXT": "Multiphoton excitation fluorescence microscopy (MPM) can image certain molecular processes in vivo. In the eye, fluorescent retinyl esters in subcellular structures called retinosomes mediate regeneration of the visual chromophore, 11-cis-retinal, by the visual cycle. But harmful fluorescent condensation products of retinoids also occur in the retina. We report that in wild-type mice, excitation with a wavelength of ∼730 nm identified retinosomes in the retinal pigment epithelium, and excitation with a wavelength of ∼910 nm revealed at least one additional retinal fluorophore. The latter fluorescence was absent in eyes of genetically modified mice lacking a functional visual cycle, but accentuated in eyes of older wild-type mice and mice with defective clearance of all-trans-retinal, an intermediate in the visual cycle. MPM, a noninvasive imaging modality that facilitates concurrent monitoring of retinosomes along with potentially harmful products in aging eyes, has the potential to detect early molecular changes due to age-related macular degeneration and other defects in retinoid metabolism.", + "TAG_DATA": [ + "51, mice, {'context': 'B-organism'}", + "87, eyes {'context': 'B-tissue/organ'}", + "91, mice {'context': 'B-organism'}", + "100, eyes {'context': 'B-tissue/organ'}", + "104, mice {'context': 'I-organism'}", + "106, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "87, eyes ['l0', 'l1']", + "91, mice ['l0', 'l2']", + "100, eyes ['l1', 'l2', 'l3']", + "104, mice ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "21052078", + "TEXT": "Neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease represent a crucial and exponentially increasing challenge to health care systems throughout the world. There is an urgent need for effective treatments that will both delay their onset and slow their inexorable progression. Many obstacles stand in the way of realizing these goals. It is expected that future advances will have a major impact on how and when the diagnosis will be made. It is hoped that these will eventually make it possible to initiate effective disease-modifying therapies long before the neurodegenerative process becomes established and symptomatic.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "21052076", + "TEXT": "Why, with all the progress in the field of neurodegeneration, do we still lack disease-modifying drugs that tackle the primary defect of severe cell loss? How much progress has been made toward this goal? Have we spent our time and resources wisely? And, most important, is there room for improvement? This commentary highlights several problems faced by researchers in studying the genetic etiology of neurodegenerative diseases and seeks to provide direction in overcoming some of these obstacles.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20972433", + "TEXT": "The TLX1 oncogene (encoding the transcription factor T cell leukemia homeobox protein-1) has a major role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL). However, the specific mechanisms of T cell transformation downstream of TLX1 remain to be elucidated. Here we show that transgenic expression of human TLX1 in mice induces T-ALL with frequent deletions and mutations in Bcl11b (encoding B cell leukemia/lymphoma-11B) and identify the presence of recurrent mutations and deletions in BCL11B in 16% of human T-ALLs. Most notably, mouse TLX1 tumors were typically aneuploid and showed a marked defect in the activation of the mitotic checkpoint. Mechanistically, TLX1 directly downregulates the expression of CHEK1 (encoding CHK1 checkpoint homolog) and additional mitotic control genes and induces loss of the mitotic checkpoint in nontransformed preleukemic thymocytes. These results identify a previously unrecognized mechanism contributing to chromosomal missegregation and aneuploidy active at the earliest stages of tumor development in the pathogenesis of cancer.", + "TAG_DATA": [ + "45, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "46, expression {'perturbing_action': 'I-gene gain-of-function'}", + "47, of {'perturbing_action': 'I-gene gain-of-function'}", + "48, human {'perturbing_action': 'I-gene gain-of-function'}", + "49, TLX1 {'perturbing_action': 'I-gene gain-of-function'}", + "51, mice {'context': 'B-organism'}", + "52, induces {'effect': 'B-positive'}", + "53, T-ALL {'phenotype': 'B-transformation'}", + "83, mouse {'context': 'B-neoplasm'}", + "84, TLX1 {'context': 'I-neoplasm'}", + "85, tumors {'context': 'I-neoplasm'}", + "126, nontransformed {'context': 'B-cells'}", + "127, preleukemic {'context': 'B-cells'}", + "128, thymocytes. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "46, expression ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "47, of ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "48, human ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "49, TLX1 ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "51, mice ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "52, induces ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "53, T-ALL ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "83, mouse ['l28', 'l29']", + "84, TLX1 ['l28', 'l30']", + "85, tumors ['l29', 'l30']", + "126, nontransformed ['l31', 'l32']", + "127, preleukemic ['l31', 'l33']", + "128, thymocytes. ['l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "of", + "human", + "TLX1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "of", + "human", + "TLX1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "of", + "human", + "TLX1" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "T-ALL" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "T-ALL" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "T-ALL" + ] + } + } + ] + }, + { + "PMID": "20871612", + "TEXT": "A drawback of electrical stimulation for muscle control is that large, fatigable motor units are preferentially recruited before smaller motor units by the lowest-intensity electrical cuff stimulation. This phenomenon limits therapeutic applications because it is precisely the opposite of the normal physiological (orderly) recruitment pattern; therefore, a mechanism to achieve orderly recruitment has been a long-sought goal in physiology, medicine and engineering. Here we demonstrate a technology for reliable orderly recruitment in vivo. We find that under optical control with microbial opsins, recruitment of motor units proceeds in the physiological recruitment sequence, as indicated by multiple independent measures of motor unit recruitment including conduction latency, contraction and relaxation times, stimulation threshold and fatigue. As a result, we observed enhanced performance and reduced fatigue in vivo. These findings point to an unanticipated new modality of neural control with broad implications for nervous system and neuromuscular physiology, disease research and therapeutic innovation.", + "TAG_DATA": [ + "84, motor {'context': 'B-cells'}", + "85, units {'context': 'B-cells'}", + "123, in {'context': 'B-in vivo'}", + "124, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "84, motor ['l0']", + "85, units ['l0']", + "123, in ['l1']", + "124, vivo. ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20871610", + "TEXT": "Mobilization of hematopoietic stem and progenitor cells (HSPCs) from bone marrow into peripheral blood by the cytokine granulocyte colony-stimulating factor (G-CSF) has become the preferred source of HSPCs for stem cell transplants. However, G-CSF fails to mobilize sufficient numbers of stem cells in up to 10% of donors, precluding autologous transplantation in those donors or substantially delaying transplant recovery time. Consequently, new regimens are needed to increase the number of stem cells in peripheral blood upon mobilization. Using a forward genetic approach in mice, we mapped the gene encoding the epidermal growth factor receptor (Egfr) to a genetic region modifying G-CSF-mediated HSPC mobilization. Amounts of EGFR in HSPCs inversely correlated with the cells' ability to be mobilized by G-CSF, implying a negative role for EGFR signaling in mobilization. In combination with G-CSF treatment, genetic reduction of EGFR activity in HSPCs (in waved-2 mutant mice) or treatment with the EGFR inhibitor erlotinib increased mobilization. Increased mobilization due to suppression of EGFR activity correlated with reduced activity of cell division control protein-42 (Cdc42), and genetic Cdc42 deficiency in vivo also enhanced G-CSF-induced mobilization. Our findings reveal a previously unknown signaling pathway regulating stem cell mobilization and provide a new pharmacological approach for improving HSPC mobilization and thereby transplantation outcomes.", + "TAG_DATA": [ + "133, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "134, reduction {'perturbing_action': 'I-gene loss-of-function'}", + "135, of {'perturbing_action': 'I-gene loss-of-function'}", + "136, EGFR {'perturbing_action': 'I-gene loss-of-function'}", + "137, activity {'perturbing_action': 'I-gene loss-of-function'}", + "139, HSPCs {'context': 'B-cells'}", + "141, waved-2 {'perturbing_action': 'B-other'}", + "142, mutant {'perturbing_action': 'I-other'}", + "143, mice) {'context': 'B-organism'}", + "172, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "173, Cdc42 {'perturbing_action': 'I-gene loss-of-function'}", + "174, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "175, in {'context': 'B-in vivo'}", + "176, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "133, genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "134, reduction ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "135, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "136, EGFR ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "137, activity ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "139, HSPCs ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "141, waved-2 ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "142, mutant ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "143, mice) ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "172, genetic ['l36', 'l37', 'l38', 'l39']", + "173, Cdc42 ['l36', 'l40', 'l41', 'l42']", + "174, deficiency ['l37', 'l40', 'l43', 'l44']", + "175, in ['l38', 'l41', 'l43', 'l45']", + "176, vivo ['l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "reduction", + "of", + "EGFR", + "activity" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSPCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "reduction", + "of", + "EGFR", + "activity" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice)" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSPCs" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "waved-2", + "mutant" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "waved-2", + "mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "Cdc42", + "deficiency" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "20852621", + "TEXT": "During fasting, mammals maintain normal glucose homeostasis by stimulating hepatic gluconeogenesis. Elevations in circulating glucagon and epinephrine, two hormones that activate hepatic gluconeogenesis, trigger the cAMP-mediated phosphorylation of cAMP response element-binding protein (Creb) and dephosphorylation of the Creb-regulated transcription coactivator-2 (Crtc2)--two key transcriptional regulators of this process. Although the underlying mechanism is unclear, hepatic gluconeogenesis is also regulated by the circadian clock, which coordinates glucose metabolism with changes in the external environment. Circadian control of gene expression is achieved by two transcriptional activators, Clock and Bmal1, which stimulate cryptochrome (Cry1 and Cry2) and Period (Per1, Per2 and Per3) repressors that feed back on Clock-Bmal1 activity. Here we show that Creb activity during fasting is modulated by Cry1 and Cry2, which are rhythmically expressed in the liver. Cry1 expression was elevated during the night-day transition, when it reduced fasting gluconeogenic gene expression by blocking glucagon-mediated increases in intracellular cAMP concentrations and in the protein kinase A-mediated phosphorylation of Creb. In biochemical reconstitution studies, we found that Cry1 inhibited accumulation of cAMP in response to G protein-coupled receptor (GPCR) activation but not to forskolin, a direct activator of adenyl cyclase. Cry proteins seemed to modulate GPCR activity directly through interaction with G(s)α. As hepatic overexpression of Cry1 lowered blood glucose concentrations and improved insulin sensitivity in insulin-resistant db/db mice, our results suggest that compounds that enhance cryptochrome activity may provide therapeutic benefit to individuals with type 2 diabetes.", + "TAG_DATA": [ + "201, hepatic {'perturbing_action': 'B-gene gain-of-function'}", + "202, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "203, of {'perturbing_action': 'I-gene gain-of-function'}", + "204, Cry1 {'perturbing_action': 'I-gene gain-of-function'}", + "214, insulin-resistant {'context': 'B-organism'}", + "215, db/db {'context': 'I-organism'}", + "216, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "201, hepatic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "202, overexpression ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "203, of ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "204, Cry1 ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "214, insulin-resistant ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "215, db/db ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "216, mice, ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hepatic", + "overexpression", + "of", + "Cry1" + ] + }, + "context": { + "val": "organism", + "words": [ + "insulin-resistant", + "db/db", + "mice," + ] + } + } + ] + }, + { + "PMID": "20802499", + "TEXT": "Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here we demonstrate that either whole-body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Similarly, inhibition of thyroid hormone receptors in the VMH reverses the weight loss associated with hyperthyroidism. This regulatory mechanism depends on AMPK inactivation, as genetic inhibition of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increases expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockade of the SNS. Thus, thyroid hormone-induced modulation of AMPK activity and lipid metabolism in the hypothalamus is a major regulator of whole-body energy homeostasis.", + "TAG_DATA": [ + "91, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "92, of {'perturbing_action': 'I-pharmacological inhibition'}", + "93, thyroid {'perturbing_action': 'I-pharmacological inhibition'}", + "94, hormone {'perturbing_action': 'I-pharmacological inhibition'}", + "95, receptors {'perturbing_action': 'I-pharmacological inhibition'}", + "96, in {'perturbing_action': 'I-pharmacological inhibition'}", + "97, the {'perturbing_action': 'I-pharmacological inhibition'}", + "98, VMH {'perturbing_action': 'I-pharmacological inhibition'}", + "114, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "115, inhibition {'perturbing_action': 'I-gene loss-of-function'}", + "116, of {'perturbing_action': 'I-gene loss-of-function'}", + "117, this {'perturbing_action': 'I-gene loss-of-function'}", + "118, enzyme {'perturbing_action': 'I-gene loss-of-function'}", + "120, the {'perturbing_action': 'I-gene loss-of-function'}", + "121, VMH {'perturbing_action': 'I-gene loss-of-function'}", + "124, rats {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "91, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "92, of ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "93, thyroid ['l1', 'l16', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "94, hormone ['l2', 'l17', 'l31', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "95, receptors ['l3', 'l18', 'l32', 'l44', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "96, in ['l4', 'l19', 'l33', 'l45', 'l57', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "97, the ['l5', 'l20', 'l34', 'l46', 'l58', 'l68', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "98, VMH ['l6', 'l21', 'l35', 'l47', 'l59', 'l69', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "114, genetic ['l7', 'l22', 'l48', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "115, inhibition ['l8', 'l23', 'l36', 'l49', 'l60', 'l90', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "116, of ['l9', 'l24', 'l37', 'l50', 'l61', 'l70', 'l91', 'l98', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "117, this ['l10', 'l25', 'l38', 'l51', 'l62', 'l71', 'l78', 'l84', 'l92', 'l99', 'l105', 'l111', 'l112', 'l113', 'l114', 'l115']", + "118, enzyme ['l11', 'l26', 'l39', 'l52', 'l63', 'l72', 'l79', 'l85', 'l93', 'l100', 'l106', 'l111', 'l116', 'l117', 'l118', 'l119']", + "119, in ['l12', 'l27', 'l40', 'l53', 'l64', 'l73', 'l80', 'l86', 'l94', 'l101', 'l107', 'l112', 'l116', 'l120', 'l121', 'l122']", + "120, the ['l13', 'l28', 'l41', 'l54', 'l65', 'l74', 'l81', 'l87', 'l95', 'l102', 'l108', 'l113', 'l117', 'l120', 'l123', 'l124']", + "121, VMH ['l14', 'l29', 'l42', 'l55', 'l66', 'l75', 'l82', 'l88', 'l96', 'l103', 'l109', 'l114', 'l118', 'l121', 'l123', 'l125']", + "124, rats ['l15', 'l30', 'l43', 'l56', 'l67', 'l76', 'l83', 'l89', 'l97', 'l104', 'l110', 'l115', 'l119', 'l122', 'l124', 'l125']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "thyroid", + "hormone", + "receptors", + "in", + "the", + "VMH" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inhibition", + "of", + "this", + "enzyme", + "the", + "VMH" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + } + ] + }, + { + "PMID": "20729865", + "TEXT": "There is no effective treatment for cocaine addiction despite extensive knowledge of the neurobiology of drug addiction. Here we show that a selective aldehyde dehydrogenase-2 (ALDH-2) inhibitor, ALDH2i, suppresses cocaine self-administration in rats and prevents cocaine- or cue-induced reinstatement in a rat model of cocaine relapse-like behavior. We also identify a molecular mechanism by which ALDH-2 inhibition reduces cocaine-seeking behavior: increases in tetrahydropapaveroline (THP) formation due to inhibition of ALDH-2 decrease cocaine-stimulated dopamine production and release in vitro and in vivo. Cocaine increases extracellular dopamine concentration, which activates dopamine D2 autoreceptors to stimulate cAMP-dependent protein kinase A (PKA) and protein kinase C (PKC) in primary ventral tegmental area (VTA) neurons. PKA and PKC phosphorylate and activate tyrosine hydroxylase, further increasing dopamine synthesis in a positive-feedback loop. Monoamine oxidase converts dopamine to 3,4-dihydroxyphenylacetaldehyde (DOPAL), a substrate for ALDH-2. Inhibition of ALDH-2 enables DOPAL to condense with dopamine to form THP in VTA neurons. THP selectively inhibits phosphorylated (activated) tyrosine hydroxylase to reduce dopamine production via negative-feedback signaling. Reducing cocaine- and craving-associated increases in dopamine release seems to account for the effectiveness of ALDH2i in suppressing cocaine-seeking behavior. Selective inhibition of ALDH-2 may have therapeutic potential for treating human cocaine addiction and preventing relapse.", + "TAG_DATA": [ + "22, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "23, aldehyde {'perturbing_action': 'I-pharmacological inhibition'}", + "24, dehydrogenase-2 {'perturbing_action': 'I-pharmacological inhibition'}", + "25, (ALDH-2) {'perturbing_action': 'I-pharmacological inhibition'}", + "26, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "27, ALDH2i, {'perturbing_action': 'I-pharmacological inhibition'}", + "32, rats {'context': 'B-organism'}", + "41, rat {'context': 'B-organism'}", + "42, model {'context': 'I-organism'}", + "55, ALDH-2 {'perturbing_action': 'B-pharmacological inhibition'}", + "56, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "67, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "68, of {'perturbing_action': 'I-pharmacological inhibition'}", + "69, ALDH-2 {'perturbing_action': 'I-pharmacological inhibition'}", + "76, in {'context': 'B-in vitro'}", + "77, vitro {'context': 'I-in vitro'}", + "79, in {'context': 'B-in vivo'}", + "80, vivo. {'context': 'I-in vivo'}", + "104, primary {'context': 'B-cells'}", + "105, ventral {'context': 'I-cells'}", + "106, tegmental {'context': 'I-cells'}", + "107, area {'context': 'I-cells'}", + "108, (VTA) {'context': 'I-cells'}", + "109, neurons. {'context': 'I-cells'}", + "137, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "138, of {'perturbing_action': 'I-pharmacological inhibition'}", + "139, ALDH-2 {'perturbing_action': 'I-pharmacological inhibition'}", + "150, VTA {'context': 'B-cells'}", + "151, neurons. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "22, selective ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "23, aldehyde ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "24, dehydrogenase-2 ['l1', 'l20', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "25, (ALDH-2) ['l2', 'l21', 'l42', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "26, inhibitor, ['l3', 'l22', 'l43', 'l63', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "27, ALDH2i, ['l4', 'l23', 'l44', 'l64', 'l78', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "32, rats ['l5', 'l24', 'l45', 'l65', 'l79', 'l92', 'l104', 'l105', 'l106']", + "41, rat ['l6', 'l25', 'l46', 'l66', 'l80', 'l93', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "42, model ['l7', 'l26', 'l47', 'l67', 'l81', 'l94', 'l107', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "55, ALDH-2 ['l8', 'l27', 'l48', 'l68', 'l82', 'l95', 'l104', 'l108', 'l117', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "56, inhibition ['l9', 'l28', 'l49', 'l69', 'l83', 'l96', 'l109', 'l118', 'l126', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "67, inhibition ['l10', 'l29', 'l50', 'l70', 'l84', 'l97', 'l110', 'l119', 'l127', 'l134', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "68, of ['l11', 'l30', 'l51', 'l71', 'l85', 'l98', 'l111', 'l120', 'l128', 'l135', 'l141', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163']", + "69, ALDH-2 ['l12', 'l31', 'l52', 'l72', 'l86', 'l99', 'l112', 'l121', 'l129', 'l136', 'l142', 'l153', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "76, in ['l13', 'l32', 'l53', 'l73', 'l87', 'l100', 'l105', 'l113', 'l122', 'l130', 'l137', 'l143', 'l154', 'l164', 'l174', 'l175', 'l176']", + "77, vitro ['l14', 'l33', 'l54', 'l74', 'l88', 'l101', 'l106', 'l114', 'l123', 'l131', 'l138', 'l144', 'l155', 'l165', 'l174', 'l177', 'l178']", + "79, in ['l15', 'l34', 'l55', 'l75', 'l89', 'l102', 'l115', 'l124', 'l132', 'l139', 'l145', 'l156', 'l166', 'l175', 'l177', 'l179']", + "80, vivo. ['l16', 'l35', 'l56', 'l76', 'l90', 'l103', 'l116', 'l125', 'l133', 'l140', 'l146', 'l157', 'l167', 'l176', 'l178', 'l179']", + "104, primary ['l17', 'l36', 'l57', 'l147', 'l158', 'l168', 'l180', 'l181', 'l182', 'l183', 'l184']", + "105, ventral ['l37', 'l58', 'l148', 'l159', 'l169', 'l180', 'l185', 'l186', 'l187', 'l188', 'l189']", + "106, tegmental ['l38', 'l59', 'l149', 'l160', 'l170', 'l181', 'l185', 'l190', 'l191', 'l192', 'l193']", + "107, area ['l18', 'l39', 'l60', 'l150', 'l161', 'l171', 'l182', 'l186', 'l190', 'l194', 'l195']", + "108, (VTA) ['l40', 'l61', 'l151', 'l162', 'l172', 'l183', 'l187', 'l191', 'l194', 'l196', 'l197']", + "109, neurons. ['l19', 'l41', 'l62', 'l77', 'l91', 'l152', 'l163', 'l173', 'l184', 'l188', 'l192', 'l195', 'l196']", + "137, Inhibition ['l198', 'l199', 'l200', 'l201']", + "138, of ['l198', 'l202', 'l203', 'l204']", + "139, ALDH-2 ['l199', 'l202', 'l205', 'l206']", + "150, VTA ['l200', 'l203', 'l205', 'l207']", + "151, neurons. ['l189', 'l193', 'l197', 'l201', 'l204', 'l206', 'l207']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "aldehyde", + "dehydrogenase-2", + "(ALDH-2)", + "inhibitor,", + "ALDH2i,", + "ALDH-2", + "inhibition", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats", + "rat", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "aldehyde", + "dehydrogenase-2", + "(ALDH-2)", + "inhibitor,", + "ALDH2i,", + "ALDH-2", + "inhibition", + "of" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "aldehyde", + "dehydrogenase-2", + "(ALDH-2)", + "inhibitor,", + "ALDH2i,", + "ALDH-2", + "inhibition", + "of" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "aldehyde", + "dehydrogenase-2", + "(ALDH-2)", + "inhibitor,", + "inhibition", + "of", + "ALDH-2", + "Inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "primary", + "area", + "neurons.", + "ventral", + "tegmental", + "(VTA)", + "VTA" + ] + } + } + ] + }, + { + "PMID": "20657581", + "TEXT": "High amounts of glutamate are found in the brains of people with multiple sclerosis, an inflammatory disease marked by progressive demyelination. Glutamate might affect neuroinflammation via effects on immune cells. Knockout mice lacking metabotropic glutamate receptor-4 (mGluR4) were markedly vulnerable to experimental autoimmune encephalomyelitis (EAE, a mouse model of multiple sclerosis) and developed responses dominated by interleukin-17-producing T helper (T(H)17) cells. In dendritic cells (DCs) from those mice, defective mGluR4 signaling-which would normally decrease intracellular cAMP formation-biased T(H) cell commitment to the T(H)17 phenotype. In wild-type mice, mGluR4 was constitutively expressed in all peripheral DCs, and this expression increased after cell activation. Treatment of wild-type mice with a selective mGluR4 enhancer increased EAE resistance via regulatory T (T(reg)) cells. The high amounts of glutamate in neuroinflammation might reflect a counterregulatory mechanism that is protective in nature and might be harnessed therapeutically for restricting immunopathology in multiple sclerosis.", + "TAG_DATA": [ + "30, Knockout {'perturbing_action': 'B-gene loss-of-function'}", + "31, mice {'context': 'B-organism'}", + "32, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "33, metabotropic {'perturbing_action': 'I-gene loss-of-function'}", + "34, glutamate {'perturbing_action': 'I-gene loss-of-function'}", + "35, receptor-4 {'perturbing_action': 'I-gene loss-of-function'}", + "36, (mGluR4) {'perturbing_action': 'I-gene loss-of-function'}", + "62, dendritic {'context': 'B-cells'}", + "63, cells {'context': 'I-cells'}", + "64, (DCs) {'context': 'I-cells'}", + "67, mice, {'context': 'B-organism'}", + "77, T(H) {'context': 'B-cells'}", + "78, cell {'context': 'I-cells'}", + "86, mice, {'context': 'B-organism'}", + "93, peripheral {'context': 'B-cells'}", + "94, DCs, {'context': 'I-cells'}", + "105, mice {'context': 'B-organism'}", + "108, selective {'perturbing_action': 'B-gene gain-of-function'}", + "109, mGluR4 {'perturbing_action': 'I-gene gain-of-function'}", + "110, enhancer {'perturbing_action': 'I-gene gain-of-function'}", + "115, regulatory {'context': 'B-cells'}", + "116, T {'context': 'I-cells'}", + "117, (T(reg)) {'context': 'I-cells'}", + "118, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "30, Knockout ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "31, mice ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "32, lacking ['l1', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "33, metabotropic ['l2', 'l13', 'l22', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "34, glutamate ['l3', 'l14', 'l23', 'l32', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "35, receptor-4 ['l4', 'l15', 'l24', 'l33', 'l41', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "36, (mGluR4) ['l5', 'l16', 'l25', 'l34', 'l42', 'l49', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "62, dendritic ['l6', 'l17', 'l26', 'l35', 'l43', 'l50', 'l56', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "63, cells ['l7', 'l18', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l68', 'l69', 'l70', 'l71']", + "64, (DCs) ['l8', 'l19', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l72', 'l73', 'l74']", + "67, mice, ['l9', 'l20', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l69', 'l72', 'l75', 'l76']", + "77, T(H) ['l10', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l70', 'l73', 'l75', 'l77', 'l78', 'l79']", + "78, cell ['l11', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l71', 'l74', 'l76', 'l77']", + "86, mice, ['l80', 'l81']", + "93, peripheral ['l78', 'l80', 'l82']", + "94, DCs, ['l67', 'l79', 'l81', 'l82']", + "105, mice ['l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "108, selective ['l83', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "109, mGluR4 ['l84', 'l90', 'l96', 'l97', 'l98', 'l99', 'l100']", + "110, enhancer ['l85', 'l91', 'l96', 'l101', 'l102', 'l103', 'l104']", + "115, regulatory ['l86', 'l92', 'l97', 'l101', 'l105', 'l106', 'l107']", + "116, T ['l87', 'l93', 'l98', 'l102', 'l105', 'l108', 'l109']", + "117, (T(reg)) ['l88', 'l94', 'l99', 'l103', 'l106', 'l108', 'l110']", + "118, cells. ['l89', 'l95', 'l100', 'l104', 'l107', 'l109', 'l110']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Knockout", + "lacking", + "metabotropic", + "glutamate", + "receptor-4", + "(mGluR4)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Knockout", + "lacking", + "metabotropic", + "glutamate", + "receptor-4", + "(mGluR4)" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells", + "(DCs)", + "T(H)", + "cell" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "selective", + "mGluR4", + "enhancer" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "selective", + "mGluR4", + "enhancer" + ] + }, + "context": { + "val": "cells", + "words": [ + "regulatory", + "T", + "(T(reg))", + "cells." + ] + } + } + ] + }, + { + "PMID": "20639891", + "TEXT": "Influenza prophylaxis would benefit from a vaccination method enabling simplified logistics and improved immunogenicity without the dangers posed by hypodermic needles. Here we introduce dissolving microneedle patches for influenza vaccination using a simple patch-based system that targets delivery to skin's antigen-presenting cells. Microneedles were fabricated using a biocompatible polymer encapsulating inactivated influenza virus vaccine for insertion and dissolution in the skin within minutes. Microneedle vaccination generated robust antibody and cellular immune responses in mice that provided complete protection against lethal challenge. Compared to conventional intramuscular injection, microneedle vaccination resulted in more efficient lung virus clearance and enhanced cellular recall responses after challenge. These results suggest that dissolving microneedle patches can provide a new technology for simpler and safer vaccination with improved immunogenicity that could facilitate increased vaccination coverage.", + "TAG_DATA": [ + "73, mice {'context': 'B-organism'}", + "92, lung {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20639889", + "TEXT": "Hypertrophic heart disease is a leading health problem in Western countries. Here we identified the small EF hand domain-containing protein Ca(2+) and integrin-binding protein-1 (CIB1) in a screen for previously unknown regulators of cardiomyocyte hypertrophy. Yeast two-hybrid screening for CIB1-interacting partners identified a related EF hand domain-containing protein, calcineurin B, the regulatory subunit of the prohypertrophic protein phosphatase calcineurin. CIB1 localizes primarily to the sarcolemma in mouse and human myocardium, where it anchors calcineurin to control its activation in coordination with the L-type Ca(2+) channel. CIB1 protein amounts and membrane association were enhanced in cardiac pathological hypertrophy, but not in physiological hypertrophy. Consistent with these observations, Cib1-deleted mice showed a marked reduction in myocardial hypertrophy, fibrosis, cardiac dysfunction and calcineurin-nuclear factor of activated T cells (NFAT) activity after pressure overload, whereas the degree of physiologic hypertrophy after swimming exercise was not altered. Transgenic mice with inducible and cardiac-specific overexpression of CIB1 showed enhanced cardiac hypertrophy in response to pressure overload or calcineurin signaling. Moreover, mice lacking Ppp3cb (encoding calcineurin A, beta isozyme) showed no enhancement in cardiac hypertrophy associated with CIB1 overexpression. Thus, CIB1 functions as a previously undescribed regulator of cardiac hypertrophy through its ability to regulate the association of calcineurin with the sarcolemma and its activation.", + "TAG_DATA": [ + "106, Cib1-deleted {'perturbing_action': 'B-gene loss-of-function'}", + "107, mice {'context': 'B-organism'}", + "142, Transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "143, mice {'context': 'I-organism'}", + "145, inducible {'perturbing_action': 'B-gene gain-of-function'}", + "146, and {'perturbing_action': 'I-gene gain-of-function'}", + "147, cardiac-specific {'perturbing_action': 'I-gene gain-of-function'}", + "148, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "149, of {'perturbing_action': 'I-gene gain-of-function'}", + "150, CIB1 {'perturbing_action': 'I-gene gain-of-function'}", + "164, mice {'context': 'B-organism'}", + "165, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "166, Ppp3cb {'perturbing_action': 'I-gene loss-of-function'}", + "167, (encoding {'perturbing_action': 'I-gene loss-of-function'}", + "180, CIB1 {'perturbing_action': 'B-gene gain-of-function'}", + "181, overexpression. {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "106, Cib1-deleted ['l0']", + "107, mice ['l0']", + "142, Transgenic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "143, mice ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "145, inducible ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "146, and ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "147, cardiac-specific ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "148, overexpression ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "149, of ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "150, CIB1 ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']", + "164, mice ['l29', 'l30', 'l31', 'l32', 'l33']", + "165, lacking ['l29', 'l34', 'l35', 'l36', 'l37']", + "166, Ppp3cb ['l30', 'l34', 'l38', 'l39', 'l40']", + "167, (encoding ['l31', 'l35', 'l38', 'l41', 'l42']", + "180, CIB1 ['l32', 'l36', 'l39', 'l41', 'l43']", + "181, overexpression. ['l33', 'l37', 'l40', 'l42', 'l43']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cib1-deleted", + "lacking", + "Ppp3cb", + "(encoding" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgenic", + "inducible", + "and", + "cardiac-specific", + "overexpression", + "of", + "CIB1", + "overexpression." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "20613742", + "TEXT": "Last month, Carolyn Bertozzi became the first woman to win the prestigious Massachusetts Institute of Technology (MIT)-Lemelson Prize, a $500,000 award that honors midcareer inventors. Bertozzi, a chemical biologist, works to understand how sugars mediate cell-to-cell communication. But she isn't content with just observing the process; her lab at the University of California-Berkeley has pioneered tools for labeling molecules inside living cells. Her biomedical inventions have contributed to the development of noninvasive methods for identifying disease tissue within the body-advances that could revolutionize both the diagnosis and the treatment of a host of diseases ranging from arthritis to cancer. Roxanne Palmer recently caught up with her by phone to discuss Bertozzi's sweet success with cell surface sugars.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20526308", + "TEXT": "In 2008, the method of taking skin cells from people suffering from disease and transforming them into embryonic-like stem cells was heralded as the 'breakthrough of the year' by publications such as Time magazine. Two years on, so-called induced pluripotent stem (iPS) cells are just beginning to shed new light on disease biology. From day one of this burgeoning area of study, stem cell pioneer George Daley of Children's Hospital in Boston, who developed the first library of disease-specific iPS cells lines, has remained involved in this fast-paced field. Ahead of the June annual meeting of the International Society for Stem Cell Research (ISSCR) in San Francisco, Elie Dolgin spoke to Daley about when and how reprogrammed stem cells will deliver.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20495569", + "TEXT": "Osteoarthritic cartilage destruction is caused by an imbalance between anabolic and catabolic factors. Here, we show that hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by EPAS1) is a catabolic transcription factor in the osteoarthritic process. HIF-2alpha directly induces the expression in chondrocytes of genes encoding catabolic factors, including matrix metalloproteinases (MMP1, MMP3, MMP9, MMP12 and MMP13), aggrecanase-1 (ADAMTS4), nitric oxide synthase-2 (NOS2) and prostaglandin-endoperoxide synthase-2 (PTGS2). HIF-2alpha expression was markedly increased in human and mouse osteoarthritic cartilage, and its ectopic expression triggered articular cartilage destruction in mice and rabbits. Moreover, mice transgenic for Epas1 only in chondrocytes showed spontaneous cartilage destruction, whereas heterozygous genetic deletion of Epas1 in mice suppressed cartilage destruction caused by destabilization of the medial meniscus (DMM) or collagenase injection, with concomitant modulation of catabolic factors. Our results collectively demonstrate that HIF-2alpha causes cartilage destruction by regulating crucial catabolic genes.", + "TAG_DATA": [ + "83, mice {'context': 'B-organism'}", + "85, rabbits. {'context': 'B-organism'}", + "87, mice {'context': 'B-organism'}", + "88, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "89, for {'perturbing_action': 'I-gene gain-of-function'}", + "90, Epas1 {'perturbing_action': 'I-gene gain-of-function'}", + "93, chondrocytes {'context': 'B-cells'}", + "99, heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "100, genetic {'perturbing_action': 'I-gene loss-of-function'}", + "101, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "102, of {'perturbing_action': 'I-gene loss-of-function'}", + "103, Epas1 {'perturbing_action': 'I-gene loss-of-function'}", + "105, mice {'context': 'B-organism'}", + "114, medial {'context': 'B-tissue/organ'}", + "115, meniscus {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "83, mice ['l0']", + "85, rabbits. ['l0']", + "87, mice ['l1', 'l2', 'l3', 'l4']", + "88, transgenic ['l1', 'l5', 'l6', 'l7']", + "89, for ['l2', 'l5', 'l8', 'l9']", + "90, Epas1 ['l3', 'l6', 'l8', 'l10']", + "93, chondrocytes ['l4', 'l7', 'l9', 'l10']", + "99, heterozygous ['l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "100, genetic ['l11', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "101, deletion ['l12', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "102, of ['l13', 'l20', 'l26', 'l32', 'l33', 'l34', 'l35', 'l36']", + "103, Epas1 ['l14', 'l21', 'l27', 'l32', 'l37', 'l38', 'l39', 'l40']", + "105, mice ['l15', 'l22', 'l28', 'l33', 'l37', 'l41', 'l42', 'l43']", + "114, medial ['l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l44', 'l45']", + "115, meniscus ['l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l46']", + "116, (DMM) ['l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l46']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "Epas1" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "Epas1" + ] + }, + "context": { + "val": "cells", + "words": [ + "chondrocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "heterozygous", + "genetic", + "deletion", + "of", + "Epas1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "heterozygous", + "genetic", + "deletion", + "of", + "Epas1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "medial", + "meniscus" + ] + } + } + ] + }, + { + "PMID": "20495567", + "TEXT": "Activating transcription factor-5 (ATF5) is highly expressed in malignant glioma and has a key role in promoting cell survival. Here we perform a genome-wide RNAi screen to identify transcriptional regulators of ATF5. Our results reveal an essential survival pathway in malignant glioma, whereby activation of a RAS-mitogen-activated protein kinase or phosphoinositide-3-kinase signaling cascade leads to induction of the transcription factor cAMP response element-binding protein-3-like-2 (CREB3L2), which directly activates ATF5 expression. ATF5, in turn, promotes survival by stimulating transcription of myeloid cell leukemia sequence-1 (MCL1), an antiapoptotic B cell leukemia-2 family member. Analysis of human malignant glioma samples indicates that ATF5 expression inversely correlates with disease prognosis. The RAF kinase inhibitor sorafenib suppresses ATF5 expression in glioma stem cells and inhibits malignant glioma growth in cell culture and mouse models. Our results demonstrate that ATF5 is essential in malignant glioma genesis and reveal that the ATF5-mediated survival pathway described here provides potential therapeutic targets for treatment of malignant glioma.", + "TAG_DATA": [ + "115, glioma {'context': 'B-transformed cells'}", + "116, stem {'context': 'I-transformed cells'}", + "117, cells {'context': 'I-transformed cells'}", + "120, malignant {'context': 'B-neoplasm'}", + "121, glioma {'context': 'I-neoplasm'}", + "124, cell {'context': 'B-cells'}", + "125, culture {'context': 'I-cells'}", + "127, mouse {'context': 'B-organism'}", + "128, models. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "115, glioma ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "116, stem ['l0', 'l6', 'l7', 'l8', 'l9']", + "117, cells ['l1', 'l6', 'l10']", + "120, malignant ['l2', 'l11', 'l12', 'l13', 'l14', 'l15']", + "121, glioma ['l3', 'l7', 'l11', 'l16', 'l17', 'l18', 'l19']", + "124, cell ['l4', 'l8', 'l12', 'l16', 'l20', 'l21', 'l22']", + "125, culture ['l5', 'l9', 'l10', 'l13', 'l17', 'l20', 'l23', 'l24']", + "127, mouse ['l14', 'l18', 'l21', 'l23', 'l25']", + "128, models. ['l15', 'l19', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20473309", + "TEXT": "Toll-like receptor (TLR) signaling is essential for intestinal tumorigenesis in Apc(min/+) mice, but the mechanisms by which Apc enhances tumor growth are unknown. Here we show that microflora-MyD88-ERK signaling in intestinal epithelial cells (IECs) promotes tumorigenesis by increasing the stability of the c-Myc oncoprotein. Activation of ERK (extracellular signal-related kinase) phosphorylates c-Myc, preventing its ubiquitination and subsequent proteasomal degradation. Accordingly, Apc(min/+)/Myd88(-/-) mice have lower phospho-ERK (p-ERK) levels and fewer and smaller IEC tumors than Apc(min/+) mice. MyD88 (myeloid differentiation primary response gene 88)-independent activation of ERK by epidermal growth factor (EGF) increased p-ERK and c-Myc and restored the multiple intestinal neoplasia (Min) phenotype in Apc(min/+)/Myd88(-/-) mice. Administration of an ERK inhibitor suppressed intestinal tumorigenesis in EGF-treated Apc(min/+)/Myd88(-/-) and Apc(min/+) mice and increased their survival. Our data reveal a new facet of oncogene-environment interaction, in which microflora-induced TLR activation regulates oncogene expression and related IEC tumor growth in a susceptible host.", + "TAG_DATA": [ + "34, promotes {'effect': 'B-positive'}", + "35, tumorigenesis {'phenotype': 'B-tumourigenesis'}", + "60, Apc(min/+)/Myd88(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "61, mice {'context': 'B-organism'}", + "71, IEC {'context': 'B-neoplasm'}", + "72, tumors {'context': 'I-neoplasm'}", + "74, Apc(min/+) {'perturbing_action': 'B-other'}", + "75, mice. {'context': 'B-organism'}", + "100, neoplasia {'phenotype': 'I-epithelial-mesenchymal transition'}", + "104, Apc(min/+)/Myd88(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "105, mice. {'context': 'B-organism'}", + "109, ERK {'perturbing_action': 'B-pharmacological inhibition'}", + "110, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "111, suppressed {'effect': 'B-negative'}", + "112, intestinal {'context': 'B-tissue/organ'}", + "113, tumorigenesis {'phenotype': 'B-tumourigenesis'}", + "116, Apc(min/+)/Myd88(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "118, Apc(min/+) {'perturbing_action': 'B-other'}", + "119, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "34, promotes ['l0', 'l1', 'l2', 'l3']", + "35, tumorigenesis ['l0', 'l4', 'l5']", + "60, Apc(min/+)/Myd88(-/-) ['l1', 'l4', 'l6', 'l7', 'l8', 'l9']", + "61, mice ['l2', 'l5', 'l6', 'l10', 'l11']", + "71, IEC ['l7', 'l10', 'l12', 'l13', 'l14', 'l15']", + "72, tumors ['l3', 'l8', 'l11', 'l12']", + "74, Apc(min/+) ['l13', 'l16', 'l17', 'l18', 'l19', 'l20']", + "75, mice. ['l9', 'l14', 'l16', 'l21', 'l22', 'l23']", + "98, multiple ['l17', 'l24', 'l25', 'l26', 'l27', 'l28']", + "99, intestinal ['l18', 'l21', 'l24', 'l29', 'l30', 'l31', 'l32']", + "100, neoplasia ['l19', 'l22', 'l25', 'l29', 'l33', 'l34', 'l35']", + "101, (Min) ['l15', 'l20', 'l23', 'l26', 'l30', 'l33', 'l36', 'l37']", + "104, Apc(min/+)/Myd88(-/-) ['l27', 'l31', 'l34', 'l36', 'l38']", + "105, mice. ['l28', 'l32', 'l35', 'l37', 'l38']", + "109, ERK ['l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "110, inhibitor ['l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "111, suppressed ['l40', 'l46', 'l52', 'l53', 'l54', 'l55']", + "112, intestinal ['l41', 'l47', 'l52', 'l56', 'l57', 'l58']", + "113, tumorigenesis ['l42', 'l48', 'l53', 'l56', 'l59', 'l60']", + "116, Apc(min/+)/Myd88(-/-) ['l43', 'l49', 'l54', 'l57', 'l59', 'l61', 'l62']", + "118, Apc(min/+) ['l44', 'l50', 'l61', 'l63']", + "119, mice ['l45', 'l51', 'l55', 'l58', 'l60', 'l62', 'l63']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apc(min/+)/Myd88(-/-)" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apc(min/+)/Myd88(-/-)" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apc(min/+)/Myd88(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apc(min/+)/Myd88(-/-)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "IEC", + "tumors" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "IEC" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Apc(min/+)" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Apc(min/+)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Apc(min/+)" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "neoplasia" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "neoplasia" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "neoplasia" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apc(min/+)/Myd88(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ERK", + "inhibitor" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ERK", + "inhibitor" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "intestinal" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ERK", + "inhibitor" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ERK", + "inhibitor" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "intestinal" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apc(min/+)/Myd88(-/-)" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "intestinal" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "intestinal" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apc(min/+)/Myd88(-/-)" + ] + } + } + ] + }, + { + "PMID": "20473306", + "TEXT": "Transplant arteriosclerosis is the hallmark of chronic allograft dysfunction (CAD) affecting transplanted organs in the long term. These fibroproliferative lesions lead to neointimal thickening of arteries in all transplanted allografts. Luminal narrowing then leads to graft ischemia and organ demise. To date, there are no known tolerance induction strategies that prevent transplant arteriosclerosis. Therefore, we designed this study to test the hypothesis that human regulatory T cells (T(reg) cells) expanded ex vivo can prevent transplant arteriosclerosis. Here we show the comparative capacity of T(reg) cells, sorted via two separate strategies, to prevent transplant arteriosclerosis in a clinically relevant chimeric humanized mouse system. We found that the in vivo development of transplant arteriosclerosis in human arteries was prevented by treatment of ex vivo-expanded human T(reg) cells. Additionally, we show that T(reg) cells sorted on the basis of low expression of CD127 provide a more potent therapy to conventional T(reg) cells. Our results demonstrate that human T(reg) cells can inhibit transplant arteriosclerosis by impairing effector function and graft infiltration. We anticipate our findings to serve as a foundation for the clinical development of therapeutics targeting transplant arteriosclerosis in both allograft transplantation and other immune-mediated causes of vasculopathy.", + "TAG_DATA": [ + "98, chimeric {'context': 'B-organism'}", + "99, humanized {'context': 'I-organism'}", + "100, mouse {'context': 'I-organism'}", + "101, system. {'context': 'I-organism'}", + "106, in {'context': 'B-in vivo'}", + "107, vivo {'context': 'B-in vivo'}", + "113, human {'context': 'B-tissue/organ'}", + "114, arteries {'context': 'I-tissue/organ'}", + "122, human {'context': 'B-cells'}", + "123, T(reg) {'context': 'I-cells'}", + "124, cells. {'context': 'I-cells'}", + "129, T(reg) {'context': 'B-cells'}", + "130, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "98, chimeric ['l0', 'l1', 'l2']", + "99, humanized ['l0', 'l3', 'l4']", + "100, mouse ['l1', 'l3', 'l5']", + "101, system. ['l2', 'l4', 'l5']", + "106, in ['l6', 'l7', 'l8']", + "107, vivo ['l6', 'l9', 'l10']", + "113, human ['l7', 'l9', 'l11']", + "114, arteries ['l8', 'l10', 'l11']", + "122, human ['l12', 'l13']", + "123, T(reg) ['l12', 'l14']", + "124, cells. ['l13', 'l14']", + "129, T(reg) ['l15']", + "130, cells ['l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20473305", + "TEXT": "Rtp801 (also known as Redd1, and encoded by Ddit4), a stress-related protein triggered by adverse environmental conditions, inhibits mammalian target of rapamycin (mTOR) by stabilizing the TSC1-TSC2 inhibitory complex and enhances oxidative stress-dependent cell death. We postulated that Rtp801 acts as a potential amplifying switch in the development of cigarette smoke-induced lung injury, leading to emphysema. Rtp801 mRNA and protein were overexpressed in human emphysematous lungs and in lungs of mice exposed to cigarette smoke. The regulation of Rtp801 expression by cigarette smoke may rely on oxidative stress-dependent activation of the CCAAT response element in its promoter. We also found that Rtp801 was necessary and sufficient for nuclear factor-kappaB (NF-kappaB) activation in cultured cells and, when forcefully expressed in mouse lungs, it promoted NF-kappaB activation, alveolar inflammation, oxidative stress and apoptosis of alveolar septal cells. In contrast, Rtp801 knockout mice were markedly protected against acute cigarette smoke-induced lung injury, partly via increased mTOR signaling, and, when exposed chronically to cigarette smoke, against emphysema. Our data support the notion that Rtp801 may represent a major molecular sensor and mediator of cigarette smoke-induced lung injury.", + "TAG_DATA": [ + "64, emphysematous {'context': 'I-tissue/organ'}", + "65, lungs {'context': 'I-tissue/organ'}", + "68, lungs {'context': 'B-tissue/organ'}", + "70, mice {'context': 'B-organism'}", + "112, cultured {'context': 'B-cells'}", + "113, cells {'context': 'I-cells'}", + "119, mouse {'context': 'B-tissue/organ'}", + "120, lungs, {'context': 'I-tissue/organ'}", + "122, promoted {'effect': 'B-positive'}", + "130, apoptosis {'phenotype': 'B-apoptosis'}", + "132, alveolar {'context': 'B-cells'}", + "133, septal {'context': 'I-cells'}", + "134, cells. {'context': 'I-cells'}", + "137, Rtp801 {'perturbing_action': 'B-gene loss-of-function'}", + "138, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "139, mice {'context': 'B-organism'}", + "147, lung {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "64, emphysematous ['l0', 'l1', 'l2', 'l3']", + "65, lungs ['l0', 'l4']", + "68, lungs ['l1', 'l4', 'l5', 'l6', 'l7']", + "70, mice ['l2', 'l5', 'l8', 'l9', 'l10']", + "112, cultured ['l6', 'l8', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "113, cells ['l3', 'l7', 'l9', 'l11', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "119, mouse ['l12', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "120, lungs, ['l13', 'l20', 'l26', 'l32', 'l33', 'l34', 'l35', 'l36']", + "122, promoted ['l10', 'l14', 'l21', 'l27', 'l32', 'l37', 'l38', 'l39', 'l40']", + "130, apoptosis ['l15', 'l22', 'l28', 'l33', 'l37', 'l41', 'l42', 'l43']", + "132, alveolar ['l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l44', 'l45']", + "133, septal ['l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l46']", + "134, cells. ['l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l46']", + "137, Rtp801 ['l47', 'l48', 'l49']", + "138, knockout ['l47', 'l50', 'l51']", + "139, mice ['l48', 'l50', 'l52']", + "147, lung ['l49', 'l51', 'l52']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "cells", + "alveolar", + "septal", + "cells." + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "cells", + "alveolar", + "septal", + "cells." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "lungs," + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "lungs," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rtp801", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rtp801", + "knockout" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + } + ] + }, + { + "PMID": "20473304", + "TEXT": "Sepsis is a systemic inflammatory condition following bacterial infection with a high mortality rate and limited therapeutic options. Here we show that interleukin-33 (IL-33) reduces mortality in mice with experimental sepsis from cecal ligation and puncture (CLP). IL-33-treated mice developed increased neutrophil influx into the peritoneal cavity and more efficient bacterial clearance than untreated mice. IL-33 reduced the systemic but not the local proinflammatory response, and it did not induce a T helper type 1 (T(H)1) to T(H)2 shift. The chemokine receptor CXCR2 is crucial for recruitment of neutrophils from the circulation to the site of infection. Activation of Toll-like receptors (TLRs) in neutrophils downregulates CXCR2 expression and impairs neutrophil migration. We show here that IL-33 prevents the downregulation of CXCR2 and inhibition of chemotaxis induced by the activation of TLR4 in mouse and human neutrophils. Furthermore, we show that IL-33 reverses the TLR4-induced reduction of CXCR2 expression in neutrophils via the inhibition of expression of G protein-coupled receptor kinase-2 (GRK2), a serine-threonine protein kinase that induces internalization of chemokine receptors. Finally, we find that individuals who did not recover from sepsis had significantly more soluble ST2 (sST2, the decoy receptor of IL-33) than those who did recover. Together, our results indicate a previously undescribed mechanism of action of IL-33 and suggest a therapeutic potential of IL-33 in sepsis.", + "TAG_DATA": [ + "27, mice {'context': 'B-organism'}", + "38, mice {'context': 'B-organism'}", + "54, mice. {'context': 'B-organism'}", + "108, impairs {'effect': 'B-negative'}", + "109, neutrophil {'context': 'B-cells'}", + "110, migration. {'phenotype': 'B-migration'}", + "122, inhibition {'effect': 'B-negative'}", + "124, chemotaxis {'phenotype': 'B-migration'}", + "132, mouse {'context': 'B-cells'}", + "133, and {'context': 'I-cells'}", + "134, human {'context': 'I-cells'}", + "135, neutrophils. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "38, mice ['l0', 'l1']", + "54, mice. ['l0', 'l2']", + "108, impairs ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "109, neutrophil ['l3', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "110, migration. ['l1', 'l2', 'l4', 'l11', 'l18', 'l19', 'l20', 'l21']", + "122, inhibition ['l5', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26']", + "124, chemotaxis ['l6', 'l13', 'l22', 'l27', 'l28', 'l29', 'l30']", + "132, mouse ['l7', 'l14', 'l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "133, and ['l8', 'l15', 'l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "134, human ['l9', 'l16', 'l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "135, neutrophils. ['l10', 'l17', 'l21', 'l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impairs", + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "neutrophil", + "mouse", + "and", + "human", + "neutrophils." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impairs", + "inhibition" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration.", + "chemotaxis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neutrophil", + "mouse", + "and", + "human", + "neutrophils." + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration.", + "chemotaxis" + ] + } + } + ] + }, + { + "PMID": "20448575", + "TEXT": "Approximately 5% of people that are hospitalized for any reason develop acute kidney failure, which, in some cases, progresses to a chronic condition resulting in fibrosis of the kidney and permanent changes in the organ’s function. Two new studies suggest that cell cycle arrest of epithelial cells and epigenetic modifications have key roles in the switch to chronic disease (pages 535–543 and 544–550).", + "TAG_DATA": [ + "41, cell {'phenotype': 'B-cell cycle arrest'}", + "42, cycle {'phenotype': 'I-cell cycle arrest'}", + "43, arrest {'phenotype': 'I-cell cycle arrest'}", + "45, epithelial {'context': 'B-cells'}", + "46, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "41, cell ['l0', 'l1', 'l2', 'l3']", + "42, cycle ['l0', 'l4', 'l5', 'l6']", + "43, arrest ['l1', 'l4', 'l7', 'l8']", + "45, epithelial ['l2', 'l5', 'l7', 'l9']", + "46, cells ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + }, + "context": { + "val": "cells", + "words": [ + "epithelial", + "cells" + ] + } + } + ] + }, + { + "PMID": "20436484", + "TEXT": "Inflammation induced by recognition of pathogen-associated molecular patterns markedly affects subsequent adaptive responses. We asked whether the adaptive immune system can also affect the character and magnitude of innate inflammatory responses. We found that the response of memory, but not naive, CD4(+) T cells enhances production of multiple innate inflammatory cytokines and chemokines (IICs) in the lung and that, during influenza infection, this leads to early control of virus. Memory CD4(+) T cell-induced IICs and viral control require cognate antigen recognition and are optimal when memory cells are either T helper type 1 (T(H)1) or T(H)17 polarized but are independent of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) production and do not require activation of conserved pathogen recognition pathways. This represents a previously undescribed mechanism by which memory CD4(+) T cells induce an early innate response that enhances immune protection against pathogens.", + "TAG_DATA": [ + "37, memory, {'context': 'B-cells'}", + "40, naive, {'context': 'B-cells'}", + "41, CD4(+) {'context': 'I-cells'}", + "42, T {'context': 'I-cells'}", + "43, cells {'context': 'I-cells'}", + "56, lung {'context': 'B-tissue/organ'}", + "85, memory {'context': 'B-cells'}", + "86, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "37, memory, ['l0', 'l1', 'l2', 'l3', 'l4']", + "40, naive, ['l0', 'l5', 'l6', 'l7', 'l8']", + "41, CD4(+) ['l1', 'l5', 'l9', 'l10', 'l11']", + "42, T ['l2', 'l6', 'l9', 'l12', 'l13']", + "43, cells ['l3', 'l7', 'l10', 'l12', 'l14']", + "56, lung ['l4', 'l8', 'l11', 'l13', 'l14']", + "71, T ['l15', 'l16']", + "85, memory ['l15', 'l17']", + "86, cells ['l16', 'l17']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20436483", + "TEXT": "Fibrosis is responsible for chronic progressive kidney failure, which is present in a large number of adults in the developed world. It is increasingly appreciated that acute kidney injury (AKI), resulting in aberrant incomplete repair, is a major contributor to chronic fibrotic kidney disease. The mechanism that triggers the fibrogenic response after injury is not well understood. In ischemic, toxic and obstructive models of AKI, we demonstrate a causal association between epithelial cell cycle G2/M arrest and a fibrotic outcome. G2/M-arrested proximal tubular cells activate c-jun NH(2)-terminal kinase (JNK) signaling, which acts to upregulate profibrotic cytokine production. Treatment with a JNK inhibitor, or bypassing the G2/M arrest by administration of a p53 inhibitor or the removal of the contralateral kidney, rescues fibrosis in the unilateral ischemic injured kidney. Hence, epithelial cell cycle arrest at G2/M and its subsequent downstream signaling are hitherto unrecognized therapeutic targets for the prevention of fibrosis and interruption of the accelerated progression of kidney disease.", + "TAG_DATA": [ + "80, G2/M-arrested {'phenotype': 'I-cell cycle arrest'}", + "81, proximal {'context': 'B-cells'}", + "82, tubular {'context': 'I-cells'}", + "83, cells {'context': 'I-cells'}", + "100, JNK {'perturbing_action': 'B-pharmacological inhibition'}", + "101, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "106, arrest {'phenotype': 'I-cell cycle arrest'}", + "111, p53 {'perturbing_action': 'B-pharmacological inhibition'}", + "112, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "119, kidney, {'context': 'I-tissue/organ'}", + "127, kidney. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "80, G2/M-arrested ['l0', 'l1', 'l2']", + "81, proximal ['l0', 'l3', 'l4']", + "82, tubular ['l1', 'l3', 'l5']", + "83, cells ['l2', 'l4', 'l5']", + "100, JNK ['l6', 'l7', 'l8', 'l9', 'l10']", + "101, inhibitor, ['l6']", + "106, arrest ['l7', 'l11', 'l12', 'l13', 'l14', 'l15']", + "111, p53 ['l8', 'l11', 'l16', 'l17', 'l18', 'l19']", + "112, inhibitor ['l9', 'l12', 'l16', 'l20', 'l21', 'l22']", + "118, contralateral ['l13', 'l17', 'l20', 'l23', 'l24']", + "119, kidney, ['l10', 'l14', 'l18', 'l21', 'l23', 'l25']", + "127, kidney. ['l15', 'l19', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G2/M-arrested" + ] + }, + "context": { + "val": "cells", + "words": [ + "proximal", + "tubular", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "JNK", + "p53", + "inhibitor" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "JNK", + "p53", + "inhibitor" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidney,", + "kidney." + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidney,", + "kidney." + ] + } + } + ] + }, + { + "PMID": "20418886", + "TEXT": "Leukemias and other cancers possess self-renewing stem cells that help to maintain the cancer. Cancer stem cell eradication is thought to be crucial for successful anticancer therapy. Using an acute myeloid leukemia (AML) model induced by the leukemia-associated monocytic leukemia zinc finger (MOZ)-TIF2 fusion protein, we show here that AML can be cured by the ablation of leukemia stem cells. The MOZ fusion proteins MOZ-TIF2 and MOZ-CBP interacted with the transcription factor PU.1 to stimulate the expression of macrophage colony-stimulating factor receptor (CSF1R, also known as M-CSFR, c-FMS or CD115). Studies using PU.1-deficient mice showed that PU.1 is essential for the ability of MOZ-TIF2 to establish and maintain AML stem cells. Cells expressing high amounts of CSF1R (CSF1R(high) cells), but not those expressing low amounts of CSF1R (CSF1R(low) cells), showed potent leukemia-initiating activity. Using transgenic mice expressing a drug-inducible suicide gene controlled by the CSF1R promoter, we cured AML by ablation of CSF1R(high) cells. Moreover, induction of AML was suppressed in CSF1R-deficient mice and CSF1R inhibitors slowed the progression of MOZ-TIF2-induced leukemia. Thus, in this subtype of AML, leukemia stem cells are contained within the CSF1R(high) cell population, and we suggest that targeting of PU.1-mediated upregulation of CSF1R expression might be a useful therapeutic approach.", + "TAG_DATA": [ + "92, PU.1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "93, mice {'context': 'B-organism'}", + "134, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "135, mice {'context': 'I-organism'}", + "148, AML {'context': 'B-neoplasm'}", + "155, induction {'effect': 'B-positive'}", + "159, suppressed {'effect': 'B-negative'}", + "161, CSF1R-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "162, mice {'context': 'B-organism'}", + "164, CSF1R {'perturbing_action': 'B-pharmacological inhibition'}", + "165, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "170, MOZ-TIF2-induced {'effect': 'B-positive'}", + "171, leukemia. {'phenotype': 'B-tumourigenesis'}" + ], + "LINK_DATA": [ + "92, PU.1-deficient ['l0']", + "93, mice ['l0']", + "134, transgenic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "135, mice ['l1', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "140, gene ['l2', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "141, controlled ['l3', 'l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "142, by ['l4', 'l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "143, the ['l5', 'l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "144, CSF1R ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "145, promoter, ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "148, AML ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "153, cells. ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']", + "155, induction ['l46', 'l47', 'l48', 'l49']", + "157, AML ['l46', 'l50', 'l51', 'l52', 'l53', 'l54']", + "159, suppressed ['l47', 'l50', 'l55', 'l56']", + "161, CSF1R-deficient ['l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "162, mice ['l48', 'l52', 'l55', 'l57', 'l62', 'l63']", + "164, CSF1R ['l58', 'l64', 'l65', 'l66']", + "165, inhibitors ['l59', 'l64', 'l67', 'l68']", + "170, MOZ-TIF2-induced ['l53', 'l60', 'l62', 'l65', 'l67', 'l69']", + "171, leukemia. ['l49', 'l54', 'l56', 'l61', 'l63', 'l66', 'l68', 'l69']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PU.1-deficient", + "CSF1R-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "AML" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction", + "MOZ-TIF2-induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction", + "MOZ-TIF2-induced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CSF1R-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "MOZ-TIF2-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CSF1R-deficient" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CSF1R", + "inhibitors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "MOZ-TIF2-induced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CSF1R", + "inhibitors" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia." + ] + } + } + ] + }, + { + "PMID": "20418884", + "TEXT": "Giardia lamblia is a human intestinal pathogen. Like many protozoan microorganisms, Giardia undergoes antigenic variation, a mechanism assumed to allow parasites to evade the host's immune response, producing chronic and/or recurrent infections. Recently, we found that the mechanism controlling variant-specific surface protein (VSP) switching in Giardia involves components of the RNA interference machinery and that disruption of this pathway generates trophozoites simultaneously expressing many VSPs. Here we use these altered trophozoites to determine the role of antigenic variation in a gerbil model of giardiasis. Our results show that either primary infection with trophozoites simultaneously expressing many VSPs or immunization with purified VSPs from the transgenic cells protects gerbils from subsequent Giardia infections. These results constitute, to our knowledge, the first experimental evidence that antigenic variation is essential for parasite survival within hosts and that artificial disruption of this mechanism might be useful in generating vaccines against major pathogens that show similar behavior.", + "TAG_DATA": [ + "80, gerbil {'context': 'B-organism'}", + "81, model {'context': 'I-organism'}", + "104, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "105, cells {'context': 'B-cells'}", + "107, gerbils {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "80, gerbil ['l0']", + "81, model ['l0']", + "104, transgenic ['l1', 'l2']", + "105, cells ['l1', 'l3']", + "107, gerbils ['l2', 'l3']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "gerbils" + ] + } + } + ] + }, + { + "PMID": "20383154", + "TEXT": "Inflammatory pain, such as arthritis pain, is a growing health problem. Inflammatory pain is generally treated with opioids and cyclooxygenase (COX) inhibitors, but both are limited by side effects. Recently, resolvins, a unique family of lipid mediators, including RvE1 and RvD1 derived from omega-3 polyunsaturated fatty acid, have shown marked potency in treating disease conditions associated with inflammation. Here we report that peripheral (intraplantar) or spinal (intrathecal) administration of RvE1 or RvD1 in mice potently reduces inflammatory pain behaviors induced by intraplantar injection of formalin, carrageenan or complete Freund's adjuvant (CFA), without affecting basal pain perception. Intrathecal RvE1 injection also inhibits spontaneous pain and heat and mechanical hypersensitivity evoked by intrathecal capsaicin and tumor necrosis factor-alpha (TNF-alpha). RvE1 has anti-inflammatory activity by reducing neutrophil infiltration, paw edema and proinflammatory cytokine expression. RvE1 also abolishes transient receptor potential vanilloid subtype-1 (TRPV1)- and TNF-alpha-induced excitatory postsynaptic current increases and TNF-alpha-evoked N-methyl-D-aspartic acid (NMDA) receptor hyperactivity in spinal dorsal horn neurons via inhibition of the extracellular signal-regulated kinase (ERK) signaling pathway. Thus, we show a previously unknown role for resolvins in normalizing the spinal synaptic plasticity that has been implicated in generating pain hypersensitivity. Given the potency of resolvins and the well-known side effects of opioids and COX inhibitors, resolvins may represent new analgesics for treating inflammatory pain.", + "TAG_DATA": [ + "73, mice {'context': 'B-organism'}", + "154, spinal {'context': 'B-cells'}", + "155, dorsal {'context': 'I-cells'}", + "156, horn {'context': 'I-cells'}", + "157, neurons {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "154, spinal ['l0', 'l1', 'l2']", + "155, dorsal ['l0', 'l3', 'l4']", + "156, horn ['l1', 'l3', 'l5']", + "157, neurons ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20376053", + "TEXT": "Understanding the molecular mechanisms of insulin resistance remains a major medical challenge of the twenty-first century. Over the last half-century, many hypotheses have been proposed to explain insulin resistance, and, most recently, inflammation associated with alterations in adipocytokines has become the prevailing hypothesis. Here we discuss diacylglycerol-mediated insulin resistance as an alternative and unifying hypothesis to explain the most common forms of insulin resistance associated with obesity and type 2 diabetes mellitus, as well as lipodystrophy and aging.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20376050", + "TEXT": "New technology has provided methods for collecting large amounts of data reflecting gene expression, metabolite and protein abundance, and post-translational modification of proteins. Integration of these various data sets enable the genetic mapping of many new phenotypes and facilitates the creation of network models that link genetic variation with intermediate traits leading to human disease. The first round of genome-wide association studies has not accounted for common human diseases to the extent that was expected. New phenotyping approaches and methods of data integration should bring these studies closer to their promised goals.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20208505", + "TEXT": "Shlomo Yanai has led the world's largest generic drug manufacturer, Teva Pharmaceutical Industries, as its chief executive officer since March 2007. Last year-barely his third in pharmaceuticals and his sixth in business-he was named the world's most influential pharma CEO by World Pharmaceutical Frontiers and Israel's top business executive by the Tel Aviv financial newspaper Calcalist. A twice-wounded veteran of the Yom Kippur War of 1973, Yanai served in the Israel Defense Forces for 32 years. This interview was conducted in Hebrew by Haim Watzman, who also translated the discussion into English.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20173753", + "TEXT": "Long-standing evidence indicates that quiescent human peripheral blood T lymphocytes (PBLs) do not support efficient HIV infection. In resting PBLs, reverse transcription of viral RNA takes longer than in activated cells, partially because formation of the late products of reverse transcription is decreased by RNA binding by apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G). In a subsequent step, integration of the viral complementary DNA that is eventually formed is markedly impaired. Here we show that cellular c-Jun N-terminal kinase (JNK), an enzyme that is not expressed in resting CD4+ T cells, regulates permissiveness to HIV-1 infection, and we unravel a new, sequential post-translational pathway of protein modification that regulates viral DNA integration. We found that, in activated T lymphocytes, viral integrase, which mediates HIV-1 cDNA integration into the host cell genome, is phosphorylated by JNK on a highly conserved serine residue in its core domain. Phosphorylated integrase, in turn, becomes a substrate for the cellular peptidyl prolyl-isomerase enzyme Pin1, which catalyzes a conformational modification of integrase. These concerted activities increase integrase stability and are required for efficient HIV-1 integration and infection. Lack of these modifications restricts viral infection in nonactivated, primary CD4+ T lymphocytes.", + "TAG_DATA": [ + "118, T {'context': 'I-cells'}", + "119, lymphocytes, {'context': 'I-cells'}", + "190, nonactivated, {'context': 'B-cells'}", + "191, primary {'context': 'I-cells'}", + "192, CD4+ {'context': 'I-cells'}", + "193, T {'context': 'I-cells'}", + "194, lymphocytes. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "118, T ['l0']", + "119, lymphocytes, ['l0']", + "190, nonactivated, ['l1', 'l2', 'l3', 'l4']", + "191, primary ['l1', 'l5', 'l6', 'l7']", + "192, CD4+ ['l2', 'l5', 'l8', 'l9']", + "193, T ['l3', 'l6', 'l8', 'l10']", + "194, lymphocytes. ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "20057411", + "TEXT": "Eric Green, the new head of the US National Human Genome Research Institute (NHGRI), has been involved with genomics since the term was first coined in the 1980s. He started at the US National Institutes of Health (NIH) as a postdoc and was a key contributor to the Human Genome Project. Nearly a decade ago, when Green was part of a team that produced one of the first human genome sequences, the potential for genomics-related medical applications seemed limitless. But most disorders have proved to be too complex to benefit from our current understanding of genomics, and some critics have argued that researchers have put too much emphasis on uncovering the genetic underpinnings of diseases. Recent demand for comparative effectiveness research in medicine has further complicated the debate, leading former head of NHGRI Francis Collins to worry that genomic differences could get \"lost in the wash.\" Erica Westly spoke with Green about where he sees the genomics field heading and what role he thinks the NHGRI should have in the American health care system.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20037595", + "TEXT": "Sterol metabolism has recently been linked to innate and adaptive immune responses through liver X receptor (LXR) signaling. Whether products of sterol metabolism interfere with antitumor responses is currently unknown. Dendritic cells (DCs) initiate immune responses, including antitumor activity after their CC chemokine receptor-7 (CCR7)-dependent migration to lymphoid organs. Here we report that human and mouse tumors produce LXR ligands that inhibit CCR7 expression on maturing DCs and, therefore, their migration to lymphoid organs. In agreement with this observation, we detected CD83(+)CCR7(-) DCs within human tumors. Mice injected with tumors expressing the LXR ligand-inactivating enzyme sulfotransferase 2B1b (SULT2B1b) successfully controlled tumor growth by regaining DC migration to tumor-draining lymph nodes and by developing overt inflammation within tumors. The control of tumor growth was also observed in chimeric mice transplanted with bone marrow from mice lacking the gene encoding LXR-alpha (Nr1h3(-/-) mice) Thus, we show a new mechanism of tumor immunoescape involving products of cholesterol metabolism. The manipulation of this pathway could restore antitumor immunity in individuals with cancer.", + "TAG_DATA": [ + "86, Mice {'context': 'B-organism'}", + "89, tumors {'context': 'B-neoplasm'}", + "90, expressing {'perturbing_action': 'B-other'}", + "91, the {'perturbing_action': 'I-other'}", + "92, LXR {'perturbing_action': 'I-other'}", + "93, ligand-inactivating {'perturbing_action': 'I-other'}", + "94, enzyme {'perturbing_action': 'I-other'}", + "95, sulfotransferase {'perturbing_action': 'I-other'}", + "96, 2B1b {'perturbing_action': 'I-other'}", + "97, (SULT2B1b) {'perturbing_action': 'I-other'}", + "99, controlled {'effect': 'B-regulates'}", + "100, tumor {'phenotype': 'B-tumour growth'}", + "101, growth {'phenotype': 'I-tumour growth'}", + "104, DC {'context': 'B-cells'}", + "105, migration {'phenotype': 'B-migration'}", + "107, tumor-draining {'context': 'B-tissue/organ'}", + "116, tumors. {'context': 'B-neoplasm'}", + "118, control {'effect': 'B-regulates'}", + "120, tumor {'phenotype': 'B-tumour growth'}", + "121, growth {'phenotype': 'I-tumour growth'}", + "126, chimeric {'context': 'B-organism'}", + "127, mice {'context': 'I-organism'}", + "133, mice {'context': 'B-organism'}", + "134, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "135, the {'perturbing_action': 'I-gene loss-of-function'}", + "136, gene {'perturbing_action': 'I-gene loss-of-function'}", + "137, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "138, LXR-alpha {'perturbing_action': 'I-gene loss-of-function'}", + "140, mice) {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "86, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "89, tumors ['l0', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "90, expressing ['l1', 'l18', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "91, the ['l2', 'l19', 'l35', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "92, LXR ['l3', 'l20', 'l36', 'l51', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "93, ligand-inactivating ['l4', 'l21', 'l37', 'l52', 'l66', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "94, enzyme ['l5', 'l22', 'l38', 'l53', 'l67', 'l80', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "95, sulfotransferase ['l6', 'l23', 'l39', 'l54', 'l68', 'l81', 'l93', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "96, 2B1b ['l7', 'l24', 'l40', 'l55', 'l69', 'l82', 'l94', 'l105', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "97, (SULT2B1b) ['l8', 'l25', 'l41', 'l56', 'l70', 'l83', 'l95', 'l106', 'l116', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "99, controlled ['l9', 'l26', 'l42', 'l57', 'l71', 'l84', 'l96', 'l107', 'l117', 'l126', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "100, tumor ['l10', 'l27', 'l43', 'l58', 'l72', 'l85', 'l97', 'l108', 'l118', 'l127', 'l135', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "101, growth ['l11', 'l28', 'l44', 'l59', 'l73', 'l86', 'l98', 'l109', 'l119', 'l128', 'l136', 'l143', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "104, DC ['l12', 'l29', 'l45', 'l60', 'l74', 'l87', 'l99', 'l110', 'l120', 'l129', 'l137', 'l144', 'l150', 'l156', 'l157', 'l158', 'l159', 'l160']", + "105, migration ['l13', 'l30', 'l46', 'l61', 'l75', 'l88', 'l100', 'l111', 'l121', 'l130', 'l138', 'l145', 'l151', 'l156', 'l161', 'l162', 'l163', 'l164']", + "107, tumor-draining ['l14', 'l31', 'l47', 'l62', 'l76', 'l89', 'l101', 'l112', 'l122', 'l131', 'l139', 'l146', 'l152', 'l157', 'l161', 'l165', 'l166', 'l167']", + "108, lymph ['l15', 'l32', 'l48', 'l63', 'l77', 'l90', 'l102', 'l113', 'l123', 'l132', 'l140', 'l147', 'l153', 'l158', 'l162', 'l165', 'l168', 'l169']", + "109, nodes ['l16', 'l33', 'l49', 'l64', 'l78', 'l91', 'l103', 'l114', 'l124', 'l133', 'l141', 'l148', 'l154', 'l159', 'l163', 'l166', 'l168', 'l170']", + "116, tumors. ['l17', 'l34', 'l50', 'l65', 'l79', 'l92', 'l104', 'l115', 'l125', 'l134', 'l142', 'l149', 'l155', 'l160', 'l164', 'l167', 'l169', 'l170']", + "118, control ['l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180']", + "120, tumor ['l171', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190']", + "121, growth ['l172', 'l181', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198']", + "126, chimeric ['l173', 'l182', 'l191', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206']", + "127, mice ['l174', 'l183', 'l192', 'l199', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213']", + "133, mice ['l175', 'l184', 'l193', 'l200', 'l207', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219']", + "134, lacking ['l176', 'l185', 'l194', 'l201', 'l208', 'l214', 'l220', 'l221', 'l222', 'l223', 'l224']", + "135, the ['l177', 'l186', 'l195', 'l202', 'l209', 'l215', 'l220', 'l225', 'l226', 'l227', 'l228']", + "136, gene ['l178', 'l187', 'l196', 'l203', 'l210', 'l216', 'l221', 'l225', 'l229', 'l230', 'l231']", + "137, encoding ['l179', 'l188', 'l197', 'l204', 'l211', 'l217', 'l222', 'l226', 'l229', 'l232', 'l233']", + "138, LXR-alpha ['l180', 'l189', 'l198', 'l205', 'l212', 'l218', 'l223', 'l227', 'l230', 'l232', 'l234']", + "140, mice) ['l190', 'l206', 'l213', 'l219', 'l224', 'l228', 'l231', 'l233', 'l234']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "the", + "LXR", + "ligand-inactivating", + "enzyme", + "sulfotransferase", + "2B1b", + "(SULT2B1b)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice", + "chimeric", + "mice" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "controlled", + "control" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice", + "chimeric", + "mice", + "mice)" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "tumors." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "the", + "LXR", + "ligand-inactivating", + "enzyme", + "sulfotransferase", + "2B1b", + "(SULT2B1b)" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "tumors." + ] + }, + "effect": { + "val": "regulates", + "words": [ + "controlled" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "tumors." + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "tumors." + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "the", + "LXR", + "ligand-inactivating", + "enzyme", + "sulfotransferase", + "2B1b", + "(SULT2B1b)" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "controlled" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "the", + "LXR", + "ligand-inactivating", + "enzyme", + "sulfotransferase", + "2B1b", + "(SULT2B1b)" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "the", + "LXR", + "ligand-inactivating", + "enzyme", + "sulfotransferase", + "2B1b", + "(SULT2B1b)" + ] + }, + "context": { + "val": "cells", + "words": [ + "DC" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "the", + "LXR", + "ligand-inactivating", + "enzyme", + "sulfotransferase", + "2B1b", + "(SULT2B1b)" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "the", + "LXR", + "ligand-inactivating", + "enzyme", + "sulfotransferase", + "2B1b", + "(SULT2B1b)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tumor-draining" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "controlled", + "control" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "controlled" + ] + }, + "context": { + "val": "cells", + "words": [ + "DC" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "controlled" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "controlled" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tumor-draining" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "cells", + "words": [ + "DC" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tumor-draining" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "DC" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tumor-draining" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "control" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "gene", + "encoding", + "LXR-alpha" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "gene", + "encoding", + "LXR-alpha" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "chimeric", + "mice", + "mice)" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "gene", + "encoding", + "LXR-alpha" + ] + } + } + ] + }, + { + "PMID": "20037594", + "TEXT": "Transfusion-related acute lung injury (TRALI) is a frequent cause of transfusion-associated morbidity and mortality. Severe TRALI is often due to antibodies in blood components directed against the human neutrophil alloantigen-3a (HNA-3a). We show here that the HNA-3a antigen arises from a nucleotide polymorphism in the choline transporter-like protein-2 gene (SLC44A2), with the resulting variation at amino acid position 154 determining the reactivity of the protein with HNA-3a-specific antibodies; the variant with an arginine at this position, rather than a glutamine, constitutes the HNA-3a antigen. The molecular identification of this antigen should facilitate the development of assays for blood donor screening to lower the risk of TRALI.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "20023637", + "TEXT": "Malfunction of the circadian clock has been linked to the pathogenesis of a variety of diseases. We show that mice lacking the core clock components Cryptochrome-1 (Cry1) and Cryptochrome-2 (Cry2) (Cry-null mice) show salt-sensitive hypertension due to abnormally high synthesis of the mineralocorticoid aldosterone by the adrenal gland. An extensive search for the underlying cause led us to identify type VI 3beta-hydroxyl-steroid dehydrogenase (Hsd3b6) as a new hypertension risk factor in mice. Hsd3b6 is expressed exclusively in aldosterone-producing cells and is under transcriptional control of the circadian clock. In Cry-null mice, Hsd3b6 messenger RNA and protein levels are constitutively high, leading to a marked increase in 3beta-hydroxysteroid dehydrogenase-isomerase (3beta-HSD) enzymatic activity and, as a consequence, enhanced aldosterone production. These data place Hsd3b6 in a pivotal position through which circadian clock malfunction is coupled to the development of hypertension. Translation of these findings to humans will require clinical examination of human HSD3B1 gene, which we found to be functionally similar to mouse Hsd3b6.", + "TAG_DATA": [ + "19, mice {'context': 'B-organism'}", + "20, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "21, the {'perturbing_action': 'I-gene loss-of-function'}", + "22, core {'perturbing_action': 'I-gene loss-of-function'}", + "23, clock {'perturbing_action': 'I-gene loss-of-function'}", + "24, components {'perturbing_action': 'I-gene loss-of-function'}", + "25, Cryptochrome-1 {'perturbing_action': 'I-gene loss-of-function'}", + "26, (Cry1) {'perturbing_action': 'I-gene loss-of-function'}", + "27, and {'perturbing_action': 'I-gene loss-of-function'}", + "28, Cryptochrome-2 {'perturbing_action': 'I-gene loss-of-function'}", + "29, (Cry2) {'perturbing_action': 'I-gene loss-of-function'}", + "30, (Cry-null {'perturbing_action': 'I-gene loss-of-function'}", + "31, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "89, Cry-null {'perturbing_action': 'B-gene loss-of-function'}", + "90, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "19, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "20, lacking ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "21, the ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "22, core ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "23, clock ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "24, components ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "25, Cryptochrome-1 ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "26, (Cry1) ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "27, and ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "28, Cryptochrome-2 ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "29, (Cry2) ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "30, (Cry-null ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "31, mice) ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "89, Cry-null ['l78']", + "90, mice, ['l78']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "core", + "clock", + "components", + "Cryptochrome-1", + "(Cry1)", + "and", + "Cryptochrome-2", + "(Cry2)", + "(Cry-null", + "mice)", + "Cry-null" + ] + } + } + ] + }, + { + "PMID": "20023634", + "TEXT": "Brain metastasis frequently occurs in individuals with cancer and is often fatal. We used multiphoton laser scanning microscopy to image the single steps of metastasis formation in real time. Thus, it was possible to track the fate of individual metastasizing cancer cells in vivo in relation to blood vessels deep in the mouse brain over minutes to months. The essential steps in this model were arrest at vascular branch points, early extravasation, persistent close contacts to microvessels and perivascular growth by vessel cooption (melanoma) or early angiogenesis (lung cancer). Inefficient steps differed between the tumor types. Long-term dormancy was only observed for single perivascular cancer cells, some of which moved continuously. Vascular endothelial growth factor-A (VEGF-A) inhibition induced long-term dormancy of lung cancer micrometastases by preventing angiogenic growth to macrometastases. The ability to image the establishment of brain metastases in vivo provides new insights into their evolution and response to therapies.", + "TAG_DATA": [ + "103, perivascular {'context': 'B-transformed cells'}", + "104, cancer {'context': 'I-transformed cells'}", + "105, cells, {'context': 'I-transformed cells'}", + "111, Vascular {'perturbing_action': 'B-pharmacological inhibition'}", + "112, endothelial {'perturbing_action': 'I-pharmacological inhibition'}", + "113, growth {'perturbing_action': 'I-pharmacological inhibition'}", + "114, factor-A {'perturbing_action': 'I-pharmacological inhibition'}", + "115, (VEGF-A) {'perturbing_action': 'I-pharmacological inhibition'}", + "116, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "121, lung {'context': 'B-neoplasm'}", + "122, cancer {'context': 'I-neoplasm'}", + "123, micrometastases {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "103, perivascular ['l0', 'l1']", + "104, cancer ['l0', 'l2']", + "105, cells, ['l1', 'l2']", + "111, Vascular ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "112, endothelial ['l3', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "113, growth ['l4', 'l11', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "114, factor-A ['l5', 'l12', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "115, (VEGF-A) ['l6', 'l13', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32']", + "116, inhibition ['l7', 'l14', 'l20', 'l25', 'l29', 'l33', 'l34', 'l35']", + "121, lung ['l8', 'l15', 'l21', 'l26', 'l30', 'l33', 'l36', 'l37']", + "122, cancer ['l9', 'l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l38']", + "123, micrometastases ['l10', 'l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Vascular", + "endothelial", + "growth", + "factor-A", + "(VEGF-A)", + "inhibition" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lung", + "cancer" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Vascular", + "endothelial", + "growth", + "factor-A", + "(VEGF-A)", + "inhibition" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "micrometastases" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "lung", + "cancer" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "micrometastases" + ] + } + } + ] + }, + { + "PMID": "19966781", + "TEXT": "Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix (ECM) proteins, which lead to distorted lung architecture and function. Given that anti-inflammatory or immunosuppressive therapy currently used for IPF does not improve disease progression therapies targeted to blocking the mechanisms of fibrogenesis are needed. Although transforming growth factor-beta (TGF-beta) functions are crucial in fibrosis, antagonizing this pathway in bleomycin-induced pulmonary fibrosis, an animal model of IPF, does not prevent fibrosis completely, indicating an additional pathway also has a key role in fibrogenesis. Given that the loss of cytosolic phospholipase A(2) (cPLA(2)) suppresses bleomycin-induced pulmonary fibrosis, we examined the roles of prostaglandins using mice lacking each prostoaglandin receptor. Here we show that loss of prostaglandin F (PGF) receptor (FP) selectively attenuates pulmonary fibrosis while maintaining similar levels of alveolar inflammation and TGF-beta stimulation as compared to wild-type (WT) mice, and that FP deficiency and inhibition of TGF-beta signaling additively decrease fibrosis. Furthermore, PGF(2alpha) is abundant in bronchoalveolar lavage fluid (BALF) of subjects with IPF and stimulates proliferation and collagen production of lung fibroblasts via FP, independently of TGF-beta. These findings show that PGF(2alpha)-FP signaling facilitates pulmonary fibrosis independently of TGF-beta and suggests this signaling pathway as a therapeutic target for IPF.", + "TAG_DATA": [ + "97, loss {'perturbing_action': 'B-gene loss-of-function'}", + "98, of {'perturbing_action': 'I-gene loss-of-function'}", + "99, cytosolic {'perturbing_action': 'I-gene loss-of-function'}", + "100, phospholipase {'perturbing_action': 'I-gene loss-of-function'}", + "101, A(2) {'perturbing_action': 'I-gene loss-of-function'}", + "102, (cPLA(2)) {'perturbing_action': 'I-gene loss-of-function'}", + "114, mice {'context': 'B-organism'}", + "123, loss {'perturbing_action': 'B-gene loss-of-function'}", + "124, of {'perturbing_action': 'I-gene loss-of-function'}", + "125, prostaglandin {'perturbing_action': 'I-gene loss-of-function'}", + "126, F {'perturbing_action': 'I-gene loss-of-function'}", + "127, (PGF) {'perturbing_action': 'I-gene loss-of-function'}", + "128, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "129, (FP) {'perturbing_action': 'I-gene loss-of-function'}", + "149, mice, {'context': 'B-organism'}", + "152, FP {'perturbing_action': 'B-gene loss-of-function'}", + "153, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "176, stimulates {'effect': 'B-positive'}", + "177, proliferation {'phenotype': 'B-proliferation'}", + "182, lung {'context': 'B-cells'}", + "183, fibroblasts {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "97, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "98, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "99, cytosolic ['l1', 'l13', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "100, phospholipase ['l2', 'l14', 'l26', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "101, A(2) ['l3', 'l15', 'l27', 'l38', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "102, (cPLA(2)) ['l4', 'l16', 'l28', 'l39', 'l49', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "114, mice ['l5', 'l17', 'l29', 'l40', 'l50', 'l59', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "123, loss ['l6', 'l18', 'l30', 'l41', 'l51', 'l60', 'l68', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "124, of ['l7', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l75', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "125, prostaglandin ['l8', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l76', 'l82', 'l88', 'l89', 'l90', 'l91', 'l92']", + "126, F ['l9', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l77', 'l83', 'l88', 'l93', 'l94', 'l95', 'l96']", + "127, (PGF) ['l10', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l78', 'l84', 'l89', 'l93', 'l97', 'l98', 'l99']", + "128, receptor ['l11', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l79', 'l85', 'l90', 'l94', 'l97', 'l100', 'l101']", + "129, (FP) ['l12', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l80', 'l86', 'l91', 'l95', 'l98', 'l100', 'l102']", + "149, mice, ['l25', 'l37', 'l48', 'l58', 'l67', 'l81', 'l87', 'l92', 'l96', 'l99', 'l101', 'l102']", + "152, FP ['l103']", + "153, deficiency ['l103']", + "176, stimulates ['l104', 'l105', 'l106']", + "177, proliferation ['l104', 'l107', 'l108']", + "182, lung ['l105', 'l107', 'l109']", + "183, fibroblasts ['l106', 'l108', 'l109']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "cytosolic", + "phospholipase", + "A(2)", + "(cPLA(2))", + "prostaglandin", + "F", + "(PGF)", + "receptor", + "(FP)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "context": { + "val": "cells", + "words": [ + "lung", + "fibroblasts" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "lung", + "fibroblasts" + ] + } + } + ] + }, + { + "PMID": "19966778", + "TEXT": "Macrophages show endoplasmic reticulum (ER) stress when exposed to lipotoxic signals associated with atherosclerosis, although the pathophysiological importance and the underlying mechanisms of this phenomenon remain unknown. Here we show that mitigation of ER stress with a chemical chaperone results in marked protection against lipotoxic death in macrophages and prevents macrophage fatty acid-binding protein-4 (aP2) expression. Using genetic and chemical models, we show that aP2 is the predominant regulator of lipid-induced macrophage ER stress. The absence of lipid chaperones incites an increase in the production of phospholipids rich in monounsaturated fatty acids and bioactive lipids that render macrophages resistant to lipid-induced ER stress. Furthermore, the impact of aP2 on macrophage lipid metabolism and the ER stress response is mediated by upregulation of key lipogenic enzymes by the liver X receptor. Our results demonstrate the central role for lipid chaperones in regulating ER homeostasis in macrophages in atherosclerosis and show that ER responses can be modified, genetically or chemically, to protect the organism against the deleterious effects of hyperlipidemia.", + "TAG_DATA": [ + "47, macrophages {'context': 'B-cells'}", + "97, macrophages {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19966776", + "TEXT": "We report that heat shock protein 90 (Hsp90) inhibitors selectively kill diffuse large B cell lymphomas (DLBCLs) that depend on the BCL-6 transcriptional repressor. We found that endogenous Hsp90 interacts with BCL-6 in DLBCL cells and can stabilize BCL-6 mRNA and protein. Hsp90 formed a complex with BCL-6 at its target promoters, and Hsp90 inhibitors derepressed BCL-6 target genes. A stable mutant of BCL-6 rescued DLBCL cells from Hsp90 inhibitor-induced apoptosis. BCL-6 and Hsp90 were almost invariantly coexpressed in the nuclei of primary DLBCL cells, suggesting that their interaction is relevant in this disease. We examined the pharmacokinetics, toxicity and efficacy of PU-H71, a recently developed purine-derived Hsp90 inhibitor. PU-H71 preferentially accumulated in lymphomas compared to normal tissues and selectively suppressed BCL-6-dependent DLBCLs in vivo, inducing reactivation of key BCL-6 target genes and apoptosis. PU-H71 also induced cell death in primary human DLBCL specimens.", + "TAG_DATA": [ + "53, Hsp90 {'perturbing_action': 'B-pharmacological inhibition'}", + "54, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "60, stable {'perturbing_action': 'B-other'}", + "61, mutant {'perturbing_action': 'I-other'}", + "62, of {'perturbing_action': 'I-other'}", + "63, BCL-6 {'perturbing_action': 'I-other'}", + "64, rescued {'effect': 'B-rescues'}", + "65, DLBCL {'context': 'B-transformed cells'}", + "66, cells {'context': 'I-transformed cells'}", + "68, Hsp90 {'perturbing_action': 'B-pharmacological inhibition'}", + "69, inhibitor-induced {'perturbing_action': 'I-pharmacological inhibition', 'effect': 'B-positive'}", + "70, apoptosis. {'phenotype': 'B-apoptosis'}", + "122, DLBCLs {'context': 'B-neoplasm'}", + "123, in {'context': 'B-in vivo'}", + "124, vivo, {'context': 'I-in vivo'}", + "125, inducing {'effect': 'B-positive'}", + "133, apoptosis. {'phenotype': 'B-apoptosis'}", + "136, induced {'effect': 'B-positive'}", + "137, cell {'phenotype': 'B-cell death'}", + "138, death {'phenotype': 'I-cell death'}", + "140, primary {'context': 'B-neoplasm'}", + "141, human {'context': 'I-transformed cells'}", + "142, DLBCL {'context': 'I-transformed cells'}", + "143, specimens. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "53, Hsp90 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "54, inhibitors ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "60, stable ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "61, mutant ['l15', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "62, of ['l1', 'l16', 'l24', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "63, BCL-6 ['l2', 'l17', 'l25', 'l32', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "64, rescued ['l3', 'l9', 'l18', 'l26', 'l33', 'l39', 'l45', 'l46', 'l47', 'l48', 'l49']", + "65, DLBCL ['l4', 'l10', 'l19', 'l27', 'l34', 'l40', 'l45', 'l50', 'l51', 'l52', 'l53']", + "66, cells ['l5', 'l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l50', 'l54']", + "68, Hsp90 ['l6', 'l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l55', 'l56']", + "69, inhibitor-induced ['l7', 'l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l57']", + "70, apoptosis. ['l8', 'l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l54', 'l56', 'l57']", + "122, DLBCLs ['l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "123, in ['l58', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "124, vivo, ['l59', 'l69', 'l79', 'l80', 'l81', 'l82', 'l83']", + "125, inducing ['l60', 'l70', 'l79', 'l84', 'l85', 'l86']", + "133, apoptosis. ['l61', 'l71', 'l80', 'l84', 'l87', 'l88', 'l89']", + "136, induced ['l62', 'l72', 'l81', 'l85', 'l87', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "137, cell ['l63', 'l73', 'l82', 'l88', 'l90', 'l96', 'l97', 'l98', 'l99', 'l100']", + "138, death ['l64', 'l74', 'l83', 'l86', 'l89', 'l91', 'l96', 'l101', 'l102', 'l103', 'l104']", + "140, primary ['l65', 'l75', 'l92', 'l97', 'l101', 'l105', 'l106', 'l107']", + "141, human ['l66', 'l76', 'l93', 'l98', 'l102', 'l105', 'l108', 'l109']", + "142, DLBCL ['l67', 'l77', 'l94', 'l99', 'l103', 'l106', 'l108', 'l110']", + "143, specimens. ['l68', 'l78', 'l95', 'l100', 'l104', 'l107', 'l109', 'l110']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Hsp90", + "inhibitors", + "inhibitor-induced" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Hsp90", + "inhibitors", + "inhibitor-induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "DLBCL", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Hsp90", + "inhibitors", + "inhibitor-induced" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inhibitor-induced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Hsp90", + "inhibitors", + "inhibitor-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "stable", + "mutant", + "of", + "BCL-6" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "stable", + "mutant", + "of", + "BCL-6" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "DLBCL", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "stable", + "mutant", + "of", + "BCL-6" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inhibitor-induced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "stable", + "mutant", + "of", + "BCL-6" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "DLBCL", + "cells" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "DLBCL", + "human", + "specimens." + ] + }, + "effect": { + "val": "positive", + "words": [ + "inhibitor-induced", + "induced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "DLBCL", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inhibitor-induced", + "inducing", + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "DLBCLs", + "primary" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inducing", + "induced" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "DLBCLs" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "DLBCLs", + "primary" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + }, + "effect": { + "val": "positive", + "words": [ + "inducing", + "induced" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing", + "induced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "death", + "cell" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "DLBCL", + "specimens." + ] + } + } + ] + }, + { + "PMID": "19898488", + "TEXT": "Active rheumatoid arthritis originates from few joints but subsequently affects the majority of joints. Thus far, the pathways of the progression of the disease are largely unknown. As rheumatoid arthritis synovial fibroblasts (RASFs) which can be found in RA synovium are key players in joint destruction and are able to migrate in vitro, we evaluated the potential of RASFs to spread the disease in vivo. To simulate the primary joint of origin, we implanted healthy human cartilage together with RASFs subcutaneously into severe combined immunodeficient (SCID) mice. At the contralateral flank, we implanted healthy cartilage without cells. RASFs showed an active movement to the naive cartilage via the vasculature independent of the site of application of RASFs into the SCID mouse, leading to a marked destruction of the target cartilage. These findings support the hypothesis that the characteristic clinical phenomenon of destructive arthritis spreading between joints is mediated, at least in part, by the transmigration of activated RASFs.", + "TAG_DATA": [ + "75, human {'context': 'I-tissue/organ'}", + "76, cartilage {'context': 'I-tissue/organ'}", + "86, mice. {'context': 'B-organism'}", + "90, flank, {'context': 'I-tissue/organ'}", + "94, cartilage {'context': 'I-tissue/organ'}", + "96, cells. {'context': 'B-cells'}", + "120, mouse, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "74, healthy ['l0', 'l1', 'l2']", + "75, human ['l0', 'l3', 'l4']", + "76, cartilage ['l1', 'l3', 'l5']", + "86, mice. ['l2', 'l4', 'l5']", + "89, contralateral ['l6', 'l7', 'l8']", + "90, flank, ['l6', 'l9', 'l10']", + "94, cartilage ['l7', 'l9', 'l11']", + "96, cells. ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19881493", + "TEXT": "Cellular apoptosis induced by hyperglycemia occurs in many vascular cells and is crucial for the initiation of diabetic pathologies. In the retina, pericyte apoptosis and the formation of acellular capillaries, the most specific vascular pathologies attributed to hyperglycemia, is linked to the loss of platelet-derived growth factor (PDGF)-mediated survival actions owing to unknown mechanisms. Here we show that hyperglycemia persistently activates protein kinase C-delta (PKC-delta, encoded by Prkcd) and p38alpha mitogen-activated protein kinase (MAPK) to increase the expression of a previously unknown target of PKC-delta signaling, Src homology-2 domain-containing phosphatase-1 (SHP-1), a protein tyrosine phosphatase. This signaling cascade leads to PDGF receptor-beta dephosphorylation and a reduction in downstream signaling from this receptor, resulting in pericyte apoptosis independently of nuclear factor-kappaB (NF-kappaB) signaling. We observed increased PKC-delta activity and an increase in the number of acellular capillaries in diabetic mouse retinas, which were not reversible with insulin treatment that achieved normoglycemia. Unlike diabetic age-matched wild-type mice, diabetic Prkcd(-/-) mice did not show activation of p38alpha MAPK or SHP-1, inhibition of PDGF signaling in vascular cells or the presence of acellular capillaries. We also observed PKC-delta, p38alpha MAPK and SHP-1 activation in brain pericytes and in the renal cortex of diabetic mice. These findings elucidate a new signaling pathway by which hyperglycemia can induce PDGF resistance and increase vascular cell apoptosis to cause diabetic vascular complications.", + "TAG_DATA": [ + "114, pericyte {'context': 'B-cells'}", + "115, apoptosis {'phenotype': 'B-apoptosis'}", + "137, diabetic {'context': 'B-tissue/organ'}", + "138, mouse {'context': 'I-tissue/organ'}", + "139, retinas, {'context': 'I-tissue/organ'}", + "155, diabetic {'context': 'B-organism'}", + "156, Prkcd(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "157, mice {'context': 'B-organism'}", + "172, vascular {'context': 'B-cells'}", + "173, cells {'context': 'I-cells'}", + "190, brain {'context': 'B-cells'}", + "191, pericytes {'context': 'I-cells'}", + "195, renal {'context': 'B-tissue/organ'}", + "196, cortex {'context': 'I-tissue/organ'}", + "198, diabetic {'context': 'B-organism'}", + "199, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "114, pericyte ['l0', 'l1', 'l2', 'l3']", + "115, apoptosis ['l0', 'l4', 'l5', 'l6']", + "137, diabetic ['l1', 'l4', 'l7', 'l8']", + "138, mouse ['l2', 'l5', 'l7', 'l9']", + "139, retinas, ['l3', 'l6', 'l8', 'l9']", + "155, diabetic ['l10', 'l11', 'l12', 'l13']", + "156, Prkcd(-/-) ['l10', 'l14', 'l15', 'l16']", + "157, mice ['l11', 'l14', 'l17', 'l18']", + "172, vascular ['l12', 'l15', 'l17', 'l19']", + "173, cells ['l13', 'l16', 'l18', 'l19']", + "190, brain ['l20', 'l21', 'l22', 'l23', 'l24']", + "191, pericytes ['l20', 'l25', 'l26', 'l27', 'l28']", + "195, renal ['l21', 'l25', 'l29', 'l30', 'l31']", + "196, cortex ['l22', 'l26', 'l29', 'l32', 'l33']", + "198, diabetic ['l23', 'l27', 'l30', 'l32', 'l34']", + "199, mice. ['l24', 'l28', 'l31', 'l33', 'l34']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "pericyte" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "diabetic", + "mouse", + "retinas," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "diabetic", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Prkcd(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Prkcd(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "vascular", + "cells" + ] + } + } + ] + }, + { + "PMID": "19838201", + "TEXT": "Type 2 diabetes is a complex disease that is marked by the dysfunction of glucose and lipid metabolism. Hepatic insulin resistance is especially pathogenic in type 2 diabetes, as it dysregulates fasting and postprandial glucose tolerance and promotes systemic dyslipidemia and nonalcoholic fatty liver disease. Mitochondrial dysfunction is closely associated with insulin resistance and might contribute to the progression of diabetes. Here we used previously generated mice with hepatic insulin resistance owing to the deletion of the genes encoding insulin receptor substrate-1 (Irs-1) and Irs-2 (referred to here as double-knockout (DKO) mice) to establish the molecular link between dysregulated insulin action and mitochondrial function. The expression of several forkhead box O1 (Foxo1) target genes increased in the DKO liver, including heme oxygenase-1 (Hmox1), which disrupts complex III and IV of the respiratory chain and lowers the NAD(+)/NADH ratio and ATP production. Although peroxisome proliferator-activated receptor-gamma coactivator-1alpha (Ppargc-1alpha) was also upregulated in DKO liver, it was acetylated and failed to promote compensatory mitochondrial biogenesis or function. Deletion of hepatic Foxo1 in DKO liver normalized the expression of Hmox1 and the NAD(+)/NADH ratio, reduced Ppargc-1alpha acetylation and restored mitochondrial oxidative metabolism and biogenesis. Thus, Foxo1 integrates insulin signaling with mitochondrial function, and inhibition of Foxo1 can improve hepatic metabolism during insulin resistance and the metabolic syndrome.", + "TAG_DATA": [ + "66, mice {'context': 'B-organism'}", + "74, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "75, of {'perturbing_action': 'I-gene loss-of-function'}", + "76, the {'perturbing_action': 'I-gene loss-of-function'}", + "77, genes {'perturbing_action': 'I-gene loss-of-function'}", + "78, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "79, insulin {'perturbing_action': 'I-gene loss-of-function'}", + "80, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "81, substrate-1 {'perturbing_action': 'I-gene loss-of-function'}", + "82, (Irs-1) {'perturbing_action': 'I-gene loss-of-function'}", + "83, and {'perturbing_action': 'I-gene loss-of-function'}", + "84, Irs-2 {'perturbing_action': 'I-gene loss-of-function'}", + "89, double-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "90, (DKO) {'perturbing_action': 'I-gene loss-of-function'}", + "118, liver, {'context': 'B-tissue/organ'}", + "152, liver, {'context': 'B-tissue/organ'}", + "165, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "166, of {'perturbing_action': 'I-gene loss-of-function'}", + "167, hepatic {'perturbing_action': 'I-gene loss-of-function'}", + "168, Foxo1 {'perturbing_action': 'I-gene loss-of-function'}", + "171, liver {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "66, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "74, deletion ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "75, of ['l1', 'l14', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "76, the ['l2', 'l15', 'l28', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "77, genes ['l3', 'l16', 'l29', 'l41', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "78, encoding ['l4', 'l17', 'l30', 'l42', 'l53', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "79, insulin ['l5', 'l18', 'l31', 'l43', 'l54', 'l64', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "80, receptor ['l6', 'l19', 'l32', 'l44', 'l55', 'l65', 'l74', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "81, substrate-1 ['l7', 'l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l83', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "82, (Irs-1) ['l8', 'l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l84', 'l91', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "83, and ['l9', 'l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l98', 'l104', 'l105', 'l106', 'l107', 'l108']", + "84, Irs-2 ['l10', 'l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l86', 'l93', 'l99', 'l104', 'l109', 'l110', 'l111', 'l112']", + "89, double-knockout ['l11', 'l24', 'l37', 'l49', 'l60', 'l70', 'l79', 'l87', 'l94', 'l100', 'l105', 'l109', 'l113', 'l114', 'l115']", + "90, (DKO) ['l12', 'l25', 'l38', 'l50', 'l61', 'l71', 'l80', 'l88', 'l95', 'l101', 'l106', 'l110', 'l113', 'l116']", + "118, liver, ['l13', 'l26', 'l39', 'l51', 'l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l107', 'l111', 'l114', 'l116', 'l117']", + "152, liver, ['l27', 'l40', 'l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l108', 'l112', 'l115', 'l117']", + "165, Deletion ['l118', 'l119', 'l120', 'l121']", + "166, of ['l118', 'l122', 'l123', 'l124']", + "167, hepatic ['l119', 'l122', 'l125', 'l126']", + "168, Foxo1 ['l120', 'l123', 'l125', 'l127']", + "171, liver ['l121', 'l124', 'l126', 'l127']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "genes", + "encoding", + "insulin", + "receptor", + "substrate-1", + "(Irs-1)", + "and", + "Irs-2", + "double-knockout", + "(DKO)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "genes", + "encoding", + "insulin", + "receptor", + "substrate-1", + "(Irs-1)", + "and", + "Irs-2", + "double-knockout", + "(DKO)", + "Deletion", + "hepatic", + "Foxo1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver,", + "liver" + ] + } + } + ] + }, + { + "PMID": "19820716", + "TEXT": "Major histocompatibility complex (MHC) genetics dictate adaptive cellular immune responses, making robust MHC genotyping methods essential for studies of infectious disease, vaccine development and transplantation. Nonhuman primates provide essential preclinical models for these areas of biomedical research. Unfortunately, given the unparalleled complexity of macaque MHCs, existing methodologies are inadequate for MHC typing of these key model animals. Here we use pyrosequencing of complementary DNA-PCR amplicons as a general approach to determine comprehensive MHC class I genotypes in nonhuman primates. More than 500 unique MHC class I sequences were resolved by sequence-based typing of rhesus, cynomolgus and pig-tailed macaques, nearly half of which have not been reported previously. The remarkable sensitivity of this approach in macaques demonstrates that pyrosequencing is viable for ultra-high-throughput MHC genotyping of primates, including humans.", + "TAG_DATA": [ + "77, nonhuman {'context': 'B-organism'}", + "78, primates. {'context': 'I-organism'}", + "96, pig-tailed {'context': 'B-organism'}", + "97, macaques, {'context': 'I-organism'}", + "114, macaques {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "77, nonhuman ['l0']", + "78, primates. ['l0']", + "93, rhesus, ['l1', 'l2']", + "96, pig-tailed ['l1', 'l3']", + "97, macaques, ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19812559", + "TEXT": "Biomedicine would be a breeze if organisms were transparent. With the ability to see through tissues, scientists could spot the development of tumors more easily in study animals. And biologists could study exactly how an animal's organs develop by observing them as they grow. In effect, the secrets of the body would be out there for everyone to see.The thought of peering into our tissues may sound like science fiction, but one day it could be science. Using ideas from genetics, electrical engineering, chemistry and solid-state physics, a handful of researchers are working on ways to render biological tissues transparent.Some have already succeeded: in 2007, Richard White, a biologist at the Dana Farber Cancer Institute in Boston, used careful breeding techniques to create a transparent adult zebrafish named casper, evoking a reference to the famous cartoon ghost by the same name. Now, more than 100 labs around the world are using these transparent fish to study cancer pathology and development in real time. \"The field of in vivo imaging-looking at things that are happening inside an actual organism-is growing rapidly,\" White says.Researchers are even making strides toward turning human tissue transparent. The primary reason we can't see what's inside of us is that light scatters when it passes through tissue. The body is densely packed with many types of substances, such as bone and fat, and light travels through them at different speeds because they have what physicists refer to as different refractive indices. The result is that light can't pass through biological tissues in a straight line, much as car headlights don't pass through dense fog. To fix this problem, scientists are working on developing ways to stop tissues from scattering light. Indeed, \"if you take away the scattering properties of human tissues, we would look more or less like jellyfish,\" explains Changhuei Yang, an electrical engineer and bioengineer at the California Institute of Technology.Though their approaches (described in the following pages) are diverse, these researchers share the common goal of making it one day possible to see what's going on deep inside of the body-a feat that would provide new insights into our biology and help doctors diagnose and treat disease much more easily. \"We're trying to push the limits in terms of what can we uncover,\" says Bernard Choi, a bioengineer at the University of California-Irvine.", + "TAG_DATA": [ + "126, zebrafish {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19812558", + "TEXT": "Hard numbers can be difficult to come by in the current debate about health care in the US. Even rarer are accurate assessments of health care systems in less developed countries. But policy makers are not completely groping in the dark when it comes to data-thanks in part to Christopher Murray. Two years ago, Murray, a physician and health economist with experience at the World Health Organization (WHO), took the helm of the newly created Institute for Health Metrics and Evaluation at the University of Washington. Since 2007, the institute, funded largely by the Bill & Melinda Gates Foundation and the state of Washington, has grown to a staff of 75 people and has begun churning out studies that that are shaping the debate on health care reform. For instance, Murray's group-along with colleagues at his former base, Harvard University in Cambridge, Massachusetts-have documented huge disparities in life expectancy and mortality in parts of the US. In some pockets of the country, life expectancy for women is even on the decline (PLoS Med. 27, e66; 2008). Murray spoke with Charlotte Schubert about how having accurate numbers can add up to progress in health care.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19801990", + "TEXT": "With an ever increasing number of people taking numerous medications, the need to safely administer drugs and limit unintended side effects has never been greater. Antidote control remains the most direct means to counteract acute side effects of drugs, but, unfortunately, it has been challenging and cost prohibitive to generate antidotes for most therapeutic agents. Here we describe the development of a set of antidote molecules that are capable of counteracting the effects of an entire class of therapeutic agents based upon aptamers. These universal antidotes exploit the fact that, when systemically administered, aptamers are the only free extracellular oligonucleotides found in circulation. We show that protein- and polymer-based molecules that capture oligonucleotides can reverse the activity of several aptamers in vitro and counteract aptamer activity in vivo. The availability of universal antidotes to control the activity of any aptamer suggests that aptamers may be a particularly safe class of therapeutics.", + "TAG_DATA": [ + "120, in {'context': 'B-in vitro'}", + "121, vitro {'context': 'I-in vitro'}", + "126, in {'context': 'B-in vivo'}", + "127, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "120, in ['l0']", + "121, vitro ['l0']", + "126, in ['l1']", + "127, vivo. ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19767733", + "TEXT": "Thyroid dysfunction is a global health concern, causing defects including neurodevelopmental disorders, dwarfism and cardiac arrhythmia. Here, we show that the potassium channel subunits KCNQ1 and KCNE2 form a thyroid-stimulating hormone-stimulated, constitutively active, thyrocyte K+ channel required for normal thyroid hormone biosynthesis. Targeted disruption of Kcne2 in mice impaired thyroid iodide accumulation up to eightfold, impaired maternal milk ejection, halved milk tetraiodothyronine (T4) content and halved litter size. Kcne2-deficient mice had hypothyroidism, dwarfism, alopecia, goiter and cardiac abnormalities including hypertrophy, fibrosis, and reduced fractional shortening. The alopecia, dwarfism and cardiac abnormalities were alleviated by triiodothyronine (T3) and T4 administration to pups, by supplementing dams with T(4) before and after they gave birth or by feeding the pups exclusively from Kcne2+/+ dams; conversely, these symptoms were elicited in Kcne2+/+ pups by feeding exclusively from Kcne2-/- dams. These data provide a new potential therapeutic target for thyroid disorders and raise the possibility of an endocrine component to previously identified KCNE2- and KCNQ1-linked human cardiac arrhythmias.", + "TAG_DATA": [ + "42, Targeted {'perturbing_action': 'B-gene loss-of-function'}", + "43, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "44, of {'perturbing_action': 'I-gene loss-of-function'}", + "45, Kcne2 {'perturbing_action': 'I-gene loss-of-function'}", + "47, mice {'context': 'B-organism'}", + "68, Kcne2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "69, mice {'context': 'B-organism'}", + "100, pups, {'context': 'B-organism'}", + "116, pups {'context': 'B-organism'}", + "127, Kcne2+/+ {'perturbing_action': 'B-gene loss-of-function'}", + "128, pups {'context': 'I-organism'}", + "133, Kcne2-/- {'perturbing_action': 'B-gene loss-of-function'}" + ], + "LINK_DATA": [ + "42, Targeted ['l0', 'l1', 'l2', 'l3']", + "43, disruption ['l0', 'l4', 'l5', 'l6']", + "44, of ['l1', 'l4', 'l7', 'l8']", + "45, Kcne2 ['l2', 'l5', 'l7', 'l9']", + "47, mice ['l3', 'l6', 'l8', 'l9']", + "68, Kcne2-deficient ['l10', 'l11']", + "69, mice ['l10']", + "100, pups, ['l11', 'l12']", + "116, pups ['l12']", + "127, Kcne2+/+ ['l13', 'l14']", + "128, pups ['l13', 'l15']", + "133, Kcne2-/- ['l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Targeted", + "disruption", + "of", + "Kcne2", + "Kcne2-deficient", + "Kcne2+/+", + "Kcne2-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "pups,", + "pups" + ] + } + } + ] + }, + { + "PMID": "19749772", + "TEXT": "Intravital multiphoton microscopy has provided powerful mechanistic insights into health and disease and has become a common instrument in the modern biological laboratory. The requisite high numerical aperture and exogenous contrast agents that enable multiphoton microscopy, however, limit the ability to investigate substantial tissue volumes or to probe dynamic changes repeatedly over prolonged periods. Here we introduce optical frequency domain imaging (OFDI) as an intravital microscopy that circumvents the technical limitations of multiphoton microscopy and, as a result, provides unprecedented access to previously unexplored, crucial aspects of tissue biology. Using unique OFDI-based approaches and entirely intrinsic mechanisms of contrast, we present rapid and repeated measurements of tumor angiogenesis, lymphangiogenesis, tissue viability and both vascular and cellular responses to therapy, thereby demonstrating the potential of OFDI to facilitate the exploration of physiological and pathological processes and the evaluation of treatment strategies.", + "TAG_DATA": [ + "106, tumor {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19718038", + "TEXT": "Bone metabolism results from a balance between osteoclast-driven bone resorption and osteoblast-mediated bone formation. Diseases such as periodontitis and rheumatoid arthritis are characterized by increased bone destruction due to enhanced osteoclastogenesis. Here we report that interferon regulatory factor-8 (IRF-8), a transcription factor expressed in immune cells, is a key regulatory molecule for osteoclastogenesis. IRF-8 expression in osteoclast precursors was downregulated during the initial phase of osteoclast differentiation induced by receptor activator of nuclear factor-kappaB ligand (RANKL), which is encoded by the Tnfsf11 gene. Mice deficient in Irf8 showed severe osteoporosis, owing to increased numbers of osteoclasts, and also showed enhanced bone destruction after lipopolysaccharide (LPS) administration. Irf8-/- osteoclast precursors underwent increased osteoclastogenesis in response to RANKL and tumor necrosis factor-alpha (TNF-alpha). IRF-8 suppressed osteoclastogenesis by inhibiting the function and expression of nuclear factor of activated T cells c1 (NFATc1). Our results show that IRF-8 inhibits osteoclast formation under physiological and pathological conditions and suggest a model where downregulation of inhibitory factors such as IRF-8 contributes to RANKL-mediated osteoclastogenesis.", + "TAG_DATA": [ + "83, Mice {'context': 'B-organism'}", + "84, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "85, in {'perturbing_action': 'I-gene loss-of-function'}", + "86, Irf8 {'perturbing_action': 'I-gene loss-of-function'}", + "106, Irf8-/- {'perturbing_action': 'B-gene loss-of-function'}", + "107, osteoclast {'context': 'B-cells'}", + "108, precursors {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "83, Mice ['l0', 'l1', 'l2']", + "84, deficient ['l0', 'l3', 'l4']", + "85, in ['l1', 'l3', 'l5']", + "86, Irf8 ['l2', 'l4', 'l5']", + "106, Irf8-/- ['l6', 'l7']", + "107, osteoclast ['l6', 'l8']", + "108, precursors ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Irf8" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Irf8-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast", + "precursors" + ] + } + } + ] + }, + { + "PMID": "19718037", + "TEXT": "Various stimuli, such as telomere dysfunction and oxidative stress, can induce irreversible cell growth arrest, which is termed 'cellular senescence'. This response is controlled by tumor suppressor proteins such as p53 and pRb. There is also evidence that senescent cells promote changes related to aging or age-related diseases. Here we show that p53 expression in adipose tissue is crucially involved in the development of insulin resistance, which underlies age-related cardiovascular and metabolic disorders. We found that excessive calorie intake led to the accumulation of oxidative stress in the adipose tissue of mice with type 2 diabetes-like disease and promoted senescence-like changes, such as increased activity of senescence-associated beta-galactosidase, increased expression of p53 and increased production of proinflammatory cytokines. Inhibition of p53 activity in adipose tissue markedly ameliorated these senescence-like changes, decreased the expression of proinflammatory cytokines and improved insulin resistance in mice with type 2 diabetes-like disease. Conversely, upregulation of p53 in adipose tissue caused an inflammatory response that led to insulin resistance. Adipose tissue from individuals with diabetes also showed senescence-like features. Our results show a previously unappreciated role of adipose tissue p53 expression in the regulation of insulin resistance and suggest that cellular aging signals in adipose tissue could be a new target for the treatment of diabetes (pages 996-967).", + "TAG_DATA": [ + "88, adipose {'context': 'B-tissue/organ'}", + "89, tissue {'context': 'I-tissue/organ'}", + "91, mice {'context': 'B-organism'}", + "118, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "119, of {'perturbing_action': 'I-pharmacological inhibition'}", + "120, p53 {'perturbing_action': 'I-pharmacological inhibition'}", + "121, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "123, adipose {'context': 'B-tissue/organ'}", + "124, tissue {'context': 'I-tissue/organ'}", + "141, mice {'context': 'B-organism'}", + "148, upregulation {'perturbing_action': 'B-gene gain-of-function'}", + "149, of {'perturbing_action': 'I-gene gain-of-function'}", + "150, p53 {'perturbing_action': 'I-gene gain-of-function'}", + "152, adipose {'context': 'B-tissue/organ'}", + "153, tissue {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "88, adipose ['l0', 'l1']", + "89, tissue ['l0', 'l2']", + "91, mice ['l1', 'l2']", + "118, Inhibition ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "119, of ['l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "120, p53 ['l4', 'l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "121, activity ['l5', 'l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "123, adipose ['l6', 'l12', 'l17', 'l21', 'l25', 'l26']", + "124, tissue ['l7', 'l13', 'l18', 'l22', 'l25', 'l27']", + "141, mice ['l8', 'l14', 'l19', 'l23', 'l26', 'l27']", + "148, upregulation ['l28', 'l29', 'l30', 'l31']", + "149, of ['l28', 'l32', 'l33', 'l34']", + "150, p53 ['l29', 'l32', 'l35', 'l36']", + "152, adipose ['l30', 'l33', 'l35', 'l37']", + "153, tissue ['l9', 'l15', 'l20', 'l24', 'l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "p53", + "activity" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "adipose", + "tissue" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "p53", + "activity" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "upregulation", + "of", + "p53" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "adipose", + "tissue" + ] + } + } + ] + }, + { + "PMID": "19701204", + "TEXT": "A subset of central glutamatergic synapses are coordinately pruned and matured by unresolved mechanisms during postnatal development. We report that the human epilepsy gene LGI1, encoding leucine-rich, glioma-inactivated protein-1 and mutated in autosomal dominant lateral temporal lobe epilepsy (ADLTE), mediates this process in hippocampus. We created transgenic mice either expressing a truncated mutant LGI1 (835delC) found in ADLTE or overexpressing a wild-type LGI1. We discovered that the normal postnatal maturation of presynaptic and postsynaptic functions was arrested by the 835delC mutant LGI1, and contrastingly, was magnified by excess wild-type LGI1. Concurrently, mutant LGI1 inhibited dendritic pruning and increased the spine density to markedly increase excitatory synaptic transmission. Inhibitory transmission, by contrast, was unaffected. Furthermore, mutant LGI1 promoted epileptiform discharge in vitro and kindling epileptogenesis in vivo with partial gamma-aminobutyric acid(A) (GABA(A)) receptor blockade. Thus, LGI1 represents a human gene mutated to promote epilepsy through impaired postnatal development of glutamatergic circuits.", + "TAG_DATA": [ + "47, mice {'context': 'B-organism'}", + "49, expressing {'perturbing_action': 'B-other'}", + "50, a {'perturbing_action': 'I-other'}", + "51, truncated {'perturbing_action': 'I-other'}", + "52, mutant {'perturbing_action': 'I-other'}", + "53, LGI1 {'perturbing_action': 'I-other'}", + "54, (835delC) {'perturbing_action': 'I-other'}", + "55, found {'perturbing_action': 'I-other'}", + "59, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "60, a {'perturbing_action': 'I-gene gain-of-function'}", + "61, wild-type {'perturbing_action': 'I-gene gain-of-function'}", + "62, LGI1. {'perturbing_action': 'I-gene gain-of-function'}", + "79, 835delC {'perturbing_action': 'B-other'}", + "80, mutant {'perturbing_action': 'I-other'}", + "81, LGI1, {'perturbing_action': 'I-other'}", + "91, mutant {'perturbing_action': 'B-other'}", + "92, LGI1 {'perturbing_action': 'I-other'}", + "114, mutant {'perturbing_action': 'B-other'}", + "115, LGI1 {'perturbing_action': 'I-other'}", + "116, promoted {'effect': 'B-positive'}", + "119, in {'context': 'B-in vitro'}", + "120, vitro {'context': 'I-in vitro'}", + "124, in {'context': 'B-in vivo'}", + "125, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "47, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "49, expressing ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "50, a ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "51, truncated ['l2', 'l11', 'l19', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "52, mutant ['l3', 'l12', 'l20', 'l29', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "53, LGI1 ['l4', 'l13', 'l21', 'l30', 'l39', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "54, (835delC) ['l5', 'l14', 'l22', 'l31', 'l40', 'l47', 'l53', 'l54', 'l55', 'l56', 'l57']", + "55, found ['l6', 'l15', 'l23', 'l32', 'l41', 'l48', 'l53', 'l58', 'l59', 'l60']", + "59, overexpressing ['l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "60, a ['l24', 'l33', 'l42', 'l61', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "61, wild-type ['l34', 'l62', 'l69', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "62, LGI1. ['l25', 'l35', 'l43', 'l49', 'l54', 'l63', 'l70', 'l76', 'l82', 'l83', 'l84', 'l85', 'l86']", + "79, 835delC ['l7', 'l16', 'l26', 'l36', 'l44', 'l50', 'l55', 'l58', 'l64', 'l71', 'l77', 'l82', 'l87', 'l88']", + "80, mutant ['l8', 'l17', 'l27', 'l37', 'l45', 'l51', 'l56', 'l59', 'l65', 'l72', 'l78', 'l83', 'l87', 'l89']", + "81, LGI1, ['l9', 'l18', 'l28', 'l38', 'l46', 'l52', 'l57', 'l60', 'l66', 'l73', 'l79', 'l84', 'l88', 'l89']", + "91, mutant ['l67', 'l74', 'l80', 'l85', 'l90']", + "92, LGI1 ['l68', 'l75', 'l81', 'l86', 'l90']", + "114, mutant ['l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "115, LGI1 ['l91', 'l97', 'l98', 'l99', 'l100', 'l101']", + "116, promoted ['l92', 'l97', 'l102', 'l103', 'l104', 'l105']", + "119, in ['l93', 'l98', 'l102', 'l106']", + "120, vitro ['l94', 'l99', 'l103', 'l106']", + "124, in ['l95', 'l100', 'l104', 'l107']", + "125, vivo ['l96', 'l101', 'l105', 'l107']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "a", + "truncated", + "mutant", + "LGI1", + "(835delC)", + "found", + "835delC", + "LGI1," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "LGI1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "LGI1" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "LGI1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "19701202", + "TEXT": "The intestinal flora may promote colon tumor formation. Here we explore immunologic mechanisms of colonic carcinogenesis by a human colonic bacterium, enterotoxigenic Bacteroides fragilis (ETBF). ETBF that secretes B. fragilis toxin (BFT) causes human inflammatory diarrhea but also asymptomatically colonizes a proportion of the human population. Our results indicate that whereas both ETBF and nontoxigenic B. fragilis (NTBF) chronically colonize mice, only ETBF triggers colitis and strongly induces colonic tumors in multiple intestinal neoplasia (Min) mice. ETBF induces robust, selective colonic signal transducer and activator of transcription-3 (Stat3) activation with colitis characterized by a selective T helper type 17 (T(H)17) response distributed between CD4+ T cell receptor-alphabeta (TCRalphabeta)+ and CD4-8-TCRgammadelta+ T cells. Antibody-mediated blockade of interleukin-17 (IL-17) as well as the receptor for IL-23, a key cytokine amplifying T(H)17 responses, inhibits ETBF-induced colitis, colonic hyperplasia and tumor formation. These results show a Stat3- and T(H)17-dependent pathway for inflammation-induced cancer by a common human commensal bacterium, providing new mechanistic insight into human colon carcinogenesis.", + "TAG_DATA": [ + "60, mice, {'context': 'B-organism'}", + "67, induces {'effect': 'B-positive'}", + "68, colonic {'phenotype': 'B-tumourigenesis'}", + "69, tumors {'phenotype': 'I-tumourigenesis'}", + "73, neoplasia {'phenotype': 'I-tumourigenesis'}", + "75, mice. {'context': 'B-organism'}", + "136, tumor {'phenotype': 'B-tumourigenesis'}", + "137, formation. {'phenotype': 'I-tumourigenesis'}" + ], + "LINK_DATA": [ + "60, mice, ['l0', 'l1', 'l2']", + "67, induces ['l0', 'l3', 'l4', 'l5']", + "68, colonic ['l1', 'l3', 'l6', 'l7']", + "69, tumors ['l2', 'l4', 'l6']", + "71, multiple ['l8', 'l9', 'l10']", + "72, intestinal ['l8', 'l11', 'l12']", + "73, neoplasia ['l9', 'l11', 'l13']", + "75, mice. ['l5', 'l7', 'l10', 'l12', 'l13']", + "136, tumor ['l14']", + "137, formation. ['l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice,", + "mice." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice,", + "mice." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "colonic", + "tumors", + "neoplasia" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "colonic", + "tumors" + ] + } + } + ] + }, + { + "PMID": "19684581", + "TEXT": "T cells are crucial mediators of the skin damage in psoriasis. We here show that interleukin-21 (IL-21), a T cell-derived cytokine, is highly expressed in the skin of individuals with psoriasis, stimulates human keratinocytes to proliferate and causes epidermal hyperplasia when injected intradermally into mice. In the human psoriasis xenograft mouse model, blockade of IL-21 activity resolves inflammation and reduces keratinocyte proliferation. Blocking IL-21 may represent a new therapeutic strategy in psoriasis.", + "TAG_DATA": [ + "31, stimulates {'effect': 'B-positive'}", + "32, human {'context': 'B-cells'}", + "33, keratinocytes {'context': 'I-cells'}", + "35, proliferate {'phenotype': 'B-proliferation'}", + "44, mice. {'context': 'B-organism'}", + "47, human {'context': 'B-xenograft'}", + "48, psoriasis {'context': 'I-xenograft'}", + "49, xenograft {'context': 'I-xenograft'}", + "50, mouse {'context': 'I-xenograft'}", + "51, model, {'context': 'I-xenograft'}", + "52, blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "53, of {'perturbing_action': 'I-pharmacological inhibition'}", + "54, IL-21 {'perturbing_action': 'I-pharmacological inhibition'}", + "55, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "59, reduces {'effect': 'B-negative'}", + "60, keratinocyte {'context': 'B-cells'}", + "61, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "31, stimulates ['l0', 'l1', 'l2', 'l3']", + "32, human ['l0', 'l4', 'l5', 'l6']", + "33, keratinocytes ['l1', 'l4', 'l7', 'l8']", + "35, proliferate ['l2', 'l5', 'l7', 'l9']", + "44, mice. ['l3', 'l6', 'l8', 'l9']", + "47, human ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "48, psoriasis ['l10', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "49, xenograft ['l11', 'l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "50, mouse ['l12', 'l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "51, model, ['l13', 'l23', 'l32', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "52, blockade ['l14', 'l24', 'l33', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "53, of ['l15', 'l25', 'l34', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "54, IL-21 ['l16', 'l26', 'l35', 'l41', 'l46', 'l52', 'l57', 'l62', 'l63', 'l64', 'l65']", + "55, activity ['l17', 'l27', 'l36', 'l42', 'l47', 'l53', 'l58', 'l62', 'l66', 'l67', 'l68']", + "59, reduces ['l18', 'l28', 'l37', 'l43', 'l48', 'l54', 'l59', 'l63', 'l66', 'l69', 'l70']", + "60, keratinocyte ['l19', 'l29', 'l38', 'l44', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l71']", + "61, proliferation. ['l20', 'l30', 'l39', 'l45', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l71']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "keratinocytes" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "keratinocytes", + "keratinocyte" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate", + "proliferation." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "human", + "psoriasis", + "xenograft", + "mouse", + "model," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "IL-21", + "activity" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "human", + "psoriasis", + "xenograft", + "mouse", + "model," + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "human", + "psoriasis", + "xenograft", + "mouse", + "model," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "IL-21", + "activity" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "IL-21", + "activity" + ] + }, + "context": { + "val": "cells", + "words": [ + "keratinocyte" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "IL-21", + "activity" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "context": { + "val": "cells", + "words": [ + "keratinocyte" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "19661981", + "TEXT": "Would you entrust your brain to a bank? Well, many people do after they die, and such brain banks-often funded by government agencies or disease charities-are essential for neuroscience research. They collect and store the healthy and diseased brain specimens that neuroscientists need to explore neurological disorders such as Alzheimer's disease, schizophrenia and autism. Each brain bank typically has a limited supply of samples and tends to operate fairly independently. This means that researchers often have to trawl through numerous brain banks to find their desired specimens. Furthermore, there is a general shortage of brain samples. To help resolve these issues in the UK, James Ironside, professor of clinical neuropathology at the University of Edinburgh, was appointed in June as the director of the new UK Brain Banks Network. An expert in human prion diseases, particularly Creutzfeldt-Jakob disease (CJD), Ironside knows all about brain banks. He established the Brain and Tissue Bank at the UK's National CJD Surveillance Unit and is involved in the Sudden Death Brain and Tissue Bank at the University of Edinburgh. Jon Evans recently caught up with Ironside to discuss his new leadership position and how the brain network will benefit neuroscience research.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19633658", + "TEXT": "Inflammation is increasingly regarded as a key process underlying metabolic diseases in obese individuals. In particular, obese adipose tissue shows features characteristic of active local inflammation. At present, however, little is known about the sequence of events that comprises the inflammatory cascade or the mechanism by which inflammation develops. We found that large numbers of CD8(+) effector T cells infiltrated obese epididymal adipose tissue in mice fed a high-fat diet, whereas the numbers of CD4(+) helper and regulatory T cells were diminished. The infiltration by CD8(+) T cells preceded the accumulation of macrophages, and immunological and genetic depletion of CD8(+) T cells lowered macrophage infiltration and adipose tissue inflammation and ameliorated systemic insulin resistance. Conversely, adoptive transfer of CD8(+) T cells to CD8-deficient mice aggravated adipose inflammation. Coculture and other in vitro experiments revealed a vicious cycle of interactions between CD8(+) T cells, macrophages and adipose tissue. Our findings suggest that obese adipose tissue activates CD8(+) T cells, which, in turn, promote the recruitment and activation of macrophages in this tissue. These results support the notion that CD8(+) T cells have an essential role in the initiation and propagation of adipose inflammation.", + "TAG_DATA": [ + "55, CD8(+) {'context': 'B-cells'}", + "56, effector {'context': 'I-cells'}", + "57, T {'context': 'I-cells'}", + "58, cells {'context': 'I-cells'}", + "60, obese {'context': 'B-tissue/organ'}", + "61, epididymal {'context': 'I-tissue/organ'}", + "62, adipose {'context': 'I-tissue/organ'}", + "63, tissue {'context': 'I-tissue/organ'}", + "65, mice {'context': 'B-organism'}", + "74, CD4(+) {'context': 'B-cells'}", + "75, helper {'context': 'I-cells'}", + "76, and {'context': 'I-cells'}", + "77, regulatory {'context': 'I-cells'}", + "78, T {'context': 'I-cells'}", + "79, cells {'context': 'I-cells'}", + "85, CD8(+) {'context': 'B-cells'}", + "86, T {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}", + "99, CD8(+) {'context': 'B-cells'}", + "100, T {'context': 'I-cells'}", + "101, cells {'context': 'I-cells'}", + "103, macrophage {'context': 'B-cells'}", + "106, adipose {'context': 'B-tissue/organ'}", + "118, CD8(+) {'context': 'B-cells'}", + "119, T {'context': 'I-cells'}", + "120, cells {'context': 'I-cells'}", + "122, CD8-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "123, mice {'context': 'B-organism'}", + "130, in {'context': 'B-in vitro'}", + "131, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "55, CD8(+) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "56, effector ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "57, T ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "58, cells ['l2', 'l21', 'l39', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "60, obese ['l3', 'l22', 'l40', 'l55', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "61, epididymal ['l4', 'l23', 'l41', 'l56', 'l70', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "62, adipose ['l5', 'l24', 'l42', 'l57', 'l71', 'l83', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "63, tissue ['l6', 'l25', 'l43', 'l58', 'l72', 'l84', 'l95', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "65, mice ['l7', 'l26', 'l44', 'l59', 'l73', 'l85', 'l96', 'l105', 'l111', 'l112', 'l113', 'l114', 'l115']", + "74, CD4(+) ['l8', 'l27', 'l45', 'l60', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "75, helper ['l9', 'l28', 'l46', 'l61', 'l74', 'l86', 'l116', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139']", + "76, and ['l10', 'l29', 'l47', 'l62', 'l75', 'l87', 'l97', 'l117', 'l129', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "77, regulatory ['l11', 'l30', 'l48', 'l63', 'l76', 'l88', 'l98', 'l118', 'l130', 'l140', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "78, T ['l12', 'l31', 'l49', 'l64', 'l77', 'l89', 'l99', 'l106', 'l111', 'l119', 'l131', 'l141', 'l150', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164']", + "79, cells ['l13', 'l32', 'l50', 'l65', 'l78', 'l90', 'l100', 'l107', 'l112', 'l120', 'l132', 'l142', 'l151', 'l158', 'l165', 'l166', 'l167', 'l168', 'l169']", + "85, CD8(+) ['l14', 'l33', 'l51', 'l66', 'l79', 'l91', 'l101', 'l108', 'l113', 'l121', 'l133', 'l143', 'l152', 'l159', 'l165', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175']", + "86, T ['l15', 'l34', 'l52', 'l67', 'l80', 'l92', 'l102', 'l109', 'l114', 'l122', 'l134', 'l144', 'l153', 'l160', 'l166', 'l170', 'l176', 'l177', 'l178', 'l179', 'l180']", + "87, cells ['l16', 'l35', 'l53', 'l68', 'l81', 'l93', 'l103', 'l110', 'l115', 'l123', 'l135', 'l145', 'l154', 'l161', 'l167', 'l171', 'l176', 'l181', 'l182', 'l183']", + "99, CD8(+) ['l184', 'l185', 'l186', 'l187', 'l188']", + "100, T ['l124', 'l184', 'l189', 'l190', 'l191', 'l192']", + "101, cells ['l125', 'l136', 'l146', 'l172', 'l177', 'l185', 'l189', 'l193', 'l194', 'l195']", + "103, macrophage ['l17', 'l36', 'l126', 'l137', 'l147', 'l155', 'l162', 'l173', 'l178', 'l181', 'l186', 'l190', 'l193', 'l196', 'l197']", + "106, adipose ['l18', 'l37', 'l127', 'l138', 'l148', 'l156', 'l163', 'l168', 'l174', 'l179', 'l182', 'l187', 'l191', 'l194', 'l196', 'l198']", + "107, tissue ['l19', 'l38', 'l54', 'l69', 'l82', 'l94', 'l104', 'l128', 'l139', 'l149', 'l157', 'l164', 'l169', 'l175', 'l180', 'l183', 'l188', 'l192', 'l195', 'l197', 'l198']", + "118, CD8(+) ['l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "119, T ['l199', 'l205', 'l206', 'l207']", + "120, cells ['l200', 'l205', 'l208', 'l209']", + "122, CD8-deficient ['l201', 'l206', 'l208', 'l210', 'l211', 'l212']", + "123, mice ['l202', 'l207', 'l209', 'l210']", + "130, in ['l203', 'l211', 'l213']", + "131, vitro ['l204', 'l212', 'l213']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "T", + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD8-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD8-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD8-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "19597504", + "TEXT": "Although the transforming growth factor-beta (TGF-beta) pathway has been implicated in breast cancer metastasis, its in vivo dynamics and temporal-spatial involvement in organ-specific metastasis have not been investigated. Here we engineered a xenograft model system with a conditional control of the TGF-beta-SMAD signaling pathway and a dual-luciferase reporter system for tracing both metastatic burden and TGF-beta signaling activity in vivo. Strong TGF-beta signaling in osteolytic bone lesions is suppressed directly by genetic and pharmacological disruption of the TGF-beta-SMAD pathway and indirectly by inhibition of osteoclast function with bisphosphonates. Notably, disruption of TGF-beta signaling early in metastasis can substantially reduce metastasis burden but becomes less effective when bone lesions are well established. Our in vivo system for real-time manipulation and detection of TGF-beta signaling provides a proof of principle for using similar strategies to analyze the in vivo dynamics of other metastasis-associated signaling pathways and will expedite the development and characterization of therapeutic agents.", + "TAG_DATA": [ + "32, xenograft {'context': 'B-xenograft'}", + "33, model {'context': 'I-xenograft'}", + "34, system {'context': 'I-xenograft'}", + "58, in {'context': 'B-in vivo'}", + "59, vivo. {'context': 'I-in vivo'}", + "98, reduce {'effect': 'B-negative'}", + "99, metastasis {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "32, xenograft ['l0', 'l1', 'l2', 'l3']", + "33, model ['l0', 'l4', 'l5', 'l6']", + "34, system ['l1', 'l4', 'l7', 'l8']", + "58, in ['l2', 'l5', 'l7', 'l9']", + "59, vivo. ['l3', 'l6', 'l8', 'l9']", + "98, reduce ['l10', 'l11']", + "99, metastasis ['l10', 'l12']", + "100, burden ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "reduce" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + } + ] + }, + { + "PMID": "19584867", + "TEXT": "Bone remodeling depends on the precise coordination of bone resorption and subsequent bone formation. Disturbances of this process are associated with skeletal diseases, such as Camurati-Engelmann disease (CED). We show using in vitro and in vivo models that active TGF-beta1 released during bone resorption coordinates bone formation by inducing migration of bone marrow stromal cells, also known as bone mesenchymal stem cells, to the bone resorptive sites and that this process is mediated through a SMAD signaling pathway. Analyzing mice carrying a CED-derived mutant TGFB1 (encoding TGF-beta1), which show the typical progressive diaphyseal dysplasia seen in the human disease, we found high levels of active TGF-beta1 in the bone marrow. Treatment with a TGF-beta type I receptor inhibitor partially rescued the uncoupled bone remodeling and prevented the fractures. Thus, as TGF-beta1 functions to couple bone resorption and formation, modulation of TGF-beta1 activity could be an effective treatment for bone remodeling diseases.", + "TAG_DATA": [ + "79, mice {'context': 'B-organism'}", + "82, CED-derived {'perturbing_action': 'B-other'}", + "83, mutant {'perturbing_action': 'I-other'}", + "84, TGFB1 {'perturbing_action': 'I-other'}", + "85, (encoding {'perturbing_action': 'I-other'}", + "86, TGF-beta1), {'perturbing_action': 'I-other'}", + "113, TGF-beta {'perturbing_action': 'B-pharmacological inhibition'}", + "114, type {'perturbing_action': 'I-pharmacological inhibition'}", + "115, I {'perturbing_action': 'I-pharmacological inhibition'}", + "116, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "117, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "79, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "82, CED-derived ['l0', 'l5', 'l6', 'l7', 'l8']", + "83, mutant ['l1', 'l5', 'l9', 'l10', 'l11']", + "84, TGFB1 ['l2', 'l6', 'l9', 'l12', 'l13']", + "85, (encoding ['l3', 'l7', 'l10', 'l12', 'l14']", + "86, TGF-beta1), ['l4', 'l8', 'l11', 'l13', 'l14']", + "113, TGF-beta ['l15', 'l16', 'l17', 'l18']", + "114, type ['l15', 'l19', 'l20', 'l21']", + "115, I ['l16', 'l19', 'l22', 'l23']", + "116, receptor ['l17', 'l20', 'l22', 'l24']", + "117, inhibitor ['l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "CED-derived", + "mutant", + "TGFB1", + "(encoding", + "TGF-beta1)," + ] + } + } + ] + }, + { + "PMID": "19584860", + "TEXT": "A monoclonal antibody directed against lymphotoxin-α (LT-α) expressed by pathogenic T cells can prompt the clearance of these cells from the body (pages 766–773). The findings bring us one step closer to targeting only the cell populations that cause harm in autoimmune diseases while leaving beneficial arms of the immune system largely intact.", + "TAG_DATA": [ + "10, T {'context': 'B-cells'}", + "11, cells {'context': 'I-cells'}", + "18, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "10, T ['l0', 'l1']", + "11, cells ['l0', 'l2']", + "18, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19525963", + "TEXT": "African green monkeys (genus Chlorocebus) can be infected with species-specific simian immunodeficiency virus (SIVagm) but do not develop AIDS. These natural hosts of SIV, like sooty mangabeys, maintain high levels of SIV replication but have evolved to avoid immunodeficiency. Elucidating the mechanisms that allow natural hosts to coexist with SIV without overt disease may provide crucial information for understanding AIDS pathogenesis. Here we show that many CD4(+) T cells from African green monkeys downregulate CD4 in vivo as they enter the memory pool; that downregulation of CD4 by memory T cells is independent of SIV infection; that the CD4(-) memory T cells maintain functions that are normally attributed to CD4(+) T cells, including production of interleukin-2 (IL-2), production of IL-17, expression of forkhead box P3 and expression of CD40 ligand; that loss of CD4 expression protects these T cells from infection by SIVagm in vivo; and that these CD4(-) T cells can maintain major histocompatibility complex class II restriction. These data show that the absence of SIV-induced disease progression in natural host species may be partially explained by preservation of a subset of T cells that maintain CD4(+) T cell function while being resistant to SIV infection in vivo.", + "TAG_DATA": [ + "66, CD4(+) {'context': 'B-cells'}", + "67, T {'context': 'I-cells'}", + "68, cells {'context': 'I-cells'}", + "70, African {'context': 'B-organism'}", + "71, green {'context': 'I-organism'}", + "72, monkeys {'context': 'I-organism'}", + "75, in {'context': 'B-in vivo'}", + "76, vivo {'context': 'I-in vivo'}", + "88, memory {'context': 'B-cells'}", + "89, T {'context': 'I-cells'}", + "90, cells {'context': 'I-cells'}", + "98, CD4(-) {'context': 'B-cells'}", + "99, memory {'context': 'I-cells'}", + "100, T {'context': 'I-cells'}", + "101, cells {'context': 'I-cells'}", + "131, loss {'perturbing_action': 'B-gene loss-of-function'}", + "132, of {'perturbing_action': 'I-gene loss-of-function'}", + "133, CD4 {'perturbing_action': 'I-gene loss-of-function'}", + "134, expression {'perturbing_action': 'I-gene loss-of-function'}", + "137, T {'context': 'B-cells'}", + "138, cells {'context': 'B-cells'}", + "143, in {'context': 'B-in vivo'}", + "144, vivo; {'context': 'I-in vivo'}", + "148, CD4(-) {'context': 'B-cells'}", + "149, T {'context': 'I-cells'}", + "150, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "66, CD4(+) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "67, T ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "68, cells ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "70, African ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "71, green ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "72, monkeys ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "75, in ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "76, vivo ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "88, memory ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "89, T ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l58', 'l59', 'l60', 'l61']", + "90, cells ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l58', 'l62', 'l63']", + "98, CD4(-) ['l54', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "99, memory ['l55', 'l59', 'l64', 'l71', 'l72', 'l73', 'l74']", + "100, T ['l56', 'l60', 'l62', 'l65', 'l71', 'l75', 'l76']", + "101, cells ['l57', 'l61', 'l63', 'l66', 'l72', 'l75']", + "131, loss ['l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "132, of ['l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "133, CD4 ['l78', 'l84', 'l90', 'l91', 'l92', 'l93', 'l94']", + "134, expression ['l79', 'l85', 'l90', 'l95', 'l96', 'l97', 'l98']", + "137, T ['l67', 'l73', 'l80', 'l86', 'l91', 'l95', 'l99', 'l100', 'l101']", + "138, cells ['l68', 'l74', 'l76', 'l81', 'l87', 'l92', 'l96', 'l99', 'l102', 'l103']", + "143, in ['l69', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l104']", + "144, vivo; ['l70', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l104']", + "148, CD4(-) ['l105', 'l106']", + "149, T ['l105', 'l107']", + "150, cells ['l106', 'l107']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "CD4", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "CD4", + "expression" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo;" + ] + } + } + ] + }, + { + "PMID": "19465928", + "TEXT": "Two distinct helper T (TH) subsets, TH1 and TH17, mediate tissue damage and inflammation in animal models of various immune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases and allergic skin disorders. These experimental findings, and the implication of these TH subsets in human diseases, suggest the need for pharmacological measures to manipulate these TH subsets. Here we show that prostaglandin E2 (PGE2) acting on its receptor EP4 on T cells and dendritic cells not only facilitates TH1 cell differentiation but also amplifies interleukin-23-mediated TH17 cell expansion in vitro. Administration of an EP4-selective antagonist in vivo decreases accumulation of both TH1 and TH17 cells in regional lymph nodes and suppresses the disease progression in mice subjected to experimental autoimmune encephalomyelitis or contact hypersensitivity. Thus, PGE2-EP4 signaling promotes immune inflammation through TH1 differentiation and TH17 expansion, and EP4 antagonism may be therapeutically useful for various immune diseases.", + "TAG_DATA": [ + "71, T {'context': 'B-cells'}", + "72, cells {'context': 'B-cells'}", + "74, dendritic {'context': 'B-cells'}", + "78, facilitates {'effect': 'B-positive'}", + "79, TH1 {'context': 'B-cells'}", + "80, cell {'context': 'I-cells'}", + "81, differentiation {'phenotype': 'B-differentiation'}", + "86, TH17 {'context': 'B-cells'}", + "87, cell {'context': 'I-cells'}", + "89, in {'context': 'B-in vitro'}", + "90, vitro. {'context': 'I-in vitro'}", + "94, EP4-selective {'perturbing_action': 'B-pharmacological inhibition'}", + "95, antagonist {'perturbing_action': 'I-pharmacological inhibition'}", + "96, in {'context': 'B-in vivo'}", + "97, vivo {'context': 'I-in vivo'}", + "102, TH1 {'context': 'B-cells'}", + "103, and {'context': 'I-cells'}", + "104, TH17 {'context': 'I-cells'}", + "105, cells {'context': 'I-cells'}", + "107, regional {'context': 'B-tissue/organ'}", + "108, lymph {'context': 'I-tissue/organ'}", + "109, nodes {'context': 'I-tissue/organ'}", + "116, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "71, T ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "72, cells ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "74, dendritic ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "78, facilitates ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "79, TH1 ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "80, cell ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "81, differentiation ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "86, TH17 ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "87, cell ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "89, in ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "90, vitro. ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "94, EP4-selective ['l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "95, antagonist ['l55', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "96, in ['l56', 'l66', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "97, vivo ['l57', 'l67', 'l76', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "102, TH1 ['l58', 'l68', 'l77', 'l85', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "103, and ['l59', 'l69', 'l78', 'l86', 'l93', 'l99', 'l100', 'l101', 'l102', 'l103']", + "104, TH17 ['l60', 'l70', 'l79', 'l87', 'l94', 'l99', 'l104', 'l105', 'l106', 'l107']", + "105, cells ['l61', 'l71', 'l80', 'l88', 'l95', 'l100', 'l104', 'l108', 'l109', 'l110']", + "107, regional ['l62', 'l72', 'l81', 'l89', 'l96', 'l101', 'l105', 'l108', 'l111', 'l112']", + "108, lymph ['l63', 'l73', 'l82', 'l90', 'l97', 'l102', 'l106', 'l109', 'l111', 'l113']", + "109, nodes ['l64', 'l74', 'l83', 'l91', 'l98', 'l103', 'l107', 'l110', 'l112', 'l113']", + "116, mice ['l65', 'l75', 'l84', 'l92']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "dendritic", + "TH1", + "cell", + "TH17" + ] + }, + "effect": { + "val": "positive", + "words": [ + "facilitates" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "dendritic", + "TH1", + "cell", + "TH17" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "facilitates" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "facilitates" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EP4-selective", + "antagonist" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EP4-selective", + "antagonist" + ] + }, + "context": { + "val": "cells", + "words": [ + "TH1", + "and", + "TH17", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EP4-selective", + "antagonist" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "regional", + "lymph", + "nodes" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EP4-selective", + "antagonist" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "19448637", + "TEXT": "An imbalance in bone formation relative to bone resorption results in the net bone loss that occurs in osteoporosis and inflammatory bone diseases. Although it is well known how bone resorption is stimulated, the molecular mechanisms that mediate impaired bone formation are poorly understood. Here we show that the time- and stage-specific inhibition of endogenous inhibitor of kappaB kinase (IKK)--nuclear factor-kappaB (NF-kappaB) in differentiated osteoblasts substantially increases trabecular bone mass and bone mineral density without affecting osteoclast activities in young mice. Moreover, inhibition of IKK-NF-kappaB in differentiated osteoblasts maintains bone formation, thereby preventing osteoporotic bone loss induced by ovariectomy in adult mice. Inhibition of IKK-NF-kappaB enhances the expression of Fos-related antigen-1 (Fra-1), an essential transcription factor involved in bone matrix formation in vitro and in vivo. Taken together, our results suggest that targeting IKK-NF-kappaB may help to promote bone formation in the treatment of osteoporosis and other bone diseases.", + "TAG_DATA": [ + "49, time- {'perturbing_action': 'B-pharmacological inhibition'}", + "50, and {'perturbing_action': 'B-pharmacological inhibition'}", + "51, stage-specific {'perturbing_action': 'B-pharmacological inhibition'}", + "52, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "53, of {'perturbing_action': 'I-pharmacological inhibition'}", + "54, endogenous {'perturbing_action': 'I-pharmacological inhibition'}", + "55, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "56, of {'perturbing_action': 'I-pharmacological inhibition'}", + "57, kappaB {'perturbing_action': 'I-pharmacological inhibition'}", + "58, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "59, (IKK)--nuclear {'perturbing_action': 'I-pharmacological inhibition'}", + "60, factor-kappaB {'perturbing_action': 'I-pharmacological inhibition'}", + "61, (NF-kappaB) {'perturbing_action': 'I-pharmacological inhibition'}", + "63, differentiated {'context': 'B-cells'}", + "64, osteoblasts {'context': 'I-cells'}", + "79, young {'context': 'B-organism'}", + "80, mice. {'context': 'I-organism'}", + "82, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "83, of {'perturbing_action': 'I-pharmacological inhibition'}", + "84, IKK-NF-kappaB {'perturbing_action': 'I-pharmacological inhibition'}", + "86, differentiated {'context': 'B-cells'}", + "87, osteoblasts {'context': 'I-cells'}", + "100, adult {'context': 'B-organism'}", + "101, mice. {'context': 'I-organism'}", + "102, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "103, of {'perturbing_action': 'I-pharmacological inhibition'}", + "104, IKK-NF-kappaB {'perturbing_action': 'I-pharmacological inhibition'}", + "121, in {'context': 'B-in vitro'}", + "122, vitro {'context': 'I-in vitro'}", + "124, in {'context': 'B-in vivo'}", + "125, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "49, time- ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "50, and ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "51, stage-specific ['l1', 'l17', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "52, inhibition ['l2', 'l18', 'l33', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "53, of ['l3', 'l19', 'l34', 'l48', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "54, endogenous ['l4', 'l20', 'l35', 'l49', 'l63', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "55, inhibitor ['l5', 'l21', 'l36', 'l50', 'l64', 'l79', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "56, of ['l6', 'l22', 'l37', 'l51', 'l65', 'l80', 'l94', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "57, kappaB ['l7', 'l23', 'l38', 'l52', 'l66', 'l81', 'l95', 'l108', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "58, kinase ['l8', 'l24', 'l39', 'l53', 'l67', 'l82', 'l96', 'l109', 'l120', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "59, (IKK)--nuclear ['l9', 'l25', 'l40', 'l54', 'l68', 'l83', 'l97', 'l110', 'l121', 'l131', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "60, factor-kappaB ['l10', 'l26', 'l41', 'l55', 'l69', 'l84', 'l98', 'l111', 'l122', 'l132', 'l141', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158']", + "61, (NF-kappaB) ['l11', 'l27', 'l42', 'l56', 'l70', 'l85', 'l99', 'l112', 'l123', 'l133', 'l142', 'l150', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "63, differentiated ['l12', 'l28', 'l43', 'l57', 'l71', 'l86', 'l100', 'l113', 'l124', 'l134', 'l143', 'l151', 'l159', 'l166', 'l167', 'l168']", + "64, osteoblasts ['l13', 'l29', 'l44', 'l58', 'l72', 'l87', 'l101', 'l114', 'l125', 'l135', 'l144', 'l152', 'l160', 'l166', 'l169', 'l170']", + "79, young ['l14', 'l30', 'l45', 'l59', 'l73', 'l88', 'l102', 'l115', 'l126', 'l136', 'l145', 'l153', 'l161', 'l167', 'l169', 'l171']", + "80, mice. ['l15', 'l31', 'l46', 'l60', 'l74', 'l89', 'l103', 'l116', 'l127', 'l137', 'l146', 'l154', 'l162', 'l168', 'l170', 'l171']", + "82, inhibition ['l172', 'l173', 'l174', 'l175', 'l176', 'l177']", + "83, of ['l172', 'l178', 'l179', 'l180', 'l181', 'l182']", + "84, IKK-NF-kappaB ['l173', 'l178', 'l183', 'l184', 'l185', 'l186']", + "86, differentiated ['l61', 'l75', 'l90', 'l104', 'l117', 'l128', 'l138', 'l147', 'l155', 'l163', 'l174', 'l179', 'l183', 'l187', 'l188', 'l189']", + "87, osteoblasts ['l16', 'l32', 'l47', 'l62', 'l76', 'l91', 'l105', 'l118', 'l129', 'l139', 'l148', 'l156', 'l164', 'l175', 'l180', 'l184', 'l187', 'l190', 'l191']", + "100, adult ['l77', 'l92', 'l106', 'l157', 'l176', 'l181', 'l185', 'l188', 'l190', 'l192']", + "101, mice. ['l78', 'l93', 'l107', 'l119', 'l130', 'l140', 'l149', 'l158', 'l165', 'l177', 'l182', 'l186', 'l189', 'l191', 'l192']", + "102, Inhibition ['l193', 'l194', 'l195', 'l196', 'l197', 'l198']", + "103, of ['l193', 'l199', 'l200', 'l201', 'l202', 'l203']", + "104, IKK-NF-kappaB ['l194', 'l199', 'l204', 'l205', 'l206', 'l207']", + "121, in ['l195', 'l200', 'l204', 'l208', 'l209', 'l210']", + "122, vitro ['l196', 'l201', 'l205', 'l208', 'l211', 'l212']", + "124, in ['l197', 'l202', 'l206', 'l209', 'l211', 'l213']", + "125, vivo. ['l198', 'l203', 'l207', 'l210', 'l212', 'l213']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "time-", + "and", + "stage-specific", + "inhibition", + "of", + "endogenous", + "inhibitor", + "kappaB", + "kinase", + "(IKK)--nuclear", + "factor-kappaB", + "(NF-kappaB)", + "IKK-NF-kappaB" + ] + }, + "context": { + "val": "cells", + "words": [ + "differentiated", + "osteoblasts" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "time-", + "and", + "stage-specific", + "inhibition", + "of", + "endogenous", + "inhibitor", + "kappaB", + "kinase", + "(IKK)--nuclear", + "factor-kappaB", + "(NF-kappaB)", + "IKK-NF-kappaB" + ] + }, + "context": { + "val": "organism", + "words": [ + "young", + "mice.", + "adult" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "IKK-NF-kappaB" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "IKK-NF-kappaB" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "19448635", + "TEXT": "Activation of osteoclasts and their acidification-dependent resorption of bone is thought to maintain proper serum calcium levels. Here we show that osteoclast dysfunction alone does not generally affect calcium homeostasis. Indeed, mice deficient in Src, encoding a tyrosine kinase critical for osteoclast activity, show signs of osteopetrosis, but without hypocalcemia or defects in bone mineralization. Mice deficient in Cckbr, encoding a gastrin receptor that affects acid secretion by parietal cells, have the expected defects in gastric acidification but also secondary hyperparathyroidism and osteoporosis and modest hypocalcemia. These results suggest that alterations in calcium homeostasis can be driven by defects in gastric acidification, especially given that calcium gluconate supplementation fully rescues the phenotype of the Cckbr-mutant mice. Finally, mice deficient in Tcirg1, encoding a subunit of the vacuolar proton pump specifically expressed in both osteoclasts and parietal cells, show hypocalcemia and osteopetrorickets. Although neither Src- nor Cckbr-deficient mice have this latter phenotype, the combined deficiency of both genes results in osteopetrorickets. Thus, we find that osteopetrosis and osteopetrorickets are distinct phenotypes, depending on the site or sites of defective acidification.", + "TAG_DATA": [ + "31, mice {'context': 'B-organism'}", + "32, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "33, in {'perturbing_action': 'I-gene loss-of-function'}", + "34, Src, {'perturbing_action': 'I-gene loss-of-function'}", + "55, Mice {'context': 'B-organism'}", + "56, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "57, in {'perturbing_action': 'I-gene loss-of-function'}", + "58, Cckbr, {'perturbing_action': 'I-gene loss-of-function'}", + "114, Cckbr-mutant {'perturbing_action': 'B-other'}", + "115, mice. {'context': 'B-organism'}", + "117, mice {'context': 'B-organism'}", + "118, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "119, in {'perturbing_action': 'I-gene loss-of-function'}", + "120, Tcirg1, {'perturbing_action': 'I-gene loss-of-function'}", + "143, Src- {'perturbing_action': 'B-gene loss-of-function'}", + "144, nor {'perturbing_action': 'B-gene loss-of-function'}", + "145, Cckbr-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "146, mice {'context': 'B-organism'}", + "154, of {'perturbing_action': 'I-gene loss-of-function'}", + "155, both {'perturbing_action': 'I-gene loss-of-function'}", + "156, genes {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "31, mice ['l0', 'l1', 'l2']", + "32, deficient ['l0', 'l3', 'l4']", + "33, in ['l1', 'l3', 'l5']", + "34, Src, ['l2', 'l4', 'l5']", + "55, Mice ['l6', 'l7', 'l8']", + "56, deficient ['l6', 'l9', 'l10', 'l11']", + "57, in ['l7', 'l9', 'l12', 'l13']", + "58, Cckbr, ['l8', 'l10', 'l12', 'l14']", + "114, Cckbr-mutant ['l15', 'l16', 'l17', 'l18', 'l19']", + "115, mice. ['l11', 'l13', 'l14', 'l15', 'l20', 'l21']", + "117, mice ['l16', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "118, deficient ['l17', 'l22', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "119, in ['l18', 'l20', 'l23', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "120, Tcirg1, ['l19', 'l21', 'l24', 'l30', 'l35', 'l40', 'l41', 'l42', 'l43']", + "143, Src- ['l25', 'l31', 'l36', 'l40', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "144, nor ['l26', 'l32', 'l37', 'l41', 'l44', 'l50', 'l51', 'l52', 'l53', 'l54']", + "145, Cckbr-deficient ['l27', 'l33', 'l38', 'l42', 'l45', 'l50', 'l55', 'l56', 'l57', 'l58']", + "146, mice ['l28', 'l34', 'l39', 'l43', 'l46', 'l51', 'l55', 'l59']", + "154, of ['l47', 'l52', 'l56', 'l60', 'l61']", + "155, both ['l48', 'l53', 'l57', 'l60', 'l62']", + "156, genes ['l49', 'l54', 'l58', 'l59', 'l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "Mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Src,", + "Cckbr,", + "Tcirg1,", + "Src-", + "nor", + "Cckbr-deficient", + "genes" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Cckbr-mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + } + ] + }, + { + "PMID": "19412172", + "TEXT": "Organized neuronal firing is crucial for cortical processing and is disrupted in schizophrenia. Using rapid amplification of 5' complementary DNA ends in human brain, we identified a primate-specific isoform (3.1) of the ether-a-go-go-related K(+) channel KCNH2 that modulates neuronal firing. KCNH2-3.1 messenger RNA levels are comparable to full-length KCNH2 (1A) levels in brain but three orders of magnitude lower in heart. In hippocampus from individuals with schizophrenia, KCNH2-3.1 expression is 2.5-fold greater than KCNH2-1A expression. A meta-analysis of five clinical data sets (367 families, 1,158 unrelated cases and 1,704 controls) shows association of single nucleotide polymorphisms in KCNH2 with schizophrenia. Risk-associated alleles predict lower intelligence quotient scores and speed of cognitive processing, altered memory-linked functional magnetic resonance imaging signals and increased KCNH2-3.1 mRNA levels in postmortem hippocampus. KCNH2-3.1 lacks a domain that is crucial for slow channel deactivation. Overexpression of KCNH2-3.1 in primary cortical neurons induces a rapidly deactivating K(+) current and a high-frequency, nonadapting firing pattern. These results identify a previously undescribed KCNH2 channel isoform involved in cortical physiology, cognition and psychosis, providing a potential new therapeutic drug target.", + "TAG_DATA": [ + "138, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "139, of {'perturbing_action': 'I-gene gain-of-function'}", + "140, KCNH2-3.1 {'perturbing_action': 'I-gene gain-of-function'}", + "142, primary {'context': 'B-cells'}", + "143, cortical {'context': 'I-cells'}", + "144, neurons {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "138, Overexpression ['l0', 'l1', 'l2', 'l3', 'l4']", + "139, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "140, KCNH2-3.1 ['l1', 'l5', 'l9', 'l10', 'l11']", + "142, primary ['l2', 'l6', 'l9', 'l12', 'l13']", + "143, cortical ['l3', 'l7', 'l10', 'l12', 'l14']", + "144, neurons ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "KCNH2-3.1" + ] + }, + "context": { + "val": "cells", + "words": [ + "primary", + "cortical", + "neurons" + ] + } + } + ] + }, + { + "PMID": "19396174", + "TEXT": "Identifying key factors that enhance immune responses is crucial for manipulating immunity to tumors. We show that after a vaccine-induced immune response, adjuvant interleukin-7 (IL-7) improves antitumor responses and survival in an animal model. The improved immune response is associated with increased IL-6 production and augmented T helper type 17 cell differentiation. Furthermore, IL-7 modulates the expression of two ubiquitin ligases: Casitas B-lineage lymphoma b (Cbl-b), a negative regulator of T cell activation, is repressed, and SMAD-specific E3 ubiquitin protein ligase-2 (Smurf2) is enhanced, which antagonizes transforming growth factor-beta signaling. Notably, we show that although short term IL-7 therapy potently enhances vaccine-mediated immunity, in the absence of vaccination it is inefficient in promoting antitumor immune responses, despite inducing homeostatic proliferation of T cells. The ability of adjuvant IL-7 to antagonize inhibitory networks at the cellular and molecular level has major implications for immunotherapy in the treatment of tumors.", + "TAG_DATA": [ + "32, animal {'context': 'B-organism'}", + "33, model. {'context': 'I-organism'}", + "45, augmented {'effect': 'B-positive'}", + "46, T {'context': 'B-cells'}", + "47, helper {'context': 'I-cells'}", + "48, type {'context': 'I-cells'}", + "49, 17 {'context': 'I-cells'}", + "50, cell {'context': 'I-cells'}", + "51, differentiation. {'phenotype': 'B-differentiation'}", + "117, inducing {'effect': 'B-positive'}", + "119, proliferation {'phenotype': 'B-proliferation'}", + "121, T {'context': 'B-cells'}", + "122, cells. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "32, animal ['l0', 'l1', 'l2', 'l3']", + "33, model. ['l0', 'l4', 'l5', 'l6']", + "45, augmented ['l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "46, T ['l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "47, helper ['l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "48, type ['l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "49, 17 ['l1', 'l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "50, cell ['l2', 'l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "51, differentiation. ['l3', 'l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "117, inducing ['l28', 'l29', 'l30']", + "119, proliferation ['l28', 'l31', 'l32']", + "121, T ['l29', 'l31', 'l33']", + "122, cells. ['l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "animal", + "model." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "augmented", + "inducing" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "helper", + "type", + "17", + "cell", + "cells." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "augmented" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "helper", + "type", + "17", + "cell" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells." + ] + } + } + ] + }, + { + "PMID": "19363497", + "TEXT": "Many studies have shown that primary prostate cancers are multifocal and are composed of multiple genetically distinct cancer cell clones. Whether or not multiclonal primary prostate cancers typically give rise to multiclonal or monoclonal prostate cancer metastases is largely unknown, although studies at single chromosomal loci are consistent with the latter case. Here we show through a high-resolution genome-wide single nucleotide polymorphism and copy number survey that most, if not all, metastatic prostate cancers have monoclonal origins and maintain a unique signature copy number pattern of the parent cancer cell while also accumulating a variable number of separate subclonally sustained changes. We find no relationship between anatomic site of metastasis and genomic copy number change pattern. Taken together with past animal and cytogenetic studies of metastasis and recent single-locus genetic data in prostate and other metastatic cancers, these data indicate that despite common genomic heterogeneity in primary cancers, most metastatic cancers arise from a single precursor cancer cell. This study establishes that genomic archeology of multiple anatomically separate metastatic cancers in individuals can be used to define the salient genomic features of a parent cancer clone of proven lethal metastatic phenotype.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19350006", + "TEXT": "Experiments in rodents identify a factor that causes the release of multipotent cells into the circulation after injury. These cells contribute to tissue repair.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19350004", + "TEXT": "Experiments in two mouse models of thromboinflammatory disease show how neutrophils stick to red blood cells and platelets—leading to reduced blood flow and damage to the microcirculation. Polarized expression of αMβ2 integrins on neutrophils helps set the process in motion (pages 384−391).", + "TAG_DATA": [ + "4, models {'context': 'I-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19330009", + "TEXT": "Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal inherited arrhythmia syndrome in which drug therapy is often ineffective. We discovered that flecainide prevents arrhythmias in a mouse model of CPVT by inhibiting cardiac ryanodine receptor-mediated Ca(2+) release and thereby directly targeting the underlying molecular defect. Flecainide completely prevented CPVT in two human subjects who had remained highly symptomatic on conventional drug therapy, indicating that this currently available drug is a promising mechanism-based therapy for CPVT.", + "TAG_DATA": [ + "27, mouse {'context': 'B-organism'}", + "28, model {'context': 'I-organism'}", + "29, of {'context': 'I-organism'}", + "30, CPVT {'context': 'I-organism'}", + "52, human {'context': 'B-organism'}", + "53, subjects {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "27, mouse ['l0', 'l1', 'l2']", + "28, model ['l0', 'l3', 'l4']", + "29, of ['l1', 'l3', 'l5']", + "30, CPVT ['l2', 'l4', 'l5']", + "52, human ['l6']", + "53, subjects ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19265821", + "TEXT": "An experimental simian immunodeficiency virus vaccine boosts production of memory T cells at the site where the virus first contacts the body—in the mucosa (293–299). The approach has the potential to result in more effective HIV vaccines than those currently under development.", + "TAG_DATA": [ + "9, memory {'context': 'B-cells'}", + "10, T {'context': 'I-cells'}", + "11, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "9, memory ['l0', 'l1']", + "10, T ['l0', 'l2']", + "11, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19219022", + "TEXT": "Gene transfer has potential as a once-only treatment that reduces viral load, preserves the immune system and avoids lifetime highly active antiretroviral therapy. This study, which is to our knowledge the first randomized, double-blind, placebo-controlled, phase 2 cell-delivered gene transfer clinical trial, was conducted in 74 HIV-1-infected adults who received a tat-vpr-specific anti-HIV ribozyme (OZ1) or placebo delivered in autologous CD34+ hematopoietic progenitor cells. There were no OZ1-related adverse events. There was no statistically significant difference in viral load between the OZ1 and placebo group at the primary end point (average at weeks 47 and 48), but time-weighted areas under the curve from weeks 40-48 and 40-100 were significantly lower in the OZ1 group. Throughout the 100 weeks, CD4+ lymphocyte counts were higher in the OZ1 group. This study indicates that cell-delivered gene transfer is safe and biologically active in individuals with HIV and can be developed as a conventional therapeutic product.", + "TAG_DATA": [ + "46, HIV-1-infected {'context': 'B-patient'}", + "47, adults {'context': 'I-organism'}", + "59, autologous {'context': 'B-xenograft'}", + "60, CD34+ {'context': 'I-cells'}", + "61, hematopoietic {'context': 'I-cells'}", + "62, progenitor {'context': 'I-cells'}", + "63, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "46, HIV-1-infected ['l0', 'l1', 'l2']", + "47, adults ['l0']", + "59, autologous ['l3', 'l4', 'l5', 'l6']", + "60, CD34+ ['l3', 'l7', 'l8', 'l9']", + "61, hematopoietic ['l4', 'l7', 'l10', 'l11']", + "62, progenitor ['l1', 'l5', 'l8', 'l10', 'l12']", + "63, cells. ['l2', 'l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "19169263", + "TEXT": "Systemic and local inflammatory processes have a key, mainly detrimental role in the pathophysiology of ischemic stroke. Currently, little is known about endogenous counterregulatory immune mechanisms. We examined the role of the key immunomodulators CD4(+)CD25(+) forkhead box P3 (Foxp3)(+) regulatory T lymphocytes (T(reg) cells), after experimental brain ischemia. Depletion of T(reg) cells profoundly increased delayed brain damage and deteriorated functional outcome. Absence of T(reg) cells augmented postischemic activation of resident and invading inflammatory cells including microglia and T cells, the main sources of deleterious cerebral tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), respectively. Early antagonization of TNF-alpha and delayed neutralization of IFN-gamma prevented infarct growth in T(reg) cell-depleted mice. Intracerebral interleukin-10 (IL-10) substitution abrogated the cytokine overexpression after T(reg) cell depletion and prevented secondary infarct growth, whereas transfer of IL-10-deficient T(reg) cells in an adoptive transfer model was ineffective. In conclusion, T(reg) cells are major cerebroprotective modulators of postischemic inflammatory brain damage targeting multiple inflammatory pathways. IL-10 signaling is essential for their immunomodulatory effect.", + "TAG_DATA": [ + "48, Depletion {'perturbing_action': 'B-gene loss-of-function'}", + "49, of {'perturbing_action': 'I-gene loss-of-function'}", + "50, T(reg) {'perturbing_action': 'I-gene loss-of-function', 'context': 'B-cells'}", + "51, cells {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "61, Absence {'perturbing_action': 'B-gene loss-of-function'}", + "62, of {'perturbing_action': 'I-gene loss-of-function'}", + "63, T(reg) {'perturbing_action': 'I-gene loss-of-function'}", + "64, cells {'perturbing_action': 'I-gene loss-of-function'}", + "77, T {'context': 'B-cells'}", + "78, cells, {'context': 'B-cells'}", + "106, T(reg) {'perturbing_action': 'B-gene loss-of-function'}", + "107, cell-depleted {'perturbing_action': 'I-gene loss-of-function'}", + "108, mice. {'context': 'B-organism'}", + "118, T(reg) {'perturbing_action': 'B-gene loss-of-function'}", + "119, cell {'perturbing_action': 'I-gene loss-of-function'}", + "120, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "129, IL-10-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "130, T(reg) {'context': 'B-cells'}", + "131, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "48, Depletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "49, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "50, T(reg) ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "51, cells ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "61, Absence ['l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "62, of ['l18', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "63, T(reg) ['l19', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "64, cells ['l3', 'l8', 'l12', 'l15', 'l20', 'l27', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "77, T ['l4', 'l9', 'l13', 'l16', 'l21', 'l28', 'l34', 'l39', 'l44', 'l45', 'l46']", + "78, cells, ['l5', 'l10', 'l14', 'l17', 'l22', 'l29', 'l35', 'l40', 'l44']", + "106, T(reg) ['l23', 'l30', 'l36', 'l41', 'l47', 'l48']", + "107, cell-depleted ['l24', 'l31', 'l37', 'l42', 'l45', 'l47', 'l49']", + "108, mice. ['l25', 'l32', 'l38', 'l43', 'l46', 'l48', 'l49']", + "118, T(reg) ['l50', 'l51']", + "119, cell ['l50', 'l52']", + "120, depletion ['l51', 'l52']", + "129, IL-10-deficient ['l53', 'l54', 'l55', 'l56']", + "130, T(reg) ['l53', 'l57', 'l58', 'l59']", + "131, cells ['l54', 'l57', 'l60', 'l61']", + "134, adoptive ['l55', 'l58', 'l60', 'l62']", + "135, transfer ['l56', 'l59', 'l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Depletion", + "of", + "T(reg)", + "cells", + "Absence", + "cell-depleted", + "IL-10-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "T(reg)", + "cells", + "T", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Absence", + "of", + "T(reg)", + "cells", + "cell-depleted" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "19151730", + "TEXT": "Copy number variants are a recently discovered source of large-scale genomic diversity present in all individuals. We capitalize on these inherent genomic differences, focusing on deletion polymorphisms, to develop informative fluorescence in situ hybridization probes with the ability to unequivocally distinguish between donor and recipient cells in situ. These probes are accurate, specific, highly polymorphic and, notably, can be used to assign genetic identity in situ in a completely gender-independent fashion. We anticipate that these polymorphic deletion probes will be useful in further understanding the dynamics of cellular chimerism after transplantation, including the details of chronic organ rejection, post-transplant lymphoproliferative disorder and graft-versus-host disease, and in optimizing future tissue engineering and pluripotent stem cell therapies.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19129774", + "TEXT": "Subcortical band heterotopia (SBH) is a neuron migration disorder characterized by an aberrant ‘band-like’ accumulation of neurons within the neocortical white matter, frequently leading to mental retardation and epilepsy. SBH can now be regressed by reactivating neuronal migration.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "19122657", + "TEXT": "Atherosclerosis is characterized by chronic inflammation of the arterial wall due to chemokine-driven mononuclear cell recruitment. Activated platelets can synergize with chemokines to exacerbate atherogenesis; for example, by deposition of the chemokines platelet factor-4 (PF4, also known as CXCL4) and RANTES (CCL5), triggering monocyte arrest on inflamed endothelium. Homo-oligomerization is required for the recruitment functions of CCL5, and chemokine heteromerization has more recently emerged as an additional regulatory mechanism, as evidenced by a mutual modulation of CXCL8 and CXCL4 activities and by enhanced monocyte arrest resulting from CCL5-CXCL4 interactions. The CCL5 antagonist Met-RANTES reduces diet-induced atherosclerosis; however, CCL5 antagonism may not be therapeutically feasible, as suggested by studies using Ccl5-deficient mice which imply that direct CCL5 blockade would severely compromise systemic immune responses, delay macrophage-mediated viral clearance and impair normal T cell functions. Here we determined structural features of CCL5-CXCL4 heteromers and designed stable peptide inhibitors that specifically disrupt proinflammatory CCL5-CXCL4 interactions, thereby attenuating monocyte recruitment and reducing atherosclerosis without the aforementioned side effects. These results establish the in vivo relevance of chemokine heteromers and show the potential of targeting heteromer formation to achieve therapeutic effects.", + "TAG_DATA": [ + "90, CCL5 {'perturbing_action': 'B-pharmacological inhibition'}", + "91, antagonist {'perturbing_action': 'I-pharmacological inhibition'}", + "92, Met-RANTES {'perturbing_action': 'I-pharmacological inhibition'}", + "97, CCL5 {'perturbing_action': 'B-pharmacological inhibition'}", + "98, antagonism {'perturbing_action': 'I-pharmacological inhibition'}", + "109, Ccl5-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "110, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "90, CCL5 ['l0', 'l1', 'l2', 'l3']", + "91, antagonist ['l0', 'l4', 'l5', 'l6']", + "92, Met-RANTES ['l1', 'l4', 'l7', 'l8']", + "97, CCL5 ['l9', 'l10', 'l11']", + "98, antagonism ['l9', 'l12', 'l13']", + "109, Ccl5-deficient ['l2', 'l5', 'l7', 'l10', 'l12', 'l14']", + "110, mice ['l3', 'l6', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CCL5", + "antagonist", + "Met-RANTES", + "antagonism" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ccl5-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "19029982", + "TEXT": "Fibrodysplasia ossificans progressiva (FOP) is a congenital disorder of progressive and widespread postnatal ossification of soft tissues and is without known effective treatments. Affected individuals harbor conserved mutations in the ACVR1 gene that are thought to cause constitutive activation of the bone morphogenetic protein (BMP) type I receptor, activin receptor-like kinase-2 (ALK2). Here we show that intramuscular expression in the mouse of an inducible transgene encoding constitutively active ALK2 (caALK2), resulting from a glutamine to aspartic acid change at amino acid position 207, leads to ectopic endochondral bone formation, joint fusion and functional impairment, thus phenocopying key aspects of human FOP. A selective inhibitor of BMP type I receptor kinases, LDN-193189 (ref. 6), inhibits activation of the BMP signaling effectors SMAD1, SMAD5 and SMAD8 in tissues expressing caALK2 induced by adenovirus specifying Cre (Ad.Cre). This treatment resulted in a reduction in ectopic ossification and functional impairment. In contrast to localized induction of caALK2 by Ad.Cre (which entails inflammation), global postnatal expression of caALK2 (induced without the use of Ad.Cre and thus without inflammation) does not lead to ectopic ossification. However, if in this context an inflammatory stimulus was provided with a control adenovirus, ectopic bone formation was induced. Like LDN-193189, corticosteroid inhibits ossification in Ad.Cre-injected mutant mice, suggesting caALK2 expression and an inflammatory milieu are both required for the development of ectopic ossification in this model. These results support the role of dysregulated ALK2 kinase activity in the pathogenesis of FOP and suggest that small molecule inhibition of BMP type I receptor activity may be useful in treating FOP and heterotopic ossification syndromes associated with excessive BMP signaling.", + "TAG_DATA": [ + "56, intramuscular {'perturbing_action': 'B-gene gain-of-function'}", + "57, expression {'perturbing_action': 'I-gene gain-of-function'}", + "60, mouse {'context': 'B-organism'}", + "61, of {'perturbing_action': 'I-gene gain-of-function'}", + "62, an {'perturbing_action': 'I-gene gain-of-function'}", + "63, inducible {'perturbing_action': 'I-gene gain-of-function'}", + "64, transgene {'perturbing_action': 'I-gene gain-of-function'}", + "65, encoding {'perturbing_action': 'I-gene gain-of-function'}", + "66, constitutively {'perturbing_action': 'I-gene gain-of-function'}", + "67, active {'perturbing_action': 'I-gene gain-of-function'}", + "68, ALK2 {'perturbing_action': 'I-gene gain-of-function'}", + "69, (caALK2), {'perturbing_action': 'I-gene gain-of-function'}", + "70, resulting {'perturbing_action': 'I-gene gain-of-function'}", + "102, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "103, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "104, of {'perturbing_action': 'I-pharmacological inhibition'}", + "105, BMP {'perturbing_action': 'I-pharmacological inhibition'}", + "106, type {'perturbing_action': 'I-pharmacological inhibition'}", + "107, I {'perturbing_action': 'I-pharmacological inhibition'}", + "108, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "109, kinases, {'perturbing_action': 'I-pharmacological inhibition'}", + "110, LDN-193189 {'perturbing_action': 'I-pharmacological inhibition'}", + "111, (ref. {'perturbing_action': 'I-pharmacological inhibition'}", + "125, tissues {'context': 'B-tissue/organ'}", + "126, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "127, caALK2 {'perturbing_action': 'I-gene gain-of-function'}", + "130, adenovirus {'perturbing_action': 'B-gene gain-of-function'}", + "131, specifying {'perturbing_action': 'I-gene gain-of-function'}", + "132, Cre {'perturbing_action': 'I-other'}", + "133, (Ad.Cre). {'perturbing_action': 'I-gene gain-of-function'}", + "158, global {'perturbing_action': 'B-gene gain-of-function'}", + "159, postnatal {'perturbing_action': 'I-gene gain-of-function'}", + "160, expression {'perturbing_action': 'I-gene gain-of-function'}", + "161, of {'perturbing_action': 'I-gene gain-of-function'}", + "162, caALK2 {'perturbing_action': 'I-gene gain-of-function'}", + "194, bone {'phenotype': 'I-tumourigenesis'}", + "195, formation {'phenotype': 'I-tumourigenesis'}", + "197, induced. {'effect': 'B-positive'}", + "204, Ad.Cre-injected {'perturbing_action': 'B-other'}", + "206, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, intramuscular ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "57, expression ['l0', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "60, mouse ['l1', 'l23', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "61, of ['l2', 'l24', 'l45', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "62, an ['l3', 'l25', 'l46', 'l64', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "63, inducible ['l4', 'l26', 'l47', 'l65', 'l84', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "64, transgene ['l5', 'l27', 'l48', 'l66', 'l85', 'l104', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "65, encoding ['l6', 'l28', 'l49', 'l67', 'l86', 'l105', 'l123', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "66, constitutively ['l7', 'l29', 'l50', 'l68', 'l87', 'l106', 'l124', 'l141', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "67, active ['l8', 'l30', 'l51', 'l69', 'l88', 'l107', 'l125', 'l142', 'l158', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "68, ALK2 ['l9', 'l31', 'l52', 'l70', 'l89', 'l108', 'l126', 'l143', 'l159', 'l174', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202']", + "69, (caALK2), ['l10', 'l32', 'l53', 'l71', 'l90', 'l109', 'l127', 'l144', 'l160', 'l175', 'l189', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215']", + "70, resulting ['l11', 'l33', 'l54', 'l72', 'l91', 'l110', 'l128', 'l145', 'l161', 'l176', 'l190', 'l203', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227']", + "71, from ['l12', 'l34', 'l55', 'l73', 'l92', 'l111', 'l129', 'l146', 'l162', 'l177', 'l191', 'l204', 'l216', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238']", + "73, glutamine ['l13', 'l35', 'l56', 'l74', 'l93', 'l112', 'l130', 'l147', 'l163', 'l178', 'l192', 'l205', 'l217', 'l228', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248']", + "77, change ['l14', 'l36', 'l57', 'l75', 'l94', 'l113', 'l131', 'l148', 'l164', 'l179', 'l193', 'l206', 'l218', 'l229', 'l239', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257']", + "102, selective ['l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273']", + "103, inhibitor ['l258', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286', 'l287', 'l288']", + "104, of ['l259', 'l274', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302']", + "105, BMP ['l260', 'l275', 'l289', 'l303', 'l304', 'l305', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315']", + "106, type ['l261', 'l276', 'l290', 'l303', 'l316', 'l317', 'l318', 'l319', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327']", + "107, I ['l262', 'l277', 'l291', 'l304', 'l316', 'l328', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334', 'l335', 'l336', 'l337', 'l338']", + "108, receptor ['l263', 'l278', 'l292', 'l305', 'l317', 'l328', 'l339', 'l340', 'l341', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348']", + "109, kinases, ['l264', 'l279', 'l293', 'l306', 'l318', 'l329', 'l339', 'l349', 'l350', 'l351', 'l352', 'l353', 'l354', 'l355', 'l356', 'l357']", + "110, LDN-193189 ['l95', 'l114', 'l132', 'l149', 'l165', 'l180', 'l194', 'l207', 'l219', 'l230', 'l240', 'l249', 'l265', 'l280', 'l294', 'l307', 'l319', 'l330', 'l340', 'l349', 'l358', 'l359', 'l360', 'l361', 'l362', 'l363', 'l364', 'l365']", + "111, (ref. ['l15', 'l37', 'l76', 'l96', 'l115', 'l133', 'l150', 'l166', 'l181', 'l195', 'l208', 'l220', 'l231', 'l241', 'l250', 'l266', 'l281', 'l295', 'l308', 'l320', 'l331', 'l341', 'l350', 'l358', 'l366', 'l367', 'l368', 'l369', 'l370', 'l371', 'l372']", + "125, tissues ['l16', 'l38', 'l58', 'l77', 'l97', 'l116', 'l134', 'l151', 'l167', 'l182', 'l196', 'l209', 'l221', 'l232', 'l242', 'l251', 'l267', 'l282', 'l296', 'l309', 'l321', 'l332', 'l342', 'l351', 'l359', 'l366', 'l373', 'l374', 'l375', 'l376', 'l377', 'l378']", + "126, expressing ['l17', 'l39', 'l59', 'l78', 'l98', 'l117', 'l135', 'l152', 'l168', 'l183', 'l197', 'l210', 'l222', 'l233', 'l243', 'l252', 'l268', 'l283', 'l297', 'l310', 'l322', 'l333', 'l343', 'l352', 'l360', 'l367', 'l373', 'l379', 'l380', 'l381', 'l382', 'l383']", + "127, caALK2 ['l18', 'l40', 'l60', 'l79', 'l99', 'l118', 'l136', 'l153', 'l169', 'l184', 'l198', 'l211', 'l223', 'l234', 'l244', 'l253', 'l269', 'l284', 'l298', 'l311', 'l323', 'l334', 'l344', 'l353', 'l361', 'l368', 'l374', 'l379', 'l384', 'l385', 'l386', 'l387']", + "130, adenovirus ['l19', 'l41', 'l61', 'l80', 'l100', 'l119', 'l137', 'l154', 'l170', 'l185', 'l199', 'l212', 'l224', 'l235', 'l245', 'l254', 'l270', 'l285', 'l299', 'l312', 'l324', 'l335', 'l345', 'l354', 'l362', 'l369', 'l375', 'l380', 'l384', 'l388', 'l389', 'l390']", + "131, specifying ['l20', 'l42', 'l81', 'l101', 'l120', 'l138', 'l155', 'l171', 'l186', 'l200', 'l213', 'l225', 'l236', 'l246', 'l255', 'l271', 'l286', 'l300', 'l313', 'l325', 'l336', 'l346', 'l355', 'l363', 'l370', 'l376', 'l381', 'l385', 'l388', 'l391', 'l392']", + "132, Cre ['l21', 'l43', 'l62', 'l82', 'l102', 'l121', 'l139', 'l156', 'l172', 'l187', 'l201', 'l214', 'l226', 'l237', 'l247', 'l256', 'l272', 'l287', 'l301', 'l314', 'l326', 'l337', 'l347', 'l356', 'l364', 'l371', 'l377', 'l382', 'l386', 'l389', 'l391', 'l393']", + "133, (Ad.Cre). ['l22', 'l44', 'l63', 'l83', 'l103', 'l122', 'l140', 'l157', 'l173', 'l188', 'l202', 'l215', 'l227', 'l238', 'l248', 'l257', 'l273', 'l288', 'l302', 'l315', 'l327', 'l338', 'l348', 'l357', 'l365', 'l372', 'l378', 'l383', 'l387', 'l390', 'l392', 'l393']", + "158, global ['l394', 'l395', 'l396', 'l397', 'l398', 'l399', 'l400']", + "159, postnatal ['l394', 'l401', 'l402', 'l403', 'l404', 'l405', 'l406']", + "160, expression ['l395', 'l401', 'l407', 'l408', 'l409', 'l410', 'l411']", + "161, of ['l396', 'l402', 'l407', 'l412', 'l413', 'l414', 'l415']", + "162, caALK2 ['l397', 'l403', 'l408', 'l412', 'l416', 'l417', 'l418']", + "194, bone ['l398', 'l404', 'l409', 'l413', 'l416', 'l419', 'l420']", + "195, formation ['l399', 'l405', 'l410', 'l414', 'l417', 'l419', 'l421']", + "197, induced. ['l400', 'l406', 'l411', 'l415', 'l418', 'l420', 'l421']", + "204, Ad.Cre-injected ['l422', 'l423']", + "205, mutant ['l422', 'l424']", + "206, mice, ['l423', 'l424']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "intramuscular", + "expression", + "of", + "an", + "inducible", + "transgene", + "encoding", + "constitutively", + "active", + "ALK2", + "(caALK2),", + "resulting", + "expressing", + "caALK2", + "adenovirus", + "(Ad.Cre)." + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "intramuscular", + "expression", + "of", + "an", + "inducible", + "transgene", + "encoding", + "constitutively", + "active", + "ALK2", + "(caALK2),", + "resulting", + "expressing", + "caALK2", + "adenovirus", + "specifying", + "(Ad.Cre)." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tissues" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "mice," + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Cre", + "Ad.Cre-injected" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "inhibitor", + "of", + "BMP", + "type", + "I", + "receptor", + "kinases,", + "LDN-193189", + "(ref." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tissues" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "tissues" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Cre" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "global", + "postnatal", + "expression", + "of", + "caALK2" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "bone", + "formation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "global", + "postnatal", + "expression", + "of", + "caALK2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "bone", + "formation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced." + ] + } + } + ] + }, + { + "PMID": "19029981", + "TEXT": "Somatic mutations that activate phosphoinositide 3-kinase (PI3K) have been identified in the p110-alpha catalytic subunit (encoded by PIK3CA). They are most frequently observed in two hotspots: the helical domain (E545K and E542K) and the kinase domain (H1047R). Although the p110-alpha mutants are transforming in vitro, their oncogenic potential has not been assessed in genetically engineered mouse models. Furthermore, clinical trials with PI3K inhibitors have recently been initiated, and it is unknown if their efficacy will be restricted to specific, genetically defined malignancies. In this study, we engineered a mouse model of lung adenocarcinomas initiated and maintained by expression of p110-alpha H1047R. Treatment of these tumors with NVP-BEZ235, a dual pan-PI3K and mammalian target of rapamycin (mTOR) inhibitor in clinical development, led to marked tumor regression as shown by positron emission tomography-computed tomography, magnetic resonance imaging and microscopic examination. In contrast, mouse lung cancers driven by mutant Kras did not substantially respond to single-agent NVP-BEZ235. However, when NVP-BEZ235 was combined with a mitogen-activated protein kinase kinase (MEK) inhibitor, ARRY-142886, there was marked synergy in shrinking these Kras-mutant cancers. These in vivo studies suggest that inhibitors of the PI3K-mTOR pathway may be active in cancers with PIK3CA mutations and, when combined with MEK inhibitors, may effectively treat KRAS mutated lung cancers.", + "TAG_DATA": [ + "88, mouse {'context': 'B-organism'}", + "89, model {'context': 'I-neoplasm'}", + "90, of {'context': 'I-neoplasm'}", + "91, lung {'context': 'I-neoplasm'}", + "92, adenocarcinomas {'context': 'I-neoplasm'}", + "104, tumors {'context': 'B-neoplasm'}", + "120, led {'effect': 'B-positive'}", + "121, to {'effect': 'I-positive'}", + "123, tumor {'phenotype': 'B-tumour regression'}", + "124, regression {'phenotype': 'I-tumour regression'}", + "140, mouse {'context': 'B-neoplasm'}", + "141, lung {'context': 'I-neoplasm'}", + "142, cancers {'context': 'I-neoplasm'}", + "145, mutant {'perturbing_action': 'B-other'}", + "146, Kras {'perturbing_action': 'I-other'}", + "161, mitogen-activated {'perturbing_action': 'B-pharmacological inhibition'}", + "162, protein {'perturbing_action': 'I-pharmacological inhibition'}", + "163, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "164, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "165, (MEK) {'perturbing_action': 'I-pharmacological inhibition'}", + "166, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "167, ARRY-142886, {'perturbing_action': 'I-pharmacological inhibition'}", + "175, Kras-mutant {'perturbing_action': 'B-other'}", + "176, cancers. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "88, mouse ['l0', 'l1', 'l2', 'l3', 'l4']", + "89, model ['l0', 'l5', 'l6', 'l7', 'l8']", + "90, of ['l1', 'l5', 'l9', 'l10', 'l11']", + "91, lung ['l2', 'l6', 'l9', 'l12', 'l13']", + "92, adenocarcinomas ['l3', 'l7', 'l10', 'l12', 'l14']", + "104, tumors ['l4', 'l8', 'l11', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "120, led ['l15', 'l19', 'l20', 'l21']", + "121, to ['l16', 'l19', 'l22', 'l23']", + "123, tumor ['l17', 'l20', 'l22', 'l24']", + "124, regression ['l18', 'l21', 'l23', 'l24']", + "140, mouse ['l25', 'l26', 'l27', 'l28']", + "141, lung ['l25', 'l29', 'l30', 'l31']", + "142, cancers ['l26', 'l29', 'l32', 'l33']", + "145, mutant ['l27', 'l30', 'l32', 'l34']", + "146, Kras ['l28', 'l31', 'l33', 'l34']", + "161, mitogen-activated ['l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "162, protein ['l35', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "163, kinase ['l36', 'l43', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "164, kinase ['l37', 'l44', 'l50', 'l56', 'l57', 'l58', 'l59', 'l60']", + "165, (MEK) ['l38', 'l45', 'l51', 'l56', 'l61', 'l62', 'l63', 'l64']", + "166, inhibitor, ['l39', 'l46', 'l52', 'l57', 'l61', 'l65', 'l66', 'l67']", + "167, ARRY-142886, ['l40', 'l47', 'l53', 'l58', 'l62', 'l65', 'l68', 'l69']", + "175, Kras-mutant ['l41', 'l48', 'l54', 'l59', 'l63', 'l66', 'l68', 'l70']", + "176, cancers. ['l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l70']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "lung", + "cancers", + "cancers." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "Kras", + "Kras-mutant" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mitogen-activated", + "protein", + "kinase", + "(MEK)", + "inhibitor,", + "ARRY-142886," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "cancers." + ] + } + } + ] + }, + { + "PMID": "19029979", + "TEXT": "A long-term goal of cancer diagnosis is to develop tumor-imaging techniques that have sufficient specificity and sensitivity. To achieve this goal, minimizing the background signal originating from nontarget tissues is crucial. Here we achieve highly specific in vivo cancer visualization by using a newly designed targeted 'activatable' fluorescent imaging probe. This agent is activated after cellular internalization by sensing the pH change in the lysosome. Novel acidic pH-activatable probes based on the boron-dipyrromethene fluorophore were synthesized and then conjugated to a cancer-targeting monoclonal antibody. As proof of concept, ex vivo and in vivo imaging of human epidermal growth factor receptor type 2-positive lung cancer cells in mice was performed. The probe was highly specific for tumors with minimal background signal. Furthermore, because the acidic pH in lysosomes is maintained by the energy-consuming proton pump, only viable cancer cells were successfully visualized. The design concept can be widely adapted to cancer-specific, cell surface-targeting molecules that result in cellular internalization.", + "TAG_DATA": [ + "91, in {'context': 'B-in vivo'}", + "92, vivo {'context': 'I-in vivo'}", + "95, human {'context': 'B-transformed cells'}", + "96, epidermal {'context': 'I-transformed cells'}", + "97, growth {'context': 'I-transformed cells'}", + "98, factor {'context': 'I-transformed cells'}", + "99, receptor {'context': 'I-transformed cells'}", + "100, type {'context': 'I-transformed cells'}", + "101, 2-positive {'context': 'I-transformed cells'}", + "102, lung {'context': 'I-transformed cells'}", + "103, cancer {'context': 'I-transformed cells'}", + "104, cells {'context': 'I-transformed cells'}", + "106, mice {'context': 'B-organism'}", + "115, tumors {'context': 'B-neoplasm'}", + "136, cancer {'context': 'B-transformed cells'}", + "137, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "91, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "92, vivo ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "95, human ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "96, epidermal ['l2', 'l13', 'l23', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "97, growth ['l3', 'l14', 'l24', 'l34', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "98, factor ['l4', 'l15', 'l25', 'l35', 'l44', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "99, receptor ['l5', 'l16', 'l26', 'l36', 'l45', 'l53', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "100, type ['l6', 'l17', 'l27', 'l37', 'l46', 'l54', 'l61', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "101, 2-positive ['l7', 'l18', 'l28', 'l38', 'l47', 'l55', 'l62', 'l68', 'l74', 'l75', 'l76', 'l77', 'l78']", + "102, lung ['l8', 'l19', 'l29', 'l39', 'l48', 'l56', 'l63', 'l69', 'l74', 'l79', 'l80', 'l81']", + "103, cancer ['l9', 'l20', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l75', 'l79', 'l82', 'l83']", + "104, cells ['l10', 'l21', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l82', 'l84']", + "106, mice ['l11', 'l22', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l83', 'l84']", + "115, tumors ['l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78']", + "136, cancer ['l85']", + "137, cells ['l85']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18978796", + "TEXT": "Genetic and epigenetic plasticity allows tumors to evade single-targeted treatments. Here we direct Bcl2-specific short interfering RNA (siRNA) with 5'-triphosphate ends (3p-siRNA) against melanoma. Recognition of 5'-triphosphate by the cytosolic antiviral helicase retinoic acid-induced protein I (Rig-I, encoded by Ddx58) activated innate immune cells such as dendritic cells and directly induced expression of interferons (IFNs) and apoptosis in tumor cells. These Rig-I-mediated activities synergized with siRNA-mediated Bcl2 silencing to provoke massive apoptosis of tumor cells in lung metastases in vivo. The therapeutic activity required natural killer cells and IFN, as well as silencing of Bcl2, as evidenced by rescue with a mutated Bcl2 target, by site-specific cleavage of Bcl2 messenger RNA in lung metastases and downregulation of Bcl-2 protein in tumor cells in vivo. Together, 3p-siRNA represents a single molecule-based approach in which Rig-I activation on both the immune- and tumor cell level corrects immune ignorance and in which gene silencing corrects key molecular events that govern tumor cell survival.", + "TAG_DATA": [ + "50, induced {'effect': 'B-positive'}", + "56, apoptosis {'phenotype': 'B-apoptosis'}", + "58, tumor {'context': 'B-transformed cells'}", + "59, cells. {'context': 'I-transformed cells'}", + "65, siRNA-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "66, Bcl2 {'perturbing_action': 'I-rnai/knockdown'}", + "67, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "69, provoke {'effect': 'B-positive'}", + "71, apoptosis {'phenotype': 'B-apoptosis'}", + "73, tumor {'context': 'B-transformed cells'}", + "74, cells {'context': 'I-transformed cells'}", + "76, lung {'phenotype': 'B-metastasis'}", + "77, metastases {'phenotype': 'I-metastasis'}", + "78, in {'context': 'B-in vivo'}", + "79, vivo. {'context': 'I-in vivo'}", + "92, silencing {'perturbing_action': 'B-rnai/knockdown'}", + "93, of {'perturbing_action': 'I-rnai/knockdown'}", + "94, Bcl2, {'perturbing_action': 'I-rnai/knockdown'}", + "101, mutated {'perturbing_action': 'B-other'}", + "102, Bcl2 {'perturbing_action': 'I-other'}", + "103, target, {'perturbing_action': 'I-other'}", + "112, lung {'context': 'B-neoplasm', 'phenotype': 'B-metastasis'}", + "113, metastases {'phenotype': 'I-metastasis'}", + "120, tumor {'context': 'B-transformed cells'}", + "121, cells {'context': 'I-transformed cells'}", + "122, in {'context': 'B-in vivo'}", + "123, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "50, induced ['l0', 'l1', 'l2']", + "56, apoptosis ['l0', 'l3', 'l4', 'l5']", + "58, tumor ['l1', 'l3', 'l6', 'l7']", + "59, cells. ['l2', 'l4', 'l6']", + "65, siRNA-mediated ['l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "66, Bcl2 ['l8', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "67, silencing ['l9', 'l18', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "69, provoke ['l10', 'l19', 'l27', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "71, apoptosis ['l11', 'l20', 'l28', 'l35', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "73, tumor ['l12', 'l21', 'l29', 'l36', 'l42', 'l48', 'l49', 'l50', 'l51', 'l52']", + "74, cells ['l5', 'l7', 'l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l53', 'l54', 'l55', 'l56']", + "76, lung ['l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l57', 'l58', 'l59']", + "77, metastases ['l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l60', 'l61']", + "78, in ['l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l58', 'l60', 'l62']", + "79, vivo. ['l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l61', 'l62']", + "92, silencing ['l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "93, of ['l63', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "94, Bcl2, ['l64', 'l74', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "101, mutated ['l65', 'l75', 'l84', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "102, Bcl2 ['l66', 'l76', 'l85', 'l93', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "103, target, ['l67', 'l77', 'l86', 'l94', 'l101', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "112, lung ['l68', 'l78', 'l87', 'l95', 'l102', 'l108', 'l114', 'l115', 'l116', 'l117', 'l118']", + "113, metastases ['l69', 'l79', 'l88', 'l96', 'l103', 'l109', 'l114', 'l119', 'l120', 'l121', 'l122']", + "120, tumor ['l70', 'l80', 'l89', 'l97', 'l104', 'l110', 'l115', 'l119', 'l123', 'l124', 'l125']", + "121, cells ['l71', 'l81', 'l90', 'l98', 'l105', 'l111', 'l116', 'l120', 'l123', 'l126', 'l127']", + "122, in ['l72', 'l82', 'l91', 'l99', 'l106', 'l112', 'l117', 'l121', 'l124', 'l126', 'l128']", + "123, vivo. ['l73', 'l83', 'l92', 'l100', 'l107', 'l113', 'l118', 'l122', 'l125', 'l127', 'l128']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced", + "provoke" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "provoke" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells.", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells.", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA-mediated", + "Bcl2", + "silencing" + ] + }, + "effect": { + "val": "positive", + "words": [ + "provoke" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA-mediated", + "Bcl2", + "silencing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA-mediated", + "Bcl2", + "silencing", + "of", + "Bcl2," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA-mediated", + "Bcl2", + "silencing", + "of", + "Bcl2," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "lung", + "metastases" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA-mediated", + "Bcl2", + "silencing", + "of", + "Bcl2," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "provoke" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "lung", + "metastases" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "provoke" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "lung", + "metastases" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "lung", + "metastases" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "of", + "Bcl2," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lung" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "lung" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "Bcl2", + "target," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "Bcl2", + "target," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "lung", + "metastases" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "Bcl2", + "target," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "Bcl2", + "target," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "18836461", + "TEXT": "Conditional control of protein function in vivo offers great potential for deconvoluting the roles of individual proteins in complicated systems. We recently developed a method in which a small protein domain, termed a destabilizing domain, confers instability to fusion protein partners in cultured cells. Instability is reversed when a cell-permeable small molecule binds this domain. Here we describe the use of this system to regulate protein function in living mammals. We show regulation of secreted proteins and their biological activity with conditional secretion of an immunomodulatory cytokine, resulting in tumor burden reduction in mouse models. Additionally, we use this approach to control the function of a specific protein after systemic delivery of the gene that encodes it to a tumor, suggesting uses for enhancing the specificity and efficacy of targeted gene-based therapies. This method represents a new strategy to regulate protein function in living organisms with a high level of control.", + "TAG_DATA": [ + "93, mouse {'context': 'B-organism'}", + "94, models. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "93, mouse ['l0']", + "94, models. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18806803", + "TEXT": "Pathogenic HIV infections of humans and simian immunodeficiency virus (SIV) infections of rhesus macaques are characterized by generalized immune activation and progressive CD4(+) T cell depletion. In contrast, natural reservoir hosts for SIV, such as sooty mangabeys, do not progress to AIDS and show a lack of aberrant immune activation and preserved CD4(+) T cell populations, despite high levels of SIV replication. Here we show that sooty mangabeys have substantially reduced levels of innate immune system activation in vivo during acute and chronic SIV infection and that sooty mangabey plasmacytoid dendritic cells (pDCs) produce markedly less interferon-alpha in response to SIV and other Toll-like receptor 7 and 9 ligands ex vivo. We propose that chronic stimulation of pDCs by SIV and HIV in non-natural hosts may drive the unrelenting immune system activation and dysfunction underlying AIDS progression. Such a vicious cycle of continuous virus replication and immunopathology is absent in natural sooty mangabey hosts.", + "TAG_DATA": [ + "66, sooty {'context': 'B-organism'}", + "67, mangabeys {'context': 'I-organism'}", + "77, in {'context': 'B-in vivo'}", + "78, vivo {'context': 'I-in vivo'}", + "87, sooty {'context': 'B-organism'}", + "88, mangabey {'context': 'I-cells'}", + "89, plasmacytoid {'context': 'I-cells'}", + "90, dendritic {'context': 'I-cells'}", + "91, cells {'context': 'I-cells'}", + "92, (pDCs) {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "66, sooty ['l0', 'l1', 'l2']", + "67, mangabeys ['l0', 'l3', 'l4']", + "77, in ['l1', 'l3', 'l5']", + "78, vivo ['l2', 'l4', 'l5']", + "87, sooty ['l6', 'l7', 'l8', 'l9', 'l10']", + "88, mangabey ['l6', 'l11', 'l12', 'l13', 'l14']", + "89, plasmacytoid ['l7', 'l11', 'l15', 'l16', 'l17']", + "90, dendritic ['l8', 'l12', 'l15', 'l18', 'l19']", + "91, cells ['l9', 'l13', 'l16', 'l18', 'l20']", + "92, (pDCs) ['l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18758447", + "TEXT": "Malaria continues to devastate sub-Saharan Africa owing to the emergence of drug resistance to established antimalarials and to the lack of an efficacious vaccine. Plasmodium species have a unique streamlined purine pathway in which the dual specificity enzyme purine nucleoside phosphorylase (PNP) functions in both purine recycling and purine salvage. To evaluate the importance of PNP in an in vivo model of malaria, we disrupted PyPNP, the gene encoding PNP in the lethal Plasmodium yoelii YM strain. P. yoelii parasites lacking PNP were attenuated and cleared in mice. Although able to form gametocytes, PNP-deficient parasites did not form oocysts in mosquito midguts and were not transmitted from mosquitoes to mice. Mice given PNP-deficient parasites were immune to subsequent challenge to a lethal inoculum of P. yoelii YM and to challenge from P. yoelii 17XNL, another strain. These in vivo studies with PNP-deficient parasites support purine salvage as a target for antimalarials. They also suggest a strategy for the development of attenuated nontransmissible metabolic mutants as blood-stage malaria vaccine strains.", + "TAG_DATA": [ + "77, P. {'context': 'B-organism'}", + "78, yoelii {'context': 'I-organism'}", + "79, parasites {'context': 'I-organism'}", + "80, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "81, PNP {'perturbing_action': 'I-gene loss-of-function'}", + "87, mice. {'context': 'B-organism'}", + "93, PNP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "94, parasites {'context': 'B-neoplasm'}", + "100, mosquito {'context': 'B-tissue/organ'}", + "101, midguts {'context': 'I-tissue/organ'}", + "107, mosquitoes {'context': 'B-organism'}", + "109, mice. {'context': 'B-organism'}", + "110, Mice {'context': 'B-organism'}", + "112, PNP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "113, parasites {'context': 'B-neoplasm'}", + "141, PNP-deficient {'perturbing_action': 'B-gene loss-of-function'}" + ], + "LINK_DATA": [ + "77, P. ['l0', 'l1', 'l2', 'l3', 'l4']", + "78, yoelii ['l0', 'l5', 'l6', 'l7', 'l8']", + "79, parasites ['l1', 'l5', 'l9', 'l10', 'l11']", + "80, lacking ['l2', 'l6', 'l9', 'l12', 'l13']", + "81, PNP ['l3', 'l7', 'l10', 'l12', 'l14', 'l15']", + "87, mice. ['l4', 'l8', 'l11', 'l13', 'l14']", + "93, PNP-deficient ['l16', 'l17', 'l18', 'l19', 'l20']", + "94, parasites ['l16', 'l21', 'l22', 'l23', 'l24']", + "100, mosquito ['l17', 'l21', 'l25', 'l26', 'l27']", + "101, midguts ['l15', 'l18', 'l22', 'l25', 'l28', 'l29']", + "107, mosquitoes ['l19', 'l23', 'l26', 'l28', 'l30']", + "109, mice. ['l20', 'l24', 'l27', 'l29', 'l30']", + "110, Mice ['l31', 'l32']", + "112, PNP-deficient ['l31', 'l33']", + "113, parasites ['l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "P.", + "yoelii", + "parasites", + "mice.", + "mosquitoes", + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "PNP", + "PNP-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PNP", + "PNP-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "midguts", + "mosquito" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PNP-deficient" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "parasites" + ] + } + } + ] + }, + { + "PMID": "18724378", + "TEXT": "Drug resistance acquired by cancer cells has led to treatment failure. To understand the regulatory network underlying docetaxel resistance in breast cancer cells and to identify molecular targets for therapy, we tested small interfering RNAs (siRNAs) against 36 genes whose expression was elevated in human nonresponders to docetaxel for the ability to promote apoptosis of docetaxel-resistant human breast cancer cells (MCF7-ADR cells). The results indicate that the downregulation of the gene encoding ribophorin [corrected] II (RPN2), which is part of an N-oligosaccharyl transferase complex, most efficiently induces apoptosis of MCF7-ADR cells in the presence of docetaxel. RPN2 silencing induced reduced glycosylation of the P-glycoprotein, as well as decreased membrane localization, thereby sensitizing MCF7-ADR cells to docetaxel. Moreover, in vivo delivery of siRNA specific for RPN2 markedly reduced tumor growth in two types of models for drug resistance. Thus, RPN2 silencing makes cancer cells hypersensitive response to docetaxel, and RPN2 might be a new target for RNA interference-based therapeutics against drug resistance.", + "TAG_DATA": [ + "52, promote {'effect': 'B-positive'}", + "53, apoptosis {'phenotype': 'B-apoptosis'}", + "55, docetaxel-resistant {'context': 'B-transformed cells'}", + "56, human {'context': 'I-transformed cells'}", + "57, breast {'context': 'I-transformed cells'}", + "58, cancer {'context': 'I-transformed cells'}", + "59, cells {'context': 'I-transformed cells'}", + "60, (MCF7-ADR {'context': 'I-transformed cells'}", + "61, cells). {'context': 'I-transformed cells'}", + "67, downregulation {'perturbing_action': 'B-rnai/knockdown'}", + "68, of {'perturbing_action': 'I-rnai/knockdown'}", + "69, the {'perturbing_action': 'I-rnai/knockdown'}", + "70, gene {'perturbing_action': 'I-rnai/knockdown'}", + "71, encoding {'perturbing_action': 'I-rnai/knockdown'}", + "72, ribophorin {'perturbing_action': 'I-rnai/knockdown'}", + "73, [corrected] {'perturbing_action': 'I-rnai/knockdown'}", + "74, II {'perturbing_action': 'I-rnai/knockdown'}", + "75, (RPN2), {'perturbing_action': 'I-rnai/knockdown'}", + "86, induces {'effect': 'B-positive'}", + "87, apoptosis {'phenotype': 'B-apoptosis'}", + "89, MCF7-ADR {'context': 'B-transformed cells'}", + "90, cells {'context': 'I-transformed cells'}", + "96, RPN2 {'perturbing_action': 'B-rnai/knockdown'}", + "97, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "112, MCF7-ADR {'context': 'B-transformed cells'}", + "113, cells {'context': 'I-transformed cells'}", + "117, in {'context': 'B-in vivo'}", + "118, vivo {'context': 'I-in vivo'}", + "121, siRNA {'perturbing_action': 'B-rnai/knockdown'}", + "122, specific {'perturbing_action': 'I-rnai/knockdown'}", + "123, for {'perturbing_action': 'I-rnai/knockdown'}", + "124, RPN2 {'perturbing_action': 'I-rnai/knockdown'}", + "126, reduced {'effect': 'B-negative'}", + "127, tumor {'phenotype': 'B-tumour growth'}", + "128, growth {'phenotype': 'I-tumour growth'}", + "138, RPN2 {'perturbing_action': 'B-rnai/knockdown'}", + "139, silencing {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "52, promote ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "53, apoptosis ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "55, docetaxel-resistant ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "56, human ['l2', 'l13', 'l23', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "57, breast ['l3', 'l14', 'l24', 'l35', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "58, cancer ['l4', 'l15', 'l25', 'l36', 'l46', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "59, cells ['l5', 'l16', 'l26', 'l37', 'l47', 'l63', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "60, (MCF7-ADR ['l6', 'l17', 'l27', 'l38', 'l48', 'l64', 'l72', 'l78', 'l79', 'l80', 'l81', 'l82']", + "61, cells). ['l7', 'l18', 'l28', 'l39', 'l49', 'l65', 'l73', 'l78', 'l83', 'l84', 'l85', 'l86']", + "67, downregulation ['l50', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "68, of ['l29', 'l40', 'l51', 'l66', 'l87', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "69, the ['l30', 'l41', 'l52', 'l67', 'l88', 'l101', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "70, gene ['l53', 'l89', 'l102', 'l114', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "71, encoding ['l54', 'l90', 'l103', 'l115', 'l126', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "72, ribophorin ['l55', 'l91', 'l104', 'l116', 'l127', 'l137', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "73, [corrected] ['l56', 'l92', 'l105', 'l117', 'l128', 'l138', 'l148', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166']", + "74, II ['l57', 'l93', 'l106', 'l118', 'l129', 'l139', 'l149', 'l158', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "75, (RPN2), ['l58', 'l94', 'l107', 'l119', 'l130', 'l140', 'l150', 'l159', 'l167', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181']", + "86, induces ['l8', 'l19', 'l31', 'l42', 'l59', 'l68', 'l74', 'l79', 'l83', 'l95', 'l108', 'l120', 'l131', 'l141', 'l151', 'l160', 'l168', 'l175', 'l182', 'l183', 'l184']", + "87, apoptosis ['l9', 'l20', 'l32', 'l43', 'l60', 'l69', 'l75', 'l80', 'l84', 'l96', 'l109', 'l121', 'l132', 'l142', 'l152', 'l161', 'l169', 'l176', 'l182', 'l185', 'l186']", + "89, MCF7-ADR ['l10', 'l21', 'l33', 'l44', 'l61', 'l70', 'l76', 'l81', 'l85', 'l97', 'l110', 'l122', 'l133', 'l143', 'l153', 'l162', 'l170', 'l177', 'l183', 'l185', 'l187']", + "90, cells ['l11', 'l22', 'l34', 'l45', 'l62', 'l71', 'l77', 'l82', 'l86', 'l98', 'l111', 'l123', 'l134', 'l144', 'l154', 'l163', 'l171', 'l178', 'l184', 'l186', 'l187']", + "96, RPN2 ['l188', 'l189', 'l190']", + "97, silencing ['l145', 'l155', 'l164', 'l172', 'l179', 'l188', 'l191', 'l192']", + "112, MCF7-ADR ['l99', 'l112', 'l124', 'l135', 'l146', 'l156', 'l165', 'l173', 'l180', 'l189', 'l191', 'l193']", + "113, cells ['l100', 'l113', 'l125', 'l136', 'l147', 'l157', 'l166', 'l174', 'l181', 'l190', 'l192', 'l193']", + "117, in ['l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203']", + "118, vivo ['l194', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212']", + "121, siRNA ['l195', 'l204', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220']", + "122, specific ['l196', 'l205', 'l213', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227']", + "123, for ['l197', 'l206', 'l214', 'l221', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233']", + "124, RPN2 ['l198', 'l207', 'l215', 'l222', 'l228', 'l234', 'l235', 'l236', 'l237', 'l238']", + "126, reduced ['l199', 'l208', 'l216', 'l223', 'l229', 'l234', 'l239', 'l240']", + "127, tumor ['l200', 'l209', 'l217', 'l224', 'l230', 'l235', 'l239', 'l241']", + "128, growth ['l201', 'l210', 'l218', 'l225', 'l231', 'l236', 'l240', 'l241']", + "138, RPN2 ['l202', 'l211', 'l219', 'l226', 'l232', 'l237', 'l242']", + "139, silencing ['l203', 'l212', 'l220', 'l227', 'l233', 'l238', 'l242']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promote", + "induces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote", + "induces" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "docetaxel-resistant", + "human", + "breast", + "cancer", + "cells", + "(MCF7-ADR", + "cells).", + "MCF7-ADR" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "docetaxel-resistant", + "human", + "breast", + "cancer", + "cells", + "(MCF7-ADR", + "cells).", + "MCF7-ADR" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "docetaxel-resistant", + "human", + "breast", + "cancer", + "MCF7-ADR", + "cells" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "the", + "downregulation", + "gene", + "encoding", + "ribophorin", + "[corrected]", + "II", + "(RPN2),", + "RPN2", + "silencing" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "downregulation", + "of", + "the", + "gene", + "encoding", + "ribophorin", + "[corrected]", + "II", + "(RPN2)," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "downregulation", + "of", + "the", + "gene", + "encoding", + "ribophorin", + "[corrected]", + "II", + "(RPN2)," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA", + "specific", + "for", + "RPN2", + "silencing" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA", + "specific", + "for", + "RPN2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA", + "specific", + "for", + "RPN2" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + } + ] + }, + { + "PMID": "18724376", + "TEXT": "We describe a transgenic mouse line, Pax8-rtTA, which, under control of the mouse Pax8 promoter, directs high levels of expression of the reverse tetracycline-dependent transactivator (rtTA) to all proximal and distal tubules and the entire collecting duct system of both embryonic and adult kidneys. Using crosses of Pax8-rtTA mice with tetracycline-responsive c-MYC mice, we established a new, inducible model of polycystic kidney disease that can mimic adult onset and that shows progression to renal malignant disease. When targeting the expression of transforming growth factor beta-1 to the kidney, we avoided early lethality by discontinuous treatment and successfully established an inducible model of renal fibrosis. Finally, a conditional knockout of the gene encoding tuberous sclerosis complex-1 was achieved, which resulted in the early outgrowth of giant polycystic kidneys reminiscent of autosomal recessive polycystic kidney disease. These experiments establish Pax8-rtTA mice as a powerful tool for modeling renal diseases in transgenic mice.", + "TAG_DATA": [ + "48, mice {'context': 'B-organism'}", + "106, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "107, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "108, of {'perturbing_action': 'I-gene loss-of-function'}", + "109, the {'perturbing_action': 'I-gene loss-of-function'}", + "110, gene {'perturbing_action': 'I-gene loss-of-function'}", + "111, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "112, tuberous {'perturbing_action': 'I-gene loss-of-function'}", + "113, sclerosis {'perturbing_action': 'I-gene loss-of-function'}", + "114, complex-1 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "106, conditional ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "107, knockout ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "108, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "109, the ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "110, gene ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "111, encoding ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "112, tuberous ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "113, sclerosis ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "114, complex-1 ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18685594", + "TEXT": "A large multicenter study shows that lung adenocarcinomas have messenger RNA expression signatures that greatly add to the use of clinical data in predicting an individual’s survival (pages 822–827).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "18660818", + "TEXT": "Protein-in-adjuvant vaccines have shown limited success against difficult diseases such as blood-stage malaria. Here we show that a recombinant adenovirus-poxvirus prime-boost immunization regime (known to induce strong T cell immunogenicity) can also induce very strong antigen-specific antibody responses, and we identify a simple complement-based adjuvant to further enhance immunogenicity. Antibodies induced against a blood-stage malaria antigen by this viral vector platform are highly effective against Plasmodium yoelii parasites in mice and against Plasmodium falciparum in vitro.", + "TAG_DATA": [ + "65, Plasmodium {'context': 'B-organism'}", + "66, yoelii {'context': 'I-organism'}", + "67, parasites {'context': 'I-organism'}", + "69, mice {'context': 'B-organism'}", + "74, in {'context': 'B-in vitro'}", + "75, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "65, Plasmodium ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "66, yoelii ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "67, parasites ['l1', 'l7', 'l13', 'l14', 'l15', 'l16']", + "69, mice ['l2', 'l8', 'l13', 'l17', 'l18', 'l19']", + "72, Plasmodium ['l3', 'l9', 'l14', 'l17', 'l20', 'l21', 'l22']", + "73, falciparum ['l4', 'l10', 'l15', 'l18', 'l20', 'l23', 'l24']", + "74, in ['l5', 'l11', 'l21', 'l23', 'l25']", + "75, vitro. ['l6', 'l12', 'l16', 'l19', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18660816", + "TEXT": "Production of bile by the liver is crucial for the absorption of lipophilic nutrients. Dysregulation of bile acid homeostasis can lead to cholestatic liver disease and endoplasmic reticulum (ER) stress. We show by global location analysis ('ChIP-on-chip') and cell type-specific gene ablation that the winged helix transcription factor Foxa2 is required for normal bile acid homeostasis. As suggested by the location analysis, deletion of Foxa2 in hepatocytes in mice using the Cre-lox system leads to decreased transcription of genes encoding bile acid transporters on both the basolateral and canalicular membranes, resulting in intrahepatic cholestasis. Foxa2-deficient mice are strikingly sensitive to a diet containing cholic acid, which results in toxic accumulation of hepatic bile salts, ER stress and liver injury. In addition, we show that expression of FOXA2 is markedly decreased in liver samples from individuals with different cholestatic syndromes, suggesting that reduced FOXA2 abundance could exacerbate the injury.", + "TAG_DATA": [ + "62, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "63, of {'perturbing_action': 'I-gene loss-of-function'}", + "64, Foxa2 {'perturbing_action': 'I-gene loss-of-function'}", + "66, hepatocytes {'context': 'B-cells'}", + "68, mice {'context': 'B-organism'}", + "94, Foxa2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "95, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "62, deletion ['l0', 'l1', 'l2', 'l3']", + "63, of ['l0', 'l4', 'l5', 'l6']", + "64, Foxa2 ['l1', 'l4', 'l7', 'l8']", + "66, hepatocytes ['l2', 'l5', 'l7', 'l9']", + "68, mice ['l3', 'l6', 'l8', 'l9']", + "94, Foxa2-deficient ['l10']", + "95, mice ['l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Foxa2" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Foxa2", + "Foxa2-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "18660815", + "TEXT": "Pre-eclampsia affects approximately 5% of pregnancies and remains a leading cause of maternal and neonatal mortality and morbidity in the United States and the world. The clinical hallmarks of this maternal disorder include hypertension, proteinuria, endothelial dysfunction and placental defects. Advanced-stage clinical symptoms include cerebral hemorrhage, renal failure and the HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome. An effective treatment of pre-eclampsia is unavailable owing to the poor understanding of the pathogenesis of the disease. Numerous recent studies have shown that women with pre-eclampsia possess autoantibodies, termed AT(1)-AAs, that bind and activate the angiotensin II receptor type 1a (AT(1) receptor). We show here that key features of pre-eclampsia, including hypertension, proteinuria, glomerular endotheliosis (a classical renal lesion of pre-eclampsia), placental abnormalities and small fetus size appeared in pregnant mice after injection with either total IgG or affinity-purified AT(1)-AAs from women with pre-eclampsia. These features were prevented by co-injection with losartan, an AT(1) receptor antagonist, or by an antibody neutralizing seven-amino-acid epitope peptide. Thus, our studies indicate that pre-eclampsia may be a pregnancy-induced autoimmune disease in which key features of the disease result from autoantibody-induced angiotensin receptor activation. This hypothesis has obvious implications regarding pre-eclampsia screening, diagnosis and therapy.", + "TAG_DATA": [ + "129, pregnant {'context': 'B-organism'}", + "130, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "129, pregnant ['l0']", + "130, mice ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18641659", + "TEXT": "Acidification of the phagosome is considered to be a major mechanism used by macrophages against bacteria, including Mycobacterium tuberculosis (Mtb). Mtb blocks phagosome acidification, but interferon-gamma (IFN-gamma) restores acidification and confers antimycobacterial activity. Nonetheless, it remains unclear whether acid kills Mtb, whether the intrabacterial pH of any pathogen falls when it is in the phagosome and whether acid resistance is required for mycobacterial virulence. In vitro at pH 4.5, Mtb survived in a simple buffer and maintained intrabacterial pH. Therefore, Mtb resists phagolysosomal concentrations of acid. Mtb also maintained its intrabacterial pH and survived when phagocytosed by IFN-gamma-activated macrophages. We used transposon mutagenesis to identify genes responsible for Mtb's acid resistance. A strain disrupted in Rv3671c, a previously uncharacterized gene encoding a membrane-associated protein, was sensitive to acid and failed to maintain intrabacterial pH in acid in vitro and in activated macrophages. Growth of the mutant was also severely attenuated in mice. Thus, Mtb is able to resist acid, owing in large part to Rv3671c, and this resistance is essential for virulence. Disruption of Mtb's acid resistance and intrabacterial pH maintenance systems is an attractive target for chemotherapy.", + "TAG_DATA": [ + "64, In {'context': 'B-in vitro'}", + "65, vitro {'context': 'I-in vitro'}", + "113, disrupted {'perturbing_action': 'B-gene loss-of-function'}", + "114, in {'perturbing_action': 'I-gene loss-of-function'}", + "115, Rv3671c, {'perturbing_action': 'I-gene loss-of-function'}", + "136, in {'context': 'B-in vitro'}", + "137, vitro {'context': 'I-in vitro'}", + "141, macrophages. {'context': 'B-cells'}", + "151, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "64, In ['l0']", + "65, vitro ['l0']", + "113, disrupted ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "114, in ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "115, Rv3671c, ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "136, in ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "137, vitro ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "140, activated ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "141, macrophages. ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "disrupted", + "in", + "Rv3671c," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "disrupted", + "in", + "Rv3671c," + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages." + ] + } + } + ] + }, + { + "PMID": "18622403", + "TEXT": "The accurate assessment of nodal involvement in prostate cancer is crucial to planning treatment, yet there is a shortage of noninvasive imaging techniques capable of visualizing nodal lesions directly. This study demonstrates the feasibility of using recombinant human adenoviral vectors to detect nodal metastases in a human prostate cancer model. This was achieved by the prostate-restricted expression of optical and positron emission tomography (PET) imaging reporter genes by the viral vector coupled with the innate lymphotropic properties of adenovirus. We show that peritumoral administration of these vectors results in the direct detection of reporter gene expression in metastatic lesions within sentinel lymph nodes. Notably, this approach parallels the current lymphoscintigraphy method but enables the direct PET visualization of sentinel lymph node metastases, eliminating the need for invasive lymphadenectomy. These findings may lead to more effective diagnostic and therapeutic strategies for individuals with advanced-stage prostate cancer.", + "TAG_DATA": [], + "LINK_DATA": [ + "47, prostate ['l0']", + "49, model. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18542051", + "TEXT": "Monitoring immune function with molecular imaging could have a considerable impact on the diagnosis and treatment evaluation of immunological disorders and therapeutic immune responses. Positron emission tomography (PET) is a molecular imaging modality with applications in cancer and other diseases. PET studies of immune function have been limited by a lack of specialized probes. We identified [(18)F]FAC (1-(2'-deoxy-2'-[(18)F]fluoroarabinofuranosyl) cytosine) by differential screening as a new PET probe for the deoxyribonucleotide salvage pathway. [(18)F]FAC enabled visualization of lymphoid organs and was sensitive to localized immune activation in a mouse model of antitumor immunity. [(18)F]FAC microPET also detected early changes in lymphoid mass in systemic autoimmunity and allowed evaluation of immunosuppressive therapy. These data support the use of [(18)F]FAC PET for immune monitoring and suggest a wide range of clinical applications in immune disorders and in certain types of cancer.", + "TAG_DATA": [ + "77, organs {'context': 'I-tissue/organ'}", + "87, mouse {'context': 'B-organism'}", + "88, model {'context': 'I-organism'}", + "100, mass {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "87, mouse ['l0']", + "88, model ['l0']", + "99, lymphoid ['l1']", + "100, mass ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18516054", + "TEXT": "The coupling of hemoglobin sensing of physiological oxygen gradients to stimulation of nitric oxide (NO) bioactivity is an established principle of hypoxic blood flow. One mechanism proposed to explain this oxygen-sensing-NO bioactivity linkage postulates an essential role for the conserved Cys93 residue of the hemoglobin beta-chain (betaCys93) and, specifically, for S-nitrosation of betaCys93 to form S-nitrosohemoglobin (SNO-Hb). The SNO-Hb hypothesis, which conceptually links hemoglobin and NO biology, has been debated intensely in recent years. This debate has precluded a consensus on physiological mechanisms and on assessment of the potential role of SNO-Hb in pathology. Here we describe new mouse models that exclusively express either human wild-type hemoglobin or human hemoglobin in which the betaCys93 residue is replaced with alanine to assess the role of SNO-Hb in red blood cell-mediated hypoxic vasodilation. Substitution of this residue, precluding hemoglobin S-nitrosation, did not change total red blood cell S-nitrosothiol abundance but did shift S-nitrosothiol distribution to lower molecular weight species, consistent with the loss of SNO-Hb. Loss of betaCys93 resulted in no deficits in systemic or pulmonary hemodynamics under basal conditions and, notably, did not affect isolated red blood cell-dependent hypoxic vasodilation. These results demonstrate that SNO-Hb is not essential for the physiologic coupling of erythrocyte deoxygenation with increased NO bioactivity in vivo.", + "TAG_DATA": [ + "98, mouse {'context': 'B-organism'}", + "99, models {'context': 'I-organism'}", + "132, of {'perturbing_action': 'I-other'}", + "133, this {'perturbing_action': 'I-other'}", + "134, residue, {'perturbing_action': 'I-other'}", + "142, red {'context': 'B-cells'}", + "143, blood {'context': 'B-cells'}", + "144, cell {'context': 'I-cells'}", + "163, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "164, of {'perturbing_action': 'I-gene loss-of-function'}", + "165, betaCys93 {'perturbing_action': 'I-gene loss-of-function'}", + "184, red {'context': 'B-cells'}", + "185, blood {'context': 'I-cells'}", + "186, cell-dependent {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "98, mouse ['l0']", + "99, models ['l0']", + "131, Substitution ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "132, of ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "133, this ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "134, residue, ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "142, red ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "143, blood ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "144, cell ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']", + "163, Loss ['l22', 'l23', 'l24', 'l25', 'l26']", + "164, of ['l22', 'l27', 'l28', 'l29', 'l30']", + "165, betaCys93 ['l23', 'l27', 'l31', 'l32', 'l33']", + "184, red ['l24', 'l28', 'l31', 'l34', 'l35']", + "185, blood ['l25', 'l29', 'l32', 'l34', 'l36']", + "186, cell-dependent ['l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "of", + "this", + "residue," + ] + }, + "context": { + "val": "cells", + "words": [ + "red", + "blood", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Loss", + "of", + "betaCys93" + ] + }, + "context": { + "val": "cells", + "words": [ + "red", + "blood", + "cell-dependent" + ] + } + } + ] + }, + { + "PMID": "18488038", + "TEXT": "We describe a method for correlating the immunoglobulin (Ig) proteomes with the B cell transcriptomes in human fluid and tissue samples, using multiple sclerosis as a paradigm. Oligoclonal Ig bands and elevated numbers of clonally expanded B cells in the cerebrospinal fluid (CSF) are diagnostic hallmarks of multiple sclerosis. Here we compared the Ig transcriptomes of B cells with the corresponding Ig proteomes in CSF samples from four subjects with multiple sclerosis. We created individual Ig transcriptome databases that contained the subject-specific mutations introduced by V(D)J recombination and somatic hypermutation and then searched the CSF for corresponding characteristic peptides by mass spectrometry. In each sample, the Ig transcriptomes and proteomes strongly overlapped, showing that CSF B cells indeed produce the oligoclonal Ig bands. This approach can be applied to other organ-specific diagnostic fluid or tissue samples to compare the Ig transcripts of local B cells with the corresponding antibody proteomes of individual subjects.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "18488036", + "TEXT": "To understand the pathogenesis of chronic inflammatory disease, we analyzed an experimental mouse model of chronic lung disease with pathology that resembles asthma and chronic obstructive pulmonary disease (COPD) in humans. In this model, chronic lung disease develops after an infection with a common type of respiratory virus is cleared to only trace levels of noninfectious virus. Chronic inflammatory disease is generally thought to depend on an altered adaptive immune response. However, here we find that this type of disease arises independently of an adaptive immune response and is driven instead by interleukin-13 produced by macrophages that have been stimulated by CD1d-dependent T cell receptor-invariant natural killer T (NKT) cells. This innate immune axis is also activated in the lungs of humans with chronic airway disease due to asthma or COPD. These findings provide new insight into the pathogenesis of chronic inflammatory disease with the discovery that the transition from respiratory viral infection into chronic lung disease requires persistent activation of a previously undescribed NKT cell-macrophage innate immune axis.", + "TAG_DATA": [ + "95, macrophages {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "18463658", + "TEXT": "Kinase inhibitors such as imatinib (Gleevec) have improved the outlook for many patients with chronic myeloid leukemia and related blood disorders. But such drugs fail to target the leukemia stem cell population and may not be curative. Krause and Van Etten discuss several clinical studies that suggest that interferon-α may provide a solution by selectively eliminating leukemic stem cells–although only more basic research will tell us whether this is true and how it may happen.", + "TAG_DATA": [ + "57, stem {'context': 'I-transformed cells'}", + "58, cells–although {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "57, stem ['l0']", + "58, cells–although ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18438415", + "TEXT": "Although it is increasingly evident that cancer is influenced by signals emanating from tumor stroma, little is known regarding how changes in stromal gene expression affect epithelial tumor progression. We used laser capture microdissection to compare gene expression profiles of tumor stroma from 53 primary breast tumors and derived signatures strongly associated with clinical outcome. We present a new stroma-derived prognostic predictor (SDPP) that stratifies disease outcome independently of standard clinical prognostic factors and published expression-based predictors. The SDPP predicts outcome in several published whole tumor-derived expression data sets, identifies poor-outcome individuals from multiple clinical subtypes, including lymph node-negative tumors, and shows increased accuracy with respect to previously published predictors, especially for HER2-positive tumors. Prognostic power increases substantially when the predictor is combined with existing outcome predictors. Genes represented in the SDPP reveal the strong prognostic capacity of differential immune responses as well as angiogenic and hypoxic responses, highlighting the importance of stromal biology in tumor progression.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "18391962", + "TEXT": "Fourteen years after transplantation into the striatum of an individual with Parkinson's disease, grafted nigral neurons were found to have Lewy body-like inclusions that stained positively for alpha-synuclein and ubiquitin and to have reduced immunostaining for dopamine transporter. These pathological changes suggest that Parkinson's disease is an ongoing process that can affect grafted cells in the striatum in a manner similar to host dopamine neurons in the substantia nigra. These findings have implications for cell-based therapies and for understanding the cause of Parkinson's disease.", + "TAG_DATA": [ + "14, nigral {'context': 'B-cells'}", + "15, neurons {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "14, nigral ['l0']", + "15, neurons ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18391922", + "TEXT": "Science funding in the United States is tight, and the application process is arduous. A recent study of NIH peer-review recommends a major overhaul of the system. Will the changes prove cosmetic or curative?", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "18376409", + "TEXT": "Cell transplantation with embryonic stem (ES) cell progeny requires immunological compatibility with host tissue. 'Therapeutic cloning' is a strategy to overcome this limitation by generating nuclear transfer (nt)ES cells that are genetically matched to an individual. Here we establish the feasibility of treating individual mice via therapeutic cloning. Derivation of 187 ntES cell lines from 24 parkinsonian mice, dopaminergic differentiation, and transplantation into individually matched host mice showed therapeutic efficacy and lack of immunological response.", + "TAG_DATA": [ + "51, ntES {'context': 'B-cells'}", + "52, cell {'context': 'I-cells'}", + "53, lines {'context': 'I-cells'}", + "56, parkinsonian {'context': 'B-organism'}", + "57, mice, {'context': 'I-organism'}", + "59, differentiation, {'phenotype': 'I-differentiation'}", + "66, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "51, ntES ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "52, cell ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "53, lines ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "56, parkinsonian ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "57, mice, ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "59, differentiation, ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "66, mice ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "ntES", + "cell", + "lines" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "parkinsonian", + "mice,", + "mice" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + } + ] + }, + { + "PMID": "18327249", + "TEXT": "Advanced imaging techniques have become a valuable tool in the study of complex biological processes at the cellular level in biomedical research. Here, we introduce a new technical platform for noninvasive in vivo fluorescence imaging of pancreatic islets using the anterior chamber of the eye as a natural body window. Islets transplanted into the mouse eye engrafted on the iris, became vascularized, retained cellular composition, responded to stimulation and reverted diabetes. Laser-scanning microscopy allowed repetitive in vivo imaging of islet vascularization, beta cell function and death at cellular resolution. Our results thus establish the basis for noninvasive in vivo investigations of complex cellular processes, like beta cell stimulus-response coupling, which can be performed longitudinally under both physiological and pathological conditions.", + "TAG_DATA": [ + "50, Islets {'context': 'B-cells'}", + "54, mouse {'context': 'B-tissue/organ'}", + "55, eye {'context': 'I-tissue/organ'}", + "59, iris, {'context': 'I-xenograft'}", + "81, beta {'context': 'B-cells'}", + "82, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "50, Islets ['l0', 'l1', 'l2', 'l3', 'l4']", + "54, mouse ['l0', 'l5', 'l6', 'l7', 'l8']", + "55, eye ['l1', 'l5', 'l9', 'l10', 'l11']", + "57, on ['l2', 'l6', 'l9', 'l12', 'l13', 'l14']", + "58, the ['l3', 'l7', 'l10', 'l12', 'l15', 'l16']", + "59, iris, ['l4', 'l8', 'l11', 'l13', 'l15']", + "81, beta ['l17']", + "82, cell ['l14', 'l16', 'l17']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18311148", + "TEXT": "p27(Kip1) (p27) blocks cell proliferation through the inhibition of cyclin-dependent kinase-2 (Cdk2). Despite its robust expression in the heart, little is known about both the function and regulation of p27 in this and other nonproliferative tissues, in which the expression of its main target, cyclin E-Cdk2, is known to be very low. Here we show that angiotensin II, a major cardiac growth factor, induces the proteasomal degradation of p27 through protein kinase CK2-alpha'-dependent phosphorylation. Conversely, unphosphorylated p27 potently inhibits CK2-alpha'. Thus, the p27-CK2-alpha' interaction is regulated by hypertrophic signaling events and represents a regulatory feedback loop in differentiated cardiomyocytes analogous to, but distinct from, the feedback loop arising from the interaction of p27 with Cdk2 that controls cell proliferation. Our data show that extracellular growth factor signaling regulates p27 stability in postmitotic cells, and that inactivation of p27 by CK2-alpha' is crucial for agonist- and stress-induced cardiac hypertrophic growth.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "18297085", + "TEXT": "Rapid assessment of cancer response to a therapeutic regimen can determine efficacy early in the course of treatment. Although biopsies of cancer can be used to rapidly assess pharmacodynamic response, certain disease sites are less accessible to repeated biopsies. Here, we simultaneously assess response in all sites of disease within days of starting therapy by use of peptide ligands selected for their ability to discern responding from nonresponding cancers. When conjugated to near-infrared imaging agents, the HVGGSSV peptide differentiates between these two types of cancer. Rapid, noninvasive assessment of the pharmacodynamic response within cancer promises to accelerate drug development and minimize the duration of treatment with ineffective regimens in cancer patients.", + "TAG_DATA": [ + "84, cancer. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "18297084", + "TEXT": "Notch signaling is a key mechanism in the control of embryogenesis. However, its in vivo function during mesenchymal cell differentiation, and, specifically, in bone homeostasis, remains largely unknown. Here, we show that osteoblast-specific gain of Notch function causes severe osteosclerosis owing to increased proliferation of immature osteoblasts. Under these pathological conditions, Notch stimulates early osteoblastic proliferation by upregulating the genes encoding cyclin D, cyclin E and Sp7 (osterix). The intracellular domain of Notch1 also regulates terminal osteoblastic differentiation by directly binding Runx2 and repressing its transactivation function. In contrast, loss of all Notch signaling in osteoblasts, generated by deletion of the genes encoding presenilin-1 and presenilin-2 in bone, is associated with late-onset, age-related osteoporosis, which in turn results from increased osteoblast-dependent osteoclastic activity due to decreased osteoprotegerin mRNA expression in these cells. Together, these findings highlight the potential dimorphic effects of Notch signaling in bone homeostasis and may provide direction for novel therapeutic applications.", + "TAG_DATA": [ + "32, osteoblast-specific {'perturbing_action': 'B-gene gain-of-function'}", + "33, gain {'perturbing_action': 'I-gene gain-of-function'}", + "34, of {'perturbing_action': 'I-gene gain-of-function'}", + "35, Notch {'perturbing_action': 'I-gene gain-of-function'}", + "36, function {'perturbing_action': 'I-gene gain-of-function'}", + "42, increased {'effect': 'B-positive'}", + "43, proliferation {'phenotype': 'B-proliferation'}", + "45, immature {'context': 'B-cells'}", + "46, osteoblasts. {'context': 'I-cells'}", + "52, stimulates {'effect': 'B-positive'}", + "55, proliferation {'phenotype': 'B-proliferation'}", + "95, osteoblasts, {'context': 'B-cells'}", + "98, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "99, of {'perturbing_action': 'I-gene loss-of-function'}", + "100, the {'perturbing_action': 'I-gene loss-of-function'}", + "101, genes {'perturbing_action': 'I-gene loss-of-function'}", + "102, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "103, presenilin-1 {'perturbing_action': 'I-gene loss-of-function'}", + "104, and {'perturbing_action': 'I-gene loss-of-function'}", + "105, presenilin-2 {'perturbing_action': 'I-gene loss-of-function'}", + "106, in {'perturbing_action': 'I-gene loss-of-function'}", + "107, bone, {'perturbing_action': 'I-gene loss-of-function'}", + "131, cells. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "32, osteoblast-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "33, gain ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "34, of ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "35, Notch ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "36, function ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "42, increased ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "43, proliferation ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "45, immature ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "46, osteoblasts. ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "52, stimulates ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "55, proliferation ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "95, osteoblasts, ['l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "98, deletion ['l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "99, of ['l61', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "100, the ['l62', 'l71', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "101, genes ['l55', 'l63', 'l72', 'l80', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "102, encoding ['l64', 'l73', 'l81', 'l88', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "103, presenilin-1 ['l56', 'l65', 'l74', 'l82', 'l89', 'l95', 'l101', 'l102', 'l103', 'l104', 'l105']", + "104, and ['l57', 'l66', 'l75', 'l83', 'l90', 'l96', 'l101', 'l106', 'l107', 'l108', 'l109']", + "105, presenilin-2 ['l58', 'l67', 'l76', 'l84', 'l91', 'l97', 'l102', 'l106', 'l110', 'l111', 'l112']", + "106, in ['l59', 'l68', 'l77', 'l85', 'l92', 'l98', 'l103', 'l107', 'l110', 'l113', 'l114']", + "107, bone, ['l60', 'l69', 'l78', 'l86', 'l93', 'l99', 'l104', 'l108', 'l111', 'l113', 'l115']", + "131, cells. ['l70', 'l79', 'l87', 'l94', 'l100', 'l105', 'l109', 'l112', 'l114', 'l115']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "osteoblast-specific", + "gain", + "of", + "Notch", + "function" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "stimulates" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "osteoblast-specific", + "gain", + "of", + "Notch", + "function" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "osteoblast-specific", + "gain", + "of", + "Notch", + "function" + ] + }, + "context": { + "val": "cells", + "words": [ + "immature", + "osteoblasts." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased", + "stimulates" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased", + "stimulates" + ] + }, + "context": { + "val": "cells", + "words": [ + "immature", + "osteoblasts." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "immature", + "osteoblasts." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoblasts,", + "cells." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genes", + "presenilin-1", + "and", + "presenilin-2", + "in", + "bone,", + "deletion", + "of", + "the", + "encoding" + ] + } + } + ] + }, + { + "PMID": "18264108", + "TEXT": "Treatment of neuropathic pain, triggered by multiple insults to the nervous system, is a clinical challenge because the underlying mechanisms of neuropathic pain development remain poorly understood. Most treatments do not differentiate between different phases of neuropathic pain pathophysiology and simply focus on blocking neurotransmission, producing transient pain relief. Here, we report that early- and late-phase neuropathic pain development in rats and mice after nerve injury require different matrix metalloproteinases (MMPs). After spinal nerve ligation, MMP-9 shows a rapid and transient upregulation in injured dorsal root ganglion (DRG) primary sensory neurons consistent with an early phase of neuropathic pain, whereas MMP-2 shows a delayed response in DRG satellite cells and spinal astrocytes consistent with a late phase of neuropathic pain. Local inhibition of MMP-9 by an intrathecal route inhibits the early phase of neuropathic pain, whereas inhibition of MMP-2 suppresses the late phase of neuropathic pain. Further, intrathecal administration of MMP-9 or MMP-2 is sufficient to produce neuropathic pain symptoms. After nerve injury, MMP-9 induces neuropathic pain through interleukin-1beta cleavage and microglial activation at early times, whereas MMP-2 maintains neuropathic pain through interleukin-1beta cleavage and astrocyte activation at later times. Inhibition of MMP may provide a novel therapeutic approach for the treatment of neuropathic pain at different phases.", + "TAG_DATA": [ + "60, rats {'context': 'B-organism'}", + "62, mice {'context': 'B-organism'}", + "84, dorsal {'context': 'B-cells'}", + "85, root {'context': 'I-cells'}", + "86, ganglion {'context': 'I-cells'}", + "87, (DRG) {'context': 'I-cells'}", + "88, primary {'context': 'I-cells'}", + "89, sensory {'context': 'I-cells'}", + "90, neurons {'context': 'I-cells'}", + "106, DRG {'context': 'B-cells'}", + "107, satellite {'context': 'I-cells'}", + "108, cells {'context': 'I-cells'}", + "110, spinal {'context': 'B-cells'}", + "111, astrocytes {'context': 'I-cells'}", + "120, Local {'perturbing_action': 'B-pharmacological inhibition'}", + "121, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "122, of {'perturbing_action': 'I-pharmacological inhibition'}", + "123, MMP-9 {'perturbing_action': 'I-pharmacological inhibition'}", + "124, by {'perturbing_action': 'I-pharmacological inhibition'}", + "126, intrathecal {'perturbing_action': 'I-pharmacological inhibition'}", + "127, route {'perturbing_action': 'I-pharmacological inhibition'}", + "136, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "137, of {'perturbing_action': 'I-pharmacological inhibition'}", + "138, MMP-2 {'perturbing_action': 'I-pharmacological inhibition'}", + "185, astrocyte {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "60, rats ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "62, mice ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "84, dorsal ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "85, root ['l2', 'l9', 'l15', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "86, ganglion ['l3', 'l10', 'l16', 'l26', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "87, (DRG) ['l4', 'l11', 'l17', 'l27', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "88, primary ['l5', 'l12', 'l18', 'l28', 'l37', 'l45', 'l53', 'l54', 'l55']", + "89, sensory ['l6', 'l13', 'l19', 'l29', 'l38', 'l46', 'l53', 'l56', 'l57']", + "90, neurons ['l7', 'l14', 'l20', 'l30', 'l39', 'l47', 'l54', 'l56']", + "106, DRG ['l21', 'l31', 'l40', 'l48', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "107, satellite ['l22', 'l32', 'l41', 'l49', 'l58', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "108, cells ['l23', 'l33', 'l42', 'l50', 'l55', 'l57', 'l59', 'l66', 'l72', 'l73']", + "110, spinal ['l24', 'l34', 'l43', 'l51', 'l60', 'l67', 'l72', 'l74', 'l75', 'l76', 'l77', 'l78']", + "111, astrocytes ['l25', 'l35', 'l44', 'l52', 'l61', 'l68', 'l73', 'l74', 'l79', 'l80', 'l81', 'l82']", + "120, Local ['l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "121, inhibition ['l83', 'l89', 'l90', 'l91', 'l92', 'l93']", + "122, of ['l84', 'l89', 'l94', 'l95', 'l96', 'l97']", + "123, MMP-9 ['l62', 'l69', 'l75', 'l79', 'l85', 'l90', 'l94', 'l98', 'l99', 'l100']", + "124, by ['l63', 'l70', 'l76', 'l80', 'l86', 'l91', 'l95', 'l98', 'l101', 'l102']", + "126, intrathecal ['l64', 'l77', 'l81', 'l87', 'l92', 'l96', 'l99', 'l101', 'l103']", + "127, route ['l65', 'l71', 'l78', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l103']", + "136, inhibition ['l104', 'l105']", + "137, of ['l104', 'l106']", + "138, MMP-2 ['l105', 'l106']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "DRG", + "satellite", + "spinal", + "astrocytes" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "MMP-9", + "by", + "intrathecal", + "route" + ] + } + } + ] + }, + { + "PMID": "18193057", + "TEXT": "Interactions between the herpesvirus entry mediator (HVEM) and the B- and T-lymphocyte attenuator (BTLA) inhibit B and T cell activation. HVEM-BTLA interactions are blocked by herpes simplex virus (HSV) glycoprotein D (gD) through binding of its N-terminal domain to the BTLA binding site of HVEM. In this study, we inserted viral antigens into the C-terminal domain of gD and expressed these antigens with plasmid or E1-deleted (replication-defective) adenovirus vectors. Viral antigens fused to gD induced T and B cell responses to the antigen that were far more potent than those elicited by the same antigen expressed without gD. The immunopotentiating effect required binding of the gD chimeric protein to HVEM. Overall, the studies demonstrate that targeting of antigen to the BTLA binding site of HVEM augments the immunogenicity of vaccines.", + "TAG_DATA": [ + "65, E1-deleted {'perturbing_action': 'B-gene loss-of-function'}", + "66, (replication-defective) {'perturbing_action': 'I-gene loss-of-function'}", + "75, T {'context': 'B-cells'}", + "76, and {'context': 'B-cells'}", + "77, B {'context': 'I-cells'}", + "78, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "65, E1-deleted ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "66, (replication-defective) ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "67, adenovirus ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "68, vectors. ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "75, T ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "76, and ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "77, B ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "78, cell ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "E1-deleted", + "(replication-defective)" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "and", + "B", + "cell" + ] + } + } + ] + }, + { + "PMID": "18157139", + "TEXT": "IL-17A is a T cell-specific cytokine that is involved in chronic inflammations, such as Mycobacterium infection, Crohn's disease, rheumatoid arthritis and multiple sclerosis. Mouse models have explained the molecular basis of IL-17A production and have shown that IL-17A has a positive effect not only on granuloma formation and neurodegeneration through unknown mechanisms, but also on bone resorption through Receptor activator of NF-kappaB ligand (RANKL) induction in osteoblasts. Langerhans cell histiocytosis (LCH) is a rare disease of unknown etiology, lacking an animal model, that cumulates symptoms that are found separately in various IL-17A-related diseases, such as aggressive chronic granuloma formation, bone resorption and soft tissue lesions with occasional neurodegeneration. We examined IL-17A in the context of LCH and found that there were high serum levels of IL-17A during active LCH and unexpected IL-17A synthesis by dendritic cells (DCs), the major cell type in LCH lesions. We also found an IL-17A-dependent pathway for DC fusion, which was highly potentiated by IFN-gamma and led to giant cells expressing three major tissue-destructive enzymes: tartrate resistant acidic phosphatase and matrix metalloproteinases 9 and 12. IFN-gamma expression has been previously documented in LCH and observed in IL-17A-related diseases. Notably, serum IL-17A-dependent fusion activity correlates with LCH activity. Thus, IL-17A and IL-17A-stimulated DCs represent targets that may have clinical value in the treatment of LCH and other IL-17A-related inflammatory disorders.", + "TAG_DATA": [ + "162, giant {'context': 'B-cells'}", + "163, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "162, giant ['l0']", + "163, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18157138", + "TEXT": "Recent successes in treating genetic immunodeficiencies have demonstrated the therapeutic potential of stem cell gene therapy. However, the use of gammaretroviral vectors in these trials led to insertional activation of nearby oncogenes and leukemias in some study subjects, prompting studies of modified or alternative vector systems. Here we describe the use of foamy virus vectors to treat canine leukocyte adhesion deficiency (CLAD). Four of five dogs with CLAD that received nonmyeloablative conditioning and infusion of autologous, CD34+ hematopoietic stem cells transduced by a foamy virus vector expressing canine CD18 had complete reversal of the CLAD phenotype, which was sustained more than 2 years after infusion. In vitro assays showed correction of the lymphocyte proliferation and neutrophil adhesion defects that characterize CLAD. There were no genotoxic complications, and integration site analysis showed polyclonality of transduced cells and a decreased risk of integration near oncogenes as compared to gammaretroviral vectors. These results represent the first successful use of a foamy virus vector to treat a genetic disease, to our knowledge, and suggest that foamy virus vectors will be effective in treating human hematopoietic diseases.", + "TAG_DATA": [ + "65, dogs {'context': 'B-organism'}", + "75, autologous, {'perturbing_action': 'I-gene gain-of-function'}", + "76, CD34+ {'context': 'I-cells'}", + "77, hematopoietic {'context': 'I-cells'}", + "78, stem {'context': 'I-cells'}", + "79, cells {'context': 'I-cells'}", + "80, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "81, by {'perturbing_action': 'I-gene gain-of-function'}", + "82, a {'perturbing_action': 'I-gene gain-of-function'}", + "83, foamy {'perturbing_action': 'I-gene gain-of-function'}", + "84, virus {'perturbing_action': 'I-gene gain-of-function'}", + "85, vector {'perturbing_action': 'I-gene gain-of-function'}", + "86, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "87, canine {'perturbing_action': 'I-gene gain-of-function'}", + "88, CD18 {'perturbing_action': 'I-gene gain-of-function'}", + "105, In {'context': 'B-in vitro'}", + "106, vitro {'context': 'I-in vitro'}", + "109, correction {'effect': 'B-regulates'}", + "112, lymphocyte {'context': 'B-cells'}", + "113, proliferation {'phenotype': 'B-proliferation'}", + "116, adhesion {'phenotype': 'B-adhesion'}", + "134, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "65, dogs ['l0', 'l1', 'l2']", + "75, autologous, ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "76, CD34+ ['l3', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "77, hematopoietic ['l0', 'l4', 'l19', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "78, stem ['l1', 'l5', 'l20', 'l36', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "79, cells ['l2', 'l6', 'l21', 'l37', 'l51', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "80, transduced ['l7', 'l22', 'l38', 'l52', 'l64', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "81, by ['l8', 'l23', 'l39', 'l53', 'l65', 'l76', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "82, a ['l9', 'l24', 'l40', 'l54', 'l66', 'l77', 'l90', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "83, foamy ['l10', 'l25', 'l41', 'l55', 'l67', 'l78', 'l91', 'l103', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "84, virus ['l11', 'l26', 'l42', 'l56', 'l68', 'l79', 'l92', 'l104', 'l115', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "85, vector ['l12', 'l27', 'l43', 'l57', 'l69', 'l80', 'l93', 'l105', 'l116', 'l126', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "86, expressing ['l13', 'l28', 'l44', 'l58', 'l70', 'l81', 'l94', 'l106', 'l117', 'l127', 'l136', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "87, canine ['l14', 'l29', 'l45', 'l59', 'l71', 'l82', 'l95', 'l107', 'l118', 'l128', 'l137', 'l145', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159']", + "88, CD18 ['l15', 'l30', 'l46', 'l60', 'l72', 'l83', 'l96', 'l108', 'l119', 'l129', 'l138', 'l146', 'l153', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "105, In ['l84', 'l97', 'l109', 'l120', 'l130', 'l139', 'l147', 'l154', 'l160', 'l166', 'l167', 'l168', 'l169', 'l170']", + "106, vitro ['l31', 'l85', 'l98', 'l110', 'l121', 'l131', 'l140', 'l148', 'l155', 'l161', 'l166', 'l171', 'l172', 'l173', 'l174']", + "109, correction ['l32', 'l47', 'l86', 'l99', 'l111', 'l122', 'l132', 'l141', 'l149', 'l156', 'l162', 'l167', 'l171', 'l175', 'l176', 'l177']", + "112, lymphocyte ['l16', 'l33', 'l48', 'l61', 'l73', 'l87', 'l100', 'l112', 'l123', 'l133', 'l142', 'l150', 'l157', 'l163', 'l168', 'l172', 'l175', 'l178', 'l179']", + "113, proliferation ['l17', 'l34', 'l49', 'l62', 'l74', 'l88', 'l101', 'l113', 'l124', 'l134', 'l143', 'l151', 'l158', 'l164', 'l169', 'l173', 'l176', 'l178', 'l180']", + "116, adhesion ['l18', 'l35', 'l50', 'l63', 'l75', 'l89', 'l102', 'l114', 'l125', 'l135', 'l144', 'l152', 'l159', 'l165', 'l170', 'l174', 'l177', 'l179', 'l180']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "autologous,", + "transduced", + "by", + "a", + "foamy", + "virus", + "vector", + "expressing", + "canine", + "CD18" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD34+", + "hematopoietic", + "stem", + "cells", + "lymphocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "autologous,", + "transduced", + "by", + "a", + "foamy", + "virus", + "vector", + "expressing", + "canine", + "CD18" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "autologous,", + "transduced", + "by", + "a", + "foamy", + "virus", + "vector", + "expressing", + "canine", + "CD18" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD34+", + "hematopoietic", + "lymphocyte" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "correction" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD34+", + "hematopoietic", + "stem", + "cells", + "lymphocyte" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD34+", + "hematopoietic", + "stem", + "cells", + "lymphocyte" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "by", + "a", + "foamy", + "virus", + "vector", + "expressing", + "canine", + "CD18" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "by", + "a", + "foamy", + "virus", + "vector", + "expressing", + "canine", + "CD18" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "correction" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "correction" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "correction" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "correction" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + } + ] + }, + { + "PMID": "18084301", + "TEXT": "Podocyte dysfunction, represented by foot process effacement and proteinuria, is often the starting point for progressive kidney disease. Therapies aimed at the cellular level of the disease are currently not available. Here we show that induction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement and urinary protein loss via a mechanism that includes lipid-dependent activation of alphavbeta3 integrin. Mice lacking uPAR (Plaur-/-) are protected from lipopolysaccharide (LPS)-mediated proteinuria but develop disease after expression of a constitutively active beta3 integrin. Gene transfer studies reveal a prerequisite for uPAR expression in podocytes, but not in endothelial cells, for the development of LPS-mediated proteinuria. Mechanistically, uPAR is required to activate alphavbeta3 integrin in podocytes, promoting cell motility and activation of the small GTPases Cdc42 and Rac1. Blockade of alphavbeta3 integrin reduces podocyte motility in vitro and lowers proteinuria in mice. Our findings show a physiological role for uPAR signaling in the regulation of kidney permeability.", + "TAG_DATA": [ + "62, Mice {'context': 'B-organism'}", + "63, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "64, uPAR {'perturbing_action': 'I-gene loss-of-function'}", + "65, (Plaur-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "114, podocytes, {'context': 'B-cells'}", + "115, promoting {'effect': 'B-positive'}", + "116, cell {'context': 'B-cells'}", + "117, motility {'phenotype': 'B-migration'}", + "127, Blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "128, of {'perturbing_action': 'I-pharmacological inhibition'}", + "129, alphavbeta3 {'perturbing_action': 'I-pharmacological inhibition'}", + "130, integrin {'perturbing_action': 'I-pharmacological inhibition'}", + "131, reduces {'effect': 'B-negative'}", + "132, podocyte {'context': 'B-cells'}", + "134, in {'context': 'B-in vitro'}", + "135, vitro {'context': 'I-in vitro'}", + "140, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "62, Mice ['l0', 'l1', 'l2']", + "63, lacking ['l0', 'l3', 'l4']", + "64, uPAR ['l1', 'l3', 'l5']", + "65, (Plaur-/-) ['l2', 'l4', 'l5']", + "114, podocytes, ['l6', 'l7', 'l8', 'l9']", + "115, promoting ['l6', 'l10', 'l11']", + "116, cell ['l7', 'l10', 'l12']", + "117, motility ['l8', 'l11', 'l12']", + "127, Blockade ['l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "128, of ['l13', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "129, alphavbeta3 ['l14', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "130, integrin ['l15', 'l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "131, reduces ['l9', 'l16', 'l23', 'l29', 'l34', 'l39', 'l40', 'l41']", + "132, podocyte ['l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l43', 'l44']", + "134, in ['l18', 'l25', 'l31', 'l36', 'l40', 'l42', 'l45']", + "135, vitro ['l19', 'l26', 'l32', 'l37', 'l41', 'l43', 'l45']", + "140, mice. ['l20', 'l27', 'l33', 'l38', 'l44']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "uPAR", + "(Plaur-/-)" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "podocytes,", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "podocytes,", + "cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "motility" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "podocytes,", + "podocyte" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "motility" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "alphavbeta3", + "integrin" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "alphavbeta3", + "integrin" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocyte" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "alphavbeta3", + "integrin" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "alphavbeta3", + "integrin" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "18066076", + "TEXT": "In many common cancers, dissemination of secondary tumors via the lymph nodes poses the most significant threat to the affected individual. Metastatic cells often reach the lymph nodes by mimicking the molecular mechanisms used by hematopoietic cells to traffic to peripheral lymphoid organs. Therefore, we exploited naive T cell trafficking in order to chaperone an oncolytic virus to lymphoid organs harboring metastatic cells. Metastatic burden was initially reduced by viral oncolysis and was then eradicated, as tumor cell killing in the lymph node and spleen generated protective antitumor immunity. Lymph node purging of tumor cells was possible even in virus-immune mice. Adoptive transfer of normal T cells loaded with oncolytic virus into individuals with cancer would be technically easy to implement both to reduce the distribution of metastases and to vaccinate the affected individual in situ against micrometastatic disease. As such, this adoptive transfer could have a great therapeutic impact, in the adjuvant setting, on many different cancer types.", + "TAG_DATA": [ + "63, Metastatic {'phenotype': 'B-metastasis'}", + "64, burden {'phenotype': 'I-metastasis'}", + "67, reduced {'effect': 'B-negative'}", + "76, tumor {'context': 'B-transformed cells'}", + "77, cell {'context': 'I-transformed cells'}", + "81, lymph {'context': 'B-tissue/organ'}", + "82, node {'context': 'B-tissue/organ'}", + "84, spleen {'context': 'B-tissue/organ'}", + "93, tumor {'context': 'B-transformed cells'}", + "94, cells {'context': 'I-transformed cells'}", + "100, mice. {'context': 'B-organism'}", + "104, normal {'context': 'B-cells'}", + "105, T {'context': 'I-cells'}", + "106, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "63, Metastatic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "64, burden ['l0', 'l7', 'l8', 'l9', 'l10']", + "67, reduced ['l1', 'l7', 'l11', 'l12', 'l13', 'l14']", + "76, tumor ['l2', 'l8', 'l11', 'l15', 'l16', 'l17', 'l18']", + "77, cell ['l3', 'l9', 'l12', 'l15', 'l19', 'l20', 'l21']", + "81, lymph ['l4', 'l13', 'l16', 'l19', 'l22', 'l23']", + "82, node ['l5', 'l10', 'l14', 'l17', 'l20', 'l22', 'l24']", + "84, spleen ['l6', 'l18', 'l21', 'l23', 'l24']", + "93, tumor ['l25', 'l26']", + "94, cells ['l25', 'l27']", + "100, mice. ['l26', 'l27']", + "104, normal ['l28', 'l29']", + "105, T ['l28', 'l30']", + "106, cells ['l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "metastasis", + "words": [ + "Metastatic", + "burden" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "Metastatic", + "burden" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "Metastatic", + "burden" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lymph", + "node", + "spleen" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lymph", + "node" + ] + } + } + ] + }, + { + "PMID": "18066074", + "TEXT": "A major challenge in transplantation medicine is controlling the very strong immune responses to foreign antigens that are responsible for graft rejection. Although immunosuppressive drugs efficiently inhibit acute graft rejection, a substantial proportion of patients suffer chronic rejection that ultimately leads to functional loss of the graft. Induction of immunological tolerance to transplants would avoid rejection and the need for lifelong treatment with immunosuppressive drugs. Tolerance to self-antigens is ensured naturally by several mechanisms; one major mechanism depends on the activity of regulatory T lymphocytes. Here we show that in mice treated with clinically acceptable levels of irradiation, regulatory CD4+CD25+Foxp3+ T cells stimulated in vitro with alloantigens induced long-term tolerance to bone marrow and subsequent skin and cardiac allografts. Regulatory T cells specific for directly presented donor antigens prevented only acute rejection, despite hematopoietic chimerism. By contrast, regulatory T cells specific for both directly and indirectly presented alloantigens prevented both acute and chronic rejection. Our findings demonstrate the potential of appropriately stimulated regulatory T cells for future cell-based therapeutic approaches to induce lifelong immunological tolerance to allogeneic transplants.", + "TAG_DATA": [ + "90, mice {'context': 'B-organism'}", + "98, regulatory {'context': 'B-cells'}", + "99, CD4+CD25+Foxp3+ {'context': 'I-cells'}", + "100, T {'context': 'I-cells'}", + "101, cells {'context': 'I-cells'}", + "103, in {'context': 'B-in vitro'}", + "104, vitro {'context': 'I-in vitro'}", + "115, skin {'context': 'B-xenograft'}", + "116, and {'context': 'I-xenograft'}", + "117, cardiac {'context': 'I-xenograft'}", + "118, allografts. {'context': 'I-xenograft'}", + "119, Regulatory {'context': 'B-cells'}", + "120, T {'context': 'I-cells'}", + "121, cells {'context': 'I-cells'}", + "137, regulatory {'context': 'B-cells'}", + "138, T {'context': 'I-cells'}", + "139, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "90, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "98, regulatory ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "99, CD4+CD25+Foxp3+ ['l1', 'l10', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "100, T ['l2', 'l11', 'l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "101, cells ['l3', 'l12', 'l21', 'l29', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "103, in ['l13', 'l22', 'l30', 'l37', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "104, vitro ['l4', 'l14', 'l23', 'l31', 'l38', 'l44', 'l50', 'l51', 'l52', 'l53', 'l54']", + "112, marrow ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l55', 'l56', 'l57', 'l58']", + "115, skin ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l59', 'l60', 'l61']", + "116, and ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l62', 'l63']", + "117, cardiac ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l62', 'l64']", + "118, allografts. ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l64']", + "119, Regulatory ['l65', 'l66']", + "120, T ['l65', 'l67']", + "121, cells ['l66', 'l67']", + "137, regulatory ['l68', 'l69']", + "138, T ['l68', 'l70']", + "139, cells ['l69', 'l70']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18064037", + "TEXT": "A major problem in hepatitis C virus (HCV) immunotherapy or vaccine design is the extreme variability of the virus. We identified human monoclonal antibodies (mAbs) that neutralize genetically diverse HCV isolates and protect against heterologous HCV quasispecies challenge in a human liver-chimeric mouse model. The results provide evidence that broadly neutralizing antibodies to HCV protect against heterologous viral infection and suggest that a prophylactic vaccine against HCV may be achievable.", + "TAG_DATA": [ + "40, human {'context': 'B-organism'}", + "41, liver-chimeric {'context': 'I-organism'}", + "42, mouse {'context': 'I-organism'}", + "43, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "40, human ['l0', 'l1', 'l2']", + "41, liver-chimeric ['l0', 'l3', 'l4']", + "42, mouse ['l1', 'l3', 'l5']", + "43, model. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "18037895", + "TEXT": "Metastasis is the primary cause of mortality from cancer, but the mechanisms leading to metastasis are poorly understood. In particular, relatively little is known about metastasis in cancers of mesenchymal origins, which are known as sarcomas. Approximately ten proteins have been characterized as 'metastasis suppressors', but how these proteins function and are regulated is, in general, not well understood. Gp78 (also known as AMFR or RNF45) is a RING finger E3 ubiquitin ligase that is integral to the endoplasmic reticulum (ER) and involved in ER-associated degradation (ERAD) of diverse substrates. Here we report that expression of gp78 has a causal role in the metastasis of an aggressive human sarcoma and that this prometastatic activity requires the E3 activity of gp78. Further, gp78 associates with and targets the transmembrane metastasis suppressor, KAI1 (also known as CD82), for degradation. Suppression of gp78 increases KAI1 abundance and reduces the metastatic potential of tumor cells, an effect that is largely blocked by concomitant suppression of KAI1. An inverse relationship between these proteins was confirmed in a human sarcoma tissue microarray. Whereas most previous efforts have focused on genetic mechanisms for the loss of metastasis suppressor genes, our results provide new evidence for post-translational downregulation of a metastasis suppressor by its ubiquitin ligase, resulting in abrogation of its metastasis-suppressing effects.", + "TAG_DATA": [ + "137, Suppression {'perturbing_action': 'B-pharmacological inhibition'}", + "138, of {'perturbing_action': 'I-pharmacological inhibition'}", + "139, gp78 {'perturbing_action': 'I-pharmacological inhibition'}", + "144, reduces {'effect': 'B-negative'}", + "146, metastatic {'phenotype': 'B-metastasis'}", + "147, potential {'phenotype': 'I-metastasis'}", + "149, tumor {'context': 'B-transformed cells'}", + "150, cells, {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "137, Suppression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "138, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "139, gp78 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "144, reduces ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "146, metastatic ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "147, potential ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "149, tumor ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "150, cells, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Suppression", + "of", + "gp78" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Suppression", + "of", + "gp78" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "potential" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Suppression", + "of", + "gp78" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "potential" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells," + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "potential" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells," + ] + } + } + ] + }, + { + "PMID": "18026114", + "TEXT": "We found that the proteome of apoptotic T cells includes prominent fragments of cellular proteins generated by caspases and that a high proportion of distinct T cell epitopes in these fragments is recognized by CD8+ T cells during HIV infection. The frequencies of effector CD8+ T cells that are specific for apoptosis-dependent epitopes correlate with the frequency of circulating apoptotic CD4+ T cells in HIV-1-infected individuals. We propose that these self-reactive effector CD8+ T cells may contribute to the systemic immune activation during chronic HIV infection. The caspase-dependent cleavage of proteins associated with apoptotic cells has a key role in the induction of self-reactive CD8+ T cell responses, as the caspase-cleaved fragments are efficiently targeted to the processing machinery and are cross-presented by dendritic cells. These findings demonstrate a previously undescribed role for caspases in immunopathology.", + "TAG_DATA": [ + "43, effector {'context': 'B-cells'}", + "44, CD8+ {'context': 'I-cells'}", + "45, T {'context': 'I-cells'}", + "46, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "43, effector ['l0', 'l1', 'l2']", + "44, CD8+ ['l0', 'l3', 'l4']", + "45, T ['l1', 'l3', 'l5']", + "46, cells ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17982463", + "TEXT": "T helper cells can support the functions of CD8(+) T cells against persistently infecting viruses such as murine lymphocytic choriomeningitis virus (LCMV), cytomegalovirus, hepatitis C virus and HIV. These viruses often resist complete elimination and remain detectable at sanctuary sites, such as the kidneys and other extralymphatic organs. The mechanisms underlying this persistence are not well understood. Here we show that mice with potent virus-specific T-cell responses have reduced levels and delayed formation of neutralizing antibodies, and these mice fail to clear LCMV from extralymphatic epithelia. Transfer of virus-specific B cells but not virus-specific T cells augmented virus clearance from persistent sites. Virus elimination from the kidneys was associated with the formation of IgG deposits in the interstitial space, presumably from kidney-infiltrating B cells. CD8(+) T cells in the kidneys of mice that did not clear virus from this site were activated but showed evidence of exhaustion. Thus, we conclude that in this model of infection, site-specific virus persistence develops as a consequence of potent immune activation coupled with reductions in virus-specific neutralizing antibodies. Our results suggest that sanctuary-site formation depends both on organ anatomy and on the induction of different adaptive immune effector mechanisms. Boosting T-cell responses alone may not reduce virus persistence.", + "TAG_DATA": [ + "61, mice {'context': 'B-organism'}", + "78, mice {'context': 'B-organism'}", + "89, B {'context': 'I-cells'}", + "90, cells {'context': 'I-cells'}", + "93, virus-specific {'context': 'B-cells'}", + "94, T {'context': 'I-cells'}", + "95, cells {'context': 'I-cells'}", + "106, kidneys {'context': 'B-tissue/organ'}", + "124, CD8(+) {'context': 'B-cells'}", + "125, T {'context': 'I-cells'}", + "126, cells {'context': 'I-cells'}", + "129, kidneys {'context': 'B-tissue/organ'}", + "131, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "61, mice ['l0']", + "78, mice ['l0']", + "89, B ['l1', 'l2', 'l3', 'l4', 'l5']", + "90, cells ['l1', 'l6', 'l7', 'l8']", + "93, virus-specific ['l2', 'l9', 'l10', 'l11']", + "94, T ['l3', 'l6', 'l9', 'l12', 'l13']", + "95, cells ['l4', 'l7', 'l10', 'l12', 'l14']", + "106, kidneys ['l5', 'l8', 'l11', 'l13', 'l14']", + "124, CD8(+) ['l15', 'l16', 'l17', 'l18']", + "125, T ['l15', 'l19', 'l20', 'l21']", + "126, cells ['l16', 'l19', 'l22', 'l23']", + "129, kidneys ['l17', 'l20', 'l22', 'l24']", + "131, mice ['l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17965721", + "TEXT": "We found that an induction immunotherapy regimen consisting of rabbit anti-thymocyte globulin (Thymoglobulin) and the monoclonal antibody to CD20 rituximab (Rituxan) promoted long-term islet allograft survival in cynomolgus macaques maintained on rapamycin monotherapy. B lymphocyte reconstitution after rituximab-mediated depletion was characterized by a preponderance of immature and transitional cells, whose persistence was associated with long-term islet allograft survival. Development of donor-specific alloantibodies was abrogated only in the setting of continued rapamycin monotherapy.", + "TAG_DATA": [ + "23, islet {'context': 'B-xenograft'}", + "24, allograft {'context': 'I-xenograft'}", + "27, cynomolgus {'context': 'B-organism'}", + "28, macaques {'context': 'I-organism'}", + "33, B {'context': 'B-cells'}", + "34, lymphocyte {'context': 'I-cells'}", + "45, immature {'context': 'B-cells'}", + "46, and {'context': 'I-cells'}", + "47, transitional {'context': 'I-cells'}", + "48, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "23, islet ['l0', 'l1', 'l2']", + "24, allograft ['l0', 'l3', 'l4']", + "27, cynomolgus ['l1', 'l3', 'l5', 'l6', 'l7', 'l8', 'l9']", + "28, macaques ['l2', 'l4', 'l5', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "33, B ['l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "34, lymphocyte ['l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "45, immature ['l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "46, and ['l6', 'l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "47, transitional ['l14', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "48, cells, ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "55, islet ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "56, allograft ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17965720", + "TEXT": "Autosomal dominant polycystic kidney disease is an important cause of end-stage renal disease, for which there is no proven therapy. Mutations in PKD1 (the gene encoding polycystin-1) are the principal cause of this disease. The disease begins in utero and is slowly progressive, but it is not known whether cystogenesis is an ongoing process during adult life. We now show that inactivation of Pkd1 in mice before postnatal day 13 results in severely cystic kidneys within 3 weeks, whereas inactivation at day 14 and later results in cysts only after 5 months. We found that cellular proliferation was not appreciably higher in cystic specimens than in age-matched controls, but the abrupt change in response to Pkd1 inactivation corresponded to a previously unrecognized brake point during renal growth and significant changes in gene expression. These findings suggest that the effects of Pkd1 inactivation are defined by a developmental switch that signals the end of the terminal renal maturation process. Our studies show that Pkd1 regulates tubular morphology in both developing and adult kidney, but the pathologic consequences of inactivation are defined by the organ's developmental status. These results have important implications for clinical understanding of the disease and therapeutic approaches.", + "TAG_DATA": [ + "61, inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "62, of {'perturbing_action': 'I-gene loss-of-function'}", + "63, Pkd1 {'perturbing_action': 'I-gene loss-of-function'}", + "65, mice {'context': 'B-organism'}", + "74, kidneys {'context': 'B-tissue/organ'}", + "96, proliferation {'phenotype': 'B-proliferation'}", + "115, Pkd1 {'perturbing_action': 'B-gene loss-of-function'}", + "116, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "140, Pkd1 {'perturbing_action': 'B-gene loss-of-function'}", + "141, inactivation {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "61, inactivation ['l0', 'l1', 'l2', 'l3']", + "62, of ['l0', 'l4', 'l5', 'l6']", + "63, Pkd1 ['l1', 'l4', 'l7', 'l8']", + "65, mice ['l2', 'l5', 'l7', 'l9']", + "74, kidneys ['l3', 'l6', 'l8', 'l9']", + "115, Pkd1 ['l10']", + "116, inactivation ['l10']", + "140, Pkd1 ['l11']", + "141, inactivation ['l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "Pkd1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "Pkd1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidneys" + ] + } + } + ] + }, + { + "PMID": "17934472", + "TEXT": "A molecular test for Alzheimer's disease could lead to better treatment and therapies. We found 18 signaling proteins in blood plasma that can be used to classify blinded samples from Alzheimer's and control subjects with close to 90% accuracy and to identify patients who had mild cognitive impairment that progressed to Alzheimer's disease 2-6 years later. Biological analysis of the 18 proteins points to systemic dysregulation of hematopoiesis, immune responses, apoptosis and neuronal support in presymptomatic Alzheimer's disease.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17922010", + "TEXT": "Histone/protein deacetylases (HDACs) regulate chromatin remodeling and gene expression as well as the functions of more than 50 transcription factors and nonhistone proteins. We found that administration of an HDAC inhibitor (HDACi) in vivo increased Foxp3 gene expression, as well as the production and suppressive function of regulatory T cells (T(reg) cells). Although T(reg) cells express multiple HDACs, HDAC9 proved particularly important in regulating Foxp3-dependent suppression. Optimal T(reg) function required acetylation of several lysines in the forkhead domain of Foxp3, and Foxp3 acetylation enhanced binding of Foxp3 to the Il2 promoter and suppressed endogenous IL-2 production. HDACi therapy in vivo enhanced T(reg)-mediated suppression of homeostatic proliferation, decreased inflammatory bowel disease through T(reg)-dependent effects, and, in conjunction with a short course of low-dose rapamycin, induced permanent, T(reg)-dependent cardiac and islet allograft survival and donor-specific allograft tolerance. Our data show that use of HDACi allows the beneficial pharmacologic enhancement of both the numbers and suppressive function of Foxp3(+) T(reg) cells.", + "TAG_DATA": [ + "32, in {'context': 'B-in vivo'}", + "33, vivo {'context': 'I-in vivo'}", + "47, regulatory {'context': 'B-cells'}", + "48, T {'context': 'I-cells'}", + "49, cells {'context': 'I-cells'}", + "50, (T(reg) {'context': 'I-cells'}", + "51, cells). {'context': 'I-cells'}", + "98, in {'context': 'B-in vivo'}", + "99, vivo {'context': 'I-in vivo'}", + "105, proliferation, {'phenotype': 'B-proliferation'}", + "126, cardiac {'context': 'B-xenograft'}", + "127, and {'context': 'I-xenograft'}", + "128, islet {'context': 'I-xenograft'}", + "129, allograft {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "32, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "33, vivo ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "47, regulatory ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "48, T ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "49, cells ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "50, (T(reg) ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "51, cells). ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "98, in ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "99, vivo ['l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "102, suppression ['l22', 'l28', 'l34']", + "105, proliferation, ['l23', 'l29', 'l34']", + "126, cardiac ['l24', 'l30', 'l35', 'l36', 'l37', 'l38']", + "127, and ['l25', 'l31', 'l35', 'l39', 'l40', 'l41']", + "128, islet ['l26', 'l32', 'l36', 'l39', 'l42', 'l43']", + "129, allograft ['l27', 'l33', 'l37', 'l40', 'l42', 'l44']", + "133, allograft ['l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + } + ] + }, + { + "PMID": "17906634", + "TEXT": "Demyelinating diseases, such as multiple sclerosis, are characterized by the loss of the myelin sheath around neurons, owing to inflammation and gliosis in the central nervous system (CNS). Current treatments therefore target anti-inflammatory mechanisms to impede or slow disease progression. The identification of a means to enhance axon myelination would present new therapeutic approaches to inhibit and possibly reverse disease progression. Previously, LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1) has been identified as an in vitro and in vivo negative regulator of oligodendrocyte differentiation and myelination. Here we show that loss of LINGO-1 function by Lingo1 gene knockout or by treatment with an antibody antagonist of LINGO-1 function leads to functional recovery from experimental autoimmune encephalomyelitis. This is reflected biologically by improved axonal integrity, as confirmed by magnetic resonance diffusion tensor imaging, and by newly formed myelin sheaths, as determined by electron microscopy. Antagonism of LINGO-1 or its pathway is therefore a promising approach for the treatment of demyelinating diseases of the CNS.", + "TAG_DATA": [ + "91, loss {'perturbing_action': 'B-gene loss-of-function'}", + "92, of {'perturbing_action': 'I-gene loss-of-function'}", + "93, LINGO-1 {'perturbing_action': 'I-gene loss-of-function'}", + "94, function {'perturbing_action': 'I-gene loss-of-function'}", + "96, Lingo1 {'perturbing_action': 'B-gene loss-of-function'}", + "97, gene {'perturbing_action': 'I-gene loss-of-function'}", + "98, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "105, antagonist {'perturbing_action': 'I-pharmacological inhibition'}", + "107, LINGO-1 {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "91, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "92, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "93, LINGO-1 ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "94, function ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "96, Lingo1 ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "97, gene ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "98, knockout ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "105, antagonist ['l21', 'l22', 'l23']", + "106, of ['l21', 'l24', 'l25']", + "107, LINGO-1 ['l22', 'l24', 'l26']", + "108, function ['l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17828203", + "TEXT": "The US should revamp rules on informed consent to ensure that people have all of the information and support they need before deciding to enroll in clinical trials.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17721546", + "TEXT": "We have identified several patient sera showing potent and broad HIV-1 neutralization. Using antibody adsorption and elution from selected gp120 variants, the neutralizing specificities of the two most broadly reactive sera were mapped to the primary receptor CD4-binding region of HIV-1 gp120. Novel antibodies to the CD4-binding site are elicited in some HIV-1-infected individuals, and new approaches to present this conserved region of gp120 to the immune system may result in improved vaccine immunogens.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17704784", + "TEXT": "The success of immunization with irradiated sporozoites is unparalleled among the current vaccination approaches against malaria, but its mechanistic underpinnings have yet to be fully elucidated. Using a model mimicking natural infection by Plasmodium yoelii, we delineated early events governing the development of protective CD8(+) T-cell responses to the circumsporozoite protein. We demonstrate that dendritic cells in cutaneous lymph nodes prime the first cohort of CD8(+) T cells after an infectious mosquito bite. Ablation of these lymphoid sites greatly impairs subsequent development of protective immunity. Activated CD8(+) T cells then travel to systemic sites, including the liver, in a sphingosine-1-phosphate (S1P)-dependent fashion. These effector cells, however, no longer require bone marrow-derived antigen-presenting cells for protection; instead, they recognize antigen on parenchymal cells-presumably parasitized hepatocytes. Therefore, we report an unexpected dichotomy in the tissue restriction of host responses during the development and execution of protective immunity to Plasmodium.", + "TAG_DATA": [ + "65, CD8(+) {'context': 'B-cells'}", + "66, T {'context': 'I-cells'}", + "67, cells {'context': 'I-cells'}", + "86, CD8(+) {'context': 'B-cells'}", + "87, T {'context': 'I-cells'}", + "88, cells {'context': 'I-cells'}", + "103, effector {'context': 'B-cells'}", + "104, cells, {'context': 'I-cells'}", + "110, marrow-derived {'context': 'I-cells'}", + "111, antigen-presenting {'context': 'I-cells'}", + "112, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "65, CD8(+) ['l0', 'l1']", + "66, T ['l0', 'l2']", + "67, cells ['l1', 'l2']", + "86, CD8(+) ['l3', 'l4', 'l5', 'l6', 'l7']", + "87, T ['l3', 'l8', 'l9']", + "88, cells ['l4', 'l8']", + "103, effector ['l10', 'l11', 'l12', 'l13']", + "104, cells, ['l10', 'l14', 'l15', 'l16']", + "110, marrow-derived ['l5', 'l11', 'l14', 'l17', 'l18']", + "111, antigen-presenting ['l6', 'l12', 'l15', 'l17', 'l19']", + "112, cells ['l7', 'l9', 'l13', 'l16', 'l18', 'l19']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17694068", + "TEXT": "The serine/threonine kinase Akt mediates mitogenic and anti-apoptotic responses that result from activation of multiple signaling cascades. It is considered a key determinant of tumor aggressiveness and is a major target for anticancer drug development. Here, we describe a new reporter molecule whose bioluminescence activity within live cells and in mice can be used to measure Akt activity. Akt activity in cultured cells and tumor xenografts was monitored quantitatively and dynamically in response to activation or inhibition of receptor tyrosine kinase, inhibition of phosphoinositide 3-kinase, or direct inhibition of Akt. The results provide unique insights into the pharmacokinetics and pharmacodynamics of agents that modulate Akt activity, revealing the usefulness of this reporter for rapid dose and schedule optimization in the drug development process.", + "TAG_DATA": [ + "61, cultured {'context': 'B-cells'}", + "62, cells {'context': 'I-cells'}", + "64, tumor {'context': 'B-xenograft'}", + "65, xenografts {'context': 'I-xenograft'}", + "76, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "77, of {'perturbing_action': 'I-pharmacological inhibition'}", + "78, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "79, tyrosine {'perturbing_action': 'I-pharmacological inhibition'}", + "80, kinase, {'perturbing_action': 'I-pharmacological inhibition'}", + "86, direct {'perturbing_action': 'B-pharmacological inhibition'}", + "87, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "88, of {'perturbing_action': 'I-pharmacological inhibition'}", + "89, Akt. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "61, cultured ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "62, cells ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "64, tumor ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "65, xenografts ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "76, inhibition ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "77, of ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "78, receptor ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "79, tyrosine ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "80, kinase, ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "86, direct ['l36', 'l37', 'l38']", + "87, inhibition ['l36', 'l39', 'l40']", + "88, of ['l37', 'l39', 'l41']", + "89, Akt. ['l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cultured", + "cells" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "receptor", + "tyrosine", + "kinase," + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "tumor", + "xenografts" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "receptor", + "tyrosine", + "kinase," + ] + } + } + ] + }, + { + "PMID": "17676052", + "TEXT": "Soft tissue sarcomas are mesenchymal tumors that are fatal in approximately one-third of patients. To explore mechanisms of sarcoma pathogenesis, we have generated a mouse model of soft tissue sarcoma. Intramuscular delivery of an adenovirus expressing Cre recombinase in mice with conditional mutations in Kras and Trp53 was sufficient to initiate high-grade sarcomas with myofibroblastic differentiation. Like human sarcomas, these tumors show a predilection for lung rather than lymph node metastasis. Using this model, we showed that a prototype handheld imaging device can identify residual tumor during intraoperative molecular imaging. Deletion of the Ink4a-Arf locus (Cdkn2a), but not Bak1 and Bax, could substitute for mutation of Trp53 in this model. Deletion of Bak1 and Bax, however, was able to substitute for mutation of Trp53 in the development of sinonasal adenocarcinoma. Therefore, the intrinsic pathway of apoptosis seems sufficient to mediate p53 tumor suppression in an epithelial cancer, but not in this model of soft tissue sarcoma.", + "TAG_DATA": [ + "24, mouse {'context': 'B-organism'}", + "25, model {'context': 'I-organism'}", + "34, adenovirus {'perturbing_action': 'B-gene loss-of-function'}", + "35, expressing {'perturbing_action': 'I-gene loss-of-function'}", + "36, Cre {'perturbing_action': 'I-gene loss-of-function'}", + "37, recombinase {'perturbing_action': 'I-gene loss-of-function'}", + "39, mice {'context': 'B-organism'}", + "41, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "42, mutations {'perturbing_action': 'I-gene loss-of-function'}", + "43, in {'perturbing_action': 'I-gene loss-of-function'}", + "44, Kras {'perturbing_action': 'I-gene loss-of-function'}", + "45, and {'perturbing_action': 'I-gene loss-of-function'}", + "46, Trp53 {'perturbing_action': 'I-gene loss-of-function'}", + "50, initiate {'effect': 'B-positive'}", + "51, high-grade {'phenotype': 'B-tumourigenesis'}", + "52, sarcomas {'phenotype': 'I-tumourigenesis'}", + "54, myofibroblastic {'phenotype': 'B-differentiation'}", + "55, differentiation. {'phenotype': 'I-differentiation'}", + "90, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "91, of {'perturbing_action': 'I-gene loss-of-function'}", + "92, the {'perturbing_action': 'I-gene loss-of-function'}", + "93, Ink4a-Arf {'perturbing_action': 'I-gene loss-of-function'}", + "94, locus {'perturbing_action': 'I-gene loss-of-function'}", + "95, (Cdkn2a), {'perturbing_action': 'I-gene loss-of-function'}", + "110, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "111, of {'perturbing_action': 'I-gene loss-of-function'}", + "112, Bak1 {'perturbing_action': 'I-gene loss-of-function'}", + "113, and {'perturbing_action': 'I-gene loss-of-function'}", + "114, Bax, {'perturbing_action': 'I-gene loss-of-function'}", + "128, sinonasal {'context': 'B-neoplasm'}", + "129, adenocarcinoma. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "24, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "25, model ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "34, adenovirus ['l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "35, expressing ['l11', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "36, Cre ['l12', 'l26', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "37, recombinase ['l13', 'l27', 'l40', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "39, mice ['l14', 'l28', 'l41', 'l53', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "41, conditional ['l15', 'l29', 'l42', 'l54', 'l65', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "42, mutations ['l16', 'l30', 'l43', 'l55', 'l66', 'l76', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "43, in ['l17', 'l31', 'l44', 'l56', 'l67', 'l77', 'l86', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "44, Kras ['l18', 'l32', 'l45', 'l57', 'l68', 'l78', 'l87', 'l95', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "45, and ['l19', 'l33', 'l46', 'l58', 'l69', 'l79', 'l88', 'l96', 'l103', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "46, Trp53 ['l20', 'l34', 'l47', 'l59', 'l70', 'l80', 'l89', 'l97', 'l104', 'l110', 'l116', 'l117', 'l118', 'l119', 'l120']", + "50, initiate ['l1', 'l6', 'l21', 'l35', 'l48', 'l60', 'l71', 'l81', 'l90', 'l98', 'l105', 'l111', 'l116', 'l121', 'l122', 'l123', 'l124']", + "51, high-grade ['l2', 'l7', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l99', 'l106', 'l112', 'l117', 'l121', 'l125', 'l126', 'l127']", + "52, sarcomas ['l3', 'l8', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l100', 'l107', 'l113', 'l118', 'l122', 'l125', 'l128', 'l129']", + "54, myofibroblastic ['l4', 'l9', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l108', 'l114', 'l119', 'l123', 'l126', 'l128', 'l130']", + "55, differentiation. ['l5', 'l10', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l115', 'l120', 'l124', 'l127', 'l129', 'l130']", + "90, Deletion ['l131', 'l132', 'l133', 'l134', 'l135']", + "91, of ['l131', 'l136', 'l137', 'l138', 'l139']", + "92, the ['l132', 'l136', 'l140', 'l141', 'l142']", + "93, Ink4a-Arf ['l133', 'l137', 'l140', 'l143', 'l144']", + "94, locus ['l134', 'l138', 'l141', 'l143', 'l145']", + "95, (Cdkn2a), ['l135', 'l139', 'l142', 'l144', 'l145']", + "110, Deletion ['l146', 'l147', 'l148', 'l149', 'l150', 'l151']", + "111, of ['l146', 'l152', 'l153', 'l154', 'l155', 'l156']", + "112, Bak1 ['l147', 'l152', 'l157', 'l158', 'l159', 'l160']", + "113, and ['l148', 'l153', 'l157', 'l161', 'l162', 'l163']", + "114, Bax, ['l149', 'l154', 'l158', 'l161', 'l164', 'l165']", + "128, sinonasal ['l150', 'l155', 'l159', 'l162', 'l164', 'l166']", + "129, adenocarcinoma. ['l151', 'l156', 'l160', 'l163', 'l165', 'l166']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "high-grade", + "sarcomas" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "mice" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "myofibroblastic", + "differentiation." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adenovirus", + "expressing", + "Cre", + "recombinase", + "conditional", + "mutations", + "in", + "Kras", + "and", + "Trp53" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adenovirus", + "expressing", + "Cre", + "recombinase", + "conditional", + "mutations", + "in", + "Kras", + "and", + "Trp53" + ] + }, + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adenovirus", + "expressing", + "Cre", + "recombinase", + "conditional", + "mutations", + "in", + "Kras", + "and", + "Trp53" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "high-grade", + "sarcomas" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adenovirus", + "expressing", + "Cre", + "recombinase", + "conditional", + "mutations", + "in", + "Kras", + "and", + "Trp53" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "myofibroblastic", + "differentiation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "high-grade", + "sarcomas" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "myofibroblastic", + "differentiation." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "Bak1", + "and", + "Bax," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "sinonasal", + "adenocarcinoma." + ] + } + } + ] + }, + { + "PMID": "17676051", + "TEXT": "Acne rosacea is an inflammatory skin disease that affects 3% of the US population over 30 years of age and is characterized by erythema, papulopustules and telangiectasia. The etiology of this disorder is unknown, although symptoms are exacerbated by factors that trigger innate immune responses, such as the release of cathelicidin antimicrobial peptides. Here we show that individuals with rosacea express abnormally high levels of cathelicidin in their facial skin and that the proteolytically processed forms of cathelicidin peptides found in rosacea are different from those present in normal individuals. These cathelicidin peptides are a result of a post-translational processing abnormality associated with an increase in stratum corneum tryptic enzyme (SCTE) in the epidermis. In mice, injection of the cathelicidin peptides found in rosacea, addition of SCTE, and increasing protease activity by targeted deletion of the serine protease inhibitor gene Spink5 each increases inflammation in mouse skin. The role of cathelicidin in enabling SCTE-mediated inflammation is verified in mice with a targeted deletion of Camp, the gene encoding cathelicidin. These findings confirm the role of cathelicidin in skin inflammatory responses and suggest an explanation for the pathogenesis of rosacea by demonstrating that an exacerbated innate immune response can reproduce elements of this disease.", + "TAG_DATA": [ + "115, mice, {'context': 'B-organism'}", + "132, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "133, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "134, of {'perturbing_action': 'I-gene loss-of-function'}", + "135, the {'perturbing_action': 'I-gene loss-of-function'}", + "136, serine {'perturbing_action': 'I-gene loss-of-function'}", + "137, protease {'perturbing_action': 'I-gene loss-of-function'}", + "138, inhibitor {'perturbing_action': 'I-gene loss-of-function'}", + "139, gene {'perturbing_action': 'I-gene loss-of-function'}", + "140, Spink5 {'perturbing_action': 'I-gene loss-of-function'}", + "145, mouse {'context': 'B-tissue/organ'}", + "146, skin. {'context': 'I-tissue/organ'}", + "158, mice {'context': 'B-organism'}", + "161, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "162, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "163, of {'perturbing_action': 'I-gene loss-of-function'}", + "164, Camp, {'perturbing_action': 'I-gene loss-of-function'}", + "165, the {'perturbing_action': 'I-gene loss-of-function'}", + "166, gene {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "132, targeted ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "133, deletion ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "134, of ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "135, the ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "136, serine ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "137, protease ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "138, inhibitor ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "139, gene ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "140, Spink5 ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "145, mouse ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "146, skin. ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "158, mice ['l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "161, targeted ['l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "162, deletion ['l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "163, of ['l57', 'l62', 'l66', 'l70', 'l71', 'l72']", + "164, Camp, ['l58', 'l63', 'l67', 'l70', 'l73', 'l74']", + "165, the ['l59', 'l64', 'l68', 'l71', 'l73', 'l75']", + "166, gene ['l60', 'l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "deletion", + "of", + "the", + "serine", + "protease", + "inhibitor", + "gene", + "Spink5" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "skin." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "deletion", + "of", + "Camp,", + "the", + "gene" + ] + } + } + ] + }, + { + "PMID": "17660829", + "TEXT": "In type I diabetes mellitus, islet transplantation provides a moment-to-moment fine regulation of insulin. Success rates vary widely, however, necessitating suitable methods to monitor islet delivery, engraftment and survival. Here magnetic resonance-trackable magnetocapsules have been used simultaneously to immunoprotect pancreatic beta-cells and to monitor, non-invasively in real-time, hepatic delivery and engraftment by magnetic resonance imaging (MRI). Magnetocapsules were detected as single capsules with an altered magnetic resonance appearance on capsule rupture. Magnetocapsules were functional in vivo because mouse beta-cells restored normal glycemia in streptozotocin-induced diabetic mice and human islets induced sustained C-peptide levels in swine. In this large-animal model, magnetocapsules could be precisely targeted for infusion by using magnetic resonance fluoroscopy, whereas MRI facilitated monitoring of liver engraftment over time. These findings are directly applicable to ongoing improvements in islet cell transplantation for human diabetes, particularly because our magnetocapsules comprise clinically applicable materials.", + "TAG_DATA": [ + "74, in {'context': 'B-in vivo'}", + "75, vivo {'context': 'I-in vivo'}", + "77, mouse {'context': 'B-cells'}", + "78, beta-cells {'context': 'I-cells'}", + "85, mice {'context': 'I-organism'}", + "87, human {'context': 'B-cells'}", + "88, islets {'context': 'I-cells'}", + "94, swine. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "74, in ['l0', 'l1', 'l2', 'l3']", + "75, vivo ['l0', 'l4', 'l5', 'l6']", + "77, mouse ['l1', 'l4', 'l7', 'l8']", + "78, beta-cells ['l2', 'l5', 'l7', 'l9']", + "85, mice ['l3', 'l6', 'l8', 'l9']", + "87, human ['l10', 'l11']", + "88, islets ['l10', 'l12']", + "94, swine. ['l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17660828", + "TEXT": "Cardiac fibrosis, associated with a decreased extent of microvasculature and with disruption of normal myocardial structures, results from excessive deposition of extracellular matrix, which is mediated by the recruitment of fibroblasts. The source of these fibroblasts is unclear and specific anti-fibrotic therapies are not currently available. Here we show that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart. Transforming growth factor-beta1 (TGF-beta1) induced endothelial cells to undergo EndMT, whereas bone morphogenic protein 7 (BMP-7) preserved the endothelial phenotype. The systemic administration of recombinant human BMP-7 (rhBMP-7) significantly inhibited EndMT and the progression of cardiac fibrosis in mouse models of pressure overload and chronic allograft rejection. Our findings show that EndMT contributes to the progression of cardiac fibrosis and that rhBMP-7 can be used to inhibit EndMT and to intervene in the progression of chronic heart disease associated with fibrosis.", + "TAG_DATA": [ + "87, induced {'effect': 'B-positive'}", + "88, endothelial {'context': 'B-cells'}", + "89, cells {'context': 'I-cells'}", + "92, EndMT, {'phenotype': 'B-epithelial-mesenchymal transition'}", + "112, inhibited {'effect': 'B-negative'}", + "113, EndMT {'phenotype': 'B-epithelial-mesenchymal transition'}", + "121, mouse {'context': 'B-organism'}", + "122, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "87, induced ['l0', 'l1', 'l2']", + "88, endothelial ['l0', 'l3', 'l4']", + "89, cells ['l1', 'l3', 'l5']", + "92, EndMT, ['l2', 'l4', 'l5']", + "112, inhibited ['l6', 'l7', 'l8']", + "113, EndMT ['l6', 'l9', 'l10']", + "121, mouse ['l7', 'l9', 'l11']", + "122, models ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EndMT," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EndMT," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EndMT" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EndMT" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + } + } + ] + }, + { + "PMID": "17632528", + "TEXT": "Most invasive bacterial infections are caused by species that more commonly colonize the human host with minimal symptoms. Although phenotypic or genetic correlates underlying a bacterium's shift to enhanced virulence have been studied, the in vivo selection pressures governing such shifts are poorly understood. The globally disseminated M1T1 clone of group A Streptococcus (GAS) is linked with the rare but life-threatening syndromes of necrotizing fasciitis and toxic shock syndrome. Mutations in the GAS control of virulence regulatory sensor kinase (covRS) operon are associated with severe invasive disease, abolishing expression of a broad-spectrum cysteine protease (SpeB) and allowing the recruitment and activation of host plasminogen on the bacterial surface. Here we describe how bacteriophage-encoded GAS DNase (Sda1), which facilitates the pathogen's escape from neutrophil extracellular traps, serves as a selective force for covRS mutation. The results provide a paradigm whereby natural selection exerted by the innate immune system generates hypervirulent bacterial variants with increased risk of systemic dissemination.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17589519", + "TEXT": "Tumor cells have a dysregulated cell cycle that may render their proliferation especially sensitive to the inhibition of cyclin-dependent kinases (CDKs), important regulators of cell cycle progression. We examined the effects of CDK1 inhibition in the context of different oncogenic signals. Cells transformed with MYC, but not cells transformed by a panel of other activated oncogenes, rapidly underwent apoptosis when treated with small-molecule CDK1 inhibitors. The inhibitor of apoptosis protein BIRC5 (survivin), a known CDK1 target, is required for the survival of cells overexpressing MYC. Inhibition of CDK1 rapidly downregulates survivin expression and induces MYC-dependent apoptosis. CDK1 inhibitor treatment of MYC-dependent mouse lymphoma and hepatoblastoma tumors decreased tumor growth and prolonged their survival. As there are no effective small-molecule inhibitors that selectively target the MYC pathway, we propose that CDK1 inhibition might therefore be useful in the treatment of human malignancies that overexpress MYC.", + "TAG_DATA": [ + "41, Cells {'context': 'B-cells'}", + "47, cells {'context': 'B-cells'}", + "57, underwent {'effect': 'B-positive'}", + "58, apoptosis {'phenotype': 'B-apoptosis'}", + "62, small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "63, CDK1 {'perturbing_action': 'I-pharmacological inhibition'}", + "64, inhibitors. {'perturbing_action': 'I-pharmacological inhibition'}", + "82, cells {'context': 'B-cells'}", + "85, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "86, of {'perturbing_action': 'I-pharmacological inhibition'}", + "87, CDK1 {'perturbing_action': 'I-pharmacological inhibition'}", + "93, induces {'effect': 'B-positive'}", + "95, apoptosis. {'phenotype': 'B-apoptosis'}", + "96, CDK1 {'perturbing_action': 'B-pharmacological inhibition'}", + "97, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "98, treatment {'perturbing_action': 'I-pharmacological inhibition'}", + "100, MYC-dependent {'context': 'B-neoplasm'}", + "101, mouse {'context': 'I-neoplasm'}", + "102, lymphoma {'context': 'I-neoplasm'}", + "104, hepatoblastoma {'context': 'B-neoplasm'}", + "105, tumors {'context': 'I-neoplasm'}", + "106, decreased {'effect': 'B-negative'}", + "107, tumor {'phenotype': 'B-tumour growth'}", + "108, growth {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "41, Cells ['l0']", + "47, cells ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "57, underwent ['l1', 'l12', 'l13', 'l14', 'l15']", + "58, apoptosis ['l2', 'l12', 'l16', 'l17', 'l18', 'l19']", + "62, small-molecule ['l3', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "63, CDK1 ['l4', 'l20', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "64, inhibitors. ['l5', 'l16', 'l21', 'l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "82, cells ['l0', 'l6', 'l13', 'l17', 'l22', 'l29', 'l35', 'l41', 'l42']", + "85, Inhibition ['l7', 'l23', 'l30', 'l36', 'l43', 'l44', 'l45', 'l46']", + "86, of ['l8', 'l24', 'l31', 'l37', 'l43', 'l47', 'l48', 'l49']", + "87, CDK1 ['l9', 'l25', 'l32', 'l38', 'l44', 'l47', 'l50', 'l51']", + "93, induces ['l10', 'l14', 'l18', 'l26', 'l33', 'l39', 'l41', 'l45', 'l48', 'l50', 'l52']", + "95, apoptosis. ['l11', 'l15', 'l19', 'l27', 'l34', 'l40', 'l42', 'l46', 'l49', 'l51', 'l52']", + "96, CDK1 ['l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "97, inhibitor ['l53', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "98, treatment ['l54', 'l63', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "100, MYC-dependent ['l55', 'l64', 'l72', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "101, mouse ['l56', 'l65', 'l73', 'l80', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "102, lymphoma ['l57', 'l66', 'l74', 'l81', 'l87', 'l93', 'l94', 'l95', 'l96', 'l97']", + "104, hepatoblastoma ['l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l98', 'l99', 'l100', 'l101']", + "105, tumors ['l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l102', 'l103', 'l104']", + "106, decreased ['l60', 'l69', 'l77', 'l84', 'l90', 'l95', 'l99', 'l102', 'l105', 'l106']", + "107, tumor ['l61', 'l70', 'l78', 'l85', 'l91', 'l96', 'l100', 'l103', 'l105', 'l107']", + "108, growth ['l62', 'l71', 'l79', 'l86', 'l92', 'l97', 'l101', 'l104', 'l106', 'l107']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "underwent", + "induces" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "CDK1", + "inhibitors.", + "Inhibition", + "of" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "underwent", + "induces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis." + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors.", + "small-molecule", + "CDK1", + "Inhibition", + "of" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "CDK1", + "inhibitors.", + "Inhibition", + "of" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK1", + "inhibitor", + "treatment" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "MYC-dependent", + "mouse", + "lymphoma", + "hepatoblastoma", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK1", + "inhibitor", + "treatment" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK1", + "inhibitor", + "treatment" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "MYC-dependent", + "mouse", + "lymphoma", + "hepatoblastoma", + "tumors" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "MYC-dependent", + "mouse", + "lymphoma", + "hepatoblastoma", + "tumors" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + } + ] + }, + { + "PMID": "17558415", + "TEXT": "CD4+ T cells have a crucial role in mediating protection against a variety of pathogens through production of specific cytokines. However, substantial heterogeneity in CD4+ T-cell cytokine responses has limited the ability to define an immune correlate of protection after vaccination. Here, using multiparameter flow cytometry to assess the immune responses after immunization, we show that the degree of protection against Leishmania major infection in mice is predicted by the frequency of CD4+ T cells simultaneously producing interferon-gamma, interleukin-2 and tumor necrosis factor. Notably, multifunctional effector cells generated by all vaccines tested are unique in their capacity to produce high amounts of interferon-gamma. These data show that the quality of a CD4+ T-cell cytokine response can be a crucial determinant in whether a vaccine is protective, and may provide a new and useful prospective immune correlate of protection for vaccines based on T-helper type 1 (TH1) cells.", + "TAG_DATA": [ + "65, mice {'context': 'B-organism'}", + "72, CD4+ {'context': 'B-cells'}", + "73, T {'context': 'I-cells'}", + "74, cells {'context': 'I-cells'}", + "85, effector {'context': 'B-cells'}", + "86, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "65, mice ['l0', 'l1', 'l2']", + "72, CD4+ ['l0', 'l3', 'l4']", + "73, T ['l1', 'l3', 'l5']", + "74, cells ['l2', 'l4', 'l5']", + "85, effector ['l6']", + "86, cells ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17546038", + "TEXT": "Mast cells contribute importantly to allergic and innate immune responses by releasing various preformed and newly synthesized mediators. Previous studies have shown mast cell accumulation in human atherosclerotic lesions. This report establishes the direct participation of mast cells in atherogenesis in low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice. Atheromata from compound mutant Ldlr(-/-) Kit(W-sh)(/W-sh) mice showed decreased lesion size, lipid deposition, T-cell and macrophage numbers, cell proliferation and apoptosis, but increased collagen content and fibrous cap development. In vivo, adoptive transfer of syngeneic wild-type or tumor necrosis factor (TNF)-alpha-deficient mast cells restored atherogenesis to Ldlr(-/-)Kit(W-sh/W-sh) mice. Notably, neither interleukin (IL)-6- nor interferon (IFN)-gamma-deficient mast cells did so, indicating that the inhibition of atherogenesis in Ldlr(-/-)Kit(W-sh/W-sh) mice resulted from the absence of mast cells and mast cell-derived IL-6 and IFN-gamma. Compared with wild-type or TNF-alpha-deficient mast cells, those lacking IL-6 or IFN-gamma did not induce expression of proatherogenic cysteine proteinase cathepsins from vascular cells in vitro or affect cathepsin and matrix metalloproteinase activities in atherosclerotic lesions, implying that mast cell-derived IL-6 and IFN-gamma promote atherogenesis by augmenting the expression of matrix-degrading proteases. These observations establish direct participation of mast cells and mast cell-derived IL-6 and IFN-gamma in mouse atherogenesis and provide new mechanistic insight into the pathogenesis of this common disease.", + "TAG_DATA": [ + "41, low-density {'perturbing_action': 'B-gene loss-of-function'}", + "43, receptor-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "44, (Ldlr(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "45, mice. {'context': 'B-organism'}", + "48, compound {'perturbing_action': 'B-other'}", + "49, mutant {'perturbing_action': 'I-other'}", + "50, Ldlr(-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "51, Kit(W-sh)(/W-sh) {'perturbing_action': 'I-gene loss-of-function'}", + "52, mice {'context': 'B-organism'}", + "54, decreased {'effect': 'B-negative'}", + "59, T-cell {'context': 'B-cells'}", + "60, and {'context': 'I-cells'}", + "61, macrophage {'context': 'I-cells'}", + "63, cell {'context': 'B-cells'}", + "64, proliferation {'phenotype': 'B-proliferation'}", + "66, apoptosis, {'phenotype': 'B-apoptosis'}", + "75, In {'context': 'B-in vivo'}", + "76, vivo, {'context': 'I-in vivo'}", + "83, tumor {'perturbing_action': 'B-gene loss-of-function'}", + "84, necrosis {'perturbing_action': 'I-gene loss-of-function'}", + "85, factor {'perturbing_action': 'I-gene loss-of-function'}", + "86, (TNF)-alpha-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "87, mast {'context': 'B-cells'}", + "88, cells {'context': 'I-cells'}", + "92, Ldlr(-/-)Kit(W-sh/W-sh) {'perturbing_action': 'B-gene loss-of-function'}", + "93, mice. {'context': 'B-organism'}", + "101, mast {'context': 'B-cells'}", + "102, cells {'context': 'I-cells'}", + "112, Ldlr(-/-)Kit(W-sh/W-sh) {'perturbing_action': 'B-gene loss-of-function'}", + "113, mice {'context': 'B-organism'}", + "119, mast {'context': 'B-cells'}", + "120, cells {'context': 'I-cells'}", + "131, TNF-alpha-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "132, mast {'context': 'B-cells'}", + "133, cells, {'context': 'I-cells'}", + "136, IL-6 {'perturbing_action': 'I-gene loss-of-function'}", + "138, IFN-gamma {'perturbing_action': 'I-gene loss-of-function'}", + "149, vascular {'context': 'B-cells'}", + "150, cells {'context': 'I-cells'}", + "151, in {'context': 'B-in vitro'}", + "152, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "41, low-density ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "43, receptor-deficient ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "44, (Ldlr(-/-)) ['l1', 'l17', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "45, mice. ['l2', 'l18', 'l32', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "48, compound ['l3', 'l19', 'l33', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "49, mutant ['l4', 'l20', 'l34', 'l46', 'l57', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "50, Ldlr(-/-) ['l5', 'l21', 'l35', 'l47', 'l58', 'l70', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "51, Kit(W-sh)(/W-sh) ['l6', 'l22', 'l36', 'l48', 'l59', 'l71', 'l82', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "52, mice ['l7', 'l23', 'l37', 'l49', 'l60', 'l72', 'l83', 'l93', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "54, decreased ['l8', 'l24', 'l38', 'l50', 'l61', 'l73', 'l84', 'l94', 'l103', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "59, T-cell ['l9', 'l25', 'l39', 'l51', 'l62', 'l74', 'l85', 'l95', 'l104', 'l110', 'l116', 'l117', 'l118', 'l119', 'l120']", + "60, and ['l10', 'l26', 'l40', 'l52', 'l63', 'l75', 'l86', 'l96', 'l105', 'l111', 'l116', 'l121', 'l122', 'l123', 'l124']", + "61, macrophage ['l11', 'l27', 'l41', 'l53', 'l64', 'l76', 'l87', 'l97', 'l106', 'l112', 'l117', 'l121', 'l125', 'l126', 'l127']", + "63, cell ['l12', 'l28', 'l42', 'l54', 'l65', 'l77', 'l88', 'l98', 'l107', 'l113', 'l118', 'l122', 'l125', 'l128', 'l129']", + "64, proliferation ['l13', 'l29', 'l43', 'l55', 'l66', 'l78', 'l89', 'l99', 'l108', 'l114', 'l119', 'l123', 'l126', 'l128', 'l130']", + "66, apoptosis, ['l14', 'l30', 'l44', 'l56', 'l67', 'l79', 'l90', 'l100', 'l109', 'l115', 'l120', 'l124', 'l127', 'l129', 'l130']", + "75, In ['l15', 'l68', 'l80', 'l91', 'l101', 'l131', 'l132']", + "76, vivo, ['l16', 'l31', 'l45', 'l69', 'l81', 'l92', 'l102', 'l131']", + "83, tumor ['l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "84, necrosis ['l133', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "85, factor ['l134', 'l144', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162']", + "86, (TNF)-alpha-deficient ['l135', 'l145', 'l154', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170']", + "87, mast ['l136', 'l146', 'l155', 'l163', 'l171', 'l172', 'l173']", + "88, cells ['l132', 'l137', 'l147', 'l156', 'l164', 'l171', 'l174', 'l175']", + "92, Ldlr(-/-)Kit(W-sh/W-sh) ['l138', 'l148', 'l157', 'l165', 'l172', 'l174', 'l176', 'l177', 'l178', 'l179']", + "93, mice. ['l139', 'l149', 'l158', 'l166', 'l173', 'l175', 'l176']", + "101, mast ['l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189']", + "102, cells ['l180', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197']", + "112, Ldlr(-/-)Kit(W-sh/W-sh) ['l140', 'l150', 'l159', 'l167', 'l181', 'l190', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "113, mice ['l141', 'l151', 'l160', 'l168', 'l177', 'l182', 'l191', 'l198', 'l205', 'l206', 'l207']", + "119, mast ['l142', 'l152', 'l161', 'l169', 'l178', 'l183', 'l192', 'l199', 'l205', 'l208', 'l209', 'l210', 'l211', 'l212']", + "120, cells ['l143', 'l153', 'l162', 'l170', 'l179', 'l184', 'l193', 'l200', 'l206', 'l208', 'l213', 'l214']", + "131, TNF-alpha-deficient ['l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222']", + "132, mast ['l215', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229']", + "133, cells, ['l216', 'l223', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235']", + "136, IL-6 ['l217', 'l224', 'l230', 'l236', 'l237', 'l238', 'l239', 'l240']", + "138, IFN-gamma ['l185', 'l218', 'l225', 'l231', 'l236', 'l241', 'l242', 'l243', 'l244']", + "149, vascular ['l186', 'l194', 'l201', 'l209', 'l213', 'l219', 'l226', 'l232', 'l237', 'l241', 'l245', 'l246', 'l247']", + "150, cells ['l187', 'l195', 'l202', 'l207', 'l210', 'l214', 'l220', 'l227', 'l233', 'l238', 'l242', 'l245', 'l248', 'l249']", + "151, in ['l188', 'l196', 'l203', 'l211', 'l221', 'l228', 'l234', 'l239', 'l243', 'l246', 'l248', 'l250']", + "152, vitro ['l189', 'l197', 'l204', 'l212', 'l222', 'l229', 'l235', 'l240', 'l244', 'l247', 'l249', 'l250']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "low-density", + "receptor-deficient", + "(Ldlr(-/-))", + "Ldlr(-/-)", + "Kit(W-sh)(/W-sh)", + "tumor", + "necrosis", + "factor", + "(TNF)-alpha-deficient", + "Ldlr(-/-)Kit(W-sh/W-sh)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "low-density", + "receptor-deficient", + "(Ldlr(-/-))", + "Ldlr(-/-)", + "Kit(W-sh)(/W-sh)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "low-density", + "receptor-deficient", + "(Ldlr(-/-))", + "Ldlr(-/-)", + "Kit(W-sh)(/W-sh)", + "tumor", + "necrosis", + "factor", + "(TNF)-alpha-deficient", + "Ldlr(-/-)Kit(W-sh/W-sh)", + "IFN-gamma", + "TNF-alpha-deficient", + "IL-6" + ] + }, + "context": { + "val": "cells", + "words": [ + "T-cell", + "and", + "macrophage", + "cell", + "mast", + "cells", + "vascular", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "low-density", + "receptor-deficient", + "(Ldlr(-/-))", + "Ldlr(-/-)", + "Kit(W-sh)(/W-sh)" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "low-density", + "receptor-deficient", + "(Ldlr(-/-))", + "Ldlr(-/-)", + "Kit(W-sh)(/W-sh)" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "low-density", + "receptor-deficient", + "(Ldlr(-/-))", + "Ldlr(-/-)", + "Kit(W-sh)(/W-sh)" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "compound" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "compound", + "mutant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "compound", + "mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "T-cell", + "and", + "macrophage", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "compound", + "mutant" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "compound", + "mutant" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "compound", + "mutant" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "context": { + "val": "cells", + "words": [ + "T-cell", + "and", + "macrophage", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T-cell", + "and", + "macrophage", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T-cell", + "and", + "macrophage", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ldlr(-/-)Kit(W-sh/W-sh)", + "TNF-alpha-deficient", + "IL-6", + "IFN-gamma" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "17515895", + "TEXT": "Calcineurin is a calcium-activated serine/threonine phosphatase critical to a number of developmental processes in the cardiovascular, nervous and immune systems. In the T-cell lineage, calcineurin activation is important for pre-T-cell receptor (TCR) signaling, TCR-mediated positive selection of thymocytes into mature T cells, and many aspects of the immune response. The critical role of calcineurin in the immune response is underscored by the fact that calcineurin inhibitors, such as cyclosporin A (CsA) and FK506, are powerful immunosuppressants in wide clinical use. We observed sustained calcineurin activation in human B- and T-cell lymphomas and in all mouse models of lymphoid malignancies analyzed. In intracellular NOTCH1 (ICN1)- and TEL-JAK2-induced T-cell lymphoblastic leukemia, two mouse models relevant to human malignancies, in vivo inhibition of calcineurin activity by CsA or FK506 induced apoptosis of leukemic cells and rapid tumor clearance, and substantially prolonged mouse survival. In contrast, ectopic expression of a constitutively activated mutant of calcineurin favored leukemia progression. Moreover, CsA treatment induced apoptosis in human lymphoma and leukemia cell lines. Thus, calcineurin activation is critical for the maintenance of the leukemic phenotype in vivo, identifying this pathway as a relevant therapeutic target in lymphoid malignancies.", + "TAG_DATA": [ + "86, human {'context': 'B-neoplasm'}", + "87, B- {'context': 'I-neoplasm'}", + "88, and {'context': 'I-neoplasm'}", + "89, T-cell {'context': 'I-neoplasm'}", + "90, lymphomas {'context': 'I-neoplasm'}", + "94, mouse {'context': 'B-neoplasm'}", + "95, models {'context': 'I-neoplasm'}", + "96, of {'context': 'I-neoplasm'}", + "97, lymphoid {'context': 'I-neoplasm'}", + "98, malignancies {'context': 'I-neoplasm'}", + "116, in {'context': 'B-in vivo'}", + "117, vivo {'context': 'I-in vivo'}", + "118, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "119, of {'perturbing_action': 'I-pharmacological inhibition'}", + "120, calcineurin {'perturbing_action': 'I-pharmacological inhibition'}", + "121, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "122, by {'perturbing_action': 'I-pharmacological inhibition'}", + "123, CsA {'perturbing_action': 'I-pharmacological inhibition'}", + "124, or {'perturbing_action': 'I-pharmacological inhibition'}", + "125, FK506 {'perturbing_action': 'I-pharmacological inhibition'}", + "126, induced {'effect': 'B-positive'}", + "127, apoptosis {'phenotype': 'B-apoptosis'}", + "129, leukemic {'context': 'B-transformed cells'}", + "130, cells {'context': 'I-transformed cells'}", + "133, tumor {'phenotype': 'B-tumour regression'}", + "134, clearance, {'phenotype': 'I-tumour regression'}", + "138, mouse {'context': 'B-organism'}", + "142, ectopic {'perturbing_action': 'B-other'}", + "143, expression {'perturbing_action': 'I-other'}", + "144, of {'perturbing_action': 'I-other'}", + "145, a {'perturbing_action': 'I-other'}", + "146, constitutively {'perturbing_action': 'I-other'}", + "147, activated {'perturbing_action': 'I-other'}", + "148, mutant {'perturbing_action': 'I-other'}", + "149, of {'perturbing_action': 'I-other'}", + "150, calcineurin {'perturbing_action': 'I-other'}", + "152, leukemia {'context': 'B-neoplasm'}", + "157, induced {'effect': 'B-positive'}", + "158, apoptosis {'phenotype': 'B-apoptosis'}", + "160, human {'context': 'B-neoplasm'}", + "161, lymphoma {'context': 'I-neoplasm'}", + "163, leukemia {'context': 'B-transformed cells'}", + "164, cell {'context': 'I-transformed cells'}", + "165, lines. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "86, human ['l0', 'l1', 'l2', 'l3']", + "87, B- ['l0', 'l4', 'l5', 'l6']", + "88, and ['l1', 'l4', 'l7', 'l8']", + "89, T-cell ['l2', 'l5', 'l7', 'l9']", + "90, lymphomas ['l3', 'l6', 'l8', 'l9']", + "94, mouse ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "95, models ['l10', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "96, of ['l11', 'l26', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "97, lymphoid ['l12', 'l27', 'l37', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "98, malignancies ['l13', 'l28', 'l38', 'l50', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "106, T-cell ['l14', 'l29', 'l39', 'l51', 'l63', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "107, lymphoblastic ['l15', 'l30', 'l40', 'l52', 'l64', 'l74', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "108, leukemia, ['l16', 'l31', 'l41', 'l53', 'l65', 'l75', 'l87', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "116, in ['l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "117, vivo ['l110', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "118, inhibition ['l111', 'l126', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "119, of ['l112', 'l127', 'l141', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "120, calcineurin ['l113', 'l128', 'l142', 'l156', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "121, activity ['l114', 'l129', 'l143', 'l157', 'l170', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "122, by ['l76', 'l88', 'l99', 'l115', 'l130', 'l144', 'l158', 'l171', 'l183', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "123, CsA ['l17', 'l54', 'l77', 'l89', 'l100', 'l116', 'l131', 'l145', 'l159', 'l172', 'l184', 'l195', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213']", + "124, or ['l18', 'l42', 'l55', 'l66', 'l78', 'l90', 'l101', 'l117', 'l132', 'l146', 'l160', 'l173', 'l185', 'l196', 'l205', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221']", + "125, FK506 ['l19', 'l43', 'l56', 'l67', 'l79', 'l91', 'l102', 'l118', 'l133', 'l147', 'l161', 'l174', 'l186', 'l197', 'l206', 'l214', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228']", + "126, induced ['l20', 'l32', 'l44', 'l57', 'l68', 'l80', 'l92', 'l103', 'l119', 'l134', 'l148', 'l162', 'l175', 'l187', 'l198', 'l207', 'l215', 'l222', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234']", + "127, apoptosis ['l21', 'l45', 'l58', 'l69', 'l81', 'l93', 'l104', 'l120', 'l135', 'l149', 'l163', 'l176', 'l188', 'l199', 'l208', 'l216', 'l223', 'l229', 'l235', 'l236', 'l237', 'l238', 'l239']", + "129, leukemic ['l22', 'l33', 'l46', 'l59', 'l70', 'l82', 'l94', 'l105', 'l121', 'l136', 'l150', 'l164', 'l177', 'l189', 'l200', 'l209', 'l217', 'l224', 'l230', 'l235', 'l240', 'l241', 'l242', 'l243']", + "130, cells ['l23', 'l34', 'l47', 'l60', 'l71', 'l83', 'l95', 'l106', 'l122', 'l137', 'l151', 'l165', 'l178', 'l190', 'l201', 'l210', 'l218', 'l225', 'l231', 'l236', 'l240', 'l244', 'l245']", + "133, tumor ['l24', 'l35', 'l48', 'l61', 'l72', 'l84', 'l96', 'l107', 'l123', 'l138', 'l152', 'l166', 'l179', 'l191', 'l202', 'l211', 'l219', 'l226', 'l232', 'l237', 'l241', 'l244', 'l246', 'l247']", + "134, clearance, ['l25', 'l36', 'l49', 'l62', 'l73', 'l85', 'l97', 'l108', 'l124', 'l139', 'l153', 'l167', 'l180', 'l192', 'l203', 'l212', 'l220', 'l227', 'l233', 'l238', 'l242', 'l245', 'l246', 'l248']", + "138, mouse ['l86', 'l98', 'l109', 'l125', 'l140', 'l154', 'l168', 'l181', 'l193', 'l204', 'l213', 'l221', 'l228', 'l234', 'l239', 'l243', 'l247', 'l248']", + "142, ectopic ['l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264']", + "143, expression ['l249', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279']", + "144, of ['l250', 'l265', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293']", + "145, a ['l251', 'l266', 'l280', 'l294', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304', 'l305', 'l306']", + "146, constitutively ['l252', 'l267', 'l281', 'l294', 'l307', 'l308', 'l309', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315', 'l316', 'l317', 'l318']", + "147, activated ['l253', 'l268', 'l282', 'l295', 'l307', 'l319', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327', 'l328', 'l329']", + "148, mutant ['l254', 'l269', 'l283', 'l296', 'l308', 'l319', 'l330', 'l331', 'l332', 'l333', 'l334', 'l335', 'l336', 'l337', 'l338', 'l339']", + "149, of ['l255', 'l270', 'l284', 'l297', 'l309', 'l320', 'l330', 'l340', 'l341', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348']", + "150, calcineurin ['l256', 'l271', 'l285', 'l298', 'l310', 'l321', 'l331', 'l340', 'l349', 'l350', 'l351', 'l352', 'l353']", + "152, leukemia ['l155', 'l169', 'l182', 'l194', 'l257', 'l272', 'l286', 'l299', 'l311', 'l322', 'l332', 'l341', 'l349']", + "157, induced ['l258', 'l273', 'l287', 'l300', 'l312', 'l323', 'l333', 'l342', 'l350', 'l354', 'l355', 'l356', 'l357', 'l358', 'l359']", + "158, apoptosis ['l259', 'l274', 'l288', 'l301', 'l313', 'l324', 'l334', 'l343', 'l354', 'l360', 'l361', 'l362', 'l363', 'l364']", + "160, human ['l260', 'l275', 'l289', 'l302', 'l314', 'l325', 'l335', 'l344', 'l355', 'l360', 'l365', 'l366', 'l367', 'l368']", + "161, lymphoma ['l261', 'l276', 'l290', 'l303', 'l315', 'l326', 'l336', 'l345', 'l351', 'l356', 'l361', 'l365', 'l369', 'l370', 'l371']", + "163, leukemia ['l262', 'l277', 'l291', 'l304', 'l316', 'l327', 'l337', 'l346', 'l357', 'l362', 'l366', 'l369', 'l372', 'l373']", + "164, cell ['l263', 'l278', 'l292', 'l305', 'l317', 'l328', 'l338', 'l347', 'l352', 'l358', 'l363', 'l367', 'l370', 'l372', 'l374']", + "165, lines. ['l264', 'l279', 'l293', 'l306', 'l318', 'l329', 'l339', 'l348', 'l353', 'l359', 'l364', 'l368', 'l371', 'l373', 'l374']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "of", + "lymphoid", + "malignancies", + "leukemia" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CsA", + "or", + "FK506", + "inhibition", + "of", + "calcineurin", + "activity" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "models", + "of", + "lymphoid", + "malignancies", + "human", + "lymphoma" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "of", + "lymphoid", + "malignancies", + "human", + "lymphoma" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "models", + "of", + "lymphoid", + "malignancies" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "clearance," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "calcineurin", + "activity", + "by", + "CsA", + "or", + "FK506" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "clearance," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "calcineurin", + "activity", + "by", + "CsA", + "or", + "FK506" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "calcineurin", + "activity", + "by", + "CsA", + "or", + "FK506" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "calcineurin", + "activity", + "by", + "CsA", + "or", + "FK506" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "leukemic", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "calcineurin", + "activity", + "by", + "CsA", + "or", + "FK506" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "clearance," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "calcineurin", + "activity", + "by", + "CsA", + "or", + "FK506" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "leukemic", + "cells", + "leukemia", + "cell", + "lines." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "clearance," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "leukemic", + "cells", + "leukemia", + "cell", + "lines." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "leukemic", + "cells" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "clearance," + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "clearance," + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "ectopic", + "expression", + "of", + "a", + "constitutively", + "activated", + "mutant", + "calcineurin" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia", + "human", + "lymphoma" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "ectopic", + "expression", + "of", + "a", + "constitutively", + "activated", + "mutant", + "calcineurin" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "ectopic", + "expression", + "of", + "a", + "constitutively", + "activated", + "mutant" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "ectopic", + "expression", + "of", + "a", + "constitutively", + "activated", + "mutant", + "calcineurin" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "leukemia", + "cell", + "lines." + ] + } + } + ] + }, + { + "PMID": "17496899", + "TEXT": "Cerebral malaria claims more than 1 million lives per year. We report that heme oxygenase-1 (HO-1, encoded by Hmox1) prevents the development of experimental cerebral malaria (ECM). BALB/c mice infected with Plasmodium berghei ANKA upregulated HO-1 expression and activity and did not develop ECM. Deletion of Hmox1 and inhibition of HO activity increased ECM incidence to 83% and 78%, respectively. HO-1 upregulation was lower in infected C57BL/6 compared to BALB/c mice, and all infected C57BL/6 mice developed ECM (100% incidence). Pharmacological induction of HO-1 and exposure to the end-product of HO-1 activity, carbon monoxide (CO), reduced ECM incidence in C57BL/6 mice to 10% and 0%, respectively. Whereas neither HO-1 nor CO affected parasitemia, both prevented blood-brain barrier (BBB) disruption, brain microvasculature congestion and neuroinflammation, including CD8(+) T-cell brain sequestration. These effects were mediated by the binding of CO to hemoglobin, preventing hemoglobin oxidation and the generation of free heme, a molecule that triggers ECM pathogenesis.", + "TAG_DATA": [ + "27, BALB/c {'context': 'B-organism'}", + "28, mice {'context': 'I-organism'}", + "44, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "45, of {'perturbing_action': 'I-gene loss-of-function'}", + "46, Hmox1 {'perturbing_action': 'I-gene loss-of-function'}", + "48, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "49, of {'perturbing_action': 'I-pharmacological inhibition'}", + "50, HO {'perturbing_action': 'I-pharmacological inhibition'}", + "51, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "66, C57BL/6 {'context': 'B-organism'}", + "74, C57BL/6 {'context': 'B-organism'}", + "75, mice {'context': 'I-organism'}", + "80, Pharmacological {'perturbing_action': 'B-pharmacological augmentation'}", + "81, induction {'perturbing_action': 'I-pharmacological augmentation'}", + "82, of {'perturbing_action': 'I-pharmacological augmentation'}", + "83, HO-1 {'perturbing_action': 'I-pharmacological augmentation'}", + "99, C57BL/6 {'context': 'B-organism'}", + "100, mice {'context': 'I-organism'}", + "119, brain {'context': 'B-tissue/organ'}", + "120, microvasculature {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "27, BALB/c ['l0', 'l1', 'l2']", + "28, mice ['l0']", + "44, Deletion ['l3', 'l4', 'l5', 'l6', 'l7']", + "45, of ['l3', 'l8', 'l9', 'l10', 'l11']", + "46, Hmox1 ['l1', 'l4', 'l8', 'l12', 'l13', 'l14']", + "48, inhibition ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "49, of ['l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "50, HO ['l16', 'l22', 'l28', 'l29', 'l30', 'l31']", + "51, activity ['l17', 'l23', 'l28', 'l32', 'l33', 'l34']", + "66, C57BL/6 ['l2', 'l5', 'l9', 'l12', 'l18', 'l24', 'l29', 'l32', 'l35', 'l36']", + "74, C57BL/6 ['l6', 'l10', 'l13', 'l19', 'l25', 'l30', 'l33', 'l35', 'l37']", + "75, mice ['l7', 'l11', 'l14', 'l20', 'l26', 'l31', 'l34', 'l36', 'l37']", + "80, Pharmacological ['l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "81, induction ['l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "82, of ['l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "83, HO-1 ['l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "99, C57BL/6 ['l41', 'l47', 'l52', 'l56', 'l60']", + "100, mice ['l21', 'l27', 'l42', 'l48', 'l53', 'l57', 'l60']", + "119, brain ['l43', 'l49', 'l54', 'l58', 'l61']", + "120, microvasculature ['l44', 'l50', 'l55', 'l59', 'l61']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "BALB/c", + "C57BL/6", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hmox1", + "Deletion", + "of" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "HO", + "activity" + ] + }, + "context": { + "val": "organism", + "words": [ + "C57BL/6", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Pharmacological", + "induction", + "of", + "HO-1" + ] + }, + "context": { + "val": "organism", + "words": [ + "C57BL/6", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Pharmacological", + "induction", + "of", + "HO-1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain", + "microvasculature" + ] + } + } + ] + }, + { + "PMID": "17486088", + "TEXT": "Cell-intrinsic checkpoints limit the proliferative capacity of primary cells in response to telomere dysfunction. It is not known, however, whether telomere dysfunction contributes to cell-extrinsic alterations that impair stem cell function and organ homeostasis. Here we show that telomere dysfunction provokes defects of the hematopoietic environment that impair B lymphopoiesis but increase myeloid proliferation in aging telomerase knockout (Terc(-/-)) mice. Moreover, the dysfunctional environment limited the engraftment of transplanted wild-type hematopoietic stem cells (HSCs). Dysfunction of the hematopoietic environment was age dependent and correlated with progressive telomere shortening in bone marrow stromal cells. Telomere dysfunction impaired mesenchymal progenitor cell function, reduced the capacity of bone marrow stromal cells to maintain functional HSCs, and increased the expression of various cytokines, including granulocyte colony-stimulating factor (G-CSF), in the plasma of aging mice. Administration of G-CSF to wild-type mice mimicked some of the defects seen in aging Terc(-/-) mice, including impairment of B lymphopoiesis and HSC engraftment. Conversely, inhibition of G-CSF improved HSC engraftment in aged Terc(-/-) mice. Taken together, these results show that telomere dysfunction induces alterations of the environment that can have implications for organismal aging and cell transplantation therapies.", + "TAG_DATA": [ + "51, increase {'effect': 'B-positive'}", + "53, proliferation {'phenotype': 'B-proliferation'}", + "56, telomerase {'perturbing_action': 'B-gene loss-of-function'}", + "57, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "58, (Terc(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "59, mice. {'context': 'B-organism'}", + "70, hematopoietic {'context': 'I-cells'}", + "71, stem {'context': 'I-cells'}", + "72, cells {'context': 'I-cells'}", + "73, (HSCs). {'context': 'I-cells'}", + "89, bone {'context': 'B-cells'}", + "90, marrow {'context': 'I-cells'}", + "91, stromal {'context': 'I-cells'}", + "92, cells. {'context': 'I-cells'}", + "96, mesenchymal {'context': 'B-cells'}", + "97, progenitor {'context': 'I-cells'}", + "98, cell {'context': 'I-cells'}", + "104, bone {'context': 'B-cells'}", + "105, marrow {'context': 'I-cells'}", + "106, stromal {'context': 'I-cells'}", + "107, cells {'context': 'I-cells'}", + "111, HSCs, {'context': 'B-cells'}", + "128, aging {'context': 'B-organism'}", + "129, mice. {'context': 'I-organism'}", + "135, mice {'context': 'B-organism'}", + "144, Terc(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "145, mice, {'context': 'B-organism'}", + "152, HSC {'context': 'B-cells'}", + "155, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "156, of {'perturbing_action': 'I-pharmacological inhibition'}", + "157, G-CSF {'perturbing_action': 'I-pharmacological inhibition'}", + "159, HSC {'context': 'B-cells'}", + "162, aged {'context': 'B-organism'}", + "163, Terc(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "164, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "51, increase ['l0', 'l1', 'l2', 'l3']", + "53, proliferation ['l0', 'l4', 'l5']", + "56, telomerase ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "57, knockout ['l6', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "58, (Terc(-/-)) ['l1', 'l4', 'l7', 'l24', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "59, mice. ['l2', 'l5', 'l8', 'l25', 'l41', 'l55']", + "69, wild-type ['l9', 'l26', 'l42', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "70, hematopoietic ['l10', 'l27', 'l43', 'l56', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "71, stem ['l11', 'l28', 'l44', 'l57', 'l74', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "72, cells ['l12', 'l29', 'l45', 'l58', 'l75', 'l91', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "73, (HSCs). ['l13', 'l30', 'l46', 'l59', 'l76', 'l92', 'l107', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "89, bone ['l14', 'l31', 'l47', 'l60', 'l77', 'l93', 'l108', 'l120', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "90, marrow ['l15', 'l32', 'l48', 'l61', 'l78', 'l94', 'l109', 'l121', 'l132', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156']", + "91, stromal ['l16', 'l33', 'l49', 'l62', 'l79', 'l95', 'l110', 'l122', 'l133', 'l145', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "92, cells. ['l3', 'l17', 'l34', 'l50', 'l55', 'l63', 'l80', 'l96', 'l111', 'l123', 'l134', 'l146', 'l157', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "96, mesenchymal ['l18', 'l35', 'l51', 'l64', 'l81', 'l97', 'l112', 'l124', 'l135', 'l147', 'l158', 'l168', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183']", + "97, progenitor ['l19', 'l36', 'l52', 'l65', 'l82', 'l98', 'l113', 'l125', 'l136', 'l148', 'l159', 'l169', 'l175', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191']", + "98, cell ['l20', 'l37', 'l53', 'l66', 'l83', 'l99', 'l114', 'l126', 'l137', 'l149', 'l160', 'l170', 'l176', 'l184', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198']", + "104, bone ['l67', 'l84', 'l100', 'l138', 'l150', 'l161', 'l177', 'l185', 'l192', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "105, marrow ['l68', 'l85', 'l101', 'l139', 'l151', 'l162', 'l178', 'l186', 'l193', 'l199', 'l205', 'l206', 'l207', 'l208', 'l209']", + "106, stromal ['l69', 'l86', 'l102', 'l115', 'l127', 'l140', 'l152', 'l163', 'l179', 'l187', 'l194', 'l200', 'l205', 'l210', 'l211', 'l212', 'l213']", + "107, cells ['l21', 'l38', 'l54', 'l70', 'l87', 'l103', 'l116', 'l128', 'l141', 'l153', 'l164', 'l171', 'l180', 'l188', 'l195', 'l201', 'l206', 'l210', 'l214', 'l215', 'l216']", + "111, HSCs, ['l22', 'l39', 'l71', 'l88', 'l104', 'l117', 'l129', 'l142', 'l154', 'l165', 'l172', 'l181', 'l189', 'l196', 'l202', 'l207', 'l211', 'l214', 'l217', 'l218']", + "128, aging ['l72', 'l89', 'l105', 'l118', 'l130', 'l143', 'l155', 'l166', 'l173', 'l182', 'l190', 'l197', 'l203', 'l208', 'l212', 'l215', 'l217', 'l219']", + "129, mice. ['l23', 'l40', 'l73', 'l90', 'l106', 'l119', 'l131', 'l144', 'l156', 'l167', 'l174', 'l183', 'l191', 'l198', 'l204', 'l209', 'l213', 'l216', 'l218', 'l219']", + "135, mice ['l220', 'l221', 'l222']", + "144, Terc(-/-) ['l220', 'l223', 'l224']", + "145, mice, ['l221', 'l223', 'l225']", + "152, HSC ['l222', 'l224', 'l225']", + "155, inhibition ['l226', 'l227', 'l228', 'l229', 'l230', 'l231']", + "156, of ['l226', 'l232', 'l233', 'l234', 'l235', 'l236']", + "157, G-CSF ['l227', 'l232', 'l237', 'l238', 'l239', 'l240']", + "159, HSC ['l228', 'l233', 'l237', 'l241', 'l242', 'l243']", + "162, aged ['l229', 'l234', 'l238', 'l241', 'l244', 'l245']", + "163, Terc(-/-) ['l230', 'l235', 'l239', 'l242', 'l244', 'l246']", + "164, mice. ['l231', 'l236', 'l240', 'l243', 'l245', 'l246']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "(Terc(-/-))" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "(Terc(-/-))" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "telomerase", + "knockout", + "(Terc(-/-))", + "Terc(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice", + "mice,", + "aged" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "telomerase", + "knockout", + "(Terc(-/-))", + "Terc(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cells", + "(HSCs).", + "bone", + "marrow", + "stromal", + "cells.", + "mesenchymal", + "progenitor", + "cell", + "HSCs,", + "HSC" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "G-CSF" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "G-CSF" + ] + }, + "context": { + "val": "organism", + "words": [ + "aged", + "mice." + ] + } + } + ] + }, + { + "PMID": "17468767", + "TEXT": "During physical exercise, increases in motor neuron activity stimulate the expression of muscle-specific genes through the myocyte enhancer factor 2 (MEF2) family of transcription factors. Elevations in intracellular calcium increase MEF2 activity via the phosphorylation-dependent inactivation of class II histone deacetylases (HDACs). In studies to determine the role of the cAMP responsive element binding protein (CREB) in skeletal muscle, we found that mice expressing a dominant-negative CREB transgene (M-ACREB mice) exhibited a dystrophic phenotype along with reduced MEF2 activity. Class II HDAC phosphorylation was decreased in M-ACREB myofibers due to a reduction in amounts of Snf1lk (encoding salt inducible kinase, SIK1), a CREB target gene that functions as a class II HDAC kinase. Inhibiting class II HDAC activity either by viral expression of Snf1lk or by the administration of a small molecule antagonist improved the dystrophic phenotype in M-ACREB mice, pointing to an important role for the SIK1-HDAC pathway in regulating muscle function.", + "TAG_DATA": [ + "62, mice {'context': 'B-organism'}", + "63, expressing {'perturbing_action': 'B-other'}", + "64, a {'perturbing_action': 'I-other'}", + "65, dominant-negative {'perturbing_action': 'I-other'}", + "66, CREB {'perturbing_action': 'I-other'}", + "67, transgene {'perturbing_action': 'I-other'}", + "68, (M-ACREB {'perturbing_action': 'I-other'}", + "69, mice) {'perturbing_action': 'I-other'}", + "87, myofibers {'context': 'I-cells'}", + "120, viral {'perturbing_action': 'B-gene gain-of-function'}", + "121, expression {'perturbing_action': 'I-gene gain-of-function'}", + "122, of {'perturbing_action': 'I-gene gain-of-function'}", + "123, Snf1lk {'perturbing_action': 'I-gene gain-of-function'}", + "138, M-ACREB {'perturbing_action': 'B-other', 'context': 'B-organism'}", + "139, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "62, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "63, expressing ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "64, a ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "65, dominant-negative ['l2', 'l8', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "66, CREB ['l3', 'l9', 'l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "67, transgene ['l4', 'l10', 'l15', 'l20', 'l24', 'l28', 'l29', 'l30']", + "68, (M-ACREB ['l5', 'l11', 'l16', 'l21', 'l25', 'l28', 'l31']", + "69, mice) ['l6', 'l12', 'l17', 'l22', 'l26', 'l29', 'l31']", + "87, myofibers ['l18', 'l23', 'l27', 'l30']", + "120, viral ['l32', 'l33', 'l34', 'l35', 'l36']", + "121, expression ['l32', 'l37', 'l38', 'l39', 'l40']", + "122, of ['l33', 'l37', 'l41', 'l42', 'l43']", + "123, Snf1lk ['l34', 'l38', 'l41', 'l44', 'l45']", + "138, M-ACREB ['l35', 'l39', 'l42', 'l44', 'l46']", + "139, mice, ['l36', 'l40', 'l43', 'l45', 'l46']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "M-ACREB" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "a", + "dominant-negative", + "CREB", + "transgene", + "(M-ACREB", + "mice)", + "M-ACREB" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "a", + "dominant-negative", + "CREB", + "transgene" + ] + }, + "context": { + "val": "cells", + "words": [ + "myofibers" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "viral", + "expression", + "of", + "Snf1lk" + ] + }, + "context": { + "val": "organism", + "words": [ + "M-ACREB", + "mice," + ] + } + } + ] + }, + { + "PMID": "17450149", + "TEXT": "Chronic obstructive pulmonary disease and emphysema are common destructive inflammatory diseases that are leading causes of death worldwide. Here we show that emphysema is an autoimmune disease characterized by the presence of antielastin antibody and T-helper type 1 (T(H)1) responses, which correlate with emphysema severity. These findings link emphysema to adaptive immunity against a specific lung antigen and suggest the potential for autoimmune pathology of other elastin-rich tissues such as the arteries and skin of smokers.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17435771", + "TEXT": "The cytokine macrophage migration inhibitory factor (MIF) plays a critical role in inflammatory diseases and atherogenesis. We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF. MIF triggered G(alphai)- and integrin-dependent arrest and chemotaxis of monocytes and T cells, rapid integrin activation and calcium influx through CXCR2 or CXCR4. MIF competed with cognate ligands for CXCR4 and CXCR2 binding, and directly bound to CXCR2. CXCR2 and CD74 formed a receptor complex, and monocyte arrest elicited by MIF in inflamed or atherosclerotic arteries involved both CXCR2 and CD74. In vivo, Mif deficiency impaired monocyte adhesion to the arterial wall in atherosclerosis-prone mice, and MIF-induced leukocyte recruitment required Il8rb (which encodes Cxcr2). Blockade of Mif but not of canonical ligands of Cxcr2 or Cxcr4 in mice with advanced atherosclerosis led to plaque regression and reduced monocyte and T-cell content in plaques. By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis. Targeting MIF in individuals with manifest atherosclerosis can potentially be used to treat this condition.", + "TAG_DATA": [ + "36, chemotaxis {'phenotype': 'B-migration'}", + "38, monocytes {'context': 'B-cells'}", + "40, T {'context': 'B-cells'}", + "41, cells, {'context': 'B-cells'}", + "75, monocyte {'context': 'B-cells'}", + "84, arteries {'context': 'B-tissue/organ'}", + "90, In {'context': 'B-in vivo'}", + "91, vivo, {'context': 'I-in vivo'}", + "92, Mif {'perturbing_action': 'B-gene loss-of-function'}", + "93, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "94, impaired {'effect': 'B-negative'}", + "95, monocyte {'context': 'B-cells'}", + "103, mice, {'context': 'B-organism'}", + "106, leukocyte {'context': 'B-cells'}", + "113, Blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "114, of {'perturbing_action': 'I-pharmacological inhibition'}", + "115, Mif {'perturbing_action': 'I-pharmacological inhibition'}", + "126, mice {'context': 'B-organism'}", + "136, monocyte {'context': 'B-cells'}", + "138, T-cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "36, chemotaxis ['l0', 'l1', 'l2', 'l3', 'l4']", + "38, monocytes ['l0', 'l5', 'l6', 'l7', 'l8']", + "40, T ['l1', 'l5', 'l9', 'l10', 'l11']", + "41, cells, ['l2', 'l6', 'l9', 'l12', 'l13']", + "75, monocyte ['l3', 'l7', 'l10', 'l12', 'l14', 'l15', 'l16', 'l17']", + "84, arteries ['l4', 'l8', 'l11', 'l13', 'l14', 'l18', 'l19', 'l20']", + "90, In ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "91, vivo, ['l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "92, Mif ['l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "93, deficiency ['l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "94, impaired ['l15', 'l18', 'l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "95, monocyte ['l16', 'l19', 'l25', 'l31', 'l36', 'l40', 'l43', 'l46']", + "103, mice, ['l17', 'l20', 'l26', 'l32', 'l37', 'l41', 'l44', 'l46']", + "106, leukocyte ['l27', 'l33', 'l38', 'l42', 'l45']", + "113, Blockade ['l47', 'l48', 'l49', 'l50', 'l51']", + "114, of ['l47', 'l52', 'l53', 'l54', 'l55']", + "115, Mif ['l48', 'l52', 'l56', 'l57', 'l58']", + "126, mice ['l49', 'l53', 'l56', 'l59', 'l60']", + "136, monocyte ['l50', 'l54', 'l57', 'l59', 'l61']", + "138, T-cell ['l51', 'l55', 'l58', 'l60', 'l61']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + }, + "context": { + "val": "cells", + "words": [ + "monocytes", + "T", + "cells,", + "monocyte" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "arteries" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "monocyte", + "leukocyte" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "arteries" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mif", + "deficiency" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mif", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mif", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "monocyte", + "leukocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mif", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "Mif" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "Mif" + ] + }, + "context": { + "val": "cells", + "words": [ + "monocyte", + "T-cell" + ] + } + } + ] + }, + { + "PMID": "17435770", + "TEXT": "Osteopontin (Opn) is important for T helper type 1 (T(H)1) immunity and autoimmunity. However, the role of this cytokine in T(H)2-mediated allergic disease as well as its effects on primary versus secondary antigenic encounters remain unclear. Here we demonstrate that OPN is expressed in the lungs of asthmatic individuals and that Opn-s, the secreted form of Opn, exerts opposing effects on mouse T(H)2 effector responses and subsequent allergic airway disease: pro-inflammatory at primary systemic sensitization, and anti-inflammatory during secondary pulmonary antigenic challenge. These effects of Opn-s are mainly mediated by the regulation of T(H)2-suppressing plasmacytoid dendritic cells (DCs) during primary sensitization and T(H)2-promoting conventional DCs during secondary antigenic challenge. Therapeutic administration of recombinant Opn during pulmonary secondary antigenic challenge decreased established T(H)2 responses and protected mice from allergic disease. These effects on T(H)2 allergic responses suggest that Opn-s is an important therapeutic target and provide new insight into its role in immunity.", + "TAG_DATA": [ + "94, plasmacytoid {'context': 'B-cells'}", + "95, dendritic {'context': 'I-cells'}", + "96, cells {'context': 'I-cells'}", + "97, (DCs) {'context': 'I-cells'}", + "104, DCs {'context': 'B-cells'}", + "125, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "94, plasmacytoid ['l0', 'l1', 'l2', 'l3']", + "95, dendritic ['l0', 'l4', 'l5', 'l6']", + "96, cells ['l1', 'l4', 'l7', 'l8']", + "97, (DCs) ['l2', 'l5', 'l7', 'l9']", + "104, DCs ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17417652", + "TEXT": "Human embryonic stem cells (hESCs) are a promising source for cell therapy in degenerative diseases. A key step in establishing the medical potential of hESCs is the development of techniques for the conversion of hESCs into tissue-restricted precursors suitable for transplantation. We recently described the derivation of multipotent mesenchymal precursors from hESCs. Nevertheless, our previous study was limited by the requirement for mouse feeders and the lack of in vivo data. Here we report a stroma-free induction system for deriving mesenchymal precursors. Selective culture conditions and fluorescence-activated cell sorting (FACS)-mediated purification yielded multipotent mesenchymal precursors and skeletal myoblasts. Skeletal muscle cells undergo in vitro maturation resulting in myotube formation and spontaneous twitching. We found that hESC-derived skeletal myoblasts were viable after transplantation into the tibialis anterior muscle of SCID/Beige mice, as assessed by bioluminescence imaging. Lack of teratoma formation and evidence of long-term myoblast engraftment suggests considerable potential for future therapeutic applications.", + "TAG_DATA": [ + "96, skeletal {'context': 'B-cells'}", + "97, myoblasts. {'context': 'I-cells'}", + "98, Skeletal {'context': 'B-cells'}", + "99, muscle {'context': 'I-cells'}", + "100, cells {'context': 'I-cells'}", + "102, in {'context': 'B-in vitro'}", + "103, vitro {'context': 'I-in vitro'}", + "115, hESC-derived {'context': 'B-cells'}", + "116, skeletal {'context': 'I-cells'}", + "117, myoblasts {'context': 'I-cells'}", + "124, tibialis {'context': 'B-tissue/organ'}", + "125, anterior {'context': 'I-tissue/organ'}", + "126, muscle {'context': 'I-tissue/organ'}", + "128, SCID/Beige {'context': 'B-organism'}", + "129, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "96, skeletal ['l0']", + "97, myoblasts. ['l0']", + "98, Skeletal ['l1', 'l2', 'l3', 'l4']", + "99, muscle ['l1', 'l5', 'l6', 'l7']", + "100, cells ['l2', 'l5', 'l8', 'l9']", + "102, in ['l3', 'l6', 'l8', 'l10']", + "103, vitro ['l4', 'l7', 'l9', 'l10']", + "115, hESC-derived ['l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "116, skeletal ['l11', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "117, myoblasts ['l12', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "124, tibialis ['l13', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32']", + "125, anterior ['l14', 'l20', 'l25', 'l29', 'l33', 'l34', 'l35']", + "126, muscle ['l15', 'l21', 'l26', 'l30', 'l33', 'l36', 'l37']", + "128, SCID/Beige ['l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l38']", + "129, mice, ['l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17417649", + "TEXT": "Sudden fibrous cap disruption of 'high-risk' atherosclerotic plaques can trigger the formation of an occlusive thrombus in coronary arteries, causing acute coronary syndromes. High-risk atherosclerotic plaques are characterized by their specific cellular and biological content (in particular, a high density of macrophages), rather than by their impact on the vessel lumen. Early identification of high-risk plaques may be useful for preventing ischemic events. One major hurdle in detecting high-risk atherosclerotic plaques in coronary arteries is the lack of an imaging modality that allows for the identification of atherosclerotic plaque composition with high spatial and temporal resolutions. Here we show that macrophages in atherosclerotic plaques of rabbits can be detected with a clinical X-ray computed tomography (CT) scanner after the intravenous injection of a contrast agent formed of iodinated nanoparticles dispersed with surfactant. This contrast agent may become an important adjunct to the clinical evaluation of coronary arteries with CT.", + "TAG_DATA": [ + "100, macrophages {'context': 'B-cells'}", + "105, rabbits {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "100, macrophages ['l0']", + "105, rabbits ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17417648", + "TEXT": "The superficial bladder epithelium is a powerful barrier to urine and also serves as a regulator of bladder volume, which is achieved by apical exocytosis of specialized fusiform vesicles during distension of the bladder. We report that type 1 fimbriated uropathogenic Escherichia coli (UPEC) circumvents the bladder barrier by harboring in these Rab27b/CD63-positive and cAMP-regulatable fusiform vesicles within bladder epithelial cells (BECs). Incorporation of UPEC into BEC fusiform compartments enabled bacteria to escape elimination during voiding and to re-emerge in the urine as the bladder distended. Notably, treatment of UPEC-infected mice with a drug that increases intracellular cAMP and induces exocytosis of fusiform vesicles reduced the number of intracellular E. coli.", + "TAG_DATA": [ + "90, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17401374", + "TEXT": "MicroRNAs (miRNAs) are endogenous noncoding RNAs, about 22 nucleotides in length, that mediate post-transcriptional gene silencing by annealing to inexactly complementary sequences in the 3'-untranslated regions of target mRNAs. Our current understanding of the functions of miRNAs relies mainly on their tissue-specific or developmental stage-dependent expression and their evolutionary conservation, and therefore is primarily limited to their involvement in developmental regulation and oncogenesis. Of more than 300 miRNAs that have been identified, miR-1 and miR-133 are considered to be muscle specific. Here we show that miR-1 is overexpressed in individuals with coronary artery disease, and that when overexpressed in normal or infarcted rat hearts, it exacerbates arrhythmogenesis. Elimination of miR-1 by an antisense inhibitor in infarcted rat hearts relieved arrhythmogenesis. miR-1 overexpression slowed conduction and depolarized the cytoplasmic membrane by post-transcriptionally repressing KCNJ2 (which encodes the K(+) channel subunit Kir2.1) and GJA1 (which encodes connexin 43), and this likely accounts at least in part for its arrhythmogenic potential. Thus, miR-1 may have important pathophysiological functions in the heart, and is a potential antiarrhythmic target.", + "TAG_DATA": [ + "102, rat {'context': 'B-tissue/organ'}", + "103, hearts, {'context': 'I-tissue/organ'}", + "107, Elimination {'perturbing_action': 'B-gene loss-of-function'}", + "108, of {'perturbing_action': 'I-gene loss-of-function'}", + "109, miR-1 {'perturbing_action': 'I-gene loss-of-function'}", + "110, by {'perturbing_action': 'I-rnai/knockdown'}", + "116, rat {'context': 'I-tissue/organ'}", + "117, hearts {'context': 'I-tissue/organ'}", + "120, miR-1 {'perturbing_action': 'B-gene gain-of-function'}", + "121, overexpression {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "102, rat ['l0']", + "103, hearts, ['l0']", + "107, Elimination ['l1', 'l2', 'l3', 'l4', 'l5']", + "108, of ['l1', 'l6', 'l7', 'l8', 'l9']", + "109, miR-1 ['l2', 'l6', 'l10', 'l11', 'l12']", + "110, by ['l3', 'l7', 'l10', 'l13', 'l14']", + "116, rat ['l4', 'l8', 'l11', 'l13', 'l15']", + "117, hearts ['l5', 'l9', 'l12', 'l14', 'l15']", + "120, miR-1 ['l16']", + "121, overexpression ['l16']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Elimination", + "of", + "miR-1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "hearts" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "by" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "hearts" + ] + } + } + ] + }, + { + "PMID": "17369837", + "TEXT": "Hepatic adeno-associated virus (AAV)-serotype 2 mediated gene transfer results in transgene product expression that is sustained in experimental animals but not in human subjects. We hypothesize that this is caused by rejection of transduced hepatocytes by AAV capsid-specific memory CD8(+) T cells reactivated by AAV vectors. Here we show that healthy subjects carry AAV capsid-specific CD8(+) T cells and that AAV-mediated gene transfer results in their expansion. No such expansion occurs in mice after AAV-mediated gene transfer. In addition, we show that AAV-2 induced human T cells proliferate upon exposure to alternate AAV serotypes, indicating that other serotypes are unlikely to evade capsid-specific immune responses.", + "TAG_DATA": [ + "72, mice {'context': 'B-organism'}", + "83, induced {'effect': 'B-positive'}", + "84, human {'context': 'B-cells'}", + "85, T {'context': 'I-cells'}", + "86, cells {'context': 'I-cells'}", + "87, proliferate {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "83, induced ['l0', 'l1', 'l2', 'l3']", + "84, human ['l0', 'l4', 'l5', 'l6']", + "85, T ['l1', 'l4', 'l7', 'l8']", + "86, cells ['l2', 'l5', 'l7', 'l9']", + "87, proliferate ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "T", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "T", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate" + ] + } + } + ] + }, + { + "PMID": "17351627", + "TEXT": "Ferritin, the iron storage protein, was recently suggested to be a candidate reporter for the detection of gene expression by magnetic resonance imaging (MRI). Here we report the generation of TET:EGFP-HAferritin (tet-hfer) transgenic mice, in which tissue-specific inducible transcriptional regulation of expression of the heavy chain of ferritin could be detected in vivo by MRI. We show organ specificity by mating the tet-hfer mice with transgenic mice expressing tetracycline transactivator (tTA) in liver hepatocytes and in vascular endothelial cells. Tetracycline-regulated overexpression of ferritin resulted in specific alterations of the transverse relaxation rate (R(2)) of water. Transgene-dependent changes in R(2) were detectable by MRI in adult mice, and we also found fetal developmental induction of transgene expression in utero. Thus, the tet-hfer MRI reporter mice provide a new transgenic mouse platform for in vivo molecular imaging of reporter gene expression by MRI during both embryonic and adult life.", + "TAG_DATA": [ + "30, TET:EGFP-HAferritin {'perturbing_action': 'B-gene gain-of-function'}", + "31, (tet-hfer) {'perturbing_action': 'I-gene gain-of-function'}", + "32, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "33, mice, {'context': 'B-organism'}", + "63, mice {'context': 'I-organism'}", + "65, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "66, mice {'context': 'I-organism'}", + "67, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "68, tetracycline {'perturbing_action': 'I-gene gain-of-function'}", + "69, transactivator {'perturbing_action': 'I-gene gain-of-function'}", + "70, (tTA) {'perturbing_action': 'I-gene gain-of-function'}", + "72, liver {'context': 'B-cells'}", + "73, hepatocytes {'context': 'I-cells'}", + "76, vascular {'context': 'B-cells'}", + "77, endothelial {'context': 'I-cells'}", + "78, cells. {'context': 'I-cells'}", + "79, Tetracycline-regulated {'perturbing_action': 'B-gene gain-of-function'}", + "80, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "81, of {'perturbing_action': 'I-gene gain-of-function'}", + "82, ferritin {'perturbing_action': 'I-gene gain-of-function'}", + "104, adult {'context': 'B-organism'}", + "105, mice, {'context': 'I-organism'}", + "116, in {'context': 'B-in vivo'}", + "117, utero. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "30, TET:EGFP-HAferritin ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "31, (tet-hfer) ['l0', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "32, transgenic ['l1', 'l18', 'l31', 'l32', 'l33', 'l34', 'l35']", + "33, mice, ['l2', 'l19', 'l31', 'l36', 'l37', 'l38', 'l39']", + "63, mice ['l3', 'l20', 'l32', 'l36', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "65, transgenic ['l4', 'l40', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "66, mice ['l5', 'l41', 'l53', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "67, expressing ['l6', 'l21', 'l42', 'l54', 'l67', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "68, tetracycline ['l7', 'l43', 'l55', 'l68', 'l80', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "69, transactivator ['l8', 'l22', 'l44', 'l56', 'l69', 'l81', 'l92', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "70, (tTA) ['l9', 'l23', 'l45', 'l57', 'l70', 'l82', 'l93', 'l103', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "72, liver ['l10', 'l24', 'l33', 'l37', 'l46', 'l58', 'l71', 'l83', 'l94', 'l104', 'l113', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "73, hepatocytes ['l11', 'l25', 'l34', 'l38', 'l47', 'l59', 'l72', 'l84', 'l95', 'l105', 'l114', 'l122', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "76, vascular ['l12', 'l26', 'l48', 'l60', 'l73', 'l85', 'l96', 'l106', 'l115', 'l123', 'l129', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "77, endothelial ['l13', 'l27', 'l49', 'l61', 'l74', 'l86', 'l97', 'l107', 'l116', 'l124', 'l130', 'l135', 'l141', 'l142', 'l143', 'l144', 'l145']", + "78, cells. ['l14', 'l28', 'l35', 'l39', 'l50', 'l62', 'l75', 'l87', 'l98', 'l108', 'l117', 'l125', 'l131', 'l136', 'l141', 'l146', 'l147', 'l148', 'l149']", + "79, Tetracycline-regulated ['l63', 'l76', 'l88', 'l99', 'l109', 'l118', 'l137', 'l142', 'l146', 'l150', 'l151', 'l152']", + "80, overexpression ['l15', 'l64', 'l77', 'l89', 'l100', 'l110', 'l119', 'l126', 'l132', 'l138', 'l143', 'l147', 'l150', 'l153', 'l154']", + "81, of ['l16', 'l29', 'l51', 'l65', 'l78', 'l90', 'l101', 'l111', 'l120', 'l127', 'l133', 'l139', 'l144', 'l148', 'l151', 'l153', 'l155']", + "82, ferritin ['l17', 'l30', 'l52', 'l66', 'l79', 'l91', 'l102', 'l112', 'l121', 'l128', 'l134', 'l140', 'l145', 'l149', 'l152', 'l154', 'l155']", + "104, adult ['l156']", + "105, mice, ['l156']", + "116, in ['l157']", + "117, utero. ['l157']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "TET:EGFP-HAferritin", + "(tet-hfer)", + "transgenic", + "expressing", + "tetracycline", + "transactivator", + "(tTA)", + "of", + "ferritin", + "Tetracycline-regulated", + "overexpression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "TET:EGFP-HAferritin", + "(tet-hfer)", + "transgenic", + "expressing", + "tetracycline", + "transactivator", + "(tTA)", + "overexpression", + "of", + "ferritin", + "Tetracycline-regulated" + ] + }, + "context": { + "val": "cells", + "words": [ + "liver", + "hepatocytes", + "vascular", + "endothelial", + "cells." + ] + } + } + ] + }, + { + "PMID": "17334373", + "TEXT": "Human immunodeficiency virus-1 (HIV-1) is primarily transmitted sexually. Dendritic cells (DCs) in the subepithelium transmit HIV-1 to T cells through the C-type lectin DC-specific intercellular adhesion molecule (ICAM)-3-grabbing nonintegrin (DC-SIGN). However, the epithelial Langerhans cells (LCs) are the first DC subset to encounter HIV-1. It has generally been assumed that LCs mediate the transmission of HIV-1 to T cells through the C-type lectin Langerin, similarly to transmission by DC-SIGN on dendritic cells (DCs). Here we show that in stark contrast to DC-SIGN, Langerin prevents HIV-1 transmission by LCs. HIV-1 captured by Langerin was internalized into Birbeck granules and degraded. Langerin inhibited LC infection and this mechanism kept LCs refractory to HIV-1 transmission; inhibition of Langerin allowed LC infection and subsequent HIV-1 transmission. Notably, LCs also inhibited T-cell infection by viral clearance through Langerin. Thus Langerin is a natural barrier to HIV-1 infection, and strategies to combat infection must enhance, preserve or, at the very least, not interfere with Langerin expression and function.", + "TAG_DATA": [ + "101, LC {'context': 'B-cells'}", + "107, LCs {'context': 'B-cells'}", + "112, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "113, of {'perturbing_action': 'I-pharmacological inhibition'}", + "114, Langerin {'perturbing_action': 'I-pharmacological inhibition'}", + "116, LC {'context': 'B-cells'}", + "126, T-cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "101, LC ['l0']", + "107, LCs ['l0', 'l1']", + "112, inhibition ['l2', 'l3', 'l4', 'l5']", + "113, of ['l2', 'l6', 'l7', 'l8']", + "114, Langerin ['l3', 'l6', 'l9', 'l10']", + "116, LC ['l1', 'l4', 'l7', 'l9']", + "126, T-cell ['l5', 'l8', 'l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "Langerin" + ] + }, + "context": { + "val": "cells", + "words": [ + "LC", + "T-cell" + ] + } + } + ] + }, + { + "PMID": "17334370", + "TEXT": "Lung cancer is the leading cause of death from cancer in the US and the world. The high mortality rate (80-85% within 5 years) results, in part, from a lack of effective tools to diagnose the disease at an early stage. Given that cigarette smoke creates a field of injury throughout the airway, we sought to determine if gene expression in histologically normal large-airway epithelial cells obtained at bronchoscopy from smokers with suspicion of lung cancer could be used as a lung cancer biomarker. Using a training set (n = 77) and gene-expression profiles from Affymetrix HG-U133A microarrays, we identified an 80-gene biomarker that distinguishes smokers with and without lung cancer. We tested the biomarker on an independent test set (n = 52), with an accuracy of 83% (80% sensitive, 84% specific), and on an additional validation set independently obtained from five medical centers (n = 35). Our biomarker had approximately 90% sensitivity for stage 1 cancer across all subjects. Combining cytopathology of lower airway cells obtained at bronchoscopy with the biomarker yielded 95% sensitivity and a 95% negative predictive value. These findings indicate that gene expression in cytologically normal large-airway epithelial cells can serve as a lung cancer biomarker, potentially owing to a cancer-specific airway-wide response to cigarette smoke.", + "TAG_DATA": [ + "163, lower {'context': 'B-cells'}", + "164, airway {'context': 'I-cells'}", + "165, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "163, lower ['l0', 'l1']", + "164, airway ['l0', 'l2']", + "165, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17322897", + "TEXT": "Transmissibility of characteristic lesions to experimental animals may help us understand the pathomechanism of human autoimmune disease. Here we show that human autoimmune disease can be reproduced using genetically engineered model mice. Bullous pemphigoid (BP) is the most common serious autoimmune blistering skin disease, with a considerable body of indirect evidence indicating that the underlying autoantigen is collagen XVII (COL17). Passive transfer of human BP autoantibodies into mice does not induce skin lesions, probably because of differences between humans and mice in the amino acid sequence of the COL17 pathogenic epitope. We injected human BP autoantibody into Col17-knockout mice rescued by the human ortholog. This resulted in BP-like skin lesions and a human disease phenotype. Humanization of autoantigens is a new approach to the study of human autoimmune diseases.", + "TAG_DATA": [ + "67, mice {'context': 'B-organism'}", + "97, Col17-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "98, mice {'context': 'B-organism'}", + "99, rescued {'effect': 'B-rescues'}" + ], + "LINK_DATA": [ + "97, Col17-knockout ['l0', 'l1']", + "98, mice ['l0', 'l2']", + "99, rescued ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Col17-knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Col17-knockout" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + } + ] + }, + { + "PMID": "17259996", + "TEXT": "Excessive retinal vascular permeability contributes to the pathogenesis of proliferative diabetic retinopathy and diabetic macular edema, leading causes of vision loss in working-age adults. Using mass spectroscopy-based proteomics, we detected 117 proteins in human vitreous and elevated levels of extracellular carbonic anhydrase-I (CA-I) in vitreous from individuals with diabetic retinopathy, suggesting that retinal hemorrhage and erythrocyte lysis contribute to the diabetic vitreous proteome. Intravitreous injection of CA-I in rats increased retinal vessel leakage and caused intraretinal edema. CA-I-induced alkalinization of vitreous increased kallikrein activity and its generation of factor XIIa, revealing a new pathway for contact system activation. CA-I-induced retinal edema was decreased by complement 1 inhibitor, neutralizing antibody to prekallikrein and bradykinin receptor antagonism. Subdural infusion of CA-I in rats induced cerebral vascular permeability, suggesting that extracellular CA-I could have broad relevance to neurovascular edema. Inhibition of extracellular CA-I and kallikrein-mediated innate inflammation could provide new therapeutic opportunities for the treatment of hemorrhage-induced retinal and cerebral edema.", + "TAG_DATA": [ + "68, rats {'context': 'B-organism'}", + "120, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17259995", + "TEXT": "Wilson disease is caused by accumulation of Cu(2+) in cells, which results in liver cirrhosis and, occasionally, anemia. Here, we show that Cu(2+) triggers hepatocyte apoptosis through activation of acid sphingomyelinase (Asm) and release of ceramide. Genetic deficiency or pharmacological inhibition of Asm prevented Cu(2+)-induced hepatocyte apoptosis and protected rats, genetically prone to develop Wilson disease, from acute hepatocyte death, liver failure and early death. Cu(2+) induced the secretion of activated Asm from leukocytes, leading to ceramide release in and phosphatidylserine exposure on erythrocytes, events also prevented by inhibition of Asm. Phosphatidylserine exposure resulted in immediate clearance of affected erythrocytes from the blood in mice. Accordingly, individuals with Wilson disease showed elevated plasma levels of Asm, and displayed a constitutive increase of ceramide- and phosphatidylserine-positive erythrocytes. Our data suggest a previously unidentified mechanism for liver cirrhosis and anemia in Wilson disease.", + "TAG_DATA": [ + "23, triggers {'effect': 'B-positive'}", + "24, hepatocyte {'context': 'B-cells'}", + "25, apoptosis {'phenotype': 'B-apoptosis'}", + "39, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "40, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "41, of {'perturbing_action': 'I-pharmacological inhibition'}", + "42, Asm {'perturbing_action': 'I-pharmacological inhibition'}", + "43, prevented {'effect': 'B-negative'}", + "44, Cu(2+)-induced {'effect': 'B-positive'}", + "45, hepatocyte {'context': 'B-cells'}", + "46, apoptosis {'phenotype': 'B-apoptosis'}", + "49, rats, {'context': 'B-organism'}", + "58, hepatocyte {'context': 'B-cells'}", + "83, erythrocytes, {'context': 'B-cells'}", + "88, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "89, of {'perturbing_action': 'I-pharmacological inhibition'}", + "90, Asm. {'perturbing_action': 'I-pharmacological inhibition'}", + "99, erythrocytes {'context': 'B-cells'}", + "104, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "23, triggers ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "24, hepatocyte ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "25, apoptosis ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "39, pharmacological ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "40, inhibition ['l15', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "41, of ['l16', 'l28', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "42, Asm ['l17', 'l29', 'l38', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "43, prevented ['l2', 'l7', 'l11', 'l18', 'l30', 'l39', 'l47', 'l54', 'l55', 'l56', 'l57', 'l58']", + "44, Cu(2+)-induced ['l3', 'l8', 'l12', 'l19', 'l31', 'l40', 'l48', 'l54', 'l59', 'l60', 'l61', 'l62']", + "45, hepatocyte ['l4', 'l9', 'l13', 'l20', 'l32', 'l41', 'l49', 'l55', 'l59', 'l63', 'l64']", + "46, apoptosis ['l5', 'l10', 'l14', 'l21', 'l33', 'l42', 'l50', 'l56', 'l60', 'l63', 'l65']", + "49, rats, ['l22', 'l34', 'l43', 'l51', 'l57', 'l61', 'l66', 'l67']", + "58, hepatocyte ['l23', 'l35', 'l44', 'l52', 'l58', 'l62', 'l64', 'l65', 'l66']", + "83, erythrocytes, ['l24', 'l36', 'l45', 'l53', 'l67']", + "88, inhibition ['l68', 'l69', 'l70', 'l71']", + "89, of ['l25', 'l68', 'l72', 'l73', 'l74']", + "90, Asm. ['l26', 'l37', 'l46', 'l69', 'l72', 'l75', 'l76']", + "99, erythrocytes ['l27', 'l70', 'l73', 'l75', 'l77']", + "104, mice. ['l71', 'l74', 'l76', 'l77']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "triggers", + "Cu(2+)-induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocyte" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggers", + "Cu(2+)-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hepatocyte" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hepatocyte" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "Asm" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "Asm" + ] + }, + "effect": { + "val": "positive", + "words": [ + "Cu(2+)-induced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "Asm", + "Asm." + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocyte", + "erythrocytes,", + "erythrocytes" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "Asm" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "Asm", + "Asm." + ] + }, + "context": { + "val": "organism", + "words": [ + "rats,", + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Cu(2+)-induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats," + ] + } + } + ] + }, + { + "PMID": "17259994", + "TEXT": "Orexins are hypothalamic peptides that play an important role in maintaining wakefulness in mammals. Permanent deficit in orexinergic function is a pathophysiological hallmark of rodent, canine and human narcolepsy. Here we report that in rats, dogs and humans, somnolence is induced by pharmacological blockade of both orexin OX(1) and OX(2) receptors. When administered orally during the active period of the circadian cycle, a dual antagonist increased, in rats, electrophysiological indices of both non-REM and, particularly, REM sleep, in contrast to GABA(A) receptor modulators; in dogs, it caused somnolence and increased surrogate markers of REM sleep; and in humans, it caused subjective and objective electrophysiological signs of sleep. No signs of cataplexy were observed, in contrast to the rodent, dog or human narcolepsy syndromes. These results open new perspectives for investigating the role of endogenous orexins in sleep-wake regulation.", + "TAG_DATA": [ + "34, rats, {'context': 'B-organism'}", + "35, dogs {'context': 'B-organism'}", + "42, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "43, blockade {'perturbing_action': 'I-pharmacological inhibition'}", + "44, of {'perturbing_action': 'I-pharmacological inhibition'}", + "45, both {'perturbing_action': 'I-pharmacological inhibition'}", + "46, orexin {'perturbing_action': 'I-pharmacological inhibition'}", + "47, OX(1) {'perturbing_action': 'I-pharmacological inhibition'}", + "48, and {'perturbing_action': 'I-pharmacological inhibition'}", + "49, OX(2) {'perturbing_action': 'I-pharmacological inhibition'}", + "50, receptors. {'perturbing_action': 'I-pharmacological inhibition'}", + "67, rats, {'context': 'B-organism'}", + "84, dogs, {'context': 'B-organism'}", + "97, humans, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "34, rats, ['l0']", + "35, dogs ['l0']", + "42, pharmacological ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "43, blockade ['l1', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "44, of ['l2', 'l11', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "45, both ['l3', 'l12', 'l20', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "46, orexin ['l4', 'l13', 'l21', 'l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "47, OX(1) ['l5', 'l14', 'l22', 'l29', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "48, and ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l46', 'l47', 'l48', 'l49']", + "49, OX(2) ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l50', 'l51', 'l52']", + "50, receptors. ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l53', 'l54']", + "67, rats, ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53']", + "84, dogs, ['l10', 'l19', 'l27', 'l34', 'l40', 'l45', 'l49', 'l52', 'l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "blockade", + "of", + "both", + "orexin", + "OX(1)", + "and", + "OX(2)", + "receptors." + ] + }, + "context": { + "val": "organism", + "words": [ + "rats,", + "dogs," + ] + } + } + ] + }, + { + "PMID": "17237794", + "TEXT": "Skeletal muscle has the ability to achieve rapid repair in response to injury or disease. Many individuals with Marfan syndrome (MFS), caused by a deficiency of extracellular fibrillin-1, exhibit myopathy and often are unable to increase muscle mass despite physical exercise. Evidence suggests that selected manifestations of MFS reflect excessive signaling by transforming growth factor (TGF)-beta (refs. 2,3). TGF-beta is a known inhibitor of terminal differentiation of cultured myoblasts; however, the functional contribution of TGF-beta signaling to disease pathogenesis in various inherited myopathic states in vivo remains unknown. Here we show that increased TGF-beta activity leads to failed muscle regeneration in fibrillin-1-deficient mice. Systemic antagonism of TGF-beta through administration of TGF-beta-neutralizing antibody or the angiotensin II type 1 receptor blocker losartan normalizes muscle architecture, repair and function in vivo. Moreover, we show TGF-beta-induced failure of muscle regeneration and a similar therapeutic response in a dystrophin-deficient mouse model of Duchenne muscular dystrophy.", + "TAG_DATA": [ + "101, fibrillin-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "102, mice. {'context': 'B-organism'}", + "104, antagonism {'perturbing_action': 'I-pharmacological inhibition'}", + "105, of {'perturbing_action': 'I-pharmacological inhibition'}", + "106, TGF-beta {'perturbing_action': 'I-pharmacological inhibition'}", + "114, angiotensin {'perturbing_action': 'B-pharmacological inhibition'}", + "115, II {'perturbing_action': 'I-pharmacological inhibition'}", + "116, type {'perturbing_action': 'I-pharmacological inhibition'}", + "117, 1 {'perturbing_action': 'I-pharmacological inhibition'}", + "118, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "119, blocker {'perturbing_action': 'I-pharmacological inhibition'}", + "122, muscle {'context': 'B-tissue/organ'}", + "127, in {'context': 'B-in vivo'}", + "128, vivo. {'context': 'I-in vivo'}", + "144, dystrophin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "145, mouse {'context': 'B-organism'}", + "146, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "98, muscle ['l0', 'l1']", + "99, regeneration ['l0', 'l2']", + "101, fibrillin-1-deficient ['l3']", + "102, mice. ['l1', 'l2', 'l3']", + "104, antagonism ['l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "105, of ['l4', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "106, TGF-beta ['l5', 'l16', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "114, angiotensin ['l6', 'l17', 'l27', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "115, II ['l7', 'l18', 'l28', 'l37', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "116, type ['l8', 'l19', 'l29', 'l38', 'l48', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "117, 1 ['l9', 'l20', 'l30', 'l39', 'l49', 'l58', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "118, receptor ['l10', 'l21', 'l31', 'l40', 'l50', 'l59', 'l67', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "119, blocker ['l11', 'l22', 'l32', 'l41', 'l51', 'l60', 'l68', 'l75', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "122, muscle ['l12', 'l23', 'l33', 'l42', 'l52', 'l61', 'l69', 'l76', 'l82', 'l88', 'l89']", + "127, in ['l13', 'l24', 'l34', 'l43', 'l53', 'l62', 'l70', 'l77', 'l83', 'l88', 'l90']", + "128, vivo. ['l14', 'l25', 'l35', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l89', 'l90']", + "144, dystrophin-deficient ['l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l91', 'l92']", + "145, mouse ['l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l93']", + "146, model ['l15', 'l26', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l93']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "fibrillin-1-deficient", + "dystrophin-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antagonism", + "of", + "TGF-beta", + "angiotensin", + "II", + "type", + "1", + "receptor", + "blocker" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscle" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antagonism", + "of", + "TGF-beta", + "angiotensin", + "II", + "type", + "1", + "receptor", + "blocker" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antagonism", + "of", + "TGF-beta", + "angiotensin", + "II", + "type", + "1", + "receptor", + "blocker" + ] + }, + "context": { + "val": "organism", + "words": [ + "model", + "mouse" + ] + } + } + ] + }, + { + "PMID": "17195839", + "TEXT": "Metabolic hormones, such as leptin, alter the input organization of hypothalamic circuits, resulting in increased pro-opiomelanocortin (POMC) tone, followed by decreased food intake and adiposity. The gonadal steroid estradiol can also reduce appetite and adiposity, and it influences synaptic plasticity. Here we report that estradiol (E2) triggers a robust increase in the number of excitatory inputs to POMC neurons in the arcuate nucleus of wild-type rats and mice. This rearrangement of synapses in the arcuate nucleus is leptin independent because it also occurred in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice, and was paralleled by decreased food intake and body weight gain as well as increased energy expenditure. However, estrogen-induced decrease in body weight was dependent on Stat3 activation in the brain. These observations support the notion that synaptic plasticity of arcuate nucleus feeding circuits is an inherent element in body weight regulation and offer alternative approaches to reducing adiposity under conditions of failed leptin receptor signaling.", + "TAG_DATA": [ + "58, neurons {'context': 'I-cells'}", + "61, arcuate {'context': 'B-cells'}", + "62, nucleus {'context': 'I-cells'}", + "65, rats {'context': 'B-organism'}", + "67, mice. {'context': 'B-organism'}", + "84, leptin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "85, (ob/ob) {'perturbing_action': 'I-gene loss-of-function'}", + "87, leptin {'perturbing_action': 'B-gene loss-of-function'}", + "88, receptor-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "89, (db/db) {'perturbing_action': 'I-gene loss-of-function'}", + "90, mice, {'context': 'B-organism'}", + "121, brain. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "58, neurons ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "61, arcuate ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "62, nucleus ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "65, rats ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "67, mice. ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "84, leptin-deficient ['l4', 'l9', 'l13', 'l16', 'l18', 'l20', 'l21']", + "85, (ob/ob) ['l5', 'l10', 'l14', 'l17', 'l19', 'l20', 'l22']", + "87, leptin ['l23', 'l24', 'l25']", + "88, receptor-deficient ['l23', 'l26', 'l27']", + "89, (db/db) ['l24', 'l26', 'l28']", + "90, mice, ['l21', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "neurons", + "arcuate", + "nucleus" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "leptin-deficient", + "(ob/ob)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rats", + "mice.", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "leptin-deficient", + "(ob/ob)", + "leptin", + "receptor-deficient", + "(db/db)" + ] + } + } + ] + }, + { + "PMID": "17187073", + "TEXT": "Successful development of ultra-sensitive molecular imaging nanoprobes for the detection of targeted biological objects is a challenging task. Although magnetic nanoprobes have the potential to perform such a role, the results from probes that are currently available have been far from optimal. Here we used artificial engineering approaches to develop innovative magnetic nanoprobes, through a process that involved the systematic evaluation of the magnetic spin, size and type of spinel metal ferrites. These magnetism-engineered iron oxide (MEIO) nanoprobes, when conjugated with antibodies, showed enhanced magnetic resonance imaging (MRI) sensitivity for the detection of cancer markers compared with probes currently available. Also, we successfully visualized small tumors implanted in a mouse. Such high-performance, nanotechnology-based molecular probes could enhance the ability to visualize other biological events critical to diagnostics and therapeutics.", + "TAG_DATA": [ + "105, tumors {'context': 'I-neoplasm'}", + "109, mouse. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "105, tumors ['l0']", + "109, mouse. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17115049", + "TEXT": "Comprehensive volumetric microscopy of epithelial, mucosal and endothelial tissues in living human patients would have a profound impact in medicine by enabling diagnostic imaging at the cellular level over large surface areas. Considering the vast area of these tissues with respect to the desired sampling interval, achieving this goal requires rapid sampling. Although noninvasive diagnostic technologies are preferred, many applications could be served by minimally invasive instruments capable of accessing remote locations within the body. We have developed a fiber-optic imaging technique termed optical frequency-domain imaging (OFDI) that satisfies these requirements by rapidly acquiring high-resolution, cross-sectional images through flexible, narrow-diameter catheters. Using a prototype system, we show comprehensive microscopy of esophageal mucosa and of coronary arteries in vivo. Our pilot study results suggest that this technology may be a useful clinical tool for comprehensive diagnostic imaging for epithelial disease and for evaluating coronary pathology and iatrogenic effects.", + "TAG_DATA": [ + "110, esophageal {'context': 'B-tissue/organ'}", + "111, mucosa {'context': 'I-tissue/organ'}", + "114, coronary {'context': 'B-tissue/organ'}", + "115, arteries {'context': 'I-tissue/organ'}", + "116, in {'context': 'B-in vivo'}", + "117, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "110, esophageal ['l0', 'l1', 'l2', 'l3']", + "111, mucosa ['l0', 'l4', 'l5', 'l6']", + "114, coronary ['l1', 'l4', 'l7', 'l8', 'l9']", + "115, arteries ['l2', 'l5', 'l7', 'l10', 'l11']", + "116, in ['l8', 'l10', 'l12']", + "117, vivo. ['l3', 'l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17115047", + "TEXT": "The continuous renewal of human epidermis is sustained by stem cells contained in the epidermal basal layer and in hair follicles. Cultured keratinocyte stem cells, known as holoclones, generate sheets of epithelium used to restore severe skin, mucosal and corneal defects. Mutations in genes encoding the basement membrane component laminin 5 (LAM5) cause junctional epidermolysis bullosa (JEB), a devastating and often fatal skin adhesion disorder. Epidermal stem cells from an adult patient affected by LAM5-beta3-deficient JEB were transduced with a retroviral vector expressing LAMB3 cDNA (encoding LAM5-beta3), and used to prepare genetically corrected cultured epidermal grafts. Nine grafts were transplanted onto surgically prepared regions of the patient's legs. Engraftment was complete after 8 d. Synthesis and proper assembly of normal levels of functional LAM5 were observed, together with the development of a firmly adherent epidermis that remained stable for the duration of the follow-up (1 year) in the absence of blisters, infections, inflammation or immune response. Retroviral integration site analysis indicated that the regenerated epidermis is maintained by a defined repertoire of transduced stem cells. These data show that ex vivo gene therapy of JEB is feasible and leads to full functional correction of the disease.", + "TAG_DATA": [ + "65, Epidermal {'context': 'B-cells'}", + "66, stem {'context': 'I-cells'}", + "67, cells {'context': 'I-cells'}", + "68, from {'context': 'I-cells'}", + "70, adult {'context': 'B-patient'}", + "71, patient {'context': 'I-patient'}", + "74, LAM5-beta3-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "77, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "78, with {'perturbing_action': 'I-gene gain-of-function'}", + "79, a {'perturbing_action': 'I-gene gain-of-function'}", + "80, retroviral {'perturbing_action': 'I-gene gain-of-function'}", + "81, vector {'perturbing_action': 'I-gene gain-of-function'}", + "82, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "83, LAMB3 {'perturbing_action': 'I-gene gain-of-function'}", + "84, cDNA {'perturbing_action': 'I-gene gain-of-function'}", + "85, (encoding {'perturbing_action': 'I-gene gain-of-function'}", + "86, LAM5-beta3), {'perturbing_action': 'I-gene gain-of-function'}", + "106, patient's {'context': 'B-tissue/organ'}", + "107, legs. {'context': 'I-tissue/organ'}", + "134, epidermis {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "65, Epidermal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "66, stem ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "67, cells ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "68, from ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "70, adult ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "71, patient ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "74, LAM5-beta3-deficient ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "75, JEB ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "77, transduced ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "78, with ['l28', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "79, a ['l29', 'l37', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "80, retroviral ['l30', 'l38', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "81, vector ['l31', 'l39', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "82, expressing ['l32', 'l40', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "83, LAMB3 ['l33', 'l41', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "84, cDNA ['l34', 'l42', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "85, (encoding ['l35', 'l43', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "86, LAM5-beta3), ['l36', 'l44', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "106, patient's ['l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90', 'l91']", + "107, legs. ['l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90', 'l92']", + "134, epidermis ['l91', 'l92']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Epidermal", + "stem", + "cells", + "from" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "LAM5-beta3-deficient" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "adult", + "patient" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "LAM5-beta3-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "with", + "a", + "retroviral", + "vector", + "expressing", + "LAMB3", + "cDNA", + "(encoding", + "LAM5-beta3)," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "legs.", + "patient's" + ] + } + } + ] + }, + { + "PMID": "17072311", + "TEXT": "Brain hemorrhage is a serious complication of tissue plasminogen activator (tPA) therapy for ischemic stroke. Here we report that activated protein C (APC), a plasma serine protease with systemic anticoagulant, anti-inflammatory and antiapoptotic activities, and direct vasculoprotective and neuroprotective activities, blocks tPA-mediated brain hemorrhage after transient brain ischemia and embolic stroke in rodents. We show that APC inhibits a pro-hemorrhagic tPA-induced, NF-kappaB-dependent matrix metalloproteinase-9 pathway in ischemic brain endothelium in vivo and in vitro by acting through protease-activated receptor 1. The present findings suggest that APC may improve thrombolytic therapy for stroke, in part, by reducing tPA-mediated hemorrhage.", + "TAG_DATA": [ + "52, rodents. {'context': 'B-organism'}", + "67, brain {'context': 'I-cells'}", + "68, endothelium {'context': 'I-cells'}", + "69, in {'context': 'B-in vivo'}", + "70, vivo {'context': 'I-in vivo'}", + "72, in {'context': 'B-in vitro'}", + "73, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "67, brain ['l0', 'l1', 'l2']", + "68, endothelium ['l0', 'l3', 'l4']", + "69, in ['l1', 'l3', 'l5']", + "70, vivo ['l2', 'l4', 'l5']", + "72, in ['l6']", + "73, vitro ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17057712", + "TEXT": "Here we show that transplantation of autologous human hematopoietic fetal liver CD34+ cells into NOD/SCID mice previously implanted with human fetal thymic and liver tissues results in long-term, systemic human T-cell homeostasis. In addition, these mice show systemic repopulation with human B cells, monocytes and macrophages, and dendritic cells (DCs). T cells in these mice generate human major histocompatibility complex class I- and class II-restricted adaptive immune responses to Epstein-Barr virus (EBV) infection and are activated by human DCs to mount a potent T-cell immune response to superantigens. Administration of the superantigen toxic shock syndrome toxin 1 (TSST-1) results in the specific systemic expansion of human Vbeta2+ T cells, release of human proinflammatory cytokines and localized, specific activation and maturation of human CD11c+ dendritic cells. This represents the first demonstration of long-term systemic human T-cell reconstitution in vivo allowing for the manifestation of the differential response by human DCs to TSST-1.", + "TAG_DATA": [ + "14, NOD/SCID {'context': 'B-organism'}", + "15, mice {'context': 'I-organism'}", + "35, mice {'context': 'B-organism'}", + "40, human {'context': 'B-cells'}", + "41, B {'context': 'I-cells'}", + "42, cells, {'context': 'I-cells'}", + "50, T {'context': 'B-cells'}", + "51, cells {'context': 'B-cells'}", + "54, mice {'context': 'B-organism'}", + "77, human {'context': 'B-cells'}", + "105, human {'context': 'B-cells'}", + "106, Vbeta2+ {'context': 'I-cells'}", + "107, T {'context': 'I-cells'}", + "108, cells, {'context': 'I-cells'}", + "121, human {'context': 'B-cells'}", + "122, CD11c+ {'context': 'I-cells'}", + "123, dendritic {'context': 'I-cells'}", + "124, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "7, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "8, hematopoietic ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "9, fetal ['l1', 'l16', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "10, liver ['l2', 'l17', 'l32', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "11, CD34+ ['l3', 'l18', 'l33', 'l47', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "12, cells ['l4', 'l19', 'l34', 'l48', 'l61', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "14, NOD/SCID ['l5', 'l20', 'l35', 'l49', 'l62', 'l74', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "15, mice ['l6', 'l21', 'l36', 'l50', 'l63', 'l75', 'l84', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "35, mice ['l7', 'l22', 'l37', 'l51', 'l64', 'l76', 'l85', 'l93', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "40, human ['l8', 'l23', 'l38', 'l52', 'l65', 'l77', 'l86', 'l94', 'l101', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "41, B ['l9', 'l24', 'l39', 'l53', 'l66', 'l78', 'l87', 'l95', 'l102', 'l108', 'l114', 'l115', 'l116', 'l117', 'l118']", + "42, cells, ['l10', 'l25', 'l40', 'l54', 'l67', 'l79', 'l88', 'l96', 'l103', 'l109', 'l114', 'l119', 'l120', 'l121', 'l122']", + "50, T ['l11', 'l26', 'l41', 'l55', 'l68', 'l80', 'l89', 'l97', 'l104', 'l110', 'l115', 'l119', 'l123', 'l124', 'l125']", + "51, cells ['l12', 'l27', 'l42', 'l56', 'l69', 'l81', 'l90', 'l98', 'l105', 'l111', 'l116', 'l120', 'l123', 'l126', 'l127']", + "54, mice ['l13', 'l28', 'l43', 'l57', 'l70', 'l82', 'l91', 'l99', 'l106', 'l112', 'l117', 'l121', 'l124', 'l126', 'l128']", + "77, human ['l14', 'l29', 'l44', 'l58', 'l71', 'l83', 'l92', 'l100', 'l107', 'l113', 'l118', 'l122', 'l125', 'l127', 'l128']", + "105, human ['l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "106, Vbeta2+ ['l129', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141']", + "107, T ['l30', 'l45', 'l59', 'l72', 'l130', 'l136', 'l142', 'l143', 'l144', 'l145', 'l146']", + "108, cells, ['l15', 'l31', 'l46', 'l60', 'l73', 'l131', 'l137', 'l142', 'l147']", + "121, human ['l132', 'l138', 'l143', 'l148', 'l149', 'l150']", + "122, CD11c+ ['l133', 'l139', 'l144', 'l148', 'l151', 'l152']", + "123, dendritic ['l134', 'l140', 'l145', 'l149', 'l151', 'l153']", + "124, cells. ['l135', 'l141', 'l146', 'l147', 'l150', 'l152', 'l153']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "17057711", + "TEXT": "We report that GTP cyclohydrolase (GCH1), the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis, is a key modulator of peripheral neuropathic and inflammatory pain. BH4 is an essential cofactor for catecholamine, serotonin and nitric oxide production. After axonal injury, concentrations of BH4 rose in primary sensory neurons, owing to upregulation of GCH1. After peripheral inflammation, BH4 also increased in dorsal root ganglia (DRGs), owing to enhanced GCH1 enzyme activity. Inhibiting this de novo BH4 synthesis in rats attenuated neuropathic and inflammatory pain and prevented nerve injury-evoked excess nitric oxide production in the DRG, whereas administering BH4 intrathecally exacerbated pain. In humans, a haplotype of the GCH1 gene (population frequency 15.4%) was significantly associated with less pain following diskectomy for persistent radicular low back pain. Healthy individuals homozygous for this haplotype exhibited reduced experimental pain sensitivity, and forskolin-stimulated immortalized leukocytes from haplotype carriers upregulated GCH1 less than did controls. BH4 is therefore an intrinsic regulator of pain sensitivity and chronicity, and the GTP cyclohydrolase haplotype is a marker for these traits.", + "TAG_DATA": [ + "75, rats {'context': 'B-organism'}", + "91, DRG, {'context': 'B-tissue/organ'}", + "124, individuals {'context': 'I-cells'}", + "125, homozygous {'perturbing_action': 'B-other'}", + "126, for {'perturbing_action': 'I-other'}", + "136, immortalized {'context': 'B-cells'}", + "137, leukocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "124, individuals ['l0', 'l1', 'l2', 'l3']", + "125, homozygous ['l0', 'l4', 'l5', 'l6', 'l7']", + "126, for ['l1', 'l4', 'l8', 'l9', 'l10']", + "128, haplotype ['l2', 'l5', 'l8', 'l11', 'l12']", + "136, immortalized ['l6', 'l9', 'l11', 'l13']", + "137, leukocytes ['l3', 'l7', 'l10', 'l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "individuals", + "immortalized", + "leukocytes" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "homozygous", + "for" + ] + } + } + ] + }, + { + "PMID": "17024189", + "TEXT": "Spain's backing of biomedical research has grown steadily over the past few years, but the direction of some of its key programs could turn this support into a wasted opportunity.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "17013384", + "TEXT": "Identification of pathogen-specific T cells has been greatly facilitated by the advent of synthetic peptide-major histocompatibility complex (MHC) tetramers. In many cases, however, specific epitopes have not been defined, necessitating detection methods that function independently of exact peptide-MHC specificity. Lymphocytes acquire surface proteins from antigen-presenting cells (APCs), and we have exploited this phenomenon to develop the T-cell recognition of APCs by protein transfer (TRAP) assay. This method is based on biotinylation and streptavidin-fluorochrome labeling of APCs, followed by subsequent acquisition of this label by antigen-specific T cells. The TRAP procedure detects MHC class I-restricted T cells regardless of their cytokine profiles or peptide-MHC affinities, and provides a versatile tool for monitoring the phenomenon of APC membrane acquisition by antigen-specific T cells.", + "TAG_DATA": [ + "94, T {'context': 'B-cells'}", + "95, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "94, T ['l0']", + "95, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16998483", + "TEXT": "In individuals with chronic myeloid leukemia (CML) treated by autologous hematopoietic stem cell (HSC) transplantation, malignant progenitors in the graft contribute to leukemic relapse, but the mechanisms of homing and engraftment of leukemic CML stem cells are unknown. Here we show that CD44 expression is increased on mouse stem-progenitor cells expressing BCR-ABL and that CD44 contributes functional E-selectin ligands. In a mouse retroviral transplantation model of CML, BCR-ABL1-transduced progenitors from CD44-mutant donors are defective in homing to recipient marrow, resulting in decreased engraftment and impaired induction of CML-like myeloproliferative disease. By contrast, CD44-deficient stem cells transduced with empty retrovirus engraft as efficiently as do wild-type HSCs. CD44 is dispensable for induction of acute B-lymphoblastic leukemia by BCR-ABL, indicating that CD44 is specifically required on leukemic cells that initiate CML. The requirement for donor CD44 is bypassed by direct intrafemoral injection of BCR-ABL1-transduced CD44-deficient stem cells or by coexpression of human CD44. Antibody to CD44 attenuates induction of CML-like leukemia in recipients. These results show that BCR-ABL-expressing leukemic stem cells depend to a greater extent on CD44 for homing and engraftment than do normal HSCs, and argue that CD44 blockade may be beneficial in autologous transplantation in CML.", + "TAG_DATA": [ + "67, BCR-ABL1-transduced {'perturbing_action': 'B-gene gain-of-function'}", + "68, progenitors {'context': 'B-cells'}", + "70, CD44-mutant {'perturbing_action': 'B-other'}", + "92, CD44-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "93, stem {'context': 'B-cells'}", + "94, cells {'context': 'I-cells'}", + "95, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "105, HSCs. {'context': 'B-cells'}", + "112, acute {'context': 'B-neoplasm'}", + "113, B-lymphoblastic {'context': 'I-neoplasm'}", + "114, leukemia {'context': 'I-neoplasm'}", + "141, BCR-ABL1-transduced {'perturbing_action': 'B-gene gain-of-function'}", + "142, CD44-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "143, stem {'context': 'B-cells'}", + "144, cells {'context': 'I-cells'}", + "147, coexpression {'perturbing_action': 'B-gene gain-of-function'}", + "148, of {'perturbing_action': 'I-gene gain-of-function'}", + "149, human {'perturbing_action': 'I-gene gain-of-function'}", + "150, CD44. {'perturbing_action': 'I-gene gain-of-function'}", + "151, Antibody {'perturbing_action': 'B-rnai/knockdown'}", + "152, to {'perturbing_action': 'I-rnai/knockdown'}", + "154, attenuates {'effect': 'B-negative'}", + "155, induction {'effect': 'B-positive'}", + "157, CML-like {'phenotype': 'B-tumourigenesis'}", + "158, leukemia {'phenotype': 'I-tumourigenesis'}" + ], + "LINK_DATA": [ + "67, BCR-ABL1-transduced ['l0', 'l1']", + "68, progenitors ['l0', 'l2']", + "70, CD44-mutant ['l1', 'l2']", + "92, CD44-deficient ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "93, stem ['l3', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "94, cells ['l4', 'l14', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "95, transduced ['l5', 'l15', 'l23', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "97, empty ['l6', 'l16', 'l24', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "98, retrovirus ['l7', 'l17', 'l25', 'l32', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "105, HSCs. ['l8', 'l18', 'l26', 'l33', 'l40', 'l46', 'l52', 'l53', 'l54', 'l55']", + "112, acute ['l9', 'l19', 'l27', 'l34', 'l41', 'l47', 'l52', 'l56', 'l57', 'l58']", + "113, B-lymphoblastic ['l10', 'l20', 'l28', 'l35', 'l42', 'l48', 'l53', 'l56', 'l59', 'l60']", + "114, leukemia ['l11', 'l21', 'l29', 'l36', 'l43', 'l49', 'l54', 'l57', 'l59', 'l61']", + "141, BCR-ABL1-transduced ['l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "142, CD44-deficient ['l62', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "143, stem ['l12', 'l37', 'l44', 'l50', 'l63', 'l68', 'l76', 'l77']", + "144, cells ['l13', 'l22', 'l30', 'l38', 'l45', 'l51', 'l55', 'l58', 'l60', 'l61', 'l64', 'l69', 'l76']", + "147, coexpression ['l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "148, of ['l70', 'l78', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "149, human ['l71', 'l79', 'l88', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "150, CD44. ['l65', 'l72', 'l80', 'l89', 'l97', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "151, Antibody ['l81', 'l90', 'l98', 'l105', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "152, to ['l82', 'l91', 'l99', 'l106', 'l112', 'l118', 'l119', 'l120', 'l121', 'l122']", + "153, CD44 ['l83', 'l92', 'l100', 'l107', 'l113', 'l118', 'l123', 'l124', 'l125', 'l126']", + "154, attenuates ['l84', 'l93', 'l101', 'l108', 'l114', 'l119', 'l123', 'l127', 'l128', 'l129']", + "155, induction ['l73', 'l85', 'l94', 'l102', 'l109', 'l115', 'l120', 'l124', 'l127', 'l130', 'l131']", + "157, CML-like ['l66', 'l74', 'l86', 'l95', 'l103', 'l110', 'l116', 'l121', 'l125', 'l128', 'l130', 'l132']", + "158, leukemia ['l67', 'l75', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l126', 'l129', 'l131', 'l132']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "BCR-ABL1-transduced", + "transduced" + ] + }, + "context": { + "val": "cells", + "words": [ + "progenitors", + "stem", + "cells", + "HSCs." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "progenitors" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "CD44-mutant" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD44-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "stem", + "cells", + "HSCs." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD44-deficient" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "acute", + "B-lymphoblastic", + "leukemia" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "acute", + "B-lymphoblastic", + "leukemia" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "BCR-ABL1-transduced", + "coexpression", + "of", + "human", + "CD44." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "CML-like", + "leukemia" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD44-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD44-deficient" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "CML-like", + "leukemia" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "stem" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "coexpression", + "of", + "human", + "CD44." + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuates" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "coexpression", + "of", + "human", + "CD44." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antibody", + "to" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuates" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antibody", + "to" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antibody", + "to" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "CML-like", + "leukemia" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuates" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "CML-like", + "leukemia" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "CML-like", + "leukemia" + ] + } + } + ] + }, + { + "PMID": "16980970", + "TEXT": "Clinical use of G-CSF can result in vascular and inflammatory complications. To investigate the molecular basis of these effects, we analyzed the adherence of G-CSF-mobilized human peripheral blood leukocytes (ML) to inflamed (TNF-alpha-stimulated) vascular endothelium. Studies using parallel plate assays under physiologic flow conditions and intravital microscopy in a mouse inflammation model each showed that ML take part in heightened adhesive interactions with endothelium compared to unmobilized (native) blood leukocytes, mediated by markedly increased E-selectin receptor-ligand interactions. Biochemical studies showed that ML express the potent E-selectin ligand HCELL (ref. 8) and another, previously unrecognized approximately 65-kDa E-selectin ligand, and possess enhanced levels of transcripts encoding glycosyltransferases (ST3GalIV, FucT-IV and FucT-VII) conferring glycan modifications associated with E-selectin ligand activity. Enzymatic treatments and physiologic binding assays showed that HCELL and the approximately 65-kDa E-selectin ligand contribute prominently to the observed G-CSF-induced myeloid cell adhesion to inflamed endothelium. Treatment of normal human bone marrow cells with a pharmacokinetically relevant concentration of G-CSF in vitro resulted in increased expression of these two molecules, coincident with increased transcripts encoding pertinent glycosyltransferases and heightened E-selectin binding. These findings provide direct evidence for a role of G-CSF in the induction of E-selectin ligands on myeloid cells, thus providing mechanistic insight into the pathobiology of G-CSF complications.", + "TAG_DATA": [ + "139, myeloid {'context': 'B-cells'}", + "140, cell {'context': 'I-cells'}", + "147, normal {'context': 'B-cells'}", + "148, human {'context': 'I-cells'}", + "149, bone {'context': 'I-cells'}", + "150, marrow {'context': 'I-cells'}", + "151, cells {'context': 'I-cells'}", + "159, in {'context': 'B-in vitro'}", + "160, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "139, myeloid ['l0']", + "140, cell ['l0']", + "147, normal ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "148, human ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "149, bone ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "150, marrow ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "151, cells ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "159, in ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "160, vitro ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16980969", + "TEXT": "The avascularity of cardiac valves is abrogated in several valvular heart diseases (VHDs). This study investigated the molecular mechanisms underlying valvular avascularity and its correlation with VHD. Chondromodulin-I, an antiangiogenic factor isolated from cartilage, is abundantly expressed in cardiac valves. Gene targeting of chondromodulin-I resulted in enhanced Vegf-A expression, angiogenesis, lipid deposition and calcification in the cardiac valves of aged mice. Echocardiography showed aortic valve thickening, calcification and turbulent flow, indicative of early changes in aortic stenosis. Conditioned medium obtained from cultured valvular interstitial cells strongly inhibited tube formation and mobilization of endothelial cells and induced their apoptosis; these effects were partially inhibited by chondromodulin-I small interfering RNA. In human VHD, including cases associated with infective endocarditis, rheumatic heart disease and atherosclerosis, VEGF-A expression, neovascularization and calcification were observed in areas of chondromodulin-I downregulation. These findings provide evidence that chondromodulin-I has a pivotal role in maintaining valvular normal function by preventing angiogenesis that may lead to VHD.", + "TAG_DATA": [ + "40, Gene {'perturbing_action': 'B-rnai/knockdown'}", + "41, targeting {'perturbing_action': 'I-rnai/knockdown'}", + "42, of {'perturbing_action': 'I-rnai/knockdown'}", + "43, chondromodulin-I {'perturbing_action': 'I-rnai/knockdown'}", + "56, cardiac {'context': 'B-tissue/organ'}", + "57, valves {'context': 'I-tissue/organ'}", + "59, aged {'context': 'B-organism'}", + "60, mice. {'context': 'I-organism'}", + "82, valvular {'context': 'B-cells'}", + "83, interstitial {'context': 'I-cells'}", + "84, cells {'context': 'I-cells'}", + "86, inhibited {'effect': 'B-negative'}", + "87, tube {'phenotype': 'B-colony formation'}", + "88, formation {'phenotype': 'I-colony formation'}", + "92, endothelial {'context': 'B-cells'}", + "93, cells {'context': 'I-cells'}", + "95, induced {'effect': 'B-positive'}", + "97, apoptosis; {'phenotype': 'B-apoptosis'}", + "104, chondromodulin-I {'perturbing_action': 'B-rnai/knockdown'}", + "105, small {'perturbing_action': 'I-rnai/knockdown'}", + "106, interfering {'perturbing_action': 'I-rnai/knockdown'}", + "107, RNA. {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "40, Gene ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "41, targeting ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "42, of ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "43, chondromodulin-I ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "56, cardiac ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "57, valves ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "59, aged ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "60, mice. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "82, valvular ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "83, interstitial ['l28', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "84, cells ['l29', 'l37', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "86, inhibited ['l30', 'l38', 'l45', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "87, tube ['l31', 'l39', 'l46', 'l52', 'l58', 'l59', 'l60', 'l61']", + "88, formation ['l32', 'l40', 'l47', 'l53', 'l58', 'l62', 'l63', 'l64']", + "92, endothelial ['l33', 'l41', 'l48', 'l54', 'l59', 'l62', 'l65', 'l66', 'l67']", + "93, cells ['l34', 'l42', 'l49', 'l55', 'l60', 'l63', 'l65', 'l68']", + "95, induced ['l35', 'l43', 'l50', 'l56', 'l61', 'l64', 'l66', 'l68', 'l69']", + "97, apoptosis; ['l36', 'l44', 'l51', 'l57', 'l67', 'l69']", + "104, chondromodulin-I ['l70', 'l71', 'l72']", + "105, small ['l70', 'l73', 'l74']", + "106, interfering ['l71', 'l73', 'l75']", + "107, RNA. ['l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Gene", + "targeting", + "of", + "chondromodulin-I" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "cardiac", + "valves" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Gene", + "targeting", + "of", + "chondromodulin-I" + ] + }, + "context": { + "val": "organism", + "words": [ + "aged", + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "valvular", + "interstitial", + "cells", + "endothelial" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "valvular", + "interstitial", + "cells", + "endothelial" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "tube", + "formation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "valvular", + "interstitial", + "cells", + "endothelial" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "valvular", + "interstitial", + "cells", + "endothelial" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis;" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "tube", + "formation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis;" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "tube", + "formation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis;" + ] + } + } + ] + }, + { + "PMID": "16951685", + "TEXT": "Apoptosis is essential for clearance of potentially injurious inflammatory cells and subsequent efficient resolution of inflammation. Here we report that human neutrophils contain functionally active cyclin-dependent kinases (CDKs), and that structurally diverse CDK inhibitors induce caspase-dependent apoptosis and override powerful anti-apoptosis signals from survival factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF). We show that the CDK inhibitor R-roscovitine (Seliciclib or CYC202) markedly enhances resolution of established neutrophil-dependent inflammation in carrageenan-elicited acute pleurisy, bleomycin-induced lung injury, and passively induced arthritis in mice. In the pleurisy model, the caspase inhibitor zVAD-fmk prevents R-roscovitine-enhanced resolution of inflammation, indicating that this CDK inhibitor augments inflammatory cell apoptosis. We also provide evidence that R-roscovitine promotes apoptosis by reducing concentrations of the anti-apoptotic protein Mcl-1. Thus, CDK inhibitors enhance the resolution of established inflammation by promoting apoptosis of inflammatory cells, thereby demonstrating a hitherto unrecognized potential for the treatment of inflammatory disorders.", + "TAG_DATA": [ + "55, CDK {'perturbing_action': 'B-pharmacological inhibition'}", + "56, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "57, R-roscovitine {'perturbing_action': 'I-pharmacological inhibition'}", + "58, (Seliciclib {'perturbing_action': 'I-pharmacological inhibition'}", + "60, CYC202) {'perturbing_action': 'I-pharmacological inhibition'}", + "73, lung {'context': 'B-tissue/organ'}", + "80, mice. {'context': 'B-organism'}", + "97, CDK {'perturbing_action': 'B-pharmacological inhibition'}", + "98, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "99, augments {'effect': 'B-positive'}", + "100, inflammatory {'context': 'B-cells'}", + "101, cell {'context': 'I-cells'}", + "102, apoptosis. {'phenotype': 'B-apoptosis'}", + "109, promotes {'effect': 'B-positive'}", + "110, apoptosis {'phenotype': 'B-apoptosis'}", + "129, promoting {'effect': 'B-positive'}", + "130, apoptosis {'phenotype': 'B-apoptosis'}", + "132, inflammatory {'context': 'B-cells'}", + "133, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "55, CDK ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "56, inhibitor ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "57, R-roscovitine ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "58, (Seliciclib ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "60, CYC202) ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "73, lung ['l4', 'l9', 'l13', 'l16', 'l18']", + "80, mice. ['l5', 'l10', 'l14', 'l17', 'l19']", + "97, CDK ['l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "98, inhibitor ['l20', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "99, augments ['l21', 'l31', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "100, inflammatory ['l22', 'l32', 'l41', 'l50', 'l51', 'l52', 'l53']", + "101, cell ['l23', 'l33', 'l42', 'l50', 'l54', 'l55', 'l56']", + "102, apoptosis. ['l24', 'l34', 'l43', 'l51', 'l54', 'l57', 'l58', 'l59', 'l60']", + "109, promotes ['l25', 'l35', 'l44', 'l52', 'l55', 'l57', 'l61', 'l62', 'l63', 'l64', 'l65']", + "110, apoptosis ['l26', 'l36', 'l45', 'l58', 'l61', 'l66', 'l67', 'l68', 'l69']", + "129, promoting ['l27', 'l37', 'l46', 'l62', 'l66', 'l70', 'l71', 'l72']", + "130, apoptosis ['l28', 'l38', 'l47', 'l63', 'l67', 'l70', 'l73', 'l74']", + "132, inflammatory ['l29', 'l39', 'l48', 'l59', 'l64', 'l68', 'l71', 'l73', 'l75']", + "133, cells, ['l30', 'l40', 'l49', 'l53', 'l56', 'l60', 'l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK", + "inhibitor", + "R-roscovitine", + "(Seliciclib", + "CYC202)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK", + "inhibitor", + "R-roscovitine", + "(Seliciclib", + "CYC202)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK", + "inhibitor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "augments", + "promotes", + "promoting" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK", + "inhibitor" + ] + }, + "context": { + "val": "cells", + "words": [ + "inflammatory", + "cell", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK", + "inhibitor" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis.", + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "augments", + "promotes", + "promoting" + ] + }, + "context": { + "val": "cells", + "words": [ + "inflammatory", + "cell", + "cells," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "augments", + "promotes", + "promoting" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis.", + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "inflammatory", + "cell", + "cells," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis.", + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "16936725", + "TEXT": "Immunoincompetence after allogeneic hematopoietic stem cell transplantation (HSCT) affects in particular the T-cell lineage and is associated with an increased risk for infections, graft failure and malignant relapse. To generate large numbers of T-cell precursors for adoptive therapy, we cultured mouse hematopoietic stem cells (HSCs) in vitro on OP9 mouse stromal cells expressing the Notch-1 ligand Delta-like-1 (OP9-DL1). We infused these cells, together with T-cell-depleted mouse bone marrow or purified HSCs, into lethally irradiated allogeneic recipients and determined their effect on T-cell reconstitution after transplantation. Recipients of OP9-DL1-derived T-cell precursors showed increased thymic cellularity and substantially improved donor T-cell chimerism (versus recipients of bone marrow or HSCs only). OP9-DL1-derived T-cell precursors gave rise to host-tolerant CD4+ and CD8+ populations with normal T-cell antigen receptor repertoires, cytokine secretion and proliferative responses to antigen. Administration of OP9-DL1-derived T-cell precursors increased resistance to infection with Listeria monocytogenes and mediated significant graft-versus-tumor (GVT) activity but not graft-versus-host disease (GVHD). We conclude that the adoptive transfer of OP9-DL1-derived T-cell precursors markedly enhances T-cell reconstitution after transplantation, resulting in GVT activity without GVHD.", + "TAG_DATA": [ + "40, mouse {'context': 'B-cells'}", + "41, hematopoietic {'context': 'I-cells'}", + "42, stem {'context': 'I-cells'}", + "43, cells {'context': 'I-cells'}", + "44, (HSCs) {'context': 'I-cells'}", + "45, in {'context': 'B-in vitro'}", + "46, vitro {'context': 'I-in vitro'}", + "48, OP9 {'context': 'B-cells'}", + "49, mouse {'context': 'I-cells'}", + "50, stromal {'context': 'I-cells'}", + "51, cells {'context': 'I-cells'}", + "87, OP9-DL1-derived {'context': 'B-cells'}", + "88, T-cell {'context': 'I-cells'}", + "89, precursors {'context': 'I-cells'}", + "97, donor {'context': 'B-cells'}", + "98, T-cell {'context': 'I-cells'}", + "108, OP9-DL1-derived {'context': 'B-cells'}", + "109, T-cell {'context': 'I-cells'}", + "110, precursors {'context': 'I-cells'}", + "115, CD4+ {'context': 'B-cells'}", + "116, and {'context': 'I-cells'}", + "117, CD8+ {'context': 'I-cells'}", + "118, populations {'context': 'I-cells'}", + "128, proliferative {'phenotype': 'B-proliferation'}", + "129, responses {'phenotype': 'I-proliferation'}", + "134, OP9-DL1-derived {'context': 'B-cells'}", + "135, T-cell {'context': 'I-cells'}", + "136, precursors {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "40, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "41, hematopoietic ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "42, stem ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "43, cells ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "44, (HSCs) ['l3', 'l12', 'l20', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "45, in ['l4', 'l13', 'l21', 'l28', 'l33', 'l39', 'l40']", + "46, vitro ['l5', 'l14', 'l22', 'l29', 'l34', 'l39', 'l41']", + "48, OP9 ['l6', 'l15', 'l23', 'l30', 'l35', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "49, mouse ['l7', 'l16', 'l24', 'l31', 'l36', 'l42', 'l46', 'l47', 'l48', 'l49', 'l50']", + "50, stromal ['l8', 'l17', 'l25', 'l37', 'l43', 'l46', 'l51', 'l52', 'l53', 'l54', 'l55']", + "51, cells ['l9', 'l18', 'l26', 'l32', 'l38', 'l44', 'l47', 'l51', 'l56', 'l57', 'l58']", + "87, OP9-DL1-derived ['l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "88, T-cell ['l52', 'l59', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "89, precursors ['l48', 'l53', 'l56', 'l60', 'l72', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "97, donor ['l49', 'l54', 'l57', 'l61', 'l73', 'l82', 'l90']", + "98, T-cell ['l45', 'l50', 'l55', 'l58', 'l62', 'l74', 'l83', 'l90']", + "108, OP9-DL1-derived ['l63', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "109, T-cell ['l64', 'l75', 'l91', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "110, precursors ['l65', 'l76', 'l84', 'l92', 'l99', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "115, CD4+ ['l66', 'l77', 'l85', 'l93', 'l100', 'l106', 'l112', 'l113', 'l114', 'l115', 'l116']", + "116, and ['l67', 'l78', 'l86', 'l94', 'l101', 'l107', 'l112', 'l117', 'l118', 'l119', 'l120']", + "117, CD8+ ['l68', 'l79', 'l87', 'l95', 'l102', 'l108', 'l113', 'l117', 'l121', 'l122', 'l123']", + "118, populations ['l69', 'l80', 'l88', 'l96', 'l103', 'l109', 'l114', 'l118', 'l121', 'l124', 'l125']", + "128, proliferative ['l70', 'l97', 'l104', 'l110', 'l115', 'l119', 'l122', 'l124', 'l126']", + "129, responses ['l71', 'l81', 'l89', 'l98', 'l105', 'l111', 'l116', 'l120', 'l123', 'l125', 'l126']", + "134, OP9-DL1-derived ['l127', 'l128']", + "135, T-cell ['l127', 'l129']", + "136, precursors ['l128', 'l129']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "OP9-DL1-derived", + "T-cell", + "precursors", + "CD4+", + "and", + "CD8+", + "populations" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "responses" + ] + } + } + ] + }, + { + "PMID": "16921377", + "TEXT": "TRAF6 has a key role in the regulation of innate immune responses by mediating signals from both TNF receptor and interleukin-1 receptor/Toll-like receptor superfamilies. Here we show that T cell-specific deletion of TRAF6 unexpectedly results in multiorgan inflammatory disease. TRAF6-deficient T cells exhibit hyperactivation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway compared with wild-type T cells and, as a result, become resistant to suppression by CD4+ CD25+ regulatory T cells. These data identify a previously unrecognized role for TRAF6 in the maintenance of peripheral tolerance, and suggest the presence of a T cell-intrinsic control mechanism to render responder T cells susceptible to tolerizing signals.", + "TAG_DATA": [ + "28, T {'perturbing_action': 'B-gene loss-of-function'}", + "29, cell-specific {'perturbing_action': 'B-gene loss-of-function'}", + "30, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "31, of {'perturbing_action': 'I-gene loss-of-function'}", + "32, TRAF6 {'perturbing_action': 'I-gene loss-of-function'}", + "39, TRAF6-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "40, T {'context': 'B-cells'}", + "41, cells {'context': 'I-cells'}", + "53, T {'context': 'B-cells'}", + "54, cells {'context': 'I-cells'}", + "64, CD4+ {'context': 'B-cells'}", + "65, CD25+ {'context': 'I-cells'}", + "66, regulatory {'context': 'I-cells'}", + "67, T {'context': 'I-cells'}", + "68, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "28, T ['l0', 'l1', 'l2', 'l3']", + "29, cell-specific ['l0', 'l4', 'l5', 'l6']", + "30, deletion ['l1', 'l4', 'l7', 'l8']", + "31, of ['l2', 'l5', 'l7', 'l9']", + "32, TRAF6 ['l3', 'l6', 'l8', 'l9']", + "39, TRAF6-deficient ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "40, T ['l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "41, cells ['l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31']", + "53, T ['l12', 'l20', 'l27', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "54, cells ['l13', 'l21', 'l28', 'l32', 'l38', 'l39', 'l40']", + "64, CD4+ ['l14', 'l22', 'l33', 'l41', 'l42', 'l43', 'l44']", + "65, CD25+ ['l15', 'l23', 'l34', 'l41', 'l45', 'l46', 'l47']", + "66, regulatory ['l16', 'l24', 'l29', 'l35', 'l38', 'l42', 'l45', 'l48', 'l49']", + "67, T ['l17', 'l25', 'l30', 'l36', 'l39', 'l43', 'l46', 'l48', 'l50']", + "68, cells. ['l18', 'l26', 'l31', 'l37', 'l40', 'l44', 'l47', 'l49', 'l50']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TRAF6-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "CD4+", + "CD25+", + "regulatory", + "cells." + ] + } + } + ] + }, + { + "PMID": "16906157", + "TEXT": "Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome characterized by loss of renal function within days to weeks and by glomerular crescents on biopsy. The pathogenesis of this disease is unclear, but circulating factors are believed to have a major role. Here, we show that deletion of the Von Hippel-Lindau gene (Vhlh) from intrinsic glomerular cells of mice is sufficient to initiate a necrotizing crescentic glomerulonephritis and the clinical features that accompany RPGN. Loss of Vhlh leads to stabilization of hypoxia-inducible factor alpha subunits (HIFs). Using gene expression profiling, we identified de novo expression of the HIF target gene Cxcr4 (ref. 3) in glomeruli from both mice and humans with RPGN. The course of RPGN is markedly improved in mice treated with a blocking antibody to Cxcr4, whereas overexpression of Cxcr4 alone in podocytes of transgenic mice is sufficient to cause glomerular disease. Collectively, these results indicate an alternative mechanism for the pathogenesis of RPGN and glomerular disease in an animal model and suggest novel molecular pathways for intervention in this disease.", + "TAG_DATA": [ + "45, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "46, of {'perturbing_action': 'I-gene loss-of-function'}", + "47, the {'perturbing_action': 'I-gene loss-of-function'}", + "48, Von {'perturbing_action': 'I-gene loss-of-function'}", + "49, Hippel-Lindau {'perturbing_action': 'I-gene loss-of-function'}", + "50, gene {'perturbing_action': 'I-gene loss-of-function'}", + "51, (Vhlh) {'perturbing_action': 'I-gene loss-of-function'}", + "53, intrinsic {'context': 'B-cells'}", + "54, glomerular {'context': 'I-cells'}", + "55, cells {'context': 'I-cells'}", + "57, mice {'context': 'B-organism'}", + "73, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "74, of {'perturbing_action': 'I-gene loss-of-function'}", + "75, Vhlh {'perturbing_action': 'I-gene loss-of-function'}", + "119, mice {'context': 'B-organism'}", + "128, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "129, of {'perturbing_action': 'I-gene gain-of-function'}", + "130, Cxcr4 {'perturbing_action': 'I-gene gain-of-function'}", + "133, podocytes {'context': 'B-cells'}", + "135, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "136, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "45, deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "46, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "47, the ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "48, Von ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "49, Hippel-Lindau ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "50, gene ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "51, (Vhlh) ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "53, intrinsic ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "54, glomerular ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "55, cells ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "57, mice ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "73, Loss ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "74, of ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "75, Vhlh ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']", + "128, overexpression ['l91', 'l92', 'l93', 'l94', 'l95']", + "129, of ['l91', 'l96', 'l97', 'l98', 'l99']", + "130, Cxcr4 ['l92', 'l96', 'l100', 'l101', 'l102']", + "133, podocytes ['l93', 'l97', 'l100', 'l103', 'l104']", + "135, transgenic ['l94', 'l98', 'l101', 'l103', 'l105']", + "136, mice ['l95', 'l99', 'l102', 'l104', 'l105']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "Von", + "Hippel-Lindau", + "gene", + "(Vhlh)", + "Loss", + "Vhlh" + ] + }, + "context": { + "val": "cells", + "words": [ + "intrinsic", + "glomerular", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "Von", + "Hippel-Lindau", + "gene", + "(Vhlh)", + "Loss", + "Vhlh" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Cxcr4", + "transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Cxcr4", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "16906156", + "TEXT": "Rhinoviruses are the major cause of asthma exacerbations, and asthmatics have increased susceptibility to rhinovirus and risk of invasive bacterial infections. Here we show deficient induction of interferon-lambdas by rhinovirus in asthmatic primary bronchial epithelial cells and alveolar macrophages, which was highly correlated with severity of rhinovirus-induced asthma exacerbation and virus load in experimentally infected human volunteers. Induction by lipopolysaccharide in asthmatic macrophages was also deficient and correlated with exacerbation severity. These results identify previously unknown mechanisms of susceptibility to infection in asthma and suggest new approaches to prevention and/or treatment of asthma exacerbations.", + "TAG_DATA": [ + "31, asthmatic {'context': 'B-cells'}", + "32, primary {'context': 'I-cells'}", + "33, bronchial {'context': 'I-cells'}", + "34, epithelial {'context': 'I-cells'}", + "35, cells {'context': 'I-cells'}", + "37, alveolar {'context': 'B-cells'}", + "38, macrophages, {'context': 'I-cells'}", + "55, human {'context': 'B-organism'}", + "56, volunteers. {'context': 'I-organism'}", + "61, asthmatic {'context': 'B-cells'}", + "62, macrophages {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "31, asthmatic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "32, primary ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "33, bronchial ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "34, epithelial ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "35, cells ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "37, alveolar ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "38, macrophages, ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "55, human ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "56, volunteers. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "61, asthmatic ['l36']", + "62, macrophages ['l36']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16892062", + "TEXT": "Human CD56(bright) NK cells accumulate in the maternal decidua during pregnancy and are found in direct contact with fetal trophoblasts. Several mechanisms have been proposed to explain the inability of NK cells to kill the semiallogeneic fetal cells. However, the actual functions of decidual NK (dNK) cells during pregnancy are mostly unknown. Here we show that dNK cells, but not peripheral blood-derived NK subsets, regulate trophoblast invasion both in vitro and in vivo by production of the interleukin-8 and interferon-inducible protein-10 chemokines. Furthermore, dNK cells are potent secretors of an array of angiogenic factors and induce vascular growth in the decidua. Notably, such functions are regulated by specific interactions between dNK-activating and dNK-inhibitory receptors and their ligands, uniquely expressed at the fetal-maternal interface. The overall results support a 'peaceful' model for reproductive immunology, in which elements of innate immunity have been incorporated in a constructive manner to support reproductive tissue development.", + "TAG_DATA": [ + "68, in {'context': 'B-in vitro'}", + "69, vitro {'context': 'I-in vitro'}", + "71, in {'context': 'B-in vivo'}", + "72, vivo {'context': 'I-in vivo'}", + "95, induce {'effect': 'B-positive'}" + ], + "LINK_DATA": [ + "68, in ['l0', 'l1', 'l2']", + "69, vitro ['l0', 'l3', 'l4']", + "71, in ['l1', 'l3', 'l5']", + "72, vivo ['l2', 'l4', 'l5']", + "95, induce ['l6']", + "100, decidua. ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16892038", + "TEXT": "Although primary and memory responses against bacteria and viruses have been studied extensively, T helper type 2 (T(H)2) effector mechanisms leading to host protection against helminthic parasites remain elusive. Examination of the intestinal epithelial submucosa of mice after primary and secondary infections by a natural gastrointestinal parasite revealed a distinct immune-cell infiltrate after challenge, featuring interleukin-4-expressing memory CD4(+) T cells that induced IL-4 receptor(hi) (IL-4R(hi)) CD206(+) alternatively activated macrophages. In turn, these alternatively activated macrophages (AAMacs) functioned as important effector cells of the protective memory response contributing to parasite elimination, demonstrating a previously unknown mechanism for host protection against intestinal helminths.", + "TAG_DATA": [ + "32, intestinal {'context': 'B-tissue/organ'}", + "33, epithelial {'context': 'I-tissue/organ'}", + "34, submucosa {'context': 'I-tissue/organ'}", + "36, mice {'context': 'B-organism'}", + "57, CD4(+) {'context': 'I-cells'}", + "58, T {'context': 'I-cells'}", + "59, cells {'context': 'I-cells'}", + "67, activated {'context': 'I-cells'}", + "68, macrophages. {'context': 'I-cells'}", + "74, macrophages {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "32, intestinal ['l0', 'l1', 'l2', 'l3', 'l4']", + "33, epithelial ['l0', 'l5', 'l6', 'l7', 'l8']", + "34, submucosa ['l1', 'l5', 'l9', 'l10', 'l11']", + "36, mice ['l2', 'l6', 'l9']", + "57, CD4(+) ['l12', 'l13', 'l14', 'l15']", + "58, T ['l3', 'l7', 'l10', 'l12', 'l16', 'l17']", + "59, cells ['l4', 'l8', 'l11', 'l13', 'l16']", + "67, activated ['l14', 'l18', 'l19']", + "68, macrophages. ['l15', 'l17', 'l18', 'l20']", + "74, macrophages ['l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16862151", + "TEXT": "Heat, oxidation and exposure to aldehydes create reactive carbonyl groups on proteins, targeting antigens to scavenger receptors. Formaldehyde is widely used in making vaccines, but has been associated with atypical enhanced disease during subsequent infection with paramyxoviruses. We show that carbonyl groups on formaldehyde-treated vaccine antigens boost T helper type 2 (T(H)2) responses and enhance respiratory syncytial virus (RSV) disease in mice, an effect partially reversible by chemical reduction of carbonyl groups.", + "TAG_DATA": [ + "47, T {'context': 'B-cells'}", + "48, helper {'context': 'I-cells'}", + "49, type {'context': 'I-cells'}", + "50, 2 {'context': 'I-cells'}", + "51, (T(H)2) {'context': 'I-cells'}", + "61, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "47, T ['l0', 'l1', 'l2', 'l3', 'l4']", + "48, helper ['l0', 'l5', 'l6', 'l7', 'l8']", + "49, type ['l1', 'l5', 'l9', 'l10', 'l11']", + "50, 2 ['l2', 'l6', 'l9', 'l12', 'l13']", + "51, (T(H)2) ['l3', 'l7', 'l10', 'l12', 'l14']", + "61, mice, ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16819550", + "TEXT": "Mice carrying mutations in both the dystrophin and utrophin genes die prematurely as a consequence of severe muscular dystrophy. Here, we show that intravascular administration of recombinant adeno-associated viral (rAAV) vectors carrying a microdystrophin gene restores expression of dystrophin in the respiratory, cardiac and limb musculature of these mice, considerably reducing skeletal muscle pathology and extending lifespan. These findings suggest rAAV vector-mediated systemic gene transfer may be useful for treatment of serious neuromuscular disorders such as Duchenne muscular dystrophy.", + "TAG_DATA": [ + "42, cardiac {'context': 'I-tissue/organ'}", + "43, and {'context': 'I-tissue/organ'}", + "44, limb {'context': 'I-tissue/organ'}", + "45, musculature {'context': 'I-tissue/organ'}", + "48, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "27, adeno-associated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "28, viral ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "29, (rAAV) ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "30, vectors ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "32, a ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "33, microdystrophin ['l4', 'l17', 'l29', 'l40', 'l50', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "34, gene ['l5', 'l18', 'l30', 'l41', 'l51', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "41, respiratory, ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "42, cardiac ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "43, and ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l90', 'l91', 'l92', 'l93', 'l94']", + "44, limb ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l95', 'l96', 'l97', 'l98']", + "45, musculature ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l99', 'l100', 'l101']", + "48, mice, ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l102', 'l103']", + "51, skeletal ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l104']", + "52, muscle ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l104']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16799557", + "TEXT": "Vascular endothelial growth factor (VEGF) exerts crucial functions during pathological angiogenesis and normal physiology. We observed increased hematocrit (60-75%) after high-grade inhibition of VEGF by diverse methods, including adenoviral expression of soluble VEGF receptor (VEGFR) ectodomains, recombinant VEGF Trap protein and the VEGFR2-selective antibody DC101. Increased production of red blood cells (erythrocytosis) occurred in both mouse and primate models, and was associated with near-complete neutralization of VEGF corneal micropocket angiogenesis. High-grade inhibition of VEGF induced hepatic synthesis of erythropoietin (Epo, encoded by Epo) >40-fold through a HIF-1alpha-independent mechanism, in parallel with suppression of renal Epo mRNA. Studies using hepatocyte-specific deletion of the Vegfa gene and hepatocyte-endothelial cell cocultures indicated that blockade of VEGF induced hepatic Epo by interfering with homeostatic VEGFR2-dependent paracrine signaling involving interactions between hepatocytes and endothelial cells. These data indicate that VEGF is a previously unsuspected negative regulator of hepatic Epo synthesis and erythropoiesis and suggest that levels of Epo and erythrocytosis could represent noninvasive surrogate markers for stringent blockade of VEGF in vivo.", + "TAG_DATA": [ + "21, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "22, of {'perturbing_action': 'I-pharmacological inhibition'}", + "23, VEGF {'perturbing_action': 'I-pharmacological inhibition'}", + "28, adenoviral {'perturbing_action': 'B-rnai/knockdown'}", + "29, expression {'perturbing_action': 'I-rnai/knockdown'}", + "30, of {'perturbing_action': 'I-rnai/knockdown'}", + "31, soluble {'perturbing_action': 'I-rnai/knockdown'}", + "32, VEGF {'perturbing_action': 'I-rnai/knockdown'}", + "33, receptor {'perturbing_action': 'I-rnai/knockdown'}", + "34, (VEGFR) {'perturbing_action': 'I-rnai/knockdown'}", + "35, ectodomains, {'perturbing_action': 'I-rnai/knockdown'}", + "37, VEGF {'perturbing_action': 'I-rnai/knockdown'}", + "38, Trap {'perturbing_action': 'I-rnai/knockdown'}", + "39, protein {'perturbing_action': 'I-rnai/knockdown'}", + "55, mouse {'context': 'B-organism'}", + "57, primate {'context': 'B-organism'}", + "58, models, {'context': 'I-organism'}", + "71, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "72, of {'perturbing_action': 'I-pharmacological inhibition'}", + "73, VEGF {'perturbing_action': 'I-pharmacological inhibition'}", + "98, hepatocyte-specific {'perturbing_action': 'B-gene loss-of-function'}", + "99, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "100, of {'perturbing_action': 'I-gene loss-of-function'}", + "101, the {'perturbing_action': 'I-gene loss-of-function'}", + "102, Vegfa {'perturbing_action': 'I-gene loss-of-function'}", + "103, gene {'perturbing_action': 'I-gene loss-of-function'}", + "105, hepatocyte-endothelial {'context': 'B-cells'}", + "106, cell {'context': 'I-cells'}", + "111, of {'perturbing_action': 'I-pharmacological inhibition'}", + "112, VEGF {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "20, high-grade ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "21, inhibition ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "22, of ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "23, VEGF ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "28, adenoviral ['l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "29, expression ['l18', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "30, of ['l19', 'l35', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "31, soluble ['l20', 'l36', 'l51', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "32, VEGF ['l21', 'l37', 'l52', 'l66', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "33, receptor ['l22', 'l38', 'l53', 'l67', 'l80', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "34, (VEGFR) ['l23', 'l39', 'l54', 'l68', 'l81', 'l93', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "35, ectodomains, ['l24', 'l40', 'l55', 'l69', 'l82', 'l94', 'l105', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "36, recombinant ['l25', 'l41', 'l56', 'l70', 'l83', 'l95', 'l106', 'l116', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "37, VEGF ['l26', 'l42', 'l57', 'l71', 'l84', 'l96', 'l107', 'l117', 'l126', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "38, Trap ['l27', 'l43', 'l58', 'l72', 'l85', 'l97', 'l108', 'l118', 'l127', 'l135', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "39, protein ['l28', 'l44', 'l59', 'l73', 'l86', 'l98', 'l109', 'l119', 'l128', 'l136', 'l143', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "55, mouse ['l3', 'l8', 'l12', 'l15', 'l29', 'l45', 'l60', 'l74', 'l87', 'l99', 'l110', 'l120', 'l129', 'l137', 'l144', 'l150', 'l156', 'l157']", + "57, primate ['l4', 'l9', 'l13', 'l16', 'l30', 'l46', 'l61', 'l75', 'l88', 'l100', 'l111', 'l121', 'l130', 'l138', 'l145', 'l151', 'l156', 'l158']", + "58, models, ['l5', 'l10', 'l14', 'l17', 'l31', 'l47', 'l62', 'l76', 'l89', 'l101', 'l112', 'l122', 'l131', 'l139', 'l146', 'l152', 'l157', 'l158']", + "71, inhibition ['l32', 'l48', 'l63', 'l77', 'l90', 'l102', 'l113', 'l123', 'l132', 'l140', 'l147', 'l153', 'l159', 'l160']", + "72, of ['l33', 'l49', 'l64', 'l78', 'l91', 'l103', 'l114', 'l124', 'l133', 'l141', 'l148', 'l154', 'l159', 'l161']", + "73, VEGF ['l34', 'l50', 'l65', 'l79', 'l92', 'l104', 'l115', 'l125', 'l134', 'l142', 'l149', 'l155', 'l160', 'l161']", + "98, hepatocyte-specific ['l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170']", + "99, deletion ['l162', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "100, of ['l163', 'l171', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185']", + "101, the ['l164', 'l172', 'l179', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191']", + "102, Vegfa ['l165', 'l173', 'l180', 'l186', 'l192', 'l193', 'l194', 'l195', 'l196']", + "103, gene ['l166', 'l174', 'l181', 'l187', 'l192', 'l197', 'l198', 'l199', 'l200']", + "105, hepatocyte-endothelial ['l167', 'l175', 'l182', 'l188', 'l193', 'l197', 'l201', 'l202', 'l203']", + "106, cell ['l168', 'l176', 'l183', 'l189', 'l194', 'l198', 'l201', 'l204', 'l205']", + "111, of ['l169', 'l177', 'l184', 'l190', 'l195', 'l199', 'l202', 'l204', 'l206']", + "112, VEGF ['l170', 'l178', 'l185', 'l191', 'l196', 'l200', 'l203', 'l205', 'l206']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "VEGF" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "primate", + "models," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "adenoviral", + "expression", + "of", + "soluble", + "VEGF", + "receptor", + "(VEGFR)", + "ectodomains,", + "Trap", + "protein" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "primate", + "models," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "hepatocyte-specific", + "deletion", + "of", + "the", + "Vegfa", + "gene" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocyte-endothelial", + "cell" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hepatocyte-endothelial", + "cell" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "of", + "VEGF" + ] + } + } + ] + }, + { + "PMID": "16799555", + "TEXT": "Certain disease states are characterized by disturbances in production, accumulation or clearance of protein. In Alzheimer disease, accumulation of amyloid-beta (Abeta) in the brain and disease-causing mutations in amyloid precursor protein or in enzymes that produce Abeta indicate dysregulation of production or clearance of Abeta. Whether dysregulation of Abeta synthesis or clearance causes the most common form of Alzheimer disease (sporadic, >99% of cases), however, is not known. Here, we describe a method to determine the production and clearance rates of proteins within the human central nervous system (CNS). We report the first measurements of the fractional production and clearance rates of Abeta in vivo in the human CNS to be 7.6% per hour and 8.3% per hour, respectively. This method may be used to search for novel biomarkers of disease, to assess underlying differences in protein metabolism that contribute to disease and to evaluate treatments in terms of their pharmacodynamic effects on proposed disease-causing pathways.", + "TAG_DATA": [ + "103, in {'context': 'B-in vivo'}", + "104, vivo {'context': 'I-in vivo'}", + "107, human {'context': 'B-tissue/organ'}", + "108, CNS {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "103, in ['l0', 'l1', 'l2']", + "104, vivo ['l0', 'l3', 'l4']", + "107, human ['l1', 'l3', 'l5']", + "108, CNS ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16732278", + "TEXT": "Multivariate analysis of 1H-NMR spectra of blood sera was reported previously to predict angiographically defined advanced coronary artery disease (CAD) with >90% accuracy and specificity. The analysis depended mainly on the major lipid regions of the spectra, but many variables, including gender and drug treatment, affect lipid composition and are potential confounders. We have determined the predictive power of the same methodology for angiographically defined CAD using plasma samples from groups of male patients, classified by statin treatment, who had normal coronary arteries (NCAs) or CAD. Predictions for NCA and CAD groups were only 80.3% correct for patients not treated with statins and 61.3% for treated patients, compared with random correct predictions of 50%. A confidence limit of >99% was achieved for 36.2% of predictions for untreated groups and 6.2% for treated groups. Detection of CAD by 1H-NMR with >99% confidence was therefore very weak compared with angiography.", + "TAG_DATA": [ + "72, male {'context': 'B-patient'}", + "73, patients, {'context': 'I-patient'}", + "97, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "72, male ['l0', 'l1']", + "73, patients, ['l0']", + "97, patients ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16715090", + "TEXT": "Despite a more than 20-year experience of therapeutic benefit, the relevant molecular and cellular targets of intravenous immunoglobulin (IVIg) in autoimmune disease remain unclear. Contrary to the prevailing theories of IVIg action in autoimmunity, we show that IVIg drives signaling through activating Fc gamma receptors (Fc gammaR) in the amelioration of mouse immune thrombocytopenic purpura (ITP). The actual administration of IVIg was unnecessary because as few as 10(5) IVIg-treated cells could, upon adoptive transfer, ameliorate ITP. IVIg did not interact with the inhibitory Fc gammaRIIB on the initiator cell, although Fc gammaRIIB does have a role in the late phase of IVIg action. Notably, only IVIg-treated CD11c+ dendritic cells could mediate these effects. We hypothesize that IVIg forms soluble immune complexes in vivo that prime dendritic-cell regulatory activity. In conclusion, the clinical effects of IVIg in ameliorating ITP seem to involve the acute interaction of IVIg with activating Fc gammaR on dendritic cells.", + "TAG_DATA": [ + "69, cells {'context': 'B-cells'}", + "87, initiator {'context': 'B-cells'}", + "88, cell, {'context': 'I-cells'}", + "106, CD11c+ {'context': 'B-cells'}", + "107, dendritic {'context': 'I-cells'}", + "108, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "69, cells ['l0']", + "87, initiator ['l1']", + "88, cell, ['l0', 'l1']", + "106, CD11c+ ['l2', 'l3']", + "107, dendritic ['l2', 'l4']", + "108, cells ['l3', 'l4']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16715089", + "TEXT": "Here we investigated the potential role of bone-resorbing osteoclasts in homeostasis and stress-induced mobilization of hematopoietic progenitors. Different stress situations induced activity of osteoclasts (OCLs) along the stem cell-rich endosteum region of bone, secretion of proteolytic enzymes and mobilization of progenitors. Specific stimulation of OCLs with RANKL recruited mainly immature progenitors to the circulation in a CXCR4- and MMP-9-dependent manner; however, RANKL did not induce mobilization in young female PTPepsilon-knockout mice with defective OCL bone adhesion and resorption. Inhibition of OCLs with calcitonin reduced progenitor egress in homeostasis, G-CSF mobilization and stress situations. RANKL-stimulated bone-resorbing OCLs also reduced the stem cell niche components SDF-1, stem cell factor (SCF) and osteopontin along the endosteum, which was associated with progenitor mobilization. Finally, the major bone-resorbing proteinase, cathepsin K, also cleaved SDF-1 and SCF. Our findings indicate involvement of OCLs in selective progenitor recruitment as part of homeostasis and host defense, linking bone remodeling with regulation of hematopoiesis.", + "TAG_DATA": [ + "44, OCLs {'context': 'B-cells'}", + "67, young {'context': 'B-organism'}", + "68, female {'context': 'I-organism'}", + "69, PTPepsilon-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "70, mice {'context': 'B-organism'}", + "73, OCL {'context': 'B-cells'}", + "80, OCLs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "44, OCLs ['l0', 'l1', 'l2', 'l3', 'l4']", + "67, young ['l0', 'l5', 'l6', 'l7', 'l8']", + "68, female ['l1', 'l5', 'l9', 'l10', 'l11']", + "69, PTPepsilon-knockout ['l2', 'l6', 'l9', 'l12', 'l13']", + "70, mice ['l3', 'l7', 'l10', 'l12', 'l14']", + "73, OCL ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "OCLs", + "OCL" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PTPepsilon-knockout" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "young", + "female", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PTPepsilon-knockout" + ] + } + } + ] + }, + { + "PMID": "16680150", + "TEXT": "Mice transgenic for antisense Notch and normal mice treated with inhibitors of the Notch-activating enzyme gamma-secretase showed reduced damage to brain cells and improved functional outcome in a model of focal ischemic stroke. Notch endangers neurons by modulating pathways that increase their vulnerability to apoptosis, and by activating microglial cells and stimulating the infiltration of proinflammatory leukocytes. These findings suggest that Notch signaling may be a therapeutic target for treatment of stroke and related neurodegenerative conditions.", + "TAG_DATA": [ + "1, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "2, for {'perturbing_action': 'I-gene gain-of-function'}", + "3, antisense {'perturbing_action': 'I-gene gain-of-function'}", + "4, Notch {'perturbing_action': 'I-gene gain-of-function'}", + "7, mice {'context': 'I-organism'}", + "10, inhibitors {'perturbing_action': 'B-pharmacological inhibition'}", + "11, of {'perturbing_action': 'I-pharmacological inhibition'}", + "12, the {'perturbing_action': 'I-pharmacological inhibition'}", + "13, Notch-activating {'perturbing_action': 'I-pharmacological inhibition'}", + "14, enzyme {'perturbing_action': 'I-pharmacological inhibition'}", + "15, gamma-secretase {'perturbing_action': 'I-pharmacological inhibition'}", + "20, brain {'context': 'B-cells'}", + "21, cells {'context': 'I-cells'}", + "35, neurons {'context': 'B-cells'}", + "44, apoptosis, {'phenotype': 'B-apoptosis'}", + "48, microglial {'context': 'B-cells'}", + "49, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "1, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "2, for ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "3, antisense ['l1', 'l17', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "4, Notch ['l2', 'l18', 'l33', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "7, mice ['l3', 'l19', 'l34', 'l48', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "10, inhibitors ['l4', 'l20', 'l35', 'l61', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "11, of ['l5', 'l21', 'l36', 'l49', 'l62', 'l74', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "12, the ['l6', 'l22', 'l37', 'l50', 'l63', 'l75', 'l86', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "13, Notch-activating ['l7', 'l23', 'l38', 'l51', 'l64', 'l76', 'l87', 'l97', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "14, enzyme ['l8', 'l24', 'l39', 'l52', 'l65', 'l77', 'l88', 'l98', 'l107', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "15, gamma-secretase ['l9', 'l25', 'l40', 'l53', 'l66', 'l78', 'l89', 'l99', 'l108', 'l116', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "20, brain ['l10', 'l26', 'l41', 'l54', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l124', 'l131', 'l132', 'l133', 'l134']", + "21, cells ['l11', 'l27', 'l42', 'l55', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l125', 'l131', 'l135', 'l136']", + "35, neurons ['l12', 'l28', 'l43', 'l56', 'l69', 'l81', 'l92', 'l102', 'l111', 'l119', 'l126', 'l132', 'l137', 'l138', 'l139', 'l140']", + "42, vulnerability ['l13', 'l29', 'l44', 'l57', 'l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l127', 'l133', 'l135', 'l137', 'l141', 'l142', 'l143']", + "44, apoptosis, ['l14', 'l30', 'l45', 'l58', 'l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l128', 'l134', 'l136', 'l138', 'l141', 'l144', 'l145']", + "48, microglial ['l15', 'l31', 'l46', 'l59', 'l72', 'l84', 'l95', 'l105', 'l114', 'l122', 'l129', 'l139', 'l142', 'l144', 'l146']", + "49, cells ['l16', 'l32', 'l47', 'l60', 'l73', 'l85', 'l96', 'l106', 'l115', 'l123', 'l130', 'l140', 'l143', 'l145', 'l146']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "antisense", + "Notch" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "antisense", + "Notch" + ] + }, + "context": { + "val": "cells", + "words": [ + "brain", + "cells", + "neurons", + "microglial" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "antisense", + "Notch" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "the", + "Notch-activating", + "enzyme", + "gamma-secretase" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "the", + "Notch-activating", + "enzyme", + "gamma-secretase" + ] + }, + "context": { + "val": "cells", + "words": [ + "brain", + "cells", + "neurons", + "microglial" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "the", + "Notch-activating", + "enzyme", + "gamma-secretase" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "brain", + "cells", + "neurons", + "microglial" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + } + ] + }, + { + "PMID": "16680149", + "TEXT": "Tumor-cell apoptosis is the basis of many cancer therapies, and tumor-specific T cells are the principal effectors of successful antitumor immunotherapies. Here we show that induction of tumor-cell apoptosis by an agonistic monoclonal antibody to DR5, the apoptosis-inducing receptor for TNF-related apoptosis-inducing ligand (TRAIL), combined with T-cell activation by agonistic monoclonal antibodies to the costimulatory molecules CD40 and CD137, potently and rapidly stimulated tumor-specific effector CD8+ T cells capable of eradicating preestablished tumors. Primary fibrosarcomas initiated with the carcinogen 3-methylcholanthrene (MCA), multiorgan metastases and a primary tumor containing as many as 90% tumor cells resistant to DR5-specific monoclonal antibody were rejected without apparent toxicity or induction of autoimmunity. This combination therapy of three monoclonal antibodies (trimAb) rapidly induced tumor-specific CD8+ T cells producing interferon (IFN)-gamma in the tumor-draining lymph node, consistent with a crucial requirement for CD8+ T cells and IFN-gamma in the tumor rejection process. These results in mice indicate that a rational monoclonal antibody-based therapy that both causes tumor-cell apoptosis through DR5 and activates T cells may be an effective strategy for cancer immunotherapy in humans.", + "TAG_DATA": [ + "25, induction {'effect': 'B-positive'}", + "28, apoptosis {'phenotype': 'B-apoptosis'}", + "46, T-cell {'context': 'B-cells'}", + "63, tumor-specific {'context': 'B-cells'}", + "64, effector {'context': 'I-cells'}", + "65, CD8+ {'context': 'I-cells'}", + "66, T {'context': 'I-cells'}", + "67, cells {'context': 'I-cells'}", + "72, tumors. {'context': 'B-neoplasm'}", + "73, Primary {'context': 'B-neoplasm'}", + "74, fibrosarcomas {'context': 'I-neoplasm'}", + "81, multiorgan {'phenotype': 'B-metastasis'}", + "82, metastases {'phenotype': 'I-metastasis'}", + "85, primary {'context': 'B-neoplasm'}", + "86, tumor {'context': 'I-neoplasm'}", + "92, tumor {'context': 'B-transformed cells'}", + "93, cells {'context': 'I-transformed cells'}", + "119, CD8+ {'context': 'I-cells'}", + "120, T {'context': 'I-cells'}", + "121, cells {'context': 'I-cells'}", + "127, tumor-draining {'context': 'B-tissue/organ'}", + "128, lymph {'context': 'I-tissue/organ'}", + "129, node, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "25, induction ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "27, tumor-cell ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "28, apoptosis ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "46, T-cell ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "63, tumor-specific ['l2', 'l9', 'l15', 'l21', 'l31', 'l32', 'l33', 'l34', 'l35']", + "64, effector ['l3', 'l10', 'l16', 'l22', 'l31', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "65, CD8+ ['l4', 'l11', 'l17', 'l23', 'l32', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "66, T ['l5', 'l12', 'l18', 'l24', 'l33', 'l37', 'l42', 'l47', 'l48', 'l49', 'l50']", + "67, cells ['l6', 'l13', 'l19', 'l25', 'l34', 'l38', 'l43', 'l47', 'l51']", + "72, tumors. ['l7', 'l14', 'l20', 'l26', 'l35', 'l39', 'l44', 'l48', 'l51']", + "73, Primary ['l27', 'l40', 'l45', 'l49', 'l52', 'l53', 'l54']", + "74, fibrosarcomas ['l28', 'l41', 'l46', 'l50', 'l52', 'l55', 'l56']", + "81, multiorgan ['l29', 'l53', 'l55', 'l57', 'l58', 'l59', 'l60']", + "82, metastases ['l30', 'l54', 'l56', 'l57', 'l61', 'l62']", + "85, primary ['l63', 'l64', 'l65']", + "86, tumor ['l58', 'l63', 'l66', 'l67']", + "92, tumor ['l59', 'l61', 'l64', 'l66', 'l68']", + "93, cells ['l60', 'l62', 'l65', 'l67', 'l68']", + "119, CD8+ ['l69', 'l70', 'l71', 'l72', 'l73']", + "120, T ['l69', 'l74', 'l75', 'l76', 'l77']", + "121, cells ['l70', 'l74', 'l78', 'l79', 'l80']", + "127, tumor-draining ['l71', 'l75', 'l78', 'l81', 'l82']", + "128, lymph ['l72', 'l76', 'l79', 'l81', 'l83']", + "129, node, ['l73', 'l77', 'l80', 'l82', 'l83']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "context": { + "val": "cells", + "words": [ + "tumor-specific", + "effector", + "CD8+", + "T", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "tumor-specific", + "effector", + "CD8+", + "T", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T-cell" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "multiorgan", + "metastases" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "Primary", + "fibrosarcomas", + "tumor" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "multiorgan", + "metastases" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "multiorgan", + "metastases" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + } + ] + }, + { + "PMID": "16648858", + "TEXT": "The growing number of recently identified negative feedback regulators of receptor tyrosine kinases (RTKs) highlights the importance of signal attenuation and modulation for correct signaling outcome. Mitogen-inducible gene 6 (Mig6 also known as RALT or Gene 33) is a multiadaptor protein thought to be involved in the regulation of RTK and stress signaling. Here, we show that deletion of the mouse gene encoding Mig6 (designated Errfi1, which stands for ERBB receptor feedback inhibitor 1) causes hyperactivation of endogenous epidermal growth factor receptor (EGFR) and sustained signaling through the mitogen-activated protein kinase (MAPK) pathway, resulting in overproliferation and impaired differentiation of epidermal keratinocytes. Furthermore, Errfi1-/- mice develop spontaneous tumors in various organs and are highly susceptible to chemically induced formation of skin tumors. A tumor-suppressive role for Mig6 is supported by our finding that MIG6 is downregulated in various human cancers. Inhibition of endogenous Egfr signaling with the Egfr inhibitor gefitinib (Iressa) or replacement of wild-type Egfr with the kinase-deficient protein encoded by the hypomorphic Egfr(wa2) allele completely rescued skin defects in Erffi1-/- mice. Carcinogen-induced tumors displayed by Errfi1-/- mice were highly sensitive to gefitinib. These results indicate that Mig6 is a specific negative regulator of Egfr signaling in skin morphogenesis and is a novel tumor suppressor of Egfr-dependent carcinogenesis.", + "TAG_DATA": [ + "57, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "58, of {'perturbing_action': 'I-gene loss-of-function'}", + "59, the {'perturbing_action': 'I-gene loss-of-function'}", + "60, mouse {'perturbing_action': 'I-gene loss-of-function'}", + "61, gene {'perturbing_action': 'I-gene loss-of-function'}", + "62, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "63, Mig6 {'perturbing_action': 'I-gene loss-of-function'}", + "64, (designated {'perturbing_action': 'I-gene loss-of-function'}", + "65, Errfi1, {'perturbing_action': 'I-gene loss-of-function'}", + "95, overproliferation {'phenotype': 'B-proliferation'}", + "97, impaired {'effect': 'B-negative'}", + "98, differentiation {'phenotype': 'B-differentiation'}", + "100, epidermal {'context': 'B-cells'}", + "101, keratinocytes. {'context': 'I-cells'}", + "103, Errfi1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "104, mice {'context': 'B-organism'}", + "107, tumors {'phenotype': 'B-tumourigenesis'}", + "110, organs {'context': 'B-tissue/organ'}", + "121, tumors. {'phenotype': 'I-tumourigenesis'}", + "152, replacement {'perturbing_action': 'B-other'}", + "153, of {'perturbing_action': 'I-other'}", + "154, wild-type {'perturbing_action': 'I-other'}", + "155, Egfr {'perturbing_action': 'I-other'}", + "156, with {'perturbing_action': 'I-other'}", + "157, the {'perturbing_action': 'I-gene loss-of-function'}", + "158, kinase-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "159, protein {'perturbing_action': 'I-gene loss-of-function'}", + "160, encoded {'perturbing_action': 'I-gene loss-of-function'}", + "161, by {'perturbing_action': 'I-gene loss-of-function'}", + "162, the {'perturbing_action': 'I-gene loss-of-function'}", + "163, hypomorphic {'perturbing_action': 'I-gene loss-of-function'}", + "164, Egfr(wa2) {'perturbing_action': 'I-gene loss-of-function'}", + "165, allele {'perturbing_action': 'I-gene loss-of-function'}", + "168, skin {'context': 'B-tissue/organ'}", + "171, Erffi1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "172, mice. {'context': 'B-organism'}", + "173, Carcinogen-induced {'phenotype': 'B-tumourigenesis'}", + "174, tumors {'phenotype': 'I-tumourigenesis'}", + "177, Errfi1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "178, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "57, deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "58, of ['l0', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "59, the ['l1', 'l18', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "60, mouse ['l2', 'l19', 'l35', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "61, gene ['l3', 'l20', 'l36', 'l51', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "62, encoding ['l4', 'l21', 'l37', 'l52', 'l66', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "63, Mig6 ['l5', 'l22', 'l38', 'l53', 'l67', 'l80', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "64, (designated ['l6', 'l23', 'l39', 'l54', 'l68', 'l81', 'l93', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "65, Errfi1, ['l7', 'l24', 'l40', 'l55', 'l69', 'l82', 'l94', 'l105', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "95, overproliferation ['l8', 'l25', 'l41', 'l56', 'l70', 'l83', 'l95', 'l106', 'l116', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "97, impaired ['l9', 'l26', 'l42', 'l57', 'l71', 'l84', 'l96', 'l107', 'l117', 'l126', 'l132', 'l133', 'l134', 'l135', 'l136']", + "98, differentiation ['l10', 'l27', 'l43', 'l58', 'l72', 'l85', 'l97', 'l108', 'l118', 'l127', 'l132', 'l137', 'l138', 'l139', 'l140', 'l141']", + "100, epidermal ['l11', 'l28', 'l44', 'l59', 'l73', 'l86', 'l98', 'l109', 'l119', 'l128', 'l133', 'l137', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "101, keratinocytes. ['l12', 'l29', 'l45', 'l60', 'l74', 'l87', 'l99', 'l110', 'l120', 'l129', 'l134', 'l138', 'l142', 'l148', 'l149', 'l150', 'l151', 'l152']", + "103, Errfi1-/- ['l13', 'l30', 'l46', 'l61', 'l75', 'l88', 'l100', 'l111', 'l121', 'l143', 'l148', 'l153', 'l154', 'l155', 'l156']", + "104, mice ['l14', 'l31', 'l47', 'l62', 'l76', 'l89', 'l101', 'l112', 'l122', 'l139', 'l144', 'l149', 'l153', 'l157', 'l158', 'l159']", + "107, tumors ['l15', 'l32', 'l48', 'l63', 'l77', 'l90', 'l102', 'l113', 'l123', 'l130', 'l135', 'l140', 'l145', 'l150', 'l154', 'l157', 'l160', 'l161']", + "110, organs ['l16', 'l33', 'l49', 'l64', 'l78', 'l91', 'l103', 'l114', 'l124', 'l131', 'l136', 'l141', 'l146', 'l151', 'l155', 'l158', 'l160', 'l162']", + "121, tumors. ['l17', 'l34', 'l50', 'l65', 'l79', 'l92', 'l104', 'l115', 'l125', 'l147', 'l152', 'l156', 'l159', 'l161', 'l162']", + "152, replacement ['l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181']", + "153, of ['l163', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199']", + "154, wild-type ['l164', 'l182', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215']", + "155, Egfr ['l165', 'l183', 'l200', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230']", + "156, with ['l166', 'l184', 'l201', 'l216', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246']", + "157, the ['l167', 'l185', 'l202', 'l217', 'l231', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261']", + "158, kinase-deficient ['l168', 'l186', 'l203', 'l218', 'l232', 'l247', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275']", + "159, protein ['l169', 'l187', 'l204', 'l219', 'l233', 'l248', 'l262', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286', 'l287', 'l288']", + "160, encoded ['l170', 'l188', 'l205', 'l220', 'l234', 'l249', 'l263', 'l276', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300']", + "161, by ['l171', 'l189', 'l206', 'l221', 'l235', 'l250', 'l264', 'l277', 'l289', 'l301', 'l302', 'l303', 'l304', 'l305', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311']", + "162, the ['l172', 'l190', 'l207', 'l222', 'l236', 'l251', 'l265', 'l278', 'l290', 'l301', 'l312', 'l313', 'l314', 'l315', 'l316', 'l317', 'l318', 'l319', 'l320', 'l321']", + "163, hypomorphic ['l173', 'l191', 'l208', 'l223', 'l237', 'l252', 'l266', 'l279', 'l291', 'l302', 'l312', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327', 'l328', 'l329', 'l330']", + "164, Egfr(wa2) ['l174', 'l192', 'l209', 'l224', 'l238', 'l253', 'l267', 'l280', 'l292', 'l303', 'l313', 'l322', 'l331', 'l332', 'l333', 'l334', 'l335', 'l336', 'l337', 'l338']", + "165, allele ['l175', 'l193', 'l210', 'l225', 'l239', 'l254', 'l268', 'l281', 'l293', 'l304', 'l314', 'l323', 'l331', 'l339', 'l340', 'l341', 'l342', 'l343']", + "168, skin ['l176', 'l194', 'l211', 'l226', 'l240', 'l255', 'l269', 'l282', 'l294', 'l305', 'l315', 'l324', 'l332', 'l339', 'l344', 'l345']", + "171, Erffi1-/- ['l177', 'l195', 'l212', 'l227', 'l241', 'l256', 'l270', 'l283', 'l295', 'l306', 'l316', 'l325', 'l333', 'l340', 'l344', 'l346']", + "172, mice. ['l178', 'l196', 'l213', 'l228', 'l242', 'l257', 'l271', 'l284', 'l296', 'l307', 'l317', 'l326', 'l334', 'l341', 'l345', 'l346']", + "173, Carcinogen-induced ['l243', 'l258', 'l272', 'l285', 'l297', 'l308', 'l318', 'l327', 'l335', 'l347', 'l348', 'l349']", + "174, tumors ['l179', 'l197', 'l214', 'l229', 'l244', 'l259', 'l273', 'l286', 'l298', 'l309', 'l319', 'l328', 'l336', 'l342', 'l347', 'l350', 'l351']", + "177, Errfi1-/- ['l180', 'l198', 'l245', 'l260', 'l274', 'l287', 'l299', 'l310', 'l320', 'l329', 'l337', 'l348', 'l350', 'l352']", + "178, mice ['l181', 'l199', 'l215', 'l230', 'l246', 'l261', 'l275', 'l288', 'l300', 'l311', 'l321', 'l330', 'l338', 'l343', 'l349', 'l351', 'l352']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "mouse", + "gene", + "encoding", + "Mig6", + "(designated", + "Errfi1," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "overproliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "mouse", + "gene", + "encoding", + "Mig6", + "(designated", + "Errfi1," + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "mouse", + "gene", + "encoding", + "Mig6", + "(designated", + "Errfi1," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "mouse", + "gene", + "encoding", + "Mig6", + "(designated", + "Errfi1,", + "Errfi1-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "epidermal", + "keratinocytes." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "mouse", + "gene", + "encoding", + "Mig6", + "(designated", + "Errfi1,", + "Errfi1-/-", + "kinase-deficient", + "protein", + "encoded", + "by", + "hypomorphic", + "Egfr(wa2)", + "allele", + "Erffi1-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "mouse", + "gene", + "encoding", + "Mig6", + "(designated", + "Errfi1,", + "Errfi1-/-", + "kinase-deficient", + "protein", + "encoded", + "by", + "hypomorphic", + "Egfr(wa2)", + "allele" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors", + "tumors.", + "Carcinogen-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "mouse", + "gene", + "encoding", + "Mig6", + "(designated", + "Errfi1,", + "Errfi1-/-", + "kinase-deficient", + "protein", + "encoded", + "by", + "hypomorphic", + "Egfr(wa2)", + "allele", + "Erffi1-/-" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "organs", + "skin" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "overproliferation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "overproliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "epidermal", + "keratinocytes." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "overproliferation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "organs" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "cells", + "words": [ + "epidermal", + "keratinocytes." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "organs" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "epidermal", + "keratinocytes." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "organs" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "epidermal", + "keratinocytes." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors", + "tumors." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors", + "tumors.", + "Carcinogen-induced" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors", + "tumors." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "organs" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "replacement", + "of", + "wild-type", + "Egfr", + "with" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skin" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "replacement", + "of", + "wild-type", + "Egfr", + "with" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "replacement", + "of", + "wild-type", + "Egfr", + "with" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors", + "Carcinogen-induced" + ] + } + } + ] + }, + { + "PMID": "16633347", + "TEXT": "Neurons have been neglected as cells with a major immune-regulatory function because they do not express major histocompatibility complex class II. Our data show that neurons are highly immune regulatory, having a crucial role in governing T-cell response and central nervous system (CNS) inflammation. Neurons induce the proliferation of activated CD4+ T cells through B7-CD28 and transforming growth factor (TGF)-beta1-TGF-beta receptor signaling pathways, resulting in amplification of T-cell receptor signaling through phosphorylated ZAP-70, interleukin (IL)-2 and IL-9. The interaction between neurons and T cells results in the conversion of encephalitogenic T cells to CD25+ TGF-beta1+ CTLA-4+ FoxP3+ T regulatory (Treg) cells that suppress encephalitogenic T cells and inhibit experimental autoimmune encephalomyelitis. Suppression is dependent on cytotoxic T lymphocyte antigen (CTLA)-4 but not TGF-beta1. Autocrine action of TGF-beta1, however, is important for the proliferative arrest of Treg cells. Blocking the B7 and TGF-beta pathways prevents the CNS-specific generation of Treg cells. These findings show that generation of neuron-dependent Treg cells in the CNS is instrumental in regulating CNS inflammation.", + "TAG_DATA": [ + "45, induce {'effect': 'B-positive'}", + "47, proliferation {'phenotype': 'B-proliferation'}", + "50, CD4+ {'context': 'B-cells'}", + "51, T {'context': 'I-cells'}", + "52, cells {'context': 'I-cells'}", + "89, encephalitogenic {'context': 'B-cells'}", + "90, T {'context': 'I-cells'}", + "91, cells {'context': 'I-cells'}", + "97, T {'context': 'I-cells'}", + "98, regulatory {'context': 'I-cells'}", + "100, cells {'context': 'I-cells'}", + "104, T {'context': 'I-cells'}", + "105, cells {'context': 'I-cells'}", + "133, arrest {'phenotype': 'I-proliferation'}", + "135, Treg {'context': 'B-cells'}", + "136, cells. {'context': 'I-cells'}", + "148, Treg {'context': 'B-cells'}", + "149, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, induce ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "47, proliferation ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "50, CD4+ ['l1', 'l6', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "51, T ['l2', 'l7', 'l11', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "52, cells ['l3', 'l8', 'l12', 'l19', 'l25', 'l26']", + "89, encephalitogenic ['l13', 'l20', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "90, T ['l4', 'l9', 'l14', 'l21', 'l25', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "91, cells ['l5', 'l10', 'l15', 'l22', 'l26', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "97, T ['l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "98, regulatory ['l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "100, cells ['l16', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "104, T ['l17', 'l23', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "105, cells ['l18', 'l24', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "133, arrest ['l55', 'l56', 'l57']", + "135, Treg ['l55', 'l58', 'l59', 'l60']", + "136, cells. ['l56', 'l58']", + "148, Treg ['l59', 'l61']", + "149, cells. ['l57', 'l60', 'l61']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation", + "arrest" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells", + "Treg", + "cells." + ] + } + } + ] + }, + { + "PMID": "16604088", + "TEXT": "Ciliary neurotrophic factor (CNTF) induces weight loss and improves glucose tolerance in humans and rodents. CNTF is thought to act centrally by inducing hypothalamic neurogenesis to modulate food intake and peripherally by altering hepatic gene expression, in a manner similar to that of leptin. Here, we show that CNTF signals through the CNTFRalpha-IL-6R-gp130beta receptor complex to increase fatty-acid oxidation and reduce insulin resistance in skeletal muscle by activating AMP-activated protein kinase (AMPK), independent of signaling through the brain. Thus, our findings further show that the antiobesogenic effects of CNTF in the periphery result from direct effects on skeletal muscle, and that these peripheral effects are not suppressed by diet-induced or genetic models of obesity, an essential requirement for the therapeutic treatment of obesity-related diseases.", + "TAG_DATA": [ + "64, skeletal {'context': 'B-tissue/organ'}", + "65, muscle {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "64, skeletal ['l0']", + "65, muscle ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16582916", + "TEXT": "Gene transfer into hematopoietic stem cells has been used successfully for correcting lymphoid but not myeloid immunodeficiencies. Here we report on two adults who received gene therapy after nonmyeloablative bone marrow conditioning for the treatment of X-linked chronic granulomatous disease (X-CGD), a primary immunodeficiency caused by a defect in the oxidative antimicrobial activity of phagocytes resulting from mutations in gp91(phox). We detected substantial gene transfer in both individuals' neutrophils that lead to a large number of functionally corrected phagocytes and notable clinical improvement. Large-scale retroviral integration site-distribution analysis showed activating insertions in MDS1-EVI1, PRDM16 or SETBP1 that had influenced regulation of long-term hematopoiesis by expanding gene-corrected myelopoiesis three- to four-fold in both individuals. Although insertional influences have probably reinforced the therapeutic efficacy in this trial, our results suggest that gene therapy in combination with bone marrow conditioning can be successfully used to treat inherited diseases affecting the myeloid compartment such as CGD.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16550190", + "TEXT": "Defects in major histocompatibility complex (MHC) class I-restricted antigen presentation are frequently observed in human cancers and result in escape of tumors from cytotoxic T lymphocyte (CTL) immune surveillance in mice. Here, we show the existence of a unique category of CTLs that can prevent this escape. The CTLs target an alternative repertoire of peptide epitopes that emerge in MHC class I at the surface of cells with impaired function of transporter associated with antigen processing (TAP), tapasin or the proteasome. These peptides, although derived from self antigens such as the commonly expressed Lass5 protein (also known as Trh4), are not presented by normal cells. This explains why they act as immunogenic neoantigens. The newly discovered epitopes can be exploited for immune intervention against processing-deficient tumors through adoptive T-cell transfer or peptide vaccination.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16550188", + "TEXT": "Adult T-cell leukemia-lymphoma (ATLL) is a group of T-cell malignancies caused by infection with human T-lymphotropic virus type I (HTLV-I). Although the pathogenesis of ATLL remains incompletely understood, the viral regulatory protein Tax is centrally involved in cellular transformation. Here we describe the generation of HTLV-I Tax transgenic mice using the Lck proximal promoter to restrict transgene expression to developing thymocytes. After prolonged latency periods, transgenic mice developed diffuse large-cell lymphomas and leukemia with clinical, pathological and immunological features characteristic of acute ATLL. Transgenic mice were functionally immunocompromised and they developed opportunistic infections. Fulminant disease also developed rapidly in SCID mice after engraftment of lymphomatous cells from transgenic mice. Flow cytometry showed that the cells were CD4(-) and CD8(-), but CD44(+), CD25(+) and cytoplasmic CD3(+). This phenotype is indicative of a thymus-derived pre-T-cell phenotype, and disease development was associated with the constitutive activation of NF-kappaB. Our model accurately reproduces human disease and will provide a tool for analysis of the molecular events in transformation and for the development of new therapeutics.", + "TAG_DATA": [ + "48, mice {'context': 'B-organism'}", + "60, thymocytes. {'context': 'B-cells'}", + "66, mice {'context': 'B-organism'}", + "72, leukemia {'context': 'B-neoplasm'}", + "84, mice {'context': 'B-organism'}", + "99, SCID {'context': 'B-organism'}", + "100, mice {'context': 'I-organism'}", + "104, lymphomatous {'context': 'B-cells'}", + "105, cells {'context': 'I-cells'}", + "108, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "48, mice ['l0', 'l1', 'l2', 'l3']", + "60, thymocytes. ['l0', 'l4', 'l5', 'l6']", + "66, mice ['l1', 'l4', 'l7', 'l8']", + "70, lymphomas ['l2', 'l5', 'l7', 'l9']", + "72, leukemia ['l3', 'l6', 'l8', 'l9']", + "99, SCID ['l10', 'l11', 'l12', 'l13']", + "100, mice ['l10', 'l14', 'l15']", + "104, lymphomatous ['l11', 'l16', 'l17']", + "105, cells ['l12', 'l14', 'l16', 'l18']", + "108, mice. ['l13', 'l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16550187", + "TEXT": "Pathological conditions in the central nervous system, including stroke and trauma, are often exacerbated by cerebral edema. We recently identified a nonselective cation channel, the NC(Ca-ATP) channel, in ischemic astrocytes that is regulated by sulfonylurea receptor 1 (SUR1), is opened by depletion of ATP and, when opened, causes cytotoxic edema. Here, we evaluated involvement of this channel in rodent models of stroke. SUR1 protein and mRNA were newly expressed in ischemic neurons, astrocytes and capillaries. Upregulation of SUR1 was linked to activation of the transcription factor Sp1 and was associated with expression of functional NC(Ca-ATP) but not K(ATP) channels. Block of SUR1 with low-dose glibenclamide reduced cerebral edema, infarct volume and mortality by 50%, with the reduction in infarct volume being associated with cortical sparing. Our findings indicate that the NC(Ca-ATP) channel is crucially involved in development of cerebral edema, and that targeting SUR1 may provide a new therapeutic approach to stroke.", + "TAG_DATA": [ + "99, Block {'perturbing_action': 'B-pharmacological inhibition'}", + "100, of {'perturbing_action': 'I-pharmacological inhibition'}", + "101, SUR1 {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "99, Block ['l0', 'l1', 'l2']", + "100, of ['l0', 'l3', 'l4']", + "101, SUR1 ['l1', 'l3', 'l5']", + "102, with ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16532004", + "TEXT": "The variability in the prognosis of individuals with hepatocellular carcinoma (HCC) suggests that HCC may comprise several distinct biological phenotypes. These phenotypes may result from activation of different oncogenic pathways during tumorigenesis and/or from a different cell of origin. Here we address whether the transcriptional characteristics of HCC can provide insight into the cellular origin of the tumor. We integrated gene expression data from rat fetal hepatoblasts and adult hepatocytes with HCC from human and mouse models. Individuals with HCC who shared a gene expression pattern with fetal hepatoblasts had a poor prognosis. The gene expression program that distinguished this subtype from other types of HCC included markers of hepatic oval cells, suggesting that HCC of this subtype may arise from hepatic progenitor cells. Analyses of gene networks showed that activation of AP-1 transcription factors in this newly identified HCC subtype might have key roles in tumor development.", + "TAG_DATA": [ + "64, rat {'context': 'B-cells'}", + "65, fetal {'context': 'I-cells'}", + "66, hepatoblasts {'context': 'I-cells'}", + "68, adult {'context': 'B-cells'}", + "69, hepatocytes {'context': 'I-cells'}", + "71, HCC {'context': 'B-neoplasm'}", + "73, human {'context': 'B-organism'}", + "74, and {'context': 'I-organism'}", + "75, mouse {'context': 'I-organism'}", + "76, models. {'context': 'I-organism'}", + "79, HCC {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "64, rat ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "65, fetal ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "66, hepatoblasts ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "68, adult ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "69, hepatocytes ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "71, HCC ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "73, human ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "74, and ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "75, mouse ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "76, models. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16491087", + "TEXT": "There is a crucial need for alternatives to native vein or artery for vascular surgery. The clinical efficacy of synthetic, allogeneic or xenogeneic vessels has been limited by thrombosis, rejection, chronic inflammation and poor mechanical properties. Using adult human fibroblasts extracted from skin biopsies harvested from individuals with advanced cardiovascular disease, we constructed tissue-engineered blood vessels (TEBVs) that serve as arterial bypass grafts in long-term animal models. These TEBVs have mechanical properties similar to human blood vessels, without relying upon synthetic or exogenous scaffolding. The TEBVs are antithrombogenic and mechanically stable for 8 months in vivo. Histological analysis showed complete tissue integration and formation of vasa vasorum. The endothelium was confluent and positive for von Willebrand factor. A smooth muscle-specific alpha-actin-positive cell population developed within the TEBV, suggesting regeneration of a vascular media. Electron microscopy showed an endothelial basement membrane, elastogenesis and a complex collagen network. These results indicate that a completely biological and clinically relevant TEBV can be assembled exclusively from an individual's own cells.", + "TAG_DATA": [ + "37, adult {'context': 'B-cells'}", + "38, human {'context': 'I-cells'}", + "39, fibroblasts {'context': 'I-cells'}", + "40, extracted {'context': 'I-cells'}", + "94, in {'context': 'B-in vivo'}", + "95, vivo. {'context': 'I-in vivo'}", + "118, smooth {'context': 'B-cells'}", + "119, muscle-specific {'context': 'I-cells'}", + "120, alpha-actin-positive {'context': 'I-cells'}", + "121, cell {'context': 'I-cells'}", + "122, population {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "37, adult ['l0', 'l1', 'l2', 'l3', 'l4']", + "38, human ['l0', 'l5', 'l6', 'l7', 'l8']", + "39, fibroblasts ['l1', 'l5', 'l9', 'l10', 'l11']", + "40, extracted ['l2', 'l6', 'l9', 'l12', 'l13']", + "94, in ['l3', 'l7', 'l10', 'l12', 'l14']", + "95, vivo. ['l4', 'l8', 'l11', 'l13', 'l14']", + "118, smooth ['l15', 'l16', 'l17', 'l18']", + "119, muscle-specific ['l15', 'l19', 'l20', 'l21']", + "120, alpha-actin-positive ['l16', 'l19', 'l22', 'l23']", + "121, cell ['l17', 'l20', 'l22', 'l24']", + "122, population ['l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16491086", + "TEXT": "Retroviral and lentiviral vector integration into host-cell chromosomes carries with it a finite chance of causing insertional mutagenesis. This risk has been highlighted by the induction of malignancy in mouse models, and development of lymphoproliferative disease in three individuals with severe combined immunodeficiency-X1 (refs. 2,3). Therefore, a key challenge for clinical therapies based on retroviral vectors is to achieve stable transgene expression while minimizing insertional mutagenesis. Recent in vitro studies have shown that integration-deficient lentiviral vectors can mediate stable transduction. With similar vectors, we now show efficient and sustained transgene expression in vivo in rodent ocular and brain tissues. We also show substantial rescue of clinically relevant rodent models of retinal degeneration. Therefore, the high efficiency of gene transfer and expression mediated by lentiviruses can be harnessed in vivo without a requirement for vector integration. For therapeutic application to postmitotic tissues, this system substantially reduces the risk of insertional mutagenesis.", + "TAG_DATA": [ + "91, in {'context': 'B-in vivo'}", + "92, vivo {'context': 'I-in vivo'}", + "94, rodent {'context': 'B-tissue/organ'}", + "95, ocular {'context': 'I-tissue/organ'}", + "96, and {'context': 'I-tissue/organ'}", + "97, brain {'context': 'I-tissue/organ'}", + "98, tissues. {'context': 'I-tissue/organ'}", + "107, rodent {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "91, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "92, vivo ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "94, rodent ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "95, ocular ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "96, and ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "97, brain ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "98, tissues. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16491084", + "TEXT": "The nature and even existence of adult pancreatic endocrine stem or progenitor cells is a subject of controversy in the field of beta-cell replacement for diabetes. One place to search for such cells is in the nonendocrine fraction of cells that remain after islet isolation, which consist of a mixture of epithelia and mesenchyme. Culture in G418 resulted in elimination of the mesenchymal cells, leaving a highly purified population of nonendocrine pancreatic epithelial cells (NEPECs). To evaluate their differentiation potential, NEPECs were heritably marked and transplanted under the kidney capsule of immunodeficient mice. When cotransplanted with fetal pancreatic cells, NEPECs were capable of endocrine differentiation. We found no evidence of beta-cell replication or cell fusion that could have explained the appearance of insulin positive cells from a source other than NEPECs. Nonendocrine-to-endocrine differentiation of NEPECs supports the existence of endocrine stem or progenitor cells within the epithelial compartment of the adult human pancreas.", + "TAG_DATA": [ + "62, mesenchymal {'context': 'B-cells'}", + "63, cells, {'context': 'I-cells'}", + "96, fetal {'context': 'B-cells'}", + "97, pancreatic {'context': 'I-cells'}", + "98, cells, {'context': 'I-cells'}", + "99, NEPECs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "62, mesenchymal ['l0']", + "63, cells, ['l0']", + "96, fetal ['l1', 'l2', 'l3']", + "97, pancreatic ['l1', 'l4', 'l5']", + "98, cells, ['l2', 'l4', 'l6']", + "99, NEPECs ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16474401", + "TEXT": "The widespread distribution of the tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) in the adult brain suggests its role in a broad range of brain functions. Here we show evidence supporting a physical interaction of PTEN with a region in the third intracellular loop (3L4F) of the serotonin 5-HT2C receptor (5-HT2cR, formerly 5-HT1c receptor) in cell cultures. PTEN limits agonist-induced phosphorylation of 5-HT2cR through its protein phosphatase activity. We showed the probable existence of PTEN:5-HT2cR complexes in putative dopaminergic neurons in the rat ventral tegmental area (VTA), a brain region in which virtually all abused drugs exert rewarding effects by activating its dopamine neurons. We synthesized the interfering peptide Tat-3L4F, which is able to disrupt PTEN coupling with 5-HT2cR. Systemic application of Tat-3L4F or the 5-HT2cR agonist Ro600175 suppressed the increased firing rate of VTA dopaminergic neurons induced by delta9-tetrahydrocannabinol (THC), the psychoactive ingredient of marijuana. Using behavioral tests, we found that Tat-3L4F or Ro600175 blocks conditioned place preference of THC or nicotine, and that Ro600175, but not Tat-3L4F, produces anxiogenic effects, penile erection, hypophagia and motor functional suppression. These results suggest a potential strategy for treating drug addiction with the Tat-3L4F peptide.", + "TAG_DATA": [ + "129, 5-HT2cR {'perturbing_action': 'I-pharmacological augmentation'}", + "130, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "131, Ro600175 {'perturbing_action': 'I-pharmacological augmentation'}", + "138, VTA {'context': 'B-cells'}", + "139, dopaminergic {'context': 'I-cells'}", + "140, neurons {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "129, 5-HT2cR ['l0', 'l1', 'l2', 'l3', 'l4']", + "130, agonist ['l0', 'l5', 'l6', 'l7', 'l8']", + "131, Ro600175 ['l1', 'l5', 'l9', 'l10', 'l11']", + "138, VTA ['l2', 'l6', 'l9', 'l12', 'l13']", + "139, dopaminergic ['l3', 'l7', 'l10', 'l12', 'l14']", + "140, neurons ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "5-HT2cR", + "agonist", + "Ro600175" + ] + }, + "context": { + "val": "cells", + "words": [ + "VTA", + "dopaminergic", + "neurons" + ] + } + } + ] + }, + { + "PMID": "16474400", + "TEXT": "We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 x 10(12) vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of approximately 8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression.", + "TAG_DATA": [ + "56, rAAV-2 {'perturbing_action': 'B-gene gain-of-function'}", + "57, vector {'perturbing_action': 'I-gene gain-of-function'}", + "58, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "59, human {'perturbing_action': 'I-gene gain-of-function'}", + "60, F.IX {'perturbing_action': 'I-gene gain-of-function'}", + "148, hepatocytes {'context': 'B-cells'}", + "175, human {'context': 'B-cells'}", + "176, hepatocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "56, rAAV-2 ['l0', 'l1', 'l2', 'l3']", + "57, vector ['l0', 'l4', 'l5', 'l6']", + "58, expressing ['l1', 'l4', 'l7', 'l8']", + "59, human ['l2', 'l5', 'l7', 'l9']", + "60, F.IX ['l3', 'l6', 'l8', 'l9']", + "148, hepatocytes ['l10', 'l11']", + "175, human ['l10', 'l12']", + "176, hepatocytes ['l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16462800", + "TEXT": "Atherosclerosis is an immunoinflammatory disease elicited by accumulation of lipids in the artery wall and leads to myocardial infarction and stroke. Here, we show that naturally arising CD4(+)CD25(+) regulatory T cells, which actively maintain immunological tolerance to self and nonself antigens, are powerful inhibitors of atherosclerosis in several mouse models. These results provide new insights into the immunopathogenesis of atherosclerosis and could lead to new therapeutic approaches that involve immune modulation using regulatory T cells.", + "TAG_DATA": [ + "43, inhibitors {'effect': 'B-negative'}", + "45, atherosclerosis {'phenotype': 'B-tumourigenesis'}", + "48, mouse {'context': 'B-organism'}", + "49, models. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "43, inhibitors ['l0', 'l1', 'l2']", + "45, atherosclerosis ['l0', 'l3', 'l4']", + "48, mouse ['l1', 'l3', 'l5']", + "49, models. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibitors" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "atherosclerosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibitors" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "atherosclerosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + } + ] + }, + { + "PMID": "16429145", + "TEXT": "The myofilament protein troponin I (TnI) has a key isoform-dependent role in the development of contractile failure during acidosis and ischemia. Here we show that cardiac performance in vitro and in vivo is enhanced when a single histidine residue present in the fetal cardiac TnI isoform is substituted into the adult cardiac TnI isoform at codon 164. The most marked effects are observed under the acute challenges of acidosis, hypoxia, ischemia and ischemia-reperfusion, in chronic heart failure in transgenic mice and in myocytes from failing human hearts. In the isolated heart, histidine-modified TnI improves systolic and diastolic function and mitigates reperfusion-associated ventricular arrhythmias. Cardiac performance is markedly enhanced in transgenic hearts during reperfusion despite a high-energy phosphate content similar to that in nontransgenic hearts, providing evidence for greater energetic economy. This pH-sensitive 'histidine button' engineered in TnI produces a titratable molecular switch that 'senses' changes in the intracellular milieu of the cardiac myocyte and responds by preferentially augmenting acute and long-term function under pathophysiological conditions. Myofilament-based inotropy may represent a therapeutic avenue to improve myocardial performance in the ischemic and failing heart.", + "TAG_DATA": [ + "27, in {'context': 'B-in vitro'}", + "28, vitro {'context': 'I-in vitro'}", + "30, in {'context': 'B-in vivo'}", + "31, vivo {'context': 'I-in vivo'}", + "78, transgenic {'context': 'B-organism'}", + "79, mice {'context': 'I-organism'}", + "82, myocytes {'context': 'B-cells'}", + "83, from {'context': 'I-cells'}", + "84, failing {'context': 'B-tissue/organ'}", + "85, human {'context': 'I-tissue/organ'}", + "86, hearts. {'context': 'I-tissue/organ'}", + "89, isolated {'context': 'B-tissue/organ'}", + "90, heart, {'context': 'I-tissue/organ'}", + "110, hearts {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "27, in ['l0', 'l1', 'l2', 'l3', 'l4']", + "28, vitro ['l0', 'l5', 'l6', 'l7', 'l8']", + "30, in ['l1', 'l5', 'l9', 'l10', 'l11', 'l12', 'l13']", + "31, vivo ['l2', 'l6', 'l9', 'l14', 'l15']", + "78, transgenic ['l3', 'l7', 'l10', 'l14', 'l16', 'l17', 'l18', 'l19']", + "79, mice ['l4', 'l8', 'l11', 'l15', 'l16', 'l20', 'l21']", + "82, myocytes ['l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "83, from ['l22', 'l28', 'l29', 'l30', 'l31', 'l32']", + "84, failing ['l17', 'l23', 'l28', 'l33', 'l34', 'l35', 'l36']", + "85, human ['l12', 'l18', 'l20', 'l24', 'l29', 'l33', 'l37', 'l38', 'l39']", + "86, hearts. ['l13', 'l19', 'l21', 'l25', 'l30', 'l34', 'l37', 'l40', 'l41']", + "89, isolated ['l26', 'l31', 'l35', 'l38', 'l40', 'l42']", + "90, heart, ['l27', 'l32', 'l36', 'l39', 'l41', 'l42']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16415877", + "TEXT": "Control of inflammation is crucial to prevent damage to the host during infection. Lipoxins and aspirin-triggered lipoxins are crucial modulators of proinflammatory responses; however, their intracellular mechanisms have not been completely elucidated. We previously showed that lipoxin A4 (LXA4) controls migration of dendritic cells (DCs) and production of interleukin (IL)-12 in vivo. In the absence of LXA4 biosynthetic pathways, the resulting uncontrolled inflammation during infection is lethal, despite pathogen clearance. Here we show that lipoxins activate two receptors in DCs, AhR and LXAR, and that this activation triggers expression of suppressor of cytokine signaling (SOCS)-2. SOCS-2-deficient DCs are hyper-responsive to microbial stimuli, as well as refractory to the inhibitory actions of LXA4, but not to IL-10. Upon infection with an intracellular pathogen, SOCS-2-deficient mice had uncontrolled production of proinflammatory cytokines, decreased microbial proliferation, aberrant leukocyte infiltration and elevated mortality. We also show that SOCS-2 is a crucial intracellular mediator of the anti-inflammatory actions of aspirin-induced lipoxins in vivo.", + "TAG_DATA": [ + "95, SOCS-2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "96, DCs {'context': 'B-cells'}", + "122, SOCS-2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "123, mice {'context': 'B-organism'}", + "130, decreased {'effect': 'B-negative'}", + "132, proliferation, {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "95, SOCS-2-deficient ['l0', 'l1', 'l2']", + "96, DCs ['l0']", + "122, SOCS-2-deficient ['l3', 'l4', 'l5']", + "123, mice ['l3', 'l6', 'l7']", + "130, decreased ['l1', 'l4', 'l6', 'l8']", + "132, proliferation, ['l2', 'l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SOCS-2-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "DCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SOCS-2-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SOCS-2-deficient" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SOCS-2-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + } + ] + }, + { + "PMID": "16380717", + "TEXT": "Type 1 diabetes mellitus is characterized by the selective destruction of insulin-producing beta cells, which leads to a deficiency in insulin secretion and, as a result, to hyperglycemia. At present, transplantation of pancreatic islets is an emerging and promising clinical modality, which can render individuals with type 1 diabetes insulin independent without increasing the incidence of hypoglycemic events. To monitor transplantation efficiency and graft survival, reliable noninvasive imaging methods are needed. If such methods were introduced into the clinic, essential information could be obtained repeatedly and noninvasively. Here we report on the in vivo detection of transplanted human pancreatic islets using magnetic resonance imaging (MRI) that allowed noninvasive monitoring of islet grafts in diabetic mice in real time. We anticipate that the information obtained in this study would ultimately result in the ability to detect and monitor islet engraftment in humans, which would greatly aid the clinical management of this disease.", + "TAG_DATA": [ + "92, in {'context': 'B-in vivo'}", + "93, vivo {'context': 'I-in vivo'}", + "97, human {'context': 'I-cells'}", + "98, pancreatic {'context': 'I-tissue/organ'}", + "99, islets {'context': 'I-tissue/organ'}", + "110, islet {'context': 'B-cells'}", + "113, diabetic {'context': 'B-organism'}", + "114, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "92, in ['l0', 'l1', 'l2', 'l3']", + "93, vivo ['l0', 'l4', 'l5', 'l6']", + "97, human ['l1', 'l4', 'l7', 'l8']", + "98, pancreatic ['l2', 'l5', 'l7', 'l9']", + "99, islets ['l3', 'l6', 'l8', 'l9']", + "110, islet ['l10', 'l11']", + "113, diabetic ['l10', 'l12']", + "114, mice ['l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16369543", + "TEXT": "The scaffolding adapter GAB2 maps to a region (11q13-14) commonly amplified in human breast cancer, and is overexpressed in breast cancer cell lines and primary tumors, but its functional role in mammary carcinogenesis has remained unexplored. We found that overexpression of GAB2 (Grb2-associated binding protein 2) increases proliferation of MCF10A mammary cells in three-dimensional culture. Coexpression of GAB2 with antiapoptotic oncogenes causes lumenal filling, whereas coexpression with Neu (also known as ErbB2 and HER2) results in an invasive phenotype. These effects of GAB2 are mediated by hyperactivation of the Shp2-Erk pathway. Furthermore, overexpression of Gab2 potentiates, whereas deficiency of Gab2 ameliorates, Neu-evoked breast carcinogenesis in mice. Finally, GAB2 is amplified in some GAB2-overexpressing human breast tumors. Our data suggest that GAB2 may be a key gene within an 11q13 amplicon in human breast cancer and propose a role for overexpression of GAB2 in mammary carcinogenesis. Agents that target GAB2 or GAB2-dependent pathways may be useful for treating breast tumors that overexpress GAB2 or HER2 or both.", + "TAG_DATA": [ + "39, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "40, of {'perturbing_action': 'I-gene gain-of-function'}", + "41, GAB2 {'perturbing_action': 'I-gene gain-of-function'}", + "42, (Grb2-associated {'perturbing_action': 'I-gene gain-of-function'}", + "43, binding {'perturbing_action': 'I-gene gain-of-function'}", + "44, protein {'perturbing_action': 'I-gene gain-of-function'}", + "45, 2) {'perturbing_action': 'I-gene gain-of-function'}", + "46, increases {'effect': 'B-positive'}", + "47, proliferation {'phenotype': 'B-proliferation'}", + "49, MCF10A {'context': 'B-transformed cells'}", + "50, mammary {'context': 'I-transformed cells'}", + "51, cells {'context': 'I-transformed cells'}", + "53, three-dimensional {'context': 'B-in vitro'}", + "54, culture. {'context': 'I-in vitro'}", + "55, Coexpression {'perturbing_action': 'B-gene gain-of-function'}", + "56, of {'perturbing_action': 'I-gene gain-of-function'}", + "57, GAB2 {'perturbing_action': 'I-gene gain-of-function'}", + "58, with {'perturbing_action': 'I-gene gain-of-function'}", + "59, antiapoptotic {'perturbing_action': 'I-gene gain-of-function'}", + "65, coexpression {'perturbing_action': 'B-gene gain-of-function'}", + "66, with {'perturbing_action': 'I-gene gain-of-function'}", + "67, Neu {'perturbing_action': 'I-gene gain-of-function'}", + "74, results {'effect': 'B-positive'}", + "92, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "93, of {'perturbing_action': 'I-gene gain-of-function'}", + "94, Gab2 {'perturbing_action': 'I-gene gain-of-function'}", + "95, potentiates, {'effect': 'B-positive'}", + "97, deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "98, of {'perturbing_action': 'I-gene loss-of-function'}", + "99, Gab2 {'perturbing_action': 'I-gene loss-of-function'}", + "100, ameliorates, {'effect': 'B-negative'}", + "101, Neu-evoked {'effect': 'B-positive'}", + "102, breast {'context': 'B-tissue/organ'}", + "103, carcinogenesis {'phenotype': 'B-tumourigenesis'}", + "105, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "39, overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "40, of ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "41, GAB2 ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "42, (Grb2-associated ['l2', 'l21', 'l39', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "43, binding ['l3', 'l22', 'l40', 'l57', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "44, protein ['l4', 'l23', 'l41', 'l58', 'l74', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "45, 2) ['l5', 'l24', 'l42', 'l59', 'l75', 'l90', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "46, increases ['l6', 'l25', 'l43', 'l60', 'l76', 'l91', 'l105', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "47, proliferation ['l7', 'l26', 'l44', 'l61', 'l77', 'l92', 'l106', 'l118', 'l124', 'l125', 'l126', 'l127', 'l128']", + "49, MCF10A ['l8', 'l27', 'l45', 'l62', 'l78', 'l93', 'l107', 'l119', 'l124', 'l129', 'l130', 'l131', 'l132']", + "50, mammary ['l9', 'l28', 'l46', 'l63', 'l79', 'l94', 'l108', 'l120', 'l125', 'l129', 'l133', 'l134', 'l135']", + "51, cells ['l10', 'l29', 'l47', 'l64', 'l80', 'l95', 'l109', 'l121', 'l126', 'l130', 'l133', 'l136', 'l137']", + "53, three-dimensional ['l11', 'l30', 'l48', 'l65', 'l81', 'l96', 'l110', 'l122', 'l127', 'l131', 'l134', 'l136', 'l138']", + "54, culture. ['l12', 'l31', 'l49', 'l66', 'l82', 'l97', 'l111', 'l123', 'l128', 'l132', 'l135', 'l137', 'l138']", + "55, Coexpression ['l13', 'l32', 'l50', 'l67', 'l83', 'l98', 'l112', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146']", + "56, of ['l14', 'l33', 'l51', 'l68', 'l84', 'l99', 'l113', 'l139', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "57, GAB2 ['l15', 'l34', 'l52', 'l69', 'l85', 'l100', 'l114', 'l140', 'l147', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159']", + "58, with ['l16', 'l35', 'l53', 'l70', 'l86', 'l101', 'l115', 'l141', 'l148', 'l154', 'l160', 'l161', 'l162', 'l163', 'l164']", + "59, antiapoptotic ['l17', 'l36', 'l54', 'l71', 'l87', 'l102', 'l116', 'l142', 'l149', 'l155', 'l160', 'l165', 'l166', 'l167', 'l168']", + "65, coexpression ['l143', 'l150', 'l156', 'l161', 'l165', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "66, with ['l144', 'l151', 'l157', 'l162', 'l166', 'l169', 'l175', 'l176', 'l177', 'l178', 'l179']", + "67, Neu ['l18', 'l37', 'l55', 'l72', 'l88', 'l103', 'l145', 'l152', 'l158', 'l163', 'l167', 'l170', 'l175', 'l180', 'l181', 'l182', 'l183']", + "74, results ['l19', 'l38', 'l56', 'l73', 'l89', 'l104', 'l117', 'l146', 'l153', 'l159', 'l164', 'l168', 'l171', 'l176', 'l180']", + "92, overexpression ['l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191']", + "93, of ['l184', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198']", + "94, Gab2 ['l185', 'l192', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "95, potentiates, ['l172', 'l177', 'l181', 'l186', 'l193', 'l199', 'l205', 'l206', 'l207', 'l208']", + "97, deficiency ['l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215']", + "98, of ['l209', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221']", + "99, Gab2 ['l210', 'l216', 'l222', 'l223', 'l224', 'l225', 'l226']", + "100, ameliorates, ['l187', 'l194', 'l200', 'l211', 'l217', 'l222', 'l227', 'l228', 'l229', 'l230']", + "101, Neu-evoked ['l188', 'l195', 'l201', 'l205', 'l212', 'l218', 'l223', 'l227', 'l231', 'l232', 'l233']", + "102, breast ['l173', 'l178', 'l182', 'l189', 'l196', 'l202', 'l206', 'l213', 'l219', 'l224', 'l228', 'l231', 'l234', 'l235']", + "103, carcinogenesis ['l174', 'l179', 'l183', 'l190', 'l197', 'l203', 'l207', 'l214', 'l220', 'l225', 'l229', 'l232', 'l234', 'l236']", + "105, mice. ['l191', 'l198', 'l204', 'l208', 'l215', 'l221', 'l226', 'l230', 'l233', 'l235', 'l236']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "GAB2", + "(Grb2-associated", + "binding", + "protein", + "2)", + "Coexpression", + "with", + "antiapoptotic", + "coexpression", + "Neu", + "Gab2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increases", + "results", + "potentiates,", + "Neu-evoked" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "GAB2", + "(Grb2-associated", + "binding", + "protein", + "2)" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "GAB2", + "(Grb2-associated", + "binding", + "protein", + "2)" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MCF10A", + "mammary", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "GAB2", + "(Grb2-associated", + "binding", + "protein", + "2)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "three-dimensional", + "culture." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MCF10A", + "mammary", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "three-dimensional", + "culture." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MCF10A", + "mammary", + "cells" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "three-dimensional", + "culture." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "coexpression", + "with", + "Neu", + "overexpression", + "of", + "Gab2" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "breast" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "coexpression", + "with", + "Neu", + "overexpression", + "of", + "Gab2" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "carcinogenesis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Gab2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "ameliorates," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Gab2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "potentiates,", + "Neu-evoked" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "breast" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "potentiates,", + "Neu-evoked" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "carcinogenesis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "potentiates,", + "Neu-evoked" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "of", + "Gab2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "ameliorates," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "of", + "Gab2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "Neu-evoked" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "of", + "Gab2" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "breast" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "of", + "Gab2" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "carcinogenesis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "of", + "Gab2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "ameliorates," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "breast" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "ameliorates," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "carcinogenesis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "ameliorates," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "breast" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "carcinogenesis" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "carcinogenesis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "16341243", + "TEXT": "Inhibitors of the kinase mammalian target of rapamycin (mTOR) have shown sporadic activity in cancer trials, leading to confusion about the appropriate clinical setting for their use. Here we show that loss of the Von Hippel-Lindau tumor suppressor gene (VHL) sensitizes kidney cancer cells to the mTOR inhibitor CCI-779 in vitro and in mouse models. Growth arrest caused by CCI-779 correlates with a block in translation of mRNA encoding hypoxia-inducible factor (HIF1A), and is rescued by expression of a VHL-resistant HIF1A cDNA lacking the 5' untranslated region. VHL-deficient tumors show increased uptake of the positron emission tomography (PET) tracer fluorodeoxyglucose (FDG) in an mTOR-dependent manner. Our findings provide preclinical rationale for prospective, biomarker-driven clinical studies of mTOR inhibitors in kidney cancer and suggest that FDG-PET scans may have use as a pharmacodynamic marker in this setting.", + "TAG_DATA": [ + "31, loss {'perturbing_action': 'B-gene loss-of-function'}", + "32, of {'perturbing_action': 'I-gene loss-of-function'}", + "33, the {'perturbing_action': 'I-gene loss-of-function'}", + "34, Von {'perturbing_action': 'I-gene loss-of-function'}", + "35, Hippel-Lindau {'perturbing_action': 'I-gene loss-of-function'}", + "36, tumor {'perturbing_action': 'I-gene loss-of-function'}", + "37, suppressor {'perturbing_action': 'I-gene loss-of-function'}", + "38, gene {'perturbing_action': 'I-gene loss-of-function'}", + "39, (VHL) {'perturbing_action': 'I-gene loss-of-function'}", + "41, kidney {'context': 'B-transformed cells'}", + "42, cancer {'context': 'I-transformed cells'}", + "43, cells {'context': 'I-transformed cells'}", + "46, mTOR {'perturbing_action': 'B-pharmacological inhibition'}", + "47, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "48, CCI-779 {'perturbing_action': 'I-pharmacological inhibition'}", + "49, in {'context': 'B-in vitro'}", + "50, vitro {'context': 'I-in vitro'}", + "53, mouse {'context': 'B-organism'}", + "54, models. {'context': 'I-organism'}", + "55, Growth {'phenotype': 'B-cell growth'}", + "56, arrest {'effect': 'B-negative'}", + "76, expression {'perturbing_action': 'B-gene gain-of-function'}", + "77, of {'perturbing_action': 'I-other'}", + "78, a {'perturbing_action': 'I-rnai/knockdown'}", + "80, HIF1A {'perturbing_action': 'I-gene gain-of-function'}", + "81, cDNA {'perturbing_action': 'I-rnai/knockdown'}", + "87, VHL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "88, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "31, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "32, of ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "33, the ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "34, Von ['l2', 'l21', 'l39', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "35, Hippel-Lindau ['l3', 'l22', 'l40', 'l57', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "36, tumor ['l4', 'l23', 'l41', 'l58', 'l74', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "37, suppressor ['l5', 'l24', 'l42', 'l59', 'l75', 'l90', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "38, gene ['l6', 'l25', 'l43', 'l60', 'l76', 'l91', 'l105', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "39, (VHL) ['l7', 'l26', 'l44', 'l61', 'l77', 'l92', 'l106', 'l119', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "41, kidney ['l8', 'l27', 'l45', 'l62', 'l78', 'l93', 'l107', 'l120', 'l132', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "42, cancer ['l9', 'l28', 'l46', 'l63', 'l79', 'l94', 'l108', 'l121', 'l133', 'l143', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "43, cells ['l10', 'l29', 'l47', 'l64', 'l80', 'l95', 'l109', 'l122', 'l134', 'l144', 'l150', 'l156', 'l157', 'l158', 'l159', 'l160']", + "46, mTOR ['l11', 'l30', 'l48', 'l65', 'l81', 'l96', 'l110', 'l123', 'l135', 'l145', 'l151', 'l156', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166']", + "47, inhibitor ['l12', 'l31', 'l49', 'l66', 'l82', 'l97', 'l111', 'l124', 'l136', 'l146', 'l152', 'l157', 'l161', 'l167', 'l168', 'l169', 'l170', 'l171']", + "48, CCI-779 ['l13', 'l32', 'l50', 'l67', 'l83', 'l98', 'l112', 'l125', 'l137', 'l147', 'l153', 'l158', 'l162', 'l167', 'l172', 'l173', 'l174', 'l175']", + "49, in ['l14', 'l33', 'l51', 'l68', 'l84', 'l99', 'l113', 'l126', 'l138', 'l148', 'l154', 'l159', 'l163', 'l168', 'l172', 'l176']", + "50, vitro ['l15', 'l34', 'l52', 'l69', 'l85', 'l100', 'l114', 'l127', 'l139', 'l149', 'l155', 'l160', 'l164', 'l169', 'l173', 'l176']", + "53, mouse ['l16', 'l35', 'l53', 'l70', 'l86', 'l101', 'l115', 'l128', 'l177', 'l178', 'l179']", + "54, models. ['l17', 'l36', 'l54', 'l71', 'l87', 'l102', 'l116', 'l129', 'l140', 'l177', 'l180', 'l181']", + "55, Growth ['l18', 'l37', 'l55', 'l72', 'l88', 'l103', 'l117', 'l130', 'l141', 'l165', 'l170', 'l174', 'l178', 'l180', 'l182']", + "56, arrest ['l19', 'l38', 'l56', 'l73', 'l89', 'l104', 'l118', 'l131', 'l142', 'l166', 'l171', 'l175', 'l179', 'l181', 'l182']", + "76, expression ['l183', 'l184', 'l185', 'l186', 'l187']", + "77, of ['l183', 'l188', 'l189', 'l190', 'l191']", + "78, a ['l184', 'l188', 'l192', 'l193', 'l194']", + "79, VHL-resistant ['l185', 'l189', 'l192', 'l195', 'l196']", + "80, HIF1A ['l186', 'l190', 'l193', 'l195', 'l197']", + "81, cDNA ['l187', 'l191', 'l194', 'l196', 'l197']", + "87, VHL-deficient ['l198']", + "88, tumors ['l198']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Von", + "Hippel-Lindau", + "tumor", + "suppressor", + "gene", + "(VHL)" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "kidney", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Von", + "Hippel-Lindau", + "tumor", + "suppressor", + "gene", + "(VHL)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Von", + "Hippel-Lindau", + "tumor", + "suppressor", + "gene", + "(VHL)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Von", + "Hippel-Lindau", + "tumor", + "suppressor", + "gene", + "(VHL)" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "Growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Von", + "Hippel-Lindau", + "tumor", + "suppressor", + "gene", + "(VHL)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "kidney", + "cancer", + "cells" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibitor", + "CCI-779" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibitor", + "CCI-779" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibitor", + "CCI-779" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "Growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibitor", + "CCI-779" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "Growth" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest" + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "Growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "VHL-deficient" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + } + ] + }, + { + "PMID": "16327802", + "TEXT": "Interleukin (IL)-13 is a major inducer of fibrosis in many chronic infectious and autoimmune diseases. In studies of the mechanisms underlying such induction, we found that IL-13 induces transforming growth factor (TGF)-beta(1) in macrophages through a two-stage process involving, first, the induction of a receptor formerly considered to function only as a decoy receptor, IL-13Ralpha(2). Such induction requires IL-13 (or IL-4) and tumor necrosis factor (TNF)-alpha. Second, it involves IL-13 signaling through IL-13Ralpha(2) to activate an AP-1 variant containing c-jun and Fra-2, which then activates the TGFB1 promoter. In vivo, we found that prevention of IL-13Ralpha(2) expression reduced production of TGF-beta(1) in oxazolone-induced colitis and that prevention of IL-13Ralpha(2) expression, Il13ra2 gene silencing or blockade of IL-13Ralpha(2) signaling led to marked downregulation of TGF-beta(1) production and collagen deposition in bleomycin-induced lung fibrosis. These data suggest that IL-13Ralpha(2) signaling during prolonged inflammation is an important therapeutic target for the prevention of TGF-beta(1)-mediated fibrosis.", + "TAG_DATA": [ + "88, In {'context': 'B-in vivo'}", + "89, vivo, {'context': 'I-in vivo'}", + "93, prevention {'perturbing_action': 'B-other'}", + "94, of {'perturbing_action': 'I-rnai/knockdown'}", + "95, IL-13Ralpha(2) {'perturbing_action': 'I-other'}", + "96, expression {'perturbing_action': 'I-other'}", + "106, prevention {'perturbing_action': 'B-other'}", + "107, of {'perturbing_action': 'I-rnai/knockdown'}", + "108, IL-13Ralpha(2) {'perturbing_action': 'I-rnai/knockdown'}", + "109, expression, {'perturbing_action': 'I-rnai/knockdown'}", + "110, Il13ra2 {'perturbing_action': 'B-rnai/knockdown'}", + "111, gene {'perturbing_action': 'I-rnai/knockdown'}", + "112, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "130, lung {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "88, In ['l0']", + "89, vivo, ['l0']", + "93, prevention ['l1', 'l2', 'l3']", + "94, of ['l1', 'l4', 'l5']", + "95, IL-13Ralpha(2) ['l2', 'l4', 'l6']", + "96, expression ['l3', 'l5', 'l6']", + "106, prevention ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "107, of ['l7', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "108, IL-13Ralpha(2) ['l8', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "109, expression, ['l9', 'l15', 'l20', 'l25', 'l26', 'l27', 'l28']", + "110, Il13ra2 ['l10', 'l16', 'l21', 'l25', 'l29', 'l30', 'l31']", + "111, gene ['l11', 'l17', 'l22', 'l26', 'l29', 'l32', 'l33']", + "112, silencing ['l12', 'l18', 'l23', 'l27', 'l30', 'l32', 'l34']", + "130, lung ['l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l34']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "prevention" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "IL-13Ralpha(2)", + "expression,", + "Il13ra2", + "gene", + "silencing" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + } + ] + }, + { + "PMID": "16286925", + "TEXT": "It is widely accepted that the p53 tumor suppressor restricts abnormal cells by induction of growth arrest or by triggering apoptosis. Here we show that, in addition, p53 protects the genome from oxidation by reactive oxygen species (ROS), a major cause of DNA damage and genetic instability. In the absence of severe stresses, relatively low levels of p53 are sufficient for upregulation of several genes with antioxidant products, which is associated with a decrease in intracellular ROS. Downregulation of p53 results in excessive oxidation of DNA, increased mutation rate and karyotype instability, which are prevented by incubation with the antioxidant N-acetylcysteine (NAC). Dietary supplementation with NAC prevented frequent lymphomas characteristic of Trp53-knockout mice, and slowed the growth of lung cancer xenografts deficient in p53. Our results provide a new paradigm for a nonrestrictive tumor suppressor function of p53 and highlight the potential importance of antioxidants in the prophylaxis and treatment of cancer.", + "TAG_DATA": [ + "77, Downregulation {'perturbing_action': 'B-gene loss-of-function'}", + "78, of {'perturbing_action': 'I-gene loss-of-function'}", + "79, p53 {'perturbing_action': 'I-gene loss-of-function'}", + "106, prevented {'effect': 'B-negative'}", + "108, lymphomas {'phenotype': 'B-tumourigenesis'}", + "111, Trp53-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "112, mice, {'context': 'B-organism'}", + "118, lung {'context': 'B-xenograft'}", + "119, cancer {'context': 'I-xenograft'}", + "120, xenografts {'context': 'I-xenograft'}", + "121, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "122, in {'perturbing_action': 'I-gene loss-of-function'}", + "123, p53. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "77, Downregulation ['l0', 'l1']", + "78, of ['l0', 'l2']", + "79, p53 ['l1', 'l2']", + "106, prevented ['l3', 'l4', 'l5']", + "108, lymphomas ['l3', 'l6', 'l7']", + "111, Trp53-knockout ['l4', 'l6', 'l8']", + "112, mice, ['l5', 'l7', 'l8']", + "118, lung ['l9', 'l10', 'l11', 'l12', 'l13']", + "119, cancer ['l9', 'l14', 'l15', 'l16', 'l17']", + "120, xenografts ['l10', 'l14', 'l18', 'l19', 'l20']", + "121, deficient ['l11', 'l15', 'l18', 'l21', 'l22']", + "122, in ['l12', 'l16', 'l19', 'l21', 'l23']", + "123, p53. ['l13', 'l17', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphomas" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trp53-knockout" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphomas" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trp53-knockout" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphomas" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trp53-knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "lung", + "cancer", + "xenografts" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "p53." + ] + } + } + ] + }, + { + "PMID": "16244652", + "TEXT": "Sonic hedgehog (Shh) is a crucial regulator of organ development during embryogenesis. We investigated whether intramyocardial gene transfer of naked DNA encoding human Shh (phShh) could promote a favorable effect on recovery from acute and chronic myocardial ischemia in adult animals, not only by promoting neovascularization, but by broader effects, consistent with the role of this morphogen in embryogenesis. After Shh gene transfer, the hedgehog pathway was upregulated in mammalian fibroblasts and cardiomyocytes. This resulted in preservation of left ventricular function in both acute and chronic myocardial ischemia by enhanced neovascularization, and reduced fibrosis and cardiac apoptosis. Shh gene transfer also enhanced the contribution of bone marrow-derived endothelial progenitor cells to myocardial neovascularization. These data suggest that Shh gene therapy may have considerable therapeutic potential in individuals with acute and chronic myocardial ischemia by triggering expression of multiple trophic factors and engendering tissue repair in the adult heart.", + "TAG_DATA": [ + "61, gene {'perturbing_action': 'I-gene gain-of-function'}", + "62, transfer, {'perturbing_action': 'I-gene gain-of-function'}", + "69, mammalian {'context': 'B-cells'}", + "70, fibroblasts {'context': 'I-cells'}", + "72, cardiomyocytes. {'context': 'B-cells'}", + "92, reduced {'effect': 'B-negative'}", + "95, cardiac {'context': 'B-cells'}", + "96, apoptosis. {'phenotype': 'B-apoptosis'}", + "98, gene {'perturbing_action': 'I-gene gain-of-function'}", + "99, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "105, bone {'context': 'B-cells'}", + "106, marrow-derived {'context': 'I-cells'}", + "107, endothelial {'context': 'I-cells'}", + "108, progenitor {'context': 'I-cells'}", + "109, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "61, gene ['l0', 'l1', 'l2', 'l3', 'l4']", + "62, transfer, ['l0', 'l5', 'l6', 'l7', 'l8']", + "69, mammalian ['l1', 'l5', 'l9', 'l10', 'l11', 'l12', 'l13']", + "70, fibroblasts ['l2', 'l6', 'l9', 'l14', 'l15']", + "72, cardiomyocytes. ['l3', 'l7', 'l10', 'l14', 'l16']", + "92, reduced ['l4', 'l8', 'l11', 'l15', 'l16', 'l17', 'l18']", + "95, cardiac ['l12', 'l17', 'l19']", + "96, apoptosis. ['l13', 'l18', 'l19']", + "97, Shh ['l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "98, gene ['l20', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "99, transfer ['l21', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "105, bone ['l22', 'l28', 'l33', 'l38', 'l39', 'l40', 'l41']", + "106, marrow-derived ['l23', 'l29', 'l34', 'l38', 'l42', 'l43', 'l44']", + "107, endothelial ['l24', 'l30', 'l35', 'l39', 'l42', 'l45', 'l46']", + "108, progenitor ['l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l47']", + "109, cells ['l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "gene", + "transfer,", + "transfer" + ] + }, + "context": { + "val": "cells", + "words": [ + "mammalian", + "fibroblasts", + "cardiomyocytes.", + "bone", + "marrow-derived", + "endothelial", + "progenitor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "gene", + "transfer," + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mammalian", + "fibroblasts", + "cardiomyocytes.", + "cardiac" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mammalian", + "cardiac" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "16227992", + "TEXT": "Akt kinases control essential cellular functions, including proliferation, apoptosis, metabolism and transcription, and have been proposed as promising targets for treatment of angiogenesis-dependent pathologies, such as cancer and ischemic injury. But their precise roles in neovascularization remain elusive. Here we show that Akt1 is the predominant isoform in vascular cells and describe the unexpected consequences of Akt1 knockout on vascular integrity and pathological angiogenesis. Angiogenic responses in three distinct in vivo models were enhanced in Akt1(-/-) mice; these enhanced responses were associated with impairment of blood vessel maturation and increased vascular permeability. Although impaired vascular maturation in Akt1(-/-) mice may be attributed to reduced activation of endothelial nitric oxide synthase (eNOS), the major phenotypic changes in vascular permeability and angiogenesis were linked to reduced expression of two endogenous vascular regulators, thrombospondins 1 (TSP-1) and 2 (TSP-2). Re-expression of TSP-1 and TSP-2 in mice transplanted with wild-type bone marrow corrected the angiogenic abnormalities in Akt1(-/-) mice. These findings establish a crucial role of an Akt-thrombospondin axis in angiogenesis.", + "TAG_DATA": [ + "56, Akt1 {'perturbing_action': 'B-gene loss-of-function'}", + "69, in {'context': 'B-in vivo'}", + "70, vivo {'context': 'I-in vivo'}", + "75, Akt1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "76, mice; {'context': 'B-organism'}", + "97, Akt1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "98, mice {'context': 'B-organism'}", + "136, Re-expression {'perturbing_action': 'B-gene gain-of-function'}", + "137, of {'perturbing_action': 'I-gene gain-of-function'}", + "138, TSP-1 {'perturbing_action': 'I-gene gain-of-function'}", + "139, and {'perturbing_action': 'I-gene gain-of-function'}", + "140, TSP-2 {'perturbing_action': 'I-gene gain-of-function'}", + "142, mice {'context': 'B-organism'}", + "153, Akt1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "154, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, Akt1 ['l0', 'l1', 'l2', 'l3']", + "69, in ['l0', 'l4', 'l5', 'l6']", + "70, vivo ['l1', 'l4', 'l7', 'l8']", + "75, Akt1(-/-) ['l2', 'l5', 'l7', 'l9']", + "76, mice; ['l3', 'l6', 'l8', 'l9']", + "97, Akt1(-/-) ['l10']", + "98, mice ['l10']", + "136, Re-expression ['l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "137, of ['l11', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "138, TSP-1 ['l12', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "139, and ['l13', 'l20', 'l26', 'l32', 'l33', 'l34', 'l35', 'l36']", + "140, TSP-2 ['l14', 'l21', 'l27', 'l32', 'l37', 'l38', 'l39', 'l40']", + "142, mice ['l15', 'l22', 'l28', 'l33', 'l37', 'l41', 'l42', 'l43']", + "147, marrow ['l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l44', 'l45']", + "153, Akt1(-/-) ['l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l46']", + "154, mice. ['l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l46']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Akt1", + "Akt1(-/-)" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Akt1", + "Akt1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice;", + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Re-expression", + "of", + "TSP-1", + "and", + "TSP-2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "16227989", + "TEXT": "T cells responsive to minor histocompatibility (H) antigens are extremely effective in curing leukemia but it remains unknown whether they can eradicate solid tumors. We report that injection of CD8(+) T cells primed against the immunodominant H7(a) minor H antigen can cure established melanomas in mice. Tumor rejection was initiated by preferential extravasation at the tumor site of interferon (IFN)-gamma-producing H7(a)-specific T cells. Intratumoral release of IFN-gamma had two crucial effects: inhibition of tumor angiogenesis and upregulation of major histocompatibility complex (MHC) class I expression on tumor cells. Despite ubiquitous expression of H7(a), dissemination of a few H7(a)-specific T cells in extralymphoid organs caused neither graft-versus-host disease (GVHD) nor vitiligo because host nonhematopoietic cells were protected by their low expression of MHC class I. Our preclinical model yields unique insights into how minor H antigen-based immunotherapy could be used to treat human solid tumors.", + "TAG_DATA": [ + "29, CD8(+) {'context': 'B-cells'}", + "30, T {'context': 'I-cells'}", + "31, cells {'context': 'I-cells'}", + "43, melanomas {'context': 'B-neoplasm'}", + "45, mice. {'context': 'B-organism'}", + "86, tumor {'context': 'B-transformed cells'}", + "87, cells. {'context': 'I-transformed cells'}", + "98, T {'context': 'I-cells'}", + "99, cells {'context': 'I-cells'}", + "102, organs {'context': 'I-tissue/organ'}", + "112, nonhematopoietic {'context': 'B-cells'}", + "113, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "29, CD8(+) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "30, T ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "31, cells ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "43, melanomas ['l2', 'l7', 'l11', 'l15']", + "45, mice. ['l3', 'l8', 'l12', 'l15']", + "86, tumor ['l4', 'l9', 'l13', 'l16']", + "87, cells. ['l5', 'l10', 'l14', 'l16']", + "98, T ['l17', 'l18', 'l19', 'l20', 'l21']", + "99, cells ['l17', 'l22', 'l23', 'l24', 'l25']", + "101, extralymphoid ['l18', 'l22', 'l26', 'l27', 'l28']", + "102, organs ['l19', 'l23', 'l26', 'l29', 'l30']", + "112, nonhematopoietic ['l20', 'l24', 'l27', 'l29', 'l31']", + "113, cells ['l21', 'l25', 'l28', 'l30', 'l31']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16227987", + "TEXT": "Inherited mutations in PARK2, the gene encoding parkin, cause selective degeneration of catecholaminergic neurons in the substantia nigra and locus coeruleus of the brainstem, resulting in early-onset parkinsonism. But the role of parkin in common, sporadic forms of Parkinson disease remains unclear. Here we report that the neurotransmitter dopamine covalently modifies parkin in living dopaminergic cells, a process that increases parkin insolubility and inactivates its E3 ubiquitin ligase function. In the brains of individuals with sporadic Parkinson disease, we observed decreases in parkin solubility consistent with its functional inactivation. Using a new biochemical method, we detected catechol-modified parkin in the substantia nigra but not other regions of normal human brain. These findings show a vulnerability of parkin to modification by dopamine, the principal transmitter lost in Parkinson disease, suggesting a mechanism for the progressive loss of parkin function in dopaminergic neurons during aging and sporadic Parkinson disease.", + "TAG_DATA": [ + "54, dopaminergic {'context': 'B-cells'}", + "55, cells, {'context': 'I-cells'}", + "100, substantia {'context': 'B-cells'}", + "101, nigra {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "54, dopaminergic ['l0']", + "55, cells, ['l0']", + "100, substantia ['l1']", + "101, nigra ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "16170323", + "TEXT": "Dysfunction of receptors for IgG (FcgammaRs) has been thought to be involved in the pathogenesis of systemic lupus erythematosus (SLE). We show that a recently described SLE-associated polymorphism of FcgammaRIIb (FcgammaRIIbT(232)), encoding a single transmembrane amino acid substitution, is functionally impaired. FcgammaRIIbT(232) is unable to inhibit activatory receptors because it is excluded from sphingolipid rafts, resulting in the unopposed proinflammatory signaling thought to promote SLE.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "16041382", + "TEXT": "We developed a new class of vaccines, based on killed but metabolically active (KBMA) bacteria, that simultaneously takes advantage of the potency of live vaccines and the safety of killed vaccines. We removed genes required for nucleotide excision repair (uvrAB), rendering microbial-based vaccines exquisitely sensitive to photochemical inactivation with psoralen and long-wavelength ultraviolet light. Colony formation of the nucleotide excision repair mutants was blocked by infrequent, randomly distributed psoralen crosslinks, but the bacterial population was able to express its genes, synthesize and secrete proteins. Using the intracellular pathogen Listeria monocytogenes as a model platform, recombinant psoralen-inactivated Lm DeltauvrAB vaccines induced potent CD4(+) and CD8(+) T-cell responses and protected mice against virus challenge in an infectious disease model and provided therapeutic benefit in a mouse cancer model. Microbial KBMA vaccines used either as a recombinant vaccine platform or as a modified form of the pathogen itself may have broad use for the treatment of infectious disease and cancer.", + "TAG_DATA": [ + "54, Colony {'phenotype': 'B-colony formation'}", + "55, formation {'phenotype': 'I-colony formation'}", + "63, blocked {'effect': 'B-negative'}", + "108, mice {'context': 'B-organism'}", + "123, mouse {'context': 'B-neoplasm'}", + "124, cancer {'context': 'I-neoplasm'}", + "125, model. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "54, Colony ['l0', 'l1']", + "55, formation ['l0', 'l2']", + "63, blocked ['l1', 'l2']", + "123, mouse ['l3', 'l4']", + "124, cancer ['l3', 'l5']", + "125, model. ['l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "colony formation", + "words": [ + "Colony", + "formation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + } + ] + }, + { + "PMID": "16025125", + "TEXT": "The molecular events that regulate engraftment and mobilization of hematopoietic stem cells and progenitors (HSC/Ps) are still incompletely defined. We have examined the role of the Rho GTPases Rac1 and Rac2 in HSC engraftment and mobilization. Rac1, but not the hematopoietic-specific Rac2, is required for the engraftment phase of hematopoietic reconstitution, because Rac1(-/-) HSCs did not rescue in vivo hematopoiesis after transplantation, but deletion of Rac1 after engraftment did not impair steady-state hematopoiesis. Rac1(-/-) HSC/Ps showed impaired spatial localization to the endosteum but near-normal homing to the medullary cavity in vivo. Interaction with the bone marrow microenvironment in vitro was markedly altered. Whereas post-engraftment deletion of Rac1 alone did not impair hematopoiesis, deficiency of both Rac1 and Rac2 led to massive mobilization of HSCs from the marrow associated with ineffective hematopoiesis and intense selection for Rac-expressing HSCs. This mobilization was reversible by re-expression of Rac1. In addition, a rationally designed, reversible small-molecule inhibitor of Rac activation led to transient mobilization of engraftable HSC/Ps. Rac proteins thus differentially regulate engraftment and mobilization phenotypes, suggesting that these biological processes and steady-state hematopoiesis are biochemically separable and that Rac proteins may be important molecular targets for stem cell modification.", + "TAG_DATA": [ + "52, Rac1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "53, HSCs {'context': 'B-cells'}", + "57, in {'context': 'B-in vivo'}", + "58, vivo {'context': 'I-in vivo'}", + "63, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "64, of {'perturbing_action': 'I-gene loss-of-function'}", + "65, Rac1 {'perturbing_action': 'I-gene loss-of-function'}", + "73, Rac1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "74, HSC/Ps {'context': 'B-cells'}", + "89, in {'context': 'B-in vivo'}", + "90, vivo. {'context': 'I-in vivo'}", + "97, in {'context': 'B-in vitro'}", + "98, vitro {'context': 'I-in vitro'}", + "104, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "105, of {'perturbing_action': 'I-gene loss-of-function'}", + "106, Rac1 {'perturbing_action': 'I-gene loss-of-function'}", + "112, deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "113, of {'perturbing_action': 'I-gene loss-of-function'}", + "114, both {'perturbing_action': 'I-gene loss-of-function'}", + "115, Rac1 {'perturbing_action': 'I-gene loss-of-function'}", + "116, and {'perturbing_action': 'I-gene loss-of-function'}", + "117, Rac2 {'perturbing_action': 'I-gene loss-of-function'}", + "123, HSCs {'context': 'B-cells'}", + "135, Rac-expressing {'context': 'B-transformed cells'}", + "136, HSCs. {'context': 'I-transformed cells'}", + "142, re-expression {'perturbing_action': 'B-gene gain-of-function'}", + "143, of {'perturbing_action': 'I-gene gain-of-function'}", + "144, Rac1. {'perturbing_action': 'I-gene gain-of-function'}", + "150, reversible {'perturbing_action': 'I-pharmacological inhibition'}", + "151, small-molecule {'perturbing_action': 'I-pharmacological inhibition'}", + "152, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "153, of {'perturbing_action': 'I-pharmacological inhibition'}", + "154, Rac {'perturbing_action': 'I-pharmacological inhibition'}", + "155, activation {'perturbing_action': 'I-pharmacological inhibition'}", + "162, HSC/Ps. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "52, Rac1(-/-) ['l0', 'l1', 'l2']", + "53, HSCs ['l0', 'l3', 'l4']", + "57, in ['l1', 'l3', 'l5']", + "58, vivo ['l2', 'l4', 'l5']", + "63, deletion ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "64, of ['l6', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "65, Rac1 ['l7', 'l14', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "73, Rac1(-/-) ['l8', 'l15', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "74, HSC/Ps ['l9', 'l16', 'l22', 'l27', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "89, in ['l10', 'l17', 'l23', 'l28', 'l36', 'l42', 'l43', 'l44']", + "90, vivo. ['l11', 'l18', 'l24', 'l29', 'l37', 'l42', 'l45', 'l46']", + "97, in ['l12', 'l19', 'l25', 'l30', 'l38', 'l43', 'l45', 'l47', 'l48', 'l49']", + "98, vitro ['l13', 'l20', 'l26', 'l31', 'l39', 'l44', 'l46', 'l47', 'l50', 'l51']", + "104, deletion ['l32', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "105, of ['l33', 'l40', 'l48', 'l50', 'l52', 'l60', 'l61', 'l62', 'l63', 'l64']", + "106, Rac1 ['l34', 'l41', 'l49', 'l51', 'l53', 'l60', 'l65', 'l66', 'l67', 'l68']", + "112, deficiency ['l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "113, of ['l69', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "114, both ['l70', 'l79', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "115, Rac1 ['l54', 'l71', 'l80', 'l89', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "116, and ['l55', 'l72', 'l81', 'l90', 'l97', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "117, Rac2 ['l56', 'l61', 'l65', 'l73', 'l82', 'l91', 'l98', 'l104', 'l110', 'l111', 'l112']", + "123, HSCs ['l35', 'l57', 'l62', 'l66', 'l74', 'l83', 'l92', 'l99', 'l105', 'l110', 'l113', 'l114']", + "135, Rac-expressing ['l58', 'l63', 'l67', 'l75', 'l84', 'l93', 'l100', 'l106', 'l111', 'l113', 'l115']", + "136, HSCs. ['l59', 'l64', 'l68', 'l76', 'l85', 'l94', 'l101', 'l107', 'l112', 'l114', 'l115']", + "142, re-expression ['l86', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "143, of ['l77', 'l87', 'l95', 'l102', 'l108', 'l116', 'l122', 'l123', 'l124', 'l125', 'l126']", + "144, Rac1. ['l78', 'l88', 'l96', 'l103', 'l109', 'l117', 'l122', 'l127', 'l128']", + "150, reversible ['l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "151, small-molecule ['l129', 'l135', 'l136', 'l137', 'l138', 'l139']", + "152, inhibitor ['l130', 'l135', 'l140', 'l141', 'l142', 'l143']", + "153, of ['l118', 'l123', 'l131', 'l136', 'l140', 'l144', 'l145', 'l146']", + "154, Rac ['l119', 'l124', 'l132', 'l137', 'l141', 'l144', 'l147', 'l148']", + "155, activation ['l120', 'l125', 'l127', 'l133', 'l138', 'l142', 'l145', 'l147', 'l149']", + "162, HSC/Ps. ['l121', 'l126', 'l128', 'l134', 'l139', 'l143', 'l146', 'l148', 'l149']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rac1(-/-)", + "deletion", + "of", + "Rac1", + "deficiency", + "both", + "and", + "Rac2" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSCs", + "HSC/Ps" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rac1(-/-)", + "deletion", + "of", + "Rac1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Rac1", + "Rac1(-/-)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Rac1", + "deficiency", + "both", + "and", + "Rac2" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "Rac-expressing", + "HSCs." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "re-expression", + "of", + "Rac1." + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC/Ps." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "reversible", + "small-molecule", + "inhibitor", + "of", + "Rac", + "activation" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC/Ps." + ] + } + } + ] + }, + { + "PMID": "15951823", + "TEXT": "Vaccination with live vaccinia virus affords long-lasting protection against variola virus, the agent of smallpox. Its mode of protection in humans, however, has not been clearly defined. Here we report that vaccinia-specific B-cell responses are essential for protection of macaques from monkeypox virus, a variola virus ortholog. Antibody-mediated depletion of B cells, but not CD4+ or CD8+ T cells, abrogated vaccine-induced protection from a lethal intravenous challenge with monkeypox virus. In addition, passive transfer of human vaccinia-neutralizing antibodies protected nonimmunized macaques from severe disease. Thus, vaccines able to induce long-lasting protective antibody responses may constitute realistic alternatives to the currently available smallpox vaccine (Dryvax).", + "TAG_DATA": [ + "50, B {'context': 'B-cells'}", + "51, cells, {'context': 'I-cells'}", + "54, CD4+ {'context': 'B-cells'}", + "56, CD8+ {'context': 'I-cells'}", + "57, T {'context': 'I-cells'}", + "58, cells, {'context': 'I-cells'}", + "80, macaques {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, B ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "51, cells, ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "54, CD4+ ['l1', 'l6', 'l11', 'l12', 'l13', 'l14', 'l15']", + "55, or ['l2', 'l7', 'l11', 'l16', 'l17', 'l18', 'l19']", + "56, CD8+ ['l3', 'l8', 'l12', 'l16', 'l20', 'l21', 'l22']", + "57, T ['l4', 'l9', 'l13', 'l17', 'l20', 'l23', 'l24']", + "58, cells, ['l5', 'l10', 'l14', 'l18', 'l21', 'l23', 'l25']", + "80, macaques ['l15', 'l19', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15951748", + "TEXT": "Hepatitis C virus (HCV) infection causes chronic liver diseases and is a global public health problem. Detailed analyses of HCV have been hampered by the lack of viral culture systems. Subgenomic replicons of the JFH1 genotype 2a strain cloned from an individual with fulminant hepatitis replicate efficiently in cell culture. Here we show that the JFH1 genome replicates efficiently and supports secretion of viral particles after transfection into a human hepatoma cell line (Huh7). Particles have a density of about 1.15-1.17 g/ml and a spherical morphology with an average diameter of about 55 nm. Secreted virus is infectious for Huh7 cells and infectivity can be neutralized by CD81-specific antibodies and by immunoglobulins from chronically infected individuals. The cell culture-generated HCV is infectious for chimpanzee. This system provides a powerful tool for studying the viral life cycle and developing antiviral strategies.", + "TAG_DATA": [ + "69, human {'context': 'B-transformed cells'}", + "70, hepatoma {'context': 'I-transformed cells'}", + "71, cell {'context': 'I-transformed cells'}", + "72, line {'context': 'I-transformed cells'}", + "73, (Huh7). {'context': 'I-transformed cells'}", + "99, Huh7 {'context': 'B-cells'}", + "100, cells {'context': 'I-cells'}", + "117, cell {'context': 'B-cells'}", + "118, culture-generated {'context': 'I-cells'}", + "123, chimpanzee. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "69, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "70, hepatoma ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "71, cell ['l1', 'l6', 'l11', 'l12', 'l13']", + "72, line ['l2', 'l7', 'l11', 'l14', 'l15']", + "73, (Huh7). ['l3', 'l8', 'l12', 'l14', 'l16']", + "99, Huh7 ['l4', 'l9', 'l17']", + "100, cells ['l5', 'l10', 'l13', 'l15', 'l16', 'l17']", + "117, cell ['l18', 'l19']", + "118, culture-generated ['l18', 'l20']", + "123, chimpanzee. ['l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15908956", + "TEXT": "The cellular targets of primary mutations and malignant transformation remain elusive in most cancers. Here, we show that clinically and genetically different subtypes of acute lymphoblastic leukemia (ALL) originate and transform at distinct stages of hematopoietic development. Primary ETV6-RUNX1 (also known as TEL-AML1) fusions and subsequent leukemic transformations were targeted to committed B-cell progenitors. Major breakpoint BCR-ABL1 fusions (encoding P210 BCR-ABL1) originated in hematopoietic stem cells (HSCs), whereas minor BCR-ABL1 fusions (encoding P190 BCR-ABL1) had a B-cell progenitor origin, suggesting that P190 and P210 BCR-ABL1 ALLs represent largely distinct tumor biological and clinical entities. The transformed leukemia-initiating stem cells in both P190 and P210 BCR-ABL1 ALLs had, as in ETV6-RUNX1 ALLs, a committed B progenitor phenotype. In all patients, normal and leukemic repopulating stem cells could successfully be separated prospectively, and notably, the size of the normal HSC compartment in ETV6-RUNX1 and P190 BCR-ABL1 ALLs was found to be unaffected by the expansive leukemic stem cell population.", + "TAG_DATA": [ + "95, transformed {'phenotype': 'B-transformation'}", + "96, leukemia-initiating {'context': 'B-cells'}", + "97, stem {'context': 'I-cells'}", + "98, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "95, transformed ['l0', 'l1', 'l2']", + "96, leukemia-initiating ['l0', 'l3', 'l4']", + "97, stem ['l1', 'l3', 'l5']", + "98, cells ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "transformation", + "words": [ + "transformed" + ] + }, + "context": { + "val": "cells", + "words": [ + "leukemia-initiating", + "stem", + "cells" + ] + } + } + ] + }, + { + "PMID": "15895074", + "TEXT": "In inflammatory arthridities such as rheumatoid arthritis, cognate lymphocytes have long been considered instigators of autoimmunity, but accumulating evidence indicates that innate immune cells such as neutrophils and mast cells are responsible for a vast majority of acute and ongoing inflammation; however, the molecular mechanisms that govern them remain largely unknown. Here we show that such inflammation requires the forkhead transcription factor Foxo3a: Foxo3a-deficient mice are resistant to two models of neutrophilic inflammation, immune complex-mediated inflammatory arthritis and thioglycollate-induced peritonitis. This reflects a need for Foxo3a to maintain neutrophil vitality during inflammation by suppressing Fas ligand; because Foxo3a can bind and suppress the Fasl promoter, Foxo3a-deficient neutrophils upregulate Fas ligand and undergo apoptosis in response to TNF-alpha and IL-1, and Fas ligand blockade renders Foxo3a-deficient mice susceptible to both arthritis and peritonitis. Thus, Foxo3a ensures neutrophil survival during inflammation, identifying Foxo3a as therapeutic target in inflammation.", + "TAG_DATA": [ + "63, Foxo3a-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "64, mice {'context': 'B-organism'}", + "105, Foxo3a-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "106, neutrophils {'context': 'B-cells'}", + "111, undergo {'effect': 'B-positive'}", + "112, apoptosis {'phenotype': 'B-apoptosis'}", + "124, Foxo3a-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "125, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "63, Foxo3a-deficient ['l0']", + "64, mice ['l0']", + "105, Foxo3a-deficient ['l1', 'l2', 'l3']", + "106, neutrophils ['l1', 'l4', 'l5']", + "111, undergo ['l2', 'l4', 'l6']", + "112, apoptosis ['l3', 'l5', 'l6']", + "124, Foxo3a-deficient ['l7']", + "125, mice ['l7']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Foxo3a-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Foxo3a-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "neutrophils" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Foxo3a-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "undergo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Foxo3a-deficient" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neutrophils" + ] + }, + "effect": { + "val": "positive", + "words": [ + "undergo" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neutrophils" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "undergo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "15864312", + "TEXT": "Breast cancer is the second leading cause of cancer death for women in the United States. In 2005, about 215,000 cases of invasive breast cancer (IBC) and 50,000 cases of ductal carcinoma in situ will be diagnosed and 40,000 women will die of IBC in the US. Yet there is presently no molecular marker that can be used to detect a precancerous state or identify which premalignant lesions will develop into invasive breast cancer. Here we report the gene expression analysis of atypical ductal hyperplastic tissues from patients with and without a history of breast cancer. We identify MMP-1 as a candidate marker that may be useful for identification of breast lesions that can develop into cancer.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15852017", + "TEXT": "Cholinergic neuron loss is a cardinal feature of Alzheimer disease. Nerve growth factor (NGF) stimulates cholinergic function, improves memory and prevents cholinergic degeneration in animal models of injury, amyloid overexpression and aging. We performed a phase 1 trial of ex vivo NGF gene delivery in eight individuals with mild Alzheimer disease, implanting autologous fibroblasts genetically modified to express human NGF into the forebrain. After mean follow-up of 22 months in six subjects, no long-term adverse effects of NGF occurred. Evaluation of the Mini-Mental Status Examination and Alzheimer Disease Assessment Scale-Cognitive subcomponent suggested improvement in the rate of cognitive decline. Serial PET scans showed significant (P < 0.05) increases in cortical 18-fluorodeoxyglucose after treatment. Brain autopsy from one subject suggested robust growth responses to NGF. Additional clinical trials of NGF for Alzheimer disease are warranted.", + "TAG_DATA": [ + "46, individuals {'context': 'B-patient'}", + "52, autologous {'context': 'B-cells'}", + "53, fibroblasts {'context': 'I-cells'}", + "54, genetically {'perturbing_action': 'I-gene gain-of-function'}", + "55, modified {'perturbing_action': 'I-gene gain-of-function'}", + "56, to {'perturbing_action': 'I-gene gain-of-function'}", + "57, express {'perturbing_action': 'I-gene gain-of-function'}", + "58, human {'perturbing_action': 'I-gene gain-of-function'}", + "59, NGF {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "46, individuals ['l0', 'l1']", + "52, autologous ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "53, fibroblasts ['l0', 'l2', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "54, genetically ['l3', 'l9', 'l15', 'l16', 'l17', 'l18', 'l19']", + "55, modified ['l4', 'l10', 'l15', 'l20', 'l21', 'l22', 'l23']", + "56, to ['l5', 'l11', 'l16', 'l20', 'l24', 'l25', 'l26']", + "57, express ['l6', 'l12', 'l17', 'l21', 'l24', 'l27', 'l28']", + "58, human ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l29']", + "59, NGF ['l1', 'l8', 'l14', 'l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "patient", + "words": [ + "individuals" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "NGF" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "autologous", + "fibroblasts" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "genetically", + "modified", + "to", + "express", + "human", + "NGF" + ] + } + } + ] + }, + { + "PMID": "15852016", + "TEXT": "Neutralization of West Nile virus (WNV) in vivo correlates with the development of an antibody response against the viral envelope (E) protein. Using random mutagenesis and yeast surface display, we defined individual contact residues of 14 newly generated monoclonal antibodies against domain III of the WNV E protein. Monoclonal antibodies that strongly neutralized WNV localized to a surface patch on the lateral face of domain III. Convalescent antibodies from individuals who had recovered from WNV infection also detected this epitope. One monoclonal antibody, E16, neutralized 10 different strains in vitro, and showed therapeutic efficacy in mice, even when administered as a single dose 5 d after infection. A humanized version of E16 was generated that retained antigen specificity, avidity and neutralizing activity. In postexposure therapeutic trials in mice, a single dose of humanized E16 protected mice against WNV-induced mortality, and may therefore be a viable treatment option against WNV infection in humans.", + "TAG_DATA": [ + "88, in {'context': 'B-in vitro'}", + "89, vitro, {'context': 'I-in vitro'}", + "95, mice, {'context': 'B-organism'}", + "127, mice, {'context': 'B-organism'}", + "135, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "88, in ['l0', 'l1']", + "89, vitro, ['l0', 'l2']", + "95, mice, ['l1', 'l2']", + "127, mice, ['l3']", + "135, mice ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15834427", + "TEXT": "One of the most clinically advanced forms of experimental disease-modifying treatment for Alzheimer disease is immunization against the amyloid beta protein (Abeta), but how this may prevent cognitive impairment is unclear. We hypothesized that antibodies to Abeta could exert a beneficial action by directly neutralizing potentially synaptotoxic soluble Abeta species in the brain. Intracerebroventricular injection of naturally secreted human Abeta inhibited long-term potentiation (LTP), a correlate of learning and memory, in rat hippocampus in vivo but a monoclonal antibody to Abeta completely prevented the inhibition of LTP when injected after Abeta. Size fractionation showed that Abeta oligomers, not monomers or fibrils, were responsible for inhibiting LTP, and an Abeta antibody again prevented such inhibition. Active immunization against Abeta was partially effective, and the effects correlated positively with levels of antibodies to Abeta oligomers. The ability of exogenous and endogenous antibodies to rapidly neutralize soluble Abeta oligomers that disrupt synaptic plasticity in vivo suggests that treatment with such antibodies might show reversible cognitive deficits in early Alzheimer disease.", + "TAG_DATA": [ + "60, inhibited {'effect': 'B-negative'}", + "71, rat {'context': 'B-tissue/organ'}", + "72, hippocampus {'context': 'I-tissue/organ'}", + "73, in {'context': 'B-in vivo'}", + "74, vivo {'context': 'I-in vivo'}", + "84, inhibition {'effect': 'B-negative'}", + "104, inhibiting {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "60, inhibited ['l0', 'l1', 'l2', 'l3', 'l4']", + "61, long-term ['l0', 'l5', 'l6', 'l7', 'l8']", + "71, rat ['l1', 'l5', 'l9', 'l10', 'l11']", + "72, hippocampus ['l2', 'l6', 'l9', 'l12', 'l13']", + "73, in ['l3', 'l7', 'l10', 'l12', 'l14']", + "74, vivo ['l4', 'l8', 'l11', 'l13', 'l14']", + "77, monoclonal ['l15', 'l16', 'l17']", + "78, antibody ['l15', 'l18', 'l19']", + "84, inhibition ['l16', 'l18']", + "104, inhibiting ['l17', 'l19']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "hippocampus" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "15821748", + "TEXT": "Nijmegen breakage syndrome (NBS), ataxia telangiectasia and ataxia telangiectasia-like disorder (ATLD) show overlapping phenotypes such as growth retardation, microcephaly, cerebellar developmental defects and ataxia. However, the molecular pathogenesis of these neurological defects remains elusive. Here we show that inactivation of the Nbn gene (also known as Nbs1) in mouse neural tissues results in a combination of the neurological anomalies characteristic of NBS, ataxia telangiectasia and ATLD, including microcephaly, growth retardation, cerebellar defects and ataxia. Loss of Nbn causes proliferation arrest of granule cell progenitors and apoptosis of postmitotic neurons in the cerebellum. Furthermore, Nbn-deficient neuroprogenitors show proliferation defects (but not increased apoptosis) and contain more chromosomal breaks, which are accompanied by ataxia telangiectasia mutated protein (ATM)-mediated p53 activation. Notably, depletion of p53 substantially rescues the neurological defects of Nbn mutant mice. This study gives insight into the physiological function of NBS1 (the Nbn gene product) and the function of the DNA damage response in the neurological anomalies of NBS, ataxia telangiectasia and ATLD.", + "TAG_DATA": [ + "38, inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "39, of {'perturbing_action': 'I-gene loss-of-function'}", + "40, the {'perturbing_action': 'I-gene loss-of-function'}", + "41, Nbn {'perturbing_action': 'I-gene loss-of-function'}", + "42, gene {'perturbing_action': 'I-gene loss-of-function'}", + "43, (also {'perturbing_action': 'I-gene loss-of-function'}", + "48, mouse {'context': 'B-tissue/organ'}", + "49, neural {'context': 'I-tissue/organ'}", + "50, tissues {'context': 'I-tissue/organ'}", + "74, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "75, of {'perturbing_action': 'I-gene loss-of-function'}", + "76, Nbn {'perturbing_action': 'I-gene loss-of-function'}", + "77, causes {'effect': 'B-positive'}", + "78, proliferation {'phenotype': 'B-proliferation'}", + "79, arrest {'effect': 'B-negative', 'phenotype': 'I-cell cycle arrest'}", + "81, granule {'context': 'B-cells'}", + "82, cell {'context': 'I-cells'}", + "83, progenitors {'context': 'I-cells'}", + "85, apoptosis {'phenotype': 'B-apoptosis'}", + "87, postmitotic {'context': 'B-cells'}", + "88, neurons {'context': 'I-cells'}", + "91, cerebellum. {'context': 'B-tissue/organ'}", + "93, Nbn-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "94, neuroprogenitors {'context': 'B-cells'}", + "96, proliferation {'phenotype': 'B-proliferation'}", + "97, defects {'effect': 'B-negative'}", + "100, increased {'effect': 'B-positive'}", + "101, apoptosis) {'phenotype': 'B-apoptosis'}", + "119, depletion {'perturbing_action': 'B-gene loss-of-function'}", + "120, of {'perturbing_action': 'I-gene loss-of-function'}", + "121, p53 {'perturbing_action': 'I-gene loss-of-function'}", + "128, Nbn {'perturbing_action': 'B-other'}", + "129, mutant {'perturbing_action': 'I-other'}", + "130, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "38, inactivation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "39, of ['l0', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "40, the ['l1', 'l21', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "41, Nbn ['l2', 'l22', 'l41', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "42, gene ['l3', 'l23', 'l42', 'l60', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "43, (also ['l4', 'l24', 'l43', 'l61', 'l78', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "48, mouse ['l5', 'l25', 'l44', 'l62', 'l79', 'l95', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "49, neural ['l6', 'l26', 'l45', 'l63', 'l80', 'l96', 'l111', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "50, tissues ['l7', 'l27', 'l46', 'l64', 'l81', 'l97', 'l112', 'l123', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "74, Loss ['l8', 'l28', 'l47', 'l65', 'l82', 'l98', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "75, of ['l9', 'l29', 'l48', 'l66', 'l83', 'l99', 'l144', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166']", + "76, Nbn ['l10', 'l30', 'l49', 'l67', 'l84', 'l100', 'l145', 'l156', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176']", + "77, causes ['l11', 'l31', 'l50', 'l68', 'l85', 'l101', 'l113', 'l124', 'l134', 'l146', 'l157', 'l167', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185']", + "78, proliferation ['l12', 'l32', 'l51', 'l69', 'l86', 'l102', 'l114', 'l125', 'l135', 'l147', 'l158', 'l168', 'l177', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "79, arrest ['l13', 'l33', 'l52', 'l70', 'l87', 'l103', 'l115', 'l126', 'l136', 'l148', 'l159', 'l169', 'l178', 'l186', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200']", + "81, granule ['l14', 'l34', 'l53', 'l71', 'l88', 'l104', 'l116', 'l127', 'l137', 'l149', 'l160', 'l170', 'l179', 'l187', 'l194', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206']", + "82, cell ['l15', 'l35', 'l54', 'l72', 'l89', 'l105', 'l117', 'l128', 'l138', 'l150', 'l161', 'l171', 'l180', 'l188', 'l195', 'l201', 'l207', 'l208', 'l209', 'l210', 'l211']", + "83, progenitors ['l16', 'l36', 'l55', 'l73', 'l90', 'l106', 'l118', 'l129', 'l139', 'l151', 'l162', 'l172', 'l181', 'l189', 'l196', 'l202', 'l207', 'l212', 'l213', 'l214', 'l215']", + "85, apoptosis ['l17', 'l37', 'l56', 'l74', 'l91', 'l107', 'l119', 'l130', 'l140', 'l152', 'l163', 'l173', 'l182', 'l190', 'l197', 'l203', 'l208', 'l212', 'l216', 'l217', 'l218']", + "87, postmitotic ['l18', 'l38', 'l57', 'l75', 'l92', 'l108', 'l120', 'l131', 'l141', 'l153', 'l164', 'l174', 'l183', 'l191', 'l198', 'l204', 'l209', 'l213', 'l216', 'l219', 'l220']", + "88, neurons ['l19', 'l39', 'l58', 'l76', 'l93', 'l109', 'l121', 'l132', 'l142', 'l154', 'l165', 'l175', 'l184', 'l192', 'l199', 'l205', 'l210', 'l214', 'l217', 'l219', 'l221']", + "91, cerebellum. ['l20', 'l40', 'l59', 'l77', 'l94', 'l110', 'l122', 'l133', 'l143', 'l155', 'l166', 'l176', 'l185', 'l193', 'l200', 'l206', 'l211', 'l215', 'l218', 'l220', 'l221']", + "93, Nbn-deficient ['l222', 'l223', 'l224', 'l225', 'l226']", + "94, neuroprogenitors ['l222', 'l227', 'l228', 'l229', 'l230']", + "96, proliferation ['l223', 'l227', 'l231', 'l232', 'l233']", + "97, defects ['l224', 'l228', 'l231', 'l234', 'l235']", + "100, increased ['l225', 'l229', 'l232', 'l234', 'l236']", + "101, apoptosis) ['l226', 'l230', 'l233', 'l235', 'l236']", + "119, depletion ['l237', 'l238', 'l239', 'l240', 'l241']", + "120, of ['l237', 'l242', 'l243', 'l244', 'l245']", + "121, p53 ['l238', 'l242', 'l246', 'l247', 'l248']", + "128, Nbn ['l239', 'l243', 'l246', 'l249', 'l250']", + "129, mutant ['l240', 'l244', 'l247', 'l249', 'l251']", + "130, mice. ['l241', 'l245', 'l248', 'l250', 'l251']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "the", + "Nbn", + "gene", + "(also", + "Loss" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "neural", + "tissues", + "cerebellum." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "the", + "Nbn", + "gene", + "(also", + "Loss", + "Nbn-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "causes", + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "the", + "Nbn", + "gene", + "(also", + "Loss", + "Nbn-deficient" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "the", + "Nbn", + "gene", + "(also", + "Loss", + "Nbn-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest", + "defects" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "the", + "Nbn", + "gene", + "(also", + "Loss" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "arrest" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "the", + "Nbn", + "gene", + "(also", + "Loss", + "Nbn-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "granule", + "cell", + "progenitors", + "postmitotic", + "neurons", + "neuroprogenitors" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "the", + "Nbn", + "gene", + "(also", + "Loss", + "Nbn-deficient" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis)" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "neural", + "tissues", + "cerebellum." + ] + }, + "effect": { + "val": "positive", + "words": [ + "causes" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "neural", + "tissues", + "cerebellum." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "neural", + "tissues", + "cerebellum." + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "neural", + "tissues", + "cerebellum." + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "neural", + "tissues", + "cerebellum." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes", + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes", + "increased" + ] + }, + "context": { + "val": "cells", + "words": [ + "granule", + "cell", + "progenitors", + "postmitotic", + "neurons", + "neuroprogenitors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes", + "increased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis)" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest", + "defects" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "granule", + "cell", + "progenitors", + "postmitotic", + "neurons", + "neuroprogenitors" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "arrest", + "defects" + ] + }, + "context": { + "val": "cells", + "words": [ + "granule", + "cell", + "progenitors", + "postmitotic", + "neurons", + "neuroprogenitors" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + }, + "context": { + "val": "cells", + "words": [ + "granule", + "cell", + "progenitors", + "postmitotic", + "neurons" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "arrest", + "defects" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis)" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "granule", + "cell", + "progenitors", + "postmitotic", + "neurons", + "neuroprogenitors" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "p53" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Nbn", + "mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "15793581", + "TEXT": "The bone morphogenetic proteins (BMPs) profoundly affect embryonic development, differentiation and disease. BMP signaling is suppressed by cysteine-rich domain proteins, such as chordin, that sequester ligands from the BMP receptor. We describe a novel protein, KCP, with 18 cysteine-rich domains. Unlike chordin, KCP enhances BMP signaling in a paracrine manner. Smad1-dependent transcription and phosphorylated Smad1 (P-Smad1) levels are increased, as KCP binds to BMP7 and enhances binding to the type I receptor. In vivo, Kcp(-/-) mice are viable and fertile. Because BMPs have a pivotal role in renal disease, we examined the phenotype of Kcp(-/-) mice in two different models of renal injury. Kcp(-/-) animals show reduced levels of P-Smad1, are more susceptible to developing renal interstitial fibrosis, are more sensitive to tubular injury and show substantial pathology after recovery. The data indicate an important role for KCP in attenuating the pathology of renal fibrotic disease.", + "TAG_DATA": [ + "72, In {'context': 'B-in vivo'}", + "73, vivo, {'context': 'I-in vivo'}", + "74, Kcp(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "75, mice {'context': 'B-organism'}", + "94, Kcp(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "95, mice {'context': 'B-organism'}", + "103, Kcp(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "104, animals {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "72, In ['l0', 'l1', 'l2']", + "73, vivo, ['l0', 'l3', 'l4']", + "74, Kcp(-/-) ['l1', 'l3', 'l5']", + "75, mice ['l2', 'l4', 'l5']", + "94, Kcp(-/-) ['l6']", + "95, mice ['l6']", + "103, Kcp(-/-) ['l7']", + "104, animals ['l7']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Kcp(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Kcp(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "animals" + ] + } + } + ] + }, + { + "PMID": "15778722", + "TEXT": "Expression of somatostatin in the brain declines during aging in various mammals including apes and humans. A prominent decrease in this neuropeptide also represents a pathological characteristic of Alzheimer disease. Using in vitro and in vivo paradigms, we show that somatostatin regulates the metabolism of amyloid beta peptide (Abeta), the primary pathogenic agent of Alzheimer disease, in the brain through modulating proteolytic degradation catalyzed by neprilysin. Among various effector candidates, only somatostatin upregulated neprilysin activity in primary cortical neurons. A genetic deficiency of somatostatin altered hippocampal neprilysin activity and localization, and increased the quantity of a hydrophobic 42-mer form of Abeta, Abeta(42), in a manner similar to presenilin gene mutations that cause familial Alzheimer disease. These results indicate that the aging-induced downregulation of somatostatin expression may be a trigger for Abeta accumulation leading to late-onset sporadic Alzheimer disease, and suggest that somatostatin receptors may be pharmacological-target candidates for prevention and treatment of Alzheimer disease.", + "TAG_DATA": [ + "76, primary {'context': 'B-cells'}", + "77, cortical {'context': 'I-cells'}", + "78, neurons. {'context': 'I-cells'}", + "80, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "81, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "82, of {'perturbing_action': 'I-gene loss-of-function'}", + "83, somatostatin {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "76, primary ['l0', 'l1']", + "77, cortical ['l0', 'l2']", + "78, neurons. ['l1', 'l2']", + "80, genetic ['l3', 'l4', 'l5']", + "81, deficiency ['l3', 'l6', 'l7']", + "82, of ['l4', 'l6', 'l8']", + "83, somatostatin ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15778720", + "TEXT": "Angiopoietin-related growth factor (AGF), a member of the angiopoietin-like protein (Angptl) family, is secreted predominantly from the liver into the systemic circulation. Here, we show that most (>80%) of the AGF-deficient mice die at about embryonic day 13, whereas the surviving AGF-deficient mice develop marked obesity, lipid accumulation in skeletal muscle and liver, and insulin resistance accompanied by reduced energy expenditure relative to controls. In parallel, mice with targeted activation of AGF show leanness and increased insulin sensitivity resulting from increased energy expenditure. They are also protected from high-fat diet-induced obesity, insulin resistance and nonadipose tissue steatosis. Hepatic overexpression of AGF by adenoviral transduction, which leads to an approximately 2.5-fold increase in serum AGF concentrations, results in a significant (P < 0.01) body weight loss and increases insulin sensitivity in mice fed a high-fat diet. This study establishes AGF as a new hepatocyte-derived circulating factor that counteracts obesity and related insulin resistance.", + "TAG_DATA": [ + "30, AGF-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "31, mice {'context': 'B-organism'}", + "41, AGF-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "42, mice {'context': 'B-organism'}", + "66, mice {'context': 'B-organism'}", + "68, targeted {'perturbing_action': 'B-other'}", + "69, activation {'perturbing_action': 'I-other'}", + "70, of {'perturbing_action': 'I-other'}", + "71, AGF {'perturbing_action': 'I-other'}", + "97, Hepatic {'perturbing_action': 'B-gene gain-of-function'}", + "98, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "99, of {'perturbing_action': 'I-gene gain-of-function'}", + "100, AGF {'perturbing_action': 'I-gene gain-of-function'}", + "101, by {'perturbing_action': 'I-gene gain-of-function'}", + "102, adenoviral {'perturbing_action': 'I-gene gain-of-function'}", + "103, transduction, {'perturbing_action': 'I-gene gain-of-function'}", + "130, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "30, AGF-deficient ['l0']", + "31, mice ['l0']", + "41, AGF-deficient ['l1', 'l2', 'l3']", + "42, mice ['l1']", + "66, mice ['l2', 'l4', 'l5']", + "68, targeted ['l6', 'l7', 'l8']", + "69, activation ['l6', 'l9', 'l10']", + "70, of ['l4', 'l7', 'l9', 'l11']", + "71, AGF ['l3', 'l5', 'l8', 'l10', 'l11']", + "97, Hepatic ['l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "98, overexpression ['l12', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "99, of ['l13', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "100, AGF ['l14', 'l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "101, by ['l15', 'l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "102, adenoviral ['l16', 'l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "103, transduction, ['l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "130, mice ['l18', 'l24', 'l29', 'l33', 'l36', 'l38', 'l39']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "AGF-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "of", + "AGF" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Hepatic", + "overexpression", + "of", + "AGF", + "by", + "adenoviral", + "transduction," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15768029", + "TEXT": "Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease resulting in the selective death of motor neurons in the brain and spinal cord. Some familial cases of ALS are caused by dominant mutations in the gene encoding superoxide dismutase (SOD1). The emergence of interfering RNA (RNAi) for specific gene silencing could be therapeutically beneficial for the treatment of such dominantly inherited diseases. We generated a lentiviral vector to mediate expression of RNAi molecules specifically targeting the human SOD1 gene (SOD1). Injection of this vector into various muscle groups of mice engineered to overexpress a mutated form of human SOD1 (SOD1(G93A)) resulted in an efficient and specific reduction of SOD1 expression and improved survival of vulnerable motor neurons in the brainstem and spinal cord. Furthermore, SOD1 silencing mediated an improved motor performance in these animals, resulting in a considerable delay in the onset of ALS symptoms by more than 100% and an extension in survival by nearly 80% of their normal life span. These data are the first to show a substantial extension of survival in an animal model of a fatal, dominantly inherited neurodegenerative condition using RNAi and provide the highest therapeutic efficacy observed in this field to date.", + "TAG_DATA": [ + "89, mice {'context': 'B-organism'}", + "91, to {'perturbing_action': 'B-other'}", + "92, overexpress {'perturbing_action': 'B-other'}", + "93, a {'perturbing_action': 'I-other'}", + "94, mutated {'perturbing_action': 'I-other'}", + "95, form {'perturbing_action': 'I-other'}", + "96, of {'perturbing_action': 'I-other'}", + "97, human {'perturbing_action': 'I-other'}", + "98, SOD1 {'perturbing_action': 'I-other'}", + "99, (SOD1(G93A)) {'perturbing_action': 'I-other'}", + "115, motor {'context': 'B-cells'}", + "116, neurons {'context': 'I-cells'}", + "117, in {'context': 'I-cells'}", + "118, the {'context': 'I-cells'}", + "119, brainstem {'context': 'B-tissue/organ'}", + "121, spinal {'context': 'I-tissue/organ'}", + "122, cord. {'context': 'I-tissue/organ'}", + "124, SOD1 {'perturbing_action': 'B-rnai/knockdown'}", + "125, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "133, animals, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "89, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "91, to ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "92, overexpress ['l1', 'l16', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "93, a ['l2', 'l17', 'l32', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "94, mutated ['l3', 'l18', 'l33', 'l48', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "95, form ['l4', 'l19', 'l34', 'l49', 'l63', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "96, of ['l5', 'l20', 'l35', 'l50', 'l64', 'l77', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "97, human ['l6', 'l21', 'l36', 'l51', 'l65', 'l78', 'l90', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "98, SOD1 ['l7', 'l22', 'l37', 'l52', 'l66', 'l79', 'l91', 'l102', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "99, (SOD1(G93A)) ['l8', 'l23', 'l38', 'l53', 'l67', 'l80', 'l92', 'l103', 'l113', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "115, motor ['l9', 'l24', 'l39', 'l54', 'l68', 'l81', 'l93', 'l104', 'l114', 'l122', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "116, neurons ['l10', 'l25', 'l40', 'l55', 'l69', 'l82', 'l94', 'l105', 'l115', 'l123', 'l131', 'l137', 'l138', 'l139', 'l140', 'l141']", + "117, in ['l11', 'l26', 'l41', 'l56', 'l70', 'l83', 'l95', 'l106', 'l116', 'l124', 'l132', 'l137', 'l142', 'l143', 'l144', 'l145']", + "118, the ['l12', 'l27', 'l42', 'l57', 'l71', 'l84', 'l96', 'l107', 'l117', 'l125', 'l133', 'l138', 'l142', 'l146', 'l147', 'l148']", + "119, brainstem ['l13', 'l28', 'l43', 'l58', 'l72', 'l85', 'l97', 'l108', 'l118', 'l126', 'l134', 'l139', 'l143', 'l146', 'l149', 'l150']", + "121, spinal ['l14', 'l29', 'l44', 'l59', 'l73', 'l86', 'l98', 'l109', 'l119', 'l127', 'l135', 'l140', 'l144', 'l147', 'l149', 'l151']", + "122, cord. ['l15', 'l30', 'l45', 'l60', 'l74', 'l87', 'l99', 'l110', 'l120', 'l128', 'l136', 'l141', 'l145', 'l148', 'l150', 'l151']", + "124, SOD1 ['l152', 'l153']", + "125, silencing ['l46', 'l61', 'l75', 'l88', 'l100', 'l111', 'l129', 'l152', 'l154']", + "133, animals, ['l31', 'l47', 'l62', 'l76', 'l89', 'l101', 'l112', 'l121', 'l130', 'l153', 'l154']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "animals," + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "to", + "overexpress", + "a", + "mutated", + "form", + "of", + "human", + "SOD1", + "(SOD1(G93A))" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "to", + "overexpress", + "a", + "mutated", + "form", + "of", + "human", + "SOD1", + "(SOD1(G93A))" + ] + }, + "context": { + "val": "cells", + "words": [ + "motor", + "neurons", + "in", + "the" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "to", + "overexpress", + "a", + "mutated", + "form", + "of", + "human", + "SOD1", + "(SOD1(G93A))" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brainstem", + "spinal", + "cord." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "SOD1", + "silencing" + ] + }, + "context": { + "val": "organism", + "words": [ + "animals," + ] + } + } + ] + }, + { + "PMID": "15768028", + "TEXT": "Mutations in Cu/Zn superoxide dismutase (encoded by SOD1), one of the causes of familial amyotrophic lateral sclerosis (ALS), lead to progressive death of motoneurons through a gain-of-function mechanism. RNA interference (RNAi) mediated by viral vectors allows for long-term reduction in gene expression and represents an attractive therapeutic approach for genetic diseases characterized by acquired toxic properties. We report that in SOD1(G93A) transgenic mice, a model for familial ALS, intraspinal injection of a lentiviral vector that produces RNAi-mediated silencing of SOD1 substantially retards both the onset and the progression rate of the disease.", + "TAG_DATA": [ + "60, SOD1(G93A) {'perturbing_action': 'B-gene gain-of-function'}", + "61, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "62, mice, {'context': 'B-organism'}", + "72, lentiviral {'perturbing_action': 'B-rnai/knockdown'}", + "73, vector {'perturbing_action': 'I-rnai/knockdown'}", + "75, produces {'perturbing_action': 'B-rnai/knockdown'}", + "76, RNAi-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "77, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "78, of {'perturbing_action': 'I-rnai/knockdown'}", + "79, SOD1 {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "60, SOD1(G93A) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "61, transgenic ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "62, mice, ['l1', 'l8', 'l14']", + "72, lentiviral ['l2', 'l9', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "73, vector ['l3', 'l10', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "75, produces ['l4', 'l11', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "76, RNAi-mediated ['l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "77, silencing ['l5', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "78, of ['l6', 'l12', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "79, SOD1 ['l7', 'l13', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "SOD1(G93A)", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "SOD1" + ] + } + } + ] + }, + { + "PMID": "15735653", + "TEXT": "Immunization with myelin antigens leads to the development of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. The disease can also be induced by the transfer of encephalitogenic CD4+ T helper (T(H)) lymphocytes into naive mice. These T cells need to re-encounter their cognate antigen in the context of major histocompatibility complex (MHC) class II-bearing antigen-presenting cells (APCs) in order to recognize their target. The cell type and location of the APC mediating T-cell entry into the central nervous system (CNS) remain unknown. Here, we show that APCs of the lymphoreticular system and of the CNS parenchyma are dispensable for the immune invasion of the CNS. We also describe that a discrete population of vessel-associated dendritic cells (DCs) is present in human brain tissue. In mice, CD11c+ DCs alone are sufficient to present antigen in vivo to primed myelin-reactive T cells in order to mediate CNS inflammation and clinical disease development.", + "TAG_DATA": [ + "126, mice, {'context': 'B-organism'}", + "127, CD11c+ {'context': 'B-cells'}", + "128, DCs {'context': 'I-cells'}", + "135, in {'context': 'B-in vivo'}", + "136, vivo {'context': 'I-in vivo'}", + "139, myelin-reactive {'context': 'B-cells'}", + "140, T {'context': 'I-cells'}", + "141, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "126, mice, ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "127, CD11c+ ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "128, DCs ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "135, in ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "136, vivo ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "139, myelin-reactive ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "140, T ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "141, cells ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15723074", + "TEXT": "Vanishing white matter disease (VWM) is a heritable leukodystrophy linked to mutations in translation initiation factor 2B (eIF2B). Although the clinical course of this disease has been relatively well described, the cellular consequences of EIF2B mutations on neural cells are unknown. Here we have established cell cultures from the brain of an individual with VWM carrying mutations in subunit 5 of eIF2B (encoded by EIF2B5). Despite the extensive demyelination apparent in this VWM patient, normal-appearing oligodendrocytes were readily generated in vitro. In contrast, few GFAP-expressing (GFAP+) astrocytes were present in primary cultures, induction of astrocytes was severely compromised, and the few astrocytes generated showed abnormal morphologies and antigenic phenotypes. Lesions in vivo also lacked GFAP+ astrocytes. RNAi targeting of EIF2B5 severely compromised the induction of GFAP+ cells from normal human glial progenitors. This raises the possibility that a deficiency in astrocyte function may contribute to the loss of white matter in VWM leukodystrophy.", + "TAG_DATA": [ + "45, cell {'context': 'B-cells'}", + "46, cultures {'context': 'I-cells'}", + "56, mutations {'perturbing_action': 'B-other'}", + "57, in {'perturbing_action': 'I-other'}", + "79, in {'context': 'B-in vitro'}", + "80, vitro. {'context': 'I-in vitro'}", + "84, GFAP-expressing {'context': 'B-cells'}", + "86, astrocytes {'context': 'I-cells'}", + "90, primary {'context': 'B-cells'}", + "91, cultures, {'context': 'I-in vitro'}", + "94, astrocytes {'context': 'B-cells'}", + "101, astrocytes {'context': 'B-cells'}", + "110, in {'context': 'B-in vivo'}", + "111, vivo {'context': 'I-in vivo'}", + "114, GFAP+ {'context': 'B-cells'}", + "115, astrocytes. {'context': 'I-cells'}", + "116, RNAi {'perturbing_action': 'B-rnai/knockdown'}", + "117, targeting {'perturbing_action': 'I-rnai/knockdown'}", + "118, of {'perturbing_action': 'I-rnai/knockdown'}", + "119, EIF2B5 {'perturbing_action': 'I-rnai/knockdown'}", + "125, GFAP+ {'context': 'B-cells'}", + "126, cells {'context': 'I-cells'}", + "128, normal {'context': 'B-cells'}", + "129, human {'context': 'I-cells'}", + "130, glial {'context': 'I-cells'}", + "131, progenitors. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, cell ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "46, cultures ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "56, mutations ['l1', 'l9', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "57, in ['l2', 'l10', 'l16', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "79, in ['l3', 'l11', 'l17', 'l23', 'l30', 'l31', 'l32']", + "80, vitro. ['l4', 'l12', 'l18', 'l24', 'l30', 'l33', 'l34']", + "84, GFAP-expressing ['l5', 'l13', 'l19', 'l25', 'l31', 'l33', 'l35', 'l36', 'l37', 'l38']", + "86, astrocytes ['l6', 'l14', 'l20', 'l26', 'l32', 'l34', 'l35', 'l39', 'l40']", + "90, primary ['l7', 'l21', 'l27', 'l36', 'l39', 'l41']", + "91, cultures, ['l8', 'l15', 'l22', 'l28', 'l37', 'l40', 'l41']", + "94, astrocytes ['l29', 'l38']", + "101, astrocytes ['l42']", + "110, in ['l43', 'l44', 'l45']", + "111, vivo ['l43', 'l46', 'l47']", + "114, GFAP+ ['l44', 'l46', 'l48']", + "115, astrocytes. ['l42', 'l45', 'l47', 'l48']", + "116, RNAi ['l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "117, targeting ['l49', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "118, of ['l50', 'l58', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "119, EIF2B5 ['l51', 'l59', 'l66', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "125, GFAP+ ['l52', 'l60', 'l67', 'l73', 'l79', 'l80', 'l81', 'l82', 'l83']", + "126, cells ['l53', 'l61', 'l68', 'l74', 'l79', 'l84', 'l85', 'l86', 'l87']", + "128, normal ['l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l88', 'l89', 'l90']", + "129, human ['l55', 'l63', 'l70', 'l76', 'l81', 'l85', 'l88', 'l91', 'l92']", + "130, glial ['l56', 'l64', 'l71', 'l77', 'l82', 'l86', 'l89', 'l91', 'l93']", + "131, progenitors. ['l57', 'l65', 'l72', 'l78', 'l83', 'l87', 'l90', 'l92', 'l93']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cell", + "cultures", + "GFAP-expressing", + "astrocytes", + "primary" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutations", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutations", + "in" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro.", + "cultures," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "RNAi", + "targeting", + "of", + "EIF2B5" + ] + }, + "context": { + "val": "cells", + "words": [ + "GFAP+", + "cells", + "normal", + "human", + "glial", + "progenitors." + ] + } + } + ] + }, + { + "PMID": "15723073", + "TEXT": "In the event of a myocardial infarction, current interventions aim to reopen the occluded vessel to reduce myocardial damage and injury. Although reperfusion is essential for tissue salvage, it can cause further damage and the onset of inflammation. We show a novel anti-inflammatory effect of a fibrin-derived peptide, Bbeta15-42. This peptide competes with the fibrin fragment N-terminal disulfide knot-II (an analog of the fibrin E1 fragment) for binding to vascular endothelial (VE)-cadherin, thereby preventing transmigration of leukocytes across endothelial cell monolayers. In acute or chronic rat models of myocardial ischemia-reperfusion injury, Bbeta15-42 substantially reduces leukocyte infiltration, infarct size and subsequent scar formation. The pathogenic role of fibrinogen products is further confirmed in fibrinogen knockout mice, in which infarct size was substantially smaller than in wild-type animals. Our findings conclude that the interplay of fibrin fragments, leukocytes and VE-cadherin contribute to the pathogenesis of myocardial damage and reperfusion injury. The naturally occurring peptide Bbeta15-42 represents a potential candidate for reperfusion therapy in humans.", + "TAG_DATA": [ + "85, rat {'context': 'B-organism'}", + "86, models {'context': 'I-organism'}", + "94, leukocyte {'context': 'B-cells'}", + "112, fibrinogen {'perturbing_action': 'B-gene loss-of-function'}", + "113, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "114, mice, {'context': 'B-organism'}", + "125, animals. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "85, rat ['l0', 'l1']", + "86, models ['l0', 'l2']", + "94, leukocyte ['l1', 'l2']", + "112, fibrinogen ['l3', 'l4', 'l5']", + "113, knockout ['l3', 'l6', 'l7']", + "114, mice, ['l4', 'l6', 'l8']", + "125, animals. ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "fibrinogen", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "animals." + ] + } + } + ] + }, + { + "PMID": "15711561", + "TEXT": "Structural allograft healing is limited because of a lack of vascularization and remodeling. To study this we developed a mouse model that recapitulates the clinical aspects of live autograft and processed allograft healing. Gene expression analyses showed that there is a substantial decrease in the genes encoding RANKL and VEGF during allograft healing. Loss-of-function studies showed that both factors are required for autograft healing. To determine whether addition of these signals could stimulate allograft vascularization and remodeling, we developed a new approach in which rAAV can be freeze-dried onto the cortical surface without losing infectivity. We show that combination rAAV-RANKL- and rAAV-VEGF-coated allografts show marked remodeling and vascularization, which leads to a new bone collar around the graft. In conclusion, we find that RANKL and VEGF are necessary and sufficient for efficient autograft remodeling and can be transferred using rAAV to revitalize structural allografts.", + "TAG_DATA": [ + "19, mouse {'context': 'B-organism'}", + "20, model {'context': 'I-organism'}", + "102, allografts {'context': 'B-xenograft'}" + ], + "LINK_DATA": [ + "19, mouse ['l0']", + "20, model ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15711559", + "TEXT": "In the mammalian auditory system, sensory cell loss resulting from aging, ototoxic drugs, infections, overstimulation and other causes is irreversible and leads to permanent sensorineural hearing loss. To restore hearing, it is necessary to generate new functional hair cells. One potential way to regenerate hair cells is to induce a phenotypic transdifferentiation of nonsensory cells that remain in the deaf cochlea. Here we report that Atoh1, a gene also known as Math1 encoding a basic helix-loop-helix transcription factor and key regulator of hair cell development, induces regeneration of hair cells and substantially improves hearing thresholds in the mature deaf inner ear after delivery to nonsensory cells through adenovectors. This is the first demonstration of cellular and functional repair in the organ of Corti of a mature deaf mammal. The data suggest a new therapeutic approach based on expressing crucial developmental genes for cellular and functional restoration in the damaged auditory epithelium and other sensory systems.", + "TAG_DATA": [ + "88, hair {'context': 'B-cells'}", + "89, cells {'context': 'I-cells'}", + "98, deaf {'context': 'I-tissue/organ'}", + "99, inner {'context': 'I-tissue/organ'}", + "100, ear {'context': 'I-tissue/organ'}", + "104, nonsensory {'context': 'B-cells'}", + "105, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "88, hair ['l0', 'l1', 'l2']", + "89, cells ['l0']", + "98, deaf ['l3', 'l4', 'l5', 'l6']", + "99, inner ['l1', 'l3', 'l7', 'l8']", + "100, ear ['l2', 'l4', 'l7']", + "104, nonsensory ['l5', 'l9']", + "105, cells ['l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15685170", + "TEXT": "Inflammation may underlie the metabolic disorders of insulin resistance and type 2 diabetes. IkappaB kinase beta (IKK-beta, encoded by Ikbkb) is a central coordinator of inflammatory responses through activation of NF-kappaB. To understand the role of IKK-beta in insulin resistance, we used mice lacking this enzyme in hepatocytes (Ikbkb(Deltahep)) or myeloid cells (Ikbkb(Deltamye)). Ikbkb(Deltahep) mice retain liver insulin responsiveness, but develop insulin resistance in muscle and fat in response to high fat diet, obesity or aging. In contrast, Ikbkb(Deltamye) mice retain global insulin sensitivity and are protected from insulin resistance. Thus, IKK-beta acts locally in liver and systemically in myeloid cells, where NF-kappaB activation induces inflammatory mediators that cause insulin resistance. These findings demonstrate the importance of liver cell IKK-beta in hepatic insulin resistance and the central role of myeloid cells in development of systemic insulin resistance. We suggest that inhibition of IKK-beta, especially in myeloid cells, may be used to treat insulin resistance.", + "TAG_DATA": [ + "42, mice {'context': 'B-organism'}", + "43, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "44, this {'perturbing_action': 'I-gene loss-of-function'}", + "45, enzyme {'perturbing_action': 'I-gene loss-of-function'}", + "46, in {'perturbing_action': 'I-gene loss-of-function'}", + "47, hepatocytes {'context': 'B-cells'}", + "50, myeloid {'context': 'B-cells'}", + "51, cells {'context': 'I-cells'}", + "53, Ikbkb(Deltahep) {'perturbing_action': 'B-gene loss-of-function'}", + "54, mice {'context': 'B-organism'}", + "56, liver {'context': 'B-tissue/organ'}", + "78, Ikbkb(Deltamye) {'perturbing_action': 'B-gene loss-of-function'}", + "79, mice {'context': 'B-organism'}", + "99, myeloid {'context': 'B-cells'}", + "100, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "42, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "43, lacking ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "44, this ['l1', 'l6', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "45, enzyme ['l2', 'l7', 'l13', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "46, in ['l3', 'l8', 'l14', 'l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "47, hepatocytes ['l4', 'l9', 'l15', 'l21', 'l26', 'l31', 'l32', 'l33', 'l34']", + "50, myeloid ['l16', 'l22', 'l27', 'l31', 'l35', 'l36', 'l37', 'l38']", + "51, cells ['l10', 'l17', 'l23', 'l28', 'l32', 'l35', 'l39', 'l40', 'l41']", + "53, Ikbkb(Deltahep) ['l36', 'l39', 'l42', 'l43']", + "54, mice ['l11', 'l18', 'l24', 'l29', 'l33', 'l37', 'l40', 'l42', 'l44']", + "56, liver ['l5', 'l12', 'l19', 'l25', 'l30', 'l34', 'l38', 'l41', 'l43', 'l44']", + "78, Ikbkb(Deltamye) ['l45', 'l46', 'l47']", + "79, mice ['l45', 'l48']", + "99, myeloid ['l46', 'l49']", + "100, cells, ['l47', 'l48', 'l49']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "this", + "enzyme", + "in", + "Ikbkb(Deltahep)", + "Ikbkb(Deltamye)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "this", + "enzyme", + "in", + "Ikbkb(Deltahep)", + "Ikbkb(Deltamye)" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes", + "cells", + "myeloid", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "this", + "enzyme", + "in", + "Ikbkb(Deltahep)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "15685168", + "TEXT": "The protein p27(Kip1) regulates cell cycle progression in mammals by inhibiting the activity of cyclin-dependent kinases (CDKs). Here we show that p27(Kip1) progressively accumulates in the nucleus of pancreatic beta cells in mice that lack either insulin receptor substrate 2 (Irs2(-/-)) or the long form of the leptin receptor (Lepr(-/-) or db/db). Deletion of the gene encoding p27(Kip1) (Cdkn1b) ameliorated hyperglycemia in these animal models of type 2 diabetes mellitus by increasing islet mass and maintaining compensatory hyperinsulinemia, effects that were attributable predominantly to stimulation of pancreatic beta-cell proliferation. Thus, p27(Kip1) contributes to beta-cell failure during the development of type 2 diabetes in Irs2(-/-) and Lepr(-/-) mice and represents a potential new target for the treatment of this condition.", + "TAG_DATA": [ + "32, mice {'context': 'B-organism'}", + "34, lack {'perturbing_action': 'B-gene loss-of-function'}", + "35, either {'perturbing_action': 'I-gene loss-of-function'}", + "36, insulin {'perturbing_action': 'I-gene loss-of-function'}", + "37, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "38, substrate {'perturbing_action': 'I-gene loss-of-function'}", + "39, 2 {'perturbing_action': 'I-gene loss-of-function'}", + "40, (Irs2(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "41, or {'perturbing_action': 'I-gene loss-of-function'}", + "42, the {'perturbing_action': 'I-gene loss-of-function'}", + "43, long {'perturbing_action': 'I-gene loss-of-function'}", + "44, form {'perturbing_action': 'I-gene loss-of-function'}", + "45, of {'perturbing_action': 'I-gene loss-of-function'}", + "46, the {'perturbing_action': 'I-gene loss-of-function'}", + "47, leptin {'perturbing_action': 'I-gene loss-of-function'}", + "48, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "49, (Lepr(-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "51, db/db). {'perturbing_action': 'I-gene loss-of-function'}", + "52, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "53, of {'perturbing_action': 'I-gene loss-of-function'}", + "54, the {'perturbing_action': 'I-gene loss-of-function'}", + "55, gene {'perturbing_action': 'I-gene loss-of-function'}", + "56, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "57, p27(Kip1) {'perturbing_action': 'I-gene loss-of-function'}", + "58, (Cdkn1b) {'perturbing_action': 'I-gene loss-of-function'}", + "63, animal {'context': 'B-organism'}", + "64, models {'context': 'I-organism'}", + "72, islet {'context': 'B-cells'}", + "84, stimulation {'effect': 'B-positive'}", + "86, pancreatic {'context': 'B-cells'}", + "87, beta-cell {'context': 'I-cells'}", + "88, proliferation. {'phenotype': 'B-proliferation'}", + "103, Irs2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "104, and {'perturbing_action': 'I-gene loss-of-function'}", + "105, Lepr(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "106, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "29, beta ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "32, mice ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "34, lack ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "35, either ['l2', 'l10', 'l17', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "36, insulin ['l3', 'l11', 'l18', 'l34', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "37, receptor ['l4', 'l12', 'l19', 'l35', 'l47', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "38, substrate ['l5', 'l13', 'l20', 'l36', 'l48', 'l62', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "39, 2 ['l6', 'l14', 'l21', 'l37', 'l49', 'l63', 'l77', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "40, (Irs2(-/-)) ['l7', 'l15', 'l22', 'l38', 'l50', 'l64', 'l78', 'l91', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "41, or ['l8', 'l16', 'l23', 'l39', 'l51', 'l65', 'l79', 'l92', 'l103', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "42, the ['l24', 'l52', 'l66', 'l80', 'l93', 'l104', 'l113', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "43, long ['l25', 'l53', 'l67', 'l81', 'l94', 'l105', 'l114', 'l124', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "44, form ['l26', 'l54', 'l68', 'l82', 'l95', 'l115', 'l125', 'l136', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "45, of ['l27', 'l40', 'l55', 'l69', 'l83', 'l96', 'l106', 'l116', 'l126', 'l137', 'l148', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "46, the ['l28', 'l41', 'l56', 'l70', 'l84', 'l97', 'l107', 'l117', 'l127', 'l138', 'l149', 'l162', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186']", + "47, leptin ['l29', 'l42', 'l57', 'l71', 'l85', 'l98', 'l108', 'l118', 'l128', 'l139', 'l150', 'l163', 'l175', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "48, receptor ['l30', 'l43', 'l58', 'l72', 'l86', 'l99', 'l109', 'l119', 'l129', 'l140', 'l151', 'l164', 'l176', 'l187', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200']", + "49, (Lepr(-/-) ['l31', 'l44', 'l59', 'l73', 'l87', 'l100', 'l110', 'l120', 'l130', 'l141', 'l152', 'l165', 'l177', 'l188', 'l194', 'l201', 'l202', 'l203', 'l204']", + "51, db/db). ['l32', 'l45', 'l60', 'l74', 'l88', 'l101', 'l111', 'l121', 'l131', 'l142', 'l153', 'l166', 'l178', 'l189', 'l195', 'l201', 'l205', 'l206', 'l207', 'l208']", + "52, Deletion ['l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221']", + "53, of ['l209', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233']", + "54, the ['l154', 'l167', 'l179', 'l210', 'l222', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244']", + "55, gene ['l155', 'l168', 'l180', 'l211', 'l223', 'l234', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254']", + "56, encoding ['l156', 'l169', 'l181', 'l212', 'l224', 'l235', 'l245', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263']", + "57, p27(Kip1) ['l143', 'l157', 'l170', 'l182', 'l196', 'l213', 'l225', 'l236', 'l246', 'l255', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271']", + "58, (Cdkn1b) ['l132', 'l144', 'l158', 'l171', 'l183', 'l190', 'l197', 'l205', 'l214', 'l226', 'l237', 'l247', 'l256', 'l264', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278']", + "63, animal ['l75', 'l89', 'l122', 'l133', 'l145', 'l159', 'l172', 'l184', 'l191', 'l198', 'l202', 'l206', 'l215', 'l227', 'l238', 'l248', 'l257', 'l265', 'l272', 'l279', 'l280']", + "64, models ['l33', 'l46', 'l61', 'l76', 'l90', 'l102', 'l112', 'l123', 'l134', 'l146', 'l160', 'l173', 'l185', 'l192', 'l199', 'l203', 'l207', 'l216', 'l228', 'l239', 'l249', 'l258', 'l266', 'l273', 'l279', 'l281']", + "72, islet ['l135', 'l147', 'l161', 'l174', 'l186', 'l193', 'l200', 'l204', 'l208', 'l217', 'l229', 'l240', 'l250', 'l259', 'l267', 'l274', 'l280', 'l281']", + "84, stimulation ['l218', 'l230', 'l241', 'l251', 'l260', 'l268', 'l275', 'l282', 'l283', 'l284']", + "86, pancreatic ['l219', 'l231', 'l242', 'l252', 'l261', 'l269', 'l276', 'l282', 'l285', 'l286']", + "87, beta-cell ['l220', 'l232', 'l243', 'l253', 'l262', 'l270', 'l277', 'l283', 'l285', 'l287']", + "88, proliferation. ['l221', 'l233', 'l244', 'l254', 'l263', 'l271', 'l278', 'l284', 'l286', 'l287']", + "103, Irs2(-/-) ['l288', 'l289', 'l290']", + "104, and ['l288', 'l291', 'l292']", + "105, Lepr(-/-) ['l289', 'l291', 'l293']", + "106, mice ['l290', 'l292', 'l293']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "models", + "animal" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "either", + "insulin", + "receptor", + "substrate", + "2", + "(Irs2(-/-))", + "or", + "the", + "long", + "form", + "of", + "leptin", + "(Lepr(-/-)", + "db/db).", + "Deletion", + "gene", + "encoding", + "p27(Kip1)", + "(Cdkn1b)", + "Irs2(-/-)", + "and", + "Lepr(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "long", + "form", + "of", + "leptin", + "receptor", + "(Lepr(-/-)", + "db/db).", + "Deletion", + "gene", + "encoding", + "p27(Kip1)", + "(Cdkn1b)" + ] + }, + "context": { + "val": "cells", + "words": [ + "islet", + "pancreatic", + "beta-cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "gene", + "encoding", + "p27(Kip1)", + "(Cdkn1b)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "gene", + "encoding", + "p27(Kip1)", + "(Cdkn1b)" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulation" + ] + }, + "context": { + "val": "cells", + "words": [ + "pancreatic", + "beta-cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulation" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pancreatic", + "beta-cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "15665832", + "TEXT": "The angiotensin-converting enzyme (ACE) is a key regulator of blood pressure. It is known to cleave small peptides, such as angiotensin I and bradykinin and changes their biological activities, leading to upregulation of blood pressure. Here we describe a new activity for ACE: a glycosylphosphatidylinositol (GPI)-anchored protein releasing activity (GPIase activity). Unlike its peptidase activity, GPIase activity is weakly inhibited by the tightly binding ACE inhibitor and not inactivated by substitutions of core amino acid residues for the peptidase activity, suggesting that the active site elements for GPIase differ from those for peptidase activity. ACE shed various GPI-anchored proteins from the cell surface, and the process was accelerated by the lipid raft disruptor filipin. The released products carried portions of the GPI anchor, indicating cleavage within the GPI moiety. Further analysis by high-performance liquid chromatography-mass spectrometry predicted the cleavage site at the mannose-mannose linkage. GPI-anchored proteins such as TESP5 and PH-20 were released from the sperm membrane of wild-type mice but not in Ace knockout sperm in vivo. Moreover, peptidase-inactivated E414D mutant ACE and also PI-PLC rescued the egg-binding deficiency of Ace knockout sperms, implying that ACE plays a crucial role in fertilization through this activity.", + "TAG_DATA": [ + "159, mice {'context': 'B-organism'}", + "163, Ace {'perturbing_action': 'B-gene loss-of-function'}", + "164, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "165, sperm {'context': 'B-cells'}", + "166, in {'context': 'B-in vivo'}", + "167, vivo. {'context': 'I-in vivo'}", + "170, E414D {'perturbing_action': 'I-other'}", + "171, mutant {'perturbing_action': 'I-other'}", + "181, Ace {'perturbing_action': 'B-gene loss-of-function'}", + "182, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "183, sperms, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "159, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "163, Ace ['l0', 'l5', 'l6', 'l7', 'l8']", + "164, knockout ['l1', 'l5', 'l9', 'l10', 'l11']", + "165, sperm ['l2', 'l6', 'l9', 'l12', 'l13']", + "166, in ['l3', 'l7', 'l10', 'l12', 'l14']", + "167, vivo. ['l4', 'l8', 'l11', 'l13', 'l14']", + "170, E414D ['l15', 'l16', 'l17', 'l18']", + "171, mutant ['l15', 'l19', 'l20', 'l21']", + "181, Ace ['l16', 'l19', 'l22', 'l23']", + "182, knockout ['l17', 'l20', 'l22', 'l24']", + "183, sperms, ['l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ace", + "knockout" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ace", + "knockout" + ] + }, + "context": { + "val": "cells", + "words": [ + "sperm", + "sperms," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ace", + "knockout" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "E414D", + "mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "sperms," + ] + } + } + ] + }, + { + "PMID": "15654327", + "TEXT": "The upregulation of TGF-beta1 and integrin expression during wound healing has implicated these molecules in this process, but their precise regulation and roles remain unclear. Here we report that, notably, mice lacking beta(3)-integrins show enhanced wound healing with re-epithelialization complete several days earlier than in wild-type mice. We show that this effect is the result of an increase in TGF-beta1 and enhanced dermal fibroblast infiltration into wounds of beta(3)-null mice. Specifically, beta(3)-integrin deficiency is associated with elevated TGF-beta receptor I and receptor II expression, reduced Smad3 levels, sustained Smad2 and Smad4 nuclear localization and enhanced TGF-beta1-mediated dermal fibroblast migration. These data indicate that alpha(v)beta(3)-integrin can suppress TGF-beta1-mediated signaling, thereby controlling the rate of wound healing, and highlight a new mechanism for TGF-beta1 regulation by beta(3)-integrins.", + "TAG_DATA": [ + "30, mice {'context': 'B-organism'}", + "31, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "32, beta(3)-integrins {'perturbing_action': 'I-gene loss-of-function'}", + "62, dermal {'context': 'B-cells'}", + "63, fibroblast {'context': 'I-cells'}", + "68, beta(3)-null {'perturbing_action': 'B-gene loss-of-function'}", + "69, mice. {'context': 'B-organism'}", + "71, beta(3)-integrin {'perturbing_action': 'B-gene loss-of-function'}", + "72, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "94, enhanced {'effect': 'B-positive'}", + "96, dermal {'context': 'B-cells'}", + "97, fibroblast {'context': 'I-cells'}", + "98, migration. {'phenotype': 'B-migration'}" + ], + "LINK_DATA": [ + "30, mice ['l0', 'l1', 'l2', 'l3']", + "31, lacking ['l0', 'l4', 'l5', 'l6']", + "32, beta(3)-integrins ['l1', 'l4', 'l7', 'l8', 'l9']", + "62, dermal ['l2', 'l5', 'l7', 'l10', 'l11', 'l12']", + "63, fibroblast ['l3', 'l6', 'l8', 'l10', 'l13']", + "68, beta(3)-null ['l9', 'l11', 'l13', 'l14']", + "69, mice. ['l12', 'l14']", + "71, beta(3)-integrin ['l15', 'l16', 'l17', 'l18', 'l19']", + "72, deficiency ['l15', 'l20', 'l21', 'l22', 'l23']", + "94, enhanced ['l16', 'l20', 'l24', 'l25', 'l26']", + "96, dermal ['l17', 'l21', 'l24', 'l27', 'l28']", + "97, fibroblast ['l18', 'l22', 'l25', 'l27', 'l29']", + "98, migration. ['l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "beta(3)-integrins", + "beta(3)-null" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "beta(3)-integrins", + "beta(3)-null", + "beta(3)-integrin", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "dermal", + "fibroblast" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "beta(3)-integrin", + "deficiency" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "beta(3)-integrin", + "deficiency" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "context": { + "val": "cells", + "words": [ + "dermal", + "fibroblast" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "dermal", + "fibroblast" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + } + ] + }, + { + "PMID": "15654325", + "TEXT": "Genetic ablation of Inppl1, which encodes SHIP2 (SH2-domain containing inositol 5-phosphatase 2), was previously reported to induce severe insulin sensitivity, leading to early postnatal death. In the previous study, the targeting construct left the first eighteen exons encoding Inppl1 intact, generating a Inppl1(EX19-28-/-) mouse, and apparently also deleted a second gene, Phox2a. We report a new SHIP2 knockout (Inppl1(-/-)) targeted to the translation-initiating ATG, which is null for Inppl1 mRNA and protein. Inppl1(-/-) mice are viable, have normal glucose and insulin levels, and normal insulin and glucose tolerances. The Inppl1(-/-) mice are, however, highly resistant to weight gain when placed on a high-fat diet. These results suggest that inhibition of SHIP2 would be useful in the effort to ameliorate diet-induced obesity, but call into question a dominant role of SHIP2 in modulating glucose homeostasis.", + "TAG_DATA": [ + "56, SHIP2 {'perturbing_action': 'B-gene loss-of-function'}", + "57, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "58, (Inppl1(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "59, targeted {'perturbing_action': 'I-gene loss-of-function'}", + "60, to {'perturbing_action': 'I-other'}", + "61, the {'perturbing_action': 'I-other'}", + "62, translation-initiating {'perturbing_action': 'I-other'}", + "63, ATG, {'perturbing_action': 'I-other'}", + "72, Inppl1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "73, mice {'context': 'B-organism'}", + "89, Inppl1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "90, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, SHIP2 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "57, knockout ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "58, (Inppl1(-/-)) ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "59, targeted ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "60, to ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "61, the ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "62, translation-initiating ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "63, ATG, ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "72, Inppl1(-/-) ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "73, mice ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "89, Inppl1(-/-) ['l45']", + "90, mice ['l45']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHIP2", + "knockout", + "(Inppl1(-/-))", + "targeted", + "Inppl1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "to", + "the", + "translation-initiating", + "ATG," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15619631", + "TEXT": "The origins of autoimmunity in systemic lupus erythematosus (SLE) are thought to involve both genetic and environmental factors. To identify environmental agents that could potentially incite autoimmunity, we have traced the autoantibody response in human SLE back in time, prior to clinical disease onset, and identified the initial autoantigenic epitope for some lupus patients positive for antibodies to 60 kDa Ro. This initial epitope directly cross-reacts with a peptide from the latent viral protein Epstein-Barr virus nuclear antigen-1 (EBNA-1). Animals immunized with either the first epitope of 60 kDa Ro or the cross-reactive EBNA-1 epitope progressively develop autoantibodies binding multiple epitopes of Ro and spliceosomal autoantigens. They eventually acquire clinical symptoms of lupus such as leukopenia, thrombocytopenia and renal dysfunction. These data support the hypothesis that some humoral autoimmunity in human lupus arises through molecular mimicry between EBNA-1 and lupus autoantigens and provide further evidence to suspect an etiologic role for Epstein-Barr virus in SLE.", + "TAG_DATA": [ + "79, Animals {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15619628", + "TEXT": "Hearts from alpha1,3-galactosyltransferase knockout pigs (GalT-KO, n = 8) were transplanted heterotopically into baboons using an anti-CD154 monoclonal antibody-based regimen. The elimination of the galactose-alpha1,3-galactose epitope prevented hyperacute rejection and extended survival of pig hearts in baboons for 2-6 months (median, 78 d); the predominant lesion associated with graft failure was a thrombotic microangiopathy, with resulting ischemic injury. There were no infectious complications directly related to the immunosuppressive regimen. The transplantation of hearts from GalT-KO pigs increased graft survival over previous studies.", + "TAG_DATA": [ + "2, alpha1,3-galactosyltransferase {'perturbing_action': 'I-gene loss-of-function'}", + "3, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "4, pigs {'context': 'B-organism'}", + "13, baboons {'context': 'B-organism'}", + "33, pig {'context': 'B-tissue/organ'}", + "34, hearts {'context': 'I-tissue/organ'}", + "36, baboons {'context': 'B-organism'}", + "72, hearts {'context': 'B-tissue/organ'}", + "74, GalT-KO {'perturbing_action': 'B-gene loss-of-function'}", + "75, pigs {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "2, alpha1,3-galactosyltransferase ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "3, knockout ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "4, pigs ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "13, baboons ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "33, pig ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "34, hearts ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "36, baboons ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "72, hearts ['l21', 'l22']", + "74, GalT-KO ['l21', 'l23']", + "75, pigs ['l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha1,3-galactosyltransferase", + "knockout", + "GalT-KO" + ] + }, + "context": { + "val": "organism", + "words": [ + "pigs", + "baboons" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha1,3-galactosyltransferase", + "knockout", + "GalT-KO" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "pig", + "hearts" + ] + } + } + ] + }, + { + "PMID": "15619626", + "TEXT": "Epithelial ovarian tumors present a complex clinical, diagnostic and therapeutic challenge because of the difficulty of early detection, lack of known precursor lesions and high mortality rates. Endometrioid ovarian carcinomas are frequently associated with endometriosis, but the mechanism for this association remains unknown. Here we present the first genetic models of peritoneal endometriosis and endometrioid ovarian adenocarcinoma in mice, both based on the activation of an oncogenic K-ras allele. In addition, we find that expression of oncogenic K-ras or conditional Pten deletion within the ovarian surface epithelium gives rise to preneoplastic ovarian lesions with an endometrioid glandular morphology. Furthermore, the combination of the two mutations in the ovary leads to the induction of invasive and widely metastatic endometrioid ovarian adenocarcinomas with complete penetrance and a disease latency of only 7 weeks. The ovarian cancer model described in this study recapitulates the specific tumor histomorphology and metastatic potential of the human disease.", + "TAG_DATA": [ + "58, mice, {'context': 'B-organism'}", + "74, expression {'perturbing_action': 'B-gene gain-of-function'}", + "75, of {'perturbing_action': 'I-gene gain-of-function'}", + "76, oncogenic {'perturbing_action': 'I-gene gain-of-function'}", + "77, K-ras {'perturbing_action': 'I-gene gain-of-function'}", + "79, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "80, Pten {'perturbing_action': 'I-gene loss-of-function'}", + "81, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "84, ovarian {'perturbing_action': 'I-gene loss-of-function', 'context': 'B-tissue/organ'}", + "85, surface {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-tissue/organ'}", + "86, epithelium {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-tissue/organ'}", + "107, ovary {'context': 'B-tissue/organ'}", + "111, induction {'effect': 'B-positive'}", + "117, endometrioid {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}", + "118, ovarian {'context': 'I-neoplasm', 'phenotype': 'I-tumourigenesis'}", + "119, adenocarcinomas {'context': 'I-neoplasm', 'phenotype': 'I-tumourigenesis'}" + ], + "LINK_DATA": [ + "74, expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "75, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "76, oncogenic ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "77, K-ras ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "79, conditional ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "80, Pten ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "81, deletion ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "84, ovarian ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "85, surface ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "86, epithelium ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "107, ovary ['l45', 'l46', 'l47', 'l48']", + "111, induction ['l45', 'l49', 'l50', 'l51']", + "117, endometrioid ['l46', 'l49', 'l52', 'l53']", + "118, ovarian ['l47', 'l50', 'l52', 'l54']", + "119, adenocarcinomas ['l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "oncogenic", + "K-ras" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "ovarian", + "surface", + "epithelium" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ovarian", + "surface", + "epithelium", + "conditional", + "Pten", + "deletion" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "ovarian", + "surface", + "epithelium" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "ovary" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "ovary" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "endometrioid", + "ovarian", + "adenocarcinomas" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "endometrioid", + "ovarian", + "adenocarcinomas" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "endometrioid", + "ovarian", + "adenocarcinomas" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "endometrioid", + "ovarian", + "adenocarcinomas" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "endometrioid", + "ovarian", + "adenocarcinomas" + ] + } + } + ] + }, + { + "PMID": "15619625", + "TEXT": "Respiratory syncytial virus (RSV) infection is one of the major causes of respiratory tract infection for which no vaccine or antiviral treatment is available. The RSV NS1 protein seems to antagonize the host interferon (IFN) response; however, its mechanism is unknown. Here, we used a plasmid-borne small interfering RNA targeting the NS1 gene (siNS1) to examine the role of NS1 in modulating RSV infection. RSV replication was reduced in A549 cells, but not IFN-deficient Vero cells, transfected with siNS1. siNS1 induced upregulated expression of IFN-beta and IFN-inducible genes in A549 cells. siNS1-transfected human dendritic cells, upon RSV infection, produced elevated type-1 IFN and induced differentiation of naive CD4+ T cells to T helper type 1 (TH1) cells. Mice treated intranasally with siNS1 nanoparticles before or after infection with RSV showed substantially decreased virus titers in the lung and decreased inflammation and airway reactivity compared to controls. Thus, siNS1 nanoparticles may provide an effective inhibition of RSV infection in humans.", + "TAG_DATA": [ + "69, A549 {'context': 'B-cells'}", + "70, cells, {'context': 'I-cells'}", + "74, Vero {'context': 'B-cells'}", + "75, cells, {'context': 'I-cells'}", + "76, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "77, with {'perturbing_action': 'I-gene gain-of-function'}", + "78, siNS1. {'perturbing_action': 'I-gene gain-of-function'}", + "79, siNS1 {'perturbing_action': 'I-rnai/knockdown'}", + "89, A549 {'context': 'B-cells'}", + "90, cells. {'context': 'I-cells'}", + "91, siNS1-transfected {'perturbing_action': 'B-gene gain-of-function'}", + "92, human {'context': 'B-cells'}", + "93, dendritic {'context': 'I-cells'}", + "94, cells, {'context': 'I-cells'}", + "103, induced {'effect': 'B-positive'}", + "104, differentiation {'phenotype': 'B-differentiation'}", + "106, naive {'context': 'B-cells'}", + "107, CD4+ {'context': 'I-cells'}", + "108, T {'context': 'I-cells'}", + "109, cells {'context': 'I-cells'}", + "111, T {'context': 'B-cells'}", + "112, helper {'context': 'I-cells'}", + "113, type {'context': 'I-cells'}", + "114, 1 {'context': 'I-cells'}", + "115, (TH1) {'context': 'I-cells'}", + "116, cells. {'context': 'I-cells'}", + "117, Mice {'context': 'B-organism'}", + "136, lung {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "69, A549 ['l0', 'l1', 'l2']", + "70, cells, ['l0']", + "74, Vero ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "75, cells, ['l1', 'l3', 'l10', 'l11', 'l12', 'l13']", + "76, transfected ['l4', 'l14', 'l15', 'l16', 'l17', 'l18']", + "77, with ['l5', 'l14', 'l19', 'l20', 'l21', 'l22', 'l23']", + "78, siNS1. ['l6', 'l10', 'l15', 'l19', 'l24', 'l25', 'l26']", + "79, siNS1 ['l7', 'l11', 'l16', 'l20', 'l24', 'l27', 'l28']", + "89, A549 ['l8', 'l12', 'l17', 'l21', 'l25', 'l27', 'l29']", + "90, cells. ['l2', 'l9', 'l13', 'l18', 'l22', 'l26', 'l28', 'l29']", + "91, siNS1-transfected ['l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "92, human ['l30', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "93, dendritic ['l31', 'l45', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "94, cells, ['l32', 'l46', 'l59', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "103, induced ['l33', 'l47', 'l60', 'l72', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "104, differentiation ['l34', 'l48', 'l61', 'l73', 'l84', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "106, naive ['l35', 'l49', 'l62', 'l74', 'l85', 'l95', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "107, CD4+ ['l36', 'l50', 'l63', 'l75', 'l86', 'l96', 'l105', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "108, T ['l37', 'l51', 'l64', 'l76', 'l87', 'l97', 'l106', 'l114', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "109, cells ['l23', 'l38', 'l52', 'l65', 'l77', 'l88', 'l98', 'l107', 'l115', 'l122', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "111, T ['l39', 'l53', 'l66', 'l78', 'l89', 'l99', 'l108', 'l116', 'l123', 'l129', 'l135', 'l136', 'l137', 'l138', 'l139']", + "112, helper ['l40', 'l54', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l124', 'l130', 'l135', 'l140', 'l141', 'l142', 'l143']", + "113, type ['l41', 'l55', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l125', 'l131', 'l136', 'l140', 'l144', 'l145', 'l146']", + "114, 1 ['l42', 'l56', 'l69', 'l81', 'l92', 'l102', 'l111', 'l119', 'l126', 'l132', 'l137', 'l141', 'l144', 'l147', 'l148']", + "115, (TH1) ['l43', 'l57', 'l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l127', 'l133', 'l138', 'l142', 'l145', 'l147', 'l149']", + "116, cells. ['l44', 'l58', 'l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l128', 'l134', 'l139', 'l143', 'l146', 'l148', 'l149']", + "117, Mice ['l150']", + "136, lung ['l150']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Vero", + "cells,", + "A549", + "cells.", + "cells", + "human", + "dendritic", + "naive", + "CD4+", + "T", + "helper", + "type", + "1", + "(TH1)" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "siNS1.", + "siNS1-transfected" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Vero", + "cells,", + "A549", + "cells." + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siNS1" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "siNS1-transfected" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "siNS1-transfected" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "dendritic", + "cells,", + "naive", + "CD4+", + "T", + "cells", + "helper", + "type", + "1", + "(TH1)", + "cells." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "dendritic", + "cells,", + "naive", + "CD4+", + "T", + "cells", + "helper", + "type", + "1", + "(TH1)", + "cells." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "15592573", + "TEXT": "Here we report that epidermal keratinocytes in psoriatic lesions are characterized by activated Stat3. Transgenic mice with keratinocytes expressing a constitutively active Stat3 (K5.Stat3C mice) develop a skin phenotype either spontaneously, or in response to wounding, that closely resembles psoriasis. Keratinocytes from K5.Stat3C mice show upregulation of several molecules linked to the pathogenesis of psoriasis. In addition, the development of psoriatic lesions in K5.Stat3C mice requires cooperation between Stat3 activation in keratinocytes and activated T cells. Finally, abrogation of Stat3 function by a decoy oligonucleotide inhibits the onset and reverses established psoriatic lesions in K5.Stat3C mice. Thus, targeting Stat3 may be potentially therapeutic in the treatment of psoriasis.", + "TAG_DATA": [ + "15, mice {'context': 'B-organism'}", + "17, keratinocytes {'context': 'B-cells'}", + "18, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "19, a {'perturbing_action': 'I-gene gain-of-function'}", + "20, constitutively {'perturbing_action': 'I-gene gain-of-function'}", + "21, active {'perturbing_action': 'I-gene gain-of-function'}", + "22, Stat3 {'perturbing_action': 'I-gene gain-of-function'}", + "40, Keratinocytes {'context': 'B-cells'}", + "42, K5.Stat3C {'perturbing_action': 'B-other'}", + "43, mice {'context': 'B-organism'}", + "63, K5.Stat3C {'perturbing_action': 'B-other'}", + "64, mice {'context': 'B-organism'}", + "77, abrogation {'perturbing_action': 'B-gene loss-of-function'}", + "78, of {'perturbing_action': 'I-gene loss-of-function'}", + "79, Stat3 {'perturbing_action': 'I-gene loss-of-function'}", + "80, function {'perturbing_action': 'I-gene loss-of-function'}", + "81, by {'perturbing_action': 'I-gene loss-of-function'}", + "82, a {'perturbing_action': 'I-rnai/knockdown'}", + "83, decoy {'perturbing_action': 'I-rnai/knockdown'}", + "84, oligonucleotide {'perturbing_action': 'I-gene loss-of-function'}", + "94, K5.Stat3C {'perturbing_action': 'B-other'}", + "95, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "15, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "17, keratinocytes ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "18, expressing ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "19, a ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "20, constitutively ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "21, active ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "22, Stat3 ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "40, Keratinocytes ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "42, K5.Stat3C ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "43, mice ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "63, K5.Stat3C ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "64, mice ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "77, abrogation ['l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "78, of ['l66', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "79, Stat3 ['l67', 'l75', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "80, function ['l68', 'l76', 'l83', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "81, by ['l69', 'l77', 'l84', 'l90', 'l96', 'l97', 'l98', 'l99', 'l100']", + "82, a ['l70', 'l78', 'l85', 'l91', 'l96', 'l101', 'l102', 'l103', 'l104']", + "83, decoy ['l71', 'l79', 'l86', 'l92', 'l97', 'l101', 'l105', 'l106', 'l107']", + "84, oligonucleotide ['l72', 'l80', 'l87', 'l93', 'l98', 'l102', 'l105', 'l108', 'l109']", + "94, K5.Stat3C ['l73', 'l81', 'l88', 'l94', 'l99', 'l103', 'l106', 'l108', 'l110']", + "95, mice. ['l74', 'l82', 'l89', 'l95', 'l100', 'l104', 'l107', 'l109', 'l110']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "a", + "constitutively", + "active", + "Stat3" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "K5.Stat3C" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "keratinocytes", + "Keratinocytes" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "a", + "constitutively", + "active", + "Stat3" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "keratinocytes", + "Keratinocytes" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "K5.Stat3C" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "abrogation", + "of", + "Stat3", + "function", + "by", + "oligonucleotide" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "a", + "decoy" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "15577935", + "TEXT": "The successful replication of a viral pathogen in a host is a complex process involving many interactions. These interactions develop from the coevolution of pathogen and host and often lead to a species specificity of the virus that can make interspecies transmissions difficult. Nevertheless, viruses do sporadically cross species barriers into other host populations, including humans. In zoonotic infections, many of these interspecies transfer events are dead end, where transmission is confined only to the animal-to-human route but sometimes viruses adapt to enable spread from human to human. A pathogen must overcome many hurdles to replicate successfully in a foreign host. The viral pathogen must enter the host cell, replicate with the assistance of host factors, evade inhibitory host products, exit the first cell and move on to the next, and possibly leave the initial host and transmit to another. Each of these stages may require adaptive changes in the pathogen. Although the factors that influence each stage of the replication and transmission of most agents have not been resolved, the genomics of both hosts and pathogens are now at hand and we have begun to understand some of the molecular changes that enable some viruses to adapt to a new host.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15577932", + "TEXT": "This special supplement of Nature Medicine, directed at the topic of emerging infectious diseases, is very timely. Recent high-profile outbreaks have highlighted the global risk that infectious agents, both new and old, represent for society. The experience of severe acute respiratory syndrome (SARS) shows the risk posed by emerging infectious diseases, but also the power of strongly coordinated global surveillance and public health measures, coupled with scientific research, to keep infection under control. Diseases such as drug-resistant malaria continue to be threats. There is a need to enhance global resources to investigate, detect and respond to emerging infections, and to appropriately coordinate and direct research efforts to meet the challenges presented by these diseases.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "15568033", + "TEXT": "We present the results of a preliminary investigation of the efficacy of a therapeutic dendritic cell (DC)-based vaccine for HIV-1. We immunized 18 chronically HIV-1-infected and currently untreated individuals showing stable viral loads for at least 6 months with autologous monocyte-derived DCs loaded with autologous aldrithiol-2-inactivated HIV-1. Plasma viral load levels were decreased by 80% (median) over the first 112 d following immunization. Prolonged suppression of viral load of more than 90% was seen in 8 individuals for at least 1 year. The suppression of viral load was positively correlated with HIV-1-specific interleukin-2 or interferon-gamma-expressing CD4(+) T cells and with HIV-1 gag-specific perforin-expressing CD8(+) effector cells, suggesting that a robust virus-specific CD4(+) T-helper type 1 (T(H)1) response is required for inducing and maintaining virus-specific CD8(+) effectors to contain HIV-1 in vivo. The results suggest that inactivated whole virus-pulsed DC vaccines could be a promising strategy for treating people with chronic HIV-1 infection.", + "TAG_DATA": [ + "39, autologous {'context': 'B-cells'}", + "40, monocyte-derived {'context': 'I-cells'}", + "41, DCs {'context': 'I-cells'}", + "95, CD4(+) {'context': 'B-cells'}", + "96, T {'context': 'I-cells'}", + "97, cells {'context': 'I-cells'}", + "103, CD8(+) {'context': 'I-cells'}", + "104, effector {'context': 'I-cells'}", + "105, cells, {'context': 'I-cells'}", + "129, in {'context': 'B-in vivo'}", + "130, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "39, autologous ['l0', 'l1', 'l2', 'l3']", + "40, monocyte-derived ['l0', 'l4', 'l5', 'l6']", + "41, DCs ['l1', 'l4']", + "95, CD4(+) ['l7', 'l8']", + "96, T ['l2', 'l5', 'l7', 'l9']", + "97, cells ['l3', 'l6', 'l8', 'l9']", + "103, CD8(+) ['l10', 'l11', 'l12', 'l13']", + "104, effector ['l10', 'l14', 'l15', 'l16']", + "105, cells, ['l11', 'l14']", + "129, in ['l12', 'l15', 'l17']", + "130, vivo. ['l13', 'l16', 'l17']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15558054", + "TEXT": "In tumors that retain wild-type p53, its tumor-suppressor function is often impaired as a result of the deregulation of HDM-2, which binds to p53 and targets it for proteasomal degradation. We have screened a chemical library and identified a small molecule named RITA (reactivation of p53 and induction of tumor cell apoptosis), which bound to p53 and induced its accumulation in tumor cells. RITA prevented p53-HDM-2 interaction in vitro and in vivo and affected p53 interaction with several negative regulators. RITA induced expression of p53 target genes and massive apoptosis in various tumor cells lines expressing wild-type p53. RITA suppressed the growth of human fibroblasts and lymphoblasts only upon oncogene expression and showed substantial p53-dependent antitumor effect in vivo. RITA may serve as a lead compound for the development of an anticancer drug that targets tumors with wild-type p53.", + "TAG_DATA": [ + "47, induction {'effect': 'B-positive'}", + "61, tumor {'context': 'B-transformed cells'}", + "62, cells. {'context': 'I-transformed cells'}", + "67, in {'context': 'B-in vitro'}", + "68, vitro {'context': 'I-in vitro'}", + "70, in {'context': 'B-in vivo'}", + "71, vivo {'context': 'I-in vivo'}", + "81, induced {'effect': 'B-positive'}", + "89, apoptosis {'phenotype': 'B-apoptosis'}", + "92, tumor {'context': 'B-transformed cells'}", + "93, cells {'context': 'I-transformed cells'}", + "94, lines {'context': 'I-transformed cells'}", + "103, human {'context': 'B-cells'}", + "104, fibroblasts {'context': 'I-cells'}", + "106, lymphoblasts {'context': 'B-cells'}", + "117, in {'context': 'B-in vivo'}", + "118, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "47, induction ['l0', 'l1']", + "61, tumor ['l0', 'l2', 'l3', 'l4']", + "62, cells. ['l1', 'l2']", + "67, in ['l3', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "68, vitro ['l4', 'l5', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "70, in ['l6', 'l13', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "71, vivo ['l7', 'l14', 'l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "81, induced ['l8', 'l15', 'l21', 'l26', 'l31', 'l32', 'l33', 'l34']", + "89, apoptosis ['l9', 'l16', 'l22', 'l27', 'l31', 'l35', 'l36', 'l37']", + "92, tumor ['l10', 'l17', 'l23', 'l28', 'l32', 'l35', 'l38', 'l39']", + "93, cells ['l11', 'l18', 'l24', 'l29', 'l33', 'l36', 'l38', 'l40']", + "94, lines ['l12', 'l19', 'l25', 'l30', 'l34', 'l37', 'l39', 'l40']", + "103, human ['l41', 'l42']", + "104, fibroblasts ['l41', 'l43']", + "106, lymphoblasts ['l42', 'l43']", + "117, in ['l44']", + "118, vivo. ['l44']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induction", + "induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells.", + "cells", + "lines" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells", + "lines" + ] + } + } + ] + }, + { + "PMID": "15516929", + "TEXT": "Although thrombolytic effects of tissue plasminogen activator (tPA) are beneficial, its neurotoxicity is problematic. Here, we report that tPA potentiates apoptosis in ischemic human brain endothelium and in mouse cortical neurons treated with N-methyl-D-aspartate (NMDA) by shifting the apoptotic pathways from caspase-9 to caspase-8, which directly activates caspase-3 without amplification through the Bid-mediated mitochondrial pathway. In vivo, tPA-induced cerebral ischemic injury in mice was reduced by intracerebroventricular administration of caspase-8 inhibitor, but not by caspase-9 inhibitor, in contrast to controls in which caspase-9 inhibitor, but not caspase-8 inhibitor, was protective. Activated protein C (APC), a serine protease with anticoagulant, anti-inflammatory and antiapoptotic activities, which is neuroprotective during transient ischemia and promotes activation of antiapoptotic mechanisms in brain cells by acting directly on endothelium and neurons, blocked tPA vascular and neuronal toxicities in vitro and in vivo. APC inhibited tPA-induced caspase-8 activation of caspase-3 in endothelium and caspase-3-dependent nuclear translocation of apoptosis-inducing factor in NMDA-treated neurons and reduced tPA-mediated cerebral ischemic injury in mice. Data suggest that tPA shifts the apoptotic signal in stressed brain cells from the intrinsic to the extrinsic pathway which requires caspase-8. APC blocks tPA's neurovascular toxicity and may add substantially to the effectiveness of tPA therapy for stroke.", + "TAG_DATA": [ + "19, potentiates {'effect': 'B-positive'}", + "20, apoptosis {'phenotype': 'B-apoptosis'}", + "23, human {'context': 'B-tissue/organ'}", + "24, brain {'context': 'I-tissue/organ'}", + "25, endothelium {'context': 'I-tissue/organ'}", + "28, mouse {'context': 'B-cells'}", + "29, cortical {'context': 'I-cells'}", + "30, neurons {'context': 'I-cells'}", + "55, In {'context': 'B-in vivo'}", + "56, vivo, {'context': 'I-in vivo'}", + "62, mice {'context': 'B-organism'}", + "69, caspase-8 {'perturbing_action': 'B-pharmacological inhibition'}", + "70, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "74, caspase-9 {'perturbing_action': 'B-pharmacological inhibition'}", + "75, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "82, caspase-9 {'perturbing_action': 'B-pharmacological inhibition'}", + "83, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "86, caspase-8 {'perturbing_action': 'B-pharmacological inhibition'}", + "87, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "131, in {'context': 'B-in vitro'}", + "132, vitro {'context': 'I-in vitro'}", + "134, in {'context': 'B-in vivo'}", + "135, vivo. {'context': 'I-in vivo'}", + "144, endothelium {'context': 'B-tissue/organ'}", + "154, neurons {'context': 'B-cells'}", + "162, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "19, potentiates ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "20, apoptosis ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "23, human ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "24, brain ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "25, endothelium ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "28, mouse ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "29, cortical ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "30, neurons ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l51', 'l52', 'l53']", + "55, In ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l51', 'l54', 'l55']", + "56, vivo, ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l52', 'l54', 'l56']", + "62, mice ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l53', 'l55', 'l56', 'l57', 'l58']", + "69, caspase-8 ['l49', 'l57', 'l59', 'l60', 'l61']", + "70, inhibitor, ['l50', 'l58', 'l59', 'l62', 'l63']", + "74, caspase-9 ['l60', 'l62', 'l64']", + "75, inhibitor, ['l61', 'l63', 'l64']", + "82, caspase-9 ['l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "83, inhibitor, ['l65', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "86, caspase-8 ['l66', 'l73', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "87, inhibitor, ['l67', 'l74', 'l80', 'l86', 'l87', 'l88', 'l89', 'l90']", + "131, in ['l68', 'l75', 'l81', 'l86', 'l91']", + "132, vitro ['l69', 'l76', 'l82', 'l87', 'l91']", + "134, in ['l70', 'l77', 'l83', 'l88', 'l92', 'l93']", + "135, vivo. ['l71', 'l78', 'l84', 'l89', 'l92', 'l94']", + "144, endothelium ['l72', 'l79', 'l85', 'l90', 'l93', 'l94', 'l95']", + "154, neurons ['l95', 'l96']", + "162, mice. ['l96']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "potentiates" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "potentiates" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "human", + "brain", + "endothelium" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "potentiates" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "cortical", + "neurons" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "potentiates" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "potentiates" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "human", + "brain", + "endothelium" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "cortical", + "neurons" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cortical" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "caspase-8", + "inhibitor," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "caspase-8", + "inhibitor," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "caspase-9", + "inhibitor,", + "caspase-8" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "caspase-9", + "inhibitor,", + "caspase-8" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "caspase-9", + "inhibitor,", + "caspase-8" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "endothelium" + ] + } + } + ] + }, + { + "PMID": "15502841", + "TEXT": "Although over 50 years have passed since its first laboratory description, intentional induction of immune tolerance to foreign antigens has remained an elusive clinical goal. We previously reported that the requirement for ABO compatibility in heart transplantation is not applicable to infants. Here, we show that ABO-incompatible heart transplantation during infancy results in development of B-cell tolerance to donor blood group A and B antigens. This mimics animal models of neonatal tolerance and indicates that the human infant is susceptible to intentional tolerance induction. Tolerance in this setting occurs by elimination of donor-reactive B lymphocytes and may be dependent upon persistence of some degree of antigen expression. These findings suggest that intentional exposure to nonself A and B antigens may prolong the window of opportunity for ABO-incompatible transplantation, and have profound implications for clinical research on tolerance induction to T-independent antigens relevant to xenotransplantation.", + "TAG_DATA": [ + "55, B-cell {'context': 'B-cells'}", + "92, donor-reactive {'context': 'B-cells'}", + "93, B {'context': 'I-cells'}", + "94, lymphocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "77, infant ['l0', 'l1', 'l2']", + "92, donor-reactive ['l0', 'l3', 'l4']", + "93, B ['l1', 'l3', 'l5']", + "94, lymphocytes ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15502840", + "TEXT": "We studied the effects of Lyn ablation on the survival of drug-resistant chronic myelogenous leukemia (CML) blast crisis cells using siRNA. Lyn siRNA reduced Lyn protein in both normal hematopoietic cells and BCR-ABL1-expressing (BCR-ABL1(+)) blasts by 80-95%. Within 48 h, siRNA-treated BCR-ABL1(+) blasts underwent apoptosis, whereas normal cells remained viable. This increased dependence on Lyn signaling for BCR-ABL1(+) blast survival provides the basis for rational treatment of drug-resistant CML blast crisis, particularly when lymphoid in nature.", + "TAG_DATA": [ + "21, Lyn {'perturbing_action': 'B-rnai/knockdown'}", + "22, siRNA {'perturbing_action': 'I-rnai/knockdown'}", + "28, normal {'context': 'B-cells'}", + "29, hematopoietic {'context': 'I-cells'}", + "30, cells {'context': 'I-cells'}", + "32, BCR-ABL1-expressing {'context': 'B-transformed cells'}", + "33, (BCR-ABL1(+)) {'context': 'I-transformed cells'}", + "34, blasts {'context': 'I-transformed cells'}", + "40, siRNA-treated {'perturbing_action': 'B-rnai/knockdown'}", + "41, BCR-ABL1(+) {'context': 'B-transformed cells'}", + "42, blasts {'context': 'I-transformed cells'}", + "44, apoptosis, {'phenotype': 'B-apoptosis'}", + "46, normal {'context': 'B-cells'}", + "47, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "21, Lyn ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "22, siRNA ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "28, normal ['l1', 'l7', 'l13', 'l14', 'l15', 'l16']", + "29, hematopoietic ['l2', 'l8', 'l13', 'l17', 'l18', 'l19', 'l20']", + "30, cells ['l3', 'l9', 'l14', 'l17', 'l21', 'l22']", + "32, BCR-ABL1-expressing ['l4', 'l10', 'l18', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "33, (BCR-ABL1(+)) ['l5', 'l11', 'l15', 'l19', 'l21', 'l23', 'l30', 'l31', 'l32', 'l33']", + "34, blasts ['l6', 'l12', 'l16', 'l20', 'l22', 'l24', 'l30', 'l34']", + "40, siRNA-treated ['l25', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "41, BCR-ABL1(+) ['l26', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "42, blasts ['l27', 'l31', 'l34', 'l36', 'l41', 'l46', 'l47']", + "43, underwent ['l28', 'l32', 'l37', 'l42', 'l46', 'l48']", + "44, apoptosis, ['l29', 'l33', 'l38', 'l43', 'l47', 'l48', 'l49']", + "46, normal ['l39', 'l44', 'l50']", + "47, cells ['l40', 'l45', 'l49', 'l50']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Lyn", + "siRNA", + "siRNA-treated" + ] + }, + "context": { + "val": "cells", + "words": [ + "normal", + "hematopoietic", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Lyn", + "siRNA", + "siRNA-treated" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "BCR-ABL1-expressing", + "(BCR-ABL1(+))", + "blasts", + "BCR-ABL1(+)" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "BCR-ABL1-expressing", + "(BCR-ABL1(+))", + "BCR-ABL1(+)", + "blasts" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA-treated" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "15475963", + "TEXT": "Fatty acid oxidation (FAO) is a primary energy source for meeting the heart's energy requirements. Peroxisome proliferator-activated receptor-delta (PPAR-delta) may have important roles in FAO. But it remains unclear whether PPAR-delta is required for maintaining basal myocardial FAO. We show that cre-loxP-mediated cardiomyocyte-restricted deletion of PPAR-delta in mice downregulates constitutive expression of key FAO genes and decreases basal myocardial FAO. These mice have cardiac dysfunction, progressive myocardial lipid accumulation, cardiac hypertrophy and congestive heart failure with reduced survival. Thus, chronic myocardial PPAR-delta deficiency leads to lipotoxic cardiomyopathy. Together, our data show that PPAR-delta is a crucial determinant of constitutive myocardial FAO and is necessary to maintain energy balance and normal cardiac function. We suggest that PPAR-delta is a potential therapeutic target in treating lipotoxic cardiomyopathy and other heart diseases.", + "TAG_DATA": [ + "41, cre-loxP-mediated {'perturbing_action': 'B-gene loss-of-function'}", + "42, cardiomyocyte-restricted {'perturbing_action': 'I-gene loss-of-function'}", + "43, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "44, of {'perturbing_action': 'I-gene loss-of-function'}", + "45, PPAR-delta {'perturbing_action': 'I-gene loss-of-function'}", + "47, mice {'context': 'B-organism'}", + "61, mice {'context': 'B-organism'}", + "79, chronic {'perturbing_action': 'B-gene loss-of-function'}", + "80, myocardial {'perturbing_action': 'I-gene loss-of-function'}", + "81, PPAR-delta {'perturbing_action': 'I-gene loss-of-function'}", + "82, deficiency {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "41, cre-loxP-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "42, cardiomyocyte-restricted ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "43, deletion ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "44, of ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "45, PPAR-delta ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "47, mice ['l4', 'l9', 'l13', 'l16', 'l18']", + "61, mice ['l5', 'l10', 'l14', 'l17', 'l19']", + "79, chronic ['l20', 'l21', 'l22']", + "80, myocardial ['l20', 'l23', 'l24']", + "81, PPAR-delta ['l21', 'l23', 'l25']", + "82, deficiency ['l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cre-loxP-mediated", + "cardiomyocyte-restricted", + "deletion", + "of", + "PPAR-delta" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15448686", + "TEXT": "Infection with Leishmania major induces a protective immune response and long-term resistance to reinfection, which is thought to depend upon persistent parasites. Here we demonstrate that although effector CD4(+) T cells are lost in the absence of parasites, central memory CD4(+) T cells are maintained. Upon secondary infection, these central memory T cells become tissue-homing effector T cells and mediate protection. Thus, immunity to L. major is mediated by at least two distinct populations of CD4(+) T cells: short-lived pathogen-dependent effector cells and long-lived pathogen-independent central memory cells. These data suggest that central memory T cells should be the targets for nonlive vaccines against infectious diseases requiring cell-mediated immunity.", + "TAG_DATA": [ + "28, CD4(+) {'context': 'I-cells'}", + "38, central {'context': 'B-cells'}", + "39, memory {'context': 'I-cells'}", + "40, CD4(+) {'context': 'I-cells'}", + "41, T {'context': 'I-cells'}", + "42, cells {'context': 'I-cells'}", + "49, central {'context': 'B-cells'}", + "50, memory {'context': 'I-cells'}", + "51, T {'context': 'I-cells'}", + "52, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "28, CD4(+) ['l0', 'l1', 'l2']", + "29, T ['l0', 'l3']", + "30, cells ['l1', 'l3']", + "38, central ['l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "39, memory ['l4', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "40, CD4(+) ['l5', 'l12', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "41, T ['l6', 'l13', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "42, cells ['l2', 'l7', 'l14', 'l20', 'l25', 'l30', 'l31']", + "49, central ['l8', 'l15', 'l21', 'l26', 'l32', 'l33', 'l34']", + "50, memory ['l9', 'l16', 'l22', 'l27', 'l32', 'l35', 'l36']", + "51, T ['l10', 'l17', 'l23', 'l28', 'l30', 'l33', 'l35', 'l37']", + "52, cells ['l11', 'l18', 'l24', 'l29', 'l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15448685", + "TEXT": "Collagen type II-induced arthritis is a CD4(+) T-cell-dependent chronic inflammation in susceptible DBA/1 mice and represents an animal model of human rheumatoid arthritis. We found that development of this condition, and even established disease, are inhibited by an agonistic anti-4-1BB monoclonal antibody. Anti-4-1BB suppressed serum antibodies to collagen type II and CD4(+) T-cell recall responses to collagen type II. Crosslinking of 4-1BB evoked an antigen-specific, active suppression mechanism that differed from the results of blocking the interaction between 4-1BB and its ligand, 4-1BBL. Anti-4-1BB monoclonal antibodies induced massive, antigen-dependent clonal expansion of CD11c(+)CD8(+) T cells and accumulation of indoleamine 2,3-dioxygenase in CD11b(+) monocytes and CD11c(+) dendritic cells. Both anti-interferon-gamma and 1-methyltryptophan, a pharmacological inhibitor of indoleamine 2,3-dioxygenase, reversed the anti-4-1BB effect. We conclude that the suppression of collagen-induced arthritis was caused by an expansion of new CD11c(+)CD8(+) T cells, and that interferon-gamma produced by these cells suppresses antigen-specific CD4(+) T cells through an indoleamine 2,3-dioxygenase-dependent mechanism.", + "TAG_DATA": [ + "51, CD4(+) {'context': 'B-cells'}", + "52, T-cell {'context': 'I-cells'}", + "92, CD11c(+)CD8(+) {'context': 'B-cells'}", + "93, T {'context': 'I-cells'}", + "94, cells {'context': 'I-cells'}", + "101, CD11b(+) {'context': 'B-cells'}", + "102, monocytes {'context': 'I-cells'}", + "104, CD11c(+) {'context': 'B-cells'}", + "105, dendritic {'context': 'I-cells'}", + "106, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "51, CD4(+) ['l0']", + "52, T-cell ['l0']", + "92, CD11c(+)CD8(+) ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "93, T ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "94, cells ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "101, CD11b(+) ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "102, monocytes ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "104, CD11c(+) ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "105, dendritic ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "106, cells. ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15448684", + "TEXT": "Neuromedin U (NMU) is a hypothalamic neuropeptide that regulates body weight and composition. Here we show that mice lacking the gene encoding NMU (Nmu(-/-) mice) develop obesity. Nmu(-/-) mice showed increased body weight and adiposity, hyperphagia, and decreased locomotor activity and energy expenditure. Obese Nmu(-/-) mice developed hyperleptinemia, hyperinsulinemia, late-onset hyperglycemia and hyperlipidemia. Notably, however, treatment with exogenous leptin was effective in reducing body weight in obese Nmu(-/-) mice. In addition, central leptin administration did not affect NMU gene expression in the hypothalamus of rats. These results indicate that NMU plays an important role in the regulation of feeding behavior and energy metabolism independent of the leptin signaling pathway. These characteristic functions of NMU may provide new insight for understanding the pathophysiological basis of obesity.", + "TAG_DATA": [ + "17, mice {'context': 'B-organism'}", + "18, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "19, the {'perturbing_action': 'I-gene loss-of-function'}", + "20, gene {'perturbing_action': 'I-gene loss-of-function'}", + "21, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "22, NMU {'perturbing_action': 'I-gene loss-of-function'}", + "23, (Nmu(-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "24, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "27, Nmu(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "28, mice {'context': 'B-organism'}", + "44, Nmu(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "45, mice {'context': 'B-organism'}", + "66, obese {'perturbing_action': 'B-gene loss-of-function'}", + "67, Nmu(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "68, mice. {'context': 'B-organism'}", + "82, hypothalamus {'context': 'B-tissue/organ'}", + "84, rats. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "17, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "18, lacking ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "19, the ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "20, gene ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "21, encoding ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "22, NMU ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "23, (Nmu(-/-) ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "24, mice) ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "27, Nmu(-/-) ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "28, mice ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "44, Nmu(-/-) ['l45']", + "45, mice ['l45']", + "66, obese ['l46', 'l47']", + "67, Nmu(-/-) ['l46', 'l48']", + "68, mice. ['l47', 'l48']", + "82, hypothalamus ['l49']", + "84, rats. ['l49']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "gene", + "encoding", + "NMU", + "(Nmu(-/-)", + "mice)", + "Nmu(-/-)", + "obese" + ] + } + } + ] + }, + { + "PMID": "15334074", + "TEXT": "Signaling through the second messengers calcium and diacylglycerol (DAG) is a critical element in many biological systems. Integration of calcium and DAG signals has been suggested to occur primarily through protein kinase C family members, which bind both calcium and DAG. However, an alternative pathway may involve members of the CalDAG-GEF/RasGRP protein family, which have structural features (calcium-binding EF hands and DAG-binding C1 domains) that suggest they can function in calcium and DAG signal integration. To gain insight into the signaling systems that may be regulated by CalDAG-GEF/RasGRP family members, we have focused on CalDAG-GEFI, which is expressed preferentially in the brain and blood. Through genetic ablation in the mouse, we have found that CalDAG-GEFI is crucial for signal integration in platelets. Mouse platelets that lack CalDAG-GEFI are severely compromised in integrin-dependent aggregation as a consequence of their inability to signal through CalDAG-GEFI to its target, the small GTPase Rap1. These results suggest that analogous signaling defects are likely to occur in the central nervous system when CalDAG-GEFI is absent or compromised in function.", + "TAG_DATA": [ + "105, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "106, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "109, mouse, {'context': 'B-organism'}", + "122, Mouse {'context': 'B-cells'}", + "123, platelets {'context': 'I-cells'}", + "125, lack {'perturbing_action': 'B-gene loss-of-function'}", + "126, CalDAG-GEFI {'perturbing_action': 'I-gene loss-of-function'}", + "129, compromised {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "105, genetic ['l0', 'l1']", + "106, ablation ['l0', 'l2']", + "109, mouse, ['l1', 'l2']", + "122, Mouse ['l3', 'l4', 'l5', 'l6']", + "123, platelets ['l3', 'l7', 'l8', 'l9']", + "125, lack ['l4', 'l7', 'l10', 'l11']", + "126, CalDAG-GEFI ['l5', 'l8', 'l10', 'l12']", + "129, compromised ['l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Mouse", + "platelets" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "CalDAG-GEFI" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Mouse", + "platelets" + ] + }, + "effect": { + "val": "negative", + "words": [ + "compromised" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "CalDAG-GEFI" + ] + }, + "effect": { + "val": "negative", + "words": [ + "compromised" + ] + } + } + ] + }, + { + "PMID": "15334073", + "TEXT": "The involvement of immune mechanisms in tumor angiogenesis is unclear. Here we describe a new mechanism of tumor vasculogenesis mediated by dendritic cell (DC) precursors through the cooperation of beta-defensins and vascular endothelial growth factor-A (Vegf-A). Expression of mouse beta-defensin-29 recruited DC precursors to tumors and enhanced tumor vascularization and growth in the presence of increased Vegf-A expression. A new leukocyte population expressing DC and endothelial markers was uncovered in mouse and human ovarian carcinomas coexpressing Vegf-A and beta-defensins. Tumor-infiltrating DCs migrated to tumor vessels and independently assembled neovasculature in vivo. Bone marrow-derived DCs underwent endothelial-like differentiation ex vivo, migrated to blood vessels and promoted the growth of tumors expressing high levels of Vegf-A. We show that beta-defensins and Vegf-A cooperate to promote tumor vasculogenesis by carrying out distinct tasks: beta-defensins chemoattract DC precursors through CCR6, whereas Vegf-A primarily induces their endothelial-like specialization and migration to vessels, which is mediated by Vegf receptor-2.", + "TAG_DATA": [ + "36, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "37, of {'perturbing_action': 'I-gene gain-of-function'}", + "38, mouse {'perturbing_action': 'I-gene gain-of-function'}", + "39, beta-defensin-29 {'perturbing_action': 'I-gene gain-of-function'}", + "41, DC {'context': 'B-cells'}", + "42, precursors {'context': 'I-cells'}", + "44, tumors {'context': 'B-neoplasm'}", + "47, tumor {'context': 'B-neoplasm'}", + "80, DCs {'context': 'B-cells'}", + "89, in {'context': 'B-in vivo'}", + "90, vivo. {'context': 'I-in vivo'}", + "91, Bone {'context': 'B-cells'}", + "92, marrow-derived {'context': 'I-cells'}", + "93, DCs {'context': 'I-cells'}", + "108, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "36, Expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "37, of ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "38, mouse ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "39, beta-defensin-29 ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "41, DC ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36']", + "42, precursors ['l4', 'l13', 'l21', 'l28', 'l34', 'l37', 'l38']", + "44, tumors ['l5', 'l14', 'l22', 'l29', 'l35', 'l37', 'l39']", + "47, tumor ['l6', 'l15', 'l23', 'l30', 'l36', 'l38', 'l39']", + "80, DCs ['l7', 'l16', 'l24', 'l31', 'l40', 'l41']", + "89, in ['l8', 'l17', 'l25', 'l32', 'l40', 'l42']", + "90, vivo. ['l9', 'l18', 'l26', 'l33', 'l41', 'l42']", + "91, Bone ['l43', 'l44', 'l45']", + "92, marrow-derived ['l43', 'l46', 'l47']", + "93, DCs ['l44', 'l46', 'l48']", + "108, tumors ['l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "mouse", + "beta-defensin-29" + ] + }, + "context": { + "val": "cells", + "words": [ + "DC", + "precursors", + "DCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "mouse", + "beta-defensin-29" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "mouse", + "beta-defensin-29" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "15322536", + "TEXT": "Regulatory T (T(reg)) cells mediate homeostatic peripheral tolerance by suppressing autoreactive T cells. Failure of host antitumor immunity may be caused by exaggerated suppression of tumor-associated antigen-reactive lymphocytes mediated by T(reg) cells; however, definitive evidence that T(reg) cells have an immunopathological role in human cancer is lacking. Here we show, in detailed studies of CD4(+)CD25(+)FOXP3(+) T(reg) cells in 104 individuals affected with ovarian carcinoma, that human tumor T(reg) cells suppress tumor-specific T cell immunity and contribute to growth of human tumors in vivo. We also show that tumor T(reg) cells are associated with a high death hazard and reduced survival. Human T(reg) cells preferentially move to and accumulate in tumors and ascites, but rarely enter draining lymph nodes in later cancer stages. Tumor cells and microenvironmental macrophages produce the chemokine CCL22, which mediates trafficking of T(reg) cells to the tumor. This specific recruitment of T(reg) cells represents a mechanism by which tumors may foster immune privilege. Thus, blocking T(reg) cell migration or function may help to defeat human cancer.", + "TAG_DATA": [ + "79, human {'context': 'B-neoplasm'}", + "80, tumors {'context': 'I-neoplasm'}", + "81, in {'context': 'B-in vivo'}", + "82, vivo. {'context': 'B-in vivo'}", + "100, Human {'context': 'B-cells'}", + "101, T(reg) {'context': 'I-cells'}", + "102, cells {'context': 'I-cells'}", + "109, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "79, human ['l0', 'l1', 'l2']", + "80, tumors ['l0', 'l3', 'l4']", + "81, in ['l1', 'l3', 'l5']", + "82, vivo. ['l2', 'l4', 'l5']", + "100, Human ['l6', 'l7', 'l8']", + "101, T(reg) ['l6', 'l9', 'l10']", + "102, cells ['l7', 'l9', 'l11']", + "109, tumors ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15311276", + "TEXT": "Thyroid autoimmune disorders comprise more than 30% of all organ-specific autoimmune diseases and are characterized by autoantibodies and infiltrating T cells. The pathologic role of infiltrating T cells is not well defined. To address this issue, we generated transgenic mice expressing a human T-cell receptor derived from the thyroid-infiltrating T cell of a patient with thyroiditis and specific for a cryptic thyroid-peroxidase epitope. Here we show that mouse major histocompatibility complex molecules sustain selection and activation of the transgenic T cells, as coexpression of histocompatibility leukocyte antigen molecules was not needed. Furthermore, the transgenic T cells had an activated phenotype in vivo, and mice spontaneously developed destructive thyroiditis with histological, clinical and hormonal signs comparable with human autoimmune hypothyroidism. These results highlight the pathogenic role of human T cells specific for cryptic self epitopes. This new 'humanized' model will provide a unique tool to investigate how human pathogenic self-reactive T cells initiate autoimmune diseases and to determine how autoimmunity can be modulated in vivo.", + "TAG_DATA": [ + "38, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "39, mice {'context': 'I-organism'}", + "40, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "41, a {'perturbing_action': 'I-gene gain-of-function'}", + "42, human {'perturbing_action': 'I-gene gain-of-function'}", + "43, T-cell {'perturbing_action': 'I-gene gain-of-function'}", + "44, receptor {'perturbing_action': 'I-gene gain-of-function'}", + "79, T {'context': 'B-cells'}", + "80, cells, {'context': 'I-cells'}", + "94, T {'context': 'B-cells'}", + "95, cells {'context': 'I-cells'}", + "100, in {'context': 'B-in vivo'}", + "101, vivo, {'context': 'I-in vivo'}", + "103, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "38, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "39, mice ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "40, expressing ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "41, a ['l2', 'l8', 'l13', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "42, human ['l3', 'l9', 'l14', 'l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "43, T-cell ['l4', 'l10', 'l15', 'l21', 'l26', 'l31', 'l32', 'l33', 'l34']", + "44, receptor ['l5', 'l11', 'l16', 'l22', 'l27', 'l31', 'l35', 'l36', 'l37']", + "45, derived ['l6', 'l12', 'l17', 'l23', 'l28', 'l32', 'l35', 'l38', 'l39']", + "78, transgenic ['l40', 'l41', 'l42']", + "79, T ['l18', 'l24', 'l29', 'l33', 'l36', 'l38', 'l40', 'l43']", + "80, cells, ['l19', 'l25', 'l30', 'l34', 'l37', 'l39', 'l41', 'l43']", + "93, transgenic ['l44', 'l45', 'l46', 'l47']", + "94, T ['l44', 'l48', 'l49', 'l50']", + "95, cells ['l42', 'l45', 'l48', 'l51', 'l52']", + "100, in ['l46', 'l49', 'l51', 'l53']", + "101, vivo, ['l47', 'l50', 'l52', 'l53']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "a", + "human", + "T-cell", + "receptor" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "a", + "human", + "T-cell", + "receptor" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells," + ] + } + } + ] + }, + { + "PMID": "15286784", + "TEXT": "Inhibiting the activity of the beta-amyloid converting enzyme 1 (BACE1) or reducing levels of BACE1 in vivo decreases the production of amyloid-beta. The reticulon family of proteins has four members, RTN1, RTN2, RTN3 and RTN4 (also known as Nogo), the last of which is well known for its role in inhibiting neuritic outgrowth after injury. Here we show that reticulon family members are binding partners of BACE1. In brain, BACE1 mainly colocalizes with RTN3 in neurons, whereas RTN4 is more enriched in oligodendrocytes. An increase in the expression of any reticulon protein substantially reduces the production of Abeta. Conversely, lowering the expression of RTN3 by RNA interference increases the secretion of Abeta, suggesting that reticulon proteins are negative modulators of BACE1 in cells. Our data support a mechanism by which reticulon proteins block access of BACE1 to amyloid precursor protein and reduce the cleavage of this protein. Thus, changes in the expression of reticulon proteins in the human brain are likely to affect cellular amyloid-beta and the formation of amyloid plaques.", + "TAG_DATA": [ + "99, lowering {'perturbing_action': 'B-rnai/knockdown'}", + "100, the {'perturbing_action': 'I-rnai/knockdown'}", + "101, expression {'perturbing_action': 'I-rnai/knockdown'}", + "102, of {'perturbing_action': 'I-rnai/knockdown'}", + "103, RTN3 {'perturbing_action': 'I-rnai/knockdown'}", + "104, by {'perturbing_action': 'I-rnai/knockdown'}", + "105, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "106, interference {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "99, lowering ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "100, the ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "101, expression ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "102, of ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "103, RTN3 ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "104, by ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "105, RNA ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "106, interference ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15258576", + "TEXT": "Allergic asthma is a complex syndrome characterized by airway obstruction, airway inflammation and airway hyper-responsiveness (AHR). Using a mouse model of allergen-induced AHR, we previously demonstrated that CD8-deficient mice develop significantly lower AHR, eosinophilic inflammation and interleukin (IL)-13 levels in bronchoalveolar lavage fluid compared with wild-type mice. These responses were restored by adoptive transfer of antigen-primed CD8(+) T cells. Previously, two distinct populations of antigen-experienced CD8(+) T cells, termed effector (T(EFF)) and central memory (T(CM)) cells, have been described. After adoptive transfer into CD8-deficient mice, T(EFF), but not T(CM), cells restored AHR, eosinophilic inflammation and IL-13 levels. T(EFF), but not T(CM), cells accumulated in the lungs, and intracellular cytokine staining showed that the transferred T(EFF) cells were a source of IL-13. These data suggest an important role for effector CD8(+) T cells in the development of AHR and airway inflammation, which may be associated with their Tc2-type cytokine production and their capacity to migrate into the lung.", + "TAG_DATA": [ + "27, CD8-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "28, mice {'context': 'B-organism'}", + "56, CD8(+) {'context': 'B-cells'}", + "57, T {'context': 'I-cells'}", + "58, cells. {'context': 'I-cells'}", + "83, CD8-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "84, mice, {'context': 'B-organism'}", + "88, T(CM), {'context': 'B-cells'}", + "89, cells {'context': 'I-cells'}", + "100, T(CM), {'context': 'B-cells'}", + "101, cells {'context': 'I-cells'}", + "105, lungs, {'context': 'B-tissue/organ'}", + "114, T(EFF) {'context': 'B-cells'}", + "115, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "27, CD8-deficient ['l0']", + "28, mice ['l0']", + "56, CD8(+) ['l1', 'l2', 'l3', 'l4', 'l5']", + "57, T ['l1', 'l6', 'l7', 'l8']", + "58, cells. ['l2', 'l6']", + "83, CD8-deficient ['l3', 'l9', 'l10', 'l11', 'l12', 'l13']", + "84, mice, ['l4', 'l7', 'l9', 'l14', 'l15']", + "88, T(CM), ['l10', 'l14', 'l16', 'l17', 'l18', 'l19']", + "89, cells ['l5', 'l8', 'l11', 'l15', 'l16']", + "100, T(CM), ['l17', 'l20', 'l21', 'l22', 'l23']", + "101, cells ['l12', 'l18', 'l20', 'l24', 'l25']", + "105, lungs, ['l13', 'l19', 'l21', 'l24', 'l26', 'l27']", + "114, T(EFF) ['l22', 'l26', 'l28']", + "115, cells ['l23', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD8-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "T(CM),", + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD8-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD8-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lungs," + ] + } + } + ] + }, + { + "PMID": "15195088", + "TEXT": "Liver repopulation with bone marrow-derived hepatocytes (BMHs) can cure the genetic liver disease fumarylacetoacetate hydrolase (Fah) deficiency. BMHs emerge from fusion between donor bone marrow-derived cells and host hepatocytes. To use such in vivo cell fusion efficiently for therapy requires knowing the nature of the hematopoietic cells that fuse with hepatocytes. Here we show that the transplantation into Fah(-/-) mice of hematopoietic stem cells (HSCs) from lymphocyte-deficient Rag1(-/-) mice, lineage-committed granulocyte-macrophage progenitors (GMPs) or bone marrow-derived macrophages (BMMs) results in the robust production of BMHs. These results provide direct evidence that committed myelomonocytic cells such as macrophages can produce functional epithelial cells by in vivo fusion. Because stable bone marrow engraftment or HSCs are not required for this process, macrophages or their highly proliferative progenitors provide potential for targeted and well-tolerated cell therapy aimed at organ regeneration.", + "TAG_DATA": [ + "58, Fah(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "59, mice {'context': 'B-organism'}", + "61, hematopoietic {'context': 'B-cells'}", + "62, stem {'context': 'I-cells'}", + "63, cells {'context': 'I-cells'}", + "64, (HSCs) {'context': 'I-cells'}", + "66, lymphocyte-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "67, Rag1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "68, mice, {'context': 'B-organism'}", + "69, lineage-committed {'context': 'B-cells'}", + "70, granulocyte-macrophage {'context': 'I-cells'}", + "71, progenitors {'context': 'I-cells'}", + "72, (GMPs) {'context': 'I-cells'}", + "74, bone {'context': 'B-cells'}", + "75, marrow-derived {'context': 'I-cells'}", + "76, macrophages {'context': 'I-cells'}", + "77, (BMMs) {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "58, Fah(-/-) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "59, mice ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "61, hematopoietic ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "62, stem ['l2', 'l9', 'l15', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "63, cells ['l3', 'l10', 'l16', 'l25', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "64, (HSCs) ['l4', 'l11', 'l17', 'l26', 'l34', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "66, lymphocyte-deficient ['l5', 'l12', 'l18', 'l27', 'l35', 'l42', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "67, Rag1(-/-) ['l6', 'l13', 'l19', 'l28', 'l36', 'l43', 'l49', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "68, mice, ['l7', 'l14', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "69, lineage-committed ['l21', 'l30', 'l38', 'l45', 'l51', 'l56', 'l61', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "70, granulocyte-macrophage ['l22', 'l31', 'l39', 'l46', 'l52', 'l57', 'l62', 'l66', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "71, progenitors ['l23', 'l32', 'l40', 'l47', 'l53', 'l58', 'l63', 'l67', 'l73', 'l79', 'l80', 'l81', 'l82', 'l83']", + "72, (GMPs) ['l24', 'l33', 'l41', 'l48', 'l54', 'l59', 'l64', 'l68', 'l74', 'l79', 'l84', 'l85', 'l86', 'l87']", + "74, bone ['l69', 'l75', 'l80', 'l84', 'l88', 'l89', 'l90']", + "75, marrow-derived ['l70', 'l76', 'l81', 'l85', 'l88', 'l91', 'l92']", + "76, macrophages ['l71', 'l77', 'l82', 'l86', 'l89', 'l91', 'l93']", + "77, (BMMs) ['l60', 'l65', 'l72', 'l78', 'l83', 'l87', 'l90', 'l92', 'l93']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fah(-/-)", + "lymphocyte-deficient", + "Rag1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fah(-/-)", + "lymphocyte-deficient", + "Rag1(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cells", + "(HSCs)", + "lineage-committed", + "granulocyte-macrophage", + "progenitors", + "(GMPs)", + "(BMMs)" + ] + } + } + ] + }, + { + "PMID": "15195086", + "TEXT": "Lysophosphatidic acid (LPA) is a bioactive lipid with activity in the nervous system mediated by G-protein-coupled receptors. Here, we examined the role of LPA signaling in the development of neuropathic pain by pharmacological and genetic approaches, including the use of mice lacking the LPA(1) receptor. Wild-type animals with nerve injury develop behavioral allodynia and hyperalgesia paralleled by demyelination in the dorsal root and increased expression of both the protein kinase C gamma-isoform within the spinal cord dorsal horn and the alpha(2)delta(1) calcium channel subunit in dorsal root ganglia. Intrathecal injection of LPA induced behavioral, morphological and biochemical changes similar to those observed after nerve ligation. In contrast, mice lacking a single LPA receptor (LPA(1), also known as EDG2) that activates the Rho-Rho kinase pathway do not develop signs of neuropathic pain after peripheral nerve injury. Inhibitors of Rho and Rho kinase also prevented these signs of neuropathic pain. These results imply that receptor-mediated LPA signaling is crucial in the initiation of neuropathic pain.", + "TAG_DATA": [ + "41, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "42, the {'perturbing_action': 'I-gene loss-of-function'}", + "43, LPA(1) {'perturbing_action': 'I-gene loss-of-function'}", + "44, receptor. {'perturbing_action': 'I-gene loss-of-function'}", + "46, animals {'context': 'B-organism'}", + "60, dorsal {'context': 'B-tissue/organ'}", + "61, root {'context': 'I-tissue/organ'}", + "77, horn {'context': 'I-tissue/organ'}", + "85, dorsal {'context': 'B-cells'}", + "86, root {'context': 'I-cells'}", + "87, ganglia. {'context': 'I-tissue/organ'}", + "107, mice {'context': 'B-organism'}", + "108, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "109, a {'perturbing_action': 'I-gene loss-of-function'}", + "110, single {'perturbing_action': 'I-gene loss-of-function'}", + "111, LPA {'perturbing_action': 'I-gene loss-of-function'}", + "112, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "113, (LPA(1), {'perturbing_action': 'I-gene loss-of-function'}", + "135, Inhibitors {'perturbing_action': 'B-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "41, lacking ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "42, the ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "43, LPA(1) ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "44, receptor. ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "46, animals ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "60, dorsal ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "61, root ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "74, spinal ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "75, cord ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l69', 'l75', 'l76', 'l77', 'l78', 'l79']", + "76, dorsal ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l70', 'l75', 'l80', 'l81', 'l82', 'l83']", + "77, horn ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l71', 'l76', 'l80', 'l84', 'l85', 'l86']", + "85, dorsal ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l72', 'l77', 'l81', 'l84', 'l87', 'l88']", + "86, root ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l73', 'l78', 'l82', 'l85', 'l87', 'l89']", + "87, ganglia. ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l89']", + "107, mice ['l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "108, lacking ['l90', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "109, a ['l91', 'l96', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "110, single ['l92', 'l97', 'l105', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "111, LPA ['l93', 'l98', 'l106', 'l113', 'l120', 'l121', 'l122', 'l123', 'l124']", + "112, receptor ['l94', 'l99', 'l107', 'l114', 'l120', 'l125', 'l126', 'l127', 'l128']", + "113, (LPA(1), ['l95', 'l100', 'l108', 'l115', 'l121', 'l125', 'l129']", + "135, Inhibitors ['l101', 'l109', 'l116', 'l130', 'l131', 'l132']", + "136, of ['l102', 'l110', 'l117', 'l122', 'l126', 'l130', 'l133', 'l134']", + "137, Rho ['l103', 'l111', 'l118', 'l123', 'l127', 'l131', 'l133', 'l135']", + "140, kinase ['l104', 'l112', 'l119', 'l124', 'l128', 'l129', 'l132', 'l134', 'l135']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "LPA(1)", + "receptor.", + "a", + "single", + "LPA", + "receptor", + "(LPA(1)," + ] + }, + "context": { + "val": "organism", + "words": [ + "animals", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "LPA(1)", + "receptor." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "dorsal", + "root", + "horn", + "ganglia." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "LPA(1)", + "receptor." + ] + }, + "context": { + "val": "cells", + "words": [ + "dorsal", + "root" + ] + } + } + ] + }, + { + "PMID": "15156202", + "TEXT": "Bone destruction is a pathological hallmark of several chronic inflammatory diseases, including rheumatoid arthritis and periodontitis. Inflammation-induced bone loss of this sort results from elevated numbers of bone-resorbing osteoclasts. Gene targeting studies have shown that the transcription factor nuclear factor-kappa B (NF-kappa B) has a crucial role in osteoclast differentiation, and blocking NF-kappa B is a potential strategy for preventing inflammatory bone resorption. We tested this approach using a cell-permeable peptide inhibitor of the I kappa B-kinase complex, a crucial component of signal transduction pathways to NF-kappa B. The peptide inhibited RANKL-stimulated NF-kappa B activation and osteoclastogenesis both in vitro and in vivo. In addition, this peptide significantly reduced the severity of collagen-induced arthritis in mice by reducing levels of tumor necrosis factor-alpha and interleukin-1 beta, abrogating joint swelling and reducing destruction of bone and cartilage. Therefore, selective inhibition of NF-kappa B activation offers an effective therapeutic approach for inhibiting chronic inflammatory diseases involving bone resorption.", + "TAG_DATA": [ + "98, in {'context': 'B-in vitro'}", + "99, vitro {'context': 'I-in vitro'}", + "101, in {'context': 'B-in vivo'}", + "102, vivo. {'context': 'I-in vivo'}", + "115, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "98, in ['l0', 'l1']", + "99, vitro ['l0', 'l2']", + "101, in ['l3']", + "102, vivo. ['l1', 'l2', 'l3']", + "115, mice ['l4']", + "127, joint ['l4']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15107844", + "TEXT": "Insulin resistance is a major hallmark in the development of type 2 diabetes, which is characterized by an impaired ability of insulin to inhibit glucose output from the liver and to promote glucose uptake in muscle. The nuclear hormone receptor coactivator PGC-1 (peroxisome proliferator-activated (PPAR)-gamma coactivator-1) has been implicated in the onset of type 2 diabetes. Hepatic PGC-1 expression is elevated in mouse models of this disease, where it promotes constitutive activation of gluconeogenesis and fatty acid oxidation through its association with the nuclear hormone receptors HNF-4 and PPAR-alpha, respectively. Here we show that PGC-1-deficient mice, generated by adenoviral delivery of PGC-1 RNA interference (RNAi) to the liver, experience fasting hypoglycemia. Hepatic insulin sensitivity was enhanced in PGC-1-deficient mice, reflecting in part the reduced expression of the mammalian tribbles homolog TRB-3, a fasting-inducible inhibitor of the serine-threonine kinase Akt/PKB (ref. 6). We show here that, in the liver, TRB-3 is a target for PPAR-alpha. Knockdown of hepatic TRB-3 expression improved glucose tolerance, whereas hepatic overexpression of TRB-3 reversed the insulin-sensitive phenotype of PGC-1-deficient mice. These results indicate a link between nuclear hormone receptor and insulin signaling pathways, and suggest a potential role for TRB-3 inhibitors in the treatment of type 2 diabetes.", + "TAG_DATA": [ + "94, PGC-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "95, mice, {'context': 'B-organism'}", + "98, adenoviral {'perturbing_action': 'B-rnai/knockdown'}", + "99, delivery {'perturbing_action': 'I-rnai/knockdown'}", + "100, of {'perturbing_action': 'I-rnai/knockdown'}", + "101, PGC-1 {'perturbing_action': 'I-rnai/knockdown'}", + "102, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "103, interference {'perturbing_action': 'I-rnai/knockdown'}", + "104, (RNAi) {'perturbing_action': 'I-rnai/knockdown'}", + "105, to {'perturbing_action': 'I-rnai/knockdown'}", + "107, liver, {'context': 'B-tissue/organ'}", + "117, PGC-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "118, mice, {'context': 'B-organism'}", + "154, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "155, of {'perturbing_action': 'I-rnai/knockdown'}", + "156, hepatic {'perturbing_action': 'I-rnai/knockdown'}", + "157, TRB-3 {'perturbing_action': 'I-rnai/knockdown'}", + "158, expression {'perturbing_action': 'I-rnai/knockdown'}", + "163, hepatic {'perturbing_action': 'B-gene gain-of-function'}", + "164, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "165, of {'perturbing_action': 'I-gene gain-of-function'}", + "166, TRB-3 {'perturbing_action': 'I-gene gain-of-function'}", + "172, PGC-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "173, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "94, PGC-1-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "95, mice, ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "98, adenoviral ['l1', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "99, delivery ['l2', 'l11', 'l17', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "100, of ['l3', 'l12', 'l18', 'l26', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "101, PGC-1 ['l4', 'l19', 'l27', 'l34', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "102, RNA ['l5', 'l20', 'l28', 'l35', 'l41', 'l48', 'l49', 'l50', 'l51', 'l52']", + "103, interference ['l6', 'l21', 'l29', 'l36', 'l42', 'l48', 'l53', 'l54', 'l55', 'l56']", + "104, (RNAi) ['l7', 'l13', 'l22', 'l30', 'l37', 'l43', 'l49', 'l53', 'l57', 'l58', 'l59']", + "105, to ['l8', 'l14', 'l23', 'l31', 'l38', 'l44', 'l50', 'l54', 'l57', 'l60', 'l61']", + "106, the ['l9', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l55', 'l58', 'l60', 'l62']", + "107, liver, ['l10', 'l16', 'l25', 'l33', 'l40', 'l46', 'l52', 'l56', 'l59', 'l61', 'l62']", + "117, PGC-1-deficient ['l63', 'l64', 'l65', 'l66']", + "118, mice, ['l47', 'l63']", + "154, Knockdown ['l67', 'l68', 'l69', 'l70']", + "155, of ['l67', 'l71', 'l72', 'l73']", + "156, hepatic ['l64', 'l68', 'l71', 'l74', 'l75']", + "157, TRB-3 ['l65', 'l69', 'l72', 'l74', 'l76']", + "158, expression ['l66', 'l70', 'l73', 'l75', 'l76']", + "163, hepatic ['l77', 'l78', 'l79', 'l80', 'l81']", + "164, overexpression ['l77', 'l82', 'l83', 'l84', 'l85']", + "165, of ['l78', 'l82', 'l86', 'l87', 'l88']", + "166, TRB-3 ['l79', 'l83', 'l86', 'l89', 'l90']", + "172, PGC-1-deficient ['l80', 'l84', 'l87', 'l89', 'l91']", + "173, mice. ['l81', 'l85', 'l88', 'l90', 'l91']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PGC-1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PGC-1-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "delivery", + "of", + "(RNAi)", + "to", + "PGC-1" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "adenoviral", + "delivery", + "of", + "PGC-1", + "RNA", + "interference", + "(RNAi)", + "to" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hepatic", + "overexpression", + "of", + "TRB-3" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "15107841", + "TEXT": "Recent studies have suggested that bone marrow cells might possess a much broader differentiation potential than previously appreciated. In most cases, the reported efficiency of such plasticity has been rather low and, at least in some instances, is a consequence of cell fusion. After myocardial infarction, however, bone marrow cells have been suggested to extensively regenerate cardiomyocytes through transdifferentiation. Although bone marrow-derived cells are already being used in clinical trials, the exact identity, longevity and fate of these cells in infarcted myocardium have yet to be investigated in detail. Here we use various approaches to induce acute myocardial injury and deliver transgenically marked bone marrow cells to the injured myocardium. We show that unfractionated bone marrow cells and a purified population of hematopoietic stem and progenitor cells efficiently engraft within the infarcted myocardium. Engraftment was transient, however, and hematopoietic in nature. In contrast, bone marrow-derived cardiomyocytes were observed outside the infarcted myocardium at a low frequency and were derived exclusively through cell fusion.", + "TAG_DATA": [ + "114, bone {'context': 'I-cells'}", + "115, marrow {'context': 'I-cells'}", + "116, cells {'context': 'I-cells'}", + "120, population {'context': 'I-cells'}", + "122, hematopoietic {'context': 'B-cells'}", + "123, stem {'context': 'I-cells'}", + "124, and {'context': 'I-cells'}", + "125, progenitor {'context': 'I-cells'}", + "126, cells {'context': 'I-cells'}", + "143, bone {'context': 'B-cells'}", + "144, marrow-derived {'context': 'I-cells'}", + "145, cardiomyocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "114, bone ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "115, marrow ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "116, cells ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19']", + "120, population ['l2', 'l9', 'l20', 'l21', 'l22', 'l23', 'l24']", + "122, hematopoietic ['l3', 'l10', 'l15', 'l20', 'l25', 'l26', 'l27', 'l28']", + "123, stem ['l4', 'l11', 'l16', 'l21', 'l25', 'l29', 'l30', 'l31']", + "124, and ['l5', 'l12', 'l17', 'l22', 'l26', 'l29', 'l32', 'l33']", + "125, progenitor ['l6', 'l13', 'l18', 'l23', 'l27', 'l30', 'l32', 'l34']", + "126, cells ['l7', 'l14', 'l19', 'l24', 'l28', 'l31', 'l33', 'l34']", + "143, bone ['l35', 'l36']", + "144, marrow-derived ['l35', 'l37']", + "145, cardiomyocytes ['l36', 'l37']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15098029", + "TEXT": "The mammalian target of rapamycin, mTOR, regulates cell growth and proliferation. Here we show that the initiation factor of translation (eIF-4E), a downstream effector of mTOR, has oncogenic effects in vivo and cooperates with c-Myc in B-cell lymphomagenesis. We found that c-Myc overrides eIF-4E-induced cellular senescence, whereas eIF-4E antagonizes c-Myc-dependent apoptosis in vivo. Our results implicate activation of eIF-4E as a key event in oncogenic transformation by phosphoinositide-3 kinase and Akt.", + "TAG_DATA": [ + "42, overrides {'effect': 'B-negative'}", + "43, eIF-4E-induced {'effect': 'B-positive'}", + "45, senescence, {'phenotype': 'B-senescence'}", + "48, antagonizes {'effect': 'B-negative'}", + "49, c-Myc-dependent {'effect': 'B-regulates'}", + "50, apoptosis {'phenotype': 'B-apoptosis'}", + "51, in {'context': 'B-in vivo'}", + "52, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "42, overrides ['l0', 'l1']", + "43, eIF-4E-induced ['l0', 'l2']", + "45, senescence, ['l1', 'l2']", + "48, antagonizes ['l3', 'l4', 'l5', 'l6']", + "49, c-Myc-dependent ['l3', 'l7', 'l8', 'l9']", + "50, apoptosis ['l4', 'l7', 'l10', 'l11']", + "51, in ['l5', 'l8', 'l10', 'l12']", + "52, vivo. ['l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "overrides" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "eIF-4E-induced" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "antagonizes" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "antagonizes" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "c-Myc-dependent" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "c-Myc-dependent" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "15098028", + "TEXT": "Skin is the most commonly affected organ in graft-versus-host disease (GVHD). To explore the role of Langerhans cells in GVHD, the principal dendritic cells of the skin, we studied the fate of these cells in mice transplanted with allogeneic bone marrow. In contrast to other dendritic cells, host Langerhans cells were replaced by donor Langerhans cells only when donor T cells were administered along with bone marrow, and the extent of Langerhans cell chimerism correlated with the dose of donor T cells injected. Donor T cells depleted host Langerhans cells through a Fas-dependent pathway and induced the production in skin of CCL20, which was required for the recruitment of donor Langerhans cells. Administration of donor T cells to bone marrow-chimeric mice with persistent host Langerhans cells, but not to mice whose Langerhans cells had been replaced, resulted in marked skin GVHD. These findings indicate a crucial role for donor T cells in host Langerhans cell replacement, and show that host dendritic cells can persist in nonlymphoid tissue for the duration of an animal's life and can trigger GVHD despite complete blood chimerism.", + "TAG_DATA": [ + "35, mice {'context': 'B-organism'}", + "47, host {'context': 'B-cells'}", + "48, Langerhans {'context': 'I-cells'}", + "49, cells {'context': 'I-cells'}", + "53, donor {'context': 'B-cells'}", + "54, Langerhans {'context': 'I-cells'}", + "55, cells {'context': 'I-cells'}", + "84, T {'context': 'I-cells'}", + "87, host {'context': 'B-cells'}", + "88, Langerhans {'context': 'B-cells'}", + "89, cells {'context': 'I-cells'}", + "99, skin {'context': 'B-tissue/organ'}", + "114, donor {'context': 'B-cells'}", + "115, T {'context': 'I-cells'}", + "116, cells {'context': 'I-cells'}", + "118, bone {'context': 'B-organism'}", + "119, marrow-chimeric {'context': 'I-organism'}", + "120, mice {'context': 'I-organism'}", + "123, host {'context': 'B-cells'}", + "124, Langerhans {'context': 'I-cells'}", + "125, cells, {'context': 'I-cells'}", + "129, mice {'context': 'B-organism'}", + "131, Langerhans {'context': 'B-cells'}", + "132, cells {'context': 'I-cells'}", + "139, skin {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "35, mice ['l0', 'l1']", + "47, host ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "48, Langerhans ['l2', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "49, cells ['l0', 'l3', 'l11', 'l19', 'l20', 'l21', 'l22']", + "53, donor ['l4', 'l12', 'l19', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "54, Langerhans ['l5', 'l13', 'l20', 'l23', 'l29', 'l30', 'l31', 'l32', 'l33']", + "55, cells ['l1', 'l6', 'l14', 'l21', 'l24', 'l29', 'l34', 'l35']", + "84, T ['l36', 'l37', 'l38', 'l39']", + "87, host ['l7', 'l15', 'l25', 'l30', 'l36', 'l40', 'l41', 'l42']", + "88, Langerhans ['l8', 'l16', 'l26', 'l31', 'l37', 'l40', 'l43', 'l44']", + "89, cells ['l9', 'l17', 'l22', 'l27', 'l32', 'l34', 'l38', 'l41', 'l43', 'l45']", + "99, skin ['l10', 'l18', 'l28', 'l33', 'l35', 'l39', 'l42', 'l44', 'l45']", + "114, donor ['l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "115, T ['l46', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "116, cells ['l47', 'l58', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "118, bone ['l48', 'l59', 'l68', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "119, marrow-chimeric ['l49', 'l60', 'l69', 'l76', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "120, mice ['l50', 'l61', 'l70', 'l77', 'l84', 'l90', 'l91', 'l92', 'l93']", + "123, host ['l51', 'l62', 'l71', 'l78', 'l85', 'l90', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "124, Langerhans ['l52', 'l63', 'l72', 'l79', 'l86', 'l91', 'l94', 'l100', 'l101', 'l102', 'l103', 'l104']", + "125, cells, ['l53', 'l64', 'l73', 'l80', 'l87', 'l92', 'l95', 'l100', 'l105', 'l106']", + "129, mice ['l54', 'l65', 'l81', 'l96', 'l101', 'l107', 'l108', 'l109']", + "131, Langerhans ['l55', 'l97', 'l102', 'l107', 'l110', 'l111']", + "132, cells ['l56', 'l66', 'l74', 'l82', 'l88', 'l98', 'l103', 'l105', 'l108', 'l110', 'l112']", + "139, skin ['l57', 'l67', 'l75', 'l83', 'l89', 'l93', 'l99', 'l104', 'l106', 'l109', 'l111', 'l112']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15077107", + "TEXT": "Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene result in defective epithelial cAMP-dependent Cl(-) secretion and increased airway Na(+) absorption. The mechanistic links between these altered ion transport processes and the pathogenesis of cystic fibrosis lung disease, however, are unclear. To test the hypothesis that accelerated Na(+) transport alone can produce cystic fibrosis-like lung disease, we generated mice with airway-specific overexpression of epithelial Na(+) channels (ENaC). Here we show that increased airway Na(+) absorption in vivo caused airway surface liquid (ASL) volume depletion, increased mucus concentration, delayed mucus transport and mucus adhesion to airway surfaces. Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation and poor bacterial clearance. We conclude that increasing airway Na(+) absorption initiates cystic fibrosis-like lung disease and produces a model for the study of the pathogenesis and therapy of this disease.", + "TAG_DATA": [ + "59, mice {'context': 'B-organism'}", + "61, airway-specific {'perturbing_action': 'B-gene gain-of-function'}", + "62, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "63, of {'perturbing_action': 'I-gene gain-of-function'}", + "64, epithelial {'perturbing_action': 'I-gene gain-of-function'}", + "65, Na(+) {'perturbing_action': 'I-gene gain-of-function'}", + "66, channels {'perturbing_action': 'I-gene gain-of-function'}", + "67, (ENaC). {'perturbing_action': 'I-gene gain-of-function'}", + "76, in {'context': 'B-in vivo'}", + "77, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "59, mice ['l0', 'l1', 'l2']", + "61, airway-specific ['l0', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "62, overexpression ['l3', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "63, of ['l4', 'l11', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "64, epithelial ['l5', 'l12', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "65, Na(+) ['l6', 'l13', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32']", + "66, channels ['l7', 'l14', 'l20', 'l25', 'l29', 'l33', 'l34', 'l35']", + "67, (ENaC). ['l8', 'l15', 'l21', 'l26', 'l30', 'l33', 'l36', 'l37']", + "76, in ['l1', 'l9', 'l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l38']", + "77, vivo ['l2', 'l10', 'l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "airway-specific" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "airway-specific", + "overexpression", + "of", + "epithelial", + "Na(+)", + "channels", + "(ENaC)." + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "15034574", + "TEXT": "Three human coronaviruses are known to exist: human coronavirus 229E (HCoV-229E), HCoV-OC43 and severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV). Here we report the identification of a fourth human coronavirus, HCoV-NL63, using a new method of virus discovery. The virus was isolated from a 7-month-old child suffering from bronchiolitis and conjunctivitis. The complete genome sequence indicates that this virus is not a recombinant, but rather a new group 1 coronavirus. The in vitro host cell range of HCoV-NL63 is notable because it replicates on tertiary monkey kidney cells and the monkey kidney LLC-MK2 cell line. The viral genome contains distinctive features, including a unique N-terminal fragment within the spike protein. Screening of clinical specimens from individuals suffering from respiratory illness identified seven additional HCoV-NL63-infected individuals, indicating that the virus was widely spread within the human population.", + "TAG_DATA": [ + "85, monkey {'context': 'I-cells'}", + "86, kidney {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}", + "90, monkey {'context': 'B-cells'}", + "91, kidney {'context': 'I-cells'}", + "92, LLC-MK2 {'context': 'I-cells'}", + "93, cell {'context': 'I-cells'}", + "94, line. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "85, monkey ['l0', 'l1', 'l2', 'l3']", + "86, kidney ['l0', 'l4', 'l5', 'l6']", + "87, cells ['l1', 'l4']", + "90, monkey ['l7', 'l8', 'l9', 'l10']", + "91, kidney ['l7', 'l11', 'l12', 'l13']", + "92, LLC-MK2 ['l8', 'l11', 'l14', 'l15']", + "93, cell ['l2', 'l5', 'l9', 'l12', 'l14', 'l16']", + "94, line. ['l3', 'l6', 'l10', 'l13', 'l15', 'l16']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "15034567", + "TEXT": "Many human T-cell responses specific for epitopes in Plasmodium falciparum have been described, but none has yet been shown to be predictive of protection against natural malaria infection. Here we report a peptide-specific T-cell assay that is strongly associated with protection of humans in The Gambia, West Africa, from both malaria infection and disease. The assay detects interferon-gamma-secreting CD4(+) T cells specific for a conserved sequence from the circumsporozoite protein, which binds to many human leukocyte antigen (HLA)-DR types. The correlation was observed using a cultured, rather than an ex vivo, ELISPOT assay that measures central memory-'type T cells rather than activated effector T cells. These findings provide direct evidence for a protective role for CD4(+) T cells in humans, and a precise target for the design of improved vaccines against P. falciparum.", + "TAG_DATA": [ + "58, CD4(+) {'context': 'B-cells'}", + "59, T {'context': 'I-cells'}", + "60, cells {'context': 'I-cells'}", + "97, T {'context': 'B-cells'}", + "98, cells {'context': 'I-cells'}", + "102, effector {'context': 'B-cells'}", + "103, T {'context': 'I-cells'}", + "104, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "58, CD4(+) ['l0', 'l1']", + "59, T ['l0', 'l2']", + "60, cells ['l1', 'l2']", + "97, T ['l3', 'l4', 'l5', 'l6']", + "98, cells ['l3', 'l7', 'l8', 'l9']", + "102, effector ['l4', 'l7', 'l10', 'l11']", + "103, T ['l5', 'l8', 'l10', 'l12']", + "104, cells. ['l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14981514", + "TEXT": "Cancers express antigens that are targets for specific cytotoxic T lymphocytes (CTLs). However, cancer cells are genetically unstable. Consequently, sub-populations of cancer cells that no longer express the target antigen may escape destruction by CTLs and grow progressively. We show that cytotoxic T cells indirectly eliminate these antigen loss variants (ALVs) in a model system when the parental cancer cells express sufficient antigen to be effectively cross-presented by the tumor stroma. When the parental tumor expressed lower levels of antigen, cytotoxic T cells eradicated the antigen-positive parental cancer cells, but the ALVs escaped, grew and killed the host. By contrast, when the parental tumor expressed higher levels of antigen, cytotoxic T cells eradicated not only the parental cancer cells but also the ALVs. This 'bystander' elimination of ALVs required stromal cells expressing major histocompatibility complex (MHC) molecules capable of presenting the antigen, and occurred in tumors showing evidence of stromal destruction. ALVs were apparently eliminated indirectly when tumor-specific CTLs killed stromal cells that were cross-presenting antigen produced by and released from antigen-positive cancer cells. These results highlight the general importance of targeting the tumor stroma to prevent the escape of variant cancer cells.", + "TAG_DATA": [ + "85, antigen-positive {'context': 'B-transformed cells'}", + "86, parental {'context': 'I-transformed cells'}", + "87, cancer {'context': 'I-transformed cells'}", + "88, cells, {'context': 'I-transformed cells'}", + "102, parental {'context': 'B-neoplasm'}", + "103, tumor {'context': 'I-neoplasm'}", + "116, parental {'context': 'B-transformed cells'}", + "117, cancer {'context': 'I-transformed cells'}", + "118, cells {'context': 'I-transformed cells'}", + "129, stromal {'context': 'B-cells'}", + "130, cells {'context': 'I-cells'}", + "145, tumors {'context': 'B-neoplasm'}", + "160, stromal {'context': 'B-cells'}", + "161, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "74, tumor ['l0', 'l1', 'l2', 'l3']", + "85, antigen-positive ['l0', 'l4', 'l5', 'l6']", + "86, parental ['l1', 'l4', 'l7', 'l8']", + "87, cancer ['l2', 'l5', 'l7', 'l9']", + "88, cells, ['l3', 'l6', 'l8', 'l9']", + "102, parental ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "103, tumor ['l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "116, parental ['l11', 'l16', 'l21', 'l22', 'l23']", + "117, cancer ['l12', 'l17', 'l21', 'l24']", + "118, cells ['l13', 'l18', 'l22', 'l24']", + "129, stromal ['l14', 'l19', 'l25', 'l26']", + "130, cells ['l15', 'l20', 'l23', 'l25', 'l27']", + "145, tumors ['l26', 'l27']", + "160, stromal ['l28']", + "161, cells ['l28']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14981511", + "TEXT": "The primary cause of severe acute respiratory syndrome (SARS) is a newly discovered coronavirus. Replication of this SARS coronavirus (SCV) occurs mainly in the lower respiratory tract, and causes diffuse alveolar damage. Lack of understanding of the pathogenesis of SARS has prevented the rational development of a therapy against this disease. Here we show extensive SCV antigen expression in type 1 pneumocytes of experimentally infected cynomolgus macaques (Macaca fascicularis) at 4 d postinfection (d.p.i.), indicating that this cell type is the primary target for SCV infection early in the disease, and explaining the subsequent pulmonary damage. We also show that prophylactic treatment of SCV-infected macaques with the antiviral agent pegylated interferon-alpha (IFN-alpha) significantly reduces viral replication and excretion, viral antigen expression by type 1 pneumocytes and pulmonary damage, compared with untreated macaques. Postexposure treatment with pegylated IFN-alpha yielded intermediate results. We therefore suggest that pegylated IFN-alpha protects type 1 pneumocytes from SCV infection, and should be considered a candidate drug for SARS therapy.", + "TAG_DATA": [ + "65, cynomolgus {'context': 'B-organism'}", + "66, macaques {'context': 'I-organism'}", + "67, (Macaca {'context': 'I-organism'}", + "68, fascicularis) {'context': 'I-organism'}", + "104, macaques {'context': 'B-organism'}", + "122, type {'context': 'B-cells'}", + "123, 1 {'context': 'B-cells'}", + "124, pneumocytes {'context': 'I-cells'}", + "131, macaques. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "65, cynomolgus ['l0', 'l1', 'l2']", + "66, macaques ['l0', 'l3', 'l4']", + "67, (Macaca ['l1', 'l3', 'l5']", + "68, fascicularis) ['l2', 'l4', 'l5']", + "104, macaques ['l6', 'l7', 'l8']", + "122, type ['l6', 'l9', 'l10']", + "123, 1 ['l7', 'l9', 'l11']", + "124, pneumocytes ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14770175", + "TEXT": "Within-patient HIV evolution reflects the strong selection pressure driving viral escape from cytotoxic T-lymphocyte (CTL) recognition. Whether this intrapatient accumulation of escape mutations translates into HIV evolution at the population level has not been evaluated. We studied over 300 patients drawn from the B- and C-clade epidemics, focusing on human leukocyte antigen (HLA) alleles HLA-B57 and HLA-B5801, which are associated with long-term HIV control and are therefore likely to exert strong selection pressure on the virus. The CTL response dominating acute infection in HLA-B57/5801-positive subjects drove positive selection of an escape mutation that reverted to wild-type after transmission to HLA-B57/5801-negative individuals. A second escape mutation within the epitope, by contrast, was maintained after transmission. These data show that the process of accumulation of escape mutations within HIV is not inevitable. Complex epitope- and residue-specific selection forces, including CTL-mediated positive selection pressure and virus-mediated purifying selection, operate in tandem to shape HIV evolution at the population level.", + "TAG_DATA": [ + "99, HLA-B57/5801-negative {'perturbing_action': 'B-gene loss-of-function'}" + ], + "LINK_DATA": [ + "99, HLA-B57/5801-negative ['l0']", + "100, individuals. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14704790", + "TEXT": "Platelet-activating factor (PAF) induces pulmonary edema and has a key role in acute lung injury (ALI). Here we show that PAF induces pulmonary edema through two mechanisms: acid sphingomyelinase (ASM)-dependent production of ceramide, and activation of the cyclooxygenase pathway. Agents that interfere with PAF-induced ceramide synthesis, such as steroids or the xanthogenate D609, attenuate pulmonary edema formation induced by PAF, endotoxin or acid instillation. Our results identify acid sphingomyelinase and ceramide as possible therapeutic targets in acute lung injury.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "14702637", + "TEXT": "Achondroplasia is the most common genetic form of human dwarfism, for which there is presently no effective therapy. C-type natriuretic peptide (CNP) is a newly identified molecule that regulates endochondral bone growth through GC-B, a subtype of particulate guanylyl cyclase. Here we show that targeted overexpression of CNP in chondrocytes counteracts dwarfism in a mouse model of achondroplasia with activated fibroblast growth factor receptor 3 (FGFR-3) in the cartilage. CNP prevented the shortening of achondroplastic bones by correcting the decreased extracellular matrix synthesis in the growth plate through inhibition of the MAPK pathway of FGF signaling. CNP had no effect on the STAT-1 pathway of FGF signaling that mediates the decreased proliferation and the delayed differentiation of achondroplastic chondrocytes. These results demonstrate that activation of the CNP-GC-B system in endochondral bone formation constitutes a new therapeutic strategy for human achondroplasia.", + "TAG_DATA": [ + "44, targeted {'perturbing_action': 'B-gene gain-of-function'}", + "45, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "46, of {'perturbing_action': 'I-gene gain-of-function'}", + "47, CNP {'perturbing_action': 'I-gene gain-of-function'}", + "49, chondrocytes {'context': 'B-cells'}", + "54, mouse {'context': 'B-organism'}", + "55, model {'context': 'I-organism'}", + "75, bones {'context': 'I-tissue/organ'}", + "110, decreased {'effect': 'B-negative'}", + "111, proliferation {'phenotype': 'B-proliferation'}", + "114, delayed {'effect': 'B-negative'}", + "115, differentiation {'phenotype': 'B-differentiation'}", + "117, achondroplastic {'context': 'B-cells'}", + "118, chondrocytes. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "44, targeted ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "45, overexpression ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "46, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "47, CNP ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "49, chondrocytes ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "54, mouse ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "55, model ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "56, of ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "74, achondroplastic ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "75, bones ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "110, decreased ['l45', 'l46', 'l47', 'l48', 'l49']", + "111, proliferation ['l45', 'l50', 'l51', 'l52', 'l53']", + "114, delayed ['l46', 'l50', 'l54', 'l55', 'l56']", + "115, differentiation ['l47', 'l51', 'l54', 'l57', 'l58']", + "117, achondroplastic ['l48', 'l52', 'l55', 'l57', 'l59']", + "118, chondrocytes. ['l49', 'l53', 'l56', 'l58', 'l59']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "targeted", + "overexpression", + "of", + "CNP" + ] + }, + "context": { + "val": "cells", + "words": [ + "chondrocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "targeted", + "overexpression", + "of", + "CNP" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "targeted", + "overexpression", + "of", + "CNP" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "bones" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased", + "delayed" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased", + "delayed" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased", + "delayed" + ] + }, + "context": { + "val": "cells", + "words": [ + "achondroplastic", + "chondrocytes." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "achondroplastic", + "chondrocytes." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "achondroplastic", + "chondrocytes." + ] + } + } + ] + }, + { + "PMID": "14702634", + "TEXT": "Although tumor progression involves processes such as tissue invasion that can activate inflammatory responses, the immune system largely ignores or tolerates disseminated cancers. The mechanisms that block initiation of immune responses during cancer development are poorly understood. We report here that constitutive activation of Stat-3, a common oncogenic signaling pathway, suppresses tumor expression of proinflammatory mediators. Blocking Stat-3 in tumor cells increases expression of proinflammatory cytokines and chemokines that activate innate immunity and dendritic cells, leading to tumor-specific T-cell responses. In addition, constitutive Stat-3 activity induces production of pleiotropic factors that inhibit dendritic cell functional maturation. Tumor-derived factors inhibit dendritic cell maturation through Stat-3 activation in progenitor cells. Thus, inhibition of antitumor immunity involves a cascade of Stat-3 activation propagating from tumor to dendritic cells. We propose that tumor Stat-3 activity can mediate immune evasion by blocking both the production and sensing of inflammatory signals by multiple components of the immune system.", + "TAG_DATA": [ + "41, constitutive {'perturbing_action': 'B-gene gain-of-function'}", + "42, activation {'perturbing_action': 'I-gene gain-of-function'}", + "43, of {'perturbing_action': 'I-gene gain-of-function'}", + "44, Stat-3, {'perturbing_action': 'I-gene gain-of-function'}", + "56, Blocking {'perturbing_action': 'B-pharmacological inhibition'}", + "57, Stat-3 {'perturbing_action': 'I-pharmacological inhibition'}", + "59, tumor {'context': 'B-transformed cells'}", + "60, cells {'context': 'I-transformed cells'}", + "82, constitutive {'perturbing_action': 'B-gene gain-of-function'}", + "83, Stat-3 {'perturbing_action': 'I-gene gain-of-function'}", + "84, activity {'perturbing_action': 'I-gene gain-of-function'}", + "92, dendritic {'context': 'B-cells'}", + "93, cell {'context': 'I-cells'}", + "99, dendritic {'context': 'B-cells'}", + "100, cell {'context': 'I-cells'}", + "106, progenitor {'context': 'B-cells'}", + "107, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "41, constitutive ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "42, activation ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "43, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "44, Stat-3, ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "56, Blocking ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "57, Stat-3 ['l4', 'l11', 'l17', 'l22', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37']", + "59, tumor ['l5', 'l12', 'l18', 'l23', 'l27', 'l33', 'l38', 'l39']", + "60, cells ['l6', 'l13', 'l19', 'l24', 'l28', 'l34', 'l38']", + "82, constitutive ['l40', 'l41', 'l42', 'l43']", + "83, Stat-3 ['l29', 'l40', 'l44', 'l45', 'l46']", + "84, activity ['l30', 'l35', 'l41', 'l44', 'l47', 'l48']", + "92, dendritic ['l31', 'l36', 'l42', 'l45', 'l47', 'l49']", + "93, cell ['l7', 'l14', 'l20', 'l25', 'l32', 'l37', 'l39', 'l43', 'l46', 'l48', 'l49']", + "99, dendritic ['l50', 'l51', 'l52']", + "100, cell ['l50', 'l53', 'l54']", + "106, progenitor ['l51', 'l53', 'l55']", + "107, cells. ['l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutive", + "activation", + "of", + "Stat-3," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutive", + "activation", + "of", + "Stat-3,", + "Stat-3", + "activity" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "dendritic" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blocking", + "Stat-3" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blocking", + "Stat-3" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cell" + ] + } + } + ] + }, + { + "PMID": "14625545", + "TEXT": "Pathogens or pathogen-associated molecular patterns can signal to cells of the innate immune system and trigger effective adaptive immunity. However, relatively little is known about how the innate immune system detects tissue injury or necrosis. Evidence suggests that the release of heat-shock proteins (HSPs) may provide adjuvant-like signals, but the ability of HSPs to promote activation or tolerance in vivo has not been addressed. In this study we show that Hsp70 promotes dendritic cell (DC) function and, together with antigen, triggers autoimmune disease in vivo.", + "TAG_DATA": [ + "72, dendritic {'context': 'B-cells'}", + "73, cell {'context': 'I-cells'}", + "74, (DC) {'context': 'I-cells'}", + "83, in {'context': 'B-in vivo'}", + "84, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "72, dendritic ['l0', 'l1', 'l2', 'l3']", + "73, cell ['l0', 'l4', 'l5', 'l6']", + "74, (DC) ['l1', 'l4', 'l7', 'l8']", + "83, in ['l2', 'l5', 'l7', 'l9']", + "84, vivo. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14625543", + "TEXT": "Cells from adult bone marrow participate in the regeneration of damaged skeletal myofibers. However, the relationship of these cells with the various hematopoietic and nonhematopoietic cell types found in bone marrow is still unclear. Here we show that the progeny of a single cell can both reconstitute the hematopoietic system and contribute to muscle regeneration. Integration of bone marrow cells into myofibers occurs spontaneously at low frequency and increases with muscle damage. Thus, classically defined single hematopoietic stem cells can give rise to both blood and muscle.", + "TAG_DATA": [ + "57, bone {'context': 'B-cells'}", + "58, marrow {'context': 'I-cells'}", + "59, cells {'context': 'I-cells'}", + "61, myofibers {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "57, bone ['l0', 'l1', 'l2']", + "58, marrow ['l0', 'l3', 'l4']", + "59, cells ['l1', 'l3', 'l5']", + "61, myofibers ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14578881", + "TEXT": "Hematopoietic stem cells (HSCs) can self-renew extensively after transplantation. The conditions supporting their in vitro expansion are still being defined. Retroviral overexpression of the human homeobox B4 (HOXB4) gene in mouse bone marrow cells enables over 40-fold expansion of HSCs in vitro. To circumvent the requirement for retroviral infection, we used recombinant human TAT-HOXB4 protein carrying the protein transduction domain of the HIV transactivating protein (TAT) as a potential growth factor for stem cells. HSCs exposed to TAT-HOXB4 for 4 d expanded by about four- to sixfold and were 8-20 times more numerous than HSCs in control cultures, indicating that HSC expansion induced by TAT-HOXB4 was comparable to that induced by the human HOXB4 retrovirus during a similar period of observation. Our results also show that TAT-HOXB4-expanded HSC populations retain their normal in vivo potential for differentiation and long-term repopulation. It is thus feasible to exploit recombinant HOXB4 protein for rapid and significant ex vivo expansion of normal HSCs.", + "TAG_DATA": [ + "40, in {'context': 'B-in vitro'}", + "41, vitro. {'context': 'I-in vitro'}", + "74, HSCs {'context': 'B-transformed cells'}", + "94, HSCs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "32, marrow ['l0', 'l1', 'l2']", + "40, in ['l0', 'l3']", + "41, vitro. ['l1', 'l3']", + "74, HSCs ['l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14566335", + "TEXT": "Group B adenoviruses, a subgenus of human Adenoviridae, are associated with a variety of often-fatal illnesses in immunocompromised individuals, including bone marrow transplant recipients and cancer and AIDS patients. Recently, group B adenovirus derivatives have gained interest as attractive gene therapy vectors because they can transduce target tissues, such as hematopoietic stem cells, dendritic cells and malignant tumor cells, that are refractory to infection by commonly used adenoviral vectors. Whereas many adenoviruses infect cells through the coxsackievirus and adenovirus receptor (CAR), group B adenoviruses use an alternate, as-yet-unidentified cellular attachment receptor. Using mass spectrometric analysis of proteins interacting with a group B fiber, we identified human CD46 as a cellular attachment receptor for most group B adenoviruses. We show that ectopic expression of human CD46 rendered nonhuman cells susceptible to infection with group B viruses in vitro and in vivo. In addition, both siRNA-mediated knockdown of CD46 and a soluble form of CD46 blocked infection of human cell lines and primary human cells. The discovery that group B adenoviruses use CD46, a ubiquitously expressed complement regulatory protein, as a cellular attachment receptor elucidates the diverse clinical manifestation of group B virus infections, and bears directly on the application of these vectors for gene therapy.", + "TAG_DATA": [ + "120, ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "121, expression {'perturbing_action': 'I-gene gain-of-function'}", + "122, of {'perturbing_action': 'I-gene gain-of-function'}", + "123, human {'perturbing_action': 'I-gene gain-of-function'}", + "124, CD46 {'perturbing_action': 'I-gene gain-of-function'}", + "126, nonhuman {'context': 'B-cells'}", + "127, cells {'context': 'I-cells'}", + "135, in {'context': 'B-in vitro'}", + "136, vitro {'context': 'I-in vitro'}", + "138, in {'context': 'B-in vivo'}", + "139, vivo. {'context': 'I-in vivo'}", + "143, siRNA-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "144, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "145, of {'perturbing_action': 'I-rnai/knockdown'}", + "146, CD46 {'perturbing_action': 'I-rnai/knockdown'}", + "150, form {'perturbing_action': 'I-gene gain-of-function'}", + "156, human {'context': 'B-cells'}", + "157, cell {'context': 'I-cells'}", + "158, lines {'context': 'I-cells'}", + "160, primary {'context': 'B-cells'}", + "161, human {'context': 'I-cells'}", + "162, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "120, ectopic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "121, expression ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "122, of ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "123, human ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "124, CD46 ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "126, nonhuman ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "127, cells ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47']", + "135, in ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l49', 'l50']", + "136, vitro ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l48', 'l51', 'l52']", + "138, in ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l49', 'l51', 'l53']", + "139, vivo. ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l47', 'l50', 'l52', 'l53']", + "143, siRNA-mediated ['l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "144, knockdown ['l54', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "145, of ['l55', 'l67', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "146, CD46 ['l56', 'l68', 'l79', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "149, soluble ['l57', 'l69', 'l80', 'l90', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "150, form ['l58', 'l70', 'l81', 'l91', 'l100', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "151, of ['l59', 'l71', 'l82', 'l92', 'l101', 'l109', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "152, CD46 ['l60', 'l72', 'l83', 'l93', 'l102', 'l110', 'l117', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "156, human ['l61', 'l73', 'l84', 'l94', 'l103', 'l111', 'l118', 'l124', 'l130', 'l131', 'l132', 'l133', 'l134']", + "157, cell ['l62', 'l74', 'l85', 'l95', 'l104', 'l112', 'l119', 'l125', 'l130', 'l135', 'l136', 'l137', 'l138']", + "158, lines ['l63', 'l75', 'l86', 'l96', 'l105', 'l113', 'l120', 'l126', 'l131', 'l135', 'l139', 'l140', 'l141']", + "160, primary ['l64', 'l76', 'l87', 'l97', 'l106', 'l114', 'l121', 'l127', 'l132', 'l136', 'l139', 'l142', 'l143']", + "161, human ['l65', 'l77', 'l88', 'l98', 'l107', 'l115', 'l122', 'l128', 'l133', 'l137', 'l140', 'l142', 'l144']", + "162, cells. ['l66', 'l78', 'l89', 'l99', 'l108', 'l116', 'l123', 'l129', 'l134', 'l138', 'l141', 'l143', 'l144']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "expression", + "of", + "human", + "CD46", + "form" + ] + }, + "context": { + "val": "cells", + "words": [ + "nonhuman", + "cells", + "human", + "cell", + "lines", + "primary", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "expression", + "of", + "human", + "CD46" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "expression", + "of", + "human", + "CD46" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA-mediated", + "knockdown", + "of", + "CD46" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "cell", + "lines", + "primary", + "cells." + ] + } + } + ] + }, + { + "PMID": "14566333", + "TEXT": "Despite improved molecular characterization of malignancies and development of targeted therapies, acute leukemia is not curable and few patients survive more than 10 years after diagnosis. Recently, combinations of different therapeutic strategies (based on mechanisms of apoptosis, differentiation and cytotoxicity) have significantly increased survival. To further improve outcome, we studied the potential efficacy of boosting the patient's immune response using specific immunotherapy. In an animal model of acute promyelocytic leukemia, we developed a DNA-based vaccine by fusing the human promyelocytic leukemia-retinoic acid receptor-alpha (PML-RARA) oncogene to tetanus fragment C (FrC) sequences. We show for the first time that a DNA vaccine specifically targeted to an oncoprotein can have a pronounced effect on survival, both alone and when combined with all-trans retinoic acid (ATRA). The survival advantage is concomitant with time-dependent antibody production and an increase in interferon-gamma (IFN-gamma). We also show that ATRA therapy on its own triggers an immune response in this model. When DNA vaccination and conventional ATRA therapy are combined, they induce protective immune responses against leukemia progression in mice and may provide a new approach to improve clinical outcome in human leukemia.", + "TAG_DATA": [ + "64, animal {'context': 'B-organism'}", + "65, model {'context': 'I-neoplasm'}", + "66, of {'context': 'I-neoplasm'}", + "67, acute {'context': 'I-neoplasm'}", + "68, promyelocytic {'context': 'I-neoplasm'}", + "69, leukemia, {'context': 'I-neoplasm'}", + "169, leukemia {'context': 'B-neoplasm'}", + "172, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "64, animal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "65, model ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "66, of ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "67, acute ['l2', 'l8', 'l13', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "68, promyelocytic ['l3', 'l9', 'l14', 'l20', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "69, leukemia, ['l4', 'l10', 'l15', 'l21', 'l28', 'l35', 'l36', 'l37', 'l38', 'l39']", + "79, promyelocytic ['l22', 'l29', 'l40', 'l41', 'l42', 'l43', 'l44']", + "80, leukemia-retinoic ['l23', 'l30', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "81, acid ['l16', 'l24', 'l31', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "82, receptor-alpha ['l17', 'l25', 'l32', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "83, (PML-RARA) ['l5', 'l11', 'l18', 'l26', 'l33', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "84, oncogene ['l6', 'l12', 'l19', 'l27', 'l34', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "169, leukemia ['l55']", + "172, mice ['l55']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14528300", + "TEXT": "The human protein apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like-3G (APOBEC3G), also known as CEM-15, mediates a newly described form of innate resistance to retroviral infection by catalyzing the deamination of deoxycytidine to deoxyuridine in viral cDNA replication intermediates. Because DNA deamination takes place after virus entry into target cells, APOBEC3G function is dependent on its association with the viral nucleoprotein complexes that synthesize cDNA and must therefore be incorporated into virions as they assemble in infected cells. Here we show that the HIV-1 virion infectivity factor (Vif) protein protects the virus from APOBEC3G-mediated inactivation by preventing its incorporation into progeny virions, thus allowing the ensuing infection to proceed without DNA deamination. In addition to helping exclude APOBEC3G from nascent virions, Vif also removes APOBEC3G from virus-producing cells by inducing its ubiquitination and subsequent degradation by the proteasome. Our findings indicate that pharmacologic strategies aimed at stabilizing APOBEC3G in HIV-1 infected cells should be explored as potential HIV/AIDS therapeutics.", + "TAG_DATA": [ + "124, virus-producing {'context': 'B-cells'}", + "125, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "124, virus-producing ['l0']", + "125, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14502284", + "TEXT": "Antivascular photodynamic therapy (PDT) of tumors with palladium-bacteriopheophorbide (TOOKAD) relies on in situ photosensitization of the circulating drug by local generation of cytotoxic reactive oxygen species, which leads to rapid vascular occlusion, stasis, necrosis and tumor eradication. Intravascular production of reactive oxygen species is associated with photoconsumption of O(2) and consequent evolution of paramagnetic deoxyhemoglobin. In this study we evaluate the use of blood oxygenation level-dependent (BOLD) contrast magnetic resonance imaging (MRI) for real-time monitoring of PDT efficacy. Using a solid tumor model, we show that TOOKAD-PDT generates appreciable attenuation (25-40%) of the magnetic resonance signal, solely at the illuminated tumor site. This phenomenon is independent of, though augmented by, ensuing changes in blood flow. These results were validated by immunohistochemistry and intravital microscopy. The concept of photosensitized BOLD-contrast MRI may have intraoperative applications in interactive guidance and monitoring of antivascular cancer therapy, PDT treatment of macular degeneration, interventional cardiology and possibly other biomedical disciplines.", + "TAG_DATA": [ + "80, solid {'context': 'B-neoplasm'}", + "81, tumor {'context': 'I-neoplasm'}", + "82, model, {'context': 'I-neoplasm'}", + "100, tumor {'context': 'B-neoplasm'}", + "101, site. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "80, solid ['l0', 'l1']", + "81, tumor ['l0', 'l2']", + "82, model, ['l1', 'l2']", + "100, tumor ['l3']", + "101, site. ['l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "14502280", + "TEXT": "To understand the integrin requirements of T-helper (T(H)) effector subsets, we investigated the contribution of CD18 (beta(2) integrin) to T(H)1 and T(H)2 function in vitro and in relevant disease models. CD18-deficient (Itgb2(-/-)) T cells showed largely normal in vitro function. Compared with wild-type mice, Itgb2(-/-) mice were better able to resolve Leishmania major infection and generated a superior T(H)1 immune response, as assessed from draining lymph nodes. In contrast, T(H)2-dependent allergic lung disease was markedly impaired in mutant mice. In both models, development of T(H)1 and T(H)2 cells in spleens was normal, but accumulation of T(H)2 (not T(H)1) cells at inflammatory sites was reduced. Thus, CD18 is selectively required for T(H)2, but not T(H)1, homing and has a minimal influence on T-effector development. These findings suggest a new integrin-based therapeutic approach in which the outcomes of diverse diseases may be favorably influenced by altering the homing of T(H)2 cells.", + "TAG_DATA": [ + "30, CD18-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "31, (Itgb2(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "32, T {'context': 'B-cells'}", + "33, cells {'context': 'I-cells'}", + "37, in {'context': 'B-in vitro'}", + "38, vitro {'context': 'I-in vitro'}", + "43, mice, {'context': 'B-organism'}", + "44, Itgb2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "45, mice {'context': 'B-organism'}", + "78, mice. {'context': 'B-organism'}", + "84, T(H)1 {'context': 'B-cells'}", + "85, and {'context': 'I-cells'}", + "86, T(H)2 {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}", + "89, spleens {'context': 'B-tissue/organ'}", + "95, T(H)2 {'context': 'B-cells'}", + "96, (not {'context': 'I-cells'}", + "98, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "30, CD18-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "31, (Itgb2(-/-)) ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "32, T ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21']", + "33, cells ['l2', 'l10', 'l17', 'l22', 'l23', 'l24']", + "37, in ['l3', 'l11', 'l18', 'l22', 'l25']", + "38, vitro ['l4', 'l12', 'l19', 'l23', 'l25']", + "43, mice, ['l5', 'l13', 'l20', 'l26', 'l27']", + "44, Itgb2(-/-) ['l6', 'l14', 'l26', 'l28', 'l29']", + "45, mice ['l7', 'l15', 'l21', 'l24', 'l27', 'l28']", + "78, mice. ['l8', 'l16', 'l29']", + "84, T(H)1 ['l30', 'l31', 'l32', 'l33']", + "85, and ['l30', 'l34', 'l35', 'l36']", + "86, T(H)2 ['l31', 'l34', 'l37', 'l38']", + "87, cells ['l32', 'l35', 'l37', 'l39']", + "89, spleens ['l33', 'l36', 'l38', 'l39']", + "95, T(H)2 ['l40', 'l41']", + "96, (not ['l40', 'l42']", + "98, cells ['l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD18-deficient", + "(Itgb2(-/-))" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD18-deficient", + "(Itgb2(-/-))" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD18-deficient", + "(Itgb2(-/-))", + "Itgb2(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "14502279", + "TEXT": "Although the underlying mechanisms are not well understood, it is generally believed that antigen recognition by T cells in the absence of costimulation may alter the immune response, leading to anergy or tolerance. Further support for this concept comes from animal models of autoimmunity and transplantation, where treatments based on costimulation blockade, in particular CD40 ligand (CD40L)-specific antibodies, have been highly effective. We investigated the mechanisms of action of an antibody to CD40L and provide evidence that its effects are dependent on the constant (Fc) region. Prolongation of graft survival is dependent on both complement- and Fc receptor-mediated mechanisms in a major histocompatibility complex (MHC)-mismatched skin transplant model. These data suggest that antibodies to CD40L act through selective depletion of activated T cells, rather than exerting immune modulation by costimulation blockade as currently postulated. This finding opens new avenues for treatment of immune disorders based on selective targeting of activated T cells.", + "TAG_DATA": [ + "88, graft {'phenotype': 'B-cell survival'}", + "89, survival {'phenotype': 'I-cell survival'}", + "105, skin {'context': 'B-tissue/organ'}", + "121, T {'context': 'B-cells'}", + "122, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "88, graft ['l0', 'l1', 'l2', 'l3']", + "89, survival ['l0', 'l4', 'l5', 'l6']", + "105, skin ['l1', 'l4', 'l7', 'l8']", + "106, transplant ['l2', 'l5', 'l7', 'l9']", + "107, model. ['l3', 'l6', 'l8', 'l9']", + "121, T ['l10']", + "122, cells, ['l10']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "cell survival", + "words": [ + "graft", + "survival" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skin" + ] + } + } + ] + }, + { + "PMID": "12960961", + "TEXT": "Although thrombolysis with tissue plasminogen activator (tPA) is a stroke therapy approved by the US Food and Drug Administration, its efficacy may be limited by neurotoxic side effects. Recently, proteolytic damage involving matrix metalloproteinases (MMPs) have been implicated. In experimental embolic stroke models, MMP inhibitors decreased cerebral hemorrhage and injury after treatment with tPA. MMPs comprise a family of zinc endopeptidases that can modify several components of the extracellular matrix. In particular, the gelatinases MMP-2 and MMP-9 can degrade neurovascular matrix integrity. MMP-9 promotes neuronal death by disrupting cell-matrix interactions, and MMP-9 knockout mice have reduced blood-brain barrier leakage and infarction after cerebral ischemia. Hence it is possible that tPA upregulates MMPs in the brain, and that subsequent matrix degradation causes brain injury. Here we show that tPA upregulates MMP-9 in cell culture and in vivo. MMP-9 levels were lower in tPA knockouts compared with wild-type mice after focal cerebral ischemia. In human cerebral microvascular endothelial cells, MMP-9 was upregulated when recombinant tPA was added. RNA interference (RNAi) suggested that this response was mediated by the low-density lipoprotein receptor-related protein (LRP), which avidly binds tPA and possesses signaling properties. Targeting the tPA-LRP signaling pathway in brain may offer new approaches for decreasing neurotoxicity and improving stroke therapy.", + "TAG_DATA": [ + "91, MMP-9 {'perturbing_action': 'B-gene loss-of-function'}", + "92, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "93, mice {'context': 'B-organism'}", + "131, cell {'context': 'B-cells'}", + "132, culture {'context': 'I-in vitro'}", + "134, in {'context': 'B-in vivo'}", + "135, vivo. {'context': 'I-in vivo'}", + "141, tPA {'perturbing_action': 'B-gene loss-of-function'}", + "142, knockouts {'perturbing_action': 'I-gene loss-of-function'}", + "146, mice {'context': 'B-organism'}", + "152, human {'context': 'B-cells'}", + "153, cerebral {'context': 'I-cells'}", + "154, microvascular {'context': 'I-cells'}", + "155, endothelial {'context': 'I-cells'}", + "156, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "91, MMP-9 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "92, knockout ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "93, mice ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "131, cell ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "132, culture ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "134, in ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "135, vivo. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "141, tPA ['l21', 'l22', 'l23', 'l24']", + "142, knockouts ['l21', 'l25', 'l26']", + "146, mice ['l22', 'l25', 'l27']", + "152, human ['l28', 'l29', 'l30', 'l31']", + "153, cerebral ['l28', 'l32', 'l33', 'l34']", + "154, microvascular ['l29', 'l32', 'l35', 'l36']", + "155, endothelial ['l23', 'l30', 'l33', 'l35', 'l37']", + "156, cells, ['l24', 'l26', 'l27', 'l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MMP-9", + "knockout", + "tPA", + "knockouts" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MMP-9", + "knockout", + "tPA", + "knockouts" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "endothelial", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MMP-9", + "knockout" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MMP-9", + "knockout" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "12949502", + "TEXT": "In mammals, the permanence of acquired hearing loss is mostly due to the incapacity of the cochlea to replace lost mechanoreceptor cells, or hair cells. In contrast, damaged vestibular organs can generate new hair cells, albeit in limited numbers. Here we show that the adult utricular sensory epithelium contains cells that display the characteristic features of stem cells. These inner ear stem cells have the capacity for self-renewal, and form spheres that express marker genes of the developing inner ear and the nervous system. Inner ear stem cells are pluripotent and can give rise to a variety of cell types in vitro and in vivo, including cells representative of ectodermal, endodermal and mesodermal lineages. Our observation that these stem cells are capable of differentiating into hair cell-like cells implies a possible use of such cells for the replacement of lost inner-ear sensory cells.", + "TAG_DATA": [ + "67, self-renewal, {'phenotype': 'B-self-renewal'}", + "101, vitro {'context': 'I-in vitro'}", + "103, in {'context': 'B-in vivo'}", + "104, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "101, vitro ['l0', 'l1']", + "103, in ['l0', 'l2']", + "104, vivo, ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12937413", + "TEXT": "Under conditions of iron overload, which are now reaching epidemic proportions worldwide, iron-overload cardiomyopathy is the most important prognostic factor in patient survival. We hypothesize that in iron-overload disorders, iron accumulation in the heart depends on ferrous iron (Fe2+) permeation through the L-type voltage-dependent Ca2+ channel (LVDCC), a promiscuous divalent cation transporter. Iron overload in mice was associated with increased mortality, systolic and diastolic dysfunction, bradycardia, hypotension, increased myocardial fibrosis and elevated oxidative stress. Treatment with LVDCC blockers (CCBs; amlodipine and verapamil) at therapeutic levels inhibited the LVDCC current in cardiomyocytes, attenuated myocardial iron accumulation and oxidative stress, improved survival, prevented hypotension and preserved heart structure and function. Consistent with the role of LVDCCs in myocardial iron uptake, iron-overloaded transgenic mice with cardiac-specific overexpression of the LVDCC alpha1-subunit had twofold higher myocardial iron and oxidative stress levels, as well as greater impairment in cardiac function, compared with littermate controls; LVDCC blockade was again protective. Our results indicate that cardiac LVDCCs are key transporters of iron into cardiomyocytes under iron-overloaded conditions, and potentially represent a new therapeutic target to reduce the cardiovascular burden from iron overload.", + "TAG_DATA": [ + "55, mice {'context': 'B-organism'}", + "90, cardiomyocytes, {'context': 'B-cells'}", + "104, heart {'context': 'B-tissue/organ'}", + "119, transgenic {'context': 'B-organism'}", + "120, mice {'context': 'I-organism'}", + "122, cardiac-specific {'perturbing_action': 'B-gene gain-of-function'}", + "123, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "124, of {'perturbing_action': 'I-gene gain-of-function'}", + "125, the {'perturbing_action': 'I-gene gain-of-function'}", + "126, LVDCC {'perturbing_action': 'I-gene gain-of-function'}", + "127, alpha1-subunit {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "90, cardiomyocytes, ['l0']", + "104, heart ['l0']", + "119, transgenic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "120, mice ['l1', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "122, cardiac-specific ['l2', 'l9', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "123, overexpression ['l3', 'l10', 'l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "124, of ['l4', 'l11', 'l17', 'l22', 'l27', 'l28', 'l29', 'l30']", + "125, the ['l5', 'l12', 'l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "126, LVDCC ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "127, alpha1-subunit ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "143, cardiac ['l8', 'l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "cardiac-specific", + "overexpression", + "of", + "the", + "LVDCC", + "alpha1-subunit" + ] + } + } + ] + }, + { + "PMID": "12925848", + "TEXT": "Glucagon-like peptide-1 (GLP-1) is a gut peptide that, together with its receptor, GLP-1R, is expressed in the brain. Here we show that intracerebroventricular (i.c.v.) GLP-1 and [Ser(2)]exendin(1-9) (HSEGTFTSD; homologous to a conserved domain in the glucagon/GLP-1 family) enhance associative and spatial learning through GLP-1R. [Ser(2)]exendin(1-9), but not GLP-1, is also active when administered peripherally. GLP-1R-deficient mice have a phenotype characterized by a learning deficit that is restored after hippocampal Glp1r gene transfer. In addition, rats overexpressing GLP-1R in the hippocampus show improved learning and memory. GLP-1R-deficient mice also have enhanced seizure severity and neuronal injury after kainate administration, with an intermediate phenotype in heterozygotes and phenotypic correction after Glp1r gene transfer in hippocampal somatic cells. Systemic administration of [Ser(2)]exendin(1-9) in wild-type animals prevents kainate-induced apoptosis of hippocampal neurons. Brain GLP-1R represents a promising new target for both cognitive-enhancing and neuroprotective agents.", + "TAG_DATA": [ + "54, GLP-1R-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "55, mice {'context': 'B-organism'}", + "68, hippocampal {'perturbing_action': 'B-gene gain-of-function'}", + "69, Glp1r {'perturbing_action': 'I-gene gain-of-function'}", + "70, gene {'perturbing_action': 'I-gene gain-of-function'}", + "71, transfer. {'perturbing_action': 'I-gene gain-of-function'}", + "74, rats {'context': 'B-organism'}", + "75, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "76, GLP-1R {'perturbing_action': 'I-gene gain-of-function'}", + "77, in {'perturbing_action': 'I-gene gain-of-function'}", + "78, the {'perturbing_action': 'I-gene gain-of-function'}", + "79, hippocampus {'context': 'B-tissue/organ'}", + "85, GLP-1R-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "86, mice {'context': 'B-organism'}", + "108, Glp1r {'perturbing_action': 'B-gene gain-of-function'}", + "109, gene {'perturbing_action': 'I-gene gain-of-function'}", + "110, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "112, hippocampal {'context': 'B-cells'}", + "113, somatic {'context': 'I-cells'}", + "114, cells. {'context': 'I-cells'}", + "121, animals {'context': 'B-organism'}", + "122, prevents {'effect': 'B-negative'}", + "123, kainate-induced {'effect': 'B-positive'}", + "124, apoptosis {'phenotype': 'B-apoptosis'}", + "126, hippocampal {'context': 'B-cells'}", + "127, neurons. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "54, GLP-1R-deficient ['l0', 'l1', 'l2', 'l3', 'l4']", + "55, mice ['l0', 'l5', 'l6', 'l7', 'l8']", + "68, hippocampal ['l1', 'l5', 'l9', 'l10', 'l11', 'l12']", + "69, Glp1r ['l2', 'l6', 'l9', 'l13', 'l14', 'l15']", + "70, gene ['l3', 'l7', 'l10', 'l13', 'l16']", + "71, transfer. ['l4', 'l8', 'l11', 'l14', 'l16']", + "74, rats ['l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "75, overexpressing ['l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "76, GLP-1R ['l18', 'l24', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "77, in ['l19', 'l25', 'l31', 'l37', 'l38', 'l39', 'l40']", + "78, the ['l20', 'l26', 'l32', 'l37', 'l41', 'l42']", + "79, hippocampus ['l12', 'l15', 'l21', 'l27', 'l33', 'l38', 'l41', 'l43']", + "85, GLP-1R-deficient ['l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "86, mice ['l22', 'l28', 'l34', 'l39', 'l42', 'l43', 'l44', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "108, Glp1r ['l45', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "109, gene ['l46', 'l52', 'l57', 'l62', 'l63', 'l64', 'l65']", + "110, transfer ['l47', 'l53', 'l58', 'l62', 'l66', 'l67', 'l68']", + "112, hippocampal ['l48', 'l54', 'l59', 'l63', 'l66', 'l69', 'l70']", + "113, somatic ['l29', 'l35', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l71']", + "114, cells. ['l23', 'l30', 'l36', 'l40', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l71']", + "121, animals ['l72', 'l73', 'l74', 'l75', 'l76']", + "122, prevents ['l72', 'l77', 'l78', 'l79', 'l80']", + "123, kainate-induced ['l73', 'l77', 'l81', 'l82', 'l83']", + "124, apoptosis ['l74', 'l78', 'l81', 'l84', 'l85']", + "126, hippocampal ['l75', 'l79', 'l82', 'l84', 'l86']", + "127, neurons. ['l76', 'l80', 'l83', 'l85', 'l86']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "GLP-1R-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "rats" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hippocampal", + "Glp1r", + "gene", + "transfer.", + "overexpressing", + "GLP-1R", + "in", + "the", + "transfer" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hippocampal", + "Glp1r", + "overexpressing", + "GLP-1R", + "in", + "the" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "GLP-1R", + "in", + "Glp1r", + "gene", + "transfer" + ] + }, + "context": { + "val": "cells", + "words": [ + "somatic", + "cells.", + "hippocampal" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "GLP-1R-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "hippocampal", + "somatic", + "cells." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animals" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animals" + ] + }, + "effect": { + "val": "positive", + "words": [ + "kainate-induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animals" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "context": { + "val": "cells", + "words": [ + "hippocampal", + "neurons." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "kainate-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "kainate-induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "hippocampal", + "neurons." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "hippocampal", + "neurons." + ] + } + } + ] + }, + { + "PMID": "12925846", + "TEXT": "Although naturally occurring smallpox was eliminated through the efforts of the World Health Organization Global Eradication Program, it remains possible that smallpox could be intentionally released. Here we examine the magnitude and duration of antiviral immunity induced by one or more smallpox vaccinations. We found that more than 90% of volunteers vaccinated 25-75 years ago still maintain substantial humoral or cellular immunity (or both) against vaccinia, the virus used to vaccinate against smallpox. Antiviral antibody responses remained stable between 1-75 years after vaccination, whereas antiviral T-cell responses declined slowly, with a half-life of 8-15 years. If these levels of immunity are considered to be at least partially protective, then the morbidity and mortality associated with an intentional smallpox outbreak would be substantially reduced because of pre-existing immunity in a large number of previously vaccinated individuals.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12910264", + "TEXT": "Although bone marrow is known as a primary lymphoid organ, its potential to serve as a secondary immune organ has hardly been explored. Here we demonstrate that naive, antigen-specific T cells home to bone marrow, where they can be primed. Antigen presentation to T cells in bone marrow is mediated via resident CD11c+ dendritic cells. They are highly efficient in taking up exogenous blood-borne antigen and processing it via major histocompatibility complex class I and class II pathways. T-cell activation correlates with dendritic cell-T cell clustering in bone marrow stroma. Primary CD4+ and CD8+ T-cell responses generated in bone marrow occur in the absence of secondary lymphoid organs. The responses are not tolerogenic and result in generation of cytotoxic T cells, protective anti-tumor immunity and immunological memory. These findings highlight the uniqueness of bone marrow as an organ important for hemato- and lymphopoiesis and for systemic T cell-mediated immunity.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12872167", + "TEXT": "In the past decade, it has become possible to use the nuclear (proton, 1H) signal of the hydrogen atoms in water for noninvasive assessment of functional and physiological parameters with magnetic resonance imaging (MRI). Here we show that it is possible to produce pH-sensitive MRI contrast by exploiting the exchange between the hydrogen atoms of water and the amide hydrogen atoms of endogenous mobile cellular proteins and peptides. Although amide proton concentrations are in the millimolar range, we achieved a detection sensitivity of several percent on the water signal (molar concentration). The pH dependence of the signal was calibrated in situ, using phosphorus spectroscopy to determine pH, and proton exchange spectroscopy to measure the amide proton transfer rate. To show the potential of amide proton transfer (APT) contrast for detecting acute stroke, pH effects were noninvasively imaged in ischemic rat brain. This observation opens the possibility of using intrinsic pH contrast, as well as protein- and/or peptide-content contrast, as diagnostic tools in clinical imaging.", + "TAG_DATA": [ + "139, rat {'context': 'I-tissue/organ'}", + "140, brain. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "139, rat ['l0']", + "140, brain. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12858170", + "TEXT": "Whereas uncoupling protein 1 (UCP-1) is clearly involved in thermogenesis, the role of UCP-2 is less clear. Using hybridization, cloning techniques and cDNA array analysis to identify inducible neuroprotective genes, we found that neuronal survival correlates with increased expression of Ucp2. In mice overexpressing human UCP-2, brain damage was diminished after experimental stroke and traumatic brain injury, and neurological recovery was enhanced. In cultured cortical neurons, UCP-2 reduced cell death and inhibited caspase-3 activation induced by oxygen and glucose deprivation. Mild mitochondrial uncoupling by 2,4-dinitrophenol (DNP) reduced neuronal death, and UCP-2 activity was enhanced by palmitic acid in isolated mitochondria. Also in isolated mitochondria, UCP-2 shifted the release of reactive oxygen species from the mitochondrial matrix to the extramitochondrial space. We propose that UCP-2 is an inducible protein that is neuroprotective by activating cellular redox signaling or by inducing mild mitochondrial uncoupling that prevents the release of apoptogenic proteins.", + "TAG_DATA": [ + "42, mice {'context': 'B-organism'}", + "43, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "44, human {'perturbing_action': 'I-gene gain-of-function'}", + "45, UCP-2, {'perturbing_action': 'I-gene gain-of-function'}", + "63, cultured {'context': 'B-cells'}", + "64, cortical {'context': 'I-cells'}", + "65, neurons, {'context': 'I-cells'}", + "67, reduced {'effect': 'B-negative'}", + "68, cell {'phenotype': 'B-cell death'}", + "69, death {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "42, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "43, overexpressing ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "44, human ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "45, UCP-2, ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "63, cultured ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "64, cortical ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "65, neurons, ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "67, reduced ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "68, cell ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "69, death ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "human", + "UCP-2," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "human", + "UCP-2," + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "cortical", + "neurons," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "human", + "UCP-2," + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "human", + "UCP-2," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "cortical", + "neurons," + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "cortical", + "neurons," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + } + ] + }, + { + "PMID": "12858169", + "TEXT": "It has been suggested that environmental contaminants that mimic the effects of estrogen contribute to disruption of the reproductive systems of animals in the wild, and to the high incidence of hormone-related cancers and diseases in Western populations. Previous studies have shown that functionally, cadmium acts like steroidal estrogens in breast cancer cells as a result of its ability to form a high-affinity complex with the hormone binding domain of the estrogen receptor. The results of the present study show that cadmium also has potent estrogen-like activity in vivo. Exposure to cadmium increased uterine wet weight, promoted growth and development of the mammary glands and induced hormone-regulated genes in ovariectomized animals. In the uterus, the increase in wet weight was accompanied by proliferation of the endometrium and induction of progesterone receptor (PgR) and complement component C3. In the mammary gland, cadmium promoted an increase in the formation of side branches and alveolar buds and the induction of casein, whey acidic protein, PgR and C3. In utero exposure to the metal also mimicked the effects of estrogens. Female offspring experienced an earlier onset of puberty and an increase in the epithelial area and the number of terminal end buds in the mammary gland.", + "TAG_DATA": [ + "102, mammary {'context': 'B-tissue/organ'}", + "103, glands {'context': 'I-tissue/organ'}", + "110, animals. {'context': 'B-organism'}", + "113, uterus, {'context': 'B-tissue/organ'}", + "122, proliferation {'phenotype': 'B-proliferation'}", + "125, endometrium {'context': 'B-tissue/organ'}", + "138, mammary {'context': 'B-tissue/organ'}", + "139, gland, {'context': 'I-tissue/organ'}", + "164, In {'context': 'B-in vivo'}", + "165, utero {'context': 'I-in vivo'}", + "176, Female {'context': 'B-organism'}", + "177, offspring {'context': 'I-organism'}", + "200, mammary {'context': 'B-tissue/organ'}", + "201, gland. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "102, mammary ['l0']", + "103, glands ['l0']", + "113, uterus, ['l1', 'l2']", + "122, proliferation ['l1', 'l3', 'l4']", + "125, endometrium ['l2', 'l3']", + "138, mammary ['l5']", + "139, gland, ['l4', 'l5']", + "164, In ['l6', 'l7', 'l8', 'l9', 'l10']", + "165, utero ['l6', 'l11', 'l12', 'l13', 'l14']", + "176, Female ['l7', 'l11', 'l15', 'l16', 'l17']", + "177, offspring ['l8', 'l12', 'l15', 'l18', 'l19']", + "200, mammary ['l9', 'l13', 'l16', 'l18', 'l20']", + "201, gland. ['l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "uterus,", + "endometrium", + "gland," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "12858168", + "TEXT": "Seizure disorders present an attractive gene therapy target, particularly because viral vectors such as adeno-associated virus (AAV) and lentivirus can stably transduce neurons. When we targeted the N-methyl-D-aspartic acid (NMDA) excitatory amino acid receptor with an AAV-delivered antisense oligonucleotide, however, the promoter determined whether focal seizure sensitivity was significantly attenuated or facilitated. One potential means to circumvent this liability would be to express an inhibitory neuroactive peptide and constitutively secrete the peptide from the transduced cell. The neuropeptide galanin can modulate seizure activity in vivo, and the laminar protein fibronectin is usually secreted through a constitutive pathway. Initially, inclusion of the fibronectin secretory signal sequence (FIB) in an AAV vector caused significant gene product secretion in vitro. More importantly, the combination of this secretory signal with the coding sequence for the active galanin peptide significantly attenuated in vivo focal seizure sensitivity, even with different promoters, and prevented kainic acid-induced hilar cell death. Thus, neuroactive peptide expression and local secretion provides a new gene therapy platform for the treatment of neurological disorders.", + "TAG_DATA": [ + "115, in {'context': 'B-in vitro'}", + "116, vitro. {'context': 'I-in vitro'}", + "136, in {'context': 'B-in vivo'}", + "137, vivo {'context': 'I-in vivo'}", + "146, prevented {'effect': 'B-negative'}", + "149, hilar {'context': 'B-tissue/organ'}", + "150, cell {'phenotype': 'B-cell death'}", + "151, death. {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "115, in ['l0']", + "116, vitro. ['l0']", + "136, in ['l1', 'l2', 'l3', 'l4', 'l5']", + "137, vivo ['l1', 'l6', 'l7', 'l8', 'l9']", + "146, prevented ['l2', 'l6', 'l10', 'l11', 'l12']", + "149, hilar ['l3', 'l7', 'l10', 'l13', 'l14']", + "150, cell ['l4', 'l8', 'l11', 'l13', 'l15']", + "151, death. ['l5', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hilar" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "hilar" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "12847522", + "TEXT": "Hypertension and diabetes are common side effects of glucocorticoid treatment. To determine whether peroxisome proliferator-activated receptor-alpha (PPAR-alpha) mediates these sequelae, mice deficient in low-density lipoprotein receptor (Ldlr-/-), with (Ppara+/+) or without (Ppara-/-) PPAR-alpha, were treated chronically with dexamethasone. Ppara+/+, but not Ppara-/-, mice developed hyperglycemia, hyperinsulinemia and hypertension. Similar effects on glucose metabolism were seen in a different model using C57BL/6 mice. Hepatic gluconeogenic gene expression was increased and insulin-mediated suppression of endogenous glucose production was less effective in dexamethasone-treated Ppara+/+ mice. Adenoviral reconstitution of PPAR-alpha in the livers of nondiabetic, normotensive, dexamethasone-treated Ppara-/- mice induced hyperglycemia, hyperinsulinemia and increased gluconeogenic gene expression. It also increased blood pressure, renin activity, sympathetic nervous activity and renal sodium retention. Human hepatocytes treated with dexamethasone and the PPAR-alpha agonist Wy14,643 induced PPARA and gluconeogenic gene expression. These results identify hepatic activation of PPAR-alpha as a mechanism underlying glucocorticoid-induced insulin resistance.", + "TAG_DATA": [ + "20, mice {'context': 'B-organism'}", + "21, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "22, in {'perturbing_action': 'I-gene loss-of-function'}", + "23, low-density {'perturbing_action': 'I-gene loss-of-function'}", + "24, lipoprotein {'perturbing_action': 'I-gene loss-of-function'}", + "25, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "26, (Ldlr-/-), {'perturbing_action': 'I-gene loss-of-function'}", + "27, with {'perturbing_action': 'B-gene loss-of-function'}", + "28, (Ppara+/+) {'perturbing_action': 'I-gene loss-of-function'}", + "30, without {'perturbing_action': 'B-gene loss-of-function'}", + "31, (Ppara-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "32, PPAR-alpha, {'perturbing_action': 'I-gene loss-of-function'}", + "41, Ppara-/-, {'perturbing_action': 'B-gene loss-of-function'}", + "42, mice {'context': 'B-organism'}", + "81, mice. {'context': 'B-organism'}", + "82, Adenoviral {'perturbing_action': 'B-gene gain-of-function'}", + "83, reconstitution {'perturbing_action': 'I-gene gain-of-function'}", + "84, of {'perturbing_action': 'I-gene gain-of-function'}", + "85, PPAR-alpha {'perturbing_action': 'I-gene gain-of-function'}", + "88, livers {'context': 'B-tissue/organ'}", + "90, nondiabetic, {'context': 'B-organism'}", + "91, normotensive, {'context': 'I-cells'}", + "93, Ppara-/- {'perturbing_action': 'B-gene loss-of-function'}", + "94, mice {'context': 'B-organism'}", + "117, Human {'context': 'B-cells'}", + "118, hepatocytes {'context': 'I-cells'}", + "124, PPAR-alpha {'perturbing_action': 'B-pharmacological augmentation'}", + "125, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "126, Wy14,643 {'perturbing_action': 'I-pharmacological augmentation'}" + ], + "LINK_DATA": [ + "20, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "21, deficient ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "22, in ['l1', 'l9', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "23, low-density ['l2', 'l10', 'l19', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "24, lipoprotein ['l3', 'l11', 'l20', 'l28', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "25, receptor ['l4', 'l12', 'l21', 'l29', 'l36', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "26, (Ldlr-/-), ['l5', 'l13', 'l22', 'l30', 'l37', 'l43', 'l49', 'l50', 'l51', 'l52', 'l53']", + "27, with ['l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "28, (Ppara+/+) ['l6', 'l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "30, without ['l55', 'l62', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "31, (Ppara-/-) ['l56', 'l63', 'l69', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "32, PPAR-alpha, ['l57', 'l64', 'l70', 'l80', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "41, Ppara-/-, ['l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l58', 'l65', 'l71', 'l81', 'l91', 'l100', 'l101', 'l102']", + "42, mice ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l59', 'l66', 'l72', 'l82', 'l92', 'l100', 'l103']", + "61, mice. ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l60', 'l67', 'l73', 'l83', 'l93', 'l101', 'l103']", + "81, mice. ['l61', 'l68', 'l74', 'l84', 'l94', 'l102']", + "82, Adenoviral ['l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "83, reconstitution ['l104', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "84, of ['l75', 'l85', 'l95', 'l105', 'l112', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "85, PPAR-alpha ['l76', 'l86', 'l96', 'l106', 'l113', 'l119', 'l125', 'l126', 'l127', 'l128', 'l129']", + "88, livers ['l77', 'l87', 'l97', 'l107', 'l114', 'l120', 'l125', 'l130', 'l131', 'l132', 'l133']", + "90, nondiabetic, ['l78', 'l88', 'l98', 'l108', 'l115', 'l121', 'l126', 'l130', 'l134', 'l135', 'l136']", + "91, normotensive, ['l89', 'l109', 'l116', 'l122', 'l127', 'l131', 'l134', 'l137', 'l138']", + "93, Ppara-/- ['l110', 'l117', 'l123', 'l128', 'l132', 'l135', 'l137', 'l139']", + "94, mice ['l79', 'l90', 'l99', 'l111', 'l118', 'l124', 'l129', 'l133', 'l136', 'l138', 'l139']", + "117, Human ['l140', 'l141', 'l142', 'l143']", + "118, hepatocytes ['l140', 'l144', 'l145', 'l146']", + "124, PPAR-alpha ['l141', 'l144', 'l147', 'l148']", + "125, agonist ['l142', 'l145', 'l147', 'l149']", + "126, Wy14,643 ['l143', 'l146', 'l148', 'l149']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "nondiabetic," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "low-density", + "lipoprotein", + "receptor", + "(Ldlr-/-),", + "(Ppara+/+)", + "with", + "without", + "(Ppara-/-)", + "PPAR-alpha,", + "Ppara-/-,", + "Ppara-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "without", + "(Ppara-/-)", + "PPAR-alpha,", + "Ppara-/-" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "livers" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "(Ppara-/-)", + "Ppara-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "normotensive," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenoviral", + "reconstitution", + "of", + "PPAR-alpha" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "livers" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenoviral", + "reconstitution", + "of", + "PPAR-alpha" + ] + }, + "context": { + "val": "organism", + "words": [ + "nondiabetic,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenoviral", + "reconstitution", + "of", + "PPAR-alpha" + ] + }, + "context": { + "val": "cells", + "words": [ + "normotensive," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Human", + "hepatocytes" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "PPAR-alpha", + "agonist", + "Wy14,643" + ] + } + } + ] + }, + { + "PMID": "12847521", + "TEXT": "As a target for gene therapy, Duchenne muscular dystrophy (DMD) presents many obstacles but also an unparalleled prospect for correction by alternative splicing. The majority of mutations in the dystrophin gene occur in the region encoding the spectrin-like central rod domain, which is largely dispensable. Thus, splicing around mutations can generate a shortened but in-frame transcript, permitting translation of a partially functional dystrophin protein. We have tested this idea in vivo in the mdx dystrophic mouse (carrying a mutation in exon 23 of the dystrophin gene) by combining a potent transfection protocol with a 2-O-methylated phosphorothioated antisense oligoribonucleotide (2OMeAO) designed to promote skipping of the mutated exon*. The treated mice show persistent production of dystrophin at normal levels in large numbers of muscle fibers and show functional improvement of the treated muscle. Repeated administration enhances dystrophin expression without eliciting immune responses. Our data establishes the realistic practicality of an approach that is applicable, in principle, to a majority of cases of severe dystrophinopathy.", + "TAG_DATA": [ + "69, in {'context': 'B-in vivo'}", + "70, vivo {'context': 'I-in vivo'}", + "73, mdx {'context': 'B-organism'}", + "74, dystrophic {'context': 'I-organism'}", + "75, mouse {'context': 'I-organism'}", + "76, (carrying {'context': 'I-organism'}", + "77, a {'perturbing_action': 'I-other'}", + "78, mutation {'perturbing_action': 'I-other'}", + "79, in {'perturbing_action': 'I-other'}", + "80, exon {'perturbing_action': 'I-other'}", + "81, 23 {'perturbing_action': 'I-other'}", + "82, of {'perturbing_action': 'I-other'}", + "83, the {'perturbing_action': 'I-other'}", + "84, dystrophin {'perturbing_action': 'I-other'}", + "85, gene) {'perturbing_action': 'I-other'}", + "109, mice {'context': 'B-organism'}", + "122, muscle {'context': 'B-cells'}", + "123, fibers {'context': 'I-cells'}", + "131, muscle. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "69, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "70, vivo ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "73, mdx ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "74, dystrophic ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "75, mouse ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "76, (carrying ['l4', 'l17', 'l29', 'l40', 'l50', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "77, a ['l5', 'l18', 'l30', 'l41', 'l51', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "78, mutation ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "79, in ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "80, exon ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l90', 'l91', 'l92', 'l93', 'l94']", + "81, 23 ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l95', 'l96', 'l97', 'l98']", + "82, of ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l99', 'l100', 'l101']", + "83, the ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l102', 'l103']", + "84, dystrophin ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l104']", + "85, gene) ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l104']", + "109, mice ['l105', 'l106', 'l107']", + "122, muscle ['l105', 'l108']", + "123, fibers ['l106', 'l108']", + "131, muscle. ['l107']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "a", + "mutation", + "in", + "exon", + "23", + "of", + "the", + "dystrophin", + "gene)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mdx", + "dystrophic", + "mouse", + "(carrying" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "a", + "mutation", + "in", + "exon", + "23", + "of", + "the", + "dystrophin", + "gene)" + ] + } + } + ] + }, + { + "PMID": "12847520", + "TEXT": "Members of the suppressor of cytokine signaling (SOCS) family are involved in the pathogenesis of many inflammatory diseases. SOCS-3 is predominantly expressed in T-helper type 2 (T(H)2) cells, but its role in T(H)2-related allergic diseases remains to be investigated. In this study we provide a strong correlation between SOCS-3 expression and the pathology of asthma and atopic dermatitis, as well as serum IgE levels in allergic human patients. SOCS-3 transgenic mice showed increased T(H)2 responses and multiple pathological features characteristic of asthma in an airway hypersensitivity model system. In contrast, dominant-negative mutant SOCS-3 transgenic mice, as well as mice with a heterozygous deletion of Socs3, had decreased T(H)2 development. These data indicate that SOCS-3 has an important role in regulating the onset and maintenance of T(H)2-mediated allergic immune disease, and suggest that SOCS-3 may be a new therapeutic target for the development of antiallergic drugs.", + "TAG_DATA": [ + "68, SOCS-3 {'perturbing_action': 'B-gene gain-of-function'}", + "69, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "70, mice {'context': 'B-organism'}", + "90, dominant-negative {'perturbing_action': 'B-other'}", + "91, mutant {'perturbing_action': 'I-other'}", + "92, SOCS-3 {'perturbing_action': 'I-other'}", + "93, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "94, mice, {'context': 'B-organism'}", + "98, mice {'context': 'B-organism'}", + "101, heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "102, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "103, of {'perturbing_action': 'I-gene loss-of-function'}", + "104, Socs3, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "68, SOCS-3 ['l0', 'l1']", + "69, transgenic ['l0', 'l2']", + "70, mice ['l1', 'l2']", + "90, dominant-negative ['l3', 'l4', 'l5', 'l6']", + "91, mutant ['l3', 'l7', 'l8', 'l9']", + "92, SOCS-3 ['l4', 'l7', 'l10', 'l11']", + "93, transgenic ['l5', 'l8', 'l10', 'l12']", + "94, mice, ['l6', 'l9', 'l11', 'l12']", + "98, mice ['l13', 'l14', 'l15', 'l16']", + "101, heterozygous ['l13', 'l17', 'l18', 'l19']", + "102, deletion ['l14', 'l17', 'l20', 'l21']", + "103, of ['l15', 'l18', 'l20', 'l22']", + "104, Socs3, ['l16', 'l19', 'l21', 'l22']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "SOCS-3", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "dominant-negative", + "mutant", + "SOCS-3" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "heterozygous", + "deletion", + "of", + "Socs3," + ] + } + } + ] + }, + { + "PMID": "12778138", + "TEXT": "Conformational conversion of proteins in disease is likely to be accompanied by molecular surface exposure of previously sequestered amino-acid side chains. We found that induction of beta-sheet structures in recombinant prion proteins is associated with increased solvent accessibility of tyrosine. Antibodies directed against the prion protein repeat motif, tyrosine-tyrosine-arginine, recognize the pathological isoform of the prion protein but not the normal cellular isoform, as assessed by immunoprecipitation, plate capture immunoassay and flow cytometry. Antibody binding to the pathological epitope is saturable and specific, and can be created in vitro by partial denaturation of normal brain prion protein. Conformation-selective exposure of Tyr-Tyr-Arg provides a probe for the distribution and structure of pathologically misfolded prion protein, and may lead to new diagnostics and therapeutics for prion diseases.", + "TAG_DATA": [ + "87, in {'context': 'B-in vitro'}", + "88, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "87, in ['l0', 'l1', 'l2']", + "88, vitro ['l0', 'l3', 'l4']", + "94, brain ['l1', 'l3', 'l5']", + "95, prion ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12754501", + "TEXT": "The enzyme carnitine palmitoyltransferase-1 (CPT1) regulates long-chain fatty acid (LCFA) entry into mitochondria, where the LCFAs undergo beta-oxidation. To investigate the mechanism(s) by which central metabolism of lipids can modulate energy balance, we selectively reduced lipid oxidation in the hypothalamus. We decreased the activity of CPT1 by administering to rats a ribozyme-containing plasmid designed specifically to decrease the expression of this enzyme or by infusing pharmacological inhibitors of its activity into the third cerebral ventricle. Either genetic or biochemical inhibition of hypothalamic CPT1 activity was sufficient to substantially diminish food intake and endogenous glucose production. These results indicated that changes in the rate of lipid oxidation in selective hypothalamic neurons signaled nutrient availability to the hypothalamus, which in turn modulated the exogenous and endogenous inputs of nutrients into the circulation.", + "TAG_DATA": [ + "41, decreased {'perturbing_action': 'B-gene loss-of-function'}", + "42, the {'perturbing_action': 'I-rnai/knockdown'}", + "43, activity {'perturbing_action': 'I-gene loss-of-function'}", + "44, of {'perturbing_action': 'I-gene loss-of-function'}", + "45, CPT1 {'perturbing_action': 'I-gene loss-of-function'}", + "49, rats {'context': 'B-organism'}", + "51, ribozyme-containing {'perturbing_action': 'B-rnai/knockdown'}", + "52, plasmid {'perturbing_action': 'I-rnai/knockdown'}", + "53, designed {'perturbing_action': 'I-rnai/knockdown'}", + "54, specifically {'perturbing_action': 'I-rnai/knockdown'}", + "55, to {'perturbing_action': 'I-rnai/knockdown'}", + "56, decrease {'perturbing_action': 'I-rnai/knockdown'}", + "57, the {'perturbing_action': 'I-rnai/knockdown'}", + "58, expression {'perturbing_action': 'I-rnai/knockdown'}", + "59, of {'perturbing_action': 'I-rnai/knockdown'}", + "60, this {'perturbing_action': 'I-rnai/knockdown'}", + "61, enzyme {'perturbing_action': 'I-rnai/knockdown'}", + "78, biochemical {'perturbing_action': 'B-pharmacological inhibition'}", + "79, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "80, of {'perturbing_action': 'I-pharmacological inhibition'}", + "81, hypothalamic {'perturbing_action': 'I-pharmacological inhibition'}", + "82, CPT1 {'perturbing_action': 'I-pharmacological inhibition'}", + "83, activity {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "41, decreased ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "42, the ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "43, activity ['l1', 'l16', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "44, of ['l2', 'l17', 'l31', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "45, CPT1 ['l3', 'l18', 'l32', 'l45', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "49, rats ['l4', 'l19', 'l33', 'l46', 'l58', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "51, ribozyme-containing ['l5', 'l20', 'l34', 'l47', 'l59', 'l70', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "52, plasmid ['l6', 'l21', 'l35', 'l48', 'l60', 'l71', 'l81', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "53, designed ['l7', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l93', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "54, specifically ['l8', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l94', 'l105', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "55, to ['l9', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l95', 'l106', 'l116', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "56, decrease ['l10', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l96', 'l107', 'l117', 'l126', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139']", + "57, the ['l11', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l97', 'l108', 'l118', 'l127', 'l134', 'l140', 'l141', 'l142', 'l143', 'l144']", + "58, expression ['l12', 'l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l98', 'l109', 'l119', 'l128', 'l135', 'l140', 'l145', 'l146', 'l147', 'l148']", + "59, of ['l13', 'l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l99', 'l110', 'l120', 'l129', 'l136', 'l141', 'l145', 'l149', 'l150', 'l151']", + "60, this ['l14', 'l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l100', 'l111', 'l121', 'l130', 'l137', 'l142', 'l146', 'l149', 'l152', 'l153']", + "61, enzyme ['l15', 'l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l101', 'l112', 'l122', 'l131', 'l138', 'l143', 'l147', 'l150', 'l152', 'l154']", + "78, biochemical ['l155', 'l156', 'l157', 'l158', 'l159']", + "79, inhibition ['l155', 'l160', 'l161', 'l162', 'l163']", + "80, of ['l156', 'l160', 'l164', 'l165', 'l166']", + "81, hypothalamic ['l102', 'l113', 'l123', 'l157', 'l161', 'l164', 'l167', 'l168']", + "82, CPT1 ['l91', 'l103', 'l114', 'l124', 'l132', 'l158', 'l162', 'l165', 'l167', 'l169']", + "83, activity ['l92', 'l104', 'l115', 'l125', 'l133', 'l139', 'l144', 'l148', 'l151', 'l153', 'l154', 'l159', 'l163', 'l166', 'l168', 'l169']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "decreased", + "activity", + "of", + "CPT1" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "the", + "ribozyme-containing", + "plasmid", + "designed", + "specifically", + "to", + "decrease", + "expression", + "of", + "this", + "enzyme" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + } + ] + }, + { + "PMID": "12740573", + "TEXT": "During the progression of atherosclerosis, autoantibodies are induced to epitopes of oxidized low-density lipoprotein (oxLDL) and active immunization of hypercholesterolemic mice with oxLDL ameliorates atherogenesis. We unexpectedly found that many autoantibodies to oxLDL derived from 'naive' atherosclerotic mice share complete genetic and structural identity with antibodies from the classic anti-phosphorylcholine B-cell clone, T15, which protect against common infectious pathogens, including pneumococci. To investigate whether in vivo exposure to pneumococci can affect atherogenesis, we immunized Ldlr(-/-) mice with Streptococcus pneumoniae. This induced high circulating levels of oxLDL-specific IgM and a persistent expansion of oxLDL-specific T15 IgM-secreting B cells primarily in the spleen, which were cross-reactive with pneumococcal determinants. Pneumococcal immunization decreased the extent of atherosclerosis, and plasma from these mice had an enhanced capacity to block the binding of oxLDL to macrophages. These studies show molecular mimicry between epitopes of oxLDL and S. pneumoniae and indicate that these immune responses can have beneficial effects.", + "TAG_DATA": [ + "74, Ldlr(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "75, mice {'context': 'B-organism'}", + "95, B {'context': 'B-cells'}", + "96, cells {'context': 'I-cells'}", + "100, spleen, {'context': 'B-tissue/organ'}", + "109, decreased {'effect': 'B-negative'}", + "113, atherosclerosis, {'phenotype': 'B-oncosis'}", + "118, mice {'context': 'B-organism'}", + "130, macrophages. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "74, Ldlr(-/-) ['l0', 'l1', 'l2', 'l3']", + "75, mice ['l0', 'l4']", + "95, B ['l1', 'l5', 'l6']", + "96, cells ['l2', 'l4', 'l5', 'l7']", + "100, spleen, ['l3', 'l6', 'l7']", + "109, decreased ['l8', 'l9']", + "113, atherosclerosis, ['l8', 'l10', 'l11']", + "118, mice ['l10', 'l12']", + "130, macrophages. ['l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ldlr(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ldlr(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "B", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ldlr(-/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "spleen," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "oncosis", + "words": [ + "atherosclerosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages." + ] + } + }, + { + "phenotype": { + "val": "oncosis", + "words": [ + "atherosclerosis," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "oncosis", + "words": [ + "atherosclerosis," + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages." + ] + } + } + ] + }, + { + "PMID": "12740572", + "TEXT": "In monkeys rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), expression of the dopamine D3 receptor was decreased. However, levodopa-induced dyskinesia (LID), similar to the debilitating and pharmacoresistant involuntary movements elicited after long-term treatment with levodopa in patients with Parkinson disease (PD), was associated with overexpression of this receptor. Administration of a D3 receptor-selective partial agonist strongly attenuated levodopa-induced dyskinesia, but left unaffected the therapeutic effect of levodopa. In contrast, attenuation of dyskinesia by D3 receptor antagonists was accompanied by the reappearance of PD-like symptoms. These results indicated that the D3 receptor participated in both dyskinesia and the therapeutic action of levodopa, and that partial agonists may normalize D3 receptor function and correct side effects of levodopa therapy in patients with PD.", + "TAG_DATA": [ + "1, monkeys {'context': 'B-organism'}", + "42, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "43, of {'perturbing_action': 'I-gene gain-of-function'}", + "44, this {'perturbing_action': 'I-gene gain-of-function'}", + "45, receptor. {'perturbing_action': 'I-gene gain-of-function'}", + "49, D3 {'perturbing_action': 'B-pharmacological augmentation'}", + "50, receptor-selective {'perturbing_action': 'I-pharmacological augmentation'}", + "51, partial {'perturbing_action': 'I-pharmacological augmentation'}", + "52, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "71, D3 {'perturbing_action': 'B-pharmacological inhibition'}", + "72, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "73, antagonists {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "1, monkeys ['l0', 'l1', 'l2', 'l3']", + "42, overexpression ['l0', 'l4', 'l5', 'l6']", + "43, of ['l1', 'l4', 'l7', 'l8']", + "44, this ['l2', 'l5', 'l7', 'l9']", + "45, receptor. ['l3', 'l6', 'l8', 'l9']", + "49, D3 ['l10', 'l11', 'l12']", + "50, receptor-selective ['l10', 'l13', 'l14']", + "51, partial ['l11', 'l13', 'l15']", + "52, agonist ['l12', 'l14', 'l15']", + "71, D3 ['l16', 'l17']", + "72, receptor ['l16', 'l18']", + "73, antagonists ['l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "monkeys" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "this", + "receptor." + ] + } + } + ] + }, + { + "PMID": "12740570", + "TEXT": "Angiogenic tumor vessels are promising targets for the activity and the selective delivery of cancer therapeutics. The bone marrow contributes different cell types to the tumor stroma, including hematopoietic cells and, as recently suggested, vascular endothelial cells (ECs). Thus, transplantation of genetically modified bone marrow progenitors may represent a vehicle for the transport of gene therapy to tumors. We transduced bone marrow progenitors with lentiviral vectors expressing genes from transcription-regulatory elements of Tie2/Tek gene. When tumors were grown in the transplanted mice, the new vector marked a distinct hematopoietic population that 'homed' to the tumor and closely interacted with vascular ECs at the tumor periphery. These Tie2-expressing mononuclear (TEM) cells had a distinguishable phenotype and were present selectively at angiogenic sites. Unexpectedly, we did not find bone marrow-derived ECs in tumor vessels when we transplanted bone marrow progenitors constitutively expressing a marker gene from the Tie2 or ubiquitously active promoters. By delivering a 'suicide' gene, we selectively eliminated the TEM cells and achieved substantial inhibition of angiogenesis and slower tumor growth without systemic toxicity. Thus, TEM cells may account for the proangiogenic activity of bone marrow-derived cells in tumors, may represent a new target for drug development and may provide the means for selective gene delivery and targeted inhibition of tumor angiogenesis.", + "TAG_DATA": [ + "60, bone {'context': 'B-cells'}", + "61, marrow {'context': 'I-cells'}", + "62, progenitors {'context': 'I-cells'}", + "81, mice, {'context': 'B-organism'}", + "106, Tie2-expressing {'context': 'B-cells'}", + "107, mononuclear {'context': 'I-cells'}", + "108, (TEM) {'context': 'I-cells'}", + "109, cells {'context': 'I-cells'}", + "126, bone {'context': 'B-cells'}", + "127, marrow-derived {'context': 'I-cells'}", + "128, ECs {'context': 'I-cells'}", + "135, bone {'context': 'B-cells'}", + "136, marrow {'context': 'I-cells'}", + "137, progenitors {'context': 'I-cells'}", + "138, constitutively {'perturbing_action': 'B-gene gain-of-function'}", + "159, TEM {'context': 'B-cells'}", + "160, cells {'context': 'I-cells'}", + "168, slower {'effect': 'B-negative'}", + "169, tumor {'phenotype': 'B-tumour growth'}", + "170, growth {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "60, bone ['l0', 'l1', 'l2', 'l3']", + "61, marrow ['l0', 'l4', 'l5', 'l6']", + "62, progenitors ['l1', 'l4', 'l7', 'l8']", + "75, tumors ['l2', 'l5', 'l7', 'l9']", + "81, mice, ['l3', 'l6', 'l8', 'l9']", + "106, Tie2-expressing ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "107, mononuclear ['l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "108, (TEM) ['l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "109, cells ['l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "126, bone ['l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "127, marrow-derived ['l14', 'l19', 'l23', 'l26', 'l28', 'l30']", + "128, ECs ['l15', 'l20', 'l24', 'l27', 'l29', 'l30']", + "135, bone ['l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "136, marrow ['l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "137, progenitors ['l32', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "138, constitutively ['l33', 'l40', 'l46', 'l52', 'l53', 'l54', 'l55', 'l56']", + "159, TEM ['l34', 'l41', 'l47', 'l52', 'l57', 'l58', 'l59', 'l60']", + "160, cells ['l35', 'l42', 'l48', 'l53', 'l57', 'l61', 'l62', 'l63']", + "168, slower ['l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l64', 'l65']", + "169, tumor ['l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l66']", + "170, growth ['l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l65', 'l66']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "bone", + "marrow", + "progenitors", + "TEM", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutively" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "bone", + "marrow", + "progenitors", + "TEM", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "slower" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "bone", + "marrow", + "progenitors", + "TEM", + "cells" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutively" + ] + }, + "effect": { + "val": "negative", + "words": [ + "slower" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutively" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "slower" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + } + ] + }, + { + "PMID": "12740569", + "TEXT": "Angiogenesis sustains tumor growth and metastasis, and recent studies indicate that the vascular endothelium regulates tissue mass. In the prostate, androgens drive angiogenic inducers to stimulate growth, whereas androgen withdrawal leads to decreased vascular endothelial growth factor, vascular regression and epithelial cell apoptosis. Here, we identify the angiogenesis inhibitor pigment epithelium-derived factor (PEDF) as a key inhibitor of stromal vasculature and epithelial tissue growth in mouse prostate and pancreas. In PEDF-deficient mice, stromal vessels were increased and associated with epithelial cell hyperplasia. Androgens inhibited prostatic PEDF expression in cultured cells. In vivo, androgen ablation increased PEDF in normal rat prostates and in human cancer biopsies. Exogenous PEDF induced tumor epithelial apoptosis in vitro and limited in vivo tumor xenograft growth, triggering endothelial apoptosis. Thus, PEDF regulates normal pancreas and prostate mass. Its androgen sensitivity makes PEDF a likely contributor to the anticancer effects of androgen ablation.", + "TAG_DATA": [ + "70, PEDF-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "71, mice, {'context': 'B-organism'}", + "88, cultured {'context': 'B-cells'}", + "89, cells. {'context': 'I-cells'}", + "90, In {'context': 'B-in vivo'}", + "91, vivo, {'context': 'I-in vivo'}", + "92, androgen {'perturbing_action': 'B-gene loss-of-function'}", + "93, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "97, normal {'context': 'B-tissue/organ'}", + "98, rat {'context': 'I-tissue/organ'}", + "99, prostates {'context': 'I-tissue/organ'}", + "102, human {'context': 'B-neoplasm'}", + "103, cancer {'context': 'I-neoplasm'}", + "104, biopsies. {'context': 'I-patient'}", + "107, induced {'effect': 'B-positive'}", + "108, tumor {'context': 'B-neoplasm'}", + "109, epithelial {'context': 'I-neoplasm'}", + "110, apoptosis {'phenotype': 'B-apoptosis'}", + "111, in {'context': 'B-in vitro'}", + "112, vitro {'context': 'I-in vitro'}", + "114, limited {'effect': 'B-negative'}", + "115, in {'context': 'B-in vivo'}", + "116, vivo {'context': 'I-in vivo'}", + "117, tumor {'context': 'B-xenograft'}", + "118, xenograft {'context': 'I-xenograft'}", + "120, triggering {'effect': 'B-positive'}", + "121, endothelial {'context': 'B-tissue/organ'}", + "122, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "70, PEDF-deficient ['l0', 'l1', 'l2']", + "71, mice, ['l0', 'l3']", + "88, cultured ['l1', 'l4']", + "89, cells. ['l2', 'l3', 'l4']", + "90, In ['l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "91, vivo, ['l5', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "92, androgen ['l6', 'l14', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "93, ablation ['l7', 'l15', 'l22', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "97, normal ['l8', 'l16', 'l23', 'l33', 'l43', 'l44', 'l45', 'l46', 'l47']", + "98, rat ['l9', 'l17', 'l24', 'l34', 'l43', 'l48', 'l49', 'l50', 'l51']", + "99, prostates ['l10', 'l18', 'l25', 'l35', 'l44', 'l48', 'l52', 'l53', 'l54']", + "102, human ['l11', 'l19', 'l26', 'l36', 'l45', 'l49', 'l52', 'l55', 'l56']", + "103, cancer ['l12', 'l20', 'l27', 'l37', 'l46', 'l50', 'l53', 'l55', 'l57']", + "104, biopsies. ['l13', 'l21', 'l28', 'l38', 'l47', 'l51', 'l54', 'l56', 'l57']", + "107, induced ['l29', 'l39', 'l58', 'l59', 'l60', 'l61', 'l62']", + "108, tumor ['l30', 'l40', 'l58', 'l63', 'l64', 'l65', 'l66']", + "109, epithelial ['l31', 'l41', 'l59', 'l63', 'l67', 'l68', 'l69']", + "110, apoptosis ['l32', 'l42', 'l60', 'l64', 'l67', 'l70', 'l71']", + "111, in ['l61', 'l65', 'l68', 'l70', 'l72']", + "112, vitro ['l62', 'l66', 'l69', 'l71', 'l72']", + "114, limited ['l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "115, in ['l73', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "116, vivo ['l74', 'l80', 'l86', 'l87', 'l88', 'l89', 'l90']", + "117, tumor ['l75', 'l81', 'l86', 'l91', 'l92', 'l93', 'l94']", + "118, xenograft ['l76', 'l82', 'l87', 'l91', 'l95', 'l96', 'l97']", + "120, triggering ['l77', 'l83', 'l88', 'l92', 'l95', 'l98', 'l99']", + "121, endothelial ['l78', 'l84', 'l89', 'l93', 'l96', 'l98', 'l100']", + "122, apoptosis. ['l79', 'l85', 'l90', 'l94', 'l97', 'l99', 'l100']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PEDF-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PEDF-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "cells." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "androgen", + "ablation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "androgen", + "ablation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "normal", + "rat", + "prostates" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "androgen", + "ablation" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "cancer", + "tumor", + "epithelial" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "androgen", + "ablation" + ] + }, + "context": { + "val": "patient", + "words": [ + "biopsies." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "androgen", + "ablation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "androgen", + "ablation" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor", + "epithelial" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "triggering" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumor", + "epithelial" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limited" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limited" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "tumor", + "xenograft" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limited" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "endothelial" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limited" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "tumor", + "xenograft" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "tumor", + "xenograft" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "endothelial" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "endothelial" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "12704385", + "TEXT": "Adoptive immunotherapy holds promise as a treatment for cancer and infectious diseases, but its development has been impeded by the lack of reproducible methods for generating therapeutic numbers of antigen-specific CD8(+) cytotoxic T lymphocytes (CTLs). As a result, there are only limited reports of expansion of antigen-specific CTLs to the levels required for clinical therapy. To address this issue, artificial antigen-presenting cells (aAPCs) were made by coupling a soluble human leukocyte antigen-immunoglobulin fusion protein (HLA-Ig) and CD28-specific antibody to beads. HLA-Ig-based aAPCs were used to induce and expand CTLs specific for cytomegalovirus (CMV) or melanoma. aAPC-induced cultures showed robust antigen-specific CTL expansion over successive rounds of stimulation, resulting in the generation of clinically relevant antigen-specific CTLs that recognized endogenous antigen-major histocompatibility complex complexes presented on melanoma cells. These studies show the value of HLA-Ig-based aAPCs for reproducible expansion of disease-specific CTLs for clinical approaches to adoptive immunotherapy.", + "TAG_DATA": [ + "88, CTLs {'context': 'B-cells'}", + "94, melanoma. {'context': 'B-neoplasm'}", + "99, antigen-specific {'context': 'B-cells'}", + "100, CTL {'context': 'I-cells'}", + "125, melanoma {'context': 'B-transformed cells'}", + "126, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "88, CTLs ['l0']", + "94, melanoma. ['l0']", + "99, antigen-specific ['l1']", + "100, CTL ['l1']", + "125, melanoma ['l2']", + "126, cells. ['l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12692542", + "TEXT": "X-linked hypohidrotic ectodermal dysplasia (XLHED; OMIM 305100) is a genetic disorder characterized by absence or deficient function of hair, teeth and sweat glands. Affected children may experience life-threatening high fever resulting from reduced ability to sweat. Mice with the Tabby phenotype share many symptoms with human XLHED patients because both phenotypes are caused by mutations of the syntenic ectodysplasin A gene (Eda) on the X chromosome. Two main splice variants of Eda, encoding EDA1 and EDA2, engage the tumor necrosis factor (TNF) family receptors EDAR and XEDAR, respectively. The EDA1 protein, acting through EDAR, is essential for proper formation of skin appendages; the functions of EDA2 and XEDAR are not known. EDA1 must be proteolytically processed to a soluble form to be active. Here, we show that treatment of pregnant Tabby mice with a recombinant form of EDA1, engineered to cross the placental barrier, permanently rescues the Tabby phenotype in the offspring. Notably, sweat glands can also be induced by EDA1 after birth. This is the first example of a developmental genetic defect that can be permanently corrected by short-term treatment with a recombinant protein.", + "TAG_DATA": [ + "130, Tabby {'context': 'B-organism'}", + "131, mice {'context': 'I-organism'}", + "134, recombinant {'perturbing_action': 'I-gene gain-of-function'}", + "135, form {'perturbing_action': 'I-gene gain-of-function'}", + "136, of {'perturbing_action': 'I-gene gain-of-function'}", + "137, EDA1, {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "130, Tabby ['l0', 'l1', 'l2', 'l3', 'l4']", + "131, mice ['l0', 'l5', 'l6', 'l7', 'l8']", + "134, recombinant ['l1', 'l5', 'l9', 'l10', 'l11']", + "135, form ['l2', 'l6', 'l9', 'l12', 'l13']", + "136, of ['l3', 'l7', 'l10', 'l12', 'l14']", + "137, EDA1, ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Tabby", + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "recombinant", + "form", + "of", + "EDA1," + ] + } + } + ] + }, + { + "PMID": "12692541", + "TEXT": "Infectious diseases have influenced population genetics and the evolution of the structure of the human genome in part by selecting for host susceptibility alleles that modify pathogenesis. Norovirus infection is associated with approximately 90% of epidemic non-bacterial acute gastroenteritis worldwide. Here, we show that resistance to Norwalk virus infection is multifactorial. Using a human challenge model, we showed that 29% of our study population was homozygous recessive for the alpha(1,2)fucosyltransferase gene (FUT2) in the ABH histo-blood group family and did not express the H type-1 oligosaccharide ligand required for Norwalk virus binding. The FUT2 susceptibility allele was fully penetrant against Norwalk virus infection as none of these individuals developed an infection after challenge, regardless of dose. Of the susceptible population that encoded a functional FUT2 gene, a portion was resistant to infection, suggesting that a memory immune response or some other unidentified factor also affords protection from Norwalk virus infection.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12692540", + "TEXT": "The live tuberculosis vaccines Mycobacterium bovis BCG (bacille Calmette-Guérin) and Mycobacterium microti both lack the potent, secreted T-cell antigens ESAT-6 (6-kDa early secretory antigenic target) and CFP-10 (10-kDa culture filtrate protein). This is a result of independent deletions in the region of deletion-1 (RD1) locus, which is intact in virulent members of the Mycobacterium tuberculosis complex. To increase their immunogenicity and protective capacity, we complemented both vaccines with different constructs containing the esxA and esxB genes, which encode ESAT-6 and CFP-10 respectively, as well as a variable number of flanking genes. Only reintroduction of the complete locus, comprising at least 11 genes, led to full secretion of the antigens and resulted in specific ESAT-6-dependent immune responses; this suggests that the flanking genes encode a secretory apparatus. Mice and guinea pigs vaccinated with the recombinant strain BCG::RD1-2F9 were better protected against challenge with M. tuberculosis, showing less severe pathology and reduced dissemination of the pathogen, as compared with control animals immunized with BCG alone.", + "TAG_DATA": [ + "126, Mice {'context': 'B-organism'}", + "128, guinea {'context': 'B-organism'}", + "129, pigs {'context': 'I-organism'}", + "158, animals {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "126, Mice ['l0', 'l1', 'l2']", + "128, guinea ['l0', 'l3', 'l4']", + "129, pigs ['l1', 'l3', 'l5']", + "158, animals ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12627227", + "TEXT": "Resistance of Streptococcus pneumoniae to antibiotics is increasing throughout the United States, with substantial variation among geographic regions. We show that patterns of geographic variation are best explained by the intensity of selection for resistance, which is reflected by differences between the proportions of resistance within individual serotypes, rather than by differences between the frequencies of particular serotypes. Using a mathematical transmission model, we analyzed temporal trends in the proportions of singly and dually resistant organisms and found that pneumococcal strains resistant to both penicillin and erythromycin are increasing faster than strains singly resistant to either. Using the model, we predict that by 1 July 2004, in the absence of a vaccine, 41% of pneumococci at the Centers for Disease Control and Prevention (CDC)'s Active Bacterial Core surveillance (ABCs) sites, taken together, will be dually resistant, with 5% resistant to penicillin only and 5% to erythromycin only.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12627226", + "TEXT": "The subcortical white matter of the adult human brain harbors a pool of glial progenitor cells. These cells can be isolated by fluorescence-activated cell sorting (FACS) after either transfection with green fluorescent protein (GFP) under the control of the CNP2 promoter, or A2B5-targeted immunotagging. Although these cells give rise largely to oligodendrocytes, in low-density culture we observed that some also generated neurons. We thus asked whether these nominally glial progenitors might include multipotential progenitor cells capable of neurogenesis. We found that adult human white-matter progenitor cells (WMPCs) could be passaged as neurospheres in vitro and that these cells generated functionally competent neurons and glia both in vitro and after xenograft to the fetal rat brain. WMPCs were able to produce neurons after their initial isolation and did not require in vitro expansion or reprogramming to do so. These experiments indicate that an abundant pool of mitotically competent neurogenic progenitor cells resides in the adult human white matter.", + "TAG_DATA": [ + "81, adult {'context': 'B-cells'}", + "82, human {'context': 'I-cells'}", + "83, white-matter {'context': 'I-cells'}", + "84, progenitor {'context': 'I-cells'}", + "85, cells {'context': 'I-cells'}", + "86, (WMPCs) {'context': 'I-cells'}", + "92, in {'context': 'B-in vitro'}", + "93, vitro {'context': 'I-in vitro'}", + "97, cells {'context': 'B-cells'}", + "101, neurons {'context': 'B-cells'}", + "103, glia {'context': 'B-cells'}", + "105, in {'context': 'B-in vitro'}", + "106, vitro {'context': 'I-in vitro'}", + "109, xenograft {'context': 'B-xenograft'}", + "110, to {'context': 'I-xenograft'}", + "111, the {'context': 'I-xenograft'}", + "112, fetal {'context': 'I-xenograft'}", + "113, rat {'context': 'I-xenograft'}", + "114, brain. {'context': 'I-xenograft'}", + "115, WMPCs {'context': 'B-cells'}", + "120, neurons {'context': 'B-cells'}", + "129, in {'context': 'B-in vitro'}", + "130, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "81, adult ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "82, human ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "83, white-matter ['l1', 'l13', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "84, progenitor ['l2', 'l14', 'l27', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "85, cells ['l3', 'l15', 'l28', 'l43', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "86, (WMPCs) ['l4', 'l16', 'l29', 'l44', 'l58', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "92, in ['l5', 'l17', 'l30', 'l45', 'l59', 'l67', 'l74', 'l75', 'l76', 'l77']", + "93, vitro ['l6', 'l18', 'l31', 'l46', 'l60', 'l68', 'l74', 'l78', 'l79', 'l80']", + "97, cells ['l7', 'l19', 'l32', 'l47', 'l61', 'l69', 'l75', 'l78', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "101, neurons ['l8', 'l20', 'l33', 'l48', 'l62', 'l70', 'l76', 'l79', 'l81', 'l87', 'l88', 'l89', 'l90', 'l91']", + "103, glia ['l9', 'l21', 'l34', 'l49', 'l63', 'l71', 'l77', 'l80', 'l82', 'l87', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "105, in ['l10', 'l22', 'l35', 'l50', 'l64', 'l72', 'l83', 'l88', 'l92', 'l99', 'l100']", + "106, vitro ['l11', 'l23', 'l36', 'l51', 'l65', 'l73', 'l84', 'l89', 'l93', 'l99', 'l101']", + "109, xenograft ['l37', 'l52', 'l94', 'l102', 'l103', 'l104', 'l105', 'l106']", + "110, to ['l12', 'l24', 'l38', 'l53', 'l66', 'l85', 'l90', 'l95', 'l100', 'l101', 'l102', 'l107', 'l108', 'l109', 'l110']", + "111, the ['l25', 'l39', 'l54', 'l96', 'l103', 'l107', 'l111', 'l112', 'l113']", + "112, fetal ['l40', 'l55', 'l104', 'l108', 'l111', 'l114', 'l115']", + "113, rat ['l41', 'l56', 'l97', 'l105', 'l109', 'l112', 'l114', 'l116']", + "114, brain. ['l26', 'l42', 'l57', 'l86', 'l91', 'l98', 'l106', 'l110', 'l113', 'l115', 'l116']", + "115, WMPCs ['l117', 'l118', 'l119']", + "120, neurons ['l117', 'l120', 'l121']", + "129, in ['l118', 'l120', 'l122']", + "130, vitro ['l119', 'l121', 'l122']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12598893", + "TEXT": "Multiple sclerosis (MS) is a devastating neuroinflammatory disorder of the central nervous system (CNS) in which T cells that are reactive with major components of myelin sheaths have a central role. The receptor for advanced glycation end products (RAGE) is present on T cells, mononuclear phagocytes and endothelium. Its pro-inflammatory ligands, S100-calgranulins, are upregulated in MS and in the related rodent model, experimental autoimmune encephalomyelitis (EAE). Blockade of RAGE suppressed EAE when disease was induced by myelin basic protein (MBP) peptide or encephalitogenic T cells, or when EAE occurred spontaneously in T-cell receptor (TCR)-transgenic mice devoid of endogenous TCR-alpha and TCR-beta chains. Inhibition of RAGE markedly decreased infiltration of the CNS by immune and inflammatory cells. Transgenic mice with targeted overexpression of dominant-negative RAGE in CD4+ T cells were resistant to MBP-induced EAE. These data reinforce the importance of RAGE-ligand interactions in modulating properties of CD4+ T cells that infiltrate the CNS.", + "TAG_DATA": [ + "66, Blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "67, of {'perturbing_action': 'I-pharmacological inhibition'}", + "68, RAGE {'perturbing_action': 'I-pharmacological inhibition'}", + "83, T {'context': 'B-cells'}", + "84, cells, {'context': 'I-cells'}", + "91, T-cell {'perturbing_action': 'B-gene gain-of-function'}", + "92, receptor {'perturbing_action': 'I-gene gain-of-function'}", + "93, (TCR)-transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "94, mice {'context': 'B-organism'}", + "102, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "103, of {'perturbing_action': 'I-pharmacological inhibition'}", + "104, RAGE {'perturbing_action': 'I-pharmacological inhibition'}", + "110, CNS {'context': 'B-tissue/organ'}", + "112, immune {'context': 'B-cells'}", + "116, Transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "117, mice {'context': 'I-organism'}", + "119, targeted {'perturbing_action': 'B-other'}", + "120, overexpression {'perturbing_action': 'I-other'}", + "121, of {'perturbing_action': 'I-other'}", + "122, dominant-negative {'perturbing_action': 'I-other'}", + "123, RAGE {'perturbing_action': 'I-other'}", + "125, CD4+ {'context': 'B-cells'}", + "126, T {'context': 'I-cells'}", + "127, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "66, Blockade ['l0', 'l1', 'l2', 'l3', 'l4']", + "67, of ['l0', 'l5', 'l6', 'l7']", + "68, RAGE ['l1', 'l5', 'l8', 'l9']", + "83, T ['l2', 'l6', 'l8', 'l10']", + "84, cells, ['l3', 'l7', 'l9', 'l10']", + "91, T-cell ['l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "92, receptor ['l11', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "93, (TCR)-transgenic ['l12', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "94, mice ['l13', 'l20', 'l26', 'l32', 'l33', 'l34', 'l35', 'l36']", + "102, Inhibition ['l14', 'l21', 'l27', 'l32', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "103, of ['l15', 'l22', 'l28', 'l33', 'l37', 'l43', 'l44', 'l45']", + "104, RAGE ['l16', 'l23', 'l29', 'l34', 'l38', 'l43', 'l46', 'l47']", + "110, CNS ['l17', 'l24', 'l30', 'l35', 'l39', 'l44', 'l46', 'l48']", + "112, immune ['l4', 'l18', 'l25', 'l31', 'l36', 'l40', 'l45', 'l47', 'l48']", + "116, Transgenic ['l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "117, mice ['l49', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "119, targeted ['l50', 'l58', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "120, overexpression ['l51', 'l59', 'l66', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "121, of ['l52', 'l60', 'l67', 'l73', 'l79', 'l80', 'l81', 'l82', 'l83']", + "122, dominant-negative ['l53', 'l61', 'l68', 'l74', 'l79', 'l84', 'l85', 'l86', 'l87']", + "123, RAGE ['l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l88', 'l89', 'l90']", + "125, CD4+ ['l55', 'l63', 'l70', 'l76', 'l81', 'l85', 'l88', 'l91', 'l92']", + "126, T ['l41', 'l56', 'l64', 'l71', 'l77', 'l82', 'l86', 'l89', 'l91', 'l93']", + "127, cells ['l42', 'l57', 'l65', 'l72', 'l78', 'l83', 'l87', 'l90', 'l92', 'l93']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "RAGE", + "Inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells,", + "immune", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "T-cell", + "receptor", + "(TCR)-transgenic", + "Transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "T-cell", + "receptor", + "(TCR)-transgenic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "CNS" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "T-cell", + "receptor", + "(TCR)-transgenic", + "Transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "immune", + "CD4+", + "T", + "cells" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "RAGE" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "RAGE" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "CNS" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "targeted", + "overexpression", + "of", + "dominant-negative", + "RAGE" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "targeted", + "overexpression", + "of", + "dominant-negative", + "RAGE" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells" + ] + } + } + ] + }, + { + "PMID": "12592400", + "TEXT": "The Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) is expressed in all KSHV-associated tumors, including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). We found that beta-catenin is overexpressed in both PEL cells and KS tissue. Introduction of anti-LANA small interfering RNA (siRNA) into PEL cells eliminated beta-catenin accumulation; LANA itself upregulated expression of beta-catenin in transfected cells. LANA stabilizes beta-catenin by binding to the negative regulator GSK-3beta, causing a cell cycle-dependent nuclear accumulation of GSK-3beta. The LANA C terminus contains sequences similar to the GSK-3beta-binding domain of Axin. Disruption of this region resulted in a mutant LANA that failed to re-localize GSK-3beta or stabilize beta-catenin. The importance of this pathway to KSHV-driven cell proliferation was highlighted by the observation that LANA, but not mutant LANA, stimulates entry into S phase. Redistribution of GSK-3beta can therefore be a source of beta-catenin dysregulation in human cancers.", + "TAG_DATA": [ + "39, anti-LANA {'perturbing_action': 'B-rnai/knockdown'}", + "40, small {'perturbing_action': 'I-rnai/knockdown'}", + "41, interfering {'perturbing_action': 'I-rnai/knockdown'}", + "42, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "43, (siRNA) {'perturbing_action': 'I-rnai/knockdown'}", + "45, PEL {'context': 'B-cells'}", + "46, cells {'context': 'I-cells'}", + "58, cells. {'context': 'B-cells'}", + "97, mutant {'perturbing_action': 'B-other'}", + "98, LANA {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "39, anti-LANA ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "40, small ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "41, interfering ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "42, RNA ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "43, (siRNA) ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "45, PEL ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "46, cells ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "97, mutant ['l21']", + "98, LANA ['l21']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "anti-LANA", + "small", + "interfering", + "RNA", + "(siRNA)" + ] + }, + "context": { + "val": "cells", + "words": [ + "PEL", + "cells" + ] + } + } + ] + }, + { + "PMID": "12563315", + "TEXT": "Nicotinic acid (niacin), a vitamin of the B complex, has been used for almost 50 years as a lipid-lowering drug. The pharmacological effect of nicotinic acid requires doses that are much higher than those provided by a normal diet. Its primary action is to decrease lipolysis in adipose tissue by inhibiting hormone-sensitive triglyceride lipase. This anti-lipolytic effect of nicotinic acid involves the inhibition of cyclic adenosine monophosphate (cAMP) accumulation in adipose tissue through a G(i)-protein-mediated inhibition of adenylyl cyclase. A G-protein-coupled receptor for nicotinic acid has been proposed in adipocytes. Here, we show that the orphan G-protein-coupled receptor, 'protein upregulated in macrophages by interferon-gamma' (mouse PUMA-G, human HM74), is highly expressed in adipose tissue and is a nicotinic acid receptor. Binding of nicotinic acid to PUMA-G or HM74 results in a G(i)-mediated decrease in cAMP levels. In mice lacking PUMA-G, the nicotinic acid-induced decrease in free fatty acid (FFA) and triglyceride plasma levels was abrogated, indicating that PUMA-G mediates the anti-lipolytic and lipid-lowering effects of nicotinic acid in vivo. The identification of the nicotinic acid receptor may be useful in the development of new drugs to treat dyslipidemia.", + "TAG_DATA": [ + "137, mice {'context': 'B-organism'}", + "138, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "139, PUMA-G, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "137, mice ['l0', 'l1']", + "138, lacking ['l0', 'l2']", + "139, PUMA-G, ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "PUMA-G," + ] + } + } + ] + }, + { + "PMID": "12539039", + "TEXT": "Pancreatic islets of Langerhans are enveloped by peri-islet Schwann cells (pSC), which express glial fibrillary acidic protein (GFAP) and S100beta. pSC-autoreactive T- and B-cell responses arise in 3- to 4-week-old diabetes-prone non-obese diabetic (NOD) mice, followed by progressive pSC destruction before detectable beta-cell death. Humans with probable prediabetes generate similar autoreactivities, and autoantibodies in islet-cell autoantibody (lCA) -positive sera co-localize to pSC. Moreover, GFAP-specific NOD T-cell lines transferred pathogenic peri-insulitis to NOD/severe combined immunodeficient (NOD/SCID) mice, and immunotherapy with GFAP or S100beta prevented diabetes. pSC survived in rat insulin promoter Iymphocytic choriomeningitis virus (rip-LCMV) glycoprotein/CD8+ T-cell receptor(gp) double-transgenic mice with virus-induced diabetes, suggesting that pSC death is not an obligate consequence of local inflammation and beta-cell destruction. However, pSC were deleted in spontaneously diabetic NOD mice carrying the CD8+/8.3 T-cell receptor transgene, a T cell receptor commonly expressed in earliest islet infiltrates. Autoimmune targeting of pancreatic nervous system tissue elements seems to be an integral, early part of natural type 1 diabetes.", + "TAG_DATA": [ + "64, NOD {'context': 'B-cells'}", + "65, T-cell {'context': 'I-cells'}", + "66, lines {'context': 'I-cells'}", + "71, NOD/severe {'context': 'B-organism'}", + "72, combined {'context': 'I-organism'}", + "73, immunodeficient {'context': 'I-organism'}", + "74, (NOD/SCID) {'context': 'I-organism'}", + "75, mice, {'context': 'I-organism'}", + "89, promoter {'perturbing_action': 'I-gene gain-of-function'}", + "90, Iymphocytic {'perturbing_action': 'I-gene gain-of-function'}", + "91, choriomeningitis {'perturbing_action': 'I-gene gain-of-function'}", + "92, virus {'perturbing_action': 'I-gene gain-of-function'}", + "93, (rip-LCMV) {'perturbing_action': 'I-gene gain-of-function'}", + "94, glycoprotein/CD8+ {'perturbing_action': 'I-gene gain-of-function'}", + "95, T-cell {'perturbing_action': 'I-gene gain-of-function'}", + "96, receptor(gp) {'perturbing_action': 'I-gene gain-of-function'}", + "97, double-transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "98, mice {'context': 'B-organism'}", + "124, NOD {'context': 'I-organism'}", + "125, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "64, NOD ['l0', 'l1', 'l2']", + "65, T-cell ['l0', 'l3', 'l4']", + "66, lines ['l1', 'l3']", + "71, NOD/severe ['l5', 'l6', 'l7', 'l8']", + "72, combined ['l5', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "73, immunodeficient ['l6', 'l9', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "74, (NOD/SCID) ['l7', 'l10', 'l16', 'l22']", + "75, mice, ['l2', 'l4', 'l8', 'l11', 'l17', 'l22']", + "87, rat ['l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "88, insulin ['l23', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "89, promoter ['l24', 'l38', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "90, Iymphocytic ['l12', 'l18', 'l25', 'l39', 'l49', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "91, choriomeningitis ['l13', 'l19', 'l26', 'l40', 'l50', 'l59', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "92, virus ['l14', 'l20', 'l27', 'l41', 'l51', 'l60', 'l67', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "93, (rip-LCMV) ['l15', 'l21', 'l28', 'l42', 'l52', 'l61', 'l68', 'l74', 'l80', 'l81', 'l82', 'l83', 'l84']", + "94, glycoprotein/CD8+ ['l29', 'l43', 'l53', 'l62', 'l69', 'l75', 'l80', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "95, T-cell ['l30', 'l44', 'l54', 'l63', 'l70', 'l76', 'l81', 'l85', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "96, receptor(gp) ['l31', 'l45', 'l55', 'l64', 'l71', 'l77', 'l82', 'l86', 'l92', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "97, double-transgenic ['l32', 'l46', 'l56', 'l65', 'l72', 'l78', 'l83', 'l87', 'l93', 'l98', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "98, mice ['l33', 'l47', 'l57', 'l66', 'l73', 'l79', 'l84', 'l88', 'l94', 'l99', 'l105']", + "118, pSC ['l34', 'l48', 'l58', 'l89', 'l95', 'l100', 'l106', 'l112', 'l113', 'l114', 'l115', 'l116']", + "124, NOD ['l101', 'l107', 'l112', 'l117', 'l118', 'l119', 'l120']", + "125, mice ['l35', 'l90', 'l96', 'l102', 'l108', 'l113', 'l117', 'l121', 'l122', 'l123']", + "129, T-cell ['l36', 'l91', 'l97', 'l103', 'l109', 'l114', 'l118', 'l121', 'l124', 'l125']", + "130, receptor ['l37', 'l104', 'l110', 'l115', 'l119', 'l122', 'l124', 'l126']", + "131, transgene, ['l111', 'l116', 'l120', 'l123', 'l125', 'l126']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "combined", + "immunodeficient", + "mice", + "NOD" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Iymphocytic", + "choriomeningitis", + "virus", + "(rip-LCMV)", + "promoter", + "glycoprotein/CD8+", + "T-cell", + "receptor(gp)", + "double-transgenic" + ] + } + } + ] + }, + { + "PMID": "12514743", + "TEXT": "The drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4) is thought to be involved in the metabolism of nearly 50% of all the drugs currently prescribed. Alteration in the activity or expression of this enzyme seems to be a key predictor of drug responsiveness and toxicity. Currently available studies indicate that the ligand-activated nuclear receptors pregnane X receptor (PXR; NR1I2) and constitutive androstane receptor (CAR; NR1I3) regulate CYP3A4 expression. However, in cell-based reporter assays, CYP3A4 promoter activity was most pronounced in liver-derived cells and minimal or modest in non-hepatic cells, indicating that a liver-specific factor is required for physiological transcriptional response. Here we show that the orphan nuclear receptor hepatocyte nuclear factor-4alpha (HNF4alpha; HNF4A) is critically involved in the PXR- and CAR-mediated transcriptional activation of CYP3A4. We identified a specific cis-acting element in the CYP3A4 gene enhancer that confers HNF4alpha binding and thereby permits PXR- and CAR-mediated gene activation. Fetal mice with conditional deletion of Hnf4alpha had reduced or absent expression of CYP3A. Furthermore, adult mice with conditional hepatic deletion of Hnf4alpha had reduced basal and inducible expression of CYP3A. These data identify HNF4alpha as an important regulator of coordinate nuclear-receptor-mediated response to xenobiotics.", + "TAG_DATA": [ + "148, Fetal {'context': 'B-organism'}", + "149, mice {'context': 'I-organism'}", + "151, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "152, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "153, of {'perturbing_action': 'I-gene loss-of-function'}", + "154, Hnf4alpha {'perturbing_action': 'I-gene loss-of-function'}", + "163, adult {'context': 'B-organism'}", + "164, mice {'context': 'I-organism'}", + "166, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "167, hepatic {'perturbing_action': 'I-gene loss-of-function'}", + "168, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "169, of {'perturbing_action': 'I-gene loss-of-function'}", + "170, Hnf4alpha {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "148, Fetal ['l0', 'l1', 'l2', 'l3', 'l4']", + "149, mice ['l0', 'l5', 'l6', 'l7', 'l8']", + "151, conditional ['l1', 'l5', 'l9', 'l10', 'l11']", + "152, deletion ['l2', 'l6', 'l9', 'l12', 'l13']", + "153, of ['l3', 'l7', 'l10', 'l12', 'l14']", + "154, Hnf4alpha ['l4', 'l8', 'l11', 'l13', 'l14']", + "163, adult ['l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "164, mice ['l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "166, conditional ['l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "167, hepatic ['l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "168, deletion ['l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "169, of ['l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "170, Hnf4alpha ['l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Fetal", + "mice", + "adult" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "deletion", + "of", + "Hnf4alpha", + "hepatic" + ] + } + } + ] + }, + { + "PMID": "12496958", + "TEXT": "Cardiac hypertrophy is an adaptive response to a variety of mechanical and hormonal stimuli, and represents an early event in the clinical course leading to heart failure. By gene inactivation, we demonstrate here a crucial role of melusin, a muscle-specific protein that interacts with the integrin beta1 cytoplasmic domain, in the hypertrophic response to mechanical overload. Melusin-null mice showed normal cardiac structure and function in physiological conditions, but when subjected to pressure overload--a condition that induces a hypertrophic response in wild-type controls--they developed an abnormal cardiac remodeling that evolved into dilated cardiomyopathy and contractile dysfunction. In contrast, the hypertrophic response was identical in wild-type and melusin-null mice after chronic administration of angiotensin II or phenylephrine at doses that do not increase blood pressure--that is, in the absence of cardiac biomechanical stress. Analysis of intracellular signaling events induced by pressure overload indicated that phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) was specifically blunted in melusin-null hearts. Thus, melusin prevents cardiac dilation during chronic pressure overload by specifically sensing mechanical stress.", + "TAG_DATA": [ + "56, Melusin-null {'perturbing_action': 'B-gene loss-of-function'}", + "57, mice {'context': 'B-organism'}", + "105, melusin-null {'perturbing_action': 'B-gene loss-of-function'}", + "106, mice {'context': 'B-organism'}", + "152, melusin-null {'perturbing_action': 'B-gene loss-of-function'}", + "153, hearts. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "56, Melusin-null ['l0']", + "57, mice ['l0']", + "105, melusin-null ['l1']", + "106, mice ['l1']", + "152, melusin-null ['l2']", + "153, hearts. ['l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Melusin-null", + "melusin-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "melusin-null" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hearts." + ] + } + } + ] + }, + { + "PMID": "12461524", + "TEXT": "Selective skewing of autoreactive interferon-gamma (IFN-gamma)-producing T helper cells (Th1) toward an interleukin-4 (IL-4)-producing (Th2) phenotype can in experimental animals alleviate autoimmune disease without inducing general immunosuppression. In a prospective dose escalation study, we assessed treatment with human IL-4 (rhuIL-4) in 20 patients with severe psoriasis. The therapy was well tolerated, and within six weeks all patients showed decreased clinical scores and 15 improved more than 68%. Stable reduction of clinical scores was significantly better at 0.2-0.5 microg rhuIL-4 than at < or =0.1 microg rhuIL-4 (P = 0.009). In psoriatic lesions, treatment with 0.2-0.5 microg/kg rhuIL-4 reduced the concentrations of IL-8 and IL-19, two cytokines directly involved in psoriasis; the number of chemokine receptor CCR5+ Th1 cells; and the IFN-gamma/IL-4 ratio. In the circulation, 0.2-0.5 microg/kg rhuIL-4 increased the number of IL-4+CD4+ T cells two- to three-fold. Thus, IL-4 therapy can induce Th2 differentiation in human CD4+ T cells and has promise as a potential treatment for psoriasis, a prototypic Th1-associated autoimmune disease.", + "TAG_DATA": [ + "42, patients {'context': 'B-patient'}", + "90, psoriatic {'context': 'B-neoplasm'}", + "91, lesions, {'context': 'I-neoplasm'}", + "132, IL-4+CD4+ {'context': 'B-cells'}", + "133, T {'context': 'I-cells'}", + "134, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "90, psoriatic ['l0']", + "91, lesions, ['l0']", + "132, IL-4+CD4+ ['l1', 'l2']", + "133, T ['l1', 'l3']", + "134, cells ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12426562", + "TEXT": "Although the deleterious vasoconstrictive effects of cell-free, hemoglobin-based blood substitutes have been appreciated, the systemic effects of chronic hemolysis on nitric oxide bioavailability have not been considered or quantified. Central to this investigation is the understanding that nitric oxide reacts at least 1,000 times more rapidly with free hemoglobin solutions than with erythrocytes. We hypothesized that decompartmentalization of hemoglobin into plasma would divert nitric oxide from homeostatic vascular function. We demonstrate here that plasma from patients with sickle-cell disease contains cell-free ferrous hemoglobin, which stoichiometrically consumes micromolar quantities of nitric oxide and abrogates forearm blood flow responses to nitric oxide donor infusions. Therapies that inactivate plasma hemoglobin by oxidation or nitric oxide ligation restore nitric oxide bioavailability. Decompartmentalization of hemoglobin and subsequent dioxygenation of nitric oxide may explain the vascular complications shared by acute and chronic hemolytic disorders.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12379849", + "TEXT": "The four MEF2 transcription factors (MEF2A, -B, -C, and -D) regulate differentiation and calcium-dependent gene expression in muscle cells. We generated mice deficient in MEF2A, the predominant Mef2 gene product expressed in post-natal cardiac muscle. Most mice lacking Mef2a died suddenly within the first week of life and exhibited pronounced dilation of the right ventricle, myofibrillar fragmentation, mitochondrial disorganization and activation of a fetal cardiac gene program. The few Mef2a(-/-) mice that survived to adulthood also showed a deficiency of cardiac mitochondria and susceptibility to sudden death. Paradoxically, MEF2 transcriptional activity, revealed by the expression of a MEF2-dependent transgene, was enhanced in the hearts of Mef2a-mutant mice, reflecting the transcriptional activation of residual MEF2D. These findings reveal specific roles for MEF2A in maintaining appropriate mitochondrial content and cyto-architectural integrity in the post-natal heart and show that other MEF2 isoforms cannot support these activities.", + "TAG_DATA": [ + "21, mice {'context': 'B-organism'}", + "22, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "36, mice {'context': 'B-organism'}", + "37, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "38, Mef2a {'perturbing_action': 'I-gene loss-of-function'}", + "69, Mef2a(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "70, mice {'context': 'B-organism'}", + "103, hearts {'context': 'B-tissue/organ'}", + "105, Mef2a-mutant {'perturbing_action': 'B-other'}", + "106, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "21, mice ['l0', 'l1', 'l2', 'l3']", + "22, deficient ['l0', 'l4', 'l5', 'l6']", + "36, mice ['l1', 'l4', 'l7', 'l8']", + "37, lacking ['l2', 'l5', 'l7', 'l9']", + "38, Mef2a ['l3', 'l6', 'l8', 'l9']", + "69, Mef2a(-/-) ['l10']", + "70, mice ['l10']", + "103, hearts ['l11', 'l12']", + "105, Mef2a-mutant ['l11', 'l13']", + "106, mice, ['l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "lacking", + "Mef2a", + "Mef2a(-/-)" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "hearts" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Mef2a-mutant" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Mef2a-mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "12379846", + "TEXT": "To characterize antibodies produced in humans in response to Abeta42 vaccination, we carried out immunohistochemical examinations of the brains of both transgenic mice and human patients with beta-amyloid pathology. We collected sera from patients with Alzheimer disease who received a primary injection of pre-aggregated Abeta42 followed by one booster injection in a placebo-controlled study. Antibodies in immune sera recognized beta-amyloid plaques, diffuse Abeta deposits and vascular beta-amyloid in brain blood vessels. The antibodies did not cross-react with native full-length beta-amyloid precursor protein or its physiological derivatives, including soluble Abeta42. These findings indicate that vaccination of AD patients with Abeta42 induces antibodies that have a high degree of selectivity for the pathogenic target structures. Whether vaccination to produce antibodies against beta-amyloid will halt the cognitive decline in AD will depend upon clinical assessments over time.", + "TAG_DATA": [ + "21, transgenic {'context': 'B-organism'}", + "22, mice {'context': 'I-organism'}", + "24, human {'context': 'B-patient'}", + "25, patients {'context': 'I-patient'}", + "33, patients {'context': 'B-patient'}", + "34, with {'context': 'I-patient'}", + "35, Alzheimer {'context': 'I-patient'}", + "36, disease {'context': 'I-patient'}", + "96, patients {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "21, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "22, mice ['l0', 'l7', 'l8']", + "24, human ['l1', 'l7', 'l9', 'l10', 'l11', 'l12', 'l13']", + "25, patients ['l2', 'l9', 'l14', 'l15', 'l16', 'l17']", + "33, patients ['l3', 'l10', 'l14', 'l18', 'l19', 'l20']", + "34, with ['l4', 'l11', 'l15', 'l18', 'l21', 'l22']", + "35, Alzheimer ['l5', 'l12', 'l16', 'l19', 'l21', 'l23']", + "36, disease ['l6', 'l8', 'l13', 'l17', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12368905", + "TEXT": "Aspirin (ASA) and dexamethasone (DEX) are widely used anti-inflammatory agents yet their mechanism(s) for blocking polymorphonuclear neutrophil (PMN) accumulation at sites of inflammation remains unclear. Here, we report that inhibition of PMN infiltration by ASA and DEX is a property shared by aspirin-triggered lipoxins (ATL) and the glucocorticoid-induced annexin 1 (ANXA1)-derived peptides that are both generated in vivo and act at the lipoxin A(4) receptor (ALXR/FPRL1) to halt PMN diapedesis. These structurally diverse ligands specifically interact directly with recombinant human ALXR demonstrated by specific radioligand binding and function as well as immunoprecipitation of PMN receptors. In addition, the combination of both ATL and ANXA1-derived peptides limited PMN infiltration and reduced production of inflammatory mediators (that is, prostaglandins and chemokines) in vivo. Together, these results indicate functional redundancies in endogenous lipid and peptide anti-inflammatory circuits that are spatially and temporally separate, where both ATL and specific ANXA1-derived peptides act in concert at ALXR to downregulate PMN recruitment to inflammatory loci.", + "TAG_DATA": [ + "106, PMN {'context': 'B-cells'}", + "119, in {'context': 'B-in vivo'}", + "120, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "106, PMN ['l0', 'l1']", + "119, in ['l0', 'l2']", + "120, vivo. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12357249", + "TEXT": "Transmembrane signaling through G protein-coupled receptors (GPCRs) controls a diverse array of cellular processes including metabolism, growth, motility, adhesion, neuronal signaling and blood coagulation. The numerous GPCRs and their key roles in both normal physiology and disease have made them the target for more than 50% of all prescribed drugs. GPCR agonists and antagonists act on the extracellular side of the receptors, whereas the intracellular surface has not yet been exploited for development of new therapeutic agents. Here, we demonstrate the utility of novel cell-penetrating peptides, termed 'pepducins', that act as intracellular inhibitors of signal transference from receptors to G proteins. Attachment of a palmitate lipid to peptides based on the third intracellular loop of protease-activated receptor 1 (PAR1) or PAR4 (refs. 3-5) yielded potent inhibitors of thrombin-mediated aggregation of human platelets. Infusion of the anti-PAR4 pepducin into mice extended bleeding time and protected against systemic platelet activation, consistent with the phenotype of PAR4-deficient mice. We show that pepducins might be used to ascertain the physiological roles of GPCRs and rapidly determine the potential therapeutic value of blockade of a particular signaling pathway.", + "TAG_DATA": [ + "130, human {'context': 'B-cells'}", + "131, platelets. {'context': 'I-cells'}", + "138, mice {'context': 'B-organism'}", + "153, PAR4-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "154, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "130, human ['l0']", + "131, platelets. ['l0']", + "153, PAR4-deficient ['l1']", + "154, mice. ['l1']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PAR4-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "12244304", + "TEXT": "Primary pulmonary hypertension is a progressive and often fatal disorder in humans that results from an increase in pulmonary blood pressure associated with abnormal vascular proliferation. Dexfenfluramine increases the risk of pulmonary hypertension in humans, and its active metabolite is a selective serotonin 5-hydroxytryptamine 2B (5-HT(2B)) receptor agonist. Thus, we investigated the contribution of the 5-HT(2B)receptor to the pathogenesis of pulmonary hypertension. Using the chronic-hypoxic-mouse model of pulmonary hypertension, we found that the hypoxia-dependent increase in pulmonary blood pressure and lung remodeling are associated with an increase in vascular proliferation, elastase activity and transforming growth factor-beta levels, and that these parameters are potentiated by dexfenfluramine treatment. In contrast, hypoxic mice with genetically or pharmacologically inactive 5-HT(2B)receptors manifested no change in any of these parameters. In both humans and mice, pulmonary hypertension is associated with a substantial increase in 5-HT(2B) receptor expression in pulmonary arteries. These data show that activation of 5-HT(2B) receptors is a limiting step in the development of pulmonary hypertension.", + "TAG_DATA": [ + "86, increase {'effect': 'B-positive'}", + "89, proliferation, {'phenotype': 'B-proliferation'}", + "108, hypoxic {'context': 'B-organism'}", + "109, mice {'context': 'I-organism'}", + "113, pharmacologically {'perturbing_action': 'I-gene loss-of-function'}", + "114, inactive {'perturbing_action': 'I-gene loss-of-function'}", + "115, 5-HT(2B)receptors {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "86, increase ['l0']", + "89, proliferation, ['l0']", + "108, hypoxic ['l1', 'l2', 'l3', 'l4', 'l5']", + "109, mice ['l1', 'l6', 'l7', 'l8', 'l9']", + "112, or ['l2', 'l6', 'l10', 'l11', 'l12']", + "113, pharmacologically ['l3', 'l7', 'l10', 'l13', 'l14']", + "114, inactive ['l4', 'l8', 'l11', 'l13', 'l15']", + "115, 5-HT(2B)receptors ['l5', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "hypoxic", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pharmacologically", + "inactive", + "5-HT(2B)receptors" + ] + } + } + ] + }, + { + "PMID": "12244302", + "TEXT": "Mechanisms linking mitogenic and growth inhibitory cytokine signaling and the cell cycle have not been fully elucidated in either cancer or in normal cells. Here we show that activation of protein kinase B (PKB)/Akt, contributes to resistance to antiproliferative signals and breast cancer progression in part by impairing the nuclear import and action of p27. Akt transfection caused cytoplasmic p27 accumulation and resistance to cytokine-mediated G1 arrest. The nuclear localization signal of p27 contains an Akt consensus site at threonine 157, and p27 phosphorylation by Akt impaired its nuclear import in vitro. Akt phosphorylated wild-type p27 but not p27T157A. In cells transfected with constitutively active Akt(T308DS473D)(PKB(DD)), p27WT mislocalized to the cytoplasm, but p27T157A was nuclear. In cells with activated Akt, p27WT failed to cause G1 arrest, while the antiproliferative effect of p27T157A was not impaired. Cytoplasmic p27 was seen in 41% (52 of 128) of primary human breast cancers in conjunction with Akt activation and was correlated with a poor patient prognosis. Thus, we show a novel mechanism whereby Akt impairs p27 function that is associated with an aggressive phenotype in human breast cancer.", + "TAG_DATA": [ + "55, Akt {'perturbing_action': 'B-gene gain-of-function'}", + "56, transfection {'perturbing_action': 'I-gene gain-of-function'}", + "62, resistance {'effect': 'B-negative'}", + "65, G1 {'phenotype': 'B-cell cycle arrest'}", + "66, arrest. {'phenotype': 'I-cell cycle arrest'}", + "100, cells {'context': 'B-cells'}", + "101, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "102, with {'perturbing_action': 'I-other'}", + "103, constitutively {'perturbing_action': 'I-other'}", + "104, active {'perturbing_action': 'I-other'}", + "105, Akt(T308DS473D)(PKB(DD)), {'perturbing_action': 'I-other'}", + "116, cells {'context': 'B-cells'}", + "118, activated {'perturbing_action': 'B-gene gain-of-function'}", + "119, Akt, {'perturbing_action': 'I-gene gain-of-function'}", + "121, failed {'effect': 'B-no effect'}", + "122, to {'effect': 'I-no effect'}", + "123, cause {'effect': 'I-no effect'}", + "124, G1 {'phenotype': 'B-cell cycle arrest'}", + "125, arrest, {'phenotype': 'I-cell cycle arrest'}" + ], + "LINK_DATA": [ + "55, Akt ['l0', 'l1', 'l2', 'l3']", + "56, transfection ['l0', 'l4', 'l5', 'l6']", + "62, resistance ['l1', 'l4', 'l7', 'l8']", + "65, G1 ['l2', 'l5', 'l7', 'l9']", + "66, arrest. ['l3', 'l6', 'l8', 'l9']", + "100, cells ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "101, transfected ['l10', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "102, with ['l11', 'l23', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "103, constitutively ['l12', 'l24', 'l35', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "104, active ['l13', 'l25', 'l36', 'l46', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "105, Akt(T308DS473D)(PKB(DD)), ['l14', 'l26', 'l37', 'l47', 'l56', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "116, cells ['l15', 'l27', 'l38', 'l48', 'l57', 'l65', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "118, activated ['l16', 'l28', 'l39', 'l49', 'l58', 'l66', 'l73', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "119, Akt, ['l17', 'l29', 'l40', 'l50', 'l59', 'l67', 'l74', 'l80', 'l86', 'l87', 'l88', 'l89', 'l90']", + "121, failed ['l18', 'l30', 'l41', 'l51', 'l60', 'l68', 'l75', 'l81', 'l86', 'l91', 'l92', 'l93', 'l94']", + "122, to ['l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l76', 'l82', 'l87', 'l91', 'l95', 'l96', 'l97']", + "123, cause ['l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l83', 'l88', 'l92', 'l95', 'l98', 'l99']", + "124, G1 ['l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l89', 'l93', 'l96', 'l98', 'l100']", + "125, arrest, ['l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l94', 'l97', 'l99', 'l100']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Akt", + "transfection" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Akt", + "transfection", + "transfected", + "activated", + "Akt," + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G1", + "arrest.", + "arrest," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G1", + "arrest." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "activated", + "Akt," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "with", + "constitutively", + "active", + "Akt(T308DS473D)(PKB(DD))," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "failed", + "to", + "cause" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G1", + "arrest," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "activated", + "Akt," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "failed", + "to", + "cause" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "with", + "constitutively", + "active", + "Akt(T308DS473D)(PKB(DD))," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "failed", + "to", + "cause" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "with", + "constitutively", + "active", + "Akt(T308DS473D)(PKB(DD))," + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G1", + "arrest," + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "failed", + "to", + "cause" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G1", + "arrest," + ] + } + } + ] + }, + { + "PMID": "12219084", + "TEXT": "Epstein-Barr virus (EBV) is etiologically linked to endemic Burkitt lymphoma (BL), but its contribution to lymphomagenesis, versus that of the chromosomal translocation leading to c-myc gene deregulation, remains unclear. The virus's growth-transforming (Latency III) program of gene expression is extinguished in tumor cells, and only a single viral protein, the EBV nuclear antigen (EBNA)1, is expressed via the alternative Latency I program. It is not known if BL arises from a B-cell subset in which EBV naturally adopts a Latency I infection or if a clone with limited antigen expression has been selected from an EBV-transformed Latency III progenitor pool. Here we identify a subset of BL tumors in which the Latency III-associated EBNA promoter Wp is active and most EBNAs are expressed, but where a gene deletion has specifically abrogated the expression of EBNA2. This implies that BL can be selected from a Latency III progenitor and that the principal selection pressure is for downregulation of the c-Myc antagonist EBNA2.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "12172541", + "TEXT": "Glioblastoma multiforme is the most undifferentiated type of brain tumor, and its prognosis is extremely poor. Glioblastoma cells exhibit highly migratory and invasive behavior, which makes surgical intervention unsuccessful. Here, we showed that glioblastoma cells express Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptors assembled from the GluR1 and/or GluR4 subunits, and that their conversion to Ca(2+)-impermeable receptors by adenovirus-mediated transfer of the GluR2 cDNA inhibited cell locomotion and induced apoptosis. In contrast, overexpression of Ca(2+)-permeable AMPA receptors facilitated migration and proliferation of the tumor cells. These findings indicate that Ca(2+)-permeable AMPA receptors have crucial roles in growth of glioblastoma. Blockage of these Ca(2+)-permeable receptors may be a useful therapeutic strategy for the prevention of glioblastoma invasion.", + "TAG_DATA": [ + "60, GluR2 {'perturbing_action': 'I-gene gain-of-function'}", + "61, cDNA {'perturbing_action': 'I-gene gain-of-function'}", + "62, inhibited {'effect': 'B-negative'}", + "63, cell {'context': 'B-cells'}", + "64, locomotion {'phenotype': 'B-migration'}", + "66, induced {'effect': 'B-positive'}", + "67, apoptosis. {'phenotype': 'B-apoptosis'}", + "70, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "71, of {'perturbing_action': 'I-gene gain-of-function'}", + "72, Ca(2+)-permeable {'perturbing_action': 'I-gene gain-of-function'}", + "73, AMPA {'perturbing_action': 'I-gene gain-of-function'}", + "74, receptors {'perturbing_action': 'I-gene gain-of-function'}", + "75, facilitated {'effect': 'B-positive'}", + "76, migration {'phenotype': 'B-migration'}", + "78, proliferation {'phenotype': 'B-proliferation'}", + "81, tumor {'context': 'B-transformed cells'}", + "82, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "60, GluR2 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "61, cDNA ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "62, inhibited ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "63, cell ['l2', 'l7', 'l11', 'l15', 'l16']", + "64, locomotion ['l3', 'l8', 'l12', 'l15', 'l17', 'l18']", + "66, induced ['l4', 'l9', 'l13', 'l16', 'l17', 'l19']", + "67, apoptosis. ['l5', 'l10', 'l14', 'l18', 'l19']", + "70, overexpression ['l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "71, of ['l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "72, Ca(2+)-permeable ['l21', 'l29', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "73, AMPA ['l22', 'l30', 'l37', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "74, receptors ['l23', 'l31', 'l38', 'l44', 'l50', 'l51', 'l52', 'l53', 'l54']", + "75, facilitated ['l24', 'l32', 'l39', 'l45', 'l50', 'l55', 'l56', 'l57', 'l58']", + "76, migration ['l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l59', 'l60', 'l61']", + "78, proliferation ['l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l62', 'l63']", + "81, tumor ['l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l62', 'l64']", + "82, cells. ['l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l64']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GluR2", + "cDNA" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GluR2", + "cDNA" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GluR2", + "cDNA", + "overexpression", + "of", + "Ca(2+)-permeable", + "AMPA", + "receptors" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "locomotion", + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GluR2", + "cDNA", + "overexpression", + "of", + "Ca(2+)-permeable", + "AMPA", + "receptors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "facilitated" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GluR2", + "cDNA" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "locomotion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "locomotion" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "locomotion", + "migration" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "facilitated" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Ca(2+)-permeable", + "AMPA", + "receptors" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Ca(2+)-permeable", + "AMPA", + "receptors" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "facilitated" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "facilitated" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + } + ] + }, + { + "PMID": "12134142", + "TEXT": "The feasibility of gene therapy for cardiomyopathy, heart failure and other chronic cardiac muscle diseases is so far unproven. Here, we developed an in vivo recombinant adeno-associated virus (rAAV) transcoronary delivery system that allows stable, high efficiency and relatively cardiac-selective gene expression. We used rAAV to express a pseudophosphorylated mutant of human phospholamban (PLN), a key regulator of cardiac sarcoplasmic reticulum (SR) Ca(2+) cycling in BIO14.6 cardiomyopathic hamsters. The rAAV/S16EPLN treatment enhanced myocardial SR Ca(2+) uptake and suppressed progressive impairment of left ventricular (LV) systolic function and contractility for 28-30 weeks, thereby protecting cardiac myocytes from cytopathic plasma-membrane disruption. Low LV systolic pressure and deterioration in LV relaxation were also largely prevented by rAAV/S16EPLN treatment. Thus, transcoronary gene transfer of S16EPLN via rAAV vector is a potential therapy for progressive dilated cardiomyopathy and associated heart failure.", + "TAG_DATA": [ + "44, rAAV {'perturbing_action': 'B-other'}", + "45, to {'perturbing_action': 'I-other'}", + "46, express {'perturbing_action': 'I-other'}", + "47, a {'perturbing_action': 'I-other'}", + "48, pseudophosphorylated {'perturbing_action': 'I-other'}", + "49, mutant {'perturbing_action': 'I-other'}", + "50, of {'perturbing_action': 'I-other'}", + "51, human {'perturbing_action': 'I-other'}", + "52, phospholamban {'perturbing_action': 'I-other'}", + "53, (PLN), {'perturbing_action': 'I-other'}", + "67, hamsters. {'context': 'B-organism'}", + "93, cardiac {'context': 'B-cells'}", + "94, myocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "44, rAAV ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "45, to ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "46, express ['l1', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "47, a ['l2', 'l13', 'l22', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "48, pseudophosphorylated ['l3', 'l14', 'l23', 'l32', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "49, mutant ['l4', 'l15', 'l24', 'l33', 'l41', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "50, of ['l5', 'l16', 'l25', 'l34', 'l42', 'l49', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "51, human ['l6', 'l17', 'l26', 'l35', 'l43', 'l50', 'l56', 'l62', 'l63', 'l64', 'l65', 'l66']", + "52, phospholamban ['l7', 'l18', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l67', 'l68', 'l69', 'l70']", + "53, (PLN), ['l8', 'l19', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l71', 'l72', 'l73']", + "67, hamsters. ['l9', 'l20', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71']", + "93, cardiac ['l10', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l74']", + "94, myocytes ['l11', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l74']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "rAAV", + "to", + "express", + "a", + "pseudophosphorylated", + "mutant", + "of", + "human", + "phospholamban", + "(PLN)," + ] + }, + "context": { + "val": "organism", + "words": [ + "hamsters." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "rAAV", + "to", + "express", + "a", + "pseudophosphorylated", + "mutant", + "of", + "human", + "phospholamban", + "(PLN)," + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiac", + "myocytes" + ] + } + } + ] + }, + { + "PMID": "12118244", + "TEXT": "Histopathology is insufficient to predict disease progression and clinical outcome in lung adenocarcinoma. Here we show that gene-expression profiles based on microarray analysis can be used to predict patient survival in early-stage lung adenocarcinomas. Genes most related to survival were identified with univariate Cox analysis. Using either two equivalent but independent training and testing sets, or 'leave-one-out' cross-validation analysis with all tumors, a risk index based on the top 50 genes identified low-risk and high-risk stage I lung adenocarcinomas, which differed significantly with respect to survival. This risk index was then validated using an independent sample of lung adenocarcinomas that predicted high- and low-risk groups. This index included genes not previously associated with survival. The identification of a set of genes that predict survival in early-stage lung adenocarcinoma allows delineation of a high-risk group that may benefit from adjuvant therapy.", + "TAG_DATA": [ + "61, tumors, {'context': 'B-neoplasm'}", + "77, lung {'context': 'B-neoplasm'}", + "78, adenocarcinomas, {'context': 'I-neoplasm'}", + "97, lung {'context': 'B-neoplasm'}", + "98, adenocarcinomas {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "61, tumors, ['l0', 'l1', 'l2']", + "77, lung ['l0', 'l3']", + "78, adenocarcinomas, ['l1', 'l3']", + "97, lung ['l4']", + "98, adenocarcinomas ['l2', 'l4']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12091906", + "TEXT": "The t(8;21) is one of the most frequent chromosomal translocations associated with acute leukemia. This translocation creates a fusion protein consisting of the acute myeloid leukemia-1 transcription factor and the eight-twenty-one corepressor (AML1 ETO), which represses transcription through AML1 (RUNX1) DNA binding sites and immortalizes hematopoietic progenitor cells. We have identified the p14(ARF) tumor suppressor, a mediator of the p53 oncogene checkpoint, as a direct transcriptional target of AML1 ETO. AML1 ETO repressed the p14(ARF) promoter and reduced endogenous levels of p14(ARF) expression in multiple cell types. In contrast, AML1 stimulated p14(ARF) expression and induced phenotypes consistent with cellular senescence. Chromatin immunoprecipitation assays demonstrated that AML1 ETO was specifically bound to the p14(ARF) promoter. In acute myeloid leukemia samples containing the t(8;21), levels of p14(ARF) mRNA were markedly lower when compared with other acute myeloid leukemias lacking this translocation. Repression of p14(ARF) may explain why p53 is not mutated in t(8;21)-containing leukemias and suggests that p14(ARF) is an important tumor suppressor in a large number of human leukemias.", + "TAG_DATA": [ + "85, cell {'context': 'B-cells'}", + "86, types. {'context': 'I-cells'}", + "94, induced {'effect': 'B-positive'}", + "99, senescence. {'phenotype': 'B-senescence'}" + ], + "LINK_DATA": [ + "85, cell ['l0']", + "86, types. ['l0']", + "94, induced ['l1']", + "99, senescence. ['l1']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence." + ] + } + } + ] + }, + { + "PMID": "12091876", + "TEXT": "B7-H1, a recently described member of the B7 family of costimulatory molecules, is thought to be involved in the regulation of cellular and humoral immune responses through the PD-1 receptor on activated T and B cells. We report here that, except for cells of the macrophage lineage, normal human tissues do not express B7-H1. In contrast, B7-H1 is abundant in human carcinomas of lung, ovary and colon and in melanomas. The pro-inflammatory cytokine interferon-gamma upregulates B7-H1 on the surface of tumor cell lines. Cancer cell-associated B7-H1 increases apoptosis of antigen-specific human T-cell clones in vitro, and the apoptotic effect of B7-H1 is mediated largely by one or more receptors other than PD-1. In addition, expression of B7-H1 on mouse P815 tumor increases apoptosis of activated tumor-reactive T cells and promotes the growth of highly immunogenic B7-1(+) tumors in vivo. These findings have implications for the design of T cell-based cancer immunotherapy.", + "TAG_DATA": [ + "80, tumor {'context': 'B-transformed cells'}", + "81, cell {'context': 'I-transformed cells'}", + "82, lines. {'context': 'I-transformed cells'}", + "86, increases {'effect': 'B-positive'}", + "87, apoptosis {'phenotype': 'B-apoptosis'}", + "89, antigen-specific {'context': 'B-cells'}", + "90, human {'context': 'I-cells'}", + "91, T-cell {'context': 'I-cells'}", + "92, clones {'context': 'I-cells'}", + "93, in {'context': 'B-in vitro'}", + "94, vitro, {'context': 'I-in vitro'}", + "97, apoptotic {'phenotype': 'B-apoptosis'}", + "98, effect {'phenotype': 'I-apoptosis'}", + "114, expression {'perturbing_action': 'B-gene gain-of-function'}", + "115, of {'perturbing_action': 'I-gene gain-of-function'}", + "116, B7-H1 {'perturbing_action': 'I-gene gain-of-function'}", + "118, mouse {'context': 'B-neoplasm'}", + "119, P815 {'context': 'I-neoplasm'}", + "120, tumor {'context': 'I-neoplasm'}", + "121, increases {'effect': 'B-positive'}", + "122, apoptosis {'phenotype': 'B-apoptosis'}", + "125, tumor-reactive {'context': 'B-cells'}", + "126, T {'context': 'I-cells'}", + "127, cells {'context': 'I-cells'}", + "133, highly {'context': 'B-neoplasm'}", + "135, B7-1(+) {'context': 'I-neoplasm'}", + "136, tumors {'context': 'I-neoplasm'}", + "137, in {'context': 'B-in vivo'}", + "138, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "80, tumor ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "81, cell ['l0', 'l7', 'l8', 'l9']", + "82, lines. ['l1', 'l7']", + "86, increases ['l2', 'l8', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "87, apoptosis ['l3', 'l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "89, antigen-specific ['l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "90, human ['l4', 'l12', 'l18', 'l23', 'l28', 'l29', 'l30', 'l31']", + "91, T-cell ['l5', 'l13', 'l19', 'l24', 'l28', 'l32', 'l33', 'l34']", + "92, clones ['l6', 'l9', 'l14', 'l20', 'l25', 'l29', 'l32', 'l35', 'l36']", + "93, in ['l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l37']", + "94, vitro, ['l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l37']", + "97, apoptotic ['l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "98, effect ['l38', 'l45', 'l46', 'l47', 'l48', 'l49']", + "114, expression ['l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "115, of ['l50', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "116, B7-H1 ['l51', 'l66', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "118, mouse ['l52', 'l67', 'l81', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "119, P815 ['l53', 'l68', 'l82', 'l95', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "120, tumor ['l39', 'l54', 'l69', 'l83', 'l96', 'l108', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "121, increases ['l40', 'l45', 'l55', 'l70', 'l84', 'l97', 'l109', 'l120', 'l131', 'l132', 'l133', 'l134']", + "122, apoptosis ['l41', 'l46', 'l56', 'l71', 'l85', 'l98', 'l110', 'l121', 'l131', 'l135', 'l136', 'l137', 'l138']", + "125, tumor-reactive ['l42', 'l47', 'l57', 'l72', 'l86', 'l99', 'l111', 'l122', 'l132', 'l135', 'l139', 'l140', 'l141', 'l142']", + "126, T ['l43', 'l48', 'l58', 'l73', 'l87', 'l100', 'l112', 'l123', 'l133', 'l136', 'l139', 'l143']", + "127, cells ['l44', 'l49', 'l59', 'l74', 'l88', 'l101', 'l113', 'l124', 'l134', 'l137', 'l140', 'l143']", + "133, highly ['l60', 'l75', 'l89', 'l102', 'l114', 'l125', 'l144', 'l145', 'l146', 'l147', 'l148']", + "134, immunogenic ['l61', 'l76', 'l90', 'l103', 'l115', 'l126', 'l141', 'l144', 'l149', 'l150', 'l151', 'l152']", + "135, B7-1(+) ['l62', 'l77', 'l91', 'l104', 'l116', 'l127', 'l145', 'l149', 'l153', 'l154', 'l155']", + "136, tumors ['l63', 'l78', 'l92', 'l105', 'l117', 'l128', 'l138', 'l142', 'l146', 'l150', 'l153', 'l156', 'l157']", + "137, in ['l64', 'l79', 'l93', 'l106', 'l118', 'l129', 'l147', 'l151', 'l154', 'l156', 'l158']", + "138, vivo. ['l65', 'l80', 'l94', 'l107', 'l119', 'l130', 'l148', 'l152', 'l155', 'l157', 'l158']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increases" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptotic", + "effect" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "context": { + "val": "cells", + "words": [ + "antigen-specific", + "human", + "T-cell", + "clones", + "tumor-reactive", + "T", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptotic", + "effect" + ] + }, + "context": { + "val": "cells", + "words": [ + "antigen-specific", + "human", + "T-cell", + "clones", + "tumor-reactive", + "T", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "apoptosis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor", + "mouse", + "P815", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "B7-H1" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "P815", + "tumor", + "highly", + "B7-1(+)", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "B7-H1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increases" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "B7-H1" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "B7-H1" + ] + }, + "context": { + "val": "cells", + "words": [ + "tumor-reactive", + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "B7-H1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "P815", + "tumor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increases" + ] + } + } + ] + }, + { + "PMID": "12042816", + "TEXT": "Recently developed major histocompatibility complex (MHC) multimer technologies allow visualization and isolation of antigen-specific T cells. However, functional analysis and in vivo transfer of MHC multimer-stained cells is hampered by the persistence of T-cell receptor (TCR) MHC interactions and subsequently induced signaling events. As MHC monomers do not stably bind to TCRs, we postulated that targeted disassembly of multimers into MHC monomers would result in dissociation of surface-bound TCR ligands. We generated a new type of MHC multimers, which can be monomerized in the presence of a competitor, resulting in rapid loss of the staining reagent. Following dissociation, the T cells are phenotypically and functionally indistinguishable from untreated cells. This 'reversible' T-cell staining procedure, which maintains the specificity and sensitivity of MHC multimer staining while preserving the functional status of T lymphocytes, may be of broad benefit for ex vivo investigation of T-cell functions and clinical applications.", + "TAG_DATA": [ + "99, T {'context': 'B-cells'}", + "100, cells {'context': 'I-cells'}", + "108, cells. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "99, T ['l0', 'l1']", + "100, cells ['l0', 'l2']", + "108, cells. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12042814", + "TEXT": "Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). So far, immunological mechanisms responsible for demyelination have been the focus of interest. However, mechanisms regulating axon maintenance as well as glial precursor-cell proliferation and oligodendrocyte survival might also influence disease outcome. The cytokine ciliary neurotrophic factor (CNTF), which was originally identified as a survival factor for isolated neurons, promotes differentiation, maturation and survival of oligodendrocytes. To investigate the role of endogenous CNTF in inflammatory demyelinating disease, we studied myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in CNTF-deficient and wild-type C57BL/6 mice. Disease was more severe in CNTF-deficient mice and recovery was poor, with a 60% decrease in the number of proliferating oligodendrocyte precursor cells (OPCs) and a more than 50% increase in the rate of oligodendrocyte apoptosis. In addition, vacuolar dystrophy of myelin and axonal damage were more severe in CNTF-deficient mice. These specific pathological features could be prevented by treatment with an antiserum against tumor necrosis factor-alpha, suggesting that endogenous CNTF may counterbalance this effect of TNF-alpha (ref. 7). Here we identify a factor that modulates, in an inflammatory environment, glial cell survival and is an outcome determinant of EAE.", + "TAG_DATA": [ + "92, CNTF-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "96, mice. {'context': 'I-organism'}", + "102, CNTF-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "103, mice {'context': 'B-organism'}", + "111, decrease {'effect': 'B-negative'}", + "116, proliferating {'context': 'B-cells'}", + "117, oligodendrocyte {'context': 'I-cells'}", + "118, precursor {'context': 'I-cells'}", + "119, cells {'context': 'I-cells'}", + "120, (OPCs) {'context': 'I-cells'}", + "126, increase {'effect': 'B-positive'}", + "131, oligodendrocyte {'context': 'B-cells'}", + "132, apoptosis. {'phenotype': 'B-apoptosis'}", + "146, CNTF-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "147, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "92, CNTF-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "96, mice. ['l0', 'l12']", + "102, CNTF-deficient ['l1', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "103, mice ['l2', 'l13', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "111, decrease ['l3', 'l14', 'l23', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "116, proliferating ['l4', 'l15', 'l24', 'l32', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "117, oligodendrocyte ['l5', 'l16', 'l25', 'l33', 'l40', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "118, precursor ['l6', 'l17', 'l26', 'l34', 'l41', 'l47', 'l53', 'l54', 'l55', 'l56', 'l57']", + "119, cells ['l7', 'l12', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l58', 'l59', 'l60', 'l61']", + "120, (OPCs) ['l8', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l62', 'l63', 'l64']", + "126, increase ['l9', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l65', 'l66']", + "131, oligodendrocyte ['l10', 'l21', 'l30', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l65', 'l67']", + "132, apoptosis. ['l11', 'l22', 'l31', 'l39', 'l46', 'l52', 'l57', 'l61', 'l64', 'l66', 'l67']", + "146, CNTF-deficient ['l68']", + "147, mice. ['l68']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CNTF-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CNTF-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decrease" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CNTF-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "proliferating", + "oligodendrocyte", + "precursor", + "cells", + "(OPCs)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CNTF-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increase" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CNTF-deficient" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decrease" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increase" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decrease" + ] + }, + "context": { + "val": "cells", + "words": [ + "proliferating", + "oligodendrocyte", + "precursor", + "cells", + "(OPCs)" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decrease" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "proliferating", + "oligodendrocyte", + "precursor", + "cells", + "(OPCs)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increase" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "proliferating", + "oligodendrocyte", + "precursor", + "cells", + "(OPCs)" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "12042813", + "TEXT": "Multiple sclerosis (MS) is a disabling inflammatory demyelinating disease of the central nervous system (CNS) that primarily affects young adults. Available therapies can inhibit the inflammatory component of MS but do not suppress progressive clinical disability. An alternative approach would be to inhibit mechanisms that drive the neuropathology of MS, which often includes the death of oligodendrocytes, the cells responsible for myelinating the CNS. Identification of molecular mechanisms that mediate the stress response of oligodendrocytes to optimize their survival would serve this need. This study shows that the neurotrophic cytokine leukemia inhibitory factor (LIF) directly prevents oligodendrocyte death in animal models of MS. We also demonstrate that this therapeutic effect complements endogenous LIF receptor signaling, which already serves to limit oligodendrocyte loss during immune attack. Our results provide a novel approach for the treatment of MS.", + "TAG_DATA": [ + "96, oligodendrocyte {'context': 'B-cells'}", + "99, animal {'context': 'B-organism'}", + "100, models {'context': 'I-organism'}", + "101, of {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "96, oligodendrocyte ['l0', 'l1', 'l2']", + "99, animal ['l0', 'l3', 'l4']", + "100, models ['l1', 'l3', 'l5']", + "101, of ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "12042777", + "TEXT": "RNA interference silences gene expression through short interfering 21 23-mer double-strand RNA segments that guide mRNA degradation in a sequence-specific fashion. Here we report that siRNAs inhibit virus production by targeting the mRNAs for either the HIV-1 cellular receptor CD4, the viral structural Gag protein or green fluorescence protein substituted for the Nef regulatory protein. siRNAs effectively inhibit pre- and/or post-integration infection events in the HIV-1 life cycle. Thus, siRNAs may have potential for therapeutic intervention in HIV-1 and other viral infections.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11984600", + "TEXT": "Noninvasive methods are needed to study the kinetic properties of viruses in living organisms. Oncolytic viruses are used increasingly for cancer therapy but there is currently no satisfactory way to measure efficiency of tumor transduction, changing levels of viral gene expression or the timing of virus elimination. We therefore generated trackable oncolytic measles viruses expressing inert (nonimmunogenic, nonfunctional and accurately measurable) soluble marker peptides. The marker peptides did not compromise virus replication. Ex vivo and in vivo kinetics of the trackable viruses could be easily followed by measuring the concentrations of virally encoded marker peptides in culture supernatant or in serum. When mice bearing human tumor xenografts were challenged with the trackable viruses, distinct kinetic profiles of marker-gene expression could be correlated with distinct therapeutic outcomes. Oncolytic viruses expressing inert soluble marker polypeptides should greatly facilitate the rational development of effective, individually tailored cancer virotherapy.", + "TAG_DATA": [ + "75, in {'context': 'B-in vivo'}", + "76, vivo {'context': 'I-in vivo'}", + "102, mice {'context': 'B-organism'}", + "104, human {'context': 'I-xenograft'}", + "105, tumor {'context': 'I-xenograft'}", + "106, xenografts {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "75, in ['l0']", + "76, vivo ['l0']", + "102, mice ['l1', 'l2', 'l3']", + "104, human ['l1', 'l4', 'l5']", + "105, tumor ['l2', 'l4', 'l6']", + "106, xenografts ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11984592", + "TEXT": "Pulmonary fibrosis is an interstitial disorder of the lung parenchyma whose mechanism is poorly understood. Potential mechanisms include the infiltration of inflammatory cells to the lungs and the generation of pro-inflammatory mediators. In particular, idiopathic pulmonary fibrosis is a progressive and fatal form of the disorder characterized by alveolar inflammation, fibroblast proliferation and collagen deposition. Here, we investigated the role of cytosolic phospholipase A(2) (cPLA(2)) in pulmonary fibrosis using cPLA(2)-null mutant mice, as cPLA(2) is a key enzyme in the generation of pro-inflammatory eicosanoids. Disruption of the gene encoding cPLA(2) (Pla2g4a) attenuated IPF and inflammation induced by bleomycin administration. Bleomycin-induced overproduction of thromboxanes and leukotrienes in lung was significantly reduced in cPLA(2)-null mice. Our data suggest that cPLA(2) has an important role in the pathogenesis of pulmonary fibrosis. The inhibition of cPLA(2)-initiated pathways might provide a novel therapeutic approach to pulmonary fibrosis, for which no pharmaceutical agents are currently available.", + "TAG_DATA": [ + "69, cPLA(2)-null {'perturbing_action': 'B-gene loss-of-function'}", + "70, mutant {'perturbing_action': 'I-gene loss-of-function'}", + "71, mice, {'context': 'B-organism'}", + "84, Disruption {'perturbing_action': 'B-gene loss-of-function'}", + "85, of {'perturbing_action': 'I-gene loss-of-function'}", + "86, the {'perturbing_action': 'I-gene loss-of-function'}", + "87, gene {'perturbing_action': 'I-gene loss-of-function'}", + "88, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "89, cPLA(2) {'perturbing_action': 'I-gene loss-of-function'}", + "90, (Pla2g4a) {'perturbing_action': 'I-gene loss-of-function'}", + "106, lung {'context': 'B-tissue/organ'}", + "111, cPLA(2)-null {'perturbing_action': 'B-gene loss-of-function'}", + "112, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "69, cPLA(2)-null ['l0', 'l1']", + "70, mutant ['l0', 'l2']", + "71, mice, ['l1', 'l2']", + "84, Disruption ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "85, of ['l3', 'l9', 'l10', 'l11', 'l12', 'l13']", + "86, the ['l4', 'l9', 'l14', 'l15', 'l16', 'l17']", + "87, gene ['l5', 'l10', 'l14', 'l18', 'l19', 'l20']", + "88, encoding ['l6', 'l11', 'l15', 'l18', 'l21', 'l22']", + "89, cPLA(2) ['l7', 'l12', 'l16', 'l19', 'l21', 'l23']", + "90, (Pla2g4a) ['l8', 'l13', 'l17', 'l20', 'l22', 'l23']", + "106, lung ['l24', 'l25']", + "111, cPLA(2)-null ['l24', 'l26']", + "112, mice. ['l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cPLA(2)-null", + "mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cPLA(2)-null" + ] + } + } + ] + }, + { + "PMID": "11984590", + "TEXT": "The inwardly rectifying K(+) channel Kir6.1 forms K(+) channels by coupling with a sulfonylurea receptor in reconstituted systems, but the physiological roles of Kir6.1-containing K(+) channels have not been determined. We report here that mice lacking the gene encoding Kir6.1 (known as Kcnj8) have a high rate of sudden death associated with spontaneous ST elevation followed by atrioventricular block as seen on an electrocardiogram. The K(+) channel opener pinacidil did not induce K(+) currents in vascular smooth-muscle cells of Kir6.1-null mice, and there was no vasodilation response to pinacidil. The administration of methylergometrine, a vasoconstrictive agent, elicited ST elevation followed by cardiac death in Kir6.1-null mice but not in wild-type mice, indicating a phenotype characterized by hypercontractility of coronary arteries and resembling Prinzmetal (or variant) angina in humans. The Kir6.1-containing K(+) channel is critical in the regulation of vascular tonus, especially in the coronary arteries, and its disruption may cause Prinzmetal angina.", + "TAG_DATA": [ + "34, mice {'context': 'B-organism'}", + "35, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "36, the {'perturbing_action': 'I-gene loss-of-function'}", + "37, gene {'perturbing_action': 'I-gene loss-of-function'}", + "38, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "39, Kir6.1 {'perturbing_action': 'I-gene loss-of-function'}", + "40, (known {'perturbing_action': 'I-gene loss-of-function'}", + "41, as {'perturbing_action': 'I-gene loss-of-function'}", + "42, Kcnj8) {'perturbing_action': 'I-gene loss-of-function'}", + "75, vascular {'context': 'B-cells'}", + "76, smooth-muscle {'context': 'I-cells'}", + "77, cells {'context': 'I-cells'}", + "79, Kir6.1-null {'perturbing_action': 'B-gene loss-of-function'}", + "80, mice, {'context': 'B-organism'}", + "104, Kir6.1-null {'perturbing_action': 'B-gene loss-of-function'}", + "105, mice {'context': 'B-organism'}", + "110, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "34, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "35, lacking ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "36, the ['l1', 'l12', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "37, gene ['l2', 'l13', 'l24', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "38, encoding ['l3', 'l14', 'l25', 'l35', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "39, Kir6.1 ['l4', 'l15', 'l26', 'l36', 'l45', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "40, (known ['l5', 'l16', 'l27', 'l37', 'l46', 'l54', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "41, as ['l6', 'l17', 'l28', 'l38', 'l47', 'l55', 'l62', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "42, Kcnj8) ['l7', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l69', 'l75', 'l76', 'l77', 'l78', 'l79']", + "75, vascular ['l8', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l75', 'l80', 'l81', 'l82', 'l83']", + "76, smooth-muscle ['l9', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l84', 'l85', 'l86']", + "77, cells ['l10', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l87', 'l88']", + "79, Kir6.1-null ['l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l87', 'l89']", + "80, mice, ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l89']", + "104, Kir6.1-null ['l90', 'l91']", + "105, mice ['l90', 'l92']", + "110, mice, ['l91', 'l92']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "gene", + "encoding", + "Kir6.1", + "(known", + "as", + "Kcnj8)", + "Kir6.1-null" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "gene", + "encoding", + "Kir6.1", + "(known", + "as", + "Kcnj8)", + "Kir6.1-null" + ] + }, + "context": { + "val": "cells", + "words": [ + "vascular", + "smooth-muscle", + "cells" + ] + } + } + ] + }, + { + "PMID": "11984589", + "TEXT": "Amplification of the gene encoding the ErbB2 (Her2/neu) receptor tyrosine kinase is critical for the progression of several forms of breast cancer. In a large-scale clinical trial, treatment with Herceptin (trastuzumab), a humanized blocking antibody against ErbB2, led to marked improvement in survival. However, cardiomyopathy was uncovered as a mitigating side effect, thereby suggesting an important role for ErbB2 signaling as a modifier of human heart failure. To investigate the physiological role of ErbB2 signaling in the adult heart, we generated mice with a ventricular-restricted deletion of Erbb2. These ErbB2-deficient conditional mutant mice were viable and displayed no overt phenotype. However, physiological analysis revealed the onset of multiple independent parameters of dilated cardiomyopathy, including chamber dilation, wall thinning and decreased contractility. Additionally, cardiomyocytes isolated from these conditional mutants were more susceptible to anthracycline toxicity. ErbB2 signaling in cardiomyocytes is therefore essential for the prevention of dilated cardiomyopathy.", + "TAG_DATA": [ + "81, mice {'context': 'B-organism'}", + "84, ventricular-restricted {'perturbing_action': 'B-gene loss-of-function'}", + "85, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "86, of {'perturbing_action': 'I-gene loss-of-function'}", + "87, Erbb2. {'perturbing_action': 'I-gene loss-of-function'}", + "89, ErbB2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "90, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "91, mutant {'perturbing_action': 'I-gene loss-of-function'}", + "92, mice {'context': 'B-organism'}", + "122, cardiomyocytes {'context': 'B-cells'}", + "127, mutants {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "81, mice ['l0']", + "84, ventricular-restricted ['l1', 'l2', 'l3', 'l4', 'l5']", + "85, deletion ['l1', 'l6', 'l7']", + "86, of ['l2', 'l6', 'l8']", + "87, Erbb2. ['l0', 'l3', 'l7', 'l8']", + "89, ErbB2-deficient ['l9', 'l10', 'l11']", + "90, conditional ['l9', 'l12', 'l13']", + "91, mutant ['l4', 'l10', 'l12', 'l14']", + "92, mice ['l5', 'l11', 'l13', 'l14']", + "122, cardiomyocytes ['l15']", + "127, mutants ['l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Erbb2.", + "ventricular-restricted", + "ErbB2-deficient", + "conditional", + "mutant" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cardiomyocytes" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutants" + ] + } + } + ] + }, + { + "PMID": "11927949", + "TEXT": "Minor histocompatibility antigens (mHags) are immunogenic peptides from polymorphic cellular proteins that induce strong T-cell responses after human leukocyte antigen (HLA)-matched, mHag-mismatched stem-cell transplantation. mHags with broad or limited tissue expression are target antigens for graft-versus-host (GvH) and graft-versus-leukemia (GvL) reactivities. Separation of these activities is crucial for adoptive immunotherapy of leukemia without GvH disease. Therefore, using a skin-explant assay we investigated the in situ activities of cytotoxic T lymphocytes (CTLs) specific for the ubiquitously expressed mHag H-Y and for the hematopoietic-restricted mHags HA-1 and HA-2. H-Y-specific CTLs, visualized by tetrameric HLA-mHag peptide complexes, infiltrated male skin sections within 24 hours, induced severe GvH reactions of grade III-IV and produced high levels of IFN-gamma. In contrast, CTLs specific for the hematopoietic system-specific mHags HA-1 and HA-2 induced no or low GvH reactions above background and produced little or no interferon-gamma, unless the skin sections were preincubated with HA-1/HA-2 synthetic peptides. These results provide the first in situ dissection of GvH effects by mHag-specific CTLs and show that ubiquitously expressed mHags are the prime targets of GvH disease.", + "TAG_DATA": [ + "142, skin {'context': 'B-tissue/organ'}", + "143, sections {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "142, skin ['l0']", + "143, sections ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11927947", + "TEXT": "The influence of maternally transmitted immunoglobulins on the development of autoimmune diabetes mellitus in genetically susceptible human progeny remains unknown. Given the presence of islet beta cell-reactive autoantibodies in prediabetic nonobese diabetic (NOD) mice, we abrogated the maternal transmission of such antibodies in order to assess their influence on the susceptibility of progeny to diabetes. First, we used B cell-deficient NOD mothers to eliminate the transmission of maternal immunoglobulins. In a complementary approach, we used immunoglobulin transgenic NOD mothers to exclude autoreactive specificities from the maternal B-cell repertoire. Finally, we implanted NOD embryos in pseudopregnant mothers of a non-autoimmune strain. The NOD progeny in all three groups were protected from spontaneous diabetes. These findings demonstrate that the maternal transmission of antibodies is a critical environmental parameter influencing the ontogeny of T cell-mediated destruction of islet beta cells in NOD mice. It will be important to definitively determine whether the transmission of maternal autoantibodies in humans affects diabetes progression in susceptible offspring.", + "TAG_DATA": [ + "58, B {'perturbing_action': 'B-gene loss-of-function'}", + "59, cell-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "60, NOD {'context': 'B-organism'}", + "61, mothers {'context': 'I-organism'}", + "77, NOD {'context': 'B-organism'}", + "78, mothers {'context': 'I-organism'}", + "91, NOD {'context': 'B-organism'}", + "92, embryos {'context': 'I-organism'}", + "95, mothers {'context': 'I-organism'}", + "99, strain. {'context': 'I-organism'}", + "101, NOD {'context': 'B-organism'}", + "102, progeny {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "58, B ['l0', 'l1', 'l2', 'l3']", + "59, cell-deficient ['l0', 'l4', 'l5', 'l6']", + "60, NOD ['l1', 'l4', 'l7']", + "61, mothers ['l2', 'l5', 'l7']", + "77, NOD ['l8', 'l9', 'l10', 'l11', 'l12']", + "78, mothers ['l3', 'l6', 'l8', 'l13', 'l14', 'l15']", + "91, NOD ['l9', 'l13', 'l16', 'l17', 'l18']", + "92, embryos ['l10', 'l14', 'l16', 'l19', 'l20']", + "95, mothers ['l11', 'l15', 'l17', 'l19', 'l21']", + "99, strain. ['l12', 'l18', 'l20', 'l21']", + "101, NOD ['l22']", + "102, progeny ['l22']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "B", + "cell-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "NOD", + "mothers" + ] + } + } + ] + }, + { + "PMID": "11927944", + "TEXT": "The viruses HIV-1, Epstein-Barr virus (EBV), cytomegalovirus (CMV) and hepatitis C virus (HCV) are characterized by the establishment of lifelong infection in the human host, where their replication is thought to be tightly controlled by virus-specific CD8+ T cells. Here we present detailed studies of the differentiation phenotype of these cells, which can be separated into three distinct subsets based on expression of the costimulatory receptors CD28 and CD27. Whereas CD8+ T cells specific for HIV, EBV and HCV exhibit similar characteristics during primary infection, there are significant enrichments at different stages of cellular differentiation in the chronic phase of persistent infection according to the viral specificity, which suggests that distinct memory T-cell populations are established in different virus infections. These findings challenge the current definitions of memory and effector subsets in humans, and suggest that ascribing effector and memory functions to subsets with different differentiation phenotypes is no longer appropriate.", + "TAG_DATA": [ + "70, CD8+ {'context': 'B-cells'}", + "71, T {'context': 'I-cells'}", + "72, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "70, CD8+ ['l0', 'l1']", + "71, T ['l0', 'l2']", + "72, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11927943", + "TEXT": "The complement cascade defines an important link between the innate and the specific immune system. Here we show that mice deficient for the third component of complement (C3-/- mice) are highly susceptible to primary infection with influenza virus. C3-/- mice showed delayed viral clearance and increased viral titers in lung, whereas mice deficient for complement receptors CR1 and CR2 (Cr2-/- mice) cleared the infection normally. Priming of T-helper cells and cytotoxic T cells (CTLs) in lung-draining lymph nodes was reduced, and the recruitment into the lung of virus-specific CD4+ and CD8+ effector T cells producing interferon-gamma was severely impaired in C3-/- but not in Cr2-/- mice. Consequently, T-helper cell-dependent IgG responses were reduced in C3-/- mice but remained intact in Cr2-/- mice. These results demonstrate that complement induces specific immunity by promoting T-cell responses.", + "TAG_DATA": [ + "19, mice {'context': 'B-organism'}", + "20, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "21, for {'perturbing_action': 'I-gene loss-of-function'}", + "22, the {'perturbing_action': 'I-gene loss-of-function'}", + "23, third {'perturbing_action': 'I-gene loss-of-function'}", + "24, component {'perturbing_action': 'I-gene loss-of-function'}", + "25, of {'perturbing_action': 'I-gene loss-of-function'}", + "26, complement {'perturbing_action': 'I-gene loss-of-function'}", + "28, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "38, C3-/- {'perturbing_action': 'B-gene loss-of-function'}", + "39, mice {'context': 'B-organism'}", + "49, lung, {'context': 'B-tissue/organ'}", + "51, mice {'context': 'B-organism'}", + "52, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "53, for {'perturbing_action': 'I-gene loss-of-function'}", + "54, complement {'perturbing_action': 'I-gene loss-of-function'}", + "55, receptors {'perturbing_action': 'I-gene loss-of-function'}", + "56, CR1 {'perturbing_action': 'I-gene loss-of-function'}", + "57, and {'perturbing_action': 'I-gene loss-of-function'}", + "58, CR2 {'perturbing_action': 'I-gene loss-of-function'}", + "59, (Cr2-/- {'perturbing_action': 'I-gene loss-of-function'}", + "60, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "67, T-helper {'context': 'B-cells'}", + "68, cells {'context': 'I-cells'}", + "75, lung-draining {'context': 'B-tissue/organ'}", + "76, lymph {'context': 'I-tissue/organ'}", + "77, nodes {'context': 'I-tissue/organ'}", + "88, CD4+ {'context': 'B-cells'}", + "89, and {'context': 'I-cells'}", + "90, CD8+ {'context': 'I-cells'}", + "91, effector {'context': 'I-cells'}", + "92, T {'context': 'I-cells'}", + "93, cells {'context': 'I-cells'}", + "100, C3-/- {'perturbing_action': 'B-gene loss-of-function'}", + "104, Cr2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "105, mice. {'context': 'B-organism'}", + "114, C3-/- {'perturbing_action': 'B-gene loss-of-function'}", + "115, mice {'context': 'B-organism'}", + "120, Cr2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "121, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "19, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "20, deficient ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "21, for ['l1', 'l12', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "22, the ['l2', 'l13', 'l26', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "23, third ['l3', 'l14', 'l27', 'l40', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "24, component ['l4', 'l15', 'l28', 'l41', 'l53', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "25, of ['l5', 'l16', 'l29', 'l42', 'l54', 'l65', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "26, complement ['l6', 'l17', 'l30', 'l43', 'l55', 'l66', 'l76', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "28, mice) ['l7', 'l18', 'l31', 'l44', 'l56', 'l67', 'l77', 'l86', 'l93', 'l94', 'l95', 'l96']", + "38, C3-/- ['l8', 'l19', 'l32', 'l45', 'l57', 'l68', 'l78', 'l87', 'l93', 'l97', 'l98']", + "39, mice ['l9', 'l20', 'l33', 'l46', 'l58', 'l69', 'l79', 'l88', 'l94', 'l97', 'l99']", + "49, lung, ['l10', 'l21', 'l34', 'l47', 'l59', 'l70', 'l80', 'l89', 'l95', 'l98', 'l99']", + "51, mice ['l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "52, deficient ['l100', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "53, for ['l101', 'l123', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "54, complement ['l102', 'l124', 'l145', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185']", + "55, receptors ['l103', 'l125', 'l146', 'l166', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "56, CR1 ['l104', 'l126', 'l147', 'l167', 'l186', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222']", + "57, and ['l105', 'l127', 'l148', 'l168', 'l187', 'l205', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239']", + "58, CR2 ['l106', 'l128', 'l149', 'l169', 'l188', 'l206', 'l223', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255']", + "59, (Cr2-/- ['l107', 'l129', 'l150', 'l170', 'l189', 'l207', 'l224', 'l240', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270']", + "60, mice) ['l108', 'l130', 'l151', 'l171', 'l190', 'l208', 'l225', 'l241', 'l256', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282']", + "67, T-helper ['l22', 'l35', 'l48', 'l60', 'l71', 'l81', 'l90', 'l109', 'l131', 'l152', 'l172', 'l191', 'l209', 'l226', 'l242', 'l257', 'l271', 'l283', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291']", + "68, cells ['l11', 'l23', 'l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l96', 'l110', 'l132', 'l153', 'l173', 'l192', 'l210', 'l227', 'l243', 'l258', 'l272', 'l283', 'l292', 'l293', 'l294']", + "75, lung-draining ['l37', 'l50', 'l62', 'l73', 'l83', 'l111', 'l133', 'l154', 'l174', 'l193', 'l211', 'l228', 'l244', 'l259', 'l273', 'l284', 'l292', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302']", + "76, lymph ['l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l112', 'l134', 'l155', 'l175', 'l194', 'l212', 'l229', 'l245', 'l260', 'l274', 'l285', 'l293', 'l295', 'l303', 'l304', 'l305', 'l306', 'l307', 'l308', 'l309']", + "77, nodes ['l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l92', 'l113', 'l135', 'l156', 'l176', 'l195', 'l213', 'l230', 'l246', 'l261', 'l275', 'l286', 'l294', 'l296', 'l303', 'l310', 'l311']", + "88, CD4+ ['l114', 'l136', 'l157', 'l177', 'l196', 'l214', 'l231', 'l247', 'l262', 'l276', 'l287', 'l297', 'l304', 'l312', 'l313', 'l314', 'l315', 'l316', 'l317', 'l318', 'l319']", + "89, and ['l115', 'l137', 'l158', 'l178', 'l197', 'l215', 'l232', 'l248', 'l263', 'l277', 'l288', 'l298', 'l305', 'l312', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326']", + "90, CD8+ ['l116', 'l138', 'l159', 'l179', 'l198', 'l216', 'l233', 'l249', 'l264', 'l278', 'l299', 'l306', 'l313', 'l320', 'l327', 'l328', 'l329', 'l330', 'l331', 'l332']", + "91, effector ['l117', 'l139', 'l160', 'l180', 'l199', 'l217', 'l234', 'l250', 'l265', 'l279', 'l289', 'l300', 'l307', 'l314', 'l321', 'l327', 'l333', 'l334', 'l335', 'l336', 'l337']", + "92, T ['l118', 'l140', 'l161', 'l181', 'l200', 'l218', 'l235', 'l251', 'l266', 'l280', 'l290', 'l301', 'l308', 'l310', 'l315', 'l322', 'l328', 'l333', 'l338', 'l339', 'l340', 'l341']", + "93, cells ['l119', 'l141', 'l162', 'l182', 'l201', 'l219', 'l236', 'l252', 'l267', 'l281', 'l291', 'l302', 'l309', 'l311', 'l316', 'l323', 'l329', 'l334', 'l338', 'l342', 'l343', 'l344']", + "100, C3-/- ['l120', 'l142', 'l163', 'l183', 'l202', 'l220', 'l237', 'l253', 'l268', 'l317', 'l324', 'l330', 'l335', 'l339', 'l342', 'l345', 'l346']", + "104, Cr2-/- ['l121', 'l143', 'l164', 'l184', 'l203', 'l221', 'l238', 'l254', 'l269', 'l318', 'l325', 'l331', 'l336', 'l340', 'l343', 'l345', 'l347']", + "105, mice. ['l122', 'l144', 'l165', 'l185', 'l204', 'l222', 'l239', 'l255', 'l270', 'l282', 'l319', 'l326', 'l332', 'l337', 'l341', 'l344', 'l346', 'l347']", + "114, C3-/- ['l348', 'l349', 'l350']", + "115, mice ['l348', 'l351', 'l352']", + "120, Cr2-/- ['l349', 'l351', 'l353']", + "121, mice. ['l350', 'l352', 'l353']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "the", + "third", + "component", + "of", + "complement", + "mice)", + "C3-/-", + "receptors", + "CR1", + "and", + "CR2", + "(Cr2-/-", + "Cr2-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "the", + "third", + "component", + "of", + "complement", + "mice)", + "C3-/-", + "receptors", + "CR1", + "and", + "CR2", + "(Cr2-/-" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung,", + "lymph", + "nodes", + "lung-draining" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "the", + "third", + "component", + "of", + "complement", + "mice)", + "receptors", + "CR1", + "and", + "CR2", + "(Cr2-/-", + "C3-/-", + "Cr2-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "T-helper", + "cells", + "CD4+", + "and", + "CD8+", + "effector", + "T" + ] + } + } + ] + }, + { + "PMID": "11927942", + "TEXT": "Specific interference with molecular mechanisms guiding tissue localization of leukocytes may be of great utility for selective immunosuppressive therapies. We have discovered and characterized efomycines, a new family of selective small-molecule inhibitors of selectin functions. Members of this family significantly inhibited leukocyte adhesion in vitro. Efomycine M, which was nontoxic and showed the most selective inhibitory effects on selectin-mediated leukocyte-endothelial adhesion in vitro, significantly diminished rolling in mouse ear venules in vivo as seen by intravital microscopy. In addition, efomycine M alleviated cutaneous inflammation in two complementary mouse models of psoriasis, one of the most common chronic inflammatory skin disorders. Molecular modeling demonstrated a spatial conformation of efomycines mimicking naturally occurring selectin ligands. Efomycine M might be efficacious in the treatment of human inflammatory disorders through a similar mechanism.", + "TAG_DATA": [ + "40, inhibited {'effect': 'B-negative'}", + "41, leukocyte {'context': 'B-cells'}", + "42, adhesion {'phenotype': 'B-adhesion'}", + "43, in {'context': 'B-in vitro'}", + "44, vitro. {'context': 'I-in vitro'}", + "61, in {'context': 'B-in vitro'}", + "62, vitro, {'context': 'I-in vitro'}", + "67, mouse {'context': 'B-tissue/organ'}", + "68, ear {'context': 'I-tissue/organ'}", + "69, venules {'context': 'I-tissue/organ'}", + "70, in {'context': 'B-in vivo'}", + "71, vivo {'context': 'I-in vivo'}", + "87, mouse {'context': 'I-organism'}", + "88, models {'context': 'I-organism'}", + "89, of {'context': 'I-organism'}", + "90, psoriasis, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "40, inhibited ['l0', 'l1', 'l2', 'l3', 'l4']", + "41, leukocyte ['l0', 'l5', 'l6', 'l7', 'l8']", + "42, adhesion ['l1', 'l5', 'l9', 'l10']", + "43, in ['l2', 'l6', 'l9', 'l11']", + "44, vitro. ['l3', 'l7', 'l10', 'l11']", + "61, in ['l4', 'l8', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "62, vitro, ['l12', 'l18', 'l19', 'l20', 'l21', 'l22']", + "67, mouse ['l13', 'l18', 'l23', 'l24', 'l25', 'l26']", + "68, ear ['l14', 'l19', 'l23', 'l27', 'l28', 'l29']", + "69, venules ['l15', 'l20', 'l24', 'l27', 'l30', 'l31']", + "70, in ['l16', 'l21', 'l25', 'l28', 'l30', 'l32']", + "71, vivo ['l17', 'l22', 'l26', 'l29', 'l31', 'l32']", + "87, mouse ['l33', 'l34', 'l35']", + "88, models ['l33', 'l36', 'l37']", + "89, of ['l34', 'l36', 'l38']", + "90, psoriasis, ['l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "leukocyte" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "leukocyte" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "11927940", + "TEXT": "Natural inhibitors of angiogenesis are able to block pathological neovascularization without harming the preexisting vasculature. Here we show that two such inhibitors, thrombospondin-1 and pigment epithelium-derived factor, derive specificity for remodeling vessels from their dependence on Fas/Fas ligand (FasL)-mediated apoptosis to block angiogenesis. Both inhibitors upregulated FasL on endothelial cells. Expression of the essential partner of FasL, Fas/CD95 receptor, was low on quiescent endothelial cells and vessels but greatly enhanced by inducers of angiogenesis, thereby specifically sensitizing the stimulated cells to apoptosis by inhibitor-generated FasL. The anti-angiogenic activity of thrombospondin-1 and pigment epithelium-derived factor both in vitro and in vivo was dependent on this dual induction of Fas and FasL and the resulting apoptosis. This example of cooperation between pro- and anti-angiogenic factors in the inhibition of angiogenesis provides one explanation for the ability of inhibitors to select remodeling capillaries for destruction.", + "TAG_DATA": [ + "48, endothelial {'context': 'B-cells'}", + "49, cells. {'context': 'I-cells'}", + "62, quiescent {'context': 'B-cells'}", + "63, endothelial {'context': 'I-cells'}", + "64, cells {'context': 'I-cells'}", + "76, sensitizing {'effect': 'B-positive'}", + "79, cells {'context': 'B-cells'}", + "81, apoptosis {'phenotype': 'B-apoptosis'}", + "95, in {'context': 'B-in vitro'}", + "96, vitro {'context': 'I-in vitro'}", + "98, in {'context': 'B-in vivo'}", + "99, vivo {'context': 'I-in vivo'}", + "113, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "48, endothelial ['l0', 'l1', 'l2', 'l3']", + "49, cells. ['l0', 'l4', 'l5']", + "62, quiescent ['l1', 'l6', 'l7', 'l8', 'l9']", + "63, endothelial ['l2', 'l4', 'l6', 'l10', 'l11']", + "64, cells ['l3', 'l5', 'l7', 'l10']", + "76, sensitizing ['l8', 'l11', 'l12', 'l13']", + "79, cells ['l9', 'l12', 'l14']", + "81, apoptosis ['l13', 'l14']", + "95, in ['l15', 'l16', 'l17', 'l18']", + "96, vitro ['l15', 'l19', 'l20', 'l21']", + "98, in ['l16', 'l19', 'l22', 'l23']", + "99, vivo ['l17', 'l20', 'l22', 'l24']", + "113, apoptosis. ['l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "quiescent", + "endothelial", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitizing" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitizing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "11875501", + "TEXT": "Prostaglandins (PGs), bioactive lipid molecules produced by cyclooxygenase enzymes (COX-1 and COX-2), have diverse biological activities, including growth-promoting actions on gastrointestinal mucosa. They are also implicated in the growth of colonic polyps and cancers. However, the precise mechanisms of these trophic actions of PGs remain unclear. As activation of the epidermal growth factor receptor (EGFR) triggers mitogenic signaling in gastrointestinal mucosa, and its expression is also upregulated in colonic cancers and most neoplasms, we investigated whether PGs transactivate EGFR. Here we provide evidence that prostaglandin E2 (PGE2) rapidly phosphorylates EGFR and triggers the extracellular signal-regulated kinase 2 (ERK2)--mitogenic signaling pathway in normal gastric epithelial (RGM1) and colon cancer (Caco-2, LoVo and HT-29) cell lines. Inactivation of EGFR kinase with selective inhibitors significantly reduces PGE2-induced ERK2 activation, c-fos mRNA expression and cell proliferation. Inhibition of matrix metalloproteinases (MMPs), transforming growth factor-alpha (TGF-alpha) or c-Src blocked PGE2-mediated EGFR transactivation and downstream signaling indicating that PGE2-induced EGFR transactivation involves signaling transduced via TGF-alpha, an EGFR ligand, likely released by c-Src-activated MMP(s). Our findings that PGE2 transactivates EGFR reveal a previously unknown mechanism by which PGE2 mediates trophic actions resulting in gastric and intestinal hypertrophy as well as growth of colonic polyps and cancers.", + "TAG_DATA": [ + "101, normal {'context': 'B-cells'}", + "102, gastric {'context': 'I-cells'}", + "103, epithelial {'context': 'I-cells'}", + "104, (RGM1) {'context': 'I-cells'}", + "105, and {'context': 'I-cells'}", + "106, colon {'context': 'I-transformed cells'}", + "107, cancer {'context': 'I-transformed cells'}", + "108, (Caco-2, {'context': 'I-transformed cells'}", + "109, LoVo {'context': 'I-transformed cells'}", + "110, and {'context': 'I-transformed cells'}", + "111, HT-29) {'context': 'I-transformed cells'}", + "112, cell {'context': 'I-transformed cells'}", + "113, lines. {'context': 'I-transformed cells'}", + "114, Inactivation {'perturbing_action': 'B-pharmacological inhibition'}", + "115, of {'perturbing_action': 'I-pharmacological inhibition'}", + "116, EGFR {'perturbing_action': 'I-pharmacological inhibition'}", + "117, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "118, with {'perturbing_action': 'I-pharmacological inhibition'}", + "119, selective {'perturbing_action': 'I-pharmacological inhibition'}", + "120, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "122, reduces {'effect': 'B-negative'}", + "130, cell {'context': 'B-cells'}", + "131, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "101, normal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "102, gastric ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "103, epithelial ['l1', 'l13', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "104, (RGM1) ['l2', 'l14', 'l27', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "105, and ['l3', 'l15', 'l28', 'l40', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "106, colon ['l4', 'l16', 'l29', 'l41', 'l52', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "107, cancer ['l5', 'l17', 'l30', 'l42', 'l53', 'l62', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "108, (Caco-2, ['l6', 'l18', 'l31', 'l43', 'l54', 'l63', 'l72', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "109, LoVo ['l7', 'l19', 'l32', 'l44', 'l55', 'l64', 'l73', 'l81', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "110, and ['l8', 'l20', 'l33', 'l45', 'l56', 'l65', 'l74', 'l82', 'l90', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "111, HT-29) ['l9', 'l21', 'l34', 'l46', 'l57', 'l66', 'l75', 'l83', 'l91', 'l102', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "112, cell ['l10', 'l22', 'l35', 'l47', 'l58', 'l67', 'l76', 'l84', 'l92', 'l103', 'l111', 'l119', 'l120']", + "113, lines. ['l11', 'l23', 'l36', 'l48', 'l59', 'l68', 'l77', 'l85', 'l93', 'l104', 'l112', 'l119', 'l121']", + "114, Inactivation ['l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "115, of ['l94', 'l122', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "116, EGFR ['l95', 'l105', 'l113', 'l123', 'l131', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145']", + "117, kinase ['l124', 'l132', 'l139', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151']", + "118, with ['l96', 'l125', 'l133', 'l140', 'l146', 'l152', 'l153', 'l154', 'l155', 'l156']", + "119, selective ['l97', 'l106', 'l114', 'l126', 'l134', 'l141', 'l147', 'l152', 'l157', 'l158', 'l159', 'l160']", + "120, inhibitors ['l86', 'l98', 'l107', 'l115', 'l127', 'l135', 'l142', 'l148', 'l153', 'l157', 'l161', 'l162', 'l163']", + "122, reduces ['l12', 'l24', 'l37', 'l49', 'l60', 'l69', 'l78', 'l87', 'l99', 'l108', 'l116', 'l120', 'l121', 'l128', 'l136', 'l143', 'l149', 'l154', 'l158', 'l161', 'l164', 'l165']", + "130, cell ['l25', 'l38', 'l50', 'l70', 'l79', 'l88', 'l100', 'l109', 'l117', 'l129', 'l137', 'l144', 'l150', 'l155', 'l159', 'l162', 'l164', 'l166']", + "131, proliferation. ['l26', 'l39', 'l51', 'l61', 'l71', 'l80', 'l89', 'l101', 'l110', 'l118', 'l130', 'l138', 'l145', 'l151', 'l156', 'l160', 'l163', 'l165', 'l166']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "normal", + "gastric", + "epithelial", + "(RGM1)", + "and", + "cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "gastric", + "epithelial", + "(RGM1)", + "and", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "colon", + "cancer", + "(Caco-2,", + "LoVo", + "and", + "HT-29)", + "cell", + "lines." + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "colon", + "cancer", + "(Caco-2,", + "LoVo", + "and", + "HT-29)" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "(Caco-2,", + "LoVo", + "and", + "HT-29)" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "EGFR", + "with", + "selective" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inactivation", + "of", + "EGFR", + "kinase", + "with", + "selective", + "inhibitors" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inactivation", + "of", + "EGFR", + "kinase", + "with", + "selective", + "inhibitors" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inactivation", + "of", + "EGFR", + "kinase", + "with", + "selective", + "inhibitors" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "11875497", + "TEXT": "Mammalian cloning using somatic cells has been accomplished successfully in several species, and its potential basic, clinical and therapeutic applications are being pursued on many fronts. Determining the long-term effects of cloning on offspring is crucial for consideration of future application of the technique. Although full-term development of animals cloned from adult somatic cells has been reported, problems in the resulting progeny indicate that the cloning procedure may not produce animals that are phenotypically identical to their cell donor. We used a mouse model to take advantage of its short generation time and lifespan. Here we report that the increased body weight of cloned B6C3F1 female mice reflects an increase of body fat in addition to a larger body size, and that these mice share many characteristics consistent with obesity. We also show that the obese phenotype is not transmitted to offspring generated by mating male and female cloned mice.", + "TAG_DATA": [ + "82, mouse {'context': 'B-organism'}", + "83, model {'context': 'I-organism'}", + "105, female {'context': 'I-organism'}", + "106, mice {'context': 'B-organism'}", + "123, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "82, mouse ['l0', 'l1', 'l2']", + "83, model ['l0', 'l3', 'l4']", + "105, female ['l1', 'l3', 'l5', 'l6']", + "106, mice ['l2', 'l4', 'l5']", + "123, mice ['l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11875496", + "TEXT": "Attempts to develop gene therapy for Duchenne muscular dystrophy (DMD) have been complicated by the enormous size of the dystrophin gene. We have performed a detailed functional analysis of dystrophin structural domains and show that multiple regions of the protein can be deleted in various combinations to generate highly functional mini- and micro-dystrophins. Studies in transgenic mdx mice, a model for DMD, reveal that a wide variety of functional characteristics of dystrophy are prevented by some of these truncated dystrophins. Muscles expressing the smallest dystrophins are fully protected against damage caused by muscle activity and are not morphologically different from normal muscle. Moreover, injection of adeno-associated viruses carrying micro-dystrophins into dystrophic muscles of immunocompetent mdx mice results in a striking reversal of histopathological features of this disease. These results demonstrate that the dystrophic pathology can be both prevented and reversed by gene therapy using micro-dystrophins.", + "TAG_DATA": [ + "55, transgenic {'perturbing_action': 'B-gene gain-of-function', 'context': 'B-organism'}", + "56, mdx {'perturbing_action': 'I-gene gain-of-function', 'context': 'I-organism'}", + "57, mice, {'context': 'I-organism'}", + "80, Muscles {'context': 'B-cells'}", + "110, dystrophic {'context': 'B-tissue/organ'}", + "111, muscles {'context': 'I-tissue/organ'}", + "113, immunocompetent {'context': 'B-organism'}", + "114, mdx {'context': 'I-organism'}", + "115, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "55, transgenic ['l0', 'l1', 'l2']", + "56, mdx ['l0', 'l3', 'l4']", + "57, mice, ['l1', 'l3', 'l5']", + "80, Muscles ['l2', 'l4', 'l5']", + "110, dystrophic ['l6', 'l7', 'l8', 'l9']", + "111, muscles ['l6', 'l10', 'l11', 'l12']", + "113, immunocompetent ['l7', 'l10', 'l13', 'l14']", + "114, mdx ['l8', 'l11', 'l13', 'l15']", + "115, mice ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "mdx" + ] + }, + "context": { + "val": "organism", + "words": [ + "transgenic", + "mdx" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "mdx" + ] + }, + "context": { + "val": "cells", + "words": [ + "Muscles" + ] + } + } + ] + }, + { + "PMID": "11821900", + "TEXT": "The skin-associated chemokine CCL27 (also called CTACK, ALP and ESkine) and its receptor CCR10 (GPR-2) mediate chemotactic responses of skin-homing T cells in vitro. Here we report that most skin-infiltrating lymphocytes in patients suffering from psoriasis, atopic or allergic-contact dermatitis express CCR10. Epidermal basal keratinocytes produced CCL27 protein that bound to extracellular matrix, mediated adhesion and was displayed on the surface of dermal endothelial cells. Tumor necrosis factor-alpha and interleukin-1beta induced CCL27 production whereas the glucocorticosteroid clobetasol propionate suppressed it. Circulating skin-homing CLA+ T cells, dermal microvascular endothelial cells and fibroblasts expressed CCR10 on their cell surface. In vivo, intracutaneous CCL27 injection attracted lymphocytes and, conversely, neutralization of CCL27-CCR10 interactions impaired lymphocyte recruitment to the skin leading to the suppression of allergen-induced skin inflammation. Together, these findings indicate that CCL27-CCR10 interactions have a pivotal role in T cell-mediated skin inflammation.", + "TAG_DATA": [ + "83, T {'context': 'I-cells'}", + "84, cells, {'context': 'I-cells'}", + "85, dermal {'context': 'B-cells'}", + "86, microvascular {'context': 'I-cells'}", + "87, endothelial {'context': 'I-cells'}", + "88, cells {'context': 'I-cells'}", + "90, fibroblasts {'context': 'B-cells'}", + "97, In {'context': 'B-in vivo'}", + "98, vivo, {'context': 'I-in vivo'}", + "103, lymphocytes {'context': 'B-cells'}", + "111, lymphocyte {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "83, T ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "84, cells, ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "85, dermal ['l1', 'l6', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "86, microvascular ['l2', 'l7', 'l11', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "87, endothelial ['l3', 'l8', 'l12', 'l18', 'l24', 'l25', 'l26', 'l27']", + "88, cells ['l4', 'l9', 'l13', 'l19', 'l24', 'l28', 'l29', 'l30']", + "90, fibroblasts ['l5', 'l10', 'l14', 'l20', 'l25', 'l28', 'l31', 'l32']", + "97, In ['l15', 'l21', 'l26', 'l29', 'l31', 'l33', 'l34', 'l35']", + "98, vivo, ['l16', 'l22', 'l27', 'l30', 'l32', 'l33', 'l36', 'l37']", + "103, lymphocytes ['l17', 'l23', 'l34', 'l36', 'l38']", + "111, lymphocyte ['l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11821895", + "TEXT": "The molecular diversity of receptors in human blood vessels remains largely unexplored. We developed a selection method in which peptides that home to specific vascular beds are identified after administration of a peptide library. Here we report the first in vivo screening of a peptide library in a patient. We surveyed 47,160 motifs that localized to different organs. This large-scale screening indicates that the tissue distribution of circulating peptides is nonrandom. High-throughput analysis of the motifs revealed similarities to ligands for differentially expressed cell-surface proteins, and a candidate ligand-receptor pair was validated. These data represent a step toward the construction of a molecular map of human vasculature and may have broad implications for the development of targeted therapies.", + "TAG_DATA": [ + "39, in {'context': 'B-in vivo'}", + "40, vivo {'context': 'B-in vivo'}", + "48, patient. {'context': 'B-in vivo'}" + ], + "LINK_DATA": [ + "39, in ['l0', 'l1']", + "40, vivo ['l0', 'l2']", + "48, patient. ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11786909", + "TEXT": "Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is curable in less than 50% of patients. Prognostic models based on pre-treatment characteristics, such as the International Prognostic Index (IPI), are currently used to predict outcome in DLBCL. However, clinical outcome models identify neither the molecular basis of clinical heterogeneity, nor specific therapeutic targets. We analyzed the expression of 6,817 genes in diagnostic tumor specimens from DLBCL patients who received cyclophosphamide, adriamycin, vincristine and prednisone (CHOP)-based chemotherapy, and applied a supervised learning prediction method to identify cured versus fatal or refractory disease. The algorithm classified two categories of patients with very different five-year overall survival rates (70% versus 12%). The model also effectively delineated patients within specific IPI risk categories who were likely to be cured or to die of their disease. Genes implicated in DLBCL outcome included some that regulate responses to B-cell-receptor signaling, critical serine/threonine phosphorylation pathways and apoptosis. Our data indicate that supervised learning classification techniques can predict outcome in DLBCL and identify rational targets for intervention.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11786908", + "TEXT": "Death domain-containing receptors of the tumor necrosis factor (TNF)/nerve growth factor (NGF) family can induce apoptosis upon activation in many cellular systems. We show here that a conserved phosphotyrosine-containing motif within the death domain of these receptors can mediate inhibitory functions. The Src homology domain 2 (SH2)-containing tyrosine phosphatase-1 (SHP-1), SHP-2 and SH2-containing inositol phosphatase (SHIP) bound to this motif in a caspase-independent but cell-dependent manner. We also found that stimulation of death receptors disrupted anti-apoptosis pathways initiated (at least under certain conditions) by survival factors in neutrophils. In these cells, activation of the tyrosine kinase Lyn, an important anti-apoptotic event, was prevented as a consequence of death-receptor stimulation, most likely through association of the receptor with activated SHP-1. Thus, we provide molecular and functional evidence for negative signaling by death receptors.", + "TAG_DATA": [ + "90, cells, {'context': 'B-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11786906", + "TEXT": "To study the safety and feasibility of T-cell reconstitution in HIV-infected individuals, we adoptively transferred activated autologous CD4+ T cells. Polyclonal peripheral blood CD4+ cells were costimulated ex vivo and subjects were given infusions of up to 3 x 1010 activated CD4+ cells. Dose-dependent increases in CD4+ cell counts and in the CD4:CD8 ratio were observed. Sustained increases in the fraction of cytokine-secreting T cells and decreases in the percentage of CD4+CCR5+ cells were noted in vivo, suggesting enhanced function and resistance to HIV infection. The frequency of CD4+Ki-67+ cells increased whereas CD4+ T cells containing T cell-receptor rearrangement excision circles (TRECs) decreased. These findings indicate that expansion of the peripheral T-cell pool mediated the increase in CD4 counts and suggest that approaches to reconstitute CD4 helper cell activity and decrease CCR5 expression may augment natural immunity to HIV infection.", + "TAG_DATA": [ + "16, autologous {'context': 'B-cells'}", + "17, CD4+ {'context': 'I-cells'}", + "18, T {'context': 'I-cells'}", + "19, cells. {'context': 'I-cells'}", + "21, peripheral {'context': 'I-cells'}", + "22, blood {'context': 'I-cells'}", + "23, CD4+ {'context': 'I-cells'}", + "24, cells {'context': 'I-cells'}", + "41, CD4+ {'context': 'B-cells'}", + "42, cells. {'context': 'I-cells'}", + "63, T {'context': 'B-cells'}", + "64, cells {'context': 'B-cells'}", + "75, in {'context': 'B-in vivo'}", + "76, vivo, {'context': 'I-in vivo'}", + "88, CD4+Ki-67+ {'context': 'B-cells'}", + "92, CD4+ {'context': 'B-cells'}", + "93, T {'context': 'I-cells'}", + "94, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "16, autologous ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "17, CD4+ ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "18, T ['l1', 'l11', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "19, cells. ['l2', 'l12', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "21, peripheral ['l3', 'l13', 'l23', 'l31', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "22, blood ['l4', 'l14', 'l24', 'l32', 'l37', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "23, CD4+ ['l5', 'l15', 'l25', 'l33', 'l38', 'l44', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "24, cells ['l6', 'l16', 'l26', 'l34', 'l39', 'l45', 'l51', 'l57', 'l58']", + "41, CD4+ ['l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "42, cells. ['l7', 'l17', 'l27', 'l40', 'l46', 'l52', 'l59', 'l65', 'l66', 'l67', 'l68']", + "63, T ['l8', 'l18', 'l28', 'l35', 'l41', 'l47', 'l53', 'l57', 'l60', 'l65', 'l69', 'l70', 'l71']", + "64, cells ['l9', 'l19', 'l29', 'l36', 'l42', 'l48', 'l54', 'l58', 'l61', 'l66', 'l69', 'l72', 'l73']", + "75, in ['l20', 'l49', 'l55', 'l62', 'l67', 'l70', 'l72', 'l74']", + "76, vivo, ['l10', 'l21', 'l30', 'l43', 'l50', 'l56', 'l63', 'l68', 'l71', 'l73', 'l74']", + "88, CD4+Ki-67+ ['l64', 'l75', 'l76']", + "92, CD4+ ['l77', 'l78']", + "93, T ['l75', 'l77', 'l79']", + "94, cells ['l76', 'l78', 'l79']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11786904", + "TEXT": "G-protein-coupled receptor (GPCR) agonists are well-known inducers of cardiac hypertrophy. We found that the shedding of heparin-binding epidermal growth factor (HB-EGF) resulting from metalloproteinase activation and subsequent transactivation of the epidermal growth factor receptor occurred when cardiomyocytes were stimulated by GPCR agonists, leading to cardiac hypertrophy. A new inhibitor of HB-EGF shedding, KB-R7785, blocked this signaling. We cloned a disintegrin and metalloprotease 12 (ADAM12) as a specific enzyme to shed HB-EGF in the heart and found that dominant-negative expression of ADAM12 abrogated this signaling. KB-R7785 bound directly to ADAM12, suggesting that inhibition of ADAM12 blocked the shedding of HB-EGF. In mice with cardiac hypertrophy, KB-R7785 inhibited the shedding of HB-EGF and attenuated hypertrophic changes. These data suggest that shedding of HB-EGF by ADAM12 plays an important role in cardiac hypertrophy, and that inhibition of HB-EGF shedding could be a potent therapeutic strategy for cardiac hypertrophy.", + "TAG_DATA": [ + "36, cardiomyocytes {'context': 'B-cells'}", + "77, dominant-negative {'perturbing_action': 'B-other'}", + "78, expression {'perturbing_action': 'I-other'}", + "79, of {'perturbing_action': 'I-other'}", + "80, ADAM12 {'perturbing_action': 'I-other'}", + "91, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "92, of {'perturbing_action': 'I-pharmacological inhibition'}", + "93, ADAM12 {'perturbing_action': 'I-pharmacological inhibition'}", + "100, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "77, dominant-negative ['l0', 'l1', 'l2', 'l3', 'l4']", + "78, expression ['l0', 'l5', 'l6', 'l7']", + "79, of ['l1', 'l5', 'l8']", + "80, ADAM12 ['l2', 'l6', 'l8']", + "91, inhibition ['l9', 'l10', 'l11']", + "92, of ['l3', 'l9', 'l12', 'l13']", + "93, ADAM12 ['l4', 'l7', 'l10', 'l12', 'l14']", + "100, mice ['l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "ADAM12" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "11786903", + "TEXT": "Inhibition of alphavbeta3 or alphavbeta5 integrin function has been reported to suppress neovascularization and tumor growth, suggesting that these integrins are critical modulators of angiogenesis. Here we report that mice lacking beta3 integrins or both beta3 and beta5 integrins not only support tumorigenesis, but have enhanced tumor growth as well. Moreover, the tumors in these integrin-deficient mice display enhanced angiogenesis, strongly suggesting that neither beta3 nor beta5 integrins are essential for neovascularization. We also observed that angiogenic responses to hypoxia and vascular endothelial growth factor (VEGF) are augmented significantly in the absence of beta3 integrins. We found no evidence that the expression or functions of other integrins were altered as a consequence of the beta3 deficiency, but we did observe elevated levels of VEGF receptor-2 (also called Flk-1) in beta3-null endothelial cells. These data indicate that alphavbeta3 and alphavbeta5 integrins are not essential for vascular development or pathological angiogenesis and highlight the need for further evaluation of the mechanisms of action of alphav-integrin antagonists in anti-angiogenic therapeutics.", + "TAG_DATA": [ + "29, mice {'context': 'B-organism'}", + "30, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "31, beta3 {'perturbing_action': 'I-gene loss-of-function'}", + "32, integrins {'perturbing_action': 'I-gene loss-of-function'}", + "33, or {'perturbing_action': 'I-gene loss-of-function'}", + "34, both {'perturbing_action': 'I-gene loss-of-function'}", + "35, beta3 {'perturbing_action': 'I-gene loss-of-function'}", + "37, beta5 {'perturbing_action': 'I-gene loss-of-function'}", + "38, integrins {'perturbing_action': 'I-gene loss-of-function'}", + "41, support {'effect': 'B-positive'}", + "42, tumorigenesis, {'phenotype': 'B-tumourigenesis'}", + "45, enhanced {'effect': 'B-positive'}", + "46, tumor {'phenotype': 'B-tumour growth'}", + "47, growth {'phenotype': 'I-tumour growth'}", + "52, tumors {'context': 'B-neoplasm'}", + "55, integrin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "56, mice {'context': 'B-organism'}", + "91, absence {'perturbing_action': 'B-gene loss-of-function'}", + "114, beta3 {'perturbing_action': 'B-gene loss-of-function'}", + "115, deficiency, {'perturbing_action': 'I-gene loss-of-function'}", + "129, beta3-null {'perturbing_action': 'B-gene loss-of-function'}", + "130, endothelial {'context': 'B-cells'}", + "131, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "29, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "30, lacking ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "31, beta3 ['l1', 'l8', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "32, integrins ['l2', 'l9', 'l18', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "33, or ['l10', 'l19', 'l31', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "34, both ['l20', 'l32', 'l43', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "35, beta3 ['l21', 'l33', 'l44', 'l55', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "37, beta5 ['l22', 'l34', 'l45', 'l56', 'l67', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "38, integrins ['l23', 'l35', 'l46', 'l57', 'l68', 'l78', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "41, support ['l3', 'l11', 'l24', 'l36', 'l47', 'l58', 'l69', 'l79', 'l88', 'l97', 'l98', 'l99', 'l100']", + "42, tumorigenesis, ['l4', 'l12', 'l25', 'l37', 'l48', 'l59', 'l70', 'l80', 'l89', 'l97', 'l101', 'l102', 'l103']", + "45, enhanced ['l5', 'l13', 'l26', 'l38', 'l49', 'l60', 'l71', 'l81', 'l90', 'l98', 'l101', 'l104', 'l105']", + "46, tumor ['l6', 'l14', 'l27', 'l39', 'l50', 'l61', 'l72', 'l82', 'l91', 'l99', 'l102', 'l104', 'l106']", + "47, growth ['l7', 'l15', 'l28', 'l40', 'l51', 'l62', 'l73', 'l83', 'l92', 'l100', 'l103', 'l105', 'l106']", + "52, tumors ['l16', 'l29', 'l41', 'l52', 'l63', 'l74', 'l84', 'l93', 'l107', 'l108']", + "55, integrin-deficient ['l53', 'l64', 'l75', 'l85', 'l94', 'l107', 'l109', 'l110']", + "56, mice ['l17', 'l30', 'l42', 'l54', 'l65', 'l76', 'l86', 'l95', 'l108', 'l109']", + "91, absence ['l66', 'l77', 'l87', 'l96', 'l110']", + "114, beta3 ['l111', 'l112', 'l113', 'l114']", + "115, deficiency, ['l111', 'l115', 'l116', 'l117']", + "129, beta3-null ['l112', 'l115', 'l118', 'l119']", + "130, endothelial ['l113', 'l116', 'l118', 'l120']", + "131, cells. ['l114', 'l117', 'l119', 'l120']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "beta3", + "integrins", + "or", + "both", + "beta5", + "integrin-deficient" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "support", + "enhanced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "beta3", + "integrins", + "or", + "both", + "beta5" + ] + }, + "effect": { + "val": "positive", + "words": [ + "support", + "enhanced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "beta3", + "integrins", + "or", + "both", + "beta5" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "beta3", + "integrins", + "or", + "both", + "beta5" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "beta3", + "integrins", + "or", + "both", + "beta5", + "integrin-deficient" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "support", + "enhanced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "support", + "enhanced" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "beta3", + "deficiency,", + "beta3-null" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells." + ] + } + } + ] + }, + { + "PMID": "11726975", + "TEXT": "Dendritic-cell (DC) trafficking and function in tumors is poorly characterized, with studies confined to myeloid DCs (DC1s). Tumors inhibit DC1 migration and function, likely hindering specific immunity. The role of plasmacytoid DCs (DC2s) in tumor immunity is unknown. We show here that malignant human ovarian epithelial tumor cells express very high levels of stromal-derived factor-1, which induces DC2 precursor (preDC2) chemotaxis and adhesion/transmigration, upregulates preDC2 very late antigen (VLA)-5, and protects preDC2s from tumor macrophage interleukin-10-induced apoptosis, all through CXC chemokine receptor-4. The VLA-5 ligand vascular-cell adhesion molecule-1 mediated preDC2 adhesion/transmigration. Tumor preDC2s induced significant T-cell interleukin-10 unrelated to preDC2 differentiation or activation state, and this contributed to poor T-cell activation. Myeloid precursor DCs (preDC1s) were not detected. Tumors may weaken immunity by attracting preDC2s and protecting them from the harsh microenvironment, and by altering preDC1 distribution.", + "TAG_DATA": [ + "43, human {'context': 'I-transformed cells'}", + "44, ovarian {'context': 'I-transformed cells'}", + "45, epithelial {'context': 'I-transformed cells'}", + "46, tumor {'context': 'I-transformed cells'}", + "47, cells {'context': 'I-transformed cells'}", + "56, induces {'effect': 'B-positive'}", + "57, DC2 {'context': 'B-cells'}", + "70, protects {'effect': 'B-negative'}", + "71, preDC2s {'context': 'B-cells'}", + "72, from {'effect': 'I-negative'}", + "75, interleukin-10-induced {'effect': 'B-positive'}", + "76, apoptosis, {'phenotype': 'B-apoptosis'}", + "91, Tumor {'context': 'B-neoplasm'}", + "109, T-cell {'context': 'B-cells'}", + "111, Myeloid {'context': 'B-cells'}", + "112, precursor {'context': 'I-cells'}", + "113, DCs {'context': 'I-cells'}", + "114, (preDC1s) {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "43, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "44, ovarian ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "45, epithelial ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "46, tumor ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "47, cells ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "56, induces ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52']", + "57, DC2 ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "58, precursor ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l53', 'l59', 'l60', 'l61']", + "70, protects ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l54', 'l59', 'l62', 'l63', 'l64', 'l65']", + "71, preDC2s ['l8', 'l19', 'l29', 'l38', 'l46', 'l55', 'l60', 'l62', 'l66', 'l67', 'l68']", + "72, from ['l9', 'l20', 'l30', 'l39', 'l47', 'l56', 'l61', 'l63', 'l66', 'l69', 'l70']", + "75, interleukin-10-induced ['l10', 'l21', 'l31', 'l40', 'l48', 'l57', 'l64', 'l67', 'l69', 'l71']", + "76, apoptosis, ['l11', 'l22', 'l32', 'l41', 'l49', 'l58', 'l65', 'l68', 'l70', 'l71']", + "91, Tumor ['l72']", + "109, T-cell ['l72', 'l73']", + "111, Myeloid ['l74', 'l75', 'l76']", + "112, precursor ['l74', 'l77', 'l78']", + "113, DCs ['l73', 'l75', 'l77', 'l79']", + "114, (preDC1s) ['l76', 'l78', 'l79']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "ovarian", + "epithelial", + "tumor", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces", + "interleukin-10-induced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "ovarian", + "epithelial", + "tumor", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protects", + "from" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "ovarian", + "epithelial", + "tumor", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "interleukin-10-induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "DC2", + "preDC2s" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "DC2", + "preDC2s" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protects", + "from" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "DC2", + "preDC2s" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "protects", + "from" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "interleukin-10-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + } + ] + }, + { + "PMID": "11726973", + "TEXT": "Highly active anti-retroviral therapies, which incorporate HIV protease inhibitors, resolve many AIDS-defining illnesses. However, patients receiving protease inhibitors develop a marked lipodystrophy and hyperlipidemia. Using cultured human and rat hepatoma cells and primary hepatocytes from transgenic mice, we demonstrate that protease inhibitor treatment inhibits proteasomal degradation of nascent apolipoprotein B, the principal protein component of triglyceride and cholesterol-rich plasma lipoproteins. Unexpectedly, protease inhibitors also inhibited the secretion of apolipoprotein B. This was associated with inhibition of cholesteryl-ester synthesis and microsomal triglyceride transfer-protein activity. However, in the presence of oleic acid, which stimulates neutral-lipid biosynthesis, protease-inhibitor treatment increased secretion of apolipoprotein B-lipoproteins above controls. These findings suggest a molecular basis for protease-inhibitor-associated hyperlipidemia, a serious adverse effect of an otherwise efficacious treatment for HIV infection.", + "TAG_DATA": [ + "26, human {'context': 'I-transformed cells'}", + "27, and {'context': 'I-transformed cells'}", + "28, rat {'context': 'I-transformed cells'}", + "29, hepatoma {'context': 'I-transformed cells'}", + "30, cells {'context': 'I-transformed cells'}", + "32, primary {'context': 'B-cells'}", + "33, hepatocytes {'context': 'I-cells'}", + "35, transgenic {'context': 'B-organism'}", + "36, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "25, cultured ['l0', 'l1', 'l2', 'l3', 'l4']", + "26, human ['l0', 'l5', 'l6', 'l7', 'l8']", + "27, and ['l1', 'l5', 'l9', 'l10', 'l11']", + "28, rat ['l2', 'l6', 'l9', 'l12', 'l13']", + "29, hepatoma ['l3', 'l7', 'l10', 'l12', 'l14']", + "30, cells ['l4', 'l8', 'l11', 'l13', 'l14']", + "32, primary ['l15', 'l16', 'l17']", + "33, hepatocytes ['l15', 'l18', 'l19']", + "35, transgenic ['l16', 'l18', 'l20']", + "36, mice, ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11726971", + "TEXT": "Retroviral Gag proteins encode sequences, termed late domains, which facilitate the final stages of particle budding from the plasma membrane. We report here that interactions between Tsg101, a factor involved in endosomal protein sorting, and short peptide motifs in the HIV-1 Gag late domain and Ebola virus matrix (EbVp40) proteins are essential for efficient egress of HIV-1 virions and Ebola virus-like particles. EbVp40 recruits Tsg101 to sites of particle assembly and a short, EbVp40-derived Tsg101-binding peptide sequence can functionally substitute for the HIV-1 Gag late domain. Notably, recruitment of Tsg101 to assembling virions restores budding competence to a late-domain-defective HIV-1 in the complete absence of viral late domain. These studies define an essential virus-host interaction that is conserved in two unrelated viruses. Because the Tsg101 is recruited by small, conserved viral sequence motifs, agents that mimic these structures are potential inhibitors of the replication of these lethal human pathogens.", + "TAG_DATA": [ + "99, HIV-1 {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11726970", + "TEXT": "While searching for alternative reading-frame peptides encoded by influenza A virus that are recognized by CD8+ T cells, we found an abundant immunogenic peptide encoded by the +1 reading frame of PB1. This peptide derives from a novel conserved 87-residue protein, PB1-F2, which has several unusual features compared with other influenza gene products in addition to its mode of translation. These include its absence from some animal (particularly swine) influenza virus isolates, variable expression in individual infected cells, rapid proteasome-dependent degradation and mitochondrial localization. Exposure of cells to a synthetic version of PB1-F2 induces apoptosis, and influenza viruses with targeted mutations that interfere with PB1-F2 expression induce less extensive apoptosis in human monocytic cells than those with intact PB1-F2. We propose that PB1-F2 functions to kill host immune cells responding to influenza virus infection.", + "TAG_DATA": [ + "86, cells {'context': 'B-cells'}", + "93, induces {'effect': 'B-positive'}", + "94, apoptosis, {'phenotype': 'B-apoptosis'}", + "99, targeted {'perturbing_action': 'B-other'}", + "100, mutations {'perturbing_action': 'I-other'}", + "101, that {'perturbing_action': 'I-other'}", + "102, interfere {'perturbing_action': 'I-other'}", + "103, with {'perturbing_action': 'I-other'}", + "104, PB1-F2 {'perturbing_action': 'I-other'}", + "105, expression {'perturbing_action': 'I-other'}", + "106, induce {'effect': 'B-positive'}", + "107, less {'effect': 'B-negative'}", + "109, apoptosis {'phenotype': 'B-apoptosis'}", + "111, human {'context': 'B-cells'}", + "112, monocytic {'context': 'I-cells'}", + "113, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "86, cells ['l0', 'l1']", + "93, induces ['l0', 'l2']", + "94, apoptosis, ['l1', 'l2']", + "99, targeted ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "100, mutations ['l3', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "101, that ['l4', 'l15', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "102, interfere ['l5', 'l16', 'l26', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "103, with ['l6', 'l17', 'l27', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "104, PB1-F2 ['l7', 'l18', 'l28', 'l37', 'l45', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "105, expression ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "106, induce ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l66', 'l67', 'l68', 'l69', 'l70']", + "107, less ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l71', 'l72', 'l73', 'l74']", + "109, apoptosis ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l75', 'l76', 'l77']", + "111, human ['l12', 'l23', 'l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l78', 'l79']", + "112, monocytic ['l13', 'l24', 'l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l76', 'l78', 'l80']", + "113, cells ['l14', 'l25', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l79', 'l80']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells", + "human", + "monocytic" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces", + "induce" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "human", + "monocytic" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis,", + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "induce" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis,", + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "targeted", + "mutations", + "that", + "interfere", + "with", + "PB1-F2", + "expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "targeted", + "mutations", + "that", + "interfere", + "with", + "PB1-F2", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "less" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "targeted", + "mutations", + "that", + "interfere", + "with", + "PB1-F2", + "expression" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "targeted", + "mutations", + "that", + "interfere", + "with", + "PB1-F2", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "monocytic", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "less" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "less" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "monocytic", + "cells" + ] + } + } + ] + }, + { + "PMID": "11726969", + "TEXT": "Microbial pathogens must evade the human immune system to survive, disseminate and cause disease. By proteome analysis of the bacterium Group A Streptococcus (GAS), we identified a secreted protein with homology to the alpha-subunit of Mac-1, a leukocyte beta2 integrin required for innate immunity to invading microbes. The GAS Mac-1-like protein (Mac) was secreted by most pathogenic strains, produced in log-phase and controlled by the covR-covS two-component gene regulatory system, which also regulates transcription of other GAS virulence factors. Patients with GAS infection had titers of antibody specific to Mac that correlated with the course of disease, demonstrating that Mac was produced in vivo. Mac bound to CD16 (FcgammaRIIIB) on the surface of human polymorphonuclear leukocytes and inhibited opsonophagocytosis and production of reactive oxygen species, which resulted in significantly decreased pathogen killing. Thus, by mimicking a host-cell receptor required for an innate immune response, the GAS Mac protein inhibits professional phagocyte function by a novel strategy that enhances pathogen survival, establishment of infection and dissemination.", + "TAG_DATA": [ + "102, in {'context': 'B-in vivo'}", + "103, vivo. {'context': 'I-in vivo'}", + "113, human {'context': 'B-cells'}", + "114, polymorphonuclear {'context': 'I-cells'}", + "115, leukocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "102, in ['l0', 'l1', 'l2', 'l3']", + "103, vivo. ['l0', 'l4', 'l5', 'l6']", + "113, human ['l1', 'l4', 'l7', 'l8']", + "114, polymorphonuclear ['l2', 'l5', 'l7', 'l9']", + "115, leukocytes ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11726968", + "TEXT": "Inflammation involves the sequential activation of signaling pathways leading to the production of both pro- and anti-inflammatory mediators. Although much attention has focused on pro-inflammatory pathways that initiate inflammation, relatively little is known about the mechanisms that switch off inflammation and resolve the inflammatory response. The transcription factor NF-kappaB is thought to have a central role in the induction of pro-inflammatory gene expression and has attracted interest as a new target for the treatment of inflammatory disease. We show here that NF-kappaB activation in leukocytes recruited during the onset of inflammation is associated with pro-inflammatory gene expression, whereas such activation during the resolution of inflammation is associated with the expression of anti-inflammatory genes and the induction of apoptosis. Inhibition of NF-kappaB during the resolution of inflammation protracts the inflammatory response and prevents apoptosis. This suggests that NF-kappaB has an anti-inflammatory role in vivo involving the regulation of inflammatory resolution.", + "TAG_DATA": [ + "115, induction {'effect': 'B-positive'}", + "118, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "119, of {'perturbing_action': 'I-pharmacological inhibition'}", + "120, NF-kappaB {'perturbing_action': 'I-pharmacological inhibition'}", + "131, prevents {'effect': 'B-negative'}", + "132, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "115, induction ['l0']", + "117, apoptosis. ['l0']", + "118, Inhibition ['l1', 'l2', 'l3', 'l4']", + "119, of ['l1', 'l5', 'l6', 'l7']", + "120, NF-kappaB ['l2', 'l5', 'l8', 'l9']", + "131, prevents ['l3', 'l6', 'l8', 'l10']", + "132, apoptosis. ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "NF-kappaB" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "NF-kappaB" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "11689892", + "TEXT": "Here we introduce a new approach for the screening, selection and sorting of cell-surface-binding peptides from phage libraries. Biopanning and rapid analysis of selective interactive ligands (termed BRASIL) is based on differential centrifugation in which a cell suspension incubated with phage in an aqueous upper phase is centrifuged through a non-miscible organic lower phase. This single-step organic phase separation is faster, more sensitive and more specific than current methods that rely on washing steps or limiting dilution. As a proof-of-principle, we screened human endothelial cells stimulated with vascular endothelial growth factor (VEGF) and constructed a peptide-based ligand-receptor map of the VEGF family. Next, we validated the motif PQPRPL as a novel chimeric ligand mimic that binds specifically to VEGF receptor-1 and to neuropilin-1. BRASIL may prove itself a superior method for probing target cell surfaces with a broad range of potential applications.", + "TAG_DATA": [ + "82, human {'context': 'B-cells'}", + "83, endothelial {'context': 'I-cells'}", + "84, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "82, human ['l0', 'l1']", + "83, endothelial ['l0', 'l2']", + "84, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11689882", + "TEXT": "In systemic lupus erythematosus, antibodies against double-stranded DNA are a major contributor to renal disease. We have previously demonstrated that the pentapeptide Asp/Glu-Trp-Asp/Glu-Tyr-Ser/Gly is a molecular mimic of double-stranded DNA. This sequence is also present in the extracellular domain of murine and human NMDA (N-methyl-D-aspartate) receptor subunits NR2a and NR2b. Here we show that the NR2 receptor is recognized by both murine and human anti-DNA antibodies. Moreover, anti-DNA antibodies with this cross-reactivity mediate apoptotic death of neurons in vivo and in vitro. Finally, we show that the cerebrospinal fluid of a patient with systemic lupus erythematosus contains these antibodies and also mediates neuronal death via an apoptotic pathway. These observations indicate that lupus antibodies cross-react with DNA and NMDA receptors, gain access to cerebrospinal fluid and may mediate non-thrombotic and non-vasculitic abnormalities of the central nervous system.", + "TAG_DATA": [ + "72, mediate {'effect': 'B-regulates'}", + "73, apoptotic {'phenotype': 'B-apoptosis'}", + "74, death {'phenotype': 'I-apoptosis'}", + "76, neurons {'context': 'B-cells'}", + "77, in {'context': 'B-in vivo'}", + "78, vivo {'context': 'I-in vivo'}", + "80, in {'context': 'B-in vitro'}", + "81, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "72, mediate ['l0', 'l1', 'l2', 'l3', 'l4']", + "73, apoptotic ['l0', 'l5', 'l6', 'l7', 'l8']", + "74, death ['l1', 'l5', 'l9', 'l10', 'l11']", + "76, neurons ['l2', 'l6', 'l9', 'l12', 'l13']", + "77, in ['l3', 'l7', 'l10', 'l12', 'l14']", + "78, vivo ['l4', 'l8', 'l11', 'l13', 'l14']", + "80, in ['l15']", + "81, vitro. ['l15']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "regulates", + "words": [ + "mediate" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "mediate" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "mediate" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "11590440", + "TEXT": "Treatment of cocaine addiction is hampered by high rates of relapse even after prolonged drug abstinence. This relapse to compulsive cocaine use can be triggered by re-exposure to cocaine, by re-exposure to stimuli previously associated with cocaine or by exposure to stress. In laboratory rats, similar events reinstate cocaine seeking after prolonged withdrawal periods, thus providing a model to study neuronal mechanisms underlying the relapse to cocaine. The endocannabinoid system has been implicated in a number of neuropsychiatric conditions, including drug addiction. The active ingredient of marijuana, Delta9-tetrahydrocannabinol, activates the mesolimbic dopamine (DA) reward system and has rewarding effects in preclinical models of drug abuse. We report here that the synthetic cannabinoid agonist, HU210 (ref. 13), provokes relapse to cocaine seeking after prolonged withdrawal periods. Furthermore, the selective CB1 receptor antagonist, SR141716A (ref. 14), attenuates relapse induced by re-exposure to cocaine-associated cues or cocaine itself, but not relapse induced by exposure to stress. These data reveal an important role of the cannabinoid system in the neuronal processes underlying relapse to cocaine seeking, and provide a rationale for the use of cannabinoid receptor antagonists for the prevention of relapse to cocaine use.", + "TAG_DATA": [ + "127, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "128, CB1 {'perturbing_action': 'I-pharmacological inhibition'}", + "129, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "130, antagonist, {'perturbing_action': 'I-pharmacological inhibition'}", + "131, SR141716A {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "127, selective ['l0', 'l1', 'l2', 'l3']", + "128, CB1 ['l0', 'l4', 'l5', 'l6']", + "129, receptor ['l1', 'l4', 'l7', 'l8']", + "130, antagonist, ['l2', 'l5', 'l7', 'l9']", + "131, SR141716A ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11590434", + "TEXT": "Despite the existence of tumor-specific antigens and demonstrated presence of tumor-specific immune cells, the majority of tumors manage to avoid immune-mediated destruction. Various mechanisms have been suggested for tumor evasion from immune response. One such mechanism is thought to be mediated by transforming growth factor-beta (TGF-beta), an immunosuppressive cytokine found at the site of most tumors. We demonstrate here that T-cell-specific blockade of TGF-beta signaling allows the generation of an immune response capable of eradicating tumors in mice challenged with live tumor cells. In addition, we provide mechanisms through which abrogation of TGF-beta signaling leads to the enhancement of anti-tumor immunity. Our data indicate that T-cell-specific blockade of TGF-beta signaling has strong therapeutic potential to shift the balance of the immune response in favor of anti-tumor immunity.", + "TAG_DATA": [ + "75, tumors {'context': 'B-neoplasm'}", + "77, mice {'context': 'B-organism'}", + "81, tumor {'context': 'B-transformed cells'}", + "82, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "75, tumors ['l0', 'l1', 'l2']", + "77, mice ['l0', 'l3', 'l4']", + "81, tumor ['l1', 'l3', 'l5']", + "82, cells. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11533711", + "TEXT": "Type 1 diabetes (T1D) in non-obese diabetic (NOD) mice may be favored by immune dysregulation leading to the hyporesponsiveness of regulatory T cells and activation of effector T-helper type 1 (Th1) cells. The immunoregulatory activity of natural killer T (NKT) cells is well documented, and both interleukin (IL)-4 and IL-10 secreted by NKT cells have important roles in mediating this activity. NKT cells are less frequent and display deficient IL-4 responses in both NOD mice and individuals at risk for T1D (ref. 8), and this deficiency may lead to T1D (refs. 1,6-9). Thus, given that NKT cells respond to the alpha-galactosylceramide (alpha-GalCer) glycolipid in a CD1d-restricted manner by secretion of Th2 cytokines, we reasoned that activation of NKT cells by alpha-GalCer might prevent the onset and/or recurrence of T1D. Here we show that alpha-GalCer treatment, even when initiated after the onset of insulitis, protects female NOD mice from T1D and prolongs the survival of pancreatic islets transplanted into newly diabetic NOD mice. In addition, when administered after the onset of insulitis, alpha-GalCer and IL-7 displayed synergistic effects, possibly via the ability of IL-7 to render NKT cells fully responsive to alpha-GalCer. Protection from T1D by alpha-GalCer was associated with the suppression of both T- and B-cell autoimmunity to islet beta cells and with a polarized Th2-like response in spleen and pancreas of these mice. These findings raise the possibility that alpha-GalCer treatment might be used therapeutically to prevent the onset and recurrence of human T1D.", + "TAG_DATA": [ + "144, female {'context': 'B-organism'}", + "145, NOD {'context': 'I-organism'}", + "146, mice {'context': 'I-organism'}", + "154, pancreatic {'context': 'B-cells'}", + "155, islets {'context': 'I-cells'}", + "160, NOD {'context': 'I-organism'}", + "161, mice. {'context': 'I-organism'}", + "185, NKT {'context': 'B-cells'}", + "186, cells {'context': 'I-cells'}", + "220, pancreas {'context': 'B-tissue/organ'}", + "223, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "144, female ['l0', 'l1', 'l2', 'l3']", + "145, NOD ['l0', 'l4', 'l5', 'l6']", + "146, mice ['l1', 'l4']", + "154, pancreatic ['l2', 'l5', 'l7', 'l8', 'l9']", + "155, islets ['l3', 'l6', 'l7', 'l10', 'l11']", + "160, NOD ['l8', 'l10', 'l12']", + "161, mice. ['l9', 'l11', 'l12']", + "185, NKT ['l13', 'l14', 'l15']", + "186, cells ['l13']", + "220, pancreas ['l14', 'l16']", + "223, mice. ['l15', 'l16']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11533708", + "TEXT": "Cyclooxygenase-2 (COX-2), a key enzyme in arachidonic acid metabolism, is overexpressed in many cancers. Inhibition of COX-2 by nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of cancer development in humans and suppresses tumor growth in animal models. The anti-cancer effect of NSAIDs seems to involve suppression of tumor angiogenesis, but the underlying mechanism is not completely understood. Integrin alpha V beta 3 is an adhesion receptor critically involved in mediating tumor angiogenesis. Here we show that inhibition of endothelial-cell COX-2 by NSAIDs suppresses alpha V beta 3-dependent activation of the small GTPases Cdc42 and Rac, resulting in inhibition of endothelial-cell spreading and migration in vitro and suppression of fibroblast growth factor-2-induced angiogenesis in vivo. These results establish a novel functional link between COX-2, integrin alpha V beta 3 and Cdc42-/Rac-dependent endothelial-cell migration. Moreover, they provide a rationale to the understanding of the anti-angiogenic activity of NSAIDs.", + "TAG_DATA": [ + "76, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "77, of {'perturbing_action': 'I-pharmacological inhibition'}", + "78, endothelial-cell {'perturbing_action': 'I-pharmacological inhibition'}", + "79, COX-2 {'perturbing_action': 'I-pharmacological inhibition'}", + "80, by {'perturbing_action': 'I-pharmacological inhibition'}", + "81, NSAIDs {'perturbing_action': 'I-pharmacological inhibition'}", + "97, inhibition {'effect': 'B-negative'}", + "99, endothelial-cell {'context': 'B-cells'}", + "102, migration {'phenotype': 'B-migration'}", + "103, in {'context': 'B-in vitro'}", + "104, vitro {'context': 'I-in vitro'}", + "112, in {'context': 'B-in vivo'}", + "113, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "76, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "77, of ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "78, endothelial-cell ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "79, COX-2 ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "80, by ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "81, NSAIDs ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "97, inhibition ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "99, endothelial-cell ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "102, migration ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "103, in ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "104, vitro ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "112, in ['l55']", + "113, vivo. ['l55']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "endothelial-cell", + "COX-2", + "by", + "NSAIDs" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "endothelial-cell", + "COX-2", + "by", + "NSAIDs" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial-cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "endothelial-cell", + "COX-2", + "by", + "NSAIDs" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "endothelial-cell", + "COX-2", + "by", + "NSAIDs" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial-cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial-cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "11479622", + "TEXT": "Peripheral T-cell tolerance is a mechanism to limit autoimmunity, but represents a major obstacle in diseases such as cancer. Tolerance is due to limited accumulation of antigen-specific T cells accompanied by functional hypo-responsiveness, and is induced by antigen encounter in a non-inflammatory environment. In contrast to advances in preventing induction of T-cell tolerance, there has been little progress in defining targets to reverse established tolerance. Here we show that signals from a single dose of an agonistic antibody against OX40 (CD134, a member of the tumor necrosis-factor family of receptors) can break an existing state of tolerance in the CD4+ T-cell compartment. OX40 signals promote T-cell expansion after the hypo-responsive phenotype is induced and restore normal functionality. These data highlight the potent costimulatory capacity of OX40, and indicate OX40 as a target for therapeutic intervention in a variety of related diseases.", + "TAG_DATA": [ + "99, CD4+ {'context': 'B-cells'}", + "100, T-cell {'context': 'I-cells'}", + "101, compartment. {'context': 'I-cells'}", + "105, T-cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "77, antibody ['l0', 'l1', 'l2', 'l3', 'l4']", + "78, against ['l0', 'l5', 'l6', 'l7', 'l8']", + "79, OX40 ['l1', 'l5', 'l9', 'l10', 'l11']", + "99, CD4+ ['l2', 'l6', 'l9', 'l12', 'l13']", + "100, T-cell ['l3', 'l7', 'l10', 'l12', 'l14']", + "101, compartment. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11433354", + "TEXT": "Intravital microscopy coupled with chronic animal window models has provided stunning insight into tumor pathophysiology, including gene expression, angiogenesis, cell adhesion and migration, vascular, interstitial and lymphatic transport, metabolic microenvironment and drug delivery. However, the findings to date have been limited to the tumor surface (< 150 microm). Here, we show that the multiphoton laser-scanning microscope can provide high three-dimensional resolution of gene expression and function in deeper regions of tumors. These insights could be critical to the development of novel therapeutics that target not only the tumor surface, but also internal regions.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11433353", + "TEXT": "Molecular therapy using viruses would benefit greatly from a non-invasive modality for assessing dissemination of viruses. Here we investigated whether positron emission tomography (PET) scanning using [(124)I]-5-iodo-2'-fluoro-1-beta-d-arabinofuranosyl-uracil (FIAU) could image cells infected with herpes simplex viruses (HSV). Using replication-competent HSV-1 oncolytic viruses with thymidine kinase (TK) under control of different promoters, we demonstrate that viral infection, proliferation and promoter characteristics all interact to influence FIAU accumulation and imaging. In vivo, as few as 1 x 107 viral particles injected into a 0.5-cm human colorectal tumor can be detected by [(124)I]FIAU PET imaging. PET signal intensity is significantly greater at 48 hours compared with that at 8 hours after viral injection, demonstrating that PET scanning can detect changes in TK activity resulting from local viral proliferation. We also show the ability of FIAU-PET scanning to detect differences in viral infectivity at 0.5 log increments. Non-invasive imaging might be useful in assessing biologically relevant distribution of virus in therapies using replication-competent HSV.", + "TAG_DATA": [ + "30, cells {'context': 'B-cells'}", + "68, In {'context': 'B-in vivo'}", + "69, vivo, {'context': 'I-in vivo'}", + "81, 0.5-cm {'context': 'B-neoplasm'}", + "82, human {'context': 'B-neoplasm'}", + "83, colorectal {'context': 'I-neoplasm'}", + "84, tumor {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "68, In ['l0', 'l1', 'l2', 'l3', 'l4']", + "69, vivo, ['l0', 'l5', 'l6', 'l7', 'l8']", + "81, 0.5-cm ['l1', 'l5', 'l9', 'l10', 'l11']", + "82, human ['l2', 'l6', 'l9', 'l12', 'l13']", + "83, colorectal ['l3', 'l7', 'l10', 'l12', 'l14']", + "84, tumor ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11385513", + "TEXT": "Long-term solid-organ allografts typically develop diffuse arterial intimal lesions (graft arterial disease; GAD), consisting of smooth-muscle cells (SMC), extracellular matrix and admixed mononuclear leukocytes. GAD eventually culminates in vascular stenosis and ischemic graft failure. Although the exact mechanisms are unknown, chronic low-level alloresponses likely induce inflammatory cells and/or dysfunctional vascular wall cells to secrete growth factors that promote SMC intimal recruitment, proliferation and matrix synthesis. Although prior work demonstrated that the endothelium and medial SMCs lining GAD lesions in cardiac allografts are donor-derived, the intimal SMC origin could not be determined. They are generally presumed to originate from the donor media, leading to interventions that target donor medial SMC proliferation, with limited efficacy. However, other reports indicate that allograft vessels may contain host-derived endothelium and SMCs (refs. 8,9). Moreover, subpopulations of bone-marrow and circulating cells can differentiate into endothelium, and implanted synthetic vascular grafts are seeded by host SMCs and endothelium. Here we used murine aortic transplants to formally identify the source of SMCs in GAD lesions. Allografts in beta-galactosidase transgenic recipients showed that intimal SMCs derived almost exclusively from host cells. Bone-marrow transplantation of beta-galactosidase--expressing cells into aortic allograft recipients demonstrated that intimal cells included those of marrow origin. Thus, smooth-muscle--like cells in GAD lesions can originate from circulating bone--marrow-derived precursors.", + "TAG_DATA": [ + "154, murine {'context': 'B-organism'}", + "155, aortic {'context': 'I-xenograft'}", + "156, transplants {'context': 'I-xenograft'}", + "167, Allografts {'context': 'B-xenograft'}", + "169, beta-galactosidase {'perturbing_action': 'B-gene gain-of-function'}", + "170, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "174, intimal {'context': 'B-cells'}", + "175, SMCs {'context': 'I-cells'}", + "188, aortic {'context': 'B-xenograft'}", + "189, allograft {'context': 'I-xenograft'}", + "190, recipients {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "154, murine ['l0', 'l1']", + "155, aortic ['l0', 'l2']", + "156, transplants ['l1', 'l2']", + "167, Allografts ['l3', 'l4', 'l5', 'l6', 'l7']", + "169, beta-galactosidase ['l3', 'l8', 'l9', 'l10', 'l11']", + "170, transgenic ['l4', 'l8', 'l12', 'l13', 'l14']", + "171, recipients ['l5', 'l9', 'l12', 'l15', 'l16']", + "174, intimal ['l6', 'l10', 'l13', 'l15', 'l17']", + "175, SMCs ['l7', 'l11', 'l14', 'l16', 'l17']", + "188, aortic ['l18', 'l19']", + "189, allograft ['l18', 'l20']", + "190, recipients ['l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "xenograft", + "words": [ + "Allografts" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "beta-galactosidase", + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "beta-galactosidase", + "transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "intimal", + "SMCs" + ] + } + } + ] + }, + { + "PMID": "11385510", + "TEXT": "From 28 young children in the Netherlands, we isolated a paramyxovirus that was identified as a tentative new member of the Metapneumovirus genus based on virological data, sequence homology and gene constellation. Previously, avian pneumovirus was the sole member of this recently assigned genus, hence the provisional name for the newly discovered virus: human metapneumovirus. The clinical symptoms of the children from whom the virus was isolated were similar to those caused by human respiratory syncytial virus infection, ranging from upper respiratory tract disease to severe bronchiolitis and pneumonia. Serological studies showed that by the age of five years, virtually all children in the Netherlands have been exposed to human metapneumovirus and that the virus has been circulating in humans for at least 50 years.", + "TAG_DATA": [ + "60, children {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11385507", + "TEXT": "The adipocyte fatty-acid-binding protein, aP2, has an important role in regulating systemic insulin resistance and lipid metabolism. Here we demonstrate that aP2 is also expressed in macrophages, has a significant role in their biological responses and contributes to the development of atherosclerosis. Apolipoprotein E (ApoE)-deficient mice also deficient for aP2 showed protection from atherosclerosis in the absence of significant differences in serum lipids or insulin sensitivity. aP2-deficient macrophages showed alterations in inflammatory cytokine production and a reduced ability to accumulate cholesterol esters when exposed to modified lipoproteins. Apoe-/- mice with Ap2+/+ adipocytes and Ap2-/- macrophages generated by bone-marrow transplantation showed a comparable reduction in atherosclerotic lesions to those with total aP2 deficiency, indicating an independent role for macrophage aP2 in atherogenesis. Through its distinct actions in adipocytes and macrophages, aP2 provides a link between features of the metabolic syndrome and could be a new therapeutic target for the prevention of atherosclerosis.", + "TAG_DATA": [ + "42, Apolipoprotein {'perturbing_action': 'B-gene loss-of-function'}", + "43, E {'perturbing_action': 'I-gene loss-of-function'}", + "44, (ApoE)-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "45, mice {'context': 'B-organism'}", + "47, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "48, for {'perturbing_action': 'I-gene loss-of-function'}", + "49, aP2 {'perturbing_action': 'I-gene loss-of-function'}", + "51, protection {'effect': 'B-negative'}", + "66, aP2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "67, macrophages {'context': 'B-cells'}", + "87, Apoe-/- {'perturbing_action': 'B-gene loss-of-function'}", + "88, mice {'context': 'B-organism'}", + "90, Ap2+/+ {'context': 'B-cells'}", + "91, adipocytes {'context': 'I-cells'}", + "93, Ap2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "94, macrophages {'context': 'B-cells'}", + "109, total {'perturbing_action': 'B-gene loss-of-function'}", + "110, aP2 {'perturbing_action': 'I-gene loss-of-function'}", + "111, deficiency, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "42, Apolipoprotein ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "43, E ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "44, (ApoE)-deficient ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "45, mice ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27']", + "47, deficient ['l3', 'l11', 'l18', 'l24', 'l28', 'l29', 'l30', 'l31', 'l32']", + "48, for ['l4', 'l12', 'l19', 'l25', 'l28', 'l33', 'l34', 'l35', 'l36']", + "49, aP2 ['l5', 'l13', 'l20', 'l26', 'l29', 'l33', 'l37', 'l38', 'l39']", + "51, protection ['l6', 'l14', 'l21', 'l27', 'l30', 'l34', 'l37']", + "66, aP2-deficient ['l7', 'l15', 'l22', 'l31', 'l35', 'l38', 'l40']", + "67, macrophages ['l8', 'l16', 'l23', 'l32', 'l36', 'l39', 'l40']", + "87, Apoe-/- ['l41', 'l42', 'l43']", + "88, mice ['l41', 'l44', 'l45']", + "90, Ap2+/+ ['l42', 'l44', 'l46']", + "91, adipocytes ['l43', 'l45', 'l46']", + "93, Ap2-/- ['l47', 'l48', 'l49', 'l50']", + "94, macrophages ['l47', 'l51', 'l52', 'l53']", + "109, total ['l48', 'l51', 'l54', 'l55']", + "110, aP2 ['l49', 'l52', 'l54', 'l56']", + "111, deficiency, ['l50', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apolipoprotein", + "E", + "(ApoE)-deficient", + "deficient", + "for", + "aP2", + "Apoe-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apolipoprotein", + "E", + "(ApoE)-deficient", + "deficient", + "for", + "aP2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protection" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apolipoprotein", + "E", + "(ApoE)-deficient", + "deficient", + "for", + "aP2", + "aP2-deficient", + "Apoe-/-", + "Ap2-/-", + "total", + "deficiency," + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages", + "Ap2+/+", + "adipocytes" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protection" + ] + } + } + ] + }, + { + "PMID": "11385504", + "TEXT": "The therapeutic and preventive activities of retinoids in cancer are due to their ability to modulate the growth, differentiation, and survival or apoptosis of cancer cells. Here we show that in NB4 acute promyelocytic leukemia cells, retinoids selective for retinoic-acid receptor-alpha induced an autoregulatory circuitry of survival programs followed by expression of the membrane-bound tumor-selective death ligand, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand, also called Apo-2L). In a paracrine mode of action, TRAIL killed NB4 as well as heterologous and retinoic-acid-resistant cells. In the leukemic blasts of freshly diagnosed acute promyelocytic leukemia patients, retinoic-acid-induced expression of TRAIL most likely caused blast apoptosis. Thus, induction of TRAIL-mediated death signaling appears to contribute to the therapeutic value of retinoids.", + "TAG_DATA": [ + "31, NB4 {'context': 'B-transformed cells'}", + "32, acute {'context': 'I-transformed cells'}", + "33, promyelocytic {'context': 'I-transformed cells'}", + "34, leukemia {'context': 'I-transformed cells'}", + "35, cells, {'context': 'I-transformed cells'}", + "74, NB4 {'context': 'B-transformed cells'}", + "84, leukemic {'context': 'B-transformed cells'}", + "85, blasts {'context': 'I-transformed cells'}", + "99, caused {'effect': 'B-positive'}", + "100, blast {'context': 'B-cells'}", + "101, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "31, NB4 ['l0', 'l1', 'l2', 'l3']", + "32, acute ['l0', 'l4', 'l5', 'l6']", + "33, promyelocytic ['l1', 'l4', 'l7', 'l8']", + "34, leukemia ['l2', 'l5', 'l7', 'l9']", + "35, cells, ['l3', 'l6', 'l8', 'l9']", + "84, leukemic ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "85, blasts ['l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "91, leukemia ['l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "92, patients, ['l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "99, caused ['l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "100, blast ['l14', 'l19', 'l23', 'l26', 'l28', 'l30']", + "101, apoptosis. ['l15', 'l20', 'l24', 'l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "leukemic", + "blasts" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "leukemic", + "blasts" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "context": { + "val": "cells", + "words": [ + "blast" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "blast" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "11329067", + "TEXT": "Early steps of infection by HIV-1 involve entry of the viral core into cells, reverse transcription to form the linear viral DNA, and integration of that DNA into a chromosome of the host. The unintegrated DNA can also follow non-productive pathways, in which it is circularized by recombination between DNA long-terminal repeats (LTRs), circularized by ligation of the DNA ends or degraded. Here we report quantitative methods that monitor formation of reverse transcription products, two-LTR circles and integrated proviruses. The integration assay employs a novel quantitative form of Alu-PCR that should be generally applicable to studies of integrating viruses and gene transfer vectors.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11329061", + "TEXT": "Although cytoskeletal mutations are known causes of genetically based forms of dilated cardiomyopathy, the pathways that link these defects with cardiomyopathy are unclear. Here we report that the alpha-actinin-associated LIM protein (ALP; Alp in mice) has an essential role in the embryonic development of the right ventricular (RV) chamber during its exposure to high biomechanical workloads in utero. Disruption of the gene encoding Alp (Alp) is associated with RV chamber dilation and dysfunction, directly implicating alpha-actinin-associated proteins in the onset of cardiomyopathy. In vitro assays showed that Alp directly enhances the capacity of alpha-actinin to cross-link actin filaments, indicating that the loss of Alp function contributes to destabilization of actin anchorage sites in cardiac muscle. Alp also colocalizes at the intercalated disc with alpha-actinin and gamma-catenin, the latter being a known disease gene for human RV dysplasia. Taken together, these studies point to a novel developmental pathway for RV dilated cardiomyopathy via instability of alpha-actinin complexes.", + "TAG_DATA": [ + "82, In {'context': 'B-in vitro'}", + "83, vitro {'context': 'I-in vitro'}", + "101, loss {'perturbing_action': 'B-gene loss-of-function'}", + "102, of {'perturbing_action': 'I-gene loss-of-function'}", + "103, Alp {'perturbing_action': 'I-gene loss-of-function'}", + "104, function {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "82, In ['l0']", + "83, vitro ['l0']", + "101, loss ['l1', 'l2', 'l3']", + "102, of ['l1', 'l4', 'l5']", + "103, Alp ['l2', 'l4', 'l6']", + "104, function ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11283677", + "TEXT": "Following peripheral exposure to transmissible spongiform encephalopathies (TSEs), infectivity usually accumulates in lymphoid tissues before neuroinvasion. The host prion protein (PrPc) is critical for TSE agent replication and accumulates as an abnormal, detergent insoluble, relatively proteinase-resistant isoform (PrPSc) in diseased tissues. Early PrPSc accumulation takes place on follicular dendritic cells (FDCs) within germinal centers in lymphoid tissues of patients with variant Creutzfeldt-Jakob disease (vCJD), sheep with natural scrapie or rodents following experimental peripheral infection with scrapie. In mouse scrapie models, the absence of FDCs blocks scrapie replication and PrPSc accumulation in the spleen, and neuroinvasion is significantly impaired. The mechanisms by which the TSE agent initially localizes to lymphoid follicles and interacts with FDCs are unknown. Antigens are trapped and retained on the surface of FDCs through interactions between complement and cellular complement receptors. Here we show that in mice, both temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays the onset of disease following peripheral infection, and reduces the early accumulation of PrPSc in the spleen. Thus, in the early stages of infection, C3 and perhaps C1q contribute to the localization of TSE infectivity in lymphoid tissue and may be therapeutic targets.", + "TAG_DATA": [ + "83, FDCs {'context': 'B-cells'}", + "92, spleen, {'context': 'B-tissue/organ'}", + "139, mice, {'context': 'B-organism'}", + "141, temporary {'perturbing_action': 'B-gene loss-of-function'}", + "142, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "143, of {'perturbing_action': 'I-gene loss-of-function'}", + "144, complement {'perturbing_action': 'I-gene loss-of-function'}", + "145, component {'perturbing_action': 'I-gene loss-of-function'}", + "146, C3 {'perturbing_action': 'I-gene loss-of-function'}", + "148, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "149, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "150, of {'perturbing_action': 'I-gene loss-of-function'}", + "151, C1q {'perturbing_action': 'I-gene loss-of-function'}", + "170, spleen. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "83, FDCs ['l0']", + "92, spleen, ['l0']", + "139, mice, ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "141, temporary ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "142, depletion ['l2', 'l8', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "143, of ['l3', 'l9', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "144, complement ['l4', 'l10', 'l18', 'l25', 'l31', 'l32', 'l33', 'l34']", + "145, component ['l5', 'l11', 'l19', 'l26', 'l31', 'l35', 'l36', 'l37']", + "146, C3 ['l6', 'l12', 'l20', 'l27', 'l32', 'l35', 'l38', 'l39']", + "148, genetic ['l40', 'l41', 'l42', 'l43']", + "149, deficiency ['l13', 'l21', 'l40', 'l44', 'l45', 'l46']", + "150, of ['l14', 'l22', 'l28', 'l41', 'l44', 'l47', 'l48']", + "151, C1q ['l15', 'l23', 'l29', 'l33', 'l36', 'l38', 'l42', 'l45', 'l47', 'l49']", + "170, spleen. ['l7', 'l16', 'l24', 'l30', 'l34', 'l37', 'l39', 'l43', 'l46', 'l48', 'l49']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "temporary", + "depletion", + "of", + "complement", + "component", + "C3" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "temporary", + "depletion", + "of", + "complement", + "component", + "C3", + "genetic", + "deficiency", + "C1q" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "spleen." + ] + } + } + ] + }, + { + "PMID": "11283675", + "TEXT": "During ischemic stroke, neurons at risk are exposed to pathologically high levels of intracellular calcium (Ca++), initiating a fatal biochemical cascade. To protect these neurons, we have developed openers of large-conductance, Ca++-activated (maxi-K or BK) potassium channels, thereby augmenting an endogenous mechanism for regulating Ca++ entry and membrane potential. The novel fluoro-oxindoles BMS-204352 and racemic compound 1 are potent, effective and uniquely Ca++-sensitive openers of maxi-K channels. In rat models of permanent large-vessel stroke, BMS-204352 provided significant levels of cortical neuroprotection when administered two hours after the onset of occlusion, but had no effects on blood pressure or cerebral blood flow. This novel approach may restrict Ca++ entry in neurons at risk while having minimal side effects.", + "TAG_DATA": [ + "68, rat {'context': 'B-organism'}", + "69, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "68, rat ['l0']", + "69, models ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11283668", + "TEXT": "Vascular endothelial growth factor (VEGF) can promote angiogenesis but may also exert certain effects to alter the rate of atherosclerotic plaque development. To evaluate this potential impact on plaque progression, we treated cholesterol-fed mice doubly deficient in apolipoprotein E/apolipoprotein B100 with low doses of VEGF (2 microg/kg) or albumin. VEGF significantly increased macrophage levels in bone marrow and peripheral blood and increased plaque area 5-, 14- and 4-fold compared with controls at weeks 1, 2 and 3, respectively. Plaque macrophage and endothelial cell content also increased disproportionately over controls. In order to confirm that the VEGF-mediated plaque progression was not species-specific, the experiment was repeated in cholesterol-fed rabbits at the three-week timepoint, which showed comparable increases in plaque progression.", + "TAG_DATA": [ + "33, mice {'context': 'B-organism'}", + "52, macrophage {'context': 'B-cells'}", + "55, bone {'context': 'B-cells'}", + "56, marrow {'context': 'I-tissue/organ'}", + "107, rabbits {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "33, mice ['l0', 'l1', 'l2']", + "52, macrophage ['l0', 'l3', 'l4']", + "55, bone ['l1', 'l3', 'l5']", + "56, marrow ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11231633", + "TEXT": "Clusterin, also known as apolipoprotein J, is a ubiquitously expressed molecule thought to influence a variety of processes including cell death. In the brain, it accumulates in dying neurons following seizures and hypoxic-ischemic (H-I) injury. Despite this, in vivo evidence that clusterin directly influences cell death is lacking. Following neonatal H-I brain injury in mice (a model of cerebral palsy), there was evidence of apoptotic changes (neuronal caspase-3 activation), as well as accumulation of clusterin in dying neurons. Clusterin-deficient mice had 50% less brain injury following neonatal H-I. Surprisingly, the absence of clusterin had no effect on caspase-3 activation, and clusterin accumulation and caspase-3 activation did not colocalize to the same cells. Studies with cultured cortical neurons demonstrated that exogenous purified astrocyte-secreted clusterin exacerbated oxygen/glucose-deprivation-induced necrotic death. These results indicate that clusterin may be a new therapeutic target to modulate non-caspase-dependent neuronal death following acute brain injury.", + "TAG_DATA": [ + "54, mice {'context': 'B-organism'}", + "77, neurons. {'context': 'B-cells'}", + "78, Clusterin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "79, mice {'context': 'B-organism'}", + "90, absence {'perturbing_action': 'B-gene loss-of-function'}", + "91, of {'perturbing_action': 'I-gene loss-of-function'}", + "92, clusterin {'perturbing_action': 'I-gene loss-of-function'}", + "111, cells. {'context': 'B-cells'}", + "114, cultured {'context': 'B-cells'}", + "115, cortical {'context': 'I-cells'}", + "116, neurons {'context': 'I-cells'}", + "123, exacerbated {'effect': 'B-positive'}", + "125, necrotic {'phenotype': 'B-necrosis'}", + "126, death. {'phenotype': 'I-necrosis'}" + ], + "LINK_DATA": [ + "54, mice ['l0']", + "77, neurons. ['l0']", + "78, Clusterin-deficient ['l1']", + "79, mice ['l1']", + "90, absence ['l2', 'l3', 'l4']", + "91, of ['l2', 'l5', 'l6']", + "92, clusterin ['l3', 'l5', 'l7']", + "111, cells. ['l4', 'l6', 'l7']", + "114, cultured ['l8', 'l9', 'l10', 'l11', 'l12']", + "115, cortical ['l8', 'l13', 'l14', 'l15', 'l16']", + "116, neurons ['l9', 'l13', 'l17', 'l18', 'l19']", + "123, exacerbated ['l10', 'l14', 'l17', 'l20', 'l21']", + "125, necrotic ['l11', 'l15', 'l18', 'l20', 'l22']", + "126, death. ['l12', 'l16', 'l19', 'l21', 'l22']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Clusterin-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "clusterin" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "cortical", + "neurons" + ] + }, + "effect": { + "val": "positive", + "words": [ + "exacerbated" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "cortical", + "neurons" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrotic", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "exacerbated" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrotic", + "death." + ] + } + } + ] + }, + { + "PMID": "11231632", + "TEXT": "Febrile seizures are the most common type of developmental seizures, affecting up to 5% of children. Experimental complex febrile seizures involving the immature rat hippocampus led to a persistent lowering of seizure threshold despite an upregulation of inhibition. Here we provide a mechanistic resolution to this paradox by showing that, in the hippocampus of rats that had febrile seizures, the long-lasting enhancement of the widely expressed intrinsic membrane conductance Ih converts the potentiated synaptic inhibition to hyperexcitability in a frequency-dependent manner. The altered gain of this molecular inhibition-excitation converter reveals a new mechanism for controlling the balance of excitation-inhibition in the limbic system. In addition, here we show for the first time that h-channels are modified in a human neurological disease paradigm.", + "TAG_DATA": [ + "52, hippocampus {'context': 'B-tissue/organ'}", + "54, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "52, hippocampus ['l0']", + "54, rats ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11231629", + "TEXT": "Metachromatic leukodystrophy (MLD) is a lipidosis caused by deficiency of arylsulfatase A (ARSA). Although the genetics of MLD are known, its pathophysiology is not understood. The disease leads to progressive demyelination and early death and no effective treatment is available. We used lentiviral vectors to deliver a functional ARSA gene (human ARSA) into the brain of adult mice with germ-line inactivation of the mouse gene encoding ARSA, As2. We report sustained expression of active enzyme throughout a large portion of the brain, with long-term protection from development of neuropathology and hippocampal-related learning impairments. We show that selective degeneration of hippocampal neurons is a central step in disease pathogenesis, and provide evidence that in vivo transfer of ARSA by lentiviral vectors reverts the disease phenotype in all investigated areas. Therefore, in vivo gene therapy offers a unique option for MLD and other storage diseases affecting the central nervous system.", + "TAG_DATA": [ + "56, adult {'context': 'B-organism'}", + "57, mice {'context': 'I-organism'}", + "59, germ-line {'perturbing_action': 'B-gene loss-of-function'}", + "60, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "61, of {'perturbing_action': 'I-gene loss-of-function'}", + "62, the {'perturbing_action': 'I-gene loss-of-function'}", + "63, mouse {'perturbing_action': 'I-gene loss-of-function'}", + "64, gene {'perturbing_action': 'I-gene loss-of-function'}", + "65, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "66, ARSA, {'perturbing_action': 'I-gene loss-of-function'}", + "67, As2. {'perturbing_action': 'I-gene loss-of-function'}", + "99, hippocampal {'context': 'B-cells'}", + "100, neurons {'context': 'I-cells'}", + "112, in {'context': 'B-in vivo'}", + "113, vivo {'context': 'B-in vivo'}" + ], + "LINK_DATA": [ + "56, adult ['l0', 'l1']", + "57, mice ['l0', 'l2']", + "59, germ-line ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "60, inactivation ['l3', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "61, of ['l4', 'l12', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "62, the ['l5', 'l13', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "63, mouse ['l6', 'l14', 'l20', 'l26', 'l32', 'l33', 'l34', 'l35', 'l36']", + "64, gene ['l7', 'l15', 'l21', 'l27', 'l32', 'l37', 'l38', 'l39', 'l40']", + "65, encoding ['l8', 'l16', 'l22', 'l28', 'l33', 'l37', 'l41', 'l42', 'l43']", + "66, ARSA, ['l9', 'l17', 'l23', 'l29', 'l34', 'l38', 'l41', 'l44', 'l45']", + "67, As2. ['l1', 'l2', 'l10', 'l18', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44']", + "99, hippocampal ['l46']", + "100, neurons ['l11', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l46']", + "112, in ['l47']", + "113, vivo ['l47']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "adult", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "As2." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "germ-line", + "of", + "the", + "mouse", + "gene", + "encoding", + "ARSA," + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons" + ] + } + } + ] + }, + { + "PMID": "11231628", + "TEXT": "The glaucomas are a group of optic neuropathies comprising the leading cause of irreversible blindness worldwide. Elevated intraocular pressure due to a reduction in normal aqueous outflow is a major causal risk factor. We found that endothelial leukocyte adhesion molecule-1 (ELAM-1), the earliest marker for the atherosclerotic plaque in the vasculature, was consistently present on trabecular meshwork (TM) cells in the outflow pathways of eyes with glaucomas of diverse etiology. We determined expression of ELAM-1 to be controlled by activation of an interleukin-1 (IL-1) autocrine feedback loop through transcription factor NF-kappaB, and activity of this signaling pathway was shown to protect TM cells against oxidative stress. These findings characterize a protective stress response specific to the eye's aqueous outflow pathways and provide the first known diagnostic indicator of glaucomatous TM cells. They further indicate that common mechanisms contribute to the pathophysiology of the glaucomas and vascular diseases.", + "TAG_DATA": [ + "101, TM {'context': 'B-cells'}", + "102, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "101, TM ['l0']", + "102, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11231613", + "TEXT": "Fas ligand (FasL) has become an enigmatic molecule: some evidence indicates that it contributes to immune privilege in tissues and tumors, whereas other data demonstrates that FasL can elicit inflammation. New findings may begin to reconcile the paradoxical effects of FasL.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11231611", + "TEXT": "Fred Sanger was awarded the rare distinction of two Nobel Prizes for Chemistry, in 1958 and 1980. The first was for his work on the structure of proteins, particularly that of insulin, the latter for his contribution concerning the determination of nucleic acid sequences, the foundation work that ultimately led to The Human Genome Project.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11175853", + "TEXT": "The growth arrest-specific gene 6 product (Gas6) is a secreted protein related to the anticoagulant protein S but its role in hemostasis is unknown. Here we show that inactivation of the Gas6 gene prevented venous and arterial thrombosis in mice, and protected against fatal collagen/epinephrine-induced thrombo embolism. Gas6-/- mice did not, however, suffer spontaneous bleeding and had normal bleeding after tail clipping. In addition, we found that Gas6 antibodies inhibited platelet aggregation in vitro and protected mice against fatal thrombo embolism without causing bleeding in vivo. Gas6 amplified platelet aggregation and secretion in response to known agonists. Platelet dysfunction in Gas6-/- mice resembled that of patients with platelet signaling transduction defects. Thus, Gas6 is a platelet-response amplifier that plays a significant role in thrombosis. These findings warrant further evaluation of the possible therapeutic use of Gas6 inhibition for prevention of thrombosis.", + "TAG_DATA": [ + "28, inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "29, of {'perturbing_action': 'I-gene loss-of-function'}", + "30, the {'perturbing_action': 'I-gene loss-of-function'}", + "31, Gas6 {'perturbing_action': 'I-gene loss-of-function'}", + "32, gene {'perturbing_action': 'I-gene loss-of-function'}", + "39, mice, {'context': 'B-organism'}", + "47, Gas6-/- {'perturbing_action': 'B-gene loss-of-function'}", + "48, mice {'context': 'B-organism'}", + "70, platelet {'context': 'B-cells'}", + "72, in {'context': 'B-in vitro'}", + "73, vitro {'context': 'I-in vitro'}", + "76, mice {'context': 'B-organism'}", + "84, in {'context': 'B-in vivo'}", + "85, vivo. {'context': 'I-in vivo'}", + "88, platelet {'context': 'B-cells'}", + "100, Gas6-/- {'perturbing_action': 'B-gene loss-of-function'}", + "101, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "28, inactivation ['l0', 'l1', 'l2', 'l3', 'l4']", + "29, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "30, the ['l1', 'l5', 'l9', 'l10', 'l11']", + "31, Gas6 ['l2', 'l6', 'l9', 'l12', 'l13']", + "32, gene ['l3', 'l7', 'l10', 'l12', 'l14']", + "39, mice, ['l4', 'l8', 'l11', 'l13', 'l14']", + "47, Gas6-/- ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "48, mice ['l15', 'l22', 'l23', 'l24', 'l25']", + "70, platelet ['l16', 'l22', 'l26', 'l27', 'l28', 'l29']", + "72, in ['l17', 'l23', 'l26', 'l30', 'l31']", + "73, vitro ['l18', 'l24', 'l27', 'l30', 'l32']", + "76, mice ['l19', 'l25', 'l28', 'l31', 'l32', 'l33']", + "84, in ['l20', 'l34']", + "85, vivo. ['l21', 'l29', 'l33', 'l34']", + "100, Gas6-/- ['l35']", + "101, mice ['l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "the", + "Gas6", + "gene", + "Gas6-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gas6-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelet" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gas6-/-" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gas6-/-" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "11175850", + "TEXT": "Metastasis of breast cancer occurs primarily through the lymphatic system, and the extent of lymph node involvement is a key prognostic factor for the disease. Whereas the significance of angiogenesis for tumor progression has been well documented, the ability of tumor cells to induce the growth of lymphatic vessels (lymphangiogenesis) and the presence of intratumoral lymphatic vessels have been controversial. Using a novel marker for lymphatic endothelium, LYVE-1, we demonstrate here the occurrence of intratumoral lymphangiogenesis within human breast cancers after orthotopic transplantation onto nude mice. Vascular endothelial growth factor (VEGF)-C overexpression in breast cancer cells potently increased intratumoral lymphangiogenesis, resulting in significantly enhanced metastasis to regional lymph nodes and to lungs. The degree of tumor lymphangiogenesis was highly correlated with the extent of lymph node and lung metastases. These results establish the occurrence and biological significance of intratumoral lymphangiogenesis in breast cancer and identify VEGF-C as a molecular link between tumor lymphangiogenesis and metastasis.", + "TAG_DATA": [ + "77, human {'context': 'B-neoplasm'}", + "78, breast {'context': 'I-neoplasm'}", + "79, cancers {'context': 'I-neoplasm'}", + "84, nude {'context': 'B-organism'}", + "85, mice. {'context': 'I-organism'}", + "86, Vascular {'perturbing_action': 'B-gene gain-of-function'}", + "87, endothelial {'perturbing_action': 'I-gene gain-of-function'}", + "88, growth {'perturbing_action': 'I-gene gain-of-function'}", + "89, factor {'perturbing_action': 'I-gene gain-of-function'}", + "90, (VEGF)-C {'perturbing_action': 'I-gene gain-of-function'}", + "91, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "93, breast {'context': 'B-transformed cells'}", + "94, cancer {'context': 'I-transformed cells'}", + "95, cells {'context': 'I-transformed cells'}", + "103, enhanced {'effect': 'B-positive'}", + "104, metastasis {'phenotype': 'B-metastasis'}", + "107, lymph {'phenotype': 'I-metastasis'}", + "108, nodes {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "77, human ['l0', 'l1', 'l2', 'l3']", + "78, breast ['l0', 'l4', 'l5', 'l6']", + "79, cancers ['l1', 'l4', 'l7', 'l8']", + "84, nude ['l2', 'l5', 'l7', 'l9']", + "85, mice. ['l3', 'l6', 'l8', 'l9']", + "86, Vascular ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "87, endothelial ['l10', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "88, growth ['l11', 'l24', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "89, factor ['l12', 'l25', 'l37', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "90, (VEGF)-C ['l13', 'l26', 'l38', 'l49', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "91, overexpression ['l14', 'l27', 'l39', 'l50', 'l60', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "93, breast ['l15', 'l28', 'l40', 'l51', 'l61', 'l70', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "94, cancer ['l16', 'l29', 'l41', 'l52', 'l62', 'l71', 'l79', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "95, cells ['l17', 'l30', 'l42', 'l53', 'l63', 'l72', 'l80', 'l87', 'l94', 'l95', 'l96', 'l97', 'l98']", + "103, enhanced ['l18', 'l31', 'l43', 'l54', 'l64', 'l73', 'l81', 'l88', 'l94', 'l99', 'l100', 'l101', 'l102', 'l103']", + "104, metastasis ['l19', 'l32', 'l44', 'l55', 'l65', 'l74', 'l82', 'l89', 'l95', 'l99', 'l104', 'l105', 'l106', 'l107']", + "106, regional ['l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l83', 'l90', 'l96', 'l100', 'l104', 'l108', 'l109', 'l110']", + "107, lymph ['l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l84', 'l91', 'l97', 'l101', 'l105', 'l108', 'l111', 'l112']", + "108, nodes ['l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l98', 'l102', 'l106', 'l109', 'l111', 'l113']", + "111, lungs. ['l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l86', 'l93', 'l103', 'l107', 'l110', 'l112', 'l113']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Vascular", + "endothelial", + "growth", + "factor", + "(VEGF)-C", + "overexpression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "breast", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Vascular", + "endothelial", + "growth", + "factor", + "(VEGF)-C", + "overexpression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Vascular", + "endothelial", + "growth", + "factor", + "(VEGF)-C", + "overexpression" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "lymph", + "nodes" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "breast", + "cancer", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "breast", + "cancer", + "cells" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "lymph", + "nodes" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "lymph", + "nodes" + ] + } + } + ] + }, + { + "PMID": "11175847", + "TEXT": "A novel mechanism by which T cells contribute to host defense against microbial pathogens is release of the antimicrobial protein granulysin. We investigated the role of granulysin in human infectious disease using leprosy as a model. Granulysin-expressing T cells were detected in cutaneous leprosy lesions at a six-fold greater frequency in patients with the localized tuberculoid as compared with the disseminated lepromatous form of the disease. In contrast, perforin, a cytolytic molecule that colocalizes with granulysin in cytotoxic granules, was expressed at similar levels across the spectrum of disease. Within leprosy lesions, granulysin colocalized in CD4+ T cells and was expressed in CD4+ T-cell lines derived from skin lesions. These CD4+ T-cell lines lysed targets by the granule exocytosis pathway and reduced the viability of mycobacteria in infected targets. Given the broad antimicrobial spectrum of granulysin, these data provide evidence that T-cell release of granulysin contributes to host defense in human infectious disease.", + "TAG_DATA": [ + "102, CD4+ {'context': 'B-cells'}", + "103, T-cell {'context': 'I-cells'}", + "104, lines {'context': 'I-cells'}", + "110, CD4+ {'context': 'B-cells'}", + "111, T-cell {'context': 'I-cells'}", + "112, lines {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "102, CD4+ ['l0', 'l1']", + "103, T-cell ['l0', 'l2']", + "104, lines ['l1', 'l2']", + "110, CD4+ ['l3', 'l4']", + "111, T-cell ['l3', 'l5']", + "112, lines ['l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11175846", + "TEXT": "The antimicrobial biocide triclosan [5-chloro-2-(2,4-dichlorophenoxy)phenol] potently inhibits the growth of Plasmodium falciparum in vitro and, in a mouse model, Plasmodium berghei in vivo. Inhibition of [14C]acetate and [14C]malonyl-CoA incorporation into fatty acids in vivo and in vitro, respectively, by triclosan implicate FabI as its target. Here we demonstrate that the enoyl-ACP reductase purified from P. falciparum is triclosan sensitive. Also, we present the evidence for the existence of FabI gene in P. falciparum. We establish the existence of the de novo fatty acid biosynthetic pathway in this parasite, and identify a key enzyme of this pathway for the development of new antimalarials.", + "TAG_DATA": [ + "10, Plasmodium {'context': 'B-organism'}", + "11, falciparum {'context': 'I-organism'}", + "12, in {'context': 'B-in vitro'}", + "13, vitro {'context': 'I-in vitro'}", + "17, mouse {'context': 'B-organism'}", + "18, model, {'context': 'I-organism'}", + "19, Plasmodium {'context': 'I-organism'}", + "20, berghei {'context': 'I-organism'}", + "21, in {'context': 'B-in vivo'}", + "22, vivo. {'context': 'I-in vivo'}", + "32, in {'context': 'B-in vivo'}", + "33, vivo {'context': 'I-in vivo'}", + "35, in {'context': 'B-in vitro'}", + "36, vitro, {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "10, Plasmodium ['l0', 'l1', 'l2']", + "11, falciparum ['l0', 'l3', 'l4']", + "12, in ['l1', 'l3', 'l5']", + "13, vitro ['l2', 'l4', 'l5']", + "17, mouse ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "18, model, ['l6', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "19, Plasmodium ['l7', 'l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "20, berghei ['l8', 'l16', 'l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "21, in ['l9', 'l17', 'l24', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "22, vivo. ['l10', 'l18', 'l25', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "32, in ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l45', 'l46', 'l47']", + "33, vivo ['l12', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l48', 'l49']", + "35, in ['l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l50']", + "36, vitro, ['l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l50']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11135624", + "TEXT": "Diabetic patients frequently suffer from retinopathy, nephropathy, neuropathy and accelerated atherosclerosis. The loss of endothelial function precedes these vascular alterations. Here we report that activation of poly(ADP-ribose) polymerase (PARP) is an important factor in the pathogenesis of endothelial dysfunction in diabetes. Destruction of islet cells with streptozotocin in mice induced hyperglycemia, intravascular oxidant production, DNA strand breakage, PARP activation and a selective loss of endothelium-dependent vasodilation. Treatment with a novel potent PARP inhibitor, starting after the time of islet destruction, maintained normal vascular responsiveness, despite the persistence of severe hyperglycemia. Endothelial cells incubated in high glucose exhibited production of reactive nitrogen and oxygen species, consequent single-strand DNA breakage, PARP activation and associated metabolic and functional impairment. Basal and high-glucose-induced nuclear factor-kappaB activation were suppressed in the PARP-deficient cells. Our results indicate that PARP may be a novel drug target for the therapy of diabetic endothelial dysfunction.", + "TAG_DATA": [ + "43, islet {'context': 'B-cells'}", + "44, cells {'context': 'I-cells'}", + "48, mice {'context': 'B-organism'}", + "90, Endothelial {'context': 'B-cells'}", + "91, cells {'context': 'I-cells'}", + "126, PARP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "127, cells. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "43, islet ['l0', 'l1']", + "44, cells ['l0', 'l2']", + "48, mice ['l1', 'l2']", + "90, Endothelial ['l3']", + "91, cells ['l3']", + "126, PARP-deficient ['l4']", + "127, cells. ['l4']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PARP-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "11135617", + "TEXT": "Tissue-plasminogen activator (t-PA) is now available for the treatment of thrombo-embolic stroke but adverse effects have been reported in some patients, particularly hemorrhaging. In contrast, the results of animal studies have indicated that t-PA could increase neuronal damage after focal cerebral ischemia. Here we report for the first time that t-PA potentiates signaling mediated by glutamatergic receptors by modifying the properties of the N-methyl-D-aspartate (NMDA) receptor. When depolarized, cortical neurons release bio-active t-PA that interacts with and cleaves the NR1 subunit of the NMDA receptor. Moreover, the treatment with recombinant t-PA leads to a 37% increase in NMDA-stimulated fura-2 fluorescence, which may reflect an increased NMDA-receptor function. These results were confirmed in vivo by the intrastriatal injection of recombinant-PA, which potentiated the excitotoxic lesions induced by NMDA. These data provide insight into the regulation of NMDA-receptor-mediated signaling and could initiate therapeutic strategies to improve the efficacy of t-PA treatment in man.", + "TAG_DATA": [ + "68, cortical {'context': 'B-cells'}", + "69, neurons {'context': 'I-cells'}", + "111, in {'context': 'B-in vivo'}", + "112, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "68, cortical ['l0']", + "69, neurons ['l0']", + "111, in ['l1']", + "112, vivo ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11135611", + "TEXT": "Although citrus fruits prevent and cure scurvy, they may not always be as good for you as you thought.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11135606", + "TEXT": "Little is known about the mechanism by which Yops, proteins that Yersinia inject into the cytosol of macrophage, cause downregulation of the inflammatory response and diseases such as the plague. Now it appears that Yops are the first bacterial member of a new family of ubiquitin-like proteases.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11135604", + "TEXT": "Studies in three different transgenic mouse models suggest that the amyloid beta-protein contributes to memory loss in Alzheimer disease. Immunization with an amyloid beta-peptide fragment reduces learning and memory impairments in mice, and this approach may eventually be used to prevent and/or treat this disease in people.", + "TAG_DATA": [ + "4, transgenic {'context': 'B-organism'}", + "5, mouse {'context': 'I-organism'}", + "6, models {'context': 'I-organism'}", + "31, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "4, transgenic ['l0', 'l1', 'l2']", + "5, mouse ['l0', 'l3', 'l4']", + "6, models ['l1', 'l3', 'l5']", + "31, mice, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11135599", + "TEXT": "The complete genome sequence of Mycobacterium tuberculosis, along with novel genetic tools, provides the foundation for a new era of post-genomic research. The challenge is now to translate these opportunities into an improved understanding of the complex biology of tuberculosis infection.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11135598", + "TEXT": "He may have stepped away from the hottest seat in biomedical research, but Nobel Laureate Harold Varmus shows no signs of withdrawing from the frontline of the biomedical research community, and he still displays the inimitable combination of political astuteness and scientific expertise that made his reign as director of the United States National Institutes of Health so successful. Varmus spoke to Nature Medicine for the first in a series of profiles that the journal will run on scientists that make a difference to biomedical research.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11100127", + "TEXT": "Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, or statins, are effective lipid-lowering agents, extensively used in medical practice. Statins have never been shown to be involved in the immune response, although a report has indicated a better outcome of cardiac transplantation in patients under Pravastatin therapy. Major histocompatibility complex class II (MHC-II) molecules are directly involved in the activation of T lymphocytes and in the control of the immune response. Whereas only a limited number of specialized cell types express MHC-II constitutively, numerous other cells become MHC-II positive upon induction by interferon gamma (IFN-gamma). This complex regulation is under the control of the transactivator CIITA (refs 6,7). Here we show that statins act as direct inhibitors of induction of MHC-II expression by IFN-gamma and thus as repressors of MHC-II-mediated T-cell activation. This effect of statins is due to inhibition of the inducible promoter IV of the transactivator CIITA and is observed in several cell types, including primary human endothelial cells (ECs) and monocyte-macrophages (Mstraight phi). It is of note that this inhibition is specific for inducible MHC-II expression and does not concern constitutive expression of CIITA and MHC-II. In repressing induction of MHC-II, and subsequent T-lymphocyte activation, statins therefore provide a new type of immunomodulation. This unexpected effect provides a scientific rationale for using statins as immunosuppressors, not only in organ transplantation but in numerous other pathologies as well.", + "TAG_DATA": [ + "153, cell {'context': 'B-cells'}", + "154, types, {'context': 'I-cells'}", + "156, primary {'context': 'B-cells'}", + "157, human {'context': 'I-cells'}", + "158, endothelial {'context': 'I-cells'}", + "159, cells {'context': 'I-cells'}", + "160, (ECs) {'context': 'I-cells'}", + "162, monocyte-macrophages {'context': 'B-cells'}", + "195, T-lymphocyte {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "153, cell ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "154, types, ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "156, primary ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "157, human ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "158, endothelial ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "159, cells ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "160, (ECs) ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "162, monocyte-macrophages ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11100119", + "TEXT": "Myeloid antigen-presenting cells (APC) are known to cross-present exogenous antigen on major histocompatibility class I molecules to CD8+ T cells and thereby induce protective immunity against infecting microorganisms. Here we report that liver sinusoidal endothelial cells (LSEC) are organ-resident, non-myeloid APC capable of cross-presenting soluble exogenous antigen to CD8+ T cells. Though LSEC employ similar molecular mechanisms for cross-presentation as dendritic cells, the outcome of cross-presentation by LSEC is CD8+ T cell tolerance rather than immunity. As uptake of circulating antigens into LSEC occurs efficiently in vivo, it is likely that cross-presentation by LSEC contributes to CD8+ T cell tolerance observed in situations where soluble antigen is present in the circulation.", + "TAG_DATA": [ + "32, liver {'context': 'B-cells'}", + "33, sinusoidal {'context': 'I-cells'}", + "34, endothelial {'context': 'I-cells'}", + "35, cells {'context': 'I-cells'}", + "36, (LSEC) {'context': 'I-cells'}", + "85, in {'context': 'B-in vivo'}", + "86, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "32, liver ['l0', 'l1', 'l2', 'l3']", + "33, sinusoidal ['l0', 'l4', 'l5', 'l6']", + "34, endothelial ['l1', 'l4', 'l7', 'l8']", + "35, cells ['l2', 'l5', 'l7', 'l9']", + "36, (LSEC) ['l3', 'l6', 'l8', 'l9']", + "85, in ['l10']", + "86, vivo, ['l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11100117", + "TEXT": "Chronic hypoxia, a hallmark of many tumors, is associated with angiogenesis and tumor progression. Strategies to treat tumors have been developed in which tumor cells are targeted with drugs or gene-therapy vectors specifically activated under hypoxic conditions. Here we report a different approach, in which the normal transcriptional response to hypoxia is selectively disrupted. Our data indicate that specific blockade of the interaction of hypoxia-inducible factor with the CH1 domain of its p300 and CREB binding protein transcriptional coactivators leads to attenuation of hypoxia-inducible gene expression and diminution of tumor growth. Thus, disrupting the normal co-activational response to hypoxia may be a new and useful therapeutic strategy.", + "TAG_DATA": [ + "87, diminution {'effect': 'B-negative'}", + "89, tumor {'phenotype': 'B-tumour growth'}", + "90, growth. {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "87, diminution ['l0', 'l1']", + "89, tumor ['l0', 'l2']", + "90, growth. ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "diminution" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + } + ] + }, + { + "PMID": "11062543", + "TEXT": "Mesenchymal stem cells are multipotent cells that can be isolated from adult bone marrow and can be induced in vitro and in vivo to differentiate into a variety of mesenchymal tissues, including bone, cartilage, tendon, fat, bone marrow stroma, and muscle. Despite their potential clinical utility for cellular and gene therapy, the fate of mesenchymal stem cells after systemic administration is mostly unknown. To address this, we transplanted a well-characterized human mesenchymal stem cell population into fetal sheep early in gestation, before and after the expected development of immunologic competence. In this xenogeneic system, human mesenchymal stem cells engrafted and persisted in multiple tissues for as long as 13 months after transplantation. Transplanted human cells underwent site-specific differentiation into chondrocytes, adipocytes, myocytes and cardiomyocytes, bone marrow stromal cells and thymic stroma. Unexpectedly, there was long-term engraftment even when cells were transplanted after the expected development of immunocompetence. Thus, mesenchymal stem cells maintain their multipotential capacity after transplantation, and seem to have unique immunologic characteristics that allow persistence in a xenogeneic environment. Our data support the possibility of the transplantability of mesenchymal stem cells and their potential utility in tissue engineering, and cellular and gene therapy applications.", + "TAG_DATA": [ + "70, human {'context': 'B-cells'}", + "71, mesenchymal {'context': 'I-cells'}", + "72, stem {'context': 'I-cells'}", + "73, cell {'context': 'I-cells'}", + "74, population {'context': 'I-cells'}", + "76, fetal {'context': 'B-organism'}", + "77, sheep {'context': 'I-organism'}", + "94, human {'context': 'B-cells'}", + "95, mesenchymal {'context': 'I-cells'}", + "96, stem {'context': 'I-cells'}", + "97, cells {'context': 'I-cells'}", + "113, human {'context': 'B-cells'}", + "114, cells {'context': 'I-cells'}", + "115, underwent {'effect': 'B-positive'}", + "117, differentiation {'phenotype': 'B-differentiation'}", + "119, chondrocytes, {'context': 'B-cells'}", + "120, adipocytes, {'context': 'B-cells'}", + "121, myocytes {'context': 'B-cells'}", + "124, bone {'context': 'B-cells'}", + "125, marrow {'context': 'I-cells'}", + "126, stromal {'context': 'I-cells'}", + "127, cells {'context': 'I-cells'}", + "138, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "70, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "71, mesenchymal ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "72, stem ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "73, cell ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "74, population ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "76, fetal ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "77, sheep ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "94, human ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "95, mesenchymal ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "96, stem ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "97, cells ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "113, human ['l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "114, cells ['l55', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "115, underwent ['l56', 'l67', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "117, differentiation ['l57', 'l68', 'l78', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "119, chondrocytes, ['l58', 'l69', 'l79', 'l88', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "120, adipocytes, ['l59', 'l70', 'l80', 'l89', 'l97', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "121, myocytes ['l60', 'l71', 'l81', 'l90', 'l98', 'l105', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "124, bone ['l61', 'l72', 'l82', 'l91', 'l99', 'l106', 'l112', 'l118', 'l119', 'l120', 'l121', 'l122']", + "125, marrow ['l62', 'l73', 'l83', 'l92', 'l100', 'l107', 'l113', 'l118', 'l123', 'l124', 'l125', 'l126']", + "126, stromal ['l63', 'l74', 'l84', 'l93', 'l101', 'l108', 'l114', 'l119', 'l123', 'l127', 'l128', 'l129']", + "127, cells ['l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l115', 'l120', 'l124', 'l127', 'l130', 'l131']", + "129, thymic ['l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l121', 'l125', 'l128', 'l130', 'l132']", + "130, stroma. ['l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l126', 'l129', 'l131', 'l132']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "cells", + "chondrocytes,", + "adipocytes,", + "myocytes", + "bone", + "marrow", + "stromal" + ] + }, + "effect": { + "val": "positive", + "words": [ + "underwent" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "cells", + "chondrocytes,", + "adipocytes,", + "myocytes", + "bone", + "marrow", + "stromal" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "underwent" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "11062541", + "TEXT": "Exfoliative toxin A, produced by Staphylococcus aureus, causes blisters in bullous impetigo and its more generalized form, staphylococcal scalded-skin syndrome. The toxin shows exquisite specificity in causing loss of cell adhesion only in the superficial epidermis. Although exfoliative toxin A has the structure of a serine protease, a target protein has not been identified. Desmoglein (Dsg) 1, a desmosomal cadherin that mediates cell-cell adhesion, may be the target of exfoliative toxin A, because it is the target of autoantibodies in pemphigus foliaceus, in which blisters form with identical tissue specificity and histology. We show here that exfoliative toxin A cleaved mouse and human Dsg1, but not closely related cadherins such as Dsg3. We demonstrate this specific cleavage in cell culture, in neonatal mouse skin and with recombinant Dsg1, and conclude that Dsg1 is the specific receptor for exfoliative toxin A cleavage. This unique proteolytic attack on the desmosome causes a blister just below the stratum corneum, which forms the epidermal barrier, presumably allowing the bacteria in bullous impetigo to proliferate and spread beneath this barrier.", + "TAG_DATA": [ + "118, cell {'context': 'B-cells'}", + "119, culture, {'context': 'I-cells'}", + "121, neonatal {'context': 'B-tissue/organ'}", + "122, mouse {'context': 'I-tissue/organ'}", + "123, skin {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "118, cell ['l0']", + "119, culture, ['l0']", + "121, neonatal ['l1', 'l2']", + "122, mouse ['l1', 'l3']", + "123, skin ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "11017151", + "TEXT": "In this 'double-blind', randomized, placebo-controlled phase II trial, we compared an altered peptide ligand of myelin basic protein with placebo, evaluating their safety and influence on magnetic resonance imaging in relapsing-remitting multiple sclerosis. A safety board suspended the trial because of hypersensitivity reactions in 9% of the patients. There were no increases in either clinical relapses or in new enhancing lesions in any patient, even those with hypersensitivity reactions. Secondary analysis of those patients completing the study showed that the volume and number of enhancing lesions were reduced at a dose of 5 mg. There was also a regulatory type 2 T helper-cell response to altered peptide ligand that cross-reacted with the native peptide.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "11017147", + "TEXT": "Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor with anti-microbial properties found in mucosal fluids. It is expressed during cutaneous wound healing. Impaired healing states are characterized by excessive proteolysis and often bacterial infection, leading to the hypothesis that SLPI may have a role in this process. We have generated mice null for the gene encoding SLPI (Slpi), which show impaired cutaneous wound healing with increased inflammation and elastase activity. The altered inflammatory profile involves enhanced activation of local TGF-beta in Slpi-null mice. We propose that SLPI is a pivotal endogenous factor necessary for optimal wound healing.", + "TAG_DATA": [ + "52, mice {'context': 'B-organism'}", + "53, null {'perturbing_action': 'B-gene loss-of-function'}", + "54, for {'perturbing_action': 'I-gene loss-of-function'}", + "55, the {'perturbing_action': 'I-gene loss-of-function'}", + "56, gene {'perturbing_action': 'I-gene loss-of-function'}", + "57, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "58, SLPI {'perturbing_action': 'I-gene loss-of-function'}", + "59, (Slpi), {'perturbing_action': 'I-gene loss-of-function'}", + "83, Slpi-null {'perturbing_action': 'B-gene loss-of-function'}", + "84, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "52, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "53, null ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "54, for ['l1', 'l7', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "55, the ['l2', 'l8', 'l14', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "56, gene ['l3', 'l9', 'l15', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "57, encoding ['l4', 'l10', 'l16', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "58, SLPI ['l5', 'l11', 'l17', 'l23', 'l28', 'l32', 'l36', 'l37']", + "59, (Slpi), ['l6', 'l12', 'l18', 'l24', 'l29', 'l33', 'l36']", + "83, Slpi-null ['l19', 'l25', 'l30', 'l34', 'l38']", + "84, mice. ['l13', 'l20', 'l26', 'l31', 'l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "null", + "for", + "the", + "gene", + "encoding", + "SLPI", + "(Slpi),", + "Slpi-null" + ] + } + } + ] + }, + { + "PMID": "11017145", + "TEXT": "Replication-selective oncolytic viruses constitute a rapidly evolving and new treatment platform for cancer. Gene-deleted viruses have been engineered for tumor selectivity, but these gene deletions also reduce the anti-cancer potency of the viruses. We have identified an E1A mutant adenovirus, dl922-947, that replicates in and lyses a broad range of cancer cells with abnormalities in cell-cycle checkpoints. This mutant demonstrated reduced S-phase induction and replication in non-proliferating normal cells, and superior in vivo potency relative to other gene-deleted adenoviruses. In some cancers, its potency was superior to even wild-type adenovirus. Intravenous administration reduced the incidence of metastases in a breast tumor xenograft model. dl922-947 holds promise as a potent, replication-selective virus for the local and systemic treatment of cancer.", + "TAG_DATA": [ + "37, E1A {'perturbing_action': 'B-other'}", + "38, mutant {'perturbing_action': 'I-other'}", + "40, dl922-947, {'perturbing_action': 'I-other'}", + "50, cancer {'context': 'B-transformed cells'}", + "51, cells {'context': 'I-transformed cells'}", + "66, non-proliferating {'context': 'B-cells'}", + "67, normal {'context': 'I-cells'}", + "68, cells, {'context': 'I-cells'}", + "71, in {'context': 'B-in vivo'}", + "72, vivo {'context': 'I-in vivo'}", + "81, cancers, {'context': 'B-neoplasm'}", + "92, reduced {'effect': 'B-negative'}", + "93, the {'effect': 'I-negative'}", + "94, incidence {'effect': 'I-negative'}", + "96, metastases {'phenotype': 'B-metastasis'}", + "99, breast {'context': 'B-xenograft'}", + "100, tumor {'context': 'I-xenograft'}", + "101, xenograft {'context': 'I-xenograft'}", + "102, model. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "37, E1A ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "38, mutant ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "40, dl922-947, ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "50, cancer ['l2', 'l11', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "51, cells ['l3', 'l12', 'l20', 'l26', 'l32', 'l33', 'l34', 'l35', 'l36']", + "66, non-proliferating ['l4', 'l13', 'l21', 'l27', 'l32', 'l37', 'l38', 'l39', 'l40']", + "67, normal ['l5', 'l14', 'l22', 'l28', 'l33', 'l37', 'l41', 'l42', 'l43']", + "68, cells, ['l6', 'l15', 'l23', 'l29', 'l34', 'l38', 'l41', 'l44', 'l45']", + "71, in ['l7', 'l16', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l46']", + "72, vivo ['l8', 'l17', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l46']", + "81, cancers, ['l9', 'l18']", + "92, reduced ['l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "93, the ['l47', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "94, incidence ['l48', 'l54', 'l60', 'l61', 'l62', 'l63', 'l64']", + "96, metastases ['l49', 'l55', 'l60', 'l65', 'l66', 'l67', 'l68']", + "99, breast ['l50', 'l56', 'l61', 'l65', 'l69', 'l70', 'l71']", + "100, tumor ['l51', 'l57', 'l62', 'l66', 'l69', 'l72', 'l73']", + "101, xenograft ['l52', 'l58', 'l63', 'l67', 'l70', 'l72', 'l74']", + "102, model. ['l53', 'l59', 'l64', 'l68', 'l71', 'l73', 'l74']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "E1A", + "mutant", + "dl922-947," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "E1A", + "mutant", + "dl922-947," + ] + }, + "context": { + "val": "cells", + "words": [ + "non-proliferating", + "normal", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "E1A", + "mutant", + "dl922-947," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "E1A", + "mutant" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "cancers," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced", + "the", + "incidence" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced", + "the", + "incidence" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "breast", + "tumor", + "xenograft", + "model." + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "breast", + "tumor", + "xenograft", + "model." + ] + } + } + ] + }, + { + "PMID": "11017142", + "TEXT": "To determine whether uncoupling respiration from oxidative phosphorylation in skeletal muscle is a suitable treatment for obesity and type 2 diabetes, we generated transgenic mice expressing the mitochondrial uncoupling protein (Ucp) in skeletal muscle. Skeletal muscle oxygen consumption was 98% higher in Ucp-L mice (with low expression) and 246% higher in Ucp-H mice (with high expression) than in wild-type mice. Ucp mice fed a chow diet had the same food intake as wild-type mice, but weighed less and had lower levels of glucose and triglycerides and better glucose tolerance than did control mice. Ucp-L mice were resistant to obesity induced by two different high-fat diets. Ucp-L mice fed a high-fat diet had less adiposity, lower levels of glucose, insulin and cholesterol, and an increased metabolic rate at rest and with exercise. They were also more responsive to insulin, and had enhanced glucose transport in skeletal muscle in the setting of increased muscle triglyceride content. These data suggest that manipulating respiratory uncoupling in muscle is a viable treatment for obesity and its metabolic sequelae.", + "TAG_DATA": [ + "23, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "24, mice {'context': 'B-organism'}", + "25, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "26, the {'perturbing_action': 'I-gene gain-of-function'}", + "27, mitochondrial {'perturbing_action': 'I-gene gain-of-function'}", + "28, uncoupling {'perturbing_action': 'I-gene gain-of-function'}", + "29, protein {'perturbing_action': 'I-gene gain-of-function'}", + "30, (Ucp) {'perturbing_action': 'I-gene gain-of-function'}", + "31, in {'perturbing_action': 'I-gene gain-of-function'}", + "32, skeletal {'context': 'B-tissue/organ'}", + "33, muscle. {'context': 'I-tissue/organ'}", + "35, muscle {'context': 'I-tissue/organ'}", + "42, Ucp-L {'perturbing_action': 'B-gene gain-of-function'}", + "43, mice {'context': 'B-organism'}", + "51, Ucp-H {'perturbing_action': 'B-gene gain-of-function'}", + "52, mice {'context': 'B-organism'}", + "60, Ucp {'context': 'B-organism'}", + "61, mice {'context': 'I-organism'}", + "93, Ucp-L {'context': 'B-organism'}", + "94, mice {'context': 'I-organism'}", + "105, Ucp-L {'context': 'B-organism'}", + "106, mice {'context': 'I-organism'}", + "144, skeletal {'context': 'B-tissue/organ'}", + "145, muscle {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "23, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "24, mice ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "25, expressing ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "26, the ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "27, mitochondrial ['l3', 'l15', 'l26', 'l36', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "28, uncoupling ['l4', 'l16', 'l27', 'l37', 'l47', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "29, protein ['l5', 'l17', 'l28', 'l38', 'l48', 'l57', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "30, (Ucp) ['l6', 'l18', 'l29', 'l39', 'l49', 'l58', 'l66', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "31, in ['l7', 'l19', 'l30', 'l40', 'l50', 'l59', 'l67', 'l74', 'l81', 'l82', 'l83', 'l84', 'l85']", + "32, skeletal ['l8', 'l20', 'l31', 'l41', 'l51', 'l60', 'l68', 'l75', 'l81', 'l86', 'l87', 'l88', 'l89']", + "33, muscle. ['l9', 'l21', 'l32', 'l42', 'l52', 'l61', 'l69', 'l76', 'l82', 'l86', 'l90', 'l91', 'l92']", + "35, muscle ['l10', 'l22', 'l33', 'l43', 'l53', 'l62', 'l70', 'l77', 'l83', 'l87', 'l90', 'l93', 'l94']", + "42, Ucp-L ['l11', 'l23', 'l34', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l88', 'l91', 'l93', 'l95', 'l96']", + "43, mice ['l12', 'l24', 'l35', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l89', 'l92', 'l94', 'l95']", + "51, Ucp-H ['l97', 'l98', 'l99']", + "52, mice ['l97', 'l100', 'l101']", + "60, Ucp ['l98', 'l100', 'l102']", + "61, mice ['l46', 'l56', 'l65', 'l73', 'l80', 'l96', 'l99', 'l101', 'l102']", + "93, Ucp-L ['l103', 'l104']", + "94, mice ['l103']", + "105, Ucp-L ['l105']", + "106, mice ['l104', 'l105']", + "144, skeletal ['l106']", + "145, muscle ['l106']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "the", + "mitochondrial", + "uncoupling", + "protein", + "(Ucp)", + "in", + "Ucp-L", + "Ucp-H" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "Ucp" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "the", + "mitochondrial", + "uncoupling", + "protein", + "(Ucp)", + "in", + "Ucp-L" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skeletal", + "muscle.", + "muscle" + ] + } + } + ] + }, + { + "PMID": "10973326", + "TEXT": "Tuberculosis treatment is shortened to six months by the indispensable addition of pyrazinamide (PZA) to the drug regimen that includes isoniazid and rifampin. PZA is a pro-drug of pyrazinoic acid (POA) (ref. 3), whose target of action has never been identified. Although PZA is active only against Mycobacterium tuberculosis, the PZA analog 5-chloro-pyrazinamide (5-Cl-PZA) displays a broader range of anti-mycobacterial activity. We have found that the eukaryotic-like fas1 gene (encoding fatty acid synthetase I, FASI) from M. avium, M. bovis BCG or M. tuberculosis confers resistance to 5-Cl-PZA when present on multi-copy vectors in M. smegmatis. 5-Cl-PZA and PZA markedly inhibited the activity of M. tuberculosis FASI, the biosynthesis of C16 to C24/C26 fatty acids from acetyl-CoA (ref. 6). Importantly, PZA inhibited FASI in M. tuberculosis in correlation with PZA susceptibility. These results indicate that FASI is a primary target of action for PZA in M. tuberculosis. Further characterization of FASI as a drug target for PZA may allow the development of new drugs to shorten the therapy against M. tuberculosis and may provide more options for treatment against M. bovis, M. avium and drug resistant M. tuberculosis.", + "TAG_DATA": [ + "104, M. {'context': 'B-neoplasm'}", + "105, tuberculosis {'context': 'B-neoplasm'}", + "124, M. {'context': 'B-organism'}", + "125, tuberculosis {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "104, M. ['l0']", + "105, tuberculosis ['l0']", + "124, M. ['l1']", + "125, tuberculosis ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10973325", + "TEXT": "Recent thymic emigrants can be identified by T cell receptor excision circles (TRECs) formed during T-cell receptor rearrangement. Decreasing numbers of TRECs have been observed with aging and in human immunodeficiency virus (HIV)-1 infected individuals, suggesting thymic impairment. Here, we show that in healthy individuals, declining thymic output will affect the TREC content only when accompanied by naive T-cell division. The rapid decline in TRECs observed during HIV-1 infection and the increase following HAART are better explained not by thymic impairment, but by changes in peripheral T-cell division rates. Our data indicate that TREC content in healthy individuals is only indirectly related to thymic output, and in HIV-1 infection is mainly affected by immune activation.", + "TAG_DATA": [ + "57, naive {'context': 'B-cells'}", + "58, T-cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "57, naive ['l0']", + "58, T-cell ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10973322", + "TEXT": "Although the immune system has long been implicated in the control of cancer, evidence for specific and efficacious immune responses in human cancer has been lacking. In the case of chronic myelogenous leukemia (CML), either allogeneic bone marrow transplant (BMT) or interferon-alpha2b (IFN-alpha2b) therapy can result in complete remission, but the mechanism for prolonged disease control is unknown and may involve immune anti-leukemic responses. We previously demonstrated that PR1, a peptide derived from proteinase 3, is a potential target for CML-specific T cells. Here we studied 38 CML patients treated with allogeneic BMT, IFN- alpha2b or chemotherapy to look for PR1-specific T cells using PR1/HLA-A*0201 tetrameric complexes. There was a strong correlation between the presence of PR1-specific T cells and clinical responses after IFN-alpha and allogeneic BMT. This provides for the first time direct evidence of a role for T-cell immunity in clearing malignant cells.", + "TAG_DATA": [ + "87, CML {'context': 'B-patient'}", + "88, patients {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "87, CML ['l0']", + "88, patients ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10973320", + "TEXT": "Recent studies suggest that statins can function to protect the vasculature in a manner that is independent of their lipid-lowering activity. We show here that statins rapidly activate the protein kinase Akt/PKB in endothelial cells. Accordingly, simvastatin enhanced phosphorylation of the endogenous Akt substrate endothelial nitric oxide synthase (eNOS), inhibited apoptosis and accelerated vascular structure formation in vitro in an Akt-dependent manner. Similar to vascular endothelial growth factor (VEGF) treatment, both simvastatin administration and enhanced Akt signaling in the endothelium promoted angiogenesis in ischemic limbs of normocholesterolemic rabbits. Therefore, activation of Akt represents a mechanism that can account for some of the beneficial side effects of statins, including the promotion of new blood vessel growth.", + "TAG_DATA": [ + "49, inhibited {'effect': 'B-negative'}", + "50, apoptosis {'phenotype': 'B-apoptosis'}", + "56, in {'context': 'B-in vitro'}", + "57, vitro {'context': 'I-in vitro'}", + "79, endothelium {'context': 'B-cells'}", + "84, limbs {'context': 'I-tissue/organ'}", + "87, rabbits. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "49, inhibited ['l0', 'l1', 'l2']", + "50, apoptosis ['l0', 'l3', 'l4']", + "56, in ['l1', 'l3', 'l5']", + "57, vitro ['l2', 'l4', 'l5']", + "79, endothelium ['l6', 'l7']", + "84, limbs ['l6', 'l8']", + "87, rabbits. ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "10932232", + "TEXT": "The prevalence of type 2 diabetes mellitus is growing worldwide. By the year 2020, 250 million people will be afflicted. Most forms of type 2 diabetes are polygenic with complex inheritance patterns, and penetrance is strongly influenced by environmental factors. The specific genes involved are not yet known, but impaired glucose uptake in skeletal muscle is an early, genetically determined defect that is present in non-diabetic relatives of diabetic subjects. The rate-limiting step in muscle glucose use is the transmembrane transport of glucose mediated by glucose transporter (GLUT) 4 (ref. 4), which is expressed mainly in skeletal muscle, heart and adipose tissue. GLUT4 mediates glucose transport stimulated by insulin and contraction/exercise. The importance of GLUT4 and glucose uptake in muscle, however, was challenged by two recent observations. Whereas heterozygous GLUT4 knockout mice show moderate glucose intolerance, homozygous whole-body GLUT4 knockout (GLUT4-null) mice have only mild perturbations in glucose homeostasis and have growth retardation, depletion of fat stores, cardiac hypertrophy and failure, and a shortened life span. Moreover, muscle-specific inactivation of the insulin receptor results in minimal, if any, change in glucose tolerance. To determine the importance of glucose uptake into muscle for glucose homeostasis, we disrupted GLUT4 selectively in mouse muscles. A profound reduction in basal glucose transport and near-absence of stimulation by insulin or contraction resulted. These mice showed severe insulin resistance and glucose intolerance from an early age. Thus, GLUT4-mediated glucose transport in muscle is essential to the maintenance of normal glucose homeostasis.", + "TAG_DATA": [ + "128, heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "129, GLUT4 {'perturbing_action': 'I-gene loss-of-function'}", + "130, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "131, mice {'context': 'B-organism'}", + "136, homozygous {'perturbing_action': 'B-gene loss-of-function'}", + "137, whole-body {'perturbing_action': 'I-gene loss-of-function'}", + "138, GLUT4 {'perturbing_action': 'I-gene loss-of-function'}", + "139, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "140, (GLUT4-null) {'perturbing_action': 'I-gene loss-of-function'}", + "141, mice {'context': 'B-organism'}", + "167, muscle-specific {'perturbing_action': 'B-gene loss-of-function'}", + "168, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "169, of {'perturbing_action': 'I-gene loss-of-function'}", + "170, the {'perturbing_action': 'I-gene loss-of-function'}", + "171, insulin {'perturbing_action': 'I-gene loss-of-function'}", + "172, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "195, disrupted {'perturbing_action': 'B-gene loss-of-function'}", + "196, GLUT4 {'perturbing_action': 'I-gene loss-of-function'}", + "199, mouse {'context': 'B-tissue/organ'}", + "200, muscles. {'context': 'I-tissue/organ'}", + "218, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "128, heterozygous ['l0', 'l1', 'l2']", + "129, GLUT4 ['l0', 'l3', 'l4']", + "130, knockout ['l1', 'l3', 'l5']", + "131, mice ['l2', 'l4', 'l5']", + "136, homozygous ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "137, whole-body ['l6', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "138, GLUT4 ['l7', 'l15', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "139, knockout ['l8', 'l16', 'l25', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "140, (GLUT4-null) ['l9', 'l17', 'l26', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "141, mice ['l10', 'l18', 'l27', 'l35', 'l40']", + "167, muscle-specific ['l19', 'l28', 'l41', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "168, inactivation ['l20', 'l29', 'l46', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "169, of ['l11', 'l21', 'l30', 'l36', 'l42', 'l47', 'l56', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "170, the ['l12', 'l22', 'l31', 'l37', 'l43', 'l48', 'l57', 'l65', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "171, insulin ['l13', 'l23', 'l32', 'l38', 'l44', 'l49', 'l58', 'l66', 'l73', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "172, receptor ['l14', 'l24', 'l33', 'l39', 'l45', 'l50', 'l59', 'l67', 'l74', 'l80', 'l86', 'l87', 'l88', 'l89', 'l90']", + "195, disrupted ['l51', 'l60', 'l68', 'l75', 'l81', 'l86', 'l91', 'l92', 'l93', 'l94']", + "196, GLUT4 ['l52', 'l61', 'l69', 'l76', 'l82', 'l87', 'l91', 'l95', 'l96', 'l97']", + "197, selectively ['l53', 'l62', 'l70', 'l77', 'l83', 'l88', 'l92', 'l95', 'l98', 'l99']", + "199, mouse ['l54', 'l63', 'l71', 'l78', 'l84', 'l89', 'l93', 'l96', 'l98', 'l100']", + "200, muscles. ['l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l94', 'l97', 'l99', 'l100']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "heterozygous", + "GLUT4", + "knockout", + "homozygous", + "whole-body", + "(GLUT4-null)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "muscle-specific", + "inactivation", + "of", + "the", + "insulin", + "receptor", + "disrupted", + "GLUT4" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "muscles." + ] + } + } + ] + }, + { + "PMID": "10932228", + "TEXT": "The facilitating cell is a rare CD8+ bone marrow subpopulation that can enhance allogeneic hematopoietic stem cell engraftment across complete major histocompatibility complex barriers without inducing acute graft-versus-host disease. Here we describe a CD3epsilon-associated complex on the facilitating cell surface that consists of the T-cell receptor beta-chain disulfide-linked to a previously unknown 33-kilodalton glycoprotein. Provisionally called FCp33, this glycoprotein does not represent any of the known protein chains or surrogates associated with CD3-T-cell receptor beta. Expression of this CD3-T-cell receptor beta-FCp33 complex directly correlates with the facilitating cell's functional ability to enhance allogeneic stem cell engraftment in vivo.", + "TAG_DATA": [ + "96, in {'context': 'B-in vivo'}", + "97, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "96, in ['l0']", + "97, vivo. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10888934", + "TEXT": "Interferons are circulating factors that bind to cell surface receptors, activating a signaling cascade, ultimately leading to both an antiviral response and an induction of growth inhibitory and/or apoptotic signals in normal and tumor cells. Attempts to exploit the ability of interferons to limit the growth of tumors in patients has met with limited results because of cancer-specific mutations of gene products in the interferon pathway. Although interferon-non-responsive cancer cells may have acquired a growth/survival advantage over their normal counterparts, they may have simultaneously compromised their antiviral response. To test this, we used vesicular stomatitis virus (VSV), an enveloped, negative-sense RNA virus exquisitely sensitive to treatment with interferon. VSV rapidly replicated in and selectively killed a variety of human tumor cell lines even in the presence of doses of interferon that completely protected normal human primary cell cultures. A single intratumoral injection of VSV was effective in reducing the tumor burden of nude mice bearing subcutaneous human melanoma xenografts. Our results support the use of VSV as a replication-competent oncolytic virus and demonstrate a new strategy for the treatment of interferon non-responsive tumors.", + "TAG_DATA": [ + "118, human {'context': 'B-transformed cells'}", + "119, tumor {'context': 'I-transformed cells'}", + "120, cell {'context': 'I-transformed cells'}", + "121, lines {'context': 'I-transformed cells'}", + "133, normal {'context': 'B-cells'}", + "134, human {'context': 'I-cells'}", + "135, primary {'context': 'I-cells'}", + "136, cell {'context': 'I-cells'}", + "137, cultures. {'context': 'I-cells'}", + "147, reducing {'effect': 'B-negative'}", + "149, tumor {'phenotype': 'B-tumourigenesis'}", + "150, burden {'phenotype': 'I-tumourigenesis'}", + "152, nude {'context': 'B-organism'}", + "153, mice {'context': 'I-organism'}", + "155, subcutaneous {'context': 'B-xenograft'}", + "156, human {'context': 'I-xenograft'}", + "157, melanoma {'context': 'I-xenograft'}", + "158, xenografts. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "118, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "119, tumor ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "120, cell ['l1', 'l7', 'l14', 'l15', 'l16', 'l17']", + "121, lines ['l2', 'l8', 'l14', 'l18', 'l19']", + "133, normal ['l9', 'l20', 'l21', 'l22', 'l23']", + "134, human ['l3', 'l10', 'l20', 'l24', 'l25', 'l26']", + "135, primary ['l4', 'l11', 'l15', 'l21', 'l24', 'l27', 'l28']", + "136, cell ['l5', 'l12', 'l16', 'l18', 'l22', 'l25', 'l27', 'l29']", + "137, cultures. ['l6', 'l13', 'l17', 'l19', 'l23', 'l26', 'l28', 'l29']", + "147, reducing ['l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "149, tumor ['l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "150, burden ['l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "152, nude ['l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "153, mice ['l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "155, subcutaneous ['l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "156, human ['l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "157, melanoma ['l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "158, xenografts. ['l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "reducing" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "burden" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reducing" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reducing" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "subcutaneous", + "human", + "melanoma", + "xenografts." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "burden" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "burden" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "subcutaneous", + "human", + "melanoma", + "xenografts." + ] + } + } + ] + }, + { + "PMID": "10888930", + "TEXT": "The dorsomedial hypothalamic nucleus harbors leptin sensitive neurons and is intrinsically connected to hypothalamic nuclei involved in feeding behavior. However, it also receives ascending input from the visceroceptive neurons of the brainstem. We have identified a unique glucagon-like-peptide-2 containing neuronal pathway connecting the nucleus of the solitary tract with the dorsomedial hypothalamic nucleus. A glucagon-like-peptide-2 fiber plexus targets neurons expressing its receptor within the dorsomedial hypothalamic nucleus. Pharmacological and behavioral studies confirmed that glucagon-like-peptide-2 signaling is a specific transmitter inhibiting rodent feeding behavior and with potential long-term effects on body weight homeostasis. The glucagon-like-peptide-1 receptor antagonist, Exendin (9-39) is also a functional antagonist of centrally applied glucagon-like-peptide-2.", + "TAG_DATA": [ + "80, rodent {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10888929", + "TEXT": "Huntington disease is an autosomal dominant neurodegenerative disease with no effective treatment. Minocycline is a tetracycline derivative with proven safety. After ischemia, minocycline inhibits caspase-1 and inducible nitric oxide synthetase upregulation, and reduces infarction. As caspase-1 and nitric oxide seem to play a role in Huntington disease, we evaluated the therapeutic efficacy of minocycline in the R6/2 mouse model of Huntington disease. We report that minocycline delays disease progression, inhibits caspase-1 and caspase-3 mRNA upregulation, and decreases inducible nitric oxide synthetase activity. In addition, effective pharmacotherapy in R6/2 mice requires caspase-1 and caspase-3 inhibition. This is the first demonstration of caspase-1 and caspase-3 transcriptional regulation in a Huntington disease model.", + "TAG_DATA": [ + "56, R6/2 {'context': 'B-organism'}", + "57, mouse {'context': 'I-organism'}", + "58, model {'context': 'I-organism'}", + "66, delays {'effect': 'B-negative'}", + "67, disease {'phenotype': 'B-tumour progression'}", + "68, progression, {'phenotype': 'I-tumour progression'}", + "87, R6/2 {'context': 'B-organism'}", + "88, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "56, R6/2 ['l0', 'l1', 'l2', 'l3', 'l4']", + "57, mouse ['l0', 'l5', 'l6', 'l7', 'l8']", + "58, model ['l1', 'l5', 'l9', 'l10', 'l11']", + "66, delays ['l2', 'l6', 'l9', 'l12', 'l13']", + "67, disease ['l3', 'l7', 'l10', 'l12', 'l14']", + "68, progression, ['l4', 'l8', 'l11', 'l13', 'l14']", + "87, R6/2 ['l15']", + "88, mice ['l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "R6/2", + "mouse", + "model" + ] + }, + "effect": { + "val": "negative", + "words": [ + "delays" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "R6/2", + "mouse", + "model" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "disease", + "progression," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "delays" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "disease", + "progression," + ] + } + } + ] + }, + { + "PMID": "10888927", + "TEXT": "Despite increasing evidence for the existence of antigen-specific regulatory T cells, the mechanisms underlying suppression remain unclear. In this study we have identified and cloned a novel subset of antigen-specific regulatory T cells and demonstrated that these T cells possess a unique combination of cell surface markers and array of cytokines. The regulatory T cells are able to inhibit the function of T cells carrying the same T-cell receptor specificity and prevent skin allograft rejection in an antigen-specific, dose-dependent manner. The regulatory T cells are able to acquire alloantigen from antigen-presenting cells, present the alloantigen to activated syngeneic CD8+ T cells and then send death signals to CD8+ T cells. These findings provide a novel mechanism of regulatory T-cell-mediated, antigen-specific suppression.", + "TAG_DATA": [ + "52, regulatory {'context': 'B-cells'}", + "53, T {'context': 'I-cells'}", + "54, cells {'context': 'I-cells'}", + "62, T {'context': 'B-cells'}", + "63, cells {'context': 'B-cells'}", + "71, prevent {'effect': 'B-negative'}", + "72, skin {'context': 'B-xenograft'}", + "73, allograft {'context': 'I-xenograft'}", + "81, regulatory {'context': 'B-cells'}", + "82, T {'context': 'I-cells'}", + "83, cells {'context': 'I-cells'}", + "97, syngeneic {'context': 'B-cells'}", + "98, CD8+ {'context': 'I-cells'}", + "99, T {'context': 'I-cells'}", + "100, cells {'context': 'I-cells'}", + "107, CD8+ {'context': 'B-cells'}", + "108, T {'context': 'I-cells'}", + "109, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "52, regulatory ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "53, T ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "54, cells ['l1', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "62, T ['l2', 'l11', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "63, cells ['l3', 'l12', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32', 'l33']", + "71, prevent ['l4', 'l13', 'l20', 'l25', 'l29', 'l34', 'l35']", + "72, skin ['l5', 'l14', 'l21', 'l26', 'l30', 'l34', 'l36']", + "73, allograft ['l6', 'l15', 'l22', 'l27', 'l31', 'l35', 'l36']", + "81, regulatory ['l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "82, T ['l37', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "83, cells ['l38', 'l46', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "97, syngeneic ['l39', 'l47', 'l54', 'l61', 'l62', 'l63', 'l64', 'l65']", + "98, CD8+ ['l7', 'l40', 'l48', 'l55', 'l61', 'l66', 'l67', 'l68', 'l69', 'l70']", + "99, T ['l8', 'l16', 'l32', 'l41', 'l49', 'l56', 'l62', 'l66', 'l71', 'l72', 'l73']", + "100, cells ['l9', 'l17', 'l23', 'l28', 'l33', 'l42', 'l50', 'l57', 'l63', 'l67', 'l71', 'l74', 'l75']", + "107, CD8+ ['l43', 'l51', 'l58', 'l68', 'l76', 'l77']", + "108, T ['l44', 'l52', 'l59', 'l64', 'l69', 'l72', 'l74', 'l76', 'l78']", + "109, cells. ['l45', 'l53', 'l60', 'l65', 'l70', 'l73', 'l75', 'l77', 'l78']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "regulatory", + "T", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "skin", + "allograft" + ] + } + } + ] + }, + { + "PMID": "10835689", + "TEXT": "Progression of pulmonary hypertension is associated with increased serine elastase activity and the proteinase-dependent deposition of the extracellular matrix smooth muscle cell survival factor tenascin-C (refs. 1,2). Tenascin-C amplifies the response of smooth muscle cells to growth factors, which are also liberated through matrix proteolysis. Recent organ culture studies using hypertrophied rat pulmonary arteries have shown that elastase inhibitors suppress tenascin-C and induce smooth muscle cell apoptosis. This initiates complete regression of the hypertrophied vessel wall by a coordinated loss of cellularity and extracellular matrix. We now report that elastase inhibitors can reverse advanced pulmonary vascular disease produced in rats by injecting monocrotaline, an endothelial toxin. We began oral administration of the peptidyl trifluoromethylketone serine elastase inhibitors M249314 or ZD0892 21 days after injection of monocrotaline. A 1-week treatment resulted in 92% survival, compared with 39% survival in untreated or vehicle-treated rats. Pulmonary artery pressure and muscularization were reduced by myocyte apoptosis and loss of extracellular matrix, specifically elastin and tenascin-C. After 2 weeks, pulmonary artery pressure and structure normalized, and survival was 86%, compared with 0% in untreated or vehicle-treated rats. Although concomitant treatment with various agents can reduce pulmonary hypertension, we have documented complete regression after establishment of malignant monocrotaline-induced disease.", + "TAG_DATA": [ + "64, muscle {'context': 'B-cells'}", + "99, rats {'context': 'B-organism'}", + "141, rats. {'context': 'B-organism'}", + "150, myocyte {'context': 'B-cells'}", + "151, apoptosis {'phenotype': 'B-apoptosis'}", + "181, rats. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "64, muscle ['l0']", + "99, rats ['l0']", + "141, rats. ['l1', 'l2']", + "150, myocyte ['l1', 'l3']", + "151, apoptosis ['l2', 'l3']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "rats." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "myocyte" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "10835682", + "TEXT": "We have identified an interferon-like cytokine, limitin, on the basis of its ability to arrest the growth of or kill lympho-hematopoietic cells. Limitin strongly inhibited B lymphopoiesis in vitro and in vivo but had little influence on either myelopoiesis or erythropoiesis. Because limitin uses the interferon alpha/beta receptors and induces interferon regulatory factor-1, it may represent a previously unknown type I interferon prototype. However, preferential B-lineage growth inhibition and activation of Janus kinase 2 in a myelomonocytic leukemia line have not been described for previously known interferons.", + "TAG_DATA": [ + "25, B {'context': 'B-cells'}", + "26, lymphopoiesis {'context': 'I-cells'}", + "27, in {'context': 'B-in vitro'}", + "28, vitro {'context': 'I-in vitro'}", + "30, in {'context': 'B-in vivo'}", + "31, vivo {'context': 'I-in vivo'}", + "34, little {'effect': 'B-no effect'}", + "35, influence {'effect': 'I-no effect'}", + "76, myelomonocytic {'context': 'B-transformed cells'}", + "77, leukemia {'context': 'I-transformed cells'}", + "78, line {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "25, B ['l0', 'l1', 'l2']", + "26, lymphopoiesis ['l0', 'l3', 'l4']", + "27, in ['l1', 'l3', 'l5']", + "28, vitro ['l2', 'l4', 'l5']", + "30, in ['l6']", + "31, vivo ['l6']", + "34, little ['l7']", + "35, influence ['l7']", + "76, myelomonocytic ['l8', 'l9']", + "77, leukemia ['l8', 'l10']", + "78, line ['l9', 'l10']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10802715", + "TEXT": "Based on the essential involvement of NF-kappaB in immune and inflammatory responses and its apoptosis-rescue function in normal and malignant cells, inhibitors of this transcription factor are potential therapeutics for the treatment of a wide range of diseases, from bronchial asthma to cancer. Yet, given the essential function of NF-kappaB in the embryonic liver, it is important to determine its necessity in the liver beyond embryogenesis. NF-kappaB is normally retained in the cytoplasm by its inhibitor IkappaB, which is eliminated upon cell stimulation through phosphorylation-dependent ubiquitin degradation. Here, we directed a degradation-resistant IkappaBalpha transgene to mouse hepatocytes in an inducible manner and showed substantial tissue specificity using various means, including a new method for live-animal imaging. Transgene expression resulted in obstruction of NF-kappaB activation, yet produced no signs of liver dysfunction, even when implemented over 15 months. However, the transgene-expressing mice were very vulnerable both to a severe immune challenge and to a systemic bacterial infection. Despite having intact immunocytes and inflammatory cells, these mice were unable to clear Listeria monocytogenes from the liver and succumbed to sepsis. These findings indicate the essential function of the hepatocyte through NF-kappaB activation in certain systemic infections, possibly by coordinating innate immunity in the liver.", + "TAG_DATA": [ + "92, IkappaBalpha {'perturbing_action': 'I-other'}", + "93, transgene {'perturbing_action': 'I-other'}", + "95, mouse {'context': 'B-cells'}", + "96, hepatocytes {'context': 'I-cells'}", + "116, Transgene {'perturbing_action': 'B-gene gain-of-function'}", + "129, liver {'context': 'B-tissue/organ'}", + "139, transgene-expressing {'perturbing_action': 'B-gene gain-of-function'}", + "140, mice {'context': 'B-organism'}", + "164, mice {'context': 'B-organism'}", + "173, liver {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "92, IkappaBalpha ['l0', 'l1', 'l2']", + "93, transgene ['l0', 'l3', 'l4']", + "95, mouse ['l1', 'l3', 'l5']", + "96, hepatocytes ['l2', 'l4', 'l5']", + "116, Transgene ['l6']", + "129, liver ['l6']", + "139, transgene-expressing ['l7', 'l8', 'l9']", + "140, mice ['l7']", + "164, mice ['l8', 'l10']", + "173, liver ['l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "IkappaBalpha", + "transgene" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "hepatocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgene", + "transgene-expressing" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgene-expressing" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "10802712", + "TEXT": "The transforming-growth-factor-beta-activated kinase TAK1 is a member of the mitogen-activated protein kinase kinase kinase family, which couples extracellular stimuli to gene transcription. The in vivo function of TAK1 is not understood. Here, we investigated the potential involvement of TAK1 in cardiac hypertrophy. In adult mouse myocardium, TAK1 kinase activity was upregulated 7 days after aortic banding, a mechanical load that induces hypertrophy and expression of transforming growth factor beta. An activating mutation of TAK1 expressed in myocardium of transgenic mice was sufficient to produce p38 mitogen-activated protein kinase phosphorylation in vivo, cardiac hypertrophy, interstitial fibrosis, severe myocardial dysfunction, 'fetal' gene induction, apoptosis and early lethality. Thus, TAK1 activity is induced as a delayed response to mechanical stress, and can suffice to elicit myocardial hypertrophy and fulminant heart failure.", + "TAG_DATA": [ + "43, adult {'context': 'B-tissue/organ'}", + "44, mouse {'context': 'I-tissue/organ'}", + "45, myocardium, {'context': 'I-tissue/organ'}", + "70, activating {'perturbing_action': 'B-other'}", + "71, mutation {'perturbing_action': 'I-other'}", + "72, of {'perturbing_action': 'I-other'}", + "73, TAK1 {'perturbing_action': 'I-other'}", + "74, expressed {'perturbing_action': 'I-other'}", + "76, myocardium {'context': 'B-tissue/organ'}", + "78, transgenic {'perturbing_action': 'B-gene gain-of-function', 'context': 'B-organism'}", + "79, mice {'context': 'I-organism'}", + "89, in {'context': 'B-in vivo'}", + "90, vivo, {'context': 'I-in vivo'}", + "101, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "43, adult ['l0', 'l1']", + "44, mouse ['l0', 'l2']", + "45, myocardium, ['l1', 'l2']", + "70, activating ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "71, mutation ['l3', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "72, of ['l4', 'l13', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "73, TAK1 ['l5', 'l14', 'l22', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "74, expressed ['l6', 'l15', 'l23', 'l30', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "76, myocardium ['l7', 'l16', 'l24', 'l31', 'l37', 'l43', 'l44', 'l45', 'l46']", + "78, transgenic ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l48', 'l49', 'l50']", + "79, mice ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l47', 'l51', 'l52']", + "89, in ['l10', 'l19', 'l27', 'l34', 'l40', 'l45', 'l48', 'l51', 'l53']", + "90, vivo, ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l49', 'l52', 'l53']", + "101, apoptosis ['l12', 'l21', 'l29', 'l36', 'l42', 'l50']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "activating", + "mutation", + "of", + "TAK1", + "expressed" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "myocardium" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "activating", + "mutation", + "of", + "TAK1", + "expressed" + ] + }, + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "activating", + "mutation", + "of", + "TAK1", + "expressed" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "activating", + "mutation", + "of", + "TAK1", + "expressed" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "myocardium" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "transgenic" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "10802710", + "TEXT": "Movement towards or away from a given stimulus guides the directional migration of prokaryotes, simple eukaryotes and neurons. As bi-directional cues may influence entry and exit of immune effector cells from tissue sites, we evaluated the migratory responses of T-cell subsets to varying concentrations of the chemokine stromal cell derived factor-1 (SDF-1). There was selective repulsion of subpopulations of T cells at high concentrations of recombinant SDF-1 or naturally occurring bone marrow-derived SDF-1, which could be inhibited by pertussis toxin and antibody against the chemokine receptor CXCR4. Distinct sensitivity profiles to genistein, herbimycin and 8-Br-cAMP biochemically distinguished movement of cells towards or away from an SDF-1 gradient. In vivo, antigen-induced T-cell recruitment into the peritoneal cavity was reversed by high but not low concentrations of SDF-1. The phenomenon of movement away from a chemokine represents a previously unknown mechanism regulating the localization of mature T cells. It adds to the functional repertoire of chemokines that may participate in immune physiology and may be applied therapeutically to alter the immune response.", + "TAG_DATA": [ + "59, T {'context': 'B-cells'}", + "60, cells {'context': 'B-cells'}", + "99, cells {'context': 'B-cells'}", + "107, In {'context': 'B-in vivo'}", + "108, vivo, {'context': 'I-in vivo'}", + "110, T-cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "59, T ['l0']", + "60, cells ['l0']", + "107, In ['l1', 'l2']", + "108, vivo, ['l1', 'l3']", + "110, T-cell ['l2', 'l3']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10742158", + "TEXT": "Attention-deficit/hyperactivity disorder is a highly heritable and prevalent neuropsychiatric disorder estimated to affect 6% of school-age children. Its clinical hallmarks are inattention, hyperactivity and impulsivity, which often respond substantially to treatment with methylphenidate or dextroamphetamine. Etiological theories suggest a deficit in corticostriatal circuits, particularly those components modulated by dopamine. We developed a new functional magnetic resonance imaging procedure (T2 relaxometry) to indirectly assess blood volume in the striatum (caudate and putamen) of boys 6-12 years of age in steady-state conditions. Boys with attention-deficit/hyperactivity disorder had higher T2 relaxation time measures in the putamen bilaterally than healthy control subjects. Relaxation times strongly correlated with the child's capacity to sit still and his accuracy in accomplishing a computerized attention task. Daily treatment with methylphenidate significantly changed the T2 relaxation times in the putamen of children with attention-deficit/hyperactivity disorder, although the magnitude and direction of the effect was strongly dependent on the child's unmedicated activity state. There was a similar but nonsignificant trend in the right caudate. T2 relaxation time measures in thalamus did not differ significantly between groups, and were not affected by methylphenidate. Attention-deficit/hyperactivity disorder symptoms may be closely tied to functional abnormalities in the putamen, which is mainly involved in the regulation of motor behavior.", + "TAG_DATA": [ + "72, boys {'context': 'B-organism'}", + "80, Boys {'context': 'B-patient'}", + "130, putamen {'context': 'B-tissue/organ'}", + "132, children {'context': 'B-patient'}", + "169, thalamus {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "72, boys ['l0']", + "80, Boys ['l0']", + "130, putamen ['l1']", + "132, children ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10742155", + "TEXT": "Infection with group A streptococci can result in acute and post-infectious pathology, including rheumatic fever and rheumatic heart disease. These diseases are associated with poverty and are increasing in incidence, particularly in developing countries and amongst indigenous populations, such as Australia's Aboriginal population, who suffer the highest incidence worldwide. Immunity to group A streptococci is mediated by antibodies against the M protein, a coiled-coil alpha helical surface protein of the bacterium. Vaccine development faces two substantial obstacles. Although opsonic antibodies directed against the N terminus of the protein are mostly responsible for serotypic immunity, more than 100 serotypes exist. Furthermore, whereas the pathogenesis of rheumatic fever is not well understood, increasing evidence indicates an autoimmune process. To develop a suitable vaccine candidate, we first identified a minimum, helical, non-host-cross-reactive peptide from the conserved C-terminal half of the protein and displayed this within a non-M-protein peptide sequence designed to maintain helical folding and antigenicity, J14 (refs. 8,9). As this region of the M protein is identical in only 70% of group A streptococci isolates, the optimal candidate might consist of the conserved determinant with common N-terminal sequences found in communities with endemic group A streptococci. We linked seven serotypic peptides with J14 using a new chemistry technique that enables the immunogen to display all the individual peptides pendant from an alkane backbone. This construct demonstrated excellent immunogenicity and protection in mice.", + "TAG_DATA": [ + "229, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10742149", + "TEXT": "The stress-inducible protein heme oxygenase-1 provides protection against oxidative stress. The anti-inflammatory properties of heme oxygenase-1 may serve as a basis for this cytoprotection. We demonstrate here that carbon monoxide, a by-product of heme catabolism by heme oxygenase, mediates potent anti-inflammatory effects. Both in vivo and in vitro, carbon monoxide at low concentrations differentially and selectively inhibited the expression of lipopolysaccharide-induced pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and macrophage inflammatory protein-1beta and increased the lipopolysaccharide-induced expression of the anti-inflammatory cytokine interleukin-10. Carbon monoxide mediated these anti-inflammatory effects not through a guanylyl cyclase-cGMP or nitric oxide pathway, but instead through a pathway involving the mitogen-activated protein kinases. These data indicate the possibility that carbon monoxide may have an important protective function in inflammatory disease states and thus has potential therapeutic uses.", + "TAG_DATA": [ + "43, in {'context': 'B-in vivo'}", + "44, vivo {'context': 'I-in vivo'}", + "46, in {'context': 'B-in vitro'}", + "47, vitro, {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "43, in ['l0', 'l1', 'l2']", + "44, vivo ['l0', 'l3', 'l4']", + "46, in ['l1', 'l3', 'l5']", + "47, vitro, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10742148", + "TEXT": "Superantigens trigger an excessive cellular immune response, leading to toxic shock. We have designed a peptide antagonist that inhibits superantigen-induced expression of human genes for interleukin-2, gamma interferon and tumor necrosis factor-b, which are cytokines that mediate shock. The peptide shows homology to a b-strand-hinge-a-helix domain that is structurally conserved in superantigens, yet is remote from known binding sites for the major histocompatibility class II molecule and T-cell receptor. Superantigens depend on this domain for T-cell activation. The peptide protected mice against lethal challenge with staphylococcal and streptococcal superantigens. Moreover, it rescued mice undergoing toxic shock. Surviving mice rapidly developed protective antibodies against superantigen that rendered them resistant to further lethal challenges, even with different superantigens. Thus, the lethal effect of superantigens can be blocked with a peptide antagonist that inhibits their action at the beginning of the toxicity cascade, before activation of T cells takes place.", + "TAG_DATA": [ + "80, mice {'context': 'B-organism'}", + "92, mice {'context': 'B-organism'}", + "97, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10742147", + "TEXT": "Ischemic peripheral neuropathy is a frequent, irreversible complication of lower extremity vascular insufficiency. We investigated whether ischemic peripheral neuropathy could be prevented and/or reversed by gene transfer of an endothelial cell mitogen designed to promote therapeutic angiogenesis. Intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor (VEGF) simultaneously with induction of hindlimb ischemia in rabbits abrogated the substantial decrease in motor and sensory nerve parameters, and nerve function recovered promptly. When gene transfer was administered 10 days after induction of ischemia, nerve function was restored earlier and/or recovered faster than in untreated rabbits. These findings are due in part to enhanced hindlimb perfusion. In addition, however, the demonstration of functional VEGF receptor expression by Schwann cells indicates a direct effect of VEGF on neural integrity as well. These findings thus constitute a new paradigm for the treatment of ischemic peripheral neuropathy.", + "TAG_DATA": [ + "37, Intramuscular {'perturbing_action': 'B-gene gain-of-function'}", + "38, gene {'perturbing_action': 'I-gene gain-of-function'}", + "39, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "40, of {'perturbing_action': 'I-gene gain-of-function'}", + "41, naked {'perturbing_action': 'I-gene gain-of-function'}", + "42, DNA {'perturbing_action': 'I-gene gain-of-function'}", + "43, encoding {'perturbing_action': 'I-gene gain-of-function'}", + "44, vascular {'perturbing_action': 'I-gene gain-of-function'}", + "45, endothelial {'perturbing_action': 'I-gene gain-of-function'}", + "46, growth {'perturbing_action': 'I-gene gain-of-function'}", + "47, factor {'perturbing_action': 'I-gene gain-of-function'}", + "48, (VEGF) {'perturbing_action': 'I-gene gain-of-function'}", + "56, rabbits {'context': 'B-organism'}", + "68, nerve {'context': 'B-cells'}", + "83, nerve {'context': 'B-cells'}", + "94, rabbits. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "37, Intramuscular ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "38, gene ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "39, transfer ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "40, of ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "41, naked ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "42, DNA ['l4', 'l17', 'l29', 'l40', 'l50', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "43, encoding ['l5', 'l18', 'l30', 'l41', 'l51', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "44, vascular ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "45, endothelial ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "46, growth ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l90', 'l91', 'l92', 'l93']", + "47, factor ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l94', 'l95', 'l96']", + "48, (VEGF) ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l94', 'l97', 'l98']", + "56, rabbits ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l95', 'l97', 'l99']", + "68, nerve ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l96', 'l98', 'l99']", + "83, nerve ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l100']", + "94, rabbits. ['l100']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Intramuscular", + "gene", + "transfer", + "of", + "naked", + "DNA", + "encoding", + "vascular", + "endothelial", + "growth", + "factor", + "(VEGF)" + ] + }, + "context": { + "val": "organism", + "words": [ + "rabbits" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Intramuscular", + "gene", + "transfer", + "of", + "naked", + "DNA", + "encoding", + "vascular", + "endothelial", + "growth", + "factor", + "(VEGF)" + ] + }, + "context": { + "val": "cells", + "words": [ + "nerve" + ] + } + } + ] + }, + { + "PMID": "10700230", + "TEXT": "LIGHT was recently described as a member of the tumor necrosis factor (TNF) 'superfamily'. We have isolated a mouse homolog of human LIGHT and investigated its immunoregulatory functions in vitro and in vivo. LIGHT has potent, CD28-independent co-stimulatory activity leading to T-cell growth and secretion of gamma interferon and granulocyte-macrophage colony-stimulating factor. Gene transfer of LIGHT induced an antigen-specific cytolytic T-cell response and therapeutic immunity against established mouse P815 tumor. In contrast, blockade of LIGHT by administration of soluble receptor or antibody led to decreased cell-mediated immunity and ameliorated graft-versus-host disease. Our studies identify a previously unknown T-cell co-stimulatory pathway as a potential therapeutic target.", + "TAG_DATA": [ + "41, T-cell {'context': 'B-cells'}", + "42, growth {'phenotype': 'I-cell growth'}", + "52, Gene {'perturbing_action': 'B-gene gain-of-function'}", + "53, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "54, of {'perturbing_action': 'I-gene gain-of-function'}", + "55, LIGHT {'perturbing_action': 'I-gene gain-of-function'}", + "67, mouse {'context': 'B-neoplasm'}", + "68, P815 {'context': 'I-neoplasm'}", + "69, tumor. {'context': 'I-neoplasm'}", + "73, of {'perturbing_action': 'I-pharmacological inhibition'}", + "74, LIGHT {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "41, T-cell ['l0']", + "42, growth ['l0']", + "52, Gene ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "53, transfer ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "54, of ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "55, LIGHT ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "67, mouse ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "68, P815 ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "69, tumor. ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']", + "73, of ['l22']", + "74, LIGHT ['l22']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T-cell" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Gene", + "transfer", + "of", + "LIGHT" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "P815", + "tumor." + ] + } + } + ] + }, + { + "PMID": "10655112", + "TEXT": "T-cell co-stimulation delivered by the molecules B7-1 or B7-2 through CD28 has a positive effect on T-cell activation, whereas engagement of cytotoxic T-lymphocyte antigen 4 (CTLA-4) by these molecules inhibits activation. In vivo administration to mice of blocking monoclonal antibodies or Fab fragments against CTLA-4 can augment antigen-specific T-cell responses and, thus, therapy with monoclonal antibody against CTLA-4 has potential applications for tumor therapy and enhancement of vaccine immunization. The effects of B7-1 and B7-2 co-stimulation through CD28 depend on the strength of the signal delivered through the T-cell receptor (TCR) and the activation state of T cells during activation. Thus, we sought to determine whether these factors similarly influence the effect of B7-mediated signals delivered through CTLA-4 during T-cell activation. Using freshly isolated human T cells and Fab fragments of a monoclonal antibody against CTLA-4, we demonstrate here that CTLA-4 blockade can enhance or inhibit the clonal expansion of different T cells that respond to the same antigen, depending on both the T-cell activation state and the strength of the T-cell receptor signal delivered during T-cell stimulation. Thus, for whole T-cell populations, blocking a negative signal may paradoxically inhibit immune responses. These results provide a theoretical framework for clinical trials in which co-stimulatory signals are manipulated in an attempt to modulate the immune response in human disease.", + "TAG_DATA": [ + "123, isolated {'context': 'I-cells'}", + "124, human {'context': 'B-cells'}", + "125, T {'context': 'I-cells'}", + "126, cells {'context': 'I-cells'}", + "143, enhance {'effect': 'B-positive'}", + "145, inhibit {'effect': 'B-negative'}", + "147, clonal {'phenotype': 'B-colony formation'}", + "148, expansion {'phenotype': 'I-colony formation'}", + "151, T {'context': 'B-cells'}", + "152, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "123, isolated ['l0', 'l1', 'l2']", + "124, human ['l0', 'l3', 'l4']", + "125, T ['l1', 'l3', 'l5']", + "126, cells ['l2', 'l4', 'l5']", + "143, enhance ['l6', 'l7', 'l8', 'l9', 'l10']", + "145, inhibit ['l6', 'l11', 'l12', 'l13', 'l14']", + "147, clonal ['l7', 'l11', 'l15', 'l16', 'l17']", + "148, expansion ['l8', 'l12', 'l15', 'l18', 'l19']", + "151, T ['l9', 'l13', 'l16', 'l18', 'l20']", + "152, cells ['l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "enhance" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonal", + "expansion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhance" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonal", + "expansion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "clonal", + "expansion" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + } + ] + }, + { + "PMID": "10655109", + "TEXT": "Maspin, a unique member of the serpin family, is a secreted protein encoded by a class II tumor suppressor gene whose downregulation is associated with the development of breast and prostate cancers. Overexpression of maspin in breast tumor cells limits their growth and metastases in vivo. In this report we demonstrate that maspin is an effective inhibitor of angiogenesis. In vitro, it acted directly on cultured endothelial cells to stop their migration towards basic fibroblast growth factor and vascular endothelial growth factor and to limit mitogenesis and tube formation. In vivo, it blocked neovascularization in the rat cornea pocket model. Maspin derivatives mutated in the serpin reactive site lost their ability to inhibit the migration of fibroblasts, keratinocytes, and breast cancer cells but were still able to block angiogenesis in vitro and in vivo. When maspin was delivered locally to human prostate tumor cells in a xenograft mouse model, it blocked tumor growth and dramatically reduced the density of tumor-associated microvessels. These data suggest that the tumor suppressor activity of maspin may depend in large part on its ability to inhibit angiogenesis and raise the possibility that maspin and similar serpins may be excellent leads for the development of drugs that modulate angiogenesis.", + "TAG_DATA": [ + "59, In {'context': 'B-in vitro'}", + "60, vitro, {'context': 'I-in vitro'}", + "65, cultured {'context': 'B-cells'}", + "66, endothelial {'context': 'I-cells'}", + "67, cells {'context': 'I-cells'}", + "84, limit {'effect': 'B-negative'}", + "87, tube {'phenotype': 'B-colony formation'}", + "88, formation. {'phenotype': 'I-colony formation'}", + "89, In {'context': 'B-in vivo'}", + "90, vivo, {'context': 'I-in vivo'}", + "96, rat {'context': 'B-tissue/organ'}", + "97, cornea {'context': 'I-tissue/organ'}", + "98, pocket {'context': 'I-tissue/organ'}", + "99, model. {'context': 'I-tissue/organ'}", + "102, mutated {'perturbing_action': 'B-other'}", + "103, in {'perturbing_action': 'I-other'}", + "104, the {'perturbing_action': 'I-other'}", + "105, serpin {'perturbing_action': 'I-other'}", + "106, reactive {'perturbing_action': 'I-other'}", + "107, site {'perturbing_action': 'I-other'}", + "112, inhibit {'effect': 'B-negative'}", + "114, migration {'phenotype': 'B-migration'}", + "116, fibroblasts, {'context': 'B-cells'}", + "117, keratinocytes, {'context': 'B-cells'}", + "119, breast {'context': 'B-transformed cells'}", + "120, cancer {'context': 'I-transformed cells'}", + "121, cells {'context': 'I-transformed cells'}", + "129, in {'context': 'B-in vitro'}", + "130, vitro {'context': 'I-in vitro'}", + "132, in {'context': 'B-in vivo'}", + "133, vivo. {'context': 'I-in vivo'}", + "140, human {'context': 'B-transformed cells'}", + "141, prostate {'context': 'I-transformed cells'}", + "142, tumor {'context': 'I-transformed cells'}", + "143, cells {'context': 'I-transformed cells'}", + "146, xenograft {'context': 'B-xenograft'}", + "147, mouse {'context': 'I-xenograft'}", + "148, model, {'context': 'I-xenograft'}", + "150, blocked {'effect': 'B-negative'}", + "151, tumor {'phenotype': 'B-tumour growth'}", + "152, growth {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "59, In ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "60, vitro, ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "65, cultured ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "66, endothelial ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "67, cells ['l3', 'l11', 'l18', 'l24', 'l31', 'l32', 'l33', 'l34']", + "84, limit ['l4', 'l12', 'l19', 'l25', 'l31', 'l35', 'l36']", + "87, tube ['l5', 'l13', 'l20', 'l26', 'l32', 'l35', 'l37']", + "88, formation. ['l6', 'l14', 'l21', 'l27', 'l33', 'l36', 'l37']", + "89, In ['l7', 'l15', 'l22', 'l28', 'l38', 'l39', 'l40', 'l41']", + "90, vivo, ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l42']", + "96, rat ['l43', 'l44', 'l45', 'l46']", + "97, cornea ['l39', 'l43', 'l47', 'l48', 'l49']", + "98, pocket ['l40', 'l44', 'l47', 'l50', 'l51']", + "99, model. ['l30', 'l41', 'l42', 'l45', 'l48', 'l50']", + "101, derivatives ['l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "102, mutated ['l52', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "103, in ['l53', 'l72', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "104, the ['l54', 'l73', 'l98', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "105, serpin ['l55', 'l74', 'l99', 'l117', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150']", + "106, reactive ['l56', 'l75', 'l100', 'l118', 'l135', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "107, site ['l57', 'l76', 'l101', 'l119', 'l136', 'l151', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177']", + "112, inhibit ['l58', 'l77', 'l102', 'l120', 'l137', 'l152', 'l166', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "114, migration ['l59', 'l78', 'l103', 'l121', 'l138', 'l153', 'l167', 'l178', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "116, fibroblasts, ['l60', 'l79', 'l104', 'l122', 'l139', 'l154', 'l168', 'l179', 'l188', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201']", + "117, keratinocytes, ['l61', 'l80', 'l105', 'l123', 'l140', 'l155', 'l169', 'l180', 'l189', 'l195', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207']", + "119, breast ['l62', 'l81', 'l106', 'l124', 'l141', 'l156', 'l170', 'l181', 'l190', 'l196', 'l202', 'l208', 'l209', 'l210', 'l211', 'l212']", + "120, cancer ['l63', 'l82', 'l107', 'l125', 'l142', 'l157', 'l171', 'l182', 'l191', 'l197', 'l203', 'l208', 'l213', 'l214', 'l215']", + "121, cells ['l46', 'l49', 'l51', 'l64', 'l83', 'l108', 'l126', 'l143', 'l158', 'l172', 'l183', 'l192', 'l198', 'l204', 'l209', 'l213', 'l216']", + "129, in ['l65', 'l84', 'l109', 'l127', 'l144', 'l159', 'l173', 'l184', 'l193', 'l199', 'l205', 'l210', 'l214', 'l217', 'l218', 'l219']", + "130, vitro ['l66', 'l85', 'l110', 'l128', 'l145', 'l160', 'l174', 'l185', 'l194', 'l200', 'l206', 'l211', 'l215', 'l216', 'l217', 'l220', 'l221']", + "132, in ['l67', 'l86', 'l111', 'l129', 'l146', 'l161', 'l175', 'l186', 'l218', 'l220', 'l222']", + "133, vivo. ['l68', 'l87', 'l112', 'l130', 'l147', 'l162', 'l176', 'l187', 'l201', 'l207', 'l212', 'l219', 'l221', 'l222']", + "140, human ['l88', 'l113', 'l131', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231']", + "141, prostate ['l69', 'l89', 'l114', 'l132', 'l148', 'l163', 'l223', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239']", + "142, tumor ['l70', 'l90', 'l115', 'l133', 'l149', 'l164', 'l224', 'l232', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246']", + "143, cells ['l71', 'l91', 'l116', 'l134', 'l150', 'l165', 'l177', 'l225', 'l233', 'l240', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252']", + "146, xenograft ['l92', 'l226', 'l234', 'l241', 'l247', 'l253', 'l254', 'l255', 'l256', 'l257']", + "147, mouse ['l93', 'l227', 'l235', 'l242', 'l248', 'l253', 'l258', 'l259', 'l260', 'l261']", + "148, model, ['l94', 'l228', 'l236', 'l243', 'l249', 'l254', 'l258', 'l262', 'l263', 'l264']", + "150, blocked ['l95', 'l229', 'l237', 'l244', 'l250', 'l255', 'l259', 'l262', 'l265', 'l266']", + "151, tumor ['l96', 'l230', 'l238', 'l245', 'l251', 'l256', 'l260', 'l263', 'l265', 'l267']", + "152, growth ['l97', 'l231', 'l239', 'l246', 'l252', 'l257', 'l261', 'l264', 'l266', 'l267']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro,", + "in", + "vitro" + ] + }, + "effect": { + "val": "negative", + "words": [ + "limit", + "inhibit" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "tube", + "formation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "endothelial", + "cells", + "fibroblasts,", + "keratinocytes," + ] + }, + "effect": { + "val": "negative", + "words": [ + "limit", + "inhibit" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "endothelial", + "cells" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "tube", + "formation." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limit" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "tube", + "formation." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "in", + "the", + "serpin", + "reactive", + "site" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibit", + "blocked" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "in", + "the", + "serpin", + "reactive", + "site" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "in", + "the", + "serpin", + "reactive", + "site" + ] + }, + "context": { + "val": "cells", + "words": [ + "fibroblasts,", + "keratinocytes," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "in", + "the", + "serpin", + "reactive", + "site" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "breast", + "cancer", + "cells", + "human", + "prostate", + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "in", + "the", + "serpin", + "reactive", + "site" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "in", + "the", + "serpin", + "reactive", + "site" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "mouse", + "model," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit", + "blocked" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "breast", + "cancer", + "cells", + "human", + "prostate", + "tumor" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "cells", + "words": [ + "fibroblasts,", + "keratinocytes," + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "breast", + "cancer", + "cells" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "prostate", + "tumor", + "cells" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "mouse", + "model," + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "mouse", + "model," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + } + ] + }, + { + "PMID": "10655102", + "TEXT": "Trypsin and mast cell tryptase cleave proteinase-activated receptor 2 and, by unknown mechanisms, induce widespread inflammation. We found that a large proportion of primary spinal afferent neurons, which express proteinase-activated receptor 2, also contain the proinflammatory neuropeptides calcitonin gene-related peptide and substance P. Trypsin and tryptase directly signal to neurons to stimulate release of these neuropeptides, which mediate inflammatory edema induced by agonists of proteinase-activated receptor 2. This new mechanism of protease-induced neurogenic inflammation may contribute to the proinflammatory effects of mast cells in human disease. Thus, tryptase inhibitors and antagonists of proteinase-activated receptor 2 may be useful anti-inflammatory agents.", + "TAG_DATA": [ + "23, primary {'context': 'B-cells'}", + "24, spinal {'context': 'I-cells'}", + "25, afferent {'context': 'I-cells'}", + "26, neurons, {'context': 'I-cells'}", + "49, neurons {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "23, primary ['l0', 'l1', 'l2', 'l3']", + "24, spinal ['l0', 'l4', 'l5', 'l6']", + "25, afferent ['l1', 'l4', 'l7', 'l8']", + "26, neurons, ['l2', 'l5', 'l7', 'l9']", + "49, neurons ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10613820", + "TEXT": "Azoospermia or oligozoospermia due to disruption of spermatogenesis are common causes of human male infertility. We used the technique of spermatogonial transplantation in two infertile mouse strains, Steel (Sl) and dominant white spotting (W), to determine if stem cells from an infertile male were capable of generating spermatogenesis. Transplantation of germ cells from infertile Sl/Sld mutant male mice to infertile W/Wv or Wv/W54 mutant male mice restored fertility to the recipient mice. Thus, transplantation of spermatogonial stem cells from an infertile donor to a permissive testicular environment can restore fertility and result in progeny with the genetic makeup of the infertile donor male.", + "TAG_DATA": [ + "25, mouse {'context': 'I-organism'}", + "50, germ {'context': 'B-cells'}", + "51, cells {'context': 'I-cells'}", + "53, infertile {'perturbing_action': 'B-other'}", + "54, Sl/Sld {'perturbing_action': 'I-other'}", + "55, mutant {'perturbing_action': 'I-other'}", + "56, male {'context': 'B-organism'}", + "57, mice {'context': 'I-organism'}", + "62, Wv/W54 {'perturbing_action': 'B-other'}", + "63, mutant {'perturbing_action': 'I-other'}", + "64, male {'context': 'B-organism'}", + "65, mice {'context': 'I-organism'}", + "71, mice. {'context': 'B-organism'}", + "76, stem {'context': 'I-cells'}", + "77, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "50, germ ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "51, cells ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "53, infertile ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "54, Sl/Sld ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "55, mutant ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "56, male ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "57, mice ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "62, Wv/W54 ['l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "63, mutant ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l55', 'l56', 'l57']", + "64, male ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l50', 'l55', 'l58', 'l59']", + "65, mice ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l51', 'l56', 'l58', 'l60']", + "71, mice. ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l52', 'l57', 'l59', 'l60']", + "76, stem ['l53', 'l61']", + "77, cells ['l54', 'l61']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "germ", + "cells", + "stem" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "infertile", + "Sl/Sld", + "mutant", + "Wv/W54" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "infertile", + "Sl/Sld", + "mutant", + "Wv/W54" + ] + }, + "context": { + "val": "organism", + "words": [ + "male", + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "10581087", + "TEXT": "The possibility that glucocorticoids upregulate the expression of anti-inflammatory mediators is an exciting prospect for therapy in inflammatory diseases, because these molecules could give the therapeutic benefits of steroids without toxic side effects. Supernatants from monocytes and macrophages cultured in the presence of glucocorticoids increase the dispersion of neutrophils from a cell pellet in the capillary tube migration assay. This supernatant factor, unlike other neutrophil agonists, promotes dispersive locomotion of neutrophils at uniform concentration, lowers their adhesion to endothelial cells, inhibits their chemotactic response to fMLP and induces distinctive morphological changes. Here we show that thymosin beta4 sulfoxide is generated by monocytes in the presence of glucocorticoids and acts as a signal to inhibit an inflammatory response. In vitro, thymosin beta4 sulfoxide inhibited neutrophil chemotaxis, and in vivo, the oxidized peptide, but not the native form, was a potent inhibitor of carrageenin-induced edema in the mouse paw. Thymosin beta4 is unique, because oxidation attenuates its intracellular G-actin sequestering activity, but greatly enhances its extracellular signaling properties. This description of methionine oxidation conferring extracellular function on a cytosolic protein may have far-reaching implications for future strategies of anti-inflammatory therapy.", + "TAG_DATA": [ + "117, In {'context': 'B-in vitro'}", + "118, vitro, {'context': 'I-in vitro'}", + "122, inhibited {'effect': 'B-negative'}", + "123, neutrophil {'context': 'B-cells'}", + "124, chemotaxis, {'phenotype': 'B-migration'}", + "126, in {'context': 'B-in vivo'}", + "127, vivo, {'context': 'I-in vivo'}", + "145, mouse {'context': 'B-tissue/organ'}", + "146, paw. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "117, In ['l0', 'l1', 'l2', 'l3']", + "118, vitro, ['l0', 'l4', 'l5', 'l6']", + "122, inhibited ['l1', 'l4', 'l7', 'l8']", + "123, neutrophil ['l2', 'l5', 'l7', 'l9']", + "124, chemotaxis, ['l3', 'l6', 'l8', 'l9']", + "126, in ['l10', 'l11', 'l12']", + "127, vivo, ['l10', 'l13', 'l14']", + "145, mouse ['l11', 'l13', 'l15']", + "146, paw. ['l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "neutrophil" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neutrophil" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis," + ] + } + } + ] + }, + { + "PMID": "10581085", + "TEXT": "Familial hypertrophic cardiomyopathy is a clinically and genetically diverse autosomal dominant disorder characterized by ventricular hypertrophy and myocyte disarray in the absence of known hypertrophic stimuli. It has been linked to many cardiac contractile proteins, including four point mutations in alpha-tropomyosin (Tm). Here we use adenoviral-mediated gene transfer into adult cardiac myocytes in vitro to show that all four hypertrophic cardiomyopathy alpha-Tm proteins can be expressed and incorporated into normal sarcomeric structures in cardiac myocytes at similar levels as normal alpha-Tm proteins after 5-6 days in culture. Isometric force recordings of single cardiac myocytes demonstrated inappropriate increased force output at submaximal calcium concentration with a specific mutant allele hierarchy. These data indicate that the severity of direct calcium-sensitizing effect of mutations in alpha-Tm may predict the clinical severity of mutant alpha-Tm-associated hypertrophic cardiomyopathy.", + "TAG_DATA": [ + "49, adult {'context': 'B-cells'}", + "50, cardiac {'context': 'I-cells'}", + "51, myocytes {'context': 'I-cells'}", + "52, in {'context': 'B-in vitro'}", + "53, vitro {'context': 'I-in vitro'}", + "73, cardiac {'context': 'B-cells'}", + "92, cardiac {'context': 'B-cells'}", + "93, myocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "49, adult ['l0', 'l1', 'l2', 'l3', 'l4']", + "50, cardiac ['l0', 'l5', 'l6', 'l7', 'l8']", + "51, myocytes ['l1', 'l5', 'l9', 'l10', 'l11']", + "52, in ['l2', 'l6', 'l9', 'l12', 'l13']", + "53, vitro ['l3', 'l7', 'l10', 'l12', 'l14']", + "73, cardiac ['l4', 'l8', 'l11', 'l13', 'l14']", + "92, cardiac ['l15']", + "93, myocytes ['l15']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10581082", + "TEXT": "We describe here a new strategy for the treatment of stroke, through the inhibition of NAALADase (N-acetylated-alpha-linked-acidic dipeptidase), an enzyme responsible for the hydrolysis of the neuropeptide NAAG (N-acetyl-aspartyl-glutamate) to N-acetyl-aspartate and glutamate. We demonstrate that the newly described NAALADase inhibitor 2-PMPA (2-(phosphonomethyl)pentanedioic acid) robustly protects against ischemic injury in a neuronal culture model of stroke and in rats after transient middle cerebral artery occlusion. Consistent with inhibition of NAALADase, we show that 2-PMPA increases NAAG and attenuates the ischemia-induced rise in glutamate. Both effects could contribute to neuroprotection. These data indicate that NAALADase inhibition may have use in neurological disorders in which excessive excitatory amino acid transmission is pathogenic.", + "TAG_DATA": [ + "51, neuronal {'context': 'B-cells'}", + "52, culture {'context': 'I-cells'}", + "53, model {'context': 'I-organism'}", + "58, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "51, neuronal ['l0', 'l1']", + "52, culture ['l0', 'l2']", + "53, model ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10581078", + "TEXT": "At present, little is known about the pathogenesis of acute virus-induced shock and pulmonary failure. A chief impediment in understanding the underlying disease mechanisms and developing treatment strategies has been the lack of a suitable animal model. This study describes a mouse model of virus-induced systemic shock and respiratory distress, and shows that blockade of the lymphotoxin beta receptor pathway reverses the disease.", + "TAG_DATA": [ + "41, mouse {'context': 'B-organism'}", + "42, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "41, mouse ['l0']", + "42, model ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10545996", + "TEXT": "With an organ transplant, hematopoietic donor cells are transferred to the recipient. To study the relevance of the resulting microchimerism for allograft acceptance, we analyzed a rat model of cyclosporine-induced tolerance for strongly incompatible heart allografts. Using a monoclonal antibody that detects a donor-specific CD45 allotype (RT7a), we selectively depleted donor leukocytes at different times after transplantation (days 0 or 18). Depletion was similarly effective at both times. However, only depletion on day 0 prevented tolerance induction and was associated with severe acute or chronic graft rejection. This indicates that passenger leukocytes have an essential immunomodulatory effect on the induction phase of allograft acceptance.", + "TAG_DATA": [ + "26, rat {'context': 'B-organism'}", + "27, model {'context': 'I-organism'}", + "50, donor {'context': 'B-cells'}", + "51, leukocytes {'context': 'I-cells'}", + "85, graft {'context': 'B-xenograft'}" + ], + "LINK_DATA": [ + "26, rat ['l0']", + "27, model ['l0']", + "50, donor ['l1']", + "51, leukocytes ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10545976", + "TEXT": "The mechanisms of protective immunity to parasite infections in humans are still elusive. Here, Woolhouse and Hagan discuss new evidence suggesting that the extremely slow development of acquired immunity to human schistosomes may depend on exposure to antigens from these worms after they die.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10502822", + "TEXT": "Idiopathic inflammatory bowel disease is a chronic relapsing condition. The role of stress in causing relapses of inflammatory bowel disease remains controversial. We now show that colitis induced in mice by dinitrobenzenesulfonic acid (DNBS) resolves by 6 weeks, but can subsequently be reactivated by stress plus a sub-threshold dose of DNBS, but not by DNBS alone. Stress reduced colonic mucin and increased colon permeability. Susceptibility to reactivation by stress required CD4+ lymphocytes and could be adoptively transferred. We conclude that stress reactivates experimental colitis by facilitating entry of luminal contents that activate previously sensitized CD4 cells in the colon.", + "TAG_DATA": [ + "29, mice {'context': 'B-organism'}", + "62, colon {'context': 'B-tissue/organ'}", + "70, CD4+ {'context': 'B-cells'}", + "71, lymphocytes {'context': 'I-cells'}", + "94, CD4 {'context': 'B-cells'}", + "95, cells {'context': 'I-cells'}", + "98, colon. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "62, colon ['l0', 'l1']", + "70, CD4+ ['l0', 'l2', 'l3', 'l4', 'l5']", + "71, lymphocytes ['l1', 'l2', 'l6', 'l7', 'l8']", + "94, CD4 ['l3', 'l6', 'l9', 'l10']", + "95, cells ['l4', 'l7', 'l9', 'l11']", + "98, colon. ['l5', 'l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10502820", + "TEXT": "Telomerase is a ribonucleoprotein enzyme that maintains the protective structures at the ends of eukaryotic chromosomes, called telomeres. In most human somatic cells, telomerase expression is repressed, and telomeres shorten progressively with each cell division. In contrast, most human tumors express telomerase, resulting in stabilized telomere length. These observations indicate that telomere maintenance is essential to the proliferation of tumor cells. We show here that expression of a mutant catalytic subunit of human telomerase results in complete inhibition of telomerase activity, reduction in telomere length and death of tumor cells. Moreover, expression of this mutant telomerase eliminated tumorigenicity in vivo. These observations demonstrate that disruption of telomere maintenance limits cellular lifespan in human cancer cells, thus validating human telomerase reverse transcriptase as an important target for the development of anti-neoplastic therapies.", + "TAG_DATA": [ + "65, expression {'perturbing_action': 'B-other'}", + "66, of {'perturbing_action': 'I-other'}", + "67, a {'perturbing_action': 'I-other'}", + "68, mutant {'perturbing_action': 'I-other'}", + "69, catalytic {'perturbing_action': 'I-other'}", + "70, subunit {'perturbing_action': 'I-other'}", + "71, of {'perturbing_action': 'I-other'}", + "72, human {'perturbing_action': 'I-other'}", + "73, telomerase {'perturbing_action': 'I-other'}", + "88, tumor {'context': 'B-transformed cells'}", + "89, cells. {'context': 'I-transformed cells'}", + "91, expression {'perturbing_action': 'B-other'}", + "92, of {'perturbing_action': 'I-other'}", + "93, this {'perturbing_action': 'I-other'}", + "94, mutant {'perturbing_action': 'I-other'}", + "95, telomerase {'perturbing_action': 'I-other'}", + "96, eliminated {'effect': 'B-negative'}", + "97, tumorigenicity {'phenotype': 'B-tumourigenesis'}", + "98, in {'context': 'B-in vivo'}", + "99, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "65, expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "66, of ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "67, a ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "68, mutant ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "69, catalytic ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "70, subunit ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "71, of ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "72, human ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "73, telomerase ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "88, tumor ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "89, cells. ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "91, expression ['l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "92, of ['l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "93, this ['l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "94, mutant ['l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "95, telomerase ['l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "96, eliminated ['l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "97, tumorigenicity ['l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "98, in ['l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "99, vivo. ['l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "a", + "mutant", + "catalytic", + "subunit", + "human", + "telomerase" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "this", + "mutant", + "telomerase" + ] + }, + "effect": { + "val": "negative", + "words": [ + "eliminated" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "this", + "mutant", + "telomerase" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "this", + "mutant", + "telomerase" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "eliminated" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "eliminated" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "10502817", + "TEXT": "The immune response to adenoviral vectors can induce inflammation and loss of transgene expression in transfected tissues. This would limit the use of adenovirus-mediated gene transfer in disease states in which long-term gene expression is required. While studying the effect of the anti-adenoviral immune response in transplantation, we found that transgene expression persisted in cardiac isografts transfected with an adenovirus encoding beta-galactosidase. Transfected grafts remained free of inflammation, despite the presence of an immune response to the vector. Thus, adenovirus-mediated gene transfer may have therapeutic value in cardiac transplantation and heart diseases. Furthermore, immunological limitations of adenoviral vectors for gene therapy are not universal for all tissue types.", + "TAG_DATA": [ + "54, cardiac {'context': 'B-tissue/organ'}", + "55, isografts {'context': 'I-xenograft'}", + "56, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "57, with {'perturbing_action': 'I-gene gain-of-function'}", + "58, an {'perturbing_action': 'I-gene gain-of-function'}", + "59, adenovirus {'perturbing_action': 'I-gene gain-of-function'}", + "63, grafts {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "54, cardiac ['l0']", + "55, isografts ['l0']", + "56, transfected ['l1', 'l2', 'l3']", + "57, with ['l1', 'l4', 'l5']", + "58, an ['l2', 'l4', 'l6']", + "59, adenovirus ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10502810", + "TEXT": "gammadelta T cells downregulate airways responsiveness to allergen challenge, possibly by controlling the 'repair' response of the airway epithelium to alphabeta T cell-mediated damage (pages 1150-1156).", + "TAG_DATA": [ + "1, T {'context': 'I-cells'}", + "2, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "1, T ['l0']", + "2, cells ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10470082", + "TEXT": "Hemophilia A is an X chromosome-linked recessive disorder resulting in defective or deficient factor VIII (FVIII) molecules, which, in its severe form, is a life-threatening and crippling hemorrhagic disease. Infusion of homologous FVIII to patients with severe hemophilia A results, in 25% of patients, in the emergence of alloantibodies against FVIII (inhibitors)( ref. 1) that inhibit FVIII procoagulant activity by steric hindrance of the interaction of FVIII either with stabilizing molecules, with molecules essential for its activity or with activating molecules. Here, we report on the proteolysis of FVIII by alloantibodies of two patients with severe hemophilia A, demonstrating a previously unknown mechanism by which FVIII inhibitors may prevent the pro-coagulant function of FVIII. The kinetic parameters of FVIII hydrolysis indicate a functional role for the catalytic immune response in the inactivation of FVIII in vivo. The characterization of alloantibodies against FVIII as site-specific proteases may provide new approaches to the treatment of FVIII inhibitors.", + "TAG_DATA": [ + "134, in {'context': 'B-in vivo'}", + "135, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "134, in ['l0']", + "135, vivo. ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10470077", + "TEXT": "CD39, or vascular adenosine triphosphate diphosphohydrolase, has been considered an important inhibitor of platelet activation. Unexpectedly, cd39-deficient mice had prolonged bleeding times with minimally perturbed coagulation parameters. Platelet interactions with injured mesenteric vasculature were considerably reduced in vivo and purified mutant platelets failed to aggregate to standard agonists in vitro. This platelet hypofunction was reversible and associated with purinergic type P2Y1 receptor desensitization. In keeping with deficient vascular protective mechanisms, fibrin deposition was found at multiple organ sites in cd39-deficient mice and in transplanted cardiac grafts. Our data indicate a dual role for adenosine triphosphate diphosphohydrolase in modulating hemostasis and thrombotic reactions.", + "TAG_DATA": [ + "16, cd39-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "17, mice {'context': 'B-organism'}", + "36, in {'context': 'B-in vivo'}", + "37, vivo {'context': 'I-in vivo'}", + "41, platelets {'context': 'B-cells'}", + "48, in {'context': 'B-in vitro'}", + "49, vitro. {'context': 'I-in vitro'}", + "79, cd39-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "80, mice {'context': 'B-organism'}", + "83, transplanted {'context': 'B-xenograft'}", + "84, cardiac {'context': 'I-xenograft'}", + "85, grafts. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "16, cd39-deficient ['l0', 'l1']", + "17, mice ['l0']", + "36, in ['l2']", + "37, vivo ['l1', 'l2']", + "41, platelets ['l3', 'l4']", + "48, in ['l3', 'l5']", + "49, vitro. ['l4', 'l5']", + "79, cd39-deficient ['l6', 'l7', 'l8', 'l9']", + "80, mice ['l6', 'l10']", + "83, transplanted ['l7', 'l11', 'l12']", + "84, cardiac ['l8', 'l11', 'l13']", + "85, grafts. ['l9', 'l10', 'l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cd39-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cd39-deficient" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cd39-deficient" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "transplanted", + "cardiac", + "grafts." + ] + } + } + ] + }, + { + "PMID": "10470065", + "TEXT": "The discovery and study of three kindreds with advanced sleep phase disorder shed light on how we can inherit tendencies to be early morning or late night kinds of people (pages 1062-1065).", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10470061", + "TEXT": "Somatic cell nuclear 'reprogramming' in livestock species is now routine in many laboratories. Here, Robert Lanza, Jose Cibelli and Michael West discuss how these techniques may soon be used to clone genetically matched cells and tissues for transplantation into patients suffering from a wide range of disorders that result from tissue loss or dysfunction.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10426317", + "TEXT": "Serotype M1 group A Streptococcus strains cause epidemic waves of human infections long thought to be mono- or pauciclonal. The gene encoding an extracellular group A Streptococcus protein (streptococcal inhibitor of complement) that inhibits human complement was sequenced in 1,132 M1 strains recovered from population-based surveillance of infections in Canada, Finland and the United States. Epidemic waves are composed of strains expressing a remarkably heterogeneous array of variants of streptococcal inhibitor of complement that arise very rapidly by natural selection on mucosal surfaces. Thus, our results enhance the understanding of pathogen population dynamics in epidemic waves and infectious disease reemergence.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10426312", + "TEXT": "Leptin, the product of the Obese (Lep) gene, orchestrates behavioral and metabolic responses to nutrient intake. Here, we demonstrate tissue-specific autoregulation of Lep. Moderate increases in circulating leptin considerably decreased Lep expression in adipose tissue and induced lep expression in skeletal muscle, a tissue that normally does not express this gene. Changes in nutrient availability resulted in rapid alterations in Lep autoregulation. These findings demonstrate negative feedback regulation of Lep in fat, and indicate that leptin secretion can function as a vehicle of 'cross-talk' between adipose tissue and skeletal muscle, leading to tissue-specific modulation of the 'leptin signal'.", + "TAG_DATA": [ + "33, adipose {'context': 'B-tissue/organ'}", + "34, tissue {'context': 'I-tissue/organ'}", + "40, skeletal {'context': 'B-tissue/organ'}", + "41, muscle, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "33, adipose ['l0']", + "34, tissue ['l0']", + "40, skeletal ['l1']", + "41, muscle, ['l1']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10426311", + "TEXT": "Febrile (fever-induced) seizures affect 3-5% of infants and young children. Despite the high incidence of febrile seizures, their contribution to the development of epilepsy later in life has remained controversial. Combining a new rat model of complex febrile seizures and patch clamp techniques, we determined that hyperthermia-induced seizures in the immature rat cause a selective presynaptic increase in inhibitory synaptic transmission in the hippocampus that lasts into adulthood. The long-lasting nature of these potent alterations in synaptic communication after febrile seizures does not support the prevalent view of the 'benign' nature of early-life febrile convulsions.", + "TAG_DATA": [ + "50, immature {'context': 'B-organism'}", + "51, rat {'context': 'I-organism'}", + "63, hippocampus {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "50, immature ['l0', 'l1']", + "51, rat ['l0', 'l2']", + "63, hippocampus ['l1', 'l2']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10426310", + "TEXT": "The occurrence of multiple tumors in an organ heralds a rapidly fatal course. Although intravascular administration may deliver oncolytic viruses/vectors to each of these tumors, its efficiency is impeded by an antiviral activity present in complement-depleted plasma of rodents and humans. Here, this activity was shown to interact with complement in a calcium-dependent fashion, and antibody neutralization studies indicated preimmune IgM has a contributing role. Short-term exposure to cyclophosphamide (CPA) partially suppressed this activity in rodents and humans. At longer time points, cyclophosphamide also abrogated neutralizing antibody responses. Cyclophosphamide treatment of rats with large single or multiple intracerebral tumors substantially increased viral survival and propagation, leading to neoplastic regression.", + "TAG_DATA": [ + "75, rodents {'context': 'B-organism'}", + "77, humans. {'context': 'B-organism'}", + "91, rats {'context': 'B-organism'}", + "97, intracerebral {'context': 'B-neoplasm'}", + "98, tumors {'context': 'I-neoplasm'}", + "105, leading {'effect': 'B-positive'}", + "106, to {'effect': 'I-positive'}", + "107, neoplastic {'phenotype': 'B-tumour regression'}", + "108, regression. {'phenotype': 'I-tumour regression'}" + ], + "LINK_DATA": [ + "75, rodents ['l0']", + "77, humans. ['l0']", + "91, rats ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "94, single ['l1', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "96, multiple ['l2', 'l9', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "97, intracerebral ['l3', 'l10', 'l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "98, tumors ['l4', 'l11', 'l17', 'l22', 'l27', 'l28', 'l29', 'l30']", + "105, leading ['l5', 'l12', 'l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "106, to ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "107, neoplastic ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "108, regression. ['l8', 'l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "rats" + ] + }, + "effect": { + "val": "positive", + "words": [ + "leading", + "to" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rats" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "neoplastic", + "regression." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "intracerebral", + "tumors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "leading", + "to" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "intracerebral", + "tumors" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "neoplastic", + "regression." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "leading", + "to" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "neoplastic", + "regression." + ] + } + } + ] + }, + { + "PMID": "10395329", + "TEXT": "'Naked' nucleic acid vaccines are potentially useful candidates for the treatment of patients with cancer, but their clinical efficacy has yet to be demonstrated. We sought to enhance the immunogenicity of a nucleic acid vaccine by making it 'self-replicating'. We accomplished this by using a gene encoding an RNA replicase polyprotein derived from the Semliki forest virus, in combination with a model antigen. A single intramuscular injection of a self-replicating RNA immunogen elicited antigen-specific antibody and CD8+ T-cell responses at doses as low as 0.1 microg. Pre-immunization with a self-replicating RNA vector protected mice from tumor challenge, and therapeutic immunization prolonged the survival of mice with established tumors. The self-replicating RNA vectors did not mediate the production of substantially more model antigen than a conventional DNA vaccine did in vitro. However, the enhanced efficacy in vivo correlated with a caspase-dependent apoptotic death in transfected cells. This death facilitated the uptake of apoptotic cells by dendritic cells, providing a potential mechanism for enhanced immunogenicity. Naked, non-infectious, self-replicating RNA may be an excellent candidate for the development of new cancer vaccines.", + "TAG_DATA": [ + "76, CD8+ {'context': 'B-cells'}", + "93, mice {'context': 'B-organism'}", + "104, mice {'context': 'B-organism'}", + "107, tumors. {'context': 'B-neoplasm'}", + "128, in {'context': 'B-in vitro'}", + "129, vitro. {'context': 'I-in vitro'}", + "134, in {'context': 'B-in vivo'}", + "135, vivo {'context': 'I-in vivo'}", + "140, apoptotic {'phenotype': 'B-apoptosis'}", + "141, death {'phenotype': 'I-apoptosis'}", + "143, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "144, cells. {'context': 'B-cells'}", + "154, dendritic {'context': 'B-cells'}", + "155, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "76, CD8+ ['l0']", + "93, mice ['l0']", + "104, mice ['l1']", + "107, tumors. ['l1']", + "128, in ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "129, vitro. ['l2', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "134, in ['l3', 'l11', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "135, vivo ['l4', 'l12', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "140, apoptotic ['l5', 'l13', 'l20', 'l26', 'l32', 'l33', 'l34', 'l35', 'l36']", + "141, death ['l6', 'l14', 'l21', 'l27', 'l32', 'l37', 'l38', 'l39', 'l40']", + "143, transfected ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l41', 'l42', 'l43']", + "144, cells. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l44', 'l45']", + "154, dendritic ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l46']", + "155, cells, ['l10', 'l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l46']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells.", + "dendritic", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells.", + "dendritic", + "cells," + ] + } + } + ] + }, + { + "PMID": "10395320", + "TEXT": "Synovial tissue affected by rheumatoid arthritis is characterized by proliferation, which leads to irreversible cartilage and bone destruction. Current and experimental treatments have been aimed mainly at correcting the underlying immune abnormalities, but these treatments often prove ineffective in preventing the invasive destruction. We studied the expression of cyclin-dependent kinase inhibitors in rheumatoid synovial cells as a means of suppressing synovial cell proliferation. Synovial cells derived from hypertrophic synovial tissue readily expressed p16INK4a when they were growth-inhibited. This was not seen in other fibroblasts, including those derived from normal and osteoarthritis-affected synovial tissues. In vivo adenoviral gene therapy with the p16INK4a gene efficiently inhibited the pathology in an animal model of rheumatoid arthritis. Thus, the induction of p16INK4a may provide a new approach to the effective treatment of rheumatoid arthritis.", + "TAG_DATA": [ + "52, rheumatoid {'context': 'B-cells'}", + "53, synovial {'context': 'I-cells'}", + "54, cells {'context': 'I-cells'}", + "59, suppressing {'effect': 'B-negative'}", + "60, synovial {'context': 'B-cells'}", + "61, cell {'context': 'I-cells'}", + "62, proliferation. {'phenotype': 'B-proliferation'}", + "63, Synovial {'context': 'B-cells'}", + "64, cells {'context': 'I-cells'}", + "65, derived {'context': 'I-cells'}", + "66, from {'context': 'I-cells'}", + "83, fibroblasts, {'context': 'B-cells'}", + "93, In {'context': 'B-in vivo'}", + "94, vivo {'context': 'I-in vivo'}", + "95, adenoviral {'perturbing_action': 'B-gene gain-of-function'}", + "96, gene {'perturbing_action': 'I-gene gain-of-function'}", + "97, therapy {'perturbing_action': 'I-gene gain-of-function'}", + "98, with {'perturbing_action': 'I-gene gain-of-function'}", + "99, the {'perturbing_action': 'I-gene gain-of-function'}", + "100, p16INK4a {'perturbing_action': 'I-gene gain-of-function'}", + "101, gene {'perturbing_action': 'I-gene gain-of-function'}", + "108, animal {'context': 'B-organism'}", + "109, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "52, rheumatoid ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "53, synovial ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "54, cells ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "59, suppressing ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "60, synovial ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "61, cell ['l4', 'l14', 'l23', 'l31', 'l38', 'l44', 'l45', 'l46']", + "62, proliferation. ['l5', 'l15', 'l24', 'l32', 'l39', 'l44', 'l47', 'l48']", + "63, Synovial ['l6', 'l16', 'l25', 'l33', 'l49', 'l50', 'l51', 'l52', 'l53']", + "64, cells ['l7', 'l17', 'l26', 'l34', 'l40', 'l45', 'l47', 'l49', 'l54', 'l55', 'l56', 'l57']", + "65, derived ['l8', 'l18', 'l27', 'l35', 'l41', 'l50', 'l54', 'l58', 'l59', 'l60']", + "66, from ['l9', 'l19', 'l28', 'l36', 'l42', 'l51', 'l55', 'l58', 'l61', 'l62']", + "69, tissue ['l10', 'l20', 'l29', 'l37', 'l43', 'l46', 'l48', 'l52', 'l56', 'l59', 'l61', 'l63']", + "83, fibroblasts, ['l53', 'l57', 'l60', 'l62', 'l63']", + "93, In ['l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "94, vivo ['l64', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "95, adenoviral ['l65', 'l74', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "96, gene ['l66', 'l75', 'l83', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "97, therapy ['l67', 'l76', 'l84', 'l91', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "98, with ['l68', 'l77', 'l85', 'l92', 'l98', 'l104', 'l105', 'l106', 'l107', 'l108']", + "99, the ['l69', 'l78', 'l86', 'l93', 'l99', 'l104', 'l109', 'l110', 'l111', 'l112']", + "100, p16INK4a ['l70', 'l79', 'l87', 'l94', 'l100', 'l105', 'l109', 'l113', 'l114', 'l115']", + "101, gene ['l71', 'l80', 'l88', 'l95', 'l101', 'l106', 'l110', 'l113', 'l116', 'l117']", + "108, animal ['l72', 'l81', 'l89', 'l96', 'l102', 'l107', 'l111', 'l114', 'l116', 'l118']", + "109, model ['l73', 'l82', 'l90', 'l97', 'l103', 'l108', 'l112', 'l115', 'l117', 'l118']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "rheumatoid", + "synovial", + "cells", + "cell", + "Synovial", + "derived", + "from" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressing" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "rheumatoid", + "synovial", + "cells", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressing" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral", + "gene", + "therapy", + "with", + "the", + "p16INK4a" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral", + "gene", + "therapy", + "with", + "the", + "p16INK4a" + ] + }, + "context": { + "val": "organism", + "words": [ + "animal", + "model" + ] + } + } + ] + }, + { + "PMID": "10371509", + "TEXT": "Serum amyloid P component (SAP), a highly conserved plasma protein named for its universal presence in amyloid deposits, is the single normal circulating protein that shows specific calcium-dependent binding to DNA and chromatin in physiological conditions. The avid binding of SAP displaces H1-type histones and thereby solubilizes native long chromatin, which is otherwise profoundly insoluble at the physiological ionic strength of extracellular fluids. Furthermore, SAP binds in vivo both to apoptotic cells, the surface blebs of which bear chromatin fragments, and to nuclear debris released by necrosis. SAP may therefore participate in handling of chromatin exposed by cell death. Here we show that mice with targeted deletion of the SAP gene spontaneously develop antinuclear autoimmunity and severe glomerulonephritis, a phenotype resembling human systemic lupus erythematosus, a serious autoimmune disease. The SAP-/- mice also have enhanced anti-DNA responses to immunization with extrinsic chromatin, and we demonstrate that degradation of long chromatin is retarded in the presence of SAP both in vitro and in vivo. These findings indicate that SAP has an important physiological role, inhibiting the formation of pathogenic autoantibodies against chromatin and DNA, probably by binding to chromatin and regulating its degradation.", + "TAG_DATA": [ + "103, mice {'context': 'B-organism'}", + "105, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "106, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "107, of {'perturbing_action': 'I-gene loss-of-function'}", + "108, the {'perturbing_action': 'I-gene loss-of-function'}", + "109, SAP {'perturbing_action': 'I-gene loss-of-function'}", + "110, gene {'perturbing_action': 'I-gene loss-of-function'}", + "130, SAP-/- {'perturbing_action': 'B-gene loss-of-function'}", + "131, mice {'context': 'B-organism'}", + "158, in {'context': 'B-in vitro'}", + "159, vitro {'context': 'I-in vitro'}", + "161, in {'context': 'B-in vivo'}", + "162, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "103, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "105, targeted ['l5', 'l6', 'l7', 'l8', 'l9']", + "106, deletion ['l0', 'l5', 'l10', 'l11', 'l12', 'l13']", + "107, of ['l1', 'l6', 'l10', 'l14', 'l15', 'l16']", + "108, the ['l2', 'l7', 'l11', 'l14', 'l17', 'l18']", + "109, SAP ['l3', 'l8', 'l12', 'l15', 'l17', 'l19']", + "110, gene ['l4', 'l9', 'l13', 'l16', 'l18', 'l19']", + "130, SAP-/- ['l20', 'l21', 'l22']", + "131, mice ['l20']", + "158, in ['l21', 'l23', 'l24', 'l25']", + "159, vitro ['l22', 'l23', 'l26', 'l27']", + "161, in ['l24', 'l26', 'l28']", + "162, vivo. ['l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "SAP", + "gene", + "SAP-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SAP-/-" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "10371503", + "TEXT": "The size of the pool of resting CD4+ T cells containing replication-competent HIV in the blood of patients receiving intermittent interleukin (IL)-2 plus highly active anti-retroviral therapy (HAART) was significantly lower than that of patients receiving HAART alone. Virus could not be isolated from the peripheral blood CD4+ T cells in three patients receiving IL-2 plus HAART, despite the fact that large numbers of resting CD4+ T cells were cultured. Lymph node biopsies were done in two of these three patients and virus could not be isolated. These results indicate that the intermittent administration of IL-2 with continuous HAART may lead to a substantial reduction in the pool of resting CD4+ T cells that contain replication-competent HIV.", + "TAG_DATA": [ + "45, peripheral {'context': 'B-cells'}", + "46, blood {'context': 'I-cells'}", + "47, CD4+ {'context': 'I-cells'}", + "48, T {'context': 'I-cells'}", + "49, cells {'context': 'I-cells'}", + "64, resting {'context': 'B-cells'}", + "65, CD4+ {'context': 'I-cells'}", + "66, T {'context': 'I-cells'}", + "67, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, peripheral ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "46, blood ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "47, CD4+ ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "48, T ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "49, cells ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "64, resting ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "65, CD4+ ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "66, T ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "67, cells ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10371502", + "TEXT": "Vaccine strategies aimed at blocking virus entry have so far failed to induce protection against heterologous viruses. Thus, the control of viral infection and the block of disease onset may represent a more achievable goal of human immunodeficiency virus (HIV) vaccine strategies. Here we show that vaccination of cynomolgus monkeys with a biologically active HIV-1 Tat protein is safe, elicits a broad (humoral and cellular) specific immune response and reduces infection with the highly pathogenic simian-human immunodeficiency virus (SHIV)-89.6P to undetectable levels, preventing the CD4+ T-cell decrease. These results may provide new opportunities for the development of a vaccine against AIDS.", + "TAG_DATA": [ + "48, cynomolgus {'context': 'B-organism'}", + "49, monkeys {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "48, cynomolgus ['l0']", + "49, monkeys ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10371501", + "TEXT": "The HIV-1 Rev protein facilitates the nuclear export of mRNA containing the Rev response element (RRE) through binding to the export receptor CRM-1. Here we show that a cellular nuclear protein, Sam68 (Src-associated protein in mitosis), specifically interacts with RRE and can partially substitute for as well as synergize with Rev in RRE-mediated gene expression and virus replication. Differential sensitivity to leptomycin B, an inhibitor of CRM-1, indicates that the export pathways mediated by Rev and Sam68 are distinct. C-terminally deleted mutants of Sam68 inhibited the transactivation of RRE-mediated expression by both wild-type Sam68 and Rev. They were retained in the cytoplasm and impeded the nuclear localization of Rev in co-expressed cells. These mutants also inhibited wild-type HIV-1 replication to the same extent as the RevM10 mutant, and may be useful as anti-viral agents in the treatment of AIDS.", + "TAG_DATA": [ + "79, C-terminally {'perturbing_action': 'B-other'}", + "80, deleted {'perturbing_action': 'I-gene loss-of-function'}", + "81, mutants {'perturbing_action': 'I-other'}", + "82, of {'perturbing_action': 'I-other'}", + "83, Sam68 {'perturbing_action': 'I-other'}", + "111, cells. {'context': 'B-cells'}", + "125, RevM10 {'perturbing_action': 'B-other'}" + ], + "LINK_DATA": [ + "79, C-terminally ['l0', 'l1', 'l2', 'l3', 'l4']", + "80, deleted ['l0', 'l5', 'l6', 'l7', 'l8']", + "81, mutants ['l1', 'l5', 'l9', 'l10', 'l11']", + "82, of ['l2', 'l6', 'l9', 'l12', 'l13']", + "83, Sam68 ['l3', 'l7', 'l10', 'l12', 'l14']", + "111, cells. ['l4', 'l8', 'l11', 'l13', 'l14']", + "125, RevM10 ['l15']", + "126, mutant, ['l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "C-terminally", + "mutants", + "of", + "Sam68" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deleted" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "10229233", + "TEXT": "The transcription factor NF-kappaB is a regulator of cell death or survival. To investigate the role of NF-kappaB in neuronal cell death, we studied its activation in a rodent model of stroke. In the ischemic hemisphere, NF-kappaB was activated, as determined by increased expression of an NF-kappaB-driven reporter transgene, nuclear translocation of NF-kappaB in neurons and enhanced DNA binding of NF-kappaB subunits RelA and p50. In p50 knockout mice, ischemic damage was significantly reduced. This indicates a cell death-promoting role of NF-kappaB in focal ischemia. NF-kappaB may provide a new pharmacological target in neurologic disease.", + "TAG_DATA": [ + "54, neurons {'context': 'B-cells'}", + "66, p50 {'perturbing_action': 'B-gene loss-of-function'}", + "67, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "68, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "66, p50 ['l0', 'l1']", + "67, knockout ['l0', 'l2']", + "68, mice, ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p50", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "10229231", + "TEXT": "Programmed cell death is a process required for the normal development of an organism. One of the best understood apoptotic pathways occurs in T lymphocytes and is mediated by Fas/Fas ligand (FasL) interaction. During studies of apoptosis induced by T cell-receptor engagement, we identified ALG-4F, a truncated transcript that prevents T cell-receptor-induced FasL upregulation and cell death. Overexpression of full-length ALG-4 induced transcription of FasL and, consequently, apoptosis. These results indicate that ALG-4 is necessary and sufficient for FasL expression. Fas/FasL interaction initiates cell death in many other systems, and its dysregulation is a mechanism by which several pathologic conditions arise. Understanding the molecular mechanisms of FasL regulation could be very useful in elucidating how these diseases develop and in identifying potential therapeutic targets.", + "TAG_DATA": [ + "49, prevents {'effect': 'B-negative'}", + "55, cell {'phenotype': 'B-cell death'}", + "56, death. {'phenotype': 'I-cell death'}", + "57, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "58, of {'perturbing_action': 'I-gene gain-of-function'}", + "59, full-length {'perturbing_action': 'I-gene gain-of-function'}", + "60, ALG-4 {'perturbing_action': 'I-gene gain-of-function'}", + "67, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "49, prevents ['l0', 'l1']", + "55, cell ['l0', 'l2']", + "56, death. ['l1', 'l2']", + "57, Overexpression ['l3', 'l4', 'l5', 'l6']", + "58, of ['l3', 'l7', 'l8', 'l9']", + "59, full-length ['l4', 'l7', 'l10', 'l11']", + "60, ALG-4 ['l5', 'l8', 'l10', 'l12']", + "67, apoptosis. ['l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "full-length", + "ALG-4" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "10229227", + "TEXT": "Combination therapy for HIV-1 infection can reduce plasma virus to undetectable levels, indicating that prolonged treatment might eradicate the infection. However, HIV-1 can persist in a latent form in resting CD4+ T cells. We measured the decay rate of this latent reservoir in 34 treated adults whose plasma virus levels were undetectable. The mean half-life of the latent reservoir was very long (43.9 months). If the latent reservoir consists of only 1 x 10(5) cells, eradication could take as long as 60 years. Thus, latent infection of resting CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective anti-retroviral therapy.", + "TAG_DATA": [ + "45, adults {'context': 'B-patient'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "10202934", + "TEXT": "Intracytoplasmic sperm injection has begun an era of considerable improvements in treating male infertility. Despite its success, questions remain about the dangers of transmitting traits responsible for male infertility, sex and autosomal chromosome aberrations and possible mental, physical and reproductive abnormalities. We report here the first births of rhesus monkeys produced by intracytoplasmic sperm injection at rates greater or equal to those reported by clinics. Essential assumptions about this process are flawed, as shown by results with the preclinical, nonhuman primate model and with clinically discarded specimens. Dynamic imaging demonstrated the variable position of the second meiotic spindle in relation to the first polar body; consequently, microinjection targeting is imprecise and potentially lethal. Intracytoplasmic sperm injection resulted in abnormal sperm decondensation, with the unusual retention of vesicle-associated membrane protein and the perinuclear theca, and the exclusion of the nuclear mitotic apparatus from the decondensing sperm nuclear apex. Male pronuclear remodeling in the injected oocytes was required before replication of either parental genome, indicating a unique G1-to-S transition checkpoint during zygotic interphase (the first cell cycle). These irregularities indicate that the intracytoplasmic sperm injection itself might lead to the observed increased chromosome anomalies.", + "TAG_DATA": [ + "48, rhesus {'context': 'B-organism'}", + "49, monkeys {'context': 'I-organism'}", + "153, oocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "48, rhesus ['l0']", + "49, monkeys ['l0']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "10086390", + "TEXT": "Familial hypertrophic cardiomyopathy (FHC) is a genetic disorder resulting from mutations in genes encoding sarcomeric proteins. This typically induces hyperdynamic ejection, impaired relaxation, delayed early filling, myocyte disarray and fibrosis, and increased chamber end-systolic stiffness. To better understand the disease pathogenesis, early (primary) abnormalities must be distinguished from evolving responses to the genetic defect. We did in vivo analysis using a mouse model of FHC with an Arg403Gln alpha-cardiac myosin heavy chain missense mutation, and used newly developed methods for assessing in situ pressure-volume relations. Hearts of young mutant mice (6 weeks old), which show no chamber morphologic or gross histologic abnormalities, had altered contraction kinetics, with considerably delayed pressure relaxation and chamber filling, yet accelerated systolic pressure rise. Older mutant mice (20 weeks old), which develop fiber disarray and fibrosis, had diastolic and systolic kinetic changes similar to if not slightly less than those of younger mice. However, the hearts of older mutant mice also showed hyperdynamic contraction, with increased end-systolic chamber stiffness, outflow tract pressure gradients and a lower cardiac index due to reduced chamber filling; all 'hallmarks' of human disease. These data provide new insights into the temporal evolution of FHC. Such data may help direct new therapeutic strategies to diminish disease progression.", + "TAG_DATA": [ + "56, in {'context': 'B-in vivo'}", + "57, vivo {'context': 'I-in vivo'}", + "61, mouse {'context': 'B-organism'}", + "62, model {'context': 'I-organism'}", + "67, Arg403Gln {'perturbing_action': 'B-other'}", + "68, alpha-cardiac {'perturbing_action': 'I-other'}", + "69, myosin {'perturbing_action': 'I-other'}", + "70, heavy {'perturbing_action': 'I-other'}", + "71, chain {'perturbing_action': 'I-other'}", + "72, missense {'perturbing_action': 'I-other'}", + "73, mutation, {'perturbing_action': 'I-other'}", + "85, Hearts {'context': 'B-tissue/organ'}", + "89, mice {'context': 'B-organism'}", + "121, mice {'context': 'B-organism'}", + "150, hearts {'context': 'B-tissue/organ'}", + "154, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "57, vivo ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "61, mouse ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "62, model ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "67, Arg403Gln ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "68, alpha-cardiac ['l4', 'l13', 'l21', 'l28', 'l34', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "69, myosin ['l5', 'l14', 'l22', 'l29', 'l35', 'l42', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "70, heavy ['l6', 'l15', 'l23', 'l30', 'l36', 'l43', 'l49', 'l55', 'l56', 'l57', 'l58', 'l59']", + "71, chain ['l7', 'l16', 'l24', 'l31', 'l37', 'l44', 'l50', 'l55', 'l60', 'l61', 'l62', 'l63']", + "72, missense ['l8', 'l17', 'l25', 'l32', 'l38', 'l45', 'l51', 'l56', 'l60', 'l64', 'l65', 'l66']", + "73, mutation, ['l9', 'l18', 'l26', 'l33', 'l39', 'l46', 'l52', 'l57', 'l61', 'l64', 'l67', 'l68']", + "85, Hearts ['l40', 'l47', 'l53', 'l58', 'l62', 'l65', 'l67', 'l69']", + "89, mice ['l41', 'l48', 'l54', 'l59', 'l63', 'l66', 'l68', 'l69']", + "150, hearts ['l70']", + "154, mice ['l70']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Arg403Gln", + "alpha-cardiac", + "myosin", + "heavy", + "chain", + "missense", + "mutation," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Arg403Gln", + "alpha-cardiac", + "myosin", + "heavy", + "chain", + "missense", + "mutation," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Arg403Gln", + "alpha-cardiac", + "myosin", + "heavy", + "chain", + "missense", + "mutation," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "Hearts" + ] + } + } + ] + }, + { + "PMID": "10086386", + "TEXT": "Human macrophages can be infected more efficiently by M-tropic than by T-tropic HIV-1 strains, despite surface expression of both CXCR4 and CCR5 co-receptors. Western blot analyses of total cell extracts and surface proteins from multiple sets of monocytes and macrophages demonstrated substantial differences between CXCR4 molecules. CXCR4 was mainly a monomer in monocytes, but was mainly a species of higher molecular weight (90 kDa) on the surface of macrophages. CCR5 was monomeric in both cell types. A constitutive association between CD4 and the co-receptors was seen in monocytes and macrophages. However, CD4 co-precipitated with CCR5 and CXCR4 monomers, but not with the high-molecular-weight forms of CXCR4, indicating that the high-molecular-weight CXCR4 species in macrophages are not available for association with CD4, which may contribute to the inefficient entry of T-tropic strains into mature macrophages.", + "TAG_DATA": [ + "75, types. {'context': 'I-cells'}" + ], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9930869", + "TEXT": "Virus-specific antibodies protect individuals against a wide variety of viral infections. To assess whether human immunodeficiency virus type 1 (HIV-1) envelope-specific antibodies confer resistance against primate lentivirus infections, we purified immunoglobulin (IgG) from chimpanzees infected with several different HIV-1 isolates, and used this for passive immunization of pig-tailed macaques. These monkeys were subsequently challenged intravenously with a chimeric simian-human immunodeficiency virus (SHIV) bearing an envelope glycoprotein derived form HIV-1DH12, a dual-tropic primary virus isolate. Here we show that anti-SHIV neutralizing activity, determined in vitro using an assay measuring loss of infectivity, is the absolute requirement for antibody-mediated protection in vivo. Using an assay that measures 100% neutralization, the titer in plasma for complete protection of the SHIV-challenged macaques was in the range of 1:5-1:8. The HIV-1-specific neutralizing antibodies studied are able to bind to native gp120 present on infectious virus particles. Administration of non-neutralizing anti-HIV IgG neither inhibited nor enhanced a subsequent SHIV infection.", + "TAG_DATA": [ + "33, chimpanzees {'context': 'B-organism'}", + "47, pig-tailed {'context': 'B-organism'}", + "48, macaques. {'context': 'I-organism'}", + "50, monkeys {'context': 'B-organism'}", + "117, macaques {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "33, chimpanzees ['l0', 'l1', 'l2']", + "47, pig-tailed ['l0', 'l3']", + "48, macaques. ['l1', 'l3']", + "50, monkeys ['l2', 'l4']", + "59, immunodeficiency ['l4']" + ], + "LINKED_TAGS": [] + }, + { + "PMID": "9930866", + "TEXT": "Here we report the genetic and proposed molecular basis for silver resistance in pathogenic microorganisms. The silver resistance determinant from a hospital burn ward Salmonella plasmid contains nine open reading frames, arranged in three measured and divergently transcribed RNAs. The resistance determinant encodes a periplasmic silver-specific binding protein (SilE) plus apparently two parallel efflux pumps: one, a P-type ATPase (SilP); the other, a membrane potential-dependent three-polypeptide cation/proton antiporter (SilCBA). The sil determinant is governed by a two-component membrane sensor and transcriptional responder comprising silS and silR, which are co-transcribed. The availability of the sil silver-resistance determinant will be the basis for mechanistic molecular and biochemical studies as well as molecular epidemiology of silver resistance in clinical settings in which silver is used as a biocide.", + "TAG_DATA": [], + "LINK_DATA": [], + "LINKED_TAGS": [] + }, + { + "PMID": "9930862", + "TEXT": "To evaluate the utility of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a cancer therapeutic, we created leucine zipper (LZ) forms of human (hu) and murine (mu) TRAIL to promote and stabilize the formation of trimers. Both were biologically active, inducing apoptosis of both human and murine target cells in vitro with similar specific activities. In contrast to the fulminant hepatotoxicity of LZ-huCD95L in vivo, administration of either LZ-huTRAIL or LZ-muTRAIL did not seem toxic to normal tissues of mice. Finally, repeated treatments with LZ-huTRAIL actively suppressed growth of the TRAIL-sensitive human mammary adenocarcinoma cell line MDA-231 in CB.17 (SCID) mice, and histologic examination of tumors from SCID mice treated with LZ-huTRAIL demonstrated clear areas of apoptotic necrosis within 9-12 hours of injection.", + "TAG_DATA": [ + "40, inducing {'effect': 'B-positive'}", + "41, apoptosis {'phenotype': 'B-apoptosis'}", + "44, human {'context': 'B-transformed cells'}", + "45, and {'context': 'I-transformed cells'}", + "46, murine {'context': 'I-transformed cells'}", + "47, target {'context': 'I-transformed cells'}", + "48, cells {'context': 'I-transformed cells'}", + "49, in {'context': 'B-in vitro'}", + "50, vitro {'context': 'I-in vitro'}", + "63, in {'context': 'B-in vivo'}", + "64, vivo, {'context': 'I-in vivo'}", + "76, normal {'context': 'B-tissue/organ'}", + "77, tissues {'context': 'I-tissue/organ'}", + "79, mice. {'context': 'B-organism'}", + "90, TRAIL-sensitive {'context': 'B-transformed cells'}", + "91, human {'context': 'I-transformed cells'}", + "92, mammary {'context': 'I-transformed cells'}", + "93, adenocarcinoma {'context': 'I-transformed cells'}", + "94, cell {'context': 'I-transformed cells'}", + "95, line {'context': 'I-transformed cells'}", + "96, MDA-231 {'context': 'I-transformed cells'}", + "98, CB.17 {'context': 'B-organism'}", + "100, mice, {'context': 'B-organism'}", + "105, tumors {'context': 'B-neoplasm'}", + "107, SCID {'context': 'B-organism'}", + "108, mice {'context': 'I-organism'}", + "116, apoptotic {'phenotype': 'B-apoptosis'}", + "117, necrosis {'phenotype': 'B-necrosis'}" + ], + "LINK_DATA": [ + "40, inducing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "41, apoptosis ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "44, human ['l1', 'l13', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "45, and ['l2', 'l14', 'l22', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "46, murine ['l3', 'l15', 'l23', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "47, target ['l4', 'l16', 'l24', 'l29', 'l34', 'l39', 'l40', 'l41']", + "48, cells ['l5', 'l17', 'l25', 'l30', 'l35', 'l39', 'l42', 'l43']", + "49, in ['l6', 'l18', 'l26', 'l31', 'l36', 'l40', 'l42', 'l44']", + "50, vitro ['l7', 'l19', 'l27', 'l32', 'l37', 'l41', 'l43', 'l44']", + "63, in ['l8', 'l45', 'l46', 'l47', 'l48']", + "64, vivo, ['l9', 'l20', 'l33', 'l38', 'l45', 'l49', 'l50', 'l51']", + "76, normal ['l10', 'l46', 'l49', 'l52', 'l53']", + "77, tissues ['l11', 'l21', 'l47', 'l50', 'l52', 'l54']", + "79, mice. ['l12', 'l48', 'l51', 'l53', 'l54']", + "90, TRAIL-sensitive ['l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "91, human ['l55', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "92, mammary ['l56', 'l67', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "93, adenocarcinoma ['l57', 'l68', 'l77', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "94, cell ['l58', 'l69', 'l78', 'l87', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "95, line ['l59', 'l70', 'l79', 'l88', 'l95', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "96, MDA-231 ['l60', 'l71', 'l80', 'l89', 'l96', 'l102', 'l108', 'l109', 'l110', 'l111', 'l112']", + "98, CB.17 ['l61', 'l72', 'l81', 'l90', 'l97', 'l103', 'l108', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "100, mice, ['l62', 'l73', 'l82', 'l91', 'l98', 'l104', 'l109', 'l113', 'l119', 'l120', 'l121', 'l122']", + "105, tumors ['l63', 'l74', 'l83', 'l92', 'l99', 'l105', 'l110', 'l114', 'l119', 'l123', 'l124', 'l125', 'l126']", + "107, SCID ['l115', 'l123', 'l127', 'l128', 'l129']", + "108, mice ['l64', 'l84', 'l116', 'l120', 'l124', 'l127', 'l130', 'l131']", + "116, apoptotic ['l65', 'l75', 'l85', 'l93', 'l100', 'l106', 'l111', 'l117', 'l121', 'l125', 'l128', 'l130', 'l132']", + "117, necrosis ['l66', 'l76', 'l86', 'l94', 'l101', 'l107', 'l112', 'l118', 'l122', 'l126', 'l129', 'l131', 'l132']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "and", + "murine", + "target", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "normal", + "tissues" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptotic" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "and", + "murine", + "target", + "cells", + "TRAIL-sensitive", + "mammary", + "adenocarcinoma", + "cell", + "line", + "MDA-231" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tissues" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "TRAIL-sensitive", + "human", + "mammary", + "adenocarcinoma", + "cell", + "line", + "MDA-231" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "CB.17", + "mice,", + "SCID", + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "CB.17", + "mice,", + "SCID", + "mice" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + } + ] + } +] \ No newline at end of file diff --git a/abstract_analysis/pubmed_tag_link_filtered.json b/abstract_analysis/pubmed_tag_link_filtered.json new file mode 100644 index 0000000..9826edc --- /dev/null +++ b/abstract_analysis/pubmed_tag_link_filtered.json @@ -0,0 +1,240610 @@ +[ + { + "PMID": "33398162", + "TEXT": "Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8+ T cells from systemic circulation. Within the liver, activated antigen-specific Fas+CD8+ T cells undergo apoptosis following their interaction with FasL+CD11b+F4/80+ monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8+ T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity.", + "TAG_DATA": [ + "60, mouse {'context': 'B-organism'}", + "61, models, {'context': 'I-organism'}", + "77, liver, {'context': 'B-tissue/organ'}", + "81, T {'context': 'I-cells'}", + "82, cells {'context': 'I-cells'}", + "83, undergo {'effect': 'B-positive'}", + "84, apoptosis {'phenotype': 'B-apoptosis'}", + "104, patients {'context': 'B-patient'}", + "107, metastases {'phenotype': 'I-metastasis'}", + "110, peripheral {'context': 'B-cells'}", + "111, T {'context': 'I-cells'}", + "112, cell {'context': 'I-cells'}", + "116, tumoral {'context': 'B-cells'}", + "117, T {'context': 'I-cells'}", + "118, cell {'context': 'I-cells'}", + "129, hepatic {'context': 'B-cells'}", + "130, macrophages, {'context': 'I-cells'}", + "132, hepatic {'context': 'B-cells'}", + "133, T {'context': 'I-cells'}", + "134, cell {'context': 'I-cells'}", + "141, T {'context': 'B-cells'}", + "142, cells. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "60, mouse ['l0', 'l1', 'l2']", + "61, models, ['l0', 'l3', 'l4']", + "77, liver, ['l1', 'l3', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "81, T ['l5', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "82, cells ['l2', 'l4', 'l6', 'l11', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "83, undergo ['l7', 'l12', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "84, apoptosis ['l8', 'l13', 'l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "104, patients ['l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "106, liver ['l34', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "107, metastases ['l35', 'l46', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "110, peripheral ['l14', 'l36', 'l47', 'l57', 'l66', 'l67', 'l68', 'l69', 'l70']", + "111, T ['l15', 'l21', 'l26', 'l30', 'l37', 'l48', 'l58', 'l66', 'l71', 'l72', 'l73', 'l74']", + "112, cell ['l9', 'l16', 'l22', 'l27', 'l31', 'l38', 'l49', 'l59', 'l67', 'l71', 'l75', 'l76', 'l77']", + "116, tumoral ['l39', 'l50', 'l60', 'l68', 'l72', 'l75', 'l78', 'l79']", + "117, T ['l17', 'l23', 'l28', 'l32', 'l40', 'l51', 'l61', 'l69', 'l73', 'l76', 'l78', 'l80']", + "118, cell ['l10', 'l18', 'l24', 'l29', 'l33', 'l41', 'l52', 'l62', 'l70', 'l74', 'l77', 'l79', 'l80']", + "123, preclinical ['l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "124, models, ['l42', 'l53', 'l63', 'l81', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "129, hepatic ['l43', 'l54', 'l64', 'l82', 'l89', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "130, macrophages, ['l44', 'l55', 'l65', 'l83', 'l90', 'l96', 'l102', 'l103', 'l104', 'l105', 'l106']", + "132, hepatic ['l84', 'l91', 'l97', 'l102', 'l107', 'l108', 'l109', 'l110']", + "133, T ['l85', 'l92', 'l98', 'l103', 'l107', 'l111', 'l112', 'l113']", + "134, cell ['l45', 'l56', 'l86', 'l93', 'l99', 'l104', 'l108', 'l111', 'l114', 'l115']", + "141, T ['l87', 'l94', 'l100', 'l105', 'l109', 'l112', 'l114', 'l116']", + "142, cells. ['l88', 'l95', 'l101', 'l106', 'l110', 'l113', 'l115', 'l116']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "liver," + ] + }, + "effect": { + "val": "positive", + "words": [ + "undergo" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "liver," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "undergo" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "undergo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + }, + "context": { + "val": "cells", + "words": [ + "peripheral", + "T", + "cell", + "tumoral", + "hepatic", + "macrophages," + ] + } + } + ] + }, + { + "PMID": "33106666", + "TEXT": "Acute liver failure (ALF) is a fulminant complication of multiple etiologies, characterized by rapid hepatic destruction, multi-organ failure and mortality. ALF treatment is mainly limited to supportive care and liver transplantation. Here we utilize the acetaminophen (APAP) and thioacetamide (TAA) ALF models in characterizing 56,527 single-cell transcriptomes to define the mouse ALF cellular atlas. We demonstrate that unique, previously uncharacterized stellate cell, endothelial cell, Kupffer cell, monocyte and neutrophil subsets, and their intricate intercellular crosstalk, drive ALF. We unravel a common MYC-dependent transcriptional program orchestrating stellate, endothelial and Kupffer cell activation during ALF, which is regulated by the gut microbiome through Toll-like receptor (TLR) signaling. Pharmacological inhibition of MYC, upstream TLR signaling checkpoints or microbiome depletion suppress this cell-specific, MYC-dependent program, thereby attenuating ALF. In humans, we demonstrate upregulated hepatic MYC expression in ALF transplant recipients compared to healthy donors. Collectively we demonstrate that detailed cellular/genetic decoding may enable pathway-specific ALF therapeutic intervention.", + "TAG_DATA": [ + "104, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "105, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "106, of {'perturbing_action': 'I-pharmacological inhibition'}", + "107, MYC, {'perturbing_action': 'I-pharmacological inhibition'}", + "124, humans, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "104, Pharmacological ['l0', 'l1', 'l2', 'l3']", + "105, inhibition ['l0', 'l4', 'l5']", + "106, of ['l1', 'l4', 'l6']", + "107, MYC, ['l2', 'l5', 'l6']", + "124, humans, ['l3']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological" + ] + }, + "context": { + "val": "organism", + "words": [ + "humans," + ] + } + } + ] + }, + { + "PMID": "33077955", + "TEXT": "An open question in aggressive cancers such as melanoma is how malignant cells can shift the immune system to pro-tumorigenic functions. Here we identify midkine (MDK) as a melanoma-secreted driver of an inflamed, but immune evasive, microenvironment that defines poor patient prognosis and resistance to immune checkpoint blockade. Mechanistically, MDK was found to control the transcriptome of melanoma cells, allowing for coordinated activation of nuclear factor-κB and downregulation of interferon-associated pathways. The resulting MDK-modulated secretome educated macrophages towards tolerant phenotypes that promoted CD8+ T cell dysfunction. In contrast, genetic targeting of MDK sensitized melanoma cells to anti-PD-1/anti-PD-L1 treatment. Emphasizing the translational relevance of these findings, the expression profile of MDK-depleted tumors was enriched in key indicators of a good response to immune checkpoint blockers in independent patient cohorts. Together, these data reveal that MDK acts as an internal modulator of autocrine and paracrine signals that maintain immune suppression in aggressive melanomas.", + "TAG_DATA": [ + "76, macrophages {'context': 'B-cells'}", + "82, CD8+ {'context': 'B-cells'}", + "83, T {'context': 'I-cells'}", + "84, cell {'context': 'I-cells'}", + "88, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "89, targeting {'perturbing_action': 'I-gene loss-of-function'}", + "90, of {'perturbing_action': 'I-gene loss-of-function'}", + "91, MDK {'perturbing_action': 'I-rnai/knockdown'}", + "93, melanoma {'context': 'B-transformed cells'}", + "94, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "76, macrophages ['l0', 'l1', 'l2']", + "82, CD8+ ['l0', 'l3', 'l4']", + "83, T ['l1', 'l3', 'l5']", + "84, cell ['l2', 'l4', 'l5']", + "88, genetic ['l6', 'l7', 'l8', 'l9', 'l10']", + "89, targeting ['l6', 'l11', 'l12', 'l13', 'l14']", + "90, of ['l7', 'l11', 'l15', 'l16', 'l17']", + "91, MDK ['l8', 'l12', 'l15', 'l18', 'l19']", + "93, melanoma ['l9', 'l13', 'l16', 'l18', 'l20']", + "94, cells ['l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "targeting", + "of" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "MDK" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cells" + ] + } + } + ] + }, + { + "PMID": "33046868", + "TEXT": "Vα24-invariant natural killer T (NKT) cells have shown potent anti-tumor properties in murine tumor models and have been linked to favorable outcomes in patients with cancer. However, low numbers of these cells in humans have hindered their clinical applications. Here we report interim results from all three patients enrolled on dose level 1 in a phase 1 dose-escalation trial of autologous NKT cells engineered to co-express a GD2-specific chimeric antigen receptor (CAR) with interleukin-15 in children with relapsed or resistant neuroblastoma (NCT03294954). Primary and secondary objectives were to assess safety and anti-tumor responses, respectively, with immune response evaluation as an additional objective. We ex vivo expanded highly pure NKT cells (mean ± s.d., 94.7 ± 3.8%) and treated patients with 3 × 106 CAR-NKT cells per square meter of body surface area after lymphodepleting conditioning with cyclophosphamide/fludarabine (Cy/Flu). Cy/Flu conditioning was the probable cause for grade 3-4 hematologic adverse events, as they occurred before CAR-NKT cell infusion, and no dose-limiting toxicities were observed. CAR-NKT cells expanded in vivo, localized to tumors and, in one patient, induced an objective response with regression of bone metastatic lesions. These initial results suggest that CAR-NKT cells can be expanded to clinical scale and safely applied to treat patients with cancer.", + "TAG_DATA": [ + "60, autologous {'context': 'B-cells'}", + "61, NKT {'context': 'I-cells'}", + "62, cells {'context': 'I-cells'}", + "75, children {'context': 'B-patient'}", + "77, relapsed {'context': 'B-neoplasm'}", + "78, or {'context': 'I-neoplasm'}", + "79, resistant {'context': 'I-neoplasm'}", + "80, neuroblastoma {'context': 'I-neoplasm'}", + "108, NKT {'context': 'I-cells'}", + "109, cells {'context': 'I-cells'}", + "118, patients {'context': 'B-patient'}", + "123, CAR-NKT {'context': 'B-cells'}", + "124, cells {'context': 'I-cells'}", + "163, CAR-NKT {'context': 'B-cells'}", + "164, cells {'context': 'I-cells'}", + "166, in {'context': 'B-in vivo'}", + "167, vivo, {'context': 'I-in vivo'}", + "170, tumors {'context': 'B-neoplasm'}", + "180, regression {'phenotype': 'B-tumour regression'}", + "182, bone {'phenotype': 'B-metastasis'}", + "183, metastatic {'phenotype': 'I-metastasis'}", + "184, lesions. {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "60, autologous ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "61, NKT ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "62, cells ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "75, children ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "77, relapsed ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "78, or ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37']", + "79, resistant ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l39', 'l40']", + "80, neuroblastoma ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l38', 'l41', 'l42']", + "108, NKT ['l7', 'l15', 'l22', 'l28', 'l33', 'l39', 'l41', 'l43', 'l44', 'l45', 'l46']", + "109, cells ['l8', 'l16', 'l23', 'l29', 'l34', 'l37', 'l40', 'l42', 'l43', 'l47']", + "118, patients ['l44', 'l48', 'l49']", + "123, CAR-NKT ['l45', 'l48', 'l50']", + "124, cells ['l46', 'l47', 'l49', 'l50']", + "163, CAR-NKT ['l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "164, cells ['l51', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "166, in ['l52', 'l59', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "167, vivo, ['l53', 'l60', 'l66', 'l72', 'l73', 'l74', 'l75', 'l76']", + "170, tumors ['l54', 'l61', 'l67', 'l72']", + "180, regression ['l55', 'l62', 'l68', 'l73', 'l77', 'l78', 'l79']", + "182, bone ['l56', 'l63', 'l69', 'l74', 'l77', 'l80', 'l81']", + "183, metastatic ['l57', 'l64', 'l70', 'l75', 'l78', 'l80', 'l82']", + "184, lesions. ['l58', 'l65', 'l71', 'l76', 'l79', 'l81', 'l82']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CAR-NKT", + "cells" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CAR-NKT", + "cells" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "bone", + "metastatic", + "lesions." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "bone", + "metastatic", + "lesions." + ] + } + } + ] + }, + { + "PMID": "33188278", + "TEXT": "Ribonucleoprotein (RNP) granules are biomolecular condensates-liquid-liquid phase-separated droplets that organize and manage messenger RNA metabolism, cell signaling, biopolymer assembly, biochemical reactions and stress granule responses to cellular adversity. Dysregulated RNP granules drive neuromuscular degenerative disease but have not previously been linked to heart failure. By exploring the molecular basis of congenital dilated cardiomyopathy (DCM) in genome-edited pigs homozygous for an RBM20 allele encoding the pathogenic R636S variant of human RNA-binding motif protein-20 (RBM20), we discovered that RNP granules accumulated abnormally in the sarcoplasm, and we confirmed this finding in myocardium and reprogrammed cardiomyocytes from patients with DCM carrying the R636S allele. Dysregulated sarcoplasmic RBM20 RNP granules displayed liquid-like material properties, docked at precisely spaced intervals along cytoskeletal elements, promoted phase partitioning of cardiac biomolecules and fused with stress granules. Our results link dysregulated RNP granules to myocardial cellular pathobiology and heart failure in gene-edited pigs and patients with DCM caused by RBM20 mutation.", + "TAG_DATA": [ + "56, pigs {'context': 'B-organism'}", + "57, homozygous {'perturbing_action': 'B-other'}", + "58, for {'perturbing_action': 'I-other'}", + "59, an {'perturbing_action': 'I-other'}", + "60, RBM20 {'perturbing_action': 'I-other'}", + "61, allele {'perturbing_action': 'I-other'}", + "62, encoding {'perturbing_action': 'I-other'}", + "63, the {'perturbing_action': 'I-other'}", + "64, pathogenic {'perturbing_action': 'I-other'}", + "65, R636S {'perturbing_action': 'I-other'}", + "66, variant {'perturbing_action': 'I-other'}", + "67, of {'perturbing_action': 'I-other'}", + "68, human {'perturbing_action': 'I-other'}", + "69, RNA-binding {'perturbing_action': 'I-other'}", + "70, motif {'perturbing_action': 'I-other'}", + "71, protein-20 {'perturbing_action': 'I-other'}", + "72, (RBM20), {'perturbing_action': 'I-other'}", + "89, myocardium {'context': 'B-tissue/organ'}", + "92, cardiomyocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "56, pigs ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "57, homozygous ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "58, for ['l1', 'l8', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "59, an ['l2', 'l9', 'l24', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "60, RBM20 ['l3', 'l10', 'l25', 'l39', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "61, allele ['l4', 'l11', 'l26', 'l40', 'l53', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "62, encoding ['l5', 'l12', 'l27', 'l41', 'l54', 'l66', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "63, the ['l6', 'l13', 'l28', 'l42', 'l55', 'l67', 'l78', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "64, pathogenic ['l14', 'l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "65, R636S ['l15', 'l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l100', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "66, variant ['l16', 'l31', 'l45', 'l58', 'l70', 'l81', 'l91', 'l101', 'l110', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "67, of ['l17', 'l32', 'l46', 'l59', 'l71', 'l82', 'l92', 'l102', 'l111', 'l119', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "68, human ['l18', 'l33', 'l47', 'l60', 'l72', 'l83', 'l93', 'l103', 'l112', 'l120', 'l127', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139']", + "69, RNA-binding ['l19', 'l34', 'l48', 'l61', 'l73', 'l84', 'l94', 'l104', 'l113', 'l121', 'l128', 'l134', 'l140', 'l141', 'l142', 'l143', 'l144']", + "70, motif ['l20', 'l35', 'l49', 'l62', 'l74', 'l85', 'l95', 'l105', 'l114', 'l122', 'l129', 'l135', 'l140', 'l145', 'l146', 'l147', 'l148']", + "71, protein-20 ['l21', 'l36', 'l50', 'l63', 'l75', 'l86', 'l96', 'l106', 'l115', 'l123', 'l130', 'l136', 'l141', 'l145', 'l149', 'l150', 'l151']", + "72, (RBM20), ['l22', 'l37', 'l51', 'l64', 'l76', 'l87', 'l97', 'l107', 'l116', 'l124', 'l131', 'l137', 'l142', 'l146', 'l149', 'l152', 'l153']", + "89, myocardium ['l7', 'l23', 'l38', 'l52', 'l65', 'l77', 'l88', 'l98', 'l108', 'l117', 'l125', 'l132', 'l138', 'l143', 'l147', 'l150', 'l152']", + "92, cardiomyocytes ['l99', 'l109', 'l118', 'l126', 'l133', 'l139', 'l144', 'l148', 'l151', 'l153']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "pigs" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "homozygous", + "for", + "an", + "RBM20", + "allele", + "encoding", + "the" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "homozygous", + "for", + "an", + "RBM20", + "allele", + "encoding", + "the", + "pathogenic", + "R636S", + "variant", + "of", + "human", + "RNA-binding", + "motif", + "protein-20", + "(RBM20)," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "myocardium" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "the", + "pathogenic", + "R636S", + "variant", + "of", + "human", + "RNA-binding", + "motif", + "protein-20", + "(RBM20)," + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes" + ] + } + } + ] + }, + { + "PMID": "33442015", + "TEXT": "Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1fl/fl;Postn-Cre mice with cabozantinib, an inhibitor of multiple tyrosine kinases, caused a reduction in PN size and number and differential modulation of kinases in cell lineages that drive PN growth. Based on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a phase II, open-label, nonrandomized Simon two-stage study to assess the safety, efficacy and biologic activity of cabozantinib in patients ≥16 years of age with NF1 and progressive or symptomatic, inoperable PN ( NCT02101736 ). The trial met its primary outcome, defined as ≥25% of patients achieving a partial response (PR, defined as ≥20% reduction in target lesion volume as assessed by magnetic resonance imaging (MRI)) after 12 cycles of therapy. Secondary outcomes included adverse events (AEs), patient-reported outcomes (PROs) assessing pain and quality of life (QOL), pharmacokinetics (PK) and the levels of circulating endothelial cells and cytokines. Eight of 19 evaluable (42%) trial participants achieved a PR. The median change in tumor volume was 15.2% (range, +2.2% to -36.9%), and no patients had disease progression while on treatment. Nine patients required dose reduction or discontinuation of therapy due to AEs; common AEs included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia. A total of 11 grade 3 AEs occurred in eight patients. Patients with PR had a significant reduction in tumor pain intensity and pain interference in daily life but no change in global QOL scores. These data indicate that cabozantinib is active in NF1-associated PN, resulting in tumor volume reduction and pain improvement.", + "TAG_DATA": [ + "21, Nf1fl/fl;Postn-Cre {'perturbing_action': 'B-gene loss-of-function'}", + "22, mice {'context': 'B-organism'}", + "80, patients {'context': 'B-patient'}", + "106, patients {'context': 'B-patient'}", + "173, tumor {'context': 'B-neoplasm'}", + "186, progression {'phenotype': 'I-tumour progression'}", + "232, tumor {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "21, Nf1fl/fl;Postn-Cre ['l0', 'l1', 'l2']", + "22, mice ['l0', 'l3', 'l4']", + "80, patients ['l1', 'l3', 'l5']", + "106, patients ['l2', 'l4', 'l5']", + "173, tumor ['l6']", + "186, progression ['l6']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nf1fl/fl;Postn-Cre" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nf1fl/fl;Postn-Cre" + ] + }, + "context": { + "val": "patient", + "words": [ + "patients" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "progression" + ] + } + } + ] + }, + { + "PMID": "33664492", + "TEXT": "Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors1. Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively coexpressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies2,3. Resistance to enzalutamide was associated with cancer cell-intrinsic epithelial-mesenchymal transition and transforming growth factor-β signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6 and NR1D2 (refs. 4-6). Additionally, a subset of patients had high expression of dysfunction markers on cytotoxic CD8+ T cells undergoing clonal expansion following enzalutamide treatment. Collectively, the transcriptional characterization of cancer and immune cells from human metastatic castration-resistant prostate cancer provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition.", + "TAG_DATA": [ + "56, adenocarcinoma {'context': 'B-transformed cells'}", + "57, cells {'context': 'I-transformed cells'}", + "89, Small {'context': 'B-transformed cells'}", + "90, cell {'context': 'I-transformed cells'}", + "91, carcinoma {'context': 'I-transformed cells'}", + "92, cells {'context': 'I-transformed cells'}", + "124, CD8+ {'context': 'I-cells'}", + "125, T {'context': 'I-cells'}", + "126, cells {'context': 'I-cells'}", + "128, clonal {'phenotype': 'B-colony formation'}", + "129, expansion {'phenotype': 'I-colony formation'}" + ], + "LINK_DATA": [ + "56, adenocarcinoma ['l0']", + "57, cells ['l0']", + "89, Small ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "90, cell ['l1', 'l7', 'l8', 'l9', 'l10']", + "91, carcinoma ['l2', 'l7', 'l11', 'l12', 'l13']", + "92, cells ['l3', 'l8', 'l11']", + "124, CD8+ ['l4', 'l14', 'l15', 'l16', 'l17']", + "125, T ['l5', 'l9', 'l12', 'l14', 'l18', 'l19', 'l20']", + "126, cells ['l6', 'l10', 'l13', 'l15', 'l18', 'l21', 'l22']", + "128, clonal ['l16', 'l19', 'l21', 'l23']", + "129, expansion ['l17', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD8+", + "T", + "cells" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonal", + "expansion" + ] + } + } + ] + }, + { + "PMID": "33558725", + "TEXT": "Genetically engineered T cell therapy can induce remarkable tumor responses in hematologic malignancies. However, it is not known if this type of therapy can be applied effectively to epithelial cancers, which account for 80-90% of human malignancies. We have conducted a first-in-human, phase 1 clinical trial of T cells engineered with a T cell receptor targeting HPV-16 E7 for the treatment of metastatic human papilloma virus-associated epithelial cancers (NCT02858310). The primary endpoint was maximum tolerated dose. Cell dose was not limited by toxicity with a maximum dose of 1 × 1011 engineered T cells administered. Tumor responses following treatment were evaluated using RECIST (Response Evaluation Criteria in Solid Tumors) guidelines. Robust tumor regression was observed with objective clinical responses in 6 of 12 patients, including 4 of 8 patients with anti-PD-1 refractory disease. Responses included extensive regression of bulky tumors and complete regression of most tumors in some patients. Genomic studies, which included intra-patient tumors with dichotomous treatment responses, revealed resistance mechanisms from defects in critical components of the antigen presentation and interferon response pathways. These findings demonstrate that engineered T cells can mediate regression of common carcinomas, and they reveal immune editing as a constraint on the curative potential of cellular therapy and possibly other immunotherapies in advanced epithelial cancer.", + "TAG_DATA": [ + "62, metastatic {'context': 'B-neoplasm'}", + "63, human {'context': 'I-neoplasm'}", + "64, papilloma {'context': 'I-neoplasm'}", + "65, virus-associated {'context': 'I-neoplasm'}", + "66, epithelial {'context': 'I-neoplasm'}", + "67, cancers {'context': 'I-neoplasm'}", + "109, tumor {'phenotype': 'B-tumour regression'}", + "110, regression {'phenotype': 'I-tumour regression'}", + "143, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "62, metastatic ['l0', 'l1', 'l2', 'l3', 'l4']", + "63, human ['l0', 'l5', 'l6', 'l7', 'l8', 'l9']", + "64, papilloma ['l1', 'l5', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "65, virus-associated ['l2', 'l6', 'l10', 'l16', 'l17', 'l18', 'l19']", + "66, epithelial ['l3', 'l7', 'l11', 'l16', 'l20']", + "67, cancers ['l4', 'l8', 'l12', 'l17', 'l20']", + "108, Robust ['l9', 'l13', 'l18', 'l21', 'l22']", + "109, tumor ['l14', 'l19', 'l21', 'l23']", + "110, regression ['l15', 'l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "papilloma", + "virus-associated" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + } + } + ] + }, + { + "PMID": "33495604", + "TEXT": "Synovial sarcoma (SyS) is an aggressive neoplasm driven by the SS18-SSX fusion, and is characterized by low T cell infiltration. Here, we studied the cancer-immune interplay in SyS using an integrative approach that combines single-cell RNA sequencing (scRNA-seq), spatial profiling and genetic and pharmacological perturbations. scRNA-seq of 16,872 cells from 12 human SyS tumors uncovered a malignant subpopulation that marks immune-deprived niches in situ and is predictive of poor clinical outcomes in two independent cohorts. Functional analyses revealed that this malignant cell state is controlled by the SS18-SSX fusion, is repressed by cytokines secreted by macrophages and T cells, and can be synergistically targeted with a combination of HDAC and CDK4/CDK6 inhibitors. This drug combination enhanced malignant-cell immunogenicity in SyS models, leading to induced T cell reactivity and T cell-mediated killing. Our study provides a blueprint for investigating heterogeneity in fusion-driven malignancies and demonstrates an interplay between immune evasion and oncogenic processes that can be co-targeted in SyS and potentially in other malignancies.", + "TAG_DATA": [ + "48, cells {'context': 'I-cells'}", + "51, human {'context': 'B-neoplasm'}", + "52, SyS {'context': 'I-neoplasm'}", + "53, tumors {'context': 'I-neoplasm'}", + "110, CDK4/CDK6 {'perturbing_action': 'B-pharmacological inhibition'}", + "111, inhibitors. {'perturbing_action': 'I-pharmacological inhibition'}", + "116, malignant-cell {'context': 'B-cells'}", + "119, SyS {'context': 'B-neoplasm'}", + "120, models, {'context': 'I-neoplasm'}", + "124, T {'context': 'B-cells'}", + "125, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "48, cells ['l0', 'l1', 'l2']", + "51, human ['l0', 'l3', 'l4']", + "52, SyS ['l1', 'l3', 'l5']", + "53, tumors ['l2', 'l4', 'l5']", + "110, CDK4/CDK6 ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "111, inhibitors. ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "116, malignant-cell ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "119, SyS ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "120, models, ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "124, T ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "125, cell ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK4/CDK6", + "inhibitors." + ] + }, + "context": { + "val": "cells", + "words": [ + "malignant-cell", + "T", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK4/CDK6", + "inhibitors." + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "SyS", + "models," + ] + } + } + ] + }, + { + "PMID": "33958797", + "TEXT": "Langerhans cell histiocytosis (LCH) is a potentially fatal condition characterized by granulomatous lesions with characteristic clonal mononuclear phagocytes (MNPs) harboring activating somatic mutations in mitogen-activated protein kinase (MAPK) pathway genes, most notably BRAFV600E. We recently discovered that the BRAFV600E mutation can also affect multipotent hematopoietic progenitor cells (HPCs) in multisystem LCH disease. How the BRAFV600E mutation in HPCs leads to LCH is not known. Here we show that enforced expression of the BRAFV600E mutation in early mouse and human multipotent HPCs induced a senescence program that led to HPC growth arrest, apoptosis resistance and a senescence-associated secretory phenotype (SASP). SASP, in turn, promoted HPC skewing toward the MNP lineage, leading to the accumulation of senescent MNPs in tissue and the formation of LCH lesions. Accordingly, elimination of senescent cells using INK-ATTAC transgenic mice, as well as pharmacologic blockade of SASP, improved LCH disease in mice. These results identify senescent cells as a new target for the treatment of LCH.", + "TAG_DATA": [ + "68, enforced {'perturbing_action': 'B-other'}", + "69, expression {'perturbing_action': 'I-other'}", + "70, of {'perturbing_action': 'I-other'}", + "71, the {'perturbing_action': 'I-other'}", + "72, BRAFV600E {'perturbing_action': 'I-other'}", + "73, mutation {'perturbing_action': 'I-other'}", + "75, early {'context': 'B-cells'}", + "76, mouse {'context': 'I-cells'}", + "77, and {'context': 'I-cells'}", + "78, human {'context': 'I-cells'}", + "79, multipotent {'context': 'I-cells'}", + "80, HPCs {'context': 'I-cells'}", + "81, induced {'effect': 'B-positive'}", + "83, senescence {'phenotype': 'B-senescence'}", + "84, program {'phenotype': 'I-senescence'}", + "86, led {'effect': 'B-positive'}", + "87, to {'effect': 'I-positive'}", + "88, HPC {'context': 'B-cells'}", + "89, growth {'phenotype': 'I-cell growth'}", + "90, arrest, {'effect': 'B-negative'}", + "91, apoptosis {'phenotype': 'B-apoptosis'}", + "92, resistance {'effect': 'B-negative'}", + "130, INK-ATTAC {'perturbing_action': 'B-gene gain-of-function'}", + "131, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "132, mice, {'context': 'B-organism'}", + "136, pharmacologic {'perturbing_action': 'B-pharmacological inhibition'}", + "137, blockade {'perturbing_action': 'I-pharmacological inhibition'}", + "138, of {'perturbing_action': 'I-pharmacological inhibition'}", + "139, SASP, {'perturbing_action': 'I-pharmacological inhibition'}", + "144, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "68, enforced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "69, expression ['l0', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "70, of ['l1', 'l21', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "71, the ['l2', 'l22', 'l41', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "72, BRAFV600E ['l3', 'l23', 'l42', 'l60', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "73, mutation ['l4', 'l24', 'l43', 'l61', 'l78', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "75, early ['l5', 'l25', 'l44', 'l62', 'l79', 'l95', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "76, mouse ['l6', 'l26', 'l45', 'l63', 'l80', 'l96', 'l111', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "77, and ['l7', 'l27', 'l46', 'l64', 'l81', 'l97', 'l112', 'l126', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "78, human ['l8', 'l28', 'l47', 'l65', 'l82', 'l98', 'l113', 'l127', 'l137', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "79, multipotent ['l9', 'l29', 'l48', 'l66', 'l83', 'l99', 'l114', 'l128', 'l138', 'l149', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168']", + "80, HPCs ['l10', 'l30', 'l49', 'l67', 'l84', 'l100', 'l115', 'l129', 'l139', 'l150', 'l158', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "81, induced ['l11', 'l31', 'l50', 'l68', 'l85', 'l101', 'l116', 'l130', 'l140', 'l151', 'l159', 'l169', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "83, senescence ['l12', 'l32', 'l51', 'l69', 'l86', 'l102', 'l117', 'l141', 'l160', 'l170', 'l179', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195']", + "84, program ['l13', 'l33', 'l52', 'l70', 'l87', 'l103', 'l118', 'l142', 'l161', 'l171', 'l180', 'l188', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202']", + "86, led ['l14', 'l34', 'l53', 'l71', 'l88', 'l104', 'l119', 'l131', 'l143', 'l152', 'l162', 'l172', 'l181', 'l189', 'l196', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208']", + "87, to ['l15', 'l35', 'l54', 'l72', 'l89', 'l105', 'l120', 'l132', 'l144', 'l153', 'l163', 'l173', 'l182', 'l190', 'l197', 'l203', 'l209', 'l210', 'l211', 'l212', 'l213']", + "88, HPC ['l16', 'l36', 'l55', 'l73', 'l90', 'l106', 'l121', 'l133', 'l145', 'l154', 'l164', 'l174', 'l183', 'l191', 'l198', 'l204', 'l209', 'l214', 'l215', 'l216', 'l217']", + "89, growth ['l17', 'l37', 'l56', 'l74', 'l91', 'l107', 'l122', 'l134', 'l146', 'l155', 'l165', 'l175', 'l184', 'l192', 'l199', 'l205', 'l210', 'l214', 'l218', 'l219', 'l220']", + "90, arrest, ['l18', 'l38', 'l57', 'l75', 'l92', 'l108', 'l123', 'l135', 'l147', 'l156', 'l166', 'l176', 'l185', 'l193', 'l200', 'l206', 'l211', 'l215', 'l218', 'l221', 'l222']", + "91, apoptosis ['l19', 'l39', 'l58', 'l76', 'l93', 'l109', 'l124', 'l167', 'l177', 'l186', 'l194', 'l201', 'l207', 'l212', 'l216', 'l219', 'l221', 'l223']", + "92, resistance ['l20', 'l40', 'l59', 'l77', 'l94', 'l110', 'l125', 'l136', 'l148', 'l157', 'l168', 'l178', 'l187', 'l195', 'l202', 'l208', 'l213', 'l217', 'l220', 'l222', 'l223']", + "130, INK-ATTAC ['l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230']", + "131, transgenic ['l224', 'l231', 'l232', 'l233', 'l234']", + "132, mice, ['l225', 'l231', 'l235']", + "136, pharmacologic ['l226', 'l236', 'l237', 'l238', 'l239']", + "137, blockade ['l227', 'l236', 'l240', 'l241', 'l242']", + "138, of ['l228', 'l232', 'l237', 'l240', 'l243', 'l244']", + "139, SASP, ['l229', 'l233', 'l238', 'l241', 'l243', 'l245']", + "144, mice. ['l230', 'l234', 'l235', 'l239', 'l242', 'l244', 'l245']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "enforced", + "expression", + "of", + "the", + "BRAFV600E", + "mutation" + ] + }, + "context": { + "val": "cells", + "words": [ + "early", + "mouse", + "and", + "human", + "multipotent", + "HPCs", + "HPC" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "enforced", + "expression", + "of", + "the", + "BRAFV600E", + "mutation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "led", + "to" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "enforced", + "expression", + "of", + "the", + "BRAFV600E", + "mutation" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence", + "program" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "enforced", + "expression", + "of", + "the", + "BRAFV600E", + "mutation" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "enforced", + "expression", + "of", + "the", + "BRAFV600E", + "mutation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest,", + "resistance" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "enforced", + "expression", + "of", + "the", + "BRAFV600E", + "mutation" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "early", + "mouse", + "and", + "human", + "multipotent", + "HPCs", + "HPC" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "led", + "to" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "early", + "and", + "multipotent", + "HPCs", + "HPC" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence", + "program" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "early", + "mouse", + "and", + "human", + "multipotent", + "HPCs", + "HPC" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "early", + "mouse", + "and", + "human", + "multipotent", + "HPCs", + "HPC" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest,", + "resistance" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "early", + "multipotent", + "HPCs", + "HPC" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "led", + "to" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence", + "program" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "led", + "to" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "led", + "to" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "senescence", + "words": [ + "senescence", + "program" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest,", + "resistance" + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest,", + "resistance" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "arrest,", + "resistance" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "INK-ATTAC", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "blockade", + "of", + "SASP," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "33707773", + "TEXT": "Hutchinson-Gilford progeria syndrome (HGPS) is a rare accelerated aging disorder characterized by premature death from myocardial infarction or stroke. It is caused by de novo single-nucleotide mutations in the LMNA gene that activate a cryptic splice donor site, resulting in the production of a toxic form of lamin A, which is termed progerin. Here we present a potential genetic therapeutic strategy that utilizes antisense peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) to block pathogenic splicing of mutant transcripts. Of several candidates, PPMO SRP-2001 provided the most significant decrease in progerin transcripts in patient fibroblasts. Intravenous delivery of SRP-2001 to a transgenic mouse model of HGPS produced significant reduction of progerin transcripts in the aorta, a particularly critical target tissue in HGPS. Long-term continuous treatment with SRP-2001 yielded a 61.6% increase in lifespan and rescue of vascular smooth muscle cell loss in large arteries. These results provide a rationale for proceeding to human trials.", + "TAG_DATA": [ + "90, patient {'context': 'B-cells'}", + "91, fibroblasts. {'context': 'I-cells'}", + "98, transgenic {'context': 'B-organism'}", + "99, mouse {'context': 'I-organism'}", + "100, model {'context': 'I-organism'}", + "101, of {'context': 'I-organism'}", + "102, HGPS {'context': 'I-organism'}", + "111, aorta, {'context': 'B-tissue/organ'}", + "131, rescue {'effect': 'B-rescues'}", + "133, vascular {'context': 'B-cells'}", + "134, smooth {'context': 'I-cells'}", + "135, muscle {'context': 'I-cells'}", + "136, cell {'context': 'I-cells'}", + "139, large {'context': 'B-tissue/organ'}", + "140, arteries. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "90, patient ['l0']", + "91, fibroblasts. ['l0']", + "98, transgenic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "99, mouse ['l1', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "100, model ['l2', 'l11', 'l17', 'l18', 'l19', 'l20', 'l21']", + "101, of ['l3', 'l12', 'l17', 'l22', 'l23', 'l24', 'l25']", + "102, HGPS ['l4', 'l13', 'l18', 'l22', 'l26']", + "111, aorta, ['l5', 'l14', 'l19', 'l23', 'l26']", + "131, rescue ['l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "133, vascular ['l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "134, smooth ['l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "135, muscle ['l6', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "136, cell ['l7', 'l15', 'l20', 'l24', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "137, loss ['l8', 'l16', 'l21', 'l25', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "139, large ['l9', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "140, arteries. ['l10', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "rescues", + "words": [ + "rescue" + ] + }, + "context": { + "val": "cells", + "words": [ + "vascular", + "smooth", + "muscle", + "cell" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescue" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "large", + "arteries." + ] + } + } + ] + }, + { + "PMID": "33603241", + "TEXT": "Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune microenvironment in operable NSCLC remain unclear. We report the results of the phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC, using major pathologic response (MPR) as the primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and 50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab resulted in higher pathologic complete response rates (10% versus 38%), less viable tumor (median 50% versus 9%), and greater frequencies of effector, tissue-resident memory and effector memory T cells. Increased abundance of gut Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances pathologic responses, tumor immune infiltrates and immunologic memory, and merits further investigation in operable NSCLC.", + "TAG_DATA": [ + "51, patients {'context': 'B-patient'}", + "52, with {'context': 'I-patient'}", + "53, operable {'context': 'I-neoplasm'}", + "54, NSCLC, {'context': 'I-neoplasm'}", + "144, less {'effect': 'B-negative'}", + "156, tissue-resident {'context': 'I-cells'}", + "157, memory {'context': 'I-cells'}", + "158, and {'context': 'I-cells'}", + "159, effector {'context': 'B-cells'}", + "160, memory {'context': 'I-cells'}", + "161, T {'context': 'I-cells'}", + "162, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "51, patients ['l0', 'l1', 'l2']", + "52, with ['l0', 'l3', 'l4']", + "53, operable ['l1', 'l3', 'l5']", + "54, NSCLC, ['l2', 'l4', 'l5']", + "144, less ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "145, viable ['l6', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "146, tumor ['l7', 'l16', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "155, effector, ['l8', 'l17', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "156, tissue-resident ['l9', 'l18', 'l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "157, memory ['l10', 'l19', 'l27', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "158, and ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "159, effector ['l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57']", + "160, memory ['l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l58', 'l59']", + "161, T ['l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58', 'l60']", + "162, cells. ['l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "less" + ] + }, + "context": { + "val": "cells", + "words": [ + "tissue-resident", + "memory", + "and", + "effector", + "T", + "cells." + ] + } + } + ] + }, + { + "PMID": "34017133", + "TEXT": "Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are prevalent liver conditions that underlie the development of life-threatening cirrhosis, liver failure and liver cancer. Chronic necro-inflammation is a critical factor in development of NASH, yet the cellular and molecular mechanisms of immune dysregulation in this disease are poorly understood. Here, using single-cell transcriptomic analysis, we comprehensively profiled the immune composition of the mouse liver during NASH. We identified a significant pathology-associated increase in hepatic conventional dendritic cells (cDCs) and further defined their source as NASH-induced boost in cycling of cDC progenitors in the bone marrow. Analysis of blood and liver from patients on the NAFLD/NASH spectrum showed that type 1 cDCs (cDC1) were more abundant and activated in disease. Sequencing of physically interacting cDC-T cell pairs from liver-draining lymph nodes revealed that cDCs in NASH promote inflammatory T cell reprogramming, previously associated with NASH worsening. Finally, depletion of cDC1 in XCR1DTA mice or using anti-XCL1-blocking antibody attenuated liver pathology in NASH mouse models. Overall, our study provides a comprehensive characterization of cDC biology in NASH and identifies XCR1+ cDC1 as an important driver of liver pathology.", + "TAG_DATA": [ + "147, depletion {'perturbing_action': 'B-gene loss-of-function'}", + "148, of {'perturbing_action': 'I-gene loss-of-function'}", + "149, cDC1 {'perturbing_action': 'I-gene loss-of-function'}", + "152, mice {'context': 'B-organism'}", + "158, liver {'context': 'B-tissue/organ'}", + "162, mouse {'context': 'B-organism'}", + "163, models. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "147, depletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "148, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "149, cDC1 ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "152, mice ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "158, liver ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "162, mouse ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "163, models. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "cDC1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "cDC1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "33619369", + "TEXT": "Multiple myeloma (MM) is a neoplastic plasma-cell disorder characterized by clonal proliferation of malignant plasma cells. Despite extensive research, disease heterogeneity within and between treatment-resistant patients is poorly characterized. In the present study, we conduct a prospective, multicenter, single-arm clinical trial (NCT04065789), combined with longitudinal single-cell RNA-sequencing (scRNA-seq) to study the molecular dynamics of MM resistance mechanisms. Newly diagnosed MM patients (41), who either failed to respond or experienced early relapse after a bortezomib-containing induction regimen, were enrolled to evaluate the safety and efficacy of a daratumumab, carfilzomib, lenalidomide and dexamethasone combination. The primary clinical endpoint was safety and tolerability. Secondary endpoints included overall response rate, progression-free survival and overall survival. Treatment was safe and well tolerated; deep and durable responses were achieved. In prespecified exploratory analyses, comparison of 41 primary refractory and early relapsed patients, with 11 healthy subjects and 15 newly diagnosed MM patients, revealed new MM molecular pathways of resistance, including hypoxia tolerance, protein folding and mitochondria respiration, which generalized to larger clinical cohorts (CoMMpass). We found peptidylprolyl isomerase A (PPIA), a central enzyme in the protein-folding response pathway, as a potential new target for resistant MM. CRISPR-Cas9 deletion of PPIA or inhibition of PPIA with a small molecule inhibitor (ciclosporin) significantly sensitizes MM tumor cells to proteasome inhibitors. Together, our study defines a roadmap for integrating scRNA-seq in clinical trials, identifies a signature of highly resistant MM patients and discovers PPIA as a potent therapeutic target for these tumors.", + "TAG_DATA": [ + "57, Newly {'context': 'B-transformed cells'}", + "58, diagnosed {'context': 'B-transformed cells'}", + "59, MM {'context': 'I-transformed cells'}", + "60, patients {'context': 'I-transformed cells'}", + "61, (41), {'context': 'I-transformed cells'}", + "190, CRISPR-Cas9 {'perturbing_action': 'B-gene loss-of-function'}", + "191, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "192, of {'perturbing_action': 'I-gene loss-of-function'}", + "193, PPIA {'perturbing_action': 'I-gene loss-of-function'}", + "195, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "196, of {'perturbing_action': 'I-pharmacological inhibition'}", + "197, PPIA {'perturbing_action': 'I-pharmacological inhibition'}", + "198, with {'perturbing_action': 'I-pharmacological inhibition'}", + "199, a {'perturbing_action': 'I-pharmacological inhibition'}", + "200, small {'perturbing_action': 'I-pharmacological inhibition'}", + "201, molecule {'perturbing_action': 'I-pharmacological inhibition'}", + "202, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "203, (ciclosporin) {'perturbing_action': 'I-pharmacological inhibition'}", + "206, MM {'context': 'B-transformed cells'}", + "207, tumor {'context': 'I-transformed cells'}", + "208, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "57, Newly ['l0', 'l1', 'l2', 'l3']", + "58, diagnosed ['l0', 'l4', 'l5', 'l6']", + "59, MM ['l1', 'l4', 'l7', 'l8']", + "60, patients ['l2', 'l5', 'l7', 'l9']", + "61, (41), ['l3', 'l6', 'l8', 'l9']", + "190, CRISPR-Cas9 ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "191, deletion ['l10', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "192, of ['l11', 'l25', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "193, PPIA ['l12', 'l26', 'l39', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "195, inhibition ['l13', 'l27', 'l40', 'l52', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "196, of ['l14', 'l28', 'l41', 'l53', 'l64', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "197, PPIA ['l15', 'l29', 'l42', 'l54', 'l65', 'l75', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "198, with ['l16', 'l30', 'l43', 'l55', 'l66', 'l76', 'l85', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "199, a ['l17', 'l31', 'l44', 'l56', 'l67', 'l77', 'l86', 'l94', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "200, small ['l18', 'l32', 'l45', 'l57', 'l68', 'l78', 'l87', 'l95', 'l102', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "201, molecule ['l19', 'l33', 'l46', 'l58', 'l69', 'l79', 'l88', 'l96', 'l103', 'l109', 'l115', 'l116', 'l117', 'l118', 'l119']", + "202, inhibitor ['l20', 'l34', 'l47', 'l59', 'l70', 'l80', 'l89', 'l97', 'l104', 'l110', 'l115', 'l120', 'l121', 'l122', 'l123']", + "203, (ciclosporin) ['l21', 'l35', 'l48', 'l60', 'l71', 'l81', 'l90', 'l98', 'l105', 'l111', 'l116', 'l120', 'l124', 'l125', 'l126']", + "206, MM ['l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l99', 'l106', 'l112', 'l117', 'l121', 'l124', 'l127', 'l128']", + "207, tumor ['l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l100', 'l107', 'l113', 'l118', 'l122', 'l125', 'l127', 'l129']", + "208, cells ['l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l108', 'l114', 'l119', 'l123', 'l126', 'l128', 'l129']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CRISPR-Cas9", + "deletion", + "of", + "PPIA" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MM", + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "PPIA", + "with", + "a", + "small", + "molecule", + "inhibitor", + "(ciclosporin)" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MM", + "tumor", + "cells" + ] + } + } + ] + }, + { + "PMID": "33649496", + "TEXT": "Degeneration of dopamine (DA) neurons in the midbrain underlies the pathogenesis of Parkinson's disease (PD). Supplement of DA via L-DOPA alleviates motor symptoms but does not prevent the progressive loss of DA neurons. A large body of experimental studies, including those in nonhuman primates, demonstrates that transplantation of fetal mesencephalic tissues improves motor symptoms in animals, which culminated in open-label and double-blinded clinical trials of fetal tissue transplantation for PD1. Unfortunately, the outcomes are mixed, primarily due to the undefined and unstandardized donor tissues1,2. Generation of induced pluripotent stem cells enables standardized and autologous transplantation therapy for PD. However, its efficacy, especially in primates, remains unclear. Here we show that over a 2-year period without immunosuppression, PD monkeys receiving autologous, but not allogenic, transplantation exhibited recovery from motor and depressive signs. These behavioral improvements were accompanied by robust grafts with extensive DA neuron axon growth as well as strong DA activity in positron emission tomography (PET). Mathematical modeling reveals correlations between the number of surviving DA neurons with PET signal intensity and behavior recovery regardless autologous or allogeneic transplant, suggesting a predictive power of PET and motor behaviors for surviving DA neuron number.", + "TAG_DATA": [ + "116, PD {'context': 'B-organism'}", + "117, monkeys {'context': 'I-organism'}", + "141, DA {'context': 'B-cells'}", + "142, neuron {'context': 'I-cells'}", + "143, axon {'phenotype': 'B-autophagy'}", + "144, growth {'phenotype': 'I-cell growth'}" + ], + "LINK_DATA": [ + "116, PD ['l0', 'l1', 'l2', 'l3', 'l4']", + "117, monkeys ['l0', 'l5', 'l6', 'l7', 'l8']", + "141, DA ['l1', 'l5', 'l9', 'l10', 'l11']", + "142, neuron ['l2', 'l6', 'l9', 'l12', 'l13']", + "143, axon ['l3', 'l7', 'l10', 'l12', 'l14']", + "144, growth ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "PD", + "monkeys" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "axon" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "PD", + "monkeys" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "DA", + "neuron" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "axon" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "DA", + "neuron" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + } + ] + }, + { + "PMID": "33941921", + "TEXT": "Durvalumab is a programmed death-ligand 1 (PD-L1) inhibitor with clinical activity in advanced urothelial cancer (AUC)1. AUC is characterized by several recurrent targetable genomic alterations2-5. This study ( NCT02546661 , BISCAY) combined durvalumab with relevant targeted therapies in biomarker-selected chemotherapy-refractory AUC populations including: (1) fibroblast growth factor receptor (FGFR) inhibitors in tumors with FGFR DNA alterations (FGFRm); (2) pharmacological inhibitor of the enzyme poly-ADP ribose polymerase (PARP) in tumors with and without DNA homologous recombination repair deficiency (HRRm); and (3) TORC1/2 inhibitors in tumors with DNA alteration to the mTOR/PI3K pathway3-5.This trial adopted a new, biomarker-driven, multiarm adaptive design. Safety, efficacy and relevant biomarkers were evaluated. Overall, 391 patients were screened of whom 135 were allocated to one of six study arms. Response rates (RRs) ranged 9-36% across the study arms, which did not meet efficacy criteria for further development. Overall survival (OS) and progression-free survival (PFS) were similar in the combination arms and durvalumab monotherapy arm. Biomarker analysis showed a correlation between circulating plasma-based DNA (ctDNA) and tissue for FGFRm. Sequential circulating tumor DNA analysis showed that changes to FGFRm correlated with clinical outcome. Our data support the clinical activity of FGFR inhibition and durvalumab monotherapy but do not show increased activity for any of the combinations. These findings question the targeted/immune therapy approach in AUC.", + "TAG_DATA": [ + "40, AUC {'context': 'B-neoplasm'}", + "51, tumors {'context': 'B-neoplasm'}", + "68, tumors {'context': 'B-neoplasm'}", + "80, TORC1/2 {'perturbing_action': 'B-pharmacological inhibition'}", + "81, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "83, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "40, AUC ['l0', 'l1']", + "51, tumors ['l0', 'l2']", + "68, tumors ['l1', 'l2']", + "80, TORC1/2 ['l3', 'l4']", + "81, inhibitors ['l3', 'l5']", + "83, tumors ['l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "TORC1/2", + "inhibitors" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + } + ] + }, + { + "PMID": "32807933", + "TEXT": "Osteoarthritis (OA) is a degenerative disease resulting in irreversible, progressive destruction of articular cartilage1. The etiology of OA is complex and involves a variety of factors, including genetic predisposition, acute injury and chronic inflammation2-4. Here we investigate the ability of resident skeletal stem-cell (SSC) populations to regenerate cartilage in relation to age, a possible contributor to the development of osteoarthritis5-7. We demonstrate that aging is associated with progressive loss of SSCs and diminished chondrogenesis in the joints of both mice and humans. However, a local expansion of SSCs could still be triggered in the chondral surface of adult limb joints in mice by stimulating a regenerative response using microfracture (MF) surgery. Although MF-activated SSCs tended to form fibrous tissues, localized co-delivery of BMP2 and soluble VEGFR1 (sVEGFR1), a VEGF receptor antagonist, in a hydrogel skewed differentiation of MF-activated SSCs toward articular cartilage. These data indicate that following MF, a resident stem-cell population can be induced to generate cartilage for treatment of localized chondral disease in OA.", + "TAG_DATA": [ + "94, chondral {'context': 'B-tissue/organ'}", + "95, surface {'context': 'I-tissue/organ'}", + "97, adult {'context': 'B-tissue/organ'}", + "98, limb {'context': 'I-tissue/organ'}", + "99, joints {'context': 'I-tissue/organ'}", + "101, mice {'context': 'B-organism'}", + "113, SSCs {'context': 'B-cells'}", + "134, skewed {'effect': 'B-positive'}", + "135, differentiation {'phenotype': 'B-differentiation'}", + "138, SSCs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "94, chondral ['l0', 'l1', 'l2', 'l3', 'l4']", + "95, surface ['l0', 'l5', 'l6', 'l7', 'l8']", + "97, adult ['l1', 'l5', 'l9', 'l10', 'l11']", + "98, limb ['l2', 'l6', 'l9', 'l12', 'l13']", + "99, joints ['l3', 'l7', 'l10', 'l12', 'l14']", + "101, mice ['l4', 'l8', 'l11', 'l13', 'l14']", + "134, skewed ['l15', 'l16']", + "135, differentiation ['l15', 'l17']", + "138, SSCs ['l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "skewed" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "skewed" + ] + }, + "context": { + "val": "cells", + "words": [ + "SSCs" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "SSCs" + ] + } + } + ] + }, + { + "PMID": "32661390", + "TEXT": "Disruption of systemic homeostasis by either chronic or acute stressors, such as obesity1 or surgery2, alters cancer pathogenesis. Patients with cancer, particularly those with breast cancer, can be at increased risk of cardiovascular disease due to treatment toxicity and changes in lifestyle behaviors3-5. While elevated risk and incidence of cardiovascular events in breast cancer is well established, whether such events impact cancer pathogenesis is not known. Here we show that myocardial infarction (MI) accelerates breast cancer outgrowth and cancer-specific mortality in mice and humans. In mouse models of breast cancer, MI epigenetically reprogrammed Ly6Chi monocytes in the bone marrow reservoir to an immunosuppressive phenotype that was maintained at the transcriptional level in monocytes in both the circulation and tumor. In parallel, MI increased circulating Ly6Chi monocyte levels and recruitment to tumors and depletion of these cells abrogated MI-induced tumor growth. Furthermore, patients with early-stage breast cancer who experienced cardiovascular events after cancer diagnosis had increased risk of recurrence and cancer-specific death. These preclinical and clinical results demonstrate that MI induces alterations in systemic homeostasis, triggering cross-disease communication that accelerates breast cancer.", + "TAG_DATA": [ + "74, breast {'context': 'B-neoplasm'}", + "75, cancer {'context': 'I-neoplasm'}", + "81, mice {'context': 'B-organism'}", + "85, mouse {'context': 'B-neoplasm'}", + "86, models {'context': 'I-neoplasm'}", + "87, of {'context': 'I-neoplasm'}", + "88, breast {'context': 'I-neoplasm'}", + "89, cancer, {'context': 'I-neoplasm'}", + "118, tumor. {'context': 'B-neoplasm'}", + "135, cells {'context': 'B-cells'}", + "136, abrogated {'effect': 'B-negative'}", + "137, MI-induced {'effect': 'B-positive'}", + "138, tumor {'phenotype': 'B-tumour growth'}", + "139, growth. {'phenotype': 'I-tumour growth'}", + "141, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "74, breast ['l0', 'l1', 'l2']", + "75, cancer ['l0', 'l3', 'l4']", + "81, mice ['l1', 'l3', 'l5', 'l6']", + "85, mouse ['l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "86, models ['l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "87, of ['l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "88, breast ['l5', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "89, cancer, ['l2', 'l4', 'l6', 'l10', 'l15', 'l19', 'l22', 'l25']", + "98, marrow ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']", + "118, tumor. ['l12', 'l17', 'l21', 'l24', 'l26']", + "135, cells ['l27', 'l28', 'l29', 'l30']", + "136, abrogated ['l27', 'l31', 'l32', 'l33']", + "137, MI-induced ['l28', 'l31', 'l34', 'l35']", + "138, tumor ['l29', 'l32', 'l34', 'l36']", + "139, growth. ['l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abrogated" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "MI-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogated" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "MI-induced" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + } + ] + }, + { + "PMID": "32066975", + "TEXT": "The involvement of host immunity in the gut microbiota-mediated colonization resistance to Clostridioides difficile infection (CDI) is incompletely understood. Here, we show that interleukin (IL)-22, induced by colonization of the gut microbiota, is crucial for the prevention of CDI in human microbiota-associated (HMA) mice. IL-22 signaling in HMA mice regulated host glycosylation, which enabled the growth of succinate-consuming bacteria Phascolarctobacterium spp. within the gut microbiome. Phascolarctobacterium reduced the availability of luminal succinate, a crucial metabolite for the growth of C. difficile, and therefore prevented the growth of C. difficile. IL-22-mediated host N-glycosylation is likely impaired in patients with ulcerative colitis (UC) and renders UC-HMA mice more susceptible to CDI. Transplantation of healthy human-derived microbiota or Phascolarctobacterium reduced luminal succinate levels and restored colonization resistance in UC-HMA mice. IL-22-mediated host glycosylation thus fosters the growth of commensal bacteria that compete with C. difficile for the nutritional niche.", + "TAG_DATA": [ + "47, HMA {'context': 'B-organism'}", + "48, mice {'context': 'I-organism'}", + "109, Transplantation {'perturbing_action': 'B-gene gain-of-function'}", + "112, human-derived {'context': 'I-cells'}", + "113, microbiota {'context': 'I-cells'}", + "125, UC-HMA {'context': 'B-organism'}", + "126, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "47, HMA ['l0']", + "48, mice ['l0']", + "109, Transplantation ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "110, of ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "111, healthy ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "112, human-derived ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "113, microbiota ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "125, UC-HMA ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "126, mice. ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transplantation" + ] + }, + "context": { + "val": "cells", + "words": [ + "human-derived", + "microbiota" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transplantation" + ] + }, + "context": { + "val": "organism", + "words": [ + "UC-HMA", + "mice." + ] + } + } + ] + }, + { + "PMID": "31959991", + "TEXT": "Mucociliary clearance, the physiological process by which mammalian conducting airways expel pathogens and unwanted surface materials from the respiratory tract, depends on the coordinated function of multiple specialized cell types, including basal stem cells, mucus-secreting goblet cells, motile ciliated cells, cystic fibrosis transmembrane conductance regulator (CFTR)-rich ionocytes, and immune cells1,2. Bronchiectasis, a syndrome of pathological airway dilation associated with impaired mucociliary clearance, may occur sporadically or as a consequence of Mendelian inheritance, for example in cystic fibrosis, primary ciliary dyskinesia (PCD), and select immunodeficiencies3. Previous studies have identified mutations that affect ciliary structure and nucleation in PCD4, but the regulation of mucociliary transport remains incompletely understood, and therapeutic targets for its modulation are lacking. Here we identify a bronchiectasis syndrome caused by mutations that inactivate NIMA-related kinase 10 (NEK10), a protein kinase with previously unknown in vivo functions in mammals. Genetically modified primary human airway cultures establish NEK10 as a ciliated-cell-specific kinase whose activity regulates the motile ciliary proteome to promote ciliary length and mucociliary transport but which is dispensable for normal ciliary number, radial structure, and beat frequency. Together, these data identify a novel and likely targetable signaling axis that controls motile ciliary function in humans and has potential implications for other respiratory disorders that are characterized by impaired mucociliary clearance.", + "TAG_DATA": [ + "125, NIMA-related {'perturbing_action': 'I-other'}", + "126, kinase {'perturbing_action': 'I-other'}", + "127, 10 {'perturbing_action': 'I-other'}", + "128, (NEK10), {'perturbing_action': 'I-other'}", + "142, primary {'context': 'B-cells'}", + "143, human {'context': 'I-cells'}", + "144, airway {'context': 'I-cells'}", + "145, cultures {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "124, inactivate ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "125, NIMA-related ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "126, kinase ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "127, 10 ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "128, (NEK10), ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "142, primary ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "143, human ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "144, airway ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "145, cultures ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "NIMA-related", + "kinase", + "10", + "(NEK10)," + ] + }, + "context": { + "val": "cells", + "words": [ + "primary", + "human", + "airway", + "cultures" + ] + } + } + ] + }, + { + "PMID": "31873312", + "TEXT": "Gene silencing with virally delivered shRNA represents a promising approach for treatment of inherited neurodegenerative disorders. In the present study we develop a subpial technique, which we show in adult animals successfully delivers adeno-associated virus (AAV) throughout the cervical, thoracic and lumbar spinal cord, as well as brain motor centers. One-time injection at cervical and lumbar levels just before disease onset in mice expressing a familial amyotrophic lateral sclerosis (ALS)-causing mutant SOD1 produces long-term suppression of motoneuron disease, including near-complete preservation of spinal α-motoneurons and muscle innervation. Treatment after disease onset potently blocks progression of disease and further α-motoneuron degeneration. A single subpial AAV9 injection in adult pigs or non-human primates using a newly designed device produces homogeneous delivery throughout the cervical spinal cord white and gray matter and brain motor centers. Thus, spinal subpial delivery in adult animals is highly effective for AAV-mediated gene delivery throughout the spinal cord and supraspinal motor centers.", + "TAG_DATA": [ + "62, mice {'context': 'B-organism'}", + "63, expressing {'perturbing_action': 'B-other'}", + "64, a {'perturbing_action': 'I-other'}", + "65, familial {'perturbing_action': 'I-other'}", + "66, amyotrophic {'perturbing_action': 'I-other'}", + "67, lateral {'perturbing_action': 'I-other'}", + "68, sclerosis {'perturbing_action': 'I-other'}", + "69, (ALS)-causing {'perturbing_action': 'I-other'}", + "70, mutant {'perturbing_action': 'I-other'}", + "71, SOD1 {'perturbing_action': 'I-other'}", + "76, motoneuron {'context': 'B-cells'}", + "82, spinal {'context': 'B-cells'}", + "83, α-motoneurons {'context': 'I-cells'}", + "85, muscle {'context': 'B-tissue/organ'}", + "98, α-motoneuron {'context': 'B-cells'}", + "106, adult {'context': 'B-organism'}", + "107, pigs {'context': 'I-organism'}", + "109, non-human {'context': 'B-organism'}", + "110, primates {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "62, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "63, expressing ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "64, a ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "65, familial ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "66, amyotrophic ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "67, lateral ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "68, sclerosis ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "69, (ALS)-causing ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "70, mutant ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "71, SOD1 ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "76, motoneuron ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "82, spinal ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "83, α-motoneurons ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "85, muscle ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']", + "106, adult ['l91', 'l92', 'l93']", + "107, pigs ['l91', 'l94', 'l95']", + "109, non-human ['l92', 'l94', 'l96']", + "110, primates ['l93', 'l95', 'l96']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "a", + "familial", + "amyotrophic", + "lateral", + "sclerosis", + "(ALS)-causing", + "mutant", + "SOD1" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "a", + "familial", + "amyotrophic", + "lateral", + "sclerosis", + "(ALS)-causing", + "mutant", + "SOD1" + ] + }, + "context": { + "val": "cells", + "words": [ + "motoneuron", + "spinal", + "α-motoneurons" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "a", + "familial", + "amyotrophic", + "lateral", + "sclerosis", + "(ALS)-causing", + "mutant", + "SOD1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscle" + ] + } + } + ] + }, + { + "PMID": "31768065", + "TEXT": "Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis.", + "TAG_DATA": [ + "63, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "64, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "65, of {'perturbing_action': 'I-pharmacological inhibition'}", + "66, RET {'perturbing_action': 'I-pharmacological inhibition'}", + "67, (selpercatinib) {'perturbing_action': 'I-pharmacological inhibition'}", + "68, and {'perturbing_action': 'I-pharmacological inhibition'}", + "72, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "63, selective ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "64, inhibition ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "65, of ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "66, RET ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "67, (selpercatinib) ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "68, and ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "72, patients ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "inhibition", + "of", + "RET", + "(selpercatinib)", + "and" + ] + }, + "context": { + "val": "patient", + "words": [ + "patients" + ] + } + } + ] + }, + { + "PMID": "31636454", + "TEXT": "Dysregulation of the mammalian target of rapamycin (mTOR) signaling, which is mediated by two structurally and functionally distinct complexes, mTORC1 and mTORC2, has been implicated in several neurological disorders1-3. Individuals carrying loss-of-function mutations in the phosphatase and tensin homolog (PTEN) gene, a negative regulator of mTOR signaling, are prone to developing macrocephaly, autism spectrum disorder (ASD), seizures and intellectual disability2,4,5. It is generally believed that the neurological symptoms associated with loss of PTEN and other mTORopathies (for example, mutations in the tuberous sclerosis genes TSC1 or TSC2) are due to hyperactivation of mTORC1-mediated protein synthesis1,2,4,6,7. Using molecular genetics, we unexpectedly found that genetic deletion of mTORC2 (but not mTORC1) activity prolonged lifespan, suppressed seizures, rescued ASD-like behaviors and long-term memory, and normalized metabolic changes in the brain of mice lacking Pten. In a more therapeutically oriented approach, we found that administration of an antisense oligonucleotide (ASO) targeting mTORC2's defining component Rictor specifically inhibits mTORC2 activity and reverses the behavioral and neurophysiological abnormalities in adolescent Pten-deficient mice. Collectively, our findings indicate that mTORC2 is the major driver underlying the neuropathophysiology associated with Pten-deficiency, and its therapeutic reduction could represent a promising and broadly effective translational therapy for neurological disorders where mTOR signaling is dysregulated.", + "TAG_DATA": [ + "102, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "103, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "104, of {'perturbing_action': 'I-gene loss-of-function'}", + "105, mTORC2 {'perturbing_action': 'I-gene loss-of-function'}", + "106, (but {'perturbing_action': 'I-gene loss-of-function'}", + "109, activity {'perturbing_action': 'I-gene loss-of-function'}", + "126, brain {'context': 'B-tissue/organ'}", + "128, mice {'context': 'B-organism'}", + "129, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "130, Pten. {'perturbing_action': 'I-gene loss-of-function'}", + "164, Pten-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "165, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "102, genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "103, deletion ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "104, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "105, mTORC2 ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "106, (but ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "109, activity ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "126, brain ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "128, mice ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "129, lacking ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "130, Pten. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "164, Pten-deficient ['l45']", + "165, mice. ['l45']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "mTORC2", + "(but", + "activity", + "lacking", + "Pten." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "mTORC2", + "(but", + "activity", + "lacking", + "Pten.", + "Pten-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "31591596", + "TEXT": "The essential product of the Duchenne muscular dystrophy (DMD) gene is dystrophin1, a rod-like protein2 that protects striated myocytes from contraction-induced injury3,4. Dystrophin-related protein (or utrophin) retains most of the structural and protein binding elements of dystrophin5. Importantly, normal thymic expression in DMD patients6 should protect utrophin by central immunologic tolerance. We designed a codon-optimized, synthetic transgene encoding a miniaturized utrophin (µUtro), deliverable by adeno-associated virus (AAV) vectors. Here, we show that µUtro is a highly functional, non-immunogenic substitute for dystrophin, preventing the most deleterious histological and physiological aspects of muscular dystrophy in small and large animal models. Following systemic administration of an AAV-µUtro to neonatal dystrophin-deficient mdx mice, histological and biochemical markers of myonecrosis and regeneration are completely suppressed throughout growth to adult weight. In the dystrophin-deficient golden retriever model, µUtro non-toxically prevented myonecrosis, even in the most powerful muscles. In a stringent test of immunogenicity, focal expression of µUtro in the deletional-null German shorthaired pointer model produced no evidence of cell-mediated immunity, in contrast to the robust T cell response against similarly constructed µDystrophin (µDystro). These findings support a model in which utrophin-derived therapies might be used to treat clinical dystrophin deficiency, with a favorable immunologic profile and preserved function in the face of extreme miniaturization.", + "TAG_DATA": [ + "106, dystrophin-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "107, mdx {'context': 'I-organism'}", + "108, mice, {'context': 'I-organism'}", + "127, dystrophin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "128, golden {'context': 'B-organism'}", + "129, retriever {'context': 'I-organism'}", + "130, model, {'context': 'I-organism'}", + "133, prevented {'effect': 'B-negative'}", + "134, myonecrosis, {'phenotype': 'B-necrosis'}", + "140, muscles. {'context': 'B-tissue/organ'}", + "147, focal {'perturbing_action': 'B-gene gain-of-function'}", + "148, expression {'perturbing_action': 'I-gene gain-of-function'}", + "149, of {'perturbing_action': 'I-gene gain-of-function'}", + "150, µUtro {'perturbing_action': 'I-gene gain-of-function'}", + "153, deletional-null {'perturbing_action': 'B-gene loss-of-function'}", + "154, German {'context': 'B-organism'}", + "155, shorthaired {'context': 'I-organism'}", + "156, pointer {'context': 'I-organism'}", + "157, model {'context': 'I-organism'}", + "169, T {'context': 'B-cells'}", + "170, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "106, dystrophin-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "107, mdx ['l0', 'l7', 'l8', 'l9', 'l10']", + "108, mice, ['l1', 'l7']", + "127, dystrophin-deficient ['l2', 'l8', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "128, golden ['l3', 'l9', 'l11', 'l17', 'l18', 'l19', 'l20', 'l21']", + "129, retriever ['l4', 'l12', 'l17', 'l22', 'l23', 'l24', 'l25']", + "130, model, ['l5', 'l10', 'l13', 'l18', 'l22', 'l26', 'l27', 'l28']", + "133, prevented ['l14', 'l19', 'l23', 'l26', 'l29', 'l30']", + "134, myonecrosis, ['l15', 'l20', 'l24', 'l27', 'l29', 'l31']", + "140, muscles. ['l6', 'l16', 'l21', 'l25', 'l28', 'l30', 'l31']", + "147, focal ['l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "148, expression ['l32', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "149, of ['l33', 'l42', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "150, µUtro ['l34', 'l43', 'l51', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "153, deletional-null ['l35', 'l44', 'l52', 'l59', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "154, German ['l36', 'l45', 'l53', 'l60', 'l66', 'l72', 'l73', 'l74', 'l75', 'l76']", + "155, shorthaired ['l37', 'l46', 'l54', 'l61', 'l67', 'l72', 'l77', 'l78', 'l79', 'l80']", + "156, pointer ['l38', 'l47', 'l55', 'l62', 'l68', 'l73', 'l77', 'l81', 'l82', 'l83']", + "157, model ['l39', 'l48', 'l56', 'l63', 'l69', 'l74', 'l78', 'l81', 'l84', 'l85']", + "169, T ['l40', 'l49', 'l57', 'l64', 'l70', 'l75', 'l79', 'l82', 'l84', 'l86']", + "170, cell ['l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l83', 'l85', 'l86']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient", + "deletional-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mdx", + "mice,", + "golden", + "retriever", + "model,", + "German", + "shorthaired", + "pointer", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscles." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "myonecrosis," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "golden", + "retriever", + "model," + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "golden", + "retriever", + "model," + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "myonecrosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "myonecrosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscles." + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "myonecrosis," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscles." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "focal", + "expression", + "of", + "µUtro" + ] + }, + "context": { + "val": "organism", + "words": [ + "German", + "shorthaired", + "pointer", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "focal", + "expression", + "of", + "µUtro" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletional-null" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + } + ] + }, + { + "PMID": "31501614", + "TEXT": "Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ+ T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3 expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3 in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3 deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3 upregulation can subvert therapy-induced anticancer immunosurveillance.", + "TAG_DATA": [ + "35, mice {'context': 'B-organism'}", + "44, transplantable {'context': 'B-neoplasm'}", + "45, tumors. {'context': 'I-neoplasm'}", + "66, dendritic {'context': 'B-cells'}", + "67, cell {'context': 'I-cells'}", + "68, (DC) {'context': 'I-cells'}", + "96, murine {'context': 'B-organism'}", + "97, models, {'context': 'I-organism'}", + "102, enforced {'perturbing_action': 'B-gene gain-of-function'}", + "103, expression {'perturbing_action': 'I-gene gain-of-function'}", + "104, of {'perturbing_action': 'I-gene gain-of-function'}", + "105, Tsc22d3 {'perturbing_action': 'I-gene gain-of-function'}", + "107, DC {'context': 'B-cells'}", + "115, tumors. {'context': 'B-neoplasm'}", + "123, DC-specific {'perturbing_action': 'B-gene loss-of-function'}", + "124, Tsc22d3 {'perturbing_action': 'I-gene loss-of-function'}", + "125, deletion {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "35, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "42, neoplasias ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "44, transplantable ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "45, tumors. ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "66, dendritic ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "67, cell ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "68, (DC) ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "96, murine ['l21', 'l22', 'l23']", + "97, models, ['l21', 'l24']", + "102, enforced ['l25', 'l26', 'l27', 'l28', 'l29']", + "103, expression ['l25', 'l30', 'l31', 'l32', 'l33']", + "104, of ['l26', 'l30', 'l34', 'l35', 'l36']", + "105, Tsc22d3 ['l27', 'l31', 'l34', 'l37', 'l38']", + "107, DC ['l22', 'l28', 'l32', 'l35', 'l37', 'l39']", + "115, tumors. ['l23', 'l24', 'l29', 'l33', 'l36', 'l38', 'l39']", + "123, DC-specific ['l40', 'l41']", + "124, Tsc22d3 ['l40', 'l42']", + "125, deletion ['l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "enforced", + "expression", + "of", + "Tsc22d3" + ] + }, + "context": { + "val": "cells", + "words": [ + "DC" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "enforced", + "expression", + "of", + "Tsc22d3" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors." + ] + } + } + ] + }, + { + "PMID": "31501599", + "TEXT": "Fanconi anemia (FA) is a DNA repair syndrome generated by mutations in any of the 22 FA genes discovered to date1,2. Mutations in FANCA account for more than 60% of FA cases worldwide3,4. Clinically, FA is associated with congenital abnormalities and cancer predisposition. However, bone marrow failure is the primary pathological feature of FA that becomes evident in 70-80% of patients with FA during the first decade of life5,6. In this clinical study (ClinicalTrials.gov, NCT03157804 ; European Clinical Trials Database, 2011-006100-12), we demonstrate that lentiviral-mediated hematopoietic gene therapy reproducibly confers engraftment and proliferation advantages of gene-corrected hematopoietic stem cells (HSCs) in non-conditioned patients with FA subtype A. Insertion-site analyses revealed the multipotent nature of corrected HSCs and showed that the repopulation advantage of these cells was not due to genotoxic integrations of the therapeutic provirus. Phenotypic correction of blood and bone marrow cells was shown by the acquired resistance of hematopoietic progenitors and T lymphocytes to DNA cross-linking agents. Additionally, an arrest of bone marrow failure progression was observed in patients with the highest levels of gene marking. The progressive engraftment of corrected HSCs in non-conditioned patients with FA supports that gene therapy should constitute an innovative low-toxicity therapeutic option for this life-threatening disorder.", + "TAG_DATA": [ + "92, proliferation {'phenotype': 'B-proliferation'}", + "93, advantages {'effect': 'B-positive'}", + "96, hematopoietic {'context': 'B-cells'}", + "97, stem {'context': 'I-cells'}", + "98, cells {'context': 'I-cells'}", + "99, (HSCs) {'context': 'I-cells'}", + "101, non-conditioned {'context': 'B-patient'}", + "102, patients {'context': 'I-patient'}", + "138, blood {'context': 'B-cells'}", + "139, and {'context': 'I-cells'}", + "140, bone {'context': 'I-cells'}", + "141, marrow {'context': 'I-cells'}", + "142, cells {'context': 'I-cells'}", + "150, hematopoietic {'context': 'B-cells'}", + "151, progenitors {'context': 'I-cells'}", + "153, T {'context': 'B-cells'}", + "154, lymphocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "92, proliferation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "93, advantages ['l0', 'l6', 'l7', 'l8']", + "96, hematopoietic ['l1', 'l9', 'l10', 'l11', 'l12', 'l13']", + "97, stem ['l2', 'l6', 'l9', 'l14', 'l15', 'l16', 'l17']", + "98, cells ['l3', 'l7', 'l10', 'l14', 'l18', 'l19', 'l20']", + "99, (HSCs) ['l4', 'l8', 'l11', 'l15', 'l18', 'l21', 'l22']", + "101, non-conditioned ['l12', 'l16', 'l19', 'l21', 'l23']", + "102, patients ['l5', 'l13', 'l17', 'l20', 'l22', 'l23']", + "138, blood ['l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "139, and ['l24', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "140, bone ['l25', 'l32', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "141, marrow ['l26', 'l33', 'l39', 'l45', 'l46', 'l47', 'l48', 'l49']", + "142, cells ['l27', 'l34', 'l40', 'l45', 'l50', 'l51', 'l52', 'l53']", + "150, hematopoietic ['l28', 'l35', 'l41', 'l46', 'l50', 'l54', 'l55', 'l56']", + "151, progenitors ['l29', 'l36', 'l42', 'l47', 'l51', 'l54', 'l57', 'l58']", + "153, T ['l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l57', 'l59']", + "154, lymphocytes ['l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58', 'l59']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "advantages" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cells", + "(HSCs)" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "patient", + "words": [ + "patients" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "advantages" + ] + }, + "context": { + "val": "cells", + "words": [ + "stem", + "cells", + "(HSCs)" + ] + } + } + ] + }, + { + "PMID": "31477906", + "TEXT": "Chimeric antigen receptor (CAR)-modified T cells targeting CD19 demonstrate unparalleled responses in relapsed/refractory acute lymphoblastic leukemia (ALL)1-5, but toxicity, including cytokine-release syndrome (CRS) and neurotoxicity, limits broader application. Moreover, 40-60% of patients relapse owing to poor CAR T cell persistence or emergence of CD19- clones. Some factors, including the choice of single-chain spacer6 and extracellular7 and costimulatory domains8, have a profound effect on CAR T cell function and persistence. However, little is known about the impact of CAR binding affinity. There is evidence of a ceiling above which increased immunoreceptor affinity may adversely affect T cell responses9-11. We generated a novel CD19 CAR (CAT) with a lower affinity than FMC63, the high-affinity binder used in many clinical studies1-4. CAT CAR T cells showed increased proliferation and cytotoxicity in vitro and had enhanced proliferative and in vivo antitumor activity compared with FMC63 CAR T cells. In a clinical study (CARPALL, NCT02443831 ), 12/14 patients with relapsed/refractory pediatric B cell acute lymphoblastic leukemia treated with CAT CAR T cells achieved molecular remission. Persistence was demonstrated in 11 of 14 patients at last follow-up, with enhanced CAR T cell expansion compared with published data. Toxicity was low, with no severe CRS. One-year overall and event-free survival were 63% and 46%, respectively.", + "TAG_DATA": [ + "120, T {'context': 'B-cells'}", + "121, cells {'context': 'I-cells'}", + "123, increased {'effect': 'B-positive'}", + "124, proliferation {'phenotype': 'B-proliferation'}", + "127, in {'context': 'B-in vitro'}", + "128, vitro {'context': 'I-in vitro'}", + "142, T {'context': 'I-cells'}", + "143, cells. {'context': 'I-cells'}", + "152, patients {'context': 'B-patient'}", + "154, relapsed/refractory {'context': 'B-neoplasm'}", + "155, pediatric {'context': 'I-neoplasm'}", + "156, B {'context': 'I-neoplasm'}", + "157, cell {'context': 'I-neoplasm'}", + "158, acute {'context': 'I-neoplasm'}", + "159, lymphoblastic {'context': 'I-neoplasm'}", + "160, leukemia {'context': 'I-neoplasm'}", + "165, T {'context': 'B-cells'}", + "166, cells {'context': 'I-cells'}", + "184, T {'context': 'B-cells'}", + "185, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "120, T ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "121, cells ['l0', 'l6', 'l7', 'l8', 'l9']", + "123, increased ['l1', 'l6', 'l10', 'l11', 'l12']", + "124, proliferation ['l2', 'l7', 'l10', 'l13', 'l14']", + "127, in ['l3', 'l8', 'l11', 'l13', 'l15']", + "128, vitro ['l4', 'l9', 'l12', 'l14', 'l15']", + "134, in ['l16', 'l17']", + "142, T ['l16', 'l18']", + "143, cells. ['l5', 'l17', 'l18']", + "152, patients ['l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "154, relapsed/refractory ['l19', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "155, pediatric ['l20', 'l28', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "156, B ['l21', 'l29', 'l36', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "157, cell ['l22', 'l30', 'l37', 'l43', 'l49', 'l50', 'l51', 'l52', 'l53']", + "158, acute ['l23', 'l31', 'l38', 'l44', 'l49', 'l54', 'l55', 'l56', 'l57']", + "159, lymphoblastic ['l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l58', 'l59', 'l60']", + "160, leukemia ['l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l58', 'l61', 'l62']", + "165, T ['l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l61', 'l63']", + "166, cells ['l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l62', 'l63']", + "184, T ['l64']", + "185, cell ['l64']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "31263281", + "TEXT": "The treatment of lymphatic anomaly, a rare devastating disease spectrum of mostly unknown etiologies, depends on the patient manifestations1. Identifying the causal genes will allow for developing affordable therapies in keeping with precision medicine implementation2. Here we identified a recurrent gain-of-function ARAF mutation (c.640T>C:p.S214P) in a 12-year-old boy with advanced anomalous lymphatic disease unresponsive to conventional sirolimus therapy and in another, unrelated, adult patient. The mutation led to loss of a conserved phosphorylation site. Cells transduced with ARAF-S214P showed elevated ERK1/2 activity, enhanced lymphangiogenic capacity, and disassembly of actin skeleton and VE-cadherin junctions, which were rescued using the MEK inhibitor trametinib. The functional relevance of the mutation was also validated by recreating a lymphatic phenotype in a zebrafish model, with rescue of the anomalous phenotype using a MEK inhibitor. Subsequent therapy of the lead proband with a MEK inhibitor led to dramatic clinical improvement, with remodeling of the patient's lymphatic system with resolution of the lymphatic edema, marked improvement in his pulmonary function tests, cessation of supplemental oxygen requirements and near normalization of daily activities. Our results provide a representative demonstration of how knowledge of genetic classification and mechanistic understanding guides biologically based medical treatments, which in our instance was life-saving.", + "TAG_DATA": [ + "74, Cells {'context': 'B-cells'}", + "75, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "76, with {'perturbing_action': 'I-gene gain-of-function'}", + "77, ARAF-S214P {'perturbing_action': 'I-gene gain-of-function'}", + "100, trametinib. {'perturbing_action': 'I-pharmacological inhibition'}", + "117, zebrafish {'context': 'B-organism'}", + "118, model, {'context': 'I-organism'}", + "127, MEK {'perturbing_action': 'B-pharmacological inhibition'}", + "128, inhibitor. {'perturbing_action': 'I-pharmacological inhibition'}", + "137, MEK {'perturbing_action': 'B-pharmacological inhibition'}", + "138, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "74, Cells ['l0', 'l1', 'l2', 'l3']", + "75, transduced ['l0', 'l4', 'l5', 'l6']", + "76, with ['l1', 'l4', 'l7', 'l8']", + "77, ARAF-S214P ['l2', 'l5', 'l7', 'l9']", + "100, trametinib. ['l3', 'l6', 'l8', 'l9', 'l10']", + "117, zebrafish ['l11', 'l12', 'l13']", + "118, model, ['l10', 'l11', 'l14', 'l15']", + "127, MEK ['l12', 'l14', 'l16']", + "128, inhibitor. ['l13', 'l15', 'l16']", + "137, MEK ['l17']", + "138, inhibitor ['l17']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "ARAF-S214P" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Cells" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "trametinib." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "trametinib.", + "MEK", + "inhibitor." + ] + }, + "context": { + "val": "organism", + "words": [ + "model,", + "zebrafish" + ] + } + } + ] + }, + { + "PMID": "30842678", + "TEXT": "Quantitative changes in leptin concentration lead to alterations in food intake and body weight, but the regulatory mechanisms that control leptin gene expression are poorly understood. Here we report that fat-specific and quantitative leptin expression is controlled by redundant cis elements and trans factors interacting with the proximal promoter together with a long noncoding RNA (lncOb). Diet-induced obese mice lacking lncOb show increased fat mass with reduced plasma leptin levels and lose weight after leptin treatment, whereas control mice do not. Consistent with this finding, large-scale genetic studies of humans reveal a significant association of single-nucleotide polymorphisms (SNPs) in the region of human lncOb with lower plasma leptin levels and obesity. These results show that reduced leptin gene expression can lead to a hypoleptinemic, leptin-responsive form of obesity and provide a framework for elucidating the pathogenic mechanism in the subset of obese patients with low endogenous leptin levels.", + "TAG_DATA": [ + "58, mice {'context': 'B-organism'}", + "59, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "60, lncOb {'perturbing_action': 'I-gene loss-of-function'}", + "78, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "58, mice ['l0', 'l1']", + "59, lacking ['l0', 'l2']", + "60, lncOb ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "lncOb" + ] + } + } + ] + }, + { + "PMID": "30833751", + "TEXT": "Cancer cells can evade immune surveillance through the expression of inhibitory ligands that bind their cognate receptors on immune effector cells. Expression of programmed death ligand 1 in tumor microenvironments is a major immune checkpoint for tumor-specific T cell responses as it binds to programmed cell death protein-1 on activated and dysfunctional T cells1. The activity of myeloid cells such as macrophages and neutrophils is likewise regulated by a balance between stimulatory and inhibitory signals. In particular, cell surface expression of the CD47 protein creates a 'don't eat me' signal on tumor cells by binding to SIRPα expressed on myeloid cells2-5. Using a haploid genetic screen, we here identify glutaminyl-peptide cyclotransferase-like protein (QPCTL) as a major component of the CD47-SIRPα checkpoint. Biochemical analysis demonstrates that QPCTL is critical for pyroglutamate formation on CD47 at the SIRPα binding site shortly after biosynthesis. Genetic and pharmacological interference with QPCTL activity enhances antibody-dependent cellular phagocytosis and cellular cytotoxicity of tumor cells. Furthermore, interference with QPCTL expression leads to a major increase in neutrophil-mediated killing of tumor cells in vivo. These data identify QPCTL as a novel target to interfere with the CD47 pathway and thereby augment antibody therapy of cancer.", + "TAG_DATA": [ + "147, activity {'perturbing_action': 'I-rnai/knockdown'}", + "148, enhances {'effect': 'B-positive'}", + "156, tumor {'context': 'B-transformed cells'}", + "157, cells. {'context': 'I-transformed cells'}", + "159, interference {'perturbing_action': 'B-rnai/knockdown'}", + "160, with {'perturbing_action': 'I-rnai/knockdown'}", + "161, QPCTL {'perturbing_action': 'I-rnai/knockdown'}", + "162, expression {'perturbing_action': 'I-rnai/knockdown'}", + "172, tumor {'context': 'B-transformed cells'}", + "173, cells {'context': 'I-transformed cells'}", + "174, in {'context': 'B-in vivo'}", + "175, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "146, QPCTL ['l0', 'l1', 'l2', 'l3']", + "147, activity ['l0', 'l4', 'l5', 'l6']", + "148, enhances ['l1', 'l4', 'l7', 'l8']", + "156, tumor ['l2', 'l5', 'l7', 'l9']", + "157, cells. ['l3', 'l6', 'l8', 'l9']", + "159, interference ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "160, with ['l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "161, QPCTL ['l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "162, expression ['l12', 'l18', 'l23', 'l28', 'l29', 'l30', 'l31']", + "172, tumor ['l13', 'l19', 'l24', 'l28', 'l32', 'l33', 'l34']", + "173, cells ['l14', 'l20', 'l25', 'l29', 'l32', 'l35', 'l36']", + "174, in ['l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l37']", + "175, vivo. ['l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "activity" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "activity", + "interference", + "with", + "QPCTL", + "expression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells.", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "interference", + "with", + "QPCTL", + "expression" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "30833748", + "TEXT": "Pancreatic ductal adenocarcinoma (PDA) was responsible for ~ 44,000 deaths in the United States in 2018 and is the epitome of a recalcitrant cancer driven by a pharmacologically intractable oncoprotein, KRAS1-4. Downstream of KRAS, the RAF→MEK→ERK signaling pathway plays a central role in pancreatic carcinogenesis5. However, paradoxically, inhibition of this pathway has provided no clinical benefit to patients with PDA6. Here we show that inhibition of KRAS→RAF→MEK→ERK signaling elicits autophagy, a process of cellular recycling that protects PDA cells from the cytotoxic effects of KRAS pathway inhibition. Mechanistically, inhibition of MEK1/2 leads to activation of the LKB1→AMPK→ULK1 signaling axis, a key regulator of autophagy. Furthermore, combined inhibition of MEK1/2 plus autophagy displays synergistic anti-proliferative effects against PDA cell lines in vitro and promotes regression of xenografted patient-derived PDA tumors in mice. The observed effect of combination trametinib plus chloroquine was not restricted to PDA as other tumors, including patient-derived xenografts (PDX) of NRAS-mutated melanoma and BRAF-mutated colorectal cancer displayed similar responses. Finally, treatment of a patient with PDA with the combination of trametinib plus hydroxychloroquine resulted in a partial, but nonetheless striking disease response. These data suggest that this combination therapy may represent a novel strategy to target RAS-driven cancers.", + "TAG_DATA": [ + "63, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "67, elicits {'effect': 'B-positive'}", + "68, autophagy, {'phenotype': 'B-autophagy'}", + "76, PDA {'context': 'B-transformed cells'}", + "77, cells {'context': 'I-transformed cells'}", + "87, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "88, of {'perturbing_action': 'I-pharmacological inhibition'}", + "89, MEK1/2 {'perturbing_action': 'I-pharmacological inhibition'}", + "105, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "106, of {'perturbing_action': 'I-pharmacological inhibition'}", + "107, MEK1/2 {'perturbing_action': 'I-pharmacological inhibition'}", + "115, PDA {'context': 'B-transformed cells'}", + "116, cell {'context': 'I-transformed cells'}", + "117, lines {'context': 'I-transformed cells'}", + "118, in {'context': 'B-in vitro'}", + "119, vitro {'context': 'I-in vitro'}", + "121, promotes {'effect': 'B-positive'}", + "122, regression {'phenotype': 'B-tumour regression'}", + "124, xenografted {'context': 'B-xenograft'}", + "125, patient-derived {'context': 'I-xenograft'}", + "126, PDA {'context': 'I-xenograft'}", + "127, tumors {'context': 'I-xenograft'}", + "129, mice. {'context': 'B-organism'}", + "145, tumors, {'context': 'B-neoplasm'}", + "147, patient-derived {'context': 'B-xenograft'}", + "148, xenografts {'context': 'I-xenograft'}", + "149, (PDX) {'context': 'I-xenograft'}", + "155, colorectal {'context': 'B-neoplasm'}", + "156, cancer {'context': 'I-neoplasm'}", + "164, patient {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "63, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "67, elicits ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "68, autophagy, ['l1', 'l15', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "76, PDA ['l2', 'l16', 'l24', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "77, cells ['l3', 'l17', 'l25', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "87, inhibition ['l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "88, of ['l46', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "89, MEK1/2 ['l47', 'l63', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "105, inhibition ['l48', 'l64', 'l79', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "106, of ['l49', 'l65', 'l80', 'l94', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "107, MEK1/2 ['l50', 'l66', 'l81', 'l95', 'l108', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "115, PDA ['l4', 'l18', 'l26', 'l34', 'l40', 'l51', 'l67', 'l82', 'l96', 'l109', 'l121', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "116, cell ['l5', 'l19', 'l27', 'l35', 'l41', 'l52', 'l68', 'l83', 'l97', 'l110', 'l122', 'l133', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "117, lines ['l6', 'l20', 'l28', 'l36', 'l42', 'l53', 'l69', 'l84', 'l98', 'l111', 'l123', 'l134', 'l144', 'l153', 'l154', 'l155', 'l156', 'l157']", + "118, in ['l7', 'l21', 'l29', 'l37', 'l43', 'l54', 'l70', 'l85', 'l99', 'l112', 'l124', 'l135', 'l145', 'l153', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "119, vitro ['l8', 'l22', 'l30', 'l38', 'l44', 'l55', 'l71', 'l86', 'l100', 'l113', 'l125', 'l136', 'l146', 'l154', 'l158', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "121, promotes ['l9', 'l23', 'l31', 'l39', 'l45', 'l56', 'l72', 'l87', 'l101', 'l114', 'l126', 'l137', 'l147', 'l155', 'l159', 'l166', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "122, regression ['l10', 'l57', 'l73', 'l88', 'l102', 'l115', 'l127', 'l138', 'l148', 'l160', 'l167', 'l173', 'l179', 'l180', 'l181', 'l182', 'l183']", + "124, xenografted ['l58', 'l74', 'l89', 'l103', 'l116', 'l128', 'l139', 'l161', 'l168', 'l174', 'l179', 'l184', 'l185', 'l186', 'l187']", + "125, patient-derived ['l11', 'l59', 'l75', 'l90', 'l104', 'l117', 'l129', 'l140', 'l149', 'l162', 'l169', 'l175', 'l180', 'l184', 'l188', 'l189', 'l190']", + "126, PDA ['l12', 'l60', 'l76', 'l91', 'l105', 'l118', 'l130', 'l141', 'l150', 'l156', 'l163', 'l170', 'l176', 'l181', 'l185', 'l188', 'l191', 'l192']", + "127, tumors ['l13', 'l32', 'l61', 'l77', 'l92', 'l106', 'l119', 'l131', 'l142', 'l151', 'l157', 'l164', 'l171', 'l177', 'l182', 'l186', 'l189', 'l191', 'l193']", + "129, mice. ['l14', 'l62', 'l78', 'l93', 'l107', 'l120', 'l132', 'l143', 'l152', 'l165', 'l172', 'l178', 'l183', 'l187', 'l190', 'l192', 'l193']", + "145, tumors, ['l194', 'l195', 'l196', 'l197', 'l198', 'l199']", + "147, patient-derived ['l194', 'l200', 'l201', 'l202', 'l203', 'l204']", + "148, xenografts ['l195', 'l200', 'l205', 'l206', 'l207', 'l208']", + "149, (PDX) ['l196', 'l201', 'l205', 'l209', 'l210', 'l211']", + "152, melanoma ['l197', 'l202', 'l206', 'l209', 'l212', 'l213']", + "155, colorectal ['l198', 'l203', 'l207', 'l210', 'l212', 'l214']", + "156, cancer ['l199', 'l204', 'l208', 'l211', 'l213', 'l214']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "MEK1/2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "elicits", + "promotes" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "MEK1/2" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "PDA", + "cells", + "cell", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "MEK1/2" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "MEK1/2" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "MEK1/2" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "patient-derived", + "PDA", + "tumors", + "xenografted" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "MEK1/2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "elicits", + "promotes" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "elicits", + "promotes" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "PDA", + "cells", + "cell", + "lines" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "elicits", + "promotes" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "PDA", + "cells", + "cell", + "lines" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + }, + "context": { + "val": "xenograft", + "words": [ + "tumors" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "PDA", + "cell" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenografted", + "patient-derived", + "PDA", + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenografted", + "patient-derived", + "PDA", + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "30742122", + "TEXT": "Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.", + "TAG_DATA": [ + "48, recurrent, {'context': 'B-neoplasm'}", + "49, surgically {'context': 'I-neoplasm'}", + "50, resectable {'context': 'I-neoplasm'}", + "51, glioblastoma. {'context': 'I-neoplasm'}", + "111, tumor, {'context': 'B-neoplasm'}", + "131, tumor {'context': 'B-neoplasm'}", + "133, enhanced {'effect': 'B-positive'}", + "134, clonal {'phenotype': 'B-colony formation'}", + "135, expansion {'phenotype': 'I-colony formation'}", + "137, T {'context': 'B-cells'}", + "138, cells, {'context': 'B-cells'}", + "143, peripheral {'context': 'B-cells'}", + "144, blood {'context': 'I-cells'}", + "145, T {'context': 'I-cells'}", + "146, cells {'context': 'I-cells'}", + "150, monocytic {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "48, recurrent, ['l0', 'l1', 'l2']", + "49, surgically ['l0', 'l3', 'l4']", + "50, resectable ['l1', 'l3', 'l5']", + "51, glioblastoma. ['l2', 'l4', 'l5']", + "131, tumor ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "133, enhanced ['l6', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "134, clonal ['l7', 'l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "135, expansion ['l8', 'l16', 'l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "137, T ['l9', 'l17', 'l24', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "138, cells, ['l10', 'l18', 'l25', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "143, peripheral ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l45', 'l46', 'l47', 'l48']", + "144, blood ['l12', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l49', 'l50']", + "145, T ['l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l49', 'l51']", + "146, cells ['l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "150, monocytic ['l48']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonal", + "expansion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonal", + "expansion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells,", + "peripheral", + "blood", + "cells" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "clonal", + "expansion" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells,", + "peripheral", + "blood", + "cells" + ] + } + } + ] + }, + { + "PMID": "30643287", + "TEXT": "Primary tumors may create the premetastatic niche in secondary organs for subsequent metastasis. Humoral immunity contributes to the progression of certain cancers, but the roles of B cells and their derived antibodies in premetastatic niche formation are poorly defined. Using a mouse model of spontaneous lymph node metastasis of breast cancer, we show that primary tumors induced B cell accumulation in draining lymph nodes. These B cells selectively promoted lymph node metastasis by producing pathogenic IgG that targeted glycosylated membrane protein HSPA4, and activated the HSPA4-binding protein ITGB5 and the downstream Src/NF-κB pathway in tumor cells for CXCR4/SDF1α-axis-mediated metastasis. High serum anti-HSPA4 IgG was correlated with high tumor HSPA4 expression and poor prognosis of breast cancer subjects. Our findings identify a key role for tumor-educated B cells and their derived antibodies in lymph node premetastatic niche formation, providing potential targets for cancer intervention.", + "TAG_DATA": [ + "41, mouse {'context': 'B-organism'}", + "42, model {'context': 'I-organism'}", + "54, primary {'context': 'B-neoplasm'}", + "55, tumors {'context': 'I-neoplasm'}", + "57, B {'context': 'B-cells'}", + "58, cell {'context': 'I-cells'}", + "61, draining {'context': 'B-tissue/organ'}", + "62, lymph {'context': 'I-tissue/organ'}", + "63, nodes. {'context': 'I-tissue/organ'}", + "65, B {'context': 'B-cells'}", + "66, cells {'context': 'I-cells'}", + "68, promoted {'effect': 'B-positive'}", + "69, lymph {'phenotype': 'B-metastasis'}", + "70, node {'phenotype': 'I-metastasis'}", + "71, metastasis {'phenotype': 'I-metastasis'}", + "94, tumor {'context': 'B-transformed cells'}", + "95, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "41, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "42, model ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "54, primary ['l1', 'l6', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "55, tumors ['l2', 'l7', 'l11', 'l19', 'l20', 'l21', 'l22', 'l23']", + "57, B ['l3', 'l8', 'l12', 'l19', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "58, cell ['l4', 'l9', 'l13', 'l20', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "61, draining ['l14', 'l21', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "62, lymph ['l15', 'l22', 'l26', 'l31', 'l35', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "63, nodes. ['l5', 'l10', 'l16', 'l23', 'l27', 'l32', 'l36', 'l43', 'l50', 'l51']", + "65, B ['l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "66, cells ['l37', 'l44', 'l52', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "68, promoted ['l38', 'l45', 'l53', 'l59', 'l65', 'l66', 'l67', 'l68', 'l69']", + "69, lymph ['l39', 'l46', 'l54', 'l60', 'l65', 'l70', 'l71', 'l72', 'l73']", + "70, node ['l17', 'l28', 'l33', 'l40', 'l47', 'l50', 'l55', 'l61', 'l66', 'l70', 'l74', 'l75', 'l76']", + "71, metastasis ['l18', 'l29', 'l34', 'l41', 'l48', 'l51', 'l56', 'l62', 'l67', 'l71', 'l74', 'l77', 'l78']", + "94, tumor ['l57', 'l63', 'l68', 'l72', 'l75', 'l77', 'l79']", + "95, cells ['l42', 'l49', 'l58', 'l64', 'l69', 'l73', 'l76', 'l78', 'l79']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "primary" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "node", + "metastasis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "B", + "cell", + "cells" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "node", + "metastasis", + "lymph" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "draining", + "lymph" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "draining", + "lymph", + "nodes." + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "lymph", + "node", + "metastasis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "B", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "lymph", + "node", + "metastasis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "lymph", + "node", + "metastasis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + } + ] + }, + { + "PMID": "30617325", + "TEXT": "Defective brain hormonal signaling has been associated with Alzheimer's disease (AD), a disorder characterized by synapse and memory failure. Irisin is an exercise-induced myokine released on cleavage of the membrane-bound precursor protein fibronectin type III domain-containing protein 5 (FNDC5), also expressed in the hippocampus. Here we show that FNDC5/irisin levels are reduced in AD hippocampi and cerebrospinal fluid, and in experimental AD models. Knockdown of brain FNDC5/irisin impairs long-term potentiation and novel object recognition memory in mice. Conversely, boosting brain levels of FNDC5/irisin rescues synaptic plasticity and memory in AD mouse models. Peripheral overexpression of FNDC5/irisin rescues memory impairment, whereas blockade of either peripheral or brain FNDC5/irisin attenuates the neuroprotective actions of physical exercise on synaptic plasticity and memory in AD mice. By showing that FNDC5/irisin is an important mediator of the beneficial effects of exercise in AD models, our findings place FNDC5/irisin as a novel agent capable of opposing synapse failure and memory impairment in AD.", + "TAG_DATA": [ + "63, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "64, of {'perturbing_action': 'I-rnai/knockdown'}", + "65, brain {'perturbing_action': 'I-rnai/knockdown'}", + "66, FNDC5/irisin {'perturbing_action': 'I-rnai/knockdown'}", + "76, mice. {'context': 'B-organism'}", + "78, boosting {'perturbing_action': 'B-gene gain-of-function'}", + "79, brain {'perturbing_action': 'I-gene gain-of-function'}", + "80, levels {'perturbing_action': 'I-gene gain-of-function'}", + "81, of {'perturbing_action': 'I-gene gain-of-function'}", + "82, FNDC5/irisin {'perturbing_action': 'I-gene gain-of-function'}", + "89, AD {'context': 'B-organism'}", + "90, mouse {'context': 'I-organism'}", + "91, models. {'context': 'I-organism'}", + "92, Peripheral {'perturbing_action': 'B-gene gain-of-function'}", + "93, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "94, of {'perturbing_action': 'I-gene gain-of-function'}", + "95, FNDC5/irisin {'perturbing_action': 'I-gene gain-of-function'}", + "101, of {'perturbing_action': 'I-rnai/knockdown'}", + "104, or {'perturbing_action': 'I-rnai/knockdown'}", + "105, brain {'perturbing_action': 'I-rnai/knockdown'}", + "106, FNDC5/irisin {'perturbing_action': 'I-rnai/knockdown'}", + "120, AD {'context': 'B-organism'}", + "121, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "63, Knockdown ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "64, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "65, brain ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "66, FNDC5/irisin ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21', 'l22']", + "76, mice. ['l3', 'l9', 'l14', 'l18']", + "78, boosting ['l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "79, brain ['l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "80, levels ['l24', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "81, of ['l19', 'l25', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "82, FNDC5/irisin ['l26', 'l32', 'l37', 'l41', 'l45', 'l46', 'l47']", + "89, AD ['l4', 'l10', 'l15', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l48', 'l49']", + "90, mouse ['l5', 'l11', 'l16', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l50']", + "91, models. ['l6', 'l12', 'l17', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l50']", + "92, Peripheral ['l51', 'l52', 'l53', 'l54', 'l55']", + "93, overexpression ['l51', 'l56', 'l57', 'l58']", + "94, of ['l52', 'l56', 'l59', 'l60']", + "95, FNDC5/irisin ['l53', 'l57', 'l59']", + "101, of ['l61', 'l62', 'l63', 'l64', 'l65']", + "104, or ['l61', 'l66', 'l67', 'l68', 'l69']", + "105, brain ['l62', 'l66', 'l70', 'l71', 'l72']", + "106, FNDC5/irisin ['l63', 'l67', 'l70', 'l73', 'l74']", + "120, AD ['l54', 'l64', 'l68', 'l71', 'l73', 'l75']", + "121, mice. ['l55', 'l58', 'l60', 'l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "brain", + "FNDC5/irisin", + "or" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "AD", + "mouse", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "boosting", + "brain", + "levels", + "of", + "FNDC5/irisin", + "Peripheral", + "overexpression" + ] + }, + "context": { + "val": "organism", + "words": [ + "AD", + "mouse", + "models.", + "mice." + ] + } + } + ] + }, + { + "PMID": "30510257", + "TEXT": "Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.", + "TAG_DATA": [ + "81, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "82, of {'perturbing_action': 'I-gene gain-of-function'}", + "83, miR-203, {'perturbing_action': 'I-gene gain-of-function'}", + "102, induces {'effect': 'B-positive'}", + "104, cell {'phenotype': 'B-cell death'}", + "105, death, {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "81, overexpression ['l0', 'l1', 'l2', 'l3', 'l4']", + "82, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "83, miR-203, ['l1', 'l5', 'l9', 'l10', 'l11']", + "102, induces ['l2', 'l6', 'l9', 'l12', 'l13']", + "104, cell ['l3', 'l7', 'l10', 'l12', 'l14']", + "105, death, ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "miR-203," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "miR-203," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + } + ] + }, + { + "PMID": "30510256", + "TEXT": "The melanoma genome is dominated by ultraviolet radiation (UVR)-induced mutations. Their relevance in disease progression is unknown. Here we classify melanomas by mutation signatures and identify ten recurrently mutated UVR signature genes that predict patient survival. We validate these findings in primary human melanomas; in mice we show that this signature is imprinted by short-wavelength UVR and that four exposures to UVR are sufficient to accelerate melanomagenesis.", + "TAG_DATA": [ + "41, primary {'context': 'B-neoplasm'}", + "42, human {'context': 'I-neoplasm'}", + "43, melanomas; {'context': 'I-neoplasm'}", + "45, mice {'context': 'B-organism'}", + "65, accelerate {'effect': 'B-positive'}", + "66, melanomagenesis. {'phenotype': 'B-tumourigenesis'}" + ], + "LINK_DATA": [ + "41, primary ['l0', 'l1', 'l2']", + "42, human ['l0', 'l3', 'l4']", + "43, melanomas; ['l1', 'l3', 'l5']", + "45, mice ['l6', 'l7']", + "65, accelerate ['l2', 'l4', 'l5', 'l6', 'l8']", + "66, melanomagenesis. ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "primary", + "human", + "melanomas;" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerate" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerate" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "melanomagenesis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "accelerate" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "melanomagenesis." + ] + } + } + ] + }, + { + "PMID": "30420752", + "TEXT": "Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Leukemia stem cells (LSCs) drive the initiation and perpetuation of AML, are quantifiably associated with worse clinical outcomes, and often persist after conventional chemotherapy resulting in relapse1-5. In this report, we show that treatment of older patients with AML with the B cell lymphoma 2 (BCL-2) inhibitor venetoclax in combination with azacitidine results in deep and durable remissions and is superior to conventional treatments. We hypothesized that these promising clinical results were due to targeting LSCs. Analysis of LSCs from patients undergoing treatment with venetoclax + azacitidine showed disruption of the tricarboxylic acid (TCA) cycle manifested by decreased α-ketoglutarate and increased succinate levels, suggesting inhibition of electron transport chain complex II. In vitro modeling confirmed inhibition of complex II via reduced glutathionylation of succinate dehydrogenase. These metabolic perturbations suppress oxidative phosphorylation (OXPHOS), which efficiently and selectively targets LSCs. Our findings show for the first time that a therapeutic intervention can eradicate LSCs in patients with AML by disrupting the metabolic machinery driving energy metabolism, resulting in promising clinical activity in a patient population with historically poor outcomes.", + "TAG_DATA": [ + "47, older {'context': 'B-patient'}", + "48, patients {'context': 'I-patient'}", + "49, with {'context': 'I-patient'}", + "50, AML {'context': 'I-patient'}", + "53, B {'perturbing_action': 'B-pharmacological inhibition'}", + "56, 2 {'perturbing_action': 'I-pharmacological inhibition'}", + "57, (BCL-2) {'perturbing_action': 'I-pharmacological inhibition'}", + "58, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "90, LSCs {'context': 'B-transformed cells'}", + "92, patients {'context': 'B-patient'}", + "121, In {'context': 'B-in vitro'}", + "122, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "47, older ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "48, patients ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "49, with ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "50, AML ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "53, B ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "54, cell ['l4', 'l13', 'l21', 'l28', 'l34', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "55, lymphoma ['l5', 'l14', 'l22', 'l29', 'l35', 'l41', 'l47', 'l48', 'l49', 'l50', 'l51']", + "56, 2 ['l6', 'l15', 'l23', 'l30', 'l36', 'l42', 'l47', 'l52', 'l53', 'l54', 'l55']", + "57, (BCL-2) ['l7', 'l16', 'l24', 'l31', 'l37', 'l43', 'l48', 'l52', 'l56', 'l57', 'l58']", + "58, inhibitor ['l8', 'l17', 'l25', 'l32', 'l38', 'l44', 'l49', 'l53', 'l56', 'l59', 'l60']", + "90, LSCs ['l9', 'l18', 'l26', 'l33', 'l39', 'l45', 'l50', 'l54', 'l57', 'l59', 'l61']", + "92, patients ['l40', 'l46', 'l51', 'l55', 'l58', 'l60', 'l61']", + "121, In ['l62']", + "122, vitro ['l62']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "patient", + "words": [ + "older", + "patients", + "with", + "AML" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "B", + "2", + "(BCL-2)", + "inhibitor" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "B", + "2", + "(BCL-2)", + "inhibitor" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "LSCs" + ] + } + } + ] + }, + { + "PMID": "30374199", + "TEXT": "Mutationally activated BRAFV600E influences the behavior of different types of cells in the brain and leads to promotion of seizures as well as brain tumors, indicating how both can be pharmacologically targeted in the clinic.", + "TAG_DATA": [ + "1, activated {'perturbing_action': 'I-other'}", + "2, BRAFV600E {'perturbing_action': 'I-other'}", + "10, cells {'context': 'B-cells'}", + "13, brain {'context': 'B-tissue/organ'}", + "17, promotion {'effect': 'B-positive'}", + "23, brain {'context': 'B-neoplasm'}", + "24, tumors, {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "1, activated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "2, BRAFV600E ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "10, cells ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "11, in ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "12, the ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "13, brain ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "17, promotion ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "23, brain ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "24, tumors, ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "activated", + "BRAFV600E" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "activated", + "BRAFV600E" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "activated", + "BRAFV600E" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotion" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "activated", + "BRAFV600E" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "brain", + "tumors," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotion" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "brain" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotion" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "brain", + "tumors," + ] + } + } + ] + }, + { + "PMID": "30374197", + "TEXT": "The discovery of the highly efficient site-specific nuclease system CRISPR-Cas9 from Streptococcus pyogenes has galvanized the field of gene therapy1,2. The immunogenicity of Cas9 nuclease has been demonstrated in mice3,4. Preexisting immunity against therapeutic gene vectors or their cargo can decrease the efficacy of a potentially curative treatment and may pose significant safety issues3-6. S. pyogenes is a common cause for infectious diseases in humans, but it remains unclear whether it induces a T cell memory against the Cas9 nuclease7,8. Here, we show the presence of a preexisting ubiquitous effector T cell response directed toward the most widely used Cas9 homolog from S. pyogenes (SpCas9) within healthy humans. We characterize SpCas9-reactive T cells within the CD4/CD8 compartments for multi-effector potency, cytotoxicity, and lineage determination. In-depth analysis of SpCas9-reactive T cells reveals a high frequency of SpCas9-reactive regulatory T cells that can mitigate SpCas9-reactive effector T cell proliferation and function in vitro. Our results shed light on T cell-mediated immunity toward CRISPR-associated nucleases and offer a possible solution to overcome the problem of preexisting immunity.", + "TAG_DATA": [ + "128, T {'context': 'I-cells'}", + "129, cells {'context': 'I-cells'}", + "136, regulatory {'context': 'B-cells'}", + "137, T {'context': 'I-cells'}", + "138, cells {'context': 'I-cells'}", + "141, mitigate {'effect': 'B-negative'}", + "143, effector {'context': 'B-cells'}", + "144, T {'context': 'I-cells'}", + "145, cell {'context': 'I-cells'}", + "146, proliferation {'phenotype': 'B-proliferation'}", + "149, in {'context': 'B-in vitro'}", + "150, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "128, T ['l0', 'l1', 'l2']", + "129, cells ['l0', 'l3', 'l4']", + "136, regulatory ['l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "137, T ['l1', 'l3', 'l5', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "138, cells ['l2', 'l4', 'l6', 'l14', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "141, mitigate ['l7', 'l15', 'l22', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "143, effector ['l8', 'l16', 'l23', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "144, T ['l9', 'l17', 'l24', 'l30', 'l35', 'l40', 'l41', 'l42', 'l43']", + "145, cell ['l10', 'l18', 'l25', 'l31', 'l36', 'l40', 'l44', 'l45', 'l46']", + "146, proliferation ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l47', 'l48']", + "149, in ['l12', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l49']", + "150, vitro. ['l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l49']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "regulatory", + "T", + "cells", + "effector", + "cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "mitigate" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "regulatory", + "T", + "cells", + "effector", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "mitigate" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "mitigate" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "30297904", + "TEXT": "CRISPR-Cas-based genome editing holds great promise for targeting genetic disorders, including inborn errors of hepatocyte metabolism. Precise correction of disease-causing mutations in adult tissues in vivo, however, is challenging. It requires repair of Cas9-induced double-stranded DNA (dsDNA) breaks by homology-directed mechanisms, which are highly inefficient in nondividing cells. Here we corrected the disease phenotype of adult phenylalanine hydroxylase (Pah)enu2 mice, a model for the human autosomal recessive liver disease phenylketonuria (PKU)1, using recently developed CRISPR-Cas-associated base editors2-4. These systems enable conversion of C∙G to T∙A base pairs and vice versa, independent of dsDNA break formation and homology-directed repair (HDR). We engineered and validated an intein-split base editor, which allows splitting of the fusion protein into two parts, thereby circumventing the limited cargo capacity of adeno-associated virus (AAV) vectors. Intravenous injection of AAV-base editor systems resulted in Pahenu2 gene correction rates that restored physiological blood phenylalanine (L-Phe) levels below 120 µmol/l [5]. We observed mRNA correction rates up to 63%, restoration of phenylalanine hydroxylase (PAH) enzyme activity, and reversion of the light fur phenotype in Pahenu2 mice. Our findings suggest that targeting genetic diseases in vivo using AAV-mediated delivery of base-editing agents is feasible, demonstrating potential for therapeutic application.", + "TAG_DATA": [ + "59, mice, {'context': 'B-organism'}", + "174, Pahenu2 {'perturbing_action': 'B-other'}", + "175, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "174, Pahenu2 ['l0']", + "175, mice. ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Pahenu2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "30297903", + "TEXT": "In utero gene editing has the potential to prenatally treat genetic diseases that result in significant morbidity and mortality before or shortly after birth. We assessed the viral vector-mediated delivery of CRISPR-Cas9 or base editor 3 in utero, seeking therapeutic modification of Pcsk9 or Hpd in wild-type mice or the murine model of hereditary tyrosinemia type 1, respectively. We observed long-term postnatal persistence of edited cells in both models, with reduction of plasma PCSK9 and cholesterol levels following in utero Pcsk9 targeting and rescue of the lethal phenotype of hereditary tyrosinemia type 1 following in utero Hpd targeting. The results of this proof-of-concept work demonstrate the possibility of efficiently performing gene editing before birth, pointing to a potential new therapeutic approach for selected congenital genetic disorders.", + "TAG_DATA": [ + "47, mice {'context': 'B-organism'}", + "50, murine {'context': 'B-organism'}", + "51, model {'context': 'I-organism'}", + "65, cells {'context': 'B-cells'}", + "80, Pcsk9 {'perturbing_action': 'I-other'}", + "81, targeting {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "47, mice ['l0', 'l1']", + "50, murine ['l0', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "51, model ['l1', 'l2', 'l8', 'l9', 'l10']", + "65, cells ['l3', 'l8', 'l11', 'l12', 'l13', 'l14']", + "78, in ['l4', 'l11', 'l15', 'l16', 'l17']", + "79, utero ['l5', 'l12', 'l15', 'l18', 'l19']", + "80, Pcsk9 ['l6', 'l9', 'l13', 'l16', 'l18', 'l20']", + "81, targeting ['l7', 'l10', 'l14', 'l17', 'l19', 'l20']", + "94, in ['l21', 'l22']", + "96, Hpd ['l21', 'l23']", + "97, targeting. ['l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "murine", + "model" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Pcsk9", + "targeting" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Pcsk9", + "targeting" + ] + } + } + ] + }, + { + "PMID": "30275566", + "TEXT": "Chronic kidney disease (CKD), a condition in which the kidneys are unable to clear waste products, affects 700 million people globally. Genome-wide association studies (GWASs) have identified sequence variants for CKD; however, the biological basis of these GWAS results remains poorly understood. To address this issue, we created an expression quantitative trait loci (eQTL) atlas for the glomerular and tubular compartments of the human kidney. Through integrating the CKD GWAS with eQTL, single-cell RNA sequencing and regulatory region maps, we identified novel genes for CKD. Putative causal genes were enriched for proximal tubule expression and endolysosomal function, where DAB2, an adaptor protein in the TGF-β pathway, formed a central node. Functional experiments confirmed that reducing Dab2 expression in renal tubules protected mice from CKD. In conclusion, compartment-specific eQTL analysis is an important avenue for the identification of novel genes and cellular pathways involved in CKD development and thus potential new opportunities for its treatment.", + "TAG_DATA": [ + "114, reducing {'perturbing_action': 'B-gene loss-of-function'}", + "115, Dab2 {'perturbing_action': 'I-rnai/knockdown'}", + "116, expression {'perturbing_action': 'I-rnai/knockdown'}", + "121, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "114, reducing ['l0', 'l1', 'l2']", + "115, Dab2 ['l0', 'l3', 'l4']", + "116, expression ['l1', 'l3', 'l5']", + "121, mice ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "reducing" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Dab2", + "expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "30224756", + "TEXT": "Pediatric brain tumors are highly associated with epileptic seizures1. However, their epileptogenic mechanisms remain unclear. Here, we show that the oncogenic BRAF somatic mutation p.Val600Glu (V600E) in developing neurons underlies intrinsic epileptogenicity in ganglioglioma, one of the leading causes of intractable epilepsy2. To do so, we developed a mouse model harboring the BRAFV600E somatic mutation during early brain development to reflect the most frequent mutation, as well as the origin and timing thereof. Therein, the BRAFV600E mutation arising in progenitor cells during brain development led to the acquisition of intrinsic epileptogenic properties in neuronal lineage cells, whereas tumorigenic properties were attributed to high proliferation of glial lineage cells. RNA sequencing analysis of patient brain tissues with the mutation revealed that BRAFV600E-induced epileptogenesis is mediated by RE1-silencing transcription factor (REST), which is a regulator of ion channels and neurotransmitter receptors associated with epilepsy. Moreover, we found that seizures in mice were significantly alleviated by an FDA-approved BRAFV600E inhibitor, vemurafenib, as well as various genetic inhibitions of Rest. Accordingly, this study provides direct evidence of a BRAF somatic mutation contributing to the intrinsic epileptogenicity in pediatric brain tumors and suggests that BRAF and REST could be treatment targets for intractable epilepsy.", + "TAG_DATA": [ + "48, mouse {'context': 'B-organism'}", + "49, model {'context': 'I-organism'}", + "93, neuronal {'context': 'B-cells'}", + "94, lineage {'context': 'I-cells'}", + "95, cells, {'context': 'I-cells'}", + "97, tumorigenic {'phenotype': 'B-tumourigenesis'}", + "103, proliferation {'phenotype': 'B-proliferation'}", + "105, glial {'context': 'B-cells'}", + "106, lineage {'context': 'I-cells'}", + "107, cells. {'context': 'I-cells'}", + "148, mice {'context': 'B-organism'}", + "155, BRAFV600E {'perturbing_action': 'B-pharmacological inhibition'}", + "156, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "48, mouse ['l0', 'l1', 'l2', 'l3']", + "49, model ['l0', 'l4', 'l5', 'l6']", + "93, neuronal ['l1', 'l4', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "94, lineage ['l2', 'l5', 'l7', 'l13']", + "95, cells, ['l3', 'l6', 'l8', 'l13']", + "97, tumorigenic ['l9', 'l14', 'l15', 'l16', 'l17']", + "103, proliferation ['l10', 'l14', 'l18', 'l19', 'l20']", + "105, glial ['l15', 'l18', 'l21', 'l22']", + "106, lineage ['l11', 'l16', 'l19', 'l21', 'l23']", + "107, cells. ['l12', 'l17', 'l20', 'l22', 'l23']", + "148, mice ['l24', 'l25']", + "155, BRAFV600E ['l24', 'l26']", + "156, inhibitor, ['l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "neuronal", + "glial", + "lineage", + "cells." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenic" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neuronal", + "glial", + "lineage", + "cells." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BRAFV600E", + "inhibitor," + ] + } + } + ] + }, + { + "PMID": "30082863", + "TEXT": "Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite that enhances both platelet responsiveness and in vivo thrombosis potential in animal models, and TMAO plasma levels predict incident atherothrombotic event risks in human clinical studies. TMAO is formed by gut microbe-dependent metabolism of trimethylamine (TMA) moiety-containing nutrients, which are abundant in a Western diet. Here, using a mechanism-based inhibitor approach targeting a major microbial TMA-generating enzyme pair, CutC and CutD (CutC/D), we developed inhibitors that are potent, time-dependent, and irreversible and that do not affect commensal viability. In animal models, a single oral dose of a CutC/D inhibitor significantly reduced plasma TMAO levels for up to 3 d and rescued diet-induced enhanced platelet responsiveness and thrombus formation, without observable toxicity or increased bleeding risk. The inhibitor selectively accumulated within intestinal microbes to millimolar levels, a concentration over 1-million-fold higher than needed for a therapeutic effect. These studies reveal that mechanism-based inhibition of gut microbial TMA and TMAO production reduces thrombosis potential, a critical adverse complication in heart disease. They also offer a generalizable approach for the selective nonlethal targeting of gut microbial enzymes linked to host disease limiting systemic exposure of the inhibitor in the host.", + "TAG_DATA": [ + "87, animal {'context': 'B-organism'}", + "88, models, {'context': 'I-organism'}", + "95, CutC/D {'perturbing_action': 'B-pharmacological inhibition'}", + "96, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "111, platelet {'context': 'B-cells'}", + "114, thrombus {'phenotype': 'B-tumourigenesis'}", + "115, formation, {'phenotype': 'I-tumourigenesis'}" + ], + "LINK_DATA": [ + "87, animal ['l0', 'l1', 'l2']", + "88, models, ['l0', 'l3', 'l4']", + "95, CutC/D ['l5', 'l6', 'l7', 'l8']", + "96, inhibitor ['l5', 'l9', 'l10', 'l11']", + "111, platelet ['l1', 'l3', 'l6', 'l9', 'l12', 'l13']", + "114, thrombus ['l7', 'l10', 'l12', 'l14']", + "115, formation, ['l2', 'l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "animal", + "models," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CutC/D", + "inhibitor" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelet" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CutC/D", + "inhibitor" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "thrombus", + "formation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "platelet" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "thrombus", + "formation," + ] + } + } + ] + }, + { + "PMID": "30038221", + "TEXT": "Cellular transformation is accompanied by extensive rewiring of many biological processes leading to augmented levels of distinct types of cellular stress, including proteotoxic stress. Cancer cells critically depend on stress-relief pathways for their survival. However, the mechanisms underlying the transcriptional initiation and maintenance of the oncogenic stress response remain elusive. Here, we show that the expression of heat shock transcription factor 1 (HSF1) and the downstream mediators of the heat shock response is transcriptionally upregulated in T cell acute lymphoblastic leukemia (T-ALL). Hsf1 ablation suppresses the growth of human T-ALL and eradicates leukemia in mouse models of T-ALL, while sparing normal hematopoiesis. HSF1 drives a compact transcriptional program and among the direct HSF1 targets, specific chaperones and co-chaperones mediate its critical role in T-ALL. Notably, we demonstrate that the central T-ALL oncogene NOTCH1 hijacks the cellular stress response machinery by inducing the expression of HSF1 and its downstream effectors. The NOTCH1 signaling status controls the levels of chaperone/co-chaperone complexes and predicts the response of T-ALL patient samples to HSP90 inhibition. Our data demonstrate an integral crosstalk between mediators of oncogene and non-oncogene addiction and reveal critical nodes of the heat shock response pathway that can be targeted therapeutically.", + "TAG_DATA": [ + "82, Hsf1 {'perturbing_action': 'B-gene loss-of-function'}", + "83, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "88, human {'context': 'B-neoplasm'}", + "89, T-ALL {'context': 'I-neoplasm'}", + "92, leukemia {'context': 'B-neoplasm'}", + "94, mouse {'context': 'B-organism'}", + "95, models {'context': 'I-neoplasm'}", + "96, of {'context': 'I-neoplasm'}", + "97, T-ALL, {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "82, Hsf1 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "83, ablation ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "88, human ['l1', 'l8', 'l15']", + "89, T-ALL ['l2', 'l9', 'l15']", + "92, leukemia ['l3', 'l10', 'l16', 'l17', 'l18', 'l19']", + "94, mouse ['l4', 'l11', 'l16', 'l20', 'l21', 'l22']", + "95, models ['l5', 'l12', 'l17', 'l20', 'l23', 'l24']", + "96, of ['l6', 'l13', 'l18', 'l21', 'l23', 'l25']", + "97, T-ALL, ['l7', 'l14', 'l19', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hsf1", + "ablation" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "T-ALL", + "leukemia", + "models", + "of", + "T-ALL," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hsf1", + "ablation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + } + ] + }, + { + "PMID": "30038218", + "TEXT": "Despite decades of research, our understanding of the processes controlling late-stage atherosclerotic plaque stability remains poor. A prevailing hypothesis is that reducing inflammation may improve advanced plaque stability, as recently tested in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial, in which post-myocardial infarction subjects were treated with an IL-1β antibody. Here, we performed intervention studies in which smooth muscle cell (SMC) lineage-tracing Apoe-/- mice with advanced atherosclerosis were treated with anti-IL-1β or IgG control antibodies. Surprisingly, we found that IL-1β antibody treatment between 18 and 26 weeks of Western diet feeding induced a marked reduction in SMC and collagen content, but increased macrophage numbers in the fibrous cap. Moreover, although IL-1β antibody treatment had no effect on lesion size, it completely inhibited beneficial outward remodeling. We also found that SMC-specific knockout of Il1r1 (encoding IL-1 receptor type 1) resulted in smaller lesions nearly devoid of SMCs and lacking a fibrous cap, whereas macrophage-selective loss of IL-1R1 had no effect on lesion size or composition. Taken together, these results show that IL-1β has multiple beneficial effects in late-stage murine atherosclerosis, including promotion of outward remodeling and formation and maintenance of an SMC- and collagen-rich fibrous cap.", + "TAG_DATA": [ + "58, smooth {'context': 'B-cells'}", + "59, muscle {'context': 'I-cells'}", + "60, cell {'context': 'I-cells'}", + "61, (SMC) {'context': 'I-cells'}", + "62, lineage-tracing {'perturbing_action': 'I-gene loss-of-function'}", + "63, Apoe-/- {'perturbing_action': 'I-gene loss-of-function'}", + "64, mice {'context': 'B-organism'}", + "96, SMC {'context': 'B-cells'}", + "102, macrophage {'context': 'B-cells'}", + "129, SMC-specific {'perturbing_action': 'B-gene loss-of-function'}", + "130, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "131, of {'perturbing_action': 'I-gene loss-of-function'}", + "132, Il1r1 {'perturbing_action': 'I-gene loss-of-function'}", + "133, (encoding {'perturbing_action': 'I-gene loss-of-function'}", + "134, IL-1 {'perturbing_action': 'I-gene loss-of-function'}", + "135, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "136, type {'perturbing_action': 'I-gene loss-of-function'}", + "137, 1) {'perturbing_action': 'I-gene loss-of-function'}", + "145, SMCs {'context': 'B-cells'}", + "152, macrophage-selective {'perturbing_action': 'B-gene loss-of-function'}", + "153, loss {'perturbing_action': 'I-gene loss-of-function'}", + "154, of {'perturbing_action': 'I-gene loss-of-function'}", + "155, IL-1R1 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "58, smooth ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "59, muscle ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "60, cell ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "61, (SMC) ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "62, lineage-tracing ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "63, Apoe-/- ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "64, mice ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "96, SMC ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33']", + "102, macrophage ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34']", + "129, SMC-specific ['l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "130, knockout ['l35', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "131, of ['l36', 'l44', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "132, Il1r1 ['l37', 'l45', 'l52', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "133, (encoding ['l38', 'l46', 'l53', 'l59', 'l65', 'l66', 'l67', 'l68', 'l69']", + "134, IL-1 ['l39', 'l47', 'l54', 'l60', 'l65', 'l70', 'l71', 'l72', 'l73']", + "135, receptor ['l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l74', 'l75', 'l76']", + "136, type ['l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l77', 'l78']", + "137, 1) ['l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l77', 'l79']", + "145, SMCs ['l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l76', 'l78', 'l79']", + "152, macrophage-selective ['l80', 'l81', 'l82']", + "153, loss ['l80', 'l83', 'l84']", + "154, of ['l81', 'l83', 'l85']", + "155, IL-1R1 ['l82', 'l84', 'l85']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "smooth", + "muscle", + "cell", + "(SMC)", + "SMC", + "macrophage", + "SMCs" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lineage-tracing", + "Apoe-/-", + "SMC-specific", + "knockout", + "of", + "Il1r1", + "(encoding", + "IL-1", + "receptor", + "type", + "1)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lineage-tracing", + "Apoe-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "29892069", + "TEXT": "The brain microenvironment imposes a particularly intense selective pressure on metastasis-initiating cells, but successful metastases bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of this microenvironment that confine brain metastasis without infiltrating the lesion. Here, we describe that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by signal transducer and activator of transcription 3 (STAT3) in a subpopulation of reactive astrocytes surrounding metastatic lesions. These reactive astrocytes benefit metastatic cells by their modulatory effect on the innate and acquired immune system. In patients, active STAT3 in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. We also show that a safe and orally bioavailable treatment that inhibits STAT3 exhibits significant antitumor effects in patients with advanced systemic disease that included brain metastasis. Responses to this therapy were notable in the central nervous system, where several complete responses were achieved. Given that brain metastasis causes substantial morbidity and mortality, our results identify a novel treatment for increasing survival in patients with secondary brain tumors.", + "TAG_DATA": [ + "112, reactive {'context': 'B-cells'}", + "113, astrocytes {'context': 'I-cells'}", + "114, reduces {'effect': 'B-negative'}", + "116, brain {'phenotype': 'B-metastasis'}", + "117, metastasis {'phenotype': 'I-metastasis'}", + "120, primary {'context': 'B-neoplasm'}", + "121, tumor {'context': 'I-neoplasm'}", + "122, sources, {'context': 'I-neoplasm'}", + "147, patients {'context': 'B-patient'}", + "154, brain {'phenotype': 'B-metastasis'}", + "155, metastasis. {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "112, reactive ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "113, astrocytes ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "114, reduces ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "116, brain ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "117, metastasis ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "120, primary ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "121, tumor ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "122, sources, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "147, patients ['l28', 'l29']", + "154, brain ['l28', 'l30']", + "155, metastasis. ['l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "reactive", + "astrocytes" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "reactive", + "astrocytes" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "brain", + "metastasis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "brain", + "metastasis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "primary", + "tumor", + "sources," + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "brain", + "metastasis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "primary", + "tumor", + "sources," + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "brain", + "metastasis." + ] + } + } + ] + }, + { + "PMID": "29892061", + "TEXT": "Lung cancer is a devastating disease that remains a top cause of cancer mortality. Despite improvements with targeted and immunotherapies, the majority of patients with lung cancer lack effective therapies, underscoring the need for additional treatment approaches. Genomic studies have identified frequent alterations in components of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A. To understand the mechanisms of tumorigenesis driven by mutations in this complex, we developed a genetically engineered mouse model of lung adenocarcinoma by ablating Smarca4 in the lung epithelium. We demonstrate that Smarca4 acts as a bona fide tumor suppressor and cooperates with p53 loss and Kras activation. Gene expression analyses revealed the signature of enhanced oxidative phosphorylation (OXPHOS) in SMARCA4 mutant tumors. We further show that SMARCA4 mutant cells have enhanced oxygen consumption and increased respiratory capacity. Importantly, SMARCA4 mutant lung cancer cell lines and xenograft tumors have marked sensitivity to inhibition of OXPHOS by a novel small molecule, IACS-010759, that is under clinical development. Mechanistically, we show that SMARCA4-deficient cells have a blunted transcriptional response to energy stress creating a therapeutically exploitable synthetic lethal interaction. These findings provide the mechanistic basis for further development of OXPHOS inhibitors as therapeutics against SWI/SNF mutant tumors.", + "TAG_DATA": [ + "70, genetically {'context': 'B-organism'}", + "71, engineered {'context': 'I-organism'}", + "72, mouse {'context': 'I-organism'}", + "73, model {'context': 'I-organism'}", + "74, of {'context': 'I-neoplasm'}", + "75, lung {'context': 'I-neoplasm'}", + "76, adenocarcinoma {'context': 'I-neoplasm'}", + "78, ablating {'perturbing_action': 'B-gene loss-of-function'}", + "79, Smarca4 {'perturbing_action': 'I-gene loss-of-function'}", + "80, in {'perturbing_action': 'I-gene loss-of-function'}", + "81, the {'perturbing_action': 'I-gene loss-of-function'}", + "82, lung {'perturbing_action': 'I-gene loss-of-function', 'context': 'B-tissue/organ'}", + "83, epithelium. {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-tissue/organ'}", + "115, SMARCA4 {'perturbing_action': 'B-other'}", + "116, mutant {'perturbing_action': 'I-other'}", + "117, tumors. {'context': 'B-neoplasm'}", + "122, SMARCA4 {'perturbing_action': 'B-other'}", + "123, mutant {'perturbing_action': 'I-other'}", + "124, cells {'context': 'B-cells'}", + "134, SMARCA4 {'perturbing_action': 'B-other'}", + "135, mutant {'perturbing_action': 'I-other'}", + "136, lung {'context': 'B-transformed cells'}", + "137, cancer {'context': 'I-transformed cells'}", + "138, cell {'context': 'I-transformed cells'}", + "139, lines {'context': 'I-transformed cells'}", + "141, xenograft {'context': 'B-xenograft'}", + "142, tumors {'context': 'I-xenograft'}", + "165, SMARCA4-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "166, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "70, genetically ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "71, engineered ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "72, mouse ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "73, model ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "74, of ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "75, lung ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "76, adenocarcinoma ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "78, ablating ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "79, Smarca4 ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "80, in ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "81, the ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "82, lung ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "83, epithelium. ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "115, SMARCA4 ['l78', 'l79', 'l80', 'l81', 'l82']", + "116, mutant ['l78', 'l83', 'l84', 'l85', 'l86']", + "117, tumors. ['l79', 'l83', 'l87', 'l88']", + "122, SMARCA4 ['l80', 'l84', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "123, mutant ['l81', 'l85', 'l87', 'l89', 'l96']", + "124, cells ['l82', 'l86', 'l88', 'l90', 'l96']", + "134, SMARCA4 ['l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "135, mutant ['l91', 'l97', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "136, lung ['l92', 'l98', 'l104', 'l110', 'l111', 'l112', 'l113', 'l114']", + "137, cancer ['l93', 'l99', 'l105', 'l110', 'l115', 'l116', 'l117', 'l118']", + "138, cell ['l94', 'l100', 'l106', 'l111', 'l115', 'l119', 'l120', 'l121']", + "139, lines ['l95', 'l101', 'l107', 'l112', 'l116', 'l119', 'l122']", + "141, xenograft ['l102', 'l108', 'l113', 'l117', 'l120', 'l123']", + "142, tumors ['l103', 'l109', 'l114', 'l118', 'l121', 'l122', 'l123']", + "165, SMARCA4-deficient ['l124']", + "166, cells ['l124']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "genetically", + "engineered", + "mouse", + "model" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablating", + "Smarca4", + "in", + "the", + "lung", + "epithelium." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lung", + "epithelium.", + "ablating", + "Smarca4", + "in", + "the" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung", + "epithelium." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "of", + "lung", + "adenocarcinoma" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablating", + "Smarca4", + "in", + "the", + "lung", + "epithelium." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "SMARCA4", + "mutant" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "SMARCA4", + "mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "SMARCA4", + "mutant" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "lung", + "cancer", + "cell", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "SMARCA4", + "mutant" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SMARCA4-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "29808010", + "TEXT": "The role of KRAS, when activated through canonical mutations, has been well established in cancer1. Here we explore a secondary means of KRAS activation in cancer: focal high-level amplification of the KRAS gene in the absence of coding mutations. These amplifications occur most commonly in esophageal, gastric and ovarian adenocarcinomas2-4. KRAS-amplified gastric cancer models show marked overexpression of the KRAS protein and are insensitive to MAPK blockade owing to their capacity to adaptively respond by rapidly increasing KRAS-GTP levels. Here we demonstrate that inhibition of the guanine-exchange factors SOS1 and SOS2 or the protein tyrosine phosphatase SHP2 can attenuate this adaptive process and that targeting these factors, both genetically and pharmacologically, can enhance the sensitivity of KRAS-amplified models to MEK inhibition in both in vitro and in vivo settings. These data demonstrate the relevance of copy-number amplification as a mechanism of KRAS activation, and uncover the therapeutic potential for targeting of these tumors through combined SHP2 and MEK inhibition.", + "TAG_DATA": [ + "83, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "84, of {'perturbing_action': 'I-pharmacological inhibition'}", + "85, the {'perturbing_action': 'I-pharmacological inhibition'}", + "86, guanine-exchange {'perturbing_action': 'I-pharmacological inhibition'}", + "87, factors {'perturbing_action': 'I-pharmacological inhibition'}", + "88, SOS1 {'perturbing_action': 'I-pharmacological inhibition'}", + "89, and {'perturbing_action': 'I-pharmacological inhibition'}", + "90, SOS2 {'perturbing_action': 'I-pharmacological inhibition'}", + "91, or {'perturbing_action': 'I-pharmacological inhibition'}", + "92, the {'perturbing_action': 'I-pharmacological inhibition'}", + "93, protein {'perturbing_action': 'I-pharmacological inhibition'}", + "94, tyrosine {'perturbing_action': 'I-pharmacological inhibition'}", + "95, phosphatase {'perturbing_action': 'I-pharmacological inhibition'}", + "96, SHP2 {'perturbing_action': 'I-pharmacological inhibition'}", + "117, models {'context': 'B-neoplasm'}", + "119, MEK {'perturbing_action': 'B-pharmacological inhibition'}", + "120, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "123, in {'context': 'B-in vitro'}", + "124, vitro {'context': 'I-in vitro'}", + "126, in {'context': 'B-in vivo'}", + "127, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "83, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "84, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "85, the ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "86, guanine-exchange ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "87, factors ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "88, SOS1 ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "89, and ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "90, SOS2 ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "91, or ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "92, the ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "93, protein ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "94, tyrosine ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l88', 'l94', 'l95', 'l96', 'l97', 'l98']", + "95, phosphatase ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l89', 'l94', 'l99', 'l100', 'l101', 'l102']", + "96, SHP2 ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l90', 'l95', 'l99', 'l103', 'l104']", + "117, models ['l85', 'l91', 'l96', 'l100', 'l103', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "119, MEK ['l105', 'l111', 'l112', 'l113', 'l114', 'l115']", + "120, inhibition ['l106', 'l111', 'l116', 'l117', 'l118', 'l119']", + "123, in ['l86', 'l92', 'l97', 'l101', 'l107', 'l112', 'l116', 'l120', 'l121', 'l122']", + "124, vitro ['l87', 'l93', 'l98', 'l102', 'l104', 'l108', 'l113', 'l117', 'l120', 'l123', 'l124']", + "126, in ['l109', 'l114', 'l118', 'l121', 'l123', 'l125']", + "127, vivo ['l110', 'l115', 'l119', 'l122', 'l124', 'l125']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "the", + "protein", + "tyrosine", + "phosphatase", + "SHP2", + "MEK", + "inhibition" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "the", + "protein", + "tyrosine", + "phosphatase", + "SHP2", + "MEK", + "inhibition" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "MEK", + "inhibition" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "29808006", + "TEXT": "RAS mutations are frequent in human cancer, especially in pancreatic, colorectal and non-small-cell lung cancers (NSCLCs)1-3. Inhibition of the RAS oncoproteins has proven difficult4, and attempts to target downstream effectors5-7 have been hampered by the activation of compensatory resistance mechanisms8. It is also well established that KRAS-mutant tumors are insensitive to inhibition of upstream growth factor receptor signaling. Thus, epidermal growth factor receptor antibody therapy is only effective in KRAS wild-type colon cancers9,10. Consistently, inhibition of SHP2 (also known as PTPN11), which links receptor tyrosine kinase signaling to the RAS-RAF-MEK-ERK pathway11,12, was shown to be ineffective in KRAS-mutant or BRAF-mutant cancer cell lines13. Our data also indicate that SHP2 inhibition in KRAS-mutant NSCLC cells under normal cell culture conditions has little effect. By contrast, SHP2 inhibition under growth factor-limiting conditions in vitro results in a senescence response. In vivo, inhibition of SHP2 in KRAS-mutant NSCLC also provokes a senescence response, which is exacerbated by MEK inhibition. Our data identify SHP2 inhibition as an unexpected vulnerability of KRAS-mutant NSCLC cells that remains undetected in cell culture and can be exploited therapeutically.", + "TAG_DATA": [ + "74, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "75, of {'perturbing_action': 'I-pharmacological inhibition'}", + "76, SHP2 {'perturbing_action': 'I-pharmacological inhibition'}", + "77, (also {'perturbing_action': 'I-pharmacological inhibition'}", + "97, KRAS-mutant {'perturbing_action': 'B-other'}", + "99, BRAF-mutant {'perturbing_action': 'B-other'}", + "100, cancer {'context': 'B-transformed cells'}", + "101, cell {'context': 'I-transformed cells'}", + "102, lines13. {'context': 'I-transformed cells'}", + "108, SHP2 {'perturbing_action': 'B-pharmacological inhibition'}", + "109, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "111, KRAS-mutant {'perturbing_action': 'B-other'}", + "112, NSCLC {'context': 'B-transformed cells'}", + "113, cells {'context': 'I-transformed cells'}", + "120, little {'effect': 'B-no effect'}", + "121, effect. {'effect': 'I-no effect'}", + "124, SHP2 {'perturbing_action': 'B-pharmacological inhibition'}", + "125, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "130, in {'context': 'B-in vitro'}", + "131, vitro {'context': 'I-in vitro'}", + "132, results {'effect': 'B-positive'}", + "133, in {'effect': 'I-positive'}", + "135, senescence {'phenotype': 'B-senescence'}", + "136, response. {'phenotype': 'I-senescence'}", + "137, In {'context': 'B-in vivo'}", + "138, vivo, {'context': 'I-in vivo'}", + "139, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "140, of {'perturbing_action': 'I-pharmacological inhibition'}", + "141, SHP2 {'perturbing_action': 'I-pharmacological inhibition'}", + "143, KRAS-mutant {'perturbing_action': 'B-other'}", + "144, NSCLC {'context': 'B-neoplasm'}", + "146, provokes {'effect': 'B-positive'}", + "148, senescence {'phenotype': 'B-senescence'}", + "149, response, {'phenotype': 'I-senescence'}", + "154, MEK {'perturbing_action': 'B-pharmacological inhibition'}", + "155, inhibition. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "74, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "75, of ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "76, SHP2 ['l1', 'l16', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "77, (also ['l2', 'l17', 'l32', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "97, KRAS-mutant ['l3', 'l18', 'l33', 'l46', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "99, BRAF-mutant ['l4', 'l19', 'l34', 'l47', 'l60', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "100, cancer ['l5', 'l20', 'l35', 'l48', 'l61', 'l66', 'l80', 'l81']", + "101, cell ['l6', 'l21', 'l36', 'l49', 'l62', 'l67', 'l80', 'l82']", + "102, lines13. ['l7', 'l22', 'l37', 'l50', 'l63', 'l68', 'l81', 'l82']", + "108, SHP2 ['l23', 'l51', 'l69', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "109, inhibition ['l8', 'l24', 'l38', 'l52', 'l70', 'l83', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "111, KRAS-mutant ['l9', 'l25', 'l39', 'l53', 'l71', 'l84', 'l97', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "112, NSCLC ['l10', 'l26', 'l40', 'l54', 'l64', 'l72', 'l85', 'l98', 'l110', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "113, cells ['l11', 'l27', 'l41', 'l55', 'l65', 'l73', 'l86', 'l99', 'l111', 'l121', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "120, little ['l12', 'l28', 'l42', 'l56', 'l74', 'l87', 'l100', 'l112', 'l122', 'l130', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "121, effect. ['l13', 'l29', 'l43', 'l57', 'l75', 'l88', 'l101', 'l113', 'l123', 'l131', 'l136', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "124, SHP2 ['l89', 'l102', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160']", + "125, inhibition ['l90', 'l103', 'l114', 'l137', 'l150', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "130, in ['l91', 'l104', 'l115', 'l124', 'l138', 'l144', 'l151', 'l161', 'l168', 'l169', 'l170', 'l171', 'l172']", + "131, vitro ['l92', 'l105', 'l116', 'l125', 'l139', 'l145', 'l152', 'l162', 'l168', 'l173', 'l174', 'l175', 'l176']", + "132, results ['l76', 'l93', 'l106', 'l117', 'l126', 'l132', 'l140', 'l146', 'l153', 'l163', 'l169', 'l173', 'l177', 'l178', 'l179']", + "133, in ['l14', 'l30', 'l44', 'l58', 'l77', 'l94', 'l107', 'l118', 'l127', 'l133', 'l141', 'l147', 'l154', 'l164', 'l170', 'l174', 'l177', 'l180', 'l181']", + "135, senescence ['l78', 'l95', 'l108', 'l119', 'l128', 'l134', 'l142', 'l148', 'l155', 'l165', 'l171', 'l175', 'l178', 'l180', 'l182']", + "136, response. ['l15', 'l31', 'l45', 'l59', 'l79', 'l96', 'l109', 'l120', 'l129', 'l135', 'l143', 'l149', 'l156', 'l166', 'l172', 'l176', 'l179', 'l181', 'l182']", + "137, In ['l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "138, vivo, ['l183', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203']", + "139, inhibition ['l184', 'l194', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212']", + "140, of ['l185', 'l195', 'l204', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220']", + "141, SHP2 ['l186', 'l196', 'l205', 'l213', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227']", + "143, KRAS-mutant ['l187', 'l197', 'l206', 'l214', 'l221', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233']", + "144, NSCLC ['l157', 'l188', 'l198', 'l207', 'l215', 'l222', 'l228', 'l234', 'l235', 'l236', 'l237', 'l238']", + "146, provokes ['l158', 'l189', 'l199', 'l208', 'l216', 'l223', 'l229', 'l234', 'l239', 'l240', 'l241', 'l242']", + "148, senescence ['l159', 'l190', 'l200', 'l209', 'l217', 'l224', 'l230', 'l235', 'l239', 'l243', 'l244', 'l245']", + "149, response, ['l160', 'l167', 'l191', 'l201', 'l210', 'l218', 'l225', 'l231', 'l236', 'l240', 'l243', 'l246']", + "154, MEK ['l192', 'l202', 'l211', 'l219', 'l226', 'l232', 'l237', 'l241', 'l244', 'l247']", + "155, inhibition. ['l193', 'l203', 'l212', 'l220', 'l227', 'l233', 'l238', 'l242', 'l245', 'l246', 'l247']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2", + "(also" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cell", + "lines13.", + "NSCLC", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2", + "(also" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "little", + "effect." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2", + "(also", + "MEK", + "inhibition." + ] + }, + "effect": { + "val": "positive", + "words": [ + "in", + "results", + "provokes" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2", + "(also", + "MEK", + "inhibition." + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "response.", + "senescence", + "response," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "KRAS-mutant", + "BRAF-mutant" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cell", + "lines13.", + "NSCLC", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BRAF-mutant", + "KRAS-mutant" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "little", + "effect." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BRAF-mutant", + "KRAS-mutant" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in", + "provokes" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BRAF-mutant", + "KRAS-mutant" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence", + "response.", + "response," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "SHP2", + "inhibition" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "KRAS-mutant" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "NSCLC", + "cells" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "little", + "effect." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "NSCLC", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "NSCLC", + "cells" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence", + "response." + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "little", + "effect." + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "little", + "effect." + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence", + "response." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "SHP2", + "inhibition", + "of", + "MEK", + "inhibition." + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "NSCLC" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence", + "response." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in", + "provokes" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence", + "response.", + "response," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2", + "MEK", + "inhibition." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "KRAS-mutant" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "effect": { + "val": "positive", + "words": [ + "provokes" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence", + "response," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "KRAS-mutant" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "NSCLC" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "NSCLC" + ] + }, + "effect": { + "val": "positive", + "words": [ + "provokes" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "NSCLC" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence", + "response," + ] + } + } + ] + }, + { + "PMID": "29785027", + "TEXT": "Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is caused by mutations in ATRX, which encodes a chromatin-remodeling protein. Genome-wide analyses in mouse and human cells indicate that ATRX tends to bind to G-rich sequences with a high potential to form G-quadruplexes. Here, we report that Atrx mutation induces aberrant upregulation of Xlr3b expression in the mouse brain, an outcome associated with neuronal pathogenesis displayed by ATR-X model mice. We show that ATRX normally binds to G-quadruplexes in CpG islands of the imprinted Xlr3b gene, regulating its expression by recruiting DNA methyltransferases. Xlr3b binds to dendritic mRNAs, and its overexpression inhibits dendritic transport of the mRNA encoding CaMKII-α, promoting synaptic dysfunction. Notably, treatment with 5-ALA, which is converted into G-quadruplex-binding metabolites, reduces RNA polymerase II recruitment and represses Xlr3b transcription in ATR-X model mice. 5-ALA treatment also rescues decreased synaptic plasticity and cognitive deficits seen in ATR-X model mice. Our findings suggest a potential therapeutic strategy to target G-quadruplexes and decrease cognitive impairment associated with ATR-X syndrome.", + "TAG_DATA": [ + "44, Atrx {'perturbing_action': 'B-other'}", + "45, mutation {'perturbing_action': 'I-other'}", + "54, mouse {'context': 'B-tissue/organ'}", + "55, brain, {'context': 'I-tissue/organ'}", + "129, ATR-X {'perturbing_action': 'B-other', 'context': 'B-organism'}", + "130, model {'context': 'I-organism'}", + "131, mice. {'context': 'B-organism'}", + "144, ATR-X {'perturbing_action': 'B-other'}", + "145, model {'context': 'I-organism'}", + "146, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "44, Atrx ['l0', 'l1', 'l2']", + "45, mutation ['l0', 'l3', 'l4']", + "54, mouse ['l1', 'l3', 'l5']", + "55, brain, ['l2', 'l4', 'l5']", + "129, ATR-X ['l6', 'l7']", + "130, model ['l6', 'l8']", + "131, mice. ['l7', 'l8']", + "144, ATR-X ['l9', 'l10']", + "145, model ['l9', 'l11']", + "146, mice. ['l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Atrx", + "mutation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "brain," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "ATR-X" + ] + }, + "context": { + "val": "organism", + "words": [ + "ATR-X", + "model", + "mice." + ] + } + } + ] + }, + { + "PMID": "29785025", + "TEXT": "Beige adipocytes have recently been shown to regulate energy dissipation when activated and help organisms defend against hypothermia and obesity. Prior reports indicate that beige-like adipocytes exist in adult humans and that they may present novel opportunities to curb the global epidemic in obesity and metabolic illnesses. In an effort to identify unique features of activated beige adipocytes, we found that expression of the cholinergic receptor nicotinic alpha 2 subunit (Chrna2) was induced in subcutaneous fat during the activation of these cells and that acetylcholine-producing immune cells within this tissue regulated this signaling pathway via paracrine mechanisms. CHRNA2 functioned selectively in uncoupling protein 1 (Ucp1)-positive beige adipocytes, increasing thermogenesis through a cAMP- and protein kinase A-dependent pathway. Furthermore, this signaling via CHRNA2 was conserved and present in human subcutaneous adipocytes. Inactivation of Chrna2 in mice compromised the cold-induced thermogenic response selectively in subcutaneous fat and exacerbated high-fat diet-induced obesity and associated metabolic disorders, indicating that even partial loss of beige fat regulation in vivo had detrimental consequences. Our results reveal a beige-selective immune-adipose interaction mediated through CHRNA2 and identify a novel function of nicotinic acetylcholine receptors in energy metabolism. These findings may lead to identification of therapeutic targets to counteract human obesity.", + "TAG_DATA": [ + "130, Inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "131, of {'perturbing_action': 'I-gene loss-of-function'}", + "132, Chrna2 {'perturbing_action': 'I-gene loss-of-function'}", + "134, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "130, Inactivation ['l0', 'l1', 'l2']", + "131, of ['l0', 'l3', 'l4']", + "132, Chrna2 ['l1', 'l3', 'l5']", + "134, mice ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Inactivation", + "of", + "Chrna2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "29662203", + "TEXT": "Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs) with mutated histone H3 K27M (H3-K27M)1-5 are aggressive and universally fatal pediatric brain cancers 6 . Chimeric antigen receptor (CAR)-expressing T cells have mediated impressive clinical activity in B cell malignancies7-10, and recent results suggest benefit in central nervous system malignancies11-13. Here, we report that patient-derived H3-K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2. Anti-GD2 CAR T cells incorporating a 4-1BBz costimulatory domain 14 demonstrated robust antigen-dependent cytokine generation and killing of DMG cells in vitro. In five independent patient-derived H3-K27M+ DMG orthotopic xenograft models, systemic administration of GD2-targeted CAR T cells cleared engrafted tumors except for a small number of residual GD2lo glioma cells. To date, GD2-targeted CAR T cells have been well tolerated in clinical trials15-17. Although GD2-targeted CAR T cell administration was tolerated in the majority of mice bearing orthotopic xenografts, peritumoral neuroinflammation during the acute phase of antitumor activity resulted in hydrocephalus that was lethal in a fraction of animals. Given the precarious neuroanatomical location of midline gliomas, careful monitoring and aggressive neurointensive care management will be required for human translation. With a cautious multidisciplinary clinical approach, GD2-targeted CAR T cell therapy for H3-K27M+ diffuse gliomas of pons, thalamus and spinal cord could prove transformative for these lethal childhood cancers.", + "TAG_DATA": [ + "56, patient-derived {'perturbing_action': 'B-other'}", + "57, H3-K27M-mutant {'perturbing_action': 'I-other'}", + "58, glioma {'context': 'B-transformed cells'}", + "59, cell {'context': 'I-transformed cells'}", + "60, cultures {'context': 'I-transformed cells'}", + "87, DMG {'context': 'B-transformed cells'}", + "88, cells {'context': 'I-transformed cells'}", + "89, in {'context': 'B-in vitro'}", + "90, vitro. {'context': 'I-in vitro'}", + "94, patient-derived {'context': 'B-xenograft'}", + "95, H3-K27M+ {'context': 'I-xenograft'}", + "96, DMG {'context': 'I-xenograft'}", + "97, orthotopic {'context': 'I-xenograft'}", + "98, xenograft {'context': 'I-xenograft'}", + "99, models, {'context': 'I-xenograft'}", + "105, T {'context': 'I-cells'}", + "106, cells {'context': 'I-cells'}", + "108, engrafted {'context': 'B-xenograft'}", + "109, tumors {'context': 'I-xenograft'}", + "118, glioma {'context': 'B-transformed cells'}", + "119, cells. {'context': 'I-transformed cells'}", + "145, mice {'context': 'B-organism'}", + "147, orthotopic {'context': 'B-xenograft'}", + "148, xenografts, {'context': 'I-xenograft'}", + "168, animals. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, patient-derived ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "57, H3-K27M-mutant ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "58, glioma ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "59, cell ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "60, cultures ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "87, DMG ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "88, cells ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "89, in ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "90, vitro. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "94, patient-derived ['l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "95, H3-K27M+ ['l36', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "96, DMG ['l37', 'l47', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "97, orthotopic ['l38', 'l48', 'l57', 'l66', 'l67', 'l68', 'l69']", + "98, xenograft ['l39', 'l49', 'l58', 'l66', 'l70']", + "99, models, ['l40', 'l50', 'l59', 'l67', 'l70']", + "105, T ['l41', 'l51', 'l60', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "106, cells ['l42', 'l52', 'l61', 'l71', 'l79', 'l80', 'l81', 'l82']", + "108, engrafted ['l43', 'l53', 'l62', 'l72', 'l79', 'l83', 'l84', 'l85']", + "109, tumors ['l44', 'l54', 'l63', 'l68', 'l73', 'l80', 'l83', 'l86', 'l87']", + "118, glioma ['l45', 'l55', 'l64', 'l74', 'l81', 'l84', 'l86', 'l88', 'l89', 'l90', 'l91']", + "119, cells. ['l46', 'l56', 'l65', 'l69', 'l75', 'l82', 'l85', 'l87', 'l88']", + "145, mice ['l76', 'l89', 'l92', 'l93', 'l94']", + "147, orthotopic ['l77', 'l90', 'l92', 'l95', 'l96']", + "148, xenografts, ['l78', 'l91', 'l93', 'l95', 'l97']", + "168, animals. ['l94', 'l96', 'l97']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "patient-derived", + "H3-K27M-mutant" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "glioma", + "cell", + "cultures", + "DMG", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "patient-derived", + "H3-K27M-mutant" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "29662201", + "TEXT": "Proliferating cells, compared with quiescent cells, are more dependent on glucose for their growth. Although glucose transport in keratinocytes is mediated largely by the Glut1 facilitative transporter, we found that keratinocyte-specific ablation of Glut1 did not compromise mouse skin development and homeostasis. Ex vivo metabolic profiling revealed altered sphingolipid, hexose, amino acid, and nucleotide metabolism in Glut1-deficient keratinocytes, thus suggesting metabolic adaptation. However, cultured Glut1-deficient keratinocytes displayed metabolic and oxidative stress and impaired proliferation. Similarly, Glut1 deficiency impaired in vivo keratinocyte proliferation and migration within wounded or UV-damaged mouse skin. Notably, both genetic and pharmacological Glut1 inactivation decreased hyperplasia in mouse models of psoriasis-like disease. Topical application of a Glut1 inhibitor also decreased inflammation in these models. Glut1 inhibition decreased the expression of pathology-associated genes in human psoriatic skin organoids. Thus, Glut1 is selectively required for injury- and inflammation-associated keratinocyte proliferation, and its inhibition offers a novel treatment strategy for psoriasis.", + "TAG_DATA": [ + "30, keratinocyte-specific {'perturbing_action': 'B-gene loss-of-function'}", + "31, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "32, of {'perturbing_action': 'I-gene loss-of-function'}", + "33, Glut1 {'perturbing_action': 'I-gene loss-of-function'}", + "56, Glut1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "57, keratinocytes, {'context': 'B-cells'}", + "64, Glut1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "65, keratinocytes {'context': 'B-cells'}", + "72, impaired {'effect': 'B-negative'}", + "73, proliferation. {'phenotype': 'B-proliferation'}", + "75, Glut1 {'perturbing_action': 'B-gene loss-of-function'}", + "76, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "77, impaired {'effect': 'B-negative'}", + "78, in {'context': 'B-in vivo'}", + "79, vivo {'context': 'B-in vivo'}", + "80, keratinocyte {'context': 'B-cells'}", + "81, proliferation {'phenotype': 'B-proliferation'}", + "83, migration {'phenotype': 'B-migration'}", + "88, mouse {'context': 'B-tissue/organ'}", + "89, skin. {'context': 'I-tissue/organ'}", + "94, pharmacological {'perturbing_action': 'B-gene loss-of-function'}", + "95, Glut1 {'perturbing_action': 'I-gene loss-of-function'}", + "96, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "100, mouse {'context': 'B-organism'}", + "101, models {'context': 'I-organism'}", + "109, Glut1 {'perturbing_action': 'B-pharmacological inhibition'}", + "110, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "117, Glut1 {'perturbing_action': 'B-pharmacological inhibition'}", + "118, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "126, human {'context': 'B-organoid'}", + "127, psoriatic {'context': 'I-organoid'}", + "128, skin {'context': 'I-organoid'}", + "129, organoids. {'context': 'I-organoid'}" + ], + "LINK_DATA": [ + "30, keratinocyte-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "31, ablation ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "32, of ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "33, Glut1 ['l2', 'l14', 'l25', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "56, Glut1-deficient ['l3', 'l15', 'l26', 'l37', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "57, keratinocytes, ['l4', 'l16', 'l27', 'l38', 'l47', 'l53', 'l54', 'l55', 'l56', 'l57']", + "64, Glut1-deficient ['l5', 'l17', 'l28', 'l39', 'l48', 'l53', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "65, keratinocytes ['l6', 'l18', 'l29', 'l40', 'l49', 'l54', 'l58', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "72, impaired ['l7', 'l19', 'l30', 'l41', 'l50', 'l55', 'l59', 'l69', 'l77']", + "73, proliferation. ['l8', 'l20', 'l31', 'l42', 'l51', 'l56', 'l60', 'l70', 'l77']", + "75, Glut1 ['l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "76, deficiency ['l78', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "77, impaired ['l9', 'l21', 'l32', 'l43', 'l61', 'l71', 'l79', 'l87', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "78, in ['l62', 'l80', 'l88', 'l95', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "79, vivo ['l63', 'l72', 'l81', 'l89', 'l96', 'l102', 'l108', 'l109', 'l110', 'l111', 'l112']", + "80, keratinocyte ['l10', 'l22', 'l33', 'l44', 'l64', 'l73', 'l82', 'l90', 'l97', 'l103', 'l108', 'l113', 'l114', 'l115', 'l116']", + "81, proliferation ['l11', 'l23', 'l34', 'l45', 'l52', 'l57', 'l65', 'l74', 'l83', 'l91', 'l98', 'l104', 'l109', 'l113', 'l117']", + "83, migration ['l12', 'l24', 'l35', 'l46', 'l66', 'l75', 'l84', 'l92', 'l99', 'l105', 'l110', 'l114', 'l117', 'l118', 'l119']", + "88, mouse ['l67', 'l85', 'l93', 'l100', 'l106', 'l111', 'l115', 'l118', 'l120']", + "89, skin. ['l36', 'l68', 'l76', 'l86', 'l94', 'l101', 'l107', 'l112', 'l116', 'l119', 'l120']", + "94, pharmacological ['l121', 'l122', 'l123', 'l124']", + "95, Glut1 ['l121', 'l125', 'l126', 'l127']", + "96, inactivation ['l122', 'l125', 'l128', 'l129']", + "100, mouse ['l123', 'l126', 'l128', 'l130']", + "101, models ['l124', 'l127', 'l129', 'l130']", + "109, Glut1 ['l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "110, inhibitor ['l131', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "117, Glut1 ['l132', 'l138', 'l144', 'l145', 'l146', 'l147', 'l148']", + "118, inhibition ['l133', 'l139', 'l144', 'l149', 'l150', 'l151', 'l152']", + "126, human ['l134', 'l140', 'l145', 'l149', 'l153', 'l154', 'l155']", + "127, psoriatic ['l135', 'l141', 'l146', 'l150', 'l153', 'l156', 'l157']", + "128, skin ['l136', 'l142', 'l147', 'l151', 'l154', 'l156', 'l158']", + "129, organoids. ['l137', 'l143', 'l148', 'l152', 'l155', 'l157', 'l158']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "keratinocyte-specific", + "ablation", + "of", + "Glut1", + "Glut1-deficient", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "keratinocytes,", + "keratinocytes", + "keratinocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "keratinocyte-specific", + "ablation", + "of", + "Glut1", + "Glut1-deficient", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "keratinocyte-specific", + "ablation", + "of", + "Glut1", + "Glut1-deficient", + "deficiency" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation.", + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "keratinocyte-specific", + "ablation", + "of", + "Glut1", + "Glut1-deficient", + "deficiency" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "Glut1-deficient", + "Glut1", + "deficiency" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skin.", + "mouse" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "keratinocytes,", + "keratinocytes", + "keratinocyte" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "keratinocytes,", + "keratinocytes", + "keratinocyte" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation.", + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Glut1-deficient", + "Glut1", + "deficiency" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "keratinocytes", + "keratinocyte" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation.", + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "skin." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "skin." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pharmacological", + "Glut1", + "inactivation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Glut1", + "inhibitor", + "inhibition" + ] + }, + "context": { + "val": "organoid", + "words": [ + "human", + "psoriatic", + "skin", + "organoids." + ] + } + } + ] + }, + { + "PMID": "29578538", + "TEXT": "Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer diagnosed in more than 200,000 women each year and is recalcitrant to targeted therapies. Although TNBCs harbor multiple hyperactive receptor tyrosine kinases (RTKs), RTK inhibitors have been largely ineffective in TNBC patients thus far. We developed a broadly effective therapeutic strategy for TNBC that is based on combined inhibition of receptors that share the negative regulator PTPN12. Previously, we and others identified the tyrosine phosphatase PTPN12 as a tumor suppressor that is frequently inactivated in TNBC. PTPN12 restrains several RTKs, suggesting that PTPN12 deficiency leads to aberrant activation of multiple RTKs and a co-dependency on these receptors. This in turn leads to the therapeutic hypothesis that PTPN12-deficient TNBCs may be responsive to combined RTK inhibition. However, the repertoire of RTKs that are restrained by PTPN12 in human cells has not been systematically explored. By methodically identifying the suite of RTK substrates (MET, PDGFRβ, EGFR, and others) inhibited by PTPN12, we rationalized a combination RTK-inhibitor therapy that induced potent tumor regression across heterogeneous models of TNBC. Orthogonal approaches revealed that PTPN12 was recruited to and inhibited these receptors after ligand stimulation, thereby serving as a feedback mechanism to limit receptor signaling. Cancer-associated mutation of PTPN12 or reduced PTPN12 protein levels diminished this feedback mechanism, leading to aberrant activity of these receptors. Restoring PTPN12 protein levels restrained signaling from RTKs, including PDGFRβ and MET, and impaired TNBC survival. In contrast with single agents, combined inhibitors targeting the PDGFRβ and MET receptors induced the apoptosis in TNBC cells in vitro and in vivo. This therapeutic strategy resulted in tumor regressions in chemo-refractory patient-derived TNBC models. Notably, response correlated with PTPN12 deficiency, suggesting that impaired receptor feedback may establish a combined addiction to these proto-oncogenic receptors. Taken together, our data provide a rationale", + "TAG_DATA": [ + "93, PTPN12 {'perturbing_action': 'B-gene loss-of-function'}", + "167, induced {'effect': 'B-positive'}", + "169, tumor {'phenotype': 'B-tumour regression'}", + "170, regression {'phenotype': 'I-tumour regression'}", + "175, TNBC. {'context': 'B-neoplasm'}", + "201, Cancer-associated {'perturbing_action': 'B-other'}", + "202, mutation {'perturbing_action': 'I-other'}", + "203, of {'perturbing_action': 'I-other'}", + "204, PTPN12 {'perturbing_action': 'I-other'}", + "206, reduced {'perturbing_action': 'B-gene loss-of-function'}", + "221, Restoring {'perturbing_action': 'B-gene gain-of-function'}", + "222, PTPN12 {'perturbing_action': 'I-gene gain-of-function'}", + "223, protein {'perturbing_action': 'I-gene gain-of-function'}", + "224, levels {'perturbing_action': 'I-gene gain-of-function'}", + "235, TNBC {'context': 'B-neoplasm'}", + "250, induced {'effect': 'B-positive'}", + "252, apoptosis {'phenotype': 'B-apoptosis'}", + "254, TNBC {'context': 'B-transformed cells'}", + "255, cells {'context': 'I-transformed cells'}", + "256, in {'context': 'B-in vitro'}", + "257, vitro {'context': 'I-in vitro'}", + "259, in {'context': 'B-in vivo'}", + "260, vivo. {'context': 'I-in vivo'}", + "264, resulted {'effect': 'B-positive'}", + "266, tumor {'phenotype': 'B-tumour regression'}", + "267, regressions {'phenotype': 'I-tumour regression'}", + "270, patient-derived {'context': 'B-neoplasm'}", + "271, TNBC {'context': 'I-neoplasm'}", + "272, models. {'context': 'I-neoplasm'}", + "277, PTPN12 {'perturbing_action': 'B-gene loss-of-function'}", + "278, deficiency, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "93, PTPN12 ['l0']", + "167, induced ['l0', 'l1', 'l2', 'l3']", + "169, tumor ['l1', 'l4', 'l5']", + "170, regression ['l2', 'l4', 'l6']", + "175, TNBC. ['l3', 'l5', 'l6']", + "201, Cancer-associated ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "202, mutation ['l7', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "203, of ['l8', 'l24', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "204, PTPN12 ['l9', 'l25', 'l39', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "206, reduced ['l10', 'l26', 'l40', 'l53', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "208, protein ['l11', 'l27', 'l41', 'l54', 'l67', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "221, Restoring ['l68', 'l84', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "222, PTPN12 ['l12', 'l55', 'l69', 'l85', 'l97', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "223, protein ['l13', 'l28', 'l42', 'l56', 'l70', 'l86', 'l98', 'l117', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "224, levels ['l14', 'l29', 'l43', 'l57', 'l71', 'l87', 'l99', 'l118', 'l136', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "235, TNBC ['l15', 'l30', 'l44', 'l58', 'l72', 'l88', 'l100', 'l119', 'l137', 'l149', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "250, induced ['l16', 'l31', 'l45', 'l59', 'l73', 'l89', 'l101', 'l120', 'l138', 'l150', 'l158', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "252, apoptosis ['l17', 'l32', 'l46', 'l60', 'l74', 'l90', 'l102', 'l121', 'l139', 'l151', 'l159', 'l166', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "254, TNBC ['l18', 'l33', 'l47', 'l61', 'l75', 'l91', 'l103', 'l122', 'l140', 'l152', 'l160', 'l167', 'l173', 'l179', 'l180', 'l181', 'l182', 'l183']", + "255, cells ['l19', 'l34', 'l48', 'l62', 'l76', 'l92', 'l104', 'l123', 'l141', 'l153', 'l161', 'l168', 'l174', 'l179', 'l184', 'l185', 'l186', 'l187']", + "256, in ['l20', 'l35', 'l49', 'l63', 'l77', 'l93', 'l105', 'l124', 'l142', 'l154', 'l162', 'l169', 'l175', 'l180', 'l184', 'l188', 'l189', 'l190']", + "257, vitro ['l21', 'l36', 'l50', 'l64', 'l78', 'l94', 'l106', 'l125', 'l143', 'l155', 'l163', 'l170', 'l176', 'l181', 'l185', 'l188', 'l191', 'l192']", + "259, in ['l22', 'l37', 'l51', 'l65', 'l79', 'l95', 'l107', 'l126', 'l144', 'l156', 'l164', 'l171', 'l177', 'l182', 'l186', 'l189', 'l191', 'l193']", + "260, vivo. ['l23', 'l38', 'l52', 'l66', 'l80', 'l96', 'l108', 'l127', 'l145', 'l157', 'l165', 'l172', 'l178', 'l183', 'l187', 'l190', 'l192', 'l193']", + "264, resulted ['l81', 'l109', 'l128', 'l146', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200']", + "266, tumor ['l82', 'l110', 'l129', 'l147', 'l194', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206']", + "267, regressions ['l83', 'l111', 'l130', 'l148', 'l195', 'l201', 'l207', 'l208', 'l209', 'l210', 'l211']", + "270, patient-derived ['l112', 'l131', 'l196', 'l202', 'l207', 'l212', 'l213', 'l214', 'l215']", + "271, TNBC ['l113', 'l132', 'l197', 'l203', 'l208', 'l212', 'l216', 'l217', 'l218']", + "272, models. ['l114', 'l133', 'l198', 'l204', 'l209', 'l213', 'l216', 'l219', 'l220']", + "277, PTPN12 ['l115', 'l134', 'l199', 'l205', 'l210', 'l214', 'l217', 'l219', 'l221']", + "278, deficiency, ['l116', 'l135', 'l200', 'l206', 'l211', 'l215', 'l218', 'l220', 'l221']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PTPN12", + "reduced", + "deficiency," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "resulted" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "resulted" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression", + "regressions" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "resulted" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "TNBC.", + "TNBC", + "patient-derived", + "models." + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression", + "regressions" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "TNBC.", + "patient-derived", + "TNBC", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Cancer-associated", + "mutation", + "of", + "PTPN12" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "TNBC" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Cancer-associated", + "mutation", + "of", + "PTPN12" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Cancer-associated", + "mutation", + "of", + "PTPN12" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Cancer-associated", + "mutation", + "of", + "PTPN12" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Cancer-associated", + "mutation", + "of", + "PTPN12" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Cancer-associated", + "mutation", + "of", + "PTPN12" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "reduced", + "PTPN12", + "deficiency," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "TNBC", + "patient-derived", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "reduced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "reduced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "reduced" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "reduced", + "PTPN12", + "deficiency," + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regressions" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoring", + "PTPN12", + "protein", + "levels" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "TNBC", + "patient-derived", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoring", + "PTPN12", + "protein", + "levels" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "resulted" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoring", + "PTPN12", + "protein", + "levels" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoring", + "PTPN12", + "protein", + "levels" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoring", + "PTPN12", + "protein", + "levels" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoring", + "PTPN12", + "protein", + "levels" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoring", + "PTPN12", + "protein" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regressions" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "TNBC" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "29505033", + "TEXT": "Most anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung tumors initially respond to small-molecule ALK inhibitors, but drug resistance often develops. Of tumors that develop resistance to highly potent second-generation ALK inhibitors, approximately half harbor resistance mutations in ALK, while the other half have other mechanisms underlying resistance. Members of the latter group often have activation of at least one of several different tyrosine kinases driving resistance. Such tumors are not expected to respond to lorlatinib-a third-generation inhibitor targeting ALK that is able to overcome all clinically identified resistant mutations in ALK-and further therapeutic options are limited. Herein, we deployed a shRNA screen of 1,000 genes in multiple ALK-inhibitor-resistant patient-derived cells (PDCs) to discover those that confer sensitivity to ALK inhibition. This approach identified SHP2, a nonreceptor protein tyrosine phosphatase, as a common targetable resistance node in multiple PDCs. SHP2 provides a parallel survival input downstream of multiple tyrosine kinases that promote resistance to ALK inhibitors. Treatment with SHP099, the recently discovered small-molecule inhibitor of SHP2, in combination with the ALK tyrosine kinase inhibitor (TKI) ceritinib halted the growth of resistant PDCs through preventing compensatory RAS and ERK1 and ERK2 (ERK1/2) reactivation. These findings suggest that combined ALK and SHP2 inhibition may be a promising therapeutic strategy for resistant cancers driven by several different ALK-independent mechanisms underlying resistance.", + "TAG_DATA": [ + "108, cells {'context': 'I-cells'}", + "156, SHP099, {'perturbing_action': 'B-pharmacological inhibition'}", + "157, the {'perturbing_action': 'I-pharmacological inhibition'}", + "160, small-molecule {'perturbing_action': 'I-pharmacological inhibition'}", + "161, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "162, of {'perturbing_action': 'I-pharmacological inhibition'}", + "163, SHP2, {'perturbing_action': 'I-pharmacological inhibition'}", + "178, resistant {'context': 'B-transformed cells'}", + "179, PDCs {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "107, patient-derived ['l0']", + "108, cells ['l0']", + "156, SHP099, ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "157, the ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "160, small-molecule ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "161, inhibitor ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "162, of ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "163, SHP2, ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "178, resistant ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "179, PDCs ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "SHP099,", + "the", + "small-molecule", + "inhibitor", + "of", + "SHP2," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "resistant", + "PDCs" + ] + } + } + ] + }, + { + "PMID": "29400710", + "TEXT": "The adoptive transfer of T cells engineered with a chimeric antigen receptor (CAR) (hereafter referred to as CAR-T cells) specific for the B lymphocyte antigen CD19 has shown impressive clinical responses in patients with refractory B cell malignancies. However, the therapeutic effects of CAR-T cells that target other malignancies have not yet resulted in significant clinical benefit. Although inefficient tumor trafficking and various immunosuppressive mechanisms can impede CAR-T cell effector responses, the signals delivered by the current CAR constructs may still be insufficient to fully activate antitumor T cell functions. Optimal T cell activation and proliferation requires multiple signals, including T cell receptor (TCR) engagement (signal 1), co-stimulation (signal 2) and cytokine engagement (signal 3). However, CAR constructs currently being tested in the clinic contain a CD3z (TCR signaling) domain and co-stimulatory domain(s) but not a domain that transmits signal 3 (refs. 13, 14, 15, 16, 17, 18). Here we have developed a novel CAR construct capable of inducing cytokine signaling after antigen stimulation. This new-generation CD19 CAR encodes a truncated cytoplasmic domain from the interleukin (IL)-2 receptor β-chain (IL-2Rβ) and a STAT3-binding tyrosine-X-X-glutamine (YXXQ) motif, together with the TCR signaling (CD3z) and co-stimulatory (CD28) domains (hereafter referred to as 28-ΔIL2RB-z(YXXQ)). The 28-ΔIL2RB-z(YXXQ) CAR-T cells showed antigen-dependent activation of the JAK kinase and of the STAT3 and STAT5 transcription factors signaling pathways, which promoted their proliferation and prevented terminal differentiation in vitro. The 28-ΔIL2RB-z(YXXQ) CAR-T cells demonstrated superior in vivo persistence and antitumor effects in models of liquid and solid tumors as compared with CAR-T cells expressing a CD28 or 4-1BB co-stimulatory domain alone. Taken", + "TAG_DATA": [ + "204, cells {'context': 'I-cells'}", + "223, promoted {'effect': 'B-positive'}", + "225, proliferation {'phenotype': 'B-proliferation'}", + "227, prevented {'effect': 'B-negative'}", + "228, terminal {'phenotype': 'B-differentiation'}", + "229, differentiation {'phenotype': 'I-differentiation'}", + "230, in {'context': 'B-in vitro'}", + "231, vitro. {'context': 'I-in vitro'}", + "235, cells {'context': 'I-cells'}", + "238, in {'context': 'B-in vivo'}", + "239, vivo {'context': 'I-in vivo'}", + "245, models {'context': 'B-neoplasm'}", + "247, liquid {'context': 'B-neoplasm'}", + "248, and {'context': 'I-neoplasm'}", + "249, solid {'context': 'I-neoplasm'}", + "250, tumors {'context': 'I-neoplasm'}", + "254, CAR-T {'context': 'B-cells'}", + "255, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "204, cells ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "223, promoted ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "225, proliferation ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "227, prevented ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "228, terminal ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "229, differentiation ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "230, in ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "231, vitro. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "235, cells ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "238, in ['l28', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "239, vivo ['l29', 'l37', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "245, models ['l30', 'l38', 'l45', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "247, liquid ['l31', 'l39', 'l46', 'l52', 'l58', 'l59', 'l60', 'l61', 'l62']", + "248, and ['l32', 'l40', 'l47', 'l53', 'l58', 'l63', 'l64', 'l65', 'l66']", + "249, solid ['l33', 'l41', 'l48', 'l54', 'l59', 'l63', 'l67', 'l68', 'l69']", + "250, tumors ['l34', 'l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l70', 'l71']", + "254, CAR-T ['l35', 'l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l72']", + "255, cells ['l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l69', 'l71', 'l72']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "terminal", + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "terminal", + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "terminal", + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "terminal", + "differentiation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "29377004", + "TEXT": "Hematopoietic stem cells (HSCs) quiescently reside in bone marrow niches and have the capacity to self-renew or differentiate to form all of the blood cells throughout the lifespan of an animal. Allogeneic HSC transplantation is a life-saving treatment for malignant and nonmalignant disorders. HSCs isolated from umbilical cord blood (CB) are used for hematopoietic cell transplantation (HCT), but due to the limited numbers of HSCs in single units of umbilical CB, a number of methods have been proposed for ex vivo expansion of human HSCs. We show here that antagonism of peroxisome proliferator-activated receptor (PPAR)-γ promotes ex vivo expansion of phenotypically and functionally defined subsets of human CB HSCs and hematopoietic progenitor cells (HSPCs). PPAR-γ antagonism in CB HSPCs strongly downregulated expression of several differentiation-associated genes, as well as fructose-bisphosphatase 1 (FBP1; which encodes a negative regulator of glycolysis), and enhanced glycolysis without compromising mitochondrial metabolism. The expansion of CB HSPCs by PPAR-γ antagonism was completely suppressed by removal of glucose or inhibition of glycolysis. Moreover, knockdown of FBP1 expression promoted glycolysis and ex vivo expansion of long-term repopulating CB HSPCs, whereas overexpression of FBP1 suppressed the expansion of CB HSPCs that was induced by PPAR-γ antagonism. Our study suggests the possibility for a new and simple means for metabolic reprogramming of CB HSPCs to improve the efficacy of HCT.", + "TAG_DATA": [ + "89, antagonism {'perturbing_action': 'B-pharmacological inhibition'}", + "90, of {'perturbing_action': 'I-pharmacological inhibition'}", + "91, peroxisome {'perturbing_action': 'I-pharmacological inhibition'}", + "92, proliferator-activated {'perturbing_action': 'I-pharmacological inhibition'}", + "93, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "94, (PPAR)-γ {'perturbing_action': 'I-pharmacological inhibition'}", + "106, human {'context': 'B-cells'}", + "107, CB {'context': 'I-cells'}", + "108, HSCs {'context': 'I-cells'}", + "110, hematopoietic {'context': 'B-cells'}", + "111, progenitor {'context': 'I-cells'}", + "112, cells {'context': 'I-cells'}", + "113, (HSPCs). {'context': 'I-cells'}", + "114, PPAR-γ {'perturbing_action': 'B-pharmacological inhibition'}", + "115, antagonism {'perturbing_action': 'I-pharmacological inhibition'}", + "117, CB {'context': 'B-cells'}", + "118, HSPCs {'context': 'I-cells'}", + "149, CB {'context': 'B-cells'}", + "150, HSPCs {'context': 'I-cells'}", + "152, PPAR-γ {'perturbing_action': 'B-pharmacological inhibition'}", + "153, antagonism {'perturbing_action': 'I-pharmacological inhibition'}", + "166, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "167, of {'perturbing_action': 'I-rnai/knockdown'}", + "168, FBP1 {'perturbing_action': 'I-rnai/knockdown'}", + "169, expression {'perturbing_action': 'I-rnai/knockdown'}", + "177, long-term {'context': 'B-cells'}", + "178, repopulating {'context': 'I-cells'}", + "179, CB {'context': 'I-cells'}", + "180, HSPCs, {'context': 'I-cells'}", + "182, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "183, of {'perturbing_action': 'I-gene gain-of-function'}", + "184, FBP1 {'perturbing_action': 'I-gene gain-of-function'}", + "189, CB {'context': 'B-cells'}", + "190, HSPCs {'context': 'I-cells'}", + "195, PPAR-γ {'perturbing_action': 'B-pharmacological inhibition'}", + "196, antagonism. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "89, antagonism ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "90, of ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "91, peroxisome ['l1', 'l17', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "92, proliferator-activated ['l2', 'l18', 'l33', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "93, receptor ['l3', 'l19', 'l34', 'l48', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "94, (PPAR)-γ ['l4', 'l20', 'l35', 'l49', 'l62', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "106, human ['l5', 'l21', 'l36', 'l50', 'l63', 'l75', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "107, CB ['l6', 'l22', 'l37', 'l51', 'l64', 'l76', 'l87', 'l93', 'l94', 'l95', 'l96', 'l97']", + "108, HSCs ['l7', 'l23', 'l38', 'l52', 'l65', 'l77', 'l88', 'l93', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "110, hematopoietic ['l8', 'l24', 'l39', 'l53', 'l66', 'l78', 'l98', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "111, progenitor ['l9', 'l25', 'l40', 'l54', 'l67', 'l79', 'l99', 'l104', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "112, cells ['l10', 'l26', 'l41', 'l55', 'l68', 'l80', 'l89', 'l94', 'l100', 'l105', 'l114', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "113, (HSPCs). ['l11', 'l27', 'l42', 'l56', 'l69', 'l81', 'l90', 'l95', 'l101', 'l106', 'l115', 'l123', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "114, PPAR-γ ['l12', 'l28', 'l43', 'l57', 'l70', 'l82', 'l107', 'l116', 'l124', 'l130', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "115, antagonism ['l13', 'l29', 'l44', 'l58', 'l71', 'l83', 'l108', 'l117', 'l125', 'l131', 'l136', 'l143', 'l144', 'l145', 'l146', 'l147']", + "117, CB ['l14', 'l30', 'l45', 'l59', 'l72', 'l84', 'l91', 'l96', 'l102', 'l109', 'l118', 'l126', 'l132', 'l137', 'l143', 'l148', 'l149']", + "118, HSPCs ['l15', 'l31', 'l46', 'l60', 'l73', 'l85', 'l92', 'l97', 'l103', 'l110', 'l119', 'l127', 'l133', 'l138', 'l144', 'l148', 'l150']", + "149, CB ['l111', 'l120', 'l128', 'l134', 'l139', 'l145', 'l151', 'l152', 'l153']", + "150, HSPCs ['l16', 'l32', 'l47', 'l61', 'l74', 'l86', 'l112', 'l121', 'l129', 'l135', 'l140', 'l146', 'l149', 'l150', 'l151', 'l154', 'l155']", + "152, PPAR-γ ['l141', 'l152', 'l154', 'l156']", + "153, antagonism ['l113', 'l122', 'l142', 'l147', 'l153', 'l155', 'l156']", + "166, knockdown ['l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163']", + "167, of ['l157', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "168, FBP1 ['l158', 'l164', 'l170', 'l171', 'l172', 'l173', 'l174']", + "169, expression ['l159', 'l165', 'l170', 'l175', 'l176', 'l177', 'l178']", + "177, long-term ['l160', 'l166', 'l171', 'l175', 'l179', 'l180', 'l181']", + "178, repopulating ['l161', 'l167', 'l172', 'l176', 'l179', 'l182', 'l183']", + "179, CB ['l162', 'l168', 'l173', 'l177', 'l180', 'l182', 'l184']", + "180, HSPCs, ['l163', 'l169', 'l174', 'l178', 'l181', 'l183', 'l184']", + "182, overexpression ['l185', 'l186', 'l187', 'l188', 'l189', 'l190']", + "183, of ['l185', 'l191', 'l192', 'l193', 'l194', 'l195']", + "184, FBP1 ['l186', 'l191', 'l196', 'l197', 'l198', 'l199']", + "189, CB ['l187', 'l192', 'l196', 'l200', 'l201', 'l202']", + "190, HSPCs ['l188', 'l193', 'l197', 'l200', 'l203', 'l204']", + "195, PPAR-γ ['l189', 'l194', 'l198', 'l201', 'l203', 'l205']", + "196, antagonism. ['l190', 'l195', 'l199', 'l202', 'l204', 'l205']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antagonism", + "of", + "peroxisome", + "proliferator-activated", + "receptor", + "(PPAR)-γ", + "PPAR-γ", + "antagonism." + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "CB", + "HSCs", + "hematopoietic", + "progenitor", + "cells", + "(HSPCs).", + "HSPCs" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "FBP1", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "long-term", + "repopulating", + "CB", + "HSPCs," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "FBP1" + ] + }, + "context": { + "val": "cells", + "words": [ + "CB", + "HSPCs" + ] + } + } + ] + }, + { + "PMID": "29334376", + "TEXT": "Metastasis results from a complex set of traits acquired by tumor cells, distinct from those necessary for tumorigenesis. Here, we investigate the contribution of enhancer elements to the metastatic phenotype of osteosarcoma. Through epigenomic profiling, we identify substantial differences in enhancer activity between primary and metastatic human tumors and between near isogenic pairs of highly lung metastatic and nonmetastatic osteosarcoma cell lines. We term these regions metastatic variant enhancer loci (Met-VELs). Met-VELs drive coordinated waves of gene expression during metastatic colonization of the lung. Met-VELs cluster nonrandomly in the genome, indicating that activity of these enhancers and expression of their associated gene targets are positively selected. As evidence of this causal association, osteosarcoma lung metastasis is inhibited by global interruptions of Met-VEL-associated gene expression via pharmacologic BET inhibition, by knockdown of AP-1 transcription factors that occupy Met-VELs, and by knockdown or functional inhibition of individual genes activated by Met-VELs, such as that encoding coagulation factor III/tissue factor (F3). We further show that genetic deletion of a single Met-VEL at the F3 locus blocks metastatic cell outgrowth in the lung. These findings indicate that Met-VELs and the genes they regulate play a functional role in metastasis and may be suitable targets for antimetastatic therapies.", + "TAG_DATA": [ + "116, inhibited {'effect': 'B-negative'}", + "129, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "162, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "163, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "164, of {'perturbing_action': 'I-gene loss-of-function'}", + "165, a {'perturbing_action': 'I-gene loss-of-function'}", + "166, single {'perturbing_action': 'I-gene loss-of-function'}", + "167, Met-VEL {'perturbing_action': 'I-gene loss-of-function'}", + "168, at {'perturbing_action': 'I-gene loss-of-function'}", + "169, the {'perturbing_action': 'I-gene loss-of-function'}", + "170, F3 {'perturbing_action': 'I-gene loss-of-function'}", + "171, locus {'perturbing_action': 'I-gene loss-of-function'}", + "172, blocks {'effect': 'B-negative'}", + "173, metastatic {'phenotype': 'B-metastasis'}", + "174, cell {'phenotype': 'I-metastasis'}", + "175, outgrowth {'phenotype': 'I-metastasis'}", + "178, lung. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "116, inhibited ['l0']", + "129, knockdown ['l0']", + "162, genetic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "163, deletion ['l1', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "164, of ['l2', 'l15', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "165, a ['l3', 'l16', 'l28', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "166, single ['l4', 'l17', 'l29', 'l40', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "167, Met-VEL ['l5', 'l18', 'l30', 'l41', 'l51', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "168, at ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "169, the ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "170, F3 ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "171, locus ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l91', 'l92', 'l93', 'l94', 'l95']", + "172, blocks ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l96', 'l97', 'l98', 'l99']", + "173, metastatic ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l100', 'l101', 'l102']", + "174, cell ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l103', 'l104']", + "175, outgrowth ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l105']", + "178, lung. ['l14', 'l27', 'l39', 'l50', 'l60', 'l69', 'l77', 'l84', 'l90', 'l95', 'l99', 'l102', 'l104', 'l105']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "a", + "single", + "Met-VEL", + "at", + "the", + "F3", + "locus" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "a", + "single", + "Met-VEL", + "at", + "the", + "F3", + "locus" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "cell", + "outgrowth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "a", + "single", + "Met-VEL", + "at", + "the", + "F3", + "locus" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "cell", + "outgrowth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung." + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "cell", + "outgrowth" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung." + ] + } + } + ] + }, + { + "PMID": "29334371", + "TEXT": "Intratumor heterogeneity is a key factor contributing to therapeutic failure and, hence, cancer lethality. Heterogeneous tumors show partial therapy responses, allowing for the emergence of drug-resistant clones that often express high levels of the receptor tyrosine kinase AXL. In melanoma, AXL-high cells are resistant to MAPK pathway inhibitors, whereas AXL-low cells are sensitive to these inhibitors, rationalizing a differential therapeutic approach. We developed an antibody-drug conjugate, AXL-107-MMAE, comprising a human AXL antibody linked to the microtubule-disrupting agent monomethyl auristatin E. We found that AXL-107-MMAE, as a single agent, displayed potent in vivo anti-tumor activity in patient-derived xenografts, including melanoma, lung, pancreas and cervical cancer. By eliminating distinct populations in heterogeneous melanoma cell pools, AXL-107-MMAE and MAPK pathway inhibitors cooperatively inhibited tumor growth. Furthermore, by inducing AXL transcription, BRAF/MEK inhibitors potentiated the efficacy of AXL-107-MMAE. These findings provide proof of concept for the premise that rationalized combinatorial targeting of distinct populations in heterogeneous tumors may improve therapeutic effect, and merit clinical validation of AXL-107-MMAE in both treatment-naive and drug-resistant cancers in mono- or combination therapy.", + "TAG_DATA": [ + "90, in {'context': 'B-in vivo'}", + "91, vivo {'context': 'B-in vivo'}", + "95, patient-derived {'context': 'B-xenograft'}", + "96, xenografts, {'context': 'I-xenograft'}", + "98, melanoma, {'context': 'B-neoplasm'}", + "99, lung, {'context': 'B-neoplasm'}", + "100, pancreas {'context': 'I-neoplasm'}", + "102, cervical {'context': 'B-neoplasm'}", + "103, cancer. {'context': 'I-neoplasm'}", + "110, melanoma {'context': 'B-transformed cells'}", + "111, cell {'context': 'I-transformed cells'}", + "119, inhibited {'effect': 'B-negative'}", + "120, tumor {'phenotype': 'B-tumour growth'}", + "121, growth. {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "90, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "91, vivo ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "95, patient-derived ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "96, xenografts, ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "98, melanoma, ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "99, lung, ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "100, pancreas ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "102, cervical ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "103, cancer. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "110, melanoma ['l36', 'l37', 'l38', 'l39']", + "111, cell ['l36', 'l40', 'l41', 'l42']", + "119, inhibited ['l37', 'l40', 'l43', 'l44']", + "120, tumor ['l38', 'l41', 'l43', 'l45']", + "121, growth. ['l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cell" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + } + ] + }, + { + "PMID": "29227477", + "TEXT": "Activation of apoptosis signal-regulating kinase 1 (ASK1) in hepatocytes is a key process in the progression of nonalcoholic steatohepatitis (NASH) and a promising target for treatment of the condition. However, the mechanism underlying ASK1 activation is still unclear, and thus the endogenous regulators of this kinase remain open to be exploited as potential therapeutic targets. In screening for proteins that interact with ASK1 in the context of NASH, we identified the deubiquitinase tumor necrosis factor alpha-induced protein 3 (TNFAIP3) as a key endogenous suppressor of ASK1 activation, and we found that TNFAIP3 directly interacts with and deubiquitinates ASK1 in hepatocytes. Hepatocyte-specific ablation of Tnfaip3 exacerbated nonalcoholic fatty liver disease- and NASH-related phenotypes in mice, including glucose metabolism disorders, lipid accumulation and enhanced inflammation, in an ASK1-dependent manner. In contrast, transgenic or adeno-associated virus-mediated TNFAIP3 gene delivery in the liver in both mouse and nonhuman primate models of NASH substantially blocked the onset and progression of the disease. These results implicate TNFAIP3 as a functionally important endogenous suppressor of ASK1 hyperactivation in the pathogenesis of NASH and identify it as a potential new molecular target for NASH therapy.", + "TAG_DATA": [ + "100, Hepatocyte-specific {'perturbing_action': 'B-gene loss-of-function'}", + "101, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "102, of {'perturbing_action': 'I-gene loss-of-function'}", + "103, Tnfaip3 {'perturbing_action': 'I-gene loss-of-function'}", + "113, mice, {'context': 'B-organism'}", + "129, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "130, or {'perturbing_action': 'I-gene gain-of-function'}", + "131, adeno-associated {'perturbing_action': 'I-gene gain-of-function'}", + "132, virus-mediated {'perturbing_action': 'I-gene gain-of-function'}", + "133, TNFAIP3 {'perturbing_action': 'I-gene gain-of-function'}", + "134, gene {'perturbing_action': 'I-gene gain-of-function'}", + "135, delivery {'perturbing_action': 'I-gene gain-of-function'}", + "138, liver {'context': 'B-tissue/organ'}", + "141, mouse {'context': 'B-organism'}", + "143, nonhuman {'context': 'B-organism'}", + "144, primate {'context': 'I-organism'}", + "145, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "100, Hepatocyte-specific ['l0', 'l1', 'l2', 'l3']", + "101, ablation ['l0', 'l4', 'l5', 'l6']", + "102, of ['l1', 'l4', 'l7', 'l8']", + "103, Tnfaip3 ['l2', 'l5', 'l7', 'l9']", + "113, mice, ['l3', 'l6', 'l8', 'l9']", + "129, transgenic ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "130, or ['l10', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "131, adeno-associated ['l11', 'l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "132, virus-mediated ['l12', 'l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "133, TNFAIP3 ['l13', 'l23', 'l32', 'l40', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "134, gene ['l14', 'l24', 'l33', 'l41', 'l48', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "135, delivery ['l15', 'l25', 'l34', 'l42', 'l49', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "138, liver ['l16', 'l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "141, mouse ['l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l70', 'l71', 'l72']", + "143, nonhuman ['l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l70', 'l73', 'l74']", + "144, primate ['l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l73', 'l75']", + "145, models ['l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hepatocyte-specific", + "ablation", + "of", + "Tnfaip3" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "or", + "adeno-associated", + "virus-mediated", + "TNFAIP3", + "gene", + "delivery" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "or", + "adeno-associated", + "virus-mediated", + "TNFAIP3", + "gene", + "delivery" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "nonhuman", + "primate", + "models" + ] + } + } + ] + }, + { + "PMID": "29035368", + "TEXT": "Nonalcoholic fatty liver disease is becoming the most common chronic liver disease in Western countries, and limited therapeutic options are available. Here we uncovered a role for intestinal hypoxia-inducible factor (HIF) in hepatic steatosis. Human-intestine biopsies from individuals with or without obesity revealed that intestinal HIF-2α signaling was positively correlated with body-mass index and hepatic toxicity. The causality of this correlation was verified in mice with an intestine-specific disruption of Hif2a, in which high-fat-diet-induced hepatic steatosis and obesity were substantially lower as compared to control mice. PT2385, a HIF-2α-specific inhibitor, had preventive and therapeutic effects on metabolic disorders that were dependent on intestine HIF-2α. Intestine HIF-2α inhibition markedly reduced intestine and serum ceramide levels. Mechanistically, intestine HIF-2α regulates ceramide metabolism mainly from the salvage pathway, by positively regulating the expression of Neu3, the gene encoding neuraminidase 3. These results suggest that intestinal HIF-2α could be a viable target for hepatic steatosis therapy.", + "TAG_DATA": [ + "64, mice {'context': 'B-organism'}", + "67, intestine-specific {'perturbing_action': 'B-gene loss-of-function'}", + "68, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "69, of {'perturbing_action': 'I-gene loss-of-function'}", + "70, Hif2a, {'perturbing_action': 'I-gene loss-of-function'}", + "85, mice. {'context': 'B-organism'}", + "86, PT2385, {'perturbing_action': 'B-pharmacological inhibition'}", + "87, a {'perturbing_action': 'I-pharmacological inhibition'}", + "88, HIF-2α-specific {'perturbing_action': 'I-pharmacological inhibition'}", + "89, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "104, Intestine {'perturbing_action': 'B-pharmacological inhibition'}", + "105, HIF-2α {'perturbing_action': 'I-pharmacological inhibition'}", + "106, inhibition {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "64, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "67, intestine-specific ['l0', 'l5', 'l6', 'l7', 'l8']", + "68, disruption ['l1', 'l5', 'l9', 'l10', 'l11']", + "69, of ['l2', 'l6', 'l9', 'l12', 'l13']", + "70, Hif2a, ['l3', 'l7', 'l10', 'l12', 'l14']", + "85, mice. ['l4', 'l8', 'l11', 'l13', 'l14']", + "86, PT2385, ['l15', 'l16', 'l17']", + "87, a ['l15', 'l18', 'l19']", + "88, HIF-2α-specific ['l16', 'l18', 'l20', 'l21']", + "89, inhibitor, ['l17', 'l19', 'l20']", + "104, Intestine ['l22', 'l23']", + "105, HIF-2α ['l22', 'l24']", + "106, inhibition ['l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "intestine-specific", + "disruption", + "of", + "Hif2a," + ] + } + } + ] + }, + { + "PMID": "28967920", + "TEXT": "Treating KRAS-mutant lung adenocarcinoma (LUAD) remains a major challenge in cancer treatment given the difficulties associated with directly inhibiting the KRAS oncoprotein. One approach to addressing this challenge is to define mutations that frequently co-occur with those in KRAS, which themselves may lead to therapeutic vulnerabilities in tumors. Approximately 20% of KRAS-mutant LUAD tumors carry loss-of-function mutations in the KEAP1 gene encoding Kelch-like ECH-associated protein 1 (refs. 2, 3, 4), a negative regulator of nuclear factor erythroid 2-like 2 (NFE2L2; hereafter NRF2), which is the master transcriptional regulator of the endogenous antioxidant response. The high frequency of mutations in KEAP1 suggests an important role for the oxidative stress response in lung tumorigenesis. Using a CRISPR-Cas9-based approach in a mouse model of KRAS-driven LUAD, we examined the effects of Keap1 loss in lung cancer progression. We show that loss of Keap1 hyperactivates NRF2 and promotes KRAS-driven LUAD in mice. Through a combination of CRISPR-Cas9-based genetic screening and metabolomic analyses, we show that Keap1- or Nrf2-mutant cancers are dependent on increased glutaminolysis, and this property can be therapeutically exploited through the pharmacological inhibition of glutaminase. Finally, we provide a rationale for stratification of human patients with lung cancer harboring KRAS/KEAP1- or KRAS/NRF2-mutant lung tumors as likely to respond to glutaminase inhibition.", + "TAG_DATA": [ + "119, model {'context': 'I-organism'}", + "128, Keap1 {'perturbing_action': 'B-gene loss-of-function'}", + "129, loss {'perturbing_action': 'I-gene loss-of-function'}", + "131, lung {'context': 'B-neoplasm'}", + "137, loss {'perturbing_action': 'B-gene loss-of-function'}", + "138, of {'perturbing_action': 'I-gene loss-of-function'}", + "139, Keap1 {'perturbing_action': 'I-gene loss-of-function'}", + "143, promotes {'effect': 'B-positive'}", + "145, LUAD {'phenotype': 'B-necrosis'}", + "147, mice. {'context': 'B-organism'}", + "161, Keap1- {'perturbing_action': 'B-other'}", + "162, or {'perturbing_action': 'I-other'}", + "163, Nrf2-mutant {'perturbing_action': 'I-other'}", + "164, cancers {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "119, model ['l0', 'l1', 'l2']", + "128, Keap1 ['l0', 'l3', 'l4', 'l5', 'l6']", + "129, loss ['l1', 'l3', 'l7', 'l8', 'l9']", + "131, lung ['l2', 'l4', 'l7']", + "137, loss ['l10', 'l11', 'l12', 'l13', 'l14']", + "138, of ['l10', 'l15', 'l16', 'l17', 'l18']", + "139, Keap1 ['l11', 'l15', 'l19', 'l20', 'l21']", + "143, promotes ['l5', 'l8', 'l12', 'l16', 'l19', 'l22', 'l23']", + "145, LUAD ['l6', 'l9', 'l13', 'l17', 'l20', 'l22', 'l24']", + "147, mice. ['l14', 'l18', 'l21', 'l23', 'l24']", + "161, Keap1- ['l25', 'l26', 'l27']", + "162, or ['l25', 'l28', 'l29']", + "163, Nrf2-mutant ['l26', 'l28', 'l30']", + "164, cancers ['l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "model", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Keap1", + "loss", + "of" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Keap1", + "loss" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Keap1", + "loss", + "of" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Keap1", + "loss", + "of" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "LUAD" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "LUAD" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "LUAD" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Keap1-", + "or", + "Nrf2-mutant" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "cancers" + ] + } + } + ] + }, + { + "PMID": "28920957", + "TEXT": "A deeper understanding of the metastatic process is required for the development of new therapies that improve patient survival. Metastatic tumor cell growth and survival in distant organs is facilitated by the formation of a pre-metastatic niche that is composed of hematopoietic cells, stromal cells and extracellular matrix (ECM). Perivascular cells, including vascular smooth muscle cells (vSMCs) and pericytes, are involved in new vessel formation and in promoting stem cell maintenance and proliferation. Given the well-described plasticity of perivascular cells, we hypothesized that perivascular cells similarly regulate tumor cell fate at metastatic sites. We used perivascular-cell-specific and pericyte-specific lineage-tracing models to trace the fate of perivascular cells in the pre-metastatic and metastatic microenvironments. We show that perivascular cells lose the expression of traditional vSMC and pericyte markers in response to tumor-secreted factors and exhibit increased proliferation, migration and ECM synthesis. Increased expression of the pluripotency gene Klf4 in these phenotypically switched perivascular cells promoted a less differentiated state, characterized by enhanced ECM production, that established a pro-metastatic fibronectin-rich environment. Genetic inactivation of Klf4 in perivascular cells decreased formation of a pre-metastatic niche and metastasis. Our data revealed a previously unidentified role for perivascular cells in pre-metastatic niche formation and uncovered novel strategies for limiting metastasis.", + "TAG_DATA": [ + "116, perivascular {'context': 'B-cells'}", + "117, cells {'context': 'I-cells'}", + "134, increased {'effect': 'B-positive'}", + "135, proliferation, {'phenotype': 'B-proliferation'}", + "136, migration {'phenotype': 'B-migration'}", + "140, Increased {'perturbing_action': 'B-gene gain-of-function'}", + "141, expression {'perturbing_action': 'I-gene gain-of-function'}", + "142, of {'perturbing_action': 'I-gene gain-of-function'}", + "143, the {'perturbing_action': 'I-gene gain-of-function'}", + "144, pluripotency {'perturbing_action': 'I-gene gain-of-function'}", + "145, gene {'perturbing_action': 'I-gene gain-of-function'}", + "146, Klf4 {'perturbing_action': 'I-gene gain-of-function'}", + "151, perivascular {'context': 'B-cells'}", + "152, cells {'context': 'I-cells'}", + "153, promoted {'effect': 'B-positive'}", + "157, state, {'phenotype': 'I-differentiation'}", + "169, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "170, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "171, of {'perturbing_action': 'I-gene loss-of-function'}", + "172, Klf4 {'perturbing_action': 'I-gene loss-of-function'}", + "174, perivascular {'context': 'B-cells'}", + "175, cells {'context': 'I-cells'}", + "176, decreased {'effect': 'B-negative'}", + "183, metastasis. {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "116, perivascular ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "117, cells ['l0', 'l8', 'l9', 'l10']", + "134, increased ['l1', 'l8', 'l11', 'l12']", + "135, proliferation, ['l2', 'l9', 'l11', 'l13']", + "136, migration ['l3', 'l10', 'l12', 'l13']", + "140, Increased ['l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "141, expression ['l14', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "142, of ['l15', 'l24', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "143, the ['l4', 'l16', 'l25', 'l33', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "144, pluripotency ['l17', 'l26', 'l34', 'l41', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "145, gene ['l5', 'l18', 'l27', 'l35', 'l42', 'l48', 'l54', 'l55', 'l56', 'l57', 'l58']", + "146, Klf4 ['l6', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l59', 'l60', 'l61', 'l62']", + "151, perivascular ['l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l63', 'l64', 'l65']", + "152, cells ['l7', 'l21', 'l30', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l66', 'l67']", + "153, promoted ['l22', 'l31', 'l39', 'l46', 'l52', 'l57', 'l61', 'l64', 'l66', 'l68']", + "157, state, ['l23', 'l32', 'l40', 'l47', 'l53', 'l58', 'l62', 'l65', 'l67', 'l68']", + "169, Genetic ['l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "170, inactivation ['l69', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "171, of ['l70', 'l76', 'l82', 'l83', 'l84', 'l85', 'l86']", + "172, Klf4 ['l71', 'l77', 'l82', 'l87', 'l88', 'l89', 'l90']", + "174, perivascular ['l72', 'l78', 'l83', 'l87', 'l91', 'l92', 'l93']", + "175, cells ['l73', 'l79', 'l84', 'l88', 'l91', 'l94', 'l95']", + "176, decreased ['l74', 'l80', 'l85', 'l89', 'l92', 'l94', 'l96']", + "183, metastasis. ['l75', 'l81', 'l86', 'l90', 'l93', 'l95', 'l96']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "perivascular", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "promoted" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "perivascular", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "perivascular", + "cells" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "perivascular", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "the", + "gene", + "Klf4", + "Increased", + "expression", + "of", + "pluripotency" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Increased", + "expression", + "of", + "the", + "pluripotency", + "gene", + "Klf4" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Increased", + "expression", + "of", + "the", + "pluripotency", + "gene", + "Klf4" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "state," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "perivascular", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "state," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "state," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "inactivation", + "of", + "Klf4" + ] + }, + "context": { + "val": "cells", + "words": [ + "perivascular", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "inactivation", + "of", + "Klf4" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "inactivation", + "of", + "Klf4" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "perivascular", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "perivascular", + "cells" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + } + ] + }, + { + "PMID": "28825715", + "TEXT": "Major depressive disorder (MDD) is a leading cause of disease burden worldwide. While the incidence, symptoms and treatment of MDD all point toward major sex differences, the molecular mechanisms underlying this sexual dimorphism remain largely unknown. Here, combining differential expression and gene coexpression network analyses, we provide a comprehensive characterization of male and female transcriptional profiles associated with MDD across six brain regions. We overlap our human profiles with those from a mouse model, chronic variable stress, and capitalize on converging pathways to define molecular and physiological mechanisms underlying the expression of stress susceptibility in males and females. Our results show a major rearrangement of transcriptional patterns in MDD, with limited overlap between males and females, an effect seen in both depressed humans and stressed mice. We identify key regulators of sex-specific gene networks underlying MDD and confirm their sex-specific impact as mediators of stress susceptibility. For example, downregulation of the female-specific hub gene Dusp6 in mouse prefrontal cortex mimicked stress susceptibility in females, but not males, by increasing ERK signaling and pyramidal neuron excitability. Such Dusp6 downregulation also recapitulated the transcriptional remodeling that occurs in prefrontal cortex of depressed females. Together our findings reveal marked sexual dimorphism at the transcriptional level in MDD and highlight the importance of studying sex-specific treatments for this disorder.", + "TAG_DATA": [ + "148, downregulation {'perturbing_action': 'B-rnai/knockdown'}", + "149, of {'perturbing_action': 'I-rnai/knockdown'}", + "150, the {'perturbing_action': 'I-rnai/knockdown'}", + "151, female-specific {'perturbing_action': 'I-rnai/knockdown'}", + "152, hub {'perturbing_action': 'I-rnai/knockdown'}", + "153, gene {'perturbing_action': 'I-rnai/knockdown'}", + "154, Dusp6 {'perturbing_action': 'I-rnai/knockdown'}", + "156, mouse {'context': 'B-tissue/organ'}", + "157, prefrontal {'context': 'I-tissue/organ'}", + "158, cortex {'context': 'I-tissue/organ'}", + "163, females, {'context': 'B-organism'}", + "172, pyramidal {'context': 'B-cells'}", + "173, neuron {'context': 'I-cells'}", + "186, prefrontal {'context': 'B-tissue/organ'}", + "187, cortex {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "148, downregulation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "149, of ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "150, the ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "151, female-specific ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "152, hub ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "153, gene ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "154, Dusp6 ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "156, mouse ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "157, prefrontal ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "158, cortex ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "163, females, ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "172, pyramidal ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "173, neuron ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "186, prefrontal ['l78']", + "187, cortex ['l78']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "downregulation", + "of", + "the", + "female-specific", + "hub", + "gene", + "Dusp6" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "prefrontal", + "cortex" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "downregulation", + "of", + "the", + "female-specific", + "hub", + "gene", + "Dusp6" + ] + }, + "context": { + "val": "organism", + "words": [ + "females," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "downregulation", + "of", + "the", + "female-specific", + "hub", + "gene", + "Dusp6" + ] + }, + "context": { + "val": "cells", + "words": [ + "pyramidal", + "neuron" + ] + } + } + ] + }, + { + "PMID": "28714990", + "TEXT": "The principles that govern the evolution of tumors exposed to targeted therapy are poorly understood. Here we modeled the selection and propagation of an amplification in the BRAF oncogene (BRAFamp) in patient-derived tumor xenografts (PDXs) that were treated with a direct inhibitor of the kinase ERK, either alone or in combination with other ERK signaling inhibitors. Single-cell sequencing and multiplex fluorescence in situ hybridization analyses mapped the emergence of extra-chromosomal amplification in parallel evolutionary trajectories that arose in the same tumor shortly after treatment. The evolutionary selection of BRAFamp was determined by the fitness threshold, the barrier that subclonal populations need to overcome to regain fitness in the presence of therapy. This differed for inhibitors of ERK signaling, suggesting that sequential monotherapy is ineffective and selects for a progressively higher BRAF copy number. Concurrent targeting of the RAF, MEK and ERK kinases, however, imposed a sufficiently high fitness threshold to prevent the propagation of subclones with high-level BRAFamp. When administered on an intermittent schedule, this treatment inhibited tumor growth in 11/11 PDXs of lung cancer or melanoma without apparent toxicity in mice. Thus, gene amplification can be acquired and expanded through parallel evolution, enabling tumors to adapt while maintaining their intratumoral heterogeneity. Treatments that impose the highest fitness threshold will likely prevent the evolution of resistance-causing alterations and, thus, merit testing in patients.", + "TAG_DATA": [ + "40, direct {'perturbing_action': 'B-pharmacological inhibition'}", + "41, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "42, of {'perturbing_action': 'I-pharmacological inhibition'}", + "43, the {'perturbing_action': 'I-pharmacological inhibition'}", + "44, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "45, ERK, {'perturbing_action': 'I-pharmacological inhibition'}", + "166, inhibited {'effect': 'B-negative'}", + "167, tumor {'phenotype': 'B-tumour growth'}", + "168, growth {'phenotype': 'I-tumour growth'}", + "173, lung {'context': 'B-neoplasm'}", + "174, cancer {'context': 'I-neoplasm'}", + "176, melanoma {'context': 'B-neoplasm'}", + "181, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "40, direct ['l0', 'l1', 'l2', 'l3', 'l4']", + "41, inhibitor ['l0', 'l5', 'l6', 'l7', 'l8']", + "42, of ['l1', 'l5', 'l9', 'l10', 'l11']", + "43, the ['l2', 'l6', 'l9', 'l12', 'l13']", + "44, kinase ['l3', 'l7', 'l10', 'l12', 'l14']", + "45, ERK, ['l4', 'l8', 'l11', 'l13', 'l14']", + "166, inhibited ['l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "167, tumor ['l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "168, growth ['l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "173, lung ['l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "174, cancer ['l18', 'l23', 'l27', 'l30', 'l33']", + "176, melanoma ['l19', 'l24', 'l28', 'l31', 'l33', 'l34']", + "181, mice. ['l20', 'l25', 'l29', 'l32', 'l34']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lung", + "cancer", + "melanoma" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lung", + "cancer", + "melanoma" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "28692064", + "TEXT": "Polo-like kinase 1 (PLK1), an essential regulator of cell division, is currently undergoing clinical evaluation as a target for cancer therapy. We report an unexpected function of Plk1 in sustaining cardiovascular homeostasis. Plk1 haploinsufficiency in mice did not induce obvious cell proliferation defects but did result in arterial structural alterations, which frequently led to aortic rupture and death. Specific ablation of Plk1 in vascular smooth muscle cells (VSMCs) led to reduced arterial elasticity, hypotension, and an impaired arterial response to angiotensin II in vivo. Mechanistically, we found that Plk1 regulated angiotensin II-dependent activation of RhoA and actomyosin dynamics in VSMCs in a mitosis-independent manner. This regulation depended on Plk1 kinase activity, and the administration of small-molecule Plk1 inhibitors to angiotensin II-treated mice led to reduced arterial fitness and an elevated risk of aneurysm and aortic rupture. We thus conclude that a partial reduction of Plk1 activity that does not block cell division can nevertheless impair aortic homeostasis. Our findings have potentially important implications for current approaches aimed at PLK1 inhibition for cancer therapy.", + "TAG_DATA": [ + "35, mice {'context': 'B-organism'}", + "38, induce {'effect': 'I-no effect'}", + "40, cell {'context': 'B-cells'}", + "41, proliferation {'phenotype': 'B-proliferation'}", + "42, defects {'effect': 'B-negative'}", + "58, Specific {'perturbing_action': 'B-gene loss-of-function'}", + "59, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "60, of {'perturbing_action': 'I-gene loss-of-function'}", + "61, Plk1 {'perturbing_action': 'I-gene loss-of-function'}", + "63, vascular {'context': 'B-cells'}", + "64, smooth {'context': 'I-cells'}", + "65, muscle {'context': 'I-cells'}", + "66, cells {'context': 'I-cells'}", + "67, (VSMCs) {'context': 'I-cells'}", + "82, in {'context': 'B-in vivo'}", + "83, vivo. {'context': 'I-in vivo'}", + "99, VSMCs {'context': 'B-cells'}", + "115, small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "116, Plk1 {'perturbing_action': 'I-pharmacological inhibition'}", + "117, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "121, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "35, mice ['l0', 'l1', 'l2', 'l3']", + "38, induce ['l0', 'l4', 'l5', 'l6']", + "40, cell ['l1', 'l4', 'l7', 'l8']", + "41, proliferation ['l2', 'l5', 'l7', 'l9']", + "42, defects ['l3', 'l6', 'l8', 'l9']", + "58, Specific ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "59, ablation ['l10', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "60, of ['l11', 'l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "61, Plk1 ['l12', 'l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "63, vascular ['l13', 'l23', 'l32', 'l40', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "64, smooth ['l14', 'l24', 'l33', 'l41', 'l48', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "65, muscle ['l15', 'l25', 'l34', 'l42', 'l49', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "66, cells ['l16', 'l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "67, (VSMCs) ['l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l70', 'l71', 'l72']", + "82, in ['l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l70', 'l73']", + "83, vivo. ['l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l73']", + "99, VSMCs ['l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72']", + "115, small-molecule ['l74', 'l75', 'l76']", + "116, Plk1 ['l74', 'l77', 'l78']", + "117, inhibitors ['l75', 'l77', 'l79']", + "121, mice ['l76', 'l78', 'l79']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defects" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defects" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defects" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Specific", + "ablation", + "of", + "Plk1" + ] + }, + "context": { + "val": "cells", + "words": [ + "vascular", + "smooth", + "muscle", + "cells", + "(VSMCs)", + "VSMCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Specific", + "ablation", + "of", + "Plk1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "Plk1", + "inhibitors" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "28436957", + "TEXT": "Diabetic nephropathy (DN) is a major cause of end-stage renal disease, and therapeutic options for preventing its progression are limited. To identify novel therapeutic strategies, we studied protective factors for DN using proteomics on glomeruli from individuals with extreme duration of diabetes (ł50 years) without DN and those with histologic signs of DN. Enzymes in the glycolytic, sorbitol, methylglyoxal and mitochondrial pathways were elevated in individuals without DN. In particular, pyruvate kinase M2 (PKM2) expression and activity were upregulated. Mechanistically, we showed that hyperglycemia and diabetes decreased PKM2 tetramer formation and activity by sulfenylation in mouse glomeruli and cultured podocytes. Pkm-knockdown immortalized mouse podocytes had higher levels of toxic glucose metabolites, mitochondrial dysfunction and apoptosis. Podocyte-specific Pkm2-knockout (KO) mice with diabetes developed worse albuminuria and glomerular pathology. Conversely, we found that pharmacological activation of PKM2 by a small-molecule PKM2 activator, TEPP-46, reversed hyperglycemia-induced elevation in toxic glucose metabolites and mitochondrial dysfunction, partially by increasing glycolytic flux and PGC-1α mRNA in cultured podocytes. In intervention studies using DBA2/J and Nos3 (eNos) KO mouse models of diabetes, TEPP-46 treatment reversed metabolic abnormalities, mitochondrial dysfunction and kidney pathology. Thus, PKM2 activation may protect against DN by increasing glucose metabolic flux, inhibiting the production of toxic glucose metabolites and inducing mitochondrial biogenesis to restore mitochondrial function.", + "TAG_DATA": [ + "95, mouse {'context': 'B-tissue/organ'}", + "96, glomeruli {'context': 'I-tissue/organ'}", + "98, cultured {'context': 'B-cells'}", + "99, podocytes. {'context': 'I-cells'}", + "100, Pkm-knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "101, immortalized {'context': 'B-cells'}", + "102, mouse {'context': 'I-cells'}", + "103, podocytes {'context': 'I-cells'}", + "114, apoptosis. {'phenotype': 'B-apoptosis'}", + "115, Podocyte-specific {'perturbing_action': 'B-gene loss-of-function'}", + "116, Pkm2-knockout {'perturbing_action': 'I-gene loss-of-function'}", + "117, (KO) {'perturbing_action': 'I-gene loss-of-function'}", + "118, mice {'context': 'B-organism'}", + "131, pharmacological {'perturbing_action': 'B-pharmacological augmentation'}", + "132, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "133, of {'perturbing_action': 'I-pharmacological augmentation'}", + "134, PKM2 {'perturbing_action': 'I-pharmacological augmentation'}", + "135, by {'perturbing_action': 'I-pharmacological augmentation'}", + "136, a {'perturbing_action': 'I-pharmacological augmentation'}", + "137, small-molecule {'perturbing_action': 'I-pharmacological augmentation'}", + "138, PKM2 {'perturbing_action': 'I-pharmacological augmentation'}", + "139, activator, {'perturbing_action': 'I-pharmacological augmentation'}", + "140, TEPP-46, {'perturbing_action': 'I-pharmacological augmentation'}", + "160, cultured {'context': 'B-cells'}", + "161, podocytes. {'context': 'I-cells'}", + "168, Nos3 {'perturbing_action': 'I-gene loss-of-function'}", + "169, (eNos) {'perturbing_action': 'I-gene loss-of-function'}", + "170, KO {'perturbing_action': 'I-gene loss-of-function'}", + "171, mouse {'context': 'B-organism'}", + "172, models {'context': 'I-organism'}", + "183, kidney {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "95, mouse ['l0', 'l1', 'l2', 'l3']", + "96, glomeruli ['l0', 'l4', 'l5', 'l6', 'l7']", + "98, cultured ['l1', 'l4', 'l8', 'l9', 'l10', 'l11']", + "99, podocytes. ['l2', 'l5', 'l8', 'l12', 'l13', 'l14']", + "100, Pkm-knockdown ['l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "101, immortalized ['l15', 'l21', 'l22', 'l23']", + "102, mouse ['l9', 'l12', 'l16', 'l21', 'l24', 'l25']", + "103, podocytes ['l6', 'l10', 'l13', 'l17', 'l22', 'l24', 'l26']", + "114, apoptosis. ['l3', 'l7', 'l11', 'l14', 'l18', 'l23', 'l25', 'l26']", + "115, Podocyte-specific ['l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "116, Pkm2-knockout ['l27', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "117, (KO) ['l19', 'l28', 'l41', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "118, mice ['l20', 'l29', 'l42', 'l55', 'l64', 'l65', 'l66']", + "131, pharmacological ['l43', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "132, activation ['l30', 'l44', 'l67', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "133, of ['l31', 'l45', 'l56', 'l68', 'l81', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "134, PKM2 ['l32', 'l46', 'l57', 'l69', 'l82', 'l91', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "135, by ['l33', 'l47', 'l58', 'l70', 'l83', 'l92', 'l100', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "136, a ['l34', 'l48', 'l59', 'l71', 'l84', 'l93', 'l101', 'l108', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "137, small-molecule ['l35', 'l49', 'l72', 'l85', 'l94', 'l102', 'l109', 'l115', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "138, PKM2 ['l36', 'l50', 'l73', 'l86', 'l95', 'l103', 'l110', 'l116', 'l122', 'l130', 'l131', 'l132', 'l133', 'l134']", + "139, activator, ['l37', 'l51', 'l60', 'l74', 'l87', 'l96', 'l104', 'l111', 'l117', 'l123', 'l130', 'l135', 'l136', 'l137', 'l138']", + "140, TEPP-46, ['l38', 'l52', 'l61', 'l64', 'l75', 'l88', 'l97', 'l105', 'l112', 'l118', 'l124', 'l131', 'l135', 'l139', 'l140']", + "160, cultured ['l39', 'l53', 'l62', 'l65', 'l76', 'l89', 'l98', 'l106', 'l113', 'l119', 'l125', 'l132', 'l136', 'l139', 'l141']", + "161, podocytes. ['l40', 'l54', 'l63', 'l66', 'l77', 'l90', 'l99', 'l107', 'l114', 'l120', 'l126', 'l133', 'l137', 'l140', 'l141']", + "166, DBA2/J ['l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "167, and ['l142', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "168, Nos3 ['l78', 'l127', 'l143', 'l149', 'l155', 'l156', 'l157', 'l158', 'l159']", + "169, (eNos) ['l79', 'l121', 'l128', 'l134', 'l138', 'l144', 'l150', 'l155', 'l160', 'l161', 'l162', 'l163']", + "170, KO ['l145', 'l151', 'l156', 'l160', 'l164', 'l165', 'l166']", + "171, mouse ['l146', 'l152', 'l157', 'l161', 'l164', 'l167', 'l168']", + "172, models ['l80', 'l129', 'l147', 'l153', 'l158', 'l162', 'l165', 'l167', 'l169']", + "183, kidney ['l148', 'l154', 'l159', 'l163', 'l166', 'l168', 'l169']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "glomeruli" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "podocytes.", + "immortalized", + "mouse", + "podocytes" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Pkm-knockdown" + ] + }, + "context": { + "val": "cells", + "words": [ + "immortalized", + "mouse", + "podocytes" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Pkm-knockdown" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Pkm-knockdown" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Podocyte-specific", + "Pkm2-knockout", + "(KO)", + "Nos3", + "(eNos)", + "KO" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "models" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Podocyte-specific", + "Pkm2-knockout", + "(KO)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "podocytes." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "models" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "TEPP-46,", + "pharmacological", + "small-molecule" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "pharmacological", + "activation", + "of", + "PKM2", + "by", + "a", + "small-molecule", + "activator,", + "TEPP-46," + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "podocytes." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nos3", + "(eNos)", + "KO" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidney" + ] + } + } + ] + }, + { + "PMID": "28414329", + "TEXT": "Adaptive thermogenesis is the process of heat generation in response to cold stimulation. It is under the control of the sympathetic nervous system, whose chief effector is the catecholamine norepinephrine (NE). NE enhances thermogenesis through β3-adrenergic receptors to activate brown adipose tissue and by 'browning' white adipose tissue. Recent studies have reported that alternative activation of macrophages in response to interleukin (IL)-4 stimulation induces the expression of tyrosine hydroxylase (TH), a key enzyme in the catecholamine synthesis pathway, and that this activation provides an alternative source of locally produced catecholamines during the thermogenic process. Here we report that the deletion of Th in hematopoietic cells of adult mice neither alters energy expenditure upon cold exposure nor reduces browning in inguinal adipose tissue. Bone marrow-derived macrophages did not release NE in response to stimulation with IL-4, and conditioned media from IL-4-stimulated macrophages failed to induce expression of thermogenic genes, such as uncoupling protein 1 (Ucp1), in adipocytes cultured with the conditioned media. Furthermore, chronic treatment with IL-4 failed to increase energy expenditure in wild-type, Ucp1-/- and interleukin-4 receptor-α double-negative (Il4ra-/-) mice. In agreement with these findings, adipose-tissue-resident macrophages did not express TH. Thus, we conclude that alternatively activated macrophages do not synthesize relevant amounts of catecholamines, and hence, are not likely to have a direct role in adipocyte metabolism or adaptive thermogenesis.", + "TAG_DATA": [ + "99, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "100, of {'perturbing_action': 'I-gene loss-of-function'}", + "101, Th {'perturbing_action': 'I-gene loss-of-function'}", + "103, hematopoietic {'context': 'B-cells'}", + "104, cells {'context': 'I-cells'}", + "106, adult {'context': 'B-organism'}", + "107, mice {'context': 'I-organism'}", + "119, inguinal {'context': 'B-tissue/organ'}", + "120, adipose {'context': 'I-tissue/organ'}", + "121, tissue. {'context': 'I-tissue/organ'}", + "122, Bone {'context': 'B-cells'}", + "123, marrow-derived {'context': 'I-cells'}", + "124, macrophages {'context': 'I-cells'}", + "140, macrophages {'context': 'B-cells'}", + "155, adipocytes {'context': 'B-cells'}", + "173, Ucp1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "175, interleukin-4 {'perturbing_action': 'B-gene loss-of-function'}", + "176, receptor-α {'perturbing_action': 'I-gene loss-of-function'}", + "177, double-negative {'perturbing_action': 'I-gene loss-of-function'}", + "178, (Il4ra-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "179, mice. {'context': 'B-organism'}", + "185, adipose-tissue-resident {'context': 'B-cells'}", + "186, macrophages {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "99, deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "100, of ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "101, Th ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "103, hematopoietic ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "104, cells ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "106, adult ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54']", + "107, mice ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l55', 'l56', 'l57']", + "119, inguinal ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l55', 'l58', 'l59', 'l60', 'l61', 'l62']", + "120, adipose ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l56', 'l58', 'l63', 'l64', 'l65', 'l66']", + "121, tissue. ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l57', 'l59', 'l63', 'l67']", + "122, Bone ['l9', 'l20', 'l30', 'l39', 'l47', 'l60', 'l64', 'l68', 'l69', 'l70', 'l71']", + "123, marrow-derived ['l10', 'l21', 'l31', 'l40', 'l48', 'l61', 'l65', 'l68', 'l72', 'l73', 'l74']", + "124, macrophages ['l11', 'l22', 'l32', 'l41', 'l49', 'l54', 'l62', 'l66', 'l67', 'l69', 'l72', 'l75', 'l76']", + "140, macrophages ['l70', 'l73', 'l75', 'l77']", + "155, adipocytes ['l71', 'l74', 'l76', 'l77']", + "173, Ucp1-/- ['l78', 'l79', 'l80', 'l81', 'l82']", + "175, interleukin-4 ['l78', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "176, receptor-α ['l79', 'l83', 'l89', 'l90', 'l91', 'l92', 'l93']", + "177, double-negative ['l80', 'l84', 'l89', 'l94', 'l95', 'l96', 'l97']", + "178, (Il4ra-/-) ['l81', 'l85', 'l90', 'l94', 'l98', 'l99', 'l100']", + "179, mice. ['l82', 'l86', 'l91', 'l95', 'l98']", + "185, adipose-tissue-resident ['l87', 'l92', 'l96', 'l99', 'l101']", + "186, macrophages ['l88', 'l93', 'l97', 'l100', 'l101']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Th", + "interleukin-4", + "receptor-α", + "double-negative", + "(Il4ra-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "cells", + "Bone", + "marrow-derived", + "macrophages", + "adipose-tissue-resident" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Th", + "Ucp1-/-", + "interleukin-4", + "receptor-α", + "double-negative", + "(Il4ra-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "adult", + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Th" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "inguinal", + "adipose", + "tissue." + ] + } + } + ] + }, + { + "PMID": "28263313", + "TEXT": "Efficient hematopoietic stem cell (HSC) homing is important for hematopoietic cell transplantation (HCT), especially when HSC numbers are limited, as in the use of cord blood (CB). In a screen of small-molecule compounds, we identified glucocorticoid (GC) hormone signaling as an activator of CXCR4 expression in human CB HSCs and hematopoietic progenitor cells (HPCs). Short-term GC pretreatment of human CB HSCs and HPCs promoted SDF-1-CXCR4-axis-mediated chemotaxis, homing, and long-term engraftment when these cells were transplanted into primary- and secondary-recipient NSG mice. Mechanistically, activated glucocorticoid receptor binds directly to a glucocorticoid response element in the CXCR4 promoter and recruits the SRC-1-p300 complex to promote H4K5 and H4K16 histone acetylation, facilitating transcription of CXCR4. These results suggest a new and readily available means to enhance the clinical efficacy of CB HCT.", + "TAG_DATA": [ + "58, human {'context': 'B-cells'}", + "59, CB {'context': 'I-cells'}", + "60, HSCs {'context': 'I-cells'}", + "62, HPCs {'context': 'B-cells'}", + "63, promoted {'effect': 'B-positive'}", + "72, cells {'context': 'B-cells'}", + "76, primary- {'context': 'B-organism'}", + "77, and {'context': 'I-cells'}", + "78, secondary-recipient {'context': 'I-organism'}", + "79, NSG {'context': 'I-organism'}", + "80, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "58, human ['l0', 'l1', 'l2', 'l3', 'l4']", + "59, CB ['l0', 'l5', 'l6', 'l7', 'l8']", + "60, HSCs ['l1', 'l5', 'l9', 'l10', 'l11']", + "62, HPCs ['l2', 'l6', 'l9', 'l12', 'l13']", + "63, promoted ['l3', 'l7', 'l10', 'l12']", + "72, cells ['l4', 'l8', 'l11', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "76, primary- ['l14', 'l19', 'l20', 'l21', 'l22']", + "77, and ['l15', 'l19', 'l23', 'l24', 'l25']", + "78, secondary-recipient ['l16', 'l20', 'l23', 'l26', 'l27']", + "79, NSG ['l17', 'l21', 'l24', 'l26', 'l28']", + "80, mice. ['l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "CB", + "HSCs", + "HPCs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + } + ] + }, + { + "PMID": "28218918", + "TEXT": "African Americans have a heightened risk of developing chronic and end-stage kidney disease, an association that is largely attributed to two common genetic variants, termed G1 and G2, in the APOL1 gene. Direct evidence demonstrating that these APOL1 risk alleles are pathogenic is still lacking because the APOL1 gene is present in only some primates and humans; thus it has been challenging to demonstrate experimental proof of causality of these risk alleles for renal disease. Here we generated mice with podocyte-specific inducible expression of the APOL1 reference allele (termed G0) or each of the risk-conferring alleles (G1 or G2). We show that mice with podocyte-specific expression of either APOL1 risk allele, but not of the G0 allele, develop functional (albuminuria and azotemia), structural (foot-process effacement and glomerulosclerosis) and molecular (gene-expression) changes that closely resemble human kidney disease. Disease development was cell-type specific and likely reversible, and the severity correlated with the level of expression of the risk allele. We further found that expression of the risk-variant APOL1 alleles interferes with endosomal trafficking and blocks autophagic flux, which ultimately leads to inflammatory-mediated podocyte death and glomerular scarring. In summary, this is the first demonstration that the expression of APOL1 risk alleles is causal for altered podocyte function and glomerular disease in vivo.", + "TAG_DATA": [ + "78, mice {'context': 'B-organism'}", + "80, podocyte-specific {'perturbing_action': 'B-gene gain-of-function'}", + "81, inducible {'perturbing_action': 'I-gene gain-of-function'}", + "82, expression {'perturbing_action': 'I-gene gain-of-function'}", + "83, of {'perturbing_action': 'I-gene gain-of-function'}", + "84, the {'perturbing_action': 'I-gene gain-of-function'}", + "85, APOL1 {'perturbing_action': 'I-gene gain-of-function'}", + "86, reference {'perturbing_action': 'I-gene gain-of-function'}", + "87, allele {'perturbing_action': 'I-gene gain-of-function'}", + "88, (termed {'perturbing_action': 'I-gene gain-of-function'}", + "89, G0) {'perturbing_action': 'I-gene gain-of-function'}", + "102, mice {'context': 'B-organism'}", + "104, podocyte-specific {'perturbing_action': 'B-gene gain-of-function'}", + "105, expression {'perturbing_action': 'I-gene gain-of-function'}", + "106, of {'perturbing_action': 'I-gene gain-of-function'}", + "107, either {'perturbing_action': 'I-gene gain-of-function'}", + "108, APOL1 {'perturbing_action': 'I-other'}", + "109, risk {'perturbing_action': 'I-gene gain-of-function'}", + "110, allele, {'perturbing_action': 'I-gene gain-of-function'}", + "173, blocks {'effect': 'B-negative'}", + "174, autophagic {'phenotype': 'B-autophagy'}", + "175, flux, {'phenotype': 'I-autophagy'}", + "181, podocyte {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "78, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "80, podocyte-specific ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "81, inducible ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "82, expression ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "83, of ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "84, the ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "85, APOL1 ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "86, reference ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "87, allele ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "88, (termed ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "89, G0) ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "102, mice ['l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "104, podocyte-specific ['l55', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "105, expression ['l56', 'l62', 'l68', 'l69', 'l70', 'l71', 'l72']", + "106, of ['l57', 'l63', 'l68', 'l73', 'l74', 'l75', 'l76']", + "107, either ['l58', 'l64', 'l69', 'l73', 'l77', 'l78', 'l79']", + "108, APOL1 ['l59', 'l65', 'l70', 'l74', 'l77', 'l80', 'l81']", + "109, risk ['l60', 'l66', 'l71', 'l75', 'l78', 'l80', 'l82']", + "110, allele, ['l61', 'l67', 'l72', 'l76', 'l79', 'l81', 'l82']", + "173, blocks ['l83', 'l84', 'l85']", + "174, autophagic ['l83', 'l86', 'l87']", + "175, flux, ['l84', 'l86', 'l88']", + "181, podocyte ['l85', 'l87', 'l88']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "podocyte-specific", + "inducible", + "expression", + "of", + "the", + "APOL1", + "reference", + "allele", + "(termed", + "G0)", + "either", + "risk", + "allele," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "APOL1" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagic", + "flux," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocyte" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagic", + "flux," + ] + }, + "context": { + "val": "cells", + "words": [ + "podocyte" + ] + } + } + ] + }, + { + "PMID": "28191885", + "TEXT": "Lung cancer is the leading cause of cancer deaths worldwide, with the majority of mortality resulting from metastatic spread. However, the molecular mechanism by which cancer cells acquire the ability to disseminate from primary tumors, seed distant organs, and grow into tissue-destructive metastases remains incompletely understood. We combined tumor barcoding in a mouse model of human lung adenocarcinoma with unbiased genomic approaches to identify a transcriptional program that confers metastatic ability and predicts patient survival. Small-scale in vivo screening identified several genes, including Cd109, that encode novel pro-metastatic factors. We uncovered signaling mediated by Janus kinases (Jaks) and the transcription factor Stat3 as a critical, pharmacologically targetable effector of CD109-driven lung cancer metastasis. In summary, by coupling the systematic genomic analysis of purified cancer cells in distinct malignant states from mouse models with extensive human validation, we uncovered several key regulators of metastatic ability, including an actionable pro-metastatic CD109-Jak-Stat3 axis.", + "TAG_DATA": [ + "52, mouse {'context': 'B-organism'}", + "53, model {'context': 'I-neoplasm'}", + "54, of {'context': 'I-neoplasm'}", + "55, human {'context': 'I-neoplasm'}", + "56, lung {'context': 'I-neoplasm'}", + "57, adenocarcinoma {'context': 'I-neoplasm'}", + "76, in {'context': 'B-in vivo'}", + "77, vivo {'context': 'B-in vivo'}", + "110, lung {'context': 'B-neoplasm'}", + "111, cancer {'context': 'I-neoplasm'}", + "112, metastasis. {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "52, mouse ['l0', 'l1', 'l2', 'l3', 'l4']", + "53, model ['l0', 'l5', 'l6', 'l7', 'l8']", + "54, of ['l1', 'l5', 'l9', 'l10', 'l11', 'l12']", + "55, human ['l2', 'l6', 'l9', 'l13', 'l14', 'l15']", + "56, lung ['l3', 'l7', 'l10', 'l13', 'l16', 'l17', 'l18']", + "57, adenocarcinoma ['l4', 'l8', 'l11', 'l14', 'l16', 'l19', 'l20']", + "76, in ['l17', 'l19', 'l21', 'l22', 'l23', 'l24']", + "77, vivo ['l12', 'l15', 'l18', 'l20', 'l21', 'l25']", + "110, lung ['l22', 'l26', 'l27']", + "111, cancer ['l23', 'l25', 'l26', 'l28']", + "112, metastasis. ['l24', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "lung", + "cancer" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + } + ] + }, + { + "PMID": "28112735", + "TEXT": "The prefrontal cortex (PFC) underlies higher cognitive processes that are modulated by nicotinic acetylcholine receptor (nAChR) activation by cholinergic inputs. PFC spontaneous default activity is altered in neuropsychiatric disorders, including schizophrenia-a disorder that can be accompanied by heavy smoking. Recently, genome-wide association studies (GWAS) identified single-nucleotide polymorphisms (SNPs) in the human CHRNA5 gene, encoding the α5 nAChR subunit, that increase the risks for both smoking and schizophrenia. Mice with altered nAChR gene function exhibit PFC-dependent behavioral deficits, but it is unknown how the corresponding human polymorphisms alter the cellular and circuit mechanisms underlying behavior. Here we show that mice expressing a human α5 SNP exhibit neurocognitive behavioral deficits in social interaction and sensorimotor gating tasks. Two-photon calcium imaging in awake mouse models showed that nicotine can differentially influence PFC pyramidal cell activity by nAChR modulation of layer II/III hierarchical inhibitory circuits. In α5-SNP-expressing and α5-knockout mice, lower activity of vasoactive intestinal polypeptide (VIP) interneurons resulted in an increased somatostatin (SOM) interneuron inhibitory drive over layer II/III pyramidal neurons. The decreased activity observed in α5-SNP-expressing mice resembles the hypofrontality observed in patients with psychiatric disorders, including schizophrenia and addiction. Chronic nicotine administration reversed this hypofrontality, suggesting that administration of nicotine may represent a therapeutic strategy for the treatment of schizophrenia, and a physiological basis for the tendency of patients with schizophrenia to self-medicate by smoking.", + "TAG_DATA": [ + "98, mice {'context': 'B-organism'}", + "99, expressing {'perturbing_action': 'B-other'}", + "100, a {'perturbing_action': 'I-other'}", + "101, human {'perturbing_action': 'I-other'}", + "102, α5 {'perturbing_action': 'I-other'}", + "103, SNP {'perturbing_action': 'I-other'}", + "119, awake {'context': 'B-organism'}", + "120, mouse {'context': 'I-organism'}", + "121, models {'context': 'I-organism'}", + "128, PFC {'context': 'B-cells'}", + "130, cell {'context': 'I-cells'}", + "142, α5-SNP-expressing {'perturbing_action': 'B-other'}", + "144, α5-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "145, mice, {'context': 'B-organism'}", + "164, layer {'context': 'B-cells'}", + "165, II/III {'context': 'I-cells'}", + "166, pyramidal {'context': 'I-cells'}", + "167, neurons. {'context': 'I-cells'}", + "174, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "98, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "99, expressing ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "100, a ['l1', 'l8', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "101, human ['l2', 'l9', 'l18', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "102, α5 ['l3', 'l10', 'l19', 'l27', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "103, SNP ['l4', 'l11', 'l20', 'l28', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "119, awake ['l12', 'l21', 'l29', 'l36', 'l41', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "120, mouse ['l5', 'l13', 'l22', 'l30', 'l37', 'l42', 'l46', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "121, models ['l6', 'l14', 'l23', 'l31', 'l38', 'l43', 'l47', 'l53', 'l59', 'l60', 'l61', 'l62']", + "128, PFC ['l15', 'l24', 'l32', 'l39', 'l44', 'l48', 'l54', 'l59', 'l63', 'l64', 'l65', 'l66']", + "130, cell ['l7', 'l16', 'l25', 'l33', 'l40', 'l45', 'l49', 'l55', 'l60', 'l63', 'l67', 'l68', 'l69']", + "142, α5-SNP-expressing ['l17', 'l26', 'l34', 'l50', 'l56', 'l61', 'l64', 'l67', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "144, α5-knockout ['l51', 'l57', 'l65', 'l68', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "145, mice, ['l52', 'l58', 'l62', 'l66', 'l69', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "164, layer ['l72', 'l77', 'l81', 'l85', 'l86', 'l87', 'l88']", + "165, II/III ['l73', 'l78', 'l82', 'l85', 'l89', 'l90', 'l91']", + "166, pyramidal ['l74', 'l79', 'l83', 'l86', 'l89', 'l92', 'l93']", + "167, neurons. ['l75', 'l80', 'l84', 'l87', 'l90', 'l92', 'l94']", + "174, mice ['l88', 'l91', 'l93', 'l94']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "awake", + "mouse", + "models", + "mice," + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "a", + "human", + "α5", + "SNP", + "α5-SNP-expressing" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "a", + "human", + "α5", + "SNP", + "α5-SNP-expressing" + ] + }, + "context": { + "val": "cells", + "words": [ + "PFC", + "cell", + "layer", + "II/III", + "pyramidal", + "neurons." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "awake", + "mouse", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "α5-knockout" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "PFC", + "cell", + "layer", + "II/III", + "pyramidal", + "neurons." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "α5-knockout" + ] + } + } + ] + }, + { + "PMID": "28067899", + "TEXT": "Heritable thoracic aortic aneurysms and dissections (TAAD), including Marfan syndrome (MFS), currently lack a cure, and causative mutations have been identified for only a fraction of affected families. Here we identify the metalloproteinase ADAMTS1 and inducible nitric oxide synthase (NOS2) as therapeutic targets in individuals with TAAD. We show that Adamts1 is a major mediator of vascular homeostasis, given that genetic haploinsufficiency of Adamts1 in mice causes TAAD similar to MFS. Aortic nitric oxide and Nos2 levels were higher in Adamts1-deficient mice and in a mouse model of MFS (hereafter referred to as MFS mice), and Nos2 inactivation protected both types of mice from aortic pathology. Pharmacological inhibition of Nos2 rapidly reversed aortic dilation and medial degeneration in young Adamts1-deficient mice and in young or old MFS mice. Patients with MFS showed elevated NOS2 and decreased ADAMTS1 protein levels in the aorta. These findings uncover a possible causative role for the ADAMTS1-NOS2 axis in human TAAD and warrant evaluation of NOS2 inhibitors for therapy.", + "TAG_DATA": [ + "80, Adamts1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "81, mice {'context': 'B-organism'}", + "85, mouse {'context': 'B-organism'}", + "86, model {'context': 'I-organism'}", + "96, Nos2 {'perturbing_action': 'B-gene loss-of-function'}", + "97, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "102, mice {'context': 'B-organism'}", + "106, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "107, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "108, of {'perturbing_action': 'I-pharmacological inhibition'}", + "109, Nos2 {'perturbing_action': 'I-pharmacological inhibition'}", + "119, Adamts1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "120, mice {'context': 'B-organism'}", + "123, young {'context': 'B-organism'}", + "124, or {'context': 'I-organism'}", + "125, old {'context': 'I-organism'}", + "127, mice. {'context': 'I-organism'}", + "141, aorta. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "63, Adamts1 ['l0', 'l1']", + "80, Adamts1-deficient ['l0', 'l2']", + "81, mice ['l1', 'l2']", + "85, mouse ['l3', 'l4', 'l5']", + "86, model ['l3', 'l6', 'l7']", + "87, of ['l4', 'l6', 'l8']", + "96, Nos2 ['l9', 'l10']", + "97, inactivation ['l9', 'l11']", + "102, mice ['l5', 'l7', 'l8', 'l10', 'l11']", + "106, Pharmacological ['l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "107, inhibition ['l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "108, of ['l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "109, Nos2 ['l14', 'l23', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "119, Adamts1-deficient ['l15', 'l24', 'l32', 'l39', 'l45', 'l46', 'l47', 'l48', 'l49']", + "120, mice ['l16', 'l25', 'l33', 'l40', 'l45', 'l50', 'l51', 'l52']", + "123, young ['l17', 'l26', 'l34', 'l41', 'l46', 'l50', 'l53', 'l54', 'l55']", + "124, or ['l18', 'l27', 'l35', 'l42', 'l47', 'l53', 'l56', 'l57']", + "125, old ['l19', 'l28', 'l36', 'l43', 'l48', 'l51', 'l54', 'l56', 'l58']", + "127, mice. ['l20', 'l29', 'l37', 'l44', 'l49', 'l52', 'l55', 'l57', 'l58']", + "141, aorta. ['l21', 'l30', 'l38']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Adamts1-deficient", + "Nos2", + "inactivation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "young", + "or", + "old", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "Nos2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "young", + "or", + "old", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "aorta." + ] + } + } + ] + }, + { + "PMID": "27991918", + "TEXT": "Type 2 diabetes and insulin resistance are associated with reduced glucose utilization in the muscle and poor exercise performance. Here we find that depletion of the epigenome modifier histone deacetylase 3 (HDAC3) specifically in skeletal muscle causes severe systemic insulin resistance in mice but markedly enhances endurance and resistance to muscle fatigue, despite reducing muscle force. This seemingly paradoxical phenotype is due to lower glucose utilization and greater lipid oxidation in HDAC3-depleted muscles, a fuel switch caused by the activation of anaplerotic reactions driven by AMP deaminase 3 (Ampd3) and catabolism of branched-chain amino acids. These findings highlight the pivotal role of amino acid catabolism in muscle fatigue and type 2 diabetes pathogenesis. Further, as genome occupancy of HDAC3 in skeletal muscle is controlled by the circadian clock, these results delineate an epigenomic regulatory mechanism through which the circadian clock governs skeletal muscle bioenergetics. These findings suggest that physical exercise at certain times of the day or pharmacological targeting of HDAC3 could potentially be harnessed to alter systemic fuel metabolism and exercise performance.", + "TAG_DATA": [ + "23, depletion {'perturbing_action': 'B-gene loss-of-function'}", + "24, of {'perturbing_action': 'I-gene loss-of-function'}", + "25, the {'perturbing_action': 'I-gene loss-of-function'}", + "26, epigenome {'perturbing_action': 'I-gene loss-of-function'}", + "27, modifier {'perturbing_action': 'I-gene loss-of-function'}", + "28, histone {'perturbing_action': 'I-gene loss-of-function'}", + "29, deacetylase {'perturbing_action': 'I-gene loss-of-function'}", + "30, 3 {'perturbing_action': 'I-gene loss-of-function'}", + "31, (HDAC3) {'perturbing_action': 'I-gene loss-of-function'}", + "32, specifically {'perturbing_action': 'I-gene loss-of-function'}", + "33, in {'perturbing_action': 'I-gene loss-of-function'}", + "34, skeletal {'perturbing_action': 'I-gene loss-of-function'}", + "35, muscle {'perturbing_action': 'I-gene loss-of-function'}", + "42, mice {'context': 'B-organism'}", + "72, muscles, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "23, depletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "24, of ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "25, the ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "26, epigenome ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "27, modifier ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "28, histone ['l4', 'l17', 'l29', 'l40', 'l50', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "29, deacetylase ['l5', 'l18', 'l30', 'l41', 'l51', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "30, 3 ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "31, (HDAC3) ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "32, specifically ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l90', 'l91', 'l92', 'l93', 'l94']", + "33, in ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l95', 'l96', 'l97', 'l98']", + "34, skeletal ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l99', 'l100', 'l101']", + "35, muscle ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l102', 'l103']", + "42, mice ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l104']", + "72, muscles, ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l104']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "the", + "epigenome", + "modifier", + "histone", + "deacetylase", + "3", + "(HDAC3)", + "specifically", + "in", + "skeletal", + "muscle" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "the", + "epigenome", + "modifier", + "histone", + "deacetylase", + "3", + "(HDAC3)", + "specifically", + "in", + "skeletal", + "muscle" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscles," + ] + } + } + ] + }, + { + "PMID": "27918564", + "TEXT": "Preterm birth (PTB) is a leading cause of neonatal death worldwide. Intrauterine and systemic infection and inflammation cause 30-40% of spontaneous preterm labor (PTL), which precedes PTB. Although antibody production is a major immune defense mechanism against infection, and B cell dysfunction has been implicated in pregnancy complications associated with PTL, the functions of B cells in pregnancy are not well known. We found that choriodecidua of women undergoing spontaneous PTL harbored functionally altered B cell populations. B cell-deficient mice were markedly more susceptible than wild-type (WT) mice to PTL after inflammation, but B cells conferred interleukin (IL)-10-independent protection against PTL. B cell deficiency in mice resulted in a lower uterine level of active progesterone-induced blocking factor 1 (PIBF1), and therapeutic administration of PIBF1 mitigated PTL and uterine inflammation in B cell-deficient mice. B cells are a significant producer of PIBF1 in human choriodecidua and mouse uterus in late gestation. PIBF1 expression by B cells is induced by the mucosal alarmin IL-33 (ref. 9). Human PTL was associated with diminished expression of the α-chain of IL-33 receptor on choriodecidual B cells and a lower level of active PIBF1 in late gestation choriodecidua. These results define a vital regulatory cascade involving IL-33, decidual B cells and PIBF1 in safeguarding term pregnancy and suggest new therapeutic approaches based on IL-33 and PIBF1 to prevent human PTL.", + "TAG_DATA": [ + "77, B {'perturbing_action': 'B-gene loss-of-function'}", + "78, cell-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "79, mice {'context': 'B-organism'}", + "87, mice {'context': 'B-organism'}", + "93, B {'context': 'B-cells'}", + "94, cells {'context': 'I-cells'}", + "101, B {'perturbing_action': 'B-gene loss-of-function'}", + "102, cell {'perturbing_action': 'I-gene loss-of-function'}", + "103, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "105, mice {'context': 'B-organism'}", + "130, B {'perturbing_action': 'B-gene loss-of-function'}", + "131, cell-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "132, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "77, B ['l0', 'l1', 'l2', 'l3', 'l4']", + "78, cell-deficient ['l0', 'l5', 'l6', 'l7', 'l8']", + "79, mice ['l1', 'l5', 'l9', 'l10', 'l11']", + "87, mice ['l2', 'l6', 'l9', 'l12', 'l13']", + "93, B ['l3', 'l7', 'l10', 'l12', 'l14']", + "94, cells ['l4', 'l8', 'l11', 'l13', 'l14']", + "101, B ['l15', 'l16', 'l17']", + "102, cell ['l15', 'l18', 'l19']", + "103, deficiency ['l16', 'l18', 'l20']", + "105, mice ['l17', 'l19', 'l20']", + "130, B ['l21', 'l22']", + "131, cell-deficient ['l21', 'l23']", + "132, mice. ['l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "B", + "cell-deficient", + "cell", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "B", + "cell-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "B", + "cells" + ] + } + } + ] + }, + { + "PMID": "27841873", + "TEXT": "Although the majority of patients with acute myeloid leukemia (AML) initially respond to chemotherapy, many of them subsequently relapse, and the mechanistic basis for AML persistence following chemotherapy has not been determined. Recurrent somatic mutations in DNA methyltransferase 3A (DNMT3A), most frequently at arginine 882 (DNMT3AR882), have been observed in AML and in individuals with clonal hematopoiesis in the absence of leukemic transformation. Patients with DNMT3AR882 AML have an inferior outcome when treated with standard-dose daunorubicin-based induction chemotherapy, suggesting that DNMT3AR882 cells persist and drive relapse. We found that Dnmt3a mutations induced hematopoietic stem cell expansion, cooperated with mutations in the FMS-like tyrosine kinase 3 gene (Flt3ITD) and the nucleophosmin gene (Npm1c) to induce AML in vivo, and promoted resistance to anthracycline chemotherapy. In patients with AML, the presence of DNMT3AR882 mutations predicts minimal residual disease, underscoring their role in AML chemoresistance. DNMT3AR882 cells showed impaired nucleosome eviction and chromatin remodeling in response to anthracycline treatment, which resulted from attenuated recruitment of histone chaperone SPT-16 following anthracycline exposure. This defect led to an inability to sense and repair DNA torsional stress, which resulted in increased mutagenesis. Our findings identify a crucial role for DNMT3AR882 mutations in driving AML chemoresistance and highlight the importance of chromatin remodeling in response to cytotoxic chemotherapy.", + "TAG_DATA": [ + "89, Dnmt3a {'perturbing_action': 'B-other'}", + "90, mutations {'perturbing_action': 'I-other'}", + "92, hematopoietic {'context': 'B-cells'}", + "93, stem {'context': 'I-cells'}", + "94, cell {'context': 'I-cells'}", + "115, in {'context': 'B-in vivo'}", + "116, vivo, {'context': 'I-in vivo'}", + "142, DNMT3AR882 {'context': 'B-cells'}", + "143, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "89, Dnmt3a ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "90, mutations ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "92, hematopoietic ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "93, stem ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "94, cell ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "114, AML ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "115, in ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "116, vivo, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "142, DNMT3AR882 ['l28']", + "143, cells ['l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Dnmt3a", + "mutations" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Dnmt3a", + "mutations" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + } + ] + }, + { + "PMID": "27775706", + "TEXT": "Checkpoint blockade with antibodies specific for cytotoxic T lymphocyte-associated protein (CTLA)-4 or programmed cell death 1 (PDCD1; also known as PD-1) elicits durable tumor regression in metastatic cancer, but these dramatic responses are confined to a minority of patients. This suboptimal outcome is probably due in part to the complex network of immunosuppressive pathways present in advanced tumors, which are unlikely to be overcome by intervention at a single signaling checkpoint. Here we describe a combination immunotherapy that recruits a variety of innate and adaptive immune cells to eliminate large tumor burdens in syngeneic tumor models and a genetically engineered mouse model of melanoma; to our knowledge tumors of this size have not previously been curable by treatments relying on endogenous immunity. Maximal antitumor efficacy required four components: a tumor-antigen-targeting antibody, a recombinant interleukin-2 with an extended half-life, anti-PD-1 and a powerful T cell vaccine. Depletion experiments revealed that CD8+ T cells, cross-presenting dendritic cells and several other innate immune cell subsets were required for tumor regression. Effective treatment induced infiltration of immune cells and production of inflammatory cytokines in the tumor, enhanced antibody-mediated tumor antigen uptake and promoted antigen spreading. These results demonstrate the capacity of an elicited endogenous immune response to destroy large, established tumors and elucidate essential characteristics of combination immunotherapies that are capable of curing a majority of tumors in experimental settings typically viewed as intractable.", + "TAG_DATA": [ + "93, syngeneic {'context': 'B-neoplasm'}", + "94, tumor {'context': 'I-neoplasm'}", + "95, models {'context': 'I-neoplasm'}", + "98, genetically {'context': 'B-organism'}", + "99, engineered {'context': 'I-organism'}", + "100, mouse {'context': 'I-organism'}", + "101, model {'context': 'I-neoplasm'}", + "102, of {'context': 'I-neoplasm'}", + "103, melanoma; {'context': 'I-neoplasm'}", + "149, CD8+ {'context': 'B-cells'}", + "150, T {'context': 'I-cells'}", + "151, cells, {'context': 'I-cells'}", + "165, tumor {'phenotype': 'B-tumour regression'}", + "166, regression. {'phenotype': 'I-tumour regression'}", + "181, tumor, {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "93, syngeneic ['l0', 'l1', 'l2', 'l3']", + "94, tumor ['l0', 'l4']", + "95, models ['l1', 'l4']", + "98, genetically ['l5', 'l6', 'l7', 'l8', 'l9']", + "99, engineered ['l5', 'l10', 'l11', 'l12', 'l13']", + "100, mouse ['l6', 'l10', 'l14', 'l15', 'l16']", + "101, model ['l7', 'l11', 'l14', 'l17', 'l18']", + "102, of ['l2', 'l8', 'l12', 'l15', 'l17', 'l19']", + "103, melanoma; ['l3', 'l9', 'l13', 'l16', 'l18', 'l19']", + "149, CD8+ ['l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "150, T ['l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "151, cells, ['l21', 'l26', 'l31', 'l32', 'l33']", + "154, cells ['l22', 'l27', 'l31', 'l34', 'l35', 'l36']", + "165, tumor ['l23', 'l28', 'l32', 'l34', 'l37']", + "166, regression. ['l24', 'l29', 'l33', 'l35', 'l37']", + "181, tumor, ['l25', 'l30', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD8+", + "T", + "cells," + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression." + ] + } + } + ] + }, + { + "PMID": "27571347", + "TEXT": "Orthopedic implants containing biodegradable magnesium have been used for fracture repair with considerable efficacy; however, the underlying mechanisms by which these implants improve fracture healing remain elusive. Here we show the formation of abundant new bone at peripheral cortical sites after intramedullary implantation of a pin containing ultrapure magnesium into the intact distal femur in rats. This response was accompanied by substantial increases of neuronal calcitonin gene-related polypeptide-α (CGRP) in both the peripheral cortex of the femur and the ipsilateral dorsal root ganglia (DRG). Surgical removal of the periosteum, capsaicin denervation of sensory nerves or knockdown in vivo of the CGRP-receptor-encoding genes Calcrl or Ramp1 substantially reversed the magnesium-induced osteogenesis that we observed in this model. Overexpression of these genes, however, enhanced magnesium-induced osteogenesis. We further found that an elevation of extracellular magnesium induces magnesium transporter 1 (MAGT1)-dependent and transient receptor potential cation channel, subfamily M, member 7 (TRPM7)-dependent magnesium entry, as well as an increase in intracellular adenosine triphosphate (ATP) and the accumulation of terminal synaptic vesicles in isolated rat DRG neurons. In isolated rat periosteum-derived stem cells, CGRP induces CALCRL- and RAMP1-dependent activation of cAMP-responsive element binding protein 1 (CREB1) and SP7 (also known as osterix), and thus enhances osteogenic differentiation of these stem cells. Furthermore, we have developed an innovative, magnesium-containing intramedullary nail that facilitates femur fracture repair in rats with ovariectomy-induced osteoporosis. Taken together, these findings reveal a previously undefined role of magnesium in promoting CGRP-mediated osteogenic differentiation, which suggests the therapeutic potential of this ion in orthopedics.", + "TAG_DATA": [ + "52, distal {'context': 'B-tissue/organ'}", + "53, femur {'context': 'I-tissue/organ'}", + "55, rats. {'context': 'B-organism'}", + "92, sensory {'context': 'B-cells'}", + "93, nerves {'context': 'I-cells'}", + "95, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "96, in {'context': 'B-in vivo'}", + "97, vivo {'context': 'I-in vivo'}", + "98, of {'perturbing_action': 'I-rnai/knockdown'}", + "99, the {'perturbing_action': 'I-rnai/knockdown'}", + "100, CGRP-receptor-encoding {'perturbing_action': 'I-rnai/knockdown'}", + "101, genes {'perturbing_action': 'I-rnai/knockdown'}", + "102, Calcrl {'perturbing_action': 'I-rnai/knockdown'}", + "103, or {'perturbing_action': 'I-rnai/knockdown'}", + "104, Ramp1 {'perturbing_action': 'I-rnai/knockdown'}", + "116, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "117, of {'perturbing_action': 'I-gene gain-of-function'}", + "118, these {'perturbing_action': 'I-gene gain-of-function'}", + "119, genes, {'perturbing_action': 'I-gene gain-of-function'}", + "170, rat {'context': 'B-cells'}", + "171, DRG {'context': 'I-cells'}", + "172, neurons. {'context': 'I-cells'}", + "175, rat {'context': 'B-cells'}", + "176, periosteum-derived {'context': 'I-cells'}", + "177, stem {'context': 'I-cells'}", + "178, cells, {'context': 'I-cells'}", + "200, enhances {'effect': 'B-positive'}", + "205, stem {'context': 'B-cells'}", + "206, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "52, distal ['l0', 'l1', 'l2', 'l3']", + "53, femur ['l0', 'l4']", + "55, rats. ['l1', 'l4']", + "92, sensory ['l2', 'l5', 'l6']", + "93, nerves ['l3', 'l5', 'l7']", + "95, knockdown ['l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "96, in ['l8', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "97, vivo ['l9', 'l20', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "98, of ['l10', 'l21', 'l31', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "99, the ['l11', 'l22', 'l32', 'l41', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "100, CGRP-receptor-encoding ['l12', 'l23', 'l33', 'l42', 'l51', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "101, genes ['l13', 'l24', 'l34', 'l43', 'l52', 'l60', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "102, Calcrl ['l14', 'l25', 'l35', 'l44', 'l53', 'l61', 'l68', 'l74', 'l75', 'l76', 'l77', 'l78']", + "103, or ['l15', 'l26', 'l36', 'l45', 'l54', 'l62', 'l69', 'l74', 'l79', 'l80', 'l81', 'l82']", + "104, Ramp1 ['l6', 'l7', 'l16', 'l27', 'l37', 'l46', 'l55', 'l63', 'l70', 'l75', 'l79', 'l83', 'l84', 'l85']", + "116, Overexpression ['l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "117, of ['l86', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "118, these ['l87', 'l99', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "119, genes, ['l47', 'l56', 'l64', 'l88', 'l100', 'l111', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "170, rat ['l17', 'l28', 'l38', 'l48', 'l57', 'l65', 'l71', 'l76', 'l80', 'l83', 'l89', 'l101', 'l112', 'l122', 'l132', 'l133']", + "171, DRG ['l18', 'l29', 'l39', 'l49', 'l58', 'l66', 'l72', 'l77', 'l81', 'l84', 'l90', 'l102', 'l113', 'l123', 'l132', 'l134']", + "172, neurons. ['l19', 'l30', 'l40', 'l50', 'l59', 'l67', 'l73', 'l78', 'l82', 'l85', 'l91', 'l103', 'l114', 'l124', 'l133', 'l134']", + "175, rat ['l92', 'l104', 'l115', 'l125', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "176, periosteum-derived ['l93', 'l105', 'l116', 'l126', 'l135', 'l141', 'l142', 'l143', 'l144', 'l145']", + "177, stem ['l94', 'l106', 'l117', 'l127', 'l136', 'l141', 'l146', 'l147', 'l148', 'l149']", + "178, cells, ['l95', 'l107', 'l118', 'l128', 'l137', 'l142', 'l146', 'l150', 'l151', 'l152']", + "200, enhances ['l96', 'l108', 'l119', 'l129', 'l138', 'l143', 'l147', 'l150', 'l153', 'l154']", + "205, stem ['l97', 'l109', 'l120', 'l130', 'l139', 'l144', 'l148', 'l151', 'l153', 'l155']", + "206, cells. ['l98', 'l110', 'l121', 'l131', 'l140', 'l145', 'l149', 'l152', 'l154', 'l155']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "sensory", + "nerves", + "rat", + "DRG", + "neurons." + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Ramp1", + "knockdown", + "of", + "the", + "CGRP-receptor-encoding", + "genes", + "Calcrl", + "or" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "the", + "CGRP-receptor-encoding", + "genes", + "Calcrl", + "or", + "Ramp1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "these", + "genes," + ] + }, + "context": { + "val": "cells", + "words": [ + "rat", + "DRG", + "neurons.", + "periosteum-derived", + "stem", + "cells,", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "these", + "genes," + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "rat", + "periosteum-derived", + "stem", + "cells,", + "cells." + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + } + } + ] + }, + { + "PMID": "27548575", + "TEXT": "Cerebral cavernous malformations (CCMs) are vascular malformations that affect the central nervous system and result in cerebral hemorrhage, seizure and stroke. CCMs arise from loss-of-function mutations in one of three genes: KRIT1 (also known as CCM1), CCM2 or PDCD10 (also known as CCM3). PDCD10 mutations in humans often result in a more severe form of the disease relative to mutations in the other two CCM genes, and PDCD10-knockout mice show severe defects, the mechanistic basis for which is unclear. We have recently reported that CCM3 regulates exocytosis mediated by the UNC13 family of exocytic regulatory proteins. Here, in investigating the role of endothelial cell exocytosis in CCM disease progression, we found that CCM3 suppresses UNC13B- and vesicle-associated membrane protein 3 (VAMP3)-dependent exocytosis of angiopoietin 2 (ANGPT2) in brain endothelial cells. CCM3 deficiency in endothelial cells augments the exocytosis and secretion of ANGPT2, which is associated with destabilized endothelial cell junctions, enlarged lumen formation and endothelial cell-pericyte dissociation. UNC13B deficiency, which blunts ANGPT2 secretion from endothelial cells, or treatment with an ANGPT2-neutralizing antibody normalizes the defects in the brain and retina caused by endothelial-cell-specific CCM3 deficiency, including the disruption of endothelial cell junctions, vessel dilation and pericyte dissociation. Thus, enhanced secretion of ANGPT2 in endothelial cells contributes to the progression of CCM disease, providing a new therapeutic approach for treating this devastating pathology.", + "TAG_DATA": [ + "127, brain {'context': 'B-cells'}", + "128, endothelial {'context': 'I-cells'}", + "129, cells. {'context': 'I-cells'}", + "130, CCM3 {'perturbing_action': 'B-gene loss-of-function'}", + "131, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "133, endothelial {'context': 'B-cells'}", + "134, cells {'context': 'I-cells'}", + "157, UNC13B {'perturbing_action': 'B-gene loss-of-function'}", + "158, deficiency, {'perturbing_action': 'I-gene loss-of-function'}", + "164, endothelial {'context': 'B-cells'}", + "165, cells, {'context': 'I-cells'}", + "177, brain {'context': 'B-tissue/organ'}", + "179, retina {'context': 'B-tissue/organ'}", + "182, endothelial-cell-specific {'perturbing_action': 'B-gene loss-of-function'}", + "183, CCM3 {'perturbing_action': 'I-gene loss-of-function'}", + "184, deficiency, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "127, brain ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "128, endothelial ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "129, cells. ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "130, CCM3 ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "131, deficiency ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "133, endothelial ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "134, cells ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "157, UNC13B ['l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "158, deficiency, ['l21', 'l27', 'l28', 'l29', 'l30']", + "164, endothelial ['l22', 'l27', 'l31', 'l32', 'l33']", + "165, cells, ['l23', 'l28', 'l31']", + "177, brain ['l24', 'l29', 'l32', 'l34', 'l35', 'l36', 'l37']", + "179, retina ['l25', 'l30', 'l33', 'l34', 'l38', 'l39', 'l40']", + "182, endothelial-cell-specific ['l35', 'l38', 'l41', 'l42']", + "183, CCM3 ['l36', 'l39', 'l41', 'l43']", + "184, deficiency, ['l26', 'l37', 'l40', 'l42', 'l43']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "brain", + "endothelial", + "cells.", + "cells", + "cells," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CCM3", + "deficiency", + "UNC13B", + "deficiency," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "UNC13B", + "deficiency,", + "endothelial-cell-specific", + "CCM3" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain", + "retina" + ] + } + } + ] + }, + { + "PMID": "27376579", + "TEXT": "Age-related changes in the niche have long been postulated to impair the function of somatic stem cells. Here we demonstrate that the aged stem cell niche in skeletal muscle contains substantially reduced levels of fibronectin (FN), leading to detrimental consequences for the function and maintenance of muscle stem cells (MuSCs). Deletion of the gene encoding FN from young regenerating muscles replicates the aging phenotype and leads to a loss of MuSC numbers. By using an extracellular matrix (ECM) library screen and pathway profiling, we characterize FN as a preferred adhesion substrate for MuSCs and demonstrate that integrin-mediated signaling through focal adhesion kinase and the p38 mitogen-activated protein kinase pathway is strongly de-regulated in MuSCs from aged mice because of insufficient attachment to the niche. Reconstitution of FN levels in the aged niche remobilizes stem cells and restores youth-like muscle regeneration. Taken together, we identify the loss of stem cell adhesion to FN in the niche ECM as a previously unknown aging mechanism.", + "TAG_DATA": [ + "50, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "51, of {'perturbing_action': 'I-gene loss-of-function'}", + "52, the {'perturbing_action': 'I-gene loss-of-function'}", + "53, gene {'perturbing_action': 'I-gene loss-of-function'}", + "54, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "55, FN {'perturbing_action': 'I-gene loss-of-function'}", + "57, young {'context': 'B-cells'}", + "58, regenerating {'context': 'I-cells'}", + "59, muscles {'context': 'I-cells'}", + "70, MuSC {'context': 'B-cells'}", + "115, aged {'context': 'B-organism'}", + "116, mice {'context': 'I-organism'}", + "130, aged {'context': 'B-tissue/organ'}", + "131, niche {'context': 'I-tissue/organ'}", + "133, stem {'context': 'B-cells'}", + "134, cells {'context': 'I-cells'}", + "138, muscle {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "50, Deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "51, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "52, the ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "53, gene ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "54, encoding ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "55, FN ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "57, young ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53']", + "58, regenerating ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l54', 'l55']", + "59, muscles ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l54', 'l56']", + "70, MuSC ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l55', 'l56']", + "115, aged ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l57']", + "116, mice ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l57']", + "130, aged ['l58', 'l59', 'l60', 'l61']", + "131, niche ['l58', 'l62', 'l63', 'l64']", + "133, stem ['l59', 'l62', 'l65', 'l66']", + "134, cells ['l60', 'l63', 'l65', 'l67']", + "138, muscle ['l61', 'l64', 'l66', 'l67']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "gene", + "encoding", + "FN" + ] + }, + "context": { + "val": "cells", + "words": [ + "young", + "regenerating", + "muscles", + "MuSC" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "gene", + "encoding", + "FN" + ] + }, + "context": { + "val": "organism", + "words": [ + "aged", + "mice" + ] + } + } + ] + }, + { + "PMID": "27294874", + "TEXT": "Despite the high response rates of individuals with myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)) to treatment with lenalidomide (LEN) and the recent identification of cereblon (CRBN) as the molecular target of LEN, the cellular mechanism by which LEN eliminates MDS clones remains elusive. Here we performed an RNA interference screen to delineate gene regulatory networks that mediate LEN responsiveness in an MDS cell line, MDSL. We identified GPR68, which encodes a G-protein-coupled receptor that has been implicated in calcium metabolism, as the top candidate gene for modulating sensitivity to LEN. LEN induced GPR68 expression via IKAROS family zinc finger 1 (IKZF1), resulting in increased cytosolic calcium levels and activation of a calcium-dependent calpain, CAPN1, which were requisite steps for induction of apoptosis in MDS cells and in acute myeloid leukemia (AML) cells. In contrast, deletion of GPR68 or inhibition of calcium and calpain activation suppressed LEN-induced cytotoxicity. Moreover, expression of calpastatin (CAST), an endogenous CAPN1 inhibitor that is encoded by a gene (CAST) deleted in del(5q) MDS, correlated with LEN responsiveness in patients with del(5q) MDS. Depletion of CAST restored responsiveness of LEN-resistant non-del(5q) MDS cells and AML cells, providing an explanation for the superior responses of patients with del(5q) MDS to LEN treatment. Our study describes a cellular mechanism by which LEN, acting through CRBN and IKZF1, has cytotoxic effects in MDS and AML that depend on a calcium- and calpain-dependent pathway.", + "TAG_DATA": [ + "122, induction {'effect': 'B-positive'}", + "124, apoptosis {'phenotype': 'B-apoptosis'}", + "126, MDS {'context': 'B-transformed cells'}", + "127, cells {'context': 'I-transformed cells'}", + "130, acute {'context': 'B-transformed cells'}", + "131, myeloid {'context': 'I-transformed cells'}", + "132, leukemia {'context': 'I-transformed cells'}", + "133, (AML) {'context': 'I-transformed cells'}", + "134, cells. {'context': 'I-transformed cells'}", + "137, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "138, of {'perturbing_action': 'I-gene loss-of-function'}", + "139, GPR68 {'perturbing_action': 'I-gene loss-of-function'}", + "179, Depletion {'perturbing_action': 'B-gene loss-of-function'}", + "180, of {'perturbing_action': 'I-gene loss-of-function'}", + "181, CAST {'perturbing_action': 'I-gene loss-of-function'}", + "185, LEN-resistant {'context': 'B-transformed cells'}", + "186, non-del(5q) {'context': 'I-transformed cells'}", + "187, MDS {'context': 'I-transformed cells'}", + "188, cells {'context': 'I-transformed cells'}", + "190, AML {'context': 'B-transformed cells'}", + "191, cells, {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "122, induction ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "124, apoptosis ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "126, MDS ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "127, cells ['l2', 'l9', 'l15', 'l21', 'l22']", + "130, acute ['l3', 'l10', 'l16', 'l23', 'l24', 'l25', 'l26']", + "131, myeloid ['l4', 'l11', 'l17', 'l23', 'l27', 'l28', 'l29', 'l30', 'l31']", + "132, leukemia ['l5', 'l12', 'l18', 'l24', 'l27', 'l32', 'l33', 'l34']", + "133, (AML) ['l6', 'l13', 'l19', 'l21', 'l25', 'l28', 'l32', 'l35']", + "134, cells. ['l7', 'l14', 'l20', 'l22', 'l26', 'l29', 'l33', 'l35']", + "137, deletion ['l36', 'l37']", + "138, of ['l30', 'l34', 'l36', 'l38']", + "139, GPR68 ['l31', 'l37', 'l38']", + "179, Depletion ['l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "180, of ['l39', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "181, CAST ['l40', 'l47', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "185, LEN-resistant ['l41', 'l48', 'l54', 'l60', 'l61', 'l62', 'l63', 'l64']", + "186, non-del(5q) ['l42', 'l49', 'l55', 'l60', 'l65', 'l66', 'l67', 'l68']", + "187, MDS ['l43', 'l50', 'l56', 'l61', 'l65', 'l69', 'l70', 'l71']", + "188, cells ['l44', 'l51', 'l57', 'l62', 'l66', 'l69', 'l72', 'l73']", + "190, AML ['l45', 'l52', 'l58', 'l63', 'l67', 'l70', 'l72', 'l74']", + "191, cells, ['l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l73', 'l74']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MDS", + "cells", + "acute", + "myeloid", + "leukemia", + "(AML)", + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MDS", + "cells", + "acute", + "myeloid", + "leukemia", + "(AML)", + "cells." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "myeloid", + "leukemia", + "LEN-resistant", + "non-del(5q)", + "MDS", + "cells", + "AML", + "cells," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "GPR68", + "Depletion", + "CAST" + ] + } + } + ] + }, + { + "PMID": "27270588", + "TEXT": "Brain metastases represent the greatest clinical challenge in treating HER2-positive breast cancer. We report the development of orthotopic patient-derived xenografts (PDXs) of HER2-expressing breast cancer brain metastases (BCBM), and their use for the identification of targeted combination therapies. Combined inhibition of PI3K and mTOR resulted in durable tumor regressions in three of five PDXs, and therapeutic response was correlated with a reduction in the phosphorylation of 4EBP1, an mTORC1 effector. The two nonresponding PDXs showed hypermutated genomes with enrichment of mutations in DNA-repair genes, which suggests an association of genomic instability with therapeutic resistance. These findings suggest that a biomarker-driven clinical trial of PI3K inhibitor in combination with an mTOR inhibitor should be conducted for patients with HER2-positive BCBM.", + "TAG_DATA": [ + "38, Combined {'perturbing_action': 'B-pharmacological inhibition'}", + "39, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "40, of {'perturbing_action': 'I-pharmacological inhibition'}", + "41, PI3K {'perturbing_action': 'I-pharmacological inhibition'}", + "42, and {'perturbing_action': 'I-pharmacological inhibition'}", + "43, mTOR {'perturbing_action': 'I-pharmacological inhibition'}", + "44, resulted {'effect': 'B-positive'}", + "45, in {'effect': 'I-positive'}", + "47, tumor {'phenotype': 'B-tumour regression'}", + "48, regressions {'phenotype': 'I-tumour regression'}" + ], + "LINK_DATA": [ + "38, Combined ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "39, inhibition ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "40, of ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "41, PI3K ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "42, and ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "43, mTOR ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "44, resulted ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "45, in ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "46, durable ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "47, tumor ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "48, regressions ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Combined", + "inhibition", + "of", + "PI3K", + "and", + "mTOR" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Combined", + "inhibition", + "of", + "PI3K", + "and", + "mTOR" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regressions" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regressions" + ] + } + } + ] + }, + { + "PMID": "27270587", + "TEXT": "The discovery of genetic mechanisms for resistance to obesity and diabetes may illuminate new therapeutic strategies for the treatment of this global health challenge. We used the polygenic 'lean' mouse model, which has been selected for low adiposity over 60 generations, to identify mitochondrial thiosulfate sulfurtransferase (Tst; also known as rhodanese) as a candidate obesity-resistance gene with selectively increased expression in adipocytes. Elevated adipose Tst expression correlated with indices of metabolic health across diverse mouse strains. Transgenic overexpression of Tst in adipocytes protected mice from diet-induced obesity and insulin-resistant diabetes. Tst-deficient mice showed markedly exacerbated diabetes, whereas pharmacological activation of TST ameliorated diabetes in mice. Mechanistically, TST selectively augmented mitochondrial function combined with degradation of reactive oxygen species and sulfide. In humans, TST mRNA expression in adipose tissue correlated positively with insulin sensitivity in adipose tissue and negatively with fat mass. Thus, the genetic identification of Tst as a beneficial regulator of adipocyte mitochondrial function may have therapeutic significance for individuals with type 2 diabetes.", + "TAG_DATA": [ + "76, Transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "77, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "78, of {'perturbing_action': 'I-gene gain-of-function'}", + "79, Tst {'perturbing_action': 'I-gene gain-of-function'}", + "81, adipocytes {'context': 'B-cells'}", + "83, mice {'context': 'B-organism'}", + "90, Tst-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "91, mice {'context': 'B-organism'}", + "97, pharmacological {'perturbing_action': 'B-pharmacological augmentation'}", + "98, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "99, of {'perturbing_action': 'I-pharmacological augmentation'}", + "100, TST {'perturbing_action': 'I-pharmacological augmentation'}", + "104, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "76, Transgenic ['l0', 'l1', 'l2', 'l3', 'l4']", + "77, overexpression ['l0', 'l5', 'l6', 'l7', 'l8']", + "78, of ['l1', 'l5', 'l9', 'l10', 'l11']", + "79, Tst ['l2', 'l6', 'l9', 'l12', 'l13']", + "81, adipocytes ['l3', 'l7', 'l10', 'l12', 'l14']", + "83, mice ['l4', 'l8', 'l11', 'l13', 'l14']", + "90, Tst-deficient ['l15']", + "91, mice ['l15']", + "97, pharmacological ['l16', 'l17', 'l18', 'l19']", + "98, activation ['l16', 'l20', 'l21', 'l22']", + "99, of ['l17', 'l20', 'l23', 'l24']", + "100, TST ['l18', 'l21', 'l23', 'l25']", + "104, mice. ['l19', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgenic", + "overexpression", + "of", + "Tst" + ] + }, + "context": { + "val": "cells", + "words": [ + "adipocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgenic", + "overexpression", + "of", + "Tst" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tst-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "pharmacological", + "activation", + "of", + "TST" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "27089513", + "TEXT": "Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality, yet antistromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor-β (TGF-β) signaling have high epithelial STAT3 activity and develop stiff, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several KRAS-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby STAT3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial STAT3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated STAT3 were associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors and highlight STAT3 and mechanics as key drivers of this phenotype.", + "TAG_DATA": [ + "52, mouse {'context': 'B-organism'}", + "53, models, {'context': 'I-organism'}", + "84, epithelial {'perturbing_action': 'B-gene loss-of-function'}", + "85, STAT3 {'perturbing_action': 'I-gene loss-of-function'}", + "86, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "87, attenuated {'effect': 'B-negative'}", + "88, tumor {'phenotype': 'B-tumour progression'}", + "89, progression {'phenotype': 'I-tumour progression'}" + ], + "LINK_DATA": [ + "52, mouse ['l0']", + "53, models, ['l0']", + "84, epithelial ['l1', 'l2', 'l3', 'l4', 'l5']", + "85, STAT3 ['l1', 'l6', 'l7', 'l8', 'l9']", + "86, ablation ['l2', 'l6', 'l10', 'l11', 'l12']", + "87, attenuated ['l3', 'l7', 'l10', 'l13', 'l14']", + "88, tumor ['l4', 'l8', 'l11', 'l13', 'l15']", + "89, progression ['l5', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "epithelial", + "STAT3", + "ablation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "epithelial", + "STAT3", + "ablation" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + } + ] + }, + { + "PMID": "27064449", + "TEXT": "Tumor necrosis factor (TNF) superfamily member 11 (TNFSF11, also known as RANKL) regulates multiple physiological or pathological functions, including osteoclast differentiation and osteoporosis. TNFRSF11A (also called RANK) is considered to be the sole receptor for RANKL. Herein we report that leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) is another receptor for RANKL. LGR4 competes with RANK to bind RANKL and suppresses canonical RANK signaling during osteoclast differentiation. RANKL binding to LGR4 activates the Gαq and GSK3-β signaling pathway, an action that suppresses the expression and activity of nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 (NFATC1) during osteoclastogenesis. Both whole-body (Lgr4(-/-)) and monocyte conditional knockout mice of Lgr4 (Lgr4 CKO) exhibit osteoclast hyperactivation (including elevation of osteoclast number, surface area, and size) and increased bone erosion. The soluble LGR4 extracellular domain (ECD) binds RANKL and inhibits osteoclast differentiation in vivo. Moreover, LGR4-ECD therapeutically abrogated RANKL-induced bone loss in three mouse models of osteoporosis. Therefore, LGR4 acts as a second RANKL receptor that negatively regulates osteoclast differentiation and bone resorption.", + "TAG_DATA": [ + "103, (Lgr4(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "105, monocyte {'perturbing_action': 'B-gene loss-of-function'}", + "106, conditional {'perturbing_action': 'I-gene loss-of-function'}", + "107, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "108, mice {'context': 'B-organism'}", + "109, of {'perturbing_action': 'I-gene loss-of-function'}", + "110, Lgr4 {'perturbing_action': 'I-gene loss-of-function'}", + "111, (Lgr4 {'perturbing_action': 'I-gene loss-of-function'}", + "112, CKO) {'perturbing_action': 'I-gene loss-of-function'}", + "138, inhibits {'effect': 'B-negative'}", + "140, differentiation {'phenotype': 'B-differentiation'}", + "141, in {'context': 'B-in vivo'}", + "142, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "103, (Lgr4(-/-)) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "105, monocyte ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "106, conditional ['l1', 'l8', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "107, knockout ['l2', 'l9', 'l16', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "108, mice ['l3', 'l10', 'l17', 'l23', 'l29', 'l30', 'l31', 'l32']", + "109, of ['l4', 'l11', 'l18', 'l24', 'l29', 'l33', 'l34', 'l35', 'l36']", + "110, Lgr4 ['l5', 'l12', 'l19', 'l25', 'l30', 'l33', 'l37', 'l38', 'l39', 'l40']", + "111, (Lgr4 ['l6', 'l13', 'l20', 'l26', 'l31', 'l34', 'l37', 'l41', 'l42']", + "112, CKO) ['l7', 'l14', 'l21', 'l27', 'l32', 'l35', 'l38', 'l41']", + "138, inhibits ['l43', 'l44', 'l45']", + "140, differentiation ['l15', 'l22', 'l28', 'l36', 'l39', 'l42', 'l43', 'l46', 'l47']", + "141, in ['l44', 'l46', 'l48']", + "142, vivo. ['l40', 'l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "(Lgr4(-/-))", + "monocyte", + "conditional", + "knockout", + "of", + "Lgr4", + "(Lgr4", + "CKO)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "monocyte", + "conditional", + "knockout", + "of", + "Lgr4", + "(Lgr4" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lgr4" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "27064447", + "TEXT": "Small RNAs can be engineered to target and eliminate expression of disease-causing genes or infectious viruses, resulting in the preclinical and clinical development of RNA interference (RNAi) therapeutics using these small RNAs. To ensure the success of RNAi therapeutics, small hairpin RNAs (shRNAs) must co-opt sufficient quantities of the endogenous microRNA machinery to elicit efficient gene knockdown without impeding normal cellular function. We previously observed liver toxicity-including hepatocyte turnover, loss of gene repression and lethality-in mice receiving high doses of a recombinant adeno-associated virus (rAAV) vector expressing shRNAs (rAAV-shRNAs); however the mechanism by which toxicity ensues has not been elucidated. Using rAAV-shRNAs we have now determined that hepatotoxicity arises when exogenous shRNAs exceed 12% of the total amount of liver microRNAs. After this threshold was surpassed, shRNAs specifically reduced the initially synthesized 22-nucleotide isoform of microRNA (miR)-122-5p without substantially affecting other microRNAs, resulting in functional de-repression of miR-122 target mRNAs. Delivery of a rAAV-shRNA vector expressing mature miR-122-5p could circumvent toxicity, despite the exogenous shRNA accounting for 70% of microRNAs. Toxicity was also not observed in Mir122-knockout mice regardless of the level or sequence of the shRNA. Our study establishes limits to the microRNA machinery that is available for therapeutic siRNAs and suggests new paradigms for the role of miR-122 in liver homeostasis in mice.", + "TAG_DATA": [ + "75, mice {'context': 'B-organism'}", + "176, Mir122-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "177, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "176, Mir122-knockout ['l0']", + "177, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mir122-knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "26974310", + "TEXT": "Phosphatase and tensin homolog (PTEN) is a negative regulator of the phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) signaling pathway and a potent tumor suppressor in many types of cancer. To test a tumor suppressive role for PTEN in pre-B acute lymphoblastic leukemia (ALL), we induced Cre-mediated deletion of Pten in mouse models of pre-B ALL. In contrast to its role as a tumor suppressor in other cancers, loss of one or both alleles of Pten caused rapid cell death of pre-B ALL cells and was sufficient to clear transplant recipient mice of leukemia. Small-molecule inhibition of PTEN in human pre-B ALL cells resulted in hyperactivation of AKT, activation of the p53 tumor suppressor cell cycle checkpoint and cell death. Loss of PTEN function in pre-B ALL cells was functionally equivalent to acute activation of autoreactive pre-B cell receptor signaling, which engaged a deletional checkpoint for the removal of autoreactive B cells. We propose that targeted inhibition of PTEN and hyperactivation of AKT triggers a checkpoint for the elimination of autoreactive B cells and represents a new strategy to overcome drug resistance in human ALL.", + "TAG_DATA": [ + "46, induced {'perturbing_action': 'B-gene loss-of-function'}", + "47, Cre-mediated {'perturbing_action': 'B-gene loss-of-function'}", + "48, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "49, of {'perturbing_action': 'I-gene loss-of-function'}", + "50, Pten {'perturbing_action': 'I-gene loss-of-function'}", + "52, mouse {'context': 'B-neoplasm'}", + "53, models {'context': 'I-neoplasm'}", + "54, of {'context': 'I-neoplasm'}", + "55, pre-B {'context': 'I-neoplasm'}", + "56, ALL. {'context': 'I-neoplasm'}", + "69, loss {'perturbing_action': 'B-gene loss-of-function'}", + "70, of {'perturbing_action': 'I-gene loss-of-function'}", + "71, one {'perturbing_action': 'I-gene loss-of-function'}", + "72, or {'perturbing_action': 'I-gene loss-of-function'}", + "73, both {'perturbing_action': 'I-gene loss-of-function'}", + "74, alleles {'perturbing_action': 'I-gene loss-of-function'}", + "75, of {'perturbing_action': 'I-gene loss-of-function'}", + "76, Pten {'perturbing_action': 'I-gene loss-of-function'}", + "77, caused {'effect': 'B-positive'}", + "79, cell {'phenotype': 'B-cell death'}", + "80, death {'phenotype': 'I-cell death'}", + "82, pre-B {'context': 'B-transformed cells'}", + "83, ALL {'context': 'I-transformed cells'}", + "84, cells {'context': 'I-transformed cells'}", + "92, mice {'context': 'B-organism'}", + "94, leukemia. {'context': 'B-neoplasm'}", + "95, Small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "96, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "97, of {'perturbing_action': 'I-pharmacological inhibition'}", + "98, PTEN {'perturbing_action': 'I-pharmacological inhibition'}", + "100, human {'context': 'B-transformed cells'}", + "101, pre-B {'context': 'I-transformed cells'}", + "102, ALL {'context': 'I-transformed cells'}", + "103, cells {'context': 'I-transformed cells'}", + "104, resulted {'effect': 'B-positive'}", + "105, in {'effect': 'I-positive'}", + "119, cell {'phenotype': 'B-cell death'}", + "120, death. {'phenotype': 'I-cell death'}", + "121, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "122, of {'perturbing_action': 'I-gene loss-of-function'}", + "123, PTEN {'perturbing_action': 'I-gene loss-of-function'}", + "124, function {'perturbing_action': 'I-gene loss-of-function'}", + "126, pre-B {'context': 'B-transformed cells'}", + "127, ALL {'context': 'I-transformed cells'}", + "128, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "46, induced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "47, Cre-mediated ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "48, deletion ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "49, of ['l2', 'l16', 'l29', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "50, Pten ['l3', 'l17', 'l30', 'l43', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "52, mouse ['l4', 'l18', 'l31', 'l44', 'l56', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "53, models ['l5', 'l19', 'l32', 'l45', 'l57', 'l67', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "54, of ['l6', 'l20', 'l33', 'l46', 'l58', 'l68', 'l77', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "55, pre-B ['l7', 'l21', 'l34', 'l47', 'l59', 'l69', 'l78', 'l86', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "56, ALL. ['l8', 'l22', 'l35', 'l48', 'l60', 'l70', 'l79', 'l87', 'l94', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "69, loss ['l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "70, of ['l107', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "71, one ['l108', 'l122', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "72, or ['l109', 'l123', 'l141', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "73, both ['l110', 'l124', 'l142', 'l158', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "74, alleles ['l111', 'l125', 'l143', 'l159', 'l174', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198']", + "75, of ['l112', 'l126', 'l144', 'l160', 'l175', 'l189', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207']", + "76, Pten ['l36', 'l49', 'l113', 'l127', 'l145', 'l161', 'l176', 'l190', 'l199', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215']", + "77, caused ['l9', 'l23', 'l37', 'l50', 'l61', 'l71', 'l80', 'l88', 'l95', 'l101', 'l114', 'l128', 'l146', 'l162', 'l177', 'l191', 'l200', 'l208', 'l216', 'l217', 'l218', 'l219', 'l220']", + "79, cell ['l10', 'l24', 'l38', 'l51', 'l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l115', 'l129', 'l147', 'l163', 'l178', 'l192', 'l201', 'l209', 'l216', 'l221', 'l222', 'l223', 'l224']", + "80, death ['l11', 'l25', 'l39', 'l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l116', 'l130', 'l148', 'l164', 'l179', 'l193', 'l202', 'l210', 'l217', 'l221', 'l225', 'l226', 'l227']", + "82, pre-B ['l12', 'l26', 'l40', 'l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l117', 'l131', 'l149', 'l165', 'l180', 'l194', 'l203', 'l211', 'l218', 'l222', 'l225', 'l228', 'l229']", + "83, ALL ['l13', 'l27', 'l41', 'l54', 'l65', 'l75', 'l84', 'l92', 'l99', 'l105', 'l118', 'l132', 'l150', 'l166', 'l181', 'l195', 'l204', 'l212', 'l219', 'l223', 'l226', 'l228', 'l230']", + "84, cells ['l14', 'l28', 'l42', 'l55', 'l66', 'l76', 'l85', 'l93', 'l100', 'l106', 'l119', 'l133', 'l151', 'l167', 'l182', 'l196', 'l205', 'l213', 'l220', 'l224', 'l227', 'l229', 'l230']", + "92, mice ['l120', 'l134', 'l152', 'l168', 'l183', 'l197', 'l206', 'l214', 'l231']", + "94, leukemia. ['l121', 'l135', 'l153', 'l169', 'l184', 'l198', 'l207', 'l215', 'l231']", + "95, Small-molecule ['l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244']", + "96, inhibition ['l232', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254']", + "97, of ['l233', 'l245', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263']", + "98, PTEN ['l234', 'l246', 'l255', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271']", + "100, human ['l235', 'l247', 'l256', 'l264', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278']", + "101, pre-B ['l236', 'l248', 'l257', 'l265', 'l272', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284']", + "102, ALL ['l136', 'l154', 'l170', 'l185', 'l237', 'l249', 'l258', 'l266', 'l273', 'l279', 'l285', 'l286', 'l287', 'l288', 'l289']", + "103, cells ['l137', 'l155', 'l171', 'l186', 'l238', 'l250', 'l259', 'l267', 'l274', 'l280', 'l285', 'l290', 'l291', 'l292', 'l293']", + "104, resulted ['l138', 'l239', 'l251', 'l260', 'l268', 'l275', 'l281', 'l286', 'l290', 'l294', 'l295', 'l296']", + "105, in ['l139', 'l156', 'l172', 'l187', 'l240', 'l252', 'l261', 'l269', 'l276', 'l282', 'l287', 'l291', 'l294', 'l297', 'l298']", + "119, cell ['l241', 'l253', 'l262', 'l270', 'l277', 'l283', 'l288', 'l292', 'l295', 'l297', 'l299']", + "120, death. ['l140', 'l157', 'l173', 'l188', 'l242', 'l254', 'l263', 'l271', 'l278', 'l284', 'l289', 'l293', 'l296', 'l298', 'l299']", + "121, Loss ['l300', 'l301', 'l302', 'l303', 'l304', 'l305']", + "122, of ['l300', 'l306', 'l307', 'l308', 'l309', 'l310']", + "123, PTEN ['l301', 'l306', 'l311', 'l312', 'l313', 'l314']", + "124, function ['l302', 'l307', 'l311', 'l315', 'l316', 'l317']", + "126, pre-B ['l303', 'l308', 'l312', 'l315', 'l318', 'l319']", + "127, ALL ['l243', 'l304', 'l309', 'l313', 'l316', 'l318', 'l320']", + "128, cells ['l244', 'l305', 'l310', 'l314', 'l317', 'l319', 'l320']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "induced", + "Cre-mediated", + "deletion", + "of", + "Pten", + "loss", + "one", + "or", + "both", + "alleles" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "models", + "of", + "pre-B", + "ALL.", + "leukemia." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "induced", + "Cre-mediated", + "deletion", + "of", + "Pten", + "loss", + "one", + "or", + "both", + "alleles" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused", + "resulted", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "induced", + "Cre-mediated", + "deletion", + "of", + "Pten", + "loss", + "one", + "or", + "both", + "alleles" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "induced", + "Cre-mediated", + "deletion", + "of", + "Pten", + "loss", + "one", + "or", + "both", + "alleles", + "Loss", + "PTEN", + "function" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "pre-B", + "ALL", + "cells" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "models", + "of", + "pre-B", + "ALL." + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "models", + "of", + "pre-B", + "ALL." + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "one", + "or", + "both", + "alleles", + "Pten" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused", + "resulted", + "in" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused", + "resulted", + "in" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "pre-B", + "ALL", + "cells", + "human" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death", + "death." + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "pre-B", + "ALL", + "cells", + "human" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Small-molecule", + "inhibition", + "of", + "PTEN" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "pre-B", + "ALL", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Small-molecule", + "inhibition", + "of", + "PTEN" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Small-molecule", + "inhibition", + "of", + "PTEN" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "26928464", + "TEXT": "Astrocytes isolated from individuals with amyotrophic lateral sclerosis (ALS) are toxic to motor neurons (MNs) and play a non-cell autonomous role in disease pathogenesis. The mechanisms underlying the susceptibility of MNs to cell death remain unclear. Here we report that astrocytes derived from either mice bearing mutations in genes associated with ALS or human subjects with ALS reduce the expression of major histocompatibility complex class I (MHCI) molecules on MNs; reduced MHCI expression makes these MNs susceptible to astrocyte-induced cell death. Increasing MHCI expression on MNs increases survival and motor performance in a mouse model of ALS and protects MNs against astrocyte toxicity. Overexpression of a single MHCI molecule, HLA-F, protects human MNs from ALS astrocyte-mediated toxicity, whereas knockdown of its receptor, the killer cell immunoglobulin-like receptor KIR3DL2, on human astrocytes results in enhanced MN death. Thus, our data indicate that, in ALS, loss of MHCI expression on MNs renders them more vulnerable to astrocyte-mediated toxicity.", + "TAG_DATA": [ + "40, astrocytes {'context': 'B-cells'}", + "44, mice {'context': 'B-organism'}", + "46, mutations {'perturbing_action': 'B-other'}", + "75, MNs {'context': 'B-cells'}", + "79, cell {'phenotype': 'B-cell death'}", + "80, death. {'phenotype': 'I-cell death'}", + "81, Increasing {'perturbing_action': 'B-gene gain-of-function'}", + "82, MHCI {'perturbing_action': 'I-gene gain-of-function'}", + "83, expression {'perturbing_action': 'I-gene gain-of-function'}", + "85, MNs {'context': 'B-cells'}", + "93, mouse {'context': 'B-organism'}", + "94, model {'context': 'I-organism'}", + "95, of {'context': 'I-organism'}", + "96, ALS {'context': 'I-organism'}", + "99, MNs {'context': 'B-cells'}", + "103, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "104, of {'perturbing_action': 'I-gene gain-of-function'}", + "105, a {'perturbing_action': 'I-gene gain-of-function'}", + "106, single {'perturbing_action': 'I-gene gain-of-function'}", + "107, MHCI {'perturbing_action': 'I-gene gain-of-function'}", + "108, molecule, {'perturbing_action': 'I-gene gain-of-function'}", + "109, HLA-F, {'perturbing_action': 'I-gene gain-of-function'}", + "111, human {'context': 'B-cells'}", + "112, MNs {'context': 'I-cells'}", + "118, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "119, of {'perturbing_action': 'I-rnai/knockdown'}", + "120, its {'perturbing_action': 'I-rnai/knockdown'}", + "121, receptor, {'perturbing_action': 'I-rnai/knockdown'}", + "122, the {'perturbing_action': 'I-rnai/knockdown'}", + "123, killer {'perturbing_action': 'I-rnai/knockdown'}", + "124, cell {'perturbing_action': 'I-rnai/knockdown'}", + "125, immunoglobulin-like {'perturbing_action': 'I-rnai/knockdown'}", + "126, receptor {'perturbing_action': 'I-rnai/knockdown'}", + "127, KIR3DL2, {'perturbing_action': 'I-rnai/knockdown'}", + "129, human {'context': 'B-cells'}", + "130, astrocytes {'context': 'I-cells'}", + "134, MN {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "40, astrocytes ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "44, mice ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "46, mutations ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "75, MNs ['l2', 'l12', 'l21', 'l33', 'l34', 'l35', 'l36', 'l37']", + "79, cell ['l3', 'l13', 'l22', 'l33', 'l38', 'l39', 'l40', 'l41']", + "80, death. ['l4', 'l14', 'l23', 'l34', 'l38', 'l42', 'l43']", + "81, Increasing ['l24', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "82, MHCI ['l25', 'l44', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "83, expression ['l5', 'l15', 'l26', 'l45', 'l52', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "85, MNs ['l6', 'l16', 'l27', 'l35', 'l39', 'l42', 'l46', 'l53', 'l59', 'l65', 'l66', 'l67', 'l68', 'l69']", + "93, mouse ['l7', 'l17', 'l28', 'l47', 'l54', 'l60', 'l65', 'l70', 'l71', 'l72', 'l73']", + "94, model ['l8', 'l18', 'l29', 'l48', 'l55', 'l61', 'l66', 'l70', 'l74', 'l75', 'l76']", + "95, of ['l9', 'l19', 'l30', 'l36', 'l40', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l77', 'l78']", + "96, ALS ['l10', 'l20', 'l31', 'l37', 'l41', 'l43', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l77', 'l79']", + "99, MNs ['l32', 'l51', 'l58', 'l64', 'l69', 'l73', 'l76', 'l78', 'l79']", + "103, Overexpression ['l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "104, of ['l80', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "105, a ['l81', 'l97', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127']", + "106, single ['l82', 'l98', 'l113', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141']", + "107, MHCI ['l83', 'l99', 'l114', 'l128', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "108, molecule, ['l84', 'l100', 'l115', 'l129', 'l142', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "109, HLA-F, ['l85', 'l101', 'l116', 'l130', 'l143', 'l155', 'l166', 'l167', 'l168', 'l169', 'l170']", + "111, human ['l86', 'l102', 'l117', 'l131', 'l144', 'l156', 'l166', 'l171']", + "112, MNs ['l87', 'l103', 'l118', 'l132', 'l145', 'l157', 'l167', 'l171']", + "118, knockdown ['l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183']", + "119, of ['l172', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "120, its ['l173', 'l184', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "121, receptor, ['l174', 'l185', 'l195', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213']", + "122, the ['l88', 'l104', 'l119', 'l133', 'l146', 'l158', 'l175', 'l186', 'l196', 'l205', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221']", + "123, killer ['l89', 'l105', 'l120', 'l134', 'l147', 'l159', 'l176', 'l187', 'l197', 'l206', 'l214', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228']", + "124, cell ['l90', 'l106', 'l121', 'l135', 'l148', 'l160', 'l177', 'l188', 'l198', 'l207', 'l215', 'l222', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234']", + "125, immunoglobulin-like ['l91', 'l107', 'l122', 'l136', 'l149', 'l161', 'l178', 'l189', 'l199', 'l208', 'l216', 'l223', 'l229', 'l235', 'l236', 'l237', 'l238', 'l239']", + "126, receptor ['l92', 'l108', 'l123', 'l137', 'l150', 'l162', 'l168', 'l179', 'l190', 'l200', 'l209', 'l217', 'l224', 'l230', 'l235', 'l240', 'l241', 'l242', 'l243']", + "127, KIR3DL2, ['l93', 'l109', 'l124', 'l138', 'l151', 'l163', 'l169', 'l180', 'l191', 'l201', 'l210', 'l218', 'l225', 'l231', 'l236', 'l240', 'l244', 'l245', 'l246']", + "129, human ['l94', 'l110', 'l125', 'l139', 'l152', 'l181', 'l192', 'l202', 'l211', 'l219', 'l226', 'l232', 'l237', 'l241', 'l244', 'l247', 'l248']", + "130, astrocytes ['l95', 'l111', 'l126', 'l140', 'l153', 'l164', 'l182', 'l193', 'l203', 'l212', 'l220', 'l227', 'l233', 'l238', 'l242', 'l245', 'l247', 'l249']", + "134, MN ['l96', 'l112', 'l127', 'l141', 'l154', 'l165', 'l170', 'l183', 'l194', 'l204', 'l213', 'l221', 'l228', 'l234', 'l239', 'l243', 'l246', 'l248', 'l249']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "astrocytes", + "MNs" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutations" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "astrocytes", + "MNs" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "astrocytes", + "MNs", + "human", + "MN" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "Increasing", + "MHCI", + "Overexpression", + "of", + "a", + "single", + "molecule,", + "HLA-F," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "model", + "of", + "ALS" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutations" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "of", + "ALS" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "model", + "of", + "ALS" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "Increasing", + "MHCI" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutations" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "its", + "receptor,", + "the", + "killer", + "cell", + "immunoglobulin-like", + "receptor", + "KIR3DL2," + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "astrocytes", + "MN" + ] + } + } + ] + }, + { + "PMID": "26878233", + "TEXT": "RAR-related orphan receptor-γt (ROR-γt) directs differentiation of proinflammatory T helper 17 (TH17) cells and is a potential therapeutic target in chronic autoimmune and inflammatory diseases. However, ROR-γt-dependent group 3 innate lymphoid cells ILC3s provide essential immunity and tissue protection in the intestine, suggesting that targeting ROR-γt could also result in impaired host defense after infection or enhanced tissue damage. Here, we demonstrate that transient chemical inhibition of ROR-γt in mice selectively reduces cytokine production from TH17 but not ILCs in the context of intestinal infection with Citrobacter rodentium, resulting in preserved innate immunity. Temporal deletion of Rorc (encoding ROR-γt) in mature ILCs also did not impair cytokine response in the steady state or during infection. Finally, pharmacologic inhibition of ROR-γt provided therapeutic benefit in mouse models of intestinal inflammation and reduced the frequency of TH17 cells but not ILCs isolated from primary intestinal samples of individuals with inflammatory bowel disease (IBD). Collectively, these results reveal differential requirements for ROR-γt in the maintenance of TH17 cell and ILC3 responses and suggest that transient inhibition of ROR-γt is a safe and effective therapeutic approach during intestinal inflammation.", + "TAG_DATA": [ + "63, transient {'perturbing_action': 'B-pharmacological inhibition'}", + "64, chemical {'perturbing_action': 'I-pharmacological inhibition'}", + "65, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "66, of {'perturbing_action': 'I-pharmacological inhibition'}", + "67, ROR-γt {'perturbing_action': 'I-pharmacological inhibition'}", + "69, mice {'context': 'B-organism'}", + "93, Temporal {'perturbing_action': 'B-gene loss-of-function'}", + "94, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "95, of {'perturbing_action': 'I-gene loss-of-function'}", + "96, Rorc {'perturbing_action': 'I-gene loss-of-function'}", + "97, (encoding {'perturbing_action': 'I-gene loss-of-function'}", + "98, ROR-γt) {'perturbing_action': 'I-gene loss-of-function'}", + "100, mature {'context': 'B-cells'}", + "101, ILCs {'context': 'I-cells'}", + "116, pharmacologic {'perturbing_action': 'B-pharmacological inhibition'}", + "117, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "118, of {'perturbing_action': 'I-pharmacological inhibition'}", + "119, ROR-γt {'perturbing_action': 'I-pharmacological inhibition'}", + "124, mouse {'context': 'B-organism'}", + "134, TH17 {'context': 'B-cells'}", + "135, cells {'context': 'I-cells'}", + "138, ILCs {'context': 'B-cells'}", + "141, primary {'context': 'B-cells'}", + "142, intestinal {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "63, transient ['l0', 'l1', 'l2', 'l3', 'l4']", + "64, chemical ['l0', 'l5', 'l6', 'l7', 'l8']", + "65, inhibition ['l1', 'l5', 'l9', 'l10', 'l11']", + "66, of ['l2', 'l6', 'l9', 'l12', 'l13']", + "67, ROR-γt ['l3', 'l7', 'l10', 'l12', 'l14']", + "69, mice ['l4', 'l8', 'l11', 'l13', 'l14']", + "93, Temporal ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "94, deletion ['l15', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "95, of ['l16', 'l25', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "96, Rorc ['l17', 'l26', 'l34', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "97, (encoding ['l18', 'l27', 'l35', 'l42', 'l48', 'l49', 'l50', 'l51', 'l52']", + "98, ROR-γt) ['l19', 'l28', 'l36', 'l43', 'l48', 'l53', 'l54', 'l55']", + "100, mature ['l20', 'l29', 'l37', 'l44', 'l49', 'l53', 'l56']", + "101, ILCs ['l21', 'l30', 'l38', 'l45', 'l50', 'l54', 'l56']", + "116, pharmacologic ['l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "117, inhibition ['l57', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "118, of ['l58', 'l68', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "119, ROR-γt ['l59', 'l69', 'l78', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "124, mouse ['l22', 'l31', 'l39', 'l46', 'l51', 'l60', 'l70', 'l79', 'l87', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "125, models ['l23', 'l32', 'l40', 'l47', 'l52', 'l55', 'l61', 'l71', 'l80', 'l88', 'l95', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "134, TH17 ['l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l108', 'l109', 'l110', 'l111', 'l112']", + "135, cells ['l24', 'l33', 'l41', 'l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l108', 'l113', 'l114', 'l115', 'l116']", + "138, ILCs ['l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l109', 'l113', 'l117', 'l118', 'l119']", + "141, primary ['l65', 'l75', 'l84', 'l92', 'l99', 'l105', 'l110', 'l114', 'l117', 'l120', 'l121']", + "142, intestinal ['l66', 'l76', 'l85', 'l93', 'l100', 'l106', 'l111', 'l115', 'l118', 'l120', 'l122']", + "143, samples ['l67', 'l77', 'l86', 'l94', 'l101', 'l107', 'l112', 'l116', 'l119', 'l121', 'l122']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "transient", + "chemical", + "inhibition", + "of", + "ROR-γt", + "pharmacologic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Temporal", + "deletion", + "of", + "Rorc", + "(encoding", + "ROR-γt)" + ] + }, + "context": { + "val": "cells", + "words": [ + "mature", + "ILCs", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Temporal", + "deletion", + "of", + "Rorc", + "(encoding" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "ROR-γt" + ] + }, + "context": { + "val": "cells", + "words": [ + "TH17", + "cells", + "ILCs", + "primary", + "intestinal" + ] + } + } + ] + }, + { + "PMID": "26855149", + "TEXT": "Patients with advanced Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant lung adenocarcinoma are currently treated with standard chemotherapy because of a lack of efficacious targeted therapies. We reasoned that the identification of mediators of Kras signaling in early mouse lung hyperplasias might bypass the difficulties that are imposed by intratumor heterogeneity in advanced tumors, and that it might unveil relevant therapeutic targets. Transcriptional profiling of Kras(G12V)-driven mouse hyperplasias revealed intertumor diversity with a subset that exhibited an aggressive transcriptional profile analogous to that of advanced human adenocarcinomas. The top-scoring gene in this profile encodes the tyrosine kinase receptor DDR1. The genetic and pharmacological inhibition of DDR1 blocked tumor initiation and tumor progression, respectively. The concomitant inhibition of both DDR1 and Notch signaling induced the regression of KRAS;TP53-mutant patient-derived lung xenografts (PDX) with a therapeutic efficacy that was at least comparable to that of standard chemotherapy. Our data indicate that the combined inhibition of DDR1 and Notch signaling could be an effective targeted therapy for patients with KRAS-mutant lung adenocarcinoma.", + "TAG_DATA": [ + "65, Kras(G12V)-driven {'perturbing_action': 'B-other'}", + "102, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "103, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "104, of {'perturbing_action': 'I-pharmacological inhibition'}", + "105, DDR1 {'perturbing_action': 'I-pharmacological inhibition'}", + "106, blocked {'effect': 'B-negative'}", + "107, tumor {'phenotype': 'B-tumour initiation'}", + "108, initiation {'phenotype': 'I-tumour initiation'}", + "110, tumor {'phenotype': 'B-tumour progression'}", + "111, progression, {'phenotype': 'I-tumour progression'}", + "122, induced {'effect': 'B-positive'}", + "124, regression {'phenotype': 'B-tumour regression'}", + "126, KRAS;TP53-mutant {'perturbing_action': 'B-other'}", + "127, patient-derived {'context': 'B-xenograft'}", + "128, lung {'context': 'I-xenograft'}", + "129, xenografts {'context': 'I-xenograft'}", + "130, (PDX) {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "102, pharmacological ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "103, inhibition ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "104, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "105, DDR1 ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "106, blocked ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "107, tumor ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "108, initiation ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "110, tumor ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "111, progression, ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "122, induced ['l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "124, regression ['l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "126, KRAS;TP53-mutant ['l37', 'l42', 'l47', 'l48', 'l49', 'l50']", + "127, patient-derived ['l38', 'l43', 'l47', 'l51', 'l52', 'l53']", + "128, lung ['l39', 'l44', 'l48', 'l51', 'l54', 'l55']", + "129, xenografts ['l40', 'l45', 'l49', 'l52', 'l54', 'l56']", + "130, (PDX) ['l41', 'l46', 'l50', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "DDR1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "DDR1" + ] + }, + "phenotype": { + "val": "tumour initiation", + "words": [ + "tumor", + "initiation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "DDR1" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "tumour initiation", + "words": [ + "tumor", + "initiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "KRAS;TP53-mutant" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "patient-derived", + "lung", + "xenografts", + "(PDX)" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "KRAS;TP53-mutant" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "patient-derived", + "lung", + "xenografts", + "(PDX)" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "KRAS;TP53-mutant" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "patient-derived", + "lung", + "xenografts", + "(PDX)" + ] + } + } + ] + }, + { + "PMID": "26828195", + "TEXT": "Although mechanisms of acquired resistance of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. Here we observe that acquired resistance caused by the EGFR(T790M) gatekeeper mutation can occur either by selection of pre-existing EGFR(T790M)-positive clones or via genetic evolution of initially EGFR(T790M)-negative drug-tolerant cells. The path to resistance impacts the biology of the resistant clone, as those that evolved from drug-tolerant cells had a diminished apoptotic response to third-generation EGFR inhibitors that target EGFR(T790M); treatment with navitoclax, an inhibitor of the anti-apoptotic factors BCL-xL and BCL-2 restored sensitivity. We corroborated these findings using cultures derived directly from EGFR inhibitor-resistant patient tumors. These findings provide evidence that clinically relevant drug-resistant cancer cells can both pre-exist and evolve from drug-tolerant cells, and they point to therapeutic opportunities to prevent or overcome resistance in the clinic.", + "TAG_DATA": [ + "81, diminished {'effect': 'B-negative'}", + "82, apoptotic {'phenotype': 'B-apoptosis'}", + "83, response {'phenotype': 'I-apoptosis'}", + "85, third-generation {'perturbing_action': 'B-pharmacological inhibition'}", + "86, EGFR {'perturbing_action': 'B-pharmacological inhibition'}", + "87, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "89, target {'perturbing_action': 'I-pharmacological inhibition'}", + "110, cultures {'context': 'B-cells'}", + "116, patient {'context': 'I-neoplasm'}", + "117, tumors. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "81, diminished ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "82, apoptotic ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "83, response ['l1', 'l6', 'l11', 'l12', 'l13']", + "85, third-generation ['l2', 'l7', 'l11', 'l14', 'l15', 'l16']", + "86, EGFR ['l3', 'l8', 'l12', 'l14', 'l17', 'l18']", + "87, inhibitors ['l4', 'l9', 'l13', 'l15', 'l17', 'l19']", + "89, target ['l5', 'l10', 'l16', 'l18', 'l19']", + "110, cultures ['l20', 'l21']", + "116, patient ['l20', 'l22']", + "117, tumors. ['l21', 'l22']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "diminished" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "response" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "diminished" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "third-generation", + "EGFR", + "inhibitors", + "target" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "response" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "third-generation", + "EGFR", + "inhibitors", + "target" + ] + } + } + ] + }, + { + "PMID": "26779812", + "TEXT": "Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials. One PARP inhibitor, olaparib (Lynparza, AstraZeneca), was recently approved by the FDA to treat ovarian cancer with mutations in BRCA genes. BRCA1 and BRCA2 have essential roles in repairing DNA double-strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition. Here we show that the receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907 (PARP1 pTyr907 or pY907). PARP1 pY907 increases PARP1 enzymatic activity and reduces binding to a PARP inhibitor, thereby rendering cancer cells resistant to PARP inhibition. The combination of c-Met and PARP1 inhibitors synergized to suppress the growth of breast cancer cells in vitro and xenograft tumor models, and we observed similar synergistic effects in a lung cancer xenograft tumor model. These results suggest that the abundance of PARP1 pY907 may predict tumor resistance to PARP inhibitors, and that treatment with a combination of c-Met and PARP inhibitors may benefit patients whose tumors show high c-Met expression and who do not respond to PARP inhibition alone.", + "TAG_DATA": [ + "97, cancer {'context': 'B-transformed cells'}", + "98, cells {'context': 'I-transformed cells'}", + "106, c-Met {'perturbing_action': 'B-pharmacological inhibition'}", + "107, and {'perturbing_action': 'I-pharmacological inhibition'}", + "108, PARP1 {'perturbing_action': 'I-pharmacological inhibition'}", + "109, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "116, breast {'context': 'B-transformed cells'}", + "117, cancer {'context': 'I-transformed cells'}", + "118, cells {'context': 'I-transformed cells'}", + "119, in {'context': 'B-in vitro'}", + "120, vitro {'context': 'I-in vitro'}", + "122, xenograft {'context': 'B-xenograft'}", + "123, tumor {'context': 'I-xenograft'}", + "124, models, {'context': 'I-xenograft'}", + "133, lung {'context': 'B-xenograft'}", + "134, cancer {'context': 'I-xenograft'}", + "135, xenograft {'context': 'I-xenograft'}", + "136, tumor {'context': 'I-xenograft'}", + "137, model. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "97, cancer ['l0', 'l1', 'l2', 'l3']", + "98, cells ['l0', 'l4', 'l5']", + "106, c-Met ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "107, and ['l6', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "108, PARP1 ['l7', 'l17', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "109, inhibitors ['l8', 'l18', 'l27', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "116, breast ['l1', 'l9', 'l19', 'l28', 'l36', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "117, cancer ['l2', 'l4', 'l10', 'l20', 'l29', 'l37', 'l44', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "118, cells ['l3', 'l5', 'l11', 'l21', 'l30', 'l38', 'l45', 'l51', 'l57', 'l58', 'l59', 'l60']", + "119, in ['l12', 'l22', 'l31', 'l39', 'l46', 'l52', 'l57', 'l61', 'l62', 'l63', 'l64']", + "120, vitro ['l13', 'l23', 'l32', 'l40', 'l47', 'l53', 'l58', 'l61', 'l65', 'l66', 'l67']", + "122, xenograft ['l14', 'l24', 'l33', 'l41', 'l48', 'l54', 'l62', 'l65', 'l68', 'l69']", + "123, tumor ['l15', 'l25', 'l34', 'l42', 'l49', 'l55', 'l59', 'l63', 'l66', 'l68', 'l70']", + "124, models, ['l16', 'l26', 'l35', 'l43', 'l50', 'l56', 'l60', 'l64', 'l67', 'l69', 'l70']", + "133, lung ['l71', 'l72', 'l73', 'l74']", + "134, cancer ['l71', 'l75', 'l76', 'l77']", + "135, xenograft ['l72', 'l75', 'l78', 'l79']", + "136, tumor ['l73', 'l76', 'l78', 'l80']", + "137, model. ['l74', 'l77', 'l79', 'l80']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "c-Met", + "and", + "PARP1", + "inhibitors" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "breast", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "c-Met", + "and", + "PARP1", + "inhibitors" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "c-Met", + "and", + "PARP1", + "inhibitors" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "tumor", + "models," + ] + } + } + ] + }, + { + "PMID": "26726878", + "TEXT": "Acute kidney injury (AKI) is associated with prolonged hospitalization and high mortality, and it predisposes individuals to chronic kidney disease. To date, no effective AKI treatments have been established. Here we show that the apoptosis inhibitor of macrophage (AIM) protein on intraluminal debris interacts with kidney injury molecule (KIM)-1 and promotes recovery from AKI. During AKI, the concentration of AIM increases in the urine, and AIM accumulates on necrotic cell debris within the kidney proximal tubules. The AIM present in this cellular debris binds to KIM-1, which is expressed on injured tubular epithelial cells, and enhances the phagocytic removal of the debris by the epithelial cells, thus contributing to kidney tissue repair. When subjected to ischemia-reperfusion (IR)-induced AKI, AIM-deficient mice exhibited abrogated debris clearance and persistent renal inflammation, resulting in higher mortality than wild-type (WT) mice due to progressive renal dysfunction. Treatment of mice with IR-induced AKI using recombinant AIM resulted in the removal of the debris, thereby ameliorating renal pathology. We observed this effect in both AIM-deficient and WT mice, but not in KIM-1-deficient mice. Our findings provide a basis for the development of potentially novel therapies for AKI.", + "TAG_DATA": [ + "118, AIM-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "119, mice {'context': 'B-organism'}", + "135, mice {'context': 'B-organism'}", + "143, mice {'context': 'B-organism'}", + "167, AIM-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "170, mice, {'context': 'B-organism'}", + "174, KIM-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "175, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "118, AIM-deficient ['l0', 'l1']", + "119, mice ['l0', 'l2']", + "135, mice ['l1', 'l2']", + "167, AIM-deficient ['l3', 'l4', 'l5']", + "170, mice, ['l3', 'l6', 'l7']", + "174, KIM-1-deficient ['l4', 'l6', 'l8']", + "175, mice. ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "AIM-deficient", + "KIM-1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice,", + "mice." + ] + } + } + ] + }, + { + "PMID": "26726877", + "TEXT": "Regulated necrosis (necroptosis) and apoptosis are crucially involved in severe cardiac pathological conditions, including myocardial infarction, ischemia-reperfusion injury and heart failure. Whereas apoptotic signaling is well defined, the mechanisms that underlie cardiomyocyte necroptosis remain elusive. Here we show that receptor-interacting protein 3 (RIP3) triggers myocardial necroptosis, in addition to apoptosis and inflammation, through activation of Ca(2+)-calmodulin-dependent protein kinase (CaMKII) rather than through the well-established RIP3 partners RIP1 and MLKL. In mice, RIP3 deficiency or CaMKII inhibition ameliorates myocardial necroptosis and heart failure induced by ischemia-reperfusion or by doxorubicin treatment. RIP3-induced activation of CaMKII, via phosphorylation or oxidation or both, triggers opening of the mitochondrial permeability transition pore and myocardial necroptosis. These findings identify CaMKII as a new RIP3 substrate and delineate a RIP3-CaMKII-mPTP myocardial necroptosis pathway, a promising target for the treatment of ischemia- and oxidative stress-induced myocardial damage and heart failure.", + "TAG_DATA": [ + "43, triggers {'effect': 'B-positive'}", + "45, necroptosis, {'phenotype': 'B-necroptosis'}", + "70, mice, {'context': 'B-organism'}", + "71, RIP3 {'perturbing_action': 'B-gene loss-of-function'}", + "72, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "74, CaMKII {'perturbing_action': 'B-pharmacological inhibition'}", + "75, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "76, ameliorates {'effect': 'B-negative'}", + "78, necroptosis {'phenotype': 'B-necroptosis'}", + "99, triggers {'effect': 'B-positive'}", + "109, necroptosis. {'phenotype': 'B-necroptosis'}" + ], + "LINK_DATA": [ + "43, triggers ['l0']", + "45, necroptosis, ['l0']", + "70, mice, ['l1', 'l2', 'l3', 'l4']", + "71, RIP3 ['l1', 'l5', 'l6', 'l7']", + "72, deficiency ['l2', 'l5', 'l8', 'l9']", + "74, CaMKII ['l10', 'l11', 'l12', 'l13', 'l14']", + "75, inhibition ['l10', 'l15', 'l16', 'l17', 'l18']", + "76, ameliorates ['l3', 'l6', 'l8', 'l11', 'l15', 'l19']", + "78, necroptosis ['l4', 'l7', 'l9', 'l12', 'l16', 'l19']", + "99, triggers ['l13', 'l17', 'l20']", + "109, necroptosis. ['l14', 'l18', 'l20']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "phenotype": { + "val": "necroptosis", + "words": [ + "necroptosis,", + "necroptosis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "RIP3", + "deficiency" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "negative", + "words": [ + "ameliorates" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "necroptosis", + "words": [ + "necroptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "RIP3", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "ameliorates" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "RIP3", + "deficiency" + ] + }, + "phenotype": { + "val": "necroptosis", + "words": [ + "necroptosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CaMKII", + "inhibition" + ] + }, + "effect": { + "val": "negative", + "words": [ + "ameliorates" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CaMKII", + "inhibition" + ] + }, + "phenotype": { + "val": "necroptosis", + "words": [ + "necroptosis", + "necroptosis." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CaMKII", + "inhibition" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "ameliorates" + ] + }, + "phenotype": { + "val": "necroptosis", + "words": [ + "necroptosis" + ] + } + } + ] + }, + { + "PMID": "26692332", + "TEXT": "The inflammasome is activated in response to a variety of pathogens and has an important role in shaping adaptive immunity, yet the spatiotemporal orchestration of inflammasome activation in vivo and the mechanisms by which it promotes an effective immune response are not fully understood. Using an in vivo reporter to visualize inflammasome assembly, we establish the distribution, kinetics and propagation of the inflammasome response to a local viral infection. We show that modified vaccinia Ankara virus induces inflammasome activation in subcapsular sinus (SCS) macrophages, which is immediately followed by cell death and release of extracellular ASC specks. This transient inflammasome signaling in the lymph node generates a robust influx of inflammatory cells and mobilizes T cells from the circulation to increase the magnitude of T cell responses. We propose that after infection, SCS macrophages deliver a burst response of inflammasome activity and cell death that translates into the broadening of T cell responses, identifying an important aspect of inflammasome-driven vaccination strategies.", + "TAG_DATA": [ + "80, subcapsular {'context': 'B-cells'}", + "81, sinus {'context': 'I-cells'}", + "82, (SCS) {'context': 'I-cells'}", + "83, macrophages, {'context': 'I-cells'}", + "89, cell {'phenotype': 'B-cell death'}", + "90, death {'phenotype': 'I-cell death'}", + "103, lymph {'context': 'B-tissue/organ'}", + "104, node {'context': 'I-tissue/organ'}", + "114, T {'context': 'B-cells'}", + "115, cells {'context': 'B-cells'}", + "124, T {'context': 'B-cells'}", + "125, cell {'context': 'B-cells'}", + "142, cell {'phenotype': 'B-cell death'}", + "143, death {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "80, subcapsular ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "81, sinus ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "82, (SCS) ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "83, macrophages, ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "89, cell ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "90, death ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "103, lymph ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27', 'l28', 'l29', 'l30', 'l31']", + "104, node ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27', 'l32', 'l33', 'l34', 'l35']", + "114, T ['l28', 'l32', 'l36', 'l37', 'l38']", + "115, cells ['l29', 'l33', 'l36', 'l39', 'l40']", + "124, T ['l30', 'l34', 'l37', 'l39', 'l41']", + "125, cell ['l31', 'l35', 'l38', 'l40', 'l41']", + "142, cell ['l42']", + "143, death ['l42']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "subcapsular", + "sinus", + "(SCS)", + "macrophages," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lymph", + "node" + ] + } + } + ] + }, + { + "PMID": "26657143", + "TEXT": "Senescent cells (SCs) accumulate with age and after genotoxic stress, such as total-body irradiation (TBI). Clearance of SCs in a progeroid mouse model using a transgenic approach delays several age-associated disorders, suggesting that SCs play a causative role in certain age-related pathologies. Thus, a 'senolytic' pharmacological agent that can selectively kill SCs holds promise for rejuvenating tissue stem cells and extending health span. To test this idea, we screened a collection of compounds and identified ABT263 (a specific inhibitor of the anti-apoptotic proteins BCL-2 and BCL-xL) as a potent senolytic drug. We show that ABT263 selectively kills SCs in culture in a cell type- and species-independent manner by inducing apoptosis. Oral administration of ABT263 to either sublethally irradiated or normally aged mice effectively depleted SCs, including senescent bone marrow hematopoietic stem cells (HSCs) and senescent muscle stem cells (MuSCs). Notably, this depletion mitigated TBI-induced premature aging of the hematopoietic system and rejuvenated the aged HSCs and MuSCs in normally aged mice. Our results demonstrate that selective clearance of SCs by a pharmacological agent is beneficial in part through its rejuvenation of aged tissue stem cells. Thus, senolytic drugs may represent a new class of radiation mitigators and anti-aging agents.", + "TAG_DATA": [ + "97, SCs {'context': 'B-cells'}", + "99, culture {'context': 'B-cells'}", + "108, inducing {'effect': 'B-positive'}", + "109, apoptosis. {'phenotype': 'B-apoptosis'}", + "120, aged {'context': 'I-organism'}", + "121, mice {'context': 'I-organism'}", + "124, SCs, {'context': 'B-cells'}", + "126, senescent {'context': 'B-cells'}", + "127, bone {'context': 'I-cells'}", + "128, marrow {'context': 'I-cells'}", + "129, hematopoietic {'context': 'I-cells'}", + "130, stem {'context': 'I-cells'}", + "131, cells {'context': 'I-cells'}", + "132, (HSCs) {'context': 'I-cells'}", + "134, senescent {'context': 'B-cells'}", + "135, muscle {'context': 'I-cells'}", + "136, stem {'context': 'I-cells'}", + "137, cells {'context': 'I-cells'}", + "138, (MuSCs). {'context': 'I-cells'}", + "148, hematopoietic {'context': 'B-tissue/organ'}", + "149, system {'context': 'I-tissue/organ'}", + "153, aged {'context': 'B-cells'}", + "154, HSCs {'context': 'I-cells'}", + "156, MuSCs {'context': 'B-cells'}", + "159, aged {'context': 'I-organism'}", + "160, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "97, SCs ['l0', 'l1', 'l2']", + "99, culture ['l0', 'l3', 'l4']", + "108, inducing ['l1', 'l3', 'l5']", + "109, apoptosis. ['l2', 'l4', 'l5']", + "120, aged ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "121, mice ['l6', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "124, SCs, ['l7', 'l20', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "126, senescent ['l8', 'l21', 'l33', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "127, bone ['l9', 'l22', 'l34', 'l45', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "128, marrow ['l10', 'l23', 'l35', 'l46', 'l56', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "129, hematopoietic ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "130, stem ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "131, cells ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "132, (HSCs) ['l14', 'l27', 'l39', 'l50', 'l60', 'l69', 'l77', 'l84', 'l90', 'l96', 'l97', 'l98', 'l99', 'l100']", + "134, senescent ['l15', 'l28', 'l40', 'l51', 'l61', 'l70', 'l78', 'l85', 'l91', 'l96', 'l101', 'l102', 'l103', 'l104', 'l105']", + "135, muscle ['l16', 'l29', 'l41', 'l52', 'l62', 'l71', 'l79', 'l86', 'l92', 'l97', 'l101', 'l106', 'l107', 'l108', 'l109', 'l110']", + "136, stem ['l17', 'l30', 'l42', 'l53', 'l63', 'l72', 'l80', 'l87', 'l93', 'l98', 'l102', 'l106', 'l111', 'l112', 'l113']", + "137, cells ['l18', 'l31', 'l43', 'l54', 'l64', 'l73', 'l81', 'l88', 'l94', 'l99', 'l103', 'l107', 'l111', 'l114', 'l115']", + "138, (MuSCs). ['l19', 'l32', 'l44', 'l55', 'l65', 'l74', 'l82', 'l89', 'l95', 'l100', 'l104', 'l108', 'l112', 'l114', 'l116']", + "148, hematopoietic ['l109', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "149, system ['l105', 'l110', 'l113', 'l115', 'l116', 'l117', 'l123', 'l124']", + "153, aged ['l118', 'l123', 'l125', 'l126', 'l127', 'l128']", + "154, HSCs ['l119', 'l124', 'l125', 'l129', 'l130', 'l131']", + "156, MuSCs ['l120', 'l126', 'l129', 'l132', 'l133']", + "159, aged ['l121', 'l127', 'l130', 'l132', 'l134']", + "160, mice. ['l122', 'l128', 'l131', 'l133', 'l134']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "SCs", + "culture" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "SCs", + "culture" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "26618722", + "TEXT": "Mitochondrial dysfunction represents a critical step during the pathogenesis of Parkinson's disease (PD), and increasing evidence suggests abnormal mitochondrial dynamics and quality control as important underlying mechanisms. The VPS35 gene, which encodes a key component of the membrane protein-recycling retromer complex, is the third autosomal-dominant gene associated with PD. However, how VPS35 mutations lead to neurodegeneration remains unclear. Here we demonstrate that PD-associated VPS35 mutations caused mitochondrial fragmentation and cell death in cultured neurons in vitro, in mouse substantia nigra neurons in vivo and in human fibroblasts from an individual with PD who has the VPS35(D620N) mutation. VPS35-induced mitochondrial deficits and neuronal dysfunction could be prevented by inhibition of mitochondrial fission. VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation. Notably, oxidative stress increased the VPS35-DLP1 interaction, which we also found to be increased in the brains of sporadic PD cases. These results revealed a novel cellular mechanism for the involvement of VPS35 in mitochondrial fission, dysregulation of which is probably involved in the pathogenesis of familial, and possibly sporadic, PD.", + "TAG_DATA": [ + "62, PD-associated {'perturbing_action': 'B-other'}", + "63, VPS35 {'perturbing_action': 'I-other'}", + "64, mutations {'perturbing_action': 'I-other'}", + "65, caused {'effect': 'B-positive'}", + "69, cell {'phenotype': 'B-cell death'}", + "70, death {'phenotype': 'I-cell death'}", + "72, cultured {'context': 'B-cells'}", + "73, neurons {'context': 'I-cells'}", + "74, in {'context': 'B-in vitro'}", + "75, vitro, {'context': 'I-in vitro'}", + "77, mouse {'context': 'B-cells'}", + "78, substantia {'context': 'I-cells'}", + "79, nigra {'context': 'I-cells'}", + "80, neurons {'context': 'I-cells'}", + "81, in {'context': 'B-in vivo'}", + "82, vivo {'context': 'I-in vivo'}", + "85, human {'context': 'B-cells'}", + "86, fibroblasts {'context': 'I-cells'}", + "94, the {'perturbing_action': 'I-other'}", + "95, VPS35(D620N) {'perturbing_action': 'B-other'}", + "96, mutation. {'perturbing_action': 'I-other'}", + "111, VPS35 {'perturbing_action': 'B-other'}", + "112, mutants {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "62, PD-associated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "63, VPS35 ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "64, mutations ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "65, caused ['l2', 'l15', 'l27', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "69, cell ['l3', 'l16', 'l28', 'l38', 'l44', 'l45', 'l46', 'l47', 'l48']", + "70, death ['l4', 'l17', 'l29', 'l39', 'l44', 'l49', 'l50', 'l51', 'l52']", + "72, cultured ['l5', 'l18', 'l30', 'l40', 'l45', 'l49', 'l53', 'l54', 'l55']", + "73, neurons ['l6', 'l19', 'l31', 'l41', 'l46', 'l50', 'l53', 'l56', 'l57']", + "74, in ['l7', 'l20', 'l32', 'l42', 'l47', 'l51', 'l54', 'l56', 'l58']", + "75, vitro, ['l8', 'l21', 'l33', 'l43', 'l48', 'l52', 'l55', 'l57', 'l58']", + "77, mouse ['l9', 'l22', 'l34', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "78, substantia ['l59', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "79, nigra ['l10', 'l23', 'l60', 'l66', 'l72', 'l73', 'l74', 'l75', 'l76']", + "80, neurons ['l11', 'l24', 'l35', 'l61', 'l67', 'l72', 'l77', 'l78', 'l79', 'l80']", + "81, in ['l12', 'l25', 'l36', 'l62', 'l68', 'l73', 'l77', 'l81', 'l82', 'l83']", + "82, vivo ['l13', 'l26', 'l37', 'l63', 'l69', 'l74', 'l78', 'l81', 'l84', 'l85']", + "85, human ['l64', 'l70', 'l75', 'l79', 'l82', 'l84', 'l86', 'l87', 'l88', 'l89']", + "86, fibroblasts ['l65', 'l71', 'l76', 'l80', 'l83', 'l85', 'l86', 'l90', 'l91', 'l92']", + "94, the ['l87', 'l90', 'l93', 'l94']", + "95, VPS35(D620N) ['l88', 'l91', 'l93', 'l95']", + "96, mutation. ['l89', 'l92', 'l94', 'l95']", + "111, VPS35 ['l96']", + "112, mutants ['l96']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "PD-associated", + "VPS35", + "mutations" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "PD-associated", + "VPS35", + "mutations" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "PD-associated", + "VPS35", + "mutations", + "the", + "VPS35(D620N)", + "mutation." + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "neurons", + "mouse", + "nigra", + "human", + "fibroblasts" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "PD-associated", + "VPS35", + "mutations" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "PD-associated", + "VPS35", + "mutations" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "neurons" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "neurons" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + } + ] + }, + { + "PMID": "26523972", + "TEXT": "Membrane-associated RING-CH 8 (MARCH8) is one of 11 members of the recently discovered MARCH family of RING (really interesting new gene)-finger E3 ubiquitin ligases. MARCH8 downregulates several host transmembrane proteins, including major histocompatibility complex (MHC)-II, CD86, interleukin (IL)-1 receptor accessory protein, TNF-related apoptosis-inducing ligand (TRAIL) receptor 1 and the transferrin receptor. However, its physiological roles remain largely unknown. Here we identify MARCH8 as a novel antiviral factor. The ectopic expression of MARCH8 in virus-producing cells does not affect levels of lentivirus production, but it does markedly reduce viral infectivity. MARCH8 blocks the incorporation of HIV-1 envelope glycoprotein into virus particles by downregulating it from the cell surface, probably through their interaction, resulting in a substantial reduction in the efficiency of viral entry. The inhibitory effect of MARCH8 on vesicular stomatitis virus G-glycoprotein is even more remarkable, suggesting a broad-spectrum inhibition of enveloped viruses by MARCH8. Notably, the endogenous expression of MARCH8 is high in monocyte-derived macrophages and dendritic cells, and MARCH8 knockdown or knockout in macrophages significantly increases the infectivity of virions produced by these cells. Our findings thus indicate that MARCH8 is highly expressed in terminally differentiated myeloid cells, and that it is a potent antiviral protein that targets viral envelope glycoproteins and reduces their incorporation into virions.", + "TAG_DATA": [ + "68, ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "69, expression {'perturbing_action': 'I-gene gain-of-function'}", + "70, of {'perturbing_action': 'I-gene gain-of-function'}", + "71, MARCH8 {'perturbing_action': 'I-gene gain-of-function'}", + "73, virus-producing {'context': 'B-cells'}", + "74, cells {'context': 'I-cells'}", + "160, MARCH8 {'perturbing_action': 'B-rnai/knockdown'}", + "161, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "165, macrophages {'context': 'B-cells'}", + "175, cells. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "68, ectopic ['l0', 'l1', 'l2', 'l3', 'l4']", + "69, expression ['l0', 'l5', 'l6', 'l7', 'l8']", + "70, of ['l1', 'l5', 'l9', 'l10', 'l11']", + "71, MARCH8 ['l2', 'l6', 'l9', 'l12', 'l13']", + "73, virus-producing ['l3', 'l7', 'l10', 'l12', 'l14']", + "74, cells ['l4', 'l8', 'l11', 'l13', 'l14']", + "160, MARCH8 ['l15', 'l16', 'l17']", + "161, knockdown ['l15', 'l18', 'l19']", + "165, macrophages ['l16', 'l18', 'l20']", + "175, cells. ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "expression", + "of", + "MARCH8" + ] + }, + "context": { + "val": "cells", + "words": [ + "virus-producing", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "MARCH8", + "knockdown" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages", + "cells." + ] + } + } + ] + }, + { + "PMID": "26501192", + "TEXT": "Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet-fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders.", + "TAG_DATA": [ + "108, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "110, antisense {'perturbing_action': 'B-rnai/knockdown'}", + "111, targeting {'perturbing_action': 'I-rnai/knockdown'}", + "112, of {'perturbing_action': 'I-rnai/knockdown'}", + "113, miR-128-1 {'perturbing_action': 'I-rnai/knockdown'}", + "114, or {'perturbing_action': 'I-rnai/knockdown'}", + "115, miR-148a {'perturbing_action': 'I-rnai/knockdown'}", + "121, Apoe-null {'perturbing_action': 'B-gene loss-of-function'}", + "122, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "108, overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "110, antisense ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "111, targeting ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "112, of ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "113, miR-128-1 ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "114, or ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "115, miR-148a ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "121, Apoe-null ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "122, mice ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antisense", + "targeting", + "of", + "miR-128-1", + "or", + "miR-148a" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apoe-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "26390242", + "TEXT": "Tauopathies, including frontotemporal dementia (FTD) and Alzheimer's disease (AD), are neurodegenerative diseases in which tau fibrils accumulate. Recent evidence supports soluble tau species as the major toxic species. How soluble tau accumulates and causes neurodegeneration remains unclear. Here we identify tau acetylation at Lys174 (K174) as an early change in AD brains and a critical determinant in tau homeostasis and toxicity in mice. The acetyl-mimicking mutant K174Q slows tau turnover and induces cognitive deficits in vivo. Acetyltransferase p300-induced tau acetylation is inhibited by salsalate and salicylate, which enhance tau turnover and reduce tau levels. In the PS19 transgenic mouse model of FTD, administration of salsalate after disease onset inhibited p300 activity, lowered levels of total tau and tau acetylated at K174, rescued tau-induced memory deficits and prevented hippocampal atrophy. The tau-lowering and protective effects of salsalate were diminished in neurons expressing K174Q tau. Targeting tau acetylation could be a new therapeutic strategy against human tauopathies.", + "TAG_DATA": [ + "65, mutant {'perturbing_action': 'I-other'}", + "66, K174Q {'perturbing_action': 'I-other'}", + "74, in {'context': 'B-in vivo'}", + "75, vivo. {'context': 'I-in vivo'}", + "96, PS19 {'perturbing_action': 'B-other'}", + "97, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "98, mouse {'context': 'B-organism'}", + "99, model {'context': 'I-organism'}", + "100, of {'context': 'I-organism'}", + "101, FTD, {'context': 'I-organism'}", + "139, neurons {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "65, mutant ['l0', 'l1', 'l2']", + "66, K174Q ['l0', 'l3', 'l4']", + "74, in ['l1', 'l3', 'l5']", + "75, vivo. ['l2', 'l4', 'l5']", + "96, PS19 ['l6', 'l7', 'l8', 'l9', 'l10']", + "97, transgenic ['l6', 'l11', 'l12', 'l13', 'l14']", + "98, mouse ['l7', 'l11', 'l15', 'l16', 'l17']", + "99, model ['l8', 'l12', 'l15', 'l18', 'l19']", + "100, of ['l9', 'l13', 'l16', 'l18', 'l20']", + "101, FTD, ['l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "K174Q" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "PS19" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "FTD," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "FTD," + ] + } + } + ] + }, + { + "PMID": "26322579", + "TEXT": "Macrophage phagocytosis of tumor cells mediated by CD47-specific blocking antibodies has been proposed to be the major effector mechanism in xenograft models. Here, using syngeneic immunocompetent mouse tumor models, we reveal that the therapeutic effects of CD47 blockade depend on dendritic cell but not macrophage cross-priming of T cell responses. The therapeutic effects of anti-CD47 antibody therapy were abrogated in T cell-deficient mice. In addition, the antitumor effects of CD47 blockade required expression of the cytosolic DNA sensor STING, but neither MyD88 nor TRIF, in CD11c+ cells, suggesting that cytosolic sensing of DNA from tumor cells is enhanced by anti-CD47 treatment, further bridging the innate and adaptive responses. Notably, the timing of administration of standard chemotherapy markedly impacted the induction of antitumor T cell responses by CD47 blockade. Together, our findings indicate that CD47 blockade drives T cell-mediated elimination of immunogenic tumors.", + "TAG_DATA": [ + "24, syngeneic {'context': 'B-neoplasm'}", + "25, immunocompetent {'context': 'I-neoplasm'}", + "26, mouse {'context': 'I-neoplasm'}", + "27, tumor {'context': 'I-neoplasm'}", + "28, models, {'context': 'I-neoplasm'}", + "60, T {'perturbing_action': 'B-gene loss-of-function'}", + "61, cell-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "62, mice. {'context': 'B-organism'}", + "85, CD11c+ {'context': 'B-cells'}", + "86, cells, {'context': 'I-cells'}", + "122, T {'context': 'B-cells'}", + "123, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "24, syngeneic ['l0', 'l1', 'l2', 'l3']", + "25, immunocompetent ['l0', 'l4', 'l5', 'l6']", + "26, mouse ['l1', 'l4', 'l7', 'l8']", + "27, tumor ['l2', 'l5', 'l7', 'l9']", + "28, models, ['l3', 'l6', 'l8', 'l9']", + "60, T ['l10', 'l11', 'l12', 'l13']", + "61, cell-deficient ['l10', 'l14', 'l15', 'l16']", + "62, mice. ['l11', 'l14', 'l17', 'l18']", + "85, CD11c+ ['l12', 'l15', 'l17', 'l19']", + "86, cells, ['l13', 'l16', 'l18', 'l19']", + "122, T ['l20']", + "123, cell ['l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "T", + "cell-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "T", + "cell-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD11c+", + "cells," + ] + } + } + ] + }, + { + "PMID": "26236991", + "TEXT": "Kidney fibrosis is marked by an epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells (TECs). Here we find that, during renal fibrosis, TECs acquire a partial EMT program during which they remain associated with their basement membrane and express markers of both epithelial and mesenchymal cells. The functional consequence of the EMT program during fibrotic injury is an arrest in the G2 phase of the cell cycle and lower expression of several solute and solvent transporters in TECs. We also found that transgenic expression of either Twist1 (encoding twist family bHLH transcription factor 1, known as Twist) or Snai1 (encoding snail family zinc finger 1, known as Snail) expression is sufficient to promote prolonged TGF-β1-induced G2 arrest of TECs, limiting the cells' potential for repair and regeneration. In mouse models of experimentally induced renal fibrosis, conditional deletion of Twist1 or Snai1 in proximal TECs resulted in inhibition of the EMT program and the maintenance of TEC integrity, while also restoring cell proliferation, dedifferentiation-associated repair and regeneration of the kidney parenchyma and attenuating interstitial fibrosis. Thus, inhibition of the EMT program in TECs during chronic renal injury represents a potential anti-fibrosis therapy.", + "TAG_DATA": [ + "81, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "82, expression {'perturbing_action': 'I-gene gain-of-function'}", + "83, of {'perturbing_action': 'I-gene gain-of-function'}", + "84, either {'perturbing_action': 'I-gene gain-of-function'}", + "85, Twist1 {'perturbing_action': 'I-gene gain-of-function'}", + "86, (encoding {'perturbing_action': 'I-gene gain-of-function'}", + "87, twist {'perturbing_action': 'I-gene gain-of-function'}", + "88, family {'perturbing_action': 'I-gene gain-of-function'}", + "89, bHLH {'perturbing_action': 'I-gene gain-of-function'}", + "90, transcription {'perturbing_action': 'I-gene gain-of-function'}", + "91, factor {'perturbing_action': 'I-gene gain-of-function'}", + "92, 1, {'perturbing_action': 'I-gene gain-of-function'}", + "93, known {'perturbing_action': 'I-gene gain-of-function'}", + "94, as {'perturbing_action': 'I-gene gain-of-function'}", + "95, Twist) {'perturbing_action': 'I-gene gain-of-function'}", + "96, or {'perturbing_action': 'I-gene gain-of-function'}", + "97, Snai1 {'perturbing_action': 'I-gene gain-of-function'}", + "107, expression {'perturbing_action': 'I-gene gain-of-function'}", + "111, promote {'effect': 'B-positive'}", + "114, G2 {'phenotype': 'B-cell cycle arrest'}", + "115, arrest {'phenotype': 'I-cell cycle arrest'}", + "117, TECs, {'context': 'B-cells'}", + "127, mouse {'context': 'B-organism'}", + "128, models {'context': 'I-organism'}", + "134, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "135, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "136, of {'perturbing_action': 'I-gene loss-of-function'}", + "137, Twist1 {'perturbing_action': 'I-gene loss-of-function'}", + "138, or {'perturbing_action': 'I-gene loss-of-function'}", + "139, Snai1 {'perturbing_action': 'I-gene loss-of-function'}", + "141, proximal {'context': 'B-cells'}", + "142, TECs {'context': 'I-cells'}", + "145, inhibition {'effect': 'B-negative'}", + "148, EMT {'phenotype': 'B-epithelial-mesenchymal transition'}", + "149, program {'phenotype': 'I-epithelial-mesenchymal transition'}", + "154, TEC {'context': 'B-cells'}", + "158, restoring {'effect': 'B-rescues'}", + "159, cell {'context': 'B-cells'}", + "160, proliferation, {'phenotype': 'B-proliferation'}", + "167, kidney {'context': 'B-tissue/organ'}", + "168, parenchyma {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "81, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "82, expression ['l0', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "83, of ['l1', 'l22', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "84, either ['l2', 'l23', 'l43', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "85, Twist1 ['l3', 'l24', 'l44', 'l62', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "86, (encoding ['l4', 'l25', 'l45', 'l63', 'l80', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "87, twist ['l5', 'l26', 'l46', 'l64', 'l81', 'l97', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "88, family ['l6', 'l27', 'l47', 'l65', 'l82', 'l98', 'l114', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "89, bHLH ['l7', 'l28', 'l48', 'l66', 'l83', 'l99', 'l115', 'l131', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163']", + "90, transcription ['l8', 'l29', 'l49', 'l67', 'l84', 'l100', 'l116', 'l132', 'l148', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "91, factor ['l9', 'l30', 'l50', 'l68', 'l85', 'l101', 'l117', 'l133', 'l149', 'l164', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191']", + "92, 1, ['l10', 'l31', 'l51', 'l69', 'l86', 'l102', 'l118', 'l134', 'l150', 'l165', 'l179', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203']", + "93, known ['l11', 'l32', 'l52', 'l70', 'l87', 'l103', 'l119', 'l135', 'l151', 'l166', 'l180', 'l192', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214']", + "94, as ['l12', 'l33', 'l53', 'l71', 'l88', 'l104', 'l120', 'l136', 'l152', 'l167', 'l181', 'l193', 'l204', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224']", + "95, Twist) ['l13', 'l34', 'l54', 'l72', 'l89', 'l105', 'l121', 'l137', 'l153', 'l168', 'l182', 'l194', 'l205', 'l215', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233']", + "96, or ['l14', 'l35', 'l55', 'l73', 'l90', 'l106', 'l122', 'l138', 'l154', 'l169', 'l183', 'l195', 'l206', 'l216', 'l225', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240']", + "97, Snai1 ['l15', 'l36', 'l56', 'l74', 'l91', 'l107', 'l123', 'l139', 'l155', 'l170', 'l184', 'l196', 'l207', 'l217', 'l226', 'l234', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249']", + "107, expression ['l16', 'l37', 'l57', 'l75', 'l92', 'l108', 'l124', 'l140', 'l156', 'l171', 'l185', 'l197', 'l208', 'l218', 'l227', 'l235', 'l241', 'l250', 'l251', 'l252', 'l253', 'l254']", + "111, promote ['l17', 'l38', 'l58', 'l76', 'l93', 'l109', 'l125', 'l141', 'l157', 'l172', 'l186', 'l198', 'l209', 'l219', 'l228', 'l236', 'l242', 'l250', 'l255', 'l256', 'l257']", + "114, G2 ['l18', 'l39', 'l59', 'l77', 'l94', 'l110', 'l126', 'l142', 'l158', 'l173', 'l187', 'l199', 'l210', 'l220', 'l229', 'l237', 'l243', 'l251', 'l255', 'l258', 'l259']", + "115, arrest ['l19', 'l40', 'l60', 'l78', 'l95', 'l111', 'l127', 'l143', 'l159', 'l174', 'l188', 'l200', 'l211', 'l221', 'l230', 'l238', 'l244', 'l252', 'l256', 'l258', 'l260']", + "117, TECs, ['l20', 'l41', 'l61', 'l79', 'l96', 'l112', 'l128', 'l144', 'l160', 'l175', 'l189', 'l201', 'l212', 'l222', 'l231', 'l239', 'l245', 'l253', 'l257', 'l259', 'l260']", + "127, mouse ['l129', 'l145', 'l161', 'l176', 'l190', 'l202', 'l213', 'l223', 'l232', 'l246', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272']", + "128, models ['l21', 'l42', 'l113', 'l130', 'l146', 'l162', 'l177', 'l191', 'l203', 'l214', 'l224', 'l233', 'l240', 'l247', 'l254', 'l261', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282']", + "134, conditional ['l283', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298']", + "135, deletion ['l283', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304', 'l305', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311', 'l312', 'l313']", + "136, of ['l284', 'l299', 'l314', 'l315', 'l316', 'l317', 'l318', 'l319', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327']", + "137, Twist1 ['l285', 'l300', 'l314', 'l328', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340']", + "138, or ['l286', 'l301', 'l315', 'l328', 'l341', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348', 'l349', 'l350', 'l351', 'l352']", + "139, Snai1 ['l287', 'l302', 'l316', 'l329', 'l341', 'l353', 'l354', 'l355', 'l356', 'l357', 'l358', 'l359', 'l360', 'l361', 'l362', 'l363']", + "141, proximal ['l262', 'l288', 'l303', 'l317', 'l330', 'l342', 'l353', 'l364', 'l365', 'l366', 'l367', 'l368', 'l369', 'l370', 'l371', 'l372', 'l373']", + "142, TECs ['l263', 'l273', 'l289', 'l304', 'l318', 'l331', 'l343', 'l354', 'l364', 'l374', 'l375', 'l376', 'l377', 'l378', 'l379', 'l380', 'l381', 'l382']", + "145, inhibition ['l264', 'l274', 'l290', 'l305', 'l319', 'l332', 'l344', 'l355', 'l365', 'l374', 'l383', 'l384', 'l385', 'l386', 'l387', 'l388', 'l389', 'l390']", + "148, EMT ['l248', 'l265', 'l275', 'l291', 'l306', 'l320', 'l333', 'l345', 'l356', 'l366', 'l375', 'l383', 'l391', 'l392', 'l393', 'l394', 'l395', 'l396', 'l397']", + "149, program ['l147', 'l163', 'l178', 'l249', 'l266', 'l276', 'l292', 'l307', 'l321', 'l334', 'l346', 'l357', 'l367', 'l376', 'l384', 'l391', 'l398', 'l399', 'l400', 'l401', 'l402', 'l403']", + "154, TEC ['l267', 'l277', 'l293', 'l308', 'l322', 'l335', 'l347', 'l358', 'l368', 'l377', 'l385', 'l392', 'l398', 'l404', 'l405', 'l406', 'l407', 'l408']", + "158, restoring ['l268', 'l278', 'l294', 'l309', 'l323', 'l336', 'l348', 'l359', 'l369', 'l378', 'l386', 'l393', 'l399', 'l404', 'l409', 'l410', 'l411', 'l412']", + "159, cell ['l269', 'l279', 'l295', 'l310', 'l324', 'l337', 'l349', 'l360', 'l370', 'l379', 'l387', 'l394', 'l400', 'l405', 'l409', 'l413', 'l414', 'l415']", + "160, proliferation, ['l270', 'l280', 'l296', 'l311', 'l325', 'l338', 'l350', 'l361', 'l371', 'l380', 'l388', 'l395', 'l401', 'l406', 'l410', 'l413', 'l416', 'l417']", + "167, kidney ['l271', 'l281', 'l297', 'l312', 'l326', 'l339', 'l351', 'l362', 'l372', 'l381', 'l389', 'l396', 'l402', 'l407', 'l411', 'l414', 'l416', 'l418']", + "168, parenchyma ['l272', 'l282', 'l298', 'l313', 'l327', 'l340', 'l352', 'l363', 'l373', 'l382', 'l390', 'l397', 'l403', 'l408', 'l412', 'l415', 'l417', 'l418']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "of", + "either", + "Twist1", + "(encoding", + "twist", + "family", + "bHLH", + "transcription", + "factor", + "1,", + "known", + "as", + "Twist)", + "or", + "Snai1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promote" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "of", + "either", + "Twist1", + "(encoding", + "twist", + "family", + "bHLH", + "transcription", + "factor", + "1,", + "known", + "as", + "Twist)", + "or", + "Snai1" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G2", + "arrest" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "of", + "either", + "Twist1", + "(encoding", + "twist", + "family", + "bHLH", + "transcription", + "factor", + "1,", + "known", + "as", + "Twist)", + "or", + "Snai1" + ] + }, + "context": { + "val": "cells", + "words": [ + "TECs," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "(encoding", + "twist", + "family", + "bHLH", + "transcription", + "factor", + "1,", + "known", + "as", + "Twist)", + "or", + "Snai1" + ] + }, + "context": { + "val": "organism", + "words": [ + "models", + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "family", + "bHLH", + "transcription", + "Snai1" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "program", + "EMT" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G2", + "arrest" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote" + ] + }, + "context": { + "val": "cells", + "words": [ + "TECs," + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G2", + "arrest" + ] + }, + "context": { + "val": "cells", + "words": [ + "TECs," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EMT", + "program" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restoring" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "deletion", + "of", + "Twist1", + "or", + "Snai1" + ] + }, + "context": { + "val": "cells", + "words": [ + "proximal", + "TECs", + "TEC", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "deletion", + "of", + "Twist1", + "or", + "Snai1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "deletion", + "of", + "Twist1", + "or", + "Snai1" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EMT", + "program" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "deletion", + "of", + "Twist1", + "or", + "Snai1" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restoring" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "deletion", + "of", + "Twist1", + "or", + "Snai1" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "deletion", + "of", + "Twist1", + "or", + "Snai1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidney", + "parenchyma" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "proximal", + "TECs", + "TEC", + "cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "proximal", + "TECs", + "TEC", + "cell" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EMT", + "program" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "proximal", + "TECs", + "TEC", + "cell" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restoring" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "proximal", + "TECs", + "TEC", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EMT", + "program" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidney", + "parenchyma" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EMT", + "program" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restoring" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EMT", + "program" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidney", + "parenchyma" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restoring" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restoring" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidney", + "parenchyma" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidney", + "parenchyma" + ] + } + } + ] + }, + { + "PMID": "26099047", + "TEXT": "Amyloid-β (Aβ) plaques and α-synuclein (α-syn)-rich Lewy bodies are the major neuropathological hallmarks of Alzheimer's disease (AD) and Parkinson's disease, respectively. An overlap of pathologies is found in most individuals with dementia with Lewy bodies (DLB) and in more than 50% of AD cases. Their brains display substantial α-syn accumulation not only in Lewy bodies, but also in dystrophic neurites decorating Aβ plaques. Several studies report binding and coaggregation of Aβ and α-syn, yet the precise role of α-syn in amyloid plaque formation remains elusive. Here we performed intracerebral injections of α-syn-containing preparations into amyloid precursor protein (APP) transgenic mice (expressing APP695(KM670/671NL) and PSEN1(L166P) under the control of the neuron-specific Thy-1 promoter; referred to here as 'APPPS1'). Unexpectedly, α-syn failed to cross-seed Aβ plaques in vivo, but rather it inhibited plaque formation in APPPS1 mice coexpressing SNCA(A30P) (referred to here as 'APPPS1 × [A30P]aSYN' double-transgenic mice). This was accompanied by increased Aβ levels in cerebrospinal fluid despite unchanged overall Aβ levels. Notably, the seeding activity of Aβ-containing brain homogenates was considerably reduced by α-syn, and Aβ deposition was suppressed in grafted tissue from [A30P]aSYN transgenic mice. Thus, we conclude that an interaction between Aβ and α-syn leads to inhibition of Aβ deposition and to reduced plaque formation.", + "TAG_DATA": [ + "94, amyloid {'perturbing_action': 'B-gene gain-of-function'}", + "96, protein {'perturbing_action': 'I-gene gain-of-function'}", + "97, (APP) {'perturbing_action': 'I-gene gain-of-function'}", + "98, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "99, mice {'context': 'B-organism'}", + "101, APP695(KM670/671NL) {'perturbing_action': 'I-gene gain-of-function'}", + "102, and {'perturbing_action': 'I-gene gain-of-function'}", + "103, PSEN1(L166P) {'perturbing_action': 'I-gene gain-of-function'}", + "104, under {'perturbing_action': 'I-gene gain-of-function'}", + "106, control {'perturbing_action': 'I-gene gain-of-function'}", + "107, of {'perturbing_action': 'I-gene gain-of-function'}", + "108, the {'perturbing_action': 'I-gene gain-of-function'}", + "109, neuron-specific {'perturbing_action': 'I-gene gain-of-function'}", + "110, Thy-1 {'perturbing_action': 'I-gene gain-of-function'}", + "111, promoter; {'perturbing_action': 'I-gene gain-of-function'}", + "124, in {'context': 'B-in vivo'}", + "125, vivo, {'context': 'I-in vivo'}", + "133, APPPS1 {'perturbing_action': 'B-other'}", + "134, mice {'context': 'I-organism'}", + "135, coexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "136, SNCA(A30P) {'perturbing_action': 'I-gene gain-of-function'}", + "183, [A30P]aSYN {'perturbing_action': 'B-gene gain-of-function'}", + "184, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "185, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "94, amyloid ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "96, protein ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "97, (APP) ['l1', 'l17', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "98, transgenic ['l2', 'l18', 'l33', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "99, mice ['l3', 'l19', 'l34', 'l48', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "101, APP695(KM670/671NL) ['l4', 'l20', 'l35', 'l49', 'l62', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "102, and ['l5', 'l21', 'l36', 'l50', 'l63', 'l75', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "103, PSEN1(L166P) ['l6', 'l22', 'l37', 'l51', 'l64', 'l76', 'l89', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "104, under ['l7', 'l23', 'l38', 'l52', 'l65', 'l77', 'l90', 'l101', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "105, the ['l8', 'l24', 'l39', 'l53', 'l66', 'l78', 'l91', 'l102', 'l113', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "106, control ['l9', 'l25', 'l40', 'l54', 'l67', 'l79', 'l92', 'l103', 'l114', 'l124', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "107, of ['l10', 'l26', 'l41', 'l55', 'l68', 'l80', 'l93', 'l104', 'l115', 'l125', 'l135', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "108, the ['l11', 'l27', 'l42', 'l56', 'l69', 'l81', 'l94', 'l105', 'l116', 'l126', 'l136', 'l145', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162']", + "109, neuron-specific ['l12', 'l28', 'l43', 'l57', 'l70', 'l82', 'l95', 'l106', 'l117', 'l127', 'l137', 'l146', 'l155', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170']", + "110, Thy-1 ['l13', 'l29', 'l44', 'l58', 'l71', 'l83', 'l96', 'l107', 'l118', 'l128', 'l138', 'l147', 'l156', 'l163', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177']", + "111, promoter; ['l14', 'l30', 'l45', 'l59', 'l72', 'l84', 'l97', 'l108', 'l119', 'l129', 'l139', 'l148', 'l157', 'l164', 'l171', 'l178', 'l179', 'l180', 'l181', 'l182']", + "124, in ['l15', 'l31', 'l46', 'l60', 'l73', 'l85', 'l98', 'l109', 'l120', 'l130', 'l140', 'l149', 'l158', 'l165', 'l172', 'l178', 'l183']", + "125, vivo, ['l16', 'l32', 'l47', 'l61', 'l74', 'l86', 'l99', 'l110', 'l121', 'l131', 'l141', 'l150', 'l159', 'l166', 'l173', 'l179', 'l183']", + "133, APPPS1 ['l87', 'l100', 'l111', 'l122', 'l132', 'l142', 'l151', 'l160', 'l167', 'l174', 'l180', 'l184', 'l185', 'l186']", + "134, mice ['l88', 'l112', 'l123', 'l133', 'l143', 'l152', 'l161', 'l168', 'l175', 'l181', 'l184', 'l187', 'l188']", + "135, coexpressing ['l153', 'l169', 'l176', 'l185', 'l187', 'l189']", + "136, SNCA(A30P) ['l134', 'l144', 'l154', 'l162', 'l170', 'l177', 'l182', 'l186', 'l188', 'l189']", + "180, grafted ['l190', 'l191', 'l192', 'l193']", + "181, tissue ['l190', 'l194', 'l195', 'l196']", + "183, [A30P]aSYN ['l191', 'l194', 'l197', 'l198']", + "184, transgenic ['l192', 'l195', 'l197', 'l199']", + "185, mice. ['l193', 'l196', 'l198', 'l199']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "amyloid", + "protein", + "(APP)", + "transgenic", + "APP695(KM670/671NL)", + "and", + "PSEN1(L166P)", + "under", + "control", + "of", + "the", + "neuron-specific", + "Thy-1", + "promoter;", + "coexpressing", + "SNCA(A30P)", + "[A30P]aSYN" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "amyloid", + "protein", + "(APP)", + "transgenic", + "APP695(KM670/671NL)", + "and", + "PSEN1(L166P)", + "under", + "control", + "of", + "the", + "neuron-specific", + "Thy-1", + "promoter;" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "APPPS1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "26053624", + "TEXT": "Depending on the inflammatory milieu, injury can result either in a tissue's complete regeneration or in its degeneration and fibrosis, the latter of which could potentially lead to permanent organ failure. Yet how inflammatory cells regulate matrix-producing cells involved in the reparative process is unknown. Here we show that in acutely damaged skeletal muscle, sequential interactions between multipotent mesenchymal progenitors and infiltrating inflammatory cells determine the outcome of the reparative process. We found that infiltrating inflammatory macrophages, through their expression of tumor necrosis factor (TNF), directly induce apoptosis of fibro/adipogenic progenitors (FAPs). In states of chronic damage, however, such as those in mdx mice, macrophages express high levels of transforming growth factor β1 (TGF-β1), which prevents the apoptosis of FAPs and induces their differentiation into matrix-producing cells. Treatment with nilotinib, a kinase inhibitor with proposed anti-fibrotic activity, can block the effect of TGF-β1 and reduce muscle fibrosis in mdx mice. Our findings reveal an unexpected anti-fibrotic role of TNF and suggest that disruption of the precisely timed progression from a TNF-rich to a TGF-β-rich environment favors fibrotic degeneration of the muscle during chronic injury.", + "TAG_DATA": [ + "86, induce {'effect': 'B-positive'}", + "87, apoptosis {'phenotype': 'B-apoptosis'}", + "104, macrophages {'context': 'B-cells'}", + "115, prevents {'effect': 'B-negative'}", + "117, apoptosis {'phenotype': 'B-apoptosis'}", + "119, FAPs {'context': 'B-cells'}", + "121, induces {'effect': 'B-positive'}", + "123, differentiation {'phenotype': 'B-differentiation'}", + "145, muscle {'context': 'B-tissue/organ'}", + "148, mdx {'context': 'B-organism'}", + "149, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "86, induce ['l0']", + "87, apoptosis ['l0']", + "104, macrophages ['l1', 'l2', 'l3', 'l4', 'l5']", + "115, prevents ['l1', 'l6', 'l7', 'l8', 'l9']", + "117, apoptosis ['l2', 'l6', 'l10', 'l11', 'l12']", + "119, FAPs ['l3', 'l7', 'l10', 'l13', 'l14']", + "121, induces ['l4', 'l8', 'l11', 'l13', 'l15']", + "123, differentiation ['l5', 'l9', 'l12', 'l14', 'l15']", + "145, muscle ['l16', 'l17']", + "148, mdx ['l16', 'l18']", + "149, mice. ['l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induce", + "induces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "macrophages", + "FAPs" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "macrophages", + "FAPs" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "macrophages", + "FAPs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "macrophages", + "FAPs" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "26005854", + "TEXT": "B cell malignancies frequently colonize the bone marrow. The mechanisms responsible for this preferential homing are incompletely understood. Here we studied multiple myeloma (MM) as a model of a terminally differentiated B cell malignancy that selectively colonizes the bone marrow. We found that extracellular CyPA (eCyPA), secreted by bone marrow endothelial cells (BMECs), promoted the colonization and proliferation of MM cells in an in vivo scaffold system via binding to its receptor, CD147, on MM cells. The expression and secretion of eCyPA by BMECs was enhanced by BCL9, a Wnt-β-catenin transcriptional coactivator that is selectively expressed by these cells. eCyPA levels were higher in bone marrow serum than in peripheral blood in individuals with MM, and eCyPA-CD147 blockade suppressed MM colonization and tumor growth in the in vivo scaffold system. eCyPA also promoted the migration of chronic lymphocytic leukemia and lymphoplasmacytic lymphoma cells, two other B cell malignancies that colonize the bone marrow and express CD147. These findings suggest that eCyPA-CD147 signaling promotes the bone marrow homing of B cell malignancies and offer a compelling rationale for exploring this axis as a therapeutic target for these malignancies.", + "TAG_DATA": [ + "53, promoted {'effect': 'B-positive'}", + "57, proliferation {'phenotype': 'B-proliferation'}", + "59, MM {'context': 'B-transformed cells'}", + "60, cells {'context': 'I-transformed cells'}", + "63, in {'context': 'B-in vivo'}", + "64, vivo {'context': 'I-in vivo'}", + "65, scaffold {'context': 'I-in vivo'}", + "66, system {'context': 'I-tissue/organ'}", + "74, MM {'context': 'B-transformed cells'}", + "75, cells. {'context': 'I-transformed cells'}", + "118, suppressed {'effect': 'B-negative'}", + "119, MM {'context': 'B-cells'}", + "122, tumor {'phenotype': 'B-tumour growth'}", + "123, growth {'phenotype': 'I-tumour growth'}", + "126, in {'context': 'B-in vivo'}", + "127, vivo {'context': 'I-in vivo'}", + "132, promoted {'effect': 'B-positive'}", + "134, migration {'phenotype': 'B-migration'}", + "136, chronic {'context': 'B-neoplasm'}", + "137, lymphocytic {'context': 'I-neoplasm'}", + "138, leukemia {'context': 'I-neoplasm'}", + "139, and {'context': 'I-transformed cells'}", + "140, lymphoplasmacytic {'context': 'B-transformed cells'}", + "141, lymphoma {'context': 'I-transformed cells'}", + "142, cells, {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "53, promoted ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "57, proliferation ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "59, MM ['l1', 'l7', 'l12', 'l13', 'l14', 'l15', 'l16']", + "60, cells ['l2', 'l8', 'l12', 'l17', 'l18', 'l19']", + "63, in ['l3', 'l9', 'l13', 'l17', 'l20', 'l21', 'l22', 'l23', 'l24']", + "64, vivo ['l4', 'l10', 'l14', 'l18', 'l20', 'l25', 'l26', 'l27', 'l28']", + "65, scaffold ['l5', 'l15', 'l21', 'l25', 'l29', 'l30', 'l31']", + "66, system ['l6', 'l11', 'l16', 'l19', 'l22', 'l26', 'l29', 'l32', 'l33']", + "74, MM ['l23', 'l27', 'l30', 'l32', 'l34']", + "75, cells. ['l24', 'l28', 'l31', 'l33', 'l34']", + "118, suppressed ['l35', 'l36', 'l37', 'l38', 'l39']", + "119, MM ['l35', 'l40', 'l41', 'l42']", + "122, tumor ['l36', 'l40', 'l43', 'l44', 'l45']", + "123, growth ['l37', 'l41', 'l43']", + "126, in ['l38', 'l44', 'l46']", + "127, vivo ['l39', 'l42', 'l45', 'l46']", + "132, promoted ['l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "134, migration ['l47', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "136, chronic ['l48', 'l55', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "137, lymphocytic ['l49', 'l56', 'l62', 'l68', 'l69', 'l70', 'l71', 'l72']", + "138, leukemia ['l50', 'l57', 'l63', 'l68', 'l73', 'l74', 'l75', 'l76']", + "139, and ['l51', 'l58', 'l64', 'l69', 'l73', 'l77', 'l78', 'l79']", + "140, lymphoplasmacytic ['l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l80', 'l81']", + "141, lymphoma ['l53', 'l60', 'l66', 'l71', 'l75', 'l78', 'l80', 'l82']", + "142, cells, ['l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l81', 'l82']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MM", + "cells", + "and", + "lymphoplasmacytic", + "lymphoma", + "cells," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "scaffold" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "system" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MM", + "cells" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "system" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "cells", + "words": [ + "MM" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "MM" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "chronic", + "lymphocytic", + "leukemia" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "chronic", + "lymphocytic", + "leukemia" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "and", + "lymphoplasmacytic", + "lymphoma", + "cells," + ] + } + } + ] + }, + { + "PMID": "25985365", + "TEXT": "Pancreatic beta cell death is a hallmark of type 1 (T1D) and type 2 (T2D) diabetes, but the molecular mechanisms underlying this aspect of diabetic pathology are poorly understood. Here we report that expression of the microRNA (miR)-200 family is strongly induced in islets of diabetic mice and that beta cell-specific overexpression of miR-200 in mice is sufficient to induce beta cell apoptosis and lethal T2D. Conversely, mir-200 ablation in mice reduces beta cell apoptosis and ameliorates T2D. We show that miR-200 negatively regulates a conserved anti-apoptotic and stress-resistance network that includes the essential beta cell chaperone Dnajc3 (also known as p58IPK) and the caspase inhibitor Xiap. We also observed that mir-200 dosage positively controls activation of the tumor suppressor Trp53 and thereby creates a pro-apoptotic gene-expression signature found in islets of diabetic mice. Consequently, miR-200-induced T2D is suppressed by interfering with the signaling of Trp53 and Bax, a proapoptotic member of the B cell lymphoma 2 protein family. Our results reveal a crucial role for the miR-200 family in beta cell survival and the pathophysiology of diabetes.", + "TAG_DATA": [ + "45, diabetic {'context': 'B-organism'}", + "46, mice {'context': 'I-organism'}", + "49, beta {'perturbing_action': 'B-gene gain-of-function'}", + "50, cell-specific {'perturbing_action': 'I-gene gain-of-function'}", + "51, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "52, of {'perturbing_action': 'I-gene gain-of-function'}", + "53, miR-200 {'perturbing_action': 'I-gene gain-of-function'}", + "55, mice {'context': 'B-organism'}", + "59, induce {'effect': 'B-positive'}", + "60, beta {'context': 'B-cells'}", + "61, cell {'context': 'I-cells'}", + "62, apoptosis {'phenotype': 'B-apoptosis'}", + "67, mir-200 {'perturbing_action': 'B-gene loss-of-function'}", + "68, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "70, mice {'context': 'B-organism'}", + "71, reduces {'effect': 'B-negative'}", + "72, beta {'context': 'B-cells'}", + "73, cell {'context': 'I-cells'}", + "74, apoptosis {'phenotype': 'B-apoptosis'}", + "133, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "45, diabetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "46, mice ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "49, beta ['l1', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "50, cell-specific ['l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "51, overexpression ['l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "52, of ['l14', 'l23', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "53, miR-200 ['l15', 'l24', 'l32', 'l40', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "55, mice ['l2', 'l7', 'l16', 'l25', 'l33', 'l41', 'l49', 'l56', 'l57', 'l58', 'l59']", + "59, induce ['l3', 'l8', 'l17', 'l26', 'l34', 'l42', 'l50', 'l56', 'l60', 'l61', 'l62']", + "60, beta ['l4', 'l9', 'l18', 'l27', 'l35', 'l43', 'l51', 'l57', 'l60', 'l63', 'l64']", + "61, cell ['l5', 'l10', 'l19', 'l28', 'l36', 'l44', 'l52', 'l58', 'l61', 'l63', 'l65']", + "62, apoptosis ['l6', 'l11', 'l20', 'l29', 'l37', 'l45', 'l53', 'l59', 'l62', 'l64', 'l65']", + "67, mir-200 ['l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "68, ablation ['l66', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "70, mice ['l67', 'l73', 'l79', 'l80', 'l81', 'l82']", + "71, reduces ['l38', 'l46', 'l54', 'l68', 'l74', 'l79', 'l83', 'l84', 'l85']", + "72, beta ['l47', 'l69', 'l75', 'l80', 'l83', 'l86', 'l87']", + "73, cell ['l21', 'l30', 'l39', 'l48', 'l55', 'l70', 'l76', 'l81', 'l84', 'l86', 'l88']", + "74, apoptosis ['l71', 'l77', 'l82', 'l85', 'l87', 'l88']", + "133, mice. ['l72', 'l78']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "diabetic", + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "beta", + "cell-specific", + "overexpression", + "of", + "miR-200" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "diabetic", + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "diabetic", + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "beta", + "cell-specific", + "overexpression", + "of", + "miR-200" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "beta", + "cell-specific", + "overexpression", + "of", + "miR-200" + ] + }, + "context": { + "val": "cells", + "words": [ + "beta", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "beta", + "cell-specific", + "overexpression", + "of", + "miR-200" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "miR-200" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "beta", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "beta", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "mir-200", + "ablation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "mir-200", + "ablation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "mir-200", + "ablation" + ] + }, + "context": { + "val": "cells", + "words": [ + "beta", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "mir-200", + "ablation" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "context": { + "val": "cells", + "words": [ + "beta", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "25849133", + "TEXT": "Metformin is a first-line therapeutic option for the treatment of type 2 diabetes, even though its underlying mechanisms of action are relatively unclear. Metformin lowers blood glucose levels by inhibiting hepatic glucose production (HGP), an effect originally postulated to be due to a hepatic AMP-activated protein kinase (AMPK)-dependent mechanism. However, studies have questioned the contribution of hepatic AMPK to the effects of metformin on lowering hyperglycemia, and a gut-brain-liver axis that mediates intestinal nutrient- and hormone-induced lowering of HGP has been identified. Thus, it is possible that metformin affects HGP through this inter-organ crosstalk. Here we show that intraduodenal infusion of metformin for 50 min activated duodenal mucosal Ampk and lowered HGP in a rat 3 d high fat diet (HFD)-induced model of insulin resistance. Inhibition of duodenal Ampk negated the HGP-lowering effect of intraduodenal metformin, and both duodenal glucagon-like peptide-1 receptor (Glp-1r)-protein kinase A (Pka) signaling and a neuronal-mediated gut-brain-liver pathway were required for metformin to lower HGP. Preabsorptive metformin also lowered HGP in rat models of 28 d HFD-induced obesity and insulin resistance and nicotinamide (NA)-streptozotocin (STZ)-HFD-induced type 2 diabetes. In an unclamped setting, inhibition of duodenal Ampk reduced the glucose-lowering effects of a bolus metformin treatment in rat models of diabetes. These findings show that, in rat models of both obesity and diabetes, metformin activates a previously unappreciated duodenal Ampk-dependent pathway to lower HGP and plasma glucose levels.", + "TAG_DATA": [ + "114, rat {'context': 'B-organism'}", + "125, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "126, of {'perturbing_action': 'I-pharmacological inhibition'}", + "127, duodenal {'perturbing_action': 'I-pharmacological inhibition'}", + "128, Ampk {'perturbing_action': 'I-pharmacological inhibition'}", + "165, rat {'context': 'B-organism'}", + "166, models {'context': 'I-organism'}", + "186, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "187, of {'perturbing_action': 'I-pharmacological inhibition'}", + "188, duodenal {'perturbing_action': 'I-pharmacological inhibition'}", + "189, Ampk {'perturbing_action': 'I-pharmacological inhibition'}", + "200, rat {'context': 'B-organism'}", + "201, models {'context': 'I-organism'}", + "202, of {'context': 'I-organism'}", + "203, diabetes. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "125, Inhibition ['l0', 'l1', 'l2', 'l3', 'l4']", + "126, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "127, duodenal ['l1', 'l5', 'l9', 'l10', 'l11']", + "128, Ampk ['l2', 'l6', 'l9', 'l12']", + "165, rat ['l3', 'l7', 'l10', 'l13']", + "166, models ['l4', 'l8', 'l11', 'l12', 'l13']", + "186, inhibition ['l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "187, of ['l14', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "188, duodenal ['l15', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "189, Ampk ['l16', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "200, rat ['l17', 'l23', 'l28', 'l32', 'l36', 'l37', 'l38']", + "201, models ['l18', 'l24', 'l29', 'l33', 'l36', 'l39', 'l40']", + "202, of ['l19', 'l25', 'l30', 'l34', 'l37', 'l39', 'l41']", + "203, diabetes. ['l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "duodenal", + "Ampk", + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "rat", + "models", + "of", + "diabetes." + ] + } + } + ] + }, + { + "PMID": "25751817", + "TEXT": "Cardiac healing after myocardial ischemia depends on the recruitment and local expansion of myeloid cells, particularly macrophages. Here we identify Reg3β as an essential regulator of macrophage trafficking to the damaged heart. Using mass spectrometry-based secretome analysis, we found that dedifferentiating cardiomyocytes release Reg3β in response to the cytokine OSM, which signals through Jak1 and Stat3. Loss of Reg3β led to a large decrease in the number of macrophages in the ischemic heart, accompanied by increased ventricular dilatation and insufficient removal of neutrophils. This defect in neutrophil removal in turn caused enhanced matrix degradation, delayed collagen deposition and increased susceptibility to cardiac rupture. Our data indicate that OSM, acting through distinct intracellular pathways, regulates both cardiomyocyte dedifferentiation and cardiomyocyte-dependent regulation of macrophage trafficking. Release of OSM from infiltrating neutrophils and macrophages initiates a positive feedback loop in which OSM-induced production of Reg3β in cardiomyocytes attracts additional OSM-secreting macrophages. The activity of the feedback loop controls the degree of macrophage accumulation in the heart, which is instrumental in myocardial healing.", + "TAG_DATA": [ + "41, cardiomyocytes {'context': 'I-cells'}", + "56, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "57, of {'perturbing_action': 'I-gene loss-of-function'}", + "58, Reg3β {'perturbing_action': 'I-gene loss-of-function'}", + "68, macrophages {'context': 'B-cells'}", + "72, heart, {'context': 'B-tissue/organ'}", + "143, cardiomyocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "41, cardiomyocytes ['l0', 'l1', 'l2', 'l3', 'l4']", + "56, Loss ['l0', 'l5', 'l6', 'l7', 'l8']", + "57, of ['l1', 'l5', 'l9', 'l10', 'l11']", + "58, Reg3β ['l2', 'l6', 'l9', 'l12', 'l13']", + "68, macrophages ['l3', 'l7', 'l10', 'l12', 'l14']", + "72, heart, ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cardiomyocytes", + "macrophages" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Loss", + "of", + "Reg3β" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Loss", + "of", + "Reg3β" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "heart," + ] + } + } + ] + }, + { + "PMID": "25706873", + "TEXT": "Metabolic reprogramming occurs in response to the cellular environment to mediate differentiation, but the fundamental mechanisms linking metabolic processes to differentiation programs remain to be elucidated. During osteoclast differentiation, a shift toward more oxidative metabolic processes occurs. In this study we identified the de novo DNA methyltransferase 3a (Dnmt3a) as a transcription factor that couples these metabolic changes to osteoclast differentiation. We also found that receptor activator of nuclear factor-κB ligand (RANKL), an essential cytokine for osteoclastogenesis, induces this metabolic shift towards oxidative metabolism, which is accompanied by an increase in S-adenosylmethionine (SAM) production. We found that SAM-mediated DNA methylation by Dnmt3a regulates osteoclastogenesis via epigenetic repression of anti-osteoclastogenic genes. The importance of Dnmt3a in bone homeostasis was underscored by the observations that Dnmt3a-deficient osteoclast precursor cells do not differentiate efficiently into osteoclasts and that mice with an osteoclast-specific deficiency in Dnmt3a have elevated bone mass due to a smaller number of osteoclasts. Furthermore, inhibition of DNA methylation by theaflavin-3,3'-digallate abrogated bone loss in models of osteoporosis. Thus, this study reveals the role of epigenetic processes in the regulation of cellular metabolism and differentiation, which may provide the molecular basis for a new therapeutic strategy for a variety of bone disorders.", + "TAG_DATA": [ + "123, Dnmt3a-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "124, osteoclast {'context': 'B-cells'}", + "125, precursor {'context': 'I-cells'}", + "126, cells {'context': 'I-cells'}", + "127, do {'effect': 'B-negative'}", + "128, not {'effect': 'I-no effect'}", + "129, differentiate {'phenotype': 'B-differentiation'}", + "135, mice {'context': 'B-organism'}", + "138, osteoclast-specific {'perturbing_action': 'B-gene loss-of-function'}", + "139, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "140, in {'perturbing_action': 'I-gene loss-of-function'}", + "141, Dnmt3a {'perturbing_action': 'I-gene loss-of-function'}", + "152, osteoclasts. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "123, Dnmt3a-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "124, osteoclast ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "125, precursor ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "126, cells ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "127, do ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "128, not ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "129, differentiate ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "135, mice ['l21', 'l22', 'l23', 'l24', 'l25']", + "138, osteoclast-specific ['l21', 'l26', 'l27', 'l28', 'l29']", + "139, deficiency ['l22', 'l26', 'l30', 'l31', 'l32']", + "140, in ['l23', 'l27', 'l30', 'l33', 'l34']", + "141, Dnmt3a ['l24', 'l28', 'l31', 'l33', 'l35']", + "152, osteoclasts. ['l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dnmt3a-deficient", + "osteoclast-specific", + "deficiency", + "in", + "Dnmt3a" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast", + "precursor", + "cells", + "osteoclasts." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dnmt3a-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "do" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dnmt3a-deficient" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dnmt3a-deficient" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoclast", + "precursor", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "do" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoclast", + "precursor", + "cells" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoclast", + "precursor", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "do" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "osteoclast-specific", + "deficiency", + "in", + "Dnmt3a" + ] + } + } + ] + }, + { + "PMID": "25581518", + "TEXT": "Paracrine-acting proteins are emerging as a central mechanism by which bone marrow cell-based therapies improve tissue repair and heart function after myocardial infarction (MI). We carried out a bioinformatic secretome analysis in bone marrow cells from patients with acute MI to identify novel secreted proteins with therapeutic potential. Functional screens revealed a secreted protein encoded by an open reading frame on chromosome 19 (C19orf10) that promotes cardiac myocyte survival and angiogenesis. We show that bone marrow-derived monocytes and macrophages produce this protein endogenously to protect and repair the heart after MI, and we named it myeloid-derived growth factor (MYDGF). Whereas Mydgf-deficient mice develop larger infarct scars and more severe contractile dysfunction compared to wild-type mice, treatment with recombinant Mydgf reduces scar size and contractile dysfunction after MI. This study is the first to assign a biological function to MYDGF, and it may serve as a prototypical example for the development of protein-based therapies for ischemic tissue repair.", + "TAG_DATA": [ + "100, Mydgf-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "101, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "100, Mydgf-deficient ['l0']", + "101, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mydgf-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "25485910", + "TEXT": "Activating mutations in genes encoding G protein α (Gα) subunits occur in 4-5% of all human cancers, but oncogenic alterations in Gβ subunits have not been defined. Here we demonstrate that recurrent mutations in the Gβ proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling. Multiple mutations in GNB1 affect the protein interface that binds Gα subunits as well as downstream effectors and disrupt Gα interactions with the Gβγ dimer. Different mutations in Gβ proteins clustered partly on the basis of lineage; for example, all 11 GNB1 K57 mutations were in myeloid neoplasms, and seven of eight GNB1 I80 mutations were in B cell neoplasms. Expression of patient-derived GNB1 variants in Cdkn2a-deficient mouse bone marrow followed by transplantation resulted in either myeloid or B cell malignancies. In vivo treatment with the dual PI3K-mTOR inhibitor BEZ235 suppressed GNB1-induced signaling and markedly increased survival. In several human tumors, mutations in the gene encoding GNB1 co-occurred with oncogenic kinase alterations, including the BCR-ABL fusion protein, the V617F substitution in JAK2 and the V600K substitution in BRAF. Coexpression of patient-derived GNB1 variants with these mutant kinases resulted in inhibitor resistance in each context. Thus, GNB1 and GNB2 alterations confer transformed and resistance phenotypes across a range of human tumors and may be targetable with inhibitors of G protein signaling.", + "TAG_DATA": [ + "110, of {'perturbing_action': 'I-other'}", + "111, patient-derived {'perturbing_action': 'I-other'}", + "112, GNB1 {'perturbing_action': 'I-other'}", + "113, variants {'perturbing_action': 'I-other'}", + "115, Cdkn2a-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "116, mouse {'context': 'B-tissue/organ'}", + "117, bone {'context': 'I-tissue/organ'}", + "118, marrow {'context': 'I-tissue/organ'}", + "125, myeloid {'context': 'B-neoplasm'}", + "126, or {'context': 'I-neoplasm'}", + "127, B {'context': 'I-neoplasm'}", + "128, cell {'context': 'I-neoplasm'}", + "129, malignancies. {'context': 'I-neoplasm'}", + "130, In {'context': 'B-in vivo'}", + "131, vivo {'context': 'I-in vivo'}", + "135, dual {'perturbing_action': 'I-pharmacological inhibition'}", + "136, PI3K-mTOR {'perturbing_action': 'I-pharmacological inhibition'}", + "137, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "138, BEZ235 {'perturbing_action': 'I-pharmacological inhibition'}", + "148, human {'context': 'B-neoplasm'}", + "177, Coexpression {'perturbing_action': 'B-gene gain-of-function'}", + "178, of {'perturbing_action': 'I-other'}", + "179, patient-derived {'perturbing_action': 'I-other'}", + "180, GNB1 {'perturbing_action': 'I-other'}", + "181, variants {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "109, Expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "110, of ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "111, patient-derived ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "112, GNB1 ['l2', 'l16', 'l29', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "113, variants ['l3', 'l17', 'l30', 'l42', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "115, Cdkn2a-deficient ['l4', 'l18', 'l31', 'l43', 'l54', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "116, mouse ['l5', 'l19', 'l32', 'l44', 'l55', 'l65', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "117, bone ['l6', 'l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "118, marrow ['l7', 'l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l82', 'l88', 'l89', 'l90', 'l91', 'l92']", + "125, myeloid ['l8', 'l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l83', 'l88', 'l93', 'l94', 'l95', 'l96']", + "126, or ['l9', 'l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l84', 'l89', 'l93', 'l97', 'l98', 'l99']", + "127, B ['l10', 'l24', 'l37', 'l49', 'l60', 'l70', 'l79', 'l85', 'l90', 'l94', 'l97', 'l100', 'l101']", + "128, cell ['l11', 'l25', 'l38', 'l50', 'l61', 'l71', 'l80', 'l86', 'l91', 'l95', 'l98', 'l100', 'l102']", + "129, malignancies. ['l12', 'l26', 'l39', 'l51', 'l62', 'l72', 'l81', 'l87', 'l92', 'l96', 'l99', 'l101', 'l102']", + "130, In ['l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "131, vivo ['l103', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "135, dual ['l104', 'l110', 'l116', 'l117', 'l118', 'l119', 'l120']", + "136, PI3K-mTOR ['l105', 'l111', 'l116', 'l121', 'l122', 'l123', 'l124']", + "137, inhibitor ['l106', 'l112', 'l117', 'l121', 'l125', 'l126', 'l127']", + "138, BEZ235 ['l107', 'l113', 'l118', 'l122', 'l125', 'l128', 'l129']", + "148, human ['l13', 'l27', 'l40', 'l52', 'l63', 'l73', 'l108', 'l114', 'l119', 'l123', 'l126', 'l128', 'l130']", + "149, tumors, ['l14', 'l28', 'l41', 'l53', 'l64', 'l74', 'l109', 'l115', 'l120', 'l124', 'l127', 'l129', 'l130']", + "177, Coexpression ['l131', 'l132', 'l133', 'l134']", + "178, of ['l131', 'l135', 'l136', 'l137']", + "179, patient-derived ['l132', 'l135', 'l138', 'l139']", + "180, GNB1 ['l133', 'l136', 'l138', 'l140']", + "181, variants ['l134', 'l137', 'l139', 'l140']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "of", + "patient-derived", + "GNB1", + "variants" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "bone", + "marrow" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "of", + "patient-derived", + "GNB1", + "variants" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "myeloid", + "or", + "B", + "cell", + "malignancies.", + "human" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cdkn2a-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "bone", + "marrow" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cdkn2a-deficient" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "myeloid", + "or", + "B", + "cell", + "malignancies.", + "human" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "dual", + "PI3K-mTOR", + "inhibitor", + "BEZ235" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "dual", + "PI3K-mTOR", + "inhibitor", + "BEZ235" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human" + ] + } + } + ] + }, + { + "PMID": "25419708", + "TEXT": "α4β7 integrin-expressing CD4(+) T cells preferentially traffic to gut-associated lymphoid tissue (GALT) and have a key role in HIV and simian immunodeficiency virus (SIV) pathogenesis. We show here that the administration of an anti-α4β7 monoclonal antibody just prior to and during acute infection protects rhesus macaques from transmission following repeated low-dose intravaginal challenges with SIVmac251. In treated animals that became infected, the GALT was significantly protected from infection and CD4(+) T cell numbers were maintained in both the blood and the GALT. Thus, targeting α4β7 reduces mucosal transmission of SIV in macaques.", + "TAG_DATA": [ + "44, rhesus {'context': 'B-organism'}", + "45, macaques {'context': 'I-organism'}", + "57, animals {'context': 'B-organism'}", + "62, GALT {'context': 'B-tissue/organ'}", + "69, CD4(+) {'context': 'B-cells'}", + "70, T {'context': 'I-cells'}", + "71, cell {'context': 'I-cells'}", + "83, targeting {'perturbing_action': 'B-other'}", + "84, α4β7 {'perturbing_action': 'I-other'}", + "91, macaques. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "44, rhesus ['l0']", + "45, macaques ['l0']", + "57, animals ['l1', 'l2', 'l3', 'l4']", + "62, GALT ['l1', 'l5', 'l6', 'l7']", + "69, CD4(+) ['l2', 'l5', 'l8', 'l9']", + "70, T ['l3', 'l6', 'l8', 'l10']", + "71, cell ['l4', 'l7', 'l9', 'l10']", + "83, targeting ['l11', 'l12']", + "84, α4β7 ['l11', 'l13']", + "91, macaques. ['l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "targeting", + "α4β7" + ] + }, + "context": { + "val": "organism", + "words": [ + "macaques." + ] + } + } + ] + }, + { + "PMID": "25344739", + "TEXT": "Lymph node biopsy is employed in many cancer surgeries to identify metastatic disease and to determine cancer stage, yet morbidity and diagnostic delays associated with lymph node biopsy could be avoided if noninvasive imaging of nodal involvement were reliable. Molecular imaging has potential in this regard; however, variable delivery and nonspecific uptake of imaging tracers have made conventional approaches ineffective clinically. Here we present a method of correcting for nonspecific uptake with injection of a second untargeted tracer that allows for quantification of tumor burden in lymph nodes. We confirmed the approach in an athymic mouse model of metastatic human breast cancer by targeting epidermal growth factor receptor, a cell surface receptor overexpressed by many cancers. We observed a significant correlation between in vivo (dual-tracer) and ex vivo measures of tumor burden (r = 0.97, P < 0.01), with an ultimate sensitivity of approximately 200 cells (potentially more sensitive than conventional lymph node biopsy).", + "TAG_DATA": [ + "94, athymic {'context': 'B-organism'}", + "95, mouse {'context': 'I-organism'}", + "96, model {'context': 'I-neoplasm'}", + "97, of {'context': 'I-neoplasm'}", + "98, metastatic {'context': 'I-neoplasm'}", + "99, human {'context': 'I-neoplasm'}", + "100, breast {'context': 'I-neoplasm'}", + "101, cancer {'context': 'I-neoplasm'}", + "105, growth {'perturbing_action': 'I-rnai/knockdown'}", + "106, factor {'perturbing_action': 'I-rnai/knockdown'}", + "107, receptor, {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "94, athymic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "95, mouse ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "96, model ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "97, of ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "98, metastatic ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "99, human ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "100, breast ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "101, cancer ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "104, epidermal ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "105, growth ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "106, factor ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "107, receptor, ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "athymic", + "mouse" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "growth", + "factor", + "receptor," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "model", + "of", + "metastatic", + "human", + "breast", + "cancer" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "growth", + "factor", + "receptor," + ] + } + } + ] + }, + { + "PMID": "25326800", + "TEXT": "Neurofibrillary tangles (NFTs), composed of truncated and hyperphosphorylated tau, are a common feature of numerous aging-related neurodegenerative diseases, including Alzheimer's disease (AD). However, the molecular mechanisms mediating tau truncation and aggregation during aging remain elusive. Here we show that asparagine endopeptidase (AEP), a lysosomal cysteine proteinase, is activated during aging and proteolytically degrades tau, abolishes its microtubule assembly function, induces tau aggregation and triggers neurodegeneration. AEP is upregulated and active during aging and is activated in human AD brain and tau P301S-transgenic mice with synaptic pathology and behavioral impairments, leading to tau truncation in NFTs. Tau P301S-transgenic mice with deletion of the gene encoding AEP show substantially reduced tau hyperphosphorylation, less synapse loss and rescue of impaired hippocampal synaptic function and cognitive deficits. Mice infected with adeno-associated virus encoding an uncleavable tau mutant showed attenuated pathological and behavioral defects compared to mice injected with adeno-associated virus encoding tau P301S. Together, these observations indicate that AEP acts as a crucial mediator of tau-related clinical and neuropathological changes. Inhibition of AEP may be therapeutically useful for treating tau-mediated neurodegenerative diseases.", + "TAG_DATA": [ + "80, tau {'perturbing_action': 'B-gene gain-of-function'}", + "81, P301S-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "82, mice {'context': 'B-organism'}", + "95, Tau {'perturbing_action': 'B-gene gain-of-function'}", + "96, P301S-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "97, mice {'context': 'B-organism'}", + "99, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "100, of {'perturbing_action': 'I-gene loss-of-function'}", + "101, the {'perturbing_action': 'I-gene loss-of-function'}", + "102, gene {'perturbing_action': 'I-gene loss-of-function'}", + "103, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "104, AEP {'perturbing_action': 'I-gene loss-of-function'}", + "123, Mice {'context': 'B-organism'}", + "141, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "80, tau ['l0', 'l1']", + "81, P301S-transgenic ['l0', 'l2']", + "82, mice ['l1', 'l2']", + "95, Tau ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "96, P301S-transgenic ['l3', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "97, mice ['l4', 'l11', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "99, deletion ['l5', 'l12', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "100, of ['l6', 'l13', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32']", + "101, the ['l7', 'l14', 'l20', 'l25', 'l29', 'l33', 'l34', 'l35']", + "102, gene ['l8', 'l15', 'l21', 'l26', 'l30', 'l33', 'l36', 'l37']", + "103, encoding ['l9', 'l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l38']", + "104, AEP ['l10', 'l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l38']", + "123, Mice ['l39']", + "141, mice ['l39']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "tau", + "P301S-transgenic", + "Tau" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "gene", + "encoding", + "AEP" + ] + } + } + ] + }, + { + "PMID": "25261994", + "TEXT": "Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months. PDAC has been linked with obesity and glucose intolerance, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from individuals with pancreatic cancer (cases) and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched-chain amino acids (BCAAs) are associated with a greater than twofold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years before diagnosis, when occult disease is probably present. We show that plasma BCAAs are also elevated in mice with early-stage pancreatic cancers driven by mutant Kras expression but not in mice with Kras-driven tumors in other tissues, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early-stage disease. Together, these findings suggest that increased whole-body protein breakdown is an early event in development of PDAC.", + "TAG_DATA": [ + "135, mice {'context': 'B-organism'}", + "137, early-stage {'context': 'B-neoplasm'}", + "138, pancreatic {'context': 'I-neoplasm'}", + "139, cancers {'context': 'I-neoplasm'}", + "142, mutant {'perturbing_action': 'B-other'}", + "143, Kras {'perturbing_action': 'I-other'}", + "144, expression {'perturbing_action': 'I-other'}", + "148, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "135, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "137, early-stage ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "138, pancreatic ['l1', 'l7', 'l12', 'l13', 'l14', 'l15']", + "139, cancers ['l2', 'l8', 'l12', 'l16', 'l17', 'l18']", + "142, mutant ['l3', 'l9', 'l13', 'l16', 'l19', 'l20', 'l21', 'l22']", + "143, Kras ['l4', 'l10', 'l14', 'l17', 'l19', 'l23', 'l24', 'l25']", + "144, expression ['l5', 'l11', 'l15', 'l18', 'l20', 'l23', 'l26', 'l27']", + "148, mice ['l21', 'l24', 'l26', 'l28']", + "151, tumors ['l6', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "Kras", + "expression" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "early-stage", + "pancreatic", + "cancers" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "Kras", + "expression" + ] + } + } + ] + }, + { + "PMID": "25198045", + "TEXT": "Disrupted differentiation of Schwann cells contributes to axonal loss in a rat model of Charcot-Marie-Tooth 1A neuropathy. Early neuregulin-1 treatment promotes Schwann cell differentiation, preserves axons and restores nerve function in this model.", + "TAG_DATA": [ + "20, promotes {'effect': 'B-positive'}", + "21, Schwann {'context': 'B-cells'}", + "22, cell {'context': 'I-cells'}", + "23, differentiation, {'phenotype': 'B-differentiation'}", + "25, axons {'context': 'B-cells'}", + "28, nerve {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "20, promotes ['l0', 'l1', 'l2', 'l3', 'l4']", + "21, Schwann ['l0', 'l5', 'l6', 'l7', 'l8']", + "22, cell ['l1', 'l5', 'l9', 'l10', 'l11']", + "23, differentiation, ['l2', 'l6', 'l9', 'l12', 'l13']", + "25, axons ['l3', 'l7', 'l10', 'l12', 'l14']", + "28, nerve ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "cells", + "words": [ + "Schwann", + "cell", + "axons" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "nerve" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Schwann", + "cell", + "axons" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "nerve" + ] + } + } + ] + }, + { + "PMID": "25194569", + "TEXT": "Diminished regenerative capacity of skeletal muscle occurs during adulthood. We identified a reduction in the intrinsic capacity of mouse adult satellite cells to contribute to muscle regeneration and repopulation of the niche. Gene expression analysis identified higher expression of JAK-STAT signaling targets in 3-week [corrected] 18-month-old mice [corrected]. Knockdown of Jak2 or Stat3 significantly stimulated symmetric satellite stem cell divisions on cultured myofibers. Genetic knockdown of Jak2 or Stat3 expression in prospectively isolated satellite cells markedly enhanced their ability to repopulate the satellite cell niche after transplantation into regenerating tibialis anterior muscle. Pharmacological inhibition of Jak2 and Stat3 activity similarly stimulated symmetric expansion of satellite cells in vitro and their engraftment in vivo. Intramuscular injection of these drugs resulted in a marked enhancement of muscle repair and force generation after cardiotoxin injury. Together these results reveal age-related intrinsic properties that functionally distinguish satellite cells and suggest a promising therapeutic avenue for the treatment of muscle-wasting diseases.", + "TAG_DATA": [ + "48, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "49, of {'perturbing_action': 'I-rnai/knockdown'}", + "50, Jak2 {'perturbing_action': 'I-rnai/knockdown'}", + "51, or {'perturbing_action': 'I-rnai/knockdown'}", + "52, Stat3 {'perturbing_action': 'I-rnai/knockdown'}", + "56, satellite {'context': 'B-cells'}", + "57, stem {'context': 'I-cells'}", + "58, cell {'context': 'I-cells'}", + "61, cultured {'context': 'B-cells'}", + "62, myofibers. {'context': 'I-cells'}", + "63, Genetic {'perturbing_action': 'B-rnai/knockdown'}", + "64, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "65, of {'perturbing_action': 'I-rnai/knockdown'}", + "66, Jak2 {'perturbing_action': 'I-rnai/knockdown'}", + "67, or {'perturbing_action': 'I-rnai/knockdown'}", + "68, Stat3 {'perturbing_action': 'I-rnai/knockdown'}", + "69, expression {'perturbing_action': 'I-rnai/knockdown'}", + "73, satellite {'context': 'B-cells'}", + "74, cells {'context': 'I-cells'}", + "88, regenerating {'context': 'B-tissue/organ'}", + "89, tibialis {'context': 'I-tissue/organ'}", + "90, anterior {'context': 'I-tissue/organ'}", + "91, muscle. {'context': 'I-tissue/organ'}", + "92, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "93, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "94, of {'perturbing_action': 'I-pharmacological inhibition'}", + "95, Jak2 {'perturbing_action': 'I-pharmacological inhibition'}", + "96, and {'perturbing_action': 'I-pharmacological inhibition'}", + "97, Stat3 {'perturbing_action': 'I-pharmacological inhibition'}", + "98, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "104, satellite {'context': 'B-cells'}", + "105, cells {'context': 'I-cells'}", + "106, in {'context': 'B-in vitro'}", + "107, vitro {'context': 'I-in vitro'}", + "111, in {'context': 'B-in vivo'}", + "112, vivo. {'context': 'I-in vivo'}", + "124, muscle {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "48, Knockdown ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "49, of ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "50, Jak2 ['l1', 'l15', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "51, or ['l2', 'l16', 'l31', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "52, Stat3 ['l3', 'l17', 'l32', 'l47', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "56, satellite ['l4', 'l18', 'l33', 'l48', 'l59', 'l70', 'l71', 'l72', 'l73']", + "57, stem ['l5', 'l19', 'l34', 'l49', 'l60', 'l70', 'l74', 'l75', 'l76']", + "58, cell ['l6', 'l20', 'l35', 'l50', 'l61', 'l71', 'l74', 'l77', 'l78']", + "61, cultured ['l7', 'l21', 'l36', 'l51', 'l62', 'l72', 'l75', 'l77', 'l79', 'l80', 'l81', 'l82']", + "62, myofibers. ['l8', 'l22', 'l37', 'l52', 'l63', 'l73', 'l76', 'l78', 'l79', 'l83', 'l84', 'l85', 'l86', 'l87']", + "63, Genetic ['l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "64, knockdown ['l88', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "65, of ['l89', 'l104', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "66, Jak2 ['l90', 'l105', 'l118', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "67, or ['l38', 'l91', 'l106', 'l119', 'l131', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "68, Stat3 ['l23', 'l39', 'l92', 'l107', 'l120', 'l132', 'l143', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "69, expression ['l24', 'l40', 'l93', 'l108', 'l121', 'l133', 'l144', 'l153', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "73, satellite ['l9', 'l25', 'l41', 'l53', 'l64', 'l83', 'l94', 'l109', 'l122', 'l134', 'l145', 'l154', 'l162', 'l170', 'l171', 'l172', 'l173', 'l174']", + "74, cells ['l10', 'l26', 'l42', 'l54', 'l65', 'l80', 'l84', 'l95', 'l110', 'l123', 'l135', 'l146', 'l155', 'l163', 'l170', 'l175', 'l176', 'l177', 'l178']", + "88, regenerating ['l11', 'l27', 'l43', 'l55', 'l66', 'l96', 'l111', 'l124', 'l136', 'l147', 'l156', 'l164', 'l171', 'l175', 'l179', 'l180', 'l181']", + "89, tibialis ['l12', 'l28', 'l44', 'l56', 'l67', 'l85', 'l97', 'l112', 'l125', 'l137', 'l148', 'l157', 'l165', 'l172', 'l176', 'l179', 'l182', 'l183']", + "90, anterior ['l13', 'l29', 'l45', 'l57', 'l68', 'l81', 'l86', 'l98', 'l113', 'l126', 'l138', 'l149', 'l158', 'l166', 'l173', 'l177', 'l180', 'l182', 'l184']", + "91, muscle. ['l14', 'l30', 'l46', 'l58', 'l69', 'l82', 'l87', 'l99', 'l114', 'l127', 'l139', 'l150', 'l159', 'l167', 'l174', 'l178', 'l181', 'l183', 'l184']", + "92, Pharmacological ['l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197']", + "93, inhibition ['l185', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208']", + "94, of ['l186', 'l198', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218']", + "95, Jak2 ['l187', 'l199', 'l209', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227']", + "96, and ['l188', 'l200', 'l210', 'l219', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235']", + "97, Stat3 ['l189', 'l201', 'l211', 'l220', 'l228', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242']", + "98, activity ['l190', 'l202', 'l212', 'l221', 'l229', 'l236', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248']", + "104, satellite ['l100', 'l115', 'l128', 'l140', 'l151', 'l160', 'l168', 'l191', 'l203', 'l213', 'l222', 'l230', 'l237', 'l243', 'l249', 'l250', 'l251', 'l252', 'l253']", + "105, cells ['l101', 'l116', 'l129', 'l141', 'l152', 'l161', 'l169', 'l192', 'l204', 'l214', 'l223', 'l231', 'l238', 'l244', 'l249', 'l254', 'l255']", + "106, in ['l102', 'l193', 'l205', 'l215', 'l224', 'l232', 'l239', 'l245', 'l250', 'l254', 'l256', 'l257', 'l258']", + "107, vitro ['l103', 'l117', 'l130', 'l142', 'l194', 'l206', 'l216', 'l225', 'l233', 'l240', 'l246', 'l251', 'l255', 'l256', 'l259', 'l260']", + "111, in ['l195', 'l207', 'l217', 'l226', 'l234', 'l241', 'l247', 'l252', 'l257', 'l259', 'l261']", + "112, vivo. ['l196', 'l208', 'l218', 'l227', 'l235', 'l242', 'l248', 'l253', 'l258', 'l260', 'l261']", + "124, muscle ['l197']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "Jak2", + "or", + "Stat3", + "Genetic", + "knockdown", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "satellite", + "stem", + "cell", + "cultured", + "myofibers.", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "Jak2", + "or", + "Stat3", + "Genetic", + "knockdown", + "expression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "regenerating", + "tibialis", + "anterior", + "muscle." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Genetic", + "knockdown", + "of", + "Jak2" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "Jak2", + "and", + "Stat3", + "activity" + ] + }, + "context": { + "val": "cells", + "words": [ + "satellite", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "Jak2", + "and", + "Stat3", + "activity" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "Jak2", + "and", + "Stat3", + "activity" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscle" + ] + } + } + ] + }, + { + "PMID": "25064128", + "TEXT": "The circadian system is an important regulator of immune function. Human inflammatory lung diseases frequently show time-of-day variation in symptom severity and lung function, but the mechanisms and cell types underlying these effects remain unclear. We show that pulmonary antibacterial responses are modulated by a circadian clock within epithelial club (Clara) cells. These drive circadian neutrophil recruitment to the lung via the chemokine CXCL5. Genetic ablation of the clock gene Bmal1 (also called Arntl or MOP3) in bronchiolar cells disrupts rhythmic Cxcl5 expression, resulting in exaggerated inflammatory responses to lipopolysaccharide and an impaired host response to Streptococcus pneumoniae infection. Adrenalectomy blocks rhythmic inflammatory responses and the circadian regulation of CXCL5, suggesting a key role for the adrenal axis in driving CXCL5 expression and pulmonary neutrophil recruitment. Glucocorticoid receptor occupancy at the Cxcl5 locus shows circadian oscillations, but this is disrupted in mice with bronchiole-specific ablation of Bmal1, leading to enhanced CXCL5 expression despite normal corticosteroid secretion. The therapeutic effects of the synthetic glucocorticoid dexamethasone depend on intact clock function in the airway. We now define a regulatory mechanism that links the circadian clock and glucocorticoid hormones to control both time-of-day variation and the magnitude of pulmonary inflammation and responses to bacterial infection.", + "TAG_DATA": [ + "64, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "65, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "66, of {'perturbing_action': 'I-gene loss-of-function'}", + "67, the {'perturbing_action': 'I-gene loss-of-function'}", + "68, clock {'perturbing_action': 'I-gene loss-of-function'}", + "69, gene {'perturbing_action': 'I-gene loss-of-function'}", + "70, Bmal1 {'perturbing_action': 'I-gene loss-of-function'}", + "71, (also {'perturbing_action': 'I-gene loss-of-function'}", + "72, called {'perturbing_action': 'I-gene loss-of-function'}", + "73, Arntl {'perturbing_action': 'I-gene loss-of-function'}", + "75, MOP3) {'perturbing_action': 'I-gene loss-of-function'}", + "77, bronchiolar {'context': 'B-cells'}", + "78, cells {'context': 'I-cells'}", + "141, mice {'context': 'B-organism'}", + "143, bronchiole-specific {'perturbing_action': 'B-gene loss-of-function'}", + "144, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "145, of {'perturbing_action': 'I-gene loss-of-function'}", + "146, Bmal1, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "64, Genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "65, ablation ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "66, of ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "67, the ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "68, clock ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "69, gene ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "70, Bmal1 ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "71, (also ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "72, called ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "73, Arntl ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "75, MOP3) ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "77, bronchiolar ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "78, cells ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "141, mice ['l78', 'l79', 'l80', 'l81']", + "143, bronchiole-specific ['l78', 'l82', 'l83', 'l84']", + "144, ablation ['l79', 'l82', 'l85', 'l86']", + "145, of ['l80', 'l83', 'l85', 'l87']", + "146, Bmal1, ['l81', 'l84', 'l86', 'l87']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "ablation", + "of", + "the", + "clock", + "gene", + "Bmal1", + "(also", + "called", + "Arntl", + "MOP3)" + ] + }, + "context": { + "val": "cells", + "words": [ + "bronchiolar", + "cells" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "bronchiole-specific", + "ablation", + "of", + "Bmal1," + ] + } + } + ] + }, + { + "PMID": "24999940", + "TEXT": "Stress has long been thought to be a major contributing factor to cardiovascular disease, although little is known about the underlying cellular mechanisms. A new study illustrates that chronic stress promotes hematopoietic stem cell proliferation in bone marrow, leading to increased leukocyte production, circulation, and recruitment to the vasculature.", + "TAG_DATA": [ + "30, promotes {'effect': 'B-positive'}", + "31, hematopoietic {'context': 'B-cells'}", + "32, stem {'context': 'I-cells'}", + "33, cell {'context': 'I-cells'}", + "34, proliferation {'phenotype': 'B-proliferation'}", + "36, bone {'context': 'B-tissue/organ'}", + "37, marrow, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "30, promotes ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "31, hematopoietic ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "32, stem ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "33, cell ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "34, proliferation ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "36, bone ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "37, marrow, ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "bone", + "marrow," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "bone", + "marrow," + ] + } + } + ] + }, + { + "PMID": "24997608", + "TEXT": "It is well known that the ω-3 fatty acids (ω-3-FAs; also known as n-3 fatty acids) can exert potent anti-inflammatory effects. Commonly consumed as fish products, dietary supplements and pharmaceuticals, ω-3-FAs have a number of health benefits ascribed to them, including reduced plasma triglyceride levels, amelioration of atherosclerosis and increased insulin sensitivity. We reported that Gpr120 is the functional receptor for these fatty acids and that ω-3-FAs produce robust anti-inflammatory, insulin-sensitizing effects, both in vivo and in vitro, in a Gpr120-dependent manner. Indeed, genetic variants that predispose to obesity and diabetes have been described in the gene encoding GPR120 in humans (FFAR4). However, the amount of fish oils that would have to be consumed to sustain chronic agonism of Gpr120 is too high to be practical, and, thus, a high-affinity small-molecule Gpr120 agonist would be of potential clinical benefit. Accordingly, Gpr120 is a widely studied drug discovery target within the pharmaceutical industry. Gpr40 is another lipid-sensing G protein-coupled receptor, and it has been difficult to identify compounds with a high degree of selectivity for Gpr120 over Gpr40 (ref. 11). Here we report that a selective high-affinity, orally available, small-molecule Gpr120 agonist (cpdA) exerts potent anti-inflammatory effects on macrophages in vitro and in obese mice in vivo. Gpr120 agonist treatment of high-fat diet-fed obese mice causes improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that Gpr120 agonists could become new insulin-sensitizing drugs for the treatment of type 2 diabetes and other human insulin-resistant states in the future.", + "TAG_DATA": [ + "197, macrophages {'context': 'B-cells'}", + "198, in {'context': 'B-in vitro'}", + "199, vitro {'context': 'I-in vitro'}", + "202, obese {'context': 'B-organism'}", + "203, mice {'context': 'I-organism'}", + "204, in {'context': 'B-in vivo'}", + "205, vivo. {'context': 'I-in vivo'}", + "206, Gpr120 {'perturbing_action': 'B-pharmacological augmentation'}", + "207, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "208, treatment {'perturbing_action': 'I-pharmacological augmentation'}", + "212, obese {'context': 'B-organism'}", + "213, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "197, macrophages ['l0', 'l1', 'l2', 'l3', 'l4']", + "198, in ['l0', 'l5', 'l6', 'l7']", + "199, vitro ['l1', 'l5', 'l8', 'l9', 'l10']", + "202, obese ['l2', 'l6', 'l8', 'l11', 'l12', 'l13']", + "203, mice ['l3', 'l7', 'l9', 'l11', 'l14', 'l15']", + "204, in ['l4', 'l10', 'l12', 'l14', 'l16']", + "205, vivo. ['l13', 'l15', 'l16']", + "206, Gpr120 ['l17', 'l18', 'l19', 'l20']", + "207, agonist ['l17', 'l21', 'l22', 'l23']", + "208, treatment ['l18', 'l21', 'l24', 'l25']", + "212, obese ['l19', 'l22', 'l24', 'l26']", + "213, mice ['l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Gpr120", + "agonist", + "treatment" + ] + }, + "context": { + "val": "organism", + "words": [ + "obese", + "mice" + ] + } + } + ] + }, + { + "PMID": "24784231", + "TEXT": "Gout is characterized by an acute inflammatory reaction and the accumulation of neutrophils in response to monosodium urate (MSU) crystals. Inflammation resolves spontaneously within a few days, although MSU crystals can still be detected in the synovial fluid and affected tissues. Here we report that neutrophils recruited to sites of inflammation undergo oxidative burst and form neutrophil extracellular traps (NETs). Under high neutrophil densities, these NETs aggregate and degrade cytokines and chemokines via serine proteases. Tophi, the pathognomonic structures of chronic gout, share characteristics with aggregated NETs, and MSU crystals can induce NETosis and aggregation of NETs. In individuals with impaired NETosis, MSU crystals induce uncontrolled production of inflammatory mediators from neutrophils and persistent inflammation. Furthermore, in models of neutrophilic inflammation, NETosis-deficient mice develop exacerbated and chronic disease that can be reduced by adoptive transfer of aggregated NETs. These findings suggest that aggregated NETs promote the resolution of neutrophilic inflammation by degrading cytokines and chemokines and disrupting neutrophil recruitment and activation.", + "TAG_DATA": [ + "121, NETosis-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "122, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "121, NETosis-deficient ['l0']", + "122, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NETosis-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "24705334", + "TEXT": "Cardiac failure is the most common cause of mortality in Friedreich's ataxia (FRDA), a mitochondrial disease characterized by neurodegeneration, hypertrophic cardiomyopathy and diabetes. FRDA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in the biosynthesis of iron-sulfur (Fe-S) clusters. Impaired mitochondrial oxidative phosphorylation, bioenergetics imbalance, deficit of Fe-S cluster enzymes and mitochondrial iron overload occur in the myocardium of individuals with FRDA. No treatment exists as yet for FRDA cardiomyopathy. A conditional mouse model with complete frataxin deletion in cardiac and skeletal muscle (Mck-Cre-Fxn(L3/L-) mice) recapitulates most features of FRDA cardiomyopathy, albeit with a more rapid and severe course. Here we show that adeno-associated virus rh10 vector expressing human FXN injected intravenously in these mice fully prevented the onset of cardiac disease. Moreover, later administration of the frataxin-expressing vector, after the onset of heart failure, was able to completely reverse the cardiomyopathy of these mice at the functional, cellular and molecular levels within a few days. Our results demonstrate that cardiomyocytes with severe energy failure and ultrastructure disorganization can be rapidly rescued and remodeled by gene therapy and establish the preclinical proof of concept for the potential of gene therapy in treating FRDA cardiomyopathy.", + "TAG_DATA": [ + "76, conditional {'context': 'B-organism'}", + "77, mouse {'context': 'B-organism'}", + "78, model {'context': 'I-organism'}", + "80, complete {'perturbing_action': 'B-gene loss-of-function'}", + "81, frataxin {'perturbing_action': 'I-gene loss-of-function'}", + "82, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "83, in {'perturbing_action': 'I-gene loss-of-function'}", + "84, cardiac {'perturbing_action': 'I-gene loss-of-function', 'context': 'B-tissue/organ'}", + "85, and {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "86, skeletal {'context': 'I-cells'}", + "87, muscle {'context': 'I-tissue/organ'}", + "108, adeno-associated {'perturbing_action': 'B-gene gain-of-function'}", + "109, virus {'perturbing_action': 'I-gene gain-of-function'}", + "110, rh10 {'perturbing_action': 'I-gene gain-of-function'}", + "111, vector {'perturbing_action': 'I-gene gain-of-function'}", + "112, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "113, human {'perturbing_action': 'I-gene gain-of-function'}", + "114, FXN {'perturbing_action': 'I-gene gain-of-function'}", + "119, mice {'context': 'B-organism'}", + "149, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "76, conditional ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "77, mouse ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "78, model ['l1', 'l11', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "80, complete ['l2', 'l12', 'l20', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "81, frataxin ['l3', 'l13', 'l21', 'l31', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "82, deletion ['l4', 'l14', 'l22', 'l32', 'l47', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "83, in ['l5', 'l15', 'l23', 'l33', 'l48', 'l62', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "84, cardiac ['l6', 'l16', 'l24', 'l34', 'l49', 'l63', 'l76', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "85, and ['l7', 'l17', 'l25', 'l35', 'l50', 'l64', 'l77', 'l89', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "86, skeletal ['l8', 'l18', 'l26', 'l36', 'l51', 'l65', 'l78', 'l90', 'l101', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "87, muscle ['l9', 'l19', 'l27', 'l37', 'l52', 'l66', 'l79', 'l91', 'l102', 'l112', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "89, mice) ['l38', 'l53', 'l67', 'l80', 'l92', 'l103', 'l113', 'l122', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "108, adeno-associated ['l39', 'l54', 'l68', 'l81', 'l93', 'l104', 'l114', 'l123', 'l131', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145']", + "109, virus ['l40', 'l55', 'l69', 'l82', 'l94', 'l105', 'l115', 'l124', 'l132', 'l139', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151']", + "110, rh10 ['l41', 'l56', 'l70', 'l83', 'l95', 'l106', 'l116', 'l125', 'l133', 'l140', 'l146', 'l152', 'l153', 'l154', 'l155', 'l156']", + "111, vector ['l42', 'l57', 'l71', 'l84', 'l96', 'l107', 'l117', 'l126', 'l134', 'l141', 'l147', 'l152', 'l157', 'l158', 'l159', 'l160']", + "112, expressing ['l43', 'l58', 'l72', 'l85', 'l97', 'l108', 'l118', 'l127', 'l135', 'l142', 'l148', 'l153', 'l157', 'l161', 'l162', 'l163']", + "113, human ['l28', 'l44', 'l59', 'l73', 'l86', 'l98', 'l109', 'l119', 'l128', 'l136', 'l143', 'l149', 'l154', 'l158', 'l161', 'l164', 'l165']", + "114, FXN ['l10', 'l29', 'l45', 'l60', 'l74', 'l87', 'l99', 'l110', 'l120', 'l129', 'l137', 'l144', 'l150', 'l155', 'l159', 'l162', 'l164', 'l166']", + "119, mice ['l30', 'l46', 'l61', 'l75', 'l88', 'l100', 'l111', 'l121', 'l130', 'l138', 'l145', 'l151', 'l156', 'l160', 'l163', 'l165', 'l166']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "conditional", + "mouse", + "model", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "complete", + "frataxin", + "deletion", + "in", + "cardiac", + "and" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cardiac", + "complete", + "frataxin", + "deletion", + "in", + "and" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "cardiac", + "muscle" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "and", + "complete", + "frataxin", + "deletion", + "in", + "cardiac" + ] + }, + "context": { + "val": "cells", + "words": [ + "and", + "skeletal" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "conditional", + "model", + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "FXN", + "human", + "adeno-associated", + "virus", + "rh10", + "vector", + "expressing" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "cardiac", + "muscle" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adeno-associated", + "virus", + "rh10", + "vector", + "expressing", + "human", + "FXN" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "and", + "skeletal" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adeno-associated", + "virus", + "rh10", + "vector", + "expressing", + "human", + "FXN" + ] + } + } + ] + }, + { + "PMID": "24681597", + "TEXT": "Kindlin-1 is an integrin tail binding protein that controls integrin activation. Mutations in the FERMT-1 gene, which encodes for Kindlin-1, lead to Kindler syndrome in man, which is characterized by skin blistering, premature skin aging and skin cancer of unknown etiology. Here we show that loss of Kindlin-1 in mouse keratinocytes recapitulates Kindler syndrome and also produces enlarged and hyperactive stem cell compartments, which lead to hyperthickened epidermis, ectopic hair follicle development and increased skin tumor susceptibility. Mechanistically, Kindlin-1 controls keratinocyte adhesion through β1-class integrins and proliferation and differentiation of cutaneous epithelial stem cells by promoting α(v)β(6) integrin-mediated transforming growth factor-β (TGF-β) activation and inhibiting Wnt-β-catenin signaling through integrin-independent regulation of Wnt ligand expression. Our findings assign Kindlin-1 the previously unknown and essential task of controlling cutaneous epithelial stem cell homeostasis by balancing TGF-β-mediated growth-inhibitory signals and Wnt-β-catenin-mediated growth-promoting signals.", + "TAG_DATA": [ + "45, loss {'perturbing_action': 'B-gene loss-of-function'}", + "46, of {'perturbing_action': 'I-gene loss-of-function'}", + "47, Kindlin-1 {'perturbing_action': 'I-gene loss-of-function'}", + "49, mouse {'context': 'B-cells'}", + "50, keratinocytes {'context': 'I-cells'}", + "74, skin {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}", + "79, controls {'effect': 'B-regulates'}", + "86, proliferation {'phenotype': 'B-proliferation'}", + "88, differentiation {'phenotype': 'B-differentiation'}", + "90, cutaneous {'context': 'B-cells'}", + "91, epithelial {'context': 'I-cells'}", + "92, stem {'context': 'I-cells'}", + "93, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "46, of ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "47, Kindlin-1 ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "49, mouse ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "50, keratinocytes ['l3', 'l14', 'l24', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "74, skin ['l4', 'l15', 'l25', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "79, controls ['l5', 'l16', 'l26', 'l44', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "86, proliferation ['l6', 'l17', 'l27', 'l35', 'l40', 'l45', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "88, differentiation ['l7', 'l18', 'l28', 'l36', 'l41', 'l46', 'l52', 'l57', 'l62', 'l63', 'l64', 'l65']", + "90, cutaneous ['l8', 'l19', 'l29', 'l47', 'l53', 'l58', 'l62', 'l66', 'l67', 'l68']", + "91, epithelial ['l9', 'l20', 'l30', 'l48', 'l54', 'l59', 'l63', 'l66', 'l69', 'l70']", + "92, stem ['l10', 'l21', 'l31', 'l37', 'l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l71']", + "93, cells ['l11', 'l22', 'l32', 'l38', 'l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l71']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Kindlin-1" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "keratinocytes", + "cutaneous", + "epithelial", + "stem", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Kindlin-1" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "skin" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Kindlin-1" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "skin" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "skin" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "skin" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Kindlin-1" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "controls" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Kindlin-1" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Kindlin-1" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "keratinocytes", + "cutaneous", + "epithelial", + "stem", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "skin" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "keratinocytes", + "cutaneous", + "epithelial", + "stem", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "keratinocytes", + "cutaneous", + "epithelial", + "stem", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "skin" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "controls" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "skin" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "controls" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "skin" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "skin" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "controls" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "controls" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "controls" + ] + }, + "context": { + "val": "cells", + "words": [ + "cutaneous", + "epithelial", + "stem", + "cells" + ] + } + } + ] + }, + { + "PMID": "24531377", + "TEXT": "The defective generation or function of regulatory T (Treg) cells in autoimmune disease contributes to chronic inflammation and tissue injury. We report the identification of FoxA1 as a transcription factor in T cells that, after ectopic expression, confers suppressive properties in a newly identified Treg cell population, herein called FoxA1(+) Treg cells. FoxA1 bound to the Pdl1 promoter, inducing programmed cell death ligand 1 (Pd-l1) expression, which was essential for the FoxA1(+) Treg cells to kill activated T cells. FoxA1(+) Treg cells develop primarily in the central nervous system in response to autoimmune inflammation, have a distinct transcriptional profile and are CD4(+)FoxA1(+)CD47(+)CD69(+)PD-L1(hi)FoxP3(-). Adoptive transfer of stable FoxA1(+) Treg cells inhibited experimental autoimmune encephalomyelitis in a FoxA1-and Pd-l1-dependent manner. The development of FoxA1(+) Treg cells is induced by interferon-β (IFN-β) and requires T cell-intrinsic IFN-α/β receptor (Ifnar) signaling, as the frequency of FoxA1(+) Treg cells was reduced in Ifnb(-/-) and Ifnar(-/-) mice. In individuals with relapsing-remitting multiple sclerosis, clinical response to treatment with IFN-β was associated with an increased frequency of suppressive FoxA1(+) Treg cells in the blood. These findings suggest that FoxA1 is a lineage-specification factor that is induced by IFN-β and supports the differentiation and suppressive function of FoxA1(+) Treg cells.", + "TAG_DATA": [ + "106, FoxA1(+) {'context': 'I-cells'}", + "107, Treg {'context': 'I-cells'}", + "108, cells {'context': 'I-cells'}", + "121, FoxA1(+) {'context': 'B-cells'}", + "122, Treg {'context': 'I-cells'}", + "141, FoxA1(+) {'context': 'B-cells'}", + "142, Treg {'context': 'I-cells'}", + "143, cells {'context': 'I-cells'}", + "147, Ifnb(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "149, Ifnar(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "150, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "106, FoxA1(+) ['l0', 'l1', 'l2', 'l3']", + "107, Treg ['l0', 'l4', 'l5', 'l6']", + "108, cells ['l1', 'l4', 'l7']", + "121, FoxA1(+) ['l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "122, Treg ['l2', 'l5', 'l8', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "123, cells ['l3', 'l6', 'l7', 'l9', 'l16', 'l22', 'l23']", + "141, FoxA1(+) ['l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28']", + "142, Treg ['l11', 'l18', 'l22', 'l24', 'l29', 'l30', 'l31', 'l32']", + "143, cells ['l12', 'l19', 'l23', 'l25', 'l29', 'l33', 'l34']", + "147, Ifnb(-/-) ['l13', 'l20', 'l26', 'l30', 'l33', 'l35', 'l36']", + "149, Ifnar(-/-) ['l14', 'l27', 'l31', 'l35', 'l37']", + "150, mice. ['l15', 'l21', 'l28', 'l32', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "FoxA1(+)", + "Treg", + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ifnb(-/-)", + "Ifnar(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ifnb(-/-)", + "Ifnar(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "24441828", + "TEXT": "Spontaneous Ca(2+) release from intracellular stores is important for various physiological and pathological processes. In cardiac muscle cells, spontaneous store overload-induced Ca(2+) release (SOICR) can result in Ca(2+) waves, a major cause of ventricular tachyarrhythmias (VTs) and sudden death. The molecular mechanism underlying SOICR has been a mystery for decades. Here we show that a point mutation, E4872A, in the helix bundle crossing region (the proposed gate) of the cardiac ryanodine receptor (RyR2) completely abolishes luminal, but not cytosolic, Ca(2+) activation of RyR2. The introduction of metal-binding histidines at this site converts RyR2 into a luminal Ni(2+)-gated channel. Mouse hearts harboring a heterozygous RyR2 mutation at this site (E4872Q) are resistant to SOICR and are completely protected against Ca(2+)-triggered VTs. These data show that the RyR2 gate directly senses luminal (store) Ca(2+), explaining the regulation of RyR2 by luminal Ca(2+), the initiation of Ca(2+) waves and Ca(2+)-triggered arrhythmias. This newly identified store-sensing gate structure is conserved in all RyR and inositol 1,4,5-trisphosphate receptor isoforms.", + "TAG_DATA": [ + "55, point {'perturbing_action': 'B-other'}", + "56, mutation, {'perturbing_action': 'I-other'}", + "57, E4872A, {'perturbing_action': 'I-other'}", + "58, in {'perturbing_action': 'I-other'}", + "59, the {'perturbing_action': 'I-other'}", + "60, helix {'perturbing_action': 'I-other'}", + "61, bundle {'perturbing_action': 'I-other'}", + "62, crossing {'perturbing_action': 'I-other'}", + "63, region {'perturbing_action': 'I-other'}", + "64, (the {'perturbing_action': 'I-other'}", + "66, gate) {'perturbing_action': 'I-other'}", + "67, of {'perturbing_action': 'I-other'}", + "68, the {'perturbing_action': 'I-other'}", + "69, cardiac {'perturbing_action': 'I-other'}", + "70, ryanodine {'perturbing_action': 'I-other'}", + "71, receptor {'perturbing_action': 'I-other'}", + "72, (RyR2) {'perturbing_action': 'I-other'}", + "98, Mouse {'context': 'B-tissue/organ'}", + "99, hearts {'context': 'I-tissue/organ'}", + "101, a {'perturbing_action': 'I-other'}", + "102, heterozygous {'perturbing_action': 'B-other'}", + "103, RyR2 {'perturbing_action': 'I-other'}", + "104, mutation {'perturbing_action': 'I-other'}", + "105, at {'perturbing_action': 'I-other'}", + "106, this {'perturbing_action': 'I-other'}", + "107, site {'perturbing_action': 'I-other'}", + "108, (E4872Q) {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "55, point ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "56, mutation, ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "57, E4872A, ['l1', 'l16', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "58, in ['l2', 'l17', 'l31', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "59, the ['l3', 'l18', 'l32', 'l45', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "60, helix ['l4', 'l19', 'l33', 'l46', 'l58', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "61, bundle ['l5', 'l20', 'l34', 'l47', 'l59', 'l70', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "62, crossing ['l6', 'l21', 'l35', 'l48', 'l60', 'l71', 'l81', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "63, region ['l7', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "64, (the ['l8', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l100', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "66, gate) ['l9', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l108', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "67, of ['l10', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l115', 'l121', 'l122', 'l123', 'l124', 'l125']", + "68, the ['l11', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l121', 'l126', 'l127', 'l128', 'l129']", + "69, cardiac ['l12', 'l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l126', 'l130', 'l131', 'l132']", + "70, ryanodine ['l13', 'l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l118', 'l123', 'l127', 'l130', 'l133', 'l134']", + "71, receptor ['l14', 'l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l113', 'l119', 'l124', 'l128', 'l131', 'l133', 'l135']", + "72, (RyR2) ['l15', 'l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l129', 'l132', 'l134', 'l135']", + "98, Mouse ['l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "99, hearts ['l136', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "101, a ['l137', 'l145', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159']", + "102, heterozygous ['l138', 'l146', 'l153', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "103, RyR2 ['l139', 'l147', 'l154', 'l160', 'l166', 'l167', 'l168', 'l169', 'l170']", + "104, mutation ['l140', 'l148', 'l155', 'l161', 'l166', 'l171', 'l172', 'l173', 'l174']", + "105, at ['l141', 'l149', 'l156', 'l162', 'l167', 'l171', 'l175', 'l176', 'l177']", + "106, this ['l142', 'l150', 'l157', 'l163', 'l168', 'l172', 'l175', 'l178', 'l179']", + "107, site ['l143', 'l151', 'l158', 'l164', 'l169', 'l173', 'l176', 'l178', 'l180']", + "108, (E4872Q) ['l144', 'l152', 'l159', 'l165', 'l170', 'l174', 'l177', 'l179', 'l180']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "Mouse", + "hearts" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "a", + "heterozygous", + "RyR2", + "mutation", + "at", + "this", + "site", + "(E4872Q)" + ] + } + } + ] + }, + { + "PMID": "24270544", + "TEXT": "Podocytes are critical in the maintenance of a healthy glomerular filter; however, they have been difficult to study in the intact kidney because of technical limitations. Here we report the development of serial multiphoton microscopy (MPM) of the same glomeruli over several days to visualize the motility of podocytes and parietal epithelial cells (PECs) in vivo. In podocin-GFP mice, podocytes formed sporadic multicellular clusters after unilateral ureteral ligation and migrated into the parietal Bowman's capsule. The tracking of single cells in podocin-confetti mice featuring cell-specific expression of CFP, GFP, YFP or RFP revealed the simultaneous migration of multiple podocytes. In phosphoenolpyruvate carboxykinase (PEPCK)-GFP mice, serial MPM found PEC-to-podocyte migration and nanotubule connections. Our data support a highly dynamic rather than a static nature of the glomerular environment and cellular composition. Future application of this new approach should advance our understanding of the mechanisms of glomerular injury and regeneration.", + "TAG_DATA": [ + "54, in {'context': 'B-in vivo'}", + "55, vivo. {'context': 'I-in vivo'}", + "57, podocin-GFP {'perturbing_action': 'B-gene gain-of-function'}", + "58, mice, {'context': 'B-organism'}", + "59, podocytes {'context': 'B-cells'}", + "82, mice {'context': 'B-organism'}", + "95, migration {'phenotype': 'B-migration'}", + "98, podocytes. {'context': 'B-cells'}", + "100, phosphoenolpyruvate {'perturbing_action': 'B-gene gain-of-function'}", + "103, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "54, in ['l0', 'l1', 'l2', 'l3']", + "55, vivo. ['l0', 'l4', 'l5', 'l6']", + "57, podocin-GFP ['l1', 'l4', 'l7', 'l8']", + "58, mice, ['l2', 'l5', 'l7', 'l9']", + "59, podocytes ['l3', 'l6', 'l8', 'l9']", + "82, mice ['l10', 'l11']", + "95, migration ['l10', 'l12']", + "98, podocytes. ['l11', 'l12']", + "100, phosphoenolpyruvate ['l13']", + "103, mice, ['l13']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "podocin-GFP" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "podocin-GFP", + "phosphoenolpyruvate" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "podocin-GFP" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocytes" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocytes." + ] + } + } + ] + }, + { + "PMID": "24185693", + "TEXT": "Hypertension and chronic kidney disease (CKD) are complex traits representing major global health problems. Multiple genome-wide association studies have identified common variants in the promoter of the UMOD gene, which encodes uromodulin, the major protein secreted in normal urine, that cause independent susceptibility to CKD and hypertension. Despite compelling genetic evidence for the association between UMOD risk variants and disease susceptibility in the general population, the underlying biological mechanism is not understood. Here, we demonstrate that UMOD risk variants increased UMOD expression in vitro and in vivo. Uromodulin overexpression in transgenic mice led to salt-sensitive hypertension and to the presence of age-dependent renal lesions similar to those observed in elderly individuals homozygous for UMOD promoter risk variants. The link between uromodulin and hypertension is due to activation of the renal sodium cotransporter NKCC2. We demonstrated the relevance of this mechanism in humans by showing that pharmacological inhibition of NKCC2 was more effective in lowering blood pressure in hypertensive patients who are homozygous for UMOD promoter risk variants than in other hypertensive patients. Our findings link genetic susceptibility to hypertension and CKD to the level of uromodulin expression and uromodulin's effect on salt reabsorption in the kidney. These findings point to uromodulin as a therapeutic target for lowering blood pressure and preserving renal function.", + "TAG_DATA": [ + "82, in {'context': 'B-in vitro'}", + "83, vitro {'context': 'I-in vitro'}", + "85, in {'context': 'B-in vivo'}", + "86, vivo. {'context': 'I-in vivo'}", + "87, Uromodulin {'perturbing_action': 'B-gene gain-of-function'}", + "88, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "90, transgenic {'perturbing_action': 'B-gene gain-of-function', 'context': 'B-cells'}", + "91, mice {'context': 'I-organism'}", + "145, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "146, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "147, of {'perturbing_action': 'I-pharmacological inhibition'}", + "148, NKCC2 {'perturbing_action': 'I-pharmacological inhibition'}", + "157, hypertensive {'context': 'B-patient'}", + "158, patients {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "82, in ['l0', 'l1', 'l2']", + "83, vitro ['l0', 'l3', 'l4']", + "85, in ['l1', 'l3', 'l5']", + "86, vivo. ['l2', 'l4', 'l5']", + "87, Uromodulin ['l6', 'l7', 'l8']", + "88, overexpression ['l6', 'l9', 'l10']", + "90, transgenic ['l7', 'l9', 'l11']", + "91, mice ['l8', 'l10', 'l11']", + "145, pharmacological ['l12', 'l13', 'l14', 'l15', 'l16']", + "146, inhibition ['l12', 'l17', 'l18', 'l19', 'l20']", + "147, of ['l13', 'l17', 'l21', 'l22', 'l23']", + "148, NKCC2 ['l14', 'l18', 'l21', 'l24', 'l25']", + "157, hypertensive ['l15', 'l19', 'l22', 'l24', 'l26']", + "158, patients ['l16', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Uromodulin", + "overexpression", + "transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Uromodulin", + "overexpression", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "NKCC2" + ] + }, + "context": { + "val": "patient", + "words": [ + "hypertensive", + "patients" + ] + } + } + ] + }, + { + "PMID": "24141423", + "TEXT": "Sirtuin 1 (Sirt1), a NAD(+)-regulated deacetylase with numerous known positive effects on cellular and whole-body metabolism, is expressed in the renal cortex and medulla. It is known to have protective effects against age-related disease, including diabetes. Here we investigated the protective role of Sirt1 in diabetic renal damage. We found that Sirt1 in proximal tubules (PTs) was downregulated before albuminuria occurred in streptozotocin-induced or obese (db/db) diabetic mice. PT-specific SIRT1 transgenic and Sirt1 knockout mice showed prevention and aggravation of the glomerular changes that occur in diabetes, respectively, and nondiabetic knockout mice exhibited albuminuria, suggesting that Sirt1 in PTs affects glomerular function. Downregulation of Sirt1 and upregulation of the tight junction protein Claudin-1 by SIRT1-mediated epigenetic regulation in podocytes contributed to albuminuria. We did not observe these phenomena in 5/6 nephrectomized mice. We also demonstrated retrograde interplay from PTs to glomeruli using nicotinamide mononucleotide (NMN) from conditioned medium, measurement of the autofluorescence of photoactivatable NMN and injection of fluorescence-labeled NMN. In human subjects with diabetes, the levels of SIRT1 and Claudin-1 were correlated with proteinuria levels. These results suggest that Sirt1 in PTs protects against albuminuria in diabetes by maintaining NMN concentrations around glomeruli, thus influencing podocyte function.", + "TAG_DATA": [ + "66, diabetic {'context': 'I-organism'}", + "67, mice. {'context': 'I-organism'}", + "68, PT-specific {'perturbing_action': 'B-gene gain-of-function'}", + "69, SIRT1 {'perturbing_action': 'I-gene gain-of-function'}", + "70, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "72, Sirt1 {'perturbing_action': 'B-gene loss-of-function'}", + "73, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "74, mice {'context': 'B-organism'}", + "91, mice {'context': 'B-organism'}", + "131, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "66, diabetic ['l0']", + "67, mice. ['l0']", + "68, PT-specific ['l1', 'l2', 'l3', 'l4', 'l5']", + "69, SIRT1 ['l1', 'l6', 'l7', 'l8', 'l9']", + "70, transgenic ['l2', 'l6', 'l10', 'l11', 'l12']", + "72, Sirt1 ['l3', 'l7', 'l10', 'l13', 'l14']", + "73, knockout ['l4', 'l8', 'l11', 'l13', 'l15']", + "74, mice ['l5', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PT-specific", + "SIRT1", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sirt1", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "24141421", + "TEXT": "Here we show that Mst1, a proapoptotic kinase, impairs protein quality control mechanisms in the heart through inhibition of autophagy. Stress-induced activation of Mst1 in cardiomyocytes promoted accumulation of p62 and aggresome formation, accompanied by the disappearance of autophagosomes. Mst1 phosphorylated the Thr108 residue in the BH3 domain of Beclin1, which enhanced the interaction between Beclin1 and Bcl-2 and/or Bcl-xL, stabilized the Beclin1 homodimer, inhibited the phosphatidylinositide 3-kinase activity of the Atg14L-Beclin1-Vps34 complex and suppressed autophagy. Furthermore, Mst1-induced sequestration of Bcl-2 and Bcl-xL by Beclin1 allows Bax to become active, thereby stimulating apoptosis. Mst1 promoted cardiac dysfunction in mice subjected to myocardial infarction by inhibiting autophagy, associated with increased levels of Thr108-phosphorylated Beclin1. Moreover, dilated cardiomyopathy in humans was associated with increased levels of Thr108-phosphorylated Beclin1 and signs of autophagic suppression. These results suggest that Mst1 coordinately regulates autophagy and apoptosis by phosphorylating Beclin1 and consequently modulating a three-way interaction among Bcl-2 proteins, Beclin1 and Bax.", + "TAG_DATA": [ + "25, cardiomyocytes {'context': 'B-cells'}", + "74, suppressed {'effect': 'B-negative'}", + "75, autophagy. {'phenotype': 'B-autophagy'}", + "91, stimulating {'effect': 'B-positive'}", + "92, apoptosis. {'phenotype': 'B-apoptosis'}", + "98, mice {'context': 'B-organism'}", + "104, inhibiting {'effect': 'B-negative'}", + "105, autophagy, {'phenotype': 'B-autophagy'}" + ], + "LINK_DATA": [ + "74, suppressed ['l0', 'l1', 'l2']", + "75, autophagy. ['l0', 'l3', 'l4']", + "91, stimulating ['l1', 'l3', 'l5']", + "92, apoptosis. ['l2', 'l4', 'l5']", + "98, mice ['l6', 'l7']", + "104, inhibiting ['l6', 'l8']", + "105, autophagy, ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "suppressed", + "inhibiting" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy.", + "autophagy," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy." + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulating" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulating" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibiting" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + } + } + ] + }, + { + "PMID": "23975026", + "TEXT": "Beta-cell dysfunction and impaired insulin production are hallmarks of diabetes, but despite the growing diabetes epidemic, the molecular mechanisms underlying this disease have remained unclear. We identified thioredoxin-interacting protein (TXNIP), a cellular redox regulator, as a crucial factor in beta-cell biology and show that beta-cell TXNIP is upregulated in diabetes, whereas TXNIP deficiency protects against diabetes by preventing beta-cell apoptosis. Here we show that TXNIP and diabetes induce beta-cell expression of a specific microRNA, miR-204, which in turn blocks insulin production by directly targeting and downregulating MAFA, a known insulin transcription factor. In particular, we first discovered the regulation of miR-204 by TXNIP by microarray analysis, followed by validation studies in INS-1 beta cells, islets of Txnip-deficient mice, diabetic mouse models and primary human islets. We then further found that TXNIP induces miR-204 by inhibiting the activity of signal transducer and activator of transcription 3 (STAT3), a transcription factor that is involved in miR-204 regulation. We also identified MAFA as a target that is downregulated by miR-204. Taken together, our results demonstrate that TXNIP controls microRNA expression and insulin production and that miR-204 is involved in beta-cell function. The newly identified TXNIP-miR-204-MAFA-insulin pathway may contribute to diabetes progression and provides new insight into TXNIP function and microRNA biology in health and disease.", + "TAG_DATA": [ + "111, INS-1 {'context': 'B-cells'}", + "112, beta {'context': 'I-cells'}", + "113, cells, {'context': 'I-cells'}", + "114, islets {'context': 'B-cells'}", + "116, Txnip-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "117, mice, {'context': 'B-organism'}", + "118, diabetic {'context': 'B-organism'}", + "119, mouse {'context': 'I-organism'}", + "120, models {'context': 'I-organism'}", + "122, primary {'context': 'B-cells'}", + "123, human {'context': 'I-cells'}", + "124, islets. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "111, INS-1 ['l0', 'l1', 'l2', 'l3', 'l4']", + "112, beta ['l0', 'l5', 'l6']", + "113, cells, ['l1', 'l5', 'l7']", + "114, islets ['l2', 'l6', 'l7', 'l8', 'l9', 'l10']", + "116, Txnip-deficient ['l3', 'l8', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "117, mice, ['l4', 'l9', 'l11', 'l17']", + "118, diabetic ['l18', 'l19', 'l20', 'l21', 'l22']", + "119, mouse ['l12', 'l18', 'l23', 'l24', 'l25', 'l26']", + "120, models ['l10', 'l13', 'l17', 'l19', 'l23', 'l27', 'l28', 'l29']", + "122, primary ['l14', 'l20', 'l24', 'l27', 'l30', 'l31']", + "123, human ['l15', 'l21', 'l25', 'l28', 'l30', 'l32']", + "124, islets. ['l16', 'l22', 'l26', 'l29', 'l31', 'l32']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "INS-1", + "islets", + "primary", + "human", + "islets." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Txnip-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Txnip-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mouse", + "models" + ] + } + } + ] + }, + { + "PMID": "23793099", + "TEXT": "Here we show that glioblastoma express high levels of branched-chain amino acid transaminase 1 (BCAT1), the enzyme that initiates the catabolism of branched-chain amino acids (BCAAs). Expression of BCAT1 was exclusive to tumors carrying wild-type isocitrate dehydrogenase 1 (IDH1) and IDH2 genes and was highly correlated with methylation patterns in the BCAT1 promoter region. BCAT1 expression was dependent on the concentration of α-ketoglutarate substrate in glioma cell lines and could be suppressed by ectopic overexpression of mutant IDH1 in immortalized human astrocytes, providing a link between IDH1 function and BCAT1 expression. Suppression of BCAT1 in glioma cell lines blocked the excretion of glutamate and led to reduced proliferation and invasiveness in vitro, as well as significant decreases in tumor growth in a glioblastoma xenograft model. These findings suggest a central role for BCAT1 in glioma pathogenesis, making BCAT1 and BCAA metabolism attractive targets for the development of targeted therapeutic approaches to treat patients with glioblastoma.", + "TAG_DATA": [ + "73, ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "74, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "75, of {'perturbing_action': 'I-gene gain-of-function'}", + "76, mutant {'perturbing_action': 'I-gene gain-of-function'}", + "77, IDH1 {'perturbing_action': 'I-gene gain-of-function'}", + "79, immortalized {'context': 'B-cells'}", + "80, human {'context': 'I-cells'}", + "81, astrocytes, {'context': 'I-cells'}", + "91, Suppression {'perturbing_action': 'B-pharmacological inhibition'}", + "92, of {'perturbing_action': 'I-pharmacological inhibition'}", + "93, BCAT1 {'perturbing_action': 'I-pharmacological inhibition'}", + "95, glioma {'context': 'B-transformed cells'}", + "96, cell {'context': 'I-transformed cells'}", + "97, lines {'context': 'I-transformed cells'}", + "106, reduced {'effect': 'B-negative'}", + "107, proliferation {'phenotype': 'B-proliferation'}", + "109, invasiveness {'phenotype': 'B-invasion'}", + "110, in {'context': 'B-in vitro'}", + "111, vitro, {'context': 'I-in vitro'}", + "116, decreases {'effect': 'B-negative'}", + "118, tumor {'phenotype': 'B-tumour growth'}", + "119, growth {'phenotype': 'I-tumour growth'}", + "122, glioblastoma {'context': 'B-xenograft'}", + "123, xenograft {'context': 'I-xenograft'}", + "124, model. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "73, ectopic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "74, overexpression ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "75, of ['l1', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "76, mutant ['l2', 'l13', 'l22', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "77, IDH1 ['l3', 'l14', 'l23', 'l32', 'l40', 'l41', 'l42']", + "79, immortalized ['l4', 'l15', 'l24', 'l33', 'l40', 'l43', 'l44']", + "80, human ['l5', 'l16', 'l25', 'l34', 'l41', 'l43', 'l45']", + "81, astrocytes, ['l6', 'l17', 'l26', 'l35', 'l42', 'l44', 'l45']", + "91, Suppression ['l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "92, of ['l46', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "93, BCAT1 ['l47', 'l62', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "95, glioma ['l48', 'l63', 'l77', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "96, cell ['l7', 'l18', 'l27', 'l36', 'l49', 'l64', 'l78', 'l91', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "97, lines ['l8', 'l19', 'l28', 'l37', 'l50', 'l65', 'l79', 'l92', 'l99', 'l105', 'l106', 'l107', 'l108', 'l109']", + "106, reduced ['l9', 'l20', 'l29', 'l38', 'l51', 'l66', 'l80', 'l93', 'l100', 'l105', 'l110', 'l111', 'l112', 'l113']", + "107, proliferation ['l10', 'l21', 'l30', 'l39', 'l52', 'l67', 'l81', 'l94', 'l101', 'l106', 'l110', 'l114', 'l115', 'l116']", + "109, invasiveness ['l11', 'l31', 'l53', 'l68', 'l82', 'l95', 'l102', 'l107', 'l111', 'l114', 'l117', 'l118']", + "110, in ['l54', 'l69', 'l83', 'l96', 'l103', 'l108', 'l112', 'l115', 'l117', 'l119']", + "111, vitro, ['l55', 'l70', 'l84', 'l97', 'l104', 'l109', 'l113', 'l116', 'l118', 'l119']", + "116, decreases ['l56', 'l71', 'l85', 'l98', 'l120', 'l121', 'l122', 'l123', 'l124']", + "118, tumor ['l57', 'l72', 'l86', 'l120', 'l125', 'l126', 'l127', 'l128']", + "119, growth ['l58', 'l73', 'l87', 'l121', 'l125', 'l129', 'l130', 'l131']", + "122, glioblastoma ['l59', 'l74', 'l88', 'l122', 'l126', 'l129', 'l132', 'l133']", + "123, xenograft ['l60', 'l75', 'l89', 'l123', 'l127', 'l130', 'l132', 'l134']", + "124, model. ['l61', 'l76', 'l90', 'l124', 'l128', 'l131', 'l133', 'l134']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "mutant", + "IDH1" + ] + }, + "context": { + "val": "cells", + "words": [ + "immortalized", + "human", + "astrocytes," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "mutant" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cell", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "mutant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "mutant" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "of" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Suppression", + "of", + "BCAT1" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "glioma", + "cell", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Suppression", + "of", + "BCAT1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced", + "decreases" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Suppression", + "of", + "BCAT1" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Suppression", + "of", + "BCAT1" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Suppression", + "of", + "BCAT1" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Suppression", + "of", + "BCAT1" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Suppression", + "of", + "BCAT1" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "glioblastoma", + "xenograft", + "model." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "glioma", + "cell", + "lines" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced", + "decreases" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "glioma", + "cell", + "lines" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "glioma", + "cell", + "lines" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreases" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreases" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "glioblastoma", + "xenograft", + "model." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "glioblastoma", + "xenograft", + "model." + ] + } + } + ] + }, + { + "PMID": "23770691", + "TEXT": "The clinical application of adeno-associated virus vectors (AAVs) is limited because of concerns about AAV integration-mediated tumorigenicity. We performed integration-site analysis after AAV1-LPL(S447X) intramuscular injection in five lipoprotein lipase-deficient subjects, revealing random nuclear integration and hotspots in mitochondria. We conclude that AAV integration is potentially safe and that vector breakage and integration may occur from each position of the vector genome. Future viral integration-site analyses should include the mitochondrial genome.", + "TAG_DATA": [ + "27, lipoprotein {'perturbing_action': 'B-gene loss-of-function'}", + "28, lipase-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "29, subjects, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "27, lipoprotein ['l0', 'l1']", + "28, lipase-deficient ['l0', 'l2']", + "29, subjects, ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lipoprotein", + "lipase-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "subjects," + ] + } + } + ] + }, + { + "PMID": "23708291", + "TEXT": "The commensal flora can promote both immunity to pathogens and mucosal inflammation. How commensal-driven inflammation is regulated in the context of infection remains poorly understood. Here, we show that during acute mucosal infection of mice with Toxoplasma gondii, inflammatory monocytes acquire a tissue-specific regulatory phenotype associated with production of the lipid mediator prostaglandin E2 (PGE2). Notably, in response to commensals, inflammatory monocytes can directly inhibit neutrophil activation in a PGE2-dependent manner. Further, in the absence of inflammatory monocytes, mice develop severe neutrophil-mediated pathology in response to pathogen challenge that can be controlled by PGE2 analog treatment. Complementing these findings, inhibition of PGE2 led to enhanced neutrophil activation and host mortality after infection. These data demonstrate a previously unappreciated dual action of inflammatory monocytes in controlling pathogen expansion while limiting commensal-mediated damage to the gut. Collectively, our results place inflammatory monocyte-derived PGE2 at the center of a commensal-driven regulatory loop required to control host-commensal dialog during pathogen-induced inflammation.", + "TAG_DATA": [ + "34, mice {'context': 'B-organism'}", + "74, absence {'perturbing_action': 'B-gene loss-of-function'}", + "75, of {'perturbing_action': 'I-gene loss-of-function'}", + "76, inflammatory {'perturbing_action': 'I-gene loss-of-function'}", + "77, monocytes, {'perturbing_action': 'I-gene loss-of-function'}", + "78, mice {'context': 'B-organism'}", + "99, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "100, of {'perturbing_action': 'I-pharmacological inhibition'}", + "101, PGE2 {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "74, absence ['l0', 'l1', 'l2', 'l3']", + "75, of ['l0', 'l4', 'l5', 'l6']", + "76, inflammatory ['l1', 'l4', 'l7', 'l8']", + "77, monocytes, ['l2', 'l5', 'l7', 'l9']", + "78, mice ['l3', 'l6', 'l8', 'l9']", + "99, inhibition ['l10', 'l11']", + "100, of ['l10', 'l12']", + "101, PGE2 ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "inflammatory", + "monocytes," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23644515", + "TEXT": "Major depressive disorder (MDD) is a cause of disability that affects approximately 16% of the world's population; however, little is known regarding the underlying biology of this disorder. Animal studies, postmortem brain analyses and imaging studies of patients with depression have implicated glial dysfunction in MDD pathophysiology. However, the molecular mechanisms through which astrocytes modulate depressive behaviors are largely uncharacterized. Here, we identified ATP as a key factor involved in astrocytic modulation of depressive-like behavior in adult mice. We observed low ATP abundance in the brains of mice that were susceptible to chronic social defeat. Furthermore, we found that the administration of ATP induced a rapid antidepressant-like effect in these mice. Both a lack of inositol 1,4,5-trisphosphate receptor type 2 and transgenic blockage of vesicular gliotransmission induced deficiencies in astrocytic ATP release, causing depressive-like behaviors that could be rescued via the administration of ATP. Using transgenic mice that express a Gq G protein-coupled receptor only in astrocytes to enable selective activation of astrocytic Ca(2+) signaling, we found that stimulating endogenous ATP release from astrocytes induced antidepressant-like effects in mouse models of depression. Moreover, we found that P2X2 receptors in the medial prefrontal cortex mediated the antidepressant-like effects of ATP. These results highlight astrocytic ATP release as a biological mechanism of MDD.", + "TAG_DATA": [ + "87, mice {'context': 'B-organism'}", + "110, mice. {'context': 'B-organism'}", + "113, lack {'perturbing_action': 'B-gene loss-of-function'}", + "145, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "146, mice {'context': 'I-organism'}", + "148, express {'perturbing_action': 'I-gene gain-of-function'}", + "149, a {'perturbing_action': 'I-gene gain-of-function'}", + "150, Gq {'perturbing_action': 'I-gene gain-of-function'}", + "151, G {'perturbing_action': 'I-gene gain-of-function'}", + "152, protein-coupled {'perturbing_action': 'I-gene gain-of-function'}", + "153, receptor {'perturbing_action': 'I-gene gain-of-function'}", + "154, only {'perturbing_action': 'I-gene gain-of-function'}", + "156, astrocytes {'context': 'B-cells'}", + "173, astrocytes {'context': 'B-cells'}", + "178, mouse {'context': 'B-organism'}", + "179, models {'context': 'I-organism'}", + "180, of {'context': 'I-organism'}", + "181, depression. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "87, mice ['l0']", + "110, mice. ['l0']", + "145, transgenic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "146, mice ['l1', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "148, express ['l2', 'l15', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "149, a ['l3', 'l16', 'l28', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "150, Gq ['l4', 'l17', 'l29', 'l40', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "151, G ['l5', 'l18', 'l30', 'l41', 'l51', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "152, protein-coupled ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "153, receptor ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "154, only ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "156, astrocytes ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l91', 'l92', 'l93', 'l94', 'l95']", + "173, astrocytes ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l96', 'l97', 'l98', 'l99']", + "178, mouse ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l100', 'l101', 'l102']", + "179, models ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l103', 'l104']", + "180, of ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l105']", + "181, depression. ['l14', 'l27', 'l39', 'l50', 'l60', 'l69', 'l77', 'l84', 'l90', 'l95', 'l99', 'l102', 'l104', 'l105']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "express", + "a", + "Gq", + "G", + "protein-coupled", + "receptor", + "only" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "models", + "of", + "depression." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "express", + "a", + "Gq", + "G", + "protein-coupled", + "receptor", + "only" + ] + }, + "context": { + "val": "cells", + "words": [ + "astrocytes" + ] + } + } + ] + }, + { + "PMID": "23584088", + "TEXT": "Platelets have a key role in atherogenesis and its complications. Both hypercholesterolemia and increased platelet production promote atherothrombosis; however, a potential link between altered cholesterol homeostasis and platelet production has not been explored. Here we show that transplantation of bone marrow deficient in ABCG4, a transporter of unknown function, into Ldlr(-/-) mice resulted in thrombocytosis, accelerated thrombosis and atherosclerosis. Although not detected in atherosclerotic lesions, Abcg4 was highly expressed in bone marrow megakaryocyte progenitors (MkPs). Abcg4(-/-) MkPs had defective cholesterol efflux to high-density lipoprotein (HDL), increased cell surface expression of the thrombopoietin (TPO) receptor (c-MPL) and enhanced proliferation. These consequences of ABCG4 deficiency seemed to reflect disruption of negative feedback regulation of c-MPL signaling by the E3 ligase c-CBL and the cholesterol-sensing LYN kinase. HDL infusion reduced platelet counts in Ldlr(-/-) mice and in a mouse model of myeloproliferative neoplasm in an ABCG4-dependent fashion. HDL infusions may offer a new approach to reducing atherothrombotic events associated with increased platelet production.", + "TAG_DATA": [ + "39, bone {'perturbing_action': 'I-gene loss-of-function', 'context': 'B-cells'}", + "40, marrow {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-tissue/organ'}", + "41, deficient {'perturbing_action': 'I-gene loss-of-function'}", + "42, in {'perturbing_action': 'I-gene loss-of-function'}", + "43, ABCG4, {'perturbing_action': 'I-gene loss-of-function'}", + "50, Ldlr(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "51, mice {'context': 'B-organism'}", + "55, accelerated {'effect': 'B-positive'}", + "75, Abcg4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "76, MkPs {'context': 'B-cells'}", + "96, enhanced {'effect': 'B-positive'}", + "97, proliferation. {'phenotype': 'B-proliferation'}", + "101, ABCG4 {'perturbing_action': 'B-gene loss-of-function'}", + "102, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "130, Ldlr(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "131, mice {'context': 'B-organism'}", + "135, mouse {'context': 'B-neoplasm'}", + "136, model {'context': 'I-neoplasm'}", + "137, of {'context': 'I-neoplasm'}", + "138, myeloproliferative {'context': 'I-neoplasm'}", + "139, neoplasm {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "39, bone ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "40, marrow ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "41, deficient ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "42, in ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "43, ABCG4, ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "50, Ldlr(-/-) ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "51, mice ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "55, accelerated ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "75, Abcg4(-/-) ['l28', 'l29', 'l30', 'l31']", + "76, MkPs ['l28', 'l32', 'l33', 'l34']", + "96, enhanced ['l29', 'l32', 'l35']", + "97, proliferation. ['l30', 'l33', 'l35', 'l36']", + "101, ABCG4 ['l37', 'l38']", + "102, deficiency ['l31', 'l34', 'l36', 'l37']", + "130, Ldlr(-/-) ['l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "131, mice ['l38', 'l39', 'l45', 'l46']", + "135, mouse ['l40', 'l47', 'l48', 'l49', 'l50']", + "136, model ['l41', 'l47', 'l51', 'l52', 'l53']", + "137, of ['l42', 'l45', 'l48', 'l51', 'l54', 'l55']", + "138, myeloproliferative ['l43', 'l49', 'l52', 'l54', 'l56']", + "139, neoplasm ['l44', 'l46', 'l50', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "bone", + "Abcg4(-/-)", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "bone", + "MkPs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "bone", + "marrow" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "marrow" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "bone", + "marrow", + "deficient", + "in", + "ABCG4,", + "Ldlr(-/-)", + "ABCG4" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "bone", + "marrow", + "deficient", + "in", + "ABCG4,", + "Ldlr(-/-)", + "Abcg4(-/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerated", + "enhanced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "bone", + "MkPs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerated", + "enhanced" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "marrow" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerated" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerated" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Abcg4(-/-)", + "deficiency" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "MkPs" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ldlr(-/-)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "myeloproliferative", + "neoplasm" + ] + } + } + ] + }, + { + "PMID": "23563706", + "TEXT": "A shift from oxidative to glycolytic metabolism has been associated with skeletal muscle insulin resistance in type 2 diabetes. However, whether this metabolic switch is deleterious or adaptive remains under debate, in part because of a limited understanding of the regulatory network that directs the metabolic and contractile specification of fast-twitch glycolytic muscle. Here we show that Baf60c (also called Smarcd3), a transcriptional cofactor enriched in fast-twitch muscle, promotes a switch from oxidative to glycolytic myofiber type through DEP domain-containing mTOR-interacting protein (Deptor)-mediated Akt activation. Muscle-specific transgenic expression of Baf60c activates a program of molecular, metabolic and contractile changes characteristic of glycolytic muscle. In addition, Baf60c is required for maintaining glycolytic capacity in adult skeletal muscle in vivo. Baf60c expression is significantly lower in skeletal muscle from obese mice compared to that from lean mice. Activation of the glycolytic muscle program by transgenic expression of Baf60c protects mice from diet-induced insulin resistance and glucose intolerance. Further mechanistic studies revealed that Deptor is induced by the Baf60c-Six4 transcriptional complex and mediates activation of Akt and glycolytic metabolism by Baf60c in a cell-autonomous manner. This work defines a fundamental mechanism underlying the specification of fast-twitch glycolytic muscle and illustrates that the oxidative-to-glycolytic metabolic shift in skeletal muscle is potentially adaptive and beneficial in the diabetic state.", + "TAG_DATA": [ + "85, Muscle-specific {'perturbing_action': 'B-gene gain-of-function'}", + "86, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "87, expression {'perturbing_action': 'I-gene gain-of-function'}", + "88, of {'perturbing_action': 'I-gene gain-of-function'}", + "89, Baf60c {'perturbing_action': 'I-gene gain-of-function'}", + "113, adult {'context': 'B-tissue/organ'}", + "114, skeletal {'context': 'I-tissue/organ'}", + "115, muscle {'context': 'I-tissue/organ'}", + "116, in {'context': 'B-in vivo'}", + "117, vivo. {'context': 'I-in vivo'}", + "142, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "143, expression {'perturbing_action': 'I-gene gain-of-function'}", + "144, of {'perturbing_action': 'I-gene gain-of-function'}", + "145, Baf60c {'perturbing_action': 'I-gene gain-of-function'}", + "147, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "85, Muscle-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "86, transgenic ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "87, expression ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "88, of ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "89, Baf60c ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "113, adult ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "114, skeletal ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "115, muscle ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "116, in ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "117, vivo. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "142, transgenic ['l45', 'l46', 'l47', 'l48']", + "143, expression ['l45', 'l49', 'l50', 'l51']", + "144, of ['l46', 'l49', 'l52', 'l53']", + "145, Baf60c ['l47', 'l50', 'l52', 'l54']", + "147, mice ['l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Muscle-specific", + "transgenic", + "expression", + "of", + "Baf60c" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "adult", + "skeletal", + "muscle" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Muscle-specific", + "transgenic", + "expression", + "of", + "Baf60c" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "of", + "Baf60c" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23542786", + "TEXT": "Peroxisome proliferator-activated receptors (PPARs) act as metabolic sensors and central regulators of fat and glucose homeostasis. Furthermore, PPARγ has been implicated as major catabolic regulator of bone mass in mice and humans. However, a potential involvement of other PPAR subtypes in the regulation of bone homeostasis has remained elusive. Here we report a previously unrecognized role of PPARβ/δ as a key regulator of bone turnover and the crosstalk between osteoblasts and osteoclasts. In contrast to activation of PPARγ, activation of PPARβ/δ amplified Wnt-dependent and β-catenin-dependent signaling and gene expression in osteoblasts, resulting in increased expression of osteoprotegerin (OPG) and attenuation of osteoblast-mediated osteoclastogenesis. Accordingly, PPARβ/δ-deficient mice had lower Wnt signaling activity, lower serum concentrations of OPG, higher numbers of osteoclasts and osteopenia. Pharmacological activation of PPARβ/δ in a mouse model of postmenopausal osteoporosis led to normalization of the altered ratio of tumor necrosis factor superfamily, member 11 (RANKL, also called TNFSF11) to OPG, a rebalancing of bone turnover and the restoration of normal bone density. Our findings identify PPARβ/δ as a promising target for an alternative approach in the treatment of osteoporosis and related diseases.", + "TAG_DATA": [ + "78, activation {'perturbing_action': 'B-pharmacological augmentation'}", + "79, of {'perturbing_action': 'I-pharmacological augmentation'}", + "80, PPARβ/δ {'perturbing_action': 'I-pharmacological augmentation'}", + "90, osteoblasts, {'context': 'B-cells'}", + "104, PPARβ/δ-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "105, mice {'context': 'B-organism'}", + "119, osteoclasts {'context': 'B-cells'}", + "122, Pharmacological {'perturbing_action': 'B-pharmacological augmentation'}", + "123, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "124, of {'perturbing_action': 'I-pharmacological augmentation'}", + "125, PPARβ/δ {'perturbing_action': 'I-pharmacological augmentation'}", + "128, mouse {'context': 'B-organism'}", + "129, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "78, activation ['l0', 'l1', 'l2', 'l3']", + "79, of ['l0', 'l4', 'l5', 'l6', 'l7']", + "80, PPARβ/δ ['l1', 'l4', 'l8', 'l9', 'l10']", + "90, osteoblasts, ['l2', 'l5', 'l8']", + "104, PPARβ/δ-deficient ['l11', 'l12']", + "105, mice ['l6', 'l9', 'l11', 'l13']", + "119, osteoclasts ['l3', 'l7', 'l10', 'l12', 'l13']", + "122, Pharmacological ['l14', 'l15', 'l16', 'l17', 'l18']", + "123, activation ['l14', 'l19', 'l20', 'l21', 'l22']", + "124, of ['l15', 'l19', 'l23', 'l24', 'l25']", + "125, PPARβ/δ ['l16', 'l20', 'l23', 'l26', 'l27']", + "128, mouse ['l17', 'l21', 'l24', 'l26', 'l28']", + "129, model ['l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "of", + "PPARβ/δ" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoblasts,", + "osteoclasts" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "of", + "PPARβ/δ", + "Pharmacological", + "activation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PPARβ/δ-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PPARβ/δ-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclasts" + ] + } + } + ] + }, + { + "PMID": "23475202", + "TEXT": "We report that K5.Smad7 mice, which express a Smad7 transgene under the control of a keratin 5 promoter, were resistant to radiation-induced oral mucositis, a painful oral ulceration. In addition to nuclear factor κB (NF-κB) activation, which is known to contribute to oral mucositis, we found activated transforming growth factor β (TGF-β) signaling in cells from this condition. Smad7 dampened both pathways to attenuate inflammation, growth inhibition and apoptosis. Additionally, Smad7 promoted oral epithelial migration to close the wound. Further analyses revealed that TGF-β signaling Smads and their co-repressor C-terminal binding protein 1 (CtBP1) transcriptionally repressed Rac1, and that Smad7 abrogated this repression. Knocking down Rac1 expression in mouse keratinocytes abrogated Smad7-induced migration. Topical application of Smad7 protein conjugated with a cell-permeable Tat tag to oral mucosa showed prophylactic and therapeutic effects on radiation-induced oral mucositis in mice. Thus, we have identified new molecular mechanisms involved in oral mucositis pathogenesis, and our data suggest an alternative therapeutic strategy to block multiple pathological processes in this condition.", + "TAG_DATA": [ + "3, K5.Smad7 {'perturbing_action': 'B-other'}", + "4, mice, {'context': 'B-organism'}", + "54, cells {'context': 'B-cells'}", + "68, apoptosis. {'phenotype': 'B-apoptosis'}", + "71, promoted {'effect': 'B-positive'}", + "103, Knocking {'perturbing_action': 'B-rnai/knockdown'}", + "104, down {'perturbing_action': 'I-rnai/knockdown'}", + "105, Rac1 {'perturbing_action': 'I-rnai/knockdown'}", + "106, expression {'perturbing_action': 'I-rnai/knockdown'}", + "108, mouse {'context': 'B-cells'}", + "109, keratinocytes {'context': 'I-cells'}", + "110, abrogated {'effect': 'B-negative'}", + "111, Smad7-induced {'effect': 'B-positive'}", + "112, migration. {'phenotype': 'B-migration'}", + "125, oral {'context': 'B-tissue/organ'}", + "126, mucosa {'context': 'I-tissue/organ'}", + "137, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "3, K5.Smad7 ['l0', 'l1', 'l2', 'l3']", + "4, mice, ['l0', 'l4', 'l5', 'l6']", + "54, cells ['l1', 'l4', 'l7']", + "68, apoptosis. ['l2', 'l5', 'l7']", + "71, promoted ['l3', 'l6']", + "103, Knocking ['l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "104, down ['l8', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "105, Rac1 ['l9', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "106, expression ['l10', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "108, mouse ['l11', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "109, keratinocytes ['l12', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "110, abrogated ['l13', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "111, Smad7-induced ['l14', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "112, migration. ['l15', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "125, oral ['l45', 'l46']", + "126, mucosa ['l16', 'l45', 'l47']", + "137, mice. ['l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "K5.Smad7" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "K5.Smad7" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "K5.Smad7" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "K5.Smad7" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knocking", + "down", + "Rac1", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "keratinocytes" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knocking", + "down", + "Rac1", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abrogated" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knocking", + "down", + "Rac1", + "expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "Smad7-induced" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knocking", + "down", + "Rac1", + "expression" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knocking" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mucosa" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "keratinocytes" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abrogated" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "keratinocytes" + ] + }, + "effect": { + "val": "positive", + "words": [ + "Smad7-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "keratinocytes" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogated" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Smad7-induced" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + } + ] + }, + { + "PMID": "23475201", + "TEXT": "The majority of HIV-infected individuals fail to produce protective antibodies and have diminished responses to new immunizations. We report here that even though there is an expansion of follicular helper T (TFH) cells in HIV-infected individuals, the cells are unable to provide adequate B cell help. We found a higher frequency of programmed cell death ligand 1 (PD-L1)(+) germinal center B cells from lymph nodes of HIV-infected individuals suggesting a potential role for PD-1-PD-L1 interaction in regulating TFH cell function. In fact, we show that engagement of PD-1 on TFH cells leads to a reduction in cell proliferation, activation, inducible T-cell co-stimulator (ICOS) expression and interleukin-21 (IL-21) cytokine secretion. Blocking PD-1 signaling enhances HIV-specific immunoglobulin production in vitro. We further show that at least part of this defect involves IL-21, as addition of this cytokine rescues antibody responses and plasma cell generation in vitro. Our results suggest that deregulation of TFH cell-mediated B cell help diminishes B cell responses during HIV infection and may be related to PD-1 triggering on TFH cells. These results demonstrate a role for TFH cell impairment in HIV pathogenesis and suggest that enhancing their function could have a major impact on the outcome and control of HIV infection, preventing future infections and improving immune responses to vaccinations.", + "TAG_DATA": [ + "89, TFH {'context': 'B-cells'}", + "90, cells {'context': 'I-cells'}", + "94, reduction {'effect': 'B-negative'}", + "96, cell {'context': 'B-cells'}", + "97, proliferation, {'phenotype': 'B-proliferation'}", + "116, in {'context': 'B-in vitro'}", + "117, vitro. {'context': 'I-in vitro'}", + "139, plasma {'context': 'B-cells'}", + "140, cell {'context': 'I-cells'}", + "142, in {'context': 'B-in vitro'}", + "143, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "89, TFH ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "90, cells ['l0', 'l6', 'l7', 'l8']", + "94, reduction ['l1', 'l6', 'l9', 'l10']", + "96, cell ['l2', 'l7', 'l9', 'l11']", + "97, proliferation, ['l3', 'l8', 'l10', 'l11']", + "116, in ['l4', 'l12']", + "117, vitro. ['l5', 'l12']", + "139, plasma ['l13', 'l14', 'l15']", + "140, cell ['l13', 'l16', 'l17']", + "142, in ['l14', 'l16', 'l18']", + "143, vitro. ['l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "TFH", + "cells", + "cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduction" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "TFH", + "cells", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduction" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + } + ] + }, + { + "PMID": "23377280", + "TEXT": "The mechanisms that regulate hematopoietic stem cell (HSC) regeneration after myelosuppressive injury are not well understood. We identified epidermal growth factor (EGF) to be highly enriched in the bone marrow serum of mice bearing deletion of Bak and Bax in TIE2-expressing cells in Tie2Cre; Bak1(-/-); Bax(flox/-) mice. These mice showed radioprotection of the HSC pool and 100% survival after a lethal dose of total-body irradiation (TBI). Bone marrow HSCs from wild-type mice expressed functional EGF receptor (EGFR), and systemic administration of EGF promoted the recovery of the HSC pool in vivo and improved the survival of mice after TBI. Conversely, administration of erlotinib, an EGFR antagonist, decreased both HSC regeneration and the survival of mice after TBI. Mice with EGFR deficiency in VAV-expressing hematopoietic cells also had delayed recovery of bone marrow stem and progenitor cells after TBI. Mechanistically, EGF reduced radiation-induced apoptosis of HSCs and mediated this effect through repression of the proapoptotic protein PUMA. Our findings show that EGFR signaling regulates HSC regeneration after myelosuppressive injury.", + "TAG_DATA": [ + "32, mice {'context': 'B-organism'}", + "34, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "35, of {'perturbing_action': 'I-gene loss-of-function'}", + "36, Bak {'perturbing_action': 'I-gene loss-of-function'}", + "37, and {'perturbing_action': 'I-gene loss-of-function'}", + "38, Bax {'perturbing_action': 'I-gene loss-of-function'}", + "40, TIE2-expressing {'context': 'B-cells'}", + "41, cells {'context': 'I-cells'}", + "43, Tie2Cre; {'perturbing_action': 'B-gene loss-of-function'}", + "44, Bak1(-/-); {'perturbing_action': 'B-gene loss-of-function'}", + "45, Bax(flox/-) {'perturbing_action': 'B-gene loss-of-function'}", + "46, mice. {'context': 'B-organism'}", + "48, mice {'context': 'B-organism'}", + "71, mice {'context': 'B-organism'}", + "87, HSC {'context': 'B-cells'}", + "89, in {'context': 'B-in vivo'}", + "90, vivo {'context': 'I-in vivo'}", + "96, mice {'context': 'B-organism'}", + "105, antagonist, {'perturbing_action': 'I-pharmacological inhibition'}", + "108, HSC {'context': 'B-cells'}", + "114, mice {'context': 'B-organism'}", + "117, Mice {'context': 'B-organism'}", + "119, EGFR {'perturbing_action': 'B-gene loss-of-function'}", + "120, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "122, VAV-expressing {'context': 'B-cells'}", + "123, hematopoietic {'context': 'I-cells'}", + "124, cells {'context': 'I-cells'}", + "130, bone {'context': 'B-cells'}", + "131, marrow {'context': 'I-cells'}", + "132, stem {'context': 'I-cells'}", + "133, and {'context': 'I-cells'}", + "134, progenitor {'context': 'I-cells'}", + "135, cells {'context': 'I-cells'}", + "140, reduced {'effect': 'B-negative'}", + "141, radiation-induced {'effect': 'B-positive'}", + "142, apoptosis {'phenotype': 'B-apoptosis'}", + "144, HSCs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "32, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "34, deletion ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "35, of ['l1', 'l8', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "36, Bak ['l2', 'l9', 'l21', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "37, and ['l3', 'l10', 'l22', 'l33', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "38, Bax ['l4', 'l11', 'l23', 'l34', 'l44', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "40, TIE2-expressing ['l5', 'l12', 'l24', 'l35', 'l45', 'l54', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "41, cells ['l6', 'l13', 'l25', 'l36', 'l46', 'l55', 'l63', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "43, Tie2Cre; ['l14', 'l26', 'l37', 'l47', 'l56', 'l64', 'l74', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "44, Bak1(-/-); ['l65', 'l75', 'l84', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "45, Bax(flox/-) ['l66', 'l76', 'l85', 'l93', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "46, mice. ['l15', 'l27', 'l38', 'l48', 'l57', 'l67', 'l77', 'l86', 'l94', 'l103', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "48, mice ['l7', 'l16', 'l28', 'l39', 'l49', 'l58', 'l68', 'l78', 'l87', 'l95', 'l104', 'l112', 'l118', 'l119', 'l120', 'l121']", + "71, mice ['l17', 'l29', 'l40', 'l50', 'l59', 'l69', 'l79', 'l88', 'l96', 'l105', 'l113', 'l118', 'l122', 'l123', 'l124', 'l125']", + "87, HSC ['l18', 'l30', 'l41', 'l51', 'l60', 'l70', 'l80', 'l89', 'l97', 'l106', 'l114', 'l119', 'l122', 'l126', 'l127']", + "89, in ['l19', 'l31', 'l42', 'l52', 'l61', 'l71', 'l81', 'l90', 'l98', 'l107', 'l115', 'l120', 'l123', 'l126', 'l128']", + "90, vivo ['l20', 'l32', 'l43', 'l53', 'l62', 'l72', 'l82', 'l91', 'l99', 'l108', 'l116', 'l121', 'l124', 'l127', 'l128']", + "96, mice ['l73', 'l83', 'l92', 'l100', 'l109', 'l117', 'l125']", + "103, an ['l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "104, EGFR ['l129', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "105, antagonist, ['l130', 'l149', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185']", + "108, HSC ['l101', 'l110', 'l131', 'l150', 'l168', 'l186']", + "114, mice ['l102', 'l111', 'l132', 'l151', 'l169', 'l186']", + "117, Mice ['l133', 'l152', 'l170', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201']", + "119, EGFR ['l134', 'l153', 'l171', 'l187', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215']", + "120, deficiency ['l135', 'l154', 'l172', 'l188', 'l202', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228']", + "122, VAV-expressing ['l136', 'l155', 'l173', 'l189', 'l203', 'l216', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240']", + "123, hematopoietic ['l137', 'l156', 'l174', 'l190', 'l204', 'l217', 'l229', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251']", + "124, cells ['l138', 'l157', 'l175', 'l191', 'l205', 'l218', 'l230', 'l241', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261']", + "130, bone ['l139', 'l158', 'l176', 'l192', 'l206', 'l219', 'l231', 'l242', 'l252', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270']", + "131, marrow ['l140', 'l159', 'l177', 'l193', 'l207', 'l220', 'l232', 'l243', 'l253', 'l262', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278']", + "132, stem ['l141', 'l160', 'l178', 'l194', 'l208', 'l221', 'l233', 'l244', 'l254', 'l263', 'l271', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285']", + "133, and ['l142', 'l161', 'l179', 'l195', 'l209', 'l222', 'l234', 'l245', 'l255', 'l264', 'l272', 'l279', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291']", + "134, progenitor ['l143', 'l162', 'l180', 'l196', 'l210', 'l223', 'l235', 'l246', 'l256', 'l265', 'l273', 'l280', 'l286', 'l292', 'l293', 'l294', 'l295', 'l296']", + "135, cells ['l144', 'l163', 'l181', 'l197', 'l211', 'l224', 'l236', 'l247', 'l257', 'l266', 'l274', 'l281', 'l287', 'l292', 'l297', 'l298', 'l299']", + "140, reduced ['l145', 'l164', 'l182', 'l198', 'l212', 'l225', 'l237', 'l248', 'l258', 'l267', 'l275', 'l282', 'l288', 'l293', 'l297', 'l300', 'l301', 'l302']", + "141, radiation-induced ['l146', 'l165', 'l183', 'l199', 'l213', 'l226', 'l238', 'l249', 'l259', 'l268', 'l276', 'l283', 'l289', 'l294', 'l300', 'l303', 'l304']", + "142, apoptosis ['l147', 'l166', 'l184', 'l200', 'l214', 'l227', 'l239', 'l250', 'l260', 'l269', 'l277', 'l284', 'l290', 'l295', 'l298', 'l301', 'l303', 'l305']", + "144, HSCs ['l148', 'l167', 'l185', 'l201', 'l215', 'l228', 'l240', 'l251', 'l261', 'l270', 'l278', 'l285', 'l291', 'l296', 'l299', 'l302', 'l304', 'l305']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Bak", + "and", + "Bax", + "Tie2Cre;", + "Bak1(-/-);", + "Bax(flox/-)", + "EGFR", + "deficiency" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Bak", + "and", + "Bax", + "Tie2Cre;", + "Bak1(-/-);", + "Bax(flox/-)", + "EGFR", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "TIE2-expressing", + "cells", + "HSC", + "VAV-expressing", + "hematopoietic", + "bone", + "marrow", + "stem", + "and", + "progenitor", + "HSCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Bak", + "and", + "Bax", + "Tie2Cre;", + "Bak1(-/-);", + "Bax(flox/-)" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antagonist," + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC", + "VAV-expressing", + "hematopoietic", + "cells", + "bone", + "marrow", + "stem", + "and", + "progenitor", + "HSCs" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antagonist," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "Mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antagonist," + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antagonist," + ] + }, + "effect": { + "val": "positive", + "words": [ + "radiation-induced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antagonist," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "radiation-induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EGFR", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EGFR", + "deficiency" + ] + }, + "effect": { + "val": "positive", + "words": [ + "radiation-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EGFR", + "deficiency" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "VAV-expressing", + "hematopoietic", + "cells", + "bone", + "marrow", + "stem", + "and", + "progenitor", + "HSCs" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "VAV-expressing", + "hematopoietic", + "cells", + "bone", + "marrow", + "stem", + "and", + "progenitor", + "HSCs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "radiation-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "VAV-expressing", + "hematopoietic", + "cells", + "bone", + "marrow", + "stem", + "and", + "progenitor", + "HSCs" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "radiation-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "23314057", + "TEXT": "Left ventricular noncompaction (LVNC) causes prominent ventricular trabeculations and reduces cardiac systolic function. The clinical presentation of LVNC ranges from asymptomatic to heart failure. We show that germline mutations in human MIB1 (mindbomb homolog 1), which encodes an E3 ubiquitin ligase that promotes endocytosis of the NOTCH ligands DELTA and JAGGED, cause LVNC in autosomal-dominant pedigrees, with affected individuals showing reduced NOTCH1 activity and reduced expression of target genes. Functional studies in cells and zebrafish embryos and in silico modeling indicate that MIB1 functions as a dimer, which is disrupted by the human mutations. Targeted inactivation of Mib1 in mouse myocardium causes LVNC, a phenotype mimicked by inactivation of myocardial Jagged1 or endocardial Notch1. Myocardial Mib1 mutants show reduced ventricular Notch1 activity, expansion of compact myocardium to proliferative, immature trabeculae and abnormal expression of cardiac development and disease genes. These results implicate NOTCH signaling in LVNC and indicate that MIB1 mutations arrest chamber myocardium development, preventing trabecular maturation and compaction.", + "TAG_DATA": [ + "27, germline {'perturbing_action': 'B-other'}", + "28, mutations {'perturbing_action': 'I-other'}", + "29, in {'perturbing_action': 'I-other'}", + "30, human {'perturbing_action': 'I-other'}", + "31, MIB1 {'perturbing_action': 'I-other'}", + "32, (mindbomb {'perturbing_action': 'I-other'}", + "72, cells {'context': 'B-cells'}", + "74, zebrafish {'context': 'B-organism'}", + "75, embryos {'context': 'I-organism'}", + "94, Targeted {'perturbing_action': 'B-gene loss-of-function'}", + "95, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "96, of {'perturbing_action': 'I-gene loss-of-function'}", + "97, Mib1 {'perturbing_action': 'I-gene loss-of-function'}", + "99, mouse {'context': 'B-tissue/organ'}", + "100, myocardium {'context': 'I-tissue/organ'}", + "107, inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "108, of {'perturbing_action': 'I-gene loss-of-function'}", + "109, myocardial {'perturbing_action': 'I-gene loss-of-function'}", + "110, Jagged1 {'perturbing_action': 'I-gene loss-of-function'}", + "111, or {'perturbing_action': 'I-gene loss-of-function'}", + "112, endocardial {'perturbing_action': 'I-gene loss-of-function'}", + "113, Notch1. {'perturbing_action': 'I-gene loss-of-function'}", + "114, Myocardial {'perturbing_action': 'B-other'}", + "115, Mib1 {'perturbing_action': 'I-other'}", + "116, mutants {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "27, germline ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "28, mutations ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "29, in ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "30, human ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "31, MIB1 ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "32, (mindbomb ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "72, cells ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "74, zebrafish ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "75, embryos ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "94, Targeted ['l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "95, inactivation ['l36', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "96, of ['l37', 'l48', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "97, Mib1 ['l38', 'l49', 'l59', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "99, mouse ['l39', 'l50', 'l60', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "100, myocardium ['l40', 'l51', 'l61', 'l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "107, inactivation ['l41', 'l52', 'l62', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "108, of ['l42', 'l53', 'l63', 'l71', 'l78', 'l84', 'l90', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "109, myocardial ['l43', 'l54', 'l64', 'l72', 'l79', 'l85', 'l91', 'l97', 'l103', 'l104', 'l105', 'l106', 'l107']", + "110, Jagged1 ['l44', 'l55', 'l65', 'l73', 'l80', 'l86', 'l92', 'l98', 'l103', 'l108', 'l109', 'l110', 'l111']", + "111, or ['l45', 'l56', 'l66', 'l74', 'l81', 'l87', 'l93', 'l99', 'l104', 'l108', 'l112', 'l113', 'l114']", + "112, endocardial ['l46', 'l57', 'l67', 'l75', 'l82', 'l88', 'l94', 'l100', 'l105', 'l109', 'l112', 'l115', 'l116']", + "113, Notch1. ['l47', 'l58', 'l68', 'l76', 'l83', 'l89', 'l95', 'l101', 'l106', 'l110', 'l113', 'l115', 'l117']", + "114, Myocardial ['l118', 'l119', 'l120']", + "115, Mib1 ['l118', 'l121', 'l122']", + "116, mutants ['l119', 'l121', 'l123']", + "125, myocardium ['l96', 'l102', 'l107', 'l111', 'l114', 'l116', 'l117', 'l120', 'l122', 'l123']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "germline", + "mutations", + "in", + "human", + "MIB1", + "(mindbomb" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "germline", + "mutations", + "in", + "human", + "MIB1", + "(mindbomb" + ] + }, + "context": { + "val": "organism", + "words": [ + "zebrafish", + "embryos" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Targeted", + "inactivation", + "of", + "Mib1", + "myocardial", + "Jagged1", + "or", + "endocardial", + "Notch1." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "myocardium" + ] + } + } + ] + }, + { + "PMID": "23291630", + "TEXT": "Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.", + "TAG_DATA": [ + "106, ABT-199. {'perturbing_action': 'I-pharmacological inhibition'}", + "113, BCL-2-dependent {'context': 'B-neoplasm'}", + "114, tumors {'context': 'I-neoplasm'}", + "115, in {'context': 'B-in vivo'}", + "116, vivo {'context': 'I-in vivo'}", + "119, human {'context': 'B-cells'}", + "120, platelets. {'context': 'I-cells'}", + "128, patients {'context': 'B-patient'}", + "131, chronic {'context': 'I-neoplasm'}", + "132, lymphocytic {'context': 'I-neoplasm'}", + "133, leukemia {'context': 'I-neoplasm'}", + "134, resulted {'effect': 'B-positive'}", + "136, tumor {'phenotype': 'B-tumour regression'}", + "137, lysis {'phenotype': 'I-tumour regression'}" + ], + "LINK_DATA": [ + "106, ABT-199. ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "113, BCL-2-dependent ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "114, tumors ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "115, in ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "116, vivo ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "119, human ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "120, platelets. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "128, patients ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "130, refractory ['l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "131, chronic ['l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "132, lymphocytic ['l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "133, leukemia ['l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "134, resulted ['l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "136, tumor ['l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "137, lysis ['l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ABT-199." + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "BCL-2-dependent", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ABT-199." + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ABT-199." + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "platelets." + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulted" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "lysis" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "chronic", + "lymphocytic", + "leukemia" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulted" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "chronic", + "lymphocytic", + "leukemia" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "lysis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulted" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "lysis" + ] + } + } + ] + }, + { + "PMID": "23242472", + "TEXT": "In contrast with many capillary beds, the glomerulus readily supports leukocyte recruitment. However, little is known regarding the actions of leukocytes following their recruitment to glomeruli. We used multiphoton confocal microscopy to examine leukocyte behavior in the glomerular microvasculature. In normal glomeruli, neutrophils and monocytes were retained in capillaries for several minutes, remaining static or migrating intravascularly. Induction of glomerular inflammation resulted in an increase in the duration of retention of static and migratory leukocytes. In response to immune complex deposition, both static and migratory neutrophils generated oxidants in inflamed glomeruli via a Mac-1-dependent mechanism. Our results describe a new paradigm for glomerular inflammation, suggesting that the major effect of acute inflammation is to increase the duration of leukocyte retention in the glomerulus. Moreover, these findings describe a previously unknown form of multicellular intravascular patrolling that involves both monocytes and neutrophils, which may underlie the susceptibility of the glomerulus to inflammation.", + "TAG_DATA": [ + "41, glomeruli, {'context': 'B-tissue/organ'}", + "73, migratory {'phenotype': 'B-migration'}", + "74, leukocytes. {'context': 'B-cells'}", + "90, glomeruli {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "73, migratory ['l0']", + "74, leukocytes. ['l0']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "migration", + "words": [ + "migratory" + ] + }, + "context": { + "val": "cells", + "words": [ + "leukocytes." + ] + } + } + ] + }, + { + "PMID": "23202296", + "TEXT": "Chemotherapeutic agents are widely used for cancer treatment. In addition to their direct cytotoxic effects, these agents harness the host's immune system, which contributes to their antitumor activity. Here we show that two clinically used chemotherapeutic agents, gemcitabine (Gem) and 5-fluorouracil (5FU), activate the NOD-like receptor family, pyrin domain containing-3 protein (Nlrp3)-dependent caspase-1 activation complex (termed the inflammasome) in myeloid-derived suppressor cells (MDSCs), leading to production of interleukin-1β (IL-1β), which curtails anticancer immunity. Chemotherapy-triggered IL-1β secretion relied on lysosomal permeabilization and the release of cathepsin B, which bound to Nlrp3 and drove caspase-1 activation. MDSC-derived IL-1β induced secretion of IL-17 by CD4(+) T cells, which blunted the anticancer efficacy of the chemotherapy. Accordingly, Gem and 5FU exerted higher antitumor effects when tumors were established in Nlrp3(-/-) or Casp1(-/-) mice or wild-type mice treated with interleukin-1 receptor antagonist (IL-1Ra). Altogether, these results identify how activation of the Nlrp3 inflammasome in MDSCs by 5FU and Gem limits the antitumor efficacy of these chemotherapeutic agents.", + "TAG_DATA": [ + "101, CD4(+) {'context': 'B-cells'}", + "102, T {'context': 'I-cells'}", + "103, cells, {'context': 'I-cells'}", + "121, tumors {'context': 'B-neoplasm'}", + "125, Nlrp3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "126, or {'perturbing_action': 'I-gene loss-of-function'}", + "127, Casp1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "128, mice {'context': 'B-organism'}", + "131, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "101, CD4(+) ['l0', 'l1']", + "102, T ['l0', 'l2']", + "103, cells, ['l1', 'l2']", + "121, tumors ['l3', 'l4', 'l5', 'l6']", + "125, Nlrp3(-/-) ['l3', 'l7', 'l8', 'l9', 'l10']", + "126, or ['l4', 'l7', 'l11', 'l12']", + "127, Casp1(-/-) ['l5', 'l8', 'l11', 'l13', 'l14']", + "128, mice ['l6', 'l9', 'l12', 'l13']", + "131, mice ['l10', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nlrp3(-/-)", + "or", + "Casp1(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nlrp3(-/-)", + "or", + "Casp1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23202295", + "TEXT": "Despite growing interest and a recent surge in papers, the role of autophagy in glucose and lipid metabolism is unclear. We produced mice with skeletal muscle-specific deletion of Atg7 (encoding autophagy-related 7). Unexpectedly, these mice showed decreased fat mass and were protected from diet-induced obesity and insulin resistance; this phenotype was accompanied by increased fatty acid oxidation and browning of white adipose tissue (WAT) owing to induction of fibroblast growth factor 21 (Fgf21). Mitochondrial dysfunction induced by autophagy deficiency increased Fgf21 expression through induction of Atf4, a master regulator of the integrated stress response. Mitochondrial respiratory chain inhibitors also induced Fgf21 in an Atf4-dependent manner. We also observed induction of Fgf21, resistance to diet-induced obesity and amelioration of insulin resistance in mice with autophagy deficiency in the liver, another insulin target tissue. These findings suggest that autophagy deficiency and subsequent mitochondrial dysfunction promote Fgf21 expression, a hormone we consequently term a 'mitokine', and together these processes promote protection from diet-induced obesity and insulin resistance.", + "TAG_DATA": [ + "22, mice {'context': 'B-organism'}", + "24, skeletal {'perturbing_action': 'B-gene loss-of-function'}", + "25, muscle-specific {'perturbing_action': 'I-gene loss-of-function'}", + "26, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "27, of {'perturbing_action': 'I-gene loss-of-function'}", + "28, Atg7 {'perturbing_action': 'I-gene loss-of-function'}", + "29, (encoding {'perturbing_action': 'I-gene loss-of-function'}", + "30, autophagy-related {'perturbing_action': 'I-gene loss-of-function'}", + "31, 7). {'perturbing_action': 'I-gene loss-of-function'}", + "34, mice {'context': 'B-organism'}", + "121, mice {'context': 'B-organism'}", + "127, liver, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "22, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "24, skeletal ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "25, muscle-specific ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "26, deletion ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "27, of ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "28, Atg7 ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "29, (encoding ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "30, autophagy-related ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "31, 7). ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "34, mice ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "121, mice ['l45']", + "127, liver, ['l45']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "skeletal", + "muscle-specific", + "deletion", + "of", + "Atg7", + "(encoding", + "autophagy-related", + "7)." + ] + } + } + ] + }, + { + "PMID": "23202293", + "TEXT": "β-arrestins are associated with numerous aspects of G protein-coupled receptor (GPCR) signaling and regulation and accordingly influence diverse physiological and pathophysiological processes. Here we report that β-arrestin 2 expression is elevated in two independent cohorts of individuals with Alzheimer's disease. Overexpression of β-arrestin 2 leads to an increase in amyloid-β (Aβ) peptide generation, whereas genetic silencing of Arrb2 (encoding β-arrestin 2) reduces generation of Aβ in cell cultures and in Arrb2(-/-) mice. Moreover, in a transgenic mouse model of Alzheimer's disease, genetic deletion of Arrb2 leads to a reduction in the production of Aβ(40) and Aβ(42). Two GPCRs implicated previously in Alzheimer's disease (GPR3 and the β(2)-adrenergic receptor) mediate their effects on Aβ generation through interaction with β-arrestin 2. β-arrestin 2 physically associates with the Aph-1a subunit of the γ-secretase complex and redistributes the complex toward detergent-resistant membranes, increasing the catalytic activity of the complex. Collectively, these studies identify β-arrestin 2 as a new therapeutic target for reducing amyloid pathology and GPCR dysfunction in Alzheimer's disease.", + "TAG_DATA": [ + "40, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "41, of {'perturbing_action': 'I-gene gain-of-function'}", + "42, β-arrestin {'perturbing_action': 'I-gene gain-of-function'}", + "43, 2 {'perturbing_action': 'I-gene gain-of-function'}", + "54, genetic {'perturbing_action': 'B-rnai/knockdown'}", + "55, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "56, of {'perturbing_action': 'I-rnai/knockdown'}", + "57, Arrb2 {'perturbing_action': 'I-rnai/knockdown'}", + "58, (encoding {'perturbing_action': 'I-rnai/knockdown'}", + "59, β-arrestin {'perturbing_action': 'I-rnai/knockdown'}", + "60, 2) {'perturbing_action': 'I-rnai/knockdown'}", + "66, cell {'context': 'B-cells'}", + "67, cultures {'context': 'I-cells'}", + "70, Arrb2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "71, mice. {'context': 'B-organism'}", + "75, transgenic {'context': 'B-organism'}", + "76, mouse {'context': 'I-organism'}", + "77, model {'context': 'I-organism'}", + "78, of {'context': 'I-organism'}", + "79, Alzheimer's {'context': 'I-organism'}", + "80, disease, {'context': 'I-organism'}", + "81, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "82, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "83, of {'perturbing_action': 'I-gene loss-of-function'}", + "84, Arrb2 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "40, Overexpression ['l0', 'l1', 'l2', 'l3', 'l4']", + "41, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "42, β-arrestin ['l1', 'l5', 'l9', 'l10', 'l11']", + "43, 2 ['l2', 'l6', 'l9', 'l12', 'l13']", + "54, genetic ['l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "55, silencing ['l14', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "56, of ['l15', 'l29', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "57, Arrb2 ['l16', 'l30', 'l44', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "58, (encoding ['l17', 'l31', 'l45', 'l58', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "59, β-arrestin ['l18', 'l32', 'l46', 'l59', 'l71', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "60, 2) ['l19', 'l33', 'l47', 'l60', 'l72', 'l83', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "66, cell ['l3', 'l7', 'l10', 'l12', 'l20', 'l34', 'l48', 'l61', 'l73', 'l84', 'l94', 'l104']", + "67, cultures ['l4', 'l8', 'l11', 'l13', 'l21', 'l35', 'l49', 'l62', 'l74', 'l85', 'l95', 'l104']", + "70, Arrb2(-/-) ['l22', 'l36', 'l50', 'l63', 'l75', 'l86', 'l96', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "71, mice. ['l23', 'l37', 'l51', 'l64', 'l76', 'l87', 'l97', 'l105', 'l112', 'l113', 'l114', 'l115', 'l116']", + "75, transgenic ['l38', 'l52', 'l65', 'l77', 'l88', 'l98', 'l106', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "76, mouse ['l24', 'l39', 'l53', 'l66', 'l78', 'l89', 'l99', 'l107', 'l112', 'l117', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "77, model ['l25', 'l40', 'l54', 'l67', 'l79', 'l90', 'l100', 'l108', 'l113', 'l118', 'l126', 'l133', 'l134', 'l135', 'l136']", + "78, of ['l26', 'l41', 'l55', 'l68', 'l80', 'l91', 'l101', 'l109', 'l114', 'l119', 'l127', 'l133', 'l137', 'l138', 'l139']", + "79, Alzheimer's ['l27', 'l42', 'l56', 'l69', 'l81', 'l92', 'l102', 'l110', 'l115', 'l120', 'l128', 'l134', 'l137', 'l140', 'l141']", + "80, disease, ['l28', 'l43', 'l57', 'l70', 'l82', 'l93', 'l103', 'l111', 'l116', 'l121', 'l129', 'l135', 'l138', 'l140', 'l142']", + "81, genetic ['l122', 'l130', 'l143', 'l144', 'l145']", + "82, deletion ['l123', 'l143', 'l146', 'l147']", + "83, of ['l124', 'l131', 'l144', 'l146', 'l148']", + "84, Arrb2 ['l125', 'l132', 'l136', 'l139', 'l141', 'l142', 'l145', 'l147', 'l148']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "β-arrestin", + "2" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "cultures" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "genetic", + "silencing", + "of", + "Arrb2", + "(encoding", + "β-arrestin", + "2)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "cultures" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "genetic", + "silencing", + "of", + "Arrb2", + "(encoding", + "β-arrestin", + "2)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mouse", + "model", + "of", + "Alzheimer's", + "disease,", + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Arrb2(-/-)", + "genetic", + "deletion", + "of", + "Arrb2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "transgenic", + "mouse", + "model", + "of", + "Alzheimer's", + "disease," + ] + } + } + ] + }, + { + "PMID": "23178246", + "TEXT": "The role of the immune response to oncolytic Herpes simplex viral (oHSV) therapy for glioblastoma is controversial because it might enhance or inhibit efficacy. We found that within hours of oHSV infection of glioblastomas in mice, activated natural killer (NK) cells are recruited to the site of infection. This response substantially diminished the efficacy of glioblastoma virotherapy. oHSV-activated NK cells coordinated macrophage and microglia activation within tumors. In vitro, human NK cells preferentially lysed oHSV-infected human glioblastoma cell lines. This enhanced killing depended on the NK cell natural cytotoxicity receptors (NCRs) NKp30 and NKp46, whose ligands are upregulated in oHSV-infected glioblastoma cells. We found that HSV titers and oHSV efficacy are increased in Ncr1(-/-) mice and a Ncr1(-/-) NK cell adoptive transfer model of glioma, respectively. These results demonstrate that glioblastoma virotherapy is limited partially by an antiviral NK cell response involving specific NCRs, uncovering new potential targets to enhance cancer virotherapy.", + "TAG_DATA": [ + "58, NK {'context': 'B-cells'}", + "59, cells {'context': 'I-cells'}", + "67, In {'context': 'B-in vitro'}", + "68, vitro, {'context': 'I-in vitro'}", + "69, human {'context': 'B-cells'}", + "70, NK {'context': 'I-cells'}", + "71, cells {'context': 'I-cells'}", + "75, human {'context': 'B-transformed cells'}", + "76, glioblastoma {'context': 'I-transformed cells'}", + "77, cell {'context': 'I-transformed cells'}", + "78, lines. {'context': 'I-transformed cells'}", + "100, glioblastoma {'context': 'B-transformed cells'}", + "101, cells. {'context': 'I-transformed cells'}", + "113, Ncr1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "114, mice {'context': 'B-organism'}", + "117, Ncr1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "118, NK {'context': 'B-cells'}", + "119, cell {'context': 'I-cells'}", + "120, adoptive {'context': 'I-xenograft'}", + "121, transfer {'context': 'I-xenograft'}", + "122, model {'context': 'I-xenograft'}", + "123, of {'context': 'I-xenograft'}", + "124, glioma, {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "58, NK ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "59, cells ['l0', 'l8', 'l9']", + "67, In ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "68, vitro, ['l1', 'l10', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "69, human ['l11', 'l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "70, NK ['l2', 'l12', 'l21', 'l29', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "71, cells ['l3', 'l13', 'l22', 'l30', 'l37', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "75, human ['l4', 'l14', 'l23', 'l31', 'l38', 'l44', 'l50', 'l51', 'l52', 'l53', 'l54']", + "76, glioblastoma ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l55', 'l56', 'l57', 'l58']", + "77, cell ['l6', 'l8', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l59', 'l60', 'l61']", + "78, lines. ['l7', 'l9', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l62', 'l63']", + "100, glioblastoma ['l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l62', 'l64']", + "101, cells. ['l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l64']", + "113, Ncr1(-/-) ['l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "114, mice ['l65', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "117, Ncr1(-/-) ['l66', 'l74', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "118, NK ['l67', 'l75', 'l82', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "119, cell ['l68', 'l76', 'l83', 'l89', 'l95', 'l96', 'l97', 'l98', 'l99']", + "120, adoptive ['l69', 'l77', 'l84', 'l90', 'l95', 'l100', 'l101', 'l102', 'l103']", + "121, transfer ['l70', 'l78', 'l85', 'l91', 'l96', 'l100', 'l104', 'l105', 'l106']", + "122, model ['l71', 'l79', 'l86', 'l92', 'l97', 'l101', 'l104', 'l107', 'l108']", + "123, of ['l72', 'l80', 'l87', 'l93', 'l98', 'l102', 'l105', 'l107', 'l109']", + "124, glioma, ['l73', 'l81', 'l88', 'l94', 'l99', 'l103', 'l106', 'l108', 'l109']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ncr1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ncr1(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "NK", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ncr1(-/-)" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "adoptive", + "transfer", + "model", + "of" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ncr1(-/-)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "glioma," + ] + } + } + ] + }, + { + "PMID": "23160239", + "TEXT": "Enhancement of hematopoietic recovery after radiation, chemotherapy, or hematopoietic stem cell (HSC) transplantation is clinically relevant. Dipeptidylpeptidase (DPP4) cleaves a wide variety of substrates, including the chemokine stromal cell-derived factor-1 (SDF-1). In the course of experiments showing that inhibition of DPP4 enhances SDF-1-mediated progenitor cell survival, ex vivo cytokine expansion and replating frequency, we unexpectedly found that DPP4 has a more general role in regulating colony-stimulating factor (CSF) activity. DPP4 cleaved within the N-termini of the CSFs granulocyte-macrophage (GM)-CSF, G-CSF, interleukin-3 (IL-3) and erythropoietin and decreased their activity. Dpp4 knockout or DPP4 inhibition enhanced CSF activities both in vitro and in vivo. The reduced activity of DPP4-truncated versus full-length human GM-CSF was mechanistically linked to effects on receptor-binding affinity, induction of GM-CSF receptor oligomerization and signaling capacity. Hematopoiesis in mice after radiation or chemotherapy was enhanced in Dpp4(-/-) mice or mice receiving an orally active DPP4 inhibitor. DPP4 inhibition enhanced engraftment in mice without compromising HSC function, suggesting the potential clinical utility of this approach.", + "TAG_DATA": [ + "38, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "39, of {'perturbing_action': 'I-pharmacological inhibition'}", + "40, DPP4 {'perturbing_action': 'I-pharmacological inhibition'}", + "43, progenitor {'context': 'B-cells'}", + "44, cell {'context': 'I-cells'}", + "88, Dpp4 {'perturbing_action': 'B-gene loss-of-function'}", + "89, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "91, DPP4 {'perturbing_action': 'B-pharmacological inhibition'}", + "92, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "97, in {'context': 'B-in vitro'}", + "98, vitro {'context': 'I-in vitro'}", + "100, in {'context': 'B-in vivo'}", + "101, vivo. {'context': 'I-in vivo'}", + "129, mice {'context': 'B-organism'}", + "137, Dpp4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "138, mice {'context': 'B-organism'}", + "140, mice {'context': 'B-organism'}", + "143, orally {'perturbing_action': 'B-pharmacological inhibition'}", + "144, active {'perturbing_action': 'B-pharmacological inhibition'}", + "145, DPP4 {'perturbing_action': 'B-pharmacological inhibition'}", + "146, inhibitor. {'perturbing_action': 'I-pharmacological inhibition'}", + "147, DPP4 {'perturbing_action': 'B-pharmacological inhibition'}", + "148, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "152, mice {'context': 'B-organism'}", + "155, HSC {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "38, inhibition ['l0', 'l1', 'l2', 'l3']", + "39, of ['l0', 'l4', 'l5', 'l6']", + "40, DPP4 ['l1', 'l4', 'l7', 'l8']", + "43, progenitor ['l2', 'l5', 'l7', 'l9']", + "44, cell ['l3', 'l6', 'l8', 'l9']", + "88, Dpp4 ['l10', 'l11', 'l12', 'l13', 'l14']", + "89, knockout ['l10', 'l15', 'l16']", + "91, DPP4 ['l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "92, inhibition ['l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "97, in ['l12', 'l15', 'l18', 'l23', 'l28', 'l29', 'l30']", + "98, vitro ['l13', 'l16', 'l19', 'l24', 'l28', 'l31', 'l32']", + "100, in ['l20', 'l25', 'l29', 'l31', 'l33', 'l34']", + "101, vivo. ['l14', 'l21', 'l26', 'l30', 'l32', 'l33', 'l35']", + "129, mice ['l22', 'l27', 'l34', 'l35', 'l36']", + "137, Dpp4(-/-) ['l37', 'l38']", + "138, mice ['l36', 'l37']", + "140, mice ['l38']", + "143, orally ['l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "144, active ['l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "145, DPP4 ['l40', 'l46', 'l52', 'l53', 'l54', 'l55', 'l56']", + "146, inhibitor. ['l41', 'l47', 'l52', 'l57', 'l58', 'l59']", + "147, DPP4 ['l42', 'l48', 'l53', 'l60', 'l61', 'l62']", + "148, inhibition ['l43', 'l49', 'l54', 'l57', 'l60', 'l63', 'l64']", + "152, mice ['l44', 'l50', 'l55', 'l58', 'l61', 'l63', 'l65']", + "155, HSC ['l45', 'l51', 'l56', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "DPP4", + "orally", + "active", + "inhibitor." + ] + }, + "context": { + "val": "cells", + "words": [ + "progenitor", + "cell", + "HSC" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dpp4", + "knockout" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dpp4" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "DPP4", + "inhibition" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "DPP4", + "inhibition" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "DPP4", + "inhibition", + "orally", + "active", + "inhibitor." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dpp4(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23160238", + "TEXT": "In multiple sclerosis, an inflammatory disease of the central nervous system (CNS), axonal and neuronal loss are major causes for irreversible neurological disability. However, which molecules contribute to axonal and neuronal injury under inflammatory conditions remains largely unknown. Here we show that the transient receptor potential melastatin 4 (TRPM4) cation channel is crucial in this process. TRPM4 is expressed in mouse and human neuronal somata, but it is also expressed in axons in inflammatory CNS lesions in experimental autoimmune encephalomyelitis (EAE) in mice and in human multiple sclerosis tissue. Deficiency or pharmacological inhibition of TRPM4 using the antidiabetic drug glibenclamide resulted in reduced axonal and neuronal degeneration and attenuated clinical disease scores in EAE, but this occurred without altering EAE-relevant immune function. Furthermore, Trpm4(-/-) mouse neurons were protected against inflammatory effector mechanisms such as excitotoxic stress and energy deficiency in vitro. Electrophysiological recordings revealed TRPM4-dependent neuronal ion influx and oncotic cell swelling upon excitotoxic stimulation. Therefore, interference with TRPM4 could translate into a new neuroprotective treatment strategy.", + "TAG_DATA": [ + "91, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "92, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "93, of {'perturbing_action': 'I-pharmacological inhibition'}", + "94, TRPM4 {'perturbing_action': 'I-pharmacological inhibition'}", + "95, using {'perturbing_action': 'I-pharmacological inhibition'}", + "96, the {'perturbing_action': 'I-pharmacological inhibition'}", + "97, antidiabetic {'perturbing_action': 'I-pharmacological inhibition'}", + "98, drug {'perturbing_action': 'I-pharmacological inhibition'}", + "99, glibenclamide {'perturbing_action': 'I-pharmacological inhibition'}", + "123, Trpm4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "124, mouse {'context': 'B-cells'}", + "125, neurons {'context': 'I-cells'}", + "139, in {'context': 'B-in vitro'}", + "140, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "91, pharmacological ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "92, inhibition ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "93, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "94, TRPM4 ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "95, using ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "96, the ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "97, antidiabetic ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "98, drug ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "99, glibenclamide ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "123, Trpm4(-/-) ['l36', 'l37', 'l38', 'l39']", + "124, mouse ['l36', 'l40', 'l41', 'l42']", + "125, neurons ['l37', 'l40', 'l43', 'l44']", + "139, in ['l38', 'l41', 'l43', 'l45']", + "140, vitro. ['l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trpm4(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "neurons" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trpm4(-/-)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "23142820", + "TEXT": "We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate that has superior sex-independent efficacy over either of the individual hormones alone to correct obesity, hyperglycemia and dyslipidemia in mice. The therapeutic benefits are driven by pleiotropic dual hormone action to improve energy, glucose and lipid metabolism, as shown by loss-of-function models and genetic action profiling. Notably, the peptide-based targeting strategy also prevents hallmark side effects of estrogen in male and female mice, such as reproductive endocrine toxicity and oncogenicity. Collectively, selective activation of estrogen receptors in GLP-1-targeted tissues produces unprecedented efficacy to enhance the metabolic benefits of GLP-1 agonism. This example of targeting the metabolic syndrome represents the discovery of a new class of therapeutics that enables synergistic co-agonism through peptide-based selective delivery of small molecules. Although our observations with the GLP-1-estrogen conjugate justify translational studies for diabetes and obesity, the multitude of other possible combinations of peptides and small molecules may offer equal promise for other diseases.", + "TAG_DATA": [ + "57, mice. {'context': 'B-organism'}", + "97, male {'context': 'B-organism'}", + "98, and {'context': 'I-organism'}", + "99, female {'context': 'I-organism'}", + "100, mice, {'context': 'I-organism'}", + "107, oncogenicity. {'phenotype': 'B-tumourigenesis'}", + "110, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "111, of {'perturbing_action': 'I-pharmacological augmentation'}", + "112, estrogen {'perturbing_action': 'I-pharmacological augmentation'}", + "113, receptors {'perturbing_action': 'I-pharmacological augmentation'}" + ], + "LINK_DATA": [ + "97, male ['l0', 'l1', 'l2', 'l3']", + "98, and ['l0', 'l4', 'l5', 'l6']", + "99, female ['l1', 'l4', 'l7', 'l8']", + "100, mice, ['l2', 'l5', 'l7', 'l9']", + "107, oncogenicity. ['l3', 'l6', 'l8', 'l9']", + "110, activation ['l10', 'l11', 'l12']", + "111, of ['l10', 'l13', 'l14']", + "112, estrogen ['l11', 'l13', 'l15']", + "113, receptors ['l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "male", + "and", + "female", + "mice," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "oncogenicity." + ] + } + } + ] + }, + { + "PMID": "23001182", + "TEXT": "We found that hematopoietic cell-specific Lyn substrate 1 (HCLS1 or HS1) is highly expressed in human myeloid cells and that stimulation with granulocyte colony-stimulating factor (G-CSF) leads to HCLS1 phosphorylation. HCLS1 binds the transcription factor lymphoid-enhancer binding factor 1 (LEF-1), transporting LEF-1 into the nucleus upon G-CSF stimulation and inducing LEF-1 autoregulation. In patients with severe congenital neutropenia, inherited mutations in the gene encoding HCLS1-associated protein X-1 (HAX1) lead to profound defects in G-CSF-triggered phosphorylation of HCLS1 and subsequently to reduced autoregulation and expression of LEF-1. Consistent with these results, HCLS1-deficient mice are neutropenic. In bone marrow biopsies of the majority of tested patients with acute myeloid leukemia, HCLS1 protein expression is substantially elevated, associated with high levels of G-CSF synthesis and, in some individuals, a four-residue insertion in a proline-rich region of HCLS1 protein known to accelerate intracellular signaling. These data demonstrate the importance of HCLS1 in myelopoiesis in vitro and in vivo.", + "TAG_DATA": [ + "58, inherited {'perturbing_action': 'B-other'}", + "59, mutations {'perturbing_action': 'I-other'}", + "60, in {'perturbing_action': 'I-other'}", + "61, the {'perturbing_action': 'I-other'}", + "62, gene {'perturbing_action': 'I-other'}", + "63, encoding {'perturbing_action': 'I-other'}", + "64, HCLS1-associated {'perturbing_action': 'I-other'}", + "65, protein {'perturbing_action': 'I-other'}", + "66, X-1 {'perturbing_action': 'I-other'}", + "67, (HAX1) {'perturbing_action': 'I-other'}", + "90, HCLS1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "91, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "58, inherited ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "59, mutations ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "60, in ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "61, the ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "62, gene ['l3', 'l11', 'l18', 'l24', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "63, encoding ['l4', 'l12', 'l19', 'l25', 'l31', 'l37', 'l38', 'l39', 'l40', 'l41']", + "64, HCLS1-associated ['l5', 'l13', 'l20', 'l26', 'l32', 'l37', 'l42', 'l43', 'l44', 'l45']", + "65, protein ['l6', 'l14', 'l21', 'l27', 'l33', 'l38', 'l42', 'l46', 'l47', 'l48']", + "66, X-1 ['l7', 'l15', 'l22', 'l28', 'l34', 'l39', 'l43', 'l46', 'l49', 'l50']", + "67, (HAX1) ['l8', 'l16', 'l23', 'l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l51']", + "90, HCLS1-deficient ['l52']", + "91, mice ['l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l51', 'l52']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "the", + "gene", + "encoding", + "HCLS1-associated", + "protein", + "X-1", + "(HAX1)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "HCLS1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "22922411", + "TEXT": "Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Disease onset and progression are variable, with survival ranging from months to decades. Factors underlying this variability may represent targets for therapeutic intervention. Here, we have screened a zebrafish model of ALS and identified Epha4, a receptor in the ephrin axonal repellent system, as a modifier of the disease phenotype in fish, rodents and humans. Genetic as well as pharmacological inhibition of Epha4 signaling rescues the mutant SOD1 phenotype in zebrafish and increases survival in mouse and rat models of ALS. Motor neurons that are most vulnerable to degeneration in ALS express higher levels of Epha4, and neuromuscular re-innervation by axotomized motor neurons is inhibited by the presence of Epha4. In humans with ALS, EPHA4 expression inversely correlates with disease onset and survival, and loss-of-function mutations in EPHA4 are associated with long survival. Furthermore, we found that knockdown of Epha4 also rescues the axonopathy induced by expression of mutant TAR DNA-binding protein 43 (TDP-43), another protein causing familial ALS, and the axonopathy induced by knockdown of survival of motor neuron 1, a model for spinomuscular atrophy. This suggests that Epha4 generically modulates the vulnerability of (motor) neurons to axonal degeneration and may represent a new target for therapeutic intervention.", + "TAG_DATA": [ + "71, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "72, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "73, of {'perturbing_action': 'I-pharmacological inhibition'}", + "74, Epha4 {'perturbing_action': 'I-pharmacological inhibition'}", + "75, signaling {'perturbing_action': 'I-pharmacological inhibition'}", + "82, zebrafish {'context': 'B-organism'}", + "87, mouse {'context': 'B-organism'}", + "88, and {'context': 'I-organism'}", + "89, rat {'context': 'I-organism'}", + "90, models {'context': 'I-organism'}", + "91, of {'context': 'I-organism'}", + "92, ALS. {'context': 'I-organism'}", + "93, Motor {'context': 'B-cells'}", + "94, neurons {'context': 'I-cells'}", + "113, motor {'context': 'I-cells'}", + "114, neurons {'context': 'I-cells'}", + "149, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "150, of {'perturbing_action': 'I-rnai/knockdown'}", + "151, Epha4 {'perturbing_action': 'I-rnai/knockdown'}", + "158, expression {'perturbing_action': 'B-other'}", + "160, mutant {'perturbing_action': 'B-other'}", + "161, TAR {'perturbing_action': 'I-other'}", + "162, DNA-binding {'perturbing_action': 'I-other'}", + "163, protein {'perturbing_action': 'I-other'}", + "164, 43 {'perturbing_action': 'I-other'}", + "165, (TDP-43), {'perturbing_action': 'I-other'}", + "176, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "177, of {'perturbing_action': 'I-rnai/knockdown'}", + "178, survival {'perturbing_action': 'I-rnai/knockdown'}", + "179, of {'perturbing_action': 'I-rnai/knockdown'}", + "180, motor {'perturbing_action': 'I-rnai/knockdown'}", + "181, neuron {'perturbing_action': 'I-rnai/knockdown', 'context': 'I-cells'}", + "182, 1, {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "71, pharmacological ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "72, inhibition ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "73, of ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "74, Epha4 ['l2', 'l16', 'l29', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "75, signaling ['l3', 'l17', 'l30', 'l42', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "82, zebrafish ['l4', 'l18', 'l31', 'l43', 'l54', 'l65', 'l66']", + "87, mouse ['l5', 'l19', 'l32', 'l44', 'l55', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "88, and ['l6', 'l20', 'l33', 'l45', 'l56', 'l67', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "89, rat ['l7', 'l21', 'l34', 'l46', 'l57', 'l68', 'l76', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "90, models ['l8', 'l22', 'l35', 'l47', 'l58', 'l69', 'l77', 'l84', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "91, of ['l9', 'l23', 'l36', 'l48', 'l59', 'l65', 'l70', 'l78', 'l85', 'l91', 'l97', 'l98', 'l99', 'l100', 'l101']", + "92, ALS. ['l10', 'l24', 'l37', 'l49', 'l60', 'l66', 'l71', 'l79', 'l86', 'l92', 'l97', 'l102', 'l103', 'l104', 'l105']", + "93, Motor ['l11', 'l25', 'l38', 'l50', 'l61', 'l72', 'l80', 'l87', 'l93', 'l98', 'l102', 'l106', 'l107', 'l108']", + "94, neurons ['l12', 'l26', 'l39', 'l51', 'l62', 'l73', 'l81', 'l88', 'l94', 'l99', 'l103', 'l106', 'l109', 'l110']", + "113, motor ['l13', 'l27', 'l40', 'l52', 'l63', 'l74', 'l82', 'l89', 'l95', 'l100', 'l104', 'l107', 'l109', 'l111']", + "114, neurons ['l14', 'l28', 'l41', 'l53', 'l64', 'l75', 'l83', 'l90', 'l96', 'l101', 'l105', 'l108', 'l110', 'l111']", + "149, knockdown ['l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127']", + "150, of ['l112', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "151, Epha4 ['l113', 'l128', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156']", + "158, expression ['l114', 'l129', 'l143', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162']", + "160, mutant ['l115', 'l130', 'l144', 'l157', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168']", + "161, TAR ['l116', 'l131', 'l145', 'l158', 'l163', 'l169', 'l170', 'l171', 'l172']", + "162, DNA-binding ['l117', 'l132', 'l146', 'l159', 'l164', 'l169', 'l173', 'l174', 'l175']", + "163, protein ['l118', 'l133', 'l147', 'l160', 'l165', 'l170', 'l173', 'l176', 'l177']", + "164, 43 ['l119', 'l134', 'l148', 'l161', 'l166', 'l171', 'l174', 'l176', 'l178']", + "165, (TDP-43), ['l120', 'l135', 'l149', 'l162', 'l167', 'l172', 'l175', 'l177', 'l178']", + "176, knockdown ['l121', 'l136', 'l150', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184']", + "177, of ['l122', 'l137', 'l151', 'l179', 'l185', 'l186', 'l187', 'l188', 'l189']", + "178, survival ['l123', 'l138', 'l152', 'l180', 'l185', 'l190', 'l191', 'l192', 'l193']", + "179, of ['l124', 'l139', 'l153', 'l181', 'l186', 'l190', 'l194', 'l195', 'l196']", + "180, motor ['l125', 'l140', 'l154', 'l182', 'l187', 'l191', 'l194', 'l197', 'l198']", + "181, neuron ['l126', 'l141', 'l155', 'l183', 'l188', 'l192', 'l195', 'l197', 'l199']", + "182, 1, ['l127', 'l142', 'l156', 'l168', 'l184', 'l189', 'l193', 'l196', 'l198', 'l199']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "Epha4", + "signaling" + ] + }, + "context": { + "val": "organism", + "words": [ + "zebrafish", + "mouse", + "and", + "rat", + "models", + "of", + "ALS." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "Epha4", + "signaling" + ] + }, + "context": { + "val": "cells", + "words": [ + "Motor", + "neurons", + "motor" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "Epha4", + "survival", + "motor", + "neuron" + ] + }, + "context": { + "val": "cells", + "words": [ + "neuron" + ] + } + } + ] + }, + { + "PMID": "22863787", + "TEXT": "Chronic low-grade adipose tissue and liver inflammation is a major cause of systemic insulin resistance and is a key component of the low degree of insulin sensitivity that exists in obesity and type 2 diabetes. Immune cells, such as macrophages, T cells, B cells, mast cells and eosinophils, have all been implicated as having a role in this process. Neutrophils are typically the first immune cells to respond to inflammation and can exacerbate the chronic inflammatory state by helping to recruit macrophages and by interacting with antigen-presenting cells. Neutrophils secrete several proteases, one of which is neutrophil elastase, which can promote inflammatory responses in several disease models. Here we show that treatment of hepatocytes with neutrophil elastase causes cellular insulin resistance and that deletion of neutrophil elastase in high-fat-diet–induced obese (DIO) mice leads to less tissue inflammation that is associated with lower adipose tissue neutrophil and macrophage content. These changes are accompanied by improved glucose tolerance and increased insulin sensitivity. Taken together, we show that neutrophils can be added to the extensive repertoire of immune cells that participate in inflammation-induced metabolic disease.", + "TAG_DATA": [ + "113, hepatocytes {'context': 'B-cells'}", + "123, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "124, of {'perturbing_action': 'I-gene loss-of-function'}", + "125, neutrophil {'perturbing_action': 'I-gene loss-of-function'}", + "126, elastase {'perturbing_action': 'I-gene loss-of-function'}", + "131, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "123, deletion ['l0', 'l1', 'l2', 'l3']", + "124, of ['l0', 'l4', 'l5', 'l6']", + "125, neutrophil ['l1', 'l4', 'l7', 'l8']", + "126, elastase ['l2', 'l5', 'l7', 'l9']", + "131, mice ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "neutrophil", + "elastase" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "22863786", + "TEXT": "Acquired resistance to anticancer treatments is a substantial barrier to reducing the morbidity and mortality that is attributable to malignant tumors. Components of tissue microenvironments are recognized to profoundly influence cellular phenotypes, including susceptibilities to toxic insults. Using a genome-wide analysis of transcriptional responses to genotoxic stress induced by cancer therapeutics, we identified a spectrum of secreted proteins derived from the tumor microenvironment that includes the Wnt family member wingless-type MMTV integration site family member 16B (WNT16B). We determined that WNT16B expression is regulated by nuclear factor of κ light polypeptide gene enhancer in B cells 1 (NF-κB) after DNA damage and subsequently signals in a paracrine manner to activate the canonical Wnt program in tumor cells. The expression of WNT16B in the prostate tumor microenvironment attenuated the effects of cytotoxic chemotherapy in vivo, promoting tumor cell survival and disease progression. These results delineate a mechanism by which genotoxic therapies given in a cyclical manner can enhance subsequent treatment resistance through cell nonautonomous effects that are contributed by the tumor microenvironment.", + "TAG_DATA": [ + "124, tumor {'context': 'I-tissue/organ'}", + "132, in {'context': 'B-in vivo'}", + "133, vivo, {'context': 'I-in vivo'}", + "134, promoting {'effect': 'B-positive'}", + "135, tumor {'context': 'B-transformed cells'}", + "136, cell {'context': 'I-transformed cells'}", + "137, survival {'phenotype': 'I-cell survival'}" + ], + "LINK_DATA": [ + "123, prostate ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "124, tumor ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "132, in ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "133, vivo, ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "134, promoting ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "135, tumor ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "136, cell ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "137, survival ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "tumor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "survival" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "survival" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "survival" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "survival" + ] + } + } + ] + }, + { + "PMID": "22797809", + "TEXT": "The ataxia telangiectasia mutated (ATM) kinase, a master regulator of the DNA damage response (DDR), acts as a barrier to cellular senescence and tumorigenesis. Aside from DDR signaling, ATM also functions in oxidative defense. Here we show that Atm in mice is activated specifically in immature vessels in response to the accumulation of reactive oxygen species (ROS). Global or endothelial-specific Atm deficiency in mice blocked pathological neoangiogenesis in the retina. This block resulted from increased amounts of ROS and excessive activation of the mitogen activated kinase p38α rather than from defects in the canonical DDR pathway. Atm deficiency also lowered tumor angiogenesis and enhanced the antiangiogenic action of vascular endothelial growth factor (Vegf) blockade. These data suggest that pathological neoangiogenesis requires ATM-mediated oxidative defense and that agents that promote excessive ROS generation may have beneficial effects in the treatment of neovascular disease.", + "TAG_DATA": [ + "59, endothelial-specific {'perturbing_action': 'B-gene loss-of-function'}", + "60, Atm {'perturbing_action': 'I-gene loss-of-function'}", + "61, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "63, mice {'context': 'B-organism'}", + "69, retina. {'context': 'B-tissue/organ'}", + "96, Atm {'perturbing_action': 'B-gene loss-of-function'}", + "97, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "100, tumor {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "59, endothelial-specific ['l0', 'l1', 'l2', 'l3']", + "60, Atm ['l0', 'l4', 'l5', 'l6']", + "61, deficiency ['l1', 'l4', 'l7', 'l8']", + "63, mice ['l2', 'l5', 'l7', 'l9']", + "69, retina. ['l3', 'l6', 'l8', 'l9']", + "96, Atm ['l10', 'l11']", + "97, deficiency ['l10', 'l12']", + "100, tumor ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "endothelial-specific", + "Atm", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "endothelial-specific", + "Atm", + "deficiency" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "retina." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atm", + "deficiency" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + } + ] + }, + { + "PMID": "22706385", + "TEXT": "In most adult humans, hepatitis B is a self-limiting disease leading to life-long protective immunity, which is the consequence of a robust adaptive immune response occurring weeks after hepatitis B virus (HBV) infection. Notably, HBV-specific T cells can be detected shortly after infection, but the mechanisms underlying this early immune priming and its consequences for subsequent control of viral replication are poorly understood. Using primary human and mouse hepatocytes and mouse models of transgenic and adenoviral HBV expression, we show that HBV-expressing hepatocytes produce endoplasmic reticulum (ER)-associated endogenous antigenic lipids including lysophospholipids that are generated by HBV-induced secretory phospholipases and that lead to activation of natural killer T (NKT) cells. The absence of NKT cells or CD1d or a defect in ER-associated transfer of lipids onto CD1d results in diminished HBV-specific T and B cell responses and delayed viral control in mice. NKT cells may therefore contribute to control of HBV infection through sensing of HBV-induced modified self-lipids.", + "TAG_DATA": [ + "64, primary {'context': 'B-cells'}", + "65, human {'context': 'I-cells'}", + "66, and {'context': 'I-cells'}", + "67, mouse {'context': 'I-cells'}", + "68, hepatocytes {'context': 'I-cells'}", + "70, mouse {'context': 'B-organism'}", + "71, models {'context': 'I-organism'}", + "72, of {'perturbing_action': 'I-gene gain-of-function'}", + "73, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "74, and {'perturbing_action': 'I-gene gain-of-function'}", + "75, adenoviral {'perturbing_action': 'I-gene gain-of-function'}", + "76, HBV {'perturbing_action': 'I-gene gain-of-function'}", + "77, expression, {'perturbing_action': 'I-gene gain-of-function'}", + "81, HBV-expressing {'context': 'B-cells'}", + "82, hepatocytes {'context': 'I-cells'}", + "105, natural {'context': 'B-cells'}", + "106, killer {'context': 'I-cells'}", + "107, T {'context': 'I-cells'}", + "108, (NKT) {'context': 'I-cells'}", + "109, cells. {'context': 'I-cells'}", + "113, NKT {'context': 'B-cells'}", + "114, cells {'context': 'I-cells'}", + "131, T {'context': 'B-cells'}", + "132, and {'context': 'I-cells'}", + "133, B {'context': 'I-cells'}", + "134, cell {'context': 'I-cells'}", + "141, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "64, primary ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "65, human ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "66, and ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "67, mouse ['l2', 'l10', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29']", + "68, hepatocytes ['l3', 'l11', 'l18', 'l25', 'l30', 'l31', 'l32', 'l33']", + "70, mouse ['l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "71, models ['l34', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "72, of ['l35', 'l48', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "73, transgenic ['l19', 'l36', 'l49', 'l61', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "74, and ['l37', 'l50', 'l62', 'l73', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "75, adenoviral ['l38', 'l51', 'l63', 'l74', 'l84', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "76, HBV ['l4', 'l12', 'l20', 'l26', 'l30', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "77, expression, ['l5', 'l13', 'l21', 'l27', 'l31', 'l40', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "81, HBV-expressing ['l6', 'l14', 'l22', 'l28', 'l32', 'l41', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "82, hepatocytes ['l7', 'l15', 'l23', 'l29', 'l33', 'l42', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l118', 'l124', 'l125', 'l126', 'l127', 'l128']", + "105, natural ['l43', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l113', 'l119', 'l124', 'l129', 'l130', 'l131', 'l132']", + "106, killer ['l44', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l129', 'l133', 'l134', 'l135']", + "107, T ['l45', 'l58', 'l70', 'l81', 'l91', 'l100', 'l108', 'l115', 'l121', 'l126', 'l130', 'l133', 'l136', 'l137']", + "108, (NKT) ['l46', 'l59', 'l71', 'l82', 'l92', 'l101', 'l109', 'l116', 'l122', 'l127', 'l131', 'l134', 'l136', 'l138']", + "109, cells. ['l8', 'l16', 'l24', 'l47', 'l60', 'l72', 'l83', 'l93', 'l102', 'l110', 'l117', 'l123', 'l128', 'l132', 'l135', 'l137', 'l138']", + "113, NKT ['l139', 'l140', 'l141', 'l142', 'l143']", + "114, cells ['l139', 'l144', 'l145', 'l146', 'l147']", + "131, T ['l140', 'l144', 'l148', 'l149', 'l150', 'l151']", + "132, and ['l141', 'l145', 'l148', 'l152', 'l153', 'l154']", + "133, B ['l142', 'l146', 'l149', 'l152', 'l155', 'l156']", + "134, cell ['l143', 'l147', 'l150', 'l153', 'l155', 'l157']", + "141, mice. ['l151', 'l154', 'l156', 'l157']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "primary", + "human", + "and", + "mouse", + "hepatocytes", + "HBV-expressing", + "natural", + "killer", + "T", + "(NKT)", + "cells." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "HBV", + "expression,", + "transgenic", + "of", + "and", + "adenoviral" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "transgenic", + "and", + "adenoviral", + "HBV", + "expression," + ] + } + } + ] + }, + { + "PMID": "22683780", + "TEXT": "Although the treatment of acute myeloid leukemia (AML) has improved substantially in the past three decades, more than half of all patients develop disease that is refractory to intensive chemotherapy. Functional genomics approaches offer a means to discover specific molecules mediating the aberrant growth and survival of cancer cells. Thus, using a loss-of-function RNA interference genomic screen, we identified the aberrant expression of hepatocyte growth factor (HGF) as a crucial element in AML pathogenesis. We found HGF expression leading to autocrine activation of its receptor tyrosine kinase, MET, in nearly half of the AML cell lines and clinical samples we studied. Genetic depletion of HGF or MET potently inhibited the growth and survival of HGF-expressing AML cells. However, leukemic cells treated with the specific MET kinase inhibitor crizotinib developed resistance resulting from compensatory upregulation of HGF expression, leading to the restoration of MET signaling. In cases of AML where MET is coactivated with other tyrosine kinases, such as fibroblast growth factor receptor 1 (FGFR1), concomitant inhibition of FGFR1 and MET blocked this compensatory HGF upregulation, resulting in sustained logarithmic cell killing both in vitro and in xenograft models in vivo. Our results show a widespread dependence of AML cells on autocrine activation of MET, as well as the key role of compensatory upregulation of HGF expression in maintaining leukemogenic signaling by this receptor. We anticipate that these findings will lead to the design of additional strategies to block adaptive cellular responses that drive compensatory ligand expression as an essential component of the targeted inhibition of oncogenic receptors in human cancers.", + "TAG_DATA": [ + "101, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "102, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "103, of {'perturbing_action': 'I-gene loss-of-function'}", + "104, HGF {'perturbing_action': 'I-gene loss-of-function'}", + "105, or {'perturbing_action': 'I-gene loss-of-function'}", + "106, MET {'perturbing_action': 'I-gene loss-of-function'}", + "114, HGF-expressing {'context': 'B-transformed cells'}", + "115, AML {'context': 'I-transformed cells'}", + "116, cells. {'context': 'I-transformed cells'}", + "118, leukemic {'context': 'B-transformed cells'}", + "119, cells {'context': 'I-transformed cells'}", + "165, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "166, of {'perturbing_action': 'I-pharmacological inhibition'}", + "167, FGFR1 {'perturbing_action': 'I-pharmacological inhibition'}", + "168, and {'perturbing_action': 'I-pharmacological inhibition'}", + "169, MET {'perturbing_action': 'I-pharmacological inhibition'}", + "179, cell {'phenotype': 'B-cell death'}", + "180, killing {'phenotype': 'I-cell death'}", + "182, in {'context': 'B-in vitro'}", + "183, vitro {'context': 'I-in vitro'}", + "186, xenograft {'context': 'B-xenograft'}", + "187, models {'context': 'I-xenograft'}", + "188, in {'context': 'B-in vivo'}", + "189, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "101, Genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "102, depletion ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "103, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "104, HGF ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28']", + "105, or ['l3', 'l11', 'l18', 'l24', 'l29', 'l30', 'l31', 'l32', 'l33']", + "106, MET ['l4', 'l12', 'l19', 'l25', 'l29', 'l34', 'l35', 'l36']", + "114, HGF-expressing ['l5', 'l13', 'l20', 'l26', 'l30', 'l34', 'l37', 'l38']", + "115, AML ['l6', 'l14', 'l21', 'l27', 'l31', 'l35', 'l37', 'l39']", + "116, cells. ['l7', 'l15', 'l22', 'l28', 'l32', 'l36', 'l38', 'l39']", + "118, leukemic ['l40', 'l41', 'l42', 'l43', 'l44']", + "119, cells ['l8', 'l16', 'l23', 'l33', 'l40', 'l45', 'l46']", + "165, inhibition ['l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "166, of ['l47', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "167, FGFR1 ['l48', 'l59', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "168, and ['l49', 'l60', 'l70', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "169, MET ['l50', 'l61', 'l71', 'l80', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "179, cell ['l41', 'l45', 'l51', 'l62', 'l72', 'l81', 'l89', 'l97', 'l98', 'l99']", + "180, killing ['l42', 'l46', 'l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l100', 'l101']", + "182, in ['l43', 'l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l100', 'l102']", + "183, vitro ['l44', 'l54', 'l65', 'l75', 'l84', 'l92', 'l99', 'l101', 'l102']", + "186, xenograft ['l55', 'l66', 'l76', 'l85', 'l93', 'l103', 'l104', 'l105']", + "187, models ['l56', 'l67', 'l77', 'l86', 'l94', 'l103', 'l106', 'l107']", + "188, in ['l57', 'l68', 'l78', 'l87', 'l95', 'l104', 'l106', 'l108']", + "189, vivo. ['l58', 'l69', 'l79', 'l88', 'l96', 'l105', 'l107', 'l108']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "depletion", + "of", + "HGF", + "or", + "MET" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HGF-expressing", + "AML", + "cells.", + "cells" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "leukemic", + "cells" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "killing" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "FGFR1", + "and", + "MET" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "killing" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "FGFR1", + "and", + "MET" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "FGFR1", + "and", + "MET" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "models" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "FGFR1", + "and", + "MET" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "killing" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "22683778", + "TEXT": "Neoadjuvant chemotherapy (NAC) induces a pathological complete response (pCR) in ~30% of patients with breast cancer. However, many patients have residual cancer after chemotherapy, which correlates with a higher risk of metastatic recurrence and poorer outcome than those who achieve a pCR. We hypothesized that molecular profiling of tumors after NAC would identify genes associated with drug resistance. Digital transcript counting was used to profile surgically resected breast cancers after NAC. Low concentrations of dual specificity protein phosphatase 4 (DUSP4), an ERK phosphatase, correlated with high post-NAC tumor cell proliferation and with basal-like breast cancer (BLBC) status. BLBC had higher DUSP4 promoter methylation and gene expression patterns of Ras-ERK pathway activation relative to other breast cancer subtypes. DUSP4 overexpression increased chemotherapy-induced apoptosis, whereas DUSP4 depletion dampened the response to chemotherapy. Reduced DUSP4 expression in primary tumors after NAC was associated with treatment-refractory high Ki-67 scores and shorter recurrence-free survival. Finally, inhibition of mitogen-activated protein kinase kinase (MEK) synergized with docetaxel treatment in BLBC xenografts. Thus, DUSP4 downregulation activates the Ras-ERK pathway in BLBC, resulting in an attenuated response to anti-cancer chemotherapy.", + "TAG_DATA": [ + "117, DUSP4 {'perturbing_action': 'B-gene gain-of-function'}", + "118, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "119, increased {'effect': 'B-positive'}", + "120, chemotherapy-induced {'effect': 'B-positive'}", + "121, apoptosis, {'phenotype': 'B-apoptosis'}", + "123, DUSP4 {'perturbing_action': 'B-gene loss-of-function'}", + "124, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "150, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "151, of {'perturbing_action': 'I-pharmacological inhibition'}", + "152, mitogen-activated {'perturbing_action': 'I-pharmacological inhibition'}", + "153, protein {'perturbing_action': 'I-pharmacological inhibition'}", + "154, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "155, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "156, (MEK) {'perturbing_action': 'I-pharmacological inhibition'}", + "162, BLBC {'context': 'B-xenograft'}", + "163, xenografts. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "117, DUSP4 ['l0', 'l1', 'l2', 'l3']", + "118, overexpression ['l0', 'l4', 'l5', 'l6']", + "119, increased ['l1', 'l4', 'l7', 'l8']", + "120, chemotherapy-induced ['l2', 'l5', 'l7', 'l9']", + "121, apoptosis, ['l3', 'l6', 'l8', 'l9']", + "123, DUSP4 ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "124, depletion ['l10']", + "150, inhibition ['l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "151, of ['l16', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "152, mitogen-activated ['l11', 'l17', 'l24', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "153, protein ['l12', 'l18', 'l25', 'l31', 'l37', 'l38', 'l39', 'l40', 'l41']", + "154, kinase ['l13', 'l19', 'l26', 'l32', 'l37', 'l42', 'l43', 'l44', 'l45']", + "155, kinase ['l14', 'l20', 'l27', 'l33', 'l38', 'l42', 'l46', 'l47', 'l48']", + "156, (MEK) ['l15', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l49', 'l50']", + "162, BLBC ['l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l51']", + "163, xenografts. ['l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l51']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "DUSP4", + "overexpression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "chemotherapy-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "DUSP4", + "overexpression" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased", + "chemotherapy-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "mitogen-activated", + "protein", + "kinase", + "(MEK)" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "BLBC", + "xenografts." + ] + } + } + ] + }, + { + "PMID": "22660634", + "TEXT": "Endometriosis is considered to be an estrogen-dependent inflammatory disease, but its etiology is unclear. Thus far, a mechanistic role for steroid receptor coactivators (SRCs) in the progression of endometriosis has not been elucidated. An SRC-1-null mouse model reveals that the mouse SRC-1 gene has an essential role in endometriosis progression. Notably, a previously unidentified 70-kDa SRC-1 proteolytic isoform is highly elevated both in the endometriotic tissue of mice with surgically induced endometriosis and in endometriotic stromal cells biopsied from patients with endometriosis compared to normal endometrium. Tnf⁻/⁻ and Mmp9⁻/⁻ mice with surgically induced endometriosis showed that activation of tumor necrosis factor a (TNF-α)-induced matrix metallopeptidase 9 (MMP9) activity mediates formation of the 70-kDa SRC-1 C-terminal isoform in endometriotic mouse tissue. In contrast to full-length SRC-1, the endometriotic 70-kDa SRC-1 C-terminal fragment prevents TNF-α-mediated apoptosis in human endometrial epithelial cells and causes the epithelial-mesenchymal transition and the invasion of human endometrial cells that are hallmarks of progressive endometriosis. Collectively, the newly identified TNF-α-MMP9-SRC-1 isoform functional axis promotes pathogenic progression of endometriosis.", + "TAG_DATA": [ + "34, SRC-1-null {'perturbing_action': 'B-gene loss-of-function'}", + "35, mouse {'context': 'B-organism'}", + "36, model {'context': 'I-organism'}", + "86, Tnf⁻/⁻ {'perturbing_action': 'B-gene loss-of-function'}", + "87, and {'perturbing_action': 'B-gene loss-of-function'}", + "88, Mmp9⁻/⁻ {'perturbing_action': 'B-gene loss-of-function'}", + "89, mice {'context': 'B-organism'}", + "131, prevents {'effect': 'B-negative'}", + "133, apoptosis {'phenotype': 'B-apoptosis'}", + "135, human {'context': 'B-cells'}", + "136, endometrial {'context': 'I-cells'}", + "137, epithelial {'context': 'I-cells'}", + "138, cells {'context': 'I-cells'}", + "140, causes {'effect': 'B-positive'}", + "142, epithelial-mesenchymal {'phenotype': 'B-epithelial-mesenchymal transition'}", + "143, transition {'phenotype': 'I-epithelial-mesenchymal transition'}", + "146, invasion {'phenotype': 'B-invasion'}", + "148, human {'context': 'B-cells'}", + "149, endometrial {'context': 'I-cells'}", + "150, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "34, SRC-1-null ['l0', 'l1']", + "35, mouse ['l0', 'l2']", + "36, model ['l1', 'l2']", + "86, Tnf⁻/⁻ ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "87, and ['l3', 'l9', 'l10', 'l11', 'l12', 'l13']", + "88, Mmp9⁻/⁻ ['l4', 'l9', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "89, mice ['l5', 'l10', 'l14', 'l22', 'l23']", + "131, prevents ['l15', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "133, apoptosis ['l16', 'l24', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "135, human ['l17', 'l25', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "136, endometrial ['l6', 'l11', 'l18', 'l26', 'l37', 'l45', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "137, epithelial ['l7', 'l12', 'l19', 'l22', 'l27', 'l38', 'l46', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "138, cells ['l8', 'l13', 'l20', 'l23', 'l28', 'l39', 'l47', 'l56', 'l63', 'l69', 'l70', 'l71']", + "140, causes ['l29', 'l40', 'l48', 'l57', 'l64', 'l69', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "142, epithelial-mesenchymal ['l30', 'l41', 'l49', 'l58', 'l65', 'l70', 'l72', 'l78', 'l79', 'l80', 'l81', 'l82']", + "143, transition ['l21', 'l31', 'l42', 'l50', 'l59', 'l66', 'l71', 'l73', 'l78', 'l83', 'l84', 'l85', 'l86']", + "146, invasion ['l32', 'l43', 'l51', 'l60', 'l67', 'l74', 'l79', 'l83', 'l87', 'l88', 'l89']", + "148, human ['l33', 'l52', 'l75', 'l80', 'l84', 'l87', 'l90', 'l91']", + "149, endometrial ['l34', 'l53', 'l61', 'l76', 'l81', 'l85', 'l88', 'l90', 'l92']", + "150, cells ['l35', 'l44', 'l54', 'l62', 'l68', 'l77', 'l82', 'l86', 'l89', 'l91', 'l92']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SRC-1-null", + "Tnf⁻/⁻", + "and", + "Mmp9⁻/⁻" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tnf⁻/⁻", + "and", + "Mmp9⁻/⁻" + ] + }, + "context": { + "val": "cells", + "words": [ + "endometrial", + "epithelial", + "cells", + "human" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mmp9⁻/⁻" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mmp9⁻/⁻" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mmp9⁻/⁻" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "transition" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "endometrial", + "epithelial", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "epithelial-mesenchymal", + "transition" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "endometrial", + "epithelial", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "causes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "endometrial", + "epithelial", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "causes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "endometrial", + "epithelial", + "cells" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "epithelial-mesenchymal", + "transition" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "endometrial", + "epithelial", + "cells" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "epithelial-mesenchymal", + "transition" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + } + ] + }, + { + "PMID": "22610277", + "TEXT": "The Wnt–β-catenin and PI3K-AKT-FOXO3a pathways have a central role in cancer. AKT phosporylates FOXO3a, relocating it from the cell nucleus to the cytoplasm, an effect that is reversed by PI3K and AKT inhibitors. Simultaneous hyperactivation of the Wnt–β-catenin pathway and inhibition of PI3K-AKT signaling promote nuclear accumulation of β-catenin and FOXO3a, respectively, promoting cell scattering and metastasis by regulating a defined set of target genes. Indeed, the anti-tumoral AKT inhibitor API-2 promotes nuclear FOXO3a accumulation and metastasis of cells with high nuclear β-catenin content. Nuclear β-catenin confers resistance to the FOXO3a-mediated apoptosis induced by PI3K and AKT inhibitors in patient-derived primary cultures and in corresponding xenograft tumors in mice. This resistance is reversed by XAV-939, an inhibitor of Wnt–β-catenin signaling. In the presence of high nuclear β-catenin content, activation of FOXO3a by PI3K or AKT inhibitors makes it behave as a metastasis inductor rather than a proapoptotic tumor suppressor. We show that it is possible to evaluate the β-catenin status of patients' carcinomas and the response of patient-derived cells to target-directed drugs that accumulate FOXO3a in the nucleus before deciding on a course of treatment. We propose that this evaluation could be essential to the provision of a safer and more effective personalized treatment.", + "TAG_DATA": [ + "71, promotes {'effect': 'B-positive'}", + "76, metastasis {'phenotype': 'B-metastasis'}", + "78, cells {'context': 'B-cells'}", + "87, resistance {'effect': 'B-negative'}", + "90, FOXO3a-mediated {'effect': 'B-regulates'}", + "91, apoptosis {'phenotype': 'B-apoptosis'}", + "92, induced {'effect': 'B-positive'}", + "94, PI3K {'perturbing_action': 'B-pharmacological inhibition'}", + "95, and {'perturbing_action': 'I-pharmacological inhibition'}", + "96, AKT {'perturbing_action': 'I-pharmacological inhibition'}", + "97, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "99, patient-derived {'context': 'B-cells'}", + "100, primary {'context': 'I-cells'}", + "101, cultures {'context': 'I-cells'}", + "105, xenograft {'context': 'B-xenograft'}", + "106, tumors {'context': 'I-xenograft'}", + "108, mice. {'context': 'B-organism'}", + "134, AKT {'perturbing_action': 'B-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "71, promotes ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "76, metastasis ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "78, cells ['l1', 'l6', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "87, resistance ['l2', 'l7', 'l14', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "90, FOXO3a-mediated ['l8', 'l15', 'l23', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "91, apoptosis ['l9', 'l16', 'l24', 'l36', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "92, induced ['l10', 'l17', 'l25', 'l37', 'l48', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "94, PI3K ['l26', 'l38', 'l49', 'l59', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "95, and ['l27', 'l39', 'l50', 'l60', 'l68', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "96, AKT ['l28', 'l40', 'l51', 'l61', 'l69', 'l77', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "97, inhibitors ['l18', 'l29', 'l41', 'l52', 'l62', 'l70', 'l78', 'l85', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "99, patient-derived ['l3', 'l11', 'l19', 'l30', 'l42', 'l53', 'l63', 'l71', 'l79', 'l86', 'l92', 'l98', 'l99', 'l100']", + "100, primary ['l4', 'l12', 'l20', 'l31', 'l43', 'l54', 'l64', 'l72', 'l80', 'l87', 'l93', 'l98', 'l101']", + "101, cultures ['l5', 'l13', 'l21', 'l32', 'l44', 'l55', 'l65', 'l73', 'l81', 'l88', 'l94', 'l99', 'l101']", + "105, xenograft ['l33', 'l45', 'l56', 'l74', 'l82', 'l89', 'l95', 'l102', 'l103']", + "106, tumors ['l22', 'l34', 'l46', 'l57', 'l66', 'l75', 'l83', 'l90', 'l96', 'l100', 'l102', 'l104']", + "108, mice. ['l35', 'l47', 'l58', 'l67', 'l76', 'l84', 'l91', 'l97', 'l103', 'l104']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promotes", + "induced" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes", + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "patient-derived", + "primary", + "cultures" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "patient-derived", + "primary", + "cultures" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "FOXO3a-mediated" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "patient-derived", + "primary", + "cultures" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "patient-derived", + "primary", + "cultures" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "FOXO3a-mediated" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "patient-derived", + "primary", + "cultures" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "patient-derived", + "primary", + "cultures" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "PI3K", + "and", + "AKT" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PI3K", + "and", + "AKT", + "inhibitors" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "tumors" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "FOXO3a-mediated" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "FOXO3a-mediated" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PI3K", + "and", + "AKT", + "inhibitors" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "FOXO3a-mediated" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "tumors" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "FOXO3a-mediated" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PI3K", + "and", + "AKT", + "inhibitors" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "tumors" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PI3K", + "and", + "AKT", + "inhibitors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PI3K", + "and", + "AKT", + "inhibitors" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PI3K", + "and", + "AKT", + "inhibitors" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "22561686", + "TEXT": "Fatty liver disease is associated with obesity and type 2 diabetes, and hepatic lipid accumulation may contribute to insulin resistance. Histone deacetylase 3 (Hdac3) controls the circadian rhythm of hepatic lipogenesis. Here we show that, despite severe hepatosteatosis, mice with liver-specific depletion of Hdac3 have higher insulin sensitivity without any changes in insulin signaling or body weight compared to wild-type mice. Hdac3 depletion reroutes metabolic precursors towards lipid synthesis and storage within lipid droplets and away from hepatic glucose production. Perilipin 2, which coats lipid droplets, is markedly induced upon Hdac3 depletion and contributes to the development of both steatosis and improved tolerance to glucose. These findings suggest that the sequestration of hepatic lipids in perilipin 2–coated droplets ameliorates insulin resistance and establish Hdac3 as a pivotal epigenomic modifier that integrates signals from the circadian clock in the regulation of hepatic intermediary metabolism.", + "TAG_DATA": [ + "38, mice {'context': 'B-organism'}", + "40, liver-specific {'perturbing_action': 'B-gene loss-of-function'}", + "41, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "42, of {'perturbing_action': 'I-gene loss-of-function'}", + "43, Hdac3 {'perturbing_action': 'I-gene loss-of-function'}", + "60, mice. {'context': 'B-organism'}", + "61, Hdac3 {'perturbing_action': 'B-gene loss-of-function'}", + "62, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "90, Hdac3 {'perturbing_action': 'B-gene loss-of-function'}", + "91, depletion {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "40, liver-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "41, depletion ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "42, of ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "43, Hdac3 ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "60, mice. ['l3', 'l8', 'l12', 'l15']", + "61, Hdac3 ['l4', 'l9', 'l13', 'l16', 'l18', 'l19', 'l20']", + "62, depletion ['l5', 'l10', 'l14', 'l17', 'l18', 'l21', 'l22']", + "90, Hdac3 ['l19', 'l21', 'l23']", + "91, depletion ['l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "liver-specific", + "depletion", + "of", + "Hdac3" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "22522563", + "TEXT": "Few effective measures exist to combat the worldwide obesity epidemic(1), and the identification of potential therapeutic targets requires a deeper understanding of the mechanisms that control energy balance. Leptin, an adipocyte-derived hormone that signals the long-term status of bodily energy stores, acts through multiple types of leptin receptor long isoform (LepRb)-expressing neurons (called here LepRb neurons) in the brain to control feeding, energy expenditure and endocrine function(2-4). The modest contributions to energy balance that are attributable to leptin action in many LepRb populations(5-9) suggest that other previously unidentified hypothalamic LepRb neurons have key roles in energy balance. Here we examine the role of LepRb in neuronal nitric oxide synthase (NOS1)-expressing LebRb (LepRb(NOS1)) neurons that comprise approximately 20% of the total hypothalamic LepRb neurons. Nos1(cre)-mediated genetic ablation of LepRb (Lepr(Nos1KO)) in mice produces hyperphagic obesity, decreased energy expenditure and hyperglycemia approaching that seen in whole-body LepRb-null mice. In contrast, the endocrine functions in Lepr(Nos1KO) mice are only modestly affected by the genetic ablation of LepRb in these neurons. Thus, hypothalamic LepRb(NOS1) neurons are a key site of action of the leptin-mediated control of systemic energy balance.", + "TAG_DATA": [ + "123, Nos1(cre)-mediated {'perturbing_action': 'B-gene loss-of-function'}", + "124, genetic {'perturbing_action': 'I-gene loss-of-function'}", + "125, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "126, of {'perturbing_action': 'I-gene loss-of-function'}", + "127, LepRb {'perturbing_action': 'I-gene loss-of-function'}", + "128, (Lepr(Nos1KO)) {'perturbing_action': 'I-gene loss-of-function'}", + "130, mice {'context': 'B-organism'}", + "144, LepRb-null {'perturbing_action': 'B-gene loss-of-function'}", + "145, mice. {'context': 'B-organism'}", + "152, Lepr(Nos1KO) {'perturbing_action': 'B-gene loss-of-function'}", + "153, mice {'context': 'B-organism'}", + "160, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "161, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "162, of {'perturbing_action': 'I-gene loss-of-function'}", + "163, LepRb {'perturbing_action': 'I-gene loss-of-function'}", + "166, neurons. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "123, Nos1(cre)-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "124, genetic ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "125, ablation ['l1', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "126, of ['l2', 'l9', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "127, LepRb ['l3', 'l10', 'l15', 'l20', 'l25', 'l26', 'l27', 'l28']", + "128, (Lepr(Nos1KO)) ['l4', 'l11', 'l16', 'l21', 'l25', 'l29', 'l30']", + "130, mice ['l5', 'l12', 'l17', 'l22', 'l26', 'l29']", + "144, LepRb-null ['l6', 'l18', 'l23', 'l27', 'l31']", + "145, mice. ['l7', 'l13', 'l19', 'l24', 'l28', 'l30', 'l31']", + "152, Lepr(Nos1KO) ['l32', 'l33', 'l34', 'l35', 'l36']", + "153, mice ['l32', 'l37']", + "160, genetic ['l38', 'l39', 'l40', 'l41']", + "161, ablation ['l33', 'l38', 'l42', 'l43', 'l44']", + "162, of ['l34', 'l39', 'l42', 'l45', 'l46']", + "163, LepRb ['l35', 'l40', 'l43', 'l45', 'l47']", + "166, neurons. ['l36', 'l37', 'l41', 'l44', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nos1(cre)-mediated", + "genetic", + "ablation", + "of", + "LepRb", + "(Lepr(Nos1KO))", + "LepRb-null", + "Lepr(Nos1KO)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lepr(Nos1KO)", + "genetic", + "ablation", + "of", + "LepRb" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons." + ] + } + } + ] + }, + { + "PMID": "22466704", + "TEXT": "Ataxia telangiectasia is a neurodegenerative disease caused by mutation of the Atm gene. Here we report that ataxia telangiectasia mutated (ATM) deficiency causes nuclear accumulation of histone deacetylase 4 (HDAC4) in neurons and promotes neurodegeneration. Nuclear HDAC4 binds to chromatin, as well as to myocyte enhancer factor 2A (MEF2A) and cAMP-responsive element binding protein (CREB), leading to histone deacetylation and altered neuronal gene expression. Blocking either HDAC4 activity or its nuclear accumulation blunts these neurodegenerative changes and rescues several behavioral abnormalities of ATM-deficient mice. Full rescue of the neurodegeneration, however, also requires the presence of HDAC4 in the cytoplasm, suggesting that the ataxia telangiectasia phenotype results both from a loss of cytoplasmic HDAC4 as well as its nuclear accumulation. To remain cytoplasmic, HDAC4 must be phosphorylated. The activity of the HDAC4 phosphatase, protein phosphatase 2A (PP2A), is downregulated by ATM-mediated phosphorylation. In ATM deficiency, enhanced PP2A activity leads to HDAC4 dephosphorylation and the nuclear accumulation of HDAC4. Our results define a crucial role of the cellular localization of HDAC4 in the events leading to ataxia telangiectasia neurodegeneration.", + "TAG_DATA": [ + "82, ATM-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "83, mice. {'context': 'B-organism'}", + "142, ATM {'perturbing_action': 'B-gene loss-of-function'}", + "143, deficiency, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "82, ATM-deficient ['l0']", + "83, mice. ['l0']", + "142, ATM ['l1']", + "143, deficiency, ['l1']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ATM-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "22466703", + "TEXT": "Alternative splicing has a major role in cardiac adaptive responses, as exemplified by the isoform switch of the sarcomeric protein titin, which adjusts ventricular filling. By positional cloning using a previously characterized rat strain with altered titin mRNA splicing, we identified a loss-of-function mutation in the gene encoding RNA binding motif protein 20 (Rbm20) as the underlying cause of pathological titin isoform expression. The phenotype of Rbm20-deficient rats resembled the pathology seen in individuals with dilated cardiomyopathy caused by RBM20 mutations. Deep sequencing of the human and rat cardiac transcriptome revealed an RBM20-dependent regulation of alternative splicing. In addition to titin (TTN), we identified a set of 30 genes with conserved splicing regulation between humans and rats. This network is enriched for genes that have previously been linked to cardiomyopathy, ion homeostasis and sarcomere biology. Our studies emphasize the key role of post-transcriptional regulation in cardiac function and provide mechanistic insights into the pathogenesis of human heart failure.", + "TAG_DATA": [ + "42, loss-of-function {'perturbing_action': 'B-gene loss-of-function'}", + "43, mutation {'perturbing_action': 'I-gene loss-of-function'}", + "44, in {'perturbing_action': 'I-gene loss-of-function'}", + "45, the {'perturbing_action': 'I-gene loss-of-function'}", + "46, gene {'perturbing_action': 'I-gene loss-of-function'}", + "47, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "48, RNA {'perturbing_action': 'I-gene loss-of-function'}", + "49, binding {'perturbing_action': 'I-gene loss-of-function'}", + "50, motif {'perturbing_action': 'I-gene loss-of-function'}", + "51, protein {'perturbing_action': 'I-gene loss-of-function'}", + "52, 20 {'perturbing_action': 'I-gene loss-of-function'}", + "53, (Rbm20) {'perturbing_action': 'I-gene loss-of-function'}", + "66, Rbm20-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "67, rats {'context': 'B-organism'}", + "79, RBM20 {'perturbing_action': 'B-other'}", + "80, mutations. {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "42, loss-of-function ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "43, mutation ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "44, in ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "45, the ['l2', 'l12', 'l21', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "46, gene ['l3', 'l13', 'l22', 'l32', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "47, encoding ['l4', 'l14', 'l23', 'l33', 'l44', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "48, RNA ['l5', 'l15', 'l24', 'l34', 'l45', 'l53', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "49, binding ['l6', 'l16', 'l25', 'l35', 'l46', 'l54', 'l63', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "50, motif ['l7', 'l17', 'l26', 'l36', 'l47', 'l55', 'l64', 'l72', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "51, protein ['l8', 'l18', 'l27', 'l37', 'l48', 'l56', 'l65', 'l73', 'l80', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "52, 20 ['l9', 'l19', 'l28', 'l38', 'l49', 'l57', 'l66', 'l74', 'l81', 'l87', 'l93', 'l94', 'l95', 'l96', 'l97']", + "53, (Rbm20) ['l10', 'l20', 'l29', 'l39', 'l50', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l98', 'l99', 'l100', 'l101']", + "66, Rbm20-deficient ['l40', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l102', 'l103', 'l104']", + "67, rats ['l30', 'l41', 'l51', 'l60', 'l69', 'l77', 'l84', 'l90', 'l95', 'l99', 'l102', 'l105', 'l106']", + "79, RBM20 ['l42', 'l61', 'l70', 'l78', 'l85', 'l91', 'l96', 'l100', 'l103', 'l105', 'l107']", + "80, mutations. ['l31', 'l43', 'l52', 'l62', 'l71', 'l79', 'l86', 'l92', 'l97', 'l101', 'l104', 'l106', 'l107']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "in", + "the", + "gene", + "encoding", + "RNA", + "binding", + "motif", + "protein", + "20", + "(Rbm20)", + "Rbm20-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rats" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "RBM20", + "mutations." + ] + } + } + ] + }, + { + "PMID": "22447074", + "TEXT": "Commensal bacteria that colonize mammalian barrier surfaces are reported to influence T helper type 2 (T(H)2) cytokine-dependent inflammation and susceptibility to allergic disease, although the mechanisms that underlie these observations are poorly understood. In this report, we find that deliberate alteration of commensal bacterial populations via oral antibiotic treatment resulted in elevated serum IgE concentrations, increased steady-state circulating basophil populations and exaggerated basophil-mediated T(H)2 cell responses and allergic inflammation. Elevated serum IgE levels correlated with increased circulating basophil populations in mice and subjects with hyperimmunoglobulinemia E syndrome. Furthermore, B cell-intrinsic expression of myeloid differentiation factor 88 (MyD88) was required to limit serum IgE concentrations and circulating basophil populations in mice. Commensal-derived signals were found to influence basophil development by limiting proliferation of bone marrow-resident precursor populations. Collectively, these results identify a previously unrecognized pathway through which commensal-derived signals influence basophil hematopoiesis and susceptibility to T(H)2 cytokine-dependent inflammation and allergic disease.", + "TAG_DATA": [ + "109, mice. {'context': 'B-organism'}", + "119, limiting {'effect': 'B-negative'}", + "120, proliferation {'phenotype': 'B-proliferation'}", + "122, bone {'context': 'B-cells'}", + "123, marrow-resident {'context': 'I-cells'}", + "124, precursor {'context': 'I-cells'}", + "125, populations. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "119, limiting ['l0', 'l1', 'l2', 'l3', 'l4']", + "120, proliferation ['l0', 'l5', 'l6', 'l7', 'l8']", + "122, bone ['l1', 'l5', 'l9', 'l10', 'l11']", + "123, marrow-resident ['l2', 'l6', 'l9', 'l12', 'l13']", + "124, precursor ['l3', 'l7', 'l10', 'l12', 'l14']", + "125, populations. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "limiting" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limiting" + ] + }, + "context": { + "val": "cells", + "words": [ + "bone", + "marrow-resident", + "precursor", + "populations." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "bone", + "marrow-resident", + "precursor", + "populations." + ] + } + } + ] + }, + { + "PMID": "22426422", + "TEXT": "Mutations in the Bdnf gene, which produces transcripts with either short or long 3' untranslated regions (3' UTRs), cause human obesity; however, the precise role of brain-derived neurotrophic factor (BDNF) in the regulation of energy balance is unknown. Here we show the relationship between Bdnf mRNA with a long 3' UTR (long 3' UTR Bdnf mRNA), leptin, neuronal activation and body weight. We found that long 3' UTR Bdnf mRNA was enriched in the dendrites of hypothalamic neurons and that insulin and leptin could stimulate its translation in dendrites. Furthermore, mice harboring a truncated long Bdnf 3' UTR developed severe hyperphagic obesity, which was completely reversed by viral expression of long 3' UTR Bdnf mRNA in the hypothalamus. In these mice, the ability of leptin to activate hypothalamic neurons and inhibit food intake was compromised despite normal activation of leptin receptors. These results reveal a novel mechanism linking leptin action to BDNF expression during hypothalamic-mediated regulation of body weight, while also implicating dendritic protein synthesis in this process.", + "TAG_DATA": [ + "90, mice {'context': 'B-organism'}", + "92, a {'perturbing_action': 'B-other'}", + "93, truncated {'perturbing_action': 'B-other'}", + "94, long {'perturbing_action': 'I-other'}", + "95, Bdnf {'perturbing_action': 'I-other'}", + "96, 3' {'perturbing_action': 'I-other'}", + "97, UTR {'perturbing_action': 'I-other'}", + "107, viral {'perturbing_action': 'B-gene gain-of-function'}", + "108, expression {'perturbing_action': 'I-gene gain-of-function'}", + "109, of {'perturbing_action': 'I-gene gain-of-function'}", + "110, long {'perturbing_action': 'I-gene gain-of-function'}", + "111, 3' {'perturbing_action': 'I-gene gain-of-function'}", + "112, UTR {'perturbing_action': 'I-gene gain-of-function'}", + "113, Bdnf {'perturbing_action': 'I-gene gain-of-function'}", + "114, mRNA {'perturbing_action': 'I-gene gain-of-function'}", + "115, in {'perturbing_action': 'I-gene gain-of-function'}", + "116, the {'perturbing_action': 'I-gene gain-of-function'}", + "117, hypothalamus. {'context': 'B-tissue/organ'}", + "120, mice, {'context': 'B-organism'}", + "127, hypothalamic {'context': 'B-cells'}", + "128, neurons {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "90, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "92, a ['l0', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "93, truncated ['l5', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "94, long ['l1', 'l6', 'l19', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "95, Bdnf ['l2', 'l7', 'l20', 'l32', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "96, 3' ['l3', 'l8', 'l21', 'l33', 'l42', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "97, UTR ['l4', 'l9', 'l22', 'l34', 'l43', 'l48', 'l56', 'l57', 'l58', 'l59']", + "107, viral ['l10', 'l23', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "108, expression ['l11', 'l24', 'l35', 'l49', 'l60', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "109, of ['l12', 'l25', 'l36', 'l50', 'l61', 'l71', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "110, long ['l62', 'l72', 'l80', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "111, 3' ['l63', 'l73', 'l81', 'l89', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "112, UTR ['l13', 'l26', 'l64', 'l74', 'l82', 'l90', 'l98', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "113, Bdnf ['l14', 'l27', 'l37', 'l51', 'l65', 'l75', 'l83', 'l91', 'l99', 'l106', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "114, mRNA ['l15', 'l28', 'l38', 'l44', 'l52', 'l56', 'l66', 'l76', 'l84', 'l92', 'l100', 'l107', 'l113', 'l119', 'l120', 'l121', 'l122']", + "115, in ['l16', 'l29', 'l39', 'l45', 'l53', 'l57', 'l67', 'l77', 'l85', 'l93', 'l101', 'l108', 'l114', 'l119', 'l123', 'l124']", + "116, the ['l17', 'l30', 'l40', 'l46', 'l54', 'l58', 'l68', 'l78', 'l86', 'l94', 'l102', 'l109', 'l115', 'l120', 'l123', 'l125']", + "117, hypothalamus. ['l18', 'l31', 'l41', 'l47', 'l55', 'l59', 'l69', 'l79', 'l87', 'l95', 'l103', 'l110', 'l116', 'l121', 'l124', 'l125']", + "120, mice, ['l126', 'l127']", + "127, hypothalamic ['l96', 'l104', 'l111', 'l117', 'l126', 'l128']", + "128, neurons ['l70', 'l88', 'l97', 'l105', 'l112', 'l118', 'l122', 'l127', 'l128']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "a", + "long", + "Bdnf", + "3'", + "UTR" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "a", + "truncated", + "long", + "Bdnf", + "3'", + "UTR" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hypothalamus." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "viral", + "expression", + "of", + "long", + "3'", + "UTR", + "Bdnf", + "mRNA", + "in", + "the" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hypothalamus." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "viral", + "of", + "long", + "3'", + "UTR", + "Bdnf", + "mRNA" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons", + "hypothalamic" + ] + } + } + ] + }, + { + "PMID": "22426419", + "TEXT": "Inflammatory bowel diseases (IBDs) are chronic relapsing and remitting conditions associated with long-term gut dysfunction resulting from alterations to the enteric nervous system and a loss of enteric neurons. The mechanisms underlying inflammation-induced enteric neuron death are unknown. Here using in vivo models of experimental colitis we report that inflammation causes enteric neuron death by activating a neuronal signaling complex composed of P2X7 receptors (P2X7Rs), pannexin-1 (Panx1) channels, the Asc adaptor protein and caspases. Inhibition of P2X7R, Panx1, Asc or caspase activity prevented inflammation-induced neuron cell death. Preservation of enteric neurons by inhibiting Panx1 in vivo prevented the onset of inflammation-induced colonic motor dysfunction. Panx1 expression was reduced in Crohn's disease but not ulcerative colitis. We conclude that activation of neuronal Panx1 underlies neuron death and the subsequent development of abnormal gut motility in IBD. Targeting Panx1 represents a new neuroprotective strategy to ameliorate the progression of IBD-associated dysmotility.", + "TAG_DATA": [ + "51, enteric {'context': 'B-cells'}", + "52, neuron {'context': 'I-cells'}", + "74, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "75, of {'perturbing_action': 'I-pharmacological inhibition'}", + "76, P2X7R, {'perturbing_action': 'I-pharmacological inhibition'}", + "77, Panx1, {'perturbing_action': 'I-pharmacological inhibition'}", + "78, Asc {'perturbing_action': 'I-pharmacological inhibition'}", + "82, prevented {'effect': 'B-negative'}", + "83, inflammation-induced {'effect': 'B-positive'}", + "84, neuron {'context': 'B-cells'}", + "85, cell {'phenotype': 'B-cell death'}", + "86, death. {'phenotype': 'I-cell death'}", + "89, enteric {'context': 'B-cells'}", + "90, neurons {'context': 'I-cells'}", + "92, inhibiting {'perturbing_action': 'B-pharmacological inhibition'}", + "93, Panx1 {'perturbing_action': 'I-pharmacological inhibition'}", + "94, in {'context': 'B-in vivo'}", + "95, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "51, enteric ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "52, neuron ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "74, Inhibition ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "75, of ['l15', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "76, P2X7R, ['l16', 'l24', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "77, Panx1, ['l1', 'l8', 'l17', 'l25', 'l32', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "78, Asc ['l2', 'l9', 'l18', 'l26', 'l33', 'l39', 'l45', 'l46', 'l47', 'l48', 'l49']", + "82, prevented ['l3', 'l10', 'l19', 'l27', 'l34', 'l40', 'l45', 'l50', 'l51', 'l52', 'l53']", + "83, inflammation-induced ['l4', 'l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l50', 'l54', 'l55', 'l56']", + "84, neuron ['l5', 'l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l54', 'l57', 'l58']", + "85, cell ['l6', 'l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l57', 'l59']", + "86, death. ['l7', 'l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58', 'l59']", + "89, enteric ['l60', 'l61', 'l62', 'l63', 'l64']", + "90, neurons ['l60', 'l65', 'l66', 'l67', 'l68']", + "92, inhibiting ['l61', 'l65', 'l69', 'l70', 'l71']", + "93, Panx1 ['l62', 'l66', 'l69', 'l72', 'l73']", + "94, in ['l63', 'l67', 'l70', 'l72', 'l74']", + "95, vivo ['l64', 'l68', 'l71', 'l73', 'l74']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "enteric", + "neuron", + "neurons" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Panx1,", + "Asc", + "Inhibition", + "of", + "P2X7R,", + "inhibiting", + "Panx1" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "enteric", + "neuron" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "enteric", + "neuron" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inflammation-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "enteric", + "neuron" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "P2X7R,", + "Panx1,", + "Asc" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "P2X7R,", + "Panx1,", + "Asc" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inflammation-induced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "P2X7R,", + "Panx1,", + "Asc" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inflammation-induced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibiting", + "Panx1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "22310680", + "TEXT": "Parkinson's disease affects more than five million people worldwide, yet no therapeutic has been identified that can slow or halt the progression of this debilitating disease. A new study in tau knockout mice suggests that tau deficiency causes impaired ferroportin-coupled iron export, by retention of the amyloid precursor protein, a neuronal ferroxidase partner, in the endoplasmic reticulum. This leads to parkinsonism through intracellular iron accumulation and degeneration of dopamine neurons (pages X-Y).", + "TAG_DATA": [ + "30, tau {'perturbing_action': 'B-gene loss-of-function'}", + "31, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "32, mice {'context': 'B-organism'}", + "35, tau {'perturbing_action': 'B-gene loss-of-function'}", + "36, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "68, dopamine {'context': 'B-cells'}", + "69, neurons {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "30, tau ['l0', 'l1', 'l2', 'l3']", + "31, knockout ['l0', 'l4', 'l5', 'l6', 'l7']", + "32, mice ['l1', 'l4', 'l8', 'l9', 'l10']", + "35, tau ['l2', 'l5', 'l8', 'l11', 'l12', 'l13']", + "36, deficiency ['l3', 'l6', 'l9', 'l11', 'l14', 'l15']", + "68, dopamine ['l12', 'l14', 'l16']", + "69, neurons ['l7', 'l10', 'l13', 'l15', 'l16']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "tau", + "knockout", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout", + "tau", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons", + "dopamine" + ] + } + } + ] + }, + { + "PMID": "22306733", + "TEXT": "Molecules associated with the transforming growth factor β (TGF-β) superfamily, such as bone morphogenic proteins (BMPs) and TGF-β, are key regulators of inflammation, apoptosis and cellular transitions. Here we show that the BMP receptor activin-like kinase 3 (Alk3) is elevated early in diseased kidneys after injury. We also found that its deletion in the tubular epithelium leads to enhanced TGF-β1-Smad family member 3 (Smad3) signaling, epithelial damage and fibrosis, suggesting a protective role for Alk3-mediated signaling in the kidney. A structure-function analysis of the BMP-Alk3-BMP receptor, type 2 (BMPR2) ligand-receptor complex, along with synthetic organic chemistry, led us to construct a library of small peptide agonists of BMP signaling that function through the Alk3 receptor. One such peptide agonist, THR-123, suppressed inflammation, apoptosis and the epithelial-to-mesenchymal transition program and reversed established fibrosis in five mouse models of acute and chronic renal injury. THR-123 acts specifically through Alk3 signaling, as mice with a targeted deletion for Alk3 in their tubular epithelium did not respond to therapy with THR-123. Combining THR-123 and the angiotensin-converting enzyme inhibitor captopril had an additive therapeutic benefit in controlling renal fibrosis. Our studies show that BMP signaling agonists constitute a new line of therapeutic agents with potential utility in the clinic to induce regeneration, repair and reverse established fibrosis.", + "TAG_DATA": [ + "55, epithelium {'context': 'I-tissue/organ'}", + "120, suppressed {'effect': 'B-negative'}", + "122, apoptosis {'phenotype': 'B-apoptosis'}", + "125, epithelial-to-mesenchymal {'phenotype': 'B-epithelial-mesenchymal transition'}", + "126, transition {'phenotype': 'I-epithelial-mesenchymal transition'}", + "127, program {'phenotype': 'I-epithelial-mesenchymal transition'}", + "134, mouse {'context': 'B-organism'}", + "135, models {'context': 'I-organism'}", + "149, mice {'context': 'B-organism'}", + "152, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "153, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "154, for {'perturbing_action': 'I-gene loss-of-function'}", + "155, Alk3 {'perturbing_action': 'I-gene loss-of-function'}", + "156, in {'perturbing_action': 'I-gene loss-of-function'}", + "157, their {'perturbing_action': 'I-gene loss-of-function'}", + "158, tubular {'perturbing_action': 'I-gene loss-of-function'}", + "159, epithelium {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "54, tubular ['l0', 'l1']", + "55, epithelium ['l0', 'l2']", + "120, suppressed ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "122, apoptosis ['l3', 'l9', 'l10', 'l11', 'l12', 'l13']", + "125, epithelial-to-mesenchymal ['l4', 'l9', 'l14', 'l15', 'l16', 'l17']", + "126, transition ['l5', 'l10', 'l14', 'l18', 'l19', 'l20']", + "127, program ['l1', 'l2', 'l6', 'l11', 'l15', 'l18', 'l21', 'l22']", + "134, mouse ['l7', 'l12', 'l16', 'l19', 'l21', 'l23']", + "135, models ['l8', 'l13', 'l17', 'l20', 'l22', 'l23']", + "149, mice ['l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "152, targeted ['l24', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "153, deletion ['l25', 'l32', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "154, for ['l26', 'l33', 'l39', 'l45', 'l46', 'l47', 'l48', 'l49']", + "155, Alk3 ['l27', 'l34', 'l40', 'l45', 'l50', 'l51', 'l52', 'l53']", + "156, in ['l28', 'l35', 'l41', 'l46', 'l50', 'l54', 'l55', 'l56']", + "157, their ['l29', 'l36', 'l42', 'l47', 'l51', 'l54', 'l57', 'l58']", + "158, tubular ['l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l57', 'l59']", + "159, epithelium ['l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58', 'l59']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "epithelium" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "program" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "epithelial-to-mesenchymal", + "transition", + "program" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "epithelial-to-mesenchymal", + "transition", + "program" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "deletion", + "for", + "Alk3", + "in", + "their", + "tubular", + "epithelium" + ] + } + } + ] + }, + { + "PMID": "22306732", + "TEXT": "Aging reduces the number of mesenchymal stem cells (MSCs) that can differentiate into osteoblasts in the bone marrow, which leads to impairment of osteogenesis. However, if MSCs could be directed toward osteogenic differentiation, they could be a viable therapeutic option for bone regeneration. We have developed a method to direct MSCs to the bone surface by attaching a synthetic high-affinity and specific peptidomimetic ligand (LLP2A) against integrin α4β1 on the MSC surface to a bisphosphonate (alendronate, Ale) that has a high affinity for bone. LLP2A-Ale induced MSC migration and osteogenic differentiation in vitro. A single intravenous injection of LLP2A-Ale increased trabecular bone formation and bone mass in both xenotransplantation studies and in immunocompetent mice. Additionally, LLP2A-Ale prevented trabecular bone loss after peak bone acquisition was achieved or as a result of estrogen deficiency. These results provide proof of principle that LLP2A-Ale can direct MSCs to the bone to form new bone and increase bone strength.", + "TAG_DATA": [ + "85, induced {'effect': 'B-positive'}", + "86, MSC {'context': 'B-cells'}", + "87, migration {'phenotype': 'B-migration'}", + "89, osteogenic {'phenotype': 'B-differentiation'}", + "90, differentiation {'phenotype': 'I-differentiation'}", + "91, in {'context': 'B-in vitro'}", + "92, vitro. {'context': 'I-in vitro'}", + "108, xenotransplantation {'context': 'B-xenograft'}", + "112, immunocompetent {'context': 'B-organism'}", + "113, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "85, induced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "86, MSC ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "87, migration ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "89, osteogenic ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "90, differentiation ['l3', 'l8', 'l12', 'l15', 'l18']", + "91, in ['l4', 'l9', 'l13', 'l16', 'l19']", + "92, vitro. ['l5', 'l10', 'l14', 'l17', 'l18', 'l19']", + "108, xenotransplantation ['l20', 'l21']", + "112, immunocompetent ['l20', 'l22']", + "113, mice. ['l21', 'l22']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "MSC" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "osteogenic", + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "MSC" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "MSC" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "osteogenic", + "differentiation" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "osteogenic", + "differentiation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "22286306", + "TEXT": "Metabolic skeletal disorders associated with impaired bone formation are a major clinical challenge. One approach to treat these defects is to silence bone-formation-inhibitory genes by small interference RNAs (siRNAs) in osteogenic-lineage cells that occupy the niche surrounding the bone-formation surfaces. We developed a targeting system involving dioleoyl trimethylammonium propane (DOTAP)-based cationic liposomes attached to six repetitive sequences of aspartate, serine, serine ((AspSerSer)(6)) for delivering siRNAs specifically to bone-formation surfaces. Using this system, we encapsulated an osteogenic siRNA that targets casein kinase-2 interacting protein-1 (encoded by Plekho1, also known as Plekho1). In vivo systemic delivery of Plekho1 siRNA in rats using our system resulted in the selective enrichment of the siRNAs in osteogenic cells and the subsequent depletion of Plekho1. A bioimaging analysis further showed that this approach markedly promoted bone formation, enhanced the bone micro-architecture and increased the bone mass in both healthy and osteoporotic rats. These results indicate (AspSerSer)(6)-liposome as a promising targeted delivery system for RNA interference-based bone anabolic therapy.", + "TAG_DATA": [ + "90, In {'context': 'B-in vivo'}", + "91, vivo {'context': 'I-in vivo'}", + "95, Plekho1 {'perturbing_action': 'B-rnai/knockdown'}", + "96, siRNA {'perturbing_action': 'I-rnai/knockdown'}", + "98, rats {'context': 'B-organism'}", + "111, osteogenic {'context': 'B-cells'}", + "112, cells {'context': 'I-cells'}", + "128, promoted {'effect': 'B-positive'}", + "129, bone {'phenotype': 'B-self-renewal'}", + "130, formation, {'phenotype': 'I-tumourigenesis'}", + "145, rats. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "90, In ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "91, vivo ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "95, Plekho1 ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "96, siRNA ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "98, rats ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "111, osteogenic ['l4', 'l9', 'l13', 'l16', 'l18', 'l20', 'l21']", + "112, cells ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "128, promoted ['l22', 'l23', 'l24']", + "129, bone ['l22', 'l25', 'l26']", + "130, formation, ['l21', 'l23', 'l25']", + "145, rats. ['l24', 'l26']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Plekho1", + "siRNA" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Plekho1", + "siRNA" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Plekho1", + "siRNA" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteogenic", + "cells" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteogenic" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "bone" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats." + ] + } + }, + { + "phenotype": { + "val": "self-renewal", + "words": [ + "bone" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats." + ] + } + } + ] + }, + { + "PMID": "22270721", + "TEXT": "Noise-induced hearing loss (NIHL) is a global health hazard with considerable pathophysiological and social consequences that has no effective treatment. In the heart, lung and other organs, cyclic guanosine monophosphate (cGMP) facilitates protective processes in response to traumatic events. We therefore analyzed NIHL in mice with a genetic deletion of the gene encoding cGMP-dependent protein kinase type I (Prkg1) and found a greater vulnerability to and markedly less recovery from NIHL in these mice as compared to mice without the deletion. Prkg1 was expressed in the sensory cells and neurons of the inner ear of wild-type mice, and its expression partly overlapped with the expression profile of cGMP-hydrolyzing phosphodiesterase 5 (Pde5). Treatment of rats and wild-type mice with the Pde5 inhibitor vardenafil almost completely prevented NIHL and caused a Prkg1-dependent upregulation of poly (ADP-ribose) in hair cells and the spiral ganglion, suggesting an endogenous protective cGMP-Prkg1 signaling pathway that culminates in the activation of poly (ADP-ribose) polymerase. These data suggest vardenafil or related drugs as possible candidates for the treatment of NIHL.", + "TAG_DATA": [ + "44, mice {'context': 'B-organism'}", + "47, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "48, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "49, of {'perturbing_action': 'I-gene loss-of-function'}", + "50, the {'perturbing_action': 'I-gene loss-of-function'}", + "51, gene {'perturbing_action': 'I-gene loss-of-function'}", + "52, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "53, cGMP-dependent {'perturbing_action': 'I-gene loss-of-function'}", + "54, protein {'perturbing_action': 'I-gene loss-of-function'}", + "55, kinase {'perturbing_action': 'I-gene loss-of-function'}", + "56, type {'perturbing_action': 'I-gene loss-of-function'}", + "57, I {'perturbing_action': 'I-gene loss-of-function'}", + "58, (Prkg1) {'perturbing_action': 'I-gene loss-of-function'}", + "73, mice {'context': 'B-organism'}", + "77, mice {'context': 'B-organism'}", + "113, rats {'context': 'B-organism'}", + "116, mice {'context': 'B-organism'}", + "119, Pde5 {'perturbing_action': 'B-pharmacological inhibition'}", + "120, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "121, vardenafil {'perturbing_action': 'I-pharmacological inhibition'}", + "135, hair {'context': 'B-cells'}", + "136, cells {'context': 'I-cells'}", + "139, spiral {'context': 'B-cells'}", + "140, ganglion, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "44, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "47, genetic ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "48, deletion ['l7', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "49, of ['l8', 'l20', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "50, the ['l9', 'l21', 'l32', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "51, gene ['l10', 'l22', 'l33', 'l43', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "52, encoding ['l11', 'l23', 'l34', 'l44', 'l53', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "53, cGMP-dependent ['l0', 'l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "54, protein ['l1', 'l13', 'l25', 'l36', 'l46', 'l55', 'l63', 'l70', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "55, kinase ['l2', 'l14', 'l26', 'l37', 'l47', 'l56', 'l64', 'l71', 'l77', 'l83', 'l84', 'l85', 'l86', 'l87']", + "56, type ['l3', 'l15', 'l27', 'l38', 'l48', 'l57', 'l65', 'l72', 'l78', 'l83', 'l88', 'l89', 'l90', 'l91']", + "57, I ['l4', 'l16', 'l28', 'l39', 'l49', 'l58', 'l66', 'l73', 'l79', 'l84', 'l88', 'l92', 'l93', 'l94']", + "58, (Prkg1) ['l5', 'l17', 'l29', 'l40', 'l50', 'l59', 'l67', 'l74', 'l80', 'l85', 'l89', 'l92', 'l95', 'l96']", + "73, mice ['l6', 'l18', 'l30', 'l41', 'l51', 'l60', 'l68', 'l75', 'l81', 'l86', 'l90', 'l93', 'l95']", + "77, mice ['l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l76', 'l82', 'l87', 'l91', 'l94', 'l96']", + "113, rats ['l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "116, mice ['l97', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "119, Pde5 ['l98', 'l105', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "120, inhibitor ['l99', 'l106', 'l112', 'l118', 'l119', 'l120', 'l121', 'l122']", + "121, vardenafil ['l100', 'l107', 'l113', 'l118', 'l123', 'l124', 'l125', 'l126']", + "135, hair ['l101', 'l108', 'l114', 'l119', 'l123', 'l127', 'l128', 'l129']", + "136, cells ['l102', 'l109', 'l115', 'l120', 'l124', 'l127', 'l130', 'l131']", + "139, spiral ['l103', 'l110', 'l116', 'l121', 'l125', 'l128', 'l130', 'l132']", + "140, ganglion, ['l104', 'l111', 'l117', 'l122', 'l126', 'l129', 'l131', 'l132']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cGMP-dependent", + "protein", + "kinase", + "type", + "I", + "(Prkg1)", + "genetic", + "deletion", + "of", + "the", + "gene", + "encoding" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rats", + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pde5", + "inhibitor", + "vardenafil" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pde5", + "inhibitor", + "vardenafil" + ] + }, + "context": { + "val": "cells", + "words": [ + "hair", + "cells", + "spiral", + "ganglion," + ] + } + } + ] + }, + { + "PMID": "22179319", + "TEXT": "Huntington's disease is a fatal neurodegenerative disorder caused by an expanded polyglutamine repeat in huntingtin (HTT) protein. We previously showed that calorie restriction ameliorated Huntington's disease pathogenesis and slowed disease progression in mice that model Huntington's disease (Huntington's disease mice). We now report that overexpression of sirtuin 1 (Sirt1), a mediator of the beneficial metabolic effects of calorie restriction, protects neurons against mutant HTT toxicity, whereas reduction of Sirt1 exacerbates mutant HTT toxicity. Overexpression of Sirt1 improves motor function, reduces brain atrophy and attenuates mutant-HTT-mediated metabolic abnormalities in Huntington's disease mice. Further mechanistic studies suggested that Sirt1 prevents the mutant-HTT-induced decline in brain-derived neurotrophic factor (BDNF) concentrations and the signaling of its receptor, TrkB, and restores dopamine- and cAMP-regulated phosphoprotein, 32 kDa (DARPP32) concentrations in the striatum. Sirt1 deacetylase activity is required for Sirt1-mediated neuroprotection in Huntington's disease cell models. Notably, we show that mutant HTT interacts with Sirt1 and inhibits Sirt1 deacetylase activity, which results in hyperacetylation of Sirt1 substrates such as forkhead box O3A (Foxo3a), thereby inhibiting its pro-survival function. Overexpression of Sirt1 counteracts the mutant-HTT-induced deacetylase deficit, enhances the deacetylation of Foxo3a and facilitates cell survival. These findings show a neuroprotective role for Sirt1 in mammalian Huntington's disease models and open new avenues for the development of neuroprotective strategies in Huntington's disease.", + "TAG_DATA": [ + "44, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "45, of {'perturbing_action': 'I-gene gain-of-function'}", + "46, sirtuin {'perturbing_action': 'I-gene gain-of-function'}", + "47, 1 {'perturbing_action': 'I-gene gain-of-function'}", + "48, (Sirt1), {'perturbing_action': 'I-gene gain-of-function'}", + "60, neurons {'context': 'B-cells'}", + "66, reduction {'perturbing_action': 'B-gene loss-of-function'}", + "67, of {'perturbing_action': 'I-gene loss-of-function'}", + "68, Sirt1 {'perturbing_action': 'I-gene loss-of-function'}", + "73, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "74, of {'perturbing_action': 'I-gene gain-of-function'}", + "75, Sirt1 {'perturbing_action': 'I-gene gain-of-function'}", + "88, Huntington's {'context': 'B-organism'}", + "89, disease {'context': 'I-organism'}", + "90, mice. {'context': 'I-organism'}", + "126, striatum. {'context': 'B-tissue/organ'}", + "172, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "173, of {'perturbing_action': 'I-gene gain-of-function'}", + "174, Sirt1 {'perturbing_action': 'I-gene gain-of-function'}", + "186, facilitates {'effect': 'B-positive'}", + "187, cell {'phenotype': 'B-cell survival'}", + "188, survival. {'phenotype': 'I-cell survival'}" + ], + "LINK_DATA": [ + "44, overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "45, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "46, sirtuin ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "47, 1 ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "48, (Sirt1), ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "60, neurons ['l4', 'l14', 'l23', 'l31', 'l38']", + "66, reduction ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "67, of ['l6', 'l16', 'l25', 'l33', 'l40', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "68, Sirt1 ['l7', 'l17', 'l26', 'l34', 'l41', 'l46', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "73, Overexpression ['l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "74, of ['l62', 'l68', 'l69', 'l70', 'l71', 'l72']", + "75, Sirt1 ['l52', 'l57', 'l63', 'l68', 'l73', 'l74', 'l75', 'l76']", + "88, Huntington's ['l8', 'l18', 'l27', 'l35', 'l42', 'l47', 'l53', 'l58', 'l64', 'l69', 'l73', 'l77', 'l78', 'l79']", + "89, disease ['l9', 'l19', 'l28', 'l36', 'l43', 'l48', 'l54', 'l59', 'l65', 'l70', 'l74', 'l77', 'l80']", + "90, mice. ['l10', 'l20', 'l29', 'l37', 'l44', 'l49', 'l55', 'l60', 'l66', 'l71', 'l75', 'l78', 'l80']", + "126, striatum. ['l50', 'l56', 'l61', 'l67', 'l72', 'l76', 'l79']", + "172, Overexpression ['l81', 'l82', 'l83', 'l84', 'l85']", + "173, of ['l81', 'l86', 'l87', 'l88', 'l89']", + "174, Sirt1 ['l82', 'l86', 'l90', 'l91', 'l92']", + "186, facilitates ['l83', 'l87', 'l90', 'l93', 'l94']", + "187, cell ['l84', 'l88', 'l91', 'l93', 'l95']", + "188, survival. ['l85', 'l89', 'l92', 'l94', 'l95']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "sirtuin", + "1", + "(Sirt1)," + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "sirtuin", + "1", + "(Sirt1),", + "Overexpression", + "Sirt1" + ] + }, + "context": { + "val": "organism", + "words": [ + "Huntington's", + "disease", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "reduction", + "of", + "Sirt1" + ] + }, + "context": { + "val": "organism", + "words": [ + "Huntington's", + "disease", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "reduction", + "of", + "Sirt1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "striatum." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "Sirt1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "striatum." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "Sirt1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "facilitates" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "Sirt1" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "survival." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "facilitates" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "survival." + ] + } + } + ] + }, + { + "PMID": "22179316", + "TEXT": "Sirt1, a NAD-dependent protein deacetylase, has emerged as a key regulator of mammalian transcription in response to cellular metabolic status and stress. Here we show that Sirt1 has a neuroprotective role in models of Huntington's disease, an inherited neurodegenerative disorder caused by a glutamine repeat expansion in huntingtin protein (HTT). Brain-specific knockout of Sirt1 results in exacerbation of brain pathology in a mouse model of Huntington's disease, whereas overexpression of Sirt1 improves survival, neuropathology and the expression of brain-derived neurotrophic factor (BDNF) in Huntington's disease mice. We show that Sirt1 deacetylase activity directly targets neurons to mediate neuroprotection from mutant HTT. The neuroprotective effect of Sirt1 requires the presence of CREB-regulated transcription coactivator 1 (TORC1), a brain-specific modulator of CREB activity. We show that under normal conditions, Sirt1 deacetylates and activates TORC1 by promoting its dephosphorylation and its interaction with CREB. We identified BDNF as a key target of Sirt1 and TORC1 transcriptional activity in both normal and Huntington's disease neurons. Mutant HTT interferes with the TORC1-CREB interaction to repress BDNF transcription, and Sirt1 rescues this defect in vitro and in vivo. These studies suggest a key role for Sirt1 in transcriptional networks in both the normal and Huntington's disease brain and offer an opportunity for therapeutic development.", + "TAG_DATA": [ + "50, Brain-specific {'perturbing_action': 'B-gene loss-of-function'}", + "51, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "52, of {'perturbing_action': 'I-gene loss-of-function'}", + "53, Sirt1 {'perturbing_action': 'I-gene loss-of-function'}", + "62, mouse {'context': 'B-organism'}", + "63, model {'context': 'I-organism'}", + "64, of {'context': 'I-organism'}", + "65, Huntington's {'context': 'I-organism'}", + "66, disease, {'context': 'I-organism'}", + "68, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "69, of {'perturbing_action': 'I-gene gain-of-function'}", + "70, Sirt1 {'perturbing_action': 'I-gene gain-of-function'}", + "83, Huntington's {'context': 'B-organism'}", + "84, disease {'context': 'I-organism'}", + "85, mice. {'context': 'B-organism'}", + "160, neurons. {'context': 'B-cells'}", + "177, in {'context': 'B-in vitro'}", + "178, vitro {'context': 'I-in vitro'}", + "180, in {'context': 'B-in vivo'}", + "181, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "50, Brain-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "51, knockout ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "52, of ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "53, Sirt1 ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "62, mouse ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "63, model ['l4', 'l14', 'l23', 'l31', 'l38', 'l44', 'l45', 'l46', 'l47', 'l48']", + "64, of ['l5', 'l15', 'l24', 'l32', 'l39', 'l44', 'l49', 'l50', 'l51', 'l52']", + "65, Huntington's ['l6', 'l16', 'l25', 'l33', 'l40', 'l45', 'l49', 'l53', 'l54', 'l55']", + "66, disease, ['l7', 'l17', 'l26', 'l34', 'l41', 'l46', 'l50', 'l53', 'l56', 'l57']", + "68, overexpression ['l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "69, of ['l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "70, Sirt1 ['l59', 'l64', 'l69', 'l70', 'l71', 'l72']", + "83, Huntington's ['l8', 'l18', 'l27', 'l35', 'l60', 'l65', 'l69', 'l73', 'l74']", + "84, disease ['l9', 'l19', 'l28', 'l36', 'l42', 'l47', 'l51', 'l54', 'l56', 'l61', 'l66', 'l70', 'l73', 'l75']", + "85, mice. ['l10', 'l20', 'l29', 'l37', 'l43', 'l48', 'l52', 'l55', 'l57', 'l62', 'l67', 'l71', 'l74', 'l75']", + "160, neurons. ['l63', 'l68', 'l72']", + "177, in ['l76', 'l77', 'l78']", + "178, vitro ['l76', 'l79', 'l80']", + "180, in ['l77', 'l79', 'l81']", + "181, vivo. ['l78', 'l80', 'l81']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Brain-specific", + "knockout", + "of", + "Sirt1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "Huntington's", + "disease,", + "disease", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Sirt1" + ] + }, + "context": { + "val": "organism", + "words": [ + "Huntington's", + "disease", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Sirt1" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons." + ] + } + } + ] + }, + { + "PMID": "22157678", + "TEXT": "Exuberant fibroproliferation is a common complication after injury for reasons that are not well understood. One key component of wound repair that is often overlooked is mechanical force, which regulates cell-matrix interactions through intracellular focal adhesion components, including focal adhesion kinase (FAK). Here we report that FAK is activated after cutaneous injury and that this process is potentiated by mechanical loading. Fibroblast-specific FAK knockout mice have substantially less inflammation and fibrosis than control mice in a model of hypertrophic scar formation. We show that FAK acts through extracellular-related kinase (ERK) to mechanically trigger the secretion of monocyte chemoattractant protein-1 (MCP-1, also known as CCL2), a potent chemokine that is linked to human fibrotic disorders. Similarly, MCP-1 knockout mice form minimal scars, indicating that inflammatory chemokine pathways are a major mechanism by which FAK mechanotransduction induces fibrosis. Small-molecule inhibition of FAK blocks these effects in human cells and reduces scar formation in vivo through attenuated MCP-1 signaling and inflammatory cell recruitment. These findings collectively indicate that physical force regulates fibrosis through inflammatory FAK-ERK-MCP-1 pathways and that molecular strategies targeting FAK can effectively uncouple mechanical force from pathologic scar formation.", + "TAG_DATA": [ + "61, Fibroblast-specific {'perturbing_action': 'B-gene loss-of-function'}", + "62, FAK {'perturbing_action': 'I-gene loss-of-function'}", + "63, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "64, mice {'context': 'B-organism'}", + "73, mice {'context': 'B-organism'}", + "115, MCP-1 {'perturbing_action': 'B-gene loss-of-function'}", + "116, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "117, mice {'context': 'B-organism'}", + "136, Small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "137, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "138, of {'perturbing_action': 'I-pharmacological inhibition'}", + "139, FAK {'perturbing_action': 'I-pharmacological inhibition'}", + "144, human {'context': 'B-cells'}", + "145, cells {'context': 'I-cells'}", + "150, in {'context': 'B-in vivo'}", + "151, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "61, Fibroblast-specific ['l0', 'l1', 'l2', 'l3']", + "62, FAK ['l0', 'l4', 'l5', 'l6']", + "63, knockout ['l1', 'l4', 'l7', 'l8']", + "64, mice ['l2', 'l5', 'l7', 'l9']", + "73, mice ['l3', 'l6', 'l8', 'l9']", + "115, MCP-1 ['l10', 'l11', 'l12', 'l13']", + "116, knockout ['l10', 'l14', 'l15']", + "117, mice ['l11', 'l14', 'l16']", + "136, Small-molecule ['l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "137, inhibition ['l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "138, of ['l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "139, FAK ['l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "144, human ['l12', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40']", + "145, cells ['l13', 'l15', 'l16', 'l21', 'l27', 'l32', 'l36', 'l39']", + "150, in ['l22', 'l28', 'l33', 'l37', 'l41']", + "151, vivo ['l23', 'l29', 'l34', 'l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fibroblast-specific", + "FAK", + "knockout", + "MCP-1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MCP-1", + "knockout" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Small-molecule", + "inhibition", + "of", + "FAK" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Small-molecule", + "inhibition", + "of", + "FAK" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "22120177", + "TEXT": "Tissue homeostasis requires an effective, limited wound-healing response to injury. In chronic disease, failure to regenerate parenchymal tissue leads to the replacement of lost cellular mass with a fibrotic matrix. The mechanisms that dictate the balance of cell regeneration and fibrogenesis are not well understood. Here we report that fibrogenic hepatic stellate cells (HSCs) in the liver are negative regulators of hepatocyte regeneration. This negative regulatory function requires stimulation of the 5-hydroxytryptamine 2B receptor (5-HT(2B)) on HSCs by serotonin, which activates expression of transforming growth factor β1 (TGF-β1), a powerful suppressor of hepatocyte proliferation, through signaling by mitogen-activated protein kinase 1 (ERK) and the transcription factor JunD. Selective antagonism of 5-HT(2B) enhanced hepatocyte growth in models of acute and chronic liver injury. We also observed similar effects in mice lacking 5-HT(2B) or JunD or upon selective depletion of HSCs in wild-type mice. Antagonism of 5-HT(2B) attenuated fibrogenesis and improved liver function in disease models in which fibrosis was pre-established and progressive. Pharmacological targeting of 5-HT(2B) is clinically safe in humans and may be therapeutic in chronic liver disease.", + "TAG_DATA": [ + "107, Selective {'perturbing_action': 'B-pharmacological inhibition'}", + "108, antagonism {'perturbing_action': 'I-pharmacological inhibition'}", + "109, of {'perturbing_action': 'I-pharmacological inhibition'}", + "110, 5-HT(2B) {'perturbing_action': 'I-pharmacological inhibition'}", + "112, hepatocyte {'context': 'B-cells'}", + "128, mice {'context': 'B-organism'}", + "129, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "130, 5-HT(2B) {'perturbing_action': 'I-gene loss-of-function'}", + "131, or {'perturbing_action': 'I-gene loss-of-function'}", + "132, JunD {'perturbing_action': 'I-gene loss-of-function'}", + "138, HSCs {'context': 'B-cells'}", + "141, mice. {'context': 'B-organism'}", + "142, Antagonism {'perturbing_action': 'B-pharmacological inhibition'}", + "143, of {'perturbing_action': 'I-pharmacological inhibition'}", + "144, 5-HT(2B) {'perturbing_action': 'I-pharmacological inhibition'}", + "149, liver {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "107, Selective ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "108, antagonism ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "109, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "110, 5-HT(2B) ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "112, hepatocyte ['l3', 'l11', 'l18', 'l24']", + "128, mice ['l4', 'l12', 'l19', 'l25', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "129, lacking ['l5', 'l13', 'l20', 'l26', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "130, 5-HT(2B) ['l6', 'l14', 'l21', 'l27', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "131, or ['l7', 'l15', 'l22', 'l28', 'l32', 'l37', 'l41', 'l45', 'l46', 'l47']", + "132, JunD ['l8', 'l16', 'l23', 'l29', 'l33', 'l38', 'l42', 'l45', 'l48', 'l49']", + "138, HSCs ['l34', 'l39', 'l43', 'l46', 'l48', 'l50']", + "141, mice. ['l35', 'l40', 'l44', 'l47', 'l49', 'l50']", + "142, Antagonism ['l51', 'l52', 'l53']", + "143, of ['l51', 'l54', 'l55']", + "144, 5-HT(2B) ['l52', 'l54', 'l56']", + "149, liver ['l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Selective", + "antagonism", + "of", + "5-HT(2B)" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocyte" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Selective", + "antagonism", + "of", + "5-HT(2B)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "5-HT(2B)", + "or", + "JunD" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "5-HT(2B)", + "or", + "JunD" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSCs" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Antagonism", + "of", + "5-HT(2B)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "22101767", + "TEXT": "Stem cell-based regenerative medicine is a promising approach in tissue reconstruction. Here we show that proinflammatory T cells inhibit the ability of exogenously added bone marrow mesenchymal stem cells (BMMSCs) to mediate bone repair. This inhibition is due to interferon γ (IFN-γ)-induced downregulation of the runt-related transcription factor 2 (Runx-2) pathway and enhancement of tumor necrosis factor α (TNF-α) signaling in the stem cells. We also found that, through inhibition of nuclear factor κB (NF-κB), TNF-α converts the signaling of the IFN-γ-activated, nonapoptotic form of TNF receptor superfamily member 6 (Fas) in BMMSCs to a caspase 3- and caspase 8-associated proapoptotic cascade, resulting in the apoptosis of these cells. Conversely, reduction of IFN-γ and TNF-α concentrations by systemic infusion of Foxp3(+) regulatory T cells, or by local administration of aspirin, markedly improved BMMSC-based bone regeneration and calvarial defect repair in C57BL/6 mice. These data collectively show a previously unrecognized role of recipient T cells in BMMSC-based tissue engineering.", + "TAG_DATA": [ + "92, BMMSCs {'context': 'B-cells'}", + "102, resulting {'effect': 'B-positive'}", + "103, in {'effect': 'I-positive'}", + "105, apoptosis {'phenotype': 'B-apoptosis'}", + "108, cells. {'context': 'B-cells'}", + "120, Foxp3(+) {'context': 'B-cells'}", + "121, regulatory {'context': 'I-cells'}", + "122, T {'context': 'I-cells'}", + "123, cells, {'context': 'I-cells'}", + "136, calvarial {'context': 'B-neoplasm'}", + "140, C57BL/6 {'context': 'B-organism'}", + "141, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "92, BMMSCs ['l0', 'l1', 'l2', 'l3']", + "102, resulting ['l0', 'l4', 'l5', 'l6']", + "103, in ['l1', 'l4', 'l7', 'l8']", + "105, apoptosis ['l2', 'l5', 'l7', 'l9']", + "108, cells. ['l3', 'l6', 'l8', 'l9']", + "120, Foxp3(+) ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "121, regulatory ['l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "122, T ['l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "123, cells, ['l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "133, bone ['l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38']", + "136, calvarial ['l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l40', 'l41']", + "137, defect ['l15', 'l22', 'l28', 'l33', 'l37', 'l39', 'l42', 'l43']", + "140, C57BL/6 ['l16', 'l23', 'l29', 'l34', 'l40', 'l42', 'l44']", + "141, mice. ['l17', 'l24', 'l30', 'l35', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "BMMSCs", + "cells." + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "BMMSCs", + "cells." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "22001906", + "TEXT": "Although the lung is a defining feature of air-breathing animals, the pathway controlling the formation of type I pneumocytes, the cells that mediate gas exchange, is poorly understood. In contrast, the glucocorticoid receptor and its cognate ligand have long been known to promote type II pneumocyte maturation; prenatal administration of glucocorticoids is commonly used to attenuate the severity of infant respiratory distress syndrome (RDS). Here we show that knock-in mutations of the nuclear co-repressor SMRT (silencing mediator of retinoid and thyroid hormone receptors) in C57BL/6 mice (SMRTmRID) produces a previously unidentified respiratory distress syndrome caused by prematurity of the type I pneumocyte. Though unresponsive to glucocorticoids, treatment with anti-thyroid hormone drugs (propylthiouracil or methimazole) completely rescues SMRT-induced RDS, suggesting an unrecognized and essential role for the thyroid hormone receptor (TR) in lung development. We show that TR and SMRT control type I pneumocyte differentiation through Klf2, which, in turn, seems to directly activate the type I pneumocyte gene program. Conversely, mice without lung Klf2 lack mature type I pneumocytes and die shortly after birth, closely recapitulating the SMRTmRID phenotype. These results identify TR as a second nuclear receptor involved in lung development, specifically type I pneumocyte differentiation, and suggest a possible new type of therapeutic option in the treatment of RDS that is unresponsive to glucocorticoids.", + "TAG_DATA": [ + "68, knock-in {'perturbing_action': 'B-rnai/knockdown'}", + "69, mutations {'perturbing_action': 'I-rnai/knockdown'}", + "70, of {'perturbing_action': 'I-rnai/knockdown'}", + "71, the {'perturbing_action': 'I-rnai/knockdown'}", + "72, nuclear {'perturbing_action': 'I-rnai/knockdown'}", + "73, co-repressor {'perturbing_action': 'I-rnai/knockdown'}", + "74, SMRT {'perturbing_action': 'I-rnai/knockdown'}", + "75, (silencing {'perturbing_action': 'I-rnai/knockdown'}", + "76, mediator {'perturbing_action': 'I-rnai/knockdown'}", + "77, of {'perturbing_action': 'I-rnai/knockdown'}", + "78, retinoid {'perturbing_action': 'I-rnai/knockdown'}", + "79, and {'perturbing_action': 'I-rnai/knockdown'}", + "80, thyroid {'perturbing_action': 'I-rnai/knockdown'}", + "81, hormone {'perturbing_action': 'I-rnai/knockdown'}", + "82, receptors) {'perturbing_action': 'I-rnai/knockdown'}", + "84, C57BL/6 {'context': 'B-organism'}", + "85, mice {'context': 'I-organism'}", + "160, mice {'context': 'B-organism'}", + "161, without {'perturbing_action': 'B-gene loss-of-function'}", + "162, lung {'perturbing_action': 'I-gene loss-of-function'}", + "163, Klf2 {'perturbing_action': 'I-gene loss-of-function'}", + "166, type {'context': 'B-cells'}", + "167, I {'context': 'B-cells'}", + "168, pneumocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "68, knock-in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "69, mutations ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "70, of ['l1', 'l16', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "71, the ['l2', 'l17', 'l31', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "72, nuclear ['l3', 'l18', 'l32', 'l45', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "73, co-repressor ['l4', 'l19', 'l33', 'l46', 'l58', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "74, SMRT ['l5', 'l20', 'l34', 'l47', 'l59', 'l70', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "75, (silencing ['l6', 'l21', 'l35', 'l48', 'l60', 'l71', 'l81', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "76, mediator ['l7', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "77, of ['l8', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l100', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "78, retinoid ['l9', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l108', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "79, and ['l10', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l115', 'l121', 'l122', 'l123', 'l124', 'l125']", + "80, thyroid ['l11', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l121', 'l126', 'l127', 'l128', 'l129']", + "81, hormone ['l12', 'l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l126', 'l130', 'l131', 'l132']", + "82, receptors) ['l13', 'l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l118', 'l123', 'l127', 'l130', 'l133', 'l134']", + "84, C57BL/6 ['l14', 'l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l113', 'l119', 'l124', 'l128', 'l131', 'l133', 'l135']", + "85, mice ['l15', 'l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l129', 'l132', 'l134', 'l135']", + "160, mice ['l136', 'l137', 'l138', 'l139', 'l140', 'l141']", + "161, without ['l136', 'l142', 'l143', 'l144', 'l145', 'l146']", + "162, lung ['l137', 'l142', 'l147', 'l148', 'l149', 'l150']", + "163, Klf2 ['l138', 'l143', 'l147', 'l151', 'l152', 'l153']", + "166, type ['l139', 'l144', 'l148', 'l151', 'l154', 'l155']", + "167, I ['l140', 'l145', 'l149', 'l152', 'l154', 'l156']", + "168, pneumocytes ['l141', 'l146', 'l150', 'l153', 'l155', 'l156']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knock-in", + "mutations", + "of", + "the", + "nuclear", + "co-repressor", + "SMRT", + "(silencing", + "mediator", + "retinoid", + "and", + "thyroid", + "hormone", + "receptors)" + ] + }, + "context": { + "val": "organism", + "words": [ + "C57BL/6", + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "without", + "lung", + "Klf2" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "without", + "lung", + "Klf2" + ] + }, + "context": { + "val": "cells", + "words": [ + "type", + "I", + "pneumocytes" + ] + } + } + ] + }, + { + "PMID": "21983857", + "TEXT": "Small-cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer for which there is no effective treatment. Using a mouse model in which deletion of Rb1 and Trp53 in the lung epithelium of adult mice induces SCLC, we found that the Hedgehog signaling pathway is activated in SCLC cells independently of the lung microenvironment. Constitutive activation of the Hedgehog signaling molecule Smoothened (Smo) promoted the clonogenicity of human SCLC in vitro and the initiation and progression of mouse SCLC in vivo. Reciprocally, deletion of Smo in Rb1 and Trp53-mutant lung epithelial cells strongly suppressed SCLC initiation and progression in mice. Furthermore, pharmacological blockade of Hedgehog signaling inhibited the growth of mouse and human SCLC, most notably following chemotherapy. These findings show a crucial cell-intrinsic role for Hedgehog signaling in the development and maintenance of SCLC and identify Hedgehog pathway inhibition as a therapeutic strategy to slow the progression of disease and delay cancer recurrence in individuals with SCLC.", + "TAG_DATA": [ + "21, mouse {'context': 'B-organism'}", + "22, model {'context': 'I-organism'}", + "25, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "26, of {'perturbing_action': 'I-gene loss-of-function'}", + "27, Rb1 {'perturbing_action': 'I-gene loss-of-function'}", + "28, and {'perturbing_action': 'I-gene loss-of-function'}", + "29, Trp53 {'perturbing_action': 'I-gene loss-of-function'}", + "30, in {'perturbing_action': 'I-gene loss-of-function'}", + "31, the {'perturbing_action': 'I-gene loss-of-function'}", + "32, lung {'perturbing_action': 'I-gene loss-of-function'}", + "33, epithelium {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-tissue/organ'}", + "35, adult {'context': 'B-organism'}", + "36, mice {'context': 'I-organism'}", + "56, Constitutive {'perturbing_action': 'B-gene gain-of-function'}", + "57, activation {'perturbing_action': 'I-gene gain-of-function'}", + "58, of {'perturbing_action': 'I-gene gain-of-function'}", + "59, the {'perturbing_action': 'I-gene gain-of-function'}", + "60, Hedgehog {'perturbing_action': 'I-gene gain-of-function'}", + "61, signaling {'perturbing_action': 'I-gene gain-of-function'}", + "62, molecule {'perturbing_action': 'I-gene gain-of-function'}", + "63, Smoothened {'perturbing_action': 'I-gene gain-of-function'}", + "64, (Smo) {'perturbing_action': 'I-gene gain-of-function'}", + "65, promoted {'effect': 'B-positive'}", + "67, clonogenicity {'phenotype': 'B-colony formation'}", + "69, human {'context': 'B-neoplasm'}", + "70, SCLC {'context': 'I-neoplasm'}", + "71, in {'context': 'B-in vitro'}", + "72, vitro {'context': 'I-in vitro'}", + "79, mouse {'context': 'B-neoplasm'}", + "80, SCLC {'context': 'I-neoplasm'}", + "81, in {'context': 'B-in vivo'}", + "82, vivo. {'context': 'I-in vivo'}", + "84, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "85, of {'perturbing_action': 'I-gene loss-of-function'}", + "86, Smo {'perturbing_action': 'I-gene loss-of-function'}", + "88, Rb1 {'perturbing_action': 'I-gene loss-of-function'}", + "89, and {'perturbing_action': 'B-other'}", + "90, Trp53-mutant {'perturbing_action': 'B-other'}", + "91, lung {'context': 'B-cells'}", + "92, epithelial {'context': 'I-cells'}", + "93, cells {'context': 'I-cells'}", + "96, SCLC {'context': 'B-neoplasm'}", + "101, mice. {'context': 'B-organism'}", + "112, mouse {'context': 'B-neoplasm'}", + "113, and {'context': 'I-neoplasm'}", + "114, human {'context': 'I-neoplasm'}", + "115, SCLC, {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "21, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "22, model ['l0', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "25, deletion ['l1', 'l30', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "26, of ['l2', 'l31', 'l60', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "27, Rb1 ['l3', 'l32', 'l61', 'l89', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "28, and ['l4', 'l33', 'l62', 'l90', 'l117', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "29, Trp53 ['l5', 'l34', 'l63', 'l91', 'l118', 'l144', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "30, in ['l6', 'l35', 'l64', 'l92', 'l119', 'l145', 'l170', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218']", + "31, the ['l7', 'l36', 'l65', 'l93', 'l120', 'l146', 'l171', 'l195', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241']", + "32, lung ['l8', 'l37', 'l66', 'l94', 'l121', 'l147', 'l172', 'l196', 'l219', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263']", + "33, epithelium ['l9', 'l38', 'l67', 'l95', 'l122', 'l148', 'l173', 'l197', 'l220', 'l242', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284']", + "35, adult ['l10', 'l39', 'l68', 'l96', 'l123', 'l149', 'l174', 'l198', 'l221', 'l243', 'l264', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304']", + "36, mice ['l11', 'l40', 'l69', 'l97', 'l124', 'l150', 'l175', 'l199', 'l222', 'l244', 'l265', 'l285', 'l305', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315', 'l316', 'l317']", + "56, Constitutive ['l41', 'l70', 'l98', 'l125', 'l151', 'l176', 'l200', 'l223', 'l245', 'l266', 'l286', 'l318', 'l319', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327', 'l328', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340']", + "57, activation ['l12', 'l42', 'l71', 'l99', 'l126', 'l152', 'l177', 'l201', 'l224', 'l246', 'l267', 'l287', 'l318', 'l341', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348', 'l349', 'l350', 'l351', 'l352', 'l353', 'l354', 'l355', 'l356', 'l357', 'l358', 'l359', 'l360']", + "58, of ['l13', 'l43', 'l72', 'l100', 'l127', 'l153', 'l178', 'l202', 'l225', 'l247', 'l268', 'l288', 'l319', 'l341', 'l361', 'l362', 'l363', 'l364', 'l365', 'l366', 'l367', 'l368', 'l369', 'l370', 'l371', 'l372', 'l373', 'l374', 'l375', 'l376', 'l377', 'l378', 'l379']", + "59, the ['l14', 'l44', 'l73', 'l101', 'l128', 'l154', 'l179', 'l203', 'l226', 'l248', 'l269', 'l289', 'l320', 'l342', 'l361', 'l380', 'l381', 'l382', 'l383', 'l384', 'l385', 'l386', 'l387', 'l388', 'l389', 'l390', 'l391', 'l392', 'l393', 'l394', 'l395', 'l396', 'l397', 'l398']", + "60, Hedgehog ['l15', 'l45', 'l74', 'l102', 'l129', 'l155', 'l180', 'l204', 'l227', 'l249', 'l270', 'l290', 'l321', 'l343', 'l362', 'l380', 'l399', 'l400', 'l401', 'l402', 'l403', 'l404', 'l405', 'l406', 'l407', 'l408', 'l409', 'l410', 'l411', 'l412', 'l413', 'l414', 'l415']", + "61, signaling ['l16', 'l46', 'l75', 'l103', 'l130', 'l156', 'l181', 'l205', 'l228', 'l250', 'l271', 'l291', 'l322', 'l344', 'l363', 'l381', 'l399', 'l416', 'l417', 'l418', 'l419', 'l420', 'l421', 'l422', 'l423', 'l424', 'l425', 'l426', 'l427', 'l428', 'l429', 'l430', 'l431']", + "62, molecule ['l17', 'l47', 'l76', 'l104', 'l131', 'l157', 'l182', 'l206', 'l229', 'l251', 'l272', 'l292', 'l305', 'l323', 'l345', 'l364', 'l382', 'l400', 'l416', 'l432', 'l433', 'l434', 'l435', 'l436', 'l437', 'l438', 'l439', 'l440', 'l441', 'l442', 'l443', 'l444', 'l445', 'l446']", + "63, Smoothened ['l18', 'l48', 'l77', 'l105', 'l132', 'l158', 'l183', 'l207', 'l230', 'l252', 'l273', 'l293', 'l306', 'l324', 'l346', 'l365', 'l383', 'l401', 'l417', 'l432', 'l447', 'l448', 'l449', 'l450', 'l451', 'l452', 'l453', 'l454', 'l455', 'l456', 'l457', 'l458', 'l459', 'l460']", + "64, (Smo) ['l19', 'l49', 'l78', 'l106', 'l133', 'l159', 'l184', 'l208', 'l231', 'l253', 'l274', 'l294', 'l307', 'l325', 'l347', 'l366', 'l384', 'l402', 'l418', 'l433', 'l447', 'l461', 'l462', 'l463', 'l464', 'l465', 'l466', 'l467', 'l468', 'l469', 'l470', 'l471']", + "65, promoted ['l20', 'l50', 'l79', 'l107', 'l134', 'l160', 'l185', 'l209', 'l232', 'l254', 'l275', 'l295', 'l308', 'l326', 'l348', 'l367', 'l385', 'l403', 'l419', 'l434', 'l448', 'l461', 'l472', 'l473', 'l474', 'l475', 'l476']", + "67, clonogenicity ['l21', 'l51', 'l80', 'l108', 'l135', 'l161', 'l186', 'l210', 'l233', 'l255', 'l276', 'l296', 'l309', 'l327', 'l349', 'l368', 'l386', 'l404', 'l420', 'l435', 'l449', 'l462', 'l472', 'l477', 'l478', 'l479', 'l480']", + "69, human ['l22', 'l52', 'l81', 'l109', 'l136', 'l162', 'l187', 'l211', 'l234', 'l256', 'l277', 'l297', 'l310', 'l328', 'l350', 'l369', 'l387', 'l405', 'l421', 'l436', 'l450', 'l463', 'l473', 'l477', 'l481', 'l482', 'l483']", + "70, SCLC ['l23', 'l53', 'l82', 'l110', 'l137', 'l163', 'l188', 'l212', 'l235', 'l257', 'l278', 'l298', 'l311', 'l329', 'l351', 'l370', 'l388', 'l406', 'l422', 'l437', 'l451', 'l464', 'l474', 'l478', 'l481', 'l484', 'l485']", + "71, in ['l24', 'l54', 'l83', 'l111', 'l138', 'l164', 'l189', 'l213', 'l236', 'l258', 'l279', 'l299', 'l312', 'l330', 'l352', 'l371', 'l389', 'l407', 'l423', 'l438', 'l452', 'l465', 'l475', 'l479', 'l482', 'l484', 'l486']", + "72, vitro ['l25', 'l55', 'l84', 'l112', 'l139', 'l165', 'l190', 'l214', 'l237', 'l259', 'l280', 'l300', 'l313', 'l331', 'l353', 'l372', 'l390', 'l408', 'l424', 'l439', 'l453', 'l466', 'l476', 'l480', 'l483', 'l485', 'l486']", + "79, mouse ['l26', 'l56', 'l85', 'l113', 'l140', 'l166', 'l191', 'l215', 'l238', 'l260', 'l281', 'l301', 'l314', 'l332', 'l354', 'l373', 'l391', 'l409', 'l425', 'l440', 'l454', 'l467', 'l487', 'l488', 'l489']", + "80, SCLC ['l27', 'l57', 'l86', 'l114', 'l141', 'l167', 'l192', 'l216', 'l239', 'l261', 'l282', 'l302', 'l315', 'l333', 'l355', 'l374', 'l392', 'l410', 'l426', 'l441', 'l455', 'l468', 'l487', 'l490', 'l491']", + "81, in ['l28', 'l58', 'l87', 'l115', 'l142', 'l168', 'l193', 'l217', 'l240', 'l262', 'l283', 'l303', 'l316', 'l334', 'l356', 'l375', 'l393', 'l411', 'l427', 'l442', 'l456', 'l469', 'l488', 'l490', 'l492']", + "82, vivo. ['l29', 'l59', 'l88', 'l116', 'l143', 'l169', 'l194', 'l218', 'l241', 'l263', 'l284', 'l304', 'l317', 'l335', 'l357', 'l376', 'l394', 'l412', 'l428', 'l443', 'l457', 'l470', 'l489', 'l491', 'l492']", + "84, deletion ['l493', 'l494', 'l495', 'l496', 'l497', 'l498', 'l499', 'l500', 'l501', 'l502']", + "85, of ['l493', 'l503', 'l504', 'l505', 'l506', 'l507', 'l508', 'l509', 'l510', 'l511']", + "86, Smo ['l494', 'l503', 'l512', 'l513', 'l514', 'l515', 'l516', 'l517', 'l518', 'l519']", + "88, Rb1 ['l495', 'l504', 'l512', 'l520', 'l521', 'l522', 'l523', 'l524', 'l525', 'l526']", + "89, and ['l496', 'l505', 'l513', 'l520', 'l527', 'l528', 'l529', 'l530', 'l531', 'l532']", + "90, Trp53-mutant ['l497', 'l506', 'l514', 'l521', 'l527', 'l533', 'l534', 'l535', 'l536', 'l537']", + "91, lung ['l336', 'l498', 'l507', 'l515', 'l522', 'l528', 'l533', 'l538', 'l539', 'l540', 'l541']", + "92, epithelial ['l337', 'l395', 'l499', 'l508', 'l516', 'l523', 'l529', 'l534', 'l538', 'l542', 'l543', 'l544']", + "93, cells ['l338', 'l358', 'l377', 'l396', 'l413', 'l429', 'l444', 'l458', 'l471', 'l500', 'l509', 'l517', 'l524', 'l530', 'l535', 'l539', 'l542', 'l545', 'l546']", + "96, SCLC ['l339', 'l359', 'l378', 'l397', 'l414', 'l430', 'l445', 'l459', 'l501', 'l510', 'l518', 'l525', 'l531', 'l536', 'l540', 'l543', 'l545', 'l547']", + "101, mice. ['l340', 'l360', 'l379', 'l398', 'l415', 'l431', 'l446', 'l460', 'l502', 'l511', 'l519', 'l526', 'l532', 'l537', 'l541', 'l544', 'l546', 'l547']", + "112, mouse ['l548', 'l549', 'l550']", + "113, and ['l548', 'l551', 'l552']", + "114, human ['l549', 'l551', 'l553']", + "115, SCLC, ['l550', 'l552', 'l553']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "adult", + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Rb1", + "and", + "Trp53", + "in", + "the", + "lung", + "epithelium", + "Smo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "epithelium", + "deletion", + "of", + "Rb1", + "and", + "Trp53", + "in", + "the", + "lung" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "epithelium" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "adult", + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "activation", + "of", + "the", + "Hedgehog", + "signaling", + "molecule", + "Smoothened", + "(Smo)", + "Constitutive" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "adult", + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "adult", + "mice" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenicity" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Rb1", + "and", + "Trp53", + "in", + "the", + "lung", + "epithelium" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Rb1", + "and", + "Trp53", + "in", + "the", + "lung", + "epithelium" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenicity" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Rb1", + "and", + "Trp53", + "in", + "the", + "lung", + "epithelium", + "Smo" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "SCLC", + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Rb1", + "and", + "Trp53", + "in", + "the", + "lung", + "epithelium" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Rb1", + "and", + "Trp53", + "in", + "the", + "lung", + "epithelium" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "epithelium" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Constitutive", + "activation", + "of", + "the", + "Hedgehog", + "signaling", + "molecule", + "Smoothened", + "(Smo)" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "epithelium" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "epithelium" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenicity" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Constitutive", + "activation", + "of", + "the", + "Hedgehog", + "signaling", + "molecule", + "Smoothened", + "(Smo)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Constitutive", + "activation", + "of", + "the", + "Hedgehog", + "signaling", + "molecule", + "Smoothened", + "(Smo)" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenicity" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Constitutive", + "activation", + "of", + "the", + "Hedgehog", + "signaling", + "molecule", + "Smoothened", + "(Smo)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "SCLC", + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Constitutive", + "activation", + "of", + "the", + "Hedgehog", + "signaling", + "molecule", + "Smoothened", + "(Smo)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Constitutive", + "activation", + "of", + "the", + "Hedgehog", + "signaling", + "molecule", + "Smoothened", + "(Smo)" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Constitutive", + "activation", + "of", + "the", + "Hedgehog", + "signaling", + "molecule", + "Smoothened", + "(Smo)" + ] + }, + "context": { + "val": "cells", + "words": [ + "lung", + "epithelial", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenicity" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "SCLC" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenicity" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "SCLC" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenicity" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Smo", + "Rb1" + ] + }, + "context": { + "val": "cells", + "words": [ + "lung", + "epithelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "and", + "Trp53-mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "lung", + "epithelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "and", + "Trp53-mutant" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "SCLC" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "and", + "Trp53-mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "21946536", + "TEXT": "BRCA1, a well-known tumor suppressor with multiple interacting partners, is predicted to have diverse biological functions. However, so far its only well-established role is in the repair of damaged DNA and cell cycle regulation. In this regard, the etiopathological study of low-penetrant variants of BRCA1 provides an opportunity to uncover its other physiologically important functions. Using this rationale, we studied the R1699Q variant of BRCA1, a potentially moderate-risk variant, and found that it does not impair DNA damage repair but abrogates the repression of microRNA-155 (miR-155), a bona fide oncomir. Mechanistically, we found that BRCA1 epigenetically represses miR-155 expression via its association with HDAC2, which deacetylates histones H2A and H3 on the miR-155 promoter. We show that overexpression of miR-155 accelerates but the knockdown of miR-155 attenuates the growth of tumor cell lines in vivo. Our findings demonstrate a new mode of tumor suppression by BRCA1 and suggest that miR-155 is a potential therapeutic target for BRCA1-deficient tumors.", + "TAG_DATA": [ + "117, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "118, of {'perturbing_action': 'I-gene gain-of-function'}", + "119, miR-155 {'perturbing_action': 'I-gene gain-of-function'}", + "123, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "124, of {'perturbing_action': 'I-rnai/knockdown'}", + "125, miR-155 {'perturbing_action': 'I-rnai/knockdown'}", + "130, tumor {'context': 'B-transformed cells'}", + "131, cell {'context': 'I-transformed cells'}", + "132, lines {'context': 'I-transformed cells'}", + "133, in {'context': 'B-in vivo'}", + "134, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "117, overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "118, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "119, miR-155 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "123, knockdown ['l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "124, of ['l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "125, miR-155 ['l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "130, tumor ['l2', 'l8', 'l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "131, cell ['l3', 'l9', 'l14', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "132, lines ['l4', 'l10', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "133, in ['l5', 'l11', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "134, vivo. ['l6', 'l12', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "miR-155" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "miR-155" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "miR-155" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "miR-155" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "21909103", + "TEXT": "Osteoclasts resorb the mineralized matrices formed by chondrocytes or osteoblasts. The cytokine receptor activator of nuclear factor-κB ligand (RANKL) is essential for osteoclast formation and thought to be supplied by osteoblasts or their precursors, thereby linking bone formation to resorption. However, RANKL is expressed by a variety of cell types, and it is unclear which of them are essential sources for osteoclast formation. Here we have used a mouse strain in which RANKL can be conditionally deleted and a series of Cre-deleter strains to demonstrate that hypertrophic chondrocytes and osteocytes, both of which are embedded in matrix, are essential sources of the RANKL that controls mineralized cartilage resorption and bone remodeling, respectively. Moreover, osteocyte RANKL is responsible for the bone loss associated with unloading. Contrary to the current paradigm, RANKL produced by osteoblasts or their progenitors does not contribute to adult bone remodeling. These results suggest that the rate-limiting step of matrix resorption is controlled by cells embedded within the matrix itself.", + "TAG_DATA": [ + "68, mouse {'context': 'B-organism'}", + "69, strain {'context': 'I-organism'}", + "72, RANKL {'perturbing_action': 'I-gene loss-of-function'}", + "73, can {'perturbing_action': 'I-gene loss-of-function'}", + "74, be {'perturbing_action': 'I-gene loss-of-function'}", + "75, conditionally {'perturbing_action': 'I-gene loss-of-function'}", + "76, deleted {'perturbing_action': 'I-gene loss-of-function'}", + "81, Cre-deleter {'perturbing_action': 'B-gene loss-of-function'}", + "86, hypertrophic {'context': 'B-cells'}", + "87, chondrocytes {'context': 'I-cells'}", + "89, osteocytes, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "68, mouse ['l0', 'l1']", + "69, strain ['l0', 'l2']", + "72, RANKL ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "73, can ['l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "74, be ['l4', 'l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "75, conditionally ['l5', 'l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "76, deleted ['l6', 'l12', 'l18', 'l23', 'l28', 'l29', 'l30']", + "81, Cre-deleter ['l13', 'l19', 'l24', 'l31', 'l32', 'l33']", + "86, hypertrophic ['l7', 'l14', 'l20', 'l25', 'l28', 'l31', 'l34', 'l35']", + "87, chondrocytes ['l8', 'l15', 'l21', 'l26', 'l29', 'l32', 'l34', 'l36']", + "89, osteocytes, ['l9', 'l16', 'l22', 'l27', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "strain" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "RANKL" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "RANKL", + "can", + "be", + "conditionally", + "deleted", + "Cre-deleter" + ] + }, + "context": { + "val": "cells", + "words": [ + "hypertrophic", + "chondrocytes", + "osteocytes," + ] + } + } + ] + }, + { + "PMID": "21892182", + "TEXT": "Here we show that p38 mitogen-activated protein kinase (p38 MAPK) phosphorylates the spliced form of X-box binding protein 1 (Xbp1s) on its Thr48 and Ser61 residues and greatly enhances its nuclear migration in mice, whereas mutation of either residue to alanine substantially reduces its nuclear translocation and activity. We also show that p38 MAPK activity is markedly reduced in the livers of obese mice compared with lean mice. Further, we show that activation of p38 MAPK by expression of constitutively active MAP kinase kinase 6 (MKK6Glu) greatly enhances nuclear translocation of Xbp1s, reduces endoplasmic reticulum stress and establishes euglycemia in severely obese and diabetic mice. Hence, our results define a crucial role for phosphorylation on Thr48 and Ser61 of Xbp1s in the maintenance of glucose homeostasis in obesity, and they suggest that p38 MAPK activation in the livers of obese mice could lead to a new therapeutic approach to the treatment of type 2 diabetes.", + "TAG_DATA": [ + "72, activation {'perturbing_action': 'B-pharmacological augmentation'}", + "73, of {'perturbing_action': 'I-pharmacological augmentation'}", + "74, p38 {'perturbing_action': 'I-pharmacological augmentation'}", + "75, MAPK {'perturbing_action': 'I-pharmacological augmentation'}", + "76, by {'perturbing_action': 'I-pharmacological augmentation'}", + "77, expression {'perturbing_action': 'B-gene gain-of-function'}", + "78, of {'perturbing_action': 'I-gene gain-of-function'}", + "79, constitutively {'perturbing_action': 'I-gene gain-of-function'}", + "80, active {'perturbing_action': 'I-gene gain-of-function'}", + "81, MAP {'perturbing_action': 'I-gene gain-of-function'}", + "82, kinase {'perturbing_action': 'I-gene gain-of-function'}", + "83, kinase {'perturbing_action': 'I-gene gain-of-function'}", + "84, 6 {'perturbing_action': 'I-gene gain-of-function'}", + "85, (MKK6Glu) {'perturbing_action': 'I-gene gain-of-function'}", + "101, obese {'context': 'B-organism'}", + "102, and {'context': 'I-organism'}", + "103, diabetic {'context': 'I-organism'}", + "104, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "38, residue ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "72, activation ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "73, of ['l1', 'l17', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "74, p38 ['l2', 'l18', 'l34', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "75, MAPK ['l3', 'l19', 'l35', 'l50', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "76, by ['l4', 'l20', 'l36', 'l51', 'l65', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "77, expression ['l5', 'l21', 'l37', 'l52', 'l66', 'l79', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "78, of ['l6', 'l22', 'l38', 'l53', 'l67', 'l80', 'l92', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "79, constitutively ['l7', 'l23', 'l39', 'l54', 'l68', 'l81', 'l93', 'l104', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "80, active ['l8', 'l24', 'l40', 'l55', 'l69', 'l82', 'l94', 'l105', 'l115', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "81, MAP ['l9', 'l25', 'l41', 'l56', 'l70', 'l83', 'l95', 'l106', 'l116', 'l125', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141']", + "82, kinase ['l10', 'l26', 'l42', 'l57', 'l71', 'l84', 'l96', 'l107', 'l117', 'l126', 'l134', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "83, kinase ['l11', 'l27', 'l43', 'l58', 'l72', 'l85', 'l97', 'l108', 'l118', 'l127', 'l135', 'l142', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "84, 6 ['l12', 'l28', 'l44', 'l59', 'l73', 'l86', 'l98', 'l109', 'l119', 'l128', 'l136', 'l143', 'l149', 'l155', 'l156', 'l157', 'l158', 'l159']", + "85, (MKK6Glu) ['l13', 'l29', 'l45', 'l60', 'l74', 'l87', 'l99', 'l110', 'l120', 'l129', 'l137', 'l144', 'l150', 'l155', 'l160', 'l161', 'l162', 'l163']", + "101, obese ['l14', 'l30', 'l46', 'l61', 'l75', 'l88', 'l100', 'l111', 'l121', 'l130', 'l138', 'l145', 'l151', 'l156', 'l160', 'l164', 'l165', 'l166']", + "102, and ['l15', 'l31', 'l47', 'l62', 'l76', 'l89', 'l101', 'l112', 'l122', 'l131', 'l139', 'l146', 'l152', 'l157', 'l161', 'l164', 'l167', 'l168']", + "103, diabetic ['l32', 'l48', 'l63', 'l77', 'l90', 'l102', 'l113', 'l123', 'l132', 'l140', 'l147', 'l153', 'l158', 'l162', 'l165', 'l167', 'l169']", + "104, mice. ['l16', 'l33', 'l49', 'l64', 'l78', 'l91', 'l103', 'l114', 'l124', 'l133', 'l141', 'l148', 'l154', 'l159', 'l163', 'l166', 'l168', 'l169']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "of", + "p38", + "MAPK", + "by" + ] + }, + "context": { + "val": "organism", + "words": [ + "obese", + "and", + "diabetic", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "constitutively", + "active", + "MAP", + "kinase", + "6", + "(MKK6Glu)" + ] + }, + "context": { + "val": "organism", + "words": [ + "obese", + "and", + "diabetic", + "mice." + ] + } + } + ] + }, + { + "PMID": "21857651", + "TEXT": "Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate genes involved in energy metabolism and inflammation. For biological activity, PPARs require cognate lipid ligands, heterodimerization with retinoic X receptors, and coactivation by PPAR-γ coactivator-1α or PPAR-γ coactivator-1β (PGC-1α or PGC-1β, encoded by Ppargc1a and Ppargc1b, respectively). Here we show that lipolysis of cellular triglycerides by adipose triglyceride lipase (patatin-like phospholipase domain containing protein 2, encoded by Pnpla2; hereafter referred to as Atgl) generates essential mediator(s) involved in the generation of lipid ligands for PPAR activation. Atgl deficiency in mice decreases mRNA levels of PPAR-α and PPAR-δ target genes. In the heart, this leads to decreased PGC-1α and PGC-1β expression and severely disrupted mitochondrial substrate oxidation and respiration; this is followed by excessive lipid accumulation, cardiac insufficiency and lethal cardiomyopathy. Reconstituting normal PPAR target gene expression by pharmacological treatment of Atgl-deficient mice with PPAR-α agonists completely reverses the mitochondrial defects, restores normal heart function and prevents premature death. These findings reveal a potential treatment for the excessive cardiac lipid accumulation and often-lethal cardiomyopathy in people with neutral lipid storage disease, a disease marked by reduced or absent ATGL activity.", + "TAG_DATA": [ + "86, Atgl {'perturbing_action': 'B-gene loss-of-function'}", + "87, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "89, mice {'context': 'B-organism'}", + "101, heart, {'context': 'B-tissue/organ'}", + "140, Atgl-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "141, mice {'context': 'B-organism'}", + "152, heart {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "86, Atgl ['l0', 'l1', 'l2']", + "87, deficiency ['l0', 'l3', 'l4']", + "89, mice ['l1', 'l3', 'l5']", + "101, heart, ['l2', 'l4', 'l5']", + "140, Atgl-deficient ['l6', 'l7']", + "141, mice ['l6', 'l8']", + "152, heart ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atgl", + "deficiency", + "Atgl-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atgl", + "deficiency", + "Atgl-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "heart,", + "heart" + ] + } + } + ] + }, + { + "PMID": "21785430", + "TEXT": "Foxp3(+) regulatory T (T(reg)) cells suppress different types of immune responses to help maintain homeostasis in the body. How T(reg) cells regulate humoral immunity, including germinal center reactions, is unclear. Here we identify a subset of T(reg) cells expressing CXCR5 and Bcl-6 that localize to the germinal centers in mice and humans. The expression of CXCR5 on T(reg) cells depends on Bcl-6. These CXCR5(+)Bcl-6(+) T(reg) cells are absent in the thymus but can be generated de novo from CXCR5(-)Foxp3(+) natural T(reg) precursors. A lack of CXCR5(+) T(reg) cells leads to greater germinal center reactions including germinal center B cells, affinity maturation of antibodies and the differentiation of plasma cells. These results unveil a Bcl-6-CXCR5 axis in T(reg) cells that drives the development of follicular regulatory T (T(FR)) cells that function to inhibit the germinal center reactions.", + "TAG_DATA": [ + "85, CXCR5(+) {'context': 'B-cells'}", + "86, T(reg) {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}", + "105, differentiation {'phenotype': 'B-differentiation'}", + "107, plasma {'context': 'B-cells'}", + "108, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "85, CXCR5(+) ['l0', 'l1', 'l2', 'l3', 'l4']", + "86, T(reg) ['l0', 'l5', 'l6', 'l7', 'l8']", + "87, cells ['l1', 'l5', 'l9', 'l10', 'l11']", + "105, differentiation ['l2', 'l6', 'l9', 'l12', 'l13']", + "107, plasma ['l3', 'l7', 'l10', 'l12', 'l14']", + "108, cells. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CXCR5(+)", + "T(reg)", + "cells", + "plasma", + "cells." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "21706028", + "TEXT": "Naturally simian immunodeficiency virus (SIV)-infected sooty mangabeys do not progress to AIDS despite high-level virus replication. We previously showed that the fraction of CD4(+)CCR5(+) T cells is lower in sooty mangabeys compared to humans and macaques. Here we found that, after in vitro stimulation, sooty mangabey CD4(+) T cells fail to upregulate CCR5 and that this phenomenon is more pronounced in CD4(+) central memory T cells (T(CM) cells). CD4(+) T cell activation was similarly uncoupled from CCR5 expression in sooty mangabeys in vivo during acute SIV infection and the homeostatic proliferation that follows antibody-mediated CD4(+) T cell depletion. Sooty mangabey CD4(+) T(CM) cells that express low amounts of CCR5 showed reduced susceptibility to SIV infection both in vivo and in vitro when compared to CD4(+) T(CM) cells of rhesus macaques. These data suggest that low CCR5 expression on sooty mangabey CD4(+) T cells favors the preservation of CD4(+) T cell homeostasis and promotes an AIDS-free status by protecting CD4(+) T(CM) cells from direct virus infection.", + "TAG_DATA": [ + "41, in {'context': 'B-in vitro'}", + "42, vitro {'context': 'I-in vitro'}", + "44, sooty {'context': 'B-cells'}", + "45, mangabey {'context': 'I-cells'}", + "46, CD4(+) {'context': 'I-cells'}", + "47, T {'context': 'I-cells'}", + "48, cells {'context': 'I-cells'}", + "61, CD4(+) {'context': 'B-cells'}", + "62, central {'context': 'I-cells'}", + "63, memory {'context': 'I-cells'}", + "64, T {'context': 'I-cells'}", + "65, cells {'context': 'I-cells'}", + "67, cells). {'context': 'I-cells'}", + "68, CD4(+) {'context': 'B-cells'}", + "69, T {'context': 'I-cells'}", + "70, cell {'context': 'I-cells'}", + "79, sooty {'context': 'B-organism'}", + "80, mangabeys {'context': 'I-organism'}", + "81, in {'context': 'B-in vivo'}", + "82, vivo {'context': 'I-in vivo'}", + "90, proliferation {'phenotype': 'B-proliferation'}", + "98, Sooty {'context': 'B-cells'}", + "99, mangabey {'context': 'I-cells'}", + "100, CD4(+) {'context': 'I-cells'}", + "101, T(CM) {'context': 'I-cells'}", + "102, cells {'context': 'I-cells'}", + "116, in {'context': 'B-in vivo'}", + "117, vivo {'context': 'I-in vivo'}", + "119, in {'context': 'B-in vitro'}", + "120, vitro {'context': 'I-in vitro'}", + "124, CD4(+) {'context': 'B-cells'}", + "125, T(CM) {'context': 'I-cells'}", + "126, cells {'context': 'I-cells'}", + "128, rhesus {'context': 'B-organism'}", + "129, macaques. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "41, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "42, vitro ['l0', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "44, sooty ['l1', 'l19', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "45, mangabey ['l2', 'l20', 'l36', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "46, CD4(+) ['l3', 'l21', 'l37', 'l53', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "47, T ['l4', 'l22', 'l38', 'l54', 'l69', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "48, cells ['l5', 'l23', 'l39', 'l55', 'l70', 'l84', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "61, CD4(+) ['l6', 'l40', 'l56', 'l71', 'l85', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "62, central ['l7', 'l24', 'l41', 'l57', 'l72', 'l86', 'l98', 'l110', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "63, memory ['l8', 'l25', 'l42', 'l58', 'l73', 'l87', 'l99', 'l111', 'l123', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145']", + "64, T ['l9', 'l26', 'l43', 'l59', 'l74', 'l88', 'l100', 'l112', 'l124', 'l135', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "65, cells ['l10', 'l27', 'l44', 'l60', 'l75', 'l89', 'l101', 'l113', 'l125', 'l136', 'l146', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164']", + "67, cells). ['l11', 'l28', 'l45', 'l61', 'l76', 'l90', 'l102', 'l114', 'l126', 'l137', 'l147', 'l156', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "68, CD4(+) ['l12', 'l29', 'l46', 'l62', 'l77', 'l91', 'l103', 'l115', 'l127', 'l138', 'l148', 'l157', 'l165', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179']", + "69, T ['l13', 'l30', 'l47', 'l63', 'l78', 'l92', 'l104', 'l116', 'l128', 'l139', 'l149', 'l158', 'l166', 'l173', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185']", + "70, cell ['l14', 'l31', 'l48', 'l64', 'l79', 'l93', 'l105', 'l117', 'l129', 'l140', 'l150', 'l159', 'l167', 'l174', 'l180', 'l186', 'l187', 'l188', 'l189', 'l190']", + "79, sooty ['l15', 'l32', 'l49', 'l65', 'l80', 'l94', 'l106', 'l118', 'l130', 'l141', 'l151', 'l160', 'l168', 'l175', 'l181', 'l186', 'l191', 'l192', 'l193', 'l194']", + "80, mangabeys ['l16', 'l33', 'l50', 'l66', 'l81', 'l95', 'l107', 'l119', 'l131', 'l142', 'l152', 'l161', 'l169', 'l176', 'l182', 'l187', 'l191', 'l195', 'l196', 'l197']", + "81, in ['l17', 'l34', 'l51', 'l67', 'l82', 'l96', 'l108', 'l120', 'l132', 'l143', 'l153', 'l162', 'l170', 'l177', 'l183', 'l188', 'l192', 'l195', 'l198']", + "82, vivo ['l18', 'l35', 'l52', 'l68', 'l83', 'l97', 'l109', 'l121', 'l133', 'l144', 'l154', 'l163', 'l171', 'l178', 'l184', 'l189', 'l193', 'l196', 'l198']", + "90, proliferation ['l122', 'l134', 'l145', 'l155', 'l164', 'l172', 'l179', 'l185', 'l190', 'l194', 'l197']", + "98, Sooty ['l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209']", + "99, mangabey ['l199', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221']", + "100, CD4(+) ['l200', 'l210', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232']", + "101, T(CM) ['l201', 'l211', 'l222', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241']", + "102, cells ['l202', 'l212', 'l223', 'l233', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250']", + "116, in ['l203', 'l213', 'l224', 'l234', 'l242', 'l251', 'l252', 'l253']", + "117, vivo ['l204', 'l214', 'l225', 'l235', 'l243', 'l251', 'l254', 'l255']", + "119, in ['l205', 'l215', 'l226', 'l236', 'l244', 'l252', 'l254', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261']", + "120, vitro ['l206', 'l216', 'l227', 'l237', 'l245', 'l253', 'l255', 'l256', 'l262', 'l263', 'l264', 'l265', 'l266']", + "124, CD4(+) ['l217', 'l228', 'l246', 'l257', 'l262', 'l267', 'l268', 'l269', 'l270']", + "125, T(CM) ['l207', 'l218', 'l229', 'l238', 'l247', 'l258', 'l263', 'l267', 'l271', 'l272', 'l273']", + "126, cells ['l208', 'l219', 'l230', 'l239', 'l248', 'l259', 'l264', 'l268', 'l271', 'l274', 'l275']", + "128, rhesus ['l220', 'l231', 'l240', 'l249', 'l260', 'l265', 'l269', 'l272', 'l274', 'l276']", + "129, macaques. ['l209', 'l221', 'l232', 'l241', 'l250', 'l261', 'l266', 'l270', 'l273', 'l275', 'l276']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "central", + "memory", + "T", + "cells", + "cells).", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "sooty", + "mangabeys" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "21685897", + "TEXT": "Chuvash polycythemia is a rare congenital form of polycythemia caused by homozygous R200W and H191D mutations in the VHL (von Hippel-Lindau) gene, whose gene product is the principal negative regulator of hypoxia-inducible factor. However, the molecular mechanisms underlying some of the hallmark abnormalities of Chuvash polycythemia, such as hypersensitivity to erythropoietin, are unclear. Here we show that VHL directly binds suppressor of cytokine signaling 1 (SOCS1) to form a heterodimeric E3 ligase that targets phosphorylated JAK2 (pJAK2) for ubiquitin-mediated destruction. In contrast, Chuvash polycythemia-associated VHL mutants have altered affinity for SOCS1 and do not engage with and degrade pJAK2. Systemic administration of a highly selective JAK2 inhibitor, TG101209, reversed the disease phenotype in Vhl(R200W/R200W) knock-in mice, an experimental model that recapitulates human Chuvash polycythemia. These results show that VHL is a SOCS1-cooperative negative regulator of JAK2 and provide biochemical and preclinical support for JAK2-targeted therapy in individuals with Chuvash polycythemia.", + "TAG_DATA": [ + "103, highly {'perturbing_action': 'I-pharmacological inhibition'}", + "104, selective {'perturbing_action': 'I-pharmacological inhibition'}", + "105, JAK2 {'perturbing_action': 'I-pharmacological inhibition'}", + "106, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "107, TG101209, {'perturbing_action': 'I-pharmacological inhibition'}", + "113, Vhl(R200W/R200W) {'perturbing_action': 'B-other'}", + "114, knock-in {'perturbing_action': 'I-rnai/knockdown'}", + "115, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "103, highly ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "104, selective ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "105, JAK2 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "106, inhibitor, ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "107, TG101209, ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "113, Vhl(R200W/R200W) ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "114, knock-in ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "115, mice, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "highly", + "selective", + "JAK2", + "inhibitor,", + "TG101209," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Vhl(R200W/R200W)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knock-in" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "21602803", + "TEXT": "Glutamate acting on N-methyl-D-aspartate (NMDA) receptors induces neuronal injury following stroke, through activation of poly(ADP-ribose) polymerase-1 (PARP-1) and generation of the death molecule poly(ADP-ribose) (PAR) polymer. Here we identify Iduna, a previously undescribed NMDA receptor-induced survival protein that is neuroprotective against glutamate NMDA receptor-mediated excitotoxicity both in vitro and in vivo and against stroke through interfering with PAR polymer-induced cell death (parthanatos). Iduna's protective effects are independent and downstream of PARP-1 activity. Iduna is a PAR polymer-binding protein, and mutation at the PAR polymer binding site abolishes the PAR binding activity of Iduna and attenuates its protective actions. Iduna is protective in vivo against NMDA-induced excitotoxicity and middle cerebral artery occlusion-induced stroke in mice. To our knowledge, these results define Iduna as the first known endogenous inhibitor of parthanatos. Interfering with PAR polymer signaling could be a new therapeutic strategy for the treatment of neurologic disorders.", + "TAG_DATA": [ + "55, interfering {'effect': 'B-negative'}", + "56, with {'effect': 'B-negative'}", + "59, cell {'phenotype': 'B-cell death'}", + "60, death {'phenotype': 'I-cell death'}", + "101, in {'context': 'B-in vivo'}", + "102, vivo {'context': 'I-in vivo'}", + "113, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "55, interfering ['l0', 'l1', 'l2']", + "56, with ['l0', 'l3', 'l4']", + "59, cell ['l1', 'l3', 'l5']", + "60, death ['l2', 'l4', 'l5']", + "101, in ['l6', 'l7']", + "102, vivo ['l6', 'l8']", + "113, mice. ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "interfering", + "with" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + } + ] + }, + { + "PMID": "21602802", + "TEXT": "The human skeleton is affected by mutations in low-density lipoprotein receptor-related protein 5 (LRP5). To understand how LRP5 influences bone properties, we generated mice with osteocyte-specific expression of inducible Lrp5 mutations that cause high and low bone mass phenotypes in humans. We found that bone properties in these mice were comparable to bone properties in mice with inherited mutations. We also induced an Lrp5 mutation in cells that form the appendicular skeleton but not in cells that form the axial skeleton; we observed that bone properties were altered in the limb but not in the spine. These data indicate that Lrp5 signaling functions locally, and they suggest that increasing LRP5 signaling in mature bone cells may be a strategy for treating human disorders associated with low bone mass, such as osteoporosis.", + "TAG_DATA": [ + "23, mice {'context': 'B-organism'}", + "25, osteocyte-specific {'perturbing_action': 'B-gene gain-of-function'}", + "26, expression {'perturbing_action': 'I-other'}", + "27, of {'perturbing_action': 'I-other'}", + "28, inducible {'perturbing_action': 'I-other'}", + "29, Lrp5 {'perturbing_action': 'I-other'}", + "30, mutations {'perturbing_action': 'I-other'}", + "48, mice {'context': 'B-organism'}", + "55, mice {'context': 'B-organism'}", + "61, induced {'perturbing_action': 'B-other'}", + "63, Lrp5 {'perturbing_action': 'B-other'}", + "64, mutation {'perturbing_action': 'I-other'}", + "66, cells {'context': 'B-cells'}", + "67, that {'context': 'B-cells'}", + "75, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "23, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "25, osteocyte-specific ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "26, expression ['l1', 'l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "27, of ['l2', 'l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "28, inducible ['l3', 'l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "29, Lrp5 ['l4', 'l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "30, mutations ['l5', 'l10', 'l15', 'l19', 'l22', 'l24']", + "48, mice ['l11', 'l16', 'l20', 'l23', 'l25']", + "55, mice ['l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "61, induced ['l26', 'l32', 'l33', 'l34', 'l35', 'l36']", + "63, Lrp5 ['l27', 'l32', 'l37', 'l38', 'l39', 'l40']", + "64, mutation ['l28', 'l33', 'l37', 'l41', 'l42', 'l43']", + "66, cells ['l29', 'l34', 'l38', 'l41', 'l44', 'l45']", + "67, that ['l30', 'l35', 'l39', 'l42', 'l44', 'l46']", + "75, cells ['l31', 'l36', 'l40', 'l43', 'l45', 'l46']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "osteocyte-specific" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "inducible", + "Lrp5", + "mutations", + "induced", + "mutation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "induced", + "Lrp5", + "mutation" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "that" + ] + } + } + ] + }, + { + "PMID": "21532595", + "TEXT": "The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear receptor that is activated by lipids to induce the expression of genes involved in lipid and glucose metabolism, thereby converting nutritional signals into metabolic consequences. PPAR-γ is the target of the thiazolidinedione (TZD) class of insulin-sensitizing drugs, which have been widely prescribed to treat type 2 diabetes mellitus. A common side effect of treatment with TZDs is weight gain. Here we report a previously unknown role for central nervous system (CNS) PPAR-γ in the regulation of energy balance. We found that both acute and chronic activation of CNS PPAR-γ, by either TZDs or hypothalamic overexpression of a fusion protein consisting of PPAR-γ and the viral transcriptional activator VP16 (VP16-PPAR-γ), led to positive energy balance in rats. Blocking the endogenous activation of CNS PPAR-γ with pharmacological antagonists or reducing its expression with shRNA led to negative energy balance, restored leptin sensitivity in high-fat-diet (HFD)-fed rats and blocked the hyperphagic response to oral TZD treatment. These findings have implications for the widespread clinical use of TZD drugs and for understanding the etiology of diet-induced obesity.", + "TAG_DATA": [ + "93, activation {'perturbing_action': 'I-gene gain-of-function'}", + "94, of {'perturbing_action': 'I-gene gain-of-function'}", + "95, CNS {'perturbing_action': 'I-gene gain-of-function'}", + "96, PPAR-γ, {'perturbing_action': 'I-gene gain-of-function'}", + "101, hypothalamic {'perturbing_action': 'B-gene gain-of-function'}", + "102, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "103, of {'perturbing_action': 'I-gene gain-of-function'}", + "104, a {'perturbing_action': 'I-gene gain-of-function'}", + "105, fusion {'perturbing_action': 'I-gene gain-of-function'}", + "106, protein {'perturbing_action': 'I-gene gain-of-function'}", + "107, consisting {'perturbing_action': 'I-gene gain-of-function'}", + "108, of {'perturbing_action': 'I-gene gain-of-function'}", + "109, PPAR-γ {'perturbing_action': 'I-gene gain-of-function'}", + "110, and {'perturbing_action': 'I-gene gain-of-function'}", + "111, the {'perturbing_action': 'I-gene gain-of-function'}", + "112, viral {'perturbing_action': 'I-gene gain-of-function'}", + "113, transcriptional {'perturbing_action': 'I-gene gain-of-function'}", + "114, activator {'perturbing_action': 'I-gene gain-of-function'}", + "115, VP16 {'perturbing_action': 'I-gene gain-of-function'}", + "116, (VP16-PPAR-γ), {'perturbing_action': 'I-gene gain-of-function'}", + "123, rats. {'context': 'B-organism'}", + "135, reducing {'perturbing_action': 'B-rnai/knockdown'}", + "136, its {'perturbing_action': 'I-rnai/knockdown'}", + "137, expression {'perturbing_action': 'I-rnai/knockdown'}", + "138, with {'perturbing_action': 'I-rnai/knockdown'}", + "139, shRNA {'perturbing_action': 'I-rnai/knockdown'}", + "151, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "93, activation ['l0', 'l1', 'l2', 'l3']", + "94, of ['l0', 'l4', 'l5', 'l6']", + "95, CNS ['l1', 'l4', 'l7', 'l8']", + "96, PPAR-γ, ['l2', 'l5', 'l7', 'l9']", + "101, hypothalamic ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "102, overexpression ['l10', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "103, of ['l11', 'l26', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "104, a ['l12', 'l27', 'l41', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "105, fusion ['l13', 'l28', 'l42', 'l55', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "106, protein ['l14', 'l29', 'l43', 'l56', 'l69', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "107, consisting ['l15', 'l30', 'l44', 'l57', 'l70', 'l82', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "108, of ['l16', 'l31', 'l45', 'l58', 'l71', 'l83', 'l94', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "109, PPAR-γ ['l17', 'l32', 'l46', 'l59', 'l72', 'l84', 'l95', 'l105', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "110, and ['l18', 'l33', 'l47', 'l60', 'l73', 'l85', 'l96', 'l106', 'l115', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "111, the ['l19', 'l34', 'l48', 'l61', 'l74', 'l86', 'l97', 'l107', 'l116', 'l124', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "112, viral ['l20', 'l35', 'l49', 'l62', 'l75', 'l87', 'l98', 'l108', 'l117', 'l125', 'l132', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "113, transcriptional ['l21', 'l36', 'l50', 'l63', 'l76', 'l88', 'l99', 'l109', 'l118', 'l126', 'l133', 'l139', 'l145', 'l146', 'l147', 'l148', 'l149']", + "114, activator ['l22', 'l37', 'l51', 'l64', 'l77', 'l89', 'l100', 'l110', 'l119', 'l127', 'l134', 'l140', 'l145', 'l150', 'l151', 'l152', 'l153']", + "115, VP16 ['l23', 'l38', 'l52', 'l65', 'l78', 'l90', 'l101', 'l111', 'l120', 'l128', 'l135', 'l141', 'l146', 'l150', 'l154', 'l155', 'l156']", + "116, (VP16-PPAR-γ), ['l24', 'l39', 'l53', 'l66', 'l79', 'l91', 'l102', 'l112', 'l121', 'l129', 'l136', 'l142', 'l147', 'l151', 'l154', 'l157', 'l158']", + "123, rats. ['l3', 'l6', 'l8', 'l9', 'l25', 'l40', 'l54', 'l67', 'l80', 'l92', 'l103', 'l113', 'l122', 'l130', 'l137', 'l143', 'l148', 'l152', 'l155', 'l157']", + "135, reducing ['l159', 'l160', 'l161', 'l162', 'l163']", + "136, its ['l159', 'l164', 'l165', 'l166', 'l167']", + "137, expression ['l160', 'l164', 'l168', 'l169', 'l170']", + "138, with ['l161', 'l165', 'l168', 'l171', 'l172']", + "139, shRNA ['l162', 'l166', 'l169', 'l171', 'l173']", + "151, rats ['l68', 'l81', 'l93', 'l104', 'l114', 'l123', 'l131', 'l138', 'l144', 'l149', 'l153', 'l156', 'l158', 'l163', 'l167', 'l170', 'l172', 'l173']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "activation", + "of", + "CNS", + "PPAR-γ,", + "hypothalamic", + "overexpression", + "a", + "fusion", + "protein", + "consisting", + "PPAR-γ", + "and", + "the", + "viral", + "transcriptional", + "activator", + "VP16", + "(VP16-PPAR-γ)," + ] + }, + "context": { + "val": "organism", + "words": [ + "rats.", + "rats" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "reducing", + "its", + "expression", + "with", + "shRNA" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + } + ] + }, + { + "PMID": "21441917", + "TEXT": "We simultaneously transduced cells with three lentiviral gene ontology (LeGO) vectors encoding red, green or blue fluorescent proteins. Individual cells were thereby marked by different combinations of inserted vectors, resulting in the generation of numerous mixed colors, a principle we named red-green-blue (RGB) marking. We show that lentiviral vector-mediated RGB marking remained stable after cell division, thus facilitating the analysis of clonal cell fates in vitro and in vivo. Particularly, we provide evidence that RGB marking allows assessment of clonality after regeneration of injured livers by transplanted primary hepatocytes. We also used RGB vectors to mark hematopoietic stem/progenitor cells that generated colored spleen colonies. Finally, based on limiting-dilution and serial transplantation assays with tumor cells, we found that clonal tumor cells retained their specific color-code over extensive periods of time. We conclude that RGB marking represents a useful tool for cell clonality studies in tissue regeneration and pathology.", + "TAG_DATA": [ + "3, cells {'context': 'B-cells'}", + "19, cells {'context': 'B-cells'}", + "54, cell {'phenotype': 'B-proliferation'}", + "55, division, {'phenotype': 'I-proliferation'}", + "65, vitro {'context': 'I-in vitro'}", + "67, in {'context': 'B-in vivo'}", + "68, vivo. {'context': 'I-in vivo'}", + "87, primary {'context': 'B-cells'}", + "88, hepatocytes. {'context': 'I-cells'}", + "96, hematopoietic {'context': 'B-cells'}", + "97, stem/progenitor {'context': 'I-cells'}", + "98, cells {'context': 'I-cells'}", + "102, spleen {'context': 'B-tissue/organ'}", + "103, colonies. {'phenotype': 'I-tumourigenesis'}", + "113, tumor {'context': 'B-transformed cells'}", + "114, cells, {'context': 'I-transformed cells'}", + "118, clonal {'context': 'B-transformed cells'}", + "119, tumor {'context': 'I-transformed cells'}", + "120, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "3, cells ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "19, cells ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "54, cell ['l1', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "55, division, ['l2', 'l11', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "65, vitro ['l3', 'l12', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32']", + "67, in ['l4', 'l13', 'l20', 'l25', 'l29', 'l33', 'l34', 'l35']", + "68, vivo. ['l5', 'l14', 'l21', 'l26', 'l30', 'l33', 'l36', 'l37']", + "87, primary ['l6', 'l15', 'l22', 'l27', 'l31', 'l34', 'l36', 'l38']", + "88, hepatocytes. ['l7', 'l16', 'l23', 'l28', 'l32', 'l35', 'l37', 'l38']", + "96, hematopoietic ['l39', 'l40', 'l41', 'l42']", + "97, stem/progenitor ['l8', 'l39', 'l43', 'l44', 'l45']", + "98, cells ['l9', 'l17', 'l40', 'l43', 'l46', 'l47']", + "102, spleen ['l41', 'l44', 'l46', 'l48']", + "103, colonies. ['l42', 'l45', 'l47', 'l48']", + "113, tumor ['l49', 'l50', 'l51', 'l52']", + "114, cells, ['l49', 'l53', 'l54', 'l55']", + "118, clonal ['l50', 'l53', 'l56', 'l57']", + "119, tumor ['l51', 'l54', 'l56', 'l58']", + "120, cells ['l52', 'l55', 'l57', 'l58']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells", + "primary", + "hepatocytes." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "vitro" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem/progenitor", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "colonies." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "spleen" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "colonies." + ] + } + } + ] + }, + { + "PMID": "21317886", + "TEXT": "To date, the only known role of the spliced form of X-box-binding protein-1 (XBP-1s) in metabolic processes has been its ability to act as a transcription factor that regulates the expression of genes that increase the endoplasmic reticulum (ER) folding capacity, thereby improving insulin sensitivity. Here we show that XBP-1s interacts with the Forkhead box O1 (FoxO1) transcription factor and directs it toward proteasome-mediated degradation. Given this new insight, we tested modest hepatic overexpression of XBP-1s in vivo in mouse models of insulin deficiency or insulin resistance and found it improved serum glucose concentrations, even without improving insulin signaling or ER folding capacity. The notion that XBP-1s can act independently of its role in the ER stress response is further supported by our finding that in the severely insulin resistant ob/ob mouse strain a DNA-binding-defective mutant of XBP-1s, which does not have the ability to increase ER folding capacity, is still capable of reducing serum glucose concentrations and increasing glucose tolerance. Our results thus provide the first evidence to our knowledge that XBP-1s, through its interaction with FoxO1, can bypass hepatic insulin resistance independent of its effects on ER folding capacity, suggesting a new therapeutic approach for the treatment of type 2 diabetes.", + "TAG_DATA": [ + "72, hepatic {'perturbing_action': 'B-gene gain-of-function'}", + "73, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "74, of {'perturbing_action': 'I-gene gain-of-function'}", + "75, XBP-1s {'perturbing_action': 'I-gene gain-of-function'}", + "76, in {'context': 'B-in vivo'}", + "77, vivo {'context': 'I-in vivo'}", + "79, mouse {'context': 'B-organism'}", + "80, models {'context': 'I-organism'}", + "130, ob/ob {'context': 'I-organism'}", + "131, mouse {'context': 'I-organism'}", + "132, strain {'context': 'I-organism'}", + "134, DNA-binding-defective {'perturbing_action': 'B-other'}", + "135, mutant {'perturbing_action': 'I-other'}", + "136, of {'perturbing_action': 'I-other'}", + "137, XBP-1s, {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "72, hepatic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "73, overexpression ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "74, of ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "75, XBP-1s ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "76, in ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "77, vivo ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "79, mouse ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "80, models ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "130, ob/ob ['l28', 'l29', 'l30', 'l31']", + "131, mouse ['l28', 'l32', 'l33', 'l34', 'l35']", + "132, strain ['l29', 'l32', 'l36', 'l37', 'l38']", + "134, DNA-binding-defective ['l39', 'l40', 'l41']", + "135, mutant ['l33', 'l36', 'l39', 'l42', 'l43']", + "136, of ['l30', 'l34', 'l37', 'l40', 'l42', 'l44']", + "137, XBP-1s, ['l31', 'l35', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hepatic", + "overexpression", + "of", + "XBP-1s" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hepatic", + "overexpression", + "of", + "XBP-1s" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "ob/ob", + "mouse", + "strain" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "of", + "XBP-1s,", + "mutant" + ] + } + } + ] + }, + { + "PMID": "21317885", + "TEXT": "The TP53 gene (encoding the p53 tumor suppressor) is rarely mutated, although frequently inactivated, in medulloblastoma and ependymoma. Recent work in mouse models showed that the loss of p53 accelerated the development of medulloblastoma. The mechanism underlying p53 inactivation in human brain tumors is not completely understood. We show that ubiquitination factor E4B (UBE4B), an E3 and E4 ubiquitin ligase, physically interacts with p53 and Hdm2 (also known as Mdm2 in mice). UBE4B promotes p53 polyubiquitination and degradation and inhibits p53-dependent transactivation and apoptosis. Notably, silencing UBE4B expression impairs xenotransplanted tumor growth in a p53-dependent manner and overexpression of UBE4B correlates with decreased expression of p53 in these tumors. We also show that UBE4B overexpression is often associated with amplification of its gene in human brain tumors. Our data indicate that amplification and overexpression of UBE4B represent previously undescribed molecular mechanisms of inactivation of p53 in brain tumors.", + "TAG_DATA": [ + "79, inhibits {'effect': 'B-negative'}", + "83, apoptosis. {'phenotype': 'B-apoptosis'}", + "85, silencing {'perturbing_action': 'B-rnai/knockdown'}", + "86, UBE4B {'perturbing_action': 'I-rnai/knockdown'}", + "87, expression {'perturbing_action': 'I-rnai/knockdown'}", + "88, impairs {'effect': 'B-negative'}", + "89, xenotransplanted {'context': 'B-xenograft'}", + "90, tumor {'phenotype': 'B-tumour growth'}", + "91, growth {'phenotype': 'I-tumour growth'}", + "108, tumors. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "79, inhibits ['l0']", + "83, apoptosis. ['l0']", + "85, silencing ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "86, UBE4B ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "87, expression ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "88, impairs ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "89, xenotransplanted ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "90, tumor ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "91, growth ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "UBE4B", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "UBE4B", + "expression" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenotransplanted" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "UBE4B", + "expression" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenotransplanted" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenotransplanted" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + } + ] + }, + { + "PMID": "21258336", + "TEXT": "Hyperglycemia is associated with greater hematoma expansion and poor clinical outcomes after intracerebral hemorrhage. We show that cerebral hematoma expansion triggered by intracerebral infusion of autologous blood is greater in diabetic rats and mice compared to nondiabetic controls and that this augmented expansion is ameliorated by plasma kallikrein (PK) inhibition or deficiency. Intracerebral injection of purified PK augmented hematoma expansion in both diabetic and acutely hyperglycemic rats, whereas injection of bradykinin, plasmin or tissue plasminogen activator did not elicit such a response. This response, which occurs rapidly, was prevented by co-injection of the glycoprotein VI agonist convulxin and was mimicked by glycoprotein VI inhibition or deficiency, implicating an effect of PK on inhibiting platelet aggregation. We show that PK inhibits collagen-induced platelet aggregation by binding collagen, a response enhanced by elevated glucose concentrations. The effect of hyperglycemia on hematoma expansion and PK-mediated inhibition of platelet aggregation could be mimicked by infusing mannitol. These findings suggest that hyperglycemia augments cerebral hematoma expansion by PK-mediated osmotic-sensitive inhibition of hemostasis.", + "TAG_DATA": [ + "66, rats, {'context': 'B-organism'}", + "93, glycoprotein {'perturbing_action': 'I-pharmacological augmentation'}", + "94, VI {'perturbing_action': 'I-pharmacological augmentation'}", + "95, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "101, glycoprotein {'perturbing_action': 'B-pharmacological inhibition'}", + "102, VI {'perturbing_action': 'I-pharmacological inhibition'}", + "103, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "119, inhibits {'effect': 'B-negative'}", + "121, platelet {'context': 'B-cells'}", + "122, aggregation {'phenotype': 'B-autophagy'}", + "144, platelet {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "93, glycoprotein ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "94, VI ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "95, agonist ['l1', 'l7', 'l14', 'l15', 'l16', 'l17', 'l18']", + "101, glycoprotein ['l8', 'l19', 'l20', 'l21', 'l22', 'l23']", + "102, VI ['l2', 'l9', 'l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "103, inhibition ['l3', 'l10', 'l15', 'l20', 'l24', 'l28', 'l29', 'l30']", + "119, inhibits ['l4', 'l11', 'l16', 'l21', 'l25', 'l28', 'l31', 'l32']", + "121, platelet ['l5', 'l12', 'l17', 'l22', 'l26', 'l29', 'l31', 'l33']", + "122, aggregation ['l6', 'l13', 'l18', 'l23', 'l27', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "glycoprotein", + "VI", + "agonist" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "glycoprotein", + "VI", + "agonist" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelet" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "glycoprotein", + "VI", + "agonist" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "aggregation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "glycoprotein", + "VI", + "inhibition" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "glycoprotein", + "VI", + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelet" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "glycoprotein", + "VI", + "inhibition" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "aggregation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelet" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "aggregation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "platelet" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "aggregation" + ] + } + } + ] + }, + { + "PMID": "21240264", + "TEXT": "Many proteins have been proposed to act as surrogate markers of organ damage, yet for many candidates the essential biomarker characteristics that link the protein to the injured organ have not yet been described. We generated an Ngal reporter mouse by inserting a double-fusion reporter gene encoding luciferase-2 and mCherry (Luc2-mC) into the Ngal (Lcn2) locus. The Ngal-Luc2-mC reporter accurately recapitulated the endogenous message and illuminated injuries in vivo in real time. In the kidney, Ngal-Luc2-mC imaging showed a sensitive, rapid, dose-dependent, reversible, and organ- and cell-specific relationship with tubular stress, which correlated with the level of urinary Ngal (uNgal). Unexpectedly, specific cells of the distal nephron were the source of uNgal. Cells isolated from Ngal-Luc2-mC mice also revealed both the onset and the resolution of the injury, and the actions of NF-κB inhibitors and antibiotics during infection. Thus, imaging of Ngal-Luc2-mC mice and cells identified injurious and reparative agents that affect kidney damage.", + "TAG_DATA": [ + "67, in {'context': 'B-in vivo'}", + "68, vivo {'context': 'I-in vivo'}", + "74, kidney, {'context': 'B-tissue/organ'}", + "102, cells {'context': 'B-cells'}", + "104, the {'context': 'I-cells'}", + "105, distal {'context': 'I-cells'}", + "106, nephron {'context': 'I-cells'}", + "112, Cells {'context': 'B-cells'}", + "115, Ngal-Luc2-mC {'perturbing_action': 'B-other'}", + "116, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "67, in ['l0', 'l1']", + "68, vivo ['l0', 'l2']", + "74, kidney, ['l1', 'l2']", + "102, cells ['l3', 'l4', 'l5']", + "104, the ['l3', 'l6', 'l7']", + "105, distal ['l4', 'l6', 'l8']", + "106, nephron ['l5', 'l7', 'l8']", + "112, Cells ['l9', 'l10']", + "115, Ngal-Luc2-mC ['l9', 'l11']", + "116, mice ['l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Cells" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Ngal-Luc2-mC" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Ngal-Luc2-mC" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "21186368", + "TEXT": "Myocardial infarction is a leading cause of mortality worldwide. Here we report that modulation of microRNA-499 (miR-499) levels affects apoptosis and the severity of myocardial infarction and cardiac dysfunction induced by ischemia-reperfusion. We found that both the α- and β-isoforms of the calcineurin catalytic subunit are direct targets of miR-499 and that miR-499 inhibits cardiomyocyte apoptosis through its suppression of calcineurin-mediated dephosphorylation of dynamin-related protein-1 (Drp1), thereby decreasing Drp1 accumulation in mitochondria and Drp1-mediated activation of the mitochondrial fission program. We also found that p53 transcriptionally downregulates miR-499 expression. Our data reveal a role for miR-499 in regulating the mitochondrial fission machinery and we suggest that modulation of miR-499 levels may provide a therapeutic approach for treating myocardial infarction.", + "TAG_DATA": [ + "53, inhibits {'effect': 'B-negative'}", + "54, cardiomyocyte {'context': 'B-cells'}", + "55, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "53, inhibits ['l0', 'l1']", + "54, cardiomyocyte ['l0', 'l2']", + "55, apoptosis ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocyte" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cardiomyocyte" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "21102457", + "TEXT": "Interleukin-6 (IL-6)-Janus kinase (JAK) signaling is viewed as crucial for persistent signal transducer and activator of transcription-3 (STAT3) activation in cancer. However, IL-6-induced STAT3 activation is normally transient. Here we identify a key mechanism for persistent STAT3 activation in tumor cells and the tumor microenvironment. We show that expression of sphingosine-1-phosphate receptor-1 (S1PR1), a G protein-coupled receptor for the lysophospholipid sphingosine-1-phosphate (S1P), is elevated in STAT3-positive tumors. STAT3 is a transcription factor for the S1pr1 gene. Reciprocally, enhanced S1pr1 expression activates STAT3 and upregulates Il6 gene expression, thereby accelerating tumor growth and metastasis in a STAT3-dependent manner. Silencing S1pr1 in tumor cells or immune cells inhibits tumor STAT3 activity, tumor growth and metastasis. S1P-S1PR1-induced STAT3 activation is persistent, in contrast to transient STAT3 activation by IL-6. S1PR1 activates STAT3 in part by upregulating JAK2 tyrosine kinase activity. We show that STAT3-induced S1PR1 expression, as well as the S1P-S1PR1 pathway reciprocal regulation of STAT3 activity, is a major positive feedback loop for persistent STAT3 activation in cancer cells and the tumor microenvironment and for malignant progression.", + "TAG_DATA": [ + "88, accelerating {'effect': 'B-positive'}", + "89, tumor {'phenotype': 'B-tumour growth'}", + "90, growth {'phenotype': 'I-tumour growth'}", + "92, metastasis {'phenotype': 'B-metastasis'}", + "97, Silencing {'perturbing_action': 'B-rnai/knockdown'}", + "98, S1pr1 {'perturbing_action': 'I-rnai/knockdown'}", + "100, tumor {'context': 'B-transformed cells'}", + "101, cells {'context': 'I-transformed cells'}", + "103, immune {'context': 'B-cells'}", + "104, cells {'context': 'I-cells'}", + "105, inhibits {'effect': 'B-negative'}", + "106, tumor {'context': 'B-neoplasm'}", + "109, tumor {'phenotype': 'B-tumour growth'}", + "110, growth {'phenotype': 'I-tumour growth'}", + "112, metastasis. {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "88, accelerating ['l0', 'l1', 'l2']", + "89, tumor ['l0', 'l3', 'l4']", + "90, growth ['l1', 'l3', 'l5']", + "92, metastasis ['l2', 'l4', 'l5']", + "97, Silencing ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "98, S1pr1 ['l6', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "100, tumor ['l7', 'l16', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "101, cells ['l8', 'l17', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "103, immune ['l9', 'l18', 'l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "104, cells ['l10', 'l19', 'l27', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "105, inhibits ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "106, tumor ['l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57']", + "109, tumor ['l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l58', 'l59']", + "110, growth ['l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58', 'l60']", + "112, metastasis. ['l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "accelerating" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "accelerating" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "S1pr1" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "S1pr1" + ] + }, + "context": { + "val": "cells", + "words": [ + "immune", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "S1pr1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "S1pr1" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "S1pr1" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "S1pr1" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "immune", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "immune", + "cells" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "immune", + "cells" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + } + ] + }, + { + "PMID": "21037588", + "TEXT": "Immunodominance is defined as restricted responsiveness of T cells to a few selected epitopes from complex antigens. Strategies currently used for elucidating CD4(+) T cell epitopes are inadequate. To understand the mechanism of epitope selection for helper T cells, we established a cell-free antigen processing system composed of defined proteins: human leukocyte antigen-DR1 (HLA-DR1), HLA-DM and cathepsins. Our reductionist system successfully identified the physiologically selected immunodominant epitopes of two model antigens: hemagglutinin-1 (HA1) from influenza virus (A/Texas/1/77) and type II collagen (CII). When applied for identification of new epitopes from a recombinant liver-stage antigen of malaria falciparum (LSA-NRC) or HA1 from H5N1 influenza virus ('avian flu'), the system selected single epitopes from each protein that were confirmed to be immunodominant by their capacity to activate CD4(+) T cells from H5N1-immunized HLA-DR1-transgenic mice and LSA-NRC-vaccinated HLA-DR1-positive human volunteers. Thus, we provide a new tool for the identification of physiologically relevant helper T cell epitopes from antigens.", + "TAG_DATA": [ + "125, CD4(+) {'context': 'B-cells'}", + "126, T {'context': 'I-cells'}", + "127, cells {'context': 'I-cells'}", + "130, HLA-DR1-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "131, mice {'context': 'B-organism'}", + "135, human {'context': 'B-organism'}", + "136, volunteers. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "125, CD4(+) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "126, T ['l0', 'l6', 'l7', 'l8', 'l9']", + "127, cells ['l1', 'l6', 'l10', 'l11']", + "130, HLA-DR1-transgenic ['l2', 'l7', 'l10', 'l12', 'l13', 'l14']", + "131, mice ['l3', 'l8', 'l11', 'l12', 'l15']", + "135, human ['l4', 'l13', 'l16']", + "136, volunteers. ['l5', 'l9', 'l14', 'l15', 'l16']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "HLA-DR1-transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "HLA-DR1-transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "human", + "volunteers." + ] + } + } + ] + }, + { + "PMID": "21037586", + "TEXT": "Autophagy is crucial in the turnover of cell components, and clearance of damaged organelles by the autophagic-lysosomal pathway is essential for tissue homeostasis. Defects of this degradative system have a role in various diseases, but little is known about autophagy in muscular dystrophies. We have previously found that muscular dystrophies linked to collagen VI deficiency show dysfunctional mitochondria and spontaneous apoptosis, leading to myofiber degeneration. Here we demonstrate that this persistence of abnormal organelles and apoptosis are caused by defective autophagy. Skeletal muscles of collagen VI-knockout (Col6a1(-/-)) mice had impaired autophagic flux, which matched the lower induction of beclin-1 and BCL-2/adenovirus E1B-interacting protein-3 (Bnip3) and the lack of autophagosomes after starvation. Forced activation of autophagy by genetic, dietary and pharmacological approaches restored myofiber survival and ameliorated the dystrophic phenotype of Col6a1(-/-) mice. Furthermore, muscle biopsies from subjects with Bethlem myopathy or Ullrich congenital muscular dystrophy had reduced protein amounts of beclin-1 and Bnip3. These findings indicate that defective activation of the autophagic machinery is pathogenic in some congenital muscular dystrophies.", + "TAG_DATA": [ + "81, Skeletal {'context': 'B-tissue/organ'}", + "82, muscles {'context': 'I-tissue/organ'}", + "84, collagen {'perturbing_action': 'B-gene loss-of-function'}", + "85, VI-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "86, (Col6a1(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "87, mice {'context': 'B-organism'}", + "89, impaired {'effect': 'B-negative'}", + "90, autophagic {'phenotype': 'B-autophagy'}", + "91, flux, {'phenotype': 'I-autophagy'}", + "111, Forced {'effect': 'B-positive'}", + "112, activation {'effect': 'B-positive'}", + "114, autophagy {'phenotype': 'B-autophagy'}", + "122, myofiber {'context': 'B-cells'}", + "130, Col6a1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "131, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "81, Skeletal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "82, muscles ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "84, collagen ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "85, VI-knockout ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "86, (Col6a1(-/-)) ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "87, mice ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "89, impaired ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "90, autophagic ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "91, flux, ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "111, Forced ['l36', 'l37', 'l38', 'l39', 'l40']", + "112, activation ['l36', 'l41', 'l42', 'l43', 'l44']", + "114, autophagy ['l37', 'l41', 'l45', 'l46', 'l47']", + "122, myofiber ['l38', 'l42', 'l45']", + "130, Col6a1(-/-) ['l39', 'l43', 'l46', 'l48']", + "131, mice. ['l40', 'l44', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "Skeletal", + "muscles" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "collagen", + "VI-knockout", + "(Col6a1(-/-))" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "Skeletal", + "muscles" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "Skeletal", + "muscles" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagic", + "flux," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "collagen", + "VI-knockout", + "(Col6a1(-/-))", + "Col6a1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "collagen", + "VI-knockout", + "(Col6a1(-/-))" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "collagen", + "VI-knockout", + "(Col6a1(-/-))", + "Col6a1(-/-)" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagic", + "flux,", + "autophagy" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagic", + "flux,", + "autophagy" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagic", + "flux," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Forced", + "activation" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Forced", + "activation" + ] + }, + "context": { + "val": "cells", + "words": [ + "myofiber" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Forced", + "activation" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Col6a1(-/-)" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Forced", + "activation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + }, + "context": { + "val": "cells", + "words": [ + "myofiber" + ] + } + } + ] + }, + { + "PMID": "20972434", + "TEXT": "Bitter taste receptors (TAS2Rs) on the tongue probably evolved to evoke signals for avoiding ingestion of plant toxins. We found expression of TAS2Rs on human airway smooth muscle (ASM) and considered these to be avoidance receptors for inhalants that, when activated, lead to ASM contraction and bronchospasm. TAS2R agonists such as saccharin, chloroquine and denatonium evoked increased intracellular calcium ([Ca²(+)](i)) in ASM in a Gβγ-, phospholipase Cβ (PLCβ)- and inositol trisphosphate (IP₃) receptor-dependent manner, which would be expected to evoke contraction. Paradoxically, bitter tastants caused relaxation of isolated ASM and dilation of airways that was threefold greater than that elicited by β-adrenergic receptor agonists. The relaxation induced by TAS2Rs is associated with a localized [Ca²(+)](i) response at the cell membrane, which opens large-conductance Ca²(+)-activated K(+) (BK(Ca)) channels, leading to ASM membrane hyperpolarization. Inhaled bitter tastants decreased airway obstruction in a mouse model of asthma. Given the need for efficacious bronchodilators for treating obstructive lung diseases, this pathway can be exploited for therapy with the thousands of known synthetic and naturally occurring bitter tastants.", + "TAG_DATA": [ + "47, TAS2R {'perturbing_action': 'B-pharmacological augmentation'}", + "48, agonists {'perturbing_action': 'I-pharmacological augmentation'}", + "61, ASM {'context': 'B-cells'}", + "88, ASM {'context': 'B-cells'}", + "92, airways {'context': 'B-tissue/organ'}", + "140, mouse {'context': 'B-organism'}", + "141, model {'context': 'I-organism'}", + "142, of {'context': 'I-organism'}", + "143, asthma. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "47, TAS2R ['l0', 'l1', 'l2']", + "48, agonists ['l0', 'l3', 'l4']", + "61, ASM ['l1', 'l3']", + "88, ASM ['l2', 'l4', 'l5']", + "92, airways ['l5']", + "140, mouse ['l6', 'l7', 'l8']", + "141, model ['l6', 'l9', 'l10']", + "142, of ['l7', 'l9', 'l11']", + "143, asthma. ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "TAS2R", + "agonists" + ] + }, + "context": { + "val": "cells", + "words": [ + "ASM" + ] + } + } + ] + }, + { + "PMID": "20835248", + "TEXT": "We propose that a C-type lectin receptor, SIGNR-1 (also called Cd209b), helps to condition dendritic cells (DCs) in the gastrointestinal lamina propria (LPDCs) for the induction of oral tolerance in a model of food-induced anaphylaxis. Oral delivery of BSA bearing 51 molecules of mannoside (Man(51)-BSA) substantially reduced the BSA-induced anaphylactic response. Man(51)-BSA selectively targeted LPDCs that expressed SIGNR1 and induced the expression of interleukin-10 (IL-10), but not IL-6 or IL-12 p70. We found the same effects in IL-10-GFP knock-in (tiger) mice treated with Man(51)-BSA. The Man(51)-BSA-SIGNR1 axis in LPDCs, both in vitro and in vivo, promoted the generation of CD4(+) type 1 regulatory T (Tr1)-like cells that expressed IL-10 and interferon-γ (IFN-γ), in a SIGNR-1- and IL-10-dependent manner, but not of CD4(+)CD25(+)Foxp3(+) regulatory T cells. The Tr1-like cells could transfer tolerance. These results suggest that sugar-modified antigens might be used to induce oral tolerance by targeting SIGNR1 and LPDCs.", + "TAG_DATA": [ + "54, LPDCs {'context': 'B-cells'}", + "77, IL-10-GFP {'perturbing_action': 'B-rnai/knockdown'}", + "78, knock-in {'perturbing_action': 'I-rnai/knockdown'}", + "79, (tiger) {'perturbing_action': 'I-rnai/knockdown'}", + "80, mice {'context': 'B-organism'}", + "88, LPDCs, {'context': 'B-cells'}", + "90, in {'context': 'B-in vitro'}", + "91, vitro {'context': 'I-in vitro'}", + "93, in {'context': 'B-in vivo'}", + "94, vivo, {'context': 'I-in vivo'}", + "99, CD4(+) {'context': 'B-cells'}", + "100, type {'context': 'I-cells'}", + "101, 1 {'context': 'I-cells'}", + "102, regulatory {'context': 'I-cells'}", + "103, T {'context': 'I-cells'}", + "104, (Tr1)-like {'context': 'I-cells'}", + "105, cells {'context': 'I-cells'}", + "121, CD4(+)CD25(+)Foxp3(+) {'context': 'B-cells'}", + "122, regulatory {'context': 'I-cells'}", + "123, T {'context': 'I-cells'}", + "124, cells. {'context': 'I-cells'}", + "126, Tr1-like {'context': 'B-cells'}", + "127, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "77, IL-10-GFP ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "78, knock-in ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "79, (tiger) ['l1', 'l11', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "80, mice ['l2', 'l12', 'l23', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "88, LPDCs, ['l13', 'l24', 'l34', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "90, in ['l14', 'l25', 'l35', 'l44', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "91, vitro ['l3', 'l15', 'l26', 'l36', 'l45', 'l59', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "93, in ['l46', 'l60', 'l70', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "94, vivo, ['l47', 'l61', 'l71', 'l80', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "99, CD4(+) ['l4', 'l16', 'l27', 'l37', 'l48', 'l62', 'l72', 'l81', 'l92', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "100, type ['l5', 'l17', 'l28', 'l38', 'l49', 'l63', 'l73', 'l82', 'l93', 'l103', 'l109', 'l110', 'l111', 'l112', 'l113']", + "101, 1 ['l6', 'l18', 'l29', 'l39', 'l50', 'l64', 'l74', 'l83', 'l94', 'l104', 'l109', 'l114', 'l115', 'l116', 'l117']", + "102, regulatory ['l7', 'l19', 'l30', 'l40', 'l51', 'l65', 'l75', 'l84', 'l95', 'l105', 'l110', 'l114', 'l118', 'l119', 'l120']", + "103, T ['l8', 'l20', 'l31', 'l41', 'l52', 'l66', 'l76', 'l85', 'l96', 'l106', 'l111', 'l115', 'l118', 'l121', 'l122']", + "104, (Tr1)-like ['l9', 'l21', 'l32', 'l42', 'l53', 'l67', 'l77', 'l86', 'l97', 'l107', 'l112', 'l116', 'l119', 'l121', 'l123']", + "105, cells ['l10', 'l22', 'l33', 'l43', 'l54', 'l68', 'l78', 'l87', 'l98', 'l108', 'l113', 'l117', 'l120', 'l122', 'l123']", + "121, CD4(+)CD25(+)Foxp3(+) ['l55', 'l88', 'l99', 'l124', 'l125', 'l126', 'l127', 'l128']", + "122, regulatory ['l56', 'l89', 'l100', 'l124', 'l129', 'l130', 'l131', 'l132']", + "123, T ['l57', 'l69', 'l79', 'l90', 'l101', 'l125', 'l129', 'l133', 'l134', 'l135']", + "124, cells. ['l58', 'l91', 'l102', 'l126', 'l130', 'l133', 'l136']", + "126, Tr1-like ['l127', 'l131', 'l134', 'l137']", + "127, cells ['l128', 'l132', 'l135', 'l136', 'l137']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "IL-10-GFP", + "knock-in", + "(tiger)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "IL-10-GFP", + "knock-in", + "(tiger)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "vitro", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "IL-10-GFP", + "knock-in", + "(tiger)" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "type", + "1", + "regulatory", + "T", + "(Tr1)-like", + "cells", + "LPDCs," + ] + } + } + ] + }, + { + "PMID": "20616797", + "TEXT": "RNA-binding proteins of the Musashi (Msi) family are expressed in stem cell compartments and in aggressive tumors, but they have not yet been widely explored in the blood. Here we demonstrate that Msi2 is the predominant form expressed in hematopoietic stem cells (HSCs), and its knockdown leads to reduced engraftment and depletion of HSCs in vivo. Overexpression of human MSI2 in a mouse model increases HSC cell cycle progression and cooperates with the chronic myeloid leukemia-associated BCR-ABL1 oncoprotein to induce an aggressive leukemia. MSI2 is overexpressed in human myeloid leukemia cell lines, and its depletion leads to decreased proliferation and increased apoptosis. Expression levels in human myeloid leukemia directly correlate with decreased survival in patients with the disease, thereby defining MSI2 expression as a new prognostic marker and as a new target for therapy in acute myeloid leukemia (AML).", + "TAG_DATA": [ + "53, HSCs {'context': 'B-cells'}", + "54, in {'context': 'B-in vivo'}", + "55, vivo. {'context': 'I-in vivo'}", + "56, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "57, of {'perturbing_action': 'I-gene gain-of-function'}", + "58, human {'perturbing_action': 'I-gene gain-of-function'}", + "59, MSI2 {'perturbing_action': 'I-gene gain-of-function'}", + "62, mouse {'context': 'B-organism'}", + "63, model {'context': 'I-organism'}", + "65, HSC {'context': 'B-cells'}", + "82, leukemia. {'context': 'B-neoplasm'}", + "87, human {'context': 'B-transformed cells'}", + "88, myeloid {'context': 'I-transformed cells'}", + "89, leukemia {'context': 'I-transformed cells'}", + "90, cell {'context': 'I-transformed cells'}", + "91, lines, {'context': 'I-transformed cells'}", + "97, decreased {'effect': 'B-negative'}", + "98, proliferation {'phenotype': 'B-proliferation'}", + "100, increased {'effect': 'B-positive'}", + "101, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "53, HSCs ['l0', 'l1']", + "54, in ['l0', 'l2']", + "55, vivo. ['l1', 'l2']", + "56, Overexpression ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "57, of ['l3', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "58, human ['l4', 'l18', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "59, MSI2 ['l5', 'l19', 'l31', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "62, mouse ['l6', 'l20', 'l32', 'l41', 'l50', 'l51', 'l52', 'l53', 'l54']", + "63, model ['l7', 'l21', 'l33', 'l42', 'l50', 'l55', 'l56']", + "65, HSC ['l8', 'l22', 'l34', 'l43', 'l51', 'l55', 'l57']", + "82, leukemia. ['l9', 'l23', 'l35', 'l44', 'l52', 'l56', 'l57', 'l58', 'l59', 'l60']", + "87, human ['l10', 'l24', 'l36', 'l45', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "88, myeloid ['l11', 'l25', 'l37', 'l46', 'l61', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "89, leukemia ['l12', 'l26', 'l38', 'l47', 'l58', 'l62', 'l69', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "90, cell ['l13', 'l27', 'l39', 'l48', 'l53', 'l59', 'l63', 'l70', 'l76', 'l82', 'l83', 'l84', 'l85', 'l86']", + "91, lines, ['l14', 'l28', 'l40', 'l49', 'l54', 'l60', 'l64', 'l71', 'l77', 'l82', 'l87', 'l88', 'l89', 'l90']", + "97, decreased ['l15', 'l29', 'l65', 'l72', 'l78', 'l83', 'l87', 'l91', 'l92', 'l93']", + "98, proliferation ['l16', 'l66', 'l73', 'l79', 'l84', 'l88', 'l91', 'l94', 'l95']", + "100, increased ['l17', 'l30', 'l67', 'l74', 'l80', 'l85', 'l89', 'l92', 'l94', 'l96']", + "101, apoptosis. ['l68', 'l75', 'l81', 'l86', 'l90', 'l93', 'l95', 'l96']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "human", + "MSI2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "human", + "MSI2" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "human", + "MSI2" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "human", + "MSI2" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "myeloid", + "leukemia", + "cell", + "lines," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "myeloid", + "leukemia", + "cell", + "lines," + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "myeloid", + "leukemia", + "cell", + "lines," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "myeloid", + "leukemia", + "cell", + "lines," + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "myeloid", + "leukemia", + "cell", + "lines," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "20581837", + "TEXT": "During pregnancy, the energy requirements of the fetus impose changes in maternal metabolism. Increasing insulin resistance in the mother maintains nutrient flow to the growing fetus, whereas prolactin and placental lactogen counterbalance this resistance and prevent maternal hyperglycemia by driving expansion of the maternal population of insulin-producing beta cells. However, the exact mechanisms by which the lactogenic hormones drive beta cell expansion remain uncertain. Here we show that serotonin acts downstream of lactogen signaling to stimulate beta cell proliferation. Expression of serotonin synthetic enzyme tryptophan hydroxylase-1 (Tph1) and serotonin production rose sharply in beta cells during pregnancy or after treatment with lactogens in vitro. Inhibition of serotonin synthesis by dietary tryptophan restriction or Tph inhibition blocked beta cell expansion and induced glucose intolerance in pregnant mice without affecting insulin sensitivity. Expression of the G alpha(q)-linked serotonin receptor 5-hydroxytryptamine receptor-2b (Htr2b) in maternal islets increased during pregnancy and normalized just before parturition, whereas expression of the G alpha(i)-linked receptor Htr1d increased at the end of pregnancy and postpartum. Blocking Htr2b signaling in pregnant mice also blocked beta cell expansion and caused glucose intolerance. These studies reveal an integrated signaling pathway linking beta cell mass to anticipated insulin need during pregnancy. Modulators of this pathway, including medications and diet, may affect the risk of gestational diabetes.", + "TAG_DATA": [ + "102, in {'context': 'B-in vitro'}", + "103, vitro. {'context': 'I-in vitro'}", + "113, Tph {'perturbing_action': 'B-pharmacological inhibition'}", + "114, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "116, beta {'context': 'B-cells'}", + "117, cell {'context': 'I-cells'}", + "124, pregnant {'context': 'B-organism'}", + "125, mice {'context': 'I-organism'}", + "141, maternal {'context': 'B-cells'}", + "142, islets {'context': 'I-cells'}", + "171, pregnant {'context': 'B-organism'}", + "172, mice {'context': 'I-organism'}", + "175, beta {'context': 'B-cells'}", + "176, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "102, in ['l0', 'l1']", + "103, vitro. ['l0', 'l2']", + "113, Tph ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "114, inhibition ['l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "116, beta ['l4', 'l10', 'l16', 'l17', 'l18']", + "117, cell ['l1', 'l2', 'l5', 'l11', 'l16', 'l19', 'l20']", + "124, pregnant ['l6', 'l12', 'l17', 'l19', 'l21', 'l22', 'l23']", + "125, mice ['l7', 'l13', 'l18', 'l20', 'l21']", + "141, maternal ['l8', 'l14', 'l22', 'l24']", + "142, islets ['l9', 'l15', 'l23', 'l24']", + "171, pregnant ['l25', 'l26', 'l27']", + "172, mice ['l25', 'l28', 'l29']", + "175, beta ['l26', 'l28', 'l30']", + "176, cell ['l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Tph", + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "beta", + "cell", + "maternal", + "islets" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Tph", + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "pregnant", + "mice" + ] + } + } + ] + }, + { + "PMID": "20418887", + "TEXT": "Obsessive-compulsive disorder (OCD) is a common psychiatric disorder defined by the presence of obsessive thoughts and repetitive compulsive actions, and it often encompasses anxiety and depressive symptoms. Recently, the corticostriatal circuitry has been implicated in the pathogenesis of OCD. However, the etiology, pathophysiology and molecular basis of OCD remain unknown. Several studies indicate that the pathogenesis of OCD has a genetic component. Here we demonstrate that loss of a neuron-specific transmembrane protein, SLIT and NTRK-like protein-5 (Slitrk5), leads to OCD-like behaviors in mice, which manifests as excessive self-grooming and increased anxiety-like behaviors, and is alleviated by the selective serotonin reuptake inhibitor fluoxetine. Slitrk5(-/-) mice show selective overactivation of the orbitofrontal cortex, abnormalities in striatal anatomy and cell morphology and alterations in glutamate receptor composition, which contribute to deficient corticostriatal neurotransmission. Thus, our studies identify Slitrk5 as an essential molecule at corticostriatal synapses and provide a new mouse model of OCD-like behaviors.", + "TAG_DATA": [ + "66, loss {'perturbing_action': 'B-gene loss-of-function'}", + "67, of {'perturbing_action': 'I-gene loss-of-function'}", + "68, a {'perturbing_action': 'I-gene loss-of-function'}", + "69, neuron-specific {'perturbing_action': 'I-gene loss-of-function'}", + "70, transmembrane {'perturbing_action': 'I-gene loss-of-function'}", + "71, protein, {'perturbing_action': 'I-gene loss-of-function'}", + "72, SLIT {'perturbing_action': 'I-gene loss-of-function'}", + "73, and {'perturbing_action': 'I-gene loss-of-function'}", + "74, NTRK-like {'perturbing_action': 'I-gene loss-of-function'}", + "75, protein-5 {'perturbing_action': 'I-gene loss-of-function'}", + "76, (Slitrk5), {'perturbing_action': 'I-gene loss-of-function'}", + "82, mice, {'context': 'B-organism'}", + "102, Slitrk5(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "103, mice {'context': 'B-organism'}", + "109, orbitofrontal {'context': 'B-tissue/organ'}", + "110, cortex, {'context': 'I-tissue/organ'}", + "116, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "66, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "67, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "68, a ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "69, neuron-specific ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "70, transmembrane ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "71, protein, ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "72, SLIT ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "73, and ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "74, NTRK-like ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "75, protein-5 ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "76, (Slitrk5), ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "82, mice, ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "102, Slitrk5(-/-) ['l66', 'l67', 'l68', 'l69']", + "103, mice ['l66', 'l70', 'l71', 'l72']", + "109, orbitofrontal ['l67', 'l70', 'l73', 'l74']", + "110, cortex, ['l68', 'l71', 'l73', 'l75']", + "116, cell ['l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "a", + "neuron-specific", + "transmembrane", + "protein,", + "SLIT", + "and", + "NTRK-like", + "protein-5", + "(Slitrk5),", + "Slitrk5(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Slitrk5(-/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "orbitofrontal", + "cortex," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Slitrk5(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + } + ] + }, + { + "PMID": "20418885", + "TEXT": "Fibrogenesis is a pathological wound repair process that fails to cease, even when the initial insult has been removed. Fibroblasts are principal mediators of fibrosis, and fibroblasts from fibrotic tissues fail to return to their quiescent stage, including when cultured in vitro. In a search for underlying molecular mechanisms, we hypothesized that this perpetuation of fibrogenesis is caused by epigenetic modifications. We demonstrate here that hypermethylation of RASAL1, encoding an inhibitor of the Ras oncoprotein, is associated with the perpetuation of fibroblast activation and fibrogenesis in the kidney. RASAL1 hypermethylation is mediated by the methyltransferase Dnmt1 in renal fibrogenesis, and kidney fibrosis is ameliorated in Dnmt1(+/-) heterozygous mice. These studies demonstrate that epigenetic modifications may provide a molecular basis for perpetuated fibroblast activation and fibrogenesis in the kidney.", + "TAG_DATA": [ + "100, kidney {'context': 'B-tissue/organ'}", + "105, Dnmt1(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "106, heterozygous {'perturbing_action': 'I-gene loss-of-function'}", + "107, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "105, Dnmt1(+/-) ['l0', 'l1']", + "106, heterozygous ['l0', 'l2']", + "107, mice. ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dnmt1(+/-)", + "heterozygous" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "20364125", + "TEXT": "Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder characterized by vascular malformations. Many affected individuals develop recurrent nosebleeds, which can severely affect their quality of life and are clinically difficult to treat. We report here that treatment with thalidomide reduced the severity and frequency of nosebleeds (epistaxis) in the majority of a small group of subjects with HHT tested. The blood hemoglobin levels of the treated individuals rose as a result of reduced hemorrhage and enhanced blood vessel stabilization. In mice heterozygous for a null mutation in the Eng gene (encoding endoglin), an experimental model of HHT, thalidomide treatment stimulated mural cell coverage and thus rescued vessel wall defects. Thalidomide treatment increased platelet-derived growth factor-B (PDGF-B) expression in endothelial cells and stimulated mural cell activation. The effects of thalidomide treatment were partially reversed by pharmacological or genetic interference with PDGF signaling from endothelial cells to pericytes. Biopsies of nasal epithelium from individuals with HHT treated or not with thalidomide showed that similar mechanisms may explain the effects of thalidomide treatment in humans. Our findings demonstrate the ability of thalidomide to induce vessel maturation, which may be useful as a therapeutic strategy for the treatment of vascular malformations.", + "TAG_DATA": [ + "80, mice {'context': 'B-organism'}", + "81, heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "82, for {'perturbing_action': 'I-gene loss-of-function'}", + "83, a {'perturbing_action': 'I-gene loss-of-function'}", + "84, null {'perturbing_action': 'I-gene loss-of-function'}", + "85, mutation {'perturbing_action': 'I-gene loss-of-function'}", + "86, in {'perturbing_action': 'I-gene loss-of-function'}", + "87, the {'perturbing_action': 'I-gene loss-of-function'}", + "88, Eng {'perturbing_action': 'I-gene loss-of-function'}", + "89, gene {'perturbing_action': 'I-gene loss-of-function'}", + "90, (encoding {'perturbing_action': 'I-gene loss-of-function'}", + "91, endoglin), {'perturbing_action': 'I-gene loss-of-function'}", + "100, mural {'context': 'B-cells'}", + "101, cell {'context': 'I-cells'}", + "118, endothelial {'context': 'B-cells'}", + "119, cells {'context': 'I-cells'}", + "122, mural {'context': 'B-cells'}", + "123, cell {'context': 'I-cells'}", + "142, endothelial {'context': 'B-cells'}", + "143, cells {'context': 'I-cells'}", + "145, pericytes. {'context': 'B-cells'}", + "148, nasal {'context': 'B-tissue/organ'}", + "149, epithelium {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "80, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "81, heterozygous ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "82, for ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "83, a ['l2', 'l14', 'l25', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "84, null ['l3', 'l15', 'l26', 'l37', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "85, mutation ['l4', 'l16', 'l27', 'l38', 'l48', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "86, in ['l5', 'l17', 'l28', 'l39', 'l49', 'l58', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "87, the ['l6', 'l18', 'l29', 'l40', 'l50', 'l59', 'l67', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "88, Eng ['l7', 'l19', 'l30', 'l41', 'l51', 'l60', 'l68', 'l75', 'l82', 'l83', 'l84', 'l85', 'l86']", + "89, gene ['l8', 'l20', 'l31', 'l42', 'l52', 'l61', 'l69', 'l76', 'l82', 'l87', 'l88', 'l89', 'l90']", + "90, (encoding ['l9', 'l21', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l83', 'l87', 'l91', 'l92', 'l93', 'l94']", + "91, endoglin), ['l10', 'l22', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l88', 'l91', 'l95', 'l96']", + "100, mural ['l11', 'l23', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l89', 'l92', 'l95', 'l97']", + "101, cell ['l12', 'l24', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l90', 'l93', 'l96', 'l97']", + "118, endothelial ['l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "119, cells ['l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l94', 'l98', 'l104', 'l105', 'l106', 'l107']", + "122, mural ['l99', 'l104', 'l108', 'l109', 'l110', 'l111']", + "123, cell ['l100', 'l105', 'l108', 'l112', 'l113']", + "142, endothelial ['l101', 'l106', 'l109', 'l112', 'l114', 'l115', 'l116', 'l117']", + "143, cells ['l102', 'l107', 'l110', 'l113', 'l114', 'l118', 'l119', 'l120']", + "145, pericytes. ['l103', 'l111', 'l115', 'l118', 'l121', 'l122']", + "148, nasal ['l116', 'l119', 'l121', 'l123']", + "149, epithelium ['l117', 'l120', 'l122', 'l123']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "heterozygous", + "for", + "a", + "null", + "mutation", + "in", + "the", + "Eng", + "gene", + "(encoding", + "endoglin)," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "heterozygous", + "for", + "a", + "null", + "mutation", + "in", + "the", + "Eng", + "gene", + "(encoding", + "endoglin)," + ] + }, + "context": { + "val": "cells", + "words": [ + "mural", + "cell", + "cells" + ] + } + } + ] + }, + { + "PMID": "20348926", + "TEXT": "Despite the fact that X-box binding protein-1 (XBP-1) is one of the main regulators of the unfolded protein response (UPR), the modulators of XBP-1 are poorly understood. Here, we show that the regulatory subunits of phosphotidyl inositol 3-kinase (PI3K), p85alpha (encoded by Pik3r1) and p85beta (encoded by Pik3r2) form heterodimers that are disrupted by insulin treatment. This disruption of heterodimerization allows the resulting monomers of p85 to interact with, and increase the nuclear translocation of, the spliced form of XBP-1 (XBP-1s). The interaction between p85 and XBP-1s is lost in ob/ob mice, resulting in a severe defect in XBP-1s translocation to the nucleus and thus in the resolution of endoplasmic reticulum (ER) stress. These defects are ameliorated when p85alpha and p85beta are overexpressed in the liver of ob/ob mice. Our results define a previously unknown insulin receptor signaling pathway and provide new mechanistic insight into the development of ER stress during obesity.", + "TAG_DATA": [ + "90, ob/ob {'perturbing_action': 'B-gene loss-of-function', 'context': 'B-organism'}", + "91, mice, {'context': 'I-organism'}", + "118, p85alpha {'perturbing_action': 'B-gene gain-of-function'}", + "119, and {'perturbing_action': 'I-gene gain-of-function'}", + "120, p85beta {'perturbing_action': 'I-gene gain-of-function'}", + "121, are {'perturbing_action': 'I-gene gain-of-function'}", + "122, overexpressed {'perturbing_action': 'I-gene gain-of-function'}", + "125, liver {'context': 'B-tissue/organ'}", + "127, ob/ob {'context': 'B-organism'}", + "128, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "90, ob/ob ['l0']", + "91, mice, ['l0']", + "118, p85alpha ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "119, and ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "120, p85beta ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "121, are ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "122, overexpressed ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "125, liver ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "127, ob/ob ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "128, mice. ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ob/ob" + ] + }, + "context": { + "val": "organism", + "words": [ + "ob/ob" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "p85alpha", + "and", + "p85beta", + "are", + "overexpressed" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "p85alpha", + "and", + "p85beta", + "are", + "overexpressed" + ] + }, + "context": { + "val": "organism", + "words": [ + "ob/ob", + "mice." + ] + } + } + ] + }, + { + "PMID": "20348923", + "TEXT": "Class Ia phosphoinositide 3-kinase (PI3K), an essential mediator of the metabolic actions of insulin, is composed of a catalytic (p110alpha or p110beta) and regulatory (p85alphaalpha, p85betaalpha or p55alpha) subunit. Here we show that p85alphaalpha interacts with X-box-binding protein-1 (XBP-1), a transcriptional mediator of the unfolded protein response (UPR), in an endoplasmic reticulum (ER) stress-dependent manner. Cell lines with knockout or knockdown of p85alphaalpha show marked alterations in the UPR, including reduced ER stress-dependent accumulation of nuclear XBP-1, decreased induction of UPR target genes and increased rates of apoptosis. This is associated with a decreased activation of inositol-requiring protein-1alpha (IRE1alpha) and activating transcription factor-6alphaalpha (ATF6alpha). Mice with deletion of p85alpha in liver (L-Pik3r1(-/-)) show a similar attenuated UPR after tunicamycin administration, leading to an increased inflammatory response. Thus, p85alphaalpha forms a previously unrecognized link between the PI3K pathway, which is central to insulin action, and the regulation of the cellular response to ER stress, a state that when unresolved leads to insulin resistance.", + "TAG_DATA": [ + "55, Cell {'context': 'B-cells'}", + "56, lines {'context': 'I-cells'}", + "60, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "61, of {'perturbing_action': 'I-rnai/knockdown'}", + "62, p85alphaalpha {'perturbing_action': 'I-rnai/knockdown'}", + "84, increased {'effect': 'B-positive'}", + "85, rates {'effect': 'I-positive'}", + "87, apoptosis. {'phenotype': 'B-apoptosis'}", + "104, Mice {'context': 'B-organism'}", + "106, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "107, of {'perturbing_action': 'I-gene loss-of-function'}", + "108, p85alpha {'perturbing_action': 'I-gene loss-of-function'}", + "110, liver {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "55, Cell ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "56, lines ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "60, knockdown ['l11', 'l12', 'l13', 'l14', 'l15']", + "61, of ['l1', 'l6', 'l11', 'l16', 'l17', 'l18', 'l19']", + "62, p85alphaalpha ['l2', 'l7', 'l12', 'l16', 'l20', 'l21', 'l22']", + "84, increased ['l3', 'l8', 'l13', 'l17', 'l20', 'l23', 'l24']", + "85, rates ['l4', 'l9', 'l14', 'l18', 'l21', 'l23', 'l25']", + "87, apoptosis. ['l5', 'l10', 'l15', 'l19', 'l22', 'l24', 'l25']", + "104, Mice ['l26', 'l27', 'l28', 'l29']", + "106, deletion ['l26', 'l30', 'l31', 'l32']", + "107, of ['l27', 'l30', 'l33', 'l34']", + "108, p85alpha ['l28', 'l31', 'l33', 'l35']", + "110, liver ['l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Cell", + "lines" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "p85alphaalpha" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Cell", + "lines" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "rates" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Cell", + "lines" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "p85alphaalpha" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "rates" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "p85alphaalpha" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased", + "rates" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "p85alpha" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "p85alpha" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "20305660", + "TEXT": "Observational clinical and ex vivo studies have established a strong association between atrial fibrillation and inflammation. However, whether inflammation is the cause or the consequence of atrial fibrillation and which specific inflammatory mediators may increase the atria's susceptibility to fibrillation remain elusive. Here we provide experimental and clinical evidence for the mechanistic involvement of myeloperoxidase (MPO), a heme enzyme abundantly expressed by neutrophils, in the pathophysiology of atrial fibrillation. MPO-deficient mice pretreated with angiotensin II (AngII) to provoke leukocyte activation showed lower atrial tissue abundance of the MPO product 3-chlorotyrosine, reduced activity of matrix metalloproteinases and blunted atrial fibrosis as compared to wild-type mice. Upon right atrial electrophysiological stimulation, MPO-deficient mice were protected from atrial fibrillation, which was reversed when MPO was restored. Humans with atrial fibrillation had higher plasma concentrations of MPO and a larger MPO burden in right atrial tissue as compared to individuals devoid of atrial fibrillation. In the atria, MPO colocalized with markedly increased formation of 3-chlorotyrosine. Our data demonstrate that MPO is a crucial prerequisite for structural remodeling of the myocardium, leading to an increased vulnerability to atrial fibrillation.", + "TAG_DATA": [ + "69, MPO-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "70, mice {'context': 'B-organism'}", + "109, MPO-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "110, mice {'context': 'B-organism'}", + "152, atria, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "69, MPO-deficient ['l0']", + "70, mice ['l0']", + "109, MPO-deficient ['l1']", + "110, mice ['l1']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MPO-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "20190767", + "TEXT": "Control of blood vessel tone is central to vascular homeostasis. Here we show that metabolism of tryptophan to kynurenine by indoleamine 2,3-dioxygenase (Ido) expressed in endothelial cells contributes to arterial vessel relaxation and the control of blood pressure. Infection of mice with malarial parasites (Plasmodium berghei) or induction of endotoxemia in mice led to endothelial expression of Ido, decreased plasma tryptophan concentration, increased kynurenine concentration and hypotension. Pharmacological inhibition of Ido increased blood pressure in systemically inflamed mice but not in mice deficient in Ido or interferon-gamma, which is required for Ido induction. Both tryptophan and kynurenine dilated preconstricted porcine coronary arteries; the dilating effect of tryptophan required the presence of active Ido and an intact endothelium, whereas the effect of kynurenine was endothelium independent. The arterial relaxation induced by kynurenine was mediated by activation of the adenylate and soluble guanylate cyclase pathways. Kynurenine administration decreased blood pressure in a dose-dependent manner in spontaneously hypertensive rats. Our results identify tryptophan metabolism by Ido as a new pathway contributing to the regulation of vascular tone.", + "TAG_DATA": [ + "40, mice {'context': 'B-organism'}", + "51, mice {'context': 'B-organism'}", + "67, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "68, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "69, of {'perturbing_action': 'I-pharmacological inhibition'}", + "70, Ido {'perturbing_action': 'I-pharmacological inhibition'}", + "77, mice {'context': 'B-organism'}", + "81, mice {'context': 'B-organism'}", + "82, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "83, in {'perturbing_action': 'I-gene loss-of-function'}", + "84, Ido {'perturbing_action': 'I-gene loss-of-function'}", + "99, porcine {'context': 'B-tissue/organ'}", + "100, coronary {'context': 'I-tissue/organ'}", + "101, arteries; {'context': 'I-tissue/organ'}", + "153, spontaneously {'context': 'B-organism'}", + "155, rats. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "40, mice ['l0']", + "51, mice ['l0']", + "67, Pharmacological ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "68, inhibition ['l1', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "69, of ['l2', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "70, Ido ['l3', 'l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "77, mice ['l4', 'l14', 'l23', 'l31', 'l39']", + "81, mice ['l5', 'l15', 'l24', 'l32', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "82, deficient ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "83, in ['l7', 'l17', 'l26', 'l34', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "84, Ido ['l8', 'l18', 'l27', 'l35', 'l39', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57']", + "99, porcine ['l9', 'l19', 'l28', 'l36', 'l43', 'l48', 'l52', 'l55', 'l58', 'l59']", + "100, coronary ['l10', 'l20', 'l29', 'l37', 'l44', 'l49', 'l53', 'l56', 'l58', 'l60']", + "101, arteries; ['l11', 'l21', 'l30', 'l38', 'l45', 'l50', 'l54', 'l57', 'l59', 'l60']", + "153, spontaneously ['l61', 'l62']", + "154, hypertensive ['l61', 'l63']", + "155, rats. ['l62', 'l63']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "Ido" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "Ido" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "porcine", + "coronary", + "arteries;" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ido", + "deficient", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Ido" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "porcine", + "coronary", + "arteries;" + ] + } + } + ] + }, + { + "PMID": "20190766", + "TEXT": "Hyperexcitability of spinal reflexes and reduced synaptic inhibition are commonly associated with spasticity after spinal cord injury (SCI). In adults, the activation of gamma-aminobutyric acid(A) (GABAA) and glycine receptors inhibits neurons as a result of low intracellular chloride (Cl-) concentration, which is maintained by the potassium-chloride cotransporter KCC2 (encoded by Slc12a5). We show that KCC2 is downregulated after SCI in rats, particularly in motoneuron membranes, thereby depolarizing the Cl- equilibrium potential and reducing the strength of postsynaptic inhibition. Blocking KCC2 in intact rats reduces the rate-dependent depression (RDD) of the Hoffmann reflex, as is observed in spasticity. RDD is also decreased in KCC2-deficient mice and in intact rats after intrathecal brain-derived neurotrophic factor (BDNF) injection, which downregulates KCC2. The early decrease in KCC2 after SCI is prevented by sequestering BDNF at the time of SCI. Conversely, after SCI, BDNF upregulates KCC2 and restores RDD. Our results open new perspectives for the development of therapeutic strategies to alleviate spasticity.", + "TAG_DATA": [ + "78, Blocking {'perturbing_action': 'B-pharmacological inhibition'}", + "79, KCC2 {'perturbing_action': 'I-pharmacological inhibition'}", + "81, intact {'context': 'B-organism'}", + "82, rats {'context': 'I-organism'}", + "102, KCC2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "103, mice {'context': 'B-organism'}", + "106, intact {'context': 'B-organism'}", + "107, rats {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "78, Blocking ['l0', 'l1', 'l2', 'l3']", + "79, KCC2 ['l0', 'l4', 'l5']", + "81, intact ['l1', 'l4', 'l6']", + "82, rats ['l2', 'l5', 'l6']", + "102, KCC2-deficient ['l7', 'l8', 'l9']", + "103, mice ['l3', 'l7', 'l10', 'l11']", + "106, intact ['l8', 'l10', 'l12']", + "107, rats ['l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blocking", + "KCC2" + ] + }, + "context": { + "val": "organism", + "words": [ + "intact", + "rats", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "KCC2-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "intact", + "rats" + ] + } + } + ] + }, + { + "PMID": "20081861", + "TEXT": "Lung cancer is the leading cause of cancer death worldwide. Recent data suggest that tumor-associated inflammatory cells may modify lung tumor growth and invasiveness. To determine the role of neutrophil elastase (encoded by Elane) on tumor progression, we used the loxP-Stop-loxP K-ras(G12D) (LSL-K-ras) model of mouse lung adenocarcinoma to generate LSL-K-ras-Elane(-/-) mice. Tumor burden was markedly reduced in LSL-K-ras-Elane(-/-) mice at all time points after induction of mutant K-ras expression. Kaplan-Meier survival analysis showed that whereas all LSL-K-ras-Elane(+/+) mice died, none of the mice lacking neutrophil elastase died. Neutrophil elastase directly induced tumor cell proliferation in both human and mouse lung adenocarcinomas by gaining access to an endosomal compartment within tumor cells, where it degraded insulin receptor substrate-1 (IRS-1). Immunoprecipitation studies showed that, as neutrophil elastase degraded IRS-1, there was increased interaction between phosphatidylinositol 3-kinase (PI3K) and the potent mitogen platelet-derived growth factor receptor (PDGFR), thereby skewing the PI3K axis toward tumor cell proliferation. The inverse relationship identified between neutrophil elastase and IRS-1 in LSL-K-ras mice was also identified in human lung adenocarcinomas, thus translating these findings to human disease. This study identifies IRS-1 as a key regulator of PI3K within malignant cells. Additionally, to our knowledge, this is the first description of a secreted proteinase gaining access to the inside of a cell and altering intracellular signaling.", + "TAG_DATA": [ + "40, loxP-Stop-loxP {'perturbing_action': 'B-other'}", + "41, K-ras(G12D) {'perturbing_action': 'I-other'}", + "42, (LSL-K-ras) {'perturbing_action': 'I-other'}", + "43, model {'perturbing_action': 'I-other'}", + "44, of {'perturbing_action': 'I-other'}", + "45, mouse {'context': 'B-neoplasm'}", + "46, lung {'context': 'I-neoplasm'}", + "47, adenocarcinoma {'context': 'I-neoplasm'}", + "50, LSL-K-ras-Elane(-/-) {'perturbing_action': 'B-other'}", + "51, mice. {'context': 'B-organism'}", + "56, reduced {'effect': 'B-negative'}", + "58, LSL-K-ras-Elane(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "59, mice {'context': 'B-organism'}", + "65, induction {'perturbing_action': 'B-other'}", + "67, mutant {'perturbing_action': 'B-other'}", + "68, K-ras {'perturbing_action': 'I-other'}", + "69, expression. {'perturbing_action': 'I-other'}", + "77, LSL-K-ras-Elane(+/+) {'perturbing_action': 'B-other'}", + "78, mice {'context': 'B-organism'}", + "83, mice {'context': 'B-organism'}", + "91, induced {'effect': 'B-positive'}", + "92, tumor {'context': 'B-transformed cells'}", + "93, cell {'context': 'I-transformed cells'}", + "94, proliferation {'phenotype': 'B-proliferation'}", + "97, human {'context': 'B-neoplasm'}", + "98, and {'context': 'I-neoplasm'}", + "99, mouse {'context': 'I-neoplasm'}", + "100, lung {'context': 'I-neoplasm'}", + "101, adenocarcinomas {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "40, loxP-Stop-loxP ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "41, K-ras(G12D) ['l0', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "42, (LSL-K-ras) ['l1', 'l24', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "43, model ['l2', 'l25', 'l46', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "44, of ['l3', 'l26', 'l47', 'l61', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "45, mouse ['l4', 'l27', 'l48', 'l62', 'l73', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "46, lung ['l5', 'l28', 'l49', 'l63', 'l74', 'l84', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "47, adenocarcinoma ['l6', 'l29', 'l50', 'l64', 'l75', 'l85', 'l91', 'l97', 'l98', 'l99', 'l100', 'l101']", + "50, LSL-K-ras-Elane(-/-) ['l7', 'l30', 'l51', 'l65', 'l76', 'l86', 'l92', 'l97', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "51, mice. ['l8', 'l31', 'l52', 'l66', 'l77', 'l87', 'l93', 'l98', 'l102', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "52, Tumor ['l9', 'l32', 'l53', 'l67', 'l78', 'l88', 'l94', 'l99', 'l103', 'l111', 'l117', 'l118']", + "56, reduced ['l10', 'l33', 'l54', 'l68', 'l79', 'l89', 'l95', 'l100', 'l104', 'l112', 'l117', 'l119']", + "58, LSL-K-ras-Elane(-/-) ['l11', 'l34', 'l55', 'l69', 'l80', 'l105', 'l113', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "59, mice ['l12', 'l35', 'l56', 'l70', 'l81', 'l90', 'l96', 'l101', 'l106', 'l114', 'l118', 'l119', 'l120', 'l134', 'l135']", + "65, induction ['l13', 'l36', 'l57', 'l71', 'l82', 'l107', 'l115', 'l121', 'l134', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "67, mutant ['l14', 'l37', 'l58', 'l108', 'l122', 'l136', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "68, K-ras ['l15', 'l38', 'l59', 'l109', 'l123', 'l137', 'l144', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166']", + "69, expression. ['l16', 'l39', 'l60', 'l72', 'l83', 'l110', 'l116', 'l124', 'l135', 'l138', 'l145', 'l155', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "77, LSL-K-ras-Elane(+/+) ['l156', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184']", + "78, mice ['l157', 'l175', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "83, mice ['l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202']", + "91, induced ['l125', 'l146', 'l158', 'l176', 'l185', 'l194', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210']", + "92, tumor ['l126', 'l147', 'l159', 'l167', 'l177', 'l186', 'l195', 'l203', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217']", + "93, cell ['l17', 'l40', 'l127', 'l139', 'l148', 'l160', 'l168', 'l178', 'l187', 'l196', 'l204', 'l211', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223']", + "94, proliferation ['l18', 'l41', 'l128', 'l149', 'l161', 'l169', 'l179', 'l188', 'l197', 'l205', 'l212', 'l218', 'l224', 'l225', 'l226', 'l227', 'l228']", + "97, human ['l19', 'l42', 'l129', 'l140', 'l150', 'l162', 'l170', 'l180', 'l189', 'l198', 'l206', 'l213', 'l219', 'l224', 'l229', 'l230', 'l231', 'l232']", + "98, and ['l20', 'l43', 'l130', 'l141', 'l151', 'l163', 'l171', 'l181', 'l190', 'l199', 'l207', 'l214', 'l220', 'l225', 'l229', 'l233', 'l234', 'l235']", + "99, mouse ['l21', 'l131', 'l152', 'l164', 'l172', 'l182', 'l191', 'l200', 'l208', 'l215', 'l221', 'l226', 'l230', 'l233', 'l236', 'l237']", + "100, lung ['l22', 'l44', 'l132', 'l142', 'l153', 'l165', 'l173', 'l183', 'l192', 'l201', 'l209', 'l216', 'l222', 'l227', 'l231', 'l234', 'l236', 'l238']", + "101, adenocarcinomas ['l23', 'l45', 'l133', 'l143', 'l154', 'l166', 'l174', 'l184', 'l193', 'l202', 'l210', 'l217', 'l223', 'l228', 'l232', 'l235', 'l237', 'l238']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "loxP-Stop-loxP", + "K-ras(G12D)", + "(LSL-K-ras)", + "model", + "of", + "LSL-K-ras-Elane(-/-)", + "induction", + "mutant", + "K-ras", + "expression.", + "LSL-K-ras-Elane(+/+)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "lung", + "adenocarcinoma", + "human", + "and", + "adenocarcinomas" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "loxP-Stop-loxP", + "K-ras(G12D)", + "(LSL-K-ras)", + "model", + "of", + "LSL-K-ras-Elane(-/-)", + "induction", + "expression.", + "K-ras", + "LSL-K-ras-Elane(+/+)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "loxP-Stop-loxP", + "K-ras(G12D)", + "(LSL-K-ras)", + "model", + "of", + "LSL-K-ras-Elane(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "loxP-Stop-loxP", + "K-ras(G12D)", + "induction", + "mutant", + "K-ras", + "expression.", + "LSL-K-ras-Elane(+/+)" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cell", + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "loxP-Stop-loxP", + "K-ras(G12D)", + "mutant", + "K-ras", + "expression.", + "LSL-K-ras-Elane(+/+)" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "lung", + "adenocarcinoma" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "LSL-K-ras-Elane(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "LSL-K-ras-Elane(-/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "LSL-K-ras-Elane(-/-)" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "LSL-K-ras-Elane(-/-)" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "LSL-K-ras-Elane(-/-)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "and", + "mouse", + "lung", + "adenocarcinomas" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "K-ras", + "LSL-K-ras-Elane(+/+)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "and", + "mouse", + "lung", + "adenocarcinomas" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "and", + "mouse", + "lung", + "adenocarcinomas" + ] + } + } + ] + }, + { + "PMID": "19966810", + "TEXT": "The identification of the genes associated with chromosomal translocation breakpoints has fundamentally changed understanding of the molecular basis of hematological malignancies. By contrast, the study of chromosomal deletions has been hampered by the large number of genes deleted and the complexity of their analysis. We report the generation of a mouse model for human 5q- syndrome using large-scale chromosomal engineering. Haploinsufficiency of the Cd74-Nid67 interval (containing Rps14, encoding the ribosomal protein S14) caused macrocytic anemia, prominent erythroid dysplasia and monolobulated megakaryocytes in the bone marrow. These effects were associated with defective bone marrow progenitor development, the appearance of bone marrow cells expressing high amounts of the tumor suppressor p53 and increased bone marrow cell apoptosis. Notably, intercrossing with p53-deficient mice completely rescued the progenitor cell defect, restoring common myeloid progenitor and megakaryocytic-erythroid progenitor, granulocyte-monocyte progenitor and hematopoietic stem cell bone marrow populations. This mouse model suggests that a p53-dependent mechanism underlies the pathophysiology of the 5q- syndrome.", + "TAG_DATA": [ + "60, Haploinsufficiency {'perturbing_action': 'B-gene loss-of-function'}", + "61, of {'perturbing_action': 'I-gene loss-of-function'}", + "62, the {'perturbing_action': 'I-gene loss-of-function'}", + "63, Cd74-Nid67 {'perturbing_action': 'I-gene loss-of-function'}", + "64, interval {'perturbing_action': 'I-gene loss-of-function'}", + "65, (containing {'perturbing_action': 'I-gene loss-of-function'}", + "98, bone {'context': 'B-cells'}", + "99, marrow {'context': 'I-cells'}", + "100, cells {'context': 'I-cells'}", + "110, increased {'effect': 'B-positive'}", + "111, bone {'context': 'B-cells'}", + "112, marrow {'context': 'I-cells'}", + "113, cell {'context': 'I-cells'}", + "114, apoptosis. {'phenotype': 'B-apoptosis'}", + "118, p53-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "119, mice {'context': 'B-organism'}", + "123, progenitor {'context': 'B-cells'}", + "124, cell {'context': 'I-cells'}", + "127, common {'context': 'B-cells'}", + "128, myeloid {'context': 'I-cells'}", + "129, progenitor {'context': 'I-cells'}", + "130, and {'context': 'I-cells'}", + "131, megakaryocytic-erythroid {'context': 'I-cells'}", + "132, progenitor, {'context': 'I-cells'}", + "133, granulocyte-monocyte {'context': 'I-cells'}", + "134, progenitor {'context': 'I-cells'}", + "136, hematopoietic {'context': 'I-cells'}", + "137, stem {'context': 'I-cells'}", + "138, cell {'context': 'I-cells'}", + "139, bone {'context': 'I-cells'}", + "140, marrow {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "60, Haploinsufficiency ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "61, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "62, the ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "63, Cd74-Nid67 ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "64, interval ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "65, (containing ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "98, bone ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "99, marrow ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "100, cells ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "110, increased ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "111, bone ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "112, marrow ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "113, cell ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "114, apoptosis. ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']", + "118, p53-deficient ['l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "119, mice ['l91', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "123, progenitor ['l92', 'l107', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "124, cell ['l93', 'l108', 'l122', 'l131', 'l132', 'l133', 'l134', 'l135']", + "127, common ['l94', 'l109', 'l123', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "128, myeloid ['l95', 'l110', 'l124', 'l131', 'l136', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158']", + "129, progenitor ['l96', 'l111', 'l125', 'l132', 'l137', 'l148', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168']", + "130, and ['l97', 'l112', 'l126', 'l133', 'l138', 'l149', 'l159', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177']", + "131, megakaryocytic-erythroid ['l98', 'l113', 'l127', 'l134', 'l139', 'l150', 'l160', 'l169', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185']", + "132, progenitor, ['l99', 'l114', 'l128', 'l135', 'l140', 'l151', 'l161', 'l170', 'l178', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192']", + "133, granulocyte-monocyte ['l100', 'l115', 'l129', 'l141', 'l152', 'l162', 'l171', 'l179', 'l186', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198']", + "134, progenitor ['l101', 'l116', 'l130', 'l142', 'l153', 'l163', 'l172', 'l180', 'l187', 'l193', 'l199', 'l200', 'l201', 'l202', 'l203']", + "136, hematopoietic ['l102', 'l117', 'l143', 'l154', 'l164', 'l173', 'l181', 'l188', 'l194', 'l199', 'l204', 'l205', 'l206', 'l207']", + "137, stem ['l103', 'l118', 'l144', 'l155', 'l165', 'l174', 'l182', 'l189', 'l195', 'l200', 'l204', 'l208', 'l209', 'l210']", + "138, cell ['l104', 'l119', 'l145', 'l156', 'l166', 'l175', 'l183', 'l190', 'l196', 'l201', 'l205', 'l208', 'l211', 'l212']", + "139, bone ['l105', 'l120', 'l146', 'l157', 'l167', 'l176', 'l184', 'l191', 'l197', 'l202', 'l206', 'l209', 'l211', 'l213']", + "140, marrow ['l106', 'l121', 'l147', 'l158', 'l168', 'l177', 'l185', 'l192', 'l198', 'l203', 'l207', 'l210', 'l212', 'l213']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Haploinsufficiency", + "of", + "the", + "Cd74-Nid67", + "interval", + "(containing", + "p53-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "bone", + "marrow", + "cells", + "cell", + "progenitor", + "common", + "myeloid", + "and", + "megakaryocytic-erythroid", + "progenitor,", + "granulocyte-monocyte", + "hematopoietic", + "stem" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Haploinsufficiency", + "of", + "the", + "Cd74-Nid67", + "interval", + "(containing" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Haploinsufficiency", + "of", + "the", + "Cd74-Nid67", + "interval", + "(containing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "bone", + "marrow", + "cells", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "bone", + "marrow", + "cells", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "19915594", + "TEXT": "Osteoarthritis is associated with the irreversible degeneration of articular cartilage. Notably, in this condition, articular cartilage chondrocytes undergo phenotypic and gene expression changes that are reminiscent of their end-stage differentiation in the growth plate during skeletal development. Hedgehog (Hh) signaling regulates normal chondrocyte growth and differentiation; however, the role of Hh signaling in chondrocytes in osteoarthritis is unknown. Here we examine human osteoarthritic samples and mice in which osteoarthritis was surgically induced and find that Hh signaling is activated in osteoarthritis. Using several genetically modified mice, we found that higher levels of Hh signaling in chondrocytes cause a more severe osteoarthritic phenotype. Furthermore, we show in mice and in human cartilage explants that pharmacological or genetic inhibition of Hh signaling reduces the severity of osteoarthritis and that runt-related transcription factor-2 (RUNX2) potentially mediates this process by regulating a disintegrin and metalloproteinase with thrombospondin type 1 motif-5 (ADAMTS5) expression. Together, these findings raise the possibility that Hh blockade can be used as a therapeutic approach to inhibit articular cartilage degeneration.", + "TAG_DATA": [ + "65, mice {'context': 'B-organism'}", + "85, mice, {'context': 'B-organism'}", + "95, chondrocytes {'context': 'B-cells'}", + "106, mice {'context': 'B-organism'}", + "109, human {'context': 'B-tissue/organ'}", + "110, cartilage {'context': 'I-tissue/organ'}", + "111, explants {'context': 'I-tissue/organ'}", + "115, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "116, inhibition {'perturbing_action': 'I-gene loss-of-function'}", + "117, of {'perturbing_action': 'I-gene loss-of-function'}", + "118, Hh {'perturbing_action': 'I-gene loss-of-function'}", + "119, signaling {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "65, mice ['l0']", + "85, mice, ['l0']", + "106, mice ['l1']", + "109, human ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "110, cartilage ['l2', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "111, explants ['l1', 'l3', 'l9', 'l15', 'l16', 'l17', 'l18', 'l19']", + "115, genetic ['l4', 'l10', 'l15', 'l20', 'l21', 'l22', 'l23']", + "116, inhibition ['l5', 'l11', 'l16', 'l20', 'l24', 'l25', 'l26']", + "117, of ['l6', 'l12', 'l17', 'l21', 'l24', 'l27', 'l28']", + "118, Hh ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l29']", + "119, signaling ['l8', 'l14', 'l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "human", + "cartilage", + "explants" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inhibition", + "of", + "Hh", + "signaling" + ] + } + } + ] + }, + { + "PMID": "19881492", + "TEXT": "Z-disks, the mechanical integration sites of heart and skeletal muscle cells, link anchorage of myofilaments to force reception and processing. The key molecules that enable the Z-disk to persistently withstand the extreme mechanical forces during muscle contraction have not yet been identified. Here we isolated nexilin (encoded by NEXN) as a novel Z-disk protein. Loss of nexilin in zebrafish led to perturbed Z-disk stability and heart failure. To evaluate the role of nexilin in human heart failure, we performed a genetic association study on individuals with dilated cardiomyopathy and found several mutations in NEXN associated with the disease. Nexilin mutation carriers showed the same cardiac Z-disk pathology as observed in nexilin-deficient zebrafish. Expression in zebrafish of nexilin proteins encoded by NEXN mutant alleles induced Z-disk damage and heart failure, demonstrating a dominant-negative effect and confirming the disease-causing nature of these mutations. Increasing mechanical strain aggravated Z-disk damage in nexilin-deficient skeletal muscle, implying a unique role of nexilin in protecting Z-disks from mechanical trauma.", + "TAG_DATA": [ + "54, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "55, of {'perturbing_action': 'I-gene loss-of-function'}", + "56, nexilin {'perturbing_action': 'I-gene loss-of-function'}", + "58, zebrafish {'context': 'B-organism'}", + "110, nexilin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "111, zebrafish. {'context': 'B-organism'}", + "112, Expression {'perturbing_action': 'B-other'}", + "114, zebrafish {'context': 'B-organism'}", + "115, of {'perturbing_action': 'I-other'}", + "116, nexilin {'perturbing_action': 'I-other'}", + "117, proteins {'perturbing_action': 'I-other'}", + "118, encoded {'perturbing_action': 'I-other'}", + "119, by {'perturbing_action': 'I-other'}", + "120, NEXN {'perturbing_action': 'I-other'}", + "121, mutant {'perturbing_action': 'I-other'}", + "122, alleles {'perturbing_action': 'I-other'}", + "148, nexilin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "149, skeletal {'context': 'B-tissue/organ'}", + "150, muscle, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "54, Loss ['l0', 'l1', 'l2']", + "55, of ['l0', 'l3', 'l4']", + "56, nexilin ['l1', 'l3', 'l5']", + "58, zebrafish ['l2', 'l4', 'l5']", + "110, nexilin-deficient ['l6']", + "111, zebrafish. ['l6']", + "112, Expression ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "114, zebrafish ['l7', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "115, of ['l8', 'l19', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "116, nexilin ['l9', 'l20', 'l30', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "117, proteins ['l10', 'l21', 'l31', 'l40', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "118, encoded ['l11', 'l22', 'l32', 'l41', 'l49', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "119, by ['l12', 'l23', 'l33', 'l42', 'l50', 'l57', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "120, NEXN ['l13', 'l24', 'l34', 'l43', 'l51', 'l58', 'l64', 'l70', 'l71', 'l72', 'l73', 'l74']", + "121, mutant ['l14', 'l25', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l75', 'l76', 'l77', 'l78']", + "122, alleles ['l15', 'l26', 'l36', 'l45', 'l53', 'l60', 'l66', 'l71', 'l75', 'l79', 'l80', 'l81']", + "148, nexilin-deficient ['l16', 'l27', 'l37', 'l46', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l82', 'l83']", + "149, skeletal ['l17', 'l28', 'l38', 'l47', 'l55', 'l62', 'l68', 'l73', 'l77', 'l80', 'l82', 'l84']", + "150, muscle, ['l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l69', 'l74', 'l78', 'l81', 'l83', 'l84']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Loss", + "of", + "nexilin", + "nexilin-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "zebrafish", + "zebrafish." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Expression", + "of", + "nexilin", + "proteins", + "encoded", + "by", + "NEXN", + "mutant", + "alleles" + ] + }, + "context": { + "val": "organism", + "words": [ + "zebrafish" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Expression", + "of", + "nexilin", + "proteins", + "encoded", + "by", + "NEXN", + "mutant", + "alleles" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skeletal", + "muscle," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nexilin-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skeletal", + "muscle," + ] + } + } + ] + }, + { + "PMID": "19855400", + "TEXT": "Notch receptor signaling is implicated in controlling smooth muscle cell proliferation and in maintaining smooth muscle cells in an undifferentiated state. Pulmonary arterial hypertension is characterized by excessive vascular resistance, smooth muscle cell proliferation in small pulmonary arteries, leading to elevation of pulmonary vascular resistance, right ventricular failure and death. Here we show that human pulmonary hypertension is characterized by overexpression of NOTCH3 in small pulmonary artery smooth muscle cells and that the severity of disease in humans and rodents correlates with the amount of NOTCH3 protein in the lung. We further show that mice with homozygous deletion of Notch3 do not develop pulmonary hypertension in response to hypoxic stimulation and that pulmonary hypertension can be successfully treated in mice by administration of N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a gamma-secretase inhibitor that blocks activation of Notch3 in smooth muscle cells. We show a mechanistic link from NOTCH3 receptor signaling through the Hairy and enhancer of Split-5 (HES-5) protein to smooth muscle cell proliferation and a shift to an undifferentiated smooth muscle cell phenotype. These results suggest that the NOTCH3-HES-5 signaling pathway is crucial for the development of pulmonary arterial hypertension and provide a target pathway for therapeutic intervention.", + "TAG_DATA": [ + "94, mice {'context': 'B-organism'}", + "96, homozygous {'perturbing_action': 'B-gene loss-of-function'}", + "97, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "98, of {'perturbing_action': 'I-gene loss-of-function'}", + "99, Notch3 {'perturbing_action': 'I-gene loss-of-function'}", + "119, mice {'context': 'B-organism'}", + "136, smooth {'context': 'B-cells'}", + "137, muscle {'context': 'B-cells'}", + "138, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "94, mice ['l0', 'l1', 'l2', 'l3']", + "96, homozygous ['l0', 'l4', 'l5', 'l6']", + "97, deletion ['l1', 'l4', 'l7', 'l8']", + "98, of ['l2', 'l5', 'l7', 'l9']", + "99, Notch3 ['l3', 'l6', 'l8', 'l9']", + "119, mice ['l10', 'l11', 'l12']", + "136, smooth ['l10', 'l13', 'l14']", + "137, muscle ['l11', 'l13', 'l15']", + "138, cells. ['l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "homozygous", + "deletion", + "of", + "Notch3" + ] + } + } + ] + }, + { + "PMID": "19838202", + "TEXT": "Macrophages rapidly engulf apoptotic cells to limit the release of noxious cellular contents and to restrict autoimmune responses against self antigens. Although factors participating in recognition and engulfment of apoptotic cells have been identified, the transcriptional basis for the sensing and the silent disposal of apoptotic cells is unknown. Here we show that peroxisome proliferator-activated receptor-delta (PPAR-delta) is induced when macrophages engulf apoptotic cells and functions as a transcriptional sensor of dying cells. Genetic deletion of PPAR-delta decreases expression of opsonins such as complement component-1qb (C1qb), resulting in impairment of apoptotic cell clearance and reduction in anti-inflammatory cytokine production. This increases autoantibody production and predisposes global and macrophage-specific Ppard(-/-) mice to autoimmune kidney disease, a phenotype resembling the human disease systemic lupus erythematosus. Thus, PPAR-delta has a pivotal role in orchestrating the timely disposal of apoptotic cells by macrophages, ensuring that tolerance to self is maintained.", + "TAG_DATA": [ + "73, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "74, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "75, of {'perturbing_action': 'I-gene loss-of-function'}", + "76, PPAR-delta {'perturbing_action': 'I-gene loss-of-function'}", + "91, cell {'phenotype': 'I-apoptosis'}", + "107, macrophage-specific {'perturbing_action': 'B-gene loss-of-function'}", + "108, Ppard(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "109, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, Genetic ['l0', 'l1', 'l2', 'l3']", + "74, deletion ['l0', 'l4', 'l5', 'l6']", + "75, of ['l1', 'l4', 'l7', 'l8']", + "76, PPAR-delta ['l2', 'l5', 'l7', 'l9']", + "91, cell ['l3', 'l6', 'l8', 'l9']", + "107, macrophage-specific ['l10', 'l11']", + "108, Ppard(-/-) ['l10', 'l12']", + "109, mice ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "deletion", + "of", + "PPAR-delta" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "macrophage-specific", + "Ppard(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "19812566", + "TEXT": "Imatinib (trade name Gleevec) preserves fertility in female mice treated with the common chemotherapeutic agent cisplatin. Imatinib seems to block an apoptotic pathway activated by cisplatin in ovarian germ cells (pages 1179– 1185). The findings could lead to new ways to protect germ cells from the damaging effects of cancer treatment.", + "TAG_DATA": [ + "7, female {'context': 'B-organism'}", + "8, mice {'context': 'I-organism'}", + "19, block {'effect': 'B-negative'}", + "21, apoptotic {'phenotype': 'B-apoptosis'}", + "22, pathway {'phenotype': 'I-apoptosis'}", + "23, activated {'effect': 'B-positive'}", + "27, ovarian {'context': 'B-transformed cells'}", + "28, germ {'context': 'I-transformed cells'}", + "29, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "7, female ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "8, mice ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "19, block ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "21, apoptotic ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "22, pathway ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "23, activated ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "27, ovarian ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "28, germ ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "29, cells ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "female", + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "block" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "female", + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "pathway" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "female", + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "activated" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "block" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "pathway" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "block" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "germ", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "pathway" + ] + }, + "effect": { + "val": "positive", + "words": [ + "activated" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "pathway" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "germ", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "activated" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "germ", + "cells" + ] + } + } + ] + }, + { + "PMID": "19767732", + "TEXT": "The therapeutic efficacy of anticancer chemotherapies may depend on dendritic cells (DCs), which present antigens from dying cancer cells to prime tumor-specific interferon-gamma (IFN-gamma)-producing T lymphocytes. Here we show that dying tumor cells release ATP, which then acts on P2X(7) purinergic receptors from DCs and triggers the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3)-dependent caspase-1 activation complex ('inflammasome'), allowing for the secretion of interleukin-1beta (IL-1beta). The priming of IFN-gamma-producing CD8+ T cells by dying tumor cells fails in the absence of a functional IL-1 receptor 1 and in Nlpr3-deficient (Nlrp3(-/-)) or caspase-1-deficient (Casp-1(-/-)) mice unless exogenous IL-1beta is provided. Accordingly, anticancer chemotherapy turned out to be inefficient against tumors established in purinergic receptor P2rx7(-/-) or Nlrp3(-/-) or Casp1(-/-) hosts. Anthracycline-treated individuals with breast cancer carrying a loss-of-function allele of P2RX7 developed metastatic disease more rapidly than individuals bearing the normal allele. These results indicate that the NLRP3 inflammasome links the innate and adaptive immune responses against dying tumor cells.", + "TAG_DATA": [ + "70, CD8+ {'context': 'B-cells'}", + "71, T {'context': 'I-cells'}", + "72, cells {'context': 'I-cells'}", + "75, tumor {'context': 'I-transformed cells'}", + "76, cells {'context': 'I-transformed cells'}", + "89, Nlpr3-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "90, (Nlrp3(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "92, caspase-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "93, (Casp-1(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "94, mice {'context': 'B-organism'}", + "109, tumors {'context': 'B-neoplasm'}", + "112, purinergic {'perturbing_action': 'B-gene loss-of-function'}", + "113, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "114, P2rx7(-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "116, Nlrp3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "117, or {'perturbing_action': 'I-gene loss-of-function'}", + "118, Casp1(-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "123, breast {'context': 'B-neoplasm'}", + "124, cancer {'context': 'I-neoplasm'}", + "126, a {'perturbing_action': 'B-gene loss-of-function'}", + "127, loss-of-function {'perturbing_action': 'B-gene loss-of-function'}", + "128, allele {'perturbing_action': 'I-gene loss-of-function'}", + "129, of {'perturbing_action': 'I-gene loss-of-function'}", + "130, P2RX7 {'perturbing_action': 'I-gene loss-of-function'}", + "131, developed {'effect': 'B-negative'}", + "132, metastatic {'phenotype': 'B-metastasis'}", + "133, disease {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "70, CD8+ ['l0', 'l1', 'l2', 'l3']", + "71, T ['l0', 'l4', 'l5', 'l6']", + "72, cells ['l1', 'l4', 'l7', 'l8']", + "75, tumor ['l2', 'l5', 'l7', 'l9']", + "76, cells ['l3', 'l6', 'l8', 'l9']", + "89, Nlpr3-deficient ['l10', 'l11', 'l12', 'l13', 'l14']", + "90, (Nlrp3(-/-)) ['l10', 'l15', 'l16', 'l17', 'l18']", + "92, caspase-1-deficient ['l11', 'l15', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "93, (Casp-1(-/-)) ['l12', 'l16', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "94, mice ['l13', 'l17', 'l20', 'l26', 'l32', 'l33', 'l34', 'l35']", + "109, tumors ['l14', 'l18', 'l21', 'l27', 'l32', 'l36', 'l37', 'l38']", + "112, purinergic ['l22', 'l28', 'l33', 'l36', 'l39', 'l40', 'l41', 'l42', 'l43']", + "113, receptor ['l23', 'l29', 'l34', 'l37', 'l39', 'l44', 'l45', 'l46', 'l47']", + "114, P2rx7(-/-) ['l24', 'l30', 'l35', 'l38', 'l40', 'l44', 'l48', 'l49', 'l50']", + "116, Nlrp3(-/-) ['l25', 'l31', 'l41', 'l45', 'l48', 'l51', 'l52', 'l53', 'l54']", + "117, or ['l42', 'l46', 'l49', 'l51', 'l55', 'l56', 'l57']", + "118, Casp1(-/-) ['l43', 'l47', 'l50', 'l52', 'l55', 'l58', 'l59']", + "123, breast ['l53', 'l56', 'l58', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "124, cancer ['l54', 'l57', 'l59', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "126, a ['l61', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "127, loss-of-function ['l62', 'l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "128, allele ['l63', 'l71', 'l78', 'l84', 'l90', 'l91', 'l92', 'l93', 'l94']", + "129, of ['l64', 'l72', 'l79', 'l85', 'l90', 'l95', 'l96', 'l97', 'l98']", + "130, P2RX7 ['l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l99', 'l100', 'l101']", + "131, developed ['l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l102', 'l103']", + "132, metastatic ['l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l104']", + "133, disease ['l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l104']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nlpr3-deficient", + "(Nlrp3(-/-))", + "caspase-1-deficient", + "(Casp-1(-/-))", + "purinergic", + "receptor", + "P2rx7(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nlpr3-deficient", + "(Nlrp3(-/-))", + "caspase-1-deficient", + "(Casp-1(-/-))", + "purinergic", + "receptor", + "P2rx7(-/-)", + "Nlrp3(-/-)", + "or", + "Casp1(-/-)", + "a", + "loss-of-function", + "allele", + "of", + "P2RX7" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "breast", + "cancer" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "breast", + "cancer" + ] + }, + "effect": { + "val": "negative", + "words": [ + "developed" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "breast", + "cancer" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "disease" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "a", + "loss-of-function", + "allele", + "of", + "P2RX7" + ] + }, + "effect": { + "val": "negative", + "words": [ + "developed" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "a", + "loss-of-function", + "allele", + "of", + "P2RX7" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "disease" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "developed" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "disease" + ] + } + } + ] + }, + { + "PMID": "19734908", + "TEXT": "Integrins regulate adhesion-dependent growth, survival and invasion of tumor cells. In particular, expression of integrin alpha(v)beta(3) is associated with progression of a variety of human tumors. Here we reveal a previously undescribed adhesion-independent role for integrin alpha(v)beta(3) in pancreatic cancer and other carcinomas. Specifically, alpha(v)beta(3) expressed in carcinoma cells enhanced anchorage-independent tumor growth in vitro and increased lymph node metastases in vivo. These effects required recruitment of c-Src to the beta(3) integrin cytoplasmic tail, leading to c-Src activation, Crk-associated substrate (CAS) phosphorylation and tumor cell survival that, unexpectedly, was independent of cell adhesion or focal adhesion kinase (FAK) activation. Pharmacological blockade of c-Src kinase activity or decreased expression of endogenous alpha(v)beta(3) integrin or c-Src not only inhibited anchorage-independent growth but also suppressed metastasis in vivo, yet these manipulations did not affect tumor cell migration or invasion. These data define an unexpected role for an integrin as a mediator of anchorage independence, suggesting that an alpha(v)beta(3)-c-Src signaling module may account for the aggressive behavior of integrin alpha(v)beta(3)-expressing tumors in humans.", + "TAG_DATA": [ + "49, enhanced {'effect': 'B-positive'}", + "51, tumor {'phenotype': 'B-tumour growth'}", + "52, growth {'phenotype': 'I-tumour growth'}", + "53, in {'context': 'B-in vitro'}", + "54, vitro {'context': 'I-in vitro'}", + "56, increased {'effect': 'B-positive'}", + "57, lymph {'phenotype': 'B-metastasis'}", + "58, node {'phenotype': 'I-metastasis'}", + "59, metastases {'phenotype': 'I-metastasis'}", + "60, in {'context': 'B-in vivo'}", + "61, vivo. {'context': 'I-in vivo'}", + "83, tumor {'context': 'B-transformed cells'}", + "84, cell {'phenotype': 'B-cell survival'}", + "85, survival {'phenotype': 'I-cell survival'}", + "99, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "100, blockade {'perturbing_action': 'I-pharmacological inhibition'}", + "101, of {'perturbing_action': 'I-pharmacological inhibition'}", + "102, c-Src {'perturbing_action': 'I-pharmacological inhibition'}", + "103, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "104, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "106, decreased {'perturbing_action': 'B-other'}", + "107, expression {'perturbing_action': 'I-rnai/knockdown'}", + "108, of {'perturbing_action': 'I-rnai/knockdown'}", + "109, endogenous {'perturbing_action': 'I-rnai/knockdown'}", + "110, alpha(v)beta(3) {'perturbing_action': 'I-rnai/knockdown'}", + "111, integrin {'perturbing_action': 'I-rnai/knockdown'}", + "112, or {'perturbing_action': 'I-rnai/knockdown'}", + "113, c-Src {'perturbing_action': 'I-rnai/knockdown'}", + "116, inhibited {'effect': 'B-negative'}", + "121, suppressed {'effect': 'B-negative'}", + "122, metastasis {'phenotype': 'B-metastasis'}", + "123, in {'context': 'B-in vivo'}", + "124, vivo, {'context': 'I-in vivo'}", + "128, did {'effect': 'B-no effect'}", + "129, not {'effect': 'I-no effect'}", + "130, affect {'effect': 'I-no effect'}", + "131, tumor {'context': 'B-transformed cells'}", + "132, cell {'context': 'I-transformed cells'}", + "133, migration {'phenotype': 'B-migration'}", + "135, invasion. {'phenotype': 'B-invasion'}" + ], + "LINK_DATA": [ + "49, enhanced ['l0', 'l1', 'l2', 'l3', 'l4']", + "51, tumor ['l0', 'l5', 'l6', 'l7']", + "52, growth ['l1', 'l5', 'l8', 'l9']", + "53, in ['l2', 'l6', 'l8', 'l10', 'l11']", + "54, vitro ['l3', 'l7', 'l9', 'l10', 'l12']", + "56, increased ['l4', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "57, lymph ['l13', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "58, node ['l14', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "59, metastases ['l15', 'l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "60, in ['l16', 'l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "61, vivo. ['l17', 'l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "83, tumor ['l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "84, cell ['l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "85, survival ['l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l48']", + "99, Pharmacological ['l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "100, blockade ['l49', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "101, of ['l50', 'l72', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "102, c-Src ['l51', 'l73', 'l90', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "103, kinase ['l52', 'l74', 'l91', 'l104', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "104, activity ['l53', 'l75', 'l92', 'l105', 'l115', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "106, decreased ['l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "107, expression ['l134', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170']", + "108, of ['l54', 'l76', 'l135', 'l153', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "109, endogenous ['l55', 'l136', 'l154', 'l171', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203']", + "110, alpha(v)beta(3) ['l56', 'l77', 'l93', 'l106', 'l116', 'l125', 'l137', 'l155', 'l172', 'l188', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218']", + "111, integrin ['l57', 'l78', 'l94', 'l107', 'l117', 'l126', 'l138', 'l156', 'l173', 'l189', 'l204', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232']", + "112, or ['l58', 'l79', 'l95', 'l108', 'l118', 'l127', 'l139', 'l157', 'l174', 'l190', 'l205', 'l219', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245']", + "113, c-Src ['l59', 'l80', 'l96', 'l109', 'l119', 'l128', 'l140', 'l158', 'l175', 'l191', 'l206', 'l220', 'l233', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257']", + "116, inhibited ['l60', 'l81', 'l97', 'l110', 'l120', 'l129', 'l141', 'l159', 'l176', 'l192', 'l207', 'l221', 'l234', 'l246', 'l258', 'l259', 'l260', 'l261']", + "121, suppressed ['l61', 'l82', 'l98', 'l111', 'l121', 'l130', 'l142', 'l160', 'l177', 'l193', 'l208', 'l222', 'l235', 'l247', 'l258', 'l262', 'l263', 'l264']", + "122, metastasis ['l62', 'l83', 'l99', 'l112', 'l122', 'l131', 'l143', 'l161', 'l178', 'l194', 'l209', 'l223', 'l236', 'l248', 'l259', 'l262', 'l265', 'l266']", + "123, in ['l63', 'l84', 'l100', 'l113', 'l123', 'l132', 'l144', 'l162', 'l179', 'l195', 'l210', 'l224', 'l237', 'l249', 'l260', 'l263', 'l265', 'l267']", + "124, vivo, ['l64', 'l85', 'l101', 'l114', 'l124', 'l133', 'l145', 'l163', 'l180', 'l196', 'l211', 'l225', 'l238', 'l250', 'l261', 'l264', 'l266', 'l267']", + "128, did ['l65', 'l86', 'l146', 'l164', 'l181', 'l197', 'l212', 'l226', 'l239', 'l251', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273']", + "129, not ['l66', 'l87', 'l147', 'l165', 'l182', 'l198', 'l213', 'l227', 'l240', 'l252', 'l268', 'l274', 'l275', 'l276', 'l277', 'l278']", + "130, affect ['l67', 'l88', 'l102', 'l148', 'l166', 'l183', 'l199', 'l214', 'l228', 'l241', 'l253', 'l269', 'l274', 'l279', 'l280', 'l281', 'l282']", + "131, tumor ['l68', 'l149', 'l167', 'l184', 'l200', 'l215', 'l229', 'l242', 'l254', 'l270', 'l275', 'l279', 'l283', 'l284', 'l285']", + "132, cell ['l69', 'l89', 'l103', 'l150', 'l168', 'l185', 'l201', 'l216', 'l230', 'l243', 'l255', 'l271', 'l276', 'l280', 'l283', 'l286', 'l287']", + "133, migration ['l70', 'l151', 'l169', 'l186', 'l202', 'l217', 'l231', 'l244', 'l256', 'l272', 'l277', 'l281', 'l284', 'l286', 'l288']", + "135, invasion. ['l71', 'l152', 'l170', 'l187', 'l203', 'l218', 'l232', 'l245', 'l257', 'l273', 'l278', 'l282', 'l285', 'l287', 'l288']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced", + "increased" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "lymph", + "node", + "metastases" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "survival" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "lymph", + "node", + "metastases", + "metastasis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo.", + "vivo," + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "lymph", + "node", + "metastases" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "survival" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "survival" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "c-Src", + "kinase", + "activity" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "c-Src", + "kinase", + "activity" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "c-Src", + "kinase", + "activity" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "affect" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "decreased" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "decreased" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "decreased" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "affect" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "decreased" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "endogenous", + "alpha(v)beta(3)", + "integrin", + "or", + "c-Src" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "endogenous", + "alpha(v)beta(3)", + "integrin", + "or", + "c-Src" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "endogenous", + "alpha(v)beta(3)", + "integrin", + "or", + "c-Src" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "endogenous", + "alpha(v)beta(3)", + "integrin", + "or", + "c-Src" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "affect" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "endogenous", + "alpha(v)beta(3)", + "integrin", + "or", + "c-Src" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "endogenous", + "alpha(v)beta(3)", + "integrin", + "or", + "c-Src" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "endogenous", + "alpha(v)beta(3)", + "integrin", + "or", + "c-Src" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "suppressed" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "suppressed" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "affect" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "affect" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "affect" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion." + ] + } + } + ] + }, + { + "PMID": "19718039", + "TEXT": "Cystic kidney disease represents a major cause of end-stage renal disease, yet the molecular mechanisms of pathogenesis remain largely unclear. Recent emphasis has been placed on a potential role for canonical Wnt signaling, but investigation of this pathway in adult renal homeostasis is lacking. Here we provide evidence of a previously unidentified canonical Wnt activity in adult mammalian kidney homeostasis, the loss of which leads to cystic kidney disease. Loss of the Jouberin (Jbn) protein in mouse leads to the cystic kidney disease nephronophthisis, owing to an unexpected decrease in endogenous Wnt activity. Jbn interacts with and facilitates beta-catenin nuclear accumulation, resulting in positive modulation of downstream transcription. Finally, we show that Jbn is required in vivo for a Wnt response to injury and renal tubule repair, the absence of which triggers cystogenesis.", + "TAG_DATA": [ + "69, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "70, of {'perturbing_action': 'I-gene loss-of-function'}", + "71, the {'perturbing_action': 'I-gene loss-of-function'}", + "72, Jouberin {'perturbing_action': 'I-gene loss-of-function'}", + "73, (Jbn) {'perturbing_action': 'I-gene loss-of-function'}", + "74, protein {'perturbing_action': 'I-gene loss-of-function'}", + "76, mouse {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "69, Loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "70, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "71, the ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "72, Jouberin ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "73, (Jbn) ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "74, protein ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "76, mouse ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Loss", + "of", + "the", + "Jouberin", + "(Jbn)", + "protein" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + } + ] + }, + { + "PMID": "19701206", + "TEXT": "Members of the NADPH oxidase (NOX) family of enzymes, which catalyze the reduction of O(2) to reactive oxygen species, have increased in number during eukaryotic evolution. Seven isoforms of the NOX gene family have been identified in mammals; however, specific roles of NOX enzymes in mammalian physiology and pathophysiology have not been fully elucidated. The best established physiological role of NOX enzymes is in host defense against pathogen invasion in diverse species, including plants. The prototypical member of this family, NOX-2 (gp91(phox)), is expressed in phagocytic cells and mediates microbicidal activities. Here we report a role for the NOX4 isoform in tissue repair functions of myofibroblasts and fibrogenesis. Transforming growth factor-beta1 (TGF-beta1) induces NOX-4 expression in lung mesenchymal cells via SMAD-3, a receptor-regulated protein that modulates gene transcription. NOX-4-dependent generation of hydrogen peroxide (H(2)O(2)) is required for TGF-beta1-induced myofibroblast differentiation, extracellular matrix (ECM) production and contractility. NOX-4 is upregulated in lungs of mice subjected to noninfectious injury and in cases of human idiopathic pulmonary fibrosis (IPF). Genetic or pharmacologic targeting of NOX-4 abrogates fibrogenesis in two murine models of lung injury. These studies support a function for NOX4 in tissue fibrogenesis and provide proof of concept for therapeutic targeting of NOX-4 in recalcitrant fibrotic disorders.", + "TAG_DATA": [ + "116, lung {'context': 'B-cells'}", + "117, mesenchymal {'context': 'I-cells'}", + "118, cells {'context': 'I-cells'}", + "138, myofibroblast {'context': 'B-cells'}", + "139, differentiation, {'phenotype': 'B-differentiation'}", + "152, mice {'context': 'B-organism'}", + "168, pharmacologic {'perturbing_action': 'B-pharmacological inhibition'}", + "169, targeting {'perturbing_action': 'I-pharmacological inhibition'}", + "170, of {'perturbing_action': 'I-pharmacological inhibition'}", + "171, NOX-4 {'perturbing_action': 'I-pharmacological inhibition'}", + "176, murine {'context': 'B-organism'}", + "177, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "116, lung ['l0', 'l1', 'l2', 'l3', 'l4']", + "117, mesenchymal ['l0', 'l5', 'l6', 'l7', 'l8', 'l9']", + "118, cells ['l1', 'l5', 'l10', 'l11', 'l12']", + "137, TGF-beta1-induced ['l6', 'l13', 'l14', 'l15']", + "138, myofibroblast ['l2', 'l7', 'l10', 'l13', 'l16', 'l17']", + "139, differentiation, ['l3', 'l8', 'l11', 'l14', 'l16', 'l18']", + "152, mice ['l4', 'l9', 'l12', 'l15', 'l17', 'l18']", + "168, pharmacologic ['l19', 'l20', 'l21', 'l22', 'l23']", + "169, targeting ['l19', 'l24', 'l25', 'l26', 'l27']", + "170, of ['l20', 'l24', 'l28', 'l29', 'l30']", + "171, NOX-4 ['l21', 'l25', 'l28', 'l31', 'l32']", + "176, murine ['l22', 'l26', 'l29', 'l31', 'l33']", + "177, models ['l23', 'l27', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "lung", + "mesenchymal", + "cells", + "myofibroblast" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "targeting", + "of", + "NOX-4" + ] + }, + "context": { + "val": "organism", + "words": [ + "murine", + "models" + ] + } + } + ] + }, + { + "PMID": "19668193", + "TEXT": "We have previously shown that a granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-15 (IL-15) 'fusokine' (GIFT15) exerts immune suppression via aberrant signaling through the IL-15 receptor on lymphomyeloid cells. We show here that ex vivo GIFT15 treatment of mouse splenocytes generates suppressive regulatory cells of B cell ontogeny (hereafter called GIFT15 B(reg) cells). Arising from CD19+ B cells, GIFT15 B(reg) cells express major histocompatibility complex class I (MHCI) and MHCII, surface IgM and IgD, and secrete IL-10, akin to previously described B10 and T2-MZP B(reg) cells, but lose expression of the transcription factor PAX5, coupled to upregulation of CD138 and reciprocal suppression of CD19. Mice with experimental autoimmune encephalomyelitis went into complete remission after intravenous infusion of GIFT15 B(reg) cells paralleled by suppressed neuroinflammation. The clinical effect was abolished when GIFT15 B(reg) cells were derived from mmicroMT (lacking B cells), MHCII-knockout, signal transducer and activator of transcription-6 (STAT-6)-knockout, IL-10-knockout or allogeneic splenocytes, consistent with a pivotal role for MHCII and IL-10 by sygeneic B cells for the observed therapeutic effect. We propose that autologous GIFT15 B(reg) cells may serve as a new treatment for autoimmune ailments.", + "TAG_DATA": [ + "37, mouse {'context': 'B-cells'}", + "38, splenocytes {'context': 'I-cells'}", + "103, Mice {'context': 'B-organism'}", + "117, B(reg) {'context': 'I-cells'}", + "118, cells {'context': 'I-cells'}", + "129, GIFT15 {'context': 'B-cells'}", + "130, B(reg) {'context': 'I-cells'}", + "131, cells {'context': 'I-cells'}", + "137, B {'context': 'B-cells'}", + "139, MHCII-knockout, {'perturbing_action': 'B-gene loss-of-function'}", + "146, (STAT-6)-knockout, {'perturbing_action': 'I-gene loss-of-function'}", + "147, IL-10-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "149, allogeneic {'context': 'B-cells'}", + "150, splenocytes, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "37, mouse ['l0']", + "38, splenocytes ['l0']", + "103, Mice ['l1', 'l2']", + "117, B(reg) ['l1', 'l3']", + "118, cells ['l2', 'l3']", + "129, GIFT15 ['l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "130, B(reg) ['l4', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "131, cells ['l5', 'l15', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "135, mmicroMT ['l6', 'l16', 'l24', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "136, (lacking ['l7', 'l17', 'l25', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "137, B ['l8', 'l18', 'l26', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "138, cells), ['l9', 'l19', 'l27', 'l35', 'l41', 'l46', 'l51', 'l52']", + "139, MHCII-knockout, ['l10', 'l20', 'l28', 'l36', 'l42', 'l47', 'l51', 'l53', 'l54', 'l55', 'l56']", + "146, (STAT-6)-knockout, ['l11', 'l21', 'l29', 'l37', 'l43', 'l48', 'l52', 'l53', 'l57', 'l58', 'l59']", + "147, IL-10-knockout ['l12', 'l22', 'l30', 'l38', 'l44', 'l49', 'l54', 'l57', 'l60', 'l61']", + "149, allogeneic ['l13', 'l31', 'l55', 'l58', 'l60', 'l62']", + "150, splenocytes, ['l14', 'l23', 'l32', 'l39', 'l45', 'l50', 'l56', 'l59', 'l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "GIFT15", + "B(reg)", + "cells", + "B", + "allogeneic", + "splenocytes," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MHCII-knockout,", + "(STAT-6)-knockout,", + "IL-10-knockout" + ] + } + } + ] + }, + { + "PMID": "19561616", + "TEXT": "Previous proteomic and transcriptional analyses of multiple sclerosis lesions revealed modulation of the renin-angiotensin and the opposing kallikrein-kinin pathways. Here we identify kinin receptor B1 (Bdkrb1) as a specific modulator of immune cell entry into the central nervous system (CNS). We demonstrate that the Bdkrb1 agonist R838 (Sar-[D-Phe]des-Arg(9)-bradykinin) markedly decreases the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in SJL mice, whereas the Bdkrb1 antagonist R715 (Ac-Lys-[D-betaNal(7), Ile(8)]des-Arg(9)-bradykinin) resulted in earlier onset and greater severity of the disease. Bdkrb1-deficient (Bdkrb1(-/-)) C57BL/6 mice immunized with a myelin oligodendrocyte glycoprotein fragment, MOG(35-55), showed more severe disease with enhanced CNS-immune cell infiltration. The same held true for mixed bone marrow-chimeric mice reconstituted with Bdkrb1(-/-) T lymphocytes, which showed enhanced T helper type 17 (T(H)17) cell invasion into the CNS. Pharmacological modulation of Bdkrb1 revealed that in vitro migration of human T(H)17 lymphocytes across blood-brain barrier endothelium is regulated by this receptor. Taken together, these results suggest that the kallikrein-kinin system is involved in the regulation of CNS inflammation, limiting encephalitogenic T lymphocyte infiltration into the CNS, and provide evidence that Bdkrb1 could be a new target for the treatment of chronic inflammatory diseases such as multiple sclerosis.", + "TAG_DATA": [ + "44, Bdkrb1 {'perturbing_action': 'B-pharmacological augmentation'}", + "45, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "46, R838 {'perturbing_action': 'I-pharmacological augmentation'}", + "59, SJL {'context': 'B-organism'}", + "60, mice, {'context': 'I-organism'}", + "63, Bdkrb1 {'perturbing_action': 'B-pharmacological inhibition'}", + "64, antagonist {'perturbing_action': 'I-pharmacological inhibition'}", + "65, R715 {'perturbing_action': 'I-pharmacological augmentation'}", + "78, Bdkrb1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "79, (Bdkrb1(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "80, C57BL/6 {'context': 'B-organism'}", + "81, mice {'context': 'I-organism'}", + "104, mixed {'context': 'B-organism'}", + "105, bone {'context': 'I-organism'}", + "106, marrow-chimeric {'context': 'I-organism'}", + "107, mice {'context': 'I-organism'}", + "110, Bdkrb1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "111, T {'context': 'B-cells'}", + "112, lymphocytes, {'context': 'I-cells'}", + "116, T {'context': 'B-cells'}", + "117, helper {'context': 'I-cells'}", + "118, type {'context': 'I-cells'}", + "119, 17 {'context': 'I-cells'}", + "120, (T(H)17) {'context': 'I-cells'}", + "121, cell {'context': 'I-cells'}", + "132, in {'context': 'B-in vitro'}", + "133, vitro {'context': 'I-in vitro'}", + "136, human {'context': 'B-cells'}", + "137, T(H)17 {'context': 'I-cells'}", + "138, lymphocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "44, Bdkrb1 ['l0', 'l1', 'l2', 'l3']", + "45, agonist ['l0', 'l4', 'l5', 'l6']", + "46, R838 ['l1', 'l4', 'l7', 'l8']", + "59, SJL ['l2', 'l5', 'l7', 'l9']", + "60, mice, ['l3', 'l6', 'l8', 'l9']", + "63, Bdkrb1 ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "64, antagonist ['l10', 'l16', 'l17', 'l18', 'l19']", + "65, R715 ['l11', 'l16', 'l20', 'l21', 'l22']", + "78, Bdkrb1-deficient ['l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "79, (Bdkrb1(-/-)) ['l13', 'l17', 'l20', 'l23', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "80, C57BL/6 ['l14', 'l18', 'l21', 'l24', 'l39', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "81, mice ['l15', 'l19', 'l22', 'l25', 'l40', 'l54', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "104, mixed ['l26', 'l41', 'l55', 'l67', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "105, bone ['l27', 'l42', 'l56', 'l68', 'l79', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "106, marrow-chimeric ['l28', 'l43', 'l57', 'l69', 'l80', 'l91', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "107, mice ['l29', 'l44', 'l58', 'l70', 'l81', 'l92', 'l102', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "110, Bdkrb1(-/-) ['l30', 'l45', 'l82', 'l93', 'l103', 'l112', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "111, T ['l31', 'l46', 'l59', 'l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "112, lymphocytes, ['l32', 'l47', 'l60', 'l72', 'l84', 'l95', 'l105', 'l114', 'l122', 'l129', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141']", + "116, T ['l33', 'l48', 'l61', 'l73', 'l85', 'l96', 'l106', 'l115', 'l123', 'l130', 'l136', 'l142', 'l143', 'l144', 'l145', 'l146']", + "117, helper ['l34', 'l49', 'l62', 'l74', 'l86', 'l97', 'l107', 'l116', 'l124', 'l131', 'l137', 'l142', 'l147', 'l148', 'l149', 'l150']", + "118, type ['l35', 'l50', 'l63', 'l75', 'l87', 'l98', 'l108', 'l117', 'l125', 'l132', 'l138', 'l143', 'l147', 'l151', 'l152', 'l153']", + "119, 17 ['l36', 'l51', 'l64', 'l76', 'l88', 'l99', 'l109', 'l118', 'l126', 'l133', 'l139', 'l144', 'l148', 'l151', 'l154', 'l155']", + "120, (T(H)17) ['l37', 'l52', 'l65', 'l77', 'l89', 'l100', 'l110', 'l119', 'l127', 'l134', 'l140', 'l145', 'l149', 'l152', 'l154', 'l156']", + "121, cell ['l38', 'l53', 'l66', 'l78', 'l90', 'l101', 'l111', 'l120', 'l128', 'l135', 'l141', 'l146', 'l150', 'l153', 'l155', 'l156']", + "132, in ['l157', 'l158', 'l159', 'l160']", + "133, vitro ['l157', 'l161', 'l162', 'l163']", + "136, human ['l158', 'l161', 'l164', 'l165']", + "137, T(H)17 ['l159', 'l162', 'l164', 'l166']", + "138, lymphocytes ['l160', 'l163', 'l165', 'l166']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Bdkrb1", + "agonist", + "R838", + "R715" + ] + }, + "context": { + "val": "organism", + "words": [ + "SJL", + "mice,", + "C57BL/6", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Bdkrb1", + "antagonist" + ] + }, + "context": { + "val": "organism", + "words": [ + "C57BL/6", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bdkrb1-deficient", + "(Bdkrb1(-/-))", + "Bdkrb1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "C57BL/6", + "mice", + "mixed", + "bone", + "marrow-chimeric" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bdkrb1-deficient", + "(Bdkrb1(-/-))", + "Bdkrb1(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "lymphocytes,", + "helper", + "type", + "17", + "(T(H)17)", + "cell" + ] + } + } + ] + }, + { + "PMID": "19483694", + "TEXT": "We describe here the paradoxical development of spontaneous experimental autoimmune encephalomyelitis (EAE) in transgenic mice expressing a myelin oligodendrocyte glycoprotein (MOG)-specific T cell antigen receptor (TCR) in the absence of MOG. We report that in Mog-deficient mice (Mog-/-), the autoimmune response by transgenic T cells is redirected to a neuronal cytoskeletal self antigen, neurofilament-M (NF-M). Although components of radically different protein classes, the cross-reacting major histocompatibility complex I-Ab-restricted epitope sequences of MOG35-55 and NF-M18-30 share essential TCR contact positions. This pattern of cross-reaction is not specific to the transgenic TCR but is also commonly seen in MOG35-55-I-Ab-reactive T cells. We propose that in the C57BL/6 mouse, MOG and NF-M response components add up to overcome the general resistance of this strain to experimental induction of autoimmunity. Similar cumulative responses against more than one autoantigen may have a role in spontaneously developing human autoimmune diseases.", + "TAG_DATA": [ + "35, Mog-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "36, mice {'context': 'B-organism'}", + "44, cells {'context': 'I-cells'}", + "98, cells. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "35, Mog-deficient ['l0', 'l1']", + "36, mice ['l0', 'l2']", + "44, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mog-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mog-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "19430489", + "TEXT": "Inflammation and oxidative stress are pathogenic mediators of many diseases, but molecules that could be therapeutic targets remain elusive. Inflammation and matrix degradation in the vasculature are crucial for abdominal aortic aneurysm (AAA) formation. Cyclophilin A (CypA, encoded by Ppia) is highly expressed in vascular smooth muscle cells (VSMCs), is secreted in response to reactive oxygen species (ROS) and promotes inflammation. Using the angiotensin II (AngII)-induced AAA model in Apoe-/- mice, we show that Apoe-/-Ppia-/- mice are completely protected from AngII-induced AAA formation, in contrast to Apoe-/-Ppia+/+ mice. Apoe-/-Ppia-/- mice show decreased inflammatory cytokine expression, elastic lamina degradation and aortic expansion. These features were not altered by reconstitution of bone marrow cells from Ppia+/+ mice. Mechanistic studies showed that VSMC-derived intracellular and extracellular CypA are required for ROS generation and matrix metalloproteinase-2 activation. These data define a previously undescribed role for CypA in AAA formation and suggest CypA as a new target for treating cardiovascular disease.", + "TAG_DATA": [ + "69, Apoe-/- {'perturbing_action': 'B-gene loss-of-function'}", + "70, mice, {'context': 'B-organism'}", + "74, Apoe-/-Ppia-/- {'perturbing_action': 'B-gene loss-of-function'}", + "75, mice {'context': 'B-organism'}", + "86, Apoe-/-Ppia+/+ {'perturbing_action': 'B-gene loss-of-function'}", + "87, mice. {'context': 'B-organism'}", + "88, Apoe-/-Ppia-/- {'perturbing_action': 'B-gene loss-of-function'}", + "89, mice {'context': 'B-organism'}", + "109, bone {'context': 'B-cells'}", + "110, marrow {'context': 'I-cells'}", + "111, cells {'context': 'I-cells'}", + "114, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "69, Apoe-/- ['l0']", + "70, mice, ['l0']", + "74, Apoe-/-Ppia-/- ['l1']", + "75, mice ['l1']", + "86, Apoe-/-Ppia+/+ ['l2']", + "87, mice. ['l2']", + "88, Apoe-/-Ppia-/- ['l3', 'l4', 'l5']", + "89, mice ['l3']", + "109, bone ['l6', 'l7', 'l8']", + "110, marrow ['l4', 'l6', 'l9', 'l10']", + "111, cells ['l5', 'l7', 'l9', 'l11']", + "114, mice. ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apoe-/-", + "Apoe-/-Ppia-/-", + "Apoe-/-Ppia+/+" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apoe-/-Ppia-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "marrow", + "cells" + ] + } + } + ] + }, + { + "PMID": "19412173", + "TEXT": "In salt-sensitive hypertension, the accumulation of Na(+) in tissue has been presumed to be accompanied by a commensurate retention of water to maintain the isotonicity of body fluids. We show here that a high-salt diet (HSD) in rats leads to interstitial hypertonic Na(+) accumulation in skin, resulting in increased density and hyperplasia of the lymphcapillary network. The mechanisms underlying these effects on lymphatics involve activation of tonicity-responsive enhancer binding protein (TonEBP) in mononuclear phagocyte system (MPS) cells infiltrating the interstitium of the skin. TonEBP binds the promoter of the gene encoding vascular endothelial growth factor-C (VEGF-C, encoded by Vegfc) and causes VEGF-C secretion by macrophages. MPS cell depletion or VEGF-C trapping by soluble VEGF receptor-3 blocks VEGF-C signaling, augments interstitial hypertonic volume retention, decreases endothelial nitric oxide synthase expression and elevates blood pressure in response to HSD. Our data show that TonEBP-VEGF-C signaling in MPS cells is a major determinant of extracellular volume and blood pressure homeostasis and identify VEGFC as an osmosensitive, hypertonicity-driven gene intimately involved in salt-induced hypertension.", + "TAG_DATA": [ + "37, rats {'context': 'B-organism'}", + "45, skin, {'context': 'B-tissue/organ'}", + "104, macrophages. {'context': 'B-cells'}", + "105, MPS {'context': 'B-cells'}", + "106, cell {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "107, depletion {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "37, rats ['l0', 'l1']", + "45, skin, ['l0']", + "104, macrophages. ['l1']", + "105, MPS ['l2', 'l3', 'l4']", + "106, cell ['l2', 'l5', 'l6']", + "107, depletion ['l3', 'l5', 'l7']", + "114, receptor-3 ['l4', 'l6', 'l7']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "MPS", + "cell" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cell", + "depletion" + ] + } + } + ] + }, + { + "PMID": "19398967", + "TEXT": "The in vitro analysis of intestinal epithelium has been hampered by a lack of suitable culture systems. Here we describe robust long-term methodology for small and large intestinal culture, incorporating an air-liquid interface and underlying stromal elements. These cultures showed prolonged intestinal epithelial expansion as sphere-like organoids with proliferation and multilineage differentiation. The Wnt growth factor family positively regulates proliferation of the intestinal epithelium in vivo. Accordingly, culture growth was inhibited by the Wnt antagonist Dickkopf-1 (Dkk1) and markedly stimulated by a fusion protein between the Wnt agonist R-spondin-1 and immunoglobulin Fc (RSpo1-Fc). Furthermore, treatment with the gamma-secretase inhibitor dibenzazepine and neurogenin-3 overexpression induced goblet cell and enteroendocrine cell differentiation, respectively, consistent with endogenous Notch signaling and lineage plasticity. Epithelial cells derived from both leucine-rich repeat-containing G protein-coupled receptor-5-positive (Lgr5(+)) and B lymphoma moloney murine leukemia virus insertion region homolog-1-positive (Bmi1(+)) lineages, representing putative intestinal stem cell (ISC) populations, were present in vitro and were expanded by treatment with RSpo1-Fc; this increased number of Lgr5(+) cells upon RSpo1-Fc treatment was subsequently confirmed in vivo. Our results indicate successful long-term intestinal culture within a microenvironment accurately recapitulating the Wnt- and Notch-dependent ISC niche.", + "TAG_DATA": [ + "64, in {'context': 'B-in vivo'}", + "65, vivo. {'context': 'I-in vivo'}", + "67, culture {'phenotype': 'B-cell growth'}", + "101, neurogenin-3 {'perturbing_action': 'B-gene gain-of-function'}", + "102, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "103, induced {'effect': 'B-positive'}", + "104, goblet {'context': 'B-cells'}", + "105, cell {'context': 'I-cells'}", + "107, enteroendocrine {'context': 'B-cells'}", + "108, cell {'context': 'I-cells'}", + "109, differentiation, {'phenotype': 'B-differentiation'}", + "119, Epithelial {'context': 'B-cells'}", + "120, cells {'context': 'I-cells'}", + "151, in {'context': 'B-in vitro'}", + "152, vitro {'context': 'I-in vitro'}", + "164, Lgr5(+) {'context': 'B-cells'}", + "165, cells {'context': 'I-cells'}", + "172, in {'context': 'B-in vivo'}", + "173, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "64, in ['l0']", + "65, vivo. ['l0']", + "101, neurogenin-3 ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "102, overexpression ['l1', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "103, induced ['l2', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26']", + "104, goblet ['l3', 'l13', 'l22', 'l27', 'l28', 'l29', 'l30', 'l31']", + "105, cell ['l4', 'l14', 'l23', 'l27', 'l32', 'l33', 'l34']", + "107, enteroendocrine ['l5', 'l15', 'l24', 'l28', 'l32', 'l35', 'l36', 'l37']", + "108, cell ['l6', 'l16', 'l25', 'l29', 'l33', 'l35', 'l38']", + "109, differentiation, ['l7', 'l17', 'l26', 'l30', 'l34', 'l36', 'l38']", + "119, Epithelial ['l8', 'l18', 'l39', 'l40', 'l41']", + "120, cells ['l9', 'l19', 'l31', 'l37', 'l39', 'l42', 'l43']", + "151, in ['l10', 'l20', 'l40', 'l42', 'l44']", + "152, vitro ['l11', 'l21', 'l41', 'l43', 'l44']", + "164, Lgr5(+) ['l45', 'l46', 'l47']", + "165, cells ['l45', 'l48', 'l49']", + "172, in ['l46', 'l48', 'l50']", + "173, vivo. ['l47', 'l49', 'l50']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "neurogenin-3", + "overexpression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "neurogenin-3", + "overexpression" + ] + }, + "context": { + "val": "cells", + "words": [ + "goblet", + "cell", + "enteroendocrine", + "Epithelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "neurogenin-3", + "overexpression" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "neurogenin-3", + "overexpression" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "goblet", + "cell", + "enteroendocrine" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "goblet", + "cell", + "enteroendocrine" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + } + ] + }, + { + "PMID": "19305413", + "TEXT": "Inhibitors of alpha(v)beta(3) and alpha(v)beta(5) integrin have entered clinical trials as antiangiogenic agents for cancer treatment but generally have been unsuccessful. Here we present in vivo evidence that low (nanomolar) concentrations of RGD-mimetic alpha(v)beta(3) and alpha(v)beta(5) inhibitors can paradoxically stimulate tumor growth and tumor angiogenesis. We show that low concentrations of these inhibitors promote VEGF-mediated angiogenesis by altering alpha(v)beta(3) integrin and vascular endothelial growth factor receptor-2 trafficking, thereby promoting endothelial cell migration to VEGF. The proangiogenic effects of low concentrations of RGD-mimetic integrin inhibitors could compromise their efficacy as anticancer agents and have major implications for the use of RGD-mimetic compounds in humans.", + "TAG_DATA": [ + "24, in {'context': 'B-in vivo'}", + "25, vivo {'context': 'I-in vivo'}", + "32, RGD-mimetic {'perturbing_action': 'B-pharmacological inhibition'}", + "33, alpha(v)beta(3) {'perturbing_action': 'I-pharmacological inhibition'}", + "34, and {'perturbing_action': 'I-pharmacological inhibition'}", + "35, alpha(v)beta(5) {'perturbing_action': 'I-pharmacological inhibition'}", + "36, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "39, stimulate {'effect': 'B-positive'}", + "40, tumor {'phenotype': 'B-tumour growth'}", + "41, growth {'phenotype': 'I-tumour growth'}", + "43, tumor {'context': 'B-neoplasm'}", + "68, promoting {'effect': 'B-positive'}", + "69, endothelial {'context': 'B-cells'}", + "70, cell {'context': 'I-cells'}", + "71, migration {'phenotype': 'B-migration'}" + ], + "LINK_DATA": [ + "24, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "25, vivo ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "32, RGD-mimetic ['l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "33, alpha(v)beta(3) ['l11', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "34, and ['l12', 'l23', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "35, alpha(v)beta(5) ['l13', 'l24', 'l34', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "36, inhibitors ['l1', 'l6', 'l14', 'l25', 'l35', 'l44', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "39, stimulate ['l2', 'l7', 'l15', 'l26', 'l36', 'l45', 'l53', 'l61', 'l62', 'l63']", + "40, tumor ['l3', 'l8', 'l16', 'l27', 'l37', 'l46', 'l54', 'l61', 'l64', 'l65']", + "41, growth ['l4', 'l9', 'l17', 'l28', 'l38', 'l47', 'l55', 'l62', 'l64', 'l66']", + "43, tumor ['l5', 'l10', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l65', 'l66']", + "68, promoting ['l19', 'l30', 'l40', 'l49', 'l57', 'l67', 'l68', 'l69']", + "69, endothelial ['l20', 'l31', 'l41', 'l50', 'l58', 'l67', 'l70', 'l71']", + "70, cell ['l21', 'l32', 'l42', 'l51', 'l59', 'l68', 'l70', 'l72']", + "71, migration ['l22', 'l33', 'l43', 'l52', 'l60', 'l69', 'l71', 'l72']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulate" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "RGD-mimetic", + "alpha(v)beta(3)", + "and", + "alpha(v)beta(5)", + "inhibitors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulate", + "promoting" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "RGD-mimetic", + "alpha(v)beta(3)", + "and", + "alpha(v)beta(5)", + "inhibitors" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "RGD-mimetic", + "alpha(v)beta(3)", + "and", + "alpha(v)beta(5)", + "inhibitors" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "RGD-mimetic", + "alpha(v)beta(3)", + "and", + "alpha(v)beta(5)", + "inhibitors" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "RGD-mimetic", + "alpha(v)beta(3)", + "and", + "alpha(v)beta(5)", + "inhibitors" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulate" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulate" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + } + ] + }, + { + "PMID": "19252502", + "TEXT": "Osteoclasts are acid-secreting polykaryons that have high energy demands and contain abundant mitochondria. How mitochondrial biogenesis is integrated with osteoclast differentiation is unknown. We found that the transcription of Ppargc1b, which encodes peroxisome proliferator-activated receptor-gamma coactivator 1beta (PGC-1beta), was induced during osteoclast differentiation by cAMP response element-binding protein (CREB) as a result of reactive oxygen species. Knockdown of Ppargc1b in vitro inhibited osteoclast differentiation and mitochondria biogenesis, whereas deletion of the Ppargc1b gene in mice resulted in increased bone mass due to impaired osteoclast function. We also observed defects in PGC-1beta-deficient osteoblasts. Owing to the heightened iron demand in osteoclast development, transferrin receptor 1 (TfR1) expression was induced post-transcriptionally via iron regulatory protein 2. TfR1-mediated iron uptake promoted osteoclast differentiation and bone-resorbing activity, associated with the induction of mitochondrial respiration, production of reactive oxygen species and accelerated Ppargc1b transcription. Iron chelation inhibited osteoclastic bone resorption and protected against bone loss following estrogen deficiency resulting from ovariectomy. These data establish mitochondrial biogenesis orchestrated by PGC-1beta, coupled with iron uptake through TfR1 and iron supply to mitochondrial respiratory proteins, as a fundamental pathway linked to osteoclast activation and bone metabolism.", + "TAG_DATA": [ + "56, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "57, of {'perturbing_action': 'I-rnai/knockdown'}", + "58, Ppargc1b {'perturbing_action': 'I-rnai/knockdown'}", + "59, in {'context': 'B-in vitro'}", + "60, vitro {'context': 'I-in vitro'}", + "61, inhibited {'effect': 'B-negative'}", + "62, osteoclast {'context': 'B-cells'}", + "63, differentiation {'phenotype': 'B-differentiation'}", + "68, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "69, of {'perturbing_action': 'I-gene loss-of-function'}", + "70, the {'perturbing_action': 'I-gene loss-of-function'}", + "71, Ppargc1b {'perturbing_action': 'I-gene loss-of-function'}", + "72, gene {'perturbing_action': 'I-gene loss-of-function'}", + "74, mice {'context': 'B-organism'}", + "90, PGC-1beta-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "91, osteoblasts. {'context': 'B-cells'}", + "117, promoted {'effect': 'B-positive'}", + "118, osteoclast {'context': 'B-cells'}", + "119, differentiation {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "56, Knockdown ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "57, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "58, Ppargc1b ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "59, in ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27']", + "60, vitro ['l3', 'l11', 'l18', 'l24', 'l28', 'l29', 'l30']", + "61, inhibited ['l4', 'l12', 'l19', 'l25', 'l28', 'l31', 'l32']", + "62, osteoclast ['l5', 'l13', 'l20', 'l26', 'l29', 'l31', 'l33']", + "63, differentiation ['l6', 'l14', 'l21', 'l27', 'l30', 'l32', 'l33']", + "68, deletion ['l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "69, of ['l34', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "70, the ['l35', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "71, Ppargc1b ['l36', 'l44', 'l51', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "72, gene ['l37', 'l45', 'l52', 'l58', 'l64', 'l65', 'l66', 'l67']", + "74, mice ['l7', 'l15', 'l22', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l69']", + "90, PGC-1beta-deficient ['l70', 'l71', 'l72', 'l73']", + "91, osteoblasts. ['l39', 'l47', 'l54', 'l60', 'l70', 'l74', 'l75', 'l76']", + "117, promoted ['l40', 'l48', 'l55', 'l61', 'l65', 'l68', 'l71', 'l74', 'l77', 'l78']", + "118, osteoclast ['l41', 'l49', 'l56', 'l62', 'l66', 'l72', 'l75', 'l77', 'l79']", + "119, differentiation ['l8', 'l16', 'l23', 'l42', 'l50', 'l57', 'l63', 'l67', 'l69', 'l73', 'l76', 'l78', 'l79']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "Ppargc1b" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "Ppargc1b" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "Ppargc1b" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "Ppargc1b" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "Ppargc1b" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoclast", + "osteoblasts." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "Ppargc1b", + "gene" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "Ppargc1b", + "gene", + "PGC-1beta-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoblasts.", + "osteoclast" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "Ppargc1b", + "gene", + "PGC-1beta-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "Ppargc1b", + "gene", + "PGC-1beta-deficient" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoblasts.", + "osteoclast" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "19198615", + "TEXT": "Profound neuronal dysfunction in the entorhinal cortex contributes to early loss of short-term memory in Alzheimer's disease. Here we show broad neuroprotective effects of entorhinal brain-derived neurotrophic factor (BDNF) administration in several animal models of Alzheimer's disease, with extension of therapeutic benefits into the degenerating hippocampus. In amyloid-transgenic mice, BDNF gene delivery, when administered after disease onset, reverses synapse loss, partially normalizes aberrant gene expression, improves cell signaling and restores learning and memory. These outcomes occur independently of effects on amyloid plaque load. In aged rats, BDNF infusion reverses cognitive decline, improves age-related perturbations in gene expression and restores cell signaling. In adult rats and primates, BDNF prevents lesion-induced death of entorhinal cortical neurons. In aged primates, BDNF reverses neuronal atrophy and ameliorates age-related cognitive impairment. Collectively, these findings indicate that BDNF exerts substantial protective effects on crucial neuronal circuitry involved in Alzheimer's disease, acting through amyloid-independent mechanisms. BDNF therapeutic delivery merits exploration as a potential therapy for Alzheimer's disease.", + "TAG_DATA": [ + "47, amyloid-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "48, mice, {'context': 'B-organism'}", + "50, gene {'perturbing_action': 'I-gene gain-of-function'}", + "51, delivery, {'perturbing_action': 'I-gene gain-of-function'}", + "84, aged {'context': 'B-organism'}", + "85, rats, {'context': 'I-organism'}", + "102, adult {'context': 'B-organism'}", + "103, rats {'context': 'I-organism'}", + "105, primates, {'context': 'I-organism'}", + "111, entorhinal {'context': 'B-cells'}", + "112, cortical {'context': 'I-cells'}", + "113, neurons. {'context': 'I-cells'}", + "115, aged {'context': 'B-organism'}", + "116, primates, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "47, amyloid-transgenic ['l0', 'l1', 'l2']", + "48, mice, ['l0', 'l3', 'l4']", + "50, gene ['l1', 'l3', 'l5']", + "51, delivery, ['l2', 'l4', 'l5']", + "84, aged ['l6', 'l7']", + "85, rats, ['l6']", + "102, adult ['l8', 'l9', 'l10', 'l11', 'l12']", + "103, rats ['l8', 'l13', 'l14', 'l15', 'l16']", + "105, primates, ['l9', 'l13', 'l17', 'l18', 'l19']", + "111, entorhinal ['l10', 'l14', 'l17', 'l20', 'l21']", + "112, cortical ['l11', 'l15', 'l18', 'l20', 'l22']", + "113, neurons. ['l7', 'l12', 'l16', 'l19', 'l21', 'l22']", + "115, aged ['l23']", + "116, primates, ['l23']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "amyloid-transgenic", + "gene", + "delivery," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "19151728", + "TEXT": "Cerebral cavernous malformation (CCM) is a common vascular dysplasia that affects both systemic and central nervous system blood vessels. Loss of function mutations in the CCM2 gene cause CCM. Here we show that targeted disruption of Ccm2 in mice results in failed lumen formation and early embryonic death through an endothelial cell autonomous mechanism. We show that CCM2 regulates endothelial cytoskeletal architecture, cell-to-cell interactions and lumen formation. Heterozygosity at Ccm2, a genotype equivalent to that in human CCM, results in impaired endothelial barrier function. On the basis of our biochemical studies indicating that loss of CCM2 results in activation of RHOA GTPase, we rescued the cellular phenotype and barrier function in heterozygous mice with simvastatin, a drug known to inhibit Rho GTPases. These data offer the prospect for pharmacological treatment of a human vascular dysplasia with a widely available and safe drug.", + "TAG_DATA": [ + "33, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "34, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "35, of {'perturbing_action': 'I-gene loss-of-function'}", + "36, Ccm2 {'perturbing_action': 'I-gene loss-of-function'}", + "38, mice {'context': 'B-organism'}", + "47, death {'phenotype': 'I-necrosis'}", + "67, Heterozygosity {'perturbing_action': 'B-other'}", + "68, at {'perturbing_action': 'I-other'}", + "69, Ccm2, {'perturbing_action': 'I-other'}", + "93, loss {'perturbing_action': 'B-gene loss-of-function'}", + "94, of {'perturbing_action': 'I-gene loss-of-function'}", + "95, CCM2 {'perturbing_action': 'I-gene loss-of-function'}", + "111, heterozygous {'perturbing_action': 'B-other'}", + "112, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "33, targeted ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "34, disruption ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "35, of ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "36, Ccm2 ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "38, mice ['l3', 'l8', 'l12', 'l15', 'l18']", + "46, embryonic ['l4', 'l9', 'l13', 'l16', 'l19']", + "47, death ['l5', 'l10', 'l14', 'l17', 'l18', 'l19']", + "67, Heterozygosity ['l20', 'l21']", + "68, at ['l20', 'l22']", + "69, Ccm2, ['l21', 'l22']", + "93, loss ['l23', 'l24']", + "94, of ['l23', 'l25']", + "95, CCM2 ['l24', 'l25']", + "111, heterozygous ['l26']", + "112, mice ['l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "disruption", + "of", + "Ccm2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "disruption", + "of", + "Ccm2" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "death" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "death" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "19151727", + "TEXT": "Cerebral cavernous malformations (CCMs) are human vascular malformations caused by mutations in three genes of unknown function: KRIT1, CCM2 and PDCD10. Here we show that the heart of glass (HEG1) receptor, which in zebrafish has been linked to ccm gene function, is selectively expressed in endothelial cells. Heg1(-/-) mice showed defective integrity of the heart, blood vessels and lymphatic vessels. Heg1(-/-); Ccm2(lacZ/+) and Ccm2(lacZ/lacZ) mice had more severe cardiovascular defects and died early in development owing to a failure of nascent endothelial cells to associate into patent vessels. This endothelial cell phenotype was shared by zebrafish embryos deficient in heg, krit1 or ccm2 and reproduced in CCM2-deficient human endothelial cells in vitro. Defects in the hearts of zebrafish lacking heg or ccm2, in the aortas of early mouse embryos lacking CCM2 and in the lymphatic vessels of neonatal mice lacking HEG1 were associated with abnormal endothelial cell junctions like those observed in human CCMs. Biochemical and cellular imaging analyses identified a cell-autonomous pathway in which the HEG1 receptor couples to KRIT1 at these cell junctions. This study identifies HEG1-CCM protein signaling as a crucial regulator of heart and vessel formation and integrity.", + "TAG_DATA": [ + "47, Heg1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "48, mice {'context': 'B-organism'}", + "60, Heg1(-/-); {'perturbing_action': 'B-gene loss-of-function'}", + "61, Ccm2(lacZ/+) {'perturbing_action': 'B-gene loss-of-function'}", + "62, and {'perturbing_action': 'I-gene loss-of-function'}", + "63, Ccm2(lacZ/lacZ) {'perturbing_action': 'B-gene loss-of-function'}", + "64, mice {'context': 'B-organism'}", + "81, endothelial {'context': 'B-cells'}", + "82, cells {'context': 'I-cells'}", + "95, zebrafish {'context': 'B-organism'}", + "96, embryos {'context': 'I-organism'}", + "97, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "98, in {'perturbing_action': 'I-gene loss-of-function'}", + "99, heg, {'perturbing_action': 'I-gene loss-of-function'}", + "100, krit1 {'perturbing_action': 'I-gene loss-of-function'}", + "101, or {'perturbing_action': 'I-gene loss-of-function'}", + "102, ccm2 {'perturbing_action': 'I-gene loss-of-function'}", + "106, CCM2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "107, human {'context': 'B-cells'}", + "108, endothelial {'context': 'I-cells'}", + "109, cells {'context': 'I-cells'}", + "110, in {'context': 'B-in vitro'}", + "111, vitro. {'context': 'I-in vitro'}", + "115, hearts {'context': 'B-tissue/organ'}", + "117, zebrafish {'context': 'B-organism'}", + "118, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "119, heg {'perturbing_action': 'I-gene loss-of-function'}", + "120, or {'perturbing_action': 'I-gene loss-of-function'}", + "121, ccm2, {'perturbing_action': 'I-gene loss-of-function'}", + "124, aortas {'context': 'B-tissue/organ'}", + "126, early {'context': 'B-organism'}", + "127, mouse {'context': 'I-organism'}", + "128, embryos {'context': 'I-organism'}", + "129, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "130, CCM2 {'perturbing_action': 'I-gene loss-of-function'}", + "134, lymphatic {'context': 'B-tissue/organ'}", + "135, vessels {'context': 'I-tissue/organ'}", + "137, neonatal {'context': 'B-organism'}", + "138, mice {'context': 'I-organism'}", + "139, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "140, HEG1 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "47, Heg1(-/-) ['l0']", + "48, mice ['l0']", + "60, Heg1(-/-); ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "61, Ccm2(lacZ/+) ['l1', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "62, and ['l2', 'l20', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "63, Ccm2(lacZ/lacZ) ['l3', 'l21', 'l38', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "64, mice ['l4', 'l22', 'l39', 'l55', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "81, endothelial ['l5', 'l23', 'l40', 'l56', 'l73', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "82, cells ['l6', 'l24', 'l41', 'l57', 'l74', 'l84', 'l90']", + "95, zebrafish ['l7', 'l25', 'l42', 'l58', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "96, embryos ['l8', 'l26', 'l43', 'l59', 'l75', 'l91', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "97, deficient ['l9', 'l27', 'l44', 'l60', 'l76', 'l92', 'l110', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "98, in ['l10', 'l28', 'l45', 'l61', 'l77', 'l93', 'l111', 'l124', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "99, heg, ['l11', 'l29', 'l46', 'l62', 'l78', 'l94', 'l112', 'l125', 'l141', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "100, krit1 ['l12', 'l30', 'l47', 'l63', 'l79', 'l85', 'l95', 'l113', 'l126', 'l142', 'l158', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184']", + "101, or ['l13', 'l31', 'l48', 'l64', 'l80', 'l86', 'l96', 'l114', 'l127', 'l143', 'l159', 'l173', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "102, ccm2 ['l14', 'l32', 'l49', 'l65', 'l81', 'l87', 'l97', 'l115', 'l128', 'l144', 'l160', 'l174', 'l185', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200']", + "106, CCM2-deficient ['l66', 'l98', 'l116', 'l129', 'l145', 'l161', 'l175', 'l186', 'l194', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212']", + "107, human ['l15', 'l33', 'l50', 'l67', 'l99', 'l117', 'l130', 'l146', 'l162', 'l176', 'l187', 'l195', 'l201', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220']", + "108, endothelial ['l16', 'l34', 'l51', 'l68', 'l82', 'l88', 'l100', 'l118', 'l131', 'l147', 'l163', 'l177', 'l188', 'l196', 'l202', 'l213', 'l221', 'l222', 'l223', 'l224', 'l225']", + "109, cells ['l17', 'l35', 'l52', 'l69', 'l83', 'l89', 'l90', 'l101', 'l119', 'l132', 'l148', 'l164', 'l178', 'l189', 'l197', 'l203', 'l214', 'l221', 'l226', 'l227']", + "110, in ['l18', 'l36', 'l53', 'l70', 'l102', 'l120', 'l133', 'l149', 'l165', 'l179', 'l190', 'l198', 'l204', 'l215', 'l222', 'l226', 'l228', 'l229']", + "111, vitro. ['l19', 'l37', 'l54', 'l71', 'l103', 'l121', 'l134', 'l150', 'l166', 'l180', 'l191', 'l199', 'l205', 'l216', 'l223', 'l227', 'l228', 'l230']", + "115, hearts ['l72', 'l104', 'l122', 'l135', 'l151', 'l167', 'l181', 'l192', 'l200', 'l206', 'l217', 'l224', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241']", + "117, zebrafish ['l152', 'l207', 'l231', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252']", + "118, lacking ['l105', 'l136', 'l153', 'l168', 'l182', 'l208', 'l218', 'l232', 'l242', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262']", + "119, heg ['l106', 'l137', 'l154', 'l169', 'l209', 'l233', 'l243', 'l253', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271']", + "120, or ['l107', 'l138', 'l155', 'l170', 'l183', 'l210', 'l219', 'l234', 'l244', 'l254', 'l263', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279']", + "121, ccm2, ['l108', 'l123', 'l139', 'l156', 'l171', 'l184', 'l193', 'l211', 'l220', 'l225', 'l235', 'l245', 'l255', 'l264', 'l272', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286']", + "124, aortas ['l109', 'l140', 'l157', 'l172', 'l212', 'l236', 'l246', 'l256', 'l265', 'l273', 'l280', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292']", + "126, early ['l237', 'l247', 'l257', 'l266', 'l274', 'l281', 'l287', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301']", + "127, mouse ['l238', 'l248', 'l258', 'l267', 'l275', 'l282', 'l288', 'l293', 'l302', 'l303', 'l304', 'l305', 'l306', 'l307', 'l308', 'l309']", + "128, embryos ['l239', 'l249', 'l259', 'l268', 'l276', 'l283', 'l289', 'l294', 'l302', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315', 'l316']", + "129, lacking ['l240', 'l250', 'l260', 'l269', 'l277', 'l284', 'l290', 'l295', 'l303', 'l310', 'l317', 'l318', 'l319', 'l320', 'l321', 'l322']", + "130, CCM2 ['l241', 'l251', 'l261', 'l270', 'l278', 'l285', 'l291', 'l296', 'l304', 'l311', 'l317', 'l323', 'l324', 'l325', 'l326', 'l327']", + "134, lymphatic ['l297', 'l305', 'l312', 'l318', 'l323', 'l328', 'l329', 'l330', 'l331', 'l332']", + "135, vessels ['l252', 'l262', 'l271', 'l279', 'l286', 'l292', 'l298', 'l306', 'l313', 'l319', 'l324', 'l328', 'l333', 'l334', 'l335', 'l336']", + "137, neonatal ['l329', 'l333', 'l337', 'l338', 'l339']", + "138, mice ['l299', 'l307', 'l314', 'l320', 'l325', 'l330', 'l334', 'l337', 'l340', 'l341']", + "139, lacking ['l300', 'l308', 'l315', 'l321', 'l326', 'l331', 'l335', 'l338', 'l340', 'l342']", + "140, HEG1 ['l301', 'l309', 'l316', 'l322', 'l327', 'l332', 'l336', 'l339', 'l341', 'l342']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Heg1(-/-)", + "Heg1(-/-);", + "Ccm2(lacZ/+)", + "and", + "Ccm2(lacZ/lacZ)", + "deficient", + "in", + "heg,", + "krit1", + "or", + "ccm2", + "CCM2-deficient", + "lacking", + "heg", + "ccm2,", + "CCM2", + "HEG1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "zebrafish", + "embryos", + "early", + "mouse", + "neonatal" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Heg1(-/-);", + "Ccm2(lacZ/+)", + "and", + "Ccm2(lacZ/lacZ)", + "krit1", + "or", + "ccm2", + "deficient", + "in", + "heg,", + "CCM2-deficient", + "lacking", + "ccm2," + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells", + "human" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Heg1(-/-);", + "Ccm2(lacZ/+)", + "and", + "Ccm2(lacZ/lacZ)", + "deficient", + "in", + "heg,", + "krit1", + "or", + "ccm2", + "CCM2-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ccm2(lacZ/lacZ)", + "deficient", + "in", + "heg,", + "krit1", + "or", + "ccm2", + "CCM2-deficient", + "lacking", + "heg", + "ccm2,", + "CCM2", + "HEG1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hearts", + "aortas", + "vessels", + "lymphatic" + ] + } + } + ] + }, + { + "PMID": "19122659", + "TEXT": "We report the development of a new method to induce glioblastoma multiforme in adult immunocompetent mice by injecting Cre-loxP-controlled lentiviral vectors expressing oncogenes. Cell type- or region-specific expression of activated forms of the oncoproteins Harvey-Ras and AKT in fewer than 60 glial fibrillary acidic protein-positive cells in the hippocampus, subventricular zone or cortex of mice heterozygous for the gene encoding the tumor suppressor Tp53 were tested. Mice developed glioblastoma multiforme when transduced either in the subventricular zone or the hippocampus. However, tumors were rarely detected when the mice were transduced in the cortex. Transplantation of brain tumor cells into naive recipient mouse brain resulted in the formation of glioblastoma multiforme-like tumors, which contained CD133(+) cells, formed tumorspheres and could differentiate into neurons and astrocytes. We suggest that the use of Cre-loxP-controlled lentiviral vectors is a novel way to generate a mouse glioblastoma multiforme model in a region- and cell type-specific manner in adult mice.", + "TAG_DATA": [ + "52, cortex {'context': 'B-tissue/organ'}", + "54, mice {'context': 'B-organism'}", + "55, heterozygous {'perturbing_action': 'B-other'}", + "56, for {'perturbing_action': 'I-other'}", + "57, the {'perturbing_action': 'I-other'}", + "58, gene {'perturbing_action': 'I-other'}", + "59, encoding {'perturbing_action': 'I-other'}", + "60, the {'perturbing_action': 'I-other'}", + "61, tumor {'perturbing_action': 'I-other'}", + "62, suppressor {'perturbing_action': 'I-other'}", + "63, Tp53 {'perturbing_action': 'I-other'}", + "66, Mice {'context': 'B-organism'}", + "71, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "76, zone {'context': 'I-tissue/organ'}", + "81, tumors {'phenotype': 'B-tumourigenesis'}", + "87, mice {'context': 'B-organism'}", + "92, cortex. {'context': 'B-tissue/organ'}", + "95, brain {'context': 'B-transformed cells'}", + "96, tumor {'context': 'I-transformed cells'}", + "97, cells {'context': 'I-transformed cells'}", + "100, recipient {'context': 'B-tissue/organ'}", + "101, mouse {'context': 'I-tissue/organ'}", + "102, brain {'context': 'I-tissue/organ'}", + "108, glioblastoma {'phenotype': 'B-tumourigenesis'}", + "109, multiforme-like {'phenotype': 'I-tumourigenesis'}", + "110, tumors, {'phenotype': 'B-tumourigenesis'}", + "116, tumorspheres {'phenotype': 'B-tumourigenesis'}", + "119, differentiate {'phenotype': 'B-differentiation'}", + "121, neurons {'context': 'B-cells', 'phenotype': 'B-differentiation'}", + "123, astrocytes. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "52, cortex ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "54, mice ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "55, heterozygous ['l1', 'l12', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "56, for ['l2', 'l13', 'l27', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "57, the ['l3', 'l14', 'l28', 'l42', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "58, gene ['l4', 'l15', 'l29', 'l43', 'l56', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "59, encoding ['l16', 'l30', 'l44', 'l57', 'l69', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "60, the ['l5', 'l17', 'l31', 'l45', 'l58', 'l70', 'l81', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "61, tumor ['l6', 'l18', 'l32', 'l46', 'l59', 'l71', 'l82', 'l92', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "62, suppressor ['l19', 'l33', 'l47', 'l60', 'l72', 'l83', 'l93', 'l102', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "63, Tp53 ['l7', 'l20', 'l34', 'l48', 'l61', 'l73', 'l84', 'l94', 'l103', 'l111', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "66, Mice ['l8', 'l21', 'l35', 'l49', 'l62', 'l74', 'l85', 'l95', 'l104', 'l112', 'l119', 'l126', 'l127', 'l128']", + "71, transduced ['l9', 'l22', 'l36', 'l50', 'l63', 'l75', 'l86', 'l96', 'l105', 'l113', 'l120', 'l126', 'l129', 'l130', 'l131', 'l132']", + "76, zone ['l10', 'l23', 'l37', 'l51', 'l64', 'l76', 'l87', 'l97', 'l106', 'l114', 'l121', 'l127', 'l129', 'l133']", + "79, hippocampus. ['l11', 'l24', 'l38', 'l52', 'l65', 'l77', 'l88', 'l98', 'l107', 'l115', 'l122', 'l128', 'l130', 'l133', 'l134', 'l135']", + "81, tumors ['l25', 'l39', 'l53', 'l66', 'l78', 'l89', 'l99', 'l108', 'l116', 'l123', 'l131', 'l134', 'l136', 'l137']", + "87, mice ['l40', 'l54', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l124', 'l136', 'l138']", + "92, cortex. ['l26', 'l41', 'l55', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l125', 'l132', 'l135', 'l137', 'l138']", + "95, brain ['l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150']", + "96, tumor ['l139', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160']", + "97, cells ['l140', 'l151', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "100, recipient ['l141', 'l152', 'l161', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176']", + "101, mouse ['l142', 'l153', 'l162', 'l168', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184']", + "102, brain ['l143', 'l154', 'l163', 'l169', 'l177', 'l185', 'l186', 'l187', 'l188']", + "108, glioblastoma ['l144', 'l155', 'l164', 'l170', 'l178', 'l185', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "109, multiforme-like ['l145', 'l156', 'l165', 'l171', 'l179', 'l186', 'l189', 'l195', 'l196', 'l197', 'l198', 'l199']", + "110, tumors, ['l146', 'l157', 'l166', 'l172', 'l180', 'l187', 'l190', 'l195', 'l200', 'l201', 'l202']", + "116, tumorspheres ['l147', 'l158', 'l167', 'l173', 'l181', 'l188', 'l191', 'l196', 'l200', 'l203', 'l204', 'l205']", + "119, differentiate ['l148', 'l174', 'l182', 'l192', 'l197', 'l203', 'l206', 'l207']", + "121, neurons ['l149', 'l159', 'l175', 'l183', 'l193', 'l198', 'l201', 'l204', 'l206', 'l208']", + "123, astrocytes. ['l150', 'l160', 'l176', 'l184', 'l194', 'l199', 'l202', 'l205', 'l207', 'l208']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "cortex", + "zone", + "cortex." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous", + "for", + "the", + "gene", + "tumor", + "Tp53", + "encoding", + "suppressor" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "cortex", + "zone", + "cortex." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "Mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous", + "for", + "the", + "gene", + "encoding", + "tumor", + "suppressor", + "Tp53" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "Mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous", + "for", + "the", + "gene", + "encoding", + "tumor", + "suppressor", + "Tp53" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors", + "glioblastoma", + "multiforme-like", + "tumors,", + "tumorspheres" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "cortex.", + "recipient", + "mouse", + "brain" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "brain", + "tumor", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "glioblastoma", + "multiforme-like", + "tumors,", + "tumorspheres" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "brain", + "tumor" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate", + "neurons" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neurons", + "astrocytes." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "neurons", + "differentiate" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "recipient", + "mouse" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate", + "neurons" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "glioblastoma", + "multiforme-like", + "tumors,", + "tumorspheres" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons", + "astrocytes." + ] + } + } + ] + }, + { + "PMID": "19098907", + "TEXT": "Gamma-secretase inhibitors (GSIs) block the activation of the oncogenic protein Notch homolog-1 (NOTCH1) in T cell acute lymphoblastic leukemia (T-ALL). However, limited antileukemic cytotoxicity and severe gastrointestinal toxicity have restricted the clinical application of these targeted drugs. Here we show that combination therapy with GSIs plus glucocorticoids can improve the antileukemic effects of GSIs and reduce their gut toxicity in vivo. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid receptor autoupregulation and induced apoptotic cell death through induction of the gene encoding BCL-2-like apoptosis initiator-11 (BCL2L11). GSI treatment resulted in cell cycle arrest and accumulation of goblet cells in the gut mediated by upregulation of the gene encoding the transcription factor Krüppel-like factor-4 (Klf4), a negative regulator of the cell cycle required for goblet cell differentiation. In contrast, glucocorticoid treatment induced transcriptional upregulation of cyclin D2 (Ccnd2) and protected mice from developing the intestinal goblet cell metaplasia typically induced by inhibition of NOTCH signaling with GSIs. These results support a role for glucocorticoids plus GSIs in the treatment of glucocorticoid-resistant T-ALL.", + "TAG_DATA": [ + "66, glucocorticoid-resistant {'context': 'B-neoplasm'}", + "67, T-ALL {'context': 'I-neoplasm'}", + "73, induced {'effect': 'B-positive'}", + "74, apoptotic {'phenotype': 'B-apoptosis'}", + "75, cell {'phenotype': 'I-apoptosis'}", + "76, death {'phenotype': 'I-apoptosis'}", + "89, resulted {'effect': 'B-positive'}", + "90, in {'effect': 'I-positive'}", + "91, cell {'phenotype': 'B-cell cycle arrest'}", + "92, cycle {'phenotype': 'I-cell cycle arrest'}", + "93, arrest {'phenotype': 'I-cell cycle arrest'}", + "97, goblet {'context': 'B-cells'}", + "98, cells {'context': 'I-cells'}", + "101, gut {'context': 'B-tissue/organ'}", + "140, mice {'context': 'B-organism'}", + "145, goblet {'context': 'I-cells'}", + "146, cell {'context': 'I-cells'}", + "147, metaplasia {'phenotype': 'B-transformation'}" + ], + "LINK_DATA": [ + "66, glucocorticoid-resistant ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "67, T-ALL ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "73, induced ['l1', 'l12', 'l22', 'l23', 'l24', 'l25']", + "74, apoptotic ['l2', 'l13', 'l22', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "75, cell ['l3', 'l14', 'l23', 'l26', 'l35', 'l36']", + "76, death ['l4', 'l15', 'l24', 'l27', 'l35', 'l37']", + "89, resulted ['l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "90, in ['l5', 'l28', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "91, cell ['l6', 'l16', 'l29', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "92, cycle ['l7', 'l17', 'l30', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "93, arrest ['l8', 'l18', 'l31', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "97, goblet ['l9', 'l19', 'l32', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "98, cells ['l10', 'l20', 'l25', 'l33', 'l36', 'l37', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "101, gut ['l11', 'l21', 'l34', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "140, mice ['l66', 'l67', 'l68', 'l69']", + "144, intestinal ['l66', 'l70', 'l71', 'l72']", + "145, goblet ['l67', 'l70', 'l73', 'l74']", + "146, cell ['l68', 'l71', 'l73', 'l75']", + "147, metaplasia ['l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "glucocorticoid-resistant", + "T-ALL" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "in" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "glucocorticoid-resistant", + "T-ALL" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "glucocorticoid-resistant", + "T-ALL" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "in" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "resulted", + "in" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "goblet" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "goblet", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "gut" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "gut" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + }, + "context": { + "val": "cells", + "words": [ + "goblet", + "cells" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "gut" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "metaplasia" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "goblet", + "cell" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "metaplasia" + ] + } + } + ] + }, + { + "PMID": "18978797", + "TEXT": "Cytotoxic T lymphocytes (CTLs) directed to nonviral tumor-associated antigens do not survive long term and have limited antitumor activity in vivo, in part because such tumor cells typically lack the appropriate costimulatory molecules. We therefore engineered Epstein-Barr virus (EBV)-specific CTLs to express a chimeric antigen receptor directed to the diasialoganglioside GD2, a nonviral tumor-associated antigen expressed by human neuroblastoma cells. We reasoned that these genetically engineered lymphocytes would receive optimal costimulation after engagement of their native receptors, enhancing survival and antitumor activity mediated through their chimeric receptors. Here we show in individuals with neuroblastoma that EBV-specific CTLs expressing a chimeric GD2-specific receptor indeed survive longer than T cells activated by the CD3-specific antibody OKT3 and expressing the same chimeric receptor but lacking virus specificity. Infusion of these genetically modified cells seemed safe and was associated with tumor regression or necrosis in half of the subjects tested. Hence, virus-specific CTLs can be modified to function as tumor-directed effector cells.", + "TAG_DATA": [ + "91, individuals {'context': 'B-patient'}", + "92, with {'context': 'I-patient'}", + "93, neuroblastoma {'context': 'B-neoplasm'}", + "95, EBV-specific {'context': 'B-cells'}", + "96, CTLs {'context': 'I-cells'}", + "106, T {'context': 'B-cells'}", + "107, cells {'context': 'B-cells'}", + "129, cells {'context': 'B-cells'}", + "136, tumor {'phenotype': 'B-tumour regression'}", + "137, regression {'phenotype': 'I-tumour regression'}", + "139, necrosis {'phenotype': 'B-necrosis'}" + ], + "LINK_DATA": [ + "91, individuals ['l0', 'l1']", + "92, with ['l0', 'l2']", + "93, neuroblastoma ['l1', 'l2', 'l3']", + "95, EBV-specific ['l4', 'l5', 'l6']", + "96, CTLs ['l3', 'l4', 'l7', 'l8']", + "106, T ['l5', 'l7', 'l9']", + "107, cells ['l6', 'l8', 'l9']", + "129, cells ['l10', 'l11', 'l12', 'l13']", + "134, associated ['l10', 'l14', 'l15', 'l16']", + "136, tumor ['l11', 'l14', 'l17', 'l18']", + "137, regression ['l12', 'l15', 'l17', 'l19']", + "139, necrosis ['l13', 'l16', 'l18', 'l19']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + } + ] + }, + { + "PMID": "18953351", + "TEXT": "Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder caused by mutations in the acidic compartment (which we define as the late endosome and the lysosome) protein, NPC1. The function of NPC1 is unknown, but when it is dysfunctional, sphingosine, glycosphingolipids, sphingomyelin and cholesterol accumulate. We have found that NPC1-mutant cells have a large reduction in the acidic compartment calcium store compared to wild-type cells. Chelating luminal endocytic calcium in normal cells with high-affinity Rhod-dextran induced an NPC disease cellular phenotype. In a drug-induced NPC disease cellular model, sphingosine storage in the acidic compartment led to calcium depletion in these organelles, which then resulted in cholesterol, sphingomyelin and glycosphingolipid storage in these compartments. Sphingosine storage is therefore an initiating factor in NPC1 disease pathogenesis that causes altered calcium homeostasis, leading to the secondary storage of sphingolipids and cholesterol. This unique calcium phenotype represents a new target for therapeutic intervention, as elevation of cytosolic calcium with curcumin normalized NPC1 disease cellular phenotypes and prolonged survival of the NPC1 mouse.", + "TAG_DATA": [ + "51, NPC1-mutant {'perturbing_action': 'B-other'}", + "52, cells {'context': 'B-cells'}", + "73, cells {'context': 'B-cells'}", + "168, NPC1 {'context': 'B-organism'}", + "169, mouse. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "51, NPC1-mutant ['l0', 'l1']", + "52, cells ['l0']", + "73, cells ['l1']", + "168, NPC1 ['l2']", + "169, mouse. ['l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "NPC1-mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "18841137", + "TEXT": "Genetic inactivation of the mitochondrial self-destruction mechanism improves cognition in a mouse model of Alzheimer’s disease (pages 1097–1105).", + "TAG_DATA": [ + "1, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "2, of {'perturbing_action': 'I-gene loss-of-function'}", + "3, the {'perturbing_action': 'I-gene loss-of-function'}", + "4, mitochondrial {'perturbing_action': 'I-gene loss-of-function'}", + "5, self-destruction {'perturbing_action': 'I-gene loss-of-function'}", + "6, mechanism {'perturbing_action': 'I-gene loss-of-function'}", + "11, mouse {'context': 'B-organism'}", + "12, model {'context': 'I-organism'}", + "13, of {'context': 'I-organism'}", + "14, Alzheimer’s {'context': 'I-organism'}", + "15, disease {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "1, inactivation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "2, of ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "3, the ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "4, mitochondrial ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "5, self-destruction ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "6, mechanism ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "11, mouse ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "12, model ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "13, of ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "14, Alzheimer’s ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "15, disease ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "the", + "mitochondrial", + "self-destruction", + "mechanism" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "Alzheimer’s", + "disease" + ] + } + } + ] + }, + { + "PMID": "18836460", + "TEXT": "Because of their abundance, resistance to proteolysis, rapid aggregation and neurotoxicity, N-terminally truncated and, in particular, pyroglutamate (pE)-modified Abeta peptides have been suggested as being important in the initiation of pathological cascades resulting in the development of Alzheimer's disease. We found that the N-terminal pE-formation is catalyzed by glutaminyl cyclase in vivo. Glutaminyl cyclase expression was upregulated in the cortices of individuals with Alzheimer's disease and correlated with the appearance of pE-modified Abeta. Oral application of a glutaminyl cyclase inhibitor resulted in reduced Abeta(3(pE)-42) burden in two different transgenic mouse models of Alzheimer's disease and in a new Drosophila model. Treatment of mice was accompanied by reductions in Abeta(x-40/42), diminished plaque formation and gliosis and improved performance in context memory and spatial learning tests. These observations are consistent with the hypothesis that Abeta(3(pE)-42) acts as a seed for Abeta aggregation by self-aggregation and co-aggregation with Abeta(1-40/42). Therefore, Abeta(3(pE)-40/42) peptides seem to represent Abeta forms with exceptional potency for disturbing neuronal function. The reduction of brain pE-Abeta by inhibition of glutaminyl cyclase offers a new therapeutic option for the treatment of Alzheimer's disease and provides implications for other amyloidoses, such as familial Danish dementia.", + "TAG_DATA": [ + "77, glutaminyl {'perturbing_action': 'B-pharmacological inhibition'}", + "78, cyclase {'perturbing_action': 'I-pharmacological inhibition'}", + "79, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "88, transgenic {'context': 'B-organism'}", + "89, mouse {'context': 'I-organism'}", + "90, models {'context': 'I-organism'}", + "91, of {'context': 'I-organism'}", + "92, Alzheimer's {'context': 'I-organism'}", + "93, disease {'context': 'I-organism'}", + "98, Drosophila {'context': 'B-organism'}", + "99, model. {'context': 'I-organism'}", + "102, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "77, glutaminyl ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "78, cyclase ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "79, inhibitor ['l1', 'l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "88, transgenic ['l2', 'l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "89, mouse ['l3', 'l12', 'l18', 'l23', 'l28', 'l29', 'l30', 'l31']", + "90, models ['l4', 'l13', 'l19', 'l24', 'l28', 'l32', 'l33', 'l34']", + "91, of ['l5', 'l14', 'l20', 'l25', 'l29', 'l32', 'l35', 'l36']", + "92, Alzheimer's ['l6', 'l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l37']", + "93, disease ['l7', 'l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l37']", + "98, Drosophila ['l8', 'l38']", + "99, model. ['l9', 'l38']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "glutaminyl", + "cyclase", + "inhibitor" + ] + }, + "context": { + "val": "organism", + "words": [ + "transgenic", + "mouse", + "models", + "of", + "Alzheimer's", + "disease", + "Drosophila", + "model." + ] + } + } + ] + }, + { + "PMID": "18836459", + "TEXT": "Vascularization is essential for tissue development and in restoration of tissue integrity after an ischemic injury. In studies of vascularization, the focus has largely been placed on vascular endothelial growth factor (VEGF), yet other factors may also orchestrate this process. Here we show that succinate accumulates in the hypoxic retina of rodents and, via its cognate receptor G protein-coupled receptor-91 (GPR91), is a potent mediator of vessel growth in the settings of both normal retinal development and proliferative ischemic retinopathy. The effects of GPR91 are mediated by retinal ganglion neurons (RGCs), which, in response to increased succinate levels, regulate the production of numerous angiogenic factors including VEGF. Accordingly, succinate did not have proangiogenic effects in RGC-deficient rats. Our observations show a pathway of metabolite signaling where succinate, acting through GPR91, governs retinal angiogenesis and show the propensity of RGCs to act as sensors of ischemic stress. These findings provide a new therapeutic target for modulating revascularization.", + "TAG_DATA": [ + "115, RGC-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "116, rats. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "115, RGC-deficient ['l0']", + "116, rats. ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "RGC-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats." + ] + } + } + ] + }, + { + "PMID": "18587407", + "TEXT": "Despite the well-documented association between gallstones and the metabolic syndrome, the mechanistic links between these two disorders remain unknown. Here we show that mice solely with hepatic insulin resistance, created by liver-specific disruption of the insulin receptor (LIRKO mice) are markedly predisposed toward cholesterol gallstone formation due to at least two distinct mechanisms. Disinhibition of the forkhead transcription factor FoxO1, increases expression of the biliary cholesterol transporters Abcg5 and Abcg8, resulting in an increase in biliary cholesterol secretion. Hepatic insulin resistance also decreases expression of the bile acid synthetic enzymes, particularly Cyp7b1, and produces partial resistance to the farnesoid X receptor, leading to a lithogenic bile salt profile. As a result, after twelve weeks on a lithogenic diet, all of the LIRKO mice develop gallstones. Thus, hepatic insulin resistance provides a crucial link between the metabolic syndrome and increased cholesterol gallstone susceptibility.", + "TAG_DATA": [ + "31, liver-specific {'perturbing_action': 'B-gene loss-of-function'}", + "32, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "33, of {'perturbing_action': 'I-gene loss-of-function'}", + "34, the {'perturbing_action': 'I-gene loss-of-function'}", + "35, insulin {'perturbing_action': 'I-gene loss-of-function'}", + "36, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "38, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "53, Disinhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "54, of {'perturbing_action': 'I-pharmacological inhibition'}", + "55, the {'perturbing_action': 'I-pharmacological inhibition'}", + "56, forkhead {'perturbing_action': 'I-pharmacological inhibition'}", + "57, transcription {'perturbing_action': 'I-pharmacological inhibition'}", + "58, factor {'perturbing_action': 'I-pharmacological inhibition'}", + "59, FoxO1, {'perturbing_action': 'I-pharmacological inhibition'}", + "121, LIRKO {'perturbing_action': 'B-gene loss-of-function'}", + "122, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "31, liver-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "32, disruption ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "33, of ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "34, the ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "35, insulin ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "36, receptor ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "38, mice) ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "53, Disinhibition ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "54, of ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "55, the ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "56, forkhead ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "57, transcription ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "58, factor ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "59, FoxO1, ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']", + "121, LIRKO ['l91']", + "122, mice ['l91']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "LIRKO" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "18568033", + "TEXT": "Tuberous sclerosis is a single-gene disorder caused by heterozygous mutations in the TSC1 (9q34) or TSC2 (16p13.3) gene and is frequently associated with mental retardation, autism and epilepsy. Even individuals with tuberous sclerosis and a normal intelligence quotient (approximately 50%) are commonly affected with specific neuropsychological problems, including long-term and working memory deficits. Here we report that mice with a heterozygous, inactivating mutation in the Tsc2 gene (Tsc2(+/-) mice) show deficits in learning and memory. Cognitive deficits in Tsc2(+/-) mice emerged in the absence of neuropathology and seizures, demonstrating that other disease mechanisms are involved. We show that hyperactive hippocampal mammalian target of rapamycin (mTOR) signaling led to abnormal long-term potentiation in the CA1 region of the hippocampus and consequently to deficits in hippocampal-dependent learning. These deficits included impairments in two spatial learning tasks and in contextual discrimination. Notably, we show that a brief treatment with the mTOR inhibitor rapamycin in adult mice rescues not only the synaptic plasticity, but also the behavioral deficits in this animal model of tuberous sclerosis. The results presented here reveal a biological basis for some of the cognitive deficits associated with tuberous sclerosis, and they show that treatment with mTOR antagonists ameliorates cognitive dysfunction in a mouse model of this disorder.", + "TAG_DATA": [ + "57, mice {'context': 'B-organism'}", + "60, heterozygous, {'perturbing_action': 'B-other'}", + "61, inactivating {'perturbing_action': 'I-other'}", + "62, mutation {'perturbing_action': 'I-other'}", + "63, in {'perturbing_action': 'I-other'}", + "64, the {'perturbing_action': 'I-other'}", + "65, Tsc2 {'perturbing_action': 'I-other'}", + "66, gene {'perturbing_action': 'I-other'}", + "68, mice) {'context': 'B-organism'}", + "78, Tsc2(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "79, mice {'context': 'B-organism'}", + "114, region {'context': 'I-cells'}", + "115, of {'context': 'I-cells'}", + "147, mTOR {'perturbing_action': 'B-pharmacological inhibition'}", + "148, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "149, rapamycin {'perturbing_action': 'I-pharmacological inhibition'}", + "151, adult {'context': 'B-organism'}", + "152, mice {'context': 'I-organism'}", + "166, animal {'context': 'B-organism'}", + "167, model {'context': 'I-organism'}", + "203, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "57, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "60, heterozygous, ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "61, inactivating ['l1', 'l13', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "62, mutation ['l2', 'l14', 'l26', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "63, in ['l3', 'l15', 'l27', 'l38', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "64, the ['l4', 'l16', 'l28', 'l39', 'l49', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "65, Tsc2 ['l5', 'l17', 'l29', 'l40', 'l50', 'l59', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "66, gene ['l6', 'l18', 'l30', 'l41', 'l51', 'l60', 'l68', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "68, mice) ['l7', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l76', 'l83', 'l84', 'l85', 'l86']", + "78, Tsc2(+/-) ['l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l87', 'l88', 'l89', 'l90', 'l91']", + "79, mice ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l87', 'l92', 'l93', 'l94', 'l95']", + "114, region ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l83', 'l88', 'l92', 'l96', 'l97', 'l98']", + "115, of ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l84', 'l89', 'l93', 'l96', 'l99', 'l100']", + "116, the ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l85', 'l90', 'l94', 'l97', 'l99', 'l101']", + "117, hippocampus ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l86', 'l91', 'l95', 'l98', 'l100', 'l101']", + "147, mTOR ['l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "148, inhibitor ['l102', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "149, rapamycin ['l103', 'l111', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "151, adult ['l104', 'l112', 'l119', 'l126', 'l127', 'l128', 'l129', 'l130']", + "152, mice ['l105', 'l113', 'l120', 'l126', 'l131', 'l132', 'l133', 'l134']", + "166, animal ['l106', 'l114', 'l121', 'l127', 'l131', 'l135', 'l136', 'l137', 'l138']", + "167, model ['l107', 'l115', 'l122', 'l128', 'l132', 'l135', 'l139', 'l140', 'l141']", + "168, of ['l108', 'l116', 'l123', 'l129', 'l133', 'l136', 'l139', 'l142', 'l143']", + "169, tuberous ['l109', 'l117', 'l124', 'l130', 'l134', 'l137', 'l140', 'l142', 'l144']", + "203, model ['l110', 'l118', 'l125', 'l138', 'l141', 'l143', 'l144']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice)" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous,", + "inactivating", + "mutation", + "in", + "the", + "Tsc2", + "gene" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous,", + "inactivating", + "mutation", + "in", + "the", + "Tsc2", + "gene" + ] + }, + "context": { + "val": "cells", + "words": [ + "region", + "of" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tsc2(+/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tsc2(+/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "region", + "of" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibitor", + "rapamycin" + ] + }, + "context": { + "val": "organism", + "words": [ + "adult", + "mice", + "animal", + "model" + ] + } + } + ] + }, + { + "PMID": "18552856", + "TEXT": "Autosomal dominant polycystic kidney disease (ADPKD) is caused by heterozygous mutations in either PKD1 or PKD2, genes that encode polycystin-1 and polycystin-2, respectively. We show here that tumor necrosis factor-alpha (TNF-alpha), an inflammatory cytokine present in the cystic fluid of humans with ADPKD, disrupts the localization of polycystin-2 to the plasma membrane and primary cilia through a scaffold protein, FIP2, which is induced by TNF-alpha. Treatment of mouse embryonic kidney organ cultures with TNF-alpha resulted in formation of cysts, and this effect was exacerbated in the Pkd2(+/-) kidneys. TNF-alpha also stimulated cyst formation in vivo in Pkd2(+/-) mice. In contrast, treatment of Pkd2(+/-) mice with the TNF-alpha inhibitor etanercept prevented cyst formation. These data reveal a pathway connecting TNF-alpha signaling, polycystins and cystogenesis, the activation of which may reduce functional polycystin-2 below a critical threshold, precipitating the ADPKD cellular phenotype.", + "TAG_DATA": [ + "67, mouse {'context': 'B-cells'}", + "68, embryonic {'context': 'I-cells'}", + "69, kidney {'context': 'I-cells'}", + "70, organ {'context': 'I-cells'}", + "71, cultures {'context': 'I-cells'}", + "86, Pkd2(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "87, kidneys. {'context': 'B-tissue/organ'}", + "90, stimulated {'effect': 'B-positive'}", + "93, in {'context': 'B-in vivo'}", + "94, vivo {'context': 'I-in vivo'}", + "96, Pkd2(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "97, mice. {'context': 'B-organism'}", + "102, Pkd2(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "103, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "67, mouse ['l0', 'l1', 'l2', 'l3', 'l4']", + "68, embryonic ['l0', 'l5', 'l6', 'l7', 'l8', 'l9']", + "69, kidney ['l1', 'l5', 'l10', 'l11', 'l12']", + "70, organ ['l2', 'l6', 'l10', 'l13']", + "71, cultures ['l3', 'l7', 'l11', 'l13']", + "86, Pkd2(+/-) ['l8', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "87, kidneys. ['l4', 'l9', 'l12', 'l14', 'l20', 'l21', 'l22', 'l23']", + "90, stimulated ['l15', 'l20', 'l24', 'l25', 'l26', 'l27']", + "91, cyst ['l16', 'l21', 'l24', 'l28', 'l29', 'l30']", + "93, in ['l17', 'l22', 'l25', 'l28', 'l31', 'l32']", + "94, vivo ['l18', 'l23', 'l26', 'l29', 'l31', 'l33']", + "96, Pkd2(+/-) ['l34']", + "97, mice. ['l19', 'l27', 'l30', 'l32', 'l33', 'l34']", + "102, Pkd2(+/-) ['l35']", + "103, mice ['l35']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "embryonic" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pkd2(+/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pkd2(+/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidneys." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pkd2(+/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pkd2(+/-)" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pkd2(+/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "kidneys." + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "18542050", + "TEXT": "Reactive oxygen species (ROS) induce chemokines responsible for the recruitment of inflammatory cells to sites of injury or infection. Here we show that the plasma membrane Ca(2+)-permeable channel TRPM2 controls ROS-induced chemokine production in monocytes. In human U937 monocytes, hydrogen peroxide (H(2)O(2)) evokes Ca(2+) influx through TRPM2 to activate Ca(2+)-dependent tyrosine kinase Pyk2 and amplify Erk signaling via Ras GTPase. This elicits nuclear translocation of nuclear factor-kappaB essential for the production of the chemokine interleukin-8 (CXCL8). In monocytes from Trpm2-deficient mice, H(2)O(2)-induced Ca(2+) influx and production of the macrophage inflammatory protein-2 (CXCL2), the mouse CXCL8 functional homolog, were impaired. In the dextran sulfate sodium-induced colitis inflammation model, CXCL2 expression, neutrophil infiltration and ulceration were attenuated by Trpm2 disruption. Thus, TRPM2 Ca(2+) influx controls the ROS-induced signaling cascade responsible for chemokine production, which aggravates inflammation. We propose functional inhibition of TRPM2 channels as a new therapeutic strategy for treating inflammatory diseases.", + "TAG_DATA": [ + "36, human {'context': 'B-cells'}", + "37, U937 {'context': 'I-cells'}", + "38, monocytes, {'context': 'I-cells'}", + "77, monocytes {'context': 'B-cells'}", + "79, Trpm2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "80, mice, {'context': 'B-organism'}", + "116, Trpm2 {'perturbing_action': 'B-gene loss-of-function'}", + "117, disruption. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "36, human ['l0', 'l1', 'l2']", + "37, U937 ['l0', 'l3', 'l4']", + "38, monocytes, ['l1', 'l3', 'l5']", + "77, monocytes ['l2', 'l4', 'l5', 'l6', 'l7']", + "79, Trpm2-deficient ['l6', 'l8']", + "80, mice, ['l7', 'l8']", + "116, Trpm2 ['l9']", + "117, disruption. ['l9']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "monocytes" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trpm2-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trpm2-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "18516053", + "TEXT": "Leptin (encoded by Lep) controls body weight by regulating food intake and fuel partitioning. Obesity is characterized by leptin resistance and increased endocannabinoid tone. Here we show that leptin infused into the mediobasal hypothalamus (MBH) of rats inhibits white adipose tissue (WAT) lipogenesis, which occurs independently of signal transducer and activator of transcription-3 (STAT3) signaling. Correspondingly, transgenic inactivation of STAT3 signaling by mutation of the leptin receptor (s/s mice) leads to reduced adipose mass compared to db/db mice (complete abrogation of leptin receptor signaling). Conversely, the ability of hypothalamic leptin to suppress WAT lipogenesis in rats is lost when hypothalamic phosphoinositide 3-kinase signaling is prevented or when sympathetic denervation of adipose tissue is performed. MBH leptin suppresses the endocannabinoid anandamide in WAT, and, when this suppression of endocannabinoid tone is prevented by systemic CB1 receptor activation, MBH leptin fails to suppress WAT lipogenesis. These data suggest that the increased endocannabinoid tone observed in obesity is linked to a failure of central leptin signaling to restrain peripheral endocannabinoids.", + "TAG_DATA": [ + "33, hypothalamus {'context': 'I-tissue/organ'}", + "34, (MBH) {'context': 'I-tissue/organ'}", + "36, rats {'context': 'B-organism'}", + "56, transgenic {'perturbing_action': 'B-gene loss-of-function'}", + "57, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "58, of {'perturbing_action': 'I-gene loss-of-function'}", + "59, STAT3 {'perturbing_action': 'I-gene loss-of-function'}", + "60, signaling {'perturbing_action': 'I-gene loss-of-function'}", + "61, by {'perturbing_action': 'I-gene loss-of-function'}", + "62, mutation {'perturbing_action': 'I-gene loss-of-function'}", + "63, of {'perturbing_action': 'I-gene loss-of-function'}", + "64, the {'perturbing_action': 'I-gene loss-of-function'}", + "65, leptin {'perturbing_action': 'I-other'}", + "66, receptor {'perturbing_action': 'I-other'}", + "67, (s/s {'perturbing_action': 'I-gene loss-of-function'}", + "68, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "76, db/db {'context': 'B-organism'}", + "77, mice {'context': 'I-organism'}", + "95, rats {'context': 'B-organism'}", + "110, adipose {'context': 'B-cells'}", + "111, tissue {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "32, mediobasal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "33, hypothalamus ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "34, (MBH) ['l1', 'l17', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "36, rats ['l2', 'l18', 'l32', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "56, transgenic ['l3', 'l19', 'l33', 'l46', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "57, inactivation ['l4', 'l20', 'l34', 'l47', 'l59', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "58, of ['l5', 'l21', 'l35', 'l48', 'l60', 'l73', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "59, STAT3 ['l6', 'l22', 'l36', 'l49', 'l61', 'l74', 'l87', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "60, signaling ['l7', 'l23', 'l37', 'l50', 'l62', 'l75', 'l88', 'l100', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "61, by ['l8', 'l24', 'l38', 'l51', 'l63', 'l76', 'l89', 'l101', 'l112', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "62, mutation ['l9', 'l25', 'l39', 'l52', 'l64', 'l77', 'l90', 'l102', 'l113', 'l123', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141']", + "63, of ['l10', 'l26', 'l40', 'l53', 'l65', 'l78', 'l91', 'l103', 'l114', 'l124', 'l133', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "64, the ['l11', 'l27', 'l41', 'l54', 'l66', 'l79', 'l92', 'l104', 'l115', 'l125', 'l134', 'l142', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156']", + "65, leptin ['l12', 'l28', 'l42', 'l55', 'l67', 'l80', 'l93', 'l105', 'l116', 'l126', 'l135', 'l143', 'l150', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162']", + "66, receptor ['l13', 'l29', 'l43', 'l56', 'l68', 'l81', 'l94', 'l106', 'l117', 'l127', 'l136', 'l144', 'l151', 'l157', 'l163', 'l164', 'l165', 'l166', 'l167']", + "67, (s/s ['l14', 'l30', 'l44', 'l57', 'l69', 'l82', 'l95', 'l107', 'l118', 'l128', 'l137', 'l145', 'l152', 'l158', 'l163', 'l168', 'l169', 'l170']", + "68, mice) ['l15', 'l31', 'l45', 'l58', 'l70', 'l83', 'l96', 'l108', 'l119', 'l129', 'l138', 'l146', 'l153', 'l159', 'l164', 'l168', 'l171']", + "76, db/db ['l71', 'l84', 'l97', 'l109', 'l120', 'l130', 'l139', 'l147', 'l154', 'l160', 'l165', 'l169', 'l172', 'l173']", + "77, mice ['l16', 'l72', 'l85', 'l98', 'l110', 'l121', 'l131', 'l140', 'l148', 'l155', 'l161', 'l166', 'l170', 'l171', 'l172', 'l174']", + "95, rats ['l86', 'l99', 'l111', 'l122', 'l132', 'l141', 'l149', 'l156', 'l162', 'l167', 'l173', 'l174']", + "110, adipose ['l175']", + "111, tissue ['l175']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "hypothalamus", + "(MBH)" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "transgenic", + "inactivation", + "of", + "STAT3", + "signaling", + "by", + "mutation", + "the", + "(s/s", + "mice)" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "hypothalamus", + "(MBH)" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "leptin", + "receptor" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rats", + "db/db", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "transgenic", + "inactivation", + "of", + "STAT3", + "signaling", + "by", + "mutation", + "the", + "(s/s", + "mice)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rats", + "db/db", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "leptin", + "receptor" + ] + } + } + ] + }, + { + "PMID": "18516052", + "TEXT": "More than 500 million people worldwide are persistently infected with hepatitis B virus or hepatitis C virus. Although both viruses are poorly cytopathic, persistence of either virus carries a risk of chronic liver inflammation, potentially resulting in liver steatosis, liver cirrhosis, end-stage liver failure or hepatocellular carcinoma. Virus-specific T cells are a major determinant of the outcome of hepatitis, as they contribute to the early control of chronic hepatitis viruses, but they also mediate immunopathology during persistent virus infection. We have analyzed the role of platelet-derived vasoactive serotonin during virus-induced CD8(+) T cell-dependent immunopathological hepatitis in mice infected with the noncytopathic lymphocytic choriomeningitis virus. After virus infection, platelets were recruited to the liver, and their activation correlated with severely reduced sinusoidal microcirculation, delayed virus elimination and increased immunopathological liver cell damage. Lack of platelet-derived serotonin in serotonin-deficient mice normalized hepatic microcirculatory dysfunction, accelerated virus clearance in the liver and reduced CD8(+) T cell-dependent liver cell damage. In keeping with these observations, serotonin treatment of infected mice delayed entry of activated CD8(+) T cells into the liver, delayed virus control and aggravated immunopathological hepatitis. Thus, vasoactive serotonin supports virus persistence in the liver and aggravates virus-induced immunopathology.", + "TAG_DATA": [ + "96, mice {'context': 'B-organism'}", + "128, liver {'context': 'B-cells'}", + "129, cell {'context': 'I-cells'}", + "136, serotonin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "137, mice {'context': 'B-organism'}", + "147, liver {'context': 'B-tissue/organ'}", + "153, liver {'context': 'B-cells'}", + "154, cell {'context': 'I-cells'}", + "165, mice {'context': 'B-organism'}", + "170, CD8(+) {'context': 'B-cells'}", + "171, T {'context': 'I-cells'}", + "172, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "96, mice ['l0', 'l1']", + "128, liver ['l0', 'l2']", + "129, cell ['l1', 'l2']", + "136, serotonin-deficient ['l3', 'l4', 'l5', 'l6']", + "137, mice ['l3', 'l7', 'l8', 'l9']", + "147, liver ['l4', 'l7']", + "153, liver ['l5', 'l8', 'l10']", + "154, cell ['l6', 'l9', 'l10']", + "165, mice ['l11', 'l12', 'l13']", + "170, CD8(+) ['l11', 'l14', 'l15']", + "171, T ['l12', 'l14', 'l16']", + "172, cells ['l13', 'l15', 'l16']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "serotonin-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "serotonin-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "serotonin-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "liver", + "cell" + ] + } + } + ] + }, + { + "PMID": "18516051", + "TEXT": "Alzheimer's disease is the most common dementia and is pathologically characterized by deposition of amyloid-beta peptide (Abeta) into beta-amyloid plaques, neuronal injury and low-level, chronic activation of brain immunity. Transforming growth factor-betas (TGF-betas) are pleiotropic cytokines that have key roles in immune cell activation, inflammation and repair after injury. We genetically interrupted TGF-beta and downstream Smad2/3 signaling (TGF-beta-Smad2/3) in innate immune cells by inducing expression of CD11c promoter-driven dominant-negative TGF-beta receptor type II in C57BL/6 mice (CD11c-DNR), crossed these mice with mice overexpressing mutant human amyloid precursor protein, the Tg2576 Alzheimer's disease mouse model, and evaluated Alzheimer's disease-like pathology. Aged double-transgenic mice showed complete mitigation of Tg2576-associated hyperactivity and partial mitigation of defective spatial working memory. Brain parenchymal and cerebrovascular beta-amyloid deposits and Abeta abundance were markedly (up to 90%) attenuated in Tg2576-CD11c-DNR mice. This was associated with increased infiltration of Abeta-containing peripheral macrophages around cerebral vessels and beta-amyloid plaques. In vitro, cultures of peripheral macrophages, but not microglia, from CD11c-DNR mice showed blockade of classical TGF-beta-activated Smad2/3 but also showed hyperactivation of alternative bone morphogenic protein-activated Smad1/5/8 signaling and increased Abeta phagocytosis. Similar effects were noted after pharmacological inhibition of activin-like kinase-5, a type I TGF-beta receptor. Taken together, our results suggest that blockade of TGF-beta-Smad2/3 signaling in peripheral macrophages represents a new therapeutic target for Alzheimer's disease.", + "TAG_DATA": [ + "59, innate {'context': 'B-cells'}", + "60, immune {'context': 'I-cells'}", + "61, cells {'context': 'I-cells'}", + "63, inducing {'perturbing_action': 'B-other'}", + "64, expression {'perturbing_action': 'I-other'}", + "65, of {'perturbing_action': 'I-other'}", + "66, CD11c {'perturbing_action': 'I-other'}", + "67, promoter-driven {'perturbing_action': 'I-other'}", + "68, dominant-negative {'perturbing_action': 'I-other'}", + "69, TGF-beta {'perturbing_action': 'I-other'}", + "70, receptor {'perturbing_action': 'I-other'}", + "71, type {'perturbing_action': 'I-other'}", + "72, II {'perturbing_action': 'I-other'}", + "74, C57BL/6 {'context': 'B-organism'}", + "75, mice {'context': 'I-organism'}", + "79, mice {'context': 'B-organism'}", + "81, mice {'context': 'B-organism'}", + "82, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "83, mutant {'perturbing_action': 'I-gene gain-of-function'}", + "84, human {'perturbing_action': 'I-gene gain-of-function'}", + "85, amyloid {'perturbing_action': 'I-gene gain-of-function'}", + "86, precursor {'perturbing_action': 'I-gene gain-of-function'}", + "87, protein, {'perturbing_action': 'I-gene gain-of-function'}", + "101, mice {'context': 'B-organism'}", + "132, Tg2576-CD11c-DNR {'perturbing_action': 'B-other'}", + "133, mice. {'context': 'B-organism'}", + "142, peripheral {'context': 'B-cells'}", + "143, macrophages {'context': 'I-cells'}", + "150, In {'context': 'B-in vitro'}", + "151, vitro, {'context': 'I-in vitro'}", + "154, peripheral {'context': 'B-cells'}", + "155, macrophages, {'context': 'I-cells'}", + "158, microglia, {'context': 'B-cells'}", + "161, mice {'context': 'B-organism'}", + "188, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "189, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "190, of {'perturbing_action': 'I-pharmacological inhibition'}", + "191, activin-like {'perturbing_action': 'I-pharmacological inhibition'}", + "192, kinase-5, {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "59, innate ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "60, immune ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "61, cells ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "63, inducing ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "64, expression ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "65, of ['l4', 'l17', 'l29', 'l40', 'l50', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "66, CD11c ['l5', 'l18', 'l30', 'l41', 'l51', 'l61', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "67, promoter-driven ['l6', 'l19', 'l31', 'l42', 'l52', 'l62', 'l71', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "68, dominant-negative ['l7', 'l20', 'l32', 'l43', 'l53', 'l63', 'l72', 'l80', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "69, TGF-beta ['l8', 'l21', 'l33', 'l44', 'l54', 'l64', 'l73', 'l81', 'l88', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "70, receptor ['l9', 'l22', 'l34', 'l45', 'l55', 'l65', 'l74', 'l82', 'l89', 'l95', 'l101', 'l102', 'l103', 'l104', 'l105']", + "71, type ['l10', 'l23', 'l35', 'l46', 'l56', 'l66', 'l75', 'l83', 'l90', 'l96', 'l101', 'l106', 'l107', 'l108', 'l109']", + "72, II ['l11', 'l24', 'l36', 'l47', 'l57', 'l67', 'l76', 'l84', 'l91', 'l97', 'l102', 'l106', 'l110', 'l111', 'l112']", + "74, C57BL/6 ['l12', 'l25', 'l37', 'l48', 'l58', 'l68', 'l77', 'l85', 'l92', 'l98', 'l103', 'l107', 'l110', 'l113', 'l114']", + "75, mice ['l13', 'l26', 'l38', 'l49', 'l59', 'l69', 'l78', 'l86', 'l93', 'l99', 'l104', 'l108', 'l111', 'l113']", + "79, mice ['l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "81, mice ['l115', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "82, overexpressing ['l116', 'l123', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "83, mutant ['l117', 'l124', 'l134', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "84, human ['l118', 'l125', 'l135', 'l144', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160']", + "85, amyloid ['l119', 'l126', 'l136', 'l145', 'l153', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "86, precursor ['l120', 'l127', 'l137', 'l146', 'l154', 'l161', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "87, protein, ['l121', 'l128', 'l138', 'l147', 'l155', 'l162', 'l168', 'l174', 'l175', 'l176', 'l177', 'l178']", + "101, mice ['l60', 'l70', 'l79', 'l87', 'l94', 'l100', 'l105', 'l109', 'l112', 'l114', 'l122', 'l129', 'l139', 'l148', 'l156', 'l163', 'l169', 'l174']", + "132, Tg2576-CD11c-DNR ['l130', 'l140', 'l149', 'l157', 'l164', 'l170', 'l175', 'l179', 'l180', 'l181']", + "133, mice. ['l131', 'l141', 'l150', 'l158', 'l165', 'l171', 'l176', 'l179', 'l182', 'l183']", + "142, peripheral ['l132', 'l142', 'l151', 'l159', 'l166', 'l172', 'l177', 'l180', 'l182', 'l184']", + "143, macrophages ['l133', 'l143', 'l152', 'l160', 'l167', 'l173', 'l178', 'l181', 'l183', 'l184']", + "150, In ['l185', 'l186', 'l187', 'l188', 'l189']", + "151, vitro, ['l185', 'l190', 'l191', 'l192', 'l193']", + "154, peripheral ['l186', 'l190', 'l194', 'l195', 'l196']", + "155, macrophages, ['l187', 'l191', 'l194', 'l197', 'l198']", + "158, microglia, ['l188', 'l192', 'l195', 'l197', 'l199']", + "161, mice ['l189', 'l193', 'l196', 'l198', 'l199']", + "188, pharmacological ['l200', 'l201', 'l202', 'l203']", + "189, inhibition ['l200', 'l204', 'l205', 'l206']", + "190, of ['l201', 'l204', 'l207', 'l208']", + "191, activin-like ['l202', 'l205', 'l207', 'l209']", + "192, kinase-5, ['l203', 'l206', 'l208', 'l209']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "innate", + "immune", + "cells", + "peripheral", + "macrophages" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "inducing", + "expression", + "of", + "CD11c", + "promoter-driven", + "dominant-negative", + "TGF-beta", + "receptor", + "type", + "II", + "Tg2576-CD11c-DNR" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "inducing", + "expression", + "of", + "CD11c", + "promoter-driven", + "dominant-negative", + "TGF-beta", + "receptor", + "type", + "II", + "Tg2576-CD11c-DNR" + ] + }, + "context": { + "val": "organism", + "words": [ + "C57BL/6", + "mice", + "mice." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "mutant", + "human", + "amyloid", + "precursor", + "protein," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "mutant", + "human", + "amyloid", + "precursor", + "protein," + ] + }, + "context": { + "val": "cells", + "words": [ + "peripheral", + "macrophages" + ] + } + } + ] + }, + { + "PMID": "18469826", + "TEXT": "An ideal vaccination strategy against tumors relies on specific antigens that are required for tumor maintenance. For lymphoma, vaccination with subject-specific immunoglobulin idiotypes has had the most promising results. Here we show that DNA vaccination with plasmids encoding portions of the cytoplasmic domain of anaplastic lymphoma kinase (ALK), which has been translocated in different fusion proteins necessary for the growth of anaplastic large cell lymphoma (ALCL), protects mice from local and systemic lymphoma growth. The protection is potent and long lasting and elicits ALK-specific interferon-gamma responses and CD8+ T cell-mediated cytotoxicity. A combination of chemotherapy and vaccination significantly enhanced the survival of mice challenged with ALK+ lymphomas. These findings indicate that ALK represents an ideal tumor antigen for vaccination-based therapies of ALCL and possibly other ALK+ human tumors.", + "TAG_DATA": [ + "36, plasmids {'perturbing_action': 'B-gene gain-of-function'}", + "37, encoding {'perturbing_action': 'I-gene gain-of-function'}", + "38, portions {'perturbing_action': 'I-gene gain-of-function'}", + "39, of {'perturbing_action': 'I-rnai/knockdown'}", + "40, the {'perturbing_action': 'I-rnai/knockdown'}", + "41, cytoplasmic {'perturbing_action': 'I-rnai/knockdown'}", + "42, domain {'perturbing_action': 'I-gene gain-of-function'}", + "43, of {'perturbing_action': 'I-rnai/knockdown'}", + "44, anaplastic {'perturbing_action': 'I-rnai/knockdown'}", + "45, lymphoma {'perturbing_action': 'I-rnai/knockdown'}", + "46, kinase {'perturbing_action': 'I-gene gain-of-function'}", + "47, (ALK), {'perturbing_action': 'I-rnai/knockdown'}", + "67, mice {'context': 'B-organism'}", + "72, lymphoma {'context': 'B-neoplasm'}", + "102, mice {'context': 'B-organism'}", + "105, ALK+ {'context': 'B-neoplasm'}", + "106, lymphomas. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "36, plasmids ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "37, encoding ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "38, portions ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "39, of ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "40, the ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "41, cytoplasmic ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "42, domain ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "43, of ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "44, anaplastic ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "45, lymphoma ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "46, kinase ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "47, (ALK), ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "67, mice ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "72, lymphoma ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']", + "102, mice ['l91', 'l92']", + "105, ALK+ ['l91', 'l93']", + "106, lymphomas. ['l92', 'l93']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "plasmids", + "encoding", + "portions", + "domain", + "kinase" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "plasmids", + "encoding", + "portions", + "domain", + "kinase" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lymphoma" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "the", + "cytoplasmic", + "anaplastic", + "lymphoma", + "(ALK)," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "the", + "cytoplasmic", + "anaplastic", + "lymphoma", + "(ALK)," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lymphoma" + ] + } + } + ] + }, + { + "PMID": "18469825", + "TEXT": "Neurodegeneration and brain edema are hallmarks of human malignant brain tumors. Here we show that genetic or pharmacological inhibition of the glutamate transporter xCT (X(c-) system, encoded by SLC7a11) in vivo leads to abrogated neurodegeneration, attenuated perifocal edema and prolonged survival. These results show a crucial role for xCT in glioma-induced neurodegeneration and brain edema, corroborating the concept that edema formation may be in part a consequence of peritumoral cell death.", + "TAG_DATA": [ + "17, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "18, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "19, of {'perturbing_action': 'I-pharmacological inhibition'}", + "20, the {'perturbing_action': 'I-pharmacological inhibition'}", + "21, glutamate {'perturbing_action': 'I-pharmacological inhibition'}", + "22, transporter {'perturbing_action': 'I-pharmacological inhibition'}", + "23, xCT {'perturbing_action': 'I-pharmacological inhibition'}", + "24, (X(c-) {'perturbing_action': 'I-pharmacological inhibition'}", + "25, system, {'perturbing_action': 'I-pharmacological inhibition'}", + "26, encoded {'perturbing_action': 'I-pharmacological inhibition'}", + "27, by {'perturbing_action': 'I-pharmacological inhibition'}", + "28, SLC7a11) {'perturbing_action': 'I-pharmacological inhibition'}", + "29, in {'context': 'B-in vivo'}", + "30, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "17, pharmacological ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "18, inhibition ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "19, of ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "20, the ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "21, glutamate ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "22, transporter ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "23, xCT ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "24, (X(c-) ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "25, system, ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "26, encoded ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "27, by ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "28, SLC7a11) ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "29, in ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "30, vivo ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "the", + "glutamate", + "transporter", + "xCT", + "(X(c-)", + "system,", + "encoded", + "by", + "SLC7a11)" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "18376408", + "TEXT": "Sepsis is a complex, incompletely understood and often fatal disorder, typically accompanied by hypotension, that is considered to represent a dysregulated host response to infection. Neurotensin (NT) is a 13-amino-acid peptide that, among its multiple effects, induces hypotension. We find that intraperitoneal and plasma concentrations of NT are increased in mice after severe cecal ligation and puncture (CLP), a model of sepsis, and that mice treated with a pharmacological antagonist of NT, or NT-deficient mice, show reduced mortality during severe CLP. In mice, mast cells can degrade NT and reduce NT-induced hypotension and CLP-associated mortality, and optimal expression of these effects requires mast cell expression of neurotensin receptor 1 and neurolysin. These findings show that NT contributes to sepsis-related mortality in mice during severe CLP and that mast cells can lower NT concentrations, and suggest that mast cell-dependent reduction in NT levels contributes to the ability of mast cells to enhance survival after CLP.", + "TAG_DATA": [ + "50, mice {'context': 'B-organism'}", + "64, mice {'context': 'B-organism'}", + "68, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "69, antagonist {'perturbing_action': 'I-pharmacological inhibition'}", + "70, of {'perturbing_action': 'I-pharmacological inhibition'}", + "71, NT, {'perturbing_action': 'I-pharmacological inhibition'}", + "73, NT-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "74, mice, {'context': 'B-organism'}", + "82, mice, {'context': 'B-organism'}", + "83, mast {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "64, mice ['l0', 'l1', 'l2', 'l3']", + "68, pharmacological ['l0', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "69, antagonist ['l1', 'l4', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "70, of ['l2', 'l5', 'l11', 'l17', 'l18', 'l19', 'l20', 'l21']", + "71, NT, ['l3', 'l6', 'l12', 'l17', 'l22', 'l23', 'l24', 'l25']", + "73, NT-deficient ['l7', 'l13', 'l18', 'l22', 'l26', 'l27', 'l28']", + "74, mice, ['l8', 'l14', 'l19', 'l23', 'l26', 'l29', 'l30']", + "82, mice, ['l9', 'l15', 'l20', 'l24', 'l27', 'l29', 'l31']", + "83, mast ['l10', 'l16', 'l21', 'l25', 'l28', 'l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "antagonist", + "of", + "NT," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "antagonist", + "of", + "NT," + ] + }, + "context": { + "val": "cells", + "words": [ + "mast" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NT-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NT-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "mast" + ] + } + } + ] + }, + { + "PMID": "18376404", + "TEXT": "Microbial lung infections are the major cause of morbidity and mortality in the hereditary metabolic disorder cystic fibrosis, yet the molecular mechanisms leading from the mutation of cystic fibrosis transmembrane conductance regulator (CFTR) to lung infection are still unclear. Here, we show that ceramide age-dependently accumulates in the respiratory tract of uninfected Cftr-deficient mice owing to an alkalinization of intracellular vesicles in Cftr-deficient cells. This change in pH results in an imbalance between acid sphingomyelinase (Asm) cleavage of sphingomyelin to ceramide and acid ceramidase consumption of ceramide, resulting in the higher levels of ceramide. The accumulation of ceramide causes Cftr-deficient mice to suffer from constitutive age-dependent pulmonary inflammation, death of respiratory epithelial cells, deposits of DNA in bronchi and high susceptibility to severe Pseudomonas aeruginosa infections. Partial genetic deficiency of Asm in Cftr(-/-)Smpd1(+/-) mice or pharmacological treatment of Cftr-deficient mice with the Asm blocker amitriptyline normalizes pulmonary ceramide and prevents all pathological findings, including susceptibility to infection. These data suggest inhibition of Asm as a new treatment strategy for cystic fibrosis.", + "TAG_DATA": [ + "52, Cftr-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "53, mice {'context': 'B-organism'}", + "62, Cftr-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "63, cells. {'context': 'B-cells'}", + "99, Cftr-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "100, mice {'context': 'B-organism'}", + "110, respiratory {'context': 'B-cells'}", + "111, epithelial {'context': 'I-cells'}", + "112, cells, {'context': 'I-cells'}", + "126, Partial {'perturbing_action': 'B-gene loss-of-function'}", + "127, genetic {'perturbing_action': 'I-gene loss-of-function'}", + "128, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "129, of {'perturbing_action': 'I-gene loss-of-function'}", + "130, Asm {'perturbing_action': 'I-gene loss-of-function'}", + "132, Cftr(-/-)Smpd1(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "133, mice {'context': 'B-organism'}", + "138, Cftr-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "139, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "52, Cftr-deficient ['l0', 'l1', 'l2', 'l3']", + "53, mice ['l0', 'l4', 'l5', 'l6']", + "62, Cftr-deficient ['l1', 'l4', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "63, cells. ['l2', 'l5', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "99, Cftr-deficient ['l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "100, mice ['l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "110, respiratory ['l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "111, epithelial ['l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "112, cells, ['l3', 'l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "126, Partial ['l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "127, genetic ['l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "128, deficiency ['l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "129, of ['l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "130, Asm ['l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "132, Cftr(-/-)Smpd1(+/-) ['l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "133, mice ['l33', 'l38', 'l42', 'l45', 'l47', 'l48']", + "138, Cftr-deficient ['l49']", + "139, mice ['l49']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cftr-deficient", + "Partial", + "genetic", + "deficiency", + "of", + "Asm", + "Cftr(-/-)Smpd1(+/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cftr-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells.", + "cells,", + "respiratory", + "epithelial" + ] + } + } + ] + }, + { + "PMID": "18311150", + "TEXT": "Regulatory T cells (T(reg) cells) suppress autoreactive immune responses and limit the efficacy of tumor vaccines; however, it remains a challenge to selectively eliminate or inhibit T(reg) cells. In this study, the zinc-finger A20, a negative regulator of the Toll-like receptor and tumor necrosis factor receptor signaling pathways, was found to play a crucial part in controlling the maturation, cytokine production and immunostimulatory potency of dendritic cells (DCs). A20-silenced DCs showed spontaneous and enhanced expression of costimulatory molecules and proinflammatory cytokines and had different effects on T cell subsets: they inhibited T(reg) cells and hyperactivated tumor-infiltrating cytotoxic T lymphocytes and T helper cells that produced interleukin-6 and tumor necrosis factor-alpha and were refractory to T(reg) cell-mediated suppression. Hence, this study identifies A20 as an antigen presentation attenuator in control of antitumor immune responses during both the priming and the effector phases and provides a strategy to overcome T(reg) cell-mediated suppression in an antigen-specific manner, reducing the need to directly target T(reg) cells.", + "TAG_DATA": [ + "68, A20-silenced {'perturbing_action': 'B-rnai/knockdown'}", + "69, DCs {'context': 'B-cells'}", + "86, T {'context': 'B-cells'}", + "87, cell {'context': 'B-cells'}", + "88, subsets: {'context': 'I-cells'}", + "91, T(reg) {'context': 'B-cells'}", + "92, cells {'context': 'I-cells'}", + "98, lymphocytes {'context': 'I-cells'}", + "100, T {'context': 'B-cells'}", + "101, helper {'context': 'I-cells'}", + "102, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "68, A20-silenced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "69, DCs ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "86, T ['l1', 'l6', 'l11', 'l12', 'l13', 'l14', 'l15']", + "87, cell ['l2', 'l7', 'l11', 'l16', 'l17', 'l18', 'l19']", + "88, subsets: ['l3', 'l8', 'l12', 'l16', 'l20', 'l21', 'l22']", + "91, T(reg) ['l4', 'l9', 'l13', 'l17', 'l20', 'l23', 'l24']", + "92, cells ['l5', 'l10', 'l14', 'l18', 'l21', 'l23']", + "98, lymphocytes ['l15', 'l19', 'l22', 'l24', 'l25', 'l26', 'l27']", + "100, T ['l25', 'l28', 'l29']", + "101, helper ['l26', 'l28', 'l30']", + "102, cells ['l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "A20-silenced" + ] + }, + "context": { + "val": "cells", + "words": [ + "DCs", + "T", + "cell", + "subsets:", + "T(reg)", + "cells" + ] + } + } + ] + }, + { + "PMID": "18311149", + "TEXT": "The persistence of central memory CD4(+) T cells (T(CM) cells) is a major correlate of immunological protection in HIV/AIDS, as the rate of T(CM) cell decline predicts HIV disease progression. In this study, we show that T(CM) cells and effector memory CD4(+) T cells (T(EM) cells) from HIV(+) elite controller (EC) subjects are less susceptible to Fas-mediated apoptosis and persist longer after multiple rounds of T cell receptor triggering when compared to T(CM) and T(EM) cells from aviremic successfully treated (ST) subjects or from HIV(-) donors. We show that persistence of T(CM) cells from EC subjects is a direct consequence of inactivation of the FOXO3a pathway. Silencing the transcriptionally active form of FOXO3a by small interfering RNA or by introducing a FOXO3a dominant-negative form (FOXO3a Nt) extended the long-term survival of T(CM) cells from ST subjects to a length of time similar to that of T(CM) cells from EC subjects. The crucial role of FOXO3a in the survival of memory cells will help shed light on the underlying immunological mechanisms that control viral replication in EC subjects.", + "TAG_DATA": [ + "36, T(CM) {'context': 'B-cells'}", + "37, cells {'context': 'I-cells'}", + "39, effector {'context': 'B-cells'}", + "40, memory {'context': 'I-cells'}", + "41, CD4(+) {'context': 'I-cells'}", + "42, T {'context': 'I-cells'}", + "43, cells {'context': 'I-cells'}", + "44, (T(EM) {'context': 'I-cells'}", + "45, cells) {'context': 'I-cells'}", + "72, T(CM) {'context': 'B-cells'}", + "73, and {'context': 'I-cells'}", + "74, T(EM) {'context': 'I-cells'}", + "75, cells {'context': 'I-cells'}", + "91, T(CM) {'context': 'B-cells'}", + "92, cells {'context': 'I-cells'}", + "106, Silencing {'perturbing_action': 'B-rnai/knockdown'}", + "107, the {'perturbing_action': 'I-rnai/knockdown'}", + "108, transcriptionally {'perturbing_action': 'I-rnai/knockdown'}", + "109, active {'perturbing_action': 'I-rnai/knockdown'}", + "110, form {'perturbing_action': 'I-rnai/knockdown'}", + "111, of {'perturbing_action': 'I-rnai/knockdown'}", + "112, FOXO3a {'perturbing_action': 'I-rnai/knockdown'}", + "113, by {'perturbing_action': 'I-rnai/knockdown'}", + "114, small {'perturbing_action': 'I-rnai/knockdown'}", + "115, interfering {'perturbing_action': 'I-rnai/knockdown'}", + "116, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "119, introducing {'perturbing_action': 'B-other'}", + "120, a {'perturbing_action': 'I-other'}", + "121, FOXO3a {'perturbing_action': 'I-other'}", + "122, dominant-negative {'perturbing_action': 'I-other'}", + "123, form {'perturbing_action': 'I-other'}", + "124, (FOXO3a {'perturbing_action': 'I-other'}", + "125, Nt) {'perturbing_action': 'I-other'}", + "131, T(CM) {'context': 'B-cells'}", + "132, cells {'context': 'I-cells'}", + "145, T(CM) {'context': 'B-cells'}", + "146, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "36, T(CM) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "37, cells ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "39, effector ['l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "40, memory ['l14', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "41, CD4(+) ['l15', 'l26', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "42, T ['l16', 'l27', 'l37', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "43, cells ['l1', 'l8', 'l17', 'l28', 'l38', 'l47', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "44, (T(EM) ['l2', 'l9', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "45, cells) ['l3', 'l10', 'l19', 'l30', 'l40', 'l49', 'l57', 'l63', 'l69', 'l70', 'l71', 'l72', 'l73']", + "72, T(CM) ['l4', 'l11', 'l20', 'l31', 'l41', 'l50', 'l58', 'l64', 'l69', 'l74', 'l75', 'l76', 'l77']", + "73, and ['l5', 'l12', 'l21', 'l32', 'l42', 'l51', 'l59', 'l65', 'l70', 'l74', 'l78', 'l79']", + "74, T(EM) ['l6', 'l22', 'l33', 'l43', 'l52', 'l60', 'l66', 'l71', 'l75', 'l78', 'l80', 'l81']", + "75, cells ['l7', 'l13', 'l23', 'l34', 'l44', 'l53', 'l61', 'l67', 'l72', 'l76', 'l79', 'l80']", + "91, T(CM) ['l24', 'l35', 'l45', 'l54', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "92, cells ['l25', 'l36', 'l46', 'l55', 'l62', 'l68', 'l73', 'l77', 'l81', 'l82', 'l92']", + "106, Silencing ['l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "107, the ['l83', 'l93', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "108, transcriptionally ['l94', 'l106', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "109, active ['l84', 'l95', 'l107', 'l117', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "110, form ['l85', 'l96', 'l108', 'l118', 'l127', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "111, of ['l86', 'l97', 'l109', 'l119', 'l128', 'l136', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "112, FOXO3a ['l87', 'l98', 'l110', 'l120', 'l129', 'l137', 'l143', 'l149', 'l150', 'l151', 'l152', 'l153']", + "113, by ['l88', 'l99', 'l111', 'l121', 'l130', 'l138', 'l144', 'l149', 'l154', 'l155', 'l156', 'l157']", + "114, small ['l89', 'l100', 'l112', 'l122', 'l131', 'l139', 'l145', 'l150', 'l154', 'l158', 'l159', 'l160']", + "115, interfering ['l90', 'l92', 'l101', 'l113', 'l123', 'l132', 'l140', 'l146', 'l151', 'l155', 'l158', 'l161']", + "116, RNA ['l91', 'l102', 'l114', 'l124', 'l133', 'l141', 'l147', 'l152', 'l156', 'l159', 'l161']", + "119, introducing ['l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171']", + "120, a ['l162', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180']", + "121, FOXO3a ['l163', 'l172', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "122, dominant-negative ['l164', 'l173', 'l181', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195']", + "123, form ['l165', 'l174', 'l182', 'l189', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201']", + "124, (FOXO3a ['l166', 'l175', 'l183', 'l190', 'l196', 'l202', 'l203', 'l204', 'l205', 'l206']", + "125, Nt) ['l167', 'l176', 'l184', 'l191', 'l197', 'l202', 'l207', 'l208', 'l209', 'l210']", + "131, T(CM) ['l103', 'l115', 'l125', 'l134', 'l168', 'l177', 'l185', 'l192', 'l198', 'l203', 'l207', 'l211', 'l212', 'l213']", + "132, cells ['l104', 'l116', 'l126', 'l135', 'l142', 'l148', 'l153', 'l157', 'l160', 'l169', 'l178', 'l186', 'l193', 'l199', 'l204', 'l208', 'l211', 'l214', 'l215']", + "145, T(CM) ['l170', 'l179', 'l187', 'l194', 'l200', 'l205', 'l209', 'l212', 'l214', 'l216']", + "146, cells ['l105', 'l171', 'l180', 'l188', 'l195', 'l201', 'l206', 'l210', 'l213', 'l215', 'l216']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T(CM)", + "cells" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "the", + "active", + "form", + "of", + "FOXO3a", + "by", + "small", + "interfering", + "RNA", + "Silencing", + "transcriptionally" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "introducing", + "a", + "FOXO3a", + "dominant-negative", + "form", + "(FOXO3a", + "Nt)" + ] + }, + "context": { + "val": "cells", + "words": [ + "T(CM)", + "cells" + ] + } + } + ] + }, + { + "PMID": "18297083", + "TEXT": "Postnatal bone marrow houses mesenchymal progenitor cells that are osteoblast precursors. These cells have established therapeutic potential, but they are difficult to maintain and expand in vitro, presumably because little is known about the mechanisms controlling their fate decisions. To investigate the potential role of Notch signaling in osteoblastogenesis, we used conditional alleles to genetically remove components of the Notch signaling system during skeletal development. We found that disruption of Notch signaling in the limb skeletogenic mesenchyme markedly increased trabecular bone mass in adolescent mice. Notably, mesenchymal progenitors were undetectable in the bone marrow of mice with high bone mass. As a result, these mice developed severe osteopenia as they aged. Moreover, Notch signaling seemed to inhibit osteoblast differentiation through Hes or Hey proteins, which diminished Runx2 transcriptional activity via physical interaction. These results support a model wherein Notch signaling in bone marrow normally acts to maintain a pool of mesenchymal progenitors by suppressing osteoblast differentiation. Thus, mesenchymal progenitors may be expanded in vitro by activating the Notch pathway, whereas bone formation in vivo may be enhanced by transiently suppressing this pathway.", + "TAG_DATA": [ + "74, limb {'context': 'B-tissue/organ'}", + "75, skeletogenic {'context': 'I-tissue/organ'}", + "76, mesenchyme {'context': 'I-tissue/organ'}", + "83, adolescent {'context': 'B-organism'}", + "84, mice. {'context': 'I-organism'}", + "95, mice {'context': 'B-organism'}", + "104, mice {'context': 'B-organism'}", + "116, inhibit {'effect': 'B-negative'}", + "117, osteoblast {'context': 'B-cells'}", + "118, differentiation {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "74, limb ['l0', 'l1', 'l2', 'l3', 'l4']", + "75, skeletogenic ['l0', 'l5', 'l6', 'l7', 'l8']", + "76, mesenchyme ['l1', 'l5', 'l9', 'l10', 'l11']", + "83, adolescent ['l2', 'l6', 'l9', 'l12']", + "84, mice. ['l3', 'l7', 'l10', 'l12']", + "95, mice ['l4', 'l8', 'l11']", + "116, inhibit ['l13', 'l14']", + "117, osteoblast ['l13', 'l15']", + "118, differentiation ['l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoblast" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoblast" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "18278052", + "TEXT": "Normalization of tumor vasculature is an emerging strategy to improve cytotoxic therapies. Here we show that eliminating nitric oxide (NO) production from tumor cells via neuronal NO synthase silencing or inhibition establishes perivascular gradients of NO in human glioma xenografts in mice and normalizes the tumor vasculature, resulting in improved tumor oxygenation and response to radiation treatment. Creation of perivascular NO gradients may be an effective strategy for normalizing abnormal vasculature.", + "TAG_DATA": [ + "25, neuronal {'perturbing_action': 'B-rnai/knockdown'}", + "26, NO {'perturbing_action': 'I-rnai/knockdown'}", + "27, synthase {'perturbing_action': 'I-rnai/knockdown'}", + "28, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "37, human {'context': 'B-xenograft'}", + "38, glioma {'context': 'I-xenograft'}", + "39, xenografts {'context': 'I-xenograft'}", + "41, mice {'context': 'B-organism'}", + "45, tumor {'context': 'B-neoplasm'}", + "50, tumor {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "25, neuronal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "26, NO ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "27, synthase ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "28, silencing ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "37, human ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "38, glioma ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32', 'l33']", + "39, xenografts ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l34', 'l35']", + "41, mice ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l34', 'l36']", + "45, tumor ['l32', 'l37']", + "50, tumor ['l7', 'l14', 'l20', 'l25', 'l29', 'l33', 'l35', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "neuronal", + "NO", + "synthase", + "silencing" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "human", + "glioma", + "xenografts" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "neuronal", + "NO", + "synthase", + "silencing" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "neuronal", + "NO", + "synthase", + "silencing" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + } + ] + }, + { + "PMID": "18246080", + "TEXT": "Beta-catenin is a central molecule in the Wnt pathway. Expression of a stable form of beta-catenin on CD4+CD25+ regulatory T (T(reg)) cells resulted in a marked enhancement of survival of these cells in vitro. Furthermore, stable beta-catenin-expressing CD4+CD25+ T(reg) cells outcompeted control T(reg) cells in vivo, and the number of T(reg) cells necessary for protection against inflammatory bowel disease could be substantially reduced when stable beta-catenin-expressing CD4+CD25+ T(reg) cells were used instead of control T(reg) cells. Expression of stable beta-catenin on potentially pathogenic CD4+CD25- T cells rendered these cells anergic, and the beta-catenin-mediated induction of anergy occurred even in Foxp3-deficient T cells. Thus, through enhanced survival of existing regulatory T cells, and through induction of unresponsiveness in precursors of T effector cells, beta-catenin stabilization has a powerful effect on the prevention of inflammatory disease.", + "TAG_DATA": [ + "10, of {'perturbing_action': 'I-gene gain-of-function'}", + "11, a {'perturbing_action': 'I-gene gain-of-function'}", + "12, stable {'perturbing_action': 'I-gene gain-of-function'}", + "13, form {'perturbing_action': 'I-gene gain-of-function'}", + "14, of {'perturbing_action': 'I-gene gain-of-function'}", + "15, beta-catenin {'perturbing_action': 'I-gene gain-of-function'}", + "17, CD4+CD25+ {'context': 'B-cells'}", + "18, regulatory {'context': 'I-cells'}", + "19, T {'context': 'I-cells'}", + "20, (T(reg)) {'context': 'I-cells'}", + "21, cells {'context': 'I-cells'}", + "31, cells {'context': 'B-cells'}", + "32, in {'context': 'B-in vitro'}", + "33, vitro. {'context': 'I-in vitro'}", + "37, CD4+CD25+ {'context': 'I-cells'}", + "38, T(reg) {'context': 'I-cells'}", + "39, cells {'context': 'I-cells'}", + "42, T(reg) {'context': 'B-cells'}", + "43, cells {'context': 'I-cells'}", + "44, in {'context': 'B-in vivo'}", + "45, vivo, {'context': 'I-in vivo'}", + "50, T(reg) {'context': 'B-cells'}", + "51, cells {'context': 'I-cells'}", + "66, CD4+CD25+ {'context': 'I-cells'}", + "67, T(reg) {'context': 'I-cells'}", + "68, cells {'context': 'I-cells'}", + "74, T(reg) {'context': 'B-cells'}", + "76, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "77, of {'perturbing_action': 'I-gene gain-of-function'}", + "78, stable {'perturbing_action': 'I-gene gain-of-function'}", + "79, beta-catenin {'perturbing_action': 'I-gene gain-of-function'}", + "83, CD4+CD25- {'context': 'B-cells'}", + "84, T {'context': 'I-cells'}", + "85, cells {'context': 'I-cells'}", + "88, cells {'context': 'B-cells'}", + "99, Foxp3-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "100, T {'context': 'B-cells'}", + "101, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "10, of ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "11, a ['l0', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "12, stable ['l1', 'l22', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "13, form ['l2', 'l23', 'l43', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "14, of ['l3', 'l24', 'l44', 'l63', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "15, beta-catenin ['l4', 'l25', 'l45', 'l64', 'l82', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "17, CD4+CD25+ ['l5', 'l26', 'l46', 'l65', 'l83', 'l100', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "18, regulatory ['l6', 'l27', 'l47', 'l66', 'l84', 'l101', 'l117', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139']", + "19, T ['l7', 'l28', 'l48', 'l67', 'l85', 'l102', 'l118', 'l130', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146']", + "20, (T(reg)) ['l8', 'l29', 'l49', 'l68', 'l86', 'l103', 'l119', 'l131', 'l140', 'l147', 'l148', 'l149', 'l150']", + "21, cells ['l9', 'l30', 'l50', 'l69', 'l87', 'l104', 'l120', 'l132', 'l141', 'l147', 'l151', 'l152', 'l153']", + "31, cells ['l10', 'l31', 'l51', 'l70', 'l88', 'l105', 'l121', 'l133', 'l142', 'l148', 'l151']", + "32, in ['l11', 'l32', 'l52', 'l71', 'l89', 'l106', 'l122', 'l134', 'l143', 'l149', 'l152', 'l154']", + "33, vitro. ['l12', 'l33', 'l53', 'l72', 'l90', 'l107', 'l123', 'l135', 'l144', 'l150', 'l153', 'l154']", + "37, CD4+CD25+ ['l13', 'l34', 'l54', 'l73', 'l91', 'l108', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168']", + "38, T(reg) ['l14', 'l35', 'l55', 'l74', 'l92', 'l109', 'l155', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180']", + "39, cells ['l15', 'l36', 'l56', 'l75', 'l93', 'l110', 'l124', 'l136', 'l156', 'l169', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "42, T(reg) ['l16', 'l37', 'l57', 'l76', 'l94', 'l111', 'l157', 'l170', 'l181', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196']", + "43, cells ['l17', 'l38', 'l58', 'l77', 'l95', 'l112', 'l125', 'l137', 'l145', 'l158', 'l171', 'l182', 'l189', 'l197', 'l198', 'l199', 'l200']", + "44, in ['l18', 'l39', 'l59', 'l78', 'l96', 'l113', 'l126', 'l159', 'l172', 'l183', 'l190', 'l197', 'l201', 'l202', 'l203', 'l204']", + "45, vivo, ['l19', 'l40', 'l60', 'l79', 'l97', 'l114', 'l127', 'l160', 'l173', 'l184', 'l191', 'l198', 'l201', 'l205', 'l206']", + "50, T(reg) ['l20', 'l41', 'l61', 'l80', 'l98', 'l115', 'l128', 'l138', 'l161', 'l174', 'l185', 'l192', 'l199', 'l202', 'l205', 'l207', 'l208', 'l209', 'l210']", + "51, cells ['l21', 'l42', 'l62', 'l81', 'l99', 'l116', 'l129', 'l139', 'l146', 'l162', 'l175', 'l186', 'l193', 'l200', 'l203', 'l206', 'l207', 'l211']", + "66, CD4+CD25+ ['l163', 'l176', 'l194', 'l208', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218']", + "67, T(reg) ['l164', 'l177', 'l187', 'l195', 'l209', 'l212', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224']", + "68, cells ['l165', 'l178', 'l188', 'l196', 'l204', 'l210', 'l211', 'l213', 'l219', 'l225', 'l226', 'l227', 'l228']", + "74, T(reg) ['l166', 'l179', 'l214', 'l220', 'l225', 'l229', 'l230', 'l231', 'l232']", + "76, Expression ['l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242']", + "77, of ['l233', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251']", + "78, stable ['l234', 'l243', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259']", + "79, beta-catenin ['l235', 'l244', 'l252', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266']", + "83, CD4+CD25- ['l215', 'l221', 'l229', 'l236', 'l245', 'l253', 'l260', 'l267', 'l268', 'l269', 'l270', 'l271']", + "84, T ['l167', 'l216', 'l222', 'l226', 'l230', 'l237', 'l246', 'l254', 'l261', 'l267', 'l272', 'l273']", + "85, cells ['l168', 'l180', 'l217', 'l223', 'l227', 'l231', 'l238', 'l247', 'l255', 'l262', 'l268', 'l272', 'l274']", + "88, cells ['l218', 'l224', 'l228', 'l232', 'l239', 'l248', 'l256', 'l263', 'l269', 'l273', 'l274']", + "99, Foxp3-deficient ['l240', 'l249', 'l257', 'l264', 'l275', 'l276']", + "100, T ['l241', 'l250', 'l258', 'l265', 'l270', 'l275', 'l277']", + "101, cells. ['l242', 'l251', 'l259', 'l266', 'l271', 'l276', 'l277']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "a", + "stable", + "form", + "beta-catenin", + "Expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+CD25+", + "regulatory", + "T", + "(T(reg))", + "cells", + "T(reg)", + "CD4+CD25-", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "a", + "stable", + "form", + "beta-catenin" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "a", + "stable", + "form", + "beta-catenin" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Foxp3-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells." + ] + } + } + ] + }, + { + "PMID": "18204461", + "TEXT": "Little progress has been made toward the use of embryonic stem (ES) cells to study and isolate skeletal muscle progenitors. This is due to the paucity of paraxial mesoderm formation during embryoid body (EB) in vitro differentiation and to the lack of reliable identification and isolation criteria for skeletal muscle precursors. Here we show that expression of the transcription factor Pax3 during embryoid body differentiation enhances both paraxial mesoderm formation and the myogenic potential of the cells within this population. Transplantation of Pax3-induced cells results in teratomas, however, indicating the presence of residual undifferentiated cells. By sorting for the PDGF-alpha receptor, a marker of paraxial mesoderm, and for the absence of Flk-1, a marker of lateral plate mesoderm, we derive a cell population from differentiating ES cell cultures that has substantial muscle regeneration potential. Intramuscular and systemic transplantation of these cells into dystrophic mice results in extensive engraftment of adult myofibers with enhanced contractile function without the formation of teratomas. These data demonstrate the therapeutic potential of ES cells in muscular dystrophy.", + "TAG_DATA": [ + "83, cells {'context': 'B-cells'}", + "84, results {'effect': 'B-positive'}", + "85, in {'effect': 'I-positive'}", + "86, teratomas, {'phenotype': 'B-tumourigenesis'}", + "142, dystrophic {'context': 'B-organism'}", + "143, mice {'context': 'I-organism'}", + "149, adult {'context': 'B-cells'}", + "150, myofibers {'context': 'I-cells'}", + "155, without {'effect': 'B-no effect'}", + "156, the {'effect': 'I-no effect'}", + "157, formation {'effect': 'I-no effect'}", + "159, teratomas. {'phenotype': 'B-tumourigenesis'}" + ], + "LINK_DATA": [ + "83, cells ['l0', 'l1', 'l2']", + "84, results ['l0', 'l3', 'l4']", + "85, in ['l1', 'l3', 'l5']", + "86, teratomas, ['l2', 'l4', 'l5']", + "126, cell ['l6', 'l7', 'l8', 'l9', 'l10']", + "142, dystrophic ['l6', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "143, mice ['l7', 'l11', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "149, adult ['l8', 'l12', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "150, myofibers ['l9', 'l13', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32']", + "155, without ['l10', 'l14', 'l20', 'l25', 'l29', 'l33', 'l34', 'l35']", + "156, the ['l15', 'l21', 'l26', 'l30', 'l33', 'l36', 'l37']", + "157, formation ['l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l38']", + "159, teratomas. ['l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "adult", + "myofibers" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "teratomas,", + "teratomas." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "teratomas," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "dystrophic", + "mice" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "without", + "the", + "formation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "dystrophic", + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "teratomas." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "adult", + "myofibers" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "without", + "the", + "formation" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "without", + "the", + "formation" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "teratomas." + ] + } + } + ] + }, + { + "PMID": "18204460", + "TEXT": "Insulin receptor substrate (IRS)-1 and IRS-2 have dominant roles in the action of insulin, but other substrates of the insulin receptor kinase, such as Gab1, c-Cbl, SH2-B and APS, are also of physiological relevance. Although the protein downstream of tyrosine kinases-1 (Dok1) is known to function as a multisite adapter molecule in insulin signaling, its role in energy homeostasis has remained unclear. Here we show that Dok1 regulates adiposity. Expression of Dok1 in white adipose tissue was markedly increased in mice fed a high-fat diet, whereas adipocytes lacking this adapter were smaller and showed a reduced hypertrophic response to this dietary manipulation. Dok1-deficient mice were leaner and showed improved glucose tolerance and insulin sensitivity compared with wild-type mice. Embryonic fibroblasts from Dok1-deficient mice were impaired in adipogenic differentiation, and this defect was accompanied by an increased activity of the protein kinase ERK and a consequent increase in the phosphorylation of peroxisome proliferator-activated receptor (PPAR)-gamma on Ser112. Mutation of this negative regulatory site for the transactivation activity of PPAR-gamma blocked development of the lean phenotype caused by Dok1 ablation. These results indicate that Dok1 promotes adipocyte hypertrophy by counteracting the inhibitory effect of ERK on PPAR-gamma and may thus confer predisposition to diet-induced obesity.", + "TAG_DATA": [ + "80, mice {'context': 'B-organism'}", + "86, adipocytes {'context': 'B-cells'}", + "102, Dok1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "103, mice {'context': 'B-organism'}", + "118, Embryonic {'context': 'B-cells'}", + "119, fibroblasts {'context': 'I-cells'}", + "121, Dok1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "122, mice {'context': 'B-organism'}", + "124, impaired {'effect': 'B-negative'}", + "126, adipogenic {'phenotype': 'B-differentiation'}", + "127, differentiation, {'phenotype': 'I-differentiation'}", + "156, Mutation {'perturbing_action': 'B-other'}", + "157, of {'perturbing_action': 'I-other'}", + "158, this {'perturbing_action': 'I-other'}", + "159, negative {'perturbing_action': 'I-other'}", + "160, regulatory {'perturbing_action': 'I-other'}", + "161, site {'perturbing_action': 'I-other'}", + "162, for {'perturbing_action': 'I-other'}", + "163, the {'perturbing_action': 'I-other'}", + "164, transactivation {'perturbing_action': 'I-other'}", + "165, activity {'perturbing_action': 'I-other'}", + "166, of {'perturbing_action': 'I-other'}", + "167, PPAR-gamma {'perturbing_action': 'I-other'}", + "176, Dok1 {'perturbing_action': 'B-gene loss-of-function'}", + "177, ablation. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "80, mice ['l0']", + "86, adipocytes ['l0']", + "102, Dok1-deficient ['l1', 'l2', 'l3', 'l4']", + "103, mice ['l1', 'l5']", + "118, Embryonic ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "119, fibroblasts ['l6', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "121, Dok1-deficient ['l7', 'l22', 'l37', 'l38', 'l39', 'l40']", + "122, mice ['l8', 'l23', 'l37', 'l41', 'l42', 'l43']", + "124, impaired ['l2', 'l9', 'l24', 'l38', 'l41', 'l44', 'l45']", + "126, adipogenic ['l3', 'l10', 'l25', 'l39', 'l42', 'l44', 'l46']", + "127, differentiation, ['l4', 'l5', 'l11', 'l26', 'l40', 'l43', 'l45', 'l46']", + "156, Mutation ['l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "157, of ['l47', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "158, this ['l12', 'l27', 'l48', 'l60', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "159, negative ['l13', 'l28', 'l49', 'l61', 'l72', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "160, regulatory ['l14', 'l29', 'l50', 'l62', 'l73', 'l83', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "161, site ['l15', 'l30', 'l51', 'l63', 'l74', 'l84', 'l93', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "162, for ['l16', 'l31', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "163, the ['l17', 'l32', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "164, transactivation ['l18', 'l33', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l123', 'l124', 'l125', 'l126', 'l127']", + "165, activity ['l19', 'l34', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l118', 'l123', 'l128', 'l129', 'l130', 'l131']", + "166, of ['l20', 'l35', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l113', 'l119', 'l124', 'l128', 'l132', 'l133', 'l134']", + "167, PPAR-gamma ['l21', 'l36', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l129', 'l132', 'l135', 'l136']", + "176, Dok1 ['l58', 'l70', 'l81', 'l91', 'l100', 'l108', 'l115', 'l121', 'l126', 'l130', 'l133', 'l135', 'l137']", + "177, ablation. ['l59', 'l71', 'l82', 'l92', 'l101', 'l109', 'l116', 'l122', 'l127', 'l131', 'l134', 'l136', 'l137']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dok1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dok1-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dok1-deficient" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "adipogenic", + "differentiation," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation,", + "adipogenic" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Embryonic", + "fibroblasts" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dok1-deficient" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Embryonic", + "fibroblasts" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Embryonic", + "fibroblasts" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "adipogenic", + "differentiation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Embryonic", + "fibroblasts" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "this", + "negative", + "regulatory", + "site", + "for", + "the", + "transactivation", + "activity", + "of", + "PPAR-gamma" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "adipogenic", + "differentiation," + ] + } + } + ] + }, + { + "PMID": "18193058", + "TEXT": "The capacity to direct migration ('homing') of blood-borne cells to a predetermined anatomic compartment is vital to stem cell-based tissue engineering and other adoptive cellular therapies. Although multipotent mesenchymal stromal cells (MSCs, also termed 'mesenchymal stem cells') hold the potential for curing generalized skeletal diseases, their clinical effectiveness is constrained by the poor osteotropism of infused MSCs (refs. 1-3). Cellular recruitment to bone occurs within specialized marrow vessels that constitutively express vascular E-selectin, a lectin that recognizes sialofucosylated determinants on its various ligands. We show here that human MSCs do not express E-selectin ligands, but express a CD44 glycoform bearing alpha-2,3-sialyl modifications. Using an alpha-1,3-fucosyltransferase preparation and enzymatic conditions specifically designed for treating live cells, we converted the native CD44 glycoform on MSCs into hematopoietic cell E-selectin/L-selectin ligand (HCELL), which conferred potent E-selectin binding without effects on cell viability or multipotency. Real-time intravital microscopy in immunocompromised (NOD/SCID) mice showed that intravenously infused HCELL(+) MSCs infiltrated marrow within hours of infusion, with ensuing rare foci of endosteally localized cells and human osteoid generation. These findings establish that the HCELL glycoform of CD44 confers tropism to bone and unveil a readily translatable roadmap for programming cellular trafficking by chemical engineering of glycans on a distinct membrane glycoprotein.", + "TAG_DATA": [ + "122, MSCs {'context': 'B-cells'}", + "134, without {'effect': 'B-no effect'}", + "135, effects {'effect': 'I-no effect'}", + "137, cell {'phenotype': 'B-cell survival'}", + "138, viability {'phenotype': 'I-cell survival'}", + "145, immunocompromised {'context': 'B-organism'}", + "146, (NOD/SCID) {'context': 'I-organism'}", + "147, mice {'context': 'B-organism'}", + "152, HCELL(+) {'context': 'B-cells'}", + "153, MSCs {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "122, MSCs ['l0', 'l1', 'l2', 'l3']", + "134, without ['l0', 'l4', 'l5', 'l6']", + "135, effects ['l1', 'l4', 'l7', 'l8']", + "137, cell ['l2', 'l5', 'l7', 'l9']", + "138, viability ['l3', 'l6', 'l8', 'l9']", + "145, immunocompromised ['l10', 'l11', 'l12', 'l13']", + "146, (NOD/SCID) ['l10', 'l14', 'l15', 'l16']", + "147, mice ['l11', 'l14', 'l17']", + "152, HCELL(+) ['l12', 'l15', 'l18']", + "153, MSCs ['l13', 'l16', 'l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "MSCs" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "without", + "effects" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "MSCs" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "viability" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "without", + "effects" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "viability" + ] + } + } + ] + }, + { + "PMID": "18157143", + "TEXT": "Spinal cord injuries (SCIs) in humans and experimental animals are often associated with varying degrees of spontaneous functional recovery during the first months after injury. Such recovery is widely attributed to axons spared from injury that descend from the brain and bypass incomplete lesions, but its mechanisms are uncertain. To investigate the neural basis of spontaneous recovery, we used kinematic, physiological and anatomical analyses to evaluate mice with various combinations of spatially and temporally separated lateral hemisections with or without the excitotoxic ablation of intrinsic spinal cord neurons. We show that propriospinal relay connections that bypass one or more injury sites are able to mediate spontaneous functional recovery and supraspinal control of stepping, even when there has been essentially total and irreversible interruption of long descending supraspinal pathways in mice. Our findings show that pronounced functional recovery can occur after severe SCI without the maintenance or regeneration of direct projections from the brain past the lesion and can be mediated by the reorganization of descending and propriospinal connections. Targeting interventions toward augmenting the remodeling of relay connections may provide new therapeutic strategies to bypass lesions and restore function after SCI and in other conditions such as stroke and multiple sclerosis.", + "TAG_DATA": [ + "66, mice {'context': 'B-organism'}", + "82, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "84, intrinsic {'context': 'B-cells'}", + "85, spinal {'context': 'I-cells'}", + "86, cord {'context': 'I-cells'}", + "87, neurons. {'context': 'I-cells'}", + "129, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "82, ablation ['l0', 'l1', 'l2', 'l3', 'l4']", + "84, intrinsic ['l0', 'l5', 'l6', 'l7', 'l8']", + "85, spinal ['l1', 'l5', 'l9', 'l10', 'l11']", + "86, cord ['l2', 'l6', 'l9', 'l12', 'l13']", + "87, neurons. ['l3', 'l7', 'l10', 'l12', 'l14']", + "129, mice. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablation" + ] + }, + "context": { + "val": "cells", + "words": [ + "intrinsic", + "spinal", + "cord", + "neurons." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "18157142", + "TEXT": "In spite of their having sufficient immunogenicity, tumor vaccines remain largely ineffective. The mechanisms underlying this lack of efficacy are still unclear. Here we report a previously undescribed mechanism by which the tumor endothelium prevents T cell homing and hinders tumor immunotherapy. Transcriptional profiling of microdissected tumor endothelial cells from human ovarian cancers revealed genes associated with the absence or presence of tumor-infiltrating lymphocytes (TILs). Overexpression of the endothelin B receptor (ET(B)R) was associated with the absence of TILs and short patient survival time. The ET(B)R inhibitor BQ-788 increased T cell adhesion to human endothelium in vitro, an effect countered by intercellular adhesion molecule-1 (ICAM-1) blockade or treatment with NO donors. In mice, ET(B)R neutralization by BQ-788 increased T cell homing to tumors; this homing required ICAM-1 and enabled tumor response to otherwise ineffective immunotherapy in vivo without changes in systemic antitumor immune response. These findings highlight a molecular mechanism with the potential to be pharmacologically manipulated to enhance the efficacy of tumor immunotherapy in humans.", + "TAG_DATA": [ + "65, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "66, of {'perturbing_action': 'I-gene gain-of-function'}", + "67, the {'perturbing_action': 'I-gene gain-of-function'}", + "68, endothelin {'perturbing_action': 'I-gene gain-of-function'}", + "69, B {'perturbing_action': 'I-gene gain-of-function'}", + "70, receptor {'perturbing_action': 'I-gene gain-of-function'}", + "71, (ET(B)R) {'perturbing_action': 'I-gene gain-of-function'}", + "85, ET(B)R {'perturbing_action': 'B-pharmacological inhibition'}", + "86, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "87, BQ-788 {'perturbing_action': 'I-pharmacological inhibition'}", + "88, increased {'effect': 'B-positive'}", + "89, T {'context': 'B-cells'}", + "90, cell {'context': 'B-cells'}", + "91, adhesion {'phenotype': 'B-adhesion'}", + "93, human {'context': 'B-tissue/organ'}", + "94, endothelium {'context': 'I-tissue/organ'}", + "95, in {'context': 'B-in vitro'}", + "96, vitro, {'context': 'I-in vitro'}", + "112, mice, {'context': 'B-organism'}", + "113, ET(B)R {'perturbing_action': 'B-pharmacological inhibition'}", + "114, neutralization {'perturbing_action': 'I-pharmacological inhibition'}", + "115, by {'perturbing_action': 'I-pharmacological inhibition'}", + "116, BQ-788 {'perturbing_action': 'I-pharmacological inhibition'}", + "118, T {'context': 'B-cells'}", + "119, cell {'context': 'B-cells'}", + "122, tumors; {'context': 'B-neoplasm'}", + "129, tumor {'context': 'B-neoplasm'}", + "135, in {'context': 'B-in vivo'}", + "136, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "65, Overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "66, of ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "67, the ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "68, endothelin ['l2', 'l16', 'l29', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "69, B ['l3', 'l17', 'l30', 'l44', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "70, receptor ['l4', 'l18', 'l31', 'l45', 'l58', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "71, (ET(B)R) ['l5', 'l19', 'l32', 'l46', 'l59', 'l71', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "85, ET(B)R ['l33', 'l47', 'l60', 'l72', 'l83', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "86, inhibitor ['l34', 'l48', 'l61', 'l73', 'l84', 'l94', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "87, BQ-788 ['l6', 'l20', 'l35', 'l49', 'l62', 'l74', 'l85', 'l95', 'l104', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "88, increased ['l7', 'l21', 'l36', 'l50', 'l63', 'l75', 'l86', 'l96', 'l105', 'l113', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127']", + "89, T ['l8', 'l22', 'l37', 'l51', 'l64', 'l76', 'l87', 'l97', 'l106', 'l114', 'l121', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "90, cell ['l9', 'l23', 'l38', 'l52', 'l65', 'l77', 'l88', 'l98', 'l107', 'l115', 'l122', 'l128', 'l134', 'l135', 'l136', 'l137', 'l138']", + "91, adhesion ['l10', 'l24', 'l39', 'l53', 'l66', 'l78', 'l89', 'l99', 'l108', 'l116', 'l123', 'l129', 'l134', 'l139', 'l140', 'l141', 'l142']", + "93, human ['l11', 'l25', 'l40', 'l54', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l124', 'l130', 'l135', 'l139', 'l143', 'l144', 'l145']", + "94, endothelium ['l12', 'l26', 'l41', 'l55', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l125', 'l131', 'l136', 'l140', 'l143', 'l146', 'l147']", + "95, in ['l13', 'l27', 'l42', 'l56', 'l69', 'l81', 'l92', 'l102', 'l111', 'l119', 'l126', 'l132', 'l137', 'l141', 'l144', 'l146', 'l148']", + "96, vitro, ['l14', 'l28', 'l43', 'l57', 'l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l127', 'l133', 'l138', 'l142', 'l145', 'l147', 'l148']", + "112, mice, ['l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158']", + "113, ET(B)R ['l149', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "114, neutralization ['l150', 'l159', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175']", + "115, by ['l151', 'l160', 'l168', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "116, BQ-788 ['l152', 'l161', 'l169', 'l176', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "118, T ['l153', 'l162', 'l170', 'l177', 'l183', 'l189', 'l190', 'l191', 'l192', 'l193']", + "119, cell ['l154', 'l163', 'l171', 'l178', 'l184', 'l189', 'l194', 'l195', 'l196', 'l197']", + "122, tumors; ['l155', 'l164', 'l172', 'l179', 'l185', 'l190', 'l194', 'l198', 'l199', 'l200']", + "129, tumor ['l156', 'l165', 'l173', 'l180', 'l186', 'l191', 'l195', 'l198', 'l201', 'l202']", + "135, in ['l157', 'l166', 'l174', 'l181', 'l187', 'l192', 'l196', 'l199', 'l201', 'l203']", + "136, vivo ['l158', 'l167', 'l175', 'l182', 'l188', 'l193', 'l197', 'l200', 'l202', 'l203']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "the", + "endothelin", + "B", + "receptor", + "(ET(B)R)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "the", + "endothelin", + "B", + "receptor", + "(ET(B)R)" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "the", + "endothelin", + "B", + "receptor", + "(ET(B)R)" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "the", + "endothelin", + "B", + "receptor", + "(ET(B)R)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "human", + "endothelium" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "the", + "endothelin", + "B", + "receptor", + "(ET(B)R)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ET(B)R", + "inhibitor", + "BQ-788" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ET(B)R", + "inhibitor", + "BQ-788", + "neutralization", + "by" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ET(B)R", + "inhibitor", + "BQ-788" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ET(B)R", + "inhibitor", + "BQ-788" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "human", + "endothelium" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ET(B)R", + "inhibitor", + "BQ-788" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "human", + "endothelium" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "human", + "endothelium" + ] + } + }, + { + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ET(B)R", + "neutralization", + "by", + "BQ-788" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ET(B)R", + "neutralization", + "by", + "BQ-788" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors;", + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ET(B)R", + "neutralization", + "by", + "BQ-788" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "18066075", + "TEXT": "Aberrant wound-healing responses to injury have been implicated in the development of pulmonary fibrosis, but the mediators directing these pathologic responses have yet to be fully identified. We show that lysophosphatidic acid levels increase in bronchoalveolar lavage fluid following lung injury in the bleomycin model of pulmonary fibrosis, and that mice lacking one of its receptors, LPA1, are markedly protected from fibrosis and mortality in this model. The absence of LPA1 led to reduced fibroblast recruitment and vascular leak, two responses that may be excessive when injury leads to fibrosis rather than to repair, whereas leukocyte recruitment was preserved during the first week after injury. In persons with idiopathic pulmonary fibrosis, lysophosphatidic acid levels in bronchoalveolar lavage fluid were also increased, and inhibition of LPA1 markedly reduced fibroblast responses to the chemotactic activity of this fluid. LPA1 therefore represents a new therapeutic target for diseases in which aberrant responses to injury contribute to fibrosis, such as idiopathic pulmonary fibrosis.", + "TAG_DATA": [ + "50, mice {'context': 'B-organism'}", + "51, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "52, one {'perturbing_action': 'I-gene loss-of-function'}", + "53, of {'perturbing_action': 'I-gene loss-of-function'}", + "54, its {'perturbing_action': 'I-gene loss-of-function'}", + "55, receptors, {'perturbing_action': 'I-gene loss-of-function'}", + "56, LPA1, {'perturbing_action': 'I-gene loss-of-function'}", + "68, absence {'perturbing_action': 'B-gene loss-of-function'}", + "69, of {'perturbing_action': 'I-gene loss-of-function'}", + "70, LPA1 {'perturbing_action': 'I-gene loss-of-function'}", + "74, fibroblast {'context': 'B-cells'}", + "122, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "123, of {'perturbing_action': 'I-pharmacological inhibition'}", + "124, LPA1 {'perturbing_action': 'I-pharmacological inhibition'}", + "127, fibroblast {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "50, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "51, lacking ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "52, one ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "53, of ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "54, its ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "55, receptors, ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "56, LPA1, ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "68, absence ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "69, of ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "70, LPA1 ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "74, fibroblast ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "122, inhibition ['l55', 'l56', 'l57']", + "123, of ['l55', 'l58', 'l59']", + "124, LPA1 ['l56', 'l58', 'l60']", + "127, fibroblast ['l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "one", + "of", + "its", + "receptors,", + "LPA1,", + "absence", + "LPA1" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "one", + "of", + "its", + "receptors,", + "LPA1,", + "absence", + "LPA1" + ] + }, + "context": { + "val": "cells", + "words": [ + "fibroblast" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "LPA1" + ] + }, + "context": { + "val": "cells", + "words": [ + "fibroblast" + ] + } + } + ] + }, + { + "PMID": "17994101", + "TEXT": "Multiple sclerosis is a neuroinflammatory disease associated with axonal degeneration. The neuronally expressed, proton-gated acid-sensing ion channel-1 (ASIC1) is permeable to Na+ and Ca2+, and excessive accumulation of these ions is associated with axonal degeneration. We tested the hypothesis that ASIC1 contributes to axonal degeneration in inflammatory lesions of the central nervous system (CNS). After induction of experimental autoimmune encephalomyelitis (EAE), Asic1-/- mice showed both a markedly reduced clinical deficit and reduced axonal degeneration compared to wild-type mice. Consistently with acidosis-mediated injury, pH measurements in the spinal cord of EAE mice showed tissue acidosis sufficient to open ASIC1. The acidosis-related protective effect of Asic1 disruption was also observed in nerve explants in vitro. Amiloride, a licensed and clinically safe blocker of ASICs, was equally neuroprotective in nerve explants and in EAE. Although ASICs are also expressed by immune cells, this expression is unlikely to explain the neuroprotective effect of Asic1 inactivation, as CNS inflammation was similar in wild-type and Asic1-/- mice. In addition, adoptive transfer of T cells from wild-type mice did not affect the protection mediated by Asic1 disruption. These results suggest that ASIC1 blockers could provide neuroprotection in multiple sclerosis.", + "TAG_DATA": [ + "61, Asic1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "62, mice {'context': 'B-organism'}", + "77, mice. {'context': 'B-organism'}", + "86, spinal {'context': 'B-tissue/organ'}", + "87, cord {'context': 'I-tissue/organ'}", + "90, mice {'context': 'B-organism'}", + "109, nerve {'context': 'B-cells'}", + "110, explants {'context': 'I-cells'}", + "111, in {'context': 'B-in vitro'}", + "112, vitro. {'context': 'I-in vitro'}", + "126, nerve {'context': 'B-tissue/organ'}", + "127, explants {'context': 'I-tissue/organ'}", + "159, Asic1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "160, mice. {'context': 'B-organism'}", + "166, T {'context': 'B-cells'}", + "167, cells {'context': 'I-cells'}", + "170, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "61, Asic1-/- ['l0', 'l1']", + "62, mice ['l0', 'l2']", + "77, mice. ['l1', 'l2']", + "86, spinal ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "87, cord ['l3', 'l9', 'l10', 'l11', 'l12', 'l13']", + "90, mice ['l4', 'l9', 'l14', 'l15', 'l16', 'l17']", + "109, nerve ['l5', 'l10', 'l14', 'l18', 'l19', 'l20']", + "110, explants ['l6', 'l11', 'l15', 'l18', 'l21', 'l22']", + "111, in ['l7', 'l12', 'l16', 'l19', 'l21', 'l23']", + "112, vitro. ['l8', 'l13', 'l17', 'l20', 'l22', 'l23']", + "126, nerve ['l24']", + "127, explants ['l24']", + "159, Asic1-/- ['l25']", + "160, mice. ['l25']", + "166, T ['l26', 'l27']", + "167, cells ['l26', 'l28']", + "170, mice ['l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Asic1-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "17891146", + "TEXT": "Toll-like receptors (TLRs) recognize conserved microbial structures called pathogen-associated molecular patterns. Signaling from TLRs leads to upregulation of co-stimulatory molecules for better priming of T cells and secretion of inflammatory cytokines by innate immune cells. Lymphocyte-deficient hosts often die of acute infection, presumably owing to their lack of an adaptive immune response to effectively clear pathogens. However, we show here that an unleashed innate immune response due to the absence of residential T cells can also be a direct cause of death. Viral infection or administration of poly(I:C), a ligand for TLR3, led to cytokine storm in T-cell- or lymphocyte-deficient mice in a fashion dependent on NK cells and tumor necrosis factor. We have further shown, through the depletion of CD4+ and CD8+ cells in wild-type mice and the transfer of T lymphocytes into Rag-1-deficient mice, respectively, that T cells are both necessary and sufficient to temper the early innate response. In addition to the effects of natural regulatory T cells, close contact of resting CD4+CD25-Foxp3- or CD8+ T cells with innate cells could also suppress the cytokine surge by various innate cells in an antigen-independent fashion. Therefore, adaptive immune cells have an unexpected role in tempering initial innate responses.", + "TAG_DATA": [ + "97, T-cell- {'perturbing_action': 'B-gene loss-of-function'}", + "98, or {'perturbing_action': 'I-gene loss-of-function'}", + "99, lymphocyte-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "100, mice {'context': 'B-organism'}", + "120, CD4+ {'context': 'B-cells'}", + "121, and {'context': 'I-cells'}", + "122, CD8+ {'context': 'I-cells'}", + "123, cells {'context': 'I-cells'}", + "126, mice {'context': 'B-organism'}", + "131, T {'context': 'B-cells'}", + "132, lymphocytes {'context': 'I-cells'}", + "134, Rag-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "135, mice, {'context': 'B-organism'}", + "181, innate {'context': 'B-cells'}", + "182, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "97, T-cell- ['l0', 'l1', 'l2']", + "98, or ['l0', 'l3', 'l4']", + "99, lymphocyte-deficient ['l1', 'l3', 'l5', 'l6', 'l7', 'l8']", + "100, mice ['l2', 'l4', 'l5']", + "120, CD4+ ['l9', 'l10', 'l11', 'l12', 'l13']", + "121, and ['l6', 'l9', 'l14', 'l15', 'l16', 'l17']", + "122, CD8+ ['l7', 'l10', 'l14', 'l18', 'l19', 'l20']", + "123, cells ['l8', 'l11', 'l15', 'l18', 'l21']", + "126, mice ['l12', 'l16', 'l19', 'l21', 'l22']", + "131, T ['l23', 'l24', 'l25', 'l26', 'l27']", + "132, lymphocytes ['l23', 'l28', 'l29', 'l30', 'l31']", + "134, Rag-1-deficient ['l24', 'l28', 'l32', 'l33', 'l34']", + "135, mice, ['l13', 'l17', 'l20', 'l22', 'l25', 'l29', 'l32', 'l35', 'l36']", + "181, innate ['l26', 'l30', 'l33', 'l35', 'l37']", + "182, cells ['l27', 'l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "T-cell-", + "or", + "lymphocyte-deficient", + "Rag-1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lymphocyte-deficient", + "Rag-1-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "and", + "CD8+", + "cells", + "T", + "lymphocytes", + "innate" + ] + } + } + ] + }, + { + "PMID": "17873882", + "TEXT": "Gain-of-function mutations in NOTCH1 are common in T-cell lymphoblastic leukemias and lymphomas (T-ALL), making this receptor a promising target for drugs such as gamma-secretase inhibitors, which block a proteolytic cleavage required for NOTCH1 activation. However, the enthusiasm for these therapies has been tempered by tumor resistance and the paucity of information on the oncogenic programs regulated by oncogenic NOTCH1. Here we show that NOTCH1 regulates the expression of PTEN (encoding phosphatase and tensin homolog) and the activity of the phosphoinositol-3 kinase (PI3K)-AKT signaling pathway in normal and leukemic T cells. Notch signaling and the PI3K-AKT pathway synergize in vivo in a Drosophila melanogaster model of Notch-induced tumorigenesis, and mutational loss of PTEN is associated with human T-ALL resistance to pharmacological inhibition of NOTCH1. Overall, these findings identify transcriptional control of PTEN and regulation of the PI3K-AKT pathway as key elements of the leukemogenic program activated by NOTCH1 and provide the basis for the design of new therapeutic strategies for T-ALL.", + "TAG_DATA": [ + "97, in {'context': 'B-in vivo'}", + "98, vivo {'context': 'I-in vivo'}", + "101, Drosophila {'context': 'B-organism'}", + "102, melanogaster {'context': 'I-organism'}", + "103, model {'context': 'I-organism'}", + "105, Notch-induced {'effect': 'B-positive'}", + "106, tumorigenesis, {'phenotype': 'B-tumourigenesis'}", + "108, mutational {'perturbing_action': 'B-gene loss-of-function'}", + "109, loss {'perturbing_action': 'I-gene loss-of-function'}", + "110, of {'perturbing_action': 'I-gene loss-of-function'}", + "111, PTEN {'perturbing_action': 'I-gene loss-of-function'}", + "120, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "121, of {'perturbing_action': 'I-pharmacological inhibition'}", + "122, NOTCH1. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "97, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "98, vivo ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "101, Drosophila ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "102, melanogaster ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "103, model ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "105, Notch-induced ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "106, tumorigenesis, ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "108, mutational ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "109, loss ['l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "110, of ['l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "111, PTEN ['l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "116, T-ALL ['l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "120, inhibition ['l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "121, of ['l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "122, NOTCH1. ['l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "Notch-induced" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Drosophila", + "melanogaster", + "model" + ] + }, + "effect": { + "val": "positive", + "words": [ + "Notch-induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Drosophila", + "melanogaster", + "model" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Notch-induced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis," + ] + } + } + ] + }, + { + "PMID": "17873881", + "TEXT": "Bone remodeling, the function affected in osteoporosis, the most common of bone diseases, comprises two phases: bone formation by matrix-producing osteoblasts and bone resorption by osteoclasts. The demonstration that the anorexigenic hormone leptin inhibits bone formation through a hypothalamic relay suggests that other molecules that affect energy metabolism in the hypothalamus could also modulate bone mass. Neuromedin U (NMU) is an anorexigenic neuropeptide that acts independently of leptin through poorly defined mechanisms. Here we show that Nmu-deficient (Nmu-/-) mice have high bone mass owing to an increase in bone formation; this is more prominent in male mice than female mice. Physiological and cell-based assays indicate that NMU acts in the central nervous system, rather than directly on bone cells, to regulate bone remodeling. Notably, leptin- or sympathetic nervous system-mediated inhibition of bone formation was abolished in Nmu-/- mice, which show an altered bone expression of molecular clock genes (mediators of the inhibition of bone formation by leptin). Moreover, treatment of wild-type mice with a natural agonist for the NMU receptor decreased bone mass. Collectively, these results suggest that NMU may be the first central mediator of leptin-dependent regulation of bone mass identified to date. Given the existence of inhibitors and activators of NMU action, our results may influence the treatment of diseases involving low bone mass, such as osteoporosis.", + "TAG_DATA": [ + "76, Nmu-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "77, (Nmu-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "78, mice {'context': 'B-organism'}", + "95, male {'context': 'B-organism'}", + "96, mice {'context': 'I-organism'}", + "136, Nmu-/- {'perturbing_action': 'B-gene loss-of-function'}", + "137, mice, {'context': 'B-organism'}", + "161, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "76, Nmu-deficient ['l0', 'l1', 'l2', 'l3']", + "77, (Nmu-/-) ['l0', 'l4', 'l5', 'l6']", + "78, mice ['l1', 'l4', 'l7', 'l8']", + "95, male ['l2', 'l5', 'l7', 'l9']", + "96, mice ['l3', 'l6', 'l8', 'l9']", + "136, Nmu-/- ['l10']", + "137, mice, ['l10']", + "161, mice ['l11']", + "165, agonist ['l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nmu-deficient", + "(Nmu-/-)", + "Nmu-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "male", + "mice," + ] + } + } + ] + }, + { + "PMID": "17873880", + "TEXT": "The cardioprotective effects of estrogen are mediated by receptors expressed in vascular cells. Here we show that 27-hydroxycholesterol (27HC), an abundant cholesterol metabolite that is elevated with hypercholesterolemia and found in atherosclerotic lesions, is a competitive antagonist of estrogen receptor action in the vasculature. 27HC inhibited both the transcription-mediated and the non-transcription-mediated estrogen-dependent production of nitric oxide by vascular cells, resulting in reduced estrogen-induced vasorelaxation of rat aorta. Furthermore, increasing 27HC levels in mice by diet-induced hypercholesterolemia, pharmacologic administration or genetic manipulation (by knocking out the gene encoding the catabolic enzyme CYP7B1) decreased estrogen-dependent expression of vascular nitric oxide synthase and repressed carotid artery reendothelialization. As well as antiestrogenic effects, there were proestrogenic actions of 27HC that were cell-type specific, indicating that 27HC functions as an endogenous selective estrogen receptor modulator (SERM). Taken together, these studies point to 27HC as a contributing factor in the loss of estrogen protection from vascular disease.", + "TAG_DATA": [ + "58, vascular {'context': 'B-cells'}", + "59, cells, {'context': 'I-cells'}", + "66, rat {'context': 'B-tissue/organ'}", + "67, aorta. {'context': 'I-tissue/organ'}", + "73, mice {'context': 'B-organism'}", + "83, knocking {'perturbing_action': 'B-gene loss-of-function'}", + "84, out {'perturbing_action': 'I-gene loss-of-function'}", + "85, the {'perturbing_action': 'I-gene loss-of-function'}", + "86, gene {'perturbing_action': 'I-gene loss-of-function'}", + "87, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "88, the {'perturbing_action': 'I-gene loss-of-function'}", + "89, catabolic {'perturbing_action': 'I-gene loss-of-function'}", + "90, enzyme {'perturbing_action': 'I-gene loss-of-function'}", + "91, CYP7B1) {'perturbing_action': 'I-gene loss-of-function'}", + "102, carotid {'context': 'B-tissue/organ'}", + "103, artery {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "58, vascular ['l0', 'l1', 'l2']", + "59, cells, ['l0', 'l3', 'l4']", + "66, rat ['l1', 'l3', 'l5']", + "67, aorta. ['l2', 'l4', 'l5']", + "83, knocking ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "84, out ['l6', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "85, the ['l7', 'l16', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "86, gene ['l8', 'l17', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "87, encoding ['l9', 'l18', 'l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "88, the ['l10', 'l19', 'l27', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "89, catabolic ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "90, enzyme ['l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57']", + "91, CYP7B1) ['l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l58', 'l59']", + "102, carotid ['l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58', 'l60']", + "103, artery ['l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knocking", + "out", + "the", + "gene", + "encoding", + "catabolic", + "enzyme", + "CYP7B1)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "carotid", + "artery" + ] + } + } + ] + }, + { + "PMID": "17828274", + "TEXT": "The repair of injured tendons remains a great challenge, largely owing to a lack of in-depth characterization of tendon cells and their precursors. We show that human and mouse tendons harbor a unique cell population, termed tendon stem/progenitor cells (TSPCs), that has universal stem cell characteristics such as clonogenicity, multipotency and self-renewal capacity. The isolated TSPCs could regenerate tendon-like tissues after extended expansion in vitro and transplantation in vivo. Moreover, we show that TSPCs reside within a unique niche predominantly comprised of an extracellular matrix, and we identify biglycan (Bgn) and fibromodulin (Fmod) as two critical components that organize this niche. Depletion of Bgn and Fmod affects the differentiation of TSPCs by modulating bone morphogenetic protein signaling and impairs tendon formation in vivo. Our results, while offering new insights into the biology of tendon cells, may assist in future strategies to treat tendon diseases.", + "TAG_DATA": [ + "55, TSPCs {'context': 'B-cells'}", + "63, in {'context': 'B-in vitro'}", + "64, vitro {'context': 'I-in vitro'}", + "67, in {'context': 'B-in vivo'}", + "68, vivo. {'context': 'I-in vivo'}", + "101, Depletion {'perturbing_action': 'B-gene loss-of-function'}", + "102, of {'perturbing_action': 'I-gene loss-of-function'}", + "103, Bgn {'perturbing_action': 'I-gene loss-of-function'}", + "104, and {'perturbing_action': 'I-gene loss-of-function'}", + "105, Fmod {'perturbing_action': 'I-gene loss-of-function'}", + "106, affects {'effect': 'B-regulates'}", + "108, differentiation {'phenotype': 'B-differentiation'}", + "110, TSPCs {'context': 'B-cells'}", + "118, impairs {'effect': 'B-negative'}", + "119, tendon {'context': 'B-tissue/organ', 'phenotype': 'B-tumourigenesis'}", + "120, formation {'phenotype': 'I-tumourigenesis'}", + "121, in {'context': 'B-in vivo'}", + "122, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "55, TSPCs ['l0', 'l1', 'l2', 'l3']", + "63, in ['l0', 'l4']", + "64, vitro ['l1', 'l4']", + "67, in ['l2', 'l5']", + "68, vivo. ['l3', 'l5']", + "101, Depletion ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "102, of ['l6', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "103, Bgn ['l7', 'l18', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "104, and ['l8', 'l19', 'l29', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "105, Fmod ['l9', 'l20', 'l30', 'l39', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "106, affects ['l10', 'l21', 'l31', 'l40', 'l48', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "108, differentiation ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "110, TSPCs ['l12', 'l23', 'l33', 'l42', 'l50', 'l57', 'l63', 'l69', 'l70', 'l71', 'l72', 'l73']", + "118, impairs ['l13', 'l24', 'l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l74', 'l75', 'l76', 'l77']", + "119, tendon ['l14', 'l25', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l78', 'l79', 'l80']", + "120, formation ['l15', 'l26', 'l36', 'l45', 'l53', 'l60', 'l66', 'l71', 'l75', 'l78', 'l81', 'l82']", + "121, in ['l16', 'l27', 'l37', 'l46', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l81', 'l83']", + "122, vivo. ['l17', 'l28', 'l38', 'l47', 'l55', 'l62', 'l68', 'l73', 'l77', 'l80', 'l82', 'l83']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Depletion", + "of", + "Bgn", + "and", + "Fmod" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "affects" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Depletion", + "of", + "Bgn", + "and", + "Fmod" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Depletion", + "of", + "Bgn", + "and", + "Fmod" + ] + }, + "context": { + "val": "cells", + "words": [ + "TSPCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Depletion", + "of", + "Bgn", + "and", + "Fmod" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Depletion", + "of", + "Bgn", + "and", + "Fmod" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tendon" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Depletion", + "of", + "Bgn", + "and", + "Fmod" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tendon", + "formation" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "tendon" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tendon" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Depletion", + "of", + "Bgn", + "and", + "Fmod" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "affects" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "affects" + ] + }, + "context": { + "val": "cells", + "words": [ + "TSPCs" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "affects" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tendon" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "affects" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tendon", + "formation" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "affects" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "TSPCs" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tendon" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "TSPCs" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "TSPCs" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tendon", + "formation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tendon" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tendon", + "formation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tendon", + "formation" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "17704785", + "TEXT": "Hepatocytes in fatty livers are hypersensitive to apoptosis and undergo escalated apoptotic activity via death receptor-mediated pathways, particularly that of Fas-FasL, causing hepatic injury that can eventually proceed to cirrhosis and end-stage liver disease. Here we report that the hepatocyte growth factor receptor, Met, plays an important part in preventing Fas-mediated apoptosis of hepatocytes by sequestering Fas. We also show that Fas antagonism by Met is abrogated in human fatty liver disease (FLD). Through structure-function studies, we found that a YLGA amino-acid motif located near the extracellular N terminus of the Met alpha-subunit is necessary and sufficient to specifically bind the extracellular portion of Fas and to act as a potent FasL antagonist and inhibitor of Fas trimerization. Using mouse models of FLD, we show that synthetic YLGA peptide tempers hepatocyte apoptosis and liver damage and therefore has therapeutic potential.", + "TAG_DATA": [ + "119, mouse {'context': 'B-organism'}", + "120, models {'context': 'I-organism'}", + "129, tempers {'effect': 'B-negative'}", + "130, hepatocyte {'context': 'B-cells'}", + "131, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "119, mouse ['l0', 'l1', 'l2', 'l3']", + "120, models ['l0', 'l4', 'l5', 'l6']", + "129, tempers ['l1', 'l4', 'l7', 'l8']", + "130, hepatocyte ['l2', 'l5', 'l7', 'l9']", + "131, apoptosis ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "effect": { + "val": "negative", + "words": [ + "tempers" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "tempers" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocyte" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "tempers" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hepatocyte" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "17676050", + "TEXT": "Treatment with glatiramer acetate (GA, copolymer-1, Copaxone), a drug approved for multiple sclerosis (MS), in a mouse model promoted development of anti-inflammatory type II monocytes, characterized by increased secretion of interleukin (IL)-10 and transforming growth factor (TGF)-beta, and decreased production of IL-12 and tumor necrosis factor (TNF). This anti-inflammatory cytokine shift was associated with reduced STAT-1 signaling. Type II monocytes directed differentiation of T(H)2 cells and CD4+CD25+FoxP3+ regulatory T cells (T(reg)) independent of antigen specificity. Type II monocyte-induced regulatory T cells specific for a foreign antigen ameliorated experimental autoimmune encephalomyelitis (EAE), indicating that neither GA specificity nor recognition of self-antigen was required for their therapeutic effect. Adoptive transfer of type II monocytes reversed EAE, suppressed T(H)17 cell development and promoted both T(H)2 differentiation and expansion of T(reg) cells in recipient mice. This demonstration of adoptive immunotherapy by type II monocytes identifies a central role for these cells in T cell immune modulation of autoimmunity.", + "TAG_DATA": [ + "16, mouse {'context': 'B-organism'}", + "17, model {'context': 'I-organism'}", + "61, differentiation {'phenotype': 'B-differentiation'}", + "63, T(H)2 {'context': 'B-cells'}", + "64, cells {'context': 'I-cells'}", + "76, II {'context': 'B-cells'}", + "77, monocyte-induced {'context': 'I-cells'}", + "78, regulatory {'context': 'I-cells'}", + "79, T {'context': 'I-cells'}", + "80, cells {'context': 'I-cells'}", + "109, type {'context': 'B-cells'}", + "110, II {'context': 'B-cells'}", + "111, monocytes {'context': 'I-cells'}", + "115, T(H)17 {'context': 'B-cells'}", + "116, cell {'context': 'I-cells'}", + "119, promoted {'effect': 'B-positive'}", + "121, T(H)2 {'context': 'B-cells'}", + "122, differentiation {'phenotype': 'B-differentiation'}", + "126, T(reg) {'context': 'B-cells'}", + "127, cells {'context': 'I-cells'}", + "130, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "16, mouse ['l0', 'l1', 'l2', 'l3']", + "17, model ['l0', 'l4', 'l5']", + "61, differentiation ['l1', 'l6', 'l7']", + "63, T(H)2 ['l2', 'l4', 'l6', 'l8']", + "64, cells ['l3', 'l5', 'l7', 'l8']", + "76, II ['l9', 'l10', 'l11', 'l12']", + "77, monocyte-induced ['l9', 'l13', 'l14', 'l15']", + "78, regulatory ['l10', 'l13', 'l16', 'l17']", + "79, T ['l11', 'l14', 'l16', 'l18']", + "80, cells ['l12', 'l15', 'l17', 'l18']", + "109, type ['l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "110, II ['l19', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "111, monocytes ['l20', 'l29', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "115, T(H)17 ['l21', 'l30', 'l38', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "116, cell ['l22', 'l31', 'l39', 'l46', 'l53']", + "119, promoted ['l23', 'l32', 'l40', 'l47', 'l54', 'l55', 'l56', 'l57', 'l58']", + "121, T(H)2 ['l24', 'l33', 'l41', 'l48', 'l54', 'l59', 'l60', 'l61', 'l62']", + "122, differentiation ['l25', 'l34', 'l42', 'l49', 'l55', 'l59', 'l63', 'l64', 'l65']", + "126, T(reg) ['l26', 'l35', 'l43', 'l50', 'l56', 'l60', 'l63', 'l66', 'l67']", + "127, cells ['l27', 'l36', 'l44', 'l51', 'l53', 'l57', 'l61', 'l64', 'l66', 'l68']", + "130, mice. ['l28', 'l37', 'l45', 'l52', 'l58', 'l62', 'l65', 'l67', 'l68']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "mice." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "T(H)2", + "cells", + "type", + "II", + "monocytes", + "T(H)17", + "T(reg)" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "type", + "II", + "monocytes", + "T(H)17", + "T(H)2", + "T(reg)", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "17603494", + "TEXT": "Psoriasis is a common T cell-mediated autoimmune inflammatory disease. We show that blocking the interaction of alpha1beta1 integrin (VLA-1) with collagen prevented accumulation of epidermal T cells and immunopathology of psoriasis. Alpha1beta1 integrin, a major collagen-binding surface receptor, was exclusively expressed by epidermal but not dermal T cells. Alpha1beta1-positive T cells showed characteristic surface markers of effector memory cells and contained high levels of interferon-gamma but not interleukin-4. Blockade of alpha1beta1 inhibited migration of T cells into the epidermis in a clinically relevant xenotransplantation model. This was paralleled by a complete inhibition of psoriasis development, comparable to that caused by tumor necrosis factor-alpha blockers. These results define a crucial role for alpha1beta1 in controlling the accumulation of epidermal type 1 polarized effector memory T cells in a common human immunopathology and provide the basis for new strategies in psoriasis treatment focusing on T cell-extracellular matrix interactions.", + "TAG_DATA": [ + "24, epidermal {'context': 'B-cells'}", + "25, T {'context': 'I-cells'}", + "26, cells {'context': 'I-cells'}", + "68, Blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "69, of {'perturbing_action': 'I-pharmacological inhibition'}", + "70, alpha1beta1 {'perturbing_action': 'I-pharmacological inhibition'}", + "71, inhibited {'effect': 'B-negative'}", + "72, migration {'phenotype': 'B-migration'}", + "74, T {'context': 'B-cells'}", + "75, cells {'context': 'B-cells'}", + "78, epidermis {'context': 'B-tissue/organ'}", + "83, xenotransplantation {'context': 'B-xenograft'}", + "84, model. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "24, epidermal ['l0', 'l1', 'l2', 'l3', 'l4']", + "25, T ['l0', 'l5']", + "26, cells ['l1', 'l5']", + "68, Blockade ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "69, of ['l6', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "70, alpha1beta1 ['l7', 'l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "71, inhibited ['l8', 'l16', 'l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "72, migration ['l2', 'l9', 'l17', 'l24', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "74, T ['l3', 'l10', 'l18', 'l25', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "75, cells ['l4', 'l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l45', 'l46', 'l47']", + "78, epidermis ['l12', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l48', 'l49']", + "83, xenotransplantation ['l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l50']", + "84, model. ['l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l50']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "epidermal", + "T", + "cells" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "alpha1beta1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "alpha1beta1" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "alpha1beta1" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "alpha1beta1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "epidermis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "alpha1beta1" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenotransplantation", + "model." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "epidermis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenotransplantation", + "model." + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "epidermis" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenotransplantation", + "model." + ] + } + } + ] + }, + { + "PMID": "17589520", + "TEXT": "Gamma-aminobutyric acid (GABA) is an important neurotransmitter that, through the subtype A GABA receptor (GABAAR), induces inhibition in the adult brain. Here we show that an excitatory, rather than inhibitory, GABAergic system exists in airway epithelial cells. Both GABAARs and the GABA synthetic enzyme glutamic acid decarboxylase (GAD) are expressed in pulmonary epithelial cells. Activation of GABAARs depolarized these cells. The expression of GAD in the cytosol and GABAARs in the apical membranes of airway epithelial cells increased markedly when mice were sensitized and then challenged with ovalbumin, an approach for inducing allergic asthmatic reactions. Similarly, GAD and GABAARs in airway epithelial cells of humans with asthma increased after allergen inhalation challenge. Intranasal application of selective GABAAR inhibitors suppressed the hyperplasia of goblet cells and the overproduction of mucus induced by ovalbumin or interleukin-13 in mice. These findings show that a previously unknown epithelial GABAergic system has an essential role in asthma.", + "TAG_DATA": [ + "74, airway {'context': 'B-cells'}", + "75, epithelial {'context': 'I-cells'}", + "76, cells {'context': 'I-cells'}", + "80, mice {'context': 'B-organism'}", + "100, airway {'context': 'B-cells'}", + "101, epithelial {'context': 'I-cells'}", + "102, cells {'context': 'I-cells'}", + "104, humans {'context': 'B-cells'}", + "115, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "116, GABAAR {'perturbing_action': 'I-pharmacological inhibition'}", + "117, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "122, goblet {'context': 'B-cells'}", + "123, cells {'context': 'I-cells'}", + "135, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "74, airway ['l0', 'l1', 'l2']", + "75, epithelial ['l0', 'l3', 'l4']", + "76, cells ['l1', 'l3', 'l5']", + "80, mice ['l2', 'l4', 'l5', 'l6']", + "100, airway ['l7', 'l8', 'l9']", + "101, epithelial ['l7', 'l10', 'l11']", + "102, cells ['l6', 'l8', 'l10', 'l12']", + "104, humans ['l9', 'l11', 'l12']", + "115, selective ['l13', 'l14', 'l15', 'l16', 'l17']", + "116, GABAAR ['l13', 'l18', 'l19', 'l20', 'l21']", + "117, inhibitors ['l14', 'l18', 'l22', 'l23', 'l24']", + "122, goblet ['l15', 'l19', 'l22', 'l25']", + "123, cells ['l16', 'l20', 'l23', 'l25']", + "135, mice. ['l17', 'l21', 'l24']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "GABAAR", + "inhibitors" + ] + }, + "context": { + "val": "cells", + "words": [ + "goblet", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "GABAAR", + "inhibitors" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "17529981", + "TEXT": "The metabolism of vitamin A and the diverse effects of its metabolites are tightly controlled by distinct retinoid-generating enzymes, retinoid-binding proteins and retinoid-activated nuclear receptors. Retinoic acid regulates differentiation and metabolism by activating the retinoic acid receptor and retinoid X receptor (RXR), indirectly influencing RXR heterodimeric partners. Retinoic acid is formed solely from retinaldehyde (Rald), which in turn is derived from vitamin A. Rald currently has no defined biologic role outside the eye. Here we show that Rald is present in rodent fat, binds retinol-binding proteins (CRBP1, RBP4), inhibits adipogenesis and suppresses peroxisome proliferator-activated receptor-gamma and RXR responses. In vivo, mice lacking the Rald-catabolizing enzyme retinaldehyde dehydrogenase 1 (Raldh1) resisted diet-induced obesity and insulin resistance and showed increased energy dissipation. In ob/ob mice, administrating Rald or a Raldh inhibitor reduced fat and increased insulin sensitivity. These results identify Rald as a distinct transcriptional regulator of the metabolic responses to a high-fat diet.", + "TAG_DATA": [ + "98, In {'context': 'B-in vivo'}", + "99, vivo, {'context': 'I-in vivo'}", + "100, mice {'context': 'B-organism'}", + "101, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "102, the {'perturbing_action': 'I-gene loss-of-function'}", + "103, Rald-catabolizing {'perturbing_action': 'I-gene loss-of-function'}", + "104, enzyme {'perturbing_action': 'I-gene loss-of-function'}", + "105, retinaldehyde {'perturbing_action': 'I-gene loss-of-function'}", + "106, dehydrogenase {'perturbing_action': 'I-gene loss-of-function'}", + "107, 1 {'perturbing_action': 'I-gene loss-of-function'}", + "108, (Raldh1) {'perturbing_action': 'I-gene loss-of-function'}", + "121, ob/ob {'context': 'B-organism'}", + "122, mice, {'context': 'I-organism'}", + "123, administrating {'perturbing_action': 'B-gene gain-of-function'}", + "124, Rald {'perturbing_action': 'I-gene gain-of-function'}", + "127, Raldh {'perturbing_action': 'B-pharmacological inhibition'}", + "128, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "98, In ['l0']", + "99, vivo, ['l0']", + "100, mice ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "101, lacking ['l1', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "102, the ['l2', 'l9', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "103, Rald-catabolizing ['l3', 'l10', 'l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "104, enzyme ['l4', 'l11', 'l17', 'l22', 'l27', 'l28', 'l29', 'l30']", + "105, retinaldehyde ['l5', 'l12', 'l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "106, dehydrogenase ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "107, 1 ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "108, (Raldh1) ['l8', 'l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l36']", + "121, ob/ob ['l37', 'l38', 'l39', 'l40', 'l41']", + "122, mice, ['l37', 'l42', 'l43']", + "123, administrating ['l38', 'l44', 'l45', 'l46']", + "124, Rald ['l39', 'l42', 'l44', 'l47', 'l48']", + "127, Raldh ['l40', 'l45', 'l47', 'l49']", + "128, inhibitor ['l41', 'l43', 'l46', 'l48', 'l49']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "Rald-catabolizing", + "enzyme", + "retinaldehyde", + "dehydrogenase", + "1", + "(Raldh1)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "ob/ob", + "mice," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "administrating", + "Rald" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "ob/ob", + "mice," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Raldh", + "inhibitor" + ] + } + } + ] + }, + { + "PMID": "17450150", + "TEXT": "Autophagy, an evolutionarily conserved process for the bulk degradation of cytoplasmic components, serves as a cell survival mechanism in starving cells. Although altered autophagy has been observed in various heart diseases, including cardiac hypertrophy and heart failure, it remains unclear whether autophagy plays a beneficial or detrimental role in the heart. Here, we report that the cardiac-specific loss of autophagy causes cardiomyopathy in mice. In adult mice, temporally controlled cardiac-specific deficiency of Atg5 (autophagy-related 5), a protein required for autophagy, led to cardiac hypertrophy, left ventricular dilatation and contractile dysfunction, accompanied by increased levels of ubiquitination. Furthermore, Atg5-deficient hearts showed disorganized sarcomere structure and mitochondrial misalignment and aggregation. On the other hand, cardiac-specific deficiency of Atg5 early in cardiogenesis showed no such cardiac phenotypes under baseline conditions, but developed cardiac dysfunction and left ventricular dilatation one week after treatment with pressure overload. These results indicate that constitutive autophagy in the heart under baseline conditions is a homeostatic mechanism for maintaining cardiomyocyte size and global cardiac structure and function, and that upregulation of autophagy in failing hearts is an adaptive response for protecting cells from hemodynamic stress.", + "TAG_DATA": [ + "63, mice. {'context': 'B-organism'}", + "65, adult {'context': 'B-organism'}", + "66, mice, {'context': 'I-organism'}", + "69, cardiac-specific {'perturbing_action': 'I-gene loss-of-function'}", + "70, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "71, of {'perturbing_action': 'I-gene loss-of-function'}", + "72, Atg5 {'perturbing_action': 'I-gene loss-of-function'}", + "73, (autophagy-related {'perturbing_action': 'I-gene loss-of-function'}", + "74, 5), {'perturbing_action': 'I-gene loss-of-function'}", + "97, Atg5-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "98, hearts {'context': 'B-tissue/organ'}", + "112, cardiac-specific {'perturbing_action': 'B-gene loss-of-function'}", + "113, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "114, of {'perturbing_action': 'I-gene loss-of-function'}", + "115, Atg5 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "63, mice. ['l0', 'l1']", + "65, adult ['l0', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "66, mice, ['l1', 'l2', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "69, cardiac-specific ['l3', 'l9', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "70, deficiency ['l4', 'l10', 'l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "71, of ['l5', 'l11', 'l16', 'l22', 'l28', 'l29', 'l30', 'l31', 'l32']", + "72, Atg5 ['l6', 'l12', 'l17', 'l23', 'l28', 'l33', 'l34', 'l35', 'l36']", + "73, (autophagy-related ['l7', 'l13', 'l18', 'l24', 'l29', 'l33', 'l37', 'l38', 'l39']", + "74, 5), ['l8', 'l14', 'l19', 'l25', 'l30', 'l34', 'l37', 'l40', 'l41']", + "97, Atg5-deficient ['l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l42']", + "98, hearts ['l21', 'l27', 'l32', 'l36', 'l39', 'l41', 'l42']", + "112, cardiac-specific ['l43', 'l44', 'l45']", + "113, deficiency ['l43', 'l46', 'l47']", + "114, of ['l44', 'l46', 'l48']", + "115, Atg5 ['l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "adult", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cardiac-specific", + "deficiency", + "of", + "Atg5", + "(autophagy-related", + "5)," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cardiac-specific", + "deficiency", + "of", + "Atg5", + "(autophagy-related", + "5),", + "Atg5-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hearts" + ] + } + } + ] + }, + { + "PMID": "17417650", + "TEXT": "Sympathetic innervation is critical for effective cardiac function. However, the developmental and regulatory mechanisms determining the density and patterning of cardiac sympathetic innervation remain unclear, as does the role of this innervation in arrhythmogenesis. Here we show that a neural chemorepellent, Sema3a, establishes cardiac sympathetic innervation patterning. Sema3a is abundantly expressed in the trabecular layer in early-stage embryos but is restricted to Purkinje fibers after birth, forming an epicardial-to-endocardial transmural sympathetic innervation patterning. Sema3a(-/-) mice lacked a cardiac sympathetic innervation gradient and exhibited stellate ganglia malformation, which led to marked sinus bradycardia due to sympathetic dysfunction. Cardiac-specific overexpression of Sema3a in transgenic mice (SemaTG) was associated with reduced sympathetic innervation and attenuation of the epicardial-to-endocardial innervation gradient. SemaTG mice demonstrated sudden death and susceptibility to ventricular tachycardia, due to catecholamine supersensitivity and prolongation of the action potential duration. We conclude that appropriate cardiac Sema3a expression is needed for sympathetic innervation patterning and is critical for heart rate control.", + "TAG_DATA": [ + "73, Sema3a(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "74, mice {'context': 'B-organism'}", + "96, Cardiac-specific {'perturbing_action': 'B-gene gain-of-function'}", + "97, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "98, of {'perturbing_action': 'I-gene gain-of-function'}", + "99, Sema3a {'perturbing_action': 'I-gene gain-of-function'}", + "101, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "102, mice {'context': 'I-organism'}", + "117, SemaTG {'perturbing_action': 'B-gene loss-of-function'}", + "118, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, Sema3a(-/-) ['l0']", + "74, mice ['l0']", + "96, Cardiac-specific ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "97, overexpression ['l1', 'l7', 'l8', 'l9', 'l10']", + "98, of ['l2', 'l7', 'l11', 'l12', 'l13']", + "99, Sema3a ['l3', 'l8', 'l11', 'l14', 'l15']", + "101, transgenic ['l4', 'l9', 'l12', 'l14', 'l16']", + "102, mice ['l5', 'l10', 'l13', 'l15', 'l16']", + "117, SemaTG ['l17']", + "118, mice ['l6', 'l17']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sema3a(-/-)", + "SemaTG" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Cardiac-specific", + "overexpression", + "of", + "Sema3a", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "17401377", + "TEXT": "The germinal matrix of premature infants is selectively vulnerable to hemorrhage within the first 48 h of life. To assess the role of vascular immaturity in germinal matrix hemorrhage (GMH), we evaluated germinal matrix angiogenesis in human fetuses and premature infants, as well as in premature rabbit pups, and noted active vessel remodeling in all three. Vascular endothelial growth factor (VEGF), angiopoietin-2 and endothelial cell proliferation were present at consistently higher levels in the germinal matrix relative to the white matter anlagen and cortical mantle. On that basis, we asked whether prenatal treatment with either of two angiogenic inhibitors, the COX-2 inhibitor celecoxib, or the VEGFR2 inhibitor ZD6474, could suppress the incidence of GMH in premature rabbit pups. Celecoxib treatment decreased angiopoietin-2 and VEGF levels as well as germinal matrix endothelial proliferation. Furthermore, treatment with celecoxib or ZD6474 substantially decreased the incidence of GMH. Thus, by suppressing germinal matrix angiogenesis, prenatal celecoxib or ZD6474 treatment may be able to reduce both the incidence and severity of GMH in susceptible premature infants.", + "TAG_DATA": [ + "45, premature {'context': 'B-organism'}", + "46, rabbit {'context': 'I-organism'}", + "47, pups, {'context': 'I-organism'}", + "100, COX-2 {'perturbing_action': 'B-pharmacological inhibition'}", + "101, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "102, celecoxib, {'perturbing_action': 'I-pharmacological inhibition'}", + "105, VEGFR2 {'perturbing_action': 'B-pharmacological inhibition'}", + "106, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "107, ZD6474, {'perturbing_action': 'I-pharmacological inhibition'}", + "115, premature {'context': 'B-organism'}", + "116, rabbit {'context': 'I-organism'}", + "117, pups. {'context': 'I-organism'}", + "120, decreased {'effect': 'B-negative'}", + "128, germinal {'context': 'B-cells'}", + "129, matrix {'context': 'I-cells'}", + "130, endothelial {'context': 'I-cells'}", + "131, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "45, premature ['l0', 'l1']", + "46, rabbit ['l0', 'l2']", + "47, pups, ['l1', 'l2']", + "100, COX-2 ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "101, inhibitor ['l3', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "102, celecoxib, ['l4', 'l16', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "105, VEGFR2 ['l5', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "106, inhibitor ['l6', 'l17', 'l35', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "107, ZD6474, ['l7', 'l18', 'l27', 'l36', 'l45', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "115, premature ['l8', 'l19', 'l28', 'l37', 'l46', 'l54', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "116, rabbit ['l9', 'l20', 'l29', 'l38', 'l47', 'l55', 'l62', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "117, pups. ['l10', 'l21', 'l30', 'l39', 'l48', 'l56', 'l63', 'l69', 'l75', 'l76', 'l77', 'l78', 'l79']", + "120, decreased ['l11', 'l22', 'l31', 'l40', 'l49', 'l57', 'l64', 'l70', 'l75', 'l80', 'l81', 'l82', 'l83']", + "128, germinal ['l12', 'l23', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l84', 'l85', 'l86']", + "129, matrix ['l13', 'l24', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l87', 'l88']", + "130, endothelial ['l14', 'l25', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l87', 'l89']", + "131, proliferation. ['l15', 'l26', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l89']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "COX-2", + "inhibitor", + "celecoxib,", + "VEGFR2", + "ZD6474," + ] + }, + "context": { + "val": "organism", + "words": [ + "premature", + "rabbit", + "pups." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "COX-2", + "inhibitor", + "celecoxib,", + "VEGFR2", + "ZD6474," + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "COX-2", + "inhibitor", + "celecoxib,", + "VEGFR2", + "ZD6474," + ] + }, + "context": { + "val": "cells", + "words": [ + "germinal", + "matrix", + "endothelial" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "COX-2", + "inhibitor", + "celecoxib,", + "VEGFR2", + "ZD6474," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "premature", + "rabbit", + "pups." + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "premature", + "rabbit", + "pups." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "context": { + "val": "cells", + "words": [ + "germinal", + "matrix", + "endothelial" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "germinal", + "matrix", + "endothelial" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "17401376", + "TEXT": "The cannabinoid system is immunomodulatory and has been targeted as a treatment for the central nervous system (CNS) autoimmune disease multiple sclerosis. Using an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), we investigated the role of the CB(1) and CB(2) cannabinoid receptors in regulating CNS autoimmunity. We found that CB(1) receptor expression by neurons, but not T cells, was required for cannabinoid-mediated EAE suppression. In contrast, CB(2) receptor expression by encephalitogenic T cells was critical for controlling inflammation associated with EAE. CB(2)-deficient T cells in the CNS during EAE exhibited reduced levels of apoptosis, a higher rate of proliferation and increased production of inflammatory cytokines, resulting in severe clinical disease. Together, our results demonstrate that the cannabinoid system within the CNS plays a critical role in regulating autoimmune inflammation, with the CNS directly suppressing T-cell effector function via the CB(2) receptor.", + "TAG_DATA": [ + "83, CB(2)-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "84, T {'context': 'B-cells'}", + "85, cells {'context': 'I-cells'}", + "88, CNS {'context': 'B-tissue/organ'}", + "92, reduced {'effect': 'B-negative'}", + "93, levels {'effect': 'I-positive'}", + "95, apoptosis, {'phenotype': 'B-apoptosis'}", + "97, higher {'effect': 'B-positive'}", + "98, rate {'effect': 'I-positive'}", + "100, proliferation {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "83, CB(2)-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "84, T ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "85, cells ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "88, CNS ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "92, reduced ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "93, levels ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "95, apoptosis, ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "97, higher ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "98, rate ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "100, proliferation ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CB(2)-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CB(2)-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "CNS" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CB(2)-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CB(2)-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "levels", + "higher", + "rate" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CB(2)-deficient" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CB(2)-deficient" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "levels", + "higher", + "rate" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "CNS" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "CNS" + ] + }, + "effect": { + "val": "positive", + "words": [ + "levels", + "higher", + "rate" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "CNS" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "CNS" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "levels", + "higher", + "rate" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "levels", + "higher", + "rate" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "17351624", + "TEXT": "Cbl-associated protein (Cap) is a member of a phosphatidylinositol 3-kinase-independent pathway for insulin-stimulated translocation of the glucose transporter GLUT4. Despite this positive role of Cap in glucose uptake, here we show that deletion of the gene encoding Cap (official gene name: Sorbs1) protects against high-fat diet (HFD)-induced insulin resistance in mice while also having an opposite, insulin-sensitizing effect, accompanied by reduced tissue markers of inflammation. Given the emerging role of chronic inflammation in insulin resistance and the macrophage in initiating this inflammatory process, we considered that Sorbs1 deletion from macrophages may have resulted in the observed protection from HFD-induced insulin resistance. Using bone marrow transplantation to generate functional Sorbs1-null macrophages, we show that the insulin-sensitive phenotype can be transferred to wild-type mice by transplantation of Sorbs1-null bone marrow. These studies show that macrophages are an important cell type in the induction of insulin resistance and that Cap has a modulatory role in this function.", + "TAG_DATA": [ + "32, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "33, of {'perturbing_action': 'I-gene loss-of-function'}", + "34, the {'perturbing_action': 'I-gene loss-of-function'}", + "35, gene {'perturbing_action': 'I-gene loss-of-function'}", + "36, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "37, Cap {'perturbing_action': 'I-gene loss-of-function'}", + "38, (official {'perturbing_action': 'I-gene loss-of-function'}", + "39, gene {'perturbing_action': 'I-gene loss-of-function'}", + "40, name: {'perturbing_action': 'I-gene loss-of-function'}", + "41, Sorbs1) {'perturbing_action': 'I-gene loss-of-function'}", + "50, mice {'context': 'B-organism'}", + "86, Sorbs1 {'perturbing_action': 'B-gene loss-of-function'}", + "87, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "89, macrophages {'context': 'B-cells'}", + "108, Sorbs1-null {'perturbing_action': 'B-gene loss-of-function'}", + "109, macrophages, {'context': 'B-cells'}", + "121, mice {'context': 'B-organism'}", + "125, Sorbs1-null {'perturbing_action': 'B-gene loss-of-function'}", + "126, bone {'context': 'B-cells'}", + "127, marrow. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "32, deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "33, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "34, the ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "35, gene ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "36, encoding ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "37, Cap ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "38, (official ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "39, gene ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "40, name: ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "41, Sorbs1) ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "50, mice ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81']", + "86, Sorbs1 ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l86', 'l87']", + "87, deletion ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l85', 'l88']", + "89, macrophages ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l86', 'l88']", + "102, bone ['l89', 'l90', 'l91']", + "103, marrow ['l87', 'l89', 'l92', 'l93']", + "108, Sorbs1-null ['l90', 'l92', 'l94']", + "109, macrophages, ['l91', 'l93', 'l94']", + "121, mice ['l95', 'l96', 'l97']", + "125, Sorbs1-null ['l95', 'l98', 'l99']", + "126, bone ['l96', 'l98', 'l100']", + "127, marrow. ['l97', 'l99', 'l100']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "gene", + "encoding", + "Cap", + "(official", + "name:", + "Sorbs1)", + "Sorbs1-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "gene", + "encoding", + "Cap", + "(official", + "name:", + "Sorbs1)", + "Sorbs1", + "Sorbs1-null" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages", + "macrophages,", + "bone", + "marrow." + ] + } + } + ] + }, + { + "PMID": "17334371", + "TEXT": "Protective cell-mediated immune responses in cancer are critically dependent on T-helper type 1 (T(H)1) cytokines such as interferon-gamma (IFN-gamma). We have previously shown that the combination of CD40 stimulation and interleukin-2 (IL-2) leads to synergistic antitumor responses in several models of advanced metastatic disease. We now report that after this treatment and other immunotherapy regimens, the CD4+ T-cell population, in contrast to CD8+ T cells, did not significantly increase but rather exhibited a substantial level of apoptosis that was dependent on IFN-gamma. Mice immunized with tumor cells and treated with an immunotherapy regimen that was initially protective were later unable to mount effective memory responses compared with immunized mice not receiving immunotherapy. Immunotherapy given to tumor-bearing Ifngr-/- mice resulted in restoration of secondary responses. Thus, although immunotherapeutic regimens inducing strong IFN-gamma responses can lead to successful early antitumor efficacy, they may also impair the development of durable antitumor responses.", + "TAG_DATA": [ + "56, CD4+ {'context': 'B-cells'}", + "57, T-cell {'context': 'I-cells'}", + "71, exhibited {'effect': 'B-positive'}", + "76, apoptosis {'phenotype': 'B-apoptosis'}", + "82, Mice {'context': 'B-organism'}", + "85, tumor {'context': 'B-transformed cells'}", + "86, cells {'context': 'I-transformed cells'}", + "108, mice {'context': 'B-organism'}", + "116, Ifngr-/- {'perturbing_action': 'B-gene loss-of-function'}", + "117, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, CD4+ ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "57, T-cell ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "58, population, ['l1', 'l7', 'l13', 'l14', 'l15', 'l16']", + "71, exhibited ['l2', 'l8', 'l13', 'l17']", + "76, apoptosis ['l3', 'l9', 'l14', 'l17', 'l18']", + "82, Mice ['l4', 'l10', 'l19', 'l20']", + "85, tumor ['l5', 'l11', 'l15', 'l19', 'l21']", + "86, cells ['l6', 'l12', 'l16', 'l18', 'l20', 'l21']", + "116, Ifngr-/- ['l22']", + "117, mice ['l22']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD4+", + "T-cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "exhibited" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4+", + "T-cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "exhibited" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ifngr-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "17322896", + "TEXT": "Type 2 diabetes is characterized by both peripheral insulin resistance and reduced insulin secretion by beta-cells. The reasons for beta-cell dysfunction in this disease are incompletely understood but may include the accumulation of toxic lipids within this cell type. We examined the role of Abca1, a cellular cholesterol transporter, in cholesterol homeostasis and insulin secretion in beta-cells. Mice with specific inactivation of Abca1 in beta-cells had markedly impaired glucose tolerance and defective insulin secretion but normal insulin sensitivity. Islets isolated from these mice showed altered cholesterol homeostasis and impaired insulin secretion in vitro. We found that rosiglitazone, an activator of the peroxisome proliferator-activated receptor-gamma, which upregulates Abca1 in beta-cells, requires beta-cell Abca1 for its beneficial effects on glucose tolerance. These experiments establish a new role for Abca1 in beta-cell cholesterol homeostasis and insulin secretion, and suggest that cholesterol accumulation may contribute to beta-cell dysfunction in type 2 diabetes.", + "TAG_DATA": [ + "57, Mice {'context': 'B-organism'}", + "59, specific {'perturbing_action': 'B-gene loss-of-function'}", + "60, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "61, of {'perturbing_action': 'I-gene loss-of-function'}", + "62, Abca1 {'perturbing_action': 'I-gene loss-of-function'}", + "64, beta-cells {'context': 'B-cells'}", + "78, Islets {'context': 'B-cells'}", + "82, mice {'context': 'B-organism'}", + "91, in {'context': 'B-in vitro'}", + "92, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "57, Mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "59, specific ['l0', 'l5', 'l6', 'l7', 'l8']", + "60, inactivation ['l1', 'l5', 'l9', 'l10', 'l11']", + "61, of ['l2', 'l6', 'l9', 'l12', 'l13']", + "62, Abca1 ['l3', 'l7', 'l10', 'l12', 'l14']", + "64, beta-cells ['l4', 'l8', 'l11', 'l13', 'l14']", + "78, Islets ['l15', 'l16', 'l17']", + "82, mice ['l15', 'l18', 'l19']", + "91, in ['l16', 'l18', 'l20']", + "92, vitro. ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "specific", + "inactivation", + "of", + "Abca1" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "specific", + "inactivation", + "of", + "Abca1" + ] + }, + "context": { + "val": "cells", + "words": [ + "beta-cells" + ] + } + } + ] + }, + { + "PMID": "17322895", + "TEXT": "In the adult heart, a variety of stresses induce re-expression of a fetal gene program in association with myocyte hypertrophy and heart failure. Here we show that histone deacetylase-2 (Hdac2) regulates expression of many fetal cardiac isoforms. Hdac2 deficiency or chemical histone deacetylase (HDAC) inhibition prevented the re-expression of fetal genes and attenuated cardiac hypertrophy in hearts exposed to hypertrophic stimuli. Resistance to hypertrophy was associated with increased expression of the gene encoding inositol polyphosphate-5-phosphatase f (Inpp5f) resulting in constitutive activation of glycogen synthase kinase 3beta (Gsk3beta) via inactivation of thymoma viral proto-oncogene (Akt) and 3-phosphoinositide-dependent protein kinase-1 (Pdk1). In contrast, Hdac2 transgenic mice had augmented hypertrophy associated with inactivated Gsk3beta. Chemical inhibition of activated Gsk3beta allowed Hdac2-deficient adults to become sensitive to hypertrophic stimulation. These results suggest that Hdac2 is an important molecular target of HDAC inhibitors in the heart and that Hdac2 and Gsk3beta are components of a regulatory pathway providing an attractive therapeutic target for the treatment of cardiac hypertrophy and heart failure.", + "TAG_DATA": [ + "37, Hdac2 {'perturbing_action': 'B-gene loss-of-function'}", + "38, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "56, hearts {'context': 'B-tissue/organ'}", + "101, Hdac2 {'perturbing_action': 'B-gene gain-of-function'}", + "102, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "103, mice {'context': 'B-organism'}", + "114, activated {'perturbing_action': 'I-pharmacological inhibition'}", + "117, Hdac2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "118, adults {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "37, Hdac2 ['l0', 'l1']", + "38, deficiency ['l0', 'l2']", + "56, hearts ['l1', 'l2']", + "101, Hdac2 ['l3', 'l4']", + "102, transgenic ['l3', 'l5']", + "103, mice ['l4', 'l5']", + "114, activated ['l6', 'l7']", + "117, Hdac2-deficient ['l6', 'l8']", + "118, adults ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hdac2", + "deficiency" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hearts" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Hdac2", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "activated" + ] + }, + "context": { + "val": "organism", + "words": [ + "adults" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hdac2-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "adults" + ] + } + } + ] + }, + { + "PMID": "17273170", + "TEXT": "Increased production of very low-density lipoprotein (VLDL) is a critical feature of the metabolic syndrome. Here we report that a selective increase in brain glucose lowered circulating triglycerides (TG) through the inhibition of TG-VLDL secretion by the liver. We found that the effect of glucose required its conversion to lactate, leading to activation of ATP-sensitive potassium channels and to decreased hepatic activity of stearoyl-CoA desaturase-1 (SCD1). SCD1 catalyzed the synthesis of oleyl-CoA from stearoyl-CoA. Curtailing the liver activity of SCD1 was sufficient to lower the hepatic levels of oleyl-CoA and to recapitulate the effects of central glucose administration on VLDL secretion. Notably, portal infusion of oleic acid restored hepatic oleyl-CoA to control levels and negated the effects of both central glucose and SCD1 deficiency on TG-VLDL secretion. These central effects of glucose (but not those of lactate) were rapidly lost in diet-induced obesity. These findings indicate that a defect in brain glucose sensing could play a critical role in the etiology of the metabolic syndrome.", + "TAG_DATA": [ + "76, liver {'context': 'B-tissue/organ'}", + "77, activity {'perturbing_action': 'I-other'}", + "78, of {'perturbing_action': 'I-other'}", + "79, SCD1 {'perturbing_action': 'I-other'}", + "122, SCD1 {'perturbing_action': 'B-gene loss-of-function'}", + "123, deficiency {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "75, the ['l0', 'l1', 'l2', 'l3']", + "76, liver ['l0', 'l4', 'l5', 'l6']", + "77, activity ['l1', 'l4', 'l7', 'l8']", + "78, of ['l2', 'l5', 'l7', 'l9']", + "79, SCD1 ['l3', 'l6', 'l8', 'l9']", + "122, SCD1 ['l10']", + "123, deficiency ['l10']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "activity", + "of", + "SCD1" + ] + } + } + ] + }, + { + "PMID": "17273169", + "TEXT": "Asymmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA) are endogenously produced amino acids that inhibit all three isoforms of nitric oxide synthase (NOS). ADMA accumulates in various disease states, including renal failure, diabetes and pulmonary hypertension, and its concentration in plasma is strongly predictive of premature cardiovascular disease and death. Both L-NMMA and ADMA are eliminated largely through active metabolism by dimethylarginine dimethylaminohydrolase (DDAH) and thus DDAH dysfunction may be a crucial unifying feature of increased cardiovascular risk. However, despite considerable interest in this pathway and in the role of ADMA as a cardiovascular risk factor, there is little evidence to support a causal role of ADMA in pathophysiology. Here we reveal the structure of human DDAH-1 and probe the function of DDAH-1 both by deleting the DDAH1 gene in mice and by using DDAH-specific inhibitors which, as we demonstrate by crystallography, bind to the active site of human DDAH-1. We show that loss of DDAH-1 activity leads to accumulation of ADMA and reduction in NO signaling. This in turn causes vascular pathophysiology, including endothelial dysfunction, increased systemic vascular resistance and elevated systemic and pulmonary blood pressure. Our results also suggest that DDAH inhibition could be harnessed therapeutically to reduce the vascular collapse associated with sepsis.", + "TAG_DATA": [ + "124, deleting {'perturbing_action': 'B-gene loss-of-function'}", + "125, the {'perturbing_action': 'I-gene loss-of-function'}", + "126, DDAH1 {'perturbing_action': 'I-gene loss-of-function'}", + "127, gene {'perturbing_action': 'I-gene loss-of-function'}", + "129, mice {'context': 'B-organism'}", + "133, DDAH-specific {'perturbing_action': 'B-pharmacological inhibition'}", + "134, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "152, loss {'perturbing_action': 'B-gene loss-of-function'}", + "153, of {'perturbing_action': 'I-gene loss-of-function'}", + "154, DDAH-1 {'perturbing_action': 'I-gene loss-of-function'}", + "155, activity {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "124, deleting ['l0', 'l1', 'l2', 'l3']", + "125, the ['l0', 'l4', 'l5', 'l6']", + "126, DDAH1 ['l1', 'l4', 'l7', 'l8']", + "127, gene ['l2', 'l5', 'l7', 'l9']", + "129, mice ['l3', 'l6', 'l8', 'l9']", + "133, DDAH-specific ['l10', 'l11', 'l12', 'l13', 'l14']", + "134, inhibitors ['l10', 'l15', 'l16', 'l17', 'l18']", + "152, loss ['l11', 'l15', 'l19', 'l20', 'l21']", + "153, of ['l12', 'l16', 'l19', 'l22', 'l23']", + "154, DDAH-1 ['l13', 'l17', 'l20', 'l22', 'l24']", + "155, activity ['l14', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deleting", + "the", + "DDAH1", + "gene" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "17187072", + "TEXT": "Anthracyclin-treated tumor cells are particularly effective in eliciting an anticancer immune response, whereas other DNA-damaging agents such as etoposide and mitomycin C do not induce immunogenic cell death. Here we show that anthracyclins induce the rapid, preapoptotic translocation of calreticulin (CRT) to the cell surface. Blockade or knockdown of CRT suppressed the phagocytosis of anthracyclin-treated tumor cells by dendritic cells and abolished their immunogenicity in mice. The anthracyclin-induced CRT translocation was mimicked by inhibition of the protein phosphatase 1/GADD34 complex. Administration of recombinant CRT or inhibitors of protein phosphatase 1/GADD34 restored the immunogenicity of cell death elicited by etoposide and mitomycin C, and enhanced their antitumor effects in vivo. These data identify CRT as a key feature determining anticancer immune responses and delineate a possible strategy for immunogenic chemotherapy.", + "TAG_DATA": [ + "47, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "48, of {'perturbing_action': 'I-rnai/knockdown'}", + "49, CRT {'perturbing_action': 'I-rnai/knockdown'}", + "50, suppressed {'effect': 'B-negative'}", + "52, phagocytosis {'phenotype': 'B-mitophagy'}", + "55, tumor {'context': 'B-transformed cells'}", + "56, cells {'context': 'I-transformed cells'}", + "58, dendritic {'context': 'B-cells'}", + "59, cells {'context': 'I-cells'}", + "65, mice. {'context': 'B-organism'}", + "85, inhibitors {'perturbing_action': 'B-pharmacological inhibition'}", + "86, of {'perturbing_action': 'I-pharmacological inhibition'}", + "87, protein {'perturbing_action': 'I-pharmacological inhibition'}", + "88, phosphatase {'perturbing_action': 'I-pharmacological inhibition'}", + "89, 1/GADD34 {'perturbing_action': 'I-pharmacological inhibition'}", + "90, restored {'effect': 'B-rescues'}", + "94, cell {'phenotype': 'B-cell death'}", + "95, death {'phenotype': 'I-cell death'}", + "107, in {'context': 'B-in vivo'}", + "108, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "47, knockdown ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "48, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "49, CRT ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "50, suppressed ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28']", + "52, phagocytosis ['l3', 'l11', 'l18', 'l24', 'l29', 'l30', 'l31', 'l32', 'l33']", + "55, tumor ['l4', 'l12', 'l19', 'l25', 'l29', 'l34', 'l35', 'l36', 'l37']", + "56, cells ['l5', 'l13', 'l20', 'l26', 'l30', 'l34', 'l38', 'l39', 'l40']", + "58, dendritic ['l6', 'l14', 'l21', 'l27', 'l31', 'l35', 'l38', 'l41', 'l42']", + "59, cells ['l7', 'l15', 'l22', 'l28', 'l32', 'l36', 'l39', 'l41', 'l43']", + "65, mice. ['l8', 'l16', 'l23', 'l33', 'l37', 'l40', 'l42', 'l43']", + "85, inhibitors ['l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "86, of ['l44', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "87, protein ['l45', 'l53', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "88, phosphatase ['l46', 'l54', 'l61', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "89, 1/GADD34 ['l47', 'l55', 'l62', 'l68', 'l74', 'l75', 'l76', 'l77', 'l78']", + "90, restored ['l48', 'l56', 'l63', 'l69', 'l74', 'l79', 'l80']", + "94, cell ['l49', 'l57', 'l64', 'l70', 'l75', 'l79', 'l81']", + "95, death ['l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l81']", + "107, in ['l51', 'l59', 'l66', 'l72', 'l77', 'l82']", + "108, vivo. ['l52', 'l60', 'l67', 'l73', 'l78', 'l82']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "CRT" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "CRT" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "CRT" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "CRT" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "CRT" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells" + ] + } + }, + { + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells" + ] + } + }, + { + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "protein", + "phosphatase", + "1/GADD34" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "protein", + "phosphatase", + "1/GADD34" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "protein", + "phosphatase", + "1/GADD34" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + } + ] + }, + { + "PMID": "17173050", + "TEXT": "T-cell acute lymphoblastic leukemia (T-ALL), unlike other ALL types, is only infrequently associated with chromosomal aberrations, but it was recently shown that most individuals with T-ALL carry activating mutations in the NOTCH1 gene. However, the signaling pathways and target genes responsible for Notch1-induced neoplastic transformation remain undefined. We report here that constitutively active Notch1 activates the NF-kappaB pathway transcriptionally and via the IkappaB kinase (IKK) complex, thereby causing increased expression of several well characterized target genes of NF-kappaB in bone marrow hematopoietic stem cells and progenitors. Our observations demonstrate that the NF-kappaB pathway is highly active in established human T-ALL and that inhibition of the pathway can efficiently restrict tumor growth both in vitro and in vivo. These findings identify NF-kappaB as one of the major mediators of Notch1-induced transformation and suggest that the NF-kappaB pathway is a potential target of future therapies of T-ALL.", + "TAG_DATA": [ + "51, constitutively {'perturbing_action': 'B-gene gain-of-function'}", + "52, active {'perturbing_action': 'I-gene gain-of-function'}", + "53, Notch1 {'perturbing_action': 'I-gene gain-of-function'}", + "108, restrict {'effect': 'B-negative'}", + "109, tumor {'phenotype': 'B-tumour growth'}", + "110, growth {'phenotype': 'I-tumour growth'}", + "112, in {'context': 'B-in vitro'}", + "113, vitro {'context': 'I-in vitro'}", + "115, in {'context': 'B-in vivo'}", + "116, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "51, constitutively ['l0', 'l1']", + "52, active ['l0', 'l2']", + "53, Notch1 ['l1', 'l2']", + "108, restrict ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "109, tumor ['l3', 'l9', 'l10', 'l11', 'l12', 'l13']", + "110, growth ['l4', 'l9', 'l14', 'l15', 'l16', 'l17']", + "112, in ['l5', 'l10', 'l14', 'l18', 'l19', 'l20']", + "113, vitro ['l6', 'l11', 'l15', 'l18', 'l21', 'l22']", + "115, in ['l7', 'l12', 'l16', 'l19', 'l21', 'l23']", + "116, vivo. ['l8', 'l13', 'l17', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "restrict" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "restrict" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "restrict" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "17159986", + "TEXT": "Advanced breast cancers frequently metastasize to bone, resulting in osteolytic lesions, yet the underlying mechanisms are poorly understood. Here we report that nuclear factor-kappaB (NF-kappaB) plays a crucial role in the osteolytic bone metastasis of breast cancer by stimulating osteoclastogenesis. Using an in vivo bone metastasis model, we found that constitutive NF-kappaB activity in breast cancer cells is crucial for the bone resorption characteristic of osteolytic bone metastasis. We identified the gene encoding granulocyte macrophage-colony stimulating factor (GM-CSF) as a key target of NF-kappaB and found that it mediates osteolytic bone metastasis of breast cancer by stimulating osteoclast development. Moreover, we observed that the expression of GM-CSF correlated with NF-kappaB activation in bone-metastatic tumor tissues from individuals with breast cancer. These results uncover a new and specific role of NF-kappaB in osteolytic bone metastasis through GM-CSF induction, suggesting that NF-kappaB is a potential target for the treatment of breast cancer and the prevention of skeletal metastasis.", + "TAG_DATA": [ + "42, in {'context': 'B-in vivo'}", + "43, vivo {'context': 'B-in vivo'}", + "44, bone {'context': 'B-in vivo', 'phenotype': 'B-metastasis'}", + "45, metastasis {'phenotype': 'I-metastasis'}", + "46, model, {'phenotype': 'I-metastasis'}", + "54, breast {'context': 'B-transformed cells'}", + "55, cancer {'context': 'I-transformed cells'}", + "56, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "42, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "43, vivo ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "44, bone ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "45, metastasis ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "46, model, ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "54, breast ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "55, cancer ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "56, cells ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "bone" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "bone", + "metastasis", + "model," + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "bone", + "metastasis", + "model," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "breast", + "cancer", + "cells" + ] + } + } + ] + }, + { + "PMID": "17128270", + "TEXT": "Matrix-producing osteoblasts and bone-resorbing osteoclasts maintain bone homeostasis. Osteoclasts are multinucleated, giant cells of hematopoietic origin formed by the fusion of mononuclear pre-osteoclasts derived from myeloid cells. Fusion-mediated giant cell formation is critical for osteoclast maturation; without it, bone resorption is inefficient. To understand how osteoclasts differ from other myeloid lineage cells, we previously compared global mRNA expression patterns in these cells and identified genes of unknown function predominantly expressed in osteoclasts, one of which is the d2 isoform of vacuolar (H(+)) ATPase (v-ATPase) V(0) domain (Atp6v0d2). Here we show that inactivation of Atp6v0d2 in mice results in markedly increased bone mass due to defective osteoclasts and enhanced bone formation. Atp6v0d2 deficiency did not affect differentiation or the v-ATPase activity of osteoclasts. Rather, Atp6v0d2 was required for efficient pre-osteoclast fusion. Increased bone formation was probably due to osteoblast-extrinsic factors, as Atp6v02 was not expressed in osteoblasts and their differentiation ex vivo was not altered in the absence of Atp6v02. Our results identify Atp6v0d2 as a regulator of osteoclast fusion and bone formation, and provide genetic data showing that it is possible to simultaneously inhibit osteoclast maturation and stimulate bone formation by therapeutically targeting the function of a single gene.", + "TAG_DATA": [ + "91, inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "92, of {'perturbing_action': 'I-gene loss-of-function'}", + "93, Atp6v0d2 {'perturbing_action': 'I-gene loss-of-function'}", + "95, mice {'context': 'B-organism'}", + "105, osteoclasts {'context': 'B-cells'}", + "110, Atp6v0d2 {'perturbing_action': 'B-gene loss-of-function'}", + "111, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "112, did {'effect': 'B-no effect'}", + "113, not {'effect': 'I-no effect'}", + "114, affect {'effect': 'I-no effect'}", + "115, differentiation {'phenotype': 'B-differentiation'}", + "121, osteoclasts. {'context': 'B-cells'}", + "148, differentiation {'phenotype': 'B-differentiation'}", + "153, altered {'effect': 'B-no effect'}", + "156, absence {'perturbing_action': 'B-gene loss-of-function'}", + "157, of {'perturbing_action': 'I-gene loss-of-function'}", + "158, Atp6v02. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "91, inactivation ['l0', 'l1', 'l2', 'l3']", + "92, of ['l0', 'l4', 'l5', 'l6']", + "93, Atp6v0d2 ['l1', 'l4', 'l7', 'l8']", + "95, mice ['l2', 'l5', 'l7', 'l9']", + "105, osteoclasts ['l3', 'l6', 'l8', 'l9']", + "110, Atp6v0d2 ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "111, deficiency ['l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "112, did ['l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "113, not ['l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "114, affect ['l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "115, differentiation ['l14', 'l19', 'l23', 'l26', 'l28', 'l30']", + "121, osteoclasts. ['l15', 'l20', 'l24', 'l27', 'l29', 'l30']", + "148, differentiation ['l31', 'l32', 'l33', 'l34']", + "153, altered ['l31', 'l35', 'l36', 'l37']", + "156, absence ['l32', 'l35', 'l38', 'l39']", + "157, of ['l33', 'l36', 'l38', 'l40']", + "158, Atp6v02. ['l34', 'l37', 'l39', 'l40']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "Atp6v0d2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "Atp6v0d2", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclasts", + "osteoclasts." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atp6v0d2", + "deficiency", + "absence", + "of", + "Atp6v02." + ] + }, + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "affect", + "altered" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atp6v0d2", + "deficiency", + "absence", + "of", + "Atp6v02." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "affect", + "altered" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "affect" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclasts." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclasts." + ] + } + } + ] + }, + { + "PMID": "17115048", + "TEXT": "Amyloid plaque is the hallmark and primary cause of Alzheimer disease. Mutations of presenilin-1, the gamma-secretase catalytic subunit, can affect amyloid-beta (Abeta) production and Alzheimer disease pathogenesis. However, it is largely unknown whether and how gamma-secretase activity and amyloid plaque formation are regulated by environmental factors such as stress, which is mediated by receptors including beta(2)-adrenergic receptor (beta(2)-AR). Here we report that activation of beta(2)-AR enhanced gamma-secretase activity and thus Abeta production. This enhancement involved the association of beta(2)-AR with presenilin-1 and required agonist-induced endocytosis of beta(2)-AR and subsequent trafficking of gamma-secretase to late endosomes and lysosomes, where Abeta production was elevated. Similar effects were observed after activation of delta-opioid receptor. Furthermore, chronic treatment with beta(2)-AR agonists increased cerebral amyloid plaques in an Alzheimer disease mouse model. Thus, beta(2)-AR activation can stimulate gamma-secretase activity and amyloid plaque formation, which suggests that abnormal activation of beta(2)-AR might contribute to Abeta accumulation in Alzheimer disease pathogenesis.", + "TAG_DATA": [ + "62, activation {'perturbing_action': 'B-pharmacological augmentation'}", + "63, of {'perturbing_action': 'I-pharmacological augmentation'}", + "64, beta(2)-AR {'perturbing_action': 'I-pharmacological augmentation'}", + "107, activation {'perturbing_action': 'B-pharmacological augmentation'}", + "110, receptor. {'perturbing_action': 'I-pharmacological augmentation'}", + "115, beta(2)-AR {'perturbing_action': 'B-pharmacological augmentation'}", + "116, agonists {'perturbing_action': 'I-pharmacological augmentation'}", + "123, Alzheimer {'context': 'B-organism'}", + "124, disease {'context': 'I-organism'}", + "125, mouse {'context': 'I-organism'}", + "126, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "62, activation ['l0', 'l1']", + "63, of ['l0', 'l2']", + "64, beta(2)-AR ['l1', 'l2']", + "107, activation ['l3', 'l4']", + "110, receptor. ['l3', 'l5', 'l6', 'l7']", + "115, beta(2)-AR ['l8', 'l9', 'l10', 'l11', 'l12']", + "116, agonists ['l8', 'l13', 'l14', 'l15', 'l16']", + "123, Alzheimer ['l5', 'l9', 'l13', 'l17', 'l18', 'l19']", + "124, disease ['l6', 'l10', 'l14', 'l17', 'l20', 'l21']", + "125, mouse ['l11', 'l15', 'l18', 'l20', 'l22']", + "126, model. ['l4', 'l7', 'l12', 'l16', 'l19', 'l21', 'l22']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "receptor.", + "beta(2)-AR", + "agonists" + ] + }, + "context": { + "val": "organism", + "words": [ + "model.", + "Alzheimer", + "disease", + "mouse" + ] + } + } + ] + }, + { + "PMID": "17099709", + "TEXT": "Axons in the adult mammalian central nervous system (CNS) exhibit little regeneration after injury. It has been suggested that several axonal growth inhibitors prevent CNS axonal regeneration. Recent research has demonstrated that semaphorin3A (Sema3A) is one of the major inhibitors of axonal regeneration. We identified a strong and selective inhibitor of Sema3A, SM-216289, from the fermentation broth of a fungal strain. To examine the effect of SM-216289 in vivo, we transected the spinal cord of adult rats and administered SM-216289 into the lesion site for 4 weeks. Rats treated with SM-216289 showed substantially enhanced regeneration and/or preservation of injured axons, robust Schwann cell-mediated myelination and axonal regeneration in the lesion site, appreciable decreases in apoptotic cell number and marked enhancement of angiogenesis, resulting in considerably better functional recovery. Thus, Sema3A is essential for the inhibition of axonal regeneration and other regenerative responses after spinal cord injury (SCI). These results support the possibility of using Sema3A inhibitors in the treatment of human SCI.", + "TAG_DATA": [ + "67, in {'context': 'B-in vivo'}", + "68, vivo, {'context': 'I-in vivo'}", + "72, spinal {'context': 'B-tissue/organ'}", + "73, cord {'context': 'I-tissue/organ'}", + "75, adult {'context': 'B-organism'}", + "76, rats {'context': 'I-organism'}", + "87, Rats {'context': 'B-organism'}", + "99, axons, {'context': 'B-cells'}", + "112, decreases {'effect': 'B-negative'}", + "114, apoptotic {'phenotype': 'B-apoptosis'}", + "115, cell {'phenotype': 'I-apoptosis'}" + ], + "LINK_DATA": [ + "67, in ['l0', 'l1', 'l2', 'l3', 'l4']", + "68, vivo, ['l0', 'l5', 'l6', 'l7', 'l8']", + "72, spinal ['l1', 'l5', 'l9', 'l10', 'l11']", + "73, cord ['l2', 'l6', 'l9', 'l12', 'l13']", + "75, adult ['l3', 'l7', 'l10', 'l12', 'l14']", + "76, rats ['l4', 'l8', 'l11', 'l13', 'l14']", + "87, Rats ['l15']", + "99, axons, ['l15']", + "112, decreases ['l16', 'l17']", + "114, apoptotic ['l16', 'l18']", + "115, cell ['l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "decreases" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell" + ] + } + } + ] + }, + { + "PMID": "17063141", + "TEXT": "We demonstrate here that lymphoid enhancer-binding factor 1 (LEF-1) mediates the proliferation, survival and differentiation of granulocyte progenitor cells. We initially documented the importance of this transcription factor in the bone marrow of individuals with severe congenital neutropenia (CN) with a 'differentiation block' at the promyelocytic stage of myelopoiesis. LEF-1 expression was greatly reduced or even absent in CN arrested promyelocytes, resulting in defective expression of the LEF-1 target genes CCND1, MYC and BIRC5, encoding cyclin D1 (ref. 2), c-Myc and survivin, respectively. In contrast, healthy individuals showed highest LEF-1 expression in promyelocytes. Reconstitution of LEF-1 in early hematopoietic progenitors of two individuals with CN corrected the defective myelopoiesis and resulted in the differentiation of these progenitors into mature granulocytes. Repression of endogenous LEF-1 by specific short hairpin RNA inhibited proliferation and induced apoptosis of CD34(+) progenitors from healthy individuals and of cells from two myeloid lines (HL-60 and K562). C/EBPalpha, a key transcription factor in granulopoiesis, was directly regulated by LEF-1. These observations indicate that LEF-1 is an instructive factor regulating neutrophilic granulopoiesis whose absence plays a critical role in the defective maturation program of myeloid progenitors in individuals with CN.", + "TAG_DATA": [ + "60, promyelocytes, {'context': 'B-cells'}", + "93, Reconstitution {'perturbing_action': 'B-gene gain-of-function'}", + "94, of {'perturbing_action': 'I-gene gain-of-function'}", + "95, LEF-1 {'perturbing_action': 'I-gene gain-of-function'}", + "97, early {'context': 'B-cells'}", + "98, hematopoietic {'context': 'B-cells'}", + "99, progenitors {'context': 'I-cells'}", + "110, resulted {'effect': 'B-positive'}", + "111, in {'effect': 'I-positive'}", + "113, differentiation {'phenotype': 'B-differentiation'}", + "116, progenitors {'context': 'B-cells'}", + "120, Repression {'perturbing_action': 'B-rnai/knockdown'}", + "121, of {'perturbing_action': 'I-rnai/knockdown'}", + "122, endogenous {'perturbing_action': 'I-rnai/knockdown'}", + "123, LEF-1 {'perturbing_action': 'I-rnai/knockdown'}", + "124, by {'perturbing_action': 'I-rnai/knockdown'}", + "125, specific {'perturbing_action': 'I-rnai/knockdown'}", + "126, short {'perturbing_action': 'I-rnai/knockdown'}", + "127, hairpin {'perturbing_action': 'I-rnai/knockdown'}", + "128, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "129, inhibited {'effect': 'B-negative'}", + "130, proliferation {'phenotype': 'B-proliferation'}", + "132, induced {'effect': 'B-positive'}", + "133, apoptosis {'phenotype': 'B-apoptosis'}", + "135, CD34(+) {'context': 'B-cells'}", + "136, progenitors {'context': 'I-cells'}", + "142, cells {'context': 'B-cells'}", + "143, from {'context': 'I-cells'}", + "144, two {'context': 'I-cells'}", + "145, myeloid {'context': 'B-cells'}", + "146, lines {'context': 'I-cells'}", + "147, (HL-60 {'context': 'I-cells'}", + "148, and {'context': 'I-cells'}", + "149, K562). {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "93, Reconstitution ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "94, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "95, LEF-1 ['l1', 'l13', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "97, early ['l2', 'l14', 'l23', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "98, hematopoietic ['l3', 'l15', 'l24', 'l32', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "99, progenitors ['l4', 'l16', 'l25', 'l33', 'l40', 'l47', 'l48', 'l49', 'l50', 'l51']", + "110, resulted ['l5', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l53', 'l54', 'l55']", + "111, in ['l6', 'l18', 'l27', 'l35', 'l42', 'l48', 'l52', 'l56', 'l57', 'l58']", + "113, differentiation ['l7', 'l19', 'l28', 'l36', 'l43', 'l49', 'l53', 'l56', 'l59', 'l60']", + "116, progenitors ['l8', 'l20', 'l29', 'l37', 'l44', 'l50', 'l54', 'l57', 'l59', 'l61']", + "119, granulocytes. ['l9', 'l21', 'l30', 'l38', 'l45', 'l51', 'l55', 'l58', 'l60', 'l61']", + "120, Repression ['l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "121, of ['l62', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "122, endogenous ['l63', 'l84', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "123, LEF-1 ['l64', 'l85', 'l105', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "124, by ['l65', 'l86', 'l106', 'l125', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "125, specific ['l66', 'l87', 'l107', 'l126', 'l144', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "126, short ['l67', 'l88', 'l108', 'l127', 'l145', 'l162', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "127, hairpin ['l68', 'l89', 'l109', 'l128', 'l146', 'l163', 'l179', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209']", + "128, RNA ['l69', 'l90', 'l110', 'l129', 'l147', 'l164', 'l180', 'l195', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223']", + "129, inhibited ['l70', 'l91', 'l111', 'l130', 'l148', 'l165', 'l181', 'l196', 'l210', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236']", + "130, proliferation ['l10', 'l71', 'l92', 'l112', 'l131', 'l149', 'l166', 'l182', 'l197', 'l211', 'l224', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244']", + "132, induced ['l72', 'l93', 'l113', 'l132', 'l150', 'l167', 'l183', 'l198', 'l212', 'l225', 'l237', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255']", + "133, apoptosis ['l73', 'l94', 'l114', 'l133', 'l151', 'l168', 'l184', 'l199', 'l213', 'l226', 'l238', 'l245', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265']", + "135, CD34(+) ['l11', 'l74', 'l95', 'l115', 'l134', 'l152', 'l169', 'l185', 'l200', 'l214', 'l227', 'l239', 'l246', 'l256', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274']", + "136, progenitors ['l12', 'l22', 'l31', 'l39', 'l46', 'l75', 'l96', 'l116', 'l135', 'l153', 'l170', 'l186', 'l201', 'l215', 'l228', 'l240', 'l247', 'l257', 'l266', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280']", + "142, cells ['l76', 'l97', 'l117', 'l136', 'l154', 'l171', 'l187', 'l202', 'l216', 'l229', 'l248', 'l258', 'l267', 'l275', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286', 'l287']", + "143, from ['l77', 'l98', 'l118', 'l137', 'l155', 'l172', 'l188', 'l203', 'l217', 'l230', 'l249', 'l259', 'l268', 'l276', 'l281', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293']", + "144, two ['l78', 'l99', 'l119', 'l138', 'l156', 'l173', 'l189', 'l204', 'l218', 'l231', 'l250', 'l260', 'l269', 'l282', 'l288', 'l294', 'l295', 'l296', 'l297', 'l298']", + "145, myeloid ['l79', 'l100', 'l120', 'l139', 'l157', 'l174', 'l190', 'l205', 'l219', 'l232', 'l251', 'l261', 'l270', 'l283', 'l289', 'l294', 'l299', 'l300', 'l301', 'l302']", + "146, lines ['l80', 'l101', 'l121', 'l140', 'l158', 'l175', 'l191', 'l206', 'l220', 'l233', 'l241', 'l252', 'l262', 'l271', 'l277', 'l284', 'l290', 'l295', 'l299', 'l303', 'l304', 'l305']", + "147, (HL-60 ['l81', 'l102', 'l122', 'l141', 'l159', 'l176', 'l192', 'l207', 'l221', 'l234', 'l242', 'l253', 'l263', 'l272', 'l278', 'l285', 'l291', 'l296', 'l300', 'l303', 'l306', 'l307']", + "148, and ['l82', 'l103', 'l123', 'l142', 'l160', 'l177', 'l193', 'l208', 'l222', 'l235', 'l243', 'l254', 'l264', 'l273', 'l279', 'l286', 'l292', 'l297', 'l301', 'l304', 'l306', 'l308']", + "149, K562). ['l83', 'l104', 'l124', 'l143', 'l161', 'l178', 'l194', 'l209', 'l223', 'l236', 'l244', 'l255', 'l265', 'l274', 'l280', 'l287', 'l293', 'l298', 'l302', 'l305', 'l307', 'l308']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reconstitution", + "of", + "LEF-1" + ] + }, + "context": { + "val": "cells", + "words": [ + "early", + "hematopoietic", + "progenitors", + "CD34(+)" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reconstitution", + "of", + "LEF-1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reconstitution", + "of", + "LEF-1" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reconstitution" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "early", + "hematopoietic", + "progenitors", + "CD34(+)", + "cells", + "from", + "two", + "myeloid", + "lines", + "(HL-60", + "and", + "K562)." + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulted", + "in", + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "early", + "hematopoietic", + "progenitors" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Repression", + "of", + "endogenous", + "LEF-1", + "by", + "specific", + "short", + "hairpin", + "RNA" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Repression", + "of", + "endogenous", + "LEF-1", + "by", + "specific", + "short", + "hairpin", + "RNA" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Repression", + "of", + "endogenous", + "LEF-1", + "by", + "specific", + "short", + "hairpin", + "RNA" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Repression", + "of", + "endogenous", + "LEF-1", + "by", + "specific", + "short", + "hairpin", + "RNA" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Repression", + "of", + "endogenous", + "LEF-1", + "by", + "specific", + "short", + "hairpin", + "RNA" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD34(+)", + "progenitors", + "cells", + "from", + "two", + "myeloid", + "lines", + "(HL-60", + "and", + "K562)." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD34(+)", + "progenitors", + "cells", + "from", + "two", + "myeloid", + "lines", + "(HL-60", + "and", + "K562)." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD34(+)", + "progenitors", + "lines", + "(HL-60", + "and", + "K562)." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD34(+)", + "progenitors", + "cells", + "from", + "two", + "myeloid", + "lines", + "(HL-60", + "and", + "K562)." + ] + } + } + ] + }, + { + "PMID": "16998484", + "TEXT": "The long-term survival of patients with acute myeloid leukemia (AML) is dismally poor. A permanent cure of AML requires elimination of leukemic stem cells (LSCs), the only cell type capable of initiating and maintaining the leukemic clonal hierarchy. We report a therapeutic approach using an activating monoclonal antibody directed to the adhesion molecule CD44. In vivo administration of this antibody to nonobese diabetic-severe combined immune-deficient mice transplanted with human AML markedly reduced leukemic repopulation. Absence of leukemia in serially transplanted mice demonstrated that AML LSCs are directly targeted. Mechanisms underlying this eradication included interference with transport to stem cell-supportive microenvironmental niches and alteration of AML-LSC fate, identifying CD44 as a key regulator of AML LSCs. The finding that AML LSCs require interaction with a niche to maintain their stem cell properties provides a therapeutic strategy to eliminate quiescent AML LSCs and may be applicable to other types of cancer stem cells.", + "TAG_DATA": [ + "54, In {'context': 'B-in vivo'}", + "55, vivo {'context': 'I-in vivo'}", + "61, nonobese {'context': 'B-organism'}", + "62, diabetic-severe {'context': 'I-organism'}", + "63, combined {'context': 'I-organism'}", + "64, immune-deficient {'context': 'I-organism'}", + "65, mice {'context': 'I-organism'}", + "76, leukemia {'phenotype': 'B-tumourigenesis'}", + "80, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "54, In ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "55, vivo ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "61, nonobese ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "62, diabetic-severe ['l2', 'l8', 'l13', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "63, combined ['l3', 'l9', 'l14', 'l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "64, immune-deficient ['l4', 'l10', 'l15', 'l21', 'l26', 'l31', 'l32', 'l33', 'l34']", + "65, mice ['l5', 'l11', 'l16', 'l22', 'l27', 'l31', 'l35']", + "69, AML ['l6', 'l12', 'l17', 'l23', 'l28', 'l32', 'l35']", + "76, leukemia ['l18', 'l24', 'l29', 'l33', 'l36']", + "80, mice ['l19', 'l25', 'l30', 'l34', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "nonobese", + "diabetic-severe", + "combined", + "immune-deficient", + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia" + ] + } + } + ] + }, + { + "PMID": "16980968", + "TEXT": "Pharmacological interventions that increase myofiber size counter the functional decline of dystrophic muscles. We show that deacetylase inhibitors increase the size of myofibers in dystrophin-deficient (MDX) and alpha-sarcoglycan (alpha-SG)-deficient mice by inducing the expression of the myostatin antagonist follistatin in satellite cells. Deacetylase inhibitor treatment conferred on dystrophic muscles resistance to contraction-coupled degeneration and alleviated both morphological and functional consequences of the primary genetic defect. These results provide a rationale for using deacetylase inhibitors in the pharmacological therapy of muscular dystrophies.", + "TAG_DATA": [ + "22, myofibers {'context': 'B-cells'}", + "24, dystrophin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "25, (MDX) {'perturbing_action': 'I-gene loss-of-function'}", + "27, alpha-sarcoglycan {'perturbing_action': 'B-gene loss-of-function'}", + "28, (alpha-SG)-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "29, mice {'context': 'B-organism'}", + "40, satellite {'context': 'B-cells'}", + "41, cells. {'context': 'I-cells'}", + "47, dystrophic {'context': 'B-tissue/organ'}", + "48, muscles {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "22, myofibers ['l0', 'l1', 'l2']", + "24, dystrophin-deficient ['l0', 'l3', 'l4', 'l5', 'l6']", + "25, (MDX) ['l1', 'l3', 'l7', 'l8']", + "27, alpha-sarcoglycan ['l9', 'l10', 'l11', 'l12', 'l13']", + "28, (alpha-SG)-deficient ['l9', 'l14', 'l15', 'l16', 'l17', 'l18']", + "29, mice ['l2', 'l4', 'l7', 'l10', 'l14', 'l19', 'l20']", + "40, satellite ['l5', 'l11', 'l15', 'l19', 'l21', 'l22']", + "41, cells. ['l6', 'l8', 'l12', 'l16', 'l20', 'l21']", + "47, dystrophic ['l17', 'l23']", + "48, muscles ['l13', 'l18', 'l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "myofibers", + "satellite", + "cells." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient", + "(MDX)", + "alpha-sarcoglycan", + "(alpha-SG)-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient", + "(MDX)", + "alpha-sarcoglycan", + "(alpha-SG)-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha-sarcoglycan", + "(alpha-SG)-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscles", + "dystrophic" + ] + } + } + ] + }, + { + "PMID": "16917489", + "TEXT": "The engagement of programmed death 1 (PD-1) to its ligands, PD-L1 and PD-L2, inhibits proliferation and cytokine production mediated by antibodies to CD3 (refs. 5,6,7). Blocking the PD-1-PD-L1 pathway in mice chronically infected with lymphocytic choriomeningitis virus restores the capacity of exhausted CD8(+) T cells to undergo proliferation, cytokine production and cytotoxic activity and, consequently, results in reduced viral load. During chronic HIV infection, HIV-specific CD8(+) T cells are functionally impaired, showing a reduced capacity to produce cytokines and effector molecules as well as an impaired capacity to proliferate. Here, we found that PD-1 was upregulated on HIV-specific CD8(+) T cells; PD-1 expression levels were significantly correlated both with viral load and with the reduced capacity for cytokine production and proliferation of HIV-specific CD8(+) T cells. Notably, cytomegalovirus (CMV)-specific CD8(+) T cells from the same donors did not upregulate PD-1 and maintained the production of high levels of cytokines. Blocking PD-1 engagement to its ligand (PD-L1) enhanced the capacity of HIV-specific CD8(+) T cells to survive and proliferate and led to an increased production of cytokines and cytotoxic molecules in response to cognate antigen. The accumulation of HIV-specific dysfunctional CD8(+) T cells in the infected host could prevent the renewal of a functionally competent HIV-specific CD8(+) repertoire.", + "TAG_DATA": [ + "30, mice {'context': 'B-organism'}", + "43, T {'context': 'I-cells'}", + "44, cells {'context': 'I-cells'}", + "114, reduced {'effect': 'B-negative'}", + "123, CD8(+) {'context': 'I-cells'}", + "124, T {'context': 'I-cells'}", + "125, cells. {'context': 'I-cells'}", + "129, CD8(+) {'context': 'B-cells'}", + "130, T {'context': 'I-cells'}", + "131, cells {'context': 'I-cells'}", + "160, HIV-specific {'context': 'B-cells'}", + "161, CD8(+) {'context': 'I-cells'}", + "162, T {'context': 'I-cells'}", + "163, cells {'context': 'I-cells'}", + "167, proliferate {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "30, mice ['l0', 'l1']", + "43, T ['l0', 'l2']", + "44, cells ['l1', 'l2']", + "114, reduced ['l3', 'l4', 'l5', 'l6']", + "123, CD8(+) ['l3', 'l7', 'l8', 'l9', 'l10', 'l11']", + "124, T ['l4', 'l7', 'l12', 'l13', 'l14', 'l15']", + "125, cells. ['l5', 'l8', 'l12', 'l16']", + "129, CD8(+) ['l9', 'l13', 'l17', 'l18', 'l19', 'l20']", + "130, T ['l10', 'l14', 'l17', 'l21']", + "131, cells ['l6', 'l11', 'l15', 'l16', 'l18', 'l21']", + "160, HIV-specific ['l22', 'l23', 'l24', 'l25']", + "161, CD8(+) ['l22', 'l26', 'l27', 'l28']", + "162, T ['l19', 'l23', 'l26', 'l29', 'l30']", + "163, cells ['l20', 'l24', 'l27', 'l29', 'l31']", + "167, proliferate ['l25', 'l28', 'l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "T", + "cells.", + "cells" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HIV-specific", + "CD8(+)", + "T", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate" + ] + } + } + ] + }, + { + "PMID": "16906154", + "TEXT": "Hepatic glucose production is crucial for glucose homeostasis, and its dysregulation contributes to the pathogenesis of diabetes. Here, we show that members of the NR4A family of ligand-independent orphan nuclear receptors are downstream mediators of cAMP action in the hormonal control of gluconeogenesis. Hepatic expression of Nur77, Nurr1 and NOR1 is induced by the cAMP axis in response to glucagon and fasting in vivo and is increased in diabetic mice that exhibit elevated gluconeogenesis. Adenoviral expression of Nur77 induces genes involved in gluconeogenesis, stimulates glucose production both in vitro and in vivo, and raises blood glucose levels. Conversely, expression of an inhibitory mutant Nur77 receptor antagonizes gluconeogenic gene expression and lowers blood glucose levels in db/db mice. These results outline a previously unrecognized role for orphan nuclear receptors in the transcriptional control of glucose homeostasis.", + "TAG_DATA": [ + "74, Adenoviral {'perturbing_action': 'B-gene gain-of-function'}", + "75, expression {'perturbing_action': 'I-gene gain-of-function'}", + "76, of {'perturbing_action': 'I-gene gain-of-function'}", + "77, Nur77 {'perturbing_action': 'I-gene gain-of-function'}", + "87, in {'context': 'B-in vitro'}", + "88, vitro {'context': 'I-in vitro'}", + "90, in {'context': 'B-in vivo'}", + "91, vivo, {'context': 'I-in vivo'}", + "98, expression {'perturbing_action': 'B-other'}", + "99, of {'perturbing_action': 'I-other'}", + "100, an {'perturbing_action': 'I-other'}", + "101, inhibitory {'perturbing_action': 'I-other'}", + "102, mutant {'perturbing_action': 'I-other'}", + "103, Nur77 {'perturbing_action': 'I-other'}", + "104, receptor {'perturbing_action': 'I-other'}", + "115, db/db {'context': 'B-organism'}", + "116, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "74, Adenoviral ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "75, expression ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "76, of ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "77, Nur77 ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "87, in ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "88, vitro ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "90, in ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "91, vivo, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "98, expression ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "99, of ['l28', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "100, an ['l29', 'l36', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "101, inhibitory ['l30', 'l37', 'l43', 'l49', 'l50', 'l51', 'l52', 'l53']", + "102, mutant ['l31', 'l38', 'l44', 'l49', 'l54', 'l55', 'l56', 'l57']", + "103, Nur77 ['l32', 'l39', 'l45', 'l50', 'l54', 'l58', 'l59', 'l60']", + "104, receptor ['l33', 'l40', 'l46', 'l51', 'l55', 'l58', 'l61', 'l62']", + "115, db/db ['l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l61', 'l63']", + "116, mice. ['l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l62', 'l63']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenoviral", + "expression", + "of", + "Nur77" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenoviral", + "expression", + "of", + "Nur77" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "an", + "inhibitory", + "mutant", + "Nur77", + "receptor" + ] + }, + "context": { + "val": "organism", + "words": [ + "db/db", + "mice." + ] + } + } + ] + }, + { + "PMID": "16892061", + "TEXT": "Vascular smooth muscle cell (VSMC) apoptosis occurs in many arterial diseases, including aneurysm formation, angioplasty restenosis and atherosclerosis. Although VSMC apoptosis promotes vessel remodeling, coagulation and inflammation, its precise contribution to these diseases is unknown, given that apoptosis frequently accompanies vessel injury or alterations to flow. To study the direct consequences of VSMC apoptosis, we generated transgenic mice expressing the human diphtheria toxin receptor (hDTR, encoded by HBEGF) from a minimal Tagln (also known as SM22alpha) promoter. Despite apoptosis inducing loss of 50-70% of VSMCs, normal arteries showed no inflammation, reactive proliferation, thrombosis, remodeling or aneurysm formation. In contrast, VSMC apoptosis in atherosclerotic plaques of SM22alpha-hDTR Apoe-/- mice induced marked thinning of fibrous cap, loss of collagen and matrix, accumulation of cell debris and intense intimal inflammation. We conclude that VSMC apoptosis is 'silent' in normal arteries, which have a large capacity to withstand cell loss. In contrast, VSMC apoptosis alone is sufficient to induce features of plaque vulnerability in atherosclerosis. SM22alpha-hDTR Apoe-/- mice may represent an important new model to test agents proposed to stabilize atherosclerotic plaques.", + "TAG_DATA": [ + "56, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "57, mice {'context': 'B-organism'}", + "58, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "59, the {'perturbing_action': 'I-gene gain-of-function'}", + "60, human {'perturbing_action': 'I-gene gain-of-function'}", + "61, diphtheria {'perturbing_action': 'I-gene gain-of-function'}", + "62, toxin {'perturbing_action': 'I-gene gain-of-function'}", + "63, receptor {'perturbing_action': 'I-gene gain-of-function'}", + "64, (hDTR, {'perturbing_action': 'I-gene gain-of-function'}", + "65, encoded {'perturbing_action': 'I-gene gain-of-function'}", + "66, by {'perturbing_action': 'I-gene gain-of-function'}", + "67, HBEGF) {'perturbing_action': 'I-gene gain-of-function'}", + "68, from {'perturbing_action': 'I-gene gain-of-function'}", + "69, a {'perturbing_action': 'I-gene gain-of-function'}", + "76, promoter. {'perturbing_action': 'I-gene gain-of-function'}", + "84, VSMCs, {'context': 'B-cells'}", + "86, arteries {'context': 'B-tissue/organ'}", + "88, no {'effect': 'B-no effect'}", + "91, proliferation, {'phenotype': 'B-proliferation'}", + "99, VSMC {'context': 'B-cells'}", + "100, apoptosis {'phenotype': 'B-apoptosis'}", + "105, SM22alpha-hDTR {'perturbing_action': 'B-gene loss-of-function'}", + "106, Apoe-/- {'perturbing_action': 'B-gene loss-of-function'}", + "107, mice {'context': 'B-organism'}", + "161, SM22alpha-hDTR {'perturbing_action': 'B-gene loss-of-function'}", + "162, Apoe-/- {'perturbing_action': 'B-gene loss-of-function'}", + "163, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "57, mice ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "58, expressing ['l1', 'l20', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "59, the ['l2', 'l21', 'l38', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "60, human ['l3', 'l22', 'l39', 'l56', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "61, diphtheria ['l4', 'l23', 'l40', 'l57', 'l73', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "62, toxin ['l5', 'l24', 'l41', 'l58', 'l74', 'l89', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "63, receptor ['l6', 'l25', 'l42', 'l59', 'l75', 'l90', 'l104', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "64, (hDTR, ['l7', 'l26', 'l43', 'l60', 'l76', 'l91', 'l105', 'l118', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "65, encoded ['l8', 'l27', 'l44', 'l61', 'l77', 'l92', 'l106', 'l119', 'l131', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "66, by ['l9', 'l28', 'l45', 'l62', 'l78', 'l93', 'l107', 'l120', 'l132', 'l143', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163']", + "67, HBEGF) ['l10', 'l29', 'l46', 'l63', 'l79', 'l94', 'l108', 'l121', 'l133', 'l144', 'l154', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "68, from ['l11', 'l30', 'l47', 'l64', 'l80', 'l95', 'l109', 'l122', 'l134', 'l145', 'l155', 'l164', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180']", + "69, a ['l12', 'l31', 'l48', 'l65', 'l81', 'l96', 'l110', 'l123', 'l135', 'l146', 'l156', 'l165', 'l173', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "70, minimal ['l13', 'l32', 'l49', 'l66', 'l82', 'l97', 'l111', 'l124', 'l136', 'l147', 'l157', 'l166', 'l174', 'l181', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "71, Tagln ['l14', 'l50', 'l67', 'l83', 'l98', 'l112', 'l125', 'l137', 'l148', 'l158', 'l167', 'l175', 'l182', 'l188', 'l194', 'l195', 'l196', 'l197', 'l198']", + "76, promoter. ['l15', 'l33', 'l51', 'l68', 'l84', 'l99', 'l113', 'l126', 'l138', 'l149', 'l159', 'l168', 'l176', 'l183', 'l189', 'l194', 'l199', 'l200', 'l201', 'l202']", + "84, VSMCs, ['l16', 'l34', 'l52', 'l69', 'l85', 'l100', 'l114', 'l127', 'l139', 'l150', 'l160', 'l169', 'l177', 'l184', 'l190', 'l195', 'l199', 'l203', 'l204', 'l205']", + "86, arteries ['l17', 'l35', 'l53', 'l70', 'l86', 'l101', 'l115', 'l128', 'l140', 'l151', 'l161', 'l170', 'l178', 'l185', 'l191', 'l196', 'l200', 'l203', 'l206', 'l207']", + "88, no ['l18', 'l36', 'l54', 'l71', 'l87', 'l102', 'l116', 'l129', 'l141', 'l152', 'l162', 'l171', 'l179', 'l186', 'l192', 'l197', 'l201', 'l204', 'l206', 'l208']", + "91, proliferation, ['l19', 'l37', 'l55', 'l72', 'l88', 'l103', 'l117', 'l130', 'l142', 'l153', 'l163', 'l172', 'l180', 'l187', 'l193', 'l198', 'l202', 'l205', 'l207', 'l208']", + "99, VSMC ['l209', 'l210', 'l211', 'l212']", + "100, apoptosis ['l209', 'l213', 'l214', 'l215']", + "105, SM22alpha-hDTR ['l210', 'l213', 'l216', 'l217']", + "106, Apoe-/- ['l211', 'l214', 'l216', 'l218']", + "107, mice ['l212', 'l215', 'l217', 'l218']", + "161, SM22alpha-hDTR ['l219', 'l220']", + "162, Apoe-/- ['l219', 'l221']", + "163, mice ['l220', 'l221']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "the", + "human", + "diphtheria", + "toxin", + "receptor", + "(hDTR,", + "encoded", + "by", + "HBEGF)", + "from", + "a", + "promoter." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "the", + "human", + "diphtheria", + "toxin", + "receptor", + "(hDTR,", + "encoded", + "by", + "HBEGF)", + "from", + "a", + "promoter." + ] + }, + "context": { + "val": "cells", + "words": [ + "VSMCs," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "the", + "human", + "diphtheria", + "toxin", + "receptor", + "(hDTR,", + "encoded", + "by", + "HBEGF)", + "from", + "a", + "promoter." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "arteries" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "the", + "human", + "diphtheria", + "toxin", + "receptor", + "(hDTR,", + "encoded", + "by", + "HBEGF)", + "from", + "a", + "promoter." + ] + }, + "effect": { + "val": "no effect", + "words": [ + "no" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "the", + "human", + "diphtheria", + "toxin", + "receptor", + "(hDTR,", + "encoded", + "by", + "HBEGF)", + "from", + "a", + "promoter." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "no" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "VSMCs," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "no" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "VSMCs," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "arteries" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "no" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "arteries" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "no" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "VSMC" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "VSMC" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SM22alpha-hDTR", + "Apoe-/-" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SM22alpha-hDTR", + "Apoe-/-" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SM22alpha-hDTR", + "Apoe-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "16892036", + "TEXT": "Bidirectional cellular communication is integral to both cancer progression and embryological development. In addition, aggressive tumor cells are phenotypically plastic, sharing many properties with embryonic cells. Owing to the similarities between these two types of cells, the developing zebrafish can be used as a biosensor for tumor-derived signals. Using this system, we show that aggressive melanoma cells secrete Nodal (a potent embryonic morphogen) and consequently can induce ectopic formation of the embryonic axis. We further show that Nodal is present in human metastatic tumors, but not in normal skin, and thus may be involved in melanoma pathogenesis. Inhibition of Nodal signaling reduces melanoma cell invasiveness, colony formation and tumorigenicity. Nodal inhibition also promotes the reversion of melanoma cells toward a melanocytic phenotype. These data suggest that Nodal signaling has a key role in melanoma cell plasticity and tumorigenicity, thereby providing a previously unknown molecular target for regulating tumor progression.", + "TAG_DATA": [ + "101, reduces {'effect': 'B-negative'}", + "102, melanoma {'context': 'B-transformed cells'}", + "103, cell {'context': 'I-transformed cells'}", + "104, invasiveness, {'phenotype': 'B-invasion'}", + "105, colony {'phenotype': 'B-colony formation'}", + "106, formation {'phenotype': 'I-colony formation'}", + "108, tumorigenicity. {'phenotype': 'B-tumourigenesis'}", + "109, Nodal {'perturbing_action': 'B-pharmacological inhibition'}", + "110, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "116, melanoma {'context': 'B-transformed cells'}", + "117, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "101, reduces ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "102, melanoma ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "103, cell ['l1', 'l6', 'l11', 'l12', 'l13']", + "104, invasiveness, ['l2', 'l7', 'l11', 'l14', 'l15', 'l16']", + "105, colony ['l3', 'l8', 'l12', 'l14', 'l17', 'l18']", + "106, formation ['l4', 'l9', 'l13', 'l15', 'l17', 'l19']", + "108, tumorigenicity. ['l5', 'l10', 'l16', 'l18', 'l19']", + "109, Nodal ['l20', 'l21', 'l22']", + "110, inhibition ['l20', 'l23', 'l24']", + "116, melanoma ['l21', 'l23', 'l25']", + "117, cells ['l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "colony", + "formation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cell" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cell" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "colony", + "formation" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "melanoma" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Nodal", + "inhibition" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cells" + ] + } + } + ] + }, + { + "PMID": "16862155", + "TEXT": "A genetic polymorphism in the human gene encoding connexin37 (CX37, encoded by GJA4, also known as CX37) has been reported as a potential prognostic marker for atherosclerosis. The expression of this gap-junction protein is altered in mouse and human atherosclerotic lesions: it disappears from the endothelium of advanced plaques but is detected in macrophages recruited to the lesions. The role of CX37 in atherogenesis, however, remains unknown. Here we have investigated the effect of deleting the mouse connexin37 (Cx37) gene (Gja4, also known as Cx37) on atherosclerosis in apolipoprotein E-deficient (Apoe(-/-)) mice, an animal model of this disease. We find that Gja4(-/-)Apoe(-/-) mice develop more aortic lesions than Gja4(+/+)Apoe(-/-) mice that express Cx37. Using in vivo adoptive transfer, we show that monocyte and macrophage recruitment is enhanced by eliminating expression of Cx37 in these leukocytes but not by eliminating its expression in the endothelium. We further show that Cx37 hemichannel activity in primary monocytes, macrophages and a macrophage cell line (H36.12j) inhibits leukocyte adhesion. This antiadhesive effect is mediated by release of ATP into the extracellular space. Thus, Cx37 hemichannels may control initiation of the development of atherosclerotic plaques by regulating monocyte adhesion. H36.12j macrophages expressing either of the two CX37 proteins encoded by a polymorphism in the human GJA4 gene show differential ATP-dependent adhesion. These results provide a potential mechanism by which a polymorphism in CX37 protects against atherosclerosis.", + "TAG_DATA": [ + "74, deleting {'perturbing_action': 'B-gene loss-of-function'}", + "75, the {'perturbing_action': 'I-gene loss-of-function'}", + "76, mouse {'perturbing_action': 'I-gene loss-of-function'}", + "77, connexin37 {'perturbing_action': 'I-gene loss-of-function'}", + "78, (Cx37) {'perturbing_action': 'I-gene loss-of-function'}", + "79, gene {'perturbing_action': 'I-gene loss-of-function'}", + "80, (Gja4, {'perturbing_action': 'I-gene loss-of-function'}", + "81, also {'perturbing_action': 'I-gene loss-of-function'}", + "84, Cx37) {'perturbing_action': 'I-gene loss-of-function'}", + "88, apolipoprotein {'perturbing_action': 'B-gene loss-of-function'}", + "89, E-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "90, (Apoe(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "91, mice, {'context': 'B-organism'}", + "101, Gja4(-/-)Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "102, mice {'context': 'B-organism'}", + "108, Gja4(+/+)Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "109, mice {'context': 'B-organism'}", + "114, in {'context': 'B-in vivo'}", + "115, vivo {'context': 'I-in vivo'}", + "128, eliminating {'perturbing_action': 'B-gene loss-of-function'}", + "129, expression {'perturbing_action': 'I-gene loss-of-function'}", + "130, of {'perturbing_action': 'I-gene loss-of-function'}", + "131, Cx37 {'perturbing_action': 'I-gene loss-of-function'}", + "134, leukocytes {'context': 'B-cells'}", + "152, primary {'context': 'B-cells'}", + "153, monocytes, {'context': 'I-cells'}", + "154, macrophages {'context': 'I-cells'}", + "157, macrophage {'context': 'B-cells'}", + "158, cell {'context': 'I-cells'}", + "159, line {'context': 'I-cells'}", + "160, (H36.12j) {'context': 'I-cells'}", + "161, inhibits {'effect': 'B-negative'}", + "162, leukocyte {'context': 'B-cells'}", + "163, adhesion. {'phenotype': 'B-adhesion'}" + ], + "LINK_DATA": [ + "74, deleting ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "75, the ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "76, mouse ['l1', 'l12', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "77, connexin37 ['l2', 'l13', 'l26', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "78, (Cx37) ['l3', 'l14', 'l27', 'l39', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "79, gene ['l4', 'l15', 'l28', 'l40', 'l51', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "80, (Gja4, ['l5', 'l16', 'l29', 'l41', 'l52', 'l62', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "81, also ['l6', 'l17', 'l30', 'l42', 'l53', 'l63', 'l71', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "84, Cx37) ['l7', 'l18', 'l31', 'l43', 'l54', 'l64', 'l72', 'l77', 'l83', 'l84', 'l85', 'l86']", + "88, apolipoprotein ['l8', 'l19', 'l32', 'l44', 'l55', 'l65', 'l73', 'l78', 'l83', 'l87', 'l88', 'l89']", + "89, E-deficient ['l9', 'l20', 'l33', 'l45', 'l56', 'l66', 'l74', 'l79', 'l84', 'l87', 'l90', 'l91']", + "90, (Apoe(-/-)) ['l10', 'l21', 'l34', 'l46', 'l57', 'l67', 'l75', 'l80', 'l85', 'l88', 'l90', 'l92']", + "91, mice, ['l11', 'l22', 'l35', 'l47', 'l58', 'l68', 'l76', 'l81', 'l86', 'l89', 'l91', 'l92']", + "101, Gja4(-/-)Apoe(-/-) ['l23', 'l36', 'l48', 'l59', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "102, mice ['l24', 'l37', 'l49', 'l60', 'l69', 'l82', 'l93', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "108, Gja4(+/+)Apoe(-/-) ['l94', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "109, mice ['l95', 'l112', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "114, in ['l96', 'l105', 'l113', 'l123', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "115, vivo ['l97', 'l106', 'l114', 'l124', 'l133', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "128, eliminating ['l98', 'l107', 'l115', 'l125', 'l134', 'l141', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "129, expression ['l99', 'l108', 'l116', 'l126', 'l135', 'l142', 'l148', 'l155', 'l156', 'l157', 'l158', 'l159']", + "130, of ['l100', 'l109', 'l117', 'l127', 'l136', 'l143', 'l149', 'l155', 'l160', 'l161', 'l162', 'l163']", + "131, Cx37 ['l101', 'l110', 'l118', 'l128', 'l137', 'l144', 'l150', 'l156', 'l160', 'l164', 'l165', 'l166']", + "134, leukocytes ['l25', 'l38', 'l50', 'l61', 'l70', 'l102', 'l111', 'l119', 'l129', 'l138', 'l145', 'l151', 'l157', 'l161', 'l164', 'l167', 'l168']", + "152, primary ['l120', 'l130', 'l152', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177']", + "153, monocytes, ['l103', 'l121', 'l131', 'l139', 'l146', 'l153', 'l158', 'l162', 'l165', 'l167', 'l169', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185']", + "154, macrophages ['l104', 'l122', 'l132', 'l140', 'l147', 'l154', 'l159', 'l163', 'l166', 'l168', 'l170', 'l178', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192']", + "157, macrophage ['l171', 'l179', 'l186', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198']", + "158, cell ['l172', 'l180', 'l187', 'l193', 'l199', 'l200', 'l201', 'l202', 'l203']", + "159, line ['l173', 'l181', 'l188', 'l194', 'l199', 'l204', 'l205', 'l206', 'l207']", + "160, (H36.12j) ['l174', 'l182', 'l189', 'l195', 'l200', 'l204', 'l208', 'l209', 'l210']", + "161, inhibits ['l175', 'l183', 'l190', 'l196', 'l201', 'l205', 'l208', 'l211', 'l212']", + "162, leukocyte ['l176', 'l184', 'l191', 'l197', 'l202', 'l206', 'l209', 'l211', 'l213']", + "163, adhesion. ['l177', 'l185', 'l192', 'l198', 'l203', 'l207', 'l210', 'l212', 'l213']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deleting", + "the", + "mouse", + "connexin37", + "(Cx37)", + "gene", + "(Gja4,", + "also", + "Cx37)", + "apolipoprotein", + "E-deficient", + "(Apoe(-/-))", + "Gja4(-/-)Apoe(-/-)", + "eliminating", + "expression", + "of", + "Cx37", + "Gja4(+/+)Apoe(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "mouse", + "connexin37", + "(Cx37)", + "gene", + "Gja4(-/-)Apoe(-/-)", + "Gja4(+/+)Apoe(-/-)", + "eliminating", + "expression", + "of", + "Cx37" + ] + }, + "context": { + "val": "cells", + "words": [ + "leukocytes", + "monocytes,", + "macrophages", + "primary" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gja4(-/-)Apoe(-/-)", + "Gja4(+/+)Apoe(-/-)", + "eliminating", + "expression", + "of", + "Cx37" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "primary", + "monocytes,", + "macrophages", + "macrophage", + "cell", + "line", + "(H36.12j)", + "leukocyte" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "primary", + "monocytes,", + "macrophages", + "macrophage", + "cell", + "line", + "(H36.12j)", + "leukocyte" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion." + ] + } + } + ] + }, + { + "PMID": "16862153", + "TEXT": "Imatinib mesylate (Gleevec) is a small-molecule inhibitor of the fusion protein Bcr-Abl, the causal agent in chronic myelogenous leukemia. Here we report ten individuals who developed severe congestive heart failure while on imatinib and we show that imatinib-treated mice develop left ventricular contractile dysfunction. Transmission electron micrographs from humans and mice treated with imatinib show mitochondrial abnormalities and accumulation of membrane whorls in both vacuoles and the sarco- (endo-) plasmic reticulum, findings suggestive of a toxic myopathy. With imatinib treatment, cardiomyocytes in culture show activation of the endoplasmic reticulum (ER) stress response, collapse of the mitochondrial membrane potential, release of cytochrome c into the cytosol, reduction in cellular ATP content and cell death. Retroviral gene transfer of an imatinib-resistant mutant of c-Abl, alleviation of ER stress or inhibition of Jun amino-terminal kinases, which are activated as a consequence of ER stress, largely rescues cardiomyocytes from imatinib-induced death. Thus, cardiotoxicity is an unanticipated side effect of inhibition of c-Abl by imatinib.", + "TAG_DATA": [ + "38, mice {'context': 'B-organism'}", + "48, humans {'context': 'B-organism'}", + "50, mice {'context': 'B-organism'}", + "80, cardiomyocytes {'context': 'B-cells'}", + "82, culture {'context': 'I-in vitro'}", + "111, cell {'phenotype': 'B-cell death'}", + "112, death. {'phenotype': 'I-cell death'}", + "113, Retroviral {'perturbing_action': 'B-other'}", + "114, gene {'perturbing_action': 'I-other'}", + "115, transfer {'perturbing_action': 'I-other'}", + "116, of {'perturbing_action': 'I-other'}", + "117, an {'perturbing_action': 'I-other'}", + "118, imatinib-resistant {'perturbing_action': 'I-other'}", + "119, mutant {'perturbing_action': 'I-other'}", + "120, of {'perturbing_action': 'I-other'}", + "121, c-Abl, {'perturbing_action': 'I-other'}", + "143, cardiomyocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "38, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "48, humans ['l0', 'l5', 'l6', 'l7', 'l8']", + "50, mice ['l1', 'l5', 'l9', 'l10', 'l11']", + "80, cardiomyocytes ['l12', 'l13', 'l14']", + "82, culture ['l2', 'l6', 'l9', 'l12', 'l15', 'l16']", + "111, cell ['l3', 'l7', 'l10', 'l13', 'l15', 'l17']", + "112, death. ['l4', 'l8', 'l11', 'l14', 'l16', 'l17']", + "113, Retroviral ['l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "114, gene ['l18', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "115, transfer ['l19', 'l27', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "116, of ['l20', 'l28', 'l35', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "117, an ['l21', 'l29', 'l36', 'l42', 'l48', 'l49', 'l50', 'l51', 'l52']", + "118, imatinib-resistant ['l22', 'l30', 'l37', 'l43', 'l48', 'l53', 'l54', 'l55', 'l56']", + "119, mutant ['l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l57', 'l58', 'l59']", + "120, of ['l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l60', 'l61']", + "121, c-Abl, ['l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l58', 'l60', 'l62']", + "143, cardiomyocytes ['l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "humans" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cardiomyocytes" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Retroviral", + "gene", + "transfer", + "of", + "an", + "imatinib-resistant", + "mutant", + "c-Abl," + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes" + ] + } + } + ] + }, + { + "PMID": "16862152", + "TEXT": "Stress can alter immunological, neurochemical and endocrinological functions, but its role in cancer progression is not well understood. Here, we show that chronic behavioral stress results in higher levels of tissue catecholamines, greater tumor burden and more invasive growth of ovarian carcinoma cells in an orthotopic mouse model. These effects are mediated primarily through activation of the tumor cell cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway by the beta(2) adrenergic receptor (encoded by ADRB2). Tumors in stressed animals showed markedly increased vascularization and enhanced expression of VEGF, MMP2 and MMP9, and we found that angiogenic processes mediated the effects of stress on tumor growth in vivo. These data identify beta-adrenergic activation of the cAMP-PKA signaling pathway as a major mechanism by which behavioral stress can enhance tumor angiogenesis in vivo and thereby promote malignant cell growth. These data also suggest that blocking ADRB-mediated angiogenesis could have therapeutic implications for the management of ovarian cancer.", + "TAG_DATA": [ + "32, greater {'effect': 'B-positive'}", + "33, tumor {'phenotype': 'B-tumourigenesis'}", + "34, burden {'phenotype': 'I-tumourigenesis'}", + "36, more {'effect': 'B-positive'}", + "37, invasive {'phenotype': 'B-tumour growth'}", + "38, growth {'phenotype': 'I-invasion'}", + "40, ovarian {'context': 'B-transformed cells'}", + "41, carcinoma {'context': 'I-transformed cells'}", + "42, cells {'context': 'I-transformed cells'}", + "45, orthotopic {'context': 'B-organism'}", + "46, mouse {'context': 'I-organism'}", + "47, model. {'context': 'I-organism'}", + "75, Tumors {'context': 'B-neoplasm'}", + "78, animals {'context': 'B-organism'}", + "103, tumor {'phenotype': 'B-tumour growth'}", + "104, growth {'phenotype': 'I-tumour growth'}", + "105, in {'context': 'B-in vivo'}", + "106, vivo. {'context': 'I-in vivo'}", + "129, in {'context': 'B-in vivo'}", + "130, vivo {'context': 'I-in vivo'}", + "133, promote {'effect': 'B-positive'}", + "135, cell {'phenotype': 'B-cell growth'}", + "136, growth. {'phenotype': 'I-cell growth'}" + ], + "LINK_DATA": [ + "32, greater ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "33, tumor ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "34, burden ['l1', 'l7', 'l12', 'l13', 'l14', 'l15']", + "36, more ['l2', 'l8', 'l12', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "37, invasive ['l3', 'l9', 'l13', 'l16', 'l23', 'l24', 'l25', 'l26', 'l27']", + "38, growth ['l4', 'l10', 'l14', 'l17', 'l23', 'l28', 'l29', 'l30', 'l31']", + "40, ovarian ['l5', 'l18', 'l24', 'l28', 'l32', 'l33', 'l34', 'l35']", + "41, carcinoma ['l19', 'l25', 'l29', 'l32', 'l36', 'l37', 'l38', 'l39']", + "42, cells ['l6', 'l11', 'l15', 'l20', 'l26', 'l30', 'l33', 'l36', 'l40']", + "45, orthotopic ['l37', 'l41', 'l42', 'l43', 'l44']", + "46, mouse ['l21', 'l34', 'l38', 'l41', 'l45']", + "47, model. ['l22', 'l27', 'l31', 'l35', 'l39', 'l40', 'l42', 'l45']", + "75, Tumors ['l43', 'l46']", + "78, animals ['l44', 'l46']", + "103, tumor ['l47', 'l48', 'l49']", + "104, growth ['l47', 'l50', 'l51']", + "105, in ['l48', 'l50', 'l52']", + "106, vivo. ['l49', 'l51', 'l52']", + "129, in ['l53', 'l54', 'l55', 'l56']", + "130, vivo ['l53', 'l57', 'l58', 'l59']", + "133, promote ['l54', 'l57', 'l60', 'l61']", + "135, cell ['l55', 'l58', 'l60', 'l62']", + "136, growth. ['l56', 'l59', 'l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "greater", + "more" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "burden" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "greater", + "more" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "invasive" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "greater", + "more" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "greater", + "more" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "cells", + "carcinoma" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "burden" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "more" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "invasive" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "carcinoma", + "cells" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "invasive" + ] + }, + "context": { + "val": "organism", + "words": [ + "model." + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "growth" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "carcinoma", + "cells" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "model." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promote" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth." + ] + } + } + ] + }, + { + "PMID": "16845389", + "TEXT": "Obesity is a major health problem and a risk factor for type 2 diabetes. Leptin, an adipocyte-secreted hormone, acts on the hypothalamus to inhibit food intake and increase energy expenditure. Most obese individuals develop hyperleptinemia and leptin resistance, limiting the therapeutic efficacy of exogenously administered leptin. Mice lacking the tyrosine phosphatase PTP1B are protected from diet-induced obesity and are hypersensitive to leptin, but the site and mechanism for these effects remain controversial. We generated tissue-specific PTP1B knockout (Ptpn1(-/-)) mice. Neuronal Ptpn1(-/-) mice have reduced weight and adiposity, and increased activity and energy expenditure. In contrast, adipose PTP1B deficiency increases body weight, whereas PTP1B deletion in muscle or liver does not affect weight. Neuronal Ptpn1(-/-) mice are hypersensitive to leptin, despite paradoxically elevated leptin levels, and show improved glucose homeostasis. Thus, PTP1B regulates body mass and adiposity primarily through actions in the brain. Furthermore, neuronal PTP1B regulates adipocyte leptin production and probably is essential for the development of leptin resistance.", + "TAG_DATA": [ + "74, tissue-specific {'perturbing_action': 'B-gene loss-of-function'}", + "75, PTP1B {'perturbing_action': 'I-gene loss-of-function'}", + "76, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "77, (Ptpn1(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "78, mice. {'context': 'B-organism'}", + "79, Neuronal {'perturbing_action': 'B-gene loss-of-function'}", + "80, Ptpn1(-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "81, mice {'context': 'B-organism'}", + "95, adipose {'perturbing_action': 'B-gene loss-of-function'}", + "96, PTP1B {'perturbing_action': 'I-gene loss-of-function'}", + "97, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "102, PTP1B {'perturbing_action': 'B-gene loss-of-function'}", + "103, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "105, muscle {'context': 'B-tissue/organ'}", + "107, liver {'context': 'B-tissue/organ'}", + "112, Neuronal {'perturbing_action': 'B-gene loss-of-function'}", + "113, Ptpn1(-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "114, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "74, tissue-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "75, PTP1B ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "76, knockout ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "77, (Ptpn1(-/-)) ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "78, mice. ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "79, Neuronal ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "80, Ptpn1(-/-) ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27', 'l28']", + "81, mice ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "95, adipose ['l29', 'l30']", + "96, PTP1B ['l29', 'l31', 'l32', 'l33']", + "97, deficiency ['l28', 'l30', 'l31']", + "102, PTP1B ['l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "103, deletion ['l34', 'l40', 'l41', 'l42']", + "105, muscle ['l35', 'l40', 'l43', 'l44']", + "106, or ['l32', 'l36', 'l41', 'l43', 'l45']", + "107, liver ['l33', 'l37', 'l42', 'l44', 'l45']", + "112, Neuronal ['l46', 'l47']", + "113, Ptpn1(-/-) ['l38', 'l46', 'l48']", + "114, mice ['l39', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "tissue-specific", + "PTP1B", + "knockout", + "(Ptpn1(-/-))", + "Neuronal", + "Ptpn1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PTP1B", + "deletion" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver", + "muscle" + ] + } + } + ] + }, + { + "PMID": "16751768", + "TEXT": "The urinary tract functions in close proximity to the outside environment, yet must remain free of microbial colonization to avoid disease. The mechanisms for establishing an antimicrobial barrier in this area are not completely understood. Here, we describe the production and function of the cathelicidin antimicrobial peptides LL-37, its precursor hCAP-18 and its ortholog CRAMP in epithelial cells of human and mouse urinary tract, respectively. Bacterial contact with epithelial cells resulted in rapid production and secretion of the respective peptides, and in humans LL-37/hCAP-18 was released into urine. Epithelium-derived cathelicidin substantially contributed to the protection of the urinary tract against infection, as shown using CRAMP-deficient and neutrophil-depleted mice. In addition, clinical E. coli strains that were more resistant to LL-37 caused more severe urinary tract infections than did susceptible strains. Thus, cathelicidin seems to be a key factor in mucosal immunity of the urinary tract.", + "TAG_DATA": [ + "56, epithelial {'context': 'B-cells'}", + "57, cells {'context': 'I-cells'}", + "59, human {'context': 'B-tissue/organ'}", + "60, and {'context': 'I-tissue/organ'}", + "61, mouse {'context': 'I-tissue/organ'}", + "62, urinary {'context': 'I-tissue/organ'}", + "63, tract, {'context': 'I-tissue/organ'}", + "97, urinary {'context': 'B-tissue/organ'}", + "98, tract {'context': 'I-tissue/organ'}", + "104, CRAMP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "107, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, epithelial ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "57, cells ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "59, human ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "60, and ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "61, mouse ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "62, urinary ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "63, tract, ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "97, urinary ['l21', 'l22']", + "98, tract ['l21', 'l23']", + "104, CRAMP-deficient ['l24']", + "107, mice. ['l22', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CRAMP-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "16751767", + "TEXT": "Preeclampsia is a pregnancy-specific hypertensive syndrome that causes substantial maternal and fetal morbidity and mortality. Maternal endothelial dysfunction mediated by excess placenta-derived soluble VEGF receptor 1 (sVEGFR1 or sFlt1) is emerging as a prominent component in disease pathogenesis. We report a novel placenta-derived soluble TGF-beta coreceptor, endoglin (sEng), which is elevated in the sera of preeclamptic individuals, correlates with disease severity and falls after delivery. sEng inhibits formation of capillary tubes in vitro and induces vascular permeability and hypertension in vivo. Its effects in pregnant rats are amplified by coadministration of sFlt1, leading to severe preeclampsia including the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and restriction of fetal growth. sEng impairs binding of TGF-beta1 to its receptors and downstream signaling including effects on activation of eNOS and vasodilation, suggesting that sEng leads to dysregulated TGF-beta signaling in the vasculature. Our results suggest that sEng may act in concert with sFlt1 to induce severe preeclampsia.", + "TAG_DATA": [ + "71, in {'context': 'B-in vitro'}", + "72, vitro {'context': 'I-in vitro'}", + "79, in {'context': 'B-in vivo'}", + "80, vivo. {'context': 'I-in vivo'}", + "84, pregnant {'context': 'B-organism'}", + "85, rats {'context': 'I-organism'}", + "90, of {'perturbing_action': 'I-gene gain-of-function'}", + "91, sFlt1, {'perturbing_action': 'I-gene gain-of-function'}", + "107, restriction {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "71, in ['l0']", + "72, vitro ['l0']", + "79, in ['l1']", + "80, vivo. ['l1']", + "84, pregnant ['l2', 'l3', 'l4', 'l5']", + "85, rats ['l2', 'l6', 'l7']", + "90, of ['l3', 'l6', 'l8', 'l9']", + "91, sFlt1, ['l4', 'l7', 'l8', 'l10']", + "107, restriction ['l5', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "pregnant", + "rats" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "sFlt1," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "pregnant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "restriction" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "sFlt1," + ] + }, + "effect": { + "val": "negative", + "words": [ + "restriction" + ] + } + } + ] + }, + { + "PMID": "16732282", + "TEXT": "Selective inhibitors of cyclooxygenase-2 (COX2) have attracted widespread media attention because of evidence of an elevated risk of cardiovascular complications in placebo-controlled trials, resulting in the market withdrawal of some members of this class. These drugs block the cyclooxygenase activity of prostaglandin H synthase-2 (PGHS2), but do not affect the associated peroxidase function. They were developed with the rationale of conserving the anti-inflammatory and analgesic actions of traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) while sparing the ability of PGHS1-derived prostaglandins to afford gastric cytoprotection. PGHS1 and PGHS2 coexist in the vasculature and in macrophages, and are upregulated together in inflammatory tissues such as rheumatoid synovia and atherosclerotic plaque. They are each believed to function as homodimers. Here, we developed a new genetic mouse model of selective COX2 inhibition using a gene-targeted point mutation, resulting in a Y385F substitution. Structural modeling and biochemical assays showed the ability of PGHS1 and PGHS2 to heterodimerize and form prostaglandins. The heterodimerization of PGHS1-PGHS2 may explain how the ductus arteriosus closes normally at birth in mice expressing PGHS2 Y385F, but not in PGHS2-null mice.", + "TAG_DATA": [ + "121, mouse {'context': 'I-organism'}", + "122, model {'context': 'I-organism'}", + "124, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "125, COX2 {'perturbing_action': 'I-pharmacological inhibition'}", + "126, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "129, gene-targeted {'perturbing_action': 'B-other'}", + "130, point {'perturbing_action': 'I-other'}", + "131, mutation, {'perturbing_action': 'I-other'}", + "169, mice {'context': 'B-organism'}", + "176, PGHS2-null {'perturbing_action': 'B-gene loss-of-function'}", + "177, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "121, mouse ['l0', 'l1', 'l2', 'l3', 'l4']", + "122, model ['l0', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "124, selective ['l1', 'l5', 'l11', 'l12', 'l13', 'l14', 'l15']", + "125, COX2 ['l2', 'l6', 'l11', 'l16', 'l17', 'l18', 'l19']", + "126, inhibition ['l3', 'l7', 'l12', 'l16', 'l20', 'l21', 'l22']", + "129, gene-targeted ['l8', 'l13', 'l17', 'l20', 'l23', 'l24']", + "130, point ['l4', 'l9', 'l14', 'l18', 'l21', 'l23', 'l25']", + "131, mutation, ['l10', 'l15', 'l19', 'l22', 'l24', 'l25']", + "169, mice ['l26', 'l27']", + "176, PGHS2-null ['l26', 'l28']", + "177, mice. ['l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "COX2", + "inhibition" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "point", + "gene-targeted", + "mutation," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PGHS2-null" + ] + } + } + ] + }, + { + "PMID": "16604089", + "TEXT": "The hypothalamus responds to circulating leptin and insulin in the control of food intake and body weight. A number of neurotransmitters in the hypothalamus, including gamma-aminobutyric acid (GABA), also have key roles in feeding. Huntingtin-associated protein 1 (Hap1) is expressed more abundantly in the hypothalamus than in other brain regions, and lack of Hap1 in mice leads to early postnatal death. Hap1 is also involved in intracellular trafficking of the GABA(A) receptor. Here, we report that fasting upregulates the expression of Hap1 in the rodent hypothalamus, whereas intracerebroventricular administration of insulin downregulates Hap1 by increasing its degradation through ubiquitination. Decreasing the expression of mouse hypothalamic Hap1 by siRNA reduces the level and activity of hypothalamic GABA(A) receptors and causes a decrease in food intake and body weight. These findings provide evidence linking hypothalamic Hap1 to GABA in the stimulation of feeding and suggest that this mechanism is involved in the feeding-inhibitory actions of insulin in the brain.", + "TAG_DATA": [ + "84, rodent {'context': 'B-tissue/organ'}", + "85, hypothalamus, {'context': 'I-tissue/organ'}", + "99, Decreasing {'perturbing_action': 'B-rnai/knockdown'}", + "100, the {'perturbing_action': 'I-rnai/knockdown'}", + "101, expression {'perturbing_action': 'I-rnai/knockdown'}", + "102, of {'perturbing_action': 'I-rnai/knockdown'}", + "103, mouse {'perturbing_action': 'I-rnai/knockdown', 'context': 'B-tissue/organ'}", + "104, hypothalamic {'perturbing_action': 'I-rnai/knockdown', 'context': 'I-tissue/organ'}", + "105, Hap1 {'perturbing_action': 'I-rnai/knockdown'}", + "106, by {'perturbing_action': 'I-rnai/knockdown'}", + "107, siRNA {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "84, rodent ['l0']", + "85, hypothalamus, ['l0']", + "99, Decreasing ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "100, the ['l1', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "101, expression ['l2', 'l9', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "102, of ['l3', 'l10', 'l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "103, mouse ['l4', 'l11', 'l17', 'l22', 'l27', 'l28', 'l29', 'l30']", + "104, hypothalamic ['l5', 'l12', 'l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "105, Hap1 ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "106, by ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "107, siRNA ['l8', 'l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Decreasing", + "the", + "expression", + "of", + "mouse", + "hypothalamic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "hypothalamic" + ] + } + } + ] + }, + { + "PMID": "16604086", + "TEXT": "Leptin controls food intake by regulating the transcription of key neuropeptides in the hypothalamus. The mechanism by which leptin regulates gene expression is unclear, however. Here we show that delivery of adenovirus encoding a constitutively nuclear mutant FoxO1, a transcription factor known to control liver metabolism and pancreatic beta-cell function, to the hypothalamic arcuate nucleus of rodents results in a loss of the ability of leptin to curtail food intake and suppress expression of Agrp. Conversely, a transactivation-deficient FoxO1 mutant prevents induction of Agrp by fasting. We also find that FoxO1 and the transcription factor Stat3 exert opposing actions on the expression of Agrp and Pomc through transcriptional squelching. FoxO1 promotes opposite patterns of coactivator-corepressor exchange at the Pomc and Agrp promoters, resulting in activation of Agrp and inhibition of Pomc. Thus, FoxO1 represents a shared component of pathways integrating food intake and peripheral metabolism.", + "TAG_DATA": [ + "31, adenovirus {'perturbing_action': 'B-other'}", + "32, encoding {'perturbing_action': 'I-other'}", + "33, a {'perturbing_action': 'I-other'}", + "34, constitutively {'perturbing_action': 'I-other'}", + "35, nuclear {'perturbing_action': 'I-other'}", + "36, mutant {'perturbing_action': 'I-other'}", + "37, FoxO1, {'perturbing_action': 'I-other'}", + "52, hypothalamic {'context': 'B-tissue/organ'}", + "53, arcuate {'context': 'I-tissue/organ'}", + "54, nucleus {'context': 'I-tissue/organ'}", + "56, rodents {'context': 'B-organism'}", + "77, transactivation-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "78, FoxO1 {'perturbing_action': 'I-other'}", + "79, mutant {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "31, adenovirus ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "32, encoding ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "33, a ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "34, constitutively ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "35, nuclear ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "36, mutant ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "37, FoxO1, ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "52, hypothalamic ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "53, arcuate ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "54, nucleus ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "56, rodents ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "77, transactivation-deficient ['l55', 'l56']", + "78, FoxO1 ['l55', 'l57']", + "79, mutant ['l56', 'l57']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "adenovirus", + "encoding", + "a", + "constitutively", + "nuclear", + "mutant", + "FoxO1," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hypothalamic", + "arcuate", + "nucleus" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "adenovirus", + "encoding", + "a", + "constitutively", + "nuclear", + "mutant", + "FoxO1," + ] + }, + "context": { + "val": "organism", + "words": [ + "rodents" + ] + } + } + ] + }, + { + "PMID": "16565722", + "TEXT": "Hematopoietic stem cells (HSCs) undergo self-renewing cell divisions and maintain blood production for their lifetime. Appropriate control of HSC self-renewal is crucial for the maintenance of hematopoietic homeostasis. Here we show that activation of p38 MAPK in response to increasing levels of reactive oxygen species (ROS) limits the lifespan of HSCs in vivo. In Atm(-/-) mice, elevation of ROS levels induces HSC-specific phosphorylation of p38 MAPK accompanied by a defect in the maintenance of HSC quiescence. Inhibition of p38 MAPK rescued ROS-induced defects in HSC repopulating capacity and in the maintenance of HSC quiescence, indicating that the ROS-p38 MAPK pathway contributes to exhaustion of the stem cell population. Furthermore, prolonged treatment with an antioxidant or an inhibitor of p38 MAPK extended the lifespan of HSCs from wild-type mice in serial transplantation experiments. These data show that inactivation of p38 MAPK protects HSCs against loss of self-renewal capacity. Our characterization of molecular mechanisms that limit HSC lifespan may lead to beneficial therapies for human disease.", + "TAG_DATA": [ + "51, in {'context': 'B-in vivo'}", + "52, vivo. {'context': 'I-in vivo'}", + "54, Atm(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "55, mice, {'context': 'B-organism'}", + "72, maintenance {'effect': 'B-negative'}", + "74, HSC {'context': 'B-cells'}", + "75, quiescence. {'phenotype': 'B-quiescence'}", + "76, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "77, of {'perturbing_action': 'I-pharmacological inhibition'}", + "78, p38 {'perturbing_action': 'I-pharmacological inhibition'}", + "79, MAPK {'perturbing_action': 'I-pharmacological inhibition'}", + "84, HSC {'context': 'B-cells'}", + "90, maintenance {'effect': 'B-regulates'}", + "92, HSC {'context': 'B-cells'}", + "93, quiescence, {'phenotype': 'B-quiescence'}", + "116, inhibitor {'perturbing_action': 'B-pharmacological inhibition'}", + "117, of {'perturbing_action': 'I-pharmacological inhibition'}", + "118, p38 {'perturbing_action': 'I-pharmacological inhibition'}", + "119, MAPK {'perturbing_action': 'I-pharmacological inhibition'}", + "124, HSCs {'context': 'B-cells'}", + "127, mice {'context': 'B-organism'}", + "136, inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "137, of {'perturbing_action': 'I-gene loss-of-function'}", + "138, p38 {'perturbing_action': 'I-gene loss-of-function'}", + "139, MAPK {'perturbing_action': 'I-gene loss-of-function'}", + "141, HSCs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "51, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "52, vivo. ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "54, Atm(-/-) ['l1', 'l6', 'l11', 'l12', 'l13', 'l14', 'l15']", + "55, mice, ['l2', 'l7', 'l11', 'l16', 'l17', 'l18']", + "72, maintenance ['l3', 'l8', 'l12', 'l16', 'l19', 'l20']", + "74, HSC ['l4', 'l9', 'l13', 'l17', 'l19', 'l21']", + "75, quiescence. ['l5', 'l10', 'l14', 'l18', 'l20', 'l21']", + "76, Inhibition ['l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "77, of ['l22', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "78, p38 ['l23', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "79, MAPK ['l24', 'l30', 'l35', 'l40', 'l41', 'l42', 'l43']", + "84, HSC ['l15', 'l25', 'l31', 'l36', 'l40', 'l44', 'l45', 'l46']", + "90, maintenance ['l26', 'l32', 'l37', 'l41', 'l44', 'l47', 'l48']", + "92, HSC ['l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l49']", + "93, quiescence, ['l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l49']", + "116, inhibitor ['l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "117, of ['l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "118, p38 ['l51', 'l57', 'l63', 'l64', 'l65', 'l66']", + "119, MAPK ['l52', 'l58', 'l63', 'l67', 'l68', 'l69']", + "124, HSCs ['l53', 'l59', 'l64', 'l67', 'l70']", + "127, mice ['l54', 'l60', 'l65', 'l68', 'l70']", + "136, inactivation ['l55', 'l61', 'l71', 'l72', 'l73', 'l74']", + "137, of ['l71', 'l75', 'l76', 'l77']", + "138, p38 ['l72', 'l75', 'l78', 'l79']", + "139, MAPK ['l73', 'l76', 'l78', 'l80']", + "141, HSCs ['l56', 'l62', 'l66', 'l69', 'l74', 'l77', 'l79', 'l80']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atm(-/-)" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "effect": { + "val": "negative", + "words": [ + "maintenance" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atm(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atm(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "maintenance" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atm(-/-)", + "inactivation", + "of", + "p38", + "MAPK" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC", + "HSCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atm(-/-)" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "negative", + "words": [ + "maintenance" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "maintenance" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "maintenance" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSC" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence.", + "quiescence," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "p38", + "MAPK", + "inhibitor" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC", + "HSCs" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "p38", + "MAPK" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "maintenance" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "p38", + "MAPK" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSC" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "maintenance" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "maintenance" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitor", + "of", + "p38", + "MAPK" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "16474399", + "TEXT": "CD8+ T cells can mediate eradication of established tumors, and strategies to amplify tumor-reactive T-cell numbers by immunization or ex vivo expansion followed by adoptive transfer are currently being explored in individuals with cancer. Generating effective CD8+ T cell-mediated responses to tumors is often impeded by T-cell tolerance to relevant tumor antigens, as most of these antigens are also expressed in normal tissues. We examined whether such tolerant T cells could be rescued and functionally restored for use in therapy of established tumors. We used a transgenic T-cell receptor (TCR) mouse model in which peripheral CD8+ T cells specific for a candidate tumor antigen also expressed in liver are tolerant, failing to proliferate or secrete interleukin (IL)-2 in response to antigen. Molecular and cellular analysis showed that these tolerant T cells expressed the IL-15 receptor alpha chain, and could be induced to proliferate in vitro in response to exogenous IL-15. Such proliferation abrogated tolerance and the rescued cells became effective in treating leukemia. Therefore, high-affinity CD8+ T cells are not necessarily deleted by encounter with self-antigen in the periphery, and can potentially be rescued and expanded for use in tumor immunotherapy.", + "TAG_DATA": [ + "86, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "87, T-cell {'perturbing_action': 'I-gene gain-of-function'}", + "88, receptor {'perturbing_action': 'I-gene gain-of-function'}", + "89, (TCR) {'perturbing_action': 'I-gene gain-of-function'}", + "90, mouse {'context': 'B-organism'}", + "91, model {'context': 'I-organism'}", + "94, peripheral {'context': 'B-cells'}", + "95, CD8+ {'context': 'I-cells'}", + "96, T {'context': 'I-cells'}", + "97, cells {'context': 'I-cells'}", + "110, failing {'effect': 'B-negative'}", + "111, to {'effect': 'I-negative'}", + "112, proliferate {'phenotype': 'B-proliferation'}", + "129, T {'context': 'B-cells'}", + "130, cells {'context': 'I-cells'}", + "140, induced {'effect': 'B-positive'}", + "142, proliferate {'phenotype': 'B-proliferation'}", + "143, in {'context': 'B-in vitro'}", + "144, vitro {'context': 'I-in vitro'}", + "151, proliferation {'phenotype': 'B-proliferation'}", + "157, cells {'context': 'B-cells'}", + "162, leukemia. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "86, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "87, T-cell ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "88, receptor ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "89, (TCR) ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "90, mouse ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "91, model ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "94, peripheral ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "95, CD8+ ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "96, T ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "97, cells ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "110, failing ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "111, to ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "112, proliferate ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "129, T ['l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "130, cells ['l78', 'l84', 'l85', 'l86', 'l87']", + "140, induced ['l79', 'l84', 'l88', 'l89', 'l90', 'l91']", + "142, proliferate ['l80', 'l85', 'l88', 'l92', 'l93', 'l94']", + "143, in ['l81', 'l86', 'l89', 'l92', 'l95', 'l96']", + "144, vitro ['l82', 'l87', 'l90', 'l93', 'l95', 'l97']", + "151, proliferation ['l83', 'l91', 'l94', 'l96', 'l97']", + "157, cells ['l98']", + "162, leukemia. ['l98']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "T-cell", + "receptor", + "(TCR)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "T-cell", + "receptor", + "(TCR)" + ] + }, + "context": { + "val": "cells", + "words": [ + "peripheral", + "CD8+", + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "T-cell", + "receptor", + "(TCR)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "failing", + "to" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "T-cell", + "receptor", + "(TCR)" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "effect": { + "val": "negative", + "words": [ + "failing", + "to" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "peripheral", + "CD8+", + "T", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "failing", + "to" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "peripheral", + "CD8+", + "T", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate", + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "failing", + "to" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate", + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate", + "proliferation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "16341242", + "TEXT": "The in vivo regulation of hematopoietic stem cell (HSC) function is poorly understood. Here, we show that hematopoietic repopulation can be augmented by administration of a glycogen synthase kinase-3 (GSK-3) inhibitor to recipient mice transplanted with mouse or human HSCs. GSK-3 inhibitor treatment improved neutrophil and megakaryocyte recovery, recipient survival and resulted in enhanced sustained long-term repopulation. The output of primitive Lin(-)c-Kit(+)Sca-1(+) cells and progenitors from HSCs increased upon GSK-3 inhibitor treatment without altering secondary repopulating ability, suggesting that the HSC pool is maintained while overall hematopoietic reconstitution is increased. GSK-3 inhibitors were found to modulate gene targets of Wnt, Hedgehog and Notch pathways in cells comprising the primitive hematopoietic compartment without affecting mature cells. Our study establishes GSK-3 as a specific in vivo modulator of HSC activity, and suggests that administration of GSK-3 inhibitors may provide a clinical means to directly enhance the repopulating capacity of transplanted HSCs.", + "TAG_DATA": [ + "26, glycogen {'perturbing_action': 'B-pharmacological inhibition'}", + "27, synthase {'perturbing_action': 'I-pharmacological inhibition'}", + "28, kinase-3 {'perturbing_action': 'I-pharmacological inhibition'}", + "29, (GSK-3) {'perturbing_action': 'I-pharmacological inhibition'}", + "30, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "33, mice {'context': 'B-organism'}", + "36, mouse {'context': 'B-transformed cells'}", + "37, or {'context': 'I-cells'}", + "38, human {'context': 'I-cells'}", + "39, HSCs. {'context': 'I-cells'}", + "40, GSK-3 {'perturbing_action': 'B-pharmacological inhibition'}", + "41, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "42, treatment {'perturbing_action': 'I-pharmacological inhibition'}", + "62, cells {'context': 'I-cells'}", + "66, HSCs {'context': 'B-cells'}", + "69, GSK-3 {'perturbing_action': 'B-pharmacological inhibition'}", + "70, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "71, treatment {'perturbing_action': 'I-pharmacological inhibition'}", + "90, GSK-3 {'perturbing_action': 'B-pharmacological inhibition'}", + "91, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "105, cells {'context': 'B-cells'}", + "106, comprising {'context': 'I-cells'}", + "109, hematopoietic {'context': 'I-cells'}", + "110, compartment {'context': 'I-cells'}", + "113, mature {'context': 'B-cells'}", + "114, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "26, glycogen ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "27, synthase ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "28, kinase-3 ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "29, (GSK-3) ['l2', 'l13', 'l23', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "30, inhibitor ['l3', 'l14', 'l24', 'l31', 'l38', 'l39', 'l40', 'l41', 'l42']", + "33, mice ['l4', 'l15', 'l25', 'l32', 'l38']", + "36, mouse ['l5', 'l16', 'l26', 'l33', 'l39', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "37, or ['l6', 'l17', 'l27', 'l34', 'l40', 'l43', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "38, human ['l7', 'l18', 'l28', 'l35', 'l41', 'l44', 'l49', 'l55', 'l56', 'l57', 'l58', 'l59']", + "39, HSCs. ['l8', 'l19', 'l29', 'l36', 'l42', 'l45', 'l50', 'l55', 'l60', 'l61', 'l62', 'l63']", + "40, GSK-3 ['l51', 'l56', 'l60', 'l64', 'l65', 'l66', 'l67', 'l68']", + "41, inhibitor ['l9', 'l20', 'l46', 'l52', 'l57', 'l61', 'l64', 'l69', 'l70', 'l71']", + "42, treatment ['l10', 'l21', 'l30', 'l37', 'l47', 'l53', 'l58', 'l62', 'l65', 'l69', 'l72', 'l73']", + "62, cells ['l11', 'l22', 'l48', 'l54', 'l59', 'l63', 'l66', 'l70', 'l72', 'l74', 'l75', 'l76']", + "66, HSCs ['l67', 'l71', 'l73', 'l74', 'l77', 'l78', 'l79']", + "69, GSK-3 ['l77', 'l80', 'l81']", + "70, inhibitor ['l75', 'l78', 'l80', 'l82']", + "71, treatment ['l68', 'l76', 'l79', 'l81', 'l82']", + "90, GSK-3 ['l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "91, inhibitors ['l83', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "105, cells ['l84', 'l91', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "106, comprising ['l85', 'l92', 'l98', 'l104', 'l105', 'l106', 'l107', 'l108']", + "107, the ['l86', 'l93', 'l99', 'l104', 'l109', 'l110', 'l111', 'l112']", + "109, hematopoietic ['l87', 'l94', 'l100', 'l105', 'l109', 'l113', 'l114', 'l115']", + "110, compartment ['l88', 'l95', 'l101', 'l106', 'l110', 'l113', 'l116', 'l117']", + "113, mature ['l89', 'l96', 'l102', 'l107', 'l111', 'l114', 'l116', 'l118']", + "114, cells. ['l90', 'l97', 'l103', 'l108', 'l112', 'l115', 'l117', 'l118']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "glycogen", + "synthase", + "kinase-3", + "(GSK-3)", + "inhibitor" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "glycogen", + "synthase", + "kinase-3", + "(GSK-3)", + "inhibitor", + "treatment" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "glycogen", + "synthase", + "kinase-3", + "(GSK-3)", + "inhibitor", + "GSK-3", + "treatment", + "inhibitors" + ] + }, + "context": { + "val": "cells", + "words": [ + "or", + "human", + "HSCs.", + "cells", + "HSCs", + "comprising", + "hematopoietic", + "compartment", + "mature", + "cells." + ] + } + } + ] + }, + { + "PMID": "16311604", + "TEXT": "We transplanted kidneys from alpha1,3-galactosyltransferase knockout (GalT-KO) pigs into six baboons using two different immunosuppressive regimens, but most of the baboons died from severe acute humoral xenograft rejection. Circulating induced antibodies to non-Gal antigens were markedly elevated at rejection, which mediated strong complement-dependent cytotoxicity against GalT-KO porcine target cells. These data suggest that antibodies to non-Gal antigens will present an additional barrier to transplantation of organs from GalT-KO pigs to humans.", + "TAG_DATA": [ + "2, kidneys {'context': 'I-tissue/organ'}", + "4, alpha1,3-galactosyltransferase {'perturbing_action': 'B-gene loss-of-function'}", + "5, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "6, (GalT-KO) {'perturbing_action': 'I-gene loss-of-function'}", + "7, pigs {'context': 'B-tissue/organ'}", + "10, baboons {'context': 'B-organism'}", + "20, baboons {'context': 'B-organism'}", + "26, xenograft {'context': 'B-xenograft'}", + "45, GalT-KO {'perturbing_action': 'B-gene loss-of-function'}", + "46, porcine {'context': 'B-cells'}", + "47, target {'context': 'I-cells'}", + "48, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "2, kidneys ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "4, alpha1,3-galactosyltransferase ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "5, knockout ['l1', 'l7', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "6, (GalT-KO) ['l2', 'l8', 'l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "7, pigs ['l3', 'l9', 'l16', 'l22', 'l28', 'l29', 'l30']", + "10, baboons ['l4', 'l10', 'l17', 'l23', 'l28', 'l31']", + "20, baboons ['l5', 'l11', 'l18', 'l24', 'l29', 'l32']", + "26, xenograft ['l6', 'l12', 'l19', 'l25', 'l30', 'l31', 'l32']", + "45, GalT-KO ['l33', 'l34', 'l35']", + "46, porcine ['l33', 'l36', 'l37']", + "47, target ['l13', 'l20', 'l26', 'l34', 'l36', 'l38']", + "48, cells. ['l14', 'l21', 'l27', 'l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "kidneys", + "pigs" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha1,3-galactosyltransferase", + "knockout", + "(GalT-KO)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha1,3-galactosyltransferase", + "knockout", + "(GalT-KO)" + ] + }, + "context": { + "val": "organism", + "words": [ + "baboons" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha1,3-galactosyltransferase", + "knockout", + "(GalT-KO)" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha1,3-galactosyltransferase", + "knockout", + "(GalT-KO)", + "GalT-KO" + ] + }, + "context": { + "val": "cells", + "words": [ + "target", + "cells.", + "porcine" + ] + } + } + ] + }, + { + "PMID": "16311603", + "TEXT": "Abdominal aortic aneurysm (AAA) is a common disease among elderly people that, when surgical treatment is inapplicable, results in progressive expansion and rupture of the aorta with high mortality. Although nonsurgical treatment for AAA is much awaited, few options are available because its molecular pathogenesis remains elusive. Here, we identify JNK as a proximal signaling molecule in the pathogenesis of AAA. Human AAA tissue showed a high level of phosphorylated JNK. We show that JNK programs a gene expression pattern in different cell types that cooperatively enhances the degradation of the extracellular matrix while suppressing biosynthetic enzymes of the extracellular matrix. Selective inhibition of JNK in vivo not only prevented the development of AAA but also caused regression of established AAA in two mouse models. Thus, JNK promotes abnormal extracellular matrix metabolism in the tissue of AAA and may represent a therapeutic target.", + "TAG_DATA": [ + "101, Selective {'perturbing_action': 'B-pharmacological inhibition'}", + "102, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "103, of {'perturbing_action': 'I-pharmacological inhibition'}", + "104, JNK {'perturbing_action': 'I-pharmacological inhibition'}", + "105, in {'context': 'B-in vivo'}", + "106, vivo {'context': 'I-in vivo'}", + "109, prevented {'effect': 'B-negative'}", + "116, caused {'effect': 'B-positive'}", + "117, regression {'phenotype': 'B-tumour regression'}", + "118, of {'phenotype': 'I-tumour regression'}", + "120, AAA {'context': 'B-neoplasm'}", + "123, mouse {'context': 'B-organism'}", + "124, models. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "101, Selective ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "102, inhibition ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "103, of ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "104, JNK ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "105, in ['l3', 'l15', 'l26', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "106, vivo ['l4', 'l16', 'l27', 'l37', 'l45', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "109, prevented ['l5', 'l17', 'l28', 'l38', 'l46', 'l54', 'l61', 'l62']", + "113, AAA ['l6', 'l18', 'l29', 'l39', 'l47', 'l55', 'l61']", + "116, caused ['l7', 'l19', 'l30', 'l40', 'l48', 'l56', 'l62', 'l63', 'l64', 'l65']", + "117, regression ['l8', 'l20', 'l31', 'l41', 'l49', 'l57', 'l63', 'l66', 'l67', 'l68', 'l69']", + "118, of ['l9', 'l21', 'l32', 'l42', 'l50', 'l58', 'l64', 'l66', 'l70', 'l71', 'l72']", + "120, AAA ['l10', 'l22', 'l33', 'l43', 'l51', 'l59', 'l65', 'l67', 'l70', 'l73', 'l74']", + "123, mouse ['l11', 'l23', 'l34', 'l52', 'l68', 'l71', 'l73', 'l75']", + "124, models. ['l12', 'l24', 'l35', 'l44', 'l53', 'l60', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Selective", + "inhibition", + "of", + "JNK" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Selective", + "inhibition", + "of", + "JNK" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Selective", + "inhibition", + "of", + "JNK" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Selective", + "inhibition", + "of", + "JNK" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression", + "of" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Selective", + "inhibition", + "of", + "JNK" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "AAA" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Selective", + "inhibition", + "of", + "JNK" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression", + "of" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression", + "of" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "AAA" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression", + "of" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "AAA" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + } + ] + }, + { + "PMID": "16311602", + "TEXT": "Nitrative stress has an important role in microvascular degeneration leading to ischemia in conditions such as diabetic retinopathy and retinopathy of prematurity. Thus far, mediators of nitrative stress have been poorly characterized. We recently described that trans-arachidonic acids are major products of NO(2)(*)-mediated isomerization of arachidonic acid within the cell membrane, but their biological relevance is unknown. Here we show that trans-arachidonic acids are generated in a model of retinal microangiopathy in vivo in a NO(*)-dependent manner. They induce a selective time- and concentration-dependent apoptosis of microvascular endothelial cells in vitro, and result in retinal microvascular degeneration ex vivo and in vivo. These effects are mediated by an upregulation of the antiangiogenic factor thrombospondin-1, independently of classical arachidonic acid metabolism. Our findings provide new insight into the molecular mechanisms of nitrative stress in microvascular injury and suggest new therapeutic avenues in the management of disorders involving nitrative stress, such as ischemic retinopathies and encephalopathies.", + "TAG_DATA": [ + "78, induce {'effect': 'B-positive'}", + "84, apoptosis {'phenotype': 'B-apoptosis'}", + "86, microvascular {'context': 'B-cells'}", + "87, endothelial {'context': 'I-cells'}", + "88, cells {'context': 'I-cells'}", + "89, in {'context': 'B-in vitro'}", + "90, vitro, {'context': 'I-in vitro'}", + "100, in {'context': 'B-in vivo'}", + "101, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "78, induce ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "84, apoptosis ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "86, microvascular ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "87, endothelial ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "88, cells ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "89, in ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "90, vitro, ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "100, in ['l21']", + "101, vivo. ['l21']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "microvascular", + "endothelial", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "microvascular", + "endothelial", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + } + ] + }, + { + "PMID": "16286923", + "TEXT": "R-Ras is a small GTPase of the Ras family that regulates cell survival and integrin activity. Despite a number of in vitro studies, the in vivo function of R-Ras remains unclear. Here, we used R-Ras-null mice to explore the in vivo function of this small GTPase. Our results show a role for R-Ras as a regulator of vascular differentiation that primarily affects the remodeling of blood vessels. We show that R-Ras-null mice, although otherwise phenotypically normal, mount excessive vascular responses. We found that in vivo R-Ras expression is largely confined to fully differentiated smooth muscle cells, including those of blood vessels, and to endothelial cells. Challenging the R-Ras-null mice with arterial injury or tumor implantation showed exaggerated neointimal thickening in response to the injury and increased angiogenesis in the tumors. In wild-type mice, R-Ras expression was greatly reduced in hyperplastic neointimal smooth muscle cells and in angiogenic endothelial cells. Forced expression of activated R-Ras suppressed mitogenic and invasive activities of growth factor-stimulated vascular cells. These results establish an unexpected role for R-Ras in blood vessel homeostasis and suggest that R-Ras signaling may offer a target for therapeutic intervention in vascular diseases.", + "TAG_DATA": [ + "34, R-Ras-null {'perturbing_action': 'B-gene loss-of-function'}", + "70, R-Ras-null {'perturbing_action': 'B-gene loss-of-function'}", + "71, mice, {'context': 'B-organism'}", + "83, in {'context': 'B-in vivo'}", + "84, vivo {'context': 'I-in vivo'}", + "107, R-Ras-null {'perturbing_action': 'B-gene loss-of-function'}", + "108, mice {'context': 'B-organism'}", + "129, tumors. {'context': 'B-neoplasm'}", + "132, mice, {'context': 'B-organism'}", + "139, hyperplastic {'context': 'B-cells'}", + "140, neointimal {'context': 'I-cells'}", + "141, smooth {'context': 'I-cells'}", + "142, muscle {'context': 'I-cells'}", + "143, cells {'context': 'I-cells'}", + "146, angiogenic {'context': 'B-cells'}", + "147, endothelial {'context': 'I-cells'}", + "148, cells. {'context': 'I-cells'}", + "149, Forced {'perturbing_action': 'B-gene gain-of-function'}", + "150, expression {'perturbing_action': 'I-gene gain-of-function'}", + "151, of {'perturbing_action': 'I-gene gain-of-function'}", + "152, activated {'perturbing_action': 'I-gene gain-of-function'}", + "153, R-Ras {'perturbing_action': 'I-gene gain-of-function'}", + "162, vascular {'context': 'B-cells'}", + "163, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "34, R-Ras-null ['l0', 'l1', 'l2', 'l3']", + "70, R-Ras-null ['l0', 'l4', 'l5', 'l6']", + "71, mice, ['l1', 'l4', 'l7', 'l8']", + "83, in ['l2', 'l5', 'l7', 'l9']", + "84, vivo ['l3', 'l6', 'l8', 'l9']", + "107, R-Ras-null ['l10', 'l11', 'l12', 'l13', 'l14']", + "108, mice ['l10', 'l15']", + "129, tumors. ['l11', 'l15', 'l16', 'l17', 'l18']", + "132, mice, ['l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "139, hyperplastic ['l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "140, neointimal ['l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "141, smooth ['l12', 'l16', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "142, muscle ['l13', 'l17', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "143, cells ['l14', 'l18', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "146, angiogenic ['l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "147, endothelial ['l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "148, cells. ['l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "149, Forced ['l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "150, expression ['l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "151, of ['l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "152, activated ['l57', 'l62', 'l66', 'l70', 'l71', 'l72']", + "153, R-Ras ['l58', 'l63', 'l67', 'l70', 'l73', 'l74']", + "162, vascular ['l59', 'l64', 'l68', 'l71', 'l73', 'l75']", + "163, cells. ['l60', 'l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "R-Ras-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "R-Ras-null" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "R-Ras-null" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "R-Ras-null" + ] + }, + "context": { + "val": "cells", + "words": [ + "smooth", + "muscle", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "expression", + "of", + "activated", + "R-Ras" + ] + }, + "context": { + "val": "cells", + "words": [ + "vascular", + "cells." + ] + } + } + ] + }, + { + "PMID": "16170322", + "TEXT": "Antigen-specific T cells circulate freely and accumulate specifically at sites of antigen expression. To enhance the survival and targeting of systemically delivered viral vectors, we exploited the observation that retroviral particles adhere nonspecifically, or 'hitchhike,' to the surface of T cells. Adoptive transfer of antigen-specific T cells, loaded with viruses encoding interleukin (IL)-12 or Herpes Simplex Virus thymidine kinase (HSVtk), cured established metastatic disease where adoptive T-cell transfer alone was not effective. Productive hand off correlated with local heparanase expression either from malignant tumor cells and/or as a result of T-cell activation by antigen, providing high levels of selectivity for viral transfer to metastatic tumors in vivo. Protection, concentration and targeting of viruses by adsorption to cell carriers represent a new technique for systemic delivery of vectors, in fully immunocompetent hosts, for a variety of diseases in which delivery of genes may be therapeutically beneficial.", + "TAG_DATA": [ + "44, antigen-specific {'context': 'B-cells'}", + "45, T {'context': 'I-cells'}", + "46, cells, {'context': 'I-cells'}", + "62, metastatic {'context': 'B-neoplasm'}", + "63, disease {'context': 'I-neoplasm', 'phenotype': 'I-metastasis'}", + "103, metastatic {'context': 'B-neoplasm'}", + "104, tumors {'context': 'I-neoplasm'}", + "105, in {'context': 'B-in vivo'}", + "106, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "44, antigen-specific ['l0', 'l1', 'l2', 'l3']", + "45, T ['l0', 'l4', 'l5', 'l6']", + "46, cells, ['l1', 'l4', 'l7', 'l8']", + "62, metastatic ['l2', 'l5', 'l7', 'l9']", + "63, disease ['l3', 'l6', 'l8', 'l9']", + "90, T-cell ['l10', 'l11', 'l12', 'l13']", + "103, metastatic ['l10', 'l14', 'l15', 'l16']", + "104, tumors ['l11', 'l14', 'l17', 'l18']", + "105, in ['l12', 'l15', 'l17', 'l19']", + "106, vivo. ['l13', 'l16', 'l18', 'l19']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "antigen-specific", + "T", + "cells," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "disease" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "disease", + "metastatic" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "disease" + ] + } + } + ] + }, + { + "PMID": "16155577", + "TEXT": "Heat-shock protein 90 (Hsp90) functions as part of a multichaperone complex that folds, activates and assembles its client proteins. Androgen receptor (AR), a pathogenic gene product in spinal and bulbar muscular atrophy (SBMA), is one of the Hsp90 client proteins. We examined the therapeutic effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG), a potent Hsp90 inhibitor, and its ability to degrade polyglutamine-expanded mutant AR. Administration of 17-AAG markedly ameliorated motor impairments in the SBMA transgenic mouse model without detectable toxicity, by reducing amounts of monomeric and aggregated mutant AR. The mutant AR showed a higher affinity for Hsp90-p23 and preferentially formed an Hsp90 chaperone complex as compared to wild-type AR; mutant AR was preferentially degraded in the presence of 17-AAG in both cells and transgenic mice as compared to wild-type AR. 17-AAG also mildly induced Hsp70 and Hsp40. 17-AAG would thus provide a new therapeutic approach to SBMA and probably to other related neurodegenerative diseases.", + "TAG_DATA": [ + "69, SBMA {'perturbing_action': 'B-gene gain-of-function'}", + "70, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "71, mouse {'context': 'I-organism'}", + "72, model {'context': 'I-organism'}", + "86, mutant {'perturbing_action': 'B-other'}", + "87, AR {'perturbing_action': 'I-other'}", + "118, cells {'context': 'B-cells'}", + "120, transgenic {'perturbing_action': 'B-gene gain-of-function', 'context': 'B-xenograft'}", + "121, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "69, SBMA ['l0', 'l1', 'l2']", + "70, transgenic ['l0', 'l3', 'l4']", + "71, mouse ['l1', 'l3', 'l5']", + "72, model ['l2', 'l4', 'l5']", + "86, mutant ['l6', 'l7']", + "87, AR ['l6', 'l8']", + "118, cells ['l7', 'l8', 'l9', 'l10']", + "120, transgenic ['l9', 'l11']", + "121, mice ['l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "SBMA", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "AR" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "transgenic" + ] + } + } + ] + }, + { + "PMID": "16127434", + "TEXT": "Hypoxia inducible factor-1 (HIF-1) is considered a crucial mediator of the cellular response to hypoxia through its regulation of genes that control angiogenesis. It represents an attractive therapeutic target in colon cancer, one of the few tumor types that shows a clinical response to antiangiogenic therapy. But it is unclear whether inhibition of HIF-1 alone is sufficient to block tumor angiogenesis. In HIF-1alpha knockdown DLD-1 colon cancer cells (DLD-1(HIF-kd)), the hypoxic induction of vascular endothelial growth factor (VEGF) was only partially blocked. Xenografts remained highly vascularized with microvessel densities identical to DLD-1 tumors that had wild-type HIF-1alpha (DLD-1(HIF-wt)). In addition to the preserved expression of VEGF, the proangiogenic cytokine interleukin (IL)-8 was induced by hypoxia in DLD-1(HIF-kd) but not DLD-1(HIF-wt) cells. This induction was mediated by the production of hydrogen peroxide and subsequent activation of NF-kappaB. Furthermore, the KRAS oncogene, which is commonly mutated in colon cancer, enhanced the hypoxic induction of IL-8. A neutralizing antibody to IL-8 substantially inhibited angiogenesis and tumor growth in DLD-1(HIF-kd) but not DLD-1(HIF-wt) xenografts, verifying the functional significance of this IL-8 response. Thus, compensatory pathways can be activated to preserve the tumor angiogenic response, and strategies that inhibit HIF-1alpha may be most effective when IL-8 is simultaneously targeted.", + "TAG_DATA": [ + "62, HIF-1alpha {'perturbing_action': 'B-rnai/knockdown'}", + "63, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "64, DLD-1 {'context': 'B-transformed cells'}", + "65, colon {'context': 'I-transformed cells'}", + "66, cancer {'context': 'I-transformed cells'}", + "67, cells {'context': 'I-transformed cells'}", + "68, (DLD-1(HIF-kd)), {'context': 'I-transformed cells'}", + "82, Xenografts {'context': 'B-xenograft'}", + "120, cells. {'context': 'B-cells'}", + "159, inhibited {'effect': 'B-negative'}", + "162, tumor {'phenotype': 'B-tumour growth'}", + "163, growth {'phenotype': 'I-tumour growth'}", + "168, DLD-1(HIF-wt) {'context': 'B-xenograft'}", + "169, xenografts, {'context': 'B-xenograft'}" + ], + "LINK_DATA": [ + "62, HIF-1alpha ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "63, knockdown ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "64, DLD-1 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "65, colon ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "66, cancer ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "67, cells ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "68, (DLD-1(HIF-kd)), ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "82, Xenografts ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "159, inhibited ['l28', 'l29', 'l30', 'l31', 'l32']", + "162, tumor ['l28', 'l33', 'l34', 'l35', 'l36']", + "163, growth ['l29', 'l33', 'l37', 'l38', 'l39']", + "165, DLD-1(HIF-kd) ['l30', 'l34', 'l37', 'l40', 'l41']", + "168, DLD-1(HIF-wt) ['l31', 'l35', 'l38', 'l40', 'l42']", + "169, xenografts, ['l32', 'l36', 'l39', 'l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "HIF-1alpha", + "knockdown" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "DLD-1", + "colon", + "cancer", + "cells", + "(DLD-1(HIF-kd))," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "HIF-1alpha", + "knockdown" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "Xenografts" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "DLD-1(HIF-wt)", + "xenografts," + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "DLD-1(HIF-wt)", + "xenografts," + ] + } + } + ] + }, + { + "PMID": "16116431", + "TEXT": "Lymph vessels control fluid homeostasis, immunity and metastasis. Unraveling the molecular basis of lymphangiogenesis has been hampered by the lack of a small animal model that can be genetically manipulated. Here, we show that Xenopus tadpoles develop lymph vessels from lymphangioblasts or, through transdifferentiation, from venous endothelial cells. Lymphangiography showed that these lymph vessels drain lymph, through the lymph heart, to the venous circulation. Morpholino-mediated knockdown of the lymphangiogenic factor Prox1 caused lymph vessel defects and lymphedema by impairing lymphatic commitment. Knockdown of vascular endothelial growth factor C (VEGF-C) also induced lymph vessel defects and lymphedema, but primarily by affecting migration of lymphatic endothelial cells. Knockdown of VEGF-C also resulted in aberrant blood vessel formation in tadpoles. This tadpole model offers opportunities for the discovery of new regulators of lymphangiogenesis.", + "TAG_DATA": [ + "34, Xenopus {'context': 'B-organism'}", + "35, tadpoles {'context': 'I-organism'}", + "64, Morpholino-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "65, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "66, of {'perturbing_action': 'I-rnai/knockdown'}", + "67, the {'perturbing_action': 'I-rnai/knockdown'}", + "68, lymphangiogenic {'perturbing_action': 'I-rnai/knockdown'}", + "69, factor {'perturbing_action': 'I-rnai/knockdown'}", + "70, Prox1 {'perturbing_action': 'I-rnai/knockdown'}", + "81, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "82, of {'perturbing_action': 'I-rnai/knockdown'}", + "83, vascular {'perturbing_action': 'I-rnai/knockdown'}", + "84, endothelial {'perturbing_action': 'I-rnai/knockdown'}", + "85, growth {'perturbing_action': 'I-rnai/knockdown'}", + "86, factor {'perturbing_action': 'I-rnai/knockdown'}", + "87, C {'perturbing_action': 'I-rnai/knockdown'}", + "88, (VEGF-C) {'perturbing_action': 'I-rnai/knockdown'}", + "99, affecting {'effect': 'B-regulates'}", + "100, migration {'phenotype': 'B-migration'}", + "102, lymphatic {'context': 'B-cells'}", + "103, endothelial {'context': 'I-cells'}", + "104, cells. {'context': 'I-cells'}", + "105, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "106, of {'perturbing_action': 'I-rnai/knockdown'}", + "107, VEGF-C {'perturbing_action': 'I-rnai/knockdown'}", + "116, tadpoles. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "34, Xenopus ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "35, tadpoles ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "64, Morpholino-mediated ['l1', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "65, knockdown ['l2', 'l8', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "66, of ['l3', 'l9', 'l15', 'l20', 'l25', 'l26', 'l27', 'l28']", + "67, the ['l4', 'l10', 'l16', 'l21', 'l25', 'l29', 'l30', 'l31']", + "68, lymphangiogenic ['l5', 'l11', 'l17', 'l22', 'l26', 'l29', 'l32', 'l33']", + "69, factor ['l6', 'l12', 'l18', 'l23', 'l27', 'l30', 'l32', 'l34']", + "70, Prox1 ['l7', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l34']", + "81, Knockdown ['l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "82, of ['l35', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "83, vascular ['l36', 'l47', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "84, endothelial ['l37', 'l48', 'l58', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "85, growth ['l38', 'l49', 'l59', 'l68', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "86, factor ['l39', 'l50', 'l60', 'l69', 'l77', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "87, C ['l40', 'l51', 'l61', 'l70', 'l78', 'l85', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "88, (VEGF-C) ['l41', 'l52', 'l62', 'l71', 'l79', 'l86', 'l92', 'l98', 'l99', 'l100', 'l101', 'l102']", + "99, affecting ['l42', 'l53', 'l63', 'l72', 'l80', 'l87', 'l93', 'l98', 'l103', 'l104', 'l105', 'l106']", + "100, migration ['l43', 'l54', 'l64', 'l73', 'l81', 'l88', 'l94', 'l99', 'l103', 'l107', 'l108', 'l109']", + "102, lymphatic ['l44', 'l55', 'l65', 'l74', 'l82', 'l89', 'l95', 'l100', 'l104', 'l107', 'l110', 'l111']", + "103, endothelial ['l45', 'l56', 'l66', 'l75', 'l83', 'l90', 'l96', 'l101', 'l105', 'l108', 'l110', 'l112']", + "104, cells. ['l46', 'l57', 'l67', 'l76', 'l84', 'l91', 'l97', 'l102', 'l106', 'l109', 'l111', 'l112']", + "105, Knockdown ['l113', 'l114', 'l115']", + "106, of ['l113', 'l116', 'l117']", + "107, VEGF-C ['l114', 'l116', 'l118']", + "116, tadpoles. ['l115', 'l117', 'l118']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Xenopus", + "tadpoles", + "tadpoles." + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Morpholino-mediated", + "knockdown", + "of", + "the", + "lymphangiogenic", + "factor", + "Prox1", + "Knockdown", + "VEGF-C" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "vascular", + "endothelial", + "growth", + "factor", + "C", + "(VEGF-C)" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "affecting" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "vascular", + "endothelial", + "growth", + "factor", + "C", + "(VEGF-C)" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "vascular", + "endothelial", + "growth", + "factor", + "C", + "(VEGF-C)" + ] + }, + "context": { + "val": "cells", + "words": [ + "lymphatic", + "endothelial", + "cells." + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "affecting" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "affecting" + ] + }, + "context": { + "val": "cells", + "words": [ + "lymphatic", + "endothelial", + "cells." + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "cells", + "words": [ + "lymphatic", + "endothelial", + "cells." + ] + } + } + ] + }, + { + "PMID": "16116430", + "TEXT": "Neurovascular dysfunction substantially contributes to Alzheimer disease. Here, we show that transcriptional profiling of human brain endothelial cells (BECs) defines a subset of genes whose expression is age-independent but is considerably altered in Alzheimer disease, including the homeobox gene MEOX2 (also known as GAX), a regulator of vascular differentiation, whose expression is low in Alzheimer disease. By using viral-mediated MEOX2 gene silencing and transfer, we show that restoring expression of the protein it encodes, GAX, in BECs from individuals with Alzheimer disease stimulates angiogenesis, transcriptionally suppresses AFX1 forkhead transcription factor-mediated apoptosis and increases the levels of a major amyloid-beta peptide (Abeta) clearance receptor, the low-density lipoprotein receptor-related protein 1 (LRP), at the blood-brain barrier. In mice, deletion of Meox2 (also known as Gax) results in reductions in brain capillary density and resting cerebral blood flow, loss of the angiogenic response to hypoxia in the brain and an impaired Abeta efflux from brain caused by reduced LRP levels. The link of MEOX2 to neurovascular dysfunction in Alzheimer disease provides new mechanistic and therapeutic insights into this illness.", + "TAG_DATA": [ + "58, viral-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "59, MEOX2 {'perturbing_action': 'I-rnai/knockdown'}", + "60, gene {'perturbing_action': 'I-rnai/knockdown'}", + "61, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "67, restoring {'perturbing_action': 'B-gene gain-of-function'}", + "68, expression {'perturbing_action': 'I-gene gain-of-function'}", + "69, of {'perturbing_action': 'I-gene gain-of-function'}", + "70, the {'perturbing_action': 'I-gene gain-of-function'}", + "71, protein {'perturbing_action': 'I-gene gain-of-function'}", + "72, it {'perturbing_action': 'I-gene gain-of-function'}", + "73, encodes, {'perturbing_action': 'I-gene gain-of-function'}", + "74, GAX, {'perturbing_action': 'I-gene gain-of-function'}", + "76, BECs {'context': 'B-cells'}", + "85, suppresses {'effect': 'B-negative'}", + "89, factor-mediated {'effect': 'B-regulates'}", + "90, apoptosis {'phenotype': 'B-apoptosis'}", + "115, mice, {'context': 'B-organism'}", + "116, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "117, of {'perturbing_action': 'I-gene loss-of-function'}", + "118, Meox2 {'perturbing_action': 'I-gene loss-of-function'}", + "119, (also {'perturbing_action': 'I-gene loss-of-function'}", + "120, known {'perturbing_action': 'I-gene loss-of-function'}", + "121, as {'perturbing_action': 'I-gene loss-of-function'}", + "122, Gax) {'perturbing_action': 'I-gene loss-of-function'}", + "127, brain {'context': 'B-tissue/organ'}", + "144, brain {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "58, viral-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "59, MEOX2 ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "60, gene ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19']", + "61, silencing ['l2', 'l9', 'l15', 'l20', 'l21', 'l22', 'l23']", + "67, restoring ['l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "68, expression ['l24', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "69, of ['l25', 'l35', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "70, the ['l26', 'l36', 'l45', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "71, protein ['l27', 'l37', 'l46', 'l54', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "72, it ['l28', 'l38', 'l47', 'l55', 'l62', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "73, encodes, ['l29', 'l39', 'l48', 'l56', 'l63', 'l69', 'l75', 'l76', 'l77', 'l78', 'l79']", + "74, GAX, ['l3', 'l10', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l75', 'l80', 'l81', 'l82', 'l83']", + "76, BECs ['l4', 'l11', 'l16', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l84', 'l85', 'l86']", + "85, suppresses ['l5', 'l12', 'l17', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l87', 'l88']", + "89, factor-mediated ['l6', 'l13', 'l18', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l87', 'l89']", + "90, apoptosis ['l7', 'l14', 'l19', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l89']", + "115, mice, ['l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "116, deletion ['l90', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "117, of ['l91', 'l99', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "118, Meox2 ['l92', 'l100', 'l107', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "119, (also ['l93', 'l101', 'l108', 'l114', 'l120', 'l121', 'l122', 'l123', 'l124']", + "120, known ['l94', 'l102', 'l109', 'l115', 'l120', 'l125', 'l126', 'l127', 'l128']", + "121, as ['l95', 'l103', 'l110', 'l116', 'l121', 'l125', 'l129', 'l130', 'l131']", + "122, Gax) ['l96', 'l104', 'l111', 'l117', 'l122', 'l126', 'l129', 'l132', 'l133']", + "127, brain ['l97', 'l105', 'l112', 'l118', 'l123', 'l127', 'l130', 'l132', 'l134']", + "144, brain ['l98', 'l106', 'l113', 'l119', 'l124', 'l128', 'l131', 'l133', 'l134']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "viral-mediated", + "MEOX2", + "gene", + "silencing" + ] + }, + "context": { + "val": "cells", + "words": [ + "BECs" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "viral-mediated", + "MEOX2", + "gene", + "silencing" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "viral-mediated", + "MEOX2", + "gene", + "silencing" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "factor-mediated" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "viral-mediated", + "MEOX2", + "gene", + "silencing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "restoring", + "expression", + "of", + "the", + "protein", + "it", + "encodes,", + "GAX," + ] + }, + "context": { + "val": "cells", + "words": [ + "BECs" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "restoring", + "expression", + "of", + "the", + "protein", + "it", + "encodes,", + "GAX," + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "restoring", + "expression", + "of", + "the", + "protein", + "it", + "encodes,", + "GAX," + ] + }, + "effect": { + "val": "regulates", + "words": [ + "factor-mediated" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "restoring", + "expression", + "of", + "the", + "protein", + "it", + "encodes,", + "GAX," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "BECs" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "BECs" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "factor-mediated" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "BECs" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "factor-mediated" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Meox2", + "(also", + "known", + "as", + "Gax)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Meox2", + "(also", + "known", + "as", + "Gax)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain" + ] + } + } + ] + }, + { + "PMID": "16007095", + "TEXT": "Thiazolidinediones (TZDs) are widely used to treat type 2 diabetes mellitus; however, their use is complicated by systemic fluid retention. Along the nephron, the pharmacological target of TZDs, peroxisome proliferator-activated receptor-gamma (PPARgamma, encoded by Pparg), is most abundant in the collecting duct. Here we show that mice treated with TZDs experience early weight gain from increased total body water. Weight gain was blocked by the collecting duct-specific diuretic amiloride and was also prevented by deletion of Pparg from the collecting duct, using Pparg (flox/flox) mice. Deletion of collecting duct Pparg decreased renal Na(+) avidity and increased plasma aldosterone. Treating cultured collecting ducts with TZDs increased amiloride-sensitive Na(+) absorption and Scnn1g mRNA (encoding the epithelial Na(+) channel ENaCgamma) expression through a PPARgamma-dependent pathway. These studies identify Scnn1g as a PPARgamma target gene in the collecting duct. Activation of this pathway mediates fluid retention associated with TZDs, and suggests amiloride might provide a specific therapy.", + "TAG_DATA": [ + "46, mice {'context': 'B-organism'}", + "74, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "75, of {'perturbing_action': 'I-gene loss-of-function'}", + "76, Pparg {'perturbing_action': 'I-gene loss-of-function'}", + "77, from {'perturbing_action': 'I-gene loss-of-function'}", + "78, the {'perturbing_action': 'I-gene loss-of-function'}", + "79, collecting {'perturbing_action': 'I-gene loss-of-function'}", + "80, duct, {'perturbing_action': 'I-gene loss-of-function'}", + "82, Pparg {'perturbing_action': 'B-gene loss-of-function'}", + "83, (flox/flox) {'perturbing_action': 'B-gene loss-of-function'}", + "84, mice. {'context': 'B-organism'}", + "85, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "86, of {'perturbing_action': 'I-gene loss-of-function'}", + "87, collecting {'perturbing_action': 'I-gene loss-of-function'}", + "88, duct {'perturbing_action': 'I-gene loss-of-function'}", + "89, Pparg {'perturbing_action': 'I-gene loss-of-function'}", + "99, cultured {'context': 'B-cells'}", + "100, collecting {'context': 'I-cells'}", + "101, ducts {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "74, deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "75, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "76, Pparg ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "77, from ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "78, the ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "79, collecting ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "80, duct, ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "82, Pparg ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "83, (flox/flox) ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "84, mice. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l49', 'l55', 'l56', 'l57']", + "85, Deletion ['l44', 'l50', 'l58', 'l59', 'l60', 'l61']", + "86, of ['l45', 'l51', 'l58', 'l62', 'l63', 'l64']", + "87, collecting ['l46', 'l52', 'l55', 'l59', 'l62', 'l65', 'l66']", + "88, duct ['l47', 'l53', 'l56', 'l60', 'l63', 'l65', 'l67']", + "89, Pparg ['l48', 'l54', 'l57', 'l61', 'l64', 'l66', 'l67']", + "99, cultured ['l68', 'l69']", + "100, collecting ['l68', 'l70']", + "101, ducts ['l69', 'l70']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Pparg", + "from", + "the", + "collecting", + "duct,", + "(flox/flox)", + "duct" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "15980864", + "TEXT": "Premature aging syndromes often result from mutations in nuclear proteins involved in the maintenance of genomic integrity. Lamin A is a major component of the nuclear lamina and nuclear skeleton. Truncation in lamin A causes Hutchinson-Gilford progerial syndrome (HGPS), a severe form of early-onset premature aging. Lack of functional Zmpste24, a metalloproteinase responsible for the maturation of prelamin A, also results in progeroid phenotypes in mice and humans. We found that Zmpste24-deficient mouse embryonic fibroblasts (MEFs) show increased DNA damage and chromosome aberrations and are more sensitive to DNA-damaging agents. Bone marrow cells isolated from Zmpste24-/- mice show increased aneuploidy and the mice are more sensitive to DNA-damaging agents. Recruitment of p53 binding protein 1 (53BP1) and Rad51 to sites of DNA lesion is impaired in Zmpste24-/- MEFs and in HGPS fibroblasts, resulting in delayed checkpoint response and defective DNA repair. Wild-type MEFs ectopically expressing unprocessible prelamin A show similar defects in checkpoint response and DNA repair. Our results indicate that unprocessed prelamin A and truncated lamin A act dominant negatively to perturb DNA damage response and repair, resulting in genomic instability which might contribute to laminopathy-based premature aging.", + "TAG_DATA": [ + "71, Zmpste24-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "72, mouse {'context': 'B-cells'}", + "73, embryonic {'context': 'I-cells'}", + "74, fibroblasts {'context': 'I-cells'}", + "75, (MEFs) {'context': 'I-cells'}", + "90, Bone {'context': 'B-cells'}", + "91, marrow {'context': 'I-cells'}", + "92, cells {'context': 'I-cells'}", + "95, Zmpste24-/- {'perturbing_action': 'B-gene loss-of-function'}", + "96, mice {'context': 'B-organism'}", + "102, mice {'context': 'B-organism'}", + "126, Zmpste24-/- {'perturbing_action': 'B-gene loss-of-function'}", + "127, MEFs {'context': 'B-cells'}", + "130, HGPS {'context': 'B-cells'}", + "131, fibroblasts, {'context': 'I-cells'}", + "142, MEFs {'context': 'B-cells'}", + "143, ectopically {'perturbing_action': 'B-gene gain-of-function'}", + "144, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "145, unprocessible {'perturbing_action': 'I-gene gain-of-function'}", + "146, prelamin {'perturbing_action': 'I-gene gain-of-function'}", + "147, A {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "71, Zmpste24-deficient ['l0', 'l1', 'l2', 'l3']", + "72, mouse ['l0', 'l4', 'l5', 'l6']", + "73, embryonic ['l1', 'l4', 'l7', 'l8']", + "74, fibroblasts ['l2', 'l5', 'l7', 'l9']", + "75, (MEFs) ['l3', 'l6', 'l8', 'l9']", + "90, Bone ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "91, marrow ['l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "92, cells ['l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "95, Zmpste24-/- ['l12', 'l20', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "96, mice ['l13', 'l21', 'l28', 'l33', 'l39', 'l40', 'l41']", + "102, mice ['l14', 'l22', 'l29', 'l34', 'l39', 'l42', 'l43', 'l44', 'l45']", + "126, Zmpste24-/- ['l15', 'l23', 'l35', 'l42', 'l46', 'l47', 'l48']", + "127, MEFs ['l16', 'l24', 'l30', 'l36', 'l40', 'l43', 'l46', 'l49', 'l50']", + "130, HGPS ['l17', 'l25', 'l31', 'l37', 'l44', 'l47', 'l49', 'l51']", + "131, fibroblasts, ['l18', 'l26', 'l32', 'l38', 'l41', 'l45', 'l48', 'l50', 'l51']", + "142, MEFs ['l52', 'l53', 'l54', 'l55', 'l56']", + "143, ectopically ['l52', 'l57', 'l58', 'l59', 'l60']", + "144, expressing ['l53', 'l57', 'l61', 'l62', 'l63']", + "145, unprocessible ['l54', 'l58', 'l61', 'l64', 'l65']", + "146, prelamin ['l55', 'l59', 'l62', 'l64', 'l66']", + "147, A ['l56', 'l60', 'l63', 'l65', 'l66']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Zmpste24-deficient", + "Zmpste24-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "embryonic", + "fibroblasts", + "(MEFs)", + "Bone", + "marrow", + "cells", + "MEFs", + "HGPS", + "fibroblasts," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Zmpste24-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "MEFs" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopically", + "expressing", + "unprocessible", + "prelamin", + "A" + ] + } + } + ] + }, + { + "PMID": "15924147", + "TEXT": "Type 2 diabetes mellitus is a widespread disease, affecting millions of people globally. Although genetics and environmental factors seem to have a role, the cause of this metabolic disorder is largely unknown. Here we report a genetic flaw that markedly reduced the intracellular expression of the high mobility group A1 (HMGA1) protein, and adversely affected insulin receptor expression in cells and tissues from four subjects with insulin resistance and type 2 diabetes. Restoration of HMGA1 protein expression in subjects' cells enhanced INSR gene transcription, and restored cell-surface insulin receptor protein expression and insulin-binding capacity. Loss of Hmga1 expression, induced in mice by disrupting the Hmga1 gene, considerably decreased insulin receptor expression in the major targets of insulin action, largely impaired insulin signaling and severely reduced insulin secretion, causing a phenotype characteristic of human type 2 diabetes.", + "TAG_DATA": [ + "72, Restoration {'perturbing_action': 'B-gene gain-of-function'}", + "73, of {'perturbing_action': 'I-gene gain-of-function'}", + "74, HMGA1 {'perturbing_action': 'I-gene gain-of-function'}", + "75, protein {'perturbing_action': 'I-gene gain-of-function'}", + "76, expression {'perturbing_action': 'I-gene gain-of-function'}", + "78, subjects' {'context': 'B-cells'}", + "79, cells {'context': 'I-cells'}", + "94, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "95, of {'perturbing_action': 'I-gene loss-of-function'}", + "96, Hmga1 {'perturbing_action': 'I-gene loss-of-function'}", + "97, expression, {'perturbing_action': 'I-gene loss-of-function'}", + "100, mice {'context': 'B-organism'}", + "102, disrupting {'perturbing_action': 'B-gene loss-of-function'}", + "103, the {'perturbing_action': 'I-gene loss-of-function'}", + "104, Hmga1 {'perturbing_action': 'I-gene loss-of-function'}", + "105, gene, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "72, Restoration ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "73, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "74, HMGA1 ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "75, protein ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "76, expression ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "78, subjects' ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "79, cells ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "94, Loss ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "95, of ['l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "96, Hmga1 ['l22', 'l29', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "97, expression, ['l23', 'l30', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "100, mice ['l24', 'l31', 'l37', 'l42', 'l47', 'l48', 'l49', 'l50']", + "102, disrupting ['l25', 'l32', 'l38', 'l43', 'l47', 'l51', 'l52', 'l53']", + "103, the ['l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l54', 'l55']", + "104, Hmga1 ['l27', 'l34', 'l40', 'l45', 'l49', 'l52', 'l54', 'l56']", + "105, gene, ['l28', 'l35', 'l41', 'l46', 'l50', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoration", + "of", + "HMGA1", + "protein", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "subjects'", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Loss", + "of", + "Hmga1", + "expression,", + "disrupting", + "the", + "gene," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15895073", + "TEXT": "Anaplastic large cell lymphomas (ALCLs) are caused by chromosomal translocations that juxtapose the anaplastic lymphoma kinase (ALK) proto-oncogene to a dimerization partner, resulting in constitutive expression of ALK and ALK tyrosine kinase activity. One substrate of activated ALK in human ALCLs is the transcription factor Stat3, and its phosphorylation is accurately recapitulated in a new nucleophosmin (NPM)-ALK transgenic mouse model of lymphomagenesis. Here we show by gene targeting that Stat3 is required for the transformation of mouse embryonic fibroblasts in vitro, for the development of B-cell lymphoma in transgenic mice and for the growth and survival of both human and mouse NPM-ALK-transformed B and T cells. Ablation of Stat3 expression by antisense oligonucleotides significantly (P < 0.0001) impaired the growth of human and mouse NPM-ALK tumors in vivo. Pharmacological ablation of Stat3 represents a new candidate approach for the treatment of human lymphoma", + "TAG_DATA": [ + "74, transformation {'phenotype': 'B-transformation'}", + "76, mouse {'context': 'B-cells'}", + "77, embryonic {'context': 'I-cells'}", + "78, fibroblasts {'context': 'I-cells'}", + "79, in {'context': 'B-in vitro'}", + "80, vitro, {'context': 'I-in vitro'}", + "85, B-cell {'phenotype': 'B-tumourigenesis'}", + "86, lymphoma {'phenotype': 'I-tumourigenesis'}", + "88, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "89, mice {'context': 'I-organism'}", + "102, B {'context': 'B-cells'}", + "103, and {'context': 'I-cells'}", + "104, T {'context': 'I-cells'}", + "105, cells. {'context': 'I-cells'}", + "106, Ablation {'perturbing_action': 'B-gene loss-of-function'}", + "107, of {'perturbing_action': 'I-gene loss-of-function'}", + "108, Stat3 {'perturbing_action': 'I-gene loss-of-function'}", + "109, expression {'perturbing_action': 'I-gene loss-of-function'}", + "121, human {'context': 'B-neoplasm'}", + "122, and {'context': 'I-neoplasm'}", + "123, mouse {'context': 'I-neoplasm'}", + "124, NPM-ALK {'context': 'I-neoplasm'}", + "125, tumors {'context': 'I-neoplasm'}", + "126, in {'context': 'B-in vivo'}", + "127, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "74, transformation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "76, mouse ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "77, embryonic ['l1', 'l7', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "78, fibroblasts ['l2', 'l8', 'l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "79, in ['l3', 'l9', 'l16', 'l23', 'l29', 'l30', 'l31', 'l32']", + "80, vitro, ['l4', 'l10', 'l17', 'l24', 'l29', 'l33', 'l34']", + "83, development ['l5', 'l11', 'l18', 'l25', 'l30', 'l33', 'l35', 'l36', 'l37', 'l38']", + "85, B-cell ['l12', 'l19', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41', 'l42']", + "86, lymphoma ['l6', 'l13', 'l20', 'l27', 'l32', 'l34', 'l36', 'l39', 'l43', 'l44']", + "88, transgenic ['l21', 'l37', 'l40', 'l43', 'l45', 'l46']", + "89, mice ['l14', 'l22', 'l28', 'l38', 'l41', 'l44', 'l45']", + "102, B ['l47', 'l48', 'l49']", + "103, and ['l47', 'l50', 'l51']", + "104, T ['l48', 'l50', 'l52']", + "105, cells. ['l42', 'l46', 'l49', 'l51', 'l52']", + "106, Ablation ['l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "107, of ['l53', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "108, Stat3 ['l54', 'l63', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "109, expression ['l55', 'l64', 'l72', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "121, human ['l56', 'l65', 'l73', 'l80', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "122, and ['l57', 'l66', 'l74', 'l81', 'l87', 'l93', 'l94', 'l95', 'l96', 'l97']", + "123, mouse ['l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l98', 'l99', 'l100', 'l101']", + "124, NPM-ALK ['l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l102', 'l103', 'l104']", + "125, tumors ['l60', 'l69', 'l77', 'l84', 'l90', 'l95', 'l99', 'l102', 'l105', 'l106']", + "126, in ['l61', 'l70', 'l78', 'l85', 'l91', 'l96', 'l100', 'l103', 'l105', 'l107']", + "127, vivo. ['l62', 'l71', 'l79', 'l86', 'l92', 'l97', 'l101', 'l104', 'l106', 'l107']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "embryonic", + "fibroblasts" + ] + } + }, + { + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "embryonic", + "fibroblasts", + "cells." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "B-cell", + "lymphoma" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "embryonic", + "cells." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "B-cell", + "lymphoma" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "B-cell", + "lymphoma" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "B-cell", + "lymphoma" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "Stat3", + "expression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "and", + "mouse", + "NPM-ALK", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "Stat3", + "expression" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "15895072", + "TEXT": "Genes involved in fatty acid catabolism have undergone extensive duplication in the genus Mycobacterium, which includes the etiologic agents of leprosy and tuberculosis. Here, we show that prokaryotic- and eukaryotic-like isoforms of the glyoxylate cycle enzyme isocitrate lyase (ICL) are jointly required for fatty acid catabolism and virulence in Mycobacterium tuberculosis. Although deletion of icl1 or icl2, the genes that encode ICL1 and ICL2, respectively, had little effect on bacterial growth in macrophages and mice, deletion of both genes resulted in complete impairment of intracellular replication and rapid elimination from the lungs. The feasibility of targeting ICL1 and ICL2 for chemical inhibition was shown using a dual-specific ICL inhibitor, which blocked growth of M. tuberculosis on fatty acids and in macrophages. The absence of ICL orthologs in mammals should facilitate the development of glyoxylate cycle inhibitors as new drugs for the treatment of tuberculosis.", + "TAG_DATA": [ + "52, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "53, of {'perturbing_action': 'I-gene loss-of-function'}", + "54, icl1 {'perturbing_action': 'I-gene loss-of-function'}", + "55, or {'perturbing_action': 'I-gene loss-of-function'}", + "56, icl2, {'perturbing_action': 'I-gene loss-of-function'}", + "66, little {'effect': 'B-no effect'}", + "67, effect {'effect': 'I-no effect'}", + "72, macrophages {'context': 'B-cells'}", + "74, mice, {'context': 'B-organism'}", + "75, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "76, of {'perturbing_action': 'I-gene loss-of-function'}", + "77, both {'perturbing_action': 'I-gene loss-of-function'}", + "78, genes {'perturbing_action': 'I-gene loss-of-function'}", + "106, dual-specific {'perturbing_action': 'B-pharmacological inhibition'}", + "107, ICL {'perturbing_action': 'I-pharmacological inhibition'}", + "108, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "113, M. {'context': 'B-organism'}", + "114, tuberculosis {'context': 'I-organism'}", + "120, macrophages. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "52, deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "53, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "54, icl1 ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "55, or ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "56, icl2, ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "66, little ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37']", + "67, effect ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l39']", + "72, macrophages ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l38', 'l40']", + "74, mice, ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l39', 'l40']", + "75, deletion ['l41', 'l42', 'l43', 'l44']", + "76, of ['l41', 'l45', 'l46', 'l47']", + "77, both ['l42', 'l45', 'l48', 'l49']", + "78, genes ['l43', 'l46', 'l48', 'l50']", + "91, lungs. ['l8', 'l16', 'l23', 'l29', 'l34', 'l44', 'l47', 'l49', 'l50']", + "106, dual-specific ['l51', 'l52', 'l53', 'l54', 'l55']", + "107, ICL ['l51', 'l56', 'l57', 'l58', 'l59']", + "108, inhibitor, ['l52', 'l56', 'l60', 'l61', 'l62']", + "113, M. ['l53', 'l57', 'l60', 'l63', 'l64']", + "114, tuberculosis ['l54', 'l58', 'l61', 'l63', 'l65']", + "120, macrophages. ['l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "icl1", + "or", + "icl2," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "little", + "effect" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "icl1", + "or", + "icl2," + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "icl1", + "or", + "icl2," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "little", + "effect" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "little", + "effect" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "dual-specific", + "ICL", + "inhibitor," + ] + }, + "context": { + "val": "organism", + "words": [ + "M.", + "tuberculosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "dual-specific", + "ICL", + "inhibitor," + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages." + ] + } + } + ] + }, + { + "PMID": "15864313", + "TEXT": "The muscular dystrophies are a heterogeneous group of disorders for which there are currently no cures. Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late-onset, progressive disease that generally presents in the fifth or sixth decade with dysphagia, ptosis and proximal limb weakness. OPMD is caused by the abnormal expansion of a (GCG)n trinucleotide repeat in the coding region of the poly-(A) binding protein nuclear 1 (PABPN1) gene. In unaffected individuals, (GCG)6 codes for the first six alanines in a homopolymeric stretch of ten alanines. In most individuals with OPMD this (GCG)6 repeat is expanded to (GCG)8-13, leading to a stretch of 12-17 alanines in mutant PABPN1. PABPN1 with an expanded polyalanine tract forms aggregates consisting of tubular filaments within the nuclei of skeletal muscle fibers. We have developed a transgenic mouse model of OPMD that manifests progressive muscle weakness accompanied by intranuclear aggregates and TUNEL-stained nuclei in skeletal muscle fibers. The onset and severity of these abnormalities were substantially delayed and attenuated by doxycycline treatment, which may exert its therapeutic effect by reducing aggregates and by distinct antiapoptotic properties. Doxycycline may represent a safe and feasible therapeutic for this disease.", + "TAG_DATA": [ + "130, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "131, mouse {'context': 'I-organism'}", + "132, model {'context': 'I-organism'}", + "148, skeletal {'context': 'B-cells'}", + "149, muscle {'context': 'I-cells'}", + "150, fibers. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "130, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "131, mouse ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "132, model ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "133, of ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "134, OPMD ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "148, skeletal ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "149, muscle ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "150, fibers. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "skeletal", + "muscle", + "fibers." + ] + } + } + ] + }, + { + "PMID": "15735652", + "TEXT": "Increased glucose production is a hallmark of type 2 diabetes and alterations in lipid metabolism have a causative role in its pathophysiology. Here we postulate that physiological increments in plasma fatty acids can be sensed within the hypothalamus and that this sensing is required to balance their direct stimulatory action on hepatic gluconeogenesis. In the presence of physiologically-relevant increases in the levels of plasma fatty acids, negating their central action on hepatic glucose fluxes through (i) inhibition of the hypothalamic esterification of fatty acids, (ii) genetic deletion (Sur1-deficient mice) of hypothalamic K(ATP) channels or pharmacological blockade (K(ATP) blocker) of their activation by fatty acids, or (iii) surgical resection of the hepatic branch of the vagus nerve led to a marked increase in liver glucose production. These findings indicate that a physiological elevation in circulating lipids can be sensed within the hypothalamus and that a defect in hypothalamic lipid sensing disrupts glucose homeostasis.", + "TAG_DATA": [ + "85, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "86, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "87, (Sur1-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "88, mice) {'context': 'B-organism'}", + "89, of {'perturbing_action': 'I-gene loss-of-function'}", + "90, hypothalamic {'perturbing_action': 'I-gene loss-of-function'}", + "91, K(ATP) {'perturbing_action': 'I-gene loss-of-function'}", + "92, channels {'perturbing_action': 'I-gene loss-of-function'}", + "94, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "96, (K(ATP) {'perturbing_action': 'I-pharmacological inhibition'}", + "97, blocker) {'perturbing_action': 'I-pharmacological inhibition'}", + "106, surgical {'perturbing_action': 'B-gene loss-of-function'}", + "107, resection {'perturbing_action': 'I-gene loss-of-function'}", + "108, of {'perturbing_action': 'I-gene loss-of-function'}", + "109, the {'perturbing_action': 'I-gene loss-of-function'}", + "110, hepatic {'perturbing_action': 'I-gene loss-of-function'}", + "111, branch {'perturbing_action': 'I-gene loss-of-function'}", + "112, of {'perturbing_action': 'I-gene loss-of-function'}", + "113, the {'perturbing_action': 'I-gene loss-of-function'}", + "114, vagus {'perturbing_action': 'I-gene loss-of-function'}", + "115, nerve {'perturbing_action': 'I-gene loss-of-function'}", + "122, liver {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "85, genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "86, deletion ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "87, (Sur1-deficient ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "88, mice) ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "89, of ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "90, hypothalamic ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26', 'l27', 'l28']", + "91, K(ATP) ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l29', 'l30', 'l31']", + "92, channels ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l29']", + "94, pharmacological ['l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "96, (K(ATP) ['l32', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "97, blocker) ['l33', 'l45', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "106, surgical ['l34', 'l46', 'l57', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "107, resection ['l35', 'l47', 'l58', 'l68', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "108, of ['l36', 'l48', 'l59', 'l69', 'l78', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "109, the ['l37', 'l49', 'l60', 'l70', 'l79', 'l87', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "110, hepatic ['l38', 'l50', 'l61', 'l71', 'l80', 'l88', 'l95', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "111, branch ['l39', 'l51', 'l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l108', 'l109', 'l110', 'l111', 'l112']", + "112, of ['l40', 'l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l108', 'l113', 'l114', 'l115', 'l116']", + "113, the ['l41', 'l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l109', 'l113', 'l117', 'l118', 'l119']", + "114, vagus ['l42', 'l54', 'l65', 'l75', 'l84', 'l92', 'l99', 'l105', 'l110', 'l114', 'l117', 'l120', 'l121']", + "115, nerve ['l27', 'l30', 'l43', 'l55', 'l66', 'l76', 'l85', 'l93', 'l100', 'l106', 'l111', 'l115', 'l118', 'l120', 'l122']", + "122, liver ['l28', 'l31', 'l44', 'l56', 'l67', 'l77', 'l86', 'l94', 'l101', 'l107', 'l112', 'l116', 'l119', 'l121', 'l122']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "(Sur1-deficient", + "of", + "hypothalamic", + "K(ATP)", + "channels" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "hypothalamic", + "K(ATP)", + "surgical", + "resection", + "of", + "the", + "hepatic", + "branch", + "vagus", + "nerve" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "(K(ATP)", + "blocker)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "15685171", + "TEXT": "Estrogen sulfotransferase (EST, encoded by SULT1E1) catalyzes the sulfoconjugation and inactivation of estrogens. Despite decades of biochemical study and the recognition that high levels of estrogen sulfates circulate in the blood of pregnant and nonpregnant women, the physiological role of estrogen sulfation remains poorly understood. Here we show that ablation of the mouse Sult1e1 gene caused placental thrombosis and spontaneous fetal loss. This phenotype was associated with elevated free estrogen levels systemically and in the amniotic fluid, increased tissue factor expression in the placenta and heightened platelet sensitivity to agonist-induced activation ex vivo. Treatment of pregnant Sult1e1-null mice with either an anticoagulant or antiestrogen prevented the fetal loss phenotype. Our results thus identify Est as a critical estrogen modulator in the placenta and suggest a link between estrogen excess and thrombotic fetal loss. These findings may have implications for understanding and treating human pregnancy failure and intrauterine growth retardation.", + "TAG_DATA": [ + "49, ablation {'perturbing_action': 'B-gene loss-of-function'}", + "50, of {'perturbing_action': 'I-gene loss-of-function'}", + "51, the {'perturbing_action': 'I-gene loss-of-function'}", + "52, mouse {'perturbing_action': 'I-gene loss-of-function'}", + "53, Sult1e1 {'perturbing_action': 'I-gene loss-of-function'}", + "54, gene {'perturbing_action': 'I-gene loss-of-function'}", + "86, platelet {'context': 'B-cells'}", + "96, Sult1e1-null {'perturbing_action': 'B-gene loss-of-function'}", + "97, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "49, ablation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "50, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "51, the ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "52, mouse ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "53, Sult1e1 ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "54, gene ['l4', 'l9', 'l13', 'l16', 'l18']", + "86, platelet ['l5', 'l10', 'l14', 'l17', 'l19']", + "96, Sult1e1-null ['l20']", + "97, mice ['l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablation", + "of", + "the", + "mouse", + "Sult1e1" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelet" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sult1e1-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15665833", + "TEXT": "Although microglial activation occurs in inflammatory, degenerative and neoplastic central nervous system (CNS) disorders, its role in pathogenesis is unclear. We studied this question by generating CD11b-HSVTK transgenic mice, which express herpes simplex thymidine kinase in macrophages and microglia. Ganciclovir treatment of organotypic brain slice cultures derived from CD11b-HSVTK mice abolished microglial release of nitrite, proinflammatory cytokines and chemokines. Systemic ganciclovir administration to CD11b-HSVTK mice elicited hematopoietic toxicity, which was prevented by transfer of wild-type bone marrow. In bone marrow chimeras, ganciclovir blocked microglial activation in the facial nucleus upon axotomy and repressed the development of experimental autoimmune encephalomyelitis. We conclude that microglial paralysis inhibits the development and maintenance of inflammatory CNS lesions. The microglial compartment thus provides a potential therapeutic target in inflammatory CNS disorders. These results validate CD11b-HSVTK mice as a tool to study the impact of microglial activation on CNS diseases in vivo.", + "TAG_DATA": [ + "26, CD11b-HSVTK {'perturbing_action': 'B-gene gain-of-function'}", + "27, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "28, mice, {'context': 'B-organism'}", + "42, organotypic {'context': 'B-cells'}", + "43, brain {'context': 'I-cells'}", + "44, slice {'context': 'I-cells'}", + "45, cultures {'context': 'I-cells'}", + "48, CD11b-HSVTK {'perturbing_action': 'B-other'}", + "49, mice {'context': 'B-organism'}", + "63, CD11b-HSVTK {'perturbing_action': 'B-other'}", + "64, mice {'context': 'B-organism'}", + "78, bone {'context': 'B-cells'}", + "79, marrow {'context': 'I-cells'}", + "87, facial {'context': 'B-tissue/organ'}", + "88, nucleus {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "26, CD11b-HSVTK ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "27, transgenic ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "28, mice, ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "42, organotypic ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "43, brain ['l3', 'l10', 'l16', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "44, slice ['l4', 'l11', 'l17', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "45, cultures ['l5', 'l12', 'l18', 'l23', 'l28', 'l32', 'l36', 'l37', 'l38']", + "48, CD11b-HSVTK ['l6', 'l13', 'l19', 'l24', 'l29', 'l33', 'l36', 'l39', 'l40']", + "49, mice ['l7', 'l14', 'l20', 'l25', 'l30', 'l34', 'l37', 'l39']", + "63, CD11b-HSVTK ['l41']", + "64, mice ['l26', 'l31', 'l35', 'l38', 'l40', 'l41']", + "78, bone ['l42', 'l43', 'l44', 'l45']", + "79, marrow ['l42', 'l46', 'l47', 'l48']", + "80, chimeras, ['l43', 'l46', 'l49', 'l50']", + "87, facial ['l44', 'l47', 'l49', 'l51']", + "88, nucleus ['l45', 'l48', 'l50', 'l51']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "CD11b-HSVTK", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "CD11b-HSVTK", + "transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "organotypic", + "brain", + "slice", + "cultures" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "CD11b-HSVTK" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "organotypic", + "brain", + "slice", + "cultures" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "CD11b-HSVTK" + ] + } + } + ] + }, + { + "PMID": "15619627", + "TEXT": "The use of animal organs could potentially alleviate the critical worldwide shortage of donor organs for clinical transplantation. Because of the strong immune response to xenografts, success will probably depend upon new strategies of immune suppression and induction of tolerance. Here we report our initial results using alpha-1,3-galactosyltransferase knockout (GalT-KO) donors and a tolerance induction approach. We have achieved life-supporting pig-to-baboon renal xenograft survivals of up to 83 d with normal creatinine levels.", + "TAG_DATA": [ + "47, alpha-1,3-galactosyltransferase {'perturbing_action': 'B-gene loss-of-function'}", + "48, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "49, (GalT-KO) {'perturbing_action': 'I-gene loss-of-function'}", + "60, pig-to-baboon {'context': 'B-xenograft'}", + "61, renal {'context': 'I-xenograft'}", + "62, xenograft {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "47, alpha-1,3-galactosyltransferase ['l0', 'l1', 'l2', 'l3', 'l4']", + "48, knockout ['l0', 'l5', 'l6', 'l7', 'l8']", + "49, (GalT-KO) ['l1', 'l5', 'l9', 'l10', 'l11']", + "60, pig-to-baboon ['l2', 'l6', 'l9', 'l12', 'l13']", + "61, renal ['l3', 'l7', 'l10', 'l12', 'l14']", + "62, xenograft ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha-1,3-galactosyltransferase", + "knockout", + "(GalT-KO)" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "pig-to-baboon", + "renal", + "xenograft" + ] + } + } + ] + }, + { + "PMID": "15531891", + "TEXT": "Innate immune responses provide the host with an early protection barrier against infectious agents, including viruses, and help shape the nature and quality of the subsequent adaptive immune responses of the host. Expression of ISG15 (UCRP), a ubiquitin-like protein, and protein ISGylation are highly increased upon viral infection. We have identified UBP43 (USP18) as an ISG15 deconjugating protease. Protein ISGylation is enhanced in cells deficient in UBP43 (ref. 6). Here we have examined the role of UBP43, encoded by the gene Usp18, in innate immunity to virus infection. Usp18(-/-) mice were resistant to the fatal lymphocytic choriomeningitis and myeloencephalitis that developed in wild-type mice after intracerebral inoculation with lymphocytic choriomeningitis virus (LCMV) or vesicular stomatitis virus (VSV), respectively. Survival of Usp18(-/-) mice after intracerebral LCMV infection correlated with a severe inhibition of LCMV RNA replication and antigen expression in the brain and increased levels of protein ISGylation. Consistent with these findings, mouse embryonic fibroblasts (MEF) and bone marrow-derived macrophages from Usp18(-/-) mice showed restricted LCMV replication. Moreover, MEF from Usp18(-/-) mice showed enhanced interferon-mediated resistance to the cytopathic effect caused by VSV and Sindbis virus (SNV). This report provides the first direct evidence that the ISG15 protease UBP43 and possibly protein ISGylation have a role in innate immunity against viral infection.", + "TAG_DATA": [ + "88, Usp18(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "89, mice {'context': 'B-organism'}", + "103, mice {'context': 'B-organism'}", + "120, Usp18(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "121, mice {'context': 'B-organism'}", + "151, mouse {'context': 'B-cells'}", + "152, embryonic {'context': 'I-cells'}", + "153, fibroblasts {'context': 'I-cells'}", + "154, (MEF) {'context': 'I-cells'}", + "156, bone {'context': 'B-cells'}", + "157, marrow-derived {'context': 'I-cells'}", + "158, macrophages {'context': 'I-cells'}", + "160, Usp18(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "161, mice {'context': 'B-organism'}", + "167, MEF {'context': 'B-cells'}", + "169, Usp18(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "170, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "88, Usp18(-/-) ['l0']", + "89, mice ['l0']", + "120, Usp18(-/-) ['l1', 'l2', 'l3', 'l4']", + "121, mice ['l1', 'l5', 'l6']", + "151, mouse ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "152, embryonic ['l2', 'l7', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "153, fibroblasts ['l3', 'l5', 'l8', 'l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "154, (MEF) ['l4', 'l6', 'l9', 'l16', 'l22', 'l28', 'l29', 'l30', 'l31', 'l32']", + "156, bone ['l10', 'l17', 'l23', 'l28', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "157, marrow-derived ['l11', 'l18', 'l24', 'l29', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "158, macrophages ['l12', 'l19', 'l25', 'l30', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47']", + "160, Usp18(-/-) ['l13', 'l20', 'l26', 'l31', 'l35', 'l40', 'l44', 'l48']", + "161, mice ['l14', 'l21', 'l27', 'l32', 'l36', 'l41', 'l45', 'l48']", + "167, MEF ['l49', 'l50']", + "169, Usp18(-/-) ['l37', 'l42', 'l46', 'l49', 'l51']", + "170, mice ['l38', 'l43', 'l47', 'l50', 'l51']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Usp18(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Usp18(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "embryonic", + "fibroblasts", + "(MEF)", + "mouse", + "bone", + "marrow-derived", + "macrophages", + "MEF" + ] + } + } + ] + }, + { + "PMID": "15502844", + "TEXT": "The Arctic mutation within the amyloid-beta (Abeta) peptide causes Alzheimer disease. In vitro, Arctic-mutant Abeta forms (proto)fibrils more effectively than wild-type Abeta. We generated transgenic mouse lines expressing Arctic-mutant human amyloid precursor proteins (hAPP). Amyloid plaques formed faster and were more extensive in Arctic mice than in hAPP mice expressing wild-type Abeta, even though Arctic mice had lower Abeta(1-42/1-40) ratios. Thus, the Arctic mutation is highly amyloidogenic in vivo.", + "TAG_DATA": [ + "24, transgenic {'perturbing_action': 'B-gene gain-of-function', 'context': 'B-xenograft'}", + "25, mouse {'context': 'I-organism'}", + "26, lines {'context': 'I-organism'}", + "28, Arctic-mutant {'perturbing_action': 'B-other'}", + "29, human {'perturbing_action': 'I-other'}", + "30, amyloid {'perturbing_action': 'I-other'}", + "31, precursor {'perturbing_action': 'I-other'}", + "32, proteins {'perturbing_action': 'I-other'}", + "33, (hAPP). {'perturbing_action': 'I-other'}", + "44, mice {'context': 'B-organism'}", + "48, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "24, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "25, mouse ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "26, lines ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "28, Arctic-mutant ['l2', 'l10', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "29, human ['l3', 'l11', 'l18', 'l23', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "30, amyloid ['l4', 'l12', 'l19', 'l24', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "31, precursor ['l5', 'l13', 'l20', 'l25', 'l30', 'l35', 'l40', 'l41', 'l42', 'l43']", + "32, proteins ['l6', 'l14', 'l21', 'l26', 'l31', 'l36', 'l40', 'l44', 'l45']", + "33, (hAPP). ['l7', 'l15', 'l22', 'l27', 'l32', 'l37', 'l41', 'l44', 'l46']", + "44, mice ['l8', 'l16', 'l28', 'l33', 'l38', 'l42', 'l45', 'l46']", + "48, mice ['l34', 'l39', 'l43']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "lines", + "mice" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "transgenic" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Arctic-mutant", + "human", + "amyloid", + "precursor", + "proteins", + "(hAPP)." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "lines", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Arctic-mutant", + "human", + "amyloid", + "precursor", + "proteins", + "(hAPP)." + ] + } + } + ] + }, + { + "PMID": "15502842", + "TEXT": "High-density array comparative genomic hybridization (CGH) showed amplification of chromosome 1q22 centered on the RAB25 small GTPase, which is implicated in apical vesicle trafficking, in approximately half of ovarian and breast cancers. RAB25 mRNA levels were selectively increased in stage III and IV serous epithelial ovarian cancers compared to other genes within the amplified region, implicating RAB25 as a driving event in the development of the amplicon. Increased DNA copy number or RNA level of RAB25 was associated with markedly decreased disease-free survival or overall survival in ovarian and breast cancers, respectively. Forced expression of RAB25 markedly increased anchorage-dependent and anchorage-independent cell proliferation, prevented apoptosis and anoikis, including that induced by chemotherapy, and increased aggressiveness of cancer cells in vivo. The inhibition of apoptosis was associated with a decrease in expression of the proapoptotic molecules, BAK and BAX, and activation of the antiapoptotic phosphatidylinositol 3 kinase (PI3K) and AKT pathway, providing potential mechanisms for the effects of RAB25 on tumor aggressiveness. Overall, these studies implicate RAB25, and thus the RAB family of small G proteins, in aggressiveness of epithelial cancers.", + "TAG_DATA": [ + "92, Forced {'perturbing_action': 'B-gene gain-of-function'}", + "93, expression {'perturbing_action': 'I-gene gain-of-function'}", + "94, of {'perturbing_action': 'I-gene gain-of-function'}", + "95, RAB25 {'perturbing_action': 'I-gene gain-of-function'}", + "97, increased {'effect': 'B-positive'}", + "101, cell {'context': 'I-cells'}", + "102, proliferation, {'phenotype': 'B-proliferation'}", + "103, prevented {'effect': 'B-negative'}", + "104, apoptosis {'phenotype': 'B-apoptosis'}", + "116, cancer {'context': 'B-transformed cells'}", + "117, cells {'context': 'I-transformed cells'}", + "118, in {'context': 'B-in vivo'}", + "119, vivo. {'context': 'I-in vivo'}", + "121, inhibition {'effect': 'B-negative'}", + "123, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "92, Forced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "93, expression ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "94, of ['l1', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "95, RAB25 ['l2', 'l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "97, increased ['l3', 'l14', 'l23', 'l31', 'l37', 'l38']", + "101, cell ['l4', 'l15', 'l24', 'l32', 'l37', 'l39']", + "102, proliferation, ['l5', 'l16', 'l25', 'l33', 'l38', 'l39']", + "103, prevented ['l6', 'l17', 'l26', 'l34', 'l40']", + "104, apoptosis ['l7', 'l18', 'l27', 'l35', 'l40']", + "116, cancer ['l8', 'l19', 'l28', 'l41', 'l42', 'l43']", + "117, cells ['l9', 'l20', 'l29', 'l36', 'l41', 'l44', 'l45']", + "118, in ['l10', 'l42', 'l44', 'l46']", + "119, vivo. ['l11', 'l21', 'l30', 'l43', 'l45', 'l46']", + "121, inhibition ['l47']", + "123, apoptosis ['l47']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "expression", + "of", + "RAB25" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "expression", + "of", + "RAB25" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "expression", + "of", + "RAB25" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "expression", + "of", + "RAB25" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "expression", + "of", + "RAB25" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "expression", + "of", + "RAB25" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "expression", + "of" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented", + "inhibition" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "15489858", + "TEXT": "The antiphospholipid syndrome (APS) is defined by thrombosis and recurrent pregnancy loss in the presence of antiphospholipid (aPL) antibodies and is generally treated with anticoagulation therapy. Because complement activation is essential and causative in aPL antibody-induced fetal injury, we hypothesized that heparin protects pregnant APS patients from complications through inhibition of complement. Treatment with heparin (unfractionated or low molecular weight) prevented complement activation in vivo and in vitro and protected mice from pregnancy complications induced by aPL antibodies. Neither fondaparinux nor hirudin, other anticoagulants, inhibited the generation of complement split products or prevented pregnancy loss, demonstrating that anticoagulation therapy is insufficient protection against APS-associated miscarriage. Our data indicate that heparins prevent obstetrical complications in women with APS because they block activation of complement induced by aPL antibodies targeted to decidual tissues, rather than by their anticoagulant effects.", + "TAG_DATA": [ + "63, in {'context': 'B-in vivo'}", + "64, vivo {'context': 'I-in vivo'}", + "66, in {'context': 'B-in vitro'}", + "67, vitro {'context': 'I-in vitro'}", + "70, mice {'context': 'B-organism'}", + "92, prevented {'effect': 'B-negative'}", + "93, pregnancy {'phenotype': 'B-cell survival'}", + "94, loss, {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "63, in ['l0', 'l1', 'l2', 'l3']", + "64, vivo ['l0', 'l4', 'l5']", + "66, in ['l1', 'l6', 'l7']", + "67, vitro ['l2', 'l4', 'l6', 'l8']", + "70, mice ['l3', 'l5', 'l7', 'l8']", + "92, prevented ['l9', 'l10']", + "93, pregnancy ['l9', 'l11']", + "94, loss, ['l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "pregnancy" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "loss," + ] + } + } + ] + }, + { + "PMID": "15448683", + "TEXT": "Inactivation of the adenosine A(2A) receptor (A(2A)R) consistently protects against ischemic brain injury and other neural insults, but the relative contribution of A(2A)Rs on peripheral inflammatory cells versus A(2A)Rs expressed on neurons and glia is unknown. We created a chimeric mouse model in which A(2A)Rs on bone marrow-derived cells (BMDCs) were selectively inactivated or reconstituted by bone marrow transplantation. Selective reconstitution of A(2A)Rs on BMDCs (A(2A)R knockout mice transplanted with wild-type bone marrow cells) largely reinstates ischemic brain injury in global A(2A)R knockout mice. Conversely, selective inactivation of A(2A)Rs on BMDCs (wild-type mice transplanted with A(2A)R knockout bone marrow cells) attenuates infarct volumes and ischemia-induced expression of several proinflammatory cytokines in the brain, but exacerbates ischemic liver injury. These results indicate that the A(2A)R-stimulated cascade in BMDCs is an important modulator of ischemic brain injury and that ischemic brain and liver injuries are regulated distinctly by A(2A)Rs on BMDCs.", + "TAG_DATA": [ + "39, chimeric {'context': 'B-organism'}", + "40, mouse {'context': 'I-organism'}", + "41, model {'context': 'I-organism'}", + "46, bone {'context': 'B-cells'}", + "47, marrow-derived {'context': 'I-cells'}", + "48, cells {'context': 'I-cells'}", + "49, (BMDCs) {'context': 'I-cells'}", + "64, BMDCs {'context': 'B-cells'}", + "66, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "67, mice {'context': 'B-organism'}", + "71, bone {'context': 'B-cells'}", + "72, marrow {'context': 'I-cells'}", + "73, cells) {'context': 'I-cells'}", + "80, global {'perturbing_action': 'B-gene loss-of-function'}", + "81, A(2A)R {'perturbing_action': 'B-gene loss-of-function'}", + "82, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "83, mice. {'context': 'B-organism'}", + "85, selective {'perturbing_action': 'B-gene loss-of-function'}", + "86, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "87, of {'perturbing_action': 'I-gene loss-of-function'}", + "88, A(2A)Rs {'perturbing_action': 'I-gene loss-of-function'}", + "90, BMDCs {'context': 'B-cells'}", + "92, mice {'context': 'B-organism'}", + "95, A(2A)R {'perturbing_action': 'B-gene loss-of-function'}", + "96, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "97, bone {'context': 'B-cells'}", + "98, marrow {'context': 'I-cells'}", + "99, cells) {'context': 'I-cells'}", + "112, brain, {'context': 'B-tissue/organ'}", + "116, liver {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "39, chimeric ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "40, mouse ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "41, model ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "46, bone ['l2', 'l7', 'l11', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "47, marrow-derived ['l3', 'l8', 'l12', 'l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "48, cells ['l4', 'l9', 'l13', 'l16', 'l22', 'l28', 'l29', 'l30']", + "49, (BMDCs) ['l5', 'l10', 'l14', 'l17', 'l23', 'l28', 'l31', 'l32', 'l33']", + "64, BMDCs ['l18', 'l24', 'l29', 'l31', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "66, knockout ['l19', 'l25', 'l34', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "67, mice ['l35', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "71, bone ['l36', 'l44', 'l51', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "72, marrow ['l37', 'l45', 'l52', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "73, cells) ['l38', 'l46', 'l53', 'l59', 'l64', 'l69', 'l70', 'l71', 'l72']", + "80, global ['l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l73', 'l74', 'l75']", + "81, A(2A)R ['l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l76', 'l77']", + "82, knockout ['l20', 'l26', 'l30', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l78']", + "83, mice. ['l21', 'l27', 'l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l77', 'l78']", + "85, selective ['l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "86, inactivation ['l79', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "87, of ['l80', 'l91', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "88, A(2A)Rs ['l81', 'l92', 'l102', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "90, BMDCs ['l82', 'l93', 'l103', 'l112', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "92, mice ['l83', 'l94', 'l104', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "95, A(2A)R ['l84', 'l95', 'l105', 'l113', 'l120', 'l127', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139']", + "96, knockout ['l85', 'l96', 'l106', 'l114', 'l121', 'l128', 'l134', 'l140', 'l141', 'l142', 'l143', 'l144']", + "97, bone ['l86', 'l97', 'l107', 'l115', 'l122', 'l129', 'l135', 'l140', 'l145', 'l146', 'l147', 'l148']", + "98, marrow ['l87', 'l98', 'l108', 'l116', 'l123', 'l130', 'l136', 'l141', 'l145', 'l149', 'l150', 'l151']", + "99, cells) ['l88', 'l99', 'l109', 'l117', 'l124', 'l131', 'l137', 'l142', 'l146', 'l149', 'l152', 'l153']", + "112, brain, ['l89', 'l100', 'l110', 'l118', 'l125', 'l132', 'l138', 'l143', 'l147', 'l150', 'l152', 'l154']", + "116, liver ['l90', 'l101', 'l111', 'l119', 'l126', 'l133', 'l139', 'l144', 'l148', 'l151', 'l153', 'l154']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "bone", + "marrow-derived", + "cells", + "(BMDCs)", + "BMDCs", + "marrow", + "cells)" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout", + "global", + "A(2A)R", + "selective", + "inactivation", + "of", + "A(2A)Rs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout", + "global", + "A(2A)R", + "selective", + "inactivation", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "inactivation", + "of", + "A(2A)Rs", + "A(2A)R", + "knockout" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain,", + "liver" + ] + } + } + ] + }, + { + "PMID": "15378054", + "TEXT": "Ectopic pregnancy is a major reproductive health issue. Although other underlying causes remain largely unknown, one cause of ectopic pregnancy is embryo retention in the fallopian tube. Here we show that genetic or pharmacologic silencing of cannabinoid receptor CB1 causes retention of a large number of embryos in the mouse oviduct, eventually leading to pregnancy failure. This is reversed by isoproterenol, a beta-adrenergic receptor agonist. Impaired oviductal embryo transport is also observed in wild-type mice treated with methanandamide. Collectively, the results suggest that aberrant cannabinoid signaling impedes coordinated oviductal smooth muscle contraction and relaxation crucial to normal oviductal embryo transport. Colocalization of CB1 and beta2-adrenergic receptors in the oviduct muscularis implies that a basal endocannabinoid tone in collaboration with adrenergic receptors coordinates oviductal motility for normal journey of embryos into the uterus. Besides uncovering a new regulatory mechanism, this study could be clinically relevant to ectopic pregnancy.", + "TAG_DATA": [ + "33, pharmacologic {'perturbing_action': 'B-rnai/knockdown'}", + "34, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "35, of {'perturbing_action': 'I-rnai/knockdown'}", + "36, cannabinoid {'perturbing_action': 'I-rnai/knockdown'}", + "37, receptor {'perturbing_action': 'I-rnai/knockdown'}", + "38, CB1 {'perturbing_action': 'I-rnai/knockdown'}", + "49, mouse {'context': 'B-tissue/organ'}", + "50, oviduct, {'context': 'I-tissue/organ'}", + "74, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "33, pharmacologic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "34, silencing ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "35, of ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "36, cannabinoid ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "37, receptor ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "38, CB1 ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "49, mouse ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "50, oviduct, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "pharmacologic", + "silencing", + "of", + "cannabinoid", + "receptor", + "CB1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "oviduct," + ] + } + } + ] + }, + { + "PMID": "15273748", + "TEXT": "X-linked immunodeficiency with hyper-IgM (HIGM1), characterized by failure of immunoglobulin isotype switching, is caused by mutations of the CD40 ligand (CD40L), which is normally expressed on activated CD4(+) T cells. As constitutive expression of CD40L induces lymphomas, we corrected the mutation while preserving the natural regulation of CD40L using pre-mRNA trans-splicing. Bone marrow from mice lacking CD40L was modified with a lentivirus trans-splicer encoding the normal CD40L exons 2-5 and was administered to syngenic CD40L-knockout mice. Recipient mice had corrected CD40L mRNA, antigen-specific IgG1 responses to keyhole limpet hemocyanin immunization, regulated CD4(+) T-cell CD40L expression after CD3 stimulation in primary and secondary transplanted mice, attenuation of Pneumocystis carinii pneumonia, and no evidence of lymphoproliferative disease over 1 year. Thus, HIGM1 can be corrected by CD40L trans-splicing, leading to functional correction of the genetic defect without the adverse consequences of unregulated expression of the CD40L gene.", + "TAG_DATA": [ + "51, Bone {'context': 'B-cells'}", + "52, marrow {'context': 'I-cells'}", + "54, mice {'context': 'B-organism'}", + "55, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "56, CD40L {'perturbing_action': 'I-gene loss-of-function'}", + "73, syngenic {'perturbing_action': 'B-gene loss-of-function'}", + "74, CD40L-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "75, mice. {'context': 'B-organism'}", + "77, mice {'context': 'I-organism'}", + "91, CD4(+) {'context': 'B-cells'}", + "100, and {'context': 'I-cells'}", + "101, secondary {'context': 'I-cells'}", + "103, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "51, Bone ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "52, marrow ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "54, mice ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "55, lacking ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "56, CD40L ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "73, syngenic ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "74, CD40L-knockout ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27', 'l28']", + "75, mice. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "77, mice ['l28', 'l29', 'l30', 'l31', 'l32']", + "91, CD4(+) ['l33', 'l34', 'l35', 'l36']", + "100, and ['l29', 'l33', 'l37', 'l38', 'l39']", + "101, secondary ['l30', 'l34', 'l37', 'l40', 'l41']", + "102, transplanted ['l31', 'l35', 'l38', 'l40', 'l42']", + "103, mice, ['l32', 'l36', 'l39', 'l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Bone", + "marrow" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "CD40L", + "syngenic", + "CD40L-knockout" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "CD40L", + "syngenic", + "CD40L-knockout" + ] + } + } + ] + }, + { + "PMID": "15184894", + "TEXT": "Several congenital muscular dystrophies caused by defects in known or putative glycosyltransferases are commonly associated with hypoglycosylation of alpha-dystroglycan (alpha-DG) and a marked reduction of its receptor function. We have investigated changes in the processing and function of alpha-DG resulting from genetic manipulation of LARGE, the putative glycosyltransferase mutated both in Large(myd) mice and in humans with congenital muscular dystrophy 1D (MDC1D). Here we show that overexpression of LARGE ameliorates the dystrophic phenotype of Large(myd) mice and induces the synthesis of glycan-enriched alpha-DG with high affinity for extracellular ligands. Notably, LARGE circumvents the alpha-DG glycosylation defect in cells from individuals with genetically distinct types of congenital muscular dystrophy. Gene transfer of LARGE into the cells of individuals with congenital muscular dystrophies restores alpha-DG receptor function, whereby glycan-enriched alpha-DG coordinates the organization of laminin on the cell surface. Our findings indicate that modulation of LARGE expression or activity is a viable therapeutic strategy for glycosyltransferase-deficient congenital muscular dystrophies.", + "TAG_DATA": [ + "66, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "67, of {'perturbing_action': 'I-gene gain-of-function'}", + "68, LARGE {'perturbing_action': 'I-gene gain-of-function'}", + "74, Large(myd) {'perturbing_action': 'B-other'}", + "75, mice {'context': 'B-organism'}", + "97, cells {'context': 'B-cells'}", + "108, Gene {'perturbing_action': 'B-gene gain-of-function'}", + "109, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "110, of {'perturbing_action': 'I-gene gain-of-function'}", + "111, LARGE {'perturbing_action': 'I-gene gain-of-function'}", + "114, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "66, overexpression ['l0', 'l1', 'l2', 'l3', 'l4']", + "67, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "68, LARGE ['l1', 'l5', 'l9', 'l10', 'l11']", + "74, Large(myd) ['l2', 'l6', 'l9', 'l12', 'l13']", + "75, mice ['l3', 'l7', 'l10', 'l12']", + "97, cells ['l4', 'l8', 'l11', 'l13']", + "108, Gene ['l14', 'l15', 'l16', 'l17']", + "109, transfer ['l14', 'l18', 'l19', 'l20']", + "110, of ['l15', 'l18', 'l21', 'l22']", + "111, LARGE ['l16', 'l19', 'l21', 'l23']", + "114, cells ['l17', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "LARGE" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "LARGE", + "Gene", + "transfer" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Large(myd)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Large(myd)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "15156204", + "TEXT": "Central neurons regenerate axons if a permissive environment is provided; after spinal cord injury, however, inhibitory molecules are present that make the local environment nonpermissive. A promising new strategy for inducing neurons to overcome inhibitory signals is to activate cAMP signaling. Here we show that cAMP levels fall in the rostral spinal cord, sensorimotor cortex and brainstem after spinal cord contusion. Inhibition of cAMP hydrolysis by the phosphodiesterase IV inhibitor rolipram prevents this decrease and when combined with Schwann cell grafts promotes significant supraspinal and proprioceptive axon sparing and myelination. Furthermore, combining rolipram with an injection of db-cAMP near the graft not only prevents the drop in cAMP levels but increases them above those in uninjured controls. This further enhances axonal sparing and myelination, promotes growth of serotonergic fibers into and beyond grafts, and significantly improves locomotion. These findings show that cAMP levels are key for protection, growth and myelination of injured CNS axons in vivo and recovery of function.", + "TAG_DATA": [ + "78, Schwann {'context': 'B-xenograft'}", + "79, cell {'context': 'I-xenograft'}", + "80, grafts {'context': 'I-xenograft'}", + "127, serotonergic {'context': 'B-cells'}", + "128, fibers {'context': 'I-cells'}", + "135, improves {'effect': 'B-positive'}", + "136, locomotion. {'phenotype': 'B-autophagy'}" + ], + "LINK_DATA": [ + "78, Schwann ['l0', 'l1']", + "79, cell ['l0', 'l2']", + "80, grafts ['l1', 'l2']", + "127, serotonergic ['l3', 'l4', 'l5']", + "128, fibers ['l3', 'l6', 'l7']", + "135, improves ['l4', 'l6', 'l8']", + "136, locomotion. ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "serotonergic", + "fibers" + ] + }, + "effect": { + "val": "positive", + "words": [ + "improves" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "serotonergic", + "fibers" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "locomotion." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "improves" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "locomotion." + ] + } + } + ] + }, + { + "PMID": "15122251", + "TEXT": "Many proteins and pathways of pharmaceutical interest impinge on ubiquitin ligases or their substrates. The cyclin-dependent kinase (Cdk) inhibitor p27, for example, is polyubiquitylated in a cell cycle-dependent manner by a ubiquitin ligase complex containing the F-box protein Skp2. Regulated turnover of p27 is due, at least partly, to its phosphorylation by Cdk2 on threonine 187, which generates a Skp2-binding site. We made a p27-luciferase (p27Luc) fusion protein and show here that its abundance, like that of p27, is regulated by Skp2 in a cell cycle-dependent manner. As predicted, p27Luc levels increased after blocking Cdk2 activity with inhibitory proteins, peptides or small interfering RNA (siRNA). Accumulation of p27Luc in response to Cdk2 inhibitory drugs (flavopiridol and R-roscovitine) was demonstrable in human tumor cells in vivo using noninvasive bioluminescent imaging. In theory, the approach described here could be used to develop bioluminescent reporters for any drug target that directly or indirectly affects the turnover of a ubiquitin ligase substrate.", + "TAG_DATA": [ + "93, blocking {'perturbing_action': 'B-pharmacological inhibition'}", + "94, Cdk2 {'perturbing_action': 'I-pharmacological inhibition'}", + "95, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "96, with {'perturbing_action': 'I-pharmacological inhibition'}", + "111, Cdk2 {'perturbing_action': 'B-pharmacological inhibition'}", + "112, inhibitory {'perturbing_action': 'I-pharmacological inhibition'}", + "113, drugs {'perturbing_action': 'I-pharmacological inhibition'}", + "120, human {'context': 'B-transformed cells'}", + "121, tumor {'context': 'I-transformed cells'}", + "122, cells {'context': 'I-transformed cells'}", + "123, in {'context': 'B-in vivo'}", + "124, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "93, blocking ['l0', 'l1', 'l2']", + "94, Cdk2 ['l0', 'l3', 'l4']", + "95, activity ['l1', 'l3', 'l5']", + "96, with ['l2', 'l4', 'l5']", + "111, Cdk2 ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "112, inhibitory ['l6', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "113, drugs ['l7', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "120, human ['l8', 'l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "121, tumor ['l9', 'l15', 'l20', 'l24', 'l28', 'l29', 'l30']", + "122, cells ['l10', 'l16', 'l21', 'l25', 'l28', 'l31', 'l32']", + "123, in ['l11', 'l17', 'l22', 'l26', 'l29', 'l31', 'l33']", + "124, vivo ['l12', 'l18', 'l23', 'l27', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Cdk2", + "inhibitory", + "drugs" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Cdk2", + "inhibitory", + "drugs" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "15107843", + "TEXT": "CD1d is a major histocompatibility complex (MHC) class I-related molecule that functions in glycolipid antigen presentation to distinct subsets of T cells that express natural killer receptors and an invariant T-cell receptor-alpha chain (invariant NKT cells). The acquisition of glycolipid antigens by CD1d occurs, in part, in endosomes through the function of resident lipid transfer proteins, namely saposins. Here we show that microsomal triglyceride transfer protein (MTP), a protein that resides in the endoplasmic reticulum of hepatocytes and intestinal epithelial cells (IECs) and is essential for lipidation of apolipoprotein B, associates with CD1d in hepatocytes. Hepatocytes from animals in which Mttp (the gene encoding MTP) has been conditionally deleted, and IECs in which Mttp gene products have been silenced, are unable to activate invariant NKT cells. Conditional deletion of the Mttp gene in hepatocytes is associated with a redistribution of CD1d expression, and Mttp-deleted mice are resistant to immunopathologies associated with invariant NKT cell-mediated hepatitis and colitis. These studies indicate that the CD1d-regulating function of MTP in the endoplasmic reticulum is complementary to that of the saposins in endosomes in vivo.", + "TAG_DATA": [ + "95, Hepatocytes {'context': 'B-cells'}", + "97, animals {'context': 'B-organism'}", + "100, Mttp {'perturbing_action': 'B-gene loss-of-function'}", + "101, (the {'perturbing_action': 'I-gene loss-of-function'}", + "102, gene {'perturbing_action': 'I-gene loss-of-function'}", + "103, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "104, MTP) {'perturbing_action': 'I-gene loss-of-function'}", + "105, has {'perturbing_action': 'I-gene loss-of-function'}", + "106, been {'perturbing_action': 'I-gene loss-of-function'}", + "107, conditionally {'perturbing_action': 'I-gene loss-of-function'}", + "108, deleted, {'perturbing_action': 'I-gene loss-of-function'}", + "110, IECs {'context': 'B-cells'}", + "113, Mttp {'perturbing_action': 'B-rnai/knockdown'}", + "114, gene {'perturbing_action': 'I-rnai/knockdown'}", + "115, products {'perturbing_action': 'I-rnai/knockdown'}", + "116, have {'perturbing_action': 'I-rnai/knockdown'}", + "117, been {'perturbing_action': 'I-rnai/knockdown'}", + "118, silenced, {'perturbing_action': 'I-rnai/knockdown'}", + "120, unable {'effect': 'B-no effect'}", + "123, invariant {'context': 'B-cells'}", + "124, NKT {'context': 'I-cells'}", + "125, cells. {'context': 'I-cells'}", + "126, Conditional {'perturbing_action': 'B-gene loss-of-function'}", + "127, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "128, of {'perturbing_action': 'I-gene loss-of-function'}", + "129, the {'perturbing_action': 'I-gene loss-of-function'}", + "130, Mttp {'perturbing_action': 'I-gene loss-of-function'}", + "131, gene {'perturbing_action': 'I-gene loss-of-function'}", + "133, hepatocytes {'context': 'B-cells'}", + "143, Mttp-deleted {'perturbing_action': 'B-gene loss-of-function'}", + "144, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "95, Hepatocytes ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "97, animals ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "100, Mttp ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "101, (the ['l2', 'l16', 'l29', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "102, gene ['l3', 'l17', 'l30', 'l43', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "103, encoding ['l4', 'l18', 'l31', 'l44', 'l56', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "104, MTP) ['l5', 'l19', 'l32', 'l45', 'l57', 'l68', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "105, has ['l6', 'l20', 'l33', 'l46', 'l58', 'l69', 'l79', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "106, been ['l7', 'l21', 'l34', 'l47', 'l59', 'l70', 'l80', 'l89', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "107, conditionally ['l8', 'l22', 'l35', 'l48', 'l60', 'l71', 'l81', 'l90', 'l98', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "108, deleted, ['l9', 'l23', 'l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l99', 'l106', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "110, IECs ['l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l100', 'l107', 'l113', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "113, Mttp ['l119', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "114, gene ['l120', 'l137', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "115, products ['l121', 'l138', 'l154', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184']", + "116, have ['l122', 'l139', 'l155', 'l170', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198']", + "117, been ['l123', 'l140', 'l156', 'l171', 'l185', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211']", + "118, silenced, ['l124', 'l141', 'l157', 'l172', 'l186', 'l199', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223']", + "120, unable ['l10', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l108', 'l114', 'l125', 'l142', 'l158', 'l173', 'l187', 'l200', 'l212', 'l224', 'l225', 'l226', 'l227']", + "122, activate ['l11', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l115', 'l126', 'l143', 'l159', 'l174', 'l188', 'l201', 'l213', 'l224', 'l228', 'l229', 'l230']", + "123, invariant ['l12', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l127', 'l144', 'l160', 'l175', 'l189', 'l202', 'l214', 'l225', 'l228', 'l231', 'l232']", + "124, NKT ['l13', 'l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l128', 'l145', 'l161', 'l176', 'l190', 'l203', 'l215', 'l226', 'l229', 'l231', 'l233']", + "125, cells. ['l14', 'l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l118', 'l129', 'l146', 'l162', 'l177', 'l191', 'l204', 'l216', 'l227', 'l230', 'l232', 'l233']", + "126, Conditional ['l130', 'l147', 'l163', 'l178', 'l192', 'l205', 'l217', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239']", + "127, deletion ['l131', 'l148', 'l164', 'l179', 'l193', 'l206', 'l218', 'l234', 'l240', 'l241', 'l242', 'l243', 'l244']", + "128, of ['l132', 'l149', 'l165', 'l180', 'l194', 'l207', 'l219', 'l235', 'l240', 'l245', 'l246', 'l247', 'l248']", + "129, the ['l133', 'l150', 'l166', 'l181', 'l195', 'l208', 'l220', 'l236', 'l241', 'l245', 'l249', 'l250', 'l251']", + "130, Mttp ['l134', 'l151', 'l167', 'l182', 'l196', 'l209', 'l221', 'l237', 'l242', 'l246', 'l249', 'l252', 'l253']", + "131, gene ['l135', 'l152', 'l168', 'l183', 'l197', 'l210', 'l222', 'l238', 'l243', 'l247', 'l250', 'l252', 'l254']", + "133, hepatocytes ['l136', 'l153', 'l169', 'l184', 'l198', 'l211', 'l223', 'l239', 'l244', 'l248', 'l251', 'l253', 'l254']", + "143, Mttp-deleted ['l255']", + "144, mice ['l255']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Hepatocytes", + "IECs", + "invariant", + "NKT", + "cells.", + "hepatocytes" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mttp", + "(the", + "gene", + "encoding", + "MTP)", + "has", + "been", + "conditionally", + "deleted,", + "Conditional", + "deletion", + "of", + "the" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Hepatocytes", + "IECs", + "invariant", + "NKT", + "cells." + ] + }, + "effect": { + "val": "no effect", + "words": [ + "unable" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animals", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mttp", + "(the", + "gene", + "encoding", + "MTP)", + "has", + "been", + "conditionally", + "deleted,", + "Mttp-deleted" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animals" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "unable" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mttp", + "(the", + "gene", + "encoding", + "MTP)", + "has", + "been", + "conditionally", + "deleted," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "unable" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "IECs", + "invariant", + "NKT", + "cells.", + "hepatocytes" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Mttp", + "gene", + "products", + "have", + "been", + "silenced," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Mttp", + "gene", + "products", + "have", + "been", + "silenced," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "unable" + ] + } + } + ] + }, + { + "PMID": "15048110", + "TEXT": "Peroxisome proliferator-activated receptor-delta (PPAR-delta; also known as PPAR-beta) is expressed at high levels in colon tumors, but its contribution to colon cancer is unclear. We examined the role of PPAR-delta in colon carcinogenesis using PPAR-delta-deficient (Ppard(-/-)) mice. In both the Min mutant and chemically induced mouse models, colon polyp formation was significantly greater in mice nullizygous for PPAR-delta. In contrast to previous reports suggesting that activation of PPAR-delta potentiates colon polyp formation, here we show that PPAR-delta attenuates colon carcinogenesis.", + "TAG_DATA": [ + "34, PPAR-delta-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "35, (Ppard(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "36, mice. {'context': 'B-organism'}", + "45, mouse {'context': 'B-organism'}", + "46, models, {'context': 'I-organism'}", + "54, mice {'context': 'B-organism'}", + "55, nullizygous {'perturbing_action': 'B-gene loss-of-function'}", + "56, for {'perturbing_action': 'I-gene gain-of-function'}", + "57, PPAR-delta. {'perturbing_action': 'I-gene gain-of-function'}", + "77, attenuates {'effect': 'B-negative'}", + "78, colon {'context': 'B-tissue/organ'}", + "79, carcinogenesis. {'phenotype': 'B-tumourigenesis'}" + ], + "LINK_DATA": [ + "34, PPAR-delta-deficient ['l0', 'l1', 'l2', 'l3', 'l4']", + "35, (Ppard(-/-)) ['l0', 'l5', 'l6', 'l7']", + "36, mice. ['l1', 'l5']", + "41, mutant ['l2', 'l6', 'l8']", + "45, mouse ['l3', 'l9', 'l10', 'l11']", + "46, models, ['l4', 'l7', 'l8', 'l9']", + "54, mice ['l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "55, nullizygous ['l12', 'l18', 'l19', 'l20', 'l21', 'l22']", + "56, for ['l13', 'l18', 'l23', 'l24', 'l25', 'l26']", + "57, PPAR-delta. ['l14', 'l19', 'l23', 'l27', 'l28', 'l29']", + "77, attenuates ['l15', 'l20', 'l24', 'l27', 'l30', 'l31']", + "78, colon ['l10', 'l16', 'l21', 'l25', 'l28', 'l30', 'l32']", + "79, carcinogenesis. ['l11', 'l17', 'l22', 'l26', 'l29', 'l31', 'l32']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PPAR-delta-deficient", + "(Ppard(-/-))", + "nullizygous" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mouse", + "models,", + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "carcinogenesis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "for", + "PPAR-delta." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuates" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nullizygous" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuates" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nullizygous" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "colon" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nullizygous" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "carcinogenesis." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "for", + "PPAR-delta." + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuates" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "for", + "PPAR-delta." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "colon" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "for", + "PPAR-delta." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "carcinogenesis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuates" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "colon" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuates" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "carcinogenesis." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "colon" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "carcinogenesis." + ] + } + } + ] + }, + { + "PMID": "14966518", + "TEXT": "The protein kinase C (PKC) family of serine/threonine kinases functions downstream of nearly all membrane-associated signal transduction pathways. Here we identify PKC-alpha as a fundamental regulator of cardiac contractility and Ca(2+) handling in myocytes. Hearts of Prkca-deficient mice are hypercontractile, whereas those of transgenic mice overexpressing Prkca are hypocontractile. Adenoviral gene transfer of dominant-negative or wild-type PKC-alpha into cardiac myocytes enhances or reduces contractility, respectively. Mechanistically, modulation of PKC-alpha activity affects dephosphorylation of the sarcoplasmic reticulum Ca(2+) ATPase-2 (SERCA-2) pump inhibitory protein phospholamban (PLB), and alters sarcoplasmic reticulum Ca(2+) loading and the Ca(2+) transient. PKC-alpha directly phosphorylates protein phosphatase inhibitor-1 (I-1), altering the activity of protein phosphatase-1 (PP-1), which may account for the effects of PKC-alpha on PLB phosphorylation. Hypercontractility caused by Prkca deletion protects against heart failure induced by pressure overload, and against dilated cardiomyopathy induced by deleting the gene encoding muscle LIM protein (Csrp3). Deletion of Prkca also rescues cardiomyopathy associated with overexpression of PP-1. Thus, PKC-alpha functions as a nodal integrator of cardiac contractility by sensing intracellular Ca(2+) and signal transduction events, which can profoundly affect propensity toward heart failure.", + "TAG_DATA": [ + "34, Hearts {'context': 'B-tissue/organ'}", + "36, Prkca-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "37, mice {'context': 'B-organism'}", + "43, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "44, mice {'perturbing_action': 'I-gene gain-of-function', 'context': 'I-organism'}", + "45, overexpressing {'perturbing_action': 'I-gene gain-of-function'}", + "46, Prkca {'perturbing_action': 'I-gene gain-of-function'}", + "49, Adenoviral {'perturbing_action': 'B-other'}", + "50, gene {'perturbing_action': 'I-other'}", + "51, transfer {'perturbing_action': 'I-other'}", + "52, of {'perturbing_action': 'I-other'}", + "53, dominant-negative {'perturbing_action': 'I-other'}", + "54, or {'perturbing_action': 'I-other'}", + "55, wild-type {'perturbing_action': 'I-other'}", + "56, PKC-alpha {'perturbing_action': 'I-other'}", + "58, cardiac {'context': 'B-cells'}", + "59, myocytes {'context': 'I-cells'}", + "122, Prkca {'perturbing_action': 'B-gene loss-of-function'}", + "123, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "138, deleting {'perturbing_action': 'B-gene loss-of-function'}", + "139, the {'perturbing_action': 'I-gene loss-of-function'}", + "140, gene {'perturbing_action': 'I-gene loss-of-function'}", + "141, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "142, muscle {'perturbing_action': 'I-gene loss-of-function'}", + "143, LIM {'perturbing_action': 'I-gene loss-of-function'}", + "144, protein {'perturbing_action': 'I-gene loss-of-function'}", + "145, (Csrp3). {'perturbing_action': 'I-gene loss-of-function'}", + "146, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "147, of {'perturbing_action': 'I-gene loss-of-function'}", + "148, Prkca {'perturbing_action': 'I-gene loss-of-function'}", + "154, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "155, of {'perturbing_action': 'I-gene gain-of-function'}", + "156, PP-1. {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "34, Hearts ['l0', 'l1', 'l2', 'l3']", + "36, Prkca-deficient ['l0', 'l4', 'l5', 'l6', 'l7']", + "37, mice ['l1', 'l4', 'l8', 'l9']", + "43, transgenic ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "44, mice ['l10', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "45, overexpressing ['l11', 'l23', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "46, Prkca ['l5', 'l12', 'l24', 'l35', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "49, Adenoviral ['l13', 'l25', 'l36', 'l46', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "50, gene ['l14', 'l26', 'l37', 'l47', 'l56', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "51, transfer ['l15', 'l27', 'l38', 'l48', 'l57', 'l65', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "52, of ['l16', 'l28', 'l39', 'l49', 'l58', 'l66', 'l73', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "53, dominant-negative ['l17', 'l29', 'l40', 'l50', 'l59', 'l67', 'l74', 'l80', 'l86', 'l87', 'l88', 'l89', 'l90']", + "54, or ['l18', 'l30', 'l41', 'l51', 'l60', 'l68', 'l75', 'l81', 'l86', 'l91', 'l92', 'l93', 'l94']", + "55, wild-type ['l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l76', 'l82', 'l87', 'l91', 'l95', 'l96', 'l97']", + "56, PKC-alpha ['l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l83', 'l88', 'l92', 'l95', 'l98', 'l99']", + "58, cardiac ['l2', 'l6', 'l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l89', 'l93', 'l96', 'l98', 'l100']", + "59, myocytes ['l3', 'l7', 'l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l94', 'l97', 'l99', 'l100']", + "122, Prkca ['l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "123, deletion ['l101', 'l110', 'l111', 'l112']", + "138, deleting ['l102', 'l110', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "139, the ['l103', 'l113', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "140, gene ['l104', 'l114', 'l120', 'l126', 'l127', 'l128', 'l129', 'l130']", + "141, encoding ['l105', 'l115', 'l121', 'l126', 'l131', 'l132', 'l133', 'l134', 'l135']", + "142, muscle ['l106', 'l116', 'l122', 'l127', 'l131', 'l136', 'l137', 'l138', 'l139']", + "143, LIM ['l107', 'l117', 'l123', 'l128', 'l132', 'l136', 'l140', 'l141', 'l142']", + "144, protein ['l108', 'l111', 'l118', 'l124', 'l129', 'l133', 'l137', 'l140', 'l143', 'l144']", + "145, (Csrp3). ['l109', 'l112', 'l119', 'l125', 'l130', 'l134', 'l138', 'l141', 'l143', 'l145']", + "146, Deletion ['l146', 'l147', 'l148', 'l149', 'l150']", + "147, of ['l146', 'l151', 'l152', 'l153', 'l154']", + "148, Prkca ['l135', 'l139', 'l142', 'l144', 'l145', 'l147', 'l151', 'l155', 'l156', 'l157']", + "154, overexpression ['l148', 'l152', 'l155', 'l158', 'l159']", + "155, of ['l149', 'l153', 'l156', 'l158', 'l160']", + "156, PP-1. ['l150', 'l154', 'l157', 'l159', 'l160']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "Hearts" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Prkca-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Prkca-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Prkca-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiac", + "myocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "mice" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "mice", + "overexpressing", + "Prkca" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiac", + "myocytes" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Adenoviral", + "gene", + "transfer", + "of", + "dominant-negative", + "or", + "wild-type", + "PKC-alpha" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Adenoviral", + "gene", + "transfer", + "of", + "dominant-negative", + "or", + "wild-type", + "PKC-alpha" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiac", + "myocytes" + ] + } + } + ] + }, + { + "PMID": "14745443", + "TEXT": "DNA containing unmethylated cytidyl guanosyl (CpG) sequences, which are underrepresented in mammalian genomes but prevalent in prokaryotes, is endocytosed by cells of the innate immune system, including macrophages, monocytes and dendritic cells, and activates a pathway involving Toll-like receptor-9 (TLR9). CpG-containing oligodeoxynucleotides (CpG-ODN) are potent stimulators of innate immunity, and are currently being tested as adjuvants of antimicrobial, antiallergic, anticancer and antiprion immunotherapy. Little is known, however, about the consequences of repeated CpG-ODN administration, which is advocated for some of these applications. Here we report that daily injection of 60 microg CpG-ODN dramatically alters the morphology and functionality of mouse lymphoid organs. By day 7, lymphoid follicles were poorly defined; follicular dendritic cells (FDC) and germinal center B lymphocytes were suppressed. Accordingly, CpG-ODN treatment for > or =7 d strongly reduced primary humoral immune responses and immunoglobulin class switching. By day 20, mice developed multifocal liver necrosis and hemorrhagic ascites. All untoward effects were strictly dependent on CpG and TLR9, as neither the CpG-ODN treatment of Tlr9(-/-) mice nor the repetitive challenge of wild-type mice with nonstimulatory ODN (AT-ODN) or with the TLR3 agonist polyinosinic:cytidylic acid (polyI:C) were immunotoxic or hepatotoxic.", + "TAG_DATA": [ + "99, mouse {'context': 'B-tissue/organ'}", + "100, lymphoid {'context': 'I-tissue/organ'}", + "101, organs. {'context': 'I-tissue/organ'}", + "110, follicular {'context': 'B-cells'}", + "111, dendritic {'context': 'I-cells'}", + "112, cells {'context': 'I-cells'}", + "113, (FDC) {'context': 'I-cells'}", + "115, germinal {'context': 'B-cells'}", + "116, center {'context': 'I-cells'}", + "117, B {'context': 'I-cells'}", + "118, lymphocytes {'context': 'I-cells'}", + "142, mice {'context': 'B-organism'}", + "145, liver {'context': 'B-tissue/organ'}", + "146, necrosis {'phenotype': 'B-necrosis'}", + "166, Tlr9(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "167, mice {'context': 'B-organism'}", + "174, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "99, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "100, lymphoid ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "101, organs. ['l1', 'l9', 'l17', 'l18', 'l19', 'l20']", + "110, follicular ['l2', 'l10', 'l17', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "111, dendritic ['l3', 'l11', 'l18', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "112, cells ['l4', 'l12', 'l19', 'l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "113, (FDC) ['l5', 'l13', 'l20', 'l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "115, germinal ['l6', 'l14', 'l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "116, center ['l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "117, B ['l7', 'l15', 'l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "118, lymphocytes ['l8', 'l16', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l48']", + "142, mice ['l49', 'l50']", + "145, liver ['l49', 'l51']", + "146, necrosis ['l50', 'l51']", + "166, Tlr9(-/-) ['l52', 'l53']", + "167, mice ['l52', 'l54']", + "174, mice ['l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tlr9(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "14702635", + "TEXT": "Human and mouse embryonic stem cells (HESCs and MESCs, respectively) self-renew indefinitely while maintaining the ability to generate all three germ-layer derivatives. Despite the importance of ESCs in developmental biology and their potential impact on tissue replacement therapy, the molecular mechanism underlying ESC self-renewal is poorly understood. Here we show that activation of the canonical Wnt pathway is sufficient to maintain self-renewal of both HESCs and MESCs. Although Stat-3 signaling is involved in MESC self-renewal, stimulation of this pathway does not support self-renewal of HESCs. Instead we find that Wnt pathway activation by 6-bromoindirubin-3'-oxime (BIO), a specific pharmacological inhibitor of glycogen synthase kinase-3 (GSK-3), maintains the undifferentiated phenotype in both types of ESCs and sustains expression of the pluripotent state-specific transcription factors Oct-3/4, Rex-1 and Nanog. Wnt signaling is endogenously activated in undifferentiated MESCs and is downregulated upon differentiation. In addition, BIO-mediated Wnt activation is functionally reversible, as withdrawal of the compound leads to normal multidifferentiation programs in both HESCs and MESCs. These results suggest that the use of GSK-3-specific inhibitors such as BIO may have practical applications in regenerative medicine.", + "TAG_DATA": [ + "95, a {'perturbing_action': 'I-pharmacological inhibition'}", + "96, specific {'perturbing_action': 'I-pharmacological inhibition'}", + "97, pharmacological {'perturbing_action': 'I-pharmacological inhibition'}", + "98, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "99, of {'perturbing_action': 'I-pharmacological inhibition'}", + "100, glycogen {'perturbing_action': 'I-pharmacological inhibition'}", + "101, synthase {'perturbing_action': 'I-pharmacological inhibition'}", + "102, kinase-3 {'perturbing_action': 'I-pharmacological inhibition'}", + "103, (GSK-3), {'perturbing_action': 'I-pharmacological inhibition'}", + "104, maintains {'effect': 'B-positive'}", + "106, undifferentiated {'phenotype': 'B-differentiation'}", + "107, phenotype {'phenotype': 'I-differentiation'}", + "112, ESCs {'context': 'B-cells'}", + "152, leads {'effect': 'B-positive'}", + "153, to {'effect': 'I-positive'}", + "155, multidifferentiation {'phenotype': 'B-differentiation'}", + "156, programs {'phenotype': 'I-differentiation'}", + "159, HESCs {'context': 'B-cells'}", + "161, MESCs. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "95, a ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "96, specific ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "97, pharmacological ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "98, inhibitor ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "99, of ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "100, glycogen ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "101, synthase ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "102, kinase-3 ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "103, (GSK-3), ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "104, maintains ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "106, undifferentiated ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "107, phenotype ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "112, ESCs ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "152, leads ['l78', 'l79', 'l80', 'l81', 'l82']", + "153, to ['l78', 'l83', 'l84', 'l85', 'l86']", + "155, multidifferentiation ['l79', 'l83', 'l87', 'l88', 'l89']", + "156, programs ['l80', 'l84', 'l87', 'l90', 'l91']", + "159, HESCs ['l81', 'l85', 'l88', 'l90', 'l92']", + "161, MESCs. ['l82', 'l86', 'l89', 'l91', 'l92']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "a", + "specific", + "pharmacological", + "inhibitor", + "of", + "glycogen", + "synthase", + "kinase-3", + "(GSK-3)," + ] + }, + "effect": { + "val": "positive", + "words": [ + "maintains" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "a", + "specific", + "pharmacological", + "inhibitor", + "of", + "glycogen", + "synthase", + "kinase-3", + "(GSK-3)," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "undifferentiated", + "phenotype" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "a", + "specific", + "pharmacological", + "inhibitor", + "of", + "glycogen", + "synthase", + "kinase-3", + "(GSK-3)," + ] + }, + "context": { + "val": "cells", + "words": [ + "ESCs" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "maintains", + "leads", + "to" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "undifferentiated", + "phenotype", + "multidifferentiation", + "programs" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "maintains", + "leads", + "to" + ] + }, + "context": { + "val": "cells", + "words": [ + "ESCs", + "HESCs", + "MESCs." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "undifferentiated", + "phenotype", + "multidifferentiation", + "programs" + ] + }, + "context": { + "val": "cells", + "words": [ + "ESCs", + "HESCs", + "MESCs." + ] + } + } + ] + }, + { + "PMID": "14702632", + "TEXT": "Using microarray-based profiling of isogenic prostate cancer xenograft models, we found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy. This increase in androgen receptor mRNA and protein was both necessary and sufficient to convert prostate cancer growth from a hormone-sensitive to a hormone-refractory stage, and was dependent on a functional ligand-binding domain. Androgen receptor antagonists showed agonistic activity in cells with increased androgen receptor levels; this antagonist-agonist conversion was associated with alterations in the recruitment of coactivators and corepressors to the promoters of androgen receptor target genes. Increased levels of androgen receptor confer resistance to antiandrogens by amplifying signal output from low levels of residual ligand, and by altering the normal response to antagonists. These findings provide insight toward the design of new antiandrogens.", + "TAG_DATA": [ + "4, isogenic {'context': 'B-xenograft'}", + "5, prostate {'context': 'I-xenograft'}", + "6, cancer {'context': 'I-xenograft'}", + "7, xenograft {'context': 'I-xenograft'}", + "8, models, {'context': 'I-xenograft'}", + "48, prostate {'context': 'B-neoplasm'}", + "49, cancer {'context': 'I-neoplasm', 'phenotype': 'B-tumour growth'}", + "50, growth {'phenotype': 'I-tumour growth'}", + "73, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "4, isogenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "5, prostate ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "6, cancer ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "7, xenograft ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "8, models, ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "48, prostate ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "49, cancer ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "50, growth ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "xenograft", + "words": [ + "isogenic", + "prostate", + "cancer", + "xenograft", + "models," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "cancer", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "cancer", + "prostate" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "cancer", + "growth" + ] + } + } + ] + }, + { + "PMID": "14608378", + "TEXT": "Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy. The predominant subtype, CMT-1A, accounts for more than 50% of all cases and is associated with an interstitial chromosomal duplication of 17p12 (refs. 2,3). We have generated a model of CMT-1A by introducing extra copies of the responsible disease gene, Pmp22 (encoding the peripheral myelin protein of 22 kDa), into transgenic rats. Here, we used this model to test whether progesterone, a regulator of the myelin genes Pmp22 and myelin protein zero (Mpz) in cultured Schwann cells, can modulate the progressive neuropathy caused by moderate overexpression of Pmp22. Male transgenic rats (n = 84) were randomly assigned into three treatment groups: progesterone, progesterone antagonist (onapristone) and placebo control. Daily administration of progesterone elevated the steady-state levels of Pmp22 and Mpz mRNA in the sciatic nerve, resulting in enhanced Schwann cell pathology and a more progressive clinical neuropathy. In contrast, administration of the selective progesterone receptor antagonist reduced overexpression of Pmp22 and improved the CMT phenotype, without obvious side effects, in wild-type or transgenic rats. Taken together, these data provide proof of principle that the progesterone receptor of myelin-forming Schwann cells is a promising pharmacological target for therapy of CMT-1A.", + "TAG_DATA": [ + "84, Schwann {'context': 'I-cells'}", + "85, cells, {'context': 'I-cells'}", + "94, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "97, Male {'context': 'B-organism'}", + "98, transgenic {'context': 'I-organism'}", + "99, rats {'context': 'I-organism'}", + "100, (n {'context': 'I-organism'}", + "132, sciatic {'context': 'B-tissue/organ'}", + "133, nerve, {'context': 'I-tissue/organ'}", + "137, Schwann {'context': 'B-cells'}", + "138, cell {'context': 'I-cells'}", + "151, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "153, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "160, improved {'effect': 'B-positive'}", + "162, CMT {'phenotype': 'B-epithelial-mesenchymal transition'}", + "163, phenotype, {'phenotype': 'I-senescence'}", + "171, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "172, rats. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "84, Schwann ['l0', 'l1', 'l2', 'l3']", + "85, cells, ['l0', 'l4', 'l5', 'l6']", + "94, overexpression ['l1', 'l4', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "97, Male ['l7', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "98, transgenic ['l8', 'l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "99, rats ['l9', 'l16', 'l22', 'l28', 'l29', 'l30', 'l31', 'l32']", + "100, (n ['l10', 'l17', 'l23', 'l28', 'l33', 'l34', 'l35', 'l36']", + "132, sciatic ['l11', 'l18', 'l24', 'l29', 'l33', 'l37', 'l38', 'l39']", + "133, nerve, ['l2', 'l5', 'l12', 'l19', 'l25', 'l30', 'l34', 'l37', 'l40', 'l41']", + "137, Schwann ['l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l42']", + "138, cell ['l3', 'l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l41', 'l42']", + "151, selective ['l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "152, progesterone ['l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "153, receptor ['l44', 'l51', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "154, antagonist ['l45', 'l52', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "160, improved ['l46', 'l53', 'l59', 'l64', 'l69', 'l70', 'l71', 'l72']", + "162, CMT ['l47', 'l54', 'l60', 'l65', 'l69', 'l73', 'l74', 'l75']", + "163, phenotype, ['l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l76', 'l77']", + "171, transgenic ['l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l78']", + "172, rats. ['l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l77', 'l78']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Schwann", + "cells,", + "cell" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "Male", + "transgenic", + "rats", + "(n", + "rats." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "sciatic", + "nerve," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "receptor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "improved" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "receptor" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "CMT" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "receptor" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "phenotype," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "receptor" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "improved" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "CMT" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "improved" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "phenotype," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "improved" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "improved" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats." + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "CMT" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "CMT" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats." + ] + } + }, + { + "phenotype": { + "val": "senescence", + "words": [ + "phenotype," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + } + }, + { + "phenotype": { + "val": "senescence", + "words": [ + "phenotype," + ] + }, + "context": { + "val": "organism", + "words": [ + "rats." + ] + } + } + ] + }, + { + "PMID": "14578882", + "TEXT": "Expansion of human hematopoietic stem cells (HSCs) is a major challenge in cellular therapy, and currently relies on the use of recombinant cytokines or on gene transfer of transcription factors. Of these, the HOXB4 homeoprotein protein is of particular interests as it promotes the expansion of mouse HSCs without inducing the development of leukemia. To eliminate any deleterious effects that might be associated with stable HOXB4 gene transfer into human cells, we took advantage of the ability of HOX proteins to passively translocate through cell membranes. Here we show that when cultured on stromal cells genetically engineered to secrete HOXB4, human long-term culture-initiating cells (LTC-ICs) and nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mouse repopulating cells (SRCs) were expanded by more than 20- and 2.5-fold, respectively, over their input numbers. This expansion was associated with enhanced stem cell repopulating capacity in vivo and maintenance of pluripotentiality. This method provides a basis for developing cell therapy strategies using expanded HSCs that are not genetically modified.", + "TAG_DATA": [ + "93, stromal {'context': 'B-cells'}", + "94, cells {'context': 'I-cells'}", + "95, genetically {'perturbing_action': 'B-gene gain-of-function'}", + "96, engineered {'perturbing_action': 'I-gene gain-of-function'}", + "97, to {'perturbing_action': 'I-gene gain-of-function'}", + "98, secrete {'perturbing_action': 'I-gene gain-of-function'}", + "99, HOXB4, {'perturbing_action': 'I-gene gain-of-function'}", + "100, human {'context': 'B-cells'}", + "101, long-term {'context': 'I-cells'}", + "102, culture-initiating {'context': 'I-cells'}", + "103, cells {'context': 'I-cells'}", + "104, (LTC-ICs) {'context': 'I-cells'}", + "106, nonobese {'context': 'B-cells'}", + "107, diabetic-severe {'context': 'I-cells'}", + "108, combined {'context': 'I-cells'}", + "109, immunodeficiency {'context': 'I-cells'}", + "110, (NOD-SCID) {'context': 'I-cells'}", + "111, mouse {'context': 'I-cells'}", + "112, repopulating {'context': 'I-cells'}", + "113, cells {'context': 'I-cells'}", + "114, (SRCs) {'context': 'I-cells'}", + "134, stem {'context': 'B-cells'}", + "138, in {'context': 'B-in vivo'}", + "139, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "93, stromal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "94, cells ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "95, genetically ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "96, engineered ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "97, to ['l3', 'l13', 'l22', 'l30', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "98, secrete ['l4', 'l14', 'l23', 'l31', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "99, HOXB4, ['l5', 'l15', 'l24', 'l32', 'l40', 'l46', 'l52', 'l53', 'l54', 'l55', 'l56']", + "100, human ['l6', 'l16', 'l25', 'l33', 'l41', 'l47', 'l52', 'l57', 'l58', 'l59', 'l60']", + "101, long-term ['l7', 'l17', 'l26', 'l34', 'l42', 'l48', 'l53', 'l57', 'l61', 'l62', 'l63']", + "102, culture-initiating ['l8', 'l18', 'l27', 'l35', 'l43', 'l49', 'l54', 'l58', 'l61', 'l64', 'l65']", + "103, cells ['l9', 'l19', 'l28', 'l36', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l66']", + "104, (LTC-ICs) ['l10', 'l20', 'l29', 'l37', 'l45', 'l51', 'l56', 'l60', 'l63', 'l65', 'l66']", + "106, nonobese ['l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "107, diabetic-severe ['l67', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "108, combined ['l68', 'l78', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "109, immunodeficiency ['l38', 'l69', 'l79', 'l88', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "110, (NOD-SCID) ['l70', 'l80', 'l89', 'l97', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "111, mouse ['l71', 'l81', 'l90', 'l98', 'l105', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "112, repopulating ['l72', 'l82', 'l91', 'l99', 'l106', 'l112', 'l118', 'l119', 'l120', 'l121', 'l122']", + "113, cells ['l73', 'l83', 'l92', 'l100', 'l107', 'l113', 'l118', 'l123']", + "114, (SRCs) ['l74', 'l84', 'l93', 'l101', 'l108', 'l114', 'l119', 'l123', 'l124', 'l125']", + "134, stem ['l75', 'l85', 'l94', 'l102', 'l109', 'l115', 'l120', 'l124', 'l126', 'l127']", + "138, in ['l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l121', 'l125', 'l126', 'l128']", + "139, vivo ['l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l127', 'l128']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "stromal", + "cells", + "human", + "long-term", + "culture-initiating", + "(LTC-ICs)", + "immunodeficiency" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "genetically", + "engineered", + "to", + "secrete", + "HOXB4," + ] + } + } + ] + }, + { + "PMID": "14566334", + "TEXT": "The study and treatment of age-related macular degeneration (AMD), a leading cause of blindness, has been hampered by a lack of animal models. Here we report that mice deficient either in monocyte chemoattractant protein-1 (Ccl-2; also known as MCP-1) or its cognate C-C chemokine receptor-2 (Ccr-2) develop cardinal features of AMD, including accumulation of lipofuscin in and drusen beneath the retinal pigmented epithelium (RPE), photoreceptor atrophy and choroidal neovascularization (CNV). Complement and IgG deposition in RPE and choroid accompanies senescence in this model, as in human AMD. RPE or choroidal endothelial production of Ccl-2 induced by complement C5a and IgG may mediate choroidal macrophage infiltration into aged wild-type choroids. Wild-type choroidal macrophages degrade C5 and IgG in eye sections of Ccl2(-/-) or Ccr2(-/-) mice. Impaired macrophage recruitment may allow accumulation of C5a and IgG, which induces vascular endothelial growth factor (VEGF) production by RPE, possibly mediating development of CNV. These models implicate macrophage dysfunction in AMD pathogenesis and may be useful as a platform for validating therapies.", + "TAG_DATA": [ + "27, mice {'context': 'B-organism'}", + "79, senescence {'phenotype': 'B-senescence'}", + "109, Wild-type {'context': 'B-cells'}", + "110, choroidal {'context': 'I-cells'}", + "111, macrophages {'context': 'I-cells'}", + "117, eye {'context': 'B-tissue/organ'}", + "120, Ccl2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "122, Ccr2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "123, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "27, mice ['l0']", + "79, senescence ['l0']", + "109, Wild-type ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "110, choroidal ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "111, macrophages ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "117, eye ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "120, Ccl2(-/-) ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "122, Ccr2(-/-) ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "123, mice. ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Wild-type", + "choroidal", + "macrophages" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ccl2(-/-)", + "Ccr2(-/-)" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "eye" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ccl2(-/-)", + "Ccr2(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ccl2(-/-)", + "Ccr2(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "14502283", + "TEXT": "The polycystic kidney diseases (PKDs) are a group of genetic disorders causing significant renal failure and death in children and adults. There are no effective treatments. Two childhood forms, autosomal recessive PKD (ARPKD) and nephronophthisis (NPH), are characterized by collecting-duct cysts. We used animal models orthologous to the human disorders to test whether a vasopressin V2 receptor (VPV2R) antagonist, OPC31260, would be effective against early or established disease. Adenosine-3',5'-cyclic monophosphate (cAMP) has a major role in cystogenesis, and the VPV2R is the major cAMP agonist in the collecting duct. OPC31260 administration lowered renal cAMP, inhibited disease development and either halted progression or caused regression of established disease. These results indicate that OPC31260 may be an effective treatment for these disorders and that clinical trials should be considered.", + "TAG_DATA": [ + "43, animal {'context': 'B-organism'}", + "44, models {'context': 'I-organism'}", + "54, vasopressin {'perturbing_action': 'B-pharmacological inhibition'}", + "55, V2 {'perturbing_action': 'I-pharmacological inhibition'}", + "56, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "57, (VPV2R) {'perturbing_action': 'I-pharmacological inhibition'}", + "58, antagonist, {'perturbing_action': 'I-pharmacological inhibition'}", + "59, OPC31260, {'perturbing_action': 'I-pharmacological inhibition'}", + "94, inhibited {'effect': 'B-negative'}", + "102, caused {'effect': 'B-positive'}" + ], + "LINK_DATA": [ + "43, animal ['l0', 'l1']", + "44, models ['l0', 'l2']", + "54, vasopressin ['l3', 'l4', 'l5', 'l6', 'l7']", + "55, V2 ['l3', 'l8', 'l9', 'l10', 'l11']", + "56, receptor ['l4', 'l8', 'l12', 'l13', 'l14']", + "57, (VPV2R) ['l5', 'l9', 'l12', 'l15', 'l16']", + "58, antagonist, ['l6', 'l10', 'l13', 'l15', 'l17']", + "59, OPC31260, ['l1', 'l2', 'l7', 'l11', 'l14', 'l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "animal", + "models" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "OPC31260," + ] + } + } + ] + }, + { + "PMID": "14502282", + "TEXT": "T lymphocytes undergo proliferation arrest when exposed to tryptophan shortage, which can be provoked by indoleamine 2,3-dioxygenase (IDO), an enzyme that is expressed in placenta and catalyzes tryptophan degradation. Here we show that most human tumors constitutively express IDO. We also observed that expression of IDO by immunogenic mouse tumor cells prevents their rejection by preimmunized mice. This effect is accompanied by a lack of accumulation of specific T cells at the tumor site and can be partly reverted by systemic treatment of mice with an inhibitor of IDO, in the absence of noticeable toxicity. These results suggest that the efficacy of therapeutic vaccination of cancer patients might be improved by concomitant administration of an IDO inhibitor.", + "TAG_DATA": [ + "43, expression {'perturbing_action': 'B-gene gain-of-function'}", + "44, of {'perturbing_action': 'I-gene gain-of-function'}", + "45, IDO {'perturbing_action': 'I-gene gain-of-function'}", + "46, by {'perturbing_action': 'I-gene gain-of-function'}", + "47, immunogenic {'context': 'B-transformed cells'}", + "48, mouse {'context': 'I-transformed cells'}", + "49, tumor {'context': 'I-transformed cells'}", + "50, cells {'context': 'I-transformed cells'}", + "56, mice. {'context': 'B-organism'}", + "68, T {'context': 'B-cells'}", + "69, cells {'context': 'B-cells'}", + "72, tumor {'context': 'B-neoplasm'}", + "83, mice {'context': 'B-organism'}", + "86, inhibitor {'perturbing_action': 'B-pharmacological inhibition'}", + "87, of {'perturbing_action': 'I-pharmacological inhibition'}", + "88, IDO, {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "43, expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "44, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "45, IDO ['l1', 'l11', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "46, by ['l2', 'l12', 'l20', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "47, immunogenic ['l3', 'l13', 'l21', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "48, mouse ['l4', 'l14', 'l22', 'l28', 'l33', 'l38', 'l39', 'l40']", + "49, tumor ['l5', 'l15', 'l23', 'l29', 'l34', 'l38', 'l41', 'l42']", + "50, cells ['l6', 'l16', 'l24', 'l30', 'l35', 'l39', 'l41', 'l43']", + "56, mice. ['l7', 'l17', 'l25', 'l31', 'l36', 'l40', 'l42', 'l43']", + "68, T ['l8', 'l44', 'l45']", + "69, cells ['l9', 'l18', 'l26', 'l32', 'l37', 'l44', 'l46']", + "72, tumor ['l10', 'l19', 'l45', 'l46']", + "83, mice ['l47', 'l48', 'l49']", + "86, inhibitor ['l47', 'l50', 'l51']", + "87, of ['l48', 'l50', 'l52']", + "88, IDO, ['l49', 'l51', 'l52']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "IDO", + "by" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "immunogenic", + "mouse", + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "IDO", + "by" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "IDO", + "by" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitor", + "of", + "IDO," + ] + } + } + ] + }, + { + "PMID": "12960962", + "TEXT": "Inhibition of the kinase suppressor of ras-1 (KSR1) gene by continuous infusion of phosphorothioate antisense oligonucleotides (ODNs) prevented growth of K-Ras-dependent human PANC-1 pancreatic and A549 non-small-cell lung carcinoma xenografts in nude mice, effected regression of established PANC-1 tumors and inhibited A549 lung metastases, all without apparent toxicity. These studies suggest KSR1 antisense ODNs as a treatment for Ras-dependent human malignancies, in particular pancreatic cancer, which lacks effective curative therapy.", + "TAG_DATA": [ + "21, human {'context': 'B-xenograft'}", + "22, PANC-1 {'context': 'I-xenograft'}", + "23, pancreatic {'context': 'I-xenograft'}", + "24, and {'context': 'I-xenograft'}", + "25, A549 {'context': 'I-xenograft'}", + "26, non-small-cell {'context': 'I-xenograft'}", + "27, lung {'context': 'I-xenograft'}", + "28, carcinoma {'context': 'I-xenograft'}", + "29, xenografts {'context': 'I-xenograft'}", + "31, nude {'context': 'B-organism'}", + "32, mice, {'context': 'I-organism'}", + "33, effected {'effect': 'B-positive'}", + "34, regression {'phenotype': 'B-tumour regression'}", + "37, PANC-1 {'context': 'B-neoplasm'}", + "38, tumors {'context': 'I-neoplasm'}", + "40, inhibited {'effect': 'B-negative'}", + "41, A549 {'context': 'B-neoplasm'}", + "42, lung {'phenotype': 'I-metastasis'}", + "43, metastases, {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "21, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "22, PANC-1 ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "23, pancreatic ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "24, and ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "25, A549 ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "26, non-small-cell ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "27, lung ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l47', 'l48', 'l49', 'l50']", + "28, carcinoma ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l47', 'l51', 'l52', 'l53']", + "29, xenografts ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l48', 'l51', 'l54', 'l55']", + "31, nude ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l49', 'l52', 'l54', 'l56']", + "32, mice, ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l50', 'l53', 'l55', 'l56']", + "33, effected ['l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "34, regression ['l57', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "35, of ['l45', 'l58', 'l65', 'l72', 'l73']", + "37, PANC-1 ['l59', 'l66', 'l72', 'l74', 'l75', 'l76', 'l77', 'l78']", + "38, tumors ['l46', 'l60', 'l67', 'l73', 'l74']", + "40, inhibited ['l61', 'l68', 'l75', 'l79', 'l80', 'l81']", + "41, A549 ['l62', 'l69', 'l76', 'l79', 'l82', 'l83']", + "42, lung ['l63', 'l70', 'l77', 'l80', 'l82', 'l84']", + "43, metastases, ['l64', 'l71', 'l78', 'l81', 'l83', 'l84']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "effected" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "effected" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "PANC-1", + "tumors", + "A549" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "effected" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "lung", + "metastases," + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "PANC-1", + "tumors", + "A549" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "PANC-1", + "A549" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "PANC-1", + "A549" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "lung", + "metastases," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "lung", + "metastases," + ] + } + } + ] + }, + { + "PMID": "12937416", + "TEXT": "CD3-specific antibodies have the unique capacity to restore self-tolerance in established autoimmunity. They induce long-term remission of overt diabetes in nonobese diabetic (NOD) mice and in human type I diabetes. The underlying mechanisms had been unclear until now. Here we report that treatment with CD3epsilon-specific antibodies induces transferable T-cell-mediated tolerance involving CD4+CD25+ cells. However, these CD4+CD25+ T cells are distinct from naturally occurring regulatory T cells that control physiological autoreactivity. CD3-specific antibody treatment induced remission in NOD Cd28-/- mice that were devoid of such regulatory cells. Remission of diabetes was abrogated by coadministration of a neutralizing transforming growth factor (TGF)-beta-specific antibody. The central role of TGF-beta was further suggested by its increased, long-lasting production by CD4+ T cells from tolerant mice. These data explain the intriguing tolerogenic effect of CD3-specific antibodies and position them as the first clinically applicable pharmacological stimulant of TGF-beta-producing regulatory CD4+ T cells.", + "TAG_DATA": [ + "76, NOD {'context': 'B-organism'}", + "77, Cd28-/- {'perturbing_action': 'B-gene loss-of-function'}", + "78, mice {'context': 'B-organism'}", + "84, regulatory {'context': 'B-cells'}", + "85, cells. {'context': 'I-cells'}", + "115, CD4+ {'context': 'B-cells'}", + "116, T {'context': 'I-cells'}", + "117, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "76, NOD ['l0', 'l1', 'l2', 'l3']", + "77, Cd28-/- ['l0', 'l4', 'l5', 'l6']", + "78, mice ['l1', 'l4', 'l7', 'l8']", + "84, regulatory ['l2', 'l5', 'l7', 'l9']", + "85, cells. ['l3', 'l6', 'l8', 'l9']", + "115, CD4+ ['l10', 'l11']", + "116, T ['l10', 'l12']", + "117, cells ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "NOD", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cd28-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cd28-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "regulatory", + "cells." + ] + } + } + ] + }, + { + "PMID": "12897779", + "TEXT": "Many mammalian species express restriction factors that confer host resistance to retroviral infection. Here we show that HIV-1 sensitivity to restriction factors is modulated by cyclophilin A (CypA), a host cell protein that binds the HIV-1 capsid protein (CA). In certain nonhuman primate cells, the CA-CypA interaction is essential for restriction: HIV-1 infectivity is increased >100-fold by cyclosporin A (CsA), a competitive inhibitor of the interaction, or by an HIV-1 CA mutation that disrupts CypA binding. Conversely, disruption of CA-CypA interaction in human cells reveals that CypA protects HIV-1 from the Ref-1 restriction factor. These findings suggest that HIV-1 has co-opted a host cell protein to counteract restriction factors expressed by human cells and that this adaptation can confer sensitivity to restriction in unnatural hosts. Manipulation of HIV-1 CA recognition by restriction factors promises to advance animal models and new therapeutic strategies for HIV-1 and AIDS.", + "TAG_DATA": [ + "69, HIV-1 {'perturbing_action': 'B-other'}", + "70, CA {'perturbing_action': 'I-other'}", + "71, mutation {'perturbing_action': 'I-other'}", + "82, human {'context': 'B-cells'}", + "83, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "69, HIV-1 ['l0', 'l1', 'l2', 'l3']", + "70, CA ['l0', 'l4', 'l5']", + "71, mutation ['l1', 'l4', 'l6', 'l7']", + "82, human ['l2', 'l6', 'l8']", + "83, cells ['l3', 'l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "HIV-1", + "CA", + "mutation" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "cells" + ] + } + } + ] + }, + { + "PMID": "12872164", + "TEXT": "The mechanisms of retinoid activity in tumors remain largely unknown. Here we establish that retinoids cause extensive apoptosis of medulloblastoma cells. In a xenograft model, retinoids largely abrogated tumor growth. Using receptor-specific retinoid agonists, we defined a subset of mRNAs that were induced by all active retinoids in retinoid-sensitive cell lines. We also identified bone morphogenetic protein-2 (BMP-2) as a candidate mediator of retinoid activity. BMP-2 protein induced medulloblastoma cell apoptosis, whereas the BMP-2 antagonist noggin blocked both retinoid and BMP-2-induced apoptosis. BMP-2 also induced p38 mitogen-activated protein kinase (MAPK), which is necessary for BMP-2- and retinoid-induced apoptosis. Retinoid-resistant medulloblastoma cells underwent apoptosis when treated with BMP-2 or when cultured with retinoid-sensitive medulloblastoma cells. Retinoid-induced expression of BMP-2 is thus necessary and sufficient for apoptosis of retinoid-responsive cells, and expression of BMP-2 by retinoid-sensitive cells is sufficient to induce apoptosis in surrounding retinoid-resistant cells.", + "TAG_DATA": [ + "23, xenograft {'context': 'B-xenograft'}", + "24, model, {'context': 'I-xenograft'}", + "27, abrogated {'effect': 'B-negative'}", + "28, tumor {'phenotype': 'B-tumour growth'}", + "29, growth. {'phenotype': 'I-tumour growth'}", + "49, cell {'context': 'I-cells'}", + "50, lines. {'context': 'I-cells'}", + "67, induced {'effect': 'B-positive'}", + "68, medulloblastoma {'context': 'B-transformed cells'}", + "69, cell {'context': 'I-transformed cells'}", + "70, apoptosis, {'phenotype': 'B-apoptosis'}", + "76, blocked {'effect': 'B-negative'}", + "80, BMP-2-induced {'effect': 'B-positive'}", + "81, apoptosis. {'phenotype': 'B-apoptosis'}", + "96, retinoid-induced {'effect': 'B-positive'}", + "97, apoptosis. {'phenotype': 'B-apoptosis'}", + "98, Retinoid-resistant {'context': 'B-transformed cells'}", + "99, medulloblastoma {'context': 'I-transformed cells'}", + "100, cells {'context': 'I-transformed cells'}", + "102, apoptosis {'phenotype': 'B-apoptosis'}", + "111, retinoid-sensitive {'context': 'B-transformed cells'}", + "112, medulloblastoma {'context': 'I-transformed cells'}", + "113, cells. {'context': 'I-transformed cells'}", + "133, retinoid-sensitive {'context': 'B-cells'}", + "134, cells {'context': 'I-cells'}", + "138, induce {'effect': 'B-positive'}", + "139, apoptosis {'phenotype': 'B-apoptosis'}", + "142, retinoid-resistant {'context': 'B-cells'}", + "143, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "23, xenograft ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "24, model, ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "27, abrogated ['l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "28, tumor ['l1', 'l9', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "29, growth. ['l2', 'l10', 'l18', 'l25', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "49, cell ['l3', 'l11', 'l19', 'l26', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "50, lines. ['l4', 'l12', 'l20', 'l27', 'l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "67, induced ['l5', 'l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "68, medulloblastoma ['l6', 'l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "69, cell ['l7', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "70, apoptosis, ['l8', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l52']", + "76, blocked ['l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "80, BMP-2-induced ['l53', 'l59', 'l60', 'l61', 'l62', 'l63']", + "81, apoptosis. ['l54', 'l59', 'l64', 'l65', 'l66']", + "96, retinoid-induced ['l55', 'l60', 'l64', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "97, apoptosis. ['l56', 'l61', 'l65', 'l67', 'l73', 'l74', 'l75']", + "98, Retinoid-resistant ['l68', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "99, medulloblastoma ['l57', 'l62', 'l69', 'l73', 'l76', 'l83', 'l84', 'l85', 'l86']", + "100, cells ['l58', 'l63', 'l66', 'l70', 'l74', 'l77', 'l83', 'l87', 'l88']", + "101, underwent ['l71', 'l75', 'l78', 'l84', 'l87', 'l89', 'l90']", + "102, apoptosis ['l72', 'l79', 'l85', 'l88', 'l89', 'l91']", + "111, retinoid-sensitive ['l80', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "112, medulloblastoma ['l81', 'l92', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "113, cells. ['l82', 'l86', 'l90', 'l91', 'l93', 'l98', 'l104', 'l105']", + "133, retinoid-sensitive ['l106', 'l107', 'l108', 'l109', 'l110']", + "134, cells ['l94', 'l99', 'l104', 'l106', 'l111', 'l112', 'l113', 'l114']", + "138, induce ['l95', 'l100', 'l107', 'l111', 'l115', 'l116', 'l117']", + "139, apoptosis ['l96', 'l101', 'l108', 'l112', 'l115', 'l118', 'l119']", + "142, retinoid-resistant ['l102', 'l109', 'l113', 'l116', 'l118', 'l120']", + "143, cells. ['l97', 'l103', 'l105', 'l110', 'l114', 'l117', 'l119', 'l120']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "model," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "model," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "model," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogated" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogated" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "lines." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogated", + "blocked" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "medulloblastoma", + "cell", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogated", + "blocked" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis,", + "apoptosis." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "lines." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "medulloblastoma", + "cell" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell", + "lines.", + "retinoid-sensitive", + "cells", + "retinoid-resistant", + "cells." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "induce" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell", + "lines.", + "retinoid-sensitive", + "cells", + "retinoid-resistant", + "cells." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis,", + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "BMP-2-induced", + "retinoid-induced", + "induce" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "medulloblastoma", + "cell", + "cells", + "Retinoid-resistant", + "retinoid-sensitive" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "BMP-2-induced", + "retinoid-induced", + "induce" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis,", + "apoptosis.", + "apoptosis" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "medulloblastoma", + "cell", + "cells", + "Retinoid-resistant", + "cells.", + "retinoid-sensitive" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis,", + "apoptosis.", + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "12858167", + "TEXT": "High plasma levels of soluble P-selectin are associated with thrombotic disorders and may predict future cardiovascular events. Mice with high levels of soluble P-selectin have more microparticles in their plasma than do normal mice. Here we show that chimeras of P-selectin and immunoglobulin (P-sel-Ig) induced formation of procoagulant microparticles in human blood through P-selectin glycoprotein ligand-1 (PSGL-1; encoded by the Psgl1 gene, officially known as Selpl). In addition, Psgl1-/- mice produced fewer microparticles after P-sel-Ig infusion and did not spontaneously increase their microparticle count in old age as do wild-type mice. Injected microparticles specifically bound to thrombi and thus could be involved in thrombin generation at sites of injury. Infusion of P-sel-Ig into hemophilia A mice produced a 20-fold increase over control immunoglobulin in microparticles containing tissue factor. This significantly improved the kinetics of fibrin formation in the hemophilia A mice and normalized their tail-bleeding time. P-sel-Ig treatment could become a new approach to sustained control of bleeding in hemophilia.", + "TAG_DATA": [ + "51, blood {'context': 'I-tissue/organ'}", + "68, Psgl1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "69, mice {'context': 'B-organism'}", + "90, mice. {'context': 'B-organism'}", + "113, hemophilia {'context': 'B-organism'}", + "114, A {'context': 'I-organism'}", + "115, mice {'context': 'I-organism'}", + "138, hemophilia {'context': 'B-organism'}", + "139, A {'context': 'I-organism'}", + "140, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "50, human ['l0']", + "51, blood ['l0']", + "68, Psgl1-/- ['l1']", + "69, mice ['l1']", + "113, hemophilia ['l2', 'l3', 'l4', 'l5', 'l6']", + "114, A ['l2', 'l7', 'l8', 'l9']", + "115, mice ['l3', 'l7', 'l10', 'l11', 'l12']", + "138, hemophilia ['l4', 'l10', 'l13', 'l14']", + "139, A ['l5', 'l8', 'l11', 'l13', 'l15']", + "140, mice ['l6', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Psgl1-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "12808451", + "TEXT": "Generation of arachidonic acid by the ubiquitously expressed cytosolic phospholipase A2 (PLA2) has a fundamental role in the regulation of cellular homeostasis, inflammation and tumorigenesis. Here we report that cytosolic PLA2 is a negative regulator of growth, specifically of striated muscle. We find that normal growth of skeletal muscle, as well as normal and pathologic stress-induced hypertrophic growth of the heart, are exaggerated in Pla2g4a-/- mice, which lack the gene encoding cytosolic PLA2. The mechanism underlying this phenotype is that cytosolic PLA2 negatively regulates insulin-like growth factor (IGF)-1 signaling. Absence of cytosolic PLA2 leads to sustained activation of the IGF-1 pathway, which results from the failure of 3-phosphoinositide-dependent protein kinase (PDK)-1 to recruit and phosphorylate protein kinase C (PKC)-zeta, a negative regulator of IGF-1 signaling. Arachidonic acid restores activation of PKC-zeta, correcting the exaggerated IGF-1 signaling. These results indicate that cytosolic PLA2 and arachidonic acid regulate striated muscle growth by modulating multiple growth-regulatory pathways.", + "TAG_DATA": [ + "47, skeletal {'context': 'B-tissue/organ'}", + "48, muscle, {'context': 'I-tissue/organ'}", + "64, Pla2g4a-/- {'perturbing_action': 'B-gene loss-of-function'}", + "65, mice, {'context': 'B-organism'}", + "67, lack {'perturbing_action': 'B-gene loss-of-function'}", + "68, the {'perturbing_action': 'I-gene loss-of-function'}", + "69, gene {'perturbing_action': 'I-gene loss-of-function'}", + "70, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "71, cytosolic {'perturbing_action': 'I-gene loss-of-function'}", + "72, PLA2. {'perturbing_action': 'I-gene loss-of-function'}", + "89, Absence {'perturbing_action': 'B-gene loss-of-function'}", + "90, of {'perturbing_action': 'I-gene loss-of-function'}", + "91, cytosolic {'perturbing_action': 'I-gene loss-of-function'}", + "92, PLA2 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "47, skeletal ['l0']", + "48, muscle, ['l0']", + "64, Pla2g4a-/- ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "65, mice, ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "67, lack ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "68, the ['l3', 'l9', 'l14', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "69, gene ['l4', 'l10', 'l15', 'l23', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "70, encoding ['l5', 'l11', 'l16', 'l24', 'l31', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "71, cytosolic ['l6', 'l12', 'l17', 'l25', 'l32', 'l38', 'l44', 'l45', 'l46', 'l47', 'l48']", + "72, PLA2. ['l7', 'l13', 'l18', 'l26', 'l33', 'l39', 'l44', 'l49', 'l50', 'l51', 'l52']", + "89, Absence ['l19', 'l27', 'l34', 'l40', 'l45', 'l49', 'l53', 'l54', 'l55']", + "90, of ['l20', 'l28', 'l35', 'l41', 'l46', 'l50', 'l53', 'l56', 'l57']", + "91, cytosolic ['l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l54', 'l56', 'l58']", + "92, PLA2 ['l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l57', 'l58']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pla2g4a-/-", + "lack", + "the", + "gene", + "encoding", + "cytosolic", + "PLA2." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "12754503", + "TEXT": "The content and structure of collagen is essential in governing the delivery of therapeutic molecules in tumors. Thus, simple histological staining of tumor tissue biopsies for collagen could be used to assess the accessibility of molecular therapeutics in tumors. Here we show that it is possible to optically image fibrillar collagen in tumors growing in mice using second-harmonic generation (SHG). Using this noninvasive technique, we estimated relative diffusive hindrance, quantified the dynamics of collagen modification after pharmacologic intervention and provided mechanistic insight into improved diffusive transport induced by the hormone relaxin. This technology could offer basic scientists and clinicians an enhanced ability to estimate the relative penetrabilities of molecular therapeutics.", + "TAG_DATA": [ + "52, tumors {'context': 'B-neoplasm'}", + "53, growing {'context': 'I-neoplasm', 'phenotype': 'I-tumour growth'}", + "55, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "52, tumors ['l0', 'l1']", + "53, growing ['l0', 'l2']", + "55, mice ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "growing" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growing" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "growing" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "12754502", + "TEXT": "Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease that affects males. It is caused by the expansion of a polyglutamine (polyQ) tract in androgen receptors. Female carriers are usually asymptomatic. No specific treatment has been established. Our transgenic mouse model carrying a full-length human androgen receptor with expanded polyQ has considerable gender-related motor impairment. This phenotype was abrogated by castration, which prevented nuclear translocation of mutant androgen receptors. We examined the effect of androgen-blockade drugs on our mouse model. Leuprorelin, a lutenizing hormone-releasing hormone (LHRH) agonist that reduces testosterone release from the testis, rescued motor dysfunction and nuclear accumulation of mutant androgen receptors in male transgenic mice. Moreover, leuprorelin treatment reversed the behavioral and histopathological phenotypes that were once caused by transient increases in serum testosterone. Flutamide, an androgen antagonist promoting nuclear translocation of androgen receptors, yielded no therapeutic effect. Leuprorelin thus seems to be a promising candidate for the treatment of SBMA.", + "TAG_DATA": [ + "42, mouse {'context': 'I-organism'}", + "43, model {'context': 'I-organism'}", + "46, full-length {'perturbing_action': 'I-other'}", + "47, human {'perturbing_action': 'I-other'}", + "81, mouse {'context': 'B-organism'}", + "82, model. {'context': 'I-organism'}", + "108, male {'context': 'B-organism'}", + "109, transgenic {'context': 'I-organism'}", + "110, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "42, mouse ['l0', 'l1', 'l2', 'l3']", + "43, model ['l0', 'l4', 'l5', 'l6', 'l7']", + "46, full-length ['l1', 'l4', 'l8', 'l9', 'l10']", + "47, human ['l2', 'l5', 'l8', 'l11', 'l12']", + "81, mouse ['l6', 'l9', 'l11', 'l13']", + "82, model. ['l3', 'l7', 'l10', 'l12', 'l13']", + "108, male ['l14', 'l15']", + "109, transgenic ['l14', 'l16']", + "110, mice. ['l15', 'l16']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "model." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "full-length", + "human" + ] + } + } + ] + }, + { + "PMID": "12692539", + "TEXT": "Ovarian tumor cells are often genomically unstable and hypersensitive to cisplatin. To understand the molecular basis for this phenotype, we examined the integrity of the Fanconi anemia-BRCA (FANC-BRCA) pathway in those cells. This pathway regulates cisplatin sensitivity and is governed by the coordinate activity of six genes associated with Fanconi anemia (FANCA, FANCC, FANCD2, FANCE, FANCF and FANCG) as well as BRCA1 and BRCA2 (FANCD1). Here we show that the FANC-BRCA pathway is disrupted in a subset of ovarian tumor lines. Mono-ubiquitination of FANCD2, a measure of the function of this pathway, and cisplatin resistance were restored by functional complementation with FANCF, a gene that is upstream in this pathway. FANCF inactivation in ovarian tumors resulted from methylation of its CpG island, and acquired cisplatin resistance correlated with demethylation of FANCF. We propose a model for ovarian tumor progression in which the initial methylation of FANCF is followed by FANCF demethylation and ultimately results in cisplatin resistance.", + "TAG_DATA": [ + "110, FANCF {'perturbing_action': 'B-gene loss-of-function'}", + "111, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "113, ovarian {'context': 'B-neoplasm'}", + "114, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "110, FANCF ['l0', 'l1', 'l2']", + "111, inactivation ['l0', 'l3', 'l4']", + "113, ovarian ['l1', 'l3', 'l5']", + "114, tumors ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FANCF", + "inactivation" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "ovarian", + "tumors" + ] + } + } + ] + }, + { + "PMID": "12669034", + "TEXT": "Using natural killer T (NKT) cell-deficient mice, we show here that allergen-induced airway hyperreactivity (AHR), a cardinal feature of asthma, does not develop in the absence of V(alpha)14i NKT cells. The failure of NKT cell-deficient mice to develop AHR is not due to an inability of these mice to produce type 2 T-helper (Th2) responses because NKT cell-deficient mice that are immunized subcutaneously at non-mucosal sites produce normal Th2-biased responses. The failure to develop AHR can be reversed by the adoptive transfer of tetramer-purified NKT cells producing interleukin (IL)-4 and IL-13 to Ja281(-/-) mice, which lack the invariant T-cell receptor (TCR) of NKT cells, or by the administration to Cd1d(-/-) mice of recombinant IL-13, which directly affects airway smooth muscle cells. Thus, pulmonary V(alpha)14i NKT cells crucially regulate the development of asthma and Th2-biased respiratory immunity against nominal exogenous antigens. Therapies that target V(alpha)14i NKT cells may be clinically effective in limiting the development of AHR and asthma.", + "TAG_DATA": [ + "33, NKT {'perturbing_action': 'B-gene loss-of-function'}", + "34, cell-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "35, mice {'context': 'B-organism'}", + "47, mice {'context': 'B-organism'}", + "56, NKT {'perturbing_action': 'B-gene loss-of-function'}", + "57, cell-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "58, mice {'context': 'B-organism'}", + "84, NKT {'context': 'B-cells'}", + "85, cells {'context': 'I-cells'}", + "92, Ja281(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "93, mice, {'context': 'B-organism'}", + "109, Cd1d(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "110, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "33, NKT ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "34, cell-deficient ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "35, mice ['l1', 'l6', 'l11', 'l12']", + "47, mice ['l2', 'l7', 'l11']", + "56, NKT ['l3', 'l8', 'l13', 'l14', 'l15', 'l16', 'l17']", + "57, cell-deficient ['l4', 'l9', 'l12', 'l13', 'l18', 'l19', 'l20']", + "58, mice ['l5', 'l10', 'l14', 'l18', 'l21', 'l22']", + "84, NKT ['l15', 'l19', 'l21', 'l23', 'l24', 'l25']", + "85, cells ['l16', 'l20', 'l22', 'l23', 'l26', 'l27']", + "92, Ja281(-/-) ['l17', 'l24', 'l26', 'l28']", + "93, mice, ['l25', 'l27', 'l28']", + "109, Cd1d(-/-) ['l29']", + "110, mice ['l29']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NKT", + "cell-deficient", + "Ja281(-/-)", + "Cd1d(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NKT", + "cell-deficient", + "Ja281(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "NKT", + "cells" + ] + } + } + ] + }, + { + "PMID": "12640447", + "TEXT": "Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies. Its high mortality rate is mainly a result of intra-hepatic metastases. We analyzed the expression profiles of HCC samples without or with intra-hepatic metastases. Using a supervised machine-learning algorithm, we generated for the first time a molecular signature that can classify metastatic HCC patients and identified genes that were relevant to metastasis and patient survival. We found that the gene expression signature of primary HCCs with accompanying metastasis was very similar to that of their corresponding metastases, implying that genes favoring metastasis progression were initiated in the primary tumors. Osteopontin, which was identified as a lead gene in the signature, was over-expressed in metastatic HCC; an osteopontin-specific antibody effectively blocked HCC cell invasion in vitro and inhibited pulmonary metastasis of HCC cells in nude mice. Thus, osteopontin acts as both a diagnostic marker and a potential therapeutic target for metastatic HCC.", + "TAG_DATA": [ + "122, blocked {'effect': 'B-negative'}", + "123, HCC {'context': 'B-transformed cells'}", + "124, cell {'context': 'I-transformed cells'}", + "125, invasion {'phenotype': 'B-invasion'}", + "126, in {'context': 'B-in vitro'}", + "127, vitro {'context': 'I-in vitro'}", + "129, inhibited {'effect': 'B-negative'}", + "130, pulmonary {'phenotype': 'B-metastasis'}", + "131, metastasis {'phenotype': 'I-metastasis'}", + "133, HCC {'context': 'B-transformed cells'}", + "134, cells {'context': 'I-transformed cells'}", + "136, nude {'context': 'B-organism'}", + "137, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "122, blocked ['l0', 'l1', 'l2', 'l3', 'l4']", + "123, HCC ['l0', 'l5', 'l6', 'l7', 'l8']", + "124, cell ['l1', 'l5', 'l9', 'l10', 'l11']", + "125, invasion ['l2', 'l6', 'l9', 'l12', 'l13']", + "126, in ['l3', 'l7', 'l10', 'l12', 'l14']", + "127, vitro ['l4', 'l8', 'l11', 'l13', 'l14']", + "129, inhibited ['l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "130, pulmonary ['l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "131, metastasis ['l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "133, HCC ['l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "134, cells ['l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "136, nude ['l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "137, mice. ['l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "blocked", + "inhibited" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HCC", + "cell", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "HCC", + "cell" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "pulmonary", + "metastasis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice." + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "pulmonary", + "metastasis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HCC", + "cells" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "pulmonary", + "metastasis" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice." + ] + } + } + ] + }, + { + "PMID": "12579195", + "TEXT": "Disruption of the mouse gene encoding the blood coagulation inhibitor thrombomodulin (Thbd) leads to embryonic lethality caused by an unknown defect in the placenta. We show that the abortion of thrombomodulin-deficient embryos is caused by tissue factor-initiated activation of the blood coagulation cascade at the feto-maternal interface. Activated coagulation factors induce cell death and growth inhibition of placental trophoblast cells by two distinct mechanisms. The death of giant trophoblast cells is caused by conversion of the thrombin substrate fibrinogen to fibrin and subsequent formation of fibrin degradation products. In contrast, the growth arrest of trophoblast cells is not mediated by fibrin, but is a likely result of engagement of protease-activated receptors (PAR)-2 and PAR-4 by coagulation factors. These findings show a new function for the thrombomodulin-protein C system in controlling the growth and survival of trophoblast cells in the placenta. This function is essential for the maintenance of pregnancy.", + "TAG_DATA": [ + "30, thrombomodulin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "31, embryos {'context': 'B-organism'}", + "50, induce {'effect': 'B-positive'}", + "51, cell {'phenotype': 'B-cell death'}", + "52, death {'phenotype': 'I-cell death'}", + "55, inhibition {'effect': 'B-negative'}", + "57, placental {'context': 'B-cells'}", + "58, trophoblast {'context': 'I-cells'}", + "59, cells {'context': 'I-cells'}", + "67, giant {'context': 'B-cells'}", + "68, trophoblast {'context': 'I-cells'}", + "69, cells {'context': 'I-cells'}", + "91, growth {'phenotype': 'B-cell growth'}", + "92, arrest {'effect': 'B-negative'}", + "94, trophoblast {'context': 'B-cells'}", + "95, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "30, thrombomodulin-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "31, embryos ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "50, induce ['l1', 'l11', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "51, cell ['l2', 'l12', 'l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "52, death ['l3', 'l13', 'l21', 'l29', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "55, inhibition ['l4', 'l14', 'l22', 'l30', 'l37', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "57, placental ['l5', 'l15', 'l23', 'l31', 'l38', 'l44', 'l50', 'l51', 'l52', 'l53', 'l54']", + "58, trophoblast ['l6', 'l16', 'l24', 'l32', 'l39', 'l45', 'l50', 'l55', 'l56', 'l57', 'l58']", + "59, cells ['l7', 'l17', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l59', 'l60', 'l61']", + "67, giant ['l8', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l62', 'l63']", + "68, trophoblast ['l9', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l62', 'l64']", + "69, cells ['l10', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l64']", + "91, growth ['l65', 'l66', 'l67']", + "92, arrest ['l65', 'l68', 'l69']", + "94, trophoblast ['l66', 'l68', 'l70']", + "95, cells ['l67', 'l69', 'l70']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "thrombomodulin-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "embryos" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "thrombomodulin-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "thrombomodulin-deficient" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "thrombomodulin-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "thrombomodulin-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "placental", + "trophoblast", + "cells", + "giant" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "embryos" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "embryos" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "embryos" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "placental", + "trophoblast", + "cells", + "giant" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "placental", + "trophoblast", + "cells", + "giant" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition", + "arrest" + ] + }, + "context": { + "val": "cells", + "words": [ + "placental", + "trophoblast", + "cells", + "giant" + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest" + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + }, + "context": { + "val": "cells", + "words": [ + "trophoblast", + "cells" + ] + } + } + ] + }, + { + "PMID": "12563314", + "TEXT": "Pseudomonas aeruginosa infection is a serious complication in patients with cystic fibrosis and in immunocompromised individuals. Here we show that P. aeruginosa infection triggers activation of the acid sphingomyelinase and the release of ceramide in sphingolipid-rich rafts. Ceramide reorganizes these rafts into larger signaling platforms that are required to internalize P. aeruginosa, induce apoptosis and regulate the cytokine response in infected cells. Failure to generate ceramide-enriched membrane platforms in infected cells results in an unabated inflammatory response, massive release of interleukin (IL)-1 and septic death of mice. Our findings show that ceramide-enriched membrane platforms are central to the host defense against this potentially lethal pathogen.", + "TAG_DATA": [ + "52, induce {'effect': 'B-positive'}", + "53, apoptosis {'phenotype': 'B-apoptosis'}", + "61, cells. {'context': 'B-cells'}", + "70, cells {'context': 'B-cells'}", + "86, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "52, induce ['l0', 'l1']", + "53, apoptosis ['l0', 'l2']", + "61, cells. ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "12539042", + "TEXT": "Immature dendritic cells are among the first cells infected by retroviruses after mucosal exposure. We explored the effects of human immunodeficiency virus-1 (HIV-1) and its Tat transactivator on these primary antigen-presenting cells using DNA microarray analysis and functional assays. We found that HIV-1 infection or Tat expression induces interferon (IFN)-responsive gene expression in immature human dendritic cells without inducing maturation. Among the induced gene products are chemokines that recruit activated T cells and macrophages, the ultimate target cells for the virus. Dendritic cells in the lymph nodes of macaques infected with simian immunodeficiency virus (SIV) have elevated levels of monocyte chemoattractant protein 2 (MCP-2), demonstrating that chemokine induction also occurs during retroviral infection in vivo. These results show that HIV-1 Tat reprograms host dendritic cell gene expression to facilitate expansion of HIV-1 infection.", + "TAG_DATA": [ + "45, Tat {'perturbing_action': 'B-gene gain-of-function'}", + "46, expression {'perturbing_action': 'I-gene gain-of-function'}", + "53, immature {'context': 'B-cells'}", + "54, human {'context': 'I-cells'}", + "55, dendritic {'context': 'I-cells'}", + "56, cells {'context': 'I-cells'}", + "81, Dendritic {'context': 'B-cells'}", + "82, cells {'context': 'I-cells'}", + "85, lymph {'context': 'B-tissue/organ'}", + "86, nodes {'context': 'I-tissue/organ'}", + "88, macaques {'context': 'B-organism'}", + "113, in {'context': 'B-in vivo'}", + "114, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "45, Tat ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "46, expression ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "53, immature ['l1', 'l8', 'l14', 'l15', 'l16']", + "54, human ['l2', 'l9', 'l14', 'l17', 'l18']", + "55, dendritic ['l3', 'l10', 'l15', 'l17', 'l19']", + "56, cells ['l4', 'l11', 'l16', 'l18', 'l19']", + "81, Dendritic ['l5', 'l12', 'l20', 'l21', 'l22', 'l23']", + "82, cells ['l6', 'l13', 'l20', 'l24', 'l25', 'l26']", + "85, lymph ['l21', 'l24', 'l27', 'l28']", + "86, nodes ['l7', 'l22', 'l25', 'l27', 'l29']", + "88, macaques ['l23', 'l26', 'l28', 'l29']", + "113, in ['l30']", + "114, vivo. ['l30']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Tat", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "immature", + "human", + "dendritic", + "cells", + "Dendritic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Tat" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "nodes" + ] + } + } + ] + }, + { + "PMID": "12524533", + "TEXT": "Annually, 1.25 million individuals suffer burns in the United States and 6.5 million experience chronic skin ulcers, often from diabetes, pressure or venous stasis. Growth factors are essential mediators of wound repair, but their success as therapeutics in wound treatment has, so far, been limited. Therefore, there is a need to identify new wound-response regulatory factors, but few have appeared in recent years. Progranulin (also called granulin or epithelin precursor, acrogranin or PC-derived growth factor) is a growth factor involved in tumorigenesis and development. Peptides derived from progranulin have been isolated from inflammatory cells, which led to suggestions that progranulin gene products are involved in the wound response, but this remains undemonstrated. We report that in murine transcutaneous puncture wounds, progranulin mRNA is expressed in the inflammatory infiltrate and is highly induced in dermal fibroblasts and endothelia following injury. When applied to a cutaneous wound, progranulin increased the accumulation of neutrophils, macrophages, blood vessels and fibroblasts in the wound. It acts directly on isolated dermal fibroblasts and endothelial cells to promote division, migration and the formation of capillary-like tubule structures. Progranulin is, therefore, a probable wound-related growth factor.", + "TAG_DATA": [ + "155, fibroblasts {'context': 'B-cells'}", + "164, dermal {'context': 'B-cells'}", + "165, fibroblasts {'context': 'I-cells'}", + "167, endothelial {'context': 'B-cells'}", + "168, cells {'context': 'I-cells'}", + "170, promote {'effect': 'B-positive'}", + "171, division, {'phenotype': 'B-proliferation'}", + "172, migration {'phenotype': 'B-migration'}" + ], + "LINK_DATA": [ + "164, dermal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "165, fibroblasts ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "167, endothelial ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "168, cells ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "170, promote ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "171, division, ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "172, migration ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "dermal", + "fibroblasts", + "endothelial", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promote" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "dermal", + "fibroblasts", + "endothelial", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "division," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "dermal", + "fibroblasts", + "endothelial", + "cells" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "division," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + } + ] + }, + { + "PMID": "12483205", + "TEXT": "Plasmodium sporozoites are transmitted through the bite of infected mosquitoes and first invade the liver of the mammalian host, as an obligatory step of the life cycle of the malaria parasite. Within hepatocytes, Plasmodium sporozoites reside in a membrane-bound vacuole, where they differentiate into exoerythrocytic forms and merozoites that subsequently infect erythrocytes and cause the malaria disease. Plasmodium sporozoite targeting to the liver is mediated by the specific binding of major sporozoite surface proteins, the circumsporozoite protein and the thrombospondin-related anonymous protein, to glycosaminoglycans on the hepatocyte surface. Still, the molecular mechanisms underlying sporozoite entry and differentiation within hepatocytes are largely unknown. Here we show that the tetraspanin CD81, a putative receptor for hepatitis C virus, is required on hepatocytes for human Plasmodium falciparum and rodent Plasmodium yoelii sporozoite infectivity. P. yoelii sporozoites fail to infect CD81-deficient mouse hepatocytes, in vivo and in vitro, and antibodies against mouse and human CD81 inhibit in vitro the hepatic development of P. yoelii and P. falciparum, respectively. We further demonstrate that the requirement for CD81 is linked to sporozoite entry into hepatocytes by formation of a parasitophorous vacuole, which is essential for parasite differentiation into exoerythrocytic forms.", + "TAG_DATA": [ + "136, CD81-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "137, mouse {'context': 'B-cells'}", + "138, hepatocytes, {'context': 'I-cells'}", + "139, in {'context': 'B-in vivo'}", + "140, vivo {'context': 'I-in vivo'}", + "142, in {'context': 'B-in vitro'}", + "143, vitro, {'context': 'I-in vitro'}", + "152, in {'context': 'B-in vitro'}", + "153, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "136, CD81-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "137, mouse ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "138, hepatocytes, ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "139, in ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "140, vivo ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "142, in ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "143, vitro, ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "146, against ['l21', 'l22', 'l23', 'l24']", + "147, mouse ['l21', 'l25', 'l26', 'l27']", + "149, human ['l22', 'l25', 'l28', 'l29']", + "152, in ['l23', 'l26', 'l28', 'l30']", + "153, vitro ['l24', 'l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD81-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "hepatocytes," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD81-deficient" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD81-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + } + ] + }, + { + "PMID": "12426560", + "TEXT": "Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that exhibits specific tumoricidal activity against a variety of tumors. It is expressed on different cells of the immune system and plays a role in natural killer cell-mediated tumor surveillance. In allogeneic hematopoietic-cell transplantation, the reactivity of the donor T cell against malignant cells is essential for the graft-versus-tumor (GVT) effect. Cytolytic activity of T cells is primarily mediated through the Fas-Fas ligand and perforin-granzyme pathways. However, T cells deficient for both Fas ligand and perforin can still exert GVT activity in vivo in mouse models. To uncover a potential role for TRAIL in donor T cell-mediated GVT activity, we compared donor T cells from TRAIL-deficient and wild-type mice in clinically relevant mouse bone-marrow transplantation models. We found that alloreactive T cells can express TRAIL, but the absence of TRAIL had no effect on their proliferative and cytokine response to alloantigens. TRAIL-deficient T cells showed significantly lower GVT activity than did TRAIL-expressing T cells, but no important differences in graft-versus-host disease, a major complication of allogeneic hematopoietic cell transplantation, were observed. These data suggest that strategies to enhance TRAIL-mediated GVT activity could decrease relapse rates of malignancies after hematopoietic cell transplantation without exacerbation of graft-versus-host disease.", + "TAG_DATA": [ + "81, T {'context': 'B-cells'}", + "82, cells {'context': 'B-cells'}", + "95, in {'context': 'B-in vivo'}", + "96, vivo {'context': 'I-in vivo'}", + "98, mouse {'context': 'B-organism'}", + "99, models. {'context': 'I-organism'}", + "115, donor {'context': 'B-cells'}", + "116, T {'context': 'I-cells'}", + "117, cells {'context': 'I-cells'}", + "119, TRAIL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "122, mice {'context': 'B-organism'}", + "133, alloreactive {'context': 'B-cells'}", + "134, T {'context': 'I-cells'}", + "135, cells {'context': 'I-cells'}", + "141, absence {'perturbing_action': 'B-gene loss-of-function'}", + "142, of {'perturbing_action': 'I-gene loss-of-function'}", + "143, TRAIL {'perturbing_action': 'I-gene loss-of-function'}", + "155, TRAIL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "156, T {'context': 'B-cells'}", + "157, cells {'context': 'I-cells'}", + "165, TRAIL-expressing {'context': 'B-cells'}", + "166, T {'context': 'I-cells'}", + "167, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "81, T ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "82, cells ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "95, in ['l1', 'l7', 'l15', 'l16', 'l17']", + "96, vivo ['l2', 'l8', 'l15', 'l18', 'l19']", + "98, mouse ['l3', 'l9', 'l16', 'l18', 'l20']", + "99, models. ['l4', 'l10', 'l17', 'l19', 'l20']", + "115, donor ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "116, T ['l5', 'l11', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "117, cells ['l6', 'l12', 'l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "119, TRAIL-deficient ['l13', 'l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "122, mice ['l14', 'l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "133, alloreactive ['l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47', 'l48', 'l49', 'l50']", + "134, T ['l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l51', 'l52', 'l53']", + "135, cells ['l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l51', 'l54', 'l55']", + "141, absence ['l48', 'l56', 'l57', 'l58', 'l59']", + "142, of ['l49', 'l52', 'l54', 'l56', 'l60', 'l61', 'l62']", + "143, TRAIL ['l50', 'l53', 'l55', 'l57', 'l60', 'l63', 'l64']", + "155, TRAIL-deficient ['l65', 'l66', 'l67', 'l68', 'l69']", + "156, T ['l58', 'l61', 'l63', 'l65', 'l70', 'l71', 'l72']", + "157, cells ['l59', 'l62', 'l64', 'l66', 'l70', 'l73', 'l74']", + "165, TRAIL-expressing ['l67', 'l75', 'l76']", + "166, T ['l68', 'l71', 'l73', 'l75', 'l77']", + "167, cells, ['l69', 'l72', 'l74', 'l76', 'l77']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells", + "donor", + "T", + "alloreactive", + "TRAIL-expressing", + "cells," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TRAIL-deficient", + "absence", + "of", + "TRAIL" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TRAIL-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "12415261", + "TEXT": "Tumor cells are elusive targets for immunotherapy due to their heterogeneity and genetic instability. Here we describe a novel, oral DNA vaccine that targets stable, proliferating endothelial cells in the tumor vasculature rather than tumor cells. Targeting occurs through upregulated vascular-endothelial growth factor receptor 2 (FLK-1) of proliferating endothelial cells in the tumor vasculature. This vaccine effectively protected mice from lethal challenges with melanoma, colon carcinoma and lung carcinoma cells and reduced growth of established metastases in a therapeutic setting. CTL-mediated killing of endothelial cells indicated breaking of peripheral immune tolerance against this self antigen, resulting in markedly reduced dissemination of spontaneous and experimental pulmonary metastases. Angiogenesis in the tumor vasculature was suppressed without impairment of fertility, neuromuscular performance or hematopoiesis, albeit with a slight delay in wound healing. Our strategy circumvents problems in targeting of genetically unstable tumor cells. This approach may provide a new strategy for the rational design of cancer therapies.", + "TAG_DATA": [ + "58, mice {'context': 'B-organism'}", + "63, melanoma, {'context': 'B-neoplasm'}", + "64, colon {'context': 'B-neoplasm'}", + "65, carcinoma {'context': 'I-neoplasm'}", + "67, lung {'context': 'B-transformed cells'}", + "68, carcinoma {'context': 'I-transformed cells'}", + "69, cells {'context': 'I-transformed cells'}", + "71, reduced {'effect': 'B-negative'}", + "75, metastases {'phenotype': 'B-metastasis'}", + "83, endothelial {'context': 'B-cells'}", + "84, cells {'context': 'I-cells'}", + "104, pulmonary {'phenotype': 'B-metastasis'}", + "105, metastases. {'phenotype': 'I-metastasis'}", + "109, tumor {'context': 'B-tissue/organ'}", + "110, vasculature {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "58, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "63, melanoma, ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "64, colon ['l1', 'l7', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "65, carcinoma ['l2', 'l8', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "67, lung ['l3', 'l9', 'l15', 'l20', 'l25', 'l26', 'l27', 'l28']", + "68, carcinoma ['l4', 'l10', 'l16', 'l21', 'l25', 'l29', 'l30', 'l31']", + "69, cells ['l5', 'l11', 'l17', 'l22', 'l26', 'l29', 'l32']", + "71, reduced ['l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "75, metastases ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l32', 'l33', 'l35']", + "83, endothelial ['l36', 'l37', 'l38']", + "84, cells ['l34', 'l35', 'l36', 'l39', 'l40']", + "104, pulmonary ['l37', 'l39', 'l41']", + "105, metastases. ['l38', 'l40', 'l41']", + "109, tumor ['l42']", + "110, vasculature ['l42']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "melanoma,", + "colon", + "carcinoma" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "melanoma,", + "colon", + "carcinoma" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "lung", + "carcinoma" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "lung", + "carcinoma", + "cells" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastases", + "pulmonary", + "metastases." + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "endothelial" + ] + } + } + ] + }, + { + "PMID": "12161749", + "TEXT": "The hematopoietic-restricted protein Src homology 2-containing inositol-5-phosphatase (SHIP) blunts phosphatidylinositol-3-kinase-initiated signaling by dephosphorylating its major substrate, phosphatidylinositol-3,4,5-trisphosphate. As SHIP(-/-) mice contain increased numbers of osteoclast precursors, that is, macrophages, we examined bones from these animals and found that osteoclast number is increased two-fold. This increased number is due to the prolonged life span of these cells and to hypersensitivity of precursors to macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappa B ligand (RANKL). Similar to pagetic osteoclasts, SHIP(-/-) osteoclasts are enlarged, containing upwards of 100 nuclei, and exhibit enhanced resorptive activity. Moreover, as in Paget disease, serum levels of interleukin-6 are markedly increased in SHIP(-/-) mice. Consistent with accelerated resorptive activity, 3D trabecular volume fraction, trabecular thickness, number and connectivity density of SHIP(-/-) long bones are reduced, resulting in a 22% loss of bone-mineral density and a 49% decrease in fracture energy. Thus, SHIP negatively regulates osteoclast formation and function and the absence of this enzyme results in severe osteoporosis.", + "TAG_DATA": [ + "18, SHIP(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "79, SHIP(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "80, osteoclasts {'context': 'B-cells'}", + "106, SHIP(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "107, mice. {'context': 'B-organism'}", + "124, SHIP(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "125, long {'context': 'B-tissue/organ'}", + "126, bones {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "79, SHIP(-/-) ['l0', 'l1', 'l2']", + "80, osteoclasts ['l0', 'l3']", + "106, SHIP(-/-) ['l1', 'l4']", + "107, mice. ['l2', 'l3', 'l4']", + "124, SHIP(-/-) ['l5', 'l6']", + "125, long ['l5', 'l7']", + "126, bones ['l6', 'l7']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHIP(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclasts" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHIP(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHIP(-/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "long", + "bones" + ] + } + } + ] + }, + { + "PMID": "12161748", + "TEXT": "In both pediatric and adult patients, cranial radiation therapy causes a debilitating cognitive decline that is poorly understood and currently untreatable. This decline is characterized by hippocampal dysfunction, and seems to involve a radiation-induced decrease in postnatal hippocampal neurogenesis. Here we show that the deficit in neurogenesis reflects alterations in the microenvironment that regulates progenitor-cell fate, as well as a defect in the proliferative capacity of the neural progenitor-cell population. Not only is hippocampal neurogenesis ablated, but the remaining neural precursors adopt glial fates and transplants of non-irradiated neural precursor cells fail to differentiate into neurons in the irradiated hippocampus. The inhibition of neurogenesis is accompanied by marked alterations in the neurogenic microenvironment, including disruption of the microvascular angiogenesis associated with adult neurogenesis and a marked increase in the number and activation status of microglia within the neurogenic zone. These findings provide clear targets for future therapeutic interventions.", + "TAG_DATA": [ + "79, neural {'context': 'B-cells'}", + "80, precursors {'context': 'I-cells'}", + "88, neural {'context': 'B-cells'}", + "89, precursor {'context': 'I-cells'}", + "90, cells {'context': 'I-cells'}", + "91, fail {'effect': 'B-negative'}", + "92, to {'effect': 'I-negative'}", + "93, differentiate {'phenotype': 'B-differentiation'}", + "95, neurons {'context': 'B-cells', 'phenotype': 'B-differentiation'}", + "99, hippocampus. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "79, neural ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "80, precursors ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "88, neural ['l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "89, precursor ['l12', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "90, cells ['l1', 'l13', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "91, fail ['l2', 'l7', 'l14', 'l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "92, to ['l3', 'l8', 'l15', 'l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "93, differentiate ['l4', 'l9', 'l16', 'l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "95, neurons ['l5', 'l10', 'l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "99, hippocampus. ['l6', 'l11', 'l18', 'l24', 'l29', 'l33', 'l36', 'l38', 'l39']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "neural", + "precursors", + "precursor", + "cells", + "neurons" + ] + }, + "effect": { + "val": "negative", + "words": [ + "fail", + "to" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neural", + "precursors", + "precursor", + "cells", + "neurons" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate", + "neurons" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "fail", + "to" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate", + "neurons" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "fail", + "to" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate", + "neurons" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus." + ] + } + } + ] + }, + { + "PMID": "12161747", + "TEXT": "In the adult brain, new neurons are continuously generated in the subventricular zone and dentate gyrus, but it is unknown whether these neurons can replace those lost following damage or disease. Here we show that stroke, caused by transient middle cerebral artery occlusion in adult rats, leads to a marked increase of cell proliferation in the subventricular zone. Stroke-generated new neurons, as well as neuroblasts probably already formed before the insult, migrate into the severely damaged area of the striatum, where they express markers of developing and mature, striatal medium-sized spiny neurons. Thus, stroke induces differentiation of new neurons into the phenotype of most of the neurons destroyed by the ischemic lesion. Here we show that the adult brain has the capacity for self-repair after insults causing extensive neuronal death. If the new neurons are functional and their formation can be stimulated, a novel therapeutic strategy might be developed for stroke in humans.", + "TAG_DATA": [ + "44, adult {'context': 'B-organism'}", + "45, rats, {'context': 'I-organism'}", + "50, increase {'effect': 'B-positive'}", + "52, cell {'context': 'B-cells'}", + "53, proliferation {'phenotype': 'B-proliferation'}", + "57, zone. {'context': 'I-tissue/organ'}", + "59, new {'context': 'B-cells'}", + "60, neurons, {'context': 'B-cells'}", + "94, induces {'effect': 'B-positive'}", + "95, differentiation {'phenotype': 'B-differentiation'}", + "97, new {'context': 'B-cells'}", + "98, neurons {'context': 'I-cells'}", + "106, neurons {'context': 'B-cells'}", + "118, brain {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "44, adult ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "45, rats, ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "50, increase ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "52, cell ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "53, proliferation ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "56, subventricular ['l4', 'l9', 'l13', 'l16', 'l18', 'l20', 'l21', 'l22']", + "57, zone. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20', 'l23']", + "59, new ['l21', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "60, neurons, ['l22', 'l23', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "94, induces ['l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "95, differentiation ['l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "97, new ['l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "98, neurons ['l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "106, neurons ['l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "117, adult ['l45']", + "118, brain ['l45']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "adult", + "rats," + ] + }, + "effect": { + "val": "positive", + "words": [ + "increase" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "adult", + "rats," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase", + "induces" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "new", + "neurons,", + "neurons" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "zone." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "zone." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "new", + "neurons,", + "neurons" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "12134144", + "TEXT": "Non-invasive imaging and transcriptional targeting can improve the safety of therapeutic approaches in cancer. Here we demonstrate the ability to identify metastases in a human-prostate cancer model, employing a prostate-specific adenovirus vector (AdPSE-BC-luc) and a charge-coupled device-imaging system. AdPSE-BC-luc, which expresses firefly luciferase from an enhanced prostate-specific antigen promoter, restricted expression in the liver but produced robust signals in prostate tumors. In fact, expression was higher in advanced, androgen-independent tumors than in androgen-dependent lesions. Repetitive imaging over a three-week period after AdPSE-BC-luc injection into tumor-bearing mice revealed that the virus could locate and illuminate metastases in the lung and spine. Systemic injection of low doses of AdPSE-BC-luc illuminated lung metastasis. These results demonstrate the potential use of a non-invasive imaging modality in therapeutic and diagnostic strategies to manage prostate cancer.", + "TAG_DATA": [ + "59, prostate {'context': 'B-neoplasm'}", + "60, tumors. {'context': 'I-neoplasm'}", + "84, tumor-bearing {'context': 'B-organism'}", + "85, mice {'context': 'I-organism'}", + "94, metastases {'phenotype': 'B-metastasis'}", + "97, lung {'context': 'B-tissue/organ'}", + "99, spine. {'context': 'B-tissue/organ'}", + "108, lung {'phenotype': 'B-metastasis'}", + "109, metastasis. {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "59, prostate ['l0']", + "60, tumors. ['l0']", + "84, tumor-bearing ['l1', 'l2', 'l3', 'l4']", + "85, mice ['l1', 'l5', 'l6', 'l7']", + "94, metastases ['l2', 'l5', 'l8', 'l9']", + "97, lung ['l3', 'l6', 'l8', 'l10']", + "99, spine. ['l4', 'l7', 'l9', 'l10']", + "107, illuminated ['l11', 'l12']", + "108, lung ['l11', 'l13']", + "109, metastasis. ['l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "tumor-bearing", + "mice" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung", + "spine." + ] + } + } + ] + }, + { + "PMID": "12134143", + "TEXT": "Heart septation and valve malformations constitute the most common anatomical birth defects. These structures arise from the endocardial cushions within the atrioventricular canal (AVC) through dynamic interactions between cushion cells and the extracellular matrix (termed cardiac jelly). Transformation of endothelial cells to mesenchymal cells is essential for the proper development of the AVC and subsequent septation and valve formation. Atrioventricular septal defects can result from incomplete endocardial cushion morphogenesis. We show that hyaluronan-deficient AVC explants from Has2(-/-) embryos, which normally lack mesenchyme formation, are rescued by heregulin treatment, which restores phosphorylation of ErbB2 and ErbB3. These events were blocked using a soluble ErbB3 molecule, as well as with an inhibitor of ErbB2, herstatin. We show further that ErbB3 is activated during hyaluronan treatment of Has2(-/-) explants. These data provide a link between extracellular matrix-hyaluronan and ErbB receptor activation during development of early heart-valve and septal mesenchyme.", + "TAG_DATA": [ + "73, AVC {'context': 'B-tissue/organ'}", + "74, explants {'context': 'I-tissue/organ'}", + "76, Has2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "77, embryos, {'context': 'B-organism'}", + "109, inhibitor {'perturbing_action': 'B-pharmacological inhibition'}", + "110, of {'perturbing_action': 'I-pharmacological inhibition'}", + "111, ErbB2, {'perturbing_action': 'I-pharmacological inhibition'}", + "112, herstatin. {'perturbing_action': 'I-pharmacological inhibition'}", + "124, Has2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "125, explants. {'context': 'B-organoid'}" + ], + "LINK_DATA": [ + "73, AVC ['l0', 'l1', 'l2']", + "74, explants ['l0', 'l3', 'l4']", + "76, Has2(-/-) ['l1', 'l3', 'l5']", + "77, embryos, ['l2', 'l4', 'l5']", + "109, inhibitor ['l6', 'l7', 'l8', 'l9', 'l10']", + "110, of ['l6', 'l11', 'l12', 'l13', 'l14']", + "111, ErbB2, ['l7', 'l11', 'l15', 'l16', 'l17']", + "112, herstatin. ['l8', 'l12', 'l15', 'l18', 'l19']", + "124, Has2(-/-) ['l9', 'l13', 'l16', 'l18', 'l20']", + "125, explants. ['l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "AVC", + "explants" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Has2(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Has2(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "embryos," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitor", + "of", + "ErbB2,", + "herstatin." + ] + }, + "context": { + "val": "organoid", + "words": [ + "explants." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Has2(-/-)" + ] + }, + "context": { + "val": "organoid", + "words": [ + "explants." + ] + } + } + ] + }, + { + "PMID": "12118246", + "TEXT": "Both enteroviral infection of the heart and mutations in the dystrophin gene can cause cardiomyopathy. Little is known, however, about the interaction between genetic and acquired forms of cardiomyopathy. We previously demonstrated that the enteroviral protease 2A cleaves dystrophin; therefore, we hypothesized that dystrophin deficiency would predispose to enterovirus-induced cardiomyopathy. We observed more severe cardiomyopathy, worsening over time, and greater viral replication in dystrophin-deficient mice infected with enterovirus than in infected wild-type mice. This difference appears to be a result of more efficient release of the virus from dystrophin-deficient myocytes. In addition, we found that expression of wild-type dystrophin in cultured cells decreased the cytopathic effect of enteroviral infection and the release of virus from the cell. We also found that expression of a cleavage-resistant mutant dystrophin further inhibited the virally mediated cytopathic effect and viral release. These results indicate that viral infection can influence the severity and penetrance of the cardiomyopathy that occurs in the hearts of dystrophin-deficient individuals.", + "TAG_DATA": [ + "63, dystrophin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "64, mice {'context': 'B-organism'}", + "72, mice. {'context': 'B-organism'}", + "88, dystrophin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "89, myocytes. {'context': 'B-cells'}", + "95, expression {'perturbing_action': 'B-other'}", + "96, of {'perturbing_action': 'I-other'}", + "97, wild-type {'perturbing_action': 'I-other'}", + "98, dystrophin {'perturbing_action': 'I-other'}", + "100, cultured {'context': 'B-cells'}", + "101, cells {'context': 'I-cells'}", + "116, cell. {'context': 'B-cells'}", + "121, expression {'perturbing_action': 'B-other'}", + "122, of {'perturbing_action': 'I-other'}", + "123, a {'perturbing_action': 'I-other'}", + "124, cleavage-resistant {'perturbing_action': 'I-other'}", + "125, mutant {'perturbing_action': 'I-other'}", + "126, dystrophin {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "63, dystrophin-deficient ['l0', 'l1', 'l2', 'l3']", + "64, mice ['l0', 'l4', 'l5']", + "72, mice. ['l1', 'l4', 'l6', 'l7', 'l8']", + "88, dystrophin-deficient ['l2', 'l6', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "89, myocytes. ['l3', 'l5', 'l7', 'l9', 'l17']", + "95, expression ['l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "96, of ['l11', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "97, wild-type ['l12', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32']", + "98, dystrophin ['l13', 'l20', 'l25', 'l29', 'l33', 'l34', 'l35']", + "100, cultured ['l14', 'l21', 'l26', 'l30', 'l33', 'l36', 'l37']", + "101, cells ['l8', 'l15', 'l17', 'l22', 'l27', 'l31', 'l34', 'l36', 'l38']", + "116, cell. ['l16', 'l23', 'l28', 'l32', 'l35', 'l37', 'l38']", + "121, expression ['l39', 'l40', 'l41', 'l42', 'l43']", + "122, of ['l39', 'l44', 'l45', 'l46', 'l47']", + "123, a ['l40', 'l44', 'l48', 'l49', 'l50']", + "124, cleavage-resistant ['l41', 'l45', 'l48', 'l51', 'l52']", + "125, mutant ['l42', 'l46', 'l49', 'l51', 'l53']", + "126, dystrophin ['l43', 'l47', 'l50', 'l52', 'l53']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "myocytes.", + "cultured", + "cells", + "cell." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "wild-type", + "dystrophin" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "cells", + "cell." + ] + } + } + ] + }, + { + "PMID": "12101409", + "TEXT": "We recently isolated a Krüppel-like zinc-finger transcription factor 5 (KLF5; also known as BTEB2 and IKLF), which is markedly induced in activated vascular smooth-muscle cells and fibroblasts. Here we describe our analysis of the in vivo function of KLF5 using heterozygous KLF5-knockout mice (Klf5(+/-)). In response to external stress, Klf5(+/-) mice showed diminished levels of arterial-wall thickening, angiogenesis, cardiac hypertrophy and interstitial fibrosis. Also, angiotensin II induced expression of KLF5, which in turn activated platelet-derived growth factor-A (PDGF-A) and transforming growth factor-beta (TGF-beta) expression. In addition, we determined that KLF5 interacted with the retinoic-acid receptor (RAR), that synthetic RAR ligands modulated KLF5 transcriptional activity, and that in vivo administration of RAR ligands affected stress responses in the cardiovascular system in a KLF5-dependent manner. KLF5 thus seems to be a key element linking external stress and cardiovascular remodeling.", + "TAG_DATA": [ + "40, heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "41, KLF5-knockout {'perturbing_action': 'I-gene loss-of-function'}", + "42, mice {'context': 'B-organism'}", + "43, (Klf5(+/-)). {'perturbing_action': 'I-gene loss-of-function'}", + "49, Klf5(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "50, mice {'context': 'B-organism'}", + "106, in {'context': 'B-in vivo'}", + "107, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "40, heterozygous ['l0', 'l1', 'l2', 'l3', 'l4']", + "41, KLF5-knockout ['l0', 'l5', 'l6', 'l7', 'l8']", + "42, mice ['l1', 'l5', 'l9', 'l10', 'l11']", + "43, (Klf5(+/-)). ['l2', 'l6', 'l9', 'l12', 'l13']", + "49, Klf5(+/-) ['l3', 'l7', 'l10', 'l12', 'l14']", + "50, mice ['l4', 'l8', 'l11', 'l13', 'l14']", + "106, in ['l15']", + "107, vivo ['l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "heterozygous", + "KLF5-knockout", + "(Klf5(+/-)).", + "Klf5(+/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "12053176", + "TEXT": "Respiratory distress syndrome (RDS) due to insufficient production of surfactant is a common and severe complication of preterm delivery. Here, we report that loss of the hypoxia-inducible transcription factor-2alpha (HIF-2alpha) caused fatal RDS in neonatal mice due to insufficient surfactant production by alveolar type 2 cells. VEGF, a target of HIF-2alpha, regulates fetal lung maturation: because VEGF levels in alveolar cells were reduced in HIF-2alpha-deficient fetuses; mice with a deficiency of the VEGF(164) and VEGF(188) isoforms or of the HIF-binding site in the VEGF promotor died of RDS; intrauterine delivery of anti-VEGF-receptor-2 antibodies caused RDS and VEGF stimulated production of surfactant proteins by cultured type 2 pneumocytes. Intrauterine delivery or postnatal intratracheal instillation of VEGF stimulated conversion of glycogen to surfactant and protected preterm mice against RDS. The pneumotrophic effect of VEGF may have therapeutic potential for lung maturation in preterm infants.", + "TAG_DATA": [ + "23, loss {'perturbing_action': 'B-gene loss-of-function'}", + "24, of {'perturbing_action': 'I-gene loss-of-function'}", + "25, the {'perturbing_action': 'I-gene loss-of-function'}", + "26, hypoxia-inducible {'perturbing_action': 'I-gene loss-of-function'}", + "27, transcription {'perturbing_action': 'I-gene loss-of-function'}", + "28, factor-2alpha {'perturbing_action': 'I-gene loss-of-function'}", + "29, (HIF-2alpha) {'perturbing_action': 'I-gene loss-of-function'}", + "34, neonatal {'context': 'B-organism'}", + "35, mice {'context': 'I-organism'}", + "64, HIF-2alpha-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "66, mice {'context': 'B-organism'}", + "69, deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "70, of {'perturbing_action': 'I-gene loss-of-function'}", + "71, the {'perturbing_action': 'I-gene loss-of-function'}", + "72, VEGF(164) {'perturbing_action': 'I-gene loss-of-function'}", + "73, and {'perturbing_action': 'I-gene loss-of-function'}", + "74, VEGF(188) {'perturbing_action': 'I-gene loss-of-function'}", + "75, isoforms {'perturbing_action': 'I-gene loss-of-function'}", + "76, or {'perturbing_action': 'I-gene loss-of-function'}", + "77, of {'perturbing_action': 'I-gene loss-of-function'}", + "78, the {'perturbing_action': 'I-gene loss-of-function'}", + "79, HIF-binding {'perturbing_action': 'I-gene loss-of-function'}", + "80, site {'perturbing_action': 'I-gene loss-of-function'}", + "81, in {'perturbing_action': 'I-gene loss-of-function'}", + "82, the {'perturbing_action': 'I-gene loss-of-function'}", + "83, VEGF {'perturbing_action': 'I-gene loss-of-function'}", + "84, promotor {'perturbing_action': 'I-gene loss-of-function'}", + "104, type {'context': 'B-cells'}", + "105, 2 {'context': 'I-cells'}", + "106, pneumocytes. {'context': 'I-cells'}", + "123, preterm {'context': 'B-organism'}", + "124, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "23, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "24, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "25, the ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "26, hypoxia-inducible ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "27, transcription ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "28, factor-2alpha ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "29, (HIF-2alpha) ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "34, neonatal ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "35, mice ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "64, HIF-2alpha-deficient ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "66, mice ['l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "69, deficiency ['l45', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "70, of ['l46', 'l59', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "71, the ['l47', 'l60', 'l77', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "72, VEGF(164) ['l48', 'l61', 'l78', 'l94', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "73, and ['l49', 'l62', 'l79', 'l95', 'l110', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "74, VEGF(188) ['l50', 'l63', 'l80', 'l96', 'l111', 'l125', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151']", + "75, isoforms ['l51', 'l64', 'l81', 'l97', 'l112', 'l126', 'l139', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163']", + "76, or ['l52', 'l65', 'l82', 'l98', 'l113', 'l127', 'l140', 'l152', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "77, of ['l66', 'l83', 'l99', 'l114', 'l128', 'l141', 'l153', 'l164', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184']", + "78, the ['l67', 'l84', 'l100', 'l115', 'l129', 'l142', 'l154', 'l165', 'l175', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "79, HIF-binding ['l68', 'l85', 'l101', 'l116', 'l130', 'l143', 'l155', 'l166', 'l176', 'l185', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201']", + "80, site ['l69', 'l86', 'l102', 'l117', 'l131', 'l144', 'l156', 'l167', 'l177', 'l186', 'l194', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208']", + "81, in ['l70', 'l87', 'l103', 'l118', 'l132', 'l145', 'l157', 'l168', 'l178', 'l187', 'l195', 'l202', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214']", + "82, the ['l53', 'l71', 'l88', 'l104', 'l119', 'l133', 'l146', 'l158', 'l169', 'l179', 'l188', 'l196', 'l203', 'l209', 'l215', 'l216', 'l217', 'l218', 'l219']", + "83, VEGF ['l54', 'l72', 'l89', 'l105', 'l120', 'l134', 'l147', 'l159', 'l170', 'l180', 'l189', 'l197', 'l204', 'l210', 'l215', 'l220', 'l221', 'l222', 'l223']", + "84, promotor ['l55', 'l73', 'l90', 'l106', 'l121', 'l135', 'l148', 'l160', 'l171', 'l181', 'l190', 'l198', 'l205', 'l211', 'l216', 'l220', 'l224', 'l225', 'l226']", + "104, type ['l56', 'l74', 'l91', 'l107', 'l122', 'l136', 'l149', 'l161', 'l172', 'l182', 'l191', 'l199', 'l206', 'l212', 'l217', 'l221', 'l224', 'l227', 'l228']", + "105, 2 ['l57', 'l75', 'l92', 'l108', 'l123', 'l137', 'l150', 'l162', 'l173', 'l183', 'l192', 'l200', 'l207', 'l213', 'l218', 'l222', 'l225', 'l227', 'l229']", + "106, pneumocytes. ['l58', 'l76', 'l93', 'l109', 'l124', 'l138', 'l151', 'l163', 'l174', 'l184', 'l193', 'l201', 'l208', 'l214', 'l219', 'l223', 'l226', 'l228', 'l229']", + "123, preterm ['l230']", + "124, mice ['l230']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "hypoxia-inducible", + "transcription", + "factor-2alpha", + "(HIF-2alpha)", + "HIF-2alpha-deficient", + "deficiency", + "VEGF(164)", + "and", + "VEGF(188)", + "isoforms", + "or", + "VEGF", + "promotor" + ] + }, + "context": { + "val": "organism", + "words": [ + "neonatal", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "of", + "the", + "VEGF(164)", + "and", + "VEGF(188)", + "isoforms", + "or", + "HIF-binding", + "site", + "in", + "VEGF", + "promotor" + ] + }, + "context": { + "val": "cells", + "words": [ + "type", + "2", + "pneumocytes." + ] + } + } + ] + }, + { + "PMID": "12053174", + "TEXT": "Loss of cardiomyocytes through programmed cell death is a key event in the development of heart failure, but the inciting molecular mechanisms are largely unknown. We used microarray analysis to identify a genetic program for myocardial apoptosis in Gq-mediated and pressure-overload cardiac hypertrophy. A critical component of this apoptotic program was Nix/Bnip3L. Nix localized to mitochondria and caused release of cytochrome c, activation of caspase-3 and apoptotic cell death, when expressed in HEK293 fibroblasts. A previously undescribed truncated Nix isoform, termed sNix, was not targeted to mitochondria but heterodimerized with Nix and protected against Nix-mediated apoptosis. Forced in vivo myocardial expression of Nix resulted in apoptotic cardiomyopathy and rapid death. Conversely, sNix protected against apoptotic peripartum cardiomyopathy in G(alpha)q-overexpressors. Thus, Nix/Bnip3L is upregulated in myocardial hypertrophy, and is both necessary and sufficient for Gq-mediated apoptosis of cardiomyocytes and resulting hypertrophy decompensation.", + "TAG_DATA": [ + "66, apoptotic {'phenotype': 'B-apoptosis'}", + "67, cell {'phenotype': 'I-apoptosis'}", + "68, death, {'phenotype': 'I-apoptosis'}", + "72, HEK293 {'context': 'B-cells'}", + "73, fibroblasts. {'context': 'I-cells'}", + "92, protected {'effect': 'B-negative'}", + "93, against {'effect': 'I-negative'}", + "94, Nix-mediated {'effect': 'B-regulates'}", + "95, apoptosis. {'phenotype': 'B-apoptosis'}", + "96, Forced {'perturbing_action': 'B-gene gain-of-function'}", + "97, in {'context': 'B-in vivo'}", + "98, vivo {'context': 'I-in vivo'}", + "99, myocardial {'perturbing_action': 'I-gene gain-of-function'}", + "100, expression {'perturbing_action': 'I-gene gain-of-function'}", + "101, of {'perturbing_action': 'I-gene gain-of-function'}", + "102, Nix {'perturbing_action': 'I-gene gain-of-function'}", + "118, G(alpha)q-overexpressors. {'perturbing_action': 'B-gene gain-of-function'}" + ], + "LINK_DATA": [ + "66, apoptotic ['l0', 'l1', 'l2', 'l3']", + "67, cell ['l0', 'l4', 'l5', 'l6']", + "68, death, ['l1', 'l4', 'l7', 'l8']", + "72, HEK293 ['l2', 'l5', 'l7', 'l9']", + "73, fibroblasts. ['l3', 'l6', 'l8', 'l9']", + "92, protected ['l10', 'l11', 'l12']", + "93, against ['l10', 'l13', 'l14']", + "94, Nix-mediated ['l11', 'l13', 'l15']", + "95, apoptosis. ['l12', 'l14', 'l15']", + "96, Forced ['l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "97, in ['l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "98, vivo ['l17', 'l22', 'l27', 'l28', 'l29', 'l30']", + "99, myocardial ['l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "100, expression ['l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "101, of ['l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "102, Nix ['l21', 'l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death," + ] + }, + "context": { + "val": "cells", + "words": [ + "HEK293", + "fibroblasts." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "protected", + "against" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "Nix-mediated" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "myocardial", + "expression", + "of", + "Nix" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "11984597", + "TEXT": "The only proven requirement for ascorbic acid (vitamin C) is in preventing scurvy, presumably because it is a cofactor for hydroxylases required for post-translational modifications that stabilize collagen. We have created mice deficient in the mouse ortholog (solute carrier family 23 member 1 or Slc23a1) of a rat ascorbic-acid transporter, Svct2 (ref. 4). Cultured embryonic fibroblasts from homozygous Slc23a1(-/-) mice had less than 5% of normal ascorbic-acid uptake. Ascorbic-acid levels were undetectable or markedly reduced in the blood and tissues of Slc23a1(-/-) mice. Prenatal supplementation of pregnant females did not elevate blood ascorbic acid in Slc23a1(-/-) fetuses, suggesting Slc23a1 is important in placental ascorbic-acid transport. Slc23a1(-/-) mice died within a few minutes of birth with respiratory failure and intraparenchymal brain hemorrhage. Lungs showed no postnatal expansion but had normal surfactant protein B levels. Brain hemorrhage was unlikely to be simply a form of scurvy since Slc23a1(-/-) mice showed no hemorrhage in any other tissues and their skin had normal skin 4-hydroxyproline levels despite low ascorbic-acid content. We conclude that Slc23a1 is required for transport of ascorbic acid into many tissues and across the placenta. Deficiency of the transporter is lethal in newborn mice, thereby revealing a previously unrecognized requirement for ascorbic acid in the perinatal period.", + "TAG_DATA": [ + "31, mice {'context': 'B-organism'}", + "32, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "33, in {'perturbing_action': 'I-gene loss-of-function'}", + "34, the {'perturbing_action': 'I-gene loss-of-function'}", + "35, mouse {'perturbing_action': 'I-gene loss-of-function'}", + "36, ortholog {'perturbing_action': 'I-gene loss-of-function'}", + "37, (solute {'perturbing_action': 'I-gene loss-of-function'}", + "38, carrier {'perturbing_action': 'I-gene loss-of-function'}", + "39, family {'perturbing_action': 'I-gene loss-of-function'}", + "40, 23 {'perturbing_action': 'I-gene loss-of-function'}", + "41, member {'perturbing_action': 'I-gene loss-of-function'}", + "42, 1 {'perturbing_action': 'I-gene loss-of-function'}", + "43, or {'perturbing_action': 'I-gene loss-of-function'}", + "44, Slc23a1) {'perturbing_action': 'I-gene loss-of-function'}", + "45, of {'perturbing_action': 'I-gene loss-of-function'}", + "54, embryonic {'context': 'I-cells'}", + "55, fibroblasts {'context': 'I-cells'}", + "57, homozygous {'perturbing_action': 'B-gene loss-of-function'}", + "58, Slc23a1(-/-) {'perturbing_action': 'I-other'}", + "59, mice {'context': 'B-organism'}", + "81, Slc23a1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "82, mice. {'context': 'B-organism'}", + "87, females {'context': 'I-organism'}", + "95, Slc23a1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "96, fetuses, {'context': 'B-organism'}", + "105, Slc23a1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "106, mice {'context': 'B-organism'}", + "121, Lungs {'context': 'B-tissue/organ'}", + "145, Slc23a1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "146, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "31, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "32, deficient ['l0', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "33, in ['l1', 'l21', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "34, the ['l2', 'l22', 'l41', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "35, mouse ['l3', 'l23', 'l42', 'l60', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "36, ortholog ['l4', 'l24', 'l43', 'l61', 'l79', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "37, (solute ['l5', 'l25', 'l44', 'l62', 'l80', 'l98', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "38, carrier ['l6', 'l26', 'l45', 'l63', 'l81', 'l99', 'l117', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "39, family ['l7', 'l27', 'l46', 'l64', 'l82', 'l100', 'l118', 'l136', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171']", + "40, 23 ['l8', 'l28', 'l47', 'l65', 'l83', 'l101', 'l119', 'l137', 'l154', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "41, member ['l9', 'l29', 'l48', 'l66', 'l84', 'l102', 'l120', 'l138', 'l155', 'l172', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "42, 1 ['l10', 'l30', 'l49', 'l67', 'l85', 'l103', 'l121', 'l139', 'l156', 'l173', 'l189', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218']", + "43, or ['l11', 'l31', 'l50', 'l68', 'l86', 'l104', 'l122', 'l140', 'l157', 'l174', 'l190', 'l205', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230']", + "44, Slc23a1) ['l12', 'l32', 'l51', 'l69', 'l87', 'l105', 'l123', 'l141', 'l158', 'l175', 'l191', 'l206', 'l219', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241']", + "45, of ['l13', 'l33', 'l52', 'l70', 'l88', 'l106', 'l124', 'l142', 'l159', 'l176', 'l192', 'l207', 'l220', 'l231', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249']", + "54, embryonic ['l14', 'l34', 'l53', 'l71', 'l89', 'l107', 'l125', 'l143', 'l160', 'l177', 'l193', 'l208', 'l221', 'l232', 'l242', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255']", + "55, fibroblasts ['l15', 'l35', 'l54', 'l72', 'l90', 'l108', 'l126', 'l144', 'l161', 'l178', 'l194', 'l209', 'l222', 'l233', 'l243', 'l250', 'l256', 'l257', 'l258', 'l259', 'l260']", + "57, homozygous ['l16', 'l36', 'l55', 'l73', 'l91', 'l109', 'l127', 'l145', 'l162', 'l179', 'l195', 'l210', 'l223', 'l234', 'l244', 'l251', 'l256', 'l261', 'l262', 'l263', 'l264']", + "58, Slc23a1(-/-) ['l17', 'l37', 'l56', 'l74', 'l92', 'l110', 'l128', 'l146', 'l163', 'l180', 'l196', 'l211', 'l224', 'l235', 'l245', 'l252', 'l257', 'l261', 'l265', 'l266', 'l267']", + "59, mice ['l18', 'l38', 'l57', 'l75', 'l93', 'l111', 'l129', 'l147', 'l164', 'l181', 'l197', 'l212', 'l225', 'l236', 'l246', 'l253', 'l258', 'l262', 'l265', 'l268']", + "81, Slc23a1(-/-) ['l19', 'l39', 'l58', 'l76', 'l94', 'l112', 'l130', 'l148', 'l165', 'l182', 'l198', 'l213', 'l226', 'l237', 'l247', 'l254', 'l259', 'l263', 'l266', 'l269']", + "82, mice. ['l20', 'l40', 'l59', 'l77', 'l95', 'l113', 'l131', 'l149', 'l166', 'l183', 'l199', 'l214', 'l227', 'l238', 'l248', 'l255', 'l260', 'l264', 'l267', 'l268', 'l269']", + "87, females ['l78', 'l96', 'l114', 'l132', 'l150', 'l167', 'l184', 'l200', 'l215', 'l228', 'l239', 'l249', 'l270', 'l271', 'l272', 'l273', 'l274']", + "95, Slc23a1(-/-) ['l168', 'l185', 'l201', 'l270', 'l275', 'l276', 'l277', 'l278']", + "96, fetuses, ['l115', 'l133', 'l151', 'l169', 'l186', 'l202', 'l216', 'l229', 'l240', 'l271', 'l275', 'l279', 'l280', 'l281']", + "105, Slc23a1(-/-) ['l134', 'l152', 'l170', 'l187', 'l203', 'l217', 'l272', 'l276', 'l279', 'l282', 'l283']", + "106, mice ['l97', 'l116', 'l135', 'l153', 'l171', 'l188', 'l204', 'l218', 'l230', 'l241', 'l273', 'l277', 'l280', 'l282', 'l284']", + "121, Lungs ['l274', 'l278', 'l281', 'l283', 'l284']", + "145, Slc23a1(-/-) ['l285']", + "146, mice ['l285']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "females", + "fetuses," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "the", + "mouse", + "ortholog", + "(solute", + "carrier", + "family", + "23", + "member", + "1", + "or", + "Slc23a1)", + "of", + "homozygous", + "Slc23a1(-/-)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Slc23a1(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "the", + "mouse", + "ortholog", + "(solute", + "carrier", + "family", + "23", + "member", + "1", + "or", + "Slc23a1)", + "of", + "homozygous", + "Slc23a1(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "embryonic", + "fibroblasts" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "embryonic", + "fibroblasts" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Slc23a1(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Slc23a1(-/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "Lungs" + ] + } + } + ] + }, + { + "PMID": "11821898", + "TEXT": "An expanded polyglutamine domain in huntingtin underlies the pathogenic events in Huntington disease (HD), characterized by chorea, dementia and severe weight loss, culminating in death. Transglutaminase (TGase) may be critical in the pathogenesis, via cross-linking huntingtin. Administration of the TGase competitive inhibitor, cystamine, to transgenic mice expressing exon 1 of huntingtin containing an expanded polyglutamine repeat, altered the course of their HD-like disease. Cystamine given intraperitoneally entered brain where it inhibited TGase activity. When treatment began after the appearance of abnormal movements, cystamine extended survival, reduced associated tremor and abnormal movements and ameliorated weight loss. Treatment did not influence the appearance or frequency of neuronal nuclear inclusions. Unexpectedly, cystamine treatment increased transcription of one of the two genes shown to be neuroprotective for polyglutamine toxicity in Drosophila, dnaj (also known as HDJ1 and Hsp40 in humans and mice, respectively). Inhibition of TGase provides a new treatment strategy for HD and other polyglutamine diseases.", + "TAG_DATA": [ + "44, transgenic {'context': 'B-organism'}", + "45, mice {'context': 'I-organism'}", + "46, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "47, exon {'perturbing_action': 'I-other'}", + "48, 1 {'perturbing_action': 'I-other'}", + "49, of {'perturbing_action': 'I-other'}", + "50, huntingtin {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "44, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "45, mice ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "46, expressing ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "47, exon ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "48, 1 ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "49, of ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "50, huntingtin ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "exon", + "1", + "of", + "huntingtin" + ] + } + } + ] + }, + { + "PMID": "11689890", + "TEXT": "The C2 domain of synaptotagmin I, which binds to anionic phospholipids in cell membranes, was shown to bind to the plasma membrane of apoptotic cells by both flow cytometry and confocal microscopy. Conjugation of the protein to superparamagnetic iron oxide nanoparticles allowed detection of this binding using magnetic resonance imaging. Detection of apoptotic cells, using this novel contrast agent, was demonstrated both in vitro, with isolated apoptotic tumor cells, and in vivo, in a tumor treated with chemotherapeutic drugs.", + "TAG_DATA": [ + "53, cells, {'phenotype': 'I-apoptosis'}", + "62, in {'context': 'B-in vitro'}", + "63, vitro, {'context': 'I-in vitro'}", + "66, apoptotic {'context': 'B-transformed cells'}", + "67, tumor {'context': 'I-transformed cells'}", + "68, cells, {'context': 'I-transformed cells'}", + "70, in {'context': 'B-in vivo'}", + "71, vivo, {'context': 'I-in vivo'}", + "74, tumor {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "53, cells, ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "62, in ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "63, vitro, ['l1', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "66, apoptotic ['l2', 'l9', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "67, tumor ['l3', 'l10', 'l15', 'l20', 'l25', 'l26', 'l27']", + "68, cells, ['l4', 'l11', 'l16', 'l21', 'l25']", + "70, in ['l5', 'l17', 'l22', 'l28', 'l29']", + "71, vivo, ['l6', 'l12', 'l18', 'l23', 'l26', 'l28', 'l30']", + "74, tumor ['l7', 'l13', 'l19', 'l24', 'l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "apoptosis", + "words": [ + "cells," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "cells," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "apoptotic", + "tumor", + "cells," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "cells," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "cells," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + } + ] + }, + { + "PMID": "11689883", + "TEXT": "The role of bone marrow (BM)-derived precursor cells in tumor angiogenesis is not known. We demonstrate here that tumor angiogenesis is associated with recruitment of hematopoietic and circulating endothelial precursor cells (CEPs). We used the angiogenic defective, tumor resistant Id-mutant mice to show that transplantation of wild-type BM or vascular endothelial growth factor (VEGF)-mobilized stem cells restore tumor angiogenesis and growth. We detected donor-derived CEPs throughout the neovessels of tumors and Matrigel-plugs in an Id1+/-Id3-/- host, which were associated with VEGF-receptor-1-positive (VEGFR1+) myeloid cells. The angiogenic defect in Id-mutant mice was due to impaired VEGF-driven mobilization of VEGFR2+ CEPs and impaired proliferation and incorporation of VEGFR1+ cells. Although targeting of either VEGFR1 or VEGFR2 alone partially blocks the growth of tumors, inhibition of both VEGFR1 and VEGFR2 was necessary to completely ablate tumor growth. These data demonstrate that recruitment of VEGF-responsive BM-derived precursors is necessary and sufficient for tumor angiogenesis and suggest new clinical strategies to block tumor growth.", + "TAG_DATA": [ + "40, mice {'context': 'B-organism'}", + "55, cells {'context': 'I-cells'}", + "57, tumor {'context': 'B-neoplasm'}", + "74, Id1+/-Id3-/- {'perturbing_action': 'B-gene loss-of-function'}", + "75, host, {'context': 'B-organism'}", + "88, Id-mutant {'perturbing_action': 'B-other'}", + "89, mice {'context': 'B-organism'}", + "100, impaired {'effect': 'B-negative'}", + "101, proliferation {'phenotype': 'B-proliferation'}", + "108, targeting {'perturbing_action': 'B-other'}", + "109, of {'perturbing_action': 'I-other'}", + "110, either {'perturbing_action': 'I-other'}", + "111, VEGFR1 {'perturbing_action': 'I-other'}", + "112, or {'perturbing_action': 'I-other'}", + "113, VEGFR2 {'perturbing_action': 'I-other'}", + "120, tumors, {'context': 'B-neoplasm'}", + "121, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "122, of {'perturbing_action': 'I-pharmacological inhibition'}", + "123, both {'perturbing_action': 'I-pharmacological inhibition'}", + "124, VEGFR1 {'perturbing_action': 'I-pharmacological inhibition'}", + "125, and {'perturbing_action': 'I-pharmacological inhibition'}", + "126, VEGFR2 {'perturbing_action': 'I-pharmacological inhibition'}", + "131, ablate {'effect': 'B-negative'}", + "132, tumor {'phenotype': 'B-tumour growth'}", + "133, growth. {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "40, mice ['l0']", + "55, cells ['l1', 'l2', 'l3', 'l4']", + "57, tumor ['l0', 'l1']", + "74, Id1+/-Id3-/- ['l2', 'l5', 'l6', 'l7']", + "75, host, ['l3', 'l5', 'l8']", + "88, Id-mutant ['l9', 'l10', 'l11']", + "89, mice ['l9', 'l12', 'l13']", + "100, impaired ['l6', 'l10', 'l12', 'l14']", + "101, proliferation ['l4', 'l7', 'l8', 'l11', 'l13', 'l14']", + "108, targeting ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "109, of ['l15', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "110, either ['l16', 'l24', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "111, VEGFR1 ['l17', 'l25', 'l32', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "112, or ['l18', 'l26', 'l33', 'l39', 'l45', 'l46', 'l47', 'l48', 'l49']", + "113, VEGFR2 ['l19', 'l27', 'l34', 'l40', 'l45', 'l50', 'l51', 'l52', 'l53']", + "120, tumors, ['l20', 'l28', 'l35', 'l41', 'l46', 'l50', 'l54', 'l55', 'l56']", + "121, inhibition ['l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "122, of ['l57', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "123, both ['l58', 'l65', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "124, VEGFR1 ['l59', 'l66', 'l72', 'l78', 'l79', 'l80', 'l81', 'l82']", + "125, and ['l60', 'l67', 'l73', 'l78', 'l83', 'l84', 'l85', 'l86']", + "126, VEGFR2 ['l61', 'l68', 'l74', 'l79', 'l83', 'l87', 'l88', 'l89']", + "131, ablate ['l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l90', 'l91']", + "132, tumor ['l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l63', 'l70', 'l76', 'l81', 'l85', 'l88', 'l90', 'l92']", + "133, growth. ['l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l64', 'l71', 'l77', 'l82', 'l86', 'l89', 'l91', 'l92']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Id1+/-Id3-/-" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Id1+/-Id3-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "host," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Id1+/-Id3-/-" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Id1+/-Id3-/-" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "host,", + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Id-mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Id-mutant", + "targeting", + "of", + "either", + "VEGFR1", + "or", + "VEGFR2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired", + "ablate" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Id-mutant" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "targeting", + "of", + "either", + "VEGFR1", + "or", + "VEGFR2" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "targeting", + "of", + "either", + "VEGFR1", + "or", + "VEGFR2" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors," + ] + }, + "effect": { + "val": "negative", + "words": [ + "ablate" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "both", + "VEGFR1", + "and", + "VEGFR2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "ablate" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "both", + "VEGFR1", + "and", + "VEGFR2" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "ablate" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + } + ] + }, + { + "PMID": "11590437", + "TEXT": "The physiological performance of an organ depends on an interplay between changes in cellular function and organ size, determined by cell growth, proliferation and death. Nowhere is this more evident than in the endocrine pancreas, where disturbances in function or mass result in severe disease. Recently, the insulin signal-transduction pathway has been implicated in both the regulation of hormone secretion from beta cells in mammals as well as the determination of cell and organ size in Drosophila melanogaster. A prominent mediator of the actions of insulin and insulin-like growth factor 1 (IGF-1) is the 3'-phosphoinositide-dependent protein kinase Akt, also known as protein kinase B (PKB). Here we report that overexpression of active Akt1 in the mouse beta cell substantially affects compartment size and function. There was a significant increase in both beta-cell size and total islet mass, accompanied by improved glucose tolerance and complete resistance to experimental diabetes.", + "TAG_DATA": [ + "109, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "110, of {'perturbing_action': 'I-gene gain-of-function'}", + "111, active {'perturbing_action': 'I-gene gain-of-function'}", + "112, Akt1 {'perturbing_action': 'I-gene gain-of-function'}", + "115, mouse {'context': 'B-cells'}", + "116, beta {'context': 'I-cells'}", + "117, cell {'context': 'I-cells'}", + "131, beta-cell {'context': 'B-cells'}", + "135, islet {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "109, overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "110, of ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "111, active ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "112, Akt1 ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "115, mouse ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28']", + "116, beta ['l4', 'l11', 'l17', 'l22', 'l26', 'l29', 'l30', 'l31']", + "117, cell ['l5', 'l12', 'l18', 'l23', 'l27', 'l29']", + "131, beta-cell ['l6', 'l13', 'l19', 'l24', 'l30', 'l32']", + "135, islet ['l7', 'l14', 'l20', 'l25', 'l28', 'l31', 'l32']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "active", + "Akt1" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "beta", + "cell", + "beta-cell", + "islet" + ] + } + } + ] + }, + { + "PMID": "11590436", + "TEXT": "All nuclear-encoded mRNAs contain a 5' cap structure (m7GpppN, where N is any nucleotide), which is recognized by the eukaryotic translation initiation factor 4E (eIF4E) subunit of the eIF4F complex. The eIF4E-binding proteins constitute a family of three polypeptides that reversibly repress cap-dependent translation by binding to eIF4E, thus preventing the formation of the eIF4F complex. We investigated the biological function of 4E-BP1 by disrupting its gene (Eif4ebp1) in the mouse. Eif4ebp1-/- mice manifest markedly smaller white fat pads than wild-type animals, and knockout males display an increase in metabolic rate. The males' white adipose tissue contains cells that exhibit the distinctive multilocular appearance of brown adipocytes, and expresses the uncoupling protein 1 (UCP1), a specific marker of brown fat. Consistent with these observations, translation of the peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC1), a transcriptional co-activator implicated in mitochondrial biogenesis and adaptive thermogenesis, is increased in white adipose tissue of Eif4ebp1-/- mice. These findings demonstrate that 4E-BP1 is a novel regulator of adipogenesis and metabolism in mammals.", + "TAG_DATA": [ + "64, disrupting {'perturbing_action': 'B-gene loss-of-function'}", + "65, its {'perturbing_action': 'I-gene loss-of-function'}", + "66, gene {'perturbing_action': 'I-gene loss-of-function'}", + "67, (Eif4ebp1) {'perturbing_action': 'I-gene loss-of-function'}", + "70, mouse. {'context': 'B-organism'}", + "71, Eif4ebp1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "72, mice {'context': 'B-organism'}", + "81, animals, {'context': 'B-organism'}", + "83, knockout {'perturbing_action': 'B-gene loss-of-function'}", + "84, males {'context': 'B-organism'}", + "92, males' {'context': 'B-tissue/organ'}", + "93, white {'context': 'I-tissue/organ'}", + "94, adipose {'context': 'I-tissue/organ'}", + "95, tissue {'context': 'I-tissue/organ'}", + "146, white {'context': 'B-tissue/organ'}", + "147, adipose {'context': 'I-tissue/organ'}", + "148, tissue {'context': 'I-tissue/organ'}", + "150, Eif4ebp1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "151, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "64, disrupting ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "65, its ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "66, gene ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "67, (Eif4ebp1) ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "70, mouse. ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "71, Eif4ebp1-/- ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "72, mice ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "81, animals, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "83, knockout ['l28', 'l29', 'l30', 'l31']", + "84, males ['l28', 'l32', 'l33', 'l34']", + "92, males' ['l29', 'l32', 'l35', 'l36', 'l37']", + "93, white ['l35', 'l38', 'l39']", + "94, adipose ['l30', 'l33', 'l36', 'l38', 'l40']", + "95, tissue ['l31', 'l34', 'l37', 'l39', 'l40']", + "146, white ['l41', 'l42', 'l43', 'l44']", + "147, adipose ['l41', 'l45', 'l46', 'l47']", + "148, tissue ['l42', 'l45', 'l48', 'l49']", + "150, Eif4ebp1-/- ['l43', 'l46', 'l48', 'l50']", + "151, mice. ['l44', 'l47', 'l49', 'l50']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "disrupting", + "its", + "gene", + "(Eif4ebp1)", + "Eif4ebp1-/-", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse.", + "mice", + "animals,", + "males", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout", + "Eif4ebp1-/-" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "males'", + "adipose", + "tissue", + "white" + ] + } + } + ] + }, + { + "PMID": "11533709", + "TEXT": "Arachidonic acid is metabolized to prostaglandin H(2) (PGH(2)) by cyclooxygenase (COX). COX-2, the inducible COX isozyme, has a key role in intestinal polyposis. Among the metabolites of PGH(2), PGE(2) is implicated in tumorigenesis because its level is markedly elevated in tissues of intestinal adenoma and colon cancer. Here we show that homozygous deletion of the gene encoding a cell-surface receptor of PGE(2), EP2, causes decreases in number and size of intestinal polyps in Apc(Delta 716) mice (a mouse model for human familial adenomatous polyposis). This effect is similar to that of COX-2 gene disruption. We also show that COX-2 expression is boosted by PGE(2) through the EP2 receptor via a positive feedback loop. Homozygous gene knockout for other PGE(2) receptors, EP1 or EP3, did not affect intestinal polyp formation in Apc(Delta 716) mice. We conclude that EP2 is the major receptor mediating the PGE2 signal generated by COX-2 upregulation in intestinal polyposis, and that increased cellular cAMP stimulates expression of more COX-2 and vascular endothelial growth factor in the polyp stroma.", + "TAG_DATA": [ + "51, homozygous {'perturbing_action': 'B-gene loss-of-function'}", + "52, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "53, of {'perturbing_action': 'I-gene loss-of-function'}", + "54, the {'perturbing_action': 'I-gene loss-of-function'}", + "55, gene {'perturbing_action': 'I-gene loss-of-function'}", + "56, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "57, a {'perturbing_action': 'I-gene loss-of-function'}", + "58, cell-surface {'perturbing_action': 'I-gene loss-of-function'}", + "59, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "60, of {'perturbing_action': 'I-gene loss-of-function'}", + "61, PGE(2), {'perturbing_action': 'I-gene loss-of-function'}", + "62, EP2, {'perturbing_action': 'I-gene loss-of-function'}", + "73, Apc(Delta {'perturbing_action': 'B-other'}", + "74, 716) {'perturbing_action': 'I-other'}", + "75, mice {'context': 'B-organism'}", + "76, (a {'context': 'B-organism'}", + "113, Homozygous {'perturbing_action': 'B-gene loss-of-function'}", + "114, gene {'perturbing_action': 'I-gene loss-of-function'}", + "115, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "116, for {'perturbing_action': 'I-gene loss-of-function'}", + "117, other {'perturbing_action': 'I-gene loss-of-function'}", + "118, PGE(2) {'perturbing_action': 'I-gene loss-of-function'}", + "119, receptors, {'perturbing_action': 'I-gene loss-of-function'}", + "120, EP1 {'perturbing_action': 'I-gene loss-of-function'}", + "121, or {'perturbing_action': 'I-gene loss-of-function'}", + "122, EP3, {'perturbing_action': 'I-gene loss-of-function'}", + "130, Apc(Delta {'perturbing_action': 'B-other'}", + "131, 716) {'perturbing_action': 'I-other'}", + "132, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "51, homozygous ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "52, deletion ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "53, of ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "54, the ['l2', 'l16', 'l29', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "55, gene ['l3', 'l17', 'l30', 'l42', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "56, encoding ['l4', 'l18', 'l31', 'l43', 'l54', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "57, a ['l5', 'l19', 'l32', 'l44', 'l55', 'l65', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "58, cell-surface ['l6', 'l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "59, receptor ['l7', 'l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l84', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "60, of ['l8', 'l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "61, PGE(2), ['l9', 'l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l86', 'l93', 'l99', 'l105', 'l106', 'l107', 'l108', 'l109']", + "62, EP2, ['l10', 'l24', 'l37', 'l49', 'l60', 'l70', 'l79', 'l87', 'l94', 'l100', 'l105', 'l110', 'l111', 'l112', 'l113']", + "73, Apc(Delta ['l11', 'l25', 'l38', 'l50', 'l61', 'l71', 'l80', 'l88', 'l95', 'l101', 'l106', 'l110', 'l114', 'l115', 'l116']", + "74, 716) ['l12', 'l26', 'l39', 'l51', 'l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l107', 'l111', 'l114', 'l117', 'l118']", + "75, mice ['l13', 'l27', 'l40', 'l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l108', 'l112', 'l115', 'l117', 'l119']", + "76, (a ['l14', 'l28', 'l41', 'l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l109', 'l113', 'l116', 'l118', 'l119']", + "113, Homozygous ['l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "114, gene ['l120', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "115, knockout ['l121', 'l132', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "116, for ['l122', 'l133', 'l143', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "117, other ['l123', 'l134', 'l144', 'l153', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "118, PGE(2) ['l124', 'l135', 'l145', 'l154', 'l162', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176']", + "119, receptors, ['l125', 'l136', 'l146', 'l155', 'l163', 'l170', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "120, EP1 ['l126', 'l137', 'l147', 'l156', 'l164', 'l171', 'l177', 'l183', 'l184', 'l185', 'l186', 'l187']", + "121, or ['l127', 'l138', 'l148', 'l157', 'l165', 'l172', 'l178', 'l183', 'l188', 'l189', 'l190', 'l191']", + "122, EP3, ['l128', 'l139', 'l149', 'l158', 'l166', 'l173', 'l179', 'l184', 'l188', 'l192', 'l193', 'l194']", + "130, Apc(Delta ['l129', 'l140', 'l150', 'l159', 'l167', 'l174', 'l180', 'l185', 'l189', 'l192', 'l195', 'l196']", + "131, 716) ['l130', 'l141', 'l151', 'l160', 'l168', 'l175', 'l181', 'l186', 'l190', 'l193', 'l195', 'l197']", + "132, mice. ['l131', 'l142', 'l152', 'l161', 'l169', 'l176', 'l182', 'l187', 'l191', 'l194', 'l196', 'l197']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "homozygous", + "deletion", + "of", + "the", + "gene", + "encoding", + "a", + "cell-surface", + "receptor", + "PGE(2),", + "EP2,", + "Homozygous", + "knockout", + "for", + "other", + "PGE(2)", + "receptors,", + "EP1", + "or", + "EP3," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "(a", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Apc(Delta", + "716)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "(a", + "mice." + ] + } + } + ] + }, + { + "PMID": "11479630", + "TEXT": "While investigating the novel anticancer drug ecteinascidin 743 (Et743), a natural marine product isolated from the Caribbean sea squirt, we discovered a new cell-killing mechanism mediated by DNA nucleotide excision repair (NER). A cancer cell line selected for resistance to Et743 had chromosome alterations in a region that included the gene implicated in the hereditary disease xeroderma pigmentosum (XPG, also known as Ercc5). Complementation with wild-type XPG restored the drug sensitivity. Xeroderma pigmentosum cells deficient in the NER genes XPG, XPA, XPD or XPF were resistant to Et743, and sensitivity was restored by complementation with wild-type genes. Moreover, studies of cells deficient in XPC or in the genes implicated in Cockayne syndrome (CSA and CSB) indicated that the drug sensitivity is specifically dependent on the transcription-coupled pathway of NER. We found that Et743 interacts with the transcription-coupled NER machinery to induce lethal DNA strand breaks.", + "TAG_DATA": [ + "33, cancer {'context': 'B-transformed cells'}", + "34, cell {'context': 'I-transformed cells'}", + "35, line {'context': 'I-transformed cells'}", + "71, Xeroderma {'context': 'B-transformed cells'}", + "72, pigmentosum {'context': 'I-transformed cells'}", + "73, cells {'context': 'I-transformed cells'}", + "74, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "75, in {'perturbing_action': 'I-gene loss-of-function'}", + "100, cells {'context': 'B-cells'}", + "101, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "102, in {'perturbing_action': 'I-gene loss-of-function'}", + "103, XPC {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "33, cancer ['l0', 'l1']", + "34, cell ['l0', 'l2']", + "35, line ['l1', 'l2']", + "71, Xeroderma ['l3', 'l4', 'l5', 'l6']", + "72, pigmentosum ['l3', 'l7', 'l8', 'l9']", + "73, cells ['l4', 'l7', 'l10', 'l11']", + "74, deficient ['l5', 'l8', 'l10', 'l12']", + "75, in ['l6', 'l9', 'l11', 'l12']", + "100, cells ['l13', 'l14', 'l15']", + "101, deficient ['l13', 'l16', 'l17']", + "102, in ['l14', 'l16', 'l18']", + "103, XPC ['l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "Xeroderma", + "pigmentosum", + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "XPC" + ] + } + } + ] + }, + { + "PMID": "11479629", + "TEXT": "A novel anti-human DR5 monoclonal antibody, TRA-8, induces apoptosis of most tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-sensitive tumor cells both in vitro and in vivo. In contrast to both the membrane-bound form of human TRAIL, which induced severe hepatitis in mice, and the soluble form of human TRAIL, which induced apoptosis of normal human hepatocytes in vitro, TRA-8 did not induce significant cell death of normal human hepatocytes. However, both primary hepatocellular carcinoma cells and an established liver cancer cell line were highly susceptible to the killing mediated by TRA-8. We show here that elevated levels of cell-surface expression of DR5 and increased susceptibility to DR5-mediated apoptosis are characteristics of malignant tumor cells. In contrast, DR5 alone is not sufficient to trigger apoptosis of normal hepatocytes. Therefore, selective, specific targeting of DR5 with an agonistic antibody might be a safe and effective strategy for cancer therapy.", + "TAG_DATA": [ + "20, in {'context': 'B-in vitro'}", + "21, vitro {'context': 'I-in vitro'}", + "23, in {'context': 'B-in vivo'}", + "24, vivo. {'context': 'I-in vivo'}", + "49, induced {'effect': 'B-positive'}", + "50, apoptosis {'phenotype': 'B-apoptosis'}", + "52, normal {'context': 'B-cells'}", + "53, human {'context': 'I-cells'}", + "54, hepatocytes {'context': 'I-cells'}", + "55, in {'context': 'B-in vitro'}", + "56, vitro, {'context': 'I-in vitro'}", + "59, not {'effect': 'I-no effect'}", + "60, induce {'effect': 'I-no effect'}", + "62, cell {'phenotype': 'B-cell death'}", + "63, death {'phenotype': 'I-cell death'}", + "65, normal {'context': 'B-cells'}", + "66, human {'context': 'I-cells'}", + "67, hepatocytes. {'context': 'I-cells'}", + "70, primary {'context': 'B-transformed cells'}", + "71, hepatocellular {'context': 'I-transformed cells'}", + "72, carcinoma {'context': 'I-transformed cells'}", + "73, cells {'context': 'I-transformed cells'}", + "77, liver {'context': 'B-transformed cells'}", + "78, cancer {'context': 'I-transformed cells'}", + "79, cell {'context': 'I-transformed cells'}", + "80, line {'context': 'I-transformed cells'}", + "103, susceptibility {'effect': 'I-positive'}", + "105, DR5-mediated {'effect': 'B-regulates'}", + "106, apoptosis {'phenotype': 'B-apoptosis'}", + "121, trigger {'effect': 'B-positive'}", + "122, apoptosis {'phenotype': 'B-apoptosis'}", + "124, normal {'context': 'B-cells'}", + "125, hepatocytes. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "20, in ['l0', 'l1', 'l2', 'l3']", + "21, vitro ['l0', 'l4', 'l5', 'l6']", + "23, in ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "24, vivo. ['l7', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "49, induced ['l8', 'l21', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "50, apoptosis ['l9', 'l22', 'l34', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "52, normal ['l1', 'l4', 'l10', 'l23', 'l35', 'l48', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "53, human ['l2', 'l5', 'l11', 'l24', 'l36', 'l49', 'l61', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "54, hepatocytes ['l3', 'l6', 'l12', 'l25', 'l37', 'l50', 'l62', 'l71', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "55, in ['l13', 'l26', 'l38', 'l51', 'l63', 'l72', 'l82', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "56, vitro, ['l14', 'l27', 'l39', 'l52', 'l64', 'l73', 'l83', 'l92', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "58, did ['l40', 'l53', 'l74', 'l84', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "59, not ['l41', 'l54', 'l75', 'l85', 'l93', 'l106', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "60, induce ['l15', 'l28', 'l42', 'l55', 'l65', 'l76', 'l86', 'l94', 'l100', 'l107', 'l116', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "62, cell ['l16', 'l29', 'l43', 'l56', 'l66', 'l77', 'l87', 'l95', 'l101', 'l108', 'l117', 'l125', 'l131', 'l132', 'l133', 'l134']", + "63, death ['l17', 'l30', 'l44', 'l57', 'l67', 'l78', 'l88', 'l96', 'l102', 'l109', 'l118', 'l126', 'l131', 'l135', 'l136', 'l137']", + "65, normal ['l18', 'l31', 'l45', 'l58', 'l68', 'l79', 'l89', 'l97', 'l103', 'l110', 'l119', 'l127', 'l132', 'l135', 'l138', 'l139', 'l140', 'l141']", + "66, human ['l19', 'l32', 'l46', 'l59', 'l69', 'l80', 'l90', 'l98', 'l104', 'l111', 'l120', 'l128', 'l133', 'l136', 'l138', 'l142', 'l143', 'l144']", + "67, hepatocytes. ['l20', 'l33', 'l47', 'l60', 'l70', 'l81', 'l91', 'l99', 'l105', 'l112', 'l121', 'l129', 'l134', 'l137', 'l139', 'l142', 'l145', 'l146']", + "70, primary ['l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "71, hepatocellular ['l113', 'l122', 'l147', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159']", + "72, carcinoma ['l114', 'l123', 'l140', 'l143', 'l145', 'l148', 'l154', 'l160', 'l161', 'l162', 'l163', 'l164']", + "73, cells ['l115', 'l124', 'l130', 'l141', 'l144', 'l146', 'l149', 'l155', 'l160', 'l165', 'l166', 'l167', 'l168']", + "77, liver ['l150', 'l156', 'l161', 'l165', 'l169', 'l170', 'l171']", + "78, cancer ['l151', 'l157', 'l162', 'l166', 'l169', 'l172', 'l173']", + "79, cell ['l152', 'l158', 'l163', 'l167', 'l170', 'l172', 'l174']", + "80, line ['l153', 'l159', 'l164', 'l168', 'l171', 'l173', 'l174']", + "103, susceptibility ['l175', 'l176', 'l177', 'l178', 'l179', 'l180']", + "105, DR5-mediated ['l175', 'l181', 'l182', 'l183', 'l184', 'l185']", + "106, apoptosis ['l176', 'l181', 'l186', 'l187', 'l188', 'l189']", + "121, trigger ['l177', 'l182', 'l186', 'l190', 'l191', 'l192']", + "122, apoptosis ['l178', 'l183', 'l187', 'l190', 'l193', 'l194']", + "124, normal ['l179', 'l184', 'l188', 'l191', 'l193', 'l195']", + "125, hepatocytes. ['l180', 'l185', 'l189', 'l192', 'l194', 'l195']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "effect": { + "val": "no effect", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "susceptibility", + "trigger" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "susceptibility", + "trigger" + ] + }, + "context": { + "val": "cells", + "words": [ + "normal", + "human", + "hepatocytes", + "hepatocytes." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "normal", + "human", + "hepatocytes", + "hepatocytes." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "induce" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "normal", + "human", + "hepatocytes", + "hepatocytes." + ] + }, + "effect": { + "val": "no effect", + "words": [ + "induce", + "not" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "normal", + "human", + "hepatocytes", + "hepatocytes." + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "induce" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "induce" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "induce" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "hepatocellular", + "carcinoma", + "cells" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "DR5-mediated" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "DR5-mediated" + ] + }, + "context": { + "val": "cells", + "words": [ + "normal", + "hepatocytes." + ] + } + } + ] + }, + { + "PMID": "11479624", + "TEXT": "Integase interactor 1 (INI1), also known as hSNF5, is a protein that interacts with HIV-1 integrase. We report here that a cytoplasmically localized fragment of INI1 (S6; aa183-294) containing the minimal integrase-interaction domain potently inhibits HIV-1 particle production and replication. Mutations in S6 or integrase that disrupt integrase-INI1 interaction abrogated the inhibitory effect. An integrase-deficient HIV-1 transcomplemented with integrase fused to Vpr was not affected by S6. INI1 was specifically incorporated into virions and was required for efficient HIV-1 particle production. These results indicate that INI1 is required for late events in the viral life cycle, and that ectopic expression of S6 inhibits HIV-1 replication in a transdominant manner via its specific interaction with integrase within the context of Gag-Pol, providing a novel strategy to control HIV-1 replication.", + "TAG_DATA": [ + "40, Mutations {'perturbing_action': 'B-other'}", + "41, in {'perturbing_action': 'I-other'}", + "42, S6 {'perturbing_action': 'I-other'}", + "54, integrase-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "55, HIV-1 {'context': 'B-cells'}", + "56, transcomplemented {'context': 'I-xenograft'}", + "58, integrase {'perturbing_action': 'I-other'}", + "59, fused {'perturbing_action': 'I-other'}", + "60, to {'perturbing_action': 'I-other'}", + "61, Vpr {'perturbing_action': 'I-other'}", + "98, ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "99, expression {'perturbing_action': 'I-gene gain-of-function'}", + "100, of {'perturbing_action': 'I-gene gain-of-function'}", + "101, S6 {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "40, Mutations ['l0', 'l1', 'l2', 'l3', 'l4']", + "41, in ['l0', 'l5', 'l6']", + "42, S6 ['l1', 'l5']", + "44, integrase ['l2', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "54, integrase-deficient ['l7', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "55, HIV-1 ['l8', 'l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "56, transcomplemented ['l9', 'l16', 'l22', 'l28', 'l29', 'l30', 'l31', 'l32']", + "57, with ['l10', 'l17', 'l23', 'l28', 'l33', 'l34', 'l35', 'l36']", + "58, integrase ['l11', 'l18', 'l24', 'l29', 'l33', 'l37', 'l38', 'l39']", + "59, fused ['l12', 'l19', 'l25', 'l30', 'l34', 'l37', 'l40', 'l41']", + "60, to ['l3', 'l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l42']", + "61, Vpr ['l4', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l41', 'l42']", + "98, ectopic ['l43', 'l44', 'l45']", + "99, expression ['l43', 'l46', 'l47']", + "100, of ['l44', 'l46', 'l48']", + "101, S6 ['l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "integrase-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "HIV-1" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "integrase-deficient" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "transcomplemented" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HIV-1" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "integrase", + "fused", + "to", + "Vpr" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "transcomplemented" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "integrase", + "fused", + "to", + "Vpr" + ] + } + } + ] + }, + { + "PMID": "11479623", + "TEXT": "Emerging evidence indicates that CD8+ and CD4+ T-cell immunity is differentially regulated. Here we have delineated differences and commonalities among antiviral T-cell responses by enumeration and functional profiling of eight specific CD8+ and CD4+ T-cell populations during primary, memory and recall responses. A high degree of coordinate regulation among all specific T-cell populations stood out against an approximately 20-fold lower peak expansion and prolonged contraction phase of specific CD4+ T-cell populations. Surprisingly, although CD8+ T-cell memory was stably maintained for life, levels of specific CD4+ memory T cells gradually declined. However, this decay, which seemed to result from less efficient rescue from apoptosis, did not affect functionality of surviving virus-specific CD4+ T cells. Our results indicate that CD4+ T-cell memory might become limiting under physiological conditions and that conditions precipitating CD4+ T-cell loss might compromise protective immunity even in the presence of unimpaired CD8+ T-cell responses.", + "TAG_DATA": [ + "84, CD4+ {'context': 'B-cells'}", + "85, memory {'context': 'I-cells'}", + "86, T {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}", + "98, less {'effect': 'B-negative'}", + "100, rescue {'effect': 'B-rescues'}", + "102, apoptosis, {'phenotype': 'B-apoptosis'}", + "110, CD4+ {'context': 'B-cells'}", + "111, T {'context': 'I-cells'}", + "112, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "84, CD4+ ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "85, memory ['l0', 'l6', 'l7', 'l8']", + "86, T ['l1', 'l6', 'l9']", + "87, cells ['l2', 'l7', 'l9']", + "98, less ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "99, efficient ['l3', 'l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "100, rescue ['l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "101, from ['l4', 'l8', 'l12', 'l18', 'l23', 'l28', 'l29', 'l30', 'l31']", + "102, apoptosis, ['l5', 'l13', 'l19', 'l24', 'l28', 'l32', 'l33', 'l34']", + "110, CD4+ ['l14', 'l20', 'l25', 'l29', 'l32', 'l35', 'l36']", + "111, T ['l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l37']", + "112, cells. ['l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "less" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "less" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells." + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescue" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescue" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells." + ] + } + } + ] + }, + { + "PMID": "11433347", + "TEXT": "Using a combined pharmacological and gene-deletion approach, we have delineated a novel mechanism of neurokinin-1 (NK-1) receptor-dependent hyperalgesia induced by proteinase-activated receptor-2 (PAR2), a G-protein-coupled receptor expressed on nociceptive primary afferent neurons. Injections into the paw of sub-inflammatory doses of PAR2 agonists in rats and mice induced a prolonged thermal and mechanical hyperalgesia and elevated spinal Fos protein expression. This hyperalgesia was markedly diminished or absent in mice lacking the NK-1 receptor, preprotachykinin-A or PAR2 genes, or in rats treated with a centrally acting cyclooxygenase inhibitor or treated by spinal cord injection of NK-1 antagonists. Here we identify a previously unrecognized nociceptive pathway with important therapeutic implications, and our results point to a direct role for proteinases and their receptors in pain transmission.", + "TAG_DATA": [ + "40, PAR2 {'perturbing_action': 'B-pharmacological augmentation'}", + "41, agonists {'perturbing_action': 'I-pharmacological augmentation'}", + "43, rats {'context': 'B-organism'}", + "45, mice {'context': 'B-organism'}", + "67, mice {'context': 'B-organism'}", + "68, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "69, the {'perturbing_action': 'I-gene loss-of-function'}", + "70, NK-1 {'perturbing_action': 'I-gene loss-of-function'}", + "71, receptor, {'perturbing_action': 'I-gene loss-of-function'}", + "72, preprotachykinin-A {'perturbing_action': 'I-rnai/knockdown'}", + "75, genes, {'perturbing_action': 'I-gene loss-of-function'}", + "78, rats {'context': 'B-organism'}", + "93, NK-1 {'perturbing_action': 'B-pharmacological inhibition'}", + "94, antagonists. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "40, PAR2 ['l0', 'l1', 'l2']", + "41, agonists ['l0', 'l3', 'l4']", + "43, rats ['l1', 'l3', 'l5']", + "45, mice ['l2', 'l4', 'l5']", + "67, mice ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "68, lacking ['l6', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "69, the ['l7', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "70, NK-1 ['l8', 'l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "71, receptor, ['l9', 'l15', 'l20', 'l24', 'l28', 'l29', 'l30']", + "72, preprotachykinin-A ['l10', 'l16', 'l21', 'l25', 'l28', 'l31', 'l32']", + "75, genes, ['l11', 'l17', 'l22', 'l26', 'l29', 'l31', 'l33']", + "78, rats ['l12', 'l18', 'l23', 'l27', 'l30', 'l32', 'l33']", + "93, NK-1 ['l34']", + "94, antagonists. ['l34']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "PAR2", + "agonists" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats", + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "rats" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "NK-1", + "receptor,", + "genes," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "rats" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "preprotachykinin-A" + ] + } + } + ] + }, + { + "PMID": "11433346", + "TEXT": "The Fanconi anemia group C protein (FANCC) plays an important role in hematopoiesis by ensuring the survival of hematopoietic progenitor cells through an unknown mechanism. We investigated the function of FANCC by identifying FANCC-binding proteins in hematopoietic cells. Here we show that glutathione S-transferase P1-1 (GSTP1) interacts with FANCC, and that overexpression of both proteins in a myeloid progenitor cell line prevents apoptosis following factor deprivation. FANCC increases GSTP1 activity after the induction of apoptosis. GSTP1 is an enzyme that catalyzes the detoxification of xenobiotics and by-products of oxidative stress, and it is frequently upregulated in neoplastic cells. Although FANCC lacks homology with conventional disulfide reductases, it functions by preventing the formation of inactivating disulfide bonds within GSTP1 during apoptosis. The prevention of protein oxidation by FANCC reveals a novel mechanism of enzyme regulation during apoptosis and has implications for the treatment of degenerative diseases with thiol reducing agents.", + "TAG_DATA": [ + "51, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "52, of {'perturbing_action': 'I-gene gain-of-function'}", + "53, both {'perturbing_action': 'I-gene gain-of-function'}", + "54, proteins {'perturbing_action': 'I-gene gain-of-function'}", + "57, myeloid {'context': 'B-cells'}", + "58, progenitor {'context': 'I-cells'}", + "59, cell {'context': 'I-cells'}", + "60, line {'context': 'I-cells'}", + "61, prevents {'effect': 'B-negative'}", + "62, apoptosis {'phenotype': 'B-apoptosis'}", + "72, induction {'effect': 'B-positive'}", + "74, apoptosis. {'phenotype': 'B-apoptosis'}", + "119, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "51, overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "52, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "53, both ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "54, proteins ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "57, myeloid ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "58, progenitor ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "59, cell ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "60, line ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "61, prevents ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "62, apoptosis ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "72, induction ['l45']", + "74, apoptosis. ['l45']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "both", + "proteins" + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "progenitor", + "cell", + "line" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "both", + "proteins" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "both", + "proteins" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "myeloid", + "progenitor", + "cell", + "line" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "myeloid", + "progenitor", + "cell", + "line" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "11433344", + "TEXT": "To assess the role of complement in renal infection, we studied a model of Escherichia coli-induced pyelonephritis in mice deficient in complement components C3 and C4. Renal infection occurred less frequently in C3- and C4-deficient mice compared with wild-type mice. In vitro, renal epithelial cells internalized fewer bacteria in the absence of C3 or in the presence of blockade of C3 bound to the bacteria. Moreover, upregulation of epithelial C3 production by stimulation with lipopolysaccharide enhanced bacterial internalization. Here we provide evidence that uropathogenic E. coli might use host C3 to invade the renal epithelium and that local complement production is sufficient for the bacteria to achieve this effect.", + "TAG_DATA": [ + "18, mice {'context': 'B-organism'}", + "19, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "32, C3- {'perturbing_action': 'B-gene loss-of-function'}", + "33, and {'perturbing_action': 'I-gene loss-of-function'}", + "34, C4-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "35, mice {'context': 'B-organism'}", + "40, In {'context': 'B-in vitro'}", + "41, vitro, {'context': 'I-in vitro'}", + "42, renal {'context': 'B-cells'}", + "43, epithelial {'context': 'I-cells'}", + "44, cells {'context': 'I-cells'}", + "66, upregulation {'perturbing_action': 'B-gene gain-of-function'}", + "67, of {'perturbing_action': 'I-gene gain-of-function'}", + "68, epithelial {'perturbing_action': 'I-gene gain-of-function'}", + "69, C3 {'perturbing_action': 'I-gene gain-of-function'}", + "70, production {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "18, mice ['l0']", + "19, deficient ['l0', 'l1', 'l2', 'l3']", + "32, C3- ['l1', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "33, and ['l4', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "34, C4-deficient ['l5', 'l12', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "35, mice ['l2', 'l6', 'l13', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "40, In ['l7', 'l14', 'l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "41, vitro, ['l8', 'l15', 'l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "42, renal ['l9', 'l16', 'l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "43, epithelial ['l10', 'l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "44, cells ['l3', 'l11', 'l18', 'l24', 'l29', 'l33', 'l36', 'l38', 'l39']", + "66, upregulation ['l40', 'l41', 'l42', 'l43']", + "67, of ['l40', 'l44', 'l45', 'l46']", + "68, epithelial ['l41', 'l44', 'l47', 'l48']", + "69, C3 ['l42', 'l45', 'l47', 'l49']", + "70, production ['l43', 'l46', 'l48', 'l49']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "C3-", + "and", + "C4-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "C3-", + "and", + "C4-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "renal", + "epithelial" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "C3-", + "and", + "C4-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + } + } + ] + }, + { + "PMID": "11385512", + "TEXT": "Elevated expression of heat-shock proteins (HSPs) can benefit a microbial pathogen struggling to penetrate host defenses during infection, but at the same time might provide a crucial signal alerting the host immune system to its presence. To determine which of these effects predominate, we constructed a mutant strain of Mycobacterium tuberculosis that constitutively overexpresses Hsp70 proteins. Although the mutant was fully virulent in the initial stage of infection, it was significantly impaired in its ability to persist during the subsequent chronic phase. Induction of microbial genes encoding HSPs might provide a novel strategy to boost the immune response of individuals with latent tuberculosis infection.", + "TAG_DATA": [ + "46, mutant {'perturbing_action': 'B-other'}", + "47, strain {'perturbing_action': 'I-other'}", + "48, of {'perturbing_action': 'I-other'}", + "49, Mycobacterium {'perturbing_action': 'I-other'}", + "50, tuberculosis {'perturbing_action': 'I-other', 'context': 'I-organism'}" + ], + "LINK_DATA": [ + "46, mutant ['l0', 'l1', 'l2', 'l3']", + "47, strain ['l0', 'l4', 'l5', 'l6']", + "48, of ['l1', 'l4', 'l7', 'l8']", + "49, Mycobacterium ['l2', 'l5', 'l7', 'l9']", + "50, tuberculosis ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "strain", + "of", + "Mycobacterium" + ] + }, + "context": { + "val": "organism", + "words": [ + "tuberculosis" + ] + } + } + ] + }, + { + "PMID": "11385508", + "TEXT": "Sonic hedgehog (Shh) is a prototypical morphogen known to regulate epithelial/mesenchymal interactions during embryonic development. We found that the hedgehog-signaling pathway is present in adult cardiovascular tissues and can be activated in vivo. Shh was able to induce robust angiogenesis, characterized by distinct large-diameter vessels. Shh also augmented blood-flow recovery and limb salvage following operatively induced hind-limb ischemia in aged mice. In vitro, Shh had no effect on endothelial-cell migration or proliferation; instead, it induced expression of two families of angiogenic cytokines, including all three vascular endothelial growth factor-1 isoforms and angiopoietins-1 and -2 from interstitial mesenchymal cells. These findings reveal a novel role for Shh as an indirect angiogenic factor regulating expression of multiple angiogenic cytokines and indicate that Shh might have potential therapeutic use for ischemic disorders.", + "TAG_DATA": [ + "59, aged {'context': 'B-organism'}", + "60, mice. {'context': 'I-organism'}", + "61, In {'context': 'B-in vitro'}", + "62, vitro, {'context': 'I-in vitro'}", + "65, no {'effect': 'B-no effect'}", + "66, effect {'effect': 'I-no effect'}", + "68, endothelial-cell {'context': 'B-cells'}", + "69, migration {'phenotype': 'B-migration'}", + "71, proliferation; {'phenotype': 'B-proliferation'}", + "95, interstitial {'context': 'B-cells'}", + "96, mesenchymal {'context': 'I-cells'}", + "97, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "59, aged ['l0', 'l1', 'l2', 'l3']", + "60, mice. ['l0', 'l4']", + "61, In ['l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "62, vitro, ['l5', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "65, no ['l6', 'l13', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "66, effect ['l7', 'l14', 'l20', 'l26', 'l27', 'l28', 'l29']", + "68, endothelial-cell ['l1', 'l8', 'l15', 'l21', 'l26', 'l30', 'l31']", + "69, migration ['l2', 'l4', 'l9', 'l16', 'l22', 'l27', 'l30', 'l32']", + "71, proliferation; ['l3', 'l10', 'l17', 'l23', 'l28', 'l31', 'l32']", + "95, interstitial ['l33', 'l34']", + "96, mesenchymal ['l11', 'l18', 'l24', 'l33', 'l35']", + "97, cells. ['l12', 'l19', 'l25', 'l29', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "aged", + "mice." + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "aged" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation;" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "no", + "effect" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation;" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "no", + "effect" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial-cell", + "mesenchymal", + "cells." + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "no", + "effect" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "no", + "effect" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation;" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial-cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial-cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation;" + ] + } + } + ] + }, + { + "PMID": "11329064", + "TEXT": "Abnormal accumulation of the amyloid-beta peptide (Abeta) in the brain appears crucial to pathogenesis in all forms of Alzheimer disease (AD), but the underlying mechanisms in the sporadic forms of AD remain unknown. Transforming growth factor beta1 (TGF-beta1), a key regulator of the brain's responses to injury and inflammation, has been implicated in Abeta deposition in vivo. Here we demonstrate that a modest increase in astroglial TGF-beta1 production in aged transgenic mice expressing the human beta-amyloid precursor protein (hAPP) results in a three-fold reduction in the number of parenchymal amyloid plaques, a 50% reduction in the overall Abeta load in the hippocampus and neocortex, and a decrease in the number of dystrophic neurites. In mice expressing hAPP and TGF-beta1, Abeta accumulated substantially in cerebral blood vessels, but not in parenchymal plaques. In human cases of AD, Abeta immunoreactivity associated with parenchymal plaques was inversely correlated with Abeta in blood vessels and cortical TGF-beta1 mRNA levels. The reduction of parenchymal plaques in hAPP/TGF-beta1 mice was associated with a strong activation of microglia and an increase in inflammatory mediators. Recombinant TGF-beta1 stimulated Abeta clearance in microglial cell cultures. These results demonstrate that TGF-beta1 is an important modifier of amyloid deposition in vivo and indicate that TGF-beta1 might promote microglial processes that inhibit the accumulation of Abeta in the brain parenchyma.", + "TAG_DATA": [ + "69, aged {'context': 'B-organism'}", + "70, transgenic {'context': 'I-organism'}", + "71, mice {'context': 'I-organism'}", + "72, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "73, the {'perturbing_action': 'I-gene gain-of-function'}", + "74, human {'perturbing_action': 'I-gene gain-of-function'}", + "75, beta-amyloid {'perturbing_action': 'I-gene gain-of-function'}", + "76, precursor {'perturbing_action': 'I-gene gain-of-function'}", + "77, protein {'perturbing_action': 'I-gene gain-of-function'}", + "78, (hAPP) {'perturbing_action': 'I-gene gain-of-function'}", + "101, hippocampus {'context': 'B-tissue/organ'}", + "103, neocortex, {'context': 'B-tissue/organ'}", + "114, mice {'context': 'B-organism'}", + "162, mice {'context': 'B-organism'}", + "170, microglia {'context': 'B-cells'}", + "183, microglial {'context': 'B-cells'}", + "184, cell {'context': 'I-cells'}", + "185, cultures. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "69, aged ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "70, transgenic ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "71, mice ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "72, expressing ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "73, the ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "74, human ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "75, beta-amyloid ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "76, precursor ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "77, protein ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "78, (hAPP) ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "101, hippocampus ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "103, neocortex, ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "162, mice ['l66']", + "170, microglia ['l66']", + "183, microglial ['l67', 'l68']", + "184, cell ['l67', 'l69']", + "185, cultures. ['l68', 'l69']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "aged", + "transgenic", + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "the", + "human", + "beta-amyloid", + "precursor", + "protein", + "(hAPP)" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "the", + "human", + "beta-amyloid", + "precursor", + "protein", + "(hAPP)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus", + "neocortex," + ] + } + } + ] + }, + { + "PMID": "11283673", + "TEXT": "The use of combination antiretroviral therapy results in a substantial reduction in viremia, a rebound of CD4+ T cells and increased survival for HIV-infected individuals. However, this treatment does not result in the total eradication of HIV. Rather, the virus is thought to remain latent in a subset of cells, where it avoids elimination by the immune system. In this state the virus is capable of reactivation of productive infection following cessation of therapy. These latently infected cells are very few in number and it has thus been difficult to determine their origin and to study the molecular nature of the latent viral genome. HIV replication is linked to cellular gene transcription and requires target cell activation. Therefore, should an activated, infected cell become transcriptionally inactive prior to cytopathic effects, the viral genome might be maintained in a latent state. We used the SCID-hu (Thy/Liv) mouse model to establish that activation-inducible HIV can be generated at high frequency during thymopoiesis, a process where previously activated cells mature towards quiescence. Moreover, we showed that these cells can be exported into the periphery where the virus remains latent until T-cell receptor stimulation, indicating that the thymus might be a source of latent HIV in humans.", + "TAG_DATA": [ + "143, SCID-hu {'perturbing_action': 'B-other'}", + "144, (Thy/Liv) {'perturbing_action': 'I-other'}", + "145, mouse {'context': 'B-organism'}", + "146, model {'context': 'I-organism'}", + "165, cells {'context': 'B-cells'}", + "168, quiescence. {'phenotype': 'B-quiescence'}" + ], + "LINK_DATA": [ + "143, SCID-hu ['l0', 'l1', 'l2', 'l3']", + "144, (Thy/Liv) ['l0', 'l4', 'l5']", + "145, mouse ['l1', 'l4', 'l6']", + "146, model ['l2', 'l5', 'l6']", + "165, cells ['l3', 'l7']", + "168, quiescence. ['l7']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "SCID-hu", + "(Thy/Liv)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "SCID-hu" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence." + ] + } + } + ] + }, + { + "PMID": "11283672", + "TEXT": "In an analysis of 84 primary-operated breast cancer patients and 11 healthy donors, we found that the bone marrow of most patients contained memory T cells with specificity for tumor-associated antigens. Patients' bone marrow and peripheral blood contained CD8+ T cells that specifically bound HLA/peptide tetramers. In short-term culture with autologous dendritic cells pre-pulsed with tumor lysates, patients' memory T cells from bone marrow (but not peripheral blood) could be specifically reactivated to interferon-gamma-producing and cytotoxic effector cells. A single transfer of restimulated bone-marrow T cells into NOD/SCID mice caused regression of autologous tumor xenotransplants associated with infiltration by human T cells and tumor-cell apoptosis and necrosis. T cells from peripheral blood showed much lower anti-tumor reactivity. Our findings reveal an innate, specific recognition of breast cancer antigens and point to a possible novel cancer therapy using patients' bone-marrow-derived memory T cells.", + "TAG_DATA": [ + "50, autologous {'context': 'B-cells'}", + "51, dendritic {'context': 'I-cells'}", + "52, cells {'context': 'I-cells'}", + "57, patients' {'context': 'B-cells'}", + "58, memory {'context': 'I-cells'}", + "59, T {'context': 'I-cells'}", + "60, cells {'context': 'I-cells'}", + "61, from {'context': 'I-cells'}", + "62, bone {'context': 'I-cells'}", + "63, marrow {'context': 'I-cells'}", + "83, bone-marrow {'context': 'B-cells'}", + "84, T {'context': 'I-cells'}", + "85, cells {'context': 'I-cells'}", + "87, NOD/SCID {'context': 'B-organism'}", + "88, mice {'context': 'I-organism'}", + "89, caused {'effect': 'B-positive'}", + "90, regression {'phenotype': 'B-tumour regression'}", + "92, autologous {'context': 'B-xenograft'}", + "93, tumor {'context': 'I-xenograft'}", + "94, xenotransplants {'context': 'I-xenograft'}", + "99, human {'context': 'B-cells'}", + "100, T {'context': 'I-cells'}", + "101, cells {'context': 'I-cells'}", + "103, tumor-cell {'context': 'B-transformed cells'}", + "104, apoptosis {'phenotype': 'B-apoptosis'}", + "106, necrosis. {'phenotype': 'B-necrosis'}", + "107, T {'context': 'B-cells'}", + "108, cells {'context': 'I-cells'}", + "109, from {'context': 'I-cells'}", + "110, peripheral {'context': 'I-cells'}", + "111, blood {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "50, autologous ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "51, dendritic ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "52, cells ['l1', 'l15', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "57, patients' ['l2', 'l16', 'l33', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "58, memory ['l3', 'l17', 'l34', 'l47', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "59, T ['l4', 'l18', 'l35', 'l48', 'l56', 'l64', 'l65', 'l66', 'l67', 'l68']", + "60, cells ['l5', 'l19', 'l36', 'l49', 'l57', 'l64', 'l69', 'l70', 'l71', 'l72']", + "61, from ['l6', 'l20', 'l37', 'l50', 'l58', 'l65', 'l69', 'l73', 'l74', 'l75']", + "62, bone ['l7', 'l21', 'l38', 'l51', 'l59', 'l66', 'l70', 'l73', 'l76']", + "63, marrow ['l8', 'l22', 'l39', 'l52', 'l60', 'l67', 'l71', 'l74', 'l76']", + "83, bone-marrow ['l23', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "84, T ['l9', 'l24', 'l40', 'l77', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "85, cells ['l10', 'l25', 'l41', 'l53', 'l61', 'l78', 'l92', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "87, NOD/SCID ['l79', 'l93', 'l106', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "88, mice ['l11', 'l26', 'l42', 'l80', 'l94', 'l107', 'l119', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139']", + "89, caused ['l27', 'l81', 'l95', 'l108', 'l120', 'l131', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "90, regression ['l82', 'l96', 'l109', 'l121', 'l132', 'l140', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156']", + "92, autologous ['l83', 'l97', 'l110', 'l122', 'l133', 'l141', 'l148', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162']", + "93, tumor ['l12', 'l28', 'l43', 'l84', 'l98', 'l111', 'l123', 'l134', 'l142', 'l149', 'l157', 'l163', 'l164', 'l165', 'l166', 'l167']", + "94, xenotransplants ['l29', 'l85', 'l99', 'l112', 'l124', 'l135', 'l143', 'l150', 'l158', 'l163', 'l168', 'l169', 'l170', 'l171']", + "99, human ['l30', 'l44', 'l86', 'l100', 'l113', 'l125', 'l136', 'l144', 'l151', 'l159', 'l164', 'l168', 'l172', 'l173', 'l174']", + "100, T ['l13', 'l31', 'l45', 'l54', 'l62', 'l87', 'l101', 'l114', 'l126', 'l137', 'l145', 'l152', 'l160', 'l165', 'l169', 'l172', 'l175', 'l176']", + "101, cells ['l14', 'l32', 'l46', 'l55', 'l63', 'l68', 'l72', 'l75', 'l88', 'l102', 'l115', 'l127', 'l138', 'l146', 'l153', 'l161', 'l166', 'l170', 'l173', 'l175']", + "103, tumor-cell ['l89', 'l103', 'l116', 'l128', 'l154', 'l177', 'l178']", + "104, apoptosis ['l90', 'l104', 'l117', 'l129', 'l139', 'l147', 'l155', 'l162', 'l167', 'l171', 'l174', 'l176', 'l177', 'l179']", + "106, necrosis. ['l91', 'l105', 'l118', 'l130', 'l156', 'l178', 'l179']", + "107, T ['l180', 'l181', 'l182', 'l183']", + "108, cells ['l180', 'l184', 'l185', 'l186']", + "109, from ['l181', 'l184', 'l187', 'l188']", + "110, peripheral ['l182', 'l185', 'l187', 'l189']", + "111, blood ['l183', 'l186', 'l188', 'l189']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "dendritic", + "bone-marrow", + "T", + "cells", + "human" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "bone-marrow", + "T", + "cells", + "human" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "bone-marrow", + "T", + "cells", + "human" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "bone-marrow", + "T", + "cells" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "NOD/SCID", + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "NOD/SCID", + "mice" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "NOD/SCID", + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "NOD/SCID" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "autologous", + "tumor", + "xenotransplants" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "autologous", + "tumor", + "xenotransplants" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor-cell" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "autologous", + "tumor", + "xenotransplants" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor-cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor-cell" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis." + ] + } + } + ] + }, + { + "PMID": "11231631", + "TEXT": "Fibronectin performs essential roles in embryonic development and is prominently expressed during tissue repair. Two forms of fibronectin have been identified: plasma fibronectin (pFn), which is expressed by hepatocytes and secreted in soluble form into plasma; and cellular fibronectin (cFn), an insoluble form expressed locally by fibroblasts and other cell types and deposited and assembled into the extracellular matrix. To investigate the role of pFn in vivo, we generated pFn-deficient adult mice using Cre-loxP conditional gene-knockout technology. Here we show that pFn-deficient mice show increased neuronal apoptosis and larger infarction areas following transient focal cerebral ischemia. However, pFn is dispensable for skin-wound healing and hemostasis.", + "TAG_DATA": [ + "69, pFn-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "70, adult {'context': 'B-organism'}", + "71, mice {'context': 'I-organism'}", + "73, Cre-loxP {'perturbing_action': 'B-gene loss-of-function'}", + "74, conditional {'perturbing_action': 'I-gene loss-of-function'}", + "75, gene-knockout {'perturbing_action': 'I-gene loss-of-function'}", + "81, pFn-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "82, mice {'context': 'B-organism'}", + "84, increased {'effect': 'B-positive'}", + "86, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "69, pFn-deficient ['l0', 'l1', 'l2', 'l3', 'l4']", + "70, adult ['l0', 'l5', 'l6', 'l7', 'l8']", + "71, mice ['l1', 'l5', 'l9', 'l10', 'l11']", + "73, Cre-loxP ['l2', 'l6', 'l9', 'l12', 'l13', 'l14', 'l15']", + "74, conditional ['l3', 'l7', 'l10', 'l12', 'l16', 'l17', 'l18']", + "75, gene-knockout ['l4', 'l8', 'l11', 'l13', 'l16', 'l19', 'l20']", + "81, pFn-deficient ['l21', 'l22', 'l23']", + "82, mice ['l21', 'l24', 'l25']", + "84, increased ['l14', 'l17', 'l19', 'l22', 'l24', 'l26']", + "86, apoptosis ['l15', 'l18', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pFn-deficient", + "Cre-loxP", + "conditional", + "gene-knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "adult", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cre-loxP", + "conditional", + "gene-knockout", + "pFn-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cre-loxP", + "conditional", + "gene-knockout", + "pFn-deficient" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "11175855", + "TEXT": "The chimeric BCR-ABL oncoprotein is the molecular hallmark of chronic myelogenous leukemia (CML). BCR-ABL contains nuclear import and export signals but it is localized only in the cytoplasm where it activates mitogenic and anti-apoptotic pathways. We have found that inhibition of the BCR-ABL tyrosine kinase, either by mutation or by the drug STI571, can stimulate its nuclear entry. By combining STI571 with leptomycin B (LMB) to block nuclear export, we trapped BCR-ABL in the nucleus and the nuclear BCR-ABL tyrosine kinase activates apoptosis. As a result, the combined treatment with STI571 and LMB causes the irreversible and complete killing of BCR-ABL transformed cells, whereas the effect of either drug alone is fully reversible. The combined treatment with STI571 and LMB also preferentially eliminates mouse bone marrow cells that express BCR-ABL. These results indicate that nuclear entrapment of BCR-ABL can be used as a therapeutic strategy to selectively kill chronic myelogenous leukemia cells.", + "TAG_DATA": [ + "39, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "40, of {'perturbing_action': 'I-pharmacological inhibition'}", + "41, the {'perturbing_action': 'I-pharmacological inhibition'}", + "42, BCR-ABL {'perturbing_action': 'I-pharmacological inhibition'}", + "43, tyrosine {'perturbing_action': 'I-pharmacological inhibition'}", + "44, kinase, {'perturbing_action': 'I-pharmacological inhibition'}", + "47, mutation {'perturbing_action': 'I-pharmacological inhibition'}", + "81, activates {'effect': 'B-positive'}", + "82, apoptosis. {'phenotype': 'B-apoptosis'}", + "101, transformed {'context': 'B-transformed cells'}", + "102, cells, {'context': 'B-cells'}", + "123, mouse {'context': 'B-cells'}", + "124, bone {'context': 'I-cells'}", + "125, marrow {'context': 'I-cells'}", + "126, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "39, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "40, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "41, the ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "42, BCR-ABL ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "43, tyrosine ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "44, kinase, ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "46, by ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "47, mutation ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "81, activates ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "82, apoptosis. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "100, BCR-ABL ['l45', 'l46']", + "101, transformed ['l45', 'l47']", + "102, cells, ['l46', 'l47']", + "123, mouse ['l48', 'l49', 'l50']", + "124, bone ['l48', 'l51', 'l52']", + "125, marrow ['l49', 'l51', 'l53']", + "126, cells ['l50', 'l52', 'l53']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "the", + "BCR-ABL", + "tyrosine", + "kinase,", + "mutation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "activates" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "the", + "BCR-ABL", + "tyrosine", + "kinase,", + "mutation" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "activates" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "11175854", + "TEXT": "Vascular endothelial growth factor (VEGF), an angiogenic factor produced in response to ischemic injury, promotes vascular permeability (VP). Evidence is provided that Src kinase regulates VEGF-mediated VP in the brain following stroke and that suppression of Src activity decreases VP thereby minimizing brain injury. Mice lacking pp60c-src are resistant to VEGF-induced VP and show decreased infarct volumes after stroke whereas mice deficient in pp59c-fyn, another Src family member, have normal VEGF-mediated VP and infarct size. Systemic application of a Src-inhibitor given up to six hours following stroke suppressed VP protecting wild-type mice from ischemia-induced brain damage without influencing VEGF expression. This was associated with reduced edema, improved cerebral perfusion and decreased infarct volume 24 hours after injury as measured by magnetic resonance imaging and histological analysis. Thus, Src represents a key intermediate and novel therapeutic target in the pathophysiology of cerebral ischemia where it appears to regulate neuronal damage by influencing VEGF-mediated VP.", + "TAG_DATA": [ + "44, Mice {'context': 'B-organism'}", + "45, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "46, pp60c-src {'perturbing_action': 'I-gene loss-of-function'}", + "60, mice {'context': 'B-organism'}", + "61, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "62, in {'perturbing_action': 'I-gene loss-of-function'}", + "63, pp59c-fyn, {'perturbing_action': 'I-gene loss-of-function'}", + "79, Src-inhibitor {'perturbing_action': 'B-pharmacological inhibition'}", + "91, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "44, Mice ['l0', 'l1']", + "45, lacking ['l0', 'l2', 'l3']", + "46, pp60c-src ['l1', 'l2', 'l4', 'l5']", + "60, mice ['l3', 'l4', 'l6', 'l7', 'l8', 'l9', 'l10']", + "61, deficient ['l6', 'l11', 'l12', 'l13', 'l14']", + "62, in ['l7', 'l11', 'l15', 'l16', 'l17']", + "63, pp59c-fyn, ['l8', 'l12', 'l15', 'l18', 'l19']", + "79, Src-inhibitor ['l9', 'l13', 'l16', 'l18', 'l20']", + "91, mice ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "pp60c-src", + "deficient", + "in", + "pp59c-fyn," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Src-inhibitor" + ] + } + } + ] + }, + { + "PMID": "11175852", + "TEXT": "The mechanism underlying suppression of immune responses by interleukin-4 (IL-4) has remained unexplained. Here we show that the antigen-presenting dendritic cell is central to counter-regulation of autoimmune disease by IL-4. IL-4 acts at the locus of the dendritic cell to decrease the cytolytic T-cell response, preventing autoimmunity. Stimulation of cytotoxic precursors by antigen pulsed dendritic cells induces their differentiation but the process is blocked by IL-4. IL-4-influenced DC produce distinct effects on CD8+ T cells depending on their state of activation. The molecular basis for this regulation is the alteration of the expression ratio of the costimulatory ligands B7.1/B7.2 on dendritic cells. Our findings demonstrate that B7.2 induces expansion of CD8+ T cells and B7.1 governs their acquisition of cytolytic activity. IL-4 influences the dendritic cell to elicit qualitative differences in T-cell responses, providing the basis for counter-regulation mediated by IL-4.", + "TAG_DATA": [ + "54, dendritic {'context': 'B-cells'}", + "55, cells {'context': 'I-cells'}", + "56, induces {'effect': 'B-positive'}", + "58, differentiation {'phenotype': 'B-differentiation'}", + "67, DC {'context': 'B-cells'}", + "72, CD8+ {'context': 'B-cells'}", + "73, T {'context': 'I-cells'}", + "74, cells {'context': 'I-cells'}", + "110, CD8+ {'context': 'B-cells'}", + "111, T {'context': 'I-cells'}", + "112, cells {'context': 'I-cells'}", + "124, dendritic {'context': 'B-cells'}", + "125, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "54, dendritic ['l0', 'l1', 'l2', 'l3']", + "55, cells ['l0', 'l4', 'l5']", + "56, induces ['l1', 'l4', 'l6']", + "58, differentiation ['l2', 'l5', 'l6']", + "67, DC ['l7', 'l8', 'l9']", + "72, CD8+ ['l7', 'l10', 'l11']", + "73, T ['l8', 'l10', 'l12']", + "74, cells ['l3', 'l9', 'l11', 'l12']", + "110, CD8+ ['l13', 'l14']", + "111, T ['l13', 'l15']", + "112, cells ['l14', 'l15']", + "124, dendritic ['l16']", + "125, cell ['l16']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "11135615", + "TEXT": "Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is highly expressed in lipid-accumulating macrophages of the coronary artery. In light of this, the wide-spread clinical use of thiazolidinediones (TZDs) in the treatment of type II diabetes raises concerns about the role of PPAR-gamma in macrophage function and disease progression. To define the role of PPAR-gamma in macrophage biology, we used homologous recombination to create embryonic stem cells that were homozygous for a null mutation in the PPAR-gamma gene. We demonstrate here that PPAR-gamma is neither essential for nor substantially affects the development of the macrophage lineage both in vitro and in vivo. In contrast, we show it is an important regulator of the scavenger receptor CD36, which has been genetically linked to lipid accumulation in macrophages. Both 15-deoxy-Delta12,14prostaglandin J2 and thiazolidinediones have anti-inflammatory effects that are independent of PPAR-gamma. We show that PPAR-gamma is required for positive effects of its ligands in modulating macrophage lipid metabolism, but that inhibitory effects on cytokine production and inflammation may be receptor independent.", + "TAG_DATA": [ + "60, embryonic {'context': 'B-cells'}", + "61, stem {'context': 'I-cells'}", + "62, cells {'context': 'I-cells'}", + "68, null {'perturbing_action': 'B-gene loss-of-function'}", + "69, mutation {'perturbing_action': 'I-gene loss-of-function'}", + "70, in {'perturbing_action': 'I-gene loss-of-function'}", + "71, the {'perturbing_action': 'I-gene loss-of-function'}", + "72, PPAR-gamma {'perturbing_action': 'I-gene loss-of-function'}", + "73, gene. {'perturbing_action': 'I-gene loss-of-function'}", + "93, in {'context': 'B-in vitro'}", + "94, vitro {'context': 'I-in vitro'}", + "96, in {'context': 'B-in vivo'}", + "97, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "60, embryonic ['l0', 'l1', 'l2', 'l3', 'l4']", + "61, stem ['l0', 'l5', 'l6', 'l7']", + "62, cells ['l1', 'l5', 'l8', 'l9']", + "66, for ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "67, a ['l10', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "68, null ['l11', 'l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "69, mutation ['l12', 'l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "70, in ['l13', 'l23', 'l32', 'l40', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "71, the ['l14', 'l24', 'l33', 'l41', 'l48', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "72, PPAR-gamma ['l15', 'l25', 'l34', 'l42', 'l49', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "73, gene. ['l2', 'l16', 'l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "93, in ['l3', 'l6', 'l8', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l70']", + "94, vitro ['l4', 'l7', 'l9', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l70']", + "96, in ['l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71']", + "97, vivo. ['l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l71']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "embryonic" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "gene." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "null", + "mutation", + "in", + "the", + "PPAR-gamma", + "gene." + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "null", + "mutation", + "in", + "the", + "PPAR-gamma", + "gene." + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "11135614", + "TEXT": "Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), the transcription factor target of the anti-diabetic thiazolidinedione (TZD) drugs, is reported to mediate macrophage differentiation and inflammatory responses. Using PPAR-gamma-deficient stem cells, we demonstrate that PPAR-gamma is neither essential for myeloid development, nor for such mature macrophage functions as phagocytosis and inflammatory cytokine production. PPAR-gamma is required for basal expression of CD36, but not for expression of the other major scavenger receptor responsible for uptake of modified lipoproteins, SR-A. In wild-type macrophages, TZD treatment divergently regulated CD36 and class A macrophage-scavenger receptor expression and failed to induce significant cellular cholesterol accumulation, indicating that TZDs may not exacerbate macrophage foam-cell formation.", + "TAG_DATA": [ + "24, PPAR-gamma-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "25, stem {'context': 'B-cells'}", + "26, cells, {'context': 'I-cells'}", + "76, macrophages, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "24, PPAR-gamma-deficient ['l0', 'l1']", + "25, stem ['l0', 'l2']", + "26, cells, ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PPAR-gamma-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "stem", + "cells," + ] + } + } + ] + }, + { + "PMID": "11100121", + "TEXT": "Caveolin-1, the primary coat protein of caveolae, has been implicated as a regulator of signal transduction through binding of its \"scaffolding domain\" to key signaling molecules. However, the physiological importance of caveolin-1 in regulating signaling has been difficult to distinguish from its traditional functions in caveolae assembly, transcytosis, and cholesterol transport. To directly address the importance of the caveolin scaffolding domain in vivo, we generated a chimeric peptide with a cellular internalization sequence fused to the caveolin-1 scaffolding domain (amino acids 82-101). The chimeric peptide was efficiently taken up into blood vessels and endothelial cells, resulting in selective inhibition of acetylcholine (Ach)-induced vasodilation and nitric oxide (NO) production, respectively. More importantly, systemic administration of the peptide to mice suppressed acute inflammation and vascular leak to the same extent as a glucocorticoid or an endothelial nitric oxide synthase (eNOS) inhibitor. These data imply that the caveolin-1 scaffolding domain can selectively regulate signal transduction to eNOS in endothelial cells and that small-molecule mimicry of this domain may provide a new therapeutic approach.", + "TAG_DATA": [ + "117, mice {'context': 'B-organism'}", + "133, endothelial {'perturbing_action': 'B-pharmacological inhibition'}", + "134, nitric {'perturbing_action': 'I-pharmacological inhibition'}", + "135, oxide {'perturbing_action': 'I-pharmacological inhibition'}", + "136, synthase {'perturbing_action': 'I-pharmacological inhibition'}", + "137, (eNOS) {'perturbing_action': 'I-pharmacological inhibition'}", + "138, inhibitor. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "117, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "133, endothelial ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "134, nitric ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "135, oxide ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "136, synthase ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "137, (eNOS) ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "138, inhibitor. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "endothelial", + "nitric", + "oxide", + "synthase", + "(eNOS)", + "inhibitor." + ] + } + } + ] + }, + { + "PMID": "11062533", + "TEXT": "The characterization of hepatic progenitor cells is of great scientific and clinical interest. Here we report that intravenous injection of adult bone marrow cells in the FAH(-/-) mouse, an animal model of tyrosinemia type I, rescued the mouse and restored the biochemical function of its liver. Moreover, within bone marrow, only rigorously purified hematopoietic stem cells gave rise to donor-derived hematopoietic and hepatic regeneration. This result seems to contradict the conventional assumptions of the germ layer origins of tissues such as the liver, and raises the question of whether the cells of the hematopoietic stem cell phenotype are pluripotent hematopoietic cells that retain the ability to transdifferentiate, or whether they are more primitive multipotent cells.", + "TAG_DATA": [ + "20, adult {'context': 'B-cells'}", + "21, bone {'context': 'I-cells'}", + "22, marrow {'context': 'I-cells'}", + "23, cells {'context': 'I-cells'}", + "26, FAH(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "27, mouse, {'context': 'B-organism'}", + "37, mouse {'context': 'B-organism'}", + "45, liver. {'context': 'B-tissue/organ'}", + "53, hematopoietic {'context': 'B-cells'}", + "54, stem {'context': 'I-cells'}", + "55, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "20, adult ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "21, bone ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "22, marrow ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "23, cells ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "26, FAH(-/-) ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "27, mouse, ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "37, mouse ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "45, liver. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "53, hematopoietic ['l28', 'l29']", + "54, stem ['l28', 'l30']", + "55, cells ['l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "adult", + "bone", + "marrow", + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FAH(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FAH(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse,", + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FAH(-/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver." + ] + } + } + ] + }, + { + "PMID": "11017144", + "TEXT": "The adenovirus mutant dl1520 (ONYX-015) does not express the E1B-55K protein that binds and inactivates p53. This virus replicates in tumor cells with mutant p53, but not in normal cells with functional p53. Although intra-tumoral injection of dl1520 shows promising responses in patients with solid tumors, previous in vitro studies have not established a close correlation between p53 status and dl1520 replication. Here we identify loss of p14ARF as a mechanism that allows dl1520 replication in tumor cells retaining wild-type p53. We demonstrate that the re-introduction of p14ARF into tumor cells with wild-type p53 suppresses replication of dl1520 in a p53-dependent manner. Our study supports the therapeutic use of dl1520 in tumors with lesions within the p53 pathway other than mutation of p53.", + "TAG_DATA": [ + "76, tumor {'context': 'B-transformed cells'}", + "77, cells {'context': 'I-transformed cells'}", + "85, re-introduction {'perturbing_action': 'B-gene gain-of-function'}", + "86, of {'perturbing_action': 'I-gene gain-of-function'}", + "87, p14ARF {'perturbing_action': 'I-gene gain-of-function'}", + "89, tumor {'context': 'B-transformed cells'}", + "90, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "76, tumor ['l0']", + "77, cells ['l0']", + "85, re-introduction ['l1', 'l2', 'l3', 'l4']", + "86, of ['l1', 'l5', 'l6', 'l7']", + "87, p14ARF ['l2', 'l5', 'l8', 'l9']", + "89, tumor ['l3', 'l6', 'l8', 'l10']", + "90, cells ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "re-introduction", + "of", + "p14ARF" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + } + ] + }, + { + "PMID": "10973317", + "TEXT": "Members of the AP-1 family of transcription factors participate in the regulation of bone cell proliferation and differentiation. We report here a potent AP-1-related regulator of osteoblast function: DeltaFosB, a naturally occurring truncated form of FosB that arises from alternative splicing of the fosB transcript and is expressed in osteoblasts. Overexpression of DeltaFosB in transgenic mice leads to increased bone formation throughout the skeleton and a continuous post-developmental increase in bone mass, leading to osteosclerosis. In contrast, DeltaFosB inhibits adipogenesis both in vivo and in vitro, and downregulates the expression of early markers of adipocyte differentiation. Because osteoblasts and adipocytes are thought to share a common precursor, it is concluded that DeltaFosB transcriptionally regulates osteoblastogenesis, possibly at the expense of adipogenesis.", + "TAG_DATA": [ + "50, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "51, of {'perturbing_action': 'I-gene gain-of-function'}", + "52, DeltaFosB {'perturbing_action': 'I-gene gain-of-function'}", + "54, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "55, mice {'context': 'I-organism'}", + "81, in {'context': 'B-in vivo'}", + "82, vivo {'context': 'I-in vivo'}", + "84, in {'context': 'B-in vitro'}", + "85, vitro, {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "50, Overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "51, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "52, DeltaFosB ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "54, transgenic ['l2', 'l7', 'l11', 'l15']", + "55, mice ['l3', 'l8', 'l12', 'l15']", + "81, in ['l4', 'l9', 'l13', 'l16', 'l17', 'l18']", + "82, vivo ['l5', 'l10', 'l14', 'l16']", + "84, in ['l17', 'l19']", + "85, vitro, ['l18', 'l19']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "DeltaFosB", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "DeltaFosB" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "10932224", + "TEXT": "ONYX-015 is an adenovirus with the E1B 55-kDa gene deleted, engineered to selectively replicate in and lyse p53-deficient cancer cells while sparing normal cells. Although ONYX-015 and chemotherapy have demonstrated anti-tumoral activity in patients with recurrent head and neck cancer, disease recurs rapidly with either therapy alone. We undertook a phase II trial of a combination of intratumoral ONYX-015 injection with cisplatin and 5-fluorouracil in patients with recurrent squamous cell cancer of the head and neck. There were substantial objective responses, including a high proportion of complete responses. By 6 months, none of the responding tumors had progressed, whereas all non-injected tumors treated with chemotherapy alone had progressed. The toxic effects that occurred were acceptable. Tumor biopsies obtained after treatment showed tumor-selective viral replication and necrosis induction.", + "TAG_DATA": [ + "65, patients {'context': 'B-patient'}", + "67, recurrent {'context': 'B-neoplasm'}", + "68, squamous {'context': 'I-neoplasm'}", + "69, cell {'context': 'I-neoplasm'}", + "70, cancer {'context': 'I-neoplasm'}", + "71, of {'context': 'I-neoplasm'}", + "72, the {'context': 'I-neoplasm'}", + "73, head {'context': 'I-neoplasm'}", + "74, and {'context': 'I-neoplasm'}", + "75, neck. {'context': 'I-neoplasm'}", + "95, tumors {'context': 'B-neoplasm'}", + "101, tumors {'context': 'B-neoplasm'}", + "115, Tumor {'context': 'B-neoplasm'}", + "125, necrosis {'phenotype': 'B-necrosis'}", + "126, induction. {'effect': 'B-positive'}" + ], + "LINK_DATA": [ + "65, patients ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "67, recurrent ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "68, squamous ['l1', 'l9', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "69, cell ['l2', 'l10', 'l18', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "70, cancer ['l3', 'l11', 'l19', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "71, of ['l4', 'l12', 'l20', 'l27', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "72, the ['l5', 'l13', 'l21', 'l28', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47']", + "73, head ['l6', 'l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l48', 'l49']", + "74, and ['l7', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l50']", + "75, neck. ['l8', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l50']", + "95, tumors ['l17', 'l25', 'l32', 'l38', 'l43', 'l47']", + "101, tumors ['l51']", + "115, Tumor ['l52', 'l53']", + "125, necrosis ['l52', 'l54']", + "126, induction. ['l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "Tumor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "Tumor" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction." + ] + } + } + ] + }, + { + "PMID": "10932223", + "TEXT": "The sodium/iodide symporter mediates active iodide transport in both healthy and cancerous thyroid tissue. By exploiting this activity, radioiodide has been used for decades with considerable success in the detection and treatment of thyroid cancer. Here we show that a specialized form of the sodium/iodide symporter in the mammary gland mediates active iodide transport in healthy lactating (but not in nonlactating) mammary gland and in mammary tumors. In addition to characterizing the hormonal regulation of the mammary gland sodium/iodide symporter, we demonstrate by scintigraphy that mammary adenocarcinomas in transgenic mice bearing Ras or Neu oncogenes actively accumulate iodide by this symporter in vivo. Moreover, more than 80% of the human breast cancer samples we analyzed by immunohistochemistry expressed the symporter, compared with none of the normal (nonlactating) samples from reductive mammoplasties. These results indicate that the mammary gland sodium/iodide symporter may be an essential breast cancer marker and that radioiodide should be studied as a possible option in the diagnosis and treatment of breast cancer.", + "TAG_DATA": [ + "85, mammary {'context': 'B-neoplasm'}", + "86, adenocarcinomas {'context': 'I-neoplasm'}", + "88, transgenic {'context': 'B-organism'}", + "89, mice {'context': 'I-organism'}", + "91, Ras {'perturbing_action': 'I-other'}", + "92, or {'perturbing_action': 'I-other'}", + "93, Neu {'perturbing_action': 'I-other'}", + "94, oncogenes {'perturbing_action': 'I-other'}", + "101, in {'context': 'B-in vivo'}", + "102, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "85, mammary ['l0', 'l1', 'l2', 'l3', 'l4']", + "86, adenocarcinomas ['l0', 'l5', 'l6']", + "88, transgenic ['l1', 'l5', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "89, mice ['l2', 'l6', 'l7', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "91, Ras ['l8', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "92, or ['l9', 'l15', 'l20', 'l25', 'l26', 'l27', 'l28']", + "93, Neu ['l3', 'l10', 'l16', 'l21', 'l25', 'l29', 'l30', 'l31']", + "94, oncogenes ['l11', 'l17', 'l22', 'l26', 'l29', 'l32', 'l33']", + "101, in ['l12', 'l18', 'l23', 'l27', 'l30', 'l32', 'l34']", + "102, vivo. ['l4', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l34']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "mammary" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Neu" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Ras", + "or", + "Neu", + "oncogenes" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Ras", + "or", + "Neu", + "oncogenes" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "10888928", + "TEXT": "Apoptosis of smooth muscle cells is a common feature of vascular lesions but its pathophysiological significance is not known. We demonstrate that signals initiated by regulated Fas-associated death domain protein overexpression in rat vascular smooth muscle cells in the carotid artery induce expression of monocyte-chemoattractant protein-1 and interleukin-8, and cause massive immigration of macrophages in vivo. These chemokines, and a specific set of other pro-inflammatory genes, are also upregulated in human vascular smooth muscle cells during Fas-induced apoptosis, in part through a process that requires interleukin-1alpha activation. Induction of a pro-inflammatory program by apoptotic vascular smooth muscle cells may thus contribute to the pathogenesis of vascular disease.", + "TAG_DATA": [ + "32, rat {'context': 'B-cells'}", + "33, vascular {'context': 'I-cells'}", + "34, smooth {'context': 'I-cells'}", + "35, muscle {'context': 'I-cells'}", + "36, cells {'context': 'I-cells'}", + "39, carotid {'context': 'B-tissue/organ'}", + "40, artery {'context': 'I-tissue/organ'}", + "53, macrophages {'context': 'B-cells'}", + "54, in {'context': 'B-in vivo'}", + "55, vivo. {'context': 'I-in vivo'}", + "70, human {'context': 'B-cells'}", + "71, vascular {'context': 'I-cells'}", + "72, smooth {'context': 'I-cells'}", + "73, muscle {'context': 'I-cells'}", + "74, cells {'context': 'I-cells'}", + "76, Fas-induced {'effect': 'B-positive'}", + "77, apoptosis, {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "32, rat ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "33, vascular ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "34, smooth ['l1', 'l9', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "35, muscle ['l2', 'l10', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "36, cells ['l3', 'l11', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "39, carotid ['l4', 'l12', 'l17', 'l22', 'l26', 'l30']", + "40, artery ['l5', 'l13', 'l18', 'l23', 'l27', 'l30']", + "53, macrophages ['l6', 'l14', 'l19', 'l24', 'l28', 'l31', 'l32']", + "54, in ['l7', 'l31', 'l33']", + "55, vivo. ['l8', 'l20', 'l25', 'l29', 'l32', 'l33']", + "70, human ['l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "71, vascular ['l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "72, smooth ['l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "73, muscle ['l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "74, cells ['l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "76, Fas-induced ['l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "77, apoptosis, ['l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "vascular", + "smooth", + "muscle", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "Fas-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "vascular", + "smooth", + "muscle", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Fas-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + } + ] + }, + { + "PMID": "10888925", + "TEXT": "The release of microparticles from eukaryotic cells is a well-recognized phenomenon. We demonstrate here that the chemokine receptor CCR5, the principal co-receptor for macrophage-tropic human immunodeficiency virus (HIV)-1, can be released through microparticles from the surface of CCR5+ Chinese hamster ovary cells and peripheral blood mononuclear cells. Microparticles containing CCR5 can transfer the receptor to CCR5- cells and render them CCR5+. The CCR5 transfer to CCR5-deficient peripheral blood mononuclear cells homozygous for a 32-base-pair deletion in the CCR5 gene enabled infection of these cells with macrophage-tropic HIV-1. In monocytes, the transfer of CCR5 could be inhibited by cytochalasin D, and transferred CCR5 could be downmodulated by chemokines. A transfer of CCR5 from peripheral blood mononuclear cells to endothelial cells during transendothelial migration could be demonstrated. Thus, the transfer of CCR5 may lead to infection of tissues without endogenous CCR5 expression. Moreover, the intercellular transfer of membrane proteins by microparticles might have broader consequences for intercellular communication beyond the effects seen for HIV-1.", + "TAG_DATA": [ + "65, CCR5-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "66, peripheral {'context': 'B-cells'}", + "67, blood {'context': 'I-cells'}", + "68, mononuclear {'context': 'I-cells'}", + "69, cells {'context': 'I-cells'}", + "70, homozygous {'perturbing_action': 'B-other'}", + "71, for {'perturbing_action': 'I-other'}", + "72, a {'perturbing_action': 'I-other'}", + "73, 32-base-pair {'perturbing_action': 'I-other'}", + "74, deletion {'perturbing_action': 'I-other'}", + "75, in {'perturbing_action': 'I-other'}", + "76, the {'perturbing_action': 'I-other'}", + "77, CCR5 {'perturbing_action': 'I-other'}", + "78, gene {'perturbing_action': 'I-other'}", + "83, cells {'context': 'B-cells'}", + "88, monocytes, {'context': 'B-cells'}", + "112, peripheral {'context': 'B-cells'}", + "113, blood {'context': 'I-cells'}", + "114, mononuclear {'context': 'I-cells'}", + "115, cells {'context': 'I-cells'}", + "117, endothelial {'context': 'B-cells'}", + "118, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "65, CCR5-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "66, peripheral ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "67, blood ['l1', 'l10', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "68, mononuclear ['l2', 'l11', 'l24', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "69, cells ['l3', 'l12', 'l25', 'l37', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "70, homozygous ['l4', 'l13', 'l26', 'l38', 'l49', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "71, for ['l14', 'l27', 'l39', 'l50', 'l60', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "72, a ['l15', 'l28', 'l40', 'l51', 'l61', 'l70', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "73, 32-base-pair ['l16', 'l29', 'l41', 'l52', 'l62', 'l71', 'l79', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "74, deletion ['l17', 'l30', 'l42', 'l53', 'l63', 'l72', 'l80', 'l87', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "75, in ['l5', 'l18', 'l31', 'l43', 'l54', 'l64', 'l73', 'l81', 'l88', 'l94', 'l100', 'l101', 'l102', 'l103', 'l104']", + "76, the ['l6', 'l19', 'l32', 'l44', 'l55', 'l65', 'l74', 'l82', 'l89', 'l95', 'l100', 'l105', 'l106', 'l107', 'l108']", + "77, CCR5 ['l7', 'l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l83', 'l90', 'l96', 'l101', 'l105', 'l109', 'l110', 'l111']", + "78, gene ['l8', 'l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l84', 'l91', 'l97', 'l102', 'l106', 'l109', 'l112', 'l113']", + "83, cells ['l9', 'l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l98', 'l103', 'l107', 'l110', 'l112']", + "88, monocytes, ['l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l86', 'l93', 'l99', 'l104', 'l108', 'l111', 'l113']", + "112, peripheral ['l114', 'l115', 'l116', 'l117', 'l118']", + "113, blood ['l114', 'l119', 'l120', 'l121', 'l122']", + "114, mononuclear ['l115', 'l119', 'l123', 'l124', 'l125']", + "115, cells ['l116', 'l120', 'l123', 'l126', 'l127']", + "117, endothelial ['l117', 'l121', 'l124', 'l126', 'l128']", + "118, cells ['l118', 'l122', 'l125', 'l127', 'l128']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CCR5-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "peripheral", + "blood", + "mononuclear", + "cells" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "peripheral", + "blood", + "mononuclear", + "cells", + "monocytes," + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "homozygous", + "for", + "a", + "32-base-pair", + "deletion", + "in", + "the", + "CCR5", + "gene" + ] + } + } + ] + }, + { + "PMID": "10835690", + "TEXT": "The androgen receptor (AR) is involved in the development, growth and progression of prostate cancer (CaP). CaP often progresses from an androgen-dependent to an androgen-independent tumor, making androgen ablation therapy ineffective. However, the mechanisms for the development of androgen-independent CaP are unclear. More than 80% of clinically androgen-independent prostate tumors show high levels of AR expression. In some CaPs, AR levels are increased because of gene amplification and/or overexpression, whereas in others, the AR is mutated. Nonetheless, the involvement of the AR in the transition of CaP to androgen-independent growth and the subsequent failure of endocrine therapy are not fully understood. Here we show that in CaP cells from a patient who failed androgen ablation therapy, a doubly mutated AR functioned as a high-affinity cortisol/cortisone receptor (ARccr). Cortisol, the main circulating glucocorticoid, and its metabolite, cortisone, both equally stimulate the growth of these CaP cells and increase the secretion of prostate-specific antigen in the absence of androgens. The physiological concentrations of free cortisol and total cortisone in men greatly exceed the binding affinity of the ARccr and would activate the receptor, promoting CaP cell proliferation. Our data demonstrate a previously unknown mechanism for the androgen-independent growth of advanced CaP. Understanding this mechanism and recognizing the presence of glucocorticoid-responsive AR mutants are important for the development of new forms of therapy for the treatment of this subset of CaP.", + "TAG_DATA": [ + "106, CaP {'context': 'B-transformed cells'}", + "107, cells {'context': 'I-transformed cells'}", + "117, doubly {'perturbing_action': 'B-other'}", + "118, mutated {'perturbing_action': 'B-other'}", + "119, AR {'perturbing_action': 'I-other'}", + "143, CaP {'context': 'B-transformed cells'}", + "144, cells {'context': 'I-transformed cells'}", + "181, promoting {'effect': 'B-positive'}", + "182, CaP {'context': 'B-transformed cells'}", + "183, cell {'context': 'I-transformed cells'}", + "184, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "106, CaP ['l0', 'l1', 'l2']", + "107, cells ['l0', 'l3', 'l4']", + "117, doubly ['l5', 'l6', 'l7', 'l8']", + "118, mutated ['l5', 'l9', 'l10', 'l11']", + "119, AR ['l6', 'l9', 'l12', 'l13']", + "143, CaP ['l1', 'l3', 'l7', 'l10', 'l12', 'l14']", + "144, cells ['l2', 'l4', 'l8', 'l11', 'l13', 'l14']", + "181, promoting ['l15', 'l16', 'l17']", + "182, CaP ['l15', 'l18', 'l19']", + "183, cell ['l16', 'l18', 'l20']", + "184, proliferation. ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "doubly", + "mutated", + "AR" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "CaP", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "CaP", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CaP", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "10835680", + "TEXT": "Accumulation of fibrils composed of amyloid A in tissues resulting in displacement of normal structures and cellular dysfunction is the characteristic feature of systemic amyloidoses. Here we show that RAGE, a multiligand immunoglobulin superfamily cell surface molecule, is a receptor for the amyloidogenic form of serum amyloid A. Interactions between RAGE and amyloid A induced cellular perturbation. In a mouse model, amyloid A accumulation, evidence of cell stress and expression of RAGE were closely linked. Antagonizing RAGE suppressed cell stress and amyloid deposition in mouse spleens. These data indicate that RAGE is a potential target for inhibiting accumulation of amyloid A and for limiting cellular dysfunction induced by amyloid A.", + "TAG_DATA": [ + "59, mouse {'context': 'B-organism'}", + "60, model, {'context': 'I-organism'}", + "75, Antagonizing {'perturbing_action': 'B-pharmacological inhibition'}", + "76, RAGE {'perturbing_action': 'I-pharmacological inhibition'}", + "84, mouse {'context': 'B-tissue/organ'}", + "85, spleens. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "59, mouse ['l0']", + "60, model, ['l0']", + "75, Antagonizing ['l1', 'l2', 'l3']", + "76, RAGE ['l1', 'l4', 'l5']", + "84, mouse ['l2', 'l4', 'l6']", + "85, spleens. ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Antagonizing", + "RAGE" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "spleens." + ] + } + } + ] + }, + { + "PMID": "10802711", + "TEXT": "Recent advances using transgenic animals or exogenous complement inhibitors have demonstrated prevention of hyperacute rejection of vascularized organs, but not graft loss due to acute vascular rejection. Using various wild-type and cytokine-deficient mice strains, we have examined the mechanisms of acute vascular rejection. C57BL/6 mice deficient in interleukin12 or gamma interferon showed faster acute vascular rejection than did wild-type mice. Furthermore, mice defective in B-cell development showed no acute vascular rejection. These results demonstrate that the axis of interleukin 12 and gamma interferon provides a survival advantage in vascularized xenografts by delaying or preventing acute vascular rejection caused by a B cell-dependent mechanism.", + "TAG_DATA": [ + "43, C57BL/6 {'context': 'B-organism'}", + "44, mice {'context': 'I-organism'}", + "45, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "46, in {'perturbing_action': 'I-gene loss-of-function'}", + "47, interleukin12 {'perturbing_action': 'I-gene loss-of-function'}", + "59, mice. {'context': 'B-organism'}", + "61, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "43, C57BL/6 ['l0', 'l1', 'l2', 'l3', 'l4']", + "44, mice ['l0', 'l5', 'l6', 'l7', 'l8']", + "45, deficient ['l1', 'l5', 'l9', 'l10', 'l11']", + "46, in ['l2', 'l6', 'l9', 'l12', 'l13']", + "47, interleukin12 ['l3', 'l7', 'l10', 'l12', 'l14']", + "59, mice. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "C57BL/6", + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "interleukin12" + ] + } + } + ] + }, + { + "PMID": "10700235", + "TEXT": "To provide long-term therapy in patients with severe toxin-induced hepatic parenchymal damage, donor hepatocytes would need to replicate and replace a large portion of the damaged parenchyma. Using a mouse model developed to reproduce this type of hepatic injury, we found that hepatocyte transplantation only slightly improved survival after transplantation despite the fact that many non-survivors showed moderate liver repopulation by donor cells. Perhaps accounting for this outcome, donor parenchyma in non-survivors did not have typical lobular organization. These results indicate that the re-creation of functional parenchyma by transplanted hepatocytes requires time, during which donor cells proliferate and then establish normal parenchymal architecture.", + "TAG_DATA": [ + "29, mouse {'context': 'B-organism'}", + "30, model {'context': 'I-organism'}", + "42, hepatocyte {'context': 'B-cells'}", + "58, liver {'context': 'B-tissue/organ'}", + "62, cells. {'context': 'I-cells'}", + "94, donor {'context': 'B-cells'}", + "95, cells {'context': 'I-cells'}", + "96, proliferate {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "29, mouse ['l0']", + "30, model ['l0']", + "42, hepatocyte ['l1', 'l2']", + "58, liver ['l1', 'l3']", + "62, cells. ['l2', 'l3']", + "94, donor ['l4', 'l5']", + "95, cells ['l4', 'l6']", + "96, proliferate ['l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "donor", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate" + ] + } + } + ] + }, + { + "PMID": "10655114", + "TEXT": "Thromboxane (Tx) A2 is a platelet agonist, smooth muscle cell constrictor, and mitogen. Urinary Tx metabolite (Tx-M) excretion is increased in syndromes of platelet activation and early in both normal pregnancies and in pregnancy-induced hypertension. A further increment occurs in patients presenting with severe preeclampsia, in whom Tx-M correlates with other indices of disease severity. TxA2 exerts its effects through a membrane receptor (TP), of which two isoforms (alpha and beta; refs. 5,6) have been cloned. Overexpression of TP in the vasculature under the control of the pre-proendothelin-1 promoter results in a murine model of intrauterine growth retardation (IUGR), which is rescued by timed suppression of Tx synthesis with indomethacin. IUGR is commonly associated with maternal diabetes or cigarette smoking, both conditions associated with increased TxA2 biosynthesis.", + "TAG_DATA": [ + "76, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "77, of {'perturbing_action': 'I-gene gain-of-function'}", + "78, TP {'perturbing_action': 'I-gene gain-of-function'}", + "81, vasculature {'context': 'B-tissue/organ'}", + "82, under {'perturbing_action': 'I-gene gain-of-function'}", + "84, control {'perturbing_action': 'I-gene gain-of-function'}", + "92, murine {'context': 'B-organism'}", + "93, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "76, Overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "77, of ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "78, TP ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "79, in ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "80, the ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "81, vasculature ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "82, under ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "84, control ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "88, promoter ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "92, murine ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "93, model ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "TP", + "under", + "control" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "vasculature" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "TP", + "under", + "control" + ] + }, + "context": { + "val": "organism", + "words": [ + "murine", + "model" + ] + } + } + ] + }, + { + "PMID": "10613826", + "TEXT": "Glutamate excitotoxicity mediated by the AMPA/kainate type of glutamate receptors damages not only neurons but also the myelin-producing cell of the central nervous system, the oligodendrocyte. In multiple sclerosis, myelin, oligodendrocytes and some axons are lost as a result of an inflammatory attack on the central nervous system. Because glutamate is released in large quantities by activated immune cells, we expected that during inflammation in MS, glutamate excitotoxicity might contribute to the lesion. We addressed this by using the AMPA/kainate antagonist NBQX to treat mice sensitized for experimental autoimmune encephalomyelitis, a demyelinating model that mimics many of the clinical and pathologic features of multiple sclerosis. Treatment resulted in substantial amelioration of disease, increased oligodendrocyte survival and reduced dephosphorylation of neurofilament H, an indicator of axonal damage. Despite the clinical differences, treatment with NBQX had no effect on lesion size and did not reduce the degree of central nervous system inflammation. In addition, NBQX did not alter the proliferative activity of antigen-primed T cells in vitro, further indicating a lack of effect on the immune system. Thus, glutamate excitotoxicity seems to be an important mechanism in autoimmune demyelination, and its prevention with AMPA/kainate antagonists may prove to be an effective therapy for multiple sclerosis.", + "TAG_DATA": [ + "84, mice {'context': 'B-organism'}", + "113, oligodendrocyte {'context': 'B-cells'}", + "153, did {'effect': 'B-no effect'}", + "154, not {'effect': 'I-no effect'}", + "155, alter {'effect': 'I-no effect'}", + "157, proliferative {'phenotype': 'B-proliferation'}", + "158, activity {'phenotype': 'I-proliferation'}", + "161, T {'context': 'B-cells'}", + "162, cells {'context': 'B-cells'}", + "163, in {'context': 'B-in vitro'}", + "164, vitro, {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "84, mice ['l0']", + "113, oligodendrocyte ['l0']", + "153, did ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "154, not ['l1', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "155, alter ['l2', 'l9', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "157, proliferative ['l3', 'l10', 'l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "158, activity ['l4', 'l11', 'l17', 'l22', 'l27', 'l28', 'l29', 'l30']", + "161, T ['l5', 'l12', 'l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "162, cells ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "163, in ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "164, vitro, ['l8', 'l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "alter" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "activity" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "alter" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "alter" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "activity" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "activity" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + } + ] + }, + { + "PMID": "10581081", + "TEXT": "Although insulin-like growth factor 1 (IGF-1) has been associated with retinopathy, proof of a direct relationship has been lacking. Here we show that an IGF-1 receptor antagonist suppresses retinal neovascularization in vivo, and infer that interactions between IGF-1 and the IGF-1 receptor are necessary for induction of maximal neovascularization by vascular endothelial growth factor (VEGF). IGF-1 receptor regulation of VEGF action is mediated at least in part through control of VEGF activation of p44/42 mitogen-activated protein kinase, establishing a hierarchical relationship between IGF-1 and VEGF receptors. These findings establish an essential role for IGF-1 in angiogenesis and demonstrate a new target for control of retinopathy. They also explain why diabetic retinopathy initially increases with the onset of insulin treatment. IGF-1 levels, low in untreated diabetes, rise with insulin therapy, permitting VEGF-induced retinopathy.", + "TAG_DATA": [ + "24, IGF-1 {'perturbing_action': 'B-pharmacological inhibition'}", + "25, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "26, antagonist {'perturbing_action': 'I-pharmacological inhibition'}", + "30, in {'context': 'B-in vivo'}", + "31, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "24, IGF-1 ['l0', 'l1', 'l2', 'l3']", + "25, receptor ['l0', 'l4', 'l5', 'l6']", + "26, antagonist ['l1', 'l4', 'l7', 'l8']", + "30, in ['l2', 'l5', 'l7', 'l9']", + "31, vivo, ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "IGF-1", + "receptor", + "antagonist" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + } + ] + }, + { + "PMID": "10546001", + "TEXT": "Pituitary tumors are commonly encountered, and result from clonal expansion of a single mutated cell. Hypothalamic hormones, local growth factors and circulating sex steroid hormones promote pituitary tumor growth and expansion into large invasive tumors. Estrogen acting directly through its receptor and by stimulation of fibroblast growth factor regulates prolactin synthesis and secretion. Fibroblast growth factor-2 (bFGF) modulates angiogenesis, tumor formation and progression in many tissues, including the anterior pituitary. A pituitary tumor-derived transforming gene (PTTG) has been isolated, which is tumorigenic in vivo, regulates bFGF secretion, and inhibits chromatid separation. The human PTTG family consists of at least three homologous genes, of which PTTG1 is located on chromosome 5q33 and is expressed at low levels in most normal human tissues but is highly expressed in malignant human cell lines and in pituitary tumors. We report here that pituitary pttg is regulated in vivo and in vitro by estrogen. Maximal induction of rat pituitary pttg mRNA in vivo occurred early in pituitary transformation (normal cell to hypertrophic/hyperplastic cell), coincident with bFGF and vascular endothelial growth factor induction and pituitary angiogenesis. We also demonstrate that pttg expression is induced by bFGF, and show concordant pttg and bFGF expression in experimental and human pituitary adenomas. As bFGF and estrogen both induce pttg, and pttg expression coincides with the early lactotrophic hyperplastic response, angiogenesis and prolactinoma development, we propose a previously unknown paracrine growth factor-mediated mechanism for pituitary tumor pathogenesis and potentially other estrogen-regulated tumors.", + "TAG_DATA": [ + "152, rat {'context': 'B-tissue/organ'}", + "153, pituitary {'context': 'I-tissue/organ'}", + "156, in {'context': 'B-in vivo'}", + "157, vivo {'context': 'I-in vivo'}", + "162, transformation {'phenotype': 'B-transformation'}" + ], + "LINK_DATA": [ + "152, rat ['l0', 'l1', 'l2', 'l3', 'l4']", + "153, pituitary ['l0', 'l5', 'l6', 'l7', 'l8']", + "156, in ['l1', 'l5', 'l9', 'l10', 'l11']", + "157, vivo ['l2', 'l6', 'l9', 'l12', 'l13']", + "161, pituitary ['l3', 'l7', 'l10', 'l12', 'l14']", + "162, transformation ['l4', 'l8', 'l11', 'l13', 'l14']", + "201, pituitary ['l15']", + "202, adenomas. ['l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "pituitary" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + } + } + ] + }, + { + "PMID": "10545999", + "TEXT": "The immune system is central in the pathogenesis of scrapie and other transmissible spongiform encephalopathies (TSEs) or 'prion' diseases. After infecting by peripheral (intraperitoneal or oral) routes, most TSE agents replicate in spleen and lymph nodes before neuroinvasion. Characterization of the cells supporting replication in these tissues is essential to understanding early pathogenesis and may indicate potential targets for therapy, for example, in 'new variant' Creutzfeldt-Jakob disease. The host 'prion' protein (PrP) is required for TSE agent replication and accumulates in modified forms in infected tissues. Abnormal PrP is detected readily on follicular dendritic cells (FDCs) in lymphoid tissues of patients with 'new variant' Creutzfeldt-Jakob disease, sheep with natural scrapie and mice experimentally infected with scrapie. The normal protein is present on FDCs in uninfected mice and, at lower levels, on lymphocytes. Studies using severe combined immunodeficiency (SCID) mice, with and without bone marrow (BM) grafts, have indicated involvement of FDCs and/or lymphocytes in scrapie pathogenesis. To clarify the separate roles of FDCs and lymphocytes, we produced chimeric mice with a mismatch in PrP status between FDCs and other cells of the immune system, by grafting bone marrow from PrP-deficient knockout mice into PrP-expressing mice and vice versa. Using these chimeric models, we obtained strong evidence that FDCs themselves produce PrP and that replication of a mouse-passaged scrapie strain in spleen depends on PrP-expressing FDCs rather than on lymphocytes or other bone marrow-derived cells.", + "TAG_DATA": [ + "138, mice, {'context': 'B-organism'}", + "167, chimeric {'context': 'B-organism'}", + "168, mice {'context': 'I-organism'}", + "187, marrow {'context': 'I-cells'}", + "189, PrP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "190, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "191, mice {'context': 'B-organism'}", + "193, PrP-expressing {'context': 'B-cells'}", + "194, mice {'context': 'I-organism'}", + "220, spleen {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "167, chimeric ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "168, mice ['l0', 'l8', 'l9']", + "186, bone ['l1', 'l8', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "187, marrow ['l2', 'l9', 'l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "189, PrP-deficient ['l3', 'l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "190, knockout ['l4', 'l12', 'l18', 'l23', 'l28', 'l29', 'l30', 'l31']", + "191, mice ['l5', 'l13', 'l19', 'l24', 'l28', 'l32', 'l33']", + "193, PrP-expressing ['l6', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "194, mice ['l7', 'l15', 'l21', 'l26', 'l30', 'l33', 'l34', 'l36']", + "220, spleen ['l16', 'l22', 'l27', 'l31', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "chimeric", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PrP-deficient", + "knockout" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "marrow", + "PrP-expressing" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PrP-deficient", + "knockout" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PrP-deficient", + "knockout" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "spleen" + ] + } + } + ] + }, + { + "PMID": "10545995", + "TEXT": "Basal cell carcinomas, the commonest human skin cancers, consistently have abnormalities of the hedgehog signaling pathway and often have PTCH gene mutations. We report here that Ptch+/- mice develop primordial follicular neoplasms resembling human trichoblastomas, and that exposure to ultraviolet radiation or ionizing radiation results in an increase in the number and size of these tumors and a shift in their histologic features so that they more closely resemble human basal cell carcinoma. The mouse basal cell carcinomas and trichoblastoma-like tumors resemble human basal cell carcinomas in their loss of normal hemidesmosomal components, presence of p53 mutations, frequent loss of the normal remaining Ptch allele, and activation of hedgehog target gene transcription. The Ptch mutant mice provide the first mouse model, to our knowledge, of ultraviolet and ionizing radiation-induced basal cell carcinoma-like tumors, and also demonstrate that Ptch inactivation and hedgehog target gene activation are essential for basal cell carcinoma tumorigenesis.", + "TAG_DATA": [ + "26, Ptch+/- {'perturbing_action': 'B-gene loss-of-function'}", + "27, mice {'context': 'B-organism'}", + "31, neoplasms {'phenotype': 'I-tumourigenesis'}", + "113, Ptch {'perturbing_action': 'B-other'}", + "114, mutant {'perturbing_action': 'I-other'}", + "115, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "26, Ptch+/- ['l0', 'l1']", + "27, mice ['l0', 'l2']", + "31, neoplasms ['l1', 'l2']", + "75, basal ['l3', 'l4']", + "76, cell ['l3', 'l5']", + "77, carcinomas ['l4', 'l5']", + "113, Ptch ['l6', 'l7']", + "114, mutant ['l6', 'l8']", + "115, mice ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ptch+/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ptch+/-" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasms" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasms" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Ptch", + "mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "10426322", + "TEXT": "In recent years, genetic defects of the mitochondrial genome (mtDNA) were shown to be associated with a heterogeneous group of disorders, known as mitochondrial diseases, but the cellular events deriving from the molecular lesions and the mechanistic basis of the specificity of the syndromes are still incompletely understood. Mitochondrial calcium (Ca2+) homeostasis depends on close contacts with the endoplasmic reticulum and is essential in modulating organelle function. Given the strong dependence of mitochondrial Ca2+ uptake on the membrane potential and the intracellular distribution of the organelle, both of which may be altered in mitochondrial diseases, we investigated the occurrence of defects in mitochondrial Ca2+ handling in living cells with either the tRNALys mutation of MERRF (myoclonic epilepsy with ragged-red fibers) or the ATPase mutation of NARP (neurogenic muscle weakness, ataxia and retinitis pigmentosa). There was a derangement of mitochondrial Ca2+ homeostasis in MERRF, but not in NARP cells, whereas cytosolic Ca2+ responses were normal in both cell types. Treatment of MERRF cells with drugs affecting organellar Ca2+ transport mostly restored both the agonist-dependent mitochondrial Ca2+ uptake and the ensuing stimulation of ATP production. These results emphasize the differences in the cellular pathogenesis of the various mtDNA defects and indicate specific pharmacological approaches to the treatment of some mitochondrial diseases.", + "TAG_DATA": [ + "106, living {'context': 'B-cells'}", + "107, cells {'context': 'I-cells'}", + "111, tRNALys {'perturbing_action': 'B-other'}", + "112, mutation {'perturbing_action': 'I-other'}", + "113, of {'perturbing_action': 'I-other'}", + "114, MERRF {'perturbing_action': 'I-other'}", + "122, ATPase {'perturbing_action': 'B-other'}", + "123, mutation {'perturbing_action': 'I-other'}", + "124, of {'perturbing_action': 'I-other'}", + "146, NARP {'context': 'B-cells'}", + "147, cells, {'context': 'I-cells'}", + "156, cell {'context': 'B-cells'}", + "157, types. {'context': 'I-cells'}", + "160, MERRF {'context': 'B-cells'}", + "161, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "106, living ['l0', 'l1', 'l2', 'l3', 'l4']", + "107, cells ['l0', 'l5', 'l6', 'l7', 'l8']", + "111, tRNALys ['l1', 'l5', 'l9', 'l10', 'l11', 'l12']", + "112, mutation ['l2', 'l6', 'l9', 'l13', 'l14', 'l15', 'l16', 'l17']", + "113, of ['l3', 'l7', 'l10', 'l13', 'l18', 'l19', 'l20']", + "114, MERRF ['l4', 'l8', 'l11', 'l14', 'l18', 'l21', 'l22', 'l23']", + "122, ATPase ['l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "123, mutation ['l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "124, of ['l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "146, NARP ['l15', 'l19', 'l21', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "147, cells, ['l12', 'l16', 'l20', 'l22', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "156, cell ['l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "157, types. ['l17', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "160, MERRF ['l45']", + "161, cells ['l45']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "living", + "cells", + "cells,", + "NARP", + "types.", + "cell" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "tRNALys", + "mutation", + "of", + "MERRF", + "ATPase" + ] + } + } + ] + }, + { + "PMID": "10426318", + "TEXT": "Dendritic cells (DCs) are special subsets of antigen-presenting cells characterized by their highly potent capacity to activate immunologically naive T cells. Here we report that DCs that are transfected with CD95 ligand (CD95L) cDNA, called 'killer' DCs, deliver death signals, instead of activation signals, to T cells after antigen-specific interaction. Injection of antigen-pulsed killer DCs into mice before sensitization induced antigen-specific immunosuppression. When administered after sensitization, killer DCs suppressed immune responses almost completely after subsequent challenge. Thus, killer DCs represent an entirely new immunomodulatory protocol, which may become directly applicable in preventing and even treating T cell-mediated inflammatory diseases.", + "TAG_DATA": [ + "25, DCs {'context': 'B-cells'}", + "28, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "29, with {'perturbing_action': 'I-gene gain-of-function'}", + "30, CD95 {'perturbing_action': 'I-gene gain-of-function'}", + "31, ligand {'perturbing_action': 'I-gene gain-of-function'}", + "32, (CD95L) {'perturbing_action': 'I-gene gain-of-function'}", + "33, cDNA, {'perturbing_action': 'I-gene gain-of-function'}", + "45, T {'context': 'B-cells'}", + "46, cells {'context': 'B-cells'}", + "53, killer {'context': 'B-cells'}", + "54, DCs {'context': 'I-cells'}", + "56, mice {'context': 'B-organism'}", + "66, killer {'context': 'B-cells'}", + "67, DCs {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "25, DCs ['l0', 'l1']", + "28, transfected ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "29, with ['l2', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "30, CD95 ['l3', 'l12', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "31, ligand ['l4', 'l13', 'l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "32, (CD95L) ['l5', 'l14', 'l22', 'l29', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "33, cDNA, ['l6', 'l15', 'l23', 'l30', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "45, T ['l0', 'l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l47', 'l48']", + "46, cells ['l1', 'l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47']", + "53, killer ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l49', 'l50']", + "54, DCs ['l10', 'l19', 'l27', 'l34', 'l40', 'l45', 'l48', 'l49', 'l51']", + "56, mice ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l50', 'l51']", + "66, killer ['l52']", + "67, DCs ['l52']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "CD95", + "ligand", + "(CD95L)", + "cDNA," + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "killer", + "DCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "CD95", + "ligand", + "(CD95L)", + "cDNA," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "10395331", + "TEXT": "The Bax protein is widely known as a pro-apoptotic Bcl-2 family member that when overexpressed can trigger apoptosis in multiple cell types and is important for the developmental cell death of neurons. However, Bax was found here to be a potent inhibitor of neuronal cell death in mice infected with Sindbis virus. Newborn mice, which are highly susceptible to a fatal infection with neurotropic Sindbis virus, were significantly protected from neuronal apoptosis and fatal disease when infected with a recombinant Sindbis virus encoding Bax. Deletion of the N terminus of Bax, which mimics cleaved Bax, converted Bax into a pro-apoptotic factor in vivo. As mice mature during the first week after birth, they acquire resistance to a fatal Sindbis virus infection. However, Bax-deficient mice remained very sensitive to fatal disease compared with their control littermates, indicating that endogenous Bax functions as a survival factor and contributes to age-dependent resistance to Sindbis virus-induced mortality. The protective effects of Bax were reproduced in cultured hippocampal neurons but not in cultured dorsal root ganglia neurons. These findings indicate that cell-specific factors determine the anti-apoptotic versus pro-apoptotic function of Bax.", + "TAG_DATA": [ + "52, Newborn {'context': 'B-organism'}", + "53, mice, {'context': 'I-organism'}", + "68, protected {'effect': 'B-negative'}", + "71, apoptosis {'phenotype': 'B-apoptosis'}", + "84, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "85, of {'perturbing_action': 'I-gene loss-of-function'}", + "86, the {'perturbing_action': 'I-gene loss-of-function'}", + "87, N {'perturbing_action': 'I-gene loss-of-function'}", + "88, terminus {'perturbing_action': 'I-gene loss-of-function'}", + "89, of {'perturbing_action': 'I-gene loss-of-function'}", + "90, Bax, {'perturbing_action': 'I-gene loss-of-function'}", + "101, in {'context': 'B-in vivo'}", + "102, vivo. {'context': 'I-in vivo'}", + "104, mice {'context': 'B-organism'}", + "122, Bax-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "123, mice {'context': 'B-organism'}", + "162, hippocampal {'context': 'I-cells'}", + "163, neurons {'context': 'I-cells'}", + "167, cultured {'context': 'B-cells'}", + "168, dorsal {'context': 'I-cells'}", + "169, root {'context': 'I-cells'}", + "170, ganglia {'context': 'I-cells'}", + "171, neurons. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "52, Newborn ['l0', 'l1', 'l2']", + "53, mice, ['l0', 'l3', 'l4']", + "68, protected ['l1', 'l3', 'l5']", + "71, apoptosis ['l2', 'l4', 'l5']", + "84, Deletion ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "85, of ['l6', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "86, the ['l7', 'l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "87, N ['l8', 'l16', 'l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "88, terminus ['l9', 'l17', 'l24', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "89, of ['l10', 'l18', 'l25', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "90, Bax, ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l45', 'l46', 'l47']", + "101, in ['l12', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l48', 'l49']", + "102, vivo. ['l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l50']", + "104, mice ['l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l50']", + "122, Bax-deficient ['l51']", + "123, mice ['l51']", + "162, hippocampal ['l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "163, neurons ['l52', 'l58', 'l59', 'l60', 'l61', 'l62']", + "167, cultured ['l53', 'l58', 'l63', 'l64', 'l65', 'l66']", + "168, dorsal ['l54', 'l59', 'l63', 'l67', 'l68', 'l69']", + "169, root ['l55', 'l60', 'l64', 'l67', 'l70', 'l71']", + "170, ganglia ['l56', 'l61', 'l65', 'l68', 'l70', 'l72']", + "171, neurons. ['l57', 'l62', 'l66', 'l69', 'l71', 'l72']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Newborn", + "mice," + ] + }, + "effect": { + "val": "negative", + "words": [ + "protected" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Newborn", + "mice," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "protected" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "N", + "terminus", + "Bax," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "N", + "terminus", + "Bax,", + "Bax-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "10395330", + "TEXT": "Given the associations between chronic inflammation and epithelial cancer, we studied susceptibility to skin carcinogenesis in mice deficient for the pro-inflammatory cytokine TNF-alpha (refs. 5,6). TNF-alpha(-/-) mice were resistant to development of benign and malignant skin tumors, whether induced by initiation with DMBA and promotion with TPA or by repeated dosing with DMBA. TNF-alpha(-/-) mice developed 5-10% the number of tumors developed by wild-type mice during initiation/promotion and 25% of those in wild-type mice after repeated carcinogen treatment. TNF-alpha could influence tumor and stromal cells during tumor development. The early stages of TPA promotion are characterized by keratinocyte hyperproliferation and inflammation. These were diminished in TNF-alpha(-/-) mice. TNF-alpha was extensively induced in the epidermis, but not the dermis, in TPA-treated wild-type skin, indicating that dermal inflammation is controlled by keratinocyte TNF-alpha production. Deletion of a TNF-alpha inducible chemokine also conferred some resistance to skin tumor development. TNF-alpha has little influence on later stages of carcinogenesis, as tumors in wild-type and TNF-alpha(-/-) mice had similar rates of malignant progression. These data provide evidence that a pro-inflammatory cytokine is required for de novo carcinogenesis and that TNF-alpha is important to the early stages of tumor promotion. Strategies that neutralize TNF-alpha production may be useful in cancer treatment and prevention.", + "TAG_DATA": [ + "16, mice {'context': 'B-organism'}", + "17, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "18, for {'perturbing_action': 'I-gene loss-of-function'}", + "25, TNF-alpha(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "26, mice {'context': 'B-organism'}", + "28, resistant {'effect': 'B-negative'}", + "30, development {'phenotype': 'B-tumourigenesis'}", + "32, benign {'phenotype': 'B-tumourigenesis'}", + "33, and {'context': 'I-neoplasm', 'phenotype': 'I-tumourigenesis'}", + "34, malignant {'context': 'I-neoplasm', 'phenotype': 'I-tumourigenesis'}", + "35, skin {'context': 'I-neoplasm'}", + "36, tumors, {'context': 'I-neoplasm', 'phenotype': 'I-tumourigenesis'}", + "38, induced {'effect': 'B-positive'}", + "53, TNF-alpha(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "54, mice {'context': 'B-organism'}", + "60, tumors {'phenotype': 'B-tumourigenesis'}", + "64, mice {'context': 'B-organism'}", + "73, mice {'context': 'B-organism'}", + "81, tumor {'context': 'B-neoplasm'}", + "86, tumor {'phenotype': 'B-tumourigenesis'}", + "87, development. {'phenotype': 'I-tumourigenesis'}", + "105, TNF-alpha(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "106, mice. {'context': 'B-organism'}", + "113, epidermis, {'context': 'B-tissue/organ'}", + "121, skin, {'context': 'B-tissue/organ'}", + "132, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "133, of {'perturbing_action': 'I-gene loss-of-function'}", + "134, a {'perturbing_action': 'I-gene loss-of-function'}", + "135, TNF-alpha {'perturbing_action': 'I-gene loss-of-function'}", + "136, inducible {'perturbing_action': 'I-gene loss-of-function'}", + "137, chemokine {'perturbing_action': 'I-gene loss-of-function'}", + "141, resistance {'effect': 'B-negative'}", + "143, skin {'context': 'B-tissue/organ'}", + "144, tumor {'phenotype': 'B-tumourigenesis'}", + "145, development. {'phenotype': 'I-tumourigenesis'}", + "156, tumors {'context': 'B-neoplasm'}", + "160, TNF-alpha(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "161, mice {'context': 'B-organism'}", + "163, similar {'effect': 'B-no effect'}", + "164, rates {'effect': 'B-negative'}", + "166, malignant {'phenotype': 'B-tumourigenesis'}", + "167, progression. {'phenotype': 'I-tumour progression'}" + ], + "LINK_DATA": [ + "16, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "17, deficient ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "18, for ['l1', 'l16', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "25, TNF-alpha(-/-) ['l2', 'l17', 'l34', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "26, mice ['l3', 'l18', 'l35', 'l52', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "28, resistant ['l4', 'l19', 'l36', 'l53', 'l68', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "29, to ['l5', 'l20', 'l37', 'l54', 'l69', 'l80', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "30, development ['l6', 'l21', 'l38', 'l55', 'l70', 'l81', 'l91', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "32, benign ['l7', 'l22', 'l39', 'l56', 'l71', 'l82', 'l92', 'l101', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "33, and ['l8', 'l23', 'l40', 'l57', 'l72', 'l83', 'l93', 'l102', 'l109', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "34, malignant ['l9', 'l24', 'l41', 'l58', 'l73', 'l84', 'l94', 'l103', 'l110', 'l116', 'l122', 'l123', 'l124', 'l125', 'l126']", + "35, skin ['l10', 'l25', 'l42', 'l59', 'l74', 'l85', 'l95', 'l104', 'l111', 'l117', 'l122', 'l127', 'l128', 'l129']", + "36, tumors, ['l11', 'l26', 'l43', 'l60', 'l75', 'l86', 'l96', 'l105', 'l112', 'l118', 'l123', 'l127', 'l130']", + "38, induced ['l12', 'l27', 'l44', 'l61', 'l76', 'l87', 'l97', 'l106', 'l113', 'l119', 'l124', 'l128', 'l130', 'l131', 'l132']", + "53, TNF-alpha(-/-) ['l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "54, mice ['l133', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "55, developed ['l28', 'l45', 'l62', 'l134', 'l145', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160']", + "60, tumors ['l29', 'l46', 'l63', 'l135', 'l146', 'l155', 'l161', 'l162', 'l163', 'l164', 'l165']", + "64, mice ['l30', 'l47', 'l64', 'l136', 'l147', 'l156', 'l161', 'l166', 'l167', 'l168', 'l169']", + "73, mice ['l48', 'l137', 'l148', 'l157', 'l162', 'l166', 'l170', 'l171', 'l172']", + "81, tumor ['l13', 'l31', 'l49', 'l65', 'l77', 'l88', 'l98', 'l138', 'l149', 'l158', 'l163', 'l167', 'l170', 'l173', 'l174']", + "86, tumor ['l14', 'l32', 'l50', 'l66', 'l78', 'l89', 'l99', 'l107', 'l114', 'l120', 'l125', 'l131', 'l139', 'l150', 'l159', 'l164', 'l168', 'l171', 'l173', 'l175']", + "87, development. ['l15', 'l33', 'l51', 'l67', 'l79', 'l90', 'l100', 'l108', 'l115', 'l121', 'l126', 'l129', 'l132', 'l140', 'l151', 'l160', 'l165', 'l169', 'l172', 'l174', 'l175']", + "105, TNF-alpha(-/-) ['l141', 'l152', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "106, mice. ['l142', 'l153', 'l176', 'l183', 'l184']", + "113, epidermis, ['l143', 'l177', 'l183', 'l185', 'l186', 'l187', 'l188', 'l189']", + "121, skin, ['l144', 'l154', 'l178', 'l184', 'l185', 'l190', 'l191', 'l192', 'l193']", + "132, Deletion ['l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209']", + "133, of ['l194', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224']", + "134, a ['l195', 'l210', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237']", + "135, TNF-alpha ['l196', 'l211', 'l225', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249']", + "136, inducible ['l197', 'l212', 'l226', 'l238', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259']", + "137, chemokine ['l198', 'l213', 'l227', 'l239', 'l250', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266']", + "141, resistance ['l179', 'l186', 'l190', 'l199', 'l214', 'l228', 'l240', 'l251', 'l260', 'l267', 'l268', 'l269']", + "143, skin ['l180', 'l187', 'l191', 'l200', 'l215', 'l229', 'l241', 'l252', 'l261', 'l267', 'l270', 'l271']", + "144, tumor ['l181', 'l188', 'l192', 'l201', 'l216', 'l230', 'l242', 'l253', 'l262', 'l268', 'l270', 'l272']", + "145, development. ['l182', 'l189', 'l193', 'l202', 'l217', 'l231', 'l243', 'l254', 'l263', 'l269', 'l271', 'l272']", + "156, tumors ['l203', 'l218', 'l232', 'l244', 'l255', 'l264', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278']", + "160, TNF-alpha(-/-) ['l204', 'l219', 'l273', 'l279', 'l280', 'l281', 'l282', 'l283']", + "161, mice ['l205', 'l220', 'l233', 'l245', 'l256', 'l274', 'l279', 'l284', 'l285', 'l286', 'l287']", + "163, similar ['l206', 'l221', 'l234', 'l246', 'l257', 'l265', 'l275', 'l280', 'l284', 'l288', 'l289', 'l290']", + "164, rates ['l207', 'l222', 'l235', 'l247', 'l258', 'l266', 'l276', 'l281', 'l285', 'l288', 'l291', 'l292']", + "166, malignant ['l208', 'l223', 'l236', 'l248', 'l277', 'l282', 'l286', 'l289', 'l291', 'l293']", + "167, progression. ['l209', 'l224', 'l237', 'l249', 'l259', 'l278', 'l283', 'l287', 'l290', 'l292', 'l293']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "TNF-alpha(-/-)", + "Deletion", + "of", + "a", + "TNF-alpha", + "inducible" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant", + "rates" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development", + "benign", + "and", + "malignant", + "tumors,", + "tumor", + "development.", + "tumors" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "and", + "malignant", + "tumors,", + "skin", + "tumor", + "tumors" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "and", + "malignant", + "tumors,", + "development", + "benign", + "development.", + "tumors", + "tumor" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "TNF-alpha(-/-)", + "Deletion", + "of", + "a", + "TNF-alpha", + "inducible", + "chemokine" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant", + "resistance", + "rates" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "TNF-alpha(-/-)", + "Deletion", + "of", + "a", + "TNF-alpha", + "inducible", + "chemokine" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development", + "benign", + "and", + "malignant", + "tumors,", + "tumors", + "tumor", + "development." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "TNF-alpha(-/-)", + "Deletion", + "of", + "a", + "TNF-alpha", + "inducible", + "chemokine" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "and", + "malignant", + "skin", + "tumors,", + "tumor", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "TNF-alpha(-/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistant", + "resistance", + "rates" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development", + "benign", + "and", + "malignant", + "tumors,", + "tumor", + "development." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistant", + "rates" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "and", + "malignant", + "skin", + "tumors,", + "tumor", + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development", + "benign", + "and", + "malignant", + "tumors,", + "tumor", + "development." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "and", + "malignant", + "skin", + "tumors," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TNF-alpha(-/-)", + "Deletion", + "of", + "a", + "TNF-alpha", + "inducible", + "chemokine" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "epidermis,", + "skin,", + "skin" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "epidermis,", + "skin,", + "skin" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "epidermis,", + "skin,", + "skin" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "a", + "TNF-alpha", + "inducible", + "chemokine", + "TNF-alpha(-/-)" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "similar" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "a", + "TNF-alpha", + "inducible", + "TNF-alpha(-/-)" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "progression." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "similar" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "progression." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "similar" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "progression." + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "similar" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "malignant" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "similar" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "progression." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "rates" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "progression." + ] + } + } + ] + }, + { + "PMID": "10395327", + "TEXT": "The mitogen-activated protein kinase pathway is thought to be essential in cellular growth and differentiation. Here we report the discovery of a highly potent and selective inhibitor of the upstream kinase MEK that is orally active. Tumor growth was inhibited as much as 80% in mice with colon carcinomas of both mouse and human origin after treatment with this inhibitor. Efficacy was achieved with a wide range of doses with no signs of toxicity, and correlated with a reduction in the levels of activated mitogen-activated protein kinase in excised tumors. These data indicate that MEK inhibitors represent a promising, noncytotoxic approach to the clinical management of colon cancer.", + "TAG_DATA": [ + "36, Tumor {'phenotype': 'B-tumour growth'}", + "37, growth {'phenotype': 'I-tumour growth'}", + "39, inhibited {'effect': 'B-negative'}", + "45, mice {'context': 'B-organism'}", + "47, colon {'context': 'B-neoplasm'}", + "48, carcinomas {'context': 'I-neoplasm'}", + "51, mouse {'context': 'I-neoplasm'}", + "52, and {'context': 'I-neoplasm'}", + "53, human {'context': 'I-neoplasm'}", + "54, origin {'context': 'I-neoplasm'}", + "89, tumors. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "36, Tumor ['l0', 'l1']", + "37, growth ['l0', 'l2']", + "39, inhibited ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "45, mice ['l3', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "47, colon ['l4', 'l12', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "48, carcinomas ['l5', 'l13', 'l20', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "49, of ['l6', 'l14', 'l21', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "50, both ['l7', 'l15', 'l22', 'l28', 'l33', 'l38', 'l39', 'l40', 'l41']", + "51, mouse ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l42', 'l43', 'l44']", + "52, and ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l45', 'l46']", + "53, human ['l10', 'l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l47']", + "54, origin ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "tumour growth", + "words": [ + "Tumor", + "growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "colon", + "carcinomas", + "mouse", + "and", + "human", + "origin" + ] + } + } + ] + }, + { + "PMID": "10395325", + "TEXT": "Heparan sulfate proteoglycans interact with many extracellular matrix constituents, growth factors and enzymes. Degradation of heparan sulfate by endoglycosidic heparanase cleavage affects a variety of biological processes. We have purified a 50-kDa heparanase from human hepatoma and placenta, and now report cloning of the cDNA and gene encoding this enzyme. Expression of the cloned cDNA in insect and mammalian cells yielded 65-kDa and 50-kDa recombinant heparanase proteins. The 50-kDa enzyme represents an N-terminally processed enzyme, at least 100-fold more active than the 65-kDa form. The heparanase mRNA and protein are preferentially expressed in metastatic cell lines and specimens of human breast, colon and liver carcinomas. Low metastatic murine T-lymphoma and melanoma cells transfected with the heparanase cDNA acquired a highly metastatic phenotype in vivo, reflected by a massive liver and lung colonization. This represents the first cloned mammalian heparanase, to our knowledge, and provides direct evidence for its role in tumor metastasis. Cloning of the heparanase gene enables the development of specific molecular probes for early detection and treatment of cancer metastasis and autoimmune disorders.", + "TAG_DATA": [ + "56, insect {'context': 'B-cells'}", + "58, mammalian {'context': 'B-cells'}", + "59, cells {'context': 'I-cells'}", + "105, Low {'context': 'B-neoplasm'}", + "106, metastatic {'context': 'I-neoplasm'}", + "107, murine {'context': 'I-neoplasm'}", + "108, T-lymphoma {'context': 'I-neoplasm'}", + "110, melanoma {'context': 'B-transformed cells'}", + "111, cells {'context': 'I-transformed cells'}", + "112, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "113, with {'perturbing_action': 'I-gene gain-of-function'}", + "114, the {'perturbing_action': 'I-gene gain-of-function'}", + "115, heparanase {'perturbing_action': 'I-gene gain-of-function'}", + "116, cDNA {'perturbing_action': 'I-gene gain-of-function'}", + "120, metastatic {'phenotype': 'B-metastasis'}", + "121, phenotype {'phenotype': 'I-metastasis'}", + "122, in {'context': 'B-in vivo'}", + "123, vivo, {'context': 'I-in vivo'}", + "128, liver {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "56, insect ['l0', 'l1']", + "58, mammalian ['l0', 'l2']", + "59, cells ['l1', 'l2']", + "105, Low ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "106, metastatic ['l3', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "107, murine ['l4', 'l12', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "108, T-lymphoma ['l5', 'l13', 'l20', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "110, melanoma ['l6', 'l14', 'l21', 'l34', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "111, cells ['l7', 'l15', 'l22', 'l35', 'l47', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "112, transfected ['l23', 'l36', 'l48', 'l59', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "113, with ['l24', 'l37', 'l49', 'l60', 'l70', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "114, the ['l25', 'l38', 'l50', 'l61', 'l71', 'l80', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "115, heparanase ['l26', 'l39', 'l51', 'l62', 'l72', 'l81', 'l89', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "116, cDNA ['l27', 'l40', 'l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "120, metastatic ['l8', 'l16', 'l28', 'l41', 'l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l110', 'l111', 'l112', 'l113', 'l114']", + "121, phenotype ['l9', 'l17', 'l29', 'l42', 'l54', 'l65', 'l75', 'l84', 'l92', 'l99', 'l105', 'l110', 'l115', 'l116', 'l117', 'l118']", + "122, in ['l10', 'l18', 'l30', 'l43', 'l55', 'l66', 'l76', 'l85', 'l93', 'l100', 'l106', 'l111', 'l115', 'l119', 'l120', 'l121']", + "123, vivo, ['l11', 'l19', 'l31', 'l44', 'l56', 'l67', 'l77', 'l86', 'l94', 'l101', 'l107', 'l112', 'l116', 'l119', 'l122', 'l123']", + "128, liver ['l32', 'l45', 'l57', 'l68', 'l78', 'l87', 'l95', 'l102', 'l108', 'l113', 'l117', 'l120', 'l122', 'l124']", + "130, lung ['l33', 'l46', 'l58', 'l69', 'l79', 'l88', 'l96', 'l103', 'l109', 'l114', 'l118', 'l121', 'l123', 'l124']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "Low", + "metastatic", + "murine", + "T-lymphoma" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "phenotype" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "murine", + "T-lymphoma" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "the", + "heparanase", + "cDNA" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "the", + "heparanase", + "cDNA" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cells" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "phenotype" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "the", + "heparanase", + "cDNA" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "phenotype" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "the", + "heparanase", + "cDNA" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "the", + "heparanase", + "cDNA" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "phenotype" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "phenotype" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "10395323", + "TEXT": "Tumor antigen-specific T-cell tolerance limits the efficacy of therapeutic cancer vaccines. Antigen-presenting cells mediate the induction of T-cell tolerance to self-antigens. We therefore assessed the fate of tumor-specific CD4+ T cells in tumor-bearing recipients after in vivo activation of antigen-presenting cells with antibodies against CD40. Such treatment not only preserved the responsiveness of this population, but resulted in their endogenous activation. Established tumors regressed in vaccinated mice treated with antibody against CD40 at a time when no response was achieved with vaccination alone. These results indicate that modulation of antigen-presenting cells may be a useful strategy for enhancing responsiveness to immunization.", + "TAG_DATA": [ + "32, tumor-bearing {'context': 'B-organism'}", + "33, recipients {'context': 'I-organism'}", + "35, in {'context': 'B-in vivo'}", + "36, vivo {'context': 'I-in vivo'}", + "39, antigen-presenting {'context': 'B-cells'}", + "40, cells {'context': 'I-cells'}", + "62, tumors {'context': 'B-neoplasm'}", + "63, regressed {'phenotype': 'B-necrosis'}", + "66, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "32, tumor-bearing ['l0']", + "33, recipients ['l0']", + "35, in ['l1', 'l2', 'l3']", + "36, vivo ['l1', 'l4', 'l5']", + "39, antigen-presenting ['l2', 'l4', 'l6']", + "40, cells ['l3', 'l5', 'l6']", + "62, tumors ['l7', 'l8']", + "63, regressed ['l7', 'l9']", + "66, mice ['l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "regressed" + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "regressed" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "10229237", + "TEXT": "Most chronic carriers of hepatitis B virus (HBV) do not respond to interferon (IFN) treatment. This limitation of IFN therapy may be due in part to scant expression of IFN receptor in the liver. Because the asialoglycoprotein (ASGP) receptor is specifically expressed in the liver at high density, the ASGP receptor-binding domain was generated within an N-glycosylated human IFN-beta molecule by the removal of sialic acid to direct this cytokine to the liver. This modified IFN (asialo-IFN-beta) demonstrated greater inhibition of HBV production in ASGP receptor-positive human liver cells transfected with a replication-competent HBV construct than did conventional IFN-alpha or IFN-beta. Furthermore, the enhanced antiviral effect of asialo-IFN-beta was supported by induction of the 2'-5' oligoadenylate synthetase, an indicator of IFN activity, at a level significantly higher than that produced by conventional IFN-beta. Moreover, mouse asialo-IFN-beta profoundly reduced viremia in vivo in HBV-transfected athymic nude mice, in contrast to conventional IFN-beta, which had no substantial effect. These experiments demonstrate that directing IFN to ASGP receptor facilitates its signaling in the liver and augments its antiviral effect, and is therefore useful in overcoming the limited antiviral effect of conventional IFNs.", + "TAG_DATA": [ + "84, ASGP {'context': 'B-cells'}", + "85, receptor-positive {'context': 'I-cells'}", + "86, human {'context': 'I-cells'}", + "87, liver {'context': 'I-cells'}", + "88, cells {'context': 'I-cells'}", + "89, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "90, with {'perturbing_action': 'I-gene gain-of-function'}", + "91, a {'perturbing_action': 'I-gene gain-of-function'}", + "92, replication-competent {'perturbing_action': 'I-gene gain-of-function'}", + "93, HBV {'perturbing_action': 'I-gene gain-of-function'}", + "94, construct {'perturbing_action': 'I-gene gain-of-function'}", + "139, in {'context': 'B-in vivo'}", + "140, vivo {'context': 'I-in vivo'}", + "142, HBV-transfected {'perturbing_action': 'B-gene gain-of-function'}", + "143, athymic {'context': 'B-organism'}", + "144, nude {'context': 'I-organism'}", + "145, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "84, ASGP ['l0', 'l1', 'l2', 'l3', 'l4']", + "85, receptor-positive ['l0', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "86, human ['l1', 'l5', 'l13', 'l14', 'l15']", + "87, liver ['l2', 'l6', 'l13', 'l16']", + "88, cells ['l3', 'l7', 'l14', 'l16']", + "89, transfected ['l4', 'l8', 'l15', 'l17', 'l18', 'l19', 'l20', 'l21']", + "90, with ['l9', 'l17', 'l22', 'l23', 'l24', 'l25']", + "91, a ['l10', 'l18', 'l22', 'l26', 'l27', 'l28']", + "92, replication-competent ['l19', 'l23', 'l26', 'l29', 'l30']", + "93, HBV ['l11', 'l20', 'l24', 'l27', 'l29', 'l31']", + "94, construct ['l12', 'l21', 'l25', 'l28', 'l30', 'l31']", + "139, in ['l32', 'l33', 'l34', 'l35', 'l36']", + "140, vivo ['l32', 'l37', 'l38', 'l39', 'l40']", + "142, HBV-transfected ['l33', 'l37', 'l41', 'l42', 'l43']", + "143, athymic ['l34', 'l38', 'l41', 'l44', 'l45']", + "144, nude ['l35', 'l39', 'l42', 'l44', 'l46']", + "145, mice, ['l36', 'l40', 'l43', 'l45', 'l46']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "ASGP", + "receptor-positive", + "human" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "a", + "HBV", + "construct" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "HBV-transfected" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "HBV-transfected" + ] + }, + "context": { + "val": "organism", + "words": [ + "athymic", + "nude", + "mice," + ] + } + } + ] + }, + { + "PMID": "10202932", + "TEXT": "Ebola virus is very pathogenic in humans. It induces an acute hemorrhagic fever that leads to death in about 70% of patients. We compared the immune responses of patients who died from Ebola virus disease with those who survived during two large outbreaks in 1996 in Gabon. In survivors, early and increasing levels of IgG, directed mainly against the nucleoprotein and the 40-kDa viral protein, were followed by clearance of circulating viral antigen and activation of cytotoxic T cells, which was indicated by the upregulation of FasL, perforin, CD28 and gamma interferon mRNA in peripheral blood mononuclear cells. In contrast, fatal infection was characterized by impaired humoral responses, with absent specific IgG and barely detectable IgM. Early activation of T cells, indicated by mRNA patterns in peripheral blood mononuclear cells and considerable release of gamma interferon in plasma, was followed in the days preceding death by the disappearance of T cell-related mRNA (including CD3 and CD8). DNA fragmentation in blood leukocytes and release of 41/7 nuclear matrix protein in plasma indicated that massive intravascular apoptosis proceeded relentlessly during the last 5 days of life. Thus, events very early in Ebola virus infection determine the control of viral replication and recovery or catastrophic illness and death.", + "TAG_DATA": [ + "119, T {'context': 'B-cells'}", + "120, cells, {'context': 'B-cells'}", + "127, blood {'context': 'I-cells'}", + "128, mononuclear {'context': 'I-cells'}", + "129, cells {'context': 'I-cells'}", + "159, blood {'context': 'B-cells'}", + "160, leukocytes {'context': 'I-cells'}", + "174, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "119, T ['l0', 'l1', 'l2', 'l3']", + "120, cells, ['l0', 'l4', 'l5', 'l6']", + "127, blood ['l1', 'l4', 'l7', 'l8']", + "128, mononuclear ['l2', 'l5', 'l7', 'l9']", + "129, cells ['l3', 'l6', 'l8', 'l9']", + "159, blood ['l10', 'l11']", + "160, leukocytes ['l10', 'l12']", + "174, apoptosis ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "blood", + "leukocytes" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "10086395", + "TEXT": "Mitochondria are particularly vulnerable to oxidative stress, and mitochondrial swelling and vacuolization are among the earliest pathologic features found in two strains of transgenic amyotrophic lateral sclerosis (ALS) mice with SOD1 mutations. Mice with the G93A human SOD1 mutation have altered electron transport enzymes, and expression of the mutant enzyme in vitro results in a loss of mitochondrial membrane potential and elevated cytosolic calcium concentration. Mitochondrial dysfunction may lead to ATP depletion, which may contribute to cell death. If this is true, then buffering intracellular energy levels could exert neuroprotective effects. Creatine kinase and its substrates creatine and phosphocreatine constitute an intricate cellular energy buffering and transport system connecting sites of energy production (mitochondria) with sites of energy consumption, and creatine administration stabilizes the mitochondrial creatine kinase and inhibits opening of the mitochondrial transition pore. We found that oral administration of creatine produced a dose-dependent improvement in motor performance and extended survival in G93A transgenic mice, and it protected mice from loss of both motor neurons and substantia nigra neurons at 120 days of age. Creatine administration protected G93A transgenic mice from increases in biochemical indices of oxidative damage. Therefore, creatine administration may be a new therapeutic strategy for ALS.", + "TAG_DATA": [ + "48, mutant {'perturbing_action': 'I-other'}", + "49, enzyme {'perturbing_action': 'I-other'}", + "153, G93A {'perturbing_action': 'B-gene gain-of-function'}", + "154, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "155, mice, {'context': 'B-organism'}", + "159, mice {'context': 'B-organism'}", + "164, motor {'context': 'B-cells'}", + "165, neurons {'context': 'I-cells'}", + "167, substantia {'context': 'B-cells'}", + "168, nigra {'context': 'I-cells'}", + "169, neurons {'context': 'I-cells'}", + "178, G93A {'perturbing_action': 'B-gene gain-of-function'}", + "179, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "180, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "48, mutant ['l0', 'l1', 'l2', 'l3', 'l4']", + "49, enzyme ['l0', 'l5', 'l6', 'l7']", + "51, vitro ['l1', 'l5', 'l8']", + "153, G93A ['l2', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "154, transgenic ['l3', 'l6', 'l9', 'l16', 'l17']", + "155, mice, ['l4', 'l7', 'l8', 'l10', 'l16']", + "159, mice ['l11', 'l18', 'l19', 'l20', 'l21', 'l22']", + "164, motor ['l12', 'l18', 'l23', 'l24', 'l25', 'l26']", + "165, neurons ['l13', 'l17', 'l19', 'l23', 'l27', 'l28', 'l29']", + "167, substantia ['l20', 'l24', 'l27', 'l30', 'l31']", + "168, nigra ['l14', 'l21', 'l25', 'l28', 'l30', 'l32']", + "169, neurons ['l15', 'l22', 'l26', 'l29', 'l31', 'l32']", + "178, G93A ['l33', 'l34']", + "179, transgenic ['l33', 'l35']", + "180, mice ['l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "enzyme" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "G93A", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "G93A", + "transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "motor", + "neurons", + "nigra" + ] + } + } + ] + }, + { + "PMID": "10086388", + "TEXT": "Human type 1 diabetes results from the selective destruction of insulin-producing pancreatic beta cells during islet inflammation. Cytokines and reactive radicals released during this process contribute to beta-cell death. Here we show that mice with a disrupted gene coding for poly (ADP-ribose) polymerase (PARP-/- mice) are completely resistant to the development of diabetes induced by the beta-cell toxin streptozocin. The mice remained normoglycemic and maintained normal levels of total pancreatic insulin content and normal islet ultrastructure. Cultivated PARP-/- islet cells resisted streptozocin-induced lysis and maintained intracellular NAD+ levels. Our results identify NAD+ depletion caused by PARP activation as the dominant metabolic event in islet-cell destruction, and provide information for the development of strategies to prevent the progression or manifestation of the disease in individuals at risk of developing type 1 diabetes.", + "TAG_DATA": [ + "33, mice {'context': 'B-organism'}", + "35, a {'perturbing_action': 'B-gene loss-of-function'}", + "36, disrupted {'perturbing_action': 'B-gene loss-of-function'}", + "37, gene {'perturbing_action': 'I-gene loss-of-function'}", + "38, coding {'perturbing_action': 'I-gene loss-of-function'}", + "39, for {'perturbing_action': 'I-gene loss-of-function'}", + "40, poly {'perturbing_action': 'I-gene loss-of-function'}", + "41, (ADP-ribose) {'perturbing_action': 'I-gene loss-of-function'}", + "42, polymerase {'perturbing_action': 'I-gene loss-of-function'}", + "44, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "60, mice {'context': 'B-organism'}", + "77, PARP-/- {'perturbing_action': 'B-gene loss-of-function'}", + "78, islet {'context': 'B-cells'}", + "79, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "33, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "35, a ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "36, disrupted ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "37, gene ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "38, coding ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "39, for ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "40, poly ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "41, (ADP-ribose) ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "42, polymerase ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "44, mice) ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "60, mice ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "77, PARP-/- ['l55', 'l56']", + "78, islet ['l55', 'l57']", + "79, cells ['l56', 'l57']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "a", + "disrupted", + "gene", + "coding", + "for", + "poly", + "(ADP-ribose)", + "polymerase", + "mice)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PARP-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "islet", + "cells" + ] + } + } + ] + }, + { + "PMID": "9930873", + "TEXT": "Liver cirrhosis is the irreversible end result of fibrous scarring and hepatocellular regeneration, characterized by diffuse disorganization of the normal hepatic structure of regenerative nodules and fibrotic tissue. It is associated with prominent morbidity and mortality, and is induced by many factors, including chronic hepatitis virus infections, alcohol drinking and drug abuse. Hepatocyte growth factor (HGF), originally identified and cloned as a potent mitogen for hepatocytes, shows mitogenic, motogenic and morphogenic activities for a wide variety of cells. Moreover, HGF plays an essential part in the development and regeneration of the liver, and shows anti-apoptotic activity in hepatocytes. In a rat model of lethal liver cirrhosis produced by dimethylnitrosamine administrations, repeated transfections of the human HGF gene into skeletal muscles induced a high plasma level of human as well as enodogenous rat HGF, and tyrosine phosphorylation of the c-Met/HGF receptor. Transduction with the HGF gene also suppressed the increase of transforming growth factor-beta1 (TGF-beta1), which plays an essential part in the progression of liver cirrhosis, inhibited fibrogenesis and hepatocyte apoptosis, and produced the complete resolution of fibrosis in the cirrhotic liver, thereby improving the survival rate of rats with this severe illness. Thus, HGF gene therapy may be potentially useful for the treatment of patients with liver cirrhosis, which is otherwise fatal and untreatable by conventional therapy.", + "TAG_DATA": [ + "100, rat {'context': 'B-organism'}", + "101, model {'context': 'I-organism'}", + "111, transfections {'perturbing_action': 'B-gene gain-of-function'}", + "112, of {'perturbing_action': 'I-gene gain-of-function'}", + "113, the {'perturbing_action': 'I-gene gain-of-function'}", + "114, human {'perturbing_action': 'I-gene gain-of-function'}", + "115, HGF {'perturbing_action': 'I-gene gain-of-function'}", + "116, gene {'perturbing_action': 'I-gene gain-of-function'}", + "118, skeletal {'context': 'B-tissue/organ'}", + "119, muscles {'context': 'I-tissue/organ'}", + "140, Transduction {'perturbing_action': 'B-gene gain-of-function'}", + "141, with {'perturbing_action': 'I-gene gain-of-function'}", + "142, the {'perturbing_action': 'I-gene gain-of-function'}", + "143, HGF {'perturbing_action': 'I-gene gain-of-function'}", + "144, gene {'perturbing_action': 'I-gene gain-of-function'}", + "165, inhibited {'effect': 'B-negative'}", + "168, hepatocyte {'context': 'B-cells'}", + "169, apoptosis, {'phenotype': 'B-apoptosis'}", + "180, liver, {'context': 'I-tissue/organ'}", + "187, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "100, rat ['l0', 'l1', 'l2', 'l3', 'l4']", + "101, model ['l0', 'l5', 'l6', 'l7']", + "111, transfections ['l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "112, of ['l8', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "113, the ['l9', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "114, human ['l1', 'l10', 'l18', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "115, HGF ['l2', 'l5', 'l11', 'l19', 'l26', 'l33', 'l39', 'l40', 'l41', 'l42']", + "116, gene ['l12', 'l20', 'l27', 'l34', 'l39', 'l43', 'l44', 'l45']", + "118, skeletal ['l3', 'l6', 'l13', 'l21', 'l28', 'l35', 'l40', 'l43', 'l46']", + "119, muscles ['l4', 'l7', 'l14', 'l22', 'l29', 'l36', 'l41', 'l44', 'l46']", + "140, Transduction ['l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "141, with ['l47', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "142, the ['l48', 'l56', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "143, HGF ['l49', 'l57', 'l65', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "144, gene ['l50', 'l58', 'l66', 'l72', 'l78', 'l79', 'l80', 'l81', 'l82']", + "165, inhibited ['l15', 'l23', 'l30', 'l37', 'l42', 'l45', 'l51', 'l59', 'l67', 'l73', 'l78', 'l83', 'l84', 'l85']", + "168, hepatocyte ['l31', 'l52', 'l60', 'l68', 'l74', 'l79', 'l83', 'l86', 'l87']", + "169, apoptosis, ['l16', 'l24', 'l32', 'l38', 'l53', 'l61', 'l69', 'l75', 'l80', 'l84', 'l86', 'l88']", + "179, cirrhotic ['l54', 'l62', 'l70', 'l76', 'l81', 'l89', 'l90']", + "180, liver, ['l55', 'l63', 'l71', 'l77', 'l82', 'l85', 'l87', 'l88', 'l89']", + "187, rats ['l64', 'l90']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "rat", + "model", + "rats" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "human", + "HGF", + "with" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfections", + "of", + "the", + "human", + "HGF", + "gene", + "Transduction", + "with" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skeletal", + "muscles", + "liver," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfections", + "of", + "the", + "human", + "HGF", + "gene", + "Transduction", + "with" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfections", + "of", + "the", + "human", + "Transduction", + "with", + "HGF", + "gene" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "the", + "Transduction", + "with", + "HGF", + "gene" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocyte" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocyte" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hepatocyte" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver," + ] + } + } + ] + }, + { + "PMID": "9930865", + "TEXT": "Closure of the ductus arteriosus requires prenatal formation of intimal cushions, which occlude the vessel lumen at birth. Survival of newborns with severe congenital heart defects, however, depends on ductal patency. We used a gene transfer approach to create a patent ductus arteriosus by targeting the fibronectin-dependent smooth muscle cell migration required for intimal cushion formation. Fetal lamb ductus arteriosus was transfected in utero with hemagglutinating virus of Japan liposomes containing plasmid encoding 'decoy' RNA to sequester the fibronectin mRNA binding protein. Fibronectin translation was inhibited and intimal cushion formation was prevented. We thus established the essential role of fibronectin-dependent smooth muscle cell migration in intimal cushion formation in the intact animal and the feasibility of incorporating biological engineering in the management of congenital heart disease.", + "TAG_DATA": [ + "47, smooth {'context': 'B-cells'}", + "48, muscle {'context': 'I-cells'}", + "49, cell {'context': 'I-cells'}", + "56, Fetal {'context': 'B-organism'}", + "57, lamb {'context': 'I-organism'}", + "58, ductus {'context': 'I-tissue/organ'}", + "59, arteriosus {'context': 'I-tissue/organ'}", + "61, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "62, in {'context': 'B-in vivo'}", + "63, utero {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "47, smooth ['l0', 'l1', 'l2', 'l3']", + "48, muscle ['l0', 'l4', 'l5', 'l6']", + "49, cell ['l1', 'l4']", + "56, Fetal ['l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "57, lamb ['l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "58, ductus ['l2', 'l5', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "59, arteriosus ['l3', 'l6', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "61, transfected ['l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "62, in ['l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "63, utero ['l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Fetal", + "lamb" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "ductus", + "arteriosus" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "utero" + ] + } + } + ] + }, + { + "PMID": "9883846", + "TEXT": "Transplantation of embryonic nigral tissue ameliorates functional deficiencies in Parkinson disease. The main practical constraints of neural grafting are the shortage of human donor tissue and the poor survival of dopaminergic neurons grafted into patients, which is estimated at 5-10% (refs. 3,4). The required amount of human tissue could be considerably reduced if the neuronal survival was augmented. Studies in rats indicate that most implanted embryonic neurons die within 1 week of transplantation, and that most of this cell death is apoptotic. Modified peptides, such as acetyl-tyrosinyl-valyl-alanyl-aspartyl-chloro-methylketone (Ac-YVAD-cmk), that specifically inhibit proteases of the caspase family effectively block apoptosis in a plethora of experimental paradigms, such as growth factor withdrawal, excitotoxicity, axotomy, cerebral ischemia and brain trauma. Here we examined the effects of caspase inhibition by Ac-YVAD-cmk on cell death immediately after donor tissue preparation and on long-term graft survival. Treatment of the embryonic nigral cell suspension with Ac-YVAD-cmk mitigated DNA fragmentation and reduced apoptosis in transplants. It also increased survival of dopaminergic neurons grafted to hemiparkinsonian rats, and thereby substantially improved functional recovery.", + "TAG_DATA": [ + "97, block {'effect': 'B-negative'}", + "98, apoptosis {'phenotype': 'B-apoptosis'}", + "128, cell {'phenotype': 'B-cell death'}", + "129, death {'phenotype': 'I-cell death'}", + "143, embryonic {'context': 'B-cells'}", + "144, nigral {'context': 'I-cells'}", + "145, cell {'context': 'I-cells'}", + "146, suspension {'context': 'I-cells'}", + "153, reduced {'effect': 'B-negative'}", + "154, apoptosis {'phenotype': 'B-apoptosis'}", + "156, transplants. {'context': 'B-organoid'}", + "162, dopaminergic {'context': 'B-cells'}", + "163, neurons {'context': 'I-cells'}", + "166, hemiparkinsonian {'context': 'B-organism'}", + "167, rats, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "97, block ['l0', 'l1', 'l2']", + "98, apoptosis ['l0', 'l3', 'l4']", + "128, cell ['l1', 'l3', 'l5']", + "129, death ['l2', 'l4', 'l5']", + "143, embryonic ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "144, nigral ['l6', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "145, cell ['l7', 'l16', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "146, suspension ['l8', 'l17', 'l23', 'l29', 'l30', 'l31', 'l32', 'l33']", + "153, reduced ['l9', 'l18', 'l24', 'l29', 'l34', 'l35']", + "154, apoptosis ['l10', 'l19', 'l25', 'l30', 'l34', 'l36']", + "156, transplants. ['l11', 'l20', 'l26', 'l31', 'l35', 'l36']", + "162, dopaminergic ['l12', 'l37', 'l38', 'l39']", + "163, neurons ['l13', 'l21', 'l27', 'l32', 'l37', 'l40', 'l41']", + "166, hemiparkinsonian ['l14', 'l38', 'l40', 'l42']", + "167, rats, ['l15', 'l22', 'l28', 'l33', 'l39', 'l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "block", + "reduced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "block" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "embryonic", + "nigral", + "cell", + "suspension" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "embryonic", + "nigral", + "cell", + "suspension" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "organoid", + "words": [ + "transplants." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "organoid", + "words": [ + "transplants." + ] + } + } + ] + }, + { + "PMID": "9846581", + "TEXT": "Although perinatal mortality rates have improved for pregnant diabetic women because of insulin therapy and tight metabolic control, infants of diabetics still experience significantly higher rates of congenital malformations and spontaneous miscarriages compared with those of non-diabetic women. Our results here indicate that hyperglycemic conditions, either in vivo or in vitro, modulate the expression of an apoptosis regulatory gene as early as the pre-implantation blastocyst stage in the mouse. Apoptosis in the mammalian pre-implantation blastocyst is a normal process, thought to protect the early embryo by eliminating abnormal cells. Here we demonstrate that expression of Bax, a Bcl-2-like protein, is increased at the blastocyst stage in the presence of high concentrations of glucose, and that these changes correlate morphologically with increased DNA fragmentation. Expression of Bax and caspase are necessary for this in vitro glucose-induced apoptotic event, and ceramide is involved in mediating this embryotoxic effect of glucose. We also show that these apoptotic cellular changes can be prevented in vivo by treating hyperglycemic mice with insulin before and immediately after conception. These findings emphasize the importance of tight glycemic control in diabetic women at the earliest stages after conception.", + "TAG_DATA": [ + "132, in {'context': 'B-in vitro'}", + "133, vitro {'context': 'I-in vitro'}", + "134, glucose-induced {'effect': 'B-positive'}", + "135, apoptotic {'phenotype': 'B-apoptosis'}", + "136, event, {'phenotype': 'I-apoptosis'}", + "159, in {'context': 'B-in vivo'}", + "160, vivo {'context': 'I-in vivo'}", + "164, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "132, in ['l0', 'l1', 'l2', 'l3']", + "133, vitro ['l0', 'l4', 'l5', 'l6']", + "134, glucose-induced ['l1', 'l4', 'l7', 'l8']", + "135, apoptotic ['l2', 'l5', 'l7', 'l9']", + "136, event, ['l3', 'l6', 'l8', 'l9']", + "159, in ['l10', 'l11']", + "160, vivo ['l10', 'l12']", + "164, mice ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "glucose-induced" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "event," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "glucose-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "event," + ] + } + } + ] + }, + { + "PMID": "9771754", + "TEXT": "Hepatocyte transplantation might represent a potential therapeutic alternative to liver transplantation in the future; however, transplanted cells have a limited capacity to repopulate the liver, as they do not proliferate under normal conditions. Recently, studies in urokinase (uPA) transgenic mice and in fumarylacetoacetate hydrolase (FAH)-deficient mice have shown that the liver can be repopulated by genetically engineered hepatocytes harboring a selective advantage over resident hepatocytes. We have reported that transgenic mice expressing human Bcl-2 in their hepatocytes are protected from Fas/CD95-mediated liver apoptosis. We now show that Bcl-2 transplanted hepatocytes selectively repopulate the liver of mice treated with nonlethal doses of the anti-Fas antibody Jo2. FK 506 immunosuppressed mice were transplanted by splenic injection with Bcl-2 hepatocytes. The livers of female recipients were repopulated by male Bcl-2 transgenic hepatocytes, as much as 16%, after 8 to 12 administrations of Jo2. This only occurred after anti-Fas treatment, confirming that resistance to Fas-induced apoptosis constituted the selective advantage of these transplanted hepatocytes. Thus, we have demonstrated a method for increasing genetic reconstitution of the liver through selective repopulation with modified transgenic hepatocytes, which will allow optimization of cell and gene therapy in the liver.", + "TAG_DATA": [ + "36, urokinase {'perturbing_action': 'B-gene gain-of-function'}", + "38, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "39, mice {'context': 'B-organism'}", + "42, fumarylacetoacetate {'perturbing_action': 'B-gene loss-of-function'}", + "43, hydrolase {'perturbing_action': 'I-gene loss-of-function'}", + "44, (FAH)-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "45, mice {'context': 'B-organism'}", + "69, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "70, mice {'context': 'I-organism'}", + "71, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "72, human {'perturbing_action': 'I-gene gain-of-function'}", + "73, Bcl-2 {'perturbing_action': 'I-gene gain-of-function'}", + "76, hepatocytes {'context': 'B-cells'}", + "78, protected {'effect': 'B-negative'}", + "87, Bcl-2 {'perturbing_action': 'B-gene gain-of-function'}", + "88, transplanted {'perturbing_action': 'I-gene gain-of-function'}", + "89, hepatocytes {'context': 'B-cells'}", + "93, liver {'context': 'B-tissue/organ'}", + "95, mice {'context': 'B-organism'}", + "108, mice {'context': 'B-organism'}", + "118, livers {'context': 'B-tissue/organ'}", + "120, female {'context': 'B-organism'}", + "121, recipients {'context': 'I-organism'}", + "125, male {'perturbing_action': 'B-gene gain-of-function'}", + "126, Bcl-2 {'perturbing_action': 'I-gene gain-of-function'}", + "127, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "128, hepatocytes, {'context': 'I-cells'}", + "148, resistance {'effect': 'B-negative'}", + "150, Fas-induced {'effect': 'B-positive'}", + "151, apoptosis {'phenotype': 'B-apoptosis'}", + "159, hepatocytes. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "36, urokinase ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "38, transgenic ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "39, mice ['l1', 'l15', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "42, fumarylacetoacetate ['l2', 'l16', 'l28', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "43, hydrolase ['l3', 'l17', 'l29', 'l40', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "44, (FAH)-deficient ['l4', 'l18', 'l30', 'l41', 'l55', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "45, mice ['l5', 'l19', 'l31', 'l42', 'l56', 'l69', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "69, transgenic ['l6', 'l20', 'l32', 'l43', 'l57', 'l70', 'l82', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "70, mice ['l7', 'l21', 'l33', 'l44', 'l58', 'l71', 'l83', 'l92', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "71, expressing ['l8', 'l22', 'l34', 'l45', 'l59', 'l72', 'l84', 'l93', 'l101', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "72, human ['l9', 'l23', 'l35', 'l46', 'l60', 'l73', 'l85', 'l94', 'l102', 'l108', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "73, Bcl-2 ['l10', 'l24', 'l36', 'l47', 'l61', 'l74', 'l86', 'l95', 'l103', 'l109', 'l117', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "76, hepatocytes ['l11', 'l25', 'l37', 'l48', 'l62', 'l75', 'l87', 'l96', 'l104', 'l110', 'l118', 'l125', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "78, protected ['l12', 'l26', 'l38', 'l49', 'l63', 'l76', 'l88', 'l97', 'l105', 'l111', 'l119', 'l126', 'l132', 'l138']", + "87, Bcl-2 ['l50', 'l64', 'l77', 'l112', 'l120', 'l127', 'l133', 'l139', 'l140', 'l141', 'l142']", + "88, transplanted ['l51', 'l65', 'l78', 'l89', 'l98', 'l113', 'l121', 'l128', 'l134', 'l139', 'l143', 'l144', 'l145']", + "89, hepatocytes ['l13', 'l27', 'l39', 'l52', 'l66', 'l79', 'l90', 'l99', 'l106', 'l114', 'l122', 'l129', 'l135', 'l138', 'l140', 'l143', 'l146', 'l147']", + "93, liver ['l14', 'l53', 'l67', 'l80', 'l91', 'l100', 'l107', 'l115', 'l123', 'l130', 'l136', 'l141', 'l144', 'l146', 'l148']", + "95, mice ['l54', 'l68', 'l81', 'l116', 'l124', 'l131', 'l137', 'l142', 'l145', 'l147', 'l148']", + "118, livers ['l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "120, female ['l149', 'l155', 'l156', 'l157', 'l158', 'l159']", + "121, recipients ['l150', 'l155', 'l160', 'l161', 'l162', 'l163']", + "125, male ['l151', 'l156', 'l160', 'l164', 'l165', 'l166', 'l167', 'l168']", + "126, Bcl-2 ['l152', 'l157', 'l161', 'l164', 'l169', 'l170', 'l171', 'l172', 'l173']", + "127, transgenic ['l153', 'l158', 'l162', 'l165', 'l169', 'l174', 'l175']", + "128, hepatocytes, ['l154', 'l159', 'l163', 'l166', 'l170', 'l174', 'l176', 'l177']", + "148, resistance ['l167', 'l171', 'l176', 'l178', 'l179', 'l180']", + "150, Fas-induced ['l172', 'l178', 'l181', 'l182']", + "151, apoptosis ['l168', 'l173', 'l175', 'l177', 'l179', 'l181', 'l183']", + "159, hepatocytes. ['l180', 'l182', 'l183']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "urokinase", + "transgenic", + "expressing", + "human", + "Bcl-2", + "transplanted", + "male" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "female", + "recipients" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "urokinase", + "transgenic", + "expressing", + "human", + "Bcl-2", + "transplanted", + "male" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes", + "hepatocytes," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "urokinase", + "transgenic", + "expressing", + "human", + "Bcl-2", + "male" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protected", + "resistance" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "urokinase", + "transgenic", + "expressing", + "human", + "Bcl-2", + "transplanted", + "male" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver", + "livers" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "fumarylacetoacetate", + "hydrolase", + "(FAH)-deficient" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protected" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "fumarylacetoacetate", + "hydrolase", + "(FAH)-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "fumarylacetoacetate", + "hydrolase", + "(FAH)-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protected" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "fumarylacetoacetate", + "hydrolase", + "(FAH)-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hepatocytes", + "hepatocytes,", + "hepatocytes." + ] + }, + "effect": { + "val": "negative", + "words": [ + "protected", + "resistance" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "male", + "Bcl-2", + "transgenic" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Bcl-2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "Fas-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hepatocytes,", + "hepatocytes." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Fas-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Fas-induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes." + ] + } + } + ] + }, + { + "PMID": "9734401", + "TEXT": "Although prostate cancer cells are often initially sensitive to androgen ablation, they eventually lose this response and continue to survive, grow and spread in the absence of androgenic steroids. The mechanism(s) that underlie resistance to androgen ablation therapy remain mostly unknown. We have demonstrated that elevated caveolin protein levels are associated with human prostate cancer progression in pathological specimens. Here we show that suppression of caveolin expression by a stably transfected antisense caveolin-1 cDNA vector converted androgen-insensitive metastatic mouse prostate cancer cells to an androgen-sensitive phenotype. Orthotopically grown tumors and low-density cell cultures derived from antisense caveolin clones had increased apoptosis in the absence of androgenic steroids, whereas similarly grown tumors and cells from vector (control) clones and parental cells were not sensitive to androgens. Studies using a representative antisense caveolin clone showed that selection for androgen resistance in vivo correlated with increased caveolin levels, and that adenovirus-mediated caveolin expression blocked androgen sensitivity. Our results identify a new candidate gene for hormone-resistant prostate cancer in man and indicate that androgen insensitivity can be an inherent property of metastatic prostate cancer.", + "TAG_DATA": [ + "63, suppression {'perturbing_action': 'B-other'}", + "64, of {'perturbing_action': 'I-other'}", + "65, caveolin {'perturbing_action': 'I-other'}", + "66, expression {'perturbing_action': 'I-other'}", + "67, by {'perturbing_action': 'I-rnai/knockdown'}", + "68, a {'perturbing_action': 'I-rnai/knockdown'}", + "69, stably {'perturbing_action': 'B-rnai/knockdown'}", + "70, transfected {'perturbing_action': 'I-rnai/knockdown'}", + "71, antisense {'perturbing_action': 'I-rnai/knockdown'}", + "72, caveolin-1 {'perturbing_action': 'I-rnai/knockdown'}", + "73, cDNA {'perturbing_action': 'I-rnai/knockdown'}", + "74, vector {'perturbing_action': 'I-rnai/knockdown'}", + "77, metastatic {'context': 'B-transformed cells'}", + "78, mouse {'context': 'I-transformed cells'}", + "79, prostate {'context': 'I-transformed cells'}", + "80, cancer {'context': 'I-transformed cells'}", + "81, cells {'context': 'I-transformed cells'}", + "88, tumors {'context': 'B-neoplasm'}", + "90, low-density {'context': 'B-cells'}", + "91, cell {'context': 'I-cells'}", + "92, cultures {'context': 'I-cells'}", + "99, increased {'effect': 'B-positive'}", + "100, apoptosis {'phenotype': 'B-apoptosis'}", + "110, tumors {'context': 'B-neoplasm'}", + "112, cells {'context': 'B-cells'}", + "118, parental {'context': 'B-cells'}", + "119, cells {'context': 'I-cells'}", + "147, adenovirus-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "148, caveolin {'perturbing_action': 'I-gene gain-of-function'}", + "149, expression {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "63, suppression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "64, of ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "65, caveolin ['l1', 'l17', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "66, expression ['l2', 'l18', 'l33', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "67, by ['l3', 'l19', 'l34', 'l48', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "68, a ['l4', 'l20', 'l35', 'l49', 'l62', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "69, stably ['l5', 'l21', 'l36', 'l50', 'l63', 'l75', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "70, transfected ['l6', 'l22', 'l37', 'l51', 'l64', 'l76', 'l90', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "71, antisense ['l7', 'l23', 'l38', 'l52', 'l65', 'l77', 'l91', 'l105', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "72, caveolin-1 ['l8', 'l24', 'l39', 'l53', 'l66', 'l78', 'l92', 'l106', 'l119', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "73, cDNA ['l9', 'l25', 'l40', 'l54', 'l67', 'l79', 'l93', 'l107', 'l120', 'l131', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "74, vector ['l10', 'l26', 'l41', 'l55', 'l68', 'l80', 'l94', 'l108', 'l121', 'l132', 'l141', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "77, metastatic ['l11', 'l27', 'l42', 'l56', 'l69', 'l81', 'l95', 'l109', 'l122', 'l133', 'l142', 'l150', 'l156', 'l157', 'l158', 'l159']", + "78, mouse ['l12', 'l28', 'l43', 'l57', 'l70', 'l82', 'l96', 'l110', 'l123', 'l134', 'l143', 'l151', 'l156', 'l160', 'l161', 'l162']", + "79, prostate ['l13', 'l29', 'l44', 'l58', 'l71', 'l83', 'l97', 'l111', 'l124', 'l135', 'l144', 'l152', 'l157', 'l160', 'l163', 'l164']", + "80, cancer ['l14', 'l30', 'l45', 'l59', 'l72', 'l84', 'l98', 'l112', 'l125', 'l136', 'l145', 'l153', 'l158', 'l161', 'l163', 'l165']", + "81, cells ['l15', 'l31', 'l46', 'l60', 'l73', 'l85', 'l99', 'l113', 'l126', 'l137', 'l146', 'l154', 'l159', 'l162', 'l164', 'l165']", + "88, tumors ['l16', 'l32', 'l47', 'l61', 'l74', 'l86', 'l100', 'l114', 'l127', 'l138', 'l147', 'l155', 'l166', 'l167', 'l168', 'l169', 'l170']", + "90, low-density ['l101', 'l115', 'l166', 'l171', 'l172', 'l173', 'l174']", + "91, cell ['l87', 'l102', 'l116', 'l128', 'l139', 'l148', 'l167', 'l171', 'l175', 'l176', 'l177']", + "92, cultures ['l88', 'l103', 'l117', 'l129', 'l140', 'l149', 'l168', 'l172', 'l175', 'l178', 'l179']", + "99, increased ['l89', 'l104', 'l118', 'l130', 'l169', 'l173', 'l176', 'l178', 'l180']", + "100, apoptosis ['l170', 'l174', 'l177', 'l179', 'l180']", + "110, tumors ['l181', 'l182']", + "112, cells ['l181', 'l183']", + "118, parental ['l184']", + "119, cells ['l182', 'l183', 'l184']", + "147, adenovirus-mediated ['l185', 'l186']", + "148, caveolin ['l185', 'l187']", + "149, expression ['l186', 'l187']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "suppression", + "of", + "caveolin", + "expression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "metastatic", + "mouse", + "prostate", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "suppression", + "of", + "caveolin", + "expression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "by", + "a", + "stably", + "transfected", + "antisense", + "caveolin-1", + "cDNA", + "vector" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "metastatic", + "mouse", + "prostate", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "by", + "a", + "stably", + "transfected", + "antisense", + "caveolin-1", + "cDNA", + "vector" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "a", + "stably", + "transfected", + "antisense", + "caveolin-1", + "cDNA" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "cultures", + "low-density" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "a", + "stably", + "transfected", + "antisense" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "low-density", + "cell", + "cultures" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "low-density", + "cell", + "cultures" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "9701244", + "TEXT": "Acquisition of invasive/metastatic potential through protease expression is an essential event in tumor progression. High levels of components of the plasminogen activation system, including urokinase, but paradoxically also its inhibitor, plasminogen activator inhibitor 1 (PAI1), have been correlated with a poor prognosis for some cancers. We report here that deficient PAI1 expression in host mice prevented local invasion and tumor vascularization of transplanted malignant keratinocytes. When this PAI1 deficiency was circumvented by intravenous injection of a replication-defective adenoviral vector expressing human PAI1, invasion and associated angiogenesis were restored. This experimental evidence demonstrates that host-produced PAI is essential for cancer cell invasion and angiogenesis.", + "TAG_DATA": [ + "49, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "50, PAI1 {'perturbing_action': 'I-gene loss-of-function'}", + "51, expression {'perturbing_action': 'I-gene loss-of-function'}", + "54, mice {'context': 'I-organism'}", + "55, prevented {'effect': 'B-negative'}", + "57, invasion {'phenotype': 'B-invasion'}", + "59, tumor {'context': 'B-neoplasm'}", + "63, malignant {'context': 'B-cells'}", + "64, keratinocytes. {'context': 'I-cells'}", + "67, PAI1 {'perturbing_action': 'B-gene loss-of-function'}", + "68, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "76, replication-defective {'perturbing_action': 'B-gene gain-of-function'}", + "77, adenoviral {'perturbing_action': 'I-gene gain-of-function'}", + "78, vector {'perturbing_action': 'I-gene gain-of-function'}", + "79, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "80, human {'perturbing_action': 'I-gene gain-of-function'}", + "81, PAI1, {'perturbing_action': 'I-gene gain-of-function'}", + "82, invasion {'phenotype': 'B-invasion'}", + "87, restored. {'effect': 'B-rescues'}" + ], + "LINK_DATA": [ + "49, deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "50, PAI1 ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "51, expression ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "54, mice ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "55, prevented ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "57, invasion ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "59, tumor ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "63, malignant ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "64, keratinocytes. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "67, PAI1 ['l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "68, deficiency ['l36', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "76, replication-defective ['l37', 'l45', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "77, adenoviral ['l38', 'l46', 'l53', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "78, vector ['l39', 'l47', 'l54', 'l60', 'l66', 'l67', 'l68', 'l69', 'l70']", + "79, expressing ['l40', 'l48', 'l55', 'l61', 'l66', 'l71', 'l72', 'l73', 'l74']", + "80, human ['l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l75', 'l76', 'l77']", + "81, PAI1, ['l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l78', 'l79']", + "82, invasion ['l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l76', 'l78', 'l80']", + "87, restored. ['l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l79', 'l80']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "PAI1", + "expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "PAI1", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "PAI1", + "expression", + "deficiency" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "PAI1", + "expression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "PAI1", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "malignant", + "keratinocytes." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "cells", + "words": [ + "malignant", + "keratinocytes." + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "cells", + "words": [ + "malignant", + "keratinocytes." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PAI1", + "deficiency" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "replication-defective", + "adenoviral", + "vector", + "expressing", + "human", + "PAI1," + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "replication-defective", + "adenoviral", + "vector", + "expressing", + "human", + "PAI1," + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored." + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored." + ] + } + } + ] + }, + { + "PMID": "9701242", + "TEXT": "Although the involvement of soluble and matrix-immobilized proteases in tumor cell invasion and metastasis is well recognized, the role of proteolytically activated cell surface receptors has not been elucidated. We report here that thrombin receptor, a member of the protease-activated receptor family, is preferentially expressed in highly metastatic human breast carcinoma cell lines and breast carcinoma biopsy specimens. Introduction of thrombin receptor antisense cDNA considerably inhibited the invasion of metastatic breast carcinoma cells in culture through a reconstituted basement membrane. During placental implantation of the human embryo, thrombin receptor is transiently expressed in the invading cytotrophoblasts. These results emphasize the involvement of thrombin receptor in cell invasion associated with tumor progression and normal embryonic development.", + "TAG_DATA": [ + "61, receptor {'perturbing_action': 'I-rnai/knockdown'}", + "62, antisense {'perturbing_action': 'I-rnai/knockdown'}", + "63, cDNA {'perturbing_action': 'I-rnai/knockdown'}", + "65, inhibited {'effect': 'B-negative'}", + "67, invasion {'phenotype': 'B-invasion'}", + "69, metastatic {'context': 'B-transformed cells'}", + "70, breast {'context': 'I-transformed cells'}", + "71, carcinoma {'context': 'I-transformed cells'}", + "72, cells {'context': 'I-transformed cells'}", + "74, culture {'context': 'I-in vitro'}", + "85, human {'context': 'B-organism'}", + "86, embryo, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "61, receptor ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "62, antisense ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "63, cDNA ['l1', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "65, inhibited ['l2', 'l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "67, invasion ['l3', 'l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "69, metastatic ['l4', 'l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "70, breast ['l5', 'l14', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "71, carcinoma ['l6', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "72, cells ['l7', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "74, culture ['l8', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']", + "85, human ['l46']", + "86, embryo, ['l9', 'l46']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "receptor", + "antisense", + "cDNA" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "receptor", + "antisense", + "cDNA" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "receptor", + "antisense", + "cDNA" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "metastatic", + "breast", + "carcinoma", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "receptor", + "antisense", + "cDNA" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "receptor" + ] + }, + "context": { + "val": "organism", + "words": [ + "embryo," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "metastatic", + "breast", + "carcinoma", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "metastatic", + "breast", + "carcinoma", + "cells" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + } + ] + }, + { + "PMID": "9623981", + "TEXT": "The p53 molecule might serve as a common tumor-associated antigen, as the tumor suppressor gene p53 is mutated and the p53 protein is often over-expressed in tumor cells. We report that effective immunity to p53 can be induced through an idiotypic network by immunization of mice with a monoclonal antibody (PAb-240) specific for mutated p53, or with a peptide derived from the complementarity determining region (CDR) 3 of the variable domain of the light chain (VL) of this antibody. The immunized mice produced IgG antibodies to p53 and mounted a cytotoxic reaction to a tumor line bearing mutated p53. The idiotypically immunized mice were resistant to challenge with the tumor cells. Thus antibodies to p53 might serve as immunogens for activating resistance to some tumors. At the basic level, these findings indicate that a network of p53 immunity may be organized naturally within the immune system.", + "TAG_DATA": [ + "45, mice {'context': 'B-organism'}", + "81, mice {'context': 'B-organism'}", + "94, tumor {'context': 'B-transformed cells'}", + "95, line {'context': 'I-transformed cells'}", + "97, mutated {'perturbing_action': 'I-other'}", + "98, p53. {'perturbing_action': 'I-other'}", + "102, mice {'context': 'B-organism'}", + "109, tumor {'context': 'B-transformed cells'}", + "110, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "45, mice ['l0', 'l1']", + "81, mice ['l0', 'l2', 'l3', 'l4', 'l5']", + "94, tumor ['l2', 'l6', 'l7', 'l8']", + "95, line ['l1', 'l3', 'l6', 'l9', 'l10']", + "97, mutated ['l4', 'l7', 'l9', 'l11']", + "98, p53. ['l5', 'l8', 'l10', 'l11']", + "102, mice ['l12', 'l13']", + "109, tumor ['l12', 'l14']", + "110, cells. ['l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "p53." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "line" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "p53." + ] + } + } + ] + }, + { + "PMID": "9585241", + "TEXT": "Cytotoxic T lymphocyte (CTL) mediated tumor immunity against major histocompatibility antigen (MHC) class I-positive but class II-negative tumors often requires help from CD4+ T cells. These CD4 cells are activated by MHC class II-positive cells that present tumor derived antigens. Considering that different antigen presenting cells, such as B cells, macrophages and dendritic cells compete for antigen and influence the outcome of an immune response, we analyzed tumor immunity in B cell-deficient mice. These mice appear normal with regard to T cell immunity and tolerance to some pure foreign antigens. We show here that the low immunogenicity of tumors is caused by B cells whose presence in the priming phase results in disabled CD4+ T cell help for CTL mediated tumor immunity. Instead, in the presence of B cells, a non-protective humoral immune response is induced. Our results may explain the enigmatic observation that tumor-reactive antibodies occur frequently in cancer patients.", + "TAG_DATA": [ + "70, B {'perturbing_action': 'B-gene loss-of-function'}", + "71, cell-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "72, mice. {'context': 'B-organism'}", + "74, mice {'context': 'B-organism'}", + "113, CD4+ {'context': 'B-cells'}", + "114, T {'context': 'I-cells'}", + "115, cell {'context': 'I-cells'}", + "127, B {'context': 'B-cells'}", + "128, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "70, B ['l0', 'l1']", + "71, cell-deficient ['l0', 'l2', 'l3']", + "72, mice. ['l1', 'l2', 'l4']", + "74, mice ['l3', 'l4']", + "113, CD4+ ['l5', 'l6']", + "114, T ['l5', 'l7']", + "115, cell ['l6', 'l7']", + "127, B ['l8']", + "128, cells, ['l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "B", + "cell-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + } + ] + }, + { + "PMID": "9546790", + "TEXT": "The human CD4 molecule (hCD4) is expressed on T lymphocytes and macrophages and acts as a key component of the cellular receptor for HIV. At baseline, hCD4 transgenic mice expressed hCD4 on microglia, the resident mononuclear phagocytes of the brain, and showed no neuronal damage. Activation of brain microglia by peripheral immune challenges elicited neurodegeneration in hCD4 mice but not in nontransgenic controls. In post-mortem brain tissues from AIDS patients with opportunistic infections, but without typical HIV encephalitis, hCD4 expression correlated with neurodegeneration. We conclude that hCD4 may function as an important mediator of indirect neuronal damage in infectious and immune-mediated diseases of the central nervous system.", + "TAG_DATA": [ + "26, hCD4 {'perturbing_action': 'B-gene gain-of-function'}", + "27, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "28, mice {'context': 'B-organism'}", + "32, microglia, {'context': 'B-cells'}", + "47, brain {'context': 'B-cells'}", + "48, microglia {'context': 'I-cells'}", + "56, hCD4 {'perturbing_action': 'B-gene gain-of-function'}", + "57, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "26, hCD4 ['l0', 'l1', 'l2', 'l3', 'l4']", + "27, transgenic ['l0', 'l5', 'l6', 'l7']", + "28, mice ['l1', 'l5', 'l8']", + "32, microglia, ['l2', 'l6', 'l8']", + "47, brain ['l3', 'l9', 'l10', 'l11']", + "48, microglia ['l4', 'l7', 'l9', 'l12', 'l13']", + "56, hCD4 ['l10', 'l12', 'l14']", + "57, mice ['l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hCD4", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hCD4", + "transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "microglia,", + "brain", + "microglia" + ] + } + } + ] + }, + { + "PMID": "9500609", + "TEXT": "The development and endocrine function of the ovarian corpus luteum (CL) are dependent on the growth of new capillary vessels. Although several molecules have been implicated as mediators of CL angiogenesis, at present there is no direct evidence for the involvement of any. Here we report the unexpected finding that treatment with truncated soluble Flt-1 receptors, which inhibit vascular endothelial growth factor (VEGF) bioactivity, resulted in virtually complete suppression of CL angiogenesis in a rat model of hormonally induced ovulation. This effect was associated with inhibition of CL development and progesterone release. Failure of maturation of the endometrium was also observed. Areas of ischemic necrosis were demonstrated in the corpora lutea (CLs) of treated animals. However, no effect on the preexisting ovarian vasculature was observed. These findings demonstrate that, in spite of the redundancy of potential mediators, VEGF is essential for CL angiogenesis. Furthermore, they have implications for the control of fertility and the treatment of ovarian disorders characterized by hypervascularity and hyperplasia.", + "TAG_DATA": [ + "52, truncated {'perturbing_action': 'B-other'}", + "53, soluble {'perturbing_action': 'I-other'}", + "54, Flt-1 {'perturbing_action': 'I-other'}", + "55, receptors, {'perturbing_action': 'I-other'}", + "74, rat {'context': 'B-organism'}", + "75, model {'context': 'I-organism'}", + "77, hormonally {'effect': 'B-positive'}", + "78, induced {'effect': 'B-positive'}", + "104, necrosis {'phenotype': 'B-necrosis'}", + "109, corpora {'context': 'B-tissue/organ'}", + "110, lutea {'context': 'I-tissue/organ'}", + "114, animals. {'context': 'B-organism'}", + "121, ovarian {'context': 'B-tissue/organ'}", + "122, vasculature {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "52, truncated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "53, soluble ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "54, Flt-1 ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "55, receptors, ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "74, rat ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45']", + "75, model ['l4', 'l15', 'l25', 'l34', 'l42', 'l46', 'l47', 'l48']", + "77, hormonally ['l5', 'l16', 'l26', 'l35', 'l43', 'l46', 'l49', 'l50']", + "78, induced ['l6', 'l17', 'l27', 'l36', 'l44', 'l47', 'l49', 'l51']", + "79, ovulation. ['l7', 'l18', 'l28', 'l37', 'l45', 'l48', 'l50', 'l51']", + "104, necrosis ['l8', 'l19', 'l29', 'l38', 'l52', 'l53', 'l54', 'l55']", + "109, corpora ['l9', 'l20', 'l30', 'l39', 'l52', 'l56', 'l57', 'l58']", + "110, lutea ['l10', 'l21', 'l31', 'l40', 'l53', 'l56', 'l59', 'l60']", + "111, (CLs) ['l11', 'l22', 'l32', 'l41', 'l54', 'l57', 'l59', 'l61']", + "114, animals. ['l55', 'l58', 'l60', 'l61']", + "121, ovarian ['l62']", + "122, vasculature ['l62']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "truncated", + "soluble", + "Flt-1", + "receptors," + ] + }, + "context": { + "val": "organism", + "words": [ + "rat", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "truncated", + "soluble", + "Flt-1", + "receptors," + ] + }, + "effect": { + "val": "positive", + "words": [ + "hormonally", + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "truncated", + "soluble", + "Flt-1", + "receptors," + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "truncated", + "soluble", + "Flt-1", + "receptors," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "corpora", + "lutea" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rat", + "model" + ] + }, + "effect": { + "val": "positive", + "words": [ + "hormonally", + "induced" + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "corpora", + "lutea" + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "animals." + ] + } + } + ] + }, + { + "PMID": "9461194", + "TEXT": "Vascular tone control is essential in blood pressure regulation, shock, ischemia-reperfusion, inflammation, vessel injury/repair, wound healing, temperature regulation, digestion, exercise physiology, and metabolism. Here we show that a well-known growth factor, FGF2, long thought to be involved in many developmental and homeostatic processes, including growth of the tissue layers of vessel walls, functions in vascular tone control. Fgf2 knockout mice are morphologically normal and display decreased vascular smooth muscle contractility, low blood pressure and thrombocytosis. Following intra-arterial mechanical injury, FGF2-deficient vessels undergo a normal hyperplastic response. These results force us to reconsider the function of FGF2 in vascular development and homeostasis in terms of vascular tone control.", + "TAG_DATA": [ + "57, Fgf2 {'perturbing_action': 'B-gene loss-of-function'}", + "58, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "59, mice {'context': 'B-organism'}", + "66, vascular {'context': 'B-cells'}", + "79, FGF2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "80, vessels {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "57, Fgf2 ['l0', 'l1', 'l2', 'l3']", + "58, knockout ['l0', 'l4', 'l5', 'l6']", + "59, mice ['l1', 'l4', 'l7', 'l8']", + "66, vascular ['l2', 'l5', 'l7', 'l9']", + "67, smooth ['l3', 'l6', 'l8', 'l9']", + "79, FGF2-deficient ['l10']", + "80, vessels ['l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fgf2", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fgf2", + "knockout" + ] + }, + "context": { + "val": "cells", + "words": [ + "vascular" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FGF2-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "vessels" + ] + } + } + ] + }, + { + "PMID": "9427610", + "TEXT": "Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by localized areas of demyelination. Although the etiology and pathogenesis of MS remain largely unknown, it is generally assumed that immune responses to myelin antigens contribute to the disease process. The exact sequence of events, as well as the molecular mediators that lead to myelin destruction, is yet to be defined. As a potent mediator of inflammation, the cytopathic cytokine, tumor necrosis factor (TNF) has been considered to be a strong candidate in the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). However, its role in immune-mediated demyelination remains to be elucidated. To determine the contribution of TNF to the pathogenesis of the MS-like disease provoked by the myelin oligodendrocyte glycoprotein (MOG), we have tested mice with an homologous disruption of the gene encoding TNF. Here we report that upon immunization with MOG, mice lacking TNF develop severe neurological impairment with high mortality and extensive inflammation and demyelination. We show further that inactivation of the TNF gene converts MOG-resistant mice to a state of high susceptibility. Furthermore, treatment with TNF dramatically reduces disease severity in both TNF-/- mice and in other TNF+/+ mice highly susceptible to the MOG-induced disease. These findings indicate that TNF is not essential for the induction and expression of inflammatory and demyelinating lesions, and that it may limit the extent and duration of severe CNS pathology.", + "TAG_DATA": [ + "132, mice {'context': 'B-organism'}", + "150, mice {'context': 'B-organism'}", + "151, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "152, TNF {'perturbing_action': 'I-gene loss-of-function'}", + "169, inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "170, of {'perturbing_action': 'I-gene loss-of-function'}", + "171, the {'perturbing_action': 'I-gene loss-of-function'}", + "172, TNF {'perturbing_action': 'I-gene loss-of-function'}", + "173, gene {'perturbing_action': 'I-gene loss-of-function'}", + "175, MOG-resistant {'context': 'B-organism'}", + "176, mice {'context': 'B-organism'}", + "193, TNF-/- {'perturbing_action': 'B-gene loss-of-function'}", + "194, mice {'context': 'B-organism'}", + "198, TNF+/+ {'perturbing_action': 'B-gene gain-of-function'}", + "199, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "132, mice ['l0', 'l1', 'l2']", + "150, mice ['l0', 'l3', 'l4']", + "151, lacking ['l1', 'l3', 'l5']", + "152, TNF ['l2', 'l4', 'l5']", + "169, inactivation ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "170, of ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "171, the ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "172, TNF ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "173, gene ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "175, MOG-resistant ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "176, mice ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']", + "193, TNF-/- ['l27', 'l28', 'l29']", + "194, mice ['l27']", + "198, TNF+/+ ['l28', 'l30']", + "199, mice ['l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "MOG-resistant" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "TNF", + "inactivation", + "of", + "the", + "gene", + "TNF-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "TNF+/+" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "9427607", + "TEXT": "Janus kinase-3 (JAK3) deficiency has recently been identified as a cause of severe combined immunodeficiency (SCID) in humans. We used a mouse model of Jak3-deficient SCID to test a gene therapy approach for treatment of this disease. Transfer of a Jak3 retroviral vector to repopulating hematopoietic stem cells resulted in increased numbers of T and B lymphocytes, reversal of hypogammaglobulinemia, restoration of T-cell activation upon stimulation with mitogens, and development of an antigen-specific immune response after immunization. Analysis for vector copy number in lymphoid and myeloid populations showed a large in vivo selective advantage for Jak3-expressing lymphoid cells. These results show that gene replacement is a feasible treatment strategy for this disease and that naturally occurring in vivo selection of corrected cells is an important advantage of this approach.", + "TAG_DATA": [ + "21, mouse {'context': 'B-organism'}", + "22, model {'context': 'I-organism'}", + "24, Jak3-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "40, Jak3 {'perturbing_action': 'I-gene gain-of-function'}", + "41, retroviral {'perturbing_action': 'I-gene gain-of-function'}", + "42, vector {'perturbing_action': 'I-gene gain-of-function'}", + "45, hematopoietic {'context': 'I-cells'}", + "46, stem {'context': 'I-cells'}", + "47, cells {'context': 'I-cells'}", + "53, T {'context': 'B-cells'}", + "54, and {'context': 'I-cells'}", + "55, B {'context': 'I-cells'}", + "56, lymphocytes, {'context': 'I-cells'}", + "62, T-cell {'context': 'B-cells'}", + "83, lymphoid {'context': 'B-cells'}", + "84, and {'context': 'I-cells'}", + "85, myeloid {'context': 'I-cells'}", + "86, populations {'context': 'I-cells'}", + "90, in {'context': 'B-in vivo'}", + "91, vivo {'context': 'I-in vivo'}", + "95, Jak3-expressing {'context': 'B-cells'}", + "96, lymphoid {'context': 'I-cells'}", + "97, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "21, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "22, model ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "24, Jak3-deficient ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "40, Jak3 ['l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "41, retroviral ['l19', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "42, vector ['l20', 'l29', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "45, hematopoietic ['l21', 'l30', 'l38', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "46, stem ['l22', 'l31', 'l39', 'l46', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "47, cells ['l13', 'l23', 'l32', 'l40', 'l47', 'l53', 'l59', 'l60', 'l61', 'l62', 'l63']", + "53, T ['l2', 'l8', 'l14', 'l24', 'l33', 'l41', 'l48', 'l54', 'l59', 'l64', 'l65', 'l66', 'l67']", + "54, and ['l3', 'l9', 'l15', 'l25', 'l34', 'l42', 'l49', 'l55', 'l60', 'l64', 'l68', 'l69', 'l70']", + "55, B ['l4', 'l10', 'l16', 'l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l71', 'l72']", + "56, lymphocytes, ['l5', 'l11', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l69', 'l71', 'l73']", + "62, T-cell ['l6', 'l12', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l70', 'l72', 'l73']", + "83, lymphoid ['l74', 'l75', 'l76']", + "84, and ['l74', 'l77', 'l78']", + "85, myeloid ['l75', 'l77', 'l79']", + "86, populations ['l76', 'l78', 'l79']", + "90, in ['l80', 'l81', 'l82', 'l83']", + "91, vivo ['l80', 'l84', 'l85', 'l86']", + "95, Jak3-expressing ['l81', 'l84', 'l87', 'l88']", + "96, lymphoid ['l82', 'l85', 'l87', 'l89']", + "97, cells. ['l83', 'l86', 'l88', 'l89']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Jak3-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Jak3-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "T", + "and", + "B", + "lymphocytes,", + "T-cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Jak3", + "retroviral", + "vector" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cells", + "T", + "and", + "B", + "lymphocytes,", + "T-cell" + ] + } + } + ] + }, + { + "PMID": "9396605", + "TEXT": "Intratumoral implantation of murine cells modified to produce retroviral vectors containing the herpes simplex virus-thymidine kinase (HSV-TK) gene induces regression of experimental brain tumors in rodents after ganciclovir (GCV) administration. We evaluated this approach in 15 patients with progressive growth of recurrent malignant brain tumors. Antitumor activity was detected in five of the smaller tumors (1.4 +/- 0.5 ml). In situ hybridization for HSV-TK demonstrated survival of vector-producing cells (VPCs) at 7 days but indicated limited gene transfer to tumors, suggesting that indirect, \"bystander,\" mechanisms provide local antitumor activity in human tumors. However, the response of only very small tumors in which a high density of vector-producing cells had been placed suggests that techniques to improve delivery and distribution of the therapeutic gene will need to be developed if clinical utility is to be achieved with this approach.", + "TAG_DATA": [ + "3, murine {'context': 'B-cells'}", + "4, cells {'context': 'I-cells'}", + "18, induces {'effect': 'B-positive'}", + "19, regression {'phenotype': 'B-tumour regression'}", + "22, brain {'context': 'B-neoplasm'}", + "23, tumors {'context': 'I-neoplasm'}", + "25, rodents {'context': 'B-organism'}", + "41, recurrent {'context': 'B-neoplasm'}", + "42, malignant {'context': 'B-neoplasm'}", + "43, brain {'context': 'I-neoplasm'}", + "44, tumors. {'context': 'I-neoplasm'}", + "54, tumors {'context': 'B-neoplasm'}", + "67, vector-producing {'context': 'B-cells'}", + "68, cells {'context': 'I-cells'}", + "79, tumors, {'context': 'B-neoplasm'}", + "90, human {'context': 'B-neoplasm'}", + "91, tumors. {'context': 'I-neoplasm'}", + "99, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "3, murine ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "4, cells ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "18, induces ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "19, regression ['l2', 'l12', 'l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "22, brain ['l3', 'l13', 'l22', 'l29', 'l37', 'l38', 'l39', 'l40']", + "23, tumors ['l4', 'l14', 'l23', 'l30', 'l37', 'l41', 'l42', 'l43']", + "25, rodents ['l5', 'l15', 'l24', 'l31', 'l38', 'l41', 'l44', 'l45']", + "41, recurrent ['l6', 'l16', 'l25', 'l32', 'l46', 'l47', 'l48', 'l49']", + "42, malignant ['l7', 'l17', 'l26', 'l33', 'l46', 'l50', 'l51', 'l52']", + "43, brain ['l8', 'l18', 'l27', 'l34', 'l39', 'l42', 'l44', 'l47', 'l50', 'l53', 'l54']", + "44, tumors. ['l9', 'l19', 'l28', 'l35', 'l40', 'l43', 'l45', 'l48', 'l51', 'l53', 'l55']", + "54, tumors ['l10', 'l20', 'l36', 'l49', 'l52', 'l54', 'l55']", + "67, vector-producing ['l56', 'l57', 'l58', 'l59']", + "68, cells ['l56', 'l60', 'l61', 'l62']", + "79, tumors, ['l57', 'l60', 'l63', 'l64']", + "90, human ['l58', 'l61', 'l63', 'l65']", + "91, tumors. ['l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "murine", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "murine", + "cells" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "brain", + "tumors", + "recurrent", + "malignant", + "tumors." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "organism", + "words": [ + "rodents" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "brain", + "tumors", + "recurrent", + "malignant", + "tumors." + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "organism", + "words": [ + "rodents" + ] + } + } + ] + }, + { + "PMID": "9334719", + "TEXT": "Nitric oxide (NO) and peroxynitrite, formed from NO and superoxide anion, have been implicated as mediators of neuronal damage following focal ischemia, but their molecular targets have not been defined. One candidate pathway is DNA damage leading to activation of the nuclear enzyme, poly(ADP-ribose) polymerase (PARP), which catalyzes attachment of ADP ribose units from NAD to nuclear proteins following DNA damage. Excessive activation of PARP can deplete NAD and ATP, which is consumed in regeneration of NAD, leading to cell death by energy depletion. We show that genetic disruption of PARP provides profound protection against glutamate-NO-mediated ischemic insults in vitro and major decreases in infarct volume after reversible middle cerebral artery occlusion. These results provide compelling evidence for a primary involvement of PARP activation in neuronal damage following focal ischemia and suggest that therapies designed towards inhibiting PARP may provide benefit in the treatment of cerebrovascular disease.", + "TAG_DATA": [ + "79, cell {'phenotype': 'B-cell death'}", + "80, death {'phenotype': 'I-cell death'}", + "87, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "88, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "89, of {'perturbing_action': 'I-gene loss-of-function'}", + "90, PARP {'perturbing_action': 'I-gene loss-of-function'}", + "98, in {'context': 'B-in vitro'}", + "99, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "79, cell ['l0', 'l1', 'l2']", + "80, death ['l0', 'l3', 'l4']", + "87, genetic ['l5', 'l6', 'l7', 'l8', 'l9']", + "88, disruption ['l5', 'l10', 'l11', 'l12', 'l13']", + "89, of ['l6', 'l10', 'l14', 'l15', 'l16']", + "90, PARP ['l7', 'l11', 'l14', 'l17', 'l18']", + "98, in ['l1', 'l3', 'l8', 'l12', 'l15', 'l17', 'l19']", + "99, vitro ['l2', 'l4', 'l9', 'l13', 'l16', 'l18', 'l19']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "disruption", + "of", + "PARP" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "9288734", + "TEXT": "In response to anticancer therapeutics, human colon cancer cells growing in vitro either enter into a stable arrest or die, depending on the integrity of their cell-cycle checkpoints. To test whether altered checkpoints can modulate sensitivity to treatment in vivo, xenografts were established from isogenic lines differing only in their p21 checkpoint status. Although all tumors with intact checkpoint function underwent regrowth after treatment with gamma-radiation, a significant fraction of checkpoint-deficient tumors were completely cured. This difference in sensitivity was not detected by the clonogenic survival assay, because both arrest and death preclude outgrowth of colonies. These results demonstrate that checkpoint status affects sensitivity to anticancer treatments in vivo, and these findings have important implications for identifying and testing new therapeutic compounds.", + "TAG_DATA": [ + "5, human {'context': 'B-transformed cells'}", + "6, colon {'context': 'I-transformed cells'}", + "7, cancer {'context': 'I-transformed cells'}", + "8, cells {'context': 'I-transformed cells'}", + "10, in {'context': 'B-in vitro'}", + "11, vitro {'context': 'I-in vitro'}", + "38, in {'context': 'B-in vivo'}", + "39, vivo, {'context': 'I-in vivo'}", + "40, xenografts {'context': 'B-xenograft'}", + "55, tumors {'context': 'B-neoplasm'}", + "71, tumors {'context': 'B-neoplasm'}", + "92, preclude {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "5, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "6, colon ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "7, cancer ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "8, cells ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "10, in ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "11, vitro ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "38, in ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "39, vivo, ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "40, xenografts ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "71, tumors ['l36']", + "92, preclude ['l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "effect": { + "val": "negative", + "words": [ + "preclude" + ] + } + } + ] + }, + { + "PMID": "9288733", + "TEXT": "Leptin is a circulating hormone that is expressed abundantly and specifically in the adipose tissue. It is involved in the regulation of energy homeostasis, as well as the neuroendocrine and reproductive systems. Here, we demonstrate production of leptin by nonadipose tissue, namely, placental trophoblasts and amnion cells from uteri of pregnant women. We show that pregnant women secrete a considerable amount of leptin from the placenta into the maternal circulation as compared with nonpregnant obese women. Leptin production was also detected in a cultured human choriocarcinoma cell line, BeWo cells, and was augmented during the course of forskolin-induced differentiation of cytotrophoblasts into syncytiotrophoblasts. Plasma leptin levels were markedly elevated in patients with hydatidiform mole or choriocarcinoma and were reduced after surgical treatment or chemotherapy. Leptin is also produced by primary cultured human amnion cells and is secreted into the amniotic fluid. The present study provides evidence for leptin as a novel placenta-derived hormone in humans and suggests the physiologic and pathophysiologic significance of leptin in normal pregnancy and gestational trophoblastic neoplasms.", + "TAG_DATA": [ + "84, human {'context': 'B-transformed cells'}", + "85, choriocarcinoma {'context': 'I-transformed cells'}", + "86, cell {'context': 'I-transformed cells'}", + "87, line, {'context': 'I-transformed cells'}", + "88, BeWo {'context': 'I-cells'}", + "89, cells, {'context': 'I-cells'}", + "97, forskolin-induced {'effect': 'B-positive'}", + "98, differentiation {'phenotype': 'B-differentiation'}", + "100, cytotrophoblasts {'context': 'B-cells'}", + "131, human {'context': 'B-cells'}", + "132, amnion {'context': 'I-cells'}", + "133, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "84, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "85, choriocarcinoma ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "86, cell ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "87, line, ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "88, BeWo ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "89, cells, ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31']", + "97, forskolin-induced ['l5', 'l12', 'l18', 'l23', 'l27', 'l32', 'l33']", + "98, differentiation ['l6', 'l13', 'l19', 'l24', 'l28', 'l30', 'l32', 'l34']", + "100, cytotrophoblasts ['l7', 'l14', 'l20', 'l25', 'l29', 'l31', 'l33', 'l34']", + "131, human ['l35', 'l36']", + "132, amnion ['l35', 'l37']", + "133, cells ['l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "choriocarcinoma", + "cell", + "line," + ] + }, + "effect": { + "val": "positive", + "words": [ + "forskolin-induced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "choriocarcinoma", + "cell", + "line," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "BeWo", + "cytotrophoblasts" + ] + }, + "effect": { + "val": "positive", + "words": [ + "forskolin-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "BeWo", + "cells,", + "cytotrophoblasts" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "forskolin-induced" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "9288732", + "TEXT": "Cataract is responsible for rendering several million people blind throughout the world and is also by far the most common cause of low visual acuity. Although cataract surgery is common, routine and effective, posterior capsule opacification (PCO) occurs in 30-50% of patients following modern cataract surgery. This condition arises from stimulated cell growth within the capsular bag after surgery. The resulting decline in visual acuity requires expensive laser treatment, and PCO therefore prevents modern cataract surgery from being carried out routinely in underdeveloped countries. The present study, using a human lens capsular bag culture system, has confirmed that cells from a wide age range of donors proliferate in the absence of added serum protein and explains why PCO is such a common problem even in aged patients. This study also provides one possible solution for PCO by using polymethylmethacrylate (PMMA) implanted intraocular lenses as a drug delivery system. PMMA lenses coated with thapsigargin, a hydrophobic inhibitor of endoplasmic reticulum (ER) (Ca2+)-ATPase, greatly reduced cell growth in the capsular bag at relatively low coating concentrations (200 nM) but, more significantly, induced total cell death of the residual anterior epithelial cells at higher concentrations (>2 microM).", + "TAG_DATA": [ + "98, cells {'context': 'B-cells'}", + "106, proliferate {'phenotype': 'B-proliferation'}", + "162, reduced {'effect': 'B-negative'}", + "163, cell {'phenotype': 'B-cell growth'}", + "164, growth {'phenotype': 'I-cell growth'}", + "167, capsular {'context': 'B-tissue/organ'}", + "168, bag {'context': 'I-tissue/organ'}", + "179, induced {'effect': 'B-positive'}", + "181, cell {'phenotype': 'B-cell death'}", + "182, death {'phenotype': 'I-cell death'}", + "185, residual {'context': 'B-cells'}", + "186, anterior {'context': 'I-cells'}", + "187, epithelial {'context': 'I-cells'}", + "188, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "98, cells ['l0']", + "106, proliferate ['l0']", + "162, reduced ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "163, cell ['l1', 'l7', 'l8', 'l9', 'l10']", + "164, growth ['l2', 'l7', 'l11', 'l12']", + "167, capsular ['l3', 'l8', 'l11', 'l13', 'l14', 'l15', 'l16']", + "168, bag ['l4', 'l9', 'l12', 'l13', 'l17', 'l18']", + "179, induced ['l5', 'l14', 'l17', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "181, cell ['l15', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "182, death ['l6', 'l10', 'l16', 'l18', 'l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "185, residual ['l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "186, anterior ['l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "187, epithelial ['l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "188, cells ['l24', 'l29', 'l33', 'l36', 'l38', 'l39']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "capsular", + "bag" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "death" + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "capsular", + "bag" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "capsular", + "bag" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "capsular", + "bag" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "residual", + "anterior", + "epithelial", + "cells" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "residual", + "anterior", + "epithelial", + "cells" + ] + } + } + ] + }, + { + "PMID": "9288727", + "TEXT": "Mortality from atherosclerotic cardiovascular disease is lower in premenopausal women than in age-matched men. It is also lower in postmenopausal women who take estrogens and progestins together rather than estrogens alone. Progesterone receptors were detected in human and rat aortic smooth muscle cells in vivo and in vitro (in subculture). We examined the effect of progesterone on proliferation of smooth muscle cells, important constituents of atherosclerotic plaques. Progesterone at physiologic levels inhibited DNA synthesis and proliferation in these cells in a dose-dependent manner, and pretreatment with the progesterone receptor antagonist RU486 blocked inhibition. Cyclin A and E messenger RNA levels decreased after progesterone treatment but those of cyclin B and D1 did not change. This cell cycle-dependent inhibition of arterial smooth muscle cell proliferation by progesterone may represent a mechanism for the hormone's protective effect against atherosclerosis.", + "TAG_DATA": [ + "36, human {'context': 'B-cells'}", + "37, and {'context': 'I-cells'}", + "38, rat {'context': 'I-cells'}", + "39, aortic {'context': 'I-cells'}", + "40, smooth {'context': 'I-cells'}", + "41, muscle {'context': 'I-cells'}", + "42, cells {'context': 'I-cells'}", + "71, inhibited {'effect': 'B-negative'}", + "75, proliferation {'phenotype': 'B-proliferation'}", + "78, cells {'context': 'B-cells'}", + "117, inhibition {'effect': 'B-negative'}", + "119, arterial {'context': 'B-cells'}", + "120, smooth {'context': 'I-cells'}", + "121, muscle {'context': 'I-cells'}", + "122, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "36, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "37, and ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "38, rat ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "39, aortic ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "40, smooth ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "41, muscle ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "42, cells ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "71, inhibited ['l21', 'l22']", + "75, proliferation ['l21', 'l23']", + "78, cells ['l22', 'l23']", + "117, inhibition ['l24', 'l25', 'l26', 'l27']", + "119, arterial ['l24', 'l28', 'l29', 'l30']", + "120, smooth ['l25', 'l28', 'l31', 'l32']", + "121, muscle ['l26', 'l29', 'l31', 'l33']", + "122, cell ['l27', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "arterial", + "smooth", + "muscle", + "cell" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "9256283", + "TEXT": "Plasma extravasation from postcapillary venules is one of the earliest steps of inflammation. Substance P (SP) and bradykinin (BK) mediate extravasation and cause hypotension. The cell-surface enzyme neutral endopeptidase (NEP) inactivates both peptides. Thus, absence of NEP may predispose development of inflammation and hypotension. We examined these possibilities in mice in which the NEP gene was deleted by homologous recombination. There was widespread basal plasma extravasation in postcapillary venular endothelia in NEP-/- mice, which was reversed by recombinant NEP and antagonists of SP (NK1) and BK (B2) receptors. Mean arterial blood pressure was 20% lower in NEP-/- animals, but this was unaffected by reintroduction of recombinant NEP and the kinin receptor antagonists. The hypotension was also independent of nitric oxide (NO), because NEP-/- mice treated with a NO synthase inhibitor remained hypotensive relative to the wild type. Thus, NEP has important roles in regulating basal microvascular permeability by degrading SP and BK, and may regulate blood pressure set point through a mechanism that is independent of SP, BK and NO. The use of NEP antagonists as candidate drugs in cardiovascular disease is suggested by the blood pressure data reported herein.", + "TAG_DATA": [ + "49, mice {'context': 'B-organism'}", + "52, the {'perturbing_action': 'I-gene loss-of-function'}", + "53, NEP {'perturbing_action': 'I-gene loss-of-function'}", + "54, gene {'perturbing_action': 'I-gene loss-of-function'}", + "55, was {'perturbing_action': 'I-gene loss-of-function'}", + "56, deleted {'perturbing_action': 'I-gene loss-of-function'}", + "71, NEP-/- {'perturbing_action': 'B-gene loss-of-function'}", + "72, mice, {'context': 'B-organism'}", + "80, antagonists {'perturbing_action': 'B-pharmacological inhibition'}", + "81, of {'perturbing_action': 'I-pharmacological inhibition'}", + "82, SP {'perturbing_action': 'I-pharmacological inhibition'}", + "83, (NK1) {'perturbing_action': 'I-pharmacological inhibition'}", + "84, and {'perturbing_action': 'I-pharmacological inhibition'}", + "85, BK {'perturbing_action': 'I-pharmacological inhibition'}", + "86, (B2) {'perturbing_action': 'I-pharmacological inhibition'}", + "87, receptors. {'perturbing_action': 'I-pharmacological inhibition'}", + "96, NEP-/- {'perturbing_action': 'B-gene loss-of-function'}", + "97, animals, {'context': 'B-organism'}", + "103, reintroduction {'perturbing_action': 'B-gene gain-of-function'}", + "104, of {'perturbing_action': 'I-gene gain-of-function'}", + "105, recombinant {'perturbing_action': 'I-gene gain-of-function'}", + "106, NEP {'perturbing_action': 'I-gene gain-of-function'}", + "122, NEP-/- {'perturbing_action': 'B-gene loss-of-function'}", + "123, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "49, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "52, the ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "53, NEP ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "54, gene ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "55, was ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "56, deleted ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "71, NEP-/- ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "72, mice, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "80, antagonists ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "81, of ['l28', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "82, SP ['l29', 'l39', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "83, (NK1) ['l30', 'l40', 'l51', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "84, and ['l31', 'l41', 'l52', 'l62', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "85, BK ['l32', 'l42', 'l53', 'l63', 'l71', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "86, (B2) ['l33', 'l43', 'l54', 'l64', 'l72', 'l80', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "87, receptors. ['l34', 'l44', 'l55', 'l65', 'l73', 'l81', 'l88', 'l95', 'l96', 'l97', 'l98']", + "96, NEP-/- ['l35', 'l45', 'l56', 'l66', 'l74', 'l82', 'l89', 'l95', 'l99', 'l100', 'l101']", + "97, animals, ['l36', 'l46', 'l57', 'l67', 'l75', 'l83', 'l90', 'l96', 'l99']", + "103, reintroduction ['l47', 'l58', 'l76', 'l84', 'l91', 'l102', 'l103', 'l104']", + "104, of ['l37', 'l48', 'l59', 'l68', 'l77', 'l85', 'l92', 'l97', 'l100', 'l102', 'l105', 'l106']", + "105, recombinant ['l49', 'l60', 'l69', 'l78', 'l86', 'l93', 'l103', 'l105', 'l107']", + "106, NEP ['l38', 'l50', 'l61', 'l70', 'l79', 'l87', 'l94', 'l98', 'l101', 'l104', 'l106', 'l107']", + "122, NEP-/- ['l108']", + "123, mice ['l108']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice,", + "animals," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "NEP", + "gene", + "was", + "deleted", + "NEP-/-" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antagonists", + "of", + "SP", + "(NK1)", + "and", + "BK", + "(B2)", + "receptors." + ] + }, + "context": { + "val": "organism", + "words": [ + "animals," + ] + } + } + ] + }, + { + "PMID": "9256282", + "TEXT": "Graft coronary arteriosclerosis, which limits the long-term survival of allograft recipients, is characterized by diffuse intimal thickening composed of proliferative smooth muscle cells. We observed that messenger RNA of the cell cycle regulatory enzyme cyclin-dependent kinase (cdk) 2 kinase, which mediates smooth muscle cell proliferation, was elevated in the thickened intima of coronary arteries of murine heterotopic cardiac allografts. We studied the effects of antisense phosphorothioate oligodeoxynucleotide (ODN) against this enzyme using gene transfer mediated by a hemagglutinating virus of Japan (HVJ)-liposome complex intraluminally delivered to inhibit the intimal hyperplasia. At 30 days after transplantation, antisense cdk2 kinase ODN treatment had dramatically inhibited neointimal formation in the allografts. Expression of vascular cell adhesion molecule-1 was also suppressed by antisense cdk2 kinase. However, these effects were not observed in the sense or scrambled ODN-treated allografts. Thus, an intraluminal administration of antisense ODN directed to a specific cell cycle regulatory gene can inhibit neointimal formation after cardiac transplantation.", + "TAG_DATA": [ + "107, allografts. {'context': 'B-xenograft'}", + "119, cdk2 {'perturbing_action': 'I-pharmacological augmentation'}", + "120, kinase. {'perturbing_action': 'I-pharmacological augmentation'}", + "133, allografts. {'context': 'B-xenograft'}" + ], + "LINK_DATA": [ + "119, cdk2 ['l0', 'l1']", + "120, kinase. ['l0', 'l2']", + "133, allografts. ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "cdk2", + "kinase." + ] + }, + "context": { + "val": "xenograft", + "words": [ + "allografts." + ] + } + } + ] + }, + { + "PMID": "9256275", + "TEXT": "The tissue amyloid deposits that characterize systemic amyloidosis, Alzheimer's disease and the transmissible spongiform encephalopathies always contain serum amyloid P component (SAP) bound to the amyloid fibrils. We have previously proposed that this normal plasma protein may contribute to amyloidogenesis by stabilizing the deposits. Here we show that the induction of reactive amyloidosis is retarded in mice with targeted deletion of the SAP gene. This first demonstration of the participation of SAP in pathogenesis of amyloidosis in vivo confirms that inhibition of SAP binding to amyloid fibrils is an attractive therapeutic target in a range of serious human diseases.", + "TAG_DATA": [ + "56, mice {'context': 'B-organism'}", + "58, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "59, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "60, of {'perturbing_action': 'I-gene loss-of-function'}", + "61, the {'perturbing_action': 'I-gene loss-of-function'}", + "62, SAP {'perturbing_action': 'I-gene loss-of-function'}", + "63, gene. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "56, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "58, targeted ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "59, deletion ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "60, of ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "61, the ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "62, SAP ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "63, gene. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "deletion", + "of", + "the", + "SAP", + "gene." + ] + } + } + ] + }, + { + "PMID": "9256273", + "TEXT": "We investigated the effect of Fas/APO1-ligand (CD95L) gene transfer on allogeneic immune responses in vivo. A colon carcinoma cell line from BALB/c mice, CT26, was stably transfected with a vector encoding mouse CD95L and was inoculated into C57BL/6 mice. CD95L expression markedly reduced allogeneic cytotoxic T lymphocyte and helper T lymphocyte activity directed toward CT26. Strikingly, expression of CD95L on these allogeneic tumors completely inhibited the generation of alloantibodies of both IgM and IgG subclasses. Thus, CD95L inhibited alloantibody production and conferred localized immune suppression through this mechanism. These results provide insight into the role of CD95L in regulating the alloantibody response and the generation of local immune responses.", + "TAG_DATA": [ + "16, colon {'context': 'B-transformed cells'}", + "17, carcinoma {'context': 'I-transformed cells'}", + "18, cell {'context': 'I-transformed cells'}", + "19, line {'context': 'I-transformed cells'}", + "20, from {'context': 'I-transformed cells'}", + "21, BALB/c {'context': 'I-organism'}", + "22, mice, {'context': 'I-transformed cells'}", + "23, CT26, {'context': 'I-transformed cells'}", + "25, stably {'perturbing_action': 'B-gene gain-of-function'}", + "26, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "27, with {'perturbing_action': 'I-gene gain-of-function'}", + "28, a {'perturbing_action': 'I-gene gain-of-function'}", + "29, vector {'perturbing_action': 'I-gene gain-of-function'}", + "30, encoding {'perturbing_action': 'I-gene gain-of-function'}", + "31, mouse {'perturbing_action': 'I-gene gain-of-function'}", + "32, CD95L {'perturbing_action': 'I-gene gain-of-function'}", + "37, C57BL/6 {'context': 'B-organism'}", + "38, mice. {'context': 'I-organism'}", + "39, CD95L {'perturbing_action': 'B-gene gain-of-function'}", + "40, expression {'perturbing_action': 'I-gene gain-of-function'}", + "48, helper {'context': 'B-cells'}", + "49, T {'context': 'I-cells'}", + "50, lymphocyte {'context': 'I-cells'}", + "56, expression {'perturbing_action': 'B-gene gain-of-function'}", + "57, of {'perturbing_action': 'I-gene gain-of-function'}", + "58, CD95L {'perturbing_action': 'I-gene gain-of-function'}", + "61, allogeneic {'context': 'B-neoplasm'}", + "62, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "16, colon ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "17, carcinoma ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "18, cell ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "19, line ['l2', 'l11', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "20, from ['l3', 'l12', 'l20', 'l26', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "21, BALB/c ['l4', 'l13', 'l21', 'l27', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "22, mice, ['l5', 'l14', 'l22', 'l28', 'l33', 'l38', 'l45', 'l46', 'l47']", + "23, CT26, ['l6', 'l15', 'l23', 'l29', 'l34', 'l39', 'l45', 'l48']", + "25, stably ['l7', 'l16', 'l24', 'l30', 'l35', 'l40', 'l46', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "26, transfected ['l8', 'l17', 'l36', 'l41', 'l49', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "27, with ['l50', 'l63', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "28, a ['l51', 'l64', 'l76', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "29, vector ['l52', 'l65', 'l77', 'l89', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "30, encoding ['l53', 'l66', 'l78', 'l90', 'l101', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "31, mouse ['l54', 'l67', 'l79', 'l91', 'l102', 'l113', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "32, CD95L ['l42', 'l55', 'l68', 'l80', 'l92', 'l103', 'l114', 'l124', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "37, C57BL/6 ['l56', 'l69', 'l81', 'l93', 'l104', 'l115', 'l125', 'l134', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150']", + "38, mice. ['l9', 'l18', 'l25', 'l31', 'l37', 'l43', 'l47', 'l48', 'l57', 'l70', 'l82', 'l94', 'l105', 'l116', 'l126', 'l135', 'l143', 'l151', 'l152', 'l153', 'l154']", + "39, CD95L ['l58', 'l71', 'l83', 'l95', 'l106', 'l117', 'l127', 'l136', 'l144', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160']", + "40, expression ['l59', 'l72', 'l84', 'l96', 'l107', 'l118', 'l128', 'l137', 'l145', 'l151', 'l155', 'l161', 'l162', 'l163', 'l164', 'l165']", + "48, helper ['l60', 'l73', 'l85', 'l97', 'l108', 'l119', 'l129', 'l138', 'l146', 'l152', 'l156', 'l161', 'l166', 'l167', 'l168']", + "49, T ['l61', 'l74', 'l86', 'l98', 'l109', 'l120', 'l130', 'l139', 'l147', 'l153', 'l157', 'l162', 'l166', 'l169', 'l170']", + "50, lymphocyte ['l44', 'l62', 'l75', 'l87', 'l99', 'l110', 'l121', 'l131', 'l140', 'l148', 'l154', 'l158', 'l163', 'l167', 'l169', 'l171']", + "56, expression ['l172', 'l173', 'l174', 'l175']", + "57, of ['l172', 'l176', 'l177', 'l178']", + "58, CD95L ['l173', 'l176', 'l179', 'l180']", + "61, allogeneic ['l111', 'l122', 'l132', 'l141', 'l149', 'l159', 'l164', 'l174', 'l177', 'l179', 'l181']", + "62, tumors ['l88', 'l100', 'l112', 'l123', 'l133', 'l142', 'l150', 'l160', 'l165', 'l168', 'l170', 'l171', 'l175', 'l178', 'l180', 'l181']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "colon", + "carcinoma", + "cell", + "line", + "from", + "mice," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "stably", + "transfected" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "BALB/c", + "C57BL/6", + "mice." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "stably", + "transfected", + "CD95L", + "with", + "a", + "vector", + "encoding", + "mouse", + "expression" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "stably", + "transfected", + "with", + "a", + "vector", + "encoding", + "mouse", + "CD95L", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "helper", + "T", + "lymphocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "with", + "a", + "vector", + "encoding", + "mouse", + "CD95L", + "expression", + "of" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "allogeneic" + ] + } + } + ] + }, + { + "PMID": "9212110", + "TEXT": "Oral administration of protein can induce antigen-specific immune hyporesponsiveness. However, the utility of oral tolerance to autoantigens in the treatment of autoimmune diseases may be limited when candidate autoantigens cannot be produced by conventional systems in quantities sufficient for clinical studies. Plants may be ideally suited for this purpose, as they can synthesize, glycosylate and assemble mammalian proteins to provide huge quantities of relatively low cost soluble proteins. Furthermore, edible transgenic plants could provide a simple and direct method of autoantigen delivery for oral tolerance. Therefore, the aim of this study was to determine whether a transgenic plant expression system was capable of synthesizing the diabetes-associated autoantigen, glutamic acid decarboxylase (GAD) in an immunogenic form and whether the oral administration of an autoantigen expressed by a plant could directly induce protective immune responses in a mouse model of diabetes. We show that a GAD-expressing transgenic plant, given as a dietary supplement, inhibits the development of diabetes in the non-obese diabetic (NOD) mouse.", + "TAG_DATA": [ + "143, GAD-expressing {'perturbing_action': 'B-gene gain-of-function'}", + "144, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "145, plant, {'perturbing_action': 'I-gene gain-of-function'}", + "158, non-obese {'context': 'B-organism'}", + "159, diabetic {'context': 'I-organism'}", + "160, (NOD) {'context': 'I-organism'}", + "161, mouse. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "143, GAD-expressing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "144, transgenic ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "145, plant, ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "158, non-obese ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "159, diabetic ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "160, (NOD) ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "161, mouse. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GAD-expressing", + "transgenic", + "plant," + ] + }, + "context": { + "val": "organism", + "words": [ + "non-obese", + "diabetic", + "(NOD)", + "mouse." + ] + } + } + ] + }, + { + "PMID": "9176488", + "TEXT": "Daily treatment of mice with recombinant human Flt3 ligand (huFlt3L) results in a dramatic numerical increase in the number of dendritic cells (DCs) in vivo. Since DCs are pivotal in the induction of immune responses, we tested whether Flt3L treatment of mice challenged with a syngeneic methylcholanthrene (MCA)-induced fibrosarcoma would augment the generation of effective antitumor immune responses in vivo. Flt3L treatment not only induced complete tumor regression in a significant proportion of mice, but also decreased tumor growth rate in the remaining mice. A preliminary characterization of the cellular mechanisms involved suggests that Flt3L may be important in the treatment of cancer in situ through the generation of specific antitumor immune responses.", + "TAG_DATA": [ + "41, mice {'context': 'B-organism'}", + "48, fibrosarcoma {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}", + "58, in {'context': 'B-in vivo'}", + "59, vivo. {'context': 'I-in vivo'}", + "64, induced {'effect': 'B-positive'}", + "66, tumor {'phenotype': 'B-tumour regression'}", + "67, regression {'phenotype': 'I-tumour regression'}", + "73, mice, {'context': 'B-organism'}", + "76, decreased {'effect': 'B-negative'}", + "77, tumor {'phenotype': 'B-tumour growth'}", + "78, growth {'phenotype': 'I-tumour growth'}", + "83, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "41, mice ['l0', 'l1', 'l2']", + "48, fibrosarcoma ['l0', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "58, in ['l1', 'l3', 'l9']", + "59, vivo. ['l2', 'l4', 'l9']", + "64, induced ['l5', 'l10', 'l11', 'l12']", + "66, tumor ['l6', 'l10', 'l13', 'l14']", + "67, regression ['l7', 'l11', 'l13', 'l15']", + "73, mice, ['l8', 'l12', 'l14', 'l15']", + "76, decreased ['l16', 'l17', 'l18']", + "77, tumor ['l16', 'l19', 'l20']", + "78, growth ['l17', 'l19', 'l21']", + "83, mice. ['l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "fibrosarcoma" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "fibrosarcoma" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "fibrosarcoma" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "fibrosarcoma" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "fibrosarcoma" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "fibrosarcoma" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "fibrosarcoma" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "9095179", + "TEXT": "Angiogenesis, the growth of new blood vessels, occurs normally in female reproductive organs. We tested the hypothesis that angiogenesis inhibition may affect fertility by studying the reproductive system in either pregnant or nonpregnant cycling mice after treatment with the angiogenesis inhibitor AGM-1470. Administration of AGM-1470 to pregnant mice resulted in complete failure of embryonic growth due to interference with decidualization, placental and yolk sac formation, and embryonic vascular development. When nonpregnant cycling female mice were chronically treated with AGM-1470, inhibition of endometrial maturation and corpora lutea was observed. These data suggest that processes in reproduction can be controlled through angiogenesis inhibition.", + "TAG_DATA": [ + "32, nonpregnant {'context': 'B-organism'}", + "33, cycling {'context': 'I-organism'}", + "34, mice {'context': 'I-organism'}", + "46, pregnant {'context': 'B-organism'}", + "47, mice {'context': 'I-organism'}", + "51, failure {'effect': 'B-negative'}", + "53, embryonic {'phenotype': 'B-tumourigenesis'}", + "54, growth {'phenotype': 'I-cell growth'}", + "57, interference {'effect': 'B-negative'}", + "70, nonpregnant {'context': 'B-organism'}", + "71, cycling {'context': 'I-organism'}", + "72, female {'context': 'I-organism'}", + "73, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "32, nonpregnant ['l0', 'l1', 'l2']", + "33, cycling ['l0', 'l3']", + "34, mice ['l1', 'l3']", + "46, pregnant ['l4', 'l5', 'l6', 'l7', 'l8']", + "47, mice ['l4', 'l9', 'l10', 'l11', 'l12']", + "51, failure ['l5', 'l9', 'l13', 'l14', 'l15']", + "53, embryonic ['l6', 'l10', 'l13', 'l16', 'l17']", + "54, growth ['l2', 'l7', 'l11', 'l14', 'l16', 'l18']", + "57, interference ['l8', 'l12', 'l15', 'l17', 'l18']", + "70, nonpregnant ['l19', 'l20', 'l21']", + "71, cycling ['l19', 'l22', 'l23']", + "72, female ['l20', 'l22', 'l24']", + "73, mice ['l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "nonpregnant", + "pregnant", + "mice" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "pregnant", + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "failure", + "interference" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "pregnant", + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "embryonic" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "failure", + "interference" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "embryonic" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "failure", + "interference" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + } + ] + }, + { + "PMID": "9095174", + "TEXT": "The Fas ligand (FasL) is expressed in activated T cells and induces apoptosis in Fas-bearing cells. A cytotoxic T lymphocyte (CTL) clone specific for hepatitis B surface antigen (HBsAg) causes an acute liver disease in HBsAg transgenic mice. Here we observed that the CTL clone killed hepatocytes expressing HBsAg in a Fas-dependent manner. Administration of the soluble form of Fas into HBsAg transgenic mice prevented the CTL-induced liver disease. In the second model, mice were primed with Propionibacterium acnes. A subsequent challenge with lipopolysaccharide (LPS) killed the mice by inducing liver injury. Neutralization of FasL rescued the mice from LPS-induced mortality, and Fas-null mice were resistant to LPS-induced mortality. These results suggest that FasL has an essential role in the development of hepatitis.", + "TAG_DATA": [ + "46, hepatocytes {'context': 'B-cells'}", + "61, HBsAg {'perturbing_action': 'B-gene gain-of-function'}", + "62, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "63, mice {'context': 'B-organism'}", + "67, liver {'context': 'B-tissue/organ'}", + "73, mice {'context': 'B-organism'}", + "87, mice {'context': 'B-organism'}", + "90, liver {'context': 'B-tissue/organ'}", + "92, Neutralization {'perturbing_action': 'B-pharmacological inhibition'}", + "93, of {'perturbing_action': 'I-rnai/knockdown'}", + "94, FasL {'perturbing_action': 'I-rnai/knockdown'}", + "97, mice {'context': 'B-organism'}", + "102, Fas-null {'perturbing_action': 'B-gene loss-of-function'}", + "103, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "46, hepatocytes ['l0']", + "61, HBsAg ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "62, transgenic ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "63, mice ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "67, liver ['l0', 'l3', 'l8', 'l12']", + "73, mice ['l4', 'l9', 'l13', 'l16', 'l17']", + "87, mice ['l5', 'l10', 'l14', 'l16', 'l18']", + "90, liver ['l6', 'l11', 'l15', 'l17', 'l18']", + "92, Neutralization ['l19', 'l20', 'l21', 'l22']", + "93, of ['l19', 'l23', 'l24']", + "94, FasL ['l20', 'l23', 'l25']", + "97, mice ['l21', 'l24', 'l25']", + "102, Fas-null ['l26']", + "103, mice ['l22', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "HBsAg", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "HBsAg", + "transgenic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Neutralization" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "FasL" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fas-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "9055865", + "TEXT": "Nucleocapsid p7 (NCp7) proteins of human immunodeficiency virus type 1 (HIV-1) contain two zinc binding domains of the sequence Cys-(X)2-Cys-(X)4-His-(X)4-Cys (CCHC). The spacing pattern and metal-chelating residues (3 Cys, 1 His) of these nucleocapside CCHC zinc fingers are highly conserved among retroviruses. These CCHC domains are required during both the early and late phases of retroviral replication, making them attractive targets for antiviral agents. toward that end, we have identified a number of antiviral chemotypes that electrophilically attack the sulfur atoms of the zinc-coordinating cysteine residues of the domains. Such nucleocapside inhibitors were directly virucidal by preventing the initiation of reverse transcription and blocked formation of infectious virus from cells through modification of CCHC domains within Gag precursors. Herein we report that azodicarbonamide (ADA) represents a new compound that inhibits HIV-1 and a broad range of retroviruses by targeting the the nucleocapsid CCHC domains. Vandevelde et al. also recently disclosed that ADA inhibits HIV-1 infection via an unidentified mechanism and that ADA was introduced into Phase I/II clinical trials in Europe for advanced AIDS. These studies distinguish ADA as the first known nucleocapsid inhibitor to progress to human trials and provide a lead compound for drug optimization.", + "TAG_DATA": [ + "96, preventing {'effect': 'B-negative'}", + "109, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "96, preventing ['l0']", + "109, cells ['l0']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "preventing" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "9018237", + "TEXT": "Psoriasis is a complex disorder involving alterations of many cell types. Although evidence suggests a T-cell pathogenesis for psoriasis, a primary role of T cells has not been directly demonstrated. Here, we show that reconstitution of scid/scid mice with minor histocompatibility mismatched naive CD4+ T lymphocytes resulted in skin alterations that strikingly resembled human psoriasis clinically, histopathologically and in cytokine expression. This skin disorder was diminished when memory T cells were coinjected. Thus, a subset of dysregulated CD4+ T cells can cause tissue alterations seen in psoriasis without the presence of CD8+ cells or a primary epithelial abnormality.", + "TAG_DATA": [ + "36, scid/scid {'perturbing_action': 'B-gene loss-of-function'}", + "37, mice {'context': 'B-organism'}", + "42, naive {'context': 'B-cells'}", + "43, CD4+ {'context': 'I-cells'}", + "44, T {'context': 'I-cells'}", + "45, lymphocytes {'context': 'I-cells'}", + "67, memory {'context': 'B-cells'}", + "68, T {'context': 'I-cells'}", + "69, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "36, scid/scid ['l0', 'l1', 'l2', 'l3', 'l4']", + "37, mice ['l0', 'l5', 'l6', 'l7', 'l8']", + "42, naive ['l1', 'l5', 'l9', 'l10', 'l11']", + "43, CD4+ ['l2', 'l6', 'l9', 'l12', 'l13']", + "44, T ['l3', 'l7', 'l10', 'l12', 'l14']", + "45, lymphocytes ['l4', 'l8', 'l11', 'l13', 'l14']", + "67, memory ['l15', 'l16']", + "68, T ['l15', 'l17']", + "69, cells ['l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "scid/scid" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "scid/scid" + ] + }, + "context": { + "val": "cells", + "words": [ + "naive", + "CD4+", + "T", + "lymphocytes" + ] + } + } + ] + }, + { + "PMID": "8946840", + "TEXT": "Genetic alterations in malignant tissues are potential targets for gene-based cancer therapies. Alternatively, aberrant expression of certain specific genes associated with malignant transformation may be envisioned to enhance the expression of chemosensitizing drugs. Epstein-Barr virus (EBV)-related B-cell lymphomas are fatal complications of immunosuppression due to AIDS, organ transplantation or congenital immune abnormalities. The malignant cells latently infected with EBV typically express the transcription factor EBNA2 as one of nine latent viral genes. We tested whether an EBNA2-responsive EBV promoter may selectively target EBV-related lymphoma cells by virus-regulated expression of a suicide gene. Using the BamC promoter driving a hygromycin-thymidine kinase fusion gene or controls, we demonstrated that sensitivity to ganciclovir was selectively enhanced in cells expressing EBNA2. Further, there was complete macroscopic regression of established B-cell lymphomas in mice with severe combined immunodeficiency disease (SCID mice) treated with a single course of ganciclovir. These data provide in vitro and in vivo support for a model of exploiting the molecular basis of tumor development to enhance the specificity of gene therapy.", + "TAG_DATA": [ + "114, cells {'context': 'B-cells'}", + "122, regression {'phenotype': 'I-tumour regression'}", + "125, B-cell {'context': 'B-neoplasm'}", + "126, lymphomas {'context': 'I-neoplasm'}", + "128, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "122, regression ['l0', 'l1', 'l2']", + "125, B-cell ['l0', 'l3', 'l4']", + "126, lymphomas ['l1', 'l3', 'l5']", + "128, mice ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "B-cell", + "lymphomas" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "8898756", + "TEXT": "Glucagon-like peptide 1 (GLP1) is postulated to regulate blood glucose and satiety, but the biological importance of GLP1 as an incretin and neuropeptide remains controversal. The regulation of nutrient-induced insulin secretion is dependent on the secretion of incretins, gut-derived peptides that potentiate insulin secretion from the pancreatic islets. To ascertain the relative physiological importance of GLP1 as a regulator of feeding behavior and insulin secretion, we have generated mice with a targeted disruption of the GLP1 receptor gene (GLP1R). These GLP1R-/- mice are viable, develop normally but exhibit increased levels of blood glucose following oral glucose challenge in association with diminished levels of circulating insulin. It is surprising that they also exhibit abnormal levels of blood glucose following intraperitoneal glucose challenge. Intracerebroventricular administration of GLP1 inhibited feeding in wild-type mice but not in GLP1R-/- mice; however, no evidence for abnormal body weight or feeding behavior was observed in GLP1R-/- mice. These observations demonstrate that GLP1 plays a central role in the regulation of glycemia; however, disruption of GLP1/GLP1R signaling in the central nervous system is not associated with perturbation of feeding behavior or obesity in vivo.", + "TAG_DATA": [ + "68, mice {'context': 'B-organism'}", + "71, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "72, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "73, of {'perturbing_action': 'I-gene loss-of-function'}", + "74, the {'perturbing_action': 'I-gene loss-of-function'}", + "75, GLP1 {'perturbing_action': 'I-gene loss-of-function'}", + "76, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "77, gene {'perturbing_action': 'I-gene loss-of-function'}", + "78, (GLP1R). {'perturbing_action': 'I-gene loss-of-function'}", + "80, GLP1R-/- {'perturbing_action': 'B-gene loss-of-function'}", + "81, mice {'context': 'B-organism'}", + "129, mice {'context': 'B-organism'}", + "133, GLP1R-/- {'perturbing_action': 'B-gene loss-of-function'}", + "134, mice; {'context': 'B-organism'}", + "148, GLP1R-/- {'perturbing_action': 'B-gene loss-of-function'}", + "149, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "68, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "71, targeted ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "72, disruption ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "73, of ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "74, the ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "75, GLP1 ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "76, receptor ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "77, gene ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "78, (GLP1R). ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "80, GLP1R-/- ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "81, mice ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "129, mice ['l55', 'l56']", + "133, GLP1R-/- ['l55', 'l57']", + "134, mice; ['l56', 'l57']", + "148, GLP1R-/- ['l58']", + "149, mice. ['l58']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice;", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "disruption", + "of", + "the", + "GLP1", + "receptor", + "gene", + "(GLP1R).", + "GLP1R-/-" + ] + } + } + ] + }, + { + "PMID": "8898746", + "TEXT": "A low proliferating fraction in solid tumors limits the effectiveness of cell cycle-dependent chemotherapeutic agents. To understand the molecular basis of such \"kinetic\" resistance we cultured tumor cells as multicellular spheroids and examined levels of p27Kip1, a cyclin-dependent kinase inhibitor known to be upregulated by intercellular contact in normal cells. When transferred from monolayer to three-dimensional culture, a consistent upregulation (up to 15-fold) of p27 protein was observed in a panel of mouse and human carcinoma cell lines. Antisense-oligonucleotide-mediated downregulation of p27 in EMT-6 mammary tumor cell spheroids reduced intercellular adhesion, increased cell proliferation, sensitized tumor cells to 4-hydroperoxycyclophosphamide, and restored drug- or radiation-induced cell-cycle perturbations repressed in spheroid culture. Our results implicate p27 as a regulator of drug resistance in solid tumors and suggest that tumor-targeted p27 antagonists may be useful chemosensitizers in conjunction with conventional anticancer therapy.", + "TAG_DATA": [ + "26, tumor {'context': 'B-transformed cells'}", + "27, cells {'context': 'I-transformed cells'}", + "72, mouse {'context': 'B-transformed cells'}", + "73, and {'context': 'I-transformed cells'}", + "74, human {'context': 'I-transformed cells'}", + "75, carcinoma {'context': 'I-transformed cells'}", + "76, cell {'context': 'I-transformed cells'}", + "77, lines. {'context': 'I-transformed cells'}", + "78, Antisense-oligonucleotide-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "79, downregulation {'perturbing_action': 'I-rnai/knockdown'}", + "80, of {'perturbing_action': 'I-rnai/knockdown'}", + "81, p27 {'perturbing_action': 'I-rnai/knockdown'}", + "83, EMT-6 {'context': 'B-transformed cells'}", + "84, mammary {'context': 'I-neoplasm'}", + "85, tumor {'context': 'I-neoplasm'}", + "86, cell {'context': 'I-neoplasm'}", + "87, spheroids {'context': 'I-organoid'}", + "88, reduced {'effect': 'B-negative'}", + "90, adhesion, {'phenotype': 'B-adhesion'}", + "91, increased {'effect': 'B-positive'}", + "92, cell {'context': 'B-cells'}", + "93, proliferation, {'phenotype': 'B-proliferation'}", + "95, tumor {'context': 'B-transformed cells'}", + "96, cells {'context': 'I-transformed cells'}", + "108, spheroid {'context': 'B-organoid'}", + "109, culture. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "26, tumor ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "27, cells ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "72, mouse ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "73, and ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "74, human ['l3', 'l9', 'l14', 'l18', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "75, carcinoma ['l4', 'l10', 'l15', 'l19', 'l26', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "76, cell ['l5', 'l11', 'l16', 'l20', 'l27', 'l34', 'l41']", + "77, lines. ['l6', 'l12', 'l17', 'l21', 'l28', 'l35', 'l41']", + "78, Antisense-oligonucleotide-mediated ['l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "79, downregulation ['l42', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "80, of ['l43', 'l58', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "81, p27 ['l44', 'l59', 'l73', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "83, EMT-6 ['l45', 'l60', 'l74', 'l87', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "84, mammary ['l46', 'l61', 'l75', 'l88', 'l100', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "85, tumor ['l22', 'l29', 'l36', 'l47', 'l62', 'l76', 'l89', 'l101', 'l112', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "86, cell ['l23', 'l30', 'l37', 'l48', 'l63', 'l77', 'l90', 'l102', 'l113', 'l123', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141']", + "87, spheroids ['l49', 'l64', 'l78', 'l91', 'l103', 'l114', 'l124', 'l133', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "88, reduced ['l24', 'l31', 'l38', 'l50', 'l65', 'l79', 'l92', 'l104', 'l115', 'l125', 'l134', 'l142', 'l150', 'l151', 'l152', 'l153', 'l154']", + "89, intercellular ['l32', 'l39', 'l51', 'l66', 'l80', 'l93', 'l105', 'l116', 'l126', 'l135', 'l143', 'l150', 'l155', 'l156', 'l157', 'l158']", + "90, adhesion, ['l25', 'l33', 'l40', 'l52', 'l67', 'l81', 'l94', 'l106', 'l117', 'l127', 'l136', 'l144', 'l151', 'l155', 'l159', 'l160', 'l161']", + "91, increased ['l53', 'l68', 'l82', 'l95', 'l107', 'l118', 'l128', 'l137', 'l145', 'l152', 'l156', 'l159', 'l162', 'l163']", + "92, cell ['l54', 'l69', 'l83', 'l96', 'l108', 'l119', 'l129', 'l138', 'l146', 'l153', 'l157', 'l160', 'l162', 'l164']", + "93, proliferation, ['l55', 'l70', 'l84', 'l97', 'l109', 'l120', 'l130', 'l139', 'l147', 'l154', 'l158', 'l161', 'l163', 'l164']", + "95, tumor ['l56', 'l71', 'l85', 'l98', 'l110', 'l121', 'l131', 'l140', 'l148', 'l165']", + "96, cells ['l57', 'l72', 'l86', 'l99', 'l111', 'l122', 'l132', 'l141', 'l149', 'l165']", + "108, spheroid ['l166']", + "109, culture. ['l166']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "and", + "human", + "carcinoma", + "EMT-6" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "and", + "human", + "carcinoma", + "EMT-6" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antisense-oligonucleotide-mediated", + "downregulation", + "of", + "p27" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "EMT-6", + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antisense-oligonucleotide-mediated", + "downregulation", + "of", + "p27" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mammary", + "tumor", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antisense-oligonucleotide-mediated", + "downregulation", + "of", + "p27" + ] + }, + "context": { + "val": "organoid", + "words": [ + "spheroids" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antisense-oligonucleotide-mediated", + "downregulation", + "of", + "p27" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antisense-oligonucleotide-mediated", + "downregulation", + "of", + "p27" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antisense-oligonucleotide-mediated", + "downregulation", + "of", + "p27" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antisense-oligonucleotide-mediated", + "downregulation", + "of", + "p27" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antisense-oligonucleotide-mediated", + "downregulation", + "of", + "p27" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "EMT-6" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "EMT-6" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mammary", + "tumor", + "cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mammary", + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mammary", + "tumor", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mammary", + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "spheroids" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "spheroids" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "spheroids" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "spheroids" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + } + ] + }, + { + "PMID": "8837614", + "TEXT": "Loss of receptor hair cells in the cochlea accounts for a significant proportion of hearing impairment in the population. Hair cells can be lost as a consequence of viral or bacterial insult, aging, and damage from intense sound or aminoglycoside antibiotics. The generation of replacement hair cells following damage by sound or drugs has been clearly demonstrated in birds; the chick is the best-studied model for auditory hair cell regeneration. New hair cells arise as progeny from an otherwise nondividing supporting cell population induced to proliferate by the damage. Functional recovery of hearing accompanies this cellular recovery process. The signals and pathways responsible for regenerative proliferation are unknown. Here we show that proliferation is induced in the undamaged receptor epithelium by agents that increase cyclic AMP levels, and that following this stimulation hair cells become labeled with proliferation markers. This remarkable proliferative response is blocked by inhibitors of the cAMP-regulated protein kinase A (PKA). In addition we show that the proliferative response induced by in vitro gentamicin damage is also significantly blocked by PKA inhibitors. These observations are the first to identify a signaling pathway that plays a role in regenerative proliferation in the auditory receptor epithelium.", + "TAG_DATA": [ + "112, proliferation {'phenotype': 'B-proliferation'}", + "114, induced {'effect': 'B-positive'}", + "118, receptor {'context': 'B-tissue/organ'}", + "119, epithelium {'context': 'I-tissue/organ'}", + "132, hair {'context': 'B-cells'}", + "133, cells {'context': 'I-cells'}", + "141, proliferative {'phenotype': 'B-proliferation'}", + "142, response {'phenotype': 'I-proliferation'}", + "144, blocked {'effect': 'B-negative'}", + "160, proliferative {'phenotype': 'B-proliferation'}", + "161, response {'phenotype': 'I-proliferation'}", + "162, induced {'effect': 'B-positive'}", + "164, in {'context': 'B-in vitro'}", + "165, vitro {'context': 'I-in vitro'}", + "171, blocked {'effect': 'B-negative'}", + "173, PKA {'perturbing_action': 'B-pharmacological inhibition'}", + "174, inhibitors. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "112, proliferation ['l0', 'l1', 'l2']", + "114, induced ['l0', 'l3', 'l4']", + "118, receptor ['l1', 'l3', 'l5', 'l6', 'l7']", + "119, epithelium ['l2', 'l4', 'l5', 'l8', 'l9']", + "132, hair ['l6', 'l8', 'l10', 'l11']", + "133, cells ['l7', 'l9', 'l10']", + "141, proliferative ['l12', 'l13']", + "142, response ['l11', 'l12', 'l14']", + "144, blocked ['l13', 'l14']", + "160, proliferative ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "161, response ['l15', 'l22', 'l23', 'l24', 'l25']", + "162, induced ['l16', 'l22', 'l26', 'l27', 'l28']", + "164, in ['l17', 'l23', 'l26', 'l29', 'l30']", + "165, vitro ['l18', 'l24', 'l27', 'l29', 'l31', 'l32']", + "171, blocked ['l19', 'l25', 'l28', 'l30', 'l31', 'l33', 'l34']", + "173, PKA ['l20', 'l33', 'l35']", + "174, inhibitors. ['l21', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation", + "proliferative", + "response" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "receptor", + "epithelium" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "receptor", + "epithelium" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hair" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "response" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "response" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "response" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PKA", + "inhibitors." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "vitro" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PKA", + "inhibitors." + ] + } + } + ] + }, + { + "PMID": "8837606", + "TEXT": "The probability of producing a specific antitumor response should be increased by multiplying the number of T lymphocytes that encounter the malignant cells. We tested this prediction in a murine model, using a recently discovered T-cell chemokine, lymphotactin (Lptn). This chemokine increased tumor cell infiltration with CD4+ lymphocytes but generated little antitumor activity. Coexpression of the T-cell growth factor interleukin-2, however, greatly expanded the T lymphocytes attracted by Lptn, affording protection from the growth of established tumor in a CD4+ and CD8+ T cell-dependent manner. Lesser synergy was seen with GM-CSF. Hence coexpression of a T-cell chemokine and T-cell growth factor potentiates antitumor responses in vivo, suggesting a general strategy to improve cancer immunotherapy.", + "TAG_DATA": [ + "29, murine {'context': 'B-organism'}", + "30, model, {'context': 'I-organism'}", + "42, tumor {'context': 'B-transformed cells'}", + "43, cell {'context': 'I-transformed cells'}", + "46, CD4+ {'context': 'B-cells'}", + "47, lymphocytes {'context': 'I-cells'}", + "53, Coexpression {'perturbing_action': 'B-gene gain-of-function'}", + "54, of {'perturbing_action': 'I-gene gain-of-function'}", + "55, the {'perturbing_action': 'I-gene gain-of-function'}", + "56, T-cell {'perturbing_action': 'I-gene gain-of-function'}", + "57, growth {'perturbing_action': 'I-gene gain-of-function'}", + "58, factor {'perturbing_action': 'I-gene gain-of-function'}", + "59, interleukin-2, {'perturbing_action': 'I-gene gain-of-function'}", + "64, T {'context': 'B-cells'}", + "65, lymphocytes {'context': 'I-cells'}", + "70, protection {'effect': 'B-negative'}", + "73, growth {'phenotype': 'B-cell growth'}", + "76, tumor {'context': 'B-neoplasm'}", + "104, in {'context': 'B-in vivo'}", + "105, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "29, murine ['l0', 'l1', 'l2', 'l3', 'l4']", + "30, model, ['l0', 'l5', 'l6', 'l7', 'l8']", + "42, tumor ['l1', 'l5', 'l9', 'l10', 'l11']", + "43, cell ['l2', 'l6', 'l9', 'l12', 'l13']", + "46, CD4+ ['l3', 'l7', 'l10', 'l12', 'l14']", + "47, lymphocytes ['l4', 'l8', 'l11', 'l13', 'l14']", + "53, Coexpression ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "54, of ['l15', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "55, the ['l16', 'l26', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "56, T-cell ['l17', 'l27', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "57, growth ['l18', 'l28', 'l37', 'l45', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "58, factor ['l19', 'l29', 'l38', 'l46', 'l53', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "59, interleukin-2, ['l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l66', 'l67', 'l68', 'l69', 'l70']", + "64, T ['l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l71', 'l72', 'l73', 'l74']", + "65, lymphocytes ['l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l75', 'l76', 'l77']", + "70, protection ['l23', 'l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l78', 'l79']", + "73, growth ['l24', 'l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l76', 'l78', 'l80']", + "76, tumor ['l25', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l79', 'l80']", + "99, growth ['l81', 'l82', 'l83']", + "100, factor ['l81', 'l84', 'l85']", + "104, in ['l82', 'l84', 'l86']", + "105, vivo, ['l83', 'l85', 'l86']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Coexpression", + "of", + "the", + "T-cell", + "growth", + "factor", + "interleukin-2," + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "lymphocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Coexpression", + "of", + "the", + "T-cell", + "growth", + "factor", + "interleukin-2," + ] + }, + "effect": { + "val": "negative", + "words": [ + "protection" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Coexpression", + "of", + "the", + "T-cell", + "growth", + "factor", + "interleukin-2," + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Coexpression", + "of", + "the", + "T-cell", + "growth", + "factor", + "interleukin-2," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "lymphocytes" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protection" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "lymphocytes" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "protection" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "protection" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + } + ] + }, + { + "PMID": "8705858", + "TEXT": "There are 3 million deaths per annum worldwide due to tuberculosis, and AIDS is compounding the problem. A better vaccine than the live mycobacterium currently in use, bacillus Calmette-Guérin (BCG), is needed. When mice were injected with plasmid DNA encoding a single mycobacterial antigen (65-kDa heat shock protein, hsp65) they made specific cellular and humoral responses to the protein and became immune to subsequent challenge with Mycobacterium tuberculosis. Protection was equivalent to that obtained by vaccinating with live BCG, whereas immunizing with the protein was ineffective. Protection was also obtained with DNA encoding another mycobacterial antigen (36-kDa proline-rich antigen). These results suggest that DNA vaccination might yield improved vaccines to replace BCG.", + "TAG_DATA": [ + "33, mice {'context': 'B-organism'}", + "37, plasmid {'perturbing_action': 'B-gene gain-of-function'}", + "38, DNA {'perturbing_action': 'I-rnai/knockdown'}", + "39, encoding {'perturbing_action': 'I-rnai/knockdown'}", + "40, a {'perturbing_action': 'I-rnai/knockdown'}", + "41, single {'perturbing_action': 'I-rnai/knockdown'}", + "42, mycobacterial {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "33, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "37, plasmid ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "38, DNA ['l0', 'l6', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "39, encoding ['l7', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "40, a ['l1', 'l8', 'l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "41, single ['l2', 'l9', 'l15', 'l20', 'l24', 'l28', 'l29', 'l30']", + "42, mycobacterial ['l3', 'l10', 'l16', 'l21', 'l25', 'l28', 'l31', 'l32']", + "43, antigen ['l4', 'l11', 'l17', 'l22', 'l26', 'l29', 'l31', 'l33']", + "44, (65-kDa ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "DNA", + "a", + "single", + "mycobacterial" + ] + } + } + ] + }, + { + "PMID": "8640555", + "TEXT": "Mutations in the beta subunit of the cGMP phosphodiesterase gene (beta PDE) can cause a recessively inherited retinal degeneration in several species, including mice, dogs and humans. We tested the possibility of altering the course of retinal degeneration in the rd mouse through subretinal injection of a recombinant replication-defective adenovirus that contains the murine cDNA for wild-type (beta PDE, Ad.CMV beta PDE. Subretinal injection of Ad.CMV beta PDE results in beta PDE transcripts and increased PDE activity and delays photoreceptor cell death by six weeks. The findings demonstrate cell rescue by in vivo gene transfer, thus supporting the feasibility of treating an inherited retinal degeneration by somatic gene therapy.", + "TAG_DATA": [ + "40, rd {'context': 'B-organism'}", + "41, mouse {'context': 'I-organism'}", + "78, delays {'effect': 'B-negative'}", + "79, photoreceptor {'context': 'B-cells'}", + "80, cell {'phenotype': 'B-cell death'}", + "81, death {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "40, rd ['l0']", + "41, mouse ['l0']", + "78, delays ['l1', 'l2', 'l3']", + "79, photoreceptor ['l1', 'l4', 'l5']", + "80, cell ['l2', 'l4', 'l6']", + "81, death ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "delays" + ] + }, + "context": { + "val": "cells", + "words": [ + "photoreceptor" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "delays" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "photoreceptor" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + } + ] + }, + { + "PMID": "8616720", + "TEXT": "Inducible nitric oxide synthase (iNOS) is a transcriptionally regulated enzyme that synthesizes nitric oxide from L-arginine that has a key role in the pathophysiology of systemic inflammation and sepsis. Transgenic animals with a null mutation for the iNOS gene are resistant to hypotension and death caused by Escherichia coli lipopolysaccharide (LPS). The regulation of peripheral iNOS has been well studied in sepsis, but little is known about iNOS regulation in the brain during systemic inflammation or sepsis. We know that at baseline there is no detectable iNOS gene expression in the brain, but a detailed neuroanatomical study reveals that early in the course of systemic inflammation there is a profound induction of iNOS messenger RNA in vascular, glial and neuronal structures of the rat brain, accompanied by the production of nitric oxide (NO) metabolites in brain parenchyma and cerebrospinal fluid (CSF). We propose that the spillover of nitrite into the CSF has the potential to be a diagnostic marker for systemic inflammation and sepsis. Pharmacological interventions aimed at regulating iNOS function in the brain might represent a new treatment strategy in sepsis. Brain iNOS may be relevant to the pathophysiology, diagnosis and treatment of systemic inflammation and sepsis.", + "TAG_DATA": [ + "33, null {'perturbing_action': 'B-gene loss-of-function'}", + "34, mutation {'perturbing_action': 'I-gene loss-of-function'}", + "35, for {'perturbing_action': 'I-gene loss-of-function'}", + "36, the {'perturbing_action': 'I-gene loss-of-function'}", + "37, iNOS {'perturbing_action': 'I-gene loss-of-function'}", + "38, gene {'perturbing_action': 'I-gene loss-of-function'}", + "123, rat {'context': 'B-tissue/organ'}", + "124, brain, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "33, null ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "34, mutation ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "35, for ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "36, the ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "37, iNOS ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "38, gene ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "123, rat ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "124, brain, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "null", + "mutation", + "for", + "the", + "iNOS", + "gene" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "brain," + ] + } + } + ] + }, + { + "PMID": "8616719", + "TEXT": "About half of human conceptions are estimated not to be implanted in the uterus, resulting in unrecognizable spontaneous abortions, and about 5% of human births have a recognizable malformation. In order to find clues to the mechanisms of malformation and abortion, we compared the incidences of radiation-induced malformations and abortions in p53 null (p53-/-) and wild-type (p53+/+) mice. After X-irradiation with 2 Gy on day 9.5 of gestation, p53-/- mice showed a 70% incidence of anomalies and a 7% incidence of deaths, whereas p53+/+ mice had a 20% incidence of anomalies and a 60% incidence of deaths. Similar results were obtained after irradiation on day 3.5 of gestation. This reciprocal relationship of radiosensitivity to anomalies and to embryonic or fetal lethality supports the notion that embryonic or fetal tissues have a p53-dependent \"guardian\" of the tissue that aborts cells bearing radiation-induced teratogenic DNA damage. In fact, after X-irradiation, the number of cells with apoptotic DNA fragments was greatly increased in tissues of the p53+/+ fetuses but not in those of the p53-/- fetuses.", + "TAG_DATA": [ + "51, p53 {'perturbing_action': 'B-gene loss-of-function'}", + "52, null {'perturbing_action': 'I-gene loss-of-function'}", + "53, (p53-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "57, mice. {'context': 'B-organism'}", + "68, p53-/- {'perturbing_action': 'B-gene loss-of-function'}", + "69, mice {'context': 'B-organism'}", + "83, p53+/+ {'perturbing_action': 'B-gene loss-of-function'}", + "84, mice {'context': 'B-organism'}", + "151, cells {'context': 'B-cells'}", + "163, p53+/+ {'perturbing_action': 'B-gene loss-of-function'}", + "171, p53-/- {'perturbing_action': 'B-gene loss-of-function'}" + ], + "LINK_DATA": [ + "51, p53 ['l0', 'l1', 'l2', 'l3', 'l4']", + "52, null ['l0', 'l5', 'l6', 'l7', 'l8']", + "53, (p53-/-) ['l1', 'l5', 'l9', 'l10', 'l11']", + "57, mice. ['l2', 'l6', 'l9', 'l12']", + "68, p53-/- ['l3', 'l7', 'l10', 'l12', 'l13']", + "69, mice ['l4', 'l8', 'l11', 'l13']", + "83, p53+/+ ['l14']", + "84, mice ['l14']", + "151, cells ['l15', 'l16', 'l17', 'l18', 'l19']", + "160, tissues ['l15', 'l20', 'l21', 'l22', 'l23']", + "163, p53+/+ ['l16', 'l20', 'l24', 'l25', 'l26']", + "164, fetuses ['l17', 'l21', 'l24', 'l27', 'l28']", + "171, p53-/- ['l18', 'l22', 'l25', 'l27', 'l29']", + "172, fetuses. ['l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53", + "null", + "(p53-/-)", + "p53-/-", + "p53+/+" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53+/+", + "p53-/-" + ] + } + } + ] + }, + { + "PMID": "8597957", + "TEXT": "Alcohol consumption is associated with increased morbidity and mortality related to infectious diseases and malignancy (1-5), although immune mediation of these relationships is controversial. Specifically, the activity of natural killer (NK) cells, which are involved in the resistance to infections and metastasis, can be suppressed in the presence of ethanol in vitro. However, acute consumption or infusion of ethanol in vivo exerts no effects on NK activity assessed in vitro thereafter. Therefore, we have developed and used a method to study the effects of ethanol on NK activity in living rats by using an NK-sensitive metastatic process and selective depletion of NK cells in vivo. Acute ethanol intoxication caused a marked suppression of NK activity in vivo and a tenfold increase in the number of MADB106 tumor metastases. Ethanol had no effect in rats selectively depleted of NK cells or when an NK-insensitive tumor (C4047) was used. These findings suggest that even acute ethanol intoxication markedly suppresses NK activity in the living organism. This suppression may underlie some aspects of the association between alcoholism, infectious disease and malignancies.", + "TAG_DATA": [ + "90, rats {'context': 'I-organism'}", + "103, in {'context': 'B-in vivo'}", + "104, vivo. {'context': 'I-in vivo'}", + "115, in {'context': 'B-in vivo'}", + "116, vivo {'context': 'I-in vivo'}", + "120, increase {'effect': 'B-positive'}", + "125, MADB106 {'context': 'B-neoplasm'}", + "126, tumor {'phenotype': 'B-tumour growth'}", + "127, metastases. {'phenotype': 'I-metastasis'}", + "133, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "103, in ['l0', 'l1', 'l2', 'l3']", + "104, vivo. ['l0', 'l4', 'l5', 'l6']", + "115, in ['l1', 'l4', 'l7', 'l8', 'l9', 'l10']", + "116, vivo ['l2', 'l5', 'l7', 'l11', 'l12', 'l13']", + "120, increase ['l3', 'l6', 'l8', 'l11', 'l14', 'l15', 'l16']", + "125, MADB106 ['l14', 'l17', 'l18']", + "126, tumor ['l9', 'l12', 'l15', 'l17', 'l19']", + "127, metastases. ['l10', 'l13', 'l16', 'l18', 'l19']", + "133, rats ['l20']", + "143, tumor ['l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo.", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increase" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "MADB106" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "MADB106" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "MADB106" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases." + ] + } + } + ] + }, + { + "PMID": "8612238", + "TEXT": "Immunotoxin LMB-1 is composed of monoclonal antibody B3 chemically linked to PE38, a genetically engineered form of Pseudomonas exotoxin. B3 recognizes a carbohydrate antigen (Le(Y)) present on many human solid tumors. LMB-1 has excellent antitumor activity in nude mice bearing Le(Y)-positive tumors. We conducted a phase I study of 38 patients with solid tumors who failed conventional therapy and whose tumors expressed the Le(Y) antigen. Objective antitumor activity was observed in 5 patients, 18 had stable disease, 15 progressed. A complete remission was observed in a patient with metastatic breast cancer to supraclavicular nodes. A greater than 75% tumor reduction and resolution of all clinical symptoms lasting for more than six months was observed in a colon cancer patient with extensive retroperitoneal and cervical metastasis. Three patients (two colon, one breast cancer) had minor responses. The maximum tolerated dose of LMB-1 is 75 microgram/kg given intravenously three times every other day. The major toxicity is vascular leak syndrome manifested by hypoalbuminemia, fluid retention, hypotension and, in one case, pulmonary edema. Although immunotoxins have been evaluated in clinical studies for more than two decades, this is the first report of antitumor activity in epithelial tumors.", + "TAG_DATA": [ + "86, patient {'context': 'B-patient'}", + "88, metastatic {'context': 'B-neoplasm'}", + "89, breast {'context': 'I-neoplasm'}", + "90, cancer {'context': 'I-neoplasm'}", + "91, to {'context': 'I-neoplasm'}", + "93, nodes. {'context': 'I-neoplasm'}", + "98, tumor {'phenotype': 'B-tumour regression'}", + "99, reduction {'phenotype': 'I-tumour regression'}", + "116, colon {'context': 'B-patient'}", + "117, cancer {'context': 'I-neoplasm'}", + "118, patient {'context': 'I-neoplasm'}", + "121, retroperitoneal {'phenotype': 'B-metastasis'}", + "122, and {'phenotype': 'I-metastasis'}", + "123, cervical {'phenotype': 'I-metastasis'}", + "124, metastasis. {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "86, patient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "88, metastatic ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "89, breast ['l1', 'l9', 'l16', 'l17', 'l18', 'l19']", + "90, cancer ['l2', 'l10', 'l16', 'l20', 'l21', 'l22', 'l23']", + "91, to ['l3', 'l11', 'l17', 'l20', 'l24', 'l25']", + "92, supraclavicular ['l4', 'l12', 'l18', 'l21', 'l24', 'l26', 'l27']", + "93, nodes. ['l5', 'l13', 'l19', 'l22', 'l25', 'l26']", + "97, 75% ['l6', 'l14', 'l23', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "98, tumor ['l7', 'l15', 'l28', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "99, reduction ['l8', 'l29', 'l37', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "116, colon ['l30', 'l38', 'l45', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "117, cancer ['l31', 'l39', 'l46', 'l52', 'l58', 'l59', 'l60', 'l61', 'l62']", + "118, patient ['l32', 'l40', 'l47', 'l53', 'l58', 'l63', 'l64', 'l65', 'l66']", + "121, retroperitoneal ['l33', 'l41', 'l48', 'l54', 'l59', 'l63', 'l67', 'l68', 'l69']", + "122, and ['l34', 'l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l70', 'l71']", + "123, cervical ['l35', 'l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l72']", + "124, metastasis. ['l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l69', 'l71', 'l72']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "patient", + "words": [ + "patient", + "colon" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "reduction" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "metastatic", + "cancer", + "patient" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "reduction" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "colon" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "retroperitoneal", + "and", + "cervical", + "metastasis." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "cancer", + "patient" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "retroperitoneal", + "and", + "cervical", + "metastasis." + ] + } + } + ] + }, + { + "PMID": "8574962", + "TEXT": "Interleukin 15 (IL-15) is a novel cytokine with interleukin-2-like activity. It is also a potent T-lymphocyte chemoattractant. Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the presence of activated T lymphocytes, macrophages and synoviocytes in the synovial membrane. The mechanisms of T-cell activation in RA are currently unclear. We report the presence of high concentrations of IL-15 in rheumatoid arthritis (RA) synovial fluid and have demonstrated its expression in the synovial membrane lining layer by immunohistochemistry. RA synovial fluids were found to contain chemotactic activity, which was attributable in part to the presence of IL-15. Moreover, in a murine model, injection of recombinant IL-15 was found to induce a local tissue inflammatory infiltrate consisting predominantly of T lymphocytes. Synovial fluid T lymphocytes proliferate in response to IL-15, demonstrating that continued responsiveness to IL-15 is a feature of T cells after entry into the synovial compartment. These data suggest that IL-15 can recruit and activate T lymphocytes in the synovial membrane, thereby contributing to RA pathogenesis.", + "TAG_DATA": [ + "100, murine {'context': 'B-organism'}", + "101, model, {'context': 'I-organism'}", + "118, T {'context': 'B-cells'}", + "119, lymphocytes. {'context': 'I-cells'}", + "120, Synovial {'context': 'B-cells'}", + "121, fluid {'context': 'I-cells'}", + "122, T {'context': 'I-cells'}", + "123, lymphocytes {'context': 'I-cells'}", + "124, proliferate {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "100, murine ['l0', 'l1', 'l2']", + "101, model, ['l0', 'l3', 'l4']", + "118, T ['l1', 'l3', 'l5']", + "119, lymphocytes. ['l2', 'l4', 'l5']", + "120, Synovial ['l6', 'l7', 'l8', 'l9']", + "121, fluid ['l6', 'l10', 'l11', 'l12']", + "122, T ['l7', 'l10', 'l13', 'l14']", + "123, lymphocytes ['l8', 'l11', 'l13', 'l15']", + "124, proliferate ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Synovial", + "fluid", + "T", + "lymphocytes" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate" + ] + } + } + ] + }, + { + "PMID": "8564838", + "TEXT": "Analysis of the events that regulate development of red blood cells or granulocytes has led to therapies altering clinical conditions associated with anemia or neutropenia. The development of therapeutic approaches to target conditions associated with lymphopenia, such as AIDS, has been thwarted by limited techniques for studying T-lymphocyte development. We describe an in vitro system in which human bone marrow CD34+ cells proliferate, acquire the expression of the lymphoid-specific RAG-2 gene and a broad repertoire of rearranged T-cell receptor genes, develop the ability to produce T cell-specific interleukin-2 and achieve a range of T-cell immunophenotypes. The cells also become susceptible to infection with the T-lymphotropic strain of human immunodeficiency virus-1, HIV-1IIIB. This culture system induces human T lymphopoiesis and may permit further analysis of the events regulating human T-lineage differentiation. It provides a preclinical model for screening stem cell gene therapies directed toward AIDS.", + "TAG_DATA": [ + "52, in {'context': 'B-in vitro'}", + "53, vitro {'context': 'I-in vitro'}", + "54, system {'context': 'I-in vitro'}", + "57, human {'context': 'B-cells'}", + "58, bone {'context': 'I-cells'}", + "59, marrow {'context': 'I-cells'}", + "60, CD34+ {'context': 'I-cells'}", + "61, cells {'context': 'I-cells'}", + "62, proliferate, {'phenotype': 'B-proliferation'}", + "96, cells {'context': 'B-cells'}", + "115, human {'context': 'B-cells'}", + "116, T {'context': 'I-cells'}", + "117, lymphopoiesis {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "52, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "53, vitro ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "54, system ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "57, human ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "58, bone ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "59, marrow ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "60, CD34+ ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "61, cells ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "62, proliferate, ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "115, human ['l36', 'l37']", + "116, T ['l36', 'l38']", + "117, lymphopoiesis ['l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro", + "system" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "bone", + "marrow", + "CD34+", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate," + ] + } + } + ] + }, + { + "PMID": "7489412", + "TEXT": "Dendritic cells, the most potent 'professional' antigen-presenting cells, hold promise for improving the immunotherapy of cancer. In three different well-characterized tumour models, naive mice injected with bone marrow-derived dendritic cells prepulsed with tumour-associated peptides previously characterized as being recognized by class I major histocompatibility complex-restricted cytotoxic T lymphocytes, developed a specific T-lymphocyte response and were protected against a subsequent lethal tumour challenge. Moreover, in the C3 sarcoma and the 3LL lung carcinoma murine models, treatment of animals bearing established macroscopic tumours (up to 1 cm2 in size) with tumour peptide-pulsed dendritic cells resulted in sustained tumour regression and tumour-free status in more than 80% of cases. These results support the clinical use of tumour peptide-pulsed dendritic cells as components in developing effective cancer vaccines and therapies.", + "TAG_DATA": [ + "22, naive {'context': 'B-organism'}", + "23, mice {'context': 'I-organism'}", + "65, C3 {'context': 'B-neoplasm'}", + "66, sarcoma {'context': 'I-neoplasm'}", + "69, 3LL {'context': 'B-neoplasm'}", + "70, lung {'context': 'I-neoplasm'}", + "71, carcinoma {'context': 'I-neoplasm'}", + "72, murine {'context': 'I-organism'}", + "73, models, {'context': 'I-neoplasm'}", + "76, animals {'context': 'B-organism'}", + "80, tumours {'context': 'I-neoplasm'}", + "92, resulted {'effect': 'B-positive'}", + "93, in {'effect': 'I-positive'}", + "95, tumour {'phenotype': 'B-tumour regression'}", + "96, regression {'phenotype': 'I-tumour regression'}" + ], + "LINK_DATA": [ + "22, naive ['l0', 'l1']", + "23, mice ['l0', 'l2']", + "28, dendritic ['l1', 'l2', 'l3', 'l4', 'l5']", + "65, C3 ['l3', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "66, sarcoma ['l4', 'l6', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "69, 3LL ['l7', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "70, lung ['l8', 'l14', 'l19', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "71, carcinoma ['l9', 'l15', 'l20', 'l28', 'l35', 'l36', 'l37', 'l38', 'l39']", + "72, murine ['l10', 'l16', 'l21', 'l29', 'l35', 'l40', 'l41']", + "73, models, ['l5', 'l11', 'l17', 'l22', 'l30', 'l36', 'l40', 'l42']", + "76, animals ['l23', 'l31', 'l37', 'l43', 'l44', 'l45', 'l46', 'l47']", + "80, tumours ['l12', 'l18', 'l24', 'l32', 'l38', 'l41', 'l42', 'l43', 'l48', 'l49', 'l50', 'l51']", + "92, resulted ['l25', 'l44', 'l48', 'l52', 'l53', 'l54']", + "93, in ['l26', 'l33', 'l39', 'l45', 'l49', 'l52', 'l55', 'l56']", + "95, tumour ['l46', 'l50', 'l53', 'l55', 'l57']", + "96, regression ['l27', 'l34', 'l47', 'l51', 'l54', 'l56', 'l57']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "3LL", + "lung", + "carcinoma", + "tumours" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "3LL", + "lung", + "tumours" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression", + "tumour" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animals" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animals" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumour", + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumour", + "regression" + ] + } + } + ] + }, + { + "PMID": "7584994", + "TEXT": "The hallmark of cell death is the development of cell membrane lesions. Such lesions in the myocardium are usually associated with acute myocardial infarction. Minimizing myocardial necrosis by thrombolytic reperfusion therapy constitutes the only major treatment to date. We envisioned a method to seal these membrane lesions using immunoliposomes as a novel adjunctive approach. An antigen to intracellular cytoskeletal myosin in hypoxic embryonic cardiocytes is used as an anchoring site, and a specific antibody on immunoliposomes as the anchor to plug and to seal the membrane lesions. H9C2 cells were used because they are cardiocytes and are propagated in tissue culture and their viability may be assessed by various methods. Viability assessed by [3H]thymidine uptake in hypoxic cardiocyte cultures (n = 6 each) treated with antimyosin-immunoliposomes (3.26 +/- 0.483 x 10(6) c.p.m.) was similar to that of normoxic cells (3.68 +/- 0.328 x 10(6) c.p.m.), but was greater than those of untreated hypoxic cells (0.115 +/- 0.155 x 10(6) c.p.m.) or hypoxic cells treated with plain liposomes (1.140 +/- 0.577 x 10(6) c.p.m.). These results were reconfirmed by trypan blue exclusion and by fluorescent, confocal and transmission electron microscopy. They indicated that cell death in hypoxic cardiocytes can be prevented by targeted cell membrane sealing. This concept of cell salvage should be applicable in the prevention of cell death in different biological systems.", + "TAG_DATA": [ + "87, H9C2 {'context': 'B-cells'}", + "88, cells {'context': 'I-cells'}", + "116, hypoxic {'context': 'B-cells'}", + "117, cardiocyte {'context': 'I-cells'}", + "118, cultures {'context': 'I-cells'}", + "119, (n {'context': 'I-cells'}", + "137, normoxic {'context': 'B-cells'}", + "138, cells {'context': 'I-cells'}", + "152, hypoxic {'context': 'B-cells'}", + "153, cells {'context': 'I-cells'}", + "161, hypoxic {'context': 'B-cells'}", + "162, cells {'context': 'I-cells'}", + "192, cell {'phenotype': 'B-cell death'}", + "193, death {'phenotype': 'I-cell death'}", + "195, hypoxic {'context': 'B-cells'}", + "196, cardiocytes {'context': 'I-cells'}", + "199, prevented {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "87, H9C2 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "88, cells ['l0', 'l7', 'l8', 'l9', 'l10']", + "116, hypoxic ['l1', 'l7', 'l11', 'l12', 'l13', 'l14', 'l15']", + "117, cardiocyte ['l2', 'l8', 'l11', 'l16', 'l17', 'l18', 'l19']", + "118, cultures ['l3', 'l9', 'l12', 'l16', 'l20', 'l21', 'l22']", + "119, (n ['l4', 'l10', 'l13', 'l17', 'l20', 'l23', 'l24']", + "137, normoxic ['l5', 'l14', 'l18', 'l21', 'l23', 'l25', 'l26', 'l27']", + "138, cells ['l6', 'l15', 'l19', 'l22', 'l24', 'l25']", + "152, hypoxic ['l26', 'l28']", + "153, cells ['l27', 'l28']", + "161, hypoxic ['l29']", + "162, cells ['l29']", + "192, cell ['l30', 'l31', 'l32', 'l33']", + "193, death ['l30', 'l34', 'l35', 'l36']", + "195, hypoxic ['l31', 'l34', 'l37', 'l38']", + "196, cardiocytes ['l32', 'l35', 'l37', 'l39']", + "199, prevented ['l33', 'l36', 'l38', 'l39']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "hypoxic", + "cardiocytes" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hypoxic", + "cardiocytes" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + } + ] + }, + { + "PMID": "7584991", + "TEXT": "The cure of micrometastases following surgery is the major goal of cancer immunotherapy. We have recently isolated tumour-associated antigen (TAA) peptides, MUT 1 and MUT 2, derived from a mutated connexin 37 gap-junction protein, from the malignant 3LL-D122 murine lung carcinoma. We now report that synthetic MUT 1 or MUT 2 induces effective antitumour cytoxic T lymphocytes. Peptide vaccines protect mice from spontaneous metastases of 3LL-D122 tumours. Moreover, peptide vaccines reduce metastatic loads in mice carrying pre-established micrometastases. Tumour-specific immunity was primarily mediated by CD8+ T cells. This is the first evidence that peptide therapy may be effective in treatment of residual tumours and provides a rationale for the development of peptide vaccines as a modality for cancer therapy.", + "TAG_DATA": [ + "60, mice {'context': 'B-organism'}", + "63, metastases {'phenotype': 'B-metastasis'}", + "65, 3LL-D122 {'context': 'B-neoplasm'}", + "66, tumours. {'context': 'I-neoplasm'}", + "70, reduce {'effect': 'B-negative'}", + "71, metastatic {'phenotype': 'B-metastasis'}", + "72, loads {'phenotype': 'I-metastasis'}", + "74, mice {'context': 'B-organism'}", + "77, micrometastases. {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "60, mice ['l0', 'l1', 'l2']", + "63, metastases ['l0', 'l3', 'l4']", + "65, 3LL-D122 ['l1', 'l3', 'l5']", + "66, tumours. ['l2', 'l4', 'l5']", + "70, reduce ['l6', 'l7', 'l8', 'l9']", + "71, metastatic ['l6', 'l10', 'l11', 'l12']", + "72, loads ['l7', 'l10', 'l13', 'l14']", + "74, mice ['l8', 'l11', 'l13', 'l15']", + "77, micrometastases. ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases", + "metastatic", + "loads", + "micrometastases." + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "3LL-D122", + "tumours." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduce" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "loads", + "micrometastases." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduce" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "7585216", + "TEXT": "Thalamic structures involved in the unpleasant emotional or affective aspect of pain are poorly understood. We now describe studies of the region of the thalamic principal somatosensory nucleus (Vc) performed before thalamotomy for tremor in a patient who also had panic disorder. Microstimulation in the region posterior to Vc evoked chest pain, including a strong affective dimension, almost identical to that occurring during his panic attacks, as measured using a questionnaire. Results in our other patients indicate that stimulation-associated pain with a strong affective dimension occurred only in those patients who had previously experienced spontaneous pain with a strong affective component. These results are consistent with stimulation-evoked activation of limbic structures, which are connected through cortex with the region posterior to Vc and involved in the affective dimension of pain through conditioning by previous experience.", + "TAG_DATA": [ + "45, region {'context': 'B-tissue/organ'}", + "46, posterior {'context': 'I-tissue/organ'}", + "47, to {'perturbing_action': 'I-rnai/knockdown', 'context': 'I-tissue/organ'}", + "48, Vc {'context': 'I-tissue/organ'}", + "89, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "45, region ['l0', 'l1', 'l2']", + "46, posterior ['l0', 'l3', 'l4']", + "47, to ['l1', 'l3', 'l5']", + "48, Vc ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "region", + "posterior", + "to" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "to" + ] + } + } + ] + }, + { + "PMID": "7585188", + "TEXT": "We used data from a population-based cohort study of blacks, Hispanics, Japanese and whites to examine the frequency of prevalent prostate and breast cancer by family history status of first-degree relatives (parents and siblings). Independent of race, the age-adjusted relative risk for prevalent prostate cancer in subjects with affected brothers was approximately two times that in subjects with affected fathers (P < 0.00005). No such excess risk for breast cancer was observed among subjects with affected sisters compared to those with affected mothers (age- and race-adjusted relative risk = 1.10, P = 0.34). The magnitude of the relative risk for prostate cancer in sibling- versus parent-affected groups was significantly different from that of the comparable relative risk for breast cancer (P < 0.00005). An excess risk of prostate cancer in men with affected brothers compared to those with affected fathers is consistent with the hypothesis of an X-linked, or recessive, model of inheritance.", + "TAG_DATA": [ + "68, breast {'context': 'B-neoplasm'}", + "69, cancer {'phenotype': 'I-tumourigenesis'}" + ], + "LINK_DATA": [ + "68, breast ['l0']", + "69, cancer ['l0']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "breast" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "cancer" + ] + } + } + ] + }, + { + "PMID": "7585181", + "TEXT": "Activation of transcription of the Egr-1 gene by X-rays is regulated by the promoter region of this gene. We linked the radiation-inducible promoter region of the Egr-1 gene to the gene encoding the radiosensitizing and tumoricidal cytokine, tumour necrosis factor-alpha (TNF-alpha) and used a replication-deficient adenovirus to deliver the Egr-TNF construct to human tumours growing in nude mice. Combined treatment with Ad5.Egr-TNF and 5,000 cGy (rad) resulted in increased intratumoral TNF-alpha production and increased tumour control compared with treatment with Ad5.Egr-TNF alone or with radiation alone. The increase in tumour control was achieved without an increase in normal tissue damage when compared to tissue injury from radiation alone. Control of gene transcription by ionizing radiation in vivo represents a novel method of spatial and temporal regulation of gene-based medical treatments.", + "TAG_DATA": [ + "44, replication-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "52, human {'context': 'B-neoplasm'}", + "53, tumours {'context': 'I-neoplasm'}", + "56, nude {'context': 'B-organism'}", + "57, mice. {'context': 'I-organism'}", + "73, increased {'effect': 'B-positive'}", + "74, tumour {'context': 'B-neoplasm'}", + "75, control {'phenotype': 'I-tumour regression'}", + "87, increase {'effect': 'B-positive'}", + "89, tumour {'context': 'B-neoplasm'}", + "90, control {'phenotype': 'I-tumour regression'}" + ], + "LINK_DATA": [ + "44, replication-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "45, adenovirus ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "52, human ['l1', 'l8', 'l15', 'l16', 'l17']", + "53, tumours ['l2', 'l9', 'l15', 'l18', 'l19']", + "56, nude ['l3', 'l10', 'l16', 'l18', 'l20']", + "57, mice. ['l4', 'l11', 'l17', 'l19', 'l20']", + "73, increased ['l5', 'l12', 'l21', 'l22']", + "74, tumour ['l6', 'l13', 'l21', 'l23']", + "75, control ['l7', 'l14', 'l22', 'l23']", + "87, increase ['l24', 'l25']", + "89, tumour ['l24', 'l26']", + "90, control ['l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "replication-deficient" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "tumours", + "tumour" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "replication-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "replication-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "replication-deficient" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "control" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased", + "increase" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumour" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased", + "increase" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "control" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumour" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "control" + ] + } + } + ] + }, + { + "PMID": "7585118", + "TEXT": "Expression of the RI alpha subunit of cAMP-dependent protein kinase type I is enhanced in human cancer cell lines, in primary tumours, in cells after transformation and in cells upon stimulation of growth. We have investigated the effect of sequence-specific inhibition of RI alpha gene expression on in vivo tumour growth. We report that single injection RI alpha antisense treatment results in a reduction in RI alpha expression and inhibition of tumour growth. Tumour cells behaved like untransformed cells by making less protein kinase type I. The RI alpha antisense, which produces a biochemical imprint for growth control, requires infrequent dosing to halt neoplastic growth in vivo.", + "TAG_DATA": [ + "69, inhibition {'effect': 'B-negative'}", + "71, tumour {'phenotype': 'B-tumour growth'}", + "72, growth. {'phenotype': 'I-tumour growth'}", + "73, Tumour {'context': 'B-transformed cells'}", + "74, cells {'context': 'I-transformed cells'}", + "102, halt {'effect': 'B-negative'}", + "103, neoplastic {'phenotype': 'B-tumour growth'}", + "104, growth {'phenotype': 'I-tumour growth'}", + "105, in {'context': 'B-in vivo'}", + "106, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "69, inhibition ['l0', 'l1', 'l2', 'l3']", + "71, tumour ['l0', 'l4', 'l5', 'l6']", + "72, growth. ['l1', 'l4']", + "73, Tumour ['l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "74, cells ['l2', 'l5', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "102, halt ['l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "103, neoplastic ['l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "104, growth ['l3', 'l6', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "105, in ['l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "106, vivo. ['l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibition", + "halt" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumour", + "growth.", + "growth", + "neoplastic" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition", + "halt" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells", + "Tumour" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumour", + "neoplastic", + "growth" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells", + "Tumour" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "halt" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "neoplastic", + "growth" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "7585066", + "TEXT": "We have evaluated the feasibility and efficacy of intraperitoneal implants (neo-organs) for protein delivery in large animals. Skin biopsies were taken from four healthy dogs. Primary fibroblast cultures were transduced with a retroviral vector coding for the human beta-glucuronidase. One to six lattices each containing 10(9) skin fibroblasts were implanted into the omentum of the donor animal. Laparotomies performed at regular intervals showed vascularized neo-organs without local inflammation. Human beta-glucuronidase levels equivalent to 0.8 to 3.1% of the endogenous canine activity were detected for up to 340 days on liver biopsy samples. These results indicate that neo-organs can be considered for the long-term delivery of therapeutic proteins or enzymes in humans.", + "TAG_DATA": [ + "24, dogs. {'context': 'I-organism'}", + "25, Primary {'context': 'B-cells'}", + "26, fibroblast {'context': 'I-cells'}", + "27, cultures {'context': 'I-cells'}", + "29, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "30, with {'perturbing_action': 'I-gene gain-of-function'}", + "31, a {'perturbing_action': 'I-gene gain-of-function'}", + "32, retroviral {'perturbing_action': 'I-gene gain-of-function'}", + "33, vector {'perturbing_action': 'I-gene gain-of-function'}", + "34, coding {'perturbing_action': 'I-gene gain-of-function'}", + "35, for {'perturbing_action': 'I-gene gain-of-function'}", + "36, the {'perturbing_action': 'I-gene gain-of-function'}", + "37, human {'perturbing_action': 'I-gene gain-of-function'}", + "38, beta-glucuronidase. {'perturbing_action': 'I-gene gain-of-function'}", + "46, skin {'context': 'B-cells'}", + "47, fibroblasts {'context': 'I-cells'}", + "52, omentum {'context': 'B-tissue/organ'}", + "55, donor {'context': 'B-organism'}", + "56, animal. {'context': 'I-organism'}", + "89, liver {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "24, dogs. ['l0', 'l1', 'l2']", + "25, Primary ['l0', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "26, fibroblast ['l1', 'l3', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "27, cultures ['l2', 'l4', 'l15', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "29, transduced ['l5', 'l16', 'l26', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "30, with ['l6', 'l17', 'l27', 'l36', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "31, a ['l7', 'l18', 'l28', 'l37', 'l47', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "32, retroviral ['l8', 'l19', 'l29', 'l38', 'l48', 'l58', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "33, vector ['l9', 'l20', 'l30', 'l39', 'l49', 'l59', 'l69', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "34, coding ['l10', 'l21', 'l31', 'l40', 'l50', 'l60', 'l70', 'l80', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "35, for ['l11', 'l22', 'l32', 'l41', 'l51', 'l61', 'l71', 'l81', 'l89', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "36, the ['l12', 'l23', 'l33', 'l42', 'l52', 'l62', 'l72', 'l82', 'l90', 'l97', 'l104', 'l105', 'l106', 'l107', 'l108']", + "37, human ['l13', 'l24', 'l34', 'l43', 'l53', 'l63', 'l73', 'l83', 'l91', 'l98', 'l104', 'l109', 'l110', 'l111']", + "38, beta-glucuronidase. ['l14', 'l25', 'l35', 'l44', 'l54', 'l64', 'l74', 'l84', 'l92', 'l99', 'l105', 'l109', 'l112', 'l113', 'l114']", + "46, skin ['l75', 'l115', 'l116', 'l117', 'l118']", + "47, fibroblasts ['l65', 'l76', 'l85', 'l93', 'l100', 'l115', 'l119', 'l120', 'l121']", + "52, omentum ['l45', 'l55', 'l66', 'l77', 'l86', 'l94', 'l101', 'l106', 'l110', 'l112', 'l116', 'l119', 'l122', 'l123']", + "55, donor ['l56', 'l67', 'l78', 'l87', 'l95', 'l102', 'l107', 'l113', 'l117', 'l120', 'l122', 'l124']", + "56, animal. ['l46', 'l57', 'l68', 'l79', 'l88', 'l96', 'l103', 'l108', 'l111', 'l114', 'l118', 'l121', 'l123', 'l124']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Primary", + "fibroblast", + "cultures", + "fibroblasts", + "skin" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "a", + "retroviral", + "vector", + "coding", + "for", + "the", + "human", + "beta-glucuronidase." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "a", + "retroviral", + "vector", + "coding", + "for", + "the", + "human", + "beta-glucuronidase." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "omentum" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "a", + "retroviral", + "vector", + "coding", + "for", + "the", + "human", + "beta-glucuronidase." + ] + }, + "context": { + "val": "organism", + "words": [ + "animal.", + "donor" + ] + } + } + ] + }, + { + "PMID": "7585014", + "TEXT": "Brain dysfunction is the most important sequelae of the fragile X (FMR-1) mutation, the most common heritable cause of developmental disability. Using magnetic resonance imaging (MRI) and quantitative morphometry, we have compared the neuroanatomy of 51 individuals with an FMR-1 mutation with matched controls and showed that subjects with an FMR-1 mutation have increased volume of the caudate nucleus and, in males, the lateral ventricle. Both caudate and lateral ventricular volumes are correlated with IQ. Caudate volume is also correlated with the methylation status of the FMR-1 gene. Neuroanatomical differences between two monozygotic twins with an FMR-1 mutation who are discordant for mental retardation are localized to the cerebellum, lateral ventricles and subcortical nuclei. These findings suggest that the FMR-1 mutation causing the fragile X syndrome leads to observable changes in neuroanatomy that may be relevant to the neurodevelopmental disability and behavioural problems observed in affected individuals.", + "TAG_DATA": [ + "40, mutation {'perturbing_action': 'I-other'}", + "50, FMR-1 {'perturbing_action': 'B-other'}", + "51, mutation {'perturbing_action': 'I-other'}", + "93, twins {'context': 'I-organism'}", + "96, FMR-1 {'perturbing_action': 'B-other'}", + "97, mutation {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "50, FMR-1 ['l0']", + "51, mutation ['l0']", + "93, twins ['l1', 'l2']", + "96, FMR-1 ['l1', 'l3']", + "97, mutation ['l2', 'l3']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "twins" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "FMR-1", + "mutation" + ] + } + } + ] + }, + { + "PMID": "7584960", + "TEXT": "ATP-induced tumour growth inhibition is accompanied by a selective decrease in the content of the tripeptide glutathione (GSH) within the cancer cells in vivo. Depletion of cellular GSH sensitizes tumours to chemotherapy and radiation, but the usefulness of this depletion depends on whether the levels of GSH can be reduced in the tumour relative to normal tissues. We report here that administration of ATP in combination with diethylmaleate and X-rays leads to complete regression of 95% of Ehrlich ascites tumours in mice. This shows that an aggressive tumour can be eliminated by using a therapy based on modulation of GSH levels in cancer cells.", + "TAG_DATA": [ + "70, leads {'effect': 'B-positive'}", + "71, to {'effect': 'I-positive'}", + "73, regression {'phenotype': 'I-tumour regression'}", + "77, Ehrlich {'context': 'B-neoplasm'}", + "78, ascites {'context': 'I-neoplasm'}", + "79, tumours {'context': 'I-neoplasm'}", + "81, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "70, leads ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "71, to ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "73, regression ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "77, Ehrlich ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "78, ascites ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "79, tumours ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "81, mice. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "leads", + "to" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "leads", + "to" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "Ehrlich", + "ascites", + "tumours" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "leads", + "to" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "Ehrlich", + "ascites", + "tumours" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "7584959", + "TEXT": "The ability to culture cells from the human nervous system provides new insight into the pathophysiology of neurological diseases and could be crucial to the development of gene replacement therapies and neural transplantation. We report that the proliferation of human Schwann cells isolated from paediatric and adult nerves is sustained in vitro by recombinant glial growth factor. Agents that increase intracellular cyclic cAMP were also mitogenic towards Schwann cells but suppress growth of contaminating fibroblasts. As the lifespan of highly enriched cultures can be extended for up to twelve population doublings, large numbers of cells can be generated from nerve biopsies.", + "TAG_DATA": [ + "37, proliferation {'phenotype': 'B-proliferation'}", + "39, human {'context': 'B-cells'}", + "40, Schwann {'context': 'I-cells'}", + "41, cells {'context': 'I-cells'}", + "42, isolated {'context': 'I-cells'}", + "43, from {'context': 'I-cells'}", + "44, paediatric {'context': 'I-cells'}", + "45, and {'context': 'I-tissue/organ'}", + "46, adult {'context': 'I-tissue/organ'}", + "47, nerves {'context': 'I-tissue/organ'}", + "49, sustained {'effect': 'B-positive'}", + "50, in {'context': 'B-in vitro'}", + "51, vitro {'context': 'I-in vitro'}", + "67, Schwann {'context': 'B-cells'}", + "68, cells {'context': 'I-cells'}", + "74, fibroblasts. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "37, proliferation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "39, human ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "40, Schwann ['l1', 'l11', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "41, cells ['l2', 'l12', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "42, isolated ['l3', 'l13', 'l20', 'l26', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "43, from ['l4', 'l14', 'l21', 'l27', 'l32', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "44, paediatric ['l5', 'l15', 'l22', 'l28', 'l33', 'l39', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "45, and ['l6', 'l16', 'l23', 'l29', 'l34', 'l40', 'l47', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "46, adult ['l7', 'l17', 'l24', 'l30', 'l35', 'l41', 'l48', 'l54', 'l60', 'l61', 'l62', 'l63', 'l64']", + "47, nerves ['l8', 'l18', 'l25', 'l31', 'l36', 'l42', 'l49', 'l55', 'l60', 'l65', 'l66']", + "49, sustained ['l9', 'l37', 'l43', 'l50', 'l56', 'l61', 'l65', 'l67', 'l68', 'l69', 'l70']", + "50, in ['l44', 'l51', 'l57', 'l62', 'l67', 'l71', 'l72', 'l73']", + "51, vitro ['l10', 'l38', 'l45', 'l52', 'l58', 'l63', 'l66', 'l68', 'l71', 'l74', 'l75']", + "67, Schwann ['l69', 'l72', 'l74', 'l76', 'l77']", + "68, cells ['l46', 'l53', 'l59', 'l64', 'l70', 'l73', 'l75', 'l76']", + "74, fibroblasts. ['l77']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "Schwann", + "cells", + "isolated", + "from", + "paediatric" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "and", + "adult", + "nerves" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sustained" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "vitro" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "isolated", + "from", + "paediatric", + "Schwann", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sustained" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "and", + "adult", + "nerves" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sustained" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sustained" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "7584952", + "TEXT": "Successful fertilization in humans, achieved when parental chromosomes intermix at first mitosis, requires centrosome restoration and microtubule-mediated motility. Imaging of inseminated human oocytes reveals that the sperm introduces the centrosome. The centrosome then nucleates the new microtubule assembly to form the sperm aster--a step essential for successful fertilization. Oocytes from some infertile patients failed to complete fertilization because of defects in uniting the sperm and egg nuclei, indicating that failure to properly effect the cytoplasmic motions uniting the nuclei results in human infertility. These discoveries have important implications for infertility diagnosis and managing reproduction.", + "TAG_DATA": [ + "48, Oocytes {'context': 'B-cells'}", + "53, failed {'effect': 'B-negative'}", + "54, to {'effect': 'I-negative'}", + "55, complete {'effect': 'I-negative'}", + "56, fertilization {'phenotype': 'B-ferroptosis'}" + ], + "LINK_DATA": [ + "48, Oocytes ['l0', 'l1', 'l2', 'l3']", + "53, failed ['l0', 'l4', 'l5', 'l6']", + "54, to ['l1', 'l4', 'l7', 'l8']", + "55, complete ['l2', 'l5', 'l7', 'l9']", + "56, fertilization ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Oocytes" + ] + }, + "effect": { + "val": "negative", + "words": [ + "failed", + "to", + "complete" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Oocytes" + ] + }, + "phenotype": { + "val": "ferroptosis", + "words": [ + "fertilization" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "failed", + "to", + "complete" + ] + }, + "phenotype": { + "val": "ferroptosis", + "words": [ + "fertilization" + ] + } + } + ] + }, + { + "PMID": "27643638", + "TEXT": "Continuous de novo fatty acid synthesis is a common feature of cancer that is required to meet the biosynthetic demands of a growing tumor. This process is controlled by the rate-limiting enzyme acetyl-CoA carboxylase (ACC), an attractive but traditionally intractable drug target. Here we provide genetic and pharmacological evidence that in preclinical models ACC is required to maintain the de novo fatty acid synthesis needed for growth and viability of non-small-cell lung cancer (NSCLC) cells. We describe the ability of ND-646-an allosteric inhibitor of the ACC enzymes ACC1 and ACC2 that prevents ACC subunit dimerization-to suppress fatty acid synthesis in vitro and in vivo. Chronic ND-646 treatment of xenograft and genetically engineered mouse models of NSCLC inhibited tumor growth. When administered as a single agent or in combination with the standard-of-care drug carboplatin, ND-646 markedly suppressed lung tumor growth in the Kras;Trp53-/- (also known as KRAS p53) and Kras;Stk11-/- (also known as KRAS Lkb1) mouse models of NSCLC. These findings demonstrate that ACC mediates a metabolic liability of NSCLC and that ACC inhibition by ND-646 is detrimental to NSCLC growth, supporting further examination of the use of ACC inhibitors in oncology.", + "TAG_DATA": [ + "80, ND-646-an {'perturbing_action': 'B-pharmacological inhibition'}", + "81, allosteric {'perturbing_action': 'I-pharmacological inhibition'}", + "82, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "83, of {'perturbing_action': 'I-pharmacological inhibition'}", + "84, the {'perturbing_action': 'I-pharmacological inhibition'}", + "85, ACC {'perturbing_action': 'I-pharmacological inhibition'}", + "86, enzymes {'perturbing_action': 'I-pharmacological inhibition'}", + "87, ACC1 {'perturbing_action': 'I-pharmacological inhibition'}", + "88, and {'perturbing_action': 'I-pharmacological inhibition'}", + "89, ACC2 {'perturbing_action': 'I-pharmacological inhibition'}", + "99, in {'context': 'B-in vitro'}", + "100, vitro {'context': 'I-in vitro'}", + "102, in {'context': 'B-in vivo'}", + "103, vivo. {'context': 'I-in vivo'}", + "108, xenograft {'context': 'B-xenograft'}", + "110, genetically {'context': 'B-organism'}", + "111, engineered {'context': 'I-xenograft'}", + "112, mouse {'context': 'I-xenograft'}", + "113, models {'context': 'I-xenograft'}", + "114, of {'context': 'I-neoplasm'}", + "115, NSCLC {'context': 'I-neoplasm'}", + "116, inhibited {'effect': 'B-negative'}", + "117, tumor {'phenotype': 'B-tumour growth'}", + "118, growth. {'phenotype': 'I-tumour growth'}", + "135, suppressed {'effect': 'B-negative'}", + "136, lung {'context': 'B-tissue/organ'}", + "137, tumor {'phenotype': 'B-tumour growth'}", + "138, growth {'phenotype': 'I-tumour growth'}", + "141, Kras;Trp53-/- {'perturbing_action': 'B-gene loss-of-function'}", + "142, (also {'perturbing_action': 'I-gene loss-of-function'}", + "148, Kras;Stk11-/- {'perturbing_action': 'B-gene loss-of-function'}", + "149, (also {'perturbing_action': 'I-gene loss-of-function'}", + "152, KRAS {'perturbing_action': 'I-gene loss-of-function'}", + "153, Lkb1) {'perturbing_action': 'I-gene loss-of-function'}", + "154, mouse {'context': 'B-neoplasm'}", + "155, models {'context': 'I-neoplasm'}", + "156, of {'context': 'I-neoplasm'}", + "157, NSCLC. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "80, ND-646-an ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "81, allosteric ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "82, inhibitor ['l1', 'l17', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "83, of ['l2', 'l18', 'l39', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "84, the ['l3', 'l19', 'l40', 'l60', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "85, ACC ['l4', 'l20', 'l41', 'l61', 'l80', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "86, enzymes ['l5', 'l21', 'l42', 'l62', 'l81', 'l99', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "87, ACC1 ['l6', 'l22', 'l43', 'l63', 'l82', 'l100', 'l117', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "88, and ['l7', 'l23', 'l44', 'l64', 'l83', 'l101', 'l118', 'l134', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164']", + "89, ACC2 ['l8', 'l24', 'l45', 'l65', 'l84', 'l102', 'l119', 'l135', 'l150', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177']", + "99, in ['l9', 'l25', 'l46', 'l66', 'l85', 'l103', 'l120', 'l136', 'l151', 'l165', 'l178']", + "100, vitro ['l10', 'l26', 'l47', 'l67', 'l86', 'l104', 'l121', 'l137', 'l152', 'l166', 'l178']", + "102, in ['l11', 'l27', 'l48', 'l68', 'l87', 'l105', 'l122', 'l138', 'l153', 'l167', 'l179', 'l180', 'l181']", + "103, vivo. ['l12', 'l28', 'l49', 'l69', 'l88', 'l106', 'l123', 'l139', 'l154', 'l168', 'l179', 'l182']", + "108, xenograft ['l29', 'l50', 'l70', 'l89', 'l107', 'l124', 'l140', 'l155', 'l169', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191']", + "110, genetically ['l30', 'l51', 'l71', 'l90', 'l108', 'l125', 'l141', 'l156', 'l170', 'l183', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199']", + "111, engineered ['l31', 'l52', 'l72', 'l91', 'l109', 'l126', 'l142', 'l157', 'l171', 'l184', 'l192', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206']", + "112, mouse ['l13', 'l32', 'l53', 'l73', 'l92', 'l110', 'l127', 'l143', 'l158', 'l172', 'l185', 'l193', 'l200', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212']", + "113, models ['l14', 'l33', 'l54', 'l74', 'l93', 'l111', 'l128', 'l144', 'l159', 'l173', 'l186', 'l194', 'l201', 'l207', 'l213', 'l214', 'l215', 'l216', 'l217']", + "114, of ['l15', 'l34', 'l55', 'l75', 'l94', 'l112', 'l129', 'l145', 'l160', 'l174', 'l180', 'l187', 'l195', 'l202', 'l208', 'l213', 'l218', 'l219', 'l220', 'l221']", + "115, NSCLC ['l16', 'l35', 'l56', 'l76', 'l95', 'l113', 'l130', 'l146', 'l161', 'l175', 'l181', 'l182', 'l188', 'l196', 'l203', 'l209', 'l214', 'l218', 'l222', 'l223']", + "116, inhibited ['l36', 'l57', 'l77', 'l96', 'l114', 'l131', 'l147', 'l162', 'l176', 'l189', 'l197', 'l204', 'l210', 'l215', 'l219', 'l222', 'l224', 'l225']", + "117, tumor ['l37', 'l58', 'l78', 'l97', 'l115', 'l132', 'l148', 'l163', 'l190', 'l198', 'l205', 'l211', 'l216', 'l220', 'l224', 'l226']", + "118, growth. ['l38', 'l59', 'l79', 'l98', 'l116', 'l133', 'l149', 'l164', 'l177', 'l191', 'l199', 'l206', 'l212', 'l217', 'l221', 'l223', 'l225', 'l226']", + "135, suppressed ['l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239']", + "136, lung ['l227', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252']", + "137, tumor ['l228', 'l240', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261']", + "138, growth ['l229', 'l241', 'l253', 'l262', 'l263', 'l264', 'l265', 'l266']", + "141, Kras;Trp53-/- ['l230', 'l242', 'l254', 'l262', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277']", + "142, (also ['l231', 'l243', 'l255', 'l263', 'l267', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286', 'l287']", + "148, Kras;Stk11-/- ['l268', 'l278', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296']", + "149, (also ['l232', 'l244', 'l256', 'l269', 'l279', 'l288', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304']", + "150, known ['l233', 'l245', 'l257', 'l270', 'l280', 'l289', 'l297', 'l305', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311']", + "151, as ['l234', 'l246', 'l258', 'l271', 'l281', 'l290', 'l298', 'l305', 'l312', 'l313', 'l314', 'l315', 'l316', 'l317']", + "152, KRAS ['l235', 'l247', 'l272', 'l282', 'l291', 'l299', 'l306', 'l312', 'l318', 'l319', 'l320', 'l321', 'l322']", + "153, Lkb1) ['l236', 'l248', 'l273', 'l283', 'l292', 'l300', 'l307', 'l313', 'l318', 'l323', 'l324', 'l325', 'l326']", + "154, mouse ['l249', 'l274', 'l284', 'l293', 'l301', 'l308', 'l314', 'l319', 'l323', 'l327', 'l328', 'l329']", + "155, models ['l237', 'l250', 'l259', 'l264', 'l275', 'l285', 'l294', 'l302', 'l309', 'l315', 'l320', 'l324', 'l327', 'l330', 'l331']", + "156, of ['l238', 'l251', 'l260', 'l265', 'l276', 'l286', 'l295', 'l303', 'l310', 'l316', 'l321', 'l325', 'l328', 'l330', 'l332']", + "157, NSCLC. ['l239', 'l252', 'l261', 'l266', 'l277', 'l287', 'l296', 'l304', 'l311', 'l317', 'l322', 'l326', 'l329', 'l331', 'l332']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ND-646-an", + "allosteric", + "inhibitor", + "of", + "the", + "ACC", + "enzymes", + "ACC1", + "and", + "ACC2" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ND-646-an", + "allosteric", + "inhibitor", + "of", + "the", + "ACC", + "enzymes", + "ACC1", + "and", + "ACC2" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ND-646-an", + "allosteric", + "inhibitor", + "of", + "the", + "ACC", + "enzymes", + "ACC1", + "and", + "ACC2" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "mouse", + "models", + "xenograft", + "engineered" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ND-646-an", + "allosteric", + "inhibitor", + "of", + "the", + "ACC", + "enzymes", + "ACC1", + "and", + "ACC2" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "of", + "NSCLC" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "allosteric", + "inhibitor", + "of", + "the", + "ACC", + "enzymes", + "ACC1", + "and", + "ACC2" + ] + }, + "context": { + "val": "organism", + "words": [ + "genetically" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "allosteric", + "inhibitor", + "of", + "the", + "ACC", + "enzymes", + "ACC1", + "and", + "ACC2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "allosteric", + "inhibitor", + "of", + "the", + "ACC", + "enzymes", + "ACC1", + "and", + "ACC2" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "engineered", + "mouse", + "models" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "engineered", + "mouse", + "models" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "genetically" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "genetically" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "of", + "NSCLC", + "models", + "NSCLC." + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "suppressed" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "of", + "NSCLC", + "models", + "NSCLC." + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth.", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "suppressed" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth.", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Kras;Trp53-/-", + "(also", + "KRAS", + "Lkb1)" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Kras;Trp53-/-", + "(also", + "KRAS", + "Lkb1)" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Kras;Trp53-/-", + "(also" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Kras;Trp53-/-", + "(also", + "Kras;Stk11-/-", + "KRAS", + "Lkb1)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "models", + "of", + "NSCLC." + ] + } + } + ] + }, + { + "PMID": "25894829", + "TEXT": "Type 2 diabetes (T2D) is characterized by chronic hyperglycemia resulting from a deficiency in insulin signaling, because of insulin resistance and/or defects in insulin secretion; it is also associated with increases in glucagon and endogenous glucose production (EGP). Gliflozins, including dapagliflozin, are a new class of approved oral antidiabetic agents that specifically inhibit sodium-glucose co-transporter 2 (SGLT2) function in the kidney, thus preventing renal glucose reabsorption and increasing glycosuria in diabetic individuals while reducing hyperglycemia. However, gliflozin treatment in subjects with T2D increases both plasma glucagon and EGP by unknown mechanisms. In spite of the rise in EGP, T2D patients treated with gliflozin have lower blood glucose levels than those receiving placebo, possibly because of increased glycosuria; however, the resulting increase in plasma glucagon levels represents a possible concerning side effect, especially in a patient population already affected by hyperglucagonemia. Here we demonstrate that SGLT2 is expressed in glucagon-secreting alpha cells of the pancreatic islets. We further found that expression of SLC5A2 (which encodes SGLT2) was lower and glucagon (GCG) gene expression was higher in islets from T2D individuals and in normal islets exposed to chronic hyperglycemia than in islets from non-diabetics. Moreover, hepatocyte nuclear factor 4-α (HNF4A) is specifically expressed in human alpha cells, in which it controls SLC5A2 expression, and its expression is downregulated by hyperglycemia. In addition, inhibition of either SLC5A2 via siRNA-induced gene silencing or SGLT2 via dapagliflozin treatment in human islets triggered glucagon secretion through KATP channel activation. Finally, we found that dapagliflozin treatment further promotes glucagon secretion and hepatic gluconeogenesis in healthy mice, thereby limiting the decrease of plasma glucose induced by fasting. Collectively, these results identify a heretofore unknown role of SGLT2 and designate dapagliflozin", + "TAG_DATA": [ + "181, normal {'context': 'B-cells'}", + "182, islets {'context': 'I-cells'}", + "220, inhibition {'perturbing_action': 'B-rnai/knockdown'}", + "221, of {'perturbing_action': 'I-rnai/knockdown'}", + "222, either {'perturbing_action': 'I-rnai/knockdown'}", + "223, SLC5A2 {'perturbing_action': 'I-rnai/knockdown'}", + "224, via {'perturbing_action': 'I-rnai/knockdown'}", + "225, siRNA-induced {'perturbing_action': 'I-rnai/knockdown'}", + "226, gene {'perturbing_action': 'I-rnai/knockdown'}", + "227, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "234, human {'context': 'B-cells'}", + "235, islets {'context': 'I-cells'}", + "258, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "181, normal ['l0']", + "182, islets ['l0']", + "220, inhibition ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "221, of ['l1', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "222, either ['l2', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "223, SLC5A2 ['l3', 'l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "224, via ['l4', 'l14', 'l23', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "225, siRNA-induced ['l5', 'l15', 'l24', 'l32', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "226, gene ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l52', 'l53', 'l54', 'l55', 'l56']", + "227, silencing ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l57', 'l58', 'l59', 'l60']", + "232, treatment ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l61', 'l62', 'l63']", + "234, human ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l64', 'l65']", + "235, islets ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64']", + "258, mice, ['l11', 'l21', 'l30', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l65']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "inhibition", + "of", + "either", + "SLC5A2", + "via", + "siRNA-induced", + "gene", + "silencing" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "islets" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "inhibition", + "of", + "either", + "SLC5A2", + "via", + "siRNA-induced", + "gene", + "silencing" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "19198614", + "TEXT": "Duchenne muscular dystrophy is characterized by progressive muscle weakness and early death resulting from dystrophin deficiency. Loss of dystrophin results in disruption of a large dystrophin glycoprotein complex, leading to pathological calcium (Ca2+)-dependent signals that damage muscle cells. We have identified a structural and functional defect in the ryanodine receptor (RyR1), a sarcoplasmic reticulum Ca2+ release channel, in the mdx mouse model of muscular dystrophy that contributes to altered Ca2+ homeostasis in dystrophic muscles. RyR1 isolated from mdx skeletal muscle showed an age-dependent increase in S-nitrosylation coincident with dystrophic changes in the muscle. RyR1 S-nitrosylation depleted the channel complex of FKBP12 (also known as calstabin-1, for calcium channel stabilizing binding protein), resulting in 'leaky' channels. Preventing calstabin-1 depletion from RyR1 with S107, a compound that binds the RyR1 channel and enhances the binding affinity of calstabin-1 to the nitrosylated channel, inhibited sarcoplasmic reticulum Ca2+ leak, reduced biochemical and histological evidence of muscle damage, improved muscle function and increased exercise performance in mdx mice. On the basis of these findings, we propose that sarcoplasmic reticulum Ca2+ leak via RyR1 due to S-nitrosylation of the channel and calstabin-1 depletion contributes to muscle weakness in muscular dystrophy, and that preventing the RyR1-mediated sarcoplasmic reticulum Ca2+ leak may provide a new therapeutic approach.", + "TAG_DATA": [ + "78, skeletal {'context': 'I-tissue/organ'}", + "79, muscle {'context': 'I-tissue/organ'}", + "119, RyR1 {'perturbing_action': 'I-gene loss-of-function'}", + "154, muscle {'context': 'B-tissue/organ'}", + "161, mdx {'context': 'B-organism'}", + "162, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "77, mdx ['l0', 'l1']", + "78, skeletal ['l0', 'l2']", + "79, muscle ['l1', 'l2']", + "119, RyR1 ['l3', 'l4', 'l5']", + "154, muscle ['l3', 'l6', 'l7']", + "161, mdx ['l4', 'l6', 'l8']", + "162, mice. ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "RyR1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscle" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "RyR1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mdx", + "mice." + ] + } + } + ] + }, + { + "PMID": "15864314", + "TEXT": "Although stem cells succumbing to reproductive death are assumed to be the single relevant targets in radiation tissue damage, recent studies showed intestinal stem cell damage is conditionally linked to crypt endothelial apoptosis, defining a two-target model. Here we report that when mouse intestines were protected against microvascular apoptosis, radiation switched as the dose escalated to a previously unrecognized crypt stem cell target, activating ceramide synthase-mediated apoptosis to initiate intestinal damage. Whereas ataxia telangiectasia-mutated (ATM) kinase normally represses ceramide synthase, its derepression in Atm(-/-) mice increased crypt stem cell radiosensitivity 3.7-fold without sensitizing the microvascular response. Discovery of this intestinal radiosensitivity mechanism allowed design of an antisense Atm oligonucleotide treatment which phenocopied the Atm(-/-) mouse, reordering ceramide synthase-mediated stem cell death to become the first-line gastrointestinal response of wild-type littermates. These experiments indicate that tissues operate multiple potential targets activated consecutively according to their inherent radiosensitivities that may be reordered therapeutically to control radiation tissue responses.", + "TAG_DATA": [ + "42, mouse {'context': 'B-tissue/organ'}", + "43, intestines {'context': 'I-tissue/organ'}", + "46, against {'effect': 'I-negative'}", + "63, activating {'effect': 'B-positive'}", + "66, apoptosis {'phenotype': 'B-apoptosis'}", + "83, Atm(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "84, mice {'context': 'B-organism'}", + "86, crypt {'context': 'B-cells'}", + "87, stem {'context': 'I-cells'}", + "88, cell {'context': 'I-cells'}", + "113, Atm(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "114, mouse, {'context': 'B-organism'}", + "118, stem {'context': 'B-cells'}", + "119, cell {'phenotype': 'B-cell death'}", + "120, death {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "42, mouse ['l0', 'l1', 'l2', 'l3']", + "43, intestines ['l0', 'l4', 'l5', 'l6']", + "46, against ['l1', 'l4', 'l7', 'l8']", + "63, activating ['l2', 'l5', 'l7', 'l9']", + "66, apoptosis ['l3', 'l6', 'l8', 'l9']", + "83, Atm(-/-) ['l10', 'l11', 'l12', 'l13']", + "84, mice ['l10', 'l14', 'l15', 'l16']", + "86, crypt ['l11', 'l14', 'l17', 'l18']", + "87, stem ['l12', 'l15', 'l17', 'l19']", + "88, cell ['l13', 'l16', 'l18', 'l19']", + "113, Atm(-/-) ['l20', 'l21', 'l22', 'l23']", + "114, mouse, ['l20', 'l24', 'l25', 'l26']", + "118, stem ['l21', 'l24', 'l27', 'l28']", + "119, cell ['l22', 'l25', 'l27', 'l29']", + "120, death ['l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "intestines" + ] + }, + "effect": { + "val": "negative", + "words": [ + "against" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "intestines" + ] + }, + "effect": { + "val": "positive", + "words": [ + "activating" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "intestines" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "against" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "activating" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atm(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mouse," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atm(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "crypt", + "stem", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atm(-/-)" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "stem" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + } + ] + }, + { + "PMID": "15558058", + "TEXT": "Patients with diabetes and other obesity-linked conditions have increased susceptibility to cardiovascular disorders. The adipocytokine adiponectin is decreased in patients with obesity-linked diseases. Here, we found that pressure overload in adiponectin-deficient mice resulted in enhanced concentric cardiac hypertrophy and increased mortality that was associated with increased extracellular signal-regulated kinase (ERK) and diminished AMP-activated protein kinase (AMPK) signaling in the myocardium. Adenovirus-mediated supplemention of adiponectin attenuated cardiac hypertrophy in response to pressure overload in adiponectin-deficient, wild-type and diabetic db/db mice. In cultures of cardiac myocytes, adiponectin activated AMPK and inhibited agonist-stimulated hypertrophy and ERK activation. Transduction with a dominant-negative form of AMPK reversed these effects, suggesting that adiponectin inhibits hypertrophic signaling in the myocardium through activation of AMPK signaling. Adiponectin may have utility for the treatment of hypertrophic cardiomyopathy associated with diabetes and other obesity-related diseases.", + "TAG_DATA": [ + "30, adiponectin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "31, mice {'context': 'B-organism'}", + "73, adiponectin-deficient, {'perturbing_action': 'B-gene loss-of-function'}", + "76, diabetic {'context': 'B-organism'}", + "77, db/db {'context': 'I-organism'}", + "78, mice. {'context': 'I-organism'}", + "80, cultures {'context': 'B-in vitro'}", + "82, cardiac {'context': 'B-cells'}", + "83, myocytes, {'context': 'I-cells'}", + "94, Transduction {'perturbing_action': 'B-other'}", + "95, with {'perturbing_action': 'I-other'}", + "96, a {'perturbing_action': 'I-other'}", + "97, dominant-negative {'perturbing_action': 'I-other'}", + "98, form {'perturbing_action': 'I-other'}", + "99, of {'perturbing_action': 'I-other'}", + "100, AMPK {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "30, adiponectin-deficient ['l0']", + "31, mice ['l0']", + "73, adiponectin-deficient, ['l1', 'l2', 'l3', 'l4']", + "76, diabetic ['l1', 'l5', 'l6', 'l7', 'l8', 'l9']", + "77, db/db ['l2', 'l5', 'l10', 'l11', 'l12', 'l13']", + "78, mice. ['l3', 'l6', 'l10', 'l14', 'l15', 'l16']", + "80, cultures ['l7', 'l11', 'l14', 'l17', 'l18']", + "82, cardiac ['l8', 'l12', 'l15', 'l17', 'l19']", + "83, myocytes, ['l4', 'l9', 'l13', 'l16', 'l18', 'l19']", + "94, Transduction ['l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "95, with ['l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "96, a ['l21', 'l26', 'l31', 'l32', 'l33', 'l34']", + "97, dominant-negative ['l22', 'l27', 'l31', 'l35', 'l36', 'l37']", + "98, form ['l23', 'l28', 'l32', 'l35', 'l38', 'l39']", + "99, of ['l24', 'l29', 'l33', 'l36', 'l38', 'l40']", + "100, AMPK ['l25', 'l30', 'l34', 'l37', 'l39', 'l40']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adiponectin-deficient", + "adiponectin-deficient," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "diabetic", + "db/db", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adiponectin-deficient," + ] + }, + "context": { + "val": "cells", + "words": [ + "myocytes," + ] + } + } + ] + }, + { + "PMID": "11984598", + "TEXT": "Human mast cells and basophils that express the high-affinity immunoglobulin E (IgE) receptor, Fc epsilon receptor 1 (Fc epsilon RI), have key roles in allergic diseases. Fc epsilon RI cross-linking stimulates the release of allergic mediators. Mast cells and basophils co-express Fc gamma RIIb, a low affinity receptor containing an immunoreceptor tyrosine-based inhibitory motif and whose co-aggregation with Fc epsilon RI can block Fc epsilon RI-mediated reactivity. Here we designed, expressed and tested the human basophil and mast-cell inhibitory function of a novel chimeric fusion protein, whose structure is gamma Hinge-CH gamma 2-CH gamma 3-15aa linker-CH epsilon 2-CH epsilon 3-CH epsilon 4. This Fc gamma Fc epsilon fusion protein was expressed as the predicted 140-kappa D dimer that reacted with anti-human epsilon- and gamma-chain specific antibodies. Fc gamma Fc epsilon bound to both human Fc epsilon RI and Fc gamma RII. It also showed dose- and time-dependent inhibition of antigen-driven IgE-mediated histamine release from fresh human basophils sensitized with IgE directed against NIP (4-hydroxy-3-iodo-5-nitrophenylacetyl). This was associated with altered Syk signaling. The fusion protein also showed increased inhibition of human anti-NP (4-hydroxy-3-nitrophenylacetyl) and anti-dansyl IgE-mediated passive cutaneous anaphylaxis in transgenic mice expressing human Fc epsilon RI alpha. Our results show that this chimeric protein is able to form complexes with both Fc epsilon RI and Fc gamma RII, and inhibit mast-cell and basophil function. This approach, using a Fc gamma Fc epsilon fusion protein to co-aggregate Fc epsilon RI with a receptor containing an immunoreceptor tyrosine-based inhibition motif, has therapeutic potential in", + "TAG_DATA": [ + "155, human {'context': 'B-cells'}", + "156, basophils {'context': 'I-cells'}", + "189, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "190, mice {'context': 'I-organism'}", + "191, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "192, human {'perturbing_action': 'I-gene gain-of-function'}", + "193, Fc {'perturbing_action': 'I-gene gain-of-function'}", + "194, epsilon {'perturbing_action': 'I-gene gain-of-function'}", + "195, RI {'perturbing_action': 'I-gene gain-of-function'}", + "196, alpha. {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "155, human ['l0']", + "156, basophils ['l0']", + "189, transgenic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "190, mice ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "191, expressing ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "192, human ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "193, Fc ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "194, epsilon ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "195, RI ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "196, alpha. ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "human", + "Fc", + "epsilon", + "RI", + "alpha." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "11017152", + "TEXT": "Systemic sclerosis is an autoimmune disease characterized by immunological and vascular abnormalities. Autoantibodies against intracellular antigens are associated with particular clinical features of the disease, whereas autoantibodies against cell surface antigens may be pathogenic by inducing endothelial cell damage, considered the primary event in the pathogenesis of the disease. Latent human cytomegalovirus infection may contribute to progression of systemic sclerosis through its ability to infect endothelial cells; however, direct links between human cytomegalovirus infection and systemic sclerosis are still lacking. Molecular mimicry is one of the mechanisms that account for the link between infection and autoimmunity. Here we have identified an immunodominant peptide using systemic sclerosis serum screening of a random peptide library; such peptide shares homology with autoantigens and with the human cytomegalovirus late protein UL94 (ref. 9). Immunoglobulin G antibodies against the peptide affinity-purified from the sera of patients with systemic sclerosis specifically recognized the viral product and autoantigens; moreover, such antibodies induced endothelial cell apoptosis through specific interaction with the cell surface integrin-NAG-2 protein complex. Our results provide evidence that antibodies against human cytomegalovirus cause apoptosis of endothelial cells, considered the initial pathogenic event of systemic sclerosis, and indicate a previously unknown mechanism for the etiological link between human cytomegalovirus infection and autoimmunity.", + "TAG_DATA": [ + "154, induced {'effect': 'B-positive'}", + "155, endothelial {'context': 'B-cells'}", + "156, cell {'context': 'I-cells'}", + "157, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "154, induced ['l0', 'l1', 'l2']", + "155, endothelial ['l0', 'l3', 'l4']", + "156, cell ['l1', 'l3', 'l5']", + "157, apoptosis ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "32451499", + "TEXT": "Understanding of the factors governing immune responses in cancer remains incomplete, limiting patient benefit. In this study, we used mass cytometry to define the systemic immune landscape in response to tumor development across five tissues in eight mouse tumor models. Systemic immunity was dramatically altered across models and time, with consistent findings in the peripheral blood of patients with breast cancer. Changes in peripheral tissues differed from those in the tumor microenvironment. Mice with tumor-experienced immune systems mounted dampened responses to orthogonal challenges, including reduced T cell activation during viral or bacterial infection. Antigen-presenting cells (APCs) mounted weaker responses in this context, whereas promoting APC activation rescued T cell activity. Systemic immune changes were reversed with surgical tumor resection, and many were prevented by interleukin-1 or granulocyte colony-stimulating factor blockade, revealing remarkable plasticity in the systemic immune state. These results demonstrate that tumor development dynamically reshapes the composition and function of the immune macroenvironment.", + "TAG_DATA": [ + "72, Mice {'context': 'B-organism'}", + "85, T {'context': 'B-cells'}", + "86, cell {'context': 'B-cells'}", + "93, Antigen-presenting {'context': 'B-cells'}", + "94, cells {'context': 'I-cells'}", + "104, APC {'context': 'B-cells'}", + "107, T {'context': 'B-cells'}", + "108, cell {'context': 'B-cells'}", + "117, tumor {'perturbing_action': 'I-gene loss-of-function'}", + "118, resection, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "72, Mice ['l0', 'l1', 'l2', 'l3']", + "85, T ['l0', 'l4']", + "86, cell ['l1', 'l4']", + "93, Antigen-presenting ['l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "94, cells ['l2', 'l5', 'l11', 'l12', 'l13', 'l14']", + "104, APC ['l6', 'l11', 'l15', 'l16', 'l17', 'l18']", + "107, T ['l7', 'l12', 'l15', 'l19', 'l20']", + "108, cell ['l3', 'l8', 'l13', 'l16', 'l19']", + "117, tumor ['l9', 'l17', 'l21']", + "118, resection, ['l10', 'l14', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Antigen-presenting", + "cells", + "APC", + "T" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "tumor", + "resection," + ] + } + } + ] + }, + { + "PMID": "31806906", + "TEXT": "Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is typically sporadic. Inborn errors of TLR3- and DBR1-mediated central nervous system cell-intrinsic immunity can account for forebrain and brainstem HSE, respectively. We report five unrelated patients with forebrain HSE, each heterozygous for one of four rare variants of SNORA31, encoding a small nucleolar RNA of the H/ACA class that are predicted to direct the isomerization of uridine residues to pseudouridine in small nuclear RNA and ribosomal RNA. We show that CRISPR/Cas9-introduced bi- and monoallelic SNORA31 deletions render human pluripotent stem cell (hPSC)-derived cortical neurons susceptible to HSV-1. Accordingly, SNORA31-mutated patient hPSC-derived cortical neurons are susceptible to HSV-1, like those from TLR3- or STAT1-deficient patients. Exogenous interferon (IFN)-β renders SNORA31- and TLR3- but not STAT1-mutated neurons resistant to HSV-1. Finally, transcriptome analysis of SNORA31-mutated neurons revealed normal responses to TLR3 and IFN-α/β stimulation but abnormal responses to HSV-1. Human SNORA31 thus controls central nervous system neuron-intrinsic immunity to HSV-1 by a distinctive mechanism.", + "TAG_DATA": [ + "77, CRISPR/Cas9-introduced {'perturbing_action': 'B-gene loss-of-function'}", + "80, monoallelic {'perturbing_action': 'I-gene loss-of-function'}", + "81, SNORA31 {'perturbing_action': 'I-gene loss-of-function'}", + "82, deletions {'perturbing_action': 'I-gene loss-of-function'}", + "84, human {'context': 'B-cells'}", + "85, pluripotent {'context': 'I-cells'}", + "86, stem {'context': 'I-cells'}", + "87, cell {'context': 'I-cells'}", + "88, (hPSC)-derived {'context': 'I-cells'}", + "89, cortical {'context': 'I-cells'}", + "90, neurons {'context': 'I-cells'}", + "95, SNORA31-mutated {'perturbing_action': 'B-other'}", + "96, patient {'context': 'B-cells'}", + "97, hPSC-derived {'context': 'I-cells'}", + "98, cortical {'context': 'I-cells'}", + "99, neurons {'context': 'I-cells'}", + "107, TLR3- {'perturbing_action': 'B-gene loss-of-function'}", + "108, or {'perturbing_action': 'I-gene loss-of-function'}", + "109, STAT1-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "121, neurons {'context': 'B-cells'}", + "129, SNORA31-mutated {'perturbing_action': 'B-other'}", + "130, neurons {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "77, CRISPR/Cas9-introduced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "80, monoallelic ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "81, SNORA31 ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "82, deletions ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "84, human ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "85, pluripotent ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "86, stem ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "87, cell ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l53', 'l59', 'l60', 'l61', 'l62', 'l63']", + "88, (hPSC)-derived ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l54', 'l59', 'l64', 'l65', 'l66', 'l67']", + "89, cortical ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l55', 'l60', 'l64', 'l68']", + "90, neurons ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l56', 'l61', 'l65', 'l68']", + "95, SNORA31-mutated ['l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "96, patient ['l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "97, hPSC-derived ['l50', 'l70', 'l77', 'l83', 'l84', 'l85', 'l86', 'l87']", + "98, cortical ['l51', 'l57', 'l62', 'l66', 'l71', 'l78', 'l83', 'l88', 'l89', 'l90', 'l91']", + "99, neurons ['l10', 'l20', 'l29', 'l37', 'l44', 'l52', 'l58', 'l63', 'l67', 'l72', 'l79', 'l84', 'l88', 'l92', 'l93', 'l94']", + "107, TLR3- ['l73', 'l80', 'l85', 'l89', 'l92', 'l95', 'l96', 'l97']", + "108, or ['l74', 'l81', 'l86', 'l90', 'l93', 'l95', 'l98', 'l99']", + "109, STAT1-deficient ['l75', 'l82', 'l87', 'l91', 'l94', 'l96', 'l98', 'l100']", + "121, neurons ['l76', 'l97', 'l99', 'l100']", + "129, SNORA31-mutated ['l101']", + "130, neurons ['l101']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CRISPR/Cas9-introduced", + "monoallelic", + "SNORA31", + "deletions", + "TLR3-", + "or", + "STAT1-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "pluripotent", + "stem", + "cell", + "(hPSC)-derived", + "cortical", + "neurons", + "patient", + "hPSC-derived" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "SNORA31-mutated" + ] + }, + "context": { + "val": "cells", + "words": [ + "patient", + "hPSC-derived", + "cortical", + "neurons" + ] + } + } + ] + }, + { + "PMID": "31700183", + "TEXT": "Type 2 diabetes is characterized by insulin resistance and a gradual loss of pancreatic beta cell mass and function1,2. Currently, there are no therapies proven to prevent beta cell loss and some, namely insulin secretagogues, have been linked to accelerated beta cell failure, thereby limiting their use in type 2 diabetes3,4. The adipokine adipsin/complement factor D controls the alternative complement pathway and generation of complement component C3a, which acts to augment beta cell insulin secretion5. In contrast to other insulin secretagogues, we show that chronic replenishment of adipsin in diabetic db/db mice ameliorates hyperglycemia and increases insulin levels while preserving beta cells by blocking dedifferentiation and death. Mechanistically, we find that adipsin/C3a decreases the phosphatase Dusp26; forced expression of Dusp26 in beta cells decreases expression of core beta cell identity genes and sensitizes to cell death. In contrast, pharmacological inhibition of DUSP26 improves hyperglycemia in diabetic mice and protects human islet cells from cell death. Pertaining to human health, we show that higher concentrations of circulating adipsin are associated with a significantly lower risk of developing future diabetes among middle-aged adults after adjusting for body mass index (BMI). Collectively, these data suggest that adipsin/C3a and DUSP26-directed therapies may represent a novel approach to achieve beta cell health to treat and prevent type 2 diabetes.", + "TAG_DATA": [ + "89, diabetic {'context': 'B-organism'}", + "90, db/db {'context': 'I-organism'}", + "91, mice {'context': 'I-organism'}", + "100, beta {'context': 'B-cells'}", + "101, cells {'context': 'I-cells'}", + "103, blocking {'effect': 'B-negative'}", + "104, dedifferentiation {'phenotype': 'B-differentiation'}", + "116, forced {'perturbing_action': 'B-gene gain-of-function'}", + "117, expression {'perturbing_action': 'I-gene gain-of-function'}", + "118, of {'perturbing_action': 'I-gene gain-of-function'}", + "119, Dusp26 {'perturbing_action': 'I-gene gain-of-function'}", + "121, beta {'context': 'B-cells'}", + "122, cells {'context': 'I-cells'}", + "132, sensitizes {'effect': 'B-positive'}", + "134, cell {'phenotype': 'B-cell death'}", + "135, death. {'phenotype': 'I-cell death'}", + "138, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "139, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "140, of {'perturbing_action': 'I-pharmacological inhibition'}", + "141, DUSP26 {'perturbing_action': 'I-pharmacological inhibition'}", + "145, diabetic {'context': 'B-organism'}", + "146, mice {'context': 'I-organism'}", + "148, protects {'effect': 'B-negative'}", + "149, human {'context': 'B-cells'}", + "150, islet {'context': 'I-cells'}", + "151, cells {'context': 'I-cells'}", + "153, cell {'phenotype': 'B-cell death'}", + "154, death. {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "89, diabetic ['l0', 'l1', 'l2', 'l3', 'l4']", + "90, db/db ['l0', 'l5', 'l6', 'l7', 'l8', 'l9']", + "91, mice ['l1', 'l5', 'l10', 'l11']", + "100, beta ['l2', 'l6', 'l10', 'l12', 'l13', 'l14']", + "101, cells ['l3', 'l7', 'l11', 'l12', 'l15']", + "103, blocking ['l4', 'l8', 'l13', 'l15', 'l16', 'l17']", + "104, dedifferentiation ['l9', 'l14', 'l16', 'l18', 'l19', 'l20', 'l21']", + "116, forced ['l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "117, expression ['l22', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "118, of ['l23', 'l35', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "119, Dusp26 ['l24', 'l36', 'l46', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "121, beta ['l25', 'l37', 'l47', 'l56', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "122, cells ['l18', 'l26', 'l38', 'l48', 'l57', 'l65', 'l71', 'l72', 'l73', 'l74', 'l75']", + "132, sensitizes ['l19', 'l27', 'l39', 'l49', 'l58', 'l66', 'l71', 'l76', 'l77', 'l78', 'l79']", + "134, cell ['l20', 'l28', 'l40', 'l50', 'l59', 'l67', 'l72', 'l76', 'l80', 'l81']", + "135, death. ['l17', 'l21', 'l29', 'l41', 'l51', 'l60', 'l68', 'l73', 'l77', 'l80']", + "138, pharmacological ['l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "139, inhibition ['l82', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "140, of ['l83', 'l93', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "141, DUSP26 ['l84', 'l94', 'l103', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "145, diabetic ['l30', 'l42', 'l52', 'l61', 'l69', 'l74', 'l78', 'l85', 'l95', 'l104', 'l112', 'l120', 'l121', 'l122', 'l123', 'l124']", + "146, mice ['l31', 'l43', 'l53', 'l62', 'l70', 'l75', 'l79', 'l81', 'l86', 'l96', 'l105', 'l113', 'l120']", + "148, protects ['l32', 'l44', 'l54', 'l63', 'l87', 'l97', 'l106', 'l114', 'l121', 'l125', 'l126', 'l127', 'l128', 'l129']", + "149, human ['l88', 'l98', 'l107', 'l115', 'l125', 'l130', 'l131', 'l132', 'l133']", + "150, islet ['l33', 'l89', 'l99', 'l108', 'l116', 'l122', 'l126', 'l130', 'l134', 'l135', 'l136']", + "151, cells ['l34', 'l45', 'l55', 'l64', 'l90', 'l100', 'l109', 'l117', 'l123', 'l127', 'l131', 'l134', 'l137', 'l138']", + "153, cell ['l91', 'l101', 'l110', 'l118', 'l128', 'l132', 'l135', 'l137', 'l139']", + "154, death. ['l92', 'l102', 'l111', 'l119', 'l124', 'l129', 'l133', 'l136', 'l138', 'l139']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "diabetic", + "db/db" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocking", + "protects" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "db/db" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "dedifferentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "beta", + "cells", + "human", + "islet" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocking", + "protects" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "beta", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "dedifferentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocking" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "dedifferentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocking", + "protects" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "death.", + "cell" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "dedifferentiation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitizes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "forced", + "expression", + "of", + "Dusp26" + ] + }, + "context": { + "val": "cells", + "words": [ + "beta", + "cells", + "islet" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "forced", + "expression", + "of", + "Dusp26" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitizes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "forced", + "expression", + "of", + "Dusp26" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "forced", + "expression", + "of", + "Dusp26" + ] + }, + "context": { + "val": "organism", + "words": [ + "diabetic", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "forced", + "expression", + "of", + "Dusp26" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protects" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "beta", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitizes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "beta", + "cells", + "human", + "islet" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitizes" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitizes" + ] + }, + "context": { + "val": "organism", + "words": [ + "diabetic", + "mice" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "diabetic" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "DUSP26" + ] + }, + "context": { + "val": "organism", + "words": [ + "diabetic", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "DUSP26" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protects" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "DUSP26" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "islet", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "DUSP26" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "31591597", + "TEXT": "Rectal cancer (RC) is a challenging disease to treat that requires chemotherapy, radiation and surgery to optimize outcomes for individual patients. No accurate model of RC exists to answer fundamental research questions relevant to patients. We established a biorepository of 65 patient-derived RC organoid cultures (tumoroids) from patients with primary, metastatic or recurrent disease. RC tumoroids retained molecular features of the tumors from which they were derived, and their ex vivo responses to clinically relevant chemotherapy and radiation treatment correlated with the clinical responses noted in individual patients' tumors. Upon engraftment into murine rectal mucosa, human RC tumoroids gave rise to invasive RC followed by metastasis to lung and liver. Importantly, engrafted tumors displayed the heterogenous sensitivity to chemotherapy observed clinically. Thus, the biology and drug sensitivity of RC clinical isolates can be efficiently interrogated using an organoid-based, ex vivo platform coupled with in vivo endoluminal propagation in animals.", + "TAG_DATA": [ + "92, murine {'context': 'B-tissue/organ'}", + "93, rectal {'context': 'I-tissue/organ'}", + "94, mucosa, {'context': 'I-tissue/organ'}", + "95, human {'context': 'B-organoid'}", + "96, RC {'context': 'I-organoid'}", + "97, tumoroids {'context': 'I-organoid'}", + "98, gave {'effect': 'B-positive'}", + "99, rise {'effect': 'I-positive'}", + "105, metastasis {'phenotype': 'B-metastasis'}", + "106, to {'phenotype': 'I-metastasis'}", + "107, lung {'phenotype': 'I-metastasis'}", + "108, and {'phenotype': 'I-metastasis'}", + "109, liver. {'phenotype': 'I-metastasis'}", + "112, tumors {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "92, murine ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "93, rectal ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "94, mucosa, ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "95, human ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "96, RC ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "97, tumoroids ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "98, gave ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "99, rise ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "103, followed ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "105, metastasis ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "106, to ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "107, lung ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "108, and ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "109, liver. ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "murine", + "rectal", + "mucosa," + ] + }, + "effect": { + "val": "positive", + "words": [ + "gave", + "rise" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "murine", + "rectal", + "mucosa," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "to", + "lung", + "and", + "liver." + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "human", + "RC", + "tumoroids" + ] + }, + "effect": { + "val": "positive", + "words": [ + "gave", + "rise" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "human", + "RC", + "tumoroids" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "to", + "lung", + "and", + "liver." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "gave", + "rise" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "to", + "lung", + "and", + "liver." + ] + } + } + ] + }, + { + "PMID": "31591592", + "TEXT": "The increasing availability of large healthcare databases is fueling an intense debate on whether real-world data should play a role in the assessment of the benefit-risk of medical treatments. In many observational studies, for example, statin users were found to have a substantially lower risk of cancer than in meta-analyses of randomized trials. Although such discrepancies are often attributed to a lack of randomization in the observational studies, they might be explained by flaws that can be avoided by explicitly emulating a target trial (the randomized trial that would answer the question of interest). Using the electronic health records of 733,804 UK adults, we emulated a target trial of statins and cancer and compared our estimates with those obtained using previously applied analytic approaches. Over the 10-yr follow-up, 28,408 individuals developed cancer. Under the target trial approach, estimated observational analogs of intention-to-treat and per-protocol 10-yr cancer-free survival differences were -0.5% (95% confidence interval (CI) -1.0%, 0.0%) and -0.3% (95% CI -1.5%, 0.5%), respectively. By contrast, previous analytic approaches yielded estimates that appeared to be strongly protective. Our findings highlight the importance of explicitly emulating a target trial to reduce bias in the effect estimates derived from observational analyses.", + "TAG_DATA": [ + "102, adults, {'context': 'I-organism'}", + "131, cancer. {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}" + ], + "LINK_DATA": [ + "101, UK ['l0', 'l1', 'l2']", + "102, adults, ['l0', 'l3']", + "130, developed ['l1', 'l4']", + "131, cancer. ['l2', 'l3', 'l4']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "cancer." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "cancer." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "adults," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "cancer." + ] + } + } + ] + }, + { + "PMID": "31270502", + "TEXT": "Bladder cancer is lethal in its advanced, muscle-invasive phase with very limited therapeutic advances1,2. Recent molecular characterization has defined new (epi)genetic drivers and potential targets for bladder cancer3,4. The immune checkpoint inhibitors have shown remarkable efficacy but only in a limited fraction of bladder cancer patients5-8. Here, we show that high G9a (EHMT2) expression is associated with poor clinical outcome in bladder cancer and that targeting G9a/DNMT methyltransferase activity with a novel inhibitor (CM-272) induces apoptosis and immunogenic cell death. Using an immunocompetent quadruple-knockout (PtenloxP/loxP; Trp53loxP/loxP; Rb1loxP/loxP; Rbl1-/-) transgenic mouse model of aggressive metastatic, muscle-invasive bladder cancer, we demonstrate that CM-272 + cisplatin treatment results in statistically significant regression of established tumors and metastases. The antitumor effect is significantly improved when CM-272 is combined with anti-programmed cell death ligand 1, even in the absence of cisplatin. These effects are associated with an endogenous antitumor immune response and immunogenic cell death with the conversion of a cold immune tumor into a hot tumor. Finally, increased G9a expression was associated with resistance to programmed cell death protein 1 inhibition in a cohort of patients with bladder cancer. In summary, these findings support new and promising opportunities for the treatment of bladder cancer using a combination of epigenetic inhibitors and immune checkpoint blockade.", + "TAG_DATA": [ + "74, induces {'effect': 'B-positive'}", + "75, apoptosis {'phenotype': 'B-apoptosis'}", + "78, cell {'phenotype': 'B-cell death'}", + "79, death. {'phenotype': 'I-cell death'}", + "82, immunocompetent {'perturbing_action': 'B-gene loss-of-function'}", + "83, quadruple-knockout {'perturbing_action': 'I-gene loss-of-function'}", + "84, (PtenloxP/loxP; {'perturbing_action': 'I-gene loss-of-function'}", + "85, Trp53loxP/loxP; {'perturbing_action': 'I-gene loss-of-function'}", + "86, Rb1loxP/loxP; {'perturbing_action': 'I-gene loss-of-function'}", + "87, Rbl1-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "88, transgenic {'perturbing_action': 'I-gene loss-of-function'}", + "89, mouse {'context': 'B-organism'}", + "90, model {'context': 'I-neoplasm'}", + "92, aggressive {'context': 'B-neoplasm'}", + "93, metastatic, {'context': 'I-neoplasm'}", + "94, muscle-invasive {'context': 'I-neoplasm'}", + "95, bladder {'context': 'I-neoplasm'}", + "96, cancer, {'context': 'I-neoplasm'}", + "102, results {'effect': 'B-positive'}", + "103, in {'effect': 'I-positive'}", + "106, regression {'phenotype': 'B-tumour regression'}", + "109, tumors {'context': 'B-neoplasm'}", + "111, metastases. {'phenotype': 'B-metastasis'}", + "147, death {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "74, induces ['l0', 'l1', 'l2']", + "75, apoptosis ['l0', 'l3', 'l4']", + "78, cell ['l1', 'l3', 'l5']", + "79, death. ['l2', 'l4', 'l5']", + "82, immunocompetent ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "83, quadruple-knockout ['l6', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "84, (PtenloxP/loxP; ['l7', 'l24', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "85, Trp53loxP/loxP; ['l8', 'l25', 'l42', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "86, Rb1loxP/loxP; ['l9', 'l26', 'l43', 'l59', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "87, Rbl1-/-) ['l10', 'l27', 'l44', 'l60', 'l75', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "88, transgenic ['l11', 'l28', 'l45', 'l61', 'l76', 'l90', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "89, mouse ['l12', 'l29', 'l46', 'l62', 'l77', 'l91', 'l104', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "90, model ['l13', 'l30', 'l47', 'l63', 'l78', 'l92', 'l105', 'l117', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "91, of ['l14', 'l31', 'l48', 'l64', 'l79', 'l93', 'l106', 'l118', 'l127', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "92, aggressive ['l15', 'l32', 'l49', 'l65', 'l80', 'l94', 'l107', 'l119', 'l128', 'l136', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150']", + "93, metastatic, ['l16', 'l33', 'l50', 'l66', 'l81', 'l95', 'l108', 'l120', 'l129', 'l137', 'l144', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156']", + "94, muscle-invasive ['l17', 'l34', 'l51', 'l67', 'l82', 'l96', 'l109', 'l121', 'l130', 'l138', 'l145', 'l151', 'l157', 'l158', 'l159', 'l160', 'l161']", + "95, bladder ['l18', 'l35', 'l52', 'l68', 'l83', 'l97', 'l110', 'l122', 'l131', 'l139', 'l146', 'l152', 'l157', 'l162', 'l163', 'l164', 'l165']", + "96, cancer, ['l19', 'l36', 'l53', 'l69', 'l84', 'l98', 'l111', 'l123', 'l132', 'l140', 'l147', 'l153', 'l158', 'l162']", + "102, results ['l20', 'l37', 'l54', 'l70', 'l85', 'l99', 'l112', 'l124', 'l133', 'l141', 'l148', 'l154', 'l159', 'l163', 'l166', 'l167', 'l168', 'l169']", + "103, in ['l21', 'l38', 'l55', 'l71', 'l86', 'l100', 'l113', 'l125', 'l134', 'l142', 'l149', 'l155', 'l160', 'l164', 'l166', 'l170', 'l171', 'l172']", + "106, regression ['l22', 'l39', 'l56', 'l72', 'l87', 'l101', 'l114', 'l167', 'l170', 'l173', 'l174']", + "109, tumors ['l23', 'l40', 'l57', 'l73', 'l88', 'l102', 'l115', 'l126', 'l135', 'l143', 'l150', 'l156', 'l161', 'l165', 'l168', 'l171', 'l173', 'l175']", + "111, metastases. ['l41', 'l58', 'l74', 'l89', 'l103', 'l116', 'l169', 'l172', 'l174', 'l175']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immunocompetent", + "quadruple-knockout", + "(PtenloxP/loxP;", + "Trp53loxP/loxP;", + "Rb1loxP/loxP;", + "Rbl1-/-)", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immunocompetent", + "quadruple-knockout", + "(PtenloxP/loxP;", + "Trp53loxP/loxP;", + "Rb1loxP/loxP;", + "Rbl1-/-)", + "transgenic" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "model", + "aggressive", + "metastatic,", + "muscle-invasive", + "bladder", + "cancer,", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immunocompetent", + "quadruple-knockout", + "(PtenloxP/loxP;", + "Trp53loxP/loxP;", + "Rb1loxP/loxP;", + "Rbl1-/-)", + "transgenic" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immunocompetent", + "quadruple-knockout", + "(PtenloxP/loxP;", + "Trp53loxP/loxP;", + "Rb1loxP/loxP;", + "Rbl1-/-)", + "transgenic" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "quadruple-knockout", + "(PtenloxP/loxP;", + "Trp53loxP/loxP;", + "Rb1loxP/loxP;", + "Rbl1-/-)", + "transgenic" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "model", + "aggressive", + "metastatic,", + "muscle-invasive", + "bladder", + "tumors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases." + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases." + ] + } + } + ] + }, + { + "PMID": "31171878", + "TEXT": "Blocking programmed death 1 (PD-1) may enhance the durability of anti-tumor responses that are induced by the combined inhibition of BRAF and MEK1. Here we performed a randomized phase 2 trial ( NCT02130466 ), in which patients with treatment-naive BRAFV600E/K-mutant, advanced melanoma received the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib together with the PD-1-blocking antibody pembrolizumab (triplet; n = 60) or placebo (doublet; n = 60). The primary end point of progression-free survival was numerically improved in the triplet group-16.0 months-compared with 10.3 months in the doublet group (hazard ratio, 0.66; P = 0.043); however, the trial did not reach the planned benefit for a statistically significant improvement. Median duration of response was 18.7 months (95% confidence interval, 10.1-22.1) and 12.5 months (95% confidence interval, 6.0-14.1); 59.8 and 27.8% of responses were estimated to have lasted for more than 18 months for triplet and doublet treatment, respectively. Grade 3-5 treatment-related adverse events occurred in 58.3 and 26.7% of patients treated with triplet and doublet therapies, respectively, which were most commonly fever, increased transaminase levels and rash. One patient who received triplet therapy died of pneumonitis. In summary, triplet therapy with dabrafenib, trametinib and pembrolizumab conferred numerically longer progression-free survival and duration of response with a higher rate of grade 3/4 adverse events compared with the doublet therapy of dabrafenib, trametinib and placebo.", + "TAG_DATA": [ + "36, patients {'context': 'B-patient'}", + "39, BRAFV600E/K-mutant, {'perturbing_action': 'B-other'}", + "40, advanced {'context': 'I-neoplasm'}", + "41, melanoma {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "36, patients ['l0', 'l1', 'l2']", + "39, BRAFV600E/K-mutant, ['l0', 'l3', 'l4']", + "40, advanced ['l1', 'l3', 'l5']", + "41, melanoma ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "BRAFV600E/K-mutant," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BRAFV600E/K-mutant," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "advanced", + "melanoma" + ] + } + } + ] + }, + { + "PMID": "31011207", + "TEXT": "Anti-CD19 chimeric antigen receptor (CAR) T cell therapies can cause severe cytokine-release syndrome (CRS) and neurotoxicity, impeding their therapeutic application. Here we generated a new anti-CD19 CAR molecule (CD19-BBz(86)) derived from the CD19-BBz prototype bearing co-stimulatory 4-1BB and CD3ζ domains. We found that CD19-BBz(86) CAR T cells produced lower levels of cytokines, expressed higher levels of antiapoptotic molecules and proliferated more slowly than the prototype CD19-BBz CAR T cells, although they retained potent cytolytic activity. We performed a phase 1 trial of CD19-BBz(86) CAR T cell therapy in patients with B cell lymphoma (ClinicalTrials.gov identifier NCT02842138 ). Complete remission occurred in 6 of 11 patients (54.5%) who each received a dose of 2 × 108-4 × 108 CD19-BBz(86) CAR T cells. Notably, no neurological toxicity or CRS (greater than grade 1) occurred in any of the 25 patients treated. No significant elevation in serum cytokine levels after CAR T cell infusion was detected in the patients treated, including in those who achieved complete remission. CD19-BBz(86) CAR T cells persistently proliferated and differentiated into memory cells in vivo. Thus, therapy with the new CD19-BBz(86) CAR T cells produces a potent and durable antilymphoma response without causing neurotoxicity or severe CRS, representing a safe and potent anti-CD19 CAR T cell therapy.", + "TAG_DATA": [ + "59, proliferated {'phenotype': 'B-proliferation'}", + "88, patients {'context': 'B-patient'}", + "90, B {'context': 'B-neoplasm'}", + "91, cell {'context': 'I-neoplasm'}", + "92, lymphoma {'context': 'I-neoplasm'}", + "162, T {'context': 'I-cells'}", + "163, cells {'context': 'I-cells'}", + "165, proliferated {'phenotype': 'B-proliferation'}", + "167, differentiated {'phenotype': 'B-differentiation'}", + "169, memory {'context': 'B-cells', 'phenotype': 'B-differentiation'}", + "170, cells {'context': 'I-cells'}", + "171, in {'context': 'B-in vivo'}", + "172, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "88, patients ['l0', 'l1', 'l2']", + "90, B ['l0', 'l3', 'l4']", + "91, cell ['l1', 'l3', 'l5']", + "92, lymphoma ['l2', 'l4', 'l5']", + "162, T ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "163, cells ['l6', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "165, proliferated ['l7', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "167, differentiated ['l8', 'l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "169, memory ['l9', 'l15', 'l20', 'l24', 'l28', 'l29', 'l30']", + "170, cells ['l10', 'l16', 'l21', 'l25', 'l28', 'l31', 'l32']", + "171, in ['l11', 'l17', 'l22', 'l26', 'l29', 'l31', 'l33']", + "172, vivo. ['l12', 'l18', 'l23', 'l27', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "memory" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferated" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "memory" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiated", + "memory" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferated" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiated", + "memory" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "30833750", + "TEXT": "Overexpression of the B7-H1 (PD-L1) molecule in the tumor microenvironment (TME) is a major immune evasion mechanism in some patients with cancer, and antibody blockade of the B7-H1/PD-1 interaction can normalize compromised immunity without excessive side-effects. Using a genome-scale T cell activity array, we identified Siglec-15 as a critical immune suppressor. While only expressed on some myeloid cells normally, Siglec-15 is broadly upregulated on human cancer cells and tumor-infiltrating myeloid cells, and its expression is mutually exclusive to B7-H1, partially due to its induction by macrophage colony-stimulating factor and downregulation by IFN-γ. We demonstrate that Siglec-15 suppresses antigen-specific T cell responses in vitro and in vivo. Genetic ablation or antibody blockade of Siglec-15 amplifies anti-tumor immunity in the TME and inhibits tumor growth in some mouse models. Taken together, our results support Siglec-15 as a potential target for normalization cancer immunotherapy.", + "TAG_DATA": [ + "98, T {'context': 'B-cells'}", + "99, cell {'context': 'I-cells'}", + "101, in {'context': 'B-in vitro'}", + "102, vitro {'context': 'I-in vitro'}", + "104, in {'context': 'B-in vivo'}", + "105, vivo. {'context': 'I-in vivo'}", + "109, antibody {'perturbing_action': 'B-pharmacological inhibition'}", + "110, blockade {'perturbing_action': 'I-pharmacological inhibition'}", + "111, of {'perturbing_action': 'I-rnai/knockdown'}", + "112, Siglec-15 {'perturbing_action': 'I-rnai/knockdown'}", + "120, inhibits {'effect': 'B-negative'}", + "121, tumor {'phenotype': 'B-tumour growth'}", + "122, growth {'phenotype': 'I-tumour growth'}", + "125, mouse {'context': 'B-organism'}", + "126, models. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "98, T ['l0', 'l1', 'l2', 'l3', 'l4']", + "99, cell ['l0', 'l5', 'l6', 'l7']", + "101, in ['l1', 'l5', 'l8', 'l9', 'l10']", + "102, vitro ['l2', 'l6', 'l8', 'l11', 'l12']", + "104, in ['l3', 'l9', 'l11', 'l13']", + "105, vivo. ['l4', 'l7', 'l10', 'l12', 'l13']", + "109, antibody ['l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "110, blockade ['l14', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "111, of ['l15', 'l22', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "112, Siglec-15 ['l16', 'l23', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "120, inhibits ['l17', 'l24', 'l30', 'l35', 'l40', 'l41', 'l42', 'l43']", + "121, tumor ['l18', 'l25', 'l31', 'l36', 'l40', 'l44', 'l45', 'l46']", + "122, growth ['l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l47', 'l48']", + "125, mouse ['l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l49']", + "126, models. ['l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l49']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antibody", + "blockade" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antibody", + "blockade" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antibody", + "blockade" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "Siglec-15" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "Siglec-15" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "Siglec-15" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + } + ] + }, + { + "PMID": "30670876", + "TEXT": "In the version of this article originally published, the figure callout in this sentence was incorrect: \"Furthermore, in S1P1-KI mice themselves, whereas PD-1 blockade was ineffectual as monotherapy, the effects of 4-1BB agonism and checkpoint blockade proved additive, with the combination prolonging median survival and producing a 50% long-term survival rate (Fig. 6f).\" The callout should have been to Supplementary Fig. 6b. The error has been corrected in the PDF and HTML versions of the article.", + "TAG_DATA": [ + "18, S1P1-KI {'perturbing_action': 'B-pharmacological inhibition'}", + "19, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "18, S1P1-KI ['l0']", + "19, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "S1P1-KI" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "30664779", + "TEXT": "Chordoma is a primary bone cancer with no approved therapy1. The identification of therapeutic targets in this disease has been challenging due to the infrequent occurrence of clinically actionable somatic mutations in chordoma tumors2,3. Here we describe the discovery of therapeutically targetable chordoma dependencies via genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling. These systematic approaches reveal that the developmental transcription factor T (brachyury; TBXT) is the top selectively essential gene in chordoma, and that transcriptional cyclin-dependent kinase (CDK) inhibitors targeting CDK7/12/13 and CDK9 potently suppress chordoma cell proliferation. In other cancer types, transcriptional CDK inhibitors have been observed to downregulate highly expressed, enhancer-associated oncogenic transcription factors4,5. In chordoma, we find that T is associated with a 1.5-Mb region containing 'super-enhancers' and is the most highly expressed super-enhancer-associated transcription factor. Notably, transcriptional CDK inhibition leads to preferential and concentration-dependent downregulation of cellular brachyury protein levels in all models tested. In vivo, CDK7/12/13-inhibitor treatment substantially reduces tumor growth. Together, these data demonstrate small-molecule targeting of brachyury transcription factor addiction in chordoma, identify a mechanism of T gene regulation that underlies this therapeutic strategy, and provide a blueprint for applying systematic genetic and chemical screening approaches to discover vulnerabilities in genomically quiet cancers.", + "TAG_DATA": [ + "75, transcriptional {'perturbing_action': 'B-pharmacological inhibition'}", + "76, cyclin-dependent {'perturbing_action': 'I-pharmacological inhibition'}", + "77, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "78, (CDK) {'perturbing_action': 'I-pharmacological inhibition'}", + "79, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "80, targeting {'perturbing_action': 'I-pharmacological inhibition'}", + "81, CDK7/12/13 {'perturbing_action': 'I-pharmacological inhibition'}", + "82, and {'perturbing_action': 'I-pharmacological inhibition'}", + "83, CDK9 {'perturbing_action': 'I-pharmacological inhibition'}", + "85, suppress {'effect': 'B-negative'}", + "86, chordoma {'context': 'B-transformed cells'}", + "87, cell {'context': 'I-transformed cells'}", + "88, proliferation. {'phenotype': 'B-proliferation'}", + "131, transcriptional {'perturbing_action': 'B-pharmacological inhibition'}", + "132, CDK {'perturbing_action': 'I-pharmacological inhibition'}", + "133, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "149, In {'context': 'B-in vivo'}", + "150, vivo, {'context': 'I-in vivo'}", + "151, CDK7/12/13-inhibitor {'perturbing_action': 'B-pharmacological inhibition'}", + "152, treatment {'perturbing_action': 'I-pharmacological inhibition'}", + "154, reduces {'effect': 'B-negative'}", + "155, tumor {'phenotype': 'B-tumour growth'}", + "156, growth. {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "75, transcriptional ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "76, cyclin-dependent ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "77, kinase ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "78, (CDK) ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "79, inhibitors ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "80, targeting ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "81, CDK7/12/13 ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "82, and ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "83, CDK9 ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "85, suppress ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "86, chordoma ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "87, cell ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "88, proliferation. ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "95, inhibitors ['l78', 'l79', 'l80']", + "131, transcriptional ['l78', 'l81', 'l82']", + "132, CDK ['l79', 'l81', 'l83']", + "133, inhibition ['l80', 'l82', 'l83']", + "149, In ['l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "150, vivo, ['l84', 'l90', 'l91', 'l92', 'l93', 'l94']", + "151, CDK7/12/13-inhibitor ['l85', 'l90', 'l95', 'l96', 'l97', 'l98']", + "152, treatment ['l86', 'l91', 'l95', 'l99', 'l100', 'l101']", + "154, reduces ['l87', 'l92', 'l96', 'l99', 'l102', 'l103']", + "155, tumor ['l88', 'l93', 'l97', 'l100', 'l102', 'l104']", + "156, growth. ['l89', 'l94', 'l98', 'l101', 'l103', 'l104']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "transcriptional", + "cyclin-dependent", + "kinase", + "(CDK)", + "inhibitors", + "targeting", + "CDK7/12/13", + "and", + "CDK9", + "CDK7/12/13-inhibitor", + "treatment" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppress", + "reduces" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "transcriptional", + "cyclin-dependent", + "kinase", + "(CDK)", + "inhibitors", + "targeting", + "CDK7/12/13", + "and", + "CDK9" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "chordoma", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "transcriptional", + "cyclin-dependent", + "kinase", + "(CDK)", + "inhibitors", + "targeting", + "CDK7/12/13", + "and", + "CDK9" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppress" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "chordoma", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppress" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "chordoma", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK7/12/13-inhibitor", + "treatment" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK7/12/13-inhibitor", + "treatment" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + } + ] + }, + { + "PMID": "30643286", + "TEXT": "Cancer cells develop mechanisms to escape immunosurveillance, among which modulating the expression of immune suppressive messenger RNAs is most well-documented. However, how this is molecularly achieved remains largely unresolved. Here, we develop an in vivo mouse model of liver cancer to study oncogene cooperation in immunosurveillance. We show that MYC overexpression (MYCTg) synergizes with KRASG12D to induce an aggressive liver tumor leading to metastasis formation and reduced mouse survival compared with KRASG12D alone. Genome-wide ribosomal footprinting of MYCTg;KRASG12 tumors compared with KRASG12D revealed potential alterations in translation of mRNAs, including programmed-death-ligand 1 (PD-L1). Further analysis revealed that PD-L1 translation is repressed in KRASG12D tumors by functional, non-canonical upstream open reading frames in its 5' untranslated region, which is bypassed in MYCTg;KRASG12D tumors to evade immune attack. We show that this mechanism of PD-L1 translational upregulation was effectively targeted by a potent, clinical compound that inhibits eIF4E phosphorylation, eFT508, which reverses the aggressive and metastatic characteristics of MYCTg;KRASG12D tumors. Together, these studies reveal how immune-checkpoint proteins are manipulated by distinct oncogenes at the level of mRNA translation, which can be exploited for new immunotherapies.", + "TAG_DATA": [ + "49, MYC {'perturbing_action': 'B-gene gain-of-function'}", + "50, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "51, (MYCTg) {'perturbing_action': 'I-gene gain-of-function'}", + "56, induce {'effect': 'B-positive'}", + "59, liver {'context': 'B-neoplasm'}", + "60, tumor {'context': 'I-neoplasm'}", + "61, leading {'effect': 'B-positive'}", + "62, to {'effect': 'I-positive'}", + "63, metastasis {'phenotype': 'B-metastasis'}", + "64, formation {'phenotype': 'I-metastasis'}", + "67, mouse {'context': 'B-organism'}", + "156, MYCTg;KRASG12D {'perturbing_action': 'B-other'}", + "157, tumors. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "49, MYC ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "50, overexpression ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "51, (MYCTg) ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "56, induce ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "59, liver ['l3', 'l12', 'l20', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "60, tumor ['l4', 'l13', 'l21', 'l28', 'l33', 'l38', 'l39', 'l40', 'l41']", + "61, leading ['l5', 'l14', 'l22', 'l29', 'l34', 'l38', 'l42', 'l43', 'l44']", + "62, to ['l6', 'l15', 'l23', 'l30', 'l35', 'l39', 'l42', 'l45', 'l46']", + "63, metastasis ['l7', 'l16', 'l24', 'l31', 'l36', 'l40', 'l43', 'l45', 'l47', 'l48']", + "64, formation ['l8', 'l17', 'l25', 'l32', 'l37', 'l41', 'l44', 'l46', 'l47']", + "67, mouse ['l9', 'l18', 'l26', 'l48']", + "156, MYCTg;KRASG12D ['l49']", + "157, tumors. ['l49']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "MYC", + "overexpression", + "(MYCTg)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce", + "leading", + "to" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "MYC", + "overexpression", + "(MYCTg)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "liver", + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "MYC", + "overexpression", + "(MYCTg)" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "formation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "MYC", + "overexpression", + "(MYCTg)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce", + "leading", + "to" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "liver", + "tumor" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce", + "leading", + "to" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "formation" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "liver", + "tumor" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "formation" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "MYCTg;KRASG12D" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors." + ] + } + } + ] + }, + { + "PMID": "30420753", + "TEXT": "The recent successes of immunotherapy have shifted the paradigm in cancer treatment, but because only a percentage of patients are responsive to immunotherapy, it is imperative to identify factors impacting outcome. Obesity is reaching pandemic proportions and is a major risk factor for certain malignancies, but the impact of obesity on immune responses, in general and in cancer immunotherapy, is poorly understood. Here, we demonstrate, across multiple species and tumor models, that obesity results in increased immune aging, tumor progression and PD-1-mediated T cell dysfunction which is driven, at least in part, by leptin. However, obesity is also associated with increased efficacy of PD-1/PD-L1 blockade in both tumor-bearing mice and clinical cancer patients. These findings advance our understanding of obesity-induced immune dysfunction and its consequences in cancer and highlight obesity as a biomarker for some cancer immunotherapies. These data indicate a paradoxical impact of obesity on cancer. There is heightened immune dysfunction and tumor progression but also greater anti-tumor efficacy and survival after checkpoint blockade which directly targets some of the pathways activated in obesity.", + "TAG_DATA": [ + "69, tumor {'context': 'B-neoplasm'}", + "70, models, {'context': 'I-neoplasm'}", + "78, tumor {'phenotype': 'B-tumour progression'}", + "79, progression {'phenotype': 'I-tumour progression'}", + "107, tumor-bearing {'context': 'B-organism'}", + "108, mice {'context': 'I-organism'}", + "110, clinical {'context': 'B-transformed cells'}", + "111, cancer {'context': 'I-transformed cells'}", + "112, patients. {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "69, tumor ['l0', 'l1', 'l2']", + "70, models, ['l0', 'l3', 'l4']", + "78, tumor ['l1', 'l3', 'l5']", + "79, progression ['l2', 'l4', 'l5']", + "107, tumor-bearing ['l6', 'l7', 'l8', 'l9']", + "108, mice ['l6']", + "110, clinical ['l7', 'l10', 'l11']", + "111, cancer ['l8', 'l10', 'l12']", + "112, patients. ['l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "tumor", + "models," + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + } + ] + }, + { + "PMID": "30150719", + "TEXT": "Metformin is a first-line drug for the treatment of individuals with type 2 diabetes, yet its precise mechanism of action remains unclear. Metformin exerts its antihyperglycemic action primarily through lowering hepatic glucose production (HGP). This suppression is thought to be mediated through inhibition of mitochondrial respiratory complex I, and thus elevation of 5'-adenosine monophosphate (AMP) levels and the activation of AMP-activated protein kinase (AMPK), though this proposition has been challenged given results in mice lacking hepatic AMPK. Here we report that the AMP-inhibited enzyme fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis, functions as a major contributor to the therapeutic action of metformin. We identified a point mutation in FBP1 that renders it insensitive to AMP while sparing regulation by fructose-2,6-bisphosphate (F-2,6-P2), and knock-in (KI) of this mutant in mice significantly reduces their response to metformin treatment. We observe this during a metformin tolerance test and in a metformin-euglycemic clamp that we have developed. The antihyperglycemic effect of metformin in high-fat diet-fed diabetic FBP1-KI mice was also significantly blunted compared to wild-type controls. Collectively, we show a new mechanism of action for metformin and provide further evidence that molecular targeting of FBP1 can have antihyperglycemic effects.", + "TAG_DATA": [ + "105, point {'perturbing_action': 'B-other'}", + "106, mutation {'perturbing_action': 'I-other'}", + "107, in {'perturbing_action': 'I-other'}", + "108, FBP1 {'perturbing_action': 'I-other'}", + "122, knock-in {'perturbing_action': 'B-rnai/knockdown'}", + "123, (KI) {'perturbing_action': 'I-rnai/knockdown'}", + "124, of {'perturbing_action': 'I-rnai/knockdown'}", + "125, this {'perturbing_action': 'I-rnai/knockdown'}", + "126, mutant {'perturbing_action': 'I-rnai/knockdown'}", + "128, mice {'context': 'B-organism'}", + "161, diabetic {'perturbing_action': 'B-other'}", + "162, FBP1-KI {'perturbing_action': 'B-other'}", + "163, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "105, point ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "106, mutation ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "107, in ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "108, FBP1 ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "122, knock-in ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "123, (KI) ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "124, of ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "125, this ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "126, mutant ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "128, mice ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "161, diabetic ['l45', 'l46']", + "162, FBP1-KI ['l45', 'l47']", + "163, mice ['l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "point", + "mutation", + "in", + "FBP1", + "diabetic", + "FBP1-KI" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knock-in", + "(KI)", + "of", + "this", + "mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "30082871", + "TEXT": "Translation of the CRISPR-Cas9 system to human therapeutics holds high promise. However, specificity remains a concern especially when modifying stem cell populations. We show that existing rationally engineered Cas9 high-fidelity variants have reduced on-target activity when using the therapeutically relevant ribonucleoprotein (RNP) delivery method. Therefore, we devised an unbiased bacterial screen to isolate variants that retain activity in the RNP format. Introduction of a single point mutation, p.R691A, in Cas9 (high-fidelity (HiFi) Cas9) retained the high on-target activity of Cas9 while reducing off-target editing. HiFi Cas9 induces robust AAV6-mediated gene targeting at five therapeutically relevant loci (HBB, IL2RG, CCR5, HEXB, and TRAC) in human CD34+ hematopoietic stem and progenitor cells (HSPCs) as well as primary T cells. We also show that HiFi Cas9 mediates high-level correction of the sickle cell disease (SCD)-causing p.E6V mutation in HSPCs derived from patients with SCD. We anticipate that HiFi Cas9 will have wide utility for both basic science and therapeutic genome-editing applications.", + "TAG_DATA": [ + "61, Introduction {'perturbing_action': 'B-other'}", + "62, of {'perturbing_action': 'I-other'}", + "63, a {'perturbing_action': 'I-other'}", + "64, single {'perturbing_action': 'I-other'}", + "65, point {'perturbing_action': 'I-other'}", + "66, mutation, {'perturbing_action': 'I-other'}", + "67, p.R691A, {'perturbing_action': 'I-other'}", + "68, in {'perturbing_action': 'I-other'}", + "69, Cas9 {'perturbing_action': 'I-other'}", + "70, (high-fidelity {'perturbing_action': 'I-other'}", + "103, human {'context': 'B-cells'}", + "104, CD34+ {'context': 'I-cells'}", + "105, hematopoietic {'context': 'I-cells'}", + "106, stem {'context': 'I-cells'}", + "107, and {'context': 'I-cells'}", + "108, progenitor {'context': 'I-cells'}", + "109, cells {'context': 'I-cells'}", + "110, (HSPCs) {'context': 'I-cells'}", + "114, primary {'context': 'B-cells'}", + "115, T {'context': 'I-cells'}", + "116, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "61, Introduction ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "62, of ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "63, a ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "64, single ['l2', 'l21', 'l39', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "65, point ['l3', 'l22', 'l40', 'l57', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "66, mutation, ['l4', 'l23', 'l41', 'l58', 'l74', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "67, p.R691A, ['l5', 'l24', 'l42', 'l59', 'l75', 'l90', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "68, in ['l6', 'l25', 'l43', 'l60', 'l76', 'l91', 'l105', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "69, Cas9 ['l7', 'l26', 'l44', 'l61', 'l77', 'l92', 'l106', 'l119', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "70, (high-fidelity ['l8', 'l27', 'l45', 'l62', 'l78', 'l93', 'l107', 'l120', 'l130', 'l139', 'l140']", + "103, human ['l9', 'l28', 'l46', 'l63', 'l79', 'l94', 'l108', 'l121', 'l131', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150']", + "104, CD34+ ['l10', 'l29', 'l47', 'l64', 'l80', 'l95', 'l109', 'l122', 'l132', 'l141', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159']", + "105, hematopoietic ['l11', 'l30', 'l48', 'l65', 'l81', 'l96', 'l110', 'l123', 'l133', 'l142', 'l151', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "106, stem ['l12', 'l31', 'l49', 'l66', 'l82', 'l97', 'l111', 'l124', 'l134', 'l143', 'l152', 'l160', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "107, and ['l13', 'l32', 'l50', 'l67', 'l83', 'l98', 'l112', 'l125', 'l135', 'l144', 'l153', 'l161', 'l168', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180']", + "108, progenitor ['l14', 'l33', 'l51', 'l68', 'l84', 'l99', 'l113', 'l126', 'l136', 'l145', 'l154', 'l162', 'l169', 'l175', 'l181', 'l182', 'l183', 'l184', 'l185']", + "109, cells ['l15', 'l34', 'l52', 'l69', 'l85', 'l100', 'l114', 'l127', 'l137', 'l139', 'l146', 'l155', 'l163', 'l170', 'l176', 'l181', 'l186', 'l187', 'l188', 'l189']", + "110, (HSPCs) ['l16', 'l35', 'l53', 'l70', 'l86', 'l101', 'l115', 'l128', 'l138', 'l140', 'l147', 'l156', 'l164', 'l171', 'l177', 'l182', 'l186', 'l190', 'l191', 'l192']", + "114, primary ['l17', 'l36', 'l54', 'l71', 'l87', 'l102', 'l116', 'l148', 'l157', 'l165', 'l172', 'l178', 'l183', 'l187', 'l190', 'l193', 'l194']", + "115, T ['l18', 'l37', 'l55', 'l72', 'l88', 'l103', 'l117', 'l149', 'l158', 'l166', 'l173', 'l179', 'l184', 'l188', 'l191', 'l193', 'l195']", + "116, cells. ['l19', 'l38', 'l56', 'l73', 'l89', 'l104', 'l118', 'l129', 'l150', 'l159', 'l167', 'l174', 'l180', 'l185', 'l189', 'l192', 'l194', 'l195']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Introduction", + "of", + "a", + "single", + "point", + "mutation,", + "p.R691A,", + "in", + "Cas9", + "(high-fidelity" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "CD34+", + "hematopoietic", + "stem", + "and", + "progenitor", + "cells", + "(HSPCs)", + "primary", + "T", + "cells." + ] + } + } + ] + }, + { + "PMID": "30038219", + "TEXT": "Metformin, the universal first-line treatment for type 2 diabetes, exerts its therapeutic glucose-lowering effects by inhibiting hepatic gluconeogenesis. However, the primary molecular mechanism of this biguanide remains unclear, though it has been suggested to act, at least partially, by mitochondrial complex I inhibition. Here we show that clinically relevant concentrations of plasma metformin achieved by acute intravenous, acute intraportal or chronic oral administration in awake normal and diabetic rats inhibit gluconeogenesis from lactate and glycerol but not from pyruvate and alanine, implicating an increased cytosolic redox state in mediating metformin's antihyperglycemic effect. All of these effects occurred independently of complex I inhibition, evidenced by unaltered hepatic energy charge and citrate synthase flux. Normalizing the cytosolic redox state by infusion of methylene blue or substrates that contribute to gluconeogenesis independently of the cytosolic redox state abrogated metformin-mediated inhibition of gluconeogenesis in vivo. Additionally, in mice expressing constitutively active acetyl-CoA carboxylase, metformin acutely decreased hepatic glucose production and increased the hepatic cytosolic redox state without altering hepatic triglyceride content or gluconeogenic enzyme expression. These studies demonstrate that metformin, at clinically relevant plasma concentrations, inhibits hepatic gluconeogenesis in a redox-dependent manner independently of reductions in citrate synthase flux, hepatic nucleotide concentrations, acetyl-CoA carboxylase activity, or gluconeogenic enzyme protein expression.", + "TAG_DATA": [ + "67, diabetic {'context': 'B-organism'}", + "68, rats {'context': 'I-organism'}", + "139, in {'context': 'B-in vivo'}", + "140, vivo. {'context': 'I-in vivo'}", + "143, mice {'context': 'B-organism'}", + "144, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "145, constitutively {'perturbing_action': 'I-gene gain-of-function'}", + "146, active {'perturbing_action': 'I-gene gain-of-function'}", + "147, acetyl-CoA {'perturbing_action': 'I-gene gain-of-function'}", + "148, carboxylase, {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "65, normal ['l0', 'l1']", + "67, diabetic ['l0', 'l2']", + "68, rats ['l1', 'l2']", + "139, in ['l3']", + "140, vivo. ['l3']", + "143, mice ['l4', 'l5', 'l6', 'l7', 'l8']", + "144, expressing ['l4', 'l9', 'l10', 'l11', 'l12']", + "145, constitutively ['l5', 'l9', 'l13', 'l14', 'l15']", + "146, active ['l6', 'l10', 'l13', 'l16', 'l17']", + "147, acetyl-CoA ['l7', 'l11', 'l14', 'l16', 'l18']", + "148, carboxylase, ['l8', 'l12', 'l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "constitutively", + "active", + "acetyl-CoA", + "carboxylase," + ] + } + } + ] + }, + { + "PMID": "30013198", + "TEXT": "Mutations in the gene encoding isocitrate dehydrogenase 2 (IDH2) occur in several types of cancer, including acute myeloid leukemia (AML). In model systems, mutant IDH2 causes hematopoietic differentiation arrest. Enasidenib, a selective small-molecule inhibitor of mutant IDH2, produces a clinical response in 40% of treated patients with relapsed/refractory AML by promoting leukemic cell differentiation. Here, we studied the clonal basis of response and acquired resistance to enasidenib treatment. Using sequential patient samples, we determined the clonal structure of hematopoietic cell populations at different stages of differentiation. Before therapy, IDH2-mutant clones showed variable differentiation arrest. Enasidenib treatment promoted hematopoietic differentiation from either terminal or ancestral mutant clones; less frequently, treatment promoted differentiation of nonmutant cells. Analysis of paired diagnosis/relapse samples did not identify second-site mutations in IDH2 at relapse. Instead, relapse arose by clonal evolution or selection of terminal or ancestral clones, thus highlighting multiple bypass pathways that could potentially be targeted to restore differentiation arrest. These results show how mapping of clonal structure in cell populations at different stages of differentiation can reveal the response and evolution of clones during treatment response and relapse.", + "TAG_DATA": [ + "88, IDH2-mutant {'perturbing_action': 'B-other'}", + "92, differentiation {'phenotype': 'B-differentiation'}", + "93, arrest. {'effect': 'B-positive', 'phenotype': 'I-senescence'}", + "96, promoted {'effect': 'B-positive'}", + "97, hematopoietic {'phenotype': 'B-differentiation'}", + "98, differentiation {'phenotype': 'I-differentiation'}", + "109, promoted {'effect': 'B-positive'}", + "110, differentiation {'phenotype': 'B-differentiation'}", + "112, nonmutant {'context': 'B-cells'}", + "113, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "88, IDH2-mutant ['l0', 'l1']", + "92, differentiation ['l0', 'l2']", + "93, arrest. ['l1', 'l2']", + "96, promoted ['l3', 'l4']", + "97, hematopoietic ['l3', 'l5']", + "98, differentiation ['l4', 'l5']", + "109, promoted ['l6', 'l7', 'l8']", + "110, differentiation ['l6', 'l9', 'l10']", + "112, nonmutant ['l7', 'l9', 'l11']", + "113, cells. ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "IDH2-mutant" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "IDH2-mutant" + ] + }, + "effect": { + "val": "positive", + "words": [ + "arrest." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "IDH2-mutant" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "arrest." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "arrest." + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "arrest." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "hematopoietic" + ] + }, + "effect": { + "val": "positive", + "words": [ + "arrest.", + "promoted" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "cells", + "words": [ + "nonmutant", + "cells." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "nonmutant", + "cells." + ] + } + } + ] + }, + { + "PMID": "29967352", + "TEXT": "The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments.", + "TAG_DATA": [ + "61, vitro {'context': 'I-in vitro'}", + "63, in {'context': 'B-in vivo'}", + "64, vivo. {'context': 'I-in vivo'}", + "123, confer {'effect': 'B-positive'}", + "124, increased {'effect': 'B-positive'}", + "125, invasion {'phenotype': 'B-invasion'}", + "127, migration {'phenotype': 'B-migration'}", + "130, cells, {'context': 'B-cells'}", + "131, in {'context': 'B-in vitro'}", + "132, vitro {'context': 'I-in vitro'}", + "134, in {'context': 'B-in vivo'}", + "135, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "61, vitro ['l0', 'l1']", + "63, in ['l0', 'l2']", + "64, vivo. ['l1', 'l2']", + "123, confer ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "124, increased ['l3', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "125, invasion ['l4', 'l11', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "127, migration ['l5', 'l12', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "130, cells, ['l6', 'l13', 'l18', 'l23', 'l28', 'l29']", + "131, in ['l7', 'l14', 'l19', 'l24', 'l28', 'l30', 'l31']", + "132, vitro ['l8', 'l15', 'l20', 'l25', 'l29', 'l30', 'l32']", + "134, in ['l9', 'l21', 'l26', 'l33']", + "135, vivo, ['l10', 'l16', 'l22', 'l27', 'l31', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "confer", + "increased" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "confer", + "increased" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "confer", + "increased" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "confer", + "increased" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "confer", + "increased" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells," + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells," + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + } + ] + }, + { + "PMID": "29967349", + "TEXT": "Small-molecule inhibitors of the serine dipeptidases DPP8 and DPP9 (DPP8/9) induce a lytic form of cell death called pyroptosis in mouse and human monocytes and macrophages1,2. In mouse myeloid cells, Dpp8/9 inhibition activates the inflammasome sensor Nlrp1b, which in turn activates pro-caspase-1 to mediate cell death3, but the mechanism of DPP8/9 inhibitor-induced pyroptosis in human myeloid cells is not yet known. Here we show that the CARD-containing protein CARD8 mediates DPP8/9 inhibitor-induced pro-caspase-1-dependent pyroptosis in human myeloid cells. We further show that DPP8/9 inhibitors induce pyroptosis in the majority of human acute myeloid leukemia (AML) cell lines and primary AML samples, but not in cells from many other lineages, and that these inhibitors inhibit human AML progression in mouse models. Overall, this work identifies an activator of CARD8 in human cells and indicates that its activation by small-molecule DPP8/9 inhibitors represents a new potential therapeutic strategy for AML.", + "TAG_DATA": [ + "69, mediates {'effect': 'B-regulates'}", + "71, inhibitor-induced {'perturbing_action': 'I-pharmacological inhibition', 'effect': 'B-positive'}", + "73, pyroptosis {'phenotype': 'B-pyroptosis'}", + "75, human {'context': 'B-cells'}", + "76, myeloid {'context': 'I-cells'}", + "77, cells. {'context': 'I-cells'}", + "82, DPP8/9 {'perturbing_action': 'B-pharmacological inhibition'}", + "83, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "84, induce {'effect': 'B-positive'}", + "85, pyroptosis {'phenotype': 'B-pyroptosis'}", + "90, human {'context': 'B-transformed cells'}", + "91, acute {'context': 'I-transformed cells'}", + "92, myeloid {'context': 'I-transformed cells'}", + "93, leukemia {'context': 'I-transformed cells'}", + "94, (AML) {'context': 'I-transformed cells'}", + "95, cell {'context': 'I-transformed cells'}", + "96, lines {'context': 'I-transformed cells'}", + "98, primary {'context': 'B-transformed cells'}", + "99, AML {'context': 'I-transformed cells'}", + "100, samples, {'context': 'I-transformed cells'}", + "104, cells {'context': 'B-cells'}", + "105, from {'context': 'I-cells'}", + "108, lineages, {'context': 'I-cells'}", + "114, human {'context': 'B-neoplasm'}", + "115, AML {'context': 'I-neoplasm'}", + "118, mouse {'context': 'B-organism'}", + "119, models. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "69, mediates ['l0', 'l1', 'l2', 'l3', 'l4']", + "71, inhibitor-induced ['l0', 'l5', 'l6', 'l7', 'l8']", + "73, pyroptosis ['l1', 'l5', 'l9', 'l10', 'l11']", + "75, human ['l2', 'l6', 'l9', 'l12', 'l13']", + "76, myeloid ['l3', 'l7', 'l10', 'l12', 'l14']", + "77, cells. ['l4', 'l8', 'l11', 'l13', 'l14']", + "82, DPP8/9 ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "83, inhibitors ['l15', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "84, induce ['l16', 'l31', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "85, pyroptosis ['l17', 'l32', 'l46', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "90, human ['l18', 'l33', 'l47', 'l59', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "91, acute ['l19', 'l34', 'l48', 'l60', 'l72', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "92, myeloid ['l20', 'l35', 'l49', 'l61', 'l73', 'l84', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "93, leukemia ['l21', 'l36', 'l50', 'l62', 'l74', 'l85', 'l95', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "94, (AML) ['l22', 'l37', 'l51', 'l63', 'l75', 'l86', 'l96', 'l105', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "95, cell ['l23', 'l38', 'l52', 'l64', 'l76', 'l87', 'l97', 'l106', 'l114', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127']", + "96, lines ['l24', 'l39', 'l53', 'l65', 'l77', 'l88', 'l98', 'l107', 'l115', 'l122', 'l128', 'l129', 'l130', 'l131']", + "98, primary ['l25', 'l40', 'l54', 'l66', 'l78', 'l89', 'l99', 'l108', 'l116', 'l123', 'l128', 'l132', 'l133', 'l134', 'l135', 'l136']", + "99, AML ['l26', 'l41', 'l55', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l124', 'l129', 'l132', 'l137', 'l138', 'l139', 'l140']", + "100, samples, ['l27', 'l42', 'l56', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l125', 'l130', 'l133', 'l137', 'l141', 'l142', 'l143']", + "104, cells ['l28', 'l43', 'l57', 'l69', 'l81', 'l92', 'l102', 'l111', 'l119', 'l126', 'l131', 'l134', 'l138', 'l141', 'l144', 'l145']", + "105, from ['l29', 'l44', 'l58', 'l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l127', 'l135', 'l139', 'l142', 'l144', 'l146']", + "108, lineages, ['l30', 'l45', 'l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l136', 'l140', 'l143', 'l145', 'l146']", + "114, human ['l147', 'l148', 'l149']", + "115, AML ['l147', 'l150', 'l151']", + "118, mouse ['l148', 'l150', 'l152']", + "119, models. ['l149', 'l151', 'l152']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "regulates", + "words": [ + "mediates" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitor-induced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitor-induced", + "DPP8/9", + "inhibitors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inhibitor-induced", + "induce" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "mediates" + ] + }, + "phenotype": { + "val": "pyroptosis", + "words": [ + "pyroptosis" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "mediates" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "myeloid", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitor-induced", + "DPP8/9", + "inhibitors" + ] + }, + "phenotype": { + "val": "pyroptosis", + "words": [ + "pyroptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inhibitor-induced", + "induce" + ] + }, + "phenotype": { + "val": "pyroptosis", + "words": [ + "pyroptosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitor-induced", + "DPP8/9", + "inhibitors" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "myeloid", + "cells.", + "cells", + "from", + "lineages," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inhibitor-induced", + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "myeloid", + "cells.", + "cells", + "from" + ] + } + }, + { + "phenotype": { + "val": "pyroptosis", + "words": [ + "pyroptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "myeloid", + "cells.", + "cells", + "from", + "lineages," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "DPP8/9", + "inhibitors" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "acute", + "myeloid", + "leukemia", + "(AML)", + "cell", + "lines", + "primary", + "AML", + "samples," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "acute", + "myeloid", + "leukemia", + "(AML)", + "cell", + "lines", + "primary", + "AML", + "samples," + ] + } + }, + { + "phenotype": { + "val": "pyroptosis", + "words": [ + "pyroptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "acute", + "myeloid", + "leukemia", + "(AML)", + "cell", + "lines", + "primary", + "AML", + "samples," + ] + } + } + ] + }, + { + "PMID": "29892070", + "TEXT": "Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors.", + "TAG_DATA": [ + "76, inhibited {'effect': 'B-negative'}", + "77, proliferation {'phenotype': 'B-proliferation'}", + "79, induced {'effect': 'B-positive'}", + "80, apoptosis {'phenotype': 'B-apoptosis'}", + "82, models {'context': 'B-neoplasm'}", + "83, of {'context': 'I-neoplasm'}", + "84, brain {'context': 'I-neoplasm'}", + "85, cancer {'context': 'I-neoplasm'}", + "87, acute {'context': 'B-neoplasm'}", + "88, myeloid {'context': 'I-neoplasm'}", + "89, leukemia {'context': 'I-neoplasm'}", + "90, (AML) {'context': 'I-neoplasm'}", + "113, models {'context': 'B-neoplasm'}", + "114, of {'context': 'I-neoplasm'}", + "115, brain {'context': 'I-neoplasm'}", + "116, cancer {'context': 'I-neoplasm'}", + "118, AML, {'context': 'I-neoplasm'}", + "119, tumor {'phenotype': 'B-tumour growth'}", + "120, growth {'phenotype': 'I-tumour growth'}", + "123, inhibited {'effect': 'B-negative'}", + "124, in {'context': 'B-in vivo'}", + "125, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "76, inhibited ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "77, proliferation ['l0', 'l7', 'l8', 'l9', 'l10']", + "79, induced ['l1', 'l7', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "80, apoptosis ['l2', 'l11', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "82, models ['l3', 'l12', 'l20', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "83, of ['l4', 'l8', 'l13', 'l21', 'l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "84, brain ['l5', 'l9', 'l14', 'l22', 'l29', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "85, cancer ['l6', 'l10', 'l15', 'l23', 'l30', 'l36', 'l41', 'l46', 'l47', 'l48', 'l49']", + "87, acute ['l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l50', 'l51', 'l52']", + "88, myeloid ['l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "89, leukemia ['l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l59', 'l60', 'l61', 'l62', 'l63']", + "90, (AML) ['l19', 'l27', 'l34', 'l40', 'l45', 'l49', 'l52', 'l54', 'l59', 'l64']", + "113, models ['l65', 'l66', 'l67', 'l68', 'l69']", + "114, of ['l55', 'l60', 'l65', 'l70', 'l71', 'l72']", + "115, brain ['l56', 'l61', 'l66', 'l70', 'l73', 'l74']", + "116, cancer ['l57', 'l62', 'l64', 'l67', 'l71', 'l73', 'l75']", + "118, AML, ['l58', 'l63', 'l68', 'l72', 'l74', 'l75']", + "119, tumor ['l76', 'l77', 'l78', 'l79']", + "120, growth ['l69', 'l76', 'l80', 'l81', 'l82']", + "123, inhibited ['l77', 'l80', 'l83', 'l84']", + "124, in ['l78', 'l81', 'l83', 'l85']", + "125, vivo ['l79', 'l82', 'l84', 'l85']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models", + "of", + "brain", + "cancer" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "of", + "brain", + "cancer" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models", + "of", + "brain", + "cancer", + "acute", + "myeloid", + "leukemia", + "(AML)" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models", + "of", + "brain", + "cancer", + "acute", + "myeloid", + "leukemia", + "(AML)" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "models" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "29892066", + "TEXT": "Activation of microglia by classical inflammatory mediators can convert astrocytes into a neurotoxic A1 phenotype in a variety of neurological diseases1,2. Development of agents that could inhibit the formation of A1 reactive astrocytes could be used to treat these diseases for which there are no disease-modifying therapies. Glucagon-like peptide-1 receptor (GLP1R) agonists have been indicated as potential neuroprotective agents for neurologic disorders such as Alzheimer's disease and Parkinson's disease3-13. The mechanisms by which GLP1R agonists are neuroprotective are not known. Here we show that a potent, brain-penetrant long-acting GLP1R agonist, NLY01, protects against the loss of dopaminergic neurons and behavioral deficits in the α-synuclein preformed fibril (α-syn PFF) mouse model of sporadic Parkinson's disease14,15. NLY01 also prolongs the life and reduces the behavioral deficits and neuropathological abnormalities in the human A53T α-synuclein (hA53T) transgenic mouse model of α-synucleinopathy-induced neurodegeneration16. We found that NLY01 is a potent GLP1R agonist with favorable properties that is neuroprotective through the direct prevention of microglial-mediated conversion of astrocytes to an A1 neurotoxic phenotype. In light of its favorable properties, NLY01 should be evaluated in the treatment of Parkinson's disease and related neurologic disorders characterized by microglial activation.", + "TAG_DATA": [ + "96, dopaminergic {'context': 'B-cells'}", + "97, neurons {'context': 'I-cells'}", + "108, mouse {'context': 'B-organism'}", + "109, model {'context': 'I-organism'}", + "129, human {'perturbing_action': 'B-gene gain-of-function'}", + "130, A53T {'perturbing_action': 'I-gene gain-of-function'}", + "131, α-synuclein {'perturbing_action': 'I-gene gain-of-function'}", + "132, (hA53T) {'perturbing_action': 'I-gene gain-of-function'}", + "133, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "134, mouse {'context': 'B-organism'}", + "135, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "96, dopaminergic ['l0', 'l1', 'l2']", + "97, neurons ['l0', 'l3']", + "108, mouse ['l1', 'l4']", + "109, model ['l2', 'l3', 'l4']", + "129, human ['l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "130, A53T ['l5', 'l11', 'l12', 'l13', 'l14', 'l15']", + "131, α-synuclein ['l6', 'l11', 'l16', 'l17', 'l18', 'l19']", + "132, (hA53T) ['l7', 'l12', 'l16', 'l20', 'l21', 'l22']", + "133, transgenic ['l8', 'l13', 'l17', 'l20', 'l23', 'l24']", + "134, mouse ['l9', 'l14', 'l18', 'l21', 'l23', 'l25']", + "135, model ['l10', 'l15', 'l19', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "human", + "A53T", + "α-synuclein", + "(hA53T)", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + } + ] + }, + { + "PMID": "29892060", + "TEXT": "It has long been assumed that p53 suppresses tumor development through induction of apoptosis, possibly with contributions by cell cycle arrest and cell senescence1,2. However, combined deficiency in these three processes does not result in spontaneous tumor formation as observed upon loss of p53, suggesting the existence of additional mechanisms that are critical mediators of p53-dependent tumor suppression function3-5. To define such mechanisms, we performed in vivo shRNA screens targeting p53-regulated genes in sensitized genetic backgrounds. We found that knockdown of Zmat3, Ctsf and Cav1, promoted lymphoma/leukemia development only when PUMA and p21, the critical effectors of p53-driven apoptosis, cell cycle arrest and senescence, were also absent. Notably, loss of the DNA repair gene Mlh1 caused lymphoma in a wild-type background, and its enforced expression was able to delay tumor development driven by loss of p53. Further examination of direct p53 target genes implicated in DNA repair showed that knockdown of Mlh1, Msh2, Rnf144b, Cav1 and Ddit4 accelerated MYC-driven lymphoma development to a similar extent as knockdown of p53. Collectively, these findings demonstrate that extensive functional overlap of several p53-regulated processes safeguards against cancer and that coordination of DNA repair appears to be an important process by which p53 suppresses tumor development.", + "TAG_DATA": [ + "65, in {'context': 'B-in vivo'}", + "66, vivo {'context': 'B-in vivo'}", + "79, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "80, of {'perturbing_action': 'I-rnai/knockdown'}", + "81, Zmat3, {'perturbing_action': 'I-rnai/knockdown'}", + "82, Ctsf {'perturbing_action': 'I-rnai/knockdown'}", + "83, and {'perturbing_action': 'I-rnai/knockdown'}", + "84, Cav1, {'perturbing_action': 'I-rnai/knockdown'}", + "85, promoted {'effect': 'B-positive'}", + "86, lymphoma/leukemia {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}", + "98, apoptosis, {'phenotype': 'B-apoptosis'}", + "99, cell {'phenotype': 'B-cell cycle arrest'}", + "100, cycle {'phenotype': 'I-cell cycle arrest'}", + "101, arrest {'phenotype': 'I-cell cycle arrest'}", + "103, senescence, {'phenotype': 'B-senescence'}", + "108, loss {'perturbing_action': 'B-gene loss-of-function'}", + "109, of {'perturbing_action': 'I-gene loss-of-function'}", + "110, the {'perturbing_action': 'I-gene loss-of-function'}", + "111, DNA {'perturbing_action': 'I-gene loss-of-function'}", + "112, repair {'perturbing_action': 'I-gene loss-of-function'}", + "113, gene {'perturbing_action': 'I-gene loss-of-function'}", + "114, Mlh1 {'perturbing_action': 'I-gene loss-of-function'}", + "115, caused {'effect': 'B-positive'}", + "116, lymphoma {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}", + "128, delay {'effect': 'B-negative'}", + "129, tumor {'phenotype': 'B-tumourigenesis'}", + "130, development {'phenotype': 'I-tumourigenesis'}", + "133, loss {'perturbing_action': 'B-gene loss-of-function'}", + "134, of {'perturbing_action': 'I-gene loss-of-function'}", + "135, p53. {'perturbing_action': 'I-gene loss-of-function'}", + "149, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "150, of {'perturbing_action': 'I-rnai/knockdown'}", + "151, Mlh1, {'perturbing_action': 'I-rnai/knockdown'}", + "152, Msh2, {'perturbing_action': 'I-rnai/knockdown'}", + "153, Rnf144b, {'perturbing_action': 'I-rnai/knockdown'}", + "154, Cav1 {'perturbing_action': 'I-rnai/knockdown'}", + "155, and {'perturbing_action': 'I-rnai/knockdown'}", + "156, Ddit4 {'perturbing_action': 'I-rnai/knockdown'}", + "157, accelerated {'effect': 'B-positive'}", + "159, lymphoma {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}", + "166, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "167, of {'perturbing_action': 'I-rnai/knockdown'}", + "168, p53. {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "65, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "66, vivo ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "79, knockdown ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "80, of ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "81, Zmat3, ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "82, Ctsf ['l4', 'l17', 'l29', 'l40', 'l50', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "83, and ['l5', 'l18', 'l30', 'l41', 'l51', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "84, Cav1, ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "85, promoted ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "86, lymphoma/leukemia ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l90', 'l91', 'l92', 'l93', 'l94']", + "98, apoptosis, ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l95', 'l96', 'l97', 'l98']", + "99, cell ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l99', 'l100', 'l101']", + "100, cycle ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l102', 'l103']", + "101, arrest ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l104']", + "103, senescence, ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l104']", + "108, loss ['l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "109, of ['l105', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "110, the ['l106', 'l119', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "111, DNA ['l107', 'l120', 'l132', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "112, repair ['l108', 'l121', 'l133', 'l144', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164']", + "113, gene ['l109', 'l122', 'l134', 'l145', 'l155', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "114, Mlh1 ['l110', 'l123', 'l135', 'l146', 'l156', 'l165', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181']", + "115, caused ['l111', 'l124', 'l136', 'l147', 'l157', 'l166', 'l174', 'l182']", + "116, lymphoma ['l112', 'l125', 'l137', 'l148', 'l158', 'l167', 'l175', 'l182']", + "128, delay ['l113', 'l126', 'l138', 'l149', 'l159', 'l168', 'l176', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190']", + "129, tumor ['l114', 'l127', 'l139', 'l150', 'l160', 'l169', 'l177', 'l183', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196']", + "130, development ['l115', 'l128', 'l140', 'l151', 'l161', 'l170', 'l178', 'l184', 'l191', 'l197', 'l198', 'l199']", + "133, loss ['l116', 'l129', 'l141', 'l152', 'l162', 'l171', 'l179', 'l185', 'l192', 'l197', 'l200', 'l201']", + "134, of ['l117', 'l130', 'l142', 'l153', 'l163', 'l172', 'l180', 'l186', 'l193', 'l198', 'l200', 'l202']", + "135, p53. ['l118', 'l131', 'l143', 'l154', 'l164', 'l173', 'l181', 'l187', 'l194', 'l199', 'l201', 'l202']", + "149, knockdown ['l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214']", + "150, of ['l203', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225']", + "151, Mlh1, ['l204', 'l215', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235']", + "152, Msh2, ['l188', 'l195', 'l205', 'l216', 'l226', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244']", + "153, Rnf144b, ['l189', 'l196', 'l206', 'l217', 'l227', 'l236', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252']", + "154, Cav1 ['l190', 'l207', 'l218', 'l228', 'l237', 'l245', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259']", + "155, and ['l208', 'l219', 'l229', 'l238', 'l246', 'l253', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265']", + "156, Ddit4 ['l209', 'l220', 'l230', 'l239', 'l247', 'l254', 'l260', 'l266', 'l267', 'l268', 'l269', 'l270']", + "157, accelerated ['l210', 'l221', 'l231', 'l240', 'l248', 'l255', 'l261', 'l266', 'l271', 'l272', 'l273', 'l274']", + "159, lymphoma ['l211', 'l222', 'l232', 'l241', 'l249', 'l256', 'l262', 'l267', 'l271', 'l275', 'l276', 'l277']", + "166, knockdown ['l212', 'l223', 'l233', 'l242', 'l250', 'l257', 'l263', 'l268', 'l272', 'l275', 'l278', 'l279']", + "167, of ['l213', 'l224', 'l234', 'l243', 'l251', 'l258', 'l264', 'l269', 'l273', 'l276', 'l278', 'l280']", + "168, p53. ['l214', 'l225', 'l235', 'l244', 'l252', 'l259', 'l265', 'l270', 'l274', 'l277', 'l279', 'l280']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "Zmat3,", + "Ctsf", + "and", + "Cav1," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma/leukemia" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "lymphoma/leukemia", + "lymphoma" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma/leukemia", + "lymphoma" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "Zmat3,", + "Ctsf", + "and", + "Cav1,", + "Mlh1,", + "Msh2,", + "Rnf144b,", + "Cav1", + "Ddit4", + "p53." + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted", + "accelerated" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "Zmat3,", + "Ctsf", + "and", + "Cav1,", + "Mlh1,", + "Msh2,", + "Rnf144b,", + "Cav1", + "Ddit4", + "p53." + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lymphoma/leukemia", + "lymphoma" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "Zmat3,", + "Ctsf", + "and", + "Cav1,", + "Msh2,", + "Rnf144b,", + "Mlh1,", + "Cav1", + "Ddit4", + "p53." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma/leukemia", + "tumor", + "lymphoma" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "Zmat3,", + "Ctsf", + "and", + "Cav1," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "Zmat3,", + "Ctsf", + "and", + "Cav1," + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "Zmat3,", + "Ctsf", + "and", + "Cav1," + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted", + "caused", + "accelerated" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lymphoma/leukemia", + "lymphoma" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted", + "caused", + "accelerated" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma/leukemia", + "lymphoma" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "lymphoma/leukemia" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "lymphoma/leukemia" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "lymphoma/leukemia" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "DNA", + "repair", + "gene", + "Mlh1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "DNA", + "repair", + "gene", + "Mlh1" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lymphoma" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "DNA", + "repair", + "gene", + "Mlh1", + "p53." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma", + "tumor", + "development" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "DNA", + "repair", + "gene", + "Mlh1", + "p53." + ] + }, + "effect": { + "val": "negative", + "words": [ + "delay" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "delay" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "delay" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Msh2,", + "Rnf144b,", + "Cav1" + ] + } + } + ] + }, + { + "PMID": "29867232", + "TEXT": "Unsuppressed hepatic glucose production (HGP) contributes substantially to glucose intolerance and diabetes, which can be modeled by the genetic inactivation of hepatic insulin receptor substrate 1 (Irs1) and Irs2 (LDKO mice). We previously showed that glucose intolerance in LDKO mice is resolved by hepatic inactivation of the transcription factor FoxO1 (that is, LTKO mice)-even though the liver remains insensitive to insulin. Here, we report that insulin sensitivity in the white adipose tissue of LDKO mice is also impaired but is restored in LTKO mice in conjunction with normal suppression of HGP by insulin. To establish the mechanism by which white adipose tissue insulin signaling and HGP was regulated by hepatic FoxO1, we identified putative hepatokines-including excess follistatin (Fst)-that were dysregulated in LDKO mice but normalized in LTKO mice. Knockdown of hepatic Fst in the LDKO mouse liver restored glucose tolerance, white adipose tissue insulin signaling and the suppression of HGP by insulin; however, the expression of Fst in the liver of healthy LTKO mice had the opposite effect. Of potential clinical significance, knockdown of Fst also improved glucose tolerance in high-fat-fed obese mice, and the level of serum Fst was reduced in parallel with glycated hemoglobin in obese individuals with diabetes who underwent therapeutic gastric bypass surgery. We conclude that Fst is a pathological hepatokine that might be targeted for diabetes therapy during hepatic insulin resistance.", + "TAG_DATA": [ + "127, mice. {'context': 'B-organism'}", + "128, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "129, of {'perturbing_action': 'I-rnai/knockdown'}", + "130, hepatic {'perturbing_action': 'I-rnai/knockdown'}", + "131, Fst {'perturbing_action': 'I-rnai/knockdown'}", + "134, LDKO {'context': 'B-cells'}", + "135, mouse {'context': 'I-tissue/organ'}", + "136, liver {'context': 'I-tissue/organ'}", + "141, adipose {'context': 'I-tissue/organ'}", + "159, liver {'context': 'B-tissue/organ'}", + "163, mice {'context': 'I-organism'}", + "172, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "173, of {'perturbing_action': 'I-rnai/knockdown'}", + "174, Fst {'perturbing_action': 'I-rnai/knockdown'}", + "181, obese {'context': 'I-organism'}", + "182, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "127, mice. ['l0', 'l1', 'l2', 'l3']", + "128, Knockdown ['l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "129, of ['l4', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "130, hepatic ['l5', 'l12', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "131, Fst ['l6', 'l13', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "134, LDKO ['l0', 'l7', 'l14', 'l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "135, mouse ['l1', 'l8', 'l15', 'l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "136, liver ['l2', 'l9', 'l16', 'l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "141, adipose ['l10', 'l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "142, tissue ['l3', 'l11', 'l18', 'l24', 'l29', 'l33', 'l36', 'l38', 'l39']", + "159, liver ['l40', 'l41', 'l42', 'l43', 'l44']", + "163, mice ['l40', 'l45', 'l46', 'l47']", + "172, knockdown ['l48', 'l49', 'l50', 'l51', 'l52']", + "173, of ['l41', 'l48', 'l53', 'l54', 'l55', 'l56']", + "174, Fst ['l42', 'l45', 'l49', 'l53', 'l57', 'l58', 'l59']", + "181, obese ['l43', 'l46', 'l50', 'l54', 'l57', 'l60']", + "182, mice, ['l44', 'l47', 'l51', 'l55', 'l58', 'l60']", + "198, individuals ['l52', 'l56', 'l59']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "hepatic", + "Fst" + ] + }, + "context": { + "val": "cells", + "words": [ + "LDKO" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "hepatic", + "Fst" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "liver", + "adipose" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "obese", + "mice," + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Fst", + "knockdown", + "of" + ] + } + } + ] + }, + { + "PMID": "29808009", + "TEXT": "The ubiquitously expressed non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, is involved in signal transduction downstream of multiple growth factor, cytokine and integrin receptors1. Its requirement for complete RAS-MAPK activation and its role as a negative regulator of JAK-STAT signaling have established SHP2 as an essential player in oncogenic signaling pathways1-7. Recently, a novel potent allosteric SHP2 inhibitor was presented as a viable therapeutic option for receptor tyrosine kinase-driven cancers, but was shown to be ineffective in KRAS-mutant tumor cell lines in vitro8. Here, we report a central and indispensable role for SHP2 in oncogenic KRAS-driven tumors. Genetic deletion of Ptpn11 profoundly inhibited tumor development in mutant KRAS-driven murine models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. We provide evidence for a critical dependence of mutant KRAS on SHP2 during carcinogenesis. Deletion or inhibition of SHP2 in established tumors delayed tumor progression but was not sufficient to achieve tumor regression. However, SHP2 was necessary for resistance mechanisms upon blockade of MEK. Synergy was observed when both SHP2 and MEK were targeted, resulting in sustained tumor growth control in murine and human patient-derived organoids and xenograft models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. Our data indicate the clinical utility of dual SHP2/MEK inhibition as a targeted therapy approach for KRAS-mutant cancers.", + "TAG_DATA": [ + "98, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "99, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "100, of {'perturbing_action': 'I-gene loss-of-function'}", + "101, Ptpn11 {'perturbing_action': 'I-gene loss-of-function'}", + "103, inhibited {'effect': 'B-negative'}", + "104, tumor {'phenotype': 'B-tumourigenesis'}", + "105, development {'phenotype': 'I-tumourigenesis'}", + "107, mutant {'perturbing_action': 'B-other'}", + "108, KRAS-driven {'perturbing_action': 'B-other'}", + "109, murine {'context': 'B-neoplasm'}", + "110, models {'context': 'I-neoplasm'}", + "111, of {'context': 'I-neoplasm'}", + "112, pancreatic {'context': 'I-neoplasm'}", + "113, ductal {'context': 'I-neoplasm'}", + "114, adenocarcinoma {'context': 'I-neoplasm'}", + "116, non-small-cell {'context': 'B-neoplasm'}", + "117, lung {'context': 'I-neoplasm'}", + "118, cancer. {'context': 'I-neoplasm'}", + "135, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "136, of {'perturbing_action': 'I-pharmacological inhibition'}", + "137, SHP2 {'perturbing_action': 'I-pharmacological inhibition'}", + "140, tumors {'context': 'B-neoplasm'}", + "141, delayed {'effect': 'B-negative'}", + "142, tumor {'phenotype': 'B-tumour progression'}", + "143, progression {'phenotype': 'I-tumour progression'}", + "149, achieve {'effect': 'I-positive'}", + "150, tumor {'phenotype': 'B-tumour regression'}", + "151, regression. {'phenotype': 'I-tumour regression'}", + "176, tumor {'phenotype': 'B-tumour growth'}", + "177, growth {'phenotype': 'I-tumour growth'}", + "178, control {'effect': 'B-regulates'}", + "180, murine {'context': 'B-organoid'}", + "181, and {'context': 'I-organoid'}", + "182, human {'context': 'I-organoid'}", + "183, patient-derived {'context': 'I-organoid'}", + "184, organoids {'context': 'I-organoid'}", + "186, xenograft {'context': 'B-xenograft'}", + "187, models {'context': 'I-xenograft'}", + "189, pancreatic {'context': 'I-xenograft'}", + "190, ductal {'context': 'I-neoplasm'}", + "191, adenocarcinoma {'context': 'I-neoplasm'}", + "193, non-small-cell {'context': 'B-neoplasm'}", + "194, lung {'context': 'I-neoplasm'}", + "195, cancer. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "98, Genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "99, deletion ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "100, of ['l1', 'l17', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "101, Ptpn11 ['l2', 'l18', 'l33', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "103, inhibited ['l3', 'l19', 'l34', 'l48', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "104, tumor ['l4', 'l20', 'l35', 'l49', 'l62', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "105, development ['l5', 'l21', 'l36', 'l50', 'l63', 'l75', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "107, mutant ['l6', 'l22', 'l37', 'l51', 'l64', 'l76', 'l87', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "108, KRAS-driven ['l7', 'l23', 'l38', 'l52', 'l65', 'l77', 'l88', 'l97', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "109, murine ['l8', 'l24', 'l39', 'l53', 'l66', 'l78', 'l89', 'l98', 'l107', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "110, models ['l9', 'l25', 'l40', 'l54', 'l67', 'l79', 'l90', 'l99', 'l108', 'l116', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "111, of ['l10', 'l26', 'l41', 'l55', 'l68', 'l80', 'l91', 'l100', 'l109', 'l117', 'l124', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "112, pancreatic ['l11', 'l27', 'l42', 'l56', 'l69', 'l81', 'l92', 'l101', 'l110', 'l118', 'l125', 'l131', 'l137', 'l138', 'l139', 'l140', 'l141']", + "113, ductal ['l12', 'l28', 'l43', 'l57', 'l70', 'l82', 'l93', 'l102', 'l111', 'l119', 'l126', 'l132', 'l137', 'l142', 'l143', 'l144', 'l145']", + "114, adenocarcinoma ['l13', 'l29', 'l44', 'l58', 'l71', 'l83', 'l94', 'l103', 'l112', 'l120', 'l127', 'l133', 'l138', 'l142', 'l146', 'l147', 'l148']", + "116, non-small-cell ['l14', 'l30', 'l45', 'l59', 'l72', 'l84', 'l104', 'l113', 'l121', 'l128', 'l134', 'l139', 'l143', 'l146', 'l149', 'l150']", + "117, lung ['l15', 'l31', 'l46', 'l60', 'l73', 'l85', 'l95', 'l105', 'l114', 'l122', 'l129', 'l135', 'l140', 'l144', 'l147', 'l149', 'l151']", + "118, cancer. ['l16', 'l32', 'l47', 'l61', 'l74', 'l86', 'l96', 'l106', 'l115', 'l123', 'l130', 'l136', 'l141', 'l145', 'l148', 'l150', 'l151']", + "135, inhibition ['l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "136, of ['l152', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "137, SHP2 ['l153', 'l166', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189']", + "140, tumors ['l154', 'l167', 'l179', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195']", + "141, delayed ['l155', 'l168', 'l180', 'l190', 'l196', 'l197', 'l198', 'l199', 'l200']", + "142, tumor ['l156', 'l169', 'l181', 'l191', 'l196', 'l201', 'l202', 'l203', 'l204']", + "143, progression ['l157', 'l170', 'l182', 'l192', 'l197', 'l201', 'l205', 'l206', 'l207']", + "149, achieve ['l158', 'l171', 'l183', 'l193', 'l198', 'l202', 'l205', 'l208', 'l209']", + "150, tumor ['l159', 'l172', 'l184', 'l194', 'l199', 'l203', 'l206', 'l208', 'l210']", + "151, regression. ['l160', 'l173', 'l185', 'l195', 'l200', 'l204', 'l207', 'l209', 'l210']", + "170, MEK ['l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227']", + "176, tumor ['l211', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243']", + "177, growth ['l212', 'l228', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258']", + "178, control ['l213', 'l229', 'l244', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272']", + "180, murine ['l161', 'l174', 'l214', 'l230', 'l245', 'l259', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285']", + "181, and ['l162', 'l175', 'l186', 'l215', 'l231', 'l246', 'l260', 'l273', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297']", + "182, human ['l163', 'l176', 'l187', 'l216', 'l232', 'l247', 'l261', 'l274', 'l286', 'l298', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304', 'l305', 'l306', 'l307', 'l308']", + "183, patient-derived ['l164', 'l177', 'l188', 'l217', 'l233', 'l248', 'l262', 'l275', 'l287', 'l298', 'l309', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315', 'l316', 'l317', 'l318']", + "184, organoids ['l165', 'l178', 'l189', 'l218', 'l234', 'l249', 'l263', 'l276', 'l288', 'l299', 'l309', 'l319', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327']", + "186, xenograft ['l219', 'l235', 'l250', 'l264', 'l277', 'l289', 'l300', 'l310', 'l319', 'l328', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334', 'l335']", + "187, models ['l220', 'l236', 'l251', 'l265', 'l278', 'l290', 'l301', 'l311', 'l320', 'l328', 'l336', 'l337', 'l338', 'l339', 'l340', 'l341', 'l342']", + "188, of ['l221', 'l237', 'l252', 'l266', 'l279', 'l291', 'l302', 'l312', 'l321', 'l329', 'l336', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348']", + "189, pancreatic ['l222', 'l238', 'l253', 'l267', 'l280', 'l292', 'l303', 'l313', 'l322', 'l330', 'l337', 'l343', 'l349', 'l350', 'l351', 'l352', 'l353']", + "190, ductal ['l223', 'l239', 'l254', 'l268', 'l281', 'l293', 'l304', 'l314', 'l323', 'l331', 'l338', 'l344', 'l349', 'l354', 'l355', 'l356', 'l357']", + "191, adenocarcinoma ['l224', 'l240', 'l255', 'l269', 'l282', 'l294', 'l305', 'l315', 'l324', 'l332', 'l339', 'l345', 'l350', 'l354', 'l358', 'l359', 'l360']", + "193, non-small-cell ['l225', 'l241', 'l256', 'l270', 'l283', 'l295', 'l306', 'l316', 'l325', 'l333', 'l340', 'l346', 'l351', 'l355', 'l358', 'l361', 'l362']", + "194, lung ['l226', 'l242', 'l257', 'l271', 'l284', 'l296', 'l307', 'l317', 'l326', 'l334', 'l341', 'l347', 'l352', 'l356', 'l359', 'l361', 'l363']", + "195, cancer. ['l227', 'l243', 'l258', 'l272', 'l285', 'l297', 'l308', 'l318', 'l327', 'l335', 'l342', 'l348', 'l353', 'l357', 'l360', 'l362', 'l363']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "deletion", + "of", + "Ptpn11" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "deletion", + "of", + "Ptpn11" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "deletion", + "of", + "Ptpn11" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "murine", + "models", + "of", + "pancreatic", + "ductal", + "adenocarcinoma", + "non-small-cell", + "lung", + "cancer." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "KRAS-driven" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "delayed" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "murine", + "models", + "of", + "pancreatic", + "ductal", + "adenocarcinoma", + "non-small-cell", + "lung", + "cancer.", + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "KRAS-driven" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "murine", + "models", + "of", + "pancreatic", + "ductal", + "adenocarcinoma", + "non-small-cell", + "lung", + "cancer." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "KRAS-driven" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "murine", + "models", + "of", + "pancreatic", + "ductal", + "adenocarcinoma", + "non-small-cell", + "lung", + "cancer." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "delayed" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "achieve" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2" + ] + }, + "context": { + "val": "organoid", + "words": [ + "murine", + "and", + "human", + "patient-derived", + "organoids" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "achieve" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "delayed" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "delayed" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression." + ] + } + }, + { + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "achieve" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "achieve" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "control" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organoid", + "words": [ + "murine", + "and", + "human", + "patient-derived", + "organoids" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "models", + "pancreatic" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "ductal", + "adenocarcinoma", + "non-small-cell", + "lung", + "cancer." + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "control" + ] + }, + "context": { + "val": "organoid", + "words": [ + "murine", + "and", + "human", + "patient-derived", + "organoids" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "control" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "models", + "pancreatic" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "control" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "ductal", + "adenocarcinoma", + "non-small-cell", + "lung", + "cancer." + ] + } + } + ] + }, + { + "PMID": "29736026", + "TEXT": "ARID1A (the AT-rich interaction domain 1A, also known as BAF250a) is one of the most commonly mutated genes in cancer1,2. The majority of ARID1A mutations are inactivating mutations and lead to loss of ARID1A expression 3 , which makes ARID1A a poor therapeutic target. Therefore, it is of clinical importance to identify molecular consequences of ARID1A deficiency that create therapeutic vulnerabilities in ARID1A-mutant tumors. In a proteomic screen, we found that ARID1A interacts with mismatch repair (MMR) protein MSH2. ARID1A recruited MSH2 to chromatin during DNA replication and promoted MMR. Conversely, ARID1A inactivation compromised MMR and increased mutagenesis. ARID1A deficiency correlated with microsatellite instability genomic signature and a predominant C>T mutation pattern and increased mutation load across multiple human cancer types. Tumors formed by an ARID1A-deficient ovarian cancer cell line in syngeneic mice displayed increased mutation load, elevated numbers of tumor-infiltrating lymphocytes, and PD-L1 expression. Notably, treatment with anti-PD-L1 antibody reduced tumor burden and prolonged survival of mice bearing ARID1A-deficient but not ARID1A-wild-type ovarian tumors. Together, these results suggest ARID1A deficiency contributes to impaired MMR and mutator phenotype in cancer, and may cooperate with immune checkpoint blockade therapy.", + "TAG_DATA": [ + "91, ARID1A {'perturbing_action': 'B-gene loss-of-function'}", + "92, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "98, ARID1A {'perturbing_action': 'B-gene loss-of-function'}", + "99, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "125, ARID1A-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "126, ovarian {'context': 'B-transformed cells'}", + "127, cancer {'context': 'I-transformed cells'}", + "128, cell {'context': 'I-transformed cells'}", + "129, line {'context': 'I-transformed cells'}", + "131, syngeneic {'context': 'B-organism'}", + "132, mice {'context': 'I-organism'}", + "151, tumor {'phenotype': 'B-tumourigenesis'}", + "152, burden {'phenotype': 'I-tumourigenesis'}", + "157, mice {'context': 'B-organism'}", + "159, ARID1A-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "163, ovarian {'context': 'B-neoplasm'}", + "164, tumors. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "91, ARID1A ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "92, inactivation ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "98, ARID1A ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "99, deficiency ['l2', 'l11', 'l19', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "121, Tumors ['l3', 'l12', 'l20', 'l28', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "125, ARID1A-deficient ['l4', 'l13', 'l21', 'l29', 'l36', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "126, ovarian ['l5', 'l14', 'l22', 'l30', 'l37', 'l43', 'l49', 'l50', 'l51', 'l52', 'l53']", + "127, cancer ['l6', 'l15', 'l23', 'l31', 'l38', 'l44', 'l49', 'l54', 'l55', 'l56', 'l57']", + "128, cell ['l7', 'l16', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l58', 'l59', 'l60']", + "129, line ['l8', 'l17', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l58', 'l61', 'l62']", + "131, syngeneic ['l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l61', 'l63']", + "132, mice ['l9', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l62', 'l63']", + "151, tumor ['l64', 'l65', 'l66', 'l67', 'l68']", + "152, burden ['l64', 'l69']", + "157, mice ['l65', 'l70', 'l71', 'l72']", + "159, ARID1A-deficient ['l66', 'l70', 'l73', 'l74']", + "163, ovarian ['l67', 'l71', 'l73', 'l75']", + "164, tumors. ['l68', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ARID1A", + "inactivation", + "deficiency", + "ARID1A-deficient" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "cancer", + "cell", + "line" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ARID1A", + "inactivation", + "deficiency", + "ARID1A-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "syngeneic" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ARID1A-deficient" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "burden" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "ovarian", + "tumors." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ARID1A-deficient" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "ovarian", + "tumors." + ] + } + } + ] + }, + { + "PMID": "29736023", + "TEXT": "Genetic defects underlying the melanocortin-4 receptor (MC4R) signaling pathway lead to severe obesity. Three severely obese LEPR-deficient individuals were administered the MC4R agonist setmelanotide, resulting in substantial and durable reductions in hyperphagia and body weight over an observation period of 45-61 weeks. Compared to formerly developed and tested MC4R agonists, setmelanotide has the unique capability of activating nuclear factor of activated T cell (NFAT) signaling and restoring function of this signaling pathway for selected MC4R variants. Our data demonstrate the potency of setmelanotide in treatment of individuals with diverse MC4R-related pathway deficiencies.", + "TAG_DATA": [ + "14, severely {'perturbing_action': 'B-gene loss-of-function', 'context': 'B-organism'}", + "15, obese {'perturbing_action': 'B-gene loss-of-function', 'context': 'I-organism'}", + "16, LEPR-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "17, individuals {'context': 'I-organism'}", + "21, MC4R {'perturbing_action': 'B-pharmacological augmentation'}", + "22, agonist {'perturbing_action': 'I-pharmacological augmentation'}" + ], + "LINK_DATA": [ + "14, severely ['l0', 'l1', 'l2', 'l3', 'l4']", + "15, obese ['l0', 'l5', 'l6', 'l7', 'l8']", + "16, LEPR-deficient ['l1', 'l5', 'l9', 'l10', 'l11']", + "17, individuals ['l2', 'l6', 'l9', 'l12', 'l13']", + "21, MC4R ['l3', 'l7', 'l10', 'l12', 'l14']", + "22, agonist ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "severely", + "obese", + "LEPR-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "severely", + "obese", + "individuals" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "severely", + "obese", + "individuals" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "MC4R", + "agonist" + ] + } + } + ] + }, + { + "PMID": "29736022", + "TEXT": "Aging of hematopoietic stem cells (HSCs) is associated with a decline in their regenerative capacity and multilineage differentiation potential, contributing to the development of blood disorders. The bone marrow microenvironment has recently been suggested to influence HSC aging, but the underlying mechanisms remain largely unknown. Here we show that HSC aging critically depends on bone marrow innervation by the sympathetic nervous system (SNS), as loss of SNS nerves or adrenoreceptor β3 signaling in the bone marrow microenvironment of young mice led to premature HSC aging, as evidenced by appearance of HSC phenotypes reminiscent of physiological aging. Strikingly, supplementation of a sympathomimetic acting selectively on adrenoreceptor β3 to old mice significantly rejuvenated the in vivo function of aged HSCs, suggesting that the preservation or restitution of bone marrow SNS innervation during aging may hold the potential for new HSC rejuvenation strategies.", + "TAG_DATA": [ + "63, loss {'perturbing_action': 'B-gene loss-of-function'}", + "64, of {'perturbing_action': 'I-gene loss-of-function'}", + "65, SNS nerves {'perturbing_action': 'I-gene loss-of-function'}", + "76, young {'context': 'B-organism'}", + "77, mice {'context': 'I-organism'}", + "81, HSC {'context': 'B-cells'}", + "105, old {'context': 'B-organism'}", + "106, mice {'context': 'I-organism'}", + "110, in {'context': 'B-in vivo'}", + "111, vivo {'context': 'I-in vivo'}", + "114, aged {'context': 'B-cells'}", + "115, HSCs, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "63, loss ['l0', 'l1', 'l2', 'l3', 'l4']", + "64, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "65, SNS nerves ['l1', 'l5', 'l9', 'l10', 'l11']", + "76, young ['l2', 'l6', 'l9', 'l12', 'l13']", + "77, mice ['l3', 'l7', 'l10', 'l12', 'l14']", + "81, HSC ['l4', 'l8', 'l11', 'l13', 'l14']", + "105, old ['l15', 'l16', 'l17', 'l18', 'l19']", + "106, mice ['l15', 'l20', 'l21', 'l22', 'l23']", + "110, in ['l16', 'l20', 'l24', 'l25', 'l26']", + "111, vivo ['l17', 'l21', 'l24', 'l27', 'l28']", + "114, aged ['l18', 'l22', 'l25', 'l27', 'l29']", + "115, HSCs, ['l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "SNS nerves" + ] + }, + "context": { + "val": "organism", + "words": [ + "young", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "SNS nerves" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC" + ] + } + } + ] + }, + { + "PMID": "29713085", + "TEXT": "Tolerance to self-antigens prevents the elimination of cancer by the immune system1,2. We used synthetic chimeric antigen receptors (CARs) to overcome immunological tolerance and mediate tumor rejection in patients with chronic lymphocytic leukemia (CLL). Remission was induced in a subset of subjects, but most did not respond. Comprehensive assessment of patient-derived CAR T cells to identify mechanisms of therapeutic success and failure has not been explored. We performed genomic, phenotypic and functional evaluations to identify determinants of response. Transcriptomic profiling revealed that CAR T cells from complete-responding patients with CLL were enriched in memory-related genes, including IL-6/STAT3 signatures, whereas T cells from nonresponders upregulated programs involved in effector differentiation, glycolysis, exhaustion and apoptosis. Sustained remission was associated with an elevated frequency of CD27+CD45RO-CD8+ T cells before CAR T cell generation, and these lymphocytes possessed memory-like characteristics. Highly functional CAR T cells from patients produced STAT3-related cytokines, and serum IL-6 correlated with CAR T cell expansion. IL-6/STAT3 blockade diminished CAR T cell proliferation. Furthermore, a mechanistically relevant population of CD27+PD-1-CD8+ CAR T cells expressing high levels of the IL-6 receptor predicts therapeutic response and is responsible for tumor control. These findings uncover new features of CAR T cell biology and underscore the potential of using pretreatment biomarkers of response to advance immunotherapies.", + "TAG_DATA": [ + "99, T {'context': 'B-cells'}", + "100, cells {'context': 'B-cells'}", + "132, lymphocytes {'context': 'B-cells'}", + "157, diminished {'effect': 'B-negative'}", + "158, CAR {'context': 'B-cells'}", + "159, T {'context': 'I-cells'}", + "160, cell {'context': 'I-cells'}", + "161, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "99, T ['l0', 'l1', 'l2']", + "100, cells ['l0', 'l3', 'l4']", + "112, apoptosis. ['l1', 'l3']", + "132, lymphocytes ['l2', 'l4']", + "157, diminished ['l5', 'l6', 'l7', 'l8']", + "158, CAR ['l5', 'l9', 'l10', 'l11']", + "159, T ['l6', 'l9', 'l12', 'l13']", + "160, cell ['l7', 'l10', 'l12', 'l14']", + "161, proliferation. ['l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "diminished" + ] + }, + "context": { + "val": "cells", + "words": [ + "CAR", + "T", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "diminished" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CAR", + "T", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "29431745", + "TEXT": "Immunotherapy offers new options for cancer treatment, but efficacy varies across cancer types. Colorectal cancers (CRCs) are largely refractory to immune-checkpoint blockade, which suggests the presence of yet uncharacterized immune-suppressive mechanisms. Here we report that the loss of adenomatosis polyposis coli (APC) in intestinal tumor cells or of the tumor suppressor PTEN in melanoma cells upregulates the expression of Dickkopf-related protein 2 (DKK2), which, together with its receptor LRP5, provides an unconventional mechanism for tumor immune evasion. DKK2 secreted by tumor cells acts on cytotoxic lymphocytes, inhibiting STAT5 signaling by impeding STAT5 nuclear localization via LRP5, but independently of LRP6 and the Wnt-β-catenin pathway. Genetic or antibody-mediated ablation of DKK2 activates natural killer (NK) cells and CD8+ T cells in tumors, impedes tumor progression, and enhances the effects of PD-1 blockade. Thus, we have identified a previously unknown tumor immune-suppressive mechanism and immunotherapeutic targets particularly relevant for CRCs and a subset of melanomas.", + "TAG_DATA": [ + "36, loss {'perturbing_action': 'B-gene loss-of-function'}", + "37, of {'perturbing_action': 'I-gene loss-of-function'}", + "38, adenomatosis {'perturbing_action': 'I-gene loss-of-function'}", + "39, polyposis {'perturbing_action': 'I-gene loss-of-function'}", + "40, coli {'perturbing_action': 'I-gene loss-of-function'}", + "41, (APC) {'perturbing_action': 'I-gene loss-of-function'}", + "43, intestinal {'context': 'B-transformed cells'}", + "44, tumor {'context': 'I-transformed cells'}", + "45, cells {'context': 'I-transformed cells'}", + "47, of {'perturbing_action': 'I-gene loss-of-function'}", + "48, the {'perturbing_action': 'I-gene loss-of-function'}", + "49, tumor {'perturbing_action': 'I-gene loss-of-function'}", + "50, suppressor {'perturbing_action': 'I-gene loss-of-function'}", + "51, PTEN {'perturbing_action': 'I-gene loss-of-function'}", + "53, melanoma {'context': 'B-transformed cells'}", + "54, cells {'context': 'I-transformed cells'}", + "106, antibody-mediated {'perturbing_action': 'B-gene loss-of-function'}", + "107, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "108, of {'perturbing_action': 'I-gene loss-of-function'}", + "109, DKK2 {'perturbing_action': 'I-gene loss-of-function'}", + "111, natural {'context': 'B-cells'}", + "112, killer {'context': 'I-cells'}", + "113, (NK) {'context': 'I-cells'}", + "114, cells {'context': 'I-cells'}", + "116, CD8+ {'context': 'B-cells'}", + "117, T {'context': 'I-cells'}", + "118, cells {'context': 'I-cells'}", + "120, tumors, {'context': 'B-neoplasm'}", + "121, impedes {'effect': 'B-negative'}", + "122, tumor {'phenotype': 'B-tumour progression'}", + "123, progression, {'phenotype': 'I-tumour progression'}" + ], + "LINK_DATA": [ + "36, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "37, of ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "38, adenomatosis ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "39, polyposis ['l2', 'l16', 'l29', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "40, coli ['l3', 'l17', 'l30', 'l42', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "41, (APC) ['l4', 'l18', 'l31', 'l43', 'l54', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "43, intestinal ['l5', 'l19', 'l32', 'l44', 'l55', 'l65', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "44, tumor ['l6', 'l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l81', 'l82', 'l83']", + "45, cells ['l7', 'l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l81', 'l84', 'l85']", + "47, of ['l8', 'l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "48, the ['l9', 'l23', 'l36', 'l48', 'l59', 'l69', 'l86', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "49, tumor ['l10', 'l24', 'l37', 'l49', 'l60', 'l70', 'l87', 'l92', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "50, suppressor ['l11', 'l25', 'l38', 'l50', 'l61', 'l71', 'l88', 'l93', 'l99', 'l106', 'l107', 'l108', 'l109', 'l110']", + "51, PTEN ['l12', 'l26', 'l39', 'l51', 'l62', 'l72', 'l78', 'l89', 'l94', 'l100', 'l106', 'l111', 'l112', 'l113']", + "53, melanoma ['l13', 'l27', 'l40', 'l52', 'l63', 'l73', 'l79', 'l82', 'l84', 'l90', 'l95', 'l101', 'l107', 'l111', 'l114']", + "54, cells ['l14', 'l28', 'l41', 'l53', 'l64', 'l74', 'l80', 'l83', 'l85', 'l91', 'l96', 'l102', 'l108', 'l112', 'l114']", + "106, antibody-mediated ['l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "107, ablation ['l115', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141']", + "108, of ['l116', 'l129', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "109, DKK2 ['l117', 'l130', 'l142', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164']", + "111, natural ['l118', 'l131', 'l143', 'l154', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "112, killer ['l119', 'l132', 'l144', 'l155', 'l165', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183']", + "113, (NK) ['l103', 'l120', 'l133', 'l145', 'l156', 'l166', 'l175', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191']", + "114, cells ['l97', 'l104', 'l109', 'l113', 'l121', 'l134', 'l146', 'l157', 'l167', 'l176', 'l184', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198']", + "116, CD8+ ['l122', 'l135', 'l147', 'l158', 'l168', 'l177', 'l185', 'l192', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "117, T ['l123', 'l136', 'l148', 'l159', 'l169', 'l178', 'l186', 'l193', 'l199', 'l205', 'l206', 'l207', 'l208', 'l209']", + "118, cells ['l98', 'l105', 'l110', 'l124', 'l137', 'l149', 'l160', 'l170', 'l179', 'l187', 'l194', 'l200', 'l205', 'l210', 'l211', 'l212', 'l213']", + "120, tumors, ['l125', 'l138', 'l150', 'l161', 'l171', 'l180', 'l188', 'l195', 'l201', 'l206', 'l210', 'l214', 'l215', 'l216']", + "121, impedes ['l126', 'l139', 'l151', 'l162', 'l172', 'l181', 'l189', 'l196', 'l202', 'l207', 'l211', 'l214', 'l217', 'l218']", + "122, tumor ['l127', 'l140', 'l152', 'l163', 'l173', 'l182', 'l190', 'l197', 'l203', 'l208', 'l212', 'l215', 'l217', 'l219']", + "123, progression, ['l128', 'l141', 'l153', 'l164', 'l174', 'l183', 'l191', 'l198', 'l204', 'l209', 'l213', 'l216', 'l218', 'l219']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "adenomatosis", + "polyposis", + "coli", + "(APC)", + "PTEN", + "the", + "tumor", + "suppressor" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "intestinal", + "tumor", + "cells", + "melanoma" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "tumor", + "suppressor", + "PTEN", + "antibody-mediated", + "ablation", + "of", + "DKK2" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "(NK)", + "natural", + "killer", + "CD8+", + "T" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "antibody-mediated", + "ablation", + "of", + "DKK2" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "antibody-mediated", + "ablation", + "of", + "DKK2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impedes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "antibody-mediated", + "ablation", + "of", + "DKK2" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "natural", + "killer", + "(NK)", + "cells", + "CD8+", + "T" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impedes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "natural", + "killer", + "(NK)", + "cells", + "CD8+", + "T" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors," + ] + }, + "effect": { + "val": "negative", + "words": [ + "impedes" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors," + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impedes" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression," + ] + } + } + ] + }, + { + "PMID": "29431742", + "TEXT": "Nuclear receptors regulate gene expression in response to environmental cues, but the molecular events governing the cell type specificity of nuclear receptors remain poorly understood. Here we outline a role for a long noncoding RNA (lncRNA) in modulating the cell type-specific actions of liver X receptors (LXRs), sterol-activated nuclear receptors that regulate the expression of genes involved in cholesterol homeostasis and that have been causally linked to the pathogenesis of atherosclerosis. We identify the lncRNA MeXis as an amplifier of LXR-dependent transcription of the gene Abca1, which is critical for regulation of cholesterol efflux. Mice lacking the MeXis gene show reduced Abca1 expression in a tissue-selective manner. Furthermore, loss of MeXis in mouse bone marrow cells alters chromosome architecture at the Abca1 locus, impairs cellular responses to cholesterol overload, and accelerates the development of atherosclerosis. Mechanistic studies reveal that MeXis interacts with and guides promoter binding of the transcriptional coactivator DDX17. The identification of MeXis as a lncRNA modulator of LXR-dependent gene expression expands understanding of the mechanisms underlying cell type-selective actions of nuclear receptors in physiology and disease.", + "TAG_DATA": [ + "94, Mice {'context': 'B-organism'}", + "95, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "96, the {'perturbing_action': 'I-gene loss-of-function'}", + "97, MeXis {'perturbing_action': 'I-gene loss-of-function'}", + "98, gene {'perturbing_action': 'I-gene loss-of-function'}", + "108, loss {'perturbing_action': 'B-gene loss-of-function'}", + "109, of {'perturbing_action': 'I-gene loss-of-function'}", + "110, MeXis {'perturbing_action': 'I-gene loss-of-function'}", + "112, mouse {'context': 'B-cells'}", + "113, bone {'context': 'I-cells'}", + "114, marrow {'context': 'I-cells'}", + "115, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "94, Mice ['l0', 'l1', 'l2', 'l3']", + "95, lacking ['l0', 'l4', 'l5', 'l6']", + "96, the ['l1', 'l4', 'l7', 'l8']", + "97, MeXis ['l2', 'l5', 'l7', 'l9']", + "98, gene ['l3', 'l6', 'l8', 'l9']", + "108, loss ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "109, of ['l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "110, MeXis ['l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "112, mouse ['l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "113, bone ['l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "114, marrow ['l14', 'l19', 'l23', 'l26', 'l28', 'l30']", + "115, cells ['l15', 'l20', 'l24', 'l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "MeXis", + "gene" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "MeXis" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "bone", + "marrow", + "cells" + ] + } + } + ] + }, + { + "PMID": "29400714", + "TEXT": "An intronic GGGGCC repeat expansion in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the pathogenic mechanism of this repeat remains unclear. Using human induced motor neurons (iMNs), we found that repeat-expanded C9ORF72 was haploinsufficient in ALS. We found that C9ORF72 interacted with endosomes and was required for normal vesicle trafficking and lysosomal biogenesis in motor neurons. Repeat expansion reduced C9ORF72 expression, triggering neurodegeneration through two mechanisms: accumulation of glutamate receptors, leading to excitotoxicity, and impaired clearance of neurotoxic dipeptide repeat proteins derived from the repeat expansion. Thus, cooperativity between gain- and loss-of-function mechanisms led to neurodegeneration. Restoring C9ORF72 levels or augmenting its function with constitutively active RAB5 or chemical modulators of RAB5 effectors rescued patient neuron survival and ameliorated neurodegenerative processes in both gain- and loss-of-function C9ORF72 mouse models. Thus, modulating vesicle trafficking was able to rescue neurodegeneration caused by the C9ORF72 repeat expansion. Coupled with rare mutations in ALS2, FIG4, CHMP2B, OPTN and SQSTM1, our results reveal mechanistic convergence on vesicle trafficking in ALS and FTD.", + "TAG_DATA": [ + "31, human {'context': 'B-cells'}", + "32, induced {'context': 'I-cells'}", + "33, motor {'context': 'I-cells'}", + "34, neurons {'context': 'I-cells'}", + "35, (iMNs), {'context': 'I-cells'}", + "109, augmenting {'perturbing_action': 'B-gene gain-of-function'}", + "111, function {'perturbing_action': 'I-gene gain-of-function'}", + "112, with {'perturbing_action': 'I-gene gain-of-function'}", + "113, constitutively {'perturbing_action': 'I-gene gain-of-function'}", + "114, active {'perturbing_action': 'I-gene gain-of-function'}", + "115, RAB5 {'perturbing_action': 'I-gene gain-of-function'}", + "117, chemical {'perturbing_action': 'B-pharmacological inhibition'}", + "118, modulators {'perturbing_action': 'I-pharmacological inhibition'}", + "119, of {'perturbing_action': 'I-pharmacological inhibition'}", + "120, RAB5 {'perturbing_action': 'I-pharmacological augmentation'}", + "121, effectors {'perturbing_action': 'I-pharmacological inhibition'}", + "124, neuron {'context': 'I-cells'}", + "132, gain- {'perturbing_action': 'B-gene gain-of-function'}", + "133, and {'perturbing_action': 'B-gene loss-of-function'}", + "134, loss-of-function {'perturbing_action': 'B-gene loss-of-function'}", + "135, C9ORF72 {'perturbing_action': 'B-gene gain-of-function'}", + "136, mouse {'context': 'B-organism'}", + "137, models. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "31, human ['l0', 'l1', 'l2', 'l3']", + "32, induced ['l0', 'l4', 'l5', 'l6']", + "33, motor ['l1', 'l4', 'l7', 'l8']", + "34, neurons ['l2', 'l5', 'l7', 'l9']", + "35, (iMNs), ['l3', 'l6', 'l8', 'l9']", + "109, augmenting ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "111, function ['l10', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "112, with ['l11', 'l27', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "113, constitutively ['l12', 'l28', 'l43', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "114, active ['l13', 'l29', 'l44', 'l58', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "115, RAB5 ['l14', 'l30', 'l45', 'l59', 'l72', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "117, chemical ['l15', 'l31', 'l46', 'l60', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "118, modulators ['l16', 'l32', 'l47', 'l61', 'l93', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "119, of ['l17', 'l33', 'l48', 'l62', 'l73', 'l83', 'l94', 'l104', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "120, RAB5 ['l18', 'l34', 'l49', 'l63', 'l74', 'l84', 'l95', 'l105', 'l114', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "121, effectors ['l19', 'l35', 'l50', 'l64', 'l75', 'l85', 'l96', 'l106', 'l115', 'l123', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "124, neuron ['l20', 'l36', 'l51', 'l65', 'l76', 'l86', 'l97', 'l107', 'l116', 'l124', 'l131']", + "132, gain- ['l21', 'l37', 'l52', 'l66', 'l77', 'l87', 'l98', 'l108', 'l117', 'l125', 'l132', 'l138', 'l139', 'l140', 'l141', 'l142']", + "133, and ['l22', 'l38', 'l53', 'l67', 'l78', 'l88', 'l99', 'l109', 'l118', 'l126', 'l133', 'l138', 'l143', 'l144', 'l145', 'l146']", + "134, loss-of-function ['l23', 'l39', 'l54', 'l68', 'l79', 'l89', 'l100', 'l110', 'l119', 'l127', 'l134', 'l139', 'l143', 'l147', 'l148', 'l149']", + "135, C9ORF72 ['l24', 'l40', 'l55', 'l69', 'l80', 'l90', 'l101', 'l111', 'l120', 'l128', 'l135', 'l140', 'l144', 'l147', 'l150', 'l151']", + "136, mouse ['l25', 'l41', 'l56', 'l70', 'l81', 'l91', 'l102', 'l112', 'l121', 'l129', 'l136', 'l141', 'l145', 'l148', 'l150', 'l152']", + "137, models. ['l26', 'l42', 'l57', 'l71', 'l82', 'l92', 'l103', 'l113', 'l122', 'l130', 'l137', 'l142', 'l146', 'l149', 'l151', 'l152']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "augmenting", + "function", + "with", + "constitutively", + "active", + "RAB5" + ] + }, + "context": { + "val": "cells", + "words": [ + "neuron" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "augmenting", + "function", + "with", + "constitutively", + "active", + "RAB5", + "gain-", + "C9ORF72" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "chemical", + "modulators", + "of", + "effectors" + ] + }, + "context": { + "val": "cells", + "words": [ + "neuron" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "chemical", + "modulators", + "of", + "effectors" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "RAB5" + ] + }, + "context": { + "val": "cells", + "words": [ + "neuron" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "RAB5" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "and", + "loss-of-function" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + } + ] + }, + { + "PMID": "29400712", + "TEXT": "Hedgehog pathway-dependent cancers can escape Smoothened (SMO) inhibition through mutations in genes encoding canonical hedgehog pathway components; however, around 50% of drug-resistant basal cell carcinomas (BCCs) lack additional variants of these genes. Here we use multidimensional genomics analysis of human and mouse drug-resistant BCCs to identify a noncanonical hedgehog activation pathway driven by the transcription factor serum response factor (SRF). Active SRF along with its coactivator megakaryoblastic leukemia 1 (MKL1) binds DNA near hedgehog target genes and forms a previously unknown protein complex with the hedgehog transcription factor glioma-associated oncogene family zinc finger-1 (GLI1), causing amplification of GLI1 transcriptional activity. We show that cytoskeletal activation through Rho and the formin family member Diaphanous (mDia) is required for SRF-MKL-driven GLI1 activation and for tumor cell viability. Remarkably, nuclear MKL1 staining served as a biomarker in tumors from mice and human subjects to predict tumor responsiveness to MKL inhibitors, highlighting the therapeutic potential of targeting this pathway. Thus, our study illuminates, for the first time, cytoskeletal-activation-driven transcription as a personalized therapeutic target for combatting drug-resistant malignancies.", + "TAG_DATA": [ + "122, tumor {'context': 'B-neoplasm'}", + "123, cell {'phenotype': 'B-cell survival'}", + "124, viability. {'phenotype': 'I-cell survival'}" + ], + "LINK_DATA": [ + "122, tumor ['l0', 'l1']", + "123, cell ['l0', 'l2']", + "124, viability. ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "viability." + ] + } + } + ] + }, + { + "PMID": "29309058", + "TEXT": "Multiple immune-cell types can infiltrate tumors and promote progression and metastasis through different mechanisms, including immunosuppression. How distinct genetic alterations in tumors affect the composition of the immune landscape is currently unclear. Here, we characterized the immune-cell composition of prostate cancers driven by the loss of the critical tumor suppressor gene Pten, either alone or in combination with the loss of Trp53, Zbtb7a or Pml. We observed a striking quantitative and qualitative heterogeneity that was directly dependent on the specific genetic events in the tumor and ranged from 'cold', noninflamed tumors to massively infiltrated landscapes-results with important therapeutic implications. Further, we showed these qualitative differences in transcriptomic analysis of human prostate cancer samples. These data suggest that patient stratification on the basis of integrated genotypic-immunophenotypic analyses may be necessary for successful clinical trials and tailored precision immunological therapies.", + "TAG_DATA": [ + "39, prostate {'context': 'B-neoplasm'}", + "40, cancers {'context': 'I-neoplasm'}", + "44, loss {'perturbing_action': 'B-gene loss-of-function'}", + "45, of {'perturbing_action': 'I-gene loss-of-function'}", + "46, the {'perturbing_action': 'I-gene loss-of-function'}", + "47, critical {'perturbing_action': 'I-gene loss-of-function'}", + "48, tumor {'perturbing_action': 'I-gene loss-of-function'}", + "49, suppressor {'perturbing_action': 'I-gene loss-of-function'}", + "50, gene {'perturbing_action': 'I-gene loss-of-function'}", + "51, Pten, {'perturbing_action': 'I-gene loss-of-function'}", + "59, loss {'perturbing_action': 'B-gene loss-of-function'}", + "60, of {'perturbing_action': 'I-gene loss-of-function'}", + "61, Trp53, {'perturbing_action': 'I-gene loss-of-function'}", + "62, Zbtb7a {'perturbing_action': 'I-gene loss-of-function'}", + "63, or {'perturbing_action': 'I-gene loss-of-function'}", + "64, Pml. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "39, prostate ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "40, cancers ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "44, loss ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "45, of ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "46, the ['l3', 'l11', 'l18', 'l24', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "47, critical ['l4', 'l12', 'l19', 'l25', 'l31', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "48, tumor ['l5', 'l13', 'l20', 'l26', 'l32', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49']", + "49, suppressor ['l6', 'l14', 'l21', 'l27', 'l33', 'l39', 'l45', 'l50', 'l51', 'l52', 'l53', 'l54']", + "50, gene ['l7', 'l15', 'l22', 'l28', 'l34', 'l40', 'l46', 'l50', 'l55']", + "51, Pten, ['l8', 'l16', 'l23', 'l29', 'l35', 'l41', 'l47', 'l51', 'l55']", + "59, loss ['l56', 'l57', 'l58', 'l59', 'l60']", + "60, of ['l56', 'l61', 'l62', 'l63', 'l64']", + "61, Trp53, ['l57', 'l61', 'l65', 'l66', 'l67']", + "62, Zbtb7a ['l42', 'l52', 'l58', 'l62', 'l65', 'l68', 'l69']", + "63, or ['l36', 'l43', 'l48', 'l53', 'l59', 'l63', 'l66', 'l68', 'l70']", + "64, Pml. ['l30', 'l37', 'l44', 'l49', 'l54', 'l60', 'l64', 'l67', 'l69', 'l70']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "prostate", + "cancers" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "critical", + "tumor", + "suppressor", + "gene", + "Pten," + ] + } + } + ] + }, + { + "PMID": "29216041", + "TEXT": "In an article published recently in Nature Medicine, the authors generate organoid models of liver neoplasia. In doing so, they highlight both the diversity of current organoid methodologies and their application to cancer modeling and therapeutics discovery.", + "TAG_DATA": [ + "11, organoid {'context': 'B-organoid'}", + "12, models {'context': 'I-organoid'}", + "14, liver {'context': 'B-tissue/organ'}", + "15, neoplasia. {'phenotype': 'B-tumourigenesis'}" + ], + "LINK_DATA": [ + "11, organoid ['l0', 'l1', 'l2']", + "12, models ['l0', 'l3', 'l4']", + "14, liver ['l1', 'l3', 'l5']", + "15, neoplasia. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organoid", + "words": [ + "organoid", + "models" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasia." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasia." + ] + } + } + ] + }, + { + "PMID": "29200204", + "TEXT": "Thyroid hormone (TH) is critical for the maintenance of cellular homeostasis during stress responses, but its role in lung fibrosis is unknown. Here we found that the activity and expression of iodothyronine deiodinase 2 (DIO2), an enzyme that activates TH, were higher in lungs from patients with idiopathic pulmonary fibrosis than in control individuals and were correlated with disease severity. We also found that Dio2-knockout mice exhibited enhanced bleomycin-induced lung fibrosis. Aerosolized TH delivery increased survival and resolved fibrosis in two models of pulmonary fibrosis in mice (intratracheal bleomycin and inducible TGF-β1). Sobetirome, a TH mimetic, also blunted bleomycin-induced lung fibrosis. After bleomycin-induced injury, TH promoted mitochondrial biogenesis, improved mitochondrial bioenergetics and attenuated mitochondria-regulated apoptosis in alveolar epithelial cells both in vivo and in vitro. TH did not blunt fibrosis in Ppargc1a- or Pink1-knockout mice, suggesting dependence on these pathways. We conclude that the antifibrotic properties of TH are associated with protection of alveolar epithelial cells and restoration of mitochondrial function and that TH may thus represent a potential therapy for pulmonary fibrosis.", + "TAG_DATA": [ + "64, Dio2-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "65, mice {'context': 'B-organism'}", + "86, mice {'context': 'B-organism'}", + "99, lung {'context': 'B-tissue/organ'}", + "112, attenuated {'effect': 'B-negative'}", + "114, apoptosis {'phenotype': 'B-apoptosis'}", + "116, alveolar {'context': 'B-cells'}", + "117, epithelial {'context': 'I-cells'}", + "118, cells {'context': 'I-cells'}", + "120, in {'context': 'B-in vivo'}", + "121, vivo {'context': 'I-in vivo'}", + "123, in {'context': 'B-in vitro'}", + "124, vitro. {'context': 'I-in vitro'}", + "131, Ppargc1a- {'perturbing_action': 'B-gene loss-of-function'}", + "132, or {'perturbing_action': 'I-gene loss-of-function'}", + "133, Pink1-knockout {'perturbing_action': 'I-gene loss-of-function'}", + "134, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "64, Dio2-knockout ['l0']", + "65, mice ['l0']", + "99, lung ['l1', 'l2', 'l3', 'l4']", + "112, attenuated ['l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "114, apoptosis ['l1', 'l5', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "116, alveolar ['l2', 'l6', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "117, epithelial ['l3', 'l7', 'l14', 'l19', 'l25', 'l26', 'l27', 'l28']", + "118, cells ['l4', 'l8', 'l15', 'l20', 'l25', 'l29', 'l30']", + "120, in ['l9', 'l16', 'l21', 'l26', 'l29', 'l31', 'l32', 'l33']", + "121, vivo ['l10', 'l17', 'l22', 'l27', 'l30', 'l31', 'l34', 'l35']", + "123, in ['l11', 'l18', 'l23', 'l28', 'l32', 'l34', 'l36']", + "124, vitro. ['l12', 'l24', 'l33', 'l35', 'l36']", + "131, Ppargc1a- ['l37', 'l38', 'l39']", + "132, or ['l37', 'l40', 'l41']", + "133, Pink1-knockout ['l38', 'l40', 'l42']", + "134, mice, ['l39', 'l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dio2-knockout", + "Ppargc1a-", + "or", + "Pink1-knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + }, + "context": { + "val": "cells", + "words": [ + "alveolar", + "epithelial", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "alveolar", + "epithelial", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in" + ] + } + } + ] + }, + { + "PMID": "29035365", + "TEXT": "Critical to the function of mast cells in immune responses including allergy is their production of lipid mediators, among which only omega-6 (ω-6) arachidonate-derived eicosanoids have been well characterized. Here, by employing comprehensive lipidomics, we identify omega-3 (ω-3) fatty acid epoxides as new mast cell-derived lipid mediators and show that they are produced by PAF-AH2, an oxidized-phospholipid-selective phospholipase A2. Genetic or pharmacological deletion of PAF-AH2 reduced the steady-state production of ω-3 epoxides, leading to attenuated mast cell activation and anaphylaxis following FcɛRI cross-linking. Mechanistically, the ω-3 epoxides promote IgE-mediated activation of mast cells by downregulating Srcin1, a Src-inhibitory protein that counteracts FcɛRI signaling, through a pathway involving PPARg. Thus, the PAF-AH2-ω-3 epoxide-Srcin1 axis presents new potential drug targets for allergic diseases.", + "TAG_DATA": [ + "61, pharmacological {'perturbing_action': 'B-gene loss-of-function'}", + "62, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "63, of {'perturbing_action': 'I-gene loss-of-function'}", + "64, PAF-AH2 {'perturbing_action': 'I-gene loss-of-function'}", + "75, mast {'context': 'B-cells'}", + "76, cell {'context': 'I-cells'}", + "91, mast {'context': 'B-cells'}", + "92, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "61, pharmacological ['l0', 'l1', 'l2', 'l3', 'l4']", + "62, deletion ['l0', 'l5', 'l6', 'l7', 'l8']", + "63, of ['l1', 'l5', 'l9', 'l10', 'l11']", + "64, PAF-AH2 ['l2', 'l6', 'l9', 'l12', 'l13']", + "75, mast ['l3', 'l7', 'l10', 'l12', 'l14']", + "76, cell ['l4', 'l8', 'l11', 'l13', 'l14']", + "91, mast ['l15']", + "92, cells ['l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pharmacological", + "deletion", + "of", + "PAF-AH2" + ] + }, + "context": { + "val": "cells", + "words": [ + "mast", + "cell" + ] + } + } + ] + }, + { + "PMID": "28869610", + "TEXT": "Basal cell carcinoma (BCC), the most common human cancer, results from aberrant activation of the Hedgehog signaling pathway. Although most cases of BCC are sporadic, some forms are inherited, such as Bazex-Dupré-Christol syndrome (BDCS)-a cancer-prone genodermatosis with an X-linked, dominant inheritance pattern. We have identified mutations in the ACTRT1 gene, which encodes actin-related protein T1 (ARP-T1), in two of the six families with BDCS that were examined in this study. High-throughput sequencing in the four remaining families identified germline mutations in noncoding sequences surrounding ACTRT1. These mutations were located in transcribed sequences encoding enhancer RNAs (eRNAs) and were shown to impair enhancer activity and ACTRT1 expression. ARP-T1 was found to directly bind to the GLI1 promoter, thus inhibiting GLI1 expression, and loss of ARP-T1 led to activation of the Hedgehog pathway in individuals with BDCS. Moreover, exogenous expression of ACTRT1 reduced the in vitro and in vivo proliferation rates of cell lines with aberrant activation of the Hedgehog signaling pathway. In summary, our study identifies a disease mechanism in BCC involving mutations in regulatory noncoding elements and uncovers the tumor-suppressor properties of ACTRT1.", + "TAG_DATA": [ + "121, loss {'perturbing_action': 'B-gene loss-of-function'}", + "122, of {'perturbing_action': 'I-gene loss-of-function'}", + "123, ARP-T1 {'perturbing_action': 'I-gene loss-of-function'}", + "136, exogenous {'perturbing_action': 'B-gene gain-of-function'}", + "137, expression {'perturbing_action': 'I-gene gain-of-function'}", + "138, of {'perturbing_action': 'I-gene gain-of-function'}", + "139, ACTRT1 {'perturbing_action': 'I-gene gain-of-function'}", + "140, reduced {'effect': 'B-negative'}", + "142, in {'context': 'B-in vitro'}", + "143, vitro {'context': 'I-in vitro'}", + "145, in {'context': 'B-in vivo'}", + "146, vivo {'context': 'I-in vivo'}", + "147, proliferation {'phenotype': 'B-proliferation'}", + "150, cell {'context': 'B-cells'}", + "151, lines {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "121, loss ['l0', 'l1']", + "122, of ['l0', 'l2']", + "123, ARP-T1 ['l1', 'l2']", + "136, exogenous ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "137, expression ['l3', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "138, of ['l4', 'l14', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "139, ACTRT1 ['l5', 'l15', 'l24', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "140, reduced ['l6', 'l16', 'l25', 'l33', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "142, in ['l7', 'l17', 'l26', 'l34', 'l41', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "143, vitro ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l54', 'l55', 'l56', 'l57', 'l58']", + "145, in ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l59', 'l60', 'l61', 'l62']", + "146, vivo ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l63', 'l64', 'l65']", + "147, proliferation ['l11', 'l21', 'l30', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l66', 'l67']", + "150, cell ['l12', 'l22', 'l31', 'l39', 'l46', 'l52', 'l57', 'l61', 'l64', 'l66', 'l68']", + "151, lines ['l13', 'l23', 'l32', 'l40', 'l47', 'l53', 'l58', 'l62', 'l65', 'l67', 'l68']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "exogenous", + "expression", + "of", + "ACTRT1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "exogenous", + "expression", + "of", + "ACTRT1" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "exogenous", + "expression", + "of", + "ACTRT1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "exogenous", + "expression", + "of", + "ACTRT1" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "exogenous", + "expression", + "of", + "ACTRT1" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "lines" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "lines" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "lines" + ] + } + } + ] + }, + { + "PMID": "28825717", + "TEXT": "Recent large-scale genetic sequencing efforts have identified rare coding variants in genes in the triglyceride-rich lipoprotein (TRL) clearance pathway that are protective against coronary heart disease (CHD), independently of LDL cholesterol (LDL-C) levels. Insight into the mechanisms of protection of these variants may facilitate the development of new therapies for lowering TRL levels. The gene APOC3 encodes apoC-III, a critical inhibitor of triglyceride (TG) lipolysis and remnant TRL clearance. Here we report a detailed interrogation of the mechanism of TRL lowering by the APOC3 Ala43Thr (A43T) variant, the only missense (rather than protein-truncating) variant in APOC3 reported to be TG lowering and protective against CHD. We found that both human APOC3 A43T heterozygotes and mice expressing human APOC3 A43T display markedly reduced circulating apoC-III levels. In mice, this reduction is due to impaired binding of A43T apoC-III to lipoproteins and accelerated renal catabolism of free apoC-III. Moreover, the reduced content of apoC-III in TRLs resulted in accelerated clearance of circulating TRLs. On the basis of this protective mechanism, we developed a monoclonal antibody targeting lipoprotein-bound human apoC-III that promotes circulating apoC-III clearance in mice expressing human APOC3 and enhances TRL catabolism in vivo. These data reveal the molecular mechanism by which a missense variant in APOC3 causes reduced circulating TG levels and, hence, protects from CHD. This protective mechanism has the potential to be exploited as a new therapeutic approach to reduce apoC-III levels and circulating TRL burden.", + "TAG_DATA": [ + "109, human {'perturbing_action': 'B-other'}", + "110, APOC3 {'perturbing_action': 'I-other'}", + "111, A43T {'perturbing_action': 'I-other'}", + "112, heterozygotes {'perturbing_action': 'I-other'}", + "114, mice {'context': 'B-organism'}", + "115, expressing {'perturbing_action': 'B-other'}", + "116, human {'perturbing_action': 'I-other'}", + "117, APOC3 {'perturbing_action': 'I-other'}", + "118, A43T {'perturbing_action': 'I-other'}", + "126, mice, {'context': 'B-organism'}", + "183, mice {'context': 'B-organism'}", + "184, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "185, human {'perturbing_action': 'I-gene gain-of-function'}", + "186, APOC3 {'perturbing_action': 'I-gene gain-of-function'}", + "191, in {'context': 'B-in vivo'}", + "192, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "109, human ['l0', 'l1', 'l2', 'l3', 'l4']", + "110, APOC3 ['l0', 'l5', 'l6', 'l7', 'l8']", + "111, A43T ['l1', 'l5', 'l9', 'l10', 'l11']", + "112, heterozygotes ['l2', 'l6', 'l9', 'l12', 'l13']", + "114, mice ['l14', 'l15', 'l16', 'l17', 'l18']", + "115, expressing ['l14', 'l19', 'l20', 'l21', 'l22']", + "116, human ['l15', 'l19', 'l23', 'l24', 'l25']", + "117, APOC3 ['l16', 'l20', 'l23', 'l26', 'l27']", + "118, A43T ['l3', 'l7', 'l10', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "126, mice, ['l4', 'l8', 'l11', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']", + "183, mice ['l29', 'l30', 'l31', 'l32', 'l33']", + "184, expressing ['l29', 'l34', 'l35', 'l36', 'l37']", + "185, human ['l30', 'l34', 'l38', 'l39', 'l40']", + "186, APOC3 ['l31', 'l35', 'l38', 'l41', 'l42']", + "191, in ['l32', 'l36', 'l39', 'l41', 'l43']", + "192, vivo. ['l33', 'l37', 'l40', 'l42', 'l43']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "human", + "APOC3", + "A43T", + "heterozygotes", + "expressing" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "human", + "APOC3" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "human", + "APOC3" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "28759052", + "TEXT": "D-mannose, a C-2 epimer of glucose, exists naturally in many plants and fruits, and is found in human blood at concentrations less than one-fiftieth of that of glucose. However, although the roles of glucose in T cell metabolism, diabetes and obesity are well characterized, the function of D-mannose in T cell immune responses remains unknown. Here we show that supraphysiological levels of D-mannose safely achievable by drinking-water supplementation suppressed immunopathology in mouse models of autoimmune diabetes and airway inflammation, and increased the proportion of Foxp3+ regulatory T cells (Treg cells) in mice. In vitro, D-mannose stimulated Treg cell differentiation in human and mouse cells by promoting TGF-β activation, which in turn was mediated by upregulation of integrin αvβ8 and reactive oxygen species generated by increased fatty acid oxidation. This previously unrecognized immunoregulatory function of D-mannose may have clinical applications for immunopathology.", + "TAG_DATA": [ + "71, mouse {'context': 'B-organism'}", + "72, models {'context': 'I-organism'}", + "84, Foxp3+ {'context': 'B-cells'}", + "85, regulatory {'context': 'I-cells'}", + "86, T {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}", + "88, (Treg {'context': 'I-cells'}", + "89, cells) {'context': 'I-cells'}", + "91, mice. {'context': 'B-organism'}", + "92, In {'context': 'B-in vitro'}", + "93, vitro, {'context': 'I-in vitro'}", + "95, stimulated {'effect': 'B-positive'}", + "96, Treg {'context': 'B-cells'}", + "97, cell {'context': 'I-cells'}", + "98, differentiation {'phenotype': 'B-differentiation'}", + "100, human {'context': 'B-cells'}", + "101, and {'context': 'I-cells'}", + "102, mouse {'context': 'I-cells'}", + "103, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "71, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "72, models ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "84, Foxp3+ ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "85, regulatory ['l2', 'l8', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "86, T ['l3', 'l9', 'l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "87, cells ['l4', 'l10', 'l15', 'l20', 'l24', 'l28', 'l29', 'l30']", + "88, (Treg ['l5', 'l11', 'l16', 'l21', 'l25', 'l28', 'l31', 'l32']", + "89, cells) ['l6', 'l12', 'l17', 'l22', 'l26', 'l29', 'l31', 'l33']", + "91, mice. ['l18', 'l23', 'l27', 'l30', 'l32', 'l33']", + "92, In ['l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "93, vitro, ['l34', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "95, stimulated ['l35', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "96, Treg ['l36', 'l44', 'l51', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "97, cell ['l37', 'l45', 'l52', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "98, differentiation ['l38', 'l46', 'l53', 'l59', 'l64', 'l69', 'l70', 'l71', 'l72']", + "100, human ['l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l73', 'l74', 'l75']", + "101, and ['l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l76', 'l77']", + "102, mouse ['l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l78']", + "103, cells ['l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l77', 'l78']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + }, + "context": { + "val": "cells", + "words": [ + "Treg", + "cell", + "human", + "and", + "mouse", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Treg", + "cell", + "human", + "and", + "mouse", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "28650457", + "TEXT": "The endocrine-derived hormone fibroblast growth factor (FGF) 19 has recently emerged as a potential target for treating metabolic disease. Given that skeletal muscle is a key metabolic organ, we explored the role of FGF19 in that tissue. Here we report a novel function of FGF19 in regulating skeletal muscle mass through enlargement of muscle fiber size, and in protecting muscle from atrophy. Treatment with FGF19 causes skeletal muscle hypertrophy in mice, while physiological and pharmacological doses of FGF19 substantially increase the size of human myotubes in vitro. These effects were not elicited by FGF21, a closely related endocrine FGF member. Both in vitro and in vivo, FGF19 stimulates the phosphorylation of the extracellular-signal-regulated protein kinase 1/2 (ERK1/2) and the ribosomal protein S6 kinase (S6K1), an mTOR-dependent master regulator of muscle cell growth. Moreover, mice with a skeletal-muscle-specific genetic deficiency of β-Klotho (KLB), an obligate co-receptor for FGF15/19 (refs. 2,3), were unresponsive to the hypertrophic effect of FGF19. Finally, in mice, FGF19 ameliorates skeletal muscle atrophy induced by glucocorticoid treatment or obesity, as well as sarcopenia. Taken together, these findings provide evidence that the enterokine FGF19 is a novel factor in the regulation of skeletal muscle mass, and that it has therapeutic potential for the treatment of muscle wasting.", + "TAG_DATA": [ + "70, mice, {'context': 'B-organism'}", + "83, human {'context': 'B-cells'}", + "84, myotubes {'context': 'I-cells'}", + "85, in {'context': 'B-in vitro'}", + "86, vitro. {'context': 'I-in vitro'}", + "101, in {'context': 'B-in vitro'}", + "102, vitro {'context': 'I-in vitro'}", + "104, in {'context': 'B-in vivo'}", + "105, vivo, {'context': 'I-in vivo'}", + "133, mice {'context': 'B-organism'}", + "136, skeletal-muscle-specific {'perturbing_action': 'B-gene loss-of-function'}", + "137, genetic {'perturbing_action': 'I-gene loss-of-function'}", + "138, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "139, of {'perturbing_action': 'I-gene loss-of-function'}", + "140, β-Klotho {'perturbing_action': 'I-gene loss-of-function'}", + "141, (KLB), {'perturbing_action': 'I-gene loss-of-function'}", + "159, mice, {'context': 'B-organism'}", + "162, skeletal {'context': 'B-tissue/organ'}", + "163, muscle {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "83, human ['l0', 'l1', 'l2']", + "84, myotubes ['l0', 'l3', 'l4']", + "85, in ['l1', 'l3', 'l5']", + "86, vitro. ['l2', 'l4', 'l5']", + "101, in ['l6', 'l7', 'l8']", + "102, vitro ['l6', 'l9', 'l10']", + "104, in ['l7', 'l9', 'l11']", + "105, vivo, ['l8', 'l10', 'l11']", + "133, mice ['l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "136, skeletal-muscle-specific ['l12', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "137, genetic ['l13', 'l18', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "138, deficiency ['l14', 'l19', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "139, of ['l15', 'l20', 'l27', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "140, β-Klotho ['l16', 'l21', 'l28', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47']", + "141, (KLB), ['l17', 'l22', 'l29', 'l35', 'l40', 'l44', 'l48', 'l49', 'l50']", + "159, mice, ['l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l51', 'l52']", + "162, skeletal ['l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l53']", + "163, muscle ['l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l53']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "skeletal-muscle-specific", + "genetic", + "deficiency", + "of", + "β-Klotho", + "(KLB)," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "skeletal-muscle-specific", + "genetic", + "deficiency", + "of", + "β-Klotho", + "(KLB)," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skeletal", + "muscle" + ] + } + } + ] + }, + { + "PMID": "28504723", + "TEXT": "Impaired learning and cognitive function often occurs during systemic infection or inflammation. Although activation of the innate immune system has been linked to the behavioral and cognitive effects that are associated with infection, the underlying mechanisms remain poorly understood. Here we mimicked viral immune activation with poly(I:C), a synthetic analog of double-stranded RNA, and longitudinally imaged postsynaptic dendritic spines of layer V pyramidal neurons in the mouse primary motor cortex using two-photon microscopy. We found that peripheral immune activation caused dendritic spine loss, impairments in learning-dependent dendritic spine formation and deficits in multiple learning tasks in mice. These observed synaptic alterations in the cortex were mediated by peripheral-monocyte-derived cells and did not require microglial function in the central nervous system. Furthermore, activation of CX3CR1highLy6Clow monocytes impaired motor learning and learning-related dendritic spine plasticity through tumor necrosis factor (TNF)-α-dependent mechanisms. Taken together, our results highlight CX3CR1high monocytes and TNF-α as potential therapeutic targets for preventing infection-induced cognitive dysfunction.", + "TAG_DATA": [ + "60, layer {'context': 'B-cells'}", + "61, V {'context': 'I-cells'}", + "62, pyramidal {'context': 'I-cells'}", + "63, neurons {'context': 'I-cells'}", + "64, in {'context': 'I-cells'}", + "65, the {'context': 'I-cells'}", + "66, mouse {'context': 'I-cells'}", + "67, primary {'context': 'I-cells'}", + "68, motor {'context': 'I-cells'}", + "69, cortex {'context': 'I-cells'}", + "96, mice. {'context': 'B-organism'}", + "121, activation {'perturbing_action': 'B-pharmacological augmentation'}", + "122, of {'perturbing_action': 'I-pharmacological augmentation'}", + "123, CX3CR1highLy6Clow {'perturbing_action': 'I-other'}", + "124, monocytes {'context': 'B-cells'}", + "125, impaired {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "60, layer ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "61, V ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "62, pyramidal ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "63, neurons ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "64, in ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "65, the ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "66, mouse ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "67, primary ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "68, motor ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "69, cortex ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "121, activation ['l45', 'l46', 'l47', 'l48']", + "122, of ['l45', 'l49', 'l50', 'l51']", + "123, CX3CR1highLy6Clow ['l46', 'l49', 'l52', 'l53']", + "124, monocytes ['l47', 'l50', 'l52', 'l54']", + "125, impaired ['l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "of" + ] + }, + "context": { + "val": "cells", + "words": [ + "monocytes" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "of" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "CX3CR1highLy6Clow" + ] + }, + "context": { + "val": "cells", + "words": [ + "monocytes" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "CX3CR1highLy6Clow" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "monocytes" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + } + ] + }, + { + "PMID": "28394332", + "TEXT": "Damage-associated molecular patterns (DAMPs) trigger sterile inflammation after tissue injury, but the mechanisms underlying the resolution of inflammation remain unclear. In this study, we demonstrate that common DAMPs, such as high-mobility-group box 1 (HMGB1), peroxiredoxins (PRXs), and S100A8 and S100A9, were internalized through the class A scavenger receptors MSR1 and MARCO in vitro. In ischemic murine brain, DAMP internalization was largely mediated by MSR1. An elevation of MSR1 levels in infiltrating myeloid cells observed 3 d after experimental stroke was dependent on the transcription factor Mafb. Combined deficiency for Msr1 and Marco, or for Mafb alone, in infiltrating myeloid cells caused impaired clearance of DAMPs, more severe inflammation, and exacerbated neuronal injury in a murine model of ischemic stroke. The retinoic acid receptor (RAR) agonist Am80 increased the expression of Mafb, thereby enhancing MSR1 expression. Am80 exhibited therapeutic efficacy when administered, even at 24 h after the onset of experimental stroke. Our findings uncover cellular mechanisms contributing to DAMP clearance in resolution of the sterile inflammation triggered by tissue injury.", + "TAG_DATA": [ + "55, murine {'context': 'B-tissue/organ'}", + "56, brain, {'context': 'I-tissue/organ'}", + "86, Combined {'perturbing_action': 'B-gene loss-of-function'}", + "87, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "88, for {'perturbing_action': 'I-gene loss-of-function'}", + "89, Msr1 {'perturbing_action': 'I-gene loss-of-function'}", + "90, and {'perturbing_action': 'I-gene loss-of-function'}", + "91, Marco, {'perturbing_action': 'I-gene loss-of-function'}", + "98, myeloid {'context': 'B-cells'}", + "99, cells {'context': 'I-cells'}", + "114, murine {'context': 'B-organism'}", + "115, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "55, murine ['l0']", + "56, brain, ['l0']", + "86, Combined ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "87, deficiency ['l1', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "88, for ['l2', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "89, Msr1 ['l3', 'l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "90, and ['l4', 'l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "91, Marco, ['l5', 'l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "98, myeloid ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "99, cells ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "114, murine ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "115, model ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Combined", + "deficiency", + "for", + "Msr1", + "and", + "Marco," + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Combined", + "deficiency", + "for", + "Msr1", + "and", + "Marco," + ] + }, + "context": { + "val": "organism", + "words": [ + "murine", + "model" + ] + } + } + ] + }, + { + "PMID": "28319094", + "TEXT": "Tyrosine-kinase inhibitor (TKI) therapy for human cancers is not curative, and relapse occurs owing to the continued presence of tumor cells, referred to as minimal residual disease (MRD). The survival of MRD stem or progenitor cells in the absence of oncogenic kinase signaling, a phenomenon referred to as intrinsic resistance, depends on diverse growth factors. Here we report that oncogenic kinase and growth-factor signaling converge to induce the expression of the signaling proteins FBJ osteosarcoma oncogene (c-FOS, encoded by Fos) and dual-specificity phosphatase 1 (DUSP1). Genetic deletion of Fos and Dusp1 suppressed tumor growth in a BCR-ABL fusion protein kinase-induced mouse model of chronic myeloid leukemia (CML). Pharmacological inhibition of c-FOS, DUSP1 and BCR-ABL eradicated MRD in multiple in vivo models, as well as in mice xenotransplanted with patient-derived primary CML cells. Growth-factor signaling also conferred TKI resistance and induced FOS and DUSP1 expression in tumor cells modeling other types of kinase-driven leukemias. Our data demonstrate that c-FOS and DUSP1 expression levels determine the threshold of TKI efficacy, such that growth-factor-induced expression of c-FOS and DUSP1 confers intrinsic resistance to TKI therapy in a wide-ranging set of leukemias, and might represent a unifying Achilles' heel of kinase-driven cancers.", + "TAG_DATA": [ + "85, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "86, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "87, of {'perturbing_action': 'I-gene loss-of-function'}", + "88, Fos {'perturbing_action': 'I-gene loss-of-function'}", + "89, and {'perturbing_action': 'I-gene loss-of-function'}", + "90, Dusp1 {'perturbing_action': 'I-gene loss-of-function'}", + "91, suppressed {'effect': 'B-negative'}", + "92, tumor {'phenotype': 'B-tumour growth'}", + "93, growth {'phenotype': 'I-tumour growth'}", + "100, mouse {'context': 'B-neoplasm'}", + "101, model {'context': 'I-neoplasm'}", + "102, of {'context': 'I-neoplasm'}", + "103, chronic {'context': 'I-neoplasm'}", + "104, myeloid {'context': 'I-neoplasm'}", + "105, leukemia {'context': 'I-neoplasm'}", + "106, (CML). {'context': 'I-neoplasm'}", + "107, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "108, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "109, of {'perturbing_action': 'I-pharmacological inhibition'}", + "110, c-FOS, {'perturbing_action': 'I-pharmacological inhibition'}", + "111, DUSP1 {'perturbing_action': 'I-pharmacological inhibition'}", + "112, and {'perturbing_action': 'I-pharmacological inhibition'}", + "113, BCR-ABL {'perturbing_action': 'I-pharmacological inhibition'}", + "118, in {'context': 'B-in vivo'}", + "119, vivo {'context': 'I-in vivo'}", + "125, mice {'context': 'B-organism'}", + "126, xenotransplanted {'context': 'I-xenograft'}", + "127, with {'context': 'I-xenograft'}", + "128, patient-derived {'context': 'I-xenograft'}", + "129, primary {'context': 'I-xenograft'}", + "130, CML {'context': 'I-xenograft'}", + "131, cells. {'context': 'I-xenograft'}", + "145, tumor {'context': 'B-transformed cells'}", + "146, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "85, Genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "86, deletion ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "87, of ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "88, Fos ['l2', 'l16', 'l29', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "89, and ['l3', 'l17', 'l30', 'l42', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "90, Dusp1 ['l4', 'l18', 'l31', 'l43', 'l54', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "91, suppressed ['l5', 'l19', 'l32', 'l44', 'l55', 'l65', 'l75', 'l76', 'l77']", + "92, tumor ['l6', 'l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l78']", + "93, growth ['l7', 'l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l78']", + "100, mouse ['l8', 'l22', 'l35', 'l47', 'l58', 'l68', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "101, model ['l9', 'l23', 'l36', 'l48', 'l59', 'l69', 'l79', 'l85', 'l86', 'l87', 'l88', 'l89']", + "102, of ['l10', 'l24', 'l37', 'l49', 'l60', 'l70', 'l77', 'l80', 'l85', 'l90', 'l91', 'l92', 'l93']", + "103, chronic ['l11', 'l25', 'l38', 'l50', 'l61', 'l71', 'l81', 'l86', 'l90', 'l94', 'l95', 'l96']", + "104, myeloid ['l12', 'l26', 'l39', 'l51', 'l62', 'l72', 'l82', 'l87', 'l91', 'l94', 'l97', 'l98']", + "105, leukemia ['l13', 'l27', 'l40', 'l52', 'l63', 'l73', 'l83', 'l88', 'l92', 'l95', 'l97', 'l99']", + "106, (CML). ['l14', 'l28', 'l41', 'l53', 'l64', 'l74', 'l84', 'l89', 'l93', 'l96', 'l98', 'l99']", + "107, Pharmacological ['l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "108, inhibition ['l100', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "109, of ['l101', 'l117', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "110, c-FOS, ['l102', 'l118', 'l133', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "111, DUSP1 ['l103', 'l119', 'l134', 'l148', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "112, and ['l104', 'l120', 'l135', 'l149', 'l162', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184']", + "113, BCR-ABL ['l105', 'l121', 'l136', 'l150', 'l163', 'l174', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "118, in ['l106', 'l122', 'l137', 'l151', 'l164', 'l175', 'l185', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202']", + "119, vivo ['l107', 'l123', 'l138', 'l152', 'l165', 'l176', 'l186', 'l195', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209']", + "125, mice ['l108', 'l124', 'l139', 'l153', 'l166', 'l177', 'l187', 'l196', 'l203', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215']", + "126, xenotransplanted ['l109', 'l125', 'l140', 'l154', 'l167', 'l178', 'l188', 'l197', 'l204', 'l210', 'l216', 'l217', 'l218', 'l219', 'l220']", + "127, with ['l110', 'l126', 'l141', 'l155', 'l168', 'l179', 'l189', 'l198', 'l205', 'l211', 'l216', 'l221', 'l222', 'l223', 'l224']", + "128, patient-derived ['l111', 'l127', 'l142', 'l156', 'l169', 'l180', 'l190', 'l199', 'l206', 'l212', 'l217', 'l221', 'l225', 'l226', 'l227', 'l228', 'l229']", + "129, primary ['l112', 'l128', 'l143', 'l157', 'l170', 'l181', 'l191', 'l200', 'l207', 'l213', 'l218', 'l222', 'l225', 'l230', 'l231']", + "130, CML ['l113', 'l129', 'l144', 'l158', 'l171', 'l182', 'l192', 'l201', 'l208', 'l214', 'l219', 'l223', 'l226', 'l230', 'l232']", + "131, cells. ['l114', 'l130', 'l145', 'l159', 'l172', 'l183', 'l193', 'l202', 'l209', 'l215', 'l220', 'l224', 'l227', 'l231', 'l232']", + "145, tumor ['l115', 'l131', 'l146', 'l160', 'l228', 'l233']", + "146, cells ['l116', 'l132', 'l147', 'l161', 'l173', 'l184', 'l194', 'l229', 'l233']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "deletion", + "of", + "Fos", + "and", + "Dusp1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "deletion", + "of", + "Fos", + "and", + "Dusp1" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "deletion", + "of", + "Fos", + "and", + "Dusp1" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "chronic", + "myeloid", + "leukemia", + "(CML)." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "of" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "c-FOS,", + "DUSP1", + "and", + "BCR-ABL" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "c-FOS,", + "DUSP1", + "and", + "BCR-ABL" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "c-FOS,", + "DUSP1", + "and", + "BCR-ABL" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenotransplanted", + "with", + "patient-derived", + "primary", + "CML", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "c-FOS,", + "DUSP1", + "and", + "BCR-ABL" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + } + ] + }, + { + "PMID": "28263309", + "TEXT": "Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor that is located in the pons and primarily affects children. Nearly 80% of DIPGs harbor mutations in histone H3 genes, wherein lysine 27 is substituted with methionine (H3K27M). H3K27M has been shown to inhibit polycomb repressive complex 2 (PRC2), a multiprotein complex responsible for the methylation of H3 at lysine 27 (H3K27me), by binding to its catalytic subunit EZH2. Although DIPGs with the H3K27M mutation show global loss of H3K27me3, several genes retain H3K27me3. Here we describe a mouse model of DIPG in which H3K27M potentiates tumorigenesis. Using this model and primary patient-derived DIPG cell lines, we show that H3K27M-expressing tumors require PRC2 for proliferation. Furthermore, we demonstrate that small-molecule EZH2 inhibitors abolish tumor cell growth through a mechanism that is dependent on the induction of the tumor-suppressor protein p16INK4A. Genome-wide enrichment analyses show that the genes that retain H3K27me3 in H3K27M cells are strong polycomb targets. Furthermore, we find a highly significant overlap between genes that retain H3K27me3 in the DIPG mouse model and in human primary DIPGs expressing H3K27M. Taken together, these results show that residual PRC2 activity is required for the proliferation of H3K27M-expressing DIPGs, and that inhibition of EZH2 is a potential therapeutic strategy for the treatment of these tumors.", + "TAG_DATA": [ + "88, mouse {'context': 'B-organism'}", + "89, model {'context': 'I-organism'}", + "95, potentiates {'effect': 'B-positive'}", + "96, tumorigenesis. {'phenotype': 'B-tumourigenesis'}", + "101, primary {'context': 'B-transformed cells'}", + "102, patient-derived {'context': 'I-transformed cells'}", + "103, DIPG {'context': 'I-transformed cells'}", + "104, cell {'context': 'I-transformed cells'}", + "105, lines, {'context': 'I-transformed cells'}", + "119, small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "120, EZH2 {'perturbing_action': 'I-pharmacological inhibition'}", + "121, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "122, abolish {'effect': 'B-negative'}", + "123, tumor {'context': 'B-neoplasm'}", + "124, cell {'phenotype': 'B-cell growth'}", + "125, growth {'phenotype': 'I-cell growth'}" + ], + "LINK_DATA": [ + "88, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "89, model ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "91, DIPG ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "95, potentiates ['l2', 'l8', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "96, tumorigenesis. ['l3', 'l9', 'l14', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30']", + "101, primary ['l4', 'l10', 'l15', 'l20', 'l26', 'l31', 'l32', 'l33', 'l34', 'l35']", + "102, patient-derived ['l21', 'l27', 'l31', 'l36', 'l37', 'l38', 'l39']", + "103, DIPG ['l16', 'l22', 'l28', 'l32', 'l36', 'l40', 'l41', 'l42']", + "104, cell ['l5', 'l11', 'l17', 'l23', 'l29', 'l33', 'l37', 'l40', 'l43', 'l44']", + "105, lines, ['l6', 'l12', 'l18', 'l24', 'l30', 'l34', 'l38', 'l41', 'l43', 'l45']", + "110, tumors ['l25', 'l35', 'l39', 'l42', 'l44', 'l45']", + "119, small-molecule ['l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "120, EZH2 ['l46', 'l52', 'l53', 'l54', 'l55', 'l56']", + "121, inhibitors ['l47', 'l52', 'l57', 'l58', 'l59', 'l60']", + "122, abolish ['l48', 'l53', 'l57', 'l61', 'l62', 'l63']", + "123, tumor ['l49', 'l54', 'l58', 'l61', 'l64', 'l65']", + "124, cell ['l50', 'l55', 'l59', 'l62', 'l64', 'l66']", + "125, growth ['l51', 'l56', 'l60', 'l63', 'l65', 'l66']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "effect": { + "val": "positive", + "words": [ + "potentiates" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "potentiates" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "potentiates" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "patient-derived", + "DIPG", + "cell", + "lines," + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "patient-derived", + "DIPG", + "cell", + "lines," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "EZH2", + "inhibitors" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abolish" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "EZH2", + "inhibitors" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "EZH2", + "inhibitors" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abolish" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abolish" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + } + ] + }, + { + "PMID": "28263307", + "TEXT": "Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor characterized by rapid and uniform patient demise. A heterozygous point mutation of histone H3 occurs in more than 80% of these tumors and results in a lysine-to-methionine substitution (H3K27M). Expression of this histone mutant is accompanied by a reduction in the levels of polycomb repressive complex 2 (PRC2)-mediated H3K27 trimethylation (H3K27me3), and this is hypothesized to be a driving event of DIPG oncogenesis. Despite a major loss of H3K27me3, PRC2 activity is still detected in DIPG cells positive for H3K27M. To investigate the functional roles of H3K27M and PRC2 in DIPG pathogenesis, we profiled the epigenome of H3K27M-mutant DIPG cells and found that H3K27M associates with increased H3K27 acetylation (H3K27ac). In accordance with previous biochemical data, the majority of the heterotypic H3K27M-K27ac nucleosomes colocalize with bromodomain proteins at the loci of actively transcribed genes, whereas PRC2 is excluded from these regions; this suggests that H3K27M does not sequester PRC2 on chromatin. Residual PRC2 activity is required to maintain DIPG proliferative potential, by repressing neuronal differentiation and function. Finally, to examine the therapeutic potential of blocking the recruitment of bromodomain proteins by heterotypic H3K27M-K27ac nucleosomes in DIPG cells, we performed treatments in vivo with BET bromodomain inhibitors and demonstrate that they efficiently inhibit tumor progression, thus identifying this class of compounds as potential therapeutics in DIPG.", + "TAG_DATA": [ + "109, H3K27M-mutant {'perturbing_action': 'B-other'}", + "110, DIPG {'context': 'B-transformed cells'}", + "111, cells {'context': 'I-transformed cells'}", + "171, proliferative {'phenotype': 'B-proliferation'}", + "172, potential, {'phenotype': 'I-proliferation'}", + "174, repressing {'effect': 'B-negative'}", + "176, differentiation {'phenotype': 'B-differentiation'}", + "197, DIPG {'context': 'B-transformed cells'}", + "198, cells, {'context': 'I-transformed cells'}", + "202, in {'context': 'B-in vivo'}", + "203, vivo {'context': 'I-in vivo'}", + "213, inhibit {'effect': 'B-negative'}", + "214, tumor {'phenotype': 'B-tumour progression'}", + "215, progression, {'phenotype': 'I-tumour progression'}" + ], + "LINK_DATA": [ + "109, H3K27M-mutant ['l0', 'l1']", + "110, DIPG ['l0', 'l2']", + "111, cells ['l1', 'l2']", + "171, proliferative ['l3', 'l4', 'l5', 'l6', 'l7']", + "172, potential, ['l3', 'l8', 'l9', 'l10', 'l11']", + "174, repressing ['l4', 'l8', 'l12', 'l13', 'l14', 'l15', 'l16']", + "176, differentiation ['l5', 'l9', 'l12', 'l17', 'l18']", + "197, DIPG ['l6', 'l10', 'l13', 'l17', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "198, cells, ['l7', 'l11', 'l14', 'l18', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "202, in ['l15', 'l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "203, vivo ['l16', 'l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "213, inhibit ['l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "214, tumor ['l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "215, progression, ['l24', 'l29', 'l33', 'l36', 'l38', 'l39']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "H3K27M-mutant" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "DIPG", + "cells" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "potential," + ] + }, + "effect": { + "val": "negative", + "words": [ + "repressing" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "potential," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "DIPG", + "cells," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "repressing" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "repressing", + "inhibit" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "DIPG", + "cells," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "repressing", + "inhibit" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "DIPG", + "cells," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "DIPG", + "cells," + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression," + ] + } + } + ] + }, + { + "PMID": "28191886", + "TEXT": "The voltage-gated cardiac Na+ channel (Nav1.5), encoded by the SCN5A gene, conducts the inward depolarizing cardiac Na+ current (INa) and is vital for normal cardiac electrical activity. Inherited loss-of-function mutations in SCN5A lead to defects in the generation and conduction of the cardiac electrical impulse and are associated with various arrhythmia phenotypes. Here we show that sirtuin 1 deacetylase (Sirt1) deacetylates Nav1.5 at lysine 1479 (K1479) and stimulates INa via lysine-deacetylation-mediated trafficking of Nav1.5 to the plasma membrane. Cardiac Sirt1 deficiency in mice induces hyperacetylation of K1479 in Nav1.5, decreases expression of Nav1.5 on the cardiomyocyte membrane, reduces INa and leads to cardiac conduction abnormalities and premature death owing to arrhythmia. The arrhythmic phenotype of cardiac-Sirt1-deficient mice recapitulated human cardiac arrhythmias resulting from loss of function of Nav1.5. Increased Sirt1 activity or expression results in decreased lysine acetylation of Nav1.5, which promotes the trafficking of Nav1.5 to the plasma membrane and stimulation of INa. As compared to wild-type Nav1.5, Nav1.5 with K1479 mutated to a nonacetylatable residue increases peak INa and is not regulated by Sirt1, whereas Nav1.5 with K1479 mutated to mimic acetylation decreases INa. Nav1.5 is hyperacetylated on K1479 in the hearts of patients with cardiomyopathy and clinical conduction disease. Thus, Sirt1, by deacetylating Nav1.5, plays an essential part in the regulation of INa and cardiac electrical activity.", + "TAG_DATA": [ + "78, Cardiac {'perturbing_action': 'B-gene loss-of-function'}", + "79, Sirt1 {'perturbing_action': 'I-gene loss-of-function'}", + "80, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "82, mice {'context': 'B-organism'}", + "115, cardiac-Sirt1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "116, mice {'context': 'B-organism'}", + "123, loss {'perturbing_action': 'B-gene loss-of-function'}", + "124, of {'perturbing_action': 'I-gene loss-of-function'}", + "125, function {'perturbing_action': 'I-gene loss-of-function'}", + "126, of {'perturbing_action': 'I-gene loss-of-function'}", + "127, Nav1.5. {'perturbing_action': 'I-gene loss-of-function'}", + "161, K1479 {'perturbing_action': 'I-other'}", + "162, mutated {'perturbing_action': 'I-other'}", + "179, K1479 {'perturbing_action': 'I-other'}", + "180, mutated {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "78, Cardiac ['l0', 'l1', 'l2']", + "79, Sirt1 ['l0', 'l3', 'l4']", + "80, deficiency ['l1', 'l3', 'l5']", + "82, mice ['l2', 'l4', 'l5']", + "115, cardiac-Sirt1-deficient ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "116, mice ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "123, loss ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "124, of ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "125, function ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "126, of ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "127, Nav1.5. ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']", + "161, K1479 ['l27', 'l28', 'l29']", + "162, mutated ['l27', 'l30', 'l31']", + "179, K1479 ['l28', 'l30', 'l32']", + "180, mutated ['l29', 'l31', 'l32']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cardiac", + "Sirt1", + "deficiency", + "cardiac-Sirt1-deficient", + "loss", + "of", + "function", + "Nav1.5." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "28165480", + "TEXT": "Cystinuria is an incompletely dominant disorder characterized by defective urinary cystine reabsorption that results in the formation of cystine-based urinary stones. Current treatment options are limited in their effectiveness at preventing stone recurrence and are often poorly tolerated. We report that the nutritional supplement α-lipoic acid inhibits cystine stone formation in the Slc3a1-/- mouse model of cystinuria by increasing the solubility of urinary cystine. These findings identify a novel therapeutic strategy for the clinical treatment of cystinuria.", + "TAG_DATA": [ + "46, inhibits {'effect': 'B-negative'}", + "49, formation {'phenotype': 'I-tumourigenesis'}", + "52, Slc3a1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "53, mouse {'context': 'B-organism'}", + "54, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "46, inhibits ['l0', 'l1', 'l2', 'l3']", + "49, formation ['l0', 'l4', 'l5']", + "52, Slc3a1-/- ['l1', 'l6', 'l7']", + "53, mouse ['l2', 'l4', 'l6', 'l8']", + "54, model ['l3', 'l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Slc3a1-/-" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Slc3a1-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + } + ] + }, + { + "PMID": "28112734", + "TEXT": "Opportunistic fungal infections are a leading cause of death among immune-compromised patients, and there is a pressing need to develop new antifungal therapeutic agents because of toxicity and resistance to the antifungal drugs currently in use. Although C-type lectin receptor- and Toll-like receptor-induced signaling pathways are key activators of host antifungal immunity, little is known about the mechanisms that negatively regulate host immune responses to a fungal infection. Here we found that JNK1 activation suppresses antifungal immunity in mice. We showed that JNK1-deficient mice had a significantly higher survival rate than wild-type control mice in response to Candida albicans infection, and the expression of JNK1 in hematopoietic innate immune cells was critical for this effect. JNK1 deficiency leads to significantly higher induction of CD23, a novel C-type lectin receptor, through NFATc1-mediated regulation of the CD23 gene promoter. Blocking either CD23 upregulation or CD23-dependent nitric oxide production eliminated the enhanced antifungal response found in JNK1-deficient mice. Notably, JNK inhibitors exerted potent antifungal therapeutic effects in both mouse and human cells infected with C. albicans, indicating that JNK1 may be a therapeutic target for treating fungal infection.", + "TAG_DATA": [ + "78, mice. {'context': 'B-organism'}", + "82, JNK1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "83, mice {'context': 'B-organism'}", + "93, mice {'context': 'B-organism'}", + "106, hematopoietic {'context': 'B-cells'}", + "107, innate {'context': 'I-cells'}", + "108, immune {'context': 'I-cells'}", + "109, cells {'context': 'I-cells'}", + "115, JNK1 {'perturbing_action': 'B-gene loss-of-function'}", + "116, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "153, JNK1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "154, mice. {'context': 'B-organism'}", + "156, JNK {'perturbing_action': 'B-pharmacological inhibition'}", + "157, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "165, mouse {'context': 'B-cells'}", + "166, and {'context': 'I-cells'}", + "167, human {'context': 'I-cells'}", + "168, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "78, mice. ['l0', 'l1', 'l2']", + "82, JNK1-deficient ['l0', 'l3', 'l4', 'l5', 'l6']", + "83, mice ['l1', 'l3', 'l7']", + "93, mice ['l2', 'l4', 'l7', 'l8']", + "106, hematopoietic ['l9', 'l10', 'l11', 'l12', 'l13']", + "107, innate ['l9', 'l14', 'l15', 'l16', 'l17']", + "108, immune ['l5', 'l10', 'l14', 'l18', 'l19']", + "109, cells ['l6', 'l8', 'l11', 'l15', 'l18']", + "115, JNK1 ['l12', 'l16', 'l20']", + "116, deficiency ['l13', 'l17', 'l19', 'l20']", + "153, JNK1-deficient ['l21']", + "154, mice. ['l21']", + "156, JNK ['l22', 'l23', 'l24', 'l25', 'l26']", + "157, inhibitors ['l22', 'l27', 'l28', 'l29', 'l30']", + "165, mouse ['l23', 'l27', 'l31', 'l32', 'l33']", + "166, and ['l24', 'l28', 'l31', 'l34', 'l35']", + "167, human ['l25', 'l29', 'l32', 'l34', 'l36']", + "168, cells ['l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "JNK1-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "JNK1-deficient", + "JNK1", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "immune", + "cells", + "hematopoietic", + "innate" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "JNK", + "inhibitors" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "and", + "human", + "cells" + ] + } + } + ] + }, + { + "PMID": "28060803", + "TEXT": "A new study shows that fasting induces the differentiation and elimination of some types of leukemia, which implicates fasting or its mimetics as a novel strategy for the treatment of leukemia.", + "TAG_DATA": [ + "6, induces {'effect': 'B-positive'}", + "8, differentiation {'phenotype': 'B-differentiation'}", + "14, of {'context': 'B-neoplasm'}", + "15, leukemia, {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "6, induces ['l0', 'l1', 'l2']", + "8, differentiation ['l0', 'l3', 'l4']", + "14, of ['l1', 'l3', 'l5']", + "15, leukemia, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "of", + "leukemia," + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "of", + "leukemia," + ] + } + } + ] + }, + { + "PMID": "27991919", + "TEXT": "The nucleoside analog cytarabine (Ara-C) is an essential component of primary and salvage chemotherapy regimens for acute myeloid leukemia (AML). After cellular uptake, Ara-C is converted into its therapeutically active triphosphate metabolite, Ara-CTP, which exerts antileukemic effects, primarily by inhibiting DNA synthesis in proliferating cells. Currently, a substantial fraction of patients with AML fail to respond effectively to Ara-C therapy, and reliable biomarkers for predicting the therapeutic response to Ara-C are lacking. SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate. Although it has been postulated that SAMHD1 sensitizes cancer cells to nucleoside-analog derivatives through the depletion of competing dNTPs, we show here that SAMHD1 reduces Ara-C cytotoxicity in AML cells. Mechanistically, dGTP-activated SAMHD1 hydrolyzes Ara-CTP, which results in a drastic reduction of Ara-CTP in leukemic cells. Loss of SAMHD1 activity-through genetic depletion, mutational inactivation of its triphosphohydrolase activity or proteasomal degradation using specialized, virus-like particles-potentiates the cytotoxicity of Ara-C in AML cells. In mouse models of retroviral AML transplantation, as well as in retrospective analyses of adult patients with AML, the response to Ara-C-containing therapy was inversely correlated with SAMHD1 expression. These results identify SAMHD1 as a potential biomarker for the stratification of patients with AML who might best respond to Ara-C-based therapy and as a target for treating Ara-C-refractory AML.", + "TAG_DATA": [ + "116, AML {'context': 'B-transformed cells'}", + "117, cells. {'context': 'I-transformed cells'}", + "132, leukemic {'context': 'B-transformed cells'}", + "133, cells. {'context': 'I-transformed cells'}", + "134, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "135, of {'perturbing_action': 'I-gene loss-of-function'}", + "136, SAMHD1 {'perturbing_action': 'I-gene loss-of-function'}", + "137, activity-through {'perturbing_action': 'I-gene loss-of-function'}", + "158, AML {'context': 'B-transformed cells'}", + "159, cells. {'context': 'I-transformed cells'}", + "161, mouse {'context': 'B-organism'}", + "162, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "116, AML ['l0', 'l1', 'l2']", + "117, cells. ['l0', 'l3']", + "132, leukemic ['l1', 'l4']", + "133, cells. ['l2', 'l3', 'l4']", + "134, Loss ['l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "135, of ['l5', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "136, SAMHD1 ['l6', 'l12', 'l18', 'l19', 'l20', 'l21', 'l22']", + "137, activity-through ['l7', 'l13', 'l18', 'l23', 'l24', 'l25', 'l26']", + "158, AML ['l8', 'l14', 'l19', 'l23', 'l27']", + "159, cells. ['l9', 'l15', 'l20', 'l24', 'l27']", + "161, mouse ['l10', 'l16', 'l21', 'l25', 'l28']", + "162, models ['l11', 'l17', 'l22', 'l26', 'l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Loss", + "of", + "SAMHD1", + "activity-through" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "AML", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Loss", + "of", + "SAMHD1", + "activity-through" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + } + } + ] + }, + { + "PMID": "27892953", + "TEXT": "Although 22q11.2 deletion syndrome (22q11DS) is associated with early-life behavioral abnormalities, affected individuals are also at high risk for the development of schizophrenia symptoms, including psychosis, later in life. Auditory thalamocortical (TC) projections recently emerged as a neural circuit that is specifically disrupted in mouse models of 22q11DS (hereafter referred to as 22q11DS mice), in which haploinsufficiency of the microRNA (miRNA)-processing-factor-encoding gene Dgcr8 results in the elevation of the dopamine receptor Drd2 in the auditory thalamus, an abnormal sensitivity of thalamocortical projections to antipsychotics, and an abnormal acoustic-startle response. Here we show that these auditory TC phenotypes have a delayed onset in 22q11DS mice and are associated with an age-dependent reduction of miR-338-3p, a miRNA that targets Drd2 and is enriched in the thalamus of both humans and mice. Replenishing depleted miR-338-3p in mature 22q11DS mice rescued the TC abnormalities, and deletion of Mir338 (which encodes miR-338-3p) or reduction of miR-338-3p expression mimicked the TC and behavioral deficits and eliminated the age dependence of these deficits. Therefore, miR-338-3p depletion is necessary and sufficient to disrupt auditory TC signaling in 22q11DS mice, and it may mediate the pathogenic mechanism of 22q11DS-related psychosis and control its late onset.", + "TAG_DATA": [ + "131, miR-338-3p {'perturbing_action': 'I-rnai/knockdown'}", + "134, 22q11DS {'context': 'B-organism'}", + "135, mice {'context': 'I-organism'}", + "141, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "142, of {'perturbing_action': 'I-gene loss-of-function'}", + "143, Mir338 {'perturbing_action': 'I-gene loss-of-function'}", + "144, (which {'perturbing_action': 'I-gene loss-of-function'}", + "145, encodes {'perturbing_action': 'I-gene loss-of-function'}", + "146, miR-338-3p) {'perturbing_action': 'I-gene loss-of-function'}", + "148, reduction {'perturbing_action': 'B-gene loss-of-function'}", + "149, of {'perturbing_action': 'I-gene loss-of-function'}", + "150, miR-338-3p {'perturbing_action': 'I-gene loss-of-function'}", + "151, expression {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "131, miR-338-3p ['l0', 'l1']", + "134, 22q11DS ['l0', 'l2']", + "135, mice ['l1', 'l2']", + "141, deletion ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "142, of ['l3', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "143, Mir338 ['l4', 'l12', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "144, (which ['l5', 'l13', 'l20', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "145, encodes ['l6', 'l14', 'l21', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "146, miR-338-3p) ['l7', 'l15', 'l22', 'l28', 'l33', 'l38', 'l39', 'l40', 'l41']", + "148, reduction ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l42', 'l43', 'l44']", + "149, of ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l45', 'l46']", + "150, miR-338-3p ['l10', 'l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l47']", + "151, expression ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "miR-338-3p" + ] + }, + "context": { + "val": "organism", + "words": [ + "22q11DS", + "mice" + ] + } + } + ] + }, + { + "PMID": "27668935", + "TEXT": "At low levels, carbon monoxide (CO) has physiological roles as a second messenger and neuromodulator. Here we assess the effects of CO in a mouse model of traumatic brain injury (TBI). Treatment with CO-releasing molecule (CORM)-3 reduced pericyte death and ameliorated the progression of neurological deficits. In contrast, although treatment with the radical scavenger N-tert-butyl-a-phenylnitrone (PBN) also reduced pericyte death, neurological outcomes were not rescued. As compared to vehicle-treated control and PBN-treated mice, CORM-3-treated mice showed higher levels of phosphorylated neural nitric oxide synthase within neural stem cells (NSCs). Inhibition of nitric oxide synthase diminished the CORM-3-mediated increase in the number of cells that stained positive for both the neuronal marker NeuN and 5-bromo-2'-deoxyuridine (BrdU; a marker for proliferating cells) in vivo, consequently interfering with neurological recovery after TBI. Because NSCs seemed to be in close proximity to pericytes, we asked whether cross-talk between pericytes and NSCs was induced by CORM-3, thereby promoting neurogenesis. In pericyte cultures that were undergoing oxygen and glucose deprivation, conditioned cell culture medium collected after CORM-3 treatment enhanced the in vitro differentiation of NSCs into mature neurons. Taken together, these findings suggest that CO treatment may provide a therapeutic approach for TBI by preventing pericyte death, rescuing cross-talk with NSCs and promoting neurogenesis.", + "TAG_DATA": [ + "37, pericyte {'context': 'B-cells'}", + "58, pericyte {'context': 'B-cells'}", + "72, mice, {'context': 'B-organism'}", + "74, mice {'context': 'B-organism'}", + "85, neural {'context': 'B-cells'}", + "86, stem {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}", + "102, cells {'context': 'B-cells'}", + "120, in {'context': 'B-in vivo'}", + "121, vivo, {'context': 'I-in vivo'}", + "155, pericyte {'context': 'B-cells'}", + "156, cultures {'context': 'I-cells'}", + "172, enhanced {'effect': 'B-positive'}", + "174, in {'context': 'B-in vitro'}", + "175, vitro {'context': 'I-in vitro'}", + "176, differentiation {'phenotype': 'B-differentiation'}", + "178, NSCs {'context': 'B-cells'}", + "180, mature {'context': 'B-cells'}", + "181, neurons. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "37, pericyte ['l0']", + "58, pericyte ['l0', 'l1']", + "72, mice, ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "74, mice ['l2', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "85, neural ['l3', 'l9', 'l15', 'l16', 'l17', 'l18', 'l19']", + "86, stem ['l4', 'l10', 'l15', 'l20', 'l21', 'l22', 'l23']", + "87, cells ['l1', 'l5', 'l11', 'l16', 'l20', 'l24', 'l25', 'l26']", + "102, cells ['l6', 'l12', 'l17', 'l21', 'l24', 'l27', 'l28']", + "120, in ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l29']", + "121, vivo, ['l8', 'l14', 'l19', 'l23', 'l26', 'l28', 'l29']", + "155, pericyte ['l30', 'l31', 'l32']", + "156, cultures ['l30']", + "172, enhanced ['l31', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "174, in ['l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "175, vitro ['l34', 'l39', 'l44', 'l45', 'l46', 'l47']", + "176, differentiation ['l35', 'l40', 'l44', 'l48', 'l49', 'l50']", + "178, NSCs ['l32', 'l36', 'l41', 'l45', 'l48', 'l51', 'l52']", + "180, mature ['l37', 'l42', 'l46', 'l49', 'l51', 'l53']", + "181, neurons. ['l38', 'l43', 'l47', 'l50', 'l52', 'l53']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "pericyte", + "NSCs", + "mature", + "neurons." + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "NSCs", + "mature", + "neurons." + ] + } + } + ] + }, + { + "PMID": "27595323", + "TEXT": "In view of the high proportion of individuals with resistance to antihypertensive medication and/or poor compliance or tolerance of this medication, new drugs to treat hypertension are urgently needed. Here we show that peripheral chemoreceptors generate aberrant signaling that contributes to high blood pressure in hypertension. We discovered that purinergic receptor P2X3 (P2rx3, also known as P2x3) mRNA expression is upregulated substantially in chemoreceptive petrosal sensory neurons in rats with hypertension. These neurons generate both tonic drive and hyperreflexia in hypertensive (but not normotensive) rats, and both phenomena are normalized by the blockade of P2X3 receptors. Antagonism of P2X3 receptors also reduces arterial pressure and basal sympathetic activity and normalizes carotid body hyperreflexia in conscious rats with hypertension; no effect was observed in rats without hypertension. We verified P2X3 receptor expression in human carotid bodies and observed hyperactivity of carotid bodies in individuals with hypertension. These data support the identification of the P2X3 receptor as a potential new target for the control of human hypertension.", + "TAG_DATA": [ + "84, rats, {'context': 'B-organism'}", + "92, blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "93, of {'perturbing_action': 'I-pharmacological inhibition'}", + "94, P2X3 {'perturbing_action': 'I-pharmacological inhibition'}", + "95, receptors. {'perturbing_action': 'I-pharmacological inhibition'}", + "96, Antagonism {'perturbing_action': 'B-pharmacological inhibition'}", + "97, of {'perturbing_action': 'I-pharmacological inhibition'}", + "98, P2X3 {'perturbing_action': 'I-pharmacological inhibition'}", + "99, receptors {'perturbing_action': 'I-pharmacological inhibition'}", + "110, carotid {'context': 'B-tissue/organ'}", + "111, body {'context': 'I-tissue/organ'}", + "114, conscious {'context': 'B-organism'}", + "115, rats {'context': 'I-organism'}", + "123, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "92, blockade ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "93, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "94, P2X3 ['l1', 'l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "95, receptors. ['l2', 'l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "96, Antagonism ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "97, of ['l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "98, P2X3 ['l22', 'l29', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "99, receptors ['l23', 'l30', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "110, carotid ['l3', 'l8', 'l13', 'l17', 'l24', 'l31', 'l37', 'l42', 'l47', 'l48', 'l49']", + "111, body ['l4', 'l9', 'l14', 'l18', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l51']", + "114, conscious ['l5', 'l10', 'l15', 'l19', 'l26', 'l33', 'l39', 'l44', 'l48', 'l50', 'l52']", + "115, rats ['l11', 'l16', 'l20', 'l27', 'l34', 'l40', 'l45', 'l49', 'l51', 'l52']", + "123, rats ['l28', 'l35', 'l41', 'l46']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "P2X3", + "receptors.", + "Antagonism", + "receptors" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "carotid", + "body" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "P2X3", + "receptors.", + "Antagonism", + "receptors" + ] + }, + "context": { + "val": "organism", + "words": [ + "conscious", + "rats" + ] + } + } + ] + }, + { + "PMID": "27571349", + "TEXT": "In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ∼6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds; we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and three-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, a category B anthelmintic drug approved by the US Food and Drug Administration, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.", + "TAG_DATA": [ + "60, neural {'context': 'B-cells'}", + "61, cells. {'context': 'I-cells'}", + "74, human {'context': 'B-cells'}", + "75, cortical {'context': 'I-cells'}", + "76, neural {'context': 'I-cells'}", + "77, progenitors {'context': 'I-cells'}", + "82, three-dimensional {'context': 'B-organoid'}", + "83, organoid {'context': 'I-organoid'}", + "84, cultures. {'context': 'I-organoid'}", + "127, protection {'effect': 'B-negative'}", + "129, human {'context': 'B-cells'}", + "130, neural {'context': 'I-cells'}", + "131, progenitors {'context': 'I-cells'}", + "133, astrocytes {'context': 'B-cells'}", + "135, ZIKV-induced {'effect': 'B-positive'}", + "136, cell {'phenotype': 'B-cell death'}", + "137, death. {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "60, neural ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "61, cells. ['l0', 'l6', 'l7', 'l8', 'l9']", + "74, human ['l1', 'l6', 'l10', 'l11', 'l12', 'l13', 'l14']", + "75, cortical ['l2', 'l7', 'l10', 'l15', 'l16', 'l17', 'l18']", + "76, neural ['l3', 'l8', 'l11', 'l15', 'l19', 'l20', 'l21']", + "77, progenitors ['l4', 'l9', 'l12', 'l16', 'l19', 'l22']", + "82, three-dimensional ['l23', 'l24']", + "83, organoid ['l13', 'l17', 'l20', 'l23', 'l25']", + "84, cultures. ['l5', 'l14', 'l18', 'l21', 'l22', 'l24', 'l25']", + "127, protection ['l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "129, human ['l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "130, neural ['l27', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "131, progenitors ['l28', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47']", + "133, astrocytes ['l29', 'l35', 'l40', 'l44', 'l48', 'l49', 'l50']", + "135, ZIKV-induced ['l30', 'l36', 'l41', 'l45', 'l48', 'l51', 'l52']", + "136, cell ['l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l53']", + "137, death. ['l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l53']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "protection" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "neural", + "progenitors", + "astrocytes" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "protection" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "neural", + "progenitors", + "astrocytes" + ] + }, + "effect": { + "val": "positive", + "words": [ + "ZIKV-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "neural", + "progenitors", + "astrocytes" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "ZIKV-induced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "27455510", + "TEXT": "Altered metabolism has been implicated in the pathogenesis of inflammatory diseases. NADPH oxidase 4 (NOX4), a source of cellular superoxide anions, has multiple biological functions that may be of importance in inflammation and in the pathogenesis of human metabolic diseases, including diabetes. However, the mechanisms by which NOX4-dependent metabolic regulation affect the innate immune response remain unclear. Here we show that deficiency of NOX4 resulted in reduced expression of carnitine palmitoyltransferase 1A (CPT1A), which is a key mitochondrial enzyme in the fatty acid oxidation (FAO) pathway. The reduced FAO resulted in less activation of the nucleotide-binding domain, leucine-rich-repeat-containing receptor (NLR), pyrin-domain-containing 3 (NLRP3) inflammasome in human and mouse macrophages. In contrast, NOX4 deficiency did not inhibit the activation of the NLR family, CARD-domain-containing 4 (NLRC4), the NLRP1 or the absent in melanoma 2 (AIM2) inflammasomes. We also found that inhibition of FAO by etomoxir treatment suppressed NLRP3 inflammasome activation. Furthermore, Nox4-deficient mice showed substantial reduction in caspase-1 activation and in interleukin (IL)-1β and IL-18 production, and there was improved survival in a mouse model of NLRP3-mediated Streptococcus pneumoniae infection. The pharmacologic inhibition of NOX4 by either GKT137831, which is currently in phase 2 clinical trials, or VAS-2870 attenuated NLRP3 inflammasome activation. Our results suggest that NOX4-mediated FAO promotes NLRP3 inflammasome activation.", + "TAG_DATA": [ + "61, deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "62, of {'perturbing_action': 'I-gene loss-of-function'}", + "63, NOX4 {'perturbing_action': 'I-gene loss-of-function'}", + "105, human {'context': 'B-cells'}", + "106, and {'context': 'I-cells'}", + "107, mouse {'context': 'I-cells'}", + "108, macrophages. {'context': 'I-cells'}", + "111, NOX4 {'perturbing_action': 'B-gene loss-of-function'}", + "112, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "140, of {'perturbing_action': 'I-pharmacological inhibition'}", + "141, FAO {'perturbing_action': 'I-pharmacological inhibition'}", + "150, Nox4-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "151, mice {'context': 'B-organism'}", + "172, mouse {'context': 'B-organism'}", + "173, model {'context': 'I-organism'}", + "180, pharmacologic {'perturbing_action': 'B-pharmacological inhibition'}", + "181, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "182, of {'perturbing_action': 'I-pharmacological inhibition'}", + "183, NOX4 {'perturbing_action': 'I-pharmacological inhibition'}", + "184, by {'perturbing_action': 'I-pharmacological inhibition'}", + "185, either {'perturbing_action': 'I-pharmacological inhibition'}", + "186, GKT137831, {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "61, deficiency ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "62, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "63, NOX4 ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "105, human ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "106, and ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "107, mouse ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "108, macrophages. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "111, NOX4 ['l21']", + "112, deficiency ['l21']", + "140, of ['l22', 'l23', 'l24', 'l25', 'l26']", + "141, FAO ['l22', 'l27', 'l28', 'l29', 'l30']", + "150, Nox4-deficient ['l23', 'l27', 'l31', 'l32', 'l33']", + "151, mice ['l24', 'l28', 'l31', 'l34', 'l35']", + "172, mouse ['l25', 'l29', 'l32', 'l34', 'l36']", + "173, model ['l26', 'l30', 'l33', 'l35', 'l36']", + "180, pharmacologic ['l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "181, inhibition ['l37', 'l43', 'l44', 'l45', 'l46', 'l47']", + "182, of ['l38', 'l43', 'l48', 'l49', 'l50', 'l51']", + "183, NOX4 ['l39', 'l44', 'l48', 'l52', 'l53', 'l54']", + "184, by ['l40', 'l45', 'l49', 'l52', 'l55', 'l56']", + "185, either ['l41', 'l46', 'l50', 'l53', 'l55', 'l57']", + "186, GKT137831, ['l42', 'l47', 'l51', 'l54', 'l56', 'l57']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "of", + "NOX4" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "and", + "mouse", + "macrophages." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "of", + "FAO" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nox4-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "model" + ] + } + } + ] + }, + { + "PMID": "27376578", + "TEXT": "In a search for mediators of the p53 tumor suppressor pathway, which induces pleiotropic and often antagonistic cellular responses, we identified the long noncoding RNA (lncRNA) NEAT1. NEAT1 is an essential architectural component of paraspeckle nuclear bodies, whose pathophysiological relevance remains unclear. Activation of p53, pharmacologically or by oncogene-induced replication stress, stimulated the formation of paraspeckles in mouse and human cells. Silencing Neat1 expression in mice, which prevents paraspeckle formation, sensitized preneoplastic cells to DNA-damage-induced cell death and impaired skin tumorigenesis. We provide mechanistic evidence that NEAT1 promotes ATR signaling in response to replication stress and is thereby engaged in a negative feedback loop that attenuates oncogene-dependent activation of p53. NEAT1 targeting in established human cancer cell lines induced synthetic lethality with genotoxic chemotherapeutics, including PARP inhibitors, and nongenotoxic activation of p53. This study establishes a key genetic link between NEAT1 paraspeckles, p53 biology and tumorigenesis and identifies NEAT1 as a promising target to enhance sensitivity of cancer cells to both chemotherapy and p53 reactivation therapy.", + "TAG_DATA": [ + "42, Activation {'perturbing_action': 'B-pharmacological augmentation'}", + "43, of {'perturbing_action': 'I-pharmacological augmentation'}", + "44, p53, {'perturbing_action': 'I-pharmacological augmentation'}", + "57, mouse {'context': 'B-cells'}", + "58, and {'context': 'I-cells'}", + "59, human {'context': 'I-cells'}", + "60, cells. {'context': 'I-cells'}", + "61, Silencing {'perturbing_action': 'B-rnai/knockdown'}", + "62, Neat1 {'perturbing_action': 'I-rnai/knockdown'}", + "63, expression {'perturbing_action': 'I-rnai/knockdown'}", + "65, mice, {'context': 'B-organism'}", + "70, sensitized {'effect': 'B-positive'}", + "71, preneoplastic {'context': 'B-transformed cells'}", + "72, cells {'context': 'I-transformed cells'}", + "75, cell {'phenotype': 'B-cell death'}", + "76, death {'phenotype': 'I-cell death'}", + "78, impaired {'effect': 'B-negative'}", + "79, skin {'context': 'B-tissue/organ'}", + "80, tumorigenesis. {'phenotype': 'B-tumourigenesis'}", + "110, NEAT1 {'perturbing_action': 'B-rnai/knockdown'}", + "111, targeting {'perturbing_action': 'I-other'}", + "114, human {'context': 'B-transformed cells'}", + "115, cancer {'context': 'I-transformed cells'}", + "116, cell {'context': 'I-transformed cells'}", + "117, lines {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "42, Activation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "43, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "44, p53, ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "57, mouse ['l2', 'l12', 'l21', 'l30', 'l31', 'l32']", + "58, and ['l3', 'l13', 'l22', 'l30', 'l33', 'l34']", + "59, human ['l4', 'l14', 'l23', 'l31', 'l33', 'l35']", + "60, cells. ['l5', 'l15', 'l24', 'l32', 'l34', 'l35']", + "61, Silencing ['l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "62, Neat1 ['l36', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "63, expression ['l37', 'l47', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "65, mice, ['l38', 'l48', 'l57', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "70, sensitized ['l6', 'l16', 'l25', 'l39', 'l49', 'l58', 'l66', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "71, preneoplastic ['l7', 'l17', 'l26', 'l40', 'l50', 'l59', 'l67', 'l74', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "72, cells ['l8', 'l18', 'l27', 'l41', 'l51', 'l60', 'l68', 'l75', 'l81', 'l87', 'l88', 'l89', 'l90']", + "75, cell ['l9', 'l19', 'l28', 'l42', 'l52', 'l61', 'l69', 'l76', 'l82', 'l87', 'l91', 'l92', 'l93', 'l94']", + "76, death ['l10', 'l20', 'l29', 'l43', 'l53', 'l62', 'l70', 'l77', 'l83', 'l88', 'l91', 'l95', 'l96', 'l97']", + "78, impaired ['l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l89', 'l92', 'l95', 'l98', 'l99']", + "79, skin ['l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l93', 'l96', 'l98', 'l100']", + "80, tumorigenesis. ['l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l90', 'l94', 'l97', 'l99', 'l100']", + "110, NEAT1 ['l101', 'l102', 'l103', 'l104', 'l105']", + "111, targeting ['l101', 'l106', 'l107', 'l108', 'l109']", + "114, human ['l102', 'l106', 'l110', 'l111', 'l112']", + "115, cancer ['l103', 'l107', 'l110', 'l113', 'l114']", + "116, cell ['l104', 'l108', 'l111', 'l113', 'l115']", + "117, lines ['l105', 'l109', 'l112', 'l114', 'l115']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "p53," + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "and", + "human", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "p53," + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "p53," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "preneoplastic", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "p53," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "Neat1", + "expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "Neat1", + "expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "Neat1", + "expression", + "NEAT1" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "preneoplastic", + "cells", + "human", + "cancer", + "cell", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "Neat1", + "expression" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "Neat1", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "Neat1", + "expression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skin" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "Neat1", + "expression" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "preneoplastic", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skin" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "preneoplastic", + "cells" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "preneoplastic", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "preneoplastic", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skin" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skin" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "skin" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "targeting" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "cancer", + "cell", + "lines" + ] + } + } + ] + }, + { + "PMID": "27376576", + "TEXT": "Single-agent immunotherapy has achieved limited clinical benefit to date in patients with pancreatic ductal adenocarcinoma (PDAC). This may be a result of the presence of a uniquely immunosuppressive tumor microenvironment (TME). Critical obstacles to immunotherapy in PDAC tumors include a high number of tumor-associated immunosuppressive cells and a uniquely desmoplastic stroma that functions as a barrier to T cell infiltration. We identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as an important regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlated with high levels of fibrosis and poor CD8(+) cytotoxic T cell infiltration. Single-agent FAK inhibition using the selective FAK inhibitor VS-4718 substantially limited tumor progression, resulting in a doubling of survival in the p48-Cre;LSL-Kras(G12D);Trp53(flox/+) (KPC) mouse model of human PDAC. This delay in tumor progression was associated with markedly reduced tumor fibrosis and decreased numbers of tumor-infiltrating immunosuppressive cells. We also found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to T cell immunotherapy and PD-1 antagonists. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and renders tumors responsive to immunotherapy.", + "TAG_DATA": [ + "107, Single-agent {'perturbing_action': 'B-pharmacological inhibition'}", + "108, FAK {'perturbing_action': 'I-pharmacological inhibition'}", + "109, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "110, using {'perturbing_action': 'I-pharmacological inhibition'}", + "111, the {'perturbing_action': 'I-pharmacological inhibition'}", + "112, selective {'perturbing_action': 'I-pharmacological inhibition'}", + "113, FAK {'perturbing_action': 'I-pharmacological inhibition'}", + "114, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "115, VS-4718 {'perturbing_action': 'I-pharmacological inhibition'}", + "117, limited {'effect': 'B-negative'}", + "118, tumor {'phenotype': 'B-tumour progression'}", + "119, progression, {'phenotype': 'I-tumour progression'}", + "128, p48-Cre;LSL-Kras(G12D);Trp53(flox/+) {'perturbing_action': 'B-other'}", + "129, (KPC) {'perturbing_action': 'I-other'}", + "130, mouse {'context': 'B-neoplasm'}", + "131, model {'context': 'I-neoplasm'}", + "132, of {'context': 'I-neoplasm'}", + "133, human {'context': 'I-neoplasm'}", + "134, PDAC. {'context': 'I-neoplasm'}", + "136, delay {'effect': 'B-negative'}", + "138, tumor {'phenotype': 'B-tumour progression'}", + "139, progression {'phenotype': 'I-tumour progression'}", + "152, immunosuppressive {'context': 'B-cells'}", + "153, cells. {'context': 'I-cells'}", + "158, FAK {'perturbing_action': 'B-pharmacological inhibition'}", + "159, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "164, KPC {'context': 'B-organism'}", + "165, mouse {'context': 'B-organism'}", + "166, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "107, Single-agent ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "108, FAK ['l0', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "109, inhibition ['l1', 'l22', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "110, using ['l2', 'l23', 'l42', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "111, the ['l3', 'l24', 'l43', 'l60', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "112, selective ['l4', 'l25', 'l44', 'l61', 'l77', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "113, FAK ['l5', 'l26', 'l45', 'l62', 'l78', 'l94', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "114, inhibitor ['l6', 'l27', 'l46', 'l63', 'l79', 'l95', 'l110', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "115, VS-4718 ['l7', 'l28', 'l47', 'l64', 'l80', 'l96', 'l111', 'l125', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "117, limited ['l8', 'l29', 'l48', 'l65', 'l81', 'l97', 'l112', 'l126', 'l138', 'l148', 'l149']", + "118, tumor ['l9', 'l30', 'l49', 'l66', 'l82', 'l98', 'l113', 'l127', 'l139', 'l148', 'l150']", + "119, progression, ['l10', 'l31', 'l50', 'l67', 'l83', 'l99', 'l114', 'l128', 'l140', 'l149', 'l150']", + "128, p48-Cre;LSL-Kras(G12D);Trp53(flox/+) ['l11', 'l32', 'l51', 'l68', 'l84', 'l100', 'l115', 'l129', 'l141', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "129, (KPC) ['l12', 'l33', 'l52', 'l69', 'l85', 'l101', 'l116', 'l130', 'l142', 'l151', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171']", + "130, mouse ['l13', 'l34', 'l53', 'l70', 'l86', 'l102', 'l117', 'l131', 'l143', 'l152', 'l162', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180']", + "131, model ['l14', 'l35', 'l54', 'l71', 'l87', 'l103', 'l118', 'l132', 'l144', 'l153', 'l163', 'l172', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "132, of ['l15', 'l36', 'l55', 'l72', 'l88', 'l104', 'l119', 'l133', 'l145', 'l154', 'l164', 'l173', 'l181', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "133, human ['l16', 'l37', 'l56', 'l73', 'l89', 'l105', 'l120', 'l134', 'l146', 'l155', 'l165', 'l174', 'l182', 'l188', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199']", + "134, PDAC. ['l17', 'l38', 'l57', 'l74', 'l90', 'l106', 'l121', 'l135', 'l147', 'l156', 'l166', 'l175', 'l183', 'l189', 'l194', 'l200', 'l201', 'l202', 'l203', 'l204']", + "136, delay ['l18', 'l39', 'l58', 'l75', 'l91', 'l107', 'l122', 'l136', 'l157', 'l167', 'l176', 'l184', 'l190', 'l195', 'l200', 'l205', 'l206', 'l207', 'l208']", + "138, tumor ['l19', 'l40', 'l92', 'l108', 'l123', 'l158', 'l168', 'l177', 'l185', 'l191', 'l196', 'l201', 'l205', 'l209', 'l210', 'l211']", + "139, progression ['l20', 'l41', 'l59', 'l76', 'l93', 'l109', 'l124', 'l137', 'l159', 'l169', 'l178', 'l186', 'l192', 'l197', 'l202', 'l206', 'l209', 'l212', 'l213']", + "152, immunosuppressive ['l160', 'l170', 'l179', 'l198', 'l203', 'l207', 'l210', 'l212', 'l214']", + "153, cells. ['l21', 'l161', 'l171', 'l180', 'l187', 'l193', 'l199', 'l204', 'l208', 'l211', 'l213', 'l214']", + "158, FAK ['l215', 'l216', 'l217', 'l218']", + "159, inhibition ['l215', 'l219', 'l220', 'l221']", + "164, KPC ['l216', 'l219', 'l222', 'l223']", + "165, mouse ['l217', 'l220', 'l222', 'l224']", + "166, model ['l218', 'l221', 'l223', 'l224']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Single-agent", + "FAK", + "inhibition", + "using", + "the", + "selective", + "inhibitor", + "VS-4718" + ] + }, + "effect": { + "val": "negative", + "words": [ + "limited", + "delay" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Single-agent", + "FAK", + "inhibition", + "using", + "the", + "selective", + "inhibitor", + "VS-4718" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression,", + "progression" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Single-agent", + "FAK", + "inhibition", + "using", + "the", + "selective", + "inhibitor", + "VS-4718" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "human", + "PDAC." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Single-agent" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limited", + "delay" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression,", + "progression" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "p48-Cre;LSL-Kras(G12D);Trp53(flox/+)", + "(KPC)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "human", + "PDAC." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "p48-Cre;LSL-Kras(G12D);Trp53(flox/+)", + "(KPC)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "delay" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "p48-Cre;LSL-Kras(G12D);Trp53(flox/+)", + "(KPC)" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "p48-Cre;LSL-Kras(G12D);Trp53(flox/+)", + "(KPC)" + ] + }, + "context": { + "val": "cells", + "words": [ + "immunosuppressive", + "cells." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "human", + "PDAC." + ] + }, + "effect": { + "val": "negative", + "words": [ + "delay" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "human", + "PDAC." + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "delay" + ] + }, + "context": { + "val": "cells", + "words": [ + "immunosuppressive", + "cells." + ] + } + }, + { + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + }, + "context": { + "val": "cells", + "words": [ + "immunosuppressive", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "FAK", + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "KPC", + "mouse", + "model" + ] + } + } + ] + }, + { + "PMID": "27348499", + "TEXT": "Genetic mutations in TAR DNA-binding protein 43 (TARDBP, also known as TDP-43) cause amyotrophic lateral sclerosis (ALS), and an increase in the presence of TDP-43 (encoded by TARDBP) in the cytoplasm is a prominent histopathological feature of degenerating neurons in various neurodegenerative diseases. However, the molecular mechanisms by which TDP-43 contributes to ALS pathophysiology remain elusive. Here we have found that TDP-43 accumulates in the mitochondria of neurons in subjects with ALS or frontotemporal dementia (FTD). Disease-associated mutations increase TDP-43 mitochondrial localization. In mitochondria, wild-type (WT) and mutant TDP-43 preferentially bind mitochondria-transcribed messenger RNAs (mRNAs) encoding respiratory complex I subunits ND3 and ND6, impair their expression and specifically cause complex I disassembly. The suppression of TDP-43 mitochondrial localization abolishes WT and mutant TDP-43-induced mitochondrial dysfunction and neuronal loss, and improves phenotypes of transgenic mutant TDP-43 mice. Thus, our studies link TDP-43 toxicity directly to mitochondrial bioenergetics and propose the targeting of TDP-43 mitochondrial localization as a promising therapeutic approach for neurodegeneration.", + "TAG_DATA": [ + "132, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "133, mutant {'perturbing_action': 'I-other'}", + "134, TDP-43 {'perturbing_action': 'I-other'}", + "135, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "132, transgenic ['l0', 'l1', 'l2']", + "133, mutant ['l0', 'l3', 'l4']", + "134, TDP-43 ['l1', 'l3', 'l5']", + "135, mice. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "TDP-43" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "27294876", + "TEXT": "Immunomodulatory drugs (IMiDs), such as thalidomide and its derivatives lenalidomide and pomalidomide, are key treatment modalities for hematologic malignancies, particularly multiple myeloma (MM) and del(5q) myelodysplastic syndrome (MDS). Cereblon (CRBN), a substrate receptor of the CRL4 ubiquitin ligase complex, is the primary target by which IMiDs mediate anticancer and teratogenic effects. Here we identify a ubiquitin-independent physiological chaperone-like function of CRBN that promotes maturation of the basigin (BSG; also known as CD147) and solute carrier family 16 member 1 (SLC16A1; also known as MCT1) proteins. This process allows for the formation and activation of the CD147-MCT1 transmembrane complex, which promotes various biological functions, including angiogenesis, proliferation, invasion and lactate export. We found that IMiDs outcompete CRBN for binding to CD147 and MCT1, leading to destabilization of the CD147-MCT1 complex. Accordingly, IMiD-sensitive MM cells lose CD147 and MCT1 expression after being exposed to IMiDs, whereas IMiD-resistant cells retain their expression. Furthermore, del(5q) MDS cells have elevated CD147 expression, which is attenuated after IMiD treatment. Finally, we show that BSG (CD147) knockdown phenocopies the teratogenic effects of thalidomide exposure in zebrafish. These findings provide a common mechanistic framework to explain both the teratogenic and pleiotropic antitumor effects of IMiDs.", + "TAG_DATA": [ + "130, IMiD-sensitive {'context': 'B-transformed cells'}", + "131, MM {'context': 'B-transformed cells'}", + "132, cells {'context': 'I-transformed cells'}", + "144, IMiD-resistant {'context': 'B-cells'}", + "145, cells {'context': 'I-cells'}", + "150, del(5q) {'perturbing_action': 'B-gene loss-of-function'}", + "151, MDS {'context': 'B-transformed cells'}", + "152, cells {'context': 'I-transformed cells'}", + "167, BSG {'perturbing_action': 'B-rnai/knockdown'}", + "168, (CD147) {'perturbing_action': 'I-rnai/knockdown'}", + "169, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "178, zebrafish. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "130, IMiD-sensitive ['l0', 'l1']", + "131, MM ['l0', 'l2']", + "132, cells ['l1', 'l2']", + "144, IMiD-resistant ['l3']", + "145, cells ['l3']", + "150, del(5q) ['l4', 'l5', 'l6']", + "151, MDS ['l4', 'l7', 'l8']", + "152, cells ['l5', 'l7']", + "167, BSG ['l9', 'l10', 'l11']", + "168, (CD147) ['l9', 'l12', 'l13']", + "169, knockdown ['l10', 'l12', 'l14']", + "178, zebrafish. ['l6', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "del(5q)" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MDS", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "del(5q)" + ] + }, + "context": { + "val": "organism", + "words": [ + "zebrafish." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "BSG", + "(CD147)", + "knockdown" + ] + }, + "context": { + "val": "organism", + "words": [ + "zebrafish." + ] + } + } + ] + }, + { + "PMID": "27294875", + "TEXT": "The persistence of latent HIV proviruses in long-lived CD4(+) T cells despite antiretroviral therapy (ART) is a major obstacle to viral eradication. Because current candidate latency-reversing agents (LRAs) induce HIV transcription, but fail to clear these cellular reservoirs, new approaches for killing these reactivated latent HIV reservoir cells are urgently needed. HIV latency depends upon the transcriptional quiescence of the integrated provirus and the circumvention of immune defense mechanisms. These defenses include cell-intrinsic innate responses that use pattern-recognition receptors (PRRs) to detect viral pathogens, and that subsequently induce apoptosis of the infected cell. Retinoic acid (RA)-inducible gene I (RIG-I, encoded by DDX58) forms one class of PRRs that mediates apoptosis and the elimination of infected cells after recognition of viral RNA. Here we show that acitretin, an RA derivative approved by the US Food and Drug Administration (FDA), enhances RIG-I signaling ex vivo, increases HIV transcription, and induces preferential apoptosis of HIV-infected cells. These effects are abrogated by DDX58 knockdown. Acitretin also decreases proviral DNA levels in CD4(+) T cells from HIV-positive subjects on suppressive ART, an effect that is amplified when combined with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor. Pharmacological enhancement of an innate cellular-defense network could provide a means by which to eliminate reactivated cells in the latent HIV reservoir.", + "TAG_DATA": [ + "147, induces {'effect': 'B-positive'}", + "149, apoptosis {'phenotype': 'B-apoptosis'}", + "152, cells. {'context': 'B-cells'}", + "158, DDX58 {'perturbing_action': 'B-rnai/knockdown'}", + "159, knockdown. {'perturbing_action': 'I-rnai/knockdown'}", + "167, CD4(+) {'context': 'B-cells'}", + "168, T {'context': 'I-cells'}", + "169, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "147, induces ['l0', 'l1']", + "149, apoptosis ['l0', 'l2']", + "152, cells. ['l1', 'l2']", + "158, DDX58 ['l3']", + "159, knockdown. ['l3']", + "167, CD4(+) ['l4', 'l5']", + "168, T ['l4', 'l6']", + "169, cells ['l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "27183216", + "TEXT": "Although somatic cell activation of the embryonic stem cell (ESC) pluripotency factor OCT4 has been reported, this previous work has been controversial and has not demonstrated a functional role for OCT4 in somatic cells. Here we demonstrate that smooth muscle cell (SMC)-specific conditional knockout of Oct4 in Apoe(-/-) mice resulted in increased lesion size and changes in lesion composition that are consistent with decreased plaque stability, including a thinner fibrous cap, increased necrotic core area, and increased intraplaque hemorrhage. Results of SMC-lineage-tracing studies showed that these effects were probably the result of marked reductions in SMC numbers within lesions and SMC investment within the fibrous cap, which may result from impaired SMC migration. The reactivation of Oct4 within SMCs was associated with hydroxymethylation of the Oct4 promoter and was hypoxia inducible factor-1α (HIF-1α, encoded by HIF1A) and Krüppel-like factor-4 (KLF4)-dependent. These results provide the first direct evidence that OCT4 has a functional role in somatic cells, and they highlight the potential role of OCT4 in normal and diseased somatic cells.", + "TAG_DATA": [ + "38, smooth {'perturbing_action': 'B-gene loss-of-function'}", + "39, muscle {'perturbing_action': 'B-gene loss-of-function'}", + "40, cell {'perturbing_action': 'I-gene loss-of-function'}", + "41, (SMC)-specific {'perturbing_action': 'I-gene loss-of-function'}", + "42, conditional {'perturbing_action': 'I-gene loss-of-function'}", + "43, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "44, of {'perturbing_action': 'I-gene loss-of-function'}", + "45, Oct4 {'perturbing_action': 'I-gene loss-of-function'}", + "47, Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "48, mice {'context': 'B-organism'}", + "95, SMC {'context': 'B-cells'}", + "110, impaired {'effect': 'B-negative'}", + "111, SMC {'context': 'B-cells'}", + "112, migration. {'phenotype': 'B-migration'}", + "118, SMCs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "38, smooth ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "39, muscle ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "40, cell ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "41, (SMC)-specific ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "42, conditional ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "43, knockout ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "44, of ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "45, Oct4 ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "47, Apoe(-/-) ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "48, mice ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "110, impaired ['l45', 'l46']", + "111, SMC ['l45', 'l47']", + "112, migration. ['l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "smooth", + "muscle", + "cell", + "(SMC)-specific", + "conditional", + "knockout", + "of", + "Oct4", + "Apoe(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "cells", + "words": [ + "SMC" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "SMC" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + } + ] + }, + { + "PMID": "27135741", + "TEXT": "Cetuximab is a monoclonal antibody that is effective in the treatment of metastatic colorectal cancer (mCRC). Cetuximab blocks epidermal growth factor receptor (EGFR)-ligand interaction and inhibits downstream RAS-ERK activation. However, only some activating mutations in RAS affect cetuximab efficacy, and it is not clear what else mediates treatment success. Here we hypothesized that cetuximab induces immunogenic cell death (ICD) that activates a potent antitumor response. We found that cetuximab, in combination with chemotherapy, fostered ICD in CRC cells, which we measured via the endoplasmic reticulum (ER) stress response and an increase in phagocytosis by dendritic cells. ICD induction depended on the mutational status of the EGFR signaling pathway and on the inhibition of the splicing of X-box binding protein 1 (XBP1), an unfolded protein response (UPR) mediator. We confirmed the enhanced immunogenicity elicited by cetuximab in a mouse model of human EGFR-expressing CRC. Overall, we demonstrate a new, immune-related mechanism of action of cetuximab that may help to tailor personalized medicine.", + "TAG_DATA": [ + "54, induces {'effect': 'B-positive'}", + "76, CRC {'context': 'B-transformed cells'}", + "77, cells, {'context': 'I-transformed cells'}", + "90, increase {'effect': 'B-positive'}", + "92, phagocytosis {'phenotype': 'B-mitophagy'}", + "94, dendritic {'context': 'B-cells'}", + "95, cells. {'context': 'I-cells'}", + "137, mouse {'context': 'B-organism'}", + "138, model {'context': 'I-neoplasm'}", + "139, of {'context': 'I-neoplasm'}", + "140, human {'context': 'I-neoplasm'}", + "141, EGFR-expressing {'context': 'I-neoplasm'}", + "142, CRC. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "54, induces ['l0', 'l1']", + "76, CRC ['l0', 'l2', 'l3', 'l4', 'l5', 'l6']", + "77, cells, ['l1', 'l2', 'l7']", + "90, increase ['l3', 'l8', 'l9', 'l10']", + "92, phagocytosis ['l4', 'l8', 'l11', 'l12']", + "94, dendritic ['l5', 'l9', 'l11', 'l13']", + "95, cells. ['l6', 'l7', 'l10', 'l12', 'l13']", + "137, mouse ['l14', 'l15', 'l16', 'l17', 'l18']", + "138, model ['l14', 'l19', 'l20', 'l21', 'l22']", + "139, of ['l15', 'l19', 'l23', 'l24', 'l25']", + "140, human ['l16', 'l20', 'l23', 'l26', 'l27']", + "141, EGFR-expressing ['l17', 'l21', 'l24', 'l26', 'l28']", + "142, CRC. ['l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induces", + "increase" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "CRC", + "cells," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CRC" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells." + ] + } + }, + { + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells." + ] + } + } + ] + }, + { + "PMID": "27135739", + "TEXT": "Cachexia is a devastating muscle-wasting syndrome that occurs in patients who have chronic diseases. It is most commonly observed in individuals with advanced cancer, presenting in 80% of these patients, and it is one of the primary causes of morbidity and mortality associated with cancer. Additionally, although many people with cachexia show hypermetabolism, the causative role of metabolism in muscle atrophy has been unclear. To understand the molecular basis of cachexia-associated muscle atrophy, it is necessary to develop accurate models of the condition. By using transcriptomics and cytokine profiling of human muscle stem cell-based models and human cancer-induced cachexia models in mice, we found that cachectic cancer cells secreted many inflammatory factors that rapidly led to high levels of fatty acid metabolism and to the activation of a p38 stress-response signature in skeletal muscles, before manifestation of cachectic muscle atrophy occurred. Metabolomics profiling revealed that factors secreted by cachectic cancer cells rapidly induce excessive fatty acid oxidation in human myotubes, which leads to oxidative stress, p38 activation and impaired muscle growth. Pharmacological blockade of fatty acid oxidation not only rescued human myotubes, but also improved muscle mass and body weight in cancer cachexia models in vivo. Therefore, fatty acid-induced oxidative stress could be targeted to prevent cancer-induced cachexia.", + "TAG_DATA": [ + "101, mice, {'context': 'B-organism'}", + "132, skeletal {'context': 'B-tissue/organ'}", + "133, muscles, {'context': 'I-tissue/organ'}", + "158, human {'context': 'B-cells'}", + "159, myotubes, {'context': 'I-cells'}", + "168, impaired {'effect': 'B-negative'}", + "169, muscle {'phenotype': 'B-tumour growth'}", + "170, growth. {'phenotype': 'I-tumour growth'}", + "180, human {'context': 'B-cells'}", + "181, myotubes, {'context': 'I-cells'}", + "194, in {'context': 'B-in vivo'}", + "195, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "101, mice, ['l0', 'l1']", + "132, skeletal ['l0', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "133, muscles, ['l1', 'l2', 'l8', 'l9', 'l10', 'l11', 'l12']", + "158, human ['l3', 'l8', 'l13', 'l14', 'l15', 'l16']", + "159, myotubes, ['l4', 'l9', 'l13', 'l17', 'l18', 'l19']", + "168, impaired ['l5', 'l10', 'l14', 'l17', 'l20', 'l21']", + "169, muscle ['l6', 'l11', 'l15', 'l18', 'l20', 'l22']", + "170, growth. ['l7', 'l12', 'l16', 'l19', 'l21', 'l22']", + "180, human ['l23']", + "181, myotubes, ['l23']", + "194, in ['l24']", + "195, vivo. ['l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "skeletal", + "muscles," + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "skeletal", + "muscles," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "muscle", + "growth." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "myotubes," + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "myotubes," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "muscle", + "growth." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "muscle", + "growth." + ] + } + } + ] + }, + { + "PMID": "27135738", + "TEXT": "B cell lymphoma and melanoma harbor recurrent mutations in the gene encoding the EZH2 histone methyltransferase (EZH2), but the carcinogenic role of these mutations is unclear. Here we describe a mouse model in which the most common somatic Ezh2 gain-of-function mutation (EZH2(Y646F) in human; Ezh2(Y641F) in mouse) is conditionally expressed. Expression of Ezh2(Y641F) in mouse B cells or melanocytes caused high-penetrance lymphoma or melanoma, respectively. Overexpression of the anti-apoptotic protein Bcl2, but not the oncoprotein Myc, or loss of the tumor suppressor protein p53 (encoded by Trp53 in mice) further accelerated lymphoma progression. Expression of the mutant Braf but not the mutant Nras oncoprotein further accelerated melanoma progression. Although expression of Ezh2(Y641F) globally increased the abundance of trimethylated Lys27 of histone H3 (H3K27me3), it also caused a widespread redistribution of this repressive mark, including a loss of H3K27me3 that was associated with increased transcription at many loci. These results suggest that Ezh2(Y641F) induces lymphoma and melanoma through a vast reorganization of chromatin structure, inducing both repression and activation of polycomb-regulated loci.", + "TAG_DATA": [ + "30, mouse {'context': 'B-organism'}", + "31, model {'context': 'I-organism'}", + "39, gain-of-function {'perturbing_action': 'I-other'}", + "40, mutation {'perturbing_action': 'I-other'}", + "50, Expression {'perturbing_action': 'B-other'}", + "51, of {'perturbing_action': 'I-other'}", + "52, Ezh2(Y641F) {'perturbing_action': 'I-other'}", + "54, mouse {'context': 'B-cells'}", + "55, B {'context': 'I-cells'}", + "56, cells {'context': 'I-cells'}", + "58, melanocytes {'context': 'B-cells'}", + "65, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "66, of {'perturbing_action': 'I-gene gain-of-function'}", + "67, the {'perturbing_action': 'I-gene gain-of-function'}", + "68, anti-apoptotic {'perturbing_action': 'I-gene gain-of-function'}", + "69, protein {'perturbing_action': 'I-gene gain-of-function'}", + "70, Bcl2, {'perturbing_action': 'I-gene gain-of-function'}", + "77, loss {'perturbing_action': 'B-gene loss-of-function'}", + "78, of {'perturbing_action': 'I-gene loss-of-function'}", + "79, the {'perturbing_action': 'I-gene loss-of-function'}", + "80, tumor {'perturbing_action': 'I-gene loss-of-function'}", + "81, suppressor {'perturbing_action': 'I-gene loss-of-function'}", + "82, protein {'perturbing_action': 'I-gene loss-of-function'}", + "83, p53 {'perturbing_action': 'I-gene loss-of-function'}", + "84, (encoded {'perturbing_action': 'I-gene loss-of-function'}", + "85, by {'perturbing_action': 'I-gene loss-of-function'}", + "86, Trp53 {'perturbing_action': 'I-gene loss-of-function'}", + "87, in {'perturbing_action': 'I-gene loss-of-function'}", + "88, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "91, lymphoma {'context': 'B-neoplasm'}", + "93, Expression {'perturbing_action': 'B-other'}", + "94, of {'perturbing_action': 'I-other'}", + "95, the {'perturbing_action': 'I-other'}", + "96, mutant {'perturbing_action': 'I-other'}", + "97, Braf {'perturbing_action': 'I-other'}", + "101, mutant {'perturbing_action': 'B-other'}", + "106, melanoma {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "30, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "31, model ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "38, Ezh2 ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "39, gain-of-function ['l2', 'l15', 'l27', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "40, mutation ['l3', 'l16', 'l28', 'l45', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "50, Expression ['l4', 'l17', 'l29', 'l46', 'l62', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "51, of ['l5', 'l18', 'l30', 'l47', 'l63', 'l78', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "52, Ezh2(Y641F) ['l6', 'l19', 'l31', 'l48', 'l64', 'l79', 'l92', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "53, in ['l7', 'l20', 'l32', 'l49', 'l65', 'l80', 'l93', 'l105', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "54, mouse ['l8', 'l21', 'l33', 'l50', 'l66', 'l81', 'l94', 'l106', 'l118', 'l127', 'l128', 'l129', 'l130']", + "55, B ['l9', 'l22', 'l34', 'l51', 'l67', 'l82', 'l95', 'l107', 'l119', 'l127', 'l131', 'l132', 'l133']", + "56, cells ['l10', 'l23', 'l35', 'l52', 'l68', 'l83', 'l96', 'l108', 'l120', 'l128', 'l131', 'l134', 'l135']", + "58, melanocytes ['l11', 'l24', 'l36', 'l53', 'l69', 'l84', 'l97', 'l109', 'l121', 'l129', 'l132', 'l134', 'l136']", + "61, lymphoma ['l12', 'l25', 'l37', 'l54', 'l70', 'l85', 'l98', 'l110', 'l122', 'l130', 'l133', 'l135', 'l136']", + "65, Overexpression ['l38', 'l55', 'l71', 'l86', 'l99', 'l111', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "66, of ['l39', 'l56', 'l72', 'l87', 'l100', 'l112', 'l137', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171']", + "67, the ['l40', 'l57', 'l73', 'l88', 'l101', 'l113', 'l123', 'l138', 'l155', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "68, anti-apoptotic ['l41', 'l58', 'l74', 'l89', 'l102', 'l114', 'l124', 'l139', 'l156', 'l172', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202']", + "69, protein ['l42', 'l59', 'l75', 'l90', 'l103', 'l115', 'l125', 'l140', 'l157', 'l173', 'l188', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216']", + "70, Bcl2, ['l13', 'l26', 'l43', 'l60', 'l76', 'l91', 'l104', 'l116', 'l126', 'l141', 'l158', 'l174', 'l189', 'l203', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229']", + "77, loss ['l142', 'l159', 'l175', 'l190', 'l204', 'l217', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241']", + "78, of ['l143', 'l160', 'l176', 'l191', 'l205', 'l218', 'l230', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252']", + "79, the ['l144', 'l161', 'l177', 'l192', 'l206', 'l219', 'l231', 'l242', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262']", + "80, tumor ['l145', 'l162', 'l178', 'l193', 'l207', 'l220', 'l232', 'l243', 'l253', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271']", + "81, suppressor ['l146', 'l163', 'l179', 'l194', 'l208', 'l221', 'l233', 'l244', 'l254', 'l263', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279']", + "82, protein ['l147', 'l164', 'l180', 'l195', 'l209', 'l222', 'l234', 'l245', 'l255', 'l264', 'l272', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286']", + "83, p53 ['l148', 'l165', 'l181', 'l196', 'l210', 'l223', 'l235', 'l246', 'l256', 'l265', 'l273', 'l280', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292']", + "84, (encoded ['l149', 'l166', 'l182', 'l197', 'l211', 'l224', 'l236', 'l247', 'l257', 'l266', 'l274', 'l281', 'l287', 'l293', 'l294', 'l295', 'l296', 'l297']", + "85, by ['l150', 'l167', 'l183', 'l198', 'l212', 'l225', 'l237', 'l248', 'l258', 'l267', 'l275', 'l282', 'l288', 'l293', 'l298', 'l299', 'l300', 'l301']", + "86, Trp53 ['l151', 'l168', 'l184', 'l199', 'l213', 'l226', 'l238', 'l249', 'l259', 'l268', 'l276', 'l283', 'l289', 'l294', 'l298', 'l302', 'l303', 'l304']", + "87, in ['l152', 'l169', 'l185', 'l200', 'l214', 'l227', 'l239', 'l250', 'l260', 'l269', 'l277', 'l284', 'l290', 'l295', 'l299', 'l302', 'l305', 'l306']", + "88, mice) ['l153', 'l170', 'l186', 'l201', 'l215', 'l228', 'l240', 'l251', 'l261', 'l270', 'l278', 'l285', 'l291', 'l296', 'l300', 'l303', 'l305', 'l307']", + "91, lymphoma ['l44', 'l61', 'l77', 'l117', 'l154', 'l171', 'l187', 'l202', 'l216', 'l229', 'l241', 'l252', 'l262', 'l271', 'l279', 'l286', 'l292', 'l297', 'l301', 'l304', 'l306', 'l307']", + "93, Expression ['l308', 'l309', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315']", + "94, of ['l308', 'l316', 'l317', 'l318', 'l319', 'l320', 'l321', 'l322']", + "95, the ['l309', 'l316', 'l323', 'l324', 'l325', 'l326', 'l327', 'l328']", + "96, mutant ['l310', 'l317', 'l323', 'l329', 'l330', 'l331', 'l332', 'l333']", + "97, Braf ['l311', 'l318', 'l324', 'l329', 'l334', 'l335', 'l336', 'l337']", + "101, mutant ['l312', 'l319', 'l325', 'l330', 'l334', 'l338', 'l339', 'l340']", + "106, melanoma ['l313', 'l320', 'l326', 'l331', 'l335', 'l338']", + "110, of ['l314', 'l321', 'l327', 'l332', 'l336', 'l339', 'l341']", + "111, Ezh2(Y641F) ['l315', 'l322', 'l328', 'l333', 'l337', 'l340', 'l341']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "gain-of-function", + "mutation", + "Expression", + "of", + "Ezh2(Y641F)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Bcl2," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "gain-of-function", + "mutation", + "Expression", + "of", + "Ezh2(Y641F)" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "B", + "cells", + "melanocytes" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "gain-of-function", + "mutation", + "Ezh2(Y641F)", + "Expression", + "of", + "the", + "mutant", + "Braf" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lymphoma", + "melanoma" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "the", + "anti-apoptotic", + "protein", + "Bcl2," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lymphoma" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "tumor", + "suppressor", + "protein", + "p53", + "(encoded", + "by", + "Trp53", + "in", + "mice)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lymphoma" + ] + } + } + ] + }, + { + "PMID": "27089514", + "TEXT": "Doxorubicin is an anthracycline chemotherapy agent effective in treating a wide range of malignancies, but it causes a dose-related cardiotoxicity that can lead to heart failure in a subset of patients. At present, it is not possible to predict which patients will be affected by doxorubicin-induced cardiotoxicity (DIC). Here we demonstrate that patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can recapitulate the predilection to DIC of individual patients at the cellular level. hiPSC-CMs derived from individuals with breast cancer who experienced DIC were consistently more sensitive to doxorubicin toxicity than hiPSC-CMs from patients who did not experience DIC, with decreased cell viability, impaired mitochondrial and metabolic function, impaired calcium handling, decreased antioxidant pathway activity, and increased reactive oxygen species production. Taken together, our data indicate that hiPSC-CMs are a suitable platform to identify and characterize the genetic basis and molecular mechanisms of DIC.", + "TAG_DATA": [ + "53, human {'context': 'I-cells'}", + "54, induced {'context': 'I-cells'}", + "55, pluripotent {'context': 'I-cells'}", + "56, stem {'context': 'I-cells'}", + "57, cell-derived {'context': 'I-cells'}", + "58, cardiomyocytes {'context': 'I-cells'}", + "73, hiPSC-CMs {'context': 'B-cells'}", + "78, breast {'context': 'B-neoplasm'}", + "79, cancer {'context': 'I-neoplasm'}", + "91, hiPSC-CMs {'context': 'B-cells'}", + "100, decreased {'effect': 'B-negative'}", + "101, cell {'phenotype': 'B-cell survival'}", + "102, viability, {'phenotype': 'I-cell survival'}" + ], + "LINK_DATA": [ + "53, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "54, induced ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "55, pluripotent ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "56, stem ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "57, cell-derived ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "58, cardiomyocytes ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "73, hiPSC-CMs ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "78, breast ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "79, cancer ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "91, hiPSC-CMs ['l36', 'l37', 'l38']", + "100, decreased ['l36', 'l39', 'l40']", + "101, cell ['l37', 'l39', 'l41']", + "102, viability, ['l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "hiPSC-CMs" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hiPSC-CMs" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "viability," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "viability," + ] + } + } + ] + }, + { + "PMID": "27064448", + "TEXT": "Cholera toxin (CT) is a potent adjuvant for inducing mucosal immune responses. However, the mechanism by which CT induces adjuvant activity remains unclear. Here we show that the microbiota is critical for inducing antigen-specific IgG production after intranasal immunization. After mucosal vaccination with CT, both antibiotic-treated and germ-free (GF) mice had reduced amounts of antigen-specific IgG, smaller recall-stimulated cytokine responses, impaired follicular helper T (TFH) cell responses and reduced numbers of plasma cells. Recognition of symbiotic bacteria via the nucleotide-binding oligomerization domain containing 2 (Nod2) sensor in cells that express the integrin CD11c (encoded by Itgax) was required for the adjuvanticity of CT. Reconstitution of GF mice with a Nod2 agonist or monocolonization with Staphylococcus sciuri, which has high Nod2-stimulatory activity, was sufficient to promote robust CT adjuvant activity, whereas bacteria with low Nod2-stimulatory activity did not. Mechanistically, CT enhanced Nod2-mediated cytokine production in dendritic cells via intracellular cyclic AMP. These results show a role for the microbiota and the intracellular receptor Nod2 in promoting the mucosal adjuvant activity of CT.", + "TAG_DATA": [ + "49, mice {'context': 'B-organism'}", + "61, follicular {'context': 'B-cells'}", + "62, helper {'context': 'I-cells'}", + "63, T {'context': 'I-cells'}", + "64, (TFH) {'context': 'I-cells'}", + "65, cell {'context': 'I-cells'}", + "71, plasma {'context': 'B-cells'}", + "72, cells. {'context': 'I-cells'}", + "87, cells {'context': 'B-cells'}", + "105, GF {'context': 'B-organism'}", + "106, mice {'context': 'I-organism'}", + "109, Nod2 {'perturbing_action': 'B-pharmacological augmentation'}", + "110, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "144, dendritic {'context': 'B-cells'}", + "145, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "49, mice ['l0']", + "61, follicular ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "62, helper ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "63, T ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "64, (TFH) ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "65, cell ['l0', 'l4', 'l10', 'l15', 'l19', 'l23', 'l24']", + "71, plasma ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l26']", + "72, cells. ['l6', 'l12', 'l17', 'l21', 'l24', 'l25']", + "87, cells ['l7', 'l13', 'l18', 'l22', 'l26', 'l27', 'l28', 'l29', 'l30']", + "105, GF ['l27', 'l31', 'l32', 'l33']", + "106, mice ['l28', 'l31', 'l34', 'l35']", + "109, Nod2 ['l29', 'l32', 'l34', 'l36']", + "110, agonist ['l30', 'l33', 'l35', 'l36']", + "144, dendritic ['l37']", + "145, cells ['l37']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Nod2", + "agonist" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "GF", + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Nod2", + "agonist" + ] + } + } + ] + }, + { + "PMID": "26974308", + "TEXT": "Tissues with high metabolic rates often use lipids, as well as glucose, for energy, conferring a survival advantage during feast and famine. Current dogma suggests that high-energy-consuming photoreceptors depend on glucose. Here we show that the retina also uses fatty acid β-oxidation for energy. Moreover, we identify a lipid sensor, free fatty acid receptor 1 (Ffar1), that curbs glucose uptake when fatty acids are available. Very-low-density lipoprotein receptor (Vldlr), which is present in photoreceptors and is expressed in other tissues with a high metabolic rate, facilitates the uptake of triglyceride-derived fatty acid. In the retinas of Vldlr(-/-) mice with low fatty acid uptake but high circulating lipid levels, we found that Ffar1 suppresses expression of the glucose transporter Glut1. Impaired glucose entry into photoreceptors results in a dual (lipid and glucose) fuel shortage and a reduction in the levels of the Krebs cycle intermediate α-ketoglutarate (α-KG). Low α-KG levels promotes stabilization of hypoxia-induced factor 1a (Hif1a) and secretion of vascular endothelial growth factor A (Vegfa) by starved Vldlr(-/-) photoreceptors, leading to neovascularization. The aberrant vessels in the Vldlr(-/-) retinas, which invade normally avascular photoreceptors, are reminiscent of the vascular defects in retinal angiomatous proliferation, a subset of neovascular age-related macular degeneration (AMD), which is associated with high vitreous VEGFA levels in humans. Dysregulated lipid and glucose photoreceptor energy metabolism may therefore be a driving force in macular telangiectasia, neovascular AMD and other retinal diseases.", + "TAG_DATA": [ + "94, retinas {'context': 'B-tissue/organ'}", + "96, Vldlr(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "97, mice {'context': 'B-organism'}", + "167, Vldlr(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "168, photoreceptors, {'context': 'B-cells'}", + "177, Vldlr(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "178, retinas, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "94, retinas ['l0', 'l1']", + "96, Vldlr(-/-) ['l0', 'l2']", + "97, mice ['l1', 'l2']", + "167, Vldlr(-/-) ['l3']", + "168, photoreceptors, ['l3']", + "177, Vldlr(-/-) ['l4']", + "178, retinas, ['l4']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "retinas", + "retinas," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Vldlr(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Vldlr(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Vldlr(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "photoreceptors," + ] + } + } + ] + }, + { + "PMID": "26928463", + "TEXT": "Tumor heterogeneity may reduce the efficacy of molecularly guided systemic therapy for cancers that have metastasized. To determine whether the genomic alterations in a single metastasis provide a reasonable assessment of the major oncogenic drivers of other dispersed metastases in an individual, we analyzed multiple tumors from men with disseminated prostate cancer through whole-exome sequencing, array comparative genomic hybridization (CGH) and RNA transcript profiling, and we compared the genomic diversity within and between individuals. In contrast to the substantial heterogeneity between men, there was limited diversity among metastases within an individual. The number of somatic mutations, the burden of genomic copy number alterations and aberrations in known oncogenic drivers were all highly concordant, as were metrics of androgen receptor (AR) activity and cell cycle activity. AR activity was inversely associated with cell proliferation, whereas the expression of Fanconi anemia (FA)-complex genes was correlated with elevated cell cycle progression, expression of the E2F transcription factor 1 (E2F1) and loss of retinoblastoma 1 (RB1). Men with somatic aberrations in FA-complex genes or in ATM serine/threonine kinase (ATM) exhibited significantly longer treatment-response durations to carboplatin than did men without defects in genes encoding DNA-repair proteins. Collectively, these data indicate that although exceptions exist, evaluating a single metastasis provides a reasonable assessment of the major oncogenic driver alterations that are present in disseminated tumors within an individual, and thus may be useful for selecting treatments on the basis of predicted molecular vulnerabilities.", + "TAG_DATA": [ + "131, cell {'context': 'B-cells'}", + "132, proliferation, {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "131, cell ['l0']", + "132, proliferation, ['l0']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + } + ] + }, + { + "PMID": "26855150", + "TEXT": "Although subtypes of pancreatic ductal adenocarcinoma (PDAC) have been described, this malignancy is clinically still treated as a single disease. Here we present patient-derived models representing the full spectrum of previously identified quasi-mesenchymal (QM-PDA), classical and exocrine-like PDAC subtypes, and identify two markers--HNF1A and KRT81--that enable stratification of tumors into different subtypes by using immunohistochemistry. Individuals with tumors of these subtypes showed substantial differences in overall survival, and their tumors differed in drug sensitivity, with the exocrine-like subtype being resistant to tyrosine kinase inhibitors and paclitaxel. Cytochrome P450 3A5 (CYP3A5) metabolizes these compounds in tumors of the exocrine-like subtype, and pharmacological or short hairpin RNA (shRNA)-mediated CYP3A5 inhibition sensitizes tumor cells to these drugs. Whereas hepatocyte nuclear factor 4, alpha (HNF4A) controls basal expression of CYP3A5, drug-induced CYP3A5 upregulation is mediated by the nuclear receptor NR1I2. CYP3A5 also contributes to acquired drug resistance in QM-PDA and classical PDAC, and it is highly expressed in several additional malignancies. These findings designate CYP3A5 as a predictor of therapy response and as a tumor cell-autonomous detoxification mechanism that must be overcome to prevent drug resistance.", + "TAG_DATA": [ + "102, short {'perturbing_action': 'B-rnai/knockdown'}", + "103, hairpin {'perturbing_action': 'I-rnai/knockdown'}", + "104, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "105, (shRNA)-mediated {'perturbing_action': 'I-rnai/knockdown'}", + "106, CYP3A5 {'perturbing_action': 'I-rnai/knockdown'}", + "107, inhibition {'perturbing_action': 'I-rnai/knockdown'}", + "109, tumor {'context': 'B-transformed cells'}", + "110, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "102, short ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "103, hairpin ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "104, RNA ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "105, (shRNA)-mediated ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "106, CYP3A5 ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "107, inhibition ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "109, tumor ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "110, cells ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "short", + "hairpin", + "RNA", + "(shRNA)-mediated", + "CYP3A5", + "inhibition" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + } + ] + }, + { + "PMID": "26808348", + "TEXT": "Uncoupling protein 1 (UCP1) is highly expressed in brown adipose tissue, where it generates heat by uncoupling electron transport from ATP production. UCP1 is also found outside classical brown adipose tissue depots, in adipocytes that are termed 'brite' (brown-in-white) or 'beige'. In humans, the presence of brite or beige (brite/beige) adipocytes is correlated with a lean, metabolically healthy phenotype, but whether a causal relationship exists is not clear. Here we report that human brite/beige adipocyte progenitors proliferate in response to pro-angiogenic factors, in association with expanding capillary networks. Adipocytes formed from these progenitors transform in response to adenylate cyclase activation from being UCP1 negative to being UCP1 positive, which is a defining feature of the beige/brite phenotype, while displaying uncoupled respiration. When implanted into normal chow-fed, or into high-fat diet (HFD)-fed, glucose-intolerant NOD-scid IL2rg(null) (NSG) mice, brite/beige adipocytes activated in vitro enhance systemic glucose tolerance. These adipocytes express neuroendocrine and secreted factors, including the pro-protein convertase PCSK1, which is strongly associated with human obesity. Pro-angiogenic conditions therefore drive the proliferation of human beige/brite adipocyte progenitors, and activated beige/brite adipocytes can affect systemic glucose homeostasis, potentially through a neuroendocrine mechanism.", + "TAG_DATA": [ + "76, proliferate {'phenotype': 'B-proliferation'}", + "132, NOD-scid {'perturbing_action': 'B-gene loss-of-function'}", + "133, IL2rg(null) {'perturbing_action': 'I-gene loss-of-function'}", + "134, (NSG) {'perturbing_action': 'I-gene loss-of-function'}", + "135, mice, {'context': 'B-organism'}", + "136, brite/beige {'context': 'B-cells'}", + "137, adipocytes {'context': 'I-cells'}", + "139, in {'context': 'B-in vitro'}", + "140, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "132, NOD-scid ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "133, IL2rg(null) ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "134, (NSG) ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "135, mice, ['l2', 'l8', 'l13', 'l18', 'l19']", + "136, brite/beige ['l3', 'l9', 'l14', 'l18', 'l20', 'l21', 'l22']", + "137, adipocytes ['l4', 'l10', 'l15', 'l19', 'l20', 'l23', 'l24']", + "139, in ['l5', 'l11', 'l16', 'l21', 'l23', 'l25']", + "140, vitro ['l6', 'l12', 'l17', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NOD-scid", + "IL2rg(null)", + "(NSG)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NOD-scid", + "IL2rg(null)", + "(NSG)" + ] + }, + "context": { + "val": "cells", + "words": [ + "brite/beige", + "adipocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NOD-scid", + "IL2rg(null)", + "(NSG)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "26779815", + "TEXT": "Electrical neuromodulation of lumbar segments improves motor control after spinal cord injury in animal models and humans. However, the physiological principles underlying the effect of this intervention remain poorly understood, which has limited the therapeutic approach to continuous stimulation applied to restricted spinal cord locations. Here we developed stimulation protocols that reproduce the natural dynamics of motoneuron activation during locomotion. For this, we computed the spatiotemporal activation pattern of muscle synergies during locomotion in healthy rats. Computer simulations identified optimal electrode locations to target each synergy through the recruitment of proprioceptive feedback circuits. This framework steered the design of spatially selective spinal implants and real-time control software that modulate extensor and flexor synergies with precise temporal resolution. Spatiotemporal neuromodulation therapies improved gait quality, weight-bearing capacity, endurance and skilled locomotion in several rodent models of spinal cord injury. These new concepts are directly translatable to strategies to improve motor control in humans.", + "TAG_DATA": [ + "74, healthy {'context': 'B-organism'}", + "75, rats. {'context': 'I-organism'}", + "128, locomotion {'phenotype': 'B-migration'}", + "131, rodent {'context': 'B-organism'}", + "132, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "74, healthy ['l0']", + "75, rats. ['l0']", + "128, locomotion ['l1', 'l2']", + "131, rodent ['l1', 'l3']", + "132, models ['l2', 'l3']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "migration", + "words": [ + "locomotion" + ] + }, + "context": { + "val": "organism", + "words": [ + "rodent", + "models" + ] + } + } + ] + }, + { + "PMID": "26752519", + "TEXT": "Chronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and genetic determinants. We have previously identified iron-responsive element-binding protein 2 (IRP2) as an important COPD susceptibility gene and have shown that IRP2 protein is increased in the lungs of individuals with COPD. Here we demonstrate that mice deficient in Irp2 were protected from cigarette smoke (CS)-induced experimental COPD. By integrating RNA immunoprecipitation followed by sequencing (RIP-seq), RNA sequencing (RNA-seq), and gene expression and functional enrichment clustering analysis, we identified Irp2 as a regulator of mitochondrial function in the lungs of mice. Irp2 increased mitochondrial iron loading and levels of cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD. Frataxin-deficient mice, which had higher mitochondrial iron loading, showed impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas mice deficient in the synthesis of cytochrome c oxidase, which have reduced COX, were protected from CS-induced pulmonary inflammation and impairment of MCC. Mice treated with a mitochondrial iron chelator or mice fed a low-iron diet were protected from CS-induced COPD. Mitochondrial iron chelation also alleviated CS-induced impairment of MCC, CS-induced pulmonary inflammation and CS-associated lung injury in mice with established COPD, suggesting a critical functional role and potential therapeutic intervention for the mitochondrial-iron axis in COPD.", + "TAG_DATA": [ + "48, mice {'context': 'B-organism'}", + "49, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "50, in {'perturbing_action': 'I-gene loss-of-function'}", + "51, Irp2 {'perturbing_action': 'I-gene loss-of-function'}", + "114, Frataxin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "115, mice, {'context': 'B-organism'}", + "135, mice {'context': 'B-organism'}", + "158, Mice {'context': 'B-organism'}", + "166, mice {'context': 'B-organism'}", + "193, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "48, mice ['l0', 'l1', 'l2']", + "49, deficient ['l0', 'l3', 'l4']", + "50, in ['l1', 'l3', 'l5']", + "51, Irp2 ['l2', 'l4', 'l5']", + "114, Frataxin-deficient ['l6']", + "115, mice, ['l6']", + "158, Mice ['l7']", + "166, mice ['l7', 'l8']", + "193, mice ['l8']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Irp2", + "Frataxin-deficient" + ] + } + } + ] + }, + { + "PMID": "26569381", + "TEXT": "Dystrophin is expressed in differentiated myofibers, in which it is required for sarcolemmal integrity, and loss-of-function mutations in the gene that encodes it result in Duchenne muscular dystrophy (DMD), a disease characterized by progressive and severe skeletal muscle degeneration. Here we found that dystrophin is also highly expressed in activated muscle stem cells (also known as satellite cells), in which it associates with the serine-threonine kinase Mark2 (also known as Par1b), an important regulator of cell polarity. In the absence of dystrophin, expression of Mark2 protein is downregulated, resulting in the inability to localize the cell polarity regulator Pard3 to the opposite side of the cell. Consequently, the number of asymmetric divisions is strikingly reduced in dystrophin-deficient satellite cells, which also display a loss of polarity, abnormal division patterns (including centrosome amplification), impaired mitotic spindle orientation and prolonged cell divisions. Altogether, these intrinsic defects strongly reduce the generation of myogenic progenitors that are needed for proper muscle regeneration. Therefore, we conclude that dystrophin has an essential role in the regulation of satellite cell polarity and asymmetric division. Our findings indicate that muscle wasting in DMD not only is caused by myofiber fragility, but also is exacerbated by impaired regeneration owing to intrinsic satellite cell dysfunction.", + "TAG_DATA": [ + "79, absence {'perturbing_action': 'B-gene loss-of-function'}", + "80, of {'perturbing_action': 'I-gene loss-of-function'}", + "81, dystrophin, {'perturbing_action': 'I-gene loss-of-function'}", + "116, dystrophin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "117, satellite {'context': 'B-cells'}", + "118, cells, {'context': 'I-cells'}", + "139, divisions. {'phenotype': 'I-proliferation'}" + ], + "LINK_DATA": [ + "79, absence ['l0', 'l1', 'l2']", + "80, of ['l0', 'l3', 'l4']", + "81, dystrophin, ['l1', 'l3', 'l5']", + "116, dystrophin-deficient ['l6', 'l7', 'l8', 'l9']", + "117, satellite ['l6', 'l10', 'l11']", + "118, cells, ['l2', 'l4', 'l5', 'l7', 'l10', 'l12']", + "138, cell ['l8', 'l13']", + "139, divisions. ['l9', 'l11', 'l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "dystrophin,", + "dystrophin-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells,", + "satellite" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "divisions." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "satellite", + "cells," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "divisions." + ] + } + } + ] + }, + { + "PMID": "26523971", + "TEXT": "Focal malformations of cortical development (FMCDs) account for the majority of drug-resistant pediatric epilepsy. Postzygotic somatic mutations activating the phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway are found in a wide range of brain diseases, including FMCDs. It remains unclear how a mutation in a small fraction of cells disrupts the architecture of the entire hemisphere. Within human FMCD-affected brain, we found that cells showing activation of the PI3K-AKT-mTOR pathway were enriched for the AKT3(E17K) mutation. Introducing the FMCD-causing mutation into mouse brain resulted in electrographic seizures and impaired hemispheric architecture. Mutation-expressing neural progenitors showed misexpression of reelin, which led to a non-cell autonomous migration defect in neighboring cells, due at least in part to derepression of reelin transcription in a manner dependent on the forkhead box (FOX) transcription factor FOXG1. Treatments aimed at either blocking downstream AKT signaling or inactivating reelin restored migration. These findings suggest a central AKT-FOXG1-reelin signaling pathway in FMCD and support pathway inhibitors as potential treatments or therapies for some forms of focal epilepsy.", + "TAG_DATA": [ + "66, cells {'context': 'B-cells'}", + "79, Introducing {'perturbing_action': 'B-other'}", + "80, the {'perturbing_action': 'I-other'}", + "81, FMCD-causing {'perturbing_action': 'I-other'}", + "82, mutation {'perturbing_action': 'I-other'}", + "84, mouse {'context': 'B-tissue/organ'}", + "85, brain {'context': 'I-tissue/organ'}", + "94, Mutation-expressing {'context': 'B-cells'}", + "95, neural {'context': 'I-cells'}", + "96, progenitors {'context': 'I-cells'}", + "107, migration {'phenotype': 'B-migration'}", + "108, defect {'effect': 'B-negative'}", + "111, cells, {'context': 'B-cells'}", + "143, inactivating {'perturbing_action': 'B-gene loss-of-function'}", + "144, reelin {'perturbing_action': 'I-gene loss-of-function'}", + "145, restored {'effect': 'B-rescues'}", + "146, migration. {'phenotype': 'B-migration'}" + ], + "LINK_DATA": [ + "79, Introducing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "80, the ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "81, FMCD-causing ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "82, mutation ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "84, mouse ['l3', 'l12', 'l20', 'l27', 'l34']", + "85, brain ['l4', 'l13', 'l21', 'l28', 'l34']", + "94, Mutation-expressing ['l35', 'l36', 'l37', 'l38', 'l39']", + "95, neural ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l41', 'l42', 'l43']", + "96, progenitors ['l6', 'l15', 'l23', 'l30', 'l36', 'l40', 'l44', 'l45', 'l46']", + "107, migration ['l7', 'l16', 'l24', 'l31', 'l37', 'l41', 'l44', 'l47', 'l48']", + "108, defect ['l8', 'l17', 'l25', 'l32', 'l38', 'l42', 'l45', 'l47', 'l49']", + "111, cells, ['l9', 'l18', 'l26', 'l33', 'l39', 'l43', 'l46', 'l48', 'l49']", + "143, inactivating ['l50', 'l51', 'l52']", + "144, reelin ['l50', 'l53', 'l54']", + "145, restored ['l51', 'l53', 'l55']", + "146, migration. ['l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Introducing", + "the", + "FMCD-causing", + "mutation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "brain" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Introducing", + "the", + "FMCD-causing", + "mutation" + ] + }, + "context": { + "val": "cells", + "words": [ + "neural", + "progenitors", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Introducing", + "the", + "FMCD-causing", + "mutation" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Introducing", + "the", + "FMCD-causing", + "mutation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defect" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Mutation-expressing", + "neural", + "progenitors", + "cells," + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Mutation-expressing", + "neural", + "progenitors", + "cells," + ] + }, + "effect": { + "val": "negative", + "words": [ + "defect" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defect" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivating", + "reelin" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivating", + "reelin" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + } + ] + }, + { + "PMID": "26523970", + "TEXT": "The TAM receptors Tyro3, Axl and Mertk are receptor tyrosine kinases that dampen host innate immune responses following engagement with their ligands Gas6 and Protein S, which recognize phosphatidylserine on apoptotic cells. In a form of apoptotic mimicry, many enveloped viruses display phosphatidylserine on the outer leaflet of their membranes, enabling TAM receptor activation and downregulation of antiviral responses. Accordingly, we hypothesized that a deficiency of TAM receptors would enhance antiviral responses and protect against viral infection. Unexpectedly, mice lacking Mertk and/or Axl, but not Tyro3, exhibited greater vulnerability to infection with neuroinvasive West Nile and La Crosse encephalitis viruses. This phenotype was associated with increased blood-brain barrier permeability, which enhanced virus entry into and infection of the brain. Activation of Mertk synergized with interferon-β to tighten cell junctions and prevent virus transit across brain microvascular endothelial cells. Because TAM receptors restrict pathogenesis of neuroinvasive viruses, these findings have implications for TAM antagonists that are currently in clinical development.", + "TAG_DATA": [ + "78, mice {'context': 'B-organism'}", + "79, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "80, Mertk {'perturbing_action': 'I-gene loss-of-function'}", + "81, and/or {'perturbing_action': 'I-gene loss-of-function'}", + "82, Axl, {'perturbing_action': 'I-gene loss-of-function'}", + "118, brain. {'context': 'B-tissue/organ'}", + "119, Activation {'perturbing_action': 'B-pharmacological augmentation'}", + "120, of {'perturbing_action': 'I-pharmacological augmentation'}", + "121, Mertk {'perturbing_action': 'I-pharmacological augmentation'}", + "134, brain {'context': 'B-cells'}", + "135, microvascular {'context': 'I-cells'}", + "136, endothelial {'context': 'I-cells'}", + "137, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "78, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "79, lacking ['l0', 'l5', 'l6', 'l7', 'l8']", + "80, Mertk ['l1', 'l5', 'l9', 'l10', 'l11']", + "81, and/or ['l2', 'l6', 'l9', 'l12', 'l13']", + "82, Axl, ['l3', 'l7', 'l10', 'l12', 'l14']", + "118, brain. ['l4', 'l8', 'l11', 'l13', 'l14']", + "119, Activation ['l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "120, of ['l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "121, Mertk ['l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "134, brain ['l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "135, microvascular ['l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "136, endothelial ['l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "137, cells. ['l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "Mertk", + "and/or", + "Axl," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "Mertk", + "and/or", + "Axl," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "Mertk" + ] + }, + "context": { + "val": "cells", + "words": [ + "brain", + "microvascular", + "endothelial", + "cells." + ] + } + } + ] + }, + { + "PMID": "26501191", + "TEXT": "There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53(R175H) induces cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. We also define culture conditions for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture and phenotypic heterogeneity of the primary tumor and retain patient-specific physiological changes, including hypoxia, oxygen consumption, epigenetic marks and differences in sensitivity to inhibition of the histone methyltransferase EZH2. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies.", + "TAG_DATA": [ + "26, human {'context': 'B-cells'}", + "43, in {'context': 'B-in vivo'}", + "44, vivo. {'context': 'I-in vivo'}", + "45, Expression {'perturbing_action': 'B-other'}", + "46, of {'perturbing_action': 'I-other'}", + "47, mutant {'perturbing_action': 'I-other'}", + "48, KRAS {'perturbing_action': 'I-other'}", + "49, or {'perturbing_action': 'I-other'}", + "50, TP53 {'perturbing_action': 'I-other'}", + "52, progenitor {'context': 'B-organoid'}", + "53, organoids {'context': 'I-organoid'}", + "58, culture {'context': 'I-in vitro'}", + "60, in {'context': 'B-in vivo'}", + "61, vivo. {'context': 'I-in vivo'}", + "62, Expression {'perturbing_action': 'B-other'}", + "63, of {'perturbing_action': 'I-other'}", + "64, TP53(R175H) {'perturbing_action': 'I-other'}", + "70, patient {'context': 'B-neoplasm'}", + "71, tumors {'context': 'I-neoplasm'}", + "73, TP53 {'perturbing_action': 'I-other'}", + "74, mutations, {'perturbing_action': 'I-other'}", + "89, generation {'phenotype': 'I-colony formation'}", + "91, tumor {'context': 'B-organoid'}", + "92, organoids {'context': 'I-organoid'}", + "96, PDAC. {'context': 'B-neoplasm'}", + "97, Tumor {'context': 'B-organoid'}", + "98, organoids {'context': 'I-organoid'}", + "99, maintain {'effect': 'B-positive'}", + "101, differentiation {'phenotype': 'B-differentiation'}", + "102, status, {'phenotype': 'I-differentiation'}", + "109, primary {'context': 'B-neoplasm'}", + "110, tumor {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "26, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "43, in ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "44, vivo. ['l1', 'l7', 'l12', 'l13', 'l14', 'l15']", + "45, Expression ['l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "46, of ['l16', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "47, mutant ['l17', 'l33', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "48, KRAS ['l18', 'l34', 'l48', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "49, or ['l19', 'l35', 'l49', 'l61', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "50, TP53 ['l20', 'l36', 'l50', 'l62', 'l70', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "52, progenitor ['l2', 'l8', 'l12', 'l21', 'l37', 'l51', 'l63', 'l71', 'l81', 'l91', 'l92', 'l93', 'l94', 'l95']", + "53, organoids ['l3', 'l9', 'l13', 'l22', 'l38', 'l52', 'l64', 'l72', 'l82', 'l91', 'l96', 'l97', 'l98']", + "58, culture ['l4', 'l10', 'l14', 'l23', 'l39', 'l53', 'l65', 'l73', 'l83', 'l92', 'l96', 'l99']", + "60, in ['l5', 'l24', 'l40', 'l54', 'l66', 'l74', 'l84', 'l93', 'l97', 'l100']", + "61, vivo. ['l6', 'l11', 'l15', 'l25', 'l41', 'l55', 'l67', 'l75', 'l85', 'l94', 'l98', 'l99', 'l100']", + "62, Expression ['l26', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "63, of ['l27', 'l42', 'l56', 'l76', 'l86', 'l101', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "64, TP53(R175H) ['l28', 'l43', 'l57', 'l77', 'l87', 'l102', 'l113', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "70, patient ['l29', 'l44', 'l58', 'l68', 'l78', 'l88', 'l103', 'l114', 'l125', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "71, tumors ['l30', 'l45', 'l59', 'l69', 'l79', 'l89', 'l95', 'l104', 'l115', 'l126', 'l135', 'l141', 'l142']", + "73, TP53 ['l31', 'l46', 'l105', 'l116', 'l127', 'l136', 'l141', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "74, mutations, ['l32', 'l47', 'l60', 'l80', 'l90', 'l106', 'l117', 'l128', 'l137', 'l142', 'l143', 'l150', 'l151', 'l152', 'l153']", + "89, generation ['l107', 'l118', 'l129', 'l138', 'l144', 'l150', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160']", + "91, tumor ['l108', 'l119', 'l130', 'l145', 'l151', 'l154', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "92, organoids ['l109', 'l120', 'l131', 'l139', 'l146', 'l152', 'l155', 'l161', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "96, PDAC. ['l110', 'l121', 'l132', 'l140', 'l147', 'l153', 'l156', 'l162', 'l168', 'l174', 'l175', 'l176', 'l177', 'l178']", + "97, Tumor ['l179', 'l180', 'l181', 'l182', 'l183', 'l184']", + "98, organoids ['l179', 'l185', 'l186', 'l187', 'l188', 'l189']", + "99, maintain ['l163', 'l169', 'l174', 'l180', 'l185', 'l190', 'l191', 'l192', 'l193']", + "101, differentiation ['l122', 'l157', 'l164', 'l170', 'l175', 'l181', 'l186', 'l190', 'l194', 'l195', 'l196']", + "102, status, ['l111', 'l123', 'l133', 'l148', 'l158', 'l165', 'l171', 'l176', 'l182', 'l187', 'l191', 'l194', 'l197', 'l198']", + "109, primary ['l159', 'l166', 'l172', 'l177', 'l183', 'l188', 'l192', 'l195', 'l197', 'l199']", + "110, tumor ['l112', 'l124', 'l134', 'l149', 'l160', 'l167', 'l173', 'l178', 'l184', 'l189', 'l193', 'l196', 'l198', 'l199']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Expression", + "of", + "mutant", + "KRAS", + "or", + "TP53", + "TP53(R175H)", + "mutations," + ] + }, + "context": { + "val": "organoid", + "words": [ + "progenitor", + "organoids", + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Expression", + "of", + "mutant", + "KRAS", + "or", + "TP53" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Expression", + "of", + "mutant", + "KRAS", + "or", + "TP53" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Expression", + "of", + "mutant", + "KRAS", + "or", + "TP53", + "TP53(R175H)", + "mutations," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "patient", + "tumors", + "PDAC.", + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Expression", + "of", + "TP53(R175H)", + "TP53", + "mutations," + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "generation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Expression", + "of", + "TP53(R175H)", + "TP53" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "status,", + "differentiation" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "patient", + "PDAC.", + "primary", + "tumor" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "generation" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "generation" + ] + }, + "context": { + "val": "organoid", + "words": [ + "tumor", + "organoids" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "tumor", + "organoids", + "Tumor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "maintain" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "tumor", + "organoids", + "Tumor" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "status," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "PDAC.", + "primary", + "tumor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "maintain" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "PDAC.", + "primary", + "tumor" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "status," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "maintain" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "status," + ] + } + } + ] + }, + { + "PMID": "26479925", + "TEXT": "Mechanical allodynia, induced by normally innocuous low-threshold mechanical stimulation, represents a cardinal feature of neuropathic pain. Blockade or ablation of high-threshold, small-diameter unmyelinated group C nerve fibers (C-fibers) has limited effects on mechanical allodynia. Although large, myelinated group A fibers, in particular Aβ-fibers, have previously been implicated in mechanical allodynia, an A-fiber-selective pharmacological blocker is still lacking. Here we report a new method for targeted silencing of A-fibers in neuropathic pain. We found that Toll-like receptor 5 (TLR5) is co-expressed with neurofilament-200 in large-diameter A-fiber neurons in the dorsal root ganglion (DRG). Activation of TLR5 with its ligand flagellin results in neuronal entry of the membrane-impermeable lidocaine derivative QX-314, leading to TLR5-dependent blockade of sodium currents, predominantly in A-fiber neurons of mouse DRGs. Intraplantar co-application of flagellin and QX-314 (flagellin/QX-314) dose-dependently suppresses mechanical allodynia after chemotherapy, nerve injury, and diabetic neuropathy, but this blockade is abrogated in Tlr5-deficient mice. In vivo electrophysiology demonstrated that co-application of flagellin/QX-314 selectively suppressed Aβ-fiber conduction in naive and chemotherapy-treated mice. TLR5-mediated Aβ-fiber blockade, but not capsaicin-mediated C-fiber blockade, also reduced chemotherapy-induced ongoing pain without impairing motor function. Finally, flagellin/QX-314 co-application suppressed sodium currents in large-diameter human DRG neurons. Thus, our findings provide a new tool for targeted silencing of Aβ-fibers and neuropathic pain treatment.", + "TAG_DATA": [ + "118, A-fiber {'context': 'B-cells'}", + "119, neurons {'context': 'I-cells'}", + "120, of {'context': 'I-cells'}", + "121, mouse {'context': 'I-cells'}", + "122, DRGs. {'context': 'I-cells'}", + "147, Tlr5-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "148, mice. {'context': 'B-organism'}", + "149, In {'context': 'B-in vivo'}", + "150, vivo {'context': 'I-in vivo'}", + "165, mice. {'context': 'B-organism'}", + "190, large-diameter {'context': 'B-cells'}", + "191, human {'context': 'I-cells'}", + "192, DRG {'context': 'I-cells'}", + "193, neurons. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "118, A-fiber ['l0', 'l1', 'l2', 'l3']", + "119, neurons ['l0', 'l4', 'l5', 'l6']", + "120, of ['l1', 'l4', 'l7', 'l8']", + "121, mouse ['l2', 'l5', 'l7', 'l9']", + "122, DRGs. ['l3', 'l6', 'l8', 'l9']", + "147, Tlr5-deficient ['l10', 'l11']", + "148, mice. ['l10', 'l12']", + "149, In ['l13', 'l14']", + "150, vivo ['l13', 'l15']", + "165, mice. ['l11', 'l12', 'l14', 'l15']", + "190, large-diameter ['l16', 'l17', 'l18']", + "191, human ['l16', 'l19', 'l20']", + "192, DRG ['l17', 'l19', 'l21']", + "193, neurons. ['l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tlr5-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "26479924", + "TEXT": "In heart failure therapy, it is generally assumed that attempts to produce a long-term increase in cardiac contractile force are almost always accompanied by structural and functional damage. Here we show that modest overexpression of the Raf kinase inhibitor protein (RKIP), encoded by Pebp1 in mice, produces a well-tolerated, persistent increase in cardiac contractility that is mediated by the β1-adrenoceptor (β1AR). This result is unexpected, as β1AR activation, a major driver of cardiac contractility, usually has long-term adverse effects. RKIP overexpression achieves this tolerance via simultaneous activation of the β2AR subtype. Analogously, RKIP deficiency exaggerates pressure overload-induced cardiac failure. We find that RKIP expression is upregulated in mouse and human heart failure, indicative of an adaptive role for RKIP. Pebp1 gene transfer in a mouse model of heart failure has beneficial effects, suggesting a new therapeutic strategy for heart failure therapy.", + "TAG_DATA": [ + "32, modest {'perturbing_action': 'B-gene gain-of-function'}", + "33, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "34, of {'perturbing_action': 'I-gene gain-of-function'}", + "35, the {'perturbing_action': 'I-gene gain-of-function'}", + "36, Raf {'perturbing_action': 'I-gene gain-of-function'}", + "37, kinase {'perturbing_action': 'I-gene gain-of-function'}", + "38, inhibitor {'perturbing_action': 'I-gene gain-of-function'}", + "39, protein {'perturbing_action': 'I-gene gain-of-function'}", + "40, (RKIP), {'perturbing_action': 'I-gene gain-of-function'}", + "41, encoded {'perturbing_action': 'I-gene gain-of-function'}", + "42, by {'perturbing_action': 'I-gene gain-of-function'}", + "43, Pebp1 {'perturbing_action': 'I-gene gain-of-function'}", + "45, mice, {'context': 'B-organism'}", + "79, RKIP {'perturbing_action': 'B-gene gain-of-function'}", + "80, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "92, RKIP {'perturbing_action': 'B-gene loss-of-function'}", + "93, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "119, Pebp1 {'perturbing_action': 'B-gene gain-of-function'}", + "120, gene {'perturbing_action': 'I-gene gain-of-function'}", + "121, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "124, mouse {'context': 'B-organism'}", + "125, model {'context': 'I-organism'}", + "126, of {'context': 'I-patient'}", + "127, heart {'context': 'I-tissue/organ'}", + "128, failure {'context': 'I-patient'}" + ], + "LINK_DATA": [ + "32, modest ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "33, overexpression ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "34, of ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "35, the ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "36, Raf ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "37, kinase ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "38, inhibitor ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "39, protein ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "40, (RKIP), ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "41, encoded ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "42, by ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "43, Pebp1 ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "45, mice, ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "79, RKIP ['l78', 'l79', 'l80']", + "80, overexpression ['l78', 'l81', 'l82']", + "92, RKIP ['l79', 'l81', 'l83']", + "93, deficiency ['l80', 'l82', 'l83']", + "119, Pebp1 ['l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "120, gene ['l84', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "121, transfer ['l85', 'l91', 'l97', 'l98', 'l99', 'l100', 'l101']", + "124, mouse ['l86', 'l92', 'l97', 'l102', 'l103', 'l104', 'l105']", + "125, model ['l87', 'l93', 'l98', 'l102', 'l106', 'l107', 'l108']", + "126, of ['l88', 'l94', 'l99', 'l103', 'l106', 'l109', 'l110']", + "127, heart ['l89', 'l95', 'l100', 'l104', 'l107', 'l109', 'l111']", + "128, failure ['l90', 'l96', 'l101', 'l105', 'l108', 'l110', 'l111']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "modest", + "overexpression", + "of", + "the", + "Raf", + "kinase", + "inhibitor", + "protein", + "(RKIP),", + "encoded", + "by", + "Pebp1", + "gene", + "transfer" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Pebp1", + "gene", + "transfer" + ] + }, + "context": { + "val": "patient", + "words": [ + "of", + "failure" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Pebp1", + "gene", + "transfer" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "heart" + ] + } + } + ] + }, + { + "PMID": "26457757", + "TEXT": "Retention of long-term repopulating hematopoietic stem cells (LT-HSCs) in the bone marrow is essential for hematopoiesis and for protection from myelotoxic injury. We report that signaling cascades that are traditionally viewed as coagulation related also control retention of endothelial protein C receptor-positive (EPCR(+)) LT-HSCs in the bone marrow and their recruitment to the blood via two pathways mediated by protease activated receptor 1 (PAR1). Thrombin-PAR1 signaling induces nitric oxide (NO) production, leading to EPCR shedding mediated by tumor necrosis factor-α-converting enzyme (TACE), enhanced CXCL12-CXCR4-induced motility and rapid stem and progenitor cell mobilization. Conversely, bone marrow blood vessels provide a microenvironment enriched with activated protein C (aPC) that retains EPCR(+) LT-HSCs by limiting NO generation, reducing Cdc42 activity and enhancing integrin VLA4 affinity and adhesion. Inhibition of NO production by aPC-EPCR-PAR1 signaling reduces progenitor cell egress from the bone marrow, increases retention of bone marrow NO(low) EPCR(+) LT-HSCs and protects mice from chemotherapy-induced hematological failure and death. Our study reveals new roles for PAR1 and EPCR in controlling NO production to balance maintenance and recruitment of bone marrow EPCR(+) LT-HSCs, with potential clinical relevance for stem cell transplantation.", + "TAG_DATA": [ + "84, motility {'phenotype': 'B-migration'}", + "87, stem {'context': 'B-cells'}", + "88, and {'context': 'I-cells'}", + "89, progenitor {'context': 'I-cells'}", + "90, cell {'context': 'I-cells'}", + "132, progenitor {'context': 'B-cells'}", + "133, cell {'context': 'I-cells'}", + "149, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "84, motility ['l0', 'l1', 'l2', 'l3']", + "87, stem ['l0', 'l4', 'l5', 'l6']", + "88, and ['l1', 'l4', 'l7', 'l8']", + "89, progenitor ['l2', 'l5', 'l7', 'l9']", + "90, cell ['l3', 'l6', 'l8', 'l9']", + "132, progenitor ['l10']", + "133, cell ['l10']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "migration", + "words": [ + "motility" + ] + }, + "context": { + "val": "cells", + "words": [ + "stem", + "and", + "progenitor", + "cell" + ] + } + } + ] + }, + { + "PMID": "26390243", + "TEXT": "Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and shows resistance to any therapeutic strategy used. Here we tested small-molecule inhibitors targeting chromatin regulators as possible therapeutic agents in PDAC. We show that JQ1, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, suppresses PDAC development in mice by inhibiting both MYC activity and inflammatory signals. The histone deacetylase (HDAC) inhibitor SAHA synergizes with JQ1 to augment cell death and more potently suppress advanced PDAC. Finally, using a CRISPR-Cas9-based method for gene editing directly in the mouse adult pancreas, we show that de-repression of p57 (also known as KIP2 or CDKN1C) upon combined BET and HDAC inhibition is required for the induction of combination therapy-induced cell death in PDAC. SAHA is approved for human use, and molecules similar to JQ1 are being tested in clinical trials. Thus, these studies identify a promising epigenetic-based therapeutic strategy that may be rapidly implemented in fatal human tumors.", + "TAG_DATA": [ + "50, PDAC {'context': 'B-neoplasm'}", + "53, mice {'context': 'B-organism'}", + "72, augment {'effect': 'B-positive'}", + "73, cell {'phenotype': 'B-cell death'}", + "74, death {'phenotype': 'I-cell death'}", + "80, PDAC. {'context': 'B-neoplasm'}", + "92, mouse {'context': 'B-tissue/organ'}", + "93, adult {'context': 'I-tissue/organ'}", + "94, pancreas, {'context': 'I-tissue/organ'}", + "98, de-repression {'perturbing_action': 'B-gene loss-of-function'}", + "99, of {'perturbing_action': 'I-gene loss-of-function'}", + "100, p57 {'perturbing_action': 'I-gene loss-of-function'}", + "101, (also {'perturbing_action': 'I-gene loss-of-function'}", + "104, KIP2 {'perturbing_action': 'I-rnai/knockdown'}", + "106, CDKN1C) {'perturbing_action': 'I-rnai/knockdown'}", + "117, induction {'effect': 'B-positive'}", + "120, therapy-induced {'effect': 'B-positive'}", + "121, cell {'phenotype': 'B-cell death'}", + "122, death {'phenotype': 'I-cell death'}", + "124, PDAC. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "50, PDAC ['l0']", + "53, mice ['l0']", + "72, augment ['l1', 'l2', 'l3']", + "73, cell ['l1', 'l4', 'l5']", + "74, death ['l2', 'l4', 'l6']", + "80, PDAC. ['l3', 'l5', 'l6']", + "92, mouse ['l7', 'l8']", + "93, adult ['l7', 'l9']", + "94, pancreas, ['l8', 'l9']", + "98, de-repression ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "99, of ['l10', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "100, p57 ['l11', 'l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "101, (also ['l12', 'l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "103, as ['l13', 'l23', 'l32', 'l40', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "104, KIP2 ['l14', 'l24', 'l33', 'l41', 'l48', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "106, CDKN1C) ['l15', 'l25', 'l34', 'l42', 'l49', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "117, induction ['l16', 'l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "120, therapy-induced ['l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l70', 'l71', 'l72']", + "121, cell ['l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l70', 'l73', 'l74']", + "122, death ['l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l73', 'l75']", + "124, PDAC. ['l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "augment", + "induction", + "therapy-induced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "augment", + "induction", + "therapy-induced" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "PDAC." + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "PDAC." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "de-repression", + "of", + "p57", + "(also" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction", + "therapy-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "de-repression", + "of", + "p57", + "(also" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "de-repression", + "of", + "p57", + "(also" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "PDAC." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "KIP2", + "CDKN1C)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction", + "therapy-induced" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "KIP2", + "CDKN1C)" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "KIP2", + "CDKN1C)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "PDAC." + ] + } + } + ] + }, + { + "PMID": "26301690", + "TEXT": "Endothelial dysfunction is a critical factor in many cardiovascular diseases, including hypertension. Although lipid signaling has been implicated in endothelial dysfunction and cardiovascular disease, specific molecular mechanisms are poorly understood. Here we report that Nogo-B, a membrane protein of the endoplasmic reticulum, regulates endothelial sphingolipid biosynthesis with direct effects on vascular function and blood pressure. Nogo-B inhibits serine palmitoyltransferase, the rate-limiting enzyme of the de novo sphingolipid biosynthetic pathway, thereby controlling production of endothelial sphingosine 1-phosphate and autocrine, G protein-coupled receptor-dependent signaling by this metabolite. Mice lacking Nogo-B either systemically or specifically in endothelial cells are hypotensive, resistant to angiotensin II-induced hypertension and have preserved endothelial function and nitric oxide release. In mice that lack Nogo-B, pharmacological inhibition of serine palmitoyltransferase with myriocin reinstates endothelial dysfunction and angiotensin II-induced hypertension. Our study identifies Nogo-B as a key inhibitor of local sphingolipid synthesis and shows that autocrine sphingolipid signaling within the endothelium is critical for vascular function and blood pressure homeostasis.", + "TAG_DATA": [ + "85, Mice {'context': 'B-organism'}", + "86, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "87, Nogo-B {'perturbing_action': 'I-gene loss-of-function'}", + "89, systemically {'perturbing_action': 'I-gene loss-of-function'}", + "93, endothelial {'context': 'B-cells'}", + "94, cells {'context': 'I-cells'}", + "112, mice {'context': 'B-organism'}", + "114, lack {'perturbing_action': 'B-gene loss-of-function'}", + "115, Nogo-B, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "85, Mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "86, lacking ['l0', 'l5', 'l6', 'l7', 'l8']", + "87, Nogo-B ['l1', 'l5', 'l9', 'l10', 'l11']", + "89, systemically ['l2', 'l6', 'l9', 'l12', 'l13']", + "93, endothelial ['l3', 'l7', 'l10', 'l12', 'l14']", + "94, cells ['l4', 'l8', 'l11', 'l13', 'l14']", + "112, mice ['l15', 'l16']", + "114, lack ['l15', 'l17']", + "115, Nogo-B, ['l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "Nogo-B", + "systemically", + "lack", + "Nogo-B," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "Nogo-B", + "systemically" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + } + } + ] + }, + { + "PMID": "26301689", + "TEXT": "One strategy for combating cancer-drug resistance is to deploy rational polytherapy up front that suppresses the survival and emergence of resistant tumor cells. Here we demonstrate in models of lung adenocarcinoma harboring the oncogenic fusion of ALK and EML4 that the GTPase RAS-mitogen-activated protein kinase (MAPK) pathway, but not other known ALK effectors, is required for tumor-cell survival. EML4-ALK activated RAS-MAPK signaling by engaging all three major RAS isoforms through the HELP domain of EML4. Reactivation of the MAPK pathway via either a gain in the number of copies of the gene encoding wild-type K-RAS (KRAS(WT)) or decreased expression of the MAPK phosphatase DUSP6 promoted resistance to ALK inhibitors in vitro, and each was associated with resistance to ALK inhibitors in individuals with EML4-ALK-positive lung adenocarcinoma. Upfront inhibition of both ALK and the kinase MEK enhanced both the magnitude and duration of the initial response in preclinical models of EML4-ALK lung adenocarcinoma. Our findings identify RAS-MAPK dependence as a hallmark of EML4-ALK lung adenocarcinoma and provide a rationale for the upfront inhibition of both ALK and MEK to forestall resistance and improve patient outcomes.", + "TAG_DATA": [ + "107, ALK {'perturbing_action': 'B-pharmacological inhibition'}", + "108, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "109, in {'context': 'B-in vitro'}", + "110, vitro, {'context': 'B-in vitro'}", + "118, ALK {'perturbing_action': 'B-pharmacological inhibition'}", + "119, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "123, EML4-ALK-positive {'context': 'B-neoplasm'}", + "124, lung {'context': 'I-neoplasm'}", + "125, adenocarcinoma. {'context': 'I-neoplasm'}", + "126, Upfront {'perturbing_action': 'B-pharmacological inhibition'}", + "127, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "128, of {'perturbing_action': 'I-pharmacological inhibition'}", + "129, both {'perturbing_action': 'I-pharmacological inhibition'}", + "130, ALK {'perturbing_action': 'I-pharmacological inhibition'}", + "131, and {'perturbing_action': 'I-pharmacological inhibition'}", + "132, the {'perturbing_action': 'I-pharmacological inhibition'}", + "133, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "134, MEK {'perturbing_action': 'I-pharmacological inhibition'}", + "146, preclinical {'context': 'B-neoplasm'}", + "147, models {'context': 'I-neoplasm'}", + "148, of {'context': 'I-neoplasm'}", + "149, EML4-ALK {'context': 'I-neoplasm'}", + "150, lung {'context': 'I-neoplasm'}", + "151, adenocarcinoma. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "107, ALK ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "108, inhibitors ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "109, in ['l1', 'l7', 'l12']", + "110, vitro, ['l2', 'l8', 'l12']", + "118, ALK ['l3', 'l9', 'l13', 'l14', 'l15', 'l16']", + "119, inhibitors ['l4', 'l10', 'l13', 'l17', 'l18', 'l19']", + "123, EML4-ALK-positive ['l14', 'l17', 'l20', 'l21']", + "124, lung ['l5', 'l15', 'l18', 'l20', 'l22']", + "125, adenocarcinoma. ['l6', 'l11', 'l16', 'l19', 'l21', 'l22']", + "126, Upfront ['l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "127, inhibition ['l23', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "128, of ['l24', 'l37', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "129, both ['l25', 'l38', 'l50', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "130, ALK ['l26', 'l39', 'l51', 'l62', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "131, and ['l27', 'l40', 'l52', 'l63', 'l73', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "132, the ['l28', 'l41', 'l53', 'l64', 'l74', 'l83', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "133, kinase ['l29', 'l42', 'l54', 'l65', 'l75', 'l84', 'l92', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "134, MEK ['l30', 'l43', 'l55', 'l66', 'l76', 'l85', 'l93', 'l100', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "146, preclinical ['l31', 'l44', 'l56', 'l67', 'l77', 'l86', 'l94', 'l101', 'l107', 'l113', 'l114', 'l115', 'l116', 'l117']", + "147, models ['l32', 'l45', 'l57', 'l68', 'l78', 'l87', 'l95', 'l102', 'l108', 'l113', 'l118', 'l119', 'l120', 'l121']", + "148, of ['l33', 'l46', 'l58', 'l69', 'l79', 'l88', 'l96', 'l103', 'l109', 'l114', 'l118', 'l122', 'l123', 'l124']", + "149, EML4-ALK ['l34', 'l47', 'l59', 'l70', 'l80', 'l89', 'l97', 'l104', 'l110', 'l115', 'l119', 'l122', 'l125', 'l126']", + "150, lung ['l35', 'l48', 'l60', 'l71', 'l81', 'l90', 'l98', 'l105', 'l111', 'l116', 'l120', 'l123', 'l125', 'l127']", + "151, adenocarcinoma. ['l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l99', 'l106', 'l112', 'l117', 'l121', 'l124', 'l126', 'l127']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ALK", + "inhibitors" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ALK", + "inhibitors", + "Upfront", + "inhibition", + "of", + "both", + "and", + "the", + "kinase", + "MEK" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lung", + "adenocarcinoma.", + "EML4-ALK-positive", + "preclinical", + "models", + "of", + "EML4-ALK" + ] + } + } + ] + }, + { + "PMID": "26280122", + "TEXT": "An increase in amyloid-β (Aβ) production is a major pathogenic mechanism associated with Alzheimer's disease (AD), but little is known about possible homeostatic control of the amyloidogenic pathway. Here we report that the amyloid precursor protein (APP) intracellular domain (AICD) downregulates Wiskott-Aldrich syndrome protein (WASP)-family verprolin homologous protein 1 (WAVE1 or WASF1) as part of a negative feedback mechanism to limit Aβ production. The AICD binds to the Wasf1 promoter, negatively regulates its transcription and downregulates Wasf1 mRNA and protein expression in Neuro 2a (N2a) cells. WAVE1 interacts and colocalizes with APP in the Golgi apparatus. Experimentally reducing WAVE1 in N2a cells decreased the budding of APP-containing vesicles and reduced cell-surface APP, thereby reducing the production of Aβ. WAVE1 downregulation was observed in mouse models of AD. Reduction of Wasf1 gene expression dramatically reduced Aβ levels and restored memory deficits in a mouse model of AD. A decrease in amounts of WASF1 mRNA was also observed in human AD brains, suggesting clinical relevance of the negative feedback circuit involved in homeostatic regulation of Aβ production.", + "TAG_DATA": [ + "96, Experimentally {'perturbing_action': 'B-gene loss-of-function'}", + "97, reducing {'perturbing_action': 'B-gene loss-of-function'}", + "98, WAVE1 {'perturbing_action': 'I-gene loss-of-function'}", + "100, N2a {'context': 'B-cells'}", + "101, cells {'context': 'I-cells'}", + "118, WAVE1 {'perturbing_action': 'B-gene loss-of-function'}", + "119, downregulation {'perturbing_action': 'I-rnai/knockdown'}", + "123, mouse {'context': 'B-organism'}", + "124, models {'context': 'I-organism'}", + "127, Reduction {'perturbing_action': 'B-gene loss-of-function'}", + "128, of {'perturbing_action': 'I-rnai/knockdown'}", + "129, Wasf1 {'perturbing_action': 'I-rnai/knockdown'}", + "130, gene {'perturbing_action': 'I-rnai/knockdown'}", + "131, expression {'perturbing_action': 'I-rnai/knockdown'}", + "142, mouse {'context': 'B-organism'}", + "143, model {'context': 'I-organism'}", + "144, of {'context': 'I-organism'}", + "145, AD. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "96, Experimentally ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "97, reducing ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "98, WAVE1 ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "100, N2a ['l2', 'l9', 'l15', 'l21', 'l22', 'l23']", + "101, cells ['l3', 'l10', 'l16', 'l21', 'l24']", + "118, WAVE1 ['l4', 'l11', 'l17', 'l25', 'l26', 'l27']", + "119, downregulation ['l5', 'l12', 'l18', 'l25', 'l28', 'l29']", + "123, mouse ['l6', 'l13', 'l19', 'l22', 'l26', 'l28', 'l30']", + "124, models ['l7', 'l14', 'l20', 'l23', 'l24', 'l27', 'l29', 'l30']", + "127, Reduction ['l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "128, of ['l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "129, Wasf1 ['l32', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "130, gene ['l33', 'l40', 'l46', 'l52', 'l53', 'l54', 'l55', 'l56']", + "131, expression ['l34', 'l41', 'l47', 'l52', 'l57', 'l58', 'l59', 'l60']", + "142, mouse ['l35', 'l42', 'l48', 'l53', 'l57', 'l61', 'l62', 'l63']", + "143, model ['l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l64', 'l65']", + "144, of ['l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l66']", + "145, AD. ['l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l65', 'l66']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Experimentally", + "reducing", + "WAVE1" + ] + }, + "context": { + "val": "cells", + "words": [ + "N2a", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Experimentally", + "reducing", + "WAVE1", + "Reduction" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "model", + "of", + "AD." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "downregulation", + "of", + "Wasf1", + "gene", + "expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "model", + "of", + "AD." + ] + } + } + ] + }, + { + "PMID": "26280119", + "TEXT": "T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) elicits antitumor activity in various tumor models; however, the underlying mechanism of action remains unclear. Here we demonstrate a crucial role for interleukin (IL)-9 in antitumor immunity generated by the GITR agonistic antibody DTA-1. IL-4 receptor knockout (Il4ra(-/-)) mice, which have reduced expression of IL-9, were resistant to tumor growth inhibition by DTA-1. Notably, neutralization of IL-9 considerably impaired tumor rejection induced by DTA-1. In particular, DTA-1-induced IL-9 promoted tumor-specific cytotoxic T lymphocyte (CTL) responses by enhancing the function of dendritic cells in vivo. Furthermore, GITR signaling enhanced the differentiation of IL-9-producing CD4(+) T-helper (TH9) cells in a TNFR-associated factor 6 (TRAF6)- and NF-κB-dependent manner and inhibited the generation of induced regulatory T cells in vitro. Our findings demonstrate that GITR co-stimulation mediates antitumor immunity by promoting TH9 cell differentiation and enhancing CTL responses and thus provide a mechanism of action for GITR agonist-mediated cancer immunotherapies.", + "TAG_DATA": [ + "46, IL-4 {'perturbing_action': 'B-gene loss-of-function'}", + "47, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "48, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "49, (Il4ra(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "50, mice, {'context': 'B-organism'}", + "58, resistant {'effect': 'B-negative'}", + "60, tumor {'phenotype': 'B-tumour growth'}", + "61, growth {'phenotype': 'I-tumour growth'}", + "62, inhibition {'effect': 'B-negative'}", + "66, neutralization {'perturbing_action': 'B-pharmacological inhibition'}", + "70, impaired {'effect': 'B-negative'}", + "71, tumor {'phenotype': 'B-tumour growth'}", + "72, rejection {'phenotype': 'I-tumour regression'}", + "92, dendritic {'context': 'B-cells'}", + "93, cells {'context': 'I-cells'}", + "94, in {'context': 'B-in vivo'}", + "95, vivo. {'context': 'I-in vivo'}", + "99, enhanced {'effect': 'B-positive'}", + "101, differentiation {'phenotype': 'B-differentiation'}", + "104, CD4(+) {'context': 'B-cells'}", + "105, T-helper {'context': 'I-cells'}", + "106, (TH9) {'context': 'I-cells'}", + "107, cells {'context': 'I-cells'}", + "123, regulatory {'context': 'B-cells'}", + "124, T {'context': 'I-cells'}", + "125, cells {'context': 'I-cells'}", + "126, in {'context': 'B-in vitro'}", + "127, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "46, IL-4 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "47, receptor ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "48, knockout ['l1', 'l15', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "49, (Il4ra(-/-)) ['l2', 'l16', 'l30', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "50, mice, ['l3', 'l17', 'l31', 'l43', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "58, resistant ['l4', 'l18', 'l32', 'l44', 'l55', 'l64', 'l65', 'l66', 'l67']", + "60, tumor ['l5', 'l19', 'l33', 'l45', 'l56', 'l64', 'l68', 'l69']", + "61, growth ['l6', 'l20', 'l34', 'l46', 'l57', 'l65', 'l68', 'l70']", + "62, inhibition ['l7', 'l21', 'l35', 'l47', 'l58', 'l66', 'l69', 'l70']", + "66, neutralization ['l22', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "70, impaired ['l8', 'l23', 'l36', 'l48', 'l59', 'l71', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "71, tumor ['l9', 'l24', 'l37', 'l49', 'l60', 'l72', 'l81', 'l87', 'l88', 'l89', 'l90', 'l91']", + "72, rejection ['l10', 'l25', 'l38', 'l50', 'l61', 'l67', 'l73', 'l82', 'l87', 'l92', 'l93']", + "92, dendritic ['l11', 'l26', 'l39', 'l51', 'l74', 'l83', 'l88', 'l94', 'l95', 'l96']", + "93, cells ['l12', 'l27', 'l40', 'l52', 'l62', 'l75', 'l84', 'l89', 'l92', 'l94', 'l97', 'l98']", + "94, in ['l13', 'l28', 'l41', 'l53', 'l76', 'l85', 'l90', 'l95', 'l97', 'l99']", + "95, vivo. ['l14', 'l29', 'l42', 'l54', 'l63', 'l77', 'l86', 'l91', 'l93', 'l96', 'l98', 'l99']", + "99, enhanced ['l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "101, differentiation ['l100', 'l107', 'l108', 'l109', 'l110', 'l111']", + "104, CD4(+) ['l101', 'l107', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "105, T-helper ['l78', 'l102', 'l108', 'l112', 'l118', 'l119', 'l120', 'l121']", + "106, (TH9) ['l79', 'l103', 'l109', 'l113', 'l118', 'l122', 'l123', 'l124']", + "107, cells ['l80', 'l104', 'l110', 'l114', 'l119', 'l122']", + "123, regulatory ['l115', 'l125', 'l126', 'l127', 'l128']", + "124, T ['l105', 'l116', 'l120', 'l123', 'l125', 'l129', 'l130', 'l131']", + "125, cells ['l106', 'l111', 'l117', 'l121', 'l124', 'l126', 'l129', 'l132', 'l133']", + "126, in ['l127', 'l130', 'l132', 'l134']", + "127, vitro. ['l128', 'l131', 'l133', 'l134']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IL-4", + "receptor", + "knockout", + "(Il4ra(-/-))" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IL-4", + "receptor", + "knockout", + "(Il4ra(-/-))" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant", + "inhibition", + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IL-4", + "receptor", + "knockout", + "(Il4ra(-/-))" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IL-4", + "receptor", + "knockout", + "(Il4ra(-/-))" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "rejection" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IL-4", + "receptor", + "knockout", + "(Il4ra(-/-))" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IL-4", + "receptor", + "knockout", + "(Il4ra(-/-))" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant", + "inhibition", + "impaired" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "rejection" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistant", + "inhibition", + "impaired" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistant", + "impaired" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "rejection" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "neutralization" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "neutralization" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "neutralization" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "rejection" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "neutralization" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells", + "T-helper", + "(TH9)" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "neutralization" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "rejection" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "rejection" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T-helper", + "(TH9)", + "cells", + "T" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T-helper", + "(TH9)", + "cells" + ] + } + } + ] + }, + { + "PMID": "26259032", + "TEXT": "Hypertension is the most common cardiovascular disease, afflicting >30% of adults. The cause of hypertension in most individuals remains unknown, suggesting that additional contributing factors have yet to be discovered. Corin is a serine protease that activates the natriuretic peptides, thereby regulating blood pressure. It is synthesized as a zymogen that is activated by proteolytic cleavage. CORIN variants and mutations impairing corin activation have been identified in people with hypertension and pre-eclampsia. To date, however, the identity of the protease that activates corin remains elusive. Here we show that proprotein convertase subtilisin/kexin-6 (PCSK6, also named PACE4; ref. 10) cleaves and activates corin. In cultured cells, we found that corin activation was inhibited by inhibitors of PCSK family proteases and by small interfering RNAs blocking PCSK6 expression. Conversely, PCSK6 overexpression enhanced corin activation. In addition, purified PCSK6 cleaved wild-type corin but not the R801A variant that lacks the conserved activation site. Pcsk6-knockout mice developed salt-sensitive hypertension, and corin activation and pro-atrial natriuretic peptide processing activity were undetectable in these mice. Moreover, we found that CORIN variants in individuals with hypertension and pre-eclampsia were defective in PCSK6-mediated activation. We also identified a PCSK6 mutation that impaired corin activation activity in a hypertensive patient. Our results indicate that PCSK6 is the long-sought corin activator and is important for sodium homeostasis and normal blood pressure.", + "TAG_DATA": [ + "103, cultured {'context': 'B-cells'}", + "104, cells, {'context': 'I-cells'}", + "120, small {'perturbing_action': 'B-rnai/knockdown'}", + "121, interfering {'perturbing_action': 'I-rnai/knockdown'}", + "122, RNAs {'perturbing_action': 'I-rnai/knockdown'}", + "123, blocking {'perturbing_action': 'I-rnai/knockdown'}", + "124, PCSK6 {'perturbing_action': 'I-rnai/knockdown'}", + "125, expression. {'perturbing_action': 'I-rnai/knockdown'}", + "127, PCSK6 {'perturbing_action': 'B-gene gain-of-function'}", + "128, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "150, Pcsk6-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "151, mice {'context': 'B-organism'}", + "168, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "103, cultured ['l0']", + "104, cells, ['l0']", + "120, small ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "121, interfering ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "122, RNAs ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "123, blocking ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "124, PCSK6 ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "125, expression. ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "127, PCSK6 ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28', 'l29']", + "128, overexpression ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']", + "150, Pcsk6-knockout ['l30', 'l31']", + "151, mice ['l29', 'l30', 'l32']", + "168, mice. ['l31', 'l32']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PCSK6" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pcsk6-knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "26147761", + "TEXT": "Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain. Here we identify β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner. B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice and young heterochronic parabionts. Exogenous B2M injected systemically, or locally in the hippocampus, impairs hippocampal-dependent cognitive function and neurogenesis in young mice. The negative effects of B2M and heterochronic parabiosis are, in part, mitigated in the hippocampus of young transporter associated with antigen processing 1 (Tap1)-deficient mice with reduced cell surface expression of MHC I. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.", + "TAG_DATA": [ + "124, young {'context': 'B-organism'}", + "125, mice. {'context': 'I-organism'}", + "140, hippocampus {'context': 'B-tissue/organ'}", + "143, transporter {'perturbing_action': 'B-gene loss-of-function'}", + "144, associated {'perturbing_action': 'I-gene loss-of-function'}", + "145, with {'perturbing_action': 'I-gene loss-of-function'}", + "146, antigen {'perturbing_action': 'I-gene loss-of-function'}", + "147, processing {'perturbing_action': 'I-gene loss-of-function'}", + "148, 1 {'perturbing_action': 'I-gene loss-of-function'}", + "149, (Tap1)-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "150, mice {'context': 'B-organism'}", + "162, endogenous {'perturbing_action': 'I-gene loss-of-function'}", + "163, B2M {'perturbing_action': 'I-gene loss-of-function'}", + "164, expression {'perturbing_action': 'I-gene loss-of-function'}", + "173, aged {'context': 'B-organism'}", + "174, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "124, young ['l0']", + "125, mice. ['l0']", + "140, hippocampus ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "143, transporter ['l1', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "144, associated ['l2', 'l9', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "145, with ['l3', 'l10', 'l18', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "146, antigen ['l4', 'l11', 'l19', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "147, processing ['l5', 'l12', 'l20', 'l27', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "148, 1 ['l6', 'l13', 'l21', 'l28', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47']", + "149, (Tap1)-deficient ['l7', 'l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l48', 'l49', 'l50']", + "150, mice ['l8', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l51', 'l52']", + "161, of ['l53', 'l54', 'l55', 'l56', 'l57']", + "162, endogenous ['l53', 'l58', 'l59', 'l60', 'l61']", + "163, B2M ['l54', 'l58', 'l62', 'l63', 'l64']", + "164, expression ['l55', 'l59', 'l62', 'l65', 'l66']", + "173, aged ['l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l56', 'l60', 'l63', 'l65', 'l67']", + "174, mice. ['l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l57', 'l61', 'l64', 'l66', 'l67']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "transporter", + "associated", + "with", + "antigen", + "processing", + "1", + "(Tap1)-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "transporter", + "associated", + "with", + "antigen", + "processing", + "1", + "(Tap1)-deficient", + "endogenous", + "B2M", + "expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "aged", + "mice." + ] + } + } + ] + }, + { + "PMID": "26076038", + "TEXT": "Genetic evidence implicates the loss of bone morphogenetic protein type II receptor (BMPR-II) signaling in the endothelium as an initiating factor in pulmonary arterial hypertension (PAH). However, selective targeting of this signaling pathway using BMP ligands has not yet been explored as a therapeutic strategy. Here, we identify BMP9 as the preferred ligand for preventing apoptosis and enhancing monolayer integrity in both pulmonary arterial endothelial cells and blood outgrowth endothelial cells from subjects with PAH who bear mutations in the gene encoding BMPR-II, BMPR2. Mice bearing a heterozygous knock-in allele of a human BMPR2 mutation, R899X, which we generated as an animal model of PAH caused by BMPR-II deficiency, spontaneously developed PAH. Administration of BMP9 reversed established PAH in these mice, as well as in two other experimental PAH models, in which PAH develops in response to either monocrotaline or VEGF receptor inhibition combined with chronic hypoxia. These results demonstrate the promise of direct enhancement of endothelial BMP signaling as a new therapeutic strategy for PAH.", + "TAG_DATA": [ + "84, Mice {'context': 'B-organism'}", + "86, a {'perturbing_action': 'B-other'}", + "87, heterozygous {'perturbing_action': 'B-other'}", + "88, knock-in {'perturbing_action': 'I-other'}", + "89, allele {'perturbing_action': 'I-other'}", + "90, of {'perturbing_action': 'I-other'}", + "91, a {'perturbing_action': 'I-other'}", + "92, human {'perturbing_action': 'I-other'}", + "93, BMPR2 {'perturbing_action': 'I-other'}", + "94, mutation, {'perturbing_action': 'I-other'}", + "95, R899X, {'perturbing_action': 'I-other'}", + "107, BMPR-II {'perturbing_action': 'B-gene loss-of-function'}", + "108, deficiency, {'perturbing_action': 'I-gene loss-of-function'}", + "120, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "84, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "86, a ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "87, heterozygous ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "88, knock-in ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "89, allele ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "90, of ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "91, a ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "92, human ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "93, BMPR2 ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "94, mutation, ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "95, R899X, ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "107, BMPR-II ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "108, deficiency, ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "a", + "heterozygous", + "knock-in", + "allele", + "of", + "human", + "BMPR2", + "mutation,", + "R899X," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "BMPR-II", + "deficiency," + ] + } + } + ] + }, + { + "PMID": "25985364", + "TEXT": "Previous studies investigating the role of smooth muscle cells (SMCs) and macrophages in the pathogenesis of atherosclerosis have provided controversial results owing to the use of unreliable methods for clearly identifying each of these cell types. Here, using Myh11-CreER(T2) ROSA floxed STOP eYFP Apoe(-/-) mice to perform SMC lineage tracing, we find that traditional methods for detecting SMCs based on immunostaining for SMC markers fail to detect >80% of SMC-derived cells within advanced atherosclerotic lesions. These unidentified SMC-derived cells exhibit phenotypes of other cell lineages, including macrophages and mesenchymal stem cells (MSCs). SMC-specific conditional knockout of Krüppel-like factor 4 (Klf4) resulted in reduced numbers of SMC-derived MSC- and macrophage-like cells, a marked reduction in lesion size, and increases in multiple indices of plaque stability, including an increase in fibrous cap thickness as compared to wild-type controls. On the basis of in vivo KLF4 chromatin immunoprecipitation-sequencing (ChIP-seq) analyses and studies of cholesterol-treated cultured SMCs, we identified >800 KLF4 target genes, including many that regulate pro-inflammatory responses of SMCs. Our findings indicate that the contribution of SMCs to atherosclerotic plaques has been greatly underestimated, and that KLF4-dependent transitions in SMC phenotype are critical in lesion pathogenesis.", + "TAG_DATA": [ + "38, Myh11-CreER(T2) {'perturbing_action': 'B-gene loss-of-function'}", + "39, ROSA {'perturbing_action': 'I-gene loss-of-function'}", + "40, floxed {'perturbing_action': 'I-gene loss-of-function'}", + "41, STOP {'perturbing_action': 'I-gene loss-of-function'}", + "42, eYFP {'perturbing_action': 'I-gene loss-of-function'}", + "43, Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "44, mice {'context': 'B-organism'}", + "92, SMC-specific {'perturbing_action': 'B-gene loss-of-function'}", + "93, conditional {'perturbing_action': 'I-gene loss-of-function'}", + "94, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "95, of {'perturbing_action': 'I-gene loss-of-function'}", + "96, Krüppel-like {'perturbing_action': 'I-gene loss-of-function'}", + "97, factor {'perturbing_action': 'I-gene loss-of-function'}", + "98, 4 {'perturbing_action': 'I-gene loss-of-function'}", + "99, (Klf4) {'perturbing_action': 'I-gene loss-of-function'}", + "105, SMC-derived {'context': 'B-cells'}", + "106, MSC- {'context': 'I-cells'}", + "107, and {'context': 'I-cells'}", + "108, macrophage-like {'context': 'I-cells'}", + "109, cells, {'context': 'I-cells'}", + "140, in {'context': 'B-in vivo'}", + "141, vivo {'context': 'I-in vivo'}", + "152, SMCs, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "38, Myh11-CreER(T2) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "39, ROSA ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "40, floxed ['l1', 'l7', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "41, STOP ['l2', 'l8', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "42, eYFP ['l3', 'l9', 'l18', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "43, Apoe(-/-) ['l4', 'l10', 'l19', 'l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "44, mice ['l5', 'l11', 'l20', 'l27', 'l34', 'l40']", + "92, SMC-specific ['l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "93, conditional ['l46', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "94, knockout ['l47', 'l58', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "95, of ['l48', 'l59', 'l69', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "96, Krüppel-like ['l49', 'l60', 'l70', 'l79', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "97, factor ['l50', 'l61', 'l71', 'l80', 'l88', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "98, 4 ['l51', 'l62', 'l72', 'l81', 'l89', 'l96', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "99, (Klf4) ['l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l109', 'l110', 'l111', 'l112', 'l113']", + "105, SMC-derived ['l12', 'l21', 'l28', 'l35', 'l41', 'l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l109', 'l114', 'l115', 'l116', 'l117']", + "106, MSC- ['l13', 'l22', 'l29', 'l36', 'l42', 'l54', 'l65', 'l75', 'l84', 'l92', 'l99', 'l105', 'l110', 'l114', 'l118', 'l119', 'l120']", + "107, and ['l14', 'l23', 'l30', 'l37', 'l43', 'l55', 'l66', 'l76', 'l85', 'l93', 'l100', 'l106', 'l111', 'l115', 'l118', 'l121', 'l122']", + "108, macrophage-like ['l15', 'l31', 'l38', 'l44', 'l56', 'l67', 'l77', 'l86', 'l94', 'l101', 'l107', 'l112', 'l116', 'l119', 'l121', 'l123']", + "109, cells, ['l6', 'l16', 'l24', 'l32', 'l39', 'l45', 'l57', 'l68', 'l78', 'l87', 'l95', 'l102', 'l108', 'l113', 'l117', 'l120', 'l122', 'l123']", + "140, in ['l124', 'l125']", + "141, vivo ['l124', 'l126']", + "152, SMCs, ['l125', 'l126']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Myh11-CreER(T2)", + "ROSA", + "floxed", + "STOP", + "eYFP", + "Apoe(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Myh11-CreER(T2)", + "ROSA", + "floxed", + "STOP", + "eYFP", + "Apoe(-/-)", + "SMC-specific", + "conditional", + "knockout", + "of", + "Krüppel-like", + "factor", + "4", + "(Klf4)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells,", + "SMC-derived", + "MSC-", + "and", + "macrophage-like" + ] + } + } + ] + }, + { + "PMID": "25939061", + "TEXT": "Here we studied cell-free plasma DNA (cfDNA) collected from subjects with advanced lung cancer whose tumors had developed resistance to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) AZD9291. We first performed next-generation sequencing of cfDNA from seven subjects and detected an acquired EGFR C797S mutation in one; expression of this mutant EGFR construct in a cell line rendered it resistant to AZD9291. We then performed droplet digital PCR on serial cfDNA specimens collected from 15 AZD9291-treated subjects. All were positive for the T790M mutation before treatment, but upon developing AZD9291 resistance three molecular subtypes emerged: six cases acquired the C797S mutation, five cases maintained the T790M mutation but did not acquire the C797S mutation and four cases lost the T790M mutation despite the presence of the underlying EGFR activating mutation. Our findings provide insight into the diversity of mechanisms through which tumors acquire resistance to AZD9291 and highlight the need for therapies that are able to overcome resistance mediated by the EGFR C797S mutation.", + "TAG_DATA": [ + "50, expression {'perturbing_action': 'B-other'}", + "51, of {'perturbing_action': 'I-other'}", + "52, this {'perturbing_action': 'I-other'}", + "53, mutant {'perturbing_action': 'I-other'}", + "54, EGFR {'perturbing_action': 'I-other'}", + "55, construct {'perturbing_action': 'I-other'}", + "58, cell {'context': 'B-cells'}", + "59, line {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "50, expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "51, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "52, this ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "53, mutant ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "54, EGFR ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "55, construct ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "58, cell ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "59, line ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "this", + "mutant", + "EGFR", + "construct" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "line" + ] + } + } + ] + }, + { + "PMID": "25849131", + "TEXT": "Resveratrol improves insulin sensitivity and lowers hepatic glucose production (HGP) in rat models of obesity and diabetes, but the underlying mechanisms for these antidiabetic effects remain elusive. One process that is considered a key feature of resveratrol action is the activation of the nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase sirtuin 1 (SIRT1) in various tissues. However, the low bioavailability of resveratrol raises questions about whether the antidiabetic effects of oral resveratrol can act directly on these tissues. We show here that acute intraduodenal infusion of resveratrol reversed a 3 d high fat diet (HFD)-induced reduction in duodenal-mucosal Sirt1 protein levels while also enhancing insulin sensitivity and lowering HGP. Further, we found that duodenum-specific knockdown of Sirt1 expression for 14 d was sufficient to induce hepatic insulin resistance in rats fed normal chow. We also found that the glucoregulatory role of duodenally acting resveratrol required activation of Sirt1 and AMP-activated protein kinase (Ampk) in this tissue to initiate a gut-brain-liver neuronal axis that improved hypothalamic insulin sensitivity and in turn, reduced HGP. In addition to the effects of duodenally acting resveratrol in an acute 3 d HFD-fed model of insulin resistance, we also found that short-term infusion of resveratrol into the duodenum lowered HGP in two other rat models of insulin resistance--a 28 d HFD-induced model of obesity and a nicotinamide (NA)-streptozotocin (STZ)-HFD-induced model of mild type 2 diabetes. Together, these studies highlight the therapeutic relevance of targeting duodenal SIRT1 to reverse insulin resistance and improve glucose homeostasis in obesity and diabetes.", + "TAG_DATA": [ + "111, duodenum-specific {'perturbing_action': 'B-rnai/knockdown'}", + "112, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "113, of {'perturbing_action': 'I-rnai/knockdown'}", + "114, Sirt1 {'perturbing_action': 'I-rnai/knockdown'}", + "115, expression {'perturbing_action': 'I-rnai/knockdown'}", + "127, rats {'context': 'B-organism'}", + "205, rat {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "111, duodenum-specific ['l0', 'l1', 'l2', 'l3', 'l4']", + "112, knockdown ['l0', 'l5', 'l6', 'l7', 'l8']", + "113, of ['l1', 'l5', 'l9', 'l10', 'l11']", + "114, Sirt1 ['l2', 'l6', 'l9', 'l12', 'l13']", + "115, expression ['l3', 'l7', 'l10', 'l12', 'l14']", + "127, rats ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "duodenum-specific", + "knockdown", + "of", + "Sirt1", + "expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + } + ] + }, + { + "PMID": "25751815", + "TEXT": "Types 1 and 2 diabetes affect some 380 million people worldwide. Both ultimately result from a deficiency of functional pancreatic insulin-producing beta cells. Beta cells proliferate in humans during a brief temporal window beginning around the time of birth, with a peak percentage (∼2%) engaged in the cell cycle in the first year of life. In embryonic life and after early childhood, beta cell replication is barely detectable. Whereas beta cell expansion seems an obvious therapeutic approach to beta cell deficiency, adult human beta cells have proven recalcitrant to such efforts. Hence, there remains an urgent need for antidiabetic therapeutic agents that can induce regeneration and expansion of adult human beta cells in vivo or ex vivo. Here, using a high-throughput small-molecule screen (HTS), we find that analogs of the small molecule harmine function as a new class of human beta cell mitogenic compounds. We also define dual-specificity tyrosine-regulated kinase-1a (DYRK1A) as the likely target of harmine and the nuclear factors of activated T cells (NFAT) family of transcription factors as likely mediators of human beta cell proliferation and differentiation. Using three different mouse and human islet in vivo-based models, we show that harmine is able to induce beta cell proliferation, increase islet mass and improve glycemic control. These observations suggest that harmine analogs may have unique therapeutic promise for human diabetes therapy. Enhancing the potency and beta cell specificity of these compounds are important future challenges.", + "TAG_DATA": [ + "183, mouse {'context': 'B-cells'}", + "184, and {'context': 'I-cells'}", + "185, human {'context': 'I-cells'}", + "186, islet {'context': 'I-cells'}", + "187, in {'context': 'B-in vivo'}", + "188, vivo-based {'context': 'I-in vivo'}", + "189, models, {'context': 'I-xenograft'}", + "197, induce {'effect': 'B-positive'}", + "198, beta {'context': 'B-cells'}", + "199, cell {'context': 'I-cells'}", + "200, proliferation, {'phenotype': 'B-proliferation'}", + "202, islet {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "183, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "184, and ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "185, human ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "186, islet ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "187, in ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "188, vivo-based ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "189, models, ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54']", + "197, induce ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l56', 'l57', 'l58']", + "198, beta ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l55', 'l59', 'l60', 'l61']", + "199, cell ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l56', 'l59', 'l62', 'l63']", + "200, proliferation, ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l57', 'l60', 'l62', 'l64']", + "202, islet ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l58', 'l61', 'l63', 'l64']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "mouse", + "and", + "human", + "islet", + "beta", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "and", + "human", + "islet", + "beta", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo-based" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo-based" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "models," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "models," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + } + ] + }, + { + "PMID": "25686104", + "TEXT": "The gene encoding ARID1A, a chromatin remodeler, shows one of the highest mutation rates across many cancer types. Notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas, which currently have no effective therapy. To date, clinically applicable targeted cancer therapy based on ARID1A mutational status has not been described. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer cells and that ARID1A mutational status correlated with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct target of ARID1A and EZH2 that is upregulated by EZH2 inhibition and contributed to the observed synthetic lethality by inhibiting PI3K-AKT signaling. Importantly, EZH2 inhibition caused regression of ARID1A-mutated ovarian tumors in vivo. To our knowledge, this is the first data set to demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. Our data indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for cancers involving ARID1A mutations.", + "TAG_DATA": [ + "69, ovarian {'context': 'B-transformed cells'}", + "70, cancer {'context': 'I-transformed cells'}", + "71, cells {'context': 'I-transformed cells'}", + "82, EZH2 {'perturbing_action': 'B-pharmacological inhibition'}", + "83, inhibitor. {'perturbing_action': 'I-pharmacological inhibition'}", + "99, EZH2 {'perturbing_action': 'B-pharmacological inhibition'}", + "100, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "113, EZH2 {'perturbing_action': 'B-pharmacological inhibition'}", + "114, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "115, caused {'effect': 'B-positive'}", + "116, regression {'phenotype': 'B-tumour regression'}", + "119, ovarian {'context': 'B-neoplasm'}", + "120, tumors {'context': 'I-neoplasm'}", + "121, in {'context': 'B-in vivo'}", + "122, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "69, ovarian ['l0', 'l1']", + "70, cancer ['l0', 'l2']", + "71, cells ['l1', 'l2']", + "82, EZH2 ['l3', 'l4', 'l5']", + "83, inhibitor. ['l3', 'l6', 'l7']", + "99, EZH2 ['l4', 'l6', 'l8']", + "100, inhibition ['l5', 'l7', 'l8']", + "113, EZH2 ['l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "114, inhibition ['l9', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "115, caused ['l10', 'l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "116, regression ['l11', 'l17', 'l22', 'l27', 'l28', 'l29', 'l30']", + "119, ovarian ['l12', 'l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "120, tumors ['l13', 'l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "121, in ['l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "122, vivo. ['l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EZH2", + "inhibition" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EZH2", + "inhibition" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EZH2", + "inhibition" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "ovarian", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EZH2", + "inhibition" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "ovarian", + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "ovarian", + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "25599133", + "TEXT": "Mutant isocitrate dehydrogenase (IDH) 1 and 2 proteins alter the epigenetic landscape in acute myeloid leukemia (AML) cells through production of the oncometabolite (R)-2-hydroxyglutarate (2-HG). Here we performed a large-scale RNA interference (RNAi) screen to identify genes that are synthetic lethal to the IDH1(R132H) mutation in AML and identified the anti-apoptotic gene BCL-2. IDH1- and IDH2-mutant primary human AML cells were more sensitive than IDH1/2 wild-type cells to ABT-199, a highly specific BCL-2 inhibitor that is currently in clinical trials for hematologic malignancies, both ex vivo and in xenotransplant models. This sensitization effect was induced by (R)-2-HG-mediated inhibition of the activity of cytochrome c oxidase (COX) in the mitochondrial electron transport chain (ETC); suppression of COX activity lowered the mitochondrial threshold to trigger apoptosis upon BCL-2 inhibition. Our findings indicate that IDH1/2 mutation status may identify patients that are likely to respond to pharmacologic BCL-2 inhibition and form the rational basis for combining agents that disrupt ETC activity with ABT-199 in future clinical studies.", + "TAG_DATA": [ + "53, IDH1- {'perturbing_action': 'B-other'}", + "54, and {'perturbing_action': 'I-other'}", + "55, IDH2-mutant {'perturbing_action': 'I-other'}", + "56, primary {'context': 'B-transformed cells'}", + "57, human {'context': 'I-transformed cells'}", + "58, AML {'context': 'I-transformed cells'}", + "59, cells {'context': 'I-transformed cells'}", + "66, cells {'context': 'B-cells'}", + "72, BCL-2 {'perturbing_action': 'I-pharmacological inhibition'}", + "73, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "88, xenotransplant {'context': 'B-xenograft'}", + "89, models. {'context': 'I-xenograft'}", + "122, trigger {'effect': 'B-positive'}", + "123, apoptosis {'phenotype': 'B-apoptosis'}", + "125, BCL-2 {'perturbing_action': 'B-pharmacological inhibition'}", + "126, inhibition. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "53, IDH1- ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "54, and ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "55, IDH2-mutant ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "56, primary ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "57, human ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "58, AML ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "59, cells ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54']", + "66, cells ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l56', 'l57', 'l58']", + "72, BCL-2 ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l55', 'l59', 'l60', 'l61']", + "73, inhibitor ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l56', 'l59', 'l62', 'l63']", + "88, xenotransplant ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l57', 'l60', 'l62', 'l64']", + "89, models. ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l54', 'l58', 'l61', 'l63', 'l64']", + "116, activity ['l65', 'l66', 'l67', 'l68']", + "122, trigger ['l65', 'l69', 'l70', 'l71']", + "123, apoptosis ['l66', 'l69', 'l72', 'l73']", + "125, BCL-2 ['l67', 'l70', 'l72', 'l74']", + "126, inhibition. ['l68', 'l71', 'l73', 'l74']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "IDH1-", + "and", + "IDH2-mutant" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "human", + "AML", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "IDH1-", + "and", + "IDH2-mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "IDH1-", + "and", + "IDH2-mutant" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenotransplant", + "models." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "primary", + "human", + "AML", + "cells" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BCL-2", + "inhibitor" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BCL-2", + "inhibitor" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BCL-2", + "inhibitor" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenotransplant", + "models." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "trigger" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "trigger" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BCL-2", + "inhibition." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BCL-2", + "inhibition." + ] + } + } + ] + }, + { + "PMID": "25419709", + "TEXT": "We searched for genetic alterations in human B cell lymphoma that affect the ubiquitin-proteasome system. This approach identified FBXO25 within a minimal common region of frequent deletion in mantle cell lymphoma (MCL). FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)(FBXO25) ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase Cδ (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1. Our analyses in primary human MCL identify monoallelic loss of FBXO25 and stabilizing HAX1 phosphodegron mutations. Accordingly, FBXO25 re-expression in FBXO25-deleted MCL cells promotes cell death, whereas expression of the HAX-1 phosphodegron mutant inhibits apoptosis. In addition, knockdown of FBXO25 significantly accelerated lymphoma development in Eμ-Myc mice and in a human MCL xenotransplant model. Together we identify a PRKCD-dependent proapoptotic mechanism controlling HAX-1 stability, and we propose that FBXO25 functions as a haploinsufficient tumor suppressor and that HAX1 is a proto-oncogene in MCL.", + "TAG_DATA": [ + "111, FBXO25 {'perturbing_action': 'B-gene gain-of-function'}", + "112, re-expression {'perturbing_action': 'I-gene gain-of-function'}", + "114, FBXO25-deleted {'perturbing_action': 'B-gene loss-of-function'}", + "115, MCL {'context': 'B-transformed cells'}", + "116, cells {'context': 'I-transformed cells'}", + "117, promotes {'effect': 'B-positive'}", + "118, cell {'phenotype': 'B-cell death'}", + "119, death, {'phenotype': 'I-cell death'}", + "121, expression {'perturbing_action': 'B-other'}", + "122, of {'perturbing_action': 'I-other'}", + "123, the {'perturbing_action': 'I-other'}", + "124, HAX-1 {'perturbing_action': 'I-other'}", + "125, phosphodegron {'perturbing_action': 'I-other'}", + "126, mutant {'perturbing_action': 'I-other'}", + "127, inhibits {'effect': 'B-negative'}", + "128, apoptosis. {'phenotype': 'B-apoptosis'}", + "131, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "132, of {'perturbing_action': 'I-rnai/knockdown'}", + "133, FBXO25 {'perturbing_action': 'I-rnai/knockdown'}", + "135, accelerated {'effect': 'B-positive'}", + "136, lymphoma {'phenotype': 'B-tumourigenesis'}", + "139, Eμ-Myc {'perturbing_action': 'B-gene loss-of-function', 'context': 'B-organism'}", + "140, mice {'context': 'B-organism'}", + "144, human {'context': 'B-xenograft'}", + "145, MCL {'context': 'I-xenograft'}", + "146, xenotransplant {'context': 'I-xenograft'}", + "147, model. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "111, FBXO25 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "112, re-expression ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "114, FBXO25-deleted ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "115, MCL ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27']", + "116, cells ['l3', 'l11', 'l18', 'l24', 'l28', 'l29', 'l30']", + "117, promotes ['l4', 'l12', 'l19', 'l25', 'l28', 'l31', 'l32']", + "118, cell ['l5', 'l13', 'l20', 'l26', 'l29', 'l31', 'l33', 'l34']", + "119, death, ['l6', 'l14', 'l21', 'l27', 'l30', 'l32', 'l33']", + "121, expression ['l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "122, of ['l35', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "123, the ['l36', 'l42', 'l48', 'l49', 'l50', 'l51', 'l52']", + "124, HAX-1 ['l37', 'l43', 'l48', 'l53', 'l54', 'l55', 'l56']", + "125, phosphodegron ['l38', 'l44', 'l49', 'l53', 'l57', 'l58', 'l59']", + "126, mutant ['l39', 'l45', 'l50', 'l54', 'l57', 'l60', 'l61']", + "127, inhibits ['l7', 'l15', 'l22', 'l40', 'l46', 'l51', 'l55', 'l58', 'l60', 'l62']", + "128, apoptosis. ['l8', 'l16', 'l23', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l61', 'l62']", + "131, knockdown ['l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "132, of ['l63', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "133, FBXO25 ['l64', 'l73', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "135, accelerated ['l65', 'l74', 'l82', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "136, lymphoma ['l66', 'l75', 'l83', 'l90', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "139, Eμ-Myc ['l67', 'l76', 'l84', 'l91', 'l97', 'l103', 'l104', 'l105', 'l106', 'l107']", + "140, mice ['l68', 'l77', 'l85', 'l92', 'l98', 'l103', 'l108', 'l109', 'l110', 'l111']", + "144, human ['l69', 'l78', 'l86', 'l93', 'l99', 'l104', 'l108', 'l112', 'l113', 'l114']", + "145, MCL ['l70', 'l79', 'l87', 'l94', 'l100', 'l105', 'l109', 'l112', 'l115', 'l116']", + "146, xenotransplant ['l71', 'l80', 'l88', 'l95', 'l101', 'l106', 'l110', 'l113', 'l115', 'l117']", + "147, model. ['l72', 'l81', 'l89', 'l96', 'l102', 'l107', 'l111', 'l114', 'l116', 'l117']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "FBXO25", + "re-expression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MCL", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "FBXO25", + "re-expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "FBXO25", + "re-expression" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "FBXO25", + "re-expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "FBXO25", + "re-expression" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FBXO25-deleted" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MCL", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FBXO25-deleted", + "Eμ-Myc" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes", + "accelerated" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FBXO25-deleted" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FBXO25-deleted" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FBXO25-deleted" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "MCL", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "MCL", + "cells" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "the", + "HAX-1", + "phosphodegron", + "mutant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "the", + "HAX-1", + "phosphodegron", + "mutant" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "FBXO25" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerated" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "FBXO25" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "FBXO25" + ] + }, + "context": { + "val": "organism", + "words": [ + "Eμ-Myc", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Eμ-Myc" + ] + }, + "context": { + "val": "organism", + "words": [ + "Eμ-Myc" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "FBXO25" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "human", + "MCL", + "xenotransplant", + "model." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "accelerated" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "accelerated" + ] + }, + "context": { + "val": "organism", + "words": [ + "Eμ-Myc", + "mice" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "accelerated" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "human", + "MCL", + "xenotransplant", + "model." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Eμ-Myc" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + }, + "context": { + "val": "organism", + "words": [ + "Eμ-Myc", + "mice" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "human", + "MCL", + "xenotransplant", + "model." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Eμ-Myc" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "human", + "MCL", + "xenotransplant", + "model." + ] + } + } + ] + }, + { + "PMID": "25419707", + "TEXT": "Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps.", + "TAG_DATA": [ + "45, mouse {'context': 'B-organism'}", + "46, model {'context': 'I-organism'}", + "85, Lgr5-negative {'context': 'B-cells'}", + "86, progenitor {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}", + "96, cells {'context': 'B-cells'}", + "100, proliferate, {'phenotype': 'B-proliferation'}", + "106, initiate {'effect': 'B-positive'}", + "107, intestinal {'context': 'B-tissue/organ'}", + "108, neoplasia, {'phenotype': 'I-tumourigenesis'}" + ], + "LINK_DATA": [ + "45, mouse ['l0', 'l1', 'l2', 'l3']", + "46, model ['l0', 'l4', 'l5', 'l6']", + "85, Lgr5-negative ['l1', 'l4', 'l7', 'l8', 'l9', 'l10']", + "86, progenitor ['l2', 'l5', 'l7', 'l11', 'l12', 'l13']", + "87, cells ['l3', 'l6', 'l8', 'l11', 'l14']", + "96, cells ['l9', 'l12', 'l14', 'l15', 'l16', 'l17', 'l18']", + "100, proliferate, ['l10', 'l13', 'l15', 'l19', 'l20', 'l21']", + "106, initiate ['l16', 'l19', 'l22', 'l23']", + "107, intestinal ['l17', 'l20', 'l22', 'l24']", + "108, neoplasia, ['l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Lgr5-negative", + "progenitor", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasia," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate," + ] + }, + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "intestinal" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "intestinal" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasia," + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "intestinal" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasia," + ] + } + } + ] + }, + { + "PMID": "25326799", + "TEXT": "Genetically engineered mouse models (GEMMs) have dramatically improved our understanding of tumor evolution and therapeutic resistance. However, sequential genetic manipulation of gene expression and targeting of the host is almost impossible using conventional Cre-loxP-based models. We have developed an inducible dual-recombinase system by combining flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies to improve GEMMs of pancreatic cancer. This enables investigation of multistep carcinogenesis, genetic manipulation of tumor subpopulations (such as cancer stem cells), selective targeting of the tumor microenvironment and genetic validation of therapeutic targets in autochthonous tumors on a genome-wide scale. As a proof of concept, we performed tumor cell-autonomous and nonautonomous targeting, recapitulated hallmarks of human multistep carcinogenesis, validated genetic therapy by 3-phosphoinositide-dependent protein kinase inactivation as well as cancer cell depletion and show that mast cells in the tumor microenvironment, which had been thought to be key oncogenic players, are dispensable for tumor formation.", + "TAG_DATA": [ + "120, cancer {'context': 'B-transformed cells'}", + "121, cell {'context': 'I-transformed cells'}", + "144, tumor {'phenotype': 'B-tumourigenesis'}", + "145, formation. {'phenotype': 'I-tumourigenesis'}" + ], + "LINK_DATA": [ + "120, cancer ['l0', 'l1', 'l2']", + "121, cell ['l0', 'l3', 'l4']", + "144, tumor ['l1', 'l3', 'l5']", + "145, formation. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cell" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "formation." + ] + } + } + ] + }, + { + "PMID": "25326798", + "TEXT": "Multiple bone marrow stromal cell types have been identified as hematopoietic stem cell (HSC)-regulating niche cells. However, whether HSC progeny can serve directly as HSC niche cells has not previously been shown. Here we report a dichotomous role of megakaryocytes (MKs) in both maintaining HSC quiescence during homeostasis and promoting HSC regeneration after chemotherapeutic stress. We show that MKs are physically associated with HSCs in the bone marrow of mice and that MK ablation led to activation of quiescent HSCs and increased HSC proliferation. RNA sequencing (RNA-seq) analysis revealed that transforming growth factor β1 (encoded by Tgfb1) is expressed at higher levels in MKs as compared to other stromal niche cells. MK ablation led to reduced levels of biologically active TGF-β1 protein in the bone marrow and nuclear-localized phosphorylated SMAD2/3 (pSMAD2/3) in HSCs, suggesting that MKs maintain HSC quiescence through TGF-β-SMAD signaling. Indeed, TGF-β1 injection into mice in which MKs had been ablated restored HSC quiescence, and conditional deletion of Tgfb1 in MKs increased HSC activation and proliferation. These data demonstrate that TGF-β1 is a dominant signal emanating from MKs that maintains HSC quiescence. However, under conditions of chemotherapeutic challenge, MK ablation resulted in a severe defect in HSC expansion. In response to stress, fibroblast growth factor 1 (FGF1) signaling from MKs transiently dominates over TGF-β inhibitory signaling to stimulate HSC expansion. Overall, these observations demonstrate that MKs serve as HSC-derived niche cells to dynamically regulate HSC function.", + "TAG_DATA": [ + "72, MK {'perturbing_action': 'B-gene loss-of-function'}", + "73, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "79, HSCs {'context': 'B-cells'}", + "81, increased {'effect': 'B-positive'}", + "82, HSC {'context': 'B-transformed cells'}", + "83, proliferation. {'phenotype': 'B-proliferation'}", + "111, MK {'perturbing_action': 'B-gene loss-of-function'}", + "112, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "132, HSCs, {'context': 'B-cells'}", + "146, mice {'context': 'B-organism'}", + "149, MKs {'perturbing_action': 'B-gene loss-of-function'}", + "151, been {'perturbing_action': 'I-gene loss-of-function'}", + "152, ablated {'perturbing_action': 'I-gene loss-of-function'}", + "153, restored {'effect': 'B-rescues'}", + "154, HSC {'context': 'B-cells'}", + "155, quiescence, {'phenotype': 'B-quiescence'}", + "157, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "158, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "159, of {'perturbing_action': 'I-gene loss-of-function'}", + "160, Tgfb1 {'perturbing_action': 'I-gene loss-of-function'}", + "162, MKs {'context': 'B-cells'}", + "163, increased {'effect': 'B-positive'}", + "164, HSC {'context': 'B-cells'}", + "167, proliferation. {'phenotype': 'B-proliferation'}", + "190, MK {'perturbing_action': 'B-gene loss-of-function'}", + "191, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "198, HSC {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "72, MK ['l0', 'l1', 'l2', 'l3', 'l4']", + "73, ablation ['l0', 'l5', 'l6', 'l7', 'l8']", + "79, HSCs ['l1', 'l5', 'l9', 'l10', 'l11']", + "81, increased ['l2', 'l6', 'l9', 'l12', 'l13']", + "82, HSC ['l3', 'l7', 'l10', 'l12', 'l14']", + "83, proliferation. ['l4', 'l8', 'l11', 'l13', 'l14']", + "111, MK ['l15', 'l16', 'l17']", + "112, ablation ['l15', 'l18', 'l19']", + "132, HSCs, ['l16', 'l18', 'l20']", + "146, mice ['l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "149, MKs ['l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "151, been ['l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "152, ablated ['l23', 'l28', 'l32', 'l36', 'l37', 'l38']", + "153, restored ['l17', 'l19', 'l20', 'l24', 'l29', 'l33', 'l36', 'l39', 'l40']", + "154, HSC ['l25', 'l30', 'l34', 'l37', 'l39', 'l41']", + "155, quiescence, ['l26', 'l31', 'l35', 'l38', 'l40', 'l41']", + "157, conditional ['l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "158, deletion ['l42', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "159, of ['l43', 'l52', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "160, Tgfb1 ['l44', 'l53', 'l61', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "162, MKs ['l45', 'l54', 'l62', 'l69', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "163, increased ['l46', 'l55', 'l63', 'l70', 'l76', 'l82', 'l83']", + "164, HSC ['l47', 'l56', 'l64', 'l71', 'l77', 'l82', 'l84']", + "167, proliferation. ['l48', 'l57', 'l65', 'l72', 'l78', 'l83', 'l84']", + "190, MK ['l49', 'l58', 'l66', 'l73', 'l79', 'l85', 'l86']", + "191, ablation ['l50', 'l59', 'l67', 'l74', 'l80', 'l85', 'l87']", + "198, HSC ['l51', 'l60', 'l68', 'l75', 'l81', 'l86', 'l87']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MK", + "ablation", + "MKs", + "been", + "ablated", + "conditional", + "deletion", + "of", + "Tgfb1" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSCs", + "HSCs,", + "HSC", + "MKs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MK", + "ablation", + "conditional", + "deletion", + "of", + "Tgfb1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MK", + "ablation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MK", + "ablation", + "conditional", + "deletion", + "of", + "Tgfb1" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSCs", + "MKs", + "HSC" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSCs", + "MKs", + "HSC" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MK", + "ablation", + "MKs", + "been", + "ablated" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSCs,", + "HSC" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MKs", + "been", + "ablated" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MKs", + "been", + "ablated" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence," + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSC" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence," + ] + } + } + ] + }, + { + "PMID": "25306233", + "TEXT": "The WNT16 locus is a major determinant of cortical bone thickness and nonvertebral fracture risk in humans. The disability, mortality and costs caused by osteoporosis-induced nonvertebral fractures are enormous. We demonstrate here that Wnt16-deficient mice develop spontaneous fractures as a result of low cortical thickness and high cortical porosity. In contrast, trabecular bone volume is not altered in these mice. Mechanistic studies revealed that WNT16 is osteoblast derived and inhibits human and mouse osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts. The signaling pathway activated by WNT16 in osteoclast progenitors is noncanonical, whereas the pathway activated in osteoblasts is both canonical and noncanonical. Conditional Wnt16 inactivation revealed that osteoblast-lineage cells are the principal source of WNT16, and its targeted deletion in osteoblasts increases fracture susceptibility. Thus, osteoblast-derived WNT16 is a previously unreported key regulator of osteoclastogenesis and fracture susceptibility. These findings open new avenues for the specific prevention or treatment of nonvertebral fractures, a substantial unmet medical need.", + "TAG_DATA": [ + "33, Wnt16-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "34, mice {'context': 'B-organism'}", + "59, mice. {'context': 'B-organism'}", + "69, inhibits {'effect': 'B-negative'}", + "70, human {'context': 'B-organism'}", + "71, and {'context': 'I-organism'}", + "72, mouse {'context': 'I-organism'}", + "73, osteoclastogenesis {'phenotype': 'B-mitophagy'}", + "113, Conditional {'perturbing_action': 'B-gene loss-of-function'}", + "114, Wnt16 {'perturbing_action': 'I-gene loss-of-function'}", + "115, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "118, osteoblast-lineage {'context': 'B-cells'}", + "119, cells {'context': 'I-cells'}", + "131, osteoblasts {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "33, Wnt16-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "34, mice ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "59, mice. ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "69, inhibits ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "70, human ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "71, and ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "72, mouse ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "73, osteoclastogenesis ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "113, Conditional ['l28', 'l29', 'l30', 'l31', 'l32']", + "114, Wnt16 ['l28', 'l33', 'l34', 'l35', 'l36']", + "115, inactivation ['l29', 'l33', 'l37', 'l38', 'l39']", + "118, osteoblast-lineage ['l30', 'l34', 'l37', 'l40', 'l41']", + "119, cells ['l31', 'l35', 'l38', 'l40', 'l42']", + "131, osteoblasts ['l32', 'l36', 'l39', 'l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Wnt16-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "human", + "and", + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Wnt16-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Wnt16-deficient" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "osteoclastogenesis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "human", + "and", + "mouse" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "human", + "and", + "mouse" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "osteoclastogenesis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "osteoclastogenesis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "Wnt16", + "inactivation" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoblast-lineage", + "cells", + "osteoblasts" + ] + } + } + ] + }, + { + "PMID": "25261995", + "TEXT": "Haploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD) and modulates an innate immune response in humans and in mouse models. GRN polymorphism may be linked to late-onset Alzheimer's disease (AD). However, the role of PGRN in AD pathogenesis is unknown. Here we show that PGRN inhibits amyloid β (Aβ) deposition. Selectively reducing microglial expression of PGRN in AD mouse models impaired phagocytosis, increased plaque load threefold and exacerbated cognitive deficits. Lentivirus-mediated PGRN overexpression lowered plaque load in AD mice with aggressive amyloid plaque pathology. Aβ plaque load correlated negatively with levels of hippocampal PGRN, showing the dose-dependent inhibitory effects of PGRN on plaque deposition. PGRN also protected against Aβ toxicity. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. The protective effects of PGRN against Aβ deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTLD and AD.", + "TAG_DATA": [ + "55, Selectively {'perturbing_action': 'B-rnai/knockdown'}", + "56, reducing {'perturbing_action': 'I-rnai/knockdown'}", + "57, microglial {'perturbing_action': 'I-rnai/knockdown'}", + "58, expression {'perturbing_action': 'I-rnai/knockdown'}", + "59, of {'perturbing_action': 'I-rnai/knockdown'}", + "60, PGRN {'perturbing_action': 'I-rnai/knockdown'}", + "62, AD {'context': 'B-organism'}", + "63, mouse {'context': 'I-organism'}", + "64, models {'context': 'I-organism'}", + "75, Lentivirus-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "76, PGRN {'perturbing_action': 'I-gene gain-of-function'}", + "77, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "82, AD {'context': 'B-organism'}", + "83, mice {'context': 'I-organism'}", + "115, Lentivirus-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "116, PGRN {'perturbing_action': 'I-gene gain-of-function'}", + "117, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "127, AD {'context': 'B-organism'}", + "128, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "55, Selectively ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "56, reducing ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "57, microglial ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "58, expression ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "59, of ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "60, PGRN ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "62, AD ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "63, mouse ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "64, models ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "75, Lentivirus-mediated ['l36', 'l37', 'l38', 'l39']", + "76, PGRN ['l36', 'l40', 'l41', 'l42']", + "77, overexpression ['l37', 'l40', 'l43', 'l44']", + "82, AD ['l38', 'l41', 'l43', 'l45']", + "83, mice ['l39', 'l42', 'l44', 'l45']", + "115, Lentivirus-mediated ['l46', 'l47', 'l48', 'l49']", + "116, PGRN ['l46', 'l50', 'l51', 'l52']", + "117, overexpression ['l47', 'l50', 'l53', 'l54']", + "127, AD ['l48', 'l51', 'l53', 'l55']", + "128, mice. ['l49', 'l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Selectively", + "reducing", + "microglial", + "expression", + "of", + "PGRN" + ] + }, + "context": { + "val": "organism", + "words": [ + "AD", + "mouse", + "models" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Lentivirus-mediated", + "PGRN", + "overexpression" + ] + }, + "context": { + "val": "organism", + "words": [ + "AD", + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "25216638", + "TEXT": "In solid tumors, resistance to therapy inevitably develops upon treatment with cytotoxic drugs or molecularly targeted therapies. Here, we describe a system that enables pooled shRNA screening directly in mouse hepatocellular carcinomas (HCC) in vivo to identify genes likely to be involved in therapy resistance. Using a focused shRNA library targeting genes located within focal genomic amplifications of human HCC, we screened for genes whose inhibition increased the therapeutic efficacy of the multikinase inhibitor sorafenib. Both shRNA-mediated and pharmacological silencing of Mapk14 (p38α) were found to sensitize mouse HCC to sorafenib therapy and prolong survival by abrogating Mapk14-dependent activation of Mek-Erk and Atf2 signaling. Elevated Mapk14-Atf2 signaling predicted poor response to sorafenib therapy in human HCC, and sorafenib resistance of p-Mapk14-expressing HCC cells could be reverted by silencing Mapk14. Our results suggest that a combination of sorafenib and Mapk14 blockade is a promising approach to overcoming therapy resistance of human HCC.", + "TAG_DATA": [ + "78, pharmacological {'perturbing_action': 'B-rnai/knockdown'}", + "79, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "80, of {'perturbing_action': 'I-rnai/knockdown'}", + "81, Mapk14 {'perturbing_action': 'I-rnai/knockdown'}", + "82, (p38α) {'perturbing_action': 'I-rnai/knockdown'}", + "87, mouse {'context': 'B-neoplasm'}", + "88, HCC {'context': 'I-neoplasm'}", + "121, HCC {'context': 'B-transformed cells'}", + "122, cells {'context': 'I-transformed cells'}", + "127, silencing {'perturbing_action': 'B-rnai/knockdown'}", + "128, Mapk14. {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "78, pharmacological ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "79, silencing ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "80, of ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "81, Mapk14 ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "82, (p38α) ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "87, mouse ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "88, HCC ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "120, p-Mapk14-expressing ['l21', 'l22', 'l23', 'l24']", + "121, HCC ['l21', 'l25', 'l26', 'l27']", + "122, cells ['l22', 'l25', 'l28', 'l29']", + "127, silencing ['l23', 'l26', 'l28', 'l30']", + "128, Mapk14. ['l24', 'l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "pharmacological", + "silencing", + "of", + "Mapk14", + "(p38α)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "HCC" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "HCC", + "cells" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "Mapk14." + ] + } + } + ] + }, + { + "PMID": "25194568", + "TEXT": "The Notch signaling pathway controls cell fates through interactions between neighboring cells by positively or negatively affecting the processes of proliferation, differentiation and apoptosis in a context-dependent manner. This pathway has been implicated in human cancer as both an oncogene and a tumor suppressor. Here we report new inactivating mutations in Notch pathway components in over 40% of human bladder cancers examined. Bladder cancer is the fourth most commonly diagnosed malignancy in the male population of the United States. Thus far, driver mutations in fibroblast growth factor receptor 3 (FGFR3) and, less commonly, in RAS proteins have been identified. We show that Notch activation in bladder cancer cells suppresses proliferation both in vitro and in vivo by directly upregulating dual-specificity phosphatases (DUSPs), thus reducing the phosphorylation of ERK1 and ERK2 (ERK1/2). In mouse models, genetic inactivation of Notch signaling leads to Erk1/2 phosphorylation, resulting in tumorigenesis in the urinary tract. Collectively our findings show that loss of Notch activity is a driving event in urothelial cancer.", + "TAG_DATA": [ + "105, bladder {'context': 'B-transformed cells'}", + "106, cancer {'context': 'I-transformed cells'}", + "107, cells {'context': 'I-transformed cells'}", + "108, suppresses {'effect': 'B-negative'}", + "109, proliferation {'phenotype': 'B-proliferation'}", + "111, in {'context': 'B-in vitro'}", + "112, vitro {'context': 'I-in vitro'}", + "114, in {'context': 'B-in vivo'}", + "115, vivo {'context': 'I-in vivo'}", + "132, mouse {'context': 'B-organism'}", + "133, models, {'context': 'I-organism'}", + "134, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "135, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "136, of {'perturbing_action': 'I-gene loss-of-function'}", + "137, Notch {'perturbing_action': 'I-gene loss-of-function'}", + "138, signaling {'perturbing_action': 'I-gene loss-of-function'}", + "143, resulting {'effect': 'B-positive'}", + "144, in {'effect': 'I-positive'}", + "145, tumorigenesis {'phenotype': 'B-tumourigenesis'}", + "148, urinary {'context': 'B-tissue/organ'}", + "149, tract. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "105, bladder ['l0', 'l1', 'l2', 'l3']", + "106, cancer ['l0', 'l4', 'l5', 'l6']", + "107, cells ['l1', 'l4', 'l7', 'l8']", + "108, suppresses ['l2', 'l5', 'l7', 'l9', 'l10', 'l11']", + "109, proliferation ['l3', 'l6', 'l8', 'l9', 'l12', 'l13']", + "111, in ['l10', 'l12', 'l14']", + "112, vitro ['l11', 'l13', 'l14']", + "114, in ['l15']", + "115, vivo ['l15']", + "132, mouse ['l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "133, models, ['l16', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "134, genetic ['l17', 'l27', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "135, inactivation ['l18', 'l28', 'l37', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "136, of ['l19', 'l29', 'l38', 'l46', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "137, Notch ['l20', 'l30', 'l39', 'l47', 'l54', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "138, signaling ['l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l67', 'l68', 'l69', 'l70', 'l71']", + "143, resulting ['l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l72', 'l73', 'l74', 'l75']", + "144, in ['l23', 'l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l76', 'l77', 'l78']", + "145, tumorigenesis ['l24', 'l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l76', 'l79', 'l80']", + "148, urinary ['l25', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l79', 'l81']", + "149, tract. ['l26', 'l36', 'l45', 'l53', 'l60', 'l66', 'l71', 'l75', 'l78', 'l80', 'l81']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "bladder", + "cancer", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "bladder", + "cancer", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inactivation", + "of", + "Notch", + "signaling" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models," + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inactivation", + "of", + "Notch", + "signaling" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inactivation", + "of", + "Notch", + "signaling" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inactivation", + "of", + "Notch", + "signaling" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "urinary", + "tract." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "urinary", + "tract." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "urinary", + "tract." + ] + } + } + ] + }, + { + "PMID": "25038826", + "TEXT": "Beige adipocytes in white adipose tissue (WAT) are similar to classical brown adipocytes in that they can burn lipids to produce heat. Thus, an increase in beige adipocyte content in WAT browning would raise energy expenditure and reduce adiposity. Here we report that adipose-specific inactivation of Notch1 or its signaling mediator Rbpj in mice results in browning of WAT and elevated expression of uncoupling protein 1 (Ucp1), a key regulator of thermogenesis. Consequently, as compared to wild-type mice, Notch mutants exhibit elevated energy expenditure, better glucose tolerance and improved insulin sensitivity and are more resistant to high fat diet-induced obesity. By contrast, adipose-specific activation of Notch1 leads to the opposite phenotypes. At the molecular level, constitutive activation of Notch signaling inhibits, whereas Notch inhibition induces, Ppargc1a and Prdm16 transcription in white adipocytes. Notably, pharmacological inhibition of Notch signaling in obese mice ameliorates obesity, reduces blood glucose and increases Ucp1 expression in white fat. Therefore, Notch signaling may be therapeutically targeted to treat obesity and type 2 diabetes.", + "TAG_DATA": [ + "43, adipose-specific {'perturbing_action': 'B-gene loss-of-function'}", + "44, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "45, of {'perturbing_action': 'I-gene loss-of-function'}", + "46, Notch1 {'perturbing_action': 'I-gene loss-of-function'}", + "47, or {'perturbing_action': 'I-gene loss-of-function'}", + "48, its {'perturbing_action': 'I-gene loss-of-function'}", + "49, signaling {'perturbing_action': 'I-gene loss-of-function'}", + "50, mediator {'perturbing_action': 'I-gene loss-of-function'}", + "51, Rbpj {'perturbing_action': 'I-gene loss-of-function'}", + "53, mice {'context': 'B-organism'}", + "78, Notch {'perturbing_action': 'B-other'}", + "79, mutants {'perturbing_action': 'I-other'}", + "102, adipose-specific {'perturbing_action': 'B-pharmacological augmentation'}", + "103, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "104, of {'perturbing_action': 'I-pharmacological augmentation'}", + "105, Notch1 {'perturbing_action': 'I-pharmacological augmentation'}", + "115, constitutive {'perturbing_action': 'B-gene gain-of-function'}", + "116, activation {'perturbing_action': 'I-gene gain-of-function'}", + "122, Notch {'perturbing_action': 'B-pharmacological inhibition'}", + "123, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "130, white {'context': 'B-cells'}", + "131, adipocytes. {'context': 'I-cells'}", + "133, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "134, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "135, of {'perturbing_action': 'I-pharmacological inhibition'}", + "136, Notch {'perturbing_action': 'I-pharmacological inhibition'}", + "137, signaling {'perturbing_action': 'I-pharmacological inhibition'}", + "139, obese {'context': 'B-organism'}", + "140, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "43, adipose-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "44, inactivation ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "45, of ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "46, Notch1 ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "47, or ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "48, its ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "49, signaling ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "50, mediator ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "51, Rbpj ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "53, mice ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "78, Notch ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "79, mutants ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "102, adipose-specific ['l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "103, activation ['l66', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "104, of ['l67', 'l77', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "105, Notch1 ['l68', 'l78', 'l86', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "115, constitutive ['l69', 'l79', 'l87', 'l94', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "116, activation ['l70', 'l80', 'l88', 'l95', 'l101', 'l107', 'l108', 'l109', 'l110', 'l111']", + "119, signaling ['l71', 'l81', 'l89', 'l96', 'l102', 'l107', 'l112', 'l113', 'l114', 'l115']", + "122, Notch ['l72', 'l82', 'l90', 'l97', 'l103', 'l108', 'l112', 'l116', 'l117', 'l118']", + "123, inhibition ['l73', 'l83', 'l91', 'l98', 'l104', 'l109', 'l113', 'l116', 'l119', 'l120']", + "130, white ['l74', 'l84', 'l92', 'l99', 'l105', 'l110', 'l114', 'l117', 'l119', 'l121']", + "131, adipocytes. ['l75', 'l85', 'l93', 'l100', 'l106', 'l111', 'l115', 'l118', 'l120', 'l121']", + "133, pharmacological ['l122', 'l123', 'l124', 'l125', 'l126', 'l127']", + "134, inhibition ['l122', 'l128', 'l129', 'l130', 'l131', 'l132']", + "135, of ['l123', 'l128', 'l133', 'l134', 'l135', 'l136']", + "136, Notch ['l124', 'l129', 'l133', 'l137', 'l138', 'l139']", + "137, signaling ['l125', 'l130', 'l134', 'l137', 'l140', 'l141']", + "139, obese ['l126', 'l131', 'l135', 'l138', 'l140', 'l142']", + "140, mice ['l76', 'l127', 'l132', 'l136', 'l139', 'l141', 'l142']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adipose-specific", + "inactivation", + "of", + "Notch1", + "or", + "its", + "signaling", + "mediator", + "Rbpj" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Notch", + "mutants" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "adipose-specific", + "activation", + "of", + "Notch1" + ] + }, + "context": { + "val": "cells", + "words": [ + "white", + "adipocytes." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "adipose-specific" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutive", + "activation" + ] + }, + "context": { + "val": "cells", + "words": [ + "white", + "adipocytes." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Notch", + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "white", + "adipocytes." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "Notch", + "signaling" + ] + }, + "context": { + "val": "organism", + "words": [ + "obese", + "mice" + ] + } + } + ] + }, + { + "PMID": "24997607", + "TEXT": "Functional screening for compounds that promote remyelination represents a major hurdle in the development of rational therapeutics for multiple sclerosis. Screening for remyelination is problematic, as myelination requires the presence of axons. Standard methods do not resolve cell-autonomous effects and are not suited for high-throughput formats. Here we describe a binary indicant for myelination using micropillar arrays (BIMA). Engineered with conical dimensions, micropillars permit resolution of the extent and length of membrane wrapping from a single two-dimensional image. Confocal imaging acquired from the base to the tip of the pillars allows for detection of concentric wrapping observed as 'rings' of myelin. The platform is formatted in 96-well plates, amenable to semiautomated random acquisition and automated detection and quantification. Upon screening 1,000 bioactive molecules, we identified a cluster of antimuscarinic compounds that enhance oligodendrocyte differentiation and remyelination. Our findings demonstrate a new high-throughput screening platform for potential regenerative therapeutics in multiple sclerosis.", + "TAG_DATA": [ + "131, enhance {'effect': 'B-positive'}", + "132, oligodendrocyte {'context': 'B-cells'}", + "133, differentiation {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "131, enhance ['l0', 'l1']", + "132, oligodendrocyte ['l0', 'l2']", + "133, differentiation ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "enhance" + ] + }, + "context": { + "val": "cells", + "words": [ + "oligodendrocyte" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhance" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "oligodendrocyte" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "24973920", + "TEXT": "Hedgehog signaling drives oncogenesis in several cancers, and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened (SMO). However, resistance to Smoothened inhibitors occurs by genetic changes of Smoothened or other downstream Hedgehog components. Here we overcome these resistance mechanisms by modulating GLI transcription through inhibition of bromo and extra C-terminal (BET) bromodomain proteins. We show that BRD4 and other BET bromodomain proteins regulate GLI transcription downstream of SMO and suppressor of fused (SUFU), and chromatin immunoprecipitation studies reveal that BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites after treatment with JQ1, a small-molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM (genetically engineered mouse model)-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists. Altogether, our results reveal BET proteins as critical regulators of Hedgehog pathway transcriptional output and nominate BET bromodomain inhibitors as a strategy for treating Hedgehog-driven tumors with emerged or a priori resistance to Smoothened antagonists.", + "TAG_DATA": [ + "103, JQ1, {'perturbing_action': 'B-pharmacological inhibition'}", + "104, a {'perturbing_action': 'I-pharmacological inhibition'}", + "105, small-molecule {'perturbing_action': 'I-pharmacological inhibition'}", + "106, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "107, targeting {'perturbing_action': 'I-pharmacological inhibition'}", + "108, BRD4. {'perturbing_action': 'I-pharmacological inhibition'}", + "140, Hedgehog-driven {'context': 'I-neoplasm'}", + "141, tumors {'context': 'I-neoplasm'}", + "142, (basal {'context': 'I-neoplasm'}", + "143, cell {'context': 'I-neoplasm'}", + "144, carcinoma, {'context': 'I-neoplasm'}", + "145, medulloblastoma {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "103, JQ1, ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "104, a ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "105, small-molecule ['l1', 'l10', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "106, inhibitor ['l2', 'l11', 'l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "107, targeting ['l3', 'l12', 'l21', 'l29', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "108, BRD4. ['l4', 'l13', 'l22', 'l30', 'l37', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "140, Hedgehog-driven ['l5', 'l14', 'l23', 'l31', 'l38', 'l44', 'l50', 'l51', 'l52', 'l53', 'l54']", + "141, tumors ['l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l55', 'l56', 'l57', 'l58']", + "142, (basal ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l59', 'l60', 'l61']", + "143, cell ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l62', 'l63']", + "144, carcinoma, ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l62', 'l64']", + "145, medulloblastoma ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l64']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "JQ1,", + "a", + "small-molecule", + "inhibitor", + "targeting", + "BRD4." + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "Hedgehog-driven", + "(basal", + "cell", + "carcinoma,", + "medulloblastoma", + "tumors" + ] + } + } + ] + }, + { + "PMID": "24859530", + "TEXT": "Immune evasion is an emerging hallmark of cancer progression. However, functional studies to understand the role of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment are limited by the lack of available specific cell surface markers. We adapted a competitive peptide phage display platform to identify candidate peptides binding MDSCs specifically and generated peptide-Fc fusion proteins (peptibodies). In multiple tumor models, intravenous peptibody injection completely depleted blood, splenic and intratumoral MDSCs in tumor-bearing mice without affecting proinflammatory immune cell types, such as dendritic cells. Whereas control Gr-1-specific antibody primarily depleted granulocytic MDSCs, peptibodies depleted both granulocytic and monocytic MDSC subsets. Peptibody treatment was associated with inhibition of tumor growth in vivo, which was superior to that achieved with Gr-1-specific antibody. Immunoprecipitation of MDSC membrane proteins identified S100 family proteins as candidate targets. Our strategy may be useful to identify new diagnostic and therapeutic surface targets on rare cell subtypes, including human MDSCs.", + "TAG_DATA": [ + "59, tumor {'context': 'B-neoplasm'}", + "60, models, {'context': 'I-neoplasm'}", + "70, MDSCs {'context': 'B-cells'}", + "72, tumor-bearing {'context': 'B-organism'}", + "73, mice {'context': 'I-organism'}", + "90, granulocytic {'context': 'B-cells'}", + "91, MDSCs, {'context': 'I-cells'}", + "95, granulocytic {'context': 'B-cells'}", + "96, and {'context': 'I-cells'}", + "97, monocytic {'context': 'I-cells'}", + "98, MDSC {'context': 'I-cells'}", + "99, subsets. {'context': 'I-cells'}", + "105, inhibition {'effect': 'B-negative'}", + "107, tumor {'phenotype': 'B-tumour growth'}", + "108, growth {'phenotype': 'I-tumour growth'}", + "109, in {'context': 'B-in vivo'}", + "110, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "59, tumor ['l0', 'l1']", + "60, models, ['l0', 'l2']", + "70, MDSCs ['l1', 'l2', 'l3']", + "72, tumor-bearing ['l4']", + "73, mice ['l3', 'l4']", + "90, granulocytic ['l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "91, MDSCs, ['l5', 'l11']", + "95, granulocytic ['l6', 'l12', 'l13', 'l14', 'l15']", + "96, and ['l7', 'l12', 'l16', 'l17', 'l18']", + "97, monocytic ['l8', 'l13', 'l16', 'l19', 'l20']", + "98, MDSC ['l9', 'l14', 'l17', 'l19', 'l21']", + "99, subsets. ['l10', 'l11', 'l15', 'l18', 'l20', 'l21']", + "105, inhibition ['l22', 'l23', 'l24', 'l25']", + "107, tumor ['l22', 'l26', 'l27', 'l28']", + "108, growth ['l23', 'l26', 'l29', 'l30']", + "109, in ['l24', 'l27', 'l29', 'l31']", + "110, vivo, ['l25', 'l28', 'l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + } + ] + }, + { + "PMID": "24836577", + "TEXT": "Cardiomyocyte T tubules are important for regulating ion flux. Bridging integrator 1 (BIN1) is a T-tubule protein associated with calcium channel trafficking that is downregulated in failing hearts. Here we find that cardiac T tubules normally contain dense protective inner membrane folds that are formed by a cardiac isoform of BIN1. In mice with cardiac Bin1 deletion, T-tubule folding is decreased, which does not change overall cardiomyocyte morphology but leads to free diffusion of local extracellular calcium and potassium ions, prolonging action-potential duration and increasing susceptibility to ventricular arrhythmias. We also found that T-tubule inner folds are rescued by expression of the BIN1 isoform BIN1+13+17, which promotes N-WASP-dependent actin polymerization to stabilize the T-tubule membrane at cardiac Z discs. BIN1+13+17 recruits actin to fold the T-tubule membrane, creating a 'fuzzy space' that protectively restricts ion flux. When the amount of the BIN1+13+17 isoform is decreased, as occurs in acquired cardiomyopathy, T-tubule morphology is altered, and arrhythmia can result.", + "TAG_DATA": [ + "52, mice {'context': 'B-organism'}", + "54, cardiac {'perturbing_action': 'B-gene loss-of-function'}", + "55, Bin1 {'perturbing_action': 'I-gene loss-of-function'}", + "56, deletion, {'perturbing_action': 'I-gene loss-of-function'}", + "99, expression {'perturbing_action': 'B-other'}", + "100, of {'perturbing_action': 'I-other'}", + "101, the {'perturbing_action': 'I-other'}", + "102, BIN1 {'perturbing_action': 'I-other'}", + "103, isoform {'perturbing_action': 'I-other'}", + "104, BIN1+13+17, {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "52, mice ['l0', 'l1', 'l2']", + "54, cardiac ['l0', 'l3', 'l4']", + "55, Bin1 ['l1', 'l3', 'l5']", + "56, deletion, ['l2', 'l4', 'l5']", + "99, expression ['l6', 'l7', 'l8', 'l9', 'l10']", + "100, of ['l6', 'l11', 'l12', 'l13', 'l14']", + "101, the ['l7', 'l11', 'l15', 'l16', 'l17']", + "102, BIN1 ['l8', 'l12', 'l15', 'l18', 'l19']", + "103, isoform ['l9', 'l13', 'l16', 'l18', 'l20']", + "104, BIN1+13+17, ['l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cardiac", + "Bin1", + "deletion," + ] + } + } + ] + }, + { + "PMID": "24813251", + "TEXT": "Oncogene-induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and the mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies, including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53-independent, proapoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway coactivator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1-induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine-threonine kinase, STK4. Notably, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a new synthetic-lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels.", + "TAG_DATA": [ + "74, triggers {'effect': 'B-positive'}", + "75, cell {'phenotype': 'B-cell death'}", + "76, death {'phenotype': 'I-cell death'}", + "87, normal {'context': 'B-cells'}", + "88, cells, {'context': 'I-cells'}", + "95, prevent {'effect': 'B-negative'}", + "97, ABL1-induced {'effect': 'B-positive'}", + "98, apoptosis {'phenotype': 'B-apoptosis'}", + "101, hematologic {'context': 'B-neoplasm'}", + "102, malignancies. {'context': 'I-neoplasm'}", + "114, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "115, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "116, of {'perturbing_action': 'I-gene loss-of-function'}", + "117, STK4 {'perturbing_action': 'I-gene loss-of-function'}", + "121, triggering {'effect': 'B-positive'}", + "122, cell {'phenotype': 'B-cell death'}", + "123, death {'phenotype': 'I-cell death'}", + "124, in {'context': 'B-in vitro'}", + "125, vitro {'context': 'I-in vitro'}", + "127, in {'context': 'B-in vivo'}", + "128, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "74, triggers ['l0', 'l1', 'l2', 'l3']", + "75, cell ['l0', 'l4', 'l5', 'l6']", + "76, death ['l1', 'l4', 'l7', 'l8']", + "87, normal ['l2', 'l5', 'l7', 'l9']", + "88, cells, ['l3', 'l6', 'l8', 'l9']", + "95, prevent ['l10', 'l11', 'l12', 'l13']", + "97, ABL1-induced ['l10', 'l14', 'l15', 'l16']", + "98, apoptosis ['l11', 'l14', 'l17', 'l18']", + "101, hematologic ['l12', 'l15', 'l17', 'l19']", + "102, malignancies. ['l13', 'l16', 'l18', 'l19']", + "114, genetic ['l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "115, inactivation ['l20', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "116, of ['l21', 'l30', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "117, STK4 ['l22', 'l31', 'l39', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "121, triggering ['l23', 'l32', 'l40', 'l47', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "122, cell ['l24', 'l33', 'l41', 'l48', 'l54', 'l60', 'l61', 'l62', 'l63', 'l64']", + "123, death ['l25', 'l34', 'l42', 'l49', 'l55', 'l60', 'l65', 'l66', 'l67']", + "124, in ['l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l69', 'l70']", + "125, vitro ['l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l68', 'l71', 'l72']", + "127, in ['l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l69', 'l71', 'l73']", + "128, vivo. ['l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l67', 'l70', 'l72', 'l73']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "triggers", + "triggering" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "context": { + "val": "cells", + "words": [ + "normal", + "cells," + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "normal", + "cells," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "hematologic", + "malignancies." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "ABL1-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "ABL1-induced" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "hematologic", + "malignancies." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "hematologic", + "malignancies." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inactivation", + "of", + "STK4" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inactivation", + "of", + "STK4" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inactivation", + "of", + "STK4" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inactivation", + "of", + "STK4" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "24793239", + "TEXT": "We describe a new mechanism regulating the tumor endothelial barrier and T cell infiltration into tumors. We detected selective expression of the death mediator Fas ligand (FasL, also called CD95L) in the vasculature of human and mouse solid tumors but not in normal vasculature. In these tumors, FasL expression was associated with scarce CD8(+) infiltration and a predominance of FoxP3(+) T regulatory (Treg) cells. Tumor-derived vascular endothelial growth factor A (VEGF-A), interleukin 10 (IL-10) and prostaglandin E2 (PGE2) cooperatively induced FasL expression in endothelial cells, which acquired the ability to kill effector CD8(+) T cells but not Treg cells because of higher levels of c-FLIP expression in Treg cells. In mice, genetic or pharmacologic suppression of FasL produced a substantial increase in the influx of tumor-rejecting CD8(+) over FoxP3(+) T cells. Pharmacologic inhibition of VEGF and PGE2 produced a marked increase in the influx of tumor-rejecting CD8(+) over FoxP3(+) T cells that was dependent on attenuation of FasL expression and led to CD8-dependent tumor growth suppression. Thus, tumor paracrine mechanisms establish a tumor endothelial death barrier, which has a critical role in establishing immune tolerance and determining the fate of tumors.", + "TAG_DATA": [ + "83, endothelial {'context': 'B-cells'}", + "84, cells, {'context': 'I-cells'}", + "110, mice, {'context': 'B-organism'}", + "113, pharmacologic {'perturbing_action': 'B-pharmacological inhibition'}", + "114, suppression {'perturbing_action': 'I-pharmacological inhibition'}", + "115, of {'perturbing_action': 'I-pharmacological inhibition'}", + "116, FasL {'perturbing_action': 'I-pharmacological inhibition'}", + "125, tumor-rejecting {'context': 'B-neoplasm'}", + "126, CD8(+) {'context': 'I-cells'}", + "128, FoxP3(+) {'context': 'B-cells'}", + "129, T {'context': 'I-cells'}", + "130, cells. {'context': 'I-cells'}", + "131, Pharmacologic {'perturbing_action': 'B-pharmacological inhibition'}", + "132, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "133, of {'perturbing_action': 'I-pharmacological inhibition'}", + "134, VEGF {'perturbing_action': 'I-pharmacological inhibition'}", + "135, and {'perturbing_action': 'I-pharmacological inhibition'}", + "136, PGE2 {'perturbing_action': 'I-pharmacological inhibition'}", + "146, CD8(+) {'context': 'I-cells'}", + "148, FoxP3(+) {'context': 'B-cells'}", + "149, T {'context': 'I-cells'}", + "150, cells {'context': 'I-cells'}", + "163, tumor {'phenotype': 'B-tumour growth'}", + "164, growth {'phenotype': 'I-tumour growth'}", + "165, suppression. {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "83, endothelial ['l0', 'l1', 'l2']", + "84, cells, ['l0']", + "110, mice, ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "113, pharmacologic ['l3', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "114, suppression ['l4', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "115, of ['l5', 'l13', 'l23', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "116, FasL ['l6', 'l14', 'l24', 'l32', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "125, tumor-rejecting ['l7', 'l15', 'l25', 'l33', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "126, CD8(+) ['l8', 'l16', 'l26', 'l34', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "128, FoxP3(+) ['l9', 'l17', 'l27', 'l35', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57']", + "129, T ['l1', 'l10', 'l18', 'l28', 'l36', 'l43', 'l48', 'l52', 'l55', 'l58']", + "130, cells. ['l2', 'l11', 'l19', 'l29', 'l37', 'l44', 'l49', 'l53', 'l56', 'l58']", + "131, Pharmacologic ['l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "132, inhibition ['l59', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "133, of ['l60', 'l72', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "134, VEGF ['l61', 'l73', 'l84', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "135, and ['l62', 'l74', 'l85', 'l95', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "136, PGE2 ['l20', 'l63', 'l75', 'l86', 'l96', 'l105', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "145, tumor-rejecting ['l64', 'l76', 'l87', 'l97', 'l106', 'l114', 'l122', 'l123', 'l124', 'l125', 'l126']", + "146, CD8(+) ['l65', 'l77', 'l88', 'l98', 'l107', 'l115', 'l122', 'l127', 'l128', 'l129', 'l130', 'l131']", + "148, FoxP3(+) ['l66', 'l78', 'l89', 'l99', 'l108', 'l116', 'l123', 'l127', 'l132', 'l133', 'l134', 'l135', 'l136']", + "149, T ['l21', 'l30', 'l38', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l124', 'l128', 'l132', 'l137']", + "150, cells ['l22', 'l31', 'l39', 'l45', 'l50', 'l54', 'l57', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l125', 'l129', 'l133', 'l137']", + "163, tumor ['l69', 'l81', 'l92', 'l102', 'l111', 'l119', 'l134', 'l138', 'l139']", + "164, growth ['l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l130', 'l135', 'l138', 'l140']", + "165, suppression. ['l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l126', 'l131', 'l136', 'l139', 'l140']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "suppression", + "of", + "FasL" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "suppression", + "of", + "FasL" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor-rejecting" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "suppression", + "of", + "FasL", + "Pharmacologic", + "inhibition", + "VEGF", + "and", + "PGE2" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "FoxP3(+)", + "T", + "cells.", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacologic", + "inhibition", + "of", + "VEGF", + "and", + "PGE2" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacologic", + "inhibition", + "of", + "VEGF", + "and", + "PGE2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppression." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "FoxP3(+)" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth", + "tumor" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "FoxP3(+)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppression." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppression." + ] + } + } + ] + }, + { + "PMID": "24793238", + "TEXT": "As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts--in which circulatory systems of young and aged animals are connected--identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.", + "TAG_DATA": [ + "113, aged {'context': 'B-organism'}", + "114, mice {'context': 'I-organism'}", + "126, learning {'phenotype': 'I-metastasis'}", + "156, aged {'context': 'B-tissue/organ'}", + "157, hippocampus. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "113, aged ['l0', 'l1', 'l2', 'l3', 'l4']", + "114, mice ['l0', 'l5', 'l6', 'l7', 'l8']", + "125, spatial ['l1', 'l5', 'l9', 'l10', 'l11']", + "126, learning ['l2', 'l6', 'l9', 'l12', 'l13']", + "127, and ['l3', 'l7', 'l10', 'l12', 'l14']", + "128, memory. ['l4', 'l8', 'l11', 'l13', 'l14']", + "156, aged ['l15']", + "157, hippocampus. ['l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "aged", + "mice" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "learning" + ] + } + } + ] + }, + { + "PMID": "24793237", + "TEXT": "Osteogenesis imperfecta (OI) is a heritable disorder, in both a dominant and recessive manner, of connective tissue characterized by brittle bones, fractures and extraskeletal manifestations. How structural mutations of type I collagen (dominant OI) or of its post-translational modification machinery (recessive OI) can cause abnormal quality and quantity of bone is poorly understood. Notably, the clinical overlap between dominant and recessive forms of OI suggests common molecular pathomechanisms. Here, we show that excessive transforming growth factor-β (TGF-β) signaling is a mechanism of OI in both recessive (Crtap(-/-)) and dominant (Col1a2(tm1.1Mcbr)) OI mouse models. In the skeleton, we find higher expression of TGF-β target genes, higher ratio of phosphorylated Smad2 to total Smad2 protein and higher in vivo Smad2 reporter activity. Moreover, the type I collagen of Crtap(-/-) mice shows reduced binding to the small leucine-rich proteoglycan decorin, a known regulator of TGF-β activity. Anti-TGF-β treatment using the neutralizing antibody 1D11 corrects the bone phenotype in both forms of OI and improves the lung abnormalities in Crtap(-/-) mice. Hence, altered TGF-β matrix-cell signaling is a primary mechanism in the pathogenesis of OI and could be a promising target for the treatment of OI.", + "TAG_DATA": [ + "85, recessive {'perturbing_action': 'B-gene loss-of-function'}", + "86, (Crtap(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "91, mouse {'context': 'B-organism'}", + "92, models. {'context': 'I-organism'}", + "115, in {'context': 'B-in vivo'}", + "116, vivo {'context': 'I-in vivo'}", + "126, Crtap(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "127, mice {'context': 'B-organism'}", + "162, lung {'context': 'B-tissue/organ'}", + "165, Crtap(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "166, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "85, recessive ['l0', 'l1', 'l2', 'l3']", + "86, (Crtap(-/-)) ['l0', 'l4', 'l5', 'l6']", + "91, mouse ['l1', 'l4', 'l7', 'l8']", + "92, models. ['l2', 'l5', 'l7', 'l9']", + "95, skeleton, ['l3', 'l6', 'l8', 'l9', 'l10']", + "115, in ['l11', 'l12']", + "116, vivo ['l10', 'l11', 'l13']", + "126, Crtap(-/-) ['l14']", + "127, mice ['l12', 'l13', 'l14']", + "162, lung ['l15', 'l16']", + "165, Crtap(-/-) ['l15', 'l17']", + "166, mice. ['l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "recessive", + "(Crtap(-/-))", + "Crtap(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models.", + "mice", + "mice." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Crtap(-/-)" + ] + } + } + ] + }, + { + "PMID": "24728411", + "TEXT": "Major depressive disorder (MDD) affects up to 17% of the population, causing profound personal suffering and economic loss. Clinical and preclinical studies have revealed that prolonged stress and MDD are associated with neuronal atrophy of cortical and limbic brain regions, but the molecular mechanisms underlying these morphological alterations have not yet been identified. Here, we show that stress increases levels of REDD1 (regulated in development and DNA damage responses-1), an inhibitor of mTORC1 (mammalian target of rapamycin complex-1; ref. 10), in rat prefrontal cortex (PFC). This is concurrent with a decrease in phosphorylation of signaling targets of mTORC1, which is implicated in protein synthesis-dependent synaptic plasticity. We also found that REDD1 levels are increased in the postmortem PFC of human subjects with MDD relative to matched controls. Mutant mice with a deletion of the gene encoding REDD1 are resilient to the behavioral, synaptic and mTORC1 signaling deficits caused by chronic unpredictable stress, whereas viral-mediated overexpression of REDD1 in rat PFC is sufficient to cause anxiety- and depressive-like behaviors and neuronal atrophy. Taken together, these postmortem and preclinical findings identify REDD1 as a critical mediator of the atrophy of neurons and depressive behavior caused by chronic stress exposure.", + "TAG_DATA": [ + "81, rat {'context': 'B-tissue/organ'}", + "82, prefrontal {'context': 'I-tissue/organ'}", + "83, cortex {'context': 'I-tissue/organ'}", + "84, (PFC). {'context': 'I-tissue/organ'}", + "127, Mutant {'context': 'B-organism'}", + "128, mice {'context': 'B-organism'}", + "131, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "132, of {'perturbing_action': 'I-gene loss-of-function'}", + "133, the {'perturbing_action': 'I-gene loss-of-function'}", + "134, gene {'perturbing_action': 'I-gene loss-of-function'}", + "135, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "136, REDD1 {'perturbing_action': 'I-gene loss-of-function'}", + "153, viral-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "154, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "155, of {'perturbing_action': 'I-gene gain-of-function'}", + "156, REDD1 {'perturbing_action': 'I-gene gain-of-function'}", + "158, rat {'context': 'B-tissue/organ'}", + "159, PFC {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "81, rat ['l0', 'l1', 'l2']", + "82, prefrontal ['l0', 'l3', 'l4']", + "83, cortex ['l1', 'l3', 'l5']", + "84, (PFC). ['l2', 'l4', 'l5']", + "127, Mutant ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "128, mice ['l6', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "131, deletion ['l7', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "132, of ['l8', 'l14', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "133, the ['l9', 'l15', 'l20', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37']", + "134, gene ['l10', 'l16', 'l21', 'l27', 'l33', 'l38', 'l39', 'l40', 'l41']", + "135, encoding ['l11', 'l17', 'l22', 'l28', 'l34', 'l38', 'l42', 'l43', 'l44']", + "136, REDD1 ['l12', 'l18', 'l23', 'l29', 'l35', 'l39', 'l42', 'l45', 'l46']", + "153, viral-mediated ['l47', 'l48', 'l49', 'l50', 'l51']", + "154, overexpression ['l47', 'l52', 'l53', 'l54', 'l55']", + "155, of ['l48', 'l52', 'l56', 'l57', 'l58']", + "156, REDD1 ['l30', 'l49', 'l53', 'l56', 'l59', 'l60']", + "158, rat ['l24', 'l31', 'l36', 'l40', 'l43', 'l45', 'l50', 'l54', 'l57', 'l59', 'l61']", + "159, PFC ['l25', 'l32', 'l37', 'l41', 'l44', 'l46', 'l51', 'l55', 'l58', 'l60', 'l61']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mutant", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "gene", + "encoding", + "REDD1" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "gene", + "encoding", + "REDD1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "PFC" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "viral-mediated", + "overexpression", + "of", + "REDD1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "PFC" + ] + } + } + ] + }, + { + "PMID": "24633305", + "TEXT": "Apoptotic cell death is a hallmark of the loss of insulin-producing beta cells in all forms of diabetes mellitus. Current treatments fail to halt the decline in functional beta cell mass, and strategies to prevent beta cell apoptosis and dysfunction are urgently needed. Here, we identified mammalian sterile 20-like kinase-1 (MST1) as a critical regulator of apoptotic beta cell death and function. Under diabetogenic conditions, MST1 was strongly activated in beta cells in human and mouse islets and specifically induced the mitochondrial-dependent pathway of apoptosis through upregulation of the BCL-2 homology-3 (BH3)-only protein BIM. MST1 directly phosphorylated the beta cell transcription factor PDX1 at T11, resulting in the latter's ubiquitination and degradation and thus in impaired insulin secretion. MST1 deficiency completely restored normoglycemia, beta cell function and survival in vitro and in vivo. We show MST1 as a proapoptotic kinase and key mediator of apoptotic signaling and beta cell dysfunction and suggest that it may serve as target for the development of new therapies for diabetes.", + "TAG_DATA": [ + "70, beta {'context': 'B-cells'}", + "71, cells {'context': 'I-cells'}", + "73, human {'context': 'B-cells'}", + "74, and {'context': 'I-cells'}", + "75, mouse {'context': 'I-cells'}", + "76, islets {'context': 'I-cells'}", + "79, induced {'effect': 'B-positive'}", + "84, apoptosis {'phenotype': 'B-apoptosis'}", + "118, MST1 {'perturbing_action': 'B-gene loss-of-function'}", + "119, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "123, beta {'context': 'B-cells'}", + "124, cell {'context': 'I-cells'}", + "128, in {'context': 'B-in vitro'}", + "129, vitro {'context': 'I-in vitro'}", + "131, in {'context': 'B-in vivo'}", + "132, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "70, beta ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "71, cells ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "73, human ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "74, and ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "75, mouse ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "76, islets ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "79, induced ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "84, apoptosis ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "118, MST1 ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "119, deficiency ['l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "123, beta ['l29', 'l35', 'l41', 'l42', 'l43']", + "124, cell ['l30', 'l36', 'l41', 'l44', 'l45']", + "128, in ['l31', 'l37', 'l42', 'l44', 'l46']", + "129, vitro ['l32', 'l38', 'l43', 'l45', 'l46']", + "131, in ['l33', 'l39', 'l47']", + "132, vivo. ['l34', 'l40', 'l47']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "beta", + "cells", + "human", + "and", + "mouse", + "islets" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "beta", + "cells", + "human", + "and", + "mouse", + "islets" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MST1", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "beta", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MST1", + "deficiency" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MST1", + "deficiency" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "24584118", + "TEXT": "During obesity, macrophage accumulation in adipose tissue propagates the chronic inflammation and insulin resistance associated with type 2 diabetes. The factors, however, that regulate the accrual of macrophages in adipose tissue are not well understood. Here we show that the neuroimmune guidance cue netrin-1 is highly expressed in obese but not lean adipose tissue of humans and mice, where it directs the retention of macrophages. Netrin-1, whose expression is induced in macrophages by the saturated fatty acid palmitate, acts via its receptor Unc5b to block their migration. In a mouse model of diet-induced obesity, we show that adipose tissue macrophages exhibit reduced migratory capacity, which can be restored by blocking netrin-1. Furthermore, hematopoietic deletion of Ntn1 facilitates adipose tissue macrophage emigration, reduces inflammation and improves insulin sensitivity. Collectively, these findings identify netrin-1 as a macrophage retention signal in adipose tissue during obesity that promotes chronic inflammation and insulin resistance.", + "TAG_DATA": [ + "89, mouse {'context': 'B-organism'}", + "90, model {'context': 'I-organism'}", + "97, adipose {'context': 'B-cells'}", + "98, tissue {'context': 'I-cells'}", + "99, macrophages {'context': 'I-cells'}", + "101, reduced {'effect': 'B-negative'}", + "102, migratory {'phenotype': 'B-migration'}", + "103, capacity, {'phenotype': 'I-migration'}", + "109, blocking {'perturbing_action': 'B-pharmacological inhibition'}", + "110, netrin-1. {'perturbing_action': 'I-pharmacological inhibition'}", + "112, hematopoietic {'perturbing_action': 'B-gene loss-of-function'}", + "113, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "114, of {'perturbing_action': 'I-gene loss-of-function'}", + "115, Ntn1 {'perturbing_action': 'I-gene loss-of-function'}", + "117, adipose {'context': 'B-cells'}", + "118, tissue {'context': 'I-cells'}", + "119, macrophage {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "89, mouse ['l0', 'l1']", + "90, model ['l0', 'l2', 'l3']", + "97, adipose ['l4', 'l5', 'l6', 'l7', 'l8']", + "98, tissue ['l1', 'l2', 'l4', 'l9', 'l10', 'l11', 'l12']", + "99, macrophages ['l3', 'l5', 'l9', 'l13', 'l14', 'l15']", + "101, reduced ['l6', 'l10', 'l13', 'l16', 'l17']", + "102, migratory ['l7', 'l11', 'l14', 'l16', 'l18']", + "103, capacity, ['l8', 'l12', 'l15', 'l17', 'l18']", + "109, blocking ['l19']", + "110, netrin-1. ['l19']", + "112, hematopoietic ['l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "113, deletion ['l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "114, of ['l21', 'l26', 'l31', 'l32', 'l33', 'l34']", + "115, Ntn1 ['l22', 'l27', 'l31', 'l35', 'l36', 'l37']", + "117, adipose ['l23', 'l28', 'l32', 'l35', 'l38', 'l39']", + "118, tissue ['l24', 'l29', 'l33', 'l36', 'l38', 'l40']", + "119, macrophage ['l25', 'l30', 'l34', 'l37', 'l39', 'l40']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "adipose", + "tissue", + "macrophages" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "adipose", + "tissue", + "macrophages" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migratory", + "capacity," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migratory", + "capacity," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "hematopoietic", + "deletion", + "of", + "Ntn1" + ] + }, + "context": { + "val": "cells", + "words": [ + "adipose", + "tissue", + "macrophage" + ] + } + } + ] + }, + { + "PMID": "24584117", + "TEXT": "Atherosclerosis, a hyperlipidemia-induced chronic inflammatory process of the arterial wall, develops preferentially at sites where disturbed laminar flow compromises endothelial cell (EC) function. Here we show that endothelial miR-126-5p maintains a proliferative reserve in ECs through suppression of the Notch1 inhibitor delta-like 1 homolog (Dlk1) and thereby prevents atherosclerotic lesion formation. Endothelial recovery after denudation was impaired in Mir126(-/-) mice because lack of miR-126-5p, but not miR-126-3p, reduced EC proliferation by derepressing Dlk1. At nonpredilection sites, high miR-126-5p levels in endothelial cells confer a proliferative reserve that compensates for the antiproliferative effects of hyperlipidemia, such that atherosclerosis was exacerbated in Mir126(-/-) mice. In contrast, downregulation of miR-126-5p by disturbed flow abrogated EC proliferation at predilection sites in response to hyperlipidemic stress through upregulation of Dlk1 expression. Administration of miR-126-5p rescued EC proliferation at predilection sites and limited atherosclerosis, introducing a potential therapeutic approach.", + "TAG_DATA": [ + "58, Mir126(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "59, mice {'context': 'B-organism'}", + "61, lack {'perturbing_action': 'B-gene loss-of-function'}", + "62, of {'perturbing_action': 'I-gene loss-of-function'}", + "63, miR-126-5p, {'perturbing_action': 'I-gene loss-of-function'}", + "67, reduced {'effect': 'B-negative'}", + "68, EC {'context': 'B-cells'}", + "69, proliferation {'phenotype': 'B-proliferation'}", + "80, endothelial {'context': 'B-cells'}", + "81, cells {'context': 'I-cells'}", + "100, Mir126(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "101, mice. {'context': 'B-organism'}", + "104, downregulation {'perturbing_action': 'B-gene loss-of-function'}", + "105, of {'perturbing_action': 'I-gene loss-of-function'}", + "106, miR-126-5p {'perturbing_action': 'I-gene loss-of-function'}", + "110, abrogated {'effect': 'B-negative'}", + "111, EC {'context': 'B-cells'}", + "112, proliferation {'phenotype': 'B-proliferation'}", + "129, rescued {'effect': 'B-rescues'}", + "130, EC {'context': 'B-cells'}", + "131, proliferation {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "58, Mir126(-/-) ['l0', 'l1', 'l2']", + "59, mice ['l0', 'l3']", + "61, lack ['l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "62, of ['l4', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "63, miR-126-5p, ['l5', 'l13', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "67, reduced ['l6', 'l14', 'l21', 'l28', 'l29', 'l30']", + "68, EC ['l1', 'l3', 'l7', 'l15', 'l22', 'l28', 'l31']", + "69, proliferation ['l2', 'l8', 'l16', 'l23', 'l29', 'l31', 'l32']", + "80, endothelial ['l9', 'l17', 'l24', 'l33', 'l34', 'l35', 'l36']", + "81, cells ['l10', 'l18', 'l25', 'l30', 'l32', 'l33', 'l37', 'l38']", + "100, Mir126(-/-) ['l11', 'l19', 'l26', 'l34', 'l37', 'l39', 'l40', 'l41', 'l42']", + "101, mice. ['l12', 'l20', 'l27', 'l35', 'l38', 'l39', 'l43']", + "104, downregulation ['l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "105, of ['l44', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "106, miR-126-5p ['l45', 'l52', 'l59', 'l60', 'l61', 'l62', 'l63']", + "110, abrogated ['l40', 'l46', 'l53', 'l59', 'l64', 'l65']", + "111, EC ['l41', 'l47', 'l54', 'l60', 'l64', 'l66']", + "112, proliferation ['l36', 'l42', 'l43', 'l48', 'l55', 'l61', 'l65', 'l66']", + "129, rescued ['l49', 'l56', 'l67', 'l68']", + "130, EC ['l50', 'l57', 'l62', 'l67', 'l69']", + "131, proliferation ['l51', 'l58', 'l63', 'l68', 'l69']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mir126(-/-)", + "lack", + "of", + "miR-126-5p," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mir126(-/-)", + "lack", + "of", + "miR-126-5p,", + "downregulation", + "miR-126-5p" + ] + }, + "context": { + "val": "cells", + "words": [ + "EC", + "endothelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mir126(-/-)", + "lack", + "of", + "miR-126-5p,", + "downregulation", + "miR-126-5p" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "miR-126-5p,", + "Mir126(-/-)", + "downregulation", + "miR-126-5p" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced", + "abrogated" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced", + "abrogated" + ] + }, + "context": { + "val": "cells", + "words": [ + "EC", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced", + "abrogated" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "EC", + "cells", + "endothelial" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "downregulation", + "of" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "context": { + "val": "cells", + "words": [ + "EC" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "24562383", + "TEXT": "Recent studies have revealed that ARID1A, encoding AT-rich interactive domain 1A (SWI-like), is frequently mutated across a variety of human cancers and also has bona fide tumor suppressor properties. Consequently, identification of vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. Here, using a broad screening approach, we identify ARID1B, an ARID1A homolog whose gene product is mutually exclusive with ARID1A in SWI/SNF complexes, as the number 1 gene preferentially required for the survival of ARID1A-mutant cancer cell lines. We show that loss of ARID1B in ARID1A-deficient backgrounds destabilizes SWI/SNF and impairs proliferation in both cancer cells and primary cells. We also find that ARID1A and ARID1B are frequently co-mutated in cancer but that ARID1A-deficient cancers retain at least one functional ARID1B allele. These results suggest that loss of ARID1A and ARID1B alleles cooperatively promotes cancer formation but also results in a unique functional dependence. The results further identify ARID1B as a potential therapeutic target for ARID1A-mutant cancers.", + "TAG_DATA": [ + "85, loss {'perturbing_action': 'B-gene loss-of-function'}", + "86, of {'perturbing_action': 'I-gene loss-of-function'}", + "87, ARID1B {'perturbing_action': 'I-gene loss-of-function'}", + "89, ARID1A-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "90, backgrounds {'context': 'B-neoplasm'}", + "94, impairs {'effect': 'B-negative'}", + "95, proliferation {'phenotype': 'B-proliferation'}", + "98, cancer {'context': 'B-transformed cells'}", + "99, cells {'context': 'I-transformed cells'}", + "101, primary {'context': 'B-transformed cells'}", + "102, cells. {'context': 'I-transformed cells'}", + "117, ARID1A-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "118, cancers {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "85, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "86, of ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "87, ARID1B ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "89, ARID1A-deficient ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "90, backgrounds ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "94, impairs ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "95, proliferation ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "98, cancer ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "99, cells ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52']", + "101, primary ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l53']", + "102, cells. ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l52', 'l53']", + "117, ARID1A-deficient ['l54']", + "118, cancers ['l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "ARID1B", + "ARID1A-deficient" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "backgrounds", + "cancers" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "ARID1B", + "ARID1A-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "ARID1B", + "ARID1A-deficient" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "ARID1B", + "ARID1A-deficient" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells", + "primary", + "cells." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "backgrounds" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "backgrounds" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells", + "primary", + "cells." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells", + "primary", + "cells." + ] + } + } + ] + }, + { + "PMID": "24441827", + "TEXT": "Gaucher's disease (GD), an inherited metabolic disorder caused by mutations in the glucocerebrosidase gene (GBA), is the most common lysosomal storage disease. Heterozygous mutations in GBA are a major risk factor for Parkinson's disease. GD is divided into three clinical subtypes based on the absence (type 1) or presence (types 2 and 3) of neurological signs. Type 1 GD was the first lysosomal storage disease (LSD) for which enzyme therapy became available, and although infusions of recombinant glucocerebrosidase (GCase) ameliorate the systemic effects of GD, the lack of efficacy for the neurological manifestations, along with the considerable expense and inconvenience of enzyme therapy for patients, renders the search for alternative or complementary therapies paramount. Glucosylceramide and glucosylsphingosine accumulation in the brain leads to massive neuronal loss in patients with neuronopathic GD (nGD) and in nGD mouse models. However, the mode of neuronal death is not known. Here, we show that modulating the receptor-interacting protein kinase-3 (Ripk3) pathway markedly improves neurological and systemic disease in a mouse model of GD. Notably, Ripk3 deficiency substantially improved the clinical course of GD mice, with increased survival and motor coordination and salutary effects on cerebral as well as hepatic injury.", + "TAG_DATA": [ + "165, mouse {'context': 'B-organism'}", + "166, model {'context': 'I-organism'}", + "167, of {'context': 'I-organism'}", + "168, GD. {'context': 'I-organism'}", + "170, Ripk3 {'perturbing_action': 'B-gene loss-of-function'}", + "171, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "179, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "165, mouse ['l0', 'l1', 'l2']", + "166, model ['l0', 'l3', 'l4']", + "167, of ['l1', 'l3', 'l5']", + "168, GD. ['l2', 'l4', 'l5']", + "170, Ripk3 ['l6', 'l7']", + "171, deficiency ['l6', 'l8']", + "179, mice, ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ripk3", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "24336249", + "TEXT": "Obesity is associated with the development of asthma, which is often difficult to control. To understand the immunological pathways that lead to obesity-associated asthma, we fed mice a high-fat diet for 12 weeks, which resulted in obesity and the development of airway hyperreactivity (AHR), a cardinal feature of asthma. This AHR was independent of adaptive immunity, as it occurred in obese Rag1(-/-) mice, which lack B and T cells, and was dependent on interleukin-17A (IL-17A) and the NLRP3 inflammasome, as it did not develop in obese Il17a(-/-) or Nlrp3(-/-) mice. AHR was also associated with the expansion of CCR6(+) type 3 innate lymphoid cells (ILCs) producing IL-17A (ILC3 cells) in the lung, which could by themselves mediate AHR when adoptively transferred into Rag2(-/-); Il2rg(-/-) mice treated with recombinant IL-1β. Macrophage-derived IL-1β production was induced by HFD and expanded the number of lung ILC3 cells. Blockade of IL-1β with an IL-1 receptor antagonist abolished obesity-induced AHR and reduced the number of ILC3 cells. As we found ILC3-like cells in the bronchoalveolar lavage fluid of individuals with asthma, we suggest that obesity-associated asthma is facilitated by inflammation mediated by NLRP3, IL-1β and ILC3 cells.", + "TAG_DATA": [ + "26, mice {'context': 'B-organism'}", + "60, obese {'perturbing_action': 'B-gene loss-of-function'}", + "61, Rag1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "62, mice, {'context': 'B-organism'}", + "85, obese {'perturbing_action': 'B-gene loss-of-function'}", + "86, Il17a(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "87, or {'perturbing_action': 'B-gene loss-of-function'}", + "88, Nlrp3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "89, mice. {'context': 'B-organism'}", + "111, lung, {'context': 'B-tissue/organ'}", + "122, Rag2(-/-); {'perturbing_action': 'B-gene loss-of-function'}", + "123, Il2rg(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "124, mice {'context': 'B-organism'}", + "141, lung {'context': 'B-cells'}", + "142, ILC3 {'context': 'I-cells'}", + "143, cells. {'context': 'I-cells'}", + "160, ILC3 {'context': 'B-cells'}", + "161, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "26, mice ['l0', 'l1', 'l2']", + "60, obese ['l0', 'l3', 'l4', 'l5', 'l6']", + "61, Rag1(-/-) ['l1', 'l3', 'l7', 'l8', 'l9']", + "62, mice, ['l2', 'l4', 'l7']", + "85, obese ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "86, Il17a(-/-) ['l5', 'l8', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "87, or ['l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "88, Nlrp3(-/-) ['l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "89, mice. ['l13', 'l20', 'l26', 'l31', 'l39', 'l40', 'l41', 'l42']", + "111, lung, ['l6', 'l9', 'l14', 'l21', 'l27', 'l32', 'l39', 'l43', 'l44', 'l45']", + "122, Rag2(-/-); ['l33', 'l46', 'l47', 'l48', 'l49', 'l50']", + "123, Il2rg(-/-) ['l34', 'l46', 'l51', 'l52', 'l53', 'l54']", + "124, mice ['l35', 'l47', 'l51', 'l55', 'l56', 'l57']", + "141, lung ['l15', 'l22', 'l28', 'l36', 'l40', 'l43', 'l48', 'l52', 'l55', 'l58', 'l59']", + "142, ILC3 ['l16', 'l23', 'l29', 'l37', 'l41', 'l44', 'l49', 'l53', 'l56', 'l58', 'l60']", + "143, cells. ['l17', 'l24', 'l30', 'l38', 'l42', 'l45', 'l50', 'l54', 'l57', 'l59', 'l60']", + "160, ILC3 ['l61']", + "161, cells. ['l61']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice,", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "obese", + "Rag1(-/-)", + "Il17a(-/-)", + "or", + "Nlrp3(-/-)", + "Rag2(-/-);", + "Il2rg(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "obese", + "Rag1(-/-)", + "Il17a(-/-)", + "or", + "Nlrp3(-/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "obese", + "Il17a(-/-)", + "or", + "Nlrp3(-/-)", + "Rag2(-/-);", + "Il2rg(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "lung", + "ILC3", + "cells." + ] + } + } + ] + }, + { + "PMID": "24317117", + "TEXT": "The molecular link between proteinuria and hyperlipidemia in nephrotic syndrome is not known. We show in the present study that plasma angiopoietin-like 4 (Angptl4) links proteinuria with hypertriglyceridemia through two negative feedback loops. In previous studies in a rat model that mimics human minimal change disease, we observed localized secretion by podocytes of hyposialylated Angptl4, a pro-proteinuric form of the protein. But in this study we noted high serum levels of Angptl4 (presumably normosialylated based on a neutral isoelectric point) in other glomerular diseases as well. Circulating Angptl4 was secreted by extrarenal organs in response to an elevated plasma ratio of free fatty acids (FFAs) to albumin when proteinuria reached nephrotic range. In a systemic feedback loop, these circulating pools of Angptl4 reduced proteinuria by interacting with glomerular endothelial αvβ5 integrin. Blocking the Angptl4-β5 integrin interaction or global knockout of Angptl4 or β5 integrin delayed recovery from peak proteinuria in animal models. But at the same time, in a local feedback loop, the elevated extrarenal pools of Angptl4 reduced tissue FFA uptake in skeletal muscle, heart and adipose tissue, subsequently resulting in hypertriglyceridemia, by inhibiting lipoprotein lipase (LPL)-mediated hydrolysis of plasma triglycerides to FFAs. Injecting recombinant human ANGPTL4 modified at a key LPL interacting site into nephrotic Buffalo Mna and Zucker Diabetic Fatty rats reduced proteinuria through the systemic loop but, by bypassing the local loop, without increasing plasma triglyceride levels. These data show that increases in circulating Angptl4 in response to nephrotic-range proteinuria reduces the degree of this pathology, but at the cost of inducing hypertriglyceridemia, while also suggesting a possible therapy to treat these linked pathologies.", + "TAG_DATA": [ + "137, global {'perturbing_action': 'B-gene loss-of-function'}", + "138, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "139, of {'perturbing_action': 'I-gene loss-of-function'}", + "140, Angptl4 {'perturbing_action': 'I-gene loss-of-function'}", + "141, or {'perturbing_action': 'I-gene loss-of-function'}", + "142, β5 {'perturbing_action': 'I-gene loss-of-function'}", + "143, integrin {'perturbing_action': 'I-gene loss-of-function'}", + "150, animal {'context': 'B-organism'}", + "151, models. {'context': 'I-organism'}", + "173, skeletal {'context': 'B-tissue/organ'}", + "174, muscle, {'context': 'I-tissue/organ'}", + "175, heart {'context': 'B-tissue/organ'}", + "177, adipose {'context': 'B-tissue/organ'}", + "178, tissue, {'context': 'I-tissue/organ'}", + "211, Diabetic {'context': 'I-organism'}", + "212, Fatty {'context': 'I-organism'}", + "213, rats {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "137, global ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "138, knockout ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "139, of ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "140, Angptl4 ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "141, or ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "142, β5 ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "143, integrin ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "150, animal ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "151, models. ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "173, skeletal ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "174, muscle, ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "175, heart ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "177, adipose ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "178, tissue, ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']", + "211, Diabetic ['l91', 'l92']", + "212, Fatty ['l91', 'l93']", + "213, rats ['l92', 'l93']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "global", + "knockout", + "of", + "Angptl4", + "or", + "β5", + "integrin" + ] + }, + "context": { + "val": "organism", + "words": [ + "animal", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "global", + "knockout", + "of", + "Angptl4", + "or", + "β5", + "integrin" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skeletal", + "muscle,", + "heart", + "adipose", + "tissue," + ] + } + } + ] + }, + { + "PMID": "24216753", + "TEXT": "Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not been developed. We report that Cre under control of the promoter of Pdgfrb (Pdgfrb-Cre) inactivates loxP-flanked genes in mouse HSCs with high efficiency. We used this system to delete the gene encoding α(v) integrin subunit because various α(v)-containing integrins have been suggested as central mediators of fibrosis in multiple organs. Such depletion protected mice from carbon tetrachloride-induced hepatic fibrosis, whereas global loss of β₃, β₅ or β₆ integrins or conditional loss of β₈ integrins in HSCs did not. We also found that Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of the α(v) integrin subunit using this system was protective in other models of organ fibrosis, including pulmonary and renal fibrosis. Pharmacological blockade of α(v)-containing integrins by a small molecule (CWHM 12) attenuated both liver and lung fibrosis, including in a therapeutic manner. These data identify a core pathway that regulates fibrosis and suggest that pharmacological targeting of all α(v) integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.", + "TAG_DATA": [ + "47, Cre {'perturbing_action': 'B-gene loss-of-function'}", + "48, under {'perturbing_action': 'I-gene gain-of-function'}", + "49, control {'perturbing_action': 'I-gene gain-of-function'}", + "50, of {'perturbing_action': 'I-gene gain-of-function'}", + "51, the {'perturbing_action': 'I-gene gain-of-function'}", + "52, promoter {'perturbing_action': 'I-gene gain-of-function'}", + "53, of {'perturbing_action': 'I-gene gain-of-function'}", + "54, Pdgfrb {'perturbing_action': 'I-gene gain-of-function'}", + "55, (Pdgfrb-Cre) {'perturbing_action': 'I-gene loss-of-function'}", + "60, mouse {'context': 'B-cells'}", + "61, HSCs {'context': 'I-cells'}", + "95, mice {'context': 'B-organism'}", + "111, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "112, loss {'perturbing_action': 'I-gene loss-of-function'}", + "113, of {'perturbing_action': 'I-gene loss-of-function'}", + "114, β₈ {'perturbing_action': 'I-gene loss-of-function'}", + "115, integrins {'perturbing_action': 'I-gene loss-of-function'}", + "117, HSCs {'context': 'B-cells'}", + "127, myofibroblasts {'context': 'B-cells'}", + "167, liver {'context': 'B-tissue/organ'}", + "168, and {'context': 'B-tissue/organ'}", + "169, lung {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "47, Cre ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "48, under ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "49, control ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "50, of ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "51, the ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "52, promoter ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "53, of ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "54, Pdgfrb ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "55, (Pdgfrb-Cre) ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "60, mouse ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63']", + "61, HSCs ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63']", + "95, mice ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62']", + "111, conditional ['l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "112, loss ['l64', 'l70', 'l71', 'l72', 'l73', 'l74']", + "113, of ['l65', 'l70', 'l75', 'l76', 'l77', 'l78']", + "114, β₈ ['l66', 'l71', 'l75', 'l79', 'l80', 'l81']", + "115, integrins ['l67', 'l72', 'l76', 'l79', 'l82', 'l83']", + "117, HSCs ['l68', 'l73', 'l77', 'l80', 'l82', 'l84']", + "127, myofibroblasts ['l69', 'l74', 'l78', 'l81', 'l83', 'l84']", + "167, liver ['l85', 'l86']", + "168, and ['l85', 'l87']", + "169, lung ['l86', 'l87']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cre", + "(Pdgfrb-Cre)", + "conditional", + "loss", + "of", + "β₈", + "integrins" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "HSCs", + "myofibroblasts" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cre", + "(Pdgfrb-Cre)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "under", + "control", + "of", + "the", + "promoter", + "Pdgfrb" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "HSCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "under", + "control", + "of", + "the", + "promoter", + "Pdgfrb" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "24100978", + "TEXT": "After myocardial infarction (MI), circulating B cells produce the chemokine Ccl7, which mobilizes inflammatory monocytes from the bone marrow into the blood, after which they are then recruited to the injured heart, a new study shows. B cell depletion after MI limits myocardial injury and improves heart function, suggesting a new approach for the management of acute MI (pages 1273–1280).", + "TAG_DATA": [ + "36, B {'perturbing_action': 'B-gene loss-of-function'}", + "37, cell {'perturbing_action': 'I-gene loss-of-function'}", + "38, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "46, heart {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "36, B ['l0', 'l1', 'l2']", + "37, cell ['l0', 'l3', 'l4']", + "38, depletion ['l1', 'l3', 'l5']", + "46, heart ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "B", + "cell", + "depletion" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "heart" + ] + } + } + ] + }, + { + "PMID": "24076664", + "TEXT": "Heterotopic ossification, the pathologic formation of extraskeletal bone, occurs as a common complication of trauma or in genetic disorders and can be disabling and lethal. However, the underlying molecular mechanisms are largely unknown. Here we demonstrate that Gαs restricts bone formation to the skeleton by inhibiting Hedgehog signaling in mesenchymal progenitor cells. In progressive osseous heteroplasia, a human disease caused by null mutations in GNAS, which encodes Gαs, Hedgehog signaling is upregulated in ectopic osteoblasts and progenitor cells. In animal models, we show that genetically-mediated ectopic Hedgehog signaling is sufficient to induce heterotopic ossification, whereas inhibition of this signaling pathway by genetic or pharmacological means strongly reduces the severity of this condition. As our previous work has shown that GNAS gain-of-function mutations upregulate WNT-β-catenin signaling in osteoblast progenitor cells, resulting in their defective differentiation and fibrous dysplasia, we identify Gαs as a key regulator of proper osteoblast differentiation through its maintenance of a balance between the Wnt-β-catenin and Hedgehog pathways. Also, given the results here of the pharmacological studies in our mouse model, we propose that Hedgehog inhibitors currently used in the clinic for other conditions, such as cancer, may possibly be repurposed for treating heterotopic ossification and other diseases caused by GNAS inactivation.", + "TAG_DATA": [ + "49, mesenchymal {'context': 'B-cells'}", + "50, progenitor {'context': 'I-cells'}", + "51, cells. {'context': 'I-cells'}", + "79, animal {'context': 'B-organism'}", + "80, models, {'context': 'I-organism'}", + "119, GNAS {'perturbing_action': 'B-gene gain-of-function'}", + "120, gain-of-function {'perturbing_action': 'I-gene gain-of-function'}", + "121, mutations {'perturbing_action': 'I-gene gain-of-function'}", + "126, osteoblast {'context': 'B-cells'}", + "127, progenitor {'context': 'I-cells'}", + "128, cells, {'context': 'I-cells'}", + "132, defective {'effect': 'B-negative'}", + "133, differentiation {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "49, mesenchymal ['l0', 'l1', 'l2', 'l3']", + "50, progenitor ['l0', 'l4', 'l5', 'l6']", + "51, cells. ['l1', 'l4', 'l7', 'l8']", + "79, animal ['l2', 'l5', 'l7', 'l9']", + "80, models, ['l3', 'l6', 'l8', 'l9']", + "119, GNAS ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "120, gain-of-function ['l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "121, mutations ['l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "126, osteoblast ['l12', 'l18', 'l23', 'l28', 'l29', 'l30', 'l31']", + "127, progenitor ['l13', 'l19', 'l24', 'l28', 'l32', 'l33', 'l34']", + "128, cells, ['l14', 'l20', 'l25', 'l29', 'l32', 'l35', 'l36']", + "132, defective ['l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l37']", + "133, differentiation ['l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GNAS", + "gain-of-function", + "mutations" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoblast", + "progenitor", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GNAS", + "gain-of-function", + "mutations" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GNAS", + "gain-of-function", + "mutations" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoblast", + "progenitor", + "cells," + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoblast", + "progenitor", + "cells," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "defective" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "24056770", + "TEXT": "In chronic kidney disease (CKD), loss of functional nephrons results in metabolic and mechanical stress in the remaining ones, resulting in further nephron loss. Here we show that Akt2 activation has an essential role in podocyte protection after nephron reduction. Glomerulosclerosis and albuminuria were substantially worsened in Akt2(-/-) but not in Akt1(-/-) mice as compared to wild-type mice. Specific deletion of Akt2 or its regulator Rictor in podocytes revealed that Akt2 has an intrinsic function in podocytes. Mechanistically, Akt2 triggers a compensatory program that involves mouse double minute 2 homolog (Mdm2), glycogen synthase kinase 3 (Gsk3) and Rac1. The defective activation of this pathway after nephron reduction leads to apoptosis and foot process effacement of the podocytes. We further show that AKT2 activation by mammalian target of rapamycin complex 2 (mTORC2) is also required for podocyte survival in human CKD. More notably, we elucidate the events underlying the adverse renal effect of sirolimus and provide a criterion for the rational use of this drug. Thus, our results disclose a new function of Akt2 and identify a potential therapeutic target for preserving glomerular function in CKD.", + "TAG_DATA": [ + "47, Akt2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "51, Akt1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "52, mice {'context': 'B-organism'}", + "57, mice. {'context': 'B-organism'}", + "58, Specific {'perturbing_action': 'B-gene loss-of-function'}", + "59, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "60, of {'perturbing_action': 'I-gene loss-of-function'}", + "61, Akt2 {'perturbing_action': 'I-gene loss-of-function'}", + "62, or {'perturbing_action': 'I-gene loss-of-function'}", + "63, its {'perturbing_action': 'I-gene loss-of-function'}", + "64, regulator {'perturbing_action': 'I-gene loss-of-function'}", + "65, Rictor {'perturbing_action': 'I-gene loss-of-function'}", + "67, podocytes {'context': 'B-cells'}", + "109, apoptosis {'phenotype': 'B-apoptosis'}", + "116, podocytes. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "47, Akt2(-/-) ['l0', 'l1']", + "51, Akt1(-/-) ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "52, mice ['l0', 'l2', 'l15']", + "57, mice. ['l3', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "58, Specific ['l4', 'l16', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "59, deletion ['l5', 'l17', 'l24', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "60, of ['l6', 'l18', 'l25', 'l34', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "61, Akt2 ['l7', 'l19', 'l26', 'l35', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "62, or ['l8', 'l20', 'l27', 'l36', 'l44', 'l51', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "63, its ['l9', 'l21', 'l28', 'l37', 'l45', 'l52', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "64, regulator ['l10', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l69', 'l70', 'l71', 'l72']", + "65, Rictor ['l11', 'l22', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l73', 'l74', 'l75']", + "67, podocytes ['l1', 'l12', 'l15', 'l23', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73']", + "109, apoptosis ['l13', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76']", + "116, podocytes. ['l14', 'l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l76']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Akt2(-/-)", + "Akt1(-/-)", + "Specific", + "deletion", + "of", + "Akt2", + "or", + "its", + "Rictor" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Akt2(-/-)", + "Akt1(-/-)", + "Specific", + "deletion", + "of", + "Akt2", + "or", + "its", + "regulator", + "Rictor" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocytes", + "podocytes." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Akt1(-/-)", + "Specific", + "deletion", + "of", + "Akt2", + "or", + "its", + "regulator", + "Rictor" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocytes." + ] + } + } + ] + }, + { + "PMID": "24037092", + "TEXT": "Neutralizing antibodies (inhibitors) to replacement factor VIII (FVIII, either plasma derived or recombinant) impair the effective management of hemophilia A. Individuals with hemophilia A due to major deletions of the FVIII gene (F8) lack antigenically cross-reactive material in their plasma (\"CRM-negative\"), and the prevalence of inhibitors in these individuals may be as high as 90%. Conversely, individuals with hemophilia A caused by F8 missense mutations are CRM-positive, and their overall prevalence of inhibitors is <10% (ref. 2). Individuals with the F8 intron 22 inversion (found in ∼50% of individuals with severe hemophilia A) have been grouped with the former on the basis of their genetic defect and CRM-negative status. However, only ∼20% of these individuals develop inhibitors. Here we demonstrate that the levels of F8 mRNA and intracellular FVIII protein in B lymphoblastoid cells and liver biopsies from individuals with the intron 22 inversion are comparable to those in healthy controls. These results support the hypothesis that most individuals with the intron 22 inversion are tolerized to FVIII and thus do not develop inhibitors. Furthermore, we developed a new pharmacogenetic algorithm that permits the stratification of inhibitor risk for individuals and subpopulations by predicting the immunogenicity of replacement FVIII using, as input, the number of putative T cell epitopes in the infused protein and the competence of major histocompatibility complex class II molecules to present such epitopes. This algorithm showed statistically significant accuracy in predicting the presence of inhibitors in 25 unrelated individuals with the intron 22 inversion.", + "TAG_DATA": [ + "131, B {'context': 'B-cells'}", + "132, lymphoblastoid {'context': 'I-cells'}", + "133, cells {'context': 'I-cells'}", + "141, intron {'perturbing_action': 'B-other'}", + "142, 22 {'perturbing_action': 'I-other'}", + "143, inversion {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "131, B ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "132, lymphoblastoid ['l0', 'l6', 'l7', 'l8', 'l9']", + "133, cells ['l1', 'l6', 'l10']", + "135, liver ['l2', 'l7', 'l10', 'l11', 'l12', 'l13']", + "141, intron ['l3', 'l11', 'l14', 'l15']", + "142, 22 ['l4', 'l8', 'l12', 'l14', 'l16']", + "143, inversion ['l5', 'l9', 'l13', 'l15', 'l16']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "B", + "lymphoblastoid" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "intron", + "22", + "inversion" + ] + } + } + ] + }, + { + "PMID": "23955711", + "TEXT": "Forkhead box P3 (Foxp3)(+) T regulatory (T(reg)) cells maintain immune homeostasis and limit autoimmunity but can also curtail host immune responses to various types of tumors. Foxp3(+) T(reg) cells are therefore considered promising targets to enhance antitumor immunity, and approaches for their therapeutic modulation are being developed. However, although studies showing that experimentally depleting Foxp3(+) T(reg) cells can enhance antitumor responses provide proof of principle, these studies lack clear translational potential and have various shortcomings. Histone/protein acetyltransferases (HATs) promote chromatin accessibility, gene transcription and the function of multiple transcription factors and nonhistone proteins. We now report that conditional deletion or pharmacologic inhibition of one HAT, p300 (also known as Ep300 or KAT3B), in Foxp3(+) T(reg) cells increased T cell receptor-induced apoptosis in T(reg) cells, impaired T(reg) cell suppressive function and peripheral T(reg) cell induction, and limited tumor growth in immunocompetent but not in immunodeficient mice. Our data thereby demonstrate that p300 is important for Foxp3(+) T(reg) cell function and homeostasis in vivo and in vitro, and identify mechanisms by which appropriate small-molecule inhibitors can diminish T(reg) cell function without overtly impairing T effector cell responses or inducing autoimmunity. Collectively, these data suggest a new approach for cancer immunotherapy.", + "TAG_DATA": [ + "100, pharmacologic {'perturbing_action': 'B-pharmacological inhibition'}", + "101, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "102, of {'perturbing_action': 'I-pharmacological inhibition'}", + "103, one {'perturbing_action': 'I-pharmacological inhibition'}", + "104, HAT, {'perturbing_action': 'I-pharmacological inhibition'}", + "105, p300 {'perturbing_action': 'I-pharmacological inhibition'}", + "106, (also {'perturbing_action': 'I-pharmacological inhibition'}", + "111, KAT3B), {'perturbing_action': 'I-pharmacological inhibition'}", + "113, Foxp3(+) {'context': 'B-cells'}", + "114, T(reg) {'context': 'I-cells'}", + "115, cells {'context': 'I-cells'}", + "116, increased {'effect': 'B-positive'}", + "118, cell {'effect': 'B-positive'}", + "119, receptor-induced {'effect': 'B-positive'}", + "120, apoptosis {'phenotype': 'B-apoptosis'}", + "122, T(reg) {'context': 'B-cells'}", + "123, cells, {'context': 'I-cells'}", + "125, T(reg) {'context': 'B-cells'}", + "130, peripheral {'context': 'B-cells'}", + "131, T(reg) {'context': 'I-cells'}", + "132, cell {'context': 'I-cells'}", + "135, limited {'effect': 'B-negative'}", + "136, tumor {'phenotype': 'B-tumour growth'}", + "137, growth {'phenotype': 'I-tumour growth'}", + "139, immunocompetent {'context': 'B-organism'}", + "143, immunodeficient {'context': 'B-organism'}", + "144, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "100, pharmacologic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "101, inhibition ['l0', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "102, of ['l1', 'l28', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "103, one ['l2', 'l29', 'l55', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "104, HAT, ['l3', 'l30', 'l56', 'l81', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127']", + "105, p300 ['l4', 'l31', 'l57', 'l82', 'l105', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "106, (also ['l5', 'l32', 'l58', 'l83', 'l106', 'l128', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170']", + "109, Ep300 ['l6', 'l33', 'l59', 'l84', 'l107', 'l129', 'l150', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190']", + "111, KAT3B), ['l7', 'l34', 'l60', 'l85', 'l108', 'l130', 'l151', 'l171', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209']", + "113, Foxp3(+) ['l8', 'l35', 'l61', 'l86', 'l109', 'l131', 'l152', 'l172', 'l191', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220']", + "114, T(reg) ['l9', 'l36', 'l62', 'l87', 'l110', 'l132', 'l153', 'l173', 'l192', 'l210', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230']", + "115, cells ['l10', 'l37', 'l63', 'l88', 'l111', 'l133', 'l154', 'l174', 'l193', 'l211', 'l221', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237']", + "116, increased ['l11', 'l38', 'l64', 'l89', 'l112', 'l134', 'l155', 'l175', 'l194', 'l212', 'l222', 'l231', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243']", + "117, T ['l12', 'l39', 'l65', 'l90', 'l113', 'l135', 'l156', 'l176', 'l195', 'l213', 'l223', 'l232', 'l238', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249']", + "118, cell ['l13', 'l40', 'l66', 'l91', 'l114', 'l136', 'l157', 'l177', 'l196', 'l214', 'l224', 'l233', 'l239', 'l244', 'l250', 'l251', 'l252', 'l253', 'l254']", + "119, receptor-induced ['l14', 'l41', 'l67', 'l92', 'l115', 'l137', 'l158', 'l178', 'l197', 'l215', 'l225', 'l234', 'l240', 'l245', 'l250', 'l255', 'l256', 'l257', 'l258']", + "120, apoptosis ['l15', 'l42', 'l68', 'l93', 'l116', 'l138', 'l159', 'l179', 'l198', 'l216', 'l226', 'l235', 'l241', 'l246', 'l251', 'l255', 'l259', 'l260', 'l261']", + "122, T(reg) ['l16', 'l43', 'l69', 'l94', 'l117', 'l139', 'l160', 'l180', 'l199', 'l217', 'l227', 'l236', 'l242', 'l247', 'l252', 'l256', 'l259', 'l262', 'l263', 'l264']", + "123, cells, ['l17', 'l44', 'l70', 'l95', 'l118', 'l140', 'l161', 'l181', 'l200', 'l218', 'l228', 'l237', 'l243', 'l248', 'l253', 'l257', 'l260', 'l262']", + "125, T(reg) ['l18', 'l45', 'l71', 'l96', 'l119', 'l141', 'l162', 'l182', 'l201', 'l219', 'l229', 'l249', 'l254', 'l258', 'l261', 'l263', 'l265', 'l266', 'l267']", + "130, peripheral ['l19', 'l46', 'l72', 'l97', 'l120', 'l142', 'l163', 'l183', 'l202', 'l265', 'l268', 'l269', 'l270', 'l271']", + "131, T(reg) ['l20', 'l47', 'l73', 'l98', 'l121', 'l143', 'l164', 'l184', 'l203', 'l266', 'l268', 'l272', 'l273', 'l274']", + "132, cell ['l21', 'l48', 'l74', 'l99', 'l122', 'l144', 'l165', 'l185', 'l204', 'l220', 'l230', 'l264', 'l267', 'l269', 'l272']", + "135, limited ['l22', 'l49', 'l75', 'l100', 'l123', 'l145', 'l166', 'l186', 'l205', 'l270', 'l273', 'l275', 'l276', 'l277', 'l278', 'l279']", + "136, tumor ['l23', 'l50', 'l76', 'l101', 'l124', 'l146', 'l167', 'l187', 'l206', 'l275', 'l280', 'l281', 'l282', 'l283']", + "137, growth ['l24', 'l51', 'l77', 'l102', 'l125', 'l147', 'l168', 'l188', 'l207', 'l271', 'l274', 'l276', 'l280', 'l284', 'l285']", + "139, immunocompetent ['l25', 'l52', 'l78', 'l103', 'l126', 'l148', 'l169', 'l189', 'l208', 'l277', 'l281', 'l284', 'l286', 'l287']", + "143, immunodeficient ['l26', 'l53', 'l79', 'l278', 'l282', 'l286', 'l288']", + "144, mice. ['l27', 'l54', 'l80', 'l104', 'l127', 'l149', 'l170', 'l190', 'l209', 'l279', 'l283', 'l285', 'l287', 'l288']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "one", + "HAT,", + "p300", + "(also", + "KAT3B)," + ] + }, + "context": { + "val": "cells", + "words": [ + "Foxp3(+)", + "T(reg)", + "cells", + "cells,", + "peripheral", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "one", + "HAT,", + "p300", + "(also", + "KAT3B)," + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "cell", + "receptor-induced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "one", + "HAT,", + "p300", + "(also", + "KAT3B)," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "one", + "HAT,", + "p300", + "(also", + "KAT3B)," + ] + }, + "effect": { + "val": "negative", + "words": [ + "limited" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "one", + "HAT,", + "p300", + "(also", + "KAT3B)," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "one", + "HAT,", + "p300", + "(also", + "KAT3B)," + ] + }, + "context": { + "val": "organism", + "words": [ + "immunocompetent", + "immunodeficient", + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Foxp3(+)", + "T(reg)", + "cells", + "cells," + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "cell", + "receptor-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Foxp3(+)", + "T(reg)", + "cells", + "cells," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased", + "cell", + "receptor-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "peripheral", + "T(reg)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "limited" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "peripheral", + "T(reg)" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limited" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limited" + ] + }, + "context": { + "val": "organism", + "words": [ + "immunocompetent", + "immunodeficient", + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "immunocompetent", + "immunodeficient", + "mice." + ] + } + } + ] + }, + { + "PMID": "23933984", + "TEXT": "Fibroblast growth factor 21 (FGF21) is a hepatokine that acts as a global starvation signal to modulate fuel partitioning and metabolism and repress growth; however, the site of action of these diverse effects remains unclear. FGF21 signals through a heteromeric cell-surface receptor composed of one of three FGF receptors (FGFR1c, FGFR2c or FGFR3c) in complex with β-Klotho, a single-pass transmembrane protein that is enriched in metabolic tissues. Here we show that in addition to its known effects on peripheral metabolism, FGF21 increases systemic glucocorticoid levels, suppresses physical activity and alters circadian behavior, which are all features of the adaptive starvation response. These effects are mediated through β-Klotho expression in the suprachiasmatic nucleus of the hypothalamus and the dorsal vagal complex of the hindbrain. Mice lacking the gene encoding β-Klotho (Klb) in these regions are refractory to these effects, as well as those on metabolism, insulin and growth. These findings demonstrate a crucial role for the nervous system in mediating the diverse physiologic and pharmacologic actions of FGF21.", + "TAG_DATA": [ + "123, Mice {'context': 'B-organism'}", + "124, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "125, the {'perturbing_action': 'I-gene loss-of-function'}", + "126, gene {'perturbing_action': 'I-gene loss-of-function'}", + "127, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "128, β-Klotho {'perturbing_action': 'I-gene loss-of-function'}", + "129, (Klb) {'perturbing_action': 'I-gene loss-of-function'}", + "130, in {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "123, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "124, lacking ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "125, the ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "126, gene ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "127, encoding ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "128, β-Klotho ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "129, (Klb) ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "130, in ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "gene", + "encoding", + "β-Klotho", + "(Klb)", + "in" + ] + } + } + ] + }, + { + "PMID": "23933981", + "TEXT": "The blood-brain barrier (BBB) is an integral part of the neurovascular unit (NVU). The NVU is comprised of endothelial cells that are interconnected by tight junctions resting on a parenchymal basement membrane ensheathed by pericytes, smooth muscle cells and a layer of astrocyte end feet. Circulating blood cells, such as leukocytes, complete the NVU. BBB disruption is common in several neurological diseases, but the molecular mechanisms involved remain largely unknown. We analyzed the role of TWIK-related potassium channel-1 (TREK1, encoded by KCNK2) in human and mouse endothelial cells and the BBB. TREK1 was downregulated in endothelial cells by treatment with interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). Blocking TREK1 increased leukocyte transmigration, whereas TREK1 activation had the opposite effect. We identified altered mitogen-activated protein (MAP) kinase signaling, actin remodeling and upregulation of cellular adhesion molecules as potential mechanisms of increased migration in TREK1-deficient (Kcnk2(-/-)) cells. In Kcnk2(-/-) mice, brain endothelial cells showed an upregulation of the cellular adhesion molecules ICAM1, VCAM1 and PECAM1 and facilitated leukocyte trafficking into the CNS. Following the induction of experimental autoimmune encephalomyelitis (EAE) by immunization with a myelin oligodendrocyte protein (MOG)35-55 peptide, Kcnk2(-/-) mice showed higher EAE severity scores that were accompanied by increased cellular infiltrates in the central nervous system (CNS). The severity of EAE was attenuated in mice given the amyotrophic lateral sclerosis drug riluzole or fed a diet enriched with linseed oil (which contains the TREK-1 activating omega-3 fatty acid α-linolenic acid). These beneficial effects were reduced in Kcnk2(-/-) mice, suggesting TREK-1", + "TAG_DATA": [ + "95, endothelial {'context': 'B-cells'}", + "96, cells {'context': 'I-cells'}", + "107, Blocking {'perturbing_action': 'B-pharmacological inhibition'}", + "108, TREK1 {'perturbing_action': 'I-pharmacological inhibition'}", + "110, leukocyte {'context': 'B-cells'}", + "113, TREK1 {'perturbing_action': 'B-pharmacological augmentation'}", + "114, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "139, increased {'effect': 'B-positive'}", + "140, migration {'phenotype': 'B-migration'}", + "142, TREK1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "143, (Kcnk2(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "144, cells. {'context': 'B-cells'}", + "146, Kcnk2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "147, mice, {'context': 'B-organism'}", + "148, brain {'context': 'B-cells'}", + "149, endothelial {'context': 'I-cells'}", + "150, cells {'context': 'I-cells'}", + "187, Kcnk2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "188, mice {'context': 'B-organism'}", + "214, mice {'context': 'B-organism'}", + "246, Kcnk2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "247, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "95, endothelial ['l0', 'l1']", + "96, cells ['l0', 'l2']", + "107, Blocking ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "108, TREK1 ['l3', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "110, leukocyte ['l1', 'l2', 'l4', 'l14', 'l23', 'l24', 'l25']", + "113, TREK1 ['l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "114, activation ['l5', 'l26', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "139, increased ['l6', 'l15', 'l23', 'l27', 'l37', 'l47', 'l48', 'l49', 'l50']", + "140, migration ['l7', 'l16', 'l24', 'l28', 'l38', 'l47', 'l51', 'l52', 'l53']", + "142, TREK1-deficient ['l8', 'l17', 'l29', 'l39', 'l48', 'l51', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "143, (Kcnk2(-/-)) ['l9', 'l18', 'l30', 'l40', 'l49', 'l52', 'l54', 'l60', 'l61', 'l62']", + "144, cells. ['l10', 'l19', 'l25', 'l31', 'l41', 'l50', 'l53', 'l55', 'l60']", + "146, Kcnk2(-/-) ['l32', 'l42', 'l63', 'l64', 'l65', 'l66']", + "147, mice, ['l11', 'l20', 'l33', 'l43', 'l56', 'l61', 'l63', 'l67', 'l68', 'l69']", + "148, brain ['l34', 'l44', 'l57', 'l64', 'l67', 'l70', 'l71']", + "149, endothelial ['l12', 'l21', 'l35', 'l45', 'l58', 'l65', 'l68', 'l70', 'l72']", + "150, cells ['l13', 'l22', 'l36', 'l46', 'l59', 'l62', 'l66', 'l69', 'l71', 'l72']", + "187, Kcnk2(-/-) ['l73']", + "188, mice ['l73']", + "214, mice ['l74', 'l75']", + "246, Kcnk2(-/-) ['l74', 'l76']", + "247, mice, ['l75', 'l76']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blocking", + "TREK1" + ] + }, + "context": { + "val": "cells", + "words": [ + "leukocyte", + "cells.", + "endothelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blocking", + "TREK1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blocking", + "TREK1" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blocking", + "TREK1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "leukocyte", + "cells." + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "leukocyte", + "cells." + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "TREK1", + "activation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "TREK1", + "activation" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "TREK1", + "activation" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells.", + "brain", + "endothelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "TREK1", + "activation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TREK1-deficient", + "(Kcnk2(-/-))" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TREK1-deficient", + "(Kcnk2(-/-))" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TREK1-deficient", + "(Kcnk2(-/-))", + "Kcnk2(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells.", + "brain", + "endothelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TREK1-deficient", + "(Kcnk2(-/-))", + "Kcnk2(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + } + ] + }, + { + "PMID": "23913125", + "TEXT": "Mitochondrial diseases are commonly caused by mutated mitochondrial DNA (mtDNA), which in most cases coexists with wild-type mtDNA, resulting in mtDNA heteroplasmy. We have engineered transcription activator-like effector nucleases (TALENs) to localize to mitochondria and cleave different classes of pathogenic mtDNA mutations. Mitochondria-targeted TALEN (mitoTALEN) expression led to permanent reductions in deletion or point-mutant mtDNA in patient-derived cells, raising the possibility that these mitochondrial nucleases can be therapeutic for some mitochondrial diseases.", + "TAG_DATA": [ + "42, Mitochondria-targeted {'perturbing_action': 'B-gene gain-of-function'}", + "43, TALEN {'perturbing_action': 'I-gene gain-of-function'}", + "44, (mitoTALEN) {'perturbing_action': 'I-gene gain-of-function'}", + "45, expression {'perturbing_action': 'I-gene gain-of-function'}", + "56, patient-derived {'context': 'B-cells'}", + "57, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "42, Mitochondria-targeted ['l0', 'l1', 'l2', 'l3', 'l4']", + "43, TALEN ['l0', 'l5', 'l6', 'l7', 'l8']", + "44, (mitoTALEN) ['l1', 'l5', 'l9', 'l10', 'l11']", + "45, expression ['l2', 'l6', 'l9', 'l12', 'l13']", + "56, patient-derived ['l3', 'l7', 'l10', 'l12', 'l14']", + "57, cells, ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Mitochondria-targeted", + "TALEN", + "(mitoTALEN)", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "patient-derived", + "cells," + ] + } + } + ] + }, + { + "PMID": "23913124", + "TEXT": "Although angiogenesis inhibitors have provided substantial clinical benefit as cancer therapeutics, their use is limited by resistance to their therapeutic effects. While ample evidence indicates that such resistance can be influenced by the tumor microenvironment, the underlying mechanisms remain incompletely understood. Here, we have uncovered a paracrine signaling network between the adaptive and innate immune systems that is associated with resistance in multiple tumor models: lymphoma, lung and colon. Tumor-infiltrating T helper type 17 (T(H)17) cells and interleukin-17 (IL-17) induced the expression of granulocyte colony-stimulating factor (G-CSF) through nuclear factor κB (NF-κB) and extracellular-related kinase (ERK) signaling, leading to immature myeloid-cell mobilization and recruitment into the tumor microenvironment. The occurrence of T(H)17 cells and Bv8-positive granulocytes was also observed in clinical tumor specimens. Tumors resistant to treatment with antibodies to VEGF were rendered sensitive in IL-17 receptor (IL-17R)-knockout hosts deficient in T(H)17 effector function. Furthermore, pharmacological blockade of T(H)17 cell function sensitized resistant tumors to therapy with antibodies to VEGF. These findings indicate that IL-17 promotes tumor resistance to VEGF inhibition, suggesting that immunomodulatory strategies could improve the efficacy of anti-angiogenic therapy.", + "TAG_DATA": [ + "123, Tumors {'context': 'B-neoplasm'}", + "135, IL-17 {'perturbing_action': 'B-gene loss-of-function'}", + "136, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "137, (IL-17R)-knockout {'perturbing_action': 'I-gene loss-of-function'}", + "148, T(H)17 {'context': 'B-cells'}", + "149, cell {'context': 'I-cells'}", + "153, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "123, Tumors ['l0', 'l1', 'l2']", + "135, IL-17 ['l0', 'l3', 'l4']", + "136, receptor ['l1', 'l3', 'l5', 'l6']", + "137, (IL-17R)-knockout ['l2', 'l4', 'l5']", + "148, T(H)17 ['l7', 'l8', 'l9']", + "149, cell ['l7', 'l10', 'l11']", + "150, function ['l8', 'l10', 'l12']", + "153, tumors ['l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "Tumors", + "tumors" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IL-17", + "receptor", + "(IL-17R)-knockout" + ] + } + } + ] + }, + { + "PMID": "23852340", + "TEXT": "Huntington's disease is caused by an expanded polyglutamine repeat in the huntingtin protein (HTT), but the pathophysiological sequence of events that trigger synaptic failure and neuronal loss are not fully understood. Alterations in N-methyl-D-aspartate (NMDA)-type glutamate receptors (NMDARs) have been implicated. Yet, it remains unclear how the HTT mutation affects NMDAR function, and direct evidence for a causative role is missing. Here we show that mutant HTT redirects an intracellular store of juvenile NMDARs containing GluN3A subunits to the surface of striatal neurons by sequestering and disrupting the subcellular localization of the endocytic adaptor PACSIN1, which is specific for GluN3A. Overexpressing GluN3A in wild-type mouse striatum mimicked the synapse loss observed in Huntington's disease mouse models, whereas genetic deletion of GluN3A prevented synapse degeneration, ameliorated motor and cognitive decline and reduced striatal atrophy and neuronal loss in the YAC128 Huntington's disease mouse model. Furthermore, GluN3A deletion corrected the abnormally enhanced NMDAR currents, which have been linked to cell death in Huntington's disease and other neurodegenerative conditions. Our findings reveal an early pathogenic role of GluN3A dysregulation in Huntington's disease and suggest that therapies targeting GluN3A or pathogenic HTT-PACSIN1 interactions might prevent or delay disease progression.", + "TAG_DATA": [ + "100, Overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "101, GluN3A {'perturbing_action': 'I-gene gain-of-function'}", + "104, mouse {'context': 'B-tissue/organ'}", + "105, striatum {'context': 'I-tissue/organ'}", + "115, models, {'context': 'I-organism'}", + "117, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "118, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "119, of {'perturbing_action': 'I-gene loss-of-function'}", + "120, GluN3A {'perturbing_action': 'I-gene loss-of-function'}", + "140, disease {'context': 'I-organism'}", + "141, mouse {'context': 'I-organism'}", + "142, model. {'context': 'I-organism'}", + "144, GluN3A {'perturbing_action': 'B-gene loss-of-function'}", + "145, deletion {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "100, Overexpressing ['l0', 'l1', 'l2', 'l3']", + "101, GluN3A ['l0', 'l4', 'l5', 'l6']", + "104, mouse ['l1', 'l4', 'l7', 'l8']", + "105, striatum ['l2', 'l5', 'l7', 'l9']", + "115, models, ['l3', 'l6', 'l8', 'l9']", + "117, genetic ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "118, deletion ['l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "119, of ['l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "120, GluN3A ['l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "140, disease ['l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "141, mouse ['l14', 'l19', 'l23', 'l26', 'l28', 'l30']", + "142, model. ['l15', 'l20', 'l24', 'l27', 'l29', 'l30']", + "144, GluN3A ['l31']", + "145, deletion ['l31']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpressing", + "GluN3A" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "striatum" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpressing", + "GluN3A" + ] + }, + "context": { + "val": "organism", + "words": [ + "models," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "GluN3A" + ] + }, + "context": { + "val": "organism", + "words": [ + "disease", + "mouse", + "model." + ] + } + } + ] + }, + { + "PMID": "23852339", + "TEXT": "The nuclear receptor Rev-erb-α modulates hepatic lipid and glucose metabolism, adipogenesis and the inflammatory response in macrophages. We show here that Rev-erb-α is highly expressed in oxidative skeletal muscle and that its deficiency in muscle leads to reduced mitochondrial content and oxidative function, as well as upregulation of autophagy. These cellular effects resulted in both impaired mitochondrial biogenesis and increased clearance of this organelle, leading to compromised exercise capacity. On a molecular level, Rev-erb-α deficiency resulted in deactivation of the Lkb1-Ampk-Sirt1-Ppargc-1α signaling pathway. These effects were recapitulated in isolated fibers and in muscle cells after knockdown of the gene encoding Rev-erb-α, Nr1d1. In complementary experiments, Rev-erb-α overexpression in vitro increased the number of mitochondria and improved respiratory capacity, whereas muscle overexpression or pharmacological activation of Rev-erb-α in vivo increased exercise capacity. This study identifies Rev-erb-α as a pharmacological target that improves muscle oxidative function by modulating gene networks controlling mitochondrial number and function.", + "TAG_DATA": [ + "73, Rev-erb-α {'perturbing_action': 'B-gene loss-of-function'}", + "74, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "89, fibers {'context': 'B-cells'}", + "92, muscle {'context': 'B-cells'}", + "93, cells {'context': 'I-cells'}", + "95, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "96, of {'perturbing_action': 'I-rnai/knockdown'}", + "97, the {'perturbing_action': 'I-rnai/knockdown'}", + "98, gene {'perturbing_action': 'I-rnai/knockdown'}", + "99, encoding {'perturbing_action': 'I-rnai/knockdown'}", + "100, Rev-erb-α, {'perturbing_action': 'I-rnai/knockdown'}", + "101, Nr1d1. {'perturbing_action': 'I-rnai/knockdown'}", + "105, Rev-erb-α {'perturbing_action': 'B-gene gain-of-function'}", + "106, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "107, in {'context': 'B-in vitro'}", + "108, vitro {'context': 'I-in vitro'}", + "119, muscle {'perturbing_action': 'B-gene gain-of-function'}", + "120, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "122, pharmacological {'perturbing_action': 'B-pharmacological augmentation'}", + "123, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "124, of {'perturbing_action': 'I-pharmacological augmentation'}", + "125, Rev-erb-α {'perturbing_action': 'I-pharmacological augmentation'}", + "126, in {'context': 'B-in vivo'}", + "127, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "73, Rev-erb-α ['l0', 'l1', 'l2']", + "74, deficiency ['l0', 'l3']", + "89, fibers ['l1', 'l3']", + "92, muscle ['l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "93, cells ['l2', 'l4', 'l11']", + "95, knockdown ['l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "96, of ['l5', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "97, the ['l6', 'l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "98, gene ['l7', 'l14', 'l23', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "99, encoding ['l8', 'l15', 'l24', 'l32', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "100, Rev-erb-α, ['l9', 'l16', 'l25', 'l33', 'l40', 'l46', 'l52', 'l53', 'l54', 'l55', 'l56']", + "101, Nr1d1. ['l10', 'l11', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l57', 'l58', 'l59', 'l60']", + "105, Rev-erb-α ['l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l61', 'l62', 'l63']", + "106, overexpression ['l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l64', 'l65']", + "107, in ['l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l66']", + "108, vitro ['l21', 'l30', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l65', 'l66']", + "119, muscle ['l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "120, overexpression ['l67', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "122, pharmacological ['l68', 'l74', 'l80', 'l81', 'l82', 'l83', 'l84']", + "123, activation ['l69', 'l75', 'l80', 'l85', 'l86', 'l87', 'l88']", + "124, of ['l70', 'l76', 'l81', 'l85', 'l89', 'l90', 'l91']", + "125, Rev-erb-α ['l71', 'l77', 'l82', 'l86', 'l89', 'l92', 'l93']", + "126, in ['l72', 'l78', 'l83', 'l87', 'l90', 'l92', 'l94']", + "127, vivo ['l73', 'l79', 'l84', 'l88', 'l91', 'l93', 'l94']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rev-erb-α", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "fibers", + "cells" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "muscle", + "cells" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "the", + "gene", + "encoding", + "Rev-erb-α,", + "Nr1d1." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "the", + "gene", + "encoding", + "Rev-erb-α,", + "Nr1d1." + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Rev-erb-α", + "overexpression" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "muscle", + "overexpression" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "pharmacological", + "activation", + "of", + "Rev-erb-α" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "23832089", + "TEXT": "Increased hepatic lipid content is an early correlate of insulin resistance and can be caused by nutrient-induced activation of mammalian target of rapamycin (mTor). This activation of mTor increases basal Akt activity, leading to a self-perpetuating lipogenic cycle. We have previously shown that the developmental Notch pathway has metabolic functions in adult mouse liver. Acute or chronic inhibition of Notch dampens hepatic glucose production and increases Akt activity and may therefore be predicted to increase hepatic lipid content. Here we now show that constitutive liver-specific ablation of Notch signaling, or its acute inhibition with a decoy Notch1 receptor, prevents hepatosteatosis by blocking mTor complex 1 (mTorc1) activity. Conversely, Notch gain of function causes fatty liver through constitutive activation of mTorc1, an effect that is reversible by treatment with rapamycin. We demonstrate that Notch signaling increases mTorc1 complex stability, augmenting mTorc1 function and sterol regulatory element binding transcription factor 1c (Srebp1c)-mediated lipogenesis. These data identify Notch as a therapeutically actionable branch point of metabolic signaling at which Akt activation in the liver can be uncoupled from hepatosteatosis.", + "TAG_DATA": [ + "83, constitutive {'perturbing_action': 'B-gene loss-of-function'}", + "84, liver-specific {'perturbing_action': 'I-gene loss-of-function'}", + "85, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "86, of {'perturbing_action': 'I-gene loss-of-function'}", + "87, Notch {'perturbing_action': 'I-gene loss-of-function'}", + "88, signaling, {'perturbing_action': 'I-gene loss-of-function'}", + "96, Notch1 {'perturbing_action': 'I-rnai/knockdown'}", + "108, Notch {'perturbing_action': 'B-gene gain-of-function'}", + "109, gain {'perturbing_action': 'I-gene gain-of-function'}", + "110, of {'perturbing_action': 'I-gene gain-of-function'}", + "111, function {'perturbing_action': 'I-gene gain-of-function'}", + "113, fatty {'context': 'B-tissue/organ'}", + "114, liver {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "83, constitutive ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "84, liver-specific ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "85, ablation ['l1', 'l7', 'l12', 'l13', 'l14']", + "86, of ['l2', 'l8', 'l12', 'l15', 'l16']", + "87, Notch ['l3', 'l9', 'l13', 'l15', 'l17']", + "88, signaling, ['l4', 'l10', 'l14', 'l16', 'l17']", + "96, Notch1 ['l5', 'l18', 'l19', 'l20']", + "97, receptor, ['l6', 'l11', 'l18', 'l21', 'l22']", + "108, Notch ['l23', 'l24', 'l25', 'l26', 'l27']", + "109, gain ['l23', 'l28', 'l29', 'l30', 'l31']", + "110, of ['l24', 'l28', 'l32', 'l33', 'l34']", + "111, function ['l25', 'l29', 'l32', 'l35', 'l36']", + "113, fatty ['l19', 'l21', 'l26', 'l30', 'l33', 'l35', 'l37']", + "114, liver ['l20', 'l22', 'l27', 'l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Notch1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "fatty", + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Notch", + "gain", + "of", + "function" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "fatty", + "liver" + ] + } + } + ] + }, + { + "PMID": "23749231", + "TEXT": "Hyperlipidemia is a risk factor for various cardiovascular and metabolic disorders. Overproduction of lipoproteins, a process that is dependent on microsomal triglyceride transfer protein (MTP), can contribute to hyperlipidemia. We show that microRNA-30c (miR-30c) interacts with the 3' untranslated region of MTP mRNA and induces its degradation, leading to reductions in MTP activity and in apolipoprotein B (APOB) secretion. miR-30c also reduces lipid synthesis independently of MTP. Hepatic overexpression of miR-30c reduced hyperlipidemia in Western diet-fed mice by decreasing lipid synthesis and the secretion of triglyceride-rich ApoB-containing lipoproteins and decreased atherosclerosis in Apoe(-/-) mice. Furthermore, inhibition of hepatic miR-30c by anti-miR-30c increased hyperlipidemia and atherosclerosis. Therefore, miR-30c coordinately reduces lipid biosynthesis and lipoprotein secretion, thereby regulating hepatic and plasma lipid concentrations. Raising miR-30c levels might be useful in treating hyperlipidemias and associated disorders.", + "TAG_DATA": [ + "67, Hepatic {'perturbing_action': 'B-gene gain-of-function'}", + "68, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "69, of {'perturbing_action': 'I-gene gain-of-function'}", + "70, miR-30c {'perturbing_action': 'I-gene gain-of-function'}", + "76, mice {'context': 'B-organism'}", + "89, decreased {'effect': 'B-negative'}", + "92, Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "93, mice. {'context': 'B-organism'}", + "95, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "96, of {'perturbing_action': 'I-pharmacological inhibition'}", + "97, hepatic {'perturbing_action': 'I-pharmacological inhibition'}", + "98, miR-30c {'perturbing_action': 'I-pharmacological inhibition'}", + "99, by {'perturbing_action': 'I-pharmacological inhibition'}", + "100, anti-miR-30c {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "67, Hepatic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "68, overexpression ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "69, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "70, miR-30c ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "76, mice ['l3', 'l10', 'l16', 'l21']", + "89, decreased ['l4', 'l11', 'l17', 'l22', 'l26', 'l27', 'l28']", + "90, atherosclerosis ['l5', 'l12', 'l18', 'l23', 'l26', 'l29', 'l30']", + "92, Apoe(-/-) ['l6', 'l13', 'l19', 'l24', 'l27', 'l29', 'l31']", + "93, mice. ['l7', 'l14', 'l20', 'l25', 'l28', 'l30', 'l31']", + "95, inhibition ['l32', 'l33', 'l34', 'l35', 'l36']", + "96, of ['l32', 'l37', 'l38', 'l39', 'l40']", + "97, hepatic ['l33', 'l37', 'l41', 'l42', 'l43']", + "98, miR-30c ['l34', 'l38', 'l41', 'l44', 'l45']", + "99, by ['l35', 'l39', 'l42', 'l44', 'l46']", + "100, anti-miR-30c ['l36', 'l40', 'l43', 'l45', 'l46']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Hepatic", + "overexpression", + "of", + "miR-30c" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Hepatic", + "overexpression", + "of", + "miR-30c" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apoe(-/-)" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apoe(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "23685842", + "TEXT": "Total anomalous pulmonary venous connection (TAPVC) is a potentially lethal congenital disorder that occurs when the pulmonary veins do not connect normally to the left atrium, allowing mixing of pulmonary and systemic blood. In contrast to the extensive knowledge of arterial vascular patterning, little is known about the patterning of veins. Here we show that the secreted guidance molecule semaphorin 3d (Sema3d) is crucial for the normal patterning of pulmonary veins. Prevailing models suggest that TAPVC occurs when the midpharyngeal endothelial strand (MES), the precursor of the common pulmonary vein, does not form at the proper location on the dorsal surface of the embryonic common atrium. However, we found that TAPVC occurs in Sema3d mutant mice despite normal formation of the MES. In these embryos, the maturing pulmonary venous plexus does not anastomose uniquely with the properly formed MES. In the absence of Sema3d, endothelial tubes form in a region that is normally avascular, resulting in aberrant connections. Normally, Sema3d provides a repulsive cue to endothelial cells in this area, establishing a boundary. Sequencing of SEMA3D in individuals with anomalous pulmonary veins identified a phenylalanine-to-leucine substitution that adversely affects SEMA3D function. These results identify Sema3d as a crucial pulmonary venous patterning cue and provide experimental evidence for an alternate developmental model to explain abnormal pulmonary venous connections.", + "TAG_DATA": [ + "113, Sema3d {'perturbing_action': 'B-other'}", + "114, mutant {'perturbing_action': 'I-other'}", + "115, mice {'context': 'B-organism'}", + "124, embryos, {'context': 'B-organism'}", + "141, absence {'perturbing_action': 'B-gene loss-of-function'}", + "142, of {'perturbing_action': 'I-gene loss-of-function'}", + "143, Sema3d, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "113, Sema3d ['l0', 'l1']", + "114, mutant ['l0', 'l2']", + "115, mice ['l1', 'l2']", + "124, embryos, ['l3', 'l4', 'l5']", + "141, absence ['l3', 'l6', 'l7']", + "142, of ['l4', 'l6', 'l8']", + "143, Sema3d, ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Sema3d", + "mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "embryos," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "Sema3d," + ] + } + } + ] + }, + { + "PMID": "23685839", + "TEXT": "Glucagon activates hepatic protein kinase A (PKA) to increase glucose production, but the gluco-stimulatory effect is transient even in the presence of continuous intravenous glucagon infusion. Continuous intravenous infusion of insulin, however, inhibits glucose production through its sustained actions in both the liver and the mediobasal hypothalamus (MBH). In a pancreatic clamp setting, MBH infusion with glucagon activated MBH PKA and inhibited hepatic glucose production (HGP) in rats, as did central glucagon infusion in mice. Inhibition of glucagon receptor-PKA signaling in the MBH and hepatic vagotomy each negated the effect of MBH glucagon in rats, whereas the central effect of glucagon was diminished in glucagon receptor knockout mice. A sustained rise in plasma glucagon concentrations transiently increased HGP, and this transiency was abolished in rats with negated MBH glucagon action. In a nonclamp setting, MBH glucagon infusion improved glucose tolerance, and inhibition of glucagon receptor-PKA signaling in the MBH enhanced the ability of intravenous glucagon injection to increase plasma glucose concentrations. We also detected a similar enhancement of glucose concentrations that was associated with a disruption in MBH glucagon signaling in rats fed a high-fat diet. We show that hypothalamic glucagon signaling inhibits HGP and suggest that hypothalamic glucagon resistance contributes to hyperglycemia in diabetes and obesity.", + "TAG_DATA": [ + "67, rats, {'context': 'B-organism'}", + "74, mice. {'context': 'B-organism'}", + "94, rats, {'context': 'B-organism'}", + "104, glucagon {'perturbing_action': 'B-gene loss-of-function'}", + "105, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "106, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "107, mice. {'context': 'B-organism'}", + "124, rats {'context': 'B-organism'}", + "181, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "67, rats, ['l0']", + "74, mice. ['l0']", + "104, glucagon ['l1', 'l2', 'l3', 'l4']", + "105, receptor ['l1', 'l5', 'l6', 'l7']", + "106, knockout ['l2', 'l5', 'l8', 'l9']", + "107, mice. ['l3', 'l6', 'l8', 'l10']", + "124, rats ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "glucagon", + "receptor", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "rats" + ] + } + } + ] + }, + { + "PMID": "23644514", + "TEXT": "Anticancer chemotherapy drugs challenge hematopoietic tissues to regenerate but commonly produce long-term sequelae. Chemotherapy-induced deficits in hematopoietic stem or stromal cell function have been described, but the mechanisms mediating hematopoietic dysfunction remain unclear. Administration of multiple cycles of cisplatin chemotherapy causes substantial sensory neuropathy. Here we demonstrate that chemotherapy-induced nerve injury in the bone marrow of mice is a crucial lesion impairing hematopoietic regeneration. Using pharmacological and genetic models, we show that the selective loss of adrenergic innervation in the bone marrow alters its regeneration after genotoxic insult. Sympathetic nerves in the marrow promote the survival of constituents of the stem cell niche that initiate recovery. Neuroprotection by deletion of Trp53 in sympathetic neurons or neuroregeneration by administration of 4-methylcatechol or glial-derived neurotrophic factor (GDNF) promotes hematopoietic recovery. These results demonstrate the potential benefit of adrenergic nerve protection for shielding hematopoietic niches from injury.", + "TAG_DATA": [ + "73, selective {'perturbing_action': 'B-gene loss-of-function'}", + "74, loss {'perturbing_action': 'I-gene loss-of-function'}", + "75, of {'perturbing_action': 'I-gene loss-of-function'}", + "76, adrenergic {'perturbing_action': 'I-gene loss-of-function'}", + "77, innervation {'perturbing_action': 'I-gene loss-of-function'}", + "78, in {'perturbing_action': 'I-gene loss-of-function'}", + "79, the {'perturbing_action': 'I-gene loss-of-function'}", + "80, bone {'perturbing_action': 'I-gene loss-of-function'}", + "81, marrow {'perturbing_action': 'I-gene loss-of-function'}", + "108, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "109, of {'perturbing_action': 'I-gene loss-of-function'}", + "110, Trp53 {'perturbing_action': 'I-gene loss-of-function'}", + "112, sympathetic {'context': 'B-cells'}", + "113, neurons {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "73, selective ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "74, loss ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "75, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "76, adrenergic ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "77, innervation ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "78, in ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "79, the ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "80, bone ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "81, marrow ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "108, deletion ['l36', 'l37', 'l38', 'l39']", + "109, of ['l36', 'l40', 'l41', 'l42']", + "110, Trp53 ['l37', 'l40', 'l43', 'l44']", + "112, sympathetic ['l38', 'l41', 'l43', 'l45']", + "113, neurons ['l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Trp53" + ] + }, + "context": { + "val": "cells", + "words": [ + "sympathetic", + "neurons" + ] + } + } + ] + }, + { + "PMID": "23603816", + "TEXT": "Upregulation of the ERK1 and ERK2 (ERK1/2) MAP kinase (MAPK) cascade occurs in >30% of cancers, often through mutational activation of receptor tyrosine kinases or other upstream genes, including KRAS and BRAF. Efforts to target endogenous MAPKs are challenged by the fact that these kinases are required for viability in mammals. Additionally, the effectiveness of new inhibitors of mutant BRAF has been diminished by acquired tumor resistance through selection for BRAF-independent mechanisms of ERK1/2 induction. Furthermore, recently identified ERK1/2-inducing mutations in MEK1 and MEK2 (MEK1/2) MAPK genes in melanoma confer resistance to emerging therapeutic MEK inhibitors, underscoring the challenges facing direct kinase inhibition in cancer. MAPK scaffolds, such as IQ motif-containing GTPase activating protein 1 (IQGAP1), assemble pathway kinases to affect signal transmission, and disrupting scaffold function therefore offers an orthogonal approach to MAPK cascade inhibition. Consistent with this, we found a requirement for IQGAP1 in RAS-driven tumorigenesis in mouse and human tissue. In addition, the ERK1/2-binding IQGAP1 WW domain peptide disrupted IQGAP1-ERK1/2 interactions, inhibited RAS- and RAF-driven tumorigenesis, bypassed acquired resistance to the BRAF inhibitor vemurafenib (PLX-4032) and acted as a systemically deliverable therapeutic to significantly increase the lifespan of tumor-bearing mice. Scaffold-kinase interaction blockade acts by a mechanism distinct from direct kinase inhibition and may be a strategy to target overactive oncogenic kinase cascades in cancer.", + "TAG_DATA": [ + "164, inhibited {'effect': 'B-negative'}", + "168, tumorigenesis, {'phenotype': 'B-tumourigenesis'}", + "191, tumor-bearing {'context': 'B-organism'}", + "192, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "164, inhibited ['l0']", + "168, tumorigenesis, ['l0']", + "191, tumor-bearing ['l1']", + "192, mice. ['l1']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis," + ] + } + } + ] + }, + { + "PMID": "23603814", + "TEXT": "Microglia are crucial for the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Here we show that the E3 ubiquitin ligase Peli1 is abundantly expressed in microglia and promotes microglial activation during the course of EAE induction. Peli1 mediates the induction of chemokines and proinflammatory cytokines in microglia and thereby promotes recruitment of T cells into the central nervous system. The severity of EAE is reduced in Peli1-deficient mice despite their competent induction of inflammatory T cells in the peripheral lymphoid organs. Notably, Peli1 regulates Toll-like receptor (TLR) pathway signaling by promoting degradation of TNF receptor-associated factor 3 (Traf3), a potent inhibitor of mitogen-activated protein kinase (MAPK) activation and gene induction. Ablation of Traf3 restores microglial activation and CNS inflammation after the induction of EAE in Peli1-deficient mice. These findings establish Peli1 as a microglia-specific mediator of autoimmune neuroinflammation and suggest a previously unknown signaling mechanism of Peli1 function.", + "TAG_DATA": [ + "71, Peli1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "72, mice {'context': 'B-organism'}", + "115, Ablation {'perturbing_action': 'B-gene loss-of-function'}", + "116, of {'perturbing_action': 'I-gene loss-of-function'}", + "117, Traf3 {'perturbing_action': 'I-gene loss-of-function'}", + "122, CNS {'context': 'B-tissue/organ'}", + "130, Peli1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "131, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "71, Peli1-deficient ['l0']", + "72, mice ['l0']", + "115, Ablation ['l1', 'l2', 'l3', 'l4', 'l5']", + "116, of ['l1', 'l6', 'l7', 'l8', 'l9']", + "117, Traf3 ['l2', 'l6', 'l10']", + "122, CNS ['l3', 'l7', 'l10', 'l11', 'l12']", + "130, Peli1-deficient ['l4', 'l8', 'l11', 'l13']", + "131, mice. ['l5', 'l9', 'l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Peli1-deficient", + "Ablation", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "Traf3", + "Peli1-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "CNS" + ] + } + } + ] + }, + { + "PMID": "23542788", + "TEXT": "Glucagon-like peptide-1 receptor (GLP-1R) agonists exert antihypertensive actions through incompletely understood mechanisms. Here we demonstrate that cardiac Glp1r expression is localized to cardiac atria and that GLP-1R activation promotes the secretion of atrial natriuretic peptide (ANP) and a reduction of blood pressure. Consistent with an indirect ANP-dependent mechanism for the antihypertensive effects of GLP-1R activation, the GLP-1R agonist liraglutide did not directly increase the amount of cyclic GMP (cGMP) or relax preconstricted aortic rings; however, conditioned medium from liraglutide-treated hearts relaxed aortic rings in an endothelium-independent, GLP-1R-dependent manner. Liraglutide did not induce ANP secretion, vasorelaxation or lower blood pressure in Glp1r(-/-) or Nppa(-/-) mice. Cardiomyocyte GLP-1R activation promoted the translocation of the Rap guanine nucleotide exchange factor Epac2 (also known as Rapgef4) to the membrane, whereas Epac2 deficiency eliminated GLP-1R-dependent stimulation of ANP secretion. Plasma ANP concentrations were increased after refeeding in wild-type but not Glp1r(-/-) mice, and liraglutide increased urine sodium excretion in wild-type but not Nppa(-/-) mice. These findings define a gut-heart GLP-1R-dependent and ANP-dependent axis that regulates blood pressure.", + "TAG_DATA": [ + "72, aortic {'context': 'B-tissue/organ'}", + "73, rings; {'context': 'I-tissue/organ'}", + "79, hearts {'context': 'B-tissue/organ'}", + "81, aortic {'context': 'B-tissue/organ'}", + "82, rings {'context': 'I-tissue/organ'}", + "100, Glp1r(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "102, Nppa(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "103, mice. {'context': 'B-organism'}", + "104, Cardiomyocyte {'context': 'B-cells'}", + "126, Epac2 {'perturbing_action': 'B-gene loss-of-function'}", + "127, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "145, Glp1r(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "146, mice, {'context': 'B-organism'}", + "157, Nppa(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "158, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "72, aortic ['l0']", + "73, rings; ['l0']", + "79, hearts ['l1', 'l2']", + "81, aortic ['l1', 'l3']", + "82, rings ['l2', 'l3']", + "100, Glp1r(-/-) ['l4', 'l5', 'l6']", + "102, Nppa(-/-) ['l4', 'l7', 'l8']", + "103, mice. ['l5', 'l7', 'l9']", + "104, Cardiomyocyte ['l6', 'l8', 'l9', 'l10', 'l11']", + "126, Epac2 ['l12', 'l13', 'l14']", + "127, deficiency ['l10', 'l12', 'l15', 'l16']", + "145, Glp1r(-/-) ['l13', 'l15', 'l17']", + "146, mice, ['l11', 'l14', 'l16', 'l17']", + "157, Nppa(-/-) ['l18']", + "158, mice. ['l18']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Glp1r(-/-)", + "Nppa(-/-)", + "Epac2", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Glp1r(-/-)", + "Nppa(-/-)", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "Cardiomyocyte" + ] + } + } + ] + }, + { + "PMID": "23502962", + "TEXT": "A role for macrophages in erythropoiesis was suggested several decades ago when erythroblastic islands in the bone marrow, composed of a central macrophage surrounded by developing erythroblasts, were described. However, the in vivo role of macrophages in erythropoiesis under homeostatic conditions or in disease remains unclear. We found that specific depletion of CD169(+) macrophages markedly reduced the number of erythroblasts in the bone marrow but did not result in overt anemia under homeostatic conditions, probably because of concomitant alterations in red blood cell clearance. However, CD169(+) macrophage depletion significantly impaired erythropoietic recovery from hemolytic anemia, acute blood loss and myeloablation. Furthermore, macrophage depletion normalized the erythroid compartment in a JAK2(V617F)-driven mouse model of polycythemia vera, suggesting that erythropoiesis in polycythemia vera remains under the control of macrophages in the bone marrow and splenic microenvironments. These results indicate that CD169(+) macrophages promote late erythroid maturation and that modulation of the macrophage compartment may be a new strategy to treat erythropoietic disorders.", + "TAG_DATA": [ + "50, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "51, of {'perturbing_action': 'I-gene loss-of-function'}", + "52, CD169(+) {'context': 'B-cells'}", + "53, macrophages {'context': 'I-cells'}", + "59, erythroblasts {'context': 'B-cells'}", + "62, bone {'context': 'B-tissue/organ'}", + "63, marrow {'context': 'I-tissue/organ'}", + "85, CD169(+) {'context': 'B-cells'}", + "86, macrophage {'context': 'I-cells'}", + "87, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "102, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "110, mouse {'context': 'B-organism'}", + "111, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "50, depletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "51, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "52, CD169(+) ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "53, macrophages ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "59, erythroblasts ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "62, bone ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "63, marrow ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "85, CD169(+) ['l21', 'l22']", + "86, macrophage ['l21', 'l23']", + "87, depletion ['l22', 'l23']", + "102, depletion ['l24', 'l25', 'l26']", + "109, JAK2(V617F)-driven ['l24', 'l27', 'l28']", + "110, mouse ['l25', 'l27', 'l29']", + "111, model ['l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD169(+)", + "macrophages", + "erythroblasts", + "macrophage" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "bone", + "marrow" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + } + ] + }, + { + "PMID": "23502960", + "TEXT": "Focal segmental glomerulosclerosis (FSGS) is a frequent and severe glomerular disease characterized by destabilization of podocyte foot processes. We report that transgenic expression of the microRNA miR-193a in mice rapidly induces FSGS with extensive podocyte foot process effacement. Mechanistically, miR-193a inhibits the expression of the Wilms' tumor protein (WT1), a transcription factor and master regulator of podocyte differentiation and homeostasis. Decreased expression levels of WT1 lead to downregulation of its target genes PODXL (podocalyxin) and NPHS1 (nephrin), as well as several other genes crucial for the architecture of podocytes, initiating a catastrophic collapse of the entire podocyte-stabilizing system. We found upregulation of miR-193a in isolated glomeruli from individuals with FSGS compared to normal kidneys or individuals with other glomerular diseases. Thus, upregulation of miR-193a provides a new pathogenic mechanism for FSGS and is a potential therapeutic target.", + "TAG_DATA": [ + "21, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "22, expression {'perturbing_action': 'I-gene gain-of-function'}", + "23, of {'perturbing_action': 'I-gene gain-of-function'}", + "24, the {'perturbing_action': 'I-gene gain-of-function'}", + "25, microRNA {'perturbing_action': 'I-gene gain-of-function'}", + "26, miR-193a {'perturbing_action': 'I-gene gain-of-function'}", + "28, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "21, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "22, expression ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "23, of ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "24, the ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "25, microRNA ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "26, miR-193a ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "28, mice ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "of", + "the", + "microRNA", + "miR-193a" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23455713", + "TEXT": "To understand why cancer vaccine-induced T cells often do not eradicate tumors, we studied immune responses in mice vaccinated with gp100 melanoma peptide in incomplete Freund's adjuvant (peptide/IFA), which is commonly used in clinical cancer vaccine trials. Peptide/IFA vaccination primed tumor-specific CD8(+) T cells, which accumulated not in tumors but rather at the persisting, antigen-rich vaccination site. Once there, primed T cells became dysfunctional and underwent antigen-driven, interferon-γ (IFN-γ)- and Fas ligand (FasL)-mediated apoptosis, resulting in hyporesponsiveness to subsequent vaccination. Provision of CD40-specific antibody, Toll-like receptor 7 (TLR7) agonist and interleukin-2 (IL-2) reduced T cell apoptosis but did not prevent vaccination-site sequestration. A nonpersisting vaccine formulation shifted T cell localization toward tumors, inducing superior antitumor activity while reducing systemic T cell dysfunction and promoting memory formation. These data show that persisting vaccine depots can induce specific T cell sequestration, dysfunction and deletion at vaccination sites; short-lived formulations may overcome these limitations and result in greater therapeutic efficacy of peptide-based cancer vaccines.", + "TAG_DATA": [ + "17, mice {'context': 'B-organism'}", + "41, CD8(+) {'context': 'B-cells'}", + "42, T {'context': 'I-cells'}", + "43, cells, {'context': 'I-cells'}", + "60, T {'context': 'B-cells'}", + "61, cells {'context': 'B-cells'}", + "73, apoptosis, {'phenotype': 'B-apoptosis'}", + "92, reduced {'effect': 'B-negative'}", + "93, T {'context': 'B-cells'}", + "94, cell {'context': 'B-cells'}", + "95, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "17, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "41, CD8(+) ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "42, T ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "43, cells, ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "60, T ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "61, cells ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "73, apoptosis, ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "92, reduced ['l21', 'l22', 'l23']", + "93, T ['l21', 'l24', 'l25']", + "94, cell ['l22', 'l24', 'l26']", + "95, apoptosis ['l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "T", + "cells,", + "cells", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis,", + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "23291631", + "TEXT": "A better understanding of human hepatocellular carcinoma (HCC) pathogenesis at the molecular level will facilitate the discovery of tumor-initiating events. Transcriptome sequencing revealed that adenosine-to-inosine (A→I) RNA editing of AZIN1 (encoding antizyme inhibitor 1) is increased in HCC specimens. A→I editing of AZIN1 transcripts, specifically regulated by ADAR1 (encoding adenosine deaminase acting on RNA-1), results in a serine-to-glycine substitution at residue 367 of AZIN1, located in β-strand 15 (β15) and predicted to cause a conformational change, induced a cytoplasmic-to-nuclear translocation and conferred gain-of-function phenotypes that were manifested by augmented tumor-initiating potential and more aggressive behavior. Compared with wild-type AZIN1 protein, the edited form has a stronger affinity to antizyme, and the resultant higher AZIN1 protein stability promotes cell proliferation through the neutralization of antizyme-mediated degradation of ornithine decarboxylase (ODC) and cyclin D1 (CCND1). Collectively, A→I RNA editing of AZIN1 may be a potential driver in the pathogenesis of human cancers, particularly HCC.", + "TAG_DATA": [ + "88, augmented {'effect': 'B-positive'}", + "89, tumor-initiating {'phenotype': 'B-tumour initiation'}", + "90, potential {'phenotype': 'I-tumour initiation'}", + "116, promotes {'effect': 'B-positive'}", + "117, cell {'context': 'B-cells'}", + "118, proliferation {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "88, augmented ['l0', 'l1']", + "89, tumor-initiating ['l0', 'l2']", + "90, potential ['l1', 'l2']", + "116, promotes ['l3', 'l4']", + "117, cell ['l3', 'l5']", + "118, proliferation ['l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "augmented" + ] + }, + "phenotype": { + "val": "tumour initiation", + "words": [ + "tumor-initiating", + "potential" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "23223058", + "TEXT": "There is a growing appreciation of the importance of circadian regulation in energy homeostasis, and the dysregulation of the circadian clock has been associated with obesity and metabolic abnormalities. A new study shows that adipocyte-specific deletion of a core circadian clock gene, Bmal1, in mice shifts the timing of their feeding behavior, resulting in obesity (aaa-bbb).", + "TAG_DATA": [ + "34, adipocyte-specific {'perturbing_action': 'B-gene loss-of-function'}", + "35, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "36, of {'perturbing_action': 'I-gene loss-of-function'}", + "37, a {'perturbing_action': 'I-gene loss-of-function'}", + "38, core {'perturbing_action': 'I-gene loss-of-function'}", + "39, circadian {'perturbing_action': 'I-gene loss-of-function'}", + "40, clock {'perturbing_action': 'I-gene loss-of-function'}", + "41, gene, {'perturbing_action': 'I-gene loss-of-function'}", + "42, Bmal1, {'perturbing_action': 'I-gene loss-of-function'}", + "44, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "34, adipocyte-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "35, deletion ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "36, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "37, a ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "38, core ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "39, circadian ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "40, clock ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "41, gene, ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "42, Bmal1, ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "44, mice ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adipocyte-specific", + "deletion", + "of", + "a", + "core", + "circadian", + "clock", + "gene,", + "Bmal1," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23202294", + "TEXT": "Skeletal muscle atrophy occurs in aging and pathological conditions, including cancer, diabetes and AIDS. Treatment of atrophy is based on either preventing protein-degradation pathways, which are activated during atrophy, or activating protein-synthesis pathways, which induce muscle hypertrophy. Here we show that neuronal nitric oxide synthase (nNOS) regulates load-induced hypertrophy by activating transient receptor potential cation channel, subfamily V, member 1 (TRPV1). The overload-induced hypertrophy was prevented in nNOS-null mice. nNOS was transiently activated within 3 min after overload. This activation promoted formation of peroxynitrite, a reaction product of nitric oxide with superoxide, which was derived from NADPH oxidase 4 (Nox4). Nitric oxide and peroxynitrite then activated Trpv1, resulting in an increase of intracellular Ca(2+) concentration ([Ca(2+)](i)) that subsequently triggered activation of mammalian target of rapamycin (mTOR). Notably, administration of the TRPV1 agonist capsaicin induced hypertrophy without overload and alleviated unloading- or denervation-induced atrophy. These findings identify nitric oxide, peroxynitrite and [Ca(2+)](i) as the crucial mediators that convert a mechanical load into an intracellular signaling pathway and lead us to suggest that TRPV1 could be a new therapeutic target for treating muscle atrophy.", + "TAG_DATA": [ + "67, nNOS-null {'perturbing_action': 'B-gene loss-of-function'}", + "68, mice. {'context': 'B-organism'}", + "130, TRPV1 {'perturbing_action': 'B-pharmacological augmentation'}", + "131, agonist {'perturbing_action': 'I-pharmacological augmentation'}" + ], + "LINK_DATA": [ + "67, nNOS-null ['l0']", + "68, mice. ['l0']", + "130, TRPV1 ['l1']", + "131, agonist ['l1']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nNOS-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "23142821", + "TEXT": "Live, attenuated RNA virus vaccines are efficacious but subject to reversion to virulence. Among RNA viruses, replication fidelity is recognized as a key determinant of virulence and escape from antiviral therapy; increased fidelity is attenuating for some viruses. Coronavirus (CoV) replication fidelity is approximately 20-fold greater than that of other RNA viruses and is mediated by a 3'→5' exonuclease (ExoN) activity that probably functions in RNA proofreading. In this study we demonstrate that engineered inactivation of severe acute respiratory syndrome (SARS)-CoV ExoN activity results in a stable mutator phenotype with profoundly decreased fidelity in vivo and attenuation of pathogenesis in young, aged and immunocompromised mice. The ExoN inactivation genotype and mutator phenotype are stable and do not revert to virulence, even after serial passage or long-term persistent infection in vivo. ExoN inactivation has potential for broad applications in the stable attenuation of CoVs and, perhaps, other RNA viruses.", + "TAG_DATA": [ + "73, engineered {'perturbing_action': 'B-gene loss-of-function'}", + "74, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "75, of {'perturbing_action': 'I-gene loss-of-function'}", + "76, severe {'perturbing_action': 'I-gene loss-of-function'}", + "77, acute {'perturbing_action': 'I-gene loss-of-function'}", + "78, respiratory {'perturbing_action': 'I-gene loss-of-function'}", + "79, syndrome {'perturbing_action': 'I-gene loss-of-function'}", + "80, (SARS)-CoV {'perturbing_action': 'I-gene loss-of-function'}", + "81, ExoN {'perturbing_action': 'I-gene loss-of-function'}", + "82, activity {'perturbing_action': 'I-gene loss-of-function'}", + "93, in {'context': 'B-in vivo'}", + "94, vivo {'context': 'I-in vivo'}", + "96, attenuation {'effect': 'B-negative'}", + "100, young, {'context': 'B-organism'}", + "101, aged {'context': 'I-organism'}", + "103, immunocompromised {'context': 'I-organism'}", + "104, mice. {'context': 'I-organism'}", + "106, ExoN {'perturbing_action': 'B-gene loss-of-function'}", + "107, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "128, in {'context': 'B-in vivo'}", + "129, vivo. {'context': 'I-in vivo'}", + "130, ExoN {'perturbing_action': 'B-gene loss-of-function'}", + "131, inactivation {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "73, engineered ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "74, inactivation ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "75, of ['l1', 'l17', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "76, severe ['l2', 'l18', 'l33', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "77, acute ['l3', 'l19', 'l34', 'l48', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "78, respiratory ['l4', 'l20', 'l35', 'l49', 'l62', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "79, syndrome ['l5', 'l21', 'l36', 'l50', 'l63', 'l75', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "80, (SARS)-CoV ['l6', 'l22', 'l37', 'l51', 'l64', 'l76', 'l87', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "81, ExoN ['l7', 'l23', 'l38', 'l52', 'l65', 'l77', 'l88', 'l98', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "82, activity ['l8', 'l24', 'l39', 'l53', 'l66', 'l78', 'l89', 'l99', 'l108', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "93, in ['l9', 'l25', 'l40', 'l54', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l125']", + "94, vivo ['l10', 'l26', 'l41', 'l55', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l125']", + "96, attenuation ['l11', 'l27', 'l42', 'l56', 'l69', 'l81', 'l92', 'l102', 'l111', 'l119', 'l126', 'l127', 'l128', 'l129', 'l130']", + "100, young, ['l12', 'l28', 'l43', 'l57', 'l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l126', 'l131', 'l132', 'l133', 'l134']", + "101, aged ['l13', 'l29', 'l44', 'l58', 'l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l127', 'l131', 'l135', 'l136', 'l137']", + "102, and ['l14', 'l30', 'l45', 'l59', 'l72', 'l84', 'l95', 'l105', 'l114', 'l122', 'l128', 'l132', 'l135', 'l138', 'l139']", + "103, immunocompromised ['l15', 'l31', 'l46', 'l60', 'l73', 'l85', 'l96', 'l106', 'l115', 'l123', 'l129', 'l133', 'l136', 'l138', 'l140']", + "104, mice. ['l16', 'l32', 'l47', 'l61', 'l74', 'l86', 'l97', 'l107', 'l116', 'l124', 'l130', 'l134', 'l137', 'l139', 'l140']", + "106, ExoN ['l141', 'l142', 'l143']", + "107, inactivation ['l141', 'l144', 'l145']", + "128, in ['l142', 'l144', 'l146']", + "129, vivo. ['l143', 'l145', 'l146']", + "130, ExoN ['l147']", + "131, inactivation ['l147']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "engineered", + "inactivation", + "of", + "severe", + "acute", + "respiratory", + "syndrome", + "(SARS)-CoV", + "ExoN", + "activity" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "engineered", + "inactivation", + "of", + "severe", + "acute", + "respiratory", + "syndrome", + "(SARS)-CoV", + "ExoN", + "activity" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "engineered", + "inactivation", + "of", + "severe", + "acute", + "respiratory", + "syndrome", + "(SARS)-CoV", + "ExoN", + "activity" + ] + }, + "context": { + "val": "organism", + "words": [ + "young,", + "aged", + "immunocompromised", + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuation" + ] + }, + "context": { + "val": "organism", + "words": [ + "young,", + "aged", + "immunocompromised", + "mice." + ] + } + } + ] + }, + { + "PMID": "23142819", + "TEXT": "Adipocytes store excess energy in the form of triglycerides and signal the levels of stored energy to the brain. Here we show that adipocyte-specific deletion of Arntl (also known as Bmal1), a gene encoding a core molecular clock component, results in obesity in mice with a shift in the diurnal rhythm of food intake, a result that is not seen when the gene is disrupted in hepatocytes or pancreatic islets. Changes in the expression of hypothalamic neuropeptides that regulate appetite are consistent with feedback from the adipocyte to the central nervous system to time feeding behavior. Ablation of the adipocyte clock is associated with a reduced number of polyunsaturated fatty acids in adipocyte triglycerides. This difference between mutant and wild-type mice is reflected in the circulating concentrations of polyunsaturated fatty acids and nonesterified polyunsaturated fatty acids in hypothalamic neurons that regulate food intake. Thus, this study reveals a role for the adipocyte clock in the temporal organization of energy regulation, highlights timing as a modulator of the adipocyte-hypothalamic axis and shows the impact of timing of food intake on body weight.", + "TAG_DATA": [ + "23, adipocyte-specific {'perturbing_action': 'B-gene loss-of-function'}", + "24, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "25, of {'perturbing_action': 'I-gene loss-of-function'}", + "26, Arntl {'perturbing_action': 'I-gene loss-of-function'}", + "27, (also {'perturbing_action': 'I-gene loss-of-function'}", + "29, as {'perturbing_action': 'I-gene loss-of-function'}", + "30, Bmal1), {'perturbing_action': 'I-gene loss-of-function'}", + "43, mice {'context': 'B-organism'}", + "64, disrupted {'perturbing_action': 'I-gene loss-of-function'}", + "66, hepatocytes {'context': 'B-cells'}", + "68, pancreatic {'context': 'B-cells'}", + "69, islets. {'context': 'I-cells'}", + "120, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "23, adipocyte-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "24, deletion ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "25, of ['l1', 'l10', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "26, Arntl ['l2', 'l11', 'l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "27, (also ['l3', 'l12', 'l21', 'l29', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "29, as ['l4', 'l13', 'l22', 'l30', 'l37', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "30, Bmal1), ['l5', 'l14', 'l23', 'l31', 'l38', 'l44', 'l50', 'l51', 'l52', 'l53', 'l54']", + "43, mice ['l6', 'l15', 'l24', 'l32', 'l39', 'l45', 'l50']", + "64, disrupted ['l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l56', 'l57']", + "66, hepatocytes ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l55', 'l58', 'l59']", + "68, pancreatic ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l56', 'l58', 'l60']", + "69, islets. ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adipocyte-specific", + "deletion", + "of", + "Arntl", + "(also", + "as", + "Bmal1)," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adipocyte-specific", + "deletion", + "of", + "Arntl", + "(also", + "as", + "Bmal1),", + "disrupted" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes", + "pancreatic", + "islets." + ] + } + } + ] + }, + { + "PMID": "23064464", + "TEXT": "Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin's lymphoma found in children and young adults. ALCLs frequently carry a chromosomal translocation that results in expression of the oncoprotein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The key molecular downstream events required for NPM-ALK-triggered lymphoma growth have been only partly unveiled. Here we show that the activator protein 1 family members JUN and JUNB promote lymphoma development and tumor dissemination through transcriptional regulation of platelet-derived growth factor receptor-β (PDGFRB) in a mouse model of NPM-ALK-triggered lymphomagenesis. Therapeutic inhibition of PDGFRB markedly prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor in transplanted NPM-ALK tumors. Notably, inhibition of PDGFRA and PDGFRB in a patient with refractory late-stage NPM-ALK(+) ALCL resulted in rapid, complete and sustained remission. Together, our data identify PDGFRB as a previously unknown JUN and JUNB target that could be a highly effective therapy for ALCL.", + "TAG_DATA": [ + "78, mouse {'context': 'B-organism'}", + "79, model {'context': 'I-organism'}", + "83, Therapeutic {'perturbing_action': 'B-pharmacological inhibition'}", + "84, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "85, of {'perturbing_action': 'I-pharmacological inhibition'}", + "86, PDGFRB {'perturbing_action': 'I-pharmacological inhibition'}", + "91, NPM-ALK {'perturbing_action': 'B-gene gain-of-function'}", + "92, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "93, mice {'context': 'B-organism'}", + "100, ALK-specific {'perturbing_action': 'B-pharmacological inhibition'}", + "101, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "103, transplanted {'context': 'B-xenograft'}", + "104, NPM-ALK {'context': 'B-neoplasm'}", + "105, tumors. {'context': 'I-neoplasm'}", + "107, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "108, of {'perturbing_action': 'I-pharmacological inhibition'}", + "109, PDGFRA {'perturbing_action': 'I-pharmacological inhibition'}", + "110, and {'perturbing_action': 'I-pharmacological inhibition'}", + "111, PDGFRB {'perturbing_action': 'I-pharmacological inhibition'}", + "114, patient {'context': 'B-patient'}", + "119, ALCL {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "78, mouse ['l0']", + "79, model ['l0']", + "83, Therapeutic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "84, inhibition ['l1', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "85, of ['l2', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "86, PDGFRB ['l3', 'l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "91, NPM-ALK ['l4', 'l14', 'l23', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43']", + "92, transgenic ['l5', 'l15', 'l24', 'l32', 'l39', 'l44', 'l45', 'l46']", + "93, mice ['l6', 'l16', 'l25', 'l33', 'l40', 'l44']", + "100, ALK-specific ['l7', 'l17', 'l26', 'l34', 'l47', 'l48', 'l49', 'l50']", + "101, inhibitor ['l8', 'l18', 'l27', 'l35', 'l47', 'l51', 'l52', 'l53']", + "103, transplanted ['l9', 'l19', 'l28', 'l36', 'l41', 'l48', 'l51', 'l54', 'l55']", + "104, NPM-ALK ['l10', 'l20', 'l29', 'l37', 'l42', 'l45', 'l49', 'l52', 'l54', 'l56']", + "105, tumors. ['l11', 'l21', 'l30', 'l38', 'l43', 'l46', 'l50', 'l53', 'l55', 'l56']", + "107, inhibition ['l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "108, of ['l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "109, PDGFRA ['l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "110, and ['l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "111, PDGFRB ['l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "114, patient ['l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "119, ALCL ['l62', 'l67', 'l71', 'l74', 'l76', 'l77']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Therapeutic", + "inhibition", + "of", + "PDGFRB" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Therapeutic", + "inhibition", + "of", + "PDGFRB", + "ALK-specific", + "inhibitor" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "transplanted" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Therapeutic", + "inhibition", + "of", + "PDGFRB", + "ALK-specific", + "inhibitor", + "PDGFRA", + "and" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "NPM-ALK", + "tumors.", + "ALCL" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "NPM-ALK", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "NPM-ALK" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "transplanted" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "NPM-ALK", + "transgenic" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "NPM-ALK", + "tumors." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "PDGFRA", + "and", + "PDGFRB" + ] + }, + "context": { + "val": "patient", + "words": [ + "patient" + ] + } + } + ] + }, + { + "PMID": "23023499", + "TEXT": "Spinal and bulbar muscular atrophy (SBMA) is a motor neuron disease caused by the expansion of the CAG triplet repeat within the androgen receptor (AR) gene. Here, we demonstrated that pathogenic AR upregulates the gene encoding calcitonin gene-related peptide α (CGRP1). In neuronal cells, overexpression of CGRP1 induced cellular damage via the activation of the c-Jun N-terminal kinase (JNK) pathway, whereas pharmacological suppression of CGRP1 or JNK attenuated the neurotoxic effects of pathogenic AR. The depletion of CGRP1 inactivated JNK and suppressed neurodegeneration in a mouse model of SBMA. Naratriptan, a serotonin 1B/1D (5-hydroxytryptamine 1B/1D, or 5-HT1B/1D) receptor agonist, decreased CGRP1 expression via the induction of dual-specificity protein phosphatase 1 (DUSP1), attenuated JNK activity and mitigated pathogenic AR-mediated neuronal damage in cellular and mouse SBMA models. These observations suggest that pharmacological activation of the 5-HT1B/1D receptor may be used therapeutically to treat SBMA and other polyglutamine-related neurodegenerative diseases.", + "TAG_DATA": [ + "42, neuronal {'context': 'B-cells'}", + "43, cells, {'context': 'I-cells'}", + "44, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "45, of {'perturbing_action': 'I-gene gain-of-function'}", + "46, CGRP1 {'perturbing_action': 'I-gene gain-of-function'}", + "61, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "62, suppression {'perturbing_action': 'I-pharmacological inhibition'}", + "63, of {'perturbing_action': 'I-pharmacological inhibition'}", + "64, CGRP1 {'perturbing_action': 'I-pharmacological inhibition'}", + "65, or {'perturbing_action': 'I-pharmacological inhibition'}", + "66, JNK {'perturbing_action': 'I-pharmacological inhibition'}", + "75, depletion {'perturbing_action': 'B-gene loss-of-function'}", + "76, of {'perturbing_action': 'I-gene loss-of-function'}", + "77, CGRP1 {'perturbing_action': 'I-gene loss-of-function'}", + "85, mouse {'context': 'B-organism'}", + "86, model {'context': 'I-organism'}", + "87, of {'context': 'I-organism'}", + "88, SBMA. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "42, neuronal ['l0', 'l1', 'l2', 'l3']", + "43, cells, ['l0', 'l4', 'l5', 'l6']", + "44, overexpression ['l1', 'l4', 'l7', 'l8']", + "45, of ['l2', 'l5', 'l7', 'l9']", + "46, CGRP1 ['l3', 'l6', 'l8', 'l9']", + "61, pharmacological ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "62, suppression ['l10', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "63, of ['l11', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "64, CGRP1 ['l12', 'l23', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "65, or ['l13', 'l24', 'l32', 'l40', 'l48', 'l49', 'l50', 'l51', 'l52']", + "66, JNK ['l14', 'l25', 'l33', 'l41', 'l48', 'l53', 'l54', 'l55', 'l56', 'l57']", + "75, depletion ['l15', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "76, of ['l16', 'l34', 'l42', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "77, CGRP1 ['l17', 'l26', 'l35', 'l43', 'l53', 'l59', 'l64', 'l69', 'l70', 'l71', 'l72']", + "85, mouse ['l18', 'l27', 'l36', 'l44', 'l49', 'l54', 'l60', 'l65', 'l69', 'l73', 'l74', 'l75']", + "86, model ['l19', 'l28', 'l37', 'l45', 'l50', 'l55', 'l61', 'l66', 'l70', 'l73', 'l76', 'l77']", + "87, of ['l20', 'l29', 'l38', 'l46', 'l51', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l78']", + "88, SBMA. ['l21', 'l30', 'l39', 'l47', 'l52', 'l57', 'l63', 'l68', 'l72', 'l75', 'l77', 'l78']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "neuronal", + "cells," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "CGRP1" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "suppression", + "of", + "CGRP1", + "or", + "JNK" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "SBMA." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "CGRP1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "SBMA." + ] + } + } + ] + }, + { + "PMID": "23001183", + "TEXT": "There is a pressing need to identify prognostic markers of metastatic disease and targets for treatment. Combining high-throughput RNA sequencing, functional characterization, mechanistic studies and clinical validation, we identify leukemia inhibitory factor receptor (LIFR) as a breast cancer metastasis suppressor downstream of the microRNA miR-9 and upstream of Hippo signaling. Restoring LIFR expression in highly malignant tumor cells suppresses metastasis by triggering a Hippo kinase cascade that leads to phosphorylation, cytoplasmic retention and functional inactivation of the transcriptional coactivator YES-associated protein (YAP). Conversely, loss of LIFR in nonmetastatic breast cancer cells induces migration, invasion and metastatic colonization through activation of YAP. LIFR is downregulated in human breast carcinomas and inversely correlates with metastasis. Notably, in approximately 1,000 nonmetastatic breast tumors, LIFR expression status correlated with metastasis-free, recurrence-free and overall survival outcomes in the patients. These findings identify LIFR as a metastasis suppressor that functions through the Hippo-YAP pathway and has significant prognostic power.", + "TAG_DATA": [ + "58, suppresses {'effect': 'B-negative'}", + "59, metastasis {'phenotype': 'B-metastasis'}", + "83, loss {'perturbing_action': 'B-gene loss-of-function'}", + "84, of {'perturbing_action': 'I-gene loss-of-function'}", + "85, LIFR {'perturbing_action': 'I-gene loss-of-function'}", + "87, nonmetastatic {'context': 'B-transformed cells'}", + "88, breast {'context': 'I-transformed cells'}", + "89, cancer {'context': 'I-transformed cells'}", + "90, cells {'context': 'I-transformed cells'}", + "91, induces {'effect': 'B-positive'}", + "92, migration, {'phenotype': 'B-migration'}", + "93, invasion {'phenotype': 'B-invasion'}", + "95, metastatic {'phenotype': 'B-metastasis'}", + "96, colonization {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "58, suppresses ['l0']", + "59, metastasis ['l0', 'l1', 'l2', 'l3']", + "83, loss ['l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "84, of ['l4', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "85, LIFR ['l5', 'l15', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "87, nonmetastatic ['l6', 'l16', 'l25', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "88, breast ['l1', 'l7', 'l17', 'l26', 'l34', 'l42', 'l43', 'l44', 'l45', 'l46']", + "89, cancer ['l2', 'l8', 'l18', 'l27', 'l35', 'l42', 'l47', 'l48', 'l49', 'l50']", + "90, cells ['l3', 'l9', 'l19', 'l28', 'l36', 'l43', 'l47', 'l51', 'l52', 'l53']", + "91, induces ['l10', 'l20', 'l29', 'l37', 'l44', 'l48', 'l51', 'l54', 'l55']", + "92, migration, ['l11', 'l21', 'l30', 'l38', 'l45', 'l49', 'l52', 'l54', 'l56']", + "93, invasion ['l12', 'l22', 'l31', 'l39', 'l46', 'l50', 'l53', 'l55', 'l56']", + "95, metastatic ['l13', 'l23', 'l32', 'l40', 'l57']", + "96, colonization ['l14', 'l24', 'l33', 'l41', 'l57']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "metastatic", + "colonization" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "breast", + "cancer", + "cells", + "nonmetastatic" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "LIFR" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "nonmetastatic", + "breast", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "LIFR" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "LIFR" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "LIFR" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "LIFR" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "colonization" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "nonmetastatic", + "breast", + "cancer", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "nonmetastatic", + "breast", + "cancer", + "cells" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "nonmetastatic", + "breast", + "cancer", + "cells" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + } + ] + }, + { + "PMID": "22983395", + "TEXT": "The class II α-isoform of phosphatidylinositol 3-kinase (PI3K-C2α) is localized in endosomes, the trans-Golgi network and clathrin-coated vesicles; however, its functional role is not well understood. Global or endothelial-cell-specific deficiency of PI3K-C2α resulted in embryonic lethality caused by defects in sprouting angiogenesis and vascular maturation. PI3K-C2α knockdown in endothelial cells resulted in a decrease in the number of PI3-phosphate-enriched endosomes, impaired endosomal trafficking, defective delivery of VE-cadherin to endothelial cell junctions and defective junction assembly. PI3K-C2α knockdown also impaired endothelial cell signaling, including vascular endothelial growth factor receptor internalization and endosomal RhoA activation. Together, the effects of PI3K-C2α knockdown led to defective endothelial cell migration, proliferation, tube formation and barrier integrity. Endothelial PI3K-C2α deficiency in vivo suppressed postischemic and tumor angiogenesis and diminished vascular barrier function with a greatly augmented susceptibility to anaphylaxis and a higher incidence of dissecting aortic aneurysm formation in response to angiotensin II infusion. Thus, PI3K-C2α has a crucial role in vascular formation and barrier integrity and represents a new therapeutic target for vascular disease.", + "TAG_DATA": [ + "28, endothelial-cell-specific {'perturbing_action': 'B-gene loss-of-function'}", + "29, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "30, of {'perturbing_action': 'I-gene loss-of-function'}", + "31, PI3K-C2α {'perturbing_action': 'I-gene loss-of-function'}", + "45, PI3K-C2α {'perturbing_action': 'B-rnai/knockdown'}", + "46, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "48, endothelial {'context': 'B-cells'}", + "49, cells {'context': 'I-cells'}", + "75, PI3K-C2α {'perturbing_action': 'B-rnai/knockdown'}", + "76, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "79, endothelial {'context': 'B-cells'}", + "80, cell {'context': 'I-cells'}", + "97, PI3K-C2α {'perturbing_action': 'B-rnai/knockdown'}", + "98, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "101, defective {'effect': 'B-negative'}", + "102, endothelial {'context': 'B-cells'}", + "103, cell {'context': 'I-cells'}", + "104, migration, {'phenotype': 'B-migration'}", + "105, proliferation, {'phenotype': 'B-proliferation'}", + "111, Endothelial {'perturbing_action': 'B-gene loss-of-function'}", + "112, PI3K-C2α {'perturbing_action': 'I-gene loss-of-function'}", + "113, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "114, in {'context': 'B-in vivo'}", + "115, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "28, endothelial-cell-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "29, deficiency ['l0', 'l8', 'l9', 'l10', 'l11']", + "30, of ['l1', 'l8', 'l12', 'l13', 'l14', 'l15']", + "31, PI3K-C2α ['l2', 'l9', 'l12', 'l16', 'l17', 'l18', 'l19']", + "45, PI3K-C2α ['l3', 'l16', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "46, knockdown ['l4', 'l13', 'l17', 'l20', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "48, endothelial ['l5', 'l10', 'l14', 'l18', 'l21', 'l30', 'l37', 'l38', 'l39', 'l40']", + "49, cells ['l6', 'l11', 'l15', 'l19', 'l22', 'l31', 'l37']", + "75, PI3K-C2α ['l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "76, knockdown ['l41', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "79, endothelial ['l23', 'l42', 'l51', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "80, cell ['l24', 'l32', 'l38', 'l43', 'l52', 'l60', 'l67', 'l68', 'l69', 'l70', 'l71']", + "97, PI3K-C2α ['l44', 'l53', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "98, knockdown ['l45', 'l54', 'l61', 'l72', 'l78', 'l79', 'l80', 'l81', 'l82']", + "101, defective ['l25', 'l46', 'l55', 'l62', 'l67', 'l73', 'l78', 'l83', 'l84', 'l85', 'l86']", + "102, endothelial ['l26', 'l33', 'l47', 'l56', 'l63', 'l68', 'l74', 'l79', 'l83', 'l87', 'l88', 'l89']", + "103, cell ['l7', 'l27', 'l34', 'l39', 'l48', 'l57', 'l64', 'l69', 'l75', 'l80', 'l84', 'l87', 'l90', 'l91']", + "104, migration, ['l28', 'l35', 'l40', 'l49', 'l58', 'l65', 'l70', 'l76', 'l81', 'l85', 'l88', 'l90', 'l92']", + "105, proliferation, ['l29', 'l36', 'l50', 'l59', 'l66', 'l71', 'l77', 'l82', 'l86', 'l89', 'l91', 'l92']", + "111, Endothelial ['l93', 'l94', 'l95', 'l96']", + "112, PI3K-C2α ['l93', 'l97', 'l98', 'l99']", + "113, deficiency ['l94', 'l97', 'l100', 'l101']", + "114, in ['l95', 'l98', 'l100', 'l102']", + "115, vivo ['l96', 'l99', 'l101', 'l102']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "endothelial-cell-specific", + "deficiency", + "of", + "PI3K-C2α" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PI3K-C2α", + "knockdown" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PI3K-C2α", + "knockdown" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PI3K-C2α", + "knockdown" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PI3K-C2α", + "knockdown" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "defective" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "defective" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Endothelial", + "PI3K-C2α", + "deficiency" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "22972397", + "TEXT": "Unlike activated CD4(+) T cells, resting CD4(+) T cells are highly resistant to productive HIV-1 infection. Early after HIV-1 entry, a major block limits reverse transcription of incoming viral genomes. Here we show that the deoxynucleoside triphosphate triphosphohydrolase SAMHD1 prevents reverse transcription of HIV-1 RNA in resting CD4(+) T cells. SAMHD1 is abundantly expressed in resting CD4(+) T cells circulating in peripheral blood and residing in lymphoid organs. The early restriction to infection in unstimulated CD4(+) T cells is overcome by HIV-1 or HIV-2 virions into which viral Vpx is artificially or naturally packaged, respectively, or by addition of exogenous deoxynucleosides. Vpx-mediated proteasomal degradation of SAMHD1 and elevation of intracellular deoxynucleotide pools precede successful infection by Vpx-carrying HIV. Resting CD4(+) T cells from healthy donors following SAMHD1 silencing or from a patient with Aicardi-Goutières syndrome homozygous for a nonsense mutation in SAMHD1 were permissive for HIV-1 infection. Thus, SAMHD1 imposes an effective restriction to HIV-1 infection in the large pool of noncycling CD4(+) T cells in vivo. Bypassing SAMHD1 was insufficient for the release of viral progeny, implicating other barriers at later stages of HIV replication. Together, these findings may unveil new ways to interfere with the immune evasion and T cell immunopathology of pandemic HIV-1.", + "TAG_DATA": [ + "75, CD4(+) {'context': 'B-cells'}", + "76, T {'context': 'I-cells'}", + "77, cells {'context': 'I-cells'}", + "118, Resting {'context': 'B-cells'}", + "119, CD4(+) {'context': 'I-cells'}", + "120, T {'context': 'I-cells'}", + "121, cells {'context': 'I-cells'}", + "124, donors {'context': 'I-cells'}", + "126, SAMHD1 {'perturbing_action': 'B-rnai/knockdown'}", + "127, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "131, patient {'context': 'B-patient'}", + "135, homozygous {'perturbing_action': 'B-other'}", + "136, for {'perturbing_action': 'I-other'}", + "137, a {'perturbing_action': 'I-other'}", + "138, nonsense {'perturbing_action': 'I-other'}", + "139, mutation {'perturbing_action': 'I-other'}", + "140, in {'perturbing_action': 'I-other'}", + "141, SAMHD1 {'perturbing_action': 'I-other'}", + "161, noncycling {'context': 'B-cells'}", + "162, CD4(+) {'context': 'I-cells'}", + "163, T {'context': 'I-cells'}", + "164, cells {'context': 'I-cells'}", + "165, in {'context': 'B-in vivo'}", + "166, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "75, CD4(+) ['l0', 'l1']", + "76, T ['l0', 'l2']", + "77, cells ['l1', 'l2']", + "118, Resting ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "119, CD4(+) ['l3', 'l9', 'l10', 'l11', 'l12', 'l13']", + "120, T ['l4', 'l9', 'l14', 'l15', 'l16', 'l17']", + "121, cells ['l5', 'l10', 'l14', 'l18', 'l19', 'l20']", + "124, donors ['l6', 'l11', 'l15', 'l18', 'l21', 'l22']", + "126, SAMHD1 ['l7', 'l12', 'l16', 'l19', 'l21', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "127, silencing ['l8', 'l13', 'l17', 'l20', 'l22', 'l23', 'l29', 'l30', 'l31', 'l32', 'l33']", + "131, patient ['l24', 'l29', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "135, homozygous ['l34', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "136, for ['l35', 'l47', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "137, a ['l36', 'l48', 'l59', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "138, nonsense ['l37', 'l49', 'l60', 'l70', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "139, mutation ['l38', 'l50', 'l61', 'l71', 'l80', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "140, in ['l25', 'l30', 'l39', 'l51', 'l62', 'l72', 'l81', 'l89', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "141, SAMHD1 ['l26', 'l31', 'l40', 'l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "161, noncycling ['l41', 'l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l110', 'l111', 'l112', 'l113', 'l114']", + "162, CD4(+) ['l42', 'l54', 'l65', 'l75', 'l84', 'l92', 'l99', 'l105', 'l110', 'l115', 'l116', 'l117', 'l118']", + "163, T ['l27', 'l32', 'l43', 'l55', 'l66', 'l76', 'l85', 'l93', 'l100', 'l106', 'l111', 'l115', 'l119', 'l120', 'l121']", + "164, cells ['l28', 'l33', 'l44', 'l56', 'l67', 'l77', 'l86', 'l94', 'l101', 'l107', 'l112', 'l116', 'l119', 'l122', 'l123']", + "165, in ['l45', 'l57', 'l68', 'l78', 'l87', 'l95', 'l102', 'l108', 'l113', 'l117', 'l120', 'l122', 'l124']", + "166, vivo. ['l46', 'l58', 'l69', 'l79', 'l88', 'l96', 'l103', 'l109', 'l114', 'l118', 'l121', 'l123', 'l124']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Resting", + "CD4(+)", + "T", + "cells", + "donors" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "SAMHD1", + "silencing" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "SAMHD1", + "silencing" + ] + }, + "context": { + "val": "patient", + "words": [ + "patient" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patient" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "homozygous", + "for", + "a", + "nonsense", + "mutation", + "in", + "SAMHD1" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "homozygous", + "for", + "a", + "nonsense", + "mutation", + "in", + "SAMHD1" + ] + }, + "context": { + "val": "cells", + "words": [ + "noncycling", + "CD4(+)", + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "homozygous", + "for", + "a", + "nonsense", + "mutation", + "in", + "SAMHD1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "22922412", + "TEXT": "Hypertension is a cardiovascular risk factor present in over two-thirds of people over age 60 in North America; elevated blood pressure correlates with increased risk of heart attack, stroke and progression to heart and kidney failure. Current therapies are insufficient to control blood pressure in almost half of these patients. The mineralocorticoid receptor (MR), acting in the kidney, is known to regulate blood pressure through aldosterone binding and stimulation of sodium retention. However, recent studies support the concept that the MR also has extrarenal actions and that defects in sodium handling alone do not fully explain the development of hypertension and associated cardiovascular mortality. We and others have identified functional MR in human vascular smooth muscle cells (SMCs), suggesting that vascular MR might directly regulate blood pressure. Here we show that mice with SMC-specific deficiency of the MR have decreased blood pressure as they age without defects in renal sodium handling or vascular structure. Aged mice lacking MR in SMCs (SMC-MR) have reduced vascular myogenic tone, agonist-dependent contraction and expression and activity of L-type calcium channels. Moreover, SMC-MR contributes to angiotensin II–induced vascular oxidative stress, vascular contraction and hypertension. This study identifies a new role for vascular MR in blood pressure control and in vascular aging and supports the emerging hypothesis that vascular tone contributes directly to systemic blood pressure.", + "TAG_DATA": [ + "131, mice {'context': 'B-organism'}", + "133, SMC-specific {'perturbing_action': 'B-gene loss-of-function'}", + "134, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "135, of {'perturbing_action': 'I-gene loss-of-function'}", + "136, the {'perturbing_action': 'I-gene loss-of-function'}", + "137, MR {'perturbing_action': 'I-gene loss-of-function'}", + "155, mice {'context': 'I-organism'}", + "156, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "157, MR {'perturbing_action': 'I-gene loss-of-function'}", + "158, in {'perturbing_action': 'I-gene loss-of-function'}", + "159, SMCs {'context': 'B-cells'}", + "160, (SMC-MR) {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "131, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "133, SMC-specific ['l0', 'l5', 'l6', 'l7', 'l8']", + "134, deficiency ['l1', 'l5', 'l9', 'l10', 'l11']", + "135, of ['l2', 'l6', 'l9', 'l12', 'l13']", + "136, the ['l3', 'l7', 'l10', 'l12', 'l14']", + "137, MR ['l4', 'l8', 'l11', 'l13', 'l14']", + "155, mice ['l15', 'l16', 'l17', 'l18', 'l19']", + "156, lacking ['l15', 'l20', 'l21', 'l22', 'l23']", + "157, MR ['l16', 'l20', 'l24', 'l25', 'l26']", + "158, in ['l17', 'l21', 'l24', 'l27', 'l28']", + "159, SMCs ['l18', 'l22', 'l25', 'l27', 'l29']", + "160, (SMC-MR) ['l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SMC-specific", + "deficiency", + "of", + "the", + "MR", + "lacking", + "in", + "(SMC-MR)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "MR", + "in", + "(SMC-MR)" + ] + }, + "context": { + "val": "cells", + "words": [ + "SMCs" + ] + } + } + ] + }, + { + "PMID": "22820644", + "TEXT": "Sepsis, a systemic inflammatory response to infection, commonly progresses to acute lung injury (ALI), an inflammatory lung disease with high morbidity. We postulated that sepsis-associated ALI is initiated by degradation of the pulmonary endothelial glycocalyx, leading to neutrophil adherence and inflammation. Using intravital microscopy, we found that endotoxemia in mice rapidly induced pulmonary microvascular glycocalyx degradation via tumor necrosis factor-α (TNF-α)-dependent mechanisms. Glycocalyx degradation involved the specific loss of heparan sulfate and coincided with activation of endothelial heparanase, a TNF-α-responsive, heparan sulfate-specific glucuronidase. Glycocalyx degradation increased the availability of endothelial surface adhesion molecules to circulating microspheres and contributed to neutrophil adhesion. Heparanase inhibition prevented endotoxemia-associated glycocalyx loss and neutrophil adhesion and, accordingly, attenuated sepsis-induced ALI and mortality in mice. These findings are potentially relevant to human disease, as sepsis-associated respiratory failure in humans was associated with higher plasma heparan sulfate degradation activity; moreover, heparanase content was higher in human lung biopsies showing diffuse alveolar damage than in normal human lung tissue.", + "TAG_DATA": [ + "49, mice {'context': 'B-organism'}", + "99, neutrophil {'context': 'B-cells'}", + "101, Heparanase {'perturbing_action': 'B-pharmacological inhibition'}", + "102, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "108, neutrophil {'context': 'B-cells'}", + "109, adhesion {'phenotype': 'B-adhesion'}", + "118, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "99, neutrophil ['l0']", + "101, Heparanase ['l1', 'l2', 'l3', 'l4']", + "102, inhibition ['l1', 'l5', 'l6', 'l7']", + "108, neutrophil ['l2', 'l5', 'l8']", + "109, adhesion ['l0', 'l3', 'l6', 'l8']", + "118, mice. ['l4', 'l7']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "neutrophil" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Heparanase", + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "neutrophil" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Heparanase", + "inhibition" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Heparanase", + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "22683779", + "TEXT": "Temporal lobe epilepsy is a common, chronic neurological disorder characterized by recurrent spontaneous seizures. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate post-transcriptional expression of protein-coding mRNAs, which may have key roles in the pathogenesis of neurological disorders. In experimental models of prolonged, injurious seizures (status epilepticus) and in human epilepsy, we found upregulation of miR-134, a brain-specific, activity-regulated miRNA that has been implicated in the control of dendritic spine morphology. Silencing of miR-134 expression in vivo using antagomirs reduced hippocampal CA3 pyramidal neuron dendrite spine density by 21% and rendered mice refractory to seizures and hippocampal injury caused by status epilepticus. Depletion of miR-134 after status epilepticus in mice reduced the later occurrence of spontaneous seizures by over 90% and mitigated the attendant pathological features of temporal lobe epilepsy. Thus, silencing miR-134 exerts prolonged seizure-suppressant and neuroprotective actions; determining whether these are anticonvulsant effects or are truly antiepileptogenic effects requires additional experimentation.", + "TAG_DATA": [ + "71, Silencing {'perturbing_action': 'B-rnai/knockdown'}", + "72, of {'perturbing_action': 'I-rnai/knockdown'}", + "73, miR-134 {'perturbing_action': 'I-rnai/knockdown'}", + "74, expression {'perturbing_action': 'I-rnai/knockdown'}", + "75, in {'context': 'B-in vivo'}", + "76, vivo {'context': 'I-in vivo'}", + "80, hippocampal {'context': 'B-cells'}", + "81, CA3 {'context': 'I-cells'}", + "82, pyramidal {'context': 'I-cells'}", + "83, neuron {'context': 'I-cells'}", + "91, mice {'context': 'B-organism'}", + "102, Depletion {'perturbing_action': 'B-gene loss-of-function'}", + "103, of {'perturbing_action': 'I-gene loss-of-function'}", + "104, miR-134 {'perturbing_action': 'I-gene loss-of-function'}", + "109, mice {'context': 'B-organism'}", + "131, silencing {'perturbing_action': 'B-rnai/knockdown'}", + "132, miR-134 {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "71, Silencing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "72, of ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "73, miR-134 ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "74, expression ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "75, in ['l3', 'l12', 'l20', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "76, vivo ['l4', 'l13', 'l21', 'l28', 'l33', 'l39', 'l40', 'l41', 'l42']", + "80, hippocampal ['l5', 'l14', 'l22', 'l29', 'l34', 'l39', 'l43', 'l44', 'l45']", + "81, CA3 ['l6', 'l15', 'l23', 'l30', 'l35', 'l40', 'l43', 'l46', 'l47', 'l48']", + "82, pyramidal ['l7', 'l16', 'l24', 'l31', 'l36', 'l41', 'l44', 'l46', 'l49', 'l50']", + "83, neuron ['l8', 'l17', 'l25', 'l32', 'l37', 'l42', 'l45', 'l47', 'l49', 'l51']", + "91, mice ['l9', 'l18', 'l26', 'l38', 'l48', 'l50', 'l51']", + "102, Depletion ['l52', 'l53', 'l54', 'l55', 'l56']", + "103, of ['l52', 'l57', 'l58', 'l59', 'l60']", + "104, miR-134 ['l53', 'l57', 'l61', 'l62']", + "109, mice ['l54', 'l58', 'l61']", + "131, silencing ['l55', 'l59', 'l63']", + "132, miR-134 ['l56', 'l60', 'l62', 'l63']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "miR-134", + "expression" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "miR-134", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "hippocampal", + "CA3", + "pyramidal", + "neuron" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "miR-134" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Depletion", + "of", + "miR-134" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "22635007", + "TEXT": "Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma(1), a highly vascularized tumor originating from lymphatic endothelial cells, and of at least two different B cell malignancies(2,3). A dimeric complex formed by the envelope glycoproteins H and L (gH-gL) is required for entry of herpesviruses into host cells(4). We show that the ephrin receptor tyrosine kinase A2 (EphA2) is a cellular receptor for KSHV gH-gL. EphA2 co-precipitated with both gH-gL and KSHV virions. Infection of human epithelial cells with a GFP-expressing recombinant KSHV strain, as measured by FACS analysis, was increased upon overexpression of EphA2. Antibodies against EphA(2) and siRNAs directed against EphA2 inhibited infection of endothelial cells. Pretreatment of KSHV with soluble EphA2 resulted in inhibition of KSHV infection by up to 90%. This marked reduction of KSHV infection was seen with all the different epithelial and endothelial cells used in this study. Similarly, pretreating epithelial or endothelial cells with the soluble EphA2 ligand ephrinA4 impaired KSHV infection. Deletion of the gene encoding EphA2 essentially abolished KSHV infection of mouse endothelial cells. Binding of gH-gL to EphA2 triggered EphA2 phosphorylation and endocytosis, a major pathway of KSHV entry(5,6). Quantitative RT-PCR and in situ histochemistry revealed a close correlation between KSHV infection and EphA2 expression both in cultured cells derived from human Kaposi's sarcoma lesions or unaffected human lymphatic endothelium, and in situ in Kaposi's sarcoma specimens, respectively. Taken together, our results identify EphA2, a tyrosine", + "TAG_DATA": [ + "77, human {'context': 'B-cells'}", + "78, epithelial {'context': 'I-cells'}", + "79, cells {'context': 'I-cells'}", + "94, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "95, of {'perturbing_action': 'I-gene gain-of-function'}", + "96, EphA2. {'perturbing_action': 'I-gene gain-of-function'}", + "101, siRNAs {'perturbing_action': 'B-rnai/knockdown'}", + "102, directed {'perturbing_action': 'I-rnai/knockdown'}", + "103, against {'perturbing_action': 'I-rnai/knockdown'}", + "104, EphA2 {'perturbing_action': 'I-rnai/knockdown'}", + "108, endothelial {'context': 'B-cells'}", + "109, cells. {'context': 'I-cells'}", + "138, epithelial {'context': 'B-cells'}", + "139, and {'context': 'I-cells'}", + "140, endothelial {'context': 'I-cells'}", + "141, cells {'context': 'I-cells'}", + "148, epithelial {'context': 'B-cells'}", + "149, or {'context': 'I-cells'}", + "150, endothelial {'context': 'I-cells'}", + "151, cells {'context': 'I-cells'}", + "161, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "162, of {'perturbing_action': 'I-gene loss-of-function'}", + "163, the {'perturbing_action': 'I-gene loss-of-function'}", + "164, gene {'perturbing_action': 'I-gene loss-of-function'}", + "165, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "166, EphA2 {'perturbing_action': 'I-gene loss-of-function'}", + "172, mouse {'context': 'B-cells'}", + "173, endothelial {'context': 'I-cells'}", + "174, cells. {'context': 'I-cells'}", + "210, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "77, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "78, epithelial ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "79, cells ['l1', 'l6', 'l11']", + "94, overexpression ['l12', 'l13', 'l14', 'l15']", + "95, of ['l2', 'l7', 'l12', 'l16', 'l17', 'l18']", + "96, EphA2. ['l3', 'l8', 'l13', 'l16', 'l19', 'l20']", + "101, siRNAs ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "102, directed ['l21', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "103, against ['l22', 'l34', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "104, EphA2 ['l23', 'l35', 'l46', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "108, endothelial ['l4', 'l9', 'l14', 'l17', 'l19', 'l24', 'l36', 'l47', 'l57', 'l67']", + "109, cells. ['l5', 'l10', 'l11', 'l15', 'l18', 'l20', 'l25', 'l37', 'l48', 'l58', 'l67']", + "138, epithelial ['l26', 'l38', 'l49', 'l59', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "139, and ['l27', 'l39', 'l50', 'l60', 'l68', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "140, endothelial ['l28', 'l40', 'l51', 'l61', 'l69', 'l75', 'l81', 'l82', 'l83', 'l84', 'l85']", + "141, cells ['l29', 'l41', 'l52', 'l62', 'l70', 'l76', 'l81', 'l86', 'l87', 'l88', 'l89']", + "148, epithelial ['l30', 'l42', 'l53', 'l63', 'l71', 'l77', 'l82', 'l86', 'l90', 'l91', 'l92']", + "149, or ['l31', 'l43', 'l54', 'l64', 'l72', 'l78', 'l83', 'l87', 'l90', 'l93', 'l94']", + "150, endothelial ['l32', 'l44', 'l55', 'l65', 'l73', 'l79', 'l84', 'l88', 'l91', 'l93', 'l95']", + "151, cells ['l33', 'l45', 'l56', 'l66', 'l74', 'l80', 'l85', 'l89', 'l92', 'l94', 'l95']", + "161, Deletion ['l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "162, of ['l96', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "163, the ['l97', 'l105', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "164, gene ['l98', 'l106', 'l113', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "165, encoding ['l99', 'l107', 'l114', 'l120', 'l126', 'l127', 'l128', 'l129', 'l130']", + "166, EphA2 ['l100', 'l108', 'l115', 'l121', 'l126', 'l131', 'l132', 'l133', 'l134']", + "172, mouse ['l101', 'l109', 'l116', 'l122', 'l127', 'l131', 'l135', 'l136', 'l137']", + "173, endothelial ['l102', 'l110', 'l117', 'l123', 'l128', 'l132', 'l135', 'l138', 'l139']", + "174, cells. ['l103', 'l111', 'l118', 'l124', 'l129', 'l133', 'l136', 'l138', 'l140']", + "210, cells ['l104', 'l112', 'l119', 'l125', 'l130', 'l134', 'l137', 'l139', 'l140']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "epithelial", + "endothelial", + "cells." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "EphA2.", + "overexpression" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNAs", + "directed", + "against", + "EphA2" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells.", + "epithelial", + "and", + "cells", + "or" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "gene", + "encoding", + "EphA2" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "endothelial", + "cells.", + "cells" + ] + } + } + ] + }, + { + "PMID": "22610279", + "TEXT": "Gastrointestinal bypass surgeries restore metabolic homeostasis in patients with type 2 diabetes and obesity(1), but the underlying mechanisms remain elusive. Duodenal-jejunal bypass surgery (DJB), an experimental surgical technique that excludes the duodenum and proximal jejunum from nutrient transit(1,2), lowers glucose concentrations in nonobese type 2 diabetic rats(2–5). Given that DJB redirects and enhances nutrient flow into the jejunum and that jejunal nutrient sensing affects feeding(6,7), the repositioned jejunum after DJB represents a junction at which nutrients could regulate glucose homeostasis. Here we found that intrajejunal nutrient administration lowered endogenous glucose production in normal rats through a gut-brain-liver network in the presence of basal plasma insulin concentrations. Inhibition of jejunal glucose uptake or formation of long chain fatty acyl-coA negated the metabolic effects of glucose or lipid, respectively, in normal rats, and altered the rapid (2 d) glucose-lowering effect induced by DJB in streptozotocin (STZ)-induced uncontrolled diabetic rats during refeeding. Lastly, in insulin-deficient autoimmune type 1 diabetic rats and STZ-induced diabetic rats, DJB lowered glucose concentrations in 2 d independently of changes in plasma insulin concentrations, food intake and body weight. These data unveil a glucoregulatory role of jejunal nutrient sensing and its relevance in the early improvement of glycemic control after DJB in rat models of uncontrolled diabetes.", + "TAG_DATA": [ + "93, rats {'context': 'I-organism'}", + "129, rats, {'context': 'I-organism'}", + "145, diabetic {'context': 'B-organism'}", + "146, rats {'context': 'I-organism'}", + "151, insulin-deficient {'perturbing_action': 'B-gene loss-of-function', 'context': 'B-organism'}", + "152, autoimmune {'context': 'I-organism'}", + "153, type {'context': 'I-organism'}", + "154, 1 {'context': 'I-organism'}", + "155, diabetic {'context': 'I-organism'}", + "156, rats {'context': 'I-organism'}", + "160, rats, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "129, rats, ['l0', 'l1']", + "145, diabetic ['l0', 'l2']", + "146, rats ['l1', 'l2']", + "151, insulin-deficient ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "152, autoimmune ['l3', 'l9', 'l10', 'l11', 'l12', 'l13']", + "153, type ['l4', 'l9', 'l14', 'l15', 'l16', 'l17']", + "154, 1 ['l5', 'l10', 'l14', 'l18', 'l19', 'l20']", + "155, diabetic ['l6', 'l11', 'l15', 'l18', 'l21', 'l22']", + "156, rats ['l7', 'l12', 'l16', 'l19', 'l21']", + "160, rats, ['l8', 'l13', 'l17', 'l20', 'l22']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "insulin-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "insulin-deficient" + ] + } + } + ] + }, + { + "PMID": "22581287", + "TEXT": "The canonical inhibitor of nuclear factor κB kinase subunit β (IKK-β)–nuclear factor of κ light polypeptide gene enhancer in B cells 1 (NF-κB1) pathway has been well documented to promote insulin resistance; however, the noncanonical NF-κB–inducing kinase (NIK)–NF-κB2 pathway is not well understood in obesity. Additionally, the contribution of counter-regulatory hormones, particularly glucagon, to hyperglycemia in obesity is unclear. Here we show that NIK promotes glucagon responses in obesity. Hepatic NIK was abnormally activated in mice with dietary or genetic obesity. Systemic deletion of Map3k14, encoding NIK, resulted in reduced glucagon responses and hepatic glucose production (HGP). Obesity is associated with high glucagon responses, and liver-specific inhibition of NIK led to lower glucagon responses and HGP and protected against hyperglycemia and glucose intolerance in obese mice. Conversely, hepatocyte-specific overexpression of NIK resulted in higher glucagon responses and HGP. In isolated mouse livers and primary hepatocytes, NIK also promoted glucagon action and glucose production, at least in part by increasing cAMP response element-binding (CREB) stability. Therefore, overactivation of liver NIK in obesity promotes hyperglycemia and glucose intolerance by increasing the hyperglycemic response to glucagon and other factors that activate CREB.", + "TAG_DATA": [ + "75, mice {'context': 'B-organism'}", + "81, Systemic {'perturbing_action': 'B-gene loss-of-function'}", + "82, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "83, of {'perturbing_action': 'I-gene loss-of-function'}", + "84, Map3k14, {'perturbing_action': 'I-gene loss-of-function'}", + "85, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "86, NIK, {'perturbing_action': 'I-gene loss-of-function'}", + "105, liver-specific {'perturbing_action': 'B-pharmacological inhibition'}", + "106, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "107, of {'perturbing_action': 'I-pharmacological inhibition'}", + "108, NIK {'perturbing_action': 'I-pharmacological inhibition'}", + "124, obese {'context': 'B-organism'}", + "125, mice. {'context': 'I-organism'}", + "127, hepatocyte-specific {'perturbing_action': 'B-gene gain-of-function'}", + "128, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "129, of {'perturbing_action': 'I-gene gain-of-function'}", + "130, NIK {'perturbing_action': 'I-gene gain-of-function'}", + "140, mouse {'context': 'B-tissue/organ'}", + "141, livers {'context': 'I-tissue/organ'}", + "143, primary {'context': 'B-cells'}", + "144, hepatocytes, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "81, Systemic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "82, deletion ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "83, of ['l1', 'l10', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "84, Map3k14, ['l2', 'l11', 'l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "85, encoding ['l3', 'l12', 'l21', 'l29', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "86, NIK, ['l4', 'l13', 'l22', 'l30', 'l37', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "105, liver-specific ['l5', 'l14', 'l23', 'l31', 'l38', 'l44', 'l50', 'l51', 'l52', 'l53', 'l54']", + "106, inhibition ['l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l55', 'l56', 'l57', 'l58']", + "107, of ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l59', 'l60', 'l61']", + "108, NIK ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l62', 'l63']", + "124, obese ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l62', 'l64']", + "125, mice. ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l64']", + "127, hepatocyte-specific ['l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "128, overexpression ['l65', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "129, of ['l66', 'l72', 'l78', 'l79', 'l80', 'l81', 'l82']", + "130, NIK ['l67', 'l73', 'l78', 'l83']", + "140, mouse ['l68', 'l74', 'l79', 'l84', 'l85', 'l86']", + "141, livers ['l69', 'l75', 'l80', 'l83', 'l84', 'l87', 'l88']", + "143, primary ['l70', 'l76', 'l81', 'l85', 'l87', 'l89']", + "144, hepatocytes, ['l71', 'l77', 'l82', 'l86', 'l88', 'l89']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Systemic", + "deletion", + "of", + "Map3k14,", + "encoding", + "NIK," + ] + }, + "context": { + "val": "organism", + "words": [ + "obese", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "liver-specific", + "inhibition", + "of", + "NIK" + ] + }, + "context": { + "val": "organism", + "words": [ + "obese", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hepatocyte-specific", + "overexpression", + "of", + "NIK" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "livers" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hepatocyte-specific", + "overexpression", + "of" + ] + }, + "context": { + "val": "cells", + "words": [ + "primary", + "hepatocytes," + ] + } + } + ] + }, + { + "PMID": "22561685", + "TEXT": "Promoting brown adipose tissue (BAT) formation and function may reduce obesity. Recent data link retinoids to energy balance, but a specific role for retinoid metabolism in white versus brown fat is unknown. Retinaldehyde dehydrogenases (Aldhs), also known as aldehyde dehydrogenases, are rate-limiting enzymes that convert retinaldehyde (Rald) to retinoic acid. Here we show that Aldh1a1 is expressed predominately in white adipose tissue (WAT), including visceral depots in mice and humans. Deficiency of the Aldh1a1 gene induced a BAT-like transcriptional program in WAT that drove uncoupled respiration and adaptive thermogenesis. WAT-selective Aldh1a1 knockdown conferred this BAT program in obese mice, limiting weight gain and improving glucose homeostasis. Rald induced uncoupling protein-1 (Ucp1) mRNA and protein levels in white adipocytes by selectively activating the retinoic acid receptor (RAR), recruiting the coactivator PGC-1α and inducing Ucp1 promoter activity. These data establish Aldh1a1 and its substrate Rald as previously unrecognized determinants of adipocyte plasticity and adaptive thermogenesis, which may have potential therapeutic implications.", + "TAG_DATA": [ + "70, Deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "71, of {'perturbing_action': 'I-gene loss-of-function'}", + "72, the {'perturbing_action': 'I-gene loss-of-function'}", + "73, Aldh1a1 {'perturbing_action': 'I-gene loss-of-function'}", + "74, gene {'perturbing_action': 'I-gene loss-of-function'}", + "89, WAT-selective {'perturbing_action': 'B-rnai/knockdown'}", + "90, Aldh1a1 {'perturbing_action': 'I-rnai/knockdown'}", + "91, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "97, obese {'context': 'B-organism'}", + "98, mice, {'context': 'I-organism'}", + "116, white {'context': 'B-cells'}", + "117, adipocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "70, Deficiency ['l0', 'l1', 'l2', 'l3']", + "71, of ['l0', 'l4', 'l5', 'l6']", + "72, the ['l1', 'l4', 'l7', 'l8']", + "73, Aldh1a1 ['l2', 'l5', 'l7', 'l9']", + "74, gene ['l3', 'l6', 'l8', 'l9']", + "89, WAT-selective ['l10', 'l11', 'l12', 'l13']", + "90, Aldh1a1 ['l10', 'l14', 'l15', 'l16']", + "91, knockdown ['l11', 'l14', 'l17', 'l18']", + "97, obese ['l12', 'l15', 'l17', 'l19']", + "98, mice, ['l13', 'l16', 'l18', 'l19']", + "116, white ['l20']", + "117, adipocytes ['l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "WAT-selective", + "Aldh1a1", + "knockdown" + ] + }, + "context": { + "val": "organism", + "words": [ + "obese", + "mice," + ] + } + } + ] + }, + { + "PMID": "22504483", + "TEXT": "Adenosine signaling has been implicated in cardiac adaptation to limited oxygen availability. In a wide search for adenosine receptor A2b (Adora2b)-elicited cardioadaptive responses, we identified the circadian rhythm protein period 2 (Per2) as an Adora2b target. Adora2b signaling led to Per2 stabilization during myocardial ischemia, and in this setting, Per2(-/-) mice had larger infarct sizes compared to wild-type mice and loss of the cardioprotection conferred by ischemic preconditioning. Metabolic studies uncovered a limited ability of ischemic hearts in Per2(-/-) mice to use carbohydrates for oxygen-efficient glycolysis. This impairment was caused by a failure to stabilize hypoxia-inducible factor-1α (Hif-1α). Moreover, stabilization of Per2 in the heart by exposing mice to intense light resulted in the transcriptional induction of glycolytic enzymes and Per2-dependent cardioprotection from ischemia. Together, these studies identify adenosine-elicited stabilization of Per2 in the control of HIF-dependent cardiac metabolism and ischemia tolerance and implicate Per2 stabilization as a potential new strategy for treating myocardial ischemia.", + "TAG_DATA": [ + "49, Per2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "50, mice {'context': 'B-organism'}", + "58, mice {'context': 'B-organism'}", + "76, hearts {'context': 'B-tissue/organ'}", + "78, Per2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "79, mice {'context': 'B-organism'}", + "104, heart {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "49, Per2(-/-) ['l0', 'l1', 'l2']", + "50, mice ['l0', 'l3']", + "58, mice ['l1', 'l3']", + "76, hearts ['l2', 'l4', 'l5']", + "78, Per2(-/-) ['l4', 'l6']", + "79, mice ['l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Per2(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Per2(-/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hearts" + ] + } + } + ] + }, + { + "PMID": "22484808", + "TEXT": "Age-related macular degeneration (AMD) is the leading cause of central vision loss worldwide. Drusen accumulation is the major pathological hallmark common to both dry and wet AMD. Although activation of the immune system has been implicated in disease progression, the pathways involved are unclear. Here we show that drusen isolated from donor AMD eyes activates the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, causing secretion of interleukin-1b (IL-1b) and IL-18. Drusen component C1Q also activates the NLRP3 inflammasome. Moreover, the oxidative-stress-related protein-modification carboxyethylpyrrole (CEP), a biomarker of AMD, primes the inflammasome. We found cleaved caspase-1 and NLRP3 in activated macrophages in the retinas of mice immunized with CEP-adducted mouse serum albumin, modeling a dry-AMD–like pathology. We show that laser-induced choroidal neovascularization (CNV), a mouse model of wet AMD, is exacerbated in Nlrp3(-/-) but not Il1r1(-/-) mice, directly implicating IL-18 in the regulation of CNV development. These findings indicate a protective role for NLRP3 and IL-18 in the progression of AMD.", + "TAG_DATA": [ + "101, macrophages {'context': 'B-cells'}", + "104, retinas {'context': 'B-tissue/organ'}", + "106, mice {'context': 'B-organism'}", + "133, Nlrp3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "136, Il1r1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "137, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "101, macrophages ['l0', 'l1']", + "104, retinas ['l0', 'l2']", + "106, mice ['l1', 'l2']", + "133, Nlrp3(-/-) ['l3', 'l4']", + "136, Il1r1(-/-) ['l3', 'l5']", + "137, mice, ['l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nlrp3(-/-)", + "Il1r1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "22447076", + "TEXT": "It is unclear whether the ability of the innate immune system to recognize distinct ligands from a single microbial pathogen via multiple pattern recognition receptors (PRRs) triggers common pathways or differentially triggers specific host responses. In the human mycobacterial infection leprosy, we found that activation of monocytes via nucleotide-binding oligomerization domain-containing protein 2 (NOD2) by its ligand muramyl dipeptide, as compared to activation via heterodimeric Toll-like receptor 2 and Toll-like receptor 1 (TLR2/1) by triacylated lipopeptide, preferentially induced differentiation into dendritic cells (DCs), which was dependent on a previously unknown interleukin-32 (IL-32)-dependent mechanism. Notably, IL-32 was sufficient to induce monocytes to rapidly differentiate into DCs, which were more efficient than granulocyte-macrophage colony-stimulating factor (GM-CSF)-derived DCs in presenting antigen to major histocompatibility complex (MHC) class I-restricted CD8(+) T cells. Expression of NOD2 and IL-32 and the frequency of CD1b(+) DCs at the site of leprosy infection correlated with the clinical presentation; they were greater in patients with limited as compared to progressive disease. The addition of recombinant IL-32 restored NOD2-induced DC differentiation in patients with the progressive form of leprosy. In conclusion, the NOD2 ligand-induced, IL-32-dependent DC differentiation pathway contributes a key and specific mechanism for host defense against microbial infection in humans.", + "TAG_DATA": [ + "77, induced {'effect': 'B-positive'}", + "78, differentiation {'phenotype': 'B-differentiation'}", + "80, dendritic {'context': 'B-cells'}", + "81, cells {'context': 'I-cells'}", + "98, induce {'effect': 'B-positive'}", + "99, monocytes {'context': 'B-cells'}", + "102, differentiate {'phenotype': 'B-differentiation'}", + "104, DCs, {'context': 'B-cells'}", + "114, DCs {'context': 'I-cells'}", + "125, CD8(+) {'context': 'B-cells'}", + "126, T {'context': 'I-cells'}", + "127, cells. {'context': 'I-cells'}", + "167, restored {'effect': 'B-rescues'}", + "169, DC {'context': 'B-cells'}", + "170, differentiation {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "77, induced ['l0', 'l1', 'l2']", + "78, differentiation ['l0', 'l3', 'l4']", + "80, dendritic ['l1', 'l3', 'l5', 'l6', 'l7', 'l8', 'l9']", + "81, cells ['l2', 'l4', 'l5', 'l10', 'l11']", + "98, induce ['l6', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "99, monocytes ['l7', 'l12', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "102, differentiate ['l8', 'l10', 'l13', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "104, DCs, ['l9', 'l11', 'l14', 'l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "114, DCs ['l15', 'l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "125, CD8(+) ['l16', 'l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "126, T ['l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "127, cells. ['l18', 'l24', 'l29', 'l33', 'l36', 'l38', 'l39']", + "167, restored ['l40', 'l41']", + "169, DC ['l40', 'l42']", + "170, differentiation ['l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced", + "induce" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "differentiate" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells", + "monocytes", + "DCs,", + "DCs", + "CD8(+)", + "T", + "cells." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "differentiate" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells", + "monocytes", + "DCs,", + "DCs", + "CD8(+)", + "T", + "cells.", + "DC" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + }, + "context": { + "val": "cells", + "words": [ + "DC" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "22406747", + "TEXT": "Acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML), characterized by the t(15;17)-associated PML-RARA fusion, has been successfully treated with therapy utilizing all-trans-retinoic acid (ATRA) to differentiate leukemic blasts. However, among patients with non-APL AML, ATRA-based treatment has not been effective. Here we show that, through epigenetic reprogramming, inhibitors of lysine-specific demethylase 1 (LSD1, also called KDM1A), including tranylcypromine (TCP), unlocked the ATRA-driven therapeutic response in non-APL AML. LSD1 inhibition did not lead to a large-scale increase in histone 3 Lys4 dimethylation (H3K4(me2)) across the genome, but it did increase H3K4(me2) and expression of myeloid-differentiation-associated genes. Notably, treatment with ATRA plus TCP markedly diminished the engraftment of primary human AML cells in vivo in nonobese diabetic (NOD)-severe combined immunodeficient (SCID) mice, suggesting that ATRA in combination with TCP may target leukemia-initiating cells. Furthermore, initiation of ATRA plus TCP treatment 15 d after engraftment of human AML cells in NOD-SCID γ (with interleukin-2 (IL-2) receptor γ chain deficiency) mice also revealed the ATRA plus TCP drug combination to have a potent anti-leukemic effect that was superior to treatment with either drug alone. These data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to AML pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for new combinatorial therapies for AML.", + "TAG_DATA": [ + "72, LSD1 {'perturbing_action': 'B-pharmacological inhibition'}", + "73, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "111, primary {'context': 'B-transformed cells'}", + "112, human {'context': 'I-transformed cells'}", + "113, AML {'context': 'I-transformed cells'}", + "114, cells {'context': 'I-transformed cells'}", + "115, in {'context': 'B-in vivo'}", + "116, vivo {'context': 'I-in vivo'}", + "118, nonobese {'context': 'B-organism'}", + "119, diabetic {'context': 'I-organism'}", + "120, (NOD)-severe {'context': 'I-organism'}", + "121, combined {'context': 'I-organism'}", + "122, immunodeficient {'context': 'I-organism'}", + "123, (SCID) {'context': 'I-organism'}", + "124, mice, {'context': 'I-organism'}", + "148, human {'context': 'B-transformed cells'}", + "149, AML {'context': 'I-transformed cells'}", + "150, cells {'context': 'I-transformed cells'}", + "152, NOD-SCID {'context': 'B-organism'}", + "153, γ {'context': 'I-organism'}", + "161, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "72, LSD1 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "73, inhibition ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "111, primary ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "112, human ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "113, AML ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54']", + "114, cells ['l4', 'l17', 'l29', 'l40', 'l50', 'l55', 'l56', 'l57']", + "115, in ['l5', 'l18', 'l30', 'l41', 'l51', 'l55', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "116, vivo ['l6', 'l19', 'l31', 'l42', 'l52', 'l56', 'l58', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "118, nonobese ['l7', 'l20', 'l32', 'l43', 'l59', 'l66', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "119, diabetic ['l8', 'l21', 'l33', 'l44', 'l60', 'l67', 'l73', 'l79', 'l80', 'l81', 'l82', 'l83']", + "120, (NOD)-severe ['l9', 'l22', 'l34', 'l45', 'l61', 'l68', 'l74', 'l79', 'l84', 'l85', 'l86', 'l87']", + "121, combined ['l10', 'l23', 'l35', 'l46', 'l62', 'l69', 'l75', 'l80', 'l84', 'l88', 'l89', 'l90']", + "122, immunodeficient ['l11', 'l24', 'l36', 'l47', 'l63', 'l70', 'l76', 'l81', 'l85', 'l88', 'l91', 'l92']", + "123, (SCID) ['l12', 'l25', 'l37', 'l48', 'l53', 'l64', 'l71', 'l77', 'l82', 'l86', 'l89', 'l91', 'l93']", + "124, mice, ['l13', 'l26', 'l38', 'l49', 'l54', 'l57', 'l65', 'l72', 'l78', 'l83', 'l87', 'l90', 'l92', 'l93']", + "148, human ['l94', 'l95']", + "149, AML ['l94', 'l96']", + "150, cells ['l95', 'l96']", + "152, NOD-SCID ['l97', 'l98']", + "153, γ ['l97', 'l99']", + "161, mice ['l98', 'l99']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "LSD1", + "inhibition" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "human", + "AML", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "LSD1", + "inhibition" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "LSD1", + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "nonobese", + "diabetic", + "(NOD)-severe", + "combined", + "immunodeficient", + "(SCID)", + "mice," + ] + } + } + ] + }, + { + "PMID": "22406746", + "TEXT": "Kidney fibrosis is a common process that leads to the progression of various types of kidney disease. We used an integrated computational and experimental systems biology approach to identify protein kinases that regulate gene expression changes in the kidneys of human immunodeficiency virus (HIV) transgenic mice (Tg26 mice), which have both tubulointerstitial fibrosis and glomerulosclerosis. We identified homeo-domain interacting protein kinase 2 (HIPK2) as a key regulator of kidney fibrosis. HIPK2 was upregulated in the kidneys of Tg26 mice and in those of patients with various kidney diseases. HIV infection increased the protein concentrations of HIPK2 by promoting oxidative stress, which inhibited the seven in absentia homolog 1 (SIAH1)-mediated proteasomal degradation of HIPK2. HIPK2 induced apoptosis and the expression of epithelial-to-mesenchymal transition markers in kidney epithelial cells by activating the p53, transforming growth factor β (TGF-β)-SMAD family member 3 (Smad3) and Wnt-Notch pathways. Knockout of HIPK2 improved renal function and attenuated proteinuria and kidney fibrosis in Tg26 mice, as well as in other murine models of kidney fibrosis. We therefore conclude that HIPK2 is a potential target for anti-fibrosis therapy.", + "TAG_DATA": [ + "45, mice {'context': 'B-organism'}", + "114, induced {'effect': 'B-positive'}", + "115, apoptosis {'phenotype': 'B-apoptosis'}", + "124, kidney {'context': 'B-cells'}", + "125, epithelial {'context': 'I-cells'}", + "126, cells {'context': 'I-cells'}", + "143, Knockout {'perturbing_action': 'B-gene loss-of-function'}", + "144, of {'perturbing_action': 'I-gene loss-of-function'}", + "145, HIPK2 {'perturbing_action': 'I-gene loss-of-function'}", + "156, Tg26 {'context': 'B-organism'}", + "157, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "114, induced ['l0', 'l1', 'l2', 'l3']", + "115, apoptosis ['l0', 'l4', 'l5', 'l6']", + "124, kidney ['l1', 'l4', 'l7', 'l8']", + "125, epithelial ['l2', 'l5', 'l7', 'l9']", + "126, cells ['l3', 'l6', 'l8', 'l9']", + "143, Knockout ['l10', 'l11', 'l12', 'l13']", + "144, of ['l10', 'l14', 'l15', 'l16']", + "145, HIPK2 ['l11', 'l14', 'l17', 'l18']", + "156, Tg26 ['l12', 'l15', 'l17', 'l19']", + "157, mice, ['l13', 'l16', 'l18', 'l19']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "kidney", + "epithelial", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "kidney", + "epithelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Knockout", + "of", + "HIPK2" + ] + }, + "context": { + "val": "organism", + "words": [ + "Tg26", + "mice," + ] + } + } + ] + }, + { + "PMID": "22388090", + "TEXT": "Bone homeostasis is maintained by the balance between osteoblastic bone formation and osteoclastic bone resorption. Osteoclasts are multinucleated cells that are formed by mononuclear preosteoclast fusion. Fat-soluble vitamins such as vitamin D are pivotal in maintaining skeletal integrity. However, the role of vitamin E in bone remodeling is unknown. Here, we show that mice deficient in α-tocopherol transfer protein (Ttpa(-/-) mice), a mouse model of genetic vitamin E deficiency, have high bone mass as a result of a decrease in bone resorption. Cell-based assays indicated that α-tocopherol stimulated osteoclast fusion, independent of its antioxidant capacity, by inducing the expression of dendritic-cell-specific transmembrane protein, an essential molecule for osteoclast fusion, through activation of mitogen-activated protein kinase 14 (p38) and microphthalmia-associated transcription factor, as well as its direct recruitment to the Tm7sf4 (a gene encoding DC-STAMP) promoter. Indeed, the bone abnormality seen in Ttpa(-/-) mice was rescued by a Tm7sf4 transgene. Moreover, wild-type mice or rats fed an α-tocopherol-supplemented diet, which contains a comparable amount of α-tocopherol to supplements consumed by many people, lost bone mass. These results show that serum vitamin E is a determinant of bone mass through its regulation of osteoclast fusion.", + "TAG_DATA": [ + "53, mice {'context': 'B-organism'}", + "54, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "55, in {'perturbing_action': 'I-gene loss-of-function'}", + "56, α-tocopherol {'perturbing_action': 'I-gene loss-of-function'}", + "57, transfer {'perturbing_action': 'I-gene loss-of-function'}", + "58, protein {'perturbing_action': 'I-gene loss-of-function'}", + "59, (Ttpa(-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "60, mice), {'perturbing_action': 'I-gene loss-of-function'}", + "141, Ttpa(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "142, mice {'context': 'B-organism'}", + "147, Tm7sf4 {'perturbing_action': 'B-gene gain-of-function'}", + "148, transgene. {'perturbing_action': 'I-gene gain-of-function'}", + "151, mice {'context': 'B-organism'}", + "153, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "53, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "54, deficient ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "55, in ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "56, α-tocopherol ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "57, transfer ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "58, protein ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "59, (Ttpa(-/-) ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "60, mice), ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "141, Ttpa(-/-) ['l28', 'l29', 'l30']", + "142, mice ['l28']", + "147, Tm7sf4 ['l29', 'l31']", + "148, transgene. ['l30', 'l31']", + "151, mice ['l32']", + "153, rats ['l32']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "α-tocopherol", + "transfer", + "protein", + "(Ttpa(-/-)", + "mice),", + "Ttpa(-/-)" + ] + } + } + ] + }, + { + "PMID": "22366952", + "TEXT": "Celiac disease is an immune-mediated disorder in which mucosal autoantibodies to the enzyme transglutaminase 2 (TG2) are generated in response to the exogenous antigen gluten in individuals who express human leukocyte antigen HLA-DQ2 or HLA-DQ8 (ref. 3). We assessed in a comprehensive and nonbiased manner the IgA anti-TG2 response by expression cloning of the antibody repertoire of ex vivo-isolated intestinal antibody-secreting cells (ASCs). We found that TG2-specific plasma cells are markedly expanded within the duodenal mucosa in individuals with active celiac disease. TG2-specific antibodies were of high affinity yet showed little adaptation by somatic mutations. Unlike infection-induced peripheral blood plasmablasts, the TG2-specific ASCs had not recently proliferated and were not short-lived ex vivo. Altogether, these observations demonstrate that there is a germline repertoire with high affinity for TG2 that may favor massive generation of autoreactive B cells. TG2-specific antibodies did not block enzymatic activity and served as substrates for TG2-mediated crosslinking when expressed as IgD or IgM but not as IgA1 or IgG1. This could result in preferential recruitment of plasma cells from naive IgD- and IgM-expressing B cells, thus possibly explaining why the antibody response to TG2 bears signs of a primary immune response despite the disease chronicity.", + "TAG_DATA": [ + "97, peripheral {'context': 'B-cells'}", + "98, blood {'context': 'I-cells'}", + "99, plasmablasts, {'context': 'I-cells'}", + "102, ASCs {'context': 'B-cells'}", + "104, not {'effect': 'B-no effect'}", + "105, recently {'effect': 'I-no effect'}", + "106, proliferated {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "97, peripheral ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "98, blood ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "99, plasmablasts, ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "102, ASCs ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "104, not ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "105, recently ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "106, proliferated ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "peripheral", + "blood", + "plasmablasts,", + "ASCs" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "recently" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "peripheral", + "blood", + "plasmablasts,", + "ASCs" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferated" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "recently" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferated" + ] + } + } + ] + }, + { + "PMID": "22366949", + "TEXT": "The TLX1 and TLX3 transcription factor oncogenes have a key role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL). Here we used reverse engineering of global transcriptional networks to decipher the oncogenic regulatory circuit controlled by TLX1 and TLX3. This systems biology analysis defined T cell leukemia homeobox 1 (TLX1) and TLX3 as master regulators of an oncogenic transcriptional circuit governing T-ALL. Notably, a network structure analysis of this hierarchical network identified RUNX1 as a key mediator of the T-ALL induced by TLX1 and TLX3 and predicted a tumor-suppressor role for RUNX1 in T cell transformation. Consistent with these results, we identified recurrent somatic loss-of-function mutations in RUNX1 in human T-ALL. Overall, these results place TLX1 and TLX3 at the top of an oncogenic transcriptional network controlling leukemia development, show the power of network analyses to identify key elements in the regulatory circuits governing human cancer and identify RUNX1 as a tumor-suppressor gene in T-ALL.", + "TAG_DATA": [ + "95, T {'context': 'B-cells'}", + "96, cell {'context': 'B-cells'}", + "97, transformation. {'phenotype': 'B-transformation'}" + ], + "LINK_DATA": [ + "95, T ['l0', 'l1']", + "96, cell ['l0', 'l2']", + "97, transformation. ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation." + ] + } + } + ] + }, + { + "PMID": "22344297", + "TEXT": "For centuries, opioid drugs have been the mainstay of chronic pain treatment. However, over time analgesic tolerance develops, leaving few treatment options. Here we show that platelet-derived growth factor receptor-β (PDGFR-β)-mediated signaling plays a key role in morphine tolerance. PDGFR-β inhibition selectively eliminates morphine tolerance in rats. PDGFR-β inhibitors are widely used and well tolerated, suggesting that clinical translation of our findings could reduce the suffering endured by individuals with intractable pain.", + "TAG_DATA": [ + "39, PDGFR-β {'perturbing_action': 'B-pharmacological inhibition'}", + "40, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "46, rats. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "39, PDGFR-β ['l0', 'l1']", + "40, inhibition ['l0', 'l2']", + "46, rats. ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PDGFR-β", + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats." + ] + } + } + ] + }, + { + "PMID": "22327624", + "TEXT": "We identified in-frame fusion transcripts of KIF5B (the kinesin family 5B gene) and the RET oncogene, which are present in 1-2% of lung adenocarcinomas (LADCs) from people from Japan and the United States, using whole-transcriptome sequencing. The KIF5B-RET fusion leads to aberrant activation of RET kinase and is considered to be a new driver mutation of LADC because it segregates from mutations or fusions in EGFR, KRAS, HER2 and ALK, and a RET tyrosine kinase inhibitor, vandetanib, suppresses the fusion-induced anchorage-independent growth activity of NIH3T3 cells.", + "TAG_DATA": [ + "77, suppresses {'effect': 'B-negative'}", + "80, anchorage-independent {'phenotype': 'B-autophagy'}", + "81, growth {'phenotype': 'I-cell growth'}", + "84, NIH3T3 {'context': 'B-cells'}", + "85, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "77, suppresses ['l0', 'l1', 'l2', 'l3']", + "80, anchorage-independent ['l0', 'l4', 'l5', 'l6']", + "81, growth ['l1', 'l4', 'l7', 'l8']", + "84, NIH3T3 ['l2', 'l5', 'l7', 'l9']", + "85, cells. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "anchorage-independent" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + }, + "context": { + "val": "cells", + "words": [ + "NIH3T3", + "cells." + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "anchorage-independent" + ] + }, + "context": { + "val": "cells", + "words": [ + "NIH3T3", + "cells." + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + }, + "context": { + "val": "cells", + "words": [ + "NIH3T3", + "cells." + ] + } + } + ] + }, + { + "PMID": "22245782", + "TEXT": "Blood pressure regulation is crucial for the maintenance of health, and hypertension is a risk factor for myocardial infarction, heart failure, stroke and renal disease. Nitric oxide (NO) and prostacyclin trigger well-defined vasodilator pathways; however, substantial vasorelaxation in response to agents such as acetylcholine persists when the synthesis of these molecules is prevented. This remaining vasorelaxation activity, termed endothelium-derived hyperpolarizing factor (EDHF), is more prevalent in resistance than in conduit blood vessels and is considered a major mechanism for blood pressure control. Hydrogen peroxide (H2O2) has been shown to be a major component of EDHF in several vascular beds in multiple species, including in humans. H2O2 causes the formation of a disulfide bond between the two α subunits of protein kinase G I-α (PKGI-α), which activates the kinase independently of the NO-cyclic guanosine monophosphate (cGMP) pathway and is coupled to vasodilation. To test the importance of PKGI-α oxidation in the EDHF mechanism and blood pressure control in vivo, we generated a knock-in mouse expressing only a C42S 'redox-dead' version of PKGI-α. This amino acid substitution, a single-atom change (an oxygen atom replacing a sulfur atom), blocked the vasodilatory action of H2O2 on resistance vessels and resulted in hypertension in vivo.", + "TAG_DATA": [ + "161, knock-in {'perturbing_action': 'B-rnai/knockdown'}", + "162, mouse {'context': 'B-organism'}", + "170, PKGI-α. {'perturbing_action': 'I-rnai/knockdown'}", + "192, resistance {'context': 'B-tissue/organ'}", + "193, vessels {'context': 'I-tissue/organ'}", + "198, in {'context': 'B-in vivo'}", + "199, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "161, knock-in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "162, mouse ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "164, only ['l1', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "165, a ['l2', 'l10', 'l16', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "168, version ['l3', 'l11', 'l17', 'l24', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "169, of ['l4', 'l12', 'l18', 'l25', 'l31', 'l37', 'l38', 'l39', 'l40', 'l41']", + "170, PKGI-α. ['l5', 'l13', 'l19', 'l26', 'l32', 'l37', 'l42', 'l43', 'l44', 'l45']", + "192, resistance ['l6', 'l14', 'l20', 'l27', 'l33', 'l38', 'l42', 'l46', 'l47', 'l48']", + "193, vessels ['l7', 'l15', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l49', 'l50']", + "198, in ['l8', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l51']", + "199, vivo. ['l9', 'l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l51']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knock-in", + "PKGI-α." + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knock-in", + "PKGI-α." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "resistance", + "vessels" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knock-in", + "PKGI-α." + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "22157681", + "TEXT": "The involvement of the MET oncogene in de novo and acquired resistance of non-small cell lung cancers (NSCLCs) to tyrosine kinase inhibitors (TKIs) has previously been reported, but the precise mechanism by which MET overexpression contributes to TKI-resistant NSCLC remains unclear. MicroRNAs (miRNAs) negatively regulate gene expression, and their dysregulation has been implicated in tumorigenesis. To understand their role in TKI-resistant NSCLCs, we examined changes in miRNA that are mediated by tyrosine kinase receptors. Here we report that miR-30b, miR-30c, miR-221 and miR-222 are modulated by both epidermal growth factor (EGF) and MET receptors, whereas miR-103 and miR-203 are controlled only by MET. We showed that these miRNAs have important roles in gefitinib-induced apoptosis and epithelial-mesenchymal transition of NSCLC cells in vitro and in vivo by inhibiting the expression of the genes encoding BCL2-like 11 (BIM), apoptotic peptidase activating factor 1 (APAF-1), protein kinase C ɛ (PKC-ɛ) and sarcoma viral oncogene homolog (SRC). These findings suggest that modulation of specific miRNAs may provide a therapeutic approach for the treatment of NSCLCs.", + "TAG_DATA": [ + "112, gefitinib-induced {'effect': 'B-positive'}", + "113, apoptosis {'phenotype': 'B-apoptosis'}", + "115, epithelial-mesenchymal {'phenotype': 'B-epithelial-mesenchymal transition'}", + "116, transition {'phenotype': 'I-epithelial-mesenchymal transition'}", + "118, NSCLC {'context': 'B-transformed cells'}", + "119, cells {'context': 'I-transformed cells'}", + "120, in {'context': 'B-in vitro'}", + "121, vitro {'context': 'I-in vitro'}", + "123, in {'context': 'B-in vivo'}", + "124, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "112, gefitinib-induced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "113, apoptosis ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "115, epithelial-mesenchymal ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "116, transition ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "118, NSCLC ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "119, cells ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "120, in ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "121, vitro ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "123, in ['l28']", + "124, vivo ['l28']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "gefitinib-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "gefitinib-induced" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "epithelial-mesenchymal", + "transition" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "gefitinib-induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "NSCLC", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "gefitinib-induced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "NSCLC", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "epithelial-mesenchymal", + "transition" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "NSCLC", + "cells" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "epithelial-mesenchymal", + "transition" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "22138753", + "TEXT": "Studies of ligand-receptor binding and the development of receptor antagonists would benefit greatly from imaging techniques that translate directly from cell-based assays to living animals. We used Gaussia luciferase protein fragment complementation to quantify the binding of chemokine (C-X-C motif) ligand 12 (CXCL12) to chemokine (C-X-C motif) receptor 4 (CXCR4) and CXCR7. Studies established that small-molecule inhibitors of CXCR4 or CXCR7 specifically blocked CXCL12 binding in cell-based assays and revealed differences in kinetics of inhibiting chemokine binding to each receptor. Bioluminescence imaging showed CXCL12-CXCR7 binding in primary and metastatic tumors in a mouse model of breast cancer. We used this imaging technique to quantify drug-mediated inhibition of CXCL12-CXCR4 binding in living mice. We expect this imaging technology to advance research in areas such as ligand-receptor interactions and the development of new therapeutic agents in cell-based assays and small animals.", + "TAG_DATA": [ + "55, small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "56, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "57, of {'perturbing_action': 'I-pharmacological inhibition'}", + "58, CXCR4 {'perturbing_action': 'I-pharmacological inhibition'}", + "59, or {'perturbing_action': 'I-pharmacological inhibition'}", + "60, CXCR7 {'perturbing_action': 'I-pharmacological inhibition'}", + "86, primary {'context': 'B-neoplasm'}", + "87, and {'context': 'I-neoplasm'}", + "88, metastatic {'context': 'I-neoplasm'}", + "89, tumors {'context': 'I-neoplasm'}", + "92, mouse {'context': 'B-neoplasm'}", + "93, model {'context': 'I-neoplasm'}", + "94, of {'context': 'I-neoplasm'}", + "95, breast {'context': 'I-neoplasm'}", + "96, cancer. {'context': 'I-neoplasm'}", + "110, living {'context': 'B-organism'}", + "111, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "55, small-molecule ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "56, inhibitors ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "57, of ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "58, CXCR4 ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "59, or ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "60, CXCR7 ['l4', 'l17', 'l29', 'l40', 'l50', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "86, primary ['l5', 'l18', 'l30', 'l41', 'l51', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "87, and ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "88, metastatic ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "89, tumors ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l90', 'l91', 'l92', 'l93', 'l94']", + "92, mouse ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l95', 'l96', 'l97', 'l98']", + "93, model ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l99', 'l100', 'l101']", + "94, of ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l102', 'l103']", + "95, breast ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l104']", + "96, cancer. ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l104']", + "110, living ['l105']", + "111, mice. ['l105']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "inhibitors", + "of", + "CXCR4", + "or", + "CXCR7" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "primary", + "and", + "metastatic", + "tumors", + "mouse", + "model", + "of", + "breast", + "cancer." + ] + } + } + ] + }, + { + "PMID": "22138752", + "TEXT": "Malignant transformation, invasion and angiogenesis rely on the coordinated reprogramming of gene expression in the cells from which the tumor originated. Although deregulated gene expression has been extensively studied at genomic and epigenetic scales, the contribution of the regulation of mRNA-specific translation to this reprogramming is not well understood. Here we show that cytoplasmic polyadenylation element binding protein 4 (CPEB4), an RNA binding protein that mediates meiotic mRNA cytoplasmic polyadenylation and translation, is overexpressed in pancreatic ductal adenocarcinomas and glioblastomas, where it supports tumor growth, vascularization and invasion. We also show that, in pancreatic tumors, the pro-oncogenic functions of CPEB4 originate in the translational activation of mRNAs that are silenced in normal tissue, including the mRNA of tissue plasminogen activator, a key contributor to pancreatic ductal adenocarcinoma malignancy. Taken together, our results document a key role for post-transcriptional gene regulation in tumor development and describe a detailed mechanism for gene expression reprogramming underlying malignant tumor progression.", + "TAG_DATA": [ + "82, supports {'effect': 'B-positive'}", + "83, tumor {'phenotype': 'B-tumour growth'}", + "84, growth, {'phenotype': 'I-tumour growth'}", + "87, invasion. {'phenotype': 'B-invasion'}" + ], + "LINK_DATA": [ + "82, supports ['l0', 'l1', 'l2']", + "83, tumor ['l0', 'l3', 'l4']", + "84, growth, ['l1', 'l3', 'l5']", + "87, invasion. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "supports" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "supports" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion." + ] + } + } + ] + }, + { + "PMID": "22127134", + "TEXT": "The presentation pathways by which allogeneic peptides induce graft-versus-host disease (GVHD) are unclear. We developed a bone marrow transplant (BMT) system in mice whereby presentation of a processed recipient peptide within major histocompatibility complex (MHC) class II molecules could be spatially and temporally quantified. Whereas donor antigen presenting cells (APCs) could induce lethal acute GVHD via MHC class II, recipient APCs were 100-1,000 times more potent in this regard. After myeloablative irradiation, T cell activation and memory differentiation occurred in lymphoid organs independently of alloantigen. Unexpectedly, professional hematopoietic-derived recipient APCs within lymphoid organs had only a limited capacity to induce GVHD, and dendritic cells were not required. In contrast, nonhematopoietic recipient APCs within target organs induced universal GVHD mortality and promoted marked alloreactive donor T cell expansion within the gastrointestinal tract and inflammatory cytokine generation. These data challenge current paradigms, suggesting that experimental lethal acute GVHD can be induced by nonhematopoietic recipient APCs.", + "TAG_DATA": [ + "22, mice {'context': 'B-organism'}", + "72, T {'context': 'B-cells'}", + "73, cell {'context': 'B-cells'}", + "76, memory {'phenotype': 'B-differentiation'}", + "77, differentiation {'phenotype': 'I-differentiation'}", + "80, lymphoid {'context': 'B-tissue/organ'}", + "81, organs {'context': 'I-tissue/organ'}", + "87, hematopoietic-derived {'context': 'I-cells'}", + "88, recipient {'context': 'I-cells'}", + "89, APCs {'context': 'I-cells'}", + "91, lymphoid {'context': 'B-tissue/organ'}", + "92, organs {'context': 'I-tissue/organ'}", + "102, dendritic {'context': 'B-cells'}", + "103, cells {'context': 'I-cells'}", + "109, nonhematopoietic {'context': 'B-cells'}", + "110, recipient {'context': 'I-cells'}", + "111, APCs {'context': 'I-cells'}", + "114, organs {'context': 'I-tissue/organ'}", + "122, alloreactive {'context': 'B-cells'}", + "123, donor {'context': 'I-cells'}", + "124, T {'context': 'I-cells'}", + "125, cell {'context': 'I-cells'}", + "129, gastrointestinal {'context': 'B-tissue/organ'}", + "130, tract {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "22, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "72, T ['l0', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "73, cell ['l1', 'l5', 'l11', 'l12', 'l13', 'l14', 'l15']", + "74, activation ['l2', 'l6', 'l11', 'l16', 'l17', 'l18', 'l19']", + "76, memory ['l7', 'l12', 'l16', 'l20', 'l21', 'l22']", + "77, differentiation ['l3', 'l8', 'l13', 'l17', 'l20', 'l23', 'l24']", + "80, lymphoid ['l9', 'l14', 'l18', 'l21', 'l23', 'l25']", + "81, organs ['l4', 'l10', 'l15', 'l19', 'l22', 'l24', 'l25']", + "87, hematopoietic-derived ['l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "88, recipient ['l26', 'l32', 'l33', 'l34', 'l35', 'l36']", + "89, APCs ['l27', 'l32', 'l37', 'l38', 'l39', 'l40']", + "91, lymphoid ['l28', 'l33', 'l37', 'l41', 'l42', 'l43']", + "92, organs ['l29', 'l34', 'l38', 'l41', 'l44']", + "102, dendritic ['l30', 'l35', 'l39', 'l42', 'l45']", + "103, cells ['l31', 'l36', 'l40', 'l43', 'l44', 'l45']", + "109, nonhematopoietic ['l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "110, recipient ['l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "111, APCs ['l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "114, organs ['l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "122, alloreactive ['l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "123, donor ['l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "124, T ['l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "125, cell ['l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "129, gastrointestinal ['l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "130, tract ['l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "memory", + "differentiation" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "memory", + "differentiation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lymphoid", + "organs" + ] + } + } + ] + }, + { + "PMID": "22101766", + "TEXT": "Breast cancer is a heterogeneous disease that has a wide range of molecular aberrations and clinical outcomes. Here we used paired-end transcriptome sequencing to explore the landscape of gene fusions in a panel of breast cancer cell lines and tissues. We observed that individual breast cancers have a variety of expressed gene fusions. We identified two classes of recurrent gene rearrangements involving genes encoding microtubule-associated serine-threonine kinase (MAST) and members of the Notch family. Both MAST and Notch-family gene fusions have substantial phenotypic effects in breast epithelial cells. Breast cancer cell lines harboring Notch gene rearrangements are uniquely sensitive to inhibition of Notch signaling, and overexpression of MAST1 or MAST2 gene fusions has a proliferative effect both in vitro and in vivo. These findings show that recurrent gene rearrangements have key roles in subsets of carcinomas and suggest that transcriptome sequencing could identify individuals with rare, targetable gene fusions.", + "TAG_DATA": [ + "85, breast {'context': 'B-cells'}", + "86, epithelial {'context': 'I-cells'}", + "87, cells. {'context': 'I-cells'}", + "88, Breast {'context': 'B-transformed cells'}", + "89, cancer {'context': 'I-transformed cells'}", + "90, cell {'context': 'I-transformed cells'}", + "91, lines {'context': 'I-transformed cells'}", + "105, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "106, of {'perturbing_action': 'I-gene gain-of-function'}", + "107, MAST1 {'perturbing_action': 'I-gene gain-of-function'}", + "108, or {'perturbing_action': 'I-gene gain-of-function'}", + "109, MAST2 {'perturbing_action': 'I-gene gain-of-function'}", + "110, gene {'perturbing_action': 'I-gene gain-of-function'}", + "111, fusions {'perturbing_action': 'I-gene gain-of-function'}", + "114, proliferative {'phenotype': 'B-proliferation'}", + "115, effect {'phenotype': 'I-proliferation'}", + "117, in {'context': 'B-in vitro'}", + "118, vitro {'context': 'I-in vitro'}", + "120, in {'context': 'B-in vivo'}", + "121, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "85, breast ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "86, epithelial ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "87, cells. ['l1', 'l6', 'l11']", + "88, Breast ['l2', 'l7', 'l12', 'l13', 'l14']", + "89, cancer ['l3', 'l8', 'l12', 'l15', 'l16']", + "90, cell ['l4', 'l9', 'l11', 'l13', 'l15', 'l17']", + "91, lines ['l5', 'l10', 'l14', 'l16', 'l17']", + "105, overexpression ['l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "106, of ['l18', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "107, MAST1 ['l19', 'l30', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "108, or ['l20', 'l31', 'l41', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "109, MAST2 ['l21', 'l32', 'l42', 'l51', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "110, gene ['l22', 'l33', 'l43', 'l52', 'l60', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "111, fusions ['l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "114, proliferative ['l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l81', 'l82', 'l83', 'l84', 'l85']", + "115, effect ['l25', 'l36', 'l46', 'l55', 'l63', 'l70', 'l76', 'l81', 'l86', 'l87', 'l88', 'l89']", + "117, in ['l26', 'l37', 'l47', 'l56', 'l64', 'l71', 'l77', 'l82', 'l86', 'l90', 'l91', 'l92']", + "118, vitro ['l27', 'l38', 'l48', 'l57', 'l65', 'l72', 'l78', 'l83', 'l87', 'l90', 'l93', 'l94']", + "120, in ['l28', 'l39', 'l49', 'l58', 'l66', 'l73', 'l79', 'l84', 'l88', 'l91', 'l93', 'l95']", + "121, vivo. ['l29', 'l40', 'l50', 'l59', 'l67', 'l74', 'l80', 'l85', 'l89', 'l92', 'l94', 'l95']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "MAST1", + "or", + "MAST2", + "gene", + "fusions" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "effect" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "MAST1", + "or", + "MAST2", + "gene", + "fusions" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "MAST1", + "or", + "MAST2", + "gene", + "fusions" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "effect" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "effect" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "22057347", + "TEXT": "Ubiquitin-tagged substrates are degraded by the 26S proteasome, which is a multisubunit complex comprising a proteolytic 20S core particle capped by 19S regulatory particles. The approval of bortezomib for the treatment of multiple myeloma validated the 20S core particle as an anticancer drug target. Here we describe the small molecule b-AP15 as a previously unidentified class of proteasome inhibitor that abrogates the deubiquitinating activity of the 19S regulatory particle. b-AP15 inhibited the activity of two 19S regulatory-particle-associated deubiquitinases, ubiquitin C-terminal hydrolase 5 (UCHL5) and ubiquitin-specific peptidase 14 (USP14), resulting in accumulation of polyubiquitin. b-AP15 induced tumor cell apoptosis that was insensitive to TP53 status and overexpression of the apoptosis inhibitor BCL2. We show that treatment with b-AP15 inhibited tumor progression in four different in vivo solid tumor models and inhibited organ infiltration in an acute myeloid leukemia model. Our results show that the deubiquitinating activity of the 19S regulatory particle is a new anticancer drug target.", + "TAG_DATA": [ + "94, induced {'effect': 'B-positive'}", + "95, tumor {'context': 'B-transformed cells'}", + "96, cell {'context': 'I-transformed cells'}", + "97, apoptosis {'phenotype': 'B-apoptosis'}", + "105, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "106, of {'perturbing_action': 'I-gene gain-of-function'}", + "107, the {'perturbing_action': 'I-gene gain-of-function'}", + "108, apoptosis {'perturbing_action': 'I-gene gain-of-function'}", + "109, inhibitor {'perturbing_action': 'I-gene gain-of-function'}", + "110, BCL2. {'perturbing_action': 'I-gene gain-of-function'}", + "117, inhibited {'effect': 'B-negative'}", + "118, tumor {'phenotype': 'B-tumour progression'}", + "119, progression {'phenotype': 'I-tumour progression'}", + "123, in {'context': 'B-in vivo'}", + "124, vivo {'context': 'B-in vivo'}", + "125, solid {'context': 'B-neoplasm'}", + "126, tumor {'context': 'I-neoplasm'}", + "127, models {'context': 'I-neoplasm'}", + "134, acute {'context': 'B-neoplasm'}", + "135, myeloid {'context': 'I-neoplasm'}", + "136, leukemia {'context': 'I-neoplasm'}", + "137, model. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "94, induced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "95, tumor ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "96, cell ['l1', 'l8', 'l16', 'l17', 'l18']", + "97, apoptosis ['l2', 'l9', 'l16', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "105, overexpression ['l10', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "106, of ['l3', 'l11', 'l20', 'l25', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "107, the ['l4', 'l12', 'l21', 'l26', 'l37', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "108, apoptosis ['l5', 'l13', 'l22', 'l27', 'l38', 'l49', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "109, inhibitor ['l6', 'l14', 'l17', 'l23', 'l28', 'l39', 'l50', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "110, BCL2. ['l7', 'l15', 'l18', 'l24', 'l29', 'l40', 'l51', 'l61', 'l69', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "117, inhibited ['l41', 'l52', 'l70', 'l78', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "118, tumor ['l30', 'l42', 'l53', 'l62', 'l71', 'l79', 'l86', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "119, progression ['l31', 'l43', 'l54', 'l63', 'l72', 'l80', 'l87', 'l97', 'l103', 'l104', 'l105', 'l106', 'l107']", + "123, in ['l32', 'l44', 'l55', 'l64', 'l73', 'l81', 'l88', 'l98', 'l103', 'l108', 'l109', 'l110', 'l111']", + "124, vivo ['l33', 'l45', 'l56', 'l65', 'l74', 'l82', 'l89', 'l99', 'l104', 'l108', 'l112', 'l113', 'l114']", + "125, solid ['l34', 'l46', 'l57', 'l66', 'l75', 'l83', 'l90', 'l100', 'l105', 'l109', 'l112', 'l115', 'l116']", + "126, tumor ['l35', 'l47', 'l58', 'l67', 'l76', 'l84', 'l91', 'l101', 'l106', 'l110', 'l113', 'l115', 'l117']", + "127, models ['l36', 'l48', 'l59', 'l68', 'l77', 'l85', 'l92', 'l102', 'l107', 'l111', 'l114', 'l116', 'l117']", + "134, acute ['l93', 'l118', 'l119', 'l120']", + "135, myeloid ['l94', 'l118', 'l121', 'l122']", + "136, leukemia ['l95', 'l119', 'l121', 'l123']", + "137, model. ['l96', 'l120', 'l122', 'l123']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "the", + "apoptosis", + "inhibitor", + "BCL2." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "the", + "apoptosis", + "inhibitor", + "BCL2." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "the", + "apoptosis", + "inhibitor", + "BCL2." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "the", + "apoptosis", + "inhibitor", + "BCL2." + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "the", + "apoptosis", + "inhibitor", + "BCL2." + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "the", + "apoptosis", + "inhibitor", + "BCL2." + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "solid", + "tumor", + "models" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "the", + "inhibitor", + "BCL2." + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "solid", + "tumor", + "models", + "acute", + "myeloid", + "leukemia", + "model." + ] + } + }, + { + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "solid", + "tumor", + "models" + ] + } + } + ] + }, + { + "PMID": "22019887", + "TEXT": "Development and preclinical testing of new cancer therapies is limited by the scarcity of in vivo models that authentically reproduce tumor growth and metastatic progression. We report new models for breast tumor growth and metastasis in the form of transplantable tumors derived directly from individuals undergoing treatment for breast cancer. These tumor grafts illustrate the diversity of human breast cancer and maintain essential features of the original tumors, including metastasis to specific sites. Co-engraftment of primary human mesenchymal stem cells maintains phenotypic stability of the grafts and increases tumor growth by promoting angiogenesis. We also report that tumor engraftment is a prognostic indicator of disease outcome for women with newly diagnosed breast cancer; orthotopic breast tumor grafting is a step toward individualized models for tumor growth, metastasis and prognosis. This bank of tumor grafts also serves as a publicly available resource for new models in which to study the biology of breast cancer.", + "TAG_DATA": [ + "75, primary {'context': 'B-cells'}", + "76, human {'context': 'I-cells'}", + "77, mesenchymal {'context': 'I-cells'}", + "78, stem {'context': 'I-cells'}", + "79, cells {'context': 'I-cells'}", + "87, increases {'effect': 'B-positive'}", + "88, tumor {'phenotype': 'B-tumour growth'}", + "89, growth {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "75, primary ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "76, human ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "77, mesenchymal ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "78, stem ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "79, cells ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "87, increases ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "88, tumor ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "89, growth ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "primary", + "human", + "mesenchymal", + "stem", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increases" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "primary", + "human", + "mesenchymal", + "stem", + "cells" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + } + ] + }, + { + "PMID": "22001908", + "TEXT": "Infertility and recurrent pregnancy loss (RPL) are prevalent but distinct causes of reproductive failure that often remain unexplained despite extensive investigations. Analysis of midsecretory endometrial samples revealed that SGK1, a kinase involved in epithelial ion transport and cell survival, is upregulated in unexplained infertility, most prominently in the luminal epithelium, but downregulated in the endometrium of women suffering from RPL. To determine the functional importance of these observations, we first expressed a constitutively active SGK1 mutant in the luminal epithelium of the mouse uterus. This prevented expression of certain endometrial receptivity genes, perturbed uterine fluid handling and abolished embryo implantation. By contrast, implantation was unhindered in Sgk1-/- mice, but pregnancy was often complicated by bleeding at the decidual-placental interface and fetal growth retardation and subsequent demise. Compared to wild-type mice, Sgk1-/- mice had gross impairment of pregnancy-dependent induction of genes involved in oxidative stress defenses. Relative SGK1 deficiency was also a hallmark of decidualizing stromal cells from human subjects with RPL and sensitized these cells to oxidative cell death. Thus, depending on the cellular compartment, deregulated SGK1 activity in cycling endometrium interferes with embryo implantation, leading to infertility, or predisposes to pregnancy complications by rendering the feto-maternal interface vulnerable to oxidative damage.", + "TAG_DATA": [ + "72, constitutively {'perturbing_action': 'I-other'}", + "73, active {'perturbing_action': 'I-other'}", + "74, SGK1 {'perturbing_action': 'I-other'}", + "75, mutant {'perturbing_action': 'I-other'}", + "76, in {'perturbing_action': 'I-other'}", + "77, the {'perturbing_action': 'I-other'}", + "78, luminal {'perturbing_action': 'I-other'}", + "79, epithelium {'perturbing_action': 'I-other', 'context': 'I-tissue/organ'}", + "80, of {'perturbing_action': 'I-other'}", + "82, mouse {'context': 'B-tissue/organ'}", + "83, uterus. {'context': 'I-tissue/organ'}", + "97, abolished {'effect': 'B-negative'}", + "102, implantation {'phenotype': 'B-autophagy'}", + "106, Sgk1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "107, mice, {'context': 'B-organism'}", + "129, mice, {'context': 'B-organism'}", + "130, Sgk1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "131, mice {'context': 'B-organism'}", + "146, SGK1 {'perturbing_action': 'B-gene loss-of-function'}", + "147, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "162, sensitized {'effect': 'B-positive'}", + "164, cells {'context': 'B-cells'}", + "167, cell {'phenotype': 'B-cell death'}", + "168, death. {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "72, constitutively ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "73, active ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "74, SGK1 ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "75, mutant ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "76, in ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "77, the ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "78, luminal ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "79, epithelium ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "80, of ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "82, mouse ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "83, uterus. ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "97, abolished ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "99, implantation. ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "102, implantation ['l78', 'l79']", + "106, Sgk1-/- ['l78', 'l80']", + "107, mice, ['l79', 'l80']", + "129, mice, ['l81', 'l82', 'l83', 'l84', 'l85']", + "130, Sgk1-/- ['l81', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "131, mice ['l82', 'l86', 'l92', 'l93', 'l94']", + "146, SGK1 ['l95', 'l96', 'l97', 'l98', 'l99']", + "147, deficiency ['l87', 'l95', 'l100', 'l101', 'l102', 'l103']", + "162, sensitized ['l88', 'l96', 'l100', 'l104', 'l105', 'l106']", + "164, cells ['l83', 'l89', 'l92', 'l97', 'l101', 'l104', 'l107', 'l108']", + "167, cell ['l84', 'l90', 'l93', 'l98', 'l102', 'l105', 'l107', 'l109']", + "168, death. ['l85', 'l91', 'l94', 'l99', 'l103', 'l106', 'l108', 'l109']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "constitutively", + "active", + "SGK1", + "mutant", + "in", + "the", + "luminal", + "epithelium", + "of" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "epithelium", + "mouse", + "uterus." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "constitutively", + "active", + "SGK1", + "mutant", + "in", + "the", + "luminal", + "epithelium", + "of" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abolished" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "epithelium", + "mouse", + "uterus." + ] + }, + "effect": { + "val": "negative", + "words": [ + "abolished" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "implantation" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sgk1-/-" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "implantation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sgk1-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sgk1-/-", + "SGK1", + "deficiency" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sgk1-/-", + "SGK1", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sgk1-/-", + "SGK1", + "deficiency" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "21983856", + "TEXT": "Chronic pain is a common neurological disease involving lasting, multifaceted maladaptations ranging from gene modulation to synaptic dysfunction and emotional disorders. Sustained pathological stimuli in many diseases alter the output activities of certain genes through epigenetic modifications, but it is unclear how epigenetic mechanisms operate in the development of chronic pain. We show here that in the rat brainstem nucleus raphe magnus, which is important for central mechanisms of chronic pain, persistent inflammatory and neuropathic pain epigenetically suppresses Gad2 (encoding glutamic acid decarboxylase 65 (GAD65)) transcription through histone deacetylase (HDAC)-mediated histone hypoacetylation, resulting in impaired γ-aminobutyric acid (GABA) synaptic inhibition. Gad2 knockout mice showed sensitized pain behavior and impaired GABA synaptic function in their brainstem neurons. In wild-type but not Gad2 knockout mice, HDAC inhibitors strongly increased GAD65 activity, restored GABA synaptic function and relieved sensitized pain behavior. These findings suggest GAD65 and HDACs as potential therapeutic targets in an epigenetic approach to the treatment of chronic pain.", + "TAG_DATA": [ + "58, brainstem {'context': 'I-tissue/organ'}", + "59, nucleus {'context': 'I-tissue/organ'}", + "60, raphe {'context': 'I-tissue/organ'}", + "61, magnus, {'context': 'I-tissue/organ'}", + "100, Gad2 {'perturbing_action': 'B-gene loss-of-function'}", + "101, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "102, mice {'context': 'B-organism'}", + "114, brainstem {'context': 'B-cells'}", + "115, neurons. {'context': 'I-cells'}", + "120, Gad2 {'perturbing_action': 'B-gene loss-of-function'}", + "121, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "122, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "58, brainstem ['l0', 'l1', 'l2']", + "59, nucleus ['l0', 'l3', 'l4', 'l5']", + "60, raphe ['l1', 'l3', 'l6']", + "61, magnus, ['l2', 'l4', 'l6', 'l7']", + "100, Gad2 ['l8', 'l9', 'l10', 'l11']", + "101, knockout ['l5', 'l7', 'l8', 'l12', 'l13', 'l14']", + "102, mice ['l9', 'l12', 'l15', 'l16']", + "114, brainstem ['l10', 'l13', 'l15', 'l17']", + "115, neurons. ['l11', 'l14', 'l16', 'l17']", + "120, Gad2 ['l18', 'l19']", + "121, knockout ['l18', 'l20']", + "122, mice, ['l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "nucleus", + "magnus," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gad2", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gad2", + "knockout" + ] + }, + "context": { + "val": "cells", + "words": [ + "brainstem", + "neurons." + ] + } + } + ] + }, + { + "PMID": "21946539", + "TEXT": "Heat shock proteins (HSPs) are necessary for cancer cell survival. We identified a mutant of HSP110 (HSP110ΔE9) in colorectal cancer showing microsatellite instability (MSI CRC), generated from an aberrantly spliced mRNA and lacking the HSP110 substrate-binding domain. This mutant was expressed at variable levels in almost all MSI CRC cell lines and primary tumors tested. HSP110ΔE9 impaired both the normal cellular localization of HSP110 and its interaction with other HSPs, thus abrogating the chaperone activity and antiapoptotic function of HSP110 in a dominant-negative manner. HSP110ΔE9 overexpression caused the sensitization of cells to anticancer agents such as oxaliplatin and 5-fluorouracil, which are routinely prescribed in the adjuvant treatment of people with CRC. The survival and response to chemotherapy of subjects with MSI CRCs was associated with the tumor expression level of HSP110ΔE9. HSP110 may thus constitute a major determinant for both prognosis and treatment response in CRC.", + "TAG_DATA": [ + "84, HSP110ΔE9 {'perturbing_action': 'B-gene gain-of-function'}", + "85, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "90, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "84, HSP110ΔE9 ['l0', 'l1']", + "85, overexpression ['l0', 'l2']", + "90, cells ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "HSP110ΔE9", + "overexpression" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "21946538", + "TEXT": "Rapidly progressive glomerulonephritis (RPGN) is a life-threatening clinical syndrome and a morphological manifestation of severe glomerular injury that is marked by a proliferative histological pattern ('crescents') with accumulation of T cells and macrophages and proliferation of intrinsic glomerular cells. We show de novo induction of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in intrinsic glomerular epithelial cells (podocytes) from both mice and humans with RPGN. HB-EGF induction increases phosphorylation of the epidermal growth factor receptor (EGFR, also known as ErbB1) in mice with RPGN. In HB-EGF-deficient mice, EGFR activation in glomeruli is absent and the course of RPGN is improved. Autocrine HB-EGF induces a phenotypic switch in podocytes in vitro. Conditional deletion of the Egfr gene from podocytes of mice alleviates the severity of RPGN. Likewise, pharmacological blockade of EGFR also improves the course of RPGN, even when started 4 d after the induction of experimental RPGN. This suggests that targeting the HB-EGF-EGFR pathway could also be beneficial in treatment of human RPGN.", + "TAG_DATA": [ + "53, intrinsic {'context': 'B-cells'}", + "54, glomerular {'context': 'I-cells'}", + "55, epithelial {'context': 'I-cells'}", + "56, cells {'context': 'I-cells'}", + "57, (podocytes) {'context': 'I-cells'}", + "81, mice {'context': 'B-organism'}", + "85, HB-EGF-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "86, mice, {'context': 'B-organism'}", + "90, glomeruli {'context': 'B-tissue/organ'}", + "107, podocytes {'context': 'B-cells'}", + "108, in {'context': 'B-in vitro'}", + "109, vitro. {'context': 'I-in vitro'}", + "110, Conditional {'perturbing_action': 'B-gene loss-of-function'}", + "111, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "112, of {'perturbing_action': 'I-gene loss-of-function'}", + "113, the {'perturbing_action': 'I-gene loss-of-function'}", + "114, Egfr {'perturbing_action': 'I-gene loss-of-function'}", + "115, gene {'perturbing_action': 'I-gene loss-of-function'}", + "117, podocytes {'context': 'B-cells'}", + "119, mice {'context': 'B-organism'}", + "126, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "127, blockade {'perturbing_action': 'I-pharmacological inhibition'}", + "128, of {'perturbing_action': 'I-pharmacological inhibition'}", + "129, EGFR {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "53, intrinsic ['l0', 'l1', 'l2', 'l3', 'l4']", + "54, glomerular ['l0', 'l5', 'l6', 'l7', 'l8']", + "55, epithelial ['l1', 'l5', 'l9', 'l10', 'l11']", + "56, cells ['l2', 'l6', 'l9', 'l12', 'l13']", + "57, (podocytes) ['l3', 'l7', 'l10', 'l12', 'l14']", + "81, mice ['l4', 'l8', 'l11', 'l13', 'l14']", + "85, HB-EGF-deficient ['l15', 'l16', 'l17', 'l18', 'l19']", + "86, mice, ['l15', 'l20']", + "90, glomeruli ['l16', 'l20', 'l21']", + "107, podocytes ['l17', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "108, in ['l18', 'l22', 'l27', 'l28']", + "109, vitro. ['l19', 'l23', 'l27', 'l29']", + "110, Conditional ['l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "111, deletion ['l30', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "112, of ['l31', 'l37', 'l43', 'l44', 'l45', 'l46', 'l47']", + "113, the ['l32', 'l38', 'l43', 'l48', 'l49', 'l50', 'l51']", + "114, Egfr ['l33', 'l39', 'l44', 'l48', 'l52', 'l53', 'l54']", + "115, gene ['l24', 'l34', 'l40', 'l45', 'l49', 'l52', 'l55', 'l56']", + "117, podocytes ['l25', 'l35', 'l41', 'l46', 'l50', 'l53', 'l55', 'l57']", + "119, mice ['l26', 'l28', 'l29', 'l36', 'l42', 'l47', 'l51', 'l54', 'l56', 'l57']", + "126, pharmacological ['l58', 'l59', 'l60']", + "127, blockade ['l58', 'l61', 'l62']", + "128, of ['l59', 'l61', 'l63']", + "129, EGFR ['l60', 'l62', 'l63']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "HB-EGF-deficient", + "Conditional", + "deletion", + "of", + "the", + "Egfr", + "gene" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "HB-EGF-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "glomeruli" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "HB-EGF-deficient", + "gene", + "Conditional", + "deletion", + "of", + "the", + "Egfr" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "HB-EGF-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "21946537", + "TEXT": "DNA mismatch repair enzymes (for example, MSH2) maintain genomic integrity, and their deficiency predisposes to several human cancers and to drug resistance. We found that leukemia cells from a substantial proportion of children (∼11%) with newly diagnosed acute lymphoblastic leukemia have low or undetectable MSH2 protein levels, despite abundant wild-type MSH2 mRNA. Leukemia cells with low levels of MSH2 contained partial or complete somatic deletions of one to four genes that regulate MSH2 degradation (FRAP1 (also known as MTOR), HERC1, PRKCZ and PIK3C2B); we also found these deletions in individuals with adult acute lymphoblastic leukemia (16%) and sporadic colorectal cancer (13.5%). Knockdown of these genes in human leukemia cells recapitulated the MSH2 protein deficiency by enhancing MSH2 degradation, leading to substantial reduction in DNA mismatch repair and increased resistance to thiopurines. These findings reveal a previously unrecognized mechanism whereby somatic deletions of genes regulating MSH2 degradation result in undetectable levels of MSH2 protein in leukemia cells, DNA mismatch repair deficiency and drug resistance.", + "TAG_DATA": [ + "52, Leukemia {'context': 'B-transformed cells'}", + "53, cells {'context': 'I-transformed cells'}", + "101, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "102, of {'perturbing_action': 'I-rnai/knockdown'}", + "103, these {'perturbing_action': 'I-rnai/knockdown'}", + "104, genes {'perturbing_action': 'I-rnai/knockdown'}", + "106, human {'context': 'B-transformed cells'}", + "107, leukemia {'context': 'I-transformed cells'}", + "108, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "52, Leukemia ['l0', 'l1', 'l2']", + "53, cells ['l0', 'l3']", + "92, acute ['l4', 'l5', 'l6', 'l7']", + "93, lymphoblastic ['l1', 'l4', 'l8', 'l9', 'l10']", + "94, leukemia ['l2', 'l3', 'l5', 'l8', 'l11', 'l12']", + "98, colorectal ['l6', 'l9', 'l11', 'l13']", + "99, cancer ['l7', 'l10', 'l12', 'l13']", + "101, Knockdown ['l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "102, of ['l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "103, these ['l15', 'l20', 'l25', 'l26', 'l27', 'l28']", + "104, genes ['l16', 'l21', 'l25', 'l29', 'l30', 'l31']", + "106, human ['l17', 'l22', 'l26', 'l29', 'l32', 'l33']", + "107, leukemia ['l18', 'l23', 'l27', 'l30', 'l32', 'l34']", + "108, cells ['l19', 'l24', 'l28', 'l31', 'l33', 'l34']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "these", + "genes" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "leukemia", + "cells" + ] + } + } + ] + }, + { + "PMID": "21892180", + "TEXT": "We report the involvement of an evolutionarily conserved set of mycobacterial genes, the esx-3 region, in evasion of bacterial killing by innate immunity. Whereas high-dose intravenous infections of mice with the rapidly growing mycobacterial species Mycobacterium smegmatis bearing an intact esx-3 locus were rapidly lethal, infection with an M. smegmatis Δesx-3 mutant (here designated as the IKE strain) was controlled and cleared by a MyD88-dependent bactericidal immune response. Introduction of the orthologous Mycobacterium tuberculosis esx-3 genes into the IKE strain resulted in a strain, designated IKEPLUS, that remained susceptible to innate immune killing and was highly attenuated in mice but had a marked ability to stimulate bactericidal immunity against challenge with virulent M. tuberculosis. Analysis of these adaptive immune responses indicated that the highly protective bactericidal immunity elicited by IKEPLUS was dependent on CD4(+) memory T cells and involved a distinct shift in the pattern of cytokine responses by CD4(+) cells. Our results establish a role for the esx-3 locus in promoting mycobacterial virulence and also identify the IKE strain as a potentially powerful candidate vaccine vector for eliciting protective immunity to M. tuberculosis.", + "TAG_DATA": [ + "28, mice {'context': 'B-organism'}", + "48, M. {'perturbing_action': 'B-other', 'context': 'B-organism'}", + "49, smegmatis {'perturbing_action': 'B-other'}", + "50, Δesx-3 {'perturbing_action': 'B-other'}", + "51, mutant {'perturbing_action': 'I-other'}", + "52, (here {'perturbing_action': 'I-other'}", + "68, Introduction {'perturbing_action': 'B-other'}", + "69, of {'perturbing_action': 'I-other'}", + "70, the {'perturbing_action': 'I-other'}", + "71, orthologous {'perturbing_action': 'I-other'}", + "72, Mycobacterium {'perturbing_action': 'I-other'}", + "73, tuberculosis {'perturbing_action': 'I-other'}", + "74, esx-3 {'perturbing_action': 'I-other'}", + "75, genes {'perturbing_action': 'I-other'}", + "76, into {'perturbing_action': 'I-other'}", + "98, mice {'context': 'B-organism'}", + "133, CD4(+) {'context': 'B-cells'}", + "134, memory {'context': 'I-cells'}", + "135, T {'context': 'I-cells'}", + "136, cells {'context': 'I-cells'}", + "149, CD4(+) {'context': 'B-cells'}", + "150, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "48, M. ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "49, smegmatis ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "50, Δesx-3 ['l1', 'l14', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "51, mutant ['l2', 'l15', 'l26', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "52, (here ['l3', 'l16', 'l27', 'l39', 'l49', 'l50']", + "68, Introduction ['l28', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "69, of ['l4', 'l17', 'l29', 'l40', 'l51', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "70, the ['l5', 'l18', 'l30', 'l41', 'l52', 'l61', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "71, orthologous ['l6', 'l19', 'l31', 'l42', 'l53', 'l62', 'l70', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "72, Mycobacterium ['l7', 'l20', 'l32', 'l43', 'l54', 'l63', 'l71', 'l78', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "73, tuberculosis ['l8', 'l21', 'l33', 'l44', 'l49', 'l55', 'l64', 'l72', 'l79', 'l85', 'l91', 'l92', 'l93', 'l94', 'l95']", + "74, esx-3 ['l9', 'l22', 'l34', 'l45', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l96', 'l97', 'l98', 'l99']", + "75, genes ['l10', 'l23', 'l35', 'l46', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l100', 'l101', 'l102']", + "76, into ['l11', 'l36', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l103', 'l104']", + "78, IKE ['l12', 'l24', 'l37', 'l47', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l105']", + "98, mice ['l13', 'l25', 'l38', 'l48', 'l50', 'l60', 'l69', 'l77', 'l84', 'l90', 'l95', 'l99', 'l102', 'l104', 'l105']", + "133, CD4(+) ['l106', 'l107', 'l108', 'l109', 'l110']", + "134, memory ['l106', 'l111', 'l112', 'l113', 'l114']", + "135, T ['l107', 'l111', 'l115', 'l116', 'l117']", + "136, cells ['l108', 'l112', 'l115', 'l118', 'l119']", + "149, CD4(+) ['l109', 'l113', 'l116', 'l118', 'l120']", + "150, cells. ['l110', 'l114', 'l117', 'l119', 'l120']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "M.", + "smegmatis", + "Δesx-3", + "mutant", + "(here", + "Introduction", + "of", + "the", + "orthologous", + "Mycobacterium", + "tuberculosis", + "esx-3", + "genes", + "into" + ] + }, + "context": { + "val": "organism", + "words": [ + "M.", + "mice" + ] + } + } + ] + }, + { + "PMID": "21857652", + "TEXT": "Coagulase-positive Staphylococcus aureus (S. aureus) is the major causal pathogen of acute endocarditis, a rapidly progressing, destructive infection of the heart valves. Bacterial colonization occurs at sites of endothelial damage, where, together with fibrin and platelets, the bacteria initiate the formation of abnormal growths known as vegetations. Here we report that an engineered analog of prothrombin could be used to detect S. aureus in endocarditic vegetations via noninvasive fluorescence or positron emission tomography (PET) imaging. These prothrombin derivatives bound staphylocoagulase and intercalated into growing bacterial vegetations. We also present evidence for bacterial quorum sensing in the regulation of staphylocoagulase expression by S. aureus. Staphylocoagulase expression was limited to the growing edge of mature vegetations, where it was exposed to the host and co-localized with the imaging probe. When endocarditis was induced with an S. aureus strain with genetic deletion of coagulases, survival of mice improved, highlighting the role of staphylocoagulase as a virulence factor.", + "TAG_DATA": [ + "133, S. {'context': 'B-transformed cells'}", + "135, strain {'context': 'I-transformed cells'}", + "137, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "138, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "139, of {'perturbing_action': 'I-gene loss-of-function'}", + "140, coagulases, {'perturbing_action': 'I-gene loss-of-function'}", + "143, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "133, S. ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "134, aureus ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "135, strain ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "137, genetic ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "138, deletion ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "139, of ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "140, coagulases, ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "143, mice ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "S.", + "strain" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "coagulases," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "coagulases," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "21822285", + "TEXT": "The prognosis of breast cancer in young women is influenced by reproductive history. Women diagnosed within 5 years postpartum have worse prognosis than nulliparous women or women diagnosed during pregnancy. Here we describe a mouse model of postpartum breast cancer that identifies mammary gland involution as a driving force of tumor progression. In this model, human breast cancer cells exposed to the involuting mammary microenvironment form large tumors that are characterized by abundant fibrillar collagen, high cyclooxygenase-2 (COX-2) expression and an invasive phenotype. In culture, tumor cells are invasive in a fibrillar collagen and COX-2-dependent manner. In the involuting mammary gland, inhibition of COX-2 reduces the collagen fibrillogenesis associated with involution, as well as tumor growth and tumor cell infiltration to the lung. These data support further research to determine whether women at high risk for postpartum breast cancer would benefit from treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) during postpartum involution.", + "TAG_DATA": [ + "55, human {'context': 'B-transformed cells'}", + "56, breast {'context': 'I-transformed cells'}", + "57, cancer {'context': 'I-transformed cells'}", + "58, cells {'context': 'I-transformed cells'}", + "85, tumor {'context': 'B-transformed cells'}", + "86, cells {'context': 'I-transformed cells'}", + "98, involuting {'context': 'B-tissue/organ'}", + "99, mammary {'context': 'I-tissue/organ'}", + "100, gland, {'context': 'I-tissue/organ'}", + "101, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "102, of {'perturbing_action': 'I-pharmacological inhibition'}", + "103, COX-2 {'perturbing_action': 'I-pharmacological inhibition'}", + "114, tumor {'phenotype': 'B-tumour growth'}", + "115, growth {'phenotype': 'I-tumour growth'}", + "117, tumor {'context': 'B-transformed cells'}", + "118, cell {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "55, human ['l0', 'l1', 'l2']", + "56, breast ['l0', 'l3', 'l4']", + "57, cancer ['l1', 'l3', 'l5']", + "58, cells ['l2', 'l4', 'l5']", + "85, tumor ['l6']", + "86, cells ['l6']", + "98, involuting ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "99, mammary ['l7', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "100, gland, ['l8', 'l16', 'l23', 'l24', 'l25', 'l26']", + "101, inhibition ['l9', 'l17', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "102, of ['l10', 'l18', 'l23', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "103, COX-2 ['l11', 'l19', 'l24', 'l28', 'l33', 'l38', 'l39', 'l40', 'l41']", + "114, tumor ['l12', 'l20', 'l25', 'l29', 'l34', 'l38', 'l42', 'l43', 'l44']", + "115, growth ['l13', 'l21', 'l26', 'l30', 'l35', 'l39', 'l42', 'l45', 'l46']", + "117, tumor ['l14', 'l31', 'l36', 'l40', 'l43', 'l45', 'l47']", + "118, cell ['l15', 'l22', 'l32', 'l37', 'l41', 'l44', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "involuting", + "mammary", + "gland," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "COX-2" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "involuting", + "mammary", + "gland," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "COX-2" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "COX-2" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + } + ] + }, + { + "PMID": "21804542", + "TEXT": "PICT1 (also known as GLTSCR2) is considered a tumor suppressor because it stabilizes phosphatase and tensin homolog (PTEN), but individuals with oligodendrogliomas lacking chromosome 19q13, where PICT1 is located, have better prognoses than other oligodendroglioma patients. To clarify the function of PICT1, we generated Pict1-deficient mice and embryonic stem (ES) cells. Pict1 is a nucleolar protein essential for embryogenesis and ES cell survival. Even without DNA damage, Pict1 loss led to p53-dependent arrest of cell cycle phase G(1) and apoptosis. Pict1-deficient cells accumulated p53, owing to impaired Mdm2 function. Pict1 binds Rpl11, and Rpl11 is released from nucleoli in the absence of Pict1. In Pict1-deficient cells, increased binding of Rpl11 to Mdm2 blocks Mdm2-mediated ubiquitination of p53. In human cancer, individuals whose tumors express less PICT1 have better prognoses. When PICT1 is depleted in tumor cells with intact P53 signaling, the cells grow more slowly and accumulate P53. Thus, PICT1 is a potent regulator of the MDM2-P53 pathway and promotes tumor progression by retaining RPL11 in the nucleolus.", + "TAG_DATA": [ + "44, Pict1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "45, mice {'context': 'B-organism'}", + "47, embryonic {'context': 'B-cells'}", + "48, stem {'context': 'I-cells'}", + "49, (ES) {'context': 'I-cells'}", + "50, cells. {'context': 'I-cells'}", + "67, Pict1 {'perturbing_action': 'B-gene loss-of-function'}", + "68, loss {'perturbing_action': 'I-gene loss-of-function'}", + "69, led {'effect': 'B-positive'}", + "70, to {'effect': 'I-positive'}", + "72, arrest {'phenotype': 'B-cell cycle arrest'}", + "73, of {'phenotype': 'I-cell cycle arrest'}", + "74, cell {'phenotype': 'I-cell cycle arrest'}", + "75, cycle {'phenotype': 'I-cell cycle arrest'}", + "76, phase {'phenotype': 'I-cell cycle arrest'}", + "77, G(1) {'phenotype': 'I-cell cycle arrest'}", + "79, apoptosis. {'phenotype': 'B-apoptosis'}", + "80, Pict1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "81, cells {'context': 'B-cells'}", + "104, Pict1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "105, cells, {'context': 'B-cells'}", + "141, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "44, Pict1-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "45, mice ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "47, embryonic ['l1', 'l16', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "48, stem ['l2', 'l17', 'l31', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "49, (ES) ['l3', 'l18', 'l32', 'l45', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "50, cells. ['l4', 'l19', 'l33', 'l46', 'l58', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "67, Pict1 ['l5', 'l20', 'l34', 'l47', 'l59', 'l70', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "68, loss ['l6', 'l21', 'l35', 'l48', 'l60', 'l71', 'l81', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "69, led ['l7', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "70, to ['l8', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l100', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "72, arrest ['l9', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l108', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "73, of ['l10', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l115', 'l121', 'l122', 'l123', 'l124', 'l125']", + "74, cell ['l11', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l121', 'l126', 'l127', 'l128', 'l129']", + "75, cycle ['l12', 'l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l126', 'l130', 'l131', 'l132']", + "76, phase ['l13', 'l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l118', 'l123', 'l127', 'l130', 'l133', 'l134']", + "77, G(1) ['l14', 'l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l113', 'l119', 'l124', 'l128', 'l131', 'l133', 'l135']", + "79, apoptosis. ['l15', 'l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l129', 'l132', 'l134', 'l135']", + "80, Pict1-deficient ['l136']", + "81, cells ['l136']", + "104, Pict1-deficient ['l137', 'l138']", + "105, cells, ['l137']", + "141, cells ['l138']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pict1-deficient", + "Pict1", + "loss" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pict1-deficient", + "Pict1", + "loss" + ] + }, + "context": { + "val": "cells", + "words": [ + "embryonic", + "stem", + "(ES)", + "cells.", + "cells", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pict1-deficient", + "Pict1", + "loss" + ] + }, + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pict1-deficient", + "Pict1", + "loss" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest", + "of", + "cell", + "cycle", + "phase", + "G(1)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pict1-deficient", + "Pict1", + "loss" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest", + "of", + "cell", + "cycle", + "phase", + "G(1)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "embryonic", + "stem", + "(ES)", + "cells." + ] + }, + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "embryonic", + "stem", + "(ES)", + "cells." + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest", + "of", + "cell", + "cycle", + "phase", + "G(1)" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "embryonic", + "stem", + "(ES)", + "cells." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest", + "of", + "cell", + "cycle", + "phase", + "G(1)" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "21785433", + "TEXT": "Follicular helper (T(FH)) cells provide crucial signals to germinal center B cells undergoing somatic hypermutation and selection that results in affinity maturation. Tight control of T(FH) numbers maintains self tolerance. We describe a population of Foxp3(+)Blimp-1(+)CD4(+) T cells constituting 10-25% of the CXCR5(high)PD-1(high)CD4(+) T cells found in the germinal center after immunization with protein antigens. These follicular regulatory T (T(FR)) cells share phenotypic characteristics with T(FH) and conventional Foxp3(+) regulatory T (T(reg)) cells yet are distinct from both. Similar to T(FH) cells, T(FR) cell development depends on Bcl-6, SLAM-associated protein (SAP), CD28 and B cells; however, T(FR) cells originate from thymic-derived Foxp3(+) precursors, not naive or T(FH) cells. T(FR) cells are suppressive in vitro and limit T(FH) cell and germinal center B cell numbers in vivo. In the absence of T(FR) cells, an outgrowth of non-antigen-specific B cells in germinal centers leads to fewer antigen-specific cells. Thus, the T(FH) differentiation pathway is co-opted by T(reg) cells to control the germinal center response.", + "TAG_DATA": [ + "108, T(FR) {'context': 'B-cells'}", + "112, in {'context': 'B-in vitro'}", + "113, vitro {'context': 'I-in vitro'}", + "116, T(FH) {'context': 'B-cells'}", + "119, germinal {'context': 'B-cells'}", + "120, center {'context': 'I-cells'}", + "121, B {'context': 'I-cells'}", + "122, cell {'context': 'I-cells'}", + "124, in {'context': 'B-in vivo'}", + "125, vivo. {'context': 'I-in vivo'}", + "128, absence {'perturbing_action': 'B-gene loss-of-function'}", + "130, T(FR) {'context': 'B-cells'}", + "131, cells, {'context': 'I-cells'}", + "135, non-antigen-specific {'context': 'B-cells'}", + "136, B {'context': 'I-cells'}", + "137, cells {'context': 'I-cells'}", + "144, antigen-specific {'context': 'B-cells'}", + "145, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "108, T(FR) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "112, in ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "113, vitro ['l1', 'l14', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "116, T(FH) ['l2', 'l15', 'l22', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "119, germinal ['l3', 'l16', 'l23', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "120, center ['l4', 'l17', 'l24', 'l30', 'l35', 'l40', 'l41', 'l42', 'l43']", + "121, B ['l5', 'l18', 'l25', 'l31', 'l36', 'l40', 'l44', 'l45', 'l46']", + "122, cell ['l6', 'l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l47']", + "124, in ['l7', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l48']", + "125, vivo. ['l8', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48']", + "128, absence ['l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "130, T(FR) ['l49', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "131, cells, ['l9', 'l50', 'l56', 'l62', 'l63', 'l64', 'l65', 'l66']", + "135, non-antigen-specific ['l10', 'l51', 'l57', 'l62', 'l67', 'l68', 'l69', 'l70']", + "136, B ['l11', 'l52', 'l58', 'l63', 'l67', 'l71', 'l72', 'l73']", + "137, cells ['l12', 'l53', 'l59', 'l64', 'l68', 'l71', 'l74', 'l75']", + "144, antigen-specific ['l54', 'l60', 'l65', 'l69', 'l72', 'l74', 'l76']", + "145, cells. ['l13', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l76']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence" + ] + }, + "context": { + "val": "cells", + "words": [ + "T(FR)", + "cells,", + "non-antigen-specific", + "B", + "cells", + "antigen-specific", + "cells." + ] + } + } + ] + }, + { + "PMID": "21785432", + "TEXT": "Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. Mutations in the 27-kDa small heat-shock protein gene (HSPB1) cause axonal CMT or distal hereditary motor neuropathy (distal HMN). We developed and characterized transgenic mice expressing two different HSPB1 mutations (S135F and P182L) in neurons only. These mice showed all features of CMT or distal HMN dependent on the mutation. Expression of mutant HSPB1 decreased acetylated α-tubulin abundance and induced severe axonal transport deficits. An increase of α-tubulin acetylation induced by pharmacological inhibition of histone deacetylase 6 (HDAC6) corrected the axonal transport defects caused by HSPB1 mutations and rescued the CMT phenotype of symptomatic mutant HSPB1 mice. Our findings demonstrate the pathogenic role of α-tubulin deacetylation in mutant HSPB1-induced neuropathies and offer perspectives for using HDAC6 inhibitors as a therapeutic strategy for hereditary axonopathies.", + "TAG_DATA": [ + "37, transgenic {'context': 'B-organism'}", + "38, mice {'context': 'I-organism'}", + "40, two {'perturbing_action': 'I-other'}", + "41, different {'perturbing_action': 'I-other'}", + "42, HSPB1 {'perturbing_action': 'I-other'}", + "43, mutations {'perturbing_action': 'I-other'}", + "44, (S135F {'perturbing_action': 'I-other'}", + "45, and {'perturbing_action': 'I-other'}", + "46, P182L) {'perturbing_action': 'I-other'}", + "48, neurons {'context': 'B-cells'}", + "49, only. {'context': 'B-cells'}", + "51, mice {'context': 'B-organism'}", + "64, Expression {'perturbing_action': 'B-other'}", + "65, of {'perturbing_action': 'I-other'}", + "66, mutant {'perturbing_action': 'I-other'}", + "67, HSPB1 {'perturbing_action': 'I-other'}", + "85, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "86, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "87, of {'perturbing_action': 'I-pharmacological inhibition'}", + "88, histone {'perturbing_action': 'I-pharmacological inhibition'}", + "89, deacetylase {'perturbing_action': 'I-pharmacological inhibition'}", + "90, 6 {'perturbing_action': 'I-pharmacological inhibition'}", + "91, (HDAC6) {'perturbing_action': 'I-pharmacological inhibition'}", + "99, HSPB1 {'perturbing_action': 'B-other'}", + "100, mutations {'perturbing_action': 'I-other'}", + "102, rescued {'effect': 'B-rescues'}", + "104, CMT {'phenotype': 'B-epithelial-mesenchymal transition'}", + "105, phenotype {'phenotype': 'I-senescence'}", + "107, symptomatic {'perturbing_action': 'B-other'}", + "108, mutant {'perturbing_action': 'I-other'}", + "109, HSPB1 {'perturbing_action': 'I-other'}", + "110, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "37, transgenic ['l0', 'l1', 'l2', 'l3']", + "38, mice ['l0', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "40, two ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "41, different ['l10', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "42, HSPB1 ['l11', 'l23', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "43, mutations ['l12', 'l24', 'l35', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "44, (S135F ['l4', 'l13', 'l25', 'l36', 'l46', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "45, and ['l5', 'l14', 'l26', 'l37', 'l47', 'l56', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "46, P182L) ['l15', 'l27', 'l38', 'l48', 'l57', 'l65', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "48, neurons ['l1', 'l6', 'l16', 'l28', 'l39', 'l49', 'l58', 'l66', 'l73', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "49, only. ['l2', 'l7', 'l17', 'l29', 'l40', 'l50', 'l59', 'l67', 'l74', 'l80', 'l86', 'l87', 'l88']", + "51, mice ['l3', 'l8', 'l18', 'l30', 'l41', 'l51', 'l60', 'l68', 'l75', 'l81', 'l86', 'l89', 'l90', 'l91', 'l92']", + "64, Expression ['l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l76', 'l82', 'l89', 'l93', 'l94', 'l95']", + "65, of ['l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l83', 'l90', 'l93', 'l96', 'l97']", + "66, mutant ['l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l87', 'l91', 'l94', 'l96', 'l98']", + "67, HSPB1 ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l88', 'l92', 'l95', 'l97', 'l98']", + "85, pharmacological ['l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "86, inhibition ['l99', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "87, of ['l100', 'l110', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "88, histone ['l101', 'l111', 'l120', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "89, deacetylase ['l102', 'l112', 'l121', 'l129', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "90, 6 ['l103', 'l113', 'l122', 'l130', 'l136', 'l143', 'l144', 'l145', 'l146', 'l147']", + "91, (HDAC6) ['l104', 'l114', 'l123', 'l131', 'l137', 'l143', 'l148', 'l149', 'l150', 'l151', 'l152']", + "99, HSPB1 ['l105', 'l115', 'l124', 'l132', 'l138', 'l144', 'l148', 'l153']", + "100, mutations ['l106', 'l116', 'l125', 'l133', 'l139', 'l145', 'l149', 'l153']", + "102, rescued ['l107', 'l117', 'l126', 'l134', 'l140', 'l146', 'l150', 'l154', 'l155', 'l156']", + "104, CMT ['l108', 'l118', 'l127', 'l141', 'l151', 'l154', 'l157', 'l158', 'l159', 'l160', 'l161']", + "105, phenotype ['l109', 'l119', 'l128', 'l135', 'l142', 'l147', 'l152', 'l155', 'l157', 'l162', 'l163', 'l164', 'l165']", + "107, symptomatic ['l158', 'l162', 'l166', 'l167', 'l168']", + "108, mutant ['l159', 'l163', 'l166', 'l169', 'l170']", + "109, HSPB1 ['l160', 'l164', 'l167', 'l169', 'l171']", + "110, mice. ['l156', 'l161', 'l165', 'l168', 'l170', 'l171']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "(S135F", + "and", + "HSPB1", + "two", + "different", + "mutations", + "P182L)", + "Expression", + "of", + "mutant", + "symptomatic" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "two", + "different", + "HSPB1", + "mutations", + "(S135F", + "and", + "P182L)", + "Expression", + "of", + "mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons", + "only." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "histone", + "deacetylase", + "6", + "(HDAC6)" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "deacetylase", + "(HDAC6)" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "CMT" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "histone", + "deacetylase", + "6", + "(HDAC6)" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "phenotype" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "CMT" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "phenotype" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "CMT" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "symptomatic", + "mutant", + "HSPB1" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "CMT" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "senescence", + "words": [ + "phenotype" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "symptomatic", + "mutant", + "HSPB1" + ] + } + }, + { + "phenotype": { + "val": "senescence", + "words": [ + "phenotype" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "21765404", + "TEXT": "Aluminum-based adjuvants (aluminum salts or alum) are widely used in human vaccination, although their mechanisms of action are poorly understood. Here we report that, in mice, alum causes cell death and the subsequent release of host cell DNA, which acts as a potent endogenous immunostimulatory signal mediating alum adjuvant activity. Furthermore, we propose that host DNA signaling differentially regulates IgE and IgG1 production after alum-adjuvanted immunization. We suggest that, on the one hand, host DNA induces primary B cell responses, including IgG1 production, through interferon response factor 3 (Irf3)-independent mechanisms. On the other hand, we suggest that host DNA also stimulates 'canonical' T helper type 2 (T(H)2) responses, associated with IgE isotype switching and peripheral effector responses, through Irf3-dependent mechanisms. The finding that host DNA released from dying cells acts as a damage-associated molecular pattern that mediates alum adjuvant activity may increase our understanding of the mechanisms of action of current vaccines and help in the design of new adjuvants.", + "TAG_DATA": [ + "25, mice, {'context': 'B-organism'}", + "27, causes {'effect': 'B-positive'}", + "28, cell {'phenotype': 'B-cell death'}", + "29, death {'phenotype': 'I-cell death'}", + "77, B {'context': 'B-cells'}", + "78, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "25, mice, ['l0', 'l1', 'l2', 'l3', 'l4']", + "27, causes ['l0', 'l5', 'l6', 'l7', 'l8']", + "28, cell ['l1', 'l5', 'l9', 'l10', 'l11']", + "29, death ['l2', 'l6', 'l9', 'l12', 'l13']", + "77, B ['l3', 'l7', 'l10', 'l12', 'l14']", + "78, cell ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "positive", + "words": [ + "causes" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes" + ] + }, + "context": { + "val": "cells", + "words": [ + "B", + "cell" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "B", + "cell" + ] + } + } + ] + }, + { + "PMID": "21743453", + "TEXT": "Carvedilol is one of the most effective beta blockers for preventing ventricular tachyarrhythmias in heart failure, but the mechanisms underlying its favorable antiarrhythmic benefits remain unclear. Spontaneous Ca(2+) waves, also called store overload-induced Ca(2+) release (SOICR), evoke ventricular tachyarrhythmias in individuals with heart failure. Here we show that carvedilol is the only beta blocker tested that effectively suppresses SOICR by directly reducing the open duration of the cardiac ryanodine receptor (RyR2). This unique anti-SOICR activity of carvedilol, combined with its beta-blocking activity, probably contributes to its favorable antiarrhythmic effect. To enable optimal titration of carvedilol's actions as a beta blocker and as a suppressor of SOICR separately, we developed a new SOICR-inhibiting, minimally beta-blocking carvedilol analog, VK-II-86. VK-II-86 prevented stress-induced ventricular tachyarrhythmias in RyR2-mutant mice and did so more effectively when combined with either of the selective beta blockers metoprolol or bisoprolol. Combining SOICR inhibition with optimal beta blockade has the potential to provide antiarrhythmic therapy that can be tailored to individual patients.", + "TAG_DATA": [ + "123, RyR2-mutant {'perturbing_action': 'B-other'}", + "124, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "123, RyR2-mutant ['l0']", + "124, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "RyR2-mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "21642978", + "TEXT": "Obesity-related hypertension has become an epidemic health problem and a major risk factor for the development of cardiovascular disease (CVD). Recent research on the pathophysiology of obesity has implicated a role for the hypothalamus in the pathogenesis of this condition. However, it remains unknown whether the often-seen coupling of hypertension with obesity can also be explained by hypothalamic dysfunction, despite the emerging appreciation that many forms of hypertension are neurogenic in origin. Our studies here revealed that acute activation of the proinflammatory protein nuclear factor κB (NF-κB) and its upstream activator IκB kinase-β (IKK-β, encoded by Ikbkb) in the mediobasal hypothalamus rapidly elevated blood pressure in mice independently of obesity. This form of hypothalamic inflammation-induced hypertension involved the sympathetic upregulation of hemodynamics and was reversed by sympathetic suppression. Loss-of-function studies further showed that NF-κB inhibition in the mediobasal hypothalamus counteracted obesity-related hypertension in a manner that was dissociable from changes in body weight. In addition, we found that pro-opiomelanocortin (POMC) neurons were crucial for the hypertensive effects of the activation of hypothalamic IKK-β and NF-κB, which underlie obesity-related hypertension. In conclusion, obesity-associated activation of IKK-β and NF-κB in the mediobasal hypothalamus--particularly in the hypothalamic POMC neurons--is a primary pathogenic link between obesity and hypertension. Breaking this pathogenic link may represent an avenue for controlling obesity-related hypertension and CVD without requiring obesity control.", + "TAG_DATA": [ + "99, mediobasal {'context': 'B-tissue/organ'}", + "100, hypothalamus {'context': 'I-tissue/organ'}", + "106, mice {'context': 'B-organism'}", + "133, NF-κB {'perturbing_action': 'B-pharmacological inhibition'}", + "134, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "137, mediobasal {'context': 'B-tissue/organ'}", + "138, hypothalamus {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "99, mediobasal ['l0', 'l1']", + "100, hypothalamus ['l0', 'l2']", + "106, mice ['l1', 'l2']", + "133, NF-κB ['l3', 'l4', 'l5']", + "134, inhibition ['l3', 'l6', 'l7']", + "137, mediobasal ['l4', 'l6', 'l8']", + "138, hypothalamus ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NF-κB", + "inhibition" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mediobasal", + "hypothalamus" + ] + } + } + ] + }, + { + "PMID": "21623381", + "TEXT": "Myotonic dystrophy is the most common muscular dystrophy in adults and the first recognized example of an RNA-mediated disease. Congenital myotonic dystrophy (CDM1) and myotonic dystrophy of type 1 (DM1) or of type 2 (DM2) are caused by the expression of mutant RNAs containing expanded CUG or CCUG repeats, respectively. These mutant RNAs sequester the splicing regulator Muscleblind-like-1 (MBNL1), resulting in specific misregulation of the alternative splicing of other pre-mRNAs. We found that alternative splicing of the bridging integrator-1 (BIN1) pre-mRNA is altered in skeletal muscle samples of people with CDM1, DM1 and DM2. BIN1 is involved in tubular invaginations of membranes and is required for the biogenesis of muscle T tubules, which are specialized skeletal muscle membrane structures essential for excitation-contraction coupling. Mutations in the BIN1 gene cause centronuclear myopathy, which shares some histopathological features with myotonic dystrophy. We found that MBNL1 binds the BIN1 pre-mRNA and regulates its alternative splicing. BIN1 missplicing results in expression of an inactive form of BIN1 lacking phosphatidylinositol 5-phosphate-binding and membrane-tubulating activities. Consistent with a defect of BIN1, muscle T tubules are altered in people with myotonic dystrophy, and membrane structures are restored upon expression of the normal splicing form of BIN1 in muscle cells of such individuals. Finally, reproducing BIN1 splicing alteration in mice is sufficient to promote T tubule alterations and muscle weakness, a predominant feature of myotonic dystrophy.", + "TAG_DATA": [ + "160, form {'perturbing_action': 'I-other'}", + "200, muscle {'context': 'B-cells'}", + "201, cells {'context': 'I-cells'}", + "211, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "160, form ['l0', 'l1']", + "200, muscle ['l0', 'l2', 'l3']", + "201, cells ['l1', 'l2']", + "211, mice ['l3']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "form" + ] + }, + "context": { + "val": "cells", + "words": [ + "muscle", + "cells" + ] + } + } + ] + }, + { + "PMID": "21499268", + "TEXT": "Attention deficit hyperactivity disorder (ADHD) is a psychiatric disorder that affects ~5% of school-aged children; however, the mechanisms underlying ADHD remain largely unclear. Here we report a previously unidentified association between G protein-coupled receptor kinase-interacting protein-1 (GIT1) and ADHD in humans. An intronic single-nucleotide polymorphism in GIT1, the minor allele of which causes reduced GIT1 expression, shows a strong association with ADHD susceptibility in humans. Git1-deficient mice show ADHD-like phenotypes, with traits including hyperactivity, enhanced electroencephalogram theta rhythms and impaired learning and memory. Hyperactivity in Git1(-/-) mice is reversed by amphetamine and methylphenidate, psychostimulants commonly used to treat ADHD. In addition, amphetamine normalizes enhanced theta rhythms and impaired memory. GIT1 deficiency in mice leads to decreases in ras-related C3 botulinum toxin substrate-1 (RAC1) signaling and inhibitory presynaptic input; furthermore, it shifts the neuronal excitation-inhibition balance in postsynaptic neurons toward excitation. Our study identifies a previously unknown involvement of GIT1 in human ADHD and shows that GIT1 deficiency in mice causes psychostimulant-responsive ADHD-like phenotypes.", + "TAG_DATA": [ + "65, Git1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "66, mice {'context': 'B-organism'}", + "85, Git1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "86, mice {'context': 'B-organism'}", + "109, GIT1 {'perturbing_action': 'B-gene loss-of-function'}", + "110, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "112, mice {'context': 'B-organism'}", + "155, GIT1 {'perturbing_action': 'B-gene loss-of-function'}", + "156, deficiency {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "65, Git1-deficient ['l0']", + "66, mice ['l0']", + "85, Git1(-/-) ['l1']", + "86, mice ['l1']", + "109, GIT1 ['l2', 'l3', 'l4']", + "110, deficiency ['l2', 'l5']", + "112, mice ['l3', 'l5']", + "155, GIT1 ['l6']", + "156, deficiency ['l4', 'l6']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Git1-deficient", + "Git1(-/-)", + "GIT1", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "21423182", + "TEXT": "In multiple sclerosis, activated CD4(+) T cells initiate an immune response in the brain and spinal cord, resulting in demyelination, degeneration and progressive paralysis. Repulsive guidance molecule-a (RGMa) is an axon guidance molecule that has a role in the visual system and in neural tube closure. Our study shows that RGMa is expressed in bone marrow-derived dendritic cells (BMDCs) and that CD4(+) T cells express neogenin, a receptor for RGMa. Binding of RGMa to CD4(+) T cells led to activation of the small GTPase Rap1 and increased adhesion of T cells to intracellular adhesion molecule-1 (ICAM-1). Neutralizing antibodies to RGMa attenuated clinical symptoms of mouse myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) and reduced invasion of inflammatory cells into the CNS. Silencing of RGMa in MOG-pulsed BMDCs reduced their capacity to induce EAE following adoptive transfer to naive C57BL/6 mice. CD4(+) T cells isolated from mice treated with an RGMa-specific antibody showed diminished proliferative responses and reduced interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-4 and IL-17 secretion. Incubation of PBMCs from patients with multiple sclerosis with an RGMa-specific antibody reduced proliferative responses and pro-inflammatory cytokine expression. These results demonstrate that an RGMa-specific antibody suppresses T cell responses, and suggest that RGMa could be a promising molecular target for the treatment of multiple sclerosis.", + "TAG_DATA": [ + "74, CD4(+) {'context': 'B-cells'}", + "75, T {'context': 'I-cells'}", + "76, cells {'context': 'I-cells'}", + "86, increased {'effect': 'B-positive'}", + "89, T {'context': 'B-cells'}", + "90, cells {'context': 'B-cells'}", + "117, inflammatory {'context': 'B-cells'}", + "118, cells {'context': 'I-cells'}", + "122, Silencing {'perturbing_action': 'B-rnai/knockdown'}", + "123, of {'perturbing_action': 'I-rnai/knockdown'}", + "124, RGMa {'perturbing_action': 'I-rnai/knockdown'}", + "127, BMDCs {'context': 'B-cells'}", + "139, C57BL/6 {'context': 'I-organism'}", + "140, mice. {'context': 'I-organism'}", + "141, CD4(+) {'context': 'B-cells'}", + "142, T {'context': 'I-cells'}", + "143, cells {'context': 'I-cells'}", + "146, mice {'context': 'B-organism'}", + "153, diminished {'effect': 'B-negative'}", + "154, proliferative {'phenotype': 'B-proliferation'}", + "155, responses {'phenotype': 'I-proliferation'}", + "168, PBMCs {'context': 'B-cells'}", + "169, from {'context': 'I-patient'}", + "170, patients {'context': 'I-patient'}", + "171, with {'context': 'I-patient'}", + "178, reduced {'effect': 'B-negative'}", + "179, proliferative {'phenotype': 'B-proliferation'}", + "180, responses {'phenotype': 'I-proliferation'}" + ], + "LINK_DATA": [ + "74, CD4(+) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "75, T ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "76, cells ['l1', 'l7', 'l12', 'l13', 'l14']", + "86, increased ['l2', 'l8', 'l12', 'l15', 'l16']", + "89, T ['l3', 'l9', 'l13', 'l15', 'l17', 'l18']", + "90, cells ['l4', 'l10', 'l14', 'l16', 'l17', 'l19']", + "117, inflammatory ['l5', 'l20']", + "118, cells ['l6', 'l11', 'l18', 'l19', 'l20']", + "122, Silencing ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "123, of ['l21', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "124, RGMa ['l22', 'l33', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "127, BMDCs ['l23', 'l34', 'l44', 'l52', 'l53']", + "139, C57BL/6 ['l24', 'l35', 'l45', 'l52', 'l54']", + "140, mice. ['l25', 'l36', 'l46', 'l53', 'l54']", + "141, CD4(+) ['l26', 'l37', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "142, T ['l27', 'l38', 'l47', 'l55', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "143, cells ['l28', 'l39', 'l48', 'l56', 'l64', 'l70', 'l71', 'l72', 'l73']", + "146, mice ['l29', 'l40', 'l57', 'l65', 'l70', 'l74', 'l75', 'l76', 'l77']", + "153, diminished ['l30', 'l41', 'l49', 'l58', 'l66', 'l71', 'l74', 'l78', 'l79']", + "154, proliferative ['l31', 'l42', 'l50', 'l59', 'l67', 'l72', 'l75', 'l78', 'l80']", + "155, responses ['l32', 'l43', 'l51', 'l60', 'l68', 'l73', 'l76', 'l79', 'l80']", + "168, PBMCs ['l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "169, from ['l61', 'l81', 'l87', 'l88', 'l89', 'l90', 'l91']", + "170, patients ['l82', 'l87', 'l92', 'l93', 'l94', 'l95']", + "171, with ['l83', 'l88', 'l92', 'l96', 'l97', 'l98']", + "178, reduced ['l84', 'l89', 'l93', 'l96', 'l99', 'l100']", + "179, proliferative ['l62', 'l85', 'l90', 'l94', 'l97', 'l99', 'l101']", + "180, responses ['l63', 'l69', 'l77', 'l86', 'l91', 'l95', 'l98', 'l100', 'l101']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "RGMa" + ] + }, + "context": { + "val": "cells", + "words": [ + "BMDCs", + "CD4(+)", + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "RGMa" + ] + }, + "context": { + "val": "organism", + "words": [ + "C57BL/6", + "mice.", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "RGMa" + ] + }, + "effect": { + "val": "negative", + "words": [ + "diminished" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "RGMa" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "responses" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cells", + "PBMCs" + ] + }, + "effect": { + "val": "negative", + "words": [ + "diminished", + "reduced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cells", + "PBMCs" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "responses" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "diminished" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "responses" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "diminished", + "reduced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "responses" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "from", + "patients", + "with" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "from", + "patients", + "with" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "responses" + ] + } + } + ] + }, + { + "PMID": "21336284", + "TEXT": "Huntington's disease is an inherited and incurable neurodegenerative disorder caused by an abnormal polyglutamine (polyQ) expansion in huntingtin (encoded by HTT). PolyQ length determines disease onset and severity, with a longer expansion causing earlier onset. The mechanisms of mutant huntingtin-mediated neurotoxicity remain unclear; however, mitochondrial dysfunction is a key event in Huntington's disease pathogenesis. Here we tested whether mutant huntingtin impairs the mitochondrial fission-fusion balance and thereby causes neuronal injury. We show that mutant huntingtin triggers mitochondrial fragmentation in rat neurons and fibroblasts of individuals with Huntington's disease in vitro and in a mouse model of Huntington's disease in vivo before the presence of neurological deficits and huntingtin aggregates. Mutant huntingtin abnormally interacts with the mitochondrial fission GTPase dynamin-related protein-1 (DRP1) in mice and humans with Huntington's disease, which, in turn, stimulates its enzymatic activity. Mutant huntingtin-mediated mitochondrial fragmentation, defects in anterograde and retrograde mitochondrial transport and neuronal cell death are all rescued by reducing DRP1 GTPase activity with the dominant-negative DRP1 K38A mutant. Thus, DRP1 might represent a new therapeutic target to combat neurodegeneration in Huntington's disease.", + "TAG_DATA": [ + "73, mutant {'perturbing_action': 'B-other'}", + "74, huntingtin {'perturbing_action': 'I-other'}", + "79, rat {'context': 'B-cells'}", + "80, neurons {'context': 'I-cells'}", + "82, fibroblasts {'context': 'B-cells'}", + "84, individuals {'context': 'B-patient'}", + "88, in {'context': 'B-in vitro'}", + "89, vitro {'context': 'I-in vitro'}", + "93, mouse {'context': 'B-organism'}", + "94, model {'context': 'I-organism'}", + "95, of {'context': 'I-organism'}", + "96, Huntington's {'context': 'I-organism'}", + "97, disease {'context': 'I-organism'}", + "98, in {'context': 'B-in vivo'}", + "99, vivo {'context': 'I-in vivo'}", + "148, cell {'phenotype': 'B-cell death'}", + "149, death {'phenotype': 'I-cell death'}", + "160, dominant-negative {'perturbing_action': 'B-other'}", + "161, DRP1 {'perturbing_action': 'I-other'}", + "162, K38A {'perturbing_action': 'I-other'}", + "163, mutant. {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "73, mutant ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "74, huntingtin ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "79, rat ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "80, neurons ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "82, fibroblasts ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "84, individuals ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "88, in ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "89, vitro ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "93, mouse ['l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "94, model ['l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "95, of ['l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "96, Huntington's ['l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "97, disease ['l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "98, in ['l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "99, vivo ['l33', 'l38', 'l42', 'l45', 'l47', 'l48']", + "148, cell ['l49']", + "149, death ['l49']", + "160, dominant-negative ['l50', 'l51', 'l52']", + "161, DRP1 ['l50', 'l53', 'l54']", + "162, K38A ['l51', 'l53', 'l55']", + "163, mutant. ['l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "huntingtin" + ] + }, + "context": { + "val": "cells", + "words": [ + "rat", + "neurons", + "fibroblasts" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "huntingtin" + ] + }, + "context": { + "val": "patient", + "words": [ + "individuals" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "huntingtin" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "21297617", + "TEXT": "Pseudomonas aeruginosa is a Gram-negative pathogen that causes severe infections in immunocompromised individuals and individuals with cystic fibrosis or chronic obstructive pulmonary disease (COPD). Here we show that kinase suppressor of Ras-1 (Ksr1)-deficient mice are highly susceptible to pulmonary P. aeruginosa infection accompanied by uncontrolled pulmonary cytokine release, sepsis and death, whereas wild-type mice clear the infection. Ksr1 recruits and assembles inducible nitric oxide (NO) synthase (iNOS) and heat shock protein-90 (Hsp90) to enhance iNOS activity and to release NO upon infection. Ksr1 deficiency prevents lung alveolar macrophages and neutrophils from activating iNOS, producing NO and killing bacteria. Restoring NO production restores the bactericidal capability of Ksr1-deficient lung alveolar macrophages and neutrophils and rescues Ksr1-deficient mice from P. aeruginosa infection. Our findings suggest that Ksr1 functions as a previously unknown scaffold that enhances iNOS activity and is therefore crucial for the pulmonary response to P. aeruginosa infections.", + "TAG_DATA": [ + "28, kinase {'perturbing_action': 'B-gene loss-of-function'}", + "29, suppressor {'perturbing_action': 'I-gene loss-of-function'}", + "30, of {'perturbing_action': 'I-gene loss-of-function'}", + "31, Ras-1 {'perturbing_action': 'I-gene loss-of-function'}", + "32, (Ksr1)-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "33, mice {'context': 'B-organism'}", + "82, Ksr1 {'perturbing_action': 'B-gene loss-of-function'}", + "83, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "85, lung {'context': 'B-cells'}", + "86, alveolar {'context': 'I-cells'}", + "87, macrophages {'context': 'I-cells'}", + "89, neutrophils {'context': 'B-cells'}", + "106, Ksr1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "107, lung {'context': 'B-cells'}", + "108, alveolar {'context': 'I-cells'}", + "109, macrophages {'context': 'I-cells'}", + "111, neutrophils {'context': 'B-cells'}", + "114, Ksr1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "115, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "28, kinase ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "29, suppressor ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "30, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "31, Ras-1 ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "32, (Ksr1)-deficient ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "33, mice ['l4', 'l12', 'l19', 'l25', 'l30']", + "82, Ksr1 ['l35', 'l36', 'l37', 'l38', 'l39']", + "83, deficiency ['l35', 'l40', 'l41', 'l42', 'l43']", + "85, lung ['l5', 'l13', 'l20', 'l26', 'l31', 'l36', 'l40', 'l44', 'l45', 'l46']", + "86, alveolar ['l6', 'l14', 'l21', 'l27', 'l32', 'l37', 'l41', 'l44', 'l47', 'l48']", + "87, macrophages ['l7', 'l15', 'l22', 'l28', 'l33', 'l38', 'l42', 'l45', 'l47', 'l49']", + "89, neutrophils ['l8', 'l16', 'l23', 'l29', 'l34', 'l39', 'l43', 'l46', 'l48', 'l49']", + "106, Ksr1-deficient ['l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "107, lung ['l50', 'l56', 'l57', 'l58', 'l59', 'l60']", + "108, alveolar ['l51', 'l56', 'l61', 'l62', 'l63', 'l64']", + "109, macrophages ['l52', 'l57', 'l61', 'l65', 'l66', 'l67']", + "111, neutrophils ['l53', 'l58', 'l62', 'l65', 'l68', 'l69']", + "114, Ksr1-deficient ['l54', 'l59', 'l63', 'l66', 'l68', 'l70']", + "115, mice ['l55', 'l60', 'l64', 'l67', 'l69', 'l70']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "kinase", + "suppressor", + "of", + "Ras-1", + "(Ksr1)-deficient", + "Ksr1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "kinase", + "suppressor", + "of", + "Ras-1", + "(Ksr1)-deficient", + "Ksr1", + "deficiency", + "Ksr1-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "lung", + "alveolar", + "macrophages", + "neutrophils" + ] + } + } + ] + }, + { + "PMID": "21151138", + "TEXT": "The main manifestations of nephrotic syndrome include proteinuria, hypoalbuminemia, edema, hyperlipidemia and lipiduria. Common causes of nephrotic syndrome are diabetic nephropathy, minimal change disease (MCD), focal and segmental glomerulosclerosis (FSGS) and membranous nephropathy. Among the primary glomerular diseases, MCD is usually sensitive to glucocorticoid treatment, whereas the other diseases show variable responses. Despite the identification of key structural proteins in the glomerular capillary loop which may contribute to defects in ultrafiltration, many of the disease mechanisms of nephrotic syndrome remain unresolved. In this study, we show that the glomerular expression of angiopoietin-like-4 (Angptl4), a secreted glycoprotein, is glucocorticoid sensitive and is highly upregulated in the serum and in podocytes in experimental models of MCD and in the human disease. Podocyte-specific transgenic overexpression of Angptl4 (NPHS2-Angptl4) in rats induced nephrotic-range, and selective, proteinuria (over 500-fold increase in albuminuria), loss of glomerular basement membrane (GBM) charge and foot process effacement, whereas transgenic expression specifically in the adipose tissue (aP2-Angptl4) resulted in increased circulating Angptl4, but no proteinuria. Angptl4(-/-) mice that were injected with lipopolysaccharide (LPS) or nephritogenic antisera developed markedly less proteinuria than did control mice. Angptl4 secreted from podocytes in some forms of nephrotic syndrome lacks normal sialylation. When we fed the sialic acid precursor N-acetyl-D-mannosamine (ManNAc) to NPHS2-Angptl4 transgenic rats it increased the sialylation of Angptl4 and decreased albuminuria by more than 40%. These results suggest that podocyte-secreted Angptl4 has a key role in nephrotic syndrome.", + "TAG_DATA": [ + "119, Podocyte-specific {'perturbing_action': 'B-gene gain-of-function'}", + "120, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "121, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "122, of {'perturbing_action': 'I-gene gain-of-function'}", + "123, Angptl4 {'perturbing_action': 'I-gene gain-of-function'}", + "124, (NPHS2-Angptl4) {'perturbing_action': 'I-gene gain-of-function'}", + "126, rats {'context': 'B-organism'}", + "149, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "150, expression {'perturbing_action': 'I-gene gain-of-function'}", + "151, specifically {'perturbing_action': 'I-gene gain-of-function'}", + "152, in {'perturbing_action': 'I-gene gain-of-function'}", + "153, the {'perturbing_action': 'I-gene gain-of-function'}", + "154, adipose {'perturbing_action': 'I-gene gain-of-function'}", + "155, tissue {'perturbing_action': 'I-gene gain-of-function'}", + "156, (aP2-Angptl4) {'perturbing_action': 'I-gene gain-of-function'}", + "165, Angptl4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "166, mice {'context': 'B-organism'}", + "183, mice. {'context': 'B-organism'}", + "207, NPHS2-Angptl4 {'perturbing_action': 'B-gene gain-of-function'}", + "208, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "209, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "119, Podocyte-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "120, transgenic ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "121, overexpression ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "122, of ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "123, Angptl4 ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "124, (NPHS2-Angptl4) ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "126, rats ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "149, transgenic ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "150, expression ['l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "151, specifically ['l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "152, in ['l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "153, the ['l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "154, adipose ['l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "155, tissue ['l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "156, (aP2-Angptl4) ['l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l48']", + "165, Angptl4(-/-) ['l49', 'l50']", + "166, mice ['l49', 'l51']", + "183, mice. ['l50', 'l51']", + "207, NPHS2-Angptl4 ['l52', 'l53']", + "208, transgenic ['l52', 'l54']", + "209, rats ['l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Podocyte-specific", + "transgenic", + "overexpression", + "of", + "Angptl4", + "(NPHS2-Angptl4)", + "NPHS2-Angptl4" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Angptl4(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "21131957", + "TEXT": "MicroRNAs are a family of regulatory molecules involved in many physiological processes, including differentiation and activation of cells of the immune system. We found that brain-specific miR-124 is expressed in microglia but not in peripheral monocytes or macrophages. When overexpressed in macrophages, miR-124 directly inhibited the transcription factor CCAAT/enhancer-binding protein-α (C/EBP-α) and its downstream target PU.1, resulting in transformation of these cells from an activated phenotype into a quiescent CD45(low), major histocompatibility complex (MHC) class II(low) phenotype resembling resting microglia. During experimental autoimmune encephalomyelitis (EAE), miR-124 was downregulated in activated microglia. Peripheral administration of miR-124 in EAE caused systemic deactivation of macrophages, reduced activation of myelin-specific T cells and marked suppression of disease. Conversely, knockdown of miR-124 in microglia and macrophages resulted in activation of these cells in vitro and in vivo. These findings identify miR-124 both as a key regulator of microglia quiescence in the central nervous system and as a previously unknown modulator of monocyte and macrophage activation.", + "TAG_DATA": [ + "41, macrophages, {'context': 'B-cells'}", + "61, cells {'context': 'B-cells'}", + "90, microglia. {'context': 'B-cells'}", + "101, macrophages, {'context': 'B-cells'}", + "105, myelin-specific {'context': 'B-cells'}", + "106, T {'context': 'I-cells'}", + "107, cells {'context': 'I-cells'}", + "114, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "115, of {'perturbing_action': 'I-rnai/knockdown'}", + "116, miR-124 {'perturbing_action': 'I-rnai/knockdown'}", + "118, microglia {'context': 'B-cells'}", + "120, macrophages {'context': 'B-cells'}", + "126, cells {'context': 'B-cells'}", + "127, in {'context': 'B-in vitro'}", + "128, vitro {'context': 'I-in vitro'}", + "130, in {'context': 'B-in vivo'}", + "131, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "41, macrophages, ['l0']", + "61, cells ['l0']", + "90, microglia. ['l1', 'l2', 'l3']", + "101, macrophages, ['l1', 'l4', 'l5', 'l6']", + "105, myelin-specific ['l4', 'l7', 'l8']", + "106, T ['l2', 'l5', 'l7', 'l9']", + "107, cells ['l3', 'l6', 'l8', 'l9']", + "114, knockdown ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "115, of ['l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "116, miR-124 ['l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "118, microglia ['l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "120, macrophages ['l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "126, cells ['l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "127, in ['l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "128, vitro ['l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "130, in ['l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "131, vivo. ['l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "miR-124" + ] + }, + "context": { + "val": "cells", + "words": [ + "microglia", + "macrophages", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "miR-124" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "miR-124" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "21076394", + "TEXT": "Basal tearing is crucial to maintaining ocular surface wetness. Corneal cold thermoreceptors sense small oscillations in ambient temperature and change their discharge accordingly. Deletion of the cold-transducing ion channel Transient receptor potential cation channel subfamily M member 8 (TRPM8) in mice abrogates cold responsiveness and reduces basal tearing without affecting nociceptor-mediated irritative tearing. Warming of the cornea in humans also decreases tearing rate. These findings indicate that TRPM8-dependent impulse activity in corneal cold receptors contributes to regulating basal tear flow.", + "TAG_DATA": [ + "23, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "24, of {'perturbing_action': 'I-gene loss-of-function'}", + "25, the {'perturbing_action': 'I-gene loss-of-function'}", + "26, cold-transducing {'perturbing_action': 'I-gene loss-of-function'}", + "27, ion {'perturbing_action': 'I-gene loss-of-function'}", + "28, channel {'perturbing_action': 'I-gene loss-of-function'}", + "29, Transient {'perturbing_action': 'I-gene loss-of-function'}", + "30, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "31, potential {'perturbing_action': 'I-gene loss-of-function'}", + "32, cation {'perturbing_action': 'I-gene loss-of-function'}", + "33, channel {'perturbing_action': 'I-gene loss-of-function'}", + "34, subfamily {'perturbing_action': 'I-gene loss-of-function'}", + "35, M {'perturbing_action': 'I-gene loss-of-function'}", + "36, member {'perturbing_action': 'I-gene loss-of-function'}", + "37, 8 {'perturbing_action': 'I-gene loss-of-function'}", + "38, (TRPM8) {'perturbing_action': 'I-gene loss-of-function'}", + "40, mice {'context': 'B-organism'}", + "56, cornea {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "23, Deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "24, of ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "25, the ['l1', 'l17', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "26, cold-transducing ['l2', 'l18', 'l33', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "27, ion ['l3', 'l19', 'l34', 'l48', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "28, channel ['l4', 'l20', 'l35', 'l49', 'l62', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "29, Transient ['l5', 'l21', 'l36', 'l50', 'l63', 'l75', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "30, receptor ['l6', 'l22', 'l37', 'l51', 'l64', 'l76', 'l87', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "31, potential ['l7', 'l23', 'l38', 'l52', 'l65', 'l77', 'l88', 'l98', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "32, cation ['l8', 'l24', 'l39', 'l53', 'l66', 'l78', 'l89', 'l99', 'l108', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "33, channel ['l9', 'l25', 'l40', 'l54', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "34, subfamily ['l10', 'l26', 'l41', 'l55', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l125', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "35, M ['l11', 'l27', 'l42', 'l56', 'l69', 'l81', 'l92', 'l102', 'l111', 'l119', 'l126', 'l132', 'l138', 'l139', 'l140', 'l141', 'l142']", + "36, member ['l12', 'l28', 'l43', 'l57', 'l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l127', 'l133', 'l138', 'l143', 'l144', 'l145', 'l146']", + "37, 8 ['l13', 'l29', 'l44', 'l58', 'l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l128', 'l134', 'l139', 'l143', 'l147', 'l148', 'l149']", + "38, (TRPM8) ['l14', 'l30', 'l45', 'l59', 'l72', 'l84', 'l95', 'l105', 'l114', 'l122', 'l129', 'l135', 'l140', 'l144', 'l147', 'l150', 'l151']", + "40, mice ['l15', 'l31', 'l46', 'l60', 'l73', 'l85', 'l96', 'l106', 'l115', 'l123', 'l130', 'l136', 'l141', 'l145', 'l148', 'l150']", + "56, cornea ['l16', 'l32', 'l47', 'l61', 'l74', 'l86', 'l97', 'l107', 'l116', 'l124', 'l131', 'l137', 'l142', 'l146', 'l149', 'l151']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "cold-transducing", + "ion", + "channel", + "Transient", + "receptor", + "potential", + "cation", + "subfamily", + "M", + "member", + "8", + "(TRPM8)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "cold-transducing", + "ion", + "channel", + "Transient", + "receptor", + "potential", + "cation", + "subfamily", + "M", + "member", + "8", + "(TRPM8)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "cornea" + ] + } + } + ] + }, + { + "PMID": "21057494", + "TEXT": "The transition from androgen-dependent to castration-resistant prostate cancer (CRPC) is a lethal event of uncertain molecular etiology. Comparing gene expression in isogenic androgen-dependent and CRPC xenografts, we found a reproducible increase in N-cadherin expression, which was also elevated in primary and metastatic tumors of individuals with CRPC. Ectopic expression of N-cadherin in nonmetastatic, androgen-dependent prostate cancer models caused castration resistance, invasion and metastasis. Monoclonal antibodies against the ectodomain of N-cadherin reduced proliferation, adhesion and invasion of prostate cancer cells in vitro. In vivo, these antibodies slowed the growth of multiple established CRPC xenografts, blocked local invasion and metastasis and, at higher doses, led to complete regression. N-cadherin-specific antibodies markedly delayed the time to emergence of castration resistance, markedly affected tumor histology and angiogenesis, and reduced both AKT serine-threonine kinase activity and serum interleukin-8 (IL-8) secretion. These data indicate that N-cadherin is a major cause of both prostate cancer metastasis and castration resistance. Therapeutic targeting of this factor with monoclonal antibodies may have considerable clinical benefit.", + "TAG_DATA": [ + "47, Ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "48, expression {'perturbing_action': 'I-gene gain-of-function'}", + "49, of {'perturbing_action': 'I-gene gain-of-function'}", + "50, N-cadherin {'perturbing_action': 'I-gene gain-of-function'}", + "52, nonmetastatic, {'context': 'B-neoplasm'}", + "53, androgen-dependent {'context': 'I-neoplasm'}", + "54, prostate {'context': 'I-neoplasm'}", + "55, cancer {'context': 'I-neoplasm'}", + "56, models {'context': 'I-neoplasm'}", + "57, caused {'effect': 'B-positive'}", + "60, invasion {'phenotype': 'B-invasion'}", + "62, metastasis. {'phenotype': 'B-metastasis'}", + "63, Monoclonal {'perturbing_action': 'B-rnai/knockdown'}", + "64, antibodies {'perturbing_action': 'I-rnai/knockdown'}", + "65, against {'perturbing_action': 'I-rnai/knockdown'}", + "66, the {'perturbing_action': 'I-rnai/knockdown'}", + "67, ectodomain {'perturbing_action': 'I-rnai/knockdown'}", + "68, of {'perturbing_action': 'I-rnai/knockdown'}", + "69, N-cadherin {'perturbing_action': 'I-rnai/knockdown'}", + "70, reduced {'effect': 'B-negative'}", + "71, proliferation, {'phenotype': 'B-proliferation'}", + "72, adhesion {'phenotype': 'B-adhesion'}", + "74, invasion {'phenotype': 'B-invasion'}", + "76, prostate {'context': 'B-transformed cells'}", + "77, cancer {'context': 'I-transformed cells'}", + "78, cells {'context': 'I-transformed cells'}", + "79, in {'context': 'B-in vitro'}", + "80, vitro. {'context': 'I-in vitro'}", + "81, In {'context': 'B-in vivo'}", + "82, vivo, {'context': 'I-in vivo'}", + "91, CRPC {'context': 'B-xenograft'}", + "92, xenografts, {'context': 'I-xenograft'}", + "93, blocked {'effect': 'B-negative'}", + "95, invasion {'phenotype': 'B-invasion'}", + "97, metastasis {'phenotype': 'B-metastasis'}", + "102, led {'effect': 'B-positive'}", + "103, to {'effect': 'I-positive'}", + "105, regression. {'phenotype': 'I-tumour regression'}", + "119, tumor {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "47, Ectopic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "48, expression ['l0', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "49, of ['l1', 'l27', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "50, N-cadherin ['l2', 'l28', 'l48', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "52, nonmetastatic, ['l3', 'l29', 'l49', 'l68', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "53, androgen-dependent ['l4', 'l30', 'l50', 'l69', 'l86', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "54, prostate ['l5', 'l31', 'l51', 'l70', 'l87', 'l102', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "55, cancer ['l6', 'l32', 'l52', 'l71', 'l88', 'l103', 'l117', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "56, models ['l7', 'l33', 'l53', 'l72', 'l89', 'l104', 'l118', 'l130', 'l141', 'l142', 'l143', 'l144', 'l145']", + "57, caused ['l8', 'l34', 'l54', 'l73', 'l90', 'l105', 'l119', 'l131', 'l141', 'l146', 'l147', 'l148']", + "60, invasion ['l9', 'l35', 'l55', 'l74', 'l91', 'l106', 'l120', 'l132', 'l142', 'l146', 'l149']", + "62, metastasis. ['l10', 'l36', 'l56', 'l75', 'l92', 'l107', 'l121', 'l133', 'l143', 'l147', 'l149', 'l150', 'l151']", + "63, Monoclonal ['l11', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "64, antibodies ['l12', 'l152', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "65, against ['l13', 'l153', 'l174', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215']", + "66, the ['l14', 'l154', 'l175', 'l195', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234']", + "67, ectodomain ['l15', 'l155', 'l176', 'l196', 'l216', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253']", + "68, of ['l16', 'l37', 'l57', 'l156', 'l177', 'l197', 'l217', 'l235', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270']", + "69, N-cadherin ['l17', 'l38', 'l58', 'l76', 'l157', 'l178', 'l198', 'l218', 'l236', 'l254', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286']", + "70, reduced ['l18', 'l39', 'l59', 'l77', 'l93', 'l108', 'l122', 'l134', 'l158', 'l179', 'l199', 'l219', 'l237', 'l255', 'l271', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294']", + "71, proliferation, ['l19', 'l40', 'l60', 'l78', 'l94', 'l109', 'l123', 'l135', 'l159', 'l180', 'l200', 'l220', 'l238', 'l256', 'l272', 'l287', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301']", + "72, adhesion ['l20', 'l41', 'l61', 'l79', 'l95', 'l110', 'l124', 'l136', 'l160', 'l181', 'l201', 'l221', 'l239', 'l257', 'l273', 'l288', 'l295', 'l302', 'l303', 'l304', 'l305', 'l306', 'l307']", + "74, invasion ['l21', 'l42', 'l62', 'l80', 'l96', 'l111', 'l125', 'l137', 'l161', 'l182', 'l202', 'l222', 'l240', 'l258', 'l274', 'l289', 'l296', 'l302', 'l308', 'l309', 'l310', 'l311']", + "76, prostate ['l22', 'l43', 'l63', 'l81', 'l97', 'l112', 'l126', 'l138', 'l162', 'l183', 'l203', 'l223', 'l241', 'l259', 'l275', 'l290', 'l297', 'l303', 'l308', 'l312', 'l313', 'l314', 'l315']", + "77, cancer ['l23', 'l44', 'l64', 'l82', 'l98', 'l113', 'l127', 'l139', 'l144', 'l150', 'l163', 'l184', 'l204', 'l224', 'l242', 'l260', 'l276', 'l291', 'l298', 'l304', 'l309', 'l312', 'l316', 'l317', 'l318']", + "78, cells ['l24', 'l45', 'l65', 'l83', 'l99', 'l114', 'l128', 'l140', 'l145', 'l148', 'l151', 'l164', 'l185', 'l205', 'l225', 'l243', 'l261', 'l277', 'l292', 'l299', 'l305', 'l310', 'l313', 'l316']", + "79, in ['l25', 'l46', 'l66', 'l84', 'l100', 'l115', 'l165', 'l186', 'l206', 'l226', 'l244', 'l262', 'l278', 'l293', 'l300', 'l306', 'l314', 'l317', 'l319']", + "80, vitro. ['l26', 'l47', 'l67', 'l85', 'l101', 'l116', 'l129', 'l166', 'l187', 'l207', 'l227', 'l245', 'l263', 'l279', 'l294', 'l301', 'l307', 'l311', 'l315', 'l318', 'l319']", + "81, In ['l167', 'l188', 'l208', 'l228', 'l246', 'l264', 'l280', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327']", + "82, vivo, ['l168', 'l189', 'l209', 'l229', 'l247', 'l265', 'l281', 'l320', 'l328', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334']", + "91, CRPC ['l169', 'l190', 'l210', 'l230', 'l248', 'l266', 'l282', 'l321', 'l328', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340', 'l341']", + "92, xenografts, ['l170', 'l191', 'l211', 'l231', 'l249', 'l267', 'l283', 'l322', 'l329', 'l335', 'l342', 'l343', 'l344', 'l345', 'l346']", + "93, blocked ['l171', 'l192', 'l212', 'l232', 'l250', 'l268', 'l284', 'l323', 'l330', 'l336', 'l342', 'l347', 'l348', 'l349', 'l350']", + "95, invasion ['l172', 'l193', 'l213', 'l233', 'l251', 'l269', 'l285', 'l324', 'l331', 'l337', 'l343', 'l347', 'l351', 'l352', 'l353']", + "97, metastasis ['l173', 'l194', 'l214', 'l234', 'l252', 'l270', 'l286', 'l325', 'l332', 'l338', 'l344', 'l348', 'l351', 'l354', 'l355', 'l356']", + "102, led ['l215', 'l253', 'l326', 'l333', 'l339', 'l345', 'l349', 'l352', 'l354', 'l357', 'l358']", + "103, to ['l327', 'l334', 'l340', 'l346', 'l350', 'l353', 'l355', 'l357', 'l359']", + "105, regression. ['l341', 'l356', 'l358', 'l359']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "N-cadherin" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "nonmetastatic,", + "androgen-dependent", + "prostate", + "cancer", + "models" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "N-cadherin" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "N-cadherin" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "N-cadherin" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "N-cadherin" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "N-cadherin" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "N-cadherin" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "N-cadherin" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "N-cadherin" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "nonmetastatic,", + "androgen-dependent", + "prostate", + "cancer", + "models" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "nonmetastatic,", + "androgen-dependent", + "prostate", + "cancer", + "models" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "nonmetastatic,", + "androgen-dependent", + "prostate", + "cancer", + "models" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "nonmetastatic,", + "androgen-dependent", + "prostate", + "cancer" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "nonmetastatic,", + "androgen-dependent", + "prostate", + "cancer" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "nonmetastatic,", + "androgen-dependent", + "prostate", + "cancer" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused", + "led", + "to" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused", + "led", + "to" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis.", + "metastasis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Monoclonal", + "antibodies", + "against", + "the", + "ectodomain", + "of", + "N-cadherin" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced", + "blocked" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Monoclonal", + "antibodies", + "against", + "the", + "ectodomain", + "of", + "N-cadherin" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Monoclonal", + "antibodies", + "against", + "the", + "ectodomain", + "of", + "N-cadherin" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Monoclonal", + "antibodies", + "against", + "the", + "ectodomain", + "of", + "N-cadherin" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Monoclonal", + "antibodies", + "against", + "the", + "ectodomain", + "of", + "N-cadherin" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Monoclonal", + "antibodies", + "against", + "the", + "ectodomain", + "of", + "N-cadherin" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Monoclonal", + "antibodies", + "against", + "the", + "ectodomain", + "of", + "N-cadherin" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Monoclonal", + "antibodies", + "against", + "the", + "ectodomain", + "of", + "N-cadherin" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "CRPC", + "xenografts," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Monoclonal", + "antibodies", + "against", + "the", + "ectodomain", + "of", + "N-cadherin" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "against", + "ectodomain" + ] + }, + "effect": { + "val": "positive", + "words": [ + "led" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced", + "blocked" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cells" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cells" + ] + } + }, + { + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cells" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "vitro." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "CRPC", + "xenografts," + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "CRPC", + "xenografts," + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "CRPC", + "xenografts," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "CRPC", + "xenografts," + ] + }, + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "CRPC" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression." + ] + } + } + ] + }, + { + "PMID": "21037587", + "TEXT": "Allergic asthma is a T helper type 2 (T(H)2)-dominated disease of the lung. In people with asthma, a fraction of CD4(+) T cells express the CX3CL1 receptor, CX3CR1, and CX3CL1 expression is increased in airway smooth muscle, lung endothelium and epithelium upon allergen challenge. Here we found that untreated CX3CR1-deficient mice or wild-type (WT) mice treated with CX3CR1-blocking reagents show reduced lung disease upon allergen sensitization and challenge. Transfer of WT CD4(+) T cells into CX3CR1-deficient mice restored the cardinal features of asthma, and CX3CR1-blocking reagents prevented airway inflammation in CX3CR1-deficient recipients injected with WT T(H)2 cells. We found that CX3CR1 signaling promoted T(H)2 survival in the inflamed lungs, and injection of B cell leukemia/lymphoma-2 protein (BCl-2)-transduced CX3CR1-deficient T(H)2 cells into CX3CR1-deficient mice restored asthma. CX3CR1-induced survival was also observed for T(H)1 cells upon airway inflammation but not under homeostatic conditions or upon peripheral inflammation. Therefore, CX3CR1 and CX3CL1 may represent attractive therapeutic targets in asthma.", + "TAG_DATA": [ + "49, CX3CR1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "50, mice {'context': 'B-organism'}", + "54, mice {'context': 'B-organism'}", + "61, lung {'context': 'B-tissue/organ'}", + "71, CD4(+) {'context': 'B-cells'}", + "72, T {'context': 'I-cells'}", + "73, cells {'context': 'I-cells'}", + "75, CX3CR1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "76, mice {'context': 'B-organism'}", + "90, CX3CR1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "91, recipients {'context': 'B-organism'}", + "95, T(H)2 {'context': 'B-cells'}", + "96, cells. {'context': 'I-cells'}", + "103, T(H)2 {'context': 'B-cells'}", + "108, lungs, {'context': 'B-tissue/organ'}", + "115, protein {'perturbing_action': 'I-gene gain-of-function'}", + "116, (BCl-2)-transduced {'perturbing_action': 'I-gene gain-of-function'}", + "117, CX3CR1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "118, T(H)2 {'context': 'B-cells'}", + "119, cells {'context': 'I-cells'}", + "121, CX3CR1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "122, mice {'context': 'B-organism'}", + "131, T(H)1 {'context': 'B-cells'}", + "132, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "49, CX3CR1-deficient ['l0', 'l1']", + "50, mice ['l0', 'l2']", + "54, mice ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "61, lung ['l1', 'l2', 'l3']", + "71, CD4(+) ['l4', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "72, T ['l5', 'l9', 'l15', 'l16', 'l17', 'l18']", + "73, cells ['l6', 'l10', 'l15', 'l19', 'l20']", + "75, CX3CR1-deficient ['l7', 'l11', 'l16', 'l19', 'l21', 'l22']", + "76, mice ['l8', 'l12', 'l17', 'l20', 'l21']", + "90, CX3CR1-deficient ['l23', 'l24', 'l25', 'l26', 'l27']", + "91, recipients ['l23', 'l28', 'l29', 'l30', 'l31']", + "95, T(H)2 ['l24', 'l28', 'l32', 'l33', 'l34']", + "96, cells. ['l13', 'l18', 'l22', 'l25', 'l29', 'l32', 'l35', 'l36']", + "103, T(H)2 ['l26', 'l30', 'l33', 'l35', 'l37']", + "108, lungs, ['l14', 'l27', 'l31', 'l34', 'l36', 'l37']", + "112, B ['l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "113, cell ['l38', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "114, leukemia/lymphoma-2 ['l39', 'l49', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "115, protein ['l40', 'l50', 'l59', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "116, (BCl-2)-transduced ['l41', 'l51', 'l60', 'l68', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "117, CX3CR1-deficient ['l42', 'l52', 'l61', 'l69', 'l76', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "118, T(H)2 ['l43', 'l53', 'l62', 'l70', 'l77', 'l83', 'l89', 'l90', 'l91', 'l92', 'l93']", + "119, cells ['l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l89', 'l94', 'l95', 'l96']", + "121, CX3CR1-deficient ['l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l94', 'l97', 'l98', 'l99']", + "122, mice ['l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l97']", + "131, T(H)1 ['l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l98', 'l100']", + "132, cells ['l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l96', 'l99', 'l100']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CX3CR1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "recipients" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CX3CR1-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung", + "lungs," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cells", + "cells.", + "T(H)2", + "T(H)1" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CX3CR1-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "protein", + "(BCl-2)-transduced" + ] + }, + "context": { + "val": "cells", + "words": [ + "T(H)2", + "cells", + "T(H)1" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "protein", + "(BCl-2)-transduced" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "20890291", + "TEXT": "CD8(+) T cells in chronic viral infections such as HIV develop functional defects including loss of interleukin-2 (IL-2) secretion and decreased proliferative potential that are collectively termed 'exhaustion'. Exhausted T cells express increased amounts of multiple inhibitory receptors, such as programmed death-1 (PD-1), that contribute to impaired virus-specific T cell function. Although reversing PD-1 inhibition is therefore an attractive therapeutic strategy, the cellular mechanisms by which PD-1 ligation results in T cell inhibition are not fully understood. PD-1 is thought to limit T cell activation by attenuating T cell receptor (TCR) signaling. It is not known whether PD-1 also acts by upregulating genes in exhausted T cells that impair their function. Here we analyzed gene expression profiles from HIV-specific CD8(+) T cells in individuals with HIV and show that PD-1 coordinately upregulates a program of genes in exhausted CD8(+) T cells from humans and mice. This program includes upregulation of basic leucine transcription factor, ATF-like (BATF), a transcription factor in the AP-1 family. Enforced expression of BATF was sufficient to impair T cell proliferation and cytokine secretion, whereas BATF knockdown reduced PD-1 inhibition. Silencing BATF in T cells from individuals with chronic viremia rescued HIV-specific T cell function. Thus, inhibitory receptors can cause T cell exhaustion by upregulating genes--such as BATF--that inhibit T cell function. Such genes may provide new therapeutic opportunities to improve T cell immunity to HIV.", + "TAG_DATA": [ + "163, Enforced {'perturbing_action': 'B-gene gain-of-function'}", + "164, expression {'perturbing_action': 'I-gene gain-of-function'}", + "165, of {'perturbing_action': 'I-gene gain-of-function'}", + "166, BATF {'perturbing_action': 'I-gene gain-of-function'}", + "170, impair {'effect': 'B-negative'}", + "171, T {'context': 'B-cells'}", + "172, cell {'context': 'B-cells'}", + "173, proliferation {'phenotype': 'B-proliferation'}", + "178, BATF {'perturbing_action': 'B-rnai/knockdown'}", + "179, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "183, Silencing {'perturbing_action': 'B-rnai/knockdown'}", + "184, BATF {'perturbing_action': 'I-rnai/knockdown'}", + "186, T {'context': 'B-cells'}", + "187, cells {'context': 'I-cells'}", + "194, HIV-specific {'context': 'B-cells'}", + "195, T {'context': 'I-cells'}", + "196, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "163, Enforced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "164, expression ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "165, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "166, BATF ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27']", + "170, impair ['l3', 'l11', 'l18', 'l24', 'l28', 'l29', 'l30']", + "171, T ['l4', 'l12', 'l19', 'l25', 'l28', 'l31', 'l32']", + "172, cell ['l5', 'l13', 'l20', 'l26', 'l29', 'l31', 'l33']", + "173, proliferation ['l6', 'l14', 'l21', 'l27', 'l30', 'l32', 'l33']", + "178, BATF ['l7', 'l15', 'l22', 'l34']", + "179, knockdown ['l8', 'l16', 'l23', 'l34']", + "183, Silencing ['l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "184, BATF ['l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "186, T ['l36', 'l41', 'l46', 'l47', 'l48', 'l49']", + "187, cells ['l37', 'l42', 'l46', 'l50', 'l51', 'l52']", + "194, HIV-specific ['l38', 'l43', 'l47', 'l50', 'l53', 'l54']", + "195, T ['l39', 'l44', 'l48', 'l51', 'l53', 'l55']", + "196, cell ['l40', 'l45', 'l49', 'l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced", + "expression", + "of", + "BATF" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impair" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced", + "expression", + "of", + "BATF" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced", + "expression", + "of", + "BATF" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impair" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impair" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "BATF" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "HIV-specific", + "cell" + ] + } + } + ] + }, + { + "PMID": "20818376", + "TEXT": "We have identified a new role for the matrix enzyme lysyl oxidase-like-2 (LOXL2) in the creation and maintenance of the pathologic microenvironment of cancer and fibrotic disease. Our analysis of biopsies from human tumors and fibrotic lung and liver tissues revealed an increase in LOXL2 in disease-associated stroma and limited expression in healthy tissues. Targeting LOXL2 with an inhibitory monoclonal antibody (AB0023) was efficacious in both primary and metastatic xenograft models of cancer, as well as in liver and lung fibrosis models. Inhibition of LOXL2 resulted in a marked reduction in activated fibroblasts, desmoplasia and endothelial cells, decreased production of growth factors and cytokines and decreased transforming growth factor-beta (TGF-beta) pathway signaling. AB0023 outperformed the small-molecule lysyl oxidase inhibitor beta-aminoproprionitrile. The efficacy and safety of LOXL2-specific AB0023 represents a new therapeutic approach with broad applicability in oncologic and fibrotic diseases.", + "TAG_DATA": [ + "54, Targeting {'perturbing_action': 'B-other'}", + "55, LOXL2 {'perturbing_action': 'I-other'}", + "56, with {'perturbing_action': 'I-other'}", + "57, an {'perturbing_action': 'I-rnai/knockdown'}", + "58, inhibitory {'perturbing_action': 'I-pharmacological inhibition'}", + "59, monoclonal {'perturbing_action': 'I-rnai/knockdown'}", + "60, antibody {'perturbing_action': 'I-rnai/knockdown'}", + "61, (AB0023) {'perturbing_action': 'I-other'}", + "66, primary {'context': 'B-xenograft'}", + "67, and {'context': 'I-xenograft'}", + "68, metastatic {'context': 'I-xenograft'}", + "69, xenograft {'context': 'I-xenograft'}", + "70, models {'context': 'I-xenograft'}", + "71, of {'context': 'I-xenograft'}", + "72, cancer, {'context': 'I-xenograft'}", + "77, liver {'context': 'B-tissue/organ'}", + "78, and {'context': 'I-tissue/organ'}", + "79, lung {'context': 'I-tissue/organ'}", + "82, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "83, of {'perturbing_action': 'I-pharmacological inhibition'}", + "84, LOXL2 {'perturbing_action': 'I-pharmacological inhibition'}", + "91, activated {'context': 'B-cells'}", + "92, fibroblasts, {'context': 'B-cells'}", + "95, endothelial {'context': 'B-cells'}", + "96, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "54, Targeting ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "55, LOXL2 ['l0', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "56, with ['l1', 'l27', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "57, an ['l2', 'l28', 'l51', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "58, inhibitory ['l3', 'l29', 'l52', 'l75', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "59, monoclonal ['l4', 'l30', 'l53', 'l76', 'l99', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "60, antibody ['l5', 'l31', 'l54', 'l77', 'l100', 'l122', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163']", + "61, (AB0023) ['l6', 'l32', 'l55', 'l78', 'l101', 'l123', 'l144', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "66, primary ['l7', 'l33', 'l56', 'l79', 'l102', 'l124', 'l145', 'l164', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190']", + "67, and ['l8', 'l34', 'l57', 'l80', 'l103', 'l125', 'l146', 'l165', 'l183', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196']", + "68, metastatic ['l9', 'l35', 'l58', 'l81', 'l104', 'l126', 'l147', 'l166', 'l184', 'l191', 'l197', 'l198', 'l199', 'l200', 'l201']", + "69, xenograft ['l10', 'l36', 'l59', 'l82', 'l105', 'l127', 'l148', 'l167', 'l185', 'l192', 'l197', 'l202', 'l203', 'l204']", + "70, models ['l11', 'l37', 'l60', 'l83', 'l106', 'l128', 'l149', 'l168', 'l186', 'l193', 'l198', 'l202', 'l205', 'l206']", + "71, of ['l12', 'l38', 'l61', 'l84', 'l107', 'l129', 'l150', 'l169', 'l187', 'l194', 'l199', 'l203', 'l205', 'l207']", + "72, cancer, ['l13', 'l39', 'l62', 'l85', 'l108', 'l130', 'l151', 'l170', 'l188', 'l195', 'l200', 'l204', 'l206', 'l207']", + "77, liver ['l14', 'l40', 'l63', 'l86', 'l109', 'l131', 'l152', 'l171', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216']", + "78, and ['l15', 'l41', 'l64', 'l87', 'l110', 'l132', 'l153', 'l172', 'l208', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224']", + "79, lung ['l16', 'l42', 'l65', 'l88', 'l111', 'l133', 'l154', 'l173', 'l209', 'l217', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231']", + "80, fibrosis ['l17', 'l43', 'l66', 'l89', 'l112', 'l134', 'l155', 'l174', 'l210', 'l218', 'l225', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237']", + "81, models. ['l18', 'l44', 'l67', 'l90', 'l113', 'l135', 'l156', 'l175', 'l189', 'l211', 'l219', 'l226', 'l232', 'l238', 'l239', 'l240', 'l241', 'l242']", + "82, Inhibition ['l19', 'l91', 'l114', 'l136', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249']", + "83, of ['l20', 'l68', 'l92', 'l115', 'l137', 'l157', 'l176', 'l243', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255']", + "84, LOXL2 ['l21', 'l45', 'l69', 'l93', 'l116', 'l138', 'l158', 'l177', 'l244', 'l250', 'l256', 'l257', 'l258', 'l259', 'l260']", + "91, activated ['l22', 'l46', 'l70', 'l94', 'l117', 'l139', 'l159', 'l178', 'l212', 'l220', 'l227', 'l233', 'l238', 'l245', 'l251', 'l256', 'l261', 'l262', 'l263', 'l264']", + "92, fibroblasts, ['l23', 'l47', 'l71', 'l95', 'l118', 'l140', 'l160', 'l179', 'l213', 'l221', 'l228', 'l234', 'l239', 'l246', 'l252', 'l257', 'l261', 'l265', 'l266', 'l267']", + "93, desmoplasia ['l24', 'l48', 'l72', 'l96', 'l119', 'l141', 'l161', 'l180', 'l214', 'l222', 'l229', 'l235', 'l240', 'l247', 'l253', 'l258', 'l262', 'l265', 'l268', 'l269']", + "95, endothelial ['l25', 'l49', 'l73', 'l97', 'l120', 'l142', 'l162', 'l181', 'l215', 'l223', 'l230', 'l236', 'l241', 'l248', 'l254', 'l259', 'l263', 'l266', 'l268', 'l270']", + "96, cells, ['l26', 'l50', 'l74', 'l98', 'l121', 'l143', 'l163', 'l182', 'l190', 'l196', 'l201', 'l216', 'l224', 'l231', 'l237', 'l242', 'l249', 'l255', 'l260', 'l264', 'l267', 'l269', 'l270']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Targeting", + "LOXL2", + "with", + "(AB0023)" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "primary", + "and", + "metastatic", + "xenograft", + "models", + "of", + "cancer," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Targeting", + "LOXL2", + "with", + "(AB0023)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver", + "and", + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Targeting", + "LOXL2", + "with", + "(AB0023)" + ] + }, + "context": { + "val": "cells", + "words": [ + "activated", + "fibroblasts,", + "endothelial", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "an", + "monoclonal", + "antibody" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "primary", + "and", + "metastatic", + "xenograft", + "models", + "of", + "cancer," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "an", + "monoclonal", + "antibody" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver", + "and", + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "an", + "monoclonal", + "antibody" + ] + }, + "context": { + "val": "cells", + "words": [ + "activated", + "fibroblasts,", + "endothelial", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitory" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "primary", + "and", + "metastatic", + "xenograft", + "models", + "of", + "cancer," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitory" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver", + "and", + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitory", + "Inhibition", + "of", + "LOXL2" + ] + }, + "context": { + "val": "cells", + "words": [ + "activated", + "fibroblasts,", + "endothelial", + "cells," + ] + } + } + ] + }, + { + "PMID": "20729864", + "TEXT": "Leucine-rich repeat kinase-2 (LRRK2) mutations are a common cause of Parkinson's disease. Here we identify inhibitors of LRRK2 kinase that are protective in in vitro and in vivo models of LRRK2-induced neurodegeneration. These results establish that LRRK2-induced degeneration of neurons in vivo is kinase dependent and that LRRK2 kinase inhibition provides a potential new neuroprotective paradigm for the treatment of Parkinson's disease.", + "TAG_DATA": [ + "15, inhibitors {'perturbing_action': 'B-pharmacological inhibition'}", + "16, of {'perturbing_action': 'I-pharmacological inhibition'}", + "17, LRRK2 {'perturbing_action': 'I-pharmacological inhibition'}", + "18, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "23, in {'context': 'B-in vitro'}", + "24, vitro {'context': 'I-in vitro'}", + "26, in {'context': 'B-in vivo'}", + "27, vivo {'context': 'I-in vivo'}", + "39, neurons {'context': 'B-cells'}", + "40, in {'context': 'B-in vivo'}", + "41, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "15, inhibitors ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "16, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "17, LRRK2 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "18, kinase ['l2', 'l8', 'l13', 'l19', 'l20', 'l21', 'l22']", + "23, in ['l3', 'l9', 'l14', 'l19', 'l23']", + "24, vitro ['l4', 'l10', 'l15', 'l20', 'l23']", + "26, in ['l5', 'l11', 'l16', 'l21', 'l24']", + "27, vivo ['l6', 'l12', 'l17', 'l22', 'l24']", + "39, neurons ['l18', 'l25', 'l26']", + "40, in ['l25', 'l27']", + "41, vivo ['l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "LRRK2", + "kinase" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "LRRK2", + "kinase" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "LRRK2" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons" + ] + } + } + ] + }, + { + "PMID": "20676106", + "TEXT": "Although it is well established that tumors initiate an angiogenic switch, the molecular basis of this process remains incompletely understood. Here we show that the miRNA miR-132 acts as an angiogenic switch by targeting p120RasGAP in the endothelium and thereby inducing neovascularization. We identified miR-132 as a highly upregulated miRNA in a human embryonic stem cell model of vasculogenesis and found that miR-132 was highly expressed in the endothelium of human tumors and hemangiomas but was undetectable in normal endothelium. Ectopic expression of miR-132 in endothelial cells in vitro increased their proliferation and tube-forming capacity, whereas intraocular injection of an antagomir targeting miR-132, anti-miR-132, reduced postnatal retinal vascular development in mice. Among the top-ranking predicted targets of miR-132 was p120RasGAP, which we found to be expressed in normal but not tumor endothelium. Endothelial expression of miR-132 suppressed p120RasGAP expression and increased Ras activity, whereas a miRNA-resistant version of p120RasGAP reversed the vascular response induced by miR-132. Notably, administration of anti-miR-132 inhibited angiogenesis in wild-type mice but not in mice with an inducible deletion of Rasa1 (encoding p120RasGAP). Finally, vessel-targeted nanoparticle delivery of anti-miR-132 restored p120RasGAP expression in the tumor endothelium, suppressed angiogenesis and decreased tumor burden in an orthotopic xenograft mouse model of human breast carcinoma. We conclude that miR-132 acts as an angiogenic switch by suppressing endothelial p120RasGAP expression, leading to Ras activation and the induction of neovascularization, whereas the application of anti-miR-132 inhibits neovascularization by maintaining vessels in the resting state.", + "TAG_DATA": [ + "80, Ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "81, expression {'perturbing_action': 'I-gene gain-of-function'}", + "82, of {'perturbing_action': 'I-gene gain-of-function'}", + "83, miR-132 {'perturbing_action': 'I-gene gain-of-function'}", + "85, endothelial {'context': 'B-cells'}", + "86, cells {'context': 'I-cells'}", + "87, in {'context': 'B-in vitro'}", + "88, vitro {'context': 'I-in vitro'}", + "89, increased {'effect': 'B-positive'}", + "91, proliferation {'phenotype': 'B-proliferation'}", + "93, tube-forming {'phenotype': 'B-colony formation'}", + "94, capacity, {'phenotype': 'I-colony formation'}", + "100, antagomir {'perturbing_action': 'B-rnai/knockdown'}", + "101, targeting {'perturbing_action': 'I-rnai/knockdown'}", + "102, miR-132, {'perturbing_action': 'I-rnai/knockdown'}", + "103, anti-miR-132, {'perturbing_action': 'I-rnai/knockdown'}", + "110, mice. {'context': 'B-organism'}", + "132, Endothelial {'perturbing_action': 'B-gene gain-of-function'}", + "133, expression {'perturbing_action': 'I-gene gain-of-function'}", + "134, of {'perturbing_action': 'I-gene gain-of-function'}", + "135, miR-132 {'perturbing_action': 'I-gene gain-of-function'}", + "164, mice {'context': 'B-organism'}", + "168, mice {'context': 'B-organism'}", + "171, inducible {'perturbing_action': 'B-gene loss-of-function'}", + "172, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "173, of {'perturbing_action': 'I-gene loss-of-function'}", + "174, Rasa1 {'perturbing_action': 'I-gene loss-of-function'}", + "175, (encoding {'perturbing_action': 'I-gene loss-of-function'}", + "176, p120RasGAP). {'perturbing_action': 'I-gene loss-of-function'}", + "188, tumor {'context': 'B-tissue/organ'}", + "189, endothelium, {'context': 'I-tissue/organ'}", + "193, decreased {'effect': 'B-negative'}", + "194, tumor {'phenotype': 'B-tumourigenesis'}", + "195, burden {'phenotype': 'I-tumourigenesis'}", + "198, orthotopic {'context': 'B-xenograft'}", + "199, xenograft {'context': 'I-xenograft'}", + "200, mouse {'context': 'I-xenograft'}", + "201, model {'context': 'I-xenograft'}", + "202, of {'context': 'I-xenograft'}", + "203, human {'context': 'I-xenograft'}", + "204, breast {'context': 'I-xenograft'}", + "205, carcinoma. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "80, Ectopic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "81, expression ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "82, of ['l1', 'l14', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "83, miR-132 ['l2', 'l15', 'l24', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "85, endothelial ['l3', 'l16', 'l25', 'l33', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "86, cells ['l4', 'l17', 'l26', 'l34', 'l41', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "87, in ['l5', 'l18', 'l27', 'l35', 'l42', 'l48', 'l54', 'l55', 'l56', 'l57', 'l58']", + "88, vitro ['l6', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l59', 'l60', 'l61', 'l62']", + "89, increased ['l7', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l63', 'l64', 'l65']", + "91, proliferation ['l8', 'l21', 'l30', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l66', 'l67']", + "93, tube-forming ['l9', 'l22', 'l31', 'l39', 'l46', 'l52', 'l57', 'l61', 'l64', 'l66', 'l68']", + "94, capacity, ['l10', 'l23', 'l32', 'l40', 'l47', 'l53', 'l58', 'l62', 'l65', 'l67', 'l68']", + "100, antagomir ['l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "101, targeting ['l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "102, miR-132, ['l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "103, anti-miR-132, ['l71', 'l78', 'l84', 'l90', 'l91', 'l92', 'l93', 'l94']", + "110, mice. ['l72', 'l79', 'l85', 'l90', 'l95', 'l96', 'l97', 'l98']", + "132, Endothelial ['l11', 'l73', 'l80', 'l86', 'l91', 'l95', 'l99', 'l100', 'l101']", + "133, expression ['l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l102', 'l103']", + "134, of ['l12', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l104']", + "135, miR-132 ['l13', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l104']", + "164, mice ['l105', 'l106', 'l107', 'l108', 'l109']", + "168, mice ['l105', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "171, inducible ['l110', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "172, deletion ['l111', 'l120', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "173, of ['l106', 'l112', 'l121', 'l138', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170']", + "174, Rasa1 ['l107', 'l113', 'l122', 'l139', 'l155', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185']", + "175, (encoding ['l108', 'l114', 'l123', 'l140', 'l156', 'l171', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199']", + "176, p120RasGAP). ['l109', 'l115', 'l124', 'l141', 'l157', 'l172', 'l186', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212']", + "188, tumor ['l125', 'l142', 'l158', 'l173', 'l187', 'l200', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224']", + "189, endothelium, ['l116', 'l126', 'l143', 'l159', 'l174', 'l188', 'l201', 'l213', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235']", + "193, decreased ['l117', 'l127', 'l144', 'l160', 'l175', 'l189', 'l202', 'l214', 'l225', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245']", + "194, tumor ['l118', 'l128', 'l145', 'l161', 'l176', 'l190', 'l203', 'l215', 'l226', 'l236', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254']", + "195, burden ['l119', 'l129', 'l146', 'l162', 'l177', 'l191', 'l204', 'l216', 'l227', 'l237', 'l246', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262']", + "198, orthotopic ['l130', 'l147', 'l163', 'l178', 'l192', 'l205', 'l217', 'l228', 'l238', 'l247', 'l255', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269']", + "199, xenograft ['l131', 'l148', 'l164', 'l179', 'l193', 'l206', 'l218', 'l229', 'l239', 'l248', 'l256', 'l263', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275']", + "200, mouse ['l132', 'l149', 'l165', 'l180', 'l194', 'l207', 'l219', 'l230', 'l240', 'l249', 'l257', 'l264', 'l270', 'l276', 'l277', 'l278', 'l279', 'l280']", + "201, model ['l133', 'l150', 'l166', 'l181', 'l195', 'l208', 'l220', 'l231', 'l241', 'l250', 'l258', 'l265', 'l271', 'l276', 'l281', 'l282', 'l283', 'l284']", + "202, of ['l134', 'l151', 'l167', 'l182', 'l196', 'l209', 'l221', 'l232', 'l242', 'l251', 'l259', 'l266', 'l272', 'l277', 'l281', 'l285', 'l286', 'l287']", + "203, human ['l135', 'l152', 'l168', 'l183', 'l197', 'l210', 'l222', 'l233', 'l243', 'l252', 'l260', 'l267', 'l273', 'l278', 'l282', 'l285', 'l288', 'l289']", + "204, breast ['l136', 'l153', 'l169', 'l184', 'l198', 'l211', 'l223', 'l234', 'l244', 'l253', 'l261', 'l268', 'l274', 'l279', 'l283', 'l286', 'l288', 'l290']", + "205, carcinoma. ['l137', 'l154', 'l170', 'l185', 'l199', 'l212', 'l224', 'l235', 'l245', 'l254', 'l262', 'l269', 'l275', 'l280', 'l284', 'l287', 'l289', 'l290']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "miR-132" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "miR-132" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "miR-132" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "miR-132" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "miR-132" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "tube-forming", + "capacity," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "tube-forming", + "capacity," + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "tube-forming", + "capacity," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "tube-forming", + "capacity," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antagomir", + "targeting", + "miR-132,", + "anti-miR-132," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Endothelial", + "expression", + "of", + "miR-132" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "Rasa1", + "(encoding", + "p120RasGAP).", + "inducible", + "deletion" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "burden" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inducible", + "deletion", + "of", + "Rasa1", + "(encoding", + "p120RasGAP)." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tumor", + "endothelium," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inducible", + "deletion", + "of", + "Rasa1", + "(encoding", + "p120RasGAP)." + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inducible", + "deletion", + "of", + "Rasa1", + "(encoding", + "p120RasGAP)." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "burden" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inducible", + "deletion", + "of", + "Rasa1", + "(encoding", + "p120RasGAP)." + ] + }, + "context": { + "val": "xenograft", + "words": [ + "orthotopic", + "xenograft", + "mouse", + "model", + "of", + "human", + "breast", + "carcinoma." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "tumor", + "endothelium," + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "tumor", + "endothelium," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "burden" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "burden" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "orthotopic", + "xenograft", + "mouse", + "model", + "of", + "human", + "breast", + "carcinoma." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "burden" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "orthotopic", + "xenograft", + "mouse", + "model", + "of", + "human", + "breast", + "carcinoma." + ] + } + } + ] + }, + { + "PMID": "20657580", + "TEXT": "Ethylmalonic encephalopathy is caused by mutations in ETHE1, a mitochondrial matrix sulfur dioxygenase, leading to failure to detoxify sulfide, a product of intestinal anaerobes and, in trace amounts, tissues. Metronidazole, a bactericide, or N-acetylcysteine, a precursor of sulfide-buffering glutathione, substantially prolonged the lifespan of Ethe1-deficient mice, with the combined treatment being additive. The same dual treatment caused marked clinical improvement in five affected children, with hardly any adverse or side effects.", + "TAG_DATA": [ + "44, Ethe1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "45, mice, {'context': 'B-organism'}", + "63, children, {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "44, Ethe1-deficient ['l0']", + "45, mice, ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ethe1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "20581836", + "TEXT": "Sarcomas are heterogeneous and aggressive mesenchymal tumors. Histological grading has so far been the best predictor for metastasis-free survival, but it has several limitations, such as moderate reproducibility and poor prognostic value for some histological types. To improve patient grading, we performed genomic and expression profiling in a training set of 183 sarcomas and established a prognostic gene expression signature, complexity index in sarcomas (CINSARC), composed of 67 genes related to mitosis and chromosome management. In a multivariate analysis, CINSARC predicts metastasis outcome in the training set and in an independent 127 sarcomas validation set. It is superior to the Fédération Francaise des Centres de Lutte Contre le Cancer grading system in determining metastatic outcome for sarcoma patients. Furthermore, it also predicts outcome for gastrointestinal stromal tumors (GISTs), breast carcinomas and lymphomas. Application of the signature will permit more selective use of adjuvant therapies for people with sarcomas, leading to decreased iatrogenic morbidity and improved outcomes for such individuals.", + "TAG_DATA": [ + "80, predicts {'effect': 'B-regulates'}", + "81, metastasis {'phenotype': 'B-metastasis'}", + "82, outcome {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "80, predicts ['l0', 'l1']", + "81, metastasis ['l0', 'l2']", + "82, outcome ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "regulates", + "words": [ + "predicts" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "outcome" + ] + } + } + ] + }, + { + "PMID": "20512126", + "TEXT": "Muscle paralysis after spinal cord injury is partly caused by a loss of brainstem-derived serotonin (5-HT), which normally maintains motoneuron excitability by regulating crucial persistent calcium currents. Here we examine how over time motoneurons compensate for lost 5-HT to regain excitability. We find that, months after a spinal transection in rats, changes in post-transcriptional editing of 5-HT2C receptor mRNA lead to increased expression of 5-HT2C receptor isoforms that are spontaneously active (constitutively active) without 5-HT. Such constitutive receptor activity restores large persistent calcium currents in motoneurons in the absence of 5-HT. We show that this helps motoneurons recover their ability to produce sustained muscle contractions and ultimately enables recovery of motor functions such as locomotion. However, without regulation from the brain, these sustained contractions can also cause debilitating muscle spasms. Accordingly, blocking constitutively active 5-HT2C receptors with SB206553 or cyproheptadine, in both rats and humans, largely eliminates these calcium currents and muscle spasms, providing a new rationale for antispastic drug therapy.", + "TAG_DATA": [ + "48, transection {'perturbing_action': 'I-gene loss-of-function'}", + "50, rats, {'context': 'B-organism'}", + "85, motoneurons {'context': 'B-cells'}", + "96, motoneurons {'context': 'B-cells'}", + "131, blocking {'perturbing_action': 'B-pharmacological inhibition'}", + "132, constitutively {'perturbing_action': 'I-gene gain-of-function'}", + "133, active {'perturbing_action': 'I-pharmacological augmentation'}", + "134, 5-HT2C {'perturbing_action': 'I-pharmacological augmentation'}", + "135, receptors {'perturbing_action': 'I-pharmacological augmentation'}", + "136, with {'perturbing_action': 'I-pharmacological inhibition'}", + "137, SB206553 {'perturbing_action': 'I-pharmacological inhibition'}", + "138, or {'perturbing_action': 'I-pharmacological inhibition'}", + "139, cyproheptadine, {'perturbing_action': 'I-pharmacological inhibition'}", + "142, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "48, transection ['l0', 'l1']", + "50, rats, ['l0']", + "85, motoneurons ['l1', 'l2']", + "96, motoneurons ['l2']", + "131, blocking ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "132, constitutively ['l3', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "133, active ['l4', 'l12', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "134, 5-HT2C ['l5', 'l13', 'l20', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "135, receptors ['l6', 'l14', 'l21', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "136, with ['l7', 'l15', 'l22', 'l28', 'l33', 'l38', 'l39', 'l40', 'l41']", + "137, SB206553 ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l42', 'l43', 'l44']", + "138, or ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l45', 'l46']", + "139, cyproheptadine, ['l10', 'l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l47']", + "142, rats ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "transection" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "transection" + ] + }, + "context": { + "val": "cells", + "words": [ + "motoneurons" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blocking", + "with", + "SB206553", + "or", + "cyproheptadine," + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutively" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "active", + "5-HT2C", + "receptors" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + } + ] + }, + { + "PMID": "20495570", + "TEXT": "Chondrocyte hypertrophy followed by cartilage matrix degradation and vascular invasion, characterized by expression of type X collagen (COL10A1), matrix metalloproteinase-13 (MMP-13) and vascular endothelial growth factor (VEGF), respectively, are central steps of endochondral ossification during normal skeletal growth and osteoarthritis development. A COL10A1 promoter assay identified hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by EPAS1) as the most potent transactivator of COL10A1. HIF-2alpha enhanced promoter activities of COL10A1, MMP13 and VEGFA through specific binding to the respective hypoxia-responsive elements. HIF-2alpha, independently of oxygen-dependent hydroxylation, was essential for endochondral ossification of cultured chondrocytes and embryonic skeletal growth in mice. HIF-2alpha expression was higher in osteoarthritic cartilages versus nondiseased cartilages of mice and humans. Epas1-heterozygous deficient mice showed resistance to osteoarthritis development, and a functional single nucleotide polymorphism (SNP) in the human EPAS1 gene was associated with knee osteoarthritis in a Japanese population. The EPAS1 promoter assay identified RELA, a nuclear factor-kappaB (NF-kappaB) family member, as a potent inducer of HIF-2alpha expression. Hence, HIF-2alpha is a central transactivator that targets several crucial genes for endochondral ossification and may represent a therapeutic target for osteoarthritis.", + "TAG_DATA": [ + "88, chondrocytes {'context': 'I-cells'}", + "109, Epas1-heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "110, deficient {'perturbing_action': 'I-gene loss-of-function'}", + "111, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "109, Epas1-heterozygous ['l0', 'l1']", + "110, deficient ['l0', 'l2']", + "111, mice ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Epas1-heterozygous", + "deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "20098432", + "TEXT": "Individuals with beta-thalassemia develop progressive systemic iron overload, resulting in high morbidity and mortality. These complications are caused by labile plasma iron, which is taken up by parenchymal cells in a dysregulated manner; in contrast, erythropoiesis depends on transferrin-bound iron uptake via the transferrin receptor. We hypothesized that the ineffective erythropoiesis and anemia observed in beta-thalassemia might be ameliorated by increasing the amount of circulating transferrin. We tested the ability of transferrin injections to modulate iron metabolism and erythropoiesis in Hbb(th1/th1) mice, an experimental model of beta-thalassemia. Injected transferrin reversed or markedly improved the thalassemia phenotype in these mice. Specifically, transferrin injections normalized labile plasma iron concentrations, increased hepcidin expression, normalized red blood cell survival and increased hemoglobin production; this treatment concomitantly decreased reticulocytosis, erythropoietin abundance and splenomegaly. These results indicate that transferrin is a limiting factor contributing to anemia in these mice and suggest that transferrin therapy might be beneficial in human beta-thalassemia.", + "TAG_DATA": [ + "80, Hbb(th1/th1) {'perturbing_action': 'B-other'}", + "81, mice, {'context': 'B-organism'}", + "98, mice. {'context': 'B-organism'}", + "111, red {'context': 'B-cells'}", + "112, blood {'context': 'I-cells'}", + "113, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "80, Hbb(th1/th1) ['l0']", + "81, mice, ['l0']", + "98, mice. ['l1', 'l2', 'l3']", + "111, red ['l1', 'l4', 'l5']", + "112, blood ['l2', 'l4', 'l6']", + "113, cell ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Hbb(th1/th1)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "20098431", + "TEXT": "Gene-modified autologous hematopoietic stem cells (HSC) can provide ample clinical benefits to subjects suffering from X-linked chronic granulomatous disease (X-CGD), a rare inherited immunodeficiency characterized by recurrent, often life-threatening bacterial and fungal infections. Here we report on the molecular and cellular events observed in two young adults with X-CGD treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both subjects showed silencing of transgene expression due to methylation of the viral promoter, and myelodysplasia with monosomy 7 as a result of insertional activation of ecotropic viral integration site 1 (EVI1). One subject died from overwhelming sepsis 27 months after gene therapy, whereas a second subject underwent an allogeneic HSC transplantation. Our data show that forced overexpression of EVI1 in human cells disrupts normal centrosome duplication, linking EVI1 activation to the development of genomic instability, monosomy 7 and clonal progression toward myelodysplasia.", + "TAG_DATA": [ + "46, adults {'context': 'I-organism'}", + "113, allogeneic {'context': 'B-xenograft'}", + "114, HSC {'context': 'I-xenograft'}", + "120, forced {'perturbing_action': 'B-gene gain-of-function'}", + "121, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "122, of {'perturbing_action': 'I-gene gain-of-function'}", + "123, EVI1 {'perturbing_action': 'I-gene gain-of-function'}", + "125, human {'context': 'B-cells'}", + "126, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "113, allogeneic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "114, HSC ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "115, transplantation. ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "120, forced ['l15', 'l16', 'l17', 'l18', 'l19']", + "121, overexpression ['l15', 'l20', 'l21', 'l22', 'l23']", + "122, of ['l2', 'l7', 'l11', 'l16', 'l20', 'l24', 'l25', 'l26']", + "123, EVI1 ['l3', 'l8', 'l12', 'l17', 'l21', 'l24', 'l27', 'l28']", + "125, human ['l4', 'l9', 'l13', 'l18', 'l22', 'l25', 'l27', 'l29']", + "126, cells ['l5', 'l10', 'l14', 'l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "xenograft", + "words": [ + "allogeneic", + "HSC" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "EVI1" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "forced", + "overexpression", + "of", + "EVI1" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "cells" + ] + } + } + ] + }, + { + "PMID": "20098430", + "TEXT": "Hypertension is one of the most frequent pathologies in the industrialized world. Although recognized to be dependent on a combination of genetic and environmental factors, its molecular basis remains elusive. Increased activity of the monomeric G protein RhoA in arteries is a common feature of hypertension. However, how RhoA is activated and whether it has a causative role in hypertension remains unclear. Here we provide evidence that Arhgef1 is the RhoA guanine exchange factor specifically responsible for angiotensin II-induced activation of RhoA signaling in arterial smooth muscle cells. We found that angiotensin II activates Arhgef1 through a previously undescribed mechanism in which Jak2 phosphorylates Tyr738 of Arhgef1. Arhgef1 inactivation in smooth muscle induced resistance to angiotensin II-dependent hypertension in mice, but did not affect normal blood pressure regulation. Our results show that control of RhoA signaling through Arhgef1 is central to the development of angiotensin II-dependent hypertension and identify Arhgef1 as a potential target for the treatment of hypertension.", + "TAG_DATA": [ + "107, Arhgef1 {'perturbing_action': 'B-gene loss-of-function'}", + "108, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "110, smooth {'context': 'B-cells'}", + "111, muscle {'context': 'I-cells'}", + "119, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "107, Arhgef1 ['l0', 'l1', 'l2', 'l3']", + "108, inactivation ['l0', 'l4', 'l5', 'l6']", + "110, smooth ['l1', 'l4', 'l7', 'l8']", + "111, muscle ['l2', 'l5', 'l7', 'l9']", + "119, mice, ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Arhgef1", + "inactivation" + ] + }, + "context": { + "val": "cells", + "words": [ + "smooth", + "muscle" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Arhgef1", + "inactivation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "20098429", + "TEXT": "Adjuvant chemotherapy for breast cancer after surgery has effectively lowered metastatic recurrence rates. However, a considerable proportion of women suffer recurrent cancer at distant metastatic sites despite adjuvant treatment. Identification of the genes crucial for tumor response to specific chemotherapy drugs is a challenge but is necessary to improve outcomes. By using integrated genomics, we identified a small number of overexpressed and amplified genes from chromosome 8q22 that were associated with early disease recurrence despite anthracycline-based adjuvant chemotherapy. We confirmed the association in an analysis of multiple independent cohorts. SiRNA-mediated knockdown of either of two of these genes, the antiapoptotic gene YWHAZ and a lysosomal gene LAPTM4B, sensitized tumor cells to anthracyclines, and overexpression of either of the genes induced anthracycline resistance. Overexpression of LAPTM4B resulted in sequestration of the anthracycline doxorubicin, delaying its appearance in the nucleus. Overexpression of these two genes was associated with poor tumor response to anthracycline treatment in a neoadjuvant chemotherapy trial in women with primary breast cancer. Our results suggest that 8q22 amplification and overexpression of LAPTM4B and YWHAZ contribute to de novo chemoresistance to anthracyclines and are permissive for metastatic recurrence. Overexpression of these two genes may predict anthracycline resistance and influence selection of chemotherapy.", + "TAG_DATA": [ + "89, SiRNA-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "90, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "91, of {'perturbing_action': 'I-rnai/knockdown'}", + "92, either {'perturbing_action': 'I-rnai/knockdown'}", + "93, of {'perturbing_action': 'I-rnai/knockdown'}", + "94, two {'perturbing_action': 'I-rnai/knockdown'}", + "95, of {'perturbing_action': 'I-rnai/knockdown'}", + "96, these {'perturbing_action': 'I-rnai/knockdown'}", + "97, genes, {'perturbing_action': 'I-rnai/knockdown'}", + "98, the {'perturbing_action': 'I-rnai/knockdown'}", + "99, antiapoptotic {'perturbing_action': 'I-rnai/knockdown'}", + "100, gene {'perturbing_action': 'I-rnai/knockdown'}", + "101, YWHAZ {'perturbing_action': 'I-rnai/knockdown'}", + "102, and {'perturbing_action': 'I-rnai/knockdown'}", + "103, a {'perturbing_action': 'I-rnai/knockdown'}", + "104, lysosomal {'perturbing_action': 'I-rnai/knockdown'}", + "105, gene {'perturbing_action': 'I-rnai/knockdown'}", + "106, LAPTM4B, {'perturbing_action': 'I-rnai/knockdown'}", + "108, tumor {'context': 'B-transformed cells'}", + "109, cells {'context': 'I-transformed cells'}", + "113, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "114, of {'perturbing_action': 'I-gene gain-of-function'}", + "115, either {'perturbing_action': 'I-gene gain-of-function'}", + "116, of {'perturbing_action': 'I-gene gain-of-function'}", + "117, the {'perturbing_action': 'I-gene gain-of-function'}", + "118, genes {'perturbing_action': 'I-gene gain-of-function'}", + "122, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "123, of {'perturbing_action': 'I-gene gain-of-function'}", + "124, LAPTM4B {'perturbing_action': 'I-gene gain-of-function'}", + "138, Overexpression {'perturbing_action': 'B-gene gain-of-function'}" + ], + "LINK_DATA": [ + "89, SiRNA-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "90, knockdown ['l0', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "91, of ['l1', 'l19', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "92, either ['l2', 'l20', 'l37', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "93, of ['l3', 'l21', 'l38', 'l54', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "94, two ['l4', 'l22', 'l39', 'l55', 'l70', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "95, of ['l5', 'l23', 'l40', 'l56', 'l71', 'l85', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "96, these ['l6', 'l24', 'l41', 'l57', 'l72', 'l86', 'l99', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "97, genes, ['l7', 'l25', 'l42', 'l58', 'l73', 'l87', 'l100', 'l112', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "98, the ['l8', 'l26', 'l43', 'l59', 'l74', 'l88', 'l101', 'l113', 'l124', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "99, antiapoptotic ['l9', 'l27', 'l44', 'l60', 'l75', 'l89', 'l102', 'l114', 'l125', 'l135', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "100, gene ['l10', 'l28', 'l45', 'l61', 'l76', 'l90', 'l103', 'l115', 'l126', 'l136', 'l145', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "101, YWHAZ ['l11', 'l29', 'l46', 'l62', 'l77', 'l91', 'l104', 'l116', 'l127', 'l137', 'l146', 'l154', 'l162', 'l163', 'l164', 'l165', 'l166']", + "102, and ['l12', 'l30', 'l47', 'l63', 'l78', 'l92', 'l105', 'l117', 'l128', 'l138', 'l147', 'l155', 'l162', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "103, a ['l13', 'l31', 'l48', 'l64', 'l79', 'l93', 'l106', 'l118', 'l129', 'l139', 'l148', 'l156', 'l163', 'l167', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "104, lysosomal ['l14', 'l32', 'l49', 'l65', 'l80', 'l94', 'l107', 'l119', 'l130', 'l140', 'l149', 'l157', 'l168', 'l173', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184']", + "105, gene ['l15', 'l33', 'l50', 'l66', 'l81', 'l95', 'l108', 'l120', 'l131', 'l141', 'l150', 'l158', 'l169', 'l174', 'l179', 'l185', 'l186', 'l187', 'l188', 'l189']", + "106, LAPTM4B, ['l16', 'l34', 'l51', 'l67', 'l82', 'l96', 'l109', 'l121', 'l132', 'l142', 'l151', 'l159', 'l164', 'l170', 'l175', 'l180', 'l185', 'l190', 'l191', 'l192']", + "108, tumor ['l17', 'l35', 'l52', 'l68', 'l83', 'l97', 'l110', 'l122', 'l133', 'l143', 'l152', 'l160', 'l165', 'l171', 'l176', 'l181', 'l186', 'l190', 'l193']", + "109, cells ['l18', 'l36', 'l53', 'l69', 'l84', 'l98', 'l111', 'l123', 'l134', 'l144', 'l153', 'l161', 'l166', 'l172', 'l177', 'l182', 'l187', 'l191', 'l193']", + "113, overexpression ['l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201']", + "114, of ['l194', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208']", + "115, either ['l195', 'l202', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214']", + "116, of ['l196', 'l203', 'l209', 'l215', 'l216', 'l217', 'l218', 'l219']", + "117, the ['l183', 'l188', 'l197', 'l204', 'l210', 'l215', 'l220', 'l221', 'l222', 'l223']", + "118, genes ['l178', 'l184', 'l189', 'l192', 'l198', 'l205', 'l211', 'l216', 'l220', 'l224', 'l225', 'l226']", + "122, Overexpression ['l199', 'l206', 'l212', 'l217', 'l221', 'l224', 'l227', 'l228']", + "123, of ['l200', 'l207', 'l213', 'l218', 'l222', 'l225', 'l227', 'l229']", + "124, LAPTM4B ['l201', 'l208', 'l214', 'l219', 'l223', 'l226', 'l228', 'l229']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "SiRNA-mediated", + "knockdown", + "of", + "either", + "two", + "these", + "genes,", + "the", + "antiapoptotic", + "gene", + "YWHAZ", + "and", + "a", + "lysosomal", + "LAPTM4B," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + } + ] + }, + { + "PMID": "20081863", + "TEXT": "Humans are colonized by a large and diverse bacterial flora (the microbiota) essential for the development of the gut immune system. A broader role for the microbiota as a major modulator of systemic immunity has been proposed; however, evidence and a mechanism for this role have remained elusive. We show that the microbiota are a source of peptidoglycan that systemically primes the innate immune system, enhancing killing by bone marrow-derived neutrophils of two major pathogens: Streptococcus pneumoniae and Staphylococcus aureus. This requires signaling via the pattern recognition receptor nucleotide-binding, oligomerization domain-containing protein-1 (Nod1, which recognizes meso-diaminopimelic acid (mesoDAP)-containing peptidoglycan found predominantly in Gram-negative bacteria), but not Nod2 (which detects peptidoglycan found in Gram-positive and Gram-negative bacteria) or Toll-like receptor 4 (Tlr4, which recognizes lipopolysaccharide). We show translocation of peptidoglycan from the gut to neutrophils in the bone marrow and show that peptidoglycan concentrations in sera correlate with neutrophil function. In vivo administration of Nod1 ligands is sufficient to restore neutrophil function after microbiota depletion. Nod1(-/-) mice are more susceptible than wild-type mice to early pneumococcal sepsis, demonstrating a role for Nod1 in priming innate defenses facilitating a rapid response to infection. These data establish a mechanism for systemic immunomodulation by the microbiota and highlight potential adverse consequences of microbiota disruption by broad-spectrum antibiotics on innate immune defense to infection.", + "TAG_DATA": [ + "149, In {'context': 'B-in vivo'}", + "150, vivo {'context': 'I-in vivo'}", + "164, Nod1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "165, mice {'context': 'B-organism'}", + "171, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "149, In ['l0']", + "150, vivo ['l0']", + "164, Nod1(-/-) ['l1', 'l2']", + "165, mice ['l1', 'l3']", + "171, mice ['l2', 'l3']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nod1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "20072130", + "TEXT": "Targeting the mammalian target of rapamycin (mTOR) protein is a promising strategy for cancer therapy. The mTOR kinase functions in two complexes, TORC1 (target of rapamycin complex-1) and TORC2 (target of rapamycin complex-2); however, neither of these complexes is fully inhibited by the allosteric inhibitor rapamycin or its analogs. We compared rapamycin with PP242, an inhibitor of the active site of mTOR in both TORC1 and TORC2 (hereafter referred to as TORC1/2), in models of acute leukemia harboring the Philadelphia chromosome (Ph) translocation. We demonstrate that PP242, but not rapamycin, causes death of mouse and human leukemia cells. In vivo, PP242 delays leukemia onset and augments the effects of the current front-line tyrosine kinase inhibitors more effectively than does rapamycin. Unexpectedly, PP242 has much weaker effects than rapamycin on the proliferation and function of normal lymphocytes. PI-103, a less selective TORC1/2 inhibitor that also targets phosphoinositide 3-kinase (PI3K), is more immunosuppressive than PP242. These findings establish that Ph(+) transformed cells are more sensitive than normal lymphocytes to selective TORC1/2 inhibitors and support the development of such inhibitors for leukemia therapy.", + "TAG_DATA": [ + "53, PP242, {'perturbing_action': 'B-pharmacological inhibition'}", + "54, an {'perturbing_action': 'I-pharmacological inhibition'}", + "55, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "56, of {'perturbing_action': 'I-pharmacological inhibition'}", + "57, the {'perturbing_action': 'I-pharmacological inhibition'}", + "58, active {'perturbing_action': 'I-pharmacological inhibition'}", + "59, site {'perturbing_action': 'I-pharmacological inhibition'}", + "60, of {'perturbing_action': 'I-pharmacological inhibition'}", + "61, mTOR {'perturbing_action': 'I-pharmacological inhibition'}", + "62, in {'perturbing_action': 'I-pharmacological inhibition'}", + "63, both {'perturbing_action': 'I-pharmacological inhibition'}", + "64, TORC1 {'perturbing_action': 'I-pharmacological inhibition'}", + "73, models {'context': 'B-neoplasm'}", + "75, acute {'context': 'B-neoplasm'}", + "76, leukemia {'context': 'I-neoplasm'}", + "93, mouse {'context': 'B-transformed cells'}", + "94, and {'context': 'I-transformed cells'}", + "95, human {'context': 'I-transformed cells'}", + "96, leukemia {'context': 'I-transformed cells'}", + "97, cells. {'context': 'I-transformed cells'}", + "98, In {'context': 'B-in vivo'}", + "99, vivo, {'context': 'I-in vivo'}", + "102, leukemia {'context': 'B-neoplasm'}", + "130, proliferation {'phenotype': 'B-proliferation'}", + "134, normal {'context': 'B-cells'}", + "135, lymphocytes. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "53, PP242, ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "54, an ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "55, inhibitor ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "56, of ['l2', 'l21', 'l39', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "57, the ['l3', 'l22', 'l40', 'l57', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "58, active ['l4', 'l23', 'l41', 'l58', 'l75', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "59, site ['l5', 'l24', 'l42', 'l59', 'l76', 'l92', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "60, of ['l6', 'l25', 'l43', 'l60', 'l77', 'l93', 'l107', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "61, mTOR ['l7', 'l26', 'l44', 'l61', 'l78', 'l94', 'l108', 'l122', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146']", + "62, in ['l8', 'l27', 'l45', 'l62', 'l79', 'l95', 'l109', 'l123', 'l135', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "63, both ['l9', 'l28', 'l46', 'l63', 'l80', 'l96', 'l110', 'l124', 'l136', 'l147', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "64, TORC1 ['l10', 'l29', 'l47', 'l64', 'l81', 'l97', 'l111', 'l125', 'l137', 'l148', 'l158', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176']", + "73, models ['l11', 'l30', 'l48', 'l65', 'l82', 'l98', 'l112', 'l126', 'l138', 'l149', 'l159', 'l168', 'l177', 'l178', 'l179', 'l180']", + "74, of ['l12', 'l31', 'l49', 'l66', 'l83', 'l99', 'l113', 'l127', 'l139', 'l150', 'l160', 'l169', 'l177', 'l181', 'l182', 'l183']", + "75, acute ['l13', 'l32', 'l50', 'l67', 'l84', 'l100', 'l114', 'l128', 'l140', 'l151', 'l161', 'l170', 'l178', 'l181', 'l184', 'l185']", + "76, leukemia ['l14', 'l33', 'l51', 'l68', 'l85', 'l101', 'l115', 'l129', 'l141', 'l152', 'l162', 'l171', 'l179', 'l182', 'l184', 'l186', 'l187']", + "93, mouse ['l15', 'l34', 'l52', 'l69', 'l86', 'l102', 'l116', 'l130', 'l142', 'l153', 'l163', 'l172', 'l188', 'l189', 'l190', 'l191']", + "94, and ['l16', 'l35', 'l53', 'l70', 'l87', 'l103', 'l117', 'l131', 'l143', 'l154', 'l164', 'l173', 'l186', 'l188', 'l192', 'l193', 'l194']", + "95, human ['l17', 'l36', 'l54', 'l71', 'l88', 'l104', 'l118', 'l132', 'l144', 'l155', 'l165', 'l174', 'l189', 'l192', 'l195', 'l196']", + "96, leukemia ['l18', 'l37', 'l55', 'l72', 'l89', 'l105', 'l119', 'l133', 'l145', 'l156', 'l166', 'l175', 'l190', 'l193', 'l195', 'l197']", + "97, cells. ['l19', 'l38', 'l56', 'l73', 'l90', 'l106', 'l120', 'l134', 'l146', 'l157', 'l167', 'l176', 'l180', 'l183', 'l185', 'l187', 'l191', 'l194', 'l196', 'l197']", + "98, In ['l198', 'l199']", + "99, vivo, ['l74', 'l91', 'l121', 'l198', 'l200']", + "102, leukemia ['l199', 'l200']", + "125, effects ['l201', 'l202', 'l203']", + "130, proliferation ['l201', 'l204', 'l205']", + "134, normal ['l202', 'l204', 'l206']", + "135, lymphocytes. ['l203', 'l205', 'l206']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PP242,", + "an", + "inhibitor", + "of", + "the", + "active", + "site", + "mTOR", + "in", + "both", + "TORC1" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models", + "acute", + "leukemia" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PP242,", + "an", + "inhibitor", + "of", + "the", + "active", + "site", + "mTOR", + "in", + "both", + "TORC1" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "mouse", + "and", + "human", + "leukemia", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "of", + "the", + "site" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "normal", + "lymphocytes." + ] + } + } + ] + }, + { + "PMID": "19966812", + "TEXT": "Nucleotide-binding oligomerization domain-containing-2 (NOD2) acts as a bacterial sensor in dendritic cells (DCs), but it is not clear how bacterial recognition links with antigen presentation after NOD2 stimulation. NOD2 variants are associated with Crohn's disease, where breakdown in self-recognition of commensal bacteria leads to gastrointestinal inflammation. Here we show NOD2 triggering by muramyldipeptide induces autophagy in DCs. This effect requires receptor-interacting serine-threonine kinase-2 (RIPK-2), autophagy-related protein-5 (ATG5), ATG7 and ATG16L1 but not NLR family, pyrin domain containing-3 (NALP3).We show that NOD2-mediated autophagy is required for both bacterial handling and generation of major histocompatibility complex (MHC) class II antigen-specific CD4(+) T cell responses in DCs. DCs from individuals with Crohn's disease expressing Crohn's disease-associated NOD2 or ATG16L1 risk variants are defective in autophagy induction, bacterial trafficking and antigen presentation. Our findings link two Crohn's disease-associated susceptibility genes in a single functional pathway and reveal defects in this pathway in Crohn's disease DCs that could lead to bacterial persistence via impaired lysosomal destruction and immune mediated clearance.", + "TAG_DATA": [ + "50, triggering {'perturbing_action': 'I-pharmacological augmentation'}", + "53, induces {'effect': 'B-positive'}", + "54, autophagy {'phenotype': 'B-autophagy'}", + "56, DCs. {'context': 'B-cells'}", + "81, autophagy {'phenotype': 'B-autophagy'}", + "103, DCs. {'context': 'B-cells'}", + "104, DCs {'context': 'B-cells'}", + "121, autophagy {'phenotype': 'B-autophagy'}", + "122, induction, {'effect': 'B-positive'}" + ], + "LINK_DATA": [ + "50, triggering ['l0', 'l1', 'l2', 'l3']", + "53, induces ['l0', 'l4', 'l5', 'l6']", + "54, autophagy ['l1', 'l4', 'l7', 'l8']", + "56, DCs. ['l2', 'l5', 'l7', 'l9']", + "81, autophagy ['l10']", + "103, DCs. ['l3', 'l6', 'l8', 'l9', 'l10']", + "104, DCs ['l11', 'l12']", + "121, autophagy ['l11', 'l13']", + "122, induction, ['l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "triggering" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "triggering" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "triggering" + ] + }, + "context": { + "val": "cells", + "words": [ + "DCs." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "induction," + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "induction," + ] + }, + "context": { + "val": "cells", + "words": [ + "DCs.", + "DCs" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + }, + "context": { + "val": "cells", + "words": [ + "DCs.", + "DCs" + ] + } + } + ] + }, + { + "PMID": "19783996", + "TEXT": "Germ cells are sensitive to genotoxins, and ovarian failure and infertility are major side effects of chemotherapy in young patients with cancer. Here we describe the c-Abl-TAp63 pathway activated by chemotherapeutic DNA-damaging drugs in model human cell lines and in mouse oocytes and its role in cell death. In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters. Similarly, in oocytes, cisplatin rapidly promotes TAp63 accumulation and eventually cell death. Treatment with the c-Abl kinase inhibitor imatinib counteracts these cisplatin-induced effects. Taken together, these data support a model in which signals initiated by DNA double-strand breaks are detected by c-Abl, which, through its kinase activity, modulates the p63 transcriptional output. Moreover, they suggest a new use for imatinib, aimed at preserving oocytes of the follicle reserve during chemotherapeutic treatments.", + "TAG_DATA": [ + "40, mouse {'context': 'B-cells'}", + "41, oocytes {'context': 'I-cells'}", + "49, cell {'context': 'B-cells'}", + "50, lines, {'context': 'I-cells'}", + "76, oocytes, {'context': 'B-cells'}", + "79, promotes {'effect': 'B-positive'}", + "84, cell {'phenotype': 'B-cell death'}", + "85, death. {'phenotype': 'I-cell death'}", + "89, c-Abl {'perturbing_action': 'I-pharmacological inhibition'}", + "90, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "91, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "40, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "41, oocytes ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "49, cell ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "50, lines, ['l2', 'l8', 'l13', 'l18', 'l19', 'l20']", + "76, oocytes, ['l3', 'l9', 'l14', 'l18', 'l21', 'l22', 'l23']", + "79, promotes ['l4', 'l10', 'l15', 'l19', 'l21', 'l24', 'l25']", + "84, cell ['l5', 'l11', 'l16', 'l22', 'l24', 'l26']", + "85, death. ['l6', 'l12', 'l17', 'l20', 'l23', 'l25', 'l26']", + "89, c-Abl ['l27', 'l28']", + "90, kinase ['l27', 'l29']", + "91, inhibitor ['l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "mouse", + "oocytes", + "cell", + "lines,", + "oocytes," + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "oocytes", + "cell", + "lines,", + "oocytes," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "19767734", + "TEXT": "Reduced food intake brings about an adaptive decrease in energy expenditure that contributes to the recidivism of obesity after weight loss. Insulin and leptin inhibit food intake through actions in the central nervous system that are partly mediated by the transcription factor FoxO1. We show that FoxO1 ablation in pro-opiomelanocortin (Pomc)-expressing neurons in mice (here called Pomc-Foxo1(-/-) mice) increases Carboxypeptidase E (Cpe) expression, resulting in selective increases of alpha-melanocyte-stimulating hormone (alpha-Msh) and carboxy-cleaved beta-endorphin, the products of Cpe-dependent processing of Pomc. This neuropeptide profile is associated with decreased food intake and normal energy expenditure in Pomc-Foxo1(-/-) mice. We show that Cpe expression is downregulated by diet-induced obesity and that FoxO1 deletion offsets the decrease, protecting against weight gain. Moreover, moderate Cpe overexpression in the arcuate nucleus phenocopies features of the FoxO1 mutation. The dissociation of food intake from energy expenditure in Pomc-Foxo1(-/-) mice represents a model for therapeutic intervention in obesity and raises the possibility of targeting Cpe to develop weight loss medications.", + "TAG_DATA": [ + "46, FoxO1 {'perturbing_action': 'B-gene loss-of-function'}", + "47, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "49, pro-opiomelanocortin {'context': 'B-cells'}", + "50, (Pomc)-expressing {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "51, neurons {'context': 'I-cells'}", + "53, mice {'context': 'B-organism'}", + "56, Pomc-Foxo1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "95, Pomc-Foxo1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "96, mice. {'context': 'B-organism'}", + "109, FoxO1 {'perturbing_action': 'B-gene loss-of-function'}", + "110, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "119, moderate {'perturbing_action': 'B-gene gain-of-function'}", + "120, Cpe {'perturbing_action': 'I-gene gain-of-function'}", + "121, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "124, arcuate {'context': 'B-tissue/organ'}", + "125, nucleus {'context': 'I-tissue/organ'}", + "130, FoxO1 {'perturbing_action': 'B-other'}", + "131, mutation. {'perturbing_action': 'I-other'}", + "141, Pomc-Foxo1(-/-) {'perturbing_action': 'B-gene loss-of-function'}" + ], + "LINK_DATA": [ + "46, FoxO1 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "47, ablation ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "49, pro-opiomelanocortin ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "50, (Pomc)-expressing ['l2', 'l8', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "51, neurons ['l3', 'l9', 'l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "53, mice ['l4', 'l10', 'l15', 'l20', 'l24', 'l28', 'l29']", + "56, Pomc-Foxo1(-/-) ['l5', 'l11', 'l16', 'l21', 'l25', 'l28', 'l30', 'l31']", + "95, Pomc-Foxo1(-/-) ['l17', 'l22', 'l26', 'l30', 'l32']", + "96, mice. ['l6', 'l12', 'l18', 'l23', 'l27', 'l29', 'l31', 'l32']", + "109, FoxO1 ['l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "110, deletion ['l33', 'l41', 'l42', 'l43', 'l44', 'l45']", + "119, moderate ['l34', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "120, Cpe ['l35', 'l46', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "121, overexpression ['l36', 'l41', 'l47', 'l53', 'l59', 'l60', 'l61', 'l62', 'l63']", + "124, arcuate ['l37', 'l42', 'l48', 'l54', 'l59', 'l64', 'l65', 'l66']", + "125, nucleus ['l38', 'l43', 'l49', 'l55', 'l60', 'l64', 'l67', 'l68']", + "130, FoxO1 ['l39', 'l44', 'l50', 'l56', 'l61', 'l65', 'l67', 'l69']", + "131, mutation. ['l40', 'l45', 'l51', 'l57', 'l62', 'l66', 'l68', 'l69']", + "141, Pomc-Foxo1(-/-) ['l52', 'l58', 'l63']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FoxO1", + "ablation", + "(Pomc)-expressing", + "Pomc-Foxo1(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "pro-opiomelanocortin", + "(Pomc)-expressing", + "neurons" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FoxO1", + "ablation", + "(Pomc)-expressing", + "Pomc-Foxo1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FoxO1", + "deletion" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "arcuate", + "nucleus" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "moderate", + "Cpe", + "overexpression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "arcuate", + "nucleus" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "arcuate", + "nucleus" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "FoxO1", + "mutation." + ] + } + } + ] + }, + { + "PMID": "19701203", + "TEXT": "Recent work has shown that primary cilia are essential for Hedgehog (Hh) signaling during mammalian development. It is also known that aberrant Hh signaling can lead to cancer, but the role of primary cilia in oncogenesis is not known. Cerebellar granule neuron precursors (GNPs) can give rise to medulloblastomas, the most common malignant brain tumor in children. The primary cilium and Hh signaling are required for GNP proliferation. We asked whether primary cilia in GNPs have a role in medulloblastoma growth in mice. Genetic ablation of primary cilia blocked medulloblastoma formation when this tumor was driven by a constitutively active Smoothened protein (Smo), an upstream activator of Hh signaling. In contrast, removal of cilia was required for medulloblastoma growth by a constitutively active glioma-associated oncogene family zinc finger-2 (GLI2), a downstream transcription factor. Thus, primary cilia are either required for or inhibit medulloblastoma formation, depending on the initiating oncogenic event. Remarkably, the presence or absence of cilia was associated with specific variants of human medulloblastomas; primary cilia were found in medulloblastomas with activation in HH or WNT signaling but not in most medulloblastomas in other distinct molecular subgroups. Primary cilia could serve as a diagnostic tool and provide new insights into the mechanism of tumorigenesis.", + "TAG_DATA": [ + "83, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "84, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "85, of {'perturbing_action': 'I-gene loss-of-function'}", + "86, primary {'perturbing_action': 'I-gene loss-of-function'}", + "87, cilia {'perturbing_action': 'I-gene loss-of-function'}", + "88, blocked {'effect': 'B-negative'}", + "89, medulloblastoma {'phenotype': 'B-tumourigenesis'}", + "90, formation {'phenotype': 'I-tumourigenesis'}", + "93, tumor {'context': 'B-neoplasm'}", + "98, constitutively {'perturbing_action': 'B-gene gain-of-function'}", + "117, medulloblastoma {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}" + ], + "LINK_DATA": [ + "83, Genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "84, ablation ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "85, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "86, primary ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "87, cilia ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "88, blocked ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37']", + "89, medulloblastoma ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l39']", + "90, formation ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l38']", + "93, tumor ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l39', 'l40']", + "98, constitutively ['l8', 'l16', 'l23', 'l29', 'l34', 'l40']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "ablation", + "of", + "primary", + "cilia" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "ablation", + "of", + "primary", + "cilia" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "medulloblastoma", + "formation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "ablation", + "of", + "primary", + "cilia" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "medulloblastoma", + "formation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "medulloblastoma" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutively" + ] + } + } + ] + }, + { + "PMID": "19668192", + "TEXT": "Disruption of the precise balance of positive and negative molecular regulators of blood and lymphatic vessel growth can lead to myriad diseases. Although dozens of natural inhibitors of hemangiogenesis have been identified, an endogenous selective inhibitor of lymphatic vessel growth has not to our knowledge been previously described. We report the existence of a splice variant of the gene encoding vascular endothelial growth factor receptor-2 (Vegfr-2) that encodes a secreted form of the protein, designated soluble Vegfr-2 (sVegfr-2), that inhibits developmental and reparative lymphangiogenesis by blocking Vegf-c function. Tissue-specific loss of sVegfr-2 in mice induced, at birth, spontaneous lymphatic invasion of the normally alymphatic cornea and hyperplasia of skin lymphatics without affecting blood vasculature. Administration of sVegfr-2 inhibited lymphangiogenesis but not hemangiogenesis induced by corneal suture injury or transplantation, enhanced corneal allograft survival and suppressed lymphangioma cellular proliferation. Naturally occurring sVegfr-2 thus acts as a molecular uncoupler of blood and lymphatic vessels; modulation of sVegfr-2 might have therapeutic effects in treating lymphatic vascular malformations, transplantation rejection and, potentially, tumor lymphangiogenesis and lymphedema (pages 993-994).", + "TAG_DATA": [ + "88, Tissue-specific {'perturbing_action': 'B-gene loss-of-function'}", + "89, loss {'perturbing_action': 'I-gene loss-of-function'}", + "90, of {'perturbing_action': 'I-gene loss-of-function'}", + "91, sVegfr-2 {'perturbing_action': 'I-gene loss-of-function'}", + "93, mice {'context': 'B-organism'}", + "130, corneal {'context': 'B-xenograft'}", + "131, allograft {'context': 'I-xenograft'}", + "134, suppressed {'effect': 'B-negative'}", + "135, lymphangioma {'context': 'B-neoplasm'}", + "136, cellular {'context': 'I-transformed cells', 'phenotype': 'B-proliferation'}", + "137, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "88, Tissue-specific ['l0', 'l1', 'l2', 'l3']", + "89, loss ['l0', 'l4', 'l5', 'l6']", + "90, of ['l1', 'l4', 'l7', 'l8']", + "91, sVegfr-2 ['l2', 'l5', 'l7', 'l9']", + "93, mice ['l3', 'l6', 'l8', 'l9']", + "130, corneal ['l10', 'l11', 'l12', 'l13', 'l14']", + "131, allograft ['l10', 'l15', 'l16', 'l17', 'l18']", + "134, suppressed ['l11', 'l15', 'l19', 'l20', 'l21']", + "135, lymphangioma ['l12', 'l16', 'l19', 'l22', 'l23']", + "136, cellular ['l13', 'l17', 'l20', 'l22', 'l24']", + "137, proliferation. ['l14', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tissue-specific", + "loss", + "of", + "sVegfr-2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "corneal", + "allograft" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "corneal", + "allograft" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cellular", + "proliferation." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "cellular" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cellular" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lymphangioma" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cellular" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cellular", + "proliferation." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "lymphangioma" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cellular", + "proliferation." + ] + } + } + ] + }, + { + "PMID": "19648929", + "TEXT": "Lymphocyte recruitment and activation have been implicated in the progression of cerebral ischemia-reperfusion (I/R) injury, but the roles of specific lymphocyte subpopulations and cytokines during stroke remain to be clarified. Here we demonstrate that the infiltration of T cells into the brain, as well as the cytokines interleukin-23 (IL-23) and IL-17, have pivotal roles in the evolution of brain infarction and accompanying neurological deficits. Blockade of T cell infiltration into the brain by the immunosuppressant FTY720 reduced I/R-induced brain damage. The expression of IL-23, which was derived mostly from infiltrated macrophages, increased on day 1 after I/R, whereas IL-17 levels were elevated after day 3, and this induction of IL-17 was dependent on IL-23. These data, together with analysis of mice genetically disrupted for IL-17 and IL-23, suggest that IL-23 functions in the immediate stage of I/R brain injury, whereas IL-17 has an important role in the delayed phase of I/R injury during which apoptotic neuronal death occurs in the penumbra. Intracellular cytokine staining revealed that gammadeltaT lymphocytes, but not CD4(+) helper T cells, were a major source of IL-17. Moreover, depletion of gammadeltaT lymphocytes ameliorated the I/R injury. We propose that T lymphocytes, including gammadeltaT lymphocytes, could be a therapeutic target for mitigating the inflammatory events that amplify the initial damage in cerebral ischemia.", + "TAG_DATA": [ + "78, brain {'context': 'B-tissue/organ'}", + "120, mice {'context': 'B-organism'}", + "121, genetically {'perturbing_action': 'I-gene loss-of-function'}", + "122, disrupted {'perturbing_action': 'I-gene loss-of-function'}", + "166, gammadeltaT {'context': 'B-cells'}", + "167, lymphocytes, {'context': 'I-cells'}", + "170, CD4(+) {'context': 'B-cells'}", + "171, helper {'context': 'I-cells'}", + "172, T {'context': 'I-cells'}", + "173, cells, {'context': 'I-cells'}", + "183, gammadeltaT {'context': 'B-cells'}", + "184, lymphocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "120, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "121, genetically ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "122, disrupted ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "166, gammadeltaT ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "167, lymphocytes, ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "170, CD4(+) ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32', 'l33']", + "171, helper ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l34', 'l35', 'l36']", + "172, T ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l34', 'l37']", + "173, cells, ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l35', 'l37']", + "183, gammadeltaT ['l38']", + "184, lymphocytes ['l33', 'l36', 'l38']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetically", + "disrupted" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetically", + "disrupted" + ] + }, + "context": { + "val": "cells", + "words": [ + "gammadeltaT", + "lymphocytes,", + "CD4(+)", + "helper", + "T", + "cells," + ] + } + } + ] + }, + { + "PMID": "19633657", + "TEXT": "Obesity and its associated metabolic syndromes represent a growing global challenge, yet mechanistic understanding of this pathology and current therapeutics are unsatisfactory. We discovered that CD4(+) T lymphocytes, resident in visceral adipose tissue (VAT), control insulin resistance in mice with diet-induced obesity (DIO). Analyses of human tissue suggest that a similar process may also occur in humans. DIO VAT-associated T cells show severely biased T cell receptor V(alpha) repertoires, suggesting antigen-specific expansion. CD4(+) T lymphocyte control of glucose homeostasis is compromised in DIO progression, when VAT accumulates pathogenic interferon-gamma (IFN-gamma)-secreting T helper type 1 (T(H)1) cells, overwhelming static numbers of T(H)2 (CD4(+)GATA-binding protein-3 (GATA-3)(+)) and regulatory forkhead box P3 (Foxp3)(+) T cells. CD4(+) (but not CD8(+)) T cell transfer into lymphocyte-free Rag1-null DIO mice reversed weight gain and insulin resistance, predominantly through T(H)2 cells. In obese WT and ob/ob (leptin-deficient) mice, brief treatment with CD3-specific antibody or its F(ab')(2) fragment, reduces the predominance of T(H)1 cells over Foxp3(+) cells, reversing insulin resistance for months, despite continuation of a high-fat diet. Our data suggest that the progression of obesity-associated metabolic abnormalities is under the pathophysiological control of CD4(+) T cells. The eventual failure of this control, with expanding adiposity and pathogenic VAT T cells, can successfully be reversed by immunotherapy.", + "TAG_DATA": [ + "116, T {'context': 'I-cells'}", + "120, lymphocyte-free {'perturbing_action': 'B-gene loss-of-function'}", + "121, Rag1-null {'perturbing_action': 'B-gene loss-of-function'}", + "123, mice {'context': 'B-organism'}", + "132, T(H)2 {'context': 'B-cells'}", + "133, cells. {'context': 'I-cells'}", + "138, ob/ob {'perturbing_action': 'B-gene loss-of-function'}", + "139, (leptin-deficient) {'perturbing_action': 'I-gene loss-of-function'}", + "140, mice, {'context': 'B-organism'}", + "154, T(H)1 {'context': 'B-cells'}", + "155, cells {'context': 'I-cells'}", + "157, Foxp3(+) {'context': 'B-cells'}", + "158, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "113, (but ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "116, T ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "120, lymphocyte-free ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "121, Rag1-null ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "123, mice ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "132, T(H)2 ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "133, cells. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "136, WT ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "138, ob/ob ['l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "139, (leptin-deficient) ['l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "140, mice, ['l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "154, T(H)1 ['l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "155, cells ['l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "157, Foxp3(+) ['l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "158, cells, ['l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "T(H)2", + "cells.", + "T(H)1", + "cells", + "Foxp3(+)", + "cells," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lymphocyte-free", + "Rag1-null", + "ob/ob", + "(leptin-deficient)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lymphocyte-free", + "Rag1-null", + "ob/ob", + "(leptin-deficient)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + } + ] + }, + { + "PMID": "19633655", + "TEXT": "Although mast cell functions have classically been related to allergic responses, recent studies indicate that these cells contribute to other common diseases such as multiple sclerosis, rheumatoid arthritis, atherosclerosis, aortic aneurysm and cancer. This study presents evidence that mast cells also contribute to diet-induced obesity and diabetes. For example, white adipose tissue (WAT) from obese humans and mice contain more mast cells than WAT from their lean counterparts. Furthermore, in the context of mice on a Western diet, genetically induced deficiency of mast cells, or their pharmacological stabilization, reduces body weight gain and levels of inflammatory cytokines, chemokines and proteases in serum and WAT, in concert with improved glucose homeostasis and energy expenditure. Mechanistic studies reveal that mast cells contribute to WAT and muscle angiogenesis and associated cell apoptosis and cathepsin activity. Adoptive transfer experiments of cytokine-deficient mast cells show that these cells, by producing interleukin-6 (IL-6) and interferon-gamma (IFN-gamma), contribute to mouse adipose tissue cysteine protease cathepsin expression, apoptosis and angiogenesis, thereby promoting diet-induced obesity and glucose intolerance. Our results showing reduced obesity and diabetes in mice treated with clinically available mast cell-stabilizing agents suggest the potential of developing new therapies for these common human metabolic disorders.", + "TAG_DATA": [ + "73, mice {'context': 'B-organism'}", + "80, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "82, mast {'context': 'B-cells'}", + "83, cells, {'context': 'I-cells'}", + "128, apoptosis {'phenotype': 'B-apoptosis'}", + "136, cytokine-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "137, mast {'context': 'B-cells'}", + "138, cells {'context': 'I-cells'}", + "142, cells, {'context': 'B-cells'}", + "152, mouse {'context': 'B-tissue/organ'}", + "153, adipose {'context': 'I-tissue/organ'}", + "154, tissue {'context': 'I-tissue/organ'}", + "159, apoptosis {'phenotype': 'B-apoptosis'}", + "177, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, mice ['l0']", + "80, deficiency ['l1', 'l2', 'l3']", + "82, mast ['l1', 'l4', 'l5']", + "83, cells, ['l0', 'l2', 'l4', 'l6']", + "128, apoptosis ['l3', 'l5', 'l6']", + "136, cytokine-deficient ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "137, mast ['l7', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "138, cells ['l8', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "142, cells, ['l9', 'l15', 'l20', 'l25', 'l26', 'l27', 'l28']", + "152, mouse ['l10', 'l16', 'l21', 'l25', 'l29', 'l30', 'l31']", + "153, adipose ['l11', 'l17', 'l22', 'l26', 'l29', 'l32', 'l33']", + "154, tissue ['l12', 'l18', 'l23', 'l27', 'l30', 'l32', 'l34']", + "159, apoptosis ['l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l34']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "cytokine-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "mast", + "cells,", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "cytokine-deficient" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mast", + "cells,", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cytokine-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "adipose", + "tissue" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "adipose", + "tissue" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "19597506", + "TEXT": "Imaging agents that enable direct visualization and quantification of apoptosis in vivo have great potential value for monitoring chemotherapeutic response as well as for early diagnosis and disease monitoring. We describe here the development of fluorescently labeled activity-based probes (ABPs) that covalently label active caspases in vivo. We used these probes to monitor apoptosis in the thymi of mice treated with dexamethasone as well as in tumor-bearing mice treated with the apoptosis-inducing monoclonal antibody Apomab (Genentech). Caspase ABPs provided direct readouts of the kinetics of apoptosis in live mice, whole organs and tissue extracts. The probes produced a maximum fluorescent signal that could be monitored noninvasively and that coincided with the peak in caspase activity, as measured by gel analysis. Overall, these studies demonstrate that caspase-specific ABPs have the potential to be used for noninvasive imaging of apoptosis in both preclinical and clinical settings.", + "TAG_DATA": [ + "53, apoptosis {'phenotype': 'B-apoptosis'}", + "56, thymi {'context': 'B-tissue/organ'}", + "58, mice {'context': 'B-organism'}", + "66, tumor-bearing {'context': 'B-organism'}", + "67, mice {'context': 'I-organism'}", + "85, apoptosis {'phenotype': 'B-apoptosis'}", + "88, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "53, apoptosis ['l0', 'l1']", + "56, thymi ['l0', 'l2']", + "58, mice ['l1', 'l2']", + "66, tumor-bearing ['l3', 'l4', 'l5']", + "67, mice ['l3', 'l6', 'l7']", + "85, apoptosis ['l4', 'l6', 'l8']", + "88, mice, ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "thymi" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "tumor-bearing", + "mice," + ] + } + } + ] + }, + { + "PMID": "19561618", + "TEXT": "Uncontrolled T helper type 1 (T(H)1) and T(H)17 cells are associated with autoimmune responses. We identify surface lymphotoxin-alpha (LT-alpha) as common to T(H)0, T(H)1 and T(H)17 cells and employ a unique strategy to target these subsets using a depleting monoclonal antibody (mAb) directed to surface LT-alpha. Depleting LT-alpha-specific mAb inhibited T cell-mediated models of delayed-type hypersensitivity and experimental autoimmune encephalomyelitis. In collagen-induced arthritis (CIA), preventive and therapeutic administration of LT-alpha-specific mAb inhibited disease, and immunoablated T cells expressing interleukin-17 (IL-17), interferon-gamma and tumor necrosis factor-alpha (TNF-alpha), whereas decoy lymphotoxin-beta receptor (LT-betaR) fusion protein had no effect. A mutation in the Fc tail, rendering the antibody incapable of Fcgamma receptor binding and antibody-dependent cellular cytotoxicity activity, abolished all in vivo effects. Efficacy in CIA was preceded by a loss of rheumatoid-associated cytokines IL-6, IL-1beta and TNF-alpha within joints. These data indicate that depleting LT-alpha-expressing lymphocytes with LT-alpha-specific mAb may be beneficial in the treatment of autoimmune disease.", + "TAG_DATA": [ + "75, T {'context': 'B-cells'}", + "76, cells {'context': 'I-cells'}", + "97, mutation {'perturbing_action': 'B-other'}", + "98, in {'perturbing_action': 'I-other'}", + "99, the {'perturbing_action': 'I-other'}", + "100, Fc {'perturbing_action': 'I-other'}", + "101, tail, {'perturbing_action': 'I-other'}", + "117, in {'context': 'B-in vivo'}", + "118, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "75, T ['l0']", + "76, cells ['l0']", + "97, mutation ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "98, in ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "99, the ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "100, Fc ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "101, tail, ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "117, in ['l5', 'l11', 'l16', 'l20', 'l23', 'l26']", + "118, vivo ['l6', 'l12', 'l17', 'l21', 'l24', 'l26']", + "136, joints. ['l7', 'l13', 'l18', 'l22', 'l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "in", + "the", + "Fc", + "tail," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "19525966", + "TEXT": "Pain is one of the most severe and debilitating symptoms associated with several forms of cancer. Various types of carcinomas and sarcomas metastasize to skeletal bones and cause spontaneous bone pain and hyperalgesia, which is accompanied by bone degradation and remodeling of peripheral nerves. Despite recent advances, the molecular mechanisms underlying the development and maintenance of cancer-evoked pain are not well understood. Several types of non-hematopoietic tumors secrete hematopoietic colony-stimulating factors that act on myeloid cells and tumor cells. Here we report that receptors and signaling mediators of granulocyte- and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF) are also functionally expressed on sensory nerves. GM-CSF sensitized nerves to mechanical stimuli in vitro and in vivo, potentiated CGRP release and caused sprouting of sensory nerve endings in the skin. Interruption of G-CSF and GM-CSF signaling in vivo led to reduced tumor growth and nerve remodeling, and abrogated bone cancer pain. The key significance of GM-CSF signaling in sensory neurons was revealed by an attenuation of tumor-evoked pain following a sensory nerve-specific knockdown of GM-CSF receptors. These results show that G-CSF and GM-CSF are important in tumor-nerve interactions and suggest that their receptors on primary afferent nerve fibers constitute potential therapeutic targets in cancer pain.", + "TAG_DATA": [ + "105, nerves {'context': 'B-cells'}", + "109, in {'context': 'B-in vitro'}", + "110, vitro {'context': 'I-in vitro'}", + "112, in {'context': 'B-in vivo'}", + "113, vivo, {'context': 'I-in vivo'}", + "121, sensory {'context': 'B-cells'}", + "122, nerve {'context': 'I-cells'}", + "123, endings {'context': 'I-cells'}", + "126, skin. {'context': 'B-tissue/organ'}", + "133, in {'context': 'B-in vivo'}", + "134, vivo {'context': 'I-in vivo'}", + "137, reduced {'effect': 'B-negative'}", + "138, tumor {'phenotype': 'B-tumour growth'}", + "139, growth {'phenotype': 'I-tumour growth'}", + "145, bone {'context': 'B-neoplasm'}", + "167, sensory {'perturbing_action': 'B-rnai/knockdown'}", + "168, nerve-specific {'perturbing_action': 'I-rnai/knockdown'}", + "169, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "170, of {'perturbing_action': 'I-rnai/knockdown'}", + "171, GM-CSF {'perturbing_action': 'I-rnai/knockdown'}", + "172, receptors. {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "105, nerves ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "109, in ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "110, vitro ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "112, in ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "113, vivo, ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "121, sensory ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "122, nerve ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "123, endings ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "126, skin. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "133, in ['l36', 'l37', 'l38', 'l39', 'l40']", + "134, vivo ['l36', 'l41', 'l42', 'l43', 'l44']", + "137, reduced ['l37', 'l41', 'l45', 'l46', 'l47']", + "138, tumor ['l38', 'l42', 'l45', 'l48', 'l49']", + "139, growth ['l39', 'l43', 'l46', 'l48', 'l50']", + "145, bone ['l40', 'l44', 'l47', 'l49', 'l50']", + "167, sensory ['l51', 'l52', 'l53', 'l54', 'l55']", + "168, nerve-specific ['l51', 'l56', 'l57', 'l58', 'l59']", + "169, knockdown ['l52', 'l56', 'l60', 'l61', 'l62']", + "170, of ['l53', 'l57', 'l60', 'l63', 'l64']", + "171, GM-CSF ['l54', 'l58', 'l61', 'l63', 'l65']", + "172, receptors. ['l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "bone" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "bone" + ] + } + } + ] + }, + { + "PMID": "19483695", + "TEXT": "Type I interferons (IFNs), a family of cytokines, orchestrate numerous biological and cellular processes1, 2, 3. Although it is well known that type I IFNs are essential for establishing the host antiviral state4, their role in hematopoietic homeostasis has not been studied. Here we show that type I IFNs induce proliferation and exhaustion in hematopoietic stem cells (HSCs) and that interferon regulatory factor-2 (IRF2), a transcriptional suppressor of type I IFN signaling5, 6, preserves the self-renewal and multilineage differentiation capacity of HSCs. HSCs were substantially less abundant in the bone marrow of Irf2-/- as compared to Irf2+/- mice. Irf2-/- HSCs showed enhanced cell cycling status and failed to produce hematopoietic cells in competitive repopulation assays, and the reconstituting capacity of Irf2-/- HSCs was restored by disabling type I IFN signaling in these cells. In wild-type mice, injection of poly(I:C), an inducer of type I IFN signaling, or IFN- induced HSC proliferation, and chronic type I IFN signaling further reduced the number of quiescent HSCs. Notably, combined poly(I:C) and 5-fluorouracil (5-FU) treatment allowed exogenous HSC engraftment and hematopoietic reconstitution in WT mice. Our findings provide insight into the molecular basis for the maintenance of HSC quiescence and may lead to improvements in bone marrow transplantation and type I IFN-based therapies for viral infection and cancer.", + "TAG_DATA": [ + "92, Irf2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "96, Irf2+/- {'perturbing_action': 'B-gene loss-of-function'}", + "97, mice. {'context': 'B-organism'}", + "98, Irf2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "99, HSCs {'context': 'B-cells'}", + "109, hematopoietic {'context': 'B-cells'}", + "110, cells {'context': 'I-cells'}", + "120, Irf2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "121, HSCs {'context': 'B-cells'}", + "132, cells. {'context': 'B-cells'}", + "135, mice, {'context': 'B-organism'}", + "147, IFN- {'effect': 'B-positive'}", + "148, induced {'effect': 'B-positive'}", + "149, HSC {'context': 'B-cells'}", + "150, proliferation, {'phenotype': 'B-proliferation'}", + "158, reduced {'effect': 'B-negative'}", + "162, quiescent {'phenotype': 'B-quiescence'}", + "163, HSCs. {'context': 'B-cells'}", + "173, HSC {'context': 'B-cells'}", + "180, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "92, Irf2-/- ['l0', 'l1', 'l2', 'l3']", + "96, Irf2+/- ['l0', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "97, mice. ['l1', 'l4', 'l11', 'l12']", + "98, Irf2-/- ['l5', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "99, HSCs ['l2', 'l6', 'l11', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "109, hematopoietic ['l7', 'l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "110, cells ['l3', 'l8', 'l12', 'l15', 'l20', 'l24', 'l28']", + "120, Irf2-/- ['l16', 'l21', 'l25', 'l29', 'l30']", + "121, HSCs ['l9', 'l17', 'l22', 'l26', 'l29', 'l31']", + "132, cells. ['l10', 'l18', 'l23', 'l27', 'l28', 'l30', 'l31']", + "135, mice, ['l32', 'l33', 'l34', 'l35', 'l36']", + "147, IFN- ['l32', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "148, induced ['l33', 'l37', 'l43', 'l44']", + "149, HSC ['l34', 'l38', 'l43', 'l45', 'l46', 'l47', 'l48']", + "150, proliferation, ['l35', 'l39', 'l44', 'l45']", + "158, reduced ['l40', 'l46', 'l49', 'l50']", + "162, quiescent ['l41', 'l47', 'l49', 'l51']", + "163, HSCs. ['l36', 'l42', 'l48', 'l50', 'l51']", + "173, HSC ['l52']", + "180, mice. ['l52']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Irf2-/-", + "Irf2+/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Irf2-/-", + "Irf2+/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSCs", + "cells", + "hematopoietic", + "cells." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "positive", + "words": [ + "IFN-", + "induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "IFN-", + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC", + "HSCs." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "IFN-", + "induced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "IFN-" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescent" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSC" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSC", + "HSCs." + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSC", + "HSCs." + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescent" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescent" + ] + } + } + ] + }, + { + "PMID": "19483693", + "TEXT": "Formation of new vessels in granulation tissue during wound healing has been assumed to occur solely through sprouting angiogenesis. In contrast, we show here that neovascularization can be accomplished by nonangiogenic expansion of preexisting vessels. Using neovascularization models based on the chick chorioallantoic membrane and the healing mouse cornea, we found that tissue tension generated by activated fibroblasts or myofibroblasts during wound contraction mediated and directed translocation of the vasculature. These mechanical forces pulled vessels from the preexisting vascular bed as vascular loops with functional circulation that expanded as an integral part of the growing granulation tissue through vessel enlargement and elongation. Blockade of vascular endothelial growth factor receptor-2 confirmed that biomechanical forces were sufficient to mediate the initial vascular growth independently of endothelial sprouting or proliferation. The neovascular network was further remodeled by splitting, sprouting and regression of individual vessels. This model explains the rapid appearance of large functional vessels in granulation tissue during wound healing.", + "TAG_DATA": [ + "47, mouse {'context': 'B-tissue/organ'}", + "48, cornea, {'context': 'I-tissue/organ'}", + "102, Blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "103, of {'perturbing_action': 'I-pharmacological inhibition'}", + "104, vascular {'perturbing_action': 'I-pharmacological inhibition'}", + "105, endothelial {'perturbing_action': 'I-pharmacological inhibition'}", + "106, growth {'perturbing_action': 'I-pharmacological inhibition'}", + "107, factor {'perturbing_action': 'I-pharmacological inhibition'}", + "108, receptor-2 {'perturbing_action': 'I-pharmacological inhibition'}", + "126, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "47, mouse ['l0']", + "48, cornea, ['l0']", + "102, Blockade ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "103, of ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "104, vascular ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "105, endothelial ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "106, growth ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "107, factor ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "108, receptor-2 ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "126, proliferation. ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "vascular", + "endothelial", + "growth", + "factor", + "receptor-2" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "19396173", + "TEXT": "Specific inhibition of the entry of encephalitogenic T lymphocytes into the central nervous system in multiple sclerosis would provide a means of inhibiting disease without compromising innate immune responses. We show here that targeting lymphocyte interactions with endothelial basement membrane laminins provides such a possibility. In mouse experimental autoimmune encephalomyelitis, T lymphocyte extravasation correlates with sites expressing laminin alpha4 and small amounts of laminin alpha5. In mice lacking laminin alpha4, laminin alpha5 is ubiquitously expressed along the vascular tree, resulting in marked and selective reduction of T lymphocyte infiltration into the brain and reduced disease susceptibility and severity. Vessel phenotype and immune response were not affected in these mice. Rather, laminin alpha5 directly inhibited integrin alpha(6)beta(1)-mediated migration of T lymphocytes through laminin alpha4. The data indicate that T lymphocytes use mechanisms distinct from other immune cells to penetrate the endothelial basement membrane barrier, permitting specific targeting of this immune cell population.", + "TAG_DATA": [ + "66, mice {'context': 'B-organism'}", + "67, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "68, laminin {'perturbing_action': 'I-gene loss-of-function'}", + "69, alpha4, {'perturbing_action': 'I-gene loss-of-function'}", + "98, Vessel {'context': 'B-tissue/organ'}", + "108, mice. {'context': 'B-organism'}", + "113, inhibited {'effect': 'B-negative'}", + "116, migration {'phenotype': 'B-migration'}", + "118, T {'context': 'B-cells'}", + "119, lymphocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "66, mice ['l0', 'l1', 'l2']", + "67, lacking ['l0', 'l3', 'l4']", + "68, laminin ['l1', 'l3', 'l5']", + "69, alpha4, ['l2', 'l4', 'l5']", + "98, Vessel ['l6']", + "108, mice. ['l6']", + "113, inhibited ['l7', 'l8', 'l9']", + "116, migration ['l7', 'l10', 'l11']", + "118, T ['l8', 'l10', 'l12']", + "119, lymphocytes ['l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "laminin", + "alpha4," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "lymphocytes" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "lymphocytes" + ] + } + } + ] + }, + { + "PMID": "19330010", + "TEXT": "Understanding the mechanisms of osteoclastogenesis is crucial for developing new drugs to treat diseases associated with bone loss, such as osteoporosis. Here we report that the C-C chemokine receptor-2 (CCR2) is crucially involved in balancing bone mass. CCR2-knockout mice have high bone mass owing to a decrease in number, size and function of osteoclasts. In normal mice, activation of CCR2 in osteoclast progenitor cells results in both nuclear factor-kappaB (NF-kappaB) and extracellular signal-related kinase 1 and 2 (ERK1/2) signaling but not that of p38 mitogen-activated protein kinase or c-Jun N-terminal kinase. The induction of NF-kappaB and ERK1/2 signaling in turn leads to increased surface expression of receptor activator of NF-kappaB (RANK, encoded by Tnfrsf11a), making the progenitor cells more susceptible to RANK ligand-induced osteoclastogenesis. In ovariectomized mice, a model of postmenopausal osteoporosis, CCR2 is upregulated on wild-type preosteoclasts, thus increasing the surface expression of RANK on these cells and their osteoclastogenic potential, whereas CCR2-knockout mice are resistant to ovariectomy-induced bone loss. These data reveal a previously undescribed pathway by which RANK, osteoclasts and bone homeostasis are regulated in health and disease.", + "TAG_DATA": [ + "37, CCR2-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "38, mice {'context': 'B-organism'}", + "55, normal {'context': 'B-organism'}", + "56, mice, {'context': 'I-organism'}", + "57, activation {'perturbing_action': 'B-pharmacological augmentation'}", + "58, of {'perturbing_action': 'I-pharmacological augmentation'}", + "59, CCR2 {'perturbing_action': 'I-pharmacological augmentation'}", + "61, osteoclast {'context': 'B-cells'}", + "62, progenitor {'context': 'I-cells'}", + "63, cells {'context': 'I-cells'}", + "116, progenitor {'context': 'B-cells'}", + "117, cells {'context': 'I-cells'}", + "126, mice, {'context': 'B-organism'}", + "153, CCR2-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "154, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "37, CCR2-knockout ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "38, mice ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "55, normal ['l1', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "56, mice, ['l2', 'l11', 'l18', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "57, activation ['l3', 'l12', 'l19', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "58, of ['l4', 'l13', 'l20', 'l27', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "59, CCR2 ['l5', 'l14', 'l21', 'l28', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "61, osteoclast ['l6', 'l15', 'l22', 'l29', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53']", + "62, progenitor ['l7', 'l16', 'l23', 'l30', 'l36', 'l42', 'l47', 'l51', 'l54', 'l55']", + "63, cells ['l8', 'l17', 'l24', 'l31', 'l37', 'l43', 'l48', 'l52', 'l54', 'l56']", + "116, progenitor ['l38', 'l44', 'l49', 'l57', 'l58']", + "117, cells ['l9', 'l25', 'l32', 'l39', 'l45', 'l50', 'l53', 'l55', 'l56', 'l57', 'l59']", + "126, mice, ['l58', 'l59']", + "153, CCR2-knockout ['l60']", + "154, mice ['l60']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CCR2-knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "normal", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CCR2-knockout" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast", + "progenitor", + "cells" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "normal", + "mice," + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "of", + "CCR2" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "of", + "CCR2" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast", + "progenitor", + "cells" + ] + } + } + ] + }, + { + "PMID": "19270709", + "TEXT": "Tissue injury may create a specific microenvironment for inducing the systemic participation of stromal-like cells in the repair process. Here we show that substance P is an injury-inducible factor that acts early in the wound healing process to induce CD29(+) stromal-like cell mobilization. Likewise, mobilization of such cells also occurs in uninjured mice, rats and rabbits if substance P is intravenously injected. Upon further characterization these substance P-mobilized CD29(+) cells were found to be similar to stromal cells from a number of connective tissues, including bone marrow (that is, bone marrow stromal cells, or BMSCs). Both substance P injection and transfusion of autologously derived substance P-mobilized CD29(+) cells from uninjured rabbits accelerated wound healing in an alkali burn model. Also, epithelial engraftment of the transfused cells into the injured tissue occurred during the wound healing. Finally, using human BMSCs as a test population, we show that substance P stimulates transmigration, cell proliferation, activation of the extracellular signal-related kinases (Erk) 1 and 2 and nuclear translocation of beta-catenin in vitro. This finding highlights a previously undescribed function of substance P as a systemically acting messenger of injury and a mobilizer of CD29(+) stromal-like cells to participate in wound healing.", + "TAG_DATA": [ + "51, uninjured {'context': 'B-organism'}", + "52, mice, {'context': 'I-organism'}", + "53, rats {'context': 'B-organism'}", + "55, rabbits {'context': 'B-organism'}", + "106, CD29(+) {'context': 'B-cells'}", + "107, cells {'context': 'I-cells'}", + "109, uninjured {'context': 'B-organism'}", + "110, rabbits {'context': 'I-organism'}", + "125, cells {'context': 'B-cells'}", + "137, human {'context': 'B-cells'}", + "138, BMSCs {'context': 'I-cells'}", + "148, stimulates {'effect': 'B-positive'}", + "150, cell {'context': 'B-cells'}", + "151, proliferation, {'phenotype': 'B-proliferation'}", + "167, in {'context': 'B-in vitro'}", + "168, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "51, uninjured ['l0', 'l1', 'l2']", + "52, mice, ['l0', 'l3', 'l4']", + "53, rats ['l1', 'l3', 'l5']", + "55, rabbits ['l2', 'l4', 'l5']", + "106, CD29(+) ['l6', 'l7', 'l8', 'l9']", + "107, cells ['l6', 'l10', 'l11', 'l12']", + "109, uninjured ['l7', 'l10', 'l13']", + "110, rabbits ['l8', 'l11', 'l13']", + "125, cells ['l9', 'l12', 'l14']", + "137, human ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "138, BMSCs ['l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "148, stimulates ['l16', 'l22', 'l28', 'l29', 'l30', 'l31', 'l32']", + "149, transmigration, ['l17', 'l23', 'l28', 'l33', 'l34', 'l35', 'l36']", + "150, cell ['l14', 'l18', 'l24', 'l29', 'l33', 'l37']", + "151, proliferation, ['l19', 'l25', 'l30', 'l34', 'l37']", + "167, in ['l20', 'l26', 'l31', 'l35', 'l38']", + "168, vitro. ['l21', 'l27', 'l32', 'l36', 'l38']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "BMSCs", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "BMSCs", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "19252503", + "TEXT": "The variable efficacy of Bacille Calmette Guerin (BCG) vaccination against tuberculosis has prompted efforts to improve the vaccine. In this study, we used autophagy to enhance vaccine efficacy against tuberculosis in a mouse model. We examined the effect of autophagy on the processing of the immunodominant mycobacterial antigen Ag85B by antigen presenting cells (APCs), macrophages and dendritic cells (DCs). We found that rapamycin-induced autophagy enhanced Ag85B presentation by APCs infected with wild-type Mycobacterium tuberculosis H37Rv, H37Rv-derived DeltafbpA attenuated candidate vaccine or BCG. Furthermore, rapamycin enhanced localization of mycobacteria with autophagosomes and lysosomes. Rapamycin-enhanced antigen presentation was attenuated when autophagy was suppressed by 3-methyladenine or by small interfering RNA against beclin-1. Notably, mice immunized with rapamycin-treated DCs infected with either DeltafbpA or BCG showed enhanced T helper type 1-mediated protection when challenged with virulent Mycobacterium tuberculosis. Finally, overexpression of Ag85B in BCG induced autophagy in APCs and enhanced immunogenicity in mice, suggesting that vaccine efficacy can be enhanced by augmenting autophagy-mediated antigen presentation.", + "TAG_DATA": [ + "63, autophagy {'phenotype': 'B-autophagy'}", + "68, APCs {'context': 'B-cells'}", + "98, autophagy {'phenotype': 'B-autophagy'}", + "100, suppressed {'effect': 'B-negative'}", + "105, small {'perturbing_action': 'B-rnai/knockdown'}", + "106, interfering {'perturbing_action': 'I-rnai/knockdown'}", + "107, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "108, against {'perturbing_action': 'I-rnai/knockdown'}", + "109, beclin-1. {'perturbing_action': 'I-rnai/knockdown'}", + "111, mice {'context': 'B-organism'}", + "115, DCs {'context': 'B-cells'}", + "136, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "137, of {'perturbing_action': 'I-gene gain-of-function'}", + "138, Ag85B {'perturbing_action': 'I-gene gain-of-function'}", + "139, in {'perturbing_action': 'I-gene gain-of-function'}", + "140, BCG {'perturbing_action': 'I-gene gain-of-function'}", + "141, induced {'effect': 'B-positive'}", + "142, autophagy {'phenotype': 'B-autophagy'}", + "144, APCs {'context': 'B-cells'}", + "149, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "63, autophagy ['l0']", + "68, APCs ['l0']", + "98, autophagy ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "100, suppressed ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "105, small ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "106, interfering ['l3', 'l9', 'l14', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "107, RNA ['l4', 'l10', 'l15', 'l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "108, against ['l5', 'l11', 'l16', 'l24', 'l30', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "109, beclin-1. ['l6', 'l12', 'l17', 'l25', 'l31', 'l37', 'l43', 'l44']", + "111, mice ['l7', 'l13', 'l18', 'l26', 'l32', 'l38', 'l43', 'l45', 'l46', 'l47', 'l48']", + "115, DCs ['l19', 'l27', 'l33', 'l39', 'l44', 'l45', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "136, overexpression ['l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "137, of ['l56', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "138, Ag85B ['l49', 'l57', 'l64', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "139, in ['l50', 'l58', 'l65', 'l71', 'l77', 'l78', 'l79', 'l80', 'l81']", + "140, BCG ['l51', 'l59', 'l66', 'l72', 'l77', 'l82', 'l83', 'l84', 'l85']", + "141, induced ['l20', 'l28', 'l34', 'l40', 'l46', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l86', 'l87', 'l88']", + "142, autophagy ['l21', 'l35', 'l41', 'l47', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l89', 'l90']", + "144, APCs ['l22', 'l29', 'l36', 'l42', 'l48', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l91']", + "149, mice, ['l55', 'l63', 'l70', 'l76', 'l81', 'l85', 'l88', 'l90', 'l91']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + }, + "context": { + "val": "cells", + "words": [ + "APCs", + "DCs" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "small", + "interfering", + "RNA", + "against", + "beclin-1." + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "small", + "interfering", + "RNA", + "against", + "beclin-1." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "small", + "interfering", + "RNA", + "against", + "beclin-1." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "small", + "interfering", + "RNA", + "against", + "beclin-1." + ] + }, + "context": { + "val": "cells", + "words": [ + "DCs", + "APCs" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "small", + "interfering", + "RNA", + "against" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "DCs", + "APCs" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ag85B", + "in", + "BCG", + "overexpression", + "of" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "DCs", + "APCs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Ag85B", + "in", + "BCG" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Ag85B", + "in", + "BCG" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Ag85B", + "in", + "BCG" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + } + ] + }, + { + "PMID": "19234463", + "TEXT": "Integrins are the major adhesion receptors of leukocytes and platelets. Beta1 and beta2 integrin function on leukocytes is crucial for a successful immune response and the platelet integrin alpha(IIb)beta3 initiates the process of blood clotting through binding fibrinogen. Integrins on circulating cells bind poorly to their ligands but become active after 'inside-out' signaling through other membrane receptors. Subjects with leukocyte adhesion deficiency-1 (LAD-I) do not express beta2 integrins because of mutations in the gene specifying the beta2 subunit, and they suffer recurrent bacterial infections. Mutations affecting alpha(IIb)beta3 integrin cause the bleeding disorder termed Glanzmann's thrombasthenia. Subjects with LAD-III show symptoms of both LAD-I and Glanzmann's thrombasthenia. Their hematopoietically-derived cells express beta1, beta2 and beta3 integrins, but defective inside-out signaling causes immune deficiency and bleeding problems. The LAD-III lesion has been attributed to a C --> A mutation in the gene encoding calcium and diacylglycerol guanine nucleotide exchange factor (CALDAGGEF1; official symbol RASGRP2) specifying the CALDAG-GEF1 protein, but we show that this change is not responsible for the LAD-III disorder. Instead, we identify mutations in the KINDLIN3 (official symbol FERMT3) gene specifying the KINDLIN-3 protein as the cause of LAD-III in Maltese and Turkish subjects. Two independent mutations result in decreased KINDLIN3 messenger RNA levels and loss of protein expression. Notably, transfection of the subjects' lymphocytes with KINDLIN3 complementary DNA but not CALDAGGEF1 cDNA reverses the LAD-III defect, restoring integrin-mediated adhesion and migration.", + "TAG_DATA": [ + "210, transfection {'perturbing_action': 'B-gene gain-of-function'}", + "213, subjects' {'context': 'B-cells'}", + "214, lymphocytes {'context': 'B-cells'}", + "215, with {'perturbing_action': 'I-gene gain-of-function'}", + "216, KINDLIN3 {'perturbing_action': 'I-gene gain-of-function'}", + "217, complementary {'perturbing_action': 'I-gene gain-of-function'}", + "218, DNA {'perturbing_action': 'I-gene gain-of-function'}", + "227, restoring {'effect': 'B-rescues'}", + "229, adhesion {'phenotype': 'B-adhesion'}", + "231, migration. {'phenotype': 'B-migration'}" + ], + "LINK_DATA": [ + "210, transfection ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "213, subjects' ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "214, lymphocytes ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "215, with ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "216, KINDLIN3 ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "217, complementary ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "218, DNA ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "227, restoring ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "229, adhesion ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "231, migration. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfection", + "with", + "KINDLIN3", + "complementary", + "DNA" + ] + }, + "context": { + "val": "cells", + "words": [ + "subjects'", + "lymphocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfection", + "with", + "KINDLIN3", + "complementary", + "DNA" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restoring" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfection", + "with", + "KINDLIN3", + "complementary", + "DNA" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfection", + "with", + "KINDLIN3", + "complementary", + "DNA" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "subjects'", + "lymphocytes" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restoring" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "subjects'", + "lymphocytes" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "subjects'", + "lymphocytes" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restoring" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restoring" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + } + ] + }, + { + "PMID": "19234461", + "TEXT": "Integrin activation is essential for the function of all blood cells, including platelets and leukocytes. The blood cell-specific FERM domain protein Kindlin-3 is required for the activation of the beta1 and beta3 integrins on platelets. Impaired activation of beta1, beta2 and beta3 integrins on platelets and leukocytes is the hallmark of a rare autosomal recessive leukocyte adhesion deficiency syndrome in humans called LAD-III, characterized by severe bleeding and impaired adhesion of leukocytes to inflamed endothelia. Here we show that Kindlin-3 also binds the beta2 integrin cytoplasmic domain and is essential for neutrophil binding and spreading on beta2 integrin-dependent ligands such as intercellular adhesion molecule-1 and the complement C3 activation product iC3b. Moreover, loss of Kindlin-3 expression abolished firm adhesion and arrest of neutrophils on activated endothelial cells in vitro and in vivo, whereas selectin-mediated rolling was unaffected. Thus, Kindlin-3 is essential to activate the beta1, beta2 and beta3 integrin classes, and loss of Kindlin-3 function is sufficient to cause a LAD-III-like phenotype in mice.", + "TAG_DATA": [ + "112, loss {'perturbing_action': 'B-gene loss-of-function'}", + "113, of {'perturbing_action': 'I-gene loss-of-function'}", + "114, Kindlin-3 {'perturbing_action': 'I-gene loss-of-function'}", + "115, expression {'perturbing_action': 'I-gene loss-of-function'}", + "116, abolished {'effect': 'B-negative'}", + "125, endothelial {'context': 'B-cells'}", + "126, cells {'context': 'I-cells'}", + "127, in {'context': 'B-in vitro'}", + "128, vitro {'context': 'I-in vitro'}", + "130, in {'context': 'B-in vivo'}", + "131, vivo, {'context': 'I-in vivo'}", + "136, unaffected. {'effect': 'B-no effect'}", + "151, loss {'perturbing_action': 'B-gene loss-of-function'}", + "152, of {'perturbing_action': 'I-gene loss-of-function'}", + "153, Kindlin-3 {'perturbing_action': 'I-gene loss-of-function'}", + "154, function {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "112, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "113, of ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "114, Kindlin-3 ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "115, expression ['l2', 'l9', 'l15', 'l22', 'l23', 'l24', 'l25', 'l26']", + "116, abolished ['l3', 'l10', 'l16', 'l22', 'l27', 'l28', 'l29', 'l30']", + "125, endothelial ['l4', 'l11', 'l17', 'l23', 'l27', 'l31', 'l32', 'l33']", + "126, cells ['l5', 'l12', 'l18', 'l24', 'l28', 'l31', 'l34', 'l35']", + "127, in ['l6', 'l13', 'l19', 'l25', 'l29', 'l32', 'l34', 'l36']", + "128, vitro ['l7', 'l14', 'l20', 'l26', 'l30', 'l33', 'l35', 'l36']", + "130, in ['l37']", + "131, vivo, ['l21', 'l37']", + "151, loss ['l38', 'l39', 'l40']", + "152, of ['l38', 'l41', 'l42']", + "153, Kindlin-3 ['l39', 'l41', 'l43']", + "154, function ['l40', 'l42', 'l43']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Kindlin-3", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abolished" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Kindlin-3", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Kindlin-3", + "expression" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Kindlin-3" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abolished" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abolished" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "19219024", + "TEXT": "The rapid onset of massive, systemic viral replication during primary HIV or simian immunodeficiency virus (SIV) infection and the immune evasion capabilities of these viruses pose fundamental problems for vaccines that depend upon initial viral replication to stimulate effector T cell expansion and differentiation. We hypothesized that vaccines designed to maintain differentiated effector memory T cell (TEM cell) responses at viral entry sites might improve efficacy by impairing viral replication at its earliest stage, and we have therefore developed SIV protein-encoding vectors based on rhesus cytomegalovirus (RhCMV), the prototypical inducer of life-long TEM cell responses. RhCMV vectors expressing SIV Gag, Rev-Tat-Nef and Env persistently infected rhesus macaques, regardless of preexisting RhCMV immunity, and primed and maintained robust, SIV-specific CD4+ and CD8+ TEM cell responses (characterized by coordinate tumor necrosis factor, interferon-gamma and macrophage inflammatory protein-1beta expression, cytotoxic degranulation and accumulation at extralymphoid sites) in the absence of neutralizing antibodies. Compared to control rhesus macaques, these vaccinated rhesus macaques showed increased resistance to acquisition of progressive SIVmac239 infection upon repeated limiting-dose intrarectal challenge, including four macaques who controlled rectal mucosal infection without progressive systemic dissemination. These data suggest a new paradigm for AIDS vaccine development--vaccines capable of generating and maintaining HIV-specific TEM cells might decrease the incidence of HIV acquisition after sexual exposure.", + "TAG_DATA": [ + "95, RhCMV {'perturbing_action': 'B-gene gain-of-function'}", + "96, vectors {'perturbing_action': 'I-gene gain-of-function'}", + "97, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "98, SIV {'perturbing_action': 'I-gene gain-of-function'}", + "99, Gag, {'perturbing_action': 'I-gene gain-of-function'}", + "100, Rev-Tat-Nef {'perturbing_action': 'I-gene gain-of-function'}", + "101, and {'perturbing_action': 'I-gene gain-of-function'}", + "102, Env {'perturbing_action': 'I-gene gain-of-function'}", + "105, rhesus {'context': 'B-organism'}", + "106, macaques, {'context': 'I-organism'}", + "118, CD4+ {'context': 'B-cells'}", + "119, and {'context': 'I-cells'}", + "120, CD8+ {'context': 'I-cells'}", + "121, TEM {'context': 'I-cells'}", + "122, cell {'context': 'I-cells'}", + "152, rhesus {'context': 'B-organism'}", + "153, macaques, {'context': 'I-organism'}", + "156, rhesus {'context': 'B-organism'}", + "157, macaques {'context': 'I-organism'}", + "174, macaques {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "95, RhCMV ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "96, vectors ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "97, expressing ['l1', 'l14', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "98, SIV ['l2', 'l15', 'l25', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "99, Gag, ['l3', 'l16', 'l26', 'l37', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "100, Rev-Tat-Nef ['l4', 'l17', 'l27', 'l38', 'l48', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "101, and ['l5', 'l18', 'l28', 'l39', 'l49', 'l58', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "102, Env ['l6', 'l19', 'l29', 'l40', 'l50', 'l59', 'l67', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "105, rhesus ['l7', 'l20', 'l30', 'l41', 'l51', 'l60', 'l68', 'l73', 'l79']", + "106, macaques, ['l8', 'l21', 'l31', 'l42', 'l52', 'l61', 'l69', 'l74', 'l79']", + "118, CD4+ ['l9', 'l32', 'l43', 'l53', 'l62', 'l75', 'l80', 'l81', 'l82', 'l83']", + "119, and ['l10', 'l22', 'l33', 'l44', 'l54', 'l63', 'l70', 'l76', 'l80', 'l84', 'l85', 'l86']", + "120, CD8+ ['l11', 'l34', 'l45', 'l55', 'l64', 'l81', 'l84', 'l87', 'l88']", + "121, TEM ['l12', 'l23', 'l35', 'l46', 'l56', 'l65', 'l71', 'l77', 'l82', 'l85', 'l87', 'l89']", + "122, cell ['l13', 'l24', 'l36', 'l47', 'l57', 'l66', 'l72', 'l78', 'l83', 'l86', 'l88', 'l89']", + "152, rhesus ['l90', 'l91', 'l92']", + "153, macaques, ['l90', 'l93', 'l94']", + "156, rhesus ['l91', 'l93', 'l95']", + "157, macaques ['l92', 'l94', 'l95']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "RhCMV", + "vectors", + "expressing", + "SIV", + "Gag,", + "Rev-Tat-Nef", + "and", + "Env" + ] + }, + "context": { + "val": "organism", + "words": [ + "rhesus", + "macaques," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "RhCMV", + "vectors", + "expressing", + "SIV", + "Gag,", + "Rev-Tat-Nef", + "and", + "Env" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "and", + "CD8+", + "TEM", + "cell" + ] + } + } + ] + }, + { + "PMID": "19219023", + "TEXT": "We developed a new approach to bioluminescent T cell imaging using a membrane-anchored form of the Gaussia luciferase (GLuc) enzyme, termed extGLuc, which we could stably express in both mouse and human primary T cells. In vitro, extGLuc+ cells emitted significantly higher bioluminescent signal when compared to cells expressing GLuc, Renilla luciferase (RLuc) or membrane-anchored RLuc (extRLuc). In vivo, mouse extGLuc+ T cells showed higher bioluminescent signal when compared to GLuc+ and RLuc+ T cells. Application of this imaging approach to human T cells genetically modified to express tumor-specific chimeric antigen receptors (CARs) enabled us to show in vivo CAR-mediated T cell accumulation in tumor, T cell persistence over time and concomitant imaging of T cells and tumor cells modified to express firefly luciferase. This sensitive imaging technology has application to many in vivo cell-based studies in a wide array of mouse models.", + "TAG_DATA": [ + "35, In {'context': 'B-in vitro'}", + "36, vitro, {'context': 'I-in vitro'}", + "37, extGLuc+ {'context': 'B-cells'}", + "38, cells {'context': 'I-cells'}", + "47, cells {'context': 'B-cells'}", + "57, In {'context': 'B-in vivo'}", + "58, vivo, {'context': 'I-in vivo'}", + "59, mouse {'context': 'B-cells'}", + "60, extGLuc+ {'context': 'I-cells'}", + "61, T {'context': 'I-cells'}", + "62, cells {'context': 'I-cells'}", + "81, human {'context': 'B-cells'}", + "82, T {'context': 'I-cells'}", + "83, cells {'context': 'I-cells'}", + "84, genetically {'perturbing_action': 'B-other'}", + "85, modified {'perturbing_action': 'B-other'}", + "86, to {'perturbing_action': 'I-other'}", + "87, express {'perturbing_action': 'I-other'}", + "88, tumor-specific {'perturbing_action': 'I-other'}", + "89, chimeric {'perturbing_action': 'I-other'}", + "97, in {'context': 'B-in vivo'}", + "98, vivo {'context': 'I-in vivo'}", + "100, T {'context': 'B-cells'}", + "101, cell {'context': 'I-cells'}", + "104, tumor, {'context': 'B-neoplasm'}", + "105, T {'context': 'B-cells'}", + "106, cell {'context': 'I-cells'}", + "114, T {'context': 'B-cells'}", + "115, cells {'context': 'B-cells'}", + "117, tumor {'context': 'B-transformed cells'}", + "118, cells {'context': 'I-transformed cells'}", + "119, modified {'perturbing_action': 'B-other'}" + ], + "LINK_DATA": [ + "35, In ['l0', 'l1', 'l2', 'l3']", + "36, vitro, ['l0', 'l4', 'l5', 'l6']", + "37, extGLuc+ ['l1', 'l4', 'l7', 'l8']", + "38, cells ['l2', 'l5', 'l7', 'l9']", + "47, cells ['l3', 'l6', 'l8', 'l9']", + "57, In ['l10', 'l11', 'l12', 'l13', 'l14']", + "58, vivo, ['l10', 'l15', 'l16', 'l17', 'l18']", + "59, mouse ['l11', 'l15', 'l19', 'l20', 'l21']", + "60, extGLuc+ ['l12', 'l16', 'l19', 'l22', 'l23']", + "61, T ['l13', 'l17', 'l20', 'l22', 'l24']", + "62, cells ['l14', 'l18', 'l21', 'l23', 'l24']", + "81, human ['l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "82, T ['l25', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "83, cells ['l26', 'l44', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "84, genetically ['l27', 'l45', 'l62', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "85, modified ['l28', 'l46', 'l63', 'l78', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "86, to ['l29', 'l47', 'l64', 'l79', 'l97', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "87, express ['l30', 'l48', 'l65', 'l80', 'l98', 'l117', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "88, tumor-specific ['l31', 'l49', 'l66', 'l81', 'l99', 'l118', 'l136', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "89, chimeric ['l32', 'l50', 'l67', 'l82', 'l100', 'l119', 'l137', 'l154', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184']", + "90, antigen ['l33', 'l51', 'l68', 'l83', 'l101', 'l120', 'l138', 'l155', 'l170', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196']", + "91, receptors ['l34', 'l52', 'l69', 'l84', 'l102', 'l121', 'l139', 'l156', 'l171', 'l185', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208']", + "92, (CARs) ['l35', 'l53', 'l70', 'l85', 'l103', 'l122', 'l140', 'l157', 'l172', 'l186', 'l197', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218']", + "97, in ['l36', 'l54', 'l71', 'l86', 'l104', 'l123', 'l141', 'l158', 'l173', 'l187', 'l198', 'l209', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226']", + "98, vivo ['l37', 'l55', 'l72', 'l87', 'l105', 'l124', 'l142', 'l159', 'l174', 'l188', 'l199', 'l210', 'l219', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233']", + "100, T ['l38', 'l56', 'l73', 'l88', 'l106', 'l125', 'l143', 'l160', 'l175', 'l189', 'l200', 'l211', 'l220', 'l227', 'l234', 'l235', 'l236', 'l237']", + "101, cell ['l39', 'l57', 'l74', 'l89', 'l107', 'l126', 'l144', 'l161', 'l176', 'l190', 'l201', 'l212', 'l221', 'l228', 'l234', 'l238', 'l239', 'l240']", + "104, tumor, ['l40', 'l58', 'l75', 'l90', 'l108', 'l127', 'l145', 'l162', 'l177', 'l191', 'l202', 'l213', 'l222', 'l229', 'l235', 'l238']", + "105, T ['l41', 'l59', 'l76', 'l91', 'l109', 'l128', 'l146', 'l163', 'l178', 'l192', 'l203', 'l214', 'l223', 'l230', 'l236', 'l239', 'l241', 'l242', 'l243', 'l244', 'l245']", + "106, cell ['l42', 'l60', 'l77', 'l92', 'l110', 'l129', 'l147', 'l164', 'l179', 'l193', 'l204', 'l215', 'l224', 'l231', 'l237', 'l240', 'l241', 'l246', 'l247']", + "114, T ['l93', 'l111', 'l130', 'l148', 'l165', 'l180', 'l194', 'l205', 'l216', 'l225', 'l232', 'l242', 'l246', 'l248', 'l249', 'l250', 'l251', 'l252']", + "115, cells ['l43', 'l61', 'l94', 'l112', 'l131', 'l149', 'l166', 'l181', 'l195', 'l206', 'l217', 'l226', 'l233', 'l243', 'l247', 'l248', 'l253', 'l254', 'l255', 'l256']", + "117, tumor ['l95', 'l113', 'l132', 'l150', 'l167', 'l182', 'l207', 'l244', 'l249', 'l253', 'l257', 'l258', 'l259']", + "118, cells ['l96', 'l114', 'l133', 'l151', 'l168', 'l183', 'l196', 'l208', 'l218', 'l245', 'l250', 'l254', 'l257', 'l260', 'l261']", + "119, modified ['l115', 'l134', 'l152', 'l251', 'l255', 'l258', 'l260', 'l262']", + "120, to ['l116', 'l135', 'l153', 'l169', 'l184', 'l252', 'l256', 'l259', 'l261', 'l262']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "T", + "cells", + "cell" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "genetically", + "modified", + "to", + "express", + "tumor-specific", + "chimeric" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetically", + "modified", + "to", + "express", + "tumor-specific", + "chimeric" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetically", + "modified", + "to", + "express", + "tumor-specific", + "chimeric" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetically", + "modified", + "to", + "express", + "tumor-specific", + "chimeric" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + } + ] + }, + { + "PMID": "19182797", + "TEXT": "We identified nicotinamide phosphoribosyltransferase (NAMPT), also known as pre-B cell colony enhancing factor (PBEF), as an essential enzyme mediating granulocyte colony-stimulating factor (G-CSF)-triggered granulopoiesis in healthy individuals and in individuals with severe congenital neutropenia. Intracellular NAMPT and NAD(+) amounts in myeloid cells, as well as plasma NAMPT and NAD(+) levels, were increased by G-CSF treatment of both healthy volunteers and individuals with congenital neutropenia. NAMPT administered both extracellularly and intracellularly induced granulocytic differentiation of CD34(+) hematopoietic progenitor cells and of the promyelocytic leukemia cell line HL-60. Treatment of healthy individuals with high doses of vitamin B3 (nicotinamide), a substrate of NAMPT, induced neutrophilic granulocyte differentiation. The molecular events triggered by NAMPT include NAD(+)-dependent sirtuin-1 activation, subsequent induction of CCAAT/enhancer binding protein-alpha and CCAAT/enhancer binding protein-beta, and, ultimately, upregulation of G-CSF synthesis and G-CSF receptor expression. G-CSF, in turn, further increases NAMPT levels. These results reveal a decisive role of the NAD(+) metabolic pathway in G-CSF-triggered myelopoiesis.", + "TAG_DATA": [ + "70, induced {'effect': 'B-positive'}", + "72, differentiation {'phenotype': 'I-differentiation'}", + "74, CD34(+) {'context': 'B-cells'}", + "75, hematopoietic {'context': 'I-cells'}", + "76, progenitor {'context': 'I-cells'}", + "77, cells {'context': 'I-cells'}", + "81, promyelocytic {'context': 'B-transformed cells'}", + "82, leukemia {'context': 'I-transformed cells'}", + "83, cell {'context': 'I-transformed cells'}", + "84, line {'context': 'I-transformed cells'}", + "85, HL-60. {'context': 'I-transformed cells'}", + "101, induced {'effect': 'B-positive'}", + "102, neutrophilic {'context': 'B-cells'}", + "103, granulocyte {'context': 'I-cells'}", + "104, differentiation. {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "70, induced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "72, differentiation ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "74, CD34(+) ['l1', 'l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "75, hematopoietic ['l2', 'l11', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "76, progenitor ['l3', 'l12', 'l18', 'l25', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "77, cells ['l4', 'l13', 'l19', 'l26', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "81, promyelocytic ['l5', 'l20', 'l27', 'l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "82, leukemia ['l6', 'l21', 'l28', 'l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "83, cell ['l7', 'l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "84, line ['l8', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "85, HL-60. ['l9', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l52']", + "101, induced ['l53', 'l54', 'l55']", + "102, neutrophilic ['l53', 'l56', 'l57']", + "103, granulocyte ['l54', 'l56', 'l58']", + "104, differentiation. ['l55', 'l57', 'l58']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "differentiation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD34(+)", + "hematopoietic", + "progenitor", + "cells", + "neutrophilic", + "granulocyte" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "promyelocytic", + "leukemia", + "cell", + "line", + "HL-60." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "differentiation." + ] + }, + "context": { + "val": "cells", + "words": [ + "CD34(+)", + "hematopoietic", + "progenitor", + "cells", + "neutrophilic", + "granulocyte" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cell", + "line", + "HL-60." + ] + } + } + ] + }, + { + "PMID": "19098909", + "TEXT": "Disorders of neuronal migration can lead to malformations of the cerebral neocortex that greatly increase the risk of seizures. It remains untested whether malformations caused by disorders in neuronal migration can be reduced by reactivating cellular migration and whether such repair can decrease seizure risk. Here we show, in a rat model of subcortical band heterotopia (SBH) generated by in utero RNA interference of the Dcx gene, that aberrantly positioned neurons can be stimulated to migrate by reexpressing Dcx after birth. Restarting migration in this way both reduces neocortical malformations and restores neuronal patterning. We further find that the capacity to reduce SBH continues into early postnatal development. Moreover, intervention after birth reduces the convulsant-induced seizure threshold to a level similar to that in malformation-free controls. These results suggest that disorders of neuronal migration may be eventually treatable by reengaging developmental programs both to reduce the size of cortical malformations and to reduce seizure risk.", + "TAG_DATA": [ + "50, rat {'context': 'B-organism'}", + "51, model {'context': 'I-organism'}", + "61, RNA {'perturbing_action': 'B-rnai/knockdown'}", + "62, interference {'perturbing_action': 'I-rnai/knockdown'}", + "63, of {'perturbing_action': 'I-rnai/knockdown'}", + "64, the {'perturbing_action': 'I-rnai/knockdown'}", + "65, Dcx {'perturbing_action': 'I-rnai/knockdown'}", + "66, gene, {'perturbing_action': 'I-rnai/knockdown'}", + "70, neurons {'context': 'B-cells'}", + "73, stimulated {'effect': 'B-positive'}", + "75, migrate {'phenotype': 'B-migration'}", + "77, reexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "78, Dcx {'perturbing_action': 'I-gene gain-of-function'}", + "82, migration {'phenotype': 'B-migration'}" + ], + "LINK_DATA": [ + "50, rat ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "51, model ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "52, of ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "53, subcortical ['l2', 'l16', 'l29', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "54, band ['l3', 'l17', 'l30', 'l42', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "55, heterotopia ['l4', 'l18', 'l31', 'l43', 'l55', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "59, in ['l5', 'l19', 'l32', 'l44', 'l56', 'l66', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "61, RNA ['l6', 'l20', 'l33', 'l45', 'l57', 'l67', 'l77', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "62, interference ['l7', 'l21', 'l34', 'l46', 'l58', 'l68', 'l78', 'l87', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "63, of ['l8', 'l22', 'l35', 'l47', 'l59', 'l69', 'l79', 'l88', 'l97', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "64, the ['l9', 'l23', 'l36', 'l48', 'l60', 'l70', 'l80', 'l89', 'l98', 'l106', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "65, Dcx ['l10', 'l24', 'l37', 'l49', 'l61', 'l71', 'l81', 'l90', 'l99', 'l107', 'l114', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "66, gene, ['l11', 'l25', 'l38', 'l50', 'l62', 'l72', 'l82', 'l91', 'l100', 'l108', 'l115', 'l121', 'l127', 'l128', 'l129', 'l130', 'l131']", + "70, neurons ['l12', 'l26', 'l39', 'l51', 'l63', 'l73', 'l83', 'l92', 'l101', 'l109', 'l116', 'l122', 'l127', 'l132', 'l133', 'l134', 'l135', 'l136']", + "73, stimulated ['l13', 'l27', 'l40', 'l52', 'l64', 'l74', 'l84', 'l93', 'l102', 'l110', 'l117', 'l123', 'l128', 'l132', 'l137', 'l138', 'l139', 'l140']", + "75, migrate ['l14', 'l28', 'l41', 'l53', 'l65', 'l75', 'l85', 'l94', 'l103', 'l111', 'l118', 'l124', 'l129', 'l133', 'l137', 'l141', 'l142', 'l143']", + "77, reexpressing ['l134', 'l138', 'l141', 'l144', 'l145']", + "78, Dcx ['l95', 'l104', 'l112', 'l119', 'l125', 'l130', 'l135', 'l139', 'l142', 'l144', 'l146']", + "82, migration ['l54', 'l76', 'l86', 'l96', 'l105', 'l113', 'l120', 'l126', 'l131', 'l136', 'l140', 'l143', 'l145', 'l146']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "rat", + "model" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "RNA", + "interference", + "of", + "the", + "Dcx", + "gene," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rat", + "model" + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rat", + "model" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migrate" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "RNA", + "interference", + "of", + "the", + "Dcx", + "gene," + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "RNA", + "interference", + "of", + "the", + "Dcx", + "gene," + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "RNA", + "interference", + "of", + "the", + "Dcx", + "gene," + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migrate", + "migration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neurons" + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neurons" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migrate", + "migration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neurons" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "reexpressing", + "Dcx" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migrate", + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "reexpressing", + "Dcx" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migrate", + "migration" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "reexpressing", + "Dcx" + ] + } + } + ] + }, + { + "PMID": "19098908", + "TEXT": "We identified a previously undescribed gene associated with colon cancer by genome-wide expression analysis in primary and metastatic carcinomas: metastasis-associated in colon cancer-1, MACC1. MACC1 expression in tumor specimens is an independent prognostic indicator of metastasis formation and metastasis-free survival. We show that the gene encoding the hepatocyte growth factor (HGF) receptor, MET, is a transcriptional target of MACC1. MACC1 promotes proliferation, invasion and HGF-induced scattering of colon cancer cells in cell culture and tumor growth and metastasis in mouse models. These phenotypes are lost in cells expressing MACC1 mutants lacking the SH3 domain or the proline-rich motif. For clinical practice, MACC1 will be useful for the identification of poor prognosis subjects with colorectal cancer and is a promising new target for intervention in metastasis formation.", + "TAG_DATA": [ + "60, promotes {'effect': 'B-positive'}", + "61, proliferation, {'phenotype': 'B-proliferation'}", + "62, invasion {'phenotype': 'B-invasion'}", + "67, colon {'context': 'B-transformed cells'}", + "68, cancer {'context': 'I-transformed cells'}", + "69, cells {'context': 'I-transformed cells'}", + "71, cell {'context': 'B-cells'}", + "72, culture {'context': 'I-in vitro'}", + "74, tumor {'phenotype': 'B-tumour growth'}", + "75, growth {'phenotype': 'I-tumour growth'}", + "77, metastasis {'phenotype': 'B-metastasis'}", + "79, mouse {'context': 'B-organism'}", + "80, models. {'context': 'I-organism'}", + "86, cells {'context': 'B-cells'}", + "88, MACC1 {'perturbing_action': 'B-other'}", + "89, mutants {'perturbing_action': 'I-other'}", + "90, lacking {'perturbing_action': 'I-other'}", + "93, domain {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "60, promotes ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "61, proliferation, ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "62, invasion ['l1', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "67, colon ['l2', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22', 'l23']", + "68, cancer ['l3', 'l10', 'l15', 'l19', 'l24', 'l25', 'l26']", + "69, cells ['l4', 'l11', 'l16', 'l20', 'l24', 'l27', 'l28']", + "71, cell ['l5', 'l12', 'l17', 'l21', 'l25', 'l27', 'l29', 'l30']", + "72, culture ['l6', 'l13', 'l18', 'l22', 'l26', 'l28', 'l29']", + "74, tumor ['l31', 'l32', 'l33', 'l34']", + "75, growth ['l7', 'l23', 'l30', 'l31', 'l35', 'l36', 'l37']", + "77, metastasis ['l32', 'l35', 'l38', 'l39']", + "79, mouse ['l33', 'l36', 'l38', 'l40']", + "80, models. ['l34', 'l37', 'l39', 'l40']", + "86, cells ['l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "88, MACC1 ['l41', 'l47', 'l48', 'l49', 'l50', 'l51']", + "89, mutants ['l42', 'l47', 'l52', 'l53', 'l54', 'l55']", + "90, lacking ['l43', 'l48', 'l52', 'l56', 'l57', 'l58']", + "91, the ['l44', 'l49', 'l53', 'l56', 'l59', 'l60']", + "92, SH3 ['l45', 'l50', 'l54', 'l57', 'l59', 'l61']", + "93, domain ['l46', 'l51', 'l55', 'l58', 'l60', 'l61']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "colon", + "cancer", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "colon", + "cancer", + "cells" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "colon", + "cancer", + "cells" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "colon" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "MACC1", + "mutants", + "lacking", + "domain" + ] + } + } + ] + }, + { + "PMID": "19029985", + "TEXT": "The mechanisms involved in the pathogenesis of epilepsy, a chronic neurological disorder that affects approximately one percent of the world population, are not well understood. Using a mouse model of epilepsy, we show that seizures induce elevated expression of vascular cell adhesion molecules and enhanced leukocyte rolling and arrest in brain vessels mediated by the leukocyte mucin P-selectin glycoprotein ligand-1 (PSGL-1, encoded by Selplg) and leukocyte integrins alpha(4)beta(1) and alpha(L)beta(2). Inhibition of leukocyte-vascular interactions, either with blocking antibodies or by genetically interfering with PSGL-1 function in mice, markedly reduced seizures. Treatment with blocking antibodies after acute seizures prevented the development of epilepsy. Neutrophil depletion also inhibited acute seizure induction and chronic spontaneous recurrent seizures. Blood-brain barrier (BBB) leakage, which is known to enhance neuronal excitability, was induced by acute seizure activity but was prevented by blockade of leukocyte-vascular adhesion, suggesting a pathogenetic link between leukocyte-vascular interactions, BBB damage and seizure generation. Consistent with the potential leukocyte involvement in epilepsy in humans, leukocytes were more abundant in brains of individuals with epilepsy than in controls. Our results suggest leukocyte-endothelial interaction as a potential target for the prevention and treatment of epilepsy.", + "TAG_DATA": [ + "51, vessels {'context': 'I-tissue/organ'}", + "80, genetically {'perturbing_action': 'B-other'}", + "81, interfering {'perturbing_action': 'B-other'}", + "82, with {'perturbing_action': 'I-other'}", + "83, PSGL-1 {'perturbing_action': 'I-other'}", + "84, function {'perturbing_action': 'I-other'}", + "86, mice, {'context': 'B-organism'}", + "105, inhibited {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "50, brain ['l0']", + "51, vessels ['l0']", + "80, genetically ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "81, interfering ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "82, with ['l2', 'l7', 'l12', 'l13', 'l14']", + "83, PSGL-1 ['l3', 'l8', 'l12', 'l15', 'l16']", + "84, function ['l4', 'l9', 'l13', 'l15', 'l17']", + "86, mice, ['l5', 'l10', 'l14', 'l16', 'l17']", + "105, inhibited ['l6', 'l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "genetically", + "interfering", + "with", + "PSGL-1", + "function" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetically", + "interfering" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + } + ] + }, + { + "PMID": "19029984", + "TEXT": "Blockade of mineralocorticoid receptor has been shown to improve the clinical outcomes of proteinuric kidney diseases. However, little is known about the regulation of mineralocorticoid receptor-dependent transcriptional activity in renal disease. Here we identify a new role for Rac1, a member of the Rho family GTPases, as a potent activator of mineralocorticoid receptor signal transduction both in vitro and in vivo. Transient transfection assays in HEK 293 cells revealed that constitutively active Rac1 (CA-Rac1) enhanced mineralocorticoid receptor-dependent reporter activity, which was accompanied by increased nuclear translocation of mineralocorticoid receptor. CA-Rac1 facilitated mineralocorticoid receptor nuclear accumulation also in podocytes via p21-activated kinase phosphorylation. In mice lacking Rho GDP-dissociation inhibitor-alpha (Arhgdia(-/-) mice), renal abnormalities, including heavy albuminuria and podocyte damage, were associated with increased Rac1 (but not RhoA) and mineralocorticoid receptor signaling in the kidney, without alteration in systemic aldosterone status. Pharmacological intervention with a Rac-specific small-molecule inhibitor diminished mineralocorticoid receptor overactivity and renal damage in this model. Furthermore, albuminuria and histological changes in Arhgdia(-/-) mice were suppressed by mineralocorticoid receptor blockade, confirming the pathological role of Rac1-mineralocorticoid receptor interaction. Our results provide evidence that signaling cross-talk between Rac1 and mineralocorticoid receptor modulates mineralocorticoid receptor activity and identify Rac1 as a therapeutic target for chronic kidney disease.", + "TAG_DATA": [ + "65, HEK {'context': 'B-cells'}", + "66, 293 {'context': 'I-cells'}", + "67, cells {'context': 'I-cells'}", + "70, constitutively {'perturbing_action': 'B-gene gain-of-function'}", + "71, active {'perturbing_action': 'I-gene gain-of-function'}", + "72, Rac1 {'perturbing_action': 'I-gene gain-of-function'}", + "73, (CA-Rac1) {'perturbing_action': 'I-gene gain-of-function'}", + "97, podocytes {'context': 'B-cells'}", + "103, mice {'context': 'B-organism'}", + "104, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "105, Rho {'perturbing_action': 'I-gene loss-of-function'}", + "106, GDP-dissociation {'perturbing_action': 'I-gene loss-of-function'}", + "107, inhibitor-alpha {'perturbing_action': 'I-gene loss-of-function'}", + "109, mice), {'perturbing_action': 'I-gene loss-of-function'}", + "143, Rac-specific {'perturbing_action': 'B-pharmacological inhibition'}", + "144, small-molecule {'perturbing_action': 'I-pharmacological inhibition'}", + "145, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "162, Arhgdia(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "163, mice {'context': 'B-organism'}", + "167, mineralocorticoid {'perturbing_action': 'B-pharmacological inhibition'}", + "168, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "169, blockade, {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "65, HEK ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "66, 293 ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "67, cells ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "70, constitutively ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "71, active ['l3', 'l9', 'l14', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "72, Rac1 ['l4', 'l10', 'l15', 'l19', 'l24', 'l29', 'l30', 'l31']", + "73, (CA-Rac1) ['l5', 'l11', 'l16', 'l20', 'l25', 'l29', 'l32', 'l33']", + "97, podocytes ['l6', 'l12', 'l17', 'l21', 'l26', 'l30', 'l32', 'l34']", + "103, mice ['l22', 'l27', 'l35', 'l36', 'l37', 'l38', 'l39']", + "104, lacking ['l35', 'l40', 'l41', 'l42', 'l43']", + "105, Rho ['l36', 'l40', 'l44', 'l45', 'l46']", + "106, GDP-dissociation ['l37', 'l41', 'l44', 'l47', 'l48']", + "107, inhibitor-alpha ['l38', 'l42', 'l45', 'l47', 'l49']", + "109, mice), ['l23', 'l28', 'l31', 'l33', 'l34', 'l39', 'l43', 'l46', 'l48', 'l49']", + "143, Rac-specific ['l50', 'l51', 'l52', 'l53']", + "144, small-molecule ['l50', 'l54', 'l55', 'l56']", + "145, inhibitor ['l51', 'l54', 'l57', 'l58']", + "162, Arhgdia(-/-) ['l52', 'l55', 'l57', 'l59', 'l60', 'l61', 'l62']", + "163, mice ['l53', 'l56', 'l58', 'l59']", + "167, mineralocorticoid ['l60', 'l63', 'l64']", + "168, receptor ['l61', 'l63', 'l65']", + "169, blockade, ['l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "HEK", + "293", + "cells", + "podocytes" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutively", + "active", + "Rac1", + "(CA-Rac1)" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutively", + "active" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "podocytes" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "mice)," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "Rho", + "GDP-dissociation", + "inhibitor-alpha", + "mice),", + "Arhgdia(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Rac-specific", + "small-molecule", + "inhibitor" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "19029980", + "TEXT": "Retinoic acid and arsenic trioxide target the protein stability and transcriptional repression activity of the fusion oncoprotein PML-RARA, resulting in regression of acute promyelocytic leukemia (APL). Phenotypically, retinoic acid induces differentiation of APL cells. Here we show that retinoic acid also triggers growth arrest of leukemia-initiating cells (LICs) ex vivo and their clearance in PML-RARA mouse APL in vivo. Retinoic acid treatment of mouse APLs expressing the fusion protein PLZF-RARA triggers full differentiation, but not LIC loss or disease remission, establishing that differentiation and LIC loss can be uncoupled. Although retinoic acid and arsenic synergize to clear LICs through cooperative PML-RARA degradation, this combination does not enhance differentiation. A cyclic AMP (cAMP)-dependent phosphorylation site in PML-RARA is crucial for retinoic acid-induced PML-RARA degradation and LIC clearance. Moreover, activation of cAMP signaling enhances LIC loss by retinoic acid, identifying cAMP as another potential APL therapy. Thus, whereas transcriptional activation of PML-RARA is likely to control differentiation, its catabolism triggers LIC eradication and long-term remission of mouse APL. Therapy-triggered degradation of oncoproteins could be a general strategy to eradicate cancer stem cells.", + "TAG_DATA": [ + "41, triggers {'effect': 'B-positive'}", + "42, growth {'phenotype': 'B-cell cycle arrest'}", + "43, arrest {'phenotype': 'I-cell cycle arrest'}", + "45, leukemia-initiating {'context': 'B-cells'}", + "46, cells {'context': 'I-cells'}", + "47, (LICs) {'context': 'I-cells'}", + "55, mouse {'context': 'B-transformed cells'}", + "56, APL {'context': 'I-transformed cells'}", + "57, in {'context': 'B-in vivo'}", + "58, vivo. {'context': 'I-in vivo'}", + "63, mouse {'context': 'B-transformed cells'}", + "64, APLs {'context': 'I-transformed cells'}", + "65, expressing {'perturbing_action': 'B-other'}", + "66, the {'perturbing_action': 'I-other'}", + "67, fusion {'perturbing_action': 'I-other'}", + "68, protein {'perturbing_action': 'I-other'}", + "69, PLZF-RARA {'perturbing_action': 'I-other'}", + "70, triggers {'effect': 'B-positive'}", + "72, differentiation, {'phenotype': 'B-differentiation'}", + "82, differentiation {'phenotype': 'B-differentiation'}", + "106, enhance {'effect': 'B-positive'}", + "107, differentiation. {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "41, triggers ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "42, growth ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "43, arrest ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "45, leukemia-initiating ['l2', 'l10', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "46, cells ['l3', 'l11', 'l18', 'l23', 'l29', 'l30', 'l31', 'l32', 'l33']", + "47, (LICs) ['l4', 'l12', 'l19', 'l24', 'l29', 'l34', 'l35', 'l36', 'l37']", + "55, mouse ['l5', 'l13', 'l25', 'l30', 'l34', 'l38', 'l39', 'l40']", + "56, APL ['l6', 'l14', 'l20', 'l26', 'l31', 'l35', 'l38', 'l41', 'l42']", + "57, in ['l7', 'l15', 'l21', 'l27', 'l32', 'l36', 'l39', 'l41', 'l43']", + "58, vivo. ['l8', 'l16', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l43']", + "63, mouse ['l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "64, APLs ['l44', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "65, expressing ['l45', 'l53', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "66, the ['l46', 'l54', 'l61', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "67, fusion ['l47', 'l55', 'l62', 'l68', 'l74', 'l75', 'l76', 'l77', 'l78']", + "68, protein ['l48', 'l56', 'l63', 'l69', 'l74', 'l79', 'l80', 'l81', 'l82']", + "69, PLZF-RARA ['l49', 'l57', 'l64', 'l70', 'l75', 'l79', 'l83', 'l84', 'l85']", + "70, triggers ['l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l83', 'l86', 'l87']", + "72, differentiation, ['l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l86', 'l88']", + "82, differentiation ['l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l87', 'l88']", + "106, enhance ['l89']", + "107, differentiation. ['l89']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "growth", + "arrest" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "context": { + "val": "cells", + "words": [ + "leukemia-initiating", + "cells", + "(LICs)" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "mouse", + "APL", + "APLs" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "growth", + "arrest" + ] + }, + "context": { + "val": "cells", + "words": [ + "leukemia-initiating", + "cells", + "(LICs)" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "growth", + "arrest" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "mouse", + "APL" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "growth", + "arrest" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "mouse", + "APLs" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "the", + "fusion", + "protein", + "PLZF-RARA" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "mouse", + "APLs" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation,", + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "the", + "fusion", + "protein", + "PLZF-RARA" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "the", + "fusion", + "protein", + "PLZF-RARA" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation,", + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggers", + "enhance" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation,", + "differentiation", + "differentiation." + ] + } + } + ] + }, + { + "PMID": "18931683", + "TEXT": "MicroRNAs (miRNAs) are noncoding small RNAs that repress protein translation by targeting specific messenger RNAs. miR-15a and miR-16-1 act as putative tumor suppressors by targeting the oncogene BCL2. These miRNAs form a cluster at the chromosomal region 13q14, which is frequently deleted in cancer. Here, we report that the miR-15a and miR-16-1 cluster targets CCND1 (encoding cyclin D1) and WNT3A, which promotes several tumorigenic features such as survival, proliferation and invasion. In cancer cells of advanced prostate tumors, the miR-15a and miR-16 level is significantly decreased, whereas the expression of BCL2, CCND1 and WNT3A is inversely upregulated. Delivery of antagomirs specific for miR-15a and miR-16 to normal mouse prostate results in marked hyperplasia, and knockdown of miR-15a and miR-16 promotes survival, proliferation and invasiveness of untransformed prostate cells, which become tumorigenic in immunodeficient NOD-SCID mice. Conversely, reconstitution of miR-15a and miR-16-1 expression results in growth arrest, apoptosis and marked regression of prostate tumor xenografts. Altogether, we propose that miR-15a and miR-16 act as tumor suppressor genes in prostate cancer through the control of cell survival, proliferation and invasion. These findings have therapeutic implications and may be exploited for future treatment of prostate cancer.", + "TAG_DATA": [ + "99, antagomirs {'perturbing_action': 'B-rnai/knockdown'}", + "100, specific {'perturbing_action': 'I-rnai/knockdown'}", + "101, for {'perturbing_action': 'I-rnai/knockdown'}", + "102, miR-15a {'perturbing_action': 'I-rnai/knockdown'}", + "103, and {'perturbing_action': 'I-rnai/knockdown'}", + "104, miR-16 {'perturbing_action': 'I-rnai/knockdown'}", + "106, normal {'context': 'B-tissue/organ'}", + "107, mouse {'context': 'I-tissue/organ'}", + "108, prostate {'context': 'I-tissue/organ'}", + "114, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "115, of {'perturbing_action': 'I-rnai/knockdown'}", + "116, miR-15a {'perturbing_action': 'I-rnai/knockdown'}", + "117, and {'perturbing_action': 'I-rnai/knockdown'}", + "118, miR-16 {'perturbing_action': 'I-rnai/knockdown'}", + "119, promotes {'effect': 'B-positive'}", + "121, proliferation {'phenotype': 'B-proliferation'}", + "123, invasiveness {'phenotype': 'B-invasion'}", + "125, untransformed {'context': 'B-cells'}", + "126, prostate {'context': 'I-transformed cells'}", + "127, cells, {'context': 'I-transformed cells'}", + "132, immunodeficient {'context': 'B-organism'}", + "133, NOD-SCID {'context': 'I-organism'}", + "134, mice. {'context': 'I-organism'}", + "136, reconstitution {'perturbing_action': 'B-gene gain-of-function'}", + "137, of {'perturbing_action': 'I-gene gain-of-function'}", + "138, miR-15a {'perturbing_action': 'I-gene gain-of-function'}", + "139, and {'perturbing_action': 'I-gene gain-of-function'}", + "140, miR-16-1 {'perturbing_action': 'I-gene gain-of-function'}", + "141, expression {'perturbing_action': 'I-gene gain-of-function'}", + "145, arrest, {'effect': 'B-negative'}", + "146, apoptosis {'phenotype': 'B-apoptosis'}", + "151, prostate {'context': 'B-xenograft'}", + "152, tumor {'context': 'I-xenograft'}", + "153, xenografts. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "99, antagomirs ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "100, specific ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "101, for ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "102, miR-15a ['l2', 'l21', 'l39', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "103, and ['l3', 'l22', 'l40', 'l57', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "104, miR-16 ['l4', 'l23', 'l41', 'l58', 'l73', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "106, normal ['l5', 'l24', 'l42', 'l59', 'l74', 'l87', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "107, mouse ['l6', 'l25', 'l43', 'l60', 'l75', 'l88', 'l99', 'l105', 'l106', 'l107', 'l108', 'l109']", + "108, prostate ['l7', 'l26', 'l44', 'l61', 'l76', 'l89', 'l100', 'l105', 'l110', 'l111', 'l112', 'l113']", + "114, knockdown ['l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "115, of ['l114', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "116, miR-15a ['l8', 'l27', 'l45', 'l115', 'l129', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "117, and ['l9', 'l28', 'l46', 'l62', 'l116', 'l130', 'l143', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "118, miR-16 ['l10', 'l29', 'l47', 'l63', 'l77', 'l117', 'l131', 'l144', 'l155', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175']", + "119, promotes ['l11', 'l30', 'l48', 'l64', 'l78', 'l90', 'l101', 'l106', 'l110', 'l118', 'l132', 'l145', 'l156', 'l166', 'l176', 'l177', 'l178', 'l179', 'l180']", + "121, proliferation ['l12', 'l31', 'l49', 'l65', 'l79', 'l91', 'l102', 'l107', 'l111', 'l119', 'l133', 'l146', 'l157', 'l167', 'l176', 'l181', 'l182', 'l183', 'l184']", + "123, invasiveness ['l13', 'l32', 'l50', 'l66', 'l80', 'l92', 'l103', 'l108', 'l112', 'l120', 'l134', 'l147', 'l158', 'l168', 'l177', 'l181', 'l185', 'l186', 'l187', 'l188', 'l189']", + "125, untransformed ['l14', 'l33', 'l51', 'l67', 'l81', 'l93', 'l121', 'l135', 'l148', 'l159', 'l169', 'l178', 'l182', 'l185', 'l190', 'l191', 'l192', 'l193', 'l194']", + "126, prostate ['l15', 'l34', 'l52', 'l68', 'l82', 'l94', 'l122', 'l136', 'l149', 'l160', 'l170', 'l179', 'l183', 'l186', 'l190', 'l195', 'l196', 'l197', 'l198']", + "127, cells, ['l16', 'l35', 'l53', 'l69', 'l83', 'l95', 'l104', 'l109', 'l113', 'l123', 'l137', 'l150', 'l161', 'l171', 'l180', 'l184', 'l187', 'l191', 'l195', 'l199', 'l200']", + "132, immunodeficient ['l17', 'l36', 'l54', 'l70', 'l84', 'l96', 'l124', 'l138', 'l151', 'l162', 'l172', 'l188', 'l192', 'l196', 'l199', 'l201', 'l202']", + "133, NOD-SCID ['l18', 'l37', 'l55', 'l71', 'l85', 'l97', 'l125', 'l139', 'l152', 'l163', 'l173', 'l193', 'l197', 'l201', 'l203']", + "134, mice. ['l19', 'l38', 'l56', 'l72', 'l86', 'l98', 'l126', 'l140', 'l153', 'l164', 'l174', 'l189', 'l194', 'l198', 'l200', 'l202', 'l203']", + "136, reconstitution ['l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213']", + "137, of ['l204', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222']", + "138, miR-15a ['l205', 'l214', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230']", + "139, and ['l206', 'l215', 'l223', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237']", + "140, miR-16-1 ['l207', 'l216', 'l224', 'l231', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243']", + "141, expression ['l208', 'l217', 'l225', 'l232', 'l238', 'l244', 'l245', 'l246', 'l247', 'l248']", + "145, arrest, ['l127', 'l141', 'l154', 'l165', 'l175', 'l209', 'l218', 'l226', 'l233', 'l239', 'l244', 'l249']", + "146, apoptosis ['l128', 'l142', 'l210', 'l219', 'l227', 'l234', 'l240', 'l245', 'l249']", + "151, prostate ['l211', 'l220', 'l228', 'l235', 'l241', 'l246', 'l250', 'l251']", + "152, tumor ['l212', 'l221', 'l229', 'l236', 'l242', 'l247', 'l250', 'l252']", + "153, xenografts. ['l213', 'l222', 'l230', 'l237', 'l243', 'l248', 'l251', 'l252']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antagomirs", + "specific", + "for", + "miR-15a", + "and", + "miR-16" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "normal", + "mouse", + "prostate" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antagomirs", + "specific", + "for", + "miR-15a", + "and", + "miR-16", + "knockdown", + "of" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antagomirs", + "specific", + "for", + "miR-15a", + "and", + "miR-16", + "knockdown", + "of" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antagomirs", + "specific", + "for", + "miR-15a", + "and", + "miR-16", + "knockdown", + "of" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antagomirs", + "specific", + "for", + "miR-15a", + "and", + "miR-16", + "knockdown", + "of" + ] + }, + "context": { + "val": "cells", + "words": [ + "untransformed" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antagomirs", + "specific", + "for", + "miR-15a", + "and", + "miR-16", + "knockdown", + "of" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antagomirs", + "specific", + "for", + "miR-15a", + "and", + "miR-16", + "knockdown", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "immunodeficient", + "NOD-SCID", + "mice." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "normal", + "mouse", + "prostate" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "normal", + "mouse", + "prostate" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "normal", + "mouse", + "prostate" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "miR-15a", + "and", + "miR-16" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "cells", + "words": [ + "untransformed" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cells," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "untransformed" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cells," + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness" + ] + }, + "context": { + "val": "cells", + "words": [ + "untransformed" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cells," + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasiveness" + ] + }, + "context": { + "val": "organism", + "words": [ + "immunodeficient", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "reconstitution", + "of", + "miR-15a", + "and", + "miR-16-1", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "reconstitution", + "of", + "miR-15a", + "and", + "miR-16-1", + "expression" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "reconstitution", + "of", + "miR-15a", + "and", + "miR-16-1", + "expression" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "prostate", + "tumor", + "xenografts." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "arrest," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "18806802", + "TEXT": "Cyclophilin D (CypD, encoded by Ppif) is an integral part of the mitochondrial permeability transition pore, whose opening leads to cell death. Here we show that interaction of CypD with mitochondrial amyloid-beta protein (Abeta) potentiates mitochondrial, neuronal and synaptic stress. The CypD-deficient cortical mitochondria are resistant to Abeta- and Ca(2+)-induced mitochondrial swelling and permeability transition. Additionally, they have an increased calcium buffering capacity and generate fewer mitochondrial reactive oxygen species. Furthermore, the absence of CypD protects neurons from Abeta- and oxidative stress-induced cell death. Notably, CypD deficiency substantially improves learning and memory and synaptic function in an Alzheimer's disease mouse model and alleviates Abeta-mediated reduction of long-term potentiation. Thus, the CypD-mediated mitochondrial permeability transition pore is directly linked to the cellular and synaptic perturbations observed in the pathogenesis of Alzheimer's disease. Blockade of CypD may be a therapeutic strategy in Alzheimer's disease.", + "TAG_DATA": [ + "41, CypD-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "42, cortical {'context': 'B-cells'}", + "43, mitochondria {'context': 'I-cells'}", + "72, absence {'perturbing_action': 'B-gene loss-of-function'}", + "73, of {'perturbing_action': 'I-gene loss-of-function'}", + "74, CypD {'perturbing_action': 'I-gene loss-of-function'}", + "75, protects {'effect': 'B-negative'}", + "76, neurons {'context': 'B-cells'}", + "82, cell {'phenotype': 'B-cell death'}", + "83, death. {'phenotype': 'I-cell death'}", + "85, CypD {'perturbing_action': 'B-gene loss-of-function'}", + "86, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "97, Alzheimer's {'context': 'B-organism'}", + "98, disease {'context': 'I-organism'}", + "99, mouse {'context': 'I-organism'}", + "100, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "41, CypD-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "42, cortical ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "43, mitochondria ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "72, absence ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "73, of ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "74, CypD ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "75, protects ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "76, neurons ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "82, cell ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "83, death. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "85, CypD ['l45', 'l46', 'l47', 'l48', 'l49']", + "86, deficiency ['l45', 'l50', 'l51', 'l52', 'l53']", + "97, Alzheimer's ['l46', 'l50', 'l54', 'l55', 'l56']", + "98, disease ['l47', 'l51', 'l54', 'l57', 'l58']", + "99, mouse ['l48', 'l52', 'l55', 'l57', 'l59']", + "100, model ['l49', 'l53', 'l56', 'l58', 'l59']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CypD-deficient", + "absence", + "of", + "CypD" + ] + }, + "context": { + "val": "cells", + "words": [ + "cortical", + "mitochondria", + "neurons" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CypD-deficient", + "absence", + "of", + "CypD" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protects" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CypD-deficient", + "absence", + "of", + "CypD" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cortical", + "mitochondria", + "neurons" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protects" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cortical", + "mitochondria", + "neurons" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "protects" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CypD", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "Alzheimer's", + "disease", + "mouse", + "model" + ] + } + } + ] + }, + { + "PMID": "18806801", + "TEXT": "Increased lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity is associated with increased risk of cardiac events, but it is not known whether Lp-PLA(2) is a causative agent. Here we show that selective inhibition of Lp-PLA(2) with darapladib reduced development of advanced coronary atherosclerosis in diabetic and hypercholesterolemic swine. Darapladib markedly inhibited plasma and lesion Lp-PLA(2) activity and reduced lesion lysophosphatidylcholine content. Analysis of coronary gene expression showed that darapladib exerted a general anti-inflammatory action, substantially reducing the expression of 24 genes associated with macrophage and T lymphocyte functioning. Darapladib treatment resulted in a considerable decrease in plaque area and, notably, a markedly reduced necrotic core area and reduced medial destruction, resulting in fewer lesions with an unstable phenotype. These data show that selective inhibition of Lp-PLA(2) inhibits progression to advanced coronary atherosclerotic lesions and confirms a crucial role of vascular inflammation independent from hypercholesterolemia in the development of lesions implicated in the pathogenesis of myocardial infarction and stroke.", + "TAG_DATA": [ + "29, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "30, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "31, of {'perturbing_action': 'I-pharmacological inhibition'}", + "32, Lp-PLA(2) {'perturbing_action': 'I-pharmacological inhibition'}", + "33, with {'perturbing_action': 'I-pharmacological inhibition'}", + "34, darapladib {'perturbing_action': 'I-pharmacological inhibition'}", + "42, diabetic {'context': 'B-organism'}", + "43, and {'context': 'I-organism'}", + "45, swine. {'context': 'I-organism'}", + "120, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "121, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "122, of {'perturbing_action': 'I-pharmacological inhibition'}", + "123, Lp-PLA(2) {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "29, selective ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "30, inhibition ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "31, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "32, Lp-PLA(2) ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "33, with ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "34, darapladib ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "42, diabetic ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "43, and ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "45, swine. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "120, selective ['l36', 'l37', 'l38']", + "121, inhibition ['l36', 'l39', 'l40']", + "122, of ['l37', 'l39', 'l41']", + "123, Lp-PLA(2) ['l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "inhibition", + "of", + "Lp-PLA(2)", + "with", + "darapladib" + ] + }, + "context": { + "val": "organism", + "words": [ + "diabetic", + "and", + "swine." + ] + } + } + ] + }, + { + "PMID": "18724377", + "TEXT": "Osteoclasts differentiate from precursor cells of the monocyte-macrophage lineage and subsequently become activated to be competent for bone resorption through programs primarily governed by receptor activator of nuclear factor-kappaB ligand in cooperation with macrophage colony-stimulating factor. Proteins prominently expressed at late phases of osteoclastogenesis and with a supportive role in osteoclast function are potential therapeutic targets for bone-remodeling disorders. In this study, we used a proteomics approach to show that abundance of the brain-type cytoplasmic creatine kinase (Ckb) is greatly increased during osteoclastogenesis. Decreasing Ckb abundance by RNA interference or blocking its enzymatic activity with a pharmacological inhibitor, cyclocreatine, suppressed the bone-resorbing activity of osteoclasts grown in vitro via combined effects on actin ring formation, RhoA GTPase activity and vacuolar ATPase function. Activities of osteoclasts derived from Ckb-/- mice were similarly affected. In vivo studies showed that Ckb-/- mice were better protected against bone loss induced by ovariectomy, lipopolysaccharide challenge or interleukin-1 treatment than wild-type controls. Furthermore, administration of cyclocreatine or adenoviruses harboring Ckb small hairpin RNA attenuated bone loss in rat and mouse models. Our findings establish an important role for Ckb in the bone-resorbing function of osteoclasts and underscore its potential as a new molecular target for antiresorptive drug development.", + "TAG_DATA": [ + "83, Decreasing {'perturbing_action': 'B-rnai/knockdown'}", + "84, Ckb {'perturbing_action': 'I-rnai/knockdown'}", + "85, abundance {'perturbing_action': 'I-rnai/knockdown'}", + "86, by {'perturbing_action': 'I-rnai/knockdown'}", + "87, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "88, interference {'perturbing_action': 'I-rnai/knockdown'}", + "104, osteoclasts {'context': 'B-cells'}", + "106, in {'context': 'B-in vitro'}", + "107, vitro {'context': 'I-in vitro'}", + "124, osteoclasts {'context': 'B-cells'}", + "127, Ckb-/- {'perturbing_action': 'B-gene loss-of-function'}", + "128, mice {'context': 'B-organism'}", + "132, In {'context': 'B-in vivo'}", + "133, vivo {'context': 'I-in vivo'}", + "137, Ckb-/- {'perturbing_action': 'B-gene loss-of-function'}", + "138, mice {'context': 'B-organism'}", + "161, adenoviruses {'perturbing_action': 'B-rnai/knockdown'}", + "162, harboring {'perturbing_action': 'I-rnai/knockdown'}", + "163, Ckb {'perturbing_action': 'I-rnai/knockdown'}", + "164, small {'perturbing_action': 'I-rnai/knockdown'}", + "165, hairpin {'perturbing_action': 'I-rnai/knockdown'}", + "166, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "171, rat {'context': 'B-organism'}", + "172, and {'context': 'I-organism'}", + "173, mouse {'context': 'I-organism'}", + "174, models. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "83, Decreasing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "84, Ckb ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "85, abundance ['l1', 'l9', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "86, by ['l2', 'l10', 'l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "87, RNA ['l3', 'l11', 'l17', 'l22', 'l27', 'l28', 'l29', 'l30']", + "88, interference ['l4', 'l12', 'l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "104, osteoclasts ['l5', 'l13', 'l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "106, in ['l6', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "107, vitro ['l7', 'l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l36']", + "124, osteoclasts ['l8', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "127, Ckb-/- ['l37', 'l43', 'l44', 'l45', 'l46', 'l47']", + "128, mice ['l38', 'l43', 'l48', 'l49', 'l50']", + "132, In ['l39', 'l44', 'l48', 'l51', 'l52', 'l53']", + "133, vivo ['l40', 'l45', 'l49', 'l51', 'l54', 'l55']", + "137, Ckb-/- ['l41', 'l46', 'l52', 'l54', 'l56']", + "138, mice ['l42', 'l47', 'l50', 'l53', 'l55', 'l56']", + "161, adenoviruses ['l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "162, harboring ['l57', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "163, Ckb ['l58', 'l66', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "164, small ['l59', 'l67', 'l74', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "165, hairpin ['l60', 'l68', 'l75', 'l81', 'l87', 'l88', 'l89', 'l90', 'l91']", + "166, RNA ['l61', 'l69', 'l76', 'l82', 'l87', 'l92', 'l93', 'l94', 'l95']", + "171, rat ['l62', 'l70', 'l77', 'l83', 'l88', 'l92', 'l96', 'l97', 'l98']", + "172, and ['l63', 'l71', 'l78', 'l84', 'l89', 'l93', 'l96', 'l99', 'l100']", + "173, mouse ['l64', 'l72', 'l79', 'l85', 'l90', 'l94', 'l97', 'l99', 'l101']", + "174, models. ['l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l98', 'l100', 'l101']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Decreasing", + "Ckb", + "abundance", + "by", + "RNA", + "interference" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclasts" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Decreasing", + "Ckb", + "abundance", + "by", + "RNA", + "interference" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoclasts" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ckb-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ckb-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ckb-/-" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "adenoviruses", + "harboring", + "Ckb", + "small", + "hairpin", + "RNA" + ] + }, + "context": { + "val": "organism", + "words": [ + "rat", + "and", + "mouse", + "models." + ] + } + } + ] + }, + { + "PMID": "18690244", + "TEXT": "Although eosinophils are considered useful in defense mechanisms against parasites, their exact function in innate immunity remains unclear. The aim of this study is to better understand the role of eosinophils within the gastrointestinal immune system. We show here that lipopolysaccharide from Gram-negative bacteria activates interleukin-5 (IL-5)- or interferon-gamma-primed eosinophils to release mitochondrial DNA in a reactive oxygen species-dependent manner, but independent of eosinophil death. Notably, the process of DNA release occurs rapidly in a catapult-like manner--in less than one second. In the extracellular space, the mitochondrial DNA and the granule proteins form extracellular structures able to bind and kill bacteria both in vitro and under inflammatory conditions in vivo. Moreover, after cecal ligation and puncture, Il5-transgenic but not wild-type mice show intestinal eosinophil infiltration and extracellular DNA deposition in association with protection against microbial sepsis. These data suggest a previously undescribed mechanism of eosinophil-mediated innate immune responses that might be crucial for maintaining the intestinal barrier function after inflammation-associated epithelial cell damage, preventing the host from uncontrolled invasion of bacteria.", + "TAG_DATA": [ + "49, eosinophils {'context': 'B-cells'}", + "102, in {'context': 'B-in vitro'}", + "103, vitro {'context': 'I-in vitro'}", + "108, in {'context': 'B-in vivo'}", + "109, vivo. {'context': 'I-in vivo'}", + "116, Il5-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "120, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "49, eosinophils ['l0']", + "102, in ['l1', 'l2', 'l3']", + "103, vitro ['l0', 'l1', 'l4', 'l5']", + "108, in ['l2', 'l4', 'l6']", + "109, vivo. ['l3', 'l5', 'l6']", + "116, Il5-transgenic ['l7']", + "120, mice ['l7']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Il5-transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "18607349", + "TEXT": "Individuals with mutations in breast cancer susceptibility genes BRCA1 and BRCA2 have up to an 80% risk of developing breast cancer by the age of 70. Sequencing-based genetic tests are now available to identify mutation carriers in an effort to reduce mortality through prevention and early diagnosis. However, lack of a suitable functional assay hinders the risk assessment of more than 1,900 BRCA1 and BRCA2 variants in the Breast Cancer Information Core database that do not clearly disrupt the gene product. We have established a simple, versatile and reliable assay to test for the functional significance of mutations in BRCA2 using mouse embryonic stem cells (ES cells) and bacterial artificial chromosomes and have used it to classify 17 sequence variants. The assay is based on the ability of human BRCA2 to complement the loss of endogenous Brca2 in mouse ES cells. This technique may also serve as a paradigm for functional analysis of mutations found in other genes linked to human diseases.", + "TAG_DATA": [ + "101, mouse {'context': 'B-cells'}", + "102, embryonic {'context': 'I-cells'}", + "103, stem {'context': 'I-cells'}", + "104, cells {'context': 'I-cells'}", + "105, (ES {'context': 'I-cells'}", + "106, cells) {'context': 'I-cells'}", + "135, endogenous {'perturbing_action': 'I-gene loss-of-function'}", + "138, mouse {'context': 'B-cells'}", + "139, ES {'context': 'I-cells'}", + "140, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "101, mouse ['l0', 'l1', 'l2', 'l3', 'l4']", + "102, embryonic ['l0', 'l5', 'l6', 'l7', 'l8']", + "103, stem ['l1', 'l5', 'l9', 'l10', 'l11']", + "104, cells ['l2', 'l6', 'l9', 'l12', 'l13']", + "105, (ES ['l3', 'l7', 'l10', 'l12', 'l14']", + "106, cells) ['l4', 'l8', 'l11', 'l13', 'l14']", + "135, endogenous ['l15', 'l16', 'l17']", + "138, mouse ['l15', 'l18', 'l19']", + "139, ES ['l16', 'l18', 'l20']", + "140, cells. ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "endogenous" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "ES", + "cells." + ] + } + } + ] + }, + { + "PMID": "18587408", + "TEXT": "Recent efforts have revealed that numerous protein-coding messenger RNAs have natural antisense transcript partners, most of which seem to be noncoding RNAs. Here we identify a conserved noncoding antisense transcript for beta-secretase-1 (BACE1), a crucial enzyme in Alzheimer's disease pathophysiology. The BACE1-antisense transcript (BACE1-AS) regulates BACE1 mRNA and subsequently BACE1 protein expression in vitro and in vivo. Upon exposure to various cell stressors including amyloid-beta 1-42 (Abeta 1-42), expression of BACE1-AS becomes elevated, increasing BACE1 mRNA stability and generating additional Abeta 1-42 through a post-transcriptional feed-forward mechanism. BACE1-AS concentrations were elevated in subjects with Alzheimer's disease and in amyloid precursor protein transgenic mice. These data show that BACE1 mRNA expression is under the control of a regulatory noncoding RNA that may drive Alzheimer's disease-associated pathophysiology. In summary, we report that a long noncoding RNA is directly implicated in the increased abundance of Abeta 1-42 in Alzheimer's disease.", + "TAG_DATA": [ + "98, amyloid {'perturbing_action': 'B-gene gain-of-function'}", + "99, precursor {'perturbing_action': 'I-gene gain-of-function'}", + "100, protein {'perturbing_action': 'I-gene gain-of-function'}", + "101, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "102, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "98, amyloid ['l0', 'l1', 'l2', 'l3']", + "99, precursor ['l0', 'l4', 'l5', 'l6']", + "100, protein ['l1', 'l4', 'l7', 'l8']", + "101, transgenic ['l2', 'l5', 'l7', 'l9']", + "102, mice. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "amyloid", + "precursor", + "protein", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "18500350", + "TEXT": "Obesity and metabolic syndrome are increasingly recognized as major risk factors for cardiovascular disease. Herein we show that Krüppel-like transcription factor 5 (KLF5) is a crucial regulator of energy metabolism. Klf5(+/-) mice were resistant to high fat-induced obesity, hypercholesterolemia and glucose intolerance, despite consuming more food than wild-type mice. This may in part reflect their enhanced energy expenditure. Expression of the genes involved in lipid oxidation and energy uncoupling, including those encoding carnitine-palmitoyl transferase-1b (Cpt1b) and uncoupling proteins 2 and 3 (Ucp2 and Ucp3), was upregulated in the soleus muscles of Klf5(+/-) mice. Under basal conditions, KLF5 modified with small ubiquitin-related modifier (SUMO) proteins was associated with transcriptionally repressive regulatory complexes containing unliganded peroxisome proliferator-activated receptor-delta (PPAR-delta) and co-repressors and thus inhibited Cpt1b, Ucp2 and Ucp3 expression. Upon agonist stimulation of PPAR-delta, KLF5 was deSUMOylated, and became associated with transcriptional activation complexes containing both the liganded PPAR-delta and CREB binding protein (CBP). This activation complex increased the expression of Cpt1b, Ucp2 and Ucp3. Thus, SUMOylation seems to be a molecular switch affecting function of KLF5 and the transcriptional regulatory programs governing lipid metabolism.", + "TAG_DATA": [ + "30, Klf5(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "31, mice {'context': 'B-organism'}", + "88, soleus {'context': 'B-tissue/organ'}", + "89, muscles {'context': 'I-tissue/organ'}", + "91, Klf5(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "92, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "30, Klf5(+/-) ['l0', 'l1', 'l2']", + "31, mice ['l0', 'l3', 'l4']", + "88, soleus ['l1', 'l3', 'l5', 'l6']", + "89, muscles ['l2', 'l4', 'l5']", + "91, Klf5(+/-) ['l7']", + "92, mice. ['l6', 'l7']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Klf5(+/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Klf5(+/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "soleus", + "muscles" + ] + } + } + ] + }, + { + "PMID": "18454155", + "TEXT": "Dendritic cells (DCs) are integral to the differentiation of T helper cells into T helper type 1 T(H)1, T(H)2 and T(H)17 subsets. Interleukin-6 (IL-6) plays an important part in regulating these three arms of the immune response by limiting the T(H)1 response and promoting the T(H)2 and T(H)17 responses. In this study, we investigated pathways in DCs that promote IL-6 production. We show that the allergen house dust mite (HDM) or the mucosal adjuvant cholera toxin promotes cell surface expression of c-Kit and its ligand, stem cell factor (SCF), on DCs. This dual upregulation of c-Kit and SCF results in sustained signaling downstream of c-Kit, promoting IL-6 secretion. Intranasal administration of antigen into c-Kit-mutant mice or neutralization of IL-6 in cultures established from the lung-draining lymph nodes of immunized wild-type mice blunted the T(H)2 and T(H)17 responses. DCs lacking functional c-Kit or those unable to express membrane-bound SCF secreted lower amounts of IL-6 in response to HDM or cholera toxin. DCs expressing nonfunctional c-Kit were unable to induce a robust T(H)2 or T(H)17 response and elicited diminished allergic airway inflammation when adoptively transferred into mice. Expression of the Notch ligand Jagged-2, which has been associated with T(H)2 differentiation, was blunted in DCs from c-Kit-mutant mice. c-Kit upregulation was specifically induced by T(H)2- and T(H)17-skewing stimuli, as the T(H)1-inducing adjuvant, CpG oligodeoxynucleotide, did not promote either c-Kit or Jagged-2 expression. DCs generated from mice expressing a catalytically inactive form of the p110delta subunit of phosphatidylinositol-3 (PI3) kinase (p110(D910A)) secreted lower amounts of IL-6 upon stimulation with cholera toxin.", + "TAG_DATA": [ + "113, c-Kit-mutant {'perturbing_action': 'B-other'}", + "114, mice {'context': 'B-organism'}", + "120, cultures {'context': 'B-cells'}", + "121, established {'context': 'I-cells'}", + "124, lung-draining {'context': 'B-tissue/organ'}", + "125, lymph {'context': 'I-tissue/organ'}", + "126, nodes {'context': 'I-tissue/organ'}", + "130, mice {'context': 'B-organism'}", + "137, DCs {'context': 'B-cells'}", + "138, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "139, functional {'perturbing_action': 'I-gene loss-of-function'}", + "140, c-Kit {'perturbing_action': 'I-gene loss-of-function'}", + "160, DCs {'context': 'B-cells'}", + "161, expressing {'perturbing_action': 'B-other'}", + "162, nonfunctional {'perturbing_action': 'B-other'}", + "163, c-Kit {'perturbing_action': 'I-other'}", + "184, mice. {'context': 'B-organism'}", + "201, DCs {'context': 'B-cells'}", + "203, c-Kit-mutant {'perturbing_action': 'B-other'}", + "204, mice. {'context': 'B-organism'}", + "229, DCs {'context': 'B-cells'}", + "232, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "113, c-Kit-mutant ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "114, mice ['l0', 'l6', 'l7', 'l8', 'l9']", + "120, cultures ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "121, established ['l10', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "122, from ['l11', 'l21', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "123, the ['l1', 'l12', 'l22', 'l32', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "124, lung-draining ['l2', 'l6', 'l13', 'l23', 'l33', 'l41', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "125, lymph ['l3', 'l7', 'l14', 'l24', 'l34', 'l42', 'l49', 'l56', 'l57', 'l58', 'l59', 'l60']", + "126, nodes ['l4', 'l8', 'l15', 'l25', 'l35', 'l43', 'l50', 'l56', 'l61', 'l62']", + "130, mice ['l5', 'l9', 'l16', 'l26', 'l36', 'l44', 'l51', 'l57', 'l61']", + "137, DCs ['l17', 'l27', 'l37', 'l45', 'l52', 'l58', 'l62', 'l63', 'l64', 'l65']", + "138, lacking ['l18', 'l28', 'l38', 'l46', 'l53', 'l63', 'l66', 'l67', 'l68']", + "139, functional ['l19', 'l29', 'l39', 'l47', 'l54', 'l59', 'l64', 'l66', 'l69', 'l70']", + "140, c-Kit ['l20', 'l30', 'l40', 'l48', 'l55', 'l60', 'l65', 'l67', 'l69', 'l71']", + "160, DCs ['l72', 'l73', 'l74']", + "161, expressing ['l72', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "162, nonfunctional ['l75', 'l81', 'l82', 'l83', 'l84', 'l85']", + "163, c-Kit ['l73', 'l76', 'l81', 'l86', 'l87', 'l88']", + "184, mice. ['l31', 'l68', 'l70', 'l71', 'l74', 'l77', 'l82', 'l86']", + "201, DCs ['l78', 'l83', 'l87', 'l89', 'l90']", + "203, c-Kit-mutant ['l79', 'l84', 'l89', 'l91']", + "204, mice. ['l80', 'l85', 'l88', 'l90', 'l91']", + "229, DCs ['l92']", + "232, mice ['l92']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "c-Kit-mutant", + "expressing", + "nonfunctional", + "c-Kit" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "c-Kit-mutant" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung-draining", + "lymph", + "nodes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultures", + "established", + "DCs" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "functional", + "c-Kit" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "lung-draining", + "lymph" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "functional", + "c-Kit" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "functional", + "c-Kit" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "DCs" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "c-Kit", + "nonfunctional", + "c-Kit-mutant" + ] + } + } + ] + }, + { + "PMID": "18425130", + "TEXT": "Beta-adrenergic receptor (betaAR) blockade is a standard therapy for cardiac failure and ischemia. G protein-coupled receptor kinases (GRKs) desensitize betaARs, suggesting that genetic GRK variants might modify outcomes in these syndromes. Re-sequencing of GRK2 and GRK5 revealed a nonsynonymous polymorphism of GRK5, common in African Americans, in which leucine is substituted for glutamine at position 41. GRK5-Leu41 uncoupled isoproterenol-stimulated responses more effectively than did GRK5-Gln41 in transfected cells and transgenic mice, and, like pharmacological betaAR blockade, GRK5-Leu41 protected against experimental catecholamine-induced cardiomyopathy. Human association studies showed a pharmacogenomic interaction between GRK5-Leu41 and beta-blocker treatment, in which the presence of the GRK5-Leu41 polymorphism was associated with decreased mortality in African Americans with heart failure or cardiac ischemia. In 375 prospectively followed African-American subjects with heart failure, GRK5-Leu41 protected against death or cardiac transplantation. Enhanced betaAR desensitization of excessive catecholamine signaling by GRK5-Leu41 provides a 'genetic beta-blockade' that improves survival in African Americans with heart failure, suggesting a reason for conflicting results of beta-blocker clinical trials in this population.", + "TAG_DATA": [ + "66, transfected {'perturbing_action': 'B-gene gain-of-function', 'context': 'B-cells'}", + "67, cells {'context': 'B-cells'}", + "69, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "70, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "66, transfected ['l0']", + "67, cells ['l0']", + "69, transgenic ['l1']", + "70, mice, ['l1']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected" + ] + }, + "context": { + "val": "cells", + "words": [ + "transfected" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "18376406", + "TEXT": "Salmonella typhimurium causes a localized enteric infection in immunocompetent individuals, whereas HIV-infected individuals develop a life-threatening bacteremia. Here we show that simian immunodeficiency virus (SIV) infection results in depletion of T helper type 17 (TH17) cells in the ileal mucosa of rhesus macaques, thereby impairing mucosal barrier functions to S. typhimurium dissemination. In SIV-negative macaques, the gene expression profile induced by S. typhimurium in ligated ileal loops was dominated by TH17 responses, including the expression of interleukin-17 (IL-17) and IL-22. TH17 cells were markedly depleted in SIV-infected rhesus macaques, resulting in blunted TH17 responses to S. typhimurium infection and increased bacterial dissemination. IL-17 receptor-deficient mice showed increased systemic dissemination of S. typhimurium from the gut, suggesting that IL-17 deficiency causes defects in mucosal barrier function. We conclude that SIV infection impairs the IL-17 axis, an arm of the mucosal immune response preventing systemic microbial dissemination from the gastrointestinal tract.", + "TAG_DATA": [ + "39, mucosa {'context': 'I-tissue/organ'}", + "41, rhesus {'context': 'B-organism'}", + "42, macaques, {'context': 'I-organism'}", + "53, SIV-negative {'context': 'B-organism'}", + "54, macaques, {'context': 'I-organism'}", + "65, ileal {'context': 'B-tissue/organ'}", + "66, loops {'context': 'I-tissue/organ'}", + "80, TH17 {'context': 'B-cells'}", + "81, cells {'context': 'I-cells'}", + "87, rhesus {'context': 'B-organism'}", + "88, macaques, {'context': 'I-organism'}", + "102, IL-17 {'perturbing_action': 'B-gene loss-of-function'}", + "103, receptor-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "104, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "39, mucosa ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "41, rhesus ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "42, macaques, ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "53, SIV-negative ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "54, macaques, ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "65, ileal ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "66, loops ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "80, TH17 ['l21', 'l22', 'l23']", + "81, cells ['l21', 'l24', 'l25']", + "87, rhesus ['l22', 'l24', 'l26']", + "88, macaques, ['l23', 'l25', 'l26']", + "102, IL-17 ['l27', 'l28']", + "103, receptor-deficient ['l27', 'l29']", + "104, mice ['l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IL-17", + "receptor-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "18376405", + "TEXT": "Cell-free human T-lymphotropic virus type 1 (HTLV-1) virions are poorly infectious in vitro for their primary target cells, CD4(+) T cells. Here, we show that HTLV-1 can efficiently infect myeloid and plasmacytoid dendritic cells (DCs). Moreover, DCs exposed to HTLV-1, both before and after being productively infected, can rapidly, efficiently and reproducibly transfer virus to autologous primary CD4(+) T cells. This DC-mediated transfer of HTLV-1 involves heparan sulfate proteoglycans and neuropilin-1 and results in long-term productive infection and interleukin-2-independent transformation of the CD4(+) T cells. These studies, along with observations of HTLV-1-infected DCs in the peripheral blood of infected individuals, indicate that DCs have a central role in HTLV-1 transmission, dissemination and persistence in vivo. In addition to altering the current paradigm concerning how HTLV-1 transmission occurs, these studies suggest that impairment of DC function after HTLV-1 infection plays a part in pathogenesis.", + "TAG_DATA": [ + "29, myeloid {'context': 'B-cells'}", + "30, and {'context': 'I-cells'}", + "31, plasmacytoid {'context': 'I-cells'}", + "32, dendritic {'context': 'I-cells'}", + "33, cells {'context': 'I-cells'}", + "34, (DCs). {'context': 'I-cells'}", + "36, DCs {'context': 'B-cells'}", + "55, autologous {'context': 'B-xenograft'}", + "56, primary {'context': 'I-cells'}", + "57, CD4(+) {'context': 'I-cells'}", + "58, T {'context': 'I-cells'}", + "59, cells. {'context': 'I-cells'}", + "72, results {'effect': 'B-positive'}", + "73, in {'effect': 'I-positive'}", + "79, transformation {'phenotype': 'B-transformation'}", + "82, CD4(+) {'context': 'B-cells'}", + "83, T {'context': 'I-cells'}", + "84, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "29, myeloid ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "30, and ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "31, plasmacytoid ['l1', 'l10', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "32, dendritic ['l2', 'l11', 'l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "33, cells ['l3', 'l12', 'l21', 'l29', 'l37', 'l38', 'l39', 'l40']", + "34, (DCs). ['l4', 'l13', 'l22', 'l30', 'l37', 'l41', 'l42']", + "36, DCs ['l5', 'l14', 'l23', 'l31', 'l38', 'l41', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "55, autologous ['l15', 'l24', 'l32', 'l43', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "56, primary ['l6', 'l16', 'l25', 'l33', 'l44', 'l50', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "57, CD4(+) ['l7', 'l17', 'l26', 'l34', 'l45', 'l51', 'l58', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "58, T ['l8', 'l18', 'l27', 'l35', 'l39', 'l46', 'l52', 'l59', 'l65', 'l71', 'l72', 'l73', 'l74', 'l75']", + "59, cells. ['l9', 'l19', 'l28', 'l36', 'l40', 'l42', 'l47', 'l53', 'l60', 'l66', 'l71', 'l76', 'l77', 'l78']", + "72, results ['l48', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l80', 'l81', 'l82', 'l83']", + "73, in ['l49', 'l55', 'l62', 'l68', 'l73', 'l77', 'l79', 'l84', 'l85', 'l86', 'l87']", + "79, transformation ['l80', 'l84', 'l88', 'l89', 'l90']", + "82, CD4(+) ['l81', 'l85', 'l88', 'l91', 'l92']", + "83, T ['l56', 'l63', 'l69', 'l74', 'l82', 'l86', 'l89', 'l91', 'l93']", + "84, cells. ['l57', 'l64', 'l70', 'l75', 'l78', 'l83', 'l87', 'l90', 'l92', 'l93']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "DCs", + "primary", + "CD4(+)", + "T", + "cells." + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "autologous" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + } + }, + { + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cells." + ] + } + } + ] + }, + { + "PMID": "18345011", + "TEXT": "Muscular dystrophies comprise a diverse group of genetic disorders that lead to muscle wasting and, in many instances, premature death. Many mutations that cause muscular dystrophy compromise the support network that connects myofilament proteins within the cell to the basal lamina outside the cell, rendering the sarcolemma more permeable or leaky. Here we show that deletion of the gene encoding cyclophilin D (Ppif) rendered mitochondria largely insensitive to the calcium overload-induced swelling associated with a defective sarcolemma, thus reducing myofiber necrosis in two distinct models of muscular dystrophy. Mice lacking delta-sarcoglycan (Scgd(-/-) mice) showed markedly less dystrophic disease in both skeletal muscle and heart in the absence of Ppif. Moreover, the premature lethality associated with deletion of Lama2, encoding the alpha-2 chain of laminin-2, was rescued, as were other indices of dystrophic disease. Treatment with the cyclophilin inhibitor Debio-025 similarly reduced mitochondrial swelling and necrotic disease manifestations in mdx mice, a model of Duchenne muscular dystrophy, and in Scgd(-/-) mice. Thus, mitochondrial-dependent necrosis represents a prominent disease mechanism in muscular dystrophy, suggesting that inhibition of cyclophilin D could provide a new pharmacologic treatment strategy for these diseases.", + "TAG_DATA": [ + "55, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "56, of {'perturbing_action': 'I-gene loss-of-function'}", + "57, the {'perturbing_action': 'I-gene loss-of-function'}", + "58, gene {'perturbing_action': 'I-gene loss-of-function'}", + "59, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "60, cyclophilin {'perturbing_action': 'I-gene loss-of-function'}", + "61, D {'perturbing_action': 'I-gene loss-of-function'}", + "62, (Ppif) {'perturbing_action': 'I-gene loss-of-function'}", + "79, myofiber {'context': 'B-cells'}", + "88, Mice {'context': 'B-organism'}", + "89, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "90, delta-sarcoglycan {'perturbing_action': 'I-gene loss-of-function'}", + "92, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "100, skeletal {'context': 'B-tissue/organ'}", + "101, muscle {'context': 'I-tissue/organ'}", + "103, heart {'context': 'B-tissue/organ'}", + "106, absence {'perturbing_action': 'B-gene loss-of-function'}", + "107, of {'perturbing_action': 'I-gene loss-of-function'}", + "108, Ppif. {'perturbing_action': 'I-gene loss-of-function'}", + "115, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "116, of {'perturbing_action': 'I-gene loss-of-function'}", + "117, Lama2, {'perturbing_action': 'I-gene loss-of-function'}", + "148, mdx {'context': 'B-organism'}", + "149, mice, {'context': 'I-organism'}", + "158, Scgd(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "159, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "55, deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "56, of ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "57, the ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "58, gene ['l2', 'l16', 'l29', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "59, encoding ['l3', 'l17', 'l30', 'l42', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "60, cyclophilin ['l4', 'l18', 'l31', 'l43', 'l54', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "61, D ['l5', 'l19', 'l32', 'l44', 'l55', 'l66', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "62, (Ppif) ['l6', 'l20', 'l33', 'l45', 'l56', 'l67', 'l76', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "79, myofiber ['l7', 'l21', 'l34', 'l46', 'l57', 'l68', 'l77', 'l85']", + "88, Mice ['l8', 'l22', 'l35', 'l47', 'l58', 'l69', 'l78', 'l86', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "89, lacking ['l9', 'l23', 'l36', 'l48', 'l59', 'l70', 'l79', 'l87', 'l92', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "90, delta-sarcoglycan ['l10', 'l24', 'l37', 'l49', 'l60', 'l71', 'l80', 'l93', 'l101', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "92, mice) ['l11', 'l25', 'l38', 'l50', 'l61', 'l72', 'l81', 'l88', 'l94', 'l102', 'l109', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "100, skeletal ['l12', 'l26', 'l39', 'l51', 'l62', 'l73', 'l82', 'l89', 'l95', 'l103', 'l110', 'l116', 'l122', 'l123']", + "101, muscle ['l13', 'l27', 'l40', 'l52', 'l63', 'l74', 'l83', 'l90', 'l96', 'l104', 'l111', 'l117', 'l122', 'l124']", + "103, heart ['l14', 'l28', 'l41', 'l53', 'l64', 'l75', 'l84', 'l91', 'l97', 'l105', 'l112', 'l118', 'l123', 'l124', 'l125', 'l126']", + "106, absence ['l98', 'l106', 'l113', 'l119', 'l127', 'l128']", + "107, of ['l65', 'l99', 'l107', 'l114', 'l120', 'l125', 'l127', 'l129']", + "108, Ppif. ['l100', 'l108', 'l115', 'l121', 'l126', 'l128', 'l129']", + "115, deletion ['l130', 'l131', 'l132', 'l133']", + "116, of ['l130', 'l134', 'l135', 'l136']", + "117, Lama2, ['l131', 'l134', 'l137', 'l138']", + "148, mdx ['l132', 'l135', 'l137', 'l139']", + "149, mice, ['l133', 'l136', 'l138', 'l139']", + "158, Scgd(-/-) ['l140']", + "159, mice. ['l140']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "gene", + "encoding", + "cyclophilin", + "D", + "(Ppif)" + ] + }, + "context": { + "val": "cells", + "words": [ + "myofiber" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "gene", + "encoding", + "cyclophilin", + "D", + "(Ppif)", + "lacking", + "delta-sarcoglycan", + "mice)", + "absence", + "Ppif.", + "Lama2,", + "Scgd(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "Mice", + "mdx", + "mice,", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "gene", + "encoding", + "cyclophilin", + "D", + "(Ppif)", + "lacking", + "delta-sarcoglycan", + "mice)", + "Ppif." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skeletal", + "muscle", + "heart" + ] + } + } + ] + }, + { + "PMID": "18311147", + "TEXT": "Albuminuria associated with sclerosis of the glomerulus leads to a progressive decline in renal function affecting millions of people. Here we report that activation of the Notch pathway, which is critical in glomerular patterning, contributes to the development of glomerular disease. Expression of the intracellular domain of Notch1 (ICN1) was increased in glomerular epithelial cells in diabetic nephropathy and in focal segmental glomerulosclerosis. Conditional re-expression of ICN1 in vivo exclusively in podocytes caused proteinuria and glomerulosclerosis. In vitro and in vivo studies showed that ICN1 induced apoptosis of podocytes through the activation of p53. Genetic deletion of a Notch transcriptional partner (Rbpj) specifically in podocytes or pharmacological inhibition of the Notch pathway (with a gamma-secretase inhibitor) protected rats with proteinuric kidney diseases. Collectively, our observations suggest that Notch activation in mature podocytes is a new mechanism in the pathogenesis of glomerular disease and thus could represent a new therapeutic target.", + "TAG_DATA": [ + "63, Conditional {'perturbing_action': 'B-gene gain-of-function'}", + "64, re-expression {'perturbing_action': 'I-gene gain-of-function'}", + "65, of {'perturbing_action': 'I-gene gain-of-function'}", + "66, ICN1 {'perturbing_action': 'I-gene gain-of-function'}", + "67, in {'context': 'B-in vivo'}", + "68, vivo {'context': 'I-in vivo'}", + "71, podocytes {'context': 'B-cells'}", + "76, In {'context': 'B-in vitro'}", + "77, vitro {'context': 'I-in vitro'}", + "79, in {'context': 'B-in vivo'}", + "80, vivo {'context': 'I-in vivo'}", + "85, induced {'effect': 'B-positive'}", + "86, apoptosis {'phenotype': 'B-apoptosis'}", + "88, podocytes {'context': 'B-cells'}", + "94, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "95, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "96, of {'perturbing_action': 'I-gene loss-of-function'}", + "97, a {'perturbing_action': 'I-gene loss-of-function'}", + "98, Notch {'perturbing_action': 'I-gene loss-of-function'}", + "99, transcriptional {'perturbing_action': 'I-gene loss-of-function'}", + "100, partner {'perturbing_action': 'I-gene loss-of-function'}", + "101, (Rbpj) {'perturbing_action': 'I-gene loss-of-function'}", + "102, specifically {'perturbing_action': 'I-gene loss-of-function'}", + "103, in {'perturbing_action': 'I-gene loss-of-function'}", + "104, podocytes {'context': 'B-cells'}", + "117, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "63, Conditional ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "64, re-expression ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "65, of ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "66, ICN1 ['l2', 'l13', 'l23', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "67, in ['l3', 'l14', 'l24', 'l32', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "68, vivo ['l4', 'l15', 'l25', 'l33', 'l40', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "71, podocytes ['l5', 'l16', 'l26', 'l34', 'l41', 'l47', 'l53', 'l54', 'l55', 'l56', 'l57']", + "76, In ['l6', 'l17', 'l27', 'l35', 'l42', 'l48', 'l53', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "77, vitro ['l7', 'l18', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "79, in ['l59', 'l64', 'l69', 'l70', 'l71', 'l72']", + "80, vivo ['l8', 'l19', 'l60', 'l65', 'l69', 'l73', 'l74', 'l75']", + "85, induced ['l9', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l61', 'l66', 'l70', 'l73', 'l76', 'l77']", + "86, apoptosis ['l10', 'l21', 'l30', 'l38', 'l45', 'l51', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l78']", + "88, podocytes ['l11', 'l22', 'l31', 'l39', 'l46', 'l52', 'l57', 'l63', 'l68', 'l72', 'l75', 'l77', 'l78']", + "94, Genetic ['l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "95, deletion ['l79', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "96, of ['l80', 'l90', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "97, a ['l81', 'l91', 'l100', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "98, Notch ['l82', 'l92', 'l101', 'l109', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "99, transcriptional ['l83', 'l93', 'l102', 'l110', 'l117', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "100, partner ['l84', 'l94', 'l103', 'l111', 'l118', 'l124', 'l130', 'l131', 'l132', 'l133', 'l134']", + "101, (Rbpj) ['l85', 'l95', 'l104', 'l112', 'l119', 'l125', 'l130', 'l135', 'l136', 'l137', 'l138']", + "102, specifically ['l86', 'l96', 'l105', 'l113', 'l120', 'l126', 'l131', 'l135', 'l139', 'l140', 'l141']", + "103, in ['l87', 'l97', 'l106', 'l114', 'l121', 'l127', 'l132', 'l136', 'l139', 'l142', 'l143']", + "104, podocytes ['l88', 'l98', 'l107', 'l115', 'l122', 'l128', 'l133', 'l137', 'l140', 'l142', 'l144']", + "117, rats ['l89', 'l99', 'l108', 'l116', 'l123', 'l129', 'l134', 'l138', 'l141', 'l143', 'l144']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Conditional", + "re-expression", + "of", + "ICN1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Conditional", + "re-expression", + "of", + "ICN1" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Conditional", + "re-expression", + "of", + "ICN1" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Conditional", + "re-expression", + "of", + "ICN1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Conditional", + "re-expression", + "of", + "ICN1" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "podocytes" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "podocytes" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "deletion", + "of", + "a", + "Notch", + "transcriptional", + "partner", + "(Rbpj)", + "specifically", + "in" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "deletion", + "of", + "a", + "Notch", + "transcriptional", + "partner", + "(Rbpj)", + "specifically", + "in" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + } + ] + }, + { + "PMID": "18264110", + "TEXT": "Emerging evidence supports the concept that T helper type 17 (T(H)17) cells, in addition to mediating autoimmunity, have key roles in mucosal immunity against extracellular pathogens. Interleukin-22 (IL-22) and IL-17A are both effector cytokines produced by the T(H)17 lineage, and both were crucial for maintaining local control of the Gram-negative pulmonary pathogen, Klebsiella pneumoniae. Although both cytokines regulated CXC chemokines and granulocyte colony-stimulating factor production in the lung, only IL-22 increased lung epithelial cell proliferation and increased transepithelial resistance to injury. These data support the concept that the T(H)17 cell lineage and its effector molecules have evolved to effect host defense against extracellular pathogens at mucosal sites.", + "TAG_DATA": [ + "67, lung, {'context': 'B-tissue/organ'}", + "70, increased {'effect': 'B-positive'}", + "71, lung {'context': 'B-cells'}", + "72, epithelial {'context': 'I-cells'}", + "73, cell {'context': 'I-cells'}", + "74, proliferation {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "67, lung, ['l0', 'l1', 'l2']", + "70, increased ['l0', 'l3', 'l4', 'l5', 'l6']", + "71, lung ['l3', 'l7', 'l8', 'l9']", + "72, epithelial ['l4', 'l7', 'l10', 'l11']", + "73, cell ['l1', 'l5', 'l8', 'l10', 'l12']", + "74, proliferation ['l2', 'l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "lung," + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "lung," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "cells", + "words": [ + "lung", + "epithelial", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "lung", + "epithelial", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "18246078", + "TEXT": "Treacher Collins syndrome (TCS) is a congenital disorder of craniofacial development arising from mutations in TCOF1, which encodes the nucleolar phosphoprotein Treacle. Haploinsufficiency of Tcof1 perturbs mature ribosome biogenesis, resulting in stabilization of p53 and the cyclin G1-mediated cell-cycle arrest that underpins the specificity of neuroepithelial apoptosis and neural crest cell hypoplasia characteristic of TCS. Here we show that inhibition of p53 prevents cyclin G1-driven apoptotic elimination of neural crest cells while rescuing the craniofacial abnormalities associated with mutations in Tcof1 and extending life span. These improvements, however, occur independently of the effects on ribosome biogenesis; thus suggesting that it is p53-dependent neuroepithelial apoptosis that is the primary mechanism underlying the pathogenesis of TCS. Our work further implies that neuroepithelial and neural crest cells are particularly sensitive to cellular stress during embryogenesis and that suppression of p53 function provides an attractive avenue for possible clinical prevention of TCS craniofacial birth defects and possibly those of other neurocristopathies.", + "TAG_DATA": [ + "59, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "60, of {'perturbing_action': 'I-pharmacological inhibition'}", + "61, p53 {'perturbing_action': 'I-pharmacological inhibition'}", + "62, prevents {'effect': 'B-negative'}", + "65, apoptotic {'phenotype': 'B-apoptosis'}", + "66, elimination {'phenotype': 'I-apoptosis'}", + "68, neural {'context': 'B-cells'}", + "69, crest {'context': 'I-cells'}", + "70, cells {'context': 'I-cells'}", + "78, mutations {'perturbing_action': 'B-other'}", + "79, in {'perturbing_action': 'I-other'}", + "80, Tcof1 {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "59, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "60, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "61, p53 ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "62, prevents ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34']", + "65, apoptotic ['l3', 'l13', 'l22', 'l30', 'l35', 'l36', 'l37', 'l38']", + "66, elimination ['l4', 'l14', 'l23', 'l31', 'l35', 'l39', 'l40', 'l41']", + "68, neural ['l5', 'l15', 'l24', 'l32', 'l36', 'l39', 'l42', 'l43']", + "69, crest ['l6', 'l16', 'l25', 'l33', 'l37', 'l40', 'l42', 'l44']", + "70, cells ['l7', 'l17', 'l26', 'l34', 'l38', 'l41', 'l43', 'l44']", + "78, mutations ['l8', 'l18', 'l27', 'l45', 'l46']", + "79, in ['l9', 'l19', 'l28', 'l45', 'l47']", + "80, Tcof1 ['l10', 'l20', 'l29', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "p53" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "p53" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "elimination" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "p53" + ] + }, + "context": { + "val": "cells", + "words": [ + "neural", + "crest", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "elimination" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "context": { + "val": "cells", + "words": [ + "neural", + "crest", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "elimination" + ] + }, + "context": { + "val": "cells", + "words": [ + "neural", + "crest", + "cells" + ] + } + } + ] + }, + { + "PMID": "18204462", + "TEXT": "The dendritic cell immunoreceptor (official gene symbol Clec4a2, called Dcir here) is a C-type lectin receptor expressed mainly in dendritic cells (DCs) that has a carbohydrate recognition domain in its extracellular portion and an immunoreceptor tyrosine-based inhibitory motif, which transduces negative signals into cells, in its cytoplasmic portion. We found high Dcir expression in the joints of two mouse rheumatoid arthritis models. Because the structural characteristics of Dcir suggest that it may have an immune regulatory role, and because autoimmune-related genes are mapped to the DCIR locus in humans, we generated Dcir-/- mice to learn more about the pathological roles of this molecule. We found that aged Dcir-/- mice spontaneously develop sialadenitis and enthesitis associated with elevated serum autoantibodies. Dcir-/- mice showed a markedly exacerbated response to collagen-induced arthritis. The DC population was expanded excessively in aged and type II collagen-immunized Dcir-/- mice. Upon treatment with granulocyte-macrophage colony-stimulating factor, Dcir-/- mouse-derived bone marrow cells (BMCs) differentiated into DCs more efficiently than did wild-type BMCs, owing to enhanced signal transducer and activator of transcription-5 phosphorylation. These observations indicate that Dcir is a negative regulator of DC expansion and has a crucial role in maintaining the homeostasis of the immune system.", + "TAG_DATA": [ + "91, Dcir-/- {'perturbing_action': 'B-gene loss-of-function'}", + "92, mice {'context': 'B-organism'}", + "107, Dcir-/- {'perturbing_action': 'B-gene loss-of-function'}", + "108, mice {'context': 'B-organism'}", + "119, Dcir-/- {'perturbing_action': 'B-gene loss-of-function'}", + "120, mice {'context': 'B-organism'}", + "130, DC {'context': 'B-cells'}", + "141, Dcir-/- {'perturbing_action': 'B-gene loss-of-function'}", + "142, mice. {'context': 'B-organism'}", + "149, Dcir-/- {'perturbing_action': 'B-gene loss-of-function'}", + "150, mouse-derived {'context': 'B-cells'}", + "151, bone {'context': 'I-cells'}", + "152, marrow {'context': 'I-cells'}", + "153, cells {'context': 'I-cells'}", + "154, (BMCs) {'context': 'I-cells'}", + "155, differentiated {'phenotype': 'B-differentiation'}", + "157, DCs {'context': 'B-cells'}", + "163, BMCs, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "91, Dcir-/- ['l0', 'l1', 'l2']", + "92, mice ['l0', 'l3', 'l4']", + "107, Dcir-/- ['l1', 'l3', 'l5']", + "108, mice ['l2', 'l4', 'l5']", + "119, Dcir-/- ['l6', 'l7', 'l8', 'l9']", + "120, mice ['l6', 'l10', 'l11', 'l12']", + "130, DC ['l7', 'l10', 'l13', 'l14']", + "141, Dcir-/- ['l8', 'l11', 'l13', 'l15']", + "142, mice. ['l9', 'l12', 'l14', 'l15']", + "149, Dcir-/- ['l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "150, mouse-derived ['l16', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "151, bone ['l17', 'l24', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "152, marrow ['l18', 'l25', 'l31', 'l37', 'l38', 'l39', 'l40']", + "153, cells ['l19', 'l26', 'l32', 'l37', 'l41', 'l42', 'l43']", + "154, (BMCs) ['l20', 'l27', 'l33', 'l38', 'l41', 'l44', 'l45', 'l46']", + "155, differentiated ['l21', 'l28', 'l34', 'l39', 'l42', 'l44', 'l47']", + "157, DCs ['l22', 'l29', 'l35', 'l40', 'l43', 'l45', 'l47', 'l48']", + "163, BMCs, ['l23', 'l30', 'l36', 'l46', 'l48']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dcir-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dcir-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "DC", + "mouse-derived", + "bone", + "marrow", + "cells", + "(BMCs)", + "DCs", + "BMCs," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dcir-/-" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiated" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse-derived", + "bone", + "marrow", + "cells", + "(BMCs)", + "DCs" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiated" + ] + } + } + ] + }, + { + "PMID": "18157140", + "TEXT": "Deep brain stimulation (DBS) is a widely used neurosurgical approach to treating tremor and other movement disorders. In addition, the use of DBS in a number of psychiatric diseases, including obsessive-compulsive disorders and depression, is currently being tested. Despite the rapid increase in the number of individuals with surgically implanted stimulation electrodes, the cellular pathways involved in mediating the effects of DBS remain unknown. Here we show that DBS is associated with a marked increase in the release of ATP, resulting in accumulation of its catabolic product, adenosine. Adenosine A1 receptor activation depresses excitatory transmission in the thalamus and reduces both tremor- and DBS-induced side effects. Intrathalamic infusion of A1 receptor agonists directly reduces tremor, whereas adenosine A1 receptor-null mice show involuntary movements and seizure at stimulation intensities below the therapeutic level. Furthermore, our data indicate that endogenous adenosine mechanisms are active in tremor, thus supporting the clinical notion that caffeine, a nonselective adenosine receptor antagonist, can trigger or exacerbate essential tremor. Our findings suggest that nonsynaptic mechanisms involving the activation of A1 receptors suppress tremor activity and limit stimulation-induced side effects, thereby providing a new pharmacological target to replace or improve the efficacy of DBS.", + "TAG_DATA": [ + "89, A1 {'perturbing_action': 'I-pharmacological augmentation'}", + "90, receptor {'perturbing_action': 'I-pharmacological augmentation'}", + "91, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "109, A1 {'perturbing_action': 'B-pharmacological augmentation'}", + "110, receptor {'perturbing_action': 'I-pharmacological augmentation'}", + "111, agonists {'perturbing_action': 'I-pharmacological augmentation'}", + "116, adenosine {'perturbing_action': 'B-gene loss-of-function'}", + "117, A1 {'perturbing_action': 'I-gene loss-of-function'}", + "118, receptor-null {'perturbing_action': 'I-gene loss-of-function'}", + "119, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "89, A1 ['l0', 'l1']", + "90, receptor ['l0', 'l2']", + "91, activation ['l1', 'l2']", + "109, A1 ['l3', 'l4']", + "110, receptor ['l3', 'l5']", + "111, agonists ['l4', 'l5']", + "116, adenosine ['l6', 'l7', 'l8']", + "117, A1 ['l6', 'l9', 'l10']", + "118, receptor-null ['l7', 'l9', 'l11']", + "119, mice ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adenosine", + "A1", + "receptor-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "18059282", + "TEXT": "Osteoclasts are bone-resorbing cells derived from hematopoietic precursors of the monocyte-macrophage lineage. Regulation of osteoclast function is central to the understanding of bone diseases such as osteoporosis, rheumatoid arthritis and osteopetrosis. Although peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been shown to inhibit osteoblast differentiation, its role, if any, in osteoclasts is unknown. This is a clinically crucial question because PPAR-gamma agonists, \"such as thiazolidinediones-\" a class of insulin-sensitizing drugs, have been reported to cause a higher rate of fractures in human patients. Here we have uncovered a pro-osteoclastogenic effect of PPAR-gamma by using a Tie2Cre/flox mouse model in which PPAR-gamma is deleted in osteoclasts but not in osteoblasts. These mice develop osteopetrosis characterized by increased bone mass, reduced medullary cavity space and extramedullary hematopoiesis in the spleen. These defects are the result of impaired osteoclast differentiation and compromised receptor activator of nuclear factor-kappaB ligand signaling and can be rescued by bone marrow transplantation. Moreover, ligand activation of PPAR-gamma by rosiglitazone exacerbates osteoclast differentiation in a receptor-dependent manner. Our examination of the underlying mechanisms suggested that PPAR-gamma functions as a direct regulator of c-fos expression, an essential mediator of osteoclastogenesis. Therefore, PPAR-gamma and its ligands have a previously unrecognized role in promoting osteoclast differentiation and bone resorption.", + "TAG_DATA": [ + "93, Tie2Cre/flox {'perturbing_action': 'B-gene loss-of-function'}", + "94, mouse {'context': 'B-organism'}", + "95, model {'context': 'I-organism'}", + "98, PPAR-gamma {'perturbing_action': 'I-gene loss-of-function'}", + "99, is {'perturbing_action': 'I-gene loss-of-function'}", + "100, deleted {'perturbing_action': 'I-gene loss-of-function'}", + "102, osteoclasts {'context': 'B-cells'}", + "106, osteoblasts. {'context': 'B-cells'}", + "108, mice {'context': 'B-organism'}", + "125, spleen. {'context': 'B-tissue/organ'}", + "132, impaired {'effect': 'B-negative'}", + "134, differentiation {'phenotype': 'B-differentiation'}", + "159, exacerbates {'effect': 'B-positive'}", + "160, osteoclast {'context': 'B-cells'}", + "161, differentiation {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "93, Tie2Cre/flox ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "94, mouse ['l0', 'l10', 'l11', 'l12', 'l13']", + "95, model ['l1', 'l10', 'l14', 'l15', 'l16']", + "98, PPAR-gamma ['l2', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "99, is ['l3', 'l11', 'l14', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "100, deleted ['l4', 'l18', 'l25', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "102, osteoclasts ['l5', 'l12', 'l15', 'l19', 'l26', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "106, osteoblasts. ['l6', 'l13', 'l16', 'l20', 'l27', 'l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "108, mice ['l7', 'l21', 'l28', 'l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "125, spleen. ['l8', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "132, impaired ['l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "134, differentiation ['l9', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l52']", + "159, exacerbates ['l53', 'l54']", + "160, osteoclast ['l53', 'l55']", + "161, differentiation ['l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tie2Cre/flox", + "is", + "PPAR-gamma", + "deleted" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tie2Cre/flox", + "PPAR-gamma", + "is", + "deleted" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclasts", + "osteoblasts." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tie2Cre/flox", + "PPAR-gamma", + "is", + "deleted" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "spleen." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tie2Cre/flox", + "PPAR-gamma", + "is", + "deleted" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PPAR-gamma", + "is", + "deleted" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoclasts", + "osteoblasts." + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoclasts", + "osteoblasts.", + "osteoclast" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "spleen." + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "spleen." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "exacerbates" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "exacerbates" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "18059281", + "TEXT": "The success of Mycobacterium tuberculosis (Mtb) as a human pathogen relies on its ability to resist eradication by the immune system. The identification of mechanisms that enable Mtb to persist is key for finding ways to limit latent tuberculosis, which affects one-third of the world's population. Here we show that conditional gene silencing can be used to determine whether an Mtb gene required for optimal growth in vitro is also important for virulence and, if so, during which phase of an infection it is required. Application of this approach to the prcBA genes, which encode the core of the mycobacterial proteasome, revealed an unpredicted requirement of the core proteasome for the persistence of Mtb during the chronic phase of infection in mice. Proteasome depletion also attenuated Mtb in interferon-gamma-deficient mice, pointing to a function of the proteasome beyond defense against the adaptive immune response. Genes that are essential for growth in vitro, in vivo or both account for approximately 20% of Mtb's genome. Conditional gene silencing could therefore facilitate the validation of up to 800 potential Mtb drug targets and improve our understanding of host-pathogen dynamics.", + "TAG_DATA": [ + "121, mice. {'context': 'B-organism'}", + "128, interferon-gamma-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "129, mice, {'context': 'B-organism'}", + "153, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "128, interferon-gamma-deficient ['l0']", + "129, mice, ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interferon-gamma-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "18059280", + "TEXT": "Surgery or radiation therapy of metastatic cancer often damages lymph nodes, leading to secondary lymphedema. Here we show, using a newly established mouse model, that collecting lymphatic vessels can be regenerated and fused to lymph node transplants after lymph node removal. Treatment of lymph node-excised mice with adenovirally delivered vascular endothelial growth factor-C (VEGF-C) or VEGF-D induced robust growth of the lymphatic capillaries, which gradually underwent intrinsic remodeling, differentiation and maturation into functional collecting lymphatic vessels, including the formation of uniform endothelial cell-cell junctions and intraluminal valves. The vessels also reacquired pericyte contacts, which downregulated lymphatic capillary markers during vessel maturation. Growth factor therapy improved the outcome of lymph node transplantation, including functional reconstitution of the immunological barrier against tumor metastasis. These results show that growth factor-induced maturation of lymphatic vessels is possible in adult mice and provide a basis for future therapy of lymphedema.", + "TAG_DATA": [ + "45, mice {'context': 'B-organism'}", + "47, adenovirally {'perturbing_action': 'B-gene gain-of-function'}", + "48, delivered {'perturbing_action': 'I-gene gain-of-function'}", + "49, vascular {'perturbing_action': 'I-gene gain-of-function'}", + "50, endothelial {'perturbing_action': 'I-gene gain-of-function'}", + "51, growth {'perturbing_action': 'I-gene gain-of-function'}", + "52, factor-C {'perturbing_action': 'I-gene gain-of-function'}", + "53, (VEGF-C) {'perturbing_action': 'I-gene gain-of-function'}", + "61, lymphatic {'context': 'B-tissue/organ'}", + "62, capillaries, {'context': 'I-tissue/organ'}", + "88, vessels {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "43, lymph ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "44, node-excised ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "45, mice ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "47, adenovirally ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "48, delivered ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "49, vascular ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "50, endothelial ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "51, growth ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "52, factor-C ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "53, (VEGF-C) ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "61, lymphatic ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75']", + "62, capillaries, ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75']", + "88, vessels ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirally", + "delivered", + "vascular", + "endothelial", + "growth", + "factor-C", + "(VEGF-C)" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirally", + "delivered", + "vascular", + "endothelial", + "growth", + "factor-C", + "(VEGF-C)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lymphatic", + "capillaries,", + "vessels" + ] + } + } + ] + }, + { + "PMID": "17982464", + "TEXT": "Data providing direct evidence for a causative link between endothelial dysfunction, microvascular disease and diabetic end-organ damage are scarce. Here we show that activated protein C (APC) formation, which is regulated by endothelial thrombomodulin, is reduced in diabetic mice and causally linked to nephropathy. Thrombomodulin-dependent APC formation mediates cytoprotection in diabetic nephropathy by inhibiting glomerular apoptosis. APC prevents glucose-induced apoptosis in endothelial cells and podocytes, the cellular components of the glomerular filtration barrier. APC modulates the mitochondrial apoptosis pathway via the protease-activated receptor PAR-1 and the endothelial protein C receptor EPCR in glucose-stressed cells. These experiments establish a new pathway, in which hyperglycemia impairs endothelial thrombomodulin-dependent APC formation. Loss of thrombomodulin-dependent APC formation interrupts cross-talk between the vascular compartment and podocytes, causing glomerular apoptosis and diabetic nephropathy. Conversely, maintaining high APC levels during long-term diabetes protects against diabetic nephropathy.", + "TAG_DATA": [ + "53, inhibiting {'effect': 'B-negative'}", + "55, apoptosis. {'phenotype': 'B-apoptosis'}", + "57, prevents {'effect': 'B-negative'}", + "58, glucose-induced {'effect': 'B-positive'}", + "59, apoptosis {'phenotype': 'B-apoptosis'}", + "61, endothelial {'context': 'B-cells'}", + "62, cells {'context': 'I-cells'}", + "64, podocytes, {'context': 'B-cells'}", + "74, modulates {'effect': 'B-regulates'}", + "77, apoptosis {'phenotype': 'B-apoptosis'}", + "78, pathway {'phenotype': 'I-apoptosis'}", + "93, cells. {'context': 'B-cells'}", + "121, causing {'effect': 'B-positive'}", + "123, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "53, inhibiting ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "55, apoptosis. ['l0', 'l6', 'l7', 'l8', 'l9']", + "57, prevents ['l1', 'l6', 'l10', 'l11', 'l12', 'l13', 'l14']", + "58, glucose-induced ['l2', 'l7', 'l10', 'l15', 'l16', 'l17', 'l18']", + "59, apoptosis ['l3', 'l11', 'l15', 'l19', 'l20', 'l21']", + "61, endothelial ['l4', 'l8', 'l12', 'l16', 'l19', 'l22', 'l23']", + "62, cells ['l5', 'l9', 'l13', 'l17', 'l20', 'l22', 'l24']", + "64, podocytes, ['l14', 'l18', 'l21', 'l23', 'l24', 'l25', 'l26']", + "74, modulates ['l27', 'l28', 'l29', 'l30', 'l31']", + "77, apoptosis ['l27', 'l32', 'l33', 'l34']", + "78, pathway ['l25', 'l28', 'l32', 'l35']", + "93, cells. ['l26', 'l29', 'l33', 'l35', 'l36', 'l37']", + "121, causing ['l30', 'l34', 'l36', 'l38']", + "123, apoptosis ['l31', 'l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibiting", + "prevents" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis.", + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibiting", + "prevents" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells", + "podocytes," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis.", + "apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "glucose-induced", + "causing" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis.", + "apoptosis", + "pathway" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells", + "podocytes,", + "cells." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "glucose-induced", + "causing" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells", + "podocytes,", + "cells." + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "modulates" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "pathway" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "modulates" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "17965722", + "TEXT": "Measurements of early tumor responses to therapy have been shown, in some cases, to predict treatment outcome. We show in lymphoma-bearing mice injected intravenously with hyperpolarized [1-(13)C]pyruvate that the lactate dehydrogenase-catalyzed flux of (13)C label between the carboxyl groups of pyruvate and lactate in the tumor can be measured using (13)C magnetic resonance spectroscopy and spectroscopic imaging, and that this flux is inhibited within 24 h of chemotherapy. The reduction in the measured flux after drug treatment and the induction of tumor cell death can be explained by loss of the coenzyme NAD(H) and decreases in concentrations of lactate and enzyme in the tumors. The technique could provide a new way to assess tumor responses to treatment in the clinic.", + "TAG_DATA": [ + "20, lymphoma-bearing {'context': 'B-organism'}", + "21, mice {'context': 'I-organism'}", + "45, tumor {'context': 'B-neoplasm'}", + "79, induction {'effect': 'B-positive'}", + "81, tumor {'context': 'B-neoplasm'}", + "82, cell {'phenotype': 'B-cell death'}", + "83, death {'phenotype': 'I-cell death'}", + "103, tumors. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "20, lymphoma-bearing ['l0', 'l1']", + "21, mice ['l0', 'l2']", + "45, tumor ['l1', 'l2']", + "79, induction ['l3', 'l4', 'l5']", + "81, tumor ['l3', 'l6', 'l7']", + "82, cell ['l4', 'l6', 'l8']", + "83, death ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + } + ] + }, + { + "PMID": "17952090", + "TEXT": "Hepatic injury is associated with a defective intestinal barrier and increased hepatic exposure to bacterial products. Here we report that the intestinal bacterial microflora and a functional Toll-like receptor 4 (TLR4), but not TLR2, are required for hepatic fibrogenesis. Using Tlr4-chimeric mice and in vivo lipopolysaccharide (LPS) challenge, we demonstrate that quiescent hepatic stellate cells (HSCs), the main precursors for myofibroblasts in the liver, are the predominant target through which TLR4 ligands promote fibrogenesis. In quiescent HSCs, TLR4 activation not only upregulates chemokine secretion and induces chemotaxis of Kupffer cells, but also downregulates the transforming growth factor (TGF)-beta pseudoreceptor Bambi to sensitize HSCs to TGF-beta-induced signals and allow for unrestricted activation by Kupffer cells. LPS-induced Bambi downregulation and sensitization to TGF-beta is mediated by a MyD88-NF-kappaB-dependent pathway. Accordingly, Myd88-deficient mice have decreased hepatic fibrosis. Thus, modulation of TGF-beta signaling by a TLR4-MyD88-NF-kappaB axis provides a novel link between proinflammatory and profibrogenic signals.", + "TAG_DATA": [ + "40, Tlr4-chimeric {'perturbing_action': 'B-other'}", + "41, mice {'context': 'I-organism'}", + "43, in {'context': 'B-in vivo'}", + "44, vivo {'context': 'I-in vivo'}", + "51, quiescent {'context': 'B-cells'}", + "52, hepatic {'context': 'I-cells'}", + "53, stellate {'context': 'I-cells'}", + "54, cells {'context': 'I-cells'}", + "55, (HSCs), {'context': 'I-cells'}", + "75, quiescent {'context': 'B-cells'}", + "76, HSCs, {'context': 'I-cells'}", + "85, induces {'effect': 'B-positive'}", + "86, chemotaxis {'phenotype': 'B-migration'}", + "88, Kupffer {'context': 'B-cells'}", + "89, cells, {'context': 'I-cells'}", + "102, HSCs {'context': 'B-cells'}", + "112, Kupffer {'context': 'B-cells'}", + "113, cells. {'context': 'I-cells'}", + "128, Myd88-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "129, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "40, Tlr4-chimeric ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "41, mice ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "43, in ['l1', 'l13', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "44, vivo ['l2', 'l14', 'l23', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "51, quiescent ['l3', 'l15', 'l24', 'l34', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "52, hepatic ['l4', 'l16', 'l25', 'l35', 'l44', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "53, stellate ['l5', 'l17', 'l26', 'l36', 'l45', 'l55', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "54, cells ['l6', 'l18', 'l27', 'l37', 'l46', 'l56', 'l65', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "55, (HSCs), ['l7', 'l19', 'l28', 'l38', 'l47', 'l57', 'l66', 'l74', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "75, quiescent ['l48', 'l58', 'l67', 'l80', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "76, HSCs, ['l8', 'l29', 'l39', 'l49', 'l59', 'l68', 'l75', 'l81', 'l86', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "85, induces ['l9', 'l20', 'l30', 'l40', 'l50', 'l60', 'l69', 'l76', 'l82', 'l87', 'l94', 'l101', 'l102', 'l103']", + "86, chemotaxis ['l10', 'l21', 'l31', 'l41', 'l51', 'l61', 'l70', 'l77', 'l83', 'l88', 'l95', 'l101', 'l104', 'l105', 'l106', 'l107']", + "88, Kupffer ['l11', 'l32', 'l42', 'l52', 'l62', 'l71', 'l78', 'l84', 'l89', 'l96', 'l102', 'l104', 'l108', 'l109', 'l110', 'l111']", + "89, cells, ['l12', 'l22', 'l33', 'l43', 'l53', 'l63', 'l72', 'l79', 'l85', 'l90', 'l97', 'l103', 'l105', 'l108', 'l112', 'l113']", + "102, HSCs ['l91', 'l98', 'l106', 'l109', 'l112', 'l114', 'l115']", + "112, Kupffer ['l92', 'l99', 'l110', 'l114', 'l116']", + "113, cells. ['l54', 'l64', 'l73', 'l93', 'l100', 'l107', 'l111', 'l113', 'l115', 'l116']", + "128, Myd88-deficient ['l117']", + "129, mice ['l117']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Tlr4-chimeric" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Tlr4-chimeric" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Tlr4-chimeric" + ] + }, + "context": { + "val": "cells", + "words": [ + "quiescent", + "hepatic", + "stellate", + "cells", + "(HSCs),", + "HSCs,", + "Kupffer", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Tlr4-chimeric" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Tlr4-chimeric" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "quiescent", + "hepatic", + "stellate", + "cells", + "(HSCs),", + "HSCs,", + "Kupffer", + "cells," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "quiescent", + "hepatic", + "stellate", + "cells", + "(HSCs),", + "HSCs,", + "Kupffer", + "cells,", + "HSCs", + "cells." + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Myd88-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "17906637", + "TEXT": "The latency of human immunodeficiency virus type 1 (HIV-1) in resting primary CD4+ T cells is the major barrier for the eradication of the virus in patients on suppressive highly active antiretroviral therapy (HAART). Even with optimal HAART treatment, replication-competent HIV-1 still exists in resting primary CD4+ T cells. Multiple restriction factors that act upon various steps of the viral life cycle could contribute to viral latency. Here we show that cellular microRNAs (miRNAs) potently inhibit HIV-1 production in resting primary CD4+ T cells. We have found that the 3' ends of HIV-1 messenger RNAs are targeted by a cluster of cellular miRNAs including miR-28, miR-125b, miR-150, miR-223 and miR-382, which are enriched in resting CD4+ T cells as compared to activated CD4+ T cells. Specific inhibitors of these miRNAs substantially counteracted their effects on the target mRNAs, measured either as HIV-1 protein translation in resting CD4+ T cells transfected with HIV-1 infectious clones, or as HIV-1 virus production from resting CD4+ T cells isolated from HIV-1-infected individuals on suppressive HAART. Our data indicate that cellular miRNAs are pivotal in HIV-1 latency and suggest that manipulation of cellular miRNAs could be a novel approach for purging the HIV-1 reservoir.", + "TAG_DATA": [ + "79, resting {'context': 'B-cells'}", + "80, primary {'context': 'I-cells'}", + "81, CD4+ {'context': 'I-cells'}", + "82, T {'context': 'I-cells'}", + "83, cells. {'context': 'I-cells'}", + "145, resting {'context': 'B-cells'}", + "146, CD4+ {'context': 'I-cells'}", + "147, T {'context': 'I-cells'}", + "148, cells {'context': 'I-cells'}", + "149, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "150, with {'perturbing_action': 'I-gene gain-of-function'}", + "151, HIV-1 {'perturbing_action': 'I-gene gain-of-function'}", + "152, infectious {'perturbing_action': 'I-gene gain-of-function'}", + "153, clones, {'perturbing_action': 'I-gene gain-of-function'}", + "160, resting {'context': 'B-cells'}", + "161, CD4+ {'context': 'I-cells'}", + "162, T {'context': 'I-cells'}", + "163, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "79, resting ['l0', 'l1', 'l2', 'l3']", + "80, primary ['l0', 'l4', 'l5', 'l6']", + "81, CD4+ ['l1', 'l4', 'l7', 'l8']", + "82, T ['l2', 'l5', 'l7', 'l9']", + "83, cells. ['l3', 'l6', 'l8', 'l9']", + "145, resting ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "146, CD4+ ['l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "147, T ['l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "148, cells ['l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "149, transfected ['l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "150, with ['l14', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "151, HIV-1 ['l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "152, infectious ['l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "153, clones, ['l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']", + "160, resting ['l46', 'l47', 'l48']", + "161, CD4+ ['l46', 'l49', 'l50']", + "162, T ['l47', 'l49', 'l51']", + "163, cells ['l48', 'l50', 'l51']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "resting", + "CD4+", + "T", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "HIV-1", + "infectious", + "clones," + ] + } + } + ] + }, + { + "PMID": "17906636", + "TEXT": "An association between inflammation and cancer has long been recognized, but the cause and effect relationship linking the two remains unclear. Myc is a pleiotropic transcription factor that is overexpressed in many human cancers and instructs many extracellular aspects of the tumor tissue phenotype, including remodeling of tumor stroma and angiogenesis. Here we show in a beta-cell tumor model that activation of Myc in vivo triggers rapid recruitment of mast cells to the tumor site-a recruitment that is absolutely required for macroscopic tumor expansion. In addition, treatment of established beta-cell tumors with a mast cell inhibitor rapidly triggers hypoxia and cell death of tumor and endothelial cells. Inhibitors of mast cell function may therefore prove therapeutically useful in restraining expansion and survival of pancreatic and other cancers.", + "TAG_DATA": [ + "56, beta-cell {'context': 'B-neoplasm'}", + "57, tumor {'context': 'I-neoplasm'}", + "58, model {'context': 'I-neoplasm'}", + "60, activation {'perturbing_action': 'B-pharmacological augmentation'}", + "61, of {'perturbing_action': 'I-pharmacological augmentation'}", + "62, Myc {'perturbing_action': 'I-pharmacological augmentation'}", + "63, in {'context': 'B-in vivo'}", + "64, vivo {'context': 'I-in vivo'}", + "89, beta-cell {'context': 'B-neoplasm'}", + "90, tumors {'context': 'I-neoplasm'}", + "93, mast {'perturbing_action': 'B-pharmacological inhibition'}", + "95, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "97, triggers {'effect': 'B-positive'}", + "100, cell {'phenotype': 'B-cell death'}", + "101, death {'phenotype': 'I-cell death'}", + "103, tumor {'context': 'B-neoplasm'}", + "105, endothelial {'context': 'B-cells'}", + "106, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "56, beta-cell ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "57, tumor ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "58, model ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "60, activation ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "61, of ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "62, Myc ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "63, in ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "64, vivo ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "89, beta-cell ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "90, tumors ['l28', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "93, mast ['l29', 'l38', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "94, cell ['l30', 'l39', 'l47', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "95, inhibitor ['l31', 'l40', 'l48', 'l55', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "97, triggers ['l32', 'l41', 'l49', 'l56', 'l62', 'l68', 'l69', 'l70', 'l71', 'l72']", + "100, cell ['l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l73', 'l74', 'l75', 'l76']", + "101, death ['l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l77', 'l78', 'l79']", + "103, tumor ['l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l80', 'l81']", + "105, endothelial ['l36', 'l45', 'l53', 'l60', 'l66', 'l71', 'l75', 'l78', 'l80', 'l82']", + "106, cells. ['l37', 'l46', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l81', 'l82']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "beta-cell", + "tumor", + "model" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "of", + "Myc" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "of", + "Myc" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "beta-cell", + "tumors", + "tumor" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mast", + "inhibitor" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "beta-cell", + "tumors", + "tumor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "beta-cell", + "tumors", + "tumor" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mast", + "inhibitor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mast", + "inhibitor" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mast", + "inhibitor" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells." + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells." + ] + } + } + ] + }, + { + "PMID": "17906635", + "TEXT": "Insulin resistance is often associated with obesity and can precipitate type 2 diabetes. To date, most known approaches that improve insulin resistance must be preceded by the amelioration of obesity and hepatosteatosis. Here, we show that this provision is not mandatory; insulin resistance and hyperglycemia are improved by the modification of hepatic fatty acid composition, even in the presence of persistent obesity and hepatosteatosis. Mice deficient for Elovl6, the gene encoding the elongase that catalyzes the conversion of palmitate to stearate, were generated and shown to become obese and develop hepatosteatosis when fed a high-fat diet or mated to leptin-deficient ob/ob mice. However, they showed marked protection from hyperinsulinemia, hyperglycemia and hyperleptinemia. Amelioration of insulin resistance was associated with restoration of hepatic insulin receptor substrate-2 and suppression of hepatic protein kinase C epsilon activity resulting in restoration of Akt phosphorylation. Collectively, these data show that hepatic fatty acid composition is a new determinant for insulin sensitivity that acts independently of cellular energy balance and stress. Inhibition of this elongase could be a new therapeutic approach for ameliorating insulin resistance, diabetes and cardiovascular risks, even in the presence of a continuing state of obesity.", + "TAG_DATA": [ + "64, Mice {'context': 'B-organism'}", + "65, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "66, for {'perturbing_action': 'I-gene loss-of-function'}", + "67, Elovl6, {'perturbing_action': 'I-gene loss-of-function'}", + "99, leptin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "100, ob/ob {'perturbing_action': 'B-gene loss-of-function'}", + "101, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "64, Mice ['l0', 'l1', 'l2']", + "65, deficient ['l0', 'l3', 'l4', 'l5', 'l6', 'l7']", + "66, for ['l1', 'l3', 'l8', 'l9', 'l10', 'l11']", + "67, Elovl6, ['l2', 'l4', 'l8', 'l12', 'l13', 'l14']", + "99, leptin-deficient ['l5', 'l9', 'l12', 'l15', 'l16']", + "100, ob/ob ['l6', 'l10', 'l13', 'l15', 'l17']", + "101, mice. ['l7', 'l11', 'l14', 'l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "Elovl6,", + "leptin-deficient", + "ob/ob" + ] + } + } + ] + }, + { + "PMID": "17721545", + "TEXT": "Dyslipidemia is associated with a prothrombotic phenotype; however, the mechanisms responsible for enhanced platelet reactivity remain unclear. Proatherosclerotic lipid abnormalities are associated with both enhanced oxidant stress and the generation of biologically active oxidized lipids, including potential ligands for the scavenger receptor CD36, a major platelet glycoprotein. Using multiple mouse in vivo thrombosis models, we now demonstrate that genetic deletion of Cd36 protects mice from hyperlipidemia-associated enhanced platelet reactivity and the accompanying prothrombotic phenotype. Structurally defined oxidized choline glycerophospholipids that serve as high-affinity ligands for CD36 were at markedly increased levels in the plasma of hyperlipidemic mice and in the plasma of humans with low HDL levels, were able to bind platelets via CD36 and, at pathophysiological levels, promoted platelet activation via CD36. Thus, interactions of platelet CD36 with specific endogenous oxidized lipids play a crucial role in the well-known clinical associations between dyslipidemia, oxidant stress and a prothrombotic phenotype.", + "TAG_DATA": [ + "49, mouse {'context': 'B-organism'}", + "50, in {'context': 'B-in vivo'}", + "58, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "59, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "60, of {'perturbing_action': 'I-gene loss-of-function'}", + "61, Cd36 {'perturbing_action': 'I-gene loss-of-function'}", + "63, mice {'context': 'B-organism'}", + "96, mice {'context': 'B-organism'}", + "111, platelets {'context': 'B-cells'}", + "119, platelet {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "49, mouse ['l0', 'l1', 'l2', 'l3', 'l4']", + "50, in ['l0', 'l5', 'l6']", + "51, vivo ['l1', 'l5', 'l7']", + "58, genetic ['l8', 'l9', 'l10', 'l11']", + "59, deletion ['l8', 'l12', 'l13', 'l14', 'l15']", + "60, of ['l2', 'l9', 'l12', 'l16', 'l17']", + "61, Cd36 ['l3', 'l6', 'l7', 'l10', 'l13', 'l16', 'l18']", + "63, mice ['l4', 'l11', 'l14', 'l17', 'l18']", + "96, mice ['l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "Cd36", + "genetic", + "deletion" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cd36" + ] + } + } + ] + }, + { + "PMID": "17694067", + "TEXT": "Transformation and cancer growth are regulated by the coordinate actions of oncogenes and tumor suppressors. Here, we show that the novel E3 ubiquitin ligase HACE1 is frequently downregulated in human tumors and maps to a region of chromosome 6q21 implicated in multiple human cancers. Genetic inactivation of HACE1 in mice results in the development of spontaneous, late-onset cancer. A second hit from either environmental triggers or genetic heterozygosity of another tumor suppressor, p53, markedly increased tumor incidence in a Hace1-deficient background. Re-expression of HACE1 in human tumor cells directly abrogates in vitro and in vivo tumor growth, whereas downregulation of HACE1 via siRNA allows non-tumorigenic human cells to form tumors in vivo. Mechanistically, the tumor-suppressor function of HACE1 is dependent on its E3 ligase activity and HACE1 controls adhesion-dependent growth and cell cycle progression during cell stress through degradation of cyclin D1. Thus, HACE1 is a candidate chromosome 6q21 tumor-suppressor gene involved in multiple cancers.", + "TAG_DATA": [ + "44, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "45, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "46, of {'perturbing_action': 'I-gene loss-of-function'}", + "47, HACE1 {'perturbing_action': 'I-gene loss-of-function'}", + "49, mice {'context': 'B-organism'}", + "57, cancer. {'phenotype': 'I-tumourigenesis'}", + "66, genetic {'perturbing_action': 'B-other'}", + "67, heterozygosity {'perturbing_action': 'I-other'}", + "68, of {'perturbing_action': 'I-other'}", + "69, another {'perturbing_action': 'I-other'}", + "70, tumor {'perturbing_action': 'I-other'}", + "71, suppressor, {'perturbing_action': 'I-other'}", + "72, p53, {'perturbing_action': 'I-other'}", + "74, increased {'effect': 'B-positive'}", + "75, tumor {'phenotype': 'B-tumourigenesis'}", + "76, incidence {'phenotype': 'I-tumourigenesis'}", + "79, Hace1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "81, Re-expression {'perturbing_action': 'B-gene gain-of-function'}", + "82, of {'perturbing_action': 'I-gene gain-of-function'}", + "83, HACE1 {'perturbing_action': 'I-gene gain-of-function'}", + "85, human {'context': 'B-transformed cells'}", + "86, tumor {'context': 'I-transformed cells'}", + "87, cells {'context': 'I-transformed cells'}", + "89, abrogates {'effect': 'B-negative'}", + "90, in {'context': 'B-in vitro'}", + "91, vitro {'context': 'I-in vitro'}", + "93, in {'context': 'B-in vivo'}", + "94, vivo {'context': 'I-in vivo'}", + "95, tumor {'phenotype': 'B-tumour growth'}", + "96, growth, {'phenotype': 'I-tumour growth'}", + "98, downregulation {'perturbing_action': 'B-rnai/knockdown'}", + "99, of {'perturbing_action': 'I-rnai/knockdown'}", + "100, HACE1 {'perturbing_action': 'I-rnai/knockdown'}", + "101, via {'perturbing_action': 'I-rnai/knockdown'}", + "102, siRNA {'perturbing_action': 'I-rnai/knockdown'}", + "103, allows {'effect': 'B-positive'}", + "104, non-tumorigenic {'context': 'B-cells'}", + "105, human {'context': 'I-cells'}", + "106, cells {'context': 'I-cells'}", + "108, form {'phenotype': 'B-tumourigenesis'}", + "109, tumors {'phenotype': 'B-tumourigenesis'}", + "110, in {'context': 'B-in vivo'}", + "111, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "44, Genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "45, inactivation ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "46, of ['l1', 'l12', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "47, HACE1 ['l2', 'l13', 'l26', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "49, mice ['l3', 'l14', 'l27', 'l37', 'l47', 'l48', 'l49', 'l50']", + "57, cancer. ['l4', 'l15', 'l28', 'l38', 'l47']", + "66, genetic ['l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "67, heterozygosity ['l51', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "68, of ['l52', 'l74', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "69, another ['l53', 'l75', 'l96', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "70, tumor ['l54', 'l76', 'l97', 'l117', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "71, suppressor, ['l55', 'l77', 'l98', 'l118', 'l137', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "72, p53, ['l16', 'l56', 'l78', 'l99', 'l119', 'l138', 'l156', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190']", + "74, increased ['l5', 'l17', 'l29', 'l39', 'l48', 'l57', 'l79', 'l100', 'l120', 'l139', 'l157', 'l174', 'l191', 'l192', 'l193', 'l194', 'l195']", + "75, tumor ['l6', 'l18', 'l30', 'l40', 'l49', 'l58', 'l80', 'l101', 'l121', 'l140', 'l158', 'l175', 'l191', 'l196', 'l197', 'l198']", + "76, incidence ['l7', 'l19', 'l31', 'l41', 'l50', 'l59', 'l81', 'l102', 'l122', 'l141', 'l159', 'l176', 'l192', 'l196', 'l199']", + "79, Hace1-deficient ['l8', 'l20', 'l32', 'l42', 'l60', 'l82', 'l103', 'l123', 'l142', 'l160', 'l177', 'l193', 'l197', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206']", + "81, Re-expression ['l61', 'l83', 'l104', 'l124', 'l143', 'l161', 'l178', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218']", + "82, of ['l62', 'l84', 'l105', 'l125', 'l144', 'l162', 'l179', 'l207', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229']", + "83, HACE1 ['l63', 'l85', 'l106', 'l126', 'l145', 'l163', 'l180', 'l208', 'l219', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239']", + "85, human ['l9', 'l21', 'l33', 'l43', 'l64', 'l86', 'l107', 'l127', 'l146', 'l164', 'l181', 'l194', 'l200', 'l209', 'l220', 'l230', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248']", + "86, tumor ['l10', 'l22', 'l34', 'l44', 'l65', 'l87', 'l108', 'l128', 'l147', 'l165', 'l182', 'l201', 'l210', 'l221', 'l231', 'l240', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256']", + "87, cells ['l11', 'l23', 'l35', 'l45', 'l66', 'l88', 'l109', 'l129', 'l148', 'l166', 'l183', 'l195', 'l198', 'l202', 'l211', 'l222', 'l232', 'l241', 'l249', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263']", + "89, abrogates ['l24', 'l67', 'l89', 'l110', 'l130', 'l149', 'l167', 'l184', 'l203', 'l212', 'l223', 'l233', 'l242', 'l250', 'l257', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269']", + "90, in ['l68', 'l90', 'l111', 'l131', 'l150', 'l168', 'l185', 'l213', 'l224', 'l234', 'l243', 'l251', 'l258', 'l264', 'l270', 'l271', 'l272', 'l273', 'l274']", + "91, vitro ['l69', 'l91', 'l112', 'l132', 'l151', 'l169', 'l186', 'l204', 'l214', 'l225', 'l235', 'l244', 'l252', 'l259', 'l265', 'l270', 'l275', 'l276', 'l277', 'l278']", + "93, in ['l70', 'l92', 'l113', 'l133', 'l152', 'l170', 'l187', 'l215', 'l226', 'l236', 'l245', 'l253', 'l260', 'l266', 'l271', 'l275', 'l279', 'l280', 'l281']", + "94, vivo ['l71', 'l93', 'l114', 'l134', 'l153', 'l171', 'l188', 'l216', 'l227', 'l237', 'l246', 'l254', 'l261', 'l267', 'l272', 'l276', 'l279', 'l282', 'l283']", + "95, tumor ['l72', 'l94', 'l115', 'l135', 'l154', 'l172', 'l189', 'l205', 'l217', 'l228', 'l238', 'l247', 'l255', 'l262', 'l268', 'l273', 'l277', 'l280', 'l282', 'l284']", + "96, growth, ['l25', 'l36', 'l46', 'l73', 'l95', 'l116', 'l136', 'l155', 'l173', 'l190', 'l206', 'l218', 'l229', 'l239', 'l248', 'l256', 'l263', 'l269', 'l274', 'l278', 'l281', 'l283', 'l284']", + "98, downregulation ['l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296']", + "99, of ['l285', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304', 'l305', 'l306', 'l307']", + "100, HACE1 ['l286', 'l297', 'l308', 'l309', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315', 'l316', 'l317']", + "101, via ['l287', 'l298', 'l308', 'l318', 'l319', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326']", + "102, siRNA ['l288', 'l299', 'l309', 'l318', 'l327', 'l328', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334']", + "103, allows ['l289', 'l300', 'l310', 'l319', 'l327', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340', 'l341']", + "104, non-tumorigenic ['l290', 'l301', 'l311', 'l320', 'l328', 'l335', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347']", + "105, human ['l291', 'l302', 'l312', 'l321', 'l329', 'l336', 'l342', 'l348', 'l349', 'l350', 'l351', 'l352']", + "106, cells ['l292', 'l303', 'l313', 'l322', 'l330', 'l337', 'l343', 'l348', 'l353', 'l354', 'l355', 'l356']", + "108, form ['l293', 'l304', 'l314', 'l323', 'l331', 'l338', 'l344', 'l349', 'l353', 'l357', 'l358', 'l359']", + "109, tumors ['l294', 'l305', 'l315', 'l324', 'l332', 'l339', 'l345', 'l350', 'l354', 'l357', 'l360', 'l361']", + "110, in ['l295', 'l306', 'l316', 'l325', 'l333', 'l340', 'l346', 'l351', 'l355', 'l358', 'l360', 'l362']", + "111, vivo. ['l296', 'l307', 'l317', 'l326', 'l334', 'l341', 'l347', 'l352', 'l356', 'l359', 'l361', 'l362']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "inactivation", + "of", + "HACE1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "inactivation", + "of", + "HACE1", + "Hace1-deficient" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "cancer.", + "tumor", + "incidence" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "inactivation", + "of", + "HACE1", + "Hace1-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "inactivation", + "of", + "HACE1", + "Hace1-deficient" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "Hace1-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "HACE1", + "Hace1-deficient" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth,", + "tumor" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "cancer.", + "tumor", + "incidence" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetic", + "heterozygosity", + "of", + "another", + "tumor", + "suppressor,", + "p53," + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetic", + "heterozygosity", + "of", + "another", + "tumor", + "suppressor,", + "p53," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "incidence" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetic", + "heterozygosity", + "of", + "another", + "tumor", + "suppressor,", + "p53," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetic", + "heterozygosity", + "of", + "another", + "tumor", + "suppressor,", + "p53," + ] + }, + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetic", + "heterozygosity", + "of", + "another", + "tumor", + "suppressor,", + "p53," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetic", + "heterozygosity", + "of", + "another", + "tumor", + "suppressor,", + "p53," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetic", + "heterozygosity", + "of", + "another", + "tumor", + "suppressor,", + "p53," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased", + "allows" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "incidence", + "form", + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "cells" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hace1-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Re-expression", + "of", + "HACE1" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Re-expression", + "of", + "HACE1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Re-expression", + "of", + "HACE1" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Re-expression", + "of", + "HACE1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Re-expression", + "of", + "HACE1" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "tumor", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "tumor", + "cells" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth," + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "downregulation", + "of", + "HACE1", + "via", + "siRNA" + ] + }, + "effect": { + "val": "positive", + "words": [ + "allows" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "downregulation", + "of", + "HACE1", + "via", + "siRNA" + ] + }, + "context": { + "val": "cells", + "words": [ + "non-tumorigenic", + "human", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "downregulation", + "of", + "HACE1", + "via", + "siRNA" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "downregulation", + "of", + "HACE1", + "via", + "siRNA" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "allows" + ] + }, + "context": { + "val": "cells", + "words": [ + "non-tumorigenic", + "human", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "allows" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "non-tumorigenic", + "human", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumors" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "17603492", + "TEXT": "The relationship between stress and obesity remains elusive. In response to stress, some people lose weight, whereas others gain. Here we report that stress exaggerates diet-induced obesity through a peripheral mechanism in the abdominal white adipose tissue that is mediated by neuropeptide Y (NPY). Stressors such as exposure to cold or aggression lead to the release of NPY from sympathetic nerves, which in turn upregulates NPY and its Y2 receptors (NPY2R) in a glucocorticoid-dependent manner in the abdominal fat. This positive feedback response by NPY leads to the growth of abdominal fat. Release of NPY and activation of NPY2R stimulates fat angiogenesis, macrophage infiltration, and the proliferation and differentiation of new adipocytes, resulting in abdominal obesity and a metabolic syndrome-like condition. NPY, like stress, stimulates mouse and human fat growth, whereas pharmacological inhibition or fat-targeted knockdown of NPY2R is anti-angiogenic and anti-adipogenic, while reducing abdominal obesity and metabolic abnormalities. Thus, manipulations of NPY2R activity within fat tissue offer new ways to remodel fat and treat obesity and metabolic syndrome.", + "TAG_DATA": [ + "99, stimulates {'effect': 'B-positive'}", + "106, proliferation {'phenotype': 'B-proliferation'}", + "108, differentiation {'phenotype': 'B-differentiation'}", + "110, new {'context': 'B-cells'}", + "111, adipocytes, {'context': 'I-cells'}", + "125, mouse {'context': 'B-tissue/organ'}", + "126, and {'context': 'I-tissue/organ'}", + "127, human {'context': 'I-tissue/organ'}", + "134, fat-targeted {'perturbing_action': 'B-rnai/knockdown'}", + "135, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "136, of {'perturbing_action': 'I-rnai/knockdown'}", + "137, NPY2R {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "99, stimulates ['l0', 'l1', 'l2', 'l3']", + "106, proliferation ['l0', 'l4', 'l5', 'l6']", + "108, differentiation ['l1', 'l4', 'l7', 'l8']", + "110, new ['l2', 'l5', 'l7', 'l9']", + "111, adipocytes, ['l3', 'l6', 'l8', 'l9']", + "125, mouse ['l10', 'l11']", + "126, and ['l10', 'l12']", + "127, human ['l11', 'l12']", + "134, fat-targeted ['l13', 'l14', 'l15']", + "135, knockdown ['l13', 'l16', 'l17']", + "136, of ['l14', 'l16', 'l18']", + "137, NPY2R ['l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "context": { + "val": "cells", + "words": [ + "new", + "adipocytes," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "new", + "adipocytes," + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "new", + "adipocytes," + ] + } + } + ] + }, + { + "PMID": "17515894", + "TEXT": "Loss of cone function in the central retina is a pivotal event in the development of severe vision impairment for many prevalent blinding diseases. Complete achromatopsia is a genetic defect resulting in cone vision loss in 1 in 30,000 individuals. Using adeno-associated virus (AAV) gene therapy, we show that it is possible to target cones and rescue both the cone-mediated electroretinogram response and visual acuity in the Gnat2 ( cpfl3 ) mouse model of achromatopsia.", + "TAG_DATA": [ + "54, cones {'context': 'B-cells'}", + "56, rescue {'effect': 'B-rescues'}", + "67, Gnat2 {'perturbing_action': 'B-other'}", + "68, ( {'perturbing_action': 'I-other'}", + "69, cpfl3 {'perturbing_action': 'I-other'}", + "70, ) {'perturbing_action': 'I-other'}", + "71, mouse {'context': 'B-organism'}", + "72, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "54, cones ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "56, rescue ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "67, Gnat2 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "68, ( ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "69, cpfl3 ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "70, ) ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "71, mouse ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "72, model ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cones" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescue" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cones" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Gnat2", + "(", + "cpfl3", + ")" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescue" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Gnat2", + "(", + "cpfl3", + ")" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescue" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Gnat2", + "(", + "cpfl3", + ")" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + } + ] + }, + { + "PMID": "17496901", + "TEXT": "We analyzed the PI3K-AKT signaling cascade in a cohort of sarcomas and found a marked induction of insulin receptor substrate-2 (IRS2) and phosphorylated AKT and a concomitant upregulation of downstream effectors in most leiomyosarcomas. To determine the role of aberrant PI3K-AKT signaling in leiomyosarcoma pathogenesis, we genetically inactivated Pten in the smooth muscle cell lineage by cross-breeding Pten(loxP/loxP) mice with Tagln-cre mice. Mice carrying homozygous deletion of Pten alleles developed widespread smooth muscle cell hyperplasia and abdominal leiomyosarcomas, with a very rapid onset and elevated incidence (approximately 80%) compared to other animal models. Constitutive mTOR activation was restricted to the leiomyosarcomas, revealing the requirement for additional molecular events besides Pten loss. The rapamycin derivative everolimus substantially decelerated tumor growth on Tagln-cre/Pten(loxP/loxP) mice and prolonged their lifespan. Our data show a new and critical role for the AKT-mTOR pathway in smooth muscle transformation and leiomyosarcoma genesis, and support treatment of selected sarcomas by the targeting of this pathway with new compounds or combinations of these with conventional chemotherapy agents.", + "TAG_DATA": [ + "46, genetically {'perturbing_action': 'B-gene loss-of-function'}", + "47, inactivated {'perturbing_action': 'I-gene loss-of-function'}", + "48, Pten {'perturbing_action': 'I-gene loss-of-function'}", + "51, smooth {'context': 'B-cells'}", + "52, muscle {'context': 'I-cells'}", + "53, cell {'context': 'I-cells'}", + "54, lineage {'context': 'I-cells'}", + "58, mice {'context': 'B-organism'}", + "62, Mice {'context': 'B-organism'}", + "64, homozygous {'perturbing_action': 'B-gene loss-of-function'}", + "65, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "66, of {'perturbing_action': 'I-gene loss-of-function'}", + "67, Pten {'perturbing_action': 'I-gene loss-of-function'}", + "68, alleles {'perturbing_action': 'I-gene loss-of-function'}", + "71, smooth {'context': 'B-cells'}", + "72, muscle {'context': 'I-cells'}", + "73, cell {'context': 'I-cells'}", + "77, leiomyosarcomas, {'phenotype': 'I-tumourigenesis'}", + "100, leiomyosarcomas, {'context': 'B-neoplasm'}", + "116, decelerated {'effect': 'B-negative'}", + "117, tumor {'phenotype': 'B-tumour growth'}", + "118, growth {'phenotype': 'I-tumour growth'}", + "120, Tagln-cre/Pten(loxP/loxP) {'perturbing_action': 'B-other'}", + "121, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "46, genetically ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "47, inactivated ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "48, Pten ['l1', 'l10', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "51, smooth ['l2', 'l11', 'l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "52, muscle ['l3', 'l12', 'l21', 'l29', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "53, cell ['l4', 'l13', 'l22', 'l30', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "54, lineage ['l5', 'l14', 'l23', 'l31', 'l37', 'l42', 'l47', 'l48', 'l49', 'l50']", + "58, mice ['l6', 'l15', 'l24', 'l32', 'l38', 'l43', 'l47', 'l51', 'l52', 'l53', 'l54', 'l55']", + "62, Mice ['l51', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "64, homozygous ['l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "65, deletion ['l56', 'l64', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "66, of ['l57', 'l65', 'l73', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "67, Pten ['l58', 'l66', 'l74', 'l81', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "68, alleles ['l59', 'l67', 'l75', 'l82', 'l88', 'l94', 'l95', 'l96', 'l97', 'l98']", + "71, smooth ['l7', 'l16', 'l25', 'l33', 'l39', 'l44', 'l48', 'l52', 'l60', 'l68', 'l76', 'l83', 'l89', 'l94', 'l99', 'l100', 'l101']", + "72, muscle ['l8', 'l17', 'l26', 'l34', 'l40', 'l45', 'l49', 'l53', 'l61', 'l69', 'l77', 'l84', 'l90', 'l95', 'l99', 'l102', 'l103']", + "73, cell ['l9', 'l18', 'l27', 'l35', 'l41', 'l46', 'l50', 'l54', 'l62', 'l70', 'l78', 'l85', 'l91', 'l96', 'l100', 'l102', 'l104']", + "77, leiomyosarcomas, ['l19', 'l28', 'l55', 'l63', 'l71', 'l79', 'l86', 'l92', 'l97', 'l101', 'l103', 'l104']", + "100, leiomyosarcomas, ['l72', 'l80', 'l87', 'l93', 'l98']", + "116, decelerated ['l105', 'l106', 'l107', 'l108']", + "117, tumor ['l105', 'l109', 'l110', 'l111']", + "118, growth ['l106', 'l109', 'l112', 'l113']", + "120, Tagln-cre/Pten(loxP/loxP) ['l107', 'l110', 'l112', 'l114']", + "121, mice ['l108', 'l111', 'l113', 'l114']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetically", + "inactivated", + "Pten", + "homozygous", + "deletion", + "of", + "alleles" + ] + }, + "context": { + "val": "cells", + "words": [ + "smooth", + "muscle", + "cell", + "lineage" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetically", + "inactivated", + "Pten", + "deletion", + "of", + "alleles" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "Mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivated", + "Pten", + "homozygous", + "deletion", + "of", + "alleles" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leiomyosarcomas," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "Mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leiomyosarcomas," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "homozygous", + "deletion", + "of", + "Pten", + "alleles" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leiomyosarcomas," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "smooth", + "muscle", + "cell" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leiomyosarcomas," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decelerated" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decelerated" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Tagln-cre/Pten(loxP/loxP)" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decelerated" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Tagln-cre/Pten(loxP/loxP)" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Tagln-cre/Pten(loxP/loxP)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "17496900", + "TEXT": "T-helper type 17 cells (T(H)17) are implicated in rodent models of immune-mediated diseases. Here we report their involvement in human uveitis and scleritis, and validate our findings in experimental autoimmune uveoretinitis (EAU), a model of uveitis. T(H)17 cells were present in human peripheral blood mononuclear cells (PBMC), and were expanded by interleukin (IL)-2 and inhibited by interferon (IFN)-gamma. Their numbers increased during active uveitis and scleritis and decreased following treatment. IL-17 was elevated in EAU and upregulated tumor necrosis factor (TNF)-alpha in retinal cells, suggesting a mechanism by which T(H)17 may contribute to ocular pathology. Furthermore, IL-27 was constitutively expressed in retinal ganglion and photoreceptor cells, was upregulated by IFN-gamma and inhibited proliferation of T(H)17. These findings suggest that T(H)1 cells may mitigate uveitis by antagonizing the T(H)17 phenotype through the IFN-gamma-mediated induction of IL-27 in target tissue. The finding that IL-2 promotes T(H)17 expansion provides explanations for the efficacy of IL-2R antibody therapy in uveitis, and suggests that antagonism of T(H)17 by IFN-gamma and/or IL-27 could be used for the treatment of chronic inflammation.", + "TAG_DATA": [ + "36, T(H)17 {'context': 'B-cells'}", + "37, cells {'context': 'I-cells'}", + "41, human {'context': 'B-cells'}", + "42, peripheral {'context': 'I-cells'}", + "43, blood {'context': 'I-cells'}", + "44, mononuclear {'context': 'I-cells'}", + "45, cells {'context': 'I-cells'}", + "46, (PBMC), {'context': 'I-cells'}", + "82, retinal {'context': 'B-cells'}", + "83, cells, {'context': 'I-cells'}", + "101, retinal {'context': 'B-cells'}", + "102, ganglion {'context': 'I-cells'}", + "103, and {'context': 'I-cells'}", + "104, photoreceptor {'context': 'I-cells'}", + "105, cells, {'context': 'I-cells'}", + "111, inhibited {'effect': 'B-negative'}", + "112, proliferation {'phenotype': 'B-proliferation'}", + "114, T(H)17. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "36, T(H)17 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "37, cells ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "41, human ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "42, peripheral ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "43, blood ['l3', 'l10', 'l16', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "44, mononuclear ['l4', 'l11', 'l17', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "45, cells ['l5', 'l12', 'l18', 'l23', 'l28', 'l32', 'l36', 'l37']", + "46, (PBMC), ['l6', 'l13', 'l19', 'l24', 'l29', 'l33', 'l36', 'l38', 'l39']", + "82, retinal ['l25', 'l30', 'l34', 'l38', 'l40', 'l41', 'l42', 'l43']", + "83, cells, ['l7', 'l14', 'l20', 'l26', 'l31', 'l35', 'l37', 'l39', 'l40']", + "101, retinal ['l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "102, ganglion ['l41', 'l44', 'l51', 'l52', 'l53', 'l54', 'l55']", + "103, and ['l42', 'l45', 'l51', 'l56', 'l57', 'l58', 'l59', 'l60']", + "104, photoreceptor ['l46', 'l52', 'l56', 'l61', 'l62', 'l63', 'l64']", + "105, cells, ['l43', 'l47', 'l53', 'l57', 'l61', 'l65']", + "111, inhibited ['l48', 'l54', 'l58', 'l62', 'l66', 'l67']", + "112, proliferation ['l49', 'l59', 'l63', 'l66', 'l68']", + "114, T(H)17. ['l50', 'l55', 'l60', 'l64', 'l65', 'l67', 'l68']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "retinal", + "ganglion", + "and", + "photoreceptor", + "T(H)17." + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "retinal", + "and", + "photoreceptor", + "T(H)17." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "17334372", + "TEXT": "Motor neuron degeneration resulting from the aggregation of the androgen receptor with an expanded polyglutamine tract (AR-polyQ) has been linked to the development of spinal and bulbar muscular atrophy (SBMA or Kennedy disease). Here we report that adding 5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one (ASC-J9) disrupts the interaction between AR and its coregulators, and also increases cell survival by decreasing AR-polyQ nuclear aggregation and increasing AR-polyQ degradation in cultured cells. Intraperitoneal injection of ASC-J9 into AR-polyQ transgenic SBMA mice markedly improved disease symptoms, as seen by a reduction in muscular atrophy. Notably, unlike previous approaches in which surgical or chemical castration was used to reduce SBMA symptoms, ASC-J9 treatment ameliorated SBMA symptoms by decreasing AR-97Q aggregation and increasing VEGF164 expression with little change of serum testosterone. Moreover, mice treated with ASC-J9 retained normal sexual function and fertility. Collectively, our results point to a better therapeutic and preventative approach to treating SBMA, by disrupting the interaction between AR and AR coregulators.", + "TAG_DATA": [ + "50, increases {'effect': 'B-positive'}", + "51, cell {'phenotype': 'B-cell survival'}", + "52, survival {'phenotype': 'I-cell survival'}", + "63, cultured {'context': 'B-cells'}", + "64, cells. {'context': 'I-cells'}", + "70, AR-polyQ {'perturbing_action': 'B-gene gain-of-function'}", + "71, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "72, SBMA {'context': 'B-organism'}", + "73, mice {'context': 'I-organism'}", + "122, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, increases ['l0', 'l1', 'l2', 'l3']", + "51, cell ['l0', 'l4', 'l5', 'l6']", + "52, survival ['l1', 'l4', 'l7', 'l8']", + "63, cultured ['l2', 'l5', 'l7', 'l9']", + "64, cells. ['l3', 'l6', 'l8', 'l9']", + "70, AR-polyQ ['l10', 'l11', 'l12']", + "71, transgenic ['l10', 'l13', 'l14']", + "72, SBMA ['l11', 'l13', 'l15']", + "73, mice ['l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "survival" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "cells." + ] + } + }, + { + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "survival" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "AR-polyQ", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "SBMA", + "mice" + ] + } + } + ] + }, + { + "PMID": "17143276", + "TEXT": "Regulatory CD4(+)CD25(+) T cells are important in suppressing immune responses. The requirements for the maintenance of peripheral CD4(+)CD25(+) T cells remain incompletely understood. Receptor activator of NF-kappaB (RANK) and its ligand (RANKL; also known as CD254, OPGL and TRANCE) are key regulators of bone remodeling, mammary gland formation, lymph node development and T-cell/dendritic cell communication. Here we report that RANKL is expressed in keratinocytes of the inflamed skin. RANKL overexpression in keratinocytes resulted in functional alterations of epidermal dendritic cells and systemic increases of regulatory CD4(+)CD25(+) T cells. Thus, epidermal RANKL expression can change dendritic cell functions to maintain the number of peripheral CD4(+)CD25(+) regulatory T cells. Epidermal RANKL mediated ultraviolet-induced immunosuppression and overexpression of epidermal RANKL suppressed allergic contact hypersensitivity responses and the development of systemic autoimmunity. Therefore, environmental stimuli at the skin can rewire the local and systemic immune system by means of RANKL.", + "TAG_DATA": [ + "68, RANKL {'perturbing_action': 'B-gene gain-of-function'}", + "69, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "71, keratinocytes {'context': 'B-cells'}", + "77, epidermal {'context': 'B-cells'}", + "78, dendritic {'context': 'I-cells'}", + "79, cells {'context': 'I-cells'}", + "113, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "114, of {'perturbing_action': 'I-gene gain-of-function'}", + "115, epidermal {'perturbing_action': 'I-gene gain-of-function'}", + "116, RANKL {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "68, RANKL ['l0', 'l1', 'l2', 'l3', 'l4']", + "69, overexpression ['l0', 'l5', 'l6', 'l7', 'l8']", + "71, keratinocytes ['l1', 'l5', 'l9', 'l10', 'l11']", + "77, epidermal ['l2', 'l6', 'l9', 'l12', 'l13']", + "78, dendritic ['l3', 'l7', 'l10', 'l12', 'l14']", + "79, cells ['l4', 'l8', 'l11', 'l13', 'l14']", + "113, overexpression ['l15', 'l16', 'l17']", + "114, of ['l15', 'l18', 'l19']", + "115, epidermal ['l16', 'l18', 'l20']", + "116, RANKL ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "RANKL", + "overexpression" + ] + }, + "context": { + "val": "cells", + "words": [ + "keratinocytes", + "epidermal", + "dendritic", + "cells" + ] + } + } + ] + }, + { + "PMID": "17099710", + "TEXT": "The role of nitric oxide (NO) in the genesis of cerebral malaria is controversial. Most investigators propose that the unfortunate consequence of the high concentrations of NO produced to kill the parasite is the development of cerebral malaria. Here we have tested this high NO bioavailability hypothesis in the setting of experimental cerebral malaria (ECM), but find instead that low NO bioavailability contributes to the genesis of ECM. Specifically, mice deficient in vascular NO synthase showed parasitemia and mortality similar to that observed in control mice. Exogenous NO did not affect parasitemia but provided marked protection against ECM; in fact, mice treated with exogenous NO were clinically indistinguishable from uninfected mice at a stage when control infected mice were moribund. Administration of exogenous NO restored NO-mediated signaling in the brain, decreased proinflammatory biomarkers in the blood, and markedly reduced vascular leak and petechial hemorrhage into the brain. Low NO bioavailability in the vasculature during ECM was caused in part by an increase in NO-scavenging free hemoglobin in the blood, by hypoargininemia, and by low blood and erythrocyte nitrite concentrations. Exogenous NO inactivated NO-scavenging free hemoglobin in the plasma and restored nitrite to concentrations observed in uninfected mice. We therefore conclude that low rather than high NO bioavailability contributes to the genesis of ECM.", + "TAG_DATA": [ + "69, mice {'context': 'B-organism'}", + "71, in {'perturbing_action': 'I-gene loss-of-function'}", + "72, vascular {'perturbing_action': 'I-gene loss-of-function'}", + "73, NO {'perturbing_action': 'I-gene loss-of-function'}", + "74, synthase {'perturbing_action': 'I-gene loss-of-function'}", + "100, mice {'context': 'B-organism'}", + "110, mice {'context': 'B-organism'}", + "117, mice {'context': 'B-organism'}", + "129, brain, {'context': 'B-tissue/organ'}", + "196, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "69, mice ['l0', 'l1', 'l2', 'l3']", + "71, in ['l0', 'l4', 'l5', 'l6', 'l7', 'l8']", + "72, vascular ['l1', 'l4', 'l9', 'l10', 'l11', 'l12']", + "73, NO ['l2', 'l5', 'l9', 'l13', 'l14', 'l15', 'l16']", + "74, synthase ['l3', 'l6', 'l10', 'l13', 'l17', 'l18', 'l19', 'l20']", + "100, mice ['l14', 'l17', 'l21', 'l22', 'l23']", + "110, mice ['l7', 'l11', 'l15', 'l18', 'l21', 'l24', 'l25']", + "117, mice ['l19', 'l22', 'l24', 'l26']", + "129, brain, ['l8', 'l12', 'l16', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "in", + "vascular", + "NO", + "synthase" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "in", + "vascular", + "NO", + "synthase" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain," + ] + } + } + ] + }, + { + "PMID": "17013385", + "TEXT": "Currently available methods for detection of tumors in vivo such as computed tomography and magnetic resonance imaging are not specific for tumors. Here we describe a new approach for visualizing tumors whose fluorescence can be detected using telomerase-specific replication-competent adenovirus expressing green fluorescent protein (GFP) (OBP-401). OBP-401 contains the replication cassette, in which the human telomerase reverse transcriptase (hTERT) promoter drives expression of E1 genes, and the GFP gene for monitoring viral replication. When OBP-401 was intratumorally injected into HT29 tumors orthotopically implanted into the rectum in BALB/c nu/nu mice, para-aortic lymph node metastasis could be visualized at laparotomy under a three-chip color cooled charged-coupled device camera. Our results indicate that OBP-401 causes viral spread into the regional lymphatic area and selectively replicates in neoplastic lesions, resulting in GFP expression in metastatic lymph nodes. This technology is adaptable to detect lymph node metastasis in vivo as a preclinical model of surgical navigation.", + "TAG_DATA": [ + "79, HT29 {'context': 'B-neoplasm'}", + "80, tumors {'context': 'I-neoplasm'}", + "87, BALB/c {'perturbing_action': 'B-other'}", + "88, nu/nu {'perturbing_action': 'B-other'}", + "89, mice, {'context': 'B-organism'}", + "90, para-aortic {'context': 'B-tissue/organ', 'phenotype': 'B-metastasis'}", + "91, lymph {'phenotype': 'I-metastasis'}", + "92, node {'phenotype': 'I-metastasis'}", + "93, metastasis {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "79, HT29 ['l0']", + "80, tumors ['l0']", + "87, BALB/c ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "88, nu/nu ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "89, mice, ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "90, para-aortic ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "91, lymph ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "92, node ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "93, metastasis ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "96, visualized ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "BALB/c", + "nu/nu" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BALB/c", + "nu/nu" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "para-aortic" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BALB/c", + "nu/nu" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "para-aortic", + "lymph", + "node", + "metastasis" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "para-aortic" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "para-aortic" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "para-aortic", + "lymph", + "node", + "metastasis" + ] + } + } + ] + }, + { + "PMID": "16892039", + "TEXT": "Demyelination is a common pathologic feature in many neurodegenerative diseases including infection with leprosy-causing Mycobacterium leprae. Because of the long incubation time and highly complex disease pathogenesis, the management of nerve damage in leprosy, as in other demyelinating diseases, is extremely difficult. Therefore, an important challenge in therapeutic interventions is to identify the molecular events that occur in the early phase before the progression of the disease. Here we provide evidence that M. leprae-induced demyelination is a result of direct bacterial ligation to and activation of ErbB2 receptor tyrosine kinase (RTK) signaling without ErbB2-ErbB3 heterodimerization, a previously unknown mechanism that bypasses the neuregulin-ErbB3-mediated ErbB2 phosphorylation. MEK-dependent Erk1 and Erk2 (hereafter referred to as Erk1/2) signaling is identified as a downstream target of M. leprae-induced ErbB2 activation that mediates demyelination. Herceptin (trastuzumab), a therapeutic humanized ErbB2-specific antibody, inhibits M. leprae binding to and activation of ErbB2 and Erk1/2 in human primary Schwann cells, and the blockade of ErbB2 activity by the small molecule dual ErbB1-ErbB2 kinase inhibitor PKI-166 (ref. 11) effectively abrogates M. leprae-induced myelin damage in in vitro and in vivo models. These results may have implications for the design of ErbB2 RTK-based therapies for both leprosy nerve damage and other demyelinating neurodegenerative diseases.", + "TAG_DATA": [ + "148, human {'context': 'B-cells'}", + "149, primary {'context': 'I-cells'}", + "150, Schwann {'context': 'I-cells'}", + "151, cells, {'context': 'I-cells'}", + "164, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "165, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "166, PKI-166 {'perturbing_action': 'I-pharmacological inhibition'}", + "176, in {'context': 'B-in vitro'}", + "177, vitro {'context': 'I-in vitro'}", + "179, in {'context': 'B-in vivo'}", + "180, vivo {'context': 'I-in vivo'}", + "181, models. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "148, human ['l0', 'l1', 'l2']", + "149, primary ['l0', 'l3', 'l4']", + "150, Schwann ['l1', 'l3', 'l5']", + "151, cells, ['l2', 'l4', 'l5']", + "163, ErbB1-ErbB2 ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "164, kinase ['l6', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "165, inhibitor ['l7', 'l14', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "166, PKI-166 ['l8', 'l15', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "176, in ['l9', 'l16', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "177, vitro ['l10', 'l17', 'l23', 'l28', 'l32', 'l36', 'l37', 'l38']", + "179, in ['l11', 'l18', 'l24', 'l29', 'l33', 'l36', 'l39', 'l40']", + "180, vivo ['l12', 'l19', 'l25', 'l30', 'l34', 'l37', 'l39', 'l41']", + "181, models. ['l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "kinase", + "inhibitor", + "PKI-166" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "kinase", + "inhibitor", + "PKI-166" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "models." + ] + } + } + ] + }, + { + "PMID": "16892037", + "TEXT": "The t(8;21)(q22;q22) translocation is one of the most common genetic abnormalities in acute myeloid leukemia (AML), identified in 15% of all cases of AML, including 40-50% of FAB M2 subtype and rare cases of M0, M1 and M4 subtypes. The most commonly known AML1-ETO fusion protein (full-length AML1-ETO) from this translocation has 752 amino acids and contains the N-terminal portion of RUNX1 (also known as AML1, CBFalpha2 or PEBP2alphaB), including its DNA binding domain, and almost the entire RUNX1T1 (also known as MTG8 or ETO) protein. Although alterations of gene expression and hematopoietic cell proliferation have been reported in the presence of AML1-ETO, its expression does not lead to the development of leukemia. Here, we report the identification of a previously unknown alternatively spliced isoform of the AML1-ETO transcript, AML1-ETO9a, that includes an extra exon, exon 9a, of the ETO gene. AML1-ETO9a encodes a C-terminally truncated AML1-ETO protein of 575 amino acids. Expression of AML1-ETO9a leads to rapid development of leukemia in a mouse retroviral transduction-transplantation model. More importantly, coexpression of AML1-ETO and AML1-ETO9a results in the substantially earlier onset of AML and blocks myeloid cell differentiation at a more immature stage. These results indicate that fusion proteins from alternatively spliced isoforms of a chromosomal translocation may work together to induce cancer development.", + "TAG_DATA": [ + "152, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "153, of {'perturbing_action': 'I-gene gain-of-function'}", + "154, AML1-ETO9a {'perturbing_action': 'I-gene gain-of-function'}", + "155, leads {'effect': 'B-positive'}", + "156, to {'effect': 'I-positive'}", + "160, leukemia {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}", + "163, mouse {'context': 'B-organism'}", + "164, retroviral {'context': 'I-xenograft'}", + "169, coexpression {'perturbing_action': 'B-gene gain-of-function'}", + "170, of {'perturbing_action': 'I-gene gain-of-function'}", + "171, AML1-ETO {'perturbing_action': 'I-gene gain-of-function'}", + "172, and {'perturbing_action': 'I-gene gain-of-function'}", + "173, AML1-ETO9a {'perturbing_action': 'I-gene gain-of-function'}", + "183, blocks {'effect': 'B-negative'}", + "184, myeloid {'context': 'B-cells'}", + "185, cell {'context': 'I-cells'}", + "186, differentiation {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "152, Expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "153, of ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "154, AML1-ETO9a ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "155, leads ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "156, to ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28']", + "160, leukemia ['l4', 'l11', 'l17', 'l22', 'l26', 'l29', 'l30', 'l31']", + "163, mouse ['l5', 'l12', 'l18', 'l23', 'l27', 'l29', 'l32', 'l33']", + "164, retroviral ['l6', 'l13', 'l19', 'l24', 'l30', 'l32', 'l34']", + "165, transduction-transplantation ['l7', 'l14', 'l20', 'l25', 'l28', 'l31', 'l33', 'l34']", + "169, coexpression ['l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "170, of ['l35', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "171, AML1-ETO ['l36', 'l43', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "172, and ['l37', 'l44', 'l50', 'l56', 'l57', 'l58', 'l59', 'l60']", + "173, AML1-ETO9a ['l38', 'l45', 'l51', 'l56', 'l61', 'l62', 'l63', 'l64']", + "183, blocks ['l39', 'l46', 'l52', 'l57', 'l61', 'l65', 'l66', 'l67']", + "184, myeloid ['l40', 'l47', 'l53', 'l58', 'l62', 'l65', 'l68', 'l69']", + "185, cell ['l41', 'l48', 'l54', 'l59', 'l63', 'l66', 'l68', 'l70']", + "186, differentiation ['l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l70']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "AML1-ETO9a" + ] + }, + "effect": { + "val": "positive", + "words": [ + "leads", + "to" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "AML1-ETO9a" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "AML1-ETO9a" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "leukemia" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "AML1-ETO9a" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "AML1-ETO9a" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "retroviral" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "leads", + "to" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "leads", + "to" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "leads", + "to" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "leads" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "retroviral" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "retroviral" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "coexpression", + "of", + "AML1-ETO", + "and", + "AML1-ETO9a" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "coexpression", + "of", + "AML1-ETO", + "and", + "AML1-ETO9a" + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "coexpression", + "of", + "AML1-ETO", + "and", + "AML1-ETO9a" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "myeloid", + "cell" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "16783372", + "TEXT": "In the injured central nervous system (CNS), reactive astrocytes form a glial scar and are considered to be detrimental for axonal regeneration, but their function remains elusive. Here we show that reactive astrocytes have a crucial role in wound healing and functional recovery by using mice with a selective deletion of the protein signal transducer and activator of transcription 3 (Stat3) or the protein suppressor of cytokine signaling 3 (Socs3) under the control of the Nes promoter-enhancer (Nes-Stat3(-/-), Nes-Socs3(-/-)). Reactive astrocytes in Nes-Stat3(-/-) mice showed limited migration and resulted in markedly widespread infiltration of inflammatory cells, neural disruption and demyelination with severe motor deficits after contusive spinal cord injury (SCI). On the contrary, we observed rapid migration of reactive astrocytes to seclude inflammatory cells, enhanced contraction of lesion area and notable improvement in functional recovery in Nes-Socs3(-/-) mice. These results suggest that Stat3 is a key regulator of reactive astrocytes in the healing process after SCI, providing a potential target for intervention in the treatment of CNS injury.", + "TAG_DATA": [ + "45, mice {'context': 'B-organism'}", + "48, selective {'perturbing_action': 'B-gene loss-of-function'}", + "49, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "50, of {'perturbing_action': 'I-gene loss-of-function'}", + "51, the {'perturbing_action': 'I-gene loss-of-function'}", + "52, protein {'perturbing_action': 'I-gene loss-of-function'}", + "53, signal {'perturbing_action': 'I-gene loss-of-function'}", + "55, and {'perturbing_action': 'I-gene loss-of-function'}", + "56, activator {'perturbing_action': 'I-gene loss-of-function'}", + "57, of {'perturbing_action': 'I-gene loss-of-function'}", + "58, transcription {'perturbing_action': 'I-gene loss-of-function'}", + "59, 3 {'perturbing_action': 'I-gene loss-of-function'}", + "60, (Stat3) {'perturbing_action': 'I-gene loss-of-function'}", + "61, or {'perturbing_action': 'I-gene loss-of-function'}", + "62, the {'perturbing_action': 'I-gene loss-of-function'}", + "63, protein {'perturbing_action': 'I-gene loss-of-function'}", + "64, suppressor {'perturbing_action': 'I-gene loss-of-function'}", + "65, of {'perturbing_action': 'I-gene loss-of-function'}", + "66, cytokine {'perturbing_action': 'I-gene loss-of-function'}", + "67, signaling {'perturbing_action': 'I-gene loss-of-function'}", + "68, 3 {'perturbing_action': 'I-gene loss-of-function'}", + "69, (Socs3) {'perturbing_action': 'I-gene loss-of-function'}", + "70, under {'perturbing_action': 'I-gene gain-of-function'}", + "71, the {'perturbing_action': 'I-gene loss-of-function'}", + "72, control {'perturbing_action': 'I-gene gain-of-function'}", + "73, of {'perturbing_action': 'I-gene loss-of-function'}", + "74, the {'perturbing_action': 'I-gene loss-of-function'}", + "75, Nes {'perturbing_action': 'I-gene loss-of-function'}", + "76, promoter-enhancer {'perturbing_action': 'I-gene gain-of-function'}", + "77, (Nes-Stat3(-/-), {'perturbing_action': 'I-gene loss-of-function'}", + "78, Nes-Socs3(-/-)). {'perturbing_action': 'I-gene loss-of-function'}", + "79, Reactive {'context': 'B-cells'}", + "80, astrocytes {'context': 'I-cells'}", + "82, Nes-Stat3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "83, mice {'context': 'B-organism'}", + "85, limited {'effect': 'B-negative'}", + "86, migration {'phenotype': 'B-migration'}", + "116, migration {'phenotype': 'B-migration'}", + "118, reactive {'context': 'B-cells'}", + "119, astrocytes {'context': 'I-cells'}", + "136, Nes-Socs3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "137, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "45, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "48, selective ['l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "49, deletion ['l5', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "50, of ['l6', 'l40', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "51, the ['l7', 'l41', 'l74', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "52, protein ['l8', 'l42', 'l75', 'l107', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "53, signal ['l9', 'l43', 'l76', 'l108', 'l139', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199']", + "55, and ['l10', 'l44', 'l77', 'l109', 'l140', 'l170', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228']", + "56, activator ['l11', 'l45', 'l78', 'l110', 'l141', 'l171', 'l200', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256']", + "57, of ['l0', 'l12', 'l46', 'l79', 'l111', 'l142', 'l172', 'l201', 'l229', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283']", + "58, transcription ['l1', 'l13', 'l47', 'l80', 'l112', 'l143', 'l173', 'l202', 'l230', 'l257', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304', 'l305', 'l306', 'l307', 'l308', 'l309']", + "59, 3 ['l2', 'l14', 'l48', 'l81', 'l113', 'l144', 'l174', 'l203', 'l231', 'l258', 'l284', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315', 'l316', 'l317', 'l318', 'l319', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327', 'l328', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334']", + "60, (Stat3) ['l3', 'l15', 'l49', 'l82', 'l114', 'l145', 'l175', 'l204', 'l232', 'l259', 'l285', 'l310', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340', 'l341', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348', 'l349', 'l350', 'l351', 'l352', 'l353', 'l354', 'l355', 'l356', 'l357', 'l358']", + "61, or ['l16', 'l50', 'l83', 'l115', 'l146', 'l176', 'l205', 'l233', 'l260', 'l286', 'l311', 'l335', 'l359', 'l360', 'l361', 'l362', 'l363', 'l364', 'l365', 'l366', 'l367', 'l368', 'l369', 'l370', 'l371', 'l372', 'l373', 'l374', 'l375', 'l376', 'l377', 'l378', 'l379', 'l380', 'l381']", + "62, the ['l17', 'l51', 'l84', 'l116', 'l147', 'l177', 'l206', 'l234', 'l261', 'l287', 'l312', 'l336', 'l359', 'l382', 'l383', 'l384', 'l385', 'l386', 'l387', 'l388', 'l389', 'l390', 'l391', 'l392', 'l393', 'l394', 'l395', 'l396', 'l397', 'l398', 'l399', 'l400', 'l401', 'l402', 'l403']", + "63, protein ['l18', 'l52', 'l85', 'l117', 'l148', 'l178', 'l207', 'l235', 'l262', 'l288', 'l313', 'l337', 'l360', 'l382', 'l404', 'l405', 'l406', 'l407', 'l408', 'l409', 'l410', 'l411', 'l412', 'l413', 'l414', 'l415', 'l416', 'l417', 'l418', 'l419', 'l420', 'l421', 'l422', 'l423', 'l424']", + "64, suppressor ['l19', 'l53', 'l86', 'l118', 'l149', 'l179', 'l208', 'l236', 'l263', 'l289', 'l314', 'l338', 'l361', 'l383', 'l404', 'l425', 'l426', 'l427', 'l428', 'l429', 'l430', 'l431', 'l432', 'l433', 'l434', 'l435', 'l436', 'l437', 'l438', 'l439', 'l440', 'l441', 'l442', 'l443', 'l444']", + "65, of ['l20', 'l54', 'l87', 'l119', 'l150', 'l180', 'l209', 'l237', 'l264', 'l290', 'l315', 'l339', 'l362', 'l384', 'l405', 'l425', 'l445', 'l446', 'l447', 'l448', 'l449', 'l450', 'l451', 'l452', 'l453', 'l454', 'l455', 'l456', 'l457', 'l458', 'l459', 'l460', 'l461', 'l462', 'l463']", + "66, cytokine ['l21', 'l55', 'l88', 'l120', 'l151', 'l181', 'l210', 'l238', 'l265', 'l291', 'l316', 'l340', 'l363', 'l385', 'l406', 'l426', 'l445', 'l464', 'l465', 'l466', 'l467', 'l468', 'l469', 'l470', 'l471', 'l472', 'l473', 'l474', 'l475', 'l476', 'l477', 'l478', 'l479', 'l480', 'l481']", + "67, signaling ['l22', 'l56', 'l89', 'l121', 'l152', 'l182', 'l211', 'l239', 'l266', 'l292', 'l317', 'l341', 'l364', 'l386', 'l407', 'l427', 'l446', 'l464', 'l482', 'l483', 'l484', 'l485', 'l486', 'l487', 'l488', 'l489', 'l490', 'l491', 'l492', 'l493', 'l494', 'l495', 'l496', 'l497', 'l498']", + "68, 3 ['l23', 'l57', 'l90', 'l122', 'l153', 'l183', 'l212', 'l240', 'l267', 'l293', 'l318', 'l342', 'l365', 'l387', 'l408', 'l428', 'l447', 'l465', 'l482', 'l499', 'l500', 'l501', 'l502', 'l503', 'l504', 'l505', 'l506', 'l507', 'l508', 'l509', 'l510', 'l511', 'l512', 'l513', 'l514']", + "69, (Socs3) ['l24', 'l58', 'l91', 'l123', 'l154', 'l184', 'l213', 'l241', 'l268', 'l294', 'l319', 'l343', 'l366', 'l388', 'l409', 'l429', 'l448', 'l466', 'l483', 'l499', 'l515', 'l516', 'l517', 'l518', 'l519', 'l520', 'l521', 'l522', 'l523', 'l524', 'l525', 'l526', 'l527', 'l528', 'l529']", + "70, under ['l25', 'l59', 'l92', 'l124', 'l155', 'l185', 'l214', 'l242', 'l269', 'l295', 'l320', 'l344', 'l367', 'l389', 'l410', 'l430', 'l449', 'l467', 'l484', 'l500', 'l515', 'l530', 'l531', 'l532', 'l533', 'l534', 'l535', 'l536', 'l537', 'l538', 'l539', 'l540', 'l541', 'l542', 'l543']", + "71, the ['l26', 'l60', 'l93', 'l125', 'l156', 'l186', 'l215', 'l243', 'l270', 'l296', 'l321', 'l345', 'l368', 'l390', 'l411', 'l431', 'l450', 'l468', 'l485', 'l501', 'l516', 'l530', 'l544', 'l545', 'l546', 'l547', 'l548', 'l549', 'l550', 'l551', 'l552', 'l553', 'l554', 'l555', 'l556']", + "72, control ['l27', 'l61', 'l94', 'l126', 'l157', 'l187', 'l216', 'l244', 'l271', 'l297', 'l322', 'l346', 'l369', 'l391', 'l412', 'l432', 'l451', 'l469', 'l486', 'l502', 'l517', 'l531', 'l544', 'l557', 'l558', 'l559', 'l560', 'l561', 'l562', 'l563', 'l564', 'l565', 'l566', 'l567', 'l568']", + "73, of ['l28', 'l62', 'l95', 'l127', 'l158', 'l188', 'l217', 'l245', 'l272', 'l298', 'l323', 'l347', 'l370', 'l392', 'l413', 'l433', 'l452', 'l470', 'l487', 'l503', 'l518', 'l532', 'l545', 'l557', 'l569', 'l570', 'l571', 'l572', 'l573', 'l574', 'l575', 'l576', 'l577', 'l578', 'l579']", + "74, the ['l29', 'l63', 'l96', 'l128', 'l159', 'l189', 'l218', 'l246', 'l273', 'l299', 'l324', 'l348', 'l371', 'l393', 'l414', 'l434', 'l453', 'l471', 'l488', 'l504', 'l519', 'l533', 'l546', 'l558', 'l569', 'l580', 'l581', 'l582', 'l583', 'l584', 'l585', 'l586', 'l587', 'l588', 'l589']", + "75, Nes ['l30', 'l64', 'l97', 'l129', 'l160', 'l190', 'l219', 'l247', 'l274', 'l300', 'l325', 'l349', 'l372', 'l394', 'l415', 'l435', 'l454', 'l472', 'l489', 'l505', 'l520', 'l534', 'l547', 'l559', 'l570', 'l580', 'l590', 'l591', 'l592', 'l593', 'l594', 'l595', 'l596', 'l597', 'l598']", + "76, promoter-enhancer ['l31', 'l65', 'l98', 'l130', 'l161', 'l191', 'l220', 'l248', 'l275', 'l301', 'l326', 'l350', 'l373', 'l395', 'l416', 'l436', 'l455', 'l473', 'l490', 'l506', 'l521', 'l535', 'l548', 'l560', 'l571', 'l581', 'l590', 'l599', 'l600', 'l601', 'l602', 'l603', 'l604', 'l605', 'l606']", + "77, (Nes-Stat3(-/-), ['l32', 'l66', 'l99', 'l131', 'l162', 'l192', 'l221', 'l249', 'l276', 'l302', 'l327', 'l351', 'l374', 'l396', 'l417', 'l437', 'l456', 'l474', 'l491', 'l507', 'l522', 'l536', 'l549', 'l561', 'l572', 'l582', 'l591', 'l599', 'l607', 'l608', 'l609', 'l610', 'l611', 'l612', 'l613']", + "78, Nes-Socs3(-/-)). ['l33', 'l67', 'l100', 'l132', 'l163', 'l193', 'l222', 'l250', 'l277', 'l303', 'l328', 'l352', 'l375', 'l397', 'l418', 'l438', 'l457', 'l475', 'l492', 'l508', 'l523', 'l537', 'l550', 'l562', 'l573', 'l583', 'l592', 'l600', 'l607', 'l614', 'l615', 'l616', 'l617', 'l618', 'l619']", + "79, Reactive ['l34', 'l68', 'l101', 'l133', 'l164', 'l194', 'l223', 'l251', 'l278', 'l304', 'l329', 'l353', 'l376', 'l398', 'l419', 'l439', 'l458', 'l476', 'l493', 'l509', 'l524', 'l538', 'l551', 'l563', 'l574', 'l584', 'l593', 'l601', 'l608', 'l614', 'l620', 'l621', 'l622', 'l623', 'l624']", + "80, astrocytes ['l4', 'l35', 'l69', 'l102', 'l134', 'l165', 'l195', 'l224', 'l252', 'l279', 'l305', 'l330', 'l354', 'l377', 'l399', 'l420', 'l440', 'l459', 'l477', 'l494', 'l510', 'l525', 'l539', 'l552', 'l564', 'l575', 'l585', 'l594', 'l602', 'l609', 'l615', 'l620', 'l625', 'l626', 'l627', 'l628']", + "82, Nes-Stat3(-/-) ['l36', 'l70', 'l103', 'l135', 'l166', 'l196', 'l225', 'l253', 'l280', 'l306', 'l331', 'l355', 'l378', 'l400', 'l421', 'l441', 'l460', 'l478', 'l495', 'l511', 'l526', 'l540', 'l553', 'l565', 'l576', 'l586', 'l595', 'l603', 'l610', 'l616', 'l621', 'l625', 'l629', 'l630', 'l631']", + "83, mice ['l37', 'l71', 'l104', 'l136', 'l167', 'l197', 'l226', 'l254', 'l281', 'l307', 'l332', 'l356', 'l379', 'l401', 'l422', 'l442', 'l461', 'l479', 'l496', 'l512', 'l527', 'l541', 'l554', 'l566', 'l577', 'l587', 'l596', 'l604', 'l611', 'l617', 'l622', 'l626', 'l629', 'l632', 'l633']", + "85, limited ['l38', 'l72', 'l105', 'l137', 'l168', 'l198', 'l227', 'l255', 'l282', 'l308', 'l333', 'l357', 'l380', 'l402', 'l423', 'l443', 'l462', 'l480', 'l497', 'l513', 'l528', 'l542', 'l555', 'l567', 'l578', 'l588', 'l597', 'l605', 'l612', 'l618', 'l623', 'l627', 'l630', 'l632', 'l634']", + "86, migration ['l39', 'l73', 'l106', 'l138', 'l169', 'l199', 'l228', 'l256', 'l283', 'l309', 'l334', 'l358', 'l381', 'l403', 'l424', 'l444', 'l463', 'l481', 'l498', 'l514', 'l529', 'l543', 'l556', 'l568', 'l579', 'l589', 'l598', 'l606', 'l613', 'l619', 'l624', 'l628', 'l631', 'l633', 'l634']", + "116, migration ['l635', 'l636', 'l637']", + "118, reactive ['l635', 'l638', 'l639', 'l640']", + "119, astrocytes ['l636', 'l638', 'l641', 'l642']", + "136, Nes-Socs3(-/-) ['l639', 'l641', 'l643']", + "137, mice. ['l637', 'l640', 'l642', 'l643']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "transcription", + "3", + "(Stat3)", + "selective", + "deletion", + "the", + "protein", + "signal", + "and", + "activator", + "or", + "suppressor", + "cytokine", + "signaling", + "(Socs3)", + "Nes", + "(Nes-Stat3(-/-),", + "Nes-Socs3(-/-)).", + "Nes-Stat3(-/-)", + "Nes-Socs3(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "deletion", + "of", + "the", + "protein", + "signal", + "and", + "activator", + "transcription", + "3", + "(Stat3)", + "or", + "suppressor", + "cytokine", + "signaling", + "(Socs3)", + "Nes", + "(Nes-Stat3(-/-),", + "Nes-Socs3(-/-)).", + "Nes-Stat3(-/-)", + "Nes-Socs3(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "Reactive", + "astrocytes", + "reactive" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "deletion", + "of", + "the", + "protein", + "signal", + "and", + "activator", + "transcription", + "3", + "(Stat3)", + "or", + "suppressor", + "cytokine", + "signaling", + "(Socs3)", + "Nes", + "(Nes-Stat3(-/-),", + "Nes-Socs3(-/-)).", + "Nes-Stat3(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "limited" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "deletion", + "of", + "the", + "protein", + "signal", + "and", + "activator", + "transcription", + "3", + "(Stat3)", + "or", + "suppressor", + "cytokine", + "signaling", + "(Socs3)", + "Nes", + "(Nes-Stat3(-/-),", + "Nes-Socs3(-/-)).", + "Nes-Stat3(-/-)" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "under", + "control", + "promoter-enhancer" + ] + }, + "context": { + "val": "cells", + "words": [ + "Reactive", + "astrocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "under", + "control", + "promoter-enhancer" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "under", + "control", + "promoter-enhancer" + ] + }, + "effect": { + "val": "negative", + "words": [ + "limited" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "under", + "control", + "promoter-enhancer" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Reactive", + "astrocytes" + ] + }, + "effect": { + "val": "negative", + "words": [ + "limited" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Reactive", + "astrocytes", + "reactive" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "limited" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limited" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + } + ] + }, + { + "PMID": "16715088", + "TEXT": "Complement-mediated tissue injury in humans occurs upon deposition of immune complexes, such as in autoimmune diseases and acute respiratory distress syndrome. Acute lung inflammatory injury in wild-type and C3-/- mice after deposition of IgG immune complexes was of equivalent intensity and was C5a dependent, but injury was greatly attenuated in Hc-/- mice (Hc encodes C5). Injury in lungs of C3-/- mice and C5a levels in bronchoalveolar lavage (BAL) fluids from these mice were greatly reduced in the presence of antithrombin III (ATIII) or hirudin but were not reduced in similarly treated C3+/+ mice. Plasma from C3-/- mice contained threefold higher levels of thrombin activity compared to plasma from C3+/+ mice. There were higher levels of F2 mRNA (encoding prothrombin) as well as prothrombin and thrombin protein in liver of C3-/- mice compared to C3+/+ mice. A potent solid-phase C5 convertase was generated using plasma from either C3+/+ or C3-/- mice. Human C5 incubated with thrombin generated C5a that was biologically active. These data suggest that, in the genetic absence of C3, thrombin substitutes for the C3-dependent C5 convertase. This linkage between the complement and coagulation pathways may represent a new pathway of complement activation.", + "TAG_DATA": [ + "28, C3-/- {'perturbing_action': 'B-gene loss-of-function'}", + "29, mice {'context': 'B-organism'}", + "50, Hc-/- {'perturbing_action': 'B-gene loss-of-function'}", + "51, mice {'context': 'B-organism'}", + "57, lungs {'context': 'B-tissue/organ'}", + "59, C3-/- {'perturbing_action': 'B-gene loss-of-function'}", + "60, mice {'context': 'B-organism'}", + "71, mice {'context': 'B-organism'}", + "95, C3-/- {'perturbing_action': 'B-gene loss-of-function'}", + "96, mice {'context': 'B-organism'}", + "127, liver {'context': 'B-tissue/organ'}", + "129, C3-/- {'perturbing_action': 'B-gene loss-of-function'}", + "130, mice {'context': 'B-organism'}", + "148, C3-/- {'perturbing_action': 'B-gene loss-of-function'}", + "149, mice. {'context': 'B-organism'}", + "150, Human {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "28, C3-/- ['l0', 'l1', 'l2', 'l3']", + "29, mice ['l0', 'l4']", + "50, Hc-/- ['l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "51, mice ['l5', 'l11', 'l12', 'l13', 'l14']", + "57, lungs ['l1', 'l4', 'l6', 'l11', 'l15', 'l16', 'l17']", + "59, C3-/- ['l2', 'l7', 'l12', 'l15', 'l18', 'l19']", + "60, mice ['l3', 'l8', 'l13', 'l16', 'l18', 'l20']", + "71, mice ['l9', 'l14', 'l17', 'l19', 'l20']", + "95, C3-/- ['l21', 'l22', 'l23']", + "96, mice ['l10', 'l21']", + "127, liver ['l22', 'l24', 'l25']", + "129, C3-/- ['l24', 'l26', 'l27']", + "130, mice ['l23', 'l25', 'l26']", + "148, C3-/- ['l28', 'l29', 'l30']", + "149, mice. ['l27', 'l28', 'l31', 'l32']", + "150, Human ['l29', 'l31', 'l33']", + "151, C5 ['l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "C3-/-", + "Hc-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "C3-/-", + "Hc-/-" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lungs", + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "C3-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "Human" + ] + } + } + ] + }, + { + "PMID": "16680148", + "TEXT": "Endochondral ossification is an essential process not only for physiological skeletal development and growth, but also for pathological disorders. We recently identified a novel cartilage-specific molecule, carminerin (also known as cystatin 10 and encoded by Cst10), which is upregulated in synchrony with cartilage maturation and stimulates the later differentiation of cultured chondrocytes. Although carminerin-deficient (Cst10-/-) mice developed and grew normally, they had a microscopic decrease in the calcification of hypertrophic chondrocytes at the growth plate. When we created experimental models of pathological endochondral ossification, we observed suppression of chondrocyte calcification during formation of osteoarthritic osteophytes, age-related ectopic ossification and healing of bone fractures in Cst10-/- mice. Cultured Cst10-/- chondrocytes showed a reduction in calcification with activation of an SRY site in the promoter of the gene encoding nucleotide pyrophosphatase phosphodiesterase 1 (NPP1, encoded by Enpp1). Functional NPP1 is required for carminerin deficiency to suppress the pathological endochondral ossifications listed above. Carminerin is the first cartilage-specific protein that contributes to chondrocyte calcification during endochondral ossification under physiological and pathological conditions through the transcriptional inhibition of NPP1.", + "TAG_DATA": [ + "53, carminerin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "54, (Cst10-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "55, mice {'context': 'B-organism'}", + "69, hypertrophic {'context': 'B-cells'}", + "70, chondrocytes {'context': 'I-cells'}", + "104, Cst10-/- {'perturbing_action': 'B-gene loss-of-function'}", + "105, mice. {'context': 'B-organism'}", + "107, Cst10-/- {'perturbing_action': 'B-gene loss-of-function'}", + "108, chondrocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "53, carminerin-deficient ['l0', 'l1', 'l2', 'l3']", + "54, (Cst10-/-) ['l0', 'l4', 'l5', 'l6']", + "55, mice ['l1', 'l4', 'l7', 'l8']", + "69, hypertrophic ['l2', 'l5', 'l7', 'l9']", + "70, chondrocytes ['l3', 'l6', 'l8', 'l9']", + "104, Cst10-/- ['l10']", + "105, mice. ['l10']", + "107, Cst10-/- ['l11']", + "108, chondrocytes ['l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "carminerin-deficient", + "(Cst10-/-)", + "Cst10-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "carminerin-deficient", + "(Cst10-/-)", + "Cst10-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "hypertrophic", + "chondrocytes" + ] + } + } + ] + }, + { + "PMID": "16617349", + "TEXT": "The protein tyrosine phosphatase SHP-1 is a well-known inhibitor of activation-promoting signaling cascades in hematopoietic cells but its potential role in insulin target tissues is unknown. Here we show that Ptpn6(me-v/me-v) (also known as viable motheaten) mice bearing a functionally deficient SHP-1 protein are markedly glucose tolerant and insulin sensitive as compared to wild-type littermates, as a result of enhanced insulin receptor signaling to IRS-PI3K-Akt in liver and muscle. Downregulation of SHP-1 activity in liver of normal mice by adenoviral expression of a catalytically inert mutant of SHP-1, or after small hairpin RNA-mediated SHP-1 silencing, further confirmed this phenotype. Tyrosine phosphorylation of CEACAM1, a modulator of hepatic insulin clearance, and clearance of serum [125I]-insulin were markedly increased in SHP-1-deficient mice or SHP-1-deficient hepatic cells in vitro. These findings show a novel role for SHP-1 in the regulation of glucose homeostasis through modulation of insulin signaling in liver and muscle as well as hepatic insulin clearance.", + "TAG_DATA": [ + "30, Ptpn6(me-v/me-v) {'perturbing_action': 'B-other'}", + "36, mice {'context': 'B-organism'}", + "39, functionally {'perturbing_action': 'B-gene loss-of-function'}", + "40, deficient {'perturbing_action': 'I-gene loss-of-function'}", + "41, SHP-1 {'perturbing_action': 'I-gene loss-of-function'}", + "42, protein {'perturbing_action': 'I-gene loss-of-function'}", + "69, Downregulation {'perturbing_action': 'B-other'}", + "70, of {'perturbing_action': 'I-gene loss-of-function'}", + "71, SHP-1 {'perturbing_action': 'I-gene loss-of-function'}", + "72, activity {'perturbing_action': 'I-gene loss-of-function'}", + "74, liver {'context': 'B-tissue/organ'}", + "77, mice {'context': 'B-organism'}", + "79, adenoviral {'perturbing_action': 'B-other'}", + "80, expression {'perturbing_action': 'I-other'}", + "81, of {'perturbing_action': 'I-other'}", + "82, a {'perturbing_action': 'I-other'}", + "83, catalytically {'perturbing_action': 'I-other'}", + "84, inert {'perturbing_action': 'I-other'}", + "85, mutant {'perturbing_action': 'I-other'}", + "86, of {'perturbing_action': 'I-other'}", + "87, SHP-1, {'perturbing_action': 'I-other'}", + "90, small {'perturbing_action': 'B-rnai/knockdown'}", + "91, hairpin {'perturbing_action': 'I-rnai/knockdown'}", + "92, RNA-mediated {'perturbing_action': 'I-rnai/knockdown'}", + "93, SHP-1 {'perturbing_action': 'I-rnai/knockdown'}", + "94, silencing, {'perturbing_action': 'I-rnai/knockdown'}", + "118, SHP-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "119, mice {'context': 'B-organism'}", + "121, SHP-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "122, hepatic {'context': 'B-cells'}", + "123, cells {'context': 'I-cells'}", + "124, in {'context': 'B-in vitro'}", + "125, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "30, Ptpn6(me-v/me-v) ['l0', 'l1', 'l2']", + "31, (also ['l0', 'l3', 'l4', 'l5']", + "36, mice ['l1', 'l3', 'l6']", + "39, functionally ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "40, deficient ['l7', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "41, SHP-1 ['l8', 'l25', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "42, protein ['l9', 'l26', 'l42', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "69, Downregulation ['l10', 'l27', 'l43', 'l58', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "70, of ['l11', 'l28', 'l44', 'l59', 'l73', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "71, SHP-1 ['l12', 'l29', 'l45', 'l60', 'l74', 'l87', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "72, activity ['l13', 'l30', 'l46', 'l61', 'l75', 'l88', 'l100', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "74, liver ['l2', 'l4', 'l6', 'l14', 'l31', 'l47', 'l62', 'l76', 'l89', 'l101', 'l112', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "77, mice ['l5', 'l15', 'l32', 'l48', 'l63', 'l77', 'l90', 'l102', 'l113', 'l123', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141']", + "79, adenoviral ['l16', 'l33', 'l49', 'l64', 'l78', 'l91', 'l103', 'l114', 'l124', 'l133', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "80, expression ['l17', 'l34', 'l50', 'l65', 'l79', 'l92', 'l104', 'l115', 'l125', 'l134', 'l142', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156']", + "81, of ['l18', 'l35', 'l51', 'l66', 'l80', 'l93', 'l105', 'l116', 'l126', 'l135', 'l143', 'l150', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162']", + "82, a ['l19', 'l36', 'l52', 'l67', 'l81', 'l94', 'l106', 'l117', 'l127', 'l136', 'l144', 'l151', 'l157', 'l163', 'l164', 'l165', 'l166', 'l167']", + "83, catalytically ['l20', 'l37', 'l53', 'l68', 'l82', 'l95', 'l107', 'l118', 'l128', 'l137', 'l145', 'l152', 'l158', 'l163', 'l168', 'l169', 'l170', 'l171']", + "84, inert ['l21', 'l38', 'l54', 'l69', 'l83', 'l96', 'l108', 'l119', 'l129', 'l138', 'l146', 'l153', 'l159', 'l164', 'l168', 'l172', 'l173', 'l174']", + "85, mutant ['l22', 'l39', 'l55', 'l70', 'l84', 'l97', 'l109', 'l120', 'l130', 'l139', 'l147', 'l154', 'l160', 'l165', 'l169', 'l172', 'l175', 'l176']", + "86, of ['l23', 'l40', 'l56', 'l71', 'l85', 'l98', 'l110', 'l121', 'l131', 'l140', 'l148', 'l155', 'l161', 'l166', 'l170', 'l173', 'l175', 'l177']", + "87, SHP-1, ['l24', 'l41', 'l57', 'l72', 'l86', 'l99', 'l111', 'l122', 'l132', 'l141', 'l149', 'l156', 'l162', 'l167', 'l171', 'l174', 'l176', 'l177']", + "90, small ['l178', 'l179', 'l180', 'l181', 'l182', 'l183']", + "91, hairpin ['l178', 'l184', 'l185', 'l186', 'l187', 'l188']", + "92, RNA-mediated ['l179', 'l184', 'l189', 'l190', 'l191', 'l192']", + "93, SHP-1 ['l180', 'l185', 'l189', 'l193', 'l194', 'l195']", + "94, silencing, ['l181', 'l186', 'l190', 'l193', 'l196', 'l197']", + "118, SHP-1-deficient ['l182', 'l187', 'l191', 'l194', 'l196', 'l198', 'l199', 'l200', 'l201', 'l202']", + "119, mice ['l183', 'l188', 'l192', 'l195', 'l197', 'l198']", + "121, SHP-1-deficient ['l199', 'l203', 'l204', 'l205', 'l206']", + "122, hepatic ['l200', 'l203', 'l207', 'l208', 'l209']", + "123, cells ['l201', 'l204', 'l207', 'l210', 'l211']", + "124, in ['l202', 'l205', 'l208', 'l210', 'l212']", + "125, vitro. ['l206', 'l209', 'l211', 'l212']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Ptpn6(me-v/me-v)", + "Downregulation", + "adenoviral", + "expression", + "of", + "a", + "catalytically", + "inert", + "mutant", + "SHP-1," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Ptpn6(me-v/me-v)", + "Downregulation", + "adenoviral", + "expression", + "of", + "a", + "catalytically", + "inert", + "mutant", + "SHP-1," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "functionally", + "deficient", + "SHP-1", + "protein", + "of", + "activity" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "functionally", + "deficient", + "SHP-1", + "protein", + "of", + "activity", + "SHP-1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "small", + "hairpin", + "RNA-mediated", + "SHP-1", + "silencing," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHP-1-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatic", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHP-1-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "16474398", + "TEXT": "We describe the tripeptide neutrophil chemoattractant N-acetyl Pro-Gly-Pro (PGP), derived from the breakdown of extracellular matrix (ECM), which shares sequence and structural homology with an important domain on alpha chemokines. PGP caused chemotaxis and production of superoxide through CXC receptors, and administration of peptide caused recruitment of neutrophils (PMNs) into lungs of control, but not CXCR2-deficient mice. PGP was generated in mouse lung after exposure to lipopolysaccharide, and in vivo and in vitro blockade of PGP with monoclonal antibody suppressed PMN responses as much as chemokine-specific monoclonal antibody. Extended PGP treatment caused alveolar enlargement and right ventricular hypertrophy in mice. PGP was detectable in substantial concentrations in a majority of bronchoalveolar lavage samples from individuals with chronic obstructive pulmonary disease, but not control individuals. Thus, PGP's activity links degradation of ECM with neutrophil recruitment in airway inflammation, and PGP may be a biomarker and therapeutic target for neutrophilic inflammatory diseases.", + "TAG_DATA": [ + "55, CXCR2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "56, mice. {'context': 'B-organism'}", + "61, mouse {'context': 'B-tissue/organ'}", + "62, lung {'context': 'I-tissue/organ'}", + "68, in {'context': 'B-in vivo'}", + "69, vivo {'context': 'I-in vivo'}", + "71, in {'context': 'B-in vitro'}", + "72, vitro {'context': 'I-in vitro'}", + "80, PMN {'context': 'B-cells'}", + "99, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "55, CXCR2-deficient ['l0', 'l1', 'l2']", + "56, mice. ['l0', 'l3', 'l4']", + "61, mouse ['l1', 'l3', 'l5']", + "62, lung ['l2', 'l4', 'l5']", + "68, in ['l6', 'l7', 'l8', 'l9']", + "69, vivo ['l6', 'l10', 'l11', 'l12']", + "71, in ['l7', 'l10', 'l13', 'l14']", + "72, vitro ['l8', 'l11', 'l13', 'l15']", + "80, PMN ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CXCR2-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CXCR2-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "lung" + ] + } + } + ] + }, + { + "PMID": "16432513", + "TEXT": "Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostanoid synthesis, has been implicated in the neurotoxicity resulting from hypoxia-ischemia, and its inhibition has therapeutic potential for ischemic stroke. However, COX-2 inhibitors increase the risk of cardiovascular complications. We therefore sought to identify the downstream effectors of COX-2 neurotoxicity, and found that prostaglandin E(2) EP1 receptors are essential for the neurotoxicity mediated by COX-2-derived prostaglandin E(2). EP1 receptors disrupt Ca(2+) homeostasis by impairing Na(+)-Ca(2+) exchange, a key mechanism by which neurons cope with excess Ca(2+) accumulation after an excitotoxic insult. Thus, EP1 receptors contribute to neurotoxicity by augmenting the Ca(2+) dysregulation underlying excitotoxic neuronal death. Pharmacological inhibition or gene inactivation of EP1 receptors ameliorates brain injury induced by excitotoxicity, oxygen glucose deprivation and middle cerebral artery (MCA) occlusion. An EP1 receptor inhibitor reduces brain injury when administered 6 hours after MCA occlusion, suggesting that EP1 receptor inhibition may be a viable therapeutic option in ischemic stroke.", + "TAG_DATA": [ + "105, gene {'perturbing_action': 'B-gene loss-of-function'}", + "106, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "107, of {'perturbing_action': 'I-gene loss-of-function'}", + "108, EP1 {'perturbing_action': 'I-gene loss-of-function'}", + "109, receptors {'perturbing_action': 'I-gene loss-of-function'}", + "111, brain {'context': 'B-tissue/organ'}", + "126, EP1 {'perturbing_action': 'B-pharmacological inhibition'}", + "127, receptor {'perturbing_action': 'B-pharmacological inhibition'}", + "128, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "130, brain {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "105, gene ['l0', 'l1', 'l2', 'l3', 'l4']", + "106, inactivation ['l0', 'l5', 'l6', 'l7', 'l8']", + "107, of ['l1', 'l5', 'l9', 'l10', 'l11']", + "108, EP1 ['l2', 'l6', 'l9', 'l12', 'l13']", + "109, receptors ['l3', 'l7', 'l10', 'l12', 'l14']", + "111, brain ['l4', 'l8', 'l11', 'l13', 'l14']", + "126, EP1 ['l15', 'l16', 'l17']", + "127, receptor ['l15', 'l18', 'l19']", + "128, inhibitor ['l16', 'l18', 'l20']", + "130, brain ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "gene", + "inactivation", + "of", + "EP1", + "receptors" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EP1", + "receptor", + "inhibitor" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain" + ] + } + } + ] + }, + { + "PMID": "16327803", + "TEXT": "Many heat-shock proteins (Hsp) are members of evolutionarily conserved families of chaperone proteins that inhibit the aggregation of unfolded polypeptides and refold denatured proteins, thereby remedying phenotypic effects that may result from protein aggregation or protein instability. Here we report that the mitochondrial chaperone Hsp40, also known as Dnaja3 or Tid1, is differentially expressed during cardiac development and pathological hypertrophy. Mice deficient in Dnaja3 developed dilated cardiomyopathy (DCM) and died before 10 weeks of age. Progressive respiratory chain deficiency and decreased copy number of mitochondrial DNA were evident in cardiomyocytes lacking Dnaja3. Profiling of Dnaja3-interacting proteins identified the alpha-subunit of DNA polymerase gamma (Polga) as a client protein. These findings suggest that Dnaja3 is crucial for mitochondrial biogenesis, at least in part, through its chaperone activity on Polga and provide genetic evidence of the necessity for mitochondrial Hsp40 in preventing DCM.", + "TAG_DATA": [ + "60, Mice {'context': 'B-organism'}", + "61, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "62, in {'perturbing_action': 'I-gene loss-of-function'}", + "63, Dnaja3 {'perturbing_action': 'I-gene loss-of-function'}", + "89, cardiomyocytes {'context': 'B-cells'}", + "90, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "91, Dnaja3. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "60, Mice ['l0', 'l1', 'l2']", + "61, deficient ['l0', 'l3', 'l4', 'l5', 'l6']", + "62, in ['l1', 'l3', 'l7', 'l8', 'l9']", + "63, Dnaja3 ['l2', 'l4', 'l7', 'l10', 'l11']", + "89, cardiomyocytes ['l5', 'l8', 'l10', 'l12', 'l13']", + "90, lacking ['l6', 'l9', 'l11', 'l12', 'l14']", + "91, Dnaja3. ['l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Dnaja3" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Dnaja3", + "lacking", + "Dnaja3." + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes" + ] + } + } + ] + }, + { + "PMID": "16327801", + "TEXT": "Using an expression cloning strategy, we have identified TFE3, a basic helix-loop-helix protein, as a transactivator of metabolic genes that are regulated through an E-box in their promoters. Adenovirus-mediated expression of TFE3 in hepatocytes in culture and in vivo strongly activated expression of IRS-2 and Akt and enhanced phosphorylation of insulin-signaling kinases such as Akt, glycogen synthase kinase 3beta and p70S6 kinase. TFE3 also induced hexokinase II (HK2) and insulin-induced gene 1 (INSIG1). These changes led to metabolic consequences, such as activation of glycogen and protein synthesis, but not lipogenesis, in liver. Collectively, plasma glucose levels were markedly reduced both in normal mice and in different mouse models of diabetes, including streptozotocin-treated, db/db and KK mice. Promoter analyses showed that IRS2, HK2 and INSIG1 are direct targets of TFE3. Activation of insulin signals in both insulin depletion and resistance suggests that TFE3 could be a therapeutic target for diabetes.", + "TAG_DATA": [ + "28, Adenovirus-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "29, expression {'perturbing_action': 'I-gene gain-of-function'}", + "30, of {'perturbing_action': 'I-gene gain-of-function'}", + "31, TFE3 {'perturbing_action': 'I-gene gain-of-function'}", + "33, hepatocytes {'context': 'B-cells'}", + "34, in {'context': 'B-in vitro'}", + "35, culture {'context': 'I-in vitro'}", + "37, in {'context': 'B-in vivo'}", + "38, vivo {'context': 'I-in vivo'}", + "91, liver. {'context': 'B-tissue/organ'}", + "102, mice {'context': 'B-organism'}", + "106, mouse {'context': 'B-organism'}", + "107, models {'context': 'I-organism'}", + "115, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "28, Adenovirus-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "29, expression ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "30, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "31, TFE3 ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "33, hepatocytes ['l3', 'l11', 'l18', 'l24', 'l30', 'l31']", + "34, in ['l4', 'l12', 'l19', 'l25', 'l30', 'l32']", + "35, culture ['l5', 'l13', 'l20', 'l26', 'l31', 'l32']", + "37, in ['l6', 'l14', 'l21', 'l27', 'l33', 'l34']", + "38, vivo ['l7', 'l15', 'l22', 'l28', 'l33', 'l35']", + "91, liver. ['l8', 'l16', 'l23', 'l29', 'l34', 'l35']", + "106, mouse ['l36', 'l37']", + "107, models ['l36', 'l38']", + "115, mice. ['l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenovirus-mediated", + "expression", + "of", + "TFE3" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenovirus-mediated", + "expression", + "of", + "TFE3" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "culture" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenovirus-mediated", + "expression", + "of", + "TFE3" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenovirus-mediated", + "expression", + "of", + "TFE3" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver." + ] + } + } + ] + }, + { + "PMID": "16286924", + "TEXT": "The IkappaB kinase complex IKK is a central component of the signaling cascade that controls NF-kappaB-dependent gene transcription. So far, its function in the brain is largely unknown. Here, we show that IKK is activated in a mouse model of stroke. To investigate the function of IKK in brain ischemia we generated mice that contain a targeted deletion of Ikbkb (which encodes IKK2) in mouse neurons and mice that express a dominant inhibitor of IKK in neurons. In both lines, inhibition of IKK activity markedly reduced infarct size. In contrast, constitutive activation of IKK2 enlarged the infarct size. A selective small-molecule inhibitor of IKK mimicked the effect of genetic IKK inhibition in neurons, reducing the infarct volume and cell death in a therapeutic time window of 4.5 h. These data indicate a key function of IKK in ischemic brain damage and suggest a potential role for IKK inhibitors in stroke therapy.", + "TAG_DATA": [ + "52, mice {'context': 'B-organism'}", + "56, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "57, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "58, of {'perturbing_action': 'I-gene loss-of-function'}", + "59, Ikbkb {'perturbing_action': 'I-gene loss-of-function'}", + "60, (which {'perturbing_action': 'I-gene loss-of-function'}", + "64, mouse {'context': 'B-cells'}", + "65, neurons {'context': 'I-cells'}", + "67, mice {'context': 'B-organism'}", + "76, neurons. {'context': 'B-cells'}", + "80, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "81, of {'perturbing_action': 'I-pharmacological inhibition'}", + "82, IKK {'perturbing_action': 'I-pharmacological inhibition'}", + "83, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "90, constitutive {'perturbing_action': 'B-gene gain-of-function'}", + "91, activation {'perturbing_action': 'I-gene gain-of-function'}", + "92, of {'perturbing_action': 'I-gene gain-of-function'}", + "93, IKK2 {'perturbing_action': 'I-gene gain-of-function'}", + "99, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "100, small-molecule {'perturbing_action': 'I-pharmacological inhibition'}", + "101, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "102, of {'perturbing_action': 'I-pharmacological inhibition'}", + "103, IKK {'perturbing_action': 'I-pharmacological inhibition'}", + "108, genetic {'perturbing_action': 'B-pharmacological inhibition'}", + "109, IKK {'perturbing_action': 'I-pharmacological inhibition'}", + "110, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "112, neurons, {'context': 'B-cells'}", + "113, reducing {'effect': 'B-negative'}", + "118, cell {'phenotype': 'B-cell death'}", + "119, death {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "52, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "56, targeted ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "57, deletion ['l0', 'l6', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "58, of ['l1', 'l7', 'l18', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "59, Ikbkb ['l2', 'l8', 'l19', 'l29', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "60, (which ['l3', 'l9', 'l20', 'l30', 'l39', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "64, mouse ['l4', 'l10', 'l21', 'l31', 'l40', 'l48', 'l56', 'l57']", + "65, neurons ['l5', 'l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l58']", + "67, mice ['l12', 'l23', 'l33', 'l42', 'l50', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "76, neurons. ['l13', 'l24', 'l34', 'l43', 'l51', 'l57', 'l58', 'l59', 'l65', 'l66', 'l67', 'l68']", + "80, inhibition ['l14', 'l25', 'l35', 'l44', 'l52', 'l60', 'l65', 'l69', 'l70', 'l71', 'l72']", + "81, of ['l15', 'l26', 'l36', 'l45', 'l53', 'l61', 'l66', 'l69', 'l73', 'l74', 'l75', 'l76']", + "82, IKK ['l16', 'l27', 'l37', 'l46', 'l54', 'l62', 'l67', 'l70', 'l73', 'l77', 'l78', 'l79']", + "83, activity ['l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l68', 'l71', 'l74', 'l77']", + "90, constitutive ['l80', 'l81', 'l82']", + "91, activation ['l80', 'l83', 'l84']", + "92, of ['l75', 'l78', 'l81', 'l83', 'l85']", + "93, IKK2 ['l64', 'l72', 'l76', 'l79', 'l82', 'l84', 'l85']", + "99, selective ['l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "100, small-molecule ['l86', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "101, inhibitor ['l87', 'l97', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "102, of ['l88', 'l98', 'l107', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "103, IKK ['l89', 'l99', 'l108', 'l116', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "108, genetic ['l90', 'l100', 'l109', 'l117', 'l124', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "109, IKK ['l91', 'l101', 'l110', 'l118', 'l125', 'l131', 'l137', 'l138', 'l139', 'l140', 'l141']", + "110, inhibition ['l92', 'l102', 'l111', 'l119', 'l126', 'l132', 'l137', 'l142', 'l143', 'l144', 'l145']", + "112, neurons, ['l93', 'l103', 'l112', 'l120', 'l127', 'l133', 'l138', 'l142', 'l146', 'l147', 'l148']", + "113, reducing ['l94', 'l104', 'l113', 'l121', 'l128', 'l134', 'l139', 'l143', 'l146', 'l149', 'l150']", + "118, cell ['l95', 'l105', 'l114', 'l122', 'l129', 'l135', 'l140', 'l144', 'l147', 'l149', 'l151']", + "119, death ['l96', 'l106', 'l115', 'l123', 'l130', 'l136', 'l141', 'l145', 'l148', 'l150', 'l151']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Ikbkb", + "(which", + "targeted" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "deletion", + "of", + "Ikbkb", + "(which" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "neurons", + "neurons." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "IKK", + "activity" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "IKK2" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neurons.", + "neurons," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "IKK", + "activity", + "selective", + "small-molecule", + "inhibitor", + "genetic" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "small-molecule", + "inhibitor", + "of", + "IKK", + "genetic", + "inhibition" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reducing" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "small-molecule", + "inhibitor", + "of", + "IKK", + "genetic", + "inhibition" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neurons," + ] + }, + "effect": { + "val": "negative", + "words": [ + "reducing" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neurons," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reducing" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + } + ] + }, + { + "PMID": "16244651", + "TEXT": "Mechanisms that regulate inflammation and repair after acute lung injury are incompletely understood. The extracellular matrix glycosaminoglycan hyaluronan is produced after tissue injury and impaired clearance results in unremitting inflammation. Here we report that hyaluronan degradation products require MyD88 and both Toll-like receptor (TLR)4 and TLR2 in vitro and in vivo to initiate inflammatory responses in acute lung injury. Hyaluronan fragments isolated from serum of individuals with acute lung injury stimulated macrophage chemokine production in a TLR4- and TLR2-dependent manner. Myd88(-/-) and Tlr4(-/-)Tlr2(-/-) mice showed impaired transepithelial migration of inflammatory cells but decreased survival and enhanced epithelial cell apoptosis after lung injury. Lung epithelial cell-specific overexpression of high-molecular-mass hyaluronan was protective against acute lung injury. Furthermore, epithelial cell-surface hyaluronan was protective against apoptosis, in part, through TLR-dependent basal activation of NF-kappaB. Hyaluronan-TLR2 and hyaluronan-TLR4 interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity and promote recovery from acute lung injury.", + "TAG_DATA": [ + "80, Myd88(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "82, Tlr4(-/-)Tlr2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "83, mice {'context': 'B-organism'}", + "85, impaired {'effect': 'B-negative'}", + "87, migration {'phenotype': 'B-migration'}", + "89, inflammatory {'context': 'B-cells'}", + "90, cells {'context': 'I-cells'}", + "95, enhanced {'effect': 'B-positive'}", + "96, epithelial {'context': 'B-cells'}", + "97, cell {'context': 'I-cells'}", + "98, apoptosis {'phenotype': 'B-apoptosis'}", + "102, Lung {'perturbing_action': 'B-gene gain-of-function'}", + "103, epithelial {'perturbing_action': 'I-gene gain-of-function'}", + "104, cell-specific {'perturbing_action': 'I-gene gain-of-function'}", + "105, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "106, of {'perturbing_action': 'I-gene gain-of-function'}", + "107, high-molecular-mass {'perturbing_action': 'I-gene gain-of-function'}", + "108, hyaluronan {'perturbing_action': 'I-gene gain-of-function'}", + "120, protective {'effect': 'B-negative'}", + "121, against {'effect': 'I-negative'}", + "122, apoptosis, {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "80, Myd88(-/-) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "82, Tlr4(-/-)Tlr2(-/-) ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "83, mice ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "85, impaired ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "87, migration ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36']", + "89, inflammatory ['l4', 'l13', 'l21', 'l28', 'l34', 'l37', 'l38', 'l39']", + "90, cells ['l5', 'l14', 'l22', 'l29', 'l35', 'l37', 'l40']", + "95, enhanced ['l6', 'l15', 'l23', 'l30', 'l38', 'l41', 'l42', 'l43']", + "96, epithelial ['l7', 'l16', 'l24', 'l31', 'l41', 'l44', 'l45']", + "97, cell ['l8', 'l17', 'l25', 'l32', 'l36', 'l39', 'l40', 'l42', 'l44', 'l46']", + "98, apoptosis ['l9', 'l18', 'l26', 'l33', 'l43', 'l45', 'l46']", + "102, Lung ['l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "103, epithelial ['l47', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "104, cell-specific ['l48', 'l56', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "105, overexpression ['l49', 'l57', 'l64', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "106, of ['l50', 'l58', 'l65', 'l71', 'l77', 'l78', 'l79', 'l80', 'l81']", + "107, high-molecular-mass ['l51', 'l59', 'l66', 'l72', 'l77', 'l82', 'l83', 'l84', 'l85']", + "108, hyaluronan ['l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l86', 'l87', 'l88']", + "120, protective ['l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l89', 'l90']", + "121, against ['l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l91']", + "122, apoptosis, ['l55', 'l63', 'l70', 'l76', 'l81', 'l85', 'l88', 'l90', 'l91']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Myd88(-/-)", + "Tlr4(-/-)Tlr2(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Myd88(-/-)", + "Tlr4(-/-)Tlr2(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Myd88(-/-)", + "Tlr4(-/-)Tlr2(-/-)" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Myd88(-/-)", + "Tlr4(-/-)Tlr2(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "inflammatory", + "cells", + "epithelial", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Myd88(-/-)", + "Tlr4(-/-)Tlr2(-/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Myd88(-/-)", + "Tlr4(-/-)Tlr2(-/-)" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "cells", + "words": [ + "inflammatory", + "cells", + "epithelial", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired", + "protective", + "against" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis," + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "cells", + "words": [ + "inflammatory", + "cells", + "cell" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "inflammatory", + "epithelial", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "epithelial", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Lung", + "epithelial", + "cell-specific", + "overexpression", + "of", + "high-molecular-mass", + "hyaluronan" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protective", + "against" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Lung", + "epithelial", + "cell-specific", + "overexpression", + "of", + "high-molecular-mass", + "hyaluronan" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + } + ] + }, + { + "PMID": "16227993", + "TEXT": "During development, activation of Cl(-)-permeable GABA(A) receptors (GABA(A)-R) excites neurons as a result of elevated intracellular Cl(-) levels and a depolarized Cl(-) equilibrium potential (E(Cl)). GABA becomes inhibitory as net outward neuronal transport of Cl(-) develops in a caudal-rostral progression. In line with this caudal-rostral developmental pattern, GABAergic anticonvulsant compounds inhibit motor manifestations of neonatal seizures but not cortical seizure activity. The Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) facilitates the accumulation of Cl(-) in neurons. The NKCC1 blocker bumetanide shifted E(Cl) negative in immature neurons, suppressed epileptiform activity in hippocampal slices in vitro and attenuated electrographic seizures in neonatal rats in vivo. Bumetanide had no effect in the presence of the GABA(A)-R antagonist bicuculline, nor in brain slices from NKCC1-knockout mice. NKCC1 expression level versus expression of the Cl(-)-extruding transporter (KCC2) in human and rat cortex showed that Cl(-) transport in perinatal human cortex is as immature as in the rat. Our results provide evidence that NKCC1 facilitates seizures in the developing brain and indicate that bumetanide should be useful in the treatment of neonatal seizures.", + "TAG_DATA": [ + "73, NKCC1 {'perturbing_action': 'B-pharmacological inhibition'}", + "74, blocker {'perturbing_action': 'I-pharmacological inhibition'}", + "75, bumetanide {'perturbing_action': 'I-pharmacological inhibition'}", + "80, immature {'context': 'B-cells'}", + "81, neurons, {'context': 'I-cells'}", + "86, hippocampal {'context': 'B-cells'}", + "87, slices {'context': 'I-cells'}", + "88, in {'context': 'B-in vitro'}", + "89, vitro {'context': 'I-in vitro'}", + "95, neonatal {'context': 'B-organism'}", + "96, rats {'context': 'I-organism'}", + "97, in {'context': 'B-in vivo'}", + "98, vivo. {'context': 'I-in vivo'}", + "113, brain {'context': 'B-tissue/organ'}", + "114, slices {'context': 'I-tissue/organ'}", + "116, NKCC1-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "117, mice. {'context': 'B-organism'}", + "129, human {'context': 'B-tissue/organ'}", + "130, and {'context': 'I-tissue/organ'}", + "131, rat {'context': 'I-tissue/organ'}", + "132, cortex {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "73, NKCC1 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "74, blocker ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "75, bumetanide ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "80, immature ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "81, neurons, ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46']", + "86, hippocampal ['l4', 'l15', 'l25', 'l34', 'l42', 'l47', 'l48', 'l49', 'l50', 'l51']", + "87, slices ['l5', 'l16', 'l26', 'l35', 'l43', 'l47', 'l52', 'l53', 'l54']", + "88, in ['l6', 'l17', 'l27', 'l36', 'l44', 'l48', 'l52', 'l55', 'l56']", + "89, vitro ['l7', 'l18', 'l28', 'l37', 'l45', 'l49', 'l53', 'l55', 'l57']", + "95, neonatal ['l8', 'l19', 'l29', 'l38', 'l58', 'l59', 'l60']", + "96, rats ['l9', 'l20', 'l30', 'l39', 'l46', 'l50', 'l54', 'l56', 'l57', 'l58', 'l61', 'l62']", + "97, in ['l10', 'l21', 'l31', 'l40', 'l59', 'l61', 'l63']", + "98, vivo. ['l11', 'l22', 'l32', 'l41', 'l51', 'l60', 'l62', 'l63']", + "113, brain ['l64', 'l65', 'l66']", + "114, slices ['l64', 'l67', 'l68']", + "116, NKCC1-knockout ['l65', 'l67', 'l69', 'l70', 'l71', 'l72', 'l73']", + "117, mice. ['l66', 'l68', 'l69', 'l74', 'l75', 'l76', 'l77']", + "129, human ['l70', 'l74', 'l78', 'l79', 'l80']", + "130, and ['l71', 'l75', 'l78', 'l81', 'l82']", + "131, rat ['l72', 'l76', 'l79', 'l81', 'l83']", + "132, cortex ['l73', 'l77', 'l80', 'l82', 'l83']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NKCC1", + "blocker", + "bumetanide" + ] + }, + "context": { + "val": "cells", + "words": [ + "immature", + "neurons,", + "hippocampal", + "slices" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NKCC1", + "blocker", + "bumetanide" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NKCC1", + "blocker", + "bumetanide" + ] + }, + "context": { + "val": "organism", + "words": [ + "neonatal", + "rats" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NKCC1", + "blocker", + "bumetanide" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "brain", + "slices", + "human", + "and", + "rat", + "cortex" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NKCC1-knockout" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NKCC1-knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "16155576", + "TEXT": "Tight glycemic control in individuals with diabetes mellitus is essential to prevent or delay its complications. Present treatments to reduce hyperglycemia mainly target the ATP-sensitive K(+) (K(ATP)) channel of pancreatic beta cells to increase insulin secretion. These current approaches are often associated with the side effect of hypoglycemia. Here we show that inhibition of the activity of cyclin-dependent kinase 5 (Cdk5) enhanced insulin secretion under conditions of stimulation by high glucose but not low glucose in MIN6 cells and pancreatic islets. The role of Cdk5 in regulation of insulin secretion was confirmed in pancreatic beta cells deficient in p35, an activator of Cdk5. p35-knockout mice also showed enhanced insulin secretion in response to a glucose challenge. Cdk5 kinase inhibition enhanced the inward whole-cell Ca(2+) channel current and increased Ca(2+) influx across the L-type voltage-dependent Ca(2+) channel (L-VDCC) upon stimulation with high glucose in beta cells, but had no effect on Ca(2+) influx without glucose stimulation. The inhibitory regulation by Cdk5 on the L-VDCC was attributed to the phosphorylation of loop II-III of the alpha(1C) subunit of L-VDCC at Ser783, which prevented the binding to SNARE proteins and subsequently resulted in a decrease of the activity of L-VDCC. These results suggest that Cdk5/p35 may be a drug target for the regulation of glucose-stimulated insulin secretion.", + "TAG_DATA": [ + "52, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "53, of {'perturbing_action': 'I-pharmacological inhibition'}", + "54, the {'perturbing_action': 'I-pharmacological inhibition'}", + "55, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "56, of {'perturbing_action': 'I-pharmacological inhibition'}", + "57, cyclin-dependent {'perturbing_action': 'I-pharmacological inhibition'}", + "58, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "59, 5 {'perturbing_action': 'I-pharmacological inhibition'}", + "60, (Cdk5) {'perturbing_action': 'I-pharmacological inhibition'}", + "76, MIN6 {'context': 'B-cells'}", + "77, cells {'context': 'I-cells'}", + "79, pancreatic {'context': 'B-cells'}", + "80, islets. {'context': 'I-cells'}", + "93, pancreatic {'context': 'B-cells'}", + "94, beta {'context': 'I-cells'}", + "95, cells {'context': 'I-cells'}", + "96, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "97, in {'perturbing_action': 'I-gene loss-of-function'}", + "98, p35, {'perturbing_action': 'I-gene loss-of-function'}", + "99, an {'perturbing_action': 'I-pharmacological inhibition'}", + "100, activator {'perturbing_action': 'I-pharmacological augmentation'}", + "101, of {'perturbing_action': 'I-pharmacological inhibition'}", + "102, Cdk5. {'perturbing_action': 'I-pharmacological augmentation'}", + "103, p35-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "104, mice {'context': 'B-organism'}", + "116, Cdk5 {'perturbing_action': 'B-pharmacological inhibition'}", + "117, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "118, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "143, beta {'context': 'B-cells'}", + "144, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "52, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "53, of ['l0', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "54, the ['l1', 'l18', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "55, activity ['l2', 'l19', 'l35', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "56, of ['l3', 'l20', 'l36', 'l51', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "57, cyclin-dependent ['l4', 'l21', 'l37', 'l52', 'l66', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "58, kinase ['l5', 'l22', 'l38', 'l53', 'l67', 'l80', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "59, 5 ['l6', 'l23', 'l39', 'l54', 'l68', 'l81', 'l93', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "60, (Cdk5) ['l7', 'l24', 'l40', 'l55', 'l69', 'l82', 'l94', 'l105', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "76, MIN6 ['l8', 'l25', 'l41', 'l56', 'l70', 'l83', 'l95', 'l106', 'l116', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "77, cells ['l9', 'l26', 'l42', 'l57', 'l71', 'l84', 'l96', 'l107', 'l117', 'l126', 'l132', 'l133', 'l134', 'l135', 'l136']", + "79, pancreatic ['l10', 'l27', 'l43', 'l58', 'l72', 'l85', 'l97', 'l108', 'l118', 'l127', 'l132', 'l137', 'l138', 'l139', 'l140', 'l141']", + "80, islets. ['l11', 'l28', 'l44', 'l59', 'l73', 'l86', 'l98', 'l109', 'l119', 'l128', 'l133', 'l137', 'l142', 'l143', 'l144', 'l145']", + "93, pancreatic ['l12', 'l29', 'l45', 'l60', 'l74', 'l87', 'l99', 'l110', 'l120', 'l129', 'l134', 'l138', 'l142', 'l146', 'l147', 'l148', 'l149', 'l150']", + "94, beta ['l13', 'l30', 'l46', 'l61', 'l75', 'l88', 'l100', 'l111', 'l121', 'l130', 'l135', 'l139', 'l143', 'l146', 'l151', 'l152']", + "95, cells ['l14', 'l31', 'l47', 'l62', 'l76', 'l89', 'l101', 'l112', 'l122', 'l131', 'l136', 'l140', 'l144', 'l147', 'l151', 'l153']", + "96, deficient ['l15', 'l32', 'l48', 'l63', 'l77', 'l90', 'l102', 'l113', 'l123', 'l141', 'l145', 'l148', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160']", + "97, in ['l16', 'l33', 'l49', 'l64', 'l78', 'l91', 'l103', 'l114', 'l124', 'l149', 'l154', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "98, p35, ['l17', 'l34', 'l50', 'l65', 'l79', 'l92', 'l104', 'l115', 'l125', 'l150', 'l155', 'l161', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "99, an ['l156', 'l162', 'l168', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180']", + "100, activator ['l157', 'l163', 'l169', 'l174', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186']", + "101, of ['l158', 'l164', 'l170', 'l175', 'l181', 'l187', 'l188', 'l189', 'l190', 'l191']", + "102, Cdk5. ['l159', 'l165', 'l171', 'l176', 'l182', 'l187', 'l192', 'l193', 'l194', 'l195']", + "103, p35-knockout ['l166', 'l172', 'l177', 'l183', 'l188', 'l192', 'l196', 'l197', 'l198']", + "104, mice ['l160', 'l167', 'l173', 'l178', 'l184', 'l189', 'l193', 'l196']", + "116, Cdk5 ['l199', 'l200', 'l201', 'l202']", + "117, kinase ['l199', 'l203', 'l204', 'l205']", + "118, inhibition ['l200', 'l203', 'l206', 'l207']", + "143, beta ['l179', 'l185', 'l190', 'l194', 'l197', 'l201', 'l204', 'l206', 'l208']", + "144, cells, ['l180', 'l186', 'l191', 'l195', 'l198', 'l202', 'l205', 'l207', 'l208']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "the", + "activity", + "cyclin-dependent", + "kinase", + "5", + "(Cdk5)", + "an", + "Cdk5" + ] + }, + "context": { + "val": "cells", + "words": [ + "MIN6", + "cells", + "pancreatic", + "islets.", + "beta", + "cells," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pancreatic", + "islets.", + "beta", + "cells", + "cells," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "p35,", + "p35-knockout" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "p35,", + "p35-knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "an", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activator", + "Cdk5." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activator", + "Cdk5." + ] + }, + "context": { + "val": "cells", + "words": [ + "beta", + "cells," + ] + } + } + ] + }, + { + "PMID": "16127435", + "TEXT": "Systemic lupus erythematosus (SLE) is a chronic inflammatory disease generated by deregulation of T cell-mediated B-cell activation, which results in glomerulonephritis and renal failure. Disease is treated with immunosuppressants and cytostatic agents that have numerous side effects. Here we examine the use of inhibitors of phosphoinositide 3-kinase (PI3K) gamma, a lipid kinase that regulates inflammation, in the MRL-lpr mouse model of SLE. Treatment reduced glomerulonephritis and prolonged lifespan, suggesting that P13Kgamma may be a useful target in the treatment of chronic inflammation.", + "TAG_DATA": [ + "43, inhibitors {'perturbing_action': 'B-pharmacological inhibition'}", + "44, of {'perturbing_action': 'I-pharmacological inhibition'}", + "45, phosphoinositide {'perturbing_action': 'I-pharmacological inhibition'}", + "46, 3-kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "47, (PI3K) {'perturbing_action': 'I-pharmacological inhibition'}", + "48, gamma, {'perturbing_action': 'I-pharmacological inhibition'}", + "57, MRL-lpr {'perturbing_action': 'B-other', 'context': 'B-organism'}", + "58, mouse {'context': 'I-organism'}", + "59, model {'context': 'I-organism'}", + "60, of {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "43, inhibitors ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "44, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "45, phosphoinositide ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "46, 3-kinase ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "47, (PI3K) ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "48, gamma, ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "57, MRL-lpr ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "58, mouse ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "59, model ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "60, of ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "phosphoinositide", + "3-kinase", + "(PI3K)", + "gamma," + ] + }, + "context": { + "val": "organism", + "words": [ + "MRL-lpr", + "mouse", + "model", + "of" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "MRL-lpr" + ] + }, + "context": { + "val": "organism", + "words": [ + "MRL-lpr" + ] + } + } + ] + }, + { + "PMID": "16116432", + "TEXT": "Development of therapeutic agents for severe acute respiratory syndrome (SARS) viral infection using short interfering RNA (siRNA) inhibitors exemplifies a powerful new means to combat emerging infectious diseases. Potent siRNA inhibitors of SARS coronavirus (SCV) in vitro were further evaluated for efficacy and safety in a rhesus macaque (Macaca mulatta) SARS model using clinically viable delivery while comparing three dosing regimens. Observations of SARS-like symptoms, measurements of SCV RNA presence and lung histopathology and immunohistochemistry consistently showed siRNA-mediated anti-SARS efficacy by either prophylactic or therapeutic regimens. The siRNAs used provided relief from SCV infection-induced fever, diminished SCV viral levels and reduced acute diffuse alveoli damage. The 10-40 mg/kg accumulated dosages of siRNA did not show any sign of siRNA-induced toxicity. These results suggest that a clinical investigation is warranted and illustrate the prospects for siRNA to enable a massive reduction in development time for new targeted therapeutic agents.", + "TAG_DATA": [ + "29, siRNA {'perturbing_action': 'I-rnai/knockdown'}", + "30, inhibitors {'perturbing_action': 'I-rnai/knockdown'}", + "31, of {'perturbing_action': 'I-rnai/knockdown'}", + "32, SARS {'perturbing_action': 'I-rnai/knockdown'}", + "33, coronavirus {'perturbing_action': 'I-rnai/knockdown'}", + "34, (SCV) {'perturbing_action': 'I-rnai/knockdown'}", + "35, in {'context': 'B-in vitro'}", + "36, vitro {'context': 'B-in vitro'}", + "46, rhesus {'context': 'B-organism'}", + "47, macaque {'context': 'I-organism'}", + "48, (Macaca {'context': 'I-organism'}", + "49, mulatta) {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "29, siRNA ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "30, inhibitors ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "31, of ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "32, SARS ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "33, coronavirus ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "34, (SCV) ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "35, in ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "36, vitro ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "46, rhesus ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "47, macaque ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "48, (Macaca ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "49, mulatta) ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA", + "inhibitors", + "of", + "SARS", + "coronavirus", + "(SCV)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA", + "inhibitors", + "of", + "SARS", + "coronavirus", + "(SCV)" + ] + }, + "context": { + "val": "organism", + "words": [ + "rhesus", + "macaque", + "(Macaca", + "mulatta)" + ] + } + } + ] + }, + { + "PMID": "16041384", + "TEXT": "Immunosuppressants are crucial in the prevention of detrimental immune reactions associated with allogenic organ transplantation, but they often cause adverse effects in a number of biological systems, including the skeletal system. Calcineurin inhibitors FK506 and cyclosporin A inhibit nuclear factor of activated T cells (NFAT) activity and induce strong immunosuppression. Among NFAT proteins, NFATc1 is crucial for the differentiation of bone-resorbing osteoclasts. Here we show FK506 administration induces the reduction of bone mass despite a blockade of osteoclast differentiation. This reduction is caused by severe impairment of bone formation, suggesting that NFAT transcription factors also have an important role in the transcriptional program of osteoblasts. In fact, bone formation is inhibited in Nfatc1- and Nfatc2-deficient cells as well as in FK506-treated osteoblasts. Overexpression of NFATc1 stimulates Osterix-dependent activation of the Col1a1 (encoding type I collagen) promoter, but not Runx2-dependent activation of the Bglap1 (encoding osteocalcin) promoter. NFAT and Osterix form a complex that binds to DNA, and this interaction is important for the transcriptional activity of Osterix. Thus, NFAT and Osterix cooperatively control osteoblastic bone formation. These results may provide important insight into the management of post-transplantation osteoporosis as well as a new strategy for promoting bone regeneration in osteopenic disease.", + "TAG_DATA": [ + "75, blockade {'effect': 'B-negative'}", + "77, osteoclast {'context': 'B-cells'}", + "78, differentiation. {'phenotype': 'B-differentiation'}", + "107, bone {'phenotype': 'B-tumourigenesis'}", + "108, formation {'phenotype': 'I-tumourigenesis'}", + "110, inhibited {'effect': 'B-negative'}", + "112, Nfatc1- {'perturbing_action': 'B-gene loss-of-function'}", + "113, and {'perturbing_action': 'I-gene loss-of-function'}", + "114, Nfatc2-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "115, cells {'context': 'B-cells'}", + "121, osteoblasts. {'context': 'B-cells'}", + "122, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "123, of {'perturbing_action': 'I-gene gain-of-function'}", + "124, NFATc1 {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "75, blockade ['l0', 'l1', 'l2', 'l3']", + "77, osteoclast ['l0', 'l4', 'l5', 'l6']", + "78, differentiation. ['l1', 'l4']", + "107, bone ['l2', 'l5', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "108, formation ['l3', 'l6', 'l7', 'l13', 'l14', 'l15', 'l16']", + "110, inhibited ['l8', 'l13', 'l17', 'l18', 'l19', 'l20']", + "112, Nfatc1- ['l9', 'l14', 'l17', 'l21', 'l22', 'l23', 'l24']", + "113, and ['l10', 'l15', 'l18', 'l21', 'l25', 'l26', 'l27']", + "114, Nfatc2-deficient ['l11', 'l19', 'l22', 'l25', 'l28', 'l29']", + "115, cells ['l12', 'l16', 'l20', 'l23', 'l26', 'l28']", + "121, osteoblasts. ['l24', 'l27', 'l29']", + "122, Overexpression ['l30', 'l31']", + "123, of ['l30', 'l32']", + "124, NFATc1 ['l31', 'l32']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "blockade", + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blockade" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blockade", + "inhibited" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "bone", + "formation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoclast", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "bone", + "formation" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "bone", + "formation" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nfatc1-", + "and", + "Nfatc2-deficient" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nfatc1-", + "and", + "Nfatc2-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nfatc1-", + "and", + "Nfatc2-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "osteoblasts." + ] + } + } + ] + }, + { + "PMID": "16041383", + "TEXT": "Mechanisms of progression of chronic renal diseases, a major healthcare burden, are poorly understood. Angiotensin II (AngII), the major renin-angiotensin system effector, is known to be involved in renal deterioration, but the molecular pathways are still unknown. Here, we show that mice overexpressing a dominant negative isoform of epidermal growth factor receptor (EGFR) were protected from renal lesions during chronic AngII infusion. Transforming growth factor-alpha (TGF-alpha) and its sheddase, TACE (also known as ADAM17), were induced by AngII treatment, TACE was redistributed to apical membranes and EGFR was phosphorylated. AngII-induced lesions were substantially reduced in mice lacking TGF-alpha or in mice given a specific TACE inhibitor. Pharmacologic inhibition of AngII prevented TGF-alpha and TACE accumulation as well as renal lesions after nephron reduction. These findings indicate a crucial role for AngII-dependent EGFR transactivation in renal deterioration and identify in TACE inhibitors a new therapeutic strategy for preventing progression of chronic renal diseases.", + "TAG_DATA": [ + "41, mice {'context': 'B-organism'}", + "42, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "43, a {'perturbing_action': 'I-gene gain-of-function'}", + "44, dominant {'perturbing_action': 'I-gene gain-of-function'}", + "45, negative {'perturbing_action': 'I-gene gain-of-function'}", + "46, isoform {'perturbing_action': 'I-gene gain-of-function'}", + "47, of {'perturbing_action': 'I-gene gain-of-function'}", + "48, epidermal {'perturbing_action': 'I-gene gain-of-function'}", + "49, growth {'perturbing_action': 'I-gene gain-of-function'}", + "50, factor {'perturbing_action': 'I-gene gain-of-function'}", + "51, receptor {'perturbing_action': 'I-gene gain-of-function'}", + "52, (EGFR) {'perturbing_action': 'I-gene gain-of-function'}", + "95, mice {'context': 'B-organism'}", + "96, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "97, TGF-alpha {'perturbing_action': 'I-gene loss-of-function'}", + "100, mice {'context': 'B-organism'}", + "103, specific {'perturbing_action': 'B-pharmacological inhibition'}", + "104, TACE {'perturbing_action': 'I-pharmacological inhibition'}", + "105, inhibitor. {'perturbing_action': 'I-pharmacological inhibition'}", + "106, Pharmacologic {'perturbing_action': 'B-pharmacological inhibition'}", + "107, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "108, of {'perturbing_action': 'I-pharmacological inhibition'}", + "109, AngII {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "41, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "42, overexpressing ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "43, a ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "44, dominant ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "45, negative ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "46, isoform ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "47, of ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "48, epidermal ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "49, growth ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "50, factor ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "51, receptor ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "52, (EGFR) ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "95, mice ['l66', 'l67']", + "96, lacking ['l66', 'l68']", + "97, TGF-alpha ['l67', 'l68', 'l69']", + "100, mice ['l69', 'l70', 'l71', 'l72']", + "103, specific ['l70', 'l73', 'l74']", + "104, TACE ['l71', 'l73', 'l75']", + "105, inhibitor. ['l72', 'l74', 'l75']", + "106, Pharmacologic ['l76', 'l77', 'l78']", + "107, inhibition ['l76', 'l79', 'l80']", + "108, of ['l77', 'l79', 'l81']", + "109, AngII ['l78', 'l80', 'l81']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "a", + "dominant", + "negative", + "isoform", + "of", + "epidermal", + "growth", + "factor", + "receptor", + "(EGFR)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "TGF-alpha" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "TACE", + "inhibitor." + ] + } + } + ] + }, + { + "PMID": "16041381", + "TEXT": "The latent transcription factor Stat3 is activated by gp130, the common receptor for the interleukin (IL)-6 cytokine family and other growth factor and cytokine receptors. Ligand-induced dimerization of gp130 leads to activation of the Stat1, Stat3 and Shp2-Ras-Erk signaling pathways. Here we assess genetically the contribution of exaggerated Stat3 activation to the phenotype of gp130 (Y757F/Y757F) mice, in which a knock-in mutation disrupts the negative feedback mechanism on gp130-dependent Stat signaling. Compared to gp130 (Y757F/Y757F) mice, reduced Stat3 activation in gp130 (Y757F/Y757F) Stat3(+/-) mice increased their lifespan, prevented splenomegaly, normalized exaggerated hepatic acute-phase response and lymphocyte trafficking, and suppressed the growth of spontaneously arising gastric adenomas in young mice. These lesions share histological features of gastric polyps in aging mice with monoallelic null mutations in Smad4, which encodes the common transducer for transforming growth factor (TGF)-beta signaling. Indeed, hyperactivation of Stat3 desensitizes gp130 (Y757F/Y757F) cells to the cytostatic effect of TGF-beta through transcriptional induction of inhibitory Smad7, thereby providing a novel link for cross-talk between Stat and Smad signaling in gastric homeostasis.", + "TAG_DATA": [ + "80, gp130 {'perturbing_action': 'B-other'}", + "81, (Y757F/Y757F) {'perturbing_action': 'B-other'}", + "82, Stat3(+/-) {'perturbing_action': 'B-other'}", + "83, mice {'context': 'B-organism'}", + "95, lymphocyte {'context': 'B-cells'}", + "104, gastric {'context': 'B-neoplasm'}", + "105, adenomas {'context': 'I-neoplasm'}", + "107, young {'context': 'B-organism'}", + "108, mice. {'context': 'I-organism'}", + "142, gp130 {'context': 'B-cells'}", + "144, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "80, gp130 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "81, (Y757F/Y757F) ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "82, Stat3(+/-) ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "83, mice ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "95, lymphocyte ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28']", + "104, gastric ['l4', 'l11', 'l17', 'l22', 'l29', 'l30', 'l31']", + "105, adenomas ['l5', 'l12', 'l18', 'l23', 'l26', 'l29', 'l32', 'l33']", + "107, young ['l6', 'l13', 'l19', 'l24', 'l27', 'l30', 'l32', 'l34']", + "108, mice. ['l7', 'l14', 'l20', 'l25', 'l28', 'l31', 'l33', 'l34']", + "142, gp130 ['l35']", + "144, cells ['l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "gp130", + "(Y757F/Y757F)", + "Stat3(+/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "young", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "gp130", + "(Y757F/Y757F)", + "Stat3(+/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "lymphocyte" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "gp130", + "(Y757F/Y757F)", + "Stat3(+/-)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "gastric", + "adenomas" + ] + } + } + ] + }, + { + "PMID": "16025126", + "TEXT": "Hypertrophy represents the major physiological response of the heart to adapt to chronically enhanced workload, but is also crucial in the development of heart failure. Although we know of numerous inducers of cardiac hypertrophy, little is known about mechanisms that limit cardiac hypertrophy. Here, we describe the transcriptional repressor NAB1 as an endogenous regulator of cardiac growth. We identified NAB1 as being upregulated in both mouse and human heart failure. Nab1 is highly expressed in mammalian cardiac myocytes and it inhibited cardiomyocyte hypertrophy through repression of its targets, transcription factor Egr. Transgenic mice with cardiac-specific overexpression of Nab1 showed that Nab1 is a potent inhibitor of cardiac growth in response to pathological stimuli in vivo. Nab1 overexpression suppressed adrenergically induced and pressure overload-induced hypertrophy, whereas physiological growth during development and in response to exercise was not affected. These findings implicate the Nab1-Egr1 axis as a crucial regulator of pathological cardiac growth.", + "TAG_DATA": [ + "92, mice {'context': 'I-organism'}", + "94, cardiac-specific {'perturbing_action': 'B-gene gain-of-function'}", + "95, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "96, of {'perturbing_action': 'I-gene gain-of-function'}", + "97, Nab1 {'perturbing_action': 'I-gene gain-of-function'}", + "113, in {'context': 'B-in vivo'}", + "114, vivo. {'context': 'I-in vivo'}", + "115, Nab1 {'perturbing_action': 'B-gene gain-of-function'}", + "116, overexpression {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "92, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "94, cardiac-specific ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "95, overexpression ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "96, of ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "97, Nab1 ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "113, in ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "114, vivo. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "115, Nab1 ['l21']", + "116, overexpression ['l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "cardiac-specific", + "overexpression", + "of", + "Nab1" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "cardiac-specific", + "overexpression", + "of", + "Nab1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "16007096", + "TEXT": "Suppressor of cytokine signaling (SOCS) 3 attenuates proinflammatory signaling mediated by the signal transducer and activator of transcription (STAT) family of proteins. But acute inflammation can occur after exposure to pathogen-derived inducers staphylococcal enterotoxin B (SEB) and lipopolysaccharide (LPS), or the lectin concanavalin A (ConA), suggesting that physiologic levels of SOCS3 are insufficient to stem proinflammatory signaling under pathogenic circumstances. To test this hypothesis, we developed recombinant cell-penetrating forms of SOCS3 (CP-SOCS3) for intracellular delivery to counteract SEB-, LPS- and ConA-induced inflammation. We found that CP-SOCS3 was distributed in multiple organs within 2 h and persisted for at least 8 h in leukocytes and lymphocytes. CP-SOCS3 protected animals from lethal effects of SEB and LPS by reducing production of inflammatory cytokines and attenuating liver apoptosis and hemorrhagic necrosis. It also reduced ConA-induced liver apoptosis. Thus, replenishing the intracellular stores of SOCS3 with CP-SOCS3 effectively suppresses the devastating effects of acute inflammation.", + "TAG_DATA": [ + "102, leukocytes {'context': 'B-cells'}", + "104, lymphocytes. {'context': 'B-cells'}", + "107, animals {'context': 'B-organism'}", + "122, attenuating {'effect': 'B-negative'}", + "123, liver {'context': 'B-tissue/organ'}", + "124, apoptosis {'phenotype': 'B-apoptosis'}", + "127, necrosis. {'phenotype': 'B-necrosis'}", + "130, reduced {'effect': 'B-negative'}", + "131, ConA-induced {'effect': 'B-positive'}", + "132, liver {'context': 'B-tissue/organ'}", + "133, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "102, leukocytes ['l0', 'l1', 'l2', 'l3', 'l4']", + "104, lymphocytes. ['l0']", + "107, animals ['l1', 'l5', 'l6', 'l7', 'l8']", + "122, attenuating ['l2', 'l5', 'l9', 'l10', 'l11']", + "123, liver ['l3', 'l6', 'l9', 'l12', 'l13']", + "124, apoptosis ['l4', 'l7', 'l10', 'l12', 'l14']", + "127, necrosis. ['l8', 'l11', 'l13', 'l14']", + "130, reduced ['l15', 'l16', 'l17']", + "131, ConA-induced ['l15', 'l18', 'l19']", + "132, liver ['l16', 'l18', 'l20']", + "133, apoptosis. ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "leukocytes" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuating" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "leukocytes" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animals" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuating" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animals" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animals" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuating", + "reduced" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuating", + "reduced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuating" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "ConA-induced" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "ConA-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "15980866", + "TEXT": "Type 2 diabetes is a disorder of hyperglycemia resulting from failure of beta cells to produce adequate insulin to accommodate an increased metabolic demand. Here we show that regulation of mRNA translation through phosphorylation of eukaryotic initiation factor 2 (eIF2alpha) is essential to preserve the integrity of the endoplasmic reticulum (ER) and to increase insulin production to meet the demand imposed by a high-fat diet. Accumulation of unfolded proteins in the ER activates phosphorylation of eIF2alpha at Ser51 and inhibits translation. To elucidate the role of this pathway in beta-cell function we studied glucose homeostasis in Eif2s1(tm1Rjk) mutant mice, which have an alanine substitution at Ser51. Heterozygous (Eif2s1(+/tm1Rjk)) mice became obese and diabetic on a high-fat diet. Profound glucose intolerance resulted from reduced insulin secretion accompanied by abnormal distension of the ER lumen, defective trafficking of proinsulin, and a reduced number of insulin granules in beta cells. We propose that translational control couples insulin synthesis with folding capacity to maintain ER integrity and that this signal is essential to prevent diet-induced type 2 diabetes.", + "TAG_DATA": [ + "96, Eif2s1(tm1Rjk) {'perturbing_action': 'B-other'}", + "97, mutant {'perturbing_action': 'I-other'}", + "98, mice, {'context': 'B-organism'}", + "106, Heterozygous {'perturbing_action': 'B-other'}", + "107, (Eif2s1(+/tm1Rjk)) {'perturbing_action': 'I-other'}", + "108, mice {'context': 'B-organism'}", + "145, beta {'context': 'B-cells'}", + "146, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "96, Eif2s1(tm1Rjk) ['l0', 'l1']", + "97, mutant ['l0', 'l2']", + "98, mice, ['l1', 'l2']", + "106, Heterozygous ['l3', 'l4', 'l5']", + "107, (Eif2s1(+/tm1Rjk)) ['l3', 'l6', 'l7', 'l8']", + "108, mice ['l4', 'l6']", + "145, beta ['l7', 'l9']", + "146, cells. ['l5', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Eif2s1(tm1Rjk)", + "mutant", + "Heterozygous", + "(Eif2s1(+/tm1Rjk))" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Heterozygous", + "(Eif2s1(+/tm1Rjk))" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells.", + "beta" + ] + } + } + ] + }, + { + "PMID": "15834428", + "TEXT": "Vascular endothelial growth factor (VEGF)-induced blood vessel growth is involved in both physiological and pathological angiogenesis and requires integrin-mediated signaling. We now show that an integrin-binding protein initially described in milk-fat globule, MFG-E8 (also known as lactadherin), is expressed in and around blood vessels and has a crucial role in VEGF-dependent neovascularization in the adult mouse. Using neutralizing antibodies and lactadherin-deficient animals, we show that lactadherin interacts with alphavbeta3 and alphavbeta5 integrins and alters both VEGF-dependent Akt phosphorylation and neovascularization. In the absence of VEGF, lactadherin administration induced alphavbeta3- and alphavbeta5-dependent Akt phosphorylation in endothelial cells in vitro and strongly improved postischemic neovascularization in vivo. These results show a crucial role for lactadherin in VEGF-dependent neovascularization and identify lactadherin as an important target for the modulation of neovascularization.", + "TAG_DATA": [ + "60, lactadherin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "61, animals, {'context': 'B-organism'}", + "82, absence {'perturbing_action': 'B-gene loss-of-function'}", + "83, of {'perturbing_action': 'I-gene loss-of-function'}", + "84, VEGF, {'perturbing_action': 'I-gene loss-of-function'}", + "94, endothelial {'context': 'B-cells'}", + "95, cells {'context': 'I-cells'}", + "96, in {'context': 'B-in vitro'}", + "97, vitro {'context': 'I-in vitro'}", + "103, in {'context': 'B-in vivo'}", + "104, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "60, lactadherin-deficient ['l0', 'l1']", + "61, animals, ['l0', 'l2', 'l3']", + "82, absence ['l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "83, of ['l2', 'l4', 'l10', 'l11', 'l12', 'l13', 'l14']", + "84, VEGF, ['l5', 'l10', 'l15', 'l16', 'l17', 'l18']", + "94, endothelial ['l6', 'l11', 'l15', 'l19', 'l20', 'l21']", + "95, cells ['l1', 'l3', 'l7', 'l12', 'l16', 'l19', 'l22', 'l23']", + "96, in ['l8', 'l13', 'l17', 'l20', 'l22', 'l24']", + "97, vitro ['l9', 'l14', 'l18', 'l21', 'l23', 'l24']", + "103, in ['l25']", + "104, vivo. ['l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lactadherin-deficient", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "animals," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lactadherin-deficient", + "absence", + "of", + "VEGF," + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "endothelial" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "VEGF," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "15821746", + "TEXT": "Although epithelial ovarian cancers (EOCs) have been thought to arise from the simple epithelium lining the ovarian surface or inclusion cysts, the major subtypes of EOCs show morphologic features that resemble those of the müllerian duct-derived epithelia of the reproductive tract. We found that HOX genes, which normally regulate mullerian duct differentiation, are not expressed in normal ovarian surface epithelium (OSE), but are expressed in different EOC subtypes according to the pattern of mullerian-like differentiation of these cancers. Ectopic expression of Hoxa9 in tumorigenic mouse OSE cells gave rise to papillary tumors resembling serous EOCs. In contrast, Hoxa10 and Hoxa11 induced morphogenesis of endometrioid-like and mucinous-like EOCs, respectively. Hoxa7 showed no lineage specificity, but promoted the abilities of Hoxa9, Hoxa10 and Hoxa11 to induce differentiation along their respective pathways. Therefore, inappropriate activation of a molecular program that controls patterning of the reproductive tract could explain the morphologic heterogeneity of EOCs and their assumption of müllerian-like features.", + "TAG_DATA": [ + "78, Ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "79, expression {'perturbing_action': 'I-gene gain-of-function'}", + "80, of {'perturbing_action': 'I-gene gain-of-function'}", + "81, Hoxa9 {'perturbing_action': 'I-gene gain-of-function'}", + "83, tumorigenic {'context': 'B-transformed cells'}", + "84, mouse {'context': 'I-transformed cells'}", + "85, OSE {'context': 'I-transformed cells'}", + "86, cells {'context': 'I-transformed cells'}", + "87, gave {'effect': 'B-positive'}", + "88, rise {'effect': 'I-positive'}", + "89, to {'effect': 'I-positive'}", + "90, papillary {'phenotype': 'B-tumourigenesis'}", + "91, tumors {'phenotype': 'I-tumourigenesis'}", + "106, EOCs, {'context': 'B-neoplasm'}", + "123, induce {'effect': 'B-positive'}", + "124, differentiation {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "78, Ectopic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "79, expression ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "80, of ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "81, Hoxa9 ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "83, tumorigenic ['l3', 'l14', 'l24', 'l33', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "84, mouse ['l4', 'l15', 'l25', 'l34', 'l41', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "85, OSE ['l5', 'l16', 'l26', 'l35', 'l42', 'l49', 'l55', 'l56', 'l57', 'l58', 'l59']", + "86, cells ['l6', 'l17', 'l27', 'l36', 'l43', 'l50', 'l55', 'l60', 'l61', 'l62', 'l63']", + "87, gave ['l7', 'l18', 'l28', 'l37', 'l44', 'l51', 'l56', 'l60', 'l64', 'l65', 'l66', 'l67']", + "88, rise ['l8', 'l19', 'l29', 'l38', 'l45', 'l52', 'l57', 'l61', 'l64', 'l68', 'l69', 'l70']", + "89, to ['l9', 'l20', 'l30', 'l39', 'l46', 'l53', 'l58', 'l62', 'l65', 'l68', 'l71', 'l72']", + "90, papillary ['l10', 'l21', 'l31', 'l47', 'l66', 'l69', 'l71', 'l73']", + "91, tumors ['l11', 'l22', 'l32', 'l40', 'l48', 'l54', 'l59', 'l63', 'l67', 'l70', 'l72', 'l73']", + "123, induce ['l74']", + "124, differentiation ['l74']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "Hoxa9" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumorigenic", + "mouse", + "OSE", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "Hoxa9" + ] + }, + "effect": { + "val": "positive", + "words": [ + "gave", + "rise", + "to" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "Hoxa9" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "papillary", + "tumors" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumorigenic", + "mouse", + "OSE", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "gave", + "rise", + "to" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumorigenic", + "mouse", + "OSE", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "papillary", + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "gave", + "rise", + "to" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "papillary", + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "15793582", + "TEXT": "Beta-adrenergic receptor (betaAR) stimulation increases cytosolic Ca(2+) to physiologically augment cardiac contraction, whereas excessive betaAR activation causes adverse cardiac remodeling, including myocardial hypertrophy, dilation and dysfunction, in individuals with myocardial infarction. The Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) is a recently identified downstream element of the betaAR-initiated signaling cascade that is linked to pathological myocardial remodeling and to regulation of key proteins involved in cardiac excitation-contraction coupling. We developed a genetic mouse model of cardiac CaMKII inhibition to test the role of CaMKII in betaAR signaling in vivo. Here we show CaMKII inhibition substantially prevented maladaptive remodeling from excessive betaAR stimulation and myocardial infarction, and induced balanced changes in excitation-contraction coupling that preserved baseline and betaAR-stimulated physiological increases in cardiac function. These findings mark CaMKII as a determinant of clinically important heart disease phenotypes, and suggest CaMKII inhibition can be a highly selective approach for targeting adverse myocardial remodeling linked to betaAR signaling.", + "TAG_DATA": [ + "69, genetic {'context': 'B-organism'}", + "70, mouse {'context': 'I-organism'}", + "71, model {'context': 'I-organism'}", + "74, CaMKII {'perturbing_action': 'I-pharmacological inhibition'}", + "75, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "90, CaMKII {'perturbing_action': 'B-pharmacological inhibition'}", + "91, inhibition {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "69, genetic ['l0', 'l1', 'l2', 'l3']", + "70, mouse ['l0', 'l4', 'l5', 'l6']", + "71, model ['l1', 'l4', 'l7', 'l8']", + "74, CaMKII ['l2', 'l5', 'l7', 'l9']", + "75, inhibition ['l3', 'l6', 'l8', 'l9']", + "90, CaMKII ['l10']", + "91, inhibition ['l10']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "genetic", + "mouse", + "model" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CaMKII", + "inhibition" + ] + } + } + ] + }, + { + "PMID": "15793580", + "TEXT": "Animal allergens are an important cause of asthma and allergic rhinitis. We designed and tested a chimeric human-cat fusion protein composed of a truncated human IgG Fcgamma1 and the major cat allergen Fel d1, as a proof of concept for a new approach to allergy immunotherapy. This Fcgamma-Fel d1 protein induced dose-dependent inhibition of Fel d1-driven IgE-mediated histamine release from cat-allergic donors' basophils and sensitized human cord blood-derived mast cells. Such inhibition was associated with altered Syk and ERK signaling. The Fcgamma-Fel d1 protein also blocked in vivo reactivity in FcepsilonRIalpha transgenic mice passively sensitized with human IgE antibody to cat and in Balb/c mice actively sensitized against Fel d1. The Fcgamma-Fel d1 protein alone did not induce mediator release. Chimeric human Fcgamma-allergen fusion proteins may provide a new therapeutic platform for the immune-based therapy of allergic disease.", + "TAG_DATA": [ + "65, human {'context': 'B-cells'}", + "66, cord {'context': 'I-cells'}", + "67, blood-derived {'context': 'I-cells'}", + "68, mast {'context': 'I-cells'}", + "69, cells. {'context': 'I-cells'}", + "86, in {'context': 'B-in vivo'}", + "87, vivo {'context': 'I-in vivo'}", + "90, FcepsilonRIalpha {'perturbing_action': 'B-gene gain-of-function'}", + "91, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "92, mice {'context': 'B-organism'}", + "103, Balb/c {'context': 'B-organism'}", + "104, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "65, human ['l0', 'l1', 'l2', 'l3']", + "66, cord ['l0', 'l4', 'l5', 'l6', 'l7']", + "67, blood-derived ['l1', 'l4', 'l8', 'l9', 'l10']", + "68, mast ['l2', 'l5', 'l8', 'l11']", + "69, cells. ['l3', 'l6', 'l9', 'l11']", + "86, in ['l12', 'l13', 'l14', 'l15']", + "87, vivo ['l7', 'l10', 'l12', 'l16', 'l17', 'l18']", + "90, FcepsilonRIalpha ['l13', 'l16', 'l19', 'l20']", + "91, transgenic ['l14', 'l17', 'l19', 'l21']", + "92, mice ['l15', 'l18', 'l20', 'l21']", + "103, Balb/c ['l22']", + "104, mice ['l22']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "FcepsilonRIalpha", + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "FcepsilonRIalpha", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15665834", + "TEXT": "Sustained cardiac pressure overload induces hypertrophy and pathological remodeling, frequently leading to heart failure. Genetically engineered hyperstimulation of guanosine 3',5'-cyclic monophosphate (cGMP) synthesis counters this response. Here, we show that blocking the intrinsic catabolism of cGMP with an oral phosphodiesterase-5A (PDE5A) inhibitor (sildenafil) suppresses chamber and myocyte hypertrophy, and improves in vivo heart function in mice exposed to chronic pressure overload induced by transverse aortic constriction. Sildenafil also reverses pre-established hypertrophy induced by pressure load while restoring chamber function to normal. cGMP catabolism by PDE5A increases in pressure-loaded hearts, leading to activation of cGMP-dependent protein kinase with inhibition of PDE5A. PDE5A inhibition deactivates multiple hypertrophy signaling pathways triggered by pressure load (the calcineurin/NFAT, phosphoinositide-3 kinase (PI3K)/Akt, and ERK1/2 signaling pathways). But it does not suppress hypertrophy induced by overexpression of calcineurin in vitro or Akt in vivo, suggesting upstream targeting of these pathways. PDE5A inhibition may provide a new treatment strategy for cardiac hypertrophy and remodeling.", + "TAG_DATA": [ + "38, oral {'perturbing_action': 'B-pharmacological inhibition'}", + "39, phosphodiesterase-5A {'perturbing_action': 'I-pharmacological inhibition'}", + "40, (PDE5A) {'perturbing_action': 'I-pharmacological inhibition'}", + "41, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "42, (sildenafil) {'perturbing_action': 'I-pharmacological inhibition'}", + "44, chamber {'context': 'B-cells'}", + "46, myocyte {'context': 'B-cells'}", + "50, in {'context': 'B-in vivo'}", + "51, vivo {'context': 'I-in vivo'}", + "52, heart {'context': 'B-tissue/organ'}", + "55, mice {'context': 'B-organism'}", + "77, chamber {'context': 'B-tissue/organ'}", + "88, hearts, {'context': 'B-tissue/organ'}", + "97, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "98, of {'perturbing_action': 'I-pharmacological inhibition'}", + "99, PDE5A. {'perturbing_action': 'I-pharmacological inhibition'}", + "100, PDE5A {'perturbing_action': 'B-pharmacological inhibition'}", + "101, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "128, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "129, of {'perturbing_action': 'I-gene gain-of-function'}", + "130, calcineurin {'perturbing_action': 'I-gene gain-of-function'}", + "131, in {'context': 'B-in vitro'}", + "132, vitro {'context': 'I-in vitro'}", + "135, in {'context': 'B-in vivo'}", + "136, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "38, oral ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "39, phosphodiesterase-5A ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "40, (PDE5A) ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "41, inhibitor ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "42, (sildenafil) ['l3', 'l14', 'l24', 'l33', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "44, chamber ['l4', 'l15', 'l25', 'l34', 'l41', 'l47', 'l48']", + "46, myocyte ['l5', 'l16', 'l26', 'l35', 'l42', 'l47']", + "50, in ['l6', 'l17', 'l27', 'l36', 'l43', 'l49', 'l50', 'l51']", + "51, vivo ['l7', 'l18', 'l28', 'l37', 'l44', 'l49', 'l52', 'l53']", + "52, heart ['l8', 'l19', 'l29', 'l38', 'l45', 'l48', 'l50', 'l52', 'l54']", + "55, mice ['l9', 'l20', 'l30', 'l39', 'l46', 'l51', 'l53', 'l54']", + "77, chamber ['l10', 'l21', 'l31', 'l55']", + "88, hearts, ['l11', 'l22', 'l32', 'l40', 'l55', 'l56', 'l57']", + "97, inhibition ['l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "98, of ['l56', 'l58', 'l65', 'l66', 'l67', 'l68']", + "99, PDE5A. ['l57', 'l59', 'l65', 'l69']", + "100, PDE5A ['l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "101, inhibition ['l60', 'l66', 'l70', 'l78', 'l79', 'l80', 'l81', 'l82']", + "128, overexpression ['l71', 'l78', 'l83', 'l84', 'l85', 'l86']", + "129, of ['l61', 'l67', 'l72', 'l79', 'l83', 'l87', 'l88', 'l89']", + "130, calcineurin ['l62', 'l68', 'l69', 'l73', 'l80', 'l84', 'l87', 'l90', 'l91']", + "131, in ['l63', 'l74', 'l81', 'l85', 'l88', 'l90', 'l92']", + "132, vitro ['l64', 'l75', 'l82', 'l86', 'l89', 'l91', 'l92']", + "135, in ['l76', 'l93']", + "136, vivo, ['l77', 'l93']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "oral", + "phosphodiesterase-5A", + "(PDE5A)", + "inhibitor", + "(sildenafil)" + ] + }, + "context": { + "val": "cells", + "words": [ + "chamber", + "myocyte" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "oral", + "phosphodiesterase-5A", + "(PDE5A)", + "inhibitor", + "(sildenafil)", + "PDE5A" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "oral", + "phosphodiesterase-5A", + "(PDE5A)", + "inhibitor", + "(sildenafil)", + "of", + "PDE5A." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "heart", + "chamber", + "hearts," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "oral", + "phosphodiesterase-5A", + "(PDE5A)", + "inhibitor", + "(sildenafil)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "PDE5A" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "calcineurin" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "15665831", + "TEXT": "Infusion of endothelial progenitor cells (EPC), but not of mature endothelial cells, promotes neovascularization after ischemia. We performed gene expression profiling of EPC and endothelial cells to identify genes that might be important for the neovascularization capacity of EPC. Notably, the protease cathepsin L (CathL) was highly expressed in EPC as opposed to endothelial cells and was essential for matrix degradation and invasion by EPC in vitro. CathL-deficient mice showed impaired functional recovery following hind limb ischemia, supporting the concept of a crucial role for CathL in postnatal neovascularization. Infused CathL-deficient progenitor cells neither homed to sites of ischemia nor augmented neovascularization. Forced expression of CathL in mature endothelial cells considerably enhanced their invasive activity and sufficed to confer their capacity for neovascularization in vivo. We concluded that CathL has a critical role in the integration of circulating EPC into ischemic tissue and is required for EPC-mediated neovascularization.", + "TAG_DATA": [ + "65, in {'context': 'B-in vitro'}", + "66, vitro. {'context': 'I-in vitro'}", + "67, CathL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "68, mice {'context': 'B-organism'}", + "90, CathL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "91, progenitor {'context': 'B-cells'}", + "92, cells {'context': 'I-cells'}", + "102, Forced {'perturbing_action': 'B-gene gain-of-function'}", + "103, expression {'perturbing_action': 'I-gene gain-of-function'}", + "104, of {'perturbing_action': 'I-gene gain-of-function'}", + "105, CathL {'perturbing_action': 'I-gene gain-of-function'}", + "107, mature {'context': 'B-cells'}", + "108, endothelial {'context': 'I-cells'}", + "109, cells {'context': 'I-cells'}", + "123, in {'context': 'B-in vivo'}", + "124, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "65, in ['l0']", + "66, vitro. ['l0']", + "67, CathL-deficient ['l1', 'l2']", + "68, mice ['l1']", + "90, CathL-deficient ['l3', 'l4']", + "91, progenitor ['l3', 'l5']", + "92, cells ['l2', 'l4', 'l5']", + "102, Forced ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "103, expression ['l6', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "104, of ['l7', 'l14', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "105, CathL ['l8', 'l15', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "107, mature ['l9', 'l16', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "108, endothelial ['l10', 'l17', 'l23', 'l28', 'l32', 'l36', 'l37', 'l38']", + "109, cells ['l11', 'l18', 'l24', 'l29', 'l33', 'l36', 'l39', 'l40']", + "123, in ['l12', 'l19', 'l25', 'l30', 'l34', 'l37', 'l39', 'l41']", + "124, vivo. ['l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CathL-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CathL-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "progenitor" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "expression", + "of", + "CathL" + ] + }, + "context": { + "val": "cells", + "words": [ + "mature", + "endothelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "expression", + "of", + "CathL" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "15619634", + "TEXT": "Histone deacetylases (HDACs) regulate transcription and specific cellular functions, such as tumor suppression by p53, and are frequently altered in cancer. Inhibitors of HDACs (HDACIs) possess antitumor activity and are well tolerated, supporting the idea that their use might develop as a specific strategy for cancer treatment. The molecular basis for their selective antitumor activity is, however, unknown. We investigated the effects of HDACIs on leukemias expressing the PML-RAR or AML1-ETO oncoproteins, known to initiate leukemogenesis through deregulation of HDACs. Here we report that: (i) HDACIs induce apoptosis of leukemic blasts, although oncogene expression is not sufficient to confer HDACI sensitivity to normal cells; (ii) apoptosis is p53 independent and depends, both in vitro and in vivo, upon activation of the death receptor pathway (TRAIL and Fas signaling pathways); (iii) TRAIL, DR5, FasL and Fas are upregulated by HDACIs in the leukemic cells, but not in normal hematopoietic progenitors. These results show that sensitivity to HDACIs in leukemias is a property of the fully transformed phenotype and depends on activation of a specific death pathway.", + "TAG_DATA": [ + "86, induce {'effect': 'B-positive'}", + "87, apoptosis {'phenotype': 'B-apoptosis'}", + "89, leukemic {'context': 'B-transformed cells'}", + "90, blasts, {'context': 'I-transformed cells'}", + "103, cells; {'context': 'I-cells'}", + "105, apoptosis {'phenotype': 'B-apoptosis'}", + "112, in {'context': 'B-in vitro'}", + "113, vitro {'context': 'I-in vitro'}", + "115, in {'context': 'B-in vivo'}", + "116, vivo, {'context': 'I-in vivo'}", + "141, leukemic {'context': 'B-transformed cells'}", + "142, cells, {'context': 'I-transformed cells'}", + "147, hematopoietic {'context': 'I-cells'}", + "148, progenitors. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "86, induce ['l0', 'l1', 'l2', 'l3']", + "87, apoptosis ['l0', 'l4', 'l5', 'l6']", + "89, leukemic ['l1', 'l4', 'l7', 'l8']", + "90, blasts, ['l2', 'l5', 'l7']", + "103, cells; ['l3', 'l6', 'l8']", + "105, apoptosis ['l9', 'l10', 'l11', 'l12']", + "112, in ['l9', 'l13', 'l14', 'l15']", + "113, vitro ['l10', 'l13', 'l16', 'l17']", + "115, in ['l11', 'l14', 'l16', 'l18']", + "116, vivo, ['l12', 'l15', 'l17', 'l18', 'l19']", + "141, leukemic ['l20', 'l21', 'l22']", + "142, cells, ['l19', 'l20', 'l23', 'l24']", + "147, hematopoietic ['l21', 'l23', 'l25']", + "148, progenitors. ['l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "leukemic", + "blasts," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells;" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "leukemic", + "blasts," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells;" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + } + ] + }, + { + "PMID": "15619633", + "TEXT": "Chromatin is a dynamic macromolecular structure epigenetically modified to regulate specific gene expression. Altered chromatin function can lead to aberrant expression of growth regulators and may, ultimately, cause cancer. That many human diseases have epigenetic etiology has stimulated the development of 'epigenetic' therapies. Inhibitors of histone deacetylases (HDACIs) induce proliferation arrest, maturation and apoptosis of cancer cells, but not normal cells, in vitro and in vivo, and are currently being tested in clinical trials. We investigated the mechanism(s) underlying this tumor selectivity. We report that HDACIs induce, in addition to p21, expression of TRAIL (Apo2L, TNFSF10) by directly activating the TNFSF10 promoter, thereby triggering tumor-selective death signaling in acute myeloid leukemia (AML) cells and the blasts of individuals with AML. RNA interference revealed that the induction of p21, TRAIL and differentiation are separable activities of HDACIs. HDACIs induced proliferation arrest, TRAIL-mediated apoptosis and suppression of AML blast clonogenicity irrespective of French-American-British (FAB) classification status, karyotype and immunophenotype. No apoptosis was seen in normal CD34(+) progenitor cells. Our results identify TRAIL as a mediator of the anticancer action of HDACIs.", + "TAG_DATA": [ + "49, proliferation {'phenotype': 'B-proliferation'}", + "50, arrest, {'phenotype': 'I-cell cycle arrest'}", + "55, cancer {'context': 'B-transformed cells'}", + "56, cells, {'context': 'I-transformed cells'}", + "59, normal {'context': 'B-cells'}", + "60, cells, {'context': 'I-cells'}", + "108, acute {'context': 'B-transformed cells'}", + "109, myeloid {'context': 'I-transformed cells'}", + "110, leukemia {'context': 'I-transformed cells'}", + "111, (AML) {'context': 'I-transformed cells'}", + "112, cells {'context': 'I-transformed cells'}", + "137, induced {'effect': 'B-positive'}", + "138, proliferation {'phenotype': 'B-cell cycle arrest'}", + "139, arrest, {'phenotype': 'I-cell cycle arrest'}", + "141, apoptosis {'phenotype': 'B-apoptosis'}", + "143, suppression {'effect': 'B-negative'}", + "145, AML {'context': 'B-transformed cells'}", + "146, blast {'context': 'I-transformed cells'}", + "147, clonogenicity {'phenotype': 'B-colony formation'}", + "157, No {'effect': 'B-no effect'}", + "158, apoptosis {'phenotype': 'B-apoptosis'}", + "163, CD34(+) {'context': 'B-cells'}", + "164, progenitor {'context': 'I-cells'}", + "165, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "49, proliferation ['l0', 'l1', 'l2', 'l3', 'l4']", + "50, arrest, ['l0', 'l5', 'l6', 'l7', 'l8']", + "55, cancer ['l1', 'l5', 'l9', 'l10', 'l11']", + "56, cells, ['l2', 'l6', 'l9', 'l12', 'l13']", + "59, normal ['l3', 'l7', 'l10', 'l12', 'l14']", + "60, cells, ['l4', 'l8', 'l11', 'l13', 'l14']", + "108, acute ['l15', 'l16', 'l17', 'l18']", + "109, myeloid ['l15', 'l19', 'l20', 'l21']", + "110, leukemia ['l16', 'l19', 'l22', 'l23']", + "111, (AML) ['l17', 'l20', 'l22', 'l24']", + "112, cells ['l18', 'l21', 'l23', 'l24']", + "137, induced ['l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "138, proliferation ['l25', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "139, arrest, ['l26', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "141, apoptosis ['l27', 'l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "143, suppression ['l28', 'l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "145, AML ['l29', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "146, blast ['l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "147, clonogenicity ['l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l52']", + "157, No ['l53', 'l54', 'l55', 'l56']", + "158, apoptosis ['l53', 'l57', 'l58', 'l59']", + "163, CD34(+) ['l54', 'l57', 'l60', 'l61']", + "164, progenitor ['l55', 'l58', 'l60', 'l62']", + "165, cells. ['l56', 'l59', 'l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "normal", + "cells," + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest,", + "proliferation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells,", + "AML", + "blast" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest," + ] + }, + "context": { + "val": "cells", + "words": [ + "normal", + "cells," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "proliferation", + "arrest," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "AML", + "blast" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenicity" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "proliferation", + "arrest," + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppression" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppression" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "AML", + "blast" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "AML", + "blast" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppression" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenicity" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "AML", + "blast" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenicity" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "No" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "No" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD34(+)", + "progenitor", + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD34(+)", + "progenitor", + "cells." + ] + } + } + ] + }, + { + "PMID": "15608650", + "TEXT": "Period (Per) genes are involved in regulation of the circadian clock and are thought to modulate several brain functions. We demonstrate that Per2(Brdm1) mutant mice, which have a deletion in the PAS domain of the Per2 protein, show alterations in the glutamatergic system. Lowered expression of the glutamate transporter Eaat1 is observed in these animals, leading to reduced uptake of glutamate by astrocytes. As a consequence, glutamate levels increase in the extracellular space of Per2(Brdm1) mutant mouse brains. This is accompanied by increased alcohol intake in these animals. In humans, variations of the PER2 gene are associated with regulation of alcohol consumption. Acamprosate, a drug used to prevent craving and relapse in alcoholic patients is thought to act by dampening a hyper-glutamatergic state. This drug reduced augmented glutamate levels and normalized increased alcohol consumption in Per2(Brdm1) mutant mice. Collectively, these data establish glutamate as a link between dysfunction of the circadian clock gene Per2 and enhanced alcohol intake.", + "TAG_DATA": [ + "22, Per2(Brdm1) {'perturbing_action': 'B-other'}", + "23, mutant {'perturbing_action': 'I-other'}", + "24, mice, {'context': 'B-organism'}", + "28, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "29, in {'perturbing_action': 'I-gene loss-of-function'}", + "30, the {'perturbing_action': 'I-gene loss-of-function'}", + "31, PAS {'perturbing_action': 'I-gene loss-of-function'}", + "32, domain {'perturbing_action': 'I-gene loss-of-function'}", + "33, of {'perturbing_action': 'I-gene loss-of-function'}", + "34, the {'perturbing_action': 'I-gene loss-of-function'}", + "35, Per2 {'perturbing_action': 'I-gene loss-of-function'}", + "36, protein, {'perturbing_action': 'I-gene loss-of-function'}", + "54, animals, {'context': 'B-organism'}", + "62, astrocytes. {'context': 'B-cells'}", + "74, Per2(Brdm1) {'perturbing_action': 'B-other'}", + "75, mutant {'perturbing_action': 'I-other'}", + "76, mouse {'context': 'B-tissue/organ'}", + "77, brains. {'context': 'I-tissue/organ'}", + "87, animals. {'context': 'B-organism'}", + "135, Per2(Brdm1) {'perturbing_action': 'B-other'}", + "136, mutant {'perturbing_action': 'I-other'}", + "137, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "22, Per2(Brdm1) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "23, mutant ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "24, mice, ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "28, deletion ['l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "29, in ['l30', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "30, the ['l31', 'l45', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "31, PAS ['l32', 'l46', 'l59', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "32, domain ['l33', 'l47', 'l60', 'l72', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "33, of ['l34', 'l48', 'l61', 'l73', 'l84', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "34, the ['l2', 'l13', 'l35', 'l49', 'l62', 'l74', 'l85', 'l95', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "35, Per2 ['l3', 'l14', 'l36', 'l50', 'l63', 'l75', 'l86', 'l96', 'l105', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "36, protein, ['l4', 'l15', 'l37', 'l51', 'l64', 'l76', 'l87', 'l97', 'l106', 'l114', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "54, animals, ['l5', 'l16', 'l23', 'l38', 'l52', 'l65', 'l77', 'l88', 'l98', 'l107', 'l115', 'l122', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "62, astrocytes. ['l6', 'l17', 'l24', 'l39', 'l53', 'l66', 'l78', 'l89', 'l99', 'l108', 'l116', 'l123', 'l129', 'l135', 'l136', 'l137', 'l138', 'l139']", + "74, Per2(Brdm1) ['l7', 'l18', 'l25', 'l40', 'l54', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l124', 'l130', 'l135', 'l140', 'l141', 'l142', 'l143']", + "75, mutant ['l8', 'l19', 'l26', 'l41', 'l55', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l125', 'l131', 'l136', 'l140', 'l144', 'l145', 'l146']", + "76, mouse ['l9', 'l20', 'l27', 'l42', 'l56', 'l69', 'l81', 'l92', 'l102', 'l111', 'l119', 'l126', 'l132', 'l137', 'l141', 'l144', 'l147', 'l148']", + "77, brains. ['l10', 'l21', 'l28', 'l43', 'l57', 'l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l127', 'l133', 'l138', 'l142', 'l145', 'l147', 'l149']", + "87, animals. ['l11', 'l22', 'l29', 'l44', 'l58', 'l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l128', 'l134', 'l139', 'l143', 'l146', 'l148', 'l149']", + "135, Per2(Brdm1) ['l150', 'l151']", + "136, mutant ['l150', 'l152']", + "137, mice. ['l151', 'l152']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Per2(Brdm1)", + "mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "animals,", + "animals.", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Per2(Brdm1)", + "mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "astrocytes." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Per2(Brdm1)", + "mutant" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "brains." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "in", + "the", + "PAS", + "domain", + "of", + "Per2", + "protein," + ] + }, + "context": { + "val": "organism", + "words": [ + "animals,", + "animals." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "in", + "the", + "PAS", + "domain", + "of", + "Per2", + "protein," + ] + }, + "context": { + "val": "cells", + "words": [ + "astrocytes." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "in", + "the", + "PAS", + "domain", + "of", + "Per2", + "protein," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "brains." + ] + } + } + ] + }, + { + "PMID": "15543153", + "TEXT": "Signaling by the calcium-dependent phosphatase calcineurin profoundly influences the growth and gene expression of cardiac and skeletal muscle. Calcineurin binds to calsarcins, a family of muscle-specific proteins of the sarcomeric Z-disc, a focal point in the pathogenesis of human cardiomyopathies. We show that calsarcin-1 negatively modulates the functions of calcineurin, such that calcineurin signaling was enhanced in striated muscles of mice that do not express calsarcin-1. As a consequence of inappropriate calcineurin activation, mice with a null mutation in calsarcin-1 showed an excess of slow skeletal muscle fibers. The absence of calsarcin-1 also activated a hypertrophic gene program, despite the absence of hypertrophy, and enhanced the cardiac growth response to pressure overload. In contrast, cardiac adaptation to other hypertrophic stimuli, such as chronic catecholamine stimulation or exercise, was not affected. These findings show important roles for calsarcins as modulators of calcineurin signaling and the transmission of a specific subset of stress signals leading to cardiac remodeling in vivo.", + "TAG_DATA": [ + "60, mice {'context': 'B-organism'}", + "73, mice {'context': 'B-organism'}", + "76, null {'perturbing_action': 'B-gene loss-of-function'}", + "77, mutation {'perturbing_action': 'I-gene loss-of-function'}", + "78, in {'perturbing_action': 'I-gene loss-of-function'}", + "79, calsarcin-1 {'perturbing_action': 'I-gene loss-of-function'}", + "85, skeletal {'context': 'I-cells'}", + "86, muscle {'context': 'I-cells'}", + "87, fibers. {'context': 'I-cells'}", + "89, absence {'perturbing_action': 'B-gene loss-of-function'}", + "90, of {'perturbing_action': 'I-gene loss-of-function'}", + "91, calsarcin-1 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "60, mice ['l0', 'l1', 'l2']", + "73, mice ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "76, null ['l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "77, mutation ['l4', 'l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "78, in ['l5', 'l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "79, calsarcin-1 ['l6', 'l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "85, skeletal ['l0', 'l7', 'l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "86, muscle ['l1', 'l8', 'l14', 'l19', 'l23', 'l26', 'l28', 'l30']", + "87, fibers. ['l2', 'l9', 'l15', 'l20', 'l24', 'l27', 'l29', 'l30']", + "89, absence ['l31', 'l32']", + "90, of ['l31', 'l33']", + "91, calsarcin-1 ['l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "null", + "mutation", + "in", + "calsarcin-1" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "null", + "mutation", + "in", + "calsarcin-1" + ] + }, + "context": { + "val": "cells", + "words": [ + "skeletal", + "muscle", + "fibers." + ] + } + } + ] + }, + { + "PMID": "15531890", + "TEXT": "The BTB/POZ transcriptional repressor and candidate oncogene BCL6 is frequently misregulated in B-cell lymphomas. The interface through which the BCL6 BTB domain mediates recruitment of the SMRT, NCoR and BCoR corepressors was recently identified. To determine the contribution of this interface to BCL6 transcriptional and biological properties, we generated a peptide that specifically binds BCL6 and blocks corepressor recruitment in vivo. This inhibitor disrupts BCL6-mediated repression and establishment of silenced chromatin, reactivates natural BCL6 target genes, and abrogates BCL6 biological function in B cells. In BCL6-positive lymphoma cells, peptide blockade caused apoptosis and cell cycle arrest. BTB domain peptide inhibitors may constitute a novel therapeutic agent for B-cell lymphomas.", + "TAG_DATA": [ + "59, in {'context': 'B-in vivo'}", + "60, vivo. {'context': 'I-in vivo'}", + "82, B {'context': 'B-cells'}", + "83, cells. {'context': 'I-cells'}", + "85, BCL6-positive {'context': 'B-transformed cells'}", + "86, lymphoma {'context': 'I-transformed cells'}", + "87, cells, {'context': 'I-transformed cells'}", + "90, caused {'effect': 'B-positive'}", + "91, apoptosis {'phenotype': 'B-apoptosis'}", + "93, cell {'phenotype': 'B-cell cycle arrest'}", + "94, cycle {'phenotype': 'I-cell cycle arrest'}", + "95, arrest. {'phenotype': 'I-cell cycle arrest'}" + ], + "LINK_DATA": [ + "59, in ['l0', 'l1', 'l2']", + "60, vivo. ['l0', 'l3', 'l4']", + "82, B ['l1', 'l3', 'l5']", + "83, cells. ['l2', 'l4', 'l5']", + "85, BCL6-positive ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "86, lymphoma ['l6', 'l13', 'l14', 'l15', 'l16']", + "87, cells, ['l7', 'l13', 'l17']", + "90, caused ['l8', 'l14', 'l17', 'l18', 'l19', 'l20', 'l21']", + "91, apoptosis ['l9', 'l15', 'l18', 'l22', 'l23', 'l24']", + "93, cell ['l10', 'l19', 'l22', 'l25', 'l26']", + "94, cycle ['l11', 'l20', 'l23', 'l25', 'l27']", + "95, arrest. ['l12', 'l16', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "BCL6-positive", + "lymphoma", + "cells," + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "BCL6-positive", + "lymphoma" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "BCL6-positive", + "lymphoma" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest." + ] + } + } + ] + }, + { + "PMID": "15322537", + "TEXT": "Lymphatic vessels are essential for the removal of interstitial fluid and prevention of tissue edema. Lymphatic capillaries lack associated mural cells, and collecting lymphatic vessels have valves, which prevent lymph backflow. In lymphedema-distichiasis (LD), lymphatic vessel function fails because of mutations affecting the forkhead transcription factor FOXC2. We report that Foxc2(-/-) mice show abnormal lymphatic vascular patterning, increased pericyte investment of lymphatic vessels, agenesis of valves and lymphatic dysfunction. In addition, an abnormally large proportion of skin lymphatic vessels was covered with smooth muscle cells in individuals with LD and in mice heterozygous for Foxc2 and for the gene encoding lymphatic endothelial receptor, Vegfr3 (also known as Flt4). Our data show that Foxc2 is essential for the morphogenesis of lymphatic valves and the establishment of a pericyte-free lymphatic capillary network and that it cooperates with Vegfr3 in the latter process. Our results indicate that an abnormal interaction between the lymphatic endothelial cells and pericytes, as well as valve defects, underlie the pathogenesis of LD.", + "TAG_DATA": [ + "50, Foxc2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "51, mice {'context': 'B-organism'}", + "91, mice {'context': 'B-organism'}", + "92, heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "93, for {'perturbing_action': 'I-gene loss-of-function'}", + "94, Foxc2 {'perturbing_action': 'I-gene loss-of-function'}", + "95, and {'perturbing_action': 'I-gene loss-of-function'}", + "96, for {'perturbing_action': 'I-gene loss-of-function'}", + "97, the {'perturbing_action': 'I-gene loss-of-function'}", + "98, gene {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "50, Foxc2(-/-) ['l0']", + "51, mice ['l0']", + "91, mice ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "92, heterozygous ['l1', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "93, for ['l2', 'l13', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "94, Foxc2 ['l3', 'l14', 'l24', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "95, and ['l4', 'l15', 'l25', 'l34', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "96, for ['l5', 'l16', 'l26', 'l35', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "97, the ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "98, gene ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "99, encoding ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l69', 'l70', 'l71', 'l72']", + "100, lymphatic ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l73', 'l74', 'l75']", + "101, endothelial ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l76', 'l77']", + "102, receptor, ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l78']", + "103, Vegfr3 ['l12', 'l23', 'l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l77', 'l78']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Foxc2(-/-)", + "heterozygous", + "for", + "Foxc2", + "and", + "the", + "gene" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15273747", + "TEXT": "A major obstacle limiting gene therapy for diseases of the heart and skeletal muscles is an inability to deliver genes systemically to muscles of an adult organism. Systemic gene transfer to striated muscles is hampered by the vascular endothelium, which represents a barrier to distribution of vectors via the circulation. Here we show the first evidence of widespread transduction of both cardiac and skeletal muscles in an adult mammal, after a single intravenous administration of recombinant adeno-associated virus pseudotype 6 vectors. The inclusion of vascular endothelium growth factor/vascular permeability factor, to achieve acute permeabilization of the peripheral microvasculature, enhanced tissue transduction at lower vector doses. This technique enabled widespread muscle-specific expression of a functional micro-dystrophin in the skeletal muscles of dystrophin-deficient mdx mice, which model Duchenne muscular dystrophy. We propose that these methods may be applicable for systemic delivery of a wide variety of genes to the striated muscles of adult mammals.", + "TAG_DATA": [ + "61, cardiac {'context': 'B-tissue/organ'}", + "62, and {'context': 'I-tissue/organ'}", + "63, skeletal {'context': 'I-tissue/organ'}", + "64, muscles {'context': 'I-tissue/organ'}", + "67, adult {'context': 'B-organism'}", + "68, mammal, {'context': 'I-organism'}", + "117, skeletal {'context': 'B-tissue/organ'}", + "118, muscles {'context': 'I-tissue/organ'}", + "120, dystrophin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "121, mdx {'perturbing_action': 'B-gene loss-of-function'}", + "122, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "61, cardiac ['l0', 'l1', 'l2', 'l3', 'l4']", + "62, and ['l0', 'l5', 'l6', 'l7', 'l8']", + "63, skeletal ['l1', 'l5', 'l9', 'l10', 'l11']", + "64, muscles ['l2', 'l6', 'l9', 'l12', 'l13']", + "67, adult ['l3', 'l7', 'l10', 'l12', 'l14']", + "68, mammal, ['l4', 'l8', 'l11', 'l13', 'l14']", + "117, skeletal ['l15', 'l16', 'l17', 'l18']", + "118, muscles ['l15', 'l19', 'l20', 'l21']", + "120, dystrophin-deficient ['l16', 'l19', 'l22', 'l23']", + "121, mdx ['l17', 'l20', 'l22', 'l24']", + "122, mice, ['l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "skeletal", + "muscles" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient", + "mdx" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient", + "mdx" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "15235598", + "TEXT": "The dominant polyglutamine expansion diseases, which include spinocerebellar ataxia type 1 (SCA1) and Huntington disease, are progressive, untreatable, neurodegenerative disorders. In inducible mouse models of SCA1 and Huntington disease, repression of mutant allele expression improves disease phenotypes. Thus, therapies designed to inhibit expression of the mutant gene would be beneficial. Here we evaluate the ability of RNA interference (RNAi) to inhibit polyglutamine-induced neurodegeneration caused by mutant ataxin-1 in a mouse model of SCA1. Upon intracerebellar injection, recombinant adeno-associated virus (AAV) vectors expressing short hairpin RNAs profoundly improved motor coordination, restored cerebellar morphology and resolved characteristic ataxin-1 inclusions in Purkinje cells of SCA1 mice. Our data demonstrate in vivo the potential use of RNAi as therapy for dominant neurodegenerative disease.", + "TAG_DATA": [ + "65, mutant {'perturbing_action': 'B-other'}", + "66, ataxin-1 {'perturbing_action': 'I-other'}", + "69, mouse {'context': 'B-organism'}", + "70, model {'context': 'I-organism'}", + "71, of {'context': 'I-organism'}", + "72, SCA1. {'context': 'I-organism'}", + "76, recombinant {'perturbing_action': 'B-rnai/knockdown'}", + "77, adeno-associated {'perturbing_action': 'I-rnai/knockdown'}", + "78, virus {'perturbing_action': 'I-rnai/knockdown'}", + "79, (AAV) {'perturbing_action': 'I-rnai/knockdown'}", + "80, vectors {'perturbing_action': 'I-rnai/knockdown'}", + "81, expressing {'perturbing_action': 'I-rnai/knockdown'}", + "82, short {'perturbing_action': 'I-rnai/knockdown'}", + "83, hairpin {'perturbing_action': 'I-rnai/knockdown'}", + "98, Purkinje {'context': 'B-cells'}", + "99, cells {'context': 'I-cells'}", + "101, SCA1 {'context': 'B-organism'}", + "102, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "65, mutant ['l0', 'l1', 'l2', 'l3', 'l4']", + "66, ataxin-1 ['l0', 'l5', 'l6', 'l7', 'l8']", + "69, mouse ['l1', 'l5', 'l9', 'l10', 'l11']", + "70, model ['l2', 'l6', 'l9', 'l12', 'l13']", + "71, of ['l3', 'l7', 'l10', 'l12', 'l14']", + "72, SCA1. ['l4', 'l8', 'l11', 'l13', 'l14']", + "76, recombinant ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "77, adeno-associated ['l15', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "78, virus ['l16', 'l26', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "79, (AAV) ['l17', 'l27', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "80, vectors ['l18', 'l28', 'l37', 'l45', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "81, expressing ['l19', 'l29', 'l38', 'l46', 'l53', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "82, short ['l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l66', 'l67', 'l68', 'l69', 'l70']", + "83, hairpin ['l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l71', 'l72', 'l73', 'l74']", + "98, Purkinje ['l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l75', 'l76', 'l77']", + "99, cells ['l23', 'l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l78', 'l79']", + "101, SCA1 ['l24', 'l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l76', 'l78', 'l80']", + "102, mice. ['l25', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l79', 'l80']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "ataxin-1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "SCA1." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "recombinant", + "adeno-associated", + "virus", + "(AAV)", + "vectors", + "expressing", + "short", + "hairpin" + ] + }, + "context": { + "val": "cells", + "words": [ + "Purkinje", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "recombinant", + "adeno-associated", + "virus", + "(AAV)", + "vectors", + "expressing", + "short", + "hairpin" + ] + }, + "context": { + "val": "organism", + "words": [ + "SCA1", + "mice." + ] + } + } + ] + }, + { + "PMID": "15220914", + "TEXT": "Leptin is an adipocyte-derived hormone that regulates energy balance and neuroendocrine function primarily by acting on specific hypothalamic pathways. Resistance to the weight reducing effects of leptin is a feature of most cases of human and rodent obesity, yet the molecular basis of leptin resistance is poorly understood. We have previously identified suppressor of cytokine signaling-3 (Socs3) as a leptin-induced negative regulator of leptin receptor signaling and potential mediator of leptin resistance. However, due to the non-viability of mice with targeted disruption of Socs3 (ref. 6), the importance of Socs3 in leptin action in vivo was unclear. To determine the functional significance of Socs3 in energy balance in vivo we undertook studies in mice with heterozygous Socs3 deficiency (Socs3(+/-)). We report here that Socs3(+/-) mice display greater leptin sensitivity than wild-type control mice: Socs3(+/-) mice show both enhanced weight loss and increased hypothalamic leptin receptor signaling in response to exogenous leptin administration. Furthermore, Socs3(+/-) mice are significantly protected against the development of diet-induced obesity and associated metabolic complications. The level of Socs3 expression is thus a critical determinant of leptin sensitivity and obesity susceptibility in vivo and this molecule is a potential target for therapeutic intervention.", + "TAG_DATA": [ + "113, mice {'context': 'B-organism'}", + "115, heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "116, Socs3 {'perturbing_action': 'I-gene loss-of-function'}", + "117, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "118, (Socs3(+/-)). {'perturbing_action': 'I-gene loss-of-function'}", + "123, Socs3(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "124, mice {'context': 'B-organism'}", + "132, mice: {'context': 'B-organism'}", + "133, Socs3(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "134, mice {'context': 'B-organism'}", + "153, Socs3(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "154, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "113, mice ['l0', 'l1', 'l2', 'l3']", + "115, heterozygous ['l0', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "116, Socs3 ['l1', 'l4', 'l10', 'l11', 'l12', 'l13', 'l14']", + "117, deficiency ['l2', 'l5', 'l10', 'l15', 'l16', 'l17', 'l18']", + "118, (Socs3(+/-)). ['l3', 'l6', 'l11', 'l15', 'l19', 'l20', 'l21']", + "123, Socs3(+/-) ['l7', 'l12', 'l16', 'l19', 'l22', 'l23', 'l24']", + "124, mice ['l8', 'l13', 'l17', 'l20', 'l22', 'l25']", + "132, mice: ['l9', 'l14', 'l18', 'l21', 'l23', 'l25', 'l26']", + "133, Socs3(+/-) ['l27']", + "134, mice ['l24', 'l26', 'l27']", + "153, Socs3(+/-) ['l28']", + "154, mice ['l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice:" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "heterozygous", + "Socs3", + "deficiency", + "(Socs3(+/-)).", + "Socs3(+/-)" + ] + } + } + ] + }, + { + "PMID": "15208705", + "TEXT": "Leptin is an adipocyte-derived hormone that plays a key role in energy homeostasis, yet resistance to leptin is a feature of most cases of obesity in humans and rodents. In vitro analysis suggested that the suppressor of cytokine signaling-3 (Socs3) is a negative-feedback regulator of leptin signaling involved in leptin resistance. To determine the functional significance of Socs3 in vivo, we generated neural cell-specific SOCS3 conditional knockout mice using the Cre-loxP system. Compared to their wild-type littermates, Socs3-deficient mice showed enhanced leptin-induced hypothalamic Stat3 tyrosine phosphorylation as well as pro-opiomelanocortin (POMC) induction, and this resulted in a greater body weight loss and suppression of food intake. Moreover, the Socs3-deficient mice were resistant to high fat diet-induced weight gain and hyperleptinemia, and insulin-sensitivity was retained. These data indicate that Socs3 is a key regulator of diet-induced leptin as well as insulin resistance. Our study demonstrates the negative regulatory role of Socs3 in leptin signaling in vivo, and thus suppression of Socs3 in the brain is a potential therapy for leptin-resistance in obesity.", + "TAG_DATA": [ + "62, neural {'perturbing_action': 'B-gene loss-of-function'}", + "63, cell-specific {'perturbing_action': 'I-gene loss-of-function'}", + "64, SOCS3 {'perturbing_action': 'I-gene loss-of-function'}", + "65, conditional {'perturbing_action': 'I-gene loss-of-function'}", + "66, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "67, mice {'context': 'B-organism'}", + "77, Socs3-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "78, mice {'context': 'B-organism'}", + "108, Socs3-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "109, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "62, neural ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "63, cell-specific ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "64, SOCS3 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "65, conditional ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "66, knockout ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "67, mice ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "77, Socs3-deficient ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "78, mice ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "108, Socs3-deficient ['l28']", + "109, mice ['l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "neural", + "cell-specific", + "SOCS3", + "conditional", + "knockout", + "Socs3-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15170210", + "TEXT": "We determine here the functional integrity of auxiliary livers in containers fashioned from the small intestine. Liver microfragments from dipeptidyl peptidase 4 (DPP4)-deficient rats were transplanted into syngeneic normal animals with isolated intestinal segments characterized by mucosal denudation but intact vascular supply. Transplanted liver fragments were restored to confluent tissue with normal hepatic architecture and development of DPP4-positive vessels, indicating angiogenesis and revascularization. Auxiliary liver units expressed multiple hepatotrophic and angiogenic genes, and transplanted tissues remained intact for up to the 6-week duration of the studies with neither ischemic injury nor significant hepatocellular proliferation. Hepatic metabolic, transport and synthetic functions were preserved in auxiliary livers, including uptake and biliary excretion of (99m)Tc-mebrofenin in syngeneic recipients of liver from F344 rats, as well as secretion of albumin in allografted Nagase analbuminemic rats. This ability to produce functionally competent auxiliary livers in vascularized intestinal segments offers therapeutic potential for liver disease and genetic deficiency.", + "TAG_DATA": [ + "19, dipeptidyl {'perturbing_action': 'B-gene loss-of-function'}", + "20, peptidase {'perturbing_action': 'I-gene loss-of-function'}", + "21, 4 {'perturbing_action': 'I-gene loss-of-function'}", + "22, (DPP4)-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "23, rats {'context': 'B-organism'}", + "27, syngeneic {'context': 'B-organism'}", + "28, normal {'context': 'I-organism'}", + "29, animals {'context': 'I-organism'}", + "43, liver {'context': 'B-tissue/organ'}", + "44, fragments {'context': 'I-tissue/organ'}", + "93, proliferation. {'phenotype': 'B-proliferation'}", + "103, auxiliary {'context': 'B-tissue/organ'}", + "104, livers, {'context': 'I-tissue/organ'}", + "114, recipients {'context': 'I-tissue/organ'}", + "116, liver {'context': 'I-cells'}", + "118, F344 {'context': 'I-cells'}", + "119, rats, {'context': 'I-cells'}", + "130, rats. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "19, dipeptidyl ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "20, peptidase ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "21, 4 ['l1', 'l9', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "22, (DPP4)-deficient ['l2', 'l10', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "23, rats ['l3', 'l11', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "27, syngeneic ['l4', 'l12', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "28, normal ['l5', 'l13', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "29, animals ['l6', 'l14', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "43, liver ['l7', 'l15', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "44, fragments ['l8', 'l16', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']", + "93, proliferation. ['l17']", + "103, auxiliary ['l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "104, livers, ['l46', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "113, syngeneic ['l47', 'l53', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "114, recipients ['l48', 'l54', 'l59', 'l65', 'l66', 'l67', 'l68', 'l69']", + "115, of ['l49', 'l55', 'l60', 'l65', 'l70', 'l71', 'l72', 'l73']", + "116, liver ['l50', 'l56', 'l61', 'l66', 'l70', 'l74', 'l75', 'l76']", + "118, F344 ['l51', 'l57', 'l62', 'l67', 'l71', 'l74', 'l77', 'l78']", + "119, rats, ['l52', 'l58', 'l63', 'l68', 'l72', 'l75', 'l77', 'l79']", + "130, rats. ['l64', 'l69', 'l73', 'l76', 'l78', 'l79']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dipeptidyl", + "peptidase", + "4", + "(DPP4)-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats", + "syngeneic", + "normal", + "animals" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dipeptidyl", + "peptidase", + "4", + "(DPP4)-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver", + "fragments" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "peptidase" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "15107845", + "TEXT": "Macrophages play host to Leishmania major, a parasite that causes leishmaniasis in 500,000 people annually. Macrophage-expressed CD40, a costimulatory molecule, induces interleukin-12 (IL-12)-dependent and interferon-gamma (IFN-gamma)-dependent host-protective immune responses to Leishmania and other intracellular pathogens. Paradoxically, IL-10, another CD40-induced cytokine in macrophages, promotes Leishmania infection. How CD40 signaling regulates the secretion of these two counteractive cytokines remains unknown. Here we show that weak CD40 signals induce extracellular stress-related kinase-1/2 (ERK-1/2)-dependent IL-10 expression, whereas stronger signals induce p38 mitogen-activated protein kinase (p38MAPK)-dependent IL-12 production. p38MAPK and ERK-1/2 therefore have counter-regulatory actions. Leishmania skews CD40 signaling toward ERK-1/2, inducing IL-10, which inhibits activation of CD40-induced p38MAPK and expression of inducible nitric oxide synthase-2 (iNOS-2) and IL-12. ERK-1/2 inhibition or IL-10 neutralization restores CD40-induced p38MAPK activation and parasite killing in macrophages and the BALB/c mouse, a susceptible host. These data uncover a new immune evasion strategy, whereby Leishmania differentially modulates CD40-engaged, reciprocally functioning signaling modules, and provide a new conceptual framework for immune homeostasis.", + "TAG_DATA": [ + "114, ERK-1/2 {'perturbing_action': 'B-pharmacological inhibition'}", + "115, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "117, IL-10 {'perturbing_action': 'B-rnai/knockdown'}", + "118, neutralization {'perturbing_action': 'I-rnai/knockdown'}", + "127, macrophages {'context': 'B-cells'}", + "130, BALB/c {'context': 'B-organism'}", + "131, mouse, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "114, ERK-1/2 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "115, inhibition ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "117, IL-10 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "118, neutralization ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "124, parasite ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "127, macrophages ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "130, BALB/c ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "131, mouse, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ERK-1/2", + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ERK-1/2", + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "BALB/c", + "mouse," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "IL-10", + "neutralization" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "IL-10", + "neutralization" + ] + }, + "context": { + "val": "organism", + "words": [ + "BALB/c", + "mouse," + ] + } + } + ] + }, + { + "PMID": "15098027", + "TEXT": "Hemostasis initiates angiogenesis-dependent wound healing, and thrombosis is frequently associated with advanced cancer. Although activation of coagulation generates potent regulators of angiogenesis, little is known about how this pathway supports angiogenesis in vivo. Here we show that the tissue factor (TF)-VIIa protease complex, independent of triggering coagulation, can promote tumor and developmental angiogenesis through protease-activated receptor-2 (PAR-2) signaling. In this context, the TF cytoplasmic domain negatively regulates PAR-2 signaling. Mice from which the TF cytoplasmic domain has been deleted (TF Delta CT mice) show enhanced PAR-2-dependent angiogenesis, in synergy with platelet-derived growth factor BB (PDGF-BB). Ocular tissue from diabetic patients shows PAR-2 colocalization with phosphorylated TF specifically on neovasculature, suggesting that phosphorylation of the TF cytoplasmic domain releases its negative regulatory control of PAR-2 signaling in angiogenesis. Targeting the TF-VIIa signaling pathway may thus enhance the efficacy of angiostatic treatments for cancer and neovascular eye diseases.", + "TAG_DATA": [ + "69, Mice {'context': 'B-organism'}", + "72, the {'perturbing_action': 'I-gene loss-of-function'}", + "73, TF {'perturbing_action': 'I-gene loss-of-function'}", + "74, cytoplasmic {'perturbing_action': 'I-gene loss-of-function'}", + "75, domain {'perturbing_action': 'I-gene loss-of-function'}", + "76, has {'perturbing_action': 'I-gene loss-of-function'}", + "77, been {'perturbing_action': 'I-gene loss-of-function'}", + "78, deleted {'perturbing_action': 'I-gene loss-of-function'}", + "80, Delta {'perturbing_action': 'B-gene loss-of-function'}", + "81, CT {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "69, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "72, the ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "73, TF ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "74, cytoplasmic ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "75, domain ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "76, has ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "77, been ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "78, deleted ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "80, Delta ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "81, CT ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "TF", + "cytoplasmic", + "domain", + "has", + "been", + "deleted", + "Delta", + "CT" + ] + } + } + ] + }, + { + "PMID": "15077108", + "TEXT": "Adiponectin (ADP) is an adipocyte hormone involved in glucose and lipid metabolism. We detected a rise in ADP in cerebrospinal fluid after intravenous (i.v.) injection, consistent with brain transport. In contrast to leptin, intracerebroventricular (i.c.v.) administration of ADP decreased body weight mainly by stimulating energy expenditure. Full-length ADP, mutant ADP with Cys39 replaced with serine, and globular ADP were effective, whereas the collagenous tail fragment was not. Lep(ob/ob) mice were especially sensitive to i.c.v. and systemic ADP, which resulted in increased thermogenesis, weight loss and reduction in serum glucose and lipid levels. ADP also potentiated the effect of leptin on thermogenesis and lipid levels. While both hormones increased expression of hypothalamic corticotropin-releasing hormone (CRH), ADP had no substantial effect on other neuropeptide targets of leptin. In addition, ADP induced distinct Fos immunoreactivity. Agouti (A(y)/a) mice did not respond to ADP or leptin, indicating the melanocortin pathway may be a common target. These results show that ADP has unique central effects on energy homeostasis.", + "TAG_DATA": [ + "67, Lep(ob/ob) {'perturbing_action': 'B-gene loss-of-function'}", + "68, mice {'context': 'B-organism'}", + "132, Agouti {'perturbing_action': 'B-other'}", + "133, (A(y)/a) {'perturbing_action': 'B-other'}", + "134, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "67, Lep(ob/ob) ['l0']", + "68, mice ['l0']", + "132, Agouti ['l1', 'l2']", + "133, (A(y)/a) ['l1', 'l3']", + "134, mice ['l2', 'l3']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lep(ob/ob)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Agouti", + "(A(y)/a)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15034566", + "TEXT": "Atherosclerosis, the leading cause of death in developed countries, has been linked to hypercholesterolemia for decades. More recently, atherosclerotic lesion progression has been shown to depend on persistent, chronic inflammation in the artery wall. Although several studies have implicated infectious agents in this process, the role of infection in atherosclerosis remains controversial. Because the involvement of monocytes and macrophages in the pathogenesis of atherosclerosis is well established, we investigated the possibility that macrophage innate immunity signaling pathways normally activated by pathogens might also be activated in response to hyperlipidemia. We examined atherosclerotic lesion development in uninfected, hyperlipidemic mice lacking expression of either lipopolysaccharide (LPS) receptor CD14 or myeloid differentiation protein-88 (MyD88), which transduces cell signaling events downstream of the Toll-like receptors (TLRs), as well as receptors for interleukin-1 (IL-1) and IL-18. Whereas the MyD88-deficient mice evinced a marked reduction in early atherosclerosis, mice deficient in CD14 had no decrease in early lesion development. Inactivation of the MyD88 pathway led to a reduction in atherosclerosis through a decrease in macrophage recruitment to the artery wall that was associated with reduced chemokine levels. These findings link elevated serum lipid levels to a proinflammatory signaling cascade that is also engaged by microbial pathogens.", + "TAG_DATA": [ + "97, mice {'context': 'B-organism'}", + "98, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "99, expression {'perturbing_action': 'I-gene loss-of-function'}", + "100, of {'perturbing_action': 'I-gene loss-of-function'}", + "101, either {'perturbing_action': 'I-gene loss-of-function'}", + "102, lipopolysaccharide {'perturbing_action': 'I-gene loss-of-function'}", + "104, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "105, CD14 {'perturbing_action': 'I-gene loss-of-function'}", + "107, myeloid {'perturbing_action': 'I-gene loss-of-function'}", + "133, MyD88-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "134, mice {'context': 'B-organism'}", + "138, reduction {'effect': 'B-negative'}", + "142, mice {'context': 'B-organism'}", + "143, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "144, in {'perturbing_action': 'I-gene loss-of-function'}", + "145, CD14 {'perturbing_action': 'I-gene loss-of-function'}", + "153, Inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "154, of {'perturbing_action': 'I-gene loss-of-function'}", + "155, the {'perturbing_action': 'I-gene loss-of-function'}", + "156, MyD88 {'perturbing_action': 'I-gene loss-of-function'}", + "157, pathway {'perturbing_action': 'I-gene loss-of-function'}", + "161, reduction {'effect': 'B-negative'}", + "168, macrophage {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "97, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "98, lacking ['l0', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "99, expression ['l5', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "100, of ['l6', 'l12', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "101, either ['l1', 'l7', 'l13', 'l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "102, lipopolysaccharide ['l2', 'l8', 'l14', 'l22', 'l29', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "104, receptor ['l3', 'l9', 'l15', 'l23', 'l30', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "105, CD14 ['l4', 'l10', 'l16', 'l24', 'l31', 'l37', 'l42', 'l47', 'l48', 'l49', 'l50']", + "107, myeloid ['l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l51', 'l52', 'l53', 'l54']", + "133, MyD88-deficient ['l11', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l55', 'l56']", + "134, mice ['l19', 'l27', 'l34', 'l40', 'l45', 'l49', 'l52', 'l55', 'l57']", + "138, reduction ['l20', 'l28', 'l35', 'l41', 'l46', 'l50', 'l53', 'l56', 'l57']", + "142, mice ['l58', 'l59', 'l60']", + "143, deficient ['l58', 'l61', 'l62']", + "144, in ['l59', 'l61', 'l63']", + "145, CD14 ['l54', 'l60', 'l62', 'l63']", + "153, Inactivation ['l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "154, of ['l64', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "155, the ['l65', 'l71', 'l77', 'l78', 'l79', 'l80', 'l81']", + "156, MyD88 ['l66', 'l72', 'l77', 'l82', 'l83', 'l84', 'l85']", + "157, pathway ['l67', 'l73', 'l78', 'l82', 'l86', 'l87', 'l88']", + "161, reduction ['l68', 'l74', 'l79', 'l83', 'l86', 'l89', 'l90']", + "163, atherosclerosis ['l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l91']", + "168, macrophage ['l70', 'l76', 'l81', 'l85', 'l88', 'l90', 'l91']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "either", + "lipopolysaccharide", + "receptor", + "CD14", + "expression", + "of", + "myeloid", + "MyD88-deficient", + "deficient", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "expression", + "of", + "either", + "lipopolysaccharide", + "receptor", + "CD14", + "myeloid", + "MyD88-deficient", + "Inactivation", + "the", + "MyD88", + "pathway" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduction" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduction" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Inactivation", + "of", + "the", + "MyD88", + "pathway" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophage" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduction" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophage" + ] + } + } + ] + }, + { + "PMID": "14981513", + "TEXT": "The Aurora kinases are essential for the regulation of chromosome segregation and cytokinesis during mitosis. Aberrant expression and activity of these kinases occur in a wide range of human tumors, and lead to aneuploidy and tumorigenesis. Here we report the discovery of a highly potent and selective small-molecule inhibitor of Aurora kinases, VX-680, that blocks cell-cycle progression and induces apoptosis in a diverse range of human tumor types. This compound causes profound inhibition of tumor growth in a variety of in vivo xenograft models, leading to regression of leukemia, colon and pancreatic tumors at well-tolerated doses. Our data indicate that Aurora kinase inhibition provides a new approach for the treatment of multiple human malignancies.", + "TAG_DATA": [ + "44, potent {'perturbing_action': 'B-pharmacological inhibition'}", + "46, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "47, small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "48, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "49, of {'perturbing_action': 'I-pharmacological inhibition'}", + "50, Aurora {'perturbing_action': 'I-pharmacological inhibition'}", + "51, kinases, {'perturbing_action': 'I-pharmacological inhibition'}", + "52, VX-680, {'perturbing_action': 'I-pharmacological inhibition'}", + "58, induces {'effect': 'B-positive'}", + "59, apoptosis {'phenotype': 'B-apoptosis'}", + "65, human {'context': 'B-neoplasm'}", + "66, tumor {'context': 'I-neoplasm'}", + "67, types. {'context': 'I-neoplasm'}", + "72, inhibition {'effect': 'B-negative'}", + "74, tumor {'phenotype': 'B-tumour growth'}", + "75, growth {'phenotype': 'I-tumour growth'}", + "80, in {'context': 'B-xenograft'}", + "81, vivo {'context': 'B-in vivo'}", + "82, xenograft {'context': 'B-xenograft'}", + "83, models, {'context': 'I-xenograft'}", + "84, leading {'effect': 'B-positive'}", + "85, to {'effect': 'I-positive'}", + "86, regression {'phenotype': 'B-tumour regression'}", + "88, leukemia, {'context': 'B-neoplasm'}", + "89, colon {'context': 'I-neoplasm'}", + "90, and {'context': 'I-neoplasm'}", + "91, pancreatic {'context': 'I-neoplasm'}", + "92, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "44, potent ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "46, selective ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "47, small-molecule ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "48, inhibitor ['l2', 'l21', 'l39', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "49, of ['l3', 'l22', 'l40', 'l60', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "50, Aurora ['l4', 'l23', 'l41', 'l61', 'l80', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "51, kinases, ['l5', 'l24', 'l42', 'l62', 'l81', 'l101', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "52, VX-680, ['l6', 'l25', 'l43', 'l63', 'l82', 'l102', 'l119', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "58, induces ['l7', 'l26', 'l44', 'l64', 'l83', 'l103', 'l120', 'l136', 'l148', 'l149', 'l150', 'l151', 'l152']", + "59, apoptosis ['l8', 'l27', 'l45', 'l65', 'l84', 'l104', 'l121', 'l137', 'l148', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158']", + "65, human ['l9', 'l28', 'l46', 'l66', 'l85', 'l105', 'l122', 'l138', 'l149', 'l153', 'l159', 'l160', 'l161']", + "66, tumor ['l10', 'l29', 'l47', 'l67', 'l86', 'l106', 'l123', 'l139', 'l150', 'l154', 'l159', 'l162', 'l163']", + "67, types. ['l11', 'l30', 'l48', 'l68', 'l87', 'l107', 'l124', 'l140', 'l151', 'l155', 'l160', 'l162', 'l164']", + "72, inhibition ['l12', 'l31', 'l49', 'l69', 'l88', 'l108', 'l125', 'l141', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171']", + "74, tumor ['l13', 'l32', 'l50', 'l70', 'l89', 'l109', 'l126', 'l142', 'l156', 'l165', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177']", + "75, growth ['l14', 'l33', 'l51', 'l71', 'l90', 'l110', 'l127', 'l143', 'l152', 'l157', 'l161', 'l163', 'l164', 'l166', 'l172', 'l178', 'l179', 'l180', 'l181']", + "80, in ['l15', 'l34', 'l52', 'l72', 'l91', 'l111', 'l128', 'l144', 'l167', 'l173', 'l178', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "81, vivo ['l16', 'l35', 'l53', 'l73', 'l92', 'l112', 'l129', 'l145', 'l168', 'l174', 'l179', 'l182', 'l189', 'l190', 'l191']", + "82, xenograft ['l17', 'l36', 'l54', 'l74', 'l93', 'l113', 'l130', 'l146', 'l169', 'l175', 'l180', 'l183', 'l189', 'l192', 'l193', 'l194']", + "83, models, ['l18', 'l37', 'l55', 'l75', 'l94', 'l114', 'l131', 'l147', 'l158', 'l170', 'l176', 'l181', 'l184', 'l190', 'l192', 'l195']", + "84, leading ['l19', 'l38', 'l56', 'l76', 'l95', 'l115', 'l132', 'l171', 'l177', 'l185', 'l191', 'l193', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201']", + "85, to ['l57', 'l77', 'l96', 'l116', 'l133', 'l186', 'l196', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207']", + "86, regression ['l202', 'l208', 'l209', 'l210', 'l211', 'l212']", + "88, leukemia, ['l197', 'l203', 'l208', 'l213', 'l214', 'l215', 'l216']", + "89, colon ['l58', 'l78', 'l97', 'l117', 'l134', 'l187', 'l194', 'l198', 'l204', 'l209', 'l213', 'l217', 'l218', 'l219']", + "90, and ['l59', 'l79', 'l98', 'l118', 'l135', 'l188', 'l199', 'l205', 'l210', 'l214', 'l217', 'l220', 'l221']", + "91, pancreatic ['l99', 'l200', 'l206', 'l211', 'l215', 'l218', 'l220', 'l222']", + "92, tumors ['l100', 'l201', 'l207', 'l212', 'l216', 'l219', 'l221', 'l222']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "potent", + "selective", + "small-molecule", + "inhibitor", + "of", + "Aurora", + "kinases,", + "VX-680," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces", + "leading", + "to" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "potent", + "selective", + "small-molecule", + "inhibitor", + "of", + "Aurora", + "kinases,", + "VX-680," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "potent", + "selective", + "small-molecule", + "inhibitor", + "of", + "Aurora", + "kinases,", + "VX-680," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "tumor", + "types.", + "colon", + "and", + "pancreatic", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "potent", + "selective", + "small-molecule", + "inhibitor", + "of", + "Aurora", + "kinases,", + "VX-680," + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "potent", + "selective", + "small-molecule", + "inhibitor", + "of", + "Aurora", + "kinases,", + "VX-680," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "potent", + "selective", + "small-molecule", + "inhibitor", + "of", + "Aurora", + "kinases,", + "VX-680," + ] + }, + "context": { + "val": "xenograft", + "words": [ + "in", + "xenograft", + "models," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "potent", + "selective", + "small-molecule", + "inhibitor", + "of", + "Aurora", + "kinases,", + "VX-680," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "leading", + "to" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "tumor", + "types.", + "leukemia,", + "colon", + "and", + "pancreatic", + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "leading" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth", + "tumor" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "tumor", + "types." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "models," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "human", + "tumor", + "types." + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "in", + "xenograft", + "models," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "in", + "xenograft", + "models," + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "in", + "xenograft", + "models," + ] + }, + "effect": { + "val": "positive", + "words": [ + "leading", + "to" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "leading" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "to" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia,", + "colon", + "and", + "pancreatic", + "tumors" + ] + } + } + ] + }, + { + "PMID": "14770177", + "TEXT": "Lipid infusion or ingestion of a high-fat diet results in insulin resistance, but the mechanism underlying this phenomenon remains unclear. Here we show that, in rats fed a high-fat diet, whole-animal, muscle and liver insulin resistance is ameliorated following hepatic overexpression of malonyl-coenzyme A (CoA) decarboxylase (MCD), an enzyme that affects lipid partitioning. MCD overexpression decreased circulating free fatty acid (FFA) and liver triglyceride content. In skeletal muscle, levels of triglyceride and long-chain acyl-CoA (LC-CoA)-two candidate mediators of insulin resistance-were either increased or unchanged. Metabolic profiling of 36 acylcarnitine species by tandem mass spectrometry revealed a unique decrease in the concentration of one lipid-derived metabolite, beta-OH-butyrate, in muscle of MCD-overexpressing animals. The best explanation for our findings is that hepatic expression of MCD lowered circulating FFA levels, which led to lowering of muscle beta-OH-butyrate levels and improvement of insulin sensitivity.", + "TAG_DATA": [ + "25, rats {'context': 'B-organism'}", + "39, hepatic {'perturbing_action': 'B-gene gain-of-function'}", + "40, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "41, of {'perturbing_action': 'I-gene gain-of-function'}", + "42, malonyl-coenzyme {'perturbing_action': 'I-gene gain-of-function'}", + "43, A {'perturbing_action': 'I-gene gain-of-function'}", + "44, (CoA) {'perturbing_action': 'I-gene gain-of-function'}", + "45, decarboxylase {'perturbing_action': 'I-gene gain-of-function'}", + "46, (MCD), {'perturbing_action': 'I-gene gain-of-function'}", + "53, MCD {'perturbing_action': 'B-gene gain-of-function'}", + "54, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "62, liver {'context': 'B-tissue/organ'}", + "66, skeletal {'context': 'B-tissue/organ'}", + "67, muscle, {'context': 'I-tissue/organ'}", + "107, muscle {'context': 'B-tissue/organ'}", + "109, MCD-overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "110, animals. {'context': 'B-organism'}", + "119, hepatic {'perturbing_action': 'B-gene gain-of-function'}", + "120, expression {'perturbing_action': 'I-gene gain-of-function'}", + "121, of {'perturbing_action': 'I-gene gain-of-function'}", + "122, MCD {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "25, rats ['l0', 'l1', 'l2']", + "31, muscle ['l0', 'l3', 'l4']", + "33, liver ['l1', 'l3', 'l5']", + "39, hepatic ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "40, overexpression ['l6', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "41, of ['l7', 'l18', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "42, malonyl-coenzyme ['l8', 'l19', 'l29', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "43, A ['l9', 'l20', 'l30', 'l39', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "44, (CoA) ['l10', 'l21', 'l31', 'l40', 'l48', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "45, decarboxylase ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "46, (MCD), ['l12', 'l23', 'l33', 'l42', 'l50', 'l57', 'l63', 'l69', 'l70', 'l71', 'l72', 'l73']", + "53, MCD ['l13', 'l24', 'l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l74', 'l75', 'l76', 'l77']", + "54, overexpression ['l14', 'l25', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l78', 'l79', 'l80']", + "62, liver ['l2', 'l4', 'l5', 'l15', 'l26', 'l36', 'l45', 'l53', 'l60', 'l66', 'l71', 'l75', 'l78']", + "66, skeletal ['l16', 'l27', 'l37', 'l46', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l81']", + "67, muscle, ['l17', 'l28', 'l38', 'l47', 'l55', 'l62', 'l68', 'l73', 'l77', 'l80', 'l81']", + "107, muscle ['l82', 'l83']", + "109, MCD-overexpressing ['l82', 'l84']", + "110, animals. ['l83', 'l84']", + "119, hepatic ['l85', 'l86', 'l87']", + "120, expression ['l85', 'l88', 'l89']", + "121, of ['l86', 'l88', 'l90']", + "122, MCD ['l87', 'l89', 'l90']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hepatic", + "overexpression", + "of", + "malonyl-coenzyme", + "A", + "(CoA)", + "decarboxylase", + "(MCD),", + "MCD", + "MCD-overexpressing" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver", + "skeletal", + "muscle,", + "muscle" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "MCD-overexpressing" + ] + }, + "context": { + "val": "organism", + "words": [ + "animals." + ] + } + } + ] + }, + { + "PMID": "14758356", + "TEXT": "We treated Apc(min) mice, which are predisposed to intestinal polyposis, with a selective synthetic agonist of peroxisome proliferator-activated receptor-delta (PPAR-delta). Exposure of Apc(min) mice to the PPAR-delta ligand GW501516 resulted in a significant increase in the number and size of intestinal polyps. The most prominent effect was on polyp size; mice treated with the PPAR-delta activator had a fivefold increase in the number of polyps larger than 2 mm. Our results implicate PPAR-delta in the regulation of intestinal adenoma growth.", + "TAG_DATA": [ + "2, Apc(min) {'perturbing_action': 'B-other'}", + "3, mice, {'context': 'B-organism'}", + "22, Apc(min) {'perturbing_action': 'B-other'}", + "23, mice {'context': 'B-organism'}", + "27, ligand {'perturbing_action': 'I-pharmacological augmentation'}", + "50, mice {'context': 'B-organism'}", + "54, PPAR-delta {'perturbing_action': 'B-pharmacological augmentation'}", + "55, activator {'perturbing_action': 'I-pharmacological augmentation'}" + ], + "LINK_DATA": [ + "2, Apc(min) ['l0', 'l1', 'l2', 'l3']", + "3, mice, ['l0', 'l4', 'l5', 'l6']", + "22, Apc(min) ['l1', 'l4', 'l7', 'l8']", + "23, mice ['l2', 'l5', 'l7']", + "27, ligand ['l3', 'l6', 'l8']", + "50, mice ['l9', 'l10']", + "54, PPAR-delta ['l9', 'l11']", + "55, activator ['l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Apc(min)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "ligand", + "PPAR-delta", + "activator" + ] + } + } + ] + }, + { + "PMID": "14758355", + "TEXT": "Colonization of the anterior nares in approximately 37% of the population is a major risk factor for severe Staphylococcus aureus infections. Here we show that wall teichoic acid (WTA), a surface-exposed staphylococcal polymer, is essential for nasal colonization and mediates interaction with human nasal epithelial cells. WTA-deficient mutants were impaired in their adherence to nasal cells, and were completely unable to colonize cotton rat nares. This study describes the first essential factor for S. aureus nasal colonization.", + "TAG_DATA": [ + "46, WTA-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "49, impaired {'effect': 'B-negative'}", + "54, nasal {'context': 'B-cells'}", + "55, cells, {'context': 'I-cells'}", + "63, rat {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "46, WTA-deficient ['l0', 'l1', 'l2', 'l3']", + "49, impaired ['l0', 'l4', 'l5']", + "54, nasal ['l1', 'l4', 'l6']", + "55, cells, ['l2', 'l5', 'l6']", + "63, rat ['l3']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "WTA-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "WTA-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "nasal", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "WTA-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "cells", + "words": [ + "nasal", + "cells," + ] + } + } + ] + }, + { + "PMID": "14716305", + "TEXT": "The transcription factor, signal transducer and activator of transcription-3 (STAT-3) contributes to various physiological processes. Here we show that mice with liver-specific deficiency in STAT-3, achieved using the Cre-loxP system, show insulin resistance associated with increased hepatic expression of gluconeogenic genes. Restoration of hepatic STAT-3 expression in these mice, using adenovirus-mediated gene transfer, corrected the metabolic abnormalities and the alterations in hepatic expression of gluconeogenic genes. Overexpression of STAT-3 in cultured hepatocytes inhibited gluconeogenic gene expression independently of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha), an upstream regulator of gluconeogenic genes. Liver-specific expression of a constitutively active form of STAT-3, achieved by infection with an adenovirus vector, markedly reduced blood glucose, plasma insulin concentrations and hepatic gluconeogenic gene expression in diabetic mice. Hepatic STAT-3 signaling is thus essential for normal glucose homeostasis and may provide new therapeutic targets for diabetes mellitus.", + "TAG_DATA": [ + "19, mice {'context': 'B-organism'}", + "21, liver-specific {'perturbing_action': 'B-gene loss-of-function'}", + "22, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "23, in {'perturbing_action': 'I-gene loss-of-function'}", + "24, STAT-3, {'perturbing_action': 'I-gene loss-of-function'}", + "41, Restoration {'perturbing_action': 'B-gene gain-of-function'}", + "42, of {'perturbing_action': 'I-gene gain-of-function'}", + "43, hepatic {'perturbing_action': 'I-gene gain-of-function'}", + "44, STAT-3 {'perturbing_action': 'I-gene gain-of-function'}", + "45, expression {'perturbing_action': 'I-gene gain-of-function'}", + "48, mice, {'context': 'B-organism'}", + "66, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "67, of {'perturbing_action': 'I-gene gain-of-function'}", + "68, STAT-3 {'perturbing_action': 'I-gene gain-of-function'}", + "70, cultured {'context': 'B-cells'}", + "71, hepatocytes {'context': 'I-cells'}", + "91, Liver-specific {'perturbing_action': 'B-gene gain-of-function'}", + "92, expression {'perturbing_action': 'I-gene gain-of-function'}", + "93, of {'perturbing_action': 'I-gene gain-of-function'}", + "94, a {'perturbing_action': 'I-gene gain-of-function'}", + "95, constitutively {'perturbing_action': 'I-gene gain-of-function'}", + "96, active {'perturbing_action': 'I-gene gain-of-function'}", + "97, form {'perturbing_action': 'I-gene gain-of-function'}", + "98, of {'perturbing_action': 'I-gene gain-of-function'}", + "99, STAT-3, {'perturbing_action': 'I-gene gain-of-function'}", + "120, diabetic {'context': 'B-organism'}", + "121, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "19, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "21, liver-specific ['l0', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "22, deficiency ['l1', 'l5', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "23, in ['l2', 'l6', 'l13', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "24, STAT-3, ['l3', 'l7', 'l14', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "41, Restoration ['l15', 'l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "42, of ['l8', 'l16', 'l23', 'l29', 'l34', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "43, hepatic ['l9', 'l17', 'l24', 'l30', 'l35', 'l44', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "44, STAT-3 ['l10', 'l18', 'l25', 'l31', 'l36', 'l45', 'l52', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "45, expression ['l11', 'l19', 'l26', 'l32', 'l37', 'l46', 'l53', 'l59', 'l65', 'l66', 'l67', 'l68', 'l69']", + "48, mice, ['l4', 'l12', 'l20', 'l27', 'l33', 'l38', 'l47', 'l54', 'l60', 'l65', 'l70']", + "66, Overexpression ['l39', 'l71', 'l72', 'l73', 'l74']", + "67, of ['l40', 'l48', 'l55', 'l61', 'l66', 'l71', 'l75', 'l76', 'l77']", + "68, STAT-3 ['l41', 'l49', 'l56', 'l62', 'l67', 'l72', 'l75', 'l78', 'l79']", + "70, cultured ['l42', 'l50', 'l57', 'l63', 'l68', 'l73', 'l76', 'l78', 'l80']", + "71, hepatocytes ['l43', 'l51', 'l58', 'l64', 'l69', 'l70', 'l74', 'l77', 'l79', 'l80']", + "91, Liver-specific ['l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "92, expression ['l81', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "93, of ['l82', 'l91', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "94, a ['l83', 'l92', 'l100', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "95, constitutively ['l84', 'l93', 'l101', 'l108', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "96, active ['l85', 'l94', 'l102', 'l109', 'l115', 'l121', 'l122', 'l123', 'l124', 'l125']", + "97, form ['l86', 'l95', 'l103', 'l110', 'l116', 'l121', 'l126', 'l127', 'l128', 'l129']", + "98, of ['l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l126', 'l130', 'l131', 'l132']", + "99, STAT-3, ['l88', 'l97', 'l105', 'l112', 'l118', 'l123', 'l127', 'l130', 'l133', 'l134']", + "120, diabetic ['l89', 'l98', 'l106', 'l113', 'l119', 'l124', 'l128', 'l131', 'l133', 'l135']", + "121, mice. ['l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l129', 'l132', 'l134', 'l135']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "liver-specific", + "deficiency", + "in", + "STAT-3," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoration", + "of", + "hepatic", + "STAT-3", + "expression", + "Liver-specific", + "a", + "constitutively", + "active", + "form", + "STAT-3," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "diabetic", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoration", + "of", + "hepatic", + "STAT-3", + "expression", + "Overexpression" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "hepatocytes" + ] + } + } + ] + }, + { + "PMID": "14647496", + "TEXT": "Despite the ease of inhibiting immune responses by blockade of T-cell costimulation in naive rodent models, it is difficult to suppress those responses in animals with memory cells. Studies demonstrating the importance of alloreactive T-cell deletion during tolerance induction have promoted use of peritransplant T-cell-depleting therapies in clinical trials. But potentially complicating wide-scale, nonspecific T-cell depletion is the finding that extensive T-cell proliferation can occur under conditions of lymphopenia. This process, termed homeostatic proliferation, may induce acquisition of functional memory T cells. Here, using clinically relevant mouse models of peripheral T-cell depletion, we show that residual nondepleted T cells undergo substantial homeostatic expansion. In this setting, costimulatory blockade neither significantly suppresses homeostatic proliferation nor prevents allograft rejection. In addition, T cells that have completed homeostatic proliferation show dominant resistance to tolerance when adoptively transferred into wild-type recipients, consistent with known properties of memory cells in vivo. These findings establish the importance of homeostatic proliferation in clinically relevant settings, demonstrate the barrier that homeostatic proliferation can present to the induction of transplantation tolerance, and have important implications for transplantation protocols that use partial or complete peripheral T-cell depletion.", + "TAG_DATA": [ + "97, T {'context': 'B-cells'}", + "98, cells {'context': 'I-cells'}", + "110, suppresses {'effect': 'B-negative'}", + "112, proliferation {'phenotype': 'B-proliferation'}", + "114, prevents {'effect': 'B-negative'}", + "115, allograft {'context': 'B-xenograft'}", + "119, T {'context': 'B-cells'}", + "120, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "97, T ['l0', 'l1', 'l2', 'l3', 'l4']", + "98, cells ['l0', 'l5', 'l6']", + "110, suppresses ['l1', 'l7', 'l8', 'l9']", + "112, proliferation ['l2', 'l5', 'l7', 'l10', 'l11']", + "114, prevents ['l3', 'l6', 'l8', 'l10', 'l12']", + "115, allograft ['l4', 'l9', 'l11', 'l12']", + "119, T ['l13']", + "120, cells ['l13']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppresses", + "prevents" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppresses", + "prevents" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppresses", + "prevents" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "allograft" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "allograft" + ] + } + } + ] + }, + { + "PMID": "14634645", + "TEXT": "Conditional mutant techniques that allow spatial and temporal control over gene expression can be used to create mice with restricted genetic modifications. These mice serve as powerful disease models in which gene function in adult tissues can be specifically dissected. Current strategies for conditional genetic manipulation are inefficient, however, and often lack sufficient spatial control. Here we use viral-mediated RNA interference (RNAi) to generate a specific knockdown of Th, the gene encoding the dopamine synthesis enzyme tyrosine hydroxylase, within midbrain neurons of adult mice. This localized gene knockdown resulted in behavioral changes, including a motor performance deficit and reduced response to a psychostimulant. These results underscore the potential of using viral-mediated RNAi for the rapid production and testing of new genetic disease models. Similar strategies may be used in other model species, and may ultimately find applications in human gene therapy.", + "TAG_DATA": [ + "58, viral-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "59, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "60, interference {'perturbing_action': 'I-rnai/knockdown'}", + "61, (RNAi) {'perturbing_action': 'I-rnai/knockdown'}", + "65, specific {'perturbing_action': 'B-rnai/knockdown'}", + "66, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "67, of {'perturbing_action': 'I-rnai/knockdown'}", + "68, Th, {'perturbing_action': 'I-rnai/knockdown'}", + "79, midbrain {'context': 'B-cells'}", + "80, neurons {'context': 'I-cells'}", + "82, adult {'context': 'B-organism'}", + "83, mice. {'context': 'I-organism'}", + "86, gene {'perturbing_action': 'I-rnai/knockdown'}", + "87, knockdown {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "58, viral-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "59, RNA ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "60, interference ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "61, (RNAi) ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "65, specific ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "66, knockdown ['l4', 'l16', 'l27', 'l37', 'l46', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "67, of ['l5', 'l17', 'l28', 'l38', 'l47', 'l53', 'l59', 'l60', 'l61', 'l62', 'l63']", + "68, Th, ['l6', 'l18', 'l29', 'l39', 'l48', 'l54', 'l59', 'l64', 'l65', 'l66', 'l67']", + "79, midbrain ['l7', 'l19', 'l30', 'l40', 'l49', 'l55', 'l60', 'l64', 'l68', 'l69', 'l70', 'l71', 'l72']", + "80, neurons ['l8', 'l20', 'l31', 'l41', 'l50', 'l56', 'l61', 'l65', 'l68', 'l73', 'l74', 'l75']", + "82, adult ['l9', 'l21', 'l32', 'l42', 'l51', 'l57', 'l62', 'l66', 'l69', 'l73', 'l76']", + "83, mice. ['l10', 'l22', 'l33', 'l43', 'l52', 'l58', 'l63', 'l67', 'l70', 'l74', 'l76']", + "86, gene ['l11', 'l23', 'l34', 'l44', 'l71', 'l77']", + "87, knockdown ['l12', 'l24', 'l35', 'l45', 'l72', 'l75', 'l77']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "viral-mediated", + "RNA", + "interference", + "(RNAi)", + "specific", + "knockdown", + "of", + "Th,", + "gene" + ] + }, + "context": { + "val": "cells", + "words": [ + "midbrain", + "neurons" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "viral-mediated", + "RNA", + "interference", + "(RNAi)", + "specific", + "knockdown", + "of", + "Th," + ] + }, + "context": { + "val": "organism", + "words": [ + "adult", + "mice." + ] + } + } + ] + }, + { + "PMID": "14625542", + "TEXT": "Thiazolidinediones (TZDs) are insulin-sensitizing drugs and are potent agonists of the nuclear peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Although muscle is the major organ responsible for insulin-stimulated glucose disposal, PPAR-gamma is more highly expressed in adipose tissue than in muscle. To address this issue, we used the Cre-loxP system to knock out Pparg, the gene encoding PPAR-gamma, in mouse skeletal muscle. As early as 4 months of age, mice with targeted disruption of PPAR-gamma in muscle showed glucose intolerance and progressive insulin resistance. Using the hyperinsulinemic-euglycemic clamp technique, the in vivo insulin-stimulated glucose disposal rate (IS-GDR) was reduced by approximately 80% and was unchanged by 3 weeks of TZD treatment. These effects reveal a crucial role for muscle PPAR-gamma in the maintenance of skeletal muscle insulin action, the etiology of insulin resistance and the action of TZDs.", + "TAG_DATA": [ + "48, knock {'perturbing_action': 'B-gene loss-of-function'}", + "49, out {'perturbing_action': 'I-gene loss-of-function'}", + "50, Pparg, {'perturbing_action': 'I-gene loss-of-function'}", + "56, mouse {'context': 'B-tissue/organ'}", + "57, skeletal {'context': 'I-tissue/organ'}", + "58, muscle. {'context': 'I-tissue/organ'}", + "66, mice {'context': 'B-organism'}", + "68, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "69, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "70, of {'perturbing_action': 'I-gene loss-of-function'}", + "71, PPAR-gamma {'perturbing_action': 'I-gene loss-of-function'}", + "72, in {'perturbing_action': 'I-gene loss-of-function'}", + "73, muscle {'perturbing_action': 'I-gene loss-of-function'}", + "87, in {'context': 'B-in vivo'}", + "88, vivo {'context': 'B-in vivo'}" + ], + "LINK_DATA": [ + "48, knock ['l0', 'l1', 'l2', 'l3', 'l4']", + "49, out ['l0', 'l5', 'l6', 'l7', 'l8']", + "50, Pparg, ['l1', 'l5', 'l9', 'l10', 'l11']", + "56, mouse ['l2', 'l6', 'l9', 'l12', 'l13']", + "57, skeletal ['l3', 'l7', 'l10', 'l12', 'l14']", + "58, muscle. ['l4', 'l8', 'l11', 'l13', 'l14']", + "66, mice ['l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "68, targeted ['l15', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "69, disruption ['l16', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "70, of ['l17', 'l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "71, PPAR-gamma ['l18', 'l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "72, in ['l19', 'l24', 'l30', 'l35', 'l39', 'l43']", + "73, muscle ['l20', 'l25', 'l31', 'l36', 'l40', 'l43']", + "87, in ['l26', 'l32', 'l37', 'l41', 'l44']", + "88, vivo ['l27', 'l33', 'l38', 'l42', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knock", + "out", + "Pparg," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "skeletal", + "muscle." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "disruption", + "of", + "PPAR-gamma", + "in", + "muscle" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "disruption", + "of", + "PPAR-gamma" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "14608380", + "TEXT": "The neural tube defects (NTDs) spina bifida and anencephaly are widely prevalent severe birth defects. The mouse mutant curly tail (ct/ct) has served as a model of NTDs for 50 years, even though the responsible genetic defect remained unrecognized. Here we show by gene targeting, mapping and genetic complementation studies that a mouse homolog of the Drosophila grainyhead (grh) gene, grainyhead-like-3 (Grhl3), is a compelling candidate for the gene underlying the curly tail phenotype. The NTDs in Grhl3-null mice are more severe than those in the curly tail strain, as the Grhl3 alleles in ct/ct mice are hypomorphic. Spina bifida in ct/ct mice is folate resistant, but its incidence can be markedly reduced by maternal inositol supplementation periconceptually. The NTDs in Grhl3-/- embryos are also folate resistant, but unlike those in ct/ct mice, they are resistant to inositol. These findings suggest that residual Grhl3 expression in ct/ct mice may be required for inositol rescue of folate-resistant NTDs.", + "TAG_DATA": [ + "77, Grhl3-null {'perturbing_action': 'B-gene loss-of-function'}", + "78, mice {'context': 'B-organism'}", + "94, ct/ct {'perturbing_action': 'B-gene loss-of-function'}", + "95, mice {'context': 'B-organism'}", + "101, ct/ct {'perturbing_action': 'B-gene loss-of-function'}", + "102, mice {'context': 'B-organism'}", + "121, Grhl3-/- {'perturbing_action': 'B-gene loss-of-function'}", + "122, embryos {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "77, Grhl3-null ['l0']", + "78, mice ['l0']", + "94, ct/ct ['l1', 'l2', 'l3']", + "95, mice ['l1', 'l4']", + "101, ct/ct ['l2', 'l5']", + "102, mice ['l3', 'l4', 'l5']", + "121, Grhl3-/- ['l6']", + "122, embryos ['l6']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Grhl3-null", + "ct/ct", + "Grhl3-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "embryos" + ] + } + } + ] + }, + { + "PMID": "14608379", + "TEXT": "Nitric oxide (NO) inhibits vascular contraction by activating cGMP-dependent protein kinase I-alpha (PKGI-alpha), which causes dephosphorylation of myosin light chain (MLC) and vascular smooth muscle relaxation. Here we show that PKGI-alpha attenuates signaling by the thrombin receptor protease-activated receptor-1 (PAR-1) through direct activation of regulator of G-protein signaling-2 (RGS-2). NO donors and cGMP cause cGMP-mediated inhibition of PAR-1 and membrane localization of RGS-2. PKGI-alpha binds directly to and phosphorylates RGS-2, which significantly increases GTPase activity of G(q), terminating PAR-1 signaling. Disruption of the RGS-2-PKGI-alpha interaction reverses inhibition of PAR-1 signaling by nitrovasodilators and cGMP. Rgs2-/- mice develop marked hypertension, and their blood vessels show enhanced contraction and decreased cGMP-mediated relaxation. Thus, PKGI-alpha binds to, phosphorylates and activates RGS-2, attenuating receptor-mediated vascular contraction. Our study shows that RGS-2 is required for normal vascular function and blood pressure and is a new drug development target for hypertension.", + "TAG_DATA": [ + "94, Rgs2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "95, mice {'context': 'B-organism'}", + "101, blood {'context': 'B-tissue/organ'}", + "102, vessels {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "94, Rgs2-/- ['l0', 'l1', 'l2']", + "95, mice ['l0', 'l3', 'l4']", + "101, blood ['l1', 'l3', 'l5']", + "102, vessels ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rgs2-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rgs2-/-" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "blood", + "vessels" + ] + } + } + ] + }, + { + "PMID": "14556003", + "TEXT": "Endothelial nitric oxide synthase (eNOS) is essential for neovascularization. Here we show that the impaired neovascularization in mice lacking eNOS is related to a defect in progenitor cell mobilization. Mice deficient in eNOS (Nos3(-/-)) show reduced vascular endothelial growth factor (VEGF)-induced mobilization of endothelial progenitor cells (EPCs) and increased mortality after myelosuppression. Intravenous infusion of wild-type progenitor cells, but not bone marrow transplantation, rescued the defective neovascularization of Nos3(-/-) mice in a model of hind-limb ischemia, suggesting that progenitor mobilization from the bone marrow is impaired in Nos3(-/-) mice. Mechanistically, matrix metalloproteinase-9 (MMP-9), which is required for stem cell mobilization, was reduced in the bone marrow of Nos3(-/-) mice. These findings indicate that eNOS expressed by bone marrow stromal cells influences recruitment of stem and progenitor cells. This may contribute to impaired regeneration processes in ischemic heart disease patients, who are characterized by a reduced systemic NO bioactivity.", + "TAG_DATA": [ + "19, eNOS {'perturbing_action': 'I-gene loss-of-function'}", + "29, Mice {'context': 'B-organism'}", + "30, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "31, in {'perturbing_action': 'I-gene loss-of-function'}", + "32, eNOS {'perturbing_action': 'I-gene loss-of-function'}", + "33, (Nos3(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "43, endothelial {'context': 'B-cells'}", + "44, progenitor {'context': 'I-cells'}", + "45, cells {'context': 'I-cells'}", + "46, (EPCs) {'context': 'I-cells'}", + "56, progenitor {'context': 'B-cells'}", + "57, cells, {'context': 'I-cells'}", + "68, Nos3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "69, mice {'context': 'B-organism'}", + "87, Nos3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "88, mice. {'context': 'B-organism'}", + "104, bone {'context': 'B-tissue/organ'}", + "105, marrow {'context': 'I-tissue/organ'}", + "107, Nos3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "108, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "19, eNOS ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "29, Mice ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "30, deficient ['l6', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "31, in ['l7', 'l14', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "32, eNOS ['l8', 'l15', 'l23', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "33, (Nos3(-/-)) ['l1', 'l9', 'l16', 'l24', 'l32', 'l39', 'l40', 'l41', 'l42']", + "43, endothelial ['l2', 'l10', 'l17', 'l25', 'l33', 'l39', 'l43', 'l44', 'l45']", + "44, progenitor ['l3', 'l11', 'l18', 'l26', 'l34', 'l40', 'l43', 'l46', 'l47']", + "45, cells ['l4', 'l12', 'l19', 'l27', 'l35', 'l41', 'l44', 'l46', 'l48']", + "46, (EPCs) ['l5', 'l13', 'l20', 'l28', 'l36', 'l42', 'l45', 'l47', 'l48']", + "56, progenitor ['l49', 'l50', 'l51', 'l52', 'l53']", + "57, cells, ['l21', 'l29', 'l37', 'l49', 'l54', 'l55', 'l56', 'l57']", + "68, Nos3(-/-) ['l30', 'l50', 'l54', 'l58']", + "69, mice ['l22', 'l31', 'l38', 'l51', 'l55', 'l58']", + "87, Nos3(-/-) ['l52', 'l56', 'l59']", + "88, mice. ['l53', 'l57', 'l59']", + "104, bone ['l60', 'l61', 'l62']", + "105, marrow ['l60', 'l63', 'l64']", + "107, Nos3(-/-) ['l61', 'l63', 'l65']", + "108, mice. ['l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "eNOS", + "deficient", + "in", + "(Nos3(-/-))", + "Nos3(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "Mice", + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "eNOS", + "deficient", + "in", + "(Nos3(-/-))", + "Nos3(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "progenitor", + "cells", + "(EPCs)", + "cells," + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "bone", + "marrow" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nos3(-/-)" + ] + } + } + ] + }, + { + "PMID": "14528298", + "TEXT": "Platelet activation at sites of vascular injury is essential for primary hemostasis, but also underlies arterial thrombosis leading to myocardial infarction or stroke. Platelet activators such as adenosine diphosphate, thrombin or thromboxane A(2) (TXA(2)) activate receptors that are coupled to heterotrimeric G proteins. Activation of platelets through these receptors involves signaling through G(q), G(i) and G(z) (refs. 4-6). However, the role and relative importance of G(12) and G(13), which are activated by various platelet stimuli, are unclear. Here we show that lack of Galpha(13), but not Galpha(12), severely reduced the potency of thrombin, TXA(2) and collagen to induce platelet shape changes and aggregation in vitro. These defects were accompanied by reduced activation of RhoA and inability to form stable platelet thrombi under high shear stress ex vivo. Galpha(13) deficiency in platelets resulted in a severe defect in primary hemostasis and complete protection against arterial thrombosis in vivo. We conclude that G(13)-mediated signaling processes are required for normal hemostasis and thrombosis and may serve as a new target for antiplatelet drugs.", + "TAG_DATA": [ + "81, lack {'perturbing_action': 'B-gene loss-of-function'}", + "82, of {'perturbing_action': 'I-gene loss-of-function'}", + "83, Galpha(13), {'perturbing_action': 'I-gene loss-of-function'}", + "97, induce {'effect': 'B-positive'}", + "98, platelet {'context': 'B-cells'}", + "102, aggregation {'phenotype': 'B-autophagy'}", + "103, in {'context': 'B-in vitro'}", + "104, vitro. {'context': 'I-in vitro'}", + "127, Galpha(13) {'perturbing_action': 'B-gene loss-of-function'}", + "128, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "130, platelets {'context': 'B-cells'}", + "145, in {'context': 'B-in vivo'}", + "146, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "81, lack ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "82, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "83, Galpha(13), ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "97, induce ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "98, platelet ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "102, aggregation ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "103, in ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "104, vitro. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "127, Galpha(13) ['l28', 'l29', 'l30', 'l31']", + "128, deficiency ['l28', 'l32', 'l33', 'l34']", + "130, platelets ['l29', 'l32', 'l35', 'l36']", + "145, in ['l30', 'l33', 'l35', 'l37']", + "146, vivo. ['l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "Galpha(13)," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "Galpha(13),", + "Galpha(13)", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelet", + "platelets" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "Galpha(13)," + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "aggregation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "Galpha(13)," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelet" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "aggregation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "platelet" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "aggregation" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "aggregation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Galpha(13)", + "deficiency" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "12960963", + "TEXT": "The role of the nuclear peroxisome proliferator-activated receptor (PPAR)-gamma in cancer has been a subject of debate. The identification of loss-of-function mutations in PPARG in colon and prostate tumors has led to the idea that this gene may function as a tumor suppressor. We have directly tested this notion using a mouse model of prostate cancer. Neither hemizygous deletion of Pparg nor complete ablation of Ppara influenced the development of prostate cancer in our experimental context.", + "TAG_DATA": [ + "51, mouse {'context': 'B-neoplasm'}", + "52, model {'context': 'I-neoplasm'}", + "53, of {'context': 'I-neoplasm'}", + "54, prostate {'context': 'I-neoplasm'}", + "55, cancer. {'context': 'I-neoplasm'}", + "57, hemizygous {'perturbing_action': 'B-gene loss-of-function'}", + "58, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "59, of {'perturbing_action': 'I-gene loss-of-function'}", + "60, Pparg {'perturbing_action': 'I-gene loss-of-function'}", + "62, complete {'perturbing_action': 'B-gene loss-of-function'}", + "63, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "64, of {'perturbing_action': 'I-gene loss-of-function'}", + "65, Ppara {'perturbing_action': 'I-gene loss-of-function'}", + "70, prostate {'context': 'B-neoplasm'}", + "71, cancer {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "51, mouse ['l0', 'l1', 'l2', 'l3']", + "52, model ['l0', 'l4', 'l5', 'l6']", + "53, of ['l1', 'l4', 'l7', 'l8']", + "54, prostate ['l2', 'l5', 'l7', 'l9']", + "55, cancer. ['l3', 'l6', 'l8', 'l9']", + "57, hemizygous ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "58, deletion ['l10', 'l16', 'l17', 'l18', 'l19']", + "59, of ['l11', 'l16', 'l20', 'l21', 'l22']", + "60, Pparg ['l12', 'l17', 'l20', 'l23', 'l24']", + "62, complete ['l25', 'l26', 'l27', 'l28', 'l29']", + "63, ablation ['l25', 'l30', 'l31', 'l32', 'l33']", + "64, of ['l26', 'l30', 'l34', 'l35', 'l36']", + "65, Ppara ['l13', 'l27', 'l31', 'l34', 'l37', 'l38']", + "70, prostate ['l14', 'l18', 'l21', 'l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "71, cancer ['l15', 'l19', 'l22', 'l24', 'l29', 'l33', 'l36', 'l38', 'l39']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "hemizygous", + "deletion", + "of", + "Pparg", + "complete", + "ablation", + "Ppara" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "prostate", + "cancer" + ] + } + } + ] + }, + { + "PMID": "12910263", + "TEXT": "The discovery of endogenous bioactive peptides has typically required a lengthy identification process. Computer-assisted analysis of cDNA and genomic DNA sequence information can markedly shorten the process. A bioinformatic analysis of full-length, enriched human cDNA libraries searching for previously unidentified bioactive peptides resulted in the identification and characterization of two related peptides of 28 and 20 amino acids, which we designated salusin-alpha and salusin-beta. Salusins are translated from an alternatively spliced mRNA of TOR2A, a gene encoding a protein of the torsion dystonia family. Intravenous administration of salusin-alpha or salusin-beta to rats causes rapid, profound hypotension and bradycardia. Salusins increase intracellular Ca2+, upregulate a variety of genes and induce cell mitogenesis. Salusin-beta stimulates the release of arginine-vasopressin from rat pituitary. Expression of TOR2A mRNA and its splicing into preprosalusin are ubiquitous, and immunoreactive salusin-alpha and salusin-beta are detected in many human tissues, plasma and urine, suggesting that salusins are endocrine and/or paracrine factors.", + "TAG_DATA": [ + "91, rats {'context': 'B-organism'}", + "108, induce {'effect': 'B-positive'}", + "109, cell {'context': 'B-cells'}", + "110, mitogenesis. {'phenotype': 'B-proliferation'}", + "118, rat {'context': 'B-tissue/organ'}", + "119, pituitary. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "91, rats ['l0', 'l1', 'l2']", + "108, induce ['l0', 'l3', 'l4']", + "109, cell ['l1', 'l3', 'l5']", + "110, mitogenesis. ['l2', 'l4', 'l5']", + "118, rat ['l6']", + "119, pituitary. ['l6']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "rats" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rats" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "mitogenesis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "mitogenesis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "mitogenesis." + ] + } + } + ] + }, + { + "PMID": "12897778", + "TEXT": "Bone-marrow minimal residual disease (MRD) causes relapse after chemotherapy in patients with acute myelogenous leukemia (AML). We postulate that the drug resistance is induced by the attachment of very late antigen (VLA)-4 on leukemic cells to fibronectin on bone-marrow stromal cells. We found that VLA-4-positive cells acquired resistance to anoikis (loss of anchorage) or drug-induced apoptosis through the phosphatidylinositol-3-kinase (PI-3K)/AKT/Bcl-2 signaling pathway, which is activated by the interaction of VLA-4 and fibronectin. This resistance was negated by VLA-4-specific antibodies. In a mouse model of MRD, we achieved a 100% survival rate by combining VLA-4-specific antibodies and cytosine arabinoside (AraC), whereas AraC alone prolonged survival only slightly. In addition, overall survival at 5 years was 100% for 10 VLA-4-negative patients and 44.4% for 15 VLA-4-positive patients. Thus, the interaction between VLA-4 on leukemic cells and fibronectin on stromal cells may be crucial in bone marrow MRD and AML prognosis.", + "TAG_DATA": [ + "44, VLA-4-positive {'context': 'B-cells'}", + "45, cells {'context': 'I-cells'}", + "54, drug-induced {'effect': 'B-positive'}", + "55, apoptosis {'phenotype': 'B-apoptosis'}", + "81, mouse {'context': 'B-organism'}", + "82, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "44, VLA-4-positive ['l0']", + "45, cells ['l0']", + "54, drug-induced ['l1', 'l2']", + "55, apoptosis ['l1']", + "81, mouse ['l3']", + "82, model ['l2', 'l3']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "drug-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "drug-induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "model" + ] + } + } + ] + }, + { + "PMID": "12808449", + "TEXT": "The blood-brain barrier (BBB) is essential for maintaining brain homeostasis and low permeability. BBB maintenance is important in the central nervous system (CNS) because disruption of the BBB may contribute to many brain disorders, including Alzheimer disease and ischemic stroke. The molecular mechanisms of BBB development remain ill-defined, however. Here we report that src-suppressed C-kinase substrate (SSeCKS) decreases the expression of vascular endothelial growth factor (VEGF) through AP-1 reduction and stimulates expression of angiopoietin-1 (Ang-1), an antipermeability factor in astrocytes. Conditioned media from SSeCKS-overexpressing astrocytes (SSeCKS-CM) blocked angiogenesis in vivo and in vitro. Moreover, SSeCKS-CM increased tight junction proteins in endothelial cells, consequently decreasing [3H]sucrose permeability. Furthermore, immunoreactivity to SSeCKS gradually increased during the BBB maturation period, and SSeCKS-expressing astrocytes closely interacted with zonula occludens (ZO)-1-expressing blood vessels in vivo. Collectively, our results suggest that SSeCKS regulates BBB differentiation by modulating both brain angiogenesis and tight junction formation.", + "TAG_DATA": [ + "79, astrocytes. {'context': 'B-cells'}", + "83, SSeCKS-overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "84, astrocytes {'context': 'B-cells'}", + "88, in {'context': 'B-in vivo'}", + "89, vivo {'context': 'I-in vivo'}", + "91, in {'context': 'B-in vitro'}", + "92, vitro. {'context': 'I-in vitro'}", + "100, endothelial {'context': 'B-cells'}", + "101, cells, {'context': 'I-cells'}", + "118, SSeCKS-expressing {'context': 'B-cells'}", + "119, astrocytes {'context': 'I-cells'}", + "128, in {'context': 'B-in vivo'}", + "129, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "79, astrocytes. ['l0']", + "83, SSeCKS-overexpressing ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "84, astrocytes ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "88, in ['l2', 'l8', 'l14']", + "89, vivo ['l0', 'l3', 'l9', 'l14']", + "91, in ['l4', 'l10', 'l15', 'l16']", + "92, vitro. ['l5', 'l11', 'l15', 'l17']", + "100, endothelial ['l6', 'l12', 'l18']", + "101, cells, ['l7', 'l13', 'l16', 'l17', 'l18']", + "118, SSeCKS-expressing ['l19', 'l20', 'l21']", + "119, astrocytes ['l19', 'l22', 'l23']", + "128, in ['l20', 'l22', 'l24']", + "129, vivo. ['l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "SSeCKS-overexpressing" + ] + }, + "context": { + "val": "cells", + "words": [ + "astrocytes", + "endothelial", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "SSeCKS-overexpressing" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "SSeCKS-overexpressing" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "12730690", + "TEXT": "Retinal ischemia can cause vision-threatening pathological neovascularization. The mechanisms of retinal ischemia are not fully understood, however. Here we have shown that leukocytes prune the retinal vasculature during normal development and obliterate it in disease. Beginning at postnatal day 5 (P5) in the normal rat, vascular pruning began centrally and extended peripherally, leaving behind a less dense, smaller-caliber vasculature. The pruning was correlated with retinal vascular expression of intercellular adhesion molecule-1 (ICAM-1) and coincided with an outward-moving wave of adherent leukocytes composed in part of cytotoxic T lymphocytes. The leukocytes adhered to the vasculature through CD18 and remodeled it through Fas ligand (FasL)-mediated endothelial cell apoptosis. In a model of oxygen-induced ischemic retinopathy, this process was exaggerated. Leukocytes used CD18 and FasL to obliterate the retinal vasculature, leaving behind large areas of ischemic retina. In vitro, T lymphocytes isolated from oxygen-exposed neonates induced a FasL-mediated apoptosis of hyperoxygenated endothelial cells. Targeting these pathways may prove useful in the treatment of retinal ischemia, a leading cause of vision loss and blindness.", + "TAG_DATA": [ + "44, rat, {'context': 'B-organism'}", + "103, endothelial {'context': 'B-cells'}", + "104, cell {'context': 'I-cells'}", + "105, apoptosis. {'phenotype': 'B-apoptosis'}", + "117, Leukocytes {'context': 'B-cells'}", + "134, In {'context': 'B-in vitro'}", + "135, vitro, {'context': 'I-in vitro'}", + "136, T {'context': 'B-cells'}", + "137, lymphocytes {'context': 'I-cells'}", + "138, isolated {'context': 'I-cells'}", + "141, neonates {'context': 'B-organism'}", + "142, induced {'effect': 'B-positive'}", + "145, apoptosis {'phenotype': 'B-apoptosis'}", + "148, endothelial {'context': 'B-cells'}", + "149, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "103, endothelial ['l0', 'l1']", + "104, cell ['l0', 'l2']", + "105, apoptosis. ['l1', 'l2']", + "134, In ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "135, vitro, ['l3', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "136, T ['l4', 'l12', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "137, lymphocytes ['l5', 'l13', 'l20', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "138, isolated ['l6', 'l14', 'l21', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "141, neonates ['l7', 'l15', 'l22', 'l28', 'l33', 'l38', 'l39', 'l40', 'l41']", + "142, induced ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l42', 'l43', 'l44']", + "145, apoptosis ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l45', 'l46']", + "148, endothelial ['l10', 'l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l47']", + "149, cells. ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell", + "T", + "lymphocytes", + "isolated", + "cells." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis.", + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "lymphocytes", + "isolated", + "endothelial", + "cells." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "neonates" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "neonates" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "12730689", + "TEXT": "Interleukin-2 (IL-2) is used to treat metastatic renal cell carcinoma and malignant melanoma, but its use is limited by the severe hypotension it produces. We have shown here that M40403, a superoxide dismutase (SOD) mimetic, blocked IL-2-induced hypotension and allowed the dose of IL-2 to be increased in mice. The reversal of IL-2-mediated hypotension was associated with an increase in plasma catecholamines. In addition, M40403 increased lymphokine-activated killer (LAK) cell cytotoxicity in vitro and in vivo, through inhibition of macrophage superoxide production. Treatment of methylcholanthrene-induced (Meth A) ascites tumors with IL-2 and > or =3 mg per kg body weight M40403 induced 50% complete remissions lasting for more than 200 d, which was longer than those of untreated mice (15-d median survival) or mice treated with IL-2 alone (22-d median). Growth of subcutaneous implants of RENCA renal carcinoma was also inhibited by the combination of IL-2 and M40403. These results established that M40403 prevented IL-2 from causing dose-limiting hypotension, while enhancing its anticancer activity.", + "TAG_DATA": [ + "48, mice. {'context': 'B-organism'}", + "71, in {'context': 'B-in vitro'}", + "72, vitro {'context': 'I-in vitro'}", + "74, in {'context': 'B-in vivo'}", + "75, vivo, {'context': 'I-in vivo'}", + "84, methylcholanthrene-induced {'context': 'B-neoplasm'}", + "85, (Meth {'context': 'I-neoplasm'}", + "86, A) {'context': 'I-neoplasm'}", + "87, ascites {'context': 'I-neoplasm'}", + "88, tumors {'context': 'I-neoplasm'}", + "118, mice {'context': 'B-organism'}", + "123, mice {'context': 'B-organism'}", + "132, subcutaneous {'context': 'B-xenograft'}", + "133, implants {'context': 'I-xenograft'}", + "135, RENCA {'context': 'B-neoplasm'}", + "136, renal {'context': 'I-neoplasm'}", + "137, carcinoma {'context': 'I-neoplasm'}", + "140, inhibited {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "48, mice. ['l0', 'l1', 'l2']", + "71, in ['l0', 'l3', 'l4', 'l5']", + "72, vitro ['l1', 'l3', 'l6', 'l7']", + "74, in ['l4', 'l6', 'l8']", + "75, vivo, ['l2', 'l5', 'l7', 'l8']", + "84, methylcholanthrene-induced ['l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "85, (Meth ['l9', 'l15', 'l16', 'l17', 'l18', 'l19']", + "86, A) ['l10', 'l15', 'l20', 'l21', 'l22', 'l23']", + "87, ascites ['l11', 'l16', 'l20', 'l24', 'l25', 'l26']", + "88, tumors ['l12', 'l17', 'l21', 'l24', 'l27', 'l28']", + "118, mice ['l13', 'l18', 'l22', 'l25', 'l27', 'l29']", + "123, mice ['l14', 'l19', 'l23', 'l26', 'l28', 'l29']", + "132, subcutaneous ['l30', 'l31', 'l32', 'l33', 'l34']", + "133, implants ['l30', 'l35', 'l36', 'l37', 'l38']", + "135, RENCA ['l31', 'l35', 'l39', 'l40', 'l41']", + "136, renal ['l32', 'l36', 'l39', 'l42', 'l43']", + "137, carcinoma ['l33', 'l37', 'l40', 'l42', 'l44']", + "140, inhibited ['l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "xenograft", + "words": [ + "subcutaneous", + "implants" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "RENCA", + "renal", + "carcinoma" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + } + ] + }, + { + "PMID": "12692546", + "TEXT": "Interleukin (IL)-2 is currently used to enhance T-cell immunity but can have both positive and negative effects on T cells. To determine whether these opposing results are due to IL-2 acting differently on T cells depending on their stage of differentiation, we examined the effects of IL-2 therapy during the expansion, contraction and memory phases of the T-cell response in lymphocytic choriomeningitis virus (LCMV)-infected mice. IL-2 treatment during the expansion phase was detrimental to the survival of rapidly dividing effector T cells. In contrast, IL-2 therapy was highly beneficial during the death phase, resulting in increased proliferation and survival of virus-specific T cells. IL-2 treatment also increased proliferation of resting memory T cells in mice that controlled the infection. Virus-specific T cells in chronically infected mice also responded to IL-2 resulting in decreased viral burden. Thus, timing of IL-2 administration and differentiation status of the T cell are critical parameters in designing IL-2 therapies.", + "TAG_DATA": [ + "64, mice. {'context': 'B-organism'}", + "79, effector {'context': 'I-cells'}", + "80, T {'context': 'I-cells'}", + "81, cells. {'context': 'I-cells'}", + "95, increased {'effect': 'B-positive'}", + "96, proliferation {'phenotype': 'B-proliferation'}", + "100, virus-specific {'context': 'B-cells'}", + "101, T {'context': 'I-cells'}", + "102, cells. {'context': 'I-cells'}", + "106, increased {'effect': 'B-positive'}", + "107, proliferation {'phenotype': 'B-proliferation'}", + "109, resting {'context': 'B-cells'}", + "110, memory {'context': 'I-cells'}", + "111, T {'context': 'I-cells'}", + "112, cells {'context': 'I-cells'}", + "114, mice {'context': 'B-organism'}", + "119, Virus-specific {'context': 'B-cells'}", + "120, T {'context': 'I-cells'}", + "121, cells {'context': 'I-cells'}", + "125, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "64, mice. ['l0', 'l1']", + "79, effector ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "80, T ['l0', 'l2', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "81, cells. ['l1', 'l3', 'l9', 'l15', 'l16', 'l17', 'l18']", + "95, increased ['l4', 'l10', 'l15', 'l19', 'l20', 'l21', 'l22']", + "96, proliferation ['l5', 'l11', 'l16', 'l19', 'l23', 'l24', 'l25']", + "100, virus-specific ['l6', 'l12', 'l20', 'l23', 'l26', 'l27']", + "101, T ['l7', 'l13', 'l17', 'l21', 'l24', 'l26', 'l28']", + "102, cells. ['l8', 'l14', 'l18', 'l22', 'l25', 'l27', 'l28']", + "106, increased ['l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "107, proliferation ['l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "109, resting ['l30', 'l35', 'l40', 'l41', 'l42', 'l43']", + "110, memory ['l31', 'l36', 'l40', 'l44', 'l45', 'l46']", + "111, T ['l32', 'l37', 'l41', 'l44', 'l47', 'l48']", + "112, cells ['l33', 'l38', 'l42', 'l45', 'l47', 'l49']", + "114, mice ['l34', 'l39', 'l43', 'l46', 'l48', 'l49']", + "119, Virus-specific ['l50', 'l51', 'l52']", + "120, T ['l50', 'l53', 'l54']", + "121, cells ['l51', 'l53', 'l55']", + "125, mice ['l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "effector", + "T", + "cells.", + "virus-specific", + "resting", + "memory", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "effector", + "T", + "cells.", + "virus-specific", + "resting", + "memory", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "12692538", + "TEXT": "We studied the role of NF-kappaB in acute inflammation caused by gut ischemia-reperfusion through selective ablation of IkappaB kinase (IKK)-beta, the catalytic subunit of IKK that is essential for NF-kappaB activation. Ablation of IKK-beta in enterocytes prevented the systemic inflammatory response, which culminates in multiple organ dysfunction syndrome (MODS) that is normally triggered by gut ischemia-reperfusion. IKK-beta removal from enterocytes, however, also resulted in severe apoptotic damage to the reperfused intestinal mucosa. These results show the dual function of the NF-kappaB system, which is responsible for both tissue protection and systemic inflammation, and underscore the caution that should be exerted in using NF-kappaB and IKK inhibitors.", + "TAG_DATA": [ + "31, Ablation {'perturbing_action': 'B-gene loss-of-function'}", + "32, of {'perturbing_action': 'I-gene loss-of-function'}", + "33, IKK-beta {'perturbing_action': 'I-gene loss-of-function'}", + "35, enterocytes {'context': 'B-cells'}", + "56, IKK-beta {'perturbing_action': 'B-gene loss-of-function'}", + "57, removal {'perturbing_action': 'I-gene loss-of-function'}", + "58, from {'perturbing_action': 'I-gene loss-of-function'}", + "59, enterocytes, {'context': 'B-cells'}", + "65, apoptotic {'phenotype': 'B-apoptosis'}", + "66, damage {'phenotype': 'I-apoptosis'}", + "70, intestinal {'context': 'B-tissue/organ'}", + "71, mucosa. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "31, Ablation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "32, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "33, IKK-beta ['l1', 'l7', 'l13', 'l14', 'l15', 'l16']", + "35, enterocytes ['l2', 'l8', 'l13']", + "56, IKK-beta ['l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "57, removal ['l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "58, from ['l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "59, enterocytes, ['l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "65, apoptotic ['l3', 'l9', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "66, damage ['l4', 'l10', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "70, intestinal ['l5', 'l11', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "71, mucosa. ['l6', 'l12', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "IKK-beta", + "removal", + "from" + ] + }, + "context": { + "val": "cells", + "words": [ + "enterocytes", + "enterocytes," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "IKK-beta", + "removal", + "from" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "damage" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "IKK-beta", + "removal", + "from" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "intestinal", + "mucosa." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "enterocytes," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "damage" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "damage" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "intestinal", + "mucosa." + ] + } + } + ] + }, + { + "PMID": "12669032", + "TEXT": "The establishment of functional and stable vascular networks is essential for angiogenic therapy. Here we report that a combination of two angiogenic factors, platelet-derived growth factor (PDGF)-BB and fibroblast growth factor (FGF)-2, synergistically induces vascular networks, which remain stable for more than a year even after depletion of angiogenic factors. In both rat and rabbit ischemic hind limb models, PDGF-BB and FGF-2 together markedly stimulated collateral arteriogenesis after ligation of the femoral artery, with a significant increase in vascularization and improvement in paw blood flow. A possible mechanism of angiogenic synergism between PDGF-BB and FGF-2 involves upregulation of the expression of PDGF receptor (PDGFR)-alpha and PDGFR-beta by FGF-2 in newly formed blood vessels. Our data show that a specific combination of angiogenic factors establishes functional and stable vascular networks, and provides guidance for the ongoing clinical trials of angiogenic factors for the treatment of ischemic diseases.", + "TAG_DATA": [ + "52, rat {'context': 'B-organism'}", + "53, and {'context': 'I-organism'}", + "54, rabbit {'context': 'I-organism'}", + "69, of {'perturbing_action': 'I-gene loss-of-function'}", + "70, the {'perturbing_action': 'I-gene loss-of-function'}", + "71, femoral {'perturbing_action': 'I-gene loss-of-function'}", + "72, artery, {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-tissue/organ'}", + "82, paw {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "52, rat ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "53, and ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "54, rabbit ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "56, hind ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "57, limb ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "68, ligation ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "69, of ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "70, the ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "71, femoral ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44', 'l45']", + "72, artery, ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "82, paw ['l45']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "rat", + "and", + "rabbit" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "the", + "femoral", + "artery," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "artery,", + "of", + "the", + "femoral" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "artery,", + "paw" + ] + } + } + ] + }, + { + "PMID": "12592402", + "TEXT": "Polymorphonuclear leukocytes (PMNs) are critical effector cells of the innate immune system that protect the host by migrating to inflammatory sites and killing pathogenic microbes. We addressed the role of chemokine receptor desensitization induced by G-protein-coupled receptor kinases (GRKs) in the feedback control of PMN migration. We show that the chemokine macrophage inflammatory protein-2 (MIP-2) induces GRK2 and GRK5 expression in PMNs through phosphoinositide-3-kinase (PI3K)-gamma signaling. We also show that lipopolysaccharide (LPS)-activated signaling through the Toll-like receptor (TLR)-4 pathway transcriptionally downregulates the expression of GRK2 and GRK5 in response to MIP-2. The reduced expression of GRKs lowers chemokine receptor desensitization and markedly augments the PMN migratory response. These data indicate that TLR4 modulation of PMN surface chemokine receptor expression subsequent to the downregulation of GRK2 and GRK5 expression is a critical determinant of PMN migration.", + "TAG_DATA": [ + "61, PMNs {'context': 'B-cells'}", + "95, GRKs {'perturbing_action': 'I-rnai/knockdown'}", + "102, augments {'effect': 'B-positive'}", + "104, PMN {'context': 'B-cells'}", + "105, migratory {'phenotype': 'B-migration'}", + "106, response. {'phenotype': 'I-migration'}" + ], + "LINK_DATA": [ + "95, GRKs ['l0', 'l1', 'l2', 'l3']", + "102, augments ['l0', 'l4', 'l5', 'l6']", + "104, PMN ['l1', 'l4', 'l7', 'l8']", + "105, migratory ['l2', 'l5', 'l7', 'l9']", + "106, response. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "GRKs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "augments" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "GRKs" + ] + }, + "context": { + "val": "cells", + "words": [ + "PMN" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "GRKs" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migratory", + "response." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "augments" + ] + }, + "context": { + "val": "cells", + "words": [ + "PMN" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "augments" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migratory", + "response." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "PMN" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migratory", + "response." + ] + } + } + ] + }, + { + "PMID": "12579197", + "TEXT": "RNA interference (RNAi) is a powerful tool to silence gene expression post-transcriptionally. However, its potential to treat or prevent disease remains unproven. Fas-mediated apoptosis is implicated in a broad spectrum of liver diseases, where inhibiting hepatocyte death is life-saving. We investigated the in vivo silencing effect of small interfering RNA (siRNA) duplexes targeting the gene Fas (also known as Tnfrsf6), encoding the Fas receptor, to protect mice from liver failure and fibrosis in two models of autoimmune hepatitis. Intravenous injection of Fas siRNA specifically reduced Fas mRNA levels and expression of Fas protein in mouse hepatocytes, and the effects persisted without diminution for 10 days. Hepatocytes isolated from mice treated with Fas siRNA were resistant to apoptosis when exposed to Fas-specific antibody or co-cultured with concanavalin A (ConA)-stimulated hepatic mononuclear cells. Treatment with Fas siRNA 2 days before ConA challenge abrogated hepatocyte necrosis and inflammatory infiltration and markedly reduced serum concentrations of transaminases. Administering Fas siRNA beginning one week after initiating weekly ConA injections protected mice from liver fibrosis. In a more fulminant hepatitis induced by injecting agonistic Fas-specific antibody, 82% of mice treated with siRNA that effectively silenced Fas survived for 10 days of observation, whereas all control mice died within 3 days. Silencing Fas expression with RNAi holds therapeutic promise to prevent liver injury by protecting hepatocytes from cytotoxicity.", + "TAG_DATA": [ + "66, mice {'context': 'B-organism'}", + "81, Fas {'perturbing_action': 'B-rnai/knockdown'}", + "82, siRNA {'perturbing_action': 'I-rnai/knockdown'}", + "94, mouse {'context': 'B-cells'}", + "95, hepatocytes, {'context': 'I-cells'}", + "105, Hepatocytes {'context': 'B-cells'}", + "106, isolated {'context': 'I-cells'}", + "108, mice {'context': 'B-organism'}", + "111, Fas {'perturbing_action': 'B-rnai/knockdown'}", + "112, siRNA {'perturbing_action': 'I-rnai/knockdown'}", + "114, resistant {'effect': 'B-negative'}", + "116, apoptosis {'phenotype': 'B-apoptosis'}", + "128, hepatic {'context': 'B-cells'}", + "129, mononuclear {'context': 'I-cells'}", + "130, cells. {'context': 'I-cells'}", + "133, Fas {'perturbing_action': 'B-rnai/knockdown'}", + "134, siRNA {'perturbing_action': 'I-rnai/knockdown'}", + "140, abrogated {'effect': 'B-negative'}", + "141, hepatocyte {'context': 'B-cells'}", + "142, necrosis {'phenotype': 'B-necrosis'}", + "154, Fas {'perturbing_action': 'B-rnai/knockdown'}", + "155, siRNA {'perturbing_action': 'I-rnai/knockdown'}", + "165, mice {'context': 'B-organism'}", + "167, liver {'context': 'B-tissue/organ'}", + "182, mice {'context': 'B-organism'}", + "185, siRNA {'perturbing_action': 'B-rnai/knockdown'}", + "188, silenced {'perturbing_action': 'I-rnai/knockdown'}", + "189, Fas {'perturbing_action': 'I-rnai/knockdown'}", + "199, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "66, mice ['l0', 'l1', 'l2', 'l3']", + "81, Fas ['l0', 'l4', 'l5', 'l6']", + "82, siRNA ['l1', 'l4', 'l7', 'l8']", + "94, mouse ['l2', 'l5', 'l7', 'l9']", + "95, hepatocytes, ['l3', 'l6', 'l8', 'l9']", + "105, Hepatocytes ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "106, isolated ['l10', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "108, mice ['l11', 'l24', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "111, Fas ['l12', 'l25', 'l37', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "112, siRNA ['l13', 'l26', 'l38', 'l49', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "114, resistant ['l14', 'l27', 'l39', 'l50', 'l60', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "116, apoptosis ['l15', 'l28', 'l40', 'l51', 'l61', 'l70', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "128, hepatic ['l16', 'l29', 'l41', 'l52', 'l62', 'l71', 'l79', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "129, mononuclear ['l17', 'l30', 'l42', 'l53', 'l63', 'l72', 'l80', 'l87', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "130, cells. ['l18', 'l31', 'l43', 'l54', 'l64', 'l73', 'l81', 'l88', 'l94', 'l100', 'l101', 'l102', 'l103', 'l104']", + "133, Fas ['l19', 'l32', 'l44', 'l55', 'l65', 'l74', 'l82', 'l89', 'l95', 'l100', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "134, siRNA ['l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l83', 'l90', 'l96', 'l101', 'l105', 'l111', 'l112', 'l113', 'l114', 'l115']", + "140, abrogated ['l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l84', 'l91', 'l97', 'l102', 'l106', 'l111', 'l116', 'l117']", + "141, hepatocyte ['l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l98', 'l103', 'l107', 'l112', 'l116', 'l118']", + "142, necrosis ['l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l86', 'l93', 'l99', 'l104', 'l108', 'l113', 'l117', 'l118']", + "154, Fas ['l119', 'l120', 'l121']", + "155, siRNA ['l119', 'l122', 'l123']", + "165, mice ['l109', 'l114', 'l120', 'l122', 'l124']", + "167, liver ['l110', 'l115', 'l121', 'l123', 'l124']", + "182, mice ['l125', 'l126', 'l127', 'l128']", + "185, siRNA ['l125', 'l129', 'l130', 'l131']", + "188, silenced ['l126', 'l129', 'l132', 'l133']", + "189, Fas ['l127', 'l130', 'l132', 'l134']", + "199, mice ['l128', 'l131', 'l133', 'l134']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Fas", + "siRNA", + "silenced" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Fas", + "siRNA" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "hepatocytes,", + "Hepatocytes", + "isolated", + "hepatic", + "mononuclear", + "cells.", + "hepatocyte" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Hepatocytes", + "isolated", + "hepatic", + "mononuclear", + "cells.", + "hepatocyte" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant", + "abrogated" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Hepatocytes", + "isolated", + "hepatic", + "mononuclear", + "cells.", + "hepatocyte" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Hepatocytes", + "isolated", + "hepatic", + "mononuclear", + "cells.", + "hepatocyte" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant", + "abrogated" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Fas", + "siRNA" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant", + "abrogated" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Fas", + "siRNA" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Fas", + "siRNA" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistant", + "abrogated" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistant", + "abrogated" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Fas", + "siRNA" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "12539038", + "TEXT": "Carbon monoxide (CO), one of the products of heme oxygenase action on heme, prevents arteriosclerotic lesions that occur following aorta transplantation; pre-exposure to 250 parts per million of CO for 1 hour before injury suppresses stenosis after carotid balloon injury in rats as well as in mice. The protective effect of CO is associated with a profound inhibition of graft leukocyte infiltration/activation as well as with inhibition of smooth muscle cell proliferation. The anti-proliferative effect of CO in vitro requires the activation of guanylate cyclase, the generation of cGMP, the activation of p38 mitogen-activated protein kinases and the expression of the cell cycle inhibitor p21Cip1. These findings demonstrate a protective role for CO in vascular injury and support its use as a therapeutic agent.", + "TAG_DATA": [ + "41, rats {'context': 'B-organism'}", + "46, mice. {'context': 'B-organism'}", + "66, inhibition {'effect': 'B-negative'}", + "68, smooth {'context': 'B-cells'}", + "69, muscle {'context': 'I-cells'}", + "70, cell {'context': 'I-cells'}", + "71, proliferation. {'phenotype': 'B-proliferation'}", + "77, in {'context': 'B-in vitro'}", + "78, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "41, rats ['l0']", + "46, mice. ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "66, inhibition ['l1', 'l6', 'l7', 'l8', 'l9']", + "68, smooth ['l2', 'l6', 'l10', 'l11', 'l12']", + "69, muscle ['l3', 'l7', 'l10', 'l13', 'l14']", + "70, cell ['l4', 'l8', 'l11', 'l13', 'l15']", + "71, proliferation. ['l5', 'l9', 'l12', 'l14', 'l15']", + "77, in ['l16']", + "78, vitro ['l16']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "smooth", + "muscle", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "smooth", + "muscle", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "12483207", + "TEXT": "We studied whether circulating activated platelets and platelet-leukocyte aggregates cause the development of atherosclerotic lesions in apolipoprotein-E-deficient (Apoe(-/-)) mice. Circulating activated platelets bound to leukocytes, preferentially monocytes, to form platelet-monocyte/leukocyte aggregates. Activated platelets and platelet-leukocyte aggregates interacted with atherosclerotic lesions. The interactions of activated platelets with monocytes and atherosclerotic arteries led to delivery of the platelet-derived chemokines CCL5 (regulated on activation, normal T cell expressed and secreted, RANTES) and CXCL4 (platelet factor 4) to the monocyte surface and endothelium of atherosclerotic arteries. The presence of activated platelets promoted leukocyte binding of vascular cell adhesion molecule-1 (VCAM-1) and increased their adhesiveness to inflamed or atherosclerotic endothelium. Injection of activated wild-type, but not P-selectin-deficient, platelets increased monocyte arrest on the surface of atherosclerotic lesions and the size of atherosclerotic lesions in Apoe(-/-) mice. Our results indicate that circulating activated platelets and platelet-leukocyte/monocyte aggregates promote formation of atherosclerotic lesions. This role of activated platelets in atherosclerosis is attributed to platelet P-selectin-mediated delivery of platelet-derived proinflammatory factors to monocytes/leukocytes and the vessel wall.", + "TAG_DATA": [ + "16, apolipoprotein-E-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "17, (Apoe(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "104, endothelium. {'context': 'I-tissue/organ'}", + "111, P-selectin-deficient, {'perturbing_action': 'B-gene loss-of-function'}", + "112, platelets {'context': 'B-cells'}", + "114, monocyte {'context': 'B-cells'}", + "129, Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "130, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "16, apolipoprotein-E-deficient ['l0', 'l1']", + "17, (Apoe(-/-)) ['l0', 'l2']", + "104, endothelium. ['l1', 'l2']", + "111, P-selectin-deficient, ['l3', 'l4', 'l5', 'l6']", + "112, platelets ['l3', 'l7', 'l8', 'l9']", + "114, monocyte ['l4', 'l7']", + "129, Apoe(-/-) ['l5', 'l8', 'l10']", + "130, mice. ['l6', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "apolipoprotein-E-deficient", + "(Apoe(-/-))" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "endothelium." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "P-selectin-deficient,", + "Apoe(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelets", + "monocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "P-selectin-deficient,", + "Apoe(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "12426559", + "TEXT": "Humans and mice deficient in Fas, a tumor necrosis factor (TNF)-receptor family member, cannot induce apoptosis of autoreactive cells, and consequently develop progressive lymphoproliferative disorders and lupus-like autoimmune diseases. Previous studies have shown that short-term administrations of agonistic monoclonal antibodies against CD137, another TNF-receptor family member, activate T cells and induce rejection of allografts and established tumors. Here we report that treatment with an agonistic monoclonal antibody to CD137 (2A) blocks lymphadenopathy and spontaneous autoimmune diseases in Fas-deficient MRL/lpr mice, ultimately leading to their prolonged survival. Notably, 2A treatment rapidly augments IFN-gamma production, and induces the depletion of autoreactive B cells and abnormal double-negative T cells, possibly by increasing their apoptosis through Fas- and TNF receptor-independent mechanisms. This study demonstrates that agonistic monoclonal antibodies specific for costimulatory molecules can be used as novel therapeutic agents to delete autoreactive lymphocytes and block autoimmune disease progression.", + "TAG_DATA": [ + "77, Fas-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "78, MRL/lpr {'context': 'B-organism'}", + "79, mice, {'context': 'I-organism'}", + "98, autoreactive {'context': 'B-cells'}", + "99, B {'context': 'I-cells'}", + "100, cells {'context': 'I-cells'}", + "103, double-negative {'context': 'B-cells'}", + "104, T {'context': 'I-cells'}", + "105, cells, {'context': 'I-cells'}", + "108, increasing {'effect': 'B-positive'}", + "110, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "77, Fas-deficient ['l0', 'l1']", + "78, MRL/lpr ['l0', 'l2']", + "79, mice, ['l1', 'l2']", + "98, autoreactive ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "99, B ['l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "100, cells ['l4', 'l10', 'l16', 'l17', 'l18', 'l19']", + "103, double-negative ['l5', 'l11', 'l20', 'l21', 'l22', 'l23']", + "104, T ['l6', 'l12', 'l16', 'l20', 'l24', 'l25', 'l26']", + "105, cells, ['l7', 'l13', 'l17', 'l21', 'l24', 'l27', 'l28']", + "108, increasing ['l8', 'l14', 'l18', 'l22', 'l25', 'l27', 'l29']", + "110, apoptosis ['l9', 'l15', 'l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fas-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "MRL/lpr", + "mice," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "autoreactive", + "B", + "cells", + "double-negative", + "T", + "cells," + ] + }, + "effect": { + "val": "positive", + "words": [ + "increasing" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "autoreactive", + "B", + "cells", + "double-negative", + "T", + "cells," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increasing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "12415262", + "TEXT": "The relationship between the structure of zinc-finger protein (ZFP) transcription factors and DNA sequence binding specificity has been extensively studied. Advances in this field have made it possible to design ZFPs de novo that will bind to specific targeted DNA sequences. It has been proposed that such designed ZFPs may eventually be useful in gene therapy. A principal advantage of this approach is that activation of an endogenous gene ensures expression of the natural array of splice variants. Preliminary studies in tissue culture have validated the feasibility of this approach. The studies reported here were intended to test whether engineered transcription factors are effective in a whole-organism model. ZFPs were designed to regulate the endogenous gene encoding vascular endothelial growth factor-A (Vegfa). Expression of these new ZFPs in vivo led to induced expression of the protein VEGF-A, stimulation of angiogenesis and acceleration of experimental wound healing. In addition, the neovasculature resulting from ZFP-induced expression of Vegfa was not hyperpermeable as was that produced by expression of murine Vegfa(164) cDNA. These data establish, for the first time, that specifically designed transcription factors can regulate an endogenous gene in vivo and evoke a potentially therapeutic biophysiologic effect.", + "TAG_DATA": [ + "127, in {'context': 'B-in vivo'}", + "128, vivo {'context': 'I-in vivo'}", + "141, acceleration {'effect': 'B-positive'}", + "164, expression {'perturbing_action': 'B-gene gain-of-function'}", + "165, of {'perturbing_action': 'I-gene gain-of-function'}", + "166, murine {'perturbing_action': 'I-gene gain-of-function'}", + "167, Vegfa(164) {'perturbing_action': 'I-gene gain-of-function'}", + "168, cDNA. {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "127, in ['l0', 'l1']", + "128, vivo ['l0', 'l2']", + "141, acceleration ['l1', 'l2']", + "164, expression ['l3', 'l4', 'l5', 'l6']", + "165, of ['l3', 'l7', 'l8', 'l9']", + "166, murine ['l4', 'l7', 'l10', 'l11']", + "167, Vegfa(164) ['l5', 'l8', 'l10', 'l12']", + "168, cDNA. ['l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "acceleration" + ] + } + } + ] + }, + { + "PMID": "12185362", + "TEXT": "Truncated Notch receptors have transforming activity in vitro and in vivo. However, the role of wild-type Notch signaling in neoplastic transformation remains unclear. Ras signaling is deregulated in a large fraction of human malignancies and is a major target for the development of novel cancer treatments. We show that oncogenic Ras activates Notch signaling and that wild-type Notch-1 is necessary to maintain the neoplastic phenotype in Ras-transformed human cells in vitro and in vivo. Oncogenic Ras increases levels and activity of the intracellular form of wild-type Notch-1, and upregulates Notch ligand Delta-1 and also presenilin-1, a protein involved in Notch processing, through a p38-mediated pathway. These observations place Notch signaling among key downstream effectors of oncogenic Ras and suggest that it might be a novel therapeutic target.", + "TAG_DATA": [ + "66, Ras-transformed {'perturbing_action': 'B-other', 'phenotype': 'B-transformation'}", + "67, human {'context': 'B-cells'}", + "68, cells {'context': 'I-cells'}", + "69, in {'context': 'B-in vitro'}", + "70, vitro {'context': 'I-in vitro'}", + "72, in {'context': 'B-in vivo'}", + "73, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "61, maintain ['l0', 'l1', 'l2', 'l3', 'l4']", + "66, Ras-transformed ['l0', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "67, human ['l1', 'l5', 'l11', 'l12', 'l13']", + "68, cells ['l2', 'l6', 'l11', 'l14', 'l15']", + "69, in ['l3', 'l7', 'l12', 'l14', 'l16']", + "70, vitro ['l4', 'l8', 'l13', 'l15', 'l16']", + "72, in ['l9', 'l17']", + "73, vivo. ['l10', 'l17']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Ras-transformed" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "Ras-transformed" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Ras-transformed" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "cells" + ] + } + }, + { + "phenotype": { + "val": "transformation", + "words": [ + "Ras-transformed" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Ras-transformed" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "transformation", + "words": [ + "Ras-transformed" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Ras-transformed" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "transformation", + "words": [ + "Ras-transformed" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "12172543", + "TEXT": "Survivin (also termed Birc5) belongs to the family of genes known as inhibitors of apoptosis, and it has been implicated in both prevention of cell death and control of mitosis. The survivin pathway is exploited in cancer, but its potential role in vascular injury is unknown. Here, we show that balloon-mediated arterial injury in rabbits resulted in expression of survivin in vascular cells. Serum or PDGF-AB stimulated survivin expression in cultured smooth-muscle cells (SMCs), which suppressed apoptosis and prevented caspase activation. Adenoviral delivery of a phosphorylation-defective survivin mutant reversed the cytoprotective effect of PDGF in SMCs without affecting mitotic progression, suppressed neointimal formation in wire-injured mouse femoral arteries, and induced vascular cell apoptosis in vivo. These data identify survivin as a critical regulator of SMC apoptosis after acute vascular injury. Disrupting the survivin pathway may provide a novel therapy to limit pathological vessel-wall remodeling.", + "TAG_DATA": [ + "54, rabbits {'context': 'B-organism'}", + "61, vascular {'context': 'B-cells'}", + "62, cells. {'context': 'I-cells'}", + "70, cultured {'context': 'B-cells'}", + "71, smooth-muscle {'context': 'I-cells'}", + "72, cells {'context': 'I-cells'}", + "73, (SMCs), {'context': 'I-cells'}", + "75, suppressed {'effect': 'B-negative'}", + "76, apoptosis {'phenotype': 'B-apoptosis'}", + "81, Adenoviral {'perturbing_action': 'B-other'}", + "85, phosphorylation-defective {'perturbing_action': 'B-other'}", + "86, survivin {'perturbing_action': 'I-other'}", + "87, mutant {'perturbing_action': 'I-other'}", + "95, SMCs {'context': 'B-cells'}", + "96, without {'effect': 'B-no effect'}", + "97, affecting {'effect': 'I-no effect'}", + "105, mouse {'context': 'B-tissue/organ'}", + "106, femoral {'context': 'I-tissue/organ'}", + "107, arteries, {'context': 'I-tissue/organ'}", + "109, induced {'effect': 'B-positive'}", + "110, vascular {'context': 'B-cells'}", + "111, cell {'context': 'I-cells'}", + "112, apoptosis {'phenotype': 'B-apoptosis'}", + "113, in {'context': 'B-in vivo'}", + "114, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "54, rabbits ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "61, vascular ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "62, cells. ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "70, cultured ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "71, smooth-muscle ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "72, cells ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "73, (SMCs), ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "75, suppressed ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "76, apoptosis ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "81, Adenoviral ['l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "85, phosphorylation-defective ['l36', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "86, survivin ['l37', 'l51', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "87, mutant ['l38', 'l52', 'l65', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "95, SMCs ['l39', 'l53', 'l66', 'l78', 'l90', 'l91', 'l92']", + "96, without ['l40', 'l54', 'l67', 'l79', 'l90', 'l93']", + "97, affecting ['l41', 'l55', 'l68', 'l80', 'l91', 'l93', 'l94']", + "105, mouse ['l42', 'l56', 'l69', 'l81', 'l95', 'l96', 'l97']", + "106, femoral ['l43', 'l57', 'l70', 'l82', 'l95', 'l98', 'l99']", + "107, arteries, ['l44', 'l58', 'l71', 'l83', 'l92', 'l94', 'l96', 'l98']", + "109, induced ['l45', 'l59', 'l72', 'l84', 'l97', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "110, vascular ['l46', 'l60', 'l73', 'l85', 'l100', 'l105', 'l106', 'l107', 'l108']", + "111, cell ['l47', 'l61', 'l74', 'l86', 'l101', 'l105', 'l109', 'l110', 'l111']", + "112, apoptosis ['l48', 'l62', 'l75', 'l87', 'l102', 'l106', 'l109', 'l112', 'l113']", + "113, in ['l49', 'l63', 'l76', 'l88', 'l103', 'l107', 'l110', 'l112', 'l114']", + "114, vivo. ['l50', 'l64', 'l77', 'l89', 'l104', 'l108', 'l111', 'l113', 'l114']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "rabbits" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rabbits" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "vascular", + "cells.", + "cultured", + "smooth-muscle", + "cells", + "(SMCs)," + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "vascular", + "cells.", + "cultured", + "smooth-muscle", + "cells", + "(SMCs),", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Adenoviral", + "phosphorylation-defective", + "survivin", + "mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "SMCs", + "vascular", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Adenoviral", + "phosphorylation-defective", + "survivin", + "mutant" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "without", + "affecting" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Adenoviral", + "phosphorylation-defective", + "survivin", + "mutant" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "femoral", + "arteries," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Adenoviral", + "phosphorylation-defective", + "survivin", + "mutant" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Adenoviral", + "phosphorylation-defective", + "survivin", + "mutant" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Adenoviral", + "phosphorylation-defective", + "survivin", + "mutant" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "SMCs" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "without", + "affecting" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "affecting" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "arteries," + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "femoral" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "vascular", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "12145646", + "TEXT": "Adult bone marrow (BM) contains cells capable of differentiating along hematopoietic (Lin(+)) or non-hematopoietic (Lin(-)) lineages. Lin(-) hematopoietic stem cells (HSCs) have recently been shown to contain a population of endothelial precursor cells (EPCs) capable of forming blood vessels. Here we show that intravitreally injected Lin(-) BM cells selectively target retinal astrocytes, cells that serve as a template for both developmental and injury-associated retinal angiogenesis. When Lin(-) BM cells were injected into neonatal mouse eyes, they extensively and stably incorporated into forming retinal vasculature. When EPC-enriched HSCs were injected into the eyes of neonatal rd/rd mice, whose vasculature ordinarily degenerates with age, they rescued and maintained a normal vasculature. In contrast, normal retinal angiogenesis was inhibited when EPCs expressing a potent angiostatic protein were injected. We have demonstrated that Lin(-) BM cells and astrocytes specifically interact with one another during normal angiogenesis and pathological vascular degeneration in the retina. Selective targeting with Lin(-) HSC may be a useful therapeutic approach for the treatment of many ocular diseases.", + "TAG_DATA": [ + "72, neonatal {'context': 'B-tissue/organ'}", + "73, mouse {'context': 'I-tissue/organ'}", + "74, eyes, {'context': 'I-tissue/organ'}", + "91, eyes {'context': 'B-tissue/organ'}", + "93, neonatal {'perturbing_action': 'B-other', 'context': 'B-organism'}", + "94, rd/rd {'perturbing_action': 'B-other', 'context': 'I-organism'}", + "95, mice, {'context': 'I-organism'}", + "117, EPCs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "67, BM ['l0', 'l1', 'l2', 'l3']", + "68, cells ['l0', 'l4', 'l5', 'l6']", + "72, neonatal ['l1', 'l4', 'l7', 'l8']", + "73, mouse ['l2', 'l5', 'l7', 'l9']", + "74, eyes, ['l3', 'l6', 'l8', 'l9']", + "91, eyes ['l10', 'l11', 'l12']", + "93, neonatal ['l10', 'l13', 'l14']", + "94, rd/rd ['l11', 'l13', 'l15']", + "95, mice, ['l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "eyes" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "neonatal", + "rd/rd" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "neonatal", + "rd/rd" + ] + }, + "context": { + "val": "organism", + "words": [ + "neonatal", + "rd/rd" + ] + } + } + ] + }, + { + "PMID": "12118245", + "TEXT": "A major concern in cancer therapy is resistance of tumors such as glioblastoma to current treatment protocols. Here, we report that transfer of the gene encoding second mitochondria-derived activator of caspase (Smac) or Smac peptides sensitized various tumor cells in vitro and malignant glioma cells in vivo for apoptosis induced by death-receptor ligation or cytotoxic drugs. Expression of a cytosolic active form of Smac or cell-permeable Smac peptides bypassed the Bcl-2 block, which prevented the release of Smac from mitochondria, and also sensitized resistant neuroblastoma or melanoma cells and patient-derived primary neuroblastoma cells ex vivo. Most importantly, Smac peptides strongly enhanced the antitumor activity of Apo-2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in an intracranial malignant glioma xenograft model in vivo. Complete eradication of established tumors and survival of mice was only achieved upon combined treatment with Smac peptides and Apo2L/TRAIL without detectable toxicity to normal brain tissue. Thus, Smac agonists are promising candidates for cancer therapy by potentiating cytotoxic therapies.", + "TAG_DATA": [ + "21, transfer {'perturbing_action': 'B-gene gain-of-function'}", + "22, of {'perturbing_action': 'I-gene gain-of-function'}", + "23, the {'perturbing_action': 'I-gene gain-of-function'}", + "24, gene {'perturbing_action': 'I-gene gain-of-function'}", + "25, encoding {'perturbing_action': 'I-gene gain-of-function'}", + "26, second {'perturbing_action': 'I-gene gain-of-function'}", + "27, mitochondria-derived {'perturbing_action': 'I-gene gain-of-function'}", + "37, tumor {'context': 'B-transformed cells'}", + "38, cells {'context': 'I-transformed cells'}", + "39, in {'context': 'B-in vitro'}", + "40, vitro {'context': 'I-in vitro'}", + "42, malignant {'context': 'B-transformed cells'}", + "43, glioma {'context': 'I-transformed cells'}", + "44, cells {'context': 'I-transformed cells'}", + "45, in {'context': 'B-in vivo'}", + "46, vivo {'context': 'I-in vivo'}", + "48, apoptosis {'phenotype': 'B-apoptosis'}", + "49, induced {'effect': 'B-positive'}", + "56, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "57, of {'perturbing_action': 'I-gene gain-of-function'}", + "58, a {'perturbing_action': 'I-gene gain-of-function'}", + "59, cytosolic {'perturbing_action': 'I-gene gain-of-function'}", + "60, active {'perturbing_action': 'I-gene gain-of-function'}", + "61, form {'perturbing_action': 'I-gene gain-of-function'}", + "62, of {'perturbing_action': 'I-gene gain-of-function'}", + "63, Smac {'perturbing_action': 'I-gene gain-of-function'}", + "83, resistant {'context': 'B-transformed cells'}", + "84, neuroblastoma {'context': 'I-transformed cells'}", + "85, or {'context': 'I-transformed cells'}", + "86, melanoma {'context': 'I-transformed cells'}", + "87, cells {'context': 'I-transformed cells'}", + "89, patient-derived {'context': 'B-transformed cells'}", + "90, primary {'context': 'I-transformed cells'}", + "91, neuroblastoma {'context': 'I-transformed cells'}", + "92, cells {'context': 'I-transformed cells'}", + "113, intracranial {'context': 'B-xenograft'}", + "114, malignant {'context': 'I-xenograft'}", + "115, glioma {'context': 'I-xenograft'}", + "116, xenograft {'context': 'I-xenograft'}", + "117, model {'context': 'I-xenograft'}", + "118, in {'context': 'B-in vivo'}", + "119, vivo. {'context': 'I-in vivo'}", + "124, tumors {'context': 'B-neoplasm'}", + "128, mice {'context': 'B-organism'}", + "145, brain {'context': 'I-tissue/organ'}", + "146, tissue. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "21, transfer ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "22, of ['l0', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "23, the ['l1', 'l23', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "24, gene ['l2', 'l24', 'l45', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "25, encoding ['l3', 'l25', 'l46', 'l66', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "26, second ['l4', 'l26', 'l47', 'l67', 'l86', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "27, mitochondria-derived ['l5', 'l27', 'l48', 'l68', 'l87', 'l105', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "28, activator ['l6', 'l28', 'l49', 'l69', 'l88', 'l106', 'l124', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156']", + "37, tumor ['l7', 'l29', 'l50', 'l70', 'l89', 'l107', 'l125', 'l141', 'l157', 'l158', 'l159']", + "38, cells ['l8', 'l30', 'l51', 'l71', 'l90', 'l108', 'l126', 'l142', 'l157', 'l160', 'l161']", + "39, in ['l9', 'l31', 'l52', 'l72', 'l91', 'l109', 'l127', 'l143', 'l158', 'l160', 'l162', 'l163', 'l164']", + "40, vitro ['l10', 'l32', 'l53', 'l73', 'l92', 'l110', 'l128', 'l144', 'l159', 'l161', 'l162']", + "42, malignant ['l11', 'l33', 'l54', 'l74', 'l93', 'l111', 'l129', 'l145', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "43, glioma ['l12', 'l34', 'l55', 'l75', 'l94', 'l112', 'l130', 'l146', 'l163', 'l165', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "44, cells ['l13', 'l35', 'l56', 'l76', 'l95', 'l113', 'l131', 'l147', 'l164', 'l166', 'l175', 'l183', 'l184', 'l185', 'l186']", + "45, in ['l14', 'l36', 'l57', 'l77', 'l96', 'l114', 'l132', 'l148', 'l167', 'l176', 'l183', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "46, vivo ['l15', 'l37', 'l58', 'l78', 'l97', 'l115', 'l133', 'l149', 'l168', 'l177', 'l184', 'l187', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201']", + "48, apoptosis ['l16', 'l38', 'l59', 'l79', 'l98', 'l116', 'l134', 'l150', 'l169', 'l178', 'l188', 'l195', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207']", + "49, induced ['l17', 'l39', 'l60', 'l80', 'l99', 'l117', 'l135', 'l151', 'l170', 'l179', 'l185', 'l189', 'l196', 'l202', 'l208', 'l209', 'l210', 'l211', 'l212']", + "56, Expression ['l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235']", + "57, of ['l213', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257']", + "58, a ['l214', 'l236', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278']", + "59, cytosolic ['l215', 'l237', 'l258', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298']", + "60, active ['l216', 'l238', 'l259', 'l279', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304', 'l305', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311', 'l312', 'l313', 'l314']", + "61, form ['l217', 'l239', 'l260', 'l280', 'l299', 'l315', 'l316', 'l317', 'l318', 'l319', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327', 'l328', 'l329']", + "62, of ['l218', 'l240', 'l261', 'l281', 'l300', 'l315', 'l330', 'l331', 'l332', 'l333', 'l334', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340', 'l341']", + "63, Smac ['l118', 'l219', 'l241', 'l262', 'l282', 'l301', 'l316', 'l330', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348', 'l349', 'l350']", + "83, resistant ['l18', 'l40', 'l61', 'l81', 'l100', 'l119', 'l136', 'l152', 'l190', 'l197', 'l203', 'l208', 'l220', 'l242', 'l263', 'l283', 'l302', 'l317', 'l331', 'l342', 'l351', 'l352', 'l353', 'l354', 'l355']", + "84, neuroblastoma ['l19', 'l41', 'l62', 'l82', 'l101', 'l120', 'l137', 'l153', 'l171', 'l191', 'l198', 'l204', 'l209', 'l221', 'l243', 'l264', 'l284', 'l303', 'l318', 'l332', 'l343', 'l351', 'l356', 'l357', 'l358', 'l359']", + "85, or ['l20', 'l42', 'l63', 'l83', 'l102', 'l121', 'l138', 'l154', 'l172', 'l180', 'l192', 'l199', 'l205', 'l210', 'l222', 'l244', 'l265', 'l285', 'l304', 'l319', 'l333', 'l344', 'l352', 'l356', 'l360', 'l361']", + "86, melanoma ['l21', 'l43', 'l64', 'l84', 'l103', 'l122', 'l139', 'l155', 'l173', 'l181', 'l193', 'l200', 'l206', 'l211', 'l223', 'l245', 'l266', 'l286', 'l305', 'l320', 'l334', 'l345', 'l353', 'l357', 'l360', 'l362', 'l363']", + "87, cells ['l22', 'l44', 'l65', 'l85', 'l104', 'l123', 'l140', 'l156', 'l174', 'l182', 'l186', 'l194', 'l201', 'l207', 'l212', 'l224', 'l246', 'l267', 'l287', 'l306', 'l321', 'l335', 'l346', 'l354', 'l358', 'l361', 'l362']", + "89, patient-derived ['l225', 'l247', 'l268', 'l288', 'l307', 'l322', 'l336', 'l347', 'l364', 'l365', 'l366', 'l367', 'l368', 'l369', 'l370']", + "90, primary ['l226', 'l248', 'l269', 'l289', 'l308', 'l323', 'l337', 'l348', 'l364', 'l371', 'l372', 'l373', 'l374', 'l375', 'l376']", + "91, neuroblastoma ['l227', 'l249', 'l270', 'l290', 'l309', 'l324', 'l338', 'l349', 'l365', 'l371', 'l377', 'l378', 'l379', 'l380', 'l381']", + "92, cells ['l228', 'l250', 'l271', 'l291', 'l310', 'l325', 'l339', 'l350', 'l355', 'l359', 'l363', 'l366', 'l372', 'l377']", + "113, intracranial ['l229', 'l251', 'l272', 'l292', 'l382', 'l383', 'l384', 'l385', 'l386', 'l387', 'l388']", + "114, malignant ['l230', 'l252', 'l273', 'l293', 'l311', 'l326', 'l367', 'l373', 'l378', 'l382', 'l389', 'l390', 'l391', 'l392', 'l393', 'l394']", + "115, glioma ['l231', 'l253', 'l274', 'l294', 'l312', 'l327', 'l340', 'l368', 'l374', 'l379', 'l383', 'l389', 'l395', 'l396', 'l397', 'l398', 'l399']", + "116, xenograft ['l232', 'l254', 'l275', 'l295', 'l313', 'l328', 'l369', 'l375', 'l380', 'l384', 'l390', 'l395', 'l400', 'l401', 'l402', 'l403']", + "117, model ['l233', 'l255', 'l276', 'l296', 'l314', 'l329', 'l341', 'l370', 'l376', 'l381', 'l385', 'l391', 'l396', 'l400', 'l404', 'l405', 'l406']", + "118, in ['l234', 'l256', 'l277', 'l297', 'l386', 'l392', 'l397', 'l401', 'l404', 'l407', 'l408']", + "119, vivo. ['l235', 'l257', 'l278', 'l298', 'l387', 'l393', 'l398', 'l402', 'l405', 'l407', 'l409']", + "124, tumors ['l388', 'l394', 'l399', 'l403', 'l406', 'l408', 'l409']", + "128, mice ['l410', 'l411', 'l412']", + "144, normal ['l410', 'l413', 'l414']", + "145, brain ['l411', 'l413', 'l415']", + "146, tissue. ['l412', 'l414', 'l415']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfer", + "of", + "the", + "gene", + "encoding", + "second", + "mitochondria-derived", + "Expression", + "a", + "cytosolic", + "active", + "form", + "Smac" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells", + "malignant", + "glioma", + "resistant", + "neuroblastoma", + "or", + "melanoma", + "patient-derived", + "primary" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfer", + "of", + "the", + "gene", + "encoding", + "second", + "mitochondria-derived" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfer", + "of", + "the", + "gene", + "encoding", + "second", + "mitochondria-derived", + "Expression", + "a", + "cytosolic" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfer", + "of", + "the", + "gene", + "encoding", + "second", + "mitochondria-derived" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfer", + "of", + "the", + "gene", + "encoding", + "second", + "mitochondria-derived" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "malignant", + "glioma", + "resistant", + "neuroblastoma", + "or", + "melanoma", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "malignant", + "glioma", + "cells", + "resistant", + "neuroblastoma", + "or", + "melanoma" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "a", + "cytosolic", + "active", + "form" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "intracranial", + "malignant", + "glioma", + "xenograft", + "model" + ] + } + } + ] + }, + { + "PMID": "12101408", + "TEXT": "The Human Combinatorial Antibody Library (HuCAL) was screened for antibodies specific to human leukocyte antigen-DR (HLA-DR) that induce programmed death of lymphoma/leukemia cells expressing the target antigen. The active Fab fragments were affinity-matured, and engineered to IgG(4) antibodies of sub-nanomolar affinity. The antibodies exhibited potent in vitro tumoricidal activity on several lymphoma and leukemia cell lines and on chronic lymphocytic leukemia patient samples. They were also active in vivo in xenograft models of non-Hodgkin lymphoma. Cell death occurred rapidly, without the need for exogenous immunological effector mechanisms, and was selective to activated/tumor-transformed cells. Although the expression of HLA-DR on normal hematopoietic cells is a potential safety concern, the antibodies caused no long-lasting hematological toxicity in primates, in vivo. Such monoclonal antibodies offer the potential for a novel therapeutic approach to lymphoid malignancies.", + "TAG_DATA": [ + "45, in {'context': 'B-in vitro'}", + "46, vitro {'context': 'I-in vitro'}", + "51, lymphoma {'context': 'B-transformed cells'}", + "52, and {'context': 'I-transformed cells'}", + "53, leukemia {'context': 'I-transformed cells'}", + "54, cell {'context': 'I-transformed cells'}", + "55, lines {'context': 'I-transformed cells'}", + "58, chronic {'context': 'B-transformed cells'}", + "59, lymphocytic {'context': 'I-transformed cells'}", + "60, leukemia {'context': 'I-transformed cells'}", + "61, patient {'context': 'I-transformed cells'}", + "62, samples. {'context': 'I-transformed cells'}", + "67, in {'context': 'B-in vivo'}", + "68, vivo {'context': 'I-in vivo'}", + "70, xenograft {'context': 'B-xenograft'}", + "71, models {'context': 'I-neoplasm'}", + "72, of {'context': 'I-neoplasm'}", + "73, non-Hodgkin {'context': 'I-neoplasm'}", + "74, lymphoma. {'context': 'I-neoplasm'}", + "75, Cell {'phenotype': 'B-cell death'}", + "76, death {'phenotype': 'I-cell death'}", + "91, activated/tumor-transformed {'context': 'B-cells'}", + "92, cells. {'context': 'I-cells'}", + "115, primates, {'context': 'B-organism'}", + "116, in {'context': 'B-in vivo'}", + "117, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "45, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "46, vitro ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "51, lymphoma ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "52, and ['l2', 'l11', 'l19', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "53, leukemia ['l3', 'l12', 'l20', 'l28', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "54, cell ['l4', 'l13', 'l21', 'l29', 'l36', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "55, lines ['l5', 'l14', 'l22', 'l30', 'l37', 'l43', 'l49', 'l50', 'l51', 'l52', 'l53']", + "58, chronic ['l23', 'l31', 'l38', 'l44', 'l49', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "59, lymphocytic ['l6', 'l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "60, leukemia ['l7', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l64', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "61, patient ['l8', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l65', 'l73', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "62, samples. ['l9', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l66', 'l74', 'l82', 'l88', 'l89']", + "67, in ['l58', 'l67', 'l75', 'l83', 'l88', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "68, vivo ['l59', 'l68', 'l76', 'l84', 'l89', 'l90', 'l98', 'l99', 'l100', 'l101', 'l102']", + "70, xenograft ['l60', 'l69', 'l77', 'l91', 'l98', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "71, models ['l61', 'l70', 'l78', 'l85', 'l92', 'l99', 'l103', 'l109', 'l110', 'l111', 'l112', 'l113']", + "72, of ['l62', 'l71', 'l79', 'l86', 'l93', 'l100', 'l104', 'l109', 'l114', 'l115', 'l116', 'l117']", + "73, non-Hodgkin ['l80', 'l94', 'l101', 'l105', 'l110', 'l114', 'l118', 'l119', 'l120', 'l121']", + "74, lymphoma. ['l63', 'l72', 'l81', 'l87', 'l95', 'l102', 'l106', 'l111', 'l115', 'l118', 'l122', 'l123', 'l124']", + "75, Cell ['l96', 'l107', 'l112', 'l116', 'l119', 'l122', 'l125', 'l126', 'l127']", + "76, death ['l97', 'l108', 'l113', 'l117', 'l120', 'l123', 'l125', 'l128']", + "91, activated/tumor-transformed ['l126', 'l129']", + "92, cells. ['l121', 'l124', 'l127', 'l128', 'l129']", + "115, primates, ['l130', 'l131']", + "116, in ['l130', 'l132']", + "117, vivo. ['l131', 'l132']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "Cell", + "death" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenograft" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "Cell", + "death" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "models", + "of", + "non-Hodgkin", + "lymphoma." + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "Cell", + "death" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "Cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "activated/tumor-transformed", + "cells." + ] + } + } + ] + }, + { + "PMID": "12068289", + "TEXT": "Here we investigated the biological functions of adiponectin/ACRP30, a fat-derived hormone, by disrupting the gene that encodes it in mice. Adiponectin/ACRP30-knockout (KO) mice showed delayed clearance of free fatty acid in plasma, low levels of fatty-acid transport protein 1 (FATP-1) mRNA in muscle, high levels of tumor necrosis factor-alpha (TNF-alpha) mRNA in adipose tissue and high plasma TNF-alpha concentrations. The KO mice exhibited severe diet-induced insulin resistance with reduced insulin-receptor substrate 1 (IRS-1)-associated phosphatidylinositol 3 kinase (PI3-kinase) activity in muscle. Viral mediated adiponectin/ACRP30 expression in KO mice reversed the reduction of FATP-1 mRNA, the increase of adipose TNF-alpha mRNA and the diet-induced insulin resistance. In cultured myocytes, TNF-alpha decreased FATP-1 mRNA, IRS-1-associated PI3-kinase activity and glucose uptake, whereas adiponectin increased these parameters. Our results indicate that adiponectin/ACRP30 deficiency and high TNF-alpha levels in KO mice reduced muscle FATP-1 mRNA and IRS-1-mediated insulin signaling, resulting in severe diet-induced insulin resistance.", + "TAG_DATA": [ + "20, Adiponectin/ACRP30-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "21, (KO) {'perturbing_action': 'I-gene loss-of-function'}", + "22, mice {'context': 'B-organism'}", + "61, mice {'context': 'B-organism'}", + "80, Viral {'perturbing_action': 'B-gene gain-of-function'}", + "81, mediated {'perturbing_action': 'I-gene gain-of-function'}", + "82, adiponectin/ACRP30 {'perturbing_action': 'I-gene gain-of-function'}", + "83, expression {'perturbing_action': 'I-gene gain-of-function'}", + "85, KO {'perturbing_action': 'B-gene loss-of-function'}", + "86, mice {'context': 'B-organism'}", + "105, cultured {'context': 'B-cells'}", + "106, myocytes, {'context': 'I-cells'}", + "126, adiponectin/ACRP30 {'perturbing_action': 'B-gene loss-of-function'}", + "127, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "134, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "20, Adiponectin/ACRP30-knockout ['l0', 'l1', 'l2', 'l3']", + "21, (KO) ['l0', 'l4', 'l5']", + "22, mice ['l1', 'l4']", + "61, mice ['l2', 'l6']", + "79, muscle. ['l3', 'l5', 'l6']", + "80, Viral ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "81, mediated ['l7', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "82, adiponectin/ACRP30 ['l8', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "83, expression ['l9', 'l15', 'l20', 'l25', 'l26', 'l27', 'l28']", + "85, KO ['l10', 'l16', 'l21', 'l25', 'l29', 'l30', 'l31']", + "86, mice ['l11', 'l17', 'l22', 'l26', 'l29']", + "105, cultured ['l12', 'l18', 'l23', 'l27', 'l30', 'l32']", + "106, myocytes, ['l13', 'l19', 'l24', 'l28', 'l31', 'l32']", + "126, adiponectin/ACRP30 ['l33', 'l34']", + "127, deficiency ['l33', 'l35']", + "134, mice ['l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Adiponectin/ACRP30-knockout", + "(KO)", + "KO", + "adiponectin/ACRP30", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Viral", + "mediated", + "adiponectin/ACRP30", + "expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Viral", + "mediated", + "adiponectin/ACRP30", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "myocytes," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "KO" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "myocytes," + ] + } + } + ] + }, + { + "PMID": "12068288", + "TEXT": "Erythropoietin (Epo) is upregulated by hypoxia and provides protection against apoptosis of erythroid progenitors in bone marrow and brain neurons. Here we show in the adult mouse retina that acute hypoxia dose-dependently stimulates expression of Epo, fibroblast growth factor 2 and vascular endothelial growth factor via hypoxia-inducible factor-1alpha (HIF-1alpha) stabilization. Hypoxic preconditioning protects retinal morphology and function against light-induced apoptosis by interfering with caspase-1 activation, a downstream event in the intracellular death cascade. In contrast, induction of activator protein-1, an early event in the light-stressed retina, is not affected by hypoxia. The Epo receptor required for Epo signaling localizes to photoreceptor cells. The protective effect of hypoxic preconditioning is mimicked by systemically applied Epo that crosses the blood retina barrier and prevents apoptosis even when given therapeutically after light insult. Application of Epo may, through the inhibition of apoptosis, be beneficial for the treatment of different forms of retinal disease.", + "TAG_DATA": [ + "25, adult {'context': 'B-tissue/organ'}", + "26, mouse {'context': 'I-tissue/organ'}", + "27, retina {'context': 'I-tissue/organ'}", + "58, light-induced {'effect': 'B-positive'}", + "59, apoptosis {'phenotype': 'B-apoptosis'}", + "121, prevents {'effect': 'B-negative'}", + "122, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "25, adult ['l0', 'l1', 'l2', 'l3']", + "26, mouse ['l0', 'l4', 'l5', 'l6']", + "27, retina ['l1', 'l4', 'l7', 'l8']", + "58, light-induced ['l2', 'l5', 'l7', 'l9']", + "59, apoptosis ['l3', 'l6', 'l8', 'l9']", + "121, prevents ['l10']", + "122, apoptosis ['l10']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "adult", + "mouse", + "retina" + ] + }, + "effect": { + "val": "positive", + "words": [ + "light-induced" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "adult", + "mouse", + "retina" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "light-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "11927945", + "TEXT": "Herpes simplex virus infections are the cause of significant morbidity, and currently used therapeutics are largely based on modified nucleoside analogs that inhibit viral DNA polymerase function. To target this disease in a new way, we have identified and optimized selective thiazolylphenyl-containing inhibitors of the herpes simplex virus (HSV) helicase-primase enzyme. The most potent compounds inhibited the helicase, the primase and the DNA-dependent ATPase activities of the enzyme with IC50 (50% inhibitory concentration) values less than 100 nM. Inhibition of the enzymatic activities was through stabilization of the interaction between the helicase-primase and DNA substrates, preventing the progression through helicase or primase catalytic cycles. Helicase-primase inhibitors also prevented viral replication as demonstrated in viral growth assays. One compound, BILS 179 BS, displayed an EC50 (effective concentration inhibiting viral growth by 50%) of 27 nM against viral growth with a selectivity index greater than 2,000. Antiviral activity was also demonstrated for multiple strains of HSV, including strains resistant to nucleoside-based therapies. Most importantly, BILS 179 BS was orally active against HSV infections in murine models of HSV-1 and HSV-2 disease and more effective than acyclovir when the treatment frequency per day was reduced or when initiation of treatment was delayed up to 65 hours after infection. These studies validate the use of helicase-primase inhibitors for the treatment of acute herpesvirus infections and provide new lead compounds for optimization and design of superior anti-HSV agents.", + "TAG_DATA": [ + "107, prevented {'effect': 'B-negative'}", + "109, replication {'phenotype': 'I-colony formation'}", + "172, murine {'context': 'B-organism'}", + "173, models {'context': 'I-organism'}", + "174, of {'context': 'I-organism'}", + "175, HSV-1 {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "107, prevented ['l0']", + "109, replication ['l0']", + "172, murine ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "173, models ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "174, of ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "175, HSV-1 ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "176, and ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "177, HSV-2 ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "178, disease ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "replication" + ] + } + } + ] + }, + { + "PMID": "11875495", + "TEXT": "CD40L, a member of the tumor necrosis factor family of ligands, plays a major role in immune responses via its receptor, CD40. Recently, CD40L has been detected on the surfaces of activated platelets and shown to activate endothelium. Here we further addressed the function of platelet CD40L. We show that absence of CD40L affects the stability of arterial thrombi and delays arterial occlusion in vivo. Infusion of recombinant soluble (rs)CD40L restored normal thrombosis, whereas rsCD40L lacking the KGD integrin-recognition sequence did not. CD40-deficient mice exhibited normal thrombogenesis. rsCD40L specifically bound to purified integrin alphaIIbbeta3 and to activated platelets in a beta3-dependent manner and induced platelet spreading. In addition, rsCD40L promoted the aggregation of either human or mouse platelets under high shear rates. Thus, CD40L appears to be an alphaIIbbeta3 ligand, a platelet agonist, and necessary for stability of arterial thrombi.", + "TAG_DATA": [ + "50, absence {'perturbing_action': 'B-gene loss-of-function'}", + "51, of {'perturbing_action': 'I-gene loss-of-function'}", + "52, CD40L {'perturbing_action': 'I-gene loss-of-function'}", + "63, in {'context': 'B-in vivo'}", + "64, vivo. {'context': 'I-in vivo'}", + "75, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "76, the {'perturbing_action': 'I-gene loss-of-function'}", + "77, KGD {'perturbing_action': 'I-gene loss-of-function'}", + "78, integrin-recognition {'perturbing_action': 'I-gene loss-of-function'}", + "79, sequence {'perturbing_action': 'I-gene loss-of-function'}", + "82, CD40-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "83, mice {'context': 'B-organism'}", + "97, platelets {'context': 'B-cells'}", + "104, platelet {'context': 'B-cells'}", + "109, promoted {'effect': 'B-positive'}", + "111, aggregation {'phenotype': 'B-autophagy'}", + "114, human {'context': 'B-cells'}", + "115, or {'context': 'I-cells'}", + "116, mouse {'context': 'I-cells'}", + "117, platelets {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "50, absence ['l0', 'l1', 'l2', 'l3']", + "51, of ['l0', 'l4', 'l5', 'l6']", + "52, CD40L ['l1', 'l4', 'l7', 'l8']", + "63, in ['l2', 'l5', 'l7', 'l9']", + "64, vivo. ['l3', 'l6', 'l8', 'l9']", + "75, lacking ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "76, the ['l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "77, KGD ['l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "78, integrin-recognition ['l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "79, sequence ['l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "82, CD40-deficient ['l14', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "83, mice ['l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "97, platelets ['l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "104, platelet ['l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']", + "109, promoted ['l46', 'l47', 'l48', 'l49', 'l50']", + "111, aggregation ['l46', 'l51', 'l52', 'l53', 'l54']", + "114, human ['l47', 'l51', 'l55', 'l56', 'l57']", + "115, or ['l48', 'l52', 'l55', 'l58', 'l59']", + "116, mouse ['l49', 'l53', 'l56', 'l58', 'l60']", + "117, platelets ['l50', 'l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "CD40L" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "KGD", + "integrin-recognition", + "sequence", + "CD40-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "KGD", + "integrin-recognition", + "sequence", + "CD40-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelets", + "platelet" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "aggregation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "or", + "mouse", + "platelets" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "aggregation" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "or", + "mouse", + "platelets" + ] + } + } + ] + }, + { + "PMID": "11821903", + "TEXT": "Obesity and insulin resistance are major risk factors for a number of metabolic disorders, such as type 2 diabetes mellitus. Insulin has been suggested to function as one of the adiposity signals to the brain for modulation of energy balance. Administration of insulin into the brain reduces food intake and body weight, and mice with a genetic deletion of neuronal insulin receptors are hyperphagic and obese. However, insulin is also an anabolic factor; when administered systemically, pharmacological levels of insulin are associated with body weight gain in patients. In this study, we investigated the efficacy and feasibility of small molecule insulin mimetic compounds to regulate key parameters of energy homeostasis. Central intracerebroventricular (i.c.v.) administration of an insulin mimetic resulted in a dose-dependent reduction of food intake and body weight in rats, and altered the expression of hypothalamic genes known to regulate food intake and body weight. Oral administration of a mimetic in a mouse model of high-fat diet-induced obesity reduced body weight gain, adiposity and insulin resistance. Thus, insulin mimetics have a unique advantage over insulin in the control of body weight and hold potential as a novel anti-obesity treatment.", + "TAG_DATA": [ + "56, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "57, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "58, of {'perturbing_action': 'I-gene loss-of-function'}", + "59, neuronal {'perturbing_action': 'I-gene loss-of-function'}", + "60, insulin {'perturbing_action': 'I-gene loss-of-function'}", + "61, receptors {'perturbing_action': 'I-gene loss-of-function'}", + "130, rats, {'context': 'B-organism'}", + "153, mouse {'context': 'B-organism'}", + "154, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "56, genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "57, deletion ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "58, of ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "59, neuronal ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "60, insulin ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "61, receptors ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "130, rats, ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "153, mouse ['l21']", + "154, model ['l21']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "neuronal", + "insulin", + "receptors" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats," + ] + } + } + ] + }, + { + "PMID": "11821896", + "TEXT": "Conventional immunosuppressive drugs have been used effectively to prevent immunologic rejection in organ transplantation. Individuals taking these drugs are at risk, however, for the development and recurrence of cancer. In the present study we show that the new immunosuppressive drug rapamycin (RAPA) may reduce the risk of cancer development while simultaneously providing effective immunosuppression. Experimentally, RAPA inhibited metastatic tumor growth and angiogenesis in in vivo mouse models. In addition, normal immunosuppressive doses of RAPA effectively controlled the growth of established tumors. In contrast, the most widely recognized immunosuppressive drug, cyclosporine, promoted tumor growth. From a mechanistic perspective, RAPA showed antiangiogenic activities linked to a decrease in production of vascular endothelial growth factor (VEGF) and to a markedly inhibited response of vascular endothelial cells to stimulation by VEGF. Thus, the use of RAPA, instead of cyclosporine, may reduce the chance of recurrent or de novo cancer in high-risk transplant patients.", + "TAG_DATA": [ + "56, inhibited {'effect': 'B-negative'}", + "57, metastatic {'phenotype': 'B-tumour growth'}", + "58, tumor {'phenotype': 'B-tumour growth'}", + "59, growth {'phenotype': 'I-tumour growth'}", + "63, in {'context': 'B-in vivo'}", + "64, vivo {'context': 'I-in vivo'}", + "65, mouse {'context': 'I-in vivo'}", + "66, models. {'context': 'I-organism'}", + "80, tumors. {'context': 'B-neoplasm'}", + "90, promoted {'effect': 'B-positive'}", + "91, tumor {'phenotype': 'B-tumour growth'}", + "92, growth. {'phenotype': 'I-tumour growth'}", + "120, vascular {'context': 'B-cells'}", + "121, endothelial {'context': 'I-cells'}", + "122, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "56, inhibited ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "57, metastatic ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "58, tumor ['l1', 'l7', 'l13', 'l14', 'l15', 'l16']", + "59, growth ['l2', 'l8', 'l13', 'l17', 'l18', 'l19']", + "63, in ['l3', 'l9', 'l20', 'l21', 'l22']", + "64, vivo ['l4', 'l10', 'l14', 'l17', 'l20', 'l23', 'l24']", + "65, mouse ['l5', 'l11', 'l15', 'l18', 'l21', 'l23', 'l25']", + "66, models. ['l6', 'l12', 'l16', 'l19', 'l22', 'l24', 'l25']", + "90, promoted ['l26', 'l27']", + "91, tumor ['l26', 'l28']", + "92, growth. ['l27', 'l28']", + "120, vascular ['l29', 'l30']", + "121, endothelial ['l29', 'l31']", + "122, cells ['l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "metastatic", + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "mouse" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "organism", + "words": [ + "models." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "metastatic", + "tumor", + "growth" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "mouse" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "metastatic", + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "models." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + } + ] + }, + { + "PMID": "11786910", + "TEXT": "The immune-modulating cytokine interleukin-6 (IL-6) is expressed both in adipose tissue and centrally in hypothalamic nuclei that regulate body composition. We investigated the impact of loss of IL-6 on body composition in mice lacking the gene encoding IL-6 (Il6-/- mice) and found that they developed mature-onset obesity that was partly reversed by IL-6 replacement. The obese Il6-/- mice had disturbed carbohydrate and lipid metabolism, increased leptin levels and decreased responsiveness to leptin treatment. To investigate the possible mechanism and site of action of the anti-obesity effect of IL-6, we injected rats centrally and peripherally with IL-6 at low doses. Intracerebroventricular, but not intraperitoneal IL-6 treatment increased energy expenditure. In conclusion, centrally acting IL-6 exerts anti-obesity effects in rodents.", + "TAG_DATA": [ + "32, mice {'context': 'B-organism'}", + "33, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "34, the {'perturbing_action': 'I-gene loss-of-function'}", + "35, gene {'perturbing_action': 'I-gene loss-of-function'}", + "36, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "37, IL-6 {'perturbing_action': 'I-gene loss-of-function'}", + "38, (Il6-/- {'perturbing_action': 'I-gene loss-of-function'}", + "39, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "56, Il6-/- {'perturbing_action': 'B-gene loss-of-function'}", + "57, mice {'context': 'B-organism'}", + "90, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "32, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "33, lacking ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "34, the ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "35, gene ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "36, encoding ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "37, IL-6 ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "38, (Il6-/- ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "39, mice) ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "56, Il6-/- ['l28']", + "57, mice ['l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "gene", + "encoding", + "IL-6", + "(Il6-/-", + "mice)", + "Il6-/-" + ] + } + } + ] + }, + { + "PMID": "11726978", + "TEXT": "Gene therapy in the central nervous system (CNS) is hindered by the presence of the blood-brain barrier, which restricts access of serum constituents and peripheral cells to the brain parenchyma. Expression of exogenously administered genes in the CNS has been achieved in vivo using highly invasive routes, or ex vivo relying on the direct implantation of genetically modified cells into the brain. Here we provide evidence for a novel, noninvasive approach for targeting potential therapeutic factors to the CNS. Genetically-modified hematopoietic cells enter the CNS and differentiate into microglia after bone-marrow transplantation. Up to a quarter of the regional microglial population is donor-derived by four months after transplantation. Microglial engraftment is enhanced by neuropathology, and gene-modified myeloid cells are specifically attracted to the sites of neuronal damage. Thus, microglia may serve as vehicles for gene delivery to the nervous system.", + "TAG_DATA": [ + "80, hematopoietic {'context': 'B-cells'}", + "81, cells {'context': 'I-cells'}", + "86, differentiate {'phenotype': 'B-differentiation'}", + "116, myeloid {'context': 'B-cells'}", + "117, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "80, hematopoietic ['l0', 'l1']", + "81, cells ['l0', 'l2']", + "86, differentiate ['l1', 'l2']", + "116, myeloid ['l3']", + "117, cells ['l3']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate" + ] + } + } + ] + }, + { + "PMID": "11689884", + "TEXT": "Acute and fulminant liver failure induced by viral hepatitis, alcohol or other hepatotoxic drugs, are associated with tumor necrosis factor (TNF) production. In a mouse model of lethal hepatitis induced by TNF, apoptosis and necrosis of hepatocytes, but also lethality, hypothermia and influx of leukocytes into the liver, are prevented by a broad-spectrum matrix metalloproteinase (MMP) inhibitor, BB-94. Mice deficient in MMP-2, MMP-3 or MMP-9 had lower levels of apoptosis and necrosis of hepatocytes, and better survival. We found induction of MMP-9 activity and fibronectin degradation. Our findings suggest that several MMPs play a critical role in acute, fulminant hepatitis by degrading the extracellular matrix and allowing massive leukocyte influx in the liver. BB-94 also prevented lethality in TNF/interferon-gamma therapy in tumor-bearing mice. A broad-spectrum MMP inhibitor may be potentially useful for the treatment of patients with acute and perhaps chronic liver failure, and in cancer therapies using inflammatory cytokines.", + "TAG_DATA": [ + "32, apoptosis {'phenotype': 'B-apoptosis'}", + "34, necrosis {'phenotype': 'B-necrosis'}", + "36, hepatocytes, {'context': 'B-cells'}", + "52, broad-spectrum {'perturbing_action': 'B-pharmacological inhibition'}", + "53, matrix {'perturbing_action': 'I-pharmacological inhibition'}", + "54, metalloproteinase {'perturbing_action': 'I-pharmacological inhibition'}", + "55, (MMP) {'perturbing_action': 'I-pharmacological inhibition'}", + "56, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "57, BB-94. {'perturbing_action': 'I-pharmacological inhibition'}", + "58, Mice {'context': 'B-organism'}", + "59, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "60, in {'perturbing_action': 'I-gene loss-of-function'}", + "61, MMP-2, {'perturbing_action': 'I-gene loss-of-function'}", + "62, MMP-3 {'perturbing_action': 'I-gene loss-of-function'}", + "63, or {'perturbing_action': 'I-gene loss-of-function'}", + "64, MMP-9 {'perturbing_action': 'I-gene loss-of-function'}", + "66, lower {'effect': 'B-negative'}", + "67, levels {'effect': 'I-positive'}", + "69, apoptosis {'phenotype': 'B-apoptosis'}", + "71, necrosis {'phenotype': 'B-necrosis'}", + "73, hepatocytes, {'context': 'B-cells'}", + "121, tumor-bearing {'context': 'B-organism'}", + "122, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "32, apoptosis ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "34, necrosis ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "36, hepatocytes, ['l1', 'l8']", + "52, broad-spectrum ['l2', 'l9', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "53, matrix ['l3', 'l10', 'l15', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "54, metalloproteinase ['l16', 'l32', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "55, (MMP) ['l4', 'l11', 'l17', 'l33', 'l48', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "56, inhibitor, ['l18', 'l34', 'l49', 'l63', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "57, BB-94. ['l5', 'l12', 'l19', 'l35', 'l50', 'l64', 'l77', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "58, Mice ['l20', 'l36', 'l51', 'l65', 'l78', 'l90', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "59, deficient ['l21', 'l37', 'l52', 'l66', 'l79', 'l100', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "60, in ['l22', 'l38', 'l53', 'l67', 'l80', 'l101', 'l111', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "61, MMP-2, ['l23', 'l39', 'l54', 'l68', 'l81', 'l91', 'l102', 'l112', 'l121', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "62, MMP-3 ['l24', 'l40', 'l55', 'l69', 'l82', 'l92', 'l103', 'l113', 'l122', 'l130', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "63, or ['l25', 'l41', 'l56', 'l70', 'l83', 'l93', 'l104', 'l114', 'l123', 'l131', 'l138', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150']", + "64, MMP-9 ['l26', 'l42', 'l57', 'l71', 'l84', 'l94', 'l105', 'l115', 'l124', 'l132', 'l139', 'l145', 'l151', 'l152', 'l153', 'l154', 'l155']", + "66, lower ['l6', 'l13', 'l27', 'l43', 'l58', 'l72', 'l85', 'l95', 'l106', 'l116', 'l125', 'l133', 'l140', 'l146', 'l151', 'l156', 'l157', 'l158', 'l159']", + "67, levels ['l7', 'l14', 'l28', 'l44', 'l59', 'l73', 'l86', 'l96', 'l107', 'l117', 'l126', 'l134', 'l141', 'l147', 'l152', 'l156', 'l160', 'l161', 'l162']", + "69, apoptosis ['l29', 'l45', 'l60', 'l74', 'l87', 'l97', 'l108', 'l118', 'l127', 'l135', 'l142', 'l148', 'l153', 'l157', 'l160', 'l163', 'l164']", + "71, necrosis ['l30', 'l46', 'l61', 'l75', 'l88', 'l98', 'l109', 'l119', 'l128', 'l136', 'l143', 'l149', 'l154', 'l158', 'l161', 'l163', 'l165']", + "73, hepatocytes, ['l31', 'l47', 'l62', 'l76', 'l89', 'l99', 'l110', 'l120', 'l129', 'l137', 'l144', 'l150', 'l155', 'l159', 'l162', 'l164', 'l165']", + "121, tumor-bearing ['l166']", + "122, mice. ['l166']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "broad-spectrum", + "matrix", + "(MMP)", + "BB-94.", + "metalloproteinase", + "inhibitor," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "levels" + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes," + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "broad-spectrum", + "matrix", + "(MMP)", + "BB-94.", + "metalloproteinase", + "inhibitor," + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "levels" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "broad-spectrum", + "matrix", + "metalloproteinase", + "(MMP)", + "inhibitor,", + "BB-94." + ] + }, + "context": { + "val": "organism", + "words": [ + "Mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "broad-spectrum", + "matrix", + "metalloproteinase", + "(MMP)", + "inhibitor,", + "BB-94." + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "broad-spectrum", + "matrix", + "metalloproteinase", + "(MMP)", + "inhibitor,", + "BB-94." + ] + }, + "effect": { + "val": "positive", + "words": [ + "levels" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "broad-spectrum", + "matrix", + "metalloproteinase", + "(MMP)", + "inhibitor,", + "BB-94." + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "MMP-2,", + "MMP-3", + "or", + "MMP-9" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "levels" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "MMP-2,", + "MMP-3", + "or", + "MMP-9" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "MMP-2,", + "MMP-3", + "or", + "MMP-9" + ] + }, + "effect": { + "val": "positive", + "words": [ + "levels" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "MMP-2,", + "MMP-3", + "or", + "MMP-9" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "MMP-2,", + "MMP-3", + "or", + "MMP-9" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "MMP-2,", + "MMP-3", + "or", + "MMP-9" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "lower" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "levels" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes," + ] + } + } + ] + }, + { + "PMID": "11590438", + "TEXT": "Inducible nitric oxide synthase (iNOS) is induced by inflammatory cytokines in skeletal muscle and fat. It has been proposed that chronic iNOS induction may cause muscle insulin resistance. Here we show that iNOS expression is increased in muscle and fat of genetic and dietary models of obesity. Moreover, mice in which the gene encoding iNOS was disrupted (Nos2-/- mice) are protected from high-fat-induced insulin resistance. Whereas both wild-type and Nos2-/- mice developed obesity on the high-fat diet, obese Nos2-/- mice exhibited improved glucose tolerance, normal insulin sensitivity in vivo and normal insulin-stimulated glucose uptake in muscles. iNOS induction in obese wild-type mice was associated with impairments in phosphatidylinositol 3-kinase and Akt activation by insulin in muscle. These defects were fully prevented in obese Nos2-/- mice. These findings provide genetic evidence that iNOS is involved in the development of muscle insulin resistance in diet-induced obesity.", + "TAG_DATA": [ + "48, mice {'context': 'B-organism'}", + "51, the {'perturbing_action': 'I-gene loss-of-function'}", + "52, gene {'perturbing_action': 'I-gene loss-of-function'}", + "53, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "54, iNOS {'perturbing_action': 'I-gene loss-of-function'}", + "55, was {'perturbing_action': 'I-gene loss-of-function'}", + "56, disrupted {'perturbing_action': 'I-gene loss-of-function'}", + "58, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "69, Nos2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "70, mice {'context': 'B-organism'}", + "77, obese {'perturbing_action': 'B-gene loss-of-function'}", + "78, Nos2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "79, mice {'context': 'B-organism'}", + "87, in {'context': 'B-in vivo'}", + "88, vivo {'context': 'I-in vivo'}", + "95, muscles. {'context': 'B-tissue/organ'}", + "101, mice {'context': 'B-organism'}", + "115, muscle. {'context': 'B-tissue/organ'}", + "123, Nos2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "124, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "48, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "51, the ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "52, gene ['l1', 'l11', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "53, encoding ['l2', 'l12', 'l25', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "54, iNOS ['l3', 'l13', 'l26', 'l38', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "55, was ['l4', 'l14', 'l27', 'l39', 'l50', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "56, disrupted ['l5', 'l15', 'l28', 'l40', 'l51', 'l61', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "58, mice) ['l6', 'l16', 'l29', 'l41', 'l52', 'l62', 'l71', 'l80', 'l81', 'l82', 'l83']", + "69, Nos2-/- ['l7', 'l17', 'l30', 'l42', 'l53', 'l63', 'l72', 'l80', 'l84', 'l85', 'l86', 'l87', 'l88']", + "70, mice ['l8', 'l18', 'l31', 'l43', 'l54', 'l64', 'l73', 'l81', 'l84', 'l89', 'l90']", + "77, obese ['l19', 'l32', 'l44', 'l55', 'l65', 'l74', 'l91', 'l92', 'l93', 'l94', 'l95']", + "78, Nos2-/- ['l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l91', 'l96', 'l97', 'l98', 'l99']", + "79, mice ['l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l85', 'l92', 'l96', 'l100', 'l101', 'l102']", + "87, in ['l9', 'l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l82', 'l86', 'l89', 'l93', 'l97', 'l100', 'l103', 'l104']", + "88, vivo ['l10', 'l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l83', 'l87', 'l90', 'l94', 'l98', 'l101', 'l103']", + "95, muscles. ['l24', 'l37', 'l49', 'l60', 'l70', 'l79', 'l88', 'l95', 'l99', 'l102', 'l104']", + "101, mice ['l105']", + "115, muscle. ['l105']", + "123, Nos2-/- ['l106']", + "124, mice. ['l106']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "gene", + "encoding", + "iNOS", + "was", + "disrupted", + "mice)", + "Nos2-/-", + "obese" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "gene", + "encoding", + "iNOS", + "was", + "disrupted", + "mice)", + "Nos2-/-", + "obese" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "gene", + "encoding", + "iNOS", + "was", + "disrupted", + "Nos2-/-", + "obese" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscles." + ] + } + } + ] + }, + { + "PMID": "11533710", + "TEXT": "Diabetes in non-obese diabetic (NOD) mice is mediated by pathogenic T-helper type 1 (Th1) cells that arise because of a deficiency in regulatory or suppressor T cells. V alpha 14-J alpha 15 natural killer T (NKT) cells recognize lipid antigens presented by the major histocompatibility complex class I-like protein CD1d (refs. 3,4). We have previously shown that in vivo activation of V alpha 14 NKT cells by alpha-galactosylceramide (alpha-GalCer) and CD1d potentiates Th2-mediated adaptive immune responses. Here we show that alpha-GalCer prevents development of diabetes in wild-type but not CD1d-deficient NOD mice. Disease prevention correlated with the ability of alpha-GalCer to suppress interferon-gamma but not interleukin-4 production by NKT cells, to increase serum immunoglobulin E levels, and to promote the generation of islet autoantigen-specific Th2 cells. Because alpha-GalCer recognition by NKT cells is conserved among mice and humans, these findings indicate that alpha-GalCer might be useful for therapeutic intervention in human diseases characterized by Th1-mediated pathology such as Type 1 diabetes.", + "TAG_DATA": [ + "57, in {'context': 'B-in vivo'}", + "58, vivo {'context': 'I-in vivo'}", + "61, V {'context': 'B-cells'}", + "62, alpha {'context': 'I-cells'}", + "63, 14 {'context': 'B-cells'}", + "64, NKT {'context': 'I-cells'}", + "65, cells {'context': 'I-cells'}", + "89, CD1d-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "90, NOD {'context': 'B-organism'}", + "91, mice. {'context': 'I-organism'}", + "108, NKT {'context': 'B-cells'}", + "109, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "57, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "58, vivo ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "61, V ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "62, alpha ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "63, 14 ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "64, NKT ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "65, cells ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "89, CD1d-deficient ['l21', 'l22', 'l23', 'l24']", + "90, NOD ['l21', 'l25', 'l26', 'l27']", + "91, mice. ['l22', 'l25', 'l28', 'l29']", + "108, NKT ['l23', 'l26', 'l28', 'l30']", + "109, cells, ['l24', 'l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD1d-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "NOD", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD1d-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "NKT", + "cells," + ] + } + } + ] + }, + { + "PMID": "11533706", + "TEXT": "Stem cells from bone marrow, skeletal muscle and possibly other tissues can be identified by the 'side-population' (SP) phenotype. Although it has been assumed that expression of ABC transporters is responsible for this phenotype, the specific molecules involved have not been defined. Here we show that expression of the Bcrp1 (also known as Abcg2 murine/ABCG2 human) gene is a conserved feature of stem cells from a wide variety of sources. Bcrp1 mRNA was expressed at high levels in primitive murine hematopoietic stem cells, and was sharply downregulated with differentiation. Enforced expression of the ABCG2 cDNA directly conferred the SP phenotype to bone-marrow cells and caused a reduction in maturing progeny both in vitro and in transplantation-based assays. These results show that expression of the Bcrp1/ABCG2 gene is an important determinant of the SP phenotype, and that it might serve as a marker for stem cells from various sources.", + "TAG_DATA": [ + "89, Enforced {'perturbing_action': 'B-gene gain-of-function'}", + "90, expression {'perturbing_action': 'I-gene gain-of-function'}", + "91, of {'perturbing_action': 'I-gene gain-of-function'}", + "92, the {'perturbing_action': 'I-gene gain-of-function'}", + "93, ABCG2 {'perturbing_action': 'I-gene gain-of-function'}", + "94, cDNA {'perturbing_action': 'I-gene gain-of-function'}", + "101, bone-marrow {'context': 'B-cells'}", + "102, cells {'context': 'I-cells'}", + "111, in {'context': 'B-in vitro'}", + "112, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "89, Enforced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "90, expression ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "91, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "92, the ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "93, ABCG2 ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "94, cDNA ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "101, bone-marrow ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "102, cells ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39']", + "111, in ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42']", + "112, vitro ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced", + "expression", + "of", + "the", + "ABCG2", + "cDNA" + ] + }, + "context": { + "val": "cells", + "words": [ + "bone-marrow", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced", + "expression", + "of", + "the", + "ABCG2", + "cDNA" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "11479625", + "TEXT": "Lack of a small animal model of the human hepatitis C virus (HCV) has impeded development of antiviral therapies against this epidemic infection. By transplanting normal human hepatocytes into SCID mice carrying a plasminogen activator transgene (Alb-uPA), we generated mice with chimeric human livers. Homozygosity of Alb-uPA was associated with significantly higher levels of human hepatocyte engraftment, and these mice developed prolonged HCV infections with high viral titers after inoculation with infected human serum. Initial increases in total viral load were up to 1950-fold, with replication confirmed by detection of negative-strand viral RNA in transplanted livers. HCV viral proteins were localized to human hepatocyte nodules, and infection was serially passaged through three generations of mice confirming both synthesis and release of infectious viral particles. These chimeric mice represent the first murine model suitable for studying the human hepatitis C virus in vivo.", + "TAG_DATA": [ + "25, normal {'context': 'B-cells'}", + "26, human {'context': 'I-cells'}", + "27, hepatocytes {'context': 'I-cells'}", + "29, SCID {'context': 'B-organism'}", + "30, mice {'context': 'I-organism'}", + "34, activator {'perturbing_action': 'I-other'}", + "35, transgene {'perturbing_action': 'I-other'}", + "39, mice {'context': 'B-organism'}", + "43, livers. {'context': 'I-tissue/organ'}", + "44, Homozygosity {'perturbing_action': 'B-other'}", + "45, of {'perturbing_action': 'I-other'}", + "46, Alb-uPA {'perturbing_action': 'I-other'}", + "54, human {'context': 'B-cells'}", + "55, hepatocyte {'context': 'I-cells'}", + "59, mice {'context': 'B-organism'}", + "95, livers. {'context': 'B-tissue/organ'}", + "114, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "25, normal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "26, human ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "27, hepatocytes ['l1', 'l17', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "29, SCID ['l2', 'l18', 'l32', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "30, mice ['l3', 'l19', 'l33', 'l46', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "32, a ['l4', 'l20', 'l34', 'l47', 'l59', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "33, plasminogen ['l5', 'l21', 'l35', 'l48', 'l60', 'l71', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "34, activator ['l6', 'l22', 'l36', 'l49', 'l61', 'l72', 'l85', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "35, transgene ['l7', 'l23', 'l37', 'l50', 'l62', 'l73', 'l86', 'l98', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "36, (Alb-uPA), ['l8', 'l24', 'l38', 'l51', 'l63', 'l74', 'l87', 'l99', 'l110', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "39, mice ['l9', 'l25', 'l39', 'l52', 'l64', 'l75', 'l88', 'l100', 'l111', 'l121', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "42, human ['l10', 'l26', 'l40', 'l53', 'l65', 'l76', 'l89', 'l101', 'l112', 'l122', 'l131', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145']", + "43, livers. ['l11', 'l27', 'l41', 'l54', 'l66', 'l77', 'l90', 'l102', 'l113', 'l123', 'l132', 'l139', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151']", + "44, Homozygosity ['l78', 'l91', 'l103', 'l114', 'l124', 'l133', 'l140', 'l146', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "45, of ['l12', 'l79', 'l92', 'l104', 'l115', 'l125', 'l134', 'l141', 'l147', 'l152', 'l158', 'l159', 'l160', 'l161', 'l162']", + "46, Alb-uPA ['l13', 'l28', 'l42', 'l55', 'l67', 'l80', 'l93', 'l105', 'l116', 'l126', 'l135', 'l142', 'l148', 'l153', 'l158', 'l163', 'l164', 'l165', 'l166']", + "54, human ['l14', 'l29', 'l43', 'l56', 'l68', 'l81', 'l94', 'l106', 'l117', 'l127', 'l136', 'l143', 'l149', 'l154', 'l159', 'l163', 'l167', 'l168']", + "55, hepatocyte ['l15', 'l30', 'l44', 'l57', 'l69', 'l82', 'l95', 'l107', 'l118', 'l128', 'l137', 'l144', 'l150', 'l155', 'l160', 'l164', 'l167', 'l169']", + "59, mice ['l16', 'l31', 'l45', 'l58', 'l70', 'l83', 'l96', 'l108', 'l119', 'l129', 'l138', 'l145', 'l151', 'l156', 'l161', 'l165', 'l168', 'l169']", + "95, livers. ['l84', 'l97', 'l109', 'l120', 'l130', 'l157', 'l162', 'l166']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "normal", + "human", + "hepatocytes", + "hepatocyte" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "activator", + "transgene", + "of", + "Alb-uPA", + "Homozygosity" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "SCID", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "activator", + "transgene", + "Alb-uPA", + "Homozygosity", + "of" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "activator", + "transgene", + "Homozygosity", + "of", + "Alb-uPA" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "livers." + ] + } + } + ] + }, + { + "PMID": "11433352", + "TEXT": "Atherosclerosis is the primary cause of cardiovascular disease, and the risk for atherosclerosis is inversely proportional to circulating levels of high-density lipoprotein (HDL) cholesterol. However, the mechanisms by which HDL is atheroprotective are complex and not well understood. Here we show that HDL stimulates endothelial nitric oxide synthase (eNOS) in cultured endothelial cells. In contrast, eNOS is not activated by purified forms of the major HDL apolipoproteins ApoA-I and ApoA-II or by low-density lipoprotein. Heterologous expression experiments in Chinese hamster ovary cells reveal that scavenger receptor-BI (SR-BI) mediates the effects of HDL on the enzyme. HDL activation of eNOS is demonstrable in isolated endothelial-cell caveolae where SR-BI and eNOS are colocalized, and the response in isolated plasma membranes is blocked by antibodies to ApoA-I and SR-BI, but not by antibody to ApoA-II. HDL also enhances endothelium- and nitric-oxide-dependent relaxation in aortae from wild-type mice, but not in aortae from homozygous null SR-BI knockout mice. Thus, HDL activates eNOS via SR-BI through a process that requires ApoA-I binding. The resulting increase in nitric-oxide production might be critical to the atheroprotective properties of HDL and ApoA-I.", + "TAG_DATA": [ + "50, cultured {'context': 'B-cells'}", + "51, endothelial {'context': 'I-cells'}", + "52, cells. {'context': 'I-cells'}", + "78, Chinese {'context': 'B-cells'}", + "79, hamster {'context': 'I-cells'}", + "80, ovary {'context': 'I-cells'}", + "81, cells {'context': 'I-cells'}", + "140, aortae {'context': 'B-tissue/organ'}", + "143, mice, {'context': 'B-organism'}", + "147, aortae {'context': 'B-tissue/organ'}", + "149, homozygous {'perturbing_action': 'B-gene loss-of-function'}", + "150, null {'perturbing_action': 'I-gene loss-of-function'}", + "151, SR-BI {'perturbing_action': 'I-gene loss-of-function'}", + "152, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "153, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, cultured ['l0', 'l1']", + "51, endothelial ['l0', 'l2', 'l3']", + "52, cells. ['l1', 'l2', 'l4']", + "78, Chinese ['l5', 'l6', 'l7']", + "79, hamster ['l5', 'l8', 'l9']", + "80, ovary ['l6', 'l8', 'l10']", + "81, cells ['l3', 'l4', 'l7', 'l9', 'l10']", + "140, aortae ['l11']", + "143, mice, ['l11']", + "147, aortae ['l12', 'l13', 'l14', 'l15', 'l16']", + "149, homozygous ['l12', 'l17', 'l18', 'l19', 'l20']", + "150, null ['l13', 'l17', 'l21', 'l22', 'l23']", + "151, SR-BI ['l14', 'l18', 'l21', 'l24', 'l25']", + "152, knockout ['l15', 'l19', 'l22', 'l24', 'l26']", + "153, mice. ['l16', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "aortae" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "homozygous", + "null", + "SR-BI", + "knockout" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "homozygous", + "null", + "SR-BI", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "11433349", + "TEXT": "We provide anatomic and functional evidence that nicotine induces angiogenesis. We also show that nicotine accelerates the growth of tumor and atheroma in association with increased neovascularization. Nicotine increased endothelial-cell growth and tube formation in vitro, and accelerated fibrovascular growth in vivo. In a mouse model of hind-limb ischemia, nicotine increased capillary and collateral growth, and enhanced tissue perfusion. In mouse models of lung cancer and atherosclerosis, we found that nicotine enhanced lesion growth in association with an increase in lesion vascularity. These effects of nicotine were mediated through nicotinic acetylcholine receptors at nicotine concentrations that are pathophysiologically relevant. The endothelial production of nitric oxide, prostacyclin and vascular endothelial growth factor might have a role in these effects.", + "TAG_DATA": [ + "28, increased {'effect': 'B-positive'}", + "30, growth {'phenotype': 'I-cell growth'}", + "32, tube {'phenotype': 'B-tumourigenesis'}", + "33, formation {'phenotype': 'I-tumourigenesis'}", + "34, in {'context': 'B-in vitro'}", + "35, vitro, {'context': 'I-in vitro'}", + "40, in {'context': 'B-in vivo'}", + "41, vivo. {'context': 'I-in vivo'}", + "44, mouse {'context': 'B-organism'}", + "45, model {'context': 'I-organism'}", + "60, mouse {'context': 'B-neoplasm'}", + "61, models {'context': 'I-neoplasm'}", + "62, of {'context': 'I-neoplasm'}", + "63, lung {'context': 'I-neoplasm'}", + "64, cancer {'context': 'I-neoplasm'}", + "71, enhanced {'effect': 'B-positive'}", + "72, lesion {'context': 'B-neoplasm', 'phenotype': 'B-tumour growth'}", + "73, growth {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "19, tumor ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "28, increased ['l0', 'l8', 'l9', 'l10', 'l11', 'l12']", + "30, growth ['l1', 'l8', 'l13', 'l14', 'l15', 'l16']", + "32, tube ['l2', 'l9', 'l13', 'l17', 'l18', 'l19']", + "33, formation ['l3', 'l10', 'l14', 'l17', 'l20', 'l21']", + "34, in ['l4', 'l11', 'l15', 'l18', 'l20', 'l22']", + "35, vitro, ['l5', 'l12', 'l16', 'l19', 'l21', 'l22']", + "40, in ['l6', 'l23']", + "41, vivo. ['l7', 'l23']", + "44, mouse ['l24']", + "45, model ['l24']", + "60, mouse ['l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "61, models ['l25', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "62, of ['l26', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "63, lung ['l27', 'l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "64, cancer ['l28', 'l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "71, enhanced ['l29', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "72, lesion ['l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "73, growth ['l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l52']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tube", + "formation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tube", + "formation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "models", + "of", + "lung", + "cancer", + "lesion" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "models", + "of", + "lung", + "cancer", + "lesion" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "lesion", + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "lesion", + "growth" + ] + } + } + ] + }, + { + "PMID": "11329062", + "TEXT": "Carbon monoxide (CO) can arrest cellular respiration, but paradoxically, it is synthesized endogenously by heme oxygenase type 1 (Ho-1) in response to ischemic stress. Ho-1-deficient (Hmox1-/-) mice exhibited lethal ischemic lung injury, but were rescued from death by inhaled CO. CO drove ischemic protection by activating soluble guanylate cyclase and thereby suppressed hypoxic induction of the gene encoding plasminogen activator inhibitor-1 (PAI-1) in mononuclear phagocytes, which reduced accrual of microvascular fibrin. CO-mediated ischemic protection observed in wild-type mice was lost in mice null for the gene encoding PAI-1 (Serpine1). These data establish a fundamental link between CO and prevention of ischemic injury based on the ability of CO to derepress the fibrinolytic axis. These data also point to a potential therapeutic use for inhaled CO.", + "TAG_DATA": [ + "24, Ho-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "25, (Hmox1-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "26, mice {'context': 'B-organism'}", + "63, mononuclear {'context': 'B-cells'}", + "64, phagocytes, {'context': 'I-cells'}", + "77, mice {'context': 'B-organism'}", + "81, mice {'context': 'B-organism'}", + "82, null {'perturbing_action': 'B-gene loss-of-function'}", + "83, for {'perturbing_action': 'I-gene loss-of-function'}", + "84, the {'perturbing_action': 'I-gene loss-of-function'}", + "85, gene {'perturbing_action': 'I-gene loss-of-function'}", + "86, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "87, PAI-1 {'perturbing_action': 'I-gene loss-of-function'}", + "88, (Serpine1). {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "24, Ho-1-deficient ['l0', 'l1', 'l2', 'l3']", + "25, (Hmox1-/-) ['l0', 'l4', 'l5', 'l6']", + "26, mice ['l1', 'l4']", + "63, mononuclear ['l2', 'l5', 'l7']", + "64, phagocytes, ['l3', 'l6', 'l7']", + "81, mice ['l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "82, null ['l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "83, for ['l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "84, the ['l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "85, gene ['l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "86, encoding ['l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "87, PAI-1 ['l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "88, (Serpine1). ['l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ho-1-deficient", + "(Hmox1-/-)", + "null", + "for", + "the", + "gene", + "encoding", + "PAI-1", + "(Serpine1)." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ho-1-deficient", + "(Hmox1-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "mononuclear", + "phagocytes," + ] + } + } + ] + }, + { + "PMID": "11329059", + "TEXT": "Vascular endothelial growth factor (VEGF) stimulates angiogenesis by activating VEGF receptor-2 (VEGFR-2). The role of its homolog, placental growth factor (PlGF), remains unknown. Both VEGF and PlGF bind to VEGF receptor-1 (VEGFR-1), but it is unknown whether VEGFR-1, which exists as a soluble or a membrane-bound type, is an inert decoy or a signaling receptor for PlGF during angiogenesis. Here, we report that embryonic angiogenesis in mice was not affected by deficiency of PlGF (Pgf-/-). VEGF-B, another ligand of VEGFR-1, did not rescue development in Pgf-/- mice. However, loss of PlGF impaired angiogenesis, plasma extravasation and collateral growth during ischemia, inflammation, wound healing and cancer. Transplantation of wild-type bone marrow rescued the impaired angiogenesis and collateral growth in Pgf-/- mice, indicating that PlGF might have contributed to vessel growth in the adult by mobilizing bone-marrow-derived cells. The synergism between PlGF and VEGF was specific, as PlGF deficiency impaired the response to VEGF, but not to bFGF or histamine. VEGFR-1 was activated by PlGF, given that anti-VEGFR-1 antibodies and a Src-kinase inhibitor blocked the endothelial response to PlGF or VEGF/PlGF. By upregulating PlGF and the signaling subtype of VEGFR-1, endothelial cells amplify their responsiveness to VEGF during the 'angiogenic switch' in many pathological disorders.", + "TAG_DATA": [ + "66, mice {'context': 'B-organism'}", + "71, deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "72, of {'perturbing_action': 'I-gene loss-of-function'}", + "73, PlGF {'perturbing_action': 'I-gene loss-of-function'}", + "74, (Pgf-/-). {'perturbing_action': 'I-gene loss-of-function'}", + "85, Pgf-/- {'perturbing_action': 'B-gene loss-of-function'}", + "86, mice. {'context': 'B-organism'}", + "88, loss {'perturbing_action': 'B-gene loss-of-function'}", + "89, of {'perturbing_action': 'I-gene loss-of-function'}", + "90, PlGF {'perturbing_action': 'I-gene loss-of-function'}", + "105, Transplantation {'perturbing_action': 'B-gene gain-of-function'}", + "106, of {'perturbing_action': 'I-gene gain-of-function'}", + "107, wild-type {'perturbing_action': 'I-gene gain-of-function'}", + "108, bone {'perturbing_action': 'I-gene loss-of-function'}", + "109, marrow {'perturbing_action': 'I-gene gain-of-function'}", + "118, Pgf-/- {'perturbing_action': 'B-gene loss-of-function'}", + "119, mice, {'context': 'B-organism'}", + "134, bone-marrow-derived {'context': 'B-cells'}", + "135, cells. {'context': 'I-cells'}", + "145, PlGF {'perturbing_action': 'B-gene loss-of-function'}", + "146, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "169, Src-kinase {'perturbing_action': 'B-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "66, mice ['l0', 'l1', 'l2', 'l3']", + "71, deficiency ['l0', 'l4', 'l5', 'l6']", + "72, of ['l1', 'l4', 'l7', 'l8']", + "73, PlGF ['l2', 'l5', 'l7', 'l9']", + "74, (Pgf-/-). ['l3', 'l6', 'l8', 'l9']", + "85, Pgf-/- ['l10']", + "86, mice. ['l10']", + "88, loss ['l11', 'l12', 'l13']", + "89, of ['l11', 'l14', 'l15', 'l16']", + "90, PlGF ['l12', 'l14', 'l17', 'l18']", + "105, Transplantation ['l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "106, of ['l19', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "107, wild-type ['l20', 'l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "108, bone ['l21', 'l29', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "109, marrow ['l22', 'l30', 'l36', 'l41', 'l46', 'l47', 'l48', 'l49']", + "118, Pgf-/- ['l23', 'l31', 'l37', 'l42', 'l46', 'l50', 'l51', 'l52']", + "119, mice, ['l24', 'l32', 'l38', 'l43', 'l47', 'l50', 'l53', 'l54']", + "134, bone-marrow-derived ['l15', 'l17', 'l25', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l55']", + "135, cells. ['l13', 'l16', 'l18', 'l26', 'l34', 'l40', 'l45', 'l49', 'l52', 'l54', 'l55']", + "145, PlGF ['l56', 'l57', 'l58']", + "146, deficiency ['l27', 'l56']", + "169, Src-kinase ['l57', 'l59']", + "170, inhibitor ['l58', 'l59']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "of", + "PlGF", + "(Pgf-/-).", + "Pgf-/-", + "bone" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "PlGF", + "bone", + "Pgf-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells.", + "bone-marrow-derived" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transplantation", + "of", + "wild-type", + "marrow" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transplantation", + "of", + "wild-type", + "marrow" + ] + }, + "context": { + "val": "cells", + "words": [ + "bone-marrow-derived", + "cells." + ] + } + } + ] + }, + { + "PMID": "11329056", + "TEXT": "Successful transplantation of allogeneic organs is an important objective in modern medicine. However, sophisticated immune defense mechanisms, primarily evolved to combat infections, often work against medical transplantation. To investigate the roles of natural and adaptive immune responses in transplant rejection, we functionally inactivated key effector systems of the innate (NK cells) and the adaptive immune system (CD28-mediated costimulation of T cells) in mice. Neither of these interventions alone led to acceptance of allogeneic vascularized cardiac grafts. In contrast, inhibition of NK-receptor-bearing cells combined with CD28-costimulation blockade established long-term graft acceptance. These results indicate a concerted interplay between innate and adaptive immune surveillance for graft rejection. Thus we suggest that inactivation of NK-receptor-bearing cells could be a new strategy for successful survival of solid-organ transplants.", + "TAG_DATA": [ + "62, mice. {'context': 'B-organism'}", + "72, allogeneic {'context': 'B-xenograft'}", + "73, vascularized {'context': 'I-xenograft'}", + "74, cardiac {'context': 'I-xenograft'}", + "75, grafts. {'context': 'I-xenograft'}", + "78, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "80, NK-receptor-bearing {'context': 'B-cells'}", + "81, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "62, mice. ['l0', 'l1']", + "72, allogeneic ['l2', 'l3', 'l4']", + "73, vascularized ['l2', 'l5', 'l6']", + "74, cardiac ['l0', 'l3', 'l5', 'l7']", + "75, grafts. ['l1', 'l4', 'l6', 'l7']", + "78, inhibition ['l8', 'l9']", + "80, NK-receptor-bearing ['l8', 'l10']", + "81, cells ['l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "NK-receptor-bearing", + "cells" + ] + } + } + ] + }, + { + "PMID": "11283670", + "TEXT": "Low oxygen tension influences tumor progression by enhancing angiogenesis; and histone deacetylases (HDAC) are implicated in alteration of chromatin assembly and tumorigenesis. Here we show induction of HDAC under hypoxia and elucidate a role for HDAC in the regulation of hypoxia-induced angiogenesis. Overexpressed wild-type HDAC1 downregulated expression of p53 and von Hippel-Lindau tumor suppressor genes and stimulated angiogenesis of human endothelial cells. A specific HDAC inhibitor, trichostatin A (TSA), upregulated p53 and von Hippel-Lindau expression and downregulated hypoxia-inducible factor-1alpha and vascular endothelial growth factor. TSA also blocked angiogenesis in vitro and in vivo. TSA specifically inhibited hypoxia-induced angiogenesis in the Lewis lung carcinoma model. These results indicate that hypoxia enhances HDAC function and that HDAC is closely involved in angiogenesis through suppression of hypoxia-responsive tumor suppressor genes.", + "TAG_DATA": [ + "42, Overexpressed {'perturbing_action': 'B-gene gain-of-function'}", + "43, wild-type {'perturbing_action': 'I-gene gain-of-function'}", + "44, HDAC1 {'perturbing_action': 'I-gene gain-of-function'}", + "59, human {'context': 'B-cells'}", + "60, endothelial {'context': 'I-cells'}", + "61, cells. {'context': 'I-cells'}", + "63, specific {'perturbing_action': 'B-pharmacological inhibition'}", + "64, HDAC {'perturbing_action': 'I-pharmacological inhibition'}", + "65, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "66, trichostatin {'perturbing_action': 'I-pharmacological inhibition'}", + "67, A {'perturbing_action': 'I-pharmacological inhibition'}", + "68, (TSA), {'perturbing_action': 'I-pharmacological inhibition'}", + "88, in {'context': 'B-in vitro'}", + "89, vitro {'context': 'I-in vitro'}", + "91, in {'context': 'B-in vivo'}", + "92, vivo. {'context': 'I-in vivo'}", + "100, Lewis {'context': 'B-neoplasm'}", + "101, lung {'context': 'I-neoplasm'}", + "102, carcinoma {'context': 'I-neoplasm'}", + "103, model. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "42, Overexpressed ['l0', 'l1', 'l2', 'l3', 'l4']", + "43, wild-type ['l0', 'l5', 'l6', 'l7', 'l8']", + "44, HDAC1 ['l1', 'l5', 'l9', 'l10', 'l11']", + "59, human ['l2', 'l6', 'l9', 'l12', 'l13']", + "60, endothelial ['l3', 'l7', 'l10', 'l12', 'l14']", + "61, cells. ['l4', 'l8', 'l11', 'l13', 'l14']", + "63, specific ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "64, HDAC ['l15', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "65, inhibitor, ['l16', 'l24', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "66, trichostatin ['l17', 'l25', 'l32', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "67, A ['l18', 'l26', 'l33', 'l39', 'l45', 'l46', 'l47', 'l48', 'l49']", + "68, (TSA), ['l19', 'l27', 'l34', 'l40', 'l45', 'l50', 'l51', 'l52', 'l53']", + "88, in ['l20', 'l28', 'l35', 'l41', 'l46', 'l50', 'l54', 'l55']", + "89, vitro ['l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l54', 'l56']", + "91, in ['l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l57']", + "92, vivo. ['l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l55', 'l56', 'l57']", + "100, Lewis ['l58', 'l59', 'l60']", + "101, lung ['l58', 'l61', 'l62']", + "102, carcinoma ['l59', 'l61', 'l63']", + "103, model. ['l60', 'l62', 'l63']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpressed", + "wild-type", + "HDAC1" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "endothelial", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "HDAC", + "inhibitor,", + "trichostatin", + "A", + "(TSA)," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "HDAC", + "inhibitor,", + "trichostatin", + "A", + "(TSA)," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "11231635", + "TEXT": "Epstein-Barr virus (EBV) is an oncogenic virus associated with a number of human malignancies including Burkitt lymphoma, nasopharyngeal carcinoma, lymphoproliferative disease and, though still debated, breast carcinoma. A subset of latent EBV antigens is required for mediating immortalization of primary B-lymphocytes. Here we demonstrate that the carboxy-terminal region of the essential latent antigen, EBNA-3C, interacts specifically with the human metastatic suppressor protein Nm23-H1. Moreover, EBNA-3C reverses the ability of Nm23-H1 to suppress the migration of Burkitt lymphoma cells and breast carcinoma cells. We propose that EBNA-3C contributes to EBV-associated human cancers by targeting and altering the role of the metastasis suppressor Nm23-H1.", + "TAG_DATA": [ + "71, suppress {'effect': 'B-negative'}", + "73, migration {'phenotype': 'B-migration'}", + "75, Burkitt {'context': 'B-transformed cells'}", + "76, lymphoma {'context': 'I-transformed cells'}", + "77, cells {'context': 'I-transformed cells'}", + "79, breast {'context': 'B-transformed cells'}", + "80, carcinoma {'context': 'I-transformed cells'}", + "81, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "71, suppress ['l0', 'l1', 'l2', 'l3']", + "73, migration ['l0', 'l4', 'l5', 'l6']", + "75, Burkitt ['l1', 'l4', 'l7', 'l8']", + "76, lymphoma ['l2', 'l5', 'l7', 'l9']", + "77, cells ['l3', 'l6', 'l8', 'l9']", + "79, breast ['l10', 'l11']", + "80, carcinoma ['l10', 'l12']", + "81, cells. ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "suppress" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppress" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "Burkitt", + "lymphoma", + "cells" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "Burkitt", + "lymphoma", + "cells" + ] + } + } + ] + }, + { + "PMID": "11175857", + "TEXT": "Clinical applications of tumor gene therapy require tumor-specific delivery or expression of therapeutic genes in order to maximize the oncolytic index and minimize side effects. This study demonstrates activation of transgene expression exclusively in hepatic metastases after systemic application of a modified first-generation (E1A/E1B-deleted) adenovirus vector (AdE1-) in mouse tumor models. The discrimination between tumors and normal liver tissue is based on selective DNA replication of AdE1- vectors in tumor cells. This new AdE1- based vector system uses homologous recombination between inverted repeats to mediate precise rearrangements within the viral genome. As a result of these rearrangements, a promoter is brought into conjunction with a reporter gene creating a functional expression cassette. Genomic rearrangements are dependent upon viral DNA replication, which in turn occurs specifically in tumor cells. In a mouse tumor model with liver metastases derived from human tumor cells, a single systemic administration of replication activated AdE1- vectors achieved transgene expression in every metastasis, whereas no extra-tumoral transgene induction was observed. Here we provide a new concept for tumor-specific gene expression that is also applicable for other conditionally replicating adenovirus vectors.", + "TAG_DATA": [ + "130, mouse {'context': 'B-neoplasm'}", + "131, tumor {'context': 'I-neoplasm'}", + "132, model {'context': 'I-neoplasm'}", + "134, liver {'phenotype': 'B-metastasis'}", + "135, metastases {'phenotype': 'I-metastasis'}", + "137, from {'context': 'I-transformed cells'}", + "138, human {'context': 'I-transformed cells'}", + "139, tumor {'context': 'I-transformed cells'}", + "140, cells, {'context': 'I-transformed cells'}", + "155, metastasis, {'context': 'B-neoplasm', 'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "130, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "131, tumor ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "132, model ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "134, liver ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "135, metastases ['l3', 'l11', 'l18', 'l24', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "136, derived ['l4', 'l12', 'l19', 'l25', 'l31', 'l37', 'l38', 'l39', 'l40', 'l41']", + "137, from ['l5', 'l13', 'l20', 'l26', 'l32', 'l37', 'l42', 'l43', 'l44', 'l45']", + "138, human ['l6', 'l14', 'l21', 'l27', 'l33', 'l38', 'l42', 'l46', 'l47', 'l48']", + "139, tumor ['l7', 'l15', 'l22', 'l28', 'l34', 'l39', 'l43', 'l46', 'l49', 'l50']", + "140, cells, ['l8', 'l16', 'l23', 'l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l51']", + "155, metastasis, ['l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l51']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "tumor", + "model", + "metastasis," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "liver", + "metastases", + "metastasis," + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "liver", + "metastases", + "metastasis," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "from", + "human", + "tumor", + "cells," + ] + } + } + ] + }, + { + "PMID": "11175856", + "TEXT": "Although the process of mammary tumorigenesis requires multiple genetic events, it is unclear to what extent carcinogenesis proceeds through preferred secondary pathways following a specific initiating oncogenic event. Similarly, the extent to which established mammary tumors remain dependent on individual mutations for maintenance of the transformed state is unknown. Here we use the tetracycline regulatory system to conditionally express the human c-MYC oncogene in the mammary epithelium of transgenic mice. MYC encodes a transcription factor implicated in multiple human cancers. In particular, amplification and overexpression of c-MYC in human breast cancers is associated with poor prognosis, although the genetic mechanisms by which c-MYC promotes tumor progression are poorly understood. We show that deregulated c-MYC expression in this inducible system results in the formation of invasive mammary adenocarcinomas, many of which fully regress following c-MYC deinduction. Approximately half of these tumors harbor spontaneous activating point mutations in the ras family of proto-oncogenes with a strong preference for Kras2 compared with Hras1. Nearly all tumors lacking activating ras mutations fully regressed following c-MYC deinduction, whereas tumors bearing ras mutations did not, suggesting that secondary mutations in ras contribute to tumor progression. These findings demonstrate that c-MYC-induced mammary tumorigenesis proceeds through a preferred secondary oncogenic pathway involving Kras2.", + "TAG_DATA": [ + "66, epithelium {'context': 'I-tissue/organ'}", + "68, transgenic {'context': 'B-organism'}", + "69, mice. {'context': 'I-organism'}", + "119, results {'effect': 'B-positive'}", + "125, mammary {'phenotype': 'B-tumourigenesis'}", + "126, adenocarcinomas, {'phenotype': 'I-tumourigenesis'}", + "139, tumors {'context': 'B-neoplasm'}", + "162, tumors {'context': 'B-neoplasm'}", + "173, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "65, mammary ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "66, epithelium ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "68, transgenic ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "69, mice. ['l2', 'l7', 'l11', 'l15', 'l16']", + "119, results ['l3', 'l8', 'l12', 'l15', 'l17', 'l18', 'l19']", + "125, mammary ['l4', 'l9', 'l13', 'l17', 'l20', 'l21']", + "126, adenocarcinomas, ['l5', 'l10', 'l14', 'l16', 'l18', 'l20', 'l22']", + "139, tumors ['l19', 'l21', 'l22']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "epithelium" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "epithelium" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "mammary", + "adenocarcinomas," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice." + ] + }, + "effect": { + "val": "positive", + "words": [ + "results" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "mammary", + "adenocarcinomas," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "mammary", + "adenocarcinomas," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "mammary", + "adenocarcinomas," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + } + ] + }, + { + "PMID": "11175851", + "TEXT": "The lymphatic vasculature transports extravasated tissue fluid, macromolecules and cells back into the blood circulation. Recent reports have focused on the molecular mechanisms regulating the lymphatic vessels. Vascular endothelial growth factor (VEGF)-C and VEGF-D have been shown to stimulate lymphangiogenesis and their receptor, VEGFR-3, has been linked to human hereditary lymphedema. Here we show that a soluble form of VEGFR-3 is a potent inhibitor of VEGF-C/VEGF-D signaling, and when expressed in the skin of transgenic mice, it inhibits fetal lymphangiogenesis and induces a regression of already formed lymphatic vessels, though the blood vasculature remains normal. Transgenic mice develop a lymphedema-like phenotype characterized by swelling of feet, edema and dermal fibrosis. They survive the neonatal period in spite of a virtually complete lack of lymphatic vessels in several tissues, and later show regeneration of the lymphatic vasculature, indicating that induction of lymphatic regeneration may also be possible in humans.", + "TAG_DATA": [ + "75, mice, {'context': 'I-organism'}", + "81, induces {'effect': 'B-positive'}", + "83, regression {'phenotype': 'B-tumour regression'}", + "96, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "72, skin ['l0', 'l1', 'l2', 'l3', 'l4']", + "75, mice, ['l0', 'l5', 'l6', 'l7', 'l8']", + "81, induces ['l1', 'l5', 'l9', 'l10', 'l11']", + "83, regression ['l2', 'l6', 'l9', 'l12', 'l13']", + "87, lymphatic ['l3', 'l7', 'l10', 'l12', 'l14']", + "88, vessels, ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + } + ] + }, + { + "PMID": "11135626", + "TEXT": "Relaxation of the smooth muscle cells in the cavernosal arterioles and sinuses results in increased blood flow into the penis, raising corpus cavernosum pressure to culminate in penile erection. Nitric oxide, released from non-adrenergic/non-cholinergic nerves, is considered the principle stimulator of cavernosal smooth muscle relaxation, however, the inhibition of vasoconstrictors (that is, norepinephrine and endothelin-1, refs. 5-9) cannot be ignored as a potential regulator of penile erection. The calcium-sensitizing rho-A/Rho-kinase pathway may play a synergistic role in cavernosal vasoconstriction to maintain penile flaccidity. Rho-kinase is known to inhibit myosin light chain phosphatase, and to directly phosphorylate myosin light-chain (in solution), altogether resulting in a net increase in activated myosin and the promotion of cellular contraction. Although Rho-kinase protein and mRNA have been detected in cavernosal tissue, the role of Rho-kinase in the regulation of cavernosal tone is unknown. Using pharmacologic antagonism (Y-27632, ref. 13, 18), we examined the role of Rho-kinase in cavernosal tone, based on the hypothesis that antagonism of Rho-kinase results in increased corpus cavernosum pressure, initiating the erectile response independently of nitric oxide. Our finding, that Rho-kinase antagonism stimulates rat penile erection independently of nitric oxide, introduces a potential alternate avenue for the treatment of erectile dysfunction.", + "TAG_DATA": [ + "159, antagonism {'perturbing_action': 'B-pharmacological inhibition'}", + "160, of {'perturbing_action': 'I-pharmacological inhibition'}", + "161, Rho-kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "179, Rho-kinase {'perturbing_action': 'B-pharmacological inhibition'}", + "180, antagonism {'perturbing_action': 'I-pharmacological inhibition'}", + "182, rat {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "159, antagonism ['l0', 'l1']", + "160, of ['l0', 'l2']", + "161, Rho-kinase ['l1', 'l2']", + "179, Rho-kinase ['l3', 'l4']", + "180, antagonism ['l3', 'l5']", + "182, rat ['l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Rho-kinase", + "antagonism" + ] + }, + "context": { + "val": "organism", + "words": [ + "rat" + ] + } + } + ] + }, + { + "PMID": "11135623", + "TEXT": "The transcription factor early growth response protein 1 (EGR1) is overexpressed in a majority of human prostate cancers and is implicated in the regulation of several genes important for prostate tumor progression. Here we have assessed the effect of Egr1 deficiency on tumor development in two transgenic mouse models of prostate cancer (CR2-T-Ag and TRAMP). Using a combination of high-resolution magnetic resonance imaging and histopathological and survival analyses, we show that tumor progression was significantly impaired in Egr1-/- mice. Tumor initiation and tumor growth rate were not affected by the lack of Egr1; however, Egr1 deficiency significantly delayed the progression from prostatic intra-epithelial neoplasia to invasive carcinoma. These results indicate a unique role for Egr1 in regulating the transition from localized, carcinoma in situ to invasive carcinoma.", + "TAG_DATA": [ + "39, Egr1 {'perturbing_action': 'B-gene loss-of-function'}", + "40, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "43, development {'phenotype': 'I-tumourigenesis'}", + "47, mouse {'context': 'I-organism'}", + "48, models {'context': 'I-neoplasm'}", + "49, of {'context': 'I-neoplasm'}", + "50, prostate {'context': 'I-neoplasm'}", + "51, cancer {'context': 'I-neoplasm'}", + "71, tumor {'phenotype': 'B-tumour progression'}", + "72, progression {'phenotype': 'I-tumour progression'}", + "75, impaired {'effect': 'B-negative'}", + "77, Egr1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "78, mice. {'context': 'B-organism'}", + "79, Tumor {'phenotype': 'B-tumour initiation'}", + "80, initiation {'phenotype': 'I-tumour initiation'}", + "82, tumor {'phenotype': 'B-tumour growth'}", + "83, growth {'phenotype': 'I-tumour growth'}", + "86, not {'effect': 'B-no effect'}", + "87, affected {'effect': 'I-no effect'}", + "90, lack {'perturbing_action': 'B-gene loss-of-function'}", + "91, of {'perturbing_action': 'I-gene loss-of-function'}", + "92, Egr1; {'perturbing_action': 'I-gene loss-of-function'}", + "94, Egr1 {'perturbing_action': 'B-gene loss-of-function'}", + "95, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "97, delayed {'effect': 'B-negative'}", + "102, intra-epithelial {'phenotype': 'I-epithelial-mesenchymal transition'}", + "103, neoplasia {'phenotype': 'I-epithelial-mesenchymal transition'}", + "105, invasive {'phenotype': 'B-tumourigenesis'}", + "106, carcinoma. {'phenotype': 'I-tumourigenesis'}" + ], + "LINK_DATA": [ + "39, Egr1 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "40, deficiency ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "43, development ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "47, mouse ['l2', 'l12', 'l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "48, models ['l3', 'l13', 'l22', 'l29', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "49, of ['l4', 'l14', 'l23', 'l30', 'l37', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "50, prostate ['l5', 'l15', 'l24', 'l31', 'l38', 'l44', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "51, cancer ['l6', 'l16', 'l25', 'l32', 'l39', 'l45', 'l50', 'l56', 'l57', 'l58', 'l59']", + "71, tumor ['l7', 'l17', 'l26', 'l33', 'l40', 'l46', 'l51', 'l56', 'l60', 'l61', 'l62']", + "72, progression ['l8', 'l18', 'l27', 'l34', 'l41', 'l47', 'l52', 'l57', 'l60', 'l63', 'l64']", + "75, impaired ['l9', 'l19', 'l28', 'l35', 'l42', 'l48', 'l53', 'l58', 'l61', 'l63', 'l65']", + "77, Egr1-/- ['l10', 'l20', 'l36', 'l43', 'l49', 'l54', 'l59', 'l62', 'l64', 'l65', 'l66']", + "78, mice. ['l55', 'l66']", + "79, Tumor ['l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "80, initiation ['l67', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "82, tumor ['l68', 'l78', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "83, growth ['l69', 'l79', 'l88', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "86, not ['l70', 'l80', 'l89', 'l97', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "87, affected ['l71', 'l81', 'l90', 'l98', 'l105', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "90, lack ['l72', 'l82', 'l91', 'l99', 'l106', 'l114', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "91, of ['l73', 'l83', 'l92', 'l100', 'l107', 'l115', 'l122', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "92, Egr1; ['l74', 'l84', 'l93', 'l101', 'l108', 'l116', 'l123', 'l129', 'l135', 'l136', 'l137']", + "94, Egr1 ['l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "95, deficiency ['l138', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150']", + "97, delayed ['l139', 'l145', 'l151', 'l152', 'l153', 'l154', 'l155']", + "101, prostatic ['l75', 'l85', 'l94', 'l102', 'l109', 'l117', 'l124', 'l130', 'l135', 'l140', 'l146', 'l151', 'l156', 'l157', 'l158', 'l159']", + "102, intra-epithelial ['l76', 'l86', 'l95', 'l103', 'l110', 'l118', 'l125', 'l131', 'l136', 'l141', 'l147', 'l152', 'l156', 'l160', 'l161', 'l162']", + "103, neoplasia ['l77', 'l87', 'l96', 'l104', 'l111', 'l119', 'l126', 'l132', 'l137', 'l142', 'l148', 'l153', 'l157', 'l160', 'l163', 'l164']", + "105, invasive ['l112', 'l120', 'l127', 'l133', 'l143', 'l149', 'l154', 'l158', 'l161', 'l163', 'l165']", + "106, carcinoma. ['l113', 'l121', 'l128', 'l134', 'l144', 'l150', 'l155', 'l159', 'l162', 'l164', 'l165']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Egr1", + "deficiency", + "lack", + "of" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development", + "invasive", + "carcinoma." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Egr1", + "deficiency", + "Egr1-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Egr1", + "deficiency", + "Egr1-/-" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models", + "of", + "prostate", + "cancer" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Egr1", + "deficiency", + "Egr1-/-" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Egr1", + "deficiency", + "Egr1-/-" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired", + "delayed" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models", + "of", + "prostate", + "cancer" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development", + "invasive", + "carcinoma." + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired", + "delayed" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "models", + "of", + "prostate", + "cancer" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "models", + "of", + "prostate", + "cancer" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "phenotype": { + "val": "tumour initiation", + "words": [ + "Tumor", + "initiation" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "affected" + ] + } + }, + { + "phenotype": { + "val": "tumour initiation", + "words": [ + "Tumor", + "initiation" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "Egr1;" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "affected" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "Egr1;" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "affected" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "Egr1;" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "affected" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "intra-epithelial", + "neoplasia" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "affected" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "invasive", + "carcinoma." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "Egr1;", + "Egr1", + "deficiency" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "intra-epithelial", + "neoplasia" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "delayed" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "intra-epithelial", + "neoplasia" + ] + } + } + ] + }, + { + "PMID": "11135616", + "TEXT": "Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate lipid and glucose metabolism and cellular differentiation. PPAR-alpha and PPAR-gamma are both expressed in human macrophages where they exert anti-inflammatory effects. The activation of PPAR-alpha may promote foam-cell formation by inducing expression of the macrophage scavenger receptor CD36. This prompted us to investigate the influence of different PPAR-activators on cholesterol metabolism and foam-cell formation of human primary and THP-1 macrophages. Here we show that PPAR-alpha and PPAR-gamma activators do not influence acetylated low density lipoprotein-induced foam-cell formation of human macrophages. In contrast, PPAR-alpha and PPAR-gamma activators induce the expression of the gene encoding ABCA1, a transporter that controls apoAI-mediated cholesterol efflux from macrophages. These effects are likely due to enhanced expression of liver-x-receptor alpha, an oxysterol-activated nuclear receptor which induces ABCA1-promoter transcription. Moreover, PPAR-alpha and PPAR-gamma activators increase apoAI-induced cholesterol efflux from normal macrophages. In contrast, PPAR-alpha or PPAR-gamma activation does not influence cholesterol efflux from macrophages isolated from patients with Tangier disease, which is due to a genetic defect in ABCA1. Here we identify a regulatory role for PPAR-alpha and PPAR-gamma in the first steps of the reverse-cholesterol-transport pathway through the activation of ABCA1-mediated cholesterol efflux in human macrophages.", + "TAG_DATA": [ + "73, PPAR-alpha {'perturbing_action': 'B-gene gain-of-function'}", + "74, and {'perturbing_action': 'I-pharmacological augmentation'}", + "75, PPAR-gamma {'perturbing_action': 'I-pharmacological augmentation'}", + "76, activators {'perturbing_action': 'I-pharmacological augmentation'}", + "78, not {'effect': 'I-no effect'}", + "79, influence {'effect': 'I-no effect'}", + "84, foam-cell {'phenotype': 'B-tumourigenesis'}", + "87, human {'context': 'B-cells'}", + "88, macrophages. {'context': 'I-cells'}", + "94, activators {'perturbing_action': 'I-pharmacological augmentation'}", + "135, activators {'perturbing_action': 'I-pharmacological augmentation'}", + "142, macrophages. {'context': 'B-cells'}", + "146, or {'perturbing_action': 'I-pharmacological augmentation'}", + "147, PPAR-gamma {'perturbing_action': 'I-pharmacological augmentation'}", + "148, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "155, macrophages {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "73, PPAR-alpha ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "74, and ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "75, PPAR-gamma ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "76, activators ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "78, not ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "79, influence ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "84, foam-cell ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "87, human ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "88, macrophages. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "91, PPAR-alpha ['l36']", + "94, activators ['l36']", + "135, activators ['l37']", + "142, macrophages. ['l37']", + "146, or ['l38', 'l39', 'l40']", + "147, PPAR-gamma ['l38', 'l41', 'l42']", + "148, activation ['l39', 'l41', 'l43']", + "155, macrophages ['l40', 'l42', 'l43']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PPAR-alpha" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "influence" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PPAR-alpha" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "foam-cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PPAR-alpha" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "macrophages." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "and", + "PPAR-gamma", + "activators" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "influence" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "and", + "PPAR-gamma", + "activators" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "foam-cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "and", + "PPAR-gamma", + "activators", + "or", + "activation" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "macrophages.", + "macrophages" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "influence" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "foam-cell" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "influence" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "macrophages." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "foam-cell" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "macrophages." + ] + } + } + ] + }, + { + "PMID": "11100122", + "TEXT": "Ovulatory dysfunction is the commonest cause of female infertility. Here we show that the co-repressor nuclear-receptor-interacting protein 1 (Nrip1; encoded by the gene Nrip1) is essential for ovulation. Mice null for this protein are viable, but female mice are infertile because of complete failure of mature follicles to release the oocyte at ovulation. In contrast, luteinization proceeds normally, resulting in a phenotype closely resembling that of luteinized unruptured follicle syndrome, often associated with infertility in women. Therefore, whereas the pre-ovulatory surge of luteinizing hormone induces both ovulation and luteinization, the ability to suppress the action of nuclear receptors is essential for the coordinated control of ovarian function with the essential process of oocyte release dependent on the activity of the transcriptional co-repressor Nrip1 (RIP40).", + "TAG_DATA": [ + "28, Mice {'context': 'B-organism'}", + "29, null {'perturbing_action': 'B-gene loss-of-function'}", + "30, for {'perturbing_action': 'I-gene loss-of-function'}", + "36, female {'context': 'B-organism'}", + "37, mice {'context': 'I-organism'}", + "45, mature {'context': 'B-cells'}", + "46, follicles {'context': 'I-cells'}", + "84, induces {'effect': 'B-positive'}" + ], + "LINK_DATA": [ + "28, Mice ['l0', 'l1', 'l2', 'l3']", + "29, null ['l0', 'l4', 'l5', 'l6']", + "30, for ['l1', 'l4', 'l7', 'l8']", + "36, female ['l9', 'l10', 'l11']", + "37, mice ['l9', 'l12', 'l13']", + "45, mature ['l2', 'l5', 'l7', 'l10', 'l12', 'l14']", + "46, follicles ['l3', 'l6', 'l8', 'l11', 'l13', 'l14']", + "84, induces ['l15']", + "88, luteinization, ['l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "null", + "for" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "null", + "for" + ] + }, + "context": { + "val": "cells", + "words": [ + "mature", + "follicles" + ] + } + } + ] + }, + { + "PMID": "11017149", + "TEXT": "The breaking of immune tolerance against autologous angiogenic endothelial cells should be a useful approach for cancer therapy. Here we show that immunotherapy of tumors using fixed xenogeneic whole endothelial cells as a vaccine was effective in affording protection from tumor growth, inducing regression of established tumors and prolonging survival of tumor-bearing mice. Furthermore, autoreactive immunity targeting to microvessels in solid tumors was induced and was probably responsible for the anti-tumor activity. These observations may provide a new vaccine strategy for cancer therapy through the induction of an autoimmune response against the tumor endothelium in a cross-reaction.", + "TAG_DATA": [ + "38, protection {'effect': 'B-negative'}", + "40, tumor {'phenotype': 'B-tumour growth'}", + "41, growth, {'phenotype': 'I-tumour growth'}", + "42, inducing {'effect': 'B-positive'}", + "43, regression {'phenotype': 'B-tumour regression'}", + "44, of {'phenotype': 'I-tumour regression'}", + "45, established {'phenotype': 'I-tumour growth'}", + "46, tumors {'context': 'B-neoplasm'}", + "51, tumor-bearing {'context': 'B-organism'}", + "52, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "38, protection ['l0', 'l1']", + "40, tumor ['l0', 'l2']", + "41, growth, ['l1', 'l2']", + "42, inducing ['l3', 'l4', 'l5', 'l6']", + "43, regression ['l3', 'l7', 'l8', 'l9']", + "44, of ['l4', 'l7', 'l10', 'l11']", + "45, established ['l5', 'l8', 'l10', 'l12']", + "46, tumors ['l6', 'l9', 'l11', 'l12']", + "51, tumor-bearing ['l13']", + "52, mice. ['l13']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "protection" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression", + "of" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "established" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression", + "of" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "established" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + } + ] + }, + { + "PMID": "11017141", + "TEXT": "The time at which ovarian failure (menopause) occurs in females is determined by the size of the oocyte reserve provided at birth, as well as by the rate at which this endowment is depleted throughout post-natal life. Here we show that disruption of the gene for acid sphingomyelinase in female mice suppressed the normal apoptotic deletion of fetal oocytes, leading to neonatal ovarian hyperplasia. Ex vivo, oocytes lacking the gene for acid sphingomyelinase or wild-type oocytes treated with sphingosine-1-phosphate resisted developmental apoptosis and apoptosis induced by anti-cancer therapy, confirming cell autonomy of the death defect. Moreover, radiation-induced oocyte loss in adult wild-type female mice, the event that drives premature ovarian failure and infertility in female cancer patients, was completely prevented by in vivo therapy with sphingosine-1-phosphate. Thus, the sphingomyelin pathway regulates developmental death of oocytes, and sphingosine-1-phosphate provides a new approach to preserve ovarian function in vivo.", + "TAG_DATA": [ + "41, disruption {'perturbing_action': 'B-gene loss-of-function'}", + "42, of {'perturbing_action': 'I-gene loss-of-function'}", + "43, the {'perturbing_action': 'I-gene loss-of-function'}", + "44, gene {'perturbing_action': 'I-gene loss-of-function'}", + "45, for {'perturbing_action': 'I-gene loss-of-function'}", + "46, acid {'perturbing_action': 'I-gene loss-of-function'}", + "47, sphingomyelinase {'perturbing_action': 'I-gene loss-of-function'}", + "49, female {'context': 'B-organism'}", + "50, mice {'context': 'I-organism'}", + "51, suppressed {'effect': 'B-negative'}", + "55, deletion {'phenotype': 'I-apoptosis'}", + "57, fetal {'context': 'B-cells'}", + "58, oocytes, {'context': 'I-cells'}", + "66, oocytes {'context': 'B-cells'}", + "67, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "68, the {'perturbing_action': 'I-gene loss-of-function'}", + "69, gene {'perturbing_action': 'I-gene loss-of-function'}", + "70, for {'perturbing_action': 'I-gene loss-of-function'}", + "71, acid {'perturbing_action': 'I-gene loss-of-function'}", + "72, sphingomyelinase {'perturbing_action': 'I-gene loss-of-function'}", + "75, oocytes {'context': 'B-cells'}", + "79, resisted {'effect': 'B-negative'}", + "81, apoptosis {'phenotype': 'B-apoptosis'}", + "83, apoptosis {'phenotype': 'B-apoptosis'}", + "84, induced {'effect': 'B-positive'}", + "97, oocyte {'context': 'B-cells'}", + "100, adult {'context': 'B-organism'}", + "101, wild-type {'context': 'I-organism'}", + "102, female {'context': 'I-organism'}", + "103, mice, {'context': 'I-organism'}", + "121, in {'context': 'B-in vivo'}", + "122, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "41, disruption ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "42, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "43, the ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "44, gene ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "45, for ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "46, acid ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "47, sphingomyelinase ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "49, female ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "50, mice ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79']", + "51, suppressed ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l81', 'l82', 'l83']", + "54, apoptotic ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l80', 'l84', 'l85', 'l86']", + "55, deletion ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l77', 'l81', 'l84', 'l87', 'l88']", + "57, fetal ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l78', 'l82', 'l85', 'l87', 'l89']", + "58, oocytes, ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l79', 'l83', 'l86', 'l88', 'l89']", + "66, oocytes ['l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "67, lacking ['l90', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "68, the ['l91', 'l101', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "69, gene ['l92', 'l102', 'l111', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127']", + "70, for ['l93', 'l103', 'l112', 'l120', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "71, acid ['l94', 'l104', 'l113', 'l121', 'l128', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "72, sphingomyelinase ['l95', 'l105', 'l114', 'l122', 'l129', 'l135', 'l141', 'l142', 'l143', 'l144', 'l145']", + "75, oocytes ['l96', 'l106', 'l115', 'l123', 'l130', 'l136', 'l141', 'l146', 'l147', 'l148', 'l149']", + "79, resisted ['l97', 'l107', 'l116', 'l124', 'l131', 'l137', 'l142', 'l146', 'l150', 'l151', 'l152']", + "81, apoptosis ['l98', 'l108', 'l117', 'l125', 'l132', 'l138', 'l143', 'l147', 'l150', 'l153', 'l154']", + "83, apoptosis ['l99', 'l109', 'l118', 'l126', 'l133', 'l139', 'l144', 'l148', 'l151', 'l153', 'l155']", + "84, induced ['l100', 'l110', 'l119', 'l127', 'l134', 'l140', 'l145', 'l149', 'l152', 'l154', 'l155']", + "97, oocyte ['l156', 'l157', 'l158', 'l159']", + "100, adult ['l156', 'l160', 'l161', 'l162']", + "101, wild-type ['l157', 'l160', 'l163', 'l164']", + "102, female ['l158', 'l161', 'l163', 'l165']", + "103, mice, ['l159', 'l162', 'l164', 'l165']", + "121, in ['l166']", + "122, vivo ['l166']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "disruption", + "of", + "the", + "gene", + "for", + "acid", + "sphingomyelinase" + ] + }, + "context": { + "val": "organism", + "words": [ + "female", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "disruption", + "of", + "the", + "gene", + "for", + "acid", + "sphingomyelinase", + "lacking" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed", + "resisted" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "disruption", + "of", + "the", + "gene", + "for", + "acid", + "sphingomyelinase", + "lacking" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "deletion", + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "disruption", + "of", + "the", + "gene", + "for", + "acid", + "sphingomyelinase", + "lacking" + ] + }, + "context": { + "val": "cells", + "words": [ + "fetal", + "oocytes,", + "oocytes" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "female", + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "female", + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "deletion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed", + "resisted" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "deletion", + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed", + "resisted" + ] + }, + "context": { + "val": "cells", + "words": [ + "fetal", + "oocytes,", + "oocytes" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "deletion", + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "fetal", + "oocytes,", + "oocytes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "oocytes" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "gene", + "for", + "acid", + "sphingomyelinase" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "10973323", + "TEXT": "A combination of two drugs afforded remarkable protection from intestinal neoplasia in APC(Min/+) mice, a murine model of human familial adenomatous polyposis (FAP). One of the drugs was sulindac, a prototypical non-steroidal anti-inflammatory drug with established chemopreventative activity. The second drug was EKI-569, a newly developed, irreversible inhibitor of the epidermal growth factor receptor kinase. Although 100% of the untreated APC(Min/+) mice developed approximately 20 polyps, nearly half the mice treated with these two agents developed no polyps at all. These results suggest a powerful strategy for the chemoprevention of human colonic neoplasia.", + "TAG_DATA": [ + "7, protection {'effect': 'B-negative'}", + "10, neoplasia {'phenotype': 'B-tumourigenesis'}", + "12, APC(Min/+) {'perturbing_action': 'B-other'}", + "13, mice, {'context': 'B-organism'}", + "60, APC(Min/+) {'perturbing_action': 'B-gene loss-of-function'}", + "61, mice {'context': 'B-organism'}", + "69, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "7, protection ['l0', 'l1', 'l2', 'l3']", + "9, intestinal ['l0', 'l4', 'l5', 'l6']", + "10, neoplasia ['l1', 'l4', 'l7', 'l8']", + "12, APC(Min/+) ['l2', 'l5', 'l7', 'l9', 'l10', 'l11']", + "13, mice, ['l3', 'l6', 'l8', 'l9']", + "60, APC(Min/+) ['l10', 'l12', 'l13']", + "61, mice ['l11', 'l12']", + "69, mice ['l13']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "protection" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasia" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "protection" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "APC(Min/+)" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "protection" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasia" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "APC(Min/+)" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasia" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "APC(Min/+)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "APC(Min/+)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "10973321", + "TEXT": "The polypeptide component of telomerase (TERT) is an attractive candidate for a broadly expressed tumor rejection antigen because telomerase is silent in normal tissues but is reactivated in more than 85% of cancers. Here we show that immunization against TERT induces immunity against tumors of unrelated origin. Immunization of mice with TERT RNA-transfected dendritic cells (DC) stimulated cytotoxic T lymphocytes (CTL), which lysed melanoma and thymoma tumor cells and inhibited the growth of three unrelated tumors in mice of distinct genetic backgrounds. TERT RNA-transfected human DC stimulated TERT-specific CTL in vitro that lysed human tumor cells, including Epstein Barr virus (EBV)-transformed B cells as well as autologous tumor targets from patients with renal and prostate cancer. Tumor RNA-transfected DC were used as surrogate targets in the CTL assays, obviating the difficulties in obtaining tumor cells from cancer patients. In one instance, where a tumor cell line was successfully established in culture from a patient with renal cancer, the patient's tumor cells were efficiently lysed by the CTL. Immunization with tumor RNA was generally more effective than immunization with TERT RNA, suggesting that an optimal immunization protocol may have to include TERT as well as additional tumor antigens.", + "TAG_DATA": [ + "49, mice {'context': 'B-organism'}", + "51, TERT {'perturbing_action': 'B-gene gain-of-function'}", + "52, RNA-transfected {'perturbing_action': 'I-gene gain-of-function'}", + "53, dendritic {'context': 'B-cells'}", + "54, cells {'context': 'I-cells'}", + "55, (DC) {'context': 'I-cells'}", + "63, melanoma {'context': 'B-transformed cells'}", + "65, thymoma {'context': 'B-transformed cells'}", + "66, tumor {'context': 'I-transformed cells'}", + "67, cells {'context': 'I-transformed cells'}", + "75, tumors {'context': 'I-neoplasm'}", + "77, mice {'context': 'B-organism'}", + "82, TERT {'perturbing_action': 'B-gene gain-of-function'}", + "83, RNA-transfected {'perturbing_action': 'I-gene gain-of-function'}", + "84, human {'context': 'B-cells'}", + "85, DC {'context': 'I-cells'}", + "89, in {'context': 'B-in vitro'}", + "90, vitro {'context': 'I-in vitro'}", + "93, human {'context': 'B-transformed cells'}", + "94, tumor {'context': 'I-transformed cells'}", + "95, cells, {'context': 'I-transformed cells'}", + "97, Epstein {'context': 'B-transformed cells'}", + "98, Barr {'context': 'B-transformed cells'}", + "99, virus {'context': 'I-transformed cells'}", + "100, (EBV)-transformed {'context': 'I-transformed cells'}", + "101, B {'context': 'I-transformed cells'}", + "102, cells {'context': 'I-transformed cells'}", + "106, autologous {'context': 'B-neoplasm'}", + "107, tumor {'context': 'I-transformed cells'}", + "108, targets {'context': 'I-transformed cells'}", + "110, patients {'context': 'B-patient'}", + "112, renal {'context': 'I-neoplasm'}", + "113, and {'context': 'I-neoplasm'}", + "114, prostate {'context': 'I-neoplasm'}", + "115, cancer. {'context': 'I-neoplasm'}", + "118, DC {'context': 'B-cells'}", + "143, tumor {'context': 'B-transformed cells'}", + "144, cell {'context': 'I-transformed cells'}", + "145, line {'context': 'I-transformed cells'}", + "153, patient {'context': 'B-patient'}", + "158, patient's {'context': 'B-transformed cells'}", + "159, tumor {'context': 'I-transformed cells'}", + "160, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "49, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "51, TERT ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "52, RNA-transfected ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "53, dendritic ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "54, cells ['l3', 'l13', 'l22', 'l30', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "55, (DC) ['l4', 'l14', 'l23', 'l31', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "63, melanoma ['l5', 'l15', 'l24', 'l32', 'l40', 'l46', 'l52', 'l53', 'l54', 'l55', 'l56']", + "65, thymoma ['l6', 'l16', 'l25', 'l33', 'l41', 'l47', 'l52', 'l57', 'l58', 'l59', 'l60']", + "66, tumor ['l7', 'l17', 'l26', 'l34', 'l42', 'l48', 'l53', 'l57', 'l61', 'l62']", + "67, cells ['l8', 'l18', 'l27', 'l35', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63']", + "75, tumors ['l9', 'l19', 'l28', 'l36', 'l44', 'l50', 'l55', 'l59', 'l62', 'l63', 'l64']", + "77, mice ['l10', 'l20', 'l29', 'l37', 'l45', 'l51', 'l56', 'l60', 'l64']", + "82, TERT ['l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "83, RNA-transfected ['l65', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "84, human ['l66', 'l88', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "85, DC ['l67', 'l89', 'l110', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150']", + "89, in ['l68', 'l90', 'l111', 'l131', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "90, vitro ['l69', 'l91', 'l112', 'l132', 'l151', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "93, human ['l70', 'l92', 'l113', 'l133', 'l152', 'l170', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "94, tumor ['l71', 'l93', 'l114', 'l134', 'l153', 'l171', 'l188', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220']", + "95, cells, ['l72', 'l94', 'l115', 'l135', 'l154', 'l172', 'l189', 'l205', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235']", + "97, Epstein ['l73', 'l95', 'l116', 'l136', 'l155', 'l173', 'l190', 'l206', 'l221', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249']", + "98, Barr ['l74', 'l96', 'l117', 'l137', 'l156', 'l174', 'l191', 'l207', 'l222', 'l236', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265']", + "99, virus ['l75', 'l97', 'l118', 'l138', 'l157', 'l175', 'l192', 'l208', 'l223', 'l237', 'l250', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280']", + "100, (EBV)-transformed ['l76', 'l98', 'l119', 'l139', 'l158', 'l176', 'l193', 'l209', 'l224', 'l238', 'l251', 'l266', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294']", + "101, B ['l77', 'l99', 'l120', 'l140', 'l159', 'l177', 'l194', 'l210', 'l225', 'l239', 'l252', 'l267', 'l281', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304']", + "102, cells ['l38', 'l78', 'l100', 'l121', 'l141', 'l160', 'l178', 'l195', 'l211', 'l226', 'l240', 'l253', 'l268', 'l282', 'l295', 'l305', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311', 'l312', 'l313']", + "106, autologous ['l79', 'l101', 'l122', 'l142', 'l161', 'l179', 'l196', 'l212', 'l227', 'l241', 'l254', 'l269', 'l283', 'l296', 'l305', 'l314', 'l315', 'l316', 'l317', 'l318', 'l319', 'l320', 'l321', 'l322', 'l323']", + "107, tumor ['l80', 'l102', 'l123', 'l143', 'l162', 'l180', 'l197', 'l213', 'l228', 'l242', 'l255', 'l270', 'l284', 'l297', 'l306', 'l314', 'l324', 'l325', 'l326', 'l327', 'l328', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334']", + "108, targets ['l81', 'l103', 'l124', 'l144', 'l163', 'l181', 'l198', 'l214', 'l229', 'l243', 'l256', 'l271', 'l285', 'l298', 'l307', 'l315', 'l324', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340']", + "110, patients ['l82', 'l104', 'l125', 'l145', 'l164', 'l182', 'l199', 'l215', 'l230', 'l244', 'l257', 'l272', 'l286', 'l299', 'l308', 'l316', 'l325', 'l335', 'l341', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348', 'l349', 'l350', 'l351', 'l352', 'l353']", + "111, with ['l83', 'l105', 'l126', 'l146', 'l165', 'l183', 'l200', 'l216', 'l231', 'l245', 'l258', 'l273', 'l287', 'l300', 'l309', 'l317', 'l326', 'l336', 'l341', 'l354', 'l355', 'l356', 'l357', 'l358', 'l359', 'l360', 'l361', 'l362', 'l363', 'l364', 'l365']", + "112, renal ['l84', 'l106', 'l127', 'l147', 'l166', 'l184', 'l201', 'l217', 'l232', 'l246', 'l259', 'l274', 'l288', 'l301', 'l310', 'l318', 'l327', 'l337', 'l342', 'l354', 'l366', 'l367', 'l368', 'l369', 'l370', 'l371', 'l372', 'l373', 'l374', 'l375', 'l376']", + "113, and ['l85', 'l107', 'l128', 'l148', 'l167', 'l185', 'l202', 'l218', 'l233', 'l247', 'l260', 'l275', 'l289', 'l302', 'l311', 'l319', 'l328', 'l338', 'l343', 'l355', 'l366', 'l377', 'l378', 'l379', 'l380', 'l381', 'l382', 'l383', 'l384', 'l385', 'l386']", + "114, prostate ['l86', 'l108', 'l129', 'l149', 'l168', 'l186', 'l203', 'l219', 'l234', 'l248', 'l261', 'l276', 'l290', 'l303', 'l312', 'l320', 'l329', 'l339', 'l344', 'l356', 'l367', 'l377', 'l387', 'l388', 'l389', 'l390', 'l391', 'l392', 'l393', 'l394', 'l395']", + "115, cancer. ['l87', 'l109', 'l130', 'l150', 'l169', 'l187', 'l204', 'l220', 'l235', 'l249', 'l262', 'l277', 'l291', 'l304', 'l313', 'l321', 'l330', 'l340', 'l345', 'l357', 'l368', 'l378', 'l387', 'l396', 'l397', 'l398', 'l399', 'l400', 'l401', 'l402']", + "118, DC ['l331', 'l346', 'l358', 'l369', 'l379', 'l388', 'l396', 'l403', 'l404', 'l405', 'l406', 'l407', 'l408', 'l409', 'l410', 'l411']", + "143, tumor ['l347', 'l359', 'l370', 'l380', 'l389', 'l397', 'l403', 'l412', 'l413', 'l414', 'l415', 'l416', 'l417', 'l418', 'l419']", + "144, cell ['l263', 'l278', 'l292', 'l322', 'l332', 'l348', 'l360', 'l371', 'l381', 'l390', 'l398', 'l404', 'l412', 'l420', 'l421', 'l422', 'l423', 'l424', 'l425', 'l426']", + "145, line ['l264', 'l279', 'l293', 'l323', 'l333', 'l349', 'l361', 'l372', 'l382', 'l391', 'l399', 'l405', 'l413', 'l420', 'l427', 'l428', 'l429', 'l430', 'l431', 'l432']", + "153, patient ['l350', 'l362', 'l373', 'l383', 'l392', 'l400', 'l406', 'l414', 'l421', 'l427', 'l433', 'l434', 'l435', 'l436', 'l437']", + "155, renal ['l351', 'l363', 'l374', 'l384', 'l393', 'l401', 'l407', 'l415', 'l422', 'l428', 'l433', 'l438', 'l439', 'l440', 'l441']", + "156, cancer, ['l265', 'l280', 'l294', 'l334', 'l352', 'l364', 'l375', 'l385', 'l394', 'l402', 'l408', 'l416', 'l423', 'l429', 'l434', 'l438', 'l442', 'l443', 'l444']", + "158, patient's ['l409', 'l417', 'l424', 'l430', 'l435', 'l439', 'l442', 'l445', 'l446']", + "159, tumor ['l410', 'l418', 'l425', 'l431', 'l436', 'l440', 'l443', 'l445', 'l447']", + "160, cells ['l353', 'l365', 'l376', 'l386', 'l395', 'l411', 'l419', 'l426', 'l432', 'l437', 'l441', 'l444', 'l446', 'l447']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "TERT", + "RNA-transfected" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "TERT", + "RNA-transfected" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells", + "(DC)", + "human", + "DC" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "TERT", + "RNA-transfected" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "thymoma", + "tumor", + "cells", + "human", + "cells,", + "Epstein", + "Barr", + "virus", + "(EBV)-transformed", + "B", + "targets" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "TERT", + "RNA-transfected" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "autologous", + "renal", + "and", + "prostate", + "cancer." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "TERT", + "RNA-transfected" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "TERT", + "RNA-transfected" + ] + }, + "context": { + "val": "patient", + "words": [ + "patients" + ] + } + } + ] + }, + { + "PMID": "10932231", + "TEXT": "Fas (CD95) is a receptor involved in induction of apoptotic cell death of Fas-bearing cells, including hepatocytes and T cells. Injection of Fas-specific antibodies into mice leads to fulminant hepatic failure and death. Fas also transduces growth-promoting signals in proliferating T cells, fibroblasts and some tumor cells. Here we show that partial hepatectomy, which triggers the immediate onset of liver regeneration, protected mice against the lethal effects of Fas-specific antibodies and prevented hepatocyte apoptosis in response to Fas engagement in vivo. Furthermore, Fas engagement accelerated liver regeneration after partial hepatectomy. Liver regeneration kinetics were delayed in mutant mice with decreased cell surface Fas expression (lpr mice). In contrast, regeneration was not delayed in lpr-cg mutant mice, which have a Fas mutation that prevents Fas-induced death but not Fas-dependent proliferative stimulation. Our results indicate that Fas engagement on cells in regenerating or healing tissues may promote cell growth.", + "TAG_DATA": [ + "59, liver {'context': 'B-tissue/organ'}", + "62, mice {'context': 'B-organism'}", + "71, prevented {'effect': 'B-negative'}", + "72, hepatocyte {'context': 'B-cells'}", + "73, apoptosis {'phenotype': 'B-apoptosis'}", + "79, in {'context': 'B-in vivo'}", + "80, vivo. {'context': 'I-in vivo'}", + "84, accelerated {'effect': 'B-positive'}", + "85, liver {'context': 'B-tissue/organ'}", + "90, Liver {'context': 'B-tissue/organ'}", + "97, mice {'context': 'B-organism'}", + "113, lpr-cg {'perturbing_action': 'B-other'}", + "114, mutant {'perturbing_action': 'I-other'}", + "115, mice, {'context': 'B-organism'}", + "119, Fas {'perturbing_action': 'I-other'}", + "120, mutation {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "52, hepatectomy, ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "59, liver ['l0', 'l7', 'l8', 'l9', 'l10']", + "62, mice ['l1', 'l7', 'l11', 'l12', 'l13', 'l14', 'l15']", + "71, prevented ['l2', 'l8', 'l11', 'l16', 'l17', 'l18', 'l19']", + "72, hepatocyte ['l3', 'l9', 'l12', 'l16', 'l20', 'l21', 'l22']", + "73, apoptosis ['l4', 'l10', 'l13', 'l17', 'l20', 'l23', 'l24']", + "79, in ['l5', 'l14', 'l18', 'l21', 'l23', 'l25']", + "80, vivo. ['l6', 'l15', 'l19', 'l22', 'l24', 'l25']", + "84, accelerated ['l26']", + "85, liver ['l26']", + "90, Liver ['l27']", + "97, mice ['l27']", + "113, lpr-cg ['l28', 'l29', 'l30', 'l31']", + "114, mutant ['l28', 'l32', 'l33', 'l34']", + "115, mice, ['l29', 'l32', 'l35', 'l36']", + "119, Fas ['l30', 'l33', 'l35', 'l37']", + "120, mutation ['l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocyte" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hepatocyte" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "accelerated" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "lpr-cg", + "mutant", + "Fas", + "mutation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "10888935", + "TEXT": "Medulloblastoma is the most malignant pediatric brain tumor. It is believed to originate from the undifferentiated external granule layer cells in the cerebellum, but the mechanism of tumorigenesis remains unknown. Here we studied three types of human medulloblastoma cells that express markers corresponding to different levels of neuronal differentiation. They expressed the neuronal repressor element 1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF; refs. 7-10) at very high levels compared with either neuronal progenitor NTera2 (NT2) cells or fully differentiated human neuron teratocarcinoma (hNT cells). To counter the effect of REST/NRSF, we used a recombinant transcription factor, REST-VP16, constructed by replacing repressor domains of REST/NRSF with the activation domain of viral protein (VP16). Transient expression of REST-VP16 in medulloblastoma cells was able to compete with the endogenous REST/NRSF for DNA binding and stimulate neuronal promoters. High-efficiency expression of REST-VP16 mediated by adenovirus vectors (Ad.REST-VP16) in medulloblastoma cells was able to counter REST/NRSF-mediated repression of neuronal promoters, stimulate expression of endogenous neuronal genes and trigger apoptosis through the activation of caspase cascades. Furthermore, intratumoral injection of Ad.REST-VP16 in established medulloblastoma tumors in nude mice inhibited their growth. Therefore, REST/NRSF may serve as a new target for therapeutic interventions for medulloblastoma through agents such as REST-VP16.", + "TAG_DATA": [ + "113, Transient {'perturbing_action': 'B-gene gain-of-function'}", + "114, expression {'perturbing_action': 'I-gene gain-of-function'}", + "115, of {'perturbing_action': 'I-gene gain-of-function'}", + "116, REST-VP16 {'perturbing_action': 'I-gene gain-of-function'}", + "118, medulloblastoma {'context': 'B-transformed cells'}", + "119, cells {'context': 'I-transformed cells'}", + "136, expression {'perturbing_action': 'I-gene gain-of-function'}", + "137, of {'perturbing_action': 'I-gene gain-of-function'}", + "138, REST-VP16 {'perturbing_action': 'I-gene gain-of-function'}", + "145, medulloblastoma {'context': 'B-transformed cells'}", + "146, cells {'context': 'I-transformed cells'}", + "163, trigger {'effect': 'B-positive'}", + "164, apoptosis {'phenotype': 'B-apoptosis'}", + "178, medulloblastoma {'context': 'B-neoplasm'}", + "179, tumors {'context': 'I-neoplasm'}", + "181, nude {'context': 'B-organism'}", + "182, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "113, Transient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "114, expression ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "115, of ['l1', 'l7', 'l12', 'l13', 'l14', 'l15']", + "116, REST-VP16 ['l2', 'l8', 'l12', 'l16', 'l17', 'l18']", + "118, medulloblastoma ['l3', 'l9', 'l13', 'l16', 'l19']", + "119, cells ['l4', 'l10', 'l14', 'l17', 'l19']", + "136, expression ['l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "137, of ['l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "138, REST-VP16 ['l21', 'l26', 'l31', 'l32', 'l33', 'l34']", + "145, medulloblastoma ['l5', 'l22', 'l27', 'l31', 'l35', 'l36', 'l37']", + "146, cells ['l6', 'l11', 'l15', 'l18', 'l23', 'l28', 'l32', 'l35', 'l38', 'l39']", + "163, trigger ['l24', 'l29', 'l33', 'l36', 'l38', 'l40']", + "164, apoptosis ['l25', 'l30', 'l34', 'l37', 'l39', 'l40']", + "178, medulloblastoma ['l41', 'l42', 'l43']", + "179, tumors ['l41', 'l44', 'l45']", + "181, nude ['l42', 'l44', 'l46']", + "182, mice ['l43', 'l45', 'l46']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transient", + "expression", + "of", + "REST-VP16" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "medulloblastoma", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "REST-VP16" + ] + }, + "effect": { + "val": "positive", + "words": [ + "trigger" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "REST-VP16" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "medulloblastoma", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "trigger" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "medulloblastoma", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "trigger" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "10888932", + "TEXT": "Exogenous application of neurotrophic growth factors has emerged as a new and particularly promising approach not only to promote functional recovery after acute brain injury but also to protect neurons against the immediate effect of the injury. Among the various growth factors and cytokines studied so far, the neuroprotective and neurotrophic profile of basic fibroblast growth factor (bFGF) is the best documented. Using an animal model of acute excitotoxic brain injury, we report here that the neuroprotective action of bFGF, which is now being tested in stroke patients, depends on the induction of activin A, a member of the transforming growth factor-beta superfamily. Our evidence for this previously unknown mechanism of action of bFGF is that bFGF strongly enhanced lesion-associated induction of activin A; in the presence of the activin-neutralizing protein follistatin, bFGF was no longer capable of rescuing neurons from excitotoxic death; and recombinant activin A exerted a neuroprotective effect by itself. Our data indicate that the development of substances influencing activin expression or receptor binding should offer new ways to fight neuronal loss in ischemic and traumatic brain injury.", + "TAG_DATA": [ + "135, longer {'effect': 'I-no effect'}", + "136, capable {'effect': 'I-no effect'}", + "139, neurons {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "135, longer ['l0', 'l1']", + "136, capable ['l0', 'l2']", + "139, neurons ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "no effect", + "words": [ + "longer", + "capable" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons" + ] + } + } + ] + }, + { + "PMID": "10888924", + "TEXT": "Mycophenolic acid, a selective inhibitor of the de novo synthesis of guanosine nucleotides in T and B lymphocytes, has been proposed to inhibit human immunodeficiency virus (HIV) replication in vitro by depleting the substrate (guanosine nucleotides) for reverse transcriptase. Here we show that mycophenolic acid induced apoptosis and cell death in a large proportion of activated CD4+ T cells, thus indicating that it may inhibit HIV infection in vitro by both virological mechanisms and immunological mechanisms (depletion of the pool of activated CD4+ T lymphocytes). Administration of mycophenolate mophetil, the ester derivate of mycophenolic acid, to HIV-infected subjects treated with anti-retroviral therapy and with undetectable viremia resulted in the reduction of the number of dividing CD4 + and CD8+ T cells and in the inhibition of virus isolation from purified CD4+ T-cell populations. Based on these results, the potential use of mycophenolate mophetil in the treatment of HIV infection deserves further investigation in controlled clinical trials.", + "TAG_DATA": [ + "45, induced {'effect': 'B-positive'}", + "46, apoptosis {'phenotype': 'B-apoptosis'}", + "48, cell {'phenotype': 'B-cell death'}", + "49, death {'phenotype': 'I-cell death'}", + "56, CD4+ {'context': 'B-cells'}", + "57, T {'context': 'I-cells'}", + "58, cells, {'context': 'I-cells'}", + "96, HIV-infected {'context': 'B-patient'}", + "97, subjects {'context': 'I-patient'}", + "115, CD4 {'context': 'B-cells'}", + "116, + {'context': 'B-cells'}", + "117, and {'context': 'I-cells'}", + "118, CD8+ {'context': 'I-cells'}", + "119, T {'context': 'I-cells'}", + "120, cells {'context': 'I-cells'}", + "130, CD4+ {'context': 'B-cells'}", + "131, T-cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, induced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "46, apoptosis ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "48, cell ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "49, death ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "56, CD4+ ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "57, T ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "58, cells, ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "96, HIV-infected ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "97, subjects ['l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "115, CD4 ['l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "116, + ['l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "117, and ['l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "118, CD8+ ['l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47', 'l48']", + "119, T ['l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l49']", + "120, cells ['l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l49']", + "130, CD4+ ['l50']", + "131, T-cell ['l48', 'l50']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells," + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells," + ] + } + } + ] + }, + { + "PMID": "10802717", + "TEXT": "The pro-inflammatory cytokine interleukin (IL)-6 (refs. 1-5) can bind to cells lacking the IL-6 receptor (IL-6R) when it forms a complex with the soluble IL-6R (sIL-6R) (trans signaling). Here, we have assessed the contribution of this system to the increased resistance of mucosal T cells against apoptosis in Crohn disease (CD), a chronic inflammatory disease of the gastrointestinal tract. A neutralizing antibody against IL-6R suppressed established experimental colitis in various animal models of CD mediated by type 1 T-helper cells, by inducing apoptosis of lamina propria T cells. Similarly, specific neutralization of sIL-6R in vivo by a newly designed gp130-Fc fusion protein caused suppression of colitis activity and induction of apoptosis, indicating that sIL-6R prevents mucosal T-cell apoptosis. In patients with CD, mucosal T cells showed strong evidence for IL-6 trans signaling, with activation of signal transducer and activator of transcription 3, bcl-2 and bcl-xl. Blockade of IL-6 trans signaling caused T-cell apoptosis, indicating that the IL-6-sIL-6R system mediates the resistance of T cells to apoptosis in CD. These data indicate that a pathway of T-cell activation driven by IL-6-sIL-6R contributes to the perpetuation of chronic intestinal inflammation. Specific targeting of this pathway may be a promising new approach for the treatment of CD.", + "TAG_DATA": [ + "70, animal {'context': 'B-organism'}", + "71, models {'context': 'I-organism'}", + "73, CD {'context': 'I-organism'}", + "81, inducing {'effect': 'B-positive'}", + "82, apoptosis {'phenotype': 'B-apoptosis'}", + "84, lamina {'context': 'B-cells'}", + "86, T {'context': 'I-cells'}", + "87, cells. {'context': 'I-cells'}", + "89, specific {'perturbing_action': 'B-pharmacological inhibition'}", + "90, neutralization {'perturbing_action': 'I-pharmacological inhibition'}", + "91, of {'perturbing_action': 'I-pharmacological inhibition'}", + "92, sIL-6R {'perturbing_action': 'I-pharmacological inhibition'}", + "93, in {'context': 'B-in vivo'}", + "94, vivo {'context': 'I-in vivo'}", + "108, induction {'effect': 'B-positive'}", + "110, apoptosis, {'phenotype': 'B-apoptosis'}", + "114, prevents {'effect': 'B-negative'}", + "115, mucosal {'context': 'B-cells'}", + "116, T-cell {'context': 'I-cells'}", + "117, apoptosis. {'phenotype': 'B-apoptosis'}", + "122, mucosal {'context': 'B-cells'}", + "123, T {'context': 'I-cells'}", + "124, cells {'context': 'I-cells'}", + "150, caused {'effect': 'B-positive'}", + "151, T-cell {'context': 'B-cells'}", + "152, apoptosis, {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "60, neutralizing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "61, antibody ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "62, against ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "63, IL-6R ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "70, animal ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "71, models ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "72, of ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "73, CD ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "81, inducing ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "82, apoptosis ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "84, lamina ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "86, T ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "87, cells. ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "89, specific ['l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "90, neutralization ['l78', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "91, of ['l79', 'l93', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "92, sIL-6R ['l80', 'l94', 'l107', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "93, in ['l81', 'l95', 'l108', 'l120', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "94, vivo ['l82', 'l96', 'l109', 'l121', 'l132', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "101, protein ['l83', 'l97', 'l110', 'l122', 'l133', 'l143', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "108, induction ['l84', 'l98', 'l111', 'l123', 'l134', 'l144', 'l153', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168']", + "110, apoptosis, ['l85', 'l99', 'l112', 'l124', 'l135', 'l145', 'l154', 'l162', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175']", + "114, prevents ['l86', 'l100', 'l113', 'l125', 'l136', 'l146', 'l155', 'l163', 'l169', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181']", + "115, mucosal ['l87', 'l101', 'l114', 'l126', 'l137', 'l147', 'l156', 'l164', 'l170', 'l176', 'l182', 'l183', 'l184', 'l185', 'l186']", + "116, T-cell ['l88', 'l102', 'l115', 'l127', 'l138', 'l148', 'l157', 'l165', 'l171', 'l177', 'l182', 'l187', 'l188', 'l189', 'l190']", + "117, apoptosis. ['l89', 'l103', 'l116', 'l128', 'l139', 'l149', 'l158', 'l166', 'l172', 'l178', 'l183', 'l187', 'l191', 'l192', 'l193']", + "122, mucosal ['l90', 'l104', 'l117', 'l129', 'l140', 'l150', 'l159', 'l173', 'l179', 'l184', 'l188', 'l191', 'l194', 'l195']", + "123, T ['l91', 'l105', 'l118', 'l130', 'l141', 'l151', 'l160', 'l167', 'l174', 'l180', 'l185', 'l189', 'l192', 'l194', 'l196']", + "124, cells ['l92', 'l106', 'l119', 'l131', 'l142', 'l152', 'l161', 'l168', 'l175', 'l181', 'l186', 'l190', 'l193', 'l195', 'l196']", + "150, caused ['l197', 'l198']", + "151, T-cell ['l197', 'l199']", + "152, apoptosis, ['l198', 'l199']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "animal", + "models", + "CD" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animal", + "models", + "CD" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing", + "induction", + "caused" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis,", + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing", + "induction", + "caused" + ] + }, + "context": { + "val": "cells", + "words": [ + "lamina", + "T", + "cells.", + "mucosal", + "T-cell", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis,", + "apoptosis." + ] + }, + "context": { + "val": "cells", + "words": [ + "lamina", + "T", + "cells.", + "mucosal", + "T-cell", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "neutralization", + "of", + "sIL-6R" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "neutralization", + "of", + "sIL-6R" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "neutralization", + "of", + "sIL-6R" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis,", + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "neutralization", + "of", + "sIL-6R" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "neutralization", + "of", + "sIL-6R" + ] + }, + "context": { + "val": "cells", + "words": [ + "mucosal", + "T-cell", + "T", + "cells" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis,", + "apoptosis." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis,", + "apoptosis." + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "context": { + "val": "cells", + "words": [ + "mucosal", + "T-cell", + "T", + "cells" + ] + } + } + ] + }, + { + "PMID": "10802713", + "TEXT": "Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to induce apoptosis in various tumor cells but not in nontransformed, normal cells. Preclinical studies in mice and nonhuman primates have shown that administration of TRAIL can induce apoptosis in human tumors, but that no cytotoxicity to normal organs or tissues is found. The susceptibility of tumor cells to TRAIL and an apparent lack of activity in normal cells has lead to a proposal to use TRAIL in cancer therapy. Here, we assessed the sensitivity of hepatocytes from rat, mouse, rhesus monkey and human livers to TRAIL-induced apoptosis. TRAIL induced apoptosis in normal human hepatocytes in culture but not in hepatocytes isolated from the other species. Human hepatocytes showed characteristic features of apoptosis, including cytoplasmic shrinkage, the activation of caspases and DNA fragmentation. Apoptosis and cell death in human hepatocytes was massive and rapid, occurring in more than 60% of the cells exposed to TRAIL within 10 hours. These results indicate that there are species differences in sensitivity to TRAIL, and that substantial liver toxicity might result if TRAIL were used in human cancer therapy.", + "TAG_DATA": [ + "85, hepatocytes {'context': 'B-cells'}", + "88, mouse, {'context': 'I-organism'}", + "89, rhesus {'context': 'B-organism'}", + "90, monkey {'context': 'I-tissue/organ'}", + "92, human {'context': 'B-tissue/organ'}", + "93, livers {'context': 'I-tissue/organ'}", + "95, TRAIL-induced {'effect': 'B-positive'}", + "98, induced {'effect': 'B-positive'}", + "99, apoptosis {'phenotype': 'B-apoptosis'}", + "101, normal {'context': 'B-cells'}", + "102, human {'context': 'I-cells'}", + "103, hepatocytes {'context': 'I-cells'}", + "105, culture {'context': 'I-in vitro'}", + "109, hepatocytes {'context': 'B-cells'}", + "110, isolated {'context': 'I-cells'}", + "115, Human {'context': 'B-cells'}", + "116, hepatocytes {'context': 'I-cells'}", + "121, apoptosis, {'phenotype': 'B-apoptosis'}", + "132, Apoptosis {'phenotype': 'B-apoptosis'}", + "134, cell {'phenotype': 'B-cell death'}", + "135, death {'phenotype': 'I-cell death'}", + "137, human {'context': 'B-cells'}", + "138, hepatocytes {'context': 'I-cells'}", + "150, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "85, hepatocytes ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "88, mouse, ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "89, rhesus ['l1', 'l6', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "90, monkey ['l2', 'l7', 'l11', 'l18', 'l19', 'l20']", + "92, human ['l3', 'l8', 'l12', 'l18', 'l21', 'l22']", + "93, livers ['l4', 'l9', 'l13', 'l19', 'l21']", + "95, TRAIL-induced ['l5', 'l10', 'l14', 'l20', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "98, induced ['l15', 'l23', 'l28', 'l29', 'l30', 'l31', 'l32']", + "99, apoptosis ['l16', 'l24', 'l28', 'l33', 'l34', 'l35', 'l36']", + "101, normal ['l17', 'l25', 'l29', 'l33', 'l37', 'l38', 'l39']", + "102, human ['l26', 'l30', 'l34', 'l37', 'l40', 'l41']", + "103, hepatocytes ['l27', 'l31', 'l35', 'l38', 'l40', 'l42']", + "105, culture ['l32', 'l36', 'l39', 'l41', 'l42']", + "109, hepatocytes ['l43', 'l44', 'l45', 'l46']", + "110, isolated ['l43', 'l47', 'l48', 'l49']", + "115, Human ['l44', 'l47', 'l50', 'l51', 'l52']", + "116, hepatocytes ['l45', 'l48', 'l50', 'l53', 'l54']", + "121, apoptosis, ['l46', 'l49', 'l51', 'l53', 'l55']", + "132, Apoptosis ['l52', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "134, cell ['l56', 'l61', 'l62', 'l63', 'l64']", + "135, death ['l57', 'l61', 'l65', 'l66', 'l67']", + "137, human ['l58', 'l62', 'l65', 'l68', 'l69']", + "138, hepatocytes ['l59', 'l63', 'l66', 'l68', 'l70']", + "150, cells ['l60', 'l64', 'l67', 'l69', 'l70']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "hepatocytes", + "normal", + "human" + ] + }, + "effect": { + "val": "positive", + "words": [ + "TRAIL-induced", + "induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse,", + "rhesus" + ] + }, + "effect": { + "val": "positive", + "words": [ + "TRAIL-induced", + "induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rhesus" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "monkey", + "human" + ] + }, + "effect": { + "val": "positive", + "words": [ + "TRAIL-induced" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "TRAIL-induced", + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis,", + "Apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "normal", + "human", + "hepatocytes", + "isolated", + "Human", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "hepatocytes", + "cells" + ] + } + } + ] + }, + { + "PMID": "10802708", + "TEXT": "Caspase 8 is a cysteine protease regulated in both a death-receptor-dependent and -independent manner during apoptosis. Here, we report that the gene for caspase 8 is frequently inactivated in neuroblastoma, a childhood tumor of the peripheral nervous system. The gene is silenced through DNA methylation as well as through gene deletion. Complete inactivation of CASP8 occurred almost exclusively in neuroblastomas with amplification of the oncogene MYCN. Caspase 8-null neuroblastoma cells were resistant to death receptor- and doxorubicin-mediated apoptosis, deficits that were corrected by programmed expression of the enzyme. Thus, caspase 8 acts as a tumor suppressor in neuroblastomas with amplification of MYCN.", + "TAG_DATA": [ + "59, neuroblastomas {'context': 'B-neoplasm'}", + "66, Caspase {'perturbing_action': 'B-gene loss-of-function'}", + "67, 8-null {'perturbing_action': 'B-gene loss-of-function'}", + "68, neuroblastoma {'context': 'B-transformed cells'}", + "69, cells {'context': 'I-transformed cells'}", + "71, resistant {'effect': 'B-negative'}", + "77, apoptosis, {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "59, neuroblastomas ['l0']", + "66, Caspase ['l1', 'l2', 'l3', 'l4', 'l5']", + "67, 8-null ['l1', 'l6', 'l7', 'l8', 'l9']", + "68, neuroblastoma ['l2', 'l6', 'l10', 'l11', 'l12']", + "69, cells ['l0', 'l3', 'l7', 'l10', 'l13', 'l14']", + "71, resistant ['l4', 'l8', 'l11', 'l13', 'l15']", + "77, apoptosis, ['l5', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Caspase", + "8-null" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "neuroblastoma", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Caspase", + "8-null" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Caspase", + "8-null" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "neuroblastoma", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "neuroblastoma", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistant" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + } + ] + }, + { + "PMID": "10742146", + "TEXT": "The amyloid beta-protein precursor gives rise to the amyloid beta-protein, the principal constituent of senile plaques and a cytotoxic fragment involved in the pathogenesis of Alzheimer disease. Here we show that amyloid beta-protein precursor was proteolytically cleaved by caspases in the C terminus to generate a second unrelated peptide, called C31. The resultant C31 peptide was a potent inducer of apoptosis. Both caspase-cleaved amyloid beta-protein precursor and activated caspase-9 were present in brains of Alzheimer disease patients but not in control brains. These findings indicate the possibility that caspase cleavage of amyloid beta-protein precursor with the generation of C31 may be involved in the neuronal death associated with Alzheimer disease.", + "TAG_DATA": [ + "58, inducer {'effect': 'B-positive'}", + "60, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "58, inducer ['l0']", + "60, apoptosis. ['l0']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "inducer" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "10700234", + "TEXT": "Delta9-Tetrahydrocannabinol, the main active component of marijuana, induces apoptosis of transformed neural cells in culture. Here, we show that intratumoral administration of Delta9-tetrahydrocannabinol and the synthetic cannabinoid agonist WIN-55,212-2 induced a considerable regression of malignant gliomas in Wistar rats and in mice deficient in recombination activating gene 2. Cannabinoid treatment did not produce any substantial neurotoxic effect in the conditions used. Experiments with two subclones of C6 glioma cells in culture showed that cannabinoids signal apoptosis by a pathway involving cannabinoid receptors, sustained ceramide accumulation and Raf1/extracellular signal-regulated kinase activation. These results may provide the basis for a new therapeutic approach for the treatment of malignant gliomas.", + "TAG_DATA": [ + "29, induced {'effect': 'B-positive'}", + "32, regression {'phenotype': 'B-tumour regression'}", + "34, malignant {'context': 'B-neoplasm'}", + "35, gliomas {'context': 'I-neoplasm'}", + "37, Wistar {'context': 'B-organism'}", + "38, rats {'context': 'I-organism'}", + "41, mice {'context': 'B-organism'}", + "42, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "43, in {'perturbing_action': 'I-gene loss-of-function'}", + "44, recombination {'perturbing_action': 'I-gene loss-of-function'}", + "45, activating {'perturbing_action': 'I-gene loss-of-function'}", + "46, gene {'perturbing_action': 'I-gene loss-of-function'}", + "47, 2. {'perturbing_action': 'I-gene loss-of-function'}", + "66, C6 {'context': 'B-transformed cells'}", + "67, glioma {'context': 'I-transformed cells'}", + "68, cells {'context': 'I-transformed cells'}", + "70, culture {'context': 'I-in vitro'}", + "74, signal {'effect': 'B-regulates'}" + ], + "LINK_DATA": [ + "29, induced ['l0', 'l1', 'l2', 'l3', 'l4']", + "32, regression ['l0', 'l5', 'l6', 'l7', 'l8']", + "34, malignant ['l1', 'l5', 'l9', 'l10', 'l11']", + "35, gliomas ['l2', 'l6', 'l9', 'l12', 'l13']", + "37, Wistar ['l3', 'l7', 'l10', 'l12', 'l14']", + "38, rats ['l4', 'l8', 'l11', 'l13', 'l14']", + "41, mice ['l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "42, deficient ['l15', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "43, in ['l16', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "44, recombination ['l17', 'l22', 'l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "45, activating ['l18', 'l23', 'l29', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "46, gene ['l19', 'l24', 'l30', 'l36', 'l41', 'l46', 'l47', 'l48']", + "47, 2. ['l20', 'l25', 'l31', 'l37', 'l42', 'l46', 'l49', 'l50']", + "66, C6 ['l32', 'l38', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "67, glioma ['l26', 'l33', 'l39', 'l44', 'l47', 'l49', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "68, cells ['l27', 'l34', 'l40', 'l45', 'l48', 'l50', 'l52', 'l57', 'l62', 'l63']", + "69, in ['l53', 'l58', 'l62', 'l64', 'l65', 'l66']", + "70, culture ['l54', 'l59', 'l63', 'l64', 'l67', 'l68']", + "74, signal ['l55', 'l60', 'l65', 'l67', 'l69']", + "75, apoptosis ['l56', 'l61', 'l66', 'l68', 'l69']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "malignant", + "gliomas" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "Wistar", + "rats" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "malignant", + "gliomas" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "organism", + "words": [ + "Wistar", + "rats" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "recombination", + "activating", + "gene", + "2." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "recombination", + "activating", + "gene", + "2." + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "glioma", + "cells", + "C6" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "C6", + "glioma" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "signal" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "signal" + ] + } + } + ] + }, + { + "PMID": "10700233", + "TEXT": "Golgi beta1,6N-acetylglucosaminyltransferase V (MGAT5) is required in the biosynthesis of beta1,6GlcNAc-branched N-linked glycans attached to cell surface and secreted glycoproteins. Amounts of MGAT5 glycan products are commonly increased in malignancies, and correlate with disease progression. To study the functions of these N-glycans in development and disease, we generated mice deficient in Mgat5 by targeted gene mutation. These Mgat5-/- mice lacked Mgat5 products and appeared normal, but differed in their responses to certain extrinsic conditions. Mammary tumor growth and metastases induced by the polyomavirus middle T oncogene was considerably less in Mgat5-/- mice than in transgenic littermates expressing Mgat5. Furthermore, Mgat5 glycan products stimulated membrane ruffling and phosphatidylinositol 3 kinase-protein kinase B activation, fueling a positive feedback loop that amplified oncogene signaling and tumor growth in vivo. Our results indicate that inhibitors of MGAT5 might be useful in the treatment of malignancies by targeting their dependency on focal adhesion signaling for growth and metastasis.", + "TAG_DATA": [ + "48, mice {'context': 'B-organism'}", + "49, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "50, in {'perturbing_action': 'I-gene loss-of-function'}", + "51, Mgat5 {'perturbing_action': 'I-gene loss-of-function'}", + "53, targeted {'perturbing_action': 'B-other'}", + "54, gene {'perturbing_action': 'I-other'}", + "55, mutation. {'perturbing_action': 'I-other'}", + "57, Mgat5-/- {'perturbing_action': 'B-gene loss-of-function'}", + "58, mice {'context': 'B-organism'}", + "74, Mammary {'context': 'B-tissue/organ'}", + "75, tumor {'phenotype': 'B-tumour growth'}", + "76, growth {'phenotype': 'I-tumour growth'}", + "78, metastases {'phenotype': 'B-metastasis'}", + "79, induced {'effect': 'B-positive'}", + "88, less {'effect': 'B-negative'}", + "90, Mgat5-/- {'perturbing_action': 'B-gene loss-of-function'}", + "91, mice {'context': 'B-organism'}", + "94, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "96, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "97, Mgat5. {'perturbing_action': 'I-gene gain-of-function'}", + "122, tumor {'phenotype': 'B-tumour growth'}", + "123, growth {'phenotype': 'I-tumour growth'}", + "124, in {'context': 'B-in vivo'}", + "125, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "48, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "49, deficient ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "50, in ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "51, Mgat5 ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "53, targeted ['l3', 'l8', 'l12', 'l15', 'l18', 'l19', 'l20']", + "54, gene ['l4', 'l9', 'l13', 'l16', 'l18', 'l21', 'l22']", + "55, mutation. ['l5', 'l10', 'l14', 'l17', 'l19', 'l21', 'l23']", + "57, Mgat5-/- ['l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "58, mice ['l20', 'l22', 'l23', 'l24', 'l33', 'l34', 'l35', 'l36']", + "74, Mammary ['l25', 'l33', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "75, tumor ['l26', 'l34', 'l37', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "76, growth ['l27', 'l35', 'l38', 'l46', 'l52', 'l53', 'l54', 'l55']", + "78, metastases ['l28', 'l39', 'l47', 'l52', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "79, induced ['l29', 'l36', 'l40', 'l48', 'l53', 'l56', 'l62', 'l63', 'l64', 'l65']", + "83, middle ['l41', 'l57', 'l62', 'l66', 'l67', 'l68', 'l69', 'l70']", + "84, T ['l30', 'l42', 'l49', 'l58', 'l63', 'l66', 'l71', 'l72', 'l73', 'l74']", + "85, oncogene ['l31', 'l43', 'l50', 'l54', 'l59', 'l64', 'l67', 'l71', 'l75', 'l76', 'l77']", + "88, less ['l32', 'l44', 'l51', 'l55', 'l60', 'l65', 'l68', 'l72', 'l75', 'l78', 'l79']", + "90, Mgat5-/- ['l69', 'l73', 'l76', 'l78', 'l80', 'l81', 'l82']", + "91, mice ['l45', 'l61', 'l70', 'l74', 'l77', 'l79', 'l80']", + "94, transgenic ['l81', 'l83', 'l84', 'l85']", + "96, expressing ['l83', 'l86', 'l87', 'l88', 'l89', 'l90']", + "97, Mgat5. ['l82', 'l84', 'l86', 'l91', 'l92', 'l93', 'l94']", + "122, tumor ['l87', 'l91', 'l95', 'l96', 'l97']", + "123, growth ['l85', 'l88', 'l92', 'l95', 'l98', 'l99']", + "124, in ['l89', 'l93', 'l96', 'l98', 'l100']", + "125, vivo. ['l90', 'l94', 'l97', 'l99', 'l100']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Mgat5", + "Mgat5-/-" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "targeted", + "gene", + "mutation." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mgat5-/-" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "Mammary" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mgat5-/-" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mgat5-/-" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mgat5-/-" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mgat5-/-" + ] + }, + "effect": { + "val": "negative", + "words": [ + "less" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "Mammary" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "Mammary" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "Mammary" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "Mammary" + ] + }, + "effect": { + "val": "negative", + "words": [ + "less" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "less" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + }, + "effect": { + "val": "negative", + "words": [ + "less" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "less" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "Mgat5." + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth", + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "Mgat5." + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "10700231", + "TEXT": "Although recent in vitro studies have begun to decipher the molecular events that characterize the anergic state, their in vivo biologic relevance and potential clinical importance remain unclear. Here, using anergic human T-cell clones and tolerant alloreactive mouse T cells that do not induce graft-versus-host disease, we show that p27kip1 cyclin-dependent kinase inhibitor is an essential regulator responsible for the blockade of clonal expansion of anergic T cells in vitro and in vivo. Moreover, in anergic cells, p27kip1 associates with the c-Jun co-activator JAB1, resulting in defective transactivation of AP-1 and interleukin 2 transcription. Therefore, pharmacological agents that upregulate the expression of or prevent the degradation of p27kip1 during antigen recognition should be part of new therapeutic strategies to induce antigen-specific T-cell unresponsiveness.", + "TAG_DATA": [ + "30, anergic {'context': 'B-cells'}", + "31, human {'context': 'I-cells'}", + "32, T-cell {'context': 'I-cells'}", + "33, clones {'context': 'I-cells'}", + "36, alloreactive {'context': 'I-cells'}", + "37, mouse {'context': 'I-cells'}", + "38, T {'context': 'I-cells'}", + "39, cells {'context': 'I-cells'}", + "60, blockade {'effect': 'B-negative'}", + "62, clonal {'phenotype': 'B-colony formation'}", + "63, expansion {'phenotype': 'I-colony formation'}", + "65, anergic {'context': 'B-cells'}", + "66, T {'context': 'I-cells'}", + "67, cells {'context': 'I-cells'}", + "68, in {'context': 'B-in vitro'}", + "69, vitro {'context': 'I-in vitro'}", + "71, in {'context': 'B-in vivo'}", + "72, vivo. {'context': 'I-in vivo'}", + "75, anergic {'context': 'B-cells'}", + "76, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "30, anergic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "31, human ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "32, T-cell ['l1', 'l13', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "33, clones ['l2', 'l14', 'l22', 'l32', 'l33', 'l34', 'l35']", + "36, alloreactive ['l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "37, mouse ['l36', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "38, T ['l3', 'l15', 'l23', 'l37', 'l49', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "39, cells ['l4', 'l16', 'l24', 'l38', 'l50', 'l59', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "60, blockade ['l5', 'l39', 'l51', 'l60', 'l68', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "62, clonal ['l6', 'l17', 'l25', 'l40', 'l52', 'l61', 'l69', 'l76', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "63, expansion ['l7', 'l18', 'l26', 'l32', 'l41', 'l53', 'l62', 'l70', 'l77', 'l85', 'l91', 'l92', 'l93', 'l94', 'l95']", + "65, anergic ['l8', 'l19', 'l27', 'l33', 'l42', 'l54', 'l63', 'l71', 'l78', 'l86', 'l91', 'l96', 'l97', 'l98', 'l99']", + "66, T ['l9', 'l20', 'l28', 'l34', 'l43', 'l55', 'l64', 'l72', 'l79', 'l87', 'l92', 'l96', 'l100', 'l101', 'l102']", + "67, cells ['l10', 'l21', 'l29', 'l35', 'l44', 'l56', 'l65', 'l73', 'l80', 'l88', 'l93', 'l97', 'l100', 'l103', 'l104']", + "68, in ['l11', 'l30', 'l45', 'l57', 'l66', 'l74', 'l81', 'l89', 'l94', 'l98', 'l101', 'l103', 'l105']", + "69, vitro ['l12', 'l31', 'l46', 'l58', 'l67', 'l75', 'l82', 'l90', 'l95', 'l99', 'l102', 'l104', 'l105', 'l106']", + "71, in ['l47', 'l83', 'l107', 'l108']", + "72, vivo. ['l48', 'l84', 'l106', 'l107']", + "75, anergic ['l109']", + "76, cells, ['l108', 'l109']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "anergic", + "alloreactive", + "mouse", + "T", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blockade" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "anergic", + "human", + "T-cell", + "clones", + "alloreactive", + "mouse", + "T", + "cells" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonal", + "expansion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blockade" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonal", + "expansion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blockade" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blockade" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "clonal", + "expansion" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "10655105", + "TEXT": "Here we show that the cell-cycle regulator p21 is involved in immune system function. T lymphocytes from p21-/- mice exhibit significant proliferative advantage over wild-type cells following prolonged stimulation, but not after primary activation. Consistent with this, p21-deficient mice accumulate abnormal amounts of CD4+ memory cells, and develop loss of tolerance towards nuclear antigens. Similar to human lupus, female p21-deficient mice develop antibodies against dsDNA, lymphadenopathy, and glomerulonephritis, leading to decreased viability. These data demonstrate a specialized role for p21 in the control of T-cell proliferation, tolerance to nuclear antigens, and female-prone lupus. These findings could be the basis for new therapeutic approaches to lupus.", + "TAG_DATA": [ + "14, T {'context': 'B-cells'}", + "15, lymphocytes {'context': 'I-cells'}", + "17, p21-/- {'perturbing_action': 'B-gene loss-of-function'}", + "18, mice {'context': 'B-organism'}", + "21, proliferative {'phenotype': 'B-proliferation'}", + "22, advantage {'phenotype': 'I-proliferation'}", + "25, cells {'context': 'B-cells'}", + "37, p21-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "38, mice {'context': 'B-organism'}", + "43, CD4+ {'context': 'B-cells'}", + "44, memory {'context': 'I-cells'}", + "45, cells, {'context': 'I-cells'}", + "58, female {'perturbing_action': 'B-gene loss-of-function'}", + "59, p21-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "60, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "14, T ['l0', 'l1', 'l2', 'l3', 'l4']", + "15, lymphocytes ['l0', 'l5', 'l6', 'l7', 'l8', 'l9']", + "17, p21-/- ['l5', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "18, mice ['l1', 'l6', 'l10', 'l17', 'l18', 'l19']", + "21, proliferative ['l2', 'l7', 'l11', 'l17', 'l20', 'l21']", + "22, advantage ['l3', 'l8', 'l12', 'l18', 'l20', 'l22']", + "25, cells ['l4', 'l9', 'l13', 'l19', 'l21', 'l22']", + "37, p21-deficient ['l23', 'l24', 'l25', 'l26', 'l27']", + "38, mice ['l23', 'l28', 'l29', 'l30']", + "43, CD4+ ['l14', 'l24', 'l28', 'l31', 'l32']", + "44, memory ['l15', 'l25', 'l29', 'l31', 'l33']", + "45, cells, ['l16', 'l26', 'l30', 'l32', 'l33']", + "58, female ['l34', 'l35']", + "59, p21-deficient ['l34', 'l36']", + "60, mice ['l27', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "lymphocytes", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "advantage" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "lymphocytes", + "cells", + "CD4+", + "memory", + "cells," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p21-/-", + "p21-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p21-/-", + "p21-deficient", + "female" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p21-/-" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "advantage" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "advantage" + ] + } + } + ] + }, + { + "PMID": "10613833", + "TEXT": "Metastasis is a frequent complication of cancer, yet the process through which circulating tumor cells form distant colonies is poorly understood. We have been able to observe the steps in early hematogenous metastasis by epifluorescence microscopy of tumor cells expressing green fluorescent protein in subpleural microvessels in intact, perfused mouse and rat lungs. Metastatic tumor cells attached to the endothelia of pulmonary pre-capillary arterioles and capillaries. Extravasation of tumor cells was rare, and it seemed that the transmigrated cells were cleared quickly by the lung, leaving only the endothelium-attached cells as the seeds of secondary tumors. Early colonies were entirely within the blood vessels. Although most models of metastasis include an extravasation step early in the process, here we show that in the lung, metastasis is initiated by attachment of tumor cells to the vascular endothelium and that hematogenous metastasis originates from the proliferation of attached intravascular tumor cells rather than from extravasated ones. Intravascular metastasis formation would make early colonies especially vulnerable to intravascular drugs, and this possibility has potential for the prevention of tumor cell attachment to the endothelium.", + "TAG_DATA": [ + "49, mouse {'context': 'B-tissue/organ'}", + "50, and {'context': 'I-tissue/organ'}", + "51, rat {'context': 'I-tissue/organ'}", + "52, lungs. {'context': 'I-tissue/organ'}", + "53, Metastatic {'context': 'B-transformed cells'}", + "54, tumor {'context': 'I-transformed cells'}", + "55, cells {'context': 'I-transformed cells'}", + "123, lung, {'context': 'B-tissue/organ'}", + "124, metastasis {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "49, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "50, and ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "51, rat ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "52, lungs. ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "53, Metastatic ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "54, tumor ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "55, cells ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "123, lung, ['l21']", + "124, metastasis ['l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "lung," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + } + ] + }, + { + "PMID": "10613832", + "TEXT": "Hepatocellular carcinoma (HCC) is one of the most common cancers in Asia and Africa, where hepatitis virus infection and exposure to specific liver carcinogens are prevalent. Although inactivation of some tumor suppressor genes such as p53 and p16INK4Ahas been identified, no known oncogene is commonly activated in hepatocellular carcinomas. Here we have isolated genes overexpressed in hepatocellular carcinomas by cDNA subtractive hybridization, and identified an oncoprotein consisting of six ankyrin repeats (gankyrin). The expression of gankyrin was increased in all 34 hepatocellular carcinomas studied. Gankyrin induced anchorage-independent growth and tumorigenicity in NIH/3T3 cells. Gankyrin bound to the product of the retinoblastoma gene (RB1), increasing its phosphorylation and releasing the activity of the transcription factor E2F-1. Gankyrin accelerated the degradation of RB1 in vitro and in vivo, and was identical to or interacted with a subunit of the 26S proteasome. These results demonstrate the importance of ubiquitin-proteasome pathway in the regulation of cell growth and oncogenic transformation, and indicate that gankyrin overexpression contributes to hepatocarcinogenesis by destabilizing RB1.", + "TAG_DATA": [ + "85, induced {'effect': 'B-positive'}", + "89, tumorigenicity {'phenotype': 'B-tumourigenesis'}", + "91, NIH/3T3 {'context': 'B-cells'}", + "92, cells. {'context': 'I-cells'}", + "121, in {'context': 'B-in vitro'}", + "122, vitro {'context': 'I-in vitro'}", + "124, in {'context': 'B-in vivo'}", + "125, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "85, induced ['l0', 'l1']", + "89, tumorigenicity ['l0', 'l2', 'l3']", + "91, NIH/3T3 ['l2', 'l4']", + "92, cells. ['l1', 'l3', 'l4']", + "121, in ['l5', 'l6', 'l7']", + "122, vitro ['l5', 'l8', 'l9']", + "124, in ['l6', 'l8', 'l10']", + "125, vivo, ['l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity" + ] + }, + "context": { + "val": "cells", + "words": [ + "NIH/3T3", + "cells." + ] + } + } + ] + }, + { + "PMID": "10613822", + "TEXT": "Thrombospondin-1 (TSP-1) is a naturally occurring inhibitor of angiogenesis that limits vessel density in normal tissues and curtails tumor growth. Here, we show that the inhibition of angiogenesis in vitro and in vivo and the induction of apoptosis by thrombospondin-1 all required the sequential activation of CD36, p59fyn, caspase-3 like proteases and p38 mitogen-activated protein kinases. We also detected increased endothelial cell apoptosis in situ at the margins of tumors in mice treated with thrombospondin-1. These results indicate that thrombospondin-1, and possibly other broad-spectrum natural inhibitors of angiogenesis, act in vivo by inducing receptor-mediated apoptosis in activated microvascular endothelial cells.", + "TAG_DATA": [ + "28, in {'context': 'B-in vitro'}", + "29, vitro {'context': 'I-in vitro'}", + "31, in {'context': 'B-in vivo'}", + "32, vivo {'context': 'I-in vivo'}", + "35, induction {'effect': 'B-positive'}", + "37, apoptosis {'phenotype': 'B-apoptosis'}", + "59, increased {'effect': 'B-positive'}", + "60, endothelial {'context': 'B-cells'}", + "61, cell {'context': 'I-cells'}", + "62, apoptosis {'phenotype': 'B-apoptosis'}", + "69, tumors {'context': 'B-neoplasm'}", + "71, mice {'context': 'B-organism'}", + "89, in {'context': 'B-in vivo'}", + "92, inducing {'effect': 'B-positive'}", + "94, apoptosis {'phenotype': 'B-apoptosis'}", + "97, microvascular {'context': 'B-cells'}", + "98, endothelial {'context': 'I-cells'}", + "99, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "28, in ['l0']", + "29, vitro ['l0']", + "31, in ['l1', 'l2', 'l3']", + "32, vivo ['l1', 'l4', 'l5']", + "35, induction ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "37, apoptosis ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "59, increased ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "60, endothelial ['l2', 'l4', 'l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "61, cell ['l3', 'l5', 'l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "62, apoptosis ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "69, tumors ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']", + "71, mice ['l27', 'l28', 'l29']", + "89, in ['l30', 'l31', 'l32', 'l33', 'l34']", + "92, inducing ['l30', 'l35', 'l36', 'l37', 'l38']", + "94, apoptosis ['l31', 'l35', 'l39', 'l40', 'l41']", + "97, microvascular ['l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "98, endothelial ['l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "99, cells. ['l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induction", + "increased", + "inducing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction", + "increased", + "inducing" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell", + "microvascular", + "cells." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction", + "increased" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell", + "microvascular", + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "10581084", + "TEXT": "Transplantation approaches using cellular bridges, fetal central nervous system cells, fibroblasts expressing neurotrophin-3 (ref. 6), hybridoma cells expressing inhibitory protein-blocking antibodies, or olfactory nerves ensheathing glial cells transplanted into the acutely injured spinal cord have produced axonal regrowth or functional benefits. Transplants of rat or cat fetal spinal cord tissue into the chronically injured cord survive and integrate with the host cord, and may be associated with some functional improvements. In addition, rats transplanted with fetal spinal cord cells have shown improvements in some gait parameters, and the delayed transplantation of fetal raphe cells can enhance reflexes. We transplanted neural differentiated mouse embryonic stem cells into a rat spinal cord 9 days after traumatic injury. Histological analysis 2-5 weeks later showed that transplant-derived cells survived and differentiated into astrocytes, oligodendrocytes and neurons, and migrated as far as 8 mm away from the lesion edge. Furthermore, gait analysis demonstrated that transplanted rats showed hindlimb weight support and partial hindlimb coordination not found in 'sham-operated' controls or control rats transplanted with adult mouse neocortical cells.", + "TAG_DATA": [ + "99, neural {'context': 'B-cells'}", + "100, differentiated {'context': 'I-cells'}", + "101, mouse {'context': 'I-cells'}", + "102, embryonic {'context': 'I-cells'}", + "103, stem {'context': 'I-cells'}", + "104, cells {'context': 'I-cells'}", + "107, rat {'context': 'B-tissue/organ'}", + "108, spinal {'context': 'I-tissue/organ'}", + "109, cord {'context': 'I-tissue/organ'}", + "123, cells {'context': 'I-cells'}", + "126, differentiated {'phenotype': 'B-differentiation'}", + "128, astrocytes, {'context': 'B-cells'}", + "129, oligodendrocytes {'context': 'B-cells'}", + "131, neurons, {'context': 'B-cells'}", + "150, rats {'context': 'B-organism'}", + "166, rats {'context': 'B-organism'}", + "169, adult {'context': 'B-cells'}", + "170, mouse {'context': 'I-cells'}", + "171, neocortical {'context': 'I-cells'}", + "172, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "99, neural ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "100, differentiated ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "101, mouse ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "102, embryonic ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "103, stem ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "104, cells ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "107, rat ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "108, spinal ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74']", + "109, cord ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l75', 'l76', 'l77']", + "123, cells ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l78', 'l79', 'l80', 'l81']", + "126, differentiated ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l71', 'l78', 'l82', 'l83', 'l84']", + "128, astrocytes, ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l72', 'l75', 'l79', 'l82', 'l85', 'l86']", + "129, oligodendrocytes ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l73', 'l76', 'l80', 'l83', 'l85', 'l87']", + "131, neurons, ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l74', 'l77', 'l81', 'l84', 'l86', 'l87']", + "150, rats ['l88', 'l89', 'l90', 'l91', 'l92']", + "166, rats ['l88', 'l93', 'l94', 'l95', 'l96']", + "169, adult ['l89', 'l93', 'l97', 'l98', 'l99']", + "170, mouse ['l90', 'l94', 'l97', 'l100', 'l101']", + "171, neocortical ['l91', 'l95', 'l98', 'l100', 'l102']", + "172, cells. ['l92', 'l96', 'l99', 'l101', 'l102']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "neural", + "differentiated", + "mouse", + "embryonic", + "stem", + "cells", + "astrocytes,", + "oligodendrocytes", + "neurons," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiated" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "spinal" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiated" + ] + } + } + ] + }, + { + "PMID": "10581080", + "TEXT": "The acceleration of atherosclerosis by polygenic (essential) hypertension is well-characterized in humans; however, the lack of an animal model that simulates human disease hinders the elucidation of pathogenic mechanisms. We report here a transgenic atherosclerosis-polygenic hypertension model in Dahl salt-sensitive hypertensive rats that overexpress the human cholesteryl ester transfer protein (Tg[hCETP]DS). Male Tg[hCETP]DS rats fed regular rat chow showed age-dependent severe combined hyperlipidemia, atherosclerotic lesions, myocardial infarctions and decreased survival. These findings differ from various mouse atherosclerosis models, demonstrating the necessity of complex disease modeling in different species. The data demonstrate that cholesteryl ester transfer protein can be proatherogenic. The interaction of polygenic hypertension and hyperlipidemia in the pathogenesis of atherosclerosis in Tg[hCETP]DS rats substantiates epidemiological observations in humans.", + "TAG_DATA": [ + "38, Dahl {'context': 'B-organism'}", + "39, salt-sensitive {'context': 'I-organism'}", + "40, hypertensive {'context': 'I-organism'}", + "41, rats {'context': 'I-organism'}", + "43, overexpress {'perturbing_action': 'B-gene gain-of-function'}", + "44, the {'perturbing_action': 'I-gene gain-of-function'}", + "45, human {'perturbing_action': 'I-gene gain-of-function'}", + "46, cholesteryl {'perturbing_action': 'I-gene gain-of-function'}", + "47, ester {'perturbing_action': 'I-gene gain-of-function'}", + "48, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "49, protein {'perturbing_action': 'I-gene gain-of-function'}", + "50, (Tg[hCETP]DS). {'perturbing_action': 'I-gene gain-of-function'}", + "51, Male {'context': 'B-organism'}", + "53, rats {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "38, Dahl ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "39, salt-sensitive ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "40, hypertensive ['l1', 'l10', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "41, rats ['l2', 'l11', 'l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "43, overexpress ['l12', 'l21', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "44, the ['l3', 'l13', 'l22', 'l29', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "45, human ['l4', 'l14', 'l23', 'l30', 'l37', 'l45', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "46, cholesteryl ['l5', 'l15', 'l24', 'l31', 'l38', 'l46', 'l53', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "47, ester ['l6', 'l16', 'l25', 'l32', 'l39', 'l47', 'l54', 'l60', 'l66', 'l67', 'l68', 'l69', 'l70']", + "48, transfer ['l7', 'l17', 'l26', 'l33', 'l40', 'l48', 'l55', 'l61', 'l66', 'l71', 'l72', 'l73', 'l74']", + "49, protein ['l8', 'l18', 'l27', 'l34', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l75', 'l76', 'l77']", + "50, (Tg[hCETP]DS). ['l9', 'l19', 'l28', 'l35', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l78', 'l79']", + "51, Male ['l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l76', 'l78', 'l80']", + "53, rats ['l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l79', 'l80']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Dahl", + "salt-sensitive", + "hypertensive", + "rats", + "Male" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "the", + "human", + "cholesteryl", + "ester", + "transfer", + "protein", + "(Tg[hCETP]DS).", + "overexpress" + ] + } + } + ] + }, + { + "PMID": "10545997", + "TEXT": "The alloimmune response against fully MHC-mismatched allografts, compared with immune responses to nominal antigens, entails an unusually large clonal size of alloreactive T cells. Thus, induction of peripheral allograft tolerance established in the absence of immune system ablation and reconstitution is a challenging task in transplantation. Here, we determined whether a reduction in the mass of alloreactive T cells due to apoptosis is an essential initial step for induction of stable allograft tolerance with non-lymphoablative therapy. Blocking both CD28-B7 and CD40-CD40 ligand interactions (co-stimulation blockade) inhibited proliferation of alloreactive T cells in vivo while allowing cell cycle-dependent T-cell apoptosis of proliferating T cells, with permanent engraftment of cardiac allografts but not skin allografts. Treatment with rapamycin plus co-stimulation blockade resulted in massive apoptosis of alloreactive T cells and produced stable skin allograft tolerance, a very stringent test of allograft tolerance. In contrast, treatment with cyclosporine A and co-stimulation blockade abolished T-cell proliferation and apoptosis, as well as the induction of stable allograft tolerance. Our data indicate that induction of T-cell apoptosis and peripheral allograft tolerance is prevented by blocking both signal 1 and signal 2 of T-cell activation.", + "TAG_DATA": [ + "85, inhibited {'effect': 'B-negative'}", + "86, proliferation {'phenotype': 'B-proliferation'}", + "88, alloreactive {'context': 'B-cells'}", + "89, T {'context': 'I-cells'}", + "90, cells {'context': 'I-cells'}", + "91, in {'context': 'B-in vivo'}", + "92, vivo {'context': 'I-in vivo'}", + "94, allowing {'effect': 'B-positive'}", + "97, T-cell {'context': 'B-cells'}", + "98, apoptosis {'phenotype': 'B-apoptosis'}", + "100, proliferating {'context': 'B-cells'}", + "101, T {'context': 'I-cells'}", + "102, cells, {'context': 'I-cells'}", + "107, cardiac {'context': 'B-tissue/organ'}", + "108, allografts {'context': 'I-xenograft'}", + "111, skin {'context': 'B-tissue/organ'}", + "112, allografts. {'context': 'I-xenograft'}", + "119, resulted {'effect': 'B-positive'}", + "120, in {'effect': 'I-positive'}", + "122, apoptosis {'phenotype': 'B-apoptosis'}", + "124, alloreactive {'context': 'B-cells'}", + "125, T {'context': 'I-cells'}", + "126, cells {'context': 'I-cells'}", + "149, abolished {'effect': 'B-negative'}", + "150, T-cell {'context': 'B-cells'}", + "151, proliferation {'phenotype': 'B-proliferation'}", + "153, apoptosis, {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "85, inhibited ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "86, proliferation ['l0', 'l8', 'l9', 'l10', 'l11', 'l12']", + "88, alloreactive ['l1', 'l8', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "89, T ['l2', 'l9', 'l13', 'l20', 'l21', 'l22', 'l23']", + "90, cells ['l3', 'l10', 'l14', 'l20', 'l24', 'l25']", + "91, in ['l4', 'l11', 'l15', 'l21', 'l24', 'l26', 'l27', 'l28']", + "92, vivo ['l5', 'l12', 'l16', 'l22', 'l25', 'l26', 'l29']", + "94, allowing ['l17', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "97, T-cell ['l30', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "98, apoptosis ['l31', 'l39', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "100, proliferating ['l32', 'l40', 'l47', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "101, T ['l6', 'l18', 'l27', 'l33', 'l41', 'l48', 'l54', 'l60', 'l61', 'l62', 'l63', 'l64']", + "102, cells, ['l7', 'l19', 'l23', 'l28', 'l29', 'l34', 'l42', 'l49', 'l55', 'l60', 'l65', 'l66', 'l67', 'l68']", + "107, cardiac ['l35', 'l43', 'l50', 'l56', 'l61', 'l65', 'l69', 'l70', 'l71']", + "108, allografts ['l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l69', 'l72', 'l73']", + "111, skin ['l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l70', 'l72', 'l74']", + "112, allografts. ['l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l73', 'l74']", + "119, resulted ['l75', 'l76', 'l77', 'l78', 'l79']", + "120, in ['l75', 'l80', 'l81', 'l82', 'l83']", + "122, apoptosis ['l76', 'l80', 'l84', 'l85', 'l86']", + "124, alloreactive ['l77', 'l81', 'l84', 'l87', 'l88']", + "125, T ['l78', 'l82', 'l85', 'l87', 'l89']", + "126, cells ['l79', 'l83', 'l86', 'l88', 'l89']", + "149, abolished ['l90', 'l91', 'l92']", + "150, T-cell ['l90', 'l93', 'l94']", + "151, proliferation ['l91', 'l93', 'l95']", + "153, apoptosis, ['l92', 'l94', 'l95']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "abolished" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "abolished" + ] + }, + "context": { + "val": "cells", + "words": [ + "alloreactive", + "T", + "cells", + "cells,", + "T-cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "alloreactive", + "T", + "cells", + "T-cell" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "alloreactive", + "T-cell", + "proliferating", + "T", + "cells,", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "allowing", + "resulted", + "in" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "allowing", + "resulted", + "in" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "allowing" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "cardiac", + "skin" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "allowing" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "allografts", + "allografts." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T-cell", + "proliferating", + "T", + "cells,", + "alloreactive", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "cardiac", + "skin" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "allografts", + "allografts." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abolished" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + } + ] + }, + { + "PMID": "10545994", + "TEXT": "Thrombospondin forms a 'molecular bridge' between phagocytic and apoptotic cells through interaction with alphavbeta3/CD36. We report here that engagement of CD47, a newly described thrombospondin receptor, by immobilized monoclonal antibody against CD47 or by thrombospondin induced in all B-cell chronic lymphocytic leukemia clones the cytoplasmic features of apoptosis (cell shrinkage, decrease in mitochondrial transmembrane potential and phosphatidylserine externalization) without the nuclear features (chromatin condensation, appearance of single-stranded DNA, DNA fragmentation and cleavage of poly ADP-ribose polymerase). These cytoplasmic events of apoptosis were not prevented by the addition of caspase inhibitor z-VAD-fmk, or by the presence of survival factors (such as interleukin-4 and gamma interferon) or cell activation. Morphological studies confirmed the integrity of the nucleus and showed swelling of the mitochondria. This caspase-independent death pathway may be relevant to the development of alternate therapeutic strategies in chronic lymphocytic leukemia, which remains an incurable disease.", + "TAG_DATA": [ + "35, induced {'effect': 'B-positive'}", + "38, B-cell {'context': 'B-transformed cells'}", + "39, chronic {'context': 'I-transformed cells'}", + "40, lymphocytic {'context': 'I-transformed cells'}", + "41, leukemia {'context': 'I-transformed cells'}", + "42, clones {'context': 'I-transformed cells'}", + "47, apoptosis {'phenotype': 'B-apoptosis'}", + "80, apoptosis {'phenotype': 'B-apoptosis'}", + "105, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "35, induced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "38, B-cell ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "39, chronic ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "40, lymphocytic ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "41, leukemia ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "42, clones ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "47, apoptosis ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "105, cell ['l21']", + "106, activation. ['l21']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "B-cell", + "chronic", + "lymphocytic", + "leukemia", + "clones" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "B-cell", + "chronic", + "lymphocytic", + "leukemia", + "clones" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "10545992", + "TEXT": "Early growth response factor-1 (Egr-1) binds to the promoters of many genes whose products influence cell movement and replication in the artery wall. Here we targeted Egr-1 using a new class of DNA-based enzyme that specifically cleaved Egr-1 mRNA, blocked induction of Egr-1 protein, and inhibited cell proliferation and wound repair in culture. The DNA enzyme also inhibited Egr-1 induction and neointima formation after balloon injury to the rat carotid artery wall. These findings demonstrate the utility of DNA enzymes as biological tools to delineate the specific functions of a given gene, and implicate catalytic nucleic acid molecules composed entirely of DNA as potential therapeutic agents.", + "TAG_DATA": [ + "45, inhibited {'effect': 'B-negative'}", + "46, cell {'context': 'B-cells'}", + "47, proliferation {'phenotype': 'B-proliferation'}", + "52, culture. {'context': 'B-cells'}", + "57, inhibited {'effect': 'B-negative'}", + "61, neointima {'phenotype': 'B-tumourigenesis'}", + "62, formation {'phenotype': 'I-tumourigenesis'}", + "68, rat {'context': 'B-tissue/organ'}", + "69, carotid {'context': 'I-tissue/organ'}", + "70, artery {'context': 'I-tissue/organ'}", + "71, wall. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "45, inhibited ['l0', 'l1', 'l2']", + "46, cell ['l0', 'l3', 'l4']", + "47, proliferation ['l1', 'l3', 'l5']", + "52, culture. ['l2', 'l4', 'l5']", + "57, inhibited ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "61, neointima ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "62, formation ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "68, rat ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "69, carotid ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "70, artery ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "71, wall. ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "culture." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell", + "culture." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neointima", + "formation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "carotid", + "artery", + "wall." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neointima", + "formation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "carotid", + "artery", + "wall." + ] + } + } + ] + }, + { + "PMID": "10502826", + "TEXT": "Platelet activation is characterized by shape change, induction of fibrinogen receptor expression and release of granular contents, leading to aggregation and plug formation. While this response is essential for hemostasis, it is also important in the pathogenesis of a broad spectrum of diseases, including myocardial infarction, stroke and unstable angina. Adenosine 5'-diphosphate (ADP) induces platelet aggregation, but the mechanism for this has not been established, and the relative contribution of ADP in hemostasis and the development of arterial thrombosis is poorly understood. We show here that the purinoceptor P2Y1 is required for platelet shape change in response to ADP and is also a principal receptor mediating ADP-induced platelet aggregation. Activation of P2Y1 resulted in increased intracellular calcium but no alteration in cyclic adenosine monophosphate (cAMP) levels. P2Y1-deficient platelets partially aggregated at higher ADP concentrations, and the lack of P2Y1 did not alter the ability of ADP to inhibit cAMP, indicating that platelets express at least one additional ADP receptor. In vivo, the lack of P2Y1 expression increased bleeding time and protected from collagen- and ADP-induced thromboembolism. These findings support the hypothesis that the ATP receptor P2Y1 is a principal receptor mediating both physiologic and pathological ADP-induced processes in platelets.", + "TAG_DATA": [ + "126, P2Y1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "127, platelets {'context': 'B-cells'}", + "136, lack {'perturbing_action': 'B-gene loss-of-function'}", + "137, of {'perturbing_action': 'I-gene loss-of-function'}", + "138, P2Y1 {'perturbing_action': 'I-gene loss-of-function'}", + "159, In {'context': 'B-in vivo'}", + "160, vivo, {'context': 'I-in vivo'}", + "162, lack {'perturbing_action': 'B-gene loss-of-function'}", + "163, of {'perturbing_action': 'I-gene loss-of-function'}", + "164, P2Y1 {'perturbing_action': 'I-gene loss-of-function'}", + "165, expression {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "126, P2Y1-deficient ['l0']", + "127, platelets ['l0']", + "136, lack ['l1', 'l2']", + "137, of ['l1', 'l3']", + "138, P2Y1 ['l2', 'l3']", + "159, In ['l4', 'l5', 'l6', 'l7', 'l8']", + "160, vivo, ['l4', 'l9', 'l10', 'l11', 'l12']", + "162, lack ['l5', 'l9', 'l13', 'l14', 'l15']", + "163, of ['l6', 'l10', 'l13', 'l16', 'l17']", + "164, P2Y1 ['l7', 'l11', 'l14', 'l16', 'l18']", + "165, expression ['l8', 'l12', 'l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "P2Y1-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelets" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "P2Y1", + "expression" + ] + } + } + ] + }, + { + "PMID": "10502824", + "TEXT": "Neuropeptide Y (NPY), a 36-amino-acid peptide widely expressed in the brain is involved in many physiological responses, including hypothalamic control of food intake and cardiovascular homeostasis. NPY mediates its effects through binding to the Y1, Y2 and Y5 G-protein-coupled receptors. Little is known of the role of the Y2 receptor in mediating the different NPY effects. We inactivated the Y2 receptor subtype in mice and found that these mice developed increased body weight, food intake and fat deposition. The null mutant mice showed an attenuated response to leptin administration but a normal response to NPY-induced food intake and intact regulation of re-feeding and body weight after starvation. An absence of the Y2 receptor subtype also affected the basal control of heart rate, but did not influence blood pressure. These findings indicate an inhibitory role for the Y2 receptor subtype in the central regulation of body weight and control of food intake.", + "TAG_DATA": [ + "57, inactivated {'perturbing_action': 'B-gene loss-of-function'}", + "58, the {'perturbing_action': 'I-gene loss-of-function'}", + "59, Y2 {'perturbing_action': 'I-gene loss-of-function'}", + "60, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "61, subtype {'perturbing_action': 'I-gene loss-of-function'}", + "63, mice {'context': 'B-organism'}", + "68, mice {'context': 'B-organism'}", + "79, null {'perturbing_action': 'B-gene loss-of-function'}", + "81, mice {'context': 'B-organism'}", + "108, absence {'perturbing_action': 'B-gene loss-of-function'}", + "109, of {'perturbing_action': 'I-gene loss-of-function'}", + "110, the {'perturbing_action': 'I-gene loss-of-function'}", + "111, Y2 {'perturbing_action': 'I-gene loss-of-function'}", + "112, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "113, subtype {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "57, inactivated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "58, the ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "59, Y2 ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "60, receptor ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "61, subtype ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "63, mice ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "68, mice ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "79, null ['l21', 'l22']", + "80, mutant ['l21', 'l23']", + "81, mice ['l22', 'l23']", + "108, absence ['l24', 'l25', 'l26', 'l27', 'l28']", + "109, of ['l24', 'l29', 'l30', 'l31', 'l32']", + "110, the ['l25', 'l29', 'l33', 'l34', 'l35']", + "111, Y2 ['l26', 'l30', 'l33', 'l36', 'l37']", + "112, receptor ['l27', 'l31', 'l34', 'l36', 'l38']", + "113, subtype ['l28', 'l32', 'l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivated", + "the", + "Y2", + "receptor", + "subtype", + "null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "10502816", + "TEXT": "Cardiac rupture is a fatal complication of acute myocardial infarction lacking treatment. Here, acute myocardial infarction resulted in rupture in wild-type mice and in mice lacking tissue-type plasminogen activator, urokinase receptor, matrix metalloproteinase stromelysin-1 or metalloelastase. Instead, deficiency of urokinase-type plasminogen activator (u-PA-/-) completely protected against rupture, whereas lack of gelatinase-B partially protected against rupture. However, u-PA-/- mice showed impaired scar formation and infarct revascularization, even after treatment with vascular endothelial growth factor, and died of cardiac failure due to depressed contractility, arrhythmias and ischemia. Temporary administration of PA inhibitor-1 or the matrix metalloproteinase-inhibitor TIMP-1 completely protected wild-type mice against rupture but did not abort infarct healing, thus constituting a new approach to prevent cardiac rupture after acute myocardial infarction.", + "TAG_DATA": [ + "21, mice {'context': 'B-organism'}", + "24, mice {'context': 'B-organism'}", + "25, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "37, deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "38, of {'perturbing_action': 'I-gene loss-of-function'}", + "39, urokinase-type {'perturbing_action': 'I-gene loss-of-function'}", + "40, plasminogen {'perturbing_action': 'I-gene loss-of-function'}", + "41, activator {'perturbing_action': 'I-gene loss-of-function'}", + "42, (u-PA-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "48, lack {'perturbing_action': 'B-gene loss-of-function'}", + "49, of {'perturbing_action': 'I-gene loss-of-function'}", + "50, gelatinase-B {'perturbing_action': 'I-gene loss-of-function'}", + "56, u-PA-/- {'perturbing_action': 'B-gene loss-of-function'}", + "57, mice {'context': 'B-organism'}", + "98, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "24, mice ['l0', 'l1']", + "25, lacking ['l0', 'l2']", + "37, deficiency ['l3', 'l4', 'l5', 'l6', 'l7']", + "38, of ['l3', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "39, urokinase-type ['l4', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "40, plasminogen ['l5', 'l9', 'l14', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "41, activator ['l6', 'l10', 'l15', 'l21', 'l27', 'l28', 'l29', 'l30']", + "42, (u-PA-/-) ['l1', 'l2', 'l7', 'l11', 'l16', 'l22', 'l27']", + "48, lack ['l17', 'l23', 'l31', 'l32', 'l33', 'l34']", + "49, of ['l18', 'l24', 'l28', 'l31', 'l35', 'l36', 'l37']", + "50, gelatinase-B ['l12', 'l19', 'l25', 'l29', 'l32', 'l35', 'l38', 'l39']", + "56, u-PA-/- ['l33', 'l36', 'l38', 'l40']", + "57, mice ['l13', 'l20', 'l26', 'l30', 'l34', 'l37', 'l39', 'l40']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "(u-PA-/-)", + "of", + "urokinase-type", + "plasminogen", + "activator", + "lack", + "gelatinase-B", + "u-PA-/-" + ] + } + } + ] + }, + { + "PMID": "10470087", + "TEXT": "Pro-opiomelanocortin (POMC)-derived peptides (the melanocortins adrenocorticotropin, alpha-, beta- and gamma-melanocyte stimulating hormone; and the endogenous opioid beta-endorphin) have a diverse array of biological activities, including roles in pigmentation, adrenocortical function and regulation of energy stores, and in the immune system and the central and peripheral nervous systems. We show here that mice lacking the POMC-derived peptides have obesity, defective adrenal development and altered pigmentation. This phenotype is similar to that of the recently identified human POMC-deficient patients. When treated with a stable alpha-melanocyte-stimulating hormone agonist, mutant mice lost more than 40% of their excess weight after 2 weeks. Our results identify the POMC-null mutant mouse as a model for studying the human POMC-null syndrome, and indicate the therapeutic use of peripheral melanocortin in the treatment of obesity.", + "TAG_DATA": [ + "51, mice {'context': 'B-organism'}", + "52, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "53, the {'perturbing_action': 'I-gene loss-of-function'}", + "54, POMC-derived {'perturbing_action': 'I-gene loss-of-function'}", + "55, peptides {'perturbing_action': 'I-gene loss-of-function'}", + "86, mice {'context': 'B-organism'}", + "102, POMC-null {'perturbing_action': 'B-gene loss-of-function'}", + "103, mutant {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "51, mice ['l0', 'l1', 'l2', 'l3']", + "52, lacking ['l0', 'l4', 'l5', 'l6']", + "53, the ['l1', 'l4', 'l7', 'l8']", + "54, POMC-derived ['l2', 'l5', 'l7', 'l9']", + "55, peptides ['l3', 'l6', 'l8', 'l9']", + "102, POMC-null ['l10']", + "103, mutant ['l10']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "POMC-derived", + "peptides" + ] + } + } + ] + }, + { + "PMID": "10470081", + "TEXT": "Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that causes life-threatening disease in patients who are immunosuppressed for bone marrow or tissue transplantation or who have AIDS (ref. 1). HCMV establishes lifelong latent infections and, after periodic reactivation from latency, uses a panel of immune evasion proteins to survive and replicate in the face of robust, fully primed host immunity. Monocyte/macrophages are important host cells for HCMV, serving as a latent reservoir and as a means of dissemination throughout the body. Macrophages and other HCMV-permissive cells, such as endothelial and glial cells, can express MHC class II proteins and present antigens to CD4+ T lymphocytes. Here, we show that the HCMV protein US2 causes degradation of two essential proteins in the MHC class II antigen presentation pathway: HLA-DR-alpha and DM-alpha. This was unexpected, as US2 has been shown to cause degradation of MHC class I (refs. 5,6), which has only limited homology with class II proteins. Expression of US2 in cells reduced or abolished their ability to present antigen to CD4+ T lymphocytes. Thus, US2 may allow HCMV-infected macrophages to remain relatively 'invisible' to CD4+ T cells, a property that would be important after virus reactivation.", + "TAG_DATA": [ + "155, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "156, of {'perturbing_action': 'I-gene gain-of-function'}", + "157, US2 {'perturbing_action': 'I-gene gain-of-function'}", + "159, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "155, Expression ['l0', 'l1', 'l2']", + "156, of ['l0', 'l3', 'l4']", + "157, US2 ['l1', 'l3', 'l5']", + "159, cells ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "US2" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "10470075", + "TEXT": "Infection of macrophage lineage cells is a feature of primate lentivirus replication, and several properties of primate lentiviruses seem to have evolved to promote the infection of macrophages. Here we demonstrate that the accessory gene product Nef induces the production of two CC-chemokines, macrophage inflammatory proteins 1alpha and 1beta, by HIV-1-infected macrophages. Adenovirus-mediated expression of Nef in primary macrophages was sufficient for chemokine induction. Supernatants from Nef-expressing macrophages induced both the chemotaxis and activation of resting T lymphocytes, permitting productive HIV-1 infection. These results indicate a role for Nef in lymphocyte recruitment and activation at sites of virus replication.", + "TAG_DATA": [ + "51, macrophages. {'context': 'B-cells'}", + "52, Adenovirus-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "53, expression {'perturbing_action': 'I-gene gain-of-function'}", + "54, of {'perturbing_action': 'I-gene gain-of-function'}", + "55, Nef {'perturbing_action': 'I-gene gain-of-function'}", + "57, primary {'context': 'B-cells'}", + "58, macrophages {'context': 'I-cells'}", + "66, Nef-expressing {'context': 'B-cells'}", + "67, macrophages {'context': 'I-cells'}", + "68, induced {'effect': 'B-positive'}", + "71, chemotaxis {'phenotype': 'B-migration'}", + "76, T {'context': 'B-cells'}", + "77, lymphocytes, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "52, Adenovirus-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "53, expression ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "54, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "55, Nef ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "57, primary ['l3', 'l11', 'l18', 'l24', 'l30']", + "58, macrophages ['l4', 'l12', 'l19', 'l25', 'l30', 'l31']", + "66, Nef-expressing ['l32', 'l33', 'l34', 'l35', 'l36']", + "67, macrophages ['l32', 'l37', 'l38', 'l39', 'l40']", + "68, induced ['l5', 'l13', 'l20', 'l26', 'l31', 'l33', 'l37', 'l41', 'l42', 'l43']", + "71, chemotaxis ['l6', 'l14', 'l21', 'l27', 'l34', 'l38', 'l41', 'l44', 'l45']", + "76, T ['l7', 'l15', 'l22', 'l28', 'l35', 'l39', 'l42', 'l44', 'l46']", + "77, lymphocytes, ['l8', 'l16', 'l23', 'l29', 'l36', 'l40', 'l43', 'l45', 'l46']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenovirus-mediated", + "expression", + "of", + "Nef" + ] + }, + "context": { + "val": "cells", + "words": [ + "primary", + "macrophages", + "T", + "lymphocytes," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenovirus-mediated", + "expression", + "of", + "Nef" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenovirus-mediated", + "expression", + "of", + "Nef" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "macrophages", + "Nef-expressing", + "T", + "lymphocytes," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Nef-expressing", + "macrophages", + "T", + "lymphocytes," + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + } + } + ] + }, + { + "PMID": "10426319", + "TEXT": "Tumor-associated antigens that can be recognized by the immune system include the MAGE-family, p53, MUC-1, HER2/neu and p21ras. Despite their expression of these distinct antigens, tumor elimination by the immune system is often inefficient. Postulated mechanisms include insufficient expression of co-stimulatory or adhesion molecules by tumor cells, or defective processing and presentation of antigens on their cell surfaces. Tumor cells may also evade immune attack by expressing CD95 (APO-1/Fas) ligand or other molecules that induce apoptosis in activated T cells. Here we describe RCAS1 (receptor-binding cancer antigen expressed on SiSo cells), a membrane molecule expressed on human cancer cells. RCAS1 acts as a ligand for a putative receptor present on various human cell lines and normal peripheral lymphocytes such as T, B and NK cells. The receptor expression was enhanced by activation of the lymphocytes. RCAS1 inhibited the in vitro growth of receptor-expressing cells and induced apoptotic cell death. Given these results, tumor cells may evade immune surveillance by expression of RCAS1, which would suppress clonal expansion and induce apoptosis in RCAS1 receptor-positive immune cells.", + "TAG_DATA": [ + "138, in {'context': 'B-in vitro'}", + "139, vitro {'context': 'I-in vitro'}", + "142, receptor-expressing {'context': 'B-cells'}", + "143, cells {'context': 'I-cells'}", + "145, induced {'effect': 'B-positive'}", + "146, apoptotic {'phenotype': 'B-apoptosis'}", + "147, cell {'phenotype': 'I-apoptosis'}", + "148, death. {'phenotype': 'I-apoptosis'}" + ], + "LINK_DATA": [ + "138, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "139, vitro ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "142, receptor-expressing ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "143, cells ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "145, induced ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "146, apoptotic ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "147, cell ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "148, death. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "receptor-expressing", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "receptor-expressing", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "10426315", + "TEXT": "The central nervous dysfunctions of lethargy, fever and anorexia are manifestations of sepsis that seem to be mediated by increased cytokine production. Here we demonstrate that tumor necrosis factor (TNF)-alpha, an essential mediator of endotoxin-induced sepsis, prevents the proteasome-dependent degradation of RGS7, a regulator of G-protein signaling. The stabilization of RGS7 by TNF-alpha requires activation of the stress-activated protein kinase p38 and the presence of candidate mitogen-activated protein kinase phosphorylation sites. In vivo, RGS7 is rapidly upregulated in mouse brain after exposure to either endotoxin or TNF-alpha, a response that is nearly abrogated in mice lacking TNF receptor 1. Our findings indicate that TNF-mediated upregulation of RGS7 may contribute to sepsis-induced changes in central nervous function.", + "TAG_DATA": [ + "71, In {'context': 'B-in vivo'}", + "72, vivo, {'context': 'I-in vivo'}", + "78, mouse {'context': 'B-tissue/organ'}", + "79, brain {'context': 'I-tissue/organ'}", + "94, mice {'context': 'B-organism'}", + "95, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "96, TNF {'perturbing_action': 'I-gene loss-of-function'}", + "97, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "98, 1. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "71, In ['l0', 'l1', 'l2']", + "72, vivo, ['l0', 'l3', 'l4']", + "78, mouse ['l1', 'l3', 'l5']", + "79, brain ['l2', 'l4', 'l5']", + "94, mice ['l6', 'l7', 'l8', 'l9']", + "95, lacking ['l6', 'l10', 'l11', 'l12']", + "96, TNF ['l7', 'l10', 'l13', 'l14']", + "97, receptor ['l8', 'l11', 'l13', 'l15']", + "98, 1. ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "TNF", + "receptor", + "1." + ] + } + } + ] + }, + { + "PMID": "10426313", + "TEXT": "Intestinal inflammatory diseases are mediated by dysregulated immune responses to undefined luminal antigens. Feeding hen egg-white lysozyme to mice expressing a transgenic T-cell receptor that recognizes hen egg-white lysozyme peptide 46-61 resulted in no intestinal pathology; however, simultaneous administration of cyclooxygenase-2 inhibitors and dietary hen egg-white lysozyme resulted in increased proliferation of lamina propria mononuclear cells and crypt epithelial cells, crypt expansion and villus blunting. Lamina propria mononuclear cells produce high levels of cyclooxygenase-2-dependent arachidonic acid metabolites, which act as immunomodulators in the immune response to dietary antigen. These findings establish that cyclooxygenase-2-dependent arachidonic acid metabolites are essential in the development and maintenance of intestinal immune homeostasis.", + "TAG_DATA": [ + "18, mice {'context': 'B-organism'}", + "19, expressing {'perturbing_action': 'B-other'}", + "20, a {'perturbing_action': 'I-gene gain-of-function'}", + "21, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "22, T-cell {'perturbing_action': 'I-other'}", + "23, receptor {'perturbing_action': 'I-other'}", + "24, that {'perturbing_action': 'I-other'}", + "25, recognizes {'perturbing_action': 'I-other'}", + "30, 46-61 {'perturbing_action': 'I-other'}", + "40, cyclooxygenase-2 {'perturbing_action': 'B-pharmacological inhibition'}", + "41, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "49, increased {'effect': 'B-positive'}", + "50, proliferation {'phenotype': 'B-proliferation'}", + "52, lamina {'context': 'B-cells'}", + "53, propria {'context': 'I-cells'}", + "54, mononuclear {'context': 'I-cells'}", + "55, cells {'context': 'I-cells'}", + "57, crypt {'context': 'B-cells'}", + "58, epithelial {'context': 'I-cells'}", + "59, cells, {'context': 'I-cells'}", + "65, Lamina {'context': 'B-cells'}", + "66, propria {'context': 'B-cells'}", + "67, mononuclear {'context': 'I-cells'}", + "68, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "18, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "19, expressing ['l0', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "20, a ['l1', 'l18', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "21, transgenic ['l2', 'l19', 'l38', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "22, T-cell ['l3', 'l20', 'l39', 'l57', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "23, receptor ['l4', 'l21', 'l40', 'l58', 'l75', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "24, that ['l5', 'l22', 'l41', 'l59', 'l76', 'l92', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "25, recognizes ['l6', 'l23', 'l42', 'l60', 'l77', 'l93', 'l108', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "26, hen ['l7', 'l24', 'l43', 'l61', 'l78', 'l94', 'l109', 'l123', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "27, egg-white ['l8', 'l25', 'l44', 'l62', 'l79', 'l95', 'l110', 'l124', 'l137', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "28, lysozyme ['l9', 'l26', 'l45', 'l63', 'l80', 'l96', 'l111', 'l125', 'l138', 'l150', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "29, peptide ['l10', 'l27', 'l46', 'l64', 'l81', 'l97', 'l112', 'l126', 'l139', 'l151', 'l162', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "30, 46-61 ['l11', 'l28', 'l47', 'l65', 'l82', 'l98', 'l113', 'l127', 'l140', 'l152', 'l163', 'l173', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "40, cyclooxygenase-2 ['l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201']", + "41, inhibitors ['l189', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213']", + "49, increased ['l29', 'l48', 'l66', 'l83', 'l99', 'l114', 'l128', 'l141', 'l153', 'l164', 'l174', 'l190', 'l202', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221']", + "50, proliferation ['l12', 'l30', 'l49', 'l67', 'l84', 'l100', 'l115', 'l129', 'l142', 'l154', 'l165', 'l175', 'l183', 'l191', 'l203', 'l214', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228']", + "52, lamina ['l13', 'l31', 'l50', 'l68', 'l85', 'l101', 'l116', 'l130', 'l143', 'l155', 'l166', 'l176', 'l184', 'l192', 'l204', 'l215', 'l222', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234']", + "53, propria ['l14', 'l32', 'l51', 'l69', 'l86', 'l102', 'l117', 'l131', 'l144', 'l156', 'l167', 'l177', 'l185', 'l193', 'l205', 'l216', 'l223', 'l229', 'l235', 'l236', 'l237', 'l238', 'l239']", + "54, mononuclear ['l15', 'l33', 'l52', 'l70', 'l87', 'l103', 'l118', 'l132', 'l145', 'l157', 'l168', 'l178', 'l186', 'l194', 'l206', 'l217', 'l224', 'l230', 'l235', 'l240', 'l241', 'l242', 'l243']", + "55, cells ['l16', 'l34', 'l53', 'l71', 'l88', 'l104', 'l119', 'l133', 'l146', 'l158', 'l169', 'l179', 'l187', 'l195', 'l207', 'l218', 'l225', 'l231', 'l236', 'l240', 'l244', 'l245', 'l246']", + "57, crypt ['l35', 'l54', 'l72', 'l89', 'l105', 'l120', 'l134', 'l147', 'l159', 'l170', 'l180', 'l196', 'l208', 'l219', 'l226', 'l232', 'l237', 'l241', 'l244', 'l247', 'l248']", + "58, epithelial ['l36', 'l55', 'l73', 'l90', 'l106', 'l121', 'l135', 'l148', 'l160', 'l171', 'l181', 'l197', 'l209', 'l220', 'l227', 'l233', 'l238', 'l242', 'l245', 'l247', 'l249']", + "59, cells, ['l17', 'l37', 'l56', 'l74', 'l91', 'l107', 'l122', 'l136', 'l149', 'l161', 'l172', 'l182', 'l188', 'l198', 'l210', 'l221', 'l228', 'l234', 'l239', 'l243', 'l246', 'l248', 'l249']", + "65, Lamina ['l250', 'l251', 'l252']", + "66, propria ['l199', 'l211', 'l250', 'l253', 'l254']", + "67, mononuclear ['l200', 'l212', 'l251', 'l253', 'l255']", + "68, cells ['l201', 'l213', 'l252', 'l254', 'l255']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "T-cell", + "receptor", + "that", + "recognizes", + "46-61" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "a", + "transgenic" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "T-cell", + "receptor", + "that", + "recognizes" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "T-cell", + "receptor", + "that", + "recognizes", + "46-61" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "T-cell", + "receptor", + "that", + "recognizes", + "46-61" + ] + }, + "context": { + "val": "cells", + "words": [ + "lamina", + "propria", + "mononuclear", + "cells", + "crypt", + "epithelial", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "a", + "transgenic" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "a", + "transgenic" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "a", + "transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "lamina", + "propria", + "mononuclear", + "cells", + "crypt", + "epithelial", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "cyclooxygenase-2", + "inhibitors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "cyclooxygenase-2", + "inhibitors" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "cyclooxygenase-2", + "inhibitors" + ] + }, + "context": { + "val": "cells", + "words": [ + "lamina", + "propria", + "mononuclear", + "cells", + "crypt", + "epithelial", + "cells," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "cells", + "words": [ + "lamina", + "propria", + "mononuclear", + "cells", + "crypt", + "epithelial", + "cells," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "lamina", + "propria", + "mononuclear", + "cells", + "crypt", + "epithelial", + "cells," + ] + } + } + ] + }, + { + "PMID": "10371506", + "TEXT": "Blockage in myeloid differentiation characterizes acute myeloid leukemia (AML); the stage of the blockage defines distinct AML subtypes (AML1/2 to AML5). Differentiation therapy in AML has recently raised interest because the survival of AML3 patients has been greatly improved using the differentiating agent retinoic acid. However, this molecule is ineffective in other AML subtypes. The CD44 surface antigen, on leukemic blasts from most AML patients, is involved in myeloid differentiation. Here, we report that ligation of CD44 with specific anti-CD44 monoclonal antibodies or with hyaluronan, its natural ligand, can reverse myeloid differentiation blockage in AML1/2 to AML5 subtypes. The differentiation of AML blasts was evidenced by the ability to produce oxidative bursts, the expression of lineage antigens and cytological modifications, all specific to normal differentiated myeloid cells. These results indicate new possibilities for the development of CD44-targeted differentiation therapy in the AML1/2 to AML5 subtypes.", + "TAG_DATA": [ + "74, ligation {'perturbing_action': 'B-other'}", + "75, of {'perturbing_action': 'I-other'}", + "76, CD44 {'perturbing_action': 'I-other'}", + "89, reverse {'effect': 'B-negative'}", + "92, blockage {'effect': 'B-negative'}", + "99, differentiation {'phenotype': 'B-differentiation'}", + "101, AML {'context': 'B-transformed cells'}", + "102, blasts {'context': 'I-transformed cells'}", + "125, myeloid {'context': 'I-cells'}", + "126, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "74, ligation ['l0', 'l1', 'l2', 'l3', 'l4']", + "75, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "76, CD44 ['l1', 'l5', 'l9', 'l10', 'l11']", + "77, with ['l2', 'l6', 'l9', 'l12', 'l13']", + "89, reverse ['l3', 'l7', 'l10', 'l12', 'l14']", + "92, blockage ['l4', 'l8', 'l11', 'l13', 'l14']", + "99, differentiation ['l15', 'l16', 'l17', 'l18', 'l19']", + "101, AML ['l15', 'l20', 'l21', 'l22', 'l23']", + "102, blasts ['l16', 'l20', 'l24', 'l25', 'l26']", + "124, differentiated ['l17', 'l21', 'l24', 'l27', 'l28']", + "125, myeloid ['l18', 'l22', 'l25', 'l27', 'l29']", + "126, cells. ['l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "ligation", + "of", + "CD44" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reverse", + "blockage" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "AML", + "blasts" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "cells." + ] + } + } + ] + }, + { + "PMID": "10371505", + "TEXT": "Resistance to chemotherapy is a principal problem in the treatment of small cell lung cancer (SCLC). We show here that SCLC is surrounded by an extensive stroma of extracellular matrix (ECM) at both primary and metastatic sites. Adhesion of SCLC cells to ECM enhances tumorigenicity and confers resistance to chemotherapeutic agents as a result of beta1 integrin-stimulated tyrosine kinase activation suppressing chemotherapy-induced apoptosis. SCLC may create a specialized microenvironment, and the survival of cells bound to ECM could explain the partial responses and local recurrence of SCLC often seen clinically after chemotherapy. Strategies based on blocking beta1 integrin-mediated survival signals may represent a new therapeutic approach to improve the response to chemotherapy in SCLC.", + "TAG_DATA": [ + "39, SCLC {'context': 'B-transformed cells'}", + "40, cells {'context': 'I-transformed cells'}", + "43, enhances {'effect': 'B-positive'}", + "44, tumorigenicity {'phenotype': 'B-tumourigenesis'}", + "60, suppressing {'effect': 'B-negative'}", + "61, chemotherapy-induced {'effect': 'B-positive'}", + "62, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "39, SCLC ['l0', 'l1', 'l2', 'l3', 'l4']", + "40, cells ['l0', 'l5', 'l6']", + "43, enhances ['l1', 'l5', 'l7']", + "44, tumorigenicity ['l2', 'l6', 'l7']", + "60, suppressing ['l3', 'l8', 'l9']", + "61, chemotherapy-induced ['l8', 'l10']", + "62, apoptosis. ['l4', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "SCLC", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "SCLC", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "SCLC" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressing" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "SCLC" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "chemotherapy-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "10202938", + "TEXT": "The mammalian brain has a high degree of plasticity, with dentate granule cell neurogenesis and glial proliferation stimulated by an enriched environment combining both complex inanimate and social stimulation. Moreover, rodents exposed to an enriched environment both before and after a cerebral insult show improved cognitive performance. One of the most robust associations of environmental enrichment is improved learning and memory in the Morris water maze, a spatial task that mainly involves the hippocampus. Furthermore, clinical evidence showing an association between higher educational attainment and reduced risk of Alzheimer and Parkinson-related dementia indicates that a stimulating environment has positive effects on cerebral health that may provide some resilience to cerebral insults. Here we show that in addition to its effects on neurogenesis, an enriched environment reduces spontaneous apoptotic cell death in the rat hippocampus by 45%. Moreover, these environmental conditions protect against kainate-induced seizures and excitotoxic injury. The enriched environment induces expression of glial-derived neurotrophic factor and brain-derived neurotrophic factor and increases phosphorylation of the transcription factor cyclic-AMP response element binding protein, indicating that the influence of the environment on spontaneous apoptosis and cerebral resistance to insults may be mediated through transcription factor activation and induction of growth factor expression.", + "TAG_DATA": [ + "125, reduces {'effect': 'B-negative'}", + "127, apoptotic {'phenotype': 'B-apoptosis'}", + "128, cell {'phenotype': 'I-apoptosis'}", + "129, death {'phenotype': 'I-apoptosis'}", + "132, rat {'context': 'B-tissue/organ'}", + "133, hippocampus {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "125, reduces ['l0', 'l1', 'l2', 'l3', 'l4']", + "127, apoptotic ['l0', 'l5', 'l6', 'l7', 'l8']", + "128, cell ['l1', 'l5', 'l9', 'l10', 'l11']", + "129, death ['l2', 'l6', 'l9', 'l12', 'l13']", + "132, rat ['l3', 'l7', 'l10', 'l12', 'l14']", + "133, hippocampus ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "hippocampus" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "hippocampus" + ] + } + } + ] + }, + { + "PMID": "10202936", + "TEXT": "Limb-girdle muscular dystrophies 2C-F represent a family of autosomal recessive diseases caused by defects in sarcoglycan genes. The cardiomyopathic hamster is a naturally occurring model for limb-girdle muscular dystrophy caused by a primary deficiency in delta-sarcoglycan. We show here that acute sarcolemmal disruption occurs in this animal model during forceful muscle contraction. A recombinant adeno-associated virus vector encoding human delta-sarcoglycan conferred efficient and stable genetic reconstitution in the adult cardiomyopathic hamster when injected directly into muscle. A quantitative assay demonstrated that vector-transduced muscle fibers are stably protected from sarcolemmal disruption; there was no associated inflammation or immunologic response to the vector-encoded protein. Efficient gene transduction with rescue of the sarcoglycan complex in muscle fibers of the distal hindlimb was also obtained after infusion of recombinant adeno-associated virus into the femoral artery in conjunction with histamine-induced endothelial permeabilization. This study provides a strong rationale for the development of gene therapy for limb-girdle muscular dystrophy.", + "TAG_DATA": [ + "53, recombinant {'perturbing_action': 'B-gene gain-of-function'}", + "54, adeno-associated {'perturbing_action': 'I-gene gain-of-function'}", + "55, virus {'perturbing_action': 'I-gene gain-of-function'}", + "56, vector {'perturbing_action': 'I-gene gain-of-function'}", + "57, encoding {'perturbing_action': 'I-gene gain-of-function'}", + "58, human {'perturbing_action': 'I-gene gain-of-function'}", + "59, delta-sarcoglycan {'perturbing_action': 'I-gene gain-of-function'}", + "68, adult {'context': 'B-organism'}", + "69, cardiomyopathic {'context': 'I-organism'}", + "70, hamster {'context': 'I-organism'}", + "82, muscle {'context': 'B-cells'}", + "83, fibers {'context': 'I-cells'}", + "112, muscle {'context': 'B-cells'}", + "113, fibers {'context': 'I-cells'}", + "116, distal {'context': 'B-tissue/organ'}", + "117, hindlimb {'context': 'I-tissue/organ'}", + "130, artery {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "53, recombinant ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "54, adeno-associated ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "55, virus ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "56, vector ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "57, encoding ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "58, human ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "59, delta-sarcoglycan ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "68, adult ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57']", + "69, cardiomyopathic ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l58']", + "70, hamster ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l58']", + "82, muscle ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l59']", + "83, fibers ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59']", + "112, muscle ['l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "113, fibers ['l60', 'l66', 'l67', 'l68', 'l69']", + "116, distal ['l61', 'l66', 'l70', 'l71', 'l72', 'l73']", + "117, hindlimb ['l62', 'l67', 'l70', 'l74', 'l75', 'l76']", + "125, adeno-associated ['l63', 'l71', 'l74', 'l77', 'l78']", + "129, femoral ['l64', 'l68', 'l72', 'l75', 'l77', 'l79']", + "130, artery ['l65', 'l69', 'l73', 'l76', 'l78', 'l79']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "recombinant", + "adeno-associated", + "virus", + "vector", + "encoding", + "human", + "delta-sarcoglycan" + ] + }, + "context": { + "val": "organism", + "words": [ + "adult", + "cardiomyopathic", + "hamster" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "recombinant", + "adeno-associated", + "virus", + "vector", + "encoding", + "human", + "delta-sarcoglycan" + ] + }, + "context": { + "val": "cells", + "words": [ + "muscle", + "fibers" + ] + } + } + ] + }, + { + "PMID": "10086391", + "TEXT": "Nitric oxide (NO) is an ubiquitous signaling molecule produced from L-arginine by NO synthase (NOS). In the vasculature, NO mediates parasympathetic endothelium-dependent vasodilation. NO may also mediate the parasympathetic control of myocardial function. This is supported by the observations that NOS3, the endothelial constitutive NOS, is expressed in normal cardiac myocytes from rodents and human, and NOS and/or guanylyl cyclase inhibitors antagonize the effect of muscarinic agonists on heart rate, atrio-ventricular conduction, contractility and L-type calcium current. Here we examine the autonomic regulation of the heart in genetically engineered mice deficient in NOS3 (NOS3-KO). We show that the chronotropic and inotropic responses to both beta-adrenergic and muscarinic agonists were unaltered in isolated cardiac tissue preparations from NOS3-KO mice, although these mice have a defective parasympathetic regulation of vascular tone. Similarly, beta-adrenergic stimulation and muscarinic inhibition of the calcium current did not differ in cardiac myocytes from NOS3-KO mice and those from wild-type mice. RT-PCR did not demonstrate upregulation of other NOS isoforms. Similarly, Gi/Go proteins and muscarinic receptor density were unaltered. These data refute the idea that NOS3 is obligatory for the normal autonomic control of cardiac muscle function.", + "TAG_DATA": [ + "87, genetically {'context': 'B-organism'}", + "88, engineered {'context': 'I-organism'}", + "89, mice {'context': 'I-organism'}", + "90, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "91, in {'perturbing_action': 'I-gene loss-of-function'}", + "92, NOS3 {'perturbing_action': 'I-gene loss-of-function'}", + "93, (NOS3-KO). {'perturbing_action': 'I-gene loss-of-function'}", + "112, cardiac {'context': 'B-tissue/organ'}", + "113, tissue {'context': 'I-tissue/organ'}", + "114, preparations {'context': 'I-tissue/organ'}", + "116, NOS3-KO {'perturbing_action': 'B-gene loss-of-function'}", + "117, mice, {'context': 'B-organism'}", + "120, mice {'context': 'B-organism'}", + "143, cardiac {'context': 'B-cells'}", + "144, myocytes {'context': 'I-cells'}", + "146, NOS3-KO {'perturbing_action': 'B-gene loss-of-function'}", + "147, mice {'context': 'B-organism'}", + "152, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "87, genetically ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "88, engineered ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "89, mice ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "90, deficient ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "91, in ['l3', 'l11', 'l18', 'l24', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "92, NOS3 ['l4', 'l12', 'l19', 'l25', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "93, (NOS3-KO). ['l5', 'l13', 'l20', 'l26', 'l32', 'l39', 'l46', 'l47', 'l48']", + "112, cardiac ['l6', 'l14', 'l21', 'l27', 'l33', 'l40', 'l46', 'l49', 'l50', 'l51', 'l52', 'l53']", + "113, tissue ['l7', 'l15', 'l22', 'l28', 'l34', 'l41', 'l47', 'l49', 'l54', 'l55', 'l56', 'l57']", + "114, preparations ['l8', 'l16', 'l23', 'l29', 'l35', 'l42', 'l48', 'l50', 'l54', 'l58', 'l59', 'l60']", + "116, NOS3-KO ['l36', 'l43', 'l51', 'l55', 'l58', 'l61', 'l62', 'l63', 'l64', 'l65']", + "117, mice, ['l30', 'l37', 'l44', 'l52', 'l56', 'l59', 'l61', 'l66']", + "120, mice ['l38', 'l45', 'l53', 'l57', 'l60', 'l62', 'l66', 'l67', 'l68', 'l69']", + "143, cardiac ['l63', 'l67', 'l70', 'l71', 'l72']", + "144, myocytes ['l64', 'l68', 'l70', 'l73', 'l74']", + "146, NOS3-KO ['l71', 'l73', 'l75']", + "147, mice ['l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "genetically", + "engineered", + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "NOS3", + "(NOS3-KO).", + "NOS3-KO" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "NOS3", + "(NOS3-KO).", + "NOS3-KO" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "cardiac", + "tissue", + "preparations" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NOS3-KO" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiac", + "myocytes" + ] + } + } + ] + }, + { + "PMID": "10086385", + "TEXT": "Half of the survivors of bacterial meningitis experience motor deficits, seizures, hearing loss or cognitive impairment, despite adequate bacterial killing by antibiotics. We demonstrate that the broad-spectrum caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl-ketone (z-VAD-fmk) prevented hippocampal neuronal cell death and white blood cell influx into the cerebrospinal fluid compartment in experimental pneumococcal meningitis. Hippocampal neuronal death was due to apoptosis derived from the inflammatory response in the cerebrospinal fluid. Apoptosis was induced in vitro in human neurons by inflamed cerebrospinal fluid and was blocked by z-VAD-fmk. As apoptosis drives neuronal loss in pneumococcal meningitis, caspase inhibitors might provide a new therapeutic option directed specifically at reducing brain damage.", + "TAG_DATA": [ + "31, prevented {'effect': 'B-negative'}", + "32, hippocampal {'context': 'B-cells'}", + "34, cell {'phenotype': 'B-cell death'}", + "35, death {'phenotype': 'I-cell death'}", + "37, white {'context': 'B-cells'}", + "38, blood {'context': 'I-cells'}", + "39, cell {'context': 'I-cells'}", + "56, apoptosis {'phenotype': 'B-apoptosis'}", + "66, Apoptosis {'phenotype': 'B-apoptosis'}", + "68, induced {'effect': 'B-positive'}", + "69, in {'context': 'B-in vitro'}", + "70, vitro {'context': 'I-in vitro'}", + "72, human {'context': 'B-cells'}", + "73, neurons {'context': 'I-cells'}", + "80, blocked {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "31, prevented ['l0', 'l1', 'l2', 'l3', 'l4']", + "32, hippocampal ['l0', 'l5', 'l6', 'l7', 'l8']", + "34, cell ['l1', 'l5', 'l9']", + "35, death ['l2', 'l6', 'l9']", + "37, white ['l3', 'l7', 'l10', 'l11', 'l12', 'l13']", + "38, blood ['l10', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "39, cell ['l4', 'l8', 'l11', 'l14', 'l22', 'l23', 'l24', 'l25', 'l26']", + "56, apoptosis ['l12', 'l15', 'l22', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "66, Apoptosis ['l16', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "68, induced ['l13', 'l17', 'l23', 'l28', 'l33', 'l38', 'l39', 'l40', 'l41']", + "69, in ['l18', 'l29', 'l34', 'l38', 'l42', 'l43', 'l44']", + "70, vitro ['l19', 'l24', 'l30', 'l35', 'l39', 'l42', 'l45', 'l46']", + "72, human ['l20', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l47']", + "73, neurons ['l21', 'l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "cells", + "words": [ + "hippocampal", + "white", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hippocampal" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "white", + "blood", + "cell", + "human", + "neurons" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "Apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "white", + "blood", + "cell", + "human", + "neurons" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "Apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "Apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "10086384", + "TEXT": "A principal cause of blindness is subretinal neovascularization associated with age-related macular degeneration. Excised neovascular membranes from patients with age-related macular degeneration demonstrated a pattern of Fas+ new vessels in the center of the vascular complex, surrounded by FasL+ retinal pigment epithelial cells. In a murine model, Fas (CD95)-deficient (Ipr) and FasL-defective (gld) mice had a significantly increased incidence of neovascularization compared with normal mice. Furthermore, in gld mice there is massive subretinal neovascularization with uncontrolled growth of vessels. We found that cultured choroidal endothelial cells were induced to undergo apoptosis by retinal pigment epithelial cells through a Fas-FasL interaction. In addition, antibody against Fas prevented vascular tube formation of choroidal endothelial cells derived from the eye in a three-dimensional in vitro assay. Thus, FasL expressed on retinal pigment epithelial cells may control the growth and development of new subretinal vessels that can damage vision.", + "TAG_DATA": [ + "45, murine {'context': 'B-organism'}", + "46, model, {'context': 'I-organism'}", + "47, Fas {'perturbing_action': 'B-gene loss-of-function'}", + "48, (CD95)-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "49, (Ipr) {'perturbing_action': 'I-gene loss-of-function'}", + "51, FasL-defective {'perturbing_action': 'B-gene loss-of-function'}", + "52, (gld) {'perturbing_action': 'I-gene loss-of-function'}", + "53, mice {'context': 'B-organism'}", + "67, gld {'perturbing_action': 'B-gene loss-of-function'}", + "68, mice {'context': 'B-organism'}", + "83, choroidal {'context': 'I-cells'}", + "84, endothelial {'context': 'I-cells'}", + "85, cells {'context': 'I-cells'}", + "87, induced {'effect': 'B-positive'}", + "90, apoptosis {'phenotype': 'B-apoptosis'}", + "92, retinal {'context': 'B-cells'}", + "93, pigment {'context': 'I-cells'}", + "94, epithelial {'context': 'I-cells'}", + "95, cells {'context': 'I-cells'}", + "110, choroidal {'context': 'B-cells'}", + "111, endothelial {'context': 'I-cells'}", + "112, cells {'context': 'I-cells'}", + "113, derived {'context': 'I-cells'}", + "114, from {'context': 'I-cells'}", + "115, the {'context': 'I-cells'}", + "116, eye {'context': 'I-tissue/organ'}", + "120, in {'context': 'B-in vitro'}", + "121, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "45, murine ['l0', 'l1', 'l2', 'l3']", + "46, model, ['l0', 'l4', 'l5', 'l6']", + "47, Fas ['l1', 'l4', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "48, (CD95)-deficient ['l7', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "49, (Ipr) ['l2', 'l5', 'l8', 'l17', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "51, FasL-defective ['l9', 'l18', 'l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "52, (gld) ['l10', 'l19', 'l29', 'l35', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "53, mice ['l3', 'l6', 'l11', 'l20', 'l30', 'l36', 'l48']", + "67, gld ['l12', 'l21', 'l31', 'l37', 'l49', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "68, mice ['l13', 'l22', 'l32', 'l38', 'l50', 'l59', 'l65', 'l66']", + "83, choroidal ['l14', 'l23', 'l39', 'l51', 'l60', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "84, endothelial ['l15', 'l24', 'l33', 'l40', 'l52', 'l61', 'l65', 'l67', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "85, cells ['l16', 'l25', 'l34', 'l41', 'l53', 'l62', 'l66', 'l68', 'l76', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "87, induced ['l42', 'l54', 'l69', 'l77', 'l84', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "89, undergo ['l26', 'l43', 'l55', 'l63', 'l70', 'l78', 'l85', 'l91', 'l97', 'l98', 'l99', 'l100', 'l101']", + "90, apoptosis ['l44', 'l56', 'l71', 'l79', 'l86', 'l92', 'l97', 'l102', 'l103', 'l104', 'l105']", + "92, retinal ['l72', 'l80', 'l87', 'l93', 'l98', 'l102', 'l106', 'l107', 'l108']", + "93, pigment ['l45', 'l73', 'l81', 'l88', 'l94', 'l99', 'l103', 'l106', 'l109', 'l110']", + "94, epithelial ['l46', 'l57', 'l74', 'l82', 'l89', 'l95', 'l100', 'l104', 'l107', 'l109', 'l111']", + "95, cells ['l27', 'l47', 'l58', 'l64', 'l75', 'l83', 'l90', 'l96', 'l101', 'l105', 'l108', 'l110', 'l111']", + "110, choroidal ['l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "111, endothelial ['l112', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "112, cells ['l113', 'l120', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "113, derived ['l114', 'l121', 'l127', 'l133', 'l134', 'l135', 'l136', 'l137']", + "114, from ['l115', 'l122', 'l128', 'l133', 'l138', 'l139', 'l140', 'l141']", + "115, the ['l116', 'l123', 'l129', 'l134', 'l138', 'l142', 'l143', 'l144']", + "116, eye ['l117', 'l124', 'l130', 'l135', 'l139', 'l142', 'l145', 'l146']", + "120, in ['l118', 'l125', 'l131', 'l136', 'l140', 'l143', 'l145', 'l147']", + "121, vitro ['l119', 'l126', 'l132', 'l137', 'l141', 'l144', 'l146', 'l147']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "murine", + "model,", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fas", + "(Ipr)", + "(CD95)-deficient", + "FasL-defective", + "(gld)", + "gld" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fas", + "(CD95)-deficient", + "(Ipr)", + "FasL-defective", + "(gld)", + "gld" + ] + }, + "context": { + "val": "cells", + "words": [ + "choroidal", + "endothelial", + "cells", + "pigment", + "epithelial" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FasL-defective", + "(gld)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FasL-defective", + "(gld)" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "choroidal", + "endothelial", + "cells", + "retinal", + "pigment", + "epithelial" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "choroidal", + "endothelial", + "cells", + "retinal", + "pigment", + "epithelial" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "10086383", + "TEXT": "As in the development of many human cancers, in a transgenic mouse model of beta-cell carcinogenesis (Rip1Tag2), expression of neural cell adhesion molecule (NCAM) changes from the 120-kDa isoform in normal tissue to the 140/180-kDa isoforms in tumors. NCAM-deficient RiplTag2 mice, generated by crossing Rip1Tag2 mice with NCAM knockout mice, develop metastases, a tumor stage that is not seen in normal Rip1Tag2 mice. In contrast, overexpression of NCAM 120 in NCAM-deficient Rip1Tag2 mice prevents tumor metastasis. The results indicate that the loss of NCAM-mediated cell adhesion is one rate-limiting step in the actual metastatic dissemination of beta tumor cells.", + "TAG_DATA": [ + "38, NCAM-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "39, RiplTag2 {'perturbing_action': 'B-gene loss-of-function'}", + "40, mice, {'context': 'B-organism'}", + "45, mice {'context': 'I-organism'}", + "47, NCAM {'perturbing_action': 'B-gene loss-of-function'}", + "48, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "49, mice, {'context': 'B-organism'}", + "50, develop {'effect': 'B-positive'}", + "51, metastases, {'phenotype': 'B-metastasis'}", + "62, mice. {'context': 'B-organism'}", + "65, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "66, of {'perturbing_action': 'I-gene gain-of-function'}", + "67, NCAM {'perturbing_action': 'I-gene gain-of-function'}", + "68, 120 {'perturbing_action': 'I-gene gain-of-function'}", + "70, NCAM-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "71, Rip1Tag2 {'perturbing_action': 'B-gene loss-of-function'}", + "72, mice {'context': 'B-organism'}", + "73, prevents {'effect': 'B-negative'}", + "74, tumor {'phenotype': 'B-metastasis'}", + "75, metastasis. {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "38, NCAM-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "39, RiplTag2 ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "40, mice, ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "45, mice ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "47, NCAM ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "48, knockout ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "49, mice, ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "50, develop ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "51, metastases, ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "62, mice. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "65, overexpression ['l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "66, of ['l45', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "67, NCAM ['l46', 'l54', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "68, 120 ['l47', 'l55', 'l62', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "70, NCAM-deficient ['l48', 'l56', 'l63', 'l69', 'l75', 'l76', 'l77', 'l78', 'l79']", + "71, Rip1Tag2 ['l49', 'l57', 'l64', 'l70', 'l75', 'l80', 'l81', 'l82', 'l83']", + "72, mice ['l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l84', 'l85', 'l86']", + "73, prevents ['l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l87', 'l88']", + "74, tumor ['l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l87', 'l89']", + "75, metastasis. ['l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l89']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NCAM-deficient", + "RiplTag2", + "NCAM", + "knockout", + "Rip1Tag2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NCAM-deficient", + "RiplTag2", + "NCAM", + "knockout" + ] + }, + "effect": { + "val": "positive", + "words": [ + "develop" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NCAM-deficient", + "RiplTag2", + "NCAM", + "knockout", + "Rip1Tag2" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases,", + "tumor", + "metastasis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice,", + "mice", + "mice." + ] + }, + "effect": { + "val": "positive", + "words": [ + "develop" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice,", + "mice", + "mice." + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases,", + "tumor", + "metastasis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "develop" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "NCAM", + "120" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "NCAM", + "120" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "NCAM", + "120" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "tumor", + "metastasis." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NCAM-deficient", + "Rip1Tag2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "tumor", + "metastasis." + ] + } + } + ] + }, + { + "PMID": "9930872", + "TEXT": "Adhesion of tumor cells to host cell layers and subsequent transcellular migration are pivotal steps in cancer invasion and metastasis. The small GTPase Rho controls cell adhesion and motility through reorganization of the actin cytoskeleton and regulation of actomyosin contractility. Cultured rat MM1 hepatoma cells migrate through a mesothelial cell monolayer in vitro in a serum-dependent, Rho-mediated manners. Among several proteins isolated as putative target molecules of Rho, the ROCK (ROK) family of Rho-associated serine-threonine protein kinases are thought to participate in the induction of focal adhesions and stress fibers in cultured cells, and to mediate calcium sensitization of smooth muscle contraction by enhancing phosphorylation of the regulatory light chain of myosin. Transfection of MM1 cells with cDNA encoding a dominant active mutant of ROCK conferred invasive activity independently of serum and Rho. In contrast, expression of a dominant negative, kinase-defective ROCK mutant substantially attenuated the invasive phenotype. A specific ROCK inhibitor (Y-27632) blocked both Rho-mediated activation of actomyosin and invasive activity of these cells. Furthermore, continuous delivery of this inhibitor using osmotic pumps considerably reduced the dissemination of MM1 cells implanted into the peritoneal cavity of syngeneic rats. These results indicate that ROCK plays an essential part in tumor cell invasion, and demonstrate its potential as a therapeutic target for the prevention of cancer invasion and metastasis.", + "TAG_DATA": [ + "112, Transfection {'perturbing_action': 'B-other'}", + "114, MM1 {'context': 'B-cells'}", + "115, cells {'context': 'I-cells'}", + "116, with {'perturbing_action': 'I-other'}", + "117, cDNA {'perturbing_action': 'I-other'}", + "118, encoding {'perturbing_action': 'I-other'}", + "119, a {'perturbing_action': 'I-other'}", + "120, dominant {'perturbing_action': 'I-other'}", + "121, active {'perturbing_action': 'I-other'}", + "122, mutant {'perturbing_action': 'I-other'}", + "123, of {'perturbing_action': 'I-other'}", + "124, ROCK {'perturbing_action': 'I-other'}", + "135, expression {'perturbing_action': 'B-other'}", + "136, of {'perturbing_action': 'I-other'}", + "137, a {'perturbing_action': 'I-other'}", + "138, dominant {'perturbing_action': 'I-other'}", + "139, negative, {'perturbing_action': 'I-other'}", + "140, kinase-defective {'perturbing_action': 'I-other'}", + "141, ROCK {'perturbing_action': 'I-other'}", + "142, mutant {'perturbing_action': 'I-other'}", + "144, attenuated {'effect': 'B-negative'}", + "149, specific {'perturbing_action': 'B-pharmacological inhibition'}", + "150, ROCK {'perturbing_action': 'I-pharmacological inhibition'}", + "151, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "152, (Y-27632) {'perturbing_action': 'I-pharmacological inhibition'}", + "153, blocked {'effect': 'B-negative'}", + "160, invasive {'phenotype': 'B-invasion'}", + "161, activity {'phenotype': 'I-invasion'}", + "164, cells. {'context': 'B-cells'}", + "179, MM1 {'context': 'B-cells'}", + "180, cells {'context': 'I-cells'}", + "187, syngeneic {'context': 'B-organism'}", + "188, rats. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "112, Transfection ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "114, MM1 ['l0', 'l11', 'l12']", + "115, cells ['l1', 'l11', 'l13', 'l14']", + "116, with ['l2', 'l12', 'l13', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "117, cDNA ['l3', 'l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "118, encoding ['l4', 'l16', 'l23', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "119, a ['l5', 'l17', 'l24', 'l36', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "120, dominant ['l6', 'l18', 'l25', 'l37', 'l48', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "121, active ['l7', 'l19', 'l26', 'l38', 'l49', 'l59', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "122, mutant ['l8', 'l20', 'l27', 'l39', 'l50', 'l60', 'l69', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "123, of ['l9', 'l21', 'l28', 'l40', 'l51', 'l61', 'l70', 'l78', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "124, ROCK ['l10', 'l14', 'l22', 'l29', 'l41', 'l52', 'l62', 'l71', 'l79', 'l86', 'l93', 'l94', 'l95', 'l96', 'l97']", + "135, expression ['l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "136, of ['l98', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "137, a ['l99', 'l116', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "138, dominant ['l100', 'l117', 'l135', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "139, negative, ['l101', 'l118', 'l136', 'l153', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185']", + "140, kinase-defective ['l102', 'l119', 'l137', 'l154', 'l170', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200']", + "141, ROCK ['l103', 'l120', 'l138', 'l155', 'l171', 'l186', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212']", + "142, mutant ['l104', 'l121', 'l139', 'l156', 'l172', 'l187', 'l201', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222']", + "144, attenuated ['l30', 'l42', 'l53', 'l63', 'l72', 'l80', 'l87', 'l93', 'l105', 'l122', 'l140', 'l157', 'l173', 'l188', 'l202', 'l213', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228']", + "146, invasive ['l31', 'l43', 'l54', 'l64', 'l73', 'l81', 'l88', 'l94', 'l106', 'l123', 'l141', 'l158', 'l174', 'l189', 'l203', 'l214', 'l223', 'l229', 'l230', 'l231', 'l232']", + "149, specific ['l107', 'l124', 'l142', 'l159', 'l175', 'l190', 'l204', 'l215', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244']", + "150, ROCK ['l108', 'l125', 'l143', 'l160', 'l176', 'l191', 'l205', 'l216', 'l233', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255']", + "151, inhibitor ['l109', 'l126', 'l144', 'l161', 'l177', 'l192', 'l206', 'l217', 'l234', 'l245', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265']", + "152, (Y-27632) ['l110', 'l127', 'l145', 'l162', 'l178', 'l193', 'l207', 'l218', 'l224', 'l235', 'l246', 'l256', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274']", + "153, blocked ['l32', 'l44', 'l55', 'l65', 'l74', 'l82', 'l89', 'l111', 'l128', 'l146', 'l163', 'l179', 'l194', 'l208', 'l219', 'l225', 'l229', 'l236', 'l247', 'l257', 'l266', 'l275', 'l276', 'l277']", + "160, invasive ['l33', 'l45', 'l56', 'l66', 'l75', 'l83', 'l90', 'l95', 'l112', 'l129', 'l147', 'l164', 'l180', 'l195', 'l209', 'l220', 'l226', 'l230', 'l237', 'l248', 'l258', 'l267', 'l275', 'l278', 'l279']", + "161, activity ['l34', 'l46', 'l57', 'l67', 'l76', 'l84', 'l91', 'l96', 'l113', 'l130', 'l148', 'l165', 'l181', 'l196', 'l210', 'l221', 'l227', 'l231', 'l238', 'l249', 'l259', 'l268', 'l276', 'l278', 'l280']", + "164, cells. ['l35', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l97', 'l114', 'l131', 'l149', 'l166', 'l182', 'l197', 'l211', 'l222', 'l228', 'l232', 'l239', 'l250', 'l260', 'l269', 'l277', 'l279', 'l280']", + "179, MM1 ['l240', 'l251', 'l261', 'l270', 'l281', 'l282', 'l283', 'l284']", + "180, cells ['l132', 'l150', 'l167', 'l183', 'l198', 'l241', 'l252', 'l262', 'l271', 'l281', 'l285', 'l286', 'l287']", + "185, cavity ['l115', 'l133', 'l151', 'l168', 'l184', 'l199', 'l212', 'l242', 'l253', 'l263', 'l272', 'l282', 'l285', 'l288', 'l289']", + "187, syngeneic ['l243', 'l254', 'l264', 'l273', 'l283', 'l286', 'l288', 'l290']", + "188, rats. ['l134', 'l152', 'l169', 'l185', 'l200', 'l244', 'l255', 'l265', 'l274', 'l284', 'l287', 'l289', 'l290']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Transfection", + "with", + "ROCK", + "cDNA", + "encoding", + "a", + "dominant", + "active", + "mutant", + "of", + "expression", + "negative,", + "kinase-defective" + ] + }, + "context": { + "val": "cells", + "words": [ + "MM1", + "cells", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "cDNA", + "encoding", + "a", + "dominant", + "active", + "mutant", + "of", + "ROCK", + "expression", + "negative,", + "kinase-defective" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuated", + "blocked" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "cDNA", + "encoding", + "a", + "dominant", + "active", + "mutant", + "of", + "ROCK", + "expression", + "negative,", + "kinase-defective" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasive", + "activity" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "of", + "a", + "dominant", + "negative,", + "kinase-defective" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated", + "blocked" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "(Y-27632)", + "specific", + "ROCK", + "inhibitor" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated", + "blocked" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasive", + "activity" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated", + "blocked" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "ROCK", + "inhibitor", + "(Y-27632)" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasive", + "activity" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "ROCK", + "inhibitor", + "(Y-27632)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells.", + "MM1", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "ROCK", + "inhibitor", + "(Y-27632)" + ] + }, + "context": { + "val": "organism", + "words": [ + "syngeneic", + "rats." + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasive", + "activity" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "9883849", + "TEXT": "Fabry disease is a disorder of glycosphingolipid metabolism caused by deficiency of lysosomal alpha-galactosidase A (alpha-Gal A), resulting in renal failure along with premature myocardial infarction and strokes. No effective treatment of this disorder is available at present. Studies of residual activities of mutant enzymes in many Fabry patients showed that some of them had kinetic properties similar to those for normal alpha-Gal A, but were significantly less stable, especially in conditions of neutral pH (refs. 3-5). The biosynthetic processing was delayed in cultured fibroblasts of a Fabry patient, and the mutant protein formed an aggregate in endoplasmic reticulum, indicating that the enzyme deficiency in some mutants was mainly caused by abortive exit from the endoplasmic reticulum, leading to excessive degradation of the enzyme. We report here that 1-deoxy-galactonojirimycin (DGJ), a potent competitive inhibitor of alpha-Gal A, effectively enhanced alpha-Gal A activity in Fabry lymphoblasts, when administrated at concentrations lower than that usually required for intracellular inhibition of the enzyme. DGJ seemed to accelerate transport and maturation of the mutant enzyme. Oral administration of DGJ to transgenic mice overexpressing a mutant alpha-Gal A substantially elevated the enzyme activity in some organs. We propose a new molecular therapeutic strategy for genetic metabolic diseases of administering competitive inhibitors as 'chemical chaperons' at sub-inhibitory intracellular concentrations.", + "TAG_DATA": [ + "84, fibroblasts {'context': 'I-cells'}", + "143, Fabry {'context': 'B-cells'}", + "144, lymphoblasts, {'context': 'I-cells'}", + "176, transgenic {'context': 'B-organism'}", + "177, mice {'context': 'I-organism'}", + "178, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "179, a {'perturbing_action': 'I-other'}", + "180, mutant {'perturbing_action': 'I-other'}", + "181, alpha-Gal {'perturbing_action': 'I-other'}", + "182, A {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "143, Fabry ['l0']", + "144, lymphoblasts, ['l0']", + "176, transgenic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "177, mice ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "178, overexpressing ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "179, a ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "180, mutant ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "181, alpha-Gal ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "182, A ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "a", + "mutant", + "alpha-Gal", + "A" + ] + } + } + ] + }, + { + "PMID": "9883847", + "TEXT": "Excitotoxicity, a form of neuronal injury in which excessive activation of glutamate receptors results in cellular calcium overload, has been implicated in the pathogenesis of Alzheimer disease (AD), although direct evidence is lacking. Mutations in the presenilin-1 (PS1) gene on chromosome 14 are causally linked to many cases of early-onset inherited AD (refs. 5,6). We generated PS1 mutant mice (PS1M146VKI) that express the PS1 M146V targeted allele at normal physiological levels. Although PS1M146VKI mice have no overt mutant phenotype, they are hypersensitive to seizure-induced synaptic degeneration and necrotic neuronal death in the hippocampus. Cultured hippocampal neurons from PS1M146VKI mice have increased vulnerability to death induced by glutamate, which is correlated with perturbed calcium homeostasis, increased oxidative stress and mitochondrial dysfunction. Agents that suppress calcium influx or release and antioxidants protect neurons against the excitotoxic action of the PS1 mutation. These findings establish a direct link between a genetic defect that causes AD and excitotoxic neuronal degeneration, and indicate new avenues for therapeutic intervention in AD patients.", + "TAG_DATA": [ + "56, PS1 {'perturbing_action': 'B-other'}", + "57, mutant {'perturbing_action': 'I-other'}", + "58, mice {'context': 'B-organism'}", + "59, (PS1M146VKI) {'perturbing_action': 'I-other'}", + "64, M146V {'perturbing_action': 'I-other'}", + "65, targeted {'perturbing_action': 'I-other'}", + "72, PS1M146VKI {'perturbing_action': 'B-other'}", + "73, mice {'context': 'B-organism'}", + "92, hippocampus. {'context': 'B-tissue/organ'}", + "93, Cultured {'context': 'B-cells'}", + "94, hippocampal {'context': 'I-cells'}", + "95, neurons {'context': 'I-cells'}", + "97, PS1M146VKI {'perturbing_action': 'B-other'}", + "98, mice {'context': 'B-organism'}", + "130, neurons {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "56, PS1 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "57, mutant ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "58, mice ['l1', 'l8', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "59, (PS1M146VKI) ['l2', 'l9', 'l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "64, M146V ['l3', 'l10', 'l17', 'l22', 'l27', 'l28', 'l29', 'l30', 'l31']", + "65, targeted ['l4', 'l11', 'l18', 'l23', 'l27', 'l32', 'l33', 'l34', 'l35']", + "66, allele ['l5', 'l12', 'l19', 'l24', 'l28', 'l32', 'l36', 'l37', 'l38']", + "72, PS1M146VKI ['l13', 'l29', 'l33', 'l36', 'l39', 'l40']", + "73, mice ['l6', 'l14', 'l20', 'l25', 'l30', 'l34', 'l37', 'l39', 'l41']", + "92, hippocampus. ['l7', 'l15', 'l21', 'l26', 'l31', 'l35', 'l38', 'l40', 'l41']", + "93, Cultured ['l42', 'l43', 'l44', 'l45']", + "94, hippocampal ['l42', 'l46', 'l47', 'l48']", + "95, neurons ['l43', 'l46', 'l49', 'l50']", + "97, PS1M146VKI ['l44', 'l47', 'l49', 'l51']", + "98, mice ['l45', 'l48', 'l50', 'l51']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "PS1", + "mutant", + "(PS1M146VKI)", + "M146V", + "targeted", + "PS1M146VKI" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "PS1", + "mutant", + "(PS1M146VKI)", + "M146V", + "targeted", + "PS1M146VKI" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Cultured", + "hippocampal", + "neurons" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "PS1M146VKI" + ] + } + } + ] + }, + { + "PMID": "9883836", + "TEXT": "At present, treatment of HIV infection uses small inhibitory molecules that target HIV protease; however, the emergence of resistant HIV strains is increasingly problematic. To circumvent this, we report here a new 'Trojan horse' strategy to kill HIV-infected cells by exploiting HIV protease. We engineered a transducing, modified, apoptosis-promoting caspase-3 protein, TAT-Casp3, that substitutes HIV proteolytic cleavage sites for endogenous ones and efficiently transduces about 100% of cells, but remains inactive in uninfected cells. In HIV-infected cells, TAT-Casp3 becomes processed into an active form by HIV protease, resulting in apoptosis of the infected cell. This strategy could also be applied to other pathogens encoding specific proteases, such as hepatitis C virus, cytomegalovirus and malaria.", + "TAG_DATA": [ + "67, cells, {'context': 'B-cells'}", + "73, cells. {'context': 'B-cells'}", + "76, cells, {'context': 'B-cells'}", + "87, resulting {'effect': 'B-positive'}", + "88, in {'effect': 'I-positive'}", + "89, apoptosis {'phenotype': 'B-apoptosis'}", + "93, cell. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "67, cells, ['l0']", + "73, cells. ['l0']", + "76, cells, ['l1', 'l2', 'l3', 'l4']", + "87, resulting ['l1', 'l5', 'l6', 'l7']", + "88, in ['l2', 'l5', 'l8', 'l9']", + "89, apoptosis ['l3', 'l6', 'l8', 'l10']", + "93, cell. ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells,", + "cell." + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells,", + "cell." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "9846586", + "TEXT": "Duchenne muscular dystrophy (DMD) is a lethal, progressive muscle wasting disease caused by a loss of sarcolemmal bound dystrophin, which results in the death of the muscle fiber leading to the gradual depletion of skeletal muscle. The molecular structure of dystrophin is very similar to that of the related protein utrophin. Utrophin is found in all tissues and is confined to the neuromuscular and myotendinous junctions in mature muscle. Sarcolemmal localization of a truncated utrophin transgene in the dystrophin-deficient mdx mouse significantly improves the dystrophic muscle phenotype. Therefore, up-regulation of utrophin by drug therapy is a plausible therapeutic approach in the treatment of DMD. Here we demonstrate that expression of full-length utrophin in mdx mice prevents the development of muscular dystrophy. We assessed muscle morphology, fiber regeneration and mechanical properties (force development and resistance to stretch) of mdx and transgenic mdx skeletal and diaphragm muscle. The utrophin levels required in muscle are significantly less than the normal endogenous utrophin levels seen in lung and kidney, and we provide evidence that the pathology depends on the amount of utrophin expression. These results also have important implications for DMD therapies in which utrophin replacement is achieved by delivery using exogenous vectors.", + "TAG_DATA": [ + "78, dystrophin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "79, mdx {'perturbing_action': 'B-gene loss-of-function', 'context': 'B-organism'}", + "80, mouse {'context': 'I-organism'}", + "108, expression {'perturbing_action': 'B-gene gain-of-function'}", + "109, of {'perturbing_action': 'I-gene gain-of-function'}", + "110, full-length {'perturbing_action': 'I-gene gain-of-function'}", + "111, utrophin {'perturbing_action': 'I-gene gain-of-function'}", + "114, mice {'context': 'B-organism'}", + "123, muscle {'context': 'B-tissue/organ'}", + "137, mdx {'perturbing_action': 'B-gene gain-of-function'}", + "139, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "140, mdx {'perturbing_action': 'I-gene gain-of-function'}", + "141, skeletal {'context': 'B-tissue/organ'}", + "142, and {'context': 'I-tissue/organ'}", + "143, diaphragm {'context': 'I-tissue/organ'}", + "144, muscle. {'context': 'I-tissue/organ'}", + "150, muscle {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "78, dystrophin-deficient ['l0', 'l1']", + "79, mdx ['l0', 'l2']", + "80, mouse ['l1', 'l2']", + "108, expression ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "109, of ['l3', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "110, full-length ['l4', 'l15', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "111, utrophin ['l5', 'l16', 'l26', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "114, mice ['l6', 'l17', 'l27', 'l36', 'l44']", + "123, muscle ['l7', 'l18', 'l28', 'l37', 'l44', 'l45', 'l46', 'l47', 'l48']", + "137, mdx ['l8', 'l19', 'l29', 'l38', 'l45', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "139, transgenic ['l9', 'l20', 'l30', 'l49', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "140, mdx ['l10', 'l21', 'l31', 'l39', 'l50', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "141, skeletal ['l11', 'l22', 'l32', 'l40', 'l46', 'l51', 'l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "142, and ['l12', 'l23', 'l33', 'l41', 'l47', 'l52', 'l57', 'l62', 'l66', 'l70', 'l71', 'l72']", + "143, diaphragm ['l13', 'l24', 'l34', 'l42', 'l53', 'l58', 'l63', 'l67', 'l70', 'l73', 'l74']", + "144, muscle. ['l14', 'l25', 'l35', 'l43', 'l48', 'l54', 'l59', 'l64', 'l68', 'l71', 'l73']", + "150, muscle ['l60', 'l65', 'l69', 'l72', 'l74']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient", + "mdx" + ] + }, + "context": { + "val": "organism", + "words": [ + "mdx", + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "full-length", + "utrophin" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "full-length", + "utrophin", + "mdx", + "transgenic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscle", + "skeletal", + "and", + "diaphragm", + "muscle." + ] + } + } + ] + }, + { + "PMID": "9846583", + "TEXT": "Prion diseases are typically initiated by infection of peripheral sites, as in the case of bovine spongiform encephalopathy, new variant Creutzfeldt-Jakob disease, kuru and most cases of iatrogenic Creutzfeldt-Jakob disease. In mouse scrapie, prion infectivity accumulates in lymphoid organs, and the absence of mature B lymphocytes prevents peripherally administered prions from inducing central nervous system disease. We have now assessed whether expression of the cellular prion protein, PrPc, is required for B lymphocytes to mediate neuroinvasion. We found that repopulation of SCID and Rag-1(-/-) mice with fetal liver cells from either PrP-expressing or PrP-deficient mice and from T-cell deficient mice, but not from B-cell deficient mice, is equally efficient in restoring neuroinvasion after intraperitoneal inoculation of scrapie prions. These results indicate that cells whose maturation depends on B cells or their products, such as follicular dendritic cells, may enhance neuroinvasion. Alternatively, B cells may transport prions to the nervous system by a PrP-independent mechanism.", + "TAG_DATA": [ + "83, Rag-1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "84, mice {'context': 'B-organism'}", + "86, fetal {'context': 'B-cells'}", + "87, liver {'context': 'I-cells'}", + "88, cells {'context': 'I-cells'}", + "93, PrP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "94, mice {'context': 'B-organism'}", + "97, T-cell {'perturbing_action': 'B-gene loss-of-function'}", + "98, deficient {'perturbing_action': 'I-gene loss-of-function'}", + "99, mice, {'context': 'B-organism'}", + "104, deficient {'perturbing_action': 'I-gene loss-of-function'}", + "105, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "83, Rag-1(-/-) ['l0', 'l1', 'l2', 'l3']", + "84, mice ['l0', 'l4', 'l5', 'l6']", + "86, fetal ['l1', 'l4', 'l7', 'l8', 'l9', 'l10']", + "87, liver ['l2', 'l5', 'l7', 'l11', 'l12', 'l13']", + "88, cells ['l3', 'l6', 'l8', 'l11', 'l14', 'l15']", + "93, PrP-deficient ['l9', 'l12', 'l14', 'l16']", + "94, mice ['l10', 'l13', 'l15', 'l16']", + "97, T-cell ['l17', 'l18', 'l19', 'l20', 'l21']", + "98, deficient ['l17', 'l22', 'l23', 'l24', 'l25']", + "99, mice, ['l18', 'l22', 'l26', 'l27', 'l28']", + "103, B-cell ['l19', 'l23', 'l26', 'l29', 'l30']", + "104, deficient ['l20', 'l24', 'l27', 'l29', 'l31']", + "105, mice, ['l21', 'l25', 'l28', 'l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rag-1(-/-)", + "PrP-deficient", + "T-cell", + "deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rag-1(-/-)", + "PrP-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "fetal", + "liver", + "cells" + ] + } + } + ] + }, + { + "PMID": "9734400", + "TEXT": "A high-fat diet increases the risk of colon, breast and prostate cancer. The molecular mechanism by which dietary lipids promote tumorigenesis is unknown. Their effects may be mediated at least in part by the peroxisome proliferator-activated receptors (PPARs). These ligand-activated nuclear receptors modulate gene expression in response to fatty acids, lipid-derived metabolites and antidiabetic drugs. To explore the role of the PPARs in diet-induced carcinogenesis, we treated mice predisposed to intestinal neoplasia with a synthetic PPARgamma ligand. Reflecting the pattern of expression of PPARgamma in the gastrointestinal tract, treated mice developed a considerably greater number of polyps in the colon but not in the small intestine, indicating that PPARgamma activation may provide a molecular link between a high-fat diet and increased risk of colorectal cancer.", + "TAG_DATA": [ + "67, mice {'context': 'B-organism'}", + "68, predisposed {'effect': 'B-positive'}", + "69, to {'effect': 'I-positive'}", + "71, neoplasia {'phenotype': 'I-tumourigenesis'}", + "89, mice {'context': 'B-organism'}", + "99, colon {'context': 'B-tissue/organ'}", + "104, small {'context': 'B-tissue/organ'}", + "105, intestine, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "67, mice ['l0', 'l1', 'l2', 'l3']", + "68, predisposed ['l0', 'l4', 'l5', 'l6']", + "69, to ['l1', 'l4', 'l7', 'l8']", + "70, intestinal ['l2', 'l5', 'l7', 'l9']", + "71, neoplasia ['l3', 'l6', 'l8', 'l9']", + "89, mice ['l10', 'l11', 'l12']", + "99, colon ['l10', 'l13', 'l14']", + "104, small ['l11', 'l13', 'l15']", + "105, intestine, ['l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "predisposed", + "to" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasia" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "predisposed", + "to" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasia" + ] + } + } + ] + }, + { + "PMID": "9734399", + "TEXT": "The development of colorectal cancer, one of the most frequent cancers, is influenced by prostaglandins and fatty acids. Decreased prostaglandin production, seen in mice with mutations in the cyclooxygenase 2 gene or in animals and humans treated with cyclooxygenase inhibitors, prevents or attenuates colon cancer development. There is also a strong correlation between the intake of fatty acids from animal origin and colon cancer. Therefore, the peroxisome proliferator-activated receptor gamma (PPARgamma), a downstream transcriptional mediator for prostaglandins and fatty acids which is highly expressed in the colon may be involved in this process. Activation of PPARgamma by two different synthetic agonists increased the frequency and size of colon tumors in C57BL/6J-APCMin/+ mice, an animal model susceptible to intestinal neoplasia. Tumor frequency was only increased in the colon, and did not change in the small intestine, coinciding with the colon-restricted expression of PPARgamma. Treatment with PPARgamma agonists increased beta-catenin levels both in the colon of C57BL/61-APCMin/+ mice and in HT-29 colon carcinoma cells. Genetic abnormalities in the Wnt/wingless/APC pathway, which enhance the transcriptional activity of the beta-catenin-T-cell factor/lymphoid enhancer factor 1 transcription complex, often underly the development of colon tumors. Our data indicate that PPARgamma activation modifies the development of colon tumors in C57BL/61-APCMin/+ mice.", + "TAG_DATA": [ + "93, Activation {'perturbing_action': 'B-pharmacological augmentation'}", + "94, of {'perturbing_action': 'I-pharmacological augmentation'}", + "95, PPARgamma {'perturbing_action': 'I-pharmacological augmentation'}", + "96, by {'perturbing_action': 'I-pharmacological augmentation'}", + "99, synthetic {'perturbing_action': 'I-pharmacological augmentation'}", + "100, agonists {'perturbing_action': 'I-pharmacological augmentation'}", + "107, colon {'context': 'B-neoplasm'}", + "108, tumors {'context': 'I-neoplasm'}", + "110, C57BL/6J-APCMin/+ {'perturbing_action': 'B-other'}", + "111, mice, {'context': 'B-organism'}", + "119, Tumor {'phenotype': 'B-tumourigenesis'}", + "126, colon, {'context': 'B-tissue/organ'}", + "133, small {'context': 'B-tissue/organ'}", + "134, intestine, {'context': 'I-tissue/organ'}", + "152, colon {'context': 'B-tissue/organ'}", + "154, C57BL/61-APCMin/+ {'perturbing_action': 'B-other'}", + "155, mice {'context': 'B-organism'}", + "158, HT-29 {'context': 'B-transformed cells'}", + "159, colon {'context': 'I-transformed cells'}", + "160, carcinoma {'context': 'I-transformed cells'}", + "161, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "93, Activation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "94, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "95, PPARgamma ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "96, by ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "99, synthetic ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "100, agonists ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "107, colon ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65']", + "108, tumors ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l66', 'l67']", + "110, C57BL/6J-APCMin/+ ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l66', 'l68', 'l69']", + "111, mice, ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l67', 'l68']", + "119, Tumor ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l70', 'l71', 'l72', 'l73']", + "126, colon, ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l69', 'l70', 'l74', 'l75']", + "133, small ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l71', 'l74', 'l76', 'l77', 'l78']", + "134, intestine, ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l72', 'l75', 'l76', 'l79']", + "152, colon ['l73', 'l77', 'l79', 'l80', 'l81', 'l82']", + "154, C57BL/61-APCMin/+ ['l80', 'l83', 'l84', 'l85', 'l86', 'l87']", + "155, mice ['l78', 'l81', 'l83', 'l88', 'l89', 'l90', 'l91']", + "158, HT-29 ['l84', 'l88', 'l92', 'l93', 'l94']", + "159, colon ['l85', 'l89', 'l92', 'l95', 'l96']", + "160, carcinoma ['l86', 'l90', 'l93', 'l95', 'l97']", + "161, cells. ['l82', 'l87', 'l91', 'l94', 'l96', 'l97']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "PPARgamma", + "by", + "synthetic", + "agonists" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "colon", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "PPARgamma", + "by", + "synthetic", + "agonists" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "PPARgamma", + "by", + "synthetic", + "agonists" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "Tumor" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "PPARgamma", + "by", + "synthetic", + "agonists" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "colon,", + "small", + "intestine," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "colon", + "tumors" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "C57BL/6J-APCMin/+" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "C57BL/6J-APCMin/+", + "C57BL/61-APCMin/+" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "C57BL/6J-APCMin/+", + "C57BL/61-APCMin/+" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "colon,", + "colon" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "Tumor" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "colon,", + "small", + "intestine,", + "colon" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "C57BL/61-APCMin/+" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HT-29", + "colon", + "carcinoma", + "cells." + ] + } + } + ] + }, + { + "PMID": "9734395", + "TEXT": "Accelerated atherosclerosis in patients with diabetes is a major cause of their morbidity and mortality, and it is unresponsive to therapy aimed at restoring relative euglycemia. In hyperglycemia, nonenzymatic glycation and oxidation of proteins and lipids results in the accumulation of irreversibly formed advanced glycation endproducts. These advanced glycation endproducts engage their receptor in cells of the blood vessel wall, thereby activating mechanisms linked to the development of vascular lesions. We report here a model of accelerated and advanced atherosclerosis in diabetic mice deficient for apolipoprotein E. Treatment of these mice with the soluble extracellular domain of the receptor for advanced glycation endproducts completely suppressed diabetic atherosclerosis in a glycemia- and lipid-independent manner. These findings indicate interaction between the advanced glycation endproducts and their receptor is involved in the development of accelerated atherosclerosis in diabetes, and identify this receptor as a new therapeutic target in diabetic macrovascular disease.", + "TAG_DATA": [ + "81, diabetic {'context': 'B-organism'}", + "82, mice {'context': 'I-organism'}", + "83, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "84, for {'perturbing_action': 'I-gene loss-of-function'}", + "85, apolipoprotein {'perturbing_action': 'I-gene loss-of-function'}", + "86, E. {'perturbing_action': 'I-gene loss-of-function'}", + "90, mice {'context': 'B-organism'}", + "104, suppressed {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "81, diabetic ['l0', 'l1', 'l2', 'l3', 'l4']", + "82, mice ['l0', 'l5', 'l6', 'l7', 'l8']", + "83, deficient ['l1', 'l5', 'l9', 'l10', 'l11']", + "84, for ['l2', 'l6', 'l9', 'l12', 'l13']", + "85, apolipoprotein ['l3', 'l7', 'l10', 'l12', 'l14']", + "86, E. ['l4', 'l8', 'l11', 'l13', 'l14']", + "90, mice ['l15', 'l16']", + "104, suppressed ['l15', 'l17']", + "106, atherosclerosis ['l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "diabetic", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "apolipoprotein", + "E." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + } + ] + }, + { + "PMID": "9701251", + "TEXT": "Prostate apoptosis response-4 (Par-4) is a protein containing both a leucine zipper and a death domain that was isolated by differential screening for genes upregulated in prostate cancer cells undergoing apoptosis. Par-4 is expressed in the nervous system, where its function is unknown. In Alzheimer disease (AD), neurons may die by apoptosis, and amyloid beta-protein (A beta) may play a role in this. We report here that Par-4 expression is increased in vulnerable neurons in AD brain and is induced in cultured neurons undergoing apoptosis. Blockade of Par-4 expression or function prevented neuronal apoptosis induced by Ab and trophic factor withdrawal. Par-4 expression was enhanced, and mitochondrial dysfunction and apoptosis exacerbated, in cells expressing presenilin-1 mutations associated with early-onset inherited AD.", + "TAG_DATA": [ + "85, Blockade {'perturbing_action': 'B-rnai/knockdown'}", + "86, of {'perturbing_action': 'I-rnai/knockdown'}", + "87, Par-4 {'perturbing_action': 'I-rnai/knockdown'}", + "88, expression {'perturbing_action': 'I-rnai/knockdown'}", + "91, prevented {'effect': 'B-negative'}", + "92, neuronal {'context': 'B-cells'}", + "93, apoptosis {'phenotype': 'B-apoptosis'}", + "94, induced {'effect': 'B-positive'}", + "109, apoptosis {'phenotype': 'B-apoptosis'}", + "110, exacerbated, {'effect': 'B-positive'}", + "112, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "85, Blockade ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "86, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "87, Par-4 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "88, expression ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "91, prevented ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "92, neuronal ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "93, apoptosis ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "94, induced ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "109, apoptosis ['l28', 'l29']", + "110, exacerbated, ['l28', 'l30']", + "112, cells ['l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Blockade", + "of", + "Par-4", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Blockade", + "of", + "Par-4", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "neuronal" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Blockade", + "of", + "Par-4", + "expression" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Blockade", + "of", + "Par-4", + "expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "cells", + "words": [ + "neuronal" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neuronal", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neuronal", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "exacerbated," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "exacerbated," + ] + } + } + ] + }, + { + "PMID": "9662378", + "TEXT": "The p53 tumor suppressor gene, which is induced by DNA damage and/or stress stimuli, causes cells to undergo G1-arrest or apoptotic death; thus it plays an essential role in human carcinogenesis. We have searched for p53-related genes by using degenerate PCR, and have identified two cDNA fragments similar to but distinct from p53: one previously reported, p73, and the other new. We cloned two major splicing variants of the latter gene and named these p51A and p51B (a human homologue of rat Ket). The p51A gene encodes a 448-amino-acid protein with a molecular weight of 50.9 kDa; and p51B, a 641-amino-acid protein with a molecular weight of 71.9 kDa. In contrast with the ubiquitous expression of p53, expression of p51 mRNA was found in a limited number of tissues, including skeletal muscle, placenta, mammary gland, prostate, trachea, thymus, salivary gland, uterus, heart and lung. In p53-deficient cells, p51A induced growth-suppression and apoptosis, and upregulated p21waf-1 through p53 regulatory elements. Mutations in p51 were found in some human epidermal tumors.", + "TAG_DATA": [ + "145, p53-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "146, cells, {'context': 'B-cells'}", + "148, induced {'effect': 'B-positive'}", + "151, apoptosis, {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "145, p53-deficient ['l0', 'l1', 'l2']", + "146, cells, ['l0', 'l3', 'l4']", + "148, induced ['l1', 'l3', 'l5']", + "151, apoptosis, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + } + ] + }, + { + "PMID": "9662377", + "TEXT": "Previously, we cloned a cDNA fragment, TSIP 2 (tumor suppressor inhibited pathway clone 2), that detects by northern blot analysis of M1-LTR6 cells a 3-kb mRNA downregulated during p53-induced apoptosis. Cloning the full-length TSIP 2 cDNA showed that it corresponds to the presenilin 1 (PS1) gene, in which mutations have been reported in early-onset familial Alzheimer's disease. Here we demonstrate that PS1 is downregulated in a series of model systems for p53-dependent and p53-independent apoptosis and tumor suppression. To investigate the biological relevance of this downregulation, we stably transfected U937 cells with antisense PS1 cDNA. The downregulation of PS1 in these U937 transfectants results in reduced growth with an increased fraction of the cells in apoptosis. When injected into mice homozygous for severe combined immunodeficiency disease (scid/scid mice), these cells show a suppression of their malignant phenotype. Our results indicate that PS1, initially identified in a neurodegenerative disease, may also be involved in the regulation of cancer-related pathways.", + "TAG_DATA": [ + "87, stably {'perturbing_action': 'B-gene gain-of-function'}", + "88, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "89, U937 {'context': 'B-cells'}", + "90, cells {'context': 'I-cells'}", + "91, with {'perturbing_action': 'I-gene gain-of-function'}", + "92, antisense {'perturbing_action': 'I-gene gain-of-function'}", + "93, PS1 {'perturbing_action': 'I-gene gain-of-function'}", + "94, cDNA. {'perturbing_action': 'I-gene gain-of-function'}", + "96, downregulation {'perturbing_action': 'B-gene loss-of-function'}", + "97, of {'perturbing_action': 'I-gene loss-of-function'}", + "98, PS1 {'perturbing_action': 'I-rnai/knockdown'}", + "101, U937 {'context': 'B-cells'}", + "102, transfectants {'context': 'I-cells'}", + "109, increased {'effect': 'B-positive'}", + "113, cells {'context': 'B-cells'}", + "115, apoptosis. {'phenotype': 'B-apoptosis'}", + "119, mice {'context': 'B-organism'}", + "120, homozygous {'perturbing_action': 'B-other'}", + "121, for {'perturbing_action': 'I-gene loss-of-function'}", + "122, severe {'perturbing_action': 'I-gene loss-of-function'}", + "123, combined {'perturbing_action': 'I-gene loss-of-function'}", + "124, immunodeficiency {'perturbing_action': 'I-gene loss-of-function'}", + "125, disease {'perturbing_action': 'I-gene loss-of-function'}", + "129, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "87, stably ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "88, transfected ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "89, U937 ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "90, cells ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43']", + "91, with ['l3', 'l16', 'l28', 'l39', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "92, antisense ['l4', 'l17', 'l29', 'l44', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "93, PS1 ['l5', 'l18', 'l30', 'l40', 'l45', 'l55', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "94, cDNA. ['l6', 'l19', 'l31', 'l41', 'l46', 'l56', 'l65', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "96, downregulation ['l47', 'l57', 'l66', 'l74', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "97, of ['l7', 'l20', 'l32', 'l48', 'l58', 'l67', 'l75', 'l82', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "98, PS1 ['l8', 'l21', 'l33', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l95', 'l96', 'l97', 'l98', 'l99']", + "101, U937 ['l9', 'l22', 'l34', 'l50', 'l60', 'l69', 'l77', 'l84', 'l90', 'l95', 'l100', 'l101', 'l102', 'l103']", + "102, transfectants ['l10', 'l23', 'l35', 'l51', 'l61', 'l70', 'l78', 'l85', 'l91', 'l96', 'l100', 'l104', 'l105', 'l106']", + "109, increased ['l11', 'l24', 'l36', 'l42', 'l52', 'l62', 'l71', 'l79', 'l86', 'l92', 'l97', 'l101', 'l104', 'l107', 'l108']", + "113, cells ['l12', 'l25', 'l37', 'l43', 'l53', 'l63', 'l72', 'l80', 'l87', 'l93', 'l98', 'l102', 'l105', 'l107', 'l109']", + "115, apoptosis. ['l13', 'l26', 'l38', 'l54', 'l64', 'l73', 'l81', 'l88', 'l94', 'l99', 'l103', 'l106', 'l108', 'l109']", + "119, mice ['l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "120, homozygous ['l110', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "121, for ['l111', 'l117', 'l123', 'l124', 'l125', 'l126', 'l127']", + "122, severe ['l112', 'l118', 'l123', 'l128', 'l129', 'l130', 'l131']", + "123, combined ['l113', 'l119', 'l124', 'l128', 'l132', 'l133', 'l134']", + "124, immunodeficiency ['l114', 'l120', 'l125', 'l129', 'l132', 'l135', 'l136']", + "125, disease ['l115', 'l121', 'l126', 'l130', 'l133', 'l135', 'l137']", + "129, cells ['l116', 'l122', 'l127', 'l131', 'l134', 'l136', 'l137']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "stably", + "transfected", + "with", + "antisense", + "PS1", + "cDNA." + ] + }, + "context": { + "val": "cells", + "words": [ + "U937", + "cells", + "transfectants" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "stably", + "transfected", + "with", + "antisense", + "PS1", + "cDNA." + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "stably", + "transfected", + "with", + "antisense", + "PS1", + "cDNA." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "U937", + "transfectants", + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "downregulation", + "for", + "severe", + "combined", + "immunodeficiency", + "disease" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "U937", + "transfectants", + "cells" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PS1" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "U937", + "cells", + "transfectants" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "U937", + "transfectants", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "downregulation", + "of" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "downregulation", + "of" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PS1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PS1" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "homozygous" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "for", + "severe", + "combined", + "immunodeficiency", + "disease" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "homozygous" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "9662375", + "TEXT": "The formation of fibrillar deposits of amyloid beta protein (Abeta) in the brain is a pathological hallmark of Alzheimer's disease (AD). A central question is whether Abeta plays a direct role in the neurodegenerative process in AD. The involvement of Abeta in the neurodegenerative process is suggested by the neurotoxicity of the fibrillar form of Abeta in vitro. However, mice transgenic for the Abeta precursor protein that develop amyloid deposits in the brain do not show the degree of neuronal loss or tau phosphorylation found in AD. Here we show that microinjection of plaque-equivalent concentrations of fibrillar, but not soluble, Abeta in the aged rhesus monkey cerebral cortex results in profound neuronal loss, tau phosphorylation and microglial proliferation. Fibrillar Abeta at plaque-equivalent concentrations is not toxic in the young adult rhesus brain. Abeta toxicity in vivo is also highly species-specific; toxicity is greater in aged rhesus monkeys than in aged marmoset monkeys, and is not significant in aged rats. These results suggest that Abeta neurotoxicity in vivo is a pathological response of the aging brain, which is most pronounced in higher order primates. Thus, longevity may contribute to the unique susceptibility of humans to Alzheimer's disease by rendering the brain vulnerable to Abeta neurotoxicity.", + "TAG_DATA": [ + "103, aged {'context': 'B-organism'}", + "104, rhesus {'context': 'I-organism'}", + "105, monkey {'context': 'I-tissue/organ'}", + "106, cerebral {'context': 'I-tissue/organ'}", + "107, cortex {'context': 'I-tissue/organ'}", + "116, microglial {'context': 'B-cells'}", + "117, proliferation. {'phenotype': 'B-proliferation'}", + "128, young {'context': 'B-organism'}", + "129, adult {'context': 'I-organism'}", + "130, rhesus {'context': 'I-tissue/organ'}", + "131, brain. {'context': 'I-tissue/organ'}", + "134, in {'context': 'B-in vivo'}", + "135, vivo {'context': 'I-in vivo'}", + "144, aged {'context': 'B-organism'}", + "145, rhesus {'context': 'I-organism'}", + "146, monkeys {'context': 'I-organism'}", + "149, aged {'context': 'B-organism'}", + "150, marmoset {'context': 'I-organism'}", + "151, monkeys, {'context': 'I-organism'}", + "157, aged {'context': 'B-organism'}", + "158, rats. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "103, aged ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "104, rhesus ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "105, monkey ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "106, cerebral ['l2', 'l7', 'l11', 'l15', 'l16']", + "107, cortex ['l3', 'l8', 'l12', 'l15', 'l17']", + "116, microglial ['l4', 'l9', 'l13', 'l18', 'l19']", + "117, proliferation. ['l5', 'l10', 'l14', 'l16', 'l17', 'l18']", + "128, young ['l20', 'l21', 'l22', 'l23', 'l24']", + "129, adult ['l20', 'l25', 'l26', 'l27']", + "130, rhesus ['l21', 'l25', 'l28', 'l29', 'l30', 'l31']", + "131, brain. ['l19', 'l22', 'l26', 'l28']", + "134, in ['l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "135, vivo ['l32', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "144, aged ['l33', 'l41', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "145, rhesus ['l34', 'l42', 'l49', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "146, monkeys ['l23', 'l27', 'l29', 'l35', 'l43', 'l50', 'l56', 'l62', 'l63', 'l64']", + "149, aged ['l30', 'l36', 'l44', 'l51', 'l57', 'l62', 'l65', 'l66']", + "150, marmoset ['l37', 'l45', 'l52', 'l58', 'l63', 'l65', 'l67', 'l68', 'l69']", + "151, monkeys, ['l24', 'l31', 'l38', 'l46', 'l53', 'l59', 'l64', 'l66', 'l67']", + "157, aged ['l39', 'l47', 'l54', 'l60', 'l68', 'l70']", + "158, rats. ['l40', 'l48', 'l55', 'l61', 'l69', 'l70']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "aged", + "rhesus" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "monkey", + "cerebral", + "cortex" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "microglial" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "9623985", + "TEXT": "Huntington's disease is an autosomal dominant, inherited disorder that results in progressive degeneration of the basal ganglia (especially the neostriatal caudate nucleus and putamen) and other forebrain structures and is associated with a clinical profile of movement, cognitive and psychiatric impairments for which there is at present no effective therapy. Neuropathological, neurochemical and behavioral features of the disease can all be reproduced in experimental animals by local injection of excitotoxic or metabolic toxins into the neostriatum. All these features of the disease can be alleviated, at least in rats, by transplantation of embryonic striatal tissue into the degenerated striatum, which was the basis for commencing the first clinical trials of striatal transplantation in Huntington's patients. However, although rat striatal xenografts may temporarily reduce apomorphine-induced dyskinesias in monkeys, there has been no demonstration that allograft techniques that work well in rats translate effectively to the much larger differentiated striatum of primates. Here we demonstrate good survival, differentiation and integration of striatal allografts in the primate neostriatum, and recovery in a test of skilled motor performance. Long-term graft survival in primates indicates probable success for clinical transplants in Huntington's disease; in addition, our data suggest that graft placement has a direct influence on the pattern and extent of functional recovery.", + "TAG_DATA": [ + "117, rat {'context': 'B-xenograft'}", + "118, striatal {'context': 'I-xenograft'}", + "119, xenografts {'context': 'I-xenograft'}", + "126, monkeys, {'context': 'B-organism'}", + "155, differentiation {'phenotype': 'B-differentiation'}", + "159, striatal {'context': 'B-xenograft'}", + "160, allografts {'context': 'I-xenograft'}", + "163, primate {'context': 'B-tissue/organ'}", + "164, neostriatum, {'context': 'I-tissue/organ'}", + "178, primates {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "93, striatal ['l0']", + "94, tissue ['l0']", + "117, rat ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "118, striatal ['l1', 'l7', 'l8', 'l9', 'l10']", + "119, xenografts ['l2', 'l7', 'l11', 'l12', 'l13']", + "126, monkeys, ['l3', 'l8', 'l11', 'l14']", + "155, differentiation ['l4', 'l9', 'l12', 'l14', 'l15', 'l16', 'l17', 'l18']", + "159, striatal ['l15', 'l19', 'l20', 'l21']", + "160, allografts ['l16', 'l19', 'l22', 'l23']", + "163, primate ['l5', 'l17', 'l20', 'l22', 'l24']", + "164, neostriatum, ['l6', 'l10', 'l13', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "xenograft", + "words": [ + "rat", + "striatal", + "xenografts", + "allografts" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "monkeys," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "primate", + "neostriatum," + ] + } + } + ] + }, + { + "PMID": "9623984", + "TEXT": "Neuropeptide Y (NPY) is a 36-amino-acid neurotransmitter which is widely distributed throughout the central and peripheral nervous system. NPY involvement has been suggested in various physiological responses including cardiovascular homeostasis and the hypothalamic control of food intake. At least six subtypes of NPY receptors have been described. Because of the lack of selective antagonists, the specific role of each receptor subtype has been difficult to establish. Here we describe mice deficient for the expression of the Y1 receptor subtype. Homozygous mutant mice demonstrate a complete absence of blood pressure response to NPY, whereas they retain normal response to other vasoconstrictors. Daily food intake, as well as NPY-stimulated feeding, are only slightly diminished, whereas fast-induced refeeding is markedly reduced. Adult mice lacking the NPY Y1 receptor are characterized by increased body fat with no change in protein content. The higher energetic efficiency of mutant mice might result, in part, from the lower metabolic rate measured during the active period, associated with reduced locomotor activity. These results demonstrate the importance of NPY Y1 receptors in NPY-mediated cardiovascular response and in the regulation of body weight through central control of energy expenditure. In addition, these data are also indicative of a role for the Y1 receptor in the control of food intake.", + "TAG_DATA": [ + "69, mice {'context': 'B-organism'}", + "70, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "71, for {'perturbing_action': 'I-gene loss-of-function'}", + "72, the {'perturbing_action': 'I-gene loss-of-function'}", + "73, expression {'perturbing_action': 'I-gene loss-of-function'}", + "74, of {'perturbing_action': 'I-gene loss-of-function'}", + "75, the {'perturbing_action': 'I-gene loss-of-function'}", + "76, Y1 {'perturbing_action': 'I-gene loss-of-function'}", + "77, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "78, subtype. {'perturbing_action': 'I-gene loss-of-function'}", + "79, Homozygous {'perturbing_action': 'B-other'}", + "81, mice {'context': 'B-organism'}", + "118, Adult {'context': 'B-organism'}", + "119, mice {'context': 'I-organism'}", + "120, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "121, the {'perturbing_action': 'I-gene loss-of-function'}", + "122, NPY {'perturbing_action': 'I-gene loss-of-function'}", + "123, Y1 {'perturbing_action': 'I-gene loss-of-function'}", + "124, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "143, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "69, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "70, deficient ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "71, for ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "72, the ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "73, expression ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "74, of ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "75, the ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "76, Y1 ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "77, receptor ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "78, subtype. ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "79, Homozygous ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "80, mutant ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "81, mice ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "118, Adult ['l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "119, mice ['l78', 'l84', 'l85', 'l86', 'l87', 'l88']", + "120, lacking ['l79', 'l84', 'l89', 'l90', 'l91', 'l92']", + "121, the ['l80', 'l85', 'l89', 'l93', 'l94', 'l95']", + "122, NPY ['l81', 'l86', 'l90', 'l93', 'l96', 'l97']", + "123, Y1 ['l82', 'l87', 'l91', 'l94', 'l96', 'l98']", + "124, receptor ['l83', 'l88', 'l92', 'l95', 'l97', 'l98']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "Adult" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "the", + "expression", + "of", + "Y1", + "receptor", + "subtype.", + "lacking", + "NPY" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Homozygous" + ] + } + } + ] + }, + { + "PMID": "9623983", + "TEXT": "Neuropeptide Y (NPY), a 36-amino-acid neuromodulator abundantly expressed in the brain, has been implicated in the regulation of food intake and body weight. Pharmacological data suggest that NPY's stimulatory effect on appetite is transduced by the G-protein-coupled NPY Y5 receptor (Y5R). We have inactivated the Y5R gene in mice and report that younger Y5R-null mice feed and grow normally; however, they develop mild late-onset obesity characterized by increased body weight, food intake and adiposity. Fasting-induced refeeding is unchanged in younger Y5R-null mice and they exhibit normal sensitivity to leptin. Their response to intracerebroventricular (i.c.v.) administration of NPY and related peptides is either reduced or absent. NPY deficiency attenuates the obesity syndrome of mice deficient for leptin (ob/ob), but these effects are not mediated by NPY signaling through the Y5R because Y5R-null ob/ob mice are equally obese. These results demonstrate that the Y5R contributes to feeding induced by centrally administered NPY and its analogs, but is not a critical physiological feeding receptor in mice.", + "TAG_DATA": [ + "43, inactivated {'perturbing_action': 'B-gene loss-of-function'}", + "44, the {'perturbing_action': 'I-gene loss-of-function'}", + "45, Y5R {'perturbing_action': 'I-gene loss-of-function'}", + "46, gene {'perturbing_action': 'I-gene loss-of-function'}", + "48, mice {'context': 'B-organism'}", + "53, Y5R-null {'perturbing_action': 'B-gene loss-of-function'}", + "54, mice {'context': 'B-organism'}", + "80, Y5R-null {'perturbing_action': 'B-gene loss-of-function'}", + "81, mice {'context': 'B-organism'}", + "105, NPY {'perturbing_action': 'B-gene loss-of-function'}", + "106, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "112, mice {'context': 'B-organism'}", + "113, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "114, for {'perturbing_action': 'I-gene loss-of-function'}", + "115, leptin {'perturbing_action': 'I-gene loss-of-function'}", + "116, (ob/ob), {'perturbing_action': 'I-gene loss-of-function'}", + "130, Y5R-null {'perturbing_action': 'B-gene loss-of-function'}", + "131, ob/ob {'perturbing_action': 'B-gene loss-of-function', 'context': 'B-organism'}", + "132, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "43, inactivated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "44, the ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "45, Y5R ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "46, gene ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "48, mice ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28']", + "53, Y5R-null ['l4', 'l11', 'l17', 'l22', 'l26', 'l29', 'l30']", + "54, mice ['l5', 'l12', 'l18', 'l23', 'l27', 'l29']", + "80, Y5R-null ['l6', 'l13', 'l19', 'l24', 'l31']", + "81, mice ['l7', 'l14', 'l20', 'l25', 'l28', 'l30', 'l31']", + "105, NPY ['l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "106, deficiency ['l32', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "112, mice ['l33', 'l41', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "113, deficient ['l34', 'l42', 'l48', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "114, for ['l35', 'l43', 'l49', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "115, leptin ['l36', 'l44', 'l50', 'l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "116, (ob/ob), ['l37', 'l45', 'l51', 'l57', 'l62', 'l66', 'l70', 'l71', 'l72']", + "130, Y5R-null ['l38', 'l52', 'l58', 'l63', 'l67', 'l70', 'l73', 'l74']", + "131, ob/ob ['l39', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l73', 'l75']", + "132, mice ['l40', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivated", + "the", + "Y5R", + "gene", + "Y5R-null", + "NPY", + "deficiency", + "deficient", + "for", + "leptin", + "(ob/ob),", + "ob/ob" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "ob/ob" + ] + } + } + ] + }, + { + "PMID": "9623979", + "TEXT": "Liver transplantation is the only therapeutic strategy for many inherited and acquired diseases. The formation of reactive oxygen species following ischemia/reperfusion is a cause of hepatocellular injury during transplantation. This report describes the therapeutic application of mitochondrial superoxide dismutase gene transfer to the liver for acute ischemia/reperfusion injury. Recombinant adenoviral expression of mitochondrial superoxide dismutase in mouse liver prior to lobar ischemia/reperfusion significantly reduced acute liver damage and associated redox activation of both NF-kappaB and AP1. These immediate early transcription factors represent common pathways by which cells respond to environmental stress. This work provides the foundation for redox-mediated gene therapies directed at ameliorating ischemia/reperfusion injury and associated acute rejection in orthotopic liver transplantation.", + "TAG_DATA": [ + "48, Recombinant {'perturbing_action': 'B-gene gain-of-function'}", + "49, adenoviral {'perturbing_action': 'I-gene gain-of-function'}", + "50, expression {'perturbing_action': 'I-gene gain-of-function'}", + "51, of {'perturbing_action': 'I-gene gain-of-function'}", + "52, mitochondrial {'perturbing_action': 'I-gene gain-of-function'}", + "53, superoxide {'perturbing_action': 'I-gene gain-of-function'}", + "54, dismutase {'perturbing_action': 'I-gene gain-of-function'}", + "56, mouse {'context': 'B-tissue/organ'}", + "57, liver {'context': 'I-tissue/organ'}", + "65, liver {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "48, Recombinant ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "49, adenoviral ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "50, expression ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "51, of ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "52, mitochondrial ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "53, superoxide ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "54, dismutase ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "56, mouse ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "57, liver ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "65, liver ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Recombinant", + "adenoviral", + "expression", + "of", + "mitochondrial", + "superoxide", + "dismutase" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "liver" + ] + } + } + ] + }, + { + "PMID": "9623977", + "TEXT": "The transfer of apoptosis genes to tumors is one of the most promising strategies for cancer gene therapy. We have shown that massive apoptosis occurs when wild-type p53 expression is induced in glioma cells carrying a p53 gene mutation. However, adenovirus-mediated p53 gene transfer is ineffective in causing apoptosis in glioma cells that retain a wild-type p53 genotype. We evaluated the effect of E2F-1 overexpression on the growth of gliomas in vitro and in vivo. In the in vitro study, the adenovirus-mediated transfer of exogenous E2F-1 protein precipitated generalized apoptosis in gliomas. The treatment with Ad5CMV-E2F-1 of nude mice carrying subcutaneous gliomas arrested tumor growth. Our results indicate that E2F-1 has anti-glioma activity in vitro and in vivo.", + "TAG_DATA": [ + "63, E2F-1 {'perturbing_action': 'B-gene gain-of-function'}", + "64, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "69, gliomas {'context': 'B-neoplasm'}", + "70, in {'context': 'B-in vitro'}", + "71, vitro {'context': 'I-in vitro'}", + "73, in {'context': 'B-in vivo'}", + "74, vivo. {'context': 'I-in vivo'}", + "77, in {'context': 'B-in vitro'}", + "78, vitro {'context': 'I-in vitro'}", + "81, adenovirus-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "82, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "83, of {'perturbing_action': 'I-gene gain-of-function'}", + "84, exogenous {'perturbing_action': 'I-gene gain-of-function'}", + "85, E2F-1 {'perturbing_action': 'I-gene gain-of-function'}", + "86, protein {'perturbing_action': 'I-gene gain-of-function'}", + "87, precipitated {'effect': 'B-positive'}", + "89, apoptosis {'phenotype': 'B-apoptosis'}", + "91, gliomas. {'context': 'B-neoplasm'}", + "97, nude {'context': 'B-organism'}", + "98, mice {'context': 'I-organism'}", + "100, subcutaneous {'context': 'B-neoplasm'}", + "101, gliomas {'context': 'I-neoplasm'}", + "102, arrested {'effect': 'B-negative'}", + "103, tumor {'phenotype': 'B-tumour growth'}", + "104, growth. {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "63, E2F-1 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "64, overexpression ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "69, gliomas ['l1', 'l17', 'l33', 'l34', 'l35', 'l36']", + "70, in ['l2', 'l18', 'l33', 'l37']", + "71, vitro ['l3', 'l19', 'l34', 'l37']", + "73, in ['l4', 'l20', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "74, vivo. ['l5', 'l21', 'l38', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "77, in ['l6', 'l22', 'l39', 'l50', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "78, vitro ['l7', 'l23', 'l35', 'l40', 'l51', 'l61', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "81, adenovirus-mediated ['l8', 'l24', 'l41', 'l52', 'l62', 'l71', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "82, transfer ['l9', 'l25', 'l42', 'l53', 'l63', 'l72', 'l80', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "83, of ['l10', 'l26', 'l43', 'l54', 'l64', 'l73', 'l81', 'l88', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "84, exogenous ['l11', 'l27', 'l44', 'l55', 'l65', 'l74', 'l82', 'l89', 'l95', 'l101', 'l102', 'l103', 'l104', 'l105']", + "85, E2F-1 ['l12', 'l28', 'l45', 'l56', 'l66', 'l75', 'l83', 'l90', 'l96', 'l101', 'l106', 'l107', 'l108', 'l109']", + "86, protein ['l13', 'l29', 'l46', 'l57', 'l67', 'l76', 'l84', 'l91', 'l97', 'l102', 'l106', 'l110', 'l111', 'l112']", + "87, precipitated ['l14', 'l30', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l98', 'l103', 'l107', 'l110', 'l113', 'l114']", + "89, apoptosis ['l15', 'l31', 'l48', 'l59', 'l69', 'l78', 'l86', 'l93', 'l99', 'l104', 'l108', 'l111', 'l113', 'l115']", + "91, gliomas. ['l16', 'l32', 'l36', 'l49', 'l60', 'l70', 'l79', 'l87', 'l94', 'l100', 'l105', 'l109', 'l112', 'l114', 'l115']", + "97, nude ['l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "98, mice ['l116', 'l122', 'l123', 'l124', 'l125', 'l126']", + "100, subcutaneous ['l117', 'l122', 'l127', 'l128', 'l129']", + "101, gliomas ['l118', 'l123', 'l127', 'l130']", + "102, arrested ['l119', 'l124', 'l128', 'l130', 'l131', 'l132']", + "103, tumor ['l120', 'l125', 'l131', 'l133']", + "104, growth. ['l121', 'l126', 'l129', 'l132', 'l133']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "E2F-1", + "overexpression", + "adenovirus-mediated", + "transfer", + "of", + "exogenous", + "protein" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "gliomas", + "gliomas." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "E2F-1", + "overexpression", + "adenovirus-mediated", + "transfer", + "of", + "exogenous", + "protein" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "E2F-1", + "overexpression", + "adenovirus-mediated", + "transfer", + "of", + "exogenous", + "protein" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "E2F-1", + "overexpression", + "adenovirus-mediated", + "transfer", + "of", + "exogenous", + "protein" + ] + }, + "effect": { + "val": "positive", + "words": [ + "precipitated" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "E2F-1", + "overexpression", + "adenovirus-mediated", + "transfer", + "of", + "exogenous", + "protein" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "effect": { + "val": "positive", + "words": [ + "precipitated" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "precipitated" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "precipitated" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "precipitated" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "gliomas." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "gliomas." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "nude", + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrested" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "nude", + "mice" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "subcutaneous", + "gliomas" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrested" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "subcutaneous" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "arrested" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + } + ] + }, + { + "PMID": "9585232", + "TEXT": "In situ killing of tumor cells using suicide gene transfer to generate death by a non-apoptotic pathway was associated with high immunogenicity and induction of heat shock protein (hsp) expression. In contrast, a syngeneic colorectal tumor line, CMT93, killed predominantly by apoptosis, showed low levels of hsp expression and less immunogenicity. When apoptosis was inhibited in CMT93 cells by overexpression of bcl-2, hsp was also induced. Furthermore, when cDNA encoding hsp70 was stably transfected into B16 and CMT93 cells, its expression significantly enhanced the immunogenicity of both tumors. Increased levels of hsp, induced by non-apoptotic cell killing, may provide an immunostimulatory signal in vivo which helps break tolerance to tumor antigens. These findings have important implications for the development of novel anti-cancer therapies aimed at promoting patients' immune responses to their own tumors.", + "TAG_DATA": [ + "33, syngeneic {'context': 'B-transformed cells'}", + "34, colorectal {'context': 'I-transformed cells'}", + "35, tumor {'context': 'I-transformed cells'}", + "36, line, {'context': 'I-transformed cells'}", + "37, CMT93, {'context': 'I-transformed cells'}", + "52, apoptosis {'phenotype': 'B-apoptosis'}", + "54, inhibited {'effect': 'B-negative'}", + "56, CMT93 {'context': 'B-cells'}", + "57, cells {'context': 'I-cells'}", + "59, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "60, of {'perturbing_action': 'I-gene gain-of-function'}", + "61, bcl-2, {'perturbing_action': 'I-gene gain-of-function'}", + "68, cDNA {'perturbing_action': 'B-gene gain-of-function'}", + "69, encoding {'perturbing_action': 'I-gene gain-of-function'}", + "70, hsp70 {'perturbing_action': 'I-gene gain-of-function'}", + "72, stably {'perturbing_action': 'B-gene gain-of-function'}", + "73, transfected {'perturbing_action': 'I-gene gain-of-function'}", + "75, B16 {'context': 'B-cells'}", + "76, and {'context': 'I-cells'}", + "77, CMT93 {'context': 'I-cells'}", + "78, cells, {'context': 'I-cells'}", + "87, tumors. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "33, syngeneic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "34, colorectal ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "35, tumor ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23']", + "36, line, ['l2', 'l11', 'l19', 'l24', 'l25']", + "37, CMT93, ['l3', 'l12', 'l20', 'l24', 'l26']", + "52, apoptosis ['l4', 'l13', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "54, inhibited ['l5', 'l14', 'l27', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "56, CMT93 ['l6', 'l15', 'l22', 'l28', 'l37', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "57, cells ['l7', 'l16', 'l23', 'l25', 'l26', 'l29', 'l38', 'l46', 'l54', 'l55', 'l56', 'l57']", + "59, overexpression ['l30', 'l39', 'l47', 'l54', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "60, of ['l8', 'l17', 'l31', 'l40', 'l48', 'l55', 'l58', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "61, bcl-2, ['l9', 'l18', 'l32', 'l41', 'l49', 'l56', 'l59', 'l67', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "68, cDNA ['l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "69, encoding ['l80', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "70, hsp70 ['l60', 'l68', 'l74', 'l81', 'l89', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "72, stably ['l82', 'l90', 'l97', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "73, transfected ['l61', 'l83', 'l91', 'l98', 'l104', 'l110', 'l111', 'l112', 'l113', 'l114']", + "75, B16 ['l33', 'l42', 'l50', 'l62', 'l69', 'l75', 'l84', 'l92', 'l99', 'l105', 'l110', 'l115', 'l116', 'l117', 'l118']", + "76, and ['l34', 'l43', 'l51', 'l63', 'l70', 'l76', 'l85', 'l93', 'l100', 'l106', 'l111', 'l115', 'l119', 'l120', 'l121']", + "77, CMT93 ['l35', 'l44', 'l52', 'l64', 'l71', 'l77', 'l86', 'l94', 'l101', 'l107', 'l112', 'l116', 'l119', 'l122', 'l123']", + "78, cells, ['l36', 'l45', 'l53', 'l57', 'l65', 'l72', 'l78', 'l87', 'l95', 'l102', 'l108', 'l113', 'l117', 'l120', 'l122', 'l124']", + "87, tumors. ['l66', 'l73', 'l79', 'l88', 'l96', 'l103', 'l109', 'l114', 'l118', 'l121', 'l123', 'l124']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "syngeneic", + "colorectal", + "tumor" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "syngeneic", + "colorectal" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "syngeneic", + "colorectal" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "bcl-2," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "CMT93", + "cells", + "B16", + "and", + "cells," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "bcl-2," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "CMT93", + "cells", + "B16", + "and", + "cells," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "bcl-2," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CMT93", + "cells", + "B16", + "and", + "cells," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "bcl-2,", + "cDNA", + "encoding", + "hsp70", + "stably", + "transfected" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "bcl-2,", + "cDNA", + "encoding", + "hsp70", + "stably", + "transfected" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors." + ] + } + } + ] + }, + { + "PMID": "9546789", + "TEXT": "At a position equivalent to the gene encoding the saimiri transforming protein (STP) of herpesvirus saimiri (HVS), Kaposi's sarcoma-associated herpesvirus (KSHV) contains a distinct open reading frame called K1. Although KSHV and HVS are related members of the rhadinovirus subgroup of gamma herpesviruses, K1 and STP exhibit no similarity in amino acid sequence or in structural organization. Since STP is required for the oncogenic potential of HVS, we investigated the functional consequence of K1 expression. Expression of the K1 gene in rodent fibroblasts produced morphologic changes and focus formation indicative of transformation. A recombinant herpesvirus in which the STP oncogene of HVS was replaced with K1, immortalized primary T lymphocytes to IL-2 independent growth and induced lymphoma in common marmosets. These results demonstrate the transforming potential of the K1 gene of KSHV.", + "TAG_DATA": [ + "75, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "76, of {'perturbing_action': 'I-gene gain-of-function'}", + "77, the {'perturbing_action': 'I-gene gain-of-function'}", + "78, K1 {'perturbing_action': 'I-gene gain-of-function'}", + "79, gene {'perturbing_action': 'I-gene gain-of-function'}", + "81, rodent {'context': 'B-cells'}", + "82, fibroblasts {'context': 'I-cells'}", + "97, the {'perturbing_action': 'I-other'}", + "98, STP {'perturbing_action': 'I-other'}", + "99, oncogene {'perturbing_action': 'I-other'}", + "100, of {'perturbing_action': 'I-other'}", + "101, HVS {'perturbing_action': 'I-other'}", + "102, was {'perturbing_action': 'I-other'}", + "103, replaced {'perturbing_action': 'I-other'}", + "104, with {'perturbing_action': 'I-other'}", + "105, K1, {'perturbing_action': 'I-other'}", + "107, primary {'context': 'B-cells'}", + "108, T {'context': 'I-cells'}", + "109, lymphocytes {'context': 'I-cells'}", + "115, induced {'effect': 'B-positive'}", + "116, lymphoma {'phenotype': 'B-tumourigenesis'}", + "118, common {'context': 'B-organism'}", + "119, marmosets. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "75, Expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "76, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "77, the ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "78, K1 ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "79, gene ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "81, rodent ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "82, fibroblasts ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "93, recombinant ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "94, herpesvirus ['l21', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "97, the ['l22', 'l38', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "98, STP ['l23', 'l39', 'l54', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "99, oncogene ['l24', 'l40', 'l55', 'l69', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "100, of ['l25', 'l41', 'l56', 'l70', 'l83', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "101, HVS ['l26', 'l42', 'l57', 'l71', 'l84', 'l96', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "102, was ['l27', 'l43', 'l58', 'l72', 'l85', 'l97', 'l108', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "103, replaced ['l28', 'l44', 'l59', 'l73', 'l86', 'l98', 'l109', 'l119', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "104, with ['l29', 'l45', 'l60', 'l74', 'l87', 'l99', 'l110', 'l120', 'l129', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145']", + "105, K1, ['l30', 'l46', 'l61', 'l75', 'l88', 'l100', 'l111', 'l121', 'l130', 'l138', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "107, primary ['l31', 'l47', 'l62', 'l76', 'l89', 'l101', 'l112', 'l122', 'l131', 'l139', 'l146', 'l153', 'l154']", + "108, T ['l32', 'l48', 'l63', 'l77', 'l90', 'l102', 'l113', 'l123', 'l132', 'l140', 'l147', 'l153', 'l155']", + "109, lymphocytes ['l33', 'l49', 'l64', 'l78', 'l91', 'l103', 'l114', 'l124', 'l133', 'l141', 'l148', 'l154', 'l155']", + "115, induced ['l34', 'l50', 'l65', 'l79', 'l92', 'l104', 'l115', 'l125', 'l134', 'l142', 'l149', 'l156', 'l157', 'l158']", + "116, lymphoma ['l35', 'l51', 'l66', 'l80', 'l93', 'l105', 'l116', 'l126', 'l135', 'l143', 'l150', 'l156', 'l159', 'l160']", + "118, common ['l36', 'l52', 'l67', 'l81', 'l94', 'l106', 'l117', 'l127', 'l136', 'l144', 'l151', 'l157', 'l159', 'l161']", + "119, marmosets. ['l37', 'l53', 'l68', 'l82', 'l95', 'l107', 'l118', 'l128', 'l137', 'l145', 'l152', 'l158', 'l160', 'l161']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "the", + "K1", + "gene" + ] + }, + "context": { + "val": "cells", + "words": [ + "rodent", + "fibroblasts" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "the", + "STP", + "oncogene", + "of", + "HVS", + "was", + "replaced", + "with", + "K1," + ] + }, + "context": { + "val": "cells", + "words": [ + "primary", + "T", + "lymphocytes" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "the", + "STP", + "oncogene", + "of", + "HVS", + "was", + "replaced", + "with", + "K1," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "the", + "STP", + "oncogene", + "of", + "HVS", + "was", + "replaced", + "with", + "K1," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "the", + "STP", + "oncogene", + "of", + "HVS", + "was", + "replaced", + "with", + "K1," + ] + }, + "context": { + "val": "organism", + "words": [ + "common", + "marmosets." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "common", + "marmosets." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + }, + "context": { + "val": "organism", + "words": [ + "common", + "marmosets." + ] + } + } + ] + }, + { + "PMID": "9546786", + "TEXT": "It is generally believed that the vascular endothelium serves as an inflammatory barrier by providing a nonadherent surface to leukocytes. Here, we report that Fas ligand (FasL) is expressed on vascular endothelial cells (ECs) and that it may function to actively inhibit leukocyte extravasation. TNFalpha downregulates FasL expression with an accompanying decrease in EC cytotoxicity toward co-cultured Fas-bearing cells. Local administration of TNFalpha to arteries downregulates endothelial FasL expression and induces mononuclear cell infiltration. Constitutive FasL expression markedly attenuates TNFalpha-induced cell infiltration and adherent mononuclear cells undergo apoptosis under these conditions. These findings suggest that endothelial FasL expression can negatively regulate leukocyte extravasation.", + "TAG_DATA": [ + "53, EC {'context': 'B-cells'}", + "57, Fas-bearing {'context': 'B-cells'}", + "58, cells. {'context': 'I-cells'}", + "64, arteries {'context': 'B-tissue/organ'}", + "71, mononuclear {'context': 'B-cells'}", + "72, cell {'context': 'I-cells'}", + "74, Constitutive {'perturbing_action': 'B-gene gain-of-function'}", + "75, FasL {'perturbing_action': 'I-gene gain-of-function'}", + "76, expression {'perturbing_action': 'I-gene gain-of-function'}", + "80, cell {'context': 'B-cells'}", + "83, adherent {'context': 'B-cells'}", + "84, mononuclear {'context': 'I-cells'}", + "85, cells {'context': 'I-cells'}", + "86, undergo {'effect': 'B-positive'}", + "87, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "53, EC ['l0', 'l1', 'l2']", + "57, Fas-bearing ['l0', 'l3', 'l4', 'l5', 'l6']", + "58, cells. ['l1', 'l3', 'l7', 'l8', 'l9']", + "64, arteries ['l4', 'l7', 'l10', 'l11']", + "71, mononuclear ['l5', 'l8', 'l10', 'l12']", + "72, cell ['l2', 'l6', 'l9', 'l11', 'l12']", + "74, Constitutive ['l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "75, FasL ['l13', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "76, expression ['l14', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "80, cell ['l15', 'l22', 'l28']", + "83, adherent ['l16', 'l23', 'l29', 'l34', 'l35', 'l36', 'l37']", + "84, mononuclear ['l17', 'l24', 'l30', 'l34', 'l38', 'l39', 'l40']", + "85, cells ['l18', 'l25', 'l31', 'l35', 'l38', 'l41', 'l42']", + "86, undergo ['l19', 'l26', 'l32', 'l36', 'l39', 'l41', 'l43']", + "87, apoptosis ['l20', 'l27', 'l33', 'l37', 'l40', 'l42', 'l43']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Constitutive", + "FasL", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "adherent", + "mononuclear", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Constitutive", + "FasL", + "expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "undergo" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Constitutive", + "FasL", + "expression" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "adherent", + "mononuclear", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "undergo" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "adherent", + "mononuclear", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "undergo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "9546785", + "TEXT": "Administration of tumor necrosis factor (TNF) and gamma interferon (IFN-gamma) to melanoma patients causes selective disruption of the tumor vasculature but the mechanism of this disruption is unknown. Here we report that exposure of human endothelial cells to TNF and IFN-gamma results in a reduced activation of integrin alphaVbeta3, an adhesion receptor that plays a key role in tumor angiogenesis, leading to a decreased alphaVbeta3-dependent endothelial cell adhesion and survival. Detachment and apoptosis of angiogenic endothelial cells was demonstrated in vivo in melanoma metastases of patients treated with TNF and IFN-gamma. These results implicate integrin alphaVbeta3 in the anti-vascular activity of TNF and IFN-gamma and demonstrate a new mechanism by which cytokines control cell adhesion.", + "TAG_DATA": [ + "34, human {'context': 'B-cells'}", + "35, endothelial {'context': 'I-cells'}", + "36, cells {'context': 'I-cells'}", + "63, decreased {'effect': 'B-negative'}", + "65, endothelial {'context': 'B-cells'}", + "66, cell {'context': 'I-cells'}", + "67, adhesion {'phenotype': 'B-adhesion'}", + "72, apoptosis {'phenotype': 'B-apoptosis'}", + "74, angiogenic {'context': 'B-cells'}", + "75, endothelial {'context': 'I-cells'}", + "76, cells {'context': 'I-cells'}", + "79, in {'context': 'B-in vivo'}", + "80, vivo {'context': 'I-in vivo'}", + "82, melanoma {'context': 'B-neoplasm'}", + "83, metastases {'context': 'I-neoplasm', 'phenotype': 'I-metastasis'}", + "85, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "34, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "35, endothelial ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "36, cells ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "63, decreased ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "65, endothelial ['l3', 'l8', 'l12', 'l15', 'l18', 'l19', 'l20', 'l21']", + "66, cell ['l4', 'l9', 'l13', 'l16', 'l18', 'l22']", + "67, adhesion ['l5', 'l10', 'l14', 'l17', 'l19', 'l22']", + "72, apoptosis ['l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "74, angiogenic ['l23', 'l30', 'l31', 'l32', 'l33']", + "75, endothelial ['l20', 'l24', 'l30', 'l34', 'l35']", + "76, cells ['l21', 'l25', 'l31', 'l34', 'l36']", + "79, in ['l26', 'l32', 'l37', 'l38', 'l39']", + "80, vivo ['l27', 'l33', 'l35', 'l36', 'l37', 'l40', 'l41']", + "82, melanoma ['l28', 'l38', 'l40', 'l42', 'l43']", + "83, metastases ['l29', 'l39', 'l41', 'l42', 'l44']", + "85, patients ['l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "endothelial", + "cells", + "cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "endothelial", + "cells", + "cell" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "angiogenic", + "endothelial", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "melanoma", + "metastases" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "metastases", + "melanoma" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + }, + "context": { + "val": "patient", + "words": [ + "patients" + ] + } + } + ] + }, + { + "PMID": "9500607", + "TEXT": "Melanoma is the main cause of death in patients with skin cancer. Cytotoxic T lymphocytes (CTLs) attack melanoma cells in an HLA-restricted and tumor antigen-specific manner. Several melanoma-associated tumor antigens have been identified. These antigens are suitable candidates for a vaccination therapy of melanoma. Dendritic cells (DCs) are antigen-presenting cells (APCs) specialized for the induction of a primary T-cell response. Mouse studies have demonstrated the potent capacity of DCs to induce antitumor immunity. In the present clinical pilot study, DCs were generated in the presence of granulocyte/macrophage-colony stimulating factor (GM-CSF) and interleukin 4 (IL-4) and were pulsed with tumor lysate or a cocktail of peptides known to be recognized by CTLs, depending on the patient's HLA haplotype. Keyhole limpet hemocyanin (KLH) was added as a CD4 helper antigen and immunological tracer molecule. Sixteen patients with advanced melanoma were immunized on an outpatient basis. Vaccination was well tolerated. No physical sign of autoimmunity was detected in any of the patients. DC vaccination induced delayed-type hypersensitivity (DTH) reactivity toward KLH in all patients, as well as a positive DTH reaction to peptide-pulsed DCs in 11 patients. Recruitment of peptide-specific CTLs to the DTH challenge site was also demonstrated. Therefore, antigen-specific immunity was induced during DC vaccination. Objective responses were evident in 5 out of 16 evaluated patients (two complete responses, three partial responses) with regression of metastases in various organs (skin, soft tissue, lung, pancreas) and one additional minor response. These data indicate that vaccination with autologous DCs generated from peripheral blood is a safe and promising approach in the treatment of metastatic melanoma. Further studies are necessary to demonstrate clinical effectiveness and impact on the survival of melanoma patients.", + "TAG_DATA": [ + "79, DCs {'context': 'B-cells'}", + "133, patients {'context': 'B-patient'}", + "134, with {'context': 'I-patient'}", + "135, advanced {'context': 'I-neoplasm'}", + "136, melanoma {'context': 'I-neoplasm'}", + "222, regression {'effect': 'B-negative', 'phenotype': 'B-tumour regression'}", + "224, metastases {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "79, DCs ['l0', 'l1', 'l2']", + "133, patients ['l0', 'l3', 'l4', 'l5']", + "134, with ['l3', 'l6', 'l7']", + "135, advanced ['l1', 'l4', 'l6', 'l8']", + "136, melanoma ['l2', 'l5', 'l7', 'l8']", + "222, regression ['l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "223, of ['l9', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "224, metastases ['l10', 'l18', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "225, in ['l11', 'l19', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "227, organs ['l12', 'l20', 'l27', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "228, (skin, ['l13', 'l21', 'l28', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47']", + "229, soft ['l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l48', 'l49', 'l50']", + "230, tissue, ['l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l51', 'l52']", + "231, lung, ['l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l53']", + "232, pancreas) ['l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l53']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "regression" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "regression" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + } + ] + }, + { + "PMID": "9461198", + "TEXT": "Intravenous tissue plasminogen activator (tPA) is used to treat acute stroke because of its thrombolytic activity and its ability to restore circulation to the brain. However, this protease also promotes neurodegeneration after intracerebral injection of excitotoxins such as glutamate, and neuronal damage after a cerebral infarct is thought to be mediated by excitotoxins. To investigate the effects of tPA on cerebral viability during ischemia/reperfusion, we occluded the middle cerebral artery in wild-type and tPA-deficient mice with an intravascular filament. This procedure allowed us to examine the role of tPA in ischemia, independent of its effect as a thrombolytic agent. tPA-deficient mice exhibited approximately 50% smaller cerebral infarcts than wild-type mice. Intravenous injection of tPA into tPA-/- or wild-type mice produced larger infarcts, indicating that tPA can increase stroke-induced injury. Since tPA promotes desirable (thrombolytic) as well as undesirable (neurotoxic) outcomes during stroke, future therapies should be aimed at countering the excitotoxic damage of tPA to afford even better neuroprotection after an acute cerebral infarct.", + "TAG_DATA": [ + "73, tPA-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "74, mice {'context': 'B-organism'}", + "99, tPA-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "100, mice {'context': 'B-organism'}", + "109, mice. {'context': 'B-organism'}", + "115, tPA-/- {'perturbing_action': 'B-gene loss-of-function'}", + "118, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, tPA-deficient ['l0']", + "74, mice ['l0']", + "99, tPA-deficient ['l1', 'l2']", + "100, mice ['l1', 'l3']", + "109, mice. ['l2', 'l3']", + "115, tPA-/- ['l4']", + "118, mice ['l4']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "tPA-deficient", + "tPA-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "9461192", + "TEXT": "Demyelination alone has been considered sufficient for development of neurological deficits following central nervous system (CNS) disease. However, extensive demyelination is not always associated with clinical deficits in patients with multiple sclerosis (MS), the most common primary demyelinating disease in humans. We used the Theiler's murine encephalomyelitis virus model of demyelination to investigate the role of major histocompatibility complex (MHC) class I and class II gene products in the development of functional and neurophysiological deficits following demyelination. We measured spontaneous clinical activity by two independent assays and recorded hind-limb motor-evoked potentials in infected class I-deficient and class II-deficient mice of an identical genetic background as well as in highly susceptible SJL/J mice. The results show that despite a similar distribution and extent of demyelinated lesions in all mice, only class I-deficient mice were functionally normal. We propose that the mechanism by which demyelinated class I-deficient mice maintain neurologic function results from increased sodium channel densities and the relative preservation of axons. These findings are the first to implicate a role for MHC class I in the development of neurological deficits following demyelination.", + "TAG_DATA": [ + "93, class {'perturbing_action': 'B-gene loss-of-function'}", + "94, I-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "96, class {'perturbing_action': 'B-gene loss-of-function'}", + "97, II-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "98, mice {'context': 'B-organism'}", + "110, SJL/J {'context': 'B-organism'}", + "111, mice. {'context': 'I-organism'}", + "127, mice, {'context': 'B-organism'}", + "129, class {'perturbing_action': 'B-gene loss-of-function'}", + "130, I-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "131, mice {'context': 'B-organism'}", + "143, class {'perturbing_action': 'B-gene loss-of-function'}", + "144, I-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "145, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "93, class ['l0', 'l1', 'l2', 'l3']", + "94, I-deficient ['l0', 'l4', 'l5', 'l6']", + "96, class ['l1', 'l4', 'l7', 'l8', 'l9']", + "97, II-deficient ['l2', 'l5', 'l7', 'l10']", + "98, mice ['l3', 'l6', 'l8', 'l10']", + "110, SJL/J ['l11', 'l12']", + "111, mice. ['l9', 'l11']", + "127, mice, ['l12']", + "129, class ['l13', 'l14', 'l15', 'l16', 'l17']", + "130, I-deficient ['l13', 'l18', 'l19', 'l20', 'l21']", + "131, mice ['l14', 'l18', 'l22', 'l23', 'l24']", + "143, class ['l15', 'l19', 'l22', 'l25', 'l26']", + "144, I-deficient ['l16', 'l20', 'l23', 'l25', 'l27']", + "145, mice ['l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "class", + "I-deficient", + "II-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "9427614", + "TEXT": "Genetic causes of Alzheimer's disease (AD) include mutations in the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) genes. The mutant APP(K670N,M671L) transgenic line, Tg2576, shows markedly elevated amyloid beta-protein (A beta) levels at an early age and, by 9-12 months, develops extracellular AD-type A beta deposits in the cortex and hippocampus. Mutant PS1 transgenic mice do not show abnormal pathology, but do display subtly elevated levels of the highly amyloidogenic 42- or 43-amino acid peptide A beta42(43). Here we demonstrate that the doubly transgenic progeny from a cross between line Tg2576 and a mutant PS1M146L transgenic line develop large numbers of fibrillar A beta deposits in cerebral cortex and hippocampus far earlier than their singly transgenic Tg2576 littermates. In the period preceding overt A beta deposition, the doubly transgenic mice show a selective 41% increase in A beta42(43) in their brains. Thus, the development of AD-like pathology is substantially enhanced when a PS1 mutation, which causes a modest increase in A beta42(43), is introduced into Tg2576-derived mice. Remarkably, both doubly and singly transgenic mice showed reduced spontaneous alternation performance in a \"Y\" maze before substantial A beta deposition was apparent. This suggests that some aspects of the behavioral phenotype in these mice may be related to an event that precedes plaque formation.", + "TAG_DATA": [ + "23, mutant {'perturbing_action': 'B-other'}", + "55, Mutant {'perturbing_action': 'B-gene gain-of-function'}", + "56, PS1 {'perturbing_action': 'I-gene gain-of-function'}", + "57, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "58, mice {'context': 'B-organism'}", + "97, mutant {'perturbing_action': 'B-other'}", + "98, PS1M146L {'perturbing_action': 'I-other'}", + "99, transgenic {'perturbing_action': 'I-other'}", + "110, cerebral {'context': 'B-tissue/organ'}", + "111, cortex {'context': 'I-tissue/organ'}", + "113, hippocampus {'context': 'B-tissue/organ'}", + "133, mice {'context': 'B-organism'}", + "156, PS1 {'perturbing_action': 'B-other'}", + "157, mutation, {'perturbing_action': 'I-other'}", + "169, Tg2576-derived {'context': 'B-cells'}", + "170, mice. {'context': 'B-organism'}", + "177, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "23, mutant ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "24, APP(K670N,M671L) ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "25, transgenic ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "55, Mutant ['l2', 'l12', 'l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "56, PS1 ['l3', 'l13', 'l22', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "57, transgenic ['l4', 'l14', 'l23', 'l30', 'l35', 'l40', 'l41']", + "58, mice ['l5', 'l15', 'l24', 'l31', 'l36', 'l40']", + "86, doubly ['l6', 'l16', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "94, Tg2576 ['l7', 'l17', 'l25', 'l42', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "97, mutant ['l43', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "98, PS1M146L ['l44', 'l57', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "99, transgenic ['l45', 'l51', 'l58', 'l64', 'l70', 'l71', 'l72', 'l73', 'l74']", + "100, line ['l46', 'l52', 'l59', 'l65', 'l70', 'l75', 'l76', 'l77', 'l78']", + "110, cerebral ['l8', 'l18', 'l26', 'l32', 'l37', 'l47', 'l53', 'l60', 'l66', 'l71', 'l75', 'l79', 'l80']", + "111, cortex ['l9', 'l19', 'l27', 'l33', 'l38', 'l41', 'l48', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l81']", + "113, hippocampus ['l10', 'l20', 'l28', 'l34', 'l39', 'l49', 'l55', 'l62', 'l68', 'l73', 'l77', 'l80', 'l81']", + "133, mice ['l50', 'l56', 'l63', 'l69', 'l74', 'l78']", + "156, PS1 ['l82', 'l83', 'l84', 'l85']", + "157, mutation, ['l82', 'l86', 'l87', 'l88']", + "169, Tg2576-derived ['l83', 'l86', 'l89', 'l90']", + "170, mice. ['l84', 'l87', 'l89', 'l91']", + "177, mice ['l85', 'l88', 'l90', 'l91']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "PS1M146L", + "transgenic", + "PS1", + "mutation," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "PS1M146L", + "transgenic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "cerebral", + "cortex", + "hippocampus" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Mutant", + "PS1", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Mutant", + "PS1", + "transgenic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "cerebral", + "cortex", + "hippocampus" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "PS1", + "mutation," + ] + }, + "context": { + "val": "cells", + "words": [ + "Tg2576-derived" + ] + } + } + ] + }, + { + "PMID": "9427611", + "TEXT": "Nitric oxide (NO) is well established as a neurotransmitter in the central and peripheral nervous systems. More recently, another gas, carbon monoxide (CO) has also been implicated in neurotransmission. In the nervous system CO is formed by a subtype of heme oxygenase (HO) designated HO2. HO2 is localized to discrete neuronal populations in the brain resembling localizations of soluble guanylyl cyclase, which is activated by CO. CO may also function in the peripheral autonomic nervous system, in conjunction with NO. The majority of ganglia in the myenteric plexus possess both HO2 and neuronal NO synthase (NOS). Defects in myenteric plexus neurotransmission occur both in mice with targeted deletion of genes for HO2 and neuronal NOS. HO2 also occurs in other autonomic ganglia including the petrosal, superior cervical and nodose ganglia. Neuronal NOS is localized to neurons regulating male reproductive behavior, such as penile erection, and NOS inhibitors prevent erection. Because of the other parallels between NO and CO, we speculated that CO may play a role in male reproductive behavior. In the present study we describe HO2 localization in neuronal structures regulating copulatory reflexes. Reflex activity of the bulbospongiosus muscle, which mediates ejaculation and ejaculatory behavior, is markedly diminished in mice with targeted deletion of the gene for HO2 (HO2-).", + "TAG_DATA": [ + "104, mice {'context': 'B-organism'}", + "106, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "107, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "108, of {'perturbing_action': 'I-gene loss-of-function'}", + "109, genes {'perturbing_action': 'I-gene loss-of-function'}", + "110, for {'perturbing_action': 'I-gene loss-of-function'}", + "111, HO2 {'perturbing_action': 'I-gene loss-of-function'}", + "188, bulbospongiosus {'context': 'B-cells'}", + "189, muscle, {'context': 'I-tissue/organ'}", + "200, mice {'context': 'B-organism'}", + "202, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "203, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "204, of {'perturbing_action': 'I-gene loss-of-function'}", + "205, the {'perturbing_action': 'I-gene loss-of-function'}", + "206, gene {'perturbing_action': 'I-gene loss-of-function'}", + "207, for {'perturbing_action': 'I-gene loss-of-function'}", + "208, HO2 {'perturbing_action': 'I-gene loss-of-function'}", + "209, (HO2-). {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "104, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "106, targeted ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "107, deletion ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "108, of ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "109, genes ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "110, for ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "111, HO2 ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "188, bulbospongiosus ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "189, muscle, ['l21', 'l31', 'l32', 'l33', 'l34', 'l35']", + "200, mice ['l22', 'l31', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "202, targeted ['l23', 'l36', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "203, deletion ['l24', 'l37', 'l44', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "204, of ['l25', 'l38', 'l45', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "205, the ['l26', 'l39', 'l46', 'l52', 'l57', 'l62', 'l63', 'l64', 'l65']", + "206, gene ['l27', 'l32', 'l40', 'l47', 'l53', 'l58', 'l62', 'l66', 'l67', 'l68']", + "207, for ['l28', 'l33', 'l41', 'l48', 'l54', 'l59', 'l63', 'l66', 'l69', 'l70']", + "208, HO2 ['l29', 'l34', 'l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l71']", + "209, (HO2-). ['l30', 'l35', 'l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l71']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "deletion", + "of", + "genes", + "for", + "HO2", + "the", + "gene", + "(HO2-)." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "bulbospongiosus" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "deletion", + "of", + "the", + "gene", + "for", + "HO2", + "(HO2-)." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "muscle," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "gene", + "for", + "HO2", + "(HO2-)." + ] + } + } + ] + }, + { + "PMID": "9396614", + "TEXT": "Excessive binding of Plasmodium falciparum-infected red blood cells (pRBCs) to the vascular endothelium (cytoadherence) and to uninfected erythrocytes (rosetting) may lead to occlusion of the microvasculature and thereby contribute directly to the acute pathology of severe human malaria. A number of endothelial receptors have been identified as targets for the pRBCs, including CD36, intercellular adhesion molecule-1 (ICAM-1) and chondroitin-4-sulfate (CSA). In vitro, CD36 is the most frequent target of strains from patients with mild as well as severe P. falciparum malaria, but is expressed at low levels on the cerebral microvasculature and therefore seems unlikely to be involved in the evolution of cerebral disease. Strains of P. falciparum that form rosettes are associated both with the occurrence of cerebral malaria and severe anemia. Here we report that malaria-infected RBCs adhere to platelet/endothelial cell adhesion molecule-1 (PECAM-1/CD31) on the vascular endothelium. pRBCs bind to endothelial cells, to PECAM-1/CD31 transfected cells, and directly to recombinant PECAM-1/CD31 absorbed onto plastic. Soluble PECAM-1/CD31 and monoclonal antibodies specific for the amino-terminal segment of PECAM-1/CD31 (domains 1-4) blocked the binding. Interferon-gamma (IFN-gamma)-essential for the development of cerebral malaria in the mouse-was found to augment adhesion of human pRBCs to PECAM-1/CD31 on endothelial cell monolayers. Our results suggest that PECAM-1/CD31 is a virulence-associated endothelial receptor of P. falciparum-infected RBCs.", + "TAG_DATA": [ + "128, RBCs {'context': 'B-cells'}", + "140, pRBCs {'context': 'B-cells'}", + "143, endothelial {'context': 'B-cells'}", + "144, cells, {'context': 'I-cells'}", + "146, PECAM-1/CD31 {'perturbing_action': 'B-gene gain-of-function'}", + "147, transfected {'perturbing_action': 'I-gene gain-of-function'}", + "148, cells, {'context': 'B-cells'}", + "190, human {'context': 'B-cells'}", + "191, pRBCs {'context': 'I-cells'}", + "195, endothelial {'context': 'B-cells'}", + "196, cell {'context': 'I-cells'}", + "197, monolayers. {'context': 'I-organoid'}" + ], + "LINK_DATA": [ + "128, RBCs ['l0', 'l1', 'l2', 'l3']", + "140, pRBCs ['l0', 'l4', 'l5', 'l6', 'l7', 'l8']", + "143, endothelial ['l1', 'l4', 'l9', 'l10', 'l11', 'l12']", + "144, cells, ['l2', 'l5', 'l9', 'l13', 'l14']", + "146, PECAM-1/CD31 ['l6', 'l10', 'l15', 'l16']", + "147, transfected ['l7', 'l11', 'l13', 'l15', 'l17']", + "148, cells, ['l3', 'l8', 'l12', 'l14', 'l16', 'l17']", + "190, human ['l18', 'l19', 'l20', 'l21']", + "191, pRBCs ['l18', 'l22', 'l23', 'l24']", + "195, endothelial ['l19', 'l22', 'l25', 'l26']", + "196, cell ['l20', 'l23', 'l25', 'l27']", + "197, monolayers. ['l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "pRBCs", + "endothelial", + "cells," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PECAM-1/CD31", + "transfected" + ] + } + } + ] + }, + { + "PMID": "9359707", + "TEXT": "The nfkb1 and nfkb2 genes encode closely related products regulating immune and inflammatory responses. Their role during development and differentiation remains unclear. The generation of nfkb1 null mice (p50-/-) resulted in altered immune responses, but had no effect on development. Similarly, nfkb2 knockout mice (p52-/-) did not show developmental defects (J.C. et al., manuscript submitted). We have investigated the potential for in vivo compensatory functions of these genes by generating double-knockout mice. The surprising result was that the animals developed osteopetrosis because of a defect in osteoclast differentiation, suggesting redundant functions of NF-kappaB1 and NF-kappaB2 proteins in the development of this cell lineage. The osteopetrotic phenotype was rescued by bone marrow transplantation, indicating that the hematopoietic component was impaired. These results define a new mouse osteopetrotic mutant and implicate NF-kappaB proteins in bone development, raising new directions in the treatment of bone disorders.", + "TAG_DATA": [ + "25, nfkb1 {'perturbing_action': 'B-gene loss-of-function'}", + "26, null {'perturbing_action': 'I-gene loss-of-function'}", + "27, mice {'context': 'B-organism'}", + "28, (p50-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "41, nfkb2 {'perturbing_action': 'B-gene loss-of-function'}", + "42, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "43, mice {'context': 'B-organism'}", + "44, (p52-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "71, mice. {'context': 'B-organism'}", + "78, animals {'context': 'B-organism'}", + "84, defect {'effect': 'B-negative'}", + "87, differentiation, {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "25, nfkb1 ['l0', 'l1', 'l2']", + "26, null ['l0', 'l3', 'l4']", + "27, mice ['l1', 'l3', 'l5']", + "28, (p50-/-) ['l2', 'l4', 'l5']", + "41, nfkb2 ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "42, knockout ['l6', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "43, mice ['l7', 'l14', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "44, (p52-/-) ['l8', 'l15', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "71, mice. ['l9', 'l16', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "78, animals ['l10', 'l17', 'l23', 'l28', 'l32', 'l36', 'l37', 'l38']", + "84, defect ['l11', 'l18', 'l24', 'l29', 'l33', 'l36', 'l39', 'l40']", + "86, osteoclast ['l12', 'l19', 'l25', 'l30', 'l34', 'l37', 'l39', 'l41']", + "87, differentiation, ['l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nfkb1", + "null", + "(p50-/-)", + "nfkb2", + "knockout", + "(p52-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "animals" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nfkb2", + "knockout", + "(p52-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defect" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nfkb2", + "knockout", + "(p52-/-)" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "animals" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defect" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "animals" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "defect" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + } + ] + }, + { + "PMID": "9359705", + "TEXT": "The multidrug resistance-associated protein (MRP) mediates the cellular excretion of many drugs, glutathione S-conjugates (GS-X) of lipophilic xenobiotics and endogenous cysteinyl leukotrienes. Increased MRP levels in tumor cells can cause multidrug resistance (MDR) by decreasing the intracellular drug concentration. The physiological role or roles of MRP remain ill-defined, however. We have generated MRP-deficient mice by using embryonic stem cell technology. Mice homozygous for the mrp mutant allele, mrp-/-, are viable and fertile, but their response to an inflammatory stimulus is impaired. We attribute this defect to a decreased secretion of leukotriene C4 (LTC4) from leukotriene-synthesizing cells. Moreover, the mrp-/- mice are hypersensitive to the anticancer drug etoposide. The phenotype of mrp-/- mice is consistent with a role for MRP as the main LTC4-exporter in leukotriene-synthesizing cells, and as an important drug exporter in drug-sensitive cells. Our results suggest that this ubiquitous GS-X pump is dispensable in mice, making treatment of MDR with MRP-specific reversal agents potentially feasible.", + "TAG_DATA": [ + "52, MRP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "53, mice {'context': 'B-organism'}", + "60, Mice {'context': 'B-organism'}", + "61, homozygous {'perturbing_action': 'B-gene loss-of-function'}", + "62, for {'perturbing_action': 'I-gene loss-of-function'}", + "63, the {'perturbing_action': 'I-gene loss-of-function'}", + "64, mrp {'perturbing_action': 'I-gene loss-of-function'}", + "65, mutant {'perturbing_action': 'I-other'}", + "66, allele, {'perturbing_action': 'I-gene loss-of-function'}", + "67, mrp-/-, {'perturbing_action': 'I-gene loss-of-function'}", + "98, mrp-/- {'perturbing_action': 'B-gene loss-of-function'}", + "99, mice {'context': 'B-organism'}", + "110, mrp-/- {'perturbing_action': 'B-gene loss-of-function'}", + "111, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "52, MRP-deficient ['l0', 'l1', 'l2']", + "53, mice ['l0', 'l3', 'l4']", + "57, stem ['l1', 'l3', 'l5']", + "58, cell ['l2', 'l4', 'l5']", + "60, Mice ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "61, homozygous ['l6', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "62, for ['l7', 'l13', 'l20', 'l21', 'l22', 'l23', 'l24']", + "63, the ['l8', 'l14', 'l20', 'l25', 'l26', 'l27', 'l28']", + "64, mrp ['l9', 'l15', 'l21', 'l25', 'l29', 'l30', 'l31']", + "65, mutant ['l10', 'l16', 'l22', 'l26', 'l29', 'l32', 'l33']", + "66, allele, ['l11', 'l17', 'l23', 'l27', 'l30', 'l32', 'l34']", + "67, mrp-/-, ['l12', 'l18', 'l24', 'l28', 'l31', 'l33', 'l34']", + "98, mrp-/- ['l35']", + "99, mice ['l19', 'l35']", + "110, mrp-/- ['l36']", + "111, mice ['l36']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MRP-deficient", + "homozygous", + "for", + "the", + "mrp", + "allele,", + "mrp-/-,", + "mrp-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "Mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutant" + ] + } + } + ] + }, + { + "PMID": "9359699", + "TEXT": "Human immunodeficiency virus (HIV)-1 infection is associated with the development of aggressive extranodal B-cell non-Hodgkin's lymphomas. Using microvascular endothelial cell (MVEC)-enriched bone marrow stromal cultures, HIV infection of stromal MVECs from lymphoma patients induced the outgrowth of malignant B cells. MVECs were the only HIV-infected cells in the stroma, and purified brain MVECs also induced a phenotype supportive of neoplastic B-cell attachment and proliferation. HIV infection of MVECs stimulated surface expression of CD40 and allowed preferential induction of the vascular cell adhesion molecule VCAM-1 after CD40 triggering. B-lymphoma cells expressed the CD40 ligand (CD40L), and blocking of CD40-CD40L interactions between HIV-infected MVECs and B-lymphoma cells inhibited B-cell attachment and proliferation. These observations suggest that HIV promotes B-lymphoma cell growth through facilitating attachment of lymphoma cells to HIV-infected MVECs and represent a novel mechanism through which viruses may induce malignancies.", + "TAG_DATA": [ + "37, malignant {'context': 'B-transformed cells'}", + "38, B {'context': 'I-transformed cells'}", + "39, cells. {'context': 'I-transformed cells'}", + "63, proliferation. {'phenotype': 'B-proliferation'}", + "67, MVECs {'context': 'B-cells'}", + "87, B-lymphoma {'context': 'B-transformed cells'}", + "88, cells {'context': 'I-transformed cells'}", + "101, MVECs {'context': 'B-cells'}", + "103, B-lymphoma {'context': 'B-transformed cells'}", + "104, cells {'context': 'I-transformed cells'}", + "105, inhibited {'effect': 'B-negative'}", + "106, B-cell {'context': 'B-cells'}", + "109, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "37, malignant ['l0', 'l1', 'l2']", + "38, B ['l0', 'l3', 'l4']", + "39, cells. ['l1', 'l3', 'l5']", + "51, brain ['l6', 'l7', 'l8']", + "52, MVECs ['l6', 'l9', 'l10']", + "63, proliferation. ['l2', 'l4', 'l5', 'l7', 'l9']", + "67, MVECs ['l8', 'l10']", + "87, B-lymphoma ['l11', 'l12', 'l13']", + "88, cells ['l11']", + "101, MVECs ['l14', 'l15', 'l16', 'l17', 'l18']", + "103, B-lymphoma ['l14', 'l19', 'l20', 'l21', 'l22']", + "104, cells ['l12', 'l15', 'l19', 'l23', 'l24', 'l25']", + "105, inhibited ['l16', 'l20', 'l23', 'l26', 'l27']", + "106, B-cell ['l17', 'l21', 'l24', 'l26', 'l28']", + "109, proliferation. ['l13', 'l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "malignant", + "B", + "cells.", + "B-lymphoma", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "MVECs", + "B-cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "MVECs", + "B-cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "B-lymphoma", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "9359698", + "TEXT": "Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States. Five-fluorouracil (5FU) remains the single most effective treatment for advanced disease, despite a response rate of only 20%. Herein, we show that the antioxidants pyrrolidinedithiocarbamate and vitamin E induce apoptosis in CRC cells. This effect is mediated by induction of p21WAF1/CIP1, a powerful inhibitor of the cell cycle, through a mechanism involving C/EBPbeta (a member of the CCAAT/enhancer binding protein family of transcription factors), independent of p53. Antioxidants significantly enhance CRC tumor growth inhibition by cytotoxic chemotherapy in vitro (5FU and doxorubicin) and in vivo (5FU). Thus, chemotherapeutic agents administered in the presence of antioxidants may provide a novel therapy for colorectal cancer.", + "TAG_DATA": [ + "43, induce {'effect': 'B-positive'}", + "44, apoptosis {'phenotype': 'B-apoptosis'}", + "46, CRC {'context': 'B-transformed cells'}", + "47, cells. {'context': 'I-transformed cells'}", + "84, enhance {'effect': 'B-positive'}", + "85, CRC {'context': 'B-neoplasm'}", + "86, tumor {'phenotype': 'B-tumour growth'}", + "87, growth {'phenotype': 'I-tumour growth'}", + "88, inhibition {'effect': 'B-negative'}", + "92, in {'context': 'B-in vitro'}", + "93, vitro {'context': 'I-in vitro'}", + "98, in {'context': 'B-in vivo'}", + "99, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "43, induce ['l0', 'l1', 'l2']", + "44, apoptosis ['l0', 'l3', 'l4']", + "46, CRC ['l1', 'l3', 'l5']", + "47, cells. ['l2', 'l4', 'l5']", + "84, enhance ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "85, CRC ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "86, tumor ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "87, growth ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "88, inhibition ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "92, in ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "93, vitro ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']", + "98, in ['l27']", + "99, vivo ['l27']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "CRC", + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "CRC", + "cells." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhance" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "CRC" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhance" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhance" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "CRC" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "CRC" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "9359697", + "TEXT": "Female sterility resulting from oocyte destruction is an unfortunate, and in many cases inevitable, consequence of chemotherapy. We show that unfertilized mouse oocytes exposed to therapeutic levels of the antitumor drug, doxorubicin (DXR), undergo apoptosis; however, fertilized oocytes do not initiate apoptosis, but enter cell-cycle arrest, when treated with DXR. Apoptosis induced by DXR in oocytes is blocked by sphingosine-1-phosphate, an inhibitor of ceramide-promoted cell death. Oocytes from Bax-deficient, but not p53-null, female mice display complete resistance to DXR-induced apoptosis in vivo and in vitro. Pretreatment of oocytes with a specific peptide inhibitor of caspases also abrogates the apoptotic response to DXR. These findings indicate that oocyte destruction caused by chemotherapy can be prevented by manipulation of apoptosis-associated signaling pathways.", + "TAG_DATA": [ + "20, unfertilized {'context': 'B-cells'}", + "21, mouse {'context': 'I-cells'}", + "22, oocytes {'context': 'I-cells'}", + "33, undergo {'effect': 'B-positive'}", + "34, apoptosis; {'phenotype': 'B-apoptosis'}", + "36, fertilized {'context': 'B-cells'}", + "37, oocytes {'context': 'I-cells'}", + "38, do {'effect': 'B-negative'}", + "39, not {'effect': 'I-no effect'}", + "40, initiate {'effect': 'I-no effect'}", + "41, apoptosis, {'phenotype': 'B-apoptosis'}", + "43, enter {'effect': 'B-positive'}", + "44, cell-cycle {'phenotype': 'B-cell cycle arrest'}", + "45, arrest, {'phenotype': 'I-cell cycle arrest'}", + "50, Apoptosis {'phenotype': 'B-apoptosis'}", + "51, induced {'effect': 'B-positive'}", + "55, oocytes {'context': 'B-cells'}", + "57, blocked {'effect': 'B-negative'}", + "64, cell {'phenotype': 'B-cell death'}", + "65, death. {'phenotype': 'I-cell death'}", + "66, Oocytes {'context': 'B-cells'}", + "68, Bax-deficient, {'perturbing_action': 'B-gene loss-of-function'}", + "71, p53-null, {'perturbing_action': 'B-gene loss-of-function'}", + "72, female {'context': 'B-organism'}", + "73, mice {'context': 'I-organism'}", + "76, resistance {'effect': 'B-negative'}", + "78, DXR-induced {'effect': 'B-positive'}", + "79, apoptosis {'phenotype': 'B-apoptosis'}", + "80, in {'context': 'B-in vivo'}", + "81, vivo {'context': 'I-in vivo'}", + "83, in {'context': 'B-in vitro'}", + "84, vitro. {'context': 'I-in vitro'}", + "87, oocytes {'context': 'B-cells'}", + "96, abrogates {'effect': 'B-negative'}", + "98, apoptotic {'phenotype': 'B-apoptosis'}", + "99, response {'phenotype': 'I-apoptosis'}" + ], + "LINK_DATA": [ + "20, unfertilized ['l0', 'l1', 'l2', 'l3', 'l4']", + "21, mouse ['l0', 'l5', 'l6', 'l7']", + "22, oocytes ['l1', 'l5', 'l8', 'l9']", + "33, undergo ['l2', 'l6', 'l8', 'l10']", + "34, apoptosis; ['l3', 'l7', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "36, fertilized ['l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "37, oocytes ['l18', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "38, do ['l19', 'l41', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "39, not ['l11', 'l20', 'l42', 'l55', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "40, initiate ['l12', 'l21', 'l43', 'l56', 'l67', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "41, apoptosis, ['l13', 'l22', 'l44', 'l57', 'l68', 'l78', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "43, enter ['l23', 'l45', 'l58', 'l69', 'l79', 'l88', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "44, cell-cycle ['l14', 'l24', 'l46', 'l59', 'l70', 'l80', 'l89', 'l97', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "45, arrest, ['l15', 'l25', 'l47', 'l60', 'l71', 'l81', 'l90', 'l98', 'l105', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "50, Apoptosis ['l26', 'l48', 'l61', 'l72', 'l82', 'l91', 'l99', 'l106', 'l112', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "51, induced ['l4', 'l16', 'l27', 'l49', 'l62', 'l73', 'l83', 'l92', 'l100', 'l107', 'l113', 'l118', 'l124', 'l125', 'l126', 'l127']", + "55, oocytes ['l17', 'l28', 'l50', 'l63', 'l74', 'l84', 'l93', 'l101', 'l108', 'l114', 'l119', 'l124', 'l128', 'l129', 'l130']", + "57, blocked ['l29', 'l51', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l115', 'l120', 'l125', 'l128', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "64, cell ['l30', 'l52', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l121', 'l126', 'l129', 'l131', 'l138', 'l139', 'l140', 'l141']", + "65, death. ['l31', 'l53', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l127', 'l130', 'l132', 'l138', 'l142', 'l143', 'l144']", + "66, Oocytes ['l32', 'l133', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "68, Bax-deficient, ['l33', 'l145', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "71, p53-null, ['l146', 'l156', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "72, female ['l34', 'l147', 'l157', 'l166', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "73, mice ['l35', 'l148', 'l158', 'l167', 'l175', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189']", + "76, resistance ['l36', 'l54', 'l123', 'l134', 'l139', 'l142', 'l149', 'l159', 'l168', 'l176', 'l183', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195']", + "78, DXR-induced ['l37', 'l150', 'l160', 'l169', 'l177', 'l184', 'l190', 'l196', 'l197', 'l198', 'l199', 'l200']", + "79, apoptosis ['l38', 'l135', 'l140', 'l143', 'l151', 'l161', 'l170', 'l178', 'l185', 'l191', 'l196', 'l201', 'l202']", + "80, in ['l39', 'l136', 'l152', 'l162', 'l171', 'l179', 'l186', 'l192', 'l197', 'l201', 'l203']", + "81, vivo ['l40', 'l137', 'l141', 'l144', 'l153', 'l163', 'l172', 'l180', 'l187', 'l193', 'l198', 'l202', 'l203']", + "83, in ['l154', 'l164', 'l173', 'l181', 'l188', 'l194', 'l199', 'l204']", + "84, vitro. ['l155', 'l165', 'l174', 'l182', 'l189', 'l195', 'l200', 'l204']", + "87, oocytes ['l205', 'l206', 'l207']", + "96, abrogates ['l205', 'l208', 'l209']", + "98, apoptotic ['l206', 'l208', 'l210']", + "99, response ['l207', 'l209', 'l210']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "unfertilized", + "mouse", + "oocytes", + "fertilized", + "Oocytes" + ] + }, + "effect": { + "val": "positive", + "words": [ + "undergo", + "induced", + "enter", + "DXR-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "unfertilized", + "mouse", + "oocytes", + "fertilized", + "Oocytes" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis;", + "apoptosis,", + "Apoptosis", + "apoptosis", + "apoptotic", + "response" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "undergo", + "induced", + "enter", + "DXR-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis;", + "apoptosis,", + "Apoptosis", + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis;", + "apoptosis,", + "Apoptosis" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "initiate" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "fertilized", + "oocytes", + "Oocytes" + ] + }, + "effect": { + "val": "negative", + "words": [ + "do", + "blocked", + "resistance", + "abrogates" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "fertilized", + "oocytes" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "initiate" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "fertilized", + "oocytes" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "fertilized", + "oocytes" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "fertilized", + "Oocytes" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bax-deficient,", + "p53-null," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "do", + "blocked", + "resistance", + "abrogates" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis,", + "Apoptosis", + "apoptosis", + "apoptotic", + "response" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "do", + "blocked" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "do", + "blocked", + "resistance" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "initiate" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest," + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "initiate" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enter", + "induced" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enter", + "induced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked", + "resistance" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bax-deficient,", + "p53-null," + ] + }, + "context": { + "val": "organism", + "words": [ + "female", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bax-deficient,", + "p53-null," + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bax-deficient,", + "p53-null," + ] + }, + "effect": { + "val": "positive", + "words": [ + "DXR-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bax-deficient,", + "p53-null," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bax-deficient,", + "p53-null," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bax-deficient,", + "p53-null," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "female", + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "female", + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "DXR-induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "female", + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "DXR-induced" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "DXR-induced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "9359696", + "TEXT": "The importance of angiogenesis in malignant tumor growth has been interpreted mainly in terms of oxygen and nutrient supply. Here we demonstrate its fundamental role for tumor invasion of malignant human keratinocytes in surface transplants on nude mice. Distinct patterns of angiogenesis and vascular endothelial growth factor receptor-2 (VEGFR-2) expression allowed us to distinguish between benign and malignant cells. Functional inactivation of VEGF-R2 by a blocking antibody disrupted ongoing angiogenesis and prevented invasion of malignant cells, without reducing tumor cell proliferation. The reversion of a malignant into a benign phenotype by halting angiogenesis demonstrates a significant function of vascular endothelium for tumor invasion.", + "TAG_DATA": [ + "59, Functional {'perturbing_action': 'B-gene loss-of-function'}", + "60, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "61, of {'perturbing_action': 'I-gene loss-of-function'}", + "62, VEGF-R2 {'perturbing_action': 'I-gene loss-of-function'}", + "63, by {'perturbing_action': 'I-gene loss-of-function'}", + "71, prevented {'effect': 'B-negative'}", + "72, invasion {'phenotype': 'B-invasion'}", + "74, malignant {'context': 'B-transformed cells'}", + "75, cells, {'context': 'I-transformed cells'}", + "76, without {'effect': 'B-no effect'}", + "77, reducing {'effect': 'I-no effect'}", + "78, tumor {'context': 'B-transformed cells'}", + "79, cell {'context': 'I-transformed cells'}", + "80, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "59, Functional ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "60, inactivation ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "61, of ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "62, VEGF-R2 ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "63, by ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "71, prevented ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58']", + "72, invasion ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l59', 'l60', 'l61']", + "74, malignant ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l59', 'l62', 'l63', 'l64', 'l65', 'l66']", + "75, cells, ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l60', 'l62']", + "76, without ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l61', 'l63', 'l67', 'l68', 'l69', 'l70']", + "77, reducing ['l9', 'l21', 'l32', 'l42', 'l51', 'l64', 'l67', 'l71', 'l72', 'l73']", + "78, tumor ['l10', 'l22', 'l33', 'l43', 'l52', 'l68', 'l71', 'l74', 'l75']", + "79, cell ['l11', 'l23', 'l34', 'l44', 'l53', 'l65', 'l69', 'l72', 'l74', 'l76']", + "80, proliferation. ['l12', 'l24', 'l35', 'l45', 'l54', 'l66', 'l70', 'l73', 'l75', 'l76']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Functional", + "inactivation", + "of", + "VEGF-R2", + "by" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Functional", + "inactivation", + "of", + "VEGF-R2", + "by" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Functional", + "inactivation", + "of", + "VEGF-R2", + "by" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "malignant", + "cells,", + "tumor", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Functional", + "inactivation", + "of", + "VEGF-R2", + "by" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "without", + "reducing" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Functional", + "inactivation", + "of", + "VEGF-R2", + "by" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "malignant", + "cells," + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "malignant", + "cells," + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "without" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "malignant", + "tumor", + "cell" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "without", + "reducing" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "malignant", + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "without", + "reducing" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "9359694", + "TEXT": "The cellular and molecular mechanisms underlying the effects of aging on human cutaneous wound healing are poorly understood, and the possible role of reproductive hormones in this process has never been investigated. We report that aging in healthy females was associated with a reduced rate of cutaneous wound healing, but an improved quality of scarring both microscopically and macroscopically, and with reduced levels of transforming growth factor-beta1 (TGF-beta1) immunostaining and steady-state mRNA in the wound. These age-related changes were reversed by the systemic administration of hormone replacement therapy (HRT). Moreover, ovariectomized young female rodents exhibited a marked delay in repair of acute incisional wounds, which was reversed by the topical application of estrogen. The cellular mechanism underlying these changes appears to involve an estrogen-induced increase in latent TGF-beta1 secretion by dermal fibroblasts. These results suggest that both the rate and quality of wound healing depend on reproductive hormone levels.", + "TAG_DATA": [ + "91, young {'context': 'B-organism'}", + "92, female {'context': 'I-organism'}", + "93, rodents {'context': 'I-organism'}", + "97, delay {'effect': 'B-negative'}", + "130, dermal {'context': 'B-cells'}", + "131, fibroblasts. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "91, young ['l0', 'l1', 'l2']", + "92, female ['l0', 'l3', 'l4']", + "93, rodents ['l1', 'l3', 'l5']", + "97, delay ['l2', 'l4', 'l5']", + "130, dermal ['l6']", + "131, fibroblasts. ['l6']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "young", + "female", + "rodents" + ] + }, + "effect": { + "val": "negative", + "words": [ + "delay" + ] + } + } + ] + }, + { + "PMID": "9334720", + "TEXT": "GLUT4, the insulin-responsive glucose transporter, plays an important role in postprandial glucose disposal. Altered GLUT4 activity is suggested to be one of the factors responsible for decreased glucose uptake in muscle and adipose tissue in obesity and diabetes. To assess the effect of GLUT4 expression on whole-body glucose homeostasis, we disrupted the murine GLUT4 gene by homologous recombination. Male mice heterozygous for the mutation (GLUT4 +/-) exhibited a decrease in GLUT4 expression in adipose tissue and skeletal muscle. This decrease in GLUT4 expression did not result in obesity but led to increased serum glucose and insulin, reduced muscle glucose uptake, hypertension, and diabetic histopathologies in the heart and liver similar to those of humans with non-insulin-dependent diabetes mellitus (NIDDM). The male GLUT4 +/- mice represent a good model for studying the development of NIDDM without the complications associated with obesity.", + "TAG_DATA": [ + "50, disrupted {'perturbing_action': 'B-gene loss-of-function'}", + "51, the {'perturbing_action': 'I-gene loss-of-function'}", + "52, murine {'perturbing_action': 'I-gene loss-of-function'}", + "53, GLUT4 {'perturbing_action': 'I-gene loss-of-function'}", + "54, gene {'perturbing_action': 'I-gene loss-of-function'}", + "58, Male {'context': 'B-organism'}", + "59, mice {'context': 'I-organism'}", + "60, heterozygous {'perturbing_action': 'B-other'}", + "61, for {'perturbing_action': 'I-other'}", + "62, the {'perturbing_action': 'I-other'}", + "63, mutation {'perturbing_action': 'I-other'}", + "64, (GLUT4 {'perturbing_action': 'I-other'}", + "65, +/-) {'perturbing_action': 'I-other'}", + "73, adipose {'context': 'B-tissue/organ'}", + "74, tissue {'context': 'I-tissue/organ'}", + "76, skeletal {'context': 'B-tissue/organ'}", + "77, muscle. {'context': 'I-tissue/organ'}", + "97, muscle {'context': 'B-tissue/organ'}", + "106, heart {'context': 'B-tissue/organ'}", + "108, liver {'context': 'B-tissue/organ'}", + "120, male {'perturbing_action': 'B-gene loss-of-function'}", + "121, GLUT4 {'perturbing_action': 'B-gene loss-of-function'}", + "122, +/- {'perturbing_action': 'B-gene loss-of-function'}", + "123, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, disrupted ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "51, the ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "52, murine ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "53, GLUT4 ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "54, gene ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "58, Male ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "59, mice ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "60, heterozygous ['l51', 'l61', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "61, for ['l52', 'l62', 'l71', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "62, the ['l53', 'l63', 'l72', 'l81', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "63, mutation ['l54', 'l64', 'l73', 'l82', 'l90', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "64, (GLUT4 ['l6', 'l17', 'l27', 'l36', 'l44', 'l55', 'l65', 'l74', 'l83', 'l91', 'l98', 'l104', 'l105', 'l106', 'l107', 'l108']", + "65, +/-) ['l7', 'l18', 'l28', 'l37', 'l45', 'l56', 'l66', 'l75', 'l84', 'l92', 'l99', 'l104', 'l109', 'l110', 'l111', 'l112']", + "73, adipose ['l8', 'l19', 'l29', 'l38', 'l46', 'l57', 'l67', 'l76', 'l85', 'l93', 'l100', 'l105', 'l109', 'l113', 'l114', 'l115']", + "74, tissue ['l9', 'l20', 'l30', 'l39', 'l47', 'l58', 'l68', 'l77', 'l86', 'l94', 'l101', 'l106', 'l110', 'l113', 'l116', 'l117']", + "76, skeletal ['l10', 'l21', 'l31', 'l40', 'l48', 'l59', 'l69', 'l78', 'l87', 'l95', 'l102', 'l107', 'l111', 'l114', 'l116', 'l118']", + "77, muscle. ['l11', 'l22', 'l32', 'l41', 'l49', 'l60', 'l70', 'l79', 'l88', 'l96', 'l103', 'l108', 'l112', 'l115', 'l117', 'l118']", + "97, muscle ['l80', 'l89', 'l97', 'l119', 'l120']", + "106, heart ['l119', 'l121']", + "108, liver ['l120', 'l121']", + "120, male ['l122', 'l123', 'l124']", + "121, GLUT4 ['l122', 'l125', 'l126']", + "122, +/- ['l123', 'l125', 'l127']", + "123, mice ['l124', 'l126', 'l127']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "disrupted", + "the", + "murine", + "GLUT4", + "gene", + "male", + "+/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "Male", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "disrupted", + "the", + "murine", + "GLUT4", + "gene" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "adipose", + "tissue", + "skeletal", + "muscle." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Male", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous", + "for", + "the", + "mutation", + "(GLUT4", + "+/-)" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous", + "for", + "the", + "mutation", + "(GLUT4", + "+/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "adipose", + "tissue", + "skeletal", + "muscle.", + "muscle" + ] + } + } + ] + }, + { + "PMID": "9288726", + "TEXT": "We show here that transient forebrain ischemia selectively elevates levels of neuronal apoptosis inhibitory protein (NAIP) in rat neurons that are resistant to the injurious effects of this treatment. This observation suggests that increasing NAIP levels may confer protection against ischemic cell death. Consistent with this proposal, we demonstrate that two other treatments that increase neuronal NAIP levels, systemic administration of the bacterial alkaloid K252a and intracerebral injection of an adenovirus vector capable of overexpressing NAIP in vivo, reduce ischemic damage in the rat hippocampus. Taken together, these findings suggest that NAIP may play a key role in conferring resistance to ischemic damage and that treatments that elevate neuronal levels of this antiapoptotic protein may have utility in the treatment of stroke.", + "TAG_DATA": [ + "70, adenovirus {'perturbing_action': 'B-gene gain-of-function'}", + "71, vector {'perturbing_action': 'I-gene gain-of-function'}", + "72, capable {'perturbing_action': 'I-gene gain-of-function'}", + "73, of {'perturbing_action': 'I-gene gain-of-function'}", + "74, overexpressing {'perturbing_action': 'I-gene gain-of-function'}", + "75, NAIP {'perturbing_action': 'I-gene gain-of-function'}", + "76, in {'context': 'B-in vivo'}", + "77, vivo, {'context': 'I-in vivo'}", + "83, rat {'context': 'B-tissue/organ'}", + "84, hippocampus. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "70, adenovirus ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "71, vector ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "72, capable ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "73, of ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "74, overexpressing ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "75, NAIP ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "76, in ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "77, vivo, ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "83, rat ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "84, hippocampus. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "vector", + "capable", + "of", + "overexpressing", + "NAIP" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "vector", + "capable", + "of", + "overexpressing", + "NAIP" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "hippocampus." + ] + } + } + ] + }, + { + "PMID": "9212100", + "TEXT": "A subset of patients with high plasma HDL concentrations have enhanced rather than reduced atherosclerosis. We have developed a new transgenic mouse model overexpressing human lecithin-cholesteryl acyltransferase (LCAT) that has elevated HDL and increased diet-induced atherosclerosis. LCAT transgenic mouse HDLs are abnormal in both composition and function. Liver uptake of [3H]cholesteryl ether incorporated in transgenic mouse HDL was reduced by 41% compared with control HDL, indicating ineffective transport of HDL-cholesterol to the liver and impaired reverse cholesterol transport. Analysis of this LCAT-transgenic mouse model provides in vivo evidence for dysfunctional HDL as a potential mechanism leading to increased atherosclerosis in the presence of high plasma HDL levels.", + "TAG_DATA": [ + "20, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "21, mouse {'context': 'B-organism'}", + "22, model {'context': 'I-organism'}", + "23, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "24, human {'perturbing_action': 'I-gene gain-of-function'}", + "25, lecithin-cholesteryl {'perturbing_action': 'I-gene gain-of-function'}", + "26, acyltransferase {'perturbing_action': 'I-gene gain-of-function'}", + "27, (LCAT) {'perturbing_action': 'I-gene gain-of-function'}", + "36, LCAT {'perturbing_action': 'B-gene gain-of-function'}", + "37, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "38, mouse {'perturbing_action': 'I-gene gain-of-function'}", + "47, Liver {'context': 'B-tissue/organ'}", + "54, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "55, mouse {'context': 'I-organism'}", + "81, LCAT-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "82, mouse {'context': 'B-organism'}", + "83, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "20, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "21, mouse ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "22, model ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "23, overexpressing ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "24, human ['l3', 'l13', 'l22', 'l30', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "25, lecithin-cholesteryl ['l4', 'l14', 'l23', 'l31', 'l39', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "26, acyltransferase ['l5', 'l15', 'l24', 'l32', 'l40', 'l47', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "27, (LCAT) ['l6', 'l16', 'l25', 'l33', 'l41', 'l48', 'l54', 'l60', 'l61', 'l62', 'l63']", + "36, LCAT ['l7', 'l17', 'l26', 'l34', 'l42', 'l49', 'l55', 'l60', 'l64', 'l65', 'l66', 'l67', 'l68']", + "37, transgenic ['l8', 'l18', 'l27', 'l35', 'l43', 'l50', 'l56', 'l61', 'l64', 'l69', 'l70', 'l71', 'l72']", + "38, mouse ['l9', 'l19', 'l28', 'l36', 'l44', 'l51', 'l57', 'l62', 'l65', 'l69', 'l73', 'l74', 'l75']", + "47, Liver ['l10', 'l20', 'l29', 'l37', 'l45', 'l52', 'l58', 'l63', 'l66', 'l70', 'l73', 'l76', 'l77']", + "54, transgenic ['l67', 'l71', 'l74', 'l76', 'l78']", + "55, mouse ['l38', 'l46', 'l53', 'l59', 'l68', 'l72', 'l75', 'l77', 'l78']", + "81, LCAT-transgenic ['l79', 'l80']", + "82, mouse ['l79', 'l81']", + "83, model ['l80', 'l81']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "overexpressing", + "human", + "lecithin-cholesteryl", + "acyltransferase", + "(LCAT)", + "LCAT", + "mouse", + "LCAT-transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "overexpressing", + "human", + "lecithin-cholesteryl", + "acyltransferase", + "(LCAT)", + "LCAT", + "mouse" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "Liver" + ] + } + } + ] + }, + { + "PMID": "9212099", + "TEXT": "Fas ligand is believed to mediate immune privilege in a variety of tissues, including the eye, testis, and a subset of tumors. We tested whether expression of Fas ligand on pancreatic islets either following adenoviral or germline gene transfer could confer immune privilege after transplantation. Islets were infected with an adenoviral vector containing the murine Fas ligand cDNA (AdFasL), and were transplanted into allogenic diabetic hosts. Paradoxically, AdFasL-infected islets underwent accelerated neutrophilic rejection. The rejection was T cell and B cell independent and required Fas protein expression by host cells, but not on islets. Similarly, transgenic mice expressing Fas ligand in pancreatic beta cells developed massive neutrophilic infiltrates and diabetes at a young age. Thus, Fas ligand expression on pancreatic islets results in neutrophilic infiltration and islet destruction. These results have important implications for the development of Fas ligand-based immunotherapies.", + "TAG_DATA": [ + "45, Islets {'context': 'B-cells'}", + "68, islets {'context': 'B-cells'}", + "93, islets. {'context': 'B-cells'}", + "95, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "96, mice {'context': 'I-organism'}", + "97, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "98, Fas {'perturbing_action': 'I-gene gain-of-function'}", + "99, ligand {'perturbing_action': 'I-gene gain-of-function'}", + "101, pancreatic {'context': 'B-cells'}", + "102, beta {'context': 'I-cells'}", + "103, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, Islets ['l0']", + "68, islets ['l0', 'l1']", + "93, islets. ['l1']", + "95, transgenic ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "96, mice ['l2', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "97, expressing ['l3', 'l9', 'l15', 'l16', 'l17', 'l18', 'l19']", + "98, Fas ['l4', 'l10', 'l15', 'l20', 'l21', 'l22', 'l23']", + "99, ligand ['l5', 'l11', 'l16', 'l20', 'l24', 'l25', 'l26']", + "101, pancreatic ['l6', 'l12', 'l17', 'l21', 'l24', 'l27', 'l28']", + "102, beta ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l29']", + "103, cells ['l8', 'l14', 'l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "Fas", + "ligand" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "Fas", + "ligand" + ] + }, + "context": { + "val": "cells", + "words": [ + "pancreatic", + "beta", + "cells" + ] + } + } + ] + }, + { + "PMID": "9212098", + "TEXT": "On the subject of acute myeloid leukemia (AML), there is little consensus about the target cell within the hematopoietic stem cell hierarchy that is susceptible to leukemic transformation, or about the mechanism that underlies the phenotypic, genotypic and clinical heterogeneity. Here we demonstrate that the cell capable of initiating human AML in non-obese diabetic mice with severe combined immunodeficiency disease (NOD/SCID mice) - termed the SCID leukemia-initiating cell, or SL-IC - possesses the differentiative and proliferative capacities and the potential for self-renewal expected of a leukemic stem cell. The SL-ICs from all subtypes of AML analyzed, regardless of the heterogeneity in maturation characteristics of the leukemic blasts, were exclusively CD34++ CD38-, similar to the cell-surface phenotype of normal SCID-repopulating cells, suggesting that normal primitive cells, rather than committed progenitor cells, are the target for leukemic transformation. The SL-ICs were able to differentiate in vivo into leukemic blasts, indicating that the leukemic clone is organized as a hierarchy.", + "TAG_DATA": [ + "45, cell {'context': 'B-cells'}", + "49, human {'context': 'B-neoplasm'}", + "50, AML {'context': 'I-neoplasm'}", + "52, non-obese {'context': 'B-organism'}", + "53, diabetic {'context': 'I-organism'}", + "54, mice {'context': 'I-organism'}", + "79, potential {'effect': 'B-positive'}", + "81, self-renewal {'phenotype': 'B-self-renewal'}", + "141, differentiate {'phenotype': 'B-differentiation'}", + "142, in {'context': 'B-in vivo'}", + "143, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "45, cell ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "48, initiating ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "49, human ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "50, AML ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "52, non-obese ['l3', 'l8', 'l12', 'l15', 'l18', 'l19', 'l20', 'l21']", + "53, diabetic ['l4', 'l9', 'l13', 'l16', 'l18', 'l22', 'l23', 'l24']", + "54, mice ['l5', 'l10', 'l14', 'l17', 'l19', 'l22', 'l25', 'l26']", + "79, potential ['l20', 'l23', 'l25', 'l27', 'l28']", + "81, self-renewal ['l21', 'l24', 'l26', 'l27', 'l29']", + "94, AML ['l28', 'l29']", + "141, differentiate ['l30', 'l31']", + "142, in ['l30', 'l32']", + "143, vivo ['l31', 'l32']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "non-obese", + "diabetic", + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "potential" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "non-obese", + "diabetic", + "mice" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "potential" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "9176493", + "TEXT": "Interleukin-16 (IL-16) is secreted by activated CD8+ T lymphocytes and acts on CD4+ T lymphocytes, monocytes and eosinophils. Recently, the C-terminal 130-amino acid portion of IL-16 was shown to suppress HIV-1 replication in vitro. To explore the potential of human IL-16 for gene therapy, this portion was transfected into HIV-1-susceptible CD4+ jurkat cells by means of a mammalian expression vector. The stable transfectants synthesized and secreted IL-16 protein. The expression of IL-16 did not alter growth rate and CD4 expression; however, HIV replication was inhibited by as much as 99%. Furthermore, during the initial phase of the infection, equal amounts of HIV-1 proviral DNA were found in cells transfected with IL-16 and with vector alone. In contrast, the 2-kilobase HIV-1 transcripts were markedly reduced and the 4-kb and 9-kb transcripts were undetectable in the cells transfected with IL-16. These findings indicate that IL-16-mediated inhibition of HIV-1 is not at the level of viral entry or reverse transcription, but at messenger RNA expression.", + "TAG_DATA": [ + "50, CD4+ {'context': 'B-cells'}", + "51, jurkat {'context': 'I-cells'}", + "52, cells {'context': 'I-cells'}", + "62, transfectants {'perturbing_action': 'I-gene gain-of-function'}", + "69, expression {'perturbing_action': 'B-gene gain-of-function'}", + "70, of {'perturbing_action': 'I-gene gain-of-function'}", + "71, IL-16 {'perturbing_action': 'I-gene gain-of-function'}", + "107, cells {'context': 'B-cells'}", + "108, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "109, with {'perturbing_action': 'I-gene gain-of-function'}", + "110, IL-16 {'perturbing_action': 'I-gene gain-of-function'}", + "134, cells {'context': 'B-cells'}", + "135, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "136, with {'perturbing_action': 'I-gene gain-of-function'}", + "137, IL-16. {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "50, CD4+ ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "51, jurkat ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "52, cells ['l1', 'l6', 'l11', 'l12']", + "62, transfectants ['l2', 'l7', 'l13', 'l14', 'l15']", + "69, expression ['l3', 'l8', 'l13', 'l16', 'l17']", + "70, of ['l4', 'l9', 'l11', 'l14', 'l16', 'l18']", + "71, IL-16 ['l5', 'l10', 'l12', 'l15', 'l17', 'l18']", + "107, cells ['l19', 'l20', 'l21']", + "108, transfected ['l19', 'l22', 'l23']", + "109, with ['l20', 'l22', 'l24']", + "110, IL-16 ['l21', 'l23', 'l24']", + "134, cells ['l25', 'l26', 'l27']", + "135, transfected ['l25', 'l28', 'l29']", + "136, with ['l26', 'l28', 'l30']", + "137, IL-16. ['l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD4+", + "jurkat", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfectants", + "expression", + "of", + "IL-16", + "transfected", + "with", + "IL-16." + ] + } + } + ] + }, + { + "PMID": "9095180", + "TEXT": "Breast cancers are either primarily resistant to chemotherapy (intrinsic resistance), or respond to chemotherapy but later recur with a multidrug-resistant phenotype because of overexpression of the multidrug transporter P-glycoprotein. The MDR1 gene encoding P-glycoprotein may be transcriptionally regulated by a Y-box transcription factor. We now report that, in multidrug-resistant MCF-7 breast cancer cells, nuclear localization of YB-1 is associated with MDR-1 gene expression. In drug-sensitive MCF-7 cells, however, YB-1 was localized to the cytoplasm. Regulated overexpression of YB-1 in drug-sensitive diploid breast epithelial cells induced MDR-1 gene expression and multidrug resistance. In 27 out of 27 untreated primary breast cancers, YB-1 protein was expressed in the cytoplasm although it was undetectable in normal breast tissue of these patients. In a subgroup of tumors (9/27), however, YB-1 was also localized to the nucleus and, in these cases, high levels of P-glycoprotein were present. These results show that in a subset of untreated primary breast cancers, nuclear localization of YB-1 protein is associated with intrinsic multidrug resistance. Our data show that YB-1 has an important role in controlling MDR1 gene transcription and this finding provides a basis for the analysis of molecular mechanisms responsible for intrinsic multidrug resistance in human breast cancer.", + "TAG_DATA": [ + "74, Regulated {'perturbing_action': 'B-gene gain-of-function'}", + "75, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "76, of {'perturbing_action': 'I-gene gain-of-function'}", + "77, YB-1 {'perturbing_action': 'I-gene gain-of-function'}", + "79, drug-sensitive {'context': 'B-cells'}", + "80, diploid {'context': 'I-cells'}", + "81, breast {'context': 'I-cells'}", + "82, epithelial {'context': 'I-cells'}", + "83, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "74, Regulated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "75, overexpression ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "76, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "77, YB-1 ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "79, drug-sensitive ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "80, diploid ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "81, breast ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "82, epithelial ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "83, cells ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Regulated", + "overexpression", + "of", + "YB-1" + ] + }, + "context": { + "val": "cells", + "words": [ + "drug-sensitive", + "diploid", + "breast", + "epithelial", + "cells" + ] + } + } + ] + }, + { + "PMID": "9095178", + "TEXT": "Chronic systemic delivery of therapeutic proteins, such as inhibitors of angiogenesis, present a number of difficult pharmacological challenges. To overcome these problems for one such protein, we constructed retroviral and adenoviral vectors that express a novel, secretable form of the antiangiogenic protein, platelet factor 4 (sPF4). Vector-mediated sPF4 transduction selectively inhibits endothelial cell proliferation in vitro, and results in hypovascular tumors that grow slowly in vivo. Additionally, tumor-associated angiogenesis is inhibited and animal survival is prolonged, following transduction of established intracerebral gliomas by an sPF4-expressing adenoviral vector. These data support the concept that targeted antiangiogenesis, using virally mediated gene transfer, represents a promising strategy for delivering antiangiogenic therapy.", + "TAG_DATA": [ + "46, Vector-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "47, sPF4 {'perturbing_action': 'I-gene gain-of-function'}", + "48, transduction {'perturbing_action': 'I-gene gain-of-function'}", + "50, inhibits {'effect': 'B-negative'}", + "51, endothelial {'context': 'B-cells'}", + "52, cell {'context': 'I-cells'}", + "53, proliferation {'phenotype': 'B-proliferation'}", + "54, in {'context': 'B-in vitro'}", + "55, vitro, {'context': 'I-in vitro'}", + "60, tumors {'context': 'B-neoplasm'}", + "64, in {'context': 'B-in vivo'}", + "65, vivo. {'context': 'I-in vivo'}", + "72, animal {'context': 'B-organism', 'phenotype': 'B-cell survival'}", + "80, intracerebral {'context': 'B-neoplasm'}", + "81, gliomas {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "46, Vector-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "47, sPF4 ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "48, transduction ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "50, inhibits ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "51, endothelial ['l3', 'l13', 'l22', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "52, cell ['l4', 'l14', 'l23', 'l31', 'l36', 'l41', 'l42', 'l43']", + "53, proliferation ['l5', 'l15', 'l24', 'l32', 'l37', 'l41', 'l44', 'l45']", + "54, in ['l6', 'l16', 'l25', 'l33', 'l38', 'l42', 'l44', 'l46', 'l47']", + "55, vitro, ['l7', 'l17', 'l26', 'l34', 'l39', 'l43', 'l45', 'l46', 'l48']", + "60, tumors ['l8', 'l18', 'l27', 'l35', 'l40', 'l47', 'l48', 'l49', 'l50']", + "64, in ['l9', 'l19', 'l28', 'l49', 'l51']", + "65, vivo. ['l10', 'l20', 'l29', 'l50', 'l51']", + "72, animal ['l52', 'l53', 'l54']", + "80, intracerebral ['l52', 'l55', 'l56', 'l57']", + "81, gliomas ['l53', 'l55', 'l58', 'l59']", + "85, adenoviral ['l56', 'l58', 'l60']", + "86, vector. ['l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Vector-mediated", + "sPF4", + "transduction" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Vector-mediated", + "sPF4", + "transduction" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Vector-mediated", + "sPF4", + "transduction" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Vector-mediated", + "sPF4", + "transduction" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Vector-mediated", + "sPF4", + "transduction" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Vector-mediated", + "sPF4", + "transduction" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animal" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "animal" + ] + } + }, + { + "phenotype": { + "val": "cell survival", + "words": [ + "animal" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "intracerebral", + "gliomas" + ] + } + } + ] + }, + { + "PMID": "9095175", + "TEXT": "We have studied the interactions of phosphodiester and phosphorothioate oligodeoxynucleotides with Mac-1 (CD11b/CD18; alpha M beta 2), a heparin-binding integrin found predominantly on the surface of polymorphonuclear leukocytes (PMNs), macrophages and natural killer cells. Binding of a homopolymer of thymidine occurred on both the alpha M and beta 2 subunits. Soluble fibrinogen, a natural ligand for Mac-1, was an excellent competitor of the binding of a phosphorothioate oligodeoxynucleotide to both TNF-alpha-activated and nonactivated PMNs. Upregulation of cell-surface Mac-1 expression increased cell-surface binding of oligodeoxynucleotides. Binding was inhibited by anti-Mac-1 monoclonal antibodies, and the increase in cell-surface binding was correlated with a three- to fourfold increase in internalization by PMNs. An oligodeoxynucleotide inhibited beta 2-dependent migration through Matrigel, but the production of reactive oxygen species in PMNs adherent to fibrinogen dramatically increased. Thus, our data demonstrate that Mac-1 is a cell-surface receptor for oligodeoxynucleotides that can mediate their internalization and that this binding may have important functional consequences.", + "TAG_DATA": [ + "74, Upregulation {'perturbing_action': 'B-gene gain-of-function'}", + "75, of {'perturbing_action': 'I-gene gain-of-function'}", + "76, cell-surface {'perturbing_action': 'I-gene gain-of-function'}", + "77, Mac-1 {'perturbing_action': 'I-gene gain-of-function'}", + "78, expression {'perturbing_action': 'I-gene gain-of-function'}", + "111, inhibited {'effect': 'B-negative'}", + "114, migration {'phenotype': 'B-migration'}", + "125, PMNs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "74, Upregulation ['l0', 'l1', 'l2', 'l3']", + "75, of ['l0', 'l4', 'l5', 'l6']", + "76, cell-surface ['l1', 'l4', 'l7', 'l8']", + "77, Mac-1 ['l2', 'l5', 'l7', 'l9']", + "78, expression ['l3', 'l6', 'l8', 'l9']", + "111, inhibited ['l10']", + "114, migration ['l10']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + } + ] + }, + { + "PMID": "9055862", + "TEXT": "Mutations in the presenilin genes are associated with early onset familial Alzheimer's disease and lead to increased accumulation of beta A4 peptide, the proteolytic product of the amyloid precursor protein (APP). To test whether presenilins interfere with APP metabolism, presenilin-2 (PS2) was coexpressed with APP in mammalian cells. Analysis of PS2 immunoprecipitates revealed that a fraction of APP was associated with the PS2 immunocomplexes. This non-covalent association was specific for the APP family of proteins and restricted to immature forms, occurring probably during transit through the endoplasmic reticulum. Additionally, coexpression with PS2 resulted in a decrease of APP secretion, suggesting a direct participation of presenilins in the intracellular sorting, trafficking and processing of APP molecules.", + "TAG_DATA": [ + "39, presenilin-2 {'perturbing_action': 'B-gene gain-of-function'}", + "40, (PS2) {'perturbing_action': 'I-gene gain-of-function'}", + "42, coexpressed {'perturbing_action': 'I-gene gain-of-function'}", + "43, with {'perturbing_action': 'I-gene gain-of-function'}", + "44, APP {'perturbing_action': 'I-gene gain-of-function'}", + "46, mammalian {'context': 'B-cells'}", + "47, cells. {'context': 'I-cells'}", + "89, coexpression {'perturbing_action': 'B-gene gain-of-function'}", + "90, with {'perturbing_action': 'I-gene gain-of-function'}", + "91, PS2 {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "39, presenilin-2 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "40, (PS2) ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "42, coexpressed ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "43, with ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "44, APP ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "46, mammalian ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "47, cells. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "89, coexpression ['l21', 'l22']", + "90, with ['l21', 'l23']", + "91, PS2 ['l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "presenilin-2", + "(PS2)", + "coexpressed", + "with", + "APP" + ] + }, + "context": { + "val": "cells", + "words": [ + "mammalian", + "cells." + ] + } + } + ] + }, + { + "PMID": "8986737", + "TEXT": "A major safety concern of using live-attenuated vaccine strategies against AIDS is the potential exposure of neonates or fetuses to vaccine virus from the mother. Here we report that high viral loads and disease were observed in only 2 of 18 neonatal monkeys infected with gene-deleted vaccine strains of simian immunodeficiency virus. Pathogenicity was restricted to neonates born to unvaccinated mothers, that is, lacking maternal immunity, and that received extremely high doses of vaccine virus orally. No in utero transmission of vaccine virus was observed in four neonates born to mothers vaccinated during the second trimester. Our results suggest that the live attenuated vaccine approach should remain a viable option for preventing HIV infection and disease in high-risk human populations.", + "TAG_DATA": [ + "41, neonatal {'context': 'B-organism'}", + "42, monkeys {'context': 'I-organism'}", + "45, gene-deleted {'perturbing_action': 'B-gene loss-of-function'}", + "56, neonates {'context': 'B-organism'}", + "77, in {'context': 'B-in vivo'}", + "78, utero {'context': 'B-in vivo'}", + "87, neonates {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "41, neonatal ['l0']", + "42, monkeys ['l0']", + "45, gene-deleted ['l1']", + "56, neonates ['l1']", + "77, in ['l2', 'l3']", + "78, utero ['l2', 'l4']", + "87, neonates ['l3', 'l4']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "gene-deleted" + ] + }, + "context": { + "val": "organism", + "words": [ + "neonates" + ] + } + } + ] + }, + { + "PMID": "8946842", + "TEXT": "The control of cell proliferation is of central importance to the proper development of a multicellular organism, the homeostatic maintenance of tissues, and the ability of certain cell types to respond appropriately to environmental cues. Disruption of normal cell growth control underlies many pathological conditions, including endothelial proliferative disorders in cardiovascular disease as well as the development of malignant tumors. Particularly critical for the control of cell growth is the pathway involving the G1 cyclin-dependent kinases that regulate the Rb family of proteins, which in turn control E2F transcription factor activity. Because E2F is critical for regulation of cell proliferation, we sought to identify and to develop specific inhibitors of E2F function that might also be useful in the control of cellular proliferation. Moreover, because the control of E2F activity appears to be the end result of G1 regulatory cascades, the ability to inhibit E2F may be particularly effective in impeding a wide variety of proliferative events. We have used in vitro selection to isolate several unique RNA species from high complexity RNA libraries that avidly bind to the E2F family of proteins. These RNAs also inhibit the DNA binding capacity of the E2F proteins. We also show that an E2F RNA ligand can block the induction of S phase in quiescent cells stimulated by serum addition. As such, these data demonstrate the critical role for E2F activity in cell proliferation and suggest that such RNA molecules may be effective as therapeutic entities to control cellular proliferation.", + "TAG_DATA": [ + "160, in {'context': 'B-in vitro'}", + "161, vitro {'context': 'I-in vitro'}", + "204, block {'effect': 'B-negative'}", + "206, induction {'effect': 'B-positive'}", + "208, S {'phenotype': 'I-cell cycle arrest'}", + "209, phase {'phenotype': 'I-cell cycle arrest'}", + "211, quiescent {'context': 'B-cells', 'phenotype': 'B-quiescence'}", + "212, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "160, in ['l0']", + "161, vitro ['l0']", + "204, block ['l1', 'l2', 'l3', 'l4', 'l5']", + "206, induction ['l1', 'l6', 'l7', 'l8', 'l9']", + "208, S ['l2', 'l6', 'l10', 'l11', 'l12']", + "209, phase ['l3', 'l7', 'l10', 'l13', 'l14']", + "211, quiescent ['l4', 'l8', 'l11', 'l13', 'l15']", + "212, cells ['l5', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "block" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "S", + "phase" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "block" + ] + }, + "context": { + "val": "cells", + "words": [ + "quiescent", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "block" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescent" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "quiescent" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescent" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "S", + "phase" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "context": { + "val": "cells", + "words": [ + "quiescent", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescent" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "S", + "phase" + ] + }, + "context": { + "val": "cells", + "words": [ + "quiescent", + "cells" + ] + } + } + ] + }, + { + "PMID": "8946834", + "TEXT": "In nonobese diabetic (NOD) mice, beta-cell reactive T-helper type 1 (Th1) responses develop spontaneously and gradually spread, creating a cascade of responses that ultimately destroys the beta-cells. The diversity of the autoreactive T-cell repertoire creates a major obstacle to the development of therapeutics. We show that even in the presence of established Th1 responses, it is possible to induce autoantigen-specific anti-inflammatory Th2 responses. Immune deviation of T-cell responses to the beta-cell autoantigen glutamate decarboxylase (GAD65), induced an active form of self-tolerance that was associated with an inhibition of disease progression in prediabetic mice and prolonged survival of syngeneic islet grafts in diabetic NOD mice. Thus, modulation of autoantigen-specific Th1/Th2 balances may provide a minimally invasive means of downregulating established pathogenic autoimmune responses.", + "TAG_DATA": [ + "86, inhibition {'effect': 'B-negative'}", + "88, disease {'phenotype': 'B-tumour progression'}", + "89, progression {'phenotype': 'I-tumour progression'}", + "91, prediabetic {'context': 'B-organism'}", + "92, mice {'context': 'I-organism'}", + "97, syngeneic {'context': 'B-xenograft'}", + "98, islet {'context': 'I-xenograft'}", + "99, grafts {'context': 'I-xenograft'}", + "101, diabetic {'context': 'B-organism'}", + "102, NOD {'context': 'I-organism'}", + "103, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "86, inhibition ['l0', 'l1', 'l2', 'l3']", + "88, disease ['l0', 'l4', 'l5', 'l6']", + "89, progression ['l1', 'l4', 'l7', 'l8']", + "91, prediabetic ['l2', 'l5', 'l7', 'l9']", + "92, mice ['l3', 'l6', 'l8', 'l9']", + "97, syngeneic ['l10', 'l11', 'l12', 'l13', 'l14']", + "98, islet ['l10', 'l15', 'l16', 'l17', 'l18']", + "99, grafts ['l11', 'l15', 'l19', 'l20', 'l21']", + "101, diabetic ['l12', 'l16', 'l19', 'l22', 'l23']", + "102, NOD ['l13', 'l17', 'l20', 'l22', 'l24']", + "103, mice. ['l14', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "disease", + "progression" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "prediabetic", + "mice" + ] + } + }, + { + "phenotype": { + "val": "tumour progression", + "words": [ + "disease", + "progression" + ] + }, + "context": { + "val": "organism", + "words": [ + "prediabetic", + "mice" + ] + } + } + ] + }, + { + "PMID": "8946830", + "TEXT": "The Dunning rat prostatic carcinoma is a model system where cell motility closely correlates with the metastatic phenotype. We have identified a novel gene, upregulated in the highly motile and metastatic Dunning cancer cell lines, that represents a new member of the thymosin-beta family, thymosin beta 15. Transfection of antisense thymosin beta 15 constructs into rat prostatic carcinoma cells demonstrates that this molecule positively regulates cell motility, a critical component of the metastatic pathway. Thymosin beta 15 levels are elevated in human prostate cancer and correlate positively with the Gleason tumor grade. Thymosin beta 15 may represent a potential new biochemical marker for human prostate cancer progression.", + "TAG_DATA": [ + "47, Transfection {'perturbing_action': 'B-gene gain-of-function'}", + "48, of {'perturbing_action': 'I-rnai/knockdown'}", + "49, antisense {'perturbing_action': 'I-rnai/knockdown'}", + "50, thymosin {'perturbing_action': 'I-rnai/knockdown'}", + "51, beta {'perturbing_action': 'I-rnai/knockdown'}", + "52, 15 {'perturbing_action': 'I-rnai/knockdown'}", + "53, constructs {'perturbing_action': 'I-rnai/knockdown'}", + "55, rat {'context': 'B-transformed cells'}", + "56, prostatic {'context': 'I-transformed cells'}", + "57, carcinoma {'context': 'I-transformed cells'}", + "58, cells {'context': 'I-transformed cells'}", + "65, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "47, Transfection ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "48, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "49, antisense ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "50, thymosin ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "51, beta ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "52, 15 ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "53, constructs ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "55, rat ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "56, prostatic ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "57, carcinoma ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "58, cells ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "65, cell ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transfection" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "rat", + "prostatic", + "carcinoma", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transfection" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "antisense", + "thymosin", + "beta", + "15", + "constructs" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "rat", + "prostatic", + "carcinoma", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "antisense", + "thymosin", + "beta", + "15", + "constructs" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + } + ] + }, + { + "PMID": "8946829", + "TEXT": "The retinoblastoma gene (RB) is the prototypic tumor suppressor. Studies to date have demonstrated cancer suppression with tumor cells reconstituted with RB ex vivo and implanted into immunodeficient mice, as well as with germline transmission of a human RB transgene into tumor-prone Rb +/- mice. To mimic the therapy of cancer more closely, spontaneous pituitary melanotroph tumors arising in immunocompetent Rb +/- mice were treated with a recombinant adenovirus carrying RB cDNA. Intratumoral RB gene transfer decreased tumor cell proliferation, reestablished innervation by growth-regulatory dopaminergic neurons, inhibited the growth of tumors, and prolonged the life spans of treated animals.", + "TAG_DATA": [ + "42, Rb {'perturbing_action': 'B-gene loss-of-function'}", + "43, +/- {'perturbing_action': 'B-gene loss-of-function'}", + "44, mice. {'context': 'B-organism'}", + "54, pituitary {'context': 'B-neoplasm'}", + "55, melanotroph {'context': 'I-neoplasm', 'phenotype': 'I-tumourigenesis'}", + "56, tumors {'context': 'I-neoplasm'}", + "59, immunocompetent {'context': 'B-organism'}", + "60, Rb {'context': 'I-organism'}", + "61, +/- {'context': 'I-organism'}", + "62, mice {'context': 'I-organism'}", + "68, adenovirus {'perturbing_action': 'I-gene gain-of-function'}", + "69, carrying {'perturbing_action': 'I-gene gain-of-function'}", + "73, RB {'perturbing_action': 'I-gene gain-of-function'}", + "74, gene {'perturbing_action': 'I-gene gain-of-function'}", + "75, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "76, decreased {'effect': 'B-negative'}", + "77, tumor {'context': 'B-transformed cells'}", + "78, cell {'context': 'I-transformed cells'}", + "79, proliferation, {'phenotype': 'B-proliferation'}", + "83, growth-regulatory {'context': 'B-cells'}", + "84, dopaminergic {'context': 'I-cells'}", + "85, neurons, {'context': 'I-cells'}", + "86, inhibited {'effect': 'B-negative'}", + "90, tumors, {'context': 'B-neoplasm'}", + "98, animals. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "42, Rb ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "43, +/- ['l0', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "44, mice. ['l1', 'l18', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "54, pituitary ['l2', 'l19', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "55, melanotroph ['l3', 'l20', 'l34', 'l42', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "56, tumors ['l4', 'l21', 'l35', 'l43', 'l57', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "59, immunocompetent ['l5', 'l22', 'l36', 'l44', 'l58', 'l73', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "60, Rb ['l6', 'l23', 'l37', 'l45', 'l59', 'l74', 'l86', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "61, +/- ['l7', 'l24', 'l38', 'l46', 'l60', 'l75', 'l87', 'l102', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "62, mice ['l8', 'l25', 'l39', 'l47', 'l61', 'l76', 'l88', 'l103', 'l117', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "68, adenovirus ['l62', 'l89', 'l104', 'l118', 'l131', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "69, carrying ['l63', 'l90', 'l105', 'l119', 'l141', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "71, cDNA. ['l91', 'l106', 'l120', 'l142', 'l156', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "73, RB ['l143', 'l157', 'l170', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "74, gene ['l144', 'l158', 'l171', 'l183', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205']", + "75, transfer ['l92', 'l107', 'l121', 'l145', 'l159', 'l172', 'l184', 'l195', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215']", + "76, decreased ['l9', 'l26', 'l48', 'l64', 'l77', 'l93', 'l108', 'l122', 'l132', 'l146', 'l160', 'l173', 'l185', 'l196', 'l206', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223']", + "77, tumor ['l10', 'l27', 'l49', 'l65', 'l78', 'l94', 'l109', 'l123', 'l133', 'l147', 'l161', 'l174', 'l186', 'l197', 'l207', 'l216', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230']", + "78, cell ['l11', 'l28', 'l40', 'l50', 'l66', 'l79', 'l95', 'l110', 'l124', 'l134', 'l148', 'l162', 'l175', 'l187', 'l198', 'l208', 'l217', 'l224', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236']", + "79, proliferation, ['l12', 'l29', 'l41', 'l51', 'l67', 'l80', 'l96', 'l111', 'l125', 'l135', 'l149', 'l163', 'l176', 'l188', 'l199', 'l209', 'l218', 'l225', 'l231', 'l237', 'l238', 'l239', 'l240', 'l241']", + "83, growth-regulatory ['l13', 'l52', 'l68', 'l81', 'l97', 'l112', 'l126', 'l136', 'l150', 'l164', 'l177', 'l189', 'l200', 'l210', 'l219', 'l226', 'l232', 'l237', 'l242', 'l243', 'l244', 'l245', 'l246']", + "84, dopaminergic ['l14', 'l30', 'l53', 'l69', 'l82', 'l98', 'l113', 'l127', 'l137', 'l151', 'l165', 'l178', 'l190', 'l201', 'l211', 'l220', 'l227', 'l233', 'l238', 'l242', 'l247', 'l248', 'l249', 'l250']", + "85, neurons, ['l15', 'l31', 'l54', 'l70', 'l83', 'l99', 'l114', 'l128', 'l138', 'l152', 'l166', 'l179', 'l191', 'l202', 'l212', 'l221', 'l228', 'l234', 'l239', 'l243', 'l247', 'l251', 'l252', 'l253']", + "86, inhibited ['l16', 'l55', 'l71', 'l84', 'l100', 'l115', 'l129', 'l139', 'l153', 'l167', 'l180', 'l192', 'l203', 'l213', 'l222', 'l229', 'l235', 'l240', 'l244', 'l248', 'l251', 'l254', 'l255']", + "90, tumors, ['l17', 'l32', 'l56', 'l72', 'l85', 'l101', 'l116', 'l130', 'l140', 'l154', 'l168', 'l181', 'l193', 'l204', 'l214', 'l223', 'l230', 'l236', 'l241', 'l245', 'l249', 'l252', 'l254']", + "98, animals. ['l155', 'l169', 'l182', 'l194', 'l205', 'l215', 'l246', 'l250', 'l253', 'l255']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rb", + "+/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "immunocompetent", + "Rb", + "+/-", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rb", + "+/-" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "pituitary", + "melanotroph", + "tumors", + "tumors," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rb", + "+/-" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "melanotroph" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "melanotroph", + "pituitary" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "melanotroph" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rb", + "+/-" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased", + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rb", + "+/-" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rb", + "+/-" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rb", + "+/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "growth-regulatory", + "dopaminergic", + "neurons," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice.", + "immunocompetent", + "Rb", + "+/-", + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "melanotroph" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice.", + "immunocompetent", + "Rb", + "+/-", + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "pituitary", + "melanotroph", + "tumors", + "tumors," + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased", + "inhibited" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "pituitary", + "melanotroph", + "tumors", + "tumors," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "melanotroph", + "tumors," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "carrying", + "RB", + "gene", + "transfer" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "melanotroph" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "carrying" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "melanotroph" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased", + "inhibited" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "melanotroph" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "melanotroph" + ] + }, + "context": { + "val": "cells", + "words": [ + "growth-regulatory", + "dopaminergic", + "neurons," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "immunocompetent", + "Rb", + "+/-", + "mice", + "animals." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "carrying", + "transfer", + "RB", + "gene" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "immunocompetent", + "Rb", + "+/-", + "mice", + "animals." + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased", + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "carrying", + "RB", + "gene", + "transfer" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased", + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "carrying", + "RB", + "gene", + "transfer" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "carrying", + "RB", + "gene", + "transfer" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "carrying", + "RB", + "gene", + "transfer" + ] + }, + "context": { + "val": "cells", + "words": [ + "growth-regulatory", + "dopaminergic", + "neurons," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased", + "inhibited" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased", + "inhibited" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased", + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "growth-regulatory", + "dopaminergic", + "neurons," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "context": { + "val": "cells", + "words": [ + "growth-regulatory", + "dopaminergic", + "neurons," + ] + } + } + ] + }, + { + "PMID": "8837612", + "TEXT": "Cocaine abuse is a major medical and public health concern in the United States, with approximately 2.1 million people dependent on cocaine. Pharmacological approaches to the treatment of cocaine addiction have thus far been disappointing, and new therapies are urgently needed. This paper describes an immunological approach to cocaine addiction. Antibody therapy for neutralization of abused drugs has been described previously, including a recent paper demonstrating the induction of anti-cocaine antibodies. However, both the rapidity of entry of cocaine into the brain and the high doses of cocaine frequently encountered have created challenges for an antibody-based therapy. Here we demonstrate that antibodies are efficacious in an animal model of addiction. Intravenous cocaine self-administration in rats was inhibited by passive transfer of an anti-cocaine monoclonal antibody. To actively induce anti-cocaine antibodies, a cocaine vaccine was developed that generated a high-titer, long-lasting antibody response in mice. Immunized mice displayed a significant change in cocaine pharmacokinetics, with decreased levels of cocaine measured in the brain of immunized mice only 30 seconds after intravenous (i.v.) administration of cocaine. These data establish the feasibility of a therapeutic cocaine vaccine for the treatment of cocaine addiction.", + "TAG_DATA": [ + "114, rats {'context': 'B-organism'}", + "116, inhibited {'effect': 'B-negative'}", + "143, mice. {'context': 'B-organism'}", + "145, mice {'context': 'B-organism'}", + "164, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "114, rats ['l0']", + "116, inhibited ['l0']", + "145, mice ['l1']", + "164, mice ['l1']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "rats" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + } + ] + }, + { + "PMID": "8782457", + "TEXT": "Chronic intestinal inflammation induced by 2,4,6,-trinitrobenzene sulfonic acid (TNBS) is characterized by a transmural granulomatous colitis that mimics some characteristics of human Crohn's disease. Here, we show that the transcription factor NF-kappa B p65 was strongly activated in TNBS-induced colitis and in colitis of interleukin-10-deficient mice. Local administration of p65 antisense phosphorothioate oligonucleotides abrogated clinical and histological signs of colitis and was more effective in treating TNBS-induced colitis than single or daily administration of glucocorticoids. The data provide direct evidence for the central importance of p65 in chronic intestinal inflammation and suggest a potential therapeutic utility of p65 antisense oligonucleotides as a novel molecular approach for the treatment of patients with Crohn's disease.", + "TAG_DATA": [ + "44, interleukin-10-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "45, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "44, interleukin-10-deficient ['l0']", + "45, mice. ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interleukin-10-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "8782456", + "TEXT": "Localization of activated natural killer (A-NK) cells in the microvasculature of growing tumors is the result of recognition of the intracellular and vascular cell-adhesion molecules ICAM-1 and VCAM-1 on the tumor endothelium, mediated by lymphocyte function-associated protein LFA-1 and vascular lymphocyte function-associated protein VLA-4. In vitro and in vivo studies of A-NK cell adhesion to endothelial cells showed that vascular endothelial growth factor (VEGF) promotes adhesion, whereas basic fibroblast growth factor (bFGF) inhibits adhesion through the regulation of these molecules on tumor vasculature. Thus, some angiogenic factors may facilitate lymphocyte recognition of angiogenic vessels, whereas others may provide such vessels with a mechanism that protects them from cytotoxic lymphocytes.", + "TAG_DATA": [ + "44, In {'context': 'B-in vitro'}", + "45, vitro {'context': 'I-in vitro'}", + "47, in {'context': 'B-in vivo'}", + "48, vivo {'context': 'I-in vivo'}", + "51, A-NK {'context': 'B-cells'}", + "52, cell {'context': 'I-cells'}", + "55, endothelial {'context': 'B-cells'}", + "56, cells {'context': 'I-cells'}", + "64, promotes {'effect': 'B-positive'}", + "65, adhesion, {'phenotype': 'B-adhesion'}", + "72, inhibits {'effect': 'B-negative'}", + "73, adhesion {'phenotype': 'B-adhesion'}" + ], + "LINK_DATA": [ + "44, In ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "45, vitro ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "47, in ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "48, vivo ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "51, A-NK ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "52, cell ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "55, endothelial ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "56, cells ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "64, promotes ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "65, adhesion, ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "72, inhibits ['l45']", + "73, adhesion ['l45']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "A-NK", + "cell", + "endothelial", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "A-NK", + "cell", + "endothelial", + "cells" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + } + ] + }, + { + "PMID": "8640562", + "TEXT": "There is now considerable direct evidence that tumor growth is angiogenesis-dependent. The most compelling evidence is based on the discovery of angiostatin, an angiogenesis inhibitor that selectively instructs endothelium to become refractory to angiogenic stimuli. Angiostatin, which specifically inhibits endothelial proliferation, induced dormancy of metastases defined by a balance of apoptosis and proliferation. We now show that systemic administration of human angiostatin potently inhibits the growth of three human and three murine primary carcinomas in mice. An almost complete inhibition of tumor growth was observed without detectable toxicity or resistance. The human carcinomas regressed to microscopic dormant foci in which tumor cell proliferation was balanced by apoptosis in the presence of blocked angiogenesis. This regression of primary tumors without toxicity has not been previously described. This is also the first demonstration of dormancy therapy, a novel anticancer strategy in which malignant tumors are regressed by prolonged blockade of angiogenesis.", + "TAG_DATA": [ + "68, human {'context': 'B-neoplasm'}", + "69, and {'context': 'I-neoplasm'}", + "71, murine {'context': 'I-neoplasm'}", + "72, primary {'context': 'I-neoplasm'}", + "73, carcinomas {'context': 'I-neoplasm'}", + "75, mice. {'context': 'B-organism'}", + "79, inhibition {'effect': 'B-negative'}", + "81, tumor {'phenotype': 'B-tumour growth'}", + "82, growth {'phenotype': 'I-tumour growth'}", + "91, human {'context': 'B-neoplasm'}", + "92, carcinomas {'context': 'I-neoplasm'}", + "100, tumor {'context': 'B-transformed cells'}", + "101, cell {'context': 'I-transformed cells'}", + "102, proliferation {'phenotype': 'B-proliferation'}", + "106, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "68, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "69, and ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "71, murine ['l1', 'l6', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "72, primary ['l2', 'l7', 'l11', 'l17', 'l18']", + "73, carcinomas ['l3', 'l8', 'l12', 'l17', 'l19']", + "75, mice. ['l4', 'l9', 'l13', 'l18', 'l19', 'l20']", + "79, inhibition ['l14', 'l21', 'l22']", + "81, tumor ['l15', 'l21', 'l23']", + "82, growth ['l5', 'l10', 'l16', 'l20', 'l22', 'l23']", + "91, human ['l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "92, carcinomas ['l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "100, tumor ['l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "101, cell ['l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "102, proliferation ['l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "104, balanced ['l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "106, apoptosis ['l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "human", + "and", + "murine" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth", + "tumor" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "murine" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "human", + "carcinomas" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "human", + "carcinomas" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "8640559", + "TEXT": "Microsatellite (MS) mutations can potentially unravel the past of mutator phenotype tumors, with greater genetic diversity expected in older regions. Rapid clonal expansions of xenografts were characterized by relatively homogenous MS alleles, whereas greater diversity was observed in a colorectal cancer with the greatest variation in its adjacent adenoma. A subcutaneous lung cancer metastasis demonstrated diversity consistent with its one-month clinical duration and evidence of active mitosis during dormancy. The genetic legacy inherent to multistep tumorigenesis provides direct estimates of tumor ages, with up to thousands of cell divisions and high death rates necessary to yield the observed diversities. MS molecular tumor clocks have the unique potential to systematically reconstruct the early and occult evolution of individual human mutator phenotype tumors.", + "TAG_DATA": [ + "50, subcutaneous {'context': 'B-neoplasm'}", + "51, lung {'context': 'I-neoplasm'}", + "52, cancer {'context': 'I-neoplasm'}", + "53, metastasis {'context': 'I-neoplasm', 'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "50, subcutaneous ['l0', 'l1', 'l2']", + "51, lung ['l0', 'l3', 'l4']", + "52, cancer ['l1', 'l3', 'l5']", + "53, metastasis ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "subcutaneous", + "lung", + "cancer" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + } + ] + }, + { + "PMID": "8640557", + "TEXT": "Naturally pyrazinamide (PZA)-resistant Mycobacterium bovis and acquired PZA-resistant M. tuberculosis strains lose pyrazinamidase (PZase). To investigate the molecular mechanism of PZA resistance, we have cloned the gene (pncA) encoding M. tuberculosis PZase. Mutations in pncA were identified in both types of PZA-resistant strains, and transformation of these strains with a functional pncA gene restored PZase activity and PZA susceptibility. These findings, besides providing the basis for understanding how PZA works, should have implications for rapid detection of PZA-resistant clinical isolates of M. tuberculosis and also for rapid differentiation of M. bovis from M. tuberculosis strains.", + "TAG_DATA": [ + "44, transformation {'perturbing_action': 'B-gene gain-of-function', 'phenotype': 'B-transformation'}", + "48, with {'perturbing_action': 'I-gene gain-of-function'}", + "49, a {'perturbing_action': 'I-gene gain-of-function'}", + "50, functional {'perturbing_action': 'I-gene gain-of-function'}", + "51, pncA {'perturbing_action': 'I-gene gain-of-function'}", + "52, gene {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "44, transformation ['l0', 'l1', 'l2', 'l3', 'l4']", + "48, with ['l0', 'l5', 'l6', 'l7', 'l8']", + "49, a ['l1', 'l5', 'l9', 'l10', 'l11']", + "50, functional ['l2', 'l6', 'l9', 'l12', 'l13']", + "51, pncA ['l3', 'l7', 'l10', 'l12', 'l14']", + "52, gene ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transformation" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + } + } + ] + }, + { + "PMID": "8616717", + "TEXT": "Cytosine arabinoside (ara-C) is a cytidine analog that incorporates into replicating DNA and induces lethal DNA strand breaks. Although ara-C is a potent antitumor agent for hematologic malignancies, it has only minimal activity against most solid tumors. The rate-limiting step in intracellular ara-C activation is phosphorylation of the prodrug by deoxycytidine kinase (dCK). The present results demonstrate that both retroviral and adenoviral vector-mediated transduction of the dCK cDNA results in marked sensitization of glioma cells lines to the cytotoxic effects of ara-C in vitro. We also demonstrate that ara-C treatment of established intradermal and intracerebral gliomas transduced with dCK results in significant antitumor effects in vivo. These data suggest that viral vector transduction of the dCK gene followed by treatment with ara-C represents a new chemosensitization strategy for cancer gene therapy.", + "TAG_DATA": [ + "59, retroviral {'perturbing_action': 'B-gene gain-of-function'}", + "60, and {'perturbing_action': 'I-gene gain-of-function'}", + "61, adenoviral {'perturbing_action': 'B-gene gain-of-function'}", + "62, vector-mediated {'perturbing_action': 'I-gene gain-of-function'}", + "63, transduction {'perturbing_action': 'I-gene gain-of-function'}", + "64, of {'perturbing_action': 'I-gene gain-of-function'}", + "65, the {'perturbing_action': 'I-gene gain-of-function'}", + "66, dCK {'perturbing_action': 'I-gene gain-of-function'}", + "67, cDNA {'perturbing_action': 'I-gene gain-of-function'}", + "73, glioma {'context': 'B-transformed cells'}", + "74, cells {'context': 'I-transformed cells'}", + "75, lines {'context': 'I-transformed cells'}", + "82, in {'context': 'B-in vitro'}", + "83, vitro. {'context': 'I-in vitro'}", + "92, intradermal {'context': 'B-neoplasm'}", + "93, and {'context': 'I-neoplasm'}", + "94, intracerebral {'context': 'B-neoplasm'}", + "95, gliomas {'context': 'I-neoplasm'}", + "96, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "97, with {'perturbing_action': 'I-gene gain-of-function'}", + "98, dCK {'perturbing_action': 'I-gene gain-of-function'}", + "104, in {'context': 'B-in vivo'}", + "105, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "59, retroviral ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "60, and ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "61, adenoviral ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "62, vector-mediated ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "63, transduction ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "64, of ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "65, the ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "66, dCK ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "67, cDNA ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "73, glioma ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "74, cells ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86']", + "75, lines ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l87', 'l88']", + "82, in ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l87', 'l89']", + "83, vitro. ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l86', 'l88', 'l89']", + "92, intradermal ['l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "93, and ['l90', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "94, intracerebral ['l91', 'l98', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "95, gliomas ['l92', 'l99', 'l105', 'l111', 'l112', 'l113', 'l114', 'l115']", + "96, transduced ['l93', 'l100', 'l106', 'l111', 'l116', 'l117', 'l118', 'l119']", + "97, with ['l94', 'l101', 'l107', 'l112', 'l116', 'l120', 'l121', 'l122']", + "98, dCK ['l95', 'l102', 'l108', 'l113', 'l117', 'l120', 'l123', 'l124']", + "104, in ['l96', 'l103', 'l109', 'l114', 'l118', 'l121', 'l123', 'l125']", + "105, vivo. ['l97', 'l104', 'l110', 'l115', 'l119', 'l122', 'l124', 'l125']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "retroviral", + "and", + "adenoviral", + "vector-mediated", + "transduction", + "of", + "the", + "dCK", + "cDNA" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "glioma", + "cells", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "retroviral", + "and", + "adenoviral", + "vector-mediated", + "transduction", + "of", + "the", + "dCK", + "cDNA" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "intradermal", + "and", + "intracerebral", + "gliomas" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "dCK" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "dCK" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "8616716", + "TEXT": "The bcr-abl oncogene, present in 95% of patients with chronic myelogenous leukemia (CML), has been implicated as the cause of this disease. A compound, designed to inhibit the Abl protein tyrosine kinase, was evaluated for its effects on cells containing the Bcr-Abl fusion protein. Cellular proliferation and tumor formation by Bcr-Abl-expressing cells were specifically inhibited by this compound. In colony-forming assays of peripheral blood or bone marrow from patients with CML, there was a 92-98% decrease in the number of bcr-abl colonies formed but no inhibition of normal colony formation. This compound may be useful in the treatment of bcr-abl-positive leukemias.", + "TAG_DATA": [ + "38, cells {'context': 'B-cells'}", + "45, proliferation {'phenotype': 'B-proliferation'}", + "47, tumor {'phenotype': 'B-tumourigenesis'}", + "48, formation {'phenotype': 'I-tumourigenesis'}", + "50, Bcr-Abl-expressing {'context': 'B-cells'}", + "51, cells {'context': 'I-cells'}", + "54, inhibited {'effect': 'B-negative'}", + "75, decrease {'effect': 'B-negative'}", + "85, inhibition {'effect': 'B-negative'}", + "88, colony {'phenotype': 'B-colony formation'}", + "89, formation. {'phenotype': 'I-colony formation'}" + ], + "LINK_DATA": [ + "38, cells ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "44, Cellular ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "45, proliferation ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "47, tumor ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "48, formation ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "50, Bcr-Abl-expressing ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "51, cells ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "54, inhibited ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "75, decrease ['l28']", + "85, inhibition ['l29', 'l30']", + "88, colony ['l29', 'l31']", + "89, formation. ['l28', 'l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells", + "Bcr-Abl-expressing" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "Bcr-Abl-expressing" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "formation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "Bcr-Abl-expressing" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "formation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decrease", + "inhibition" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "formation.", + "colony" + ] + } + } + ] + }, + { + "PMID": "8597951", + "TEXT": "There are currently no effective therapies for progressive fibrotic diseases. Recent evidence has implicated overproduction of transforming growth factor-beta1 (TGF-beta1) as a major cause of tissue fibrosis. Furthermore, this evidence implies that inhibitors of TGF-beta1 may be clinically useful as antifibrotic agents. The proteoglycan decorin is a known inhibitor of TGF-beta1. In a rat model of glomerulonephritis we have shown that fibrosis is mediated by TGF-beta1. We report here that transfer of decorin cDNA into rat skeletal muscle increases the amount of decorin messenger RNA and protein present in skeletal muscle and decorin present in kidney, where it has a marked therapeutic effect on fibrosis induced by glomerulonephritis. Transfected glomerulonephritic rats showed a significant reduction in levels of glomerular TGF-beta1 mRNA and TGF-beta1 protein, extracellular matrix accumulation and proteinuria. These results demonstrate the potential of gene therapy as a novel treatment for fibrotic diseases caused by TGF-beta1.", + "TAG_DATA": [ + "71, of {'perturbing_action': 'I-gene gain-of-function'}", + "72, decorin {'perturbing_action': 'I-gene gain-of-function'}", + "73, cDNA {'perturbing_action': 'I-gene gain-of-function'}", + "75, rat {'context': 'B-tissue/organ'}", + "76, skeletal {'context': 'I-tissue/organ'}", + "77, muscle {'context': 'I-tissue/organ'}", + "90, muscle {'context': 'I-tissue/organ'}", + "110, rats {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "70, transfer ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "71, of ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "72, decorin ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "73, cDNA ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "75, rat ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "76, skeletal ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "77, muscle ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "89, skeletal ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "90, muscle ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "decorin", + "cDNA" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "skeletal", + "muscle" + ] + } + } + ] + }, + { + "PMID": "8612227", + "TEXT": "Catalytically active thrombin, acting locally, is thought to mediate neointima formation after arterial injury. We constructed an adenovirus vector, AdHV-1.2, containing a complementary DNA for the thrombin inhibitor hirudin. AdHV-1.2 directed the synthesis and secretion of biologically active hirudin from vascular cells in vitro. In vivo gene transfer of hirudin into smooth muscle cells of injured rat carotid arteries resulted in peak secretion of at least 34+/-23 pg hirudin per vessel per 24 hours, and resulted in a significant (P<0.05) 35% reduction in neointima formation. Systemic partial thromboplastin times were not affected by local hirudin expression. These results support the hypothesis that local thrombin activity contributes to neointima formation after arterial injury and suggest that local delivery of a highly specific antithrombin may constitute an effective intervention for arterial proliferative disease.", + "TAG_DATA": [ + "40, vascular {'context': 'B-cells'}", + "41, cells {'context': 'I-cells'}", + "42, in {'context': 'B-in vitro'}", + "43, vitro. {'context': 'I-in vitro'}", + "44, In {'context': 'B-in vivo'}", + "45, vivo {'context': 'I-in vivo'}", + "46, gene {'perturbing_action': 'B-gene gain-of-function'}", + "47, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "48, of {'perturbing_action': 'I-gene gain-of-function'}", + "49, hirudin {'perturbing_action': 'I-gene gain-of-function'}", + "51, smooth {'context': 'B-cells'}", + "52, muscle {'context': 'I-cells'}", + "53, cells {'context': 'I-cells'}", + "56, rat {'context': 'B-tissue/organ'}", + "57, carotid {'context': 'I-tissue/organ'}", + "58, arteries {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "40, vascular ['l0', 'l1', 'l2', 'l3', 'l4']", + "41, cells ['l0', 'l5', 'l6']", + "42, in ['l1', 'l5', 'l7', 'l8']", + "43, vitro. ['l2', 'l6', 'l7', 'l9']", + "44, In ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "45, vivo ['l10', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "46, gene ['l11', 'l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "47, transfer ['l12', 'l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "48, of ['l13', 'l23', 'l32', 'l40', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "49, hirudin ['l14', 'l24', 'l33', 'l41', 'l48', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "51, smooth ['l15', 'l25', 'l34', 'l42', 'l49', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "52, muscle ['l16', 'l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "53, cells ['l3', 'l8', 'l9', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l70', 'l71', 'l72']", + "56, rat ['l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l70', 'l73', 'l74']", + "57, carotid ['l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l73', 'l75']", + "58, arteries ['l4', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "gene", + "transfer", + "of", + "hirudin" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "gene", + "transfer", + "of", + "hirudin" + ] + }, + "context": { + "val": "cells", + "words": [ + "smooth", + "muscle", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "gene", + "transfer", + "of", + "hirudin" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "carotid", + "arteries" + ] + } + } + ] + }, + { + "PMID": "8612226", + "TEXT": "Activation of plasminogen (Plg) has been proposed to play a role in proteolytic degradation of extracellular matrices in tissue remodeling events, including wound healing. However, there has been no definitive proof of involvement of Plg in such processes. We now report that healing of skin wounds is severely impaired in mice made deficient in Plg by targeted gene disruption. The results demonstrate that Plg is required for normal repair of skin wounds in mice and support the assumption that it also plays a central role in other disease processes involving extracellular matrix degradation, such as cancer invasion.", + "TAG_DATA": [ + "44, skin {'context': 'B-neoplasm'}", + "50, mice {'context': 'B-organism'}", + "52, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "53, in {'perturbing_action': 'I-gene loss-of-function'}", + "54, Plg {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "44, skin ['l0']", + "45, wounds ['l0']", + "50, mice ['l1', 'l2', 'l3']", + "52, deficient ['l1', 'l4', 'l5']", + "53, in ['l2', 'l4', 'l6']", + "54, Plg ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Plg" + ] + } + } + ] + }, + { + "PMID": "8564845", + "TEXT": "Fetal grafts of normal cerebellar tissue were implanted into the cerebellum of Purkinje cell degeneration mutant mice (pcd/pcd), a model of adult-onset recessively inherited cerebello-olivary atrophy, in an attempt at correcting their cellular and motor impairment. Donor cerebellar cells engrafted in the appropriate sites, as evidenced by the pattern of expression of insulin-like growth factor-I (IGF-I) system genes. Bilateral cerebellar grafts led to an improvement of motor behaviors in balance rod tests and in the open field, providing evidence for functional integration into the atrophic mouse cerebellum and underscoring the potential of neural transplantation for counteracting the human cerebellar ataxias.", + "TAG_DATA": [ + "10, cerebellum {'context': 'B-tissue/organ'}", + "12, Purkinje {'perturbing_action': 'B-other'}", + "14, degeneration {'perturbing_action': 'I-gene loss-of-function'}", + "15, mutant {'perturbing_action': 'I-gene loss-of-function'}", + "16, mice {'context': 'B-organism'}", + "17, (pcd/pcd), {'perturbing_action': 'I-other'}", + "36, Donor {'context': 'B-cells'}", + "37, cerebellar {'context': 'I-cells'}", + "38, cells {'context': 'I-cells'}", + "60, grafts {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "4, cerebellar ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "5, tissue ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "10, cerebellum ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "12, Purkinje ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "13, cell ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "14, degeneration ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "15, mutant ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "16, mice ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "17, (pcd/pcd), ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "36, Donor ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "37, cerebellar ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "38, cells ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "59, cerebellar ['l66']", + "60, grafts ['l66']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "cerebellum" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Purkinje", + "(pcd/pcd)," + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "cerebellum" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "degeneration", + "mutant" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Purkinje", + "(pcd/pcd)," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Purkinje", + "(pcd/pcd)," + ] + }, + "context": { + "val": "cells", + "words": [ + "Donor", + "cerebellar", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "degeneration", + "mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "degeneration", + "mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "Donor", + "cerebellar", + "cells" + ] + } + } + ] + }, + { + "PMID": "7489415", + "TEXT": "The regulation of body weight and composition involves input from genes and the environment, demonstrated, for example, by the variable susceptibility of inbred strains of mice to obesity when offered a high-fat diet. The identification of the gene responsible for obesity in the ob/ob mouse provides a new approach to defining links between diet and genetics in the regulation of body weight. The ob gene protein product, leptin, is an adipocyte-derived circulating protein. Administration of recombinant leptin reduces food intake and increases energy expenditure in ob/ob mice, suggesting that it signals to the brain the magnitude of fat stores. Information on the regulation of this protein is limited. In several rodent models of obesity including db/db, fa/fa, yellow (Ay/a) VMH-lesioned, and those induced by gold thioglucose, monosodium glutamate, and transgenic ablation of brown adipose tissue, leptin mRNA expression and the level of circulating leptin are increased, suggesting resistance to one or more of its actions. We have assessed the impact of increased dietary fat on circulating leptin levels in normal FVB mice and FVB mice with transgene-induced ablation of brown adipose tissue. We find that high-fat diet evokes a sustained increase in circulating leptin in both normal and transgenic mice, with leptin levels accurately reflecting the amount of body lipid across a broad range of body fat. However, despite increased leptin levels, animals fed a high-fat diet became obese without decreasing their caloric intake, suggesting that a high content of dietary fat changes the 'set point' for body weight, at least in part by limiting the action of leptin.", + "TAG_DATA": [ + "85, ob/ob {'context': 'B-organism'}", + "86, mice, {'context': 'I-organism'}", + "129, transgenic {'perturbing_action': 'B-gene loss-of-function'}", + "130, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "131, of {'perturbing_action': 'I-gene loss-of-function'}", + "132, brown {'perturbing_action': 'I-gene loss-of-function'}", + "133, adipose {'perturbing_action': 'I-gene loss-of-function'}", + "134, tissue, {'perturbing_action': 'I-gene loss-of-function'}", + "170, FVB {'context': 'B-organism'}", + "171, mice {'context': 'I-organism'}", + "173, FVB {'context': 'B-organism'}", + "174, mice {'context': 'I-organism'}", + "176, transgene-induced {'perturbing_action': 'B-gene loss-of-function'}", + "177, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "178, of {'perturbing_action': 'I-gene loss-of-function'}", + "179, brown {'perturbing_action': 'I-gene loss-of-function'}", + "180, adipose {'perturbing_action': 'I-gene loss-of-function'}", + "181, tissue. {'perturbing_action': 'I-gene loss-of-function'}", + "198, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "199, mice, {'context': 'B-organism'}", + "222, animals {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "85, ob/ob ['l0']", + "86, mice, ['l0']", + "129, transgenic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "130, ablation ['l1', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "131, of ['l2', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "132, brown ['l3', 'l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "133, adipose ['l4', 'l12', 'l19', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37']", + "134, tissue, ['l5', 'l13', 'l20', 'l26', 'l33', 'l38', 'l39', 'l40']", + "170, FVB ['l6', 'l14', 'l21', 'l27', 'l34', 'l38', 'l41', 'l42', 'l43']", + "171, mice ['l7', 'l15', 'l22', 'l28', 'l35', 'l39', 'l41']", + "173, FVB ['l8', 'l16', 'l23', 'l29', 'l36', 'l42', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "174, mice ['l44', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "176, transgene-induced ['l45', 'l52', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "177, ablation ['l46', 'l53', 'l59', 'l66', 'l67', 'l68', 'l69', 'l70']", + "178, of ['l30', 'l47', 'l54', 'l60', 'l66', 'l71', 'l72', 'l73', 'l74']", + "179, brown ['l48', 'l55', 'l61', 'l67', 'l71', 'l75', 'l76', 'l77', 'l78']", + "180, adipose ['l31', 'l49', 'l56', 'l62', 'l68', 'l72', 'l75', 'l79', 'l80', 'l81']", + "181, tissue. ['l9', 'l17', 'l24', 'l32', 'l37', 'l40', 'l43', 'l50', 'l57', 'l63', 'l69', 'l73', 'l76', 'l79', 'l82']", + "198, transgenic ['l64', 'l77', 'l80', 'l83']", + "199, mice, ['l51', 'l58', 'l65', 'l70', 'l74', 'l78', 'l81', 'l82', 'l83']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "transgenic", + "ablation", + "of", + "brown", + "adipose", + "tissue,", + "tissue.", + "transgene-induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "FVB", + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "7489361", + "TEXT": "As a result of bioassay-guided fractionation, betulinic acid, a pentacyclic triterpene, was identified as a melanoma-specific cytotoxic agent. In follow-up studies conducted with athymic mice carrying human melanomas, tumour growth was completely inhibited without toxicity. As judged by a variety of cellular responses, antitumour activity was mediated by the induction of apoptosis. Betulinic acid is inexpensive and available in abundant supply from common natural sources, notably the bark of white birch trees. The compound is currently undergoing preclinical development for the treatment or prevention of malignant melanoma.", + "TAG_DATA": [ + "23, athymic {'context': 'B-organism'}", + "24, mice {'context': 'I-organism'}", + "26, human {'context': 'B-neoplasm'}", + "27, melanomas, {'context': 'I-neoplasm'}", + "28, tumour {'phenotype': 'B-tumour growth'}", + "29, growth {'phenotype': 'I-tumour growth'}", + "32, inhibited {'effect': 'B-negative'}", + "49, induction {'effect': 'B-positive'}", + "51, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "23, athymic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "24, mice ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "26, human ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "27, melanomas, ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "28, tumour ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "29, growth ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "32, inhibited ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "49, induction ['l21']", + "51, apoptosis. ['l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "athymic", + "mice" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumour", + "growth" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "athymic", + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "human", + "melanomas," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumour", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "human", + "melanomas," + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumour", + "growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "7585221", + "TEXT": "We have created a double mutant of the herpes simplex virus (HSV) type 1 (termed G207) with favourable properties for treating human malignant brain tumours: replication-competence in glioblastoma cells (and other dividing cells), attenuated neurovirulence, temperature sensitivity, ganciclovir hypersensitivity, and the presence of an easily detectable histochemical marker. G207 has deletions at both gamma 34.5 (RL1) loci and a lacZ gene insertion inactivating the ICP6 gene (UL39). G207 kills human glioma cells in monolayer cultures. In nude mice harbouring subcutaneous or intracerebral U-87MG gliomas, intraneoplastic inoculation with G207 causes decreased tumour growth and/or prolonged survival. G207 is avirulent upon intracerebral inoculation of mice and HSV-sensitive non-human primates. These results suggest that G207 should be considered for clinical evaluation in the treatment of glioblastomas.", + "TAG_DATA": [ + "69, human {'context': 'B-transformed cells'}", + "70, glioma {'context': 'I-transformed cells'}", + "71, cells {'context': 'I-transformed cells'}", + "73, monolayer {'context': 'B-in vitro'}", + "74, cultures. {'context': 'I-in vitro'}", + "76, nude {'context': 'B-organism'}", + "77, mice {'context': 'I-organism'}", + "83, gliomas, {'context': 'B-neoplasm'}", + "89, decreased {'effect': 'B-negative'}", + "90, tumour {'phenotype': 'B-tumour growth'}", + "91, growth {'phenotype': 'I-tumour growth'}", + "102, mice {'context': 'B-organism'}", + "105, non-human {'context': 'B-organism'}", + "106, primates. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "69, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "70, glioma ['l0', 'l6', 'l7', 'l8', 'l9']", + "71, cells ['l1', 'l6', 'l10', 'l11']", + "73, monolayer ['l2', 'l7', 'l10', 'l12', 'l13', 'l14']", + "74, cultures. ['l3', 'l8', 'l11', 'l12']", + "76, nude ['l4', 'l13', 'l15', 'l16']", + "77, mice ['l5', 'l9', 'l14', 'l15', 'l17']", + "83, gliomas, ['l16', 'l17']", + "89, decreased ['l18', 'l19']", + "90, tumour ['l18', 'l20']", + "91, growth ['l19', 'l20']", + "102, mice ['l21', 'l22']", + "105, non-human ['l21', 'l23']", + "106, primates. ['l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumour", + "growth" + ] + } + } + ] + }, + { + "PMID": "7585187", + "TEXT": "A partial cDNA sequence for the gene linked to the von Hippel-Lindau (VHL) syndrome was reported in 1993. Mutation or loss of both VHL alleles has been documented in sporadic renal cell carcinomas and in the neoplasms that arise in von Hippel-Lindau kindreds. We have determined that the protein product of the VHL gene is an approximately 30 kilodalton cytoplasmic protein. The renal carcinoma cell line 786-O is known to harbour a VHL mutation and, as shown here, fails to produce a wild-type VHL protein. Reintroduction of wild-type, but not mutant, VHL into these cells had no demonstrable effect on their growth in vitro but inhibited their ability to form tumours in nude mice.", + "TAG_DATA": [ + "62, renal {'context': 'B-transformed cells'}", + "63, carcinoma {'context': 'I-transformed cells'}", + "64, cell {'context': 'I-transformed cells'}", + "65, line {'context': 'I-transformed cells'}", + "66, 786-O {'context': 'I-transformed cells'}", + "85, Reintroduction {'perturbing_action': 'B-gene gain-of-function'}", + "86, of {'perturbing_action': 'I-gene gain-of-function'}", + "87, wild-type, {'perturbing_action': 'I-gene gain-of-function'}", + "91, VHL {'perturbing_action': 'I-gene gain-of-function'}", + "94, cells {'context': 'B-cells'}", + "102, in {'context': 'B-in vitro'}", + "103, vitro {'context': 'I-in vitro'}", + "105, inhibited {'effect': 'B-negative'}", + "107, ability {'effect': 'I-negative'}", + "109, form {'phenotype': 'B-tumourigenesis'}", + "110, tumours {'phenotype': 'I-tumourigenesis'}", + "112, nude {'context': 'B-organism'}", + "113, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "62, renal ['l0', 'l1', 'l2', 'l3']", + "63, carcinoma ['l0', 'l4', 'l5', 'l6']", + "64, cell ['l1', 'l4', 'l7', 'l8']", + "65, line ['l2', 'l5', 'l7', 'l9']", + "66, 786-O ['l3', 'l6', 'l8', 'l9']", + "85, Reintroduction ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "86, of ['l10', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "87, wild-type, ['l11', 'l22', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "91, VHL ['l12', 'l23', 'l33', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "94, cells ['l13', 'l24', 'l34', 'l43', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "102, in ['l14', 'l25', 'l35', 'l44', 'l52', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "103, vitro ['l15', 'l26', 'l36', 'l45', 'l53', 'l60', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "105, inhibited ['l16', 'l27', 'l37', 'l46', 'l54', 'l61', 'l67', 'l73', 'l74', 'l75', 'l76', 'l77']", + "107, ability ['l17', 'l28', 'l38', 'l47', 'l55', 'l62', 'l68', 'l73', 'l78', 'l79', 'l80', 'l81']", + "109, form ['l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l69', 'l74', 'l78', 'l82', 'l83', 'l84']", + "110, tumours ['l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l75', 'l79', 'l82', 'l85', 'l86']", + "112, nude ['l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l83', 'l85', 'l87']", + "113, mice. ['l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l86', 'l87']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reintroduction", + "of", + "wild-type,", + "VHL" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reintroduction", + "of", + "wild-type,", + "VHL" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reintroduction", + "of", + "wild-type,", + "VHL" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "ability" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reintroduction", + "of", + "wild-type,", + "VHL" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumours" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reintroduction", + "of", + "wild-type,", + "VHL" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "ability" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumours" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "ability" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumours" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "ability" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumours" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "ability" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumours" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice." + ] + } + } + ] + }, + { + "PMID": "7585182", + "TEXT": "For Ras oncoproteins to transform mammalian cells, they must be post-translationally modified with a farnesyl group in a reaction catalysed by the enzyme farnesyl-protein transferase (FPTase). Inhibitors of FPTase have therefore been proposed as anti-cancer agents. We show that L-744,832, which mimics the CaaX motif to which the farnesyl group is added, is a potent and selective inhibitor of FPTase. In MMTV-v-Ha-ras mice bearing palpable tumours, daily administration of L-744,832 caused tumour regression. Following cessation of treatment, tumours reappeared, the majority of which regressed upon retreatment. No systemic toxicity was found upon necropsy of L-744,832-treated mice. This first demonstration of anti-FPTase-mediated tumour regression suggests that FPTase inhibitors may be safe and effective anti-tumour agents in some cancers.", + "TAG_DATA": [ + "61, MMTV-v-Ha-ras {'perturbing_action': 'B-other'}", + "62, mice {'context': 'B-organism'}", + "64, palpable {'context': 'B-neoplasm'}", + "65, tumours, {'context': 'I-neoplasm'}", + "70, caused {'effect': 'B-positive'}", + "71, tumour {'phenotype': 'B-tumour regression'}", + "72, regression. {'phenotype': 'I-tumour regression'}", + "77, tumours {'phenotype': 'B-tumour regression'}", + "78, reappeared, {'phenotype': 'I-tumour regression'}", + "95, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "61, MMTV-v-Ha-ras ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "62, mice ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "64, palpable ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "65, tumours, ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "70, caused ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "71, tumour ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "72, regression. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "77, tumours ['l21']", + "78, reappeared, ['l21']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "MMTV-v-Ha-ras" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "MMTV-v-Ha-ras" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "palpable", + "tumours," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "MMTV-v-Ha-ras" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "MMTV-v-Ha-ras" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumour", + "regression." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumour", + "regression." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "palpable", + "tumours," + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "palpable", + "tumours," + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumour", + "regression." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumour", + "regression." + ] + } + } + ] + }, + { + "PMID": "7585143", + "TEXT": "To investigate how overexpression of MAD, an antagonist of MYC oncogenes influences the malignant phenotype of human cancer cells, an adenovirus vector system was used to transfer the human MAD gene (AdMAD) into human astrocytoma cells. Decreased growth potential of AdMAD-infected cells was evidenced by a decrease in [3H]thymidine incorporation, an increase in cell doubling time and alteration of cell-cycle distribution. Diminished malignant potential of AdMAD-infected cells was manifested by their loss of anchorage-independent growth in soft agar and by their inability, in general, to induce tumorigenesis in a xenograft animal model. These studies indicate that adenovirus constructs encoding MAD dramatically inhibit the proliferation and tumorigenicity of human astrocytoma cells and support the use of MAD for gene therapy of human tumours.", + "TAG_DATA": [ + "33, human {'context': 'B-transformed cells'}", + "34, astrocytoma {'context': 'I-transformed cells'}", + "35, cells. {'context': 'I-transformed cells'}", + "41, cells {'context': 'B-cells'}", + "53, cell {'context': 'B-cells'}", + "66, cells {'context': 'B-cells'}", + "71, loss {'effect': 'B-negative'}", + "81, inability, {'effect': 'B-negative'}", + "84, to {'effect': 'I-no effect'}", + "85, induce {'effect': 'B-positive'}", + "86, tumorigenesis {'phenotype': 'B-tumourigenesis'}", + "89, xenograft {'context': 'B-xenograft'}", + "90, animal {'context': 'I-xenograft'}", + "91, model. {'context': 'I-xenograft'}", + "101, inhibit {'effect': 'B-negative'}", + "103, proliferation {'phenotype': 'B-proliferation'}", + "105, tumorigenicity {'phenotype': 'B-tumourigenesis'}", + "107, human {'context': 'B-transformed cells'}", + "108, astrocytoma {'context': 'I-transformed cells'}", + "109, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "33, human ['l0', 'l1', 'l2', 'l3']", + "34, astrocytoma ['l0', 'l4', 'l5', 'l6']", + "35, cells. ['l1', 'l4', 'l7']", + "41, cells ['l2', 'l5', 'l7', 'l8']", + "53, cell ['l3', 'l6', 'l8']", + "66, cells ['l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "71, loss ['l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "81, inability, ['l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "84, to ['l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "85, induce ['l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "86, tumorigenesis ['l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "89, xenograft ['l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "90, animal ['l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "91, model. ['l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "101, inhibit ['l45', 'l46', 'l47', 'l48', 'l49']", + "103, proliferation ['l45', 'l50', 'l51', 'l52', 'l53']", + "105, tumorigenicity ['l46', 'l50', 'l54', 'l55', 'l56']", + "107, human ['l47', 'l51', 'l54', 'l57', 'l58']", + "108, astrocytoma ['l48', 'l52', 'l55', 'l57', 'l59']", + "109, cells ['l49', 'l53', 'l56', 'l58', 'l59']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss", + "inability," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "to" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "loss", + "inability,", + "inhibit" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis", + "tumorigenicity" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "loss", + "inability," + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "animal", + "model." + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "to" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "to" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "animal", + "model." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "animal", + "model." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "animal", + "model." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "astrocytoma", + "cells" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "astrocytoma", + "cells" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "astrocytoma", + "cells" + ] + } + } + ] + }, + { + "PMID": "7585090", + "TEXT": "Previous work from our laboratory demonstrated that selenium deficiency in the mouse allows a normally benign (amyocarditic) cloned and sequenced Coxackievirus to cause significant heart damage. Furthermore, Coxsackievirus recovered from the hearts of selenium-deficient mice inoculated into selenium-adequate mice still induced significant heart damage, suggesting that the amyocarditic Coxsackievirus had mutated to a virulent phenotype. Here we report that sequence analysis revealed six nucleotide changes between the virulent virus recovered from the selenium-deficient host and the avirulent input virus. These nucleotide changes are consistent with known differences in base composition between virulent and avirulent strains of Coxsackievirus. To the best of our knowledge, this is the first report of a specific nutritional deficiency driving changes in a viral genome, permitting an avirulent virus to acquire virulence due to genetic mutation.", + "TAG_DATA": [ + "31, hearts {'context': 'B-tissue/organ'}", + "33, selenium-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "34, mice {'context': 'B-organism'}", + "38, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "31, hearts ['l0', 'l1']", + "33, selenium-deficient ['l0', 'l2']", + "34, mice ['l1', 'l2', 'l3']", + "38, mice ['l3']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "hearts" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selenium-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selenium-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "7584951", + "TEXT": "We report the results of a double-blind, placebo-controlled trial in nine cystic fibrosis (CF) subjects receiving cationic liposome complexed with a complementary DNA encoding the CF transmembrane conductance regulator (CFTR), and six CF subjects receiving only liposome to the nasal epithelium. No adverse clinical effects were seen and nasal biopsies showed no histological or immuno-histological changes. A partial restoration of the deficit between CF and non-CF subjects of 20% was seen for the response to low Cl- perfusion following CFTR cDNA administration. This was maximal around day three and had reverted to pretreatment values by day seven. In some cases the response to low Cl- was within the range for non-CF subjects. Plasmid DNA and transgene-derived RNA were detected in the majority of treated subjects. Although these data are encouraging, it is likely that transfection efficiency and the duration of expression will need to be increased for therapeutic benefit.", + "TAG_DATA": [ + "11, cystic {'context': 'B-organism'}", + "12, fibrosis {'context': 'I-organism'}", + "13, (CF) {'context': 'I-organism'}", + "14, subjects {'context': 'I-organism'}", + "32, CF {'context': 'B-organism'}", + "33, subjects {'context': 'I-organism'}", + "63, CF {'context': 'B-patient'}", + "65, non-CF {'context': 'I-cells'}", + "66, subjects {'context': 'I-organism'}", + "79, CFTR {'perturbing_action': 'B-rnai/knockdown'}", + "80, cDNA {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "11, cystic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "12, fibrosis ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "13, (CF) ['l1', 'l8', 'l15', 'l16', 'l17']", + "14, subjects ['l2', 'l9', 'l15']", + "32, CF ['l3', 'l10', 'l16', 'l18', 'l19', 'l20', 'l21']", + "33, subjects ['l4', 'l11', 'l17', 'l18', 'l22', 'l23', 'l24']", + "63, CF ['l5', 'l12', 'l19', 'l22', 'l25', 'l26', 'l27', 'l28']", + "65, non-CF ['l6', 'l13', 'l20', 'l23', 'l25', 'l29', 'l30', 'l31']", + "66, subjects ['l7', 'l14', 'l21', 'l24', 'l26', 'l29', 'l32', 'l33']", + "79, CFTR ['l27', 'l30', 'l32', 'l34']", + "80, cDNA ['l28', 'l31', 'l33', 'l34']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "patient", + "words": [ + "CF" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "CFTR", + "cDNA" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "non-CF" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "CFTR", + "cDNA" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "subjects" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "CFTR", + "cDNA" + ] + } + } + ] + }, + { + "PMID": "18836458", + "TEXT": "Pauci-immune focal necrotizing glomerulonephritis (FNGN) is a severe inflammatory disease associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA). Here we characterize autoantibodies to lysosomal membrane protein-2 (LAMP-2) and show that they are a new ANCA subtype present in almost all individuals with FNGN. Consequently, its prevalence is nearly twice that of the classical ANCAs that recognize myeloperoxidase or proteinase-3. Furthermore, antibodies to LAMP-2 cause pauci-immune FNGN when injected into rats, and a monoclonal antibody to human LAMP-2 (H4B4) induces apoptosis of human microvascular endothelium in vitro. The autoantibodies in individuals with pauci-immune FNGN commonly recognize a human LAMP-2 epitope (designated P(41-49)) with 100% homology to the bacterial adhesin FimH, with which they cross-react. Rats immunized with FimH develop pauci-immune FNGN and also develop antibodies to rat and human LAMP-2. Finally, we show that infections with fimbriated pathogens are common before the onset of FNGN. Thus, FimH-triggered autoimmunity to LAMP-2 provides a previously undescribed clinically relevant molecular mechanism for the development of pauci-immune FNGN.", + "TAG_DATA": [ + "69, rats, {'context': 'B-organism'}", + "72, monoclonal {'perturbing_action': 'B-other'}", + "74, to {'perturbing_action': 'I-rnai/knockdown'}", + "75, human {'perturbing_action': 'I-other'}", + "76, LAMP-2 {'perturbing_action': 'I-other'}", + "77, (H4B4) {'perturbing_action': 'I-rnai/knockdown'}", + "78, induces {'effect': 'B-positive'}", + "79, apoptosis {'phenotype': 'B-apoptosis'}", + "81, human {'context': 'B-cells'}", + "82, microvascular {'context': 'I-cells'}", + "83, endothelium {'context': 'I-cells'}", + "84, in {'context': 'B-in vitro'}", + "85, vitro. {'context': 'I-in vitro'}", + "113, Rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "72, monoclonal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "73, antibody ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "74, to ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "75, human ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "76, LAMP-2 ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "77, (H4B4) ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "78, induces ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "79, apoptosis ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "81, human ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "82, microvascular ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "83, endothelium ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "84, in ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "85, vitro. ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "monoclonal", + "human", + "LAMP-2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "monoclonal", + "human", + "LAMP-2" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "monoclonal", + "human", + "LAMP-2" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "microvascular", + "endothelium" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "monoclonal", + "human", + "LAMP-2" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "to", + "(H4B4)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "to", + "(H4B4)" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "to", + "(H4B4)" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "microvascular", + "endothelium" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "to", + "(H4B4)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "microvascular", + "endothelium" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "microvascular", + "endothelium" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "16155579", + "TEXT": "Obesity-related disorders are associated with the development of ischemic heart disease. Adiponectin is a circulating adipose-derived cytokine that is downregulated in obese individuals and after myocardial infarction. Here, we examine the role of adiponectin in myocardial remodeling in response to acute injury. Ischemia-reperfusion in adiponectin-deficient (APN-KO) mice resulted in increased myocardial infarct size, myocardial apoptosis and tumor necrosis factor (TNF)-alpha expression compared with wild-type mice. Administration of adiponectin diminished infarct size, apoptosis and TNF-alpha production in both APN-KO and wild-type mice. In cultured cardiac cells, adiponectin inhibited apoptosis and TNF-alpha production. Dominant negative AMP-activated protein kinase (AMPK) reversed the inhibitory effects of adiponectin on apoptosis but had no effect on the suppressive effect of adiponectin on TNF-alpha production. Adiponectin induced cyclooxygenase (COX)-2-dependent synthesis of prostaglandin E(2) in cardiac cells, and COX-2 inhibition reversed the inhibitory effects of adiponectin on TNF-alpha production and infarct size. These data suggest that adiponectin protects the heart from ischemia-reperfusion injury through both AMPK- and COX-2-dependent mechanisms.", + "TAG_DATA": [ + "44, adiponectin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "45, (APN-KO) {'perturbing_action': 'I-gene loss-of-function'}", + "46, mice {'context': 'B-organism'}", + "54, apoptosis {'phenotype': 'B-apoptosis'}", + "64, mice. {'context': 'B-organism'}", + "71, apoptosis {'phenotype': 'B-apoptosis'}", + "77, APN-KO {'perturbing_action': 'B-gene loss-of-function'}", + "80, mice. {'context': 'B-organism'}", + "82, cultured {'context': 'B-cells'}", + "83, cardiac {'context': 'I-cells'}", + "84, cells, {'context': 'I-cells'}", + "86, inhibited {'effect': 'B-negative'}", + "87, apoptosis {'phenotype': 'B-apoptosis'}", + "91, Dominant {'perturbing_action': 'B-rnai/knockdown'}", + "99, inhibitory {'effect': 'B-negative'}", + "104, apoptosis {'phenotype': 'B-apoptosis'}", + "127, cardiac {'context': 'B-cells'}", + "128, cells, {'context': 'I-cells'}", + "130, COX-2 {'perturbing_action': 'B-pharmacological inhibition'}", + "131, inhibition {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "44, adiponectin-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "45, (APN-KO) ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "46, mice ['l1', 'l6', 'l11', 'l12', 'l13']", + "53, myocardial ['l2', 'l7', 'l11', 'l14', 'l15']", + "54, apoptosis ['l3', 'l8', 'l12', 'l14', 'l16']", + "64, mice. ['l4', 'l9', 'l13', 'l15', 'l16']", + "71, apoptosis ['l5', 'l10']", + "77, APN-KO ['l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "80, mice. ['l17', 'l23']", + "82, cultured ['l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "83, cardiac ['l19', 'l24', 'l29', 'l30', 'l31', 'l32', 'l33']", + "84, cells, ['l20', 'l23', 'l25', 'l29', 'l34', 'l35', 'l36']", + "86, inhibited ['l21', 'l26', 'l30', 'l34', 'l37', 'l38', 'l39']", + "87, apoptosis ['l22', 'l27', 'l31', 'l35', 'l37', 'l40']", + "91, Dominant ['l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "92, negative ['l41', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "93, AMP-activated ['l42', 'l50', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "94, protein ['l43', 'l51', 'l58', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "95, kinase ['l44', 'l52', 'l59', 'l65', 'l71', 'l72', 'l73', 'l74', 'l75']", + "96, (AMPK) ['l45', 'l53', 'l60', 'l66', 'l71', 'l76', 'l77', 'l78', 'l79']", + "99, inhibitory ['l32', 'l38', 'l46', 'l54', 'l61', 'l67', 'l72', 'l76', 'l80', 'l81', 'l82']", + "104, apoptosis ['l28', 'l33', 'l36', 'l39', 'l40', 'l47', 'l55', 'l62', 'l68', 'l73', 'l77', 'l80', 'l83']", + "127, cardiac ['l48', 'l56', 'l63', 'l69', 'l74', 'l78', 'l81', 'l84']", + "128, cells, ['l49', 'l57', 'l64', 'l70', 'l75', 'l79', 'l82', 'l83', 'l84']", + "130, COX-2 ['l85']", + "131, inhibition ['l85']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adiponectin-deficient", + "(APN-KO)", + "APN-KO" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adiponectin-deficient", + "(APN-KO)", + "APN-KO" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "APN-KO" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "cardiac", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "APN-KO" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "cardiac", + "cells," + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "inhibitory" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "cardiac", + "cells," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "inhibitory" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Dominant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibitory" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Dominant" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Dominant" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiac", + "cells," + ] + } + } + ] + }, + { + "PMID": "32451497", + "TEXT": "Common germline variants of the APOE gene are major risk modifiers of neurodegenerative and atherosclerotic diseases1-3, but their effect on cancer outcome is poorly defined. Here we report that, in a reversal of their effect on Alzheimer's disease, the APOE4 and APOE2 variants confer favorable and poor outcomes in melanoma, respectively. Mice expressing the human APOE4 allele exhibited reduced melanoma progression and metastasis relative to APOE2 mice. APOE4 mice exhibited enhanced anti-tumor immune activation relative to APOE2 mice, and T cell depletion experiments showed that the effect of APOE genotype on melanoma progression was mediated by altered anti-tumor immunity. Consistently, patients with melanoma carrying the APOE4 variant experienced improved survival in comparison to carriers of APOE2. Notably, APOE4 mice also showed improved outcomes under PD1 immune checkpoint blockade relative to APOE2 mice, and patients carrying APOE4 experienced improved anti-PD1 immunotherapy survival after progression on frontline regimens. Finally, enhancing APOE expression via pharmacologic activation of liver X receptors, previously shown to boost anti-tumor immunity4, exhibited therapeutic efficacy in APOE4 mice but not in APOE2 mice. These findings demonstrate that pre-existing hereditary genetics can impact progression and survival outcomes of a future malignancy and warrant prospective investigation of APOE genotype as a biomarker for melanoma outcome and therapeutic response.", + "TAG_DATA": [ + "51, Mice {'context': 'B-organism'}", + "52, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "53, the {'perturbing_action': 'I-gene gain-of-function'}", + "54, human {'perturbing_action': 'I-gene gain-of-function'}", + "55, APOE4 {'perturbing_action': 'I-other'}", + "56, allele {'perturbing_action': 'I-gene gain-of-function'}", + "58, reduced {'effect': 'B-negative'}", + "59, melanoma {'context': 'B-neoplasm'}", + "62, metastasis {'phenotype': 'B-metastasis'}", + "68, mice {'context': 'B-organism'}", + "91, melanoma {'context': 'B-neoplasm'}", + "100, patients {'context': 'B-patient'}", + "102, melanoma {'context': 'B-neoplasm'}", + "105, APOE4 {'perturbing_action': 'I-other'}", + "106, variant {'perturbing_action': 'I-other'}", + "118, mice {'context': 'B-organism'}", + "133, patients {'context': 'B-patient'}", + "147, enhancing {'perturbing_action': 'B-gene gain-of-function'}", + "148, APOE {'perturbing_action': 'I-gene gain-of-function'}", + "149, expression {'perturbing_action': 'I-gene gain-of-function'}", + "168, mice {'context': 'B-organism'}", + "173, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "51, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "52, expressing ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "53, the ['l1', 'l8', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "54, human ['l2', 'l9', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "55, APOE4 ['l3', 'l10', 'l18', 'l25', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "56, allele ['l4', 'l11', 'l19', 'l26', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "58, reduced ['l5', 'l12', 'l20', 'l27', 'l33', 'l38', 'l43', 'l44']", + "59, melanoma ['l6', 'l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l45']", + "62, metastasis ['l7', 'l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l45']", + "68, mice ['l15', 'l23', 'l30', 'l36', 'l41', 'l46']", + "91, melanoma ['l16', 'l24', 'l31', 'l37', 'l42', 'l46']", + "100, patients ['l47', 'l48', 'l49']", + "102, melanoma ['l47', 'l50', 'l51']", + "105, APOE4 ['l48', 'l50', 'l52']", + "106, variant ['l49', 'l51', 'l52']", + "147, enhancing ['l53', 'l54', 'l55', 'l56']", + "148, APOE ['l53', 'l57', 'l58', 'l59']", + "149, expression ['l54', 'l57', 'l60', 'l61']", + "168, mice ['l55', 'l58', 'l60', 'l62']", + "173, mice. ['l56', 'l59', 'l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice", + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "the", + "human", + "allele", + "enhancing", + "APOE", + "expression" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "APOE4" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "the", + "human", + "allele" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "the", + "human", + "allele" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "melanoma" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "the", + "human", + "allele" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "APOE4" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "APOE4", + "variant" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "melanoma" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "APOE4" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "melanoma" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "melanoma" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "APOE4", + "variant" + ] + } + } + ] + }, + { + "PMID": "32231295", + "TEXT": "The National Institute of Mental Health (NIMH) 'fast-fail' approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia with a POM study determining whether robust target engagement favorably impacts the brain circuitry hypothesized to mediate clinical effects. Here we report the results from a multicenter, 8-week, double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder (selective KOR antagonist (JNJ-67953964, 10 mg; n = 45) and placebo (n = 44)). JNJ-67953964 significantly increased functional magnetic resonance imaging (fMRI) ventral striatum activation during reward anticipation (primary outcome) as compared to placebo (baseline-adjusted mean: JNJ-67953964, 0.72 (s.d. = 0.67); placebo, 0.33 (s.d. = 0.68); F(1,86) = 5.58, P < 0.01; effect size = 0.58 (95% confidence interval, 0.13-0.99)). JNJ-67953964, generally well tolerated, was not associated with any serious adverse events. This study supports proceeding with assessment of the clinical impact of target engagement and serves as a model for implementing the 'fast-fail' approach.", + "TAG_DATA": [ + "78, patients {'context': 'B-patient'}", + "88, KOR {'perturbing_action': 'I-pharmacological inhibition'}", + "89, antagonist {'perturbing_action': 'I-pharmacological inhibition'}", + "90, (JNJ-67953964, {'perturbing_action': 'I-pharmacological inhibition'}", + "91, 10 mg; {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "78, patients ['l0', 'l1', 'l2', 'l3']", + "88, KOR ['l0', 'l4', 'l5', 'l6']", + "89, antagonist ['l1', 'l4', 'l7', 'l8']", + "90, (JNJ-67953964, ['l2', 'l5', 'l7', 'l9']", + "91, 10 mg; ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "KOR", + "antagonist", + "(JNJ-67953964,", + "10 mg;" + ] + } + } + ] + }, + { + "PMID": "32094925", + "TEXT": "Retinal gene therapy has shown great promise in treating retinitis pigmentosa (RP), a primary photoreceptor degeneration that leads to severe sight loss in young people. In the present study, we report the first-in-human phase 1/2, dose-escalation clinical trial for X-linked RP caused by mutations in the RP GTPase regulator (RPGR) gene in 18 patients over up to 6 months of follow-up (https://clinicaltrials.gov/: NCT03116113). The primary outcome of the study was safety, and secondary outcomes included visual acuity, microperimetry and central retinal thickness. Apart from steroid-responsive subretinal inflammation in patients at the higher doses, there were no notable safety concerns after subretinal delivery of an adeno-associated viral vector encoding codon-optimized human RPGR (AAV8-coRPGR), meeting the pre-specified primary endpoint. Visual field improvements beginning at 1 month and maintained to the last point of follow-up were observed in six patients.", + "TAG_DATA": [ + "43, mutations {'perturbing_action': 'B-other'}", + "44, in {'perturbing_action': 'I-other'}", + "45, the {'perturbing_action': 'I-other'}", + "46, RP {'perturbing_action': 'I-other'}", + "47, GTPase {'perturbing_action': 'I-other'}", + "48, regulator {'perturbing_action': 'I-other'}", + "49, (RPGR) {'perturbing_action': 'I-other'}", + "50, gene {'perturbing_action': 'I-other'}", + "53, patients {'context': 'B-patient'}", + "87, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "39, X-linked ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "43, mutations ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "44, in ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "45, the ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "46, RP ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "47, GTPase ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "48, regulator ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "49, (RPGR) ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "50, gene ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "53, patients ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutations", + "in", + "the", + "RP", + "GTPase", + "regulator", + "(RPGR)", + "gene" + ] + }, + "context": { + "val": "patient", + "words": [ + "patients" + ] + } + } + ] + }, + { + "PMID": "32094924", + "TEXT": "Transmembrane protein 30A (TMEM30A) maintains the asymmetric distribution of phosphatidylserine, an integral component of the cell membrane and 'eat-me' signal recognized by macrophages. Integrative genomic and transcriptomic analysis of diffuse large B-cell lymphoma (DLBCL) from the British Columbia population-based registry uncovered recurrent biallelic TMEM30A loss-of-function mutations, which were associated with a favorable outcome and uniquely observed in DLBCL. Using TMEM30A-knockout systems, increased accumulation of chemotherapy drugs was observed in TMEM30A-knockout cell lines and TMEM30A-mutated primary cells, explaining the improved treatment outcome. Furthermore, we found increased tumor-associated macrophages and an enhanced effect of anti-CD47 blockade limiting tumor growth in TMEM30A-knockout models. By contrast, we show that TMEM30A loss-of-function increases B-cell signaling following antigen stimulation-a mechanism conferring selective advantage during B-cell lymphoma development. Our data highlight a multifaceted role for TMEM30A in B-cell lymphomagenesis, and characterize intrinsic and extrinsic vulnerabilities of cancer cells that can be therapeutically exploited.", + "TAG_DATA": [ + "59, TMEM30A-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "69, TMEM30A-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "70, cell {'context': 'B-cells'}", + "71, lines {'context': 'I-cells'}", + "73, TMEM30A-mutated {'perturbing_action': 'B-other'}", + "74, primary {'context': 'B-cells'}", + "75, cells, {'context': 'I-cells'}", + "85, tumor-associated {'context': 'B-cells'}", + "86, macrophages {'context': 'I-cells'}", + "94, limiting {'effect': 'B-negative'}", + "95, tumor {'phenotype': 'B-tumour growth'}", + "96, growth {'phenotype': 'I-tumour growth'}", + "98, TMEM30A-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "99, models. {'context': 'B-neoplasm'}", + "105, TMEM30A {'perturbing_action': 'B-gene loss-of-function'}", + "106, loss-of-function {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "59, TMEM30A-knockout ['l0', 'l1', 'l2', 'l3', 'l4']", + "69, TMEM30A-knockout ['l0', 'l5', 'l6', 'l7', 'l8']", + "70, cell ['l1', 'l5', 'l9']", + "71, lines ['l2', 'l6', 'l9']", + "73, TMEM30A-mutated ['l10', 'l11', 'l12']", + "74, primary ['l3', 'l7', 'l10', 'l13']", + "75, cells, ['l4', 'l8', 'l11', 'l13']", + "85, tumor-associated ['l14', 'l15', 'l16', 'l17', 'l18']", + "86, macrophages ['l12', 'l14', 'l19', 'l20', 'l21']", + "94, limiting ['l15', 'l19', 'l22', 'l23', 'l24', 'l25']", + "95, tumor ['l16', 'l20', 'l22', 'l26', 'l27', 'l28']", + "96, growth ['l17', 'l21', 'l23', 'l26', 'l29', 'l30']", + "98, TMEM30A-knockout ['l24', 'l27', 'l29', 'l31']", + "99, models. ['l18', 'l25', 'l28', 'l30', 'l31']", + "105, TMEM30A ['l32']", + "106, loss-of-function ['l32']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TMEM30A-knockout" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "lines", + "primary", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "TMEM30A-mutated" + ] + }, + "context": { + "val": "cells", + "words": [ + "primary", + "cells,", + "macrophages" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "tumor-associated", + "macrophages" + ] + }, + "effect": { + "val": "negative", + "words": [ + "limiting" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "tumor-associated", + "macrophages" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limiting" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limiting" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TMEM30A-knockout" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limiting" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TMEM30A-knockout" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TMEM30A-knockout" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models." + ] + } + } + ] + }, + { + "PMID": "31873309", + "TEXT": "Immune checkpoint therapy with anti-CTLA-4 and anti-PD-1/PD-L1 has revolutionized the treatment of many solid tumors. However, the clinical efficacy of immune checkpoint therapy is limited to a subset of patients with specific tumor types1,2. Multiple clinical trials with combinatorial immune checkpoint strategies are ongoing; however, the mechanistic rationale for tumor-specific targeting of immune checkpoints is elusive. To garner an insight into tumor-specific immunomodulatory targets, we analyzed 94 patients representing five different cancer types, including those that respond relatively well to immune checkpoint therapy and those that do not, such as glioblastoma multiforme, prostate cancer and colorectal cancer. Through mass cytometry and single-cell RNA sequencing, we identified a unique population of CD73hi macrophages in glioblastoma multiforme that persists after anti-PD-1 treatment. To test if targeting CD73 would be important for a successful combination strategy in glioblastoma multiforme, we performed reverse translational studies using CD73-/- mice. We found that the absence of CD73 improved survival in a murine model of glioblastoma multiforme treated with anti-CTLA-4 and anti-PD-1. Our data identified CD73 as a specific immunotherapeutic target to improve antitumor immune responses to immune checkpoint therapy in glioblastoma multiforme and demonstrate that comprehensive human and reverse translational studies can be used for rational design of combinatorial immune checkpoint strategies.", + "TAG_DATA": [ + "142, CD73-/- {'perturbing_action': 'B-gene loss-of-function'}", + "143, mice. {'context': 'B-organism'}", + "148, absence {'perturbing_action': 'B-gene loss-of-function'}", + "149, of {'perturbing_action': 'I-gene loss-of-function'}", + "150, CD73 {'perturbing_action': 'I-gene loss-of-function'}", + "155, murine {'context': 'B-organism'}", + "156, model {'context': 'I-neoplasm'}", + "157, of {'context': 'I-neoplasm'}", + "158, glioblastoma {'context': 'I-neoplasm'}", + "159, multiforme {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "142, CD73-/- ['l0']", + "143, mice. ['l0']", + "148, absence ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "149, of ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "150, CD73 ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "155, murine ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "156, model ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "157, of ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "158, glioblastoma ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "159, multiforme ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD73-/-", + "absence", + "of", + "CD73" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "murine" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "CD73" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "model", + "of", + "glioblastoma", + "multiforme" + ] + } + } + ] + }, + { + "PMID": "31359001", + "TEXT": "In response to various stimuli, vascular smooth muscle cells (SMCs) can de-differentiate, proliferate and migrate in a process known as phenotypic modulation. However, the phenotype of modulated SMCs in vivo during atherosclerosis and the influence of this process on coronary artery disease (CAD) risk have not been clearly established. Using single-cell RNA sequencing, we comprehensively characterized the transcriptomic phenotype of modulated SMCs in vivo in atherosclerotic lesions of both mouse and human arteries and found that these cells transform into unique fibroblast-like cells, termed 'fibromyocytes', rather than into a classical macrophage phenotype. SMC-specific knockout of TCF21-a causal CAD gene-markedly inhibited SMC phenotypic modulation in mice, leading to the presence of fewer fibromyocytes within lesions as well as within the protective fibrous cap of the lesions. Moreover, TCF21 expression was strongly associated with SMC phenotypic modulation in diseased human coronary arteries, and higher levels of TCF21 expression were associated with decreased CAD risk in human CAD-relevant tissues. These results establish a protective role for both TCF21 and SMC phenotypic modulation in this disease.", + "TAG_DATA": [ + "61, SMCs {'context': 'B-cells'}", + "62, in {'context': 'B-in vivo'}", + "63, vivo {'context': 'I-in vivo'}", + "69, mouse {'context': 'B-tissue/organ'}", + "70, and {'context': 'I-tissue/organ'}", + "71, human {'context': 'I-tissue/organ'}", + "72, arteries {'context': 'I-tissue/organ'}", + "92, SMC-specific {'perturbing_action': 'B-gene loss-of-function'}", + "93, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "94, of {'perturbing_action': 'I-gene loss-of-function'}", + "95, TCF21-a {'perturbing_action': 'I-gene loss-of-function'}", + "100, SMC {'context': 'B-cells'}", + "104, mice, {'context': 'B-organism'}", + "111, fibromyocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "61, SMCs ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "62, in ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "63, vivo ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "69, mouse ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "70, and ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "71, human ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "72, arteries ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "92, SMC-specific ['l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "93, knockout ['l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "94, of ['l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "95, TCF21-a ['l23', 'l28', 'l32', 'l36', 'l37', 'l38']", + "100, SMC ['l24', 'l29', 'l33', 'l36', 'l39', 'l40']", + "104, mice, ['l25', 'l30', 'l34', 'l37', 'l39', 'l41']", + "111, fibromyocytes ['l26', 'l31', 'l35', 'l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SMC-specific", + "knockout", + "of", + "TCF21-a" + ] + }, + "context": { + "val": "cells", + "words": [ + "SMC", + "fibromyocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SMC-specific", + "knockout", + "of", + "TCF21-a" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "31285633", + "TEXT": "The ability to safely control transgene expression with simple synthetic gene switches is critical for effective gene- and cell-based therapies. In the present study, the signaling pathway controlled by human transient receptor potential (TRP) melastatin 8 (hTRPM8), a TRP channel family member1, is harnessed to control transgene expression. Human TRPM8 signaling is stimulated by menthol, an innocuous, natural, cooling compound, or by exposure to a cool environment (15-18 °C). By functionally linking hTRPM8-induced signaling to a synthetic promoter containing elements that bind nuclear factor of activated T cells, a synthetic gene circuit was designed that can be adjusted by exposure to either a cool environment or menthol. It was shown that this gene switch is functional in various cell types and human primary cells, as well as in mice implanted with engineered cells. In response to transdermal delivery of menthol, microencapsulated cell implants harboring this gene circuit, coupled to expression of either of two therapeutic proteins, insulin or a modified, activin type IIB, receptor ligand trap protein (mActRIIBECD-hFc), could alleviate hyperglycemia in alloxan-treated mice (a model of type 1 diabetes) or reverse muscle atrophy in dexamethasone-treated mice (a model of muscle wasting), respectively. This fully human-derived orthogonal transgene switch should be amenable to a wide range of clinical applications.", + "TAG_DATA": [ + "117, cell {'context': 'B-cells'}", + "118, types {'context': 'I-cells'}", + "120, human {'context': 'B-cells'}", + "121, primary {'context': 'I-cells'}", + "122, cells, {'context': 'I-cells'}", + "127, mice {'context': 'B-organism'}", + "172, mice {'context': 'B-organism'}", + "173, (a {'context': 'B-organism'}", + "180, reverse {'effect': 'B-negative'}", + "185, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "117, cell ['l0', 'l1', 'l2', 'l3']", + "118, types ['l0', 'l4', 'l5', 'l6']", + "120, human ['l1', 'l4', 'l7', 'l8']", + "121, primary ['l2', 'l5', 'l7', 'l9']", + "122, cells, ['l3', 'l6', 'l8', 'l9']", + "172, mice ['l10']", + "173, (a ['l10']", + "180, reverse ['l11', 'l12']", + "181, muscle ['l11', 'l13']", + "185, mice ['l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "reverse" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "31270506", + "TEXT": "Salmonella Typhi is a human host-restricted pathogen that is responsible for typhoid fever in approximately 10.9 million people annually1. The typhoid toxin is postulated to have a central role in disease pathogenesis, the establishment of chronic infection and human host restriction2-6. However, its precise role in typhoid disease in humans is not fully defined. We studied the role of typhoid toxin in acute infection using a randomized, double-blind S. Typhi human challenge model7. Forty healthy volunteers were randomized (1:1) to oral challenge with 104 colony-forming units of wild-type or an isogenic typhoid toxin deletion mutant (TN) of S. Typhi. We observed no significant difference in the rate of typhoid infection (fever ≥38 °C for ≥12 h and/or S. Typhi bacteremia) between participants challenged with wild-type or TN S. Typhi (15 out of 21 (71%) versus 15 out of 19 (79%); P = 0.58). The duration of bacteremia was significantly longer in participants challenged with the TN strain compared with wild-type (47.6 hours (28.9-97.0) versus 30.3(3.6-49.4); P ≤ 0.001). The clinical syndrome was otherwise indistinguishable between wild-type and TN groups. These data suggest that the typhoid toxin is not required for infection and the development of early typhoid fever symptoms within the context of a human challenge model. Further clinical data are required to assess the role of typhoid toxin in severe disease or the establishment of bacterial carriage.", + "TAG_DATA": [ + "75, volunteers {'context': 'I-organism'}", + "90, isogenic {'perturbing_action': 'B-gene loss-of-function'}", + "91, typhoid {'perturbing_action': 'I-gene loss-of-function'}", + "92, toxin {'perturbing_action': 'I-gene loss-of-function'}", + "93, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "94, mutant {'perturbing_action': 'I-gene loss-of-function'}", + "95, (TN) {'perturbing_action': 'I-gene loss-of-function'}", + "96, of {'perturbing_action': 'I-gene loss-of-function'}", + "97, S. {'perturbing_action': 'I-gene loss-of-function'}", + "98, Typhi. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "75, volunteers ['l0', 'l1']", + "90, isogenic ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "91, typhoid ['l2', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "92, toxin ['l3', 'l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "93, deletion ['l4', 'l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "94, mutant ['l5', 'l12', 'l18', 'l23', 'l28', 'l29', 'l30', 'l31']", + "95, (TN) ['l6', 'l13', 'l19', 'l24', 'l28', 'l32', 'l33', 'l34']", + "96, of ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l35', 'l36']", + "97, S. ['l0', 'l8', 'l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l37']", + "98, Typhi. ['l1', 'l9', 'l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "volunteers" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "S.", + "Typhi." + ] + } + } + ] + }, + { + "PMID": "31270504", + "TEXT": "Synthetic biology is driving a new era of medicine through the genetic programming of living cells1,2. This transformative approach allows for the creation of engineered systems that intelligently sense and respond to diverse environments, ultimately adding specificity and efficacy that extends beyond the capabilities of molecular-based therapeutics3-6. One particular area of focus has been the engineering of bacteria as therapeutic delivery systems to selectively release therapeutic payloads in vivo7-11. Here we engineered a non-pathogenic Escherichia coli strain to specifically lyse within the tumor microenvironment and release an encoded nanobody antagonist of CD47 (CD47nb)12, an anti-phagocytic receptor that is commonly overexpressed in several human cancer types13,14. We show that delivery of CD47nb by tumor-colonizing bacteria increases activation of tumor-infiltrating T cells, stimulates rapid tumor regression, prevents metastasis and leads to long-term survival in a syngeneic tumor model in mice. Moreover, we report that local injection of CD47nb-expressing bacteria stimulates systemic tumor-antigen-specific immune responses that reduce the growth of untreated tumors, providing proof-of-concept for an abscopal effect induced by an engineered bacterial immunotherapy. Thus, engineered bacteria may be used for safe and local delivery of immunotherapeutic payloads leading to systemic antitumor immunity.", + "TAG_DATA": [ + "73, non-pathogenic {'context': 'B-cells'}", + "119, cells, {'context': 'I-cells'}", + "120, stimulates {'effect': 'B-positive'}", + "122, tumor {'phenotype': 'B-tumour regression'}", + "123, regression, {'phenotype': 'I-tumour regression'}", + "124, prevents {'effect': 'B-negative'}", + "125, metastasis {'phenotype': 'B-metastasis'}", + "133, syngeneic {'context': 'B-neoplasm'}", + "134, tumor {'context': 'I-neoplasm'}", + "135, model {'context': 'I-neoplasm'}", + "137, mice. {'context': 'B-organism'}", + "158, tumors, {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "73, non-pathogenic ['l0', 'l1', 'l2', 'l3', 'l4']", + "119, cells, ['l0', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "120, stimulates ['l1', 'l5', 'l13', 'l14', 'l15', 'l16']", + "122, tumor ['l2', 'l6', 'l13', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "123, regression, ['l3', 'l7', 'l14', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "124, prevents ['l4', 'l8', 'l15', 'l18', 'l23', 'l28', 'l29', 'l30']", + "125, metastasis ['l9', 'l16', 'l19', 'l24', 'l28', 'l31', 'l32', 'l33', 'l34']", + "133, syngeneic ['l31', 'l35', 'l36', 'l37']", + "134, tumor ['l10', 'l20', 'l25', 'l29', 'l32', 'l35', 'l38', 'l39']", + "135, model ['l11', 'l21', 'l26', 'l30', 'l33', 'l36', 'l38', 'l40']", + "137, mice. ['l12', 'l22', 'l27', 'l34', 'l37', 'l39', 'l40']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "non-pathogenic", + "cells," + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "non-pathogenic", + "cells," + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "non-pathogenic", + "cells," + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression," + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor", + "model" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor", + "model" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "syngeneic", + "tumor", + "model" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "31270503", + "TEXT": "Since most dominant human mutations are single nucleotide substitutions1,2, we explored gene editing strategies to disrupt dominant mutations efficiently and selectively without affecting wild-type alleles. However, single nucleotide discrimination can be difficult to achieve3 because commonly used endonucleases, such as Streptococcus pyogenes Cas9 (SpCas9), can tolerate up to seven mismatches between guide RNA (gRNA) and target DNA. Furthermore, the protospacer-adjacent motif (PAM) in some Cas9 enzymes can tolerate mismatches with the target DNA3,4. To circumvent these limitations, we screened 14 Cas9/gRNA combinations for specific and efficient disruption of a nucleotide substitution that causes the dominant progressive hearing loss, DFNA36. As a model for DFNA36, we used Beethoven mice5, which harbor a point mutation in Tmc1, a gene required for hearing that encodes a pore-forming subunit of mechanosensory transduction channels in inner-ear hair cells6. We identified a PAM variant of Staphylococcus aureus Cas9 (SaCas9-KKH) that selectively and efficiently disrupted the mutant allele, but not the wild-type Tmc1/TMC1 allele, in Beethoven mice and in a DFNA36 human cell line. Adeno-associated virus (AAV)-mediated SaCas9-KKH delivery prevented deafness in Beethoven mice up to one year post injection. Analysis of current ClinVar entries revealed that ~21% of dominant human mutations could be targeted using a similar approach.", + "TAG_DATA": [ + "107, mice5, {'context': 'B-organism'}", + "110, a {'perturbing_action': 'I-other'}", + "111, point {'perturbing_action': 'I-other'}", + "112, mutation {'perturbing_action': 'I-other'}", + "113, in {'perturbing_action': 'I-other'}", + "114, Tmc1, {'perturbing_action': 'I-other'}", + "159, mice {'context': 'B-organism'}", + "164, human {'context': 'I-cells'}", + "165, cell {'context': 'I-cells'}", + "166, line. {'context': 'I-cells'}", + "167, Adeno-associated {'perturbing_action': 'B-gene gain-of-function'}", + "168, virus {'perturbing_action': 'I-gene gain-of-function'}", + "169, (AAV)-mediated {'perturbing_action': 'I-gene gain-of-function'}", + "176, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "107, mice5, ['l0', 'l1', 'l2', 'l3', 'l4']", + "110, a ['l0', 'l5', 'l6', 'l7', 'l8', 'l9']", + "111, point ['l1', 'l5', 'l10', 'l11', 'l12', 'l13']", + "112, mutation ['l2', 'l6', 'l10', 'l14', 'l15', 'l16']", + "113, in ['l3', 'l7', 'l11', 'l14', 'l17', 'l18']", + "114, Tmc1, ['l4', 'l8', 'l12', 'l15', 'l17', 'l19']", + "159, mice ['l9', 'l13', 'l16', 'l18', 'l19']", + "164, human ['l20', 'l21']", + "165, cell ['l20', 'l22']", + "166, line. ['l21', 'l22']", + "167, Adeno-associated ['l23', 'l24', 'l25']", + "168, virus ['l23', 'l26', 'l27']", + "169, (AAV)-mediated ['l24', 'l26', 'l28']", + "176, mice ['l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice5,", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "a", + "point", + "mutation", + "in", + "Tmc1," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adeno-associated", + "virus", + "(AAV)-mediated" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "31209335", + "TEXT": "Neonates are protected from colonizing bacteria by antibodies secreted into maternal milk. Necrotizing enterocolitis (NEC) is a disease of neonatal preterm infants with high morbidity and mortality that is associated with intestinal inflammation driven by the microbiota1-3. The incidence of NEC is substantially lower in infants fed with maternal milk, although the mechanisms that underlie this benefit are not clear4-6. Here we show that maternal immunoglobulin A (IgA) is an important factor for protection against NEC. Analysis of IgA binding to fecal bacteria from preterm infants indicated that maternal milk was the predominant source of IgA in the first month of life and that a relative decrease in IgA-bound bacteria is associated with the development of NEC. Sequencing of IgA-bound and unbound bacteria revealed that before the onset of disease, NEC was associated with increasing domination by Enterobacteriaceae in the IgA-unbound fraction of the microbiota. Furthermore, we confirmed that IgA is critical for preventing NEC in a mouse model, in which pups that are reared by IgA-deficient mothers are susceptible to disease despite exposure to maternal milk. Our findings show that maternal IgA shapes the host-microbiota relationship of preterm neonates and that IgA in maternal milk is a critical and necessary factor for the prevention of NEC.", + "TAG_DATA": [ + "157, mouse {'context': 'B-organism'}", + "158, model, {'context': 'I-organism'}", + "161, pups {'context': 'B-organism'}", + "166, IgA-deficient {'perturbing_action': 'B-gene loss-of-function'}" + ], + "LINK_DATA": [ + "157, mouse ['l0', 'l1', 'l2']", + "158, model, ['l0']", + "161, pups ['l1', 'l3']", + "166, IgA-deficient ['l2', 'l3']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "pups" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IgA-deficient" + ] + } + } + ] + }, + { + "PMID": "31171876", + "TEXT": "Melanoma treatment has progressed in the past decade with the development and approval of immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand (PD-L1) and cytotoxic T lymphocyte-associated antigen 4, as well as small molecule inhibitors of BRAF and/or MEK for the subgroup of patients with BRAFV600 mutations1-9. BRAF/MEK-targeted therapies have effects on the tumor microenvironment that support their combination with PD-1/PD-L1 inhibitors10-20. This phase Ib study (ClinicalTrials.gov, number NCT01656642 ) evaluated the safety and anti-tumor activity of combining atezolizumab (anti-PD-L1) with vemurafenib (BRAF inhibitor), or cobimetinib (MEK inhibitor) + vemurafenib, in patients with BRAFV600-mutated metastatic melanoma. Triple combination therapy with atezolizumab + cobimetinib + vemurafenib, after a 28-d run-in period with cobimetinib + vemurafenib, had substantial but manageable toxicity. Exploratory biomarker data show that the cobimetinib + vemurafenib run-in was associated with an increase in proliferating CD4+ T-helper cells but not with an increase in T-regulatory cells, as observed in the vemurafenib-only run-in period. The confirmed objective response rate was 71.8% (95% confidence interval 55.1-85.0). The estimated median duration of response was 17.4 months (95% confidence interval 10.6-25.3) with ongoing response in 39.3% of patients after 29.9 months of follow-up. Further investigation in a phase III trial is underway.", + "TAG_DATA": [ + "89, (MEK {'perturbing_action': 'I-pharmacological inhibition'}", + "90, inhibitor) + vemurafenib, {'perturbing_action': 'I-pharmacological inhibition'}", + "92, patients {'context': 'B-patient'}", + "95, metastatic {'context': 'B-neoplasm'}", + "96, melanoma. {'context': 'I-neoplasm'}", + "130, CD4+ {'context': 'I-cells'}", + "131, T-helper {'context': 'I-cells'}", + "132, cells {'context': 'I-cells'}", + "139, T-regulatory {'context': 'B-cells'}", + "140, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "86, inhibitor), ['l0', 'l1', 'l2', 'l3', 'l4']", + "89, (MEK ['l0', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "90, inhibitor) + vemurafenib, ['l1', 'l5', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "92, patients ['l2', 'l6', 'l14', 'l21', 'l22']", + "95, metastatic ['l3', 'l7', 'l15', 'l21', 'l23']", + "96, melanoma. ['l4', 'l8', 'l16', 'l22', 'l23']", + "127, increase ['l9', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28']", + "130, CD4+ ['l10', 'l18', 'l24', 'l29', 'l30', 'l31', 'l32']", + "131, T-helper ['l11', 'l19', 'l25', 'l29', 'l33', 'l34', 'l35']", + "132, cells ['l12', 'l20', 'l26', 'l30', 'l33', 'l36', 'l37']", + "139, T-regulatory ['l27', 'l31', 'l34', 'l36', 'l38']", + "140, cells, ['l13', 'l28', 'l32', 'l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "(MEK", + "inhibitor) + vemurafenib," + ] + }, + "context": { + "val": "patient", + "words": [ + "patients" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "(MEK", + "inhibitor) + vemurafenib," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "metastatic", + "melanoma." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "(MEK", + "inhibitor) + vemurafenib," + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "T-helper", + "cells", + "cells," + ] + } + } + ] + }, + { + "PMID": "31036879", + "TEXT": "Modulating T cell homeostatic mechanisms with checkpoint blockade can efficiently promote endogenous anti-tumor T cell responses1-11. However, many patients still do not benefit from checkpoint blockade12, highlighting the need for targeting of alternative immune pathways13. Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) is an attractive target for immunotherapy, owing to its capacity to promote effector T cell (Teff) functions14,15 and hamper regulatory T cell (Treg) suppression16-20. On the basis of the potent preclinical anti-tumor activity of agonist anti-GITR antibodies, reported by us and others16,21,22, we initiated the first in-human phase 1 trial of GITR agonism with the anti-GITR antibody TRX518 ( NCT01239134 ). Here, we report the safety profile and immune effects of TRX518 monotherapy in patients with advanced cancer and provide mechanistic preclinical evidence to rationally combine GITR agonism with checkpoint blockade in future clinical trials. We demonstrate that TRX518 reduces circulating and intratumoral Treg cells to similar extents, providing an easily assessable biomarker of anti-GITR activity. Despite Treg reductions and increased Teff:Treg ratios, substantial clinical responses were not seen. Similarly, in mice with advanced tumors, GITR agonism was not sufficient to activate cytolytic T cells due to persistent exhaustion. We demonstrate that T cell reinvigoration with PD-1 blockade can overcome resistance of advanced tumors to anti-GITR monotherapy. These findings led us to start investigating TRX518 with PD-1 pathway blockade in patients with advanced refractory tumors ( NCT02628574 ).", + "TAG_DATA": [ + "119, cancer {'context': 'I-neoplasm'}", + "173, mice {'context': 'B-organism'}", + "175, advanced {'context': 'I-neoplasm'}", + "176, tumors, {'context': 'I-neoplasm'}", + "178, agonism {'perturbing_action': 'I-pharmacological augmentation'}", + "204, advanced {'context': 'B-neoplasm'}", + "205, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "173, mice ['l0', 'l1', 'l2']", + "175, advanced ['l0', 'l3', 'l4']", + "176, tumors, ['l1', 'l3', 'l5']", + "178, agonism ['l2', 'l4', 'l5', 'l6', 'l7']", + "204, advanced ['l6', 'l8']", + "205, tumors ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "agonism" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "advanced", + "tumors,", + "tumors" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "agonism" + ] + } + } + ] + }, + { + "PMID": "30833749", + "TEXT": "Celastrol, a pentacyclic triterpene, is the most potent antiobesity agent that has been reported thus far1. The mechanism of celastrol's leptin-sensitizing and antiobesity effects has not yet been elucidated. In this study, we identified interleukin-1 receptor 1 (IL1R1) as a mediator of celastrol's action by using temporally resolved analysis of the hypothalamic transcriptome in celastrol-treated DIO, lean, and db/db mice. We demonstrate that IL1R1-deficient mice are completely resistant to the effects of celastrol in leptin sensitization and treatment of obesity, diabetes, and nonalcoholic steatohepatitis. Thus, we conclude that IL1R1 is a gatekeeper for celastrol's metabolic actions.", + "TAG_DATA": [ + "58, db/db {'context': 'B-organism'}", + "59, mice. {'context': 'I-organism'}", + "63, IL1R1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "64, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "58, db/db ['l0', 'l1']", + "59, mice. ['l0']", + "63, IL1R1-deficient ['l1', 'l2']", + "64, mice ['l2']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "db/db", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IL1R1-deficient" + ] + } + } + ] + }, + { + "PMID": "30833747", + "TEXT": "Spitzoid melanoma is a specific morphologic variant of melanoma that most commonly affects children and adolescents, and ranges on the spectrum of malignancy from low grade to overtly malignant. These tumors are generally driven by fusions of ALK, RET, NTRK1/3, MET, ROS1 and BRAF1,2. However, in approximately 50% of cases no genetic driver has been established2. Clinical whole-genome and transcriptome sequencing (RNA-Seq) of a spitzoid tumor from an adolescent revealed a novel gene fusion of MAP3K8, encoding a serine-threonine kinase that activates MEK3,4. The patient, who had exhausted all other therapeutic options, was treated with a MEK inhibitor and underwent a transient clinical response. We subsequently analyzed spitzoid tumors from 49 patients by RNA-Seq and found in-frame fusions or C-terminal truncations of MAP3K8 in 33% of cases. The fusion transcripts and truncated genes all contained MAP3K8 exons 1-8 but lacked the autoinhibitory final exon. Data mining of RNA-Seq from the Cancer Genome Atlas (TCGA) uncovered analogous MAP3K8 rearrangements in 1.5% of adult melanomas. Thus, MAP3K8 rearrangements-uncovered by comprehensive clinical sequencing of a single case-are the most common genetic event in spitzoid melanoma, are present in adult melanomas and could be amenable to MEK inhibition.", + "TAG_DATA": [ + "96, MEK {'perturbing_action': 'B-pharmacological inhibition'}", + "97, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "107, spitzoid {'context': 'B-neoplasm'}", + "108, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "64, spitzoid ['l0']", + "65, tumor ['l0']", + "96, MEK ['l1', 'l2', 'l3']", + "97, inhibitor ['l1', 'l4', 'l5']", + "107, spitzoid ['l2', 'l4', 'l6']", + "108, tumors ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "MEK", + "inhibitor" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "spitzoid", + "tumors" + ] + } + } + ] + }, + { + "PMID": "30804514", + "TEXT": "MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Heterozygous loss-of-function point mutations of miRNA genes are associated with several human congenital disorders1-5, but neomorphic (gain-of-new-function) mutations in miRNAs due to nucleotide substitutions have not been reported. Here we describe a neomorphic seed region mutation in the chondrocyte-specific, super-enhancer-associated MIR140 gene encoding microRNA-140 (miR-140) in a novel autosomal dominant human skeletal dysplasia. Mice with the corresponding single nucleotide substitution show skeletal abnormalities similar to those of the patients but distinct from those of miR-140-null mice6. This mutant miRNA gene yields abundant mutant miR-140-5p expression without miRNA-processing defects. In chondrocytes, the mutation causes widespread derepression of wild-type miR-140-5p targets and repression of mutant miR-140-5p targets, indicating that the mutation produces both loss-of-function and gain-of-function effects. Furthermore, the mutant miR-140-5p seed competes with the conserved RNA-binding protein Ybx1 for overlapping binding sites. This finding may explain the potent target repression and robust in vivo effect by this mutant miRNA even in the absence of evolutionary selection of miRNA-target RNA interactions, which contributes to the strong regulatory effects of conserved miRNAs7,8. Our study presents the first case of a pathogenic gain-of-function miRNA mutation and provides molecular insight into neomorphic actions of emerging and/or mutant miRNAs.", + "TAG_DATA": [ + "61, Mice {'context': 'B-organism'}", + "82, miR-140-null {'perturbing_action': 'B-gene loss-of-function'}", + "97, chondrocytes, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "61, Mice ['l0']", + "82, miR-140-null ['l0']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "miR-140-null" + ] + } + } + ] + }, + { + "PMID": "30559422", + "TEXT": "Interferons (IFNs) are cytokines that play a critical role in limiting infectious and malignant diseases 1-4 . Emerging data suggest that the strength and duration of IFN signaling can differentially impact cancer therapies, including immune checkpoint blockade 5-7 . Here, we characterize the output of IFN signaling, specifically IFN-stimulated gene (ISG) signatures, in primary tumors from The Cancer Genome Atlas. While immune infiltration correlates with the ISG signature in some primary tumors, the existence of ISG signature-positive tumors without evident infiltration of IFN-producing immune cells suggests that cancer cells per se can be a source of IFN production. Consistent with this hypothesis, analysis of patient-derived tumor xenografts propagated in immune-deficient mice shows evidence of ISG-positive tumors that correlates with expression of human type I and III IFNs derived from the cancer cells. Mechanistic studies using cell line models from the Cancer Cell Line Encyclopedia that harbor ISG signatures demonstrate that this is a by-product of a STING-dependent pathway resulting in chronic tumor-derived IFN production. This imposes a transcriptional state on the tumor, poising it to respond to the aberrant accumulation of double-stranded RNA (dsRNA) due to increased sensor levels (MDA5, RIG-I and PKR). By interrogating our functional short-hairpin RNA screen dataset across 398 cancer cell lines, we show that this ISG transcriptional state creates a novel genetic vulnerability. ISG signature-positive cancer cells are sensitive to the loss of ADAR, a dsRNA-editing enzyme that is also an ISG. A genome-wide CRISPR genetic suppressor screen reveals that the entire type I IFN pathway and the dsRNA-activated kinase, PKR, are required for the lethality induced by ADAR depletion. Therefore, tumor-derived IFN resulting in chronic signaling creates a cellular state primed to respond to dsRNA accumulation, rendering ISG-positive tumors susceptible to ADAR loss.", + "TAG_DATA": [ + "104, patient-derived {'context': 'B-xenograft'}", + "105, tumor {'context': 'I-xenograft'}", + "106, xenografts {'context': 'I-xenograft'}", + "109, immune-deficient {'perturbing_action': 'B-gene loss-of-function', 'context': 'B-organism'}", + "110, mice {'context': 'I-organism'}", + "203, cancer {'context': 'B-transformed cells'}", + "204, cell {'context': 'I-transformed cells'}", + "205, lines, {'context': 'I-transformed cells'}", + "218, ISG {'context': 'B-transformed cells'}", + "220, cancer {'context': 'I-transformed cells'}", + "221, cells {'context': 'I-transformed cells'}", + "264, depletion. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "104, patient-derived ['l0', 'l1', 'l2', 'l3']", + "105, tumor ['l0', 'l4', 'l5', 'l6']", + "106, xenografts ['l1', 'l4', 'l7', 'l8']", + "109, immune-deficient ['l2', 'l5', 'l7', 'l9']", + "110, mice ['l3', 'l6', 'l8', 'l9']", + "203, cancer ['l10', 'l11', 'l12', 'l13', 'l14']", + "204, cell ['l10', 'l15', 'l16', 'l17', 'l18']", + "205, lines, ['l11', 'l15', 'l19', 'l20', 'l21']", + "218, ISG ['l12', 'l16', 'l19', 'l22', 'l23', 'l24']", + "220, cancer ['l13', 'l17', 'l20', 'l22', 'l25']", + "221, cells ['l14', 'l18', 'l21', 'l23', 'l25']", + "264, depletion. ['l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "xenograft", + "words": [ + "patient-derived", + "tumor", + "xenografts" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immune-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immune-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "immune-deficient" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "ISG" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion." + ] + } + } + ] + }, + { + "PMID": "30559420", + "TEXT": "Photoreceptor ciliopathies constitute the most common molecular mechanism of the childhood blindness Leber congenital amaurosis. Ten patients with Leber congenital amaurosis carrying the c.2991+1655A>G allele in the ciliopathy gene centrosomal protein 290 (CEP290) were treated (ClinicalTrials.gov no. NCT03140969 ) with intravitreal injections of an antisense oligonucleotide to restore correct splicing. There were no serious adverse events, and vision improved at 3 months. The visual acuity of one exceptional responder improved from light perception to 20/400.", + "TAG_DATA": [ + "16, patients {'context': 'B-patient'}", + "22, the {'perturbing_action': 'I-other'}", + "23, c.2991+1655A>G {'perturbing_action': 'I-other'}", + "24, allele {'perturbing_action': 'I-other'}", + "25, in {'perturbing_action': 'I-other'}", + "26, the {'perturbing_action': 'I-other'}", + "27, ciliopathy {'perturbing_action': 'I-other'}", + "28, gene {'perturbing_action': 'I-other'}", + "29, centrosomal {'perturbing_action': 'I-other'}", + "30, protein {'perturbing_action': 'I-other'}", + "31, 290 {'perturbing_action': 'I-other'}", + "32, (CEP290) {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "16, patients ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "22, the ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "23, c.2991+1655A>G ['l1', 'l6', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "24, allele ['l2', 'l7', 'l16', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "25, in ['l3', 'l8', 'l17', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "26, the ['l4', 'l9', 'l18', 'l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "27, ciliopathy ['l10', 'l19', 'l27', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "28, gene ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "29, centrosomal ['l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57']", + "30, protein ['l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l58', 'l59']", + "31, 290 ['l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58', 'l60']", + "32, (CEP290) ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "the", + "c.2991+1655A>G", + "allele", + "in", + "(CEP290)" + ] + } + } + ] + }, + { + "PMID": "30397357", + "TEXT": "Human microbiome studies have revealed the intricate interplay of host immunity and bacterial communities to achieve homeostatic balance. Healthy skin microbial communities are dominated by bacteria with low viral representation1-3, mainly bacteriophage. Specific eukaryotic viruses have been implicated in both common and rare skin diseases, but cataloging skin viral communities has been limited. Alterations in host immunity provide an opportunity to expand our understanding of microbial-host interactions. Primary immunodeficient patients manifest with various viral, bacterial, fungal, and parasitic infections, including skin infections4. Dedicator of cytokinesis 8 (DOCK8) deficiency is a rare primary human immunodeficiency characterized by recurrent cutaneous and systemic infections, as well as atopy and cancer susceptibility5. DOCK8, encoding a guanine nucleotide exchange factor highly expressed in lymphocytes, regulates actin cytoskeleton, which is critical for migration through collagen-dense tissues such as skin6. Analyzing deep metagenomic sequencing data from DOCK8-deficient skin samples demonstrated a notable increase in eukaryotic viral representation and diversity compared with healthy volunteers. De novo assembly approaches identified hundreds of novel human papillomavirus genomes, illuminating microbial dark matter. Expansion of the skin virome in DOCK8-deficient patients underscores the importance of immune surveillance in controlling eukaryotic viral colonization and infection.", + "TAG_DATA": [ + "139, DOCK8-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "140, skin {'context': 'B-tissue/organ'}", + "141, samples {'context': 'I-patient'}", + "177, DOCK8-deficient {'perturbing_action': 'B-gene loss-of-function'}" + ], + "LINK_DATA": [ + "139, DOCK8-deficient ['l0', 'l1']", + "140, skin ['l0', 'l2']", + "141, samples ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "DOCK8-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skin" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "DOCK8-deficient" + ] + }, + "context": { + "val": "patient", + "words": [ + "samples" + ] + } + } + ] + }, + { + "PMID": "30127395", + "TEXT": "Nicotinamide adenine dinucleotide (NAD+) extends longevity in experimental organisms, raising interest in its impact on human health. De novo NAD+ biosynthesis from tryptophan is evolutionarily conserved yet considered supplanted among higher species by biosynthesis from nicotinamide (NAM). Here we show that a bottleneck enzyme in de novo biosynthesis, quinolinate phosphoribosyltransferase (QPRT), defends renal NAD+ and mediates resistance to acute kidney injury (AKI). Following murine AKI, renal NAD+ fell, quinolinate rose, and QPRT declined. QPRT+/- mice exhibited higher quinolinate, lower NAD+, and higher AKI susceptibility. Metabolomics suggested an elevated urinary quinolinate/tryptophan ratio (uQ/T) as an indicator of reduced QPRT. Elevated uQ/T predicted AKI and other adverse outcomes in critically ill patients. A phase 1 placebo-controlled study of oral NAM demonstrated a dose-related increase in circulating NAD+ metabolites. NAM was well tolerated and was associated with less AKI. Therefore, impaired NAD+ biosynthesis may be a feature of high-risk hospitalizations for which NAD+ augmentation could be beneficial.", + "TAG_DATA": [ + "73, QPRT+/- {'perturbing_action': 'B-gene loss-of-function'}", + "74, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, QPRT+/- ['l0']", + "74, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "QPRT+/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "30127391", + "TEXT": "Tuberous sclerosis complex (TSC) is a multisystem developmental disorder caused by mutations in the TSC1 or TSC2 genes, whose protein products are negative regulators of mechanistic target of rapamycin complex 1 signaling. Hallmark pathologies of TSC are cortical tubers-regions of dysmorphic, disorganized neurons and glia in the cortex that are linked to epileptogenesis. To determine the developmental origin of tuber cells, we established human cellular models of TSC by CRISPR-Cas9-mediated gene editing of TSC1 or TSC2 in human pluripotent stem cells (hPSCs). Using heterozygous TSC2 hPSCs with a conditional mutation in the functional allele, we show that mosaic biallelic inactivation during neural progenitor expansion is necessary for the formation of dysplastic cells and increased glia production in three-dimensional cortical spheroids. Our findings provide support for the second-hit model of cortical tuber formation and suggest that variable developmental timing of somatic mutations could contribute to the heterogeneity in the neurological presentation of TSC.", + "TAG_DATA": [ + "69, CRISPR-Cas9-mediated {'perturbing_action': 'B-gene loss-of-function'}", + "70, gene {'perturbing_action': 'I-gene loss-of-function'}", + "71, editing {'perturbing_action': 'I-gene loss-of-function'}", + "72, of {'perturbing_action': 'I-gene loss-of-function'}", + "73, TSC1 {'perturbing_action': 'I-gene loss-of-function'}", + "74, or {'perturbing_action': 'I-gene loss-of-function'}", + "75, TSC2 {'perturbing_action': 'I-gene loss-of-function'}", + "77, human {'context': 'B-cells'}", + "78, pluripotent {'context': 'I-cells'}", + "79, stem {'context': 'I-cells'}", + "80, cells {'context': 'I-cells'}", + "81, (hPSCs). {'context': 'I-cells'}", + "83, heterozygous {'perturbing_action': 'B-other'}", + "84, TSC2 {'perturbing_action': 'I-gene loss-of-function'}", + "85, hPSCs {'context': 'I-cells'}", + "88, conditional {'perturbing_action': 'B-other'}", + "89, mutation {'perturbing_action': 'I-other'}", + "90, in {'perturbing_action': 'I-other'}", + "91, the {'perturbing_action': 'I-other'}", + "92, functional {'perturbing_action': 'I-other'}", + "93, allele, {'perturbing_action': 'I-other'}", + "114, glia {'context': 'B-cells'}", + "117, three-dimensional {'context': 'B-organoid'}", + "118, cortical {'context': 'I-organoid'}", + "119, spheroids. {'context': 'I-organoid'}" + ], + "LINK_DATA": [ + "69, CRISPR-Cas9-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "70, gene ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "71, editing ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "72, of ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "73, TSC1 ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "74, or ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "75, TSC2 ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "77, human ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "78, pluripotent ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "79, stem ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "80, cells ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "81, (hPSCs). ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "83, heterozygous ['l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "84, TSC2 ['l66', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "85, hPSCs ['l67', 'l78', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "88, conditional ['l68', 'l79', 'l87', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "89, mutation ['l69', 'l80', 'l88', 'l97', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "90, in ['l70', 'l81', 'l89', 'l98', 'l106', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "91, the ['l71', 'l82', 'l90', 'l99', 'l107', 'l114', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "92, functional ['l72', 'l83', 'l91', 'l100', 'l108', 'l115', 'l121', 'l127', 'l128', 'l129', 'l130', 'l131']", + "93, allele, ['l73', 'l84', 'l92', 'l101', 'l109', 'l116', 'l122', 'l127', 'l132', 'l133', 'l134', 'l135']", + "114, glia ['l74', 'l85', 'l93', 'l102', 'l110', 'l117', 'l123', 'l128', 'l132', 'l136', 'l137', 'l138']", + "117, three-dimensional ['l75', 'l94', 'l103', 'l111', 'l118', 'l124', 'l129', 'l133', 'l136', 'l139', 'l140']", + "118, cortical ['l76', 'l95', 'l104', 'l112', 'l119', 'l125', 'l130', 'l134', 'l137', 'l139', 'l141']", + "119, spheroids. ['l77', 'l86', 'l96', 'l105', 'l113', 'l120', 'l126', 'l131', 'l135', 'l138', 'l140', 'l141']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CRISPR-Cas9-mediated", + "gene", + "editing", + "of", + "TSC1", + "or", + "TSC2" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "pluripotent", + "stem", + "cells", + "(hPSCs).", + "hPSCs", + "glia" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous", + "conditional", + "mutation", + "in", + "the", + "functional", + "allele," + ] + }, + "context": { + "val": "cells", + "words": [ + "hPSCs", + "glia" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous", + "conditional", + "mutation", + "in", + "the", + "functional", + "allele," + ] + }, + "context": { + "val": "organoid", + "words": [ + "three-dimensional", + "cortical", + "spheroids." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TSC2" + ] + }, + "context": { + "val": "organoid", + "words": [ + "spheroids." + ] + } + } + ] + }, + { + "PMID": "30013199", + "TEXT": "For inherited genetic diseases, fetal gene therapy offers the potential of prophylaxis against early, irreversible and lethal pathological change. To explore this, we studied neuronopathic Gaucher disease (nGD), caused by mutations in GBA. In adult patients, the milder form presents with hepatomegaly, splenomegaly and occasional lung and bone disease; this is managed, symptomatically, by enzyme replacement therapy. The acute childhood lethal form of nGD is untreatable since enzyme cannot cross the blood-brain barrier. Patients with nGD exhibit signs consistent with hindbrain neurodegeneration, including neck hyperextension, strabismus and, often, fatal apnea1. We selected a mouse model of nGD carrying a loxP-flanked neomycin disruption of Gba plus Cre recombinase regulated by the keratinocyte-specific K14 promoter. Exclusive skin expression of Gba prevents fatal neonatal dehydration. Instead, mice develop fatal neurodegeneration within 15 days2. Using this model, fetal intracranial injection of adeno-associated virus (AAV) vector reconstituted neuronal glucocerebrosidase expression. Mice lived for up to at least 18 weeks, were fertile and fully mobile. Neurodegeneration was abolished and neuroinflammation ameliorated. Neonatal intervention also rescued mice but less effectively. As the next step to clinical translation, we also demonstrated the feasibility of ultrasound-guided global AAV gene transfer to fetal macaque brains.", + "TAG_DATA": [ + "93, mouse {'context': 'B-organism'}", + "94, model {'context': 'I-organism'}", + "113, Exclusive {'perturbing_action': 'B-gene gain-of-function'}", + "114, skin {'perturbing_action': 'I-gene gain-of-function'}", + "115, expression {'perturbing_action': 'I-gene gain-of-function'}", + "116, of {'perturbing_action': 'I-gene gain-of-function'}", + "117, Gba {'perturbing_action': 'I-gene gain-of-function'}", + "123, mice {'context': 'B-organism'}", + "144, Mice {'context': 'B-organism'}", + "168, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "93, mouse ['l0', 'l1', 'l2']", + "94, model ['l0', 'l3', 'l4', 'l5']", + "113, Exclusive ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "114, skin ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "115, expression ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "116, of ['l3', 'l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "117, Gba ['l1', 'l4', 'l9', 'l14', 'l18', 'l21', 'l24']", + "123, mice ['l2', 'l5', 'l10', 'l15', 'l19', 'l22', 'l24']", + "144, Mice ['l11', 'l16', 'l20', 'l23']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "mice", + "Mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Gba", + "of", + "Exclusive", + "skin", + "expression" + ] + } + } + ] + }, + { + "PMID": "29988130", + "TEXT": "Physical function declines in old age, portending disability, increased health expenditures, and mortality. Cellular senescence, leading to tissue dysfunction, may contribute to these consequences of aging, but whether senescence can directly drive age-related pathology and be therapeutically targeted is still unclear. Here we demonstrate that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues. Transplanting even fewer senescent cells had the same effect in older recipients and was accompanied by reduced survival, indicating the potency of senescent cells in shortening health- and lifespan. The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells, decreased the number of naturally occurring senescent cells and their secretion of frailty-related proinflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell-transplanted young mice and naturally aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%. Our study provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, while senolytics can enhance remaining health- and lifespan in old mice.", + "TAG_DATA": [ + "51, cells {'context': 'I-cells'}", + "53, young {'context': 'B-organism'}", + "54, mice {'context': 'I-organism'}", + "75, senescent {'context': 'B-cells'}", + "76, cells {'context': 'I-cells'}", + "120, senescent {'context': 'B-cells', 'phenotype': 'B-senescence'}", + "121, cells {'context': 'I-cells'}", + "130, explants {'context': 'B-tissue/organ'}", + "131, of {'context': 'I-tissue/organ'}", + "132, human {'context': 'I-tissue/organ'}", + "133, adipose {'context': 'I-tissue/organ'}", + "134, tissue. {'context': 'I-tissue/organ'}", + "143, senescent {'context': 'B-cells'}", + "144, cell-transplanted {'context': 'I-cells'}", + "145, young {'context': 'B-organism'}", + "146, mice {'context': 'I-organism'}", + "148, naturally {'context': 'B-organism'}", + "149, aged {'context': 'I-organism'}", + "150, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "51, cells ['l0', 'l1', 'l2', 'l3']", + "53, young ['l0', 'l4', 'l5']", + "54, mice ['l1', 'l4', 'l6']", + "75, senescent ['l2', 'l7', 'l8', 'l9', 'l10']", + "76, cells ['l3', 'l5', 'l6', 'l7']", + "120, senescent ['l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "121, cells ['l8', 'l11', 'l17', 'l18', 'l19', 'l20', 'l21']", + "130, explants ['l12', 'l17', 'l22', 'l23', 'l24', 'l25']", + "131, of ['l9', 'l13', 'l18', 'l22', 'l26', 'l27', 'l28']", + "132, human ['l14', 'l19', 'l23', 'l26', 'l29', 'l30']", + "133, adipose ['l15', 'l20', 'l24', 'l27', 'l29', 'l31']", + "134, tissue. ['l10', 'l16', 'l21', 'l25', 'l28', 'l30', 'l31']", + "143, senescent ['l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "144, cell-transplanted ['l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "145, young ['l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "146, mice ['l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "148, naturally ['l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "149, aged ['l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "150, mice ['l37', 'l42', 'l46', 'l49', 'l51', 'l52']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "senescent" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescent" + ] + } + }, + { + "phenotype": { + "val": "senescence", + "words": [ + "senescent" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "explants", + "of", + "human", + "adipose", + "tissue." + ] + } + } + ] + }, + { + "PMID": "29988126", + "TEXT": "Idiopathic pulmonary fibrosis is characterized by excessive deposition of collagen in the lung, leading to chronically impaired gas exchange and death1-3. Oxidative stress is believed to be critical in this disease pathogenesis4-6, although the exact mechanisms remain enigmatic. Protein S-glutathionylation (PSSG) is a post-translational modification of proteins that can be reversed by glutaredoxin-1 (GLRX)7. It remains unknown whether GLRX and PSSG play a role in lung fibrosis. Here, we explored the impact of GLRX and PSSG status on the pathogenesis of pulmonary fibrosis, using lung tissues from subjects with idiopathic pulmonary fibrosis, transgenic mouse models and direct administration of recombinant Glrx to airways of mice with existing fibrosis. We demonstrate that GLRX enzymatic activity was strongly decreased in fibrotic lungs, in accordance with increases in PSSG. Mice lacking Glrx were far more susceptible to bleomycin- or adenovirus encoding active transforming growth factor beta-1 (AdTGFB1)-induced pulmonary fibrosis, whereas transgenic overexpression of Glrx in the lung epithelium attenuated fibrosis. We furthermore show that endogenous GLRX was inactivated through an oxidative mechanism and that direct administration of the Glrx protein into airways augmented Glrx activity and reversed increases in collagen in mice with TGFB1- or bleomycin-induced fibrosis, even when administered to fibrotic, aged animals. Collectively, these findings suggest the therapeutic potential of exogenous GLRX in treating lung fibrosis.", + "TAG_DATA": [ + "93, mouse {'context': 'I-organism'}", + "94, models {'context': 'I-organism'}", + "104, mice {'context': 'B-organism'}", + "126, Mice {'context': 'B-organism'}", + "127, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "128, Glrx {'perturbing_action': 'I-gene loss-of-function'}", + "136, adenovirus {'perturbing_action': 'B-gene gain-of-function'}", + "137, encoding {'perturbing_action': 'I-gene gain-of-function'}", + "138, active {'perturbing_action': 'I-gene gain-of-function'}", + "139, transforming {'perturbing_action': 'I-gene gain-of-function'}", + "140, growth {'perturbing_action': 'I-gene gain-of-function'}", + "141, factor {'perturbing_action': 'I-gene gain-of-function'}", + "142, beta-1 {'perturbing_action': 'I-gene gain-of-function'}", + "143, (AdTGFB1)-induced {'perturbing_action': 'I-gene gain-of-function'}", + "147, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "148, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "149, of {'perturbing_action': 'I-gene gain-of-function'}", + "150, Glrx {'perturbing_action': 'I-gene gain-of-function'}", + "151, in {'perturbing_action': 'I-gene gain-of-function'}", + "152, the {'perturbing_action': 'I-gene gain-of-function'}", + "153, lung {'perturbing_action': 'I-gene loss-of-function', 'context': 'B-tissue/organ'}", + "154, epithelium {'context': 'I-tissue/organ'}", + "188, mice {'context': 'B-organism'}", + "199, aged {'context': 'I-organism'}", + "200, animals. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "93, mouse ['l0', 'l1']", + "94, models ['l0', 'l2']", + "104, mice ['l3', 'l4', 'l5', 'l6']", + "119, lungs, ['l1', 'l2', 'l3']", + "126, Mice ['l4', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "127, lacking ['l5', 'l7', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "128, Glrx ['l6', 'l8', 'l17', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "136, adenovirus ['l9', 'l18', 'l26', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "137, encoding ['l10', 'l19', 'l27', 'l34', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "138, active ['l11', 'l20', 'l28', 'l35', 'l42', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "139, transforming ['l12', 'l21', 'l29', 'l36', 'l43', 'l55', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "140, growth ['l13', 'l22', 'l30', 'l37', 'l44', 'l56', 'l66', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "141, factor ['l14', 'l23', 'l31', 'l38', 'l45', 'l57', 'l67', 'l76', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "142, beta-1 ['l15', 'l24', 'l32', 'l39', 'l46', 'l58', 'l68', 'l77', 'l85', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "143, (AdTGFB1)-induced ['l16', 'l25', 'l33', 'l40', 'l47', 'l59', 'l69', 'l78', 'l86', 'l93', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "147, transgenic ['l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "148, overexpression ['l48', 'l106', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "149, of ['l49', 'l60', 'l70', 'l79', 'l87', 'l94', 'l100', 'l107', 'l114', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "150, Glrx ['l50', 'l61', 'l71', 'l80', 'l88', 'l95', 'l101', 'l108', 'l115', 'l121', 'l127', 'l128', 'l129', 'l130', 'l131']", + "151, in ['l51', 'l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l109', 'l116', 'l122', 'l127', 'l132', 'l133', 'l134', 'l135']", + "152, the ['l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l110', 'l117', 'l123', 'l128', 'l132', 'l136', 'l137', 'l138']", + "153, lung ['l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l111', 'l118', 'l124', 'l129', 'l133', 'l136', 'l139', 'l140']", + "154, epithelium ['l41', 'l54', 'l65', 'l75', 'l84', 'l92', 'l99', 'l105', 'l112', 'l119', 'l125', 'l130', 'l134', 'l137', 'l139']", + "188, mice ['l113', 'l120', 'l126', 'l131', 'l135', 'l138', 'l140']", + "199, aged ['l141']", + "200, animals. ['l141']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "Glrx", + "lung" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice", + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "encoding", + "active", + "transforming", + "growth", + "factor", + "beta-1", + "(AdTGFB1)-induced", + "transgenic", + "overexpression", + "of", + "Glrx", + "in", + "the" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "encoding", + "active", + "transforming", + "growth", + "factor", + "beta-1", + "(AdTGFB1)-induced", + "transgenic", + "overexpression", + "of", + "Glrx", + "in", + "the" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "epithelium", + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lung" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + } + ] + }, + { + "PMID": "29808007", + "TEXT": "In the clinic, chimeric antigen receptor-modified T (CAR T) cell therapy is frequently associated with life-threatening cytokine-release syndrome (CRS) and neurotoxicity. Understanding the nature of these pathologies and developing treatments for them are hampered by the lack of appropriate animal models. Herein, we describe a mouse model recapitulating key features of CRS and neurotoxicity. In humanized mice with high leukemia burden, CAR T cell-mediated clearance of cancer triggered high fever and elevated IL-6 levels, which are hallmarks of CRS. Human monocytes were the major source of IL-1 and IL-6 during CRS. Accordingly, the syndrome was prevented by monocyte depletion or by blocking IL-6 receptor with tocilizumab. Nonetheless, tocilizumab failed to protect mice from delayed lethal neurotoxicity, characterized by meningeal inflammation. Instead, the IL-1 receptor antagonist anakinra abolished both CRS and neurotoxicity, resulting in substantially extended leukemia-free survival. These findings offer a therapeutic strategy to tackle neurotoxicity and open new avenues to safer CAR T cell therapies.", + "TAG_DATA": [ + "55, humanized {'context': 'B-organism'}", + "56, mice {'context': 'I-organism'}", + "79, Human {'context': 'B-cells'}", + "80, monocytes {'context': 'I-cells'}", + "101, blocking {'perturbing_action': 'B-pharmacological inhibition'}", + "102, IL-6 {'perturbing_action': 'I-pharmacological inhibition'}", + "103, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "104, with {'perturbing_action': 'I-pharmacological inhibition'}", + "105, tocilizumab. {'perturbing_action': 'I-pharmacological inhibition'}", + "111, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "55, humanized ['l0', 'l1', 'l2']", + "56, mice ['l0', 'l3', 'l4']", + "79, Human ['l1', 'l3', 'l5', 'l6']", + "80, monocytes ['l2', 'l4', 'l5', 'l7']", + "101, blocking ['l8', 'l9', 'l10', 'l11', 'l12']", + "102, IL-6 ['l8', 'l13', 'l14', 'l15', 'l16']", + "103, receptor ['l9', 'l13', 'l17', 'l18', 'l19']", + "104, with ['l10', 'l14', 'l17', 'l20', 'l21']", + "105, tocilizumab. ['l6', 'l7', 'l11', 'l15', 'l18', 'l20']", + "111, mice ['l12', 'l16', 'l19', 'l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Human", + "monocytes" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "tocilizumab." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blocking", + "IL-6", + "receptor", + "with" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "29785026", + "TEXT": "The lysine methyltransferase KMT2C (also known as MLL3), a subunit of the COMPASS complex, implements monomethylation of Lys4 on histone H3 (H3K4) at gene enhancers. KMT2C (hereafter referred to as MLL3) frequently incurs point mutations across a range of human tumor types, but precisely how these lesions alter MLL3 function and contribute to oncogenesis is unclear. Here we report a cancer mutational hotspot in MLL3 within the region encoding its plant homeodomain (PHD) repeats and demonstrate that this domain mediates association of MLL3 with the histone H2A deubiquitinase and tumor suppressor BAP1. Cancer-associated mutations in the sequence encoding the MLL3 PHD repeats disrupt the interaction between MLL3 and BAP1 and correlate with poor patient survival. Cancer cells that had PHD-associated MLL3 mutations or lacked BAP1 showed reduced recruitment of MLL3 and the H3K27 demethylase KDM6A (also known as UTX) to gene enhancers. As a result, inhibition of the H3K27 methyltransferase activity of the Polycomb repressive complex 2 (PRC2) in tumor cells harboring BAP1 or MLL3 mutations restored normal gene expression patterns and impaired cell proliferation in vivo. This study provides mechanistic insight into the oncogenic effects of PHD-associated mutations in MLL3 and suggests that restoration of a balanced state of Polycomb-COMPASS activity may have therapeutic efficacy in tumors that bear mutations in the genes encoding these epigenetic factors.", + "TAG_DATA": [ + "115, Cancer {'context': 'B-transformed cells'}", + "116, cells {'context': 'I-transformed cells'}", + "119, PHD-associated {'perturbing_action': 'B-other'}", + "120, MLL3 {'perturbing_action': 'I-other'}", + "121, mutations {'perturbing_action': 'I-other'}", + "123, lacked {'perturbing_action': 'B-gene loss-of-function'}", + "124, BAP1 {'perturbing_action': 'I-gene loss-of-function'}", + "159, tumor {'context': 'B-transformed cells'}", + "160, cells {'context': 'I-transformed cells'}", + "162, BAP1 {'perturbing_action': 'B-other'}", + "163, or {'perturbing_action': 'I-other'}", + "164, MLL3 {'perturbing_action': 'I-other'}", + "165, mutations {'perturbing_action': 'I-other'}", + "172, impaired {'effect': 'B-negative'}", + "173, cell {'context': 'B-cells'}", + "174, proliferation {'phenotype': 'B-proliferation'}", + "175, in {'context': 'B-in vivo'}", + "176, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "115, Cancer ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "116, cells ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "119, PHD-associated ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "120, MLL3 ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "121, mutations ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "123, lacked ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "124, BAP1 ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "159, tumor ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "160, cells ['l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "162, BAP1 ['l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "163, or ['l23', 'l32', 'l40', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "164, MLL3 ['l24', 'l33', 'l41', 'l48', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "165, mutations ['l25', 'l34', 'l42', 'l49', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "172, impaired ['l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "173, cell ['l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l70', 'l71', 'l72']", + "174, proliferation ['l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l70', 'l73', 'l74']", + "175, in ['l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l73', 'l75']", + "176, vivo. ['l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "Cancer", + "cells", + "tumor" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "PHD-associated", + "MLL3", + "mutations", + "BAP1", + "or" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "Cancer", + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacked", + "BAP1" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BAP1", + "or", + "MLL3", + "mutations" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BAP1", + "or", + "MLL3", + "mutations" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BAP1", + "or", + "MLL3", + "mutations" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BAP1", + "or", + "MLL3", + "mutations" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "29686424", + "TEXT": "Although most activating mutations of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancers (NSCLCs) are sensitive to available EGFR tyrosine kinase inhibitors (TKIs), a subset with alterations in exon 20 of EGFR and HER2 are intrinsically resistant and lack an effective therapy. We used in silico, in vitro, and in vivo testing to model structural alterations induced by exon 20 mutations and to identify effective inhibitors. 3D modeling indicated alterations restricted the size of the drug-binding pocket, limiting the binding of large, rigid inhibitors. We found that poziotinib, owing to its small size and flexibility, can circumvent these steric changes and is a potent inhibitor of the most common EGFR and HER2 exon 20 mutants. Poziotinib demonstrated greater activity than approved EGFR TKIs in vitro and in patient-derived xenograft models of EGFR or HER2 exon 20 mutant NSCLC and in genetically engineered mouse models of NSCLC. In a phase 2 trial, the first 11 patients with NSCLC with EGFR exon 20 mutations receiving poziotinib had a confirmed objective response rate of 64%. These data identify poziotinib as a potent, clinically active inhibitor of EGFR and HER2 exon 20 mutations and illuminate the molecular features of TKIs that may circumvent steric changes induced by these mutations.", + "TAG_DATA": [ + "50, in {'context': 'B-in vivo'}", + "51, vivo {'context': 'B-in vivo'}", + "124, in {'context': 'B-in vitro'}", + "125, vitro {'context': 'I-in vitro'}", + "128, patient-derived {'context': 'B-xenograft'}", + "129, xenograft {'context': 'I-xenograft'}", + "130, models {'context': 'I-xenograft'}", + "132, EGFR {'context': 'I-xenograft'}", + "133, or {'perturbing_action': 'I-other'}", + "134, HER2 {'perturbing_action': 'I-other'}", + "135, exon {'perturbing_action': 'I-other'}", + "136, 20 {'perturbing_action': 'I-other'}", + "137, mutant {'perturbing_action': 'I-other'}", + "138, NSCLC {'context': 'B-neoplasm'}", + "141, genetically {'context': 'B-organism'}", + "142, engineered {'context': 'I-xenograft'}", + "143, mouse {'context': 'I-neoplasm'}", + "144, models {'context': 'I-neoplasm'}", + "145, of {'context': 'I-neoplasm'}", + "146, NSCLC. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "50, in ['l0']", + "51, vivo ['l0']", + "124, in ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "125, vitro ['l1', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "128, patient-derived ['l2', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "129, xenograft ['l3', 'l13', 'l22', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "130, models ['l4', 'l14', 'l23', 'l33', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "132, EGFR ['l5', 'l15', 'l24', 'l34', 'l41', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "133, or ['l6', 'l16', 'l25', 'l35', 'l42', 'l48', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "134, HER2 ['l7', 'l17', 'l26', 'l36', 'l43', 'l49', 'l59', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "135, exon ['l8', 'l18', 'l27', 'l37', 'l44', 'l50', 'l60', 'l69', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "136, 20 ['l9', 'l19', 'l28', 'l38', 'l45', 'l51', 'l61', 'l70', 'l79', 'l87', 'l88', 'l89', 'l90']", + "137, mutant ['l10', 'l20', 'l29', 'l39', 'l46', 'l52', 'l62', 'l71', 'l80', 'l87', 'l91', 'l92', 'l93']", + "138, NSCLC ['l11', 'l21', 'l30', 'l40', 'l47', 'l53', 'l63', 'l72', 'l81', 'l88', 'l91']", + "141, genetically ['l54', 'l64', 'l73', 'l82', 'l94', 'l95', 'l96', 'l97', 'l98']", + "142, engineered ['l55', 'l65', 'l74', 'l83', 'l94', 'l99', 'l100', 'l101', 'l102']", + "143, mouse ['l75', 'l95', 'l99', 'l103', 'l104', 'l105']", + "144, models ['l56', 'l66', 'l76', 'l84', 'l96', 'l100', 'l103', 'l106', 'l107']", + "145, of ['l31', 'l57', 'l67', 'l77', 'l85', 'l89', 'l92', 'l97', 'l101', 'l104', 'l106', 'l108']", + "146, NSCLC. ['l32', 'l58', 'l68', 'l78', 'l86', 'l90', 'l93', 'l98', 'l102', 'l105', 'l107', 'l108']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "or", + "HER2", + "exon", + "20", + "mutant" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "patient-derived", + "xenograft", + "models", + "EGFR", + "engineered" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "or", + "HER2", + "exon", + "20", + "mutant" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "or", + "HER2", + "exon", + "20", + "mutant" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "NSCLC", + "models", + "of", + "NSCLC.", + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "or", + "HER2", + "exon" + ] + }, + "context": { + "val": "organism", + "words": [ + "genetically" + ] + } + } + ] + }, + { + "PMID": "29632371", + "TEXT": "Efforts to develop drugs for Alzheimer's disease (AD) have shown promise in animal studies, only to fail in human trials, suggesting a pressing need to study AD in human model systems. Using human neurons derived from induced pluripotent stem cells that expressed apolipoprotein E4 (ApoE4), a variant of the APOE gene product and the major genetic risk factor for AD, we demonstrated that ApoE4-expressing neurons had higher levels of tau phosphorylation, unrelated to their increased production of amyloid-β (Aβ) peptides, and that they displayed GABAergic neuron degeneration. ApoE4 increased Aβ production in human, but not in mouse, neurons. Converting ApoE4 to ApoE3 by gene editing rescued these phenotypes, indicating the specific effects of ApoE4. Neurons that lacked APOE behaved similarly to those expressing ApoE3, and the introduction of ApoE4 expression recapitulated the pathological phenotypes, suggesting a gain of toxic effects from ApoE4. Treatment of ApoE4-expressing neurons with a small-molecule structure corrector ameliorated the detrimental effects, thus showing that correcting the pathogenic conformation of ApoE4 is a viable therapeutic approach for ApoE4-related AD.", + "TAG_DATA": [ + "32, human {'context': 'B-cells'}", + "33, neurons {'context': 'I-cells'}", + "34, derived {'context': 'I-cells'}", + "35, from {'context': 'I-cells'}", + "36, induced {'context': 'I-cells'}", + "37, pluripotent {'context': 'I-cells'}", + "38, stem {'context': 'I-cells'}", + "39, cells {'context': 'I-cells'}", + "64, neurons {'context': 'I-cells'}", + "92, human, {'context': 'B-cells'}", + "96, mouse, {'context': 'B-cells'}", + "97, neurons. {'context': 'I-cells'}", + "98, Converting {'perturbing_action': 'B-other'}", + "99, ApoE4 {'perturbing_action': 'I-other'}", + "100, to {'perturbing_action': 'I-other'}", + "101, ApoE3 {'perturbing_action': 'I-other'}", + "102, by {'perturbing_action': 'I-other'}", + "103, gene {'perturbing_action': 'I-other'}", + "104, editing {'perturbing_action': 'I-other'}", + "114, Neurons {'context': 'B-cells'}", + "128, ApoE4 {'perturbing_action': 'I-gene gain-of-function'}", + "129, expression {'perturbing_action': 'I-gene gain-of-function'}", + "144, ApoE4-expressing {'context': 'B-cells'}", + "145, neurons {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "32, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "33, neurons ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "34, derived ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "35, from ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "36, induced ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "37, pluripotent ['l4', 'l13', 'l21', 'l28', 'l34', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "38, stem ['l5', 'l14', 'l22', 'l29', 'l35', 'l41', 'l47', 'l48', 'l49', 'l50', 'l51']", + "39, cells ['l6', 'l15', 'l23', 'l30', 'l36', 'l42', 'l47', 'l52', 'l53', 'l54']", + "64, neurons ['l7', 'l16', 'l24', 'l31', 'l37', 'l43', 'l48', 'l52']", + "92, human, ['l8', 'l17', 'l25', 'l32', 'l38', 'l44', 'l49', 'l53', 'l55', 'l56']", + "96, mouse, ['l39', 'l45', 'l50', 'l55', 'l57']", + "97, neurons. ['l9', 'l18', 'l26', 'l33', 'l40', 'l46', 'l51', 'l54', 'l56', 'l57']", + "98, Converting ['l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "99, ApoE4 ['l58', 'l65', 'l66', 'l67', 'l68', 'l69']", + "100, to ['l59', 'l65', 'l70', 'l71', 'l72', 'l73']", + "101, ApoE3 ['l60', 'l66', 'l70', 'l74', 'l75', 'l76']", + "102, by ['l61', 'l67', 'l71', 'l74', 'l77', 'l78']", + "103, gene ['l62', 'l68', 'l72', 'l75', 'l77', 'l79']", + "104, editing ['l63', 'l69', 'l73', 'l76', 'l78', 'l79']", + "114, Neurons ['l64', 'l80', 'l81']", + "128, ApoE4 ['l80', 'l82']", + "129, expression ['l81', 'l82']", + "144, ApoE4-expressing ['l83']", + "145, neurons ['l83']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Converting" + ] + }, + "context": { + "val": "cells", + "words": [ + "Neurons" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Neurons" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ApoE4", + "expression" + ] + } + } + ] + }, + { + "PMID": "29529016", + "TEXT": "Memories become less precise and generalized over time as memory traces reorganize in hippocampal-cortical networks. Increased time-dependent loss of memory precision is characterized by an overgeneralization of fear in individuals with post-traumatic stress disorder (PTSD) or age-related cognitive impairments. In the hippocampal dentate gyrus (DG), memories are thought to be encoded by so-called 'engram-bearing' dentate granule cells (eDGCs). Here we show, using rodents, that contextual fear conditioning increases connectivity between eDGCs and inhibitory interneurons (INs) in the downstream hippocampal CA3 region. We identify actin-binding LIM protein 3 (ABLIM3) as a mossy-fiber-terminal-localized cytoskeletal factor whose levels decrease after learning. Downregulation of ABLIM3 expression in DGCs was sufficient to increase connectivity with CA3 stratum lucidum INs (SLINs), promote parvalbumin (PV)-expressing SLIN activation, enhance feedforward inhibition onto CA3 and maintain a fear memory engram in the DG over time. Furthermore, downregulation of ABLIM3 expression in DGCs conferred conditioned context-specific reactivation of memory traces in hippocampal-cortical and amygdalar networks and decreased fear memory generalization at remote (i.e., distal) time points. Consistent with the observation of age-related hyperactivity of CA3, learning failed to increase DGC-SLIN connectivity in 17-month-old mice, whereas downregulation of ABLIM3 expression was sufficient to restore DGC-SLIN connectivity, increase PV+ SLIN activation and improve the precision of remote memories. These studies exemplify a connectivity-based strategy that targets a molecular brake of feedforward inhibition in DG-CA3 and may be harnessed to decrease time-dependent memory generalization in individuals with PTSD and improve memory precision in aging individuals.", + "TAG_DATA": [ + "62, rodents, {'context': 'B-organism'}", + "98, Downregulation {'perturbing_action': 'B-gene loss-of-function'}", + "99, of {'perturbing_action': 'I-gene loss-of-function'}", + "100, ABLIM3 {'perturbing_action': 'I-gene loss-of-function'}", + "101, expression {'perturbing_action': 'I-gene loss-of-function'}", + "103, DGCs {'context': 'B-cells'}", + "137, downregulation {'perturbing_action': 'B-gene loss-of-function'}", + "138, of {'perturbing_action': 'I-gene loss-of-function'}", + "139, ABLIM3 {'perturbing_action': 'I-gene loss-of-function'}", + "140, expression {'perturbing_action': 'I-gene loss-of-function'}", + "142, DGCs {'context': 'B-cells'}", + "151, hippocampal-cortical {'context': 'B-tissue/organ'}", + "152, and {'context': 'I-tissue/organ'}", + "153, amygdalar {'context': 'I-tissue/organ'}", + "154, networks {'context': 'I-tissue/organ'}", + "183, mice, {'context': 'B-organism'}", + "185, downregulation {'perturbing_action': 'B-gene loss-of-function'}", + "186, of {'perturbing_action': 'I-gene loss-of-function'}", + "187, ABLIM3 {'perturbing_action': 'I-gene loss-of-function'}", + "188, expression {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "62, rodents, ['l0', 'l1', 'l2', 'l3', 'l4']", + "98, Downregulation ['l0', 'l5', 'l6', 'l7', 'l8']", + "99, of ['l1', 'l5', 'l9', 'l10', 'l11']", + "100, ABLIM3 ['l2', 'l6', 'l9', 'l12', 'l13']", + "101, expression ['l3', 'l7', 'l10', 'l12', 'l14']", + "103, DGCs ['l4', 'l8', 'l11', 'l13', 'l14']", + "137, downregulation ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "138, of ['l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "139, ABLIM3 ['l16', 'l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "140, expression ['l17', 'l24', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "142, DGCs ['l18', 'l25', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "151, hippocampal-cortical ['l19', 'l26', 'l32', 'l37', 'l41', 'l45', 'l46', 'l47']", + "152, and ['l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l48', 'l49']", + "153, amygdalar ['l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l50']", + "154, networks ['l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l50']", + "185, downregulation ['l51', 'l52', 'l53']", + "186, of ['l51', 'l54', 'l55']", + "187, ABLIM3 ['l52', 'l54', 'l56']", + "188, expression ['l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "rodents," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Downregulation", + "of", + "ABLIM3", + "expression" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Downregulation", + "of", + "ABLIM3", + "expression", + "downregulation" + ] + }, + "context": { + "val": "cells", + "words": [ + "DGCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "downregulation", + "of", + "ABLIM3", + "expression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hippocampal-cortical", + "and", + "amygdalar", + "networks" + ] + } + } + ] + }, + { + "PMID": "29505034", + "TEXT": "Leukemia stem cells (LSCs) in individuals with chronic myelogenous leukemia (CML) (hereafter referred to as CML LSCs) are responsible for initiating and maintaining clonal hematopoiesis. These cells persist in the bone marrow (BM) despite effective inhibition of BCR-ABL kinase activity by tyrosine kinase inhibitors (TKIs). Here we show that although the microRNA (miRNA) miR-126 supported the quiescence, self-renewal and engraftment capacity of CML LSCs, miR-126 levels were lower in CML LSCs than in long-term hematopoietic stem cells (LT-HSCs) from healthy individuals. Downregulation of miR-126 levels in CML LSCs was due to phosphorylation of Sprouty-related EVH1-domain-containing 1 (SPRED1) by BCR-ABL, which led to inhibition of the RAN-exportin-5-RCC1 complex that mediates miRNA maturation. Endothelial cells (ECs) in the BM supply miR-126 to CML LSCs to support quiescence and leukemia growth, as shown using mouse models of CML in which Mir126a (encoding miR-126) was conditionally knocked out in ECs and/or LSCs. Inhibition of BCR-ABL by TKI treatment caused an undesired increase in endogenous miR-126 levels, which enhanced LSC quiescence and persistence. Mir126a knockout in LSCs and/or ECs, or treatment with a miR-126 inhibitor that targets miR-126 expression in both LSCs and ECs, enhanced the in vivo anti-leukemic effects of TKI treatment and strongly diminished LSC leukemia-initiating capacity, providing a new strategy for the elimination of LSCs in individuals with CML.", + "TAG_DATA": [ + "111, Endothelial {'context': 'B-cells'}", + "112, cells {'context': 'I-cells'}", + "113, (ECs) {'context': 'I-cells'}", + "120, CML {'context': 'B-transformed cells'}", + "121, LSCs {'context': 'I-transformed cells'}", + "123, support {'effect': 'B-positive'}", + "124, quiescence {'phenotype': 'B-quiescence'}", + "126, leukemia {'context': 'B-neoplasm'}", + "131, mouse {'context': 'B-neoplasm'}", + "132, models {'context': 'I-neoplasm'}", + "133, of {'context': 'I-neoplasm'}", + "134, CML {'context': 'I-neoplasm'}", + "137, Mir126a {'perturbing_action': 'B-rnai/knockdown'}", + "138, (encoding {'perturbing_action': 'I-rnai/knockdown'}", + "139, miR-126) {'perturbing_action': 'I-rnai/knockdown'}", + "140, was {'perturbing_action': 'I-gene loss-of-function'}", + "141, conditionally {'perturbing_action': 'B-gene loss-of-function'}", + "142, knocked {'perturbing_action': 'I-gene loss-of-function'}", + "143, out {'perturbing_action': 'I-gene loss-of-function'}", + "145, ECs {'context': 'B-cells'}", + "147, LSCs. {'context': 'B-transformed cells'}", + "148, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "149, of {'perturbing_action': 'I-pharmacological inhibition'}", + "150, BCR-ABL {'perturbing_action': 'I-pharmacological inhibition'}", + "163, enhanced {'effect': 'B-positive'}", + "164, LSC {'context': 'B-transformed cells'}", + "165, quiescence {'phenotype': 'B-quiescence'}", + "168, Mir126a {'perturbing_action': 'B-gene loss-of-function'}", + "169, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "171, LSCs {'context': 'B-transformed cells'}", + "173, ECs, {'context': 'B-transformed cells'}", + "178, miR-126 {'perturbing_action': 'B-pharmacological inhibition'}", + "179, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "111, Endothelial ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "112, cells ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "113, (ECs) ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "120, CML ['l2', 'l21', 'l39', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "121, LSCs ['l3', 'l22', 'l40', 'l57', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "123, support ['l4', 'l23', 'l41', 'l58', 'l73', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "124, quiescence ['l5', 'l24', 'l42', 'l59', 'l74', 'l88', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "126, leukemia ['l6', 'l25', 'l43', 'l60', 'l75', 'l89', 'l101', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "131, mouse ['l7', 'l26', 'l44', 'l61', 'l76', 'l90', 'l102', 'l114', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "132, models ['l8', 'l27', 'l45', 'l62', 'l77', 'l91', 'l103', 'l115', 'l126', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "133, of ['l9', 'l28', 'l46', 'l63', 'l78', 'l92', 'l104', 'l116', 'l127', 'l138', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158']", + "134, CML ['l10', 'l29', 'l47', 'l64', 'l79', 'l93', 'l105', 'l117', 'l128', 'l139', 'l149', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "137, Mir126a ['l11', 'l30', 'l48', 'l65', 'l80', 'l94', 'l106', 'l118', 'l129', 'l140', 'l150', 'l159', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "138, (encoding ['l12', 'l31', 'l49', 'l66', 'l81', 'l95', 'l107', 'l119', 'l130', 'l141', 'l151', 'l160', 'l168', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "139, miR-126) ['l13', 'l32', 'l50', 'l67', 'l82', 'l96', 'l108', 'l120', 'l131', 'l142', 'l152', 'l161', 'l169', 'l179', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197']", + "140, was ['l14', 'l33', 'l51', 'l68', 'l83', 'l97', 'l109', 'l121', 'l132', 'l143', 'l153', 'l162', 'l170', 'l180', 'l189', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "141, conditionally ['l15', 'l34', 'l52', 'l133', 'l144', 'l154', 'l163', 'l171', 'l181', 'l190', 'l198', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211']", + "142, knocked ['l16', 'l35', 'l53', 'l69', 'l84', 'l110', 'l122', 'l134', 'l145', 'l155', 'l164', 'l172', 'l182', 'l191', 'l199', 'l205', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217']", + "143, out ['l17', 'l36', 'l54', 'l70', 'l85', 'l98', 'l111', 'l123', 'l135', 'l146', 'l156', 'l165', 'l173', 'l183', 'l192', 'l200', 'l206', 'l212', 'l218', 'l219', 'l220']", + "145, ECs ['l18', 'l37', 'l55', 'l71', 'l86', 'l99', 'l112', 'l124', 'l136', 'l147', 'l157', 'l166', 'l174', 'l184', 'l193', 'l201', 'l207', 'l213', 'l218', 'l221']", + "147, LSCs. ['l19', 'l38', 'l56', 'l72', 'l87', 'l100', 'l113', 'l125', 'l137', 'l148', 'l158', 'l167', 'l175', 'l185', 'l194', 'l202', 'l208', 'l214', 'l219', 'l221']", + "148, Inhibition ['l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230']", + "149, of ['l222', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238']", + "150, BCR-ABL ['l223', 'l231', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245']", + "163, enhanced ['l176', 'l186', 'l195', 'l203', 'l209', 'l215', 'l220', 'l224', 'l232', 'l239', 'l246', 'l247', 'l248']", + "164, LSC ['l177', 'l187', 'l196', 'l210', 'l216', 'l225', 'l233', 'l240', 'l246', 'l249', 'l250']", + "165, quiescence ['l178', 'l188', 'l197', 'l204', 'l211', 'l217', 'l226', 'l234', 'l241', 'l247', 'l249', 'l251']", + "168, Mir126a ['l227', 'l235', 'l242', 'l252', 'l253', 'l254', 'l255', 'l256']", + "169, knockout ['l228', 'l236', 'l243', 'l252', 'l257', 'l258']", + "171, LSCs ['l229', 'l237', 'l244', 'l253', 'l257', 'l259']", + "173, ECs, ['l230', 'l238', 'l245', 'l248', 'l250', 'l251', 'l254', 'l258', 'l259']", + "178, miR-126 ['l255', 'l260']", + "179, inhibitor ['l256', 'l260']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Endothelial", + "cells", + "(ECs)", + "ECs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "support" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Endothelial", + "cells", + "(ECs)", + "ECs" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Endothelial", + "cells", + "(ECs)", + "ECs" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Mir126a", + "(encoding", + "miR-126)" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Endothelial", + "cells", + "(ECs)", + "ECs" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "was", + "conditionally", + "knocked", + "out" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CML", + "LSCs", + "LSCs.", + "LSC", + "ECs," + ] + }, + "effect": { + "val": "positive", + "words": [ + "support", + "enhanced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CML", + "LSCs", + "LSCs.", + "LSC", + "ECs," + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CML", + "LSCs", + "LSCs.", + "LSC" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Mir126a", + "(encoding", + "miR-126)" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CML", + "LSCs", + "LSCs.", + "LSC", + "ECs," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "was", + "knocked", + "out", + "conditionally", + "Mir126a", + "knockout" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "support", + "enhanced" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "support" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia", + "mouse", + "models", + "of", + "CML" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "support", + "enhanced" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Mir126a", + "(encoding", + "miR-126)" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "support", + "enhanced" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "was", + "out", + "conditionally", + "knocked" + ] + } + }, + { + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia", + "mouse", + "models", + "of", + "CML" + ] + } + }, + { + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Mir126a", + "(encoding", + "miR-126)" + ] + } + }, + { + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "was", + "knocked", + "out", + "conditionally" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "leukemia", + "mouse", + "models", + "of", + "CML" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Mir126a", + "(encoding", + "miR-126)" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "leukemia", + "mouse", + "models", + "of", + "CML" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "was", + "knocked", + "out", + "conditionally" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "BCR-ABL" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "BCR-ABL" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "LSC", + "LSCs", + "ECs," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "BCR-ABL" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + } + } + ] + }, + { + "PMID": "29505031", + "TEXT": "Lung-innervating nociceptor sensory neurons detect noxious or harmful stimuli and consequently protect organisms by mediating coughing, pain, and bronchoconstriction. However, the role of sensory neurons in pulmonary host defense is unclear. Here, we found that TRPV1+ nociceptors suppressed protective immunity against lethal Staphylococcus aureus pneumonia. Targeted TRPV1+-neuron ablation increased survival, cytokine induction, and lung bacterial clearance. Nociceptors suppressed the recruitment and surveillance of neutrophils, and altered lung γδ T cell numbers, which are necessary for immunity. Vagal ganglia TRPV1+ afferents mediated immunosuppression through release of the neuropeptide calcitonin gene-related peptide (CGRP). Targeting neuroimmunological signaling may be an effective approach to treat lung infections and bacterial pneumonia.", + "TAG_DATA": [ + "45, Targeted {'perturbing_action': 'B-gene loss-of-function'}", + "46, TRPV1+-neuron {'perturbing_action': 'I-gene loss-of-function'}", + "47, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "53, lung {'context': 'B-tissue/organ'}", + "66, lung {'context': 'B-tissue/organ'}", + "67, γδ {'context': 'B-cells'}", + "68, T {'context': 'I-cells'}", + "69, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, Targeted ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "46, TRPV1+-neuron ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "47, ablation ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "53, lung ['l2', 'l8', 'l13']", + "66, lung ['l3', 'l9', 'l14', 'l18', 'l19', 'l20']", + "67, γδ ['l4', 'l10', 'l15', 'l18', 'l21', 'l22']", + "68, T ['l5', 'l11', 'l16', 'l19', 'l21', 'l23']", + "69, cell ['l6', 'l12', 'l17', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Targeted", + "TRPV1+-neuron", + "ablation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Targeted", + "TRPV1+-neuron", + "ablation" + ] + }, + "context": { + "val": "cells", + "words": [ + "γδ", + "T", + "cell" + ] + } + } + ] + }, + { + "PMID": "29431743", + "TEXT": "Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD+ leukemia cells. This synergized with the allogeneic CD8+ T cell response, leading to long-term survival in six mouse models of FLT3-ITD+ AML. Sorafenib-related IL-15 production caused an increase in CD8+CD107a+IFN-γ+ T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD+ AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8+ T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.", + "TAG_DATA": [ + "49, FLT3-ITD+ {'context': 'B-transformed cells'}", + "50, leukemia {'context': 'I-transformed cells'}", + "51, cells. {'context': 'I-transformed cells'}", + "67, mouse {'context': 'B-neoplasm'}", + "68, models {'context': 'I-neoplasm'}", + "69, of {'context': 'I-neoplasm'}", + "70, FLT3-ITD+ {'context': 'I-neoplasm'}", + "71, AML. {'context': 'I-neoplasm'}", + "96, leukemia {'context': 'B-neoplasm'}", + "125, IRF7 {'perturbing_action': 'B-rnai/knockdown'}", + "126, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "128, ATF4 {'perturbing_action': 'B-gene gain-of-function'}", + "129, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "131, leukemia {'context': 'B-transformed cells'}", + "132, cells {'context': 'I-transformed cells'}", + "137, in {'context': 'B-in vitro'}", + "138, vitro. {'context': 'I-in vitro'}", + "139, Human {'context': 'B-transformed cells'}", + "140, FLT3-ITD+ {'context': 'I-transformed cells'}", + "141, AML {'context': 'I-transformed cells'}", + "142, cells {'context': 'I-transformed cells'}", + "173, CD8+ {'context': 'B-cells'}", + "174, T {'context': 'I-cells'}", + "175, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "49, FLT3-ITD+ ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "50, leukemia ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "51, cells. ['l1', 'l7', 'l13', 'l14']", + "67, mouse ['l2', 'l8', 'l15', 'l16', 'l17', 'l18']", + "68, models ['l3', 'l9', 'l13', 'l15', 'l19', 'l20', 'l21']", + "69, of ['l4', 'l10', 'l14', 'l16', 'l19', 'l22', 'l23', 'l24']", + "70, FLT3-ITD+ ['l5', 'l11', 'l17', 'l20', 'l22', 'l25', 'l26']", + "71, AML. ['l6', 'l12', 'l18', 'l21', 'l23', 'l25', 'l27']", + "96, leukemia ['l24', 'l26', 'l27']", + "125, IRF7 ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "126, knockdown ['l28', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "128, ATF4 ['l29', 'l37', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "129, overexpression ['l30', 'l38', 'l43', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "131, leukemia ['l31', 'l39', 'l44', 'l52', 'l60', 'l61', 'l62']", + "132, cells ['l32', 'l40', 'l45', 'l53', 'l60', 'l63', 'l64']", + "137, in ['l33', 'l41', 'l46', 'l54', 'l61', 'l63', 'l65']", + "138, vitro. ['l34', 'l42', 'l47', 'l55', 'l62', 'l64', 'l65']", + "139, Human ['l48', 'l56', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "140, FLT3-ITD+ ['l49', 'l57', 'l66', 'l72', 'l73', 'l74', 'l75', 'l76']", + "141, AML ['l35', 'l50', 'l58', 'l67', 'l72', 'l77', 'l78', 'l79']", + "142, cells ['l36', 'l51', 'l59', 'l68', 'l73', 'l77', 'l80', 'l81']", + "173, CD8+ ['l69', 'l74', 'l82', 'l83']", + "174, T ['l70', 'l75', 'l78', 'l80', 'l82', 'l84']", + "175, cells ['l71', 'l76', 'l79', 'l81', 'l83', 'l84']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "IRF7", + "knockdown" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "leukemia", + "cells", + "AML" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "IRF7", + "knockdown" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ATF4", + "overexpression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "leukemia", + "cells", + "Human", + "FLT3-ITD+", + "AML" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ATF4", + "overexpression" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "29334372", + "TEXT": "The unique metabolic demands of cancer cells underscore potentially fruitful opportunities for drug discovery in the era of precision medicine. However, therapeutic targeting of cancer metabolism has led to surprisingly few new drugs to date. The neutral amino acid glutamine serves as a key intermediate in numerous metabolic processes leveraged by cancer cells, including biosynthesis, cell signaling, and oxidative protection. Herein we report the preclinical development of V-9302, a competitive small molecule antagonist of transmembrane glutamine flux that selectively and potently targets the amino acid transporter ASCT2. Pharmacological blockade of ASCT2 with V-9302 resulted in attenuated cancer cell growth and proliferation, increased cell death, and increased oxidative stress, which collectively contributed to antitumor responses in vitro and in vivo. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of glutamine transport in oncology, representing a new class of targeted therapy and laying a framework for paradigm-shifting therapies targeting cancer cell metabolism.", + "TAG_DATA": [ + "87, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "88, blockade {'perturbing_action': 'I-pharmacological inhibition'}", + "89, of {'perturbing_action': 'I-pharmacological inhibition'}", + "90, ASCT2 {'perturbing_action': 'I-pharmacological inhibition'}", + "91, with {'perturbing_action': 'I-pharmacological inhibition'}", + "92, V-9302 {'perturbing_action': 'I-pharmacological inhibition'}", + "95, attenuated {'effect': 'B-negative'}", + "96, cancer {'context': 'B-neoplasm'}", + "97, cell {'phenotype': 'B-cell growth'}", + "98, growth {'phenotype': 'I-cell growth'}", + "100, proliferation, {'phenotype': 'B-proliferation'}", + "101, increased {'effect': 'B-positive'}", + "102, cell {'phenotype': 'B-cell death'}", + "103, death, {'phenotype': 'I-cell death'}", + "114, in {'context': 'B-in vitro'}", + "115, vitro {'context': 'I-in vitro'}", + "117, in {'context': 'B-in vivo'}", + "118, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "87, Pharmacological ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "88, blockade ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "89, of ['l1', 'l16', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "90, ASCT2 ['l2', 'l17', 'l31', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "91, with ['l3', 'l18', 'l32', 'l44', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "92, V-9302 ['l4', 'l19', 'l33', 'l45', 'l56', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "95, attenuated ['l5', 'l20', 'l34', 'l46', 'l57', 'l67', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "96, cancer ['l6', 'l21', 'l35', 'l47', 'l58', 'l68', 'l77', 'l84', 'l85', 'l86']", + "97, cell ['l7', 'l22', 'l36', 'l48', 'l59', 'l69', 'l78', 'l84', 'l87', 'l88']", + "98, growth ['l8', 'l23', 'l37', 'l49', 'l60', 'l70', 'l79', 'l85', 'l87', 'l89']", + "100, proliferation, ['l9', 'l24', 'l38', 'l50', 'l61', 'l71', 'l80', 'l86', 'l88', 'l89']", + "101, increased ['l10', 'l25', 'l39', 'l51', 'l62', 'l72', 'l81', 'l90', 'l91']", + "102, cell ['l11', 'l26', 'l40', 'l52', 'l63', 'l73', 'l82', 'l90', 'l92']", + "103, death, ['l12', 'l27', 'l41', 'l53', 'l64', 'l74', 'l83', 'l91', 'l92']", + "114, in ['l13', 'l28', 'l42', 'l54', 'l65', 'l75', 'l93']", + "115, vitro ['l14', 'l29', 'l43', 'l55', 'l66', 'l76', 'l93']", + "117, in ['l94']", + "118, vivo. ['l15', 'l30', 'l94']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "ASCT2", + "with", + "V-9302" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "ASCT2", + "with", + "V-9302" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "cancer" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "ASCT2", + "with", + "V-9302" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "ASCT2", + "with", + "V-9302" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "ASCT2", + "with", + "V-9302" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "ASCT2", + "with", + "V-9302" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "ASCT2", + "with", + "V-9302" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "cancer" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "cancer" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "cancer" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + } + ] + }, + { + "PMID": "29291352", + "TEXT": "Hemophagocytic syndrome (HPS) is a fatal hyperinflammatory disease with a poorly understood mechanism that occurs most frequently in extranodal natural killer/T cell lymphoma (ENKTL). Through exome sequencing of ENKTL tumor-normal samples, we have identified a hotspot mutation (c.419T>C) in the evolutionarily conserved signaling intermediate in Toll pathway (ECSIT) gene, encoding a V140A variant of ECSIT. ECSIT-V140A activated NF-κB more potently than the wild-type protein owing to its increased affinity for the S100A8 and S100A9 heterodimer, which promotes NADPH oxidase activity. ECSIT-T419C knock-in mice showed higher peritoneal NADPH oxidase activity than mice with wild-type ECSIT in response to LPS. ECSIT-T419C-transfected ENKTL cell lines produced tumor necrosis factor (TNF)-α and interferon (IFN)-γ, which induced macrophage activation and massive cytokine secretion in cell culture and mouse xenografts. In individuals with ENKTL, ECSIT-V140A was associated with activation of NF-κB, higher HPS incidence, and poor prognosis. The immunosuppressive drug thalidomide prevented NF-κB from binding to the promoters of its target genes (including TNF and IFNG), and combination treatment with thalidomide and dexamethasone extended survival of mice engrafted with ECSIT-T419C-transfected ENKTL cells. We added thalidomide to the conventional dexamethasone-containing therapy regimen for two patients with HPS who expressed ECSIT-V140A, and we observed reversal of their HPS and disease-free survival for longer than 3 years. These findings provide mechanistic insights and a potential therapeutic strategy for ENKTL-associated HPS.", + "TAG_DATA": [ + "80, ECSIT-T419C {'perturbing_action': 'B-rnai/knockdown'}", + "81, knock-in {'perturbing_action': 'I-rnai/knockdown'}", + "82, mice {'context': 'B-organism'}", + "90, mice {'context': 'B-organism'}", + "98, ECSIT-T419C-transfected {'perturbing_action': 'B-gene gain-of-function'}", + "99, ENKTL {'context': 'B-transformed cells'}", + "100, cell {'context': 'I-transformed cells'}", + "101, lines {'context': 'I-transformed cells'}", + "112, macrophage {'context': 'B-cells'}", + "119, cell {'context': 'B-cells'}", + "120, culture {'context': 'I-in vitro'}", + "122, mouse {'context': 'B-xenograft'}", + "123, xenografts. {'context': 'I-xenograft'}", + "170, mice {'context': 'B-xenograft'}", + "171, engrafted {'context': 'I-xenograft'}", + "172, with {'context': 'I-xenograft'}", + "173, ECSIT-T419C-transfected {'perturbing_action': 'B-gene gain-of-function'}", + "174, ENKTL {'context': 'B-transformed cells'}", + "175, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "80, ECSIT-T419C ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "81, knock-in ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "82, mice ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "90, mice ['l2', 'l13', 'l23', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "98, ECSIT-T419C-transfected ['l3', 'l14', 'l32', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "99, ENKTL ['l4', 'l15', 'l24', 'l33', 'l41', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "100, cell ['l5', 'l16', 'l25', 'l34', 'l42', 'l49', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "101, lines ['l6', 'l17', 'l26', 'l35', 'l43', 'l50', 'l56', 'l62', 'l63', 'l64', 'l65', 'l66']", + "112, macrophage ['l7', 'l18', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l67', 'l68', 'l69', 'l70']", + "119, cell ['l8', 'l19', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l71', 'l72']", + "120, culture ['l9', 'l20', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71']", + "122, mouse ['l10', 'l21', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l73']", + "123, xenografts. ['l11', 'l22', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l72', 'l73']", + "170, mice ['l74', 'l75', 'l76', 'l77', 'l78']", + "171, engrafted ['l74', 'l79', 'l80', 'l81', 'l82']", + "172, with ['l75', 'l79', 'l83', 'l84', 'l85']", + "173, ECSIT-T419C-transfected ['l76', 'l80', 'l83', 'l86', 'l87']", + "174, ENKTL ['l77', 'l81', 'l84', 'l86', 'l88']", + "175, cells. ['l78', 'l82', 'l85', 'l87', 'l88']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "ECSIT-T419C", + "knock-in" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "ECSIT-T419C", + "knock-in" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ENKTL", + "cell", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "ECSIT-T419C", + "knock-in" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophage", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "ECSIT-T419C", + "knock-in" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "ECSIT-T419C", + "knock-in" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "mouse", + "xenografts." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ECSIT-T419C-transfected" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ECSIT-T419C-transfected" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ENKTL", + "cell", + "lines", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ECSIT-T419C-transfected" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophage", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ECSIT-T419C-transfected" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ECSIT-T419C-transfected" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "mouse", + "xenografts.", + "mice", + "engrafted", + "with" + ] + } + } + ] + }, + { + "PMID": "29291351", + "TEXT": "Nonalcoholic steatohepatitis (NASH) is a common clinical condition that can lead to advanced liver diseases. Lack of effective pharmacotherapies for NASH is largely attributable to an incomplete understanding of its pathogenesis. The deubiquitinase cylindromatosis (CYLD) plays key roles in inflammation and cancer. Here we identified CYLD as a suppressor of NASH in mice and in monkeys. CYLD is progressively degraded upon interaction with the E3 ligase TRIM47 in proportion to NASH severity. We observed that overexpression of Cyld in hepatocytes concomitantly inhibits lipid accumulation, insulin resistance, inflammation and fibrosis in mice with NASH induced in an experimental setting. Mechanistically, CYLD interacts directly with the kinase TAK1 and removes its K63-linked polyubiquitin chain, which blocks downstream activation of the JNK-p38 cascades. Notably, reconstitution of hepatic CYLD expression effectively reverses disease progression in mice with dietary or genetically induced NASH and in high-fat diet-fed monkeys predisposed to metabolic syndrome. Collectively, our findings demonstrate that CYLD mitigates NASH severity and identify the CYLD-TAK1 axis as a promising therapeutic target for management of the disease.", + "TAG_DATA": [ + "75, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "76, of {'perturbing_action': 'I-gene gain-of-function'}", + "77, Cyld {'perturbing_action': 'I-gene gain-of-function'}", + "79, hepatocytes {'context': 'B-cells'}", + "90, mice {'context': 'B-organism'}", + "121, reconstitution {'perturbing_action': 'B-gene gain-of-function'}", + "122, of {'perturbing_action': 'I-gene gain-of-function'}", + "123, hepatic {'perturbing_action': 'I-gene gain-of-function'}", + "124, CYLD {'perturbing_action': 'I-gene gain-of-function'}", + "125, expression {'perturbing_action': 'I-gene gain-of-function'}", + "131, mice {'context': 'B-organism'}", + "142, monkeys {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "75, overexpression ['l0', 'l1', 'l2', 'l3']", + "76, of ['l0', 'l4', 'l5', 'l6']", + "77, Cyld ['l1', 'l4', 'l7', 'l8']", + "79, hepatocytes ['l2', 'l5', 'l7', 'l9']", + "90, mice ['l3', 'l6', 'l8', 'l9']", + "121, reconstitution ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "122, of ['l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "123, hepatic ['l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "124, CYLD ['l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "125, expression ['l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "131, mice ['l14', 'l19', 'l23', 'l26', 'l28']", + "142, monkeys ['l15', 'l20', 'l24', 'l27', 'l29']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Cyld" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Cyld", + "reconstitution", + "hepatic", + "CYLD", + "expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "monkeys" + ] + } + } + ] + }, + { + "PMID": "29227475", + "TEXT": "Hepatic ischemia-reperfusion (IR) injury is a common clinical issue lacking effective therapy and validated pharmacological targets. Here, using integrative 'omics' analysis, we identified an arachidonate 12-lipoxygenase (ALOX12)-12-hydroxyeicosatetraenoic acid (12-HETE)-G-protein-coupled receptor 31 (GPR31) signaling axis as a key determinant of the hepatic IR process. We found that ALOX12 was markedly upregulated in hepatocytes during ischemia to promote 12-HETE accumulation and that 12-HETE then directly binds to GPR31, triggering an inflammatory response that exacerbates liver damage. Notably, blocking 12-HETE production inhibits IR-induced liver dysfunction, inflammation and cell death in mice and pigs. Furthermore, we established a nonhuman primate hepatic IR model that closely recapitulates clinical liver dysfunction following liver resection. Most strikingly, blocking 12-HETE accumulation effectively attenuated all pathologies of hepatic IR in this model. Collectively, this study has revealed previously uncharacterized metabolic reprogramming involving an ALOX12-12-HETE-GPR31 axis that functionally determines hepatic IR procession. We have also provided proof of concept that blocking 12-HETE production is a promising strategy for preventing and treating IR-induced liver damage.", + "TAG_DATA": [ + "78, inhibits {'effect': 'B-negative'}", + "80, liver {'context': 'B-tissue/organ'}", + "84, cell {'phenotype': 'B-cell death'}", + "85, death {'phenotype': 'I-cell death'}", + "87, mice {'context': 'B-organism'}", + "89, pigs. {'context': 'B-organism'}", + "94, nonhuman {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "78, inhibits ['l0', 'l1', 'l2', 'l3', 'l4']", + "80, liver ['l0', 'l5', 'l6', 'l7', 'l8']", + "84, cell ['l1', 'l5', 'l9', 'l10', 'l11']", + "85, death ['l2', 'l6', 'l9', 'l12', 'l13']", + "87, mice ['l3', 'l7', 'l10', 'l12', 'l14']", + "89, pigs. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "pigs." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "pigs." + ] + } + } + ] + }, + { + "PMID": "29155425", + "TEXT": "Endothelial cells are a critical component of the bone marrow (BM) stromal network, which maintains and regulates hematopoietic cells. Vascular regeneration precedes, and is necessary for, successful hematopoietic stem cell (HSC) transplantation, the only cure for most hematopoietic diseases. Recent data suggest that mature hematopoietic cells regulate BM stromal-cell function. Whether a similar cross-talk regulates the BM vasculature is not known. Here we found that donor hematopoietic cells act on sinusoidal endothelial cells and induce host blood vessel and hematopoietic regeneration after BM transplantation in mice. Adoptive transfer of BM, but not peripheral, granulocytes prevented the death of mice transplanted with limited numbers of HSCs and accelerated recovery of host vessels and hematopoietic cells. Moreover, selective granulocyte ablation in vivo impaired vascular and hematopoietic regeneration after BM transplantation. Gene expression analyses indicated that granulocytes are the main source of the cytokine TNFα, whereas its receptor TNFR1 is selectively upregulated in regenerating blood vessels. In adoptive transfer experiments, wild type, but not Tnfa-/-, granulocytes induced vascular recovery, and wild-type granulocyte transfer did not prevent death or promote vascular regeneration in Tnfr1-/-; Tnfr2-/- mice. Thus, by delivering TNFα to endothelial cells, granulocytes promote blood vessel growth and hematopoietic regeneration. Manipulation of the cross-talk between granulocytes and endothelial cells may lead to new therapeutic approaches to improve blood vessel regeneration and increase survival and hematopoietic recovery after HSC transplantation.", + "TAG_DATA": [ + "85, mice. {'context': 'B-organism'}", + "92, peripheral, {'context': 'B-cells'}", + "93, granulocytes {'context': 'I-cells'}", + "98, mice {'context': 'B-organism'}", + "104, HSCs {'context': 'B-cells'}", + "112, hematopoietic {'context': 'B-cells'}", + "113, cells. {'context': 'I-cells'}", + "115, selective {'perturbing_action': 'B-gene loss-of-function'}", + "116, granulocyte {'perturbing_action': 'I-gene loss-of-function'}", + "117, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "118, in {'context': 'B-in vivo'}", + "119, vivo {'context': 'I-in vivo'}", + "161, Tnfa-/-, {'perturbing_action': 'B-gene loss-of-function'}", + "162, granulocytes {'context': 'B-cells'}", + "168, granulocyte {'context': 'B-cells'}", + "179, Tnfr1-/-; {'perturbing_action': 'B-gene loss-of-function'}", + "180, Tnfr2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "181, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "92, peripheral, ['l0', 'l1', 'l2', 'l3', 'l4']", + "93, granulocytes ['l0', 'l5', 'l6', 'l7', 'l8']", + "98, mice ['l1', 'l5', 'l9', 'l10', 'l11']", + "104, HSCs ['l2', 'l6', 'l9', 'l12', 'l13']", + "112, hematopoietic ['l3', 'l7', 'l10', 'l12', 'l14']", + "113, cells. ['l4', 'l8', 'l11', 'l13', 'l14']", + "115, selective ['l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "116, granulocyte ['l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "117, ablation ['l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "118, in ['l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "119, vivo ['l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "161, Tnfa-/-, ['l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "162, granulocytes ['l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "168, granulocyte ['l36', 'l37', 'l38']", + "179, Tnfr1-/-; ['l36', 'l39', 'l40']", + "180, Tnfr2-/- ['l37', 'l39', 'l41']", + "181, mice. ['l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "granulocyte", + "ablation", + "Tnfa-/-," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "granulocyte", + "ablation", + "Tnfa-/-,", + "Tnfr1-/-;", + "Tnfr2-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "granulocytes", + "granulocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tnfr1-/-;", + "Tnfr2-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "29106401", + "TEXT": "Interferon regulatory factor 3 (IRF3) and type I interferons (IFNs) protect against infections and cancer, but excessive IRF3 activation and type I IFN production cause autoinflammatory conditions such as Aicardi-Goutières syndrome and STING-associated vasculopathy of infancy (SAVI). Myocardial infarction (MI) elicits inflammation, but the dominant molecular drivers of MI-associated inflammation remain unclear. Here we show that ischemic cell death and uptake of cell debris by macrophages in the heart fuel a fatal response to MI by activating IRF3 and type I IFN production. In mice, single-cell RNA-seq analysis of 4,215 leukocytes isolated from infarcted and non-infarcted hearts showed that MI provokes activation of an IRF3-interferon axis in a distinct population of interferon-inducible cells (IFNICs) that were classified as cardiac macrophages. Mice genetically deficient in cyclic GMP-AMP synthase (cGAS), its adaptor STING, IRF3, or the type I IFN receptor IFNAR exhibited impaired interferon-stimulated gene (ISG) expression and, in the case of mice deficient in IRF3 or IFNAR, improved survival after MI as compared to controls. Interruption of IRF3-dependent signaling resulted in decreased cardiac expression of inflammatory cytokines and chemokines and decreased inflammatory cell infiltration of the heart, as well as in attenuated ventricular dilation and improved cardiac function. Similarly, treatment of mice with an IFNAR-neutralizing antibody after MI ablated the interferon response and improved left ventricular dysfunction and survival. These results identify IRF3 and the type I IFN response as a potential therapeutic target for post-MI cardioprotection.", + "TAG_DATA": [ + "84, mice, {'context': 'B-organism'}", + "96, hearts {'context': 'I-tissue/organ'}", + "120, Mice {'context': 'B-organism'}", + "150, mice {'context': 'B-organism'}", + "151, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "152, in {'perturbing_action': 'I-gene loss-of-function'}", + "153, IRF3 {'perturbing_action': 'I-gene loss-of-function'}", + "154, or {'perturbing_action': 'I-gene loss-of-function'}", + "155, IFNAR, {'perturbing_action': 'I-gene loss-of-function'}", + "200, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "84, mice, ['l0']", + "96, hearts ['l0']", + "120, Mice ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "150, mice ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "151, deficient ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "152, in ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "153, IRF3 ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "154, or ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "155, IFNAR, ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "IRF3", + "or", + "IFNAR," + ] + } + } + ] + }, + { + "PMID": "29106398", + "TEXT": "Asprosin is a recently discovered fasting-induced hormone that promotes hepatic glucose production. Here we demonstrate that asprosin in the circulation crosses the blood-brain barrier and directly activates orexigenic AgRP+ neurons via a cAMP-dependent pathway. This signaling results in inhibition of downstream anorexigenic proopiomelanocortin (POMC)-positive neurons in a GABA-dependent manner, which then leads to appetite stimulation and a drive to accumulate adiposity and body weight. In humans, a genetic deficiency in asprosin causes a syndrome characterized by low appetite and extreme leanness; this is phenocopied by mice carrying similar mutations and can be fully rescued by asprosin. Furthermore, we found that obese humans and mice had pathologically elevated concentrations of circulating asprosin, and neutralization of asprosin in the blood with a monoclonal antibody reduced appetite and body weight in obese mice, in addition to improving their glycemic profile. Thus, in addition to performing a glucogenic function, asprosin is a centrally acting orexigenic hormone that is a potential therapeutic target in the treatment of both obesity and diabetes.", + "TAG_DATA": [ + "67, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "68, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "69, in {'perturbing_action': 'I-gene loss-of-function'}", + "70, asprosin {'perturbing_action': 'I-gene loss-of-function'}", + "85, mice {'context': 'B-organism'}", + "128, obese {'context': 'B-organism'}", + "129, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "67, genetic ['l0', 'l1', 'l2', 'l3']", + "68, deficiency ['l0', 'l4', 'l5', 'l6']", + "69, in ['l1', 'l4', 'l7', 'l8']", + "70, asprosin ['l2', 'l5', 'l7', 'l9']", + "85, mice ['l3', 'l6', 'l8', 'l9']", + "128, obese ['l10']", + "129, mice, ['l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deficiency", + "in", + "asprosin" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "29058717", + "TEXT": "Maladaptive wound healing responses to chronic tissue injury result in organ fibrosis. Fibrosis, which entails excessive extracellular matrix (ECM) deposition and tissue remodeling by activated myofibroblasts, leads to loss of proper tissue architecture and organ function; however, the molecular mediators of myofibroblast activation have yet to be fully identified. Here we identify soluble ephrin-B2 (sEphrin-B2) as a new profibrotic mediator in lung and skin fibrosis. We provide molecular, functional and translational evidence that the ectodomain of membrane-bound ephrin-B2 is shed from fibroblasts into the alveolar airspace after lung injury. Shedding of sEphrin-B2 promotes fibroblast chemotaxis and activation via EphB3 and/or EphB4 receptor signaling. We found that mice lacking ephrin-B2 in fibroblasts are protected from skin and lung fibrosis and that a disintegrin and metalloproteinase 10 (ADAM10) is the major ephrin-B2 sheddase in fibroblasts. ADAM10 expression is increased by transforming growth factor (TGF)-β1, and ADAM10-mediated sEphrin-B2 generation is required for TGF-β1-induced myofibroblast activation. Pharmacological inhibition of ADAM10 reduces sEphrin-B2 levels in bronchoalveolar lavage and prevents lung fibrosis in mice. Consistent with the mouse data, ADAM10-sEphrin-B2 signaling is upregulated in fibroblasts from human subjects with idiopathic pulmonary fibrosis. These results uncover a new molecular mechanism of tissue fibrogenesis and identify sEphrin-B2, its receptors EphB3 and EphB4 and ADAM10 as potential therapeutic targets in the treatment of fibrotic diseases.", + "TAG_DATA": [ + "92, promotes {'effect': 'B-positive'}", + "93, fibroblast {'context': 'B-cells'}", + "94, chemotaxis {'phenotype': 'B-migration'}", + "106, mice {'context': 'B-organism'}", + "107, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "108, ephrin-B2 {'perturbing_action': 'I-gene loss-of-function'}", + "110, fibroblasts {'context': 'B-cells'}", + "150, myofibroblast {'context': 'B-cells'}", + "152, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "153, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "154, of {'perturbing_action': 'I-pharmacological inhibition'}", + "155, ADAM10 {'perturbing_action': 'I-pharmacological inhibition'}", + "164, lung {'context': 'B-tissue/organ'}", + "167, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "92, promotes ['l0', 'l1', 'l2', 'l3']", + "93, fibroblast ['l0', 'l4', 'l5', 'l6']", + "94, chemotaxis ['l1', 'l4', 'l7', 'l8']", + "106, mice ['l2', 'l5', 'l7', 'l9', 'l10', 'l11']", + "107, lacking ['l9', 'l12', 'l13']", + "108, ephrin-B2 ['l10', 'l12', 'l14']", + "110, fibroblasts ['l3', 'l6', 'l8', 'l11', 'l13', 'l14']", + "152, Pharmacological ['l15', 'l16', 'l17', 'l18', 'l19']", + "153, inhibition ['l15', 'l20', 'l21', 'l22', 'l23']", + "154, of ['l16', 'l20', 'l24', 'l25', 'l26']", + "155, ADAM10 ['l17', 'l21', 'l24', 'l27', 'l28']", + "164, lung ['l18', 'l22', 'l25', 'l27', 'l29']", + "167, mice. ['l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "cells", + "words": [ + "fibroblast", + "fibroblasts" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "fibroblast", + "fibroblasts" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "ephrin-B2" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "ephrin-B2" + ] + }, + "context": { + "val": "cells", + "words": [ + "fibroblasts" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "ADAM10" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "ADAM10" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "29035364", + "TEXT": "The cellular mechanism(s) linking macrophages to norepinephrine (NE)-mediated regulation of thermogenesis have been a topic of debate. Here we identify sympathetic neuron-associated macrophages (SAMs) as a population of cells that mediate clearance of NE via expression of solute carrier family 6 member 2 (SLC6A2), an NE transporter, and monoamine oxidase A (MAOA), a degradation enzyme. Optogenetic activation of the sympathetic nervous system (SNS) upregulates NE uptake by SAMs and shifts the SAM profile to a more proinflammatory state. NE uptake by SAMs is prevented by genetic deletion of Slc6a2 or inhibition of the encoded transporter. We also observed an increased proportion of SAMs in the SNS of two mouse models of obesity. Genetic ablation of Slc6a2 in SAMs increases brown adipose tissue (BAT) content, causes browning of white fat, increases thermogenesis, and leads to substantial and sustained weight loss in obese mice. We further show that this pathway is conserved, as human sympathetic ganglia also contain SAMs expressing the analogous molecular machinery for NE clearance, which thus constitutes a potential target for obesity treatment.", + "TAG_DATA": [ + "85, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "86, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "87, of {'perturbing_action': 'I-gene loss-of-function'}", + "88, Slc6a2 {'perturbing_action': 'I-gene loss-of-function'}", + "112, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "113, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "114, of {'perturbing_action': 'I-gene loss-of-function'}", + "115, Slc6a2 {'perturbing_action': 'I-gene loss-of-function'}", + "117, SAMs {'context': 'B-cells'}", + "140, obese {'context': 'B-organism'}", + "141, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "85, genetic ['l0', 'l1', 'l2']", + "86, deletion ['l0', 'l3', 'l4']", + "87, of ['l1', 'l3', 'l5']", + "88, Slc6a2 ['l2', 'l4', 'l5']", + "112, Genetic ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "113, ablation ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "114, of ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "115, Slc6a2 ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "117, SAMs ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "140, obese ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "141, mice. ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "ablation", + "of", + "Slc6a2" + ] + }, + "context": { + "val": "cells", + "words": [ + "SAMs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "ablation", + "of", + "Slc6a2" + ] + }, + "context": { + "val": "organism", + "words": [ + "obese", + "mice." + ] + } + } + ] + }, + { + "PMID": "28920960", + "TEXT": "Targeting EGFR is a validated approach in the treatment of squamous-cell cancers (SCCs), although there are no established biomarkers for predicting response. We have identified a synonymous mutation in EGFR, c.2361G>A (encoding p.Gln787Gln), in two patients with head and neck SCC (HNSCC) who were exceptional responders to gefitinib, and we showed in patient-derived cultures that the A/A genotype was associated with greater sensitivity to tyrosine kinase inhibitors (TKIs) as compared to the G/A and G/G genotypes. Remarkably, single-copy G>A nucleotide editing in isogenic models conferred a 70-fold increase in sensitivity due to decreased stability of the EGFR-AS1 long noncoding RNA (lncRNA). In the appropriate context, sensitivity could be recapitulated through EGFR-AS1 knockdown in vitro and in vivo, whereas overexpression was sufficient to induce resistance to TKIs. Reduced EGFR-AS1 levels shifted splicing toward EGFR isoform D, leading to ligand-mediated pathway activation. In co-clinical trials involving patients and patient-derived xenograft (PDX) models, tumor shrinkage was most pronounced in the context of the A/A genotype for EGFR-Q787Q, low expression of EGFR-AS1 and high expression of EGFR isoform D. Our study reveals how a 'silent' mutation influences the levels of a lncRNA, resulting in noncanonical EGFR addiction, and delineates a new predictive biomarker suite for response to EGFR TKIs.", + "TAG_DATA": [ + "52, patient-derived {'context': 'B-cells'}", + "53, cultures {'context': 'I-cells'}", + "110, EGFR-AS1 {'perturbing_action': 'B-rnai/knockdown'}", + "111, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "112, in {'context': 'B-in vitro'}", + "113, vitro {'context': 'I-in vitro'}", + "115, in {'context': 'B-in vivo'}", + "116, vivo, {'context': 'I-in vivo'}", + "146, patient-derived {'context': 'B-xenograft'}", + "147, xenograft {'context': 'I-xenograft'}", + "148, (PDX) {'context': 'I-xenograft'}", + "149, models, {'context': 'I-xenograft'}", + "150, tumor {'phenotype': 'B-tumour regression'}", + "151, shrinkage {'phenotype': 'I-tumour regression'}" + ], + "LINK_DATA": [ + "38, and ['l0', 'l1', 'l2', 'l3']", + "39, neck ['l0', 'l4', 'l5', 'l6']", + "40, SCC ['l1', 'l4', 'l7', 'l8']", + "52, patient-derived ['l2', 'l5', 'l7', 'l9']", + "53, cultures ['l3', 'l6', 'l8', 'l9']", + "110, EGFR-AS1 ['l10', 'l11', 'l12', 'l13', 'l14']", + "111, knockdown ['l10', 'l15', 'l16', 'l17', 'l18']", + "112, in ['l11', 'l15', 'l19', 'l20', 'l21']", + "113, vitro ['l12', 'l16', 'l19', 'l22', 'l23']", + "115, in ['l13', 'l17', 'l20', 'l22', 'l24']", + "116, vivo, ['l14', 'l18', 'l21', 'l23', 'l24']", + "146, patient-derived ['l25', 'l26', 'l27', 'l28', 'l29']", + "147, xenograft ['l25', 'l30', 'l31', 'l32', 'l33']", + "148, (PDX) ['l26', 'l30', 'l34', 'l35', 'l36']", + "149, models, ['l27', 'l31', 'l34', 'l37', 'l38']", + "150, tumor ['l28', 'l32', 'l35', 'l37', 'l39']", + "151, shrinkage ['l29', 'l33', 'l36', 'l38', 'l39']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "EGFR-AS1", + "knockdown" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "EGFR-AS1", + "knockdown" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "patient-derived", + "xenograft", + "(PDX)", + "models," + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "shrinkage" + ] + } + } + ] + }, + { + "PMID": "28892064", + "TEXT": "Embryonal tumors with multilayered rosettes (ETMRs) have recently been described as a new entity of rare pediatric brain tumors with a fatal outcome. We show here that ETMRs are characterized by a parallel activation of Shh and Wnt signaling. Co-activation of these pathways in mouse neural precursors is sufficient to induce ETMR-like tumors in vivo that resemble their human counterparts on the basis of histology and global gene-expression analyses, and that point to apical radial glia cells as the possible tumor cell of origin. Overexpression of LIN28A, which is a hallmark of human ETMRs, augments Sonic-hedgehog (Shh) and Wnt signaling in these precursor cells through the downregulation of let7-miRNA, and LIN28A/let7a interaction with the Shh pathway was detected at the level of Gli mRNA. Finally, human ETMR cells that were transplanted into immunocompromised host mice were responsive to the SHH inhibitor arsenic trioxide (ATO). Our work provides a novel mouse model in which to study this tumor type, demonstrates the driving role of Wnt and Shh activation in the growth of ETMRs and proposes downstream inhibition of Shh signaling as a therapeutic option for patients with ETMRs.", + "TAG_DATA": [ + "44, mouse {'context': 'B-cells'}", + "45, neural {'context': 'I-cells'}", + "46, precursors {'context': 'I-cells'}", + "51, ETMR-like {'phenotype': 'B-tumourigenesis'}", + "52, tumors {'phenotype': 'I-tumourigenesis'}", + "53, in {'context': 'B-in vivo'}", + "54, vivo {'context': 'I-in vivo'}", + "84, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "85, of {'perturbing_action': 'I-gene gain-of-function'}", + "86, LIN28A, {'perturbing_action': 'I-gene gain-of-function'}", + "102, precursor {'context': 'B-cells'}", + "103, cells {'context': 'I-cells'}", + "125, human {'context': 'B-transformed cells'}", + "126, ETMR {'context': 'I-transformed cells'}", + "127, cells {'context': 'I-transformed cells'}", + "133, host {'context': 'I-organism'}", + "134, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "44, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "45, neural ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "46, precursors ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "51, ETMR-like ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "52, tumors ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37']", + "53, in ['l4', 'l13', 'l21', 'l28', 'l34', 'l38', 'l39', 'l40', 'l41', 'l42']", + "54, vivo ['l5', 'l14', 'l22', 'l29', 'l35', 'l38', 'l43', 'l44']", + "84, Overexpression ['l45', 'l46', 'l47', 'l48']", + "85, of ['l6', 'l15', 'l23', 'l30', 'l39', 'l45', 'l49', 'l50', 'l51']", + "86, LIN28A, ['l7', 'l16', 'l24', 'l31', 'l40', 'l46', 'l49', 'l52', 'l53']", + "102, precursor ['l8', 'l17', 'l25', 'l32', 'l36', 'l41', 'l43', 'l47', 'l50', 'l52', 'l54']", + "103, cells ['l9', 'l18', 'l26', 'l33', 'l37', 'l42', 'l44', 'l48', 'l51', 'l53', 'l54']", + "125, human ['l55', 'l56', 'l57', 'l58']", + "126, ETMR ['l55', 'l59', 'l60', 'l61']", + "127, cells ['l56', 'l59', 'l62', 'l63']", + "133, host ['l57', 'l60', 'l62', 'l64']", + "134, mice ['l58', 'l61', 'l63', 'l64']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "mouse", + "neural", + "precursors", + "precursor", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "ETMR-like", + "tumors" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "neural", + "precursors", + "precursor", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "LIN28A,", + "Overexpression" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "ETMR-like", + "tumors" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "ETMR-like" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "LIN28A," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "LIN28A," + ] + } + } + ] + }, + { + "PMID": "28846099", + "TEXT": "Growth differentiation factor 15 (GDF15; also known as MIC-1) is a divergent member of the TGF-β superfamily and is associated with body-weight regulation in humans and rodents. However, the cognate receptor of GDF15 is unknown. Here we show that GDF15 binds specifically to GDNF family receptor α-like (GFRAL) with high affinity, and that GFRAL requires association with the coreceptor RET to elicit intracellular signaling in response to GDF15 stimulation. We also found that GDF15-mediated reductions in food intake and body weight of mice with obesity were abolished in GFRAL-knockout mice. We further found that GFRAL expression was limited to hindbrain neurons and not present in peripheral tissues, which suggests that GDF15-GFRAL-mediated regulation of food intake is by a central mechanism. Lastly, given that GDF15 did not increase energy expenditure in treated mice with obesity, the anti-obesity actions of the cytokine are likely driven primarily by a reduction in food intake.", + "TAG_DATA": [ + "82, mice {'context': 'B-organism'}", + "88, GFRAL-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "89, mice. {'context': 'B-organism'}", + "131, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "88, GFRAL-knockout ['l0']", + "89, mice. ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "GFRAL-knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "28846098", + "TEXT": "Growth/differentiation factor 15 (GDF15), also known as MIC-1, is a distant member of the transforming growth factor-β (TGF-β) superfamily and has been implicated in various biological functions, including cancer cachexia, renal and heart failure, atherosclerosis and metabolism. A connection between GDF15 and body-weight regulation was initially suggested on the basis of an observation that increasing GDF15 levels in serum correlated with weight loss in individuals with advanced prostate cancer. In animal models, overexpression of GDF15 leads to a lean phenotype, hypophagia and other improvements in metabolic parameters, suggesting that recombinant GDF15 protein could potentially be used in the treatment of obesity and type 2 diabetes. However, the signaling and mechanism of action of GDF15 are poorly understood owing to the absence of a clearly identified cognate receptor. Here we report that GDNF-family receptor α-like (GFRAL), an orphan member of the GFR-α family, is a high-affinity receptor for GDF15. GFRAL binds to GDF15 in vitro and is required for the metabolic actions of GDF15 with respect to body weight and food intake in vivo in mice. Gfral-/- mice were refractory to the effects of recombinant human GDF15 on body-weight, food-intake and glucose parameters. Blocking the interaction between GDF15 and GFRAL with a monoclonal antibody prevented the metabolic effects of GDF15 in rats. Gfral mRNA is highly expressed in the area postrema of mouse, rat and monkey, in accordance with previous reports implicating this region of the brain in the metabolic actions of GDF15 (refs. 4,5,6). Together, our data demonstrate that GFRAL is a receptor for GDF15 that mediates the metabolic effects of GDF15.", + "TAG_DATA": [ + "70, animal {'context': 'B-organism'}", + "71, models, {'context': 'I-organism'}", + "72, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "73, of {'perturbing_action': 'I-gene gain-of-function'}", + "74, GDF15 {'perturbing_action': 'I-gene gain-of-function'}", + "172, vivo {'context': 'I-in vivo'}", + "174, mice. {'context': 'B-organism'}", + "175, Gfral-/- {'perturbing_action': 'B-gene loss-of-function'}", + "176, mice {'context': 'B-organism'}", + "210, rats. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "70, animal ['l0', 'l1', 'l2', 'l3']", + "71, models, ['l0', 'l4', 'l5', 'l6']", + "72, overexpression ['l1', 'l4', 'l7', 'l8', 'l9', 'l10']", + "73, of ['l2', 'l5', 'l7', 'l11', 'l12', 'l13']", + "74, GDF15 ['l3', 'l6', 'l8', 'l11', 'l14', 'l15']", + "172, vivo ['l9', 'l12', 'l14', 'l16']", + "174, mice. ['l10', 'l13', 'l15', 'l16']", + "175, Gfral-/- ['l17']", + "176, mice ['l17']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "animal", + "models,", + "mice." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "GDF15" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "GDF15" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gfral-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "28846097", + "TEXT": "Growth differentiation factor 15 (GDF15), a distant member of the transforming growth factor (TGF)-β family, is a secreted protein that circulates as a 25-kDa dimer. In humans, elevated GDF15 correlates with weight loss, and the administration of GDF15 to mice with obesity reduces body weight, at least in part, by decreasing food intake. The mechanisms through which GDF15 reduces body weight remain poorly understood, because the cognate receptor for GDF15 is unknown. Here we show that recombinant GDF15 induces weight loss in mice fed a high-fat diet and in nonhuman primates with spontaneous obesity. Furthermore, we find that GDF15 binds with high affinity to GDNF family receptor α-like (GFRAL), a distant relative of receptors for a distinct class of the TGF-β superfamily ligands. Gfral is expressed in neurons of the area postrema and nucleus of the solitary tract in mice and humans, and genetic deletion of the receptor abrogates the ability of GDF15 to decrease food intake and body weight in mice. In addition, diet-induced obesity and insulin resistance are exacerbated in GFRAL-deficient mice, suggesting a homeostatic role for this receptor in metabolism. Finally, we demonstrate that GDF15-induced cell signaling requires the interaction of GFRAL with the coreceptor RET. Our data identify GFRAL as a new regulator of body weight and as the bona fide receptor mediating the metabolic effects of GDF15, enabling a more comprehensive assessment of GDF15 as a potential pharmacotherapy for the treatment of obesity.", + "TAG_DATA": [ + "82, mice {'context': 'B-organism'}", + "89, nonhuman {'context': 'B-organism'}", + "90, primates {'context': 'I-organism'}", + "143, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "144, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "145, of {'perturbing_action': 'I-gene loss-of-function'}", + "146, the {'perturbing_action': 'I-gene loss-of-function'}", + "147, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "161, mice. {'context': 'B-organism'}", + "172, GFRAL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "173, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "89, nonhuman ['l0']", + "90, primates ['l0']", + "143, genetic ['l1', 'l2', 'l3', 'l4', 'l5']", + "144, deletion ['l1', 'l6', 'l7', 'l8', 'l9']", + "145, of ['l2', 'l6', 'l10', 'l11', 'l12']", + "146, the ['l3', 'l7', 'l10', 'l13', 'l14']", + "147, receptor ['l4', 'l8', 'l11', 'l13', 'l15']", + "161, mice. ['l5', 'l9', 'l12', 'l14', 'l15']", + "172, GFRAL-deficient ['l16']", + "173, mice, ['l16']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "the", + "receptor", + "GFRAL-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice," + ] + } + } + ] + }, + { + "PMID": "28805820", + "TEXT": "The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer. Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer; they are therefore being pursued as attractive therapeutic targets for selective inhibition in patients with cancer. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed and have shown promising outcomes in early clinical trials. Although resistance to BET inhibitors has been documented in preclinical models, the molecular mechanisms underlying acquired resistance are largely unknown. Here we report that cullin-3SPOP earmarks BET proteins, including BRD2, BRD3 and BRD4, for ubiquitination-mediated degradation. Pathologically, prostate cancer-associated SPOP mutants fail to interact with and promote the degradation of BET proteins, leading to their elevated abundance in SPOP-mutant prostate cancer. As a result, prostate cancer cell lines and organoids derived from individuals harboring SPOP mutations are more resistant to BET-inhibitor-induced cell growth arrest and apoptosis. Therefore, our results elucidate the tumor-suppressor role of SPOP in prostate cancer in which it acts as a negative regulator of BET protein stability and also provide a molecular mechanism for resistance to BET inhibitors in individuals with prostate cancer bearing SPOP mutations.", + "TAG_DATA": [ + "193, prostate {'context': 'B-neoplasm'}", + "198, prostate {'context': 'B-transformed cells'}", + "199, cancer {'context': 'I-transformed cells'}", + "200, cell {'context': 'I-transformed cells'}", + "201, lines {'context': 'I-transformed cells'}", + "203, organoids {'context': 'B-organoid'}", + "208, SPOP {'perturbing_action': 'B-other'}", + "209, mutations {'perturbing_action': 'I-other'}", + "211, more {'effect': 'B-negative'}", + "212, resistant {'effect': 'B-negative'}", + "214, BET-inhibitor-induced {'perturbing_action': 'B-pharmacological inhibition'}", + "215, cell {'phenotype': 'B-cell growth'}", + "216, growth {'phenotype': 'I-cell growth'}", + "217, arrest {'effect': 'B-negative', 'phenotype': 'I-cell cycle arrest'}", + "219, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "198, prostate ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "199, cancer ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "200, cell ['l1', 'l13', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "201, lines ['l2', 'l14', 'l24', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "203, organoids ['l3', 'l15', 'l25', 'l34', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "208, SPOP ['l4', 'l43', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "209, mutations ['l5', 'l16', 'l26', 'l35', 'l44', 'l52', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "211, more ['l6', 'l17', 'l27', 'l36', 'l45', 'l53', 'l60', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "212, resistant ['l7', 'l18', 'l28', 'l37', 'l46', 'l54', 'l61', 'l67', 'l73', 'l74', 'l75', 'l76', 'l77']", + "214, BET-inhibitor-induced ['l8', 'l19', 'l29', 'l38', 'l47', 'l55', 'l62', 'l68', 'l73', 'l78', 'l79', 'l80', 'l81']", + "215, cell ['l9', 'l20', 'l30', 'l39', 'l48', 'l56', 'l63', 'l69', 'l74', 'l78', 'l82', 'l83', 'l84']", + "216, growth ['l10', 'l21', 'l31', 'l40', 'l49', 'l57', 'l64', 'l70', 'l75', 'l79', 'l82', 'l85', 'l86']", + "217, arrest ['l11', 'l22', 'l32', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l83', 'l85', 'l87']", + "219, apoptosis. ['l12', 'l23', 'l33', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l86', 'l87']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cell", + "lines" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "SPOP", + "mutations" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cell", + "lines" + ] + }, + "effect": { + "val": "negative", + "words": [ + "more", + "resistant", + "arrest" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cell", + "lines" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BET-inhibitor-induced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cell", + "lines" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cell", + "lines" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "arrest", + "more", + "resistant" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "cell", + "lines" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "organoids" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "SPOP", + "mutations" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "organoids" + ] + }, + "effect": { + "val": "negative", + "words": [ + "more", + "resistant", + "arrest" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "organoids" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BET-inhibitor-induced" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "organoids" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "organoids" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "organoids" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "SPOP", + "mutations" + ] + }, + "effect": { + "val": "negative", + "words": [ + "more", + "resistant", + "arrest" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "SPOP", + "mutations" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "SPOP", + "mutations" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "SPOP", + "mutations" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "more", + "resistant", + "arrest" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BET-inhibitor-induced" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "more", + "resistant", + "arrest" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "more", + "resistant", + "arrest" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BET-inhibitor-induced" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BET-inhibitor-induced" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BET-inhibitor-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "28714991", + "TEXT": "Inflammatory diseases such as arthritis are chronic conditions that fail to resolve spontaneously. While the cytokine and cellular pathways triggering arthritis are well defined, those responsible for the resolution of inflammation are incompletely characterized. Here we identified interleukin (IL)-9-producing type 2 innate lymphoid cells (ILC2s) as the mediators of a molecular and cellular pathway that orchestrates the resolution of chronic inflammation. In mice, the absence of IL-9 impaired ILC2 proliferation and activation of regulatory T (Treg) cells, and resulted in chronic arthritis with excessive cartilage destruction and bone loss. In contrast, treatment with IL-9 promoted ILC2-dependent Treg activation and effectively induced resolution of inflammation and protection of bone. Patients with rheumatoid arthritis in remission exhibited high numbers of IL-9+ ILC2s in joints and the circulation. Hence, fostering IL-9-mediated ILC2 activation may offer a novel therapeutic approach inducing resolution of inflammation rather than suppression of inflammatory responses.", + "TAG_DATA": [ + "62, mice, {'context': 'B-organism'}", + "64, absence {'perturbing_action': 'B-gene loss-of-function'}", + "65, of {'perturbing_action': 'I-gene loss-of-function'}", + "66, IL-9 {'perturbing_action': 'I-gene loss-of-function'}", + "67, impaired {'effect': 'B-negative'}", + "68, ILC2 {'context': 'B-cells'}", + "69, proliferation {'phenotype': 'B-proliferation'}", + "73, regulatory {'context': 'B-cells'}", + "74, T {'context': 'I-cells'}", + "75, (Treg) {'context': 'I-cells'}", + "76, cells, {'context': 'I-cells'}", + "96, Treg {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "62, mice, ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "64, absence ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "65, of ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "66, IL-9 ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "67, impaired ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "68, ILC2 ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "69, proliferation ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "73, regulatory ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "74, T ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "75, (Treg) ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "76, cells, ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "IL-9" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "IL-9" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "IL-9" + ] + }, + "context": { + "val": "cells", + "words": [ + "ILC2", + "regulatory", + "T", + "(Treg)", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "IL-9" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "cells", + "words": [ + "ILC2", + "regulatory", + "T", + "(Treg)", + "cells," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "ILC2", + "regulatory", + "T", + "(Treg)", + "cells," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "28604702", + "TEXT": "The extracellular matrix (ECM) is a master regulator of cellular phenotype and behavior. It has a crucial role in both normal tissue homeostasis and disease pathology. Here we present a fast and efficient approach to enhance the study of ECM composition and structure. Termed in situ decellularization of tissues (ISDoT), it allows whole organs to be decellularized, leaving native ECM architecture intact. These three-dimensional decellularized tissues can be studied using high-resolution fluorescence and second harmonic imaging, and can be used for quantitative proteomic interrogation of the ECM. Our method is superior to other methods tested in its ability to preserve the structural integrity of the ECM, facilitate high-resolution imaging and quantitatively detect ECM proteins. In particular, we performed high-resolution sub-micron imaging of matrix topography in normal tissue and over the course of primary tumor development and progression to metastasis in mice, providing the first detailed imaging of the metastatic niche. These data show that cancer-driven ECM remodeling is organ specific, and that it is accompanied by comprehensive changes in ECM composition and topological structure. We also describe differing patterns of basement-membrane organization surrounding different types of blood vessels in healthy and diseased tissues. The ISDoT procedure allows for the study of native ECM structure under normal and pathological conditions in unprecedented detail.", + "TAG_DATA": [ + "132, primary {'context': 'B-neoplasm'}", + "133, tumor {'context': 'I-neoplasm'}", + "134, development {'phenotype': 'I-tumourigenesis'}", + "138, metastasis {'phenotype': 'B-metastasis'}", + "140, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "132, primary ['l0', 'l1', 'l2', 'l3', 'l4']", + "133, tumor ['l0', 'l5', 'l6', 'l7', 'l8']", + "134, development ['l1', 'l5', 'l9', 'l10', 'l11']", + "136, progression ['l2', 'l6', 'l9', 'l12', 'l13']", + "138, metastasis ['l3', 'l7', 'l10', 'l12', 'l14']", + "140, mice, ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "primary", + "tumor" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "primary", + "tumor" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "28504725", + "TEXT": "Fragile X syndrome (FXS) is the leading monogenic cause of autism spectrum disorders (ASD). Trinucleotide repeat expansions in FMR1 abolish FMRP expression, leading to hyperactivation of ERK and mTOR signaling upstream of mRNA translation. Here we show that metformin, the most widely used drug for type 2 diabetes, rescues core phenotypes in Fmr1-/y mice and selectively normalizes ERK signaling, eIF4E phosphorylation and the expression of MMP-9. Thus, metformin is a potential FXS therapeutic.", + "TAG_DATA": [ + "52, Fmr1-/y {'perturbing_action': 'B-gene loss-of-function'}", + "53, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "52, Fmr1-/y ['l0']", + "53, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fmr1-/y" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "28459438", + "TEXT": "Blood vessels in the central nervous system (CNS) are controlled by neuronal activity. For example, widespread vessel constriction (vessel tone) is induced by brainstem neurons that release the monoamines serotonin and noradrenaline, and local vessel dilation is induced by glutamatergic neuron activity. Here we examined how vessel tone adapts to the loss of neuron-derived monoamines after spinal cord injury (SCI) in rats. We find that, months after the imposition of SCI, the spinal cord below the site of injury is in a chronic state of hypoxia owing to paradoxical excess activity of monoamine receptors (5-HT1) on pericytes, despite the absence of monoamines. This monoamine-receptor activity causes pericytes to locally constrict capillaries, which reduces blood flow to ischemic levels. Receptor activation in the absence of monoamines results from the production of trace amines (such as tryptamine) by pericytes that ectopically express the enzyme aromatic L-amino acid decarboxylase (AADC), which synthesizes trace amines directly from dietary amino acids (such as tryptophan). Inhibition of monoamine receptors or of AADC, or even an increase in inhaled oxygen, produces substantial relief from hypoxia and improves motoneuron and locomotor function after SCI.", + "TAG_DATA": [ + "72, spinal {'context': 'B-tissue/organ'}", + "73, cord {'context': 'I-tissue/organ'}", + "106, pericytes {'context': 'B-cells'}", + "136, pericytes {'context': 'B-cells'}", + "138, ectopically {'perturbing_action': 'B-gene gain-of-function'}", + "139, express {'perturbing_action': 'I-gene gain-of-function'}", + "140, the {'perturbing_action': 'I-gene gain-of-function'}", + "141, enzyme {'perturbing_action': 'I-gene gain-of-function'}", + "142, aromatic {'perturbing_action': 'I-gene gain-of-function'}", + "143, L-amino {'perturbing_action': 'I-gene gain-of-function'}", + "144, acid {'perturbing_action': 'I-gene gain-of-function'}", + "145, decarboxylase {'perturbing_action': 'I-gene gain-of-function'}", + "146, (AADC), {'perturbing_action': 'I-gene gain-of-function'}", + "180, motoneuron {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "72, spinal ['l0', 'l1']", + "73, cord ['l0', 'l2']", + "106, pericytes ['l1', 'l2']", + "136, pericytes ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "138, ectopically ['l3', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "139, express ['l4', 'l14', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "140, the ['l5', 'l15', 'l24', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "141, enzyme ['l6', 'l16', 'l25', 'l33', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "142, aromatic ['l7', 'l17', 'l26', 'l34', 'l41', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "143, L-amino ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l54', 'l55', 'l56', 'l57', 'l58']", + "144, acid ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l59', 'l60', 'l61', 'l62']", + "145, decarboxylase ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l63', 'l64', 'l65']", + "146, (AADC), ['l11', 'l21', 'l30', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l66', 'l67']", + "162, receptors ['l12', 'l22', 'l31', 'l39', 'l46', 'l52', 'l57', 'l61', 'l64', 'l66', 'l68']", + "180, motoneuron ['l13', 'l23', 'l32', 'l40', 'l47', 'l53', 'l58', 'l62', 'l65', 'l67', 'l68']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "pericytes", + "motoneuron" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopically", + "express", + "the", + "enzyme", + "aromatic", + "L-amino", + "acid", + "decarboxylase", + "(AADC)," + ] + } + } + ] + }, + { + "PMID": "28414328", + "TEXT": "Splenic marginal zone B (MZB) cells, positioned at the interface between circulating blood and lymphoid tissue, detect and respond to blood-borne antigens. Here we show that MZB cells in mice activate a homeostatic program in response to a high-cholesterol diet (HCD) and regulate both the differentiation and accumulation of T follicular helper (TFH) cells. Feeding mice an HCD resulted in upregulated MZB cell surface expression of the immunoregulatory ligand PDL1 in an ATF3-dependent manner and increased the interaction between MZB cells and pre-TFH cells, leading to PDL1-mediated suppression of TFH cell motility, alteration of TFH cell differentiation, reduced TFH abundance and suppression of the proatherogenic TFH response. Our findings reveal a previously unsuspected role for MZB cells in controlling the TFH-germinal center response to a cholesterol-rich diet and uncover a PDL1-dependent mechanism through which MZB cells use their innate immune properties to limit an exaggerated adaptive immune response.", + "TAG_DATA": [ + "55, mice {'context': 'B-organism'}", + "82, pre-TFH {'context': 'B-cells'}", + "83, cells, {'context': 'I-cells'}", + "87, suppression {'effect': 'B-negative'}", + "89, TFH {'context': 'B-cells'}", + "90, cell {'context': 'I-cells'}", + "91, motility, {'phenotype': 'B-migration'}", + "92, alteration {'effect': 'B-regulates'}", + "94, TFH {'context': 'B-cells'}", + "95, cell {'context': 'I-cells'}", + "96, differentiation, {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "55, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "82, pre-TFH ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "83, cells, ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "87, suppression ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "89, TFH ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38']", + "90, cell ['l4', 'l13', 'l21', 'l28', 'l34', 'l39', 'l40', 'l41']", + "91, motility, ['l5', 'l14', 'l22', 'l29', 'l35', 'l39', 'l42', 'l43']", + "92, alteration ['l6', 'l15', 'l23', 'l30', 'l36', 'l44', 'l45', 'l46']", + "94, TFH ['l7', 'l16', 'l24', 'l31', 'l44', 'l47', 'l48']", + "95, cell ['l8', 'l17', 'l25', 'l32', 'l37', 'l40', 'l42', 'l45', 'l47', 'l49']", + "96, differentiation, ['l9', 'l18', 'l26', 'l33', 'l38', 'l41', 'l43', 'l46', 'l48', 'l49']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppression" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "motility," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "alteration" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pre-TFH", + "cells,", + "TFH", + "cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppression" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pre-TFH", + "cells,", + "TFH", + "cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "motility," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pre-TFH", + "cells,", + "TFH", + "cell" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "alteration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pre-TFH", + "cells,", + "TFH", + "cell" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppression" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "motility," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppression" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "alteration" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + } + ] + }, + { + "PMID": "28092666", + "TEXT": "Opioid pain medications have detrimental side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). Tolerance and OIH counteract opioid analgesia and drive dose escalation. The cell types and receptors on which opioids act to initiate these maladaptive processes remain disputed, which has prevented the development of therapies to maximize and sustain opioid analgesic efficacy. We found that μ opioid receptors (MORs) expressed by primary afferent nociceptors initiate tolerance and OIH development. RNA sequencing and histological analysis revealed that MORs are expressed by nociceptors, but not by spinal microglia. Deletion of MORs specifically in nociceptors eliminated morphine tolerance, OIH and pronociceptive synaptic long-term potentiation without altering antinociception. Furthermore, we found that co-administration of methylnaltrexone bromide, a peripherally restricted MOR antagonist, was sufficient to abrogate morphine tolerance and OIH without diminishing antinociception in perioperative and chronic pain models. Collectively, our data support the idea that opioid agonists can be combined with peripheral MOR antagonists to limit analgesic tolerance and OIH.", + "TAG_DATA": [ + "88, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "89, of {'perturbing_action': 'I-gene loss-of-function'}", + "90, MORs {'perturbing_action': 'I-gene loss-of-function'}", + "91, specifically {'perturbing_action': 'I-gene loss-of-function'}", + "93, nociceptors {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "88, Deletion ['l0', 'l1', 'l2', 'l3']", + "89, of ['l0', 'l4', 'l5', 'l6']", + "90, MORs ['l1', 'l4', 'l7', 'l8']", + "91, specifically ['l2', 'l5', 'l7', 'l9']", + "93, nociceptors ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "MORs", + "specifically" + ] + }, + "context": { + "val": "cells", + "words": [ + "nociceptors" + ] + } + } + ] + }, + { + "PMID": "28067901", + "TEXT": "The cytostatic deoxycytidine analog cytarabine (ara-C) is the most active agent available against acute myelogenous leukemia (AML). Together with anthracyclines, ara-C forms the backbone of AML treatment for children and adults. In AML, both the cytotoxicity of ara-C in vitro and the clinical response to ara-C therapy are correlated with the ability of AML blasts to accumulate the active metabolite ara-C triphosphate (ara-CTP), which causes DNA damage through perturbation of DNA synthesis. Differences in expression levels of known transporters or metabolic enzymes relevant to ara-C only partially account for patient-specific differential ara-CTP accumulation in AML blasts and response to ara-C treatment. Here we demonstrate that the deoxynucleoside triphosphate (dNTP) triphosphohydrolase SAM domain and HD domain 1 (SAMHD1) promotes the detoxification of intracellular ara-CTP pools. Recombinant SAMHD1 exhibited ara-CTPase activity in vitro, and cells in which SAMHD1 expression was transiently reduced by treatment with the simian immunodeficiency virus (SIV) protein Vpx were dramatically more sensitive to ara-C-induced cytotoxicity. CRISPR-Cas9-mediated disruption of the gene encoding SAMHD1 sensitized cells to ara-C, and this sensitivity could be abrogated by ectopic expression of wild-type (WT), but not dNTPase-deficient, SAMHD1. Mouse models of AML lacking SAMHD1 were hypersensitive to ara-C, and treatment ex vivo with Vpx sensitized primary patient-derived AML blasts to ara-C. Finally, we identified SAMHD1 as a risk factor in cohorts of both pediatric and adult patients with de novo AML who received ara-C treatment. Thus, SAMHD1 expression levels dictate patient sensitivity to ara-C, providing proof-of-concept that the targeting of SAMHD1 by Vpx could be an attractive therapeutic", + "TAG_DATA": [ + "129, in {'context': 'B-in vitro'}", + "130, vitro, {'context': 'I-in vitro'}", + "132, cells {'context': 'B-cells'}", + "157, CRISPR-Cas9-mediated {'perturbing_action': 'B-gene loss-of-function'}", + "158, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "159, of {'perturbing_action': 'I-gene loss-of-function'}", + "160, the {'perturbing_action': 'I-gene loss-of-function'}", + "161, gene {'perturbing_action': 'I-gene loss-of-function'}", + "162, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "163, SAMHD1 {'perturbing_action': 'I-gene loss-of-function'}", + "165, cells {'context': 'B-cells'}", + "175, ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "176, expression {'perturbing_action': 'I-gene gain-of-function'}", + "177, of {'perturbing_action': 'I-gene gain-of-function'}", + "178, wild-type {'perturbing_action': 'I-gene gain-of-function'}", + "179, (WT), {'perturbing_action': 'I-gene gain-of-function'}", + "183, SAMHD1. {'perturbing_action': 'I-gene loss-of-function'}", + "184, Mouse {'context': 'B-organism'}", + "185, models {'context': 'I-neoplasm'}", + "186, of {'context': 'I-neoplasm'}", + "187, AML {'context': 'I-neoplasm'}", + "188, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "189, SAMHD1 {'perturbing_action': 'I-gene loss-of-function'}", + "201, primary {'context': 'B-transformed cells'}", + "202, patient-derived {'context': 'I-transformed cells'}", + "203, AML {'context': 'I-transformed cells'}", + "204, blasts {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "129, in ['l0', 'l1']", + "130, vitro, ['l0', 'l2']", + "132, cells ['l1', 'l2']", + "157, CRISPR-Cas9-mediated ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "158, disruption ['l3', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "159, of ['l4', 'l15', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "160, the ['l5', 'l16', 'l25', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "161, gene ['l6', 'l17', 'l26', 'l34', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "162, encoding ['l7', 'l18', 'l27', 'l35', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "163, SAMHD1 ['l8', 'l19', 'l28', 'l36', 'l44', 'l51', 'l58']", + "165, cells ['l9', 'l20', 'l29', 'l37', 'l45', 'l52', 'l58']", + "175, ectopic ['l10', 'l21', 'l30', 'l38', 'l46', 'l53', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "176, expression ['l11', 'l22', 'l31', 'l39', 'l47', 'l54', 'l59', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "177, of ['l12', 'l23', 'l32', 'l40', 'l48', 'l55', 'l60', 'l71', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "178, wild-type ['l61', 'l72', 'l84', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "179, (WT), ['l13', 'l41', 'l49', 'l56', 'l62', 'l73', 'l85', 'l96', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "183, SAMHD1. ['l14', 'l24', 'l33', 'l42', 'l50', 'l57', 'l63', 'l74', 'l86', 'l97', 'l108', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "184, Mouse ['l64', 'l75', 'l87', 'l98', 'l109', 'l119', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "185, models ['l65', 'l76', 'l88', 'l99', 'l110', 'l120', 'l129', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145']", + "186, of ['l66', 'l77', 'l89', 'l100', 'l111', 'l121', 'l130', 'l138', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "187, AML ['l67', 'l78', 'l90', 'l101', 'l112', 'l122', 'l131', 'l139', 'l146', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158']", + "188, lacking ['l68', 'l79', 'l91', 'l102', 'l113', 'l123', 'l132', 'l140', 'l147', 'l153', 'l159', 'l160', 'l161', 'l162', 'l163']", + "189, SAMHD1 ['l69', 'l80', 'l92', 'l103', 'l114', 'l124', 'l133', 'l141', 'l148', 'l154', 'l159', 'l164', 'l165', 'l166', 'l167']", + "201, primary ['l104', 'l115', 'l125', 'l134', 'l142', 'l149', 'l155', 'l160', 'l164', 'l168', 'l169', 'l170']", + "202, patient-derived ['l81', 'l93', 'l105', 'l116', 'l126', 'l135', 'l143', 'l150', 'l156', 'l161', 'l165', 'l168', 'l171', 'l172']", + "203, AML ['l82', 'l94', 'l106', 'l117', 'l127', 'l136', 'l144', 'l151', 'l157', 'l162', 'l166', 'l169', 'l171', 'l173']", + "204, blasts ['l70', 'l83', 'l95', 'l107', 'l118', 'l128', 'l137', 'l145', 'l152', 'l158', 'l163', 'l167', 'l170', 'l172', 'l173']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CRISPR-Cas9-mediated", + "disruption", + "of", + "the", + "gene", + "encoding", + "SAMHD1" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "expression", + "of", + "wild-type", + "(WT)," + ] + }, + "context": { + "val": "organism", + "words": [ + "Mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "expression", + "of", + "wild-type", + "(WT)," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models", + "of", + "AML" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "expression", + "of", + "wild-type", + "(WT)," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "blasts", + "patient-derived", + "AML", + "primary" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SAMHD1.", + "lacking", + "SAMHD1" + ] + }, + "context": { + "val": "organism", + "words": [ + "Mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SAMHD1.", + "lacking", + "SAMHD1" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "models", + "of", + "AML" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SAMHD1.", + "lacking", + "SAMHD1" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "patient-derived", + "AML", + "blasts" + ] + } + } + ] + }, + { + "PMID": "28024084", + "TEXT": "Prader-Willi syndrome (PWS) is an imprinting disorder caused by a deficiency of paternally expressed gene(s) in the 15q11-q13 chromosomal region. The regulation of imprinted gene expression in this region is coordinated by an imprinting center (PWS-IC). In individuals with PWS, genes responsible for PWS on the maternal chromosome are present, but repressed epigenetically, which provides an opportunity for the use of epigenetic therapy to restore expression from the maternal copies of PWS-associated genes. Through a high-content screen (HCS) of >9,000 small molecules, we discovered that UNC0638 and UNC0642-two selective inhibitors of euchromatic histone lysine N-methyltransferase-2 (EHMT2, also known as G9a)-activated the maternal (m) copy of candidate genes underlying PWS, including the SnoRNA cluster SNORD116, in cells from humans with PWS and also from a mouse model of PWS carrying a paternal (p) deletion from small nuclear ribonucleoprotein N (Snrpn (S)) to ubiquitin protein ligase E3A (Ube3a (U)) (mouse model referred to hereafter as m+/pΔS-U). Both UNC0642 and UNC0638 caused a selective reduction of the dimethylation of histone H3 lysine 9 (H3K9me2) at PWS-IC, without changing DNA methylation, when analyzed by bisulfite genomic sequencing. This indicates that histone modification is essential for the imprinting of candidate genes underlying PWS. UNC0642 displayed therapeutic effects in the PWS mouse model by improving the survival and the growth of m+/pΔS-U newborn pups. This study provides the first proof of principle for an epigenetics-based therapy for PWS.", + "TAG_DATA": [ + "115, cells {'context': 'B-cells'}", + "124, mouse {'context': 'B-organism'}", + "125, model {'context': 'I-organism'}", + "126, of {'context': 'I-organism'}", + "127, PWS {'context': 'I-organism'}", + "130, paternal {'perturbing_action': 'B-gene loss-of-function'}", + "132, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "204, PWS {'context': 'B-organism'}", + "205, mouse {'context': 'I-organism'}", + "206, model {'context': 'I-organism'}", + "216, newborn {'context': 'B-organism'}", + "217, pups. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "124, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "125, model ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "126, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "127, PWS ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "130, paternal ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "131, (p) ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "132, deletion ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "140, to ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "144, E3A ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "204, PWS ['l36', 'l37', 'l38', 'l39']", + "205, mouse ['l36', 'l40', 'l41', 'l42']", + "206, model ['l37', 'l40', 'l43', 'l44']", + "216, newborn ['l38', 'l41', 'l43', 'l45']", + "217, pups. ['l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "PWS" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "paternal", + "deletion" + ] + } + } + ] + }, + { + "PMID": "27941793", + "TEXT": "New therapeutic approaches are needed to treat leukemia effectively. Dietary restriction regimens, including fasting, have been considered for the prevention and treatment of certain solid tumor types. However, whether and how dietary restriction affects hematopoietic malignancies is unknown. Here we report that fasting alone robustly inhibits the initiation and reverses the leukemic progression of both B cell and T cell acute lymphoblastic leukemia (B-ALL and T-ALL, respectively), but not acute myeloid leukemia (AML), in mouse models of these tumors. Mechanistically, we found that attenuated leptin-receptor (LEPR) expression is essential for the development and maintenance of ALL, and that fasting inhibits ALL development by upregulation of LEPR and its downstream signaling through the protein PR/SET domain 1 (PRDM1). The expression of LEPR signaling-related genes correlated with the prognosis of pediatric patients with pre-B-ALL, and fasting effectively inhibited B-ALL growth in a human xenograft model. Our results indicate that the effects of fasting on tumor growth are cancer-type dependent, and they suggest new avenues for the development of treatment strategies for leukemia.", + "TAG_DATA": [ + "45, inhibits {'effect': 'B-negative'}", + "49, reverses {'effect': 'B-negative'}", + "51, leukemic {'context': 'B-neoplasm', 'phenotype': 'B-autophagy'}", + "52, progression {'phenotype': 'I-tumour progression'}", + "55, B {'context': 'B-neoplasm'}", + "56, cell {'context': 'I-neoplasm'}", + "57, and {'context': 'I-neoplasm'}", + "58, T {'context': 'I-neoplasm'}", + "59, cell {'context': 'I-neoplasm'}", + "60, acute {'context': 'I-neoplasm'}", + "61, lymphoblastic {'context': 'I-neoplasm'}", + "62, leukemia {'context': 'I-neoplasm'}", + "63, (B-ALL {'context': 'I-neoplasm'}", + "65, T-ALL, {'context': 'I-transformed cells'}", + "69, acute {'context': 'B-neoplasm'}", + "70, myeloid {'context': 'I-neoplasm'}", + "71, leukemia {'context': 'I-neoplasm'}", + "72, (AML), {'context': 'I-neoplasm'}", + "74, mouse {'context': 'B-organism'}", + "75, models {'context': 'I-neoplasm'}", + "76, of {'context': 'I-neoplasm'}", + "77, these {'context': 'I-neoplasm'}", + "78, tumors. {'context': 'I-neoplasm'}", + "99, inhibits {'effect': 'B-negative'}", + "100, ALL {'context': 'B-neoplasm'}", + "136, B-ALL {'context': 'B-neoplasm'}", + "140, human {'context': 'B-xenograft'}", + "141, xenograft {'context': 'I-xenograft'}", + "142, model. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "45, inhibits ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "49, reverses ['l0', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "51, leukemic ['l1', 'l22', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "52, progression ['l2', 'l23', 'l42', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "55, B ['l3', 'l24', 'l43', 'l62', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "56, cell ['l4', 'l25', 'l44', 'l63', 'l77', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "57, and ['l5', 'l26', 'l45', 'l64', 'l78', 'l95', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127']", + "58, T ['l6', 'l27', 'l46', 'l65', 'l79', 'l96', 'l112', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "59, cell ['l7', 'l28', 'l47', 'l66', 'l80', 'l97', 'l113', 'l128', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156']", + "60, acute ['l8', 'l29', 'l48', 'l67', 'l81', 'l98', 'l114', 'l129', 'l143', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "61, lymphoblastic ['l9', 'l30', 'l49', 'l68', 'l82', 'l99', 'l115', 'l130', 'l144', 'l157', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181']", + "62, leukemia ['l10', 'l31', 'l50', 'l69', 'l83', 'l100', 'l116', 'l131', 'l145', 'l158', 'l170', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192']", + "63, (B-ALL ['l11', 'l32', 'l51', 'l70', 'l84', 'l101', 'l117', 'l132', 'l146', 'l159', 'l171', 'l182', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202']", + "65, T-ALL, ['l12', 'l33', 'l52', 'l71', 'l85', 'l102', 'l118', 'l133', 'l147', 'l160', 'l172', 'l183', 'l193', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211']", + "69, acute ['l13', 'l34', 'l53', 'l86', 'l103', 'l119', 'l134', 'l148', 'l161', 'l173', 'l184', 'l194', 'l203', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219']", + "70, myeloid ['l14', 'l54', 'l87', 'l104', 'l120', 'l135', 'l149', 'l162', 'l174', 'l185', 'l195', 'l204', 'l212', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226']", + "71, leukemia ['l15', 'l35', 'l55', 'l88', 'l105', 'l121', 'l136', 'l150', 'l163', 'l175', 'l186', 'l196', 'l205', 'l213', 'l220', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232']", + "72, (AML), ['l16', 'l36', 'l56', 'l89', 'l106', 'l122', 'l137', 'l151', 'l164', 'l176', 'l187', 'l197', 'l206', 'l214', 'l221', 'l227', 'l233', 'l234', 'l235', 'l236', 'l237']", + "74, mouse ['l17', 'l37', 'l57', 'l72', 'l90', 'l107', 'l123', 'l138', 'l152', 'l165', 'l177', 'l188', 'l198', 'l207', 'l215', 'l222', 'l228', 'l233', 'l238', 'l239', 'l240', 'l241']", + "75, models ['l18', 'l38', 'l58', 'l73', 'l91', 'l108', 'l124', 'l139', 'l153', 'l166', 'l178', 'l189', 'l199', 'l208', 'l216', 'l223', 'l229', 'l234', 'l238', 'l242', 'l243', 'l244']", + "76, of ['l19', 'l39', 'l59', 'l74', 'l92', 'l109', 'l125', 'l140', 'l154', 'l167', 'l179', 'l190', 'l200', 'l209', 'l217', 'l224', 'l230', 'l235', 'l239', 'l242', 'l245', 'l246']", + "77, these ['l20', 'l40', 'l60', 'l75', 'l93', 'l110', 'l126', 'l141', 'l155', 'l168', 'l180', 'l191', 'l201', 'l210', 'l218', 'l225', 'l231', 'l236', 'l240', 'l243', 'l245', 'l247']", + "78, tumors. ['l21', 'l41', 'l61', 'l76', 'l94', 'l111', 'l127', 'l142', 'l156', 'l169', 'l181', 'l192', 'l202', 'l211', 'l219', 'l226', 'l232', 'l237', 'l241', 'l244', 'l246', 'l247']", + "99, inhibits ['l248']", + "100, ALL ['l248']", + "136, B-ALL ['l249', 'l250', 'l251']", + "140, human ['l249', 'l252', 'l253']", + "141, xenograft ['l250', 'l252', 'l254']", + "142, model. ['l251', 'l253', 'l254']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "reverses" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemic", + "B", + "cell", + "and", + "T", + "acute", + "lymphoblastic", + "leukemia", + "(B-ALL", + "myeloid", + "(AML),", + "models", + "of", + "these", + "tumors.", + "ALL" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "reverses" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "leukemic" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "leukemic" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "leukemic" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "reverses" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "progression" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "reverses" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "T-ALL," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "reverses" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "leukemic", + "B", + "cell", + "and", + "T", + "acute", + "lymphoblastic", + "leukemia", + "(B-ALL", + "models", + "of", + "these", + "tumors." + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "progression" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "leukemic" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "T-ALL," + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "leukemic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "phenotype": { + "val": "tumour progression", + "words": [ + "progression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "T-ALL," + ] + } + }, + { + "phenotype": { + "val": "tumour progression", + "words": [ + "progression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + } + ] + }, + { + "PMID": "27918563", + "TEXT": "The role of osteolineage cells in regulating hematopoietic stem cell (HSC) regeneration following myelosuppression is not well understood. Here we show that deletion of the pro-apoptotic genes Bak and Bax in osterix (Osx, also known as Sp7 transcription factor 7)-expressing cells in mice promotes HSC regeneration and hematopoietic radioprotection following total body irradiation. These mice showed increased bone marrow (BM) levels of the protein dickkopf-1 (Dkk1), which was produced in Osx-expressing BM cells. Treatment of irradiated HSCs with Dkk1 in vitro increased the recovery of both long-term repopulating HSCs and progenitor cells, and systemic administration of Dkk1 to irradiated mice increased hematopoietic recovery and improved survival. Conversely, inducible deletion of one allele of Dkk1 in Osx-expressing cells in adult mice inhibited the recovery of BM stem and progenitor cells and of complete blood counts following irradiation. Dkk1 promoted hematopoietic regeneration via both direct effects on HSCs, in which treatment with Dkk1 decreased the levels of mitochondrial reactive oxygen species and suppressed senescence, and indirect effects on BM endothelial cells, in which treatment with Dkk1 induced epidermal growth factor (EGF) secretion. Accordingly, blockade of the EGF receptor partially abrogated Dkk1-mediated hematopoietic recovery. These data identify Dkk1 as a regulator of hematopoietic regeneration and demonstrate paracrine cross-talk between BM osteolineage cells and endothelial cells in regulating hematopoietic reconstitution following injury.", + "TAG_DATA": [ + "22, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "23, of {'perturbing_action': 'I-gene loss-of-function'}", + "24, the {'perturbing_action': 'I-gene loss-of-function'}", + "25, pro-apoptotic {'perturbing_action': 'I-gene loss-of-function'}", + "26, genes {'perturbing_action': 'I-gene loss-of-function'}", + "27, Bak {'perturbing_action': 'I-gene loss-of-function'}", + "28, and {'perturbing_action': 'I-gene loss-of-function'}", + "29, Bax {'perturbing_action': 'I-gene loss-of-function'}", + "30, in {'perturbing_action': 'I-gene loss-of-function'}", + "31, osterix {'perturbing_action': 'I-gene loss-of-function'}", + "32, (Osx, {'perturbing_action': 'I-gene loss-of-function'}", + "36, Sp7 {'perturbing_action': 'I-gene loss-of-function'}", + "37, transcription {'perturbing_action': 'I-gene loss-of-function'}", + "38, factor {'perturbing_action': 'I-gene loss-of-function'}", + "39, 7)-expressing {'perturbing_action': 'I-gene loss-of-function'}", + "40, cells {'perturbing_action': 'I-gene loss-of-function'}", + "42, mice {'context': 'B-organism'}", + "54, mice {'context': 'B-organism'}", + "76, HSCs {'context': 'B-cells'}", + "79, in {'context': 'B-in vitro'}", + "80, vitro {'context': 'I-in vitro'}", + "88, HSCs {'context': 'I-cells'}", + "90, progenitor {'context': 'B-cells'}", + "91, cells, {'context': 'I-cells'}", + "99, mice {'context': 'B-organism'}", + "107, inducible {'perturbing_action': 'B-gene loss-of-function'}", + "108, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "109, of {'perturbing_action': 'I-gene loss-of-function'}", + "110, one {'perturbing_action': 'I-gene loss-of-function'}", + "111, allele {'perturbing_action': 'I-gene loss-of-function'}", + "112, of {'perturbing_action': 'I-gene loss-of-function'}", + "113, Dkk1 {'perturbing_action': 'I-gene loss-of-function'}", + "115, Osx-expressing {'context': 'B-cells'}", + "116, cells {'context': 'I-cells'}", + "118, adult {'context': 'B-organism'}", + "119, mice {'context': 'I-organism'}", + "124, BM {'context': 'B-cells'}", + "125, stem {'context': 'I-cells'}", + "126, and {'context': 'I-cells'}", + "127, progenitor {'context': 'I-cells'}", + "128, cells {'context': 'I-cells'}", + "145, HSCs, {'context': 'B-cells'}", + "160, suppressed {'effect': 'B-negative'}", + "161, senescence, {'phenotype': 'B-senescence'}", + "166, BM {'context': 'B-cells'}", + "167, endothelial {'context': 'I-cells'}", + "168, cells, {'context': 'I-cells'}", + "181, blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "182, of {'perturbing_action': 'I-pharmacological inhibition'}", + "183, the {'perturbing_action': 'I-pharmacological inhibition'}", + "184, EGF {'perturbing_action': 'I-pharmacological inhibition'}", + "185, receptor {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "22, deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "23, of ['l0', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "24, the ['l1', 'l25', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "25, pro-apoptotic ['l2', 'l26', 'l49', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "26, genes ['l3', 'l27', 'l50', 'l72', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "27, Bak ['l4', 'l28', 'l51', 'l73', 'l94', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "28, and ['l5', 'l29', 'l52', 'l74', 'l95', 'l115', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "29, Bax ['l6', 'l30', 'l53', 'l75', 'l96', 'l116', 'l135', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171']", + "30, in ['l7', 'l31', 'l54', 'l76', 'l97', 'l117', 'l136', 'l154', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "31, osterix ['l8', 'l32', 'l55', 'l77', 'l98', 'l118', 'l137', 'l155', 'l172', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "32, (Osx, ['l9', 'l33', 'l56', 'l78', 'l99', 'l119', 'l138', 'l156', 'l173', 'l189', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219']", + "33, also ['l10', 'l34', 'l57', 'l79', 'l100', 'l120', 'l139', 'l157', 'l174', 'l190', 'l205', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234']", + "36, Sp7 ['l11', 'l35', 'l58', 'l80', 'l101', 'l121', 'l140', 'l158', 'l175', 'l191', 'l206', 'l220', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248']", + "37, transcription ['l12', 'l36', 'l59', 'l81', 'l102', 'l122', 'l141', 'l159', 'l176', 'l192', 'l207', 'l221', 'l235', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261']", + "38, factor ['l13', 'l37', 'l60', 'l82', 'l103', 'l123', 'l142', 'l160', 'l177', 'l193', 'l208', 'l222', 'l236', 'l249', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273']", + "39, 7)-expressing ['l14', 'l38', 'l61', 'l83', 'l104', 'l124', 'l143', 'l161', 'l178', 'l194', 'l209', 'l223', 'l237', 'l250', 'l262', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284']", + "40, cells ['l15', 'l39', 'l62', 'l84', 'l105', 'l125', 'l144', 'l162', 'l179', 'l195', 'l210', 'l224', 'l238', 'l251', 'l263', 'l274', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292']", + "42, mice ['l16', 'l40', 'l63', 'l85', 'l106', 'l126', 'l145', 'l163', 'l180', 'l196', 'l211', 'l225', 'l239', 'l252', 'l264', 'l275', 'l285', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298']", + "54, mice ['l17', 'l41', 'l64', 'l86', 'l107', 'l127', 'l146', 'l164', 'l181', 'l197', 'l212', 'l226', 'l240', 'l253', 'l265', 'l276', 'l286', 'l293', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304']", + "76, HSCs ['l18', 'l42', 'l65', 'l87', 'l108', 'l128', 'l147', 'l165', 'l182', 'l198', 'l213', 'l227', 'l241', 'l254', 'l266', 'l277', 'l287', 'l294', 'l299', 'l305', 'l306', 'l307', 'l308', 'l309']", + "79, in ['l19', 'l43', 'l66', 'l88', 'l109', 'l129', 'l148', 'l166', 'l183', 'l199', 'l214', 'l228', 'l242', 'l255', 'l267', 'l278', 'l288', 'l295', 'l300', 'l305', 'l310', 'l311', 'l312', 'l313']", + "80, vitro ['l20', 'l44', 'l67', 'l89', 'l110', 'l130', 'l149', 'l167', 'l184', 'l200', 'l215', 'l229', 'l243', 'l256', 'l268', 'l279', 'l289', 'l296', 'l301', 'l306', 'l310', 'l314', 'l315', 'l316']", + "88, HSCs ['l21', 'l45', 'l68', 'l90', 'l111', 'l131', 'l150', 'l168', 'l185', 'l201', 'l216', 'l230', 'l244', 'l257', 'l269', 'l280', 'l290', 'l297', 'l302', 'l307', 'l311', 'l314', 'l317', 'l318']", + "90, progenitor ['l22', 'l46', 'l69', 'l91', 'l112', 'l132', 'l151', 'l169', 'l186', 'l202', 'l217', 'l231', 'l245', 'l258', 'l270', 'l281', 'l291', 'l303', 'l308', 'l312', 'l315', 'l317', 'l319']", + "91, cells, ['l23', 'l47', 'l70', 'l92', 'l113', 'l133', 'l152', 'l170', 'l187', 'l203', 'l218', 'l232', 'l246', 'l259', 'l271', 'l282', 'l292', 'l298', 'l304', 'l309', 'l313', 'l316', 'l318', 'l319']", + "99, mice ['l24', 'l48', 'l71', 'l93', 'l114', 'l134', 'l153', 'l171', 'l188', 'l204', 'l219', 'l233', 'l247', 'l260', 'l272', 'l283']", + "107, inducible ['l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327', 'l328', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340']", + "108, deletion ['l320', 'l341', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348', 'l349', 'l350', 'l351', 'l352', 'l353', 'l354', 'l355', 'l356', 'l357', 'l358', 'l359', 'l360']", + "109, of ['l321', 'l341', 'l361', 'l362', 'l363', 'l364', 'l365', 'l366', 'l367', 'l368', 'l369', 'l370', 'l371', 'l372', 'l373', 'l374', 'l375', 'l376', 'l377', 'l378', 'l379']", + "110, one ['l322', 'l342', 'l361', 'l380', 'l381', 'l382', 'l383', 'l384', 'l385', 'l386', 'l387', 'l388', 'l389', 'l390', 'l391', 'l392', 'l393', 'l394', 'l395', 'l396', 'l397']", + "111, allele ['l323', 'l343', 'l362', 'l380', 'l398', 'l399', 'l400', 'l401', 'l402', 'l403', 'l404', 'l405', 'l406', 'l407', 'l408', 'l409', 'l410', 'l411', 'l412', 'l413', 'l414']", + "112, of ['l324', 'l344', 'l363', 'l381', 'l398', 'l415', 'l416', 'l417', 'l418', 'l419', 'l420', 'l421', 'l422', 'l423', 'l424', 'l425', 'l426', 'l427', 'l428', 'l429', 'l430']", + "113, Dkk1 ['l325', 'l345', 'l364', 'l382', 'l399', 'l415', 'l431', 'l432', 'l433', 'l434', 'l435', 'l436', 'l437', 'l438', 'l439', 'l440', 'l441', 'l442', 'l443', 'l444', 'l445']", + "115, Osx-expressing ['l326', 'l346', 'l365', 'l383', 'l400', 'l416', 'l431', 'l446', 'l447', 'l448', 'l449', 'l450', 'l451', 'l452', 'l453', 'l454', 'l455', 'l456', 'l457']", + "116, cells ['l327', 'l347', 'l366', 'l384', 'l401', 'l417', 'l432', 'l446', 'l458', 'l459', 'l460', 'l461', 'l462', 'l463', 'l464', 'l465', 'l466', 'l467', 'l468']", + "118, adult ['l328', 'l348', 'l367', 'l385', 'l402', 'l418', 'l433', 'l447', 'l458', 'l469', 'l470', 'l471', 'l472', 'l473', 'l474', 'l475', 'l476', 'l477', 'l478']", + "119, mice ['l329', 'l349', 'l368', 'l386', 'l403', 'l419', 'l434', 'l448', 'l459', 'l469', 'l479', 'l480', 'l481', 'l482', 'l483', 'l484', 'l485', 'l486']", + "124, BM ['l330', 'l350', 'l369', 'l387', 'l404', 'l420', 'l435', 'l449', 'l460', 'l470', 'l479', 'l487', 'l488', 'l489', 'l490', 'l491', 'l492', 'l493']", + "125, stem ['l331', 'l351', 'l370', 'l388', 'l405', 'l421', 'l436', 'l450', 'l461', 'l471', 'l480', 'l487', 'l494', 'l495', 'l496', 'l497', 'l498', 'l499']", + "126, and ['l332', 'l352', 'l371', 'l389', 'l406', 'l422', 'l437', 'l451', 'l462', 'l472', 'l481', 'l488', 'l494', 'l500', 'l501', 'l502', 'l503']", + "127, progenitor ['l333', 'l353', 'l372', 'l390', 'l407', 'l423', 'l438', 'l452', 'l463', 'l473', 'l482', 'l489', 'l495', 'l500', 'l504', 'l505', 'l506', 'l507']", + "128, cells ['l234', 'l248', 'l261', 'l273', 'l284', 'l334', 'l354', 'l373', 'l391', 'l408', 'l424', 'l439', 'l453', 'l464', 'l474', 'l483', 'l490', 'l496', 'l501', 'l504']", + "145, HSCs, ['l335', 'l355', 'l374', 'l392', 'l409', 'l425', 'l440', 'l454', 'l465', 'l475', 'l484', 'l491', 'l497', 'l502', 'l505', 'l508', 'l509', 'l510', 'l511', 'l512']", + "160, suppressed ['l336', 'l356', 'l375', 'l393', 'l410', 'l426', 'l441', 'l455', 'l466', 'l476', 'l485', 'l492', 'l498', 'l503', 'l506', 'l508', 'l513', 'l514', 'l515']", + "161, senescence, ['l337', 'l357', 'l376', 'l394', 'l411', 'l427', 'l442', 'l456', 'l467', 'l477', 'l486', 'l493', 'l499', 'l507', 'l509', 'l513', 'l516', 'l517', 'l518']", + "166, BM ['l338', 'l358', 'l377', 'l395', 'l412', 'l428', 'l443', 'l510', 'l516', 'l519', 'l520']", + "167, endothelial ['l339', 'l359', 'l378', 'l396', 'l413', 'l429', 'l444', 'l511', 'l514', 'l517', 'l519', 'l521']", + "168, cells, ['l340', 'l360', 'l379', 'l397', 'l414', 'l430', 'l445', 'l457', 'l468', 'l478', 'l512', 'l515', 'l518', 'l520', 'l521']", + "181, blockade ['l522', 'l523', 'l524', 'l525']", + "182, of ['l522', 'l526', 'l527', 'l528']", + "183, the ['l523', 'l526', 'l529', 'l530']", + "184, EGF ['l524', 'l527', 'l529', 'l531']", + "185, receptor ['l525', 'l528', 'l530', 'l531']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "pro-apoptotic", + "genes", + "Bak", + "and", + "Bax", + "in", + "osterix", + "(Osx,", + "Sp7", + "transcription", + "factor", + "7)-expressing", + "cells", + "inducible", + "one", + "allele", + "Dkk1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "adult" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "pro-apoptotic", + "genes", + "Bak", + "and", + "Bax", + "in", + "osterix", + "(Osx,", + "Sp7", + "transcription", + "factor", + "7)-expressing", + "cells", + "inducible", + "one", + "allele", + "Dkk1" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSCs", + "progenitor", + "cells,", + "cells", + "Osx-expressing", + "BM", + "stem", + "and", + "HSCs,", + "endothelial" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "pro-apoptotic", + "genes", + "Bak", + "and", + "Bax", + "in", + "osterix", + "(Osx,", + "Sp7", + "transcription", + "factor", + "7)-expressing", + "cells" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inducible", + "deletion", + "of", + "one", + "allele", + "Dkk1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inducible", + "deletion", + "of", + "one", + "allele", + "Dkk1" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Osx-expressing", + "cells", + "BM", + "stem", + "and", + "progenitor", + "HSCs,", + "endothelial", + "cells," + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Osx-expressing", + "cells", + "BM", + "stem", + "progenitor", + "HSCs,", + "endothelial", + "cells," + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "adult", + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "adult", + "mice" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence," + ] + } + } + ] + }, + { + "PMID": "27869803", + "TEXT": "Forward genetic screens with CRISPR-Cas9 genome editing enable high-resolution detection of genetic vulnerabilities in cancer cells. We conducted genome-wide CRISPR-Cas9 screens in RNF43-mutant pancreatic ductal adenocarcinoma (PDAC) cells, which rely on Wnt signaling for proliferation. Through these screens, we discovered a unique requirement for a Wnt signaling circuit: engaging FZD5, one of the ten Frizzled receptors encoded in the human genome. Our results uncover an underappreciated level of context-dependent specificity at the Wnt receptor level. We further derived a panel of recombinant antibodies that reports the expression of nine FZD proteins and confirms that FZD5 functional specificity cannot be explained by protein expression patterns. Additionally, antibodies that specifically bind FZD5 and FZD8 robustly inhibited the growth of RNF43-mutant PDAC cells grown in vitro and as xenografts in vivo, providing orthogonal support for the functional specificity observed genetically. Proliferation of a patient-derived PDAC cell line harboring an RNF43 variant was also selectively inhibited by the FZD5 antibodies, further demonstrating their use as a potential targeted therapy. Tumor organoid cultures from colorectal carcinoma patients that carried RNF43 mutations were also sensitive to the FZD5 antibodies, highlighting the potential generalizability of these findings beyond PDAC. Our results show that CRIPSR-based genetic screens can be leveraged to identify and validate cell surface targets for antibody development and therapy.", + "TAG_DATA": [ + "117, RNF43-mutant {'perturbing_action': 'B-other'}", + "118, PDAC {'context': 'B-transformed cells'}", + "119, cells {'context': 'I-transformed cells'}", + "121, in {'context': 'B-in vitro'}", + "122, vitro {'context': 'I-in vitro'}", + "125, xenografts {'context': 'B-xenograft'}", + "126, in {'context': 'B-in vivo'}", + "127, vivo, {'context': 'I-in vivo'}", + "137, Proliferation {'phenotype': 'B-proliferation'}", + "140, patient-derived {'context': 'B-transformed cells'}", + "141, PDAC {'context': 'I-transformed cells'}", + "142, cell {'context': 'I-transformed cells'}", + "143, line {'context': 'I-transformed cells'}", + "146, RNF43 {'perturbing_action': 'I-other'}", + "147, variant {'perturbing_action': 'I-other'}", + "151, inhibited {'effect': 'B-negative'}", + "165, Tumor {'context': 'B-organoid'}", + "166, organoid {'context': 'I-organoid'}", + "167, cultures {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "117, RNF43-mutant ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "118, PDAC ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "119, cells ['l1', 'l7', 'l13', 'l14']", + "121, in ['l2', 'l8', 'l13', 'l15', 'l16']", + "122, vitro ['l3', 'l9', 'l14', 'l15']", + "125, xenografts ['l4', 'l10', 'l17', 'l18']", + "126, in ['l5', 'l11', 'l17', 'l19']", + "127, vivo, ['l6', 'l12', 'l16', 'l18', 'l19']", + "137, Proliferation ['l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "140, patient-derived ['l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "141, PDAC ['l21', 'l29', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "142, cell ['l22', 'l30', 'l36', 'l42', 'l43', 'l44', 'l45']", + "143, line ['l23', 'l31', 'l37', 'l42', 'l46', 'l47', 'l48']", + "146, RNF43 ['l24', 'l32', 'l38', 'l43', 'l46', 'l49', 'l50', 'l51']", + "147, variant ['l25', 'l33', 'l39', 'l44', 'l47', 'l49', 'l52', 'l53']", + "151, inhibited ['l26', 'l34', 'l40', 'l45', 'l48', 'l50', 'l52', 'l54']", + "165, Tumor ['l55', 'l56']", + "166, organoid ['l27', 'l55', 'l57']", + "167, cultures ['l28', 'l35', 'l41', 'l51', 'l53', 'l54', 'l56', 'l57']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "RNF43-mutant", + "RNF43", + "variant" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "PDAC", + "cells", + "patient-derived", + "cell", + "line" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "RNF43-mutant" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "RNF43-mutant", + "RNF43", + "variant" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenografts", + "cultures" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "RNF43-mutant" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "Proliferation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "patient-derived", + "PDAC", + "cell", + "line" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "Proliferation" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "RNF43", + "variant" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "Proliferation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "Proliferation" + ] + }, + "context": { + "val": "organoid", + "words": [ + "organoid" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "Proliferation" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "cultures" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "patient-derived", + "PDAC", + "cell", + "line" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "RNF43", + "variant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "cultures" + ] + } + } + ] + }, + { + "PMID": "27841876", + "TEXT": "Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease.", + "TAG_DATA": [ + "40, old {'context': 'B-organism'}", + "41, mice. {'context': 'I-organism'}", + "44, enhanced {'effect': 'B-positive'}", + "46, autophagy, {'phenotype': 'B-autophagy'}", + "47, mitophagy {'phenotype': 'B-mitophagy'}", + "59, cardiomyocytes {'context': 'B-cells'}", + "60, in {'context': 'B-in vivo'}", + "61, vivo, {'context': 'I-in vivo'}", + "78, mice {'context': 'B-organism'}", + "86, cardiomyocytes. {'context': 'B-cells'}", + "88, Dahl {'context': 'B-organism'}", + "89, salt-sensitive {'context': 'I-organism'}", + "90, rats {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "40, old ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "41, mice. ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "44, enhanced ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "46, autophagy, ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "47, mitophagy ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "59, cardiomyocytes ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "60, in ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "61, vivo, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "78, mice ['l28', 'l29']", + "86, cardiomyocytes. ['l28', 'l30']", + "88, Dahl ['l31', 'l32']", + "89, salt-sensitive ['l31', 'l33']", + "90, rats ['l29', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "old", + "mice." + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "old", + "mice." + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "old", + "mice." + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "mitophagy" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "mitophagy" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "phenotype": { + "val": "mitophagy", + "words": [ + "mitophagy" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes" + ] + } + }, + { + "phenotype": { + "val": "mitophagy", + "words": [ + "mitophagy" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + } + ] + }, + { + "PMID": "27775705", + "TEXT": "Triple-negative breast cancer (TNBC), in which cells lack expression of the estrogen receptor (ER), the progesterone receptor (PR) and the ERBB2 (also known as HER2) receptor, is the breast cancer subtype with the poorest outcome. No targeted therapy is available against this subtype of cancer owing to a lack of validated molecular targets. We previously reported that signaling involving MYC-an essential, pleiotropic transcription factor that regulates the expression of hundreds of genes-is disproportionally higher in triple-negative (TN) tumors than in receptor-positive (RP) tumors. Direct inhibition of the oncogenic transcriptional activity of MYC has been challenging to achieve. Here, by conducting a shRNA screen targeting the kinome, we identified PIM1, a non-essential serine-threonine kinase, in a synthetic lethal interaction with MYC. PIM1 expression was higher in TN tumors than in RP tumors and was associated with poor prognosis in patients with hormone- and HER2-negative tumors. Small-molecule PIM kinase inhibitors halted the growth of human TN tumors with elevated MYC expression in patient-derived tumor xenograft (PDX) and MYC-driven transgenic mouse models of breast cancer by inhibiting the oncogenic transcriptional activity of MYC and restoring the function of the endogenous cell cycle inhibitor, p27. Our findings warrant clinical evaluation of PIM kinase inhibitors in patients with TN tumors that have elevated MYC expression.", + "TAG_DATA": [ + "144, Small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "145, PIM {'perturbing_action': 'I-pharmacological inhibition'}", + "146, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "147, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "152, human {'context': 'B-neoplasm'}", + "153, TN {'context': 'I-neoplasm'}", + "154, tumors {'context': 'I-neoplasm'}", + "160, patient-derived {'context': 'B-xenograft'}", + "161, tumor {'context': 'I-xenograft'}", + "162, xenograft {'context': 'I-xenograft'}", + "163, (PDX) {'context': 'I-xenograft'}", + "167, mouse {'context': 'I-neoplasm'}", + "168, models {'context': 'I-neoplasm'}", + "169, of {'context': 'I-neoplasm'}", + "170, breast {'context': 'I-neoplasm'}", + "171, cancer {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "144, Small-molecule ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "145, PIM ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "146, kinase ['l1', 'l16', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "147, inhibitors ['l2', 'l17', 'l31', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "152, human ['l3', 'l18', 'l32', 'l45', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "153, TN ['l4', 'l19', 'l33', 'l46', 'l58', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "154, tumors ['l5', 'l20', 'l34', 'l47', 'l59', 'l67', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "160, patient-derived ['l6', 'l21', 'l35', 'l48', 'l60', 'l68', 'l76', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "161, tumor ['l7', 'l22', 'l36', 'l49', 'l61', 'l69', 'l77', 'l84', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "162, xenograft ['l8', 'l23', 'l37', 'l50', 'l62', 'l70', 'l78', 'l85', 'l93', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "163, (PDX) ['l9', 'l24', 'l38', 'l51', 'l63', 'l71', 'l79', 'l86', 'l94', 'l101', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "166, transgenic ['l10', 'l25', 'l39', 'l52', 'l87', 'l95', 'l102', 'l108', 'l114', 'l115', 'l116', 'l117', 'l118']", + "167, mouse ['l11', 'l26', 'l40', 'l53', 'l88', 'l96', 'l103', 'l109', 'l114', 'l119', 'l120', 'l121', 'l122']", + "168, models ['l12', 'l27', 'l41', 'l54', 'l64', 'l72', 'l80', 'l89', 'l97', 'l104', 'l110', 'l115', 'l119', 'l123', 'l124', 'l125']", + "169, of ['l13', 'l28', 'l42', 'l55', 'l65', 'l73', 'l81', 'l90', 'l98', 'l105', 'l111', 'l116', 'l120', 'l123', 'l126', 'l127']", + "170, breast ['l14', 'l29', 'l43', 'l56', 'l74', 'l82', 'l91', 'l99', 'l106', 'l112', 'l117', 'l121', 'l124', 'l126', 'l128']", + "171, cancer ['l15', 'l30', 'l44', 'l57', 'l66', 'l75', 'l83', 'l92', 'l100', 'l107', 'l113', 'l118', 'l122', 'l125', 'l127', 'l128']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Small-molecule", + "PIM", + "kinase", + "inhibitors" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "TN", + "tumors", + "mouse", + "models", + "of", + "breast", + "cancer" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Small-molecule", + "PIM", + "kinase", + "inhibitors" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "patient-derived", + "tumor", + "xenograft", + "(PDX)" + ] + } + } + ] + }, + { + "PMID": "27748747", + "TEXT": "The efficacy of angiogenesis inhibitors in cancer is limited by resistance mechanisms that are poorly understood. Notably, instead of through the induction of angiogenesis, tumor vascularization can occur through the nonangiogenic mechanism of vessel co-option. Here we show that vessel co-option is associated with a poor response to the anti-angiogenic agent bevacizumab in patients with colorectal cancer liver metastases. Moreover, we find that vessel co-option is also prevalent in human breast cancer liver metastases, a setting in which results with anti-angiogenic therapy have been disappointing. In preclinical mechanistic studies, we found that cancer cell motility mediated by the actin-related protein 2/3 complex (Arp2/3) is required for vessel co-option in liver metastases in vivo and that, in this setting, combined inhibition of angiogenesis and vessel co-option is more effective than the inhibition of angiogenesis alone. Vessel co-option is therefore a clinically relevant mechanism of resistance to anti-angiogenic therapy and combined inhibition of angiogenesis and vessel co-option might be a warranted therapeutic strategy.", + "TAG_DATA": [ + "92, cancer {'context': 'B-transformed cells'}", + "93, cell {'context': 'I-transformed cells'}", + "109, liver {'phenotype': 'B-metastasis'}", + "110, metastases {'context': 'I-neoplasm', 'phenotype': 'I-metastasis'}", + "111, in {'context': 'B-in vivo'}", + "112, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "92, cancer ['l0', 'l1', 'l2', 'l3', 'l4']", + "93, cell ['l0', 'l5', 'l6', 'l7', 'l8']", + "109, liver ['l1', 'l5', 'l9', 'l10', 'l11']", + "110, metastases ['l2', 'l6', 'l9', 'l12', 'l13']", + "111, in ['l3', 'l7', 'l10', 'l12', 'l14']", + "112, vivo ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cell" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "liver", + "metastases" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "metastases" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases", + "liver" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "liver", + "metastases" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "27723722", + "TEXT": "In Alzheimer's disease (AD) and other tauopathies, the tau protein forms fibrils, which are believed to be neurotoxic. However, fibrillar tau has been dissociated from neuron death and network dysfunction, suggesting the involvement of nonfibrillar species. Here we describe a novel pathological process in which caspase-2 cleavage of tau at Asp314 impairs cognitive and synaptic function in animal and cellular models of tauopathies by promoting the missorting of tau to dendritic spines. The truncation product, Δtau314, resists fibrillation and is present at higher levels in brains from cognitively impaired mice and humans with AD. The expression of tau mutants that resisted caspase-2 cleavage prevented tau from infiltrating spines, dislocating glutamate receptors and impairing synaptic function in cultured neurons, and it prevented memory deficits and neurodegeneration in mice. Decreasing the levels of caspase-2 restored long-term memory in mice that had existing deficits. Our results suggest an overall treatment strategy for re-establishing synaptic function and restoring memory in patients with AD by preventing tau from accumulating in dendritic spines.", + "TAG_DATA": [ + "95, expression {'perturbing_action': 'B-other'}", + "96, of {'perturbing_action': 'I-other'}", + "97, tau {'perturbing_action': 'I-other'}", + "98, mutants {'perturbing_action': 'I-other'}", + "116, cultured {'context': 'B-cells'}", + "117, neurons, {'context': 'I-cells'}", + "126, mice. {'context': 'B-organism'}", + "127, Decreasing {'perturbing_action': 'B-gene loss-of-function'}", + "128, the {'perturbing_action': 'I-rnai/knockdown'}", + "129, levels {'perturbing_action': 'I-rnai/knockdown'}", + "130, of {'perturbing_action': 'I-rnai/knockdown'}", + "131, caspase-2 {'perturbing_action': 'I-rnai/knockdown'}", + "136, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "95, expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "96, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "97, tau ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "98, mutants ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "116, cultured ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "117, neurons, ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "126, mice. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "127, Decreasing ['l21', 'l22', 'l23', 'l24', 'l25']", + "128, the ['l21', 'l26', 'l27', 'l28', 'l29']", + "129, levels ['l22', 'l26', 'l30', 'l31', 'l32']", + "130, of ['l23', 'l27', 'l30', 'l33', 'l34']", + "131, caspase-2 ['l24', 'l28', 'l31', 'l33', 'l35']", + "136, mice ['l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "tau", + "mutants" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "neurons," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "tau", + "mutants" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Decreasing" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "the", + "levels", + "of", + "caspase-2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "27694932", + "TEXT": "Successful recovery from lung injury requires the repair and regeneration of alveolar epithelial cells to restore the integrity of gas-exchanging regions within the lung and preserve organ function. Improper regeneration of the alveolar epithelium is often associated with severe pulmonary fibrosis, the latter of which involves the recruitment and activation of fibroblasts, as well as matrix accumulation. Type 2 alveolar epithelial cells (AEC2s) are stem cells in the adult lung that contribute to the lung repair process. The mechanisms that regulate AEC2 renewal are incompletely understood. We provide evidence that expression of the innate immune receptor Toll-like receptor 4 (TLR4) and the extracellular matrix glycosaminoglycan hyaluronan (HA) on AEC2s are important for AEC2 renewal, repair of lung injury and limiting the extent of fibrosis. Either deletion of TLR4 or HA synthase 2 in surfactant-protein-C-positive AEC2s leads to impaired renewal capacity, severe fibrosis and mortality. Furthermore, AEC2s from patients with severe pulmonary fibrosis have reduced cell surface HA and impaired renewal capacity, suggesting that HA and TLR4 are key contributors to lung stem cell renewal and that severe pulmonary fibrosis is the result of distal epithelial stem cell failure.", + "TAG_DATA": [ + "125, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "126, of {'perturbing_action': 'I-gene loss-of-function'}", + "127, TLR4 {'perturbing_action': 'I-gene loss-of-function'}", + "128, or {'perturbing_action': 'I-gene loss-of-function'}", + "133, surfactant-protein-C-positive {'context': 'B-cells'}", + "134, AEC2s {'context': 'I-cells'}", + "137, impaired {'effect': 'B-negative'}", + "138, renewal {'phenotype': 'B-self-renewal'}", + "145, AEC2s {'context': 'B-cells'}", + "158, impaired {'effect': 'B-negative'}", + "159, renewal {'phenotype': 'B-self-renewal'}" + ], + "LINK_DATA": [ + "125, deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "126, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "127, TLR4 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "128, or ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "133, surfactant-protein-C-positive ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "134, AEC2s ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "137, impaired ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "138, renewal ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "145, AEC2s ['l28', 'l29']", + "158, impaired ['l28', 'l30']", + "159, renewal ['l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "TLR4", + "or" + ] + }, + "context": { + "val": "cells", + "words": [ + "surfactant-protein-C-positive", + "AEC2s" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "TLR4", + "or" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "TLR4", + "or" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "renewal" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "surfactant-protein-C-positive", + "AEC2s" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "surfactant-protein-C-positive", + "AEC2s" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "renewal" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "renewal" + ] + } + } + ] + }, + { + "PMID": "27618649", + "TEXT": "The MYCN proto-oncogene is amplified in a number of advanced-stage human tumors, such as neuroblastomas. Similar to other members of the MYC family of oncoproteins, MYCN (also known as N-Myc) is a transcription factor, and its stability and activity are tightly controlled by ubiquitination-dependent proteasome degradation. Although numerous studies have demonstrated that N-Myc is a driver of neuroblastoma tumorigenesis, therapies that directly suppress N-Myc activity in human tumors are limited. Here we have identified ubiquitin-specific protease 7 (USP7; also known as HAUSP) as a regulator of N-Myc function in neuroblastoma. HAUSP interacts with N-Myc, and HAUSP expression induces deubiquitination and subsequent stabilization of N-Myc. Conversely, RNA interference (RNAi)-mediated knockdown of USP7 in neuroblastoma cancer cell lines, or genetic ablation of Usp7 in the mouse brain, destabilizes N-Myc, which leads to inhibition of N-Myc function. Notably, HAUSP is more abundant in patients with neuroblastoma who have poorer prognosis, and HAUSP expression substantially correlates with N-Myc transcriptional activity. Furthermore, small-molecule inhibitors of HAUSP's deubiquitinase activity markedly suppress the growth of MYCN-amplified human neuroblastoma cell lines in xenograft mouse models. Taken together, our findings demonstrate a crucial role of HAUSP in regulating N-Myc function in vivo and suggest that HAUSP inhibition is a potential therapy for MYCN-amplified tumors.", + "TAG_DATA": [ + "105, RNA {'perturbing_action': 'B-rnai/knockdown'}", + "106, interference {'perturbing_action': 'B-rnai/knockdown'}", + "107, (RNAi)-mediated {'perturbing_action': 'I-rnai/knockdown'}", + "108, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "109, of {'perturbing_action': 'I-rnai/knockdown'}", + "110, USP7 {'perturbing_action': 'I-rnai/knockdown'}", + "112, neuroblastoma {'context': 'B-transformed cells'}", + "113, cancer {'context': 'I-transformed cells'}", + "114, cell {'context': 'I-transformed cells'}", + "115, lines, {'context': 'I-transformed cells'}", + "117, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "118, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "119, of {'perturbing_action': 'I-gene loss-of-function'}", + "120, Usp7 {'perturbing_action': 'I-gene loss-of-function'}", + "123, mouse {'context': 'B-tissue/organ'}", + "124, brain, {'context': 'I-tissue/organ'}", + "169, human {'context': 'I-transformed cells'}", + "170, neuroblastoma {'context': 'I-transformed cells'}", + "171, cell {'context': 'I-transformed cells'}", + "172, lines {'context': 'I-transformed cells'}", + "174, xenograft {'context': 'B-xenograft'}", + "175, mouse {'context': 'I-xenograft'}", + "176, models. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "105, RNA ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "106, interference ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "107, (RNAi)-mediated ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "108, knockdown ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "109, of ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "110, USP7 ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "112, neuroblastoma ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "113, cancer ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "114, cell ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "115, lines, ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "117, genetic ['l45', 'l46', 'l47', 'l48', 'l49']", + "118, ablation ['l45', 'l50', 'l51', 'l52', 'l53']", + "119, of ['l46', 'l50', 'l54', 'l55', 'l56']", + "120, Usp7 ['l47', 'l51', 'l54', 'l57', 'l58']", + "123, mouse ['l48', 'l52', 'l55', 'l57', 'l59']", + "124, brain, ['l49', 'l53', 'l56', 'l58', 'l59']", + "168, MYCN-amplified ['l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "169, human ['l60', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "170, neuroblastoma ['l61', 'l67', 'l73', 'l74', 'l75', 'l76', 'l77']", + "171, cell ['l62', 'l68', 'l73', 'l78', 'l79', 'l80', 'l81']", + "172, lines ['l63', 'l69', 'l74', 'l78', 'l82', 'l83', 'l84']", + "174, xenograft ['l64', 'l70', 'l75', 'l79', 'l82', 'l85', 'l86']", + "175, mouse ['l65', 'l71', 'l76', 'l80', 'l83', 'l85', 'l87']", + "176, models. ['l66', 'l72', 'l77', 'l81', 'l84', 'l86', 'l87']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "RNA", + "interference", + "(RNAi)-mediated", + "knockdown", + "of", + "USP7" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "neuroblastoma", + "cancer", + "cell", + "lines," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "Usp7" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "brain," + ] + } + } + ] + }, + { + "PMID": "27479084", + "TEXT": "Mechanisms by which regulatory T (Treg) cells fail to control inflammation in asthma remain poorly understood. We show that a severe asthma-associated polymorphism in the gene encoding the interleukin (IL)-4 receptor alpha chain (Il4ra(R576)) promotes conversion of induced Treg (iTreg) cells toward a T helper 17 (TH17) cell fate. This skewing is mediated by the recruitment by IL-4Rα(R576) of the growth-factor-receptor-bound protein 2 (GRB2) adaptor protein, which drives IL-17 expression by activating a pathway that involves extracellular-signal-regulated kinase, IL-6 and the transcription factor STAT3. Treg cell-specific deletion of genes that regulate TH17 cell differentiation, including Il6ra and RAR-related orphan receptor gamma (Rorc), but not of Il4 or Il13, prevented exacerbated airway inflammation in mice expressing Il4ra(R576) (hereafter referred to as Il4ra(R576) mice). Furthermore, treatment of Il4ra(R576) mice with a neutralizing IL-6-specific antibody prevented iTreg cell reprogramming into TH17-like cells and protected against severe airway inflammation. These findings identify a previously unknown mechanism for the development of mixed TH2-TH17 cell inflammation in genetically prone individuals and point to interventions that stabilize iTreg cells as potentially effective therapeutic strategies.", + "TAG_DATA": [ + "84, Treg {'perturbing_action': 'B-gene loss-of-function'}", + "85, cell-specific {'perturbing_action': 'I-gene loss-of-function'}", + "86, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "87, of {'perturbing_action': 'I-gene loss-of-function'}", + "113, mice {'context': 'B-organism'}", + "125, Il4ra(R576) {'perturbing_action': 'B-other'}", + "126, mice {'context': 'B-organism'}", + "133, iTreg {'context': 'B-cells'}", + "137, TH17-like {'context': 'B-cells'}", + "138, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "84, Treg ['l0', 'l1', 'l2', 'l3']", + "85, cell-specific ['l0', 'l4', 'l5', 'l6']", + "86, deletion ['l1', 'l4', 'l7', 'l8']", + "87, of ['l2', 'l5', 'l7', 'l9']", + "113, mice ['l3', 'l6', 'l8', 'l9']", + "125, Il4ra(R576) ['l10', 'l11', 'l12', 'l13', 'l14']", + "126, mice ['l10', 'l15', 'l16', 'l17', 'l18']", + "133, iTreg ['l11', 'l15', 'l19', 'l20', 'l21']", + "134, cell ['l12', 'l16', 'l19', 'l22', 'l23']", + "137, TH17-like ['l13', 'l17', 'l20', 'l22', 'l24']", + "138, cells ['l14', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Treg", + "cell-specific", + "deletion", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Il4ra(R576)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Il4ra(R576)" + ] + }, + "context": { + "val": "cells", + "words": [ + "iTreg", + "TH17-like", + "cells" + ] + } + } + ] + }, + { + "PMID": "27428901", + "TEXT": "Fungal infections claim an estimated 1.5 million lives each year. Mechanisms that protect from fungal infections are still elusive. Recognition of fungal pathogens relies on C-type lectin receptors (CLRs) and their downstream signaling kinase SYK. Here we report that the E3 ubiquitin ligase CBLB controls proximal CLR signaling in macrophages and dendritic cells. We show that CBLB associates with SYK and ubiquitinates SYK, dectin-1, and dectin-2 after fungal recognition. Functionally, CBLB deficiency results in increased inflammasome activation, enhanced reactive oxygen species production, and increased fungal killing. Genetic deletion of Cblb protects mice from morbidity caused by cutaneous infection and markedly improves survival after a lethal systemic infection with Candida albicans. On the basis of these findings, we engineered a cell-permeable CBLB inhibitory peptide that protects mice from lethal C. albicans infections. We thus describe a key role for Cblb in the regulation of innate antifungal immunity and establish a novel paradigm for the treatment of fungal sepsis.", + "TAG_DATA": [ + "70, CBLB {'perturbing_action': 'B-gene loss-of-function'}", + "71, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "86, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "87, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "88, of {'perturbing_action': 'I-gene loss-of-function'}", + "89, Cblb {'perturbing_action': 'I-gene loss-of-function'}", + "91, mice {'context': 'B-organism'}", + "125, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "70, CBLB ['l0']", + "71, deficiency ['l0']", + "86, Genetic ['l1', 'l2', 'l3', 'l4']", + "87, deletion ['l1', 'l5', 'l6', 'l7']", + "88, of ['l2', 'l5', 'l8', 'l9']", + "89, Cblb ['l3', 'l6', 'l8', 'l10']", + "91, mice ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "deletion", + "of", + "Cblb" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "27400265", + "TEXT": "The biological effects of urolithins remain poorly characterized, despite wide-spread human exposure via the dietary consumption of their metabolic precursors, the ellagitannins, which are found in the pomegranate fruit, as well as in nuts and berries. We identified urolithin A (UA) as a first-in-class natural compound that induces mitophagy both in vitro and in vivo following oral consumption. In C. elegans, UA prevented the accumulation of dysfunctional mitochondria with age and extended lifespan. Likewise, UA prolonged normal activity during aging in C. elegans, including mobility and pharyngeal pumping, while maintaining mitochondrial respiratory capacity. These effects translated to rodents, where UA improved exercise capacity in two different mouse models of age-related decline of muscle function, as well as in young rats. Our findings highlight the health benefits of urolithin A and its potential application in strategies to improve mitochondrial and muscle function.", + "TAG_DATA": [ + "47, induces {'effect': 'B-positive'}", + "48, mitophagy {'phenotype': 'B-mitophagy'}", + "50, in {'context': 'B-in vitro'}", + "51, vitro {'context': 'I-in vitro'}", + "53, in {'context': 'B-in vivo'}", + "54, vivo {'context': 'I-in vivo'}", + "59, C. {'context': 'B-organism'}", + "60, elegans, {'context': 'I-organism'}", + "81, C. {'context': 'B-organism'}", + "82, elegans, {'context': 'B-organism'}", + "97, rodents, {'context': 'B-organism'}", + "106, mouse {'context': 'B-organism'}", + "107, models {'context': 'I-organism'}", + "118, young {'context': 'B-organism'}", + "119, rats. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "47, induces ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "48, mitophagy ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "50, in ['l1', 'l7', 'l13', 'l14', 'l15']", + "51, vitro ['l2', 'l8', 'l13', 'l16', 'l17']", + "53, in ['l3', 'l9', 'l18', 'l19', 'l20']", + "54, vivo ['l4', 'l10', 'l18', 'l21', 'l22']", + "59, C. ['l5', 'l11', 'l14', 'l16', 'l19', 'l21', 'l23']", + "60, elegans, ['l6', 'l12', 'l15', 'l17', 'l20', 'l22', 'l23']", + "81, C. ['l24']", + "82, elegans, ['l24']", + "97, rodents, ['l25', 'l26']", + "106, mouse ['l25', 'l27', 'l28', 'l29']", + "107, models ['l26', 'l27', 'l30', 'l31']", + "118, young ['l28', 'l30', 'l32']", + "119, rats. ['l29', 'l31', 'l32']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "mitophagy" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "organism", + "words": [ + "C.", + "elegans," + ] + } + }, + { + "phenotype": { + "val": "mitophagy", + "words": [ + "mitophagy" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "mitophagy", + "words": [ + "mitophagy" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "mitophagy", + "words": [ + "mitophagy" + ] + }, + "context": { + "val": "organism", + "words": [ + "C.", + "elegans," + ] + } + } + ] + }, + { + "PMID": "27376575", + "TEXT": "Interactions between stem cells and their microenvironment, or niche, are essential for stem cell maintenance and function. Our knowledge of the niche for the skeletal muscle stem cell, i.e., the satellite cell (SC), is incomplete. Here we show that β1-integrin is an essential niche molecule that maintains SC homeostasis, and sustains the expansion and self-renewal of this stem cell pool during regeneration. We further show that β1-integrin cooperates with fibroblast growth factor 2 (Fgf2), a potent growth factor for SCs, to synergistically activate their common downstream effectors, the mitogen-activated protein (MAP) kinase Erk and protein kinase B (Akt). Notably, SCs in aged mice show altered β1-integrin activity and insensitivity to Fgf2. Augmenting β1-integrin activity with a monoclonal antibody restores Fgf2 sensitivity and improves regeneration after experimentally induced muscle injury. The same treatment also enhances regeneration and function of dystrophic muscles in mdx mice, a model for Duchenne muscular dystrophy. Therefore, β1-integrin senses the SC niche to maintain responsiveness to Fgf2, and this integrin represents a potential therapeutic target for pathological conditions of the muscle in which the stem cell niche is compromised.", + "TAG_DATA": [ + "99, SCs {'context': 'B-cells'}", + "101, aged {'context': 'B-organism'}", + "102, mice {'context': 'I-organism'}", + "127, muscle {'context': 'B-tissue/organ'}", + "138, dystrophic {'context': 'B-tissue/organ'}", + "139, muscles {'context': 'I-tissue/organ'}", + "141, mdx {'perturbing_action': 'B-other', 'context': 'B-organism'}", + "142, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "99, SCs ['l0', 'l1']", + "101, aged ['l0', 'l2']", + "102, mice ['l1', 'l2']", + "138, dystrophic ['l3', 'l4', 'l5']", + "139, muscles ['l3', 'l6', 'l7']", + "141, mdx ['l4', 'l6', 'l8']", + "142, mice, ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "dystrophic", + "muscles" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mdx" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mdx" + ] + }, + "context": { + "val": "organism", + "words": [ + "mdx" + ] + } + } + ] + }, + { + "PMID": "27322743", + "TEXT": "Individuals who have mutations in the breast-cancer-susceptibility gene BRCA1 (hereafter referred to as BRCA1-mutation carriers) frequently undergo prophylactic mastectomy to minimize their risk of breast cancer. The identification of an effective prevention therapy therefore remains a 'holy grail' for the field. Precancerous BRCA1(mut/+) tissue harbors an aberrant population of luminal progenitor cells, and deregulated progesterone signaling has been implicated in BRCA1-associated oncogenesis. Coupled with the findings that tumor necrosis factor superfamily member 11 (TNFSF11; also known as RANKL) is a key paracrine effector of progesterone signaling and that RANKL and its receptor TNFRSF11A (also known as RANK) contribute to mammary tumorigenesis, we investigated a role for this pathway in the pre-neoplastic phase of BRCA1-mutation carriers. We identified two subsets of luminal progenitors (RANK(+) and RANK(-)) in histologically normal tissue of BRCA1-mutation carriers and showed that RANK(+) cells are highly proliferative, have grossly aberrant DNA repair and bear a molecular signature similar to that of basal-like breast cancer. These data suggest that RANK(+) and not RANK(-) progenitors are a key target population in these women. Inhibition of RANKL signaling by treatment with denosumab in three-dimensional breast organoids derived from pre-neoplastic BRCA1(mut/+) tissue attenuated progesterone-induced proliferation. Notably, proliferation was markedly reduced in breast biopsies from BRCA1-mutation carriers who were treated with denosumab. Furthermore, inhibition of RANKL in a Brca1-deficient mouse model substantially curtailed mammary tumorigenesis. Taken together, these findings identify a targetable pathway in a putative cell-of-origin population in BRCA1-mutation carriers and implicate RANKL blockade as a promising strategy in the prevention of breast cancer.", + "TAG_DATA": [ + "183, three-dimensional {'context': 'B-organoid'}", + "184, breast {'context': 'I-organoid'}", + "185, organoids {'context': 'I-organoid'}", + "188, pre-neoplastic {'context': 'B-cells'}", + "189, BRCA1(mut/+) {'context': 'I-tissue/organ'}", + "190, tissue {'context': 'I-tissue/organ'}", + "191, attenuated {'effect': 'B-negative'}", + "192, progesterone-induced {'effect': 'B-positive'}", + "193, proliferation. {'phenotype': 'B-proliferation'}", + "195, proliferation {'phenotype': 'B-proliferation'}", + "198, reduced {'effect': 'B-negative'}", + "200, breast {'context': 'B-transformed cells'}", + "201, biopsies {'context': 'I-patient'}", + "211, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "212, of {'perturbing_action': 'I-pharmacological inhibition'}", + "213, RANKL {'perturbing_action': 'I-pharmacological inhibition'}", + "216, Brca1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "217, mouse {'context': 'B-organism'}", + "218, model {'context': 'I-organism'}", + "220, curtailed {'effect': 'B-negative'}", + "221, mammary {'context': 'B-tissue/organ'}", + "222, tumorigenesis. {'phenotype': 'B-tumourigenesis'}" + ], + "LINK_DATA": [ + "183, three-dimensional ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "184, breast ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "185, organoids ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "188, pre-neoplastic ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "189, BRCA1(mut/+) ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "190, tissue ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54']", + "191, attenuated ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l55', 'l56', 'l57', 'l58']", + "192, progesterone-induced ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l55', 'l59', 'l60', 'l61']", + "193, proliferation. ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l56', 'l59']", + "195, proliferation ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l57', 'l60', 'l62', 'l63', 'l64']", + "198, reduced ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l58', 'l61', 'l62', 'l65', 'l66']", + "200, breast ['l10', 'l21', 'l31', 'l40', 'l48', 'l63', 'l65', 'l67']", + "201, biopsies ['l11', 'l22', 'l32', 'l41', 'l49', 'l64', 'l66', 'l67']", + "211, inhibition ['l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "212, of ['l68', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "213, RANKL ['l69', 'l76', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "216, Brca1-deficient ['l70', 'l77', 'l83', 'l89', 'l90', 'l91', 'l92', 'l93']", + "217, mouse ['l71', 'l78', 'l84', 'l89', 'l94', 'l95', 'l96', 'l97']", + "218, model ['l72', 'l79', 'l85', 'l90', 'l94', 'l98', 'l99', 'l100']", + "220, curtailed ['l73', 'l80', 'l86', 'l91', 'l95', 'l98', 'l101', 'l102']", + "221, mammary ['l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l101', 'l103']", + "222, tumorigenesis. ['l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l103']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organoid", + "words": [ + "three-dimensional", + "breast", + "organoids" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuated", + "reduced" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "three-dimensional", + "breast", + "organoids" + ] + }, + "effect": { + "val": "positive", + "words": [ + "progesterone-induced" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "three-dimensional", + "breast", + "organoids" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation.", + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pre-neoplastic" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuated", + "reduced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pre-neoplastic" + ] + }, + "effect": { + "val": "positive", + "words": [ + "progesterone-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pre-neoplastic" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation.", + "proliferation" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "BRCA1(mut/+)", + "tissue", + "mammary" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuated", + "reduced", + "curtailed" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "BRCA1(mut/+)", + "tissue" + ] + }, + "effect": { + "val": "positive", + "words": [ + "progesterone-induced" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "BRCA1(mut/+)", + "tissue" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation.", + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated", + "reduced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation.", + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "progesterone-induced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation.", + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "breast" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "patient", + "words": [ + "biopsies" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "breast" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "patient", + "words": [ + "biopsies" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "RANKL" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "RANKL" + ] + }, + "effect": { + "val": "negative", + "words": [ + "curtailed" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "RANKL" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mammary" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "RANKL" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Brca1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Brca1-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "curtailed" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Brca1-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mammary" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Brca1-deficient" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "effect": { + "val": "negative", + "words": [ + "curtailed" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "curtailed" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mammary" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis." + ] + } + } + ] + }, + { + "PMID": "27270589", + "TEXT": "Humans with obesity differ in their susceptibility to developing insulin resistance and type 2 diabetes (T2D). This variation may relate to the extent of adipose tissue (AT) inflammation that develops as their obesity progresses. The state of macrophage activation has a central role in determining the degree of AT inflammation and thus its dysfunction, and these states are driven by epigenomic alterations linked to gene expression. The underlying mechanisms that regulate these alterations, however, are poorly defined. Here we demonstrate that a co-repressor complex containing G protein pathway suppressor 2 (GPS2) crucially controls the macrophage epigenome during activation by metabolic stress. The study of AT from humans with and without obesity revealed correlations between reduced GPS2 expression in macrophages, elevated systemic and AT inflammation, and diabetic status. The causality of this relationship was confirmed by using macrophage-specific Gps2-knockout (KO) mice, in which inappropriate co-repressor complex function caused enhancer activation, pro-inflammatory gene expression and hypersensitivity toward metabolic-stress signals. By contrast, transplantation of GPS2-overexpressing bone marrow into two mouse models of obesity (ob/ob and diet-induced obesity) reduced inflammation and improved insulin sensitivity. Thus, our data reveal a potentially reversible disease mechanism that links co-repressor-dependent epigenomic alterations in macrophages to AT inflammation and the development of T2D.", + "TAG_DATA": [ + "136, macrophage-specific {'perturbing_action': 'B-gene loss-of-function'}", + "137, Gps2-knockout {'perturbing_action': 'I-gene loss-of-function'}", + "138, (KO) {'perturbing_action': 'I-gene loss-of-function'}", + "139, mice, {'context': 'B-organism'}", + "161, GPS2-overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "162, bone {'context': 'B-tissue/organ'}", + "163, marrow {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "136, macrophage-specific ['l0', 'l1', 'l2']", + "137, Gps2-knockout ['l0', 'l3', 'l4']", + "138, (KO) ['l1', 'l3', 'l5']", + "139, mice, ['l2', 'l4', 'l5']", + "161, GPS2-overexpressing ['l6', 'l7']", + "162, bone ['l6', 'l8']", + "163, marrow ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "macrophage-specific", + "Gps2-knockout", + "(KO)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GPS2-overexpressing" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "bone", + "marrow" + ] + } + } + ] + }, + { + "PMID": "27213815", + "TEXT": "MYC oncoproteins are involved in the genesis and maintenance of the majority of human tumors but are considered undruggable. By using a direct in vivo shRNA screen, we show that liver cancer cells that have mutations in the gene encoding the tumor suppressor protein p53 (Trp53 in mice and TP53 in humans) and that are driven by the oncoprotein NRAS become addicted to MYC stabilization via a mechanism mediated by aurora kinase A (AURKA). This MYC stabilization enables the tumor cells to overcome a latent G2/M cell cycle arrest that is mediated by AURKA and the tumor suppressor protein p19(ARF). MYC directly binds to AURKA, and inhibition of this protein-protein interaction by conformation-changing AURKA inhibitors results in subsequent MYC degradation and cell death. These conformation-changing AURKA inhibitors, with one of them currently being tested in early clinical trials, suppressed tumor growth and prolonged survival in mice bearing Trp53-deficient, NRAS-driven MYC-expressing hepatocellular carcinomas (HCCs). TP53-mutated human HCCs revealed increased AURKA expression and a positive correlation between AURKA and MYC expression. In xenograft models, mice bearing TP53-mutated or TP53-deleted human HCCs were hypersensitive to treatment with conformation-changing AURKA inhibitors, thus suggesting a therapeutic strategy for this subgroup of human HCCs.", + "TAG_DATA": [ + "30, liver {'context': 'B-transformed cells'}", + "31, cancer {'context': 'I-transformed cells'}", + "32, cells {'context': 'I-transformed cells'}", + "79, tumor {'context': 'B-transformed cells'}", + "80, cells {'context': 'I-transformed cells'}", + "85, G2/M {'phenotype': 'I-cell cycle arrest'}", + "86, cell {'phenotype': 'I-cell cycle arrest'}", + "87, cycle {'phenotype': 'I-cell cycle arrest'}", + "88, arrest {'phenotype': 'I-cell cycle arrest'}", + "112, conformation-changing {'perturbing_action': 'B-pharmacological inhibition'}", + "113, AURKA {'perturbing_action': 'B-pharmacological inhibition'}", + "114, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "115, results {'effect': 'B-positive'}", + "116, in {'effect': 'I-positive'}", + "121, cell {'phenotype': 'B-cell death'}", + "122, death. {'phenotype': 'I-cell death'}", + "124, conformation-changing {'perturbing_action': 'B-pharmacological inhibition'}", + "125, AURKA {'perturbing_action': 'I-pharmacological inhibition'}", + "126, inhibitors, {'perturbing_action': 'I-pharmacological inhibition'}", + "138, suppressed {'effect': 'B-negative'}", + "139, tumor {'phenotype': 'B-tumour growth'}", + "140, growth {'phenotype': 'I-tumour growth'}", + "145, mice {'context': 'B-organism'}", + "147, Trp53-deficient, {'perturbing_action': 'B-gene loss-of-function'}", + "149, MYC-expressing {'context': 'I-neoplasm'}", + "150, hepatocellular {'context': 'I-neoplasm'}", + "151, carcinomas {'context': 'I-neoplasm'}", + "152, (HCCs). {'context': 'I-neoplasm'}", + "155, HCCs {'context': 'I-neoplasm'}", + "170, xenograft {'context': 'B-xenograft'}", + "171, models, {'context': 'I-xenograft'}", + "172, mice {'context': 'B-organism'}", + "174, TP53-mutated {'perturbing_action': 'B-other'}", + "176, TP53-deleted {'perturbing_action': 'B-gene loss-of-function'}", + "177, human {'context': 'B-neoplasm'}", + "178, HCCs {'context': 'I-neoplasm'}", + "184, conformation-changing {'perturbing_action': 'B-pharmacological inhibition'}", + "185, AURKA {'perturbing_action': 'I-pharmacological inhibition'}", + "186, inhibitors, {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "30, liver ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "31, cancer ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "32, cells ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "79, tumor ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "80, cells ['l3', 'l10', 'l16', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32']", + "85, G2/M ['l4', 'l11', 'l17', 'l22', 'l28', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "86, cell ['l5', 'l12', 'l18', 'l23', 'l29', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "87, cycle ['l6', 'l13', 'l19', 'l24', 'l30', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "88, arrest ['l7', 'l14', 'l20', 'l25', 'l31', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "112, conformation-changing ['l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "113, AURKA ['l55', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "114, inhibitors ['l56', 'l75', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "115, results ['l36', 'l42', 'l47', 'l51', 'l57', 'l76', 'l94', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "116, in ['l37', 'l43', 'l48', 'l52', 'l58', 'l77', 'l95', 'l112', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "121, cell ['l26', 'l38', 'l44', 'l49', 'l53', 'l59', 'l78', 'l96', 'l113', 'l125', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145']", + "122, death. ['l27', 'l32', 'l39', 'l45', 'l50', 'l54', 'l60', 'l79', 'l97', 'l114', 'l126', 'l137', 'l146', 'l147', 'l148', 'l149', 'l150']", + "124, conformation-changing ['l61', 'l80', 'l98', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163']", + "125, AURKA ['l62', 'l81', 'l99', 'l151', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175']", + "126, inhibitors, ['l63', 'l82', 'l100', 'l152', 'l164', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186']", + "138, suppressed ['l64', 'l83', 'l101', 'l115', 'l127', 'l138', 'l146', 'l153', 'l165', 'l176', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195']", + "139, tumor ['l65', 'l84', 'l102', 'l116', 'l128', 'l139', 'l147', 'l154', 'l166', 'l177', 'l187', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203']", + "140, growth ['l66', 'l85', 'l103', 'l117', 'l129', 'l140', 'l148', 'l155', 'l167', 'l178', 'l188', 'l196', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210']", + "145, mice ['l67', 'l86', 'l104', 'l118', 'l130', 'l141', 'l156', 'l168', 'l179', 'l189', 'l197', 'l204', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217']", + "147, Trp53-deficient, ['l68', 'l87', 'l105', 'l119', 'l131', 'l157', 'l169', 'l180', 'l190', 'l198', 'l205', 'l211', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223']", + "148, NRAS-driven ['l69', 'l88', 'l106', 'l120', 'l132', 'l158', 'l170', 'l181', 'l191', 'l199', 'l206', 'l212', 'l218', 'l224', 'l225', 'l226', 'l227', 'l228']", + "149, MYC-expressing ['l70', 'l89', 'l107', 'l121', 'l133', 'l142', 'l159', 'l171', 'l182', 'l192', 'l200', 'l207', 'l213', 'l219', 'l224', 'l229', 'l230', 'l231', 'l232']", + "150, hepatocellular ['l71', 'l90', 'l108', 'l122', 'l134', 'l143', 'l160', 'l172', 'l183', 'l193', 'l201', 'l208', 'l214', 'l220', 'l225', 'l229', 'l233', 'l234', 'l235']", + "151, carcinomas ['l72', 'l91', 'l109', 'l123', 'l135', 'l144', 'l149', 'l161', 'l173', 'l184', 'l194', 'l202', 'l209', 'l215', 'l221', 'l226', 'l230', 'l233', 'l236', 'l237']", + "152, (HCCs). ['l73', 'l92', 'l110', 'l124', 'l136', 'l145', 'l150', 'l162', 'l174', 'l185', 'l195', 'l203', 'l210', 'l216', 'l222', 'l227', 'l231', 'l234', 'l236', 'l238']", + "155, HCCs ['l74', 'l93', 'l111', 'l163', 'l175', 'l186', 'l217', 'l223', 'l228', 'l232', 'l235', 'l237', 'l238']", + "170, xenograft ['l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247']", + "171, models, ['l239', 'l248', 'l249', 'l250', 'l251', 'l252']", + "172, mice ['l240', 'l248', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259']", + "174, TP53-mutated ['l241', 'l249', 'l253', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265']", + "176, TP53-deleted ['l242', 'l250', 'l254', 'l260', 'l266', 'l267', 'l268', 'l269', 'l270']", + "177, human ['l243', 'l251', 'l255', 'l261', 'l266', 'l271', 'l272', 'l273', 'l274']", + "178, HCCs ['l244', 'l252', 'l256', 'l262', 'l267', 'l271', 'l275', 'l276', 'l277']", + "184, conformation-changing ['l245', 'l257', 'l263', 'l268', 'l272', 'l275', 'l278', 'l279']", + "185, AURKA ['l246', 'l258', 'l264', 'l269', 'l273', 'l276', 'l278', 'l280']", + "186, inhibitors, ['l247', 'l259', 'l265', 'l270', 'l274', 'l277', 'l279', 'l280']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "liver", + "cancer", + "cells", + "tumor" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G2/M", + "cell", + "cycle", + "arrest" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G2/M", + "cell", + "cycle", + "arrest" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "conformation-changing", + "AURKA", + "inhibitors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "conformation-changing", + "AURKA", + "inhibitors" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "conformation-changing", + "AURKA", + "inhibitors", + "inhibitors," + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "conformation-changing", + "AURKA", + "inhibitors", + "inhibitors," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "conformation-changing", + "AURKA", + "inhibitors", + "inhibitors," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "conformation-changing", + "AURKA", + "inhibitors", + "inhibitors," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "MYC-expressing", + "hepatocellular", + "carcinomas", + "(HCCs).", + "HCCs", + "human" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trp53-deficient," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "MYC-expressing", + "hepatocellular", + "carcinomas", + "(HCCs)." + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "MYC-expressing", + "hepatocellular", + "carcinomas", + "(HCCs)." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trp53-deficient," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "MYC-expressing", + "hepatocellular", + "carcinomas", + "(HCCs)." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trp53-deficient," + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "MYC-expressing", + "hepatocellular", + "carcinomas", + "(HCCs)." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trp53-deficient,", + "TP53-deleted" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trp53-deficient,", + "TP53-deleted" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "MYC-expressing", + "hepatocellular", + "carcinomas", + "(HCCs).", + "HCCs", + "human" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "models," + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "TP53-mutated" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "models," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TP53-deleted" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenograft" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "conformation-changing", + "AURKA", + "inhibitors," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "TP53-mutated" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "TP53-mutated" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "HCCs" + ] + } + } + ] + }, + { + "PMID": "27158904", + "TEXT": "Complex interactions between the host and the gut microbiota govern intestinal homeostasis but remain poorly understood. Here we reveal a relationship between gut microbiota and caspase recruitment domain family member 9 (CARD9), a susceptibility gene for inflammatory bowel disease (IBD) that functions in the immune response against microorganisms. CARD9 promotes recovery from colitis by promoting interleukin (IL)-22 production, and Card9(-/-) mice are more susceptible to colitis. The microbiota is altered in Card9(-/-) mice, and transfer of the microbiota from Card9(-/-) to wild-type, germ-free recipients increases their susceptibility to colitis. The microbiota from Card9(-/-) mice fails to metabolize tryptophan into metabolites that act as aryl hydrocarbon receptor (AHR) ligands. Intestinal inflammation is attenuated after inoculation of mice with three Lactobacillus strains capable of metabolizing tryptophan or by treatment with an AHR agonist. Reduced production of AHR ligands is also observed in the microbiota from individuals with IBD, particularly in those with CARD9 risk alleles associated with IBD. Our findings reveal that host genes affect the composition and function of the gut microbiota, altering the production of microbial metabolites and intestinal inflammation.", + "TAG_DATA": [ + "59, Card9(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "60, mice {'context': 'B-organism'}", + "71, Card9(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "72, mice, {'context': 'B-organism'}", + "79, Card9(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "92, Card9(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "93, mice {'context': 'B-organism'}", + "115, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "59, Card9(-/-) ['l0', 'l1', 'l2']", + "60, mice ['l0', 'l3', 'l4']", + "71, Card9(-/-) ['l1', 'l3', 'l5', 'l6']", + "72, mice, ['l2', 'l4', 'l5']", + "79, Card9(-/-) ['l6']", + "92, Card9(-/-) ['l7', 'l8']", + "93, mice ['l7', 'l9']", + "115, mice ['l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Card9(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + } + ] + }, + { + "PMID": "27089515", + "TEXT": "Bacteroides fragilis is the leading cause of anaerobic bacteremia and sepsis. Enterotoxigenic strains that produce B. fragilis toxin (BFT, fragilysin) contribute to colitis and intestinal malignancy, yet are also isolated in bloodstream infection. It is not known whether these strains harbor unique genetic determinants that confer virulence in extra-intestinal disease. We demonstrate that BFT contributes to sepsis in mice, and we identify a B. fragilis protease called fragipain (Fpn) that is required for the endogenous activation of BFT through the removal of its auto-inhibitory prodomain. Structural analysis of Fpn reveals a His-Cys catalytic dyad that is characteristic of C11-family cysteine proteases that are conserved in multiple pathogenic Bacteroides spp. and Clostridium spp. Fpn-deficient, enterotoxigenic B. fragilis has an attenuated ability to induce sepsis in mice; however, Fpn is dispensable in B. fragilis colitis, wherein host proteases mediate BFT activation. Our findings define a role for B. fragilis enterotoxin and its activating protease in the pathogenesis of bloodstream infection, which indicates a greater complexity of cellular targeting and activity of BFT than previously recognized. The expression of fpn by both toxigenic and nontoxigenic strains suggests that this protease may contribute to anaerobic sepsis in ways that extend beyond its role in toxin activation. It could thus potentially serve as a target for disease modification.", + "TAG_DATA": [ + "112, Fpn-deficient, {'perturbing_action': 'B-gene loss-of-function'}", + "124, mice; {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "112, Fpn-deficient, ['l0']", + "124, mice; ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fpn-deficient," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice;" + ] + } + } + ] + }, + { + "PMID": "27043494", + "TEXT": "Inflammation-associated pathways are active in intestinal epithelial cells (IECs) and contribute to the pathogenesis of colorectal cancer (CRC). Calcineurin, a phosphatase required for the activation of the nuclear factor of activated T cells (NFAT) family of transcription factors, shows increased expression in CRC. We therefore investigated the role of calcineurin in intestinal tumor development. We demonstrate that calcineurin and NFAT factors are constitutively expressed by primary IECs and selectively activated in intestinal tumors as a result of impaired stratification of the tumor-associated microbiota and toll-like receptor signaling. Epithelial calcineurin supports the survival and proliferation of cancer stem cells in an NFAT-dependent manner and promotes the development of intestinal tumors in mice. Moreover, somatic mutations that have been identified in human CRC are associated with constitutive activation of calcineurin, whereas nuclear translocation of NFAT is associated with increased death from CRC. These findings highlight an epithelial cell-intrinsic pathway that integrates signals derived from the commensal microbiota to promote intestinal tumor development.", + "TAG_DATA": [ + "89, supports {'effect': 'B-positive'}", + "93, proliferation {'phenotype': 'B-proliferation'}", + "95, cancer {'context': 'B-transformed cells'}", + "96, stem {'context': 'I-transformed cells'}", + "97, cells {'context': 'I-transformed cells'}", + "103, promotes {'effect': 'B-positive'}", + "105, development {'phenotype': 'I-tumourigenesis'}", + "107, intestinal {'phenotype': 'B-tumourigenesis'}", + "108, tumors {'phenotype': 'I-tumourigenesis'}", + "110, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "89, supports ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "93, proliferation ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "95, cancer ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "96, stem ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "97, cells ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33']", + "103, promotes ['l4', 'l12', 'l19', 'l25', 'l30', 'l34', 'l35', 'l36', 'l37']", + "105, development ['l5', 'l13', 'l20', 'l26', 'l31', 'l34', 'l38', 'l39', 'l40']", + "107, intestinal ['l6', 'l14', 'l21', 'l27', 'l35', 'l38', 'l41', 'l42']", + "108, tumors ['l7', 'l15', 'l22', 'l28', 'l32', 'l36', 'l39', 'l41', 'l43']", + "110, mice. ['l8', 'l16', 'l23', 'l29', 'l33', 'l37', 'l40', 'l42', 'l43']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "supports", + "promotes" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "supports", + "promotes" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "stem", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "supports", + "promotes" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development", + "intestinal", + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "supports", + "promotes" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "stem", + "cells" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "stem", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development", + "intestinal", + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development", + "intestinal", + "tumors" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "27019329", + "TEXT": "The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC). However, the determinants of AR overexpression in CRPC are poorly defined. Here we show that retinoic acid receptor-related orphan receptor γ (ROR-γ) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors. ROR-γ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an AR-ROR response element (RORE) to stimulate AR gene transcription. ROR-γ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-γ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR target gene network. Finally, ROR-γ antagonists suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPC tumors to enzalutamide, without overt toxicity, in mice. Taken together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa.", + "TAG_DATA": [ + "81, ROR-γ {'perturbing_action': 'B-pharmacological inhibition'}", + "82, antagonists {'perturbing_action': 'I-pharmacological inhibition'}", + "94, prostate {'context': 'B-transformed cells'}", + "95, cancer {'context': 'I-transformed cells'}", + "96, (PCa) {'context': 'I-transformed cells'}", + "97, cell {'context': 'I-transformed cells'}", + "98, lines {'context': 'I-transformed cells'}", + "100, tumors. {'context': 'B-neoplasm'}", + "101, ROR-γ {'perturbing_action': 'B-pharmacological inhibition'}", + "102, antagonists {'perturbing_action': 'I-pharmacological inhibition'}", + "120, ROR-γ {'perturbing_action': 'B-pharmacological inhibition'}", + "121, antagonists {'perturbing_action': 'I-pharmacological inhibition'}", + "122, suppressed {'effect': 'B-negative'}", + "123, tumor {'phenotype': 'B-tumour growth'}", + "124, growth {'phenotype': 'I-tumour growth'}", + "131, xenograft {'context': 'I-xenograft'}", + "132, PCa {'context': 'I-neoplasm'}", + "133, models, {'context': 'I-neoplasm'}", + "138, CRPC {'context': 'B-neoplasm'}", + "139, tumors {'context': 'I-neoplasm'}", + "146, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "81, ROR-γ ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "82, antagonists ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "94, prostate ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "95, cancer ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "96, (PCa) ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "97, cell ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "98, lines ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "100, tumors. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "101, ROR-γ ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "102, antagonists ['l28', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "120, ROR-γ ['l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "121, antagonists ['l29', 'l36', 'l43', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "122, suppressed ['l30', 'l37', 'l44', 'l53', 'l62', 'l63', 'l64', 'l65', 'l66']", + "123, tumor ['l31', 'l38', 'l45', 'l54', 'l62', 'l67', 'l68', 'l69', 'l70']", + "124, growth ['l32', 'l39', 'l46', 'l55', 'l63', 'l67', 'l71', 'l72', 'l73']", + "131, xenograft ['l33', 'l40', 'l47', 'l56', 'l64', 'l68', 'l71', 'l74', 'l75', 'l76']", + "132, PCa ['l34', 'l41', 'l48', 'l57', 'l65', 'l69', 'l72', 'l74', 'l77']", + "133, models, ['l35', 'l42', 'l49', 'l58', 'l66', 'l70', 'l73', 'l75', 'l77']", + "138, CRPC ['l50', 'l59', 'l78', 'l79']", + "139, tumors ['l51', 'l60', 'l76', 'l78', 'l80']", + "146, mice. ['l52', 'l61', 'l79', 'l80']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ROR-γ", + "antagonists" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cancer", + "(PCa)", + "cell", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ROR-γ", + "antagonists" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors.", + "PCa", + "models,", + "CRPC", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ROR-γ", + "antagonists" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ROR-γ", + "antagonists" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ROR-γ", + "antagonists" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ROR-γ", + "antagonists" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "PCa", + "models," + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "PCa", + "models," + ] + } + } + ] + }, + { + "PMID": "26950360", + "TEXT": "Expression of the oncogenic transcription factor MYC is disproportionately elevated in triple-negative breast cancer (TNBC), as compared to estrogen receptor-, progesterone receptor- or human epidermal growth factor 2 receptor-positive (RP) breast cancer. We and others have shown that MYC alters metabolism during tumorigenesis. However, the role of MYC in TNBC metabolism remains mostly unexplored. We hypothesized that MYC-dependent metabolic dysregulation is essential for the growth of MYC-overexpressing TNBC cells and may identify new therapeutic targets for this clinically challenging subset of breast cancer. Using a targeted metabolomics approach, we identified fatty acid oxidation (FAO) intermediates as being dramatically upregulated in a MYC-driven model of TNBC. We also identified a lipid metabolism gene signature in patients with TNBC that were identified from The Cancer Genome Atlas database and from multiple other clinical data sets, implicating FAO as a dysregulated pathway that is critical for TNBC cell metabolism. We found that pharmacologic inhibition of FAO catastrophically decreased energy metabolism in MYC-overexpressing TNBC cells and blocked tumor growth in a MYC-driven transgenic TNBC model and in a MYC-overexpressing TNBC patient-derived xenograft. These findings demonstrate that MYC-overexpressing TNBC shows an increased bioenergetic reliance on FAO and identify the inhibition of FAO as a potential therapeutic strategy for this subset of breast cancer.", + "TAG_DATA": [ + "149, pharmacologic {'perturbing_action': 'B-pharmacological inhibition'}", + "150, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "151, of {'perturbing_action': 'I-pharmacological inhibition'}", + "152, FAO {'perturbing_action': 'I-pharmacological inhibition'}", + "158, MYC-overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "159, TNBC {'context': 'B-transformed cells'}", + "160, cells {'context': 'I-transformed cells'}", + "162, blocked {'effect': 'B-negative'}", + "163, tumor {'phenotype': 'B-tumour growth'}", + "164, growth {'phenotype': 'I-tumour growth'}", + "168, transgenic {'context': 'I-xenograft'}", + "169, TNBC {'context': 'I-neoplasm'}", + "170, model {'context': 'I-neoplasm'}", + "174, MYC-overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "175, TNBC {'context': 'B-xenograft'}", + "176, patient-derived {'context': 'I-xenograft'}", + "177, xenograft. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "149, pharmacologic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "150, inhibition ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "151, of ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "152, FAO ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "158, MYC-overexpressing ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44']", + "159, TNBC ['l4', 'l15', 'l25', 'l34', 'l42', 'l45']", + "160, cells ['l5', 'l16', 'l26', 'l35', 'l43', 'l45']", + "162, blocked ['l6', 'l17', 'l27', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50']", + "163, tumor ['l7', 'l18', 'l28', 'l37', 'l46', 'l51', 'l52', 'l53', 'l54']", + "164, growth ['l8', 'l19', 'l29', 'l38', 'l47', 'l51', 'l55', 'l56', 'l57']", + "168, transgenic ['l9', 'l20', 'l30', 'l39', 'l48', 'l52', 'l55', 'l58', 'l59']", + "169, TNBC ['l10', 'l21', 'l31', 'l40', 'l49', 'l53', 'l56', 'l58', 'l60']", + "170, model ['l11', 'l22', 'l32', 'l41', 'l44', 'l50', 'l54', 'l57', 'l59', 'l60']", + "174, MYC-overexpressing ['l61', 'l62', 'l63']", + "175, TNBC ['l61', 'l64', 'l65']", + "176, patient-derived ['l62', 'l64', 'l66']", + "177, xenograft. ['l63', 'l65', 'l66']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "FAO" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "FAO" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "FAO" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "FAO" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "FAO" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "TNBC", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "MYC-overexpressing" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "MYC-overexpressing" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "model" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "transgenic" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "TNBC", + "model" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "transgenic" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "TNBC", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "MYC-overexpressing" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "TNBC", + "patient-derived", + "xenograft." + ] + } + } + ] + }, + { + "PMID": "26878232", + "TEXT": "Impaired erythropoiesis in the deletion 5q (del(5q)) subtype of myelodysplastic syndrome (MDS) has been linked to heterozygous deletion of RPS14, which encodes the ribosomal protein small subunit 14. We generated mice with conditional inactivation of Rps14 and demonstrated an erythroid differentiation defect that is dependent on the tumor suppressor protein p53 (encoded by Trp53 in mice) and is characterized by apoptosis at the transition from polychromatic to orthochromatic erythroblasts. This defect resulted in age-dependent progressive anemia, megakaryocyte dysplasia and loss of hematopoietic stem cell (HSC) quiescence. As assessed by quantitative proteomics, mutant erythroblasts expressed higher levels of proteins involved in innate immune signaling, notably the heterodimeric S100 calcium-binding proteins S100a8 and S100a9. S100a8--whose expression was increased in mutant erythroblasts, monocytes and macrophages--is functionally involved in the erythroid defect caused by the Rps14 deletion, as addition of recombinant S100a8 was sufficient to induce a differentiation defect in wild-type erythroid cells, and genetic inactivation of S100a8 expression rescued the erythroid differentiation defect of Rps14-haploinsufficient HSCs. Our data link Rps14 haploinsufficiency in del(5q) MDS to activation of the innate immune system and induction of S100A8-S100A9 expression, leading to a p53-dependent erythroid differentiation defect.", + "TAG_DATA": [ + "30, mice {'context': 'B-organism'}", + "32, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "33, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "34, of {'perturbing_action': 'I-gene loss-of-function'}", + "35, Rps14 {'perturbing_action': 'I-gene loss-of-function'}", + "79, loss {'effect': 'B-negative'}", + "81, hematopoietic {'context': 'B-cells'}", + "82, stem {'context': 'I-cells'}", + "83, cell {'context': 'I-cells'}", + "84, (HSC) {'context': 'I-cells'}", + "85, quiescence. {'phenotype': 'B-quiescence'}", + "92, erythroblasts {'context': 'B-cells'}", + "131, Rps14 {'perturbing_action': 'B-gene loss-of-function'}", + "132, deletion, {'perturbing_action': 'I-gene loss-of-function'}", + "141, induce {'effect': 'B-positive'}", + "143, differentiation {'phenotype': 'B-differentiation'}", + "144, defect {'effect': 'B-negative', 'phenotype': 'I-differentiation'}", + "147, erythroid {'context': 'B-cells'}", + "148, cells, {'context': 'I-cells'}", + "150, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "151, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "152, of {'perturbing_action': 'I-gene loss-of-function'}", + "153, S100a8 {'perturbing_action': 'I-gene loss-of-function'}", + "154, expression {'perturbing_action': 'I-gene loss-of-function'}", + "155, rescued {'effect': 'B-rescues'}", + "158, differentiation {'phenotype': 'I-differentiation'}", + "159, defect {'effect': 'B-negative'}", + "161, Rps14-haploinsufficient {'perturbing_action': 'B-gene loss-of-function'}", + "162, HSCs. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "30, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "32, conditional ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "33, inactivation ['l1', 'l10', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "34, of ['l2', 'l11', 'l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "35, Rps14 ['l3', 'l12', 'l21', 'l29', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "79, loss ['l4', 'l13', 'l22', 'l30', 'l37', 'l44', 'l45', 'l46', 'l47', 'l48']", + "81, hematopoietic ['l5', 'l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "82, stem ['l6', 'l15', 'l24', 'l32', 'l39', 'l45', 'l49', 'l56', 'l57', 'l58', 'l59', 'l60']", + "83, cell ['l7', 'l16', 'l25', 'l33', 'l40', 'l46', 'l50', 'l56', 'l61', 'l62', 'l63', 'l64']", + "84, (HSC) ['l8', 'l17', 'l26', 'l34', 'l41', 'l47', 'l51', 'l57', 'l61', 'l65', 'l66', 'l67']", + "85, quiescence. ['l9', 'l18', 'l27', 'l35', 'l42', 'l48', 'l52', 'l58', 'l62', 'l65', 'l68']", + "92, erythroblasts ['l19', 'l28', 'l36', 'l43', 'l53', 'l59', 'l63', 'l66', 'l68', 'l69', 'l70', 'l71']", + "131, Rps14 ['l54', 'l69', 'l72', 'l73', 'l74', 'l75', 'l76']", + "132, deletion, ['l55', 'l60', 'l64', 'l67', 'l70', 'l72', 'l77']", + "141, induce ['l73', 'l78', 'l79', 'l80', 'l81']", + "143, differentiation ['l74', 'l78', 'l82', 'l83', 'l84']", + "144, defect ['l75', 'l79', 'l82', 'l85', 'l86']", + "147, erythroid ['l80', 'l83', 'l85', 'l87']", + "148, cells, ['l71', 'l76', 'l77', 'l81', 'l84', 'l86', 'l87']", + "150, genetic ['l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "151, inactivation ['l88', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "152, of ['l89', 'l97', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "153, S100a8 ['l90', 'l98', 'l105', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "154, expression ['l91', 'l99', 'l106', 'l112', 'l118', 'l119', 'l120', 'l121', 'l122']", + "155, rescued ['l92', 'l100', 'l107', 'l113', 'l118', 'l123', 'l124', 'l125', 'l126']", + "158, differentiation ['l93', 'l101', 'l108', 'l114', 'l119', 'l123', 'l127', 'l128', 'l129']", + "159, defect ['l94', 'l102', 'l109', 'l115', 'l120', 'l124', 'l127', 'l130', 'l131']", + "161, Rps14-haploinsufficient ['l95', 'l103', 'l110', 'l116', 'l121', 'l125', 'l128', 'l130', 'l132']", + "162, HSCs. ['l96', 'l104', 'l111', 'l117', 'l122', 'l126', 'l129', 'l131', 'l132']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "inactivation", + "of", + "Rps14" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "inactivation", + "of", + "Rps14", + "genetic", + "S100a8", + "expression", + "Rps14-haploinsufficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss", + "defect" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "inactivation", + "of", + "Rps14", + "deletion,", + "genetic", + "S100a8", + "expression", + "Rps14-haploinsufficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cell", + "(HSC)", + "erythroblasts", + "cells,", + "HSCs." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "inactivation", + "of", + "Rps14" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "loss", + "defect" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cell", + "(HSC)", + "erythroid", + "cells,", + "HSCs." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "loss" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cell", + "(HSC)", + "erythroblasts" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rps14" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rps14", + "genetic", + "inactivation", + "of", + "S100a8", + "expression", + "Rps14-haploinsufficient" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "defect" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "defect" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "defect", + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "defect" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "erythroid", + "cells," + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "defect" + ] + }, + "context": { + "val": "cells", + "words": [ + "erythroid", + "cells,", + "HSCs." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inactivation", + "of", + "S100a8", + "expression", + "Rps14-haploinsufficient" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSCs." + ] + } + } + ] + }, + { + "PMID": "26752518", + "TEXT": "Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death. Acute mortality from AP-MODS exceeds 20% (ref. 3), and the lifespans of those who survive the initial episode are typically shorter than those of the general population. There are no specific therapies available to protect individuals from AP-MODS. Here we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism, is central to the pathogenesis of AP-MODS. We created a mouse strain that is deficient for Kmo (encoding KMO) and that has a robust biochemical phenotype that protects against extrapancreatic tissue injury to the lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of the oxazolidinone GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in the levels of kynurenine pathway metabolites in vivo, and it afforded therapeutic protection against MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS, and they open up a new area for drug discovery in critical illness.", + "TAG_DATA": [ + "93, mouse {'context': 'B-organism'}", + "94, strain {'context': 'I-organism'}", + "97, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "98, for {'perturbing_action': 'I-gene loss-of-function'}", + "99, Kmo {'perturbing_action': 'I-gene loss-of-function'}", + "100, (encoding {'perturbing_action': 'I-gene loss-of-function'}", + "101, KMO) {'perturbing_action': 'I-gene loss-of-function'}", + "184, in {'context': 'B-in vivo'}", + "185, vivo, {'context': 'I-in vivo'}", + "195, rat {'context': 'B-organism'}", + "196, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "93, mouse ['l0', 'l1', 'l2', 'l3', 'l4']", + "94, strain ['l0', 'l5', 'l6', 'l7', 'l8']", + "97, deficient ['l1', 'l5', 'l9', 'l10', 'l11', 'l12']", + "98, for ['l2', 'l6', 'l9', 'l13', 'l14', 'l15']", + "99, Kmo ['l3', 'l7', 'l10', 'l13', 'l16', 'l17']", + "100, (encoding ['l4', 'l8', 'l11', 'l14', 'l16', 'l18']", + "101, KMO) ['l12', 'l15', 'l17', 'l18']", + "184, in ['l19']", + "185, vivo, ['l19']", + "195, rat ['l20']", + "196, model ['l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "strain" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "Kmo", + "(encoding" + ] + } + } + ] + }, + { + "PMID": "26692333", + "TEXT": "AIRAPL (arsenite-inducible RNA-associated protein-like) is an evolutionarily conserved regulator of cellular proteostasis linked to longevity in nematodes, but its biological function in mammals is unknown. We show herein that AIRAPL-deficient mice develop a fully-penetrant myeloproliferative neoplastic process. Proteomic analysis of AIRAPL-deficient mice revealed that this protein exerts its antineoplastic function through the regulation of the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. We demonstrate that AIRAPL interacts with newly synthesized insulin-related growth factor-1 receptor (IGF1R) polypeptides, promoting their ubiquitination and proteasome-mediated degradation. Accordingly, genetic and pharmacological IGF1R inhibitory strategies prevent the hematological disease found in AIRAPL-deficient mice as well as that in mice carrying the Jak2(V617F) mutation, thereby demonstrating the causal involvement of this pathway in the pathogenesis of myeloproliferative neoplasms. Consistent with its proposed role as a tumor suppressor of myeloid transformation, AIRAPL expression is widely abrogated in human myeloproliferative disorders. Collectively, these findings support the oncogenic relevance of proteostasis deregulation in hematopoietic cells, and they unveil novel therapeutic targets for these frequent hematological neoplasias.", + "TAG_DATA": [ + "29, AIRAPL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "30, mice {'context': 'B-organism'}", + "40, AIRAPL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "41, mice {'context': 'B-organism'}", + "86, IGF1R {'perturbing_action': 'I-pharmacological inhibition'}", + "87, inhibitory {'perturbing_action': 'I-pharmacological inhibition'}", + "95, AIRAPL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "96, mice {'context': 'B-organism'}", + "102, mice {'context': 'B-organism'}", + "104, the {'perturbing_action': 'I-other'}", + "105, Jak2(V617F) {'perturbing_action': 'B-other'}", + "106, mutation, {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "29, AIRAPL-deficient ['l0', 'l1', 'l2']", + "30, mice ['l0', 'l3', 'l4']", + "40, AIRAPL-deficient ['l1', 'l3', 'l5']", + "41, mice ['l2', 'l4', 'l5']", + "86, IGF1R ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "87, inhibitory ['l6', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "88, strategies ['l7', 'l14', 'l21', 'l22', 'l23', 'l24', 'l25']", + "95, AIRAPL-deficient ['l8', 'l15', 'l21', 'l26']", + "96, mice ['l9', 'l16', 'l22', 'l26']", + "102, mice ['l10', 'l17', 'l23', 'l27', 'l28', 'l29']", + "104, the ['l11', 'l18', 'l27', 'l30', 'l31']", + "105, Jak2(V617F) ['l12', 'l19', 'l24', 'l28', 'l30', 'l32']", + "106, mutation, ['l13', 'l20', 'l25', 'l29', 'l31', 'l32']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "AIRAPL-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "IGF1R", + "inhibitory" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "the", + "Jak2(V617F)", + "mutation," + ] + } + } + ] + }, + { + "PMID": "26569380", + "TEXT": "Brown adipose tissue (BAT) promotes a lean and healthy phenotype and improves insulin sensitivity. In response to cold or exercise, brown fat cells also emerge in the white adipose tissue (WAT; also known as beige cells), a process known as browning. Here we show that the development of functional beige fat in the inguinal subcutaneous adipose tissue (ingSAT) and perigonadal visceral adipose tissue (pgVAT) is promoted by the depletion of microbiota either by means of antibiotic treatment or in germ-free mice. This leads to improved glucose tolerance and insulin sensitivity and decreased white fat and adipocyte size in lean mice, obese leptin-deficient (ob/ob) mice and high-fat diet (HFD)-fed mice. Such metabolic improvements are mediated by eosinophil infiltration, enhanced type 2 cytokine signaling and M2 macrophage polarization in the subcutaneous white fat depots of microbiota-depleted animals. The metabolic phenotype and the browning of the subcutaneous fat are impaired by the suppression of type 2 cytokine signaling, and they are reversed by recolonization of the antibiotic-treated or germ-free mice with microbes. These results provide insight into the microbiota-fat signaling axis and beige-fat development in health and metabolic disease.", + "TAG_DATA": [ + "80, mice. {'context': 'I-organism'}", + "98, lean {'context': 'B-organism'}", + "99, mice, {'context': 'I-organism'}", + "100, obese {'perturbing_action': 'B-gene loss-of-function'}", + "101, leptin-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "102, (ob/ob) {'perturbing_action': 'I-gene loss-of-function'}", + "103, mice {'context': 'I-organism'}", + "108, mice. {'context': 'B-organism'}", + "134, animals. {'context': 'B-organism'}", + "166, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "80, mice. ['l0', 'l1']", + "98, lean ['l0', 'l2']", + "99, mice, ['l1', 'l2']", + "100, obese ['l3', 'l4', 'l5', 'l6', 'l7']", + "101, leptin-deficient ['l3', 'l8', 'l9', 'l10', 'l11', 'l12']", + "102, (ob/ob) ['l4', 'l8', 'l13', 'l14', 'l15', 'l16']", + "103, mice ['l5', 'l9', 'l13', 'l17', 'l18']", + "108, mice. ['l10', 'l14', 'l19', 'l20', 'l21']", + "129, white ['l6', 'l11', 'l15', 'l17', 'l19', 'l22', 'l23']", + "130, fat ['l7', 'l12', 'l16', 'l18', 'l20', 'l22', 'l24']", + "134, animals. ['l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "obese", + "leptin-deficient", + "(ob/ob)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "26523969", + "TEXT": "Human tumors show a high level of genetic heterogeneity, but the processes that influence the timing and route of metastatic dissemination of the subclones are unknown. Here we have used whole-exome sequencing of 103 matched benign, malignant and metastatic skin tumors from genetically heterogeneous mice to demonstrate that most metastases disseminate synchronously from the primary tumor, supporting parallel rather than linear evolution as the predominant model of metastasis. Shared mutations between primary carcinomas and their matched metastases have the distinct A-to-T signature of the initiating carcinogen dimethylbenzanthracene, but non-shared mutations are primarily G-to-T, a signature associated with oxidative stress. The existence of carcinomas that either did or did not metastasize in the same host animal suggests that there are tumor-intrinsic factors that influence metastatic seeding. We also demonstrate the importance of germline polymorphisms in determining allele-specific mutations, and we identify somatic genetic alterations that are specifically related to initiation of carcinogenesis by Hras or Kras mutations. Mouse tumors that mimic the genetic heterogeneity of human cancers can aid our understanding of the clonal evolution of metastasis and provide a realistic model for the testing of novel therapies.", + "TAG_DATA": [ + "35, benign, {'context': 'B-neoplasm'}", + "36, malignant {'context': 'I-neoplasm'}", + "37, and {'context': 'I-neoplasm'}", + "38, metastatic {'context': 'I-neoplasm'}", + "39, skin {'context': 'I-neoplasm'}", + "40, tumors {'context': 'I-neoplasm'}", + "102, carcinomas {'context': 'B-neoplasm'}", + "105, did {'effect': 'B-negative'}", + "107, did {'effect': 'B-negative'}", + "108, not {'effect': 'B-no effect'}", + "109, metastasize {'phenotype': 'B-metastasis'}", + "113, host {'context': 'B-organism'}", + "114, animal {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "35, benign, ['l0', 'l1', 'l2', 'l3', 'l4']", + "36, malignant ['l0', 'l5', 'l6', 'l7', 'l8']", + "37, and ['l1', 'l5', 'l9', 'l10', 'l11']", + "38, metastatic ['l2', 'l6', 'l9', 'l12', 'l13']", + "39, skin ['l3', 'l7', 'l10', 'l12', 'l14']", + "40, tumors ['l4', 'l8', 'l11', 'l13', 'l14']", + "102, carcinomas ['l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "105, did ['l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "107, did ['l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "108, not ['l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "109, metastasize ['l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "113, host ['l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "114, animal ['l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "carcinomas" + ] + }, + "effect": { + "val": "negative", + "words": [ + "did" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "carcinomas" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "carcinomas" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasize" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "did" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasize" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "did" + ] + }, + "context": { + "val": "organism", + "words": [ + "host", + "animal" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasize" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not" + ] + }, + "context": { + "val": "organism", + "words": [ + "host", + "animal" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasize" + ] + }, + "context": { + "val": "organism", + "words": [ + "host", + "animal" + ] + } + } + ] + }, + { + "PMID": "26457758", + "TEXT": "Cancer-associated muscle weakness is a poorly understood phenomenon, and there is no effective treatment. Here we find that seven different mouse models of human osteolytic bone metastases-representing breast, lung and prostate cancers, as well as multiple myeloma-exhibited impaired muscle function, implicating a role for the tumor-bone microenvironment in cancer-associated muscle weakness. We found that transforming growth factor (TGF)-β, released from the bone surface as a result of metastasis-induced bone destruction, upregulated NADPH oxidase 4 (Nox4), resulting in elevated oxidization of skeletal muscle proteins, including the ryanodine receptor and calcium (Ca(2+)) release channel (RyR1). The oxidized RyR1 channels leaked Ca(2+), resulting in lower intracellular signaling, which is required for proper muscle contraction. We found that inhibiting RyR1 leakage, TGF-β signaling, TGF-β release from bone or Nox4 activity improved muscle function in mice with MDA-MB-231 bone metastases. Humans with breast- or lung cancer-associated bone metastases also had oxidized skeletal muscle RyR1 that is not seen in normal muscle. Similarly, skeletal muscle weakness, increased Nox4 binding to RyR1 and oxidation of RyR1 were present in a mouse model of Camurati-Engelmann disease, a nonmalignant metabolic bone disorder associated with increased TGF-β activity. Thus, pathological TGF-β release from bone contributes to muscle weakness by decreasing Ca(2+)-induced muscle force production.", + "TAG_DATA": [ + "127, muscle {'context': 'B-tissue/organ'}", + "130, mice {'context': 'B-organism'}", + "133, bone {'phenotype': 'I-metastasis'}", + "134, metastases. {'phenotype': 'I-metastasis'}", + "135, Humans {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "127, muscle ['l0']", + "130, mice ['l0', 'l1', 'l2', 'l3']", + "132, MDA-MB-231 ['l1', 'l4', 'l5']", + "133, bone ['l2', 'l4', 'l6']", + "134, metastases. ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "bone", + "metastases." + ] + } + } + ] + }, + { + "PMID": "26343801", + "TEXT": "Modest transcriptional changes caused by genetic or epigenetic mechanisms are frequent in human cancer. Although loss or near-complete loss of the hematopoietic transcription factor PU.1 induces acute myeloid leukemia (AML) in mice, a similar degree of PU.1 impairment is exceedingly rare in human AML; yet, moderate PU.1 inhibition is common in AML patients. We assessed functional consequences of modest reductions in PU.1 expression on leukemia development in mice harboring DNA lesions resembling those acquired during human stem cell aging. Heterozygous deletion of an enhancer of PU.1, which resulted in a 35% reduction of PU.1 expression, was sufficient to induce myeloid-biased preleukemic stem cells and their subsequent transformation to AML in a DNA mismatch repair-deficient background. AML progression was mediated by inhibition of expression of a PU.1-cooperating transcription factor, Irf8. Notably, we found marked molecular similarities between the disease in these mice and human myelodysplastic syndrome and AML. This study demonstrates that minimal reduction of a key lineage-specific transcription factor, which commonly occurs in human disease, is sufficient to initiate cancer development, and it provides mechanistic insight into the formation and progression of preleukemic stem cells in AML.", + "TAG_DATA": [ + "67, mice {'context': 'B-organism'}", + "79, Heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "80, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "81, of {'perturbing_action': 'I-gene loss-of-function'}", + "82, an {'perturbing_action': 'I-gene loss-of-function'}", + "83, enhancer {'perturbing_action': 'I-gene loss-of-function'}", + "84, of {'perturbing_action': 'I-gene loss-of-function'}", + "85, PU.1, {'perturbing_action': 'I-gene loss-of-function'}", + "98, induce {'effect': 'B-positive'}", + "100, preleukemic {'context': 'B-cells'}", + "101, stem {'context': 'I-cells'}", + "102, cells {'context': 'I-cells'}", + "106, transformation {'phenotype': 'B-transformation'}", + "107, to {'phenotype': 'B-transformation'}", + "108, AML {'phenotype': 'B-transformation'}" + ], + "LINK_DATA": [ + "79, Heterozygous ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "80, deletion ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "81, of ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "82, an ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "83, enhancer ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "84, of ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "85, PU.1, ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "98, induce ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "100, preleukemic ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "101, stem ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "102, cells ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "106, transformation ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "107, to ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "108, AML ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Heterozygous", + "deletion", + "of", + "an", + "enhancer", + "PU.1," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Heterozygous", + "deletion", + "of", + "an", + "enhancer", + "PU.1," + ] + }, + "context": { + "val": "cells", + "words": [ + "preleukemic", + "stem", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Heterozygous", + "deletion", + "of", + "an", + "enhancer", + "PU.1," + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation", + "to", + "AML" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "preleukemic", + "stem", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation", + "to", + "AML" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "preleukemic", + "stem", + "cells" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation", + "to", + "AML" + ] + } + } + ] + }, + { + "PMID": "26280121", + "TEXT": "Tumor necrosis factor-α (TNF-α), one of the major stress-induced proinflammatory cytokines, is upregulated in the heart after tissue injury, and its sustained expression can contribute to the development of heart failure. Whether TNF-α also exerts cytoprotective effects in heart failure is not known. Here we provide evidence for a cardioprotective function of TNF-α in a genetic heart failure model, desmin-deficient mice. The cardioprotective effects of TNF-α are a consequence of nuclear factor-κB (NF-κB)-mediated ectopic expression in cardiomyocytes of keratin 8 (K8) and keratin 18 (K18), two epithelial-specific intermediate filament proteins. In cardiomyocytes, K8 and K18 (K8/K18) formed an alternative cytoskeletal network that localized mainly at intercalated discs (IDs) and conferred cardioprotection by maintaining normal ID structure and mitochondrial integrity and function. Ectopic induction of K8/K18 expression in cardiomyocytes also occurred in other genetic and experimental models of heart failure. Loss of the K8/K18 network resulted in a maladaptive cardiac phenotype following transverse aortic constriction. In human failing myocardium, where TNF-α expression is upregulated, K8/K18 were also ectopically expressed and localized primarily at IDs, which did not contain detectable amounts of desmin. Thus, TNF-α- and NF-κB-mediated formation of an alternative, stress-induced intermediate filament cytoskeleton has cardioprotective function in mice and potentially in humans.", + "TAG_DATA": [ + "59, desmin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "60, mice. {'context': 'B-organism'}", + "91, cardiomyocytes, {'context': 'B-cells'}", + "121, Ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "122, induction {'perturbing_action': 'I-gene gain-of-function'}", + "123, of {'perturbing_action': 'I-gene gain-of-function'}", + "124, K8/K18 {'perturbing_action': 'I-gene gain-of-function'}", + "125, expression {'perturbing_action': 'I-gene gain-of-function'}", + "127, cardiomyocytes {'context': 'B-cells'}", + "139, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "140, of {'perturbing_action': 'I-gene loss-of-function'}", + "141, the {'perturbing_action': 'I-gene loss-of-function'}", + "142, K8/K18 {'perturbing_action': 'I-gene loss-of-function'}", + "143, network {'perturbing_action': 'I-gene loss-of-function'}", + "155, human {'context': 'B-tissue/organ'}", + "156, failing {'context': 'I-tissue/organ'}", + "157, myocardium, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "59, desmin-deficient ['l0', 'l1', 'l2']", + "60, mice. ['l0', 'l3']", + "91, cardiomyocytes, ['l1', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "121, Ectopic ['l4', 'l10', 'l11', 'l12', 'l13', 'l14']", + "122, induction ['l5', 'l10', 'l15', 'l16', 'l17', 'l18']", + "123, of ['l6', 'l11', 'l15', 'l19', 'l20', 'l21']", + "124, K8/K18 ['l7', 'l12', 'l16', 'l19', 'l22', 'l23']", + "125, expression ['l8', 'l13', 'l17', 'l20', 'l22', 'l24']", + "127, cardiomyocytes ['l2', 'l9', 'l14', 'l18', 'l21', 'l23', 'l24']", + "139, Loss ['l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "140, of ['l25', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "141, the ['l26', 'l31', 'l37', 'l38', 'l39', 'l40', 'l41']", + "142, K8/K18 ['l27', 'l32', 'l37', 'l42', 'l43', 'l44', 'l45']", + "143, network ['l28', 'l33', 'l38', 'l42']", + "155, human ['l34', 'l39', 'l43', 'l46', 'l47']", + "156, failing ['l29', 'l35', 'l40', 'l44', 'l46', 'l48']", + "157, myocardium, ['l30', 'l36', 'l41', 'l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "desmin-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "desmin-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes,", + "cardiomyocytes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cardiomyocytes,", + "cardiomyocytes" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "induction", + "of", + "K8/K18", + "expression" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Loss", + "of", + "the", + "K8/K18" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "failing", + "myocardium,", + "human" + ] + } + } + ] + }, + { + "PMID": "26236992", + "TEXT": "Myostatin (also known as growth and differentiation factor 8) is a secreted member of the transforming growth factor-β (TGF-β) family that is mainly expressed in skeletal muscle, which is also its primary target tissue. Deletion of the myostatin gene (Mstn) in mice leads to muscle hypertrophy, and animal studies support the concept that myostatin is a negative regulator of muscle growth and regeneration. However, myostatin deficiency also increases bone formation, mainly through loading-associated effects on bone. Here we report a previously unknown direct role for myostatin in osteoclastogenesis and in the progressive loss of articular bone in rheumatoid arthritis (RA). We demonstrate that myostatin is highly expressed in the synovial tissues of RA subjects and of human tumor necrosis factor (TNF)-α transgenic (hTNFtg) mice, a model for human RA. Myostatin strongly accelerates receptor activator of nuclear factor κB ligand (RANKL)-mediated osteoclast formation in vitro through transcription factor SMAD2-dependent regulation of nuclear factor of activated T-cells (NFATC1). Myostatin deficiency or antibody-mediated inhibition leads to an amelioration of arthritis severity in hTNFtg mice, chiefly reflected by less bone destruction. Consistent with these effects in hTNFtg mice, the lack of myostatin leads to increased grip strength and less bone erosion in the K/BxN serum-induced arthritis model in mice. The results strongly suggest that myostatin is a potent therapeutic target for interfering with osteoclast formation and joint destruction in RA.", + "TAG_DATA": [ + "116, human {'perturbing_action': 'B-gene gain-of-function'}", + "117, tumor {'perturbing_action': 'I-gene gain-of-function'}", + "118, necrosis {'perturbing_action': 'I-gene gain-of-function'}", + "119, factor {'perturbing_action': 'I-gene gain-of-function'}", + "121, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "122, (hTNFtg) {'perturbing_action': 'I-gene gain-of-function'}", + "123, mice, {'context': 'B-organism'}", + "142, in {'context': 'B-in vitro'}", + "143, vitro {'context': 'I-in vitro'}", + "156, Myostatin {'perturbing_action': 'B-gene loss-of-function'}", + "157, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "169, hTNFtg {'perturbing_action': 'B-other'}", + "170, mice, {'context': 'B-organism'}", + "182, hTNFtg {'perturbing_action': 'B-other'}", + "183, mice, {'context': 'B-organism'}", + "185, lack {'perturbing_action': 'B-gene loss-of-function'}", + "186, of {'perturbing_action': 'I-gene loss-of-function'}", + "187, myostatin {'perturbing_action': 'I-gene loss-of-function'}", + "204, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "116, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "117, tumor ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "118, necrosis ['l1', 'l10', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "119, factor ['l2', 'l11', 'l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "121, transgenic ['l3', 'l12', 'l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "122, (hTNFtg) ['l4', 'l13', 'l23', 'l32', 'l40', 'l47', 'l48', 'l49']", + "123, mice, ['l5', 'l14', 'l24', 'l33', 'l41', 'l47', 'l50', 'l51']", + "142, in ['l6', 'l15', 'l25', 'l34', 'l42', 'l48', 'l50', 'l52']", + "143, vitro ['l7', 'l16', 'l26', 'l35', 'l43', 'l49', 'l51', 'l52']", + "156, Myostatin ['l17', 'l27', 'l36', 'l53', 'l54', 'l55']", + "157, deficiency ['l18', 'l28', 'l37', 'l44', 'l53', 'l56', 'l57']", + "169, hTNFtg ['l8', 'l19', 'l29', 'l38', 'l45', 'l54', 'l56', 'l58']", + "170, mice, ['l9', 'l20', 'l30', 'l39', 'l46', 'l55', 'l57', 'l58']", + "182, hTNFtg ['l59']", + "183, mice, ['l59']", + "185, lack ['l60', 'l61', 'l62']", + "186, of ['l60', 'l63', 'l64']", + "187, myostatin ['l61', 'l63', 'l65']", + "204, mice. ['l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "human", + "tumor", + "necrosis", + "factor", + "transgenic", + "(hTNFtg)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "human", + "tumor", + "necrosis", + "factor", + "transgenic", + "(hTNFtg)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Myostatin", + "deficiency", + "lack", + "of", + "myostatin" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "hTNFtg" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "26236990", + "TEXT": "Endogenous mechanisms leading to host protection and resolution of infections without immunosuppression are of wide interest. Here we elucidate the structures of four new host-protective molecules produced in neutrophil-endothelial cocultures and present in human and mouse tissues after sterile inflammation or infection. The bioactive molecules contain conjugated triene and diene double bonds, carry an alcohol at C13 and are derived from n-3 docosapentaenoic acid (DPA, C22:5). These compounds, termed 13-series resolvins (RvTs), demonstrated potent protective actions increasing mice survival during Escherichia coli infections. RvTs also regulated human and mouse phagocyte responses stimulating bacterial phagocytosis and regulating inflammasome components. Their biosynthesis during neutrophil-endothelial cell interactions was initiated by endothelial cyclooxygenase-2 (COX-2), increased by atorvastatin via S-nitrosylation of COX-2 and reduced by COX-2 inhibitors. The actions of atorvastatin and RvTs were additive in E. coli infections in mice, where they accelerated resolution of inflammation and increased survival >60%. Taken together, these results document host-protective molecules in bacterial infections, namely RvTs, derived from n-3 DPA via transcellular biosynthesis and increased by atorvastatin. These molecules regulate key innate protective responses in the resolution of infectious inflammation.", + "TAG_DATA": [ + "77, mice {'context': 'B-organism'}", + "120, COX-2 {'perturbing_action': 'B-pharmacological inhibition'}", + "121, inhibitors. {'perturbing_action': 'I-pharmacological inhibition'}", + "135, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "120, COX-2 ['l0', 'l1']", + "121, inhibitors. ['l0']", + "135, mice, ['l1']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "COX-2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "26214837", + "TEXT": "Inflammation is a pathological hallmark of Alzheimer's disease, and innate immune cells have been shown to contribute to disease pathogenesis. In two transgenic models of Alzheimer's disease (5xFAD and 3xTg-AD mice), neutrophils extravasated and were present in areas with amyloid-β (Aβ) deposits, where they released neutrophil extracellular traps (NETs) and IL-17. Aβ42 peptide triggered the LFA-1 integrin high-affinity state and rapid neutrophil adhesion to integrin ligands. In vivo, LFA-1 integrin controlled neutrophil extravasation into the CNS and intraparenchymal motility. In transgenic Alzheimer's disease models, neutrophil depletion or inhibition of neutrophil trafficking via LFA-1 blockade reduced Alzheimer's disease-like neuropathology and improved memory in mice already showing cognitive dysfunction. Temporary depletion of neutrophils for 1 month at early stages of disease led to sustained improvements in memory. Transgenic Alzheimer's disease model mice lacking LFA-1 were protected from cognitive decline and had reduced gliosis. In humans with Alzheimer's disease, neutrophils adhered to and spread inside brain venules and were present in the parenchyma, along with NETs. Our results demonstrate that neutrophils contribute to Alzheimer's disease pathogenesis and cognitive impairment and suggest that the inhibition of neutrophil trafficking may be beneficial in Alzheimer's disease.", + "TAG_DATA": [ + "66, In {'context': 'B-in vivo'}", + "67, vivo, {'context': 'I-in vivo'}", + "80, transgenic {'context': 'B-organism'}", + "102, mice {'context': 'B-organism'}", + "125, Transgenic {'context': 'B-organism'}", + "126, Alzheimer's {'context': 'I-organism'}", + "127, disease {'context': 'I-organism'}", + "128, model {'context': 'I-organism'}", + "129, mice {'context': 'I-organism'}", + "130, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "131, LFA-1 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "66, In ['l0', 'l1', 'l2', 'l3', 'l4']", + "67, vivo, ['l0', 'l5', 'l6', 'l7', 'l8']", + "80, transgenic ['l1', 'l5', 'l9', 'l10', 'l11', 'l12']", + "81, Alzheimer's ['l2', 'l6', 'l9', 'l13', 'l14', 'l15']", + "82, disease ['l3', 'l7', 'l10', 'l13', 'l16', 'l17']", + "83, models, ['l4', 'l8', 'l11', 'l14', 'l16', 'l18']", + "102, mice ['l12', 'l15', 'l17', 'l18']", + "125, Transgenic ['l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "126, Alzheimer's ['l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "127, disease ['l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "128, model ['l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "129, mice ['l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "130, lacking ['l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "131, LFA-1 ['l24', 'l29', 'l33', 'l36', 'l38', 'l39']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Transgenic", + "Alzheimer's", + "disease", + "model", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "LFA-1" + ] + } + } + ] + }, + { + "PMID": "26099046", + "TEXT": "Interleukin-18 (IL18) participates in atherogenesis through several putative mechanisms. Interruption of IL18 action reduces atherosclerosis in mice. Here, we show that absence of the IL18 receptor (IL18r) does not affect atherosclerosis in apolipoprotein E-deficient (Apoe(-/-)) mice, nor does it affect IL18 cell surface binding to or signaling in endothelial cells. As identified initially by co-immunoprecipitation with IL18, we found that IL18 interacts with the Na-Cl co-transporter (NCC; also known as SLC12A3), a 12-transmembrane-domain ion transporter protein preferentially expressed in the kidney. NCC is expressed in atherosclerotic lesions, where it colocalizes with IL18r. In Apoe(-/-) mice, combined deficiency of IL18r and NCC, but not single deficiency of either protein, protects mice from atherosclerosis. Peritoneal macrophages from Apoe(-/-) mice or from Apoe(-/-) mice lacking IL18r or NCC show IL18 binding and induction of cell signaling and cytokine and chemokine expression, but macrophages from Apoe(-/-) mice with combined deficiency of IL18r and NCC have a blunted response. An interaction between NCC and IL18r on macrophages was detected by co-immunoprecipitation. IL18 binds to the cell surface of NCC-transfected COS-7 cells, which do not express IL18r, and induces cell signaling and cytokine expression. This study identifies NCC as an IL18-binding protein that collaborates with IL18r in cell signaling, inflammatory molecule expression, and experimental atherogenesis.", + "TAG_DATA": [ + "21, absence {'perturbing_action': 'B-gene loss-of-function'}", + "22, of {'perturbing_action': 'I-gene loss-of-function'}", + "23, the {'perturbing_action': 'I-gene loss-of-function'}", + "25, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "26, (IL18r) {'perturbing_action': 'I-gene loss-of-function'}", + "32, apolipoprotein {'perturbing_action': 'B-gene loss-of-function'}", + "33, E-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "34, (Apoe(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "35, mice, {'context': 'B-organism'}", + "93, Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "94, mice, {'context': 'B-organism'}", + "95, combined {'perturbing_action': 'B-gene loss-of-function'}", + "96, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "97, of {'perturbing_action': 'I-gene loss-of-function'}", + "98, IL18r {'perturbing_action': 'I-gene loss-of-function'}", + "99, and {'perturbing_action': 'I-gene loss-of-function'}", + "100, NCC, {'perturbing_action': 'I-gene loss-of-function'}", + "109, mice {'context': 'B-organism'}", + "112, Peritoneal {'context': 'B-cells'}", + "113, macrophages {'context': 'I-cells'}", + "115, Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "116, mice {'context': 'B-organism'}", + "119, Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "120, mice {'context': 'B-organism'}", + "121, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "122, IL18r {'perturbing_action': 'I-gene loss-of-function'}", + "123, or {'perturbing_action': 'I-gene loss-of-function'}", + "124, NCC {'perturbing_action': 'I-gene loss-of-function'}", + "139, macrophages {'context': 'B-cells'}", + "141, Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "142, mice {'context': 'B-organism'}", + "144, combined {'perturbing_action': 'B-gene loss-of-function'}", + "145, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "146, of {'perturbing_action': 'I-gene loss-of-function'}", + "147, IL18r {'perturbing_action': 'I-gene loss-of-function'}", + "148, and {'perturbing_action': 'I-gene loss-of-function'}", + "149, NCC {'perturbing_action': 'I-gene loss-of-function'}", + "161, macrophages {'context': 'B-cells'}", + "173, NCC-transfected {'perturbing_action': 'B-gene gain-of-function'}", + "174, COS-7 {'context': 'B-cells'}", + "175, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "21, absence ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "22, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "23, the ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "25, receptor ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "26, (IL18r) ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "32, apolipoprotein ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "33, E-deficient ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "34, (Apoe(-/-)) ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "35, mice, ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56']", + "93, Apoe(-/-) ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "94, mice, ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l60', 'l71', 'l72', 'l73']", + "95, combined ['l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "96, deficiency ['l61', 'l74', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "97, of ['l62', 'l75', 'l90', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "98, IL18r ['l63', 'l71', 'l76', 'l91', 'l105', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "99, and ['l64', 'l77', 'l92', 'l106', 'l119', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "100, NCC, ['l65', 'l72', 'l78', 'l93', 'l107', 'l120', 'l132', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "109, mice ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l66', 'l73', 'l79', 'l94', 'l108', 'l121', 'l133', 'l144', 'l155', 'l156', 'l157', 'l158']", + "112, Peritoneal ['l67', 'l80', 'l95', 'l109', 'l122', 'l134', 'l145', 'l155', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "113, macrophages ['l68', 'l81', 'l96', 'l110', 'l123', 'l135', 'l146', 'l156', 'l159', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175']", + "115, Apoe(-/-) ['l69', 'l82', 'l97', 'l111', 'l124', 'l136', 'l147', 'l157', 'l160', 'l168', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "116, mice ['l70', 'l83', 'l98', 'l112', 'l125', 'l137', 'l148', 'l158', 'l161', 'l169', 'l176', 'l183', 'l184', 'l185']", + "119, Apoe(-/-) ['l84', 'l99', 'l113', 'l126', 'l138', 'l149', 'l162', 'l170', 'l177', 'l186', 'l187', 'l188', 'l189', 'l190']", + "120, mice ['l85', 'l100', 'l114', 'l127', 'l139', 'l150', 'l163', 'l171', 'l178', 'l186', 'l191', 'l192', 'l193', 'l194']", + "121, lacking ['l86', 'l101', 'l115', 'l128', 'l140', 'l151', 'l164', 'l172', 'l179', 'l187', 'l191', 'l195', 'l196', 'l197']", + "122, IL18r ['l87', 'l102', 'l116', 'l129', 'l141', 'l152', 'l165', 'l173', 'l180', 'l183', 'l188', 'l192', 'l195', 'l198', 'l199']", + "123, or ['l88', 'l103', 'l117', 'l130', 'l142', 'l153', 'l166', 'l174', 'l181', 'l184', 'l189', 'l193', 'l196', 'l198', 'l200']", + "124, NCC ['l89', 'l104', 'l118', 'l131', 'l143', 'l154', 'l167', 'l175', 'l182', 'l185', 'l190', 'l194', 'l197', 'l199', 'l200']", + "139, macrophages ['l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208']", + "141, Apoe(-/-) ['l201', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217']", + "142, mice ['l202', 'l209', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224']", + "144, combined ['l203', 'l210', 'l218', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233']", + "145, deficiency ['l204', 'l211', 'l219', 'l225', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239']", + "146, of ['l205', 'l212', 'l220', 'l226', 'l234', 'l240', 'l241', 'l242', 'l243', 'l244']", + "147, IL18r ['l206', 'l213', 'l221', 'l227', 'l235', 'l240', 'l245', 'l246']", + "148, and ['l207', 'l214', 'l222', 'l228', 'l236', 'l241', 'l245', 'l247']", + "149, NCC ['l208', 'l215', 'l223', 'l229', 'l237', 'l242', 'l246', 'l247']", + "161, macrophages ['l216', 'l224', 'l230', 'l238', 'l243', 'l248', 'l249', 'l250']", + "173, NCC-transfected ['l231', 'l248', 'l251', 'l252']", + "174, COS-7 ['l232', 'l249', 'l251', 'l253']", + "175, cells, ['l217', 'l233', 'l239', 'l244', 'l250', 'l252', 'l253']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "the", + "receptor", + "(IL18r)", + "apolipoprotein", + "E-deficient", + "(Apoe(-/-))", + "Apoe(-/-)", + "IL18r", + "NCC,", + "combined", + "deficiency", + "and", + "or", + "NCC", + "lacking" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apoe(-/-)", + "combined", + "deficiency", + "of", + "IL18r", + "and", + "NCC,", + "lacking", + "or", + "NCC" + ] + }, + "context": { + "val": "cells", + "words": [ + "Peritoneal", + "macrophages", + "cells,", + "COS-7" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "macrophages", + "COS-7", + "cells," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "NCC-transfected" + ] + } + } + ] + }, + { + "PMID": "26030178", + "TEXT": "Metastasis is responsible for most cancer-related deaths, and, among common tumor types, melanoma is one with great potential to metastasize. Here we study the contribution of epigenetic changes to the dissemination process by analyzing the changes that occur at the DNA methylation level between primary cancer cells and metastases. We found a hypomethylation event that reactivates a cryptic transcript of the Rab GTPase activating protein TBC1D16 (TBC1D16-47 kDa; referred to hereafter as TBC1D16-47KD) to be a characteristic feature of the metastatic cascade. This short isoform of TBC1D16 exacerbates melanoma growth and metastasis both in vitro and in vivo. By combining immunoprecipitation and mass spectrometry, we identified RAB5C as a new TBC1D16 target and showed that it regulates EGFR in melanoma cells. We also found that epigenetic reactivation of TBC1D16-47KD is associated with poor clinical outcome in melanoma, while conferring greater sensitivity to BRAF and MEK inhibitors.", + "TAG_DATA": [ + "87, exacerbates {'effect': 'B-positive'}", + "88, melanoma {'context': 'B-neoplasm'}", + "91, metastasis {'phenotype': 'B-metastasis'}", + "93, in {'context': 'B-in vitro'}", + "94, vitro {'context': 'I-in vitro'}", + "96, in {'context': 'B-in vivo'}", + "97, vivo. {'context': 'I-in vivo'}", + "119, melanoma {'context': 'B-transformed cells'}", + "120, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "87, exacerbates ['l0', 'l1', 'l2', 'l3', 'l4']", + "88, melanoma ['l0', 'l5', 'l6', 'l7']", + "91, metastasis ['l1', 'l5', 'l8', 'l9']", + "93, in ['l2', 'l6', 'l8', 'l10']", + "94, vitro ['l3', 'l7', 'l9', 'l10']", + "96, in ['l11']", + "97, vivo. ['l4', 'l11']", + "119, melanoma ['l12']", + "120, cells. ['l12']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "exacerbates" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "melanoma" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "exacerbates" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "exacerbates" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "exacerbates" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "melanoma" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "25939064", + "TEXT": "Accumulation of visceral adipose tissue correlates with elevated inflammation and increased risk of metabolic diseases. However, little is known about the molecular mechanisms that control its pathological expansion. Transcription factor interferon regulatory factor 5 (IRF5) has been implicated in polarizing macrophages towards an inflammatory phenotype. Here we demonstrate that mice lacking Irf5, when placed on a high-fat diet, show no difference in the growth of their epididymal white adipose tissue (epiWAT) but they show expansion of their subcutaneous white adipose tissue, as compared to wild-type (WT) mice on the same diet. EpiWAT from Irf5-deficient mice is marked by accumulation of alternatively activated macrophages, higher collagen deposition that restricts adipocyte size, and enhanced insulin sensitivity compared to epiWAT from WT mice. In obese individuals, IRF5 expression is negatively associated with insulin sensitivity and collagen deposition in visceral adipose tissue. Genome-wide analysis of gene expression in adipose tissue macrophages highlights the transforming growth factor β1 (TGFB1) gene itself as a direct target of IRF5-mediated inhibition. This study uncovers a new function for IRF5 in controlling the relative mass of different adipose tissue depots and thus insulin sensitivity in obesity, and it suggests that inhibition of IRF5 may promote a healthy metabolic state during this condition.", + "TAG_DATA": [ + "49, mice {'context': 'B-organism'}", + "50, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "51, Irf5, {'perturbing_action': 'I-gene loss-of-function'}", + "93, Irf5-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "94, mice {'context': 'B-organism'}", + "102, macrophages, {'context': 'B-cells'}", + "108, adipocyte {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "49, mice ['l0', 'l1']", + "50, lacking ['l0', 'l2']", + "51, Irf5, ['l1', 'l2']", + "93, Irf5-deficient ['l3', 'l4', 'l5']", + "94, mice ['l3', 'l6', 'l7']", + "102, macrophages, ['l4', 'l6', 'l8']", + "108, adipocyte ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "Irf5,", + "Irf5-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Irf5-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages,", + "adipocyte" + ] + } + } + ] + }, + { + "PMID": "25915831", + "TEXT": "Neuropathic pain is a major, intractable clinical problem and its pathophysiology is not well understood. Although recent gene expression profiling studies have enabled the identification of novel targets for pain therapy, classical study designs provide unclear results owing to the differential expression of hundreds of genes across sham and nerve-injured groups, which can be difficult to validate, particularly with respect to the specificity of pain modulation. To circumvent this, we used two outbred lines of rats, which are genetically similar except for being genetically segregated as a result of selective breeding for differences in neuropathic pain hypersensitivity. SerpinA3N, a serine protease inhibitor, was upregulated in the dorsal root ganglia (DRG) after nerve injury, which was further validated for its mouse homolog. Mice lacking SerpinA3N developed more neuropathic mechanical allodynia than wild-type (WT) mice, and exogenous delivery of SerpinA3N attenuated mechanical allodynia in WT mice. T lymphocytes infiltrate the DRG after nerve injury and release leukocyte elastase (LE), which was inhibited by SerpinA3N derived from DRG neurons. Genetic loss of LE or exogenous application of a LE inhibitor (Sivelastat) in WT mice attenuated neuropathic mechanical allodynia. Overall, we reveal a novel and clinically relevant role for a member of the serpin superfamily and a leukocyte elastase and crosstalk between neurons and T cells in the modulation of neuropathic pain.", + "TAG_DATA": [ + "72, outbred {'context': 'B-organism'}", + "73, lines {'context': 'I-organism'}", + "75, rats, {'context': 'I-organism'}", + "121, Mice {'context': 'B-organism'}", + "122, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "123, SerpinA3N {'perturbing_action': 'I-gene loss-of-function'}", + "132, mice, {'context': 'B-organism'}", + "143, mice. {'context': 'B-organism'}", + "144, T {'context': 'B-cells'}", + "145, lymphocytes {'context': 'I-cells'}", + "164, DRG {'context': 'B-cells'}", + "165, neurons. {'context': 'I-cells'}", + "166, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "167, loss {'perturbing_action': 'I-gene loss-of-function'}", + "168, of {'perturbing_action': 'I-gene loss-of-function'}", + "169, LE {'perturbing_action': 'I-gene loss-of-function'}", + "175, LE {'perturbing_action': 'B-pharmacological inhibition'}", + "176, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "177, (Sivelastat) {'perturbing_action': 'I-pharmacological inhibition'}", + "180, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "72, outbred ['l0', 'l1', 'l2', 'l3', 'l4']", + "73, lines ['l0', 'l5', 'l6', 'l7']", + "75, rats, ['l1', 'l5', 'l8', 'l9', 'l10']", + "121, Mice ['l2', 'l8', 'l11', 'l12', 'l13']", + "122, lacking ['l3', 'l6', 'l9', 'l11', 'l14', 'l15']", + "123, SerpinA3N ['l4', 'l7', 'l10', 'l12', 'l14', 'l16']", + "132, mice, ['l13', 'l15', 'l16', 'l17']", + "143, mice. ['l18', 'l19', 'l20', 'l21']", + "144, T ['l18', 'l22', 'l23', 'l24']", + "145, lymphocytes ['l17', 'l19', 'l22', 'l25', 'l26']", + "164, DRG ['l20', 'l23', 'l25', 'l27']", + "165, neurons. ['l21', 'l24', 'l26', 'l27']", + "166, Genetic ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "167, loss ['l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "168, of ['l29', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "169, LE ['l30', 'l36', 'l41', 'l46', 'l47', 'l48', 'l49']", + "175, LE ['l31', 'l37', 'l42', 'l46', 'l50', 'l51', 'l52']", + "176, inhibitor ['l32', 'l38', 'l43', 'l47', 'l50', 'l53', 'l54']", + "177, (Sivelastat) ['l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l55']", + "180, mice ['l34', 'l40', 'l45', 'l49', 'l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "outbred", + "lines", + "rats,", + "Mice", + "mice,", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "SerpinA3N", + "Genetic", + "loss", + "of", + "LE" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "LE", + "inhibitor", + "(Sivelastat)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "25849135", + "TEXT": "A common key regulator of oncogenic signaling pathways in multiple tumor types is the unique isomerase Pin1. However, available Pin1 inhibitors lack the required specificity and potency for inhibiting Pin1 function in vivo. By using mechanism-based screening, here we find that all-trans retinoic acid (ATRA)--a therapy for acute promyelocytic leukemia (APL) that is considered the first example of targeted therapy in cancer, but whose drug target remains elusive--inhibits and degrades active Pin1 selectively in cancer cells by directly binding to the substrate phosphate- and proline-binding pockets in the Pin1 active site. ATRA-induced Pin1 ablation degrades the protein encoded by the fusion oncogene PML-RARA and treats APL in APL cell and animal models as well as in human patients. ATRA-induced Pin1 ablation also potently inhibits triple-negative breast cancer cell growth in human cells and in animal models by acting on many Pin1 substrate oncogenes and tumor suppressors. Thus, ATRA simultaneously blocks multiple Pin1-regulated cancer-driving pathways, an attractive property for treating aggressive and drug-resistant tumors.", + "TAG_DATA": [ + "74, cancer {'context': 'B-transformed cells'}", + "75, cells {'context': 'I-transformed cells'}", + "91, ATRA-induced {'perturbing_action': 'B-gene loss-of-function'}", + "92, Pin1 {'perturbing_action': 'B-gene loss-of-function'}", + "93, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "107, APL {'context': 'B-transformed cells'}", + "108, cell {'context': 'I-transformed cells'}", + "110, animal {'context': 'B-organism'}", + "111, models {'context': 'I-transformed cells'}", + "118, ATRA-induced {'perturbing_action': 'B-gene loss-of-function'}", + "119, Pin1 {'perturbing_action': 'B-gene loss-of-function'}", + "120, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "123, inhibits {'effect': 'B-negative'}", + "124, triple-negative {'context': 'B-neoplasm'}", + "125, breast {'context': 'I-neoplasm'}", + "126, cancer {'context': 'I-neoplasm'}", + "127, cell {'phenotype': 'B-cell growth'}", + "128, growth {'phenotype': 'I-cell growth'}", + "130, human {'context': 'B-cells'}", + "131, cells {'context': 'I-cells'}", + "134, animal {'context': 'B-organism'}", + "135, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "74, cancer ['l0', 'l1', 'l2']", + "75, cells ['l0', 'l3', 'l4']", + "91, ATRA-induced ['l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "92, Pin1 ['l5', 'l11', 'l12', 'l13', 'l14', 'l15']", + "93, ablation ['l6', 'l11', 'l16', 'l17', 'l18', 'l19']", + "107, APL ['l7', 'l12', 'l16', 'l20', 'l21', 'l22']", + "108, cell ['l1', 'l3', 'l8', 'l13', 'l17', 'l20', 'l23', 'l24']", + "110, animal ['l9', 'l14', 'l18', 'l21', 'l23', 'l25']", + "111, models ['l2', 'l4', 'l10', 'l15', 'l19', 'l22', 'l24', 'l25']", + "118, ATRA-induced ['l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "119, Pin1 ['l26', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "120, ablation ['l27', 'l38', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "123, inhibits ['l28', 'l39', 'l49', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "124, triple-negative ['l29', 'l40', 'l50', 'l59', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "125, breast ['l30', 'l41', 'l51', 'l60', 'l68', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "126, cancer ['l31', 'l42', 'l52', 'l61', 'l69', 'l76', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "127, cell ['l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l83', 'l89', 'l90', 'l91', 'l92', 'l93']", + "128, growth ['l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l89', 'l94', 'l95', 'l96', 'l97']", + "130, human ['l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l94', 'l98', 'l99', 'l100']", + "131, cells ['l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l98', 'l101', 'l102']", + "134, animal ['l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l101', 'l103']", + "135, models ['l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l103']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ATRA-induced", + "Pin1", + "ablation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "APL", + "cell", + "models" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ATRA-induced", + "Pin1", + "ablation" + ] + }, + "context": { + "val": "organism", + "words": [ + "animal", + "models" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ATRA-induced", + "Pin1", + "ablation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ATRA-induced", + "Pin1", + "ablation" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "triple-negative", + "breast", + "cancer" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ATRA-induced", + "Pin1", + "ablation" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ATRA-induced", + "Pin1", + "ablation" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "triple-negative", + "breast", + "cancer" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "organism", + "words": [ + "animal", + "models" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "triple-negative", + "breast", + "cancer" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "cells" + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "animal", + "models" + ] + } + } + ] + }, + { + "PMID": "25822366", + "TEXT": "Rearrangements of MLL (encoding lysine-specific methyltransferase 2A and officially known as KMT2A; herein referred to as MLL to denote the gene associated with mixed-lineage leukemia) generate MLL fusion proteins that bind DNA and drive leukemogenic gene expression. This gene expression program is dependent on the disruptor of telomeric silencing 1-like histone 3 lysine 79 (H3K79) methyltransferase DOT1L, and small-molecule DOT1L inhibitors show promise as therapeutics for these leukemias. However, the mechanisms underlying this dependency are unclear. We conducted a genome-scale RNAi screen and found that the histone deacetylase SIRT1 is required for the establishment of a heterochromatin-like state around MLL fusion target genes after DOT1L inhibition. DOT1L inhibits chromatin localization of a repressive complex composed of SIRT1 and the H3K9 methyltransferase SUV39H1, thereby maintaining an open chromatin state with elevated H3K9 acetylation and minimal H3K9 methylation at MLL fusion target genes. Furthermore, the combination of SIRT1 activators and DOT1L inhibitors shows enhanced antiproliferative activity against MLL-rearranged leukemia cells. These results indicate that the dynamic interplay between chromatin regulators controlling the activation and repression of gene expression could provide novel opportunities for combination therapy.", + "TAG_DATA": [ + "104, DOT1L {'perturbing_action': 'B-pharmacological inhibition'}", + "105, inhibition. {'perturbing_action': 'I-pharmacological inhibition'}", + "148, DOT1L {'perturbing_action': 'B-pharmacological inhibition'}", + "149, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "156, leukemia {'context': 'I-transformed cells'}", + "157, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "104, DOT1L ['l0']", + "105, inhibition. ['l0']", + "148, DOT1L ['l1', 'l2', 'l3']", + "149, inhibitors ['l1', 'l4', 'l5']", + "156, leukemia ['l2', 'l4', 'l6']", + "157, cells. ['l3', 'l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "DOT1L", + "inhibitors" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "leukemia", + "cells." + ] + } + } + ] + }, + { + "PMID": "25799227", + "TEXT": "Focal cortical dysplasia type II (FCDII) is a sporadic developmental malformation of the cerebral cortex characterized by dysmorphic neurons, dyslamination and medically refractory epilepsy. It has been hypothesized that FCD is caused by somatic mutations in affected regions. Here, we used deep whole-exome sequencing (read depth, 412-668×) validated by site-specific amplicon sequencing (100-347,499×) in paired brain-blood DNA from four subjects with FCDII and uncovered a de novo brain somatic mutation, mechanistic target of rapamycin (MTOR) c.7280T>C (p.Leu2427Pro) in two subjects. Deep sequencing of the MTOR gene in an additional 73 subjects with FCDII using hybrid capture and PCR amplicon sequencing identified eight different somatic missense mutations found in multiple brain tissue samples of ten subjects. The identified mutations accounted for 15.6% of all subjects with FCDII studied (12 of 77). The identified mutations induced the hyperactivation of mTOR kinase. Focal cortical expression of mutant MTOR by in utero electroporation in mice was sufficient to disrupt neuronal migration and cause spontaneous seizures and cytomegalic neurons. Inhibition of mTOR with rapamycin suppressed cytomegalic neurons and epileptic seizures. This study provides, to our knowledge, the first evidence that brain somatic activating mutations in MTOR cause FCD and identifies mTOR as a treatment target for intractable epilepsy in FCD.", + "TAG_DATA": [ + "139, Focal {'perturbing_action': 'B-gene gain-of-function'}", + "140, cortical {'perturbing_action': 'I-gene gain-of-function'}", + "141, expression {'perturbing_action': 'I-other'}", + "142, of {'perturbing_action': 'I-other'}", + "143, mutant {'perturbing_action': 'I-other'}", + "144, MTOR {'perturbing_action': 'I-other'}", + "150, mice {'context': 'B-organism'}", + "154, disrupt {'effect': 'B-negative'}", + "156, migration {'phenotype': 'B-migration'}", + "163, neurons. {'context': 'I-cells'}", + "164, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "165, of {'perturbing_action': 'I-pharmacological inhibition'}", + "166, mTOR {'perturbing_action': 'I-pharmacological inhibition'}", + "167, with {'perturbing_action': 'I-pharmacological inhibition'}", + "168, rapamycin {'perturbing_action': 'I-pharmacological inhibition'}", + "170, cytomegalic {'context': 'B-cells'}", + "171, neurons {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "139, Focal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "140, cortical ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "141, expression ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "142, of ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "143, mutant ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "144, MTOR ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "145, by ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "150, mice ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66']", + "154, disrupt ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l68', 'l69']", + "156, migration ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l67', 'l70']", + "163, neurons. ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l68', 'l70', 'l71']", + "164, Inhibition ['l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "165, of ['l72', 'l78', 'l79', 'l80', 'l81', 'l82']", + "166, mTOR ['l73', 'l78', 'l83', 'l84', 'l85', 'l86']", + "167, with ['l74', 'l79', 'l83', 'l87', 'l88', 'l89']", + "168, rapamycin ['l75', 'l80', 'l84', 'l87', 'l90', 'l91']", + "170, cytomegalic ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l76', 'l81', 'l85', 'l88', 'l90', 'l92']", + "171, neurons ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l66', 'l69', 'l71', 'l77', 'l82', 'l86', 'l89', 'l91', 'l92']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Focal", + "cortical" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Focal", + "cortical" + ] + }, + "effect": { + "val": "negative", + "words": [ + "disrupt" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Focal", + "cortical" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Focal", + "cortical" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons.", + "cytomegalic", + "neurons" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "mutant", + "MTOR" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "mutant", + "MTOR" + ] + }, + "effect": { + "val": "negative", + "words": [ + "disrupt" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "mutant", + "MTOR" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "mutant", + "MTOR" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons.", + "cytomegalic", + "neurons" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "disrupt" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "disrupt" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "disrupt" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons.", + "neurons" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "mTOR", + "with", + "rapamycin" + ] + }, + "context": { + "val": "cells", + "words": [ + "cytomegalic", + "neurons" + ] + } + } + ] + }, + { + "PMID": "25730264", + "TEXT": "Detection of cyclic-di-adenosine monophosphate (c-di-AMP), a bacterial second messenger, by the host cytoplasmic surveillance pathway (CSP) is known to elicit type I interferon (IFN) responses, which are crucial to antimicrobial defense. However, the mechanisms and role of c-di-AMP signaling in Mycobacterium tuberculosis virulence remain unclear. Here we show that resistance to tuberculosis requires CSP-mediated detection of c-di-AMP produced by M. tuberculosis and that levels of c-di-AMP modulate the fate of infection. We found that a di-adenylate cyclase (disA or dacA)-overexpressing M. tuberculosis strain that secretes excess c-di-AMP activates the interferon regulatory factor (IRF) pathway with enhanced levels of IFN-β, elicits increased macrophage autophagy, and exhibits substantial virulence attenuation in mice. We show that c-di-AMP-mediated IFN-β induction during M. tuberculosis infection requires stimulator of interferon genes (STING)-signaling. We observed that c-di-AMP induction of IFN-β is independent of the cytosolic nucleic acid receptor cyclic GMP-AMP (cGAMP) synthase (cGAS), but cGAS nevertheless contributes substantially to the overall IFN-β response to M. tuberculosis infection. In sum, our results reveal c-di-AMP to be a key mycobacterial pathogen-associated molecular pattern (PAMP) driving host type I IFN responses and autophagy. These findings suggest that modulating the levels of this small molecule may lead to novel immunotherapeutic strategies against tuberculosis.", + "TAG_DATA": [ + "75, di-adenylate {'perturbing_action': 'B-gene gain-of-function'}", + "77, (disA {'perturbing_action': 'I-gene gain-of-function'}", + "78, or {'perturbing_action': 'I-gene gain-of-function'}", + "79, dacA)-overexpressing {'perturbing_action': 'I-gene gain-of-function'}", + "80, M. {'context': 'B-transformed cells'}", + "81, tuberculosis {'perturbing_action': 'I-other', 'context': 'I-transformed cells'}", + "82, strain {'perturbing_action': 'I-other', 'context': 'I-transformed cells'}", + "99, elicits {'effect': 'B-positive'}", + "100, increased {'effect': 'B-positive'}", + "101, macrophage {'context': 'B-cells'}", + "102, autophagy, {'phenotype': 'B-autophagy'}", + "109, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "75, di-adenylate ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "77, (disA ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "78, or ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "79, dacA)-overexpressing ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "80, M. ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "81, tuberculosis ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "82, strain ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "99, elicits ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58']", + "100, increased ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l60']", + "101, macrophage ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l59', 'l61']", + "102, autophagy, ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l60', 'l61']", + "109, mice. ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "di-adenylate", + "(disA", + "or", + "dacA)-overexpressing" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "M.", + "tuberculosis", + "strain" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "tuberculosis", + "strain" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tuberculosis", + "strain", + "M." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "di-adenylate", + "(disA", + "or", + "dacA)-overexpressing" + ] + }, + "effect": { + "val": "positive", + "words": [ + "elicits", + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "di-adenylate", + "(disA", + "or", + "dacA)-overexpressing" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophage" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "di-adenylate", + "(disA", + "or", + "dacA)-overexpressing" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "di-adenylate", + "(disA", + "or", + "dacA)-overexpressing" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "M.", + "tuberculosis", + "strain" + ] + }, + "effect": { + "val": "positive", + "words": [ + "elicits", + "increased" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "M.", + "tuberculosis", + "strain" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "tuberculosis", + "strain" + ] + }, + "effect": { + "val": "positive", + "words": [ + "elicits", + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "tuberculosis", + "strain" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophage" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "tuberculosis", + "strain" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "tuberculosis", + "strain" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "elicits", + "increased" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophage" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "elicits", + "increased" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "macrophage" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy," + ] + } + } + ] + }, + { + "PMID": "25581519", + "TEXT": "Type 2 diabetes is a major health problem worldwide, and one of its key features is the inability of elevated glucose to stimulate the release of sufficient amounts of insulin from pancreatic beta cells to maintain normal blood glucose levels. New therapeutic strategies to improve beta cell function are therefore believed to be beneficial. Here we demonstrate that the short-chain fatty acid receptors FFA2 (encoded by FFAR2) and FFA3 (encoded by FFAR3) are expressed in mouse and human pancreatic beta cells and mediate an inhibition of insulin secretion by coupling to Gi-type G proteins. We also provide evidence that mice with dietary-induced obesity and type 2 diabetes, as compared to non-obese control mice, have increased local formation by pancreatic islets of acetate, an endogenous agonist of FFA2 and FFA3, as well as increased systemic levels. This elevation may contribute to the insufficient capacity of beta cells to respond to hyperglycemia in obese states. Indeed, we found that genetic deletion of both receptors, either on the whole-body level or specifically in pancreatic beta cells, leads to greater insulin secretion and a profound improvement of glucose tolerance when mice are on a high-fat diet compared to controls. On the other hand, deletion of Ffar2 and Ffar3 in intestinal cells did not alter glucose tolerance in diabetic animals, suggesting these receptors act in a cell-autonomous manner in beta cells to regulate insulin secretion. In summary, under diabetic conditions elevated acetate acts on FFA2 and FFA3 to inhibit proper glucose-stimulated insulin secretion, and we expect antagonists of FFA2 and FFA3 to improve insulin secretion in type 2 diabetes.", + "TAG_DATA": [ + "99, mice {'context': 'B-organism'}", + "157, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "158, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "159, of {'perturbing_action': 'I-gene loss-of-function'}", + "160, both {'perturbing_action': 'I-gene loss-of-function'}", + "161, receptors, {'perturbing_action': 'I-gene loss-of-function'}", + "170, pancreatic {'context': 'B-cells'}", + "171, beta {'context': 'I-cells'}", + "172, cells, {'context': 'I-cells'}", + "186, mice {'context': 'B-organism'}", + "199, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "200, of {'perturbing_action': 'I-gene loss-of-function'}", + "201, Ffar2 {'perturbing_action': 'I-gene loss-of-function'}", + "202, and {'perturbing_action': 'I-gene loss-of-function'}", + "203, Ffar3 {'perturbing_action': 'I-gene loss-of-function'}", + "205, intestinal {'context': 'B-cells'}", + "206, cells {'context': 'I-cells'}", + "213, diabetic {'context': 'B-organism'}", + "214, animals, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "157, genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "158, deletion ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "159, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "160, both ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "161, receptors, ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "170, pancreatic ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "171, beta ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "172, cells, ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "186, mice ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "199, deletion ['l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "200, of ['l36', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "201, Ffar2 ['l37', 'l44', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "202, and ['l38', 'l45', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "203, Ffar3 ['l39', 'l46', 'l52', 'l57', 'l62', 'l63', 'l64', 'l65']", + "205, intestinal ['l40', 'l47', 'l53', 'l58', 'l62', 'l66', 'l67', 'l68']", + "206, cells ['l41', 'l48', 'l54', 'l59', 'l63', 'l66', 'l69', 'l70']", + "213, diabetic ['l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l71']", + "214, animals, ['l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l71']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "both", + "receptors,", + "Ffar2", + "and", + "Ffar3" + ] + }, + "context": { + "val": "cells", + "words": [ + "pancreatic", + "beta", + "cells,", + "intestinal", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "both", + "receptors,", + "Ffar2", + "and", + "Ffar3" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "diabetic", + "animals," + ] + } + } + ] + }, + { + "PMID": "25581517", + "TEXT": "Mesenchymal responses are an essential aspect of tissue repair. Failure to terminate this repair process correctly, however, results in fibrosis and organ dysfunction. Therapies that block fibrosis and restore tissue homeostasis are not yet available for clinical use. Here we characterize the nuclear receptor NR4A1 as an endogenous inhibitor of transforming growth factor-β (TGF-β) signaling and as a potential target for anti-fibrotic therapies. NR4A1 recruits a repressor complex comprising SP1, SIN3A, CoREST, LSD1, and HDAC1 to TGF-β target genes, thereby limiting pro-fibrotic TGF-β effects. Even though temporary upregulation of TGF-β in physiologic wound healing induces NR4A1 expression and thereby creates a negative feedback loop, the persistent activation of TGF-β signaling in fibrotic diseases uses AKT- and HDAC-dependent mechanisms to inhibit NR4A1 expression and activation. Small-molecule NR4A1 agonists can overcome this lack of active NR4A1 and inhibit experimentally-induced skin, lung, liver, and kidney fibrosis in mice. Our data demonstrate a regulatory role of NR4A1 in TGF-β signaling and fibrosis, providing the first proof of concept for targeting NR4A1 in fibrotic diseases.", + "TAG_DATA": [ + "124, Small-molecule {'perturbing_action': 'B-pharmacological augmentation'}", + "125, NR4A1 {'perturbing_action': 'I-pharmacological augmentation'}", + "126, agonists {'perturbing_action': 'I-pharmacological augmentation'}", + "137, skin, {'context': 'B-tissue/organ'}", + "138, lung, {'context': 'I-tissue/organ'}", + "139, liver, {'context': 'I-tissue/organ'}", + "140, and {'context': 'I-tissue/organ'}", + "141, kidney {'context': 'I-tissue/organ'}", + "144, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "124, Small-molecule ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "125, NR4A1 ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "126, agonists ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "137, skin, ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "138, lung, ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "139, liver, ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "140, and ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "141, kidney ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "144, mice. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Small-molecule", + "NR4A1", + "agonists" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skin,", + "lung,", + "liver,", + "and", + "kidney" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Small-molecule", + "NR4A1", + "agonists" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "25559344", + "TEXT": "The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver. However, unlike systemic agonism, we find that Fex reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue (WAT). These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome.", + "TAG_DATA": [ + "50, gut-restricted {'perturbing_action': 'B-pharmacological augmentation'}", + "51, FXR {'perturbing_action': 'I-pharmacological augmentation'}", + "52, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "53, fexaramine {'perturbing_action': 'I-pharmacological augmentation'}", + "54, (Fex) {'perturbing_action': 'I-pharmacological augmentation'}", + "79, liver. {'context': 'B-tissue/organ'}", + "104, white {'context': 'B-tissue/organ'}", + "105, adipose {'context': 'I-tissue/organ'}", + "106, tissue {'context': 'I-tissue/organ'}", + "107, (WAT). {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "50, gut-restricted ['l0', 'l1', 'l2', 'l3', 'l4']", + "51, FXR ['l0', 'l5', 'l6', 'l7', 'l8']", + "52, agonist ['l1', 'l5', 'l9', 'l10', 'l11']", + "53, fexaramine ['l2', 'l6', 'l9', 'l12', 'l13']", + "54, (Fex) ['l3', 'l7', 'l10', 'l12', 'l14']", + "79, liver. ['l4', 'l8', 'l11', 'l13', 'l14']", + "104, white ['l15', 'l16', 'l17']", + "105, adipose ['l15', 'l18', 'l19']", + "106, tissue ['l16', 'l18', 'l20']", + "107, (WAT). ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "gut-restricted", + "FXR", + "agonist", + "fexaramine", + "(Fex)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver." + ] + } + } + ] + }, + { + "PMID": "25473916", + "TEXT": "Diffuse intrinsic pontine glioma is a uniformly lethal malignant tumor of infancy with no effective therapies. A new study reveals that inhibition of JMJD3 has robust antitumor activity in diffuse intrinsic pontine glioma xenografts.", + "TAG_DATA": [ + "21, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "22, of {'perturbing_action': 'I-pharmacological inhibition'}", + "23, JMJD3 {'perturbing_action': 'I-pharmacological inhibition'}", + "29, diffuse {'context': 'B-xenograft'}", + "30, intrinsic {'context': 'I-xenograft'}", + "31, pontine {'context': 'I-xenograft'}", + "32, glioma {'context': 'I-xenograft'}", + "33, xenografts. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "21, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "22, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "23, JMJD3 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "29, diffuse ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "30, intrinsic ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "31, pontine ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "32, glioma ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "33, xenografts. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "JMJD3" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "diffuse", + "intrinsic", + "pontine", + "glioma", + "xenografts." + ] + } + } + ] + }, + { + "PMID": "25419706", + "TEXT": "We have identified a rare coding mutation, T835M (rs137875858), in the UNC5C netrin receptor gene that segregated with disease in an autosomal dominant pattern in two families enriched for late-onset Alzheimer's disease and that was associated with disease across four large case-control cohorts (odds ratio = 2.15, Pmeta = 0.0095). T835M alters a conserved residue in the hinge region of UNC5C, and in vitro studies demonstrate that this mutation leads to increased cell death in human HEK293T cells and in rodent neurons. Furthermore, neurons expressing T835M UNC5C are more susceptible to cell death from multiple neurotoxic stimuli, including β-amyloid (Aβ), glutamate and staurosporine. On the basis of these data and the enriched hippocampal expression of UNC5C in the adult nervous system, we propose that one possible mechanism in which T835M UNC5C contributes to the risk of Alzheimer's disease is by increasing susceptibility to neuronal cell death, particularly in vulnerable regions of the Alzheimer's disease brain.", + "TAG_DATA": [ + "62, in {'context': 'B-in vitro'}", + "63, vitro {'context': 'I-in vitro'}", + "69, leads {'effect': 'B-positive'}", + "70, to {'effect': 'I-positive'}", + "71, increased {'effect': 'B-positive'}", + "72, cell {'phenotype': 'B-cell death'}", + "73, death {'phenotype': 'I-cell death'}", + "75, human {'context': 'B-cells'}", + "76, HEK293T {'context': 'I-cells'}", + "77, cells {'context': 'I-cells'}", + "80, rodent {'context': 'B-cells'}", + "81, neurons. {'context': 'I-cells'}", + "83, neurons {'context': 'B-cells'}", + "88, more {'effect': 'B-positive'}", + "89, susceptible {'effect': 'I-positive'}", + "90, to {'effect': 'I-positive'}", + "91, cell {'phenotype': 'B-cell death'}", + "92, death {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "62, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "63, vitro ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "69, leads ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "70, to ['l2', 'l12', 'l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "71, increased ['l3', 'l13', 'l22', 'l29', 'l36', 'l37', 'l38', 'l39', 'l40']", + "72, cell ['l4', 'l14', 'l23', 'l30', 'l36', 'l41', 'l42', 'l43', 'l44']", + "73, death ['l5', 'l15', 'l24', 'l31', 'l37', 'l41', 'l45', 'l46', 'l47']", + "75, human ['l6', 'l16', 'l25', 'l32', 'l38', 'l42', 'l45', 'l48', 'l49', 'l50']", + "76, HEK293T ['l7', 'l17', 'l26', 'l33', 'l39', 'l43', 'l46', 'l48', 'l51', 'l52', 'l53']", + "77, cells ['l8', 'l18', 'l27', 'l34', 'l40', 'l44', 'l47', 'l49', 'l51']", + "80, rodent ['l9', 'l19', 'l52', 'l54']", + "81, neurons. ['l10', 'l20', 'l28', 'l35', 'l50', 'l53', 'l54']", + "83, neurons ['l55', 'l56', 'l57', 'l58', 'l59']", + "88, more ['l55', 'l60', 'l61', 'l62', 'l63']", + "89, susceptible ['l56', 'l60', 'l64', 'l65', 'l66']", + "90, to ['l57', 'l61', 'l64', 'l67', 'l68']", + "91, cell ['l58', 'l62', 'l65', 'l67', 'l69']", + "92, death ['l59', 'l63', 'l66', 'l68', 'l69']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "leads", + "to", + "increased" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "leads", + "to", + "increased", + "more", + "susceptible" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "leads", + "to", + "increased", + "more", + "susceptible" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "HEK293T", + "cells", + "neurons.", + "neurons" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "HEK293T", + "cells", + "neurons" + ] + } + } + ] + }, + { + "PMID": "25419705", + "TEXT": "Renal fibrosis is the histological manifestation of a progressive, usually irreversible process causing chronic and end-stage kidney disease. We performed genome-wide transcriptome studies of a large cohort (n = 95) of normal and fibrotic human kidney tubule samples followed by systems and network analyses and identified inflammation and metabolism as the top dysregulated pathways in the diseased kidneys. In particular, we found that humans and mouse models with tubulointerstitial fibrosis had lower expression of key enzymes and regulators of fatty acid oxidation (FAO) and higher intracellular lipid deposition compared to controls. In vitro experiments indicated that inhibition of FAO in tubule epithelial cells caused ATP depletion, cell death, dedifferentiation and intracellular lipid deposition, phenotypes observed in fibrosis. In contrast, restoring fatty acid metabolism by genetic or pharmacological methods protected mice from tubulointerstitial fibrosis. Our results raise the possibility that correcting the metabolic defect in FAO may be useful for preventing and treating chronic kidney disease.", + "TAG_DATA": [ + "91, In {'context': 'B-in vitro'}", + "92, vitro {'context': 'I-in vitro'}", + "96, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "97, of {'perturbing_action': 'I-pharmacological inhibition'}", + "98, FAO {'perturbing_action': 'I-pharmacological inhibition'}", + "100, tubule {'context': 'B-cells'}", + "101, epithelial {'context': 'I-cells'}", + "102, cells {'context': 'I-cells'}", + "103, caused {'effect': 'B-positive'}", + "106, cell {'phenotype': 'B-cell death'}", + "107, death, {'phenotype': 'I-cell death'}", + "108, dedifferentiation {'phenotype': 'B-differentiation'}", + "129, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "91, In ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "92, vitro ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "96, inhibition ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "97, of ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "98, FAO ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "100, tubule ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "101, epithelial ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "102, cells ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "103, caused ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "106, cell ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "107, death, ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "108, dedifferentiation ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "FAO" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "dedifferentiation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "FAO" + ] + }, + "context": { + "val": "cells", + "words": [ + "tubule", + "epithelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "FAO" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "FAO" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "FAO" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "dedifferentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "tubule", + "epithelial", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "tubule", + "epithelial", + "cells" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "tubule", + "epithelial", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "dedifferentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "dedifferentiation" + ] + } + } + ] + }, + { + "PMID": "25401693", + "TEXT": "Pediatric brainstem gliomas often harbor oncogenic K27M mutation of histone H3.3. Here we show that GSKJ4 pharmacologic inhibition of K27 demethylase JMJD3 increases cellular H3K27 methylation in K27M tumor cells and demonstrate potent antitumor activity both in vitro against K27M cells and in vivo against K27M xenografts. Our results demonstrate that increasing H3K27 methylation by inhibiting K27 demethylase is a valid therapeutic strategy for treating K27M-expressing brainstem glioma.", + "TAG_DATA": [ + "15, GSKJ4 {'perturbing_action': 'B-pharmacological inhibition'}", + "16, pharmacologic {'perturbing_action': 'I-pharmacological inhibition'}", + "17, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "18, of {'perturbing_action': 'I-pharmacological inhibition'}", + "19, K27 {'perturbing_action': 'I-pharmacological inhibition'}", + "20, demethylase {'perturbing_action': 'I-pharmacological inhibition'}", + "21, JMJD3 {'perturbing_action': 'I-pharmacological inhibition'}", + "27, K27M {'context': 'B-transformed cells'}", + "28, tumor {'context': 'I-transformed cells'}", + "29, cells {'context': 'I-transformed cells'}", + "36, in {'context': 'B-in vitro'}", + "37, vitro {'context': 'I-in vitro'}", + "39, K27M {'context': 'B-transformed cells'}", + "40, cells {'context': 'I-transformed cells'}", + "42, in {'context': 'B-in vivo'}", + "43, vivo {'context': 'I-in vivo'}", + "45, K27M {'context': 'B-xenograft'}", + "46, xenografts. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "15, GSKJ4 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "16, pharmacologic ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "17, inhibition ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "18, of ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "19, K27 ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "20, demethylase ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "21, JMJD3 ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "27, K27M ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71']", + "28, tumor ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l72']", + "29, cells ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l72']", + "36, in ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l73', 'l74', 'l75']", + "37, vitro ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l76', 'l77']", + "39, K27M ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l76', 'l78', 'l79']", + "40, cells ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l77', 'l78']", + "42, in ['l80', 'l81', 'l82']", + "43, vivo ['l79', 'l80', 'l83', 'l84']", + "45, K27M ['l81', 'l83', 'l85']", + "46, xenografts. ['l82', 'l84', 'l85']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "GSKJ4", + "pharmacologic", + "inhibition", + "of", + "K27", + "demethylase", + "JMJD3" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "K27M", + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "GSKJ4", + "pharmacologic", + "inhibition", + "of", + "K27", + "demethylase", + "JMJD3" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "25362254", + "TEXT": "Peripheral artery disease (PAD) generates tissue ischemia through arterial occlusions and insufficient collateral vessel formation. Vascular insufficiency in PAD occurs despite higher circulating levels of vascular endothelial growth factor A (VEGF-A), a key regulator of angiogenesis. Here we show that clinical PAD is associated with elevated levels of an antiangiogenic VEGF-A splice isoform (VEGF-A165b) and a corresponding reduction in levels of the proangiogenic VEGF-A165a splice isoform. In mice, VEGF-A165b expression was upregulated by conditions associated with impaired limb revascularization, including leptin deficiency, diet-induced obesity, genetic ablation of the secreted frizzled-related protein 5 (Sfrp5) adipokine and transgenic overexpression of Wnt5a in myeloid cells. In a mouse model of PAD, delivery of VEGF-A165b inhibited revascularization of ischemic hind limbs, whereas treatment with an isoform-specific neutralizing antibody reversed impaired revascularization caused by metabolic dysfunction or perturbations in the Wnt5a-Sfrp5 regulatory system. These results indicate that inflammation-driven expression of the antiangiogenic VEGF-A isoform can contribute to impaired collateralization in ischemic cardiovascular disease.", + "TAG_DATA": [ + "67, mice, {'context': 'B-organism'}", + "84, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "85, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "86, of {'perturbing_action': 'I-gene loss-of-function'}", + "87, the {'perturbing_action': 'I-gene loss-of-function'}", + "88, secreted {'perturbing_action': 'I-gene loss-of-function'}", + "89, frizzled-related {'perturbing_action': 'I-gene loss-of-function'}", + "90, protein {'perturbing_action': 'I-gene loss-of-function'}", + "91, 5 {'perturbing_action': 'I-gene loss-of-function'}", + "92, (Sfrp5) {'perturbing_action': 'I-gene loss-of-function'}", + "93, adipokine {'perturbing_action': 'I-gene loss-of-function'}", + "95, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "96, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "97, of {'perturbing_action': 'I-gene gain-of-function'}", + "98, Wnt5a {'perturbing_action': 'I-gene gain-of-function'}", + "100, myeloid {'context': 'B-cells'}", + "101, cells. {'context': 'I-cells'}", + "104, mouse {'context': 'B-organism'}", + "105, model {'context': 'I-organism'}", + "115, hind {'context': 'B-tissue/organ'}", + "116, limbs, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "84, genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "85, ablation ['l0', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "86, of ['l1', 'l18', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "87, the ['l2', 'l19', 'l35', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "88, secreted ['l3', 'l20', 'l36', 'l52', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "89, frizzled-related ['l4', 'l21', 'l37', 'l53', 'l68', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "90, protein ['l5', 'l22', 'l38', 'l54', 'l69', 'l83', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "91, 5 ['l6', 'l23', 'l39', 'l55', 'l70', 'l84', 'l97', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "92, (Sfrp5) ['l7', 'l24', 'l40', 'l56', 'l71', 'l85', 'l98', 'l110', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "93, adipokine ['l8', 'l25', 'l41', 'l57', 'l72', 'l86', 'l99', 'l111', 'l122', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "95, transgenic ['l9', 'l26', 'l42', 'l58', 'l73', 'l87', 'l100', 'l112', 'l123', 'l133', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151']", + "96, overexpression ['l10', 'l27', 'l43', 'l59', 'l74', 'l88', 'l101', 'l113', 'l124', 'l134', 'l143', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159']", + "97, of ['l11', 'l28', 'l44', 'l60', 'l75', 'l89', 'l102', 'l114', 'l125', 'l135', 'l144', 'l152', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166']", + "98, Wnt5a ['l12', 'l29', 'l45', 'l61', 'l76', 'l90', 'l103', 'l115', 'l126', 'l136', 'l145', 'l153', 'l160', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "100, myeloid ['l13', 'l30', 'l46', 'l62', 'l77', 'l91', 'l104', 'l116', 'l127', 'l137', 'l146', 'l154', 'l161', 'l167', 'l173', 'l174', 'l175', 'l176']", + "101, cells. ['l14', 'l31', 'l47', 'l63', 'l78', 'l92', 'l105', 'l117', 'l128', 'l138', 'l147', 'l155', 'l162', 'l168', 'l173', 'l177', 'l178']", + "104, mouse ['l15', 'l32', 'l48', 'l64', 'l79', 'l93', 'l106', 'l118', 'l129', 'l139', 'l148', 'l156', 'l163', 'l169', 'l174', 'l177', 'l179', 'l180', 'l181']", + "105, model ['l16', 'l33', 'l49', 'l65', 'l80', 'l94', 'l107', 'l119', 'l130', 'l140', 'l149', 'l157', 'l164', 'l170', 'l175', 'l178', 'l179', 'l182', 'l183']", + "115, hind ['l50', 'l66', 'l81', 'l95', 'l108', 'l120', 'l131', 'l141', 'l150', 'l158', 'l165', 'l171', 'l180', 'l182', 'l184']", + "116, limbs, ['l17', 'l34', 'l51', 'l67', 'l82', 'l96', 'l109', 'l121', 'l132', 'l142', 'l151', 'l159', 'l166', 'l172', 'l176', 'l181', 'l183', 'l184']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "the", + "secreted", + "frizzled-related", + "protein", + "5", + "(Sfrp5)", + "adipokine" + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "the", + "secreted", + "frizzled-related", + "protein", + "5", + "(Sfrp5)", + "adipokine" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "the", + "secreted", + "frizzled-related", + "protein", + "5", + "(Sfrp5)", + "adipokine" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "limbs,", + "hind" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "overexpression", + "of", + "Wnt5a" + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "overexpression", + "of", + "Wnt5a" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "overexpression", + "of", + "Wnt5a" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hind", + "limbs," + ] + } + } + ] + }, + { + "PMID": "25362253", + "TEXT": "In type 2 diabetes, hyperglycemia is present when an increased demand for insulin, typically due to insulin resistance, is not met as a result of progressive pancreatic beta cell dysfunction. This defect in beta cell activity is typically characterized by impaired insulin biosynthesis and secretion, usually accompanied by oxidative and endoplasmic reticulum (ER) stress. We demonstrate that multiple inflammatory cytokines elevated in diabetic pancreatic islets induce beta cell oxidative and ER stress, with interleukin-23 (IL-23), IL-24 and IL-33 being the most potent. Conversely, we show that islet-endogenous and exogenous IL-22, by regulating oxidative stress pathways, suppresses oxidative and ER stress caused by cytokines or glucolipotoxicity in mouse and human beta cells. In obese mice, antibody neutralization of IL-23 or IL-24 partially reduced beta cell ER stress and improved glucose tolerance, whereas IL-22 administration modulated oxidative stress regulatory genes in islets, suppressed ER stress and inflammation, promoted secretion of high-quality efficacious insulin and fully restored glucose homeostasis followed by restitution of insulin sensitivity. Thus, therapeutic manipulation of immune regulators of beta cell stress reverses the hyperglycemia central to diabetes pathology.", + "TAG_DATA": [ + "106, mouse {'context': 'B-cells'}", + "107, and {'context': 'I-cells'}", + "108, human {'context': 'I-cells'}", + "109, beta {'context': 'I-cells'}", + "110, cells. {'context': 'I-cells'}", + "112, obese {'context': 'B-organism'}", + "113, mice, {'context': 'I-organism'}", + "114, antibody {'perturbing_action': 'B-rnai/knockdown'}", + "122, beta {'context': 'B-cells'}", + "123, cell {'context': 'I-cells'}", + "139, islets, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "106, mouse ['l0', 'l1', 'l2', 'l3']", + "107, and ['l0', 'l4', 'l5', 'l6']", + "108, human ['l1', 'l4', 'l7', 'l8']", + "109, beta ['l2', 'l5', 'l7', 'l9']", + "110, cells. ['l3', 'l6', 'l8', 'l9']", + "112, obese ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "113, mice, ['l10', 'l16', 'l17']", + "114, antibody ['l11', 'l18', 'l19', 'l20', 'l21', 'l22']", + "115, neutralization ['l12', 'l18', 'l23', 'l24', 'l25', 'l26']", + "116, of ['l13', 'l19', 'l23', 'l27', 'l28', 'l29']", + "122, beta ['l14', 'l16', 'l20', 'l24', 'l27', 'l30']", + "123, cell ['l15', 'l17', 'l21', 'l25', 'l28', 'l30']", + "139, islets, ['l22', 'l26', 'l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "obese" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antibody" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antibody" + ] + }, + "context": { + "val": "cells", + "words": [ + "beta", + "cell", + "islets," + ] + } + } + ] + }, + { + "PMID": "25344740", + "TEXT": "Pulmonary hypertension (PH) is characterized by increased proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs). Forkhead box O (FoxO) transcription factors are key regulators of cellular proliferation. Here we show that in pulmonary vessels and PASMCs of human and experimental PH lungs, FoxO1 expression is downregulated and FoxO1 is inactivated via phosphorylation and nuclear exclusion. These findings could be reproduced using ex vivo exposure of PASMCs to growth factors and inflammatory cytokines. Pharmacological inhibition and genetic ablation of FoxO1 in smooth muscle cells reproduced PH features in vitro and in vivo. Either pharmacological reconstitution of FoxO1 activity using intravenous or inhaled paclitaxel, or reconstitution of the transcriptional activity of FoxO1 by gene therapy, restored the physiologically quiescent PASMC phenotype in vitro, linked to changes in cell cycle control and bone morphogenic protein receptor type 2 (BMPR2) signaling, and reversed vascular remodeling and right-heart hypertrophy in vivo. Thus, PASMC FoxO1 is a critical integrator of multiple signaling pathways driving PH, and reconstitution of FoxO1 activity offers a potential therapeutic option for PH.", + "TAG_DATA": [ + "68, PASMCs {'context': 'B-cells'}", + "78, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "79, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "80, of {'perturbing_action': 'I-gene loss-of-function'}", + "81, FoxO1 {'perturbing_action': 'I-gene loss-of-function'}", + "83, smooth {'context': 'B-cells'}", + "84, muscle {'context': 'I-cells'}", + "85, cells {'context': 'I-cells'}", + "89, in {'context': 'B-in vitro'}", + "90, vitro {'context': 'I-in vitro'}", + "92, in {'context': 'B-in vivo'}", + "93, vivo. {'context': 'I-in vivo'}", + "95, pharmacological {'perturbing_action': 'B-gene gain-of-function'}", + "96, reconstitution {'perturbing_action': 'I-gene loss-of-function'}", + "97, of {'perturbing_action': 'I-gene gain-of-function'}", + "98, FoxO1 {'perturbing_action': 'I-gene gain-of-function'}", + "99, activity {'perturbing_action': 'I-gene gain-of-function'}", + "100, using {'perturbing_action': 'I-gene loss-of-function'}", + "111, of {'perturbing_action': 'I-gene gain-of-function'}", + "112, FoxO1 {'perturbing_action': 'I-gene gain-of-function'}", + "120, PASMC {'context': 'B-cells'}", + "122, in {'context': 'B-in vitro'}", + "123, vitro, {'context': 'I-in vitro'}", + "147, in {'context': 'B-in vivo'}", + "148, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "68, PASMCs ['l0', 'l1']", + "78, genetic ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "79, ablation ['l2', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "80, of ['l3', 'l14', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "81, FoxO1 ['l4', 'l15', 'l25', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "83, smooth ['l5', 'l16', 'l26', 'l35', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "84, muscle ['l0', 'l6', 'l17', 'l27', 'l36', 'l43', 'l49', 'l50', 'l51', 'l52']", + "85, cells ['l1', 'l7', 'l18', 'l28', 'l37', 'l44', 'l49', 'l53', 'l54']", + "89, in ['l8', 'l19', 'l29', 'l38', 'l45', 'l50', 'l53', 'l55']", + "90, vitro ['l9', 'l20', 'l30', 'l39', 'l46', 'l51', 'l54', 'l55']", + "92, in ['l10', 'l21', 'l31', 'l40', 'l47', 'l56']", + "93, vivo. ['l11', 'l22', 'l32', 'l41', 'l48', 'l52', 'l56']", + "95, pharmacological ['l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "96, reconstitution ['l57', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "97, of ['l58', 'l68', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "98, FoxO1 ['l59', 'l69', 'l77', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "99, activity ['l60', 'l70', 'l78', 'l85', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "100, using ['l61', 'l71', 'l79', 'l86', 'l92', 'l98', 'l99', 'l100', 'l101', 'l102']", + "101, intravenous ['l12', 'l23', 'l33', 'l42', 'l62', 'l72', 'l80', 'l87', 'l93', 'l98', 'l103', 'l104', 'l105', 'l106']", + "103, inhaled ['l13', 'l24', 'l34', 'l63', 'l73', 'l81', 'l88', 'l94', 'l99', 'l103', 'l107', 'l108', 'l109']", + "109, transcriptional ['l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "110, activity ['l110', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "111, of ['l111', 'l118', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "112, FoxO1 ['l112', 'l119', 'l125', 'l131', 'l132', 'l133', 'l134', 'l135']", + "120, PASMC ['l64', 'l74', 'l82', 'l89', 'l95', 'l100', 'l104', 'l107', 'l113', 'l120', 'l126', 'l131', 'l136', 'l137', 'l138', 'l139']", + "122, in ['l65', 'l75', 'l83', 'l90', 'l96', 'l101', 'l105', 'l108', 'l114', 'l121', 'l127', 'l132', 'l136', 'l140', 'l141', 'l142']", + "123, vitro, ['l66', 'l76', 'l84', 'l91', 'l97', 'l102', 'l106', 'l109', 'l115', 'l122', 'l128', 'l133', 'l137', 'l140', 'l143']", + "147, in ['l116', 'l123', 'l129', 'l134', 'l138', 'l141', 'l144']", + "148, vivo. ['l67', 'l117', 'l124', 'l130', 'l135', 'l139', 'l142', 'l143', 'l144']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "FoxO1", + "reconstitution", + "using" + ] + }, + "context": { + "val": "cells", + "words": [ + "smooth", + "muscle", + "cells", + "PASMC" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "FoxO1", + "reconstitution", + "using" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro", + "vitro," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "FoxO1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "pharmacological", + "of", + "FoxO1", + "activity" + ] + }, + "context": { + "val": "cells", + "words": [ + "PASMC" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "pharmacological", + "of", + "FoxO1", + "activity" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "pharmacological", + "of", + "FoxO1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo.", + "in" + ] + } + } + ] + }, + { + "PMID": "25329329", + "TEXT": "The protein cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of immune responses, and its loss causes fatal autoimmunity in mice. We studied a large family in which five individuals presented with a complex, autosomal dominant immune dysregulation syndrome characterized by hypogammaglobulinemia, recurrent infections and multiple autoimmune clinical features. We identified a heterozygous nonsense mutation in exon 1 of CTLA4. Screening of 71 unrelated patients with comparable clinical phenotypes identified five additional families (nine individuals) with previously undescribed splice site and missense mutations in CTLA4. Clinical penetrance was incomplete (eight adults of a total of 19 genetically proven CTLA4 mutation carriers were considered unaffected). However, CTLA-4 protein expression was decreased in regulatory T cells (Treg cells) in both patients and carriers with CTLA4 mutations. Whereas Treg cells were generally present at elevated numbers in these individuals, their suppressive function, CTLA-4 ligand binding and transendocytosis of CD80 were impaired. Mutations in CTLA4 were also associated with decreased circulating B cell numbers. Taken together, mutations in CTLA4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding result in disrupted T and B cell homeostasis and a complex immune dysregulation syndrome.", + "TAG_DATA": [ + "113, regulatory {'context': 'B-cells'}", + "114, T {'context': 'I-cells'}", + "115, cells {'context': 'I-cells'}", + "117, cells) {'context': 'I-cells'}", + "124, CTLA4 {'perturbing_action': 'B-other'}", + "125, mutations. {'perturbing_action': 'I-other'}", + "127, Treg {'context': 'B-cells'}", + "128, cells {'context': 'I-cells'}", + "159, B {'context': 'B-cells'}", + "160, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "113, regulatory ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "114, T ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "115, cells ['l1', 'l7', 'l13', 'l14', 'l15']", + "116, (Treg ['l2', 'l8', 'l13', 'l16', 'l17']", + "117, cells) ['l3', 'l9', 'l14', 'l16']", + "124, CTLA4 ['l4', 'l10', 'l18', 'l19', 'l20']", + "125, mutations. ['l5', 'l11', 'l15', 'l17', 'l18', 'l21', 'l22']", + "127, Treg ['l19', 'l21', 'l23']", + "128, cells ['l6', 'l12', 'l20', 'l22', 'l23']", + "159, B ['l24']", + "160, cell ['l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "regulatory", + "T", + "cells", + "Treg" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "CTLA4", + "mutations." + ] + } + } + ] + }, + { + "PMID": "25216637", + "TEXT": "The integrity of the plasma membrane is maintained through an active repair process, especially in skeletal and cardiac muscle cells, in which contraction-induced mechanical damage frequently occurs in vivo. Muscular dystrophies (MDs) are a group of muscle diseases characterized by skeletal muscle wasting and weakness. An important cause of these group of diseases is defective repair of sarcolemmal injuries, which normally requires Ca(2+) sensor proteins and Ca(2+)-dependent delivery of intracellular vesicles to the sites of injury. MCOLN1 (also known as TRPML1, ML1) is an endosomal and lysosomal Ca(2+) channel whose human mutations cause mucolipidosis IV (ML4), a neurodegenerative disease with motor disabilities. Here we report that ML1-null mice develop a primary, early-onset MD independent of neural degeneration. Although the dystrophin-glycoprotein complex and the known membrane repair proteins are expressed normally, membrane resealing was defective in ML1-null muscle fibers and also upon acute and pharmacological inhibition of ML1 channel activity or vesicular Ca(2+) release. Injury facilitated the trafficking and exocytosis of vesicles by upmodulating ML1 channel activity. In the dystrophic mdx mouse model, overexpression of ML1 decreased muscle pathology. Collectively, our data have identified an intracellular Ca(2+) channel that regulates membrane repair in skeletal muscle via Ca(2+)-dependent vesicle exocytosis.", + "TAG_DATA": [ + "106, ML1-null {'perturbing_action': 'B-gene loss-of-function'}", + "107, mice {'context': 'B-organism'}", + "135, ML1-null {'perturbing_action': 'B-gene loss-of-function'}", + "136, muscle {'context': 'B-cells'}", + "137, fibers {'context': 'I-cells'}", + "143, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "144, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "145, of {'perturbing_action': 'I-pharmacological inhibition'}", + "146, ML1 {'perturbing_action': 'I-pharmacological inhibition'}", + "147, channel {'perturbing_action': 'I-pharmacological inhibition'}", + "148, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "168, dystrophic {'context': 'B-organism'}", + "169, mdx {'context': 'I-organism'}", + "170, mouse {'context': 'I-organism'}", + "171, model, {'context': 'I-organism'}", + "172, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "173, of {'perturbing_action': 'I-gene gain-of-function'}", + "174, ML1 {'perturbing_action': 'I-gene gain-of-function'}", + "176, muscle {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "106, ML1-null ['l0', 'l1', 'l2', 'l3']", + "107, mice ['l0', 'l4', 'l5', 'l6']", + "135, ML1-null ['l1', 'l4', 'l7', 'l8', 'l9', 'l10', 'l11']", + "136, muscle ['l2', 'l5', 'l7', 'l12']", + "137, fibers ['l3', 'l6', 'l8', 'l12']", + "143, pharmacological ['l13', 'l14', 'l15', 'l16', 'l17']", + "144, inhibition ['l13', 'l18', 'l19', 'l20', 'l21']", + "145, of ['l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "146, ML1 ['l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "147, channel ['l16', 'l20', 'l23', 'l25', 'l27']", + "148, activity ['l11', 'l17', 'l21', 'l24', 'l26', 'l27']", + "168, dystrophic ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "169, mdx ['l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "170, mouse ['l29', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "171, model, ['l30', 'l36', 'l41', 'l46', 'l47', 'l48']", + "172, overexpression ['l31', 'l37', 'l42', 'l49', 'l50', 'l51']", + "173, of ['l32', 'l38', 'l43', 'l46', 'l49', 'l52', 'l53']", + "174, ML1 ['l33', 'l39', 'l44', 'l47', 'l50', 'l52', 'l54']", + "176, muscle ['l34', 'l40', 'l45', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ML1-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ML1-null" + ] + }, + "context": { + "val": "cells", + "words": [ + "muscle", + "fibers" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "dystrophic", + "mdx", + "mouse", + "model," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "ML1" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "ML1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscle" + ] + } + } + ] + }, + { + "PMID": "25194572", + "TEXT": "The progressive loss of muscle regenerative capacity with age or disease results in part from a decline in the number and function of satellite cells, the direct cellular contributors to muscle repair. However, little is known about the molecular effectors underlying satellite cell impairment and depletion. Elevated levels of inflammatory cytokines, including interleukin-6 (IL-6), are associated with both age-related and muscle-wasting conditions. The levels of STAT3, a downstream effector of IL-6, are also elevated with muscle wasting, and STAT3 has been implicated in the regulation of self-renewal and stem cell fate in several tissues. Here we show that IL-6-activated Stat3 signaling regulates satellite cell behavior, promoting myogenic lineage progression through myogenic differentiation 1 (Myod1) regulation. Conditional ablation of Stat3 in Pax7-expressing satellite cells resulted in their increased expansion during regeneration, but compromised myogenic differentiation prevented the contribution of these cells to regenerating myofibers. In contrast, transient Stat3 inhibition promoted satellite cell expansion and enhanced tissue repair in both aged and dystrophic muscle. The effects of STAT3 inhibition on cell fate and proliferation were conserved in human myoblasts. The results of this study indicate that pharmacological manipulation of STAT3 activity can be used to counteract the functional exhaustion of satellite cells in pathological conditions, thereby maintaining the endogenous regenerative response and ameliorating muscle-wasting diseases.", + "TAG_DATA": [ + "115, Conditional {'perturbing_action': 'B-gene loss-of-function'}", + "116, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "117, of {'perturbing_action': 'I-gene loss-of-function'}", + "118, Stat3 {'perturbing_action': 'I-gene loss-of-function'}", + "120, Pax7-expressing {'context': 'B-cells'}", + "121, satellite {'context': 'I-cells'}", + "122, cells {'context': 'I-cells'}", + "131, compromised {'effect': 'B-negative'}", + "132, myogenic {'phenotype': 'B-differentiation'}", + "133, differentiation {'phenotype': 'I-differentiation'}", + "139, cells {'context': 'B-cells'}", + "145, transient {'perturbing_action': 'B-pharmacological inhibition'}", + "146, Stat3 {'perturbing_action': 'I-pharmacological inhibition'}", + "147, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "149, satellite {'context': 'B-cells'}", + "150, cell {'context': 'I-cells'}", + "158, aged {'context': 'B-tissue/organ'}", + "160, dystrophic {'context': 'B-tissue/organ'}", + "161, muscle. {'context': 'I-tissue/organ'}", + "165, STAT3 {'perturbing_action': 'B-pharmacological inhibition'}", + "166, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "171, proliferation {'phenotype': 'B-proliferation'}", + "175, human {'context': 'B-cells'}", + "176, myoblasts. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "115, Conditional ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "116, ablation ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "117, of ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "118, Stat3 ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "120, Pax7-expressing ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "121, satellite ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47']", + "122, cells ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l48']", + "131, compromised ['l6', 'l16', 'l25', 'l33', 'l40', 'l49', 'l50', 'l51', 'l52']", + "132, myogenic ['l7', 'l17', 'l26', 'l34', 'l41', 'l49', 'l53', 'l54', 'l55']", + "133, differentiation ['l8', 'l18', 'l27', 'l35', 'l42', 'l46', 'l50', 'l53', 'l56', 'l57']", + "139, cells ['l9', 'l19', 'l28', 'l36', 'l43', 'l47', 'l48', 'l51', 'l54', 'l56', 'l58']", + "142, myofibers. ['l10', 'l20', 'l29', 'l37', 'l44', 'l52', 'l55', 'l57', 'l58']", + "145, transient ['l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "146, Stat3 ['l59', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "147, inhibition ['l60', 'l71', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "149, satellite ['l61', 'l72', 'l81', 'l88', 'l89', 'l90', 'l91']", + "150, cell ['l62', 'l73', 'l82', 'l88', 'l92', 'l93', 'l94']", + "158, aged ['l63', 'l74', 'l83', 'l89', 'l92', 'l95', 'l96']", + "160, dystrophic ['l64', 'l75', 'l84', 'l90', 'l93', 'l95', 'l97']", + "161, muscle. ['l65', 'l76', 'l85', 'l91', 'l94', 'l96', 'l97']", + "165, STAT3 ['l66', 'l98', 'l99', 'l100', 'l101']", + "166, inhibition ['l67', 'l77', 'l98', 'l102', 'l103', 'l104']", + "171, proliferation ['l68', 'l78', 'l99', 'l102', 'l105', 'l106']", + "175, human ['l69', 'l79', 'l86', 'l100', 'l103', 'l105', 'l107']", + "176, myoblasts. ['l70', 'l80', 'l87', 'l101', 'l104', 'l106', 'l107']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "ablation", + "of", + "Stat3" + ] + }, + "context": { + "val": "cells", + "words": [ + "Pax7-expressing", + "satellite", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "ablation", + "of", + "Stat3" + ] + }, + "effect": { + "val": "negative", + "words": [ + "compromised" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "ablation", + "of", + "Stat3" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "myogenic", + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Pax7-expressing", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "compromised" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Pax7-expressing", + "satellite", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "myogenic", + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "compromised" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "myogenic", + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "transient", + "Stat3", + "inhibition", + "STAT3" + ] + }, + "context": { + "val": "cells", + "words": [ + "satellite", + "cell", + "human", + "myoblasts." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "transient", + "Stat3", + "inhibition" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "aged", + "dystrophic", + "muscle." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "transient", + "Stat3", + "STAT3", + "inhibition" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "myoblasts." + ] + } + } + ] + }, + { + "PMID": "25194570", + "TEXT": "Efforts to identify and annotate cancer driver genetic lesions have been focused primarily on the analysis of protein-coding genes; however, most genetic abnormalities found in human cancer are located in intergenic regions. Here we identify a new long range-acting MYC enhancer controlled by NOTCH1 that is targeted by recurrent chromosomal duplications in human T cell acute lymphoblastic leukemia (T-ALL). This highly conserved regulatory element, hereby named N-Me for NOTCH MYC enhancer, is located within a broad super-enhancer region +1.47 Mb from the MYC transcription initiating site, interacts with the MYC proximal promoter and induces orientation-independent MYC expression in reporter assays. Moreover, analysis of N-Me knockout mice demonstrates a selective and essential role of this regulatory element during thymocyte development and in NOTCH1-induced T-ALL. Together these results identify N-Me as a long-range oncogenic enhancer implicated directly in the pathogenesis of human leukemia and highlight the importance of the NOTCH1-MYC regulatory axis in T cell transformation and as a therapeutic target in T-ALL.", + "TAG_DATA": [ + "103, N-Me {'perturbing_action': 'B-gene loss-of-function'}", + "104, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "105, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "103, N-Me ['l0', 'l1']", + "104, knockout ['l0', 'l2']", + "105, mice ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "N-Me", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "25108526", + "TEXT": "Aging-related bone loss and osteoporosis affect millions of people worldwide. Chronic inflammation associated with aging promotes bone resorption and impairs bone formation. Here we show that Wnt4 attenuates bone loss in osteoporosis and skeletal aging mouse models by inhibiting nuclear factor-κB (NF-κB) via noncanonical Wnt signaling. Transgenic mice expressing Wnt4 from osteoblasts were significantly protected from bone loss and chronic inflammation induced by ovariectomy, tumor necrosis factor or natural aging. In addition to promoting bone formation, Wnt4 inhibited osteoclast formation and bone resorption. Mechanistically, Wnt4 inhibited NF-κB activation mediated by transforming growth factor-β-activated kinase-1 (Tak1) in macrophages and osteoclast precursors independently of β-catenin. Moreover, recombinant Wnt4 alleviated bone loss and inflammation by inhibiting NF-κB in vivo in mouse models of bone disease. Given its dual role in promoting bone formation and inhibiting bone resorption, our results suggest that Wnt4 signaling could be an attractive therapeutic target for treating osteoporosis and preventing skeletal aging.", + "TAG_DATA": [ + "35, mouse {'context': 'B-organism'}", + "36, models {'context': 'I-organism'}", + "46, Transgenic {'perturbing_action': 'B-gene gain-of-function', 'context': 'B-organism'}", + "47, mice {'context': 'I-organism'}", + "48, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "49, Wnt4 {'perturbing_action': 'I-gene gain-of-function'}", + "50, from {'perturbing_action': 'I-gene gain-of-function'}", + "51, osteoblasts {'perturbing_action': 'I-gene gain-of-function', 'context': 'B-cells'}", + "96, macrophages {'context': 'B-cells'}", + "98, osteoclast {'context': 'B-cells'}", + "114, in {'context': 'B-in vivo'}", + "115, vivo {'context': 'I-in vivo'}", + "117, mouse {'context': 'B-organism'}", + "118, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "35, mouse ['l0', 'l1']", + "36, models ['l0', 'l2']", + "46, Transgenic ['l3', 'l4', 'l5', 'l6', 'l7']", + "47, mice ['l3', 'l8', 'l9', 'l10', 'l11']", + "48, expressing ['l4', 'l8', 'l12', 'l13', 'l14']", + "49, Wnt4 ['l5', 'l9', 'l12', 'l15', 'l16']", + "50, from ['l6', 'l10', 'l13', 'l15', 'l17']", + "51, osteoblasts ['l1', 'l2', 'l7', 'l11', 'l14', 'l16', 'l17']", + "96, macrophages ['l18']", + "98, osteoclast ['l18']", + "114, in ['l19', 'l20', 'l21']", + "115, vivo ['l19', 'l22', 'l23']", + "117, mouse ['l20', 'l22', 'l24']", + "118, models ['l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "Transgenic", + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "osteoblasts", + "Transgenic", + "expressing", + "Wnt4", + "from" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "osteoblasts", + "Transgenic", + "expressing", + "Wnt4", + "from" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoblasts" + ] + } + } + ] + }, + { + "PMID": "24997609", + "TEXT": "Individuals with neurofibromatosis type-1 (NF1) can manifest focal skeletal dysplasias that remain extremely difficult to treat. NF1 is caused by mutations in the NF1 gene, which encodes the RAS GTPase-activating protein neurofibromin. We report here that ablation of Nf1 in bone-forming cells leads to supraphysiologic accumulation of pyrophosphate (PPi), a strong inhibitor of hydroxyapatite formation, and that a chronic extracellular signal-regulated kinase (ERK)-dependent increase in expression of genes promoting PPi synthesis and extracellular transport, namely Enpp1 and Ank, causes this phenotype. Nf1 ablation also prevents bone morphogenic protein-2-induced osteoprogenitor differentiation and, consequently, expression of alkaline phosphatase and PPi breakdown, further contributing to PPi accumulation. The short stature and impaired bone mineralization and strength in mice lacking Nf1 in osteochondroprogenitors or osteoblasts can be corrected by asfotase-α enzyme therapy aimed at reducing PPi concentration. These results establish neurofibromin as an essential regulator of bone mineralization. They also suggest that altered PPi homeostasis contributes to the skeletal dysplasias associated with NF1 and that some of the NF1 skeletal conditions could be prevented pharmacologically.", + "TAG_DATA": [ + "36, ablation {'perturbing_action': 'B-gene loss-of-function'}", + "37, of {'perturbing_action': 'I-gene loss-of-function'}", + "38, Nf1 {'perturbing_action': 'I-gene loss-of-function'}", + "40, bone-forming {'context': 'B-cells'}", + "41, cells {'context': 'I-cells'}", + "81, Nf1 {'perturbing_action': 'B-gene loss-of-function'}", + "82, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "84, prevents {'effect': 'B-negative'}", + "87, protein-2-induced {'effect': 'B-positive'}", + "88, osteoprogenitor {'context': 'B-cells', 'phenotype': 'B-differentiation'}", + "89, differentiation {'phenotype': 'B-differentiation'}", + "114, mice {'context': 'B-organism'}", + "115, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "116, Nf1 {'perturbing_action': 'I-gene loss-of-function'}", + "118, osteochondroprogenitors {'context': 'B-cells'}", + "120, osteoblasts {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "36, ablation ['l0', 'l1', 'l2', 'l3']", + "37, of ['l0', 'l4', 'l5', 'l6']", + "38, Nf1 ['l1', 'l4', 'l7', 'l8']", + "40, bone-forming ['l2', 'l5', 'l7', 'l9']", + "41, cells ['l3', 'l6', 'l8', 'l9']", + "81, Nf1 ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "82, ablation ['l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "84, prevents ['l11', 'l16', 'l21', 'l22', 'l23']", + "87, protein-2-induced ['l12', 'l17', 'l21', 'l24', 'l25']", + "88, osteoprogenitor ['l13', 'l18', 'l22', 'l24', 'l26']", + "89, differentiation ['l14', 'l19', 'l23', 'l25', 'l26']", + "114, mice ['l27', 'l28', 'l29', 'l30']", + "115, lacking ['l27', 'l31', 'l32', 'l33']", + "116, Nf1 ['l28', 'l31', 'l34', 'l35']", + "118, osteochondroprogenitors ['l15', 'l20', 'l29', 'l32', 'l34', 'l36']", + "120, osteoblasts ['l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablation", + "of", + "Nf1", + "lacking" + ] + }, + "context": { + "val": "cells", + "words": [ + "bone-forming", + "cells", + "osteoprogenitor", + "osteochondroprogenitors", + "osteoblasts" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nf1", + "ablation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nf1", + "ablation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "protein-2-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nf1", + "ablation" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "osteoprogenitor", + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoprogenitor" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "osteoprogenitor" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoprogenitor" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "osteoprogenitor", + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "protein-2-induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoprogenitor" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "protein-2-induced" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "osteoprogenitor", + "differentiation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "Nf1" + ] + } + } + ] + }, + { + "PMID": "24952648", + "TEXT": "Ribosomal protein haploinsufficiency occurs in diverse human diseases including Diamond-Blackfan anemia (DBA), congenital asplenia and T cell leukemia. Yet, how mutations in genes encoding ubiquitously expressed proteins such as these result in cell-type- and tissue-specific defects remains unknown. Here, we identify mutations in GATA1, encoding the critical hematopoietic transcription factor GATA-binding protein-1, that reduce levels of full-length GATA1 protein and cause DBA in rare instances. We show that ribosomal protein haploinsufficiency, the more common cause of DBA, can lead to decreased GATA1 mRNA translation, possibly resulting from a higher threshold for initiation of translation of this mRNA in comparison with other mRNAs. In primary hematopoietic cells from patients with mutations in RPS19, encoding ribosomal protein S19, the amplitude of a transcriptional signature of GATA1 target genes was globally and specifically reduced, indicating that the activity, but not the mRNA level, of GATA1 is decreased in patients with DBA associated with mutations affecting ribosomal proteins. Moreover, the defective hematopoiesis observed in patients with DBA associated with ribosomal protein haploinsufficiency could be partially overcome by increasing GATA1 protein levels. Our results provide a paradigm by which selective defects in translation due to mutations affecting ubiquitous ribosomal proteins can result in human disease.", + "TAG_DATA": [ + "103, primary {'context': 'B-cells'}", + "104, hematopoietic {'context': 'I-cells'}", + "105, cells {'context': 'I-cells'}", + "107, patients {'context': 'B-patient'}", + "109, mutations {'perturbing_action': 'B-other'}", + "110, in {'perturbing_action': 'I-other'}", + "111, RPS19, {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "103, primary ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "104, hematopoietic ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "105, cells ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "107, patients ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "109, mutations ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "110, in ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "111, RPS19, ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "primary", + "hematopoietic", + "cells" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutations", + "in", + "RPS19," + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutations", + "in", + "RPS19," + ] + } + } + ] + }, + { + "PMID": "24952646", + "TEXT": "Exposure to psychosocial stress is a risk factor for many diseases, including atherosclerosis. Although incompletely understood, interaction between the psyche and the immune system provides one potential mechanism linking stress and disease inception and progression. Known cross-talk between the brain and immune system includes the hypothalamic-pituitary-adrenal axis, which centrally drives glucocorticoid production in the adrenal cortex, and the sympathetic-adrenal-medullary axis, which controls stress-induced catecholamine release in support of the fight-or-flight reflex. It remains unknown, however, whether chronic stress changes hematopoietic stem cell activity. Here we show that stress increases proliferation of these most primitive hematopoietic progenitors, giving rise to higher levels of disease-promoting inflammatory leukocytes. We found that chronic stress induced monocytosis and neutrophilia in humans. While investigating the source of leukocytosis in mice, we discovered that stress activates upstream hematopoietic stem cells. Under conditions of chronic variable stress in mice, sympathetic nerve fibers released surplus noradrenaline, which signaled bone marrow niche cells to decrease CXCL12 levels through the β3-adrenergic receptor. Consequently, hematopoietic stem cell proliferation was elevated, leading to an increased output of neutrophils and inflammatory monocytes. When atherosclerosis-prone Apoe(-/-) mice were subjected to chronic stress, accelerated hematopoiesis promoted plaque features associated with vulnerable lesions that cause myocardial infarction and stroke in humans.", + "TAG_DATA": [ + "88, increases {'effect': 'B-positive'}", + "89, proliferation {'phenotype': 'B-proliferation'}", + "140, mice, {'context': 'B-organism'}", + "141, sympathetic {'context': 'B-cells'}", + "142, nerve {'context': 'I-cells'}", + "143, fibers {'context': 'I-cells'}", + "162, hematopoietic {'context': 'B-cells'}", + "163, stem {'context': 'I-cells'}", + "164, cell {'context': 'I-cells'}", + "165, proliferation {'phenotype': 'B-proliferation'}", + "167, elevated, {'effect': 'B-positive'}", + "179, atherosclerosis-prone {'perturbing_action': 'B-gene loss-of-function'}", + "180, Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "181, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "88, increases ['l0']", + "89, proliferation ['l0']", + "140, mice, ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "141, sympathetic ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "142, nerve ['l2', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "143, fibers ['l3', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "162, hematopoietic ['l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "163, stem ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "164, cell ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "165, proliferation ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "167, elevated, ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "179, atherosclerosis-prone ['l36', 'l37']", + "180, Apoe(-/-) ['l36', 'l38']", + "181, mice ['l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "increases", + "elevated," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "positive", + "words": [ + "elevated," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "sympathetic", + "nerve", + "fibers", + "hematopoietic", + "stem", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "sympathetic", + "nerve", + "fibers", + "hematopoietic", + "stem", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "elevated," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "atherosclerosis-prone", + "Apoe(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "24880616", + "TEXT": "Despite the fact that genitourinary defects are among the most common birth defects in newborns, little is known about their etiology. Here we analyzed children born with congenital genitourinary tract masculinization disorders by array-comparative genomic hybridization, which revealed in 1.35% of cases the presence of de novo copy number gains at Xq28 encompassing the VAMP7 gene, which encodes a vesicle-trafficking protein that is part of the SNARE complex. Transgenic mice carrying a bacterial artificial chromosome encoding human VAMP7 mimicked the defective urogenital traits observed in boys with masculinization disorders such as cryptorchidism, urethral defects and hypospadias. Transgenic mice also exhibited reduced penile length, focal spermatogenic anomalies, diminished sperm motility and subfertility. VAMP7 colocalized with estrogen receptor α (ESR1) in the presence of its cognate ligand, 17β-estradiol. Elevated levels of VAMP7 markedly intensified ESR1-potentiated transcriptional activity by increasing ESR1 protein cellular content upon ligand stimulation and upregulated the expression of estrogen-responsive genes including ATF3, CYR61 and CTGF, all of which have been implicated in human hypospadias. Hence, increased gene dosage of VAMP7, and thus higher expression levels of its protein product, enhances estrogen receptor action in male genitourinary tissues, affects the virilization of the reproductive tract and results in genitourinary birth defects in humans.", + "TAG_DATA": [ + "68, Transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "69, mice {'context': 'I-organism'}", + "70, carrying {'perturbing_action': 'B-gene gain-of-function'}", + "71, a {'perturbing_action': 'I-gene gain-of-function'}", + "72, bacterial {'perturbing_action': 'I-gene gain-of-function'}", + "73, artificial {'perturbing_action': 'I-gene gain-of-function'}", + "74, chromosome {'perturbing_action': 'I-gene gain-of-function'}", + "75, encoding {'perturbing_action': 'I-gene gain-of-function'}", + "76, human {'perturbing_action': 'I-gene gain-of-function'}", + "77, VAMP7 {'perturbing_action': 'I-gene gain-of-function'}", + "96, Transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "97, mice {'context': 'B-organism'}", + "106, diminished {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "68, Transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "69, mice ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "70, carrying ['l1', 'l9', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "71, a ['l2', 'l10', 'l15', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "72, bacterial ['l3', 'l16', 'l24', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "73, artificial ['l4', 'l17', 'l25', 'l34', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "74, chromosome ['l5', 'l11', 'l18', 'l26', 'l35', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "75, encoding ['l6', 'l12', 'l19', 'l27', 'l36', 'l44', 'l51', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "76, human ['l7', 'l13', 'l20', 'l28', 'l37', 'l45', 'l52', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "77, VAMP7 ['l8', 'l14', 'l21', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l69', 'l70']", + "96, Transgenic ['l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l71', 'l72', 'l73']", + "97, mice ['l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l71', 'l74', 'l75']", + "106, diminished ['l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l69', 'l72', 'l74', 'l76']", + "107, sperm ['l23', 'l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l70', 'l73', 'l75', 'l76']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgenic", + "carrying", + "a", + "chromosome", + "encoding", + "human", + "VAMP7", + "bacterial", + "artificial" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "carrying", + "a", + "bacterial", + "artificial", + "chromosome", + "encoding", + "human", + "VAMP7", + "Transgenic" + ] + }, + "effect": { + "val": "negative", + "words": [ + "diminished" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "diminished" + ] + } + } + ] + }, + { + "PMID": "24813250", + "TEXT": "We previously demonstrated that low biosynthesis of ω-3 fatty acid-derived proresolution mediators, termed protectins, is associated with an impaired global resolution capacity, inflammation and insulin resistance in obese high-fat diet-fed mice. These findings prompted a more direct study of the therapeutic potential of protectins for the treatment of metabolic disorders. Herein we show that protectin DX (PDX) exerts an unanticipated glucoregulatory activity that is distinct from its anti-inflammatory actions. We found that PDX selectively stimulated the release of the prototypic myokine interleukin-6 (IL-6) from skeletal muscle and thereby initiated a myokine-liver signaling axis, which blunted hepatic glucose production via signal transducer and activator of transcription 3 (STAT3)-mediated transcriptional suppression of the gluconeogenic program. These effects of PDX were abrogated in Il6-null mice. PDX also activated AMP-activated protein kinase (AMPK); however, it did so in an IL-6-independent manner. Notably, we demonstrated that administration of PDX to obese diabetic db/db mice raises skeletal muscle IL-6 levels and substantially improves their insulin sensitivity without any impact on adipose tissue inflammation. Our findings thus support the development of PDX-based selective muscle IL-6 secretagogues as a new class of therapy for the treatment of insulin resistance and type 2 diabetes.", + "TAG_DATA": [ + "84, skeletal {'context': 'B-tissue/organ'}", + "85, muscle {'context': 'I-tissue/organ'}", + "120, Il6-null {'perturbing_action': 'B-gene loss-of-function'}", + "121, mice. {'context': 'B-organism'}", + "145, obese {'context': 'B-organism'}", + "146, diabetic {'context': 'I-organism'}", + "147, db/db {'context': 'I-organism'}", + "148, mice {'context': 'I-organism'}", + "150, skeletal {'context': 'B-tissue/organ'}", + "151, muscle {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "84, skeletal ['l0']", + "85, muscle ['l0']", + "120, Il6-null ['l1']", + "121, mice. ['l1']", + "145, obese ['l2', 'l3', 'l4', 'l5', 'l6']", + "146, diabetic ['l2', 'l7', 'l8', 'l9', 'l10']", + "147, db/db ['l3', 'l7', 'l11', 'l12', 'l13']", + "148, mice ['l4', 'l8', 'l11', 'l14', 'l15']", + "150, skeletal ['l5', 'l9', 'l12', 'l14', 'l16']", + "151, muscle ['l6', 'l10', 'l13', 'l15', 'l16']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Il6-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "24813249", + "TEXT": "Epidemiological data point toward a critical period in early life during which environmental cues can set an individual on a trajectory toward respiratory health or disease. The neonatal immune system matures during this period, although little is known about the signals that lead to its maturation. Here we report that the formation of the lung microbiota is a key parameter in this process. Immediately following birth, neonatal mice were prone to develop exaggerated airway eosinophilia, release type 2 helper T cell cytokines and exhibit airway hyper-responsiveness following exposure to house dust mite allergens, even though their lungs harbored high numbers of natural CD4(+)Foxp3(+)CD25(+)Helios(+) regulatory T (Treg) cells. During the first 2 weeks after birth, the bacterial load in the lungs increased, and representation of the bacterial phyla shifts from a predominance of Gammaproteobacteria and Firmicutes towards Bacteroidetes. The changes in the microbiota were associated with decreased aeroallergen responsiveness and the emergence of a Helios(-) Treg cell subset that required interaction with programmed death ligand 1 (PD-L1) for development. Absence of microbial colonization(10) or blockade of PD-L1 during the first 2 weeks postpartum maintained exaggerated responsiveness to allergens through to adulthood. Adoptive transfer of Treg cells from adult mice to neonates before aeroallergen exposure ameliorated disease. Thus, formation of the airway microbiota induces regulatory cells early in life, which, when dysregulated, can lead to sustained susceptibility to allergic airway inflammation in adulthood.", + "TAG_DATA": [ + "66, neonatal {'context': 'B-organism'}", + "67, mice {'context': 'I-organism'}", + "96, lungs {'context': 'B-tissue/organ'}", + "119, lungs {'context': 'B-tissue/organ'}", + "153, Helios(-) {'context': 'B-cells'}", + "154, Treg {'context': 'I-cells'}", + "155, cell {'context': 'I-cells'}", + "156, subset {'context': 'I-cells'}", + "173, blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "174, of {'perturbing_action': 'I-pharmacological inhibition'}", + "175, PD-L1 {'perturbing_action': 'I-pharmacological inhibition'}", + "193, Treg {'context': 'B-cells'}", + "194, cells {'context': 'I-cells'}", + "196, adult {'context': 'B-organism'}", + "197, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "66, neonatal ['l0', 'l1']", + "67, mice ['l0', 'l2']", + "96, lungs ['l1', 'l2', 'l3']", + "119, lungs ['l3', 'l4']", + "153, Helios(-) ['l5', 'l6', 'l7']", + "154, Treg ['l5', 'l8', 'l9']", + "155, cell ['l4', 'l6', 'l8', 'l10']", + "156, subset ['l7', 'l9', 'l10']", + "173, blockade ['l11', 'l12', 'l13']", + "174, of ['l11', 'l14', 'l15']", + "175, PD-L1 ['l12', 'l14', 'l16']", + "193, Treg ['l17', 'l18', 'l19']", + "194, cells ['l13', 'l15', 'l16', 'l17', 'l20', 'l21']", + "196, adult ['l18', 'l20', 'l22']", + "197, mice ['l19', 'l21', 'l22']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "PD-L1" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "24784232", + "TEXT": "Interferon-α (IFN-α) is essential for antiviral immunity, but in the absence of matrix metalloproteinase-12 (MMP-12) or IκBα (encoded by NFKBIA) we show that IFN-α is retained in the cytosol of virus-infected cells and is not secreted. Our findings suggest that activated IκBα mediates the export of IFN-α from virus-infected cells and that the inability of cells in Mmp12(-/-) but not wild-type mice to express IκBα and thus export IFN-α makes coxsackievirus type B3 infection lethal and renders respiratory syncytial virus more pathogenic. We show here that after macrophage secretion, MMP-12 is transported into virus-infected cells. In HeLa cells MMP-12 is also translocated to the nucleus, where it binds to the NFKBIA promoter, driving transcription. We also identified dual-regulated substrates that are repressed both by MMP-12 binding to the substrate's gene exons and by MMP-12-mediated cleavage of the substrate protein itself. Whereas intracellular MMP-12 mediates NFKBIA transcription, leading to IFN-α secretion and host protection, extracellular MMP-12 cleaves off the IFN-α receptor 2 binding site of systemic IFN-α, preventing an unchecked immune response. Consistent with an unexpected role for MMP-12 in clearing systemic IFN-α, treatment of coxsackievirus type B3-infected wild-type mice with a membrane-impermeable MMP-12 inhibitor elevates systemic IFN-α levels and reduces viral replication in pancreas while sparing intracellular MMP-12. These findings suggest that inhibiting extracellular MMP-12 could be a new avenue for the development of antiviral treatments.", + "TAG_DATA": [ + "55, cells {'context': 'B-cells'}", + "57, Mmp12(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "61, mice {'context': 'B-organism'}", + "188, mice {'context': 'B-organism'}", + "191, membrane-impermeable {'perturbing_action': 'B-pharmacological inhibition'}", + "192, MMP-12 {'perturbing_action': 'I-pharmacological inhibition'}", + "193, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "203, pancreas {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "55, cells ['l0', 'l1', 'l2']", + "57, Mmp12(-/-) ['l0', 'l3', 'l4']", + "61, mice ['l1', 'l3', 'l5']", + "97, cells ['l2', 'l4', 'l5']", + "188, mice ['l6', 'l7', 'l8', 'l9']", + "191, membrane-impermeable ['l6', 'l10', 'l11', 'l12']", + "192, MMP-12 ['l7', 'l10', 'l13', 'l14']", + "193, inhibitor ['l8', 'l11', 'l13', 'l15']", + "203, pancreas ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mmp12(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mmp12(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "membrane-impermeable", + "MMP-12", + "inhibitor" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "membrane-impermeable", + "MMP-12", + "inhibitor" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "pancreas" + ] + } + } + ] + }, + { + "PMID": "24747746", + "TEXT": "Inflammation has a critical role in the development of insulin resistance. Recent evidence points to a contribution by the central nervous system in the modulation of peripheral inflammation through the anti-inflammatory reflex. However, the importance of this phenomenon remains elusive in type 2 diabetes pathogenesis. Here we show that rat insulin-2 promoter (Rip)-mediated deletion of Pten, a gene encoding a negative regulator of PI3K signaling, led to activation of the cholinergic anti-inflammatory pathway that is mediated by M2 activated macrophages in peripheral tissues. As such, Rip-cre(+) Pten(flox/flox) mice showed lower systemic inflammation and greater insulin sensitivity under basal conditions compared to littermate controls, which were abolished when the mice were treated with an acetylcholine receptor antagonist or when macrophages were depleted. After feeding with a high-fat diet, the Pten-deleted mice remained markedly insulin sensitive, which correlated with massive subcutaneous fat expansion. They also exhibited more adipogenesis with M2 macrophage infiltration, both of which were abolished after disruption of the anti-inflammatory efferent pathway by left vagotomy. In summary, we show that Pten expression in Rip(+) neurons has a critical role in diabetes pathogenesis through mediating the anti-inflammatory reflex.", + "TAG_DATA": [ + "49, rat {'perturbing_action': 'B-gene loss-of-function'}", + "50, insulin-2 {'perturbing_action': 'I-gene loss-of-function'}", + "51, promoter {'perturbing_action': 'I-gene loss-of-function'}", + "52, (Rip)-mediated {'perturbing_action': 'I-gene loss-of-function'}", + "53, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "54, of {'perturbing_action': 'I-gene loss-of-function'}", + "55, Pten, {'perturbing_action': 'I-gene loss-of-function'}", + "85, Rip-cre(+) {'perturbing_action': 'B-gene loss-of-function'}", + "86, Pten(flox/flox) {'perturbing_action': 'I-gene loss-of-function'}", + "87, mice {'context': 'B-organism'}", + "108, mice {'context': 'B-organism'}", + "118, macrophages {'context': 'B-cells'}", + "128, Pten-deleted {'perturbing_action': 'B-gene loss-of-function'}", + "129, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "49, rat ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "50, insulin-2 ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "51, promoter ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "52, (Rip)-mediated ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "53, deletion ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "54, of ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "55, Pten, ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "85, Rip-cre(+) ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "86, Pten(flox/flox) ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "87, mice ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "108, mice ['l45']", + "118, macrophages ['l45']", + "128, Pten-deleted ['l46']", + "129, mice ['l46']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "rat", + "insulin-2", + "promoter", + "(Rip)-mediated", + "deletion", + "of", + "Pten,", + "Rip-cre(+)", + "Pten(flox/flox)", + "Pten-deleted" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "24747745", + "TEXT": "Vaccination has been the most widely used strategy to protect against viral infections for centuries. However, the molecular mechanisms governing the long-term persistence of immunological memory in response to vaccines remain unclear. Here we show that autophagy has a critical role in the maintenance of memory B cells that protect against influenza virus infection. Memory B cells displayed elevated levels of basal autophagy with increased expression of genes that regulate autophagy initiation or autophagosome maturation. Mice with B cell-specific deletion of Atg7 (B/Atg7(-/-) mice) showed normal primary antibody responses after immunization against influenza but failed to generate protective secondary antibody responses when challenged with influenza viruses, resulting in high viral loads, widespread lung destruction and increased fatality. Our results suggest that autophagy is essential for the survival of virus-specific memory B cells in mice and the maintenance of protective antibody responses required to combat infections.", + "TAG_DATA": [ + "54, Memory {'context': 'B-cells'}", + "55, B {'context': 'I-cells'}", + "56, cells {'context': 'I-cells'}", + "62, autophagy {'phenotype': 'B-autophagy'}", + "75, Mice {'context': 'B-organism'}", + "77, B {'perturbing_action': 'B-gene loss-of-function'}", + "78, cell-specific {'perturbing_action': 'I-gene loss-of-function'}", + "79, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "80, of {'perturbing_action': 'I-gene loss-of-function'}", + "81, Atg7 {'perturbing_action': 'I-gene loss-of-function'}", + "82, (B/Atg7(-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "83, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "112, lung {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "54, Memory ['l0', 'l1', 'l2']", + "55, B ['l0', 'l3', 'l4']", + "56, cells ['l1', 'l3', 'l5']", + "62, autophagy ['l2', 'l4', 'l5']", + "75, Mice ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "77, B ['l6', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "78, cell-specific ['l7', 'l14', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "79, deletion ['l8', 'l15', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "80, of ['l9', 'l16', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "81, Atg7 ['l10', 'l17', 'l23', 'l28', 'l32', 'l36', 'l37', 'l38']", + "82, (B/Atg7(-/-) ['l11', 'l18', 'l24', 'l29', 'l33', 'l36', 'l39', 'l40']", + "83, mice) ['l12', 'l19', 'l25', 'l30', 'l34', 'l37', 'l39', 'l41']", + "112, lung ['l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Memory", + "B", + "cells" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "B", + "cell-specific", + "deletion", + "of", + "Atg7", + "(B/Atg7(-/-)", + "mice)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "B", + "cell-specific", + "deletion", + "of", + "Atg7", + "(B/Atg7(-/-)", + "mice)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + } + ] + }, + { + "PMID": "24743305", + "TEXT": "Interleukin-10 (IL-10)-producing regulatory B (Breg) cells suppress autoimmune disease, and increased numbers of Breg cells prevent host defense to infection and promote tumor growth and metastasis by converting resting CD4(+) T cells to regulatory T (Treg) cells. The mechanisms mediating the induction and development of Breg cells remain unclear. Here we show that IL-35 induces Breg cells and promotes their conversion to a Breg subset that produces IL-35 as well as IL-10. Treatment of mice with IL-35 conferred protection from experimental autoimmune uveitis (EAU), and mice lacking IL-35 (p35 knockout (KO) mice) or defective in IL-35 signaling (IL-12Rβ2 KO mice) produced less Breg cells endogenously or after treatment with IL-35 and developed severe uveitis. Adoptive transfer of Breg cells induced by recombinant IL-35 suppressed EAU when transferred to mice with established disease, inhibiting pathogenic T helper type 17 (TH17) and TH1 cells while promoting Treg cell expansion. In B cells, IL-35 activates STAT1 and STAT3 through the IL-35 receptor comprising the IL-12Rβ2 and IL-27Rα subunits. As IL-35 also induced the conversion of human B cells into Breg cells, these findings suggest that IL-35 may be used to induce autologous Breg and IL-35(+) Breg cells and treat autoimmune and inflammatory disease.", + "TAG_DATA": [ + "74, mice {'context': 'B-organism'}", + "85, mice {'context': 'B-organism'}", + "86, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "87, IL-35 {'perturbing_action': 'I-gene loss-of-function'}", + "88, (p35 {'perturbing_action': 'I-gene loss-of-function'}", + "89, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "90, (KO) {'perturbing_action': 'I-gene loss-of-function'}", + "91, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "97, (IL-12Rβ2 {'perturbing_action': 'I-gene loss-of-function'}", + "98, KO {'perturbing_action': 'I-gene loss-of-function'}", + "99, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "102, Breg {'context': 'B-cells'}", + "103, cells {'context': 'I-cells'}", + "117, Breg {'context': 'B-cells'}", + "118, cells {'context': 'I-cells'}", + "128, mice {'context': 'B-organism'}", + "135, helper {'context': 'I-cells'}", + "136, type {'context': 'I-cells'}", + "139, and {'context': 'I-cells'}", + "140, TH1 {'context': 'I-cells'}", + "141, cells {'context': 'I-cells'}", + "144, Treg {'context': 'B-cells'}", + "145, cell {'context': 'I-cells'}", + "148, B {'context': 'B-cells'}", + "149, cells, {'context': 'I-cells'}", + "172, human {'context': 'B-cells'}", + "173, B {'context': 'I-cells'}", + "174, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "85, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "86, lacking ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "87, IL-35 ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "88, (p35 ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "89, knockout ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "90, (KO) ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "91, mice) ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "97, (IL-12Rβ2 ['l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "98, KO ['l35', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "99, mice) ['l36', 'l47', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "102, Breg ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l37', 'l48', 'l58', 'l68']", + "103, cells ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l38', 'l49', 'l59', 'l68']", + "117, Breg ['l39', 'l50', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "118, cells ['l40', 'l51', 'l61', 'l69', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "128, mice ['l41', 'l52', 'l62', 'l70', 'l79', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "135, helper ['l42', 'l53', 'l63', 'l71', 'l80', 'l86', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "136, type ['l43', 'l54', 'l64', 'l72', 'l81', 'l87', 'l94', 'l100', 'l101', 'l102', 'l103', 'l104']", + "139, and ['l44', 'l55', 'l65', 'l73', 'l82', 'l88', 'l95', 'l100', 'l105', 'l106', 'l107']", + "140, TH1 ['l45', 'l56', 'l66', 'l74', 'l83', 'l89', 'l96', 'l101', 'l105', 'l108', 'l109', 'l110', 'l111']", + "141, cells ['l46', 'l57', 'l67', 'l75', 'l84', 'l90', 'l97', 'l102', 'l106', 'l108', 'l112']", + "144, Treg ['l76', 'l91', 'l109', 'l113', 'l114', 'l115']", + "145, cell ['l77', 'l85', 'l92', 'l98', 'l103', 'l107', 'l110', 'l112', 'l113', 'l116', 'l117']", + "148, B ['l114', 'l116', 'l118', 'l119', 'l120', 'l121']", + "149, cells, ['l78', 'l93', 'l99', 'l104', 'l111', 'l115', 'l117', 'l118', 'l122', 'l123']", + "172, human ['l119', 'l124', 'l125']", + "173, B ['l120', 'l122', 'l124', 'l126']", + "174, cells ['l121', 'l123', 'l125', 'l126']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "IL-35", + "(p35", + "knockout", + "(KO)", + "mice)", + "(IL-12Rβ2", + "KO" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "IL-35", + "(p35", + "knockout", + "(KO)", + "mice)", + "(IL-12Rβ2", + "KO" + ] + }, + "context": { + "val": "cells", + "words": [ + "Breg", + "cells", + "helper", + "type", + "and", + "TH1" + ] + } + } + ] + }, + { + "PMID": "24658075", + "TEXT": "In response to microbial infection, expression of the defensin-like peptide hepcidin (encoded by Hamp) is induced in hepatocytes to decrease iron release from macrophages. To elucidate the mechanism by which Salmonella enterica var. Typhimurium (S. typhimurium), an intramacrophage bacterium, alters host iron metabolism for its own survival, we examined the role of nuclear receptor family members belonging to the NR3B subfamily in mouse hepatocytes. Here, we report that estrogen-related receptor γ (ERRγ, encoded by Esrrg) modulates the intramacrophage proliferation of S. typhimurium by altering host iron homeostasis, and we demonstrate an antimicrobial effect of an ERRγ inverse agonist. Hepatic ERRγ expression was induced by S. typhimurium-stimulated interleukin-6 signaling, resulting in an induction of hepcidin and eventual hypoferremia in mice. Conversely, ablation of ERRγ mRNA expression in liver attenuated the S. typhimurium-mediated induction of hepcidin and normalized the hypoferremia caused by S. typhimurium infection. An inverse agonist of ERRγ ameliorated S. typhimurium-mediated hypoferremia through reduction of ERRγ-mediated hepcidin mRNA expression and exerted a potent antimicrobial effect on the S. typhimurium infection, thereby improving host survival. Taken together, these findings suggest an alternative approach to control multidrug-resistant intracellular bacteria by modulating host iron homeostasis.", + "TAG_DATA": [ + "118, mice. {'context': 'B-organism'}", + "120, ablation {'perturbing_action': 'B-gene loss-of-function'}", + "121, of {'perturbing_action': 'I-gene loss-of-function'}", + "122, ERRγ {'perturbing_action': 'I-gene loss-of-function'}", + "123, mRNA {'perturbing_action': 'I-gene loss-of-function'}", + "124, expression {'perturbing_action': 'I-gene loss-of-function'}", + "126, liver {'context': 'B-tissue/organ'}", + "144, inverse {'perturbing_action': 'B-pharmacological augmentation'}", + "145, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "146, of {'perturbing_action': 'I-pharmacological augmentation'}", + "147, ERRγ {'perturbing_action': 'I-pharmacological augmentation'}" + ], + "LINK_DATA": [ + "120, ablation ['l0', 'l1', 'l2', 'l3', 'l4']", + "121, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "122, ERRγ ['l1', 'l5', 'l9', 'l10', 'l11']", + "123, mRNA ['l2', 'l6', 'l9', 'l12', 'l13']", + "124, expression ['l3', 'l7', 'l10', 'l12', 'l14']", + "126, liver ['l4', 'l8', 'l11', 'l13', 'l14']", + "144, inverse ['l15', 'l16', 'l17']", + "145, agonist ['l15', 'l18', 'l19']", + "146, of ['l16', 'l18', 'l20']", + "147, ERRγ ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablation", + "of", + "ERRγ", + "mRNA", + "expression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "24562381", + "TEXT": "Previous anti-inflammatory strategies against sepsis, a leading cause of death in hospitals, had limited efficacy in clinical trials, in part because they targeted single cytokines and the experimental models failed to mimic clinical settings. Neuronal networks represent physiological mechanisms, selected by evolution to control inflammation, that can be exploited for the treatment of inflammatory and infectious disorders. Here, we report that sciatic nerve activation with electroacupuncture controls systemic inflammation and rescues mice from polymicrobial peritonitis. Electroacupuncture at the sciatic nerve controls systemic inflammation by inducing vagal activation of aromatic L-amino acid decarboxylase, leading to the production of dopamine in the adrenal medulla. Experimental models with adrenolectomized mice mimic clinical adrenal insufficiency, increase the susceptibility to sepsis and prevent the anti-inflammatory effects of electroacupuncture. Dopamine inhibits cytokine production via dopamine type 1 (D1) receptors. D1 receptor agonists suppress systemic inflammation and rescue mice with adrenal insufficiency from polymicrobial peritonitis. Our results suggest a new anti-inflammatory mechanism mediated by the sciatic and vagus nerves that modulates the production of catecholamines in the adrenal glands. From a pharmacological perspective, the effects of selective dopamine agonists mimic the anti-inflammatory effects of electroacupuncture and can provide therapeutic advantages to control inflammation in infectious and inflammatory disorders.", + "TAG_DATA": [ + "71, mice {'context': 'B-organism'}", + "106, mice {'context': 'B-organism'}", + "135, agonists {'perturbing_action': 'I-pharmacological augmentation'}", + "141, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "135, agonists ['l0']", + "141, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "agonists" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "24336247", + "TEXT": "Hypercholesterolemia, typically due to excessive cholesterol uptake, is a major risk factor for cardiovascular disease, which is responsible for ∼50% of all deaths in developed societies. Although it has been shown that intestinal cholesterol absorption is mediated by vesicular endocytosis of the Niemann-Pick C1-like 1 (NPC1L1) protein, the mechanism of sterol-stimulated NPC1L1 internalization is still mysterious. Here, we identified an endocytic peptide signal, YVNXXF (where X stands for any amino acid), in the cytoplasmic C-terminal tail of NPC1L1. Cholesterol binding on the N-terminal domain of NPC1L1 released the YVNXXF-containing region of NPC1L1 from association with the plasma membrane and enabled Numb binding. We also found that Numb, a clathrin adaptor, specifically recognized this motif and recruited clathrin for internalization. Disrupting the NPC1L1-Numb interaction decreased cholesterol uptake. Ablation of Numb in mouse intestine significantly reduced dietary cholesterol absorption and plasma cholesterol level. Together, these data show that Numb is a pivotal protein for intestinal cholesterol absorption and may provide a therapeutic target for hypercholesterolemia.", + "TAG_DATA": [ + "126, Ablation {'perturbing_action': 'B-gene loss-of-function'}", + "127, of {'perturbing_action': 'I-gene loss-of-function'}", + "128, Numb {'perturbing_action': 'I-gene loss-of-function'}", + "130, mouse {'context': 'B-tissue/organ'}", + "131, intestine {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "126, Ablation ['l0', 'l1', 'l2', 'l3']", + "127, of ['l0', 'l4', 'l5', 'l6']", + "128, Numb ['l1', 'l4', 'l7', 'l8']", + "130, mouse ['l2', 'l5', 'l7', 'l9']", + "131, intestine ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "Numb" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "intestine" + ] + } + } + ] + }, + { + "PMID": "24317118", + "TEXT": "Human CD4(+)CD25(high)CD127(-)FoxP3(+) regulatory T (Treg) cells suppress immune responses in vitro and in vivo. Reduced suppressive function and/or number of peripheral Treg cells has been previously reported in autoimmune disorders. Treg cells represent the most actively replicating compartment within the CD4(+) cells in vivo, but they are hyporesponsive to classical T cell receptor (TCR) stimulation in vitro, a condition that is secondary to their overactive metabolic state. Here we report that proliferation of Treg cells after TCR stimulation is impaired in subjects with relapsing-remitting multiple sclerosis (RRMS) because of altered interleukin-2 (IL-2) secretion and IL-2 receptor (IL-2R)-signal transducer and activator of transcription 5 (STAT5) signaling. This is associated with decreased expression of the forkhead box P3 (FoxP3) 44- and 47-kDa splicing forms, overactivation of S6 ribosomal protein (a downstream target of the mammalian target of rapamycin, mTOR) and altered activity of the cyclin-dependent kinase inhibitor p27 (p27(kip1)) and extracellular signal-related kinases 1 and 2 (ERK1/2). The impaired capacity of Treg cells to proliferate in RRMS correlates with the clinical state of the subject, where increasing disease severity is associated with a decline in Treg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of Treg cells in autoimmune disease.", + "TAG_DATA": [ + "71, proliferation {'phenotype': 'B-proliferation'}", + "73, Treg {'context': 'B-cells'}", + "74, cells {'context': 'I-cells'}", + "79, impaired {'effect': 'B-negative'}", + "156, impaired {'effect': 'B-negative'}", + "157, capacity {'effect': 'I-negative'}", + "159, Treg {'context': 'B-cells'}", + "160, cells {'context': 'I-cells'}", + "162, proliferate {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "71, proliferation ['l0', 'l1', 'l2']", + "73, Treg ['l0', 'l3', 'l4']", + "74, cells ['l1', 'l3', 'l5']", + "79, impaired ['l2', 'l4', 'l5']", + "156, impaired ['l6', 'l7', 'l8', 'l9']", + "157, capacity ['l6', 'l10', 'l11', 'l12']", + "159, Treg ['l7', 'l10', 'l13', 'l14']", + "160, cells ['l8', 'l11', 'l13', 'l15']", + "162, proliferate ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation", + "proliferate" + ] + }, + "context": { + "val": "cells", + "words": [ + "Treg", + "cells" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation", + "proliferate" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired", + "capacity" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Treg", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired", + "capacity" + ] + } + } + ] + }, + { + "PMID": "24162815", + "TEXT": "We identified new gene fusions in patients with lung cancer harboring the kinase domain of the NTRK1 gene that encodes the high-affinity nerve growth factor receptor (TRKA protein). Both the MPRIP-NTRK1 and CD74-NTRK1 fusions lead to constitutive TRKA kinase activity and are oncogenic. Treatment of cells expressing NTRK1 fusions with inhibitors of TRKA kinase activity inhibited autophosphorylation of TRKA and cell growth. Tumor samples from 3 of 91 patients with lung cancer (3.3%) without known oncogenic alterations assayed by next-generation sequencing or fluorescence in situ hybridization demonstrated evidence of NTRK1 gene fusions.", + "TAG_DATA": [ + "45, cells {'context': 'B-cells'}", + "55, inhibited {'effect': 'B-negative'}", + "60, cell {'phenotype': 'B-cell growth'}", + "61, growth. {'phenotype': 'I-cell growth'}" + ], + "LINK_DATA": [ + "45, cells ['l0', 'l1', 'l2']", + "55, inhibited ['l0', 'l3', 'l4']", + "60, cell ['l1', 'l3', 'l5']", + "61, growth. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth." + ] + } + } + ] + }, + { + "PMID": "24097189", + "TEXT": "A systemic inflammatory response is observed in patients undergoing hemorrhagic shock and sepsis. Here we report increased levels of cold-inducible RNA-binding protein (CIRP) in the blood of individuals admitted to the surgical intensive care unit with hemorrhagic shock. In animal models of hemorrhage and sepsis, CIRP is upregulated in the heart and liver and released into the circulation. In macrophages under hypoxic stress, CIRP translocates from the nucleus to the cytosol and is released. Recombinant CIRP stimulates the release of tumor necrosis factor-α (TNF-α) and HMGB1 from macrophages and induces inflammatory responses and causes tissue injury when injected in vivo. Hemorrhage-induced TNF-α and HMGB1 release and lethality were reduced in CIRP-deficient mice. Blockade of CIRP using antisera to CIRP attenuated inflammatory cytokine release and mortality after hemorrhage and sepsis. The activity of extracellular CIRP is mediated through the Toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex. Surface plasmon resonance analysis indicated that CIRP binds to the TLR4-MD2 complex, as well as to TLR4 and MD2 individually. In particular, human CIRP amino acid residues 106-125 bind to MD2 with high affinity. Thus, CIRP is a damage-associated molecular pattern molecule that promotes inflammatory responses in shock and sepsis.", + "TAG_DATA": [ + "87, macrophages {'context': 'B-cells'}", + "98, in {'context': 'B-in vivo'}", + "99, vivo. {'context': 'I-in vivo'}", + "110, CIRP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "111, mice. {'context': 'B-organism'}", + "112, Blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "113, of {'perturbing_action': 'I-pharmacological inhibition'}", + "114, CIRP {'perturbing_action': 'I-pharmacological inhibition'}", + "115, using {'perturbing_action': 'I-pharmacological inhibition'}", + "116, antisera {'perturbing_action': 'I-pharmacological inhibition'}", + "117, to {'perturbing_action': 'I-pharmacological inhibition'}", + "118, CIRP {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "87, macrophages ['l0', 'l1']", + "98, in ['l0', 'l2']", + "99, vivo. ['l1', 'l2']", + "110, CIRP-deficient ['l3']", + "111, mice. ['l3']", + "112, Blockade ['l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "113, of ['l4', 'l10', 'l11', 'l12', 'l13', 'l14']", + "114, CIRP ['l5', 'l10', 'l15', 'l16', 'l17', 'l18']", + "115, using ['l6', 'l11', 'l15', 'l19', 'l20', 'l21']", + "116, antisera ['l7', 'l12', 'l16', 'l19', 'l22', 'l23']", + "117, to ['l8', 'l13', 'l17', 'l20', 'l22', 'l24']", + "118, CIRP ['l9', 'l14', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CIRP-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "24056773", + "TEXT": "Glioblastoma multiforme (GBM) comprises several molecular subtypes, including proneural GBM. Most therapeutic approaches targeting glioma cells have failed. An alternative strategy is to target cells in the glioma microenvironment, such as tumor-associated macrophages and microglia (TAMs). Macrophages depend on colony stimulating factor-1 (CSF-1) for differentiation and survival. We used an inhibitor of the CSF-1 receptor (CSF-1R) to target TAMs in a mouse proneural GBM model, which significantly increased survival and regressed established tumors. CSF-1R blockade additionally slowed intracranial growth of patient-derived glioma xenografts. Surprisingly, TAMs were not depleted in treated mice. Instead, glioma-secreted factors, including granulocyte-macrophage CSF (GM-CSF) and interferon-γ (IFN-γ), facilitated TAM survival in the context of CSF-1R inhibition. Expression of alternatively activated M2 markers decreased in surviving TAMs, which is consistent with impaired tumor-promoting functions. These gene signatures were associated with enhanced survival in patients with proneural GBM. Our results identify TAMs as a promising therapeutic target for proneural gliomas and establish the translational potential of CSF-1R inhibition for GBM.", + "TAG_DATA": [ + "50, inhibitor {'perturbing_action': 'B-pharmacological inhibition'}", + "51, of {'perturbing_action': 'I-pharmacological inhibition'}", + "52, the {'perturbing_action': 'I-pharmacological inhibition'}", + "53, CSF-1 {'perturbing_action': 'I-pharmacological inhibition'}", + "54, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "55, (CSF-1R) {'perturbing_action': 'I-pharmacological inhibition'}", + "61, mouse {'context': 'B-neoplasm'}", + "62, proneural {'context': 'I-neoplasm'}", + "63, GBM {'context': 'I-neoplasm'}", + "64, model, {'context': 'I-neoplasm'}", + "72, tumors. {'context': 'B-neoplasm'}", + "80, patient-derived {'context': 'B-xenograft'}", + "81, glioma {'context': 'I-xenograft'}", + "82, xenografts. {'context': 'I-xenograft'}", + "84, TAMs {'context': 'B-cells'}", + "90, mice. {'context': 'B-organism'}", + "102, TAM {'context': 'B-cells'}", + "108, CSF-1R {'perturbing_action': 'B-pharmacological inhibition'}", + "109, inhibition. {'perturbing_action': 'I-pharmacological inhibition'}", + "119, TAMs, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "50, inhibitor ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "51, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "52, the ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "53, CSF-1 ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "54, receptor ['l3', 'l15', 'l26', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "55, (CSF-1R) ['l4', 'l16', 'l27', 'l37', 'l45', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "61, mouse ['l5', 'l17', 'l28', 'l38', 'l46', 'l53', 'l60', 'l61', 'l62', 'l63', 'l64']", + "62, proneural ['l6', 'l18', 'l29', 'l39', 'l47', 'l54', 'l60', 'l65', 'l66', 'l67', 'l68']", + "63, GBM ['l7', 'l19', 'l30', 'l40', 'l48', 'l55', 'l61', 'l65', 'l69', 'l70', 'l71']", + "64, model, ['l8', 'l20', 'l31', 'l41', 'l49', 'l56', 'l62', 'l66', 'l69', 'l72', 'l73']", + "70, regressed ['l9', 'l21', 'l32', 'l42', 'l50', 'l57', 'l63', 'l67', 'l70', 'l72', 'l74']", + "72, tumors. ['l10', 'l22', 'l33', 'l43', 'l51', 'l58', 'l64', 'l68', 'l71', 'l73', 'l74']", + "80, patient-derived ['l75', 'l76']", + "81, glioma ['l11', 'l23', 'l34', 'l44', 'l52', 'l59', 'l75', 'l77']", + "82, xenografts. ['l12', 'l24', 'l35', 'l76', 'l77']", + "84, TAMs ['l78']", + "90, mice. ['l78']", + "102, TAM ['l79', 'l80']", + "108, CSF-1R ['l79', 'l81']", + "109, inhibition. ['l80', 'l81']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitor", + "of", + "the", + "CSF-1", + "receptor", + "(CSF-1R)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "proneural", + "GBM", + "model,", + "tumors." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitor", + "of", + "the", + "CSF-1", + "receptor", + "(CSF-1R)" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "glioma", + "xenografts." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "TAM" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CSF-1R", + "inhibition." + ] + } + } + ] + }, + { + "PMID": "24037094", + "TEXT": "Insulin initiates diverse hepatic metabolic responses, including gluconeogenic suppression and induction of glycogen synthesis and lipogenesis. The liver possesses a rich sinusoidal capillary network with a higher degree of hypoxia and lower gluconeogenesis in the perivenous zone as compared to the rest of the organ. Here, we show that diverse vascular endothelial growth factor (VEGF) inhibitors improved glucose tolerance in nondiabetic C57BL/6 and diabetic db/db mice, potentiating hepatic insulin signaling with lower gluconeogenic gene expression, higher glycogen storage and suppressed hepatic glucose production. VEGF inhibition induced hepatic hypoxia through sinusoidal vascular regression and sensitized liver insulin signaling through hypoxia-inducible factor-2α (Hif-2α, encoded by Epas1) stabilization. Notably, liver-specific constitutive activation of HIF-2α, but not HIF-1α, was sufficient to augment hepatic insulin signaling through direct and indirect induction of insulin receptor substrate-2 (Irs2), an essential insulin receptor adaptor protein. Further, liver Irs2 was both necessary and sufficient to mediate Hif-2α and Vegf inhibition effects on glucose tolerance and hepatic insulin signaling. These results demonstrate an unsuspected intersection between Hif-2α-mediated hypoxic signaling and hepatic insulin action through Irs2 induction, which can be co-opted by Vegf inhibitors to modulate glucose metabolism. These studies also indicate distinct roles in hepatic metabolism for Hif-1α, which promotes glycolysis, and Hif-2α, which suppresses gluconeogenesis, and suggest new treatment approaches for type 2 diabetes mellitus.", + "TAG_DATA": [ + "50, vascular {'perturbing_action': 'B-pharmacological inhibition'}", + "51, endothelial {'perturbing_action': 'I-pharmacological inhibition'}", + "52, growth {'perturbing_action': 'I-pharmacological inhibition'}", + "53, factor {'perturbing_action': 'I-pharmacological inhibition'}", + "54, (VEGF) {'perturbing_action': 'I-pharmacological inhibition'}", + "55, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "60, nondiabetic {'context': 'B-organism'}", + "61, C57BL/6 {'context': 'I-organism'}", + "63, diabetic {'context': 'B-organism'}", + "64, db/db {'context': 'I-organism'}", + "65, mice, {'context': 'I-organism'}", + "94, liver {'context': 'B-tissue/organ'}", + "106, liver-specific {'perturbing_action': 'B-gene gain-of-function'}", + "107, constitutive {'perturbing_action': 'I-gene gain-of-function'}", + "108, activation {'perturbing_action': 'I-gene gain-of-function'}", + "109, of {'perturbing_action': 'I-gene gain-of-function'}", + "110, HIF-2α, {'perturbing_action': 'I-gene gain-of-function'}", + "138, liver {'context': 'B-tissue/organ'}", + "149, Vegf {'perturbing_action': 'B-pharmacological inhibition'}", + "150, inhibition {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "50, vascular ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "51, endothelial ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "52, growth ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "53, factor ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "54, (VEGF) ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "55, inhibitors ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "60, nondiabetic ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "61, C57BL/6 ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "63, diabetic ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "64, db/db ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "65, mice, ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "106, liver-specific ['l55', 'l56', 'l57', 'l58']", + "107, constitutive ['l55', 'l59', 'l60', 'l61']", + "108, activation ['l56', 'l59', 'l62', 'l63']", + "109, of ['l57', 'l60', 'l62', 'l64']", + "110, HIF-2α, ['l58', 'l61', 'l63', 'l64']", + "138, liver ['l65', 'l66']", + "149, Vegf ['l65', 'l67']", + "150, inhibition ['l66', 'l67']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "vascular", + "endothelial", + "growth", + "factor", + "(VEGF)", + "inhibitors" + ] + }, + "context": { + "val": "organism", + "words": [ + "nondiabetic", + "C57BL/6", + "diabetic", + "db/db", + "mice," + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Vegf", + "inhibition" + ] + } + } + ] + }, + { + "PMID": "23955714", + "TEXT": "α-secretase-mediated cleavage of amyloid precursor protein (APP) precludes formation of neurotoxic amyloid-β (Aβ) peptides, and α-cleavage of cellular prion protein (PrP(C)) prevents its conversion into misfolded, pathogenic prions (PrP(Sc)). The mechanisms leading to decreased α-secretase activity in Alzheimer's and prion disease remain unclear. Here, we find that tumor necrosis factor-α-converting enzyme (TACE)-mediated α-secretase activity is impaired at the surface of neurons infected with PrP(Sc) or isolated from APP-transgenic mice with amyloid pathology. 3-phosphoinositide-dependent kinase-1 (PDK1) activity is increased in neurons infected with prions or affected by Aβ deposition and in the brains of individuals with Alzheimer's disease. PDK1 induces phosphorylation and caveolin-1-mediated internalization of TACE. This dysregulation of TACE increases PrP(Sc) and Aβ accumulation and reduces shedding of TNF-α receptor type 1 (TNFR1). Inhibition of PDK1 promotes localization of TACE to the plasma membrane, restores TACE-dependent α-secretase activity and cleavage of APP, PrP(C) and TNFR1, and attenuates PrP(Sc)- and Aβ-induced neurotoxicity. In mice, inhibition or siRNA-mediated silencing of PDK1 extends survival and reduces motor impairment following PrP(Sc) infection and in APP-transgenic mice reduces Alzheimer's disease-like pathology and memory impairment.", + "TAG_DATA": [ + "60, neurons {'context': 'B-cells'}", + "67, APP-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "68, mice {'context': 'B-organism'}", + "79, neurons {'context': 'B-cells'}", + "123, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "124, of {'perturbing_action': 'I-pharmacological inhibition'}", + "125, PDK1 {'perturbing_action': 'I-pharmacological inhibition'}", + "152, mice, {'context': 'B-organism'}", + "155, siRNA-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "156, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "157, of {'perturbing_action': 'I-rnai/knockdown'}", + "158, PDK1 {'perturbing_action': 'I-rnai/knockdown'}", + "170, APP-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "171, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "60, neurons ['l0', 'l1', 'l2']", + "67, APP-transgenic ['l0', 'l3', 'l4']", + "68, mice ['l1', 'l3', 'l5']", + "79, neurons ['l2', 'l4', 'l5']", + "123, Inhibition ['l6', 'l7', 'l8']", + "124, of ['l6', 'l9', 'l10']", + "125, PDK1 ['l7', 'l9', 'l11']", + "152, mice, ['l8', 'l10', 'l11', 'l12', 'l13']", + "155, siRNA-mediated ['l14', 'l15', 'l16', 'l17', 'l18']", + "156, silencing ['l14', 'l19', 'l20', 'l21', 'l22']", + "157, of ['l15', 'l19', 'l23', 'l24', 'l25']", + "158, PDK1 ['l12', 'l16', 'l20', 'l23', 'l26', 'l27']", + "170, APP-transgenic ['l17', 'l21', 'l24', 'l26', 'l28']", + "171, mice ['l13', 'l18', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "neurons" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "APP-transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "APP-transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "PDK1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PDK1", + "siRNA-mediated", + "silencing", + "of" + ] + } + } + ] + }, + { + "PMID": "23955712", + "TEXT": "Type 2 diabetes mellitus (T2DM) progresses from compensated insulin resistance to beta cell failure resulting in uncompensated hyperglycemia, a process replicated in the Zucker diabetic fatty (ZDF) rat. The Nlrp3 inflammasome has been implicated in obesity-induced insulin resistance and beta cell failure. Endocannabinoids contribute to insulin resistance through activation of peripheral CB1 receptors (CB₁Rs) and also promote beta cell failure. Here we show that beta cell failure in adult ZDF rats is not associated with CB₁R signaling in beta cells, but rather in M1 macrophages infiltrating into pancreatic islets, and that this leads to activation of the Nlrp3-ASC inflammasome in the macrophages. These effects are replicated in vitro by incubating wild-type human or rodent macrophages, but not macrophages from CB₁R-deficient (Cnr1(-/-)) or Nlrp3(-/-) mice, with the endocannabinoid anandamide. Peripheral CB₁R blockade, in vivo depletion of macrophages or macrophage-specific knockdown of CB₁R reverses or prevents these changes and restores normoglycemia and glucose-induced insulin secretion. These findings implicate endocannabinoids and inflammasome activation in beta cell failure and identify macrophage-expressed CB₁R as a therapeutic target in T2DM.", + "TAG_DATA": [ + "106, in {'context': 'B-in vitro'}", + "107, vitro {'context': 'I-in vitro'}", + "111, human {'context': 'B-cells'}", + "112, or {'context': 'I-cells'}", + "113, rodent {'context': 'I-cells'}", + "114, macrophages, {'context': 'I-cells'}", + "117, macrophages {'context': 'B-cells'}", + "119, CB₁R-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "120, (Cnr1(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "122, Nlrp3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "123, mice, {'context': 'B-organism'}", + "131, in {'context': 'B-in vivo'}", + "132, vivo {'context': 'I-in vivo'}", + "135, macrophages {'context': 'B-cells'}", + "137, macrophage-specific {'perturbing_action': 'B-rnai/knockdown'}", + "138, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "139, of {'perturbing_action': 'I-rnai/knockdown'}", + "140, CB₁R {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "106, in ['l0', 'l1', 'l2', 'l3', 'l4']", + "107, vitro ['l0', 'l5', 'l6', 'l7', 'l8']", + "111, human ['l1', 'l5', 'l9', 'l10', 'l11', 'l12']", + "112, or ['l2', 'l6', 'l9', 'l13', 'l14', 'l15']", + "113, rodent ['l3', 'l7', 'l10', 'l13', 'l16', 'l17', 'l18']", + "114, macrophages, ['l4', 'l8', 'l11', 'l14', 'l16', 'l19', 'l20']", + "117, macrophages ['l12', 'l15', 'l17', 'l19', 'l21', 'l22', 'l23', 'l24']", + "119, CB₁R-deficient ['l21', 'l25', 'l26', 'l27']", + "120, (Cnr1(-/-)) ['l18', 'l20', 'l22', 'l25', 'l28', 'l29']", + "122, Nlrp3(-/-) ['l23', 'l26', 'l28', 'l30', 'l31']", + "123, mice, ['l24', 'l27', 'l29', 'l30']", + "131, in ['l32', 'l33', 'l34']", + "132, vivo ['l32', 'l35', 'l36', 'l37']", + "135, macrophages ['l31', 'l33', 'l35']", + "137, macrophage-specific ['l38', 'l39', 'l40']", + "138, knockdown ['l38', 'l41', 'l42']", + "139, of ['l36', 'l39', 'l41', 'l43']", + "140, CB₁R ['l34', 'l37', 'l40', 'l42', 'l43']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "rodent", + "macrophages,", + "macrophages" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "(Cnr1(-/-))", + "CB₁R-deficient", + "Nlrp3(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CB₁R-deficient", + "(Cnr1(-/-))", + "Nlrp3(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "CB₁R", + "of" + ] + } + } + ] + }, + { + "PMID": "23933983", + "TEXT": "Preventing reproduction during nutritional deprivation is an adaptive process that is conserved and essential for the survival of species. In mammals, the mechanisms that inhibit fertility during starvation are complex and incompletely understood. Here we show that exposure of female mice to fibroblast growth factor 21 (FGF21), a fasting-induced hepatokine, mimics infertility secondary to starvation. Mechanistically, FGF21 acts on the suprachiasmatic nucleus (SCN) in the hypothalamus to suppress the vasopressin-kisspeptin signaling cascade, thereby inhibiting the proestrus surge in luteinizing hormone. Mice lacking the FGF21 co-receptor, β-Klotho, in the SCN are refractory to the inhibitory effect of FGF21 on female fertility. Thus, FGF21 defines an important liver-neuroendocrine axis that modulates female reproduction in response to nutritional challenge.", + "TAG_DATA": [ + "39, female {'context': 'B-organism'}", + "40, mice {'context': 'I-organism'}", + "80, Mice {'context': 'B-organism'}", + "81, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "82, the {'perturbing_action': 'I-gene loss-of-function'}", + "83, FGF21 {'perturbing_action': 'I-gene loss-of-function'}", + "84, co-receptor, {'perturbing_action': 'I-gene loss-of-function'}", + "85, β-Klotho, {'perturbing_action': 'I-gene loss-of-function'}", + "86, in {'perturbing_action': 'I-gene loss-of-function'}", + "87, the {'perturbing_action': 'I-gene loss-of-function'}", + "88, SCN {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "39, female ['l0']", + "40, mice ['l0']", + "80, Mice ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "81, lacking ['l1', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "82, the ['l2', 'l9', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "83, FGF21 ['l3', 'l10', 'l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "84, co-receptor, ['l4', 'l11', 'l17', 'l22', 'l27', 'l28', 'l29', 'l30']", + "85, β-Klotho, ['l5', 'l12', 'l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "86, in ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "87, the ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "88, SCN ['l8', 'l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "FGF21", + "co-receptor,", + "β-Klotho,", + "in", + "SCN" + ] + } + } + ] + }, + { + "PMID": "23817023", + "TEXT": "Successful pregnancy requires coordination of an array of signals and factors from multiple tissues. One such element, liver receptor homolog-1 (Lrh-1), is an orphan nuclear receptor that regulates metabolism and hormone synthesis. It is strongly expressed in granulosa cells of ovarian follicles and in the corpus luteum of rodents and humans. Germline ablation of Nr5a2 (also called Lrh-1), the gene coding for Lrh-1, in mice is embryonically lethal at gastrulation. Depletion of Lrh-1 in the ovarian follicle shows that it regulates genes required for both steroid synthesis and ovulation. To study the effects of Lrh-1 on mouse gestation, we genetically disrupted its expression in the corpus luteum, resulting in luteal insufficiency. Hormone replacement permitted embryo implantation but was followed by gestational failure with impaired endometrial decidualization, compromised placental formation, fetal growth retardation and fetal death. Lrh-1 is also expressed in the mouse and human endometrium, and in a primary culture of human endometrial stromal cells, reduction of NR5A2 transcript abundance by RNA interference abrogated decidualization. These findings show that Lrh-1 is necessary for maintenance of the corpus luteum, for promotion of decidualization and for formation of the placenta. It therefore has multiple, indispensible roles in establishing and sustaining pregnancy.", + "TAG_DATA": [ + "51, Germline {'perturbing_action': 'B-gene loss-of-function'}", + "52, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "53, of {'perturbing_action': 'I-gene loss-of-function'}", + "54, Nr5a2 {'perturbing_action': 'I-gene loss-of-function'}", + "55, (also {'perturbing_action': 'I-gene loss-of-function'}", + "56, called {'perturbing_action': 'I-gene loss-of-function'}", + "57, Lrh-1), {'perturbing_action': 'I-gene loss-of-function'}", + "70, Depletion {'perturbing_action': 'B-gene loss-of-function'}", + "71, of {'perturbing_action': 'I-gene loss-of-function'}", + "72, Lrh-1 {'perturbing_action': 'I-gene loss-of-function'}", + "73, in {'perturbing_action': 'I-gene loss-of-function'}", + "100, disrupted {'perturbing_action': 'I-gene loss-of-function'}", + "102, expression {'perturbing_action': 'I-gene loss-of-function'}", + "103, in {'perturbing_action': 'I-gene loss-of-function'}", + "105, corpus {'context': 'B-tissue/organ'}", + "106, luteum, {'context': 'I-tissue/organ'}", + "113, permitted {'effect': 'B-positive'}", + "114, embryo {'context': 'B-organism'}", + "115, implantation {'phenotype': 'B-self-renewal'}", + "148, primary {'context': 'B-cells'}", + "149, culture {'context': 'I-cells'}", + "150, of {'context': 'I-cells'}", + "151, human {'context': 'I-cells'}", + "152, endometrial {'context': 'I-cells'}", + "153, stromal {'context': 'I-cells'}", + "154, cells, {'context': 'I-cells'}", + "155, reduction {'perturbing_action': 'B-rnai/knockdown'}", + "156, of {'perturbing_action': 'I-rnai/knockdown'}", + "157, NR5A2 {'perturbing_action': 'I-rnai/knockdown'}", + "158, transcript {'perturbing_action': 'I-rnai/knockdown'}", + "159, abundance {'perturbing_action': 'I-rnai/knockdown'}", + "161, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "162, interference {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "51, Germline ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "52, ablation ['l0', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "53, of ['l1', 'l19', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "54, Nr5a2 ['l2', 'l20', 'l36', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "55, (also ['l3', 'l21', 'l37', 'l52', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "56, called ['l4', 'l22', 'l38', 'l53', 'l68', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "57, Lrh-1), ['l5', 'l23', 'l39', 'l54', 'l69', 'l83', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "70, Depletion ['l6', 'l24', 'l40', 'l55', 'l70', 'l84', 'l98', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "71, of ['l7', 'l25', 'l41', 'l56', 'l71', 'l85', 'l99', 'l111', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "72, Lrh-1 ['l8', 'l26', 'l42', 'l57', 'l72', 'l86', 'l100', 'l112', 'l122', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "73, in ['l9', 'l27', 'l43', 'l58', 'l73', 'l87', 'l101', 'l113', 'l123', 'l131', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145']", + "100, disrupted ['l10', 'l28', 'l44', 'l59', 'l74', 'l88', 'l102', 'l114', 'l124', 'l132', 'l139', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151']", + "101, its ['l11', 'l29', 'l45', 'l60', 'l75', 'l89', 'l103', 'l115', 'l125', 'l133', 'l140', 'l146', 'l152', 'l153', 'l154', 'l155', 'l156']", + "102, expression ['l12', 'l30', 'l46', 'l61', 'l76', 'l90', 'l104', 'l116', 'l126', 'l134', 'l141', 'l147', 'l152', 'l157', 'l158', 'l159', 'l160']", + "103, in ['l13', 'l31', 'l47', 'l62', 'l77', 'l91', 'l105', 'l117', 'l127', 'l135', 'l142', 'l148', 'l153', 'l157', 'l161', 'l162', 'l163', 'l164', 'l165']", + "104, the ['l14', 'l32', 'l48', 'l63', 'l78', 'l92', 'l106', 'l118', 'l128', 'l136', 'l143', 'l149', 'l154', 'l158', 'l161', 'l166', 'l167', 'l168', 'l169']", + "105, corpus ['l15', 'l33', 'l49', 'l64', 'l79', 'l93', 'l107', 'l119', 'l129', 'l137', 'l144', 'l150', 'l155', 'l159', 'l162', 'l166', 'l170', 'l171', 'l172']", + "106, luteum, ['l16', 'l34', 'l50', 'l65', 'l80', 'l94', 'l108', 'l120', 'l130', 'l138', 'l145', 'l151', 'l156', 'l160', 'l163', 'l167', 'l170', 'l173', 'l174']", + "113, permitted ['l95', 'l175', 'l176']", + "114, embryo ['l17', 'l66', 'l81', 'l96', 'l109', 'l164', 'l168', 'l171', 'l173', 'l175', 'l177']", + "115, implantation ['l18', 'l35', 'l51', 'l67', 'l82', 'l97', 'l110', 'l121', 'l165', 'l169', 'l172', 'l174', 'l176', 'l177']", + "148, primary ['l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185']", + "149, culture ['l178', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191']", + "150, of ['l179', 'l186', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198']", + "151, human ['l180', 'l187', 'l192', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208']", + "152, endometrial ['l181', 'l188', 'l193', 'l199', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216']", + "153, stromal ['l182', 'l189', 'l194', 'l200', 'l209', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222']", + "154, cells, ['l183', 'l190', 'l195', 'l201', 'l210', 'l217', 'l223', 'l224']", + "155, reduction ['l202', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230']", + "156, of ['l203', 'l211', 'l225', 'l231', 'l232', 'l233', 'l234', 'l235']", + "157, NR5A2 ['l184', 'l191', 'l196', 'l204', 'l212', 'l218', 'l223', 'l226', 'l231', 'l236', 'l237', 'l238', 'l239']", + "158, transcript ['l205', 'l213', 'l219', 'l227', 'l232', 'l236', 'l240', 'l241', 'l242']", + "159, abundance ['l206', 'l214', 'l220', 'l228', 'l233', 'l237', 'l240', 'l243', 'l244']", + "161, RNA ['l197', 'l207', 'l215', 'l221', 'l229', 'l234', 'l238', 'l241', 'l243', 'l245']", + "162, interference ['l185', 'l198', 'l208', 'l216', 'l222', 'l224', 'l230', 'l235', 'l239', 'l242', 'l244', 'l245']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Germline", + "ablation", + "of", + "Nr5a2", + "(also", + "called", + "Lrh-1),", + "Depletion", + "Lrh-1", + "in", + "disrupted", + "expression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "corpus", + "luteum," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Germline", + "Nr5a2", + "(also", + "called", + "Lrh-1),", + "in" + ] + }, + "context": { + "val": "organism", + "words": [ + "embryo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Germline", + "ablation", + "of", + "Nr5a2", + "(also", + "called", + "Lrh-1),", + "Depletion", + "in" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "implantation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "called" + ] + }, + "effect": { + "val": "positive", + "words": [ + "permitted" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "corpus", + "luteum," + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "implantation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "permitted" + ] + }, + "context": { + "val": "organism", + "words": [ + "embryo" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "permitted" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "implantation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "embryo" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "implantation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "primary", + "culture", + "of", + "human", + "endometrial", + "stromal", + "cells," + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "NR5A2", + "interference", + "RNA", + "reduction", + "of", + "transcript", + "abundance" + ] + } + } + ] + }, + { + "PMID": "23817021", + "TEXT": "Studies of ETS-mediated prostate oncogenesis have been hampered by a lack of suitable experimental systems. Here we describe a new conditional mouse model that shows robust, homogenous ERG expression throughout the prostate. When combined with homozygous Pten loss, the mice developed accelerated, highly penetrant invasive prostate cancer. In mouse prostate tissue, ERG markedly increased androgen receptor (AR) binding. Robust ERG-mediated transcriptional changes, observed only in the setting of Pten loss, included the restoration of AR transcriptional output and upregulation of genes involved in cell death, migration, inflammation and angiogenesis. Similarly, ETS variant 1 (ETV1) positively regulated the AR cistrome and transcriptional output in ETV1-translocated, PTEN-deficient human prostate cancer cells. In two large clinical cohorts, expression of ERG and ETV1 correlated with higher AR transcriptional output in PTEN-deficient prostate cancer specimens. We propose that ETS factors cause prostate-specific transformation by altering the AR cistrome, priming the prostate epithelium to respond to aberrant upstream signals such as PTEN loss.", + "TAG_DATA": [ + "35, homozygous {'perturbing_action': 'B-gene loss-of-function'}", + "36, Pten {'perturbing_action': 'I-gene loss-of-function'}", + "37, loss, {'perturbing_action': 'I-gene loss-of-function'}", + "39, mice {'context': 'B-organism'}", + "44, invasive {'phenotype': 'B-tumourigenesis'}", + "45, prostate {'phenotype': 'I-tumourigenesis'}", + "46, cancer. {'phenotype': 'I-tumourigenesis'}", + "48, mouse {'context': 'B-tissue/organ'}", + "49, prostate {'context': 'I-tissue/organ'}", + "50, tissue, {'context': 'I-tissue/organ'}", + "68, Pten {'perturbing_action': 'B-gene loss-of-function'}", + "69, loss, {'perturbing_action': 'I-gene loss-of-function'}", + "104, PTEN-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "105, human {'context': 'B-transformed cells'}", + "106, prostate {'context': 'I-transformed cells'}", + "107, cancer {'context': 'I-transformed cells'}", + "108, cells. {'context': 'I-transformed cells'}", + "126, PTEN-deficient {'perturbing_action': 'B-gene loss-of-function'}" + ], + "LINK_DATA": [ + "35, homozygous ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "36, Pten ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "37, loss, ['l1', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "39, mice ['l2', 'l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "44, invasive ['l3', 'l14', 'l23', 'l31', 'l37', 'l38', 'l39', 'l40', 'l41']", + "45, prostate ['l4', 'l15', 'l24', 'l32', 'l37', 'l42', 'l43', 'l44', 'l45']", + "46, cancer. ['l5', 'l16', 'l25', 'l33', 'l38', 'l42', 'l46']", + "48, mouse ['l6', 'l17', 'l26', 'l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "49, prostate ['l7', 'l18', 'l27', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51', 'l52']", + "50, tissue, ['l8', 'l19', 'l28', 'l36', 'l41', 'l45', 'l46', 'l48', 'l50', 'l53']", + "68, Pten ['l9', 'l20', 'l29', 'l51', 'l54', 'l55', 'l56', 'l57', 'l58']", + "69, loss, ['l10', 'l21', 'l30', 'l49', 'l52', 'l53', 'l54', 'l59']", + "104, PTEN-deficient ['l60', 'l61', 'l62', 'l63']", + "105, human ['l55', 'l60', 'l64', 'l65', 'l66']", + "106, prostate ['l56', 'l61', 'l64', 'l67', 'l68']", + "107, cancer ['l57', 'l62', 'l65', 'l67', 'l69']", + "108, cells. ['l11', 'l58', 'l59', 'l63', 'l66', 'l68', 'l69']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "homozygous", + "Pten", + "loss," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "homozygous", + "Pten", + "loss," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "invasive", + "prostate", + "cancer." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "homozygous", + "Pten", + "loss," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "prostate", + "tissue," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "homozygous", + "Pten", + "loss,", + "PTEN-deficient" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells.", + "human", + "prostate", + "cancer" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "invasive", + "prostate", + "cancer." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "invasive", + "prostate", + "cancer." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "prostate", + "tissue," + ] + } + } + ] + }, + { + "PMID": "23770692", + "TEXT": "Major depression is a highly prevalent severe mood disorder that is treated with antidepressants. The molecular targets of antidepressants require definition. We investigated the role of the acid sphingomyelinase (Asm)-ceramide system as a target for antidepressants. Therapeutic concentrations of the antidepressants amitriptyline and fluoxetine reduced Asm activity and ceramide concentrations in the hippocampus, increased neuronal proliferation, maturation and survival and improved behavior in mouse models of stress-induced depression. Genetic Asm deficiency abrogated these effects. Mice overexpressing Asm, heterozygous for acid ceramidase, treated with blockers of ceramide metabolism or directly injected with C16 ceramide in the hippocampus had higher ceramide concentrations and lower rates of neuronal proliferation, maturation and survival compared with controls and showed depression-like behavior even in the absence of stress. The decrease of ceramide abundance achieved by antidepressant-mediated inhibition of Asm normalized these effects. Lowering ceramide abundance may thus be a central goal for the future development of antidepressants.", + "TAG_DATA": [ + "53, increased {'effect': 'B-positive'}", + "55, proliferation, {'phenotype': 'B-proliferation'}", + "63, mouse {'context': 'B-organism'}", + "64, models {'context': 'I-organism'}", + "68, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "69, Asm {'perturbing_action': 'I-gene loss-of-function'}", + "70, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "74, Mice {'context': 'B-organism'}", + "75, overexpressing {'perturbing_action': 'I-gene gain-of-function'}", + "76, Asm, {'perturbing_action': 'I-gene gain-of-function'}", + "95, hippocampus {'context': 'B-tissue/organ'}", + "101, lower {'effect': 'B-negative'}", + "105, proliferation, {'phenotype': 'B-proliferation'}", + "129, antidepressant-mediated {'perturbing_action': 'B-pharmacological inhibition'}", + "130, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "131, of {'perturbing_action': 'I-pharmacological inhibition'}", + "132, Asm {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "52, hippocampus, ['l0', 'l1', 'l2', 'l3']", + "53, increased ['l0', 'l4', 'l5']", + "55, proliferation, ['l1', 'l4', 'l6', 'l7']", + "63, mouse ['l2', 'l6', 'l8']", + "64, models ['l3', 'l5', 'l7', 'l8']", + "68, Genetic ['l9', 'l10', 'l11', 'l12']", + "69, Asm ['l9', 'l13', 'l14']", + "70, deficiency ['l10', 'l13', 'l15']", + "74, Mice ['l16', 'l17', 'l18', 'l19', 'l20']", + "75, overexpressing ['l16', 'l21', 'l22', 'l23', 'l24']", + "76, Asm, ['l17', 'l21', 'l25', 'l26', 'l27']", + "95, hippocampus ['l18', 'l22', 'l25', 'l28', 'l29']", + "101, lower ['l11', 'l19', 'l23', 'l26', 'l28', 'l30']", + "105, proliferation, ['l12', 'l14', 'l15', 'l20', 'l24', 'l27', 'l29', 'l30']", + "129, antidepressant-mediated ['l31', 'l32', 'l33']", + "130, inhibition ['l31', 'l34', 'l35']", + "131, of ['l32', 'l34', 'l36']", + "132, Asm ['l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "organism", + "words": [ + "models" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "Mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "Asm", + "deficiency" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "Asm," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "Asm," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "Asm," + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "Asm," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "lower" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + } + ] + }, + { + "PMID": "23749230", + "TEXT": "Parasites of the Leishmania genus are the causative agents of leishmaniasis in humans, a disease that affects more than 12 million people worldwide. These parasites replicate intracellularly in macrophages, and the primary mechanisms underlying host resistance involve the production of nitric oxide (NO). In this study we show that the Nlrp3 inflammasome is activated in response to Leishmania infection and is important for the restriction of parasite replication both in macrophages and in vivo as demonstrated through the infection of inflammasome-deficient mice with Leishmania amazonensis, Leishmania braziliensis and Leishmania infantum chagasi. Inflammasome-driven interleukin-1β (IL-1β) production facilitated host resistance to infection, as signaling through IL-1 receptor (IL-1R) and MyD88 was necessary and sufficient to trigger inducible nitric oxide synthase (NOS2)-mediated production of NO. In this manuscript we identify a major signaling platform for host resistance to Leishmania spp. infection and describe the molecular mechanisms underlying Leishmania-induced NO production.", + "TAG_DATA": [ + "80, inflammasome-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "81, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "80, inflammasome-deficient ['l0']", + "81, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inflammasome-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23727931", + "TEXT": "We recently established conditions allowing for long-term expansion of epithelial organoids from intestine, recapitulating essential features of the in vivo tissue architecture. Here we apply this technology to study primary intestinal organoids of people suffering from cystic fibrosis, a disease caused by mutations in CFTR, encoding cystic fibrosis transmembrane conductance regulator. Forskolin induces rapid swelling of organoids derived from healthy controls or wild-type mice, but this effect is strongly reduced in organoids of subjects with cystic fibrosis or in mice carrying the Cftr F508del mutation and is absent in Cftr-deficient organoids. This pattern is phenocopied by CFTR-specific inhibitors. Forskolin-induced swelling of in vitro-expanded human control and cystic fibrosis organoids corresponds quantitatively with forskolin-induced anion currents in freshly excised ex vivo rectal biopsies. Function of the CFTR F508del mutant protein is restored by incubation at low temperature, as well as by CFTR-restoring compounds. This relatively simple and robust assay will facilitate diagnosis, functional studies, drug development and personalized medicine approaches in cystic fibrosis.", + "TAG_DATA": [ + "56, organoids {'context': 'B-organoid'}", + "63, mice, {'context': 'B-organism'}", + "71, organoids {'context': 'B-organoid'}", + "79, mice {'context': 'B-organism'}", + "81, the {'perturbing_action': 'I-other'}", + "82, Cftr {'perturbing_action': 'I-other'}", + "83, F508del {'perturbing_action': 'I-other'}", + "84, mutation {'perturbing_action': 'I-other'}", + "89, Cftr-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "90, organoids. {'context': 'B-organoid'}", + "96, CFTR-specific {'perturbing_action': 'B-pharmacological inhibition'}", + "97, inhibitors. {'perturbing_action': 'I-pharmacological inhibition'}", + "101, in {'context': 'B-in vitro'}", + "102, vitro-expanded {'context': 'I-in vitro'}", + "103, human {'context': 'B-organoid'}", + "104, control {'context': 'I-organoid'}", + "105, and {'context': 'I-organoid'}", + "106, cystic {'context': 'B-organoid'}", + "107, fibrosis {'context': 'I-organoid'}", + "108, organoids {'context': 'I-organoid'}", + "125, CFTR {'perturbing_action': 'B-other'}", + "126, F508del {'perturbing_action': 'I-other'}", + "127, mutant {'perturbing_action': 'I-other'}", + "128, protein {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "56, organoids ['l0', 'l1']", + "63, mice, ['l0', 'l2']", + "71, organoids ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "79, mice ['l3', 'l8', 'l9', 'l10', 'l11', 'l12']", + "81, the ['l4', 'l8', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "82, Cftr ['l5', 'l9', 'l13', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "83, F508del ['l6', 'l10', 'l14', 'l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "84, mutation ['l7', 'l11', 'l15', 'l21', 'l26', 'l31', 'l32']", + "89, Cftr-deficient ['l16', 'l22', 'l27', 'l31', 'l33', 'l34', 'l35']", + "90, organoids. ['l12', 'l17', 'l23', 'l28', 'l32', 'l33', 'l36', 'l37']", + "96, CFTR-specific ['l18', 'l24', 'l29', 'l34', 'l36', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "97, inhibitors. ['l19', 'l25', 'l30', 'l35', 'l37', 'l38', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "101, in ['l39', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "102, vitro-expanded ['l40', 'l47', 'l54', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "103, human ['l41', 'l48', 'l55', 'l63', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "104, control ['l42', 'l49', 'l56', 'l64', 'l71', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "105, and ['l43', 'l50', 'l57', 'l65', 'l72', 'l78', 'l84', 'l85', 'l86', 'l87', 'l88']", + "106, cystic ['l44', 'l51', 'l58', 'l66', 'l73', 'l79', 'l84', 'l89', 'l90', 'l91', 'l92']", + "107, fibrosis ['l45', 'l52', 'l59', 'l67', 'l74', 'l80', 'l85', 'l89', 'l93', 'l94', 'l95']", + "108, organoids ['l46', 'l53', 'l60', 'l68', 'l75', 'l81', 'l86', 'l90', 'l93', 'l96', 'l97']", + "120, rectal ['l61', 'l69', 'l76', 'l82', 'l87', 'l91', 'l94', 'l96', 'l98']", + "121, biopsies. ['l62', 'l70', 'l77', 'l83', 'l88', 'l92', 'l95', 'l97', 'l98']", + "125, CFTR ['l99', 'l100', 'l101']", + "126, F508del ['l99', 'l102', 'l103']", + "127, mutant ['l100', 'l102', 'l104']", + "128, protein ['l101', 'l103', 'l104']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organoid", + "words": [ + "organoids", + "organoids." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "the", + "Cftr", + "F508del", + "mutation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "the", + "Cftr", + "F508del", + "mutation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cftr-deficient" + ] + }, + "context": { + "val": "organoid", + "words": [ + "organoids." + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "organoids.", + "human", + "control", + "and", + "cystic", + "fibrosis", + "organoids" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CFTR-specific", + "inhibitors." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CFTR-specific", + "inhibitors." + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro-expanded" + ] + } + } + ] + }, + { + "PMID": "23708290", + "TEXT": "Oxidative damage from elevated production of reactive oxygen species (ROS) contributes to ischemia-reperfusion injury in myocardial infarction and stroke. The mechanism by which the increase in ROS occurs is not known, and it is unclear how this increase can be prevented. A wide variety of nitric oxide donors and S-nitrosating agents protect the ischemic myocardium from infarction, but the responsible mechanisms are unclear. Here we used a mitochondria-selective S-nitrosating agent, MitoSNO, to determine how mitochondrial S-nitrosation at the reperfusion phase of myocardial infarction is cardioprotective in vivo in mice. We found that protection is due to the S-nitrosation of mitochondrial complex I, which is the entry point for electrons from NADH into the respiratory chain. Reversible S-nitrosation of complex I slows the reactivation of mitochondria during the crucial first minutes of the reperfusion of ischemic tissue, thereby decreasing ROS production, oxidative damage and tissue necrosis. Inhibition of complex I is afforded by the selective S-nitrosation of Cys39 on the ND3 subunit, which becomes susceptible to modification only after ischemia. Our results identify rapid complex I reactivation as a central pathological feature of ischemia-reperfusion injury and show that preventing this reactivation by modification of a cysteine switch is a robust cardioprotective mechanism and hence a rational therapeutic strategy.", + "TAG_DATA": [ + "85, in {'context': 'B-in vivo'}", + "86, vivo {'context': 'I-in vivo'}", + "88, mice. {'context': 'B-organism'}", + "137, decreasing {'effect': 'B-negative'}", + "144, necrosis. {'phenotype': 'B-necrosis'}" + ], + "LINK_DATA": [ + "85, in ['l0', 'l1']", + "86, vivo ['l0', 'l2']", + "88, mice. ['l1', 'l2']", + "137, decreasing ['l3', 'l4']", + "143, tissue ['l3', 'l5']", + "144, necrosis. ['l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "decreasing" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis." + ] + } + } + ] + }, + { + "PMID": "23624599", + "TEXT": "CD4(+) type 1 T regulatory (Tr1) cells are induced in the periphery and have a pivotal role in promoting and maintaining tolerance. The absence of surface markers that uniquely identify Tr1 cells has limited their study and clinical applications. By gene expression profiling of human Tr1 cell clones, we identified the surface markers CD49b and lymphocyte activation gene 3 (LAG-3) as being stably and selectively coexpressed on mouse and human Tr1 cells. We showed the specificity of these markers in mouse models of intestinal inflammation and helminth infection and in the peripheral blood of healthy volunteers. The coexpression of CD49b and LAG-3 enables the isolation of highly suppressive human Tr1 cells from in vitro anergized cultures and allows the tracking of Tr1 cells in the peripheral blood of subjects who developed tolerance after allogeneic hematopoietic stem cell transplantation. The use of these markers makes it feasible to track Tr1 cells in vivo and purify Tr1 cells for cell therapy to induce or restore tolerance in subjects with immune-mediated diseases.", + "TAG_DATA": [ + "80, mouse {'context': 'B-organism'}", + "81, models {'context': 'I-organism'}", + "91, peripheral {'context': 'B-cells'}", + "92, blood {'context': 'I-tissue/organ'}", + "97, coexpression {'perturbing_action': 'B-gene gain-of-function'}", + "98, of {'perturbing_action': 'I-gene gain-of-function'}", + "99, CD49b {'perturbing_action': 'I-gene gain-of-function'}", + "100, and {'perturbing_action': 'I-gene gain-of-function'}", + "101, LAG-3 {'perturbing_action': 'I-gene gain-of-function'}", + "108, human {'context': 'B-cells'}", + "109, Tr1 {'context': 'I-cells'}", + "110, cells {'context': 'I-cells'}", + "112, in {'context': 'B-in vitro'}", + "113, vitro {'context': 'I-in vitro'}", + "121, Tr1 {'context': 'B-cells'}", + "122, cells {'context': 'I-cells'}", + "125, peripheral {'context': 'B-cells'}", + "126, blood {'context': 'I-cells'}", + "134, hematopoietic {'context': 'I-cells'}", + "135, stem {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "80, mouse ['l0', 'l1', 'l2']", + "81, models ['l0', 'l3', 'l4']", + "91, peripheral ['l1', 'l3', 'l5']", + "92, blood ['l2', 'l4', 'l5']", + "97, coexpression ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "98, of ['l6', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "99, CD49b ['l7', 'l24', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "100, and ['l8', 'l25', 'l41', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "101, LAG-3 ['l9', 'l26', 'l42', 'l56', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "108, human ['l10', 'l27', 'l43', 'l57', 'l68', 'l78', 'l79', 'l80', 'l81', 'l82']", + "109, Tr1 ['l11', 'l28', 'l44', 'l58', 'l69', 'l78', 'l83', 'l84', 'l85', 'l86']", + "110, cells ['l12', 'l29', 'l45', 'l59', 'l70', 'l79', 'l83', 'l87', 'l88', 'l89']", + "112, in ['l13', 'l30', 'l46', 'l60', 'l71', 'l80', 'l84', 'l87', 'l90', 'l91']", + "113, vitro ['l14', 'l31', 'l47', 'l61', 'l72', 'l81', 'l85', 'l88', 'l90', 'l92']", + "115, cultures ['l15', 'l32', 'l48', 'l62', 'l73', 'l82', 'l86', 'l89', 'l91', 'l92']", + "121, Tr1 ['l16', 'l33', 'l49', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "122, cells ['l17', 'l34', 'l50', 'l63', 'l74', 'l93', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "125, peripheral ['l18', 'l35', 'l51', 'l64', 'l75', 'l94', 'l100', 'l106', 'l107', 'l108', 'l109', 'l110']", + "126, blood ['l19', 'l36', 'l52', 'l65', 'l76', 'l95', 'l101', 'l106', 'l111', 'l112', 'l113', 'l114']", + "133, allogeneic ['l20', 'l37', 'l96', 'l102', 'l107', 'l111', 'l115', 'l116', 'l117']", + "134, hematopoietic ['l21', 'l38', 'l53', 'l97', 'l103', 'l108', 'l112', 'l115', 'l118', 'l119']", + "135, stem ['l22', 'l39', 'l54', 'l66', 'l98', 'l104', 'l109', 'l113', 'l116', 'l118', 'l120']", + "136, cell ['l23', 'l40', 'l55', 'l67', 'l77', 'l99', 'l105', 'l110', 'l114', 'l117', 'l119', 'l120']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "coexpression", + "of", + "CD49b", + "and", + "LAG-3" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "Tr1", + "cells", + "peripheral", + "blood", + "hematopoietic", + "stem" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "coexpression", + "of", + "CD49b", + "and", + "LAG-3" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "23542787", + "TEXT": "Fragile X syndrome (FXS), the most common monogenic cause of inherited intellectual disability and autism, is caused by the silencing of the FMR1 gene, leading to the loss of fragile X mental retardation protein (FMRP), a synaptically expressed RNA-binding protein regulating translation. The Fmr1 knockout model recapitulates the main traits of the disease. Uncontrolled activity of metabotropic glutamate receptor 5 (mGluR5) and mammalian target of rapamycin (mTOR) signaling seem crucial in the pathology of this disease. The endocannabinoid system (ECS) is a key modulator of synaptic plasticity, cognitive performance, anxiety, nociception and seizure susceptibility, all of which are affected in FXS. The cannabinoid receptors CB1 (CB1R) and CB2 (CB2R) are activated by phospholipid-derived endocannabinoids, and CB1R-driven long-term regulation of synaptic strength, as a consequence of mGluR5 activation, is altered in several brain areas of Fmr1 knockout mice. We found that CB1R blockade in male Fmr1 knockout (Fmr1(-/y)) mice through pharmacological and genetic approaches normalized cognitive impairment, nociceptive desensitization, susceptibility to audiogenic seizures, overactivated mTOR signaling and altered spine morphology, whereas pharmacological blockade of CB2R normalized anxiolytic-like behavior. Some of these traits were also reversed by pharmacological inhibition of mTOR or mGluR5. Thus, blockade of ECS is a potential therapeutic approach to normalize specific alterations in FXS.", + "TAG_DATA": [ + "134, Fmr1 {'perturbing_action': 'B-gene loss-of-function'}", + "135, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "140, CB1R {'perturbing_action': 'B-pharmacological inhibition'}", + "141, blockade {'perturbing_action': 'I-gene loss-of-function'}", + "144, Fmr1 {'perturbing_action': 'B-gene loss-of-function'}", + "145, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "146, (Fmr1(-/y)) {'perturbing_action': 'I-gene loss-of-function'}", + "147, mice {'context': 'B-organism'}", + "170, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "171, blockade {'perturbing_action': 'I-pharmacological inhibition'}", + "172, of {'perturbing_action': 'I-pharmacological inhibition'}", + "173, CB2R {'perturbing_action': 'I-pharmacological inhibition'}", + "185, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "186, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "187, of {'perturbing_action': 'I-pharmacological inhibition'}", + "188, mTOR {'perturbing_action': 'I-pharmacological inhibition'}", + "189, or {'perturbing_action': 'I-pharmacological inhibition'}", + "190, mGluR5. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "134, Fmr1 ['l0', 'l1', 'l2']", + "135, knockout ['l0', 'l3', 'l4']", + "140, CB1R ['l1', 'l3', 'l5', 'l6', 'l7', 'l8', 'l9']", + "141, blockade ['l2', 'l4', 'l5', 'l10', 'l11', 'l12', 'l13']", + "144, Fmr1 ['l6', 'l10', 'l14', 'l15', 'l16', 'l17']", + "145, knockout ['l7', 'l11', 'l14', 'l18', 'l19', 'l20']", + "146, (Fmr1(-/y)) ['l8', 'l12', 'l15', 'l18', 'l21', 'l22']", + "147, mice ['l9', 'l13', 'l16', 'l19', 'l21', 'l23']", + "167, spine ['l17', 'l20', 'l22', 'l23']", + "170, pharmacological ['l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "171, blockade ['l24', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "172, of ['l25', 'l33', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "173, CB2R ['l26', 'l34', 'l41', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "185, pharmacological ['l27', 'l35', 'l42', 'l48', 'l54', 'l55', 'l56', 'l57', 'l58']", + "186, inhibition ['l28', 'l36', 'l43', 'l49', 'l54', 'l59', 'l60', 'l61', 'l62']", + "187, of ['l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l63', 'l64', 'l65']", + "188, mTOR ['l30', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l66', 'l67']", + "189, or ['l31', 'l39', 'l46', 'l52', 'l57', 'l61', 'l64', 'l66', 'l68']", + "190, mGluR5. ['l32', 'l40', 'l47', 'l53', 'l58', 'l62', 'l65', 'l67', 'l68']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CB1R" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "blockade", + "Fmr1", + "knockout", + "(Fmr1(-/y))" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23524343", + "TEXT": "Sorting nexin 27 (SNX27), a brain-enriched PDZ domain protein, regulates endocytic sorting and trafficking. Here we show that Snx27(-/-) mice have severe neuronal deficits in the hippocampus and cortex. Although Snx27(+/-) mice have grossly normal neuroanatomy, we found defects in synaptic function, learning and memory and a reduction in the amounts of ionotropic glutamate receptors (NMDA and AMPA receptors) in these mice. SNX27 interacts with these receptors through its PDZ domain, regulating their recycling to the plasma membrane. We demonstrate a concomitant reduced expression of SNX27 and CCAAT/enhancer binding protein β (C/EBPβ) in Down's syndrome brains and identify C/EBPβ as a transcription factor for SNX27. Down's syndrome causes overexpression of miR-155, a chromosome 21-encoded microRNA that negatively regulates C/EBPβ, thereby reducing SNX27 expression and resulting in synaptic dysfunction. Upregulating SNX27 in the hippocampus of Down's syndrome mice rescues synaptic and cognitive deficits. Our identification of the role of SNX27 in synaptic function establishes a new molecular mechanism of Down's syndrome pathogenesis.", + "TAG_DATA": [ + "18, Snx27(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "19, mice {'context': 'B-organism'}", + "30, Snx27(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "31, mice {'context': 'B-organism'}", + "128, Upregulating {'perturbing_action': 'B-gene gain-of-function'}", + "129, SNX27 {'perturbing_action': 'I-gene gain-of-function'}", + "132, hippocampus {'context': 'B-tissue/organ'}", + "134, Down's {'context': 'B-organism'}", + "135, syndrome {'context': 'B-organism'}", + "136, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "18, Snx27(-/-) ['l0', 'l1']", + "19, mice ['l0']", + "30, Snx27(+/-) ['l2']", + "31, mice ['l1', 'l2']", + "128, Upregulating ['l3', 'l4', 'l5', 'l6', 'l7']", + "129, SNX27 ['l3', 'l8', 'l9', 'l10', 'l11']", + "132, hippocampus ['l4', 'l8', 'l12', 'l13', 'l14']", + "134, Down's ['l5', 'l9', 'l12', 'l15', 'l16']", + "135, syndrome ['l6', 'l10', 'l13', 'l15', 'l17']", + "136, mice ['l7', 'l11', 'l14', 'l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Snx27(-/-)", + "Snx27(+/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Upregulating", + "SNX27" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Upregulating", + "SNX27" + ] + }, + "context": { + "val": "organism", + "words": [ + "Down's", + "syndrome", + "mice" + ] + } + } + ] + }, + { + "PMID": "23502961", + "TEXT": "Regulation of erythropoiesis is achieved by the integration of distinct signals. Among them, macrophages are emerging as erythropoietin-complementary regulators of erythroid development, particularly under stress conditions. We investigated the contribution of macrophages to physiological and pathological conditions of enhanced erythropoiesis. We used mouse models of induced anemia, polycythemia vera and β-thalassemia in which macrophages were chemically depleted. Our data indicate that macrophages contribute decisively to recovery from induced anemia, as well as the pathological progression of polycythemia vera and β-thalassemia, by modulating erythroid proliferation and differentiation. We validated these observations in primary human cultures, showing a direct impact of macrophages on the proliferation and enucleation of erythroblasts from healthy individuals and patients with polycythemia vera or β-thalassemia. The contribution of macrophages to stress and pathological erythropoiesis, which we have termed stress erythropoiesis macrophage-supporting activity, may have therapeutic implications.", + "TAG_DATA": [ + "42, mouse {'context': 'B-organism'}", + "43, models {'context': 'I-organism'}", + "53, macrophages {'context': 'B-cells'}", + "81, modulating {'effect': 'B-regulates'}", + "83, proliferation {'phenotype': 'B-proliferation'}", + "91, primary {'context': 'B-cells'}", + "92, human {'context': 'I-cells'}", + "93, cultures, {'context': 'I-cells'}", + "102, proliferation {'phenotype': 'B-proliferation'}", + "106, erythroblasts {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "42, mouse ['l0', 'l1']", + "43, models ['l0', 'l2']", + "53, macrophages ['l3', 'l4']", + "81, modulating ['l3', 'l5']", + "83, proliferation ['l1', 'l2', 'l4', 'l5']", + "91, primary ['l6', 'l7', 'l8']", + "92, human ['l6', 'l9', 'l10']", + "93, cultures, ['l7', 'l9']", + "102, proliferation ['l8', 'l10', 'l11']", + "106, erythroblasts ['l11']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "macrophages" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "modulating" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "macrophages", + "primary", + "human", + "erythroblasts" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "modulating" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "23435171", + "TEXT": "Previous attempts to identify neuroprotective targets by studying the ischemic cascade and devising ways to suppress it have failed to translate to efficacious therapies for acute ischemic stroke. We hypothesized that studying the molecular determinants of endogenous neuroprotection in two well-established paradigms, the resistance of CA3 hippocampal neurons to global ischemia and the tolerance conferred by ischemic preconditioning (IPC), would reveal new neuroprotective targets. We found that the product of the tuberous sclerosis complex 1 gene (TSC1), hamartin, is selectively induced by ischemia in hippocampal CA3 neurons. In CA1 neurons, hamartin was unaffected by ischemia but was upregulated by IPC preceding ischemia, which protects the otherwise vulnerable CA1 cells. Suppression of hamartin expression with TSC1 shRNA viral vectors both in vitro and in vivo increased the vulnerability of neurons to cell death following oxygen glucose deprivation (OGD) and ischemia. In vivo, suppression of TSC1 expression increased locomotor activity and decreased habituation in a hippocampal-dependent task. Overexpression of hamartin increased resistance to OGD by inducing productive autophagy through an mTORC1-dependent mechanism.", + "TAG_DATA": [ + "88, CA1 {'context': 'B-cells'}", + "89, neurons, {'context': 'I-cells'}", + "107, CA1 {'context': 'B-cells'}", + "109, Suppression {'perturbing_action': 'B-rnai/knockdown'}", + "110, of {'perturbing_action': 'I-rnai/knockdown'}", + "111, hamartin {'perturbing_action': 'I-rnai/knockdown'}", + "112, expression {'perturbing_action': 'I-rnai/knockdown'}", + "113, with {'perturbing_action': 'I-rnai/knockdown'}", + "114, TSC1 {'perturbing_action': 'I-rnai/knockdown'}", + "115, shRNA {'perturbing_action': 'I-rnai/knockdown'}", + "116, viral {'perturbing_action': 'I-rnai/knockdown'}", + "117, vectors {'perturbing_action': 'I-rnai/knockdown'}", + "119, in {'context': 'B-in vitro'}", + "120, vitro {'context': 'I-in vitro'}", + "122, in {'context': 'B-in vivo'}", + "123, vivo {'context': 'I-in vivo'}", + "124, increased {'effect': 'B-positive'}", + "128, neurons {'context': 'B-cells'}", + "130, cell {'phenotype': 'B-cell death'}", + "131, death {'phenotype': 'I-cell death'}", + "139, In {'context': 'B-in vivo'}", + "140, vivo, {'context': 'I-in vivo'}", + "141, suppression {'perturbing_action': 'B-rnai/knockdown'}", + "142, of {'perturbing_action': 'I-rnai/knockdown'}", + "143, TSC1 {'perturbing_action': 'I-rnai/knockdown'}", + "144, expression {'perturbing_action': 'I-rnai/knockdown'}", + "155, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "156, of {'perturbing_action': 'I-gene gain-of-function'}", + "157, hamartin {'perturbing_action': 'I-gene gain-of-function'}", + "163, inducing {'effect': 'B-positive'}", + "165, autophagy {'phenotype': 'B-autophagy'}" + ], + "LINK_DATA": [ + "88, CA1 ['l0', 'l1']", + "89, neurons, ['l0', 'l2']", + "107, CA1 ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "109, Suppression ['l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "110, of ['l12', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "111, hamartin ['l13', 'l32', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "112, expression ['l14', 'l33', 'l50', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "113, with ['l15', 'l34', 'l51', 'l65', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "114, TSC1 ['l16', 'l35', 'l52', 'l66', 'l79', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "115, shRNA ['l17', 'l36', 'l53', 'l67', 'l80', 'l93', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "116, viral ['l18', 'l37', 'l54', 'l68', 'l81', 'l94', 'l108', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "117, vectors ['l19', 'l38', 'l55', 'l69', 'l82', 'l95', 'l109', 'l123', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "119, in ['l3', 'l20', 'l39', 'l56', 'l70', 'l83', 'l96', 'l110', 'l124', 'l136', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "120, vitro ['l4', 'l21', 'l40', 'l57', 'l71', 'l84', 'l97', 'l111', 'l125', 'l137', 'l148', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162']", + "122, in ['l5', 'l22', 'l41', 'l58', 'l72', 'l85', 'l98', 'l112', 'l126', 'l138', 'l149', 'l156', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168']", + "123, vivo ['l6', 'l23', 'l42', 'l59', 'l73', 'l86', 'l99', 'l113', 'l127', 'l139', 'l150', 'l157', 'l163', 'l169', 'l170', 'l171', 'l172', 'l173']", + "124, increased ['l7', 'l24', 'l43', 'l60', 'l74', 'l87', 'l100', 'l114', 'l128', 'l140', 'l151', 'l158', 'l164', 'l169', 'l174', 'l175', 'l176', 'l177']", + "126, vulnerability ['l8', 'l25', 'l44', 'l61', 'l75', 'l88', 'l101', 'l115', 'l129', 'l141', 'l152', 'l159', 'l165', 'l170', 'l174', 'l178', 'l179', 'l180']", + "128, neurons ['l9', 'l26', 'l45', 'l62', 'l76', 'l89', 'l102', 'l116', 'l130', 'l142', 'l153', 'l160', 'l166', 'l171', 'l175', 'l178', 'l181', 'l182']", + "130, cell ['l10', 'l27', 'l46', 'l63', 'l77', 'l90', 'l103', 'l117', 'l131', 'l143', 'l154', 'l161', 'l167', 'l172', 'l176', 'l179', 'l181', 'l183']", + "131, death ['l11', 'l28', 'l47', 'l64', 'l78', 'l91', 'l104', 'l118', 'l132', 'l144', 'l155', 'l162', 'l168', 'l173', 'l177', 'l180', 'l182', 'l183']", + "139, In ['l29', 'l48', 'l92', 'l105', 'l119', 'l133', 'l145', 'l184', 'l185', 'l186', 'l187', 'l188']", + "140, vivo, ['l30', 'l49', 'l106', 'l120', 'l134', 'l146', 'l184', 'l189', 'l190', 'l191', 'l192']", + "141, suppression ['l185', 'l189', 'l193', 'l194', 'l195']", + "142, of ['l186', 'l190', 'l193', 'l196', 'l197']", + "143, TSC1 ['l121', 'l187', 'l191', 'l194', 'l196', 'l198']", + "144, expression ['l31', 'l107', 'l122', 'l135', 'l147', 'l188', 'l192', 'l195', 'l197', 'l198']", + "155, Overexpression ['l199', 'l200', 'l201', 'l202']", + "156, of ['l199', 'l203', 'l204', 'l205']", + "157, hamartin ['l200', 'l203', 'l206', 'l207']", + "163, inducing ['l201', 'l204', 'l206', 'l208']", + "165, autophagy ['l202', 'l205', 'l207', 'l208']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CA1", + "neurons" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CA1", + "neurons" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Suppression", + "of", + "hamartin", + "expression", + "with", + "TSC1", + "shRNA", + "viral", + "vectors" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Suppression", + "of", + "hamartin", + "expression", + "with", + "TSC1", + "shRNA", + "viral", + "vectors", + "suppression" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "In", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Suppression", + "of", + "hamartin", + "expression", + "with", + "TSC1", + "shRNA", + "viral", + "vectors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Suppression", + "of", + "hamartin", + "expression", + "with", + "TSC1", + "shRNA", + "viral", + "vectors" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Suppression", + "of", + "hamartin", + "expression", + "with", + "TSC1", + "shRNA", + "viral", + "vectors" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "hamartin" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "hamartin" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + } + ] + }, + { + "PMID": "23416703", + "TEXT": "Depression induces structural and functional synaptic plasticity in brain reward circuits, although the mechanisms promoting these changes and their relevance to behavioral outcomes are unknown. Transcriptional profiling of the nucleus accumbens (NAc) for Rho GTPase-related genes, which are known regulators of synaptic structure, revealed a sustained reduction in RAS-related C3 botulinum toxin substrate 1 (Rac1) expression after chronic social defeat stress. This was associated with a repressive chromatin state surrounding the proximal promoter of Rac1. Inhibition of class 1 histone deacetylases (HDACs) with MS-275 rescued both the decrease in Rac1 transcription after social defeat stress and depression-related behavior, such as social avoidance. We found a similar repressive chromatin state surrounding the RAC1 promoter in the NAc of subjects with depression, which corresponded with reduced RAC1 transcription. Viral-mediated reduction of Rac1 expression or inhibition of Rac1 activity in the NAc increases social defeat-induced social avoidance and anhedonia in mice. Chronic social defeat stress induces the formation of stubby excitatory spines through a Rac1-dependent mechanism involving the redistribution of synaptic cofilin, an actin-severing protein downstream of Rac1. Overexpression of constitutively active Rac1 in the NAc of mice after chronic social defeat stress reverses depression-related behaviors and prunes stubby spines. Taken together, our data identify epigenetic regulation of RAC1 in the NAc as a disease mechanism in depression and reveal a functional role for Rac1 in rodents in regulating stress-related behaviors.", + "TAG_DATA": [ + "126, Viral-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "127, reduction {'perturbing_action': 'I-rnai/knockdown'}", + "128, of {'perturbing_action': 'I-rnai/knockdown'}", + "129, Rac1 {'perturbing_action': 'I-rnai/knockdown'}", + "130, expression {'perturbing_action': 'I-rnai/knockdown'}", + "132, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "133, of {'perturbing_action': 'I-pharmacological inhibition'}", + "134, Rac1 {'perturbing_action': 'I-pharmacological inhibition'}", + "135, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "136, in {'perturbing_action': 'I-pharmacological inhibition'}", + "137, the {'perturbing_action': 'I-pharmacological inhibition'}", + "138, NAc {'perturbing_action': 'I-pharmacological inhibition'}", + "147, mice. {'context': 'B-organism'}", + "175, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "176, of {'perturbing_action': 'I-gene gain-of-function'}", + "177, constitutively {'perturbing_action': 'I-gene gain-of-function'}", + "178, active {'perturbing_action': 'I-gene gain-of-function'}", + "179, Rac1 {'perturbing_action': 'I-gene gain-of-function'}", + "182, NAc {'context': 'B-tissue/organ'}", + "184, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "126, Viral-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "127, reduction ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "128, of ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "129, Rac1 ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "130, expression ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "132, inhibition ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "133, of ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "134, Rac1 ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l58', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "135, activity ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l59', 'l65', 'l71', 'l72', 'l73', 'l74']", + "136, in ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l60', 'l66', 'l71', 'l75', 'l76', 'l77']", + "137, the ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l61', 'l67', 'l72', 'l75', 'l78', 'l79']", + "138, NAc ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l62', 'l68', 'l73', 'l76', 'l78', 'l80']", + "147, mice. ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l63', 'l69', 'l74', 'l77', 'l79', 'l80']", + "175, Overexpression ['l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "176, of ['l81', 'l87', 'l88', 'l89', 'l90', 'l91']", + "177, constitutively ['l82', 'l87', 'l92', 'l93', 'l94', 'l95']", + "178, active ['l83', 'l88', 'l92', 'l96', 'l97', 'l98']", + "179, Rac1 ['l84', 'l89', 'l93', 'l96', 'l99', 'l100']", + "182, NAc ['l57', 'l64', 'l70', 'l85', 'l90', 'l94', 'l97', 'l99', 'l101']", + "184, mice ['l86', 'l91', 'l95', 'l98', 'l100', 'l101']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Viral-mediated", + "reduction", + "of", + "Rac1", + "expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "Rac1", + "activity", + "in", + "the", + "NAc" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "Rac1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "NAc" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "constitutively", + "active", + "Rac1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "NAc" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "constitutively", + "active", + "Rac1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23416702", + "TEXT": "Enhanced fetal γ-globin synthesis alleviates symptoms of β-globinopathies such as sickle cell disease and β-thalassemia, but current γ-globin-inducing drugs offer limited beneficial effects. We show here that lysine-specific demethylase 1 (LSD1) inhibition by RNAi in human erythroid cells or by the monoamine oxidase inhibitor tranylcypromine in human erythroid cells or β-type globin-transgenic mice enhances γ-globin expression. LSD1 is thus a promising therapeutic target for γ-globin induction, and tranylcypromine may serve as a lead compound for the development of a new γ-globin inducer.", + "TAG_DATA": [ + "27, lysine-specific {'perturbing_action': 'B-pharmacological inhibition'}", + "28, demethylase {'perturbing_action': 'I-pharmacological inhibition'}", + "29, 1 {'perturbing_action': 'I-pharmacological inhibition'}", + "30, (LSD1) {'perturbing_action': 'I-pharmacological inhibition'}", + "31, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "32, by {'perturbing_action': 'I-rnai/knockdown'}", + "33, RNAi {'perturbing_action': 'I-rnai/knockdown'}", + "35, human {'context': 'B-cells'}", + "36, erythroid {'context': 'I-cells'}", + "37, cells {'context': 'I-cells'}", + "46, human {'context': 'B-cells'}", + "47, erythroid {'context': 'I-cells'}", + "48, cells {'context': 'I-cells'}", + "50, β-type {'perturbing_action': 'B-gene gain-of-function'}", + "51, globin-transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "52, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "27, lysine-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "28, demethylase ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "29, 1 ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "30, (LSD1) ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "31, inhibition ['l3', 'l15', 'l26', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "32, by ['l4', 'l16', 'l27', 'l37', 'l45', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "33, RNAi ['l5', 'l17', 'l28', 'l38', 'l46', 'l53', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "35, human ['l6', 'l18', 'l29', 'l39', 'l47', 'l54', 'l60', 'l66', 'l67', 'l68', 'l69', 'l70']", + "36, erythroid ['l7', 'l19', 'l30', 'l40', 'l48', 'l55', 'l61', 'l66', 'l71', 'l72', 'l73', 'l74']", + "37, cells ['l8', 'l20', 'l31', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l75']", + "46, human ['l9', 'l21', 'l32', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l76', 'l77', 'l78', 'l79', 'l80']", + "47, erythroid ['l10', 'l22', 'l33', 'l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l76', 'l81', 'l82', 'l83', 'l84']", + "48, cells ['l11', 'l23', 'l34', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l75', 'l77', 'l81', 'l85', 'l86', 'l87']", + "50, β-type ['l78', 'l82', 'l85', 'l88', 'l89']", + "51, globin-transgenic ['l12', 'l24', 'l35', 'l79', 'l83', 'l86', 'l88', 'l90']", + "52, mice ['l80', 'l84', 'l87', 'l89', 'l90']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "lysine-specific", + "demethylase", + "1", + "(LSD1)", + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "erythroid", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "by", + "RNAi" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "erythroid", + "cells" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "erythroid", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "β-type", + "globin-transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "β-type", + "globin-transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23178247", + "TEXT": "The pathology of Alzheimer's disease has an inflammatory component that is characterized by upregulation of proinflammatory cytokines, particularly in response to amyloid-β (Aβ). Using the APPPS1 Alzheimer's disease mouse model, we found increased production of the common interleukin-12 (IL-12) and IL-23 subunit p40 by microglia. Genetic ablation of the IL-12/IL-23 signaling molecules p40, p35 or p19, in which deficiency of p40 or its receptor complex had the strongest effect, resulted in decreased cerebral amyloid load. Although deletion of IL-12/IL-23 signaling from the radiation-resistant glial compartment of the brain was most efficient in mitigating cerebral amyloidosis, peripheral administration of a neutralizing p40-specific antibody likewise resulted in a reduction of cerebral amyloid load in APPPS1 mice. Furthermore, intracerebroventricular delivery of antibodies to p40 significantly reduced the concentration of soluble Aβ species and reversed cognitive deficits in aged APPPS1 mice. The concentration of p40 was also increased in the cerebrospinal fluid of subjects with Alzheimer's disease, which suggests that inhibition of the IL-12/IL-23 pathway may attenuate Alzheimer's disease pathology and cognitive deficits.", + "TAG_DATA": [ + "44, microglia. {'context': 'B-cells'}", + "45, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "46, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "47, of {'perturbing_action': 'I-gene loss-of-function'}", + "48, the {'perturbing_action': 'I-gene loss-of-function'}", + "49, IL-12/IL-23 {'perturbing_action': 'I-gene loss-of-function'}", + "50, signaling {'perturbing_action': 'I-gene loss-of-function'}", + "51, molecules {'perturbing_action': 'I-gene loss-of-function'}", + "52, p40, {'perturbing_action': 'I-gene loss-of-function'}", + "53, p35 {'perturbing_action': 'I-gene loss-of-function'}", + "54, or {'perturbing_action': 'I-gene loss-of-function'}", + "55, p19, {'perturbing_action': 'I-gene loss-of-function'}", + "58, deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "59, of {'perturbing_action': 'I-gene loss-of-function'}", + "60, p40 {'perturbing_action': 'I-gene loss-of-function'}", + "61, or {'perturbing_action': 'I-gene loss-of-function'}", + "62, its {'perturbing_action': 'I-gene loss-of-function'}", + "63, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "64, complex {'perturbing_action': 'I-gene loss-of-function'}", + "81, the {'perturbing_action': 'I-gene loss-of-function'}", + "82, radiation-resistant {'context': 'B-cells'}", + "83, glial {'context': 'I-cells'}", + "84, compartment {'context': 'I-cells'}", + "85, of {'context': 'I-cells'}", + "112, APPPS1 {'context': 'B-organism'}", + "113, mice. {'context': 'I-organism'}", + "134, aged {'context': 'B-organism'}", + "135, APPPS1 {'context': 'I-organism'}", + "136, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "45, Genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "46, ablation ['l0', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "47, of ['l1', 'l24', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "48, the ['l2', 'l25', 'l48', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "49, IL-12/IL-23 ['l3', 'l26', 'l49', 'l71', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "50, signaling ['l4', 'l27', 'l50', 'l72', 'l93', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "51, molecules ['l5', 'l28', 'l51', 'l73', 'l94', 'l114', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "52, p40, ['l6', 'l29', 'l52', 'l74', 'l95', 'l115', 'l134', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170']", + "53, p35 ['l7', 'l30', 'l53', 'l75', 'l96', 'l116', 'l135', 'l153', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "54, or ['l8', 'l31', 'l54', 'l76', 'l97', 'l117', 'l136', 'l154', 'l171', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203']", + "55, p19, ['l9', 'l32', 'l55', 'l77', 'l98', 'l118', 'l137', 'l155', 'l172', 'l188', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218']", + "58, deficiency ['l10', 'l33', 'l56', 'l78', 'l99', 'l119', 'l138', 'l156', 'l173', 'l189', 'l204', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233']", + "59, of ['l11', 'l34', 'l57', 'l79', 'l100', 'l120', 'l139', 'l157', 'l174', 'l190', 'l205', 'l219', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247']", + "60, p40 ['l12', 'l35', 'l58', 'l80', 'l101', 'l121', 'l140', 'l158', 'l175', 'l191', 'l206', 'l220', 'l234', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261']", + "61, or ['l13', 'l36', 'l59', 'l81', 'l102', 'l122', 'l141', 'l159', 'l176', 'l192', 'l207', 'l221', 'l235', 'l248', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274']", + "62, its ['l14', 'l37', 'l60', 'l82', 'l103', 'l123', 'l142', 'l160', 'l177', 'l193', 'l208', 'l222', 'l236', 'l249', 'l262', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286']", + "63, receptor ['l15', 'l38', 'l61', 'l83', 'l104', 'l124', 'l143', 'l161', 'l178', 'l194', 'l209', 'l223', 'l237', 'l250', 'l263', 'l275', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297']", + "64, complex ['l16', 'l39', 'l62', 'l84', 'l105', 'l125', 'l144', 'l162', 'l179', 'l195', 'l210', 'l224', 'l238', 'l251', 'l264', 'l276', 'l287', 'l298', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304', 'l305', 'l306']", + "80, from ['l40', 'l63', 'l85', 'l106', 'l126', 'l145', 'l163', 'l180', 'l196', 'l211', 'l225', 'l239', 'l252', 'l265', 'l277', 'l288', 'l298', 'l307', 'l308', 'l309', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315']", + "81, the ['l17', 'l41', 'l64', 'l86', 'l107', 'l127', 'l146', 'l164', 'l181', 'l197', 'l212', 'l226', 'l240', 'l253', 'l266', 'l278', 'l289', 'l299', 'l307', 'l316', 'l317', 'l318', 'l319', 'l320', 'l321', 'l322', 'l323']", + "82, radiation-resistant ['l18', 'l42', 'l65', 'l87', 'l108', 'l128', 'l147', 'l165', 'l182', 'l198', 'l213', 'l227', 'l241', 'l254', 'l267', 'l279', 'l290', 'l300', 'l308', 'l316', 'l324', 'l325', 'l326', 'l327', 'l328', 'l329', 'l330']", + "83, glial ['l19', 'l43', 'l66', 'l88', 'l109', 'l129', 'l148', 'l166', 'l183', 'l199', 'l214', 'l228', 'l242', 'l255', 'l268', 'l280', 'l291', 'l301', 'l309', 'l317', 'l324', 'l331', 'l332', 'l333', 'l334', 'l335', 'l336']", + "84, compartment ['l20', 'l44', 'l67', 'l89', 'l110', 'l130', 'l149', 'l167', 'l184', 'l200', 'l215', 'l229', 'l243', 'l256', 'l269', 'l281', 'l292', 'l302', 'l310', 'l318', 'l325', 'l331', 'l337', 'l338', 'l339', 'l340', 'l341']", + "85, of ['l21', 'l45', 'l68', 'l90', 'l111', 'l131', 'l150', 'l168', 'l185', 'l201', 'l216', 'l230', 'l244', 'l257', 'l270', 'l282', 'l293', 'l303', 'l311', 'l319', 'l326', 'l332', 'l337', 'l342', 'l343', 'l344', 'l345']", + "86, the ['l22', 'l46', 'l69', 'l91', 'l112', 'l132', 'l151', 'l169', 'l186', 'l202', 'l217', 'l231', 'l245', 'l258', 'l271', 'l283', 'l294', 'l304', 'l312', 'l320', 'l327', 'l333', 'l338', 'l342', 'l346', 'l347', 'l348']", + "87, brain ['l23', 'l47', 'l70', 'l92', 'l113', 'l133', 'l152', 'l170', 'l187', 'l203', 'l218', 'l232', 'l246', 'l259', 'l272', 'l284', 'l295', 'l305', 'l313', 'l321', 'l328', 'l334', 'l339', 'l343', 'l346', 'l349', 'l350']", + "112, APPPS1 ['l260', 'l273', 'l285', 'l296', 'l314', 'l322', 'l329', 'l335', 'l340', 'l344', 'l347', 'l349', 'l351']", + "113, mice. ['l233', 'l247', 'l261', 'l274', 'l286', 'l297', 'l306', 'l315', 'l323', 'l330', 'l336', 'l341', 'l345', 'l348', 'l350', 'l351']", + "134, aged ['l352', 'l353']", + "135, APPPS1 ['l352', 'l354']", + "136, mice. ['l353', 'l354']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "ablation", + "of", + "the", + "IL-12/IL-23", + "signaling", + "molecules", + "p40,", + "p35", + "or", + "p19,", + "deficiency", + "p40", + "its", + "receptor", + "complex" + ] + }, + "context": { + "val": "cells", + "words": [ + "radiation-resistant", + "glial", + "compartment", + "of" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "of", + "p40", + "or", + "its", + "receptor", + "complex", + "the" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "APPPS1" + ] + } + } + ] + }, + { + "PMID": "23086476", + "TEXT": "The microenvironment, or niche, surrounding a stem cell largely governs its cellular fate. Two anatomical niches for hematopoietic stem cells (HSCs) have been reported in the bone marrow, but a distinct function for each of these niches remains unclear. Here we report a new role for the adhesion molecule E-selectin expressed exclusively by bone marrow endothelial cells in the vascular HSC niche. HSC quiescence was enhanced and self-renewal potential was increased in E-selectin knockout (Sele(-/-)) mice or after administration of an E-selectin antagonist, demonstrating that E-selectin promotes HSC proliferation and is a crucial component of the vascular niche. These effects are not mediated by canonical E-selectin ligands. Deletion or blockade of E-selectin enhances HSC survival threefold to sixfold after treatment of mice with chemotherapeutic agents or irradiation and accelerates blood neutrophil recovery. As bone marrow suppression is a severe side effect of high-dose chemotherapy, transient blockade of E-selectin is potentially a promising treatment for the protection of HSCs during chemotherapy or irradiation.", + "TAG_DATA": [ + "62, HSC {'context': 'B-transformed cells'}", + "63, quiescence {'phenotype': 'B-quiescence'}", + "65, enhanced {'effect': 'B-positive'}", + "67, self-renewal {'phenotype': 'B-self-renewal'}", + "68, potential {'phenotype': 'I-colony formation'}", + "70, increased {'effect': 'B-positive'}", + "72, E-selectin {'perturbing_action': 'B-gene loss-of-function'}", + "73, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "74, (Sele(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "75, mice {'context': 'B-organism'}", + "81, E-selectin {'perturbing_action': 'B-pharmacological inhibition'}", + "82, antagonist, {'perturbing_action': 'I-pharmacological inhibition'}", + "86, promotes {'effect': 'B-positive'}", + "88, proliferation {'phenotype': 'B-proliferation'}", + "109, blockade {'perturbing_action': 'B-gene loss-of-function'}", + "110, of {'perturbing_action': 'I-gene loss-of-function'}", + "111, E-selectin {'perturbing_action': 'I-gene loss-of-function'}", + "113, HSC {'context': 'B-transformed cells'}", + "121, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "62, HSC ['l0', 'l1']", + "63, quiescence ['l0', 'l2']", + "65, enhanced ['l1', 'l2']", + "67, self-renewal ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "68, potential ['l3', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "70, increased ['l4', 'l11', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "72, E-selectin ['l5', 'l12', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "73, knockout ['l6', 'l13', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32', 'l33']", + "74, (Sele(-/-)) ['l7', 'l14', 'l20', 'l25', 'l29', 'l34', 'l35', 'l36', 'l37', 'l38']", + "75, mice ['l8', 'l15', 'l21', 'l26', 'l30', 'l34', 'l39', 'l40']", + "81, E-selectin ['l35', 'l41', 'l42', 'l43']", + "82, antagonist, ['l31', 'l36', 'l41', 'l44', 'l45']", + "86, promotes ['l9', 'l16', 'l22', 'l27', 'l32', 'l37', 'l39', 'l42', 'l44', 'l46']", + "88, proliferation ['l10', 'l17', 'l23', 'l28', 'l33', 'l38', 'l40', 'l43', 'l45', 'l46']", + "109, blockade ['l47', 'l48', 'l49', 'l50']", + "110, of ['l47', 'l51', 'l52', 'l53']", + "111, E-selectin ['l48', 'l51', 'l54', 'l55']", + "113, HSC ['l49', 'l52', 'l54', 'l56']", + "121, mice ['l50', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "promotes" + ] + } + }, + { + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "E-selectin", + "knockout", + "(Sele(-/-))" + ] + } + }, + { + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "potential" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "promotes" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "potential" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "E-selectin", + "knockout", + "(Sele(-/-))" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "potential" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased", + "promotes" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "E-selectin", + "knockout", + "(Sele(-/-))" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased", + "promotes" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased", + "promotes" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "E-selectin", + "knockout", + "(Sele(-/-))", + "blockade", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "E-selectin", + "knockout", + "(Sele(-/-))" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "E-selectin", + "antagonist," + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "E-selectin", + "antagonist," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "blockade", + "of", + "E-selectin" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + } + } + ] + }, + { + "PMID": "23023500", + "TEXT": "The ability of the human immune system to respond to vaccination declines with age. We identified an age-associated defect in T cell receptor (TCR)-induced extracellular signal-regulated kinase (ERK) phosphorylation in naive CD4(+) T cells, whereas other signals, such as ζ chain-associated protein kinase 70 (ZAP70) and phospholipase C-γ1 phosphorylation, were not impaired. The defective ERK signaling was caused by the dual specific phosphatase 6 (DUSP6), whose protein expression increased with age due to a decline in repression by miR-181a. Reconstitution of miR-181a lowered DUSP6 expression in naive CD4(+) T cells in elderly individuals. DUSP6 repression using miR-181a or specific siRNA and DUSP6 inhibition by the allosteric inhibitor (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one improved CD4(+) T cell responses, as seen by increased expression of activation markers, improved proliferation and supported preferential T helper type 1 cell differentiation. DUSP6 is a potential intervention target for restoring T cell responses in the elderly, which may augment the effectiveness of vaccination.", + "TAG_DATA": [ + "86, naive {'context': 'B-cells'}", + "87, CD4(+) {'context': 'I-cells'}", + "88, T {'context': 'I-cells'}", + "89, cells {'context': 'I-cells'}", + "93, DUSP6 {'perturbing_action': 'B-rnai/knockdown'}", + "94, repression {'perturbing_action': 'I-rnai/knockdown'}", + "95, using {'perturbing_action': 'I-rnai/knockdown'}", + "96, miR-181a {'perturbing_action': 'I-rnai/knockdown'}", + "98, specific {'perturbing_action': 'B-rnai/knockdown'}", + "99, siRNA {'perturbing_action': 'I-rnai/knockdown'}", + "101, DUSP6 {'perturbing_action': 'B-pharmacological inhibition'}", + "102, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "103, by {'perturbing_action': 'I-pharmacological inhibition'}", + "104, the {'perturbing_action': 'I-pharmacological inhibition'}", + "105, allosteric {'perturbing_action': 'I-pharmacological inhibition'}", + "106, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "107, (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one {'perturbing_action': 'I-pharmacological inhibition'}", + "109, CD4(+) {'context': 'B-cells'}", + "110, T {'context': 'I-cells'}", + "111, cell {'context': 'I-cells'}", + "121, improved {'effect': 'B-positive'}", + "122, proliferation {'phenotype': 'B-proliferation'}", + "124, supported {'effect': 'B-positive'}", + "126, T {'context': 'B-cells'}", + "127, helper {'context': 'I-cells'}", + "128, type {'context': 'I-cells'}", + "129, 1 {'context': 'I-cells'}", + "130, cell {'context': 'I-cells'}", + "131, differentiation. {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "86, naive ['l0', 'l1', 'l2']", + "87, CD4(+) ['l0', 'l3', 'l4']", + "88, T ['l1', 'l3', 'l5']", + "89, cells ['l2', 'l4', 'l5']", + "93, DUSP6 ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "94, repression ['l6', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "95, using ['l7', 'l28', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "96, miR-181a ['l8', 'l29', 'l48', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "98, specific ['l9', 'l30', 'l49', 'l64', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "99, siRNA ['l10', 'l31', 'l50', 'l65', 'l82', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "101, DUSP6 ['l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "102, inhibition ['l115', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "103, by ['l11', 'l116', 'l133', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "104, the ['l12', 'l32', 'l66', 'l83', 'l99', 'l117', 'l134', 'l150', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180']", + "105, allosteric ['l13', 'l33', 'l67', 'l84', 'l100', 'l118', 'l135', 'l151', 'l166', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "106, inhibitor ['l14', 'l34', 'l51', 'l68', 'l85', 'l101', 'l119', 'l136', 'l152', 'l167', 'l181', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207']", + "107, (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one ['l15', 'l35', 'l52', 'l69', 'l86', 'l102', 'l120', 'l137', 'l153', 'l168', 'l182', 'l195', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219']", + "109, CD4(+) ['l16', 'l36', 'l53', 'l70', 'l87', 'l103', 'l121', 'l138', 'l154', 'l169', 'l183', 'l196', 'l208', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230']", + "110, T ['l17', 'l37', 'l54', 'l71', 'l88', 'l104', 'l122', 'l139', 'l155', 'l170', 'l184', 'l197', 'l209', 'l220', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240']", + "111, cell ['l18', 'l38', 'l55', 'l72', 'l89', 'l105', 'l123', 'l140', 'l156', 'l171', 'l185', 'l198', 'l210', 'l221', 'l231', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247']", + "121, improved ['l19', 'l39', 'l56', 'l73', 'l90', 'l106', 'l124', 'l141', 'l157', 'l172', 'l186', 'l199', 'l211', 'l222', 'l232', 'l241', 'l248', 'l249']", + "122, proliferation ['l20', 'l40', 'l57', 'l74', 'l91', 'l107', 'l125', 'l142', 'l158', 'l173', 'l187', 'l200', 'l212', 'l223', 'l233', 'l242', 'l248', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256']", + "124, supported ['l21', 'l41', 'l58', 'l75', 'l92', 'l108', 'l126', 'l143', 'l159', 'l174', 'l188', 'l201', 'l213', 'l224', 'l234', 'l243', 'l250', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262']", + "126, T ['l22', 'l42', 'l76', 'l93', 'l109', 'l127', 'l144', 'l160', 'l175', 'l189', 'l202', 'l214', 'l225', 'l235', 'l251', 'l257', 'l263', 'l264', 'l265', 'l266', 'l267']", + "127, helper ['l23', 'l43', 'l59', 'l77', 'l94', 'l110', 'l128', 'l145', 'l161', 'l176', 'l190', 'l203', 'l215', 'l226', 'l236', 'l252', 'l258', 'l263', 'l268', 'l269', 'l270', 'l271']", + "128, type ['l24', 'l44', 'l60', 'l78', 'l95', 'l111', 'l129', 'l146', 'l162', 'l177', 'l191', 'l204', 'l216', 'l227', 'l237', 'l244', 'l253', 'l259', 'l264', 'l268', 'l272', 'l273', 'l274']", + "129, 1 ['l25', 'l45', 'l61', 'l79', 'l96', 'l112', 'l130', 'l147', 'l163', 'l178', 'l192', 'l205', 'l217', 'l228', 'l238', 'l245', 'l254', 'l260', 'l265', 'l269', 'l272', 'l275', 'l276']", + "130, cell ['l26', 'l46', 'l62', 'l80', 'l97', 'l113', 'l131', 'l148', 'l164', 'l179', 'l193', 'l206', 'l218', 'l229', 'l239', 'l246', 'l255', 'l261', 'l266', 'l270', 'l273', 'l275', 'l277']", + "131, differentiation. ['l27', 'l47', 'l63', 'l81', 'l98', 'l114', 'l132', 'l149', 'l165', 'l180', 'l194', 'l207', 'l219', 'l230', 'l240', 'l247', 'l249', 'l256', 'l262', 'l267', 'l271', 'l274', 'l276', 'l277']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "DUSP6", + "repression", + "using", + "miR-181a", + "specific", + "siRNA" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cell", + "helper", + "type", + "1" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "DUSP6", + "repression", + "using", + "miR-181a", + "specific", + "siRNA" + ] + }, + "effect": { + "val": "positive", + "words": [ + "improved", + "supported" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "DUSP6", + "repression", + "using", + "miR-181a", + "specific", + "siRNA" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "DUSP6", + "repression", + "using", + "miR-181a", + "specific", + "siRNA" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "DUSP6", + "inhibition", + "by", + "the", + "allosteric", + "inhibitor", + "(E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cell", + "helper", + "type", + "1" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "DUSP6", + "inhibition", + "by", + "the", + "allosteric", + "inhibitor", + "(E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one" + ] + }, + "effect": { + "val": "positive", + "words": [ + "improved", + "supported" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "DUSP6", + "inhibition", + "by", + "the", + "allosteric", + "inhibitor", + "(E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "DUSP6", + "inhibition", + "by", + "the", + "allosteric", + "inhibitor", + "(E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cell", + "helper", + "type", + "1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "improved", + "supported" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cell", + "helper", + "type", + "1" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cell", + "helper", + "type", + "1" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "improved", + "supported" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "improved", + "supported" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + } + ] + }, + { + "PMID": "22983397", + "TEXT": "Conventional photodynamic therapy (PDT) is limited by the penetration depth of visible light needed for its activation. Here we used mesoporous-silica-coated upconversion fluorescent nanoparticles (UCNs) as a nanotransducer to convert deeply penetrating near-infrared light to visible wavelengths and a carrier of photosensitizers. We also used the multicolor-emission capability of the UCNs at a single excitation wavelength for simultaneous activation of two photosensitizers for enhanced PDT. We showed a greater PDT efficacy with the dual-photosensitizer approach compared to approaches using a single photosensitizer, as determined by enhanced generation of singlet oxygen and reduced cell viability. In vivo studies also showed tumor growth inhibition in PDT-treated mice by direct injection of UCNs into melanoma tumors or intravenous injection of UCNs conjugated with a tumor-targeting agent into tumor-bearing mice. As the first demonstration, to the best of our knowledge, of the photosensitizer-loaded UCN as an in vivo-targeted PDT agent, this finding may serve as a platform for future noninvasive deep-cancer therapy.", + "TAG_DATA": [ + "91, reduced {'effect': 'B-negative'}", + "92, cell {'phenotype': 'B-cell survival'}", + "93, viability. {'phenotype': 'I-cell survival'}", + "94, In {'context': 'B-in vivo'}", + "95, vivo {'context': 'I-in vivo'}", + "99, tumor {'phenotype': 'B-tumour growth'}", + "100, growth {'phenotype': 'I-tumour growth'}", + "101, inhibition {'effect': 'B-negative'}", + "104, mice {'context': 'B-organism'}", + "111, melanoma {'context': 'B-neoplasm'}", + "112, tumors {'context': 'I-neoplasm'}", + "124, tumor-bearing {'context': 'B-organism'}", + "125, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "91, reduced ['l0', 'l1']", + "92, cell ['l0', 'l2']", + "93, viability. ['l1', 'l2']", + "94, In ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "95, vivo ['l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "99, tumor ['l4', 'l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "100, growth ['l5', 'l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "101, inhibition ['l6', 'l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "104, mice ['l7', 'l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "111, melanoma ['l8', 'l14', 'l19', 'l23', 'l26', 'l28', 'l30']", + "112, tumors ['l9', 'l15', 'l20', 'l24', 'l27', 'l29', 'l30']", + "124, tumor-bearing ['l31']", + "125, mice. ['l31']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "viability." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "melanoma", + "tumors" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "melanoma", + "tumors" + ] + } + } + ] + }, + { + "PMID": "22941275", + "TEXT": "Cilia are evolutionarily conserved microtubule-based organelles that are crucial for diverse biological functions, including motility, cell signaling and sensory perception. In humans, alterations in the formation and function of cilia manifest clinically as ciliopathies, a growing class of pleiotropic genetic disorders. Despite the substantial progress that has been made in identifying genes that cause ciliopathies, therapies for these disorders are not yet available to patients. Although mice with a hypomorphic mutation in the intraflagellar transport protein IFT88 (Ift88Tg737Rpw mice, also known as ORPK mice)5 have been well studied, the relevance of IFT88 mutations to human pathology is unknown. We show that a mutation in IFT88 causes a hitherto unknown human ciliopathy. In vivo complementation assays in zebrafish and mIMCD3 cells show the pathogenicity of this newly discovered allele. We further show that ORPK mice are functionally anosmic as a result of the loss of cilia on their olfactory sensory neurons (OSNs). Notably, adenoviral-mediated expression of IFT88 in mature, fully differentiated OSNs of ORPK mice is sufficient to restore ciliary structures and rescue olfactory function. These studies are the first to use in vivo therapeutic treatment to reestablish cilia in a mammalian ciliopathy. More broadly, our studies indicate that gene therapy is a viable option for cellular and functional rescue of the complex ciliary organelle in established differentiated cells.", + "TAG_DATA": [ + "111, In {'context': 'B-in vivo'}", + "112, vivo {'context': 'I-in vivo'}", + "116, zebrafish {'context': 'B-organism'}", + "118, mIMCD3 {'context': 'B-cells'}", + "119, cells {'context': 'I-cells'}", + "133, mice {'context': 'B-organism'}", + "147, olfactory {'context': 'B-cells'}", + "148, sensory {'context': 'I-cells'}", + "149, neurons {'context': 'I-cells'}", + "150, (OSNs). {'context': 'I-cells'}", + "152, adenoviral-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "153, expression {'perturbing_action': 'I-gene gain-of-function'}", + "154, of {'perturbing_action': 'I-gene gain-of-function'}", + "155, IFT88 {'perturbing_action': 'I-gene gain-of-function'}", + "157, mature, {'context': 'B-cells'}", + "158, fully {'context': 'I-cells'}", + "159, differentiated {'context': 'I-cells'}", + "160, OSNs {'context': 'I-cells'}", + "162, ORPK {'perturbing_action': 'B-other', 'context': 'B-organism'}", + "163, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "111, In ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "112, vivo ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "116, zebrafish ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "118, mIMCD3 ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "119, cells ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "133, mice ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "147, olfactory ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "148, sensory ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "149, neurons ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "150, (OSNs). ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "152, adenoviral-mediated ['l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "153, expression ['l45', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "154, of ['l46', 'l54', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "155, IFT88 ['l47', 'l55', 'l62', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "157, mature, ['l48', 'l56', 'l63', 'l69', 'l75', 'l76', 'l77', 'l78', 'l79']", + "158, fully ['l49', 'l57', 'l64', 'l70', 'l75', 'l80', 'l81', 'l82', 'l83']", + "159, differentiated ['l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l84', 'l85', 'l86']", + "160, OSNs ['l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l87', 'l88']", + "162, ORPK ['l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l87', 'l89']", + "163, mice ['l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l89']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral-mediated", + "expression", + "of", + "IFT88" + ] + }, + "context": { + "val": "cells", + "words": [ + "mature,", + "fully", + "differentiated", + "OSNs" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral-mediated", + "expression", + "of", + "IFT88" + ] + }, + "context": { + "val": "organism", + "words": [ + "ORPK", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "ORPK" + ] + }, + "context": { + "val": "organism", + "words": [ + "ORPK" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mature,", + "fully", + "differentiated", + "OSNs" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "ORPK" + ] + } + } + ] + }, + { + "PMID": "22869182", + "TEXT": "There is currently much interest in dissecting the mechanisms of tumor immunity. A new study shows that a subset of CD4+ T cells that produce the cytokine interleukin-9 (IL-9) mediate inhibition of melanoma growth in mice and that analogous IL-9-producing T cells are present in human skin (pages 1248–1253). Could such cells be manipulated to develop new therapeutic strategies for melanoma?", + "TAG_DATA": [ + "30, inhibition {'effect': 'B-negative'}", + "32, melanoma {'context': 'B-neoplasm'}", + "33, growth {'phenotype': 'I-tumour growth'}", + "35, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "30, inhibition ['l0', 'l1', 'l2']", + "32, melanoma ['l0', 'l3', 'l4']", + "33, growth ['l1', 'l3', 'l5']", + "35, mice ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "melanoma" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "melanoma" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "22842477", + "TEXT": "Toll-like receptor 4 (TLR4) has a key role in innate immunity by activating an inflammatory signaling pathway. Free fatty acids (FFAs) stimulate adipose tissue inflammation through the TLR4 pathway, resulting in insulin resistance. However, current evidence suggests that FFAs do not directly bind to TLR4, but an endogenous ligand for TLR4 remains to be identified. Here we show that fetuin-A (FetA) could be this endogenous ligand and that it has a crucial role in regulating insulin sensitivity via Tlr4 signaling in mice. FetA (officially known as Ahsg) knockdown in mice with insulin resistance caused by a high-fat diet (HFD) resulted in downregulation of Tlr4-mediated inflammatory signaling in adipose tissue, whereas selective administration of FetA induced inflammatory signaling and insulin resistance. FFA-induced proinflammatory cytokine expression in adipocytes occurred only in the presence of both FetA and Tlr4; removing either of them prevented FFA-induced insulin resistance. We further found that FetA, through its terminal galactoside moiety, directly binds the residues of Leu100-Gly123 and Thr493-Thr516 in Tlr4. FFAs did not produce insulin resistance in adipocytes with mutated Tlr4 or galactoside-cleaved FetA. Taken together, our results suggest that FetA fulfills the requirement of an endogenous ligand for TLR4 through which lipids induce insulin resistance. This may position FetA as a new therapeutic target for managing insulin resistance and type 2 diabetes.", + "TAG_DATA": [ + "82, FetA {'perturbing_action': 'B-rnai/knockdown'}", + "83, (officially {'perturbing_action': 'I-rnai/knockdown'}", + "84, known {'perturbing_action': 'I-rnai/knockdown'}", + "85, as {'perturbing_action': 'I-rnai/knockdown'}", + "86, Ahsg) {'perturbing_action': 'I-rnai/knockdown'}", + "87, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "89, mice {'context': 'B-organism'}", + "107, adipose {'context': 'B-tissue/organ'}", + "108, tissue, {'context': 'I-tissue/organ'}", + "125, adipocytes {'context': 'B-cells'}", + "171, adipocytes {'context': 'B-cells'}", + "173, mutated {'perturbing_action': 'B-other'}", + "174, Tlr4 {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "82, FetA ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "83, (officially ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "84, known ['l1', 'l8', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "85, as ['l2', 'l9', 'l16', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "86, Ahsg) ['l3', 'l10', 'l17', 'l23', 'l29', 'l30', 'l31', 'l32']", + "87, knockdown ['l4', 'l11', 'l18', 'l24', 'l29', 'l33', 'l34', 'l35']", + "89, mice ['l5', 'l12', 'l19', 'l25', 'l30', 'l33', 'l36', 'l37']", + "107, adipose ['l6', 'l13', 'l20', 'l26', 'l31', 'l34', 'l36', 'l38']", + "108, tissue, ['l7', 'l14', 'l21', 'l27', 'l32', 'l35', 'l37', 'l38']", + "125, adipocytes ['l15', 'l22', 'l28']", + "171, adipocytes ['l39', 'l40']", + "173, mutated ['l39', 'l41']", + "174, Tlr4 ['l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "FetA", + "(officially", + "known", + "as", + "Ahsg)", + "knockdown" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "FetA", + "(officially", + "known", + "as", + "Ahsg)", + "knockdown" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "adipose", + "tissue," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "(officially", + "known", + "as" + ] + }, + "context": { + "val": "cells", + "words": [ + "adipocytes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "adipocytes" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "Tlr4" + ] + } + } + ] + }, + { + "PMID": "22772463", + "TEXT": "Exposure to ultraviolet B (UVB) radiation from the sun can result in sunburn, premature aging and carcinogenesis, but the mechanism responsible for acute inflammation of the skin is not well understood. Here we show that RNA is released from keratinocytes after UVB exposure and that this stimulates production of the inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) from nonirradiated keratinocytes and peripheral blood mononuclear cells (PBMCs). Whole-transcriptome sequencing revealed that UVB irradiation of keratinocytes induced alterations in the double-stranded domains of some noncoding RNAs. We found that this UVB-damaged RNA was sufficient to induce cytokine production from nonirradiated cells, as UVB irradiation of a purified noncoding RNA (U1 RNA) reproduced the same response as the one we observed to UVB-damaged keratinocytes. The responses to both UVB-damaged self-RNAs and UVB-damaged keratinocytes were dependent on Toll-like receptor 3 (TLR3) and Toll-like receptor adaptor molecule 1 (TRIF). In response to UVB exposure, Tlr3(-/-) mice did not upregulate TNF-α in the skin. Moreover, TLR3 was also necessary for UVB-radiation-induced immune suppression. These findings establish that UVB damage is detected by TLR3 and that self-RNA is a damage-associated molecular pattern that serves as an endogenous signal of solar injury.", + "TAG_DATA": [ + "76, keratinocytes {'context': 'B-cells'}", + "101, cells, {'context': 'I-cells'}", + "123, keratinocytes. {'context': 'B-cells'}", + "132, keratinocytes {'context': 'B-cells'}", + "152, Tlr3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "153, mice {'context': 'B-organism'}", + "160, skin. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "76, keratinocytes ['l0']", + "101, cells, ['l0']", + "123, keratinocytes. ['l1']", + "132, keratinocytes ['l1', 'l2']", + "152, Tlr3(-/-) ['l3', 'l4']", + "153, mice ['l3', 'l5']", + "160, skin. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tlr3(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tlr3(-/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skin." + ] + } + } + ] + }, + { + "PMID": "22706386", + "TEXT": "Duplication of PLP1 (proteolipid protein gene 1) and the subsequent overexpression of the myelin protein PLP (also known as DM20) in oligodendrocytes is the most frequent cause of Pelizaeus-Merzbacher disease (PMD), a fatal leukodystrophy without therapeutic options. PLP binds cholesterol and is contained within membrane lipid raft microdomains. Cholesterol availability is the rate-limiting factor of central nervous system myelin synthesis. Transgenic mice with extra copies of the Plp1 gene are accurate models of PMD. Dysmyelination followed by demyelination, secondary inflammation and axon damage contribute to the severe motor impairment in these mice. The finding that in Plp1-transgenic oligodendrocytes, PLP and cholesterol accumulate in late endosomes and lysosomes (endo/lysosomes), prompted us to further investigate the role of cholesterol in PMD. Here we show that cholesterol itself promotes normal PLP trafficking and that dietary cholesterol influences PMD pathology. In a preclinical trial, PMD mice were fed a cholesterol-enriched diet. This restored oligodendrocyte numbers and ameliorated intracellular PLP accumulation. Moreover, myelin content increased, inflammation and gliosis were reduced and motor defects improved. Even after onset of clinical symptoms, cholesterol treatment prevented disease progression. Dietary cholesterol did not reduce Plp1 overexpression but facilitated incorporation of PLP into myelin membranes. These findings may have implications for therapeutic interventions in patients with PMD.", + "TAG_DATA": [ + "96, Plp1-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "97, oligodendrocytes, {'context': 'B-cells'}", + "140, PMD {'context': 'B-organism'}", + "141, mice {'context': 'I-organism'}", + "149, oligodendrocyte {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "96, Plp1-transgenic ['l0', 'l1']", + "97, oligodendrocytes, ['l0']", + "140, PMD ['l2', 'l3']", + "141, mice ['l2', 'l4']", + "149, oligodendrocyte ['l1', 'l3', 'l4']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Plp1-transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "oligodendrocytes,", + "oligodendrocyte" + ] + } + } + ] + }, + { + "PMID": "22581285", + "TEXT": "This study establishes a mechanism for metabolic hyperalgesia based on the glycolytic metabolite methylglyoxal. We found that concentrations of plasma methylglyoxal above 600 nM discriminate between diabetes-affected individuals with pain and those without pain. Methylglyoxal depolarizes sensory neurons and induces post-translational modifications of the voltage-gated sodium channel Na(v)1.8, which are associated with increased electrical excitability and facilitated firing of nociceptive neurons, whereas it promotes the slow inactivation of Na(v)1.7. In mice, treatment with methylglyoxal reduces nerve conduction velocity, facilitates neurosecretion of calcitonin gene-related peptide, increases cyclooxygenase-2 (COX-2) expression and evokes thermal and mechanical hyperalgesia. This hyperalgesia is reflected by increased blood flow in brain regions that are involved in pain processing. We also found similar changes in streptozotocin-induced and genetic mouse models of diabetes but not in Na(v)1.8 knockout (Scn10(-/-)) mice. Several strategies that include a methylglyoxal scavenger are effective in reducing methylglyoxal- and diabetes-induced hyperalgesia. This previously undescribed concept of metabolically driven hyperalgesia provides a new basis for the design of therapeutic interventions for painful diabetic neuropathy.", + "TAG_DATA": [ + "70, mice, {'context': 'B-organism'}", + "120, mouse {'context': 'B-organism'}", + "121, models {'context': 'I-organism'}", + "127, Na(v)1.8 {'perturbing_action': 'B-gene loss-of-function'}", + "128, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "129, (Scn10(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "130, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "120, mouse ['l0', 'l1', 'l2', 'l3']", + "121, models ['l0', 'l4', 'l5']", + "127, Na(v)1.8 ['l1', 'l4', 'l6', 'l7', 'l8']", + "128, knockout ['l2', 'l5', 'l6', 'l9', 'l10']", + "129, (Scn10(-/-)) ['l3', 'l7', 'l9', 'l11']", + "130, mice. ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Na(v)1.8", + "knockout", + "(Scn10(-/-))" + ] + } + } + ] + }, + { + "PMID": "22561687", + "TEXT": "T cell immunity can potentially eradicate malignant cells and lead to clinical remission in a minority of patients with cancer. In the majority of these individuals, however, there is a failure of the specific T cell receptor (TCR)–mediated immune recognition and activation process. Here we describe the engineering and characterization of new reagents termed immune-mobilizing monoclonal TCRs against cancer (ImmTACs). Four such ImmTACs, each comprising a distinct tumor-associated epitope-specific monoclonal TCR with picomolar affinity fused to a humanized cluster of differentiation 3 (CD3)-specific single-chain antibody fragment (scFv), effectively redirected T cells to kill cancer cells expressing extremely low surface epitope densities. Furthermore, these reagents potently suppressed tumor growth in vivo. Thus, ImmTACs overcome immune tolerance to cancer and represent a new approach to tumor immunotherapy.", + "TAG_DATA": [ + "89, T {'context': 'B-cells'}", + "90, cells {'context': 'B-cells'}", + "93, cancer {'context': 'B-transformed cells'}", + "94, cells {'context': 'I-transformed cells'}", + "105, suppressed {'effect': 'B-negative'}", + "106, tumor {'phenotype': 'B-tumour growth'}", + "107, growth {'phenotype': 'I-tumour growth'}", + "108, in {'context': 'B-in vivo'}", + "109, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "89, T ['l0', 'l1', 'l2']", + "90, cells ['l0', 'l3', 'l4']", + "93, cancer ['l1', 'l3', 'l5']", + "94, cells ['l2', 'l4', 'l5']", + "105, suppressed ['l6', 'l7', 'l8', 'l9']", + "106, tumor ['l6', 'l10', 'l11', 'l12']", + "107, growth ['l7', 'l10', 'l13', 'l14']", + "108, in ['l8', 'l11', 'l13', 'l15']", + "109, vivo. ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "22447075", + "TEXT": "Chronic pain is highly variable between individuals, as is the response to analgesics. Although much of the variability in chronic pain and analgesic response is heritable, an understanding of the genetic determinants underlying this variability is rudimentary. Here we show that variation within the coding sequence of the gene encoding the P2X7 receptor (P2X7R) affects chronic pain sensitivity in both mice and humans. P2X7Rs, which are members of the family of ionotropic ATP-gated receptors, have two distinct modes of function: they can function through their intrinsic cationic channel or by forming nonselective pores that are permeable to molecules with a mass of up to 900 Da. Using genome-wide linkage analyses, we discovered an association between nerve-injury-induced pain behavior (mechanical allodynia) and the P451L mutation of the mouse P2rx7 gene, such that mice in which P2X7Rs have impaired pore formation as a result of this mutation showed less allodynia than mice with the pore-forming P2rx7 allele. Administration of a peptide corresponding to the P2X7R C-terminal domain, which blocked pore formation but not cation channel activity, selectively reduced nerve injury and inflammatory allodynia only in mice with the pore-forming P2rx7 allele. Moreover, in two independent human chronic pain cohorts, a cohort with pain after mastectomy and a cohort with osteoarthritis, we observed a genetic association between lower pain intensity and the hypofunctional His270 (rs7958311) allele of P2RX7. Our findings suggest that selectively targeting P2X7R pore formation may be a new strategy for individualizing the treatment of chronic pain.", + "TAG_DATA": [ + "122, P451L {'perturbing_action': 'B-other'}", + "123, mutation {'perturbing_action': 'I-other'}", + "124, of {'perturbing_action': 'I-other'}", + "125, the {'perturbing_action': 'I-other'}", + "126, mouse {'perturbing_action': 'I-other'}", + "127, P2rx7 {'perturbing_action': 'I-other'}", + "128, gene, {'perturbing_action': 'I-other'}", + "131, mice {'context': 'B-organism'}", + "149, mice {'context': 'B-organism'}", + "183, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "122, P451L ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "123, mutation ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "124, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "125, the ['l2', 'l9', 'l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "126, mouse ['l3', 'l10', 'l16', 'l22', 'l28', 'l29', 'l30', 'l31']", + "127, P2rx7 ['l4', 'l11', 'l17', 'l23', 'l28', 'l32', 'l33', 'l34']", + "128, gene, ['l5', 'l12', 'l18', 'l24', 'l29', 'l32', 'l35']", + "131, mice ['l6', 'l13', 'l19', 'l25', 'l30', 'l33', 'l35', 'l36', 'l37', 'l38']", + "149, mice ['l7', 'l14', 'l20', 'l26', 'l31', 'l34', 'l36', 'l39', 'l40']", + "153, P2rx7 ['l37', 'l39', 'l41']", + "154, allele. ['l21', 'l27', 'l38', 'l40', 'l41']", + "183, mice ['l42', 'l43']", + "187, P2rx7 ['l42', 'l44']", + "188, allele. ['l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "P451L", + "mutation", + "of", + "the", + "mouse", + "P2rx7", + "gene," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "22366950", + "TEXT": "CD4-unhelped CD8(+) T cells are functionally defective T cells primed in the absence of CD4(+) T cell help. Given the co-stimulatory role of natural-killer group 2, member D protein (NKG2D) on CD8(+) T cells, we investigated its ability to rescue these immunologically impotent cells. We demonstrate that augmented co-stimulation through NKG2D during priming paradoxically rescues memory, but not effector, CD8(+) T cell responses. NKG2D-mediated rescue is characterized by reversal of elevated transcription factor T-box expressed in T cells (T-bet) expression and recovery of interleukin-2 and interferon-γ production and cytolytic responses. Rescue is abrogated in CD8(+) T cells lacking NKG2D. Augmented co-stimulation through NKG2D confers a high rate of survival to mice lacking CD4(+) T cells in a CD4-dependent influenza model and rescues HIV-specific CD8(+) T cell responses from CD4-deficient HIV-positive donors. These findings demonstrate that augmented co-stimulation through NKG2D is effective in rescuing CD4-unhelped CD8(+) T cells from their pathophysiological fate and may provide therapeutic benefits.", + "TAG_DATA": [ + "58, effector, {'context': 'B-cells'}", + "59, CD8(+) {'context': 'B-cells'}", + "60, T {'context': 'I-cells'}", + "61, cell {'context': 'I-cells'}", + "94, CD8(+) {'context': 'B-cells'}", + "95, T {'context': 'I-cells'}", + "96, cells {'context': 'I-cells'}", + "97, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "98, NKG2D. {'perturbing_action': 'I-gene loss-of-function'}", + "110, mice {'context': 'B-organism'}", + "112, CD4(+) {'context': 'B-cells'}", + "113, T {'context': 'I-cells'}", + "114, cells {'context': 'I-cells'}", + "123, CD8(+) {'context': 'B-cells'}", + "124, T {'context': 'I-cells'}", + "125, cell {'context': 'I-cells'}", + "128, CD4-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "129, HIV-positive {'context': 'B-organism'}", + "130, donors. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "58, effector, ['l0', 'l1', 'l2']", + "59, CD8(+) ['l0', 'l3', 'l4']", + "60, T ['l1', 'l3', 'l5']", + "61, cell ['l2', 'l4', 'l5']", + "94, CD8(+) ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "95, T ['l6', 'l14', 'l15', 'l16', 'l17', 'l18']", + "96, cells ['l7', 'l14', 'l19', 'l20', 'l21', 'l22']", + "97, lacking ['l8', 'l15', 'l19', 'l23', 'l24', 'l25', 'l26', 'l27']", + "98, NKG2D. ['l9', 'l16', 'l20', 'l23', 'l28', 'l29', 'l30', 'l31']", + "110, mice ['l10', 'l24', 'l28', 'l32', 'l33', 'l34', 'l35', 'l36']", + "112, CD4(+) ['l11', 'l25', 'l29', 'l32', 'l37', 'l38', 'l39', 'l40']", + "113, T ['l12', 'l17', 'l21', 'l26', 'l30', 'l33', 'l37', 'l41']", + "114, cells ['l13', 'l18', 'l22', 'l27', 'l31', 'l34', 'l38', 'l41']", + "123, CD8(+) ['l42', 'l43', 'l44', 'l45', 'l46']", + "124, T ['l35', 'l39', 'l42', 'l47', 'l48', 'l49', 'l50']", + "125, cell ['l36', 'l40', 'l43', 'l47', 'l51', 'l52', 'l53']", + "128, CD4-deficient ['l44', 'l48', 'l51', 'l54', 'l55']", + "129, HIV-positive ['l45', 'l49', 'l52', 'l54', 'l56']", + "130, donors. ['l46', 'l50', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "T", + "cells", + "CD4(+)", + "cell" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "NKG2D.", + "CD4-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "NKG2D.", + "CD4-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "HIV-positive", + "donors." + ] + } + } + ] + }, + { + "PMID": "22344298", + "TEXT": "In advanced cancer, including glioblastoma, the transforming growth factor β (TGF-β) pathway acts as an oncogenic factor and is considered to be a therapeutic target. Using a functional RNAi screen, we identified the deubiquitinating enzyme ubiquitin-specific peptidase 15 (USP15) as a key component of the TGF-β signaling pathway. USP15 binds to the SMAD7-SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) complex and deubiquitinates and stabilizes type I TGF-β receptor (TβR-I), leading to an enhanced TGF-β signal. High expression of USP15 correlates with high TGF-β activity, and the USP15 gene is found amplified in glioblastoma, breast and ovarian cancer. USP15 amplification confers poor prognosis in individuals with glioblastoma. Downregulation or inhibition of USP15 in a patient-derived orthotopic mouse model of glioblastoma decreases TGF-β activity. Moreover, depletion of USP15 decreases the oncogenic capacity of patient-derived glioma-initiating cells due to the repression of TGF-β signaling. Our results show that USP15 regulates the TGF-β pathway and is a key factor in glioblastoma pathogenesis.", + "TAG_DATA": [ + "109, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "110, of {'perturbing_action': 'I-pharmacological inhibition'}", + "111, USP15 {'perturbing_action': 'I-pharmacological inhibition'}", + "114, patient-derived {'context': 'B-organism'}", + "115, orthotopic {'context': 'I-neoplasm'}", + "116, mouse {'context': 'I-neoplasm'}", + "117, model {'context': 'I-neoplasm'}", + "118, of {'context': 'I-neoplasm'}", + "119, glioblastoma {'context': 'I-neoplasm'}", + "124, depletion {'perturbing_action': 'B-gene loss-of-function'}", + "125, of {'perturbing_action': 'I-gene loss-of-function'}", + "126, USP15 {'perturbing_action': 'I-gene loss-of-function'}", + "127, decreases {'effect': 'B-negative'}", + "129, oncogenic {'phenotype': 'B-tumourigenesis'}", + "130, capacity {'phenotype': 'I-tumour initiation'}", + "132, patient-derived {'context': 'B-cells'}", + "133, glioma-initiating {'context': 'I-cells'}", + "134, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "109, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "110, of ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "111, USP15 ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "114, patient-derived ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "115, orthotopic ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "116, mouse ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "117, model ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "118, of ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "119, glioblastoma ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "124, depletion ['l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "125, of ['l36', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "126, USP15 ['l37', 'l44', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "127, decreases ['l38', 'l45', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "129, oncogenic ['l39', 'l46', 'l52', 'l57', 'l62', 'l63', 'l64', 'l65']", + "130, capacity ['l40', 'l47', 'l53', 'l58', 'l62', 'l66', 'l67', 'l68']", + "132, patient-derived ['l41', 'l48', 'l54', 'l59', 'l63', 'l66', 'l69', 'l70']", + "133, glioma-initiating ['l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l71']", + "134, cells ['l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l71']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "USP15" + ] + }, + "context": { + "val": "organism", + "words": [ + "patient-derived" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "USP15" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "orthotopic", + "mouse", + "model", + "of", + "glioblastoma" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "USP15" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreases" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "USP15" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "oncogenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "USP15" + ] + }, + "phenotype": { + "val": "tumour initiation", + "words": [ + "capacity" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "USP15" + ] + }, + "context": { + "val": "cells", + "words": [ + "patient-derived", + "glioma-initiating", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreases" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "oncogenic" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreases" + ] + }, + "phenotype": { + "val": "tumour initiation", + "words": [ + "capacity" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreases" + ] + }, + "context": { + "val": "cells", + "words": [ + "patient-derived", + "glioma-initiating", + "cells" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "oncogenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "patient-derived", + "glioma-initiating", + "cells" + ] + } + }, + { + "phenotype": { + "val": "tumour initiation", + "words": [ + "capacity" + ] + }, + "context": { + "val": "cells", + "words": [ + "patient-derived", + "glioma-initiating", + "cells" + ] + } + } + ] + }, + { + "PMID": "22344295", + "TEXT": "Considerable data support the idea that forkhead box O1 (Foxo1) drives the liver transcriptional program during fasting and is then inhibited by thymoma viral proto-oncogene 1 (Akt) after feeding. Here we show that mice with hepatic deletion of Akt1 and Akt2 were glucose intolerant, insulin resistant and defective in their transcriptional response to feeding in the liver. These defects were normalized with concomitant liver-specific deletion of Foxo1. Notably, in the absence of both Akt and Foxo1, mice adapted appropriately to both the fasted and fed state, and insulin suppressed hepatic glucose production normally. A gene expression analysis revealed that deletion of Akt in liver led to the constitutive activation of Foxo1-dependent gene expression, but again, concomitant ablation of Foxo1 restored postprandial regulation, preventing the inhibition of the metabolic response to nutrient intake caused by deletion of Akt. These results are inconsistent with the canonical model of hepatic metabolism in which Akt is an obligate intermediate for proper insulin signaling. Rather, they show that a major role of hepatic Akt is to restrain the activity of Foxo1 and that in the absence of Foxo1, Akt is largely dispensable for insulin- and nutrient-mediated hepatic metabolic regulation in vivo.", + "TAG_DATA": [ + "33, mice {'context': 'B-organism'}", + "35, hepatic {'perturbing_action': 'B-gene loss-of-function'}", + "36, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "37, of {'perturbing_action': 'I-gene loss-of-function'}", + "38, Akt1 {'perturbing_action': 'I-gene loss-of-function'}", + "39, and {'perturbing_action': 'I-gene loss-of-function'}", + "40, Akt2 {'perturbing_action': 'I-gene loss-of-function'}", + "56, liver. {'context': 'B-tissue/organ'}", + "62, concomitant {'perturbing_action': 'B-gene loss-of-function'}", + "63, liver-specific {'perturbing_action': 'B-gene loss-of-function'}", + "64, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "65, of {'perturbing_action': 'I-gene loss-of-function'}", + "66, Foxo1. {'perturbing_action': 'I-gene loss-of-function'}", + "70, absence {'perturbing_action': 'B-gene loss-of-function'}", + "71, of {'perturbing_action': 'I-gene loss-of-function'}", + "72, both {'perturbing_action': 'I-gene loss-of-function'}", + "73, Akt {'perturbing_action': 'I-gene loss-of-function'}", + "74, and {'perturbing_action': 'I-gene loss-of-function'}", + "75, Foxo1, {'perturbing_action': 'I-gene loss-of-function'}", + "76, mice {'context': 'B-organism'}", + "99, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "100, of {'perturbing_action': 'I-gene loss-of-function'}", + "101, Akt {'perturbing_action': 'I-gene loss-of-function'}", + "103, liver {'context': 'B-tissue/organ'}", + "116, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "117, of {'perturbing_action': 'I-gene loss-of-function'}", + "118, Foxo1 {'perturbing_action': 'I-gene loss-of-function'}", + "134, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "135, of {'perturbing_action': 'I-gene loss-of-function'}", + "136, Akt. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "33, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "35, hepatic ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "36, deletion ['l1', 'l7', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "37, of ['l2', 'l8', 'l18', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "38, Akt1 ['l3', 'l9', 'l19', 'l32', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "39, and ['l4', 'l10', 'l20', 'l33', 'l47', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "40, Akt2 ['l5', 'l11', 'l21', 'l34', 'l48', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67']", + "56, liver. ['l6', 'l12', 'l22', 'l35', 'l49', 'l56', 'l63']", + "62, concomitant ['l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "63, liver-specific ['l13', 'l23', 'l36', 'l50', 'l57', 'l64', 'l68', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "64, deletion ['l14', 'l24', 'l37', 'l51', 'l58', 'l69', 'l83', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "65, of ['l15', 'l25', 'l38', 'l52', 'l59', 'l65', 'l70', 'l84', 'l96', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "66, Foxo1. ['l16', 'l26', 'l39', 'l53', 'l60', 'l66', 'l71', 'l85', 'l97', 'l109', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "70, absence ['l27', 'l40', 'l72', 'l86', 'l98', 'l110', 'l120', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139']", + "71, of ['l41', 'l73', 'l87', 'l99', 'l111', 'l121', 'l130', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "72, both ['l42', 'l74', 'l88', 'l100', 'l112', 'l122', 'l131', 'l140', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156']", + "73, Akt ['l28', 'l43', 'l75', 'l89', 'l101', 'l113', 'l123', 'l132', 'l141', 'l149', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163']", + "74, and ['l29', 'l44', 'l76', 'l90', 'l102', 'l114', 'l124', 'l133', 'l142', 'l150', 'l157', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "75, Foxo1, ['l30', 'l45', 'l61', 'l77', 'l91', 'l103', 'l115', 'l125', 'l134', 'l143', 'l151', 'l158', 'l164', 'l170', 'l171', 'l172', 'l173', 'l174']", + "76, mice ['l17', 'l31', 'l46', 'l54', 'l62', 'l67', 'l78', 'l92', 'l104', 'l116', 'l126', 'l135', 'l144', 'l152', 'l159', 'l165', 'l170']", + "99, deletion ['l79', 'l105', 'l136', 'l145', 'l153', 'l160', 'l166', 'l171', 'l175', 'l176', 'l177']", + "100, of ['l80', 'l93', 'l106', 'l117', 'l127', 'l137', 'l146', 'l154', 'l161', 'l167', 'l172', 'l175', 'l178', 'l179']", + "101, Akt ['l81', 'l94', 'l107', 'l118', 'l128', 'l138', 'l147', 'l155', 'l162', 'l168', 'l173', 'l176', 'l178', 'l180']", + "103, liver ['l82', 'l95', 'l108', 'l119', 'l129', 'l139', 'l148', 'l156', 'l163', 'l169', 'l174', 'l177', 'l179', 'l180']", + "116, ablation ['l181', 'l182', 'l183', 'l184', 'l185']", + "117, of ['l181', 'l186', 'l187', 'l188', 'l189']", + "118, Foxo1 ['l182', 'l186', 'l190', 'l191', 'l192']", + "134, deletion ['l183', 'l187', 'l190', 'l193', 'l194']", + "135, of ['l184', 'l188', 'l191', 'l193', 'l195']", + "136, Akt. ['l185', 'l189', 'l192', 'l194', 'l195']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "hepatic", + "deletion", + "of", + "Akt1", + "and", + "Akt2", + "concomitant", + "liver-specific", + "Foxo1.", + "absence", + "both", + "Akt", + "Foxo1," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "hepatic", + "deletion", + "of", + "Akt1", + "and", + "Akt2", + "concomitant", + "liver-specific", + "Foxo1.", + "absence", + "both", + "Akt", + "Foxo1," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver.", + "liver" + ] + } + } + ] + }, + { + "PMID": "22231558", + "TEXT": "In addition to allelic mutations, cancers are known to harbor alterations in their chromatin landscape. Here we show that genomic ablation of Smad ubiquitin regulatory factor 2 (Smurf2), a HECT-domain E3 ubiquitin ligase, results in dysregulation of both the DNA damage response and genomic stability, culminating in increased susceptibility to various types of cancers in aged mice. We show that Smurf2 regulates the monoubiquitination of histone H2B as well as the trimethylation of histone H3 at Lys4 and Lys79 by targeting ring finger protein 20 (RNF20) for proteasomal degradation in both mouse and human cells. We also show that Smurf2 and RNF20 are colocalized at the γ-H2AX foci of double-stranded DNA breaks in the nucleus. Thus, Smurf2 has a tumor suppression function that normally maintains genomic stability by controlling the epigenetic landscape of histone modifications through RNF20.", + "TAG_DATA": [ + "19, genomic {'perturbing_action': 'B-gene loss-of-function'}", + "20, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "21, of {'perturbing_action': 'I-gene loss-of-function'}", + "22, Smad {'perturbing_action': 'I-gene loss-of-function'}", + "23, ubiquitin {'perturbing_action': 'I-gene loss-of-function'}", + "24, regulatory {'perturbing_action': 'I-gene loss-of-function'}", + "25, factor {'perturbing_action': 'I-gene loss-of-function'}", + "26, 2 {'perturbing_action': 'I-gene loss-of-function'}", + "27, (Smurf2), {'perturbing_action': 'I-gene loss-of-function'}", + "53, cancers {'context': 'B-neoplasm'}", + "55, aged {'context': 'B-organism'}", + "56, mice. {'context': 'I-organism'}", + "91, mouse {'context': 'B-cells'}", + "92, and {'context': 'I-cells'}", + "93, human {'context': 'I-cells'}", + "94, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "19, genomic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "20, ablation ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "21, of ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "22, Smad ['l2', 'l16', 'l29', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "23, ubiquitin ['l3', 'l17', 'l30', 'l42', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "24, regulatory ['l4', 'l18', 'l31', 'l43', 'l54', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "25, factor ['l5', 'l19', 'l32', 'l44', 'l55', 'l65', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "26, 2 ['l6', 'l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "27, (Smurf2), ['l7', 'l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l84', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "53, cancers ['l8', 'l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l99', 'l100']", + "55, aged ['l9', 'l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l86', 'l93', 'l99', 'l101']", + "56, mice. ['l10', 'l24', 'l37', 'l49', 'l60', 'l70', 'l79', 'l87', 'l94', 'l100', 'l101']", + "91, mouse ['l11', 'l25', 'l38', 'l50', 'l61', 'l71', 'l80', 'l88', 'l95', 'l102', 'l103', 'l104']", + "92, and ['l12', 'l26', 'l39', 'l51', 'l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l105', 'l106']", + "93, human ['l13', 'l27', 'l40', 'l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l105', 'l107']", + "94, cells. ['l14', 'l28', 'l41', 'l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l106', 'l107']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genomic", + "ablation", + "of", + "Smad", + "ubiquitin", + "regulatory", + "factor", + "2", + "(Smurf2)," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "cancers" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genomic", + "ablation", + "of", + "Smad", + "ubiquitin", + "regulatory", + "factor", + "2", + "(Smurf2)," + ] + }, + "context": { + "val": "organism", + "words": [ + "aged", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genomic", + "ablation", + "of", + "Smad", + "ubiquitin", + "regulatory", + "factor", + "2", + "(Smurf2)," + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "and", + "human", + "cells." + ] + } + } + ] + }, + { + "PMID": "22231557", + "TEXT": "Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. With ∼170 million individuals infected and current interferon-based treatment having toxic side effects and marginal efficacy, more effective antivirals are crucially needed. Although HCV protease inhibitors were just approved by the US Food and Drug Administration (FDA), optimal HCV therapy, analogous to HIV therapy, will probably require a combination of antivirals targeting multiple aspects of the viral lifecycle. Viral entry represents a potential multifaceted target for antiviral intervention; however, to date, FDA-approved inhibitors of HCV cell entry are unavailable. Here we show that the cellular Niemann-Pick C1-like 1 (NPC1L1) cholesterol uptake receptor is an HCV entry factor amendable to therapeutic intervention. Specifically, NPC1L1 expression is necessary for HCV infection, as silencing or antibody-mediated blocking of NPC1L1 impairs cell culture-derived HCV (HCVcc) infection initiation. In addition, the clinically available FDA-approved NPC1L1 antagonist ezetimibe potently blocks HCV uptake in vitro via a virion cholesterol-dependent step before virion-cell membrane fusion. Moreover, ezetimibe inhibits infection by all major HCV genotypes in vitro and in vivo delays the establishment of HCV genotype 1b infection in mice with human liver grafts. Thus, we have not only identified NPC1L1 as an HCV cell entry factor but also discovered a new antiviral target and potential therapeutic agent.", + "TAG_DATA": [ + "124, antibody-mediated {'perturbing_action': 'B-pharmacological inhibition'}", + "125, blocking {'perturbing_action': 'I-pharmacological inhibition'}", + "126, of {'perturbing_action': 'I-pharmacological inhibition'}", + "127, NPC1L1 {'perturbing_action': 'I-pharmacological inhibition'}", + "129, cell {'context': 'B-cells'}", + "130, culture-derived {'context': 'I-cells'}", + "141, NPC1L1 {'perturbing_action': 'I-pharmacological inhibition'}", + "142, antagonist {'perturbing_action': 'I-pharmacological inhibition'}", + "148, in {'context': 'B-in vitro'}", + "149, vitro {'context': 'I-in vitro'}", + "168, in {'context': 'B-in vitro'}", + "169, vitro {'context': 'I-in vitro'}", + "171, in {'context': 'B-in vivo'}", + "172, vivo {'context': 'I-in vivo'}", + "182, mice {'context': 'B-organism'}", + "184, human {'context': 'B-xenograft'}", + "185, liver {'context': 'I-xenograft'}", + "186, grafts. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "124, antibody-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "125, blocking ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "126, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "127, NPC1L1 ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "129, cell ['l3', 'l11', 'l18', 'l24', 'l30']", + "130, culture-derived ['l4', 'l12', 'l19', 'l25', 'l30']", + "141, NPC1L1 ['l5', 'l13', 'l20', 'l26', 'l31', 'l32', 'l33', 'l34', 'l35']", + "142, antagonist ['l6', 'l14', 'l21', 'l27', 'l31', 'l36', 'l37', 'l38', 'l39']", + "148, in ['l7', 'l15', 'l22', 'l28', 'l32', 'l36', 'l40', 'l41']", + "149, vitro ['l8', 'l16', 'l23', 'l29', 'l33', 'l37', 'l40', 'l42']", + "168, in ['l34', 'l38', 'l41', 'l42', 'l43']", + "169, vitro ['l35', 'l39', 'l43']", + "171, in ['l44', 'l45', 'l46', 'l47', 'l48']", + "172, vivo ['l44', 'l49', 'l50', 'l51', 'l52']", + "182, mice ['l45', 'l49', 'l53', 'l54', 'l55']", + "184, human ['l46', 'l50', 'l53', 'l56', 'l57']", + "185, liver ['l47', 'l51', 'l54', 'l56', 'l58']", + "186, grafts. ['l48', 'l52', 'l55', 'l57', 'l58']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antibody-mediated", + "blocking", + "of", + "NPC1L1" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "culture-derived" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antibody-mediated", + "blocking", + "of", + "NPC1L1", + "antagonist" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "22179317", + "TEXT": "Sepsis, sepsis-induced hyperinflammation and subsequent sepsis-associated immunosuppression (SAIS) are important causes of death. Here we show in humans that the loss of the major reactive oxygen species (ROS) scavenger, glutathione (GSH), during SAIS directly correlates with an increase in the expression of activating transcription factor 3 (ATF3). In endotoxin-stimulated monocytes, ROS stress strongly superinduced NF-E2-related factor 2 (NRF2)-dependent ATF3. In vivo, this ROS-mediated superinduction of ATF3 protected against endotoxic shock by inhibiting innate cytokines, as Atf3(-/-) mice remained susceptible to endotoxic shock even under conditions of ROS stress. Although it protected against endotoxic shock, this ROS-mediated superinduction of ATF3 caused high susceptibility to bacterial and fungal infections through the suppression of interleukin 6 (IL-6). As a result, Atf3(-/-) mice were protected against bacterial and fungal infections, even under conditions of ROS stress, whereas Atf3(-/-)Il6(-/-) mice were highly susceptible to these infections. Moreover, in a model of SAIS, secondary infections caused considerably less mortality in Atf3(-/-) mice than in wild-type mice, indicating that ROS-induced ATF3 crucially determines susceptibility to secondary infections during SAIS.", + "TAG_DATA": [ + "49, monocytes, {'context': 'B-cells'}", + "59, In {'context': 'B-in vivo'}", + "60, vivo, {'context': 'I-in vivo'}", + "75, Atf3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "76, mice {'context': 'B-organism'}", + "117, Atf3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "118, mice {'context': 'B-organism'}", + "133, Atf3(-/-)Il6(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "134, mice {'context': 'B-organism'}", + "154, Atf3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "155, mice {'context': 'B-organism'}", + "159, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "49, monocytes, ['l0', 'l1']", + "59, In ['l0', 'l2']", + "60, vivo, ['l1', 'l2']", + "75, Atf3(-/-) ['l3']", + "76, mice ['l3']", + "117, Atf3(-/-) ['l4']", + "118, mice ['l4']", + "133, Atf3(-/-)Il6(-/-) ['l5']", + "134, mice ['l5']", + "154, Atf3(-/-) ['l6', 'l7']", + "155, mice ['l6', 'l8']", + "159, mice, ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atf3(-/-)", + "Atf3(-/-)Il6(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + } + ] + }, + { + "PMID": "22157680", + "TEXT": "Congenital disorder of glycosylation-Ia (CDG-Ia, also known as PMM2-CDG) is caused by mutations in the gene that encodes phosphomannomutase 2 (PMM2, EC 5.4.2.8) leading to a multisystemic disease with severe psychomotor and mental retardation. In a hypomorphic Pmm2 mouse model, we were able to overcome embryonic lethality by feeding mannose to pregnant dams. The results underline the essential role of glycosylation in embryonic development and may open new treatment options for this disease.", + "TAG_DATA": [ + "36, hypomorphic {'perturbing_action': 'B-other'}", + "37, Pmm2 {'perturbing_action': 'I-other'}", + "38, mouse {'context': 'I-organism'}", + "39, model, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "36, hypomorphic ['l0', 'l1', 'l2']", + "37, Pmm2 ['l0', 'l3', 'l4']", + "38, mouse ['l1', 'l3', 'l5']", + "39, model, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "hypomorphic", + "Pmm2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model," + ] + } + } + ] + }, + { + "PMID": "22138751", + "TEXT": "Mechanisms of epithelial cell renewal remain poorly understood in the mammalian kidney, particularly in the glomerulus, a site of cellular damage in chronic kidney disease. Within the glomerulus, podocytes--differentiated epithelial cells crucial for filtration--are thought to lack substantial capacity for regeneration. Here we show that podocytes rapidly lose differentiation markers and enter the cell cycle in adult mice in which the telomerase protein component TERT is conditionally expressed. Transgenic TERT expression in mice induces marked upregulation of Wnt signaling and disrupts glomerular structure, resulting in a collapsing glomerulopathy resembling those in human disease, including HIV-associated nephropathy (HIVAN). Human and mouse HIVAN kidneys show increased expression of TERT and activation of Wnt signaling, indicating that these are general features of collapsing glomerulopathies. Silencing transgenic TERT expression or inhibiting Wnt signaling through systemic expression of the Wnt inhibitor Dkk1 in either TERT transgenic mice or in a mouse model of HIVAN results in marked normalization of podocytes, including rapid cell-cycle exit, re-expression of differentiation markers and improved filtration barrier function. These data reveal an unexpected capacity of podocytes to reversibly enter the cell cycle, suggest that podocyte renewal may contribute to glomerular homeostasis and implicate the telomerase and Wnt-β-catenin pathways in podocyte proliferation and disease.", + "TAG_DATA": [ + "56, adult {'context': 'B-organism'}", + "57, mice {'context': 'I-organism'}", + "68, Transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "69, TERT {'perturbing_action': 'I-gene gain-of-function'}", + "70, expression {'perturbing_action': 'I-gene gain-of-function'}", + "72, mice {'context': 'B-organism'}", + "121, Silencing {'perturbing_action': 'B-rnai/knockdown'}", + "122, transgenic {'perturbing_action': 'I-rnai/knockdown'}", + "123, TERT {'perturbing_action': 'I-rnai/knockdown'}", + "124, expression {'perturbing_action': 'I-rnai/knockdown'}", + "139, TERT {'perturbing_action': 'B-gene gain-of-function'}", + "140, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "141, mice {'context': 'B-organism'}", + "145, mouse {'context': 'B-organism'}", + "146, model {'context': 'I-organism'}", + "154, podocytes, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "56, adult ['l0', 'l1', 'l2', 'l3', 'l4']", + "57, mice ['l0', 'l5', 'l6', 'l7', 'l8']", + "68, Transgenic ['l1', 'l5', 'l9', 'l10', 'l11', 'l12']", + "69, TERT ['l2', 'l6', 'l9', 'l13', 'l14', 'l15']", + "70, expression ['l3', 'l7', 'l10', 'l13', 'l16', 'l17']", + "72, mice ['l4', 'l8', 'l11', 'l14', 'l16']", + "101, kidneys ['l12', 'l15', 'l17']", + "121, Silencing ['l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "122, transgenic ['l18', 'l26', 'l27', 'l28', 'l29', 'l30']", + "123, TERT ['l19', 'l26', 'l31', 'l32', 'l33', 'l34']", + "124, expression ['l20', 'l27', 'l31']", + "139, TERT ['l21', 'l35', 'l36', 'l37', 'l38', 'l39']", + "140, transgenic ['l22', 'l28', 'l32', 'l35', 'l40', 'l41', 'l42', 'l43']", + "141, mice ['l23', 'l29', 'l33', 'l36', 'l40', 'l44', 'l45', 'l46']", + "145, mouse ['l37', 'l41', 'l44', 'l47', 'l48']", + "146, model ['l24', 'l38', 'l42', 'l45', 'l47', 'l49']", + "154, podocytes, ['l25', 'l30', 'l34', 'l39', 'l43', 'l46', 'l48', 'l49']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "adult", + "mice", + "mouse", + "model" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgenic", + "TERT", + "expression", + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "transgenic", + "TERT" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "transgenic", + "TERT" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocytes," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "TERT", + "transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocytes," + ] + } + } + ] + }, + { + "PMID": "22101765", + "TEXT": "Although there is evidence that redox regulation has an essential role in malignancies, its impact on tumor prognosis remains unclear. Here we show crosstalk between oxidative stress and the miR-200 family of microRNAs that affects tumorigenesis and chemosensitivity. miR-141 and miR-200a target p38α and modulate the oxidative stress response. Enhanced expression of these microRNAs mimics p38α deficiency and increases tumor growth in mouse models, but it also improves the response to chemotherapeutic agents. High-grade human ovarian adenocarcinomas that accumulate miR-200a have low concentrations of p38α and an associated oxidative stress signature. The miR200a-dependent stress signature correlates with improved survival of patients in response to treatment. Therefore, the role of miR-200a in stress could be a predictive marker for clinical outcome in ovarian cancer. In addition, although oxidative stress promotes tumor growth, it also sensitizes tumors to treatment, which could account for the limited success of antioxidants in clinical trials.", + "TAG_DATA": [ + "49, Enhanced {'perturbing_action': 'B-gene gain-of-function'}", + "50, expression {'perturbing_action': 'I-gene gain-of-function'}", + "51, of {'perturbing_action': 'I-gene gain-of-function'}", + "52, these {'perturbing_action': 'I-gene gain-of-function'}", + "53, microRNAs {'perturbing_action': 'I-gene gain-of-function'}", + "58, increases {'effect': 'B-positive'}", + "59, tumor {'phenotype': 'B-tumour growth'}", + "60, growth {'phenotype': 'I-tumour growth'}", + "62, mouse {'context': 'B-organism'}", + "63, models, {'context': 'I-organism'}", + "74, human {'context': 'I-neoplasm'}", + "75, ovarian {'context': 'I-neoplasm'}", + "76, adenocarcinomas {'context': 'I-neoplasm'}", + "128, promotes {'effect': 'B-positive'}", + "129, tumor {'phenotype': 'B-tumour growth'}", + "130, growth, {'phenotype': 'I-tumour growth'}", + "134, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "49, Enhanced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "50, expression ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "51, of ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "52, these ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "53, microRNAs ['l3', 'l14', 'l24', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "58, increases ['l4', 'l15', 'l25', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47']", + "59, tumor ['l5', 'l16', 'l26', 'l35', 'l40', 'l44', 'l48', 'l49', 'l50']", + "60, growth ['l6', 'l17', 'l27', 'l36', 'l41', 'l45', 'l48', 'l51', 'l52']", + "62, mouse ['l7', 'l18', 'l28', 'l37', 'l42', 'l46', 'l49', 'l51', 'l53']", + "63, models, ['l8', 'l19', 'l29', 'l38', 'l43', 'l47', 'l50', 'l52', 'l53']", + "74, human ['l9', 'l20', 'l30', 'l54', 'l55']", + "75, ovarian ['l10', 'l21', 'l31', 'l54', 'l56']", + "76, adenocarcinomas ['l11', 'l22', 'l32', 'l55', 'l56']", + "128, promotes ['l57', 'l58', 'l59']", + "129, tumor ['l57', 'l60', 'l61']", + "130, growth, ['l58', 'l60', 'l62']", + "134, tumors ['l59', 'l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enhanced", + "expression", + "of", + "these", + "microRNAs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increases" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enhanced", + "expression", + "of", + "these", + "microRNAs" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enhanced", + "expression", + "of", + "these", + "microRNAs" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enhanced", + "expression", + "of" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "ovarian", + "adenocarcinomas" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases", + "promotes" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth", + "growth," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models," + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + } + ] + }, + { + "PMID": "22081024", + "TEXT": "RAF kinases regulate cell proliferation and survival and can be dysregulated in tumors. The role of RAF in cell proliferation has been linked to its ability to activate mitogen-activated protein kinase kinase 1 (MEK) and mitogen-activated protein kinase 1 (ERK). Here we identify a MEK-independent role for RAF in tumor growth. Specifically, in mitotic cells, CRAF becomes phosphorylated on Ser338 and localizes to the mitotic spindle of proliferating tumor cells in vitro as well as in murine tumor models and in biopsies from individuals with cancer. Treatment of tumors with allosteric inhibitors, but not ATP-competitive RAF inhibitors, prevents CRAF phosphorylation on Ser338 and localization to the mitotic spindle and causes cell-cycle arrest at prometaphase. Furthermore, we identify phospho-Ser338 CRAF as a potential biomarker for tumor progression and a surrogate marker for allosteric RAF blockade. Mechanistically, CRAF, but not BRAF, associates with Aurora kinase A (Aurora-A) and Polo-like kinase 1 (Plk1) at the centrosomes and spindle poles during G2/M. Indeed, allosteric or genetic inhibition of phospho-Ser338 CRAF impairs Plk1 activation and accumulation at the kinetochores, causing prometaphase arrest, whereas a phospho-mimetic Ser338D CRAF mutant potentiates Plk1 activation, mitosis and tumor progression in mice. These findings show a previously undefined role for RAF in tumor progression beyond the RAF-MEK-ERK paradigm, opening new avenues for targeting RAF in cancer.", + "TAG_DATA": [ + "88, tumors {'context': 'B-neoplasm'}", + "109, causes {'effect': 'B-positive'}", + "110, cell-cycle {'phenotype': 'B-cell cycle arrest'}", + "111, arrest {'phenotype': 'I-cell cycle arrest'}", + "161, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "162, inhibition {'perturbing_action': 'I-gene loss-of-function'}", + "163, of {'perturbing_action': 'I-gene loss-of-function'}", + "164, phospho-Ser338 {'perturbing_action': 'I-gene loss-of-function'}", + "165, CRAF {'perturbing_action': 'I-gene loss-of-function'}", + "174, causing {'effect': 'B-positive'}", + "175, prometaphase {'phenotype': 'B-cell cycle arrest'}", + "176, arrest, {'phenotype': 'I-cell cycle arrest'}", + "179, phospho-mimetic {'perturbing_action': 'B-other'}", + "180, Ser338D {'perturbing_action': 'I-other'}", + "181, CRAF {'perturbing_action': 'I-other'}", + "182, mutant {'perturbing_action': 'I-other'}", + "188, tumor {'phenotype': 'B-tumour progression'}", + "189, progression {'phenotype': 'I-tumour progression'}", + "191, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "88, tumors ['l0', 'l1', 'l2']", + "109, causes ['l0', 'l3', 'l4']", + "110, cell-cycle ['l1', 'l3', 'l5']", + "111, arrest ['l2', 'l4', 'l5']", + "161, genetic ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "162, inhibition ['l6', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "163, of ['l7', 'l14', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "164, phospho-Ser338 ['l8', 'l15', 'l23', 'l31', 'l32', 'l33', 'l34', 'l35']", + "165, CRAF ['l9', 'l16', 'l24', 'l31', 'l36', 'l37', 'l38']", + "174, causing ['l10', 'l17', 'l25', 'l32', 'l36', 'l39', 'l40']", + "175, prometaphase ['l11', 'l18', 'l26', 'l33', 'l37', 'l39', 'l41']", + "176, arrest, ['l12', 'l19', 'l27', 'l34', 'l38', 'l40', 'l41']", + "179, phospho-mimetic ['l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "180, Ser338D ['l42', 'l48', 'l49', 'l50', 'l51', 'l52']", + "181, CRAF ['l43', 'l48', 'l53', 'l54', 'l55', 'l56']", + "182, mutant ['l44', 'l49', 'l53', 'l57', 'l58', 'l59']", + "188, tumor ['l20', 'l28', 'l45', 'l50', 'l54', 'l57', 'l60', 'l61']", + "189, progression ['l13', 'l21', 'l29', 'l35', 'l46', 'l51', 'l55', 'l58', 'l60', 'l62']", + "191, mice. ['l22', 'l30', 'l47', 'l52', 'l56', 'l59', 'l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "causes" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes", + "causing" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest", + "prometaphase", + "arrest," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inhibition", + "of", + "phospho-Ser338", + "CRAF" + ] + }, + "effect": { + "val": "positive", + "words": [ + "causing" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inhibition", + "of", + "phospho-Ser338", + "CRAF" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "prometaphase", + "arrest," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inhibition", + "of", + "phospho-Ser338" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "progression", + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inhibition", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "phospho-mimetic", + "Ser338D", + "CRAF", + "mutant" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "phospho-mimetic", + "Ser338D", + "CRAF", + "mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "progression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "22037646", + "TEXT": "Intra-abdominal tumors, such as ovarian cancer, have a clear predilection for metastasis to the omentum, an organ primarily composed of adipocytes. Currently, it is unclear why tumor cells preferentially home to and proliferate in the omentum, yet omental metastases typically represent the largest tumor in the abdominal cavities of women with ovarian cancer. We show here that primary human omental adipocytes promote homing, migration and invasion of ovarian cancer cells, and that adipokines including interleukin-8 (IL-8) mediate these activities. Adipocyte-ovarian cancer cell coculture led to the direct transfer of lipids from adipocytes to ovarian cancer cells and promoted in vitro and in vivo tumor growth. Furthermore, coculture induced lipolysis in adipocytes and β-oxidation in cancer cells, suggesting adipocytes act as an energy source for the cancer cells. A protein array identified upregulation of fatty acid-binding protein 4 (FABP4, also known as aP2) in omental metastases as compared to primary ovarian tumors, and FABP4 expression was detected in ovarian cancer cells at the adipocyte-tumor cell interface. FABP4 deficiency substantially impaired metastatic tumor growth in mice, indicating that FABP4 has a key role in ovarian cancer metastasis. These data indicate adipocytes provide fatty acids for rapid tumor growth, identifying lipid metabolism and transport as new targets for the treatment of cancers where adipocytes are a major component of the microenvironment.", + "TAG_DATA": [ + "65, invasion {'phenotype': 'B-invasion'}", + "67, ovarian {'context': 'B-transformed cells'}", + "68, cancer {'context': 'I-transformed cells'}", + "69, cells, {'context': 'I-transformed cells'}", + "80, cancer {'context': 'I-transformed cells'}", + "93, ovarian {'context': 'B-transformed cells'}", + "94, cancer {'context': 'I-transformed cells'}", + "95, cells {'context': 'I-transformed cells'}", + "97, promoted {'effect': 'B-positive'}", + "98, in {'context': 'B-in vitro'}", + "99, vitro {'context': 'I-in vitro'}", + "101, in {'context': 'B-in vivo'}", + "102, vivo {'context': 'I-in vivo'}", + "103, tumor {'phenotype': 'B-tumour growth'}", + "104, growth. {'phenotype': 'I-tumour growth'}", + "114, cancer {'context': 'B-transformed cells'}", + "115, cells, {'context': 'I-transformed cells'}", + "165, FABP4 {'perturbing_action': 'B-gene loss-of-function'}", + "166, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "168, impaired {'effect': 'B-negative'}", + "169, metastatic {'phenotype': 'B-metastasis'}", + "170, tumor {'phenotype': 'I-tumour growth'}", + "171, growth {'phenotype': 'I-tumour growth'}", + "173, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "65, invasion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "67, ovarian ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "68, cancer ['l1', 'l9', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "69, cells, ['l2', 'l10', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "80, cancer ['l3', 'l11', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "93, ovarian ['l4', 'l12', 'l20', 'l26', 'l31', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "94, cancer ['l5', 'l13', 'l21', 'l27', 'l32', 'l41', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "95, cells ['l6', 'l14', 'l22', 'l28', 'l33', 'l42', 'l49', 'l55', 'l56', 'l57', 'l58']", + "97, promoted ['l7', 'l15', 'l23', 'l29', 'l34', 'l43', 'l50', 'l55', 'l59', 'l60', 'l61', 'l62']", + "98, in ['l35', 'l44', 'l51', 'l59', 'l63', 'l64', 'l65', 'l66']", + "99, vitro ['l36', 'l45', 'l52', 'l56', 'l60', 'l63', 'l67', 'l68', 'l69']", + "101, in ['l37', 'l70', 'l71', 'l72']", + "102, vivo ['l38', 'l46', 'l64', 'l67', 'l70', 'l73', 'l74']", + "103, tumor ['l16', 'l39', 'l47', 'l53', 'l57', 'l61', 'l65', 'l68', 'l71', 'l73', 'l75']", + "104, growth. ['l8', 'l17', 'l24', 'l30', 'l40', 'l48', 'l54', 'l58', 'l62', 'l66', 'l69', 'l72', 'l74', 'l75']", + "114, cancer ['l76']", + "115, cells, ['l76']", + "165, FABP4 ['l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "166, deficiency ['l77', 'l83', 'l84', 'l85', 'l86', 'l87']", + "168, impaired ['l78', 'l83', 'l88', 'l89', 'l90', 'l91']", + "169, metastatic ['l79', 'l84', 'l88', 'l92', 'l93', 'l94']", + "170, tumor ['l80', 'l85', 'l89', 'l92', 'l95', 'l96']", + "171, growth ['l81', 'l86', 'l90', 'l93', 'l95', 'l97']", + "173, mice, ['l82', 'l87', 'l91', 'l94', 'l96', 'l97']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "cancer", + "cells,", + "cells" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "cancer", + "cells,", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "cancer", + "cells,", + "cells" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FABP4", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FABP4", + "deficiency" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FABP4", + "deficiency" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FABP4", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "22019888", + "TEXT": "Most of the currently available drugs for osteoporosis inhibit osteoclastic bone resorption; only a few drugs promote osteoblastic bone formation. It is thus becoming increasingly necessary to identify the factors that regulate bone formation. We found that osteoclasts express semaphorin 4D (Sema4D), previously shown to be an axon guidance molecule, which potently inhibits bone formation. The binding of Sema4D to its receptor Plexin-B1 on osteoblasts resulted in the activation of the small GTPase RhoA, which inhibits bone formation by suppressing insulin-like growth factor-1 (IGF-1) signaling and by modulating osteoblast motility. Sema4d-/- mice, Plxnb1-/- mice and mice expressing a dominant-negative RhoA specifically in osteoblasts showed an osteosclerotic phenotype due to augmented bone formation. Notably, Sema4D-specific antibody treatment markedly prevented bone loss in a model of postmenopausal osteoporosis. Thus, Sema4D has emerged as a new therapeutic target for the discovery and development of bone-increasing drugs.", + "TAG_DATA": [ + "64, osteoblasts {'context': 'B-cells'}", + "88, osteoblast {'context': 'B-cells'}", + "90, Sema4d-/- {'perturbing_action': 'B-gene loss-of-function'}", + "91, mice, {'context': 'B-organism'}", + "92, Plxnb1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "93, mice {'context': 'B-organism'}", + "95, mice {'context': 'B-organism'}", + "97, a {'perturbing_action': 'I-other'}", + "98, dominant-negative {'perturbing_action': 'I-other'}", + "99, RhoA {'perturbing_action': 'I-other'}", + "102, osteoblasts {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "64, osteoblasts ['l0', 'l1']", + "88, osteoblast ['l0', 'l2']", + "90, Sema4d-/- ['l1', 'l2', 'l3', 'l4', 'l5']", + "91, mice, ['l3']", + "92, Plxnb1-/- ['l4', 'l6', 'l7']", + "93, mice ['l5', 'l6']", + "95, mice ['l8', 'l9', 'l10', 'l11']", + "97, a ['l8', 'l12', 'l13', 'l14']", + "98, dominant-negative ['l9', 'l12', 'l15', 'l16']", + "99, RhoA ['l10', 'l13', 'l15', 'l17']", + "102, osteoblasts ['l7', 'l11', 'l14', 'l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "osteoblasts", + "osteoblast" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sema4d-/-", + "Plxnb1-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sema4d-/-", + "Plxnb1-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "a", + "dominant-negative", + "RhoA" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "a", + "dominant-negative", + "RhoA" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoblasts" + ] + } + } + ] + }, + { + "PMID": "22019886", + "TEXT": "Anemia because of insufficient production of and/or response to erythropoietin (Epo) is a major complication of chronic kidney disease and cancer. The mechanisms modulating the sensitivity of erythroblasts to Epo remain poorly understood. We show that, when cultured with Epo at suboptimal concentrations, the growth and clonogenic potential of erythroblasts was rescued by transferrin receptor 1 (TfR1)-bound polymeric IgA1 (pIgA1). Under homeostatic conditions, erythroblast numbers were increased in mice expressing human IgA1 compared to control mice. Hypoxic stress of these mice led to increased amounts of pIgA1 and erythroblast expansion. Expression of human IgA1 or treatment of wild-type mice with the TfR1 ligands pIgA1 or iron-loaded transferrin (Fe-Tf) accelerated recovery from acute anemia. TfR1 engagement by either pIgA1 or Fe-Tf increased cell sensitivity to Epo by inducing activation of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways. These cellular responses were mediated through the TfR1-internalization motif, YXXΦ. Our results show that pIgA1 and TfR1 are positive regulators of erythropoiesis in both physiological and pathological situations. Targeting this pathway may provide alternate approaches to the treatment of ineffective erythropoiesis and anemia.", + "TAG_DATA": [ + "46, clonogenic {'phenotype': 'B-colony formation'}", + "47, potential {'phenotype': 'I-colony formation'}", + "49, erythroblasts {'context': 'B-cells'}", + "51, rescued {'effect': 'B-rescues'}", + "63, erythroblast {'context': 'B-cells'}", + "68, mice {'context': 'B-organism'}", + "69, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "70, human {'perturbing_action': 'I-gene gain-of-function'}", + "71, IgA1 {'perturbing_action': 'I-gene gain-of-function'}", + "80, mice {'context': 'B-organism'}", + "88, erythroblast {'context': 'B-cells'}", + "90, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "91, of {'perturbing_action': 'I-gene gain-of-function'}", + "92, human {'perturbing_action': 'I-gene gain-of-function'}", + "93, IgA1 {'perturbing_action': 'I-gene gain-of-function'}", + "98, mice {'context': 'B-organism'}", + "121, cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "46, clonogenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "47, potential ['l0', 'l7', 'l8', 'l9', 'l10']", + "49, erythroblasts ['l1', 'l7', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "51, rescued ['l2', 'l8', 'l11', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "63, erythroblast ['l3', 'l9', 'l12', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "68, mice ['l4', 'l10', 'l13', 'l18', 'l23', 'l28', 'l29', 'l30', 'l31', 'l32']", + "69, expressing ['l14', 'l19', 'l24', 'l28', 'l33', 'l34', 'l35', 'l36']", + "70, human ['l20', 'l25', 'l29', 'l33', 'l37', 'l38', 'l39']", + "71, IgA1 ['l5', 'l15', 'l21', 'l26', 'l30', 'l34', 'l37', 'l40', 'l41']", + "80, mice ['l6', 'l16', 'l22', 'l27', 'l31', 'l35', 'l38', 'l40', 'l42']", + "88, erythroblast ['l32', 'l36', 'l39', 'l41', 'l42']", + "90, Expression ['l43', 'l44', 'l45']", + "91, of ['l43', 'l46', 'l47']", + "92, human ['l44', 'l46', 'l48']", + "93, IgA1 ['l45', 'l47', 'l48']", + "98, mice ['l49']", + "121, cell ['l49']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenic", + "potential" + ] + }, + "context": { + "val": "cells", + "words": [ + "erythroblasts", + "erythroblast" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenic", + "potential" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenic", + "potential" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenic" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "IgA1" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "erythroblasts", + "erythroblast" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "erythroblasts", + "erythroblast" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "IgA1", + "human" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "human", + "IgA1" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "human", + "IgA1" + ] + } + } + ] + }, + { + "PMID": "22019885", + "TEXT": "Tissue factor, the initiator of the coagulation cascade, mediates coagulation factor VIIa-dependent activation of protease-activated receptor 2 (PAR2). Here we delineate a role for this signaling pathway in obesity and its complications. Mice lacking PAR2 (F2rl1) or the cytoplasmic domain of tissue factor were protected from weight gain and insulin resistance induced by a high-fat diet. In hematopoietic cells, genetic ablation of tissue factor-PAR2 signaling reduced adipose tissue macrophage inflammation, and specific pharmacological inhibition of macrophage tissue factor signaling rapidly ameliorated insulin resistance. In contrast, nonhematopoietic cell tissue factor-VIIa-PAR2 signaling specifically promoted obesity. Mechanistically, adipocyte tissue factor cytoplasmic domain-dependent VIIa signaling suppressed Akt phosphorylation with concordant adverse transcriptional changes of key regulators of obesity and metabolism. Pharmacological blockade of adipocyte tissue factor in vivo reversed these effects of tissue factor-VIIa signaling and rapidly increased energy expenditure. Thus, inhibition of tissue factor signaling is a potential therapeutic avenue for improving impaired metabolism and insulin resistance in obesity.", + "TAG_DATA": [ + "32, Mice {'context': 'B-organism'}", + "33, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "34, PAR2 {'perturbing_action': 'I-gene loss-of-function'}", + "35, (F2rl1) {'perturbing_action': 'I-gene loss-of-function'}", + "36, or {'perturbing_action': 'I-gene loss-of-function'}", + "37, the {'perturbing_action': 'I-gene loss-of-function'}", + "38, cytoplasmic {'perturbing_action': 'I-gene loss-of-function'}", + "39, domain {'perturbing_action': 'I-gene loss-of-function'}", + "40, of {'perturbing_action': 'I-gene loss-of-function'}", + "41, tissue {'perturbing_action': 'I-gene loss-of-function'}", + "42, factor {'perturbing_action': 'I-gene loss-of-function'}", + "57, hematopoietic {'context': 'B-cells'}", + "58, cells, {'context': 'I-cells'}", + "59, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "60, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "61, of {'perturbing_action': 'I-gene loss-of-function'}", + "62, tissue {'perturbing_action': 'I-gene loss-of-function'}", + "63, factor-PAR2 {'perturbing_action': 'I-gene loss-of-function'}", + "64, signaling {'perturbing_action': 'I-gene loss-of-function'}", + "66, adipose {'context': 'B-cells'}", + "67, tissue {'context': 'I-cells'}", + "68, macrophage {'context': 'I-cells'}", + "71, specific {'perturbing_action': 'B-pharmacological inhibition'}", + "72, pharmacological {'perturbing_action': 'I-pharmacological inhibition'}", + "73, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "74, of {'perturbing_action': 'I-pharmacological inhibition'}", + "75, macrophage {'perturbing_action': 'I-pharmacological inhibition'}", + "76, tissue {'perturbing_action': 'I-pharmacological inhibition'}", + "77, factor {'perturbing_action': 'I-pharmacological inhibition'}", + "78, signaling {'perturbing_action': 'I-pharmacological inhibition'}", + "85, nonhematopoietic {'context': 'B-cells'}", + "86, cell {'context': 'I-cells'}", + "116, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "117, blockade {'perturbing_action': 'I-pharmacological inhibition'}", + "118, of {'perturbing_action': 'I-pharmacological inhibition'}", + "119, adipocyte {'perturbing_action': 'I-pharmacological inhibition'}", + "120, tissue {'perturbing_action': 'I-pharmacological inhibition'}", + "121, factor {'perturbing_action': 'I-pharmacological inhibition'}", + "122, in {'context': 'B-in vivo'}", + "123, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "32, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "33, lacking ['l0', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "34, PAR2 ['l1', 'l23', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "35, (F2rl1) ['l2', 'l24', 'l51', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "36, or ['l3', 'l25', 'l52', 'l78', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "37, the ['l26', 'l53', 'l79', 'l104', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "38, cytoplasmic ['l27', 'l54', 'l80', 'l105', 'l129', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175']", + "39, domain ['l28', 'l55', 'l81', 'l106', 'l130', 'l153', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197']", + "40, of ['l4', 'l29', 'l56', 'l82', 'l107', 'l131', 'l154', 'l176', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218']", + "41, tissue ['l5', 'l30', 'l57', 'l83', 'l108', 'l132', 'l155', 'l177', 'l198', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238']", + "42, factor ['l6', 'l31', 'l58', 'l84', 'l109', 'l133', 'l156', 'l178', 'l199', 'l219', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256']", + "57, hematopoietic ['l7', 'l32', 'l59', 'l85', 'l110', 'l134', 'l157', 'l179', 'l200', 'l220', 'l239', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269']", + "58, cells, ['l8', 'l33', 'l60', 'l86', 'l111', 'l135', 'l158', 'l180', 'l201', 'l221', 'l240', 'l257', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278']", + "59, genetic ['l9', 'l34', 'l61', 'l87', 'l112', 'l136', 'l159', 'l181', 'l202', 'l222', 'l241', 'l258', 'l270', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290']", + "60, ablation ['l10', 'l35', 'l62', 'l88', 'l113', 'l137', 'l160', 'l182', 'l203', 'l223', 'l242', 'l259', 'l271', 'l279', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302', 'l303']", + "61, of ['l11', 'l36', 'l63', 'l89', 'l114', 'l138', 'l161', 'l183', 'l204', 'l224', 'l243', 'l260', 'l272', 'l280', 'l291', 'l304', 'l305', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315', 'l316']", + "62, tissue ['l12', 'l37', 'l64', 'l90', 'l115', 'l139', 'l162', 'l184', 'l205', 'l225', 'l244', 'l261', 'l273', 'l281', 'l292', 'l304', 'l317', 'l318', 'l319', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327', 'l328']", + "63, factor-PAR2 ['l13', 'l38', 'l65', 'l91', 'l116', 'l140', 'l163', 'l185', 'l206', 'l226', 'l245', 'l262', 'l274', 'l282', 'l293', 'l305', 'l317', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340']", + "64, signaling ['l14', 'l39', 'l66', 'l92', 'l117', 'l141', 'l164', 'l186', 'l207', 'l227', 'l246', 'l263', 'l275', 'l283', 'l294', 'l306', 'l318', 'l329', 'l341', 'l342', 'l343', 'l344', 'l345', 'l346']", + "66, adipose ['l15', 'l40', 'l67', 'l93', 'l118', 'l142', 'l165', 'l187', 'l208', 'l228', 'l247', 'l264', 'l276', 'l284', 'l295', 'l307', 'l319', 'l330', 'l341', 'l347', 'l348', 'l349']", + "67, tissue ['l16', 'l41', 'l68', 'l94', 'l119', 'l143', 'l166', 'l188', 'l209', 'l229', 'l248', 'l265', 'l277', 'l285', 'l296', 'l308', 'l320', 'l331', 'l342', 'l347', 'l350']", + "68, macrophage ['l17', 'l42', 'l69', 'l95', 'l120', 'l144', 'l167', 'l189', 'l210', 'l230', 'l249', 'l266', 'l278', 'l286', 'l297', 'l309', 'l321', 'l332', 'l343', 'l348', 'l350']", + "71, specific ['l43', 'l70', 'l96', 'l121', 'l145', 'l168', 'l190', 'l211', 'l231', 'l250', 'l298', 'l310', 'l322', 'l333', 'l351', 'l352', 'l353', 'l354', 'l355', 'l356', 'l357']", + "72, pharmacological ['l44', 'l71', 'l97', 'l122', 'l146', 'l169', 'l191', 'l212', 'l232', 'l334', 'l351', 'l358', 'l359', 'l360', 'l361', 'l362', 'l363']", + "73, inhibition ['l45', 'l72', 'l98', 'l123', 'l147', 'l170', 'l192', 'l213', 'l233', 'l251', 'l311', 'l323', 'l335', 'l352', 'l358', 'l364', 'l365', 'l366', 'l367', 'l368']", + "74, of ['l18', 'l46', 'l73', 'l99', 'l124', 'l148', 'l171', 'l193', 'l214', 'l234', 'l252', 'l299', 'l312', 'l324', 'l336', 'l353', 'l359', 'l364', 'l369', 'l370', 'l371', 'l372']", + "75, macrophage ['l19', 'l47', 'l74', 'l100', 'l125', 'l149', 'l172', 'l194', 'l215', 'l235', 'l253', 'l287', 'l300', 'l313', 'l325', 'l337', 'l354', 'l360', 'l365', 'l369', 'l373', 'l374', 'l375']", + "76, tissue ['l20', 'l48', 'l75', 'l101', 'l126', 'l150', 'l173', 'l195', 'l216', 'l236', 'l254', 'l267', 'l288', 'l301', 'l314', 'l326', 'l338', 'l344', 'l355', 'l361', 'l366', 'l370', 'l373', 'l376', 'l377']", + "77, factor ['l21', 'l49', 'l76', 'l102', 'l127', 'l151', 'l174', 'l196', 'l217', 'l237', 'l255', 'l268', 'l289', 'l302', 'l315', 'l327', 'l339', 'l345', 'l356', 'l362', 'l367', 'l371', 'l374', 'l376', 'l378']", + "78, signaling ['l22', 'l50', 'l77', 'l103', 'l128', 'l152', 'l175', 'l197', 'l218', 'l238', 'l256', 'l269', 'l290', 'l303', 'l316', 'l328', 'l340', 'l346', 'l349', 'l357', 'l363', 'l368', 'l372', 'l375', 'l377', 'l378']", + "85, nonhematopoietic ['l379']", + "86, cell ['l379']", + "116, Pharmacological ['l380', 'l381', 'l382', 'l383', 'l384', 'l385', 'l386']", + "117, blockade ['l380', 'l387', 'l388', 'l389', 'l390', 'l391', 'l392']", + "118, of ['l381', 'l387', 'l393', 'l394', 'l395', 'l396', 'l397']", + "119, adipocyte ['l382', 'l388', 'l393', 'l398', 'l399', 'l400', 'l401']", + "120, tissue ['l383', 'l389', 'l394', 'l398', 'l402', 'l403', 'l404']", + "121, factor ['l384', 'l390', 'l395', 'l399', 'l402', 'l405', 'l406']", + "122, in ['l385', 'l391', 'l396', 'l400', 'l403', 'l405', 'l407']", + "123, vivo ['l386', 'l392', 'l397', 'l401', 'l404', 'l406', 'l407']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "PAR2", + "(F2rl1)", + "or", + "of", + "tissue", + "factor", + "genetic", + "ablation", + "factor-PAR2", + "signaling" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "of", + "macrophage", + "tissue", + "factor", + "signaling" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "PAR2", + "(F2rl1)", + "or", + "the", + "cytoplasmic", + "domain", + "of", + "tissue", + "factor", + "genetic", + "ablation", + "factor-PAR2", + "signaling" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "cells,", + "adipose", + "tissue", + "macrophage" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "adipose" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "tissue", + "factor", + "signaling" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "adipocyte", + "tissue", + "factor" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "21963515", + "TEXT": "Calcineurin inhibitors (CNIs) are immunosuppressive drugs that are used widely to prevent rejection of transplanted organs and to treat autoimmune disease. Hypertension and renal tubule dysfunction, including hyperkalemia, hypercalciuria and acidosis, often complicate their use. These side effects resemble familial hyperkalemic hypertension, a genetic disease characterized by overactivity of the renal sodium chloride cotransporter (NCC) and caused by mutations in genes encoding WNK kinases. We hypothesized that CNIs induce hypertension by stimulating NCC. In wild-type mice, the CNI tacrolimus caused salt-sensitive hypertension and increased the abundance of phosphorylated NCC and the NCC-regulatory kinases WNK3, WNK4 and SPAK. We demonstrated the functional importance of NCC in this response by showing that tacrolimus did not affect blood pressure in NCC-knockout mice, whereas the hypertensive response to tacrolimus was exaggerated in mice overexpressing NCC. Moreover, hydrochlorothiazide, an NCC-blocking drug, reversed tacrolimus-induced hypertension. These observations were extended to humans by showing that kidney transplant recipients treated with tacrolimus had a greater fractional chloride excretion in response to bendroflumethiazide, another NCC-blocking drug, than individuals not treated with tacrolimus; renal NCC abundance was also greater. Together, these findings indicate that tacrolimus-induced chronic hypertension is mediated largely by NCC activation, and suggest that inexpensive and well-tolerated thiazide diuretics may be especially effective in preventing the complications of CNI treatment.", + "TAG_DATA": [ + "75, mice, {'context': 'B-organism'}", + "117, NCC-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "118, mice, {'context': 'B-organism'}", + "128, mice {'context': 'B-organism'}", + "129, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "130, NCC. {'perturbing_action': 'I-gene gain-of-function'}", + "148, kidney {'context': 'B-xenograft'}", + "149, transplant {'context': 'I-xenograft'}", + "150, recipients {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "75, mice, ['l0']", + "117, NCC-knockout ['l0', 'l1']", + "118, mice, ['l1']", + "128, mice ['l2', 'l3']", + "129, overexpressing ['l2', 'l4']", + "130, NCC. ['l3', 'l4']", + "148, kidney ['l5', 'l6']", + "149, transplant ['l5', 'l7']", + "150, recipients ['l6', 'l7']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NCC-knockout" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "NCC." + ] + } + } + ] + }, + { + "PMID": "21926977", + "TEXT": "Immunological memory is thought to depend on a stem cell-like, self-renewing population of lymphocytes capable of differentiating into effector cells in response to antigen re-exposure. Here we describe a long-lived human memory T cell population that has an enhanced capacity for self-renewal and a multipotent ability to derive central memory, effector memory and effector T cells. These cells, specific to multiple viral and self-tumor antigens, were found within a CD45RO(-), CCR7(+), CD45RA(+), CD62L(+), CD27(+), CD28(+) and IL-7Rα(+) T cell compartment characteristic of naive T cells. However, they expressed large amounts of CD95, IL-2Rβ, CXCR3, and LFA-1, and showed numerous functional attributes distinctive of memory cells. Compared with known memory populations, these lymphocytes had increased proliferative capacity and more efficiently reconstituted immunodeficient hosts, and they mediated superior antitumor responses in a humanized mouse model. The identification of a human stem cell-like memory T cell population is of direct relevance to the design of vaccines and T cell therapies.", + "TAG_DATA": [ + "111, lymphocytes {'context': 'B-cells'}", + "113, increased {'effect': 'B-positive'}", + "114, proliferative {'phenotype': 'B-proliferation'}", + "115, capacity {'phenotype': 'I-proliferation'}", + "130, humanized {'context': 'B-organism'}", + "131, mouse {'context': 'I-organism'}", + "132, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "111, lymphocytes ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "113, increased ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "114, proliferative ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "115, capacity ['l2', 'l7', 'l11', 'l15']", + "130, humanized ['l3', 'l8', 'l12', 'l16', 'l17']", + "131, mouse ['l4', 'l9', 'l13', 'l16', 'l18']", + "132, model. ['l5', 'l10', 'l14', 'l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "lymphocytes" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "lymphocytes" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "capacity" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "capacity" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "organism", + "words": [ + "humanized", + "mouse", + "model." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "capacity" + ] + }, + "context": { + "val": "organism", + "words": [ + "humanized", + "mouse", + "model." + ] + } + } + ] + }, + { + "PMID": "21909105", + "TEXT": "Osteocytes embedded in bone have been postulated to orchestrate bone homeostasis by regulating both bone-forming osteoblasts and bone-resorbing osteoclasts. We find here that purified osteocytes express a much higher amount of receptor activator of nuclear factor-κB ligand (RANKL) and have a greater capacity to support osteoclastogenesis in vitro than osteoblasts and bone marrow stromal cells. Furthermore, the severe osteopetrotic phenotype that we observe in mice lacking RANKL specifically in osteocytes indicates that osteocytes are the major source of RANKL in bone remodeling in vivo.", + "TAG_DATA": [ + "46, in {'context': 'B-in vitro'}", + "47, vitro {'context': 'I-in vitro'}", + "49, osteoblasts {'context': 'B-cells'}", + "51, bone {'context': 'B-cells'}", + "52, marrow {'context': 'I-cells'}", + "53, stromal {'context': 'I-cells'}", + "54, cells. {'context': 'I-cells'}", + "64, mice {'context': 'B-organism'}", + "65, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "66, RANKL {'perturbing_action': 'I-gene loss-of-function'}", + "67, specifically {'perturbing_action': 'I-gene loss-of-function'}", + "68, in {'perturbing_action': 'I-gene loss-of-function'}", + "69, osteocytes {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "46, in ['l0', 'l1', 'l2']", + "47, vitro ['l0', 'l3', 'l4']", + "49, osteoblasts ['l1', 'l3', 'l5', 'l6', 'l7', 'l8']", + "51, bone ['l5', 'l9', 'l10', 'l11']", + "52, marrow ['l6', 'l9', 'l12', 'l13']", + "53, stromal ['l7', 'l10', 'l12', 'l14']", + "54, cells. ['l2', 'l4', 'l8', 'l11', 'l13', 'l14']", + "64, mice ['l15', 'l16', 'l17', 'l18', 'l19']", + "65, lacking ['l15', 'l20', 'l21', 'l22', 'l23']", + "66, RANKL ['l16', 'l20', 'l24', 'l25', 'l26']", + "67, specifically ['l17', 'l21', 'l24', 'l27', 'l28']", + "68, in ['l18', 'l22', 'l25', 'l27', 'l29']", + "69, osteocytes ['l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "RANKL", + "specifically", + "in", + "osteocytes" + ] + } + } + ] + }, + { + "PMID": "21857653", + "TEXT": "The global prevalence of severe Clostridium difficile infection highlights the profound clinical significance of clostridial glucosylating toxins. Virulence is dependent on the autoactivation of a toxin cysteine protease, which is promoted by the allosteric cofactor inositol hexakisphosphate (InsP(6)). Host mechanisms that protect against such exotoxins are poorly understood. It is increasingly appreciated that the pleiotropic functions attributed to nitric oxide (NO), including host immunity, are in large part mediated by S-nitrosylation of proteins. Here we show that C. difficile toxins are S-nitrosylated by the infected host and that S-nitrosylation attenuates virulence by inhibiting toxin self-cleavage and cell entry. Notably, InsP(6)- and inositol pyrophosphate (InsP(7))-induced conformational changes in the toxin enabled host S-nitrosothiols to transnitrosylate the toxin catalytic cysteine, which forms part of a structurally conserved nitrosylation motif. Moreover, treatment with exogenous InsP(6) enhanced the therapeutic actions of oral S-nitrosothiols in mouse models of C. difficile infection. Allostery in bacterial proteins has thus been successfully exploited in the evolutionary development of nitrosothiol-based innate immunity and may provide an avenue to new therapeutic approaches.", + "TAG_DATA": [ + "89, attenuates {'effect': 'B-negative'}", + "92, inhibiting {'effect': 'B-negative'}", + "96, cell {'context': 'B-cells', 'phenotype': 'B-cell growth'}", + "97, entry. {'phenotype': 'B-mitophagy'}", + "140, mouse {'context': 'B-organism'}", + "141, models {'context': 'I-organism'}", + "142, of {'context': 'I-organism'}", + "143, C. {'context': 'I-organism'}", + "144, difficile {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "89, attenuates ['l0', 'l1', 'l2']", + "92, inhibiting ['l0', 'l3', 'l4']", + "96, cell ['l1', 'l3', 'l5']", + "97, entry. ['l2', 'l4', 'l5']", + "140, mouse ['l6', 'l7', 'l8', 'l9']", + "141, models ['l6', 'l10', 'l11', 'l12']", + "142, of ['l7', 'l10', 'l13', 'l14']", + "143, C. ['l8', 'l11', 'l13', 'l15']", + "144, difficile ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "attenuates", + "inhibiting" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuates", + "inhibiting" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuates", + "inhibiting" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "entry." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "entry." + ] + } + } + ] + }, + { + "PMID": "21822286", + "TEXT": "Although the role of miR-200s in regulating E-cadherin expression and epithelial-to-mesenchymal transition is well established, their influence on metastatic colonization remains controversial. Here we have used clinical and experimental models of breast cancer metastasis to discover a pro-metastatic role of miR-200s that goes beyond their regulation of E-cadherin and epithelial phenotype. Overexpression of miR-200s is associated with increased risk of metastasis in breast cancer and promotes metastatic colonization in mouse models, phenotypes that cannot be recapitulated by E-cadherin expression alone. Genomic and proteomic analyses revealed global shifts in gene expression upon miR-200 overexpression toward that of highly metastatic cells. miR-200s promote metastatic colonization partly through direct targeting of Sec23a, which mediates secretion of metastasis-suppressive proteins, including Igfbp4 and Tinagl1, as validated by functional and clinical correlation studies. Overall, these findings suggest a pleiotropic role of miR-200s in promoting metastatic colonization by influencing E-cadherin-dependent epithelial traits and Sec23a-mediated tumor cell secretome.", + "TAG_DATA": [ + "51, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "52, of {'perturbing_action': 'I-gene gain-of-function'}", + "53, miR-200s {'perturbing_action': 'I-gene gain-of-function'}", + "65, promotes {'effect': 'B-positive'}", + "66, metastatic {'phenotype': 'B-metastasis'}", + "67, colonization {'phenotype': 'I-metastasis'}", + "69, mouse {'context': 'B-organism'}", + "70, models, {'context': 'I-organism'}", + "91, miR-200 {'perturbing_action': 'B-gene gain-of-function'}", + "92, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "100, promote {'effect': 'B-positive'}", + "101, metastatic {'phenotype': 'B-metastasis'}", + "102, colonization {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "51, Overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "52, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "53, miR-200s ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "65, promotes ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "66, metastatic ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "67, colonization ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "69, mouse ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "70, models, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "91, miR-200 ['l28']", + "92, overexpression ['l28']", + "100, promote ['l29', 'l30']", + "101, metastatic ['l29', 'l31']", + "102, colonization ['l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "miR-200s" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "miR-200s" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "colonization" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "miR-200s" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes", + "promote" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "colonization" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models," + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "colonization" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models," + ] + } + } + ] + }, + { + "PMID": "21738155", + "TEXT": "A new combinatorial approach harnesses the power of immuno- and virotherapy in a vesicular stomatitis virus (VSV) vector carrying a cDNA library that expresses normal human prostate antigens, thus providing proof of principle that this vaccine can induce prostate tumor rejection in mice (pages 854–859). This strategy might bypass many of the issues associated with conventional cancer immuno- or virotherapy.", + "TAG_DATA": [ + "37, induce {'effect': 'B-positive'}", + "38, prostate {'context': 'B-neoplasm'}", + "39, tumor {'phenotype': 'B-tumour regression'}", + "40, rejection {'phenotype': 'I-tumour regression'}", + "42, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "37, induce ['l0', 'l1', 'l2', 'l3']", + "38, prostate ['l0', 'l4', 'l5', 'l6']", + "39, tumor ['l1', 'l4', 'l7', 'l8']", + "40, rejection ['l2', 'l5', 'l7', 'l9']", + "42, mice ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "prostate" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "rejection" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "prostate" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "rejection" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "rejection" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "21725296", + "TEXT": "In cancer treatment, apoptosis is a well-recognized cell death mechanism through which cytotoxic agents kill tumor cells. Here we report that dying tumor cells use the apoptotic process to generate potent growth-stimulating signals to stimulate the repopulation of tumors undergoing radiotherapy. Furthermore, activated caspase 3, a key executioner in apoptosis, is involved in the growth stimulation. One downstream effector that caspase 3 regulates is prostaglandin E(2) (PGE(2)), which can potently stimulate growth of surviving tumor cells. Deficiency of caspase 3 either in tumor cells or in tumor stroma caused substantial tumor sensitivity to radiotherapy in xenograft or mouse tumors. In human subjects with cancer, higher amounts of activated caspase 3 in tumor tissues are correlated with markedly increased rate of recurrence and death. We propose the existence of a cell death-induced tumor repopulation pathway in which caspase 3 has a major role.", + "TAG_DATA": [ + "74, tumor {'context': 'B-transformed cells'}", + "75, cells. {'context': 'I-transformed cells'}", + "76, Deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "77, of {'perturbing_action': 'I-gene loss-of-function'}", + "78, caspase {'perturbing_action': 'I-gene loss-of-function'}", + "79, 3 {'perturbing_action': 'I-gene loss-of-function'}", + "82, tumor {'context': 'B-transformed cells'}", + "83, cells {'context': 'I-transformed cells'}", + "86, tumor {'context': 'B-neoplasm'}", + "90, tumor {'context': 'B-neoplasm'}", + "95, xenograft {'context': 'B-xenograft'}", + "97, mouse {'context': 'B-neoplasm'}", + "98, tumors. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "74, tumor ['l0']", + "75, cells. ['l0']", + "76, Deficiency ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "77, of ['l1', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "78, caspase ['l2', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "79, 3 ['l3', 'l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "80, either ['l4', 'l14', 'l23', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "82, tumor ['l5', 'l15', 'l24', 'l32', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "83, cells ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l52', 'l53', 'l54', 'l55']", + "86, tumor ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l56', 'l57', 'l58', 'l59']", + "90, tumor ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l52', 'l56', 'l60', 'l61', 'l62']", + "95, xenograft ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l53', 'l57', 'l60', 'l63', 'l64']", + "97, mouse ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l54', 'l58', 'l61', 'l63', 'l65']", + "98, tumors. ['l11', 'l21', 'l30', 'l38', 'l45', 'l51', 'l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deficiency", + "of", + "caspase", + "3" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deficiency", + "of", + "caspase", + "3" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor", + "mouse", + "tumors." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deficiency", + "of", + "caspase", + "3" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft" + ] + } + } + ] + }, + { + "PMID": "21706030", + "TEXT": "Cells that are deficient in homologous recombination, such as those that lack functional breast cancer-associated 1 (BRCA1) or BRCA2, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, BRCA-deficient tumors represent only a small fraction of adult cancers, which might restrict the therapeutic utility of PARP inhibitor monotherapy. Cyclin-dependent kinase 1 (Cdk1) phosphorylates BRCA1, and this is essential for efficient formation of BRCA1 foci. Here we show that depletion or inhibition of Cdk1 compromises the ability of cells to repair DNA by homologous recombination. Combined inhibition of Cdk1 and PARP in BRCA-wild-type cancer cells resulted in reduced colony formation, delayed growth of human tumor xenografts and tumor regression with prolonged survival in a mouse model of lung adenocarcinoma. Inhibition of Cdk1 did not sensitize nontransformed cells or tissues to inhibition of PARP. Because reduced Cdk1 activity impaired BRCA1 function and consequently, repair by homologous recombination, inhibition of Cdk1 represents a plausible strategy for expanding the utility of PARP inhibitors to BRCA-proficient cancers.", + "TAG_DATA": [ + "70, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "71, of {'perturbing_action': 'I-pharmacological inhibition'}", + "72, Cdk1 {'perturbing_action': 'I-pharmacological inhibition'}", + "77, cells {'context': 'B-cells'}", + "84, Combined {'perturbing_action': 'B-pharmacological inhibition'}", + "85, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "86, of {'perturbing_action': 'I-pharmacological inhibition'}", + "87, Cdk1 {'perturbing_action': 'I-pharmacological inhibition'}", + "88, and {'perturbing_action': 'I-pharmacological inhibition'}", + "89, PARP {'perturbing_action': 'I-pharmacological inhibition'}", + "91, BRCA-wild-type {'context': 'B-transformed cells'}", + "92, cancer {'context': 'B-transformed cells'}", + "93, cells {'context': 'I-transformed cells'}", + "96, reduced {'effect': 'B-negative'}", + "97, colony {'phenotype': 'B-colony formation'}", + "98, formation, {'phenotype': 'I-colony formation'}", + "102, human {'context': 'B-xenograft'}", + "103, tumor {'context': 'I-xenograft'}", + "104, xenografts {'context': 'I-xenograft'}", + "106, tumor {'phenotype': 'B-tumour regression'}", + "107, regression {'phenotype': 'I-tumour regression'}", + "113, mouse {'context': 'B-neoplasm'}", + "114, model {'context': 'I-neoplasm'}", + "115, of {'context': 'I-neoplasm'}", + "116, lung {'context': 'I-neoplasm'}", + "117, adenocarcinoma. {'context': 'I-neoplasm'}", + "118, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "119, of {'perturbing_action': 'I-pharmacological inhibition'}", + "120, Cdk1 {'perturbing_action': 'I-pharmacological inhibition'}", + "124, nontransformed {'context': 'B-cells'}", + "125, cells {'context': 'I-cells'}", + "129, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "130, of {'perturbing_action': 'I-pharmacological inhibition'}", + "131, PARP. {'perturbing_action': 'I-pharmacological inhibition'}", + "133, reduced {'perturbing_action': 'B-other'}", + "134, Cdk1 {'perturbing_action': 'I-rnai/knockdown'}", + "135, activity {'perturbing_action': 'I-rnai/knockdown'}", + "145, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "146, of {'perturbing_action': 'I-pharmacological inhibition'}", + "147, Cdk1 {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "70, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "71, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "72, Cdk1 ['l1', 'l11', 'l19', 'l20', 'l21', 'l22']", + "77, cells ['l2', 'l12', 'l19']", + "84, Combined ['l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "85, inhibition ['l23', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "86, of ['l3', 'l24', 'l44', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "87, Cdk1 ['l25', 'l45', 'l64', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "88, and ['l4', 'l26', 'l46', 'l65', 'l83', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "89, PARP ['l27', 'l47', 'l66', 'l84', 'l101', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "91, BRCA-wild-type ['l5', 'l13', 'l28', 'l48', 'l67', 'l85', 'l102', 'l118', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145']", + "92, cancer ['l6', 'l14', 'l20', 'l29', 'l49', 'l68', 'l86', 'l103', 'l119', 'l134', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "93, cells ['l7', 'l15', 'l21', 'l30', 'l50', 'l69', 'l87', 'l104', 'l120', 'l135', 'l146', 'l153', 'l154', 'l155', 'l156']", + "96, reduced ['l8', 'l16', 'l31', 'l51', 'l70', 'l88', 'l105', 'l121', 'l136', 'l147', 'l153', 'l157', 'l158', 'l159', 'l160']", + "97, colony ['l9', 'l17', 'l32', 'l52', 'l71', 'l89', 'l106', 'l122', 'l137', 'l148', 'l154', 'l157', 'l161', 'l162']", + "98, formation, ['l10', 'l18', 'l22', 'l33', 'l53', 'l72', 'l90', 'l107', 'l123', 'l138', 'l149', 'l155', 'l158', 'l161']", + "102, human ['l34', 'l54', 'l73', 'l91', 'l108', 'l124', 'l139', 'l150', 'l159', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170']", + "103, tumor ['l35', 'l55', 'l74', 'l92', 'l109', 'l125', 'l140', 'l151', 'l163', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "104, xenografts ['l36', 'l56', 'l75', 'l93', 'l110', 'l126', 'l141', 'l152', 'l156', 'l160', 'l162', 'l164', 'l171', 'l179', 'l180', 'l181', 'l182', 'l183']", + "106, tumor ['l37', 'l57', 'l76', 'l94', 'l111', 'l127', 'l142', 'l165', 'l172', 'l179', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189']", + "107, regression ['l38', 'l58', 'l77', 'l95', 'l112', 'l128', 'l143', 'l166', 'l173', 'l180', 'l184', 'l190', 'l191', 'l192', 'l193', 'l194']", + "113, mouse ['l39', 'l59', 'l78', 'l96', 'l113', 'l129', 'l174', 'l185', 'l190', 'l195', 'l196', 'l197', 'l198']", + "114, model ['l40', 'l60', 'l79', 'l97', 'l114', 'l130', 'l144', 'l167', 'l175', 'l181', 'l186', 'l191', 'l195', 'l199', 'l200', 'l201']", + "115, of ['l41', 'l61', 'l80', 'l98', 'l115', 'l131', 'l145', 'l168', 'l176', 'l182', 'l187', 'l192', 'l196', 'l199', 'l202', 'l203']", + "116, lung ['l42', 'l62', 'l81', 'l99', 'l116', 'l132', 'l169', 'l177', 'l188', 'l193', 'l197', 'l200', 'l202', 'l204']", + "117, adenocarcinoma. ['l43', 'l63', 'l82', 'l100', 'l117', 'l133', 'l170', 'l178', 'l183', 'l189', 'l194', 'l198', 'l201', 'l203', 'l204']", + "118, Inhibition ['l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218']", + "119, of ['l205', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231']", + "120, Cdk1 ['l206', 'l219', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243']", + "124, nontransformed ['l207', 'l220', 'l232', 'l244', 'l245', 'l246', 'l247', 'l248']", + "125, cells ['l208', 'l221', 'l233', 'l244', 'l249', 'l250', 'l251', 'l252']", + "127, tissues ['l209', 'l222', 'l234', 'l245', 'l249', 'l253', 'l254', 'l255']", + "129, inhibition ['l210', 'l223', 'l235', 'l246', 'l250', 'l253', 'l256', 'l257', 'l258', 'l259', 'l260']", + "130, of ['l211', 'l224', 'l236', 'l247', 'l251', 'l254', 'l256', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266']", + "131, PARP. ['l212', 'l225', 'l237', 'l248', 'l252', 'l255', 'l257', 'l261', 'l267']", + "133, reduced ['l213', 'l226', 'l238', 'l258', 'l262', 'l268', 'l269', 'l270', 'l271', 'l272']", + "134, Cdk1 ['l214', 'l227', 'l239', 'l259', 'l263', 'l268', 'l273', 'l274', 'l275', 'l276']", + "135, activity ['l215', 'l228', 'l240', 'l260', 'l264', 'l267', 'l269', 'l273', 'l277', 'l278', 'l279']", + "145, inhibition ['l216', 'l229', 'l241', 'l265', 'l270', 'l274', 'l277', 'l280', 'l281']", + "146, of ['l217', 'l230', 'l242', 'l266', 'l271', 'l275', 'l278', 'l280', 'l282']", + "147, Cdk1 ['l218', 'l231', 'l243', 'l272', 'l276', 'l279', 'l281', 'l282']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "Cdk1", + "Inhibition", + "PARP." + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "nontransformed" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "Cdk1", + "Combined", + "and", + "PARP" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "BRCA-wild-type", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "Combined", + "Cdk1", + "and", + "PARP" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "Cdk1", + "Combined", + "and", + "PARP" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "colony", + "formation," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Combined", + "inhibition", + "of", + "Cdk1", + "and", + "PARP" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "human", + "tumor", + "xenografts" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Combined", + "inhibition", + "of", + "Cdk1", + "and", + "PARP" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Combined", + "inhibition", + "of", + "Cdk1", + "and", + "PARP" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "lung", + "adenocarcinoma." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "BRCA-wild-type", + "cancer", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "BRCA-wild-type", + "cancer", + "cells" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "colony", + "formation," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "BRCA-wild-type" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "colony", + "formation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "human", + "xenografts" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "colony" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenografts" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "human", + "tumor", + "xenografts" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "lung", + "adenocarcinoma." + ] + } + } + ] + }, + { + "PMID": "21572428", + "TEXT": "Endocrine resistance is a major obstacle to hormonal therapy for breast cancers. Although reduced expression of estrogen receptor-α (ER-α) is a known contributing factor to endocrine resistance, the mechanism of ER-α downregulation in endocrine resistance is still not fully understood. Here we report that CUE domain-containing protein-2 (CUEDC2), a ubiquitin-binding motif-containing protein, is a key factor in endocrine resistance in breast cancer. We show that CUEDC2 modulates ER-α protein stability through the ubiquitin-proteasome pathway. Through the study of specimens from a large cohort of subjects with breast cancer, we found a strong inverse correlation between CUEDC2 and ER-α protein expression. Notably, subjects with tumors that highly expressed CUEDC2 had poor responsiveness to tamoxifen treatment and high potential for relapse. We further show that ectopic CUEDC2 expression impaired the responsiveness of breast cancer cells to tamoxifen. Therefore, our findings suggest that CUEDC2 is a crucial determinant of resistance to endocrine therapies in breast cancer.", + "TAG_DATA": [ + "123, ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "124, CUEDC2 {'perturbing_action': 'I-gene gain-of-function'}", + "125, expression {'perturbing_action': 'I-gene gain-of-function'}", + "130, breast {'context': 'B-transformed cells'}", + "131, cancer {'context': 'I-transformed cells'}", + "132, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "123, ectopic ['l0', 'l1', 'l2', 'l3', 'l4']", + "124, CUEDC2 ['l0', 'l5', 'l6', 'l7', 'l8']", + "125, expression ['l1', 'l5', 'l9', 'l10', 'l11']", + "130, breast ['l2', 'l6', 'l9', 'l12', 'l13']", + "131, cancer ['l3', 'l7', 'l10', 'l12', 'l14']", + "132, cells ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "CUEDC2", + "expression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "breast", + "cancer", + "cells" + ] + } + } + ] + }, + { + "PMID": "21532596", + "TEXT": "In adipose tissue, muscle, liver and macrophages, signaling by the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ) is a determinant of insulin sensitivity and this receptor mediates the insulin-sensitizing effects of thiazolidinediones (TZDs). As PPAR-γ is also expressed in neurons, we generated mice with neuron-specific Pparg knockout (Pparg brain knockout (BKO)) to determine whether neuronal PPAR-γ signaling contributes to either weight gain or insulin sensitivity. During high-fat diet (HFD) feeding, food intake was reduced and energy expenditure increased in Pparg-BKO mice compared to Pparg(f/f) mice, resulting in reduced weight gain. Pparg-BKO mice also responded better to leptin administration than Pparg(f/f) mice. When treated with the TZD rosiglitazone, Pparg-BKO mice were resistant to rosiglitazone-induced hyperphagia and weight gain and, relative to rosiglitazone-treated Pparg(f/f) mice, experienced only a marginal improvement in glucose metabolism. Hyperinsulinemic euglycemic clamp studies showed that the increase in hepatic insulin sensitivity induced by rosiglitazone treatment during HFD feeding was completely abolished in Pparg-BKO mice, an effect associated with the failure of rosiglitazone to improve liver insulin receptor signal transduction. We conclude that excess weight gain induced by HFD feeding depends in part on the effect of neuronal PPAR-γ signaling to limit thermogenesis and increase food intake. Neuronal PPAR-γ signaling is also required for the hepatic insulin sensitizing effects of TZDs.", + "TAG_DATA": [ + "41, mice {'context': 'B-organism'}", + "43, neuron-specific {'perturbing_action': 'B-gene loss-of-function'}", + "44, Pparg {'perturbing_action': 'I-gene loss-of-function'}", + "45, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "46, (Pparg {'perturbing_action': 'I-gene loss-of-function'}", + "47, brain {'perturbing_action': 'I-gene loss-of-function'}", + "48, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "49, (BKO)) {'perturbing_action': 'I-gene loss-of-function'}", + "78, Pparg-BKO {'perturbing_action': 'B-gene loss-of-function'}", + "79, mice {'context': 'B-organism'}", + "82, Pparg(f/f) {'perturbing_action': 'B-other'}", + "89, Pparg-BKO {'perturbing_action': 'B-gene loss-of-function'}", + "90, mice {'context': 'B-organism'}", + "98, Pparg(f/f) {'perturbing_action': 'B-other'}", + "99, mice. {'context': 'B-organism'}", + "106, Pparg-BKO {'perturbing_action': 'B-gene loss-of-function'}", + "107, mice {'context': 'B-organism'}", + "120, Pparg(f/f) {'perturbing_action': 'B-other'}", + "121, mice, {'context': 'B-organism'}", + "153, Pparg-BKO {'perturbing_action': 'B-gene loss-of-function'}", + "154, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "41, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "43, neuron-specific ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "44, Pparg ['l1', 'l10', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "45, knockout ['l2', 'l11', 'l20', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "46, (Pparg ['l3', 'l12', 'l21', 'l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "47, brain ['l4', 'l13', 'l22', 'l29', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "48, knockout ['l5', 'l14', 'l23', 'l30', 'l36', 'l41', 'l46', 'l47', 'l48', 'l49']", + "49, (BKO)) ['l6', 'l15', 'l24', 'l31', 'l37', 'l42', 'l46', 'l50', 'l51', 'l52']", + "78, Pparg-BKO ['l7', 'l16', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l53', 'l54']", + "79, mice ['l8', 'l17', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53']", + "82, Pparg(f/f) ['l9', 'l18', 'l27', 'l34', 'l40', 'l45', 'l49', 'l52', 'l54', 'l55']", + "89, Pparg-BKO ['l56', 'l57', 'l58', 'l59']", + "90, mice ['l19', 'l55', 'l56', 'l60']", + "98, Pparg(f/f) ['l57', 'l61', 'l62']", + "99, mice. ['l58', 'l60', 'l61']", + "106, Pparg-BKO ['l63', 'l64', 'l65']", + "107, mice ['l59', 'l62', 'l63', 'l66', 'l67']", + "120, Pparg(f/f) ['l64', 'l66', 'l68']", + "121, mice, ['l65', 'l67', 'l68']", + "153, Pparg-BKO ['l69']", + "154, mice, ['l69']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "neuron-specific", + "Pparg", + "knockout", + "(Pparg", + "brain", + "(BKO))", + "Pparg-BKO" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "mice," + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Pparg(f/f)" + ] + } + } + ] + }, + { + "PMID": "21516088", + "TEXT": "Deficiency in fragile X mental retardation protein (FMRP) results in fragile X syndrome (FXS), an inherited form of intellectual disability. Despite extensive research, it is unclear how FMRP deficiency contributes to the cognitive deficits in FXS. Fmrp-null mice show reduced adult hippocampal neurogenesis. As Fmrp is also enriched in mature neurons, we investigated the function of Fmrp expression in neural stem and progenitor cells (aNSCs) and its role in adult neurogenesis. Here we show that ablation of Fmrp in aNSCs by inducible gene recombination leads to reduced hippocampal neurogenesis in vitro and in vivo, as well as markedly impairing hippocampus-dependent learning in mice. Conversely, restoration of Fmrp expression specifically in aNSCs rescues these learning deficits in Fmrp-deficient mice. These data suggest that defective adult neurogenesis may contribute to the learning impairment seen in FXS, and these learning deficits can be rectified by delayed restoration of Fmrp specifically in aNSCs.", + "TAG_DATA": [ + "36, Fmrp-null {'perturbing_action': 'B-gene loss-of-function'}", + "75, ablation {'perturbing_action': 'B-gene loss-of-function'}", + "76, of {'perturbing_action': 'I-gene loss-of-function'}", + "77, Fmrp {'perturbing_action': 'I-gene loss-of-function'}", + "79, aNSCs {'context': 'B-cells'}", + "80, by {'perturbing_action': 'I-gene loss-of-function'}", + "81, inducible {'perturbing_action': 'I-gene loss-of-function'}", + "82, gene {'perturbing_action': 'I-gene loss-of-function'}", + "83, recombination {'perturbing_action': 'I-gene loss-of-function'}", + "89, in {'context': 'B-in vitro'}", + "90, vitro {'context': 'I-in vitro'}", + "92, in {'context': 'B-in vivo'}", + "93, vivo, {'context': 'I-in vivo'}", + "102, mice. {'context': 'B-organism'}", + "104, restoration {'perturbing_action': 'B-gene gain-of-function'}", + "105, of {'perturbing_action': 'I-gene gain-of-function'}", + "106, Fmrp {'perturbing_action': 'I-gene gain-of-function'}", + "107, expression {'perturbing_action': 'I-gene gain-of-function'}", + "108, specifically {'perturbing_action': 'I-gene gain-of-function'}", + "110, aNSCs {'context': 'B-cells'}", + "116, Fmrp-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "117, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "36, Fmrp-null ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "75, ablation ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "76, of ['l6', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "77, Fmrp ['l0', 'l7', 'l18', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "79, aNSCs ['l1', 'l8', 'l19', 'l29', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "80, by ['l2', 'l9', 'l20', 'l30', 'l39', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "81, inducible ['l10', 'l21', 'l31', 'l40', 'l48', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "82, gene ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "83, recombination ['l12', 'l23', 'l33', 'l42', 'l50', 'l57', 'l63', 'l69', 'l70', 'l71', 'l72', 'l73']", + "89, in ['l3', 'l13', 'l24', 'l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l74', 'l75']", + "90, vitro ['l4', 'l14', 'l25', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l76']", + "92, in ['l15', 'l26', 'l36', 'l45', 'l53', 'l60', 'l66', 'l71', 'l77', 'l78']", + "93, vivo, ['l5', 'l16', 'l27', 'l37', 'l46', 'l54', 'l61', 'l67', 'l72', 'l75', 'l76', 'l77', 'l79']", + "102, mice. ['l17', 'l28', 'l38', 'l47', 'l55', 'l62', 'l68', 'l73', 'l78', 'l79']", + "104, restoration ['l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "105, of ['l80', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "106, Fmrp ['l81', 'l87', 'l93', 'l94', 'l95', 'l96', 'l97']", + "107, expression ['l82', 'l88', 'l93', 'l98', 'l99', 'l100', 'l101']", + "108, specifically ['l83', 'l89', 'l94', 'l98', 'l102', 'l103', 'l104']", + "110, aNSCs ['l84', 'l90', 'l95', 'l99', 'l102', 'l105', 'l106']", + "116, Fmrp-deficient ['l85', 'l91', 'l96', 'l100', 'l103', 'l105', 'l107']", + "117, mice. ['l86', 'l92', 'l97', 'l101', 'l104', 'l106', 'l107']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fmrp-null", + "ablation", + "of", + "Fmrp", + "by", + "inducible", + "gene", + "recombination", + "Fmrp-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "aNSCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fmrp-null", + "ablation", + "of", + "Fmrp", + "by", + "inducible", + "gene", + "recombination" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fmrp-null", + "ablation", + "of", + "Fmrp", + "by", + "inducible", + "gene", + "recombination" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo,", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablation", + "of", + "Fmrp", + "by", + "inducible", + "gene", + "recombination", + "Fmrp-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "restoration", + "of", + "Fmrp", + "expression", + "specifically" + ] + }, + "context": { + "val": "cells", + "words": [ + "aNSCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "restoration", + "of", + "Fmrp", + "expression", + "specifically" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "21516086", + "TEXT": "Inflammatory cell recruitment after myocardial infarction needs to be tightly controlled to permit infarct healing while avoiding fatal complications such as cardiac rupture. Growth differentiation factor-15 (GDF-15), a transforming growth factor-β (TGF-β)-related cytokine, is induced in the infarcted heart of mice and humans. We show that coronary artery ligation in Gdf15-deficient mice led to enhanced recruitment of polymorphonuclear leukocytes (PMNs) into the infarcted myocardium and an increased incidence of cardiac rupture. Conversely, infusion of recombinant GDF-15 repressed PMN recruitment after myocardial infarction. In vitro, GDF-15 inhibited PMN adhesion, arrest under flow and transendothelial migration. Mechanistically, GDF-15 counteracted chemokine-triggered conformational activation and clustering of β(2) integrins on PMNs by activating the small GTPase Cdc42 and inhibiting activation of the small GTPase Rap1. Intravital microscopy in vivo in Gdf15-deficient mice showed that Gdf-15 is required to prevent excessive chemokine-activated leukocyte arrest on the endothelium. Genetic ablation of β(2) integrins in myeloid cells rescued the mortality of Gdf15-deficient mice after myocardial infarction. To our knowledge, GDF-15 is the first cytokine identified as an inhibitor of PMN recruitment by direct interference with chemokine signaling and integrin activation. Loss of this anti-inflammatory mechanism leads to fatal cardiac rupture after myocardial infarction.", + "TAG_DATA": [ + "50, Gdf15-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "51, mice {'context': 'B-organism'}", + "77, PMN {'context': 'B-cells'}", + "82, In {'context': 'B-in vitro'}", + "83, vitro, {'context': 'I-in vitro'}", + "85, inhibited {'effect': 'B-negative'}", + "86, PMN {'context': 'B-cells'}", + "87, adhesion, {'phenotype': 'B-adhesion'}", + "123, in {'context': 'B-in vivo'}", + "124, vivo {'context': 'I-in vivo'}", + "126, Gdf15-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "127, mice {'context': 'B-organism'}", + "137, leukocyte {'context': 'B-cells'}", + "142, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "143, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "144, of {'perturbing_action': 'I-gene loss-of-function'}", + "145, β(2) {'perturbing_action': 'I-gene loss-of-function'}", + "146, integrins {'perturbing_action': 'I-gene loss-of-function'}", + "148, myeloid {'context': 'B-cells'}", + "149, cells {'context': 'I-cells'}", + "154, Gdf15-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "155, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, Gdf15-deficient ['l0', 'l1']", + "51, mice ['l0', 'l2']", + "77, PMN ['l1', 'l2']", + "82, In ['l3', 'l4', 'l5', 'l6']", + "83, vitro, ['l3', 'l7', 'l8', 'l9']", + "85, inhibited ['l4', 'l7', 'l10', 'l11', 'l12']", + "86, PMN ['l5', 'l8', 'l10', 'l13']", + "87, adhesion, ['l6', 'l9', 'l11', 'l13']", + "123, in ['l14', 'l15', 'l16', 'l17']", + "124, vivo ['l14', 'l18', 'l19', 'l20']", + "126, Gdf15-deficient ['l15', 'l18', 'l21', 'l22', 'l23']", + "127, mice ['l16', 'l19', 'l21', 'l24']", + "137, leukocyte ['l12', 'l17', 'l20', 'l22', 'l24']", + "142, Genetic ['l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "143, ablation ['l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "144, of ['l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "145, β(2) ['l27', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "146, integrins ['l28', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "148, myeloid ['l29', 'l36', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57']", + "149, cells ['l23', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l58', 'l59']", + "154, Gdf15-deficient ['l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58', 'l60']", + "155, mice ['l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gdf15-deficient", + "Genetic", + "ablation", + "of", + "β(2)", + "integrins" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gdf15-deficient", + "Genetic", + "ablation", + "of", + "β(2)", + "integrins" + ] + }, + "context": { + "val": "cells", + "words": [ + "PMN", + "leukocyte", + "cells", + "myeloid" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "PMN", + "leukocyte" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "PMN" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gdf15-deficient" + ] + } + } + ] + }, + { + "PMID": "21499269", + "TEXT": "Chronic inflammation characterized by T cell and macrophage infiltration of visceral adipose tissue (VAT) is a hallmark of obesity-associated insulin resistance and glucose intolerance. Here we show a fundamental pathogenic role for B cells in the development of these metabolic abnormalities. B cells accumulate in VAT in diet-induced obese (DIO) mice, and DIO mice lacking B cells are protected from disease despite weight gain. B cell effects on glucose metabolism are mechanistically linked to the activation of proinflammatory macrophages and T cells and to the production of pathogenic IgG antibodies. Treatment with a B cell-depleting CD20 antibody attenuates disease, whereas transfer of IgG from DIO mice rapidly induces insulin resistance and glucose intolerance. Moreover, insulin resistance in obese humans is associated with a unique profile of IgG autoantibodies. These results establish the importance of B cells and adaptive immunity in insulin resistance and suggest new diagnostic and therapeutic modalities for managing the disease.", + "TAG_DATA": [ + "50, mice, {'context': 'B-organism'}", + "53, mice {'context': 'I-organism'}", + "54, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "55, B {'context': 'B-cells'}", + "56, cells {'context': 'I-cells'}", + "93, B {'perturbing_action': 'B-gene loss-of-function'}", + "94, cell-depleting {'perturbing_action': 'I-gene loss-of-function'}", + "95, CD20 {'perturbing_action': 'I-gene loss-of-function'}", + "96, antibody {'perturbing_action': 'I-gene loss-of-function'}", + "105, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "53, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "54, lacking ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "55, B ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "56, cells ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "93, B ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "94, cell-depleting ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "95, CD20 ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "96, antibody ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "B", + "cell-depleting", + "CD20", + "antibody" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "B", + "cell-depleting", + "CD20", + "antibody" + ] + }, + "context": { + "val": "cells", + "words": [ + "B", + "cells" + ] + } + } + ] + }, + { + "PMID": "21460849", + "TEXT": "Heterotopic ossification consists of ectopic bone formation within soft tissues after surgery or trauma. It can have debilitating consequences, but there is no definitive cure. Here we show that heterotopic ossification was essentially prevented in mice receiving a nuclear retinoic acid receptor-γ (RAR-γ) agonist. Side effects were minimal, and there was no significant rebound effect. To uncover the mechanisms of these responses, we treated mouse mesenchymal stem cells with an RAR-γ agonist and transplanted them into nude mice. Whereas control cells formed ectopic bone masses, cells that had been pretreated with the RAR-γ agonist did not, suggesting that they had lost their skeletogenic potential. The cells became unresponsive to rBMP-2 treatment in vitro and showed decreases in phosphorylation of Smad1, Smad5 and Smad8 and in overall levels of Smad proteins. In addition, an RAR-γ agonist blocked heterotopic ossification in transgenic mice expressing activin receptor-like kinase-2 (ALK2) Q207D, a constitutively active form of the receptor that is related to ALK2 R206H found in individuals with fibrodysplasia ossificans progressiva. The data indicate that RAR-γ agonists are potent inhibitors of heterotopic ossification in mouse models and, thus, may also be effective against injury-induced and congenital heterotopic ossification in humans.", + "TAG_DATA": [ + "35, mice {'context': 'B-organism'}", + "64, mouse {'context': 'B-cells'}", + "65, mesenchymal {'context': 'I-cells'}", + "66, stem {'context': 'I-cells'}", + "67, cells {'context': 'I-cells'}", + "71, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "76, nude {'context': 'B-organism'}", + "77, mice. {'context': 'I-organism'}", + "80, cells {'context': 'B-cells'}", + "85, cells {'context': 'B-cells'}", + "105, cells {'context': 'B-cells'}", + "111, in {'context': 'B-in vitro'}", + "112, vitro {'context': 'I-in vitro'}", + "133, RAR-γ {'perturbing_action': 'B-pharmacological augmentation'}", + "134, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "139, transgenic {'context': 'B-organism'}", + "140, mice {'context': 'I-organism'}", + "141, expressing {'perturbing_action': 'B-other'}", + "142, activin {'perturbing_action': 'I-other'}", + "143, receptor-like {'perturbing_action': 'I-other'}", + "144, kinase-2 {'perturbing_action': 'I-other'}", + "145, (ALK2) {'perturbing_action': 'I-other'}", + "146, Q207D, {'perturbing_action': 'I-other'}", + "147, a {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "35, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "64, mouse ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "65, mesenchymal ['l1', 'l8', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "66, stem ['l2', 'l9', 'l16', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "67, cells ['l3', 'l10', 'l17', 'l23', 'l29', 'l30', 'l31', 'l32', 'l33']", + "70, RAR-γ ['l4', 'l11', 'l18', 'l24', 'l29', 'l34', 'l35', 'l36', 'l37']", + "71, agonist ['l5', 'l12', 'l19', 'l25', 'l30', 'l34', 'l38', 'l39', 'l40']", + "76, nude ['l6', 'l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l41']", + "77, mice. ['l7', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l41']", + "80, cells ['l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42']", + "85, cells ['l42', 'l43', 'l44']", + "105, cells ['l43', 'l45', 'l46']", + "111, in ['l45', 'l47']", + "112, vitro ['l44', 'l46', 'l47']", + "133, RAR-γ ['l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "134, agonist ['l48', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "139, transgenic ['l49', 'l58', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "140, mice ['l50', 'l59', 'l67', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "141, expressing ['l51', 'l60', 'l68', 'l75', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "142, activin ['l52', 'l61', 'l69', 'l76', 'l82', 'l88', 'l89', 'l90', 'l91', 'l92']", + "143, receptor-like ['l53', 'l62', 'l70', 'l77', 'l83', 'l88', 'l93', 'l94', 'l95', 'l96']", + "144, kinase-2 ['l54', 'l63', 'l71', 'l78', 'l84', 'l89', 'l93', 'l97', 'l98', 'l99']", + "145, (ALK2) ['l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l94', 'l97', 'l100', 'l101']", + "146, Q207D, ['l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l98', 'l100', 'l102']", + "147, a ['l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l101', 'l102']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "nude", + "mice.", + "transgenic" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "agonist", + "RAR-γ" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "mesenchymal", + "stem", + "cells" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "agonist" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "activin", + "receptor-like", + "kinase-2", + "(ALK2)", + "Q207D,", + "a" + ] + } + } + ] + }, + { + "PMID": "21297610", + "TEXT": "Cystic fibrosis can manifest in many organs, but infection and inflammation of the airways cause the most severe morbidity and mortality. Early studies suggested that increased epithelial Na+ reabsorption may be a key initiating event in cystic fibrosis lung disease. However, the importance of Na+ hyperabsorption and the consequent depletion of pericellular airway liquid in cystic fibrosis lung disease has been called into question by a recent study by Jeng-Haur Chen et al.. Newborn pigs lacking cystic fibrosis transmembrane conductance regulator (CFTR−/− pigs) developed lung pathology reminiscent of human cystic fibrosis. Although epithelia from these pigs had reduced Cl− and HCO3− transport, there were no alterations in Na+ or liquid absorption, suggesting that defective anion transport is responsible for cystic fibrosis lung disease. Here three experts comment on how these findings might affect our understanding of cystic fibrosis lung pathogenesis and strategies for cystic fibrosis therapy.", + "TAG_DATA": [ + "73, Newborn {'context': 'B-organism'}", + "74, pigs {'context': 'I-organism'}", + "75, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "76, cystic {'perturbing_action': 'I-gene loss-of-function'}", + "77, fibrosis {'perturbing_action': 'I-gene loss-of-function'}", + "78, transmembrane {'perturbing_action': 'I-gene loss-of-function'}", + "79, conductance {'perturbing_action': 'I-gene loss-of-function'}", + "80, regulator {'perturbing_action': 'I-gene loss-of-function'}", + "81, (CFTR−/− {'perturbing_action': 'I-gene loss-of-function'}", + "82, pigs) {'perturbing_action': 'I-gene loss-of-function'}", + "95, pigs {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, Newborn ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "74, pigs ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "75, lacking ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "76, cystic ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "77, fibrosis ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "78, transmembrane ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "79, conductance ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "80, regulator ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "81, (CFTR−/− ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "82, pigs) ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60']", + "92, epithelia ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63']", + "95, pigs ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l63']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Newborn", + "pigs" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "cystic", + "fibrosis", + "transmembrane", + "conductance", + "regulator", + "(CFTR−/−", + "pigs)" + ] + } + } + ] + }, + { + "PMID": "21240262", + "TEXT": "Cancer stem cells (CSCs), or tumor-initiating cells, are involved in tumor progression and metastasis. MicroRNAs (miRNAs) regulate both normal stem cells and CSCs, and dysregulation of miRNAs has been implicated in tumorigenesis. CSCs in many tumors--including cancers of the breast, pancreas, head and neck, colon, small intestine, liver, stomach, bladder and ovary--have been identified using the adhesion molecule CD44, either individually or in combination with other marker(s). Prostate CSCs with enhanced clonogenic and tumor-initiating and metastatic capacities are enriched in the CD44(+) cell population, but whether miRNAs regulate CD44(+) prostate cancer cells and prostate cancer metastasis remains unclear. Here we show, through expression analysis, that miR-34a, a p53 target, was underexpressed in CD44(+) prostate cancer cells purified from xenograft and primary tumors. Enforced expression of miR-34a in bulk or purified CD44(+) prostate cancer cells inhibited clonogenic expansion, tumor regeneration, and metastasis. In contrast, expression of miR-34a antagomirs in CD44(-) prostate cancer cells promoted tumor development and metastasis. Systemically delivered miR-34a inhibited prostate cancer metastasis and extended survival of tumor-bearing mice. We identified and validated CD44 as a direct and functional target of miR-34a and found that CD44 knockdown phenocopied miR-34a overexpression in inhibiting prostate cancer regeneration and metastasis. Our study shows that miR-34a is a key negative regulator of CD44(+) prostate cancer cells and establishes a strong rationale for developing miR-34a as a novel therapeutic agent against prostate CSCs.", + "TAG_DATA": [ + "112, CD44(+) {'context': 'B-transformed cells'}", + "122, Enforced {'perturbing_action': 'B-gene gain-of-function'}", + "123, expression {'perturbing_action': 'I-gene gain-of-function'}", + "124, of {'perturbing_action': 'I-gene gain-of-function'}", + "125, miR-34a {'perturbing_action': 'I-gene gain-of-function'}", + "130, CD44(+) {'context': 'B-transformed cells'}", + "131, prostate {'context': 'I-transformed cells'}", + "132, cancer {'context': 'I-transformed cells'}", + "133, cells {'context': 'I-transformed cells'}", + "134, inhibited {'effect': 'B-negative'}", + "135, clonogenic {'phenotype': 'B-colony formation'}", + "136, expansion, {'phenotype': 'I-colony formation'}", + "137, tumor {'phenotype': 'B-tumour progression'}", + "138, regeneration, {'phenotype': 'I-tumour progression'}", + "140, metastasis. {'phenotype': 'B-metastasis'}", + "143, expression {'perturbing_action': 'B-rnai/knockdown'}", + "144, of {'perturbing_action': 'I-rnai/knockdown'}", + "145, miR-34a {'perturbing_action': 'I-rnai/knockdown'}", + "146, antagomirs {'perturbing_action': 'I-rnai/knockdown'}", + "148, CD44(-) {'context': 'B-transformed cells'}", + "149, prostate {'context': 'I-transformed cells'}", + "150, cancer {'context': 'I-transformed cells'}", + "151, cells {'context': 'I-transformed cells'}", + "152, promoted {'effect': 'B-positive'}", + "153, tumor {'phenotype': 'B-tumourigenesis'}", + "154, development {'phenotype': 'I-tumourigenesis'}", + "156, metastasis. {'phenotype': 'B-metastasis'}", + "157, Systemically {'perturbing_action': 'B-gene gain-of-function'}", + "158, delivered {'perturbing_action': 'I-gene gain-of-function'}", + "159, miR-34a {'perturbing_action': 'I-gene gain-of-function'}", + "160, inhibited {'effect': 'B-negative'}", + "161, prostate {'context': 'B-neoplasm'}", + "162, cancer {'context': 'I-neoplasm'}", + "163, metastasis {'phenotype': 'B-metastasis'}", + "168, tumor-bearing {'context': 'B-organism'}", + "169, mice. {'context': 'I-organism'}", + "186, CD44 {'perturbing_action': 'B-rnai/knockdown'}", + "187, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "189, miR-34a {'perturbing_action': 'B-gene gain-of-function'}", + "190, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "192, inhibiting {'effect': 'B-negative'}", + "193, prostate {'context': 'B-neoplasm'}", + "194, cancer {'context': 'I-neoplasm'}", + "197, metastasis. {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "112, CD44(+) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "113, prostate ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "114, cancer ['l1', 'l15', 'l26', 'l27', 'l28', 'l29']", + "122, Enforced ['l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "123, expression ['l2', 'l30', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "124, of ['l3', 'l16', 'l31', 'l48', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "125, miR-34a ['l4', 'l17', 'l32', 'l49', 'l63', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "130, CD44(+) ['l5', 'l18', 'l33', 'l50', 'l64', 'l77', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "131, prostate ['l6', 'l19', 'l26', 'l34', 'l51', 'l65', 'l78', 'l89', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "132, cancer ['l7', 'l20', 'l27', 'l35', 'l52', 'l66', 'l79', 'l90', 'l100', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "133, cells ['l8', 'l21', 'l28', 'l36', 'l53', 'l67', 'l80', 'l91', 'l101', 'l108', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "134, inhibited ['l9', 'l22', 'l37', 'l54', 'l68', 'l81', 'l92', 'l102', 'l109', 'l115', 'l121', 'l122', 'l123', 'l124', 'l125']", + "135, clonogenic ['l10', 'l23', 'l38', 'l55', 'l69', 'l82', 'l93', 'l103', 'l110', 'l116', 'l121', 'l126', 'l127', 'l128', 'l129']", + "136, expansion, ['l11', 'l24', 'l29', 'l39', 'l56', 'l70', 'l83', 'l94', 'l104', 'l111', 'l117', 'l122', 'l126', 'l130', 'l131', 'l132']", + "137, tumor ['l12', 'l40', 'l57', 'l71', 'l84', 'l95', 'l105', 'l112', 'l118', 'l123', 'l127', 'l130', 'l133', 'l134']", + "138, regeneration, ['l13', 'l25', 'l41', 'l58', 'l72', 'l85', 'l96', 'l106', 'l113', 'l119', 'l124', 'l128', 'l131', 'l133', 'l135']", + "140, metastasis. ['l14', 'l42', 'l59', 'l73', 'l86', 'l97', 'l107', 'l114', 'l120', 'l125', 'l129', 'l132', 'l134', 'l135']", + "143, expression ['l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146']", + "144, of ['l136', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "145, miR-34a ['l137', 'l147', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166']", + "146, antagomirs ['l138', 'l148', 'l158', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175']", + "148, CD44(-) ['l139', 'l149', 'l159', 'l167', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "149, prostate ['l140', 'l150', 'l160', 'l168', 'l176', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "150, cancer ['l43', 'l60', 'l74', 'l141', 'l151', 'l161', 'l169', 'l177', 'l183', 'l189', 'l190', 'l191', 'l192', 'l193']", + "151, cells ['l44', 'l61', 'l75', 'l87', 'l98', 'l142', 'l152', 'l162', 'l170', 'l178', 'l184', 'l189', 'l194', 'l195', 'l196', 'l197']", + "152, promoted ['l45', 'l143', 'l153', 'l163', 'l171', 'l179', 'l185', 'l190', 'l194', 'l198', 'l199', 'l200']", + "153, tumor ['l46', 'l144', 'l154', 'l164', 'l172', 'l180', 'l186', 'l191', 'l195', 'l198', 'l201', 'l202']", + "154, development ['l47', 'l62', 'l76', 'l88', 'l99', 'l145', 'l155', 'l165', 'l173', 'l181', 'l187', 'l192', 'l196', 'l199', 'l201', 'l203']", + "156, metastasis. ['l146', 'l156', 'l166', 'l174', 'l182', 'l188', 'l193', 'l197', 'l200', 'l202', 'l203']", + "157, Systemically ['l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219']", + "158, delivered ['l204', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234']", + "159, miR-34a ['l205', 'l220', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248']", + "160, inhibited ['l206', 'l221', 'l235', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257']", + "161, prostate ['l207', 'l222', 'l236', 'l249', 'l258', 'l259', 'l260', 'l261', 'l262']", + "162, cancer ['l157', 'l175', 'l208', 'l223', 'l237', 'l250', 'l258', 'l263', 'l264', 'l265']", + "163, metastasis ['l209', 'l224', 'l238', 'l251', 'l259', 'l263', 'l266', 'l267']", + "168, tumor-bearing ['l210', 'l225', 'l239', 'l252', 'l260', 'l264', 'l266', 'l268', 'l269', 'l270', 'l271', 'l272']", + "169, mice. ['l211', 'l226', 'l240', 'l253', 'l261', 'l265', 'l267', 'l268', 'l273', 'l274', 'l275', 'l276']", + "186, CD44 ['l212', 'l227', 'l241', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283']", + "187, knockdown ['l213', 'l228', 'l242', 'l277', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289']", + "189, miR-34a ['l214', 'l229', 'l243', 'l278', 'l284', 'l290', 'l291', 'l292', 'l293', 'l294']", + "190, overexpression ['l215', 'l230', 'l244', 'l279', 'l285', 'l290', 'l295', 'l296', 'l297', 'l298']", + "192, inhibiting ['l216', 'l231', 'l245', 'l254', 'l269', 'l273', 'l280', 'l286', 'l291', 'l295', 'l299', 'l300', 'l301']", + "193, prostate ['l217', 'l232', 'l246', 'l255', 'l270', 'l274', 'l281', 'l287', 'l292', 'l296', 'l299', 'l302', 'l303']", + "194, cancer ['l218', 'l233', 'l247', 'l256', 'l262', 'l271', 'l275', 'l282', 'l288', 'l293', 'l297', 'l300', 'l302', 'l304']", + "197, metastasis. ['l219', 'l234', 'l248', 'l257', 'l272', 'l276', 'l283', 'l289', 'l294', 'l298', 'l301', 'l303', 'l304']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "CD44(+)", + "prostate", + "cancer", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "miR-34a", + "Enforced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CD44(+)", + "prostate", + "cancer", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CD44(+)", + "prostate", + "cancer", + "cells" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenic", + "expansion," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CD44(+)", + "prostate", + "cancer", + "cells" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "regeneration," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CD44(+)", + "prostate", + "cancer", + "cells", + "CD44(-)" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced", + "expression", + "of", + "miR-34a", + "Systemically", + "delivered", + "overexpression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "inhibiting" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced", + "expression", + "of", + "miR-34a" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenic", + "expansion," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced", + "expression", + "of", + "miR-34a" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "regeneration," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced", + "expression", + "of", + "miR-34a", + "Systemically", + "delivered", + "overexpression" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis.", + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced", + "expression", + "of", + "miR-34a" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CD44(+)", + "CD44(-)", + "prostate", + "cancer", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "development", + "tumor" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenic", + "expansion," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor", + "regeneration," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "inhibiting" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis.", + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "miR-34a", + "antagomirs" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "CD44(-)", + "prostate", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "miR-34a", + "antagomirs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "miR-34a", + "antagomirs" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "miR-34a", + "antagomirs", + "CD44", + "knockdown" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "antagomirs", + "CD44", + "knockdown" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "cancer", + "prostate" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "CD44(-)", + "prostate", + "cancer", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Systemically", + "delivered", + "miR-34a", + "overexpression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "prostate", + "cancer" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Systemically", + "delivered", + "miR-34a" + ] + }, + "context": { + "val": "organism", + "words": [ + "tumor-bearing", + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "inhibiting" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "prostate", + "cancer" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "inhibiting" + ] + }, + "context": { + "val": "organism", + "words": [ + "tumor-bearing", + "mice." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "prostate", + "cancer" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "metastasis." + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "metastasis." + ] + }, + "context": { + "val": "organism", + "words": [ + "tumor-bearing", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "CD44", + "knockdown" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibiting" + ] + } + } + ] + }, + { + "PMID": "21217695", + "TEXT": "The emergence of chronic inflammation during obesity in the absence of overt infection or well-defined autoimmune processes is a puzzling phenomenon. The Nod-like receptor (NLR) family of innate immune cell sensors, such as the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (Nlrp3, but also known as Nalp3 or cryopyrin) inflammasome are implicated in recognizing certain nonmicrobial originated 'danger signals' leading to caspase-1 activation and subsequent interleukin-1β (IL-1β) and IL-18 secretion. We show that calorie restriction and exercise-mediated weight loss in obese individuals with type 2 diabetes is associated with a reduction in adipose tissue expression of Nlrp3 as well as with decreased inflammation and improved insulin sensitivity. We further found that the Nlrp3 inflammasome senses lipotoxicity-associated increases in intracellular ceramide to induce caspase-1 cleavage in macrophages and adipose tissue. Ablation of Nlrp3 in mice prevents obesity-induced inflammasome activation in fat depots and liver as well as enhances insulin signaling. Furthermore, elimination of Nlrp3 in obese mice reduces IL-18 and adipose tissue interferon-γ (IFN-γ) expression, increases naive T cell numbers and reduces effector T cell numbers in adipose tissue. Collectively, these data establish that the Nlrp3 inflammasome senses obesity-associated danger signals and contributes to obesity-induced inflammation and insulin resistance.", + "TAG_DATA": [ + "128, Ablation {'perturbing_action': 'B-gene loss-of-function'}", + "129, of {'perturbing_action': 'I-gene loss-of-function'}", + "130, Nlrp3 {'perturbing_action': 'I-gene loss-of-function'}", + "132, mice {'context': 'B-organism'}", + "141, liver {'context': 'B-tissue/organ'}", + "149, elimination {'perturbing_action': 'B-gene loss-of-function'}", + "150, of {'perturbing_action': 'I-gene loss-of-function'}", + "151, Nlrp3 {'perturbing_action': 'I-gene loss-of-function'}", + "153, obese {'context': 'B-organism'}", + "154, mice {'context': 'I-organism'}", + "164, naive {'context': 'B-cells'}", + "165, T {'context': 'I-cells'}", + "166, cell {'context': 'I-cells'}", + "170, effector {'context': 'B-cells'}", + "171, T {'context': 'I-cells'}", + "172, cell {'context': 'I-cells'}", + "175, adipose {'context': 'B-tissue/organ'}", + "176, tissue. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "128, Ablation ['l0', 'l1', 'l2', 'l3']", + "129, of ['l0', 'l4', 'l5', 'l6']", + "130, Nlrp3 ['l1', 'l4', 'l7', 'l8']", + "132, mice ['l2', 'l5', 'l7', 'l9']", + "141, liver ['l3', 'l6', 'l8', 'l9']", + "149, elimination ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "150, of ['l10', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "151, Nlrp3 ['l11', 'l22', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "153, obese ['l12', 'l23', 'l33', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "154, mice ['l13', 'l24', 'l34', 'l43', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "164, naive ['l14', 'l25', 'l35', 'l44', 'l52', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "165, T ['l15', 'l26', 'l36', 'l45', 'l53', 'l60', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "166, cell ['l16', 'l27', 'l37', 'l46', 'l54', 'l61', 'l67', 'l73', 'l74', 'l75', 'l76']", + "170, effector ['l17', 'l28', 'l38', 'l47', 'l55', 'l62', 'l68', 'l77', 'l78', 'l79', 'l80']", + "171, T ['l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l69', 'l73', 'l77', 'l81', 'l82', 'l83']", + "172, cell ['l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l74', 'l78', 'l81', 'l84', 'l85']", + "175, adipose ['l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l75', 'l79', 'l82', 'l84', 'l86']", + "176, tissue. ['l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l76', 'l80', 'l83', 'l85', 'l86']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "Nlrp3", + "elimination" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "obese" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "Nlrp3", + "elimination" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver", + "adipose", + "tissue." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "elimination", + "of", + "Nlrp3" + ] + }, + "context": { + "val": "cells", + "words": [ + "naive", + "T", + "cell", + "effector" + ] + } + } + ] + }, + { + "PMID": "21186369", + "TEXT": "The adipocyte-derived secretory factor adiponectin promotes insulin sensitivity, decreases inflammation and promotes cell survival. No unifying mechanism has yet explained how adiponectin can exert such a variety of beneficial systemic effects. Here, we show that adiponectin potently stimulates a ceramidase activity associated with its two receptors, AdipoR1 and AdipoR2, and enhances ceramide catabolism and formation of its antiapoptotic metabolite--sphingosine-1-phosphate (S1P)--independently of AMP-dependent kinase (AMPK). Using models of inducible apoptosis in pancreatic beta cells and cardiomyocytes, we show that transgenic overproduction of adiponectin decreases caspase-8-mediated death, whereas genetic ablation of adiponectin enhances apoptosis in vivo through a sphingolipid-mediated pathway. Ceramidase activity is impaired in cells lacking both adiponectin receptor isoforms, leading to elevated ceramide levels and enhanced susceptibility to palmitate-induced cell death. Combined, our observations suggest a unifying mechanism of action for the beneficial systemic effects exerted by adiponectin, with sphingolipid metabolism as its core upstream signaling component.", + "TAG_DATA": [ + "67, inducible {'effect': 'B-positive'}", + "68, apoptosis {'phenotype': 'B-apoptosis'}", + "70, pancreatic {'context': 'B-cells'}", + "71, beta {'context': 'I-cells'}", + "72, cells {'context': 'I-cells'}", + "74, cardiomyocytes, {'context': 'B-cells'}", + "78, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "79, overproduction {'perturbing_action': 'I-gene gain-of-function'}", + "80, of {'perturbing_action': 'I-gene gain-of-function'}", + "81, adiponectin {'perturbing_action': 'I-gene gain-of-function'}", + "86, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "87, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "88, of {'perturbing_action': 'I-gene loss-of-function'}", + "89, adiponectin {'perturbing_action': 'I-gene loss-of-function'}", + "90, enhances {'effect': 'B-positive'}", + "91, apoptosis {'phenotype': 'B-apoptosis'}", + "92, in {'context': 'B-in vivo'}", + "93, vivo {'context': 'I-in vivo'}", + "103, cells {'context': 'B-cells'}", + "104, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "105, both {'perturbing_action': 'I-gene loss-of-function'}", + "106, adiponectin {'perturbing_action': 'I-gene loss-of-function'}", + "107, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "108, isoforms, {'perturbing_action': 'I-gene loss-of-function'}", + "115, enhanced {'effect': 'B-positive'}", + "116, susceptibility {'effect': 'I-positive'}", + "118, palmitate-induced {'effect': 'B-positive'}", + "119, cell {'phenotype': 'B-cell death'}", + "120, death. {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "67, inducible ['l0', 'l1', 'l2', 'l3', 'l4']", + "68, apoptosis ['l0', 'l5', 'l6', 'l7', 'l8']", + "70, pancreatic ['l1', 'l5', 'l9', 'l10', 'l11']", + "71, beta ['l2', 'l6', 'l9', 'l12', 'l13']", + "72, cells ['l3', 'l7', 'l10', 'l12', 'l14']", + "74, cardiomyocytes, ['l4', 'l8', 'l11', 'l13', 'l14', 'l15', 'l16']", + "78, transgenic ['l17', 'l18', 'l19']", + "79, overproduction ['l17', 'l20', 'l21']", + "80, of ['l15', 'l18', 'l20', 'l22']", + "81, adiponectin ['l16', 'l19', 'l21', 'l22']", + "86, genetic ['l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "87, ablation ['l23', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "88, of ['l24', 'l39', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "89, adiponectin ['l25', 'l40', 'l55', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "90, enhances ['l26', 'l41', 'l56', 'l70', 'l79', 'l80', 'l81']", + "91, apoptosis ['l27', 'l42', 'l57', 'l71', 'l79', 'l82', 'l83']", + "92, in ['l28', 'l43', 'l58', 'l72', 'l80', 'l82', 'l84']", + "93, vivo ['l29', 'l44', 'l59', 'l73', 'l81', 'l83', 'l84']", + "103, cells ['l30', 'l45', 'l60', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "104, lacking ['l85', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "105, both ['l46', 'l61', 'l86', 'l95', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "106, adiponectin ['l31', 'l47', 'l62', 'l87', 'l96', 'l104', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "107, receptor ['l32', 'l48', 'l63', 'l88', 'l97', 'l105', 'l112', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "108, isoforms, ['l33', 'l49', 'l64', 'l89', 'l98', 'l106', 'l113', 'l119', 'l125', 'l126', 'l127', 'l128', 'l129']", + "115, enhanced ['l34', 'l50', 'l65', 'l74', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l130', 'l131', 'l132', 'l133']", + "116, susceptibility ['l35', 'l51', 'l66', 'l75', 'l91', 'l100', 'l108', 'l115', 'l121', 'l126', 'l130', 'l134', 'l135', 'l136']", + "118, palmitate-induced ['l36', 'l52', 'l67', 'l76', 'l92', 'l101', 'l109', 'l116', 'l122', 'l127', 'l131', 'l134', 'l137', 'l138']", + "119, cell ['l37', 'l53', 'l68', 'l77', 'l93', 'l102', 'l110', 'l117', 'l123', 'l128', 'l132', 'l135', 'l137', 'l139']", + "120, death. ['l38', 'l54', 'l69', 'l78', 'l94', 'l103', 'l111', 'l118', 'l124', 'l129', 'l133', 'l136', 'l138', 'l139']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "inducible", + "enhances" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducible", + "enhanced", + "susceptibility", + "palmitate-induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "pancreatic", + "beta", + "cells", + "cardiomyocytes," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "pancreatic", + "beta", + "cells", + "cardiomyocytes," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cardiomyocytes," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "adiponectin" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "adiponectin", + "lacking", + "both", + "receptor", + "isoforms," + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances", + "enhanced", + "susceptibility", + "palmitate-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "adiponectin" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "adiponectin" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "lacking", + "both", + "adiponectin", + "receptor", + "isoforms," + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "adiponectin", + "lacking", + "both", + "receptor", + "isoforms," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced", + "susceptibility", + "palmitate-induced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "21170048", + "TEXT": "It remains difficult to distinguish tumor recurrence from radiation necrosis after brain tumor therapy. Here we show that these lesions can be distinguished using the amide proton transfer (APT) magnetic resonance imaging (MRI) signals of endogenous cellular proteins and peptides as an imaging biomarker. When comparing two models of orthotopic glioma (SF188/V+ glioma and 9L gliosarcoma) with a model of radiation necrosis in rats, we could clearly differentiate viable glioma (hyperintense) from radiation necrosis (hypointense to isointense) by APT MRI. When we irradiated rats with U87MG gliomas, the APT signals in the irradiated tumors had decreased substantially by 3 d and 6 d after radiation. The amide protons that can be detected by APT provide a unique and noninvasive MRI biomarker for distinguishing viable malignancy from radiation necrosis and predicting tumor response to therapy.", + "TAG_DATA": [ + "61, necrosis {'phenotype': 'B-necrosis'}", + "63, rats, {'context': 'B-organism'}", + "83, rats {'context': 'B-organism'}", + "85, U87MG {'context': 'B-neoplasm'}", + "86, gliomas, {'context': 'I-neoplasm'}", + "93, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "50, glioma ['l0', 'l1']", + "61, necrosis ['l0', 'l2']", + "63, rats, ['l1', 'l2']", + "83, rats ['l3', 'l4', 'l5']", + "85, U87MG ['l3', 'l6', 'l7']", + "86, gliomas, ['l4', 'l6', 'l8']", + "93, tumors ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats," + ] + } + } + ] + }, + { + "PMID": "21170046", + "TEXT": "Hypoxia can act as an initial trigger to induce erythrocyte sickling and eventual end organ damage in sickle cell disease (SCD). Many factors and metabolites are altered in response to hypoxia and may contribute to the pathogenesis of the disease. Using metabolomic profiling, we found that the steady-state concentration of adenosine in the blood was elevated in a transgenic mouse model of SCD. Adenosine concentrations were similarly elevated in the blood of humans with SCD. Increased adenosine levels promoted sickling, hemolysis and damage to multiple tissues in SCD transgenic mice and promoted sickling of human erythrocytes. Using biochemical, genetic and pharmacological approaches, we showed that adenosine A(2B) receptor (A(2B)R)-mediated induction of 2,3-diphosphoglycerate, an erythrocyte-specific metabolite that decreases the oxygen binding affinity of hemoglobin, underlies the induction of erythrocyte sickling by excess adenosine both in cultured human red blood cells and in SCD transgenic mice. Thus, excessive adenosine signaling through the A(2B)R has a pathological role in SCD. These findings may provide new therapeutic possibilities for this disease.", + "TAG_DATA": [ + "87, SCD {'perturbing_action': 'B-gene gain-of-function'}", + "88, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "89, mice {'context': 'I-organism'}", + "94, human {'context': 'B-cells'}", + "95, erythrocytes. {'context': 'I-cells'}", + "135, human {'context': 'I-cells'}", + "136, red {'context': 'I-cells'}", + "137, blood {'context': 'I-cells'}", + "138, cells {'context': 'I-cells'}", + "141, SCD {'perturbing_action': 'B-gene gain-of-function'}", + "142, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "143, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "87, SCD ['l0', 'l1']", + "88, transgenic ['l0', 'l2']", + "89, mice ['l1', 'l2']", + "94, human ['l3']", + "95, erythrocytes. ['l3']", + "135, human ['l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "136, red ['l4', 'l10', 'l11', 'l12', 'l13', 'l14']", + "137, blood ['l5', 'l10', 'l15', 'l16', 'l17', 'l18']", + "138, cells ['l6', 'l11', 'l15']", + "141, SCD ['l7', 'l12', 'l16', 'l19', 'l20']", + "142, transgenic ['l8', 'l13', 'l17', 'l19', 'l21']", + "143, mice. ['l9', 'l14', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "SCD", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "red", + "blood" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "SCD", + "transgenic" + ] + } + } + ] + }, + { + "PMID": "21113155", + "TEXT": "Localized abdominal surgery can lead to disruption of motility in the entire gastrointestinal tract (postoperative ileus). Intestinal macrophages produce mediators that paralyze myocytes, but it is unclear how the macrophages are activated, especially those in unmanipulated intestinal areas. Here we show that intestinal surgery activates intestinal CD103(+)CD11b(+) dendritic cells (DCs) to produce interleukin-12 (IL-12). This promotes interferon-γ (IFN-γ) secretion by CCR9(+) memory T helper type 1 (T(H)1) cells which activates the macrophages. IL-12 also caused some T(H)1 cells to migrate from surgically manipulated sites through the bloodstream to unmanipulated intestinal areas where they induced ileus. Preventing T cell migration with the drug FTY720 or inhibition of IL-12, T-bet (T(H)1-specific T box transcription factor) or IFN-γ prevented postoperative ileus. CCR9(+) T(H)1 memory cells were detected in the venous blood of subjects 1 h after abdominal surgery. These findings indicate that postoperative ileus is a T(H)1 immune-mediated disease and identify potential targets for disease monitoring and therapy.", + "TAG_DATA": [ + "71, macrophages. {'context': 'B-cells'}", + "76, T(H)1 {'context': 'B-cells'}", + "77, cells {'context': 'I-cells'}", + "96, T {'context': 'B-cells'}", + "97, cell {'context': 'I-cells'}", + "98, migration {'phenotype': 'B-migration'}", + "104, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "105, of {'perturbing_action': 'I-pharmacological inhibition'}", + "106, IL-12, {'perturbing_action': 'I-pharmacological inhibition'}", + "107, T-bet {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "71, macrophages. ['l0', 'l1']", + "76, T(H)1 ['l0', 'l2']", + "77, cells ['l1', 'l2']", + "96, T ['l3', 'l4']", + "97, cell ['l3', 'l5']", + "98, migration ['l4', 'l5']", + "104, inhibition ['l6', 'l7', 'l8']", + "105, of ['l6', 'l9', 'l10']", + "106, IL-12, ['l7', 'l9', 'l11']", + "107, T-bet ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + } + ] + }, + { + "PMID": "21102460", + "TEXT": "Mesenchymal stem cells can give rise to several cell types, but varying results depending on isolation methods and tissue source have led to controversies about their usefulness in clinical medicine. Here we show that vascular endothelial cells can transform into multipotent stem-like cells by an activin-like kinase-2 (ALK2) receptor-dependent mechanism. In lesions from individuals with fibrodysplasia ossificans progressiva (FOP), a disease in which heterotopic ossification occurs as a result of activating ALK2 mutations, or from transgenic mice expressing constitutively active ALK2, chondrocytes and osteoblasts expressed endothelial markers. Lineage tracing of heterotopic ossification in mice using a Tie2-Cre construct also suggested an endothelial origin of these cell types. Expression of constitutively active ALK2 in endothelial cells caused endothelial-to-mesenchymal transition and acquisition of a stem cell-like phenotype. Similar results were obtained by treatment of untransfected endothelial cells with the ligands transforming growth factor-β2 (TGF-β2) or bone morphogenetic protein-4 (BMP4) in an ALK2-dependent manner. These stem-like cells could be triggered to differentiate into osteoblasts, chondrocytes or adipocytes. We suggest that conversion of endothelial cells to stem-like cells may provide a new approach to tissue engineering.", + "TAG_DATA": [ + "75, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "76, mice {'context': 'I-organism'}", + "77, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "78, constitutively {'perturbing_action': 'I-gene gain-of-function'}", + "79, active {'perturbing_action': 'I-gene gain-of-function'}", + "80, ALK2, {'perturbing_action': 'I-gene gain-of-function'}", + "93, mice {'context': 'B-organism'}", + "107, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "108, of {'perturbing_action': 'I-gene gain-of-function'}", + "109, constitutively {'perturbing_action': 'I-gene gain-of-function'}", + "110, active {'perturbing_action': 'I-gene gain-of-function'}", + "111, ALK2 {'perturbing_action': 'I-gene gain-of-function'}", + "113, endothelial {'context': 'B-cells'}", + "114, cells {'context': 'I-cells'}", + "115, caused {'effect': 'B-positive'}", + "116, endothelial-to-mesenchymal {'phenotype': 'B-epithelial-mesenchymal transition'}", + "117, transition {'phenotype': 'I-epithelial-mesenchymal transition'}", + "133, endothelial {'context': 'B-cells'}", + "134, cells {'context': 'I-cells'}", + "152, stem-like {'context': 'B-cells'}", + "153, cells {'context': 'I-cells'}", + "156, triggered {'effect': 'B-positive'}", + "158, differentiate {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "75, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "76, mice ['l0', 'l6', 'l7', 'l8', 'l9']", + "77, expressing ['l1', 'l6', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "78, constitutively ['l2', 'l7', 'l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "79, active ['l3', 'l8', 'l11', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29']", + "80, ALK2, ['l4', 'l9', 'l12', 'l18', 'l25', 'l30', 'l31']", + "93, mice ['l5', 'l13', 'l19', 'l26', 'l30', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "96, Tie2-Cre ['l14', 'l20', 'l27', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "107, Expression ['l38', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "108, of ['l39', 'l48', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "109, constitutively ['l40', 'l49', 'l59', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "110, active ['l41', 'l50', 'l60', 'l69', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "111, ALK2 ['l42', 'l51', 'l61', 'l70', 'l78', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "113, endothelial ['l33', 'l43', 'l52', 'l62', 'l71', 'l79', 'l85', 'l91', 'l92', 'l93', 'l94']", + "114, cells ['l21', 'l34', 'l44', 'l53', 'l63', 'l72', 'l80', 'l86', 'l91', 'l95', 'l96', 'l97']", + "115, caused ['l15', 'l22', 'l28', 'l35', 'l45', 'l54', 'l64', 'l73', 'l81', 'l87', 'l92', 'l95', 'l98', 'l99']", + "116, endothelial-to-mesenchymal ['l23', 'l36', 'l46', 'l55', 'l65', 'l74', 'l82', 'l88', 'l93', 'l96', 'l98', 'l100']", + "117, transition ['l16', 'l24', 'l29', 'l31', 'l37', 'l47', 'l56', 'l66', 'l75', 'l83', 'l89', 'l94', 'l97', 'l99', 'l100']", + "133, endothelial ['l57', 'l67', 'l76', 'l101', 'l102']", + "134, cells ['l58', 'l68', 'l77', 'l84', 'l90', 'l101']", + "152, stem-like ['l103', 'l104', 'l105']", + "153, cells ['l102', 'l103', 'l106', 'l107']", + "156, triggered ['l104', 'l106', 'l108']", + "158, differentiate ['l105', 'l107', 'l108']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "constitutively", + "active", + "ALK2," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "constitutively", + "active", + "Expression", + "of", + "ALK2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "constitutively", + "active", + "ALK2,", + "Expression", + "of", + "ALK2" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "transition", + "endothelial-to-mesenchymal" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutively", + "Expression", + "of", + "active", + "ALK2" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "endothelial" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "endothelial-to-mesenchymal", + "transition" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells", + "stem-like" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused", + "triggered" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "endothelial-to-mesenchymal", + "transition" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "endothelial-to-mesenchymal", + "transition" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "stem-like", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggered" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate" + ] + } + } + ] + }, + { + "PMID": "20953200", + "TEXT": "The lifetime prevalence (∼16%) and the economic burden ($100 billion annually) associated with major depressive disorder (MDD) make it one of the most common and debilitating neurobiological illnesses. To date, the exact cellular and molecular mechanisms underlying the pathophysiology of MDD have not been identified. Here we use whole-genome expression profiling of postmortem tissue and show significantly increased expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1, encoded by DUSP1, but hereafter called MKP-1) in the hippocampal subfields of subjects with MDD compared to matched controls. MKP-1, also known as dual-specificity phosphatase-1 (DUSP1), is a member of a family of proteins that dephosphorylate both threonine and tyrosine residues and thereby serves as a key negative regulator of the MAPK cascade, a major signaling pathway involved in neuronal plasticity, function and survival. We tested the role of altered MKP-1 expression in rat and mouse models of depression and found that increased hippocampal MKP-1 expression, as a result of stress or viral-mediated gene transfer, causes depressive behaviors. Conversely, chronic antidepressant treatment normalizes stress-induced MKP-1 expression and behavior, and mice lacking MKP-1 are resilient to stress. These postmortem and preclinical studies identify MKP-1 as a key factor in MDD pathophysiology and as a new target for therapeutic interventions.", + "TAG_DATA": [ + "175, mice {'context': 'B-organism'}", + "176, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "177, MKP-1 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "175, mice ['l0', 'l1']", + "176, lacking ['l0', 'l2']", + "177, MKP-1 ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "MKP-1" + ] + } + } + ] + }, + { + "PMID": "20871609", + "TEXT": "Inactivation of the p53 tumor suppressor pathway allows cell survival in times of stress and occurs in many human cancers; however, normal embryonic stem cells and some cancers such as neuroblastoma maintain wild-type human TP53 and mouse Trp53 (referred to collectively as p53 herein). Here we describe a miRNA, miR-380-5p, that represses p53 expression via a conserved sequence in the p53 3' untranslated region (UTR). miR-380-5p is highly expressed in mouse embryonic stem cells and neuroblastomas, and high expression correlates with poor outcome in neuroblastomas with neuroblastoma derived v-myc myelocytomatosis viral-related oncogene (MYCN) amplification. miR-380 overexpression cooperates with activated HRAS oncoprotein to transform primary cells, block oncogene-induced senescence and form tumors in mice. Conversely, inhibition of endogenous miR-380-5p in embryonic stem or neuroblastoma cells results in induction of p53, and extensive apoptotic cell death. In vivo delivery of a miR-380-5p antagonist decreases tumor size in an orthotopic mouse model of neuroblastoma. We demonstrate a new mechanism of p53 regulation in cancer and stem cells and uncover a potential therapeutic target for neuroblastoma.", + "TAG_DATA": [ + "94, miR-380 {'perturbing_action': 'B-gene gain-of-function'}", + "95, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "103, primary {'context': 'B-cells'}", + "104, cells, {'context': 'I-cells'}", + "105, block {'effect': 'B-negative'}", + "106, oncogene-induced {'effect': 'B-positive'}", + "107, senescence {'phenotype': 'B-senescence'}", + "109, form {'phenotype': 'B-tumourigenesis'}", + "110, tumors {'phenotype': 'B-tumourigenesis'}", + "112, mice. {'context': 'B-organism'}", + "114, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "115, of {'perturbing_action': 'I-pharmacological inhibition'}", + "116, endogenous {'perturbing_action': 'I-pharmacological inhibition'}", + "117, miR-380-5p {'perturbing_action': 'I-pharmacological inhibition'}", + "119, embryonic {'context': 'B-transformed cells'}", + "120, stem {'context': 'I-transformed cells'}", + "121, or {'context': 'I-transformed cells'}", + "122, neuroblastoma {'context': 'I-transformed cells'}", + "123, cells {'context': 'I-transformed cells'}", + "131, apoptotic {'phenotype': 'B-apoptosis'}", + "132, cell {'phenotype': 'I-apoptosis'}", + "133, death. {'phenotype': 'I-apoptosis'}", + "134, In {'context': 'B-in vivo'}", + "135, vivo {'context': 'I-in vivo'}", + "141, decreases {'effect': 'B-negative'}", + "142, tumor {'phenotype': 'B-tumourigenesis'}", + "143, size {'phenotype': 'I-tumourigenesis'}", + "146, orthotopic {'context': 'B-neoplasm'}", + "147, mouse {'context': 'I-neoplasm'}", + "148, model {'context': 'I-neoplasm'}", + "149, of {'context': 'I-neoplasm'}", + "150, neuroblastoma. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "94, miR-380 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "95, overexpression ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "103, primary ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "104, cells, ['l2', 'l12', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32']", + "105, block ['l3', 'l13', 'l22', 'l28', 'l33', 'l34', 'l35', 'l36', 'l37']", + "106, oncogene-induced ['l4', 'l14', 'l23', 'l33', 'l38', 'l39', 'l40', 'l41', 'l42']", + "107, senescence ['l5', 'l15', 'l24', 'l29', 'l34', 'l38', 'l43', 'l44', 'l45']", + "109, form ['l6', 'l16', 'l25', 'l30', 'l35', 'l39', 'l43', 'l46', 'l47']", + "110, tumors ['l7', 'l17', 'l26', 'l31', 'l36', 'l40', 'l44', 'l46', 'l48']", + "112, mice. ['l8', 'l18', 'l27', 'l32', 'l37', 'l41', 'l45', 'l47', 'l48']", + "114, inhibition ['l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "115, of ['l49', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "116, endogenous ['l50', 'l61', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "117, miR-380-5p ['l51', 'l62', 'l74', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "119, embryonic ['l52', 'l63', 'l75', 'l83', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "120, stem ['l9', 'l19', 'l53', 'l64', 'l76', 'l84', 'l91', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "121, or ['l54', 'l65', 'l77', 'l85', 'l92', 'l98', 'l104', 'l105', 'l106', 'l107', 'l108']", + "122, neuroblastoma ['l55', 'l66', 'l78', 'l86', 'l93', 'l99', 'l104', 'l109', 'l110', 'l111', 'l112']", + "123, cells ['l10', 'l20', 'l42', 'l56', 'l67', 'l79', 'l87', 'l94', 'l100', 'l105', 'l109', 'l113', 'l114', 'l115']", + "131, apoptotic ['l57', 'l68', 'l80', 'l88', 'l95', 'l101', 'l106', 'l110', 'l113', 'l116', 'l117']", + "132, cell ['l58', 'l69', 'l81', 'l89', 'l96', 'l102', 'l107', 'l111', 'l114', 'l116', 'l118']", + "133, death. ['l59', 'l70', 'l82', 'l90', 'l97', 'l103', 'l108', 'l112', 'l115', 'l117', 'l118']", + "134, In ['l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127']", + "135, vivo ['l119', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "141, decreases ['l120', 'l128', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "142, tumor ['l121', 'l129', 'l136', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "143, size ['l60', 'l71', 'l122', 'l130', 'l137', 'l143', 'l149', 'l150', 'l151', 'l152', 'l153']", + "146, orthotopic ['l123', 'l131', 'l138', 'l144', 'l149', 'l154', 'l155', 'l156', 'l157']", + "147, mouse ['l124', 'l132', 'l139', 'l145', 'l150', 'l154', 'l158', 'l159', 'l160']", + "148, model ['l125', 'l133', 'l140', 'l146', 'l151', 'l155', 'l158', 'l161', 'l162']", + "149, of ['l72', 'l126', 'l134', 'l141', 'l147', 'l152', 'l156', 'l159', 'l161', 'l163']", + "150, neuroblastoma. ['l73', 'l127', 'l135', 'l142', 'l148', 'l153', 'l157', 'l160', 'l162', 'l163']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "miR-380", + "overexpression" + ] + }, + "context": { + "val": "cells", + "words": [ + "primary", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "miR-380", + "overexpression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "block" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "miR-380", + "overexpression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "oncogene-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "miR-380", + "overexpression" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "miR-380", + "overexpression" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "miR-380", + "overexpression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "miR-380", + "overexpression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "stem", + "cells" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "primary", + "cells," + ] + }, + "effect": { + "val": "negative", + "words": [ + "block" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "primary" + ] + }, + "effect": { + "val": "positive", + "words": [ + "oncogene-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "primary", + "cells," + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "primary", + "cells," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumors" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "block" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "block", + "decreases" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumors", + "tumor", + "size" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "block" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "oncogene-induced" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "oncogene-induced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "oncogene-induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "oncogene-induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells" + ] + } + }, + { + "phenotype": { + "val": "senescence", + "words": [ + "senescence" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "form", + "tumors" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "endogenous", + "miR-380-5p" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "embryonic", + "stem", + "or", + "neuroblastoma", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "endogenous", + "miR-380-5p" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "size" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "of" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "of", + "neuroblastoma." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "embryonic", + "stem", + "or", + "neuroblastoma", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreases" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "size" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreases" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "orthotopic", + "mouse", + "model", + "of", + "neuroblastoma." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "size" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "orthotopic", + "mouse", + "model", + "of", + "neuroblastoma." + ] + } + } + ] + }, + { + "PMID": "20852622", + "TEXT": "Pneumonia remains the leading cause of death from infection in the US, yet fundamentally new conceptual models underlying its pathogenesis have not emerged. We show that humans and mice with bacterial pneumonia have markedly elevated amounts of cardiolipin, a rare, mitochondrial-specific phospholipid, in lung fluid and find that it potently disrupts surfactant function. Intratracheal cardiolipin administration in mice recapitulates the clinical phenotype of pneumonia, including impaired lung mechanics, modulation of cell survival and cytokine networks and lung consolidation. We have identified and characterized the activity of a unique cardiolipin transporter, the P-type ATPase transmembrane lipid pump Atp8b1, a mutant version of which is associated with severe pneumonia in humans and mice. Atp8b1 bound and internalized cardiolipin from extracellular fluid via a basic residue-enriched motif. Administration of a peptide encompassing the cardiolipin binding motif or Atp8b1 gene transfer in mice lessened bacteria-induced lung injury and improved survival. The results unveil a new paradigm whereby Atp8b1 is a cardiolipin importer whose capacity to remove cardiolipin from lung fluid is exceeded during inflammation or when Atp8b1 is defective. This discovery opens the door for new therapeutic strategies directed at modulating the abundance or molecular interactions of cardiolipin in pneumonia.", + "TAG_DATA": [ + "57, mice {'context': 'B-organism'}", + "134, Atp8b1 {'perturbing_action': 'B-gene gain-of-function'}", + "135, gene {'perturbing_action': 'I-gene gain-of-function'}", + "136, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "138, mice {'context': 'B-organism'}", + "141, lung {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "134, Atp8b1 ['l0', 'l1', 'l2', 'l3']", + "135, gene ['l0', 'l4', 'l5', 'l6']", + "136, transfer ['l1', 'l4', 'l7', 'l8']", + "138, mice ['l2', 'l5', 'l7', 'l9']", + "141, lung ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Atp8b1", + "gene", + "transfer" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Atp8b1", + "gene", + "transfer" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + } + ] + }, + { + "PMID": "20711198", + "TEXT": "A major limitation of cell therapies is the rapid decline in viability and function of the transplanted cells. Here we describe a strategy to enhance cell therapy via the conjugation of adjuvant drug-loaded nanoparticles to the surfaces of therapeutic cells. With this method of providing sustained pseudoautocrine stimulation to donor cells, we elicited marked enhancements in tumor elimination in a model of adoptive T cell therapy for cancer. We also increased the in vivo repopulation rate of hematopoietic stem cell grafts with very low doses of adjuvant drugs that were ineffective when given systemically. This approach is a simple and generalizable strategy to augment cytoreagents while minimizing the systemic side effects of adjuvant drugs. In addition, these results suggest therapeutic cells are promising vectors for actively targeted drug delivery.", + "TAG_DATA": [ + "54, enhancements {'effect': 'B-positive'}", + "56, tumor {'phenotype': 'B-tumour regression'}", + "57, elimination {'phenotype': 'I-tumour regression'}", + "67, cancer. {'context': 'B-neoplasm'}", + "70, increased {'effect': 'B-positive'}", + "72, in {'context': 'B-in vivo'}", + "73, vivo {'context': 'B-in vivo'}", + "77, hematopoietic {'context': 'B-xenograft'}", + "78, stem {'context': 'I-xenograft'}", + "79, cell {'context': 'I-xenograft'}", + "80, grafts {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "54, enhancements ['l0', 'l1', 'l2']", + "56, tumor ['l0', 'l3', 'l4']", + "57, elimination ['l1', 'l3', 'l5']", + "67, cancer. ['l2', 'l4', 'l5']", + "70, increased ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "72, in ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "73, vivo ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "77, hematopoietic ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "78, stem ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "79, cell ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "80, grafts ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "enhancements" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "elimination" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhancements" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "cancer." + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "elimination" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "cancer." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "hematopoietic", + "stem", + "cell", + "grafts" + ] + } + } + ] + }, + { + "PMID": "20613753", + "TEXT": "A popular—and controversial—theory is that tumors are initiated and maintained by a fixed population of stem cell–like tumor cells. Research on human cells and mice adds a twist to this theory, suggesting that such stem cell–like cells might be more plastic than previously thought. Alexander Roesch et al. find that a group of cells, which divide slowly, can sustain melanoma growth and self-renew—hallmarks of cancer stem cells. However, the cells can switch phenotype through epigenetic changes mediated by JARID1B, a histone modifier, suggesting a plastic process. They found that human cells expressing JAR1D1B could initiate and sustain melanoma growth when implanted into mice, whereas JARD1B-negative cells could only initiate tumors. JARD1B-negative cells, however, could switch on JARD1B to support tumor growth. Might cancer stem cells be ‘moving’ targets? What, then, are the therapeutic implications?", + "TAG_DATA": [ + "89, human {'context': 'B-cells'}", + "90, cells {'context': 'I-cells'}", + "91, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "92, JAR1D1B {'perturbing_action': 'I-gene gain-of-function'}", + "94, initiate {'effect': 'B-positive'}", + "97, melanoma {'context': 'B-neoplasm'}", + "102, mice, {'context': 'B-organism'}", + "104, JARD1B-negative {'perturbing_action': 'B-gene loss-of-function', 'context': 'B-cells'}", + "105, cells {'context': 'I-cells'}", + "108, initiate {'effect': 'B-positive'}", + "109, tumors. {'phenotype': 'B-tumourigenesis'}", + "110, JARD1B-negative {'context': 'B-cells'}", + "111, cells, {'context': 'I-cells'}", + "118, support {'effect': 'B-positive'}", + "119, tumor {'phenotype': 'B-tumour growth'}", + "120, growth. {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "89, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "90, cells ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "91, expressing ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "92, JAR1D1B ['l2', 'l7', 'l11', 'l15', 'l16', 'l17', 'l18']", + "94, initiate ['l3', 'l8', 'l12', 'l15', 'l19', 'l20']", + "97, melanoma ['l4', 'l9', 'l13', 'l16', 'l19', 'l21']", + "102, mice, ['l5', 'l10', 'l14', 'l17', 'l20', 'l21']", + "104, JARD1B-negative ['l22', 'l23', 'l24']", + "105, cells ['l18', 'l22', 'l25', 'l26']", + "108, initiate ['l23', 'l25', 'l27']", + "109, tumors. ['l24', 'l26', 'l27']", + "110, JARD1B-negative ['l28', 'l29', 'l30', 'l31']", + "111, cells, ['l28', 'l32', 'l33', 'l34']", + "118, support ['l29', 'l32', 'l35', 'l36']", + "119, tumor ['l30', 'l33', 'l35', 'l37']", + "120, growth. ['l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "JAR1D1B" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "cells", + "JARD1B-negative", + "cells," + ] + }, + "effect": { + "val": "positive", + "words": [ + "initiate", + "support" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "JAR1D1B" + ] + }, + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "JAR1D1B" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "melanoma" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "JAR1D1B" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "melanoma" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "JARD1B-negative" + ] + }, + "context": { + "val": "cells", + "words": [ + "JARD1B-negative" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "JARD1B-negative" + ] + }, + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "JARD1B-negative" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "JARD1B-negative", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "JARD1B-negative", + "cells," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "support" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + } + ] + }, + { + "PMID": "20601951", + "TEXT": "Candida albicans is a major fungal pathogen that causes serious systemic and mucosal infections in immunocompromised individuals. In yeast, histone H3 Lys56 acetylation (H3K56ac) is an abundant modification regulated by enzymes that have fungal-specific properties, making them appealing targets for antifungal therapy. Here we demonstrate that H3K56ac in C. albicans is regulated by the RTT109 and HST3 genes, which respectively encode the H3K56 acetyltransferase (Rtt109p) and deacetylase (Hst3p). We show that reduced levels of H3K56ac sensitize C. albicans to genotoxic and antifungal agents. Inhibition of Hst3p activity by conditional gene repression or nicotinamide treatment results in a loss of cell viability associated with abnormal filamentous growth, histone degradation and gross aberrations in DNA staining. We show that genetic or pharmacological alterations in H3K56ac levels reduce virulence in a mouse model of C. albicans infection. Our results demonstrate that modulation of H3K56ac is a unique strategy for treatment of C. albicans and, possibly, other fungal infections.", + "TAG_DATA": [ + "76, C. {'context': 'B-organism'}", + "77, albicans {'context': 'I-organism'}", + "83, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "84, of {'perturbing_action': 'I-other'}", + "85, Hst3p {'perturbing_action': 'I-other'}", + "86, activity {'perturbing_action': 'I-other'}", + "87, by {'perturbing_action': 'I-other'}", + "88, conditional {'perturbing_action': 'I-other'}", + "89, gene {'perturbing_action': 'I-other'}", + "90, repression {'perturbing_action': 'I-other'}", + "97, loss {'effect': 'B-negative'}", + "99, cell {'phenotype': 'B-cell survival'}", + "100, viability {'phenotype': 'I-cell survival'}", + "124, reduce {'effect': 'B-negative'}", + "128, mouse {'context': 'B-organism'}", + "129, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "76, C. ['l0', 'l1', 'l2', 'l3']", + "77, albicans ['l0', 'l4', 'l5', 'l6']", + "83, Inhibition ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "84, of ['l7', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "85, Hst3p ['l8', 'l17', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "86, activity ['l9', 'l18', 'l26', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "87, by ['l10', 'l19', 'l27', 'l34', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "88, conditional ['l11', 'l20', 'l28', 'l35', 'l41', 'l47', 'l48', 'l49', 'l50', 'l51']", + "89, gene ['l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l52', 'l53', 'l54', 'l55']", + "90, repression ['l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l56', 'l57', 'l58']", + "97, loss ['l1', 'l4', 'l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l59', 'l60']", + "99, cell ['l2', 'l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l59', 'l61']", + "100, viability ['l3', 'l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l58', 'l60', 'l61']", + "124, reduce ['l62', 'l63']", + "128, mouse ['l62', 'l64']", + "129, model ['l63', 'l64']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "C.", + "albicans", + "mouse", + "model" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss", + "reduce" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "C.", + "albicans" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "viability" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "viability" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "of", + "Hst3p", + "activity", + "by", + "conditional", + "gene", + "repression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "of", + "Hst3p", + "activity", + "by", + "conditional", + "gene", + "repression" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "viability" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "loss" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "viability" + ] + } + } + ] + }, + { + "PMID": "20562878", + "TEXT": "Polycystic kidney disease (PKD) represents a family of genetic disorders characterized by renal cystic growth and progression to kidney failure. No treatment is currently available for people with PKD, although possible therapeutic interventions are emerging. Despite genetic and clinical heterogeneity, PKDs have in common defects of cystic epithelia, including increased proliferation, apoptosis and activation of growth regulatory pathways. Sphingolipids and glycosphingolipids are emerging as major regulators of these cellular processes. We sought to evaluate the therapeutic potential for glycosphingolipid modulation as a new approach to treat PKD. Here we demonstrate that kidney glucosylceramide (GlcCer) and ganglioside GM3 levels are higher in human and mouse PKD tissue as compared to normal tissue, regardless of the causative mutation. Blockade of GlcCer accumulation with the GlcCer synthase inhibitor Genz-123346 effectively inhibits cystogenesis in mouse models orthologous to human autosomal dominant PKD (Pkd1 conditional knockout mice) and nephronophthisis (jck and pcy mice). Molecular analysis in vitro and in vivo indicates that Genz-123346 acts through inhibition of the two key pathways dysregulated in PKD: Akt protein kinase-mammalian target of rapamycin signaling and cell cycle machinery. Taken together, our data suggest that inhibition of GlcCer synthesis represents a new and effective treatment option for PKD.", + "TAG_DATA": [ + "130, mouse {'context': 'B-organism'}", + "131, models {'context': 'I-organism'}", + "133, to {'perturbing_action': 'I-other'}", + "134, human {'perturbing_action': 'I-other'}", + "135, autosomal {'perturbing_action': 'I-other'}", + "136, dominant {'perturbing_action': 'I-other'}", + "137, PKD {'perturbing_action': 'I-gene loss-of-function'}", + "139, conditional {'perturbing_action': 'I-gene loss-of-function'}", + "140, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "141, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "154, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "130, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "131, models ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "132, orthologous ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "133, to ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "134, human ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "135, autosomal ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "136, dominant ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "137, PKD ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "139, conditional ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "140, knockout ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "141, mice) ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "to", + "human", + "autosomal", + "dominant" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PKD", + "conditional", + "knockout", + "mice)" + ] + } + } + ] + }, + { + "PMID": "20526349", + "TEXT": "Although recurrent gene fusions involving erythroblastosis virus E26 transformation-specific (ETS) family transcription factors are common in prostate cancer, their products are considered 'undruggable' by conventional approaches. Recently, rare targetable gene fusions involving the anaplastic lymphoma receptor tyrosine kinase (ALK) gene, have been identified in 1-5% of lung cancers, suggesting that similar rare gene fusions may occur in other common epithelial cancers, including prostate cancer. Here we used paired-end transcriptome sequencing to screen ETS rearrangement-negative prostate cancers for targetable gene fusions and identified the SLC45A3-BRAF (solute carrier family 45, member 3-v-raf murine sarcoma viral oncogene homolog B1) and ESRP1-RAF1 (epithelial splicing regulatory protein-1-v-raf-1 murine leukemia viral oncogene homolog-1) gene fusions. Expression of SLC45A3-BRAF or ESRP1-RAF1 in prostate cells induced a neoplastic phenotype that was sensitive to RAF and mitogen-activated protein kinase kinase (MAP2K1) inhibitors. Screening a large cohort of patients, we found that, although rare, recurrent rearrangements in the RAF pathway tend to occur in advanced prostate cancers, gastric cancers and melanoma. Taken together, our results emphasize the key role of RAF family gene rearrangements in cancer, suggest that RAF and MEK inhibitors may be useful in a subset of gene fusion-harboring solid tumors and demonstrate that sequencing of tumor transcriptomes and genomes may lead to the identification of rare targetable fusions across cancer types.", + "TAG_DATA": [ + "109, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "110, of {'perturbing_action': 'I-gene gain-of-function'}", + "111, SLC45A3-BRAF {'perturbing_action': 'I-gene gain-of-function'}", + "112, or {'perturbing_action': 'I-gene gain-of-function'}", + "113, ESRP1-RAF1 {'perturbing_action': 'I-gene gain-of-function'}", + "115, prostate {'context': 'B-transformed cells'}", + "116, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "109, Expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "110, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "111, SLC45A3-BRAF ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "112, or ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "113, ESRP1-RAF1 ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "115, prostate ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "116, cells ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "SLC45A3-BRAF", + "or", + "ESRP1-RAF1" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate", + "cells" + ] + } + } + ] + }, + { + "PMID": "20512127", + "TEXT": "In systemic lupus erythematosus (SLE), self-reactive antibodies can target the kidney (lupus nephritis), leading to functional failure and possible mortality. We report that activation of basophils by autoreactive IgE causes their homing to lymph nodes, promoting T helper type 2 (T(H)2) cell differentiation and enhancing the production of self-reactive antibodies that cause lupus-like nephritis in mice lacking the Src family protein tyrosine kinase Lyn (Lyn(-/-) mice). Individuals with SLE also have elevated serum IgE, self-reactive IgEs and activated basophils that express CD62 ligand (CD62L) and the major histocompatibility complex (MHC) class II molecule human leukocyte antigen-DR (HLA-DR), parameters that are associated with increased disease activity and active lupus nephritis. Basophils were also present in the lymph nodes and spleen of subjects with SLE. Thus, in Lyn(-/-) mice, basophils and IgE autoantibodies amplify autoantibody production that leads to lupus nephritis, and in individuals with SLE IgE autoantibodies and activated basophils are factors associated with disease activity and nephritis.", + "TAG_DATA": [ + "35, promoting {'effect': 'B-positive'}", + "55, mice {'context': 'B-organism'}", + "56, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "57, the {'perturbing_action': 'I-gene loss-of-function'}", + "58, Src {'perturbing_action': 'I-gene loss-of-function'}", + "59, family {'perturbing_action': 'I-gene loss-of-function'}", + "60, protein {'perturbing_action': 'I-gene loss-of-function'}", + "61, tyrosine {'perturbing_action': 'I-gene loss-of-function'}", + "62, kinase {'perturbing_action': 'I-gene loss-of-function'}", + "63, Lyn {'perturbing_action': 'I-gene loss-of-function'}", + "64, (Lyn(-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "65, mice). {'perturbing_action': 'I-gene loss-of-function'}", + "125, Lyn(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "126, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "35, promoting ['l0', 'l1']", + "55, mice ['l0', 'l2', 'l3']", + "56, lacking ['l2', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "57, the ['l4', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "58, Src ['l5', 'l13', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "59, family ['l6', 'l14', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "60, protein ['l7', 'l15', 'l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "61, tyrosine ['l8', 'l16', 'l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "62, kinase ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "63, Lyn ['l10', 'l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "64, (Lyn(-/-) ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "65, mice). ['l1', 'l3', 'l12', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l48']", + "125, Lyn(-/-) ['l49']", + "126, mice, ['l49']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "mice)." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "mice).", + "Lyn(-/-)" + ] + } + } + ] + }, + { + "PMID": "20512124", + "TEXT": "Although vaccination is most effective when used to prevent disease, cancer vaccine development has focused predominantly on providing therapy against established growing tumors. The difficulty in developing prophylactic cancer vaccines is primarily due to the fact that tumor antigens are variations of self proteins and would probably mediate profound autoimmune complications if used in a preventive vaccine setting. Here we use several mouse breast cancer models to define a prototypic strategy for prophylactic cancer vaccination. We selected alpha-lactalbumin as our target vaccine autoantigen because it is a breast-specific differentiation protein expressed in high amounts in the majority of human breast carcinomas and in mammary epithelial cells only during lactation. We found that immunoreactivity against alpha-lactalbumin provides substantial protection and therapy against growth of autochthonous tumors in transgenic mouse models of breast cancer and against 4T1 transplantable breast tumors in BALB/c mice. Because alpha-lactalbumin is conditionally expressed only during lactation, vaccination-induced prophylaxis occurs without any detectable inflammation in normal nonlactating breast tissue. Thus, alpha-lactalbumin vaccination may provide safe and effective protection against the development of breast cancer for women in their post-child-bearing, premenopausal years, when lactation is readily avoidable and risk for developing breast cancer is high.", + "TAG_DATA": [ + "123, autochthonous {'context': 'B-neoplasm', 'phenotype': 'I-tumour regression'}", + "124, tumors {'context': 'I-neoplasm'}", + "126, transgenic {'context': 'B-organism'}", + "127, mouse {'context': 'I-organism'}", + "128, models {'context': 'I-organism'}", + "129, of {'context': 'I-neoplasm'}", + "130, breast {'context': 'I-neoplasm'}", + "131, cancer {'context': 'I-neoplasm'}", + "135, transplantable {'phenotype': 'I-tumour regression'}", + "136, breast {'context': 'I-neoplasm'}", + "137, tumors {'context': 'I-neoplasm'}", + "139, BALB/c {'context': 'B-organism'}", + "140, mice. {'context': 'I-organism'}", + "158, nonlactating {'context': 'B-tissue/organ'}", + "159, breast {'context': 'I-tissue/organ'}", + "160, tissue. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "63, breast ['l0']", + "64, cancer ['l0']", + "123, autochthonous ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "124, tumors ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "126, transgenic ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "127, mouse ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "128, models ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "129, of ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "130, breast ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "131, cancer ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']", + "134, 4T1 ['l29', 'l30', 'l31', 'l32', 'l33']", + "135, transplantable ['l29', 'l34', 'l35', 'l36', 'l37']", + "136, breast ['l30', 'l34', 'l38', 'l39', 'l40']", + "137, tumors ['l31', 'l35', 'l38', 'l41', 'l42']", + "139, BALB/c ['l32', 'l36', 'l39', 'l41', 'l43']", + "140, mice. ['l33', 'l37', 'l40', 'l42', 'l43']", + "158, nonlactating ['l44', 'l45']", + "159, breast ['l44', 'l46']", + "160, tissue. ['l45', 'l46']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "autochthonous", + "breast", + "tumors" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "autochthonous", + "transplantable" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "autochthonous", + "transplantable" + ] + }, + "context": { + "val": "organism", + "words": [ + "transgenic", + "mouse", + "models", + "BALB/c", + "mice." + ] + } + } + ] + }, + { + "PMID": "20348922", + "TEXT": "Brain inflammation is a major factor in epilepsy, but the impact of specific inflammatory mediators on neuronal excitability is incompletely understood. Using models of acute and chronic seizures in C57BL/6 mice, we discovered a proconvulsant pathway involving high-mobility group box-1 (HMGB1) release from neurons and glia and its interaction with Toll-like receptor 4 (TLR4), a key receptor of innate immunity. Antagonists of HMGB1 and TLR4 retard seizure precipitation and decrease acute and chronic seizure recurrence. TLR4-defective C3H/HeJ mice are resistant to kainate-induced seizures. The proconvulsant effects of HMGB1, like those of interleukin-1beta (IL-1beta), are partly mediated by ifenprodil-sensitive N-methyl-d-aspartate (NMDA) receptors. Increased expression of HMGB1 and TLR4 in human epileptogenic tissue, like that observed in the mouse model of chronic seizures, suggests a role for the HMGB1-TLR4 axis in human epilepsy. Thus, HMGB1-TLR4 signaling may contribute to generating and perpetuating seizures in humans and might be targeted to attain anticonvulsant effects in epilepsies that are currently resistant to drugs.", + "TAG_DATA": [ + "29, C57BL/6 {'context': 'B-organism'}", + "30, mice, {'context': 'I-organism'}", + "60, Antagonists {'perturbing_action': 'B-pharmacological inhibition'}", + "61, of {'perturbing_action': 'I-pharmacological inhibition'}", + "62, HMGB1 {'perturbing_action': 'I-pharmacological inhibition'}", + "63, and {'perturbing_action': 'I-pharmacological inhibition'}", + "64, TLR4 {'perturbing_action': 'I-pharmacological inhibition'}", + "75, TLR4-defective {'perturbing_action': 'B-other'}", + "76, C3H/HeJ {'context': 'B-organism'}", + "77, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "29, C57BL/6 ['l0', 'l1', 'l2', 'l3']", + "30, mice, ['l0', 'l4']", + "60, Antagonists ['l5', 'l6', 'l7', 'l8']", + "61, of ['l5', 'l9', 'l10', 'l11']", + "62, HMGB1 ['l1', 'l6', 'l9', 'l12', 'l13']", + "63, and ['l2', 'l7', 'l10', 'l12', 'l14']", + "64, TLR4 ['l3', 'l4', 'l8', 'l11', 'l13', 'l14']", + "75, TLR4-defective ['l15', 'l16']", + "76, C3H/HeJ ['l15', 'l17']", + "77, mice ['l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "C57BL/6", + "mice," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "HMGB1", + "and", + "TLR4" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "TLR4-defective" + ] + }, + "context": { + "val": "organism", + "words": [ + "C3H/HeJ", + "mice" + ] + } + } + ] + }, + { + "PMID": "20305661", + "TEXT": "The peptidoglycan layer is a vital component of the bacterial cell wall. The existing paradigm describes the peptidoglycan network as a static structure that is cross-linked predominantly by 4-->3 transpeptide linkages. However, the nonclassical 3-->3 linkages predominate the transpeptide networking of the peptidoglycan layer of nonreplicating Mycobacterium tuberculosis. The molecular basis of these linkages and their role in the physiology of the peptidoglycan layer, virulence and susceptibility of M. tuberculosis to drugs remain undefined. Here we identify MT2594 as an L,D-transpeptidase that generates 3-->3 linkages in M. tuberculosis. We show that the loss of this protein leads to altered colony morphology, loss of virulence and increased susceptibility to amoxicillin-clavulanate during the chronic phase of infection. This suggests that 3-->3 cross-linking is vital to the physiology of the peptidoglycan layer. Although a functional homolog exists, expression of ldtMt2 is dominant throughout the growth phases of M. tuberculosis. 4-->3 transpeptide linkages are targeted by one of the most widely used classes of antibacterial drugs in human clinical use today, beta-lactams. Recently, meropenem-clavulanate was shown to be effective against drug-resistant M. tuberculosis. Our study suggests that a combination of L,D-transpeptidase and beta-lactamase inhibitors could effectively target persisting bacilli during the chronic phase of tuberculosis.", + "TAG_DATA": [ + "92, loss {'perturbing_action': 'B-gene loss-of-function'}", + "93, of {'perturbing_action': 'I-gene loss-of-function'}", + "94, this {'perturbing_action': 'I-gene loss-of-function'}", + "95, protein {'perturbing_action': 'I-gene loss-of-function'}", + "99, colony {'phenotype': 'B-colony formation'}", + "100, morphology, {'phenotype': 'I-colony formation'}", + "101, loss {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "92, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "93, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "94, this ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "95, protein ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "98, altered ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "99, colony ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "100, morphology, ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "101, loss ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "this", + "protein" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "colony", + "morphology," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "this", + "protein" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "colony", + "morphology," + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + } + ] + }, + { + "PMID": "20154697", + "TEXT": "Metastasis is responsible for the majority of prostate cancer-related deaths; however, little is known about the molecular mechanisms that underlie this process. Here we identify an oncogene-tumor suppressor cascade that promotes prostate cancer growth and metastasis by coordinately activating the small GTPase Ras and nuclear factor-kappaB (NF-kappaB). Specifically, we show that loss of the Ras GTPase-activating protein (RasGAP) gene DAB2IP induces metastatic prostate cancer in an orthotopic mouse tumor model. Notably, DAB2IP functions as a signaling scaffold that coordinately regulates Ras and NF-kappaB through distinct domains to promote tumor growth and metastasis, respectively. DAB2IP is suppressed in human prostate cancer, where its expression inversely correlates with tumor grade and predicts prognosis. Moreover, we report that epigenetic silencing of DAB2IP is a key mechanism by which the polycomb-group protein histone-lysine N-methyltransferase EZH2 activates Ras and NF-kappaB and triggers metastasis. These studies define the mechanism by which two major pathways can be simultaneously activated in metastatic prostate cancer and establish EZH2 as a driver of metastasis.", + "TAG_DATA": [ + "51, loss {'perturbing_action': 'B-gene loss-of-function'}", + "52, of {'perturbing_action': 'I-gene loss-of-function'}", + "53, the {'perturbing_action': 'I-gene loss-of-function'}", + "54, Ras {'perturbing_action': 'I-gene loss-of-function'}", + "55, GTPase-activating {'perturbing_action': 'I-gene loss-of-function'}", + "56, protein {'perturbing_action': 'I-gene loss-of-function'}", + "57, (RasGAP) {'perturbing_action': 'I-gene loss-of-function'}", + "58, gene {'perturbing_action': 'I-gene loss-of-function'}", + "59, DAB2IP {'perturbing_action': 'I-gene loss-of-function'}", + "60, induces {'effect': 'B-positive'}", + "61, metastatic {'phenotype': 'B-tumourigenesis'}", + "62, prostate {'phenotype': 'I-tumourigenesis'}", + "63, cancer {'phenotype': 'I-tumourigenesis'}", + "66, orthotopic {'context': 'B-organism'}", + "67, mouse {'context': 'I-neoplasm'}", + "68, tumor {'context': 'I-neoplasm'}", + "69, model. {'context': 'I-neoplasm'}", + "87, promote {'effect': 'B-positive'}", + "88, tumor {'phenotype': 'B-tumour growth'}", + "89, growth {'phenotype': 'I-tumour growth'}", + "91, metastasis, {'phenotype': 'B-metastasis'}", + "116, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "117, of {'perturbing_action': 'I-rnai/knockdown'}", + "118, DAB2IP {'perturbing_action': 'I-rnai/knockdown'}", + "136, triggers {'effect': 'B-positive'}", + "137, metastasis. {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "51, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "52, of ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "53, the ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "54, Ras ['l2', 'l21', 'l39', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "55, GTPase-activating ['l3', 'l22', 'l40', 'l57', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "56, protein ['l4', 'l23', 'l41', 'l58', 'l74', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "57, (RasGAP) ['l5', 'l24', 'l42', 'l59', 'l75', 'l90', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "58, gene ['l6', 'l25', 'l43', 'l60', 'l76', 'l91', 'l105', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "59, DAB2IP ['l7', 'l26', 'l44', 'l61', 'l77', 'l92', 'l106', 'l119', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "60, induces ['l8', 'l27', 'l45', 'l62', 'l78', 'l93', 'l107', 'l120', 'l132', 'l144', 'l145', 'l146']", + "61, metastatic ['l9', 'l28', 'l46', 'l63', 'l79', 'l94', 'l108', 'l121', 'l133', 'l144', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "62, prostate ['l10', 'l29', 'l47', 'l64', 'l80', 'l95', 'l109', 'l122', 'l134', 'l145', 'l147', 'l153', 'l154']", + "63, cancer ['l11', 'l30', 'l48', 'l65', 'l81', 'l96', 'l110', 'l123', 'l135', 'l146', 'l148', 'l153']", + "66, orthotopic ['l12', 'l31', 'l49', 'l66', 'l82', 'l97', 'l111', 'l124', 'l136', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "67, mouse ['l13', 'l32', 'l50', 'l67', 'l83', 'l98', 'l112', 'l125', 'l137', 'l155', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "68, tumor ['l14', 'l33', 'l51', 'l68', 'l84', 'l99', 'l113', 'l126', 'l138', 'l149', 'l156', 'l162', 'l168', 'l169', 'l170', 'l171', 'l172']", + "69, model. ['l15', 'l34', 'l52', 'l69', 'l85', 'l100', 'l114', 'l127', 'l139', 'l150', 'l154', 'l157', 'l163', 'l168', 'l173', 'l174', 'l175', 'l176']", + "87, promote ['l16', 'l35', 'l53', 'l70', 'l86', 'l101', 'l115', 'l128', 'l140', 'l151', 'l158', 'l164', 'l169', 'l173', 'l177', 'l178', 'l179']", + "88, tumor ['l17', 'l36', 'l54', 'l71', 'l87', 'l102', 'l116', 'l129', 'l141', 'l159', 'l165', 'l170', 'l174', 'l177', 'l180', 'l181']", + "89, growth ['l18', 'l37', 'l55', 'l72', 'l88', 'l103', 'l117', 'l130', 'l142', 'l152', 'l160', 'l166', 'l171', 'l175', 'l178', 'l180', 'l182']", + "91, metastasis, ['l19', 'l38', 'l56', 'l73', 'l89', 'l104', 'l118', 'l131', 'l143', 'l161', 'l167', 'l172', 'l176', 'l179', 'l181', 'l182']", + "116, silencing ['l183', 'l184', 'l185', 'l186']", + "117, of ['l183', 'l187', 'l188', 'l189']", + "118, DAB2IP ['l184', 'l187', 'l190', 'l191']", + "136, triggers ['l185', 'l188', 'l190', 'l192']", + "137, metastasis. ['l186', 'l189', 'l191', 'l192']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Ras", + "GTPase-activating", + "protein", + "(RasGAP)", + "gene", + "DAB2IP" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces", + "promote" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Ras", + "GTPase-activating", + "protein", + "(RasGAP)", + "gene", + "DAB2IP" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "metastatic", + "prostate", + "cancer" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Ras", + "GTPase-activating", + "protein", + "(RasGAP)", + "gene", + "DAB2IP" + ] + }, + "context": { + "val": "organism", + "words": [ + "orthotopic" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Ras", + "GTPase-activating", + "protein", + "(RasGAP)", + "gene", + "DAB2IP" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "tumor", + "model." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Ras", + "GTPase-activating", + "protein", + "(RasGAP)", + "gene", + "DAB2IP" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Ras", + "GTPase-activating", + "protein", + "(RasGAP)", + "gene", + "DAB2IP" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "promote" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "metastatic", + "prostate", + "cancer" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "metastatic", + "prostate" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor", + "model." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "orthotopic" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promote" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "orthotopic" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "orthotopic" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "tumor", + "model." + ] + }, + "effect": { + "val": "positive", + "words": [ + "promote" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "tumor", + "model." + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "tumor", + "model." + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote", + "triggers" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis,", + "metastasis." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "of", + "DAB2IP" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "of", + "DAB2IP" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + } + ] + }, + { + "PMID": "20154695", + "TEXT": "Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (encoded by Cftr) that impair its role as an apical chloride channel that supports bicarbonate transport. Individuals with cystic fibrosis show retained, thickened mucus that plugs airways and obstructs luminal organs as well as numerous other abnormalities that include inflammation of affected organs, alterations in lipid metabolism and insulin resistance. Here we show that colonic epithelial cells and whole lung tissue from Cftr-deficient mice show a defect in peroxisome proliferator-activated receptor-gamma (PPAR-gamma, encoded by Pparg) function that contributes to a pathological program of gene expression. Lipidomic analysis of colonic epithelial cells suggests that this defect results in part from reduced amounts of the endogenous PPAR-gamma ligand 15-keto-prostaglandin E(2) (15-keto-PGE(2)). Treatment of Cftr-deficient mice with the synthetic PPAR-gamma ligand rosiglitazone partially normalizes the altered gene expression pattern associated with Cftr deficiency and reduces disease severity. Rosiglitazone has no effect on chloride secretion in the colon, but it increases expression of the genes encoding carbonic anhydrases 4 and 2 (Car4 and Car2), increases bicarbonate secretion and reduces mucus retention. These studies reveal a reversible defect in PPAR-gamma signaling in Cftr-deficient cells that can be pharmacologically corrected to ameliorate the severity of the cystic fibrosis phenotype in mice.", + "TAG_DATA": [ + "67, colonic {'context': 'B-cells'}", + "68, epithelial {'context': 'I-cells'}", + "69, cells {'context': 'I-cells'}", + "72, lung {'context': 'I-tissue/organ'}", + "73, tissue {'context': 'I-tissue/organ'}", + "75, Cftr-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "76, mice {'context': 'B-organism'}", + "101, colonic {'context': 'B-cells'}", + "102, epithelial {'context': 'I-cells'}", + "103, cells {'context': 'I-cells'}", + "124, Cftr-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "125, mice {'context': 'B-organism'}", + "141, Cftr {'perturbing_action': 'B-gene loss-of-function'}", + "142, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "156, colon, {'context': 'B-tissue/organ'}", + "190, Cftr-deficient {'perturbing_action': 'B-gene loss-of-function'}" + ], + "LINK_DATA": [ + "67, colonic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "68, epithelial ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "69, cells ['l1', 'l7', 'l15', 'l16', 'l17', 'l18', 'l19']", + "72, lung ['l2', 'l8', 'l15', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "73, tissue ['l3', 'l9', 'l16', 'l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "75, Cftr-deficient ['l4', 'l10', 'l17', 'l21', 'l26', 'l31', 'l32', 'l33', 'l34']", + "76, mice ['l5', 'l11', 'l18', 'l22', 'l27', 'l31', 'l35', 'l36']", + "101, colonic ['l12', 'l23', 'l28', 'l32', 'l35', 'l37', 'l38', 'l39']", + "102, epithelial ['l13', 'l24', 'l29', 'l33', 'l37', 'l40', 'l41']", + "103, cells ['l6', 'l14', 'l19', 'l25', 'l30', 'l34', 'l36', 'l38', 'l40', 'l42']", + "124, Cftr-deficient ['l43', 'l44', 'l45', 'l46']", + "125, mice ['l43', 'l47', 'l48', 'l49']", + "141, Cftr ['l44', 'l47', 'l50']", + "142, deficiency ['l39', 'l41', 'l42', 'l45', 'l48', 'l50']", + "156, colon, ['l46', 'l49']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "colonic", + "epithelial", + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cftr-deficient", + "deficiency" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "lung", + "tissue", + "colon," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cftr-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cftr-deficient", + "Cftr", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "19966811", + "TEXT": "Hepatocyte nuclear factor-1beta (HNF-1beta) is a transcription factor required for the expression of several renal cystic genes and whose prenatal deletion leads to polycystic kidney disease (PKD). We show here that inactivation of Hnf1b from postnatal day 10 onward does not elicit cystic dilations in tubules after their proliferative morphogenetic elongation is over. Cystogenic resistance is intrinsically linked to the quiescent state of cells. In fact, when Hnf1b deficient quiescent cells are forced to proliferate by an ischemia-reperfusion injury, they give rise to cysts, owing to loss of oriented cell division. Remarkably, in quiescent cells, the transcription of crucial cystogenic target genes is maintained even in the absence of HNF-1beta. However, their expression is lost as soon as cells proliferate and the chromatin of target genes acquires heterochromatin marks. These results unveil a previously undescribed aspect of gene regulation. It is well established that transcription is shut off during the mitotic condensation of chromatin. We propose that transcription factors such as HNF-1beta might be involved in reprogramming gene expression after transcriptional silencing is induced by mitotic chromatin condensation. Notably, HNF-1beta remains associated with the mitotically condensed chromosomal barrels. This association suggests that HNF-1beta is a bookmarking factor that is necessary for reopening the chromatin of target genes after mitotic silencing.", + "TAG_DATA": [ + "31, inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "32, of {'perturbing_action': 'I-gene loss-of-function'}", + "33, Hnf1b {'perturbing_action': 'I-gene loss-of-function'}", + "67, Hnf1b {'perturbing_action': 'B-gene loss-of-function'}", + "68, deficient {'perturbing_action': 'I-gene loss-of-function'}", + "69, quiescent {'context': 'B-cells'}", + "70, cells {'context': 'I-cells'}", + "72, forced {'effect': 'B-positive'}", + "74, proliferate {'phenotype': 'B-proliferation'}", + "86, loss {'effect': 'B-negative'}", + "89, cell {'phenotype': 'B-proliferation'}", + "90, division. {'phenotype': 'I-proliferation'}", + "93, quiescent {'context': 'B-cells'}", + "94, cells, {'context': 'I-cells'}", + "118, cells {'context': 'B-cells'}", + "119, proliferate {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "31, inactivation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "32, of ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "33, Hnf1b ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "67, Hnf1b ['l2', 'l13', 'l23', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "68, deficient ['l3', 'l14', 'l24', 'l32', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "69, quiescent ['l4', 'l15', 'l25', 'l33', 'l41', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "70, cells ['l5', 'l16', 'l26', 'l34', 'l42', 'l49', 'l56', 'l57', 'l58', 'l59', 'l60']", + "72, forced ['l6', 'l17', 'l27', 'l35', 'l43', 'l50', 'l56', 'l61', 'l62', 'l63', 'l64', 'l65']", + "74, proliferate ['l7', 'l18', 'l28', 'l36', 'l44', 'l51', 'l57', 'l61', 'l66', 'l67', 'l68', 'l69']", + "86, loss ['l8', 'l19', 'l29', 'l37', 'l45', 'l52', 'l58', 'l62', 'l66', 'l70', 'l71', 'l72']", + "89, cell ['l9', 'l20', 'l30', 'l38', 'l46', 'l53', 'l59', 'l63', 'l67', 'l70', 'l73', 'l74']", + "90, division. ['l10', 'l21', 'l31', 'l39', 'l47', 'l54', 'l60', 'l64', 'l68', 'l71', 'l73', 'l75']", + "93, quiescent ['l76', 'l77', 'l78']", + "94, cells, ['l11', 'l22', 'l40', 'l48', 'l55', 'l65', 'l69', 'l72', 'l74', 'l75', 'l76', 'l79', 'l80']", + "118, cells ['l77', 'l79', 'l81']", + "119, proliferate ['l78', 'l80', 'l81']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "Hnf1b", + "deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "quiescent", + "cells", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "Hnf1b", + "deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "forced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "Hnf1b", + "deficient" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate", + "cell", + "division." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "Hnf1b", + "deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "quiescent", + "cells", + "cells," + ] + }, + "effect": { + "val": "positive", + "words": [ + "forced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "quiescent", + "cells", + "cells," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate", + "cell", + "division." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "quiescent", + "cells", + "cells," + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "forced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate", + "cell", + "division." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate", + "cell", + "division." + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + } + ] + }, + { + "PMID": "19915593", + "TEXT": "Huntington's disease is caused by an expanded CAG repeat in the gene encoding huntingtin (HTT), resulting in loss of striatal and cortical neurons. Given that the gene product is widely expressed, it remains unclear why neurons are selectively targeted. Here we show the relationship between synaptic and extrasynaptic activity, inclusion formation of mutant huntingtin protein (mtHtt) and neuronal survival. Synaptic N-methyl-D-aspartate-type glutamate receptor (NMDAR) activity induces mtHtt inclusions via a T complex-1 (TCP-1) ring complex (TRiC)-dependent mechanism, rendering neurons more resistant to mtHtt-mediated cell death. In contrast, stimulation of extrasynaptic NMDARs increases the vulnerability of mtHtt-containing neurons to cell death by impairing the neuroprotective cyclic AMP response element-binding protein (CREB)-peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) cascade and increasing the level of the small guanine nucleotide-binding protein Rhes, which is known to sumoylate and disaggregate mtHtt. Treatment of transgenic mice expressing a yeast artificial chromosome containing 128 CAG repeats (YAC128) with low-dose memantine blocks extrasynaptic (but not synaptic) NMDARs and ameliorates neuropathological and behavioral manifestations. By contrast, high-dose memantine, which blocks both extrasynaptic and synaptic NMDAR activity, decreases neuronal inclusions and worsens these outcomes. Our findings offer a rational therapeutic approach for protecting susceptible neurons in Huntington's disease.", + "TAG_DATA": [ + "78, neurons {'context': 'B-cells'}", + "79, more {'effect': 'B-positive'}", + "80, resistant {'effect': 'I-positive'}", + "81, to {'effect': 'I-positive'}", + "83, cell {'phenotype': 'B-cell death'}", + "84, death. {'phenotype': 'I-cell death'}", + "96, neurons {'context': 'B-cells'}", + "98, cell {'phenotype': 'B-cell death'}", + "99, death {'phenotype': 'I-cell death'}", + "136, transgenic {'perturbing_action': 'B-other', 'context': 'B-organism'}", + "137, mice {'context': 'I-organism'}", + "138, expressing {'perturbing_action': 'B-other'}", + "139, a {'perturbing_action': 'I-other'}", + "140, yeast {'perturbing_action': 'I-other'}", + "141, artificial {'perturbing_action': 'I-other'}", + "142, chromosome {'perturbing_action': 'I-other'}", + "143, containing {'perturbing_action': 'I-other'}", + "144, 128 {'perturbing_action': 'I-other'}", + "145, CAG {'perturbing_action': 'I-other'}", + "146, repeats {'perturbing_action': 'I-other'}", + "147, (YAC128) {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "78, neurons ['l0', 'l1', 'l2', 'l3', 'l4']", + "79, more ['l0', 'l5', 'l6', 'l7', 'l8']", + "80, resistant ['l1', 'l5', 'l9', 'l10', 'l11']", + "81, to ['l2', 'l6', 'l9', 'l12', 'l13']", + "83, cell ['l3', 'l7', 'l10', 'l12', 'l14']", + "84, death. ['l4', 'l8', 'l11', 'l13', 'l14']", + "96, neurons ['l15', 'l16']", + "98, cell ['l15', 'l17']", + "99, death ['l16', 'l17']", + "136, transgenic ['l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "137, mice ['l18', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "138, expressing ['l19', 'l29', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "139, a ['l20', 'l30', 'l39', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "140, yeast ['l21', 'l31', 'l40', 'l48', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "141, artificial ['l22', 'l32', 'l41', 'l49', 'l56', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "142, chromosome ['l23', 'l33', 'l42', 'l50', 'l57', 'l63', 'l69', 'l70', 'l71', 'l72', 'l73']", + "143, containing ['l24', 'l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l74', 'l75', 'l76', 'l77']", + "144, 128 ['l25', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l78', 'l79', 'l80']", + "145, CAG ['l26', 'l36', 'l45', 'l53', 'l60', 'l66', 'l71', 'l75', 'l78', 'l81', 'l82']", + "146, repeats ['l27', 'l37', 'l46', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l81', 'l83']", + "147, (YAC128) ['l28', 'l38', 'l47', 'l55', 'l62', 'l68', 'l73', 'l77', 'l80', 'l82', 'l83']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "neurons" + ] + }, + "effect": { + "val": "positive", + "words": [ + "more", + "resistant", + "to" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neurons" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death.", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "more", + "resistant", + "to" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "transgenic", + "expressing", + "a", + "yeast", + "artificial", + "chromosome", + "containing", + "128", + "CAG", + "repeats", + "(YAC128)" + ] + }, + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + } + } + ] + }, + { + "PMID": "19898489", + "TEXT": "5q- syndrome is a subtype of myelodysplastic syndrome characterized by severe anemia and variable neutropenia but normal or high platelet counts with dysplastic megakaryocytes. We examined expression of microRNAs (miRNAs) encoded on chromosome 5q as a possible cause of haploinsufficiency. We show that deletion of chromosome 5q correlates with loss of two miRNAs that are abundant in hematopoietic stem/progenitor cells (HSPCs), miR-145 and miR-146a, and we identify Toll-interleukin-1 receptor domain-containing adaptor protein (TIRAP) and tumor necrosis factor receptor-associated factor-6 (TRAF6) as respective targets of these miRNAs. TIRAP is known to lie upstream of TRAF6 in innate immune signaling. Knockdown of miR-145 and miR-146a together or enforced expression of TRAF6 in mouse HSPCs resulted in thrombocytosis, mild neutropenia and megakaryocytic dysplasia. A subset of mice transplanted with TRAF6-expressing marrow progressed either to marrow failure or acute myeloid leukemia. Thus, inappropriate activation of innate immune signals in HSPCs phenocopies several clinical features of 5q- syndrome.", + "TAG_DATA": [ + "98, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "99, of {'perturbing_action': 'I-rnai/knockdown'}", + "100, miR-145 {'perturbing_action': 'I-rnai/knockdown'}", + "101, and {'perturbing_action': 'I-rnai/knockdown'}", + "102, miR-146a {'perturbing_action': 'I-rnai/knockdown'}", + "105, enforced {'perturbing_action': 'B-gene gain-of-function'}", + "106, expression {'perturbing_action': 'I-gene gain-of-function'}", + "107, of {'perturbing_action': 'I-gene gain-of-function'}", + "108, TRAF6 {'perturbing_action': 'I-gene gain-of-function'}", + "110, mouse {'context': 'B-cells'}", + "111, HSPCs {'context': 'I-cells'}", + "123, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "98, Knockdown ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "99, of ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "100, miR-145 ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "101, and ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "102, miR-146a ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "105, enforced ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "106, expression ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "107, of ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "108, TRAF6 ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "110, mouse ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "111, HSPCs ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "miR-145", + "and", + "miR-146a" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "HSPCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "enforced", + "expression", + "of", + "TRAF6" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "HSPCs" + ] + } + } + ] + }, + { + "PMID": "19734909", + "TEXT": "Lissencephaly is a devastating neurological disorder caused by defective neuronal migration. LIS1 (official symbol PAFAH1B1, for platelet-activating factor acetylhydrolase, isoform 1b, subunit 1) was identified as the gene mutated in individuals with lissencephaly, and it was found to regulate cytoplasmic dynein function and localization. Here we show that inhibition or knockdown of calpains protects LIS1 from proteolysis, resulting in the augmentation of LIS1 amounts in Lis1(+/-) mouse embryonic fibroblast cells and rescue of the aberrant distribution of cytoplasmic dynein, mitochondria and beta-COP-positive vesicles. We also show that calpain inhibitors improve neuronal migration of Lis1(+/-) cerebellar granular neurons. Intraperitoneal injection of the calpain inhibitor ALLN to pregnant Lis1(+/-) dams rescued apoptotic neuronal cell death and neuronal migration defects in Lis1(+/-) offspring. Furthermore, in utero knockdown of calpain by short hairpin RNA rescued defective cortical layering in Lis1(+/-) mice. Thus, calpain inhibition is a potential therapeutic intervention for lissencephaly.", + "TAG_DATA": [ + "50, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "51, of {'perturbing_action': 'I-rnai/knockdown'}", + "52, calpains {'perturbing_action': 'I-rnai/knockdown'}", + "65, Lis1(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "66, mouse {'context': 'B-cells'}", + "67, embryonic {'context': 'I-cells'}", + "68, fibroblast {'context': 'I-cells'}", + "69, cells {'context': 'I-cells'}", + "87, calpain {'perturbing_action': 'B-pharmacological inhibition'}", + "88, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "89, improve {'effect': 'B-positive'}", + "91, migration {'phenotype': 'B-migration'}", + "93, Lis1(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "94, cerebellar {'context': 'B-cells'}", + "95, granular {'context': 'I-cells'}", + "96, neurons. {'context': 'I-cells'}", + "101, calpain {'perturbing_action': 'I-pharmacological inhibition'}", + "102, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "103, ALLN {'perturbing_action': 'I-pharmacological inhibition'}", + "106, Lis1(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "107, dams {'context': 'I-organism'}", + "108, rescued {'effect': 'B-rescues'}", + "109, apoptotic {'phenotype': 'B-apoptosis'}", + "110, neuronal {'phenotype': 'I-apoptosis'}", + "111, cell {'phenotype': 'I-apoptosis'}", + "112, death {'phenotype': 'I-apoptosis'}", + "118, Lis1(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "119, offspring. {'context': 'B-organism'}", + "121, in {'context': 'B-in vivo'}", + "122, utero {'context': 'I-in vivo'}", + "123, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "124, of {'perturbing_action': 'I-rnai/knockdown'}", + "125, calpain {'perturbing_action': 'I-rnai/knockdown'}", + "126, by {'perturbing_action': 'I-rnai/knockdown'}", + "127, short {'perturbing_action': 'I-rnai/knockdown'}", + "128, hairpin {'perturbing_action': 'I-rnai/knockdown'}", + "129, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "135, Lis1(+/-) {'perturbing_action': 'B-gene loss-of-function'}", + "136, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, knockdown ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "51, of ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "52, calpains ['l1', 'l14', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "65, Lis1(+/-) ['l2', 'l15', 'l26', 'l37', 'l38', 'l39', 'l40', 'l41']", + "66, mouse ['l3', 'l16', 'l27', 'l37', 'l42', 'l43', 'l44', 'l45', 'l46']", + "67, embryonic ['l4', 'l17', 'l28', 'l38', 'l42', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "68, fibroblast ['l5', 'l18', 'l29', 'l39', 'l43', 'l47', 'l53', 'l54', 'l55', 'l56', 'l57']", + "69, cells ['l6', 'l19', 'l30', 'l40', 'l44', 'l48', 'l53']", + "87, calpain ['l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "88, inhibitors ['l7', 'l58', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "89, improve ['l8', 'l20', 'l31', 'l49', 'l54', 'l59', 'l75', 'l88', 'l89', 'l90', 'l91', 'l92']", + "91, migration ['l9', 'l21', 'l32', 'l41', 'l45', 'l50', 'l55', 'l60', 'l76', 'l88', 'l93', 'l94', 'l95', 'l96']", + "93, Lis1(+/-) ['l10', 'l22', 'l33', 'l51', 'l56', 'l61', 'l77', 'l89', 'l93', 'l97', 'l98', 'l99', 'l100', 'l101']", + "94, cerebellar ['l11', 'l23', 'l34', 'l62', 'l78', 'l90', 'l94', 'l97', 'l102', 'l103', 'l104', 'l105', 'l106']", + "95, granular ['l12', 'l24', 'l35', 'l63', 'l79', 'l91', 'l95', 'l98', 'l102', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "96, neurons. ['l13', 'l25', 'l36', 'l46', 'l52', 'l57', 'l64', 'l80', 'l92', 'l96', 'l99', 'l103', 'l107', 'l114', 'l115']", + "101, calpain ['l65', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "102, inhibitor ['l66', 'l116', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "103, ALLN ['l67', 'l117', 'l127', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145']", + "106, Lis1(+/-) ['l68', 'l81', 'l108', 'l118', 'l128', 'l137', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "107, dams ['l69', 'l82', 'l119', 'l129', 'l138', 'l146', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160']", + "108, rescued ['l70', 'l83', 'l109', 'l120', 'l130', 'l139', 'l147', 'l154', 'l161', 'l162', 'l163', 'l164', 'l165']", + "109, apoptotic ['l71', 'l84', 'l110', 'l121', 'l131', 'l140', 'l148', 'l155', 'l161', 'l166', 'l167', 'l168', 'l169']", + "110, neuronal ['l72', 'l85', 'l104', 'l111', 'l122', 'l132', 'l141', 'l149', 'l156', 'l162', 'l166', 'l170', 'l171', 'l172']", + "111, cell ['l73', 'l86', 'l100', 'l105', 'l112', 'l114', 'l123', 'l133', 'l142', 'l150', 'l157', 'l163', 'l167', 'l170', 'l173']", + "112, death ['l74', 'l87', 'l101', 'l106', 'l113', 'l115', 'l124', 'l134', 'l143', 'l151', 'l158', 'l164', 'l168', 'l171', 'l173']", + "118, Lis1(+/-) ['l125', 'l135', 'l144', 'l152', 'l159', 'l165', 'l169', 'l172', 'l174']", + "119, offspring. ['l126', 'l136', 'l145', 'l153', 'l160', 'l174']", + "121, in ['l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184']", + "122, utero ['l175', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "123, knockdown ['l176', 'l185', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201']", + "124, of ['l177', 'l186', 'l194', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208']", + "125, calpain ['l178', 'l187', 'l195', 'l202', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214']", + "126, by ['l179', 'l188', 'l196', 'l203', 'l209', 'l215', 'l216', 'l217', 'l218', 'l219']", + "127, short ['l180', 'l189', 'l197', 'l204', 'l210', 'l215', 'l220', 'l221', 'l222', 'l223']", + "128, hairpin ['l181', 'l190', 'l198', 'l205', 'l211', 'l216', 'l220', 'l224', 'l225', 'l226']", + "129, RNA ['l182', 'l191', 'l199', 'l206', 'l212', 'l217', 'l221', 'l224', 'l227', 'l228']", + "135, Lis1(+/-) ['l183', 'l192', 'l200', 'l207', 'l213', 'l218', 'l222', 'l225', 'l227', 'l229']", + "136, mice. ['l184', 'l193', 'l201', 'l208', 'l214', 'l219', 'l223', 'l226', 'l228', 'l229']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "calpains" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "embryonic", + "fibroblast", + "cells", + "cerebellar", + "granular", + "neurons." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "calpains" + ] + }, + "effect": { + "val": "positive", + "words": [ + "improve" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "calpains" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lis1(+/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "embryonic", + "fibroblast", + "cells", + "cerebellar", + "granular", + "neurons." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lis1(+/-)" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mouse", + "embryonic", + "fibroblast", + "cerebellar", + "granular", + "neurons." + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "embryonic", + "fibroblast", + "cerebellar", + "granular", + "neurons." + ] + }, + "effect": { + "val": "positive", + "words": [ + "improve" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "calpain", + "inhibitors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "improve" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "calpain", + "inhibitors" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "calpain", + "inhibitors" + ] + }, + "context": { + "val": "cells", + "words": [ + "cerebellar", + "granular", + "neurons." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "calpain", + "inhibitors", + "inhibitor", + "ALLN" + ] + }, + "context": { + "val": "organism", + "words": [ + "dams", + "offspring." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "calpain", + "inhibitors", + "inhibitor", + "ALLN" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "calpain", + "inhibitors", + "inhibitor", + "ALLN" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "neuronal", + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "improve" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "improve" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lis1(+/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lis1(+/-)" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "cell", + "death", + "apoptotic", + "neuronal" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cerebellar", + "granular", + "neurons." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "neuronal", + "cell", + "death", + "apoptotic" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "granular" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lis1(+/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "dams", + "offspring.", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lis1(+/-)" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "dams" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "dams" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "neuronal", + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "neuronal", + "cell", + "death" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "utero" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "calpain", + "by", + "short", + "hairpin", + "RNA" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "utero" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lis1(+/-)" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "calpain", + "by", + "short", + "hairpin", + "RNA" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "19701205", + "TEXT": "Primary cilia are present on most mammalian cells and are implicated in transducing Hedgehog (Hh) signals during development; however, the prevalence of cilia on human tumors remains unclear, and the role of cilia in cancer has not been examined. Here we show that human basal cell carcinomas (BCCs) are frequently ciliated, and we test the role of cilia in BCC by conditionally deleting Kif3a (encoding kinesin family member 3A) or Ift88 (encoding intraflagellar transport protein 88), genes required for ciliogenesis, in two Hh pathway-dependent mouse tumor models. Ciliary ablation strongly inhibited BCC-like tumors induced by an activated form of Smoothened. In contrast, removal of cilia accelerated tumors induced by activated Gli2, a transcriptional effector of Hh signaling. These seemingly paradoxical effects are consistent with a dual role for cilia in mediating both the activation and the repression of the Hh signaling pathway. Our findings demonstrate that cilia function as unique signaling organelles that can either mediate or suppress tumorigenesis depending on the nature of the oncogenic initiating event.", + "TAG_DATA": [ + "61, conditionally {'perturbing_action': 'B-gene loss-of-function'}", + "62, deleting {'perturbing_action': 'B-gene loss-of-function'}", + "63, Kif3a {'perturbing_action': 'I-gene loss-of-function'}", + "84, mouse {'context': 'B-neoplasm'}", + "85, tumor {'context': 'I-neoplasm'}", + "86, models. {'context': 'I-neoplasm'}", + "87, Ciliary {'perturbing_action': 'B-gene loss-of-function'}", + "88, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "90, inhibited {'effect': 'B-negative'}", + "91, BCC-like {'context': 'B-neoplasm'}", + "92, tumors {'context': 'I-neoplasm'}", + "105, accelerated {'effect': 'B-positive'}", + "106, tumors {'phenotype': 'B-tumourigenesis'}", + "107, induced {'effect': 'B-positive'}" + ], + "LINK_DATA": [ + "61, conditionally ['l0', 'l1', 'l2', 'l3', 'l4']", + "62, deleting ['l0', 'l5', 'l6', 'l7', 'l8']", + "63, Kif3a ['l1', 'l5', 'l9', 'l10', 'l11', 'l12', 'l13']", + "84, mouse ['l2', 'l6', 'l9', 'l14', 'l15']", + "85, tumor ['l3', 'l7', 'l10', 'l14', 'l16']", + "86, models. ['l4', 'l8', 'l11', 'l15', 'l16']", + "87, Ciliary ['l17', 'l18', 'l19', 'l20']", + "88, ablation ['l17', 'l21', 'l22', 'l23']", + "90, inhibited ['l18', 'l21', 'l24', 'l25']", + "91, BCC-like ['l12', 'l19', 'l22', 'l24', 'l26']", + "92, tumors ['l13', 'l20', 'l23', 'l25', 'l26']", + "105, accelerated ['l27', 'l28']", + "106, tumors ['l27', 'l29']", + "107, induced ['l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditionally", + "deleting", + "Kif3a", + "Ciliary", + "ablation" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "tumor", + "models.", + "BCC-like", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ciliary", + "ablation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "BCC-like", + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "accelerated", + "induced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors" + ] + } + } + ] + }, + { + "PMID": "19684582", + "TEXT": "Aggrecan cleavage by a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 5 (ADAMTS-5) is crucial for the breakdown of cartilage matrix during osteoarthritis, a degenerative joint disease that leads to the progressive destruction of articular structures. The mechanisms of ADAMTS-5 activation and their links to the pathogenesis of osteoarthritis remain poorly understood, but syndecans have been shown to be involved in the activation of ADAMTS-4 (ref. 3). Here we show that syndecan-4 is specifically induced in type X collagen-producing chondrocytes both in human osteoarthritis and in murine models of the disease. The loss of syndecan-4 in genetically modified mice and intra-articular injections of syndecan-4-specific antibodies into wild-type mice protect from proteoglycan loss and thereby prevent osteoarthritic cartilage damage in a surgically induced model of osteoarthritis. The occurrence of less severe osteoarthritis-like cartilage destruction in both syndecan-4-deficient mice and syndecan-4-specific antibody-treated wild-type mice results from a marked decrease in ADAMTS-5 activity. Syndecan-4 controls the activation of ADAMTS-5 through direct interaction with the protease and through regulating mitogen-activated protein kinase (MAPK)-dependent synthesis of matrix metalloproteinase-3 (MMP-3). Our data suggest that strategies aimed at the inhibition of syndecan-4 will be of great value for the treatment of cartilage damage in osteoarthritis.", + "TAG_DATA": [ + "95, loss {'perturbing_action': 'B-gene loss-of-function'}", + "96, of {'perturbing_action': 'I-gene loss-of-function'}", + "97, syndecan-4 {'perturbing_action': 'I-gene loss-of-function'}", + "100, modified {'context': 'I-organism'}", + "101, mice {'context': 'I-organism'}", + "110, mice {'context': 'B-organism'}", + "138, syndecan-4-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "139, mice {'context': 'B-organism'}", + "144, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "95, loss ['l0', 'l1', 'l2', 'l3', 'l4']", + "96, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "97, syndecan-4 ['l1', 'l5', 'l9', 'l10', 'l11', 'l12']", + "99, genetically ['l2', 'l6', 'l9', 'l13', 'l14']", + "100, modified ['l3', 'l7', 'l10', 'l13', 'l15']", + "101, mice ['l4', 'l8', 'l11', 'l14', 'l15']", + "110, mice ['l12']", + "138, syndecan-4-deficient ['l16']", + "139, mice ['l16']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "syndecan-4", + "syndecan-4-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "modified", + "mice" + ] + } + } + ] + }, + { + "PMID": "19648928", + "TEXT": "Basal-like breast cancers arising in women carrying mutations in the BRCA1 gene, encoding the tumor suppressor protein BRCA1, are thought to develop from the mammary stem cell. To explore early cellular changes that occur in BRCA1 mutation carriers, we have prospectively isolated distinct epithelial subpopulations from normal mammary tissue and preneoplastic specimens from individuals heterozygous for a BRCA1 mutation. We describe three epithelial subsets including basal stem/progenitor, luminal progenitor and mature luminal cells. Unexpectedly, we found that breast tissue from BRCA1 mutation carriers harbors an expanded luminal progenitor population that shows factor-independent growth in vitro. Moreover, gene expression profiling revealed that breast tissue heterozygous for a BRCA1 mutation and basal breast tumors were more similar to normal luminal progenitor cells than any other subset, including the stem cell-enriched population. The c-KIT tyrosine kinase receptor (encoded by KIT) emerged as a key marker of luminal progenitor cells and was more highly expressed in BRCA1-associated preneoplastic tissue and tumors. Our findings suggest that an aberrant luminal progenitor population is a target for transformation in BRCA1-associated basal tumors .", + "TAG_DATA": [ + "93, in {'context': 'B-in vitro'}", + "94, vitro. {'context': 'B-in vitro'}", + "101, breast {'context': 'B-neoplasm'}", + "102, tissue {'context': 'I-neoplasm'}", + "103, heterozygous {'perturbing_action': 'B-other'}", + "104, for {'perturbing_action': 'I-other'}", + "105, a {'perturbing_action': 'I-other'}", + "106, BRCA1 {'perturbing_action': 'I-other'}", + "107, mutation {'perturbing_action': 'I-other'}", + "109, basal {'context': 'B-neoplasm'}", + "110, breast {'context': 'I-neoplasm'}", + "111, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "93, in ['l0']", + "94, vitro. ['l0']", + "101, breast ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "102, tissue ['l1', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "103, heterozygous ['l2', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "104, for ['l3', 'l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "105, a ['l4', 'l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "106, BRCA1 ['l5', 'l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "107, mutation ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "109, basal ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "110, breast ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "111, tumors ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "breast", + "tissue", + "basal", + "tumors" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous", + "for", + "a", + "BRCA1", + "mutation" + ] + } + } + ] + }, + { + "PMID": "19584866", + "TEXT": "Many sarcomas and leukemias carry nonrandom chromosomal translocations encoding tumor-specific mutant fusion transcription factors that are essential to their molecular pathogenesis. Ewing's sarcoma family tumors (ESFTs) contain a characteristic t(11;22) translocation leading to expression of the oncogenic fusion protein EWS-FLI1. EWS-FLI1 is a disordered protein that precludes standard structure-based small-molecule inhibitor design. EWS-FLI1 binding to RNA helicase A (RHA) is important for its oncogenic function. We therefore used surface plasmon resonance screening to identify compounds that bind EWS-FLI1 and might block its interaction with RHA. YK-4-279, a derivative of the lead compound from the screen, blocks RHA binding to EWS-FLI1, induces apoptosis in ESFT cells and reduces the growth of ESFT orthotopic xenografts. These findings provide proof of principle that inhibiting the interaction of mutant cancer-specific transcription factors with the normal cellular binding partners required for their oncogenic activity provides a promising strategy for the development of uniquely effective, tumor-specific anticancer agents.", + "TAG_DATA": [ + "100, induces {'effect': 'B-positive'}", + "101, apoptosis {'phenotype': 'B-apoptosis'}", + "103, ESFT {'context': 'B-transformed cells'}", + "104, cells {'context': 'I-transformed cells'}", + "110, ESFT {'context': 'B-xenograft'}", + "111, orthotopic {'context': 'I-xenograft'}", + "112, xenografts. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "100, induces ['l0', 'l1', 'l2']", + "101, apoptosis ['l0', 'l3', 'l4']", + "103, ESFT ['l1', 'l3', 'l5']", + "104, cells ['l2', 'l4', 'l5']", + "110, ESFT ['l6', 'l7']", + "111, orthotopic ['l6', 'l8']", + "112, xenografts. ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ESFT", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ESFT", + "cells" + ] + } + } + ] + }, + { + "PMID": "19584865", + "TEXT": "Memory T cells promote allograft rejection particularly in co-stimulation blockade-based immunosuppressive regimens. Here we show that the CD2-specific fusion protein alefacept (lymphocyte function-associated antigen-3-Ig; LFA -3-Ig) selectively eliminates memory T cells and, when combined with a co-stimulation blockade-based regimen using cytotoxic T lymphocyte antigen-4 (CTLA-4)-Ig, a CD80- and CD86-specific fusion protein, prevents renal allograft rejection and alloantibody formation in nonhuman primates. These results support the immediate translation of a regimen for the prevention of allograft rejection without the use of calcineurin inhibitors, steroids or pan-T cell depletion.", + "TAG_DATA": [ + "28, memory {'context': 'B-cells'}", + "29, T {'context': 'I-cells'}", + "30, cells {'context': 'I-cells'}", + "51, prevents {'effect': 'B-negative'}", + "52, renal {'context': 'B-tissue/organ'}", + "59, nonhuman {'context': 'B-organism'}", + "60, primates. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "28, memory ['l0', 'l1', 'l2', 'l3', 'l4']", + "29, T ['l0', 'l5', 'l6', 'l7', 'l8']", + "30, cells ['l1', 'l5', 'l9', 'l10', 'l11']", + "51, prevents ['l2', 'l6', 'l9', 'l12', 'l13', 'l14', 'l15']", + "52, renal ['l3', 'l7', 'l10', 'l12', 'l16', 'l17', 'l18']", + "53, allograft ['l4', 'l8', 'l11', 'l13', 'l16', 'l19', 'l20']", + "59, nonhuman ['l14', 'l17', 'l19', 'l21']", + "60, primates. ['l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "memory", + "T", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "renal" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "context": { + "val": "organism", + "words": [ + "nonhuman", + "primates." + ] + } + } + ] + }, + { + "PMID": "19543284", + "TEXT": "Enterovirus 71 (EV71) is a major causative agent of hand, foot and mouth disease (HFMD), a common febrile disease occurring mainly in young children. Although clinical manifestations of HFMD are usually mild and self limiting, a severe EV71 outbreak can lead to a diverse array of neurological diseases. Identification of the specific cellular receptors is crucial for elucidating the mechanism of early virus-host interactions and the pathogenesis of enteroviruses. Here we identify human P-selectin glycoprotein ligand-1 (PSGL-1; CD162), a sialomucin membrane protein expressed on leukocytes that has a major role in early stages of inflammation, as a functional receptor for EV71 using an expression cloning method by panning. The N-terminal region of PSGL-1 binds specifically to EV71. Stable PSGL-1 expression allowed EV71 entry and replication, and development of cytopathic effects in nonsusceptible mouse L929 cells. Five out of eight EV71 strains bound soluble PSGL-1 and used intact PSGL-1 as the primary receptor for infection of Jurkat T cells. Three other EV71 strains did not use PSGL-1, suggesting the presence of strain-specific replication of EV71 in leukocytes. EV71 replicated in nonleukocyte cell lines in a PSGL-1-independent manner, indicating the presence of alternative receptor(s) for EV71. The identification of PSGL-1 as a receptor for EV71 sheds new light on a role for PSGL-1-positive leukocytes in cell tropism and pathogenesis during the course of HFMD and other EV71-mediated diseases.", + "TAG_DATA": [ + "117, Stable {'perturbing_action': 'B-gene gain-of-function'}", + "118, PSGL-1 {'perturbing_action': 'I-gene gain-of-function'}", + "119, expression {'perturbing_action': 'I-gene gain-of-function'}", + "132, mouse {'context': 'B-cells'}", + "133, L929 {'context': 'I-cells'}", + "134, cells. {'context': 'I-cells'}", + "155, Jurkat {'context': 'B-cells'}", + "156, T {'context': 'I-cells'}", + "157, cells. {'context': 'I-cells'}", + "179, nonleukocyte {'context': 'B-cells'}", + "180, cell {'context': 'I-cells'}", + "181, lines {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "117, Stable ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "118, PSGL-1 ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "119, expression ['l1', 'l7', 'l12', 'l13', 'l14']", + "132, mouse ['l2', 'l8', 'l12', 'l15', 'l16']", + "133, L929 ['l3', 'l9', 'l13', 'l15', 'l17']", + "134, cells. ['l4', 'l10', 'l14', 'l16', 'l17']", + "155, Jurkat ['l18', 'l19']", + "156, T ['l5', 'l18', 'l20']", + "157, cells. ['l6', 'l11', 'l19', 'l20']", + "179, nonleukocyte ['l21', 'l22']", + "180, cell ['l21', 'l23']", + "181, lines ['l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Stable", + "PSGL-1", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "L929", + "cells.", + "T" + ] + } + } + ] + }, + { + "PMID": "19543282", + "TEXT": "Enterovirus 71 (EV71) belongs to human enterovirus species A of the genus Enterovirus within the family Picornaviridae. EV71, together with coxsackievirus A16 (CVA16), are most frequently associated with hand, foot and mouth disease (HFMD). Although HFMD is considered a mild exanthematous infection, infections involving EV71, but not CVA16, can progress to severe neurological disease, including fatal encephalitis, aseptic meningitis and acute flaccid paralysis. In recent years, epidemic and sporadic outbreaks of neurovirulent EV71 infections have been reported in Taiwan, Malaysia, Singapore, Japan and China. Here, we show that human scavenger receptor class B, member 2 (SCARB2, also known as lysosomal integral membrane protein II or CD36b like-2) is a receptor for EV71. EV71 binds soluble SCARB2 or cells expressing SCARB2, and the binding is inhibited by an antibody to SCARB2. Expression of human SCARB2 enables normally unsusceptible cell lines to support EV71 propagation and develop cytopathic effects. EV71 infection is hampered by the antibody to SCARB2 and soluble SCARB2. SCARB2 also supports the infection of the milder pathogen CVA16. The identification of SCARB2 as an EV71 and CVA16 receptor contributes to a better understanding of the pathogenicity of these viruses.", + "TAG_DATA": [ + "117, cells {'context': 'B-cells'}", + "130, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "131, of {'perturbing_action': 'I-gene gain-of-function'}", + "132, human {'perturbing_action': 'I-gene gain-of-function'}", + "133, SCARB2 {'perturbing_action': 'I-gene gain-of-function'}", + "137, cell {'context': 'B-cells'}", + "138, lines {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "130, Expression ['l0', 'l1', 'l2', 'l3', 'l4']", + "131, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "132, human ['l1', 'l5', 'l9', 'l10', 'l11']", + "133, SCARB2 ['l2', 'l6', 'l9', 'l12', 'l13']", + "137, cell ['l3', 'l7', 'l10', 'l12', 'l14']", + "138, lines ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "human", + "SCARB2" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "lines" + ] + } + } + ] + }, + { + "PMID": "19525965", + "TEXT": "Neutralizing antibodies are thought to be crucial for HIV vaccine protection, but studies in animal models suggest that high antibody concentrations are required. This is a major potential hurdle for vaccine design. However, these studies typically apply a large virus inoculum to ensure infection in control animals in single-challenge experiments. In contrast, most human infection via sexual encounter probably involves repeated exposures to much lower doses of virus. Therefore, animal studies may have provided an overestimate of the levels of antibodies required for protection in humans. We investigated whether plasma concentrations of antibody corresponding to relatively modest neutralization titers in vitro could protect macaques from repeated intravaginal exposure to low doses of a simian immunodeficiency virus-HIV chimera (SHIV) that uses the CC chemokine receptor 5 (CCR5) co-receptor. An effector function-deficient variant of the neutralizing antibody was also included. The results show that a substantially larger number of challenges is required to infect macaques treated with neutralizing antibody than control antibody-treated macaques, and support the notion that effector function may contribute to antibody protection. Overall, the results imply that lower amounts of antibody than previously considered protective may provide benefit in the context of typical human exposure to HIV-1.", + "TAG_DATA": [ + "103, macaques {'context': 'B-organism'}", + "128, effector {'perturbing_action': 'B-gene loss-of-function'}", + "129, function-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "152, macaques {'context': 'B-organism'}", + "160, macaques, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "128, effector ['l0', 'l1', 'l2']", + "129, function-deficient ['l0', 'l3', 'l4']", + "152, macaques ['l1', 'l3', 'l5']", + "160, macaques, ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "effector", + "function-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "macaques", + "macaques," + ] + } + } + ] + }, + { + "PMID": "19525962", + "TEXT": "Self-renewing cell populations such as hematopoietic stem cells and memory B and T lymphocytes might be regulated by shared signaling pathways. The Wnt-beta-catenin pathway is an evolutionarily conserved pathway that promotes hematopoietic stem cell self-renewal and multipotency by limiting stem cell proliferation and differentiation, but its role in the generation and maintenance of memory T cells is unknown. We found that induction of Wnt-beta-catenin signaling by inhibitors of glycogen sythase kinase-3beta or the Wnt protein family member Wnt3a arrested CD8(+) T cell development into effector cells. By blocking T cell differentiation, Wnt signaling promoted the generation of CD44(low)CD62L(high)Sca-1(high)CD122(high)Bcl-2(high) self-renewing multipotent CD8(+) memory stem cells with proliferative and antitumor capacities exceeding those of central and effector memory T cell subsets. These findings reveal a key role for Wnt signaling in the maintenance of 'stemness' in mature memory CD8(+) T cells and have major implications for the design of new vaccination strategies and adoptive immunotherapies.", + "TAG_DATA": [ + "66, inhibitors {'perturbing_action': 'B-pharmacological inhibition'}", + "67, of {'perturbing_action': 'I-pharmacological inhibition'}", + "68, glycogen {'perturbing_action': 'I-pharmacological inhibition'}", + "69, sythase {'perturbing_action': 'I-pharmacological inhibition'}", + "70, kinase-3beta {'perturbing_action': 'I-pharmacological inhibition'}", + "71, or {'perturbing_action': 'I-pharmacological inhibition'}", + "72, the {'perturbing_action': 'I-pharmacological inhibition'}", + "77, Wnt3a {'perturbing_action': 'I-pharmacological inhibition'}", + "79, CD8(+) {'context': 'B-cells'}", + "80, T {'context': 'I-cells'}", + "81, cell {'context': 'I-cells'}", + "85, cells. {'context': 'I-cells'}", + "87, blocking {'effect': 'B-negative'}", + "88, T {'context': 'B-cells'}", + "89, cell {'context': 'B-cells'}", + "90, differentiation, {'phenotype': 'B-differentiation'}", + "100, CD8(+) {'context': 'B-cells'}", + "101, memory {'context': 'I-cells'}", + "102, stem {'context': 'I-cells'}", + "103, cells {'context': 'I-cells'}", + "112, central {'context': 'B-cells'}", + "113, and {'context': 'I-cells'}", + "114, effector {'context': 'I-cells'}", + "115, memory {'context': 'I-cells'}", + "116, T {'context': 'I-cells'}", + "117, cell {'context': 'I-cells'}", + "118, subsets. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "66, inhibitors ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "67, of ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "68, glycogen ['l1', 'l16', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "69, sythase ['l2', 'l17', 'l31', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "70, kinase-3beta ['l3', 'l18', 'l32', 'l45', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "71, or ['l4', 'l19', 'l33', 'l46', 'l58', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "72, the ['l5', 'l20', 'l34', 'l47', 'l59', 'l70', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "73, Wnt ['l6', 'l21', 'l35', 'l48', 'l60', 'l71', 'l81', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "77, Wnt3a ['l7', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "79, CD8(+) ['l8', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l100', 'l108', 'l109', 'l110']", + "80, T ['l9', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l108', 'l111', 'l112']", + "81, cell ['l10', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l111', 'l113']", + "85, cells. ['l11', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l112', 'l113']", + "87, blocking ['l12', 'l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l114', 'l115', 'l116']", + "88, T ['l13', 'l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l114', 'l117', 'l118']", + "89, cell ['l14', 'l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l115', 'l117', 'l119']", + "90, differentiation, ['l15', 'l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l116', 'l118', 'l119']", + "100, CD8(+) ['l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "101, memory ['l120', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "102, stem ['l121', 'l130', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "103, cells ['l122', 'l131', 'l139']", + "112, central ['l123', 'l132', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150']", + "113, and ['l124', 'l133', 'l140', 'l145', 'l151', 'l152', 'l153', 'l154', 'l155']", + "114, effector ['l125', 'l134', 'l146', 'l151', 'l156', 'l157', 'l158', 'l159']", + "115, memory ['l126', 'l135', 'l141', 'l147', 'l152', 'l156', 'l160', 'l161', 'l162']", + "116, T ['l127', 'l136', 'l142', 'l148', 'l153', 'l157', 'l160', 'l163', 'l164']", + "117, cell ['l128', 'l137', 'l143', 'l149', 'l154', 'l158', 'l161', 'l163', 'l165']", + "118, subsets. ['l129', 'l138', 'l144', 'l150', 'l155', 'l159', 'l162', 'l164', 'l165']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "glycogen", + "sythase", + "kinase-3beta", + "or", + "the", + "Wnt3a" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "T", + "cell", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "glycogen", + "sythase", + "kinase-3beta", + "or", + "the", + "Wnt3a" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocking" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "glycogen", + "sythase", + "kinase-3beta", + "or", + "the", + "Wnt3a" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocking" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocking" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + } + ] + }, + { + "PMID": "19525961", + "TEXT": "The immunoproteasome, a distinct class of proteasome found predominantly in monocytes and lymphocytes, is known to shape the antigenic repertoire presented on class I major histocompatibility complexes (MHC-I). However, a specific role for the immunoproteasome in regulating other facets of immune responses has not been established. We describe here the characterization of PR-957, a selective inhibitor of low-molecular mass polypeptide-7 (LMP7, encoded by Psmb8), the chymotrypsin-like subunit of the immunoproteasome. PR-957 blocked presentation of LMP7-specific, MHC-I-restricted antigens in vitro and in vivo. Selective inhibition of LMP7 by PR-957 blocked production of interleukin-23 (IL-23) by activated monocytes and interferon-gamma and IL-2 by T cells. In mouse models of rheumatoid arthritis, PR-957 treatment reversed signs of disease and resulted in reductions in cellular infiltration, cytokine production and autoantibody levels. These studies reveal a unique role for LMP7 in controlling pathogenic immune responses and provide a therapeutic rationale for targeting LMP7 in autoimmune disorders.", + "TAG_DATA": [ + "77, in {'context': 'B-in vitro'}", + "78, vitro {'context': 'I-in vitro'}", + "80, in {'context': 'B-in vivo'}", + "81, vivo. {'context': 'I-in vivo'}", + "82, Selective {'perturbing_action': 'B-pharmacological inhibition'}", + "83, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "84, of {'perturbing_action': 'I-pharmacological inhibition'}", + "85, LMP7 {'perturbing_action': 'I-pharmacological inhibition'}", + "86, by {'perturbing_action': 'I-pharmacological inhibition'}", + "87, PR-957 {'perturbing_action': 'I-pharmacological inhibition'}", + "95, monocytes {'context': 'B-cells'}", + "101, T {'context': 'B-cells'}", + "102, cells. {'context': 'B-cells'}", + "104, mouse {'context': 'B-organism'}", + "105, models {'context': 'I-organism'}", + "106, of {'context': 'I-organism'}", + "107, rheumatoid {'context': 'I-organism'}", + "108, arthritis, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "77, in ['l0']", + "78, vitro ['l0']", + "80, in ['l1', 'l2', 'l3']", + "81, vivo. ['l1', 'l4', 'l5']", + "82, Selective ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "83, inhibition ['l6', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "84, of ['l7', 'l19', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "85, LMP7 ['l8', 'l20', 'l31', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "86, by ['l9', 'l21', 'l32', 'l42', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "87, PR-957 ['l10', 'l22', 'l33', 'l43', 'l51', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "95, monocytes ['l2', 'l4', 'l11', 'l23', 'l34', 'l44', 'l52', 'l59', 'l66', 'l67']", + "101, T ['l12', 'l24', 'l35', 'l45', 'l53', 'l60', 'l66', 'l68']", + "102, cells. ['l3', 'l5', 'l13', 'l25', 'l36', 'l46', 'l54', 'l61', 'l67', 'l68']", + "104, mouse ['l14', 'l26', 'l37', 'l69', 'l70', 'l71', 'l72']", + "105, models ['l15', 'l27', 'l38', 'l47', 'l55', 'l62', 'l69', 'l73', 'l74', 'l75']", + "106, of ['l16', 'l28', 'l39', 'l48', 'l56', 'l63', 'l70', 'l73', 'l76', 'l77']", + "107, rheumatoid ['l17', 'l29', 'l40', 'l49', 'l57', 'l64', 'l71', 'l74', 'l76', 'l78']", + "108, arthritis, ['l18', 'l30', 'l41', 'l50', 'l58', 'l65', 'l72', 'l75', 'l77', 'l78']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Selective", + "inhibition", + "of", + "LMP7", + "by", + "PR-957" + ] + }, + "context": { + "val": "cells", + "words": [ + "monocytes", + "T", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Selective", + "inhibition", + "of", + "LMP7", + "by", + "PR-957" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "of", + "rheumatoid", + "arthritis," + ] + } + } + ] + }, + { + "PMID": "19465927", + "TEXT": "Staphylococcal superantigens are pyrogenic exotoxins that cause massive T cell activation leading to toxic shock syndrome and death. Despite the strong adaptive immune response induced by these toxins, infections by superantigen-producing staphylococci are very common clinical events. We hypothesized that this may be partly a result of staphylococcal strains having developed strategies that downregulate the T cell response to these toxins. Here we show that the human interleukin-2 response to staphylococcal superantigens is inhibited by the simultaneous presence of bacteria. Such a downregulatory effect is the result of peptidoglycan-embedded molecules binding to Toll-like receptor 2 and inducing interleukin-10 production and apoptosis of antigen-presenting cells. We corroborated these findings in vivo by showing substantial prevention of mortality after simultaneous administration of staphylococcal enterotoxin B with either heat-killed staphylococci or Staphylococcus aureus peptidoglycan in mouse models of superantigen-induced toxic shock syndrome.", + "TAG_DATA": [ + "96, inducing {'effect': 'B-positive'}", + "100, apoptosis {'phenotype': 'B-apoptosis'}", + "102, antigen-presenting {'context': 'B-cells'}", + "103, cells. {'context': 'I-cells'}", + "108, in {'context': 'B-in vivo'}", + "109, vivo {'context': 'I-in vivo'}", + "132, mouse {'context': 'B-organism'}", + "133, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "96, inducing ['l0', 'l1', 'l2', 'l3']", + "100, apoptosis ['l0', 'l4', 'l5']", + "102, antigen-presenting ['l1', 'l4', 'l6']", + "103, cells. ['l2', 'l5', 'l6']", + "108, in ['l7', 'l8']", + "109, vivo ['l3', 'l7', 'l9']", + "132, mouse ['l10']", + "133, models ['l8', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "cells", + "words": [ + "antigen-presenting", + "cells." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "antigen-presenting", + "cells." + ] + } + } + ] + }, + { + "PMID": "19377486", + "TEXT": "H2A histone family member X (H2AX, encoded by H2AFX) and its C-terminal phosphorylation (gamma-H2AX) participates in the DNA damage response and mediates DNA repair. Hypoxia is a physiological stress that induces a replication-associated DNA damage response. Moreover, hypoxia is the major driving force for neovascularization, as the hypoxia-mediated induction of vascular growth factors triggers endothelial cell proliferation. Here we studied the role of the hypoxia-induced DNA damage response in endothelial cell function and in hypoxia-driven neovascularization in vivo. Hypoxia induced replication-associated generation of gamma-H2AX in endothelial cells in vitro and in mice. Both in cultured cells and in mice, endothelial cell proliferation under hypoxic conditions was reduced by H2AX deficiency. Whereas developmental angiogenesis was not affected in H2afx(-/-) mice, hypoxia-induced neovascularization during pathologic proliferative retinopathy, in response to hind limb ischemia or during tumor angiogenesis was substantially lower in H2afx(-/-) mice. Moreover, endothelial-specific H2afx deletion resulted in reduced hypoxia-driven retina neovascularization and tumor neovascularization. Our findings establish that H2AX, and hence activation of the DNA repair response, is needed for endothelial cells to maintain their proliferation under hypoxic conditions and is crucial for hypoxia-driven neovascularization.", + "TAG_DATA": [ + "85, endothelial {'context': 'B-cells'}", + "86, cells {'context': 'I-cells'}", + "87, in {'context': 'B-in vitro'}", + "88, vitro {'context': 'I-in vitro'}", + "91, mice. {'context': 'B-organism'}", + "94, cultured {'context': 'B-cells'}", + "95, cells {'context': 'I-cells'}", + "98, mice, {'context': 'B-organism'}", + "99, endothelial {'context': 'B-cells'}", + "100, cell {'context': 'I-cells'}", + "101, proliferation {'phenotype': 'B-proliferation'}", + "106, reduced {'effect': 'B-negative'}", + "108, H2AX {'perturbing_action': 'B-gene loss-of-function'}", + "109, deficiency. {'perturbing_action': 'I-gene loss-of-function'}", + "117, H2afx(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "118, mice, {'context': 'B-organism'}", + "139, H2afx(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "140, mice. {'context': 'B-organism'}", + "142, endothelial-specific {'perturbing_action': 'B-gene loss-of-function'}", + "143, H2afx {'perturbing_action': 'I-gene loss-of-function'}", + "144, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "152, tumor {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "85, endothelial ['l0', 'l1', 'l2', 'l3']", + "86, cells ['l0', 'l4', 'l5']", + "87, in ['l1', 'l4', 'l6']", + "88, vitro ['l2', 'l5', 'l6']", + "91, mice. ['l3', 'l7', 'l8']", + "94, cultured ['l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "95, cells ['l7', 'l9', 'l15', 'l16', 'l17', 'l18']", + "98, mice, ['l10', 'l15', 'l19', 'l20', 'l21', 'l22', 'l23']", + "99, endothelial ['l11', 'l16', 'l19', 'l24', 'l25', 'l26', 'l27']", + "100, cell ['l8', 'l12', 'l17', 'l20', 'l24', 'l28', 'l29']", + "101, proliferation ['l13', 'l18', 'l21', 'l25', 'l28', 'l30', 'l31']", + "106, reduced ['l22', 'l26', 'l30', 'l32', 'l33', 'l34', 'l35']", + "108, H2AX ['l32', 'l36', 'l37', 'l38']", + "109, deficiency. ['l14', 'l23', 'l27', 'l29', 'l31', 'l33', 'l36', 'l39', 'l40']", + "117, H2afx(-/-) ['l34', 'l37', 'l39', 'l41', 'l42', 'l43']", + "118, mice, ['l35', 'l38', 'l40', 'l41', 'l44']", + "139, H2afx(-/-) ['l42', 'l44', 'l45']", + "140, mice. ['l43', 'l45']", + "142, endothelial-specific ['l46', 'l47', 'l48', 'l49']", + "143, H2afx ['l46', 'l50', 'l51', 'l52']", + "144, deletion ['l47', 'l50', 'l53', 'l54']", + "149, retina ['l48', 'l51', 'l53', 'l55']", + "152, tumor ['l49', 'l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cultured", + "cells", + "endothelial", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "endothelial", + "cell" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice,", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency.", + "H2AX", + "H2afx(-/-)" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "H2AX", + "deficiency.", + "H2afx(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "endothelial-specific", + "H2afx", + "deletion" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + } + ] + }, + { + "PMID": "19330007", + "TEXT": "Barrier epithelial cells and airway dendritic cells (DCs) make up the first line of defense against inhaled substances such as house dust mite (HDM) allergen and endotoxin (lipopolysaccharide, LPS). We hypothesized that these cells need to communicate with each other to cause allergic disease. We show in irradiated chimeric mice that Toll-like receptor 4 (TLR4) expression on radioresistant lung structural cells, but not on DCs, is necessary and sufficient for DC activation in the lung and for priming of effector T helper responses to HDM. TLR4 triggering on structural cells caused production of the innate proallergic cytokines thymic stromal lymphopoietin, granulocyte-macrophage colony-stimulating factor, interleukin-25 and interleukin-33. The absence of TLR4 on structural cells, but not on hematopoietic cells, abolished HDM-driven allergic airway inflammation. Finally, inhalation of a TLR4 antagonist to target exposed epithelial cells suppressed the salient features of asthma, including bronchial hyperreactivity. Our data identify an innate immune function of airway epithelial cells that drives allergic inflammation via activation of mucosal DCs.", + "TAG_DATA": [ + "48, chimeric {'context': 'B-organism'}", + "49, mice {'context': 'I-organism'}", + "88, structural {'context': 'B-cells'}", + "89, cells {'context': 'I-cells'}", + "107, absence {'perturbing_action': 'B-gene loss-of-function'}", + "108, of {'perturbing_action': 'I-gene loss-of-function'}", + "109, TLR4 {'perturbing_action': 'I-gene loss-of-function'}", + "111, structural {'context': 'B-cells'}", + "112, cells, {'context': 'I-cells'}", + "116, hematopoietic {'context': 'B-cells'}", + "117, cells, {'context': 'I-cells'}", + "127, TLR4 {'perturbing_action': 'B-pharmacological inhibition'}", + "128, antagonist {'perturbing_action': 'I-pharmacological inhibition'}", + "132, epithelial {'context': 'B-cells'}", + "133, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "48, chimeric ['l0', 'l1', 'l2']", + "49, mice ['l0', 'l3']", + "88, structural ['l1', 'l4', 'l5', 'l6']", + "89, cells ['l2', 'l3', 'l4']", + "107, absence ['l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "108, of ['l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "109, TLR4 ['l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "111, structural ['l5', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "112, cells, ['l6', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "116, hematopoietic ['l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "117, cells, ['l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "127, TLR4 ['l28', 'l29', 'l30']", + "128, antagonist ['l28', 'l31', 'l32']", + "132, epithelial ['l29', 'l31', 'l33']", + "133, cells ['l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "TLR4" + ] + }, + "context": { + "val": "cells", + "words": [ + "structural", + "cells,", + "hematopoietic" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "TLR4", + "antagonist" + ] + }, + "context": { + "val": "cells", + "words": [ + "epithelial", + "cells" + ] + } + } + ] + }, + { + "PMID": "19305414", + "TEXT": "The myeloperoxidase (MPO) system of activated phagocytes is central to normal host defense mechanisms, and dysregulated MPO contributes to the pathogenesis of inflammatory disease states ranging from atherosclerosis to cancer. Here we show that upon systemic administration, the small molecule luminol enables noninvasive bioluminescence imaging (BLI) of MPO activity in vivo. Luminol-BLI allowed quantitative longitudinal monitoring of MPO activity in animal models of acute dermatitis, mixed allergic contact hypersensitivity, focal arthritis and spontaneous large granular lymphocytic tumors. Bioluminescence colocalized with histological sites of inflammation and was totally abolished in gene-deleted Mpo(-/-) mice, despite massive tissue infiltration of neutrophils and activated eosinophils, indicating that eosinophil peroxidase did not contribute to luminol-BLI in vivo. Thus, luminol-BLI provides a noninvasive, specific and highly sensitive optical readout of phagocyte-mediated MPO activity in vivo and may enable new diagnostic applications in a wide range of acute and chronic inflammatory conditions.", + "TAG_DATA": [ + "89, gene-deleted {'perturbing_action': 'B-gene loss-of-function'}", + "90, Mpo(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "91, mice, {'context': 'B-organism'}", + "100, eosinophils, {'context': 'B-cells'}", + "110, in {'context': 'B-in vivo'}", + "111, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "89, gene-deleted ['l0', 'l1', 'l2']", + "90, Mpo(-/-) ['l0', 'l3', 'l4']", + "91, mice, ['l1', 'l3']", + "100, eosinophils, ['l2', 'l4', 'l5', 'l6']", + "110, in ['l5', 'l7']", + "111, vivo. ['l6', 'l7']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "gene-deleted", + "Mpo(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "gene-deleted", + "Mpo(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "eosinophils," + ] + } + } + ] + }, + { + "PMID": "19287392", + "TEXT": "Animals are remarkably efficient in absorbing dietary fat and assimilating this energy-dense nutrient into the white adipose tissue (WAT) for storage. Although this metabolic efficiency may confer an advantage in times of calorie deprivation, it contributes to obesity and associated metabolic disorders when dietary fat is abundant. Here we show that the intestinal lipid synthesis enzyme acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) has a crucial role in the assimilation of dietary fat and the accretion of body fat in mice. Mice lacking MGAT2 have a normal phenotype on a low-fat diet. However, on a high-fat diet, MGAT2-deficient mice are protected against developing obesity, glucose intolerance, hypercholesterolemia and fatty livers. Caloric intake is normal in MGAT2-deficient mice, and dietary fat is absorbed fully. However, entry of dietary fat into the circulation occurs at a reduced rate. This altered kinetics of fat absorption apparently results in more partitioning of dietary fat toward energy dissipation rather than toward storage in the WAT. Thus, our studies identify MGAT2 as a key determinant of energy metabolism in response to dietary fat and suggest that the inhibition of this enzyme may prove to be a useful strategy for treating obesity and other metabolic diseases associated with excessive fat intake.", + "TAG_DATA": [ + "78, Mice {'context': 'B-organism'}", + "79, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "80, MGAT2 {'perturbing_action': 'I-gene loss-of-function'}", + "94, MGAT2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "95, mice {'context': 'B-organism'}", + "112, MGAT2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "113, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "78, Mice ['l0', 'l1']", + "79, lacking ['l0', 'l2']", + "80, MGAT2 ['l1', 'l2']", + "94, MGAT2-deficient ['l3', 'l4', 'l5']", + "95, mice ['l3']", + "112, MGAT2-deficient ['l4', 'l6']", + "113, mice, ['l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice", + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "MGAT2", + "MGAT2-deficient" + ] + } + } + ] + }, + { + "PMID": "19287391", + "TEXT": "Amyloid-beta (Abeta) peptides, found in Alzheimer's disease brain, accumulate rapidly after traumatic brain injury (TBI) in both humans and animals. Here we show that blocking either beta- or gamma-secretase, enzymes required for production of Abeta from amyloid precursor protein (APP), can ameliorate motor and cognitive deficits and reduce cell loss after experimental TBI in mice. Thus, APP secretases are promising targets for treatment of TBI.", + "TAG_DATA": [ + "24, blocking {'perturbing_action': 'B-pharmacological inhibition'}", + "47, reduce {'effect': 'B-negative'}", + "48, cell {'phenotype': 'B-cell death'}", + "49, loss {'phenotype': 'I-cell death'}", + "54, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "24, blocking ['l0', 'l1', 'l2', 'l3']", + "47, reduce ['l0', 'l4', 'l5', 'l6']", + "48, cell ['l1', 'l4', 'l7', 'l8']", + "49, loss ['l2', 'l5', 'l7', 'l9']", + "54, mice. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blocking" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduce" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blocking" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "loss" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blocking" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduce" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "loss" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduce" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "loss" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "19169264", + "TEXT": "The role of transient receptor potential M4 (Trpm4), an unusual member of the Trp family of ion channels, is poorly understood. Using rodent models of spinal cord injury, we studied involvement of Trpm4 in the progressive expansion of secondary hemorrhage associated with capillary fragmentation, the most destructive mechanism of secondary injury in the central nervous system. Trpm4 mRNA and protein were abundantly upregulated in capillaries preceding their fragmentation and formation of petechial hemorrhages. Trpm4 expression in vitro rendered COS-7 cells highly susceptible to oncotic swelling and oncotic death following ATP depletion. After spinal cord injury, in vivo gene suppression in rats treated with Trpm4 antisense or in Trpm4(-/-) mice preserved capillary structural integrity, eliminated secondary hemorrhage, yielded a threefold to fivefold reduction in lesion volume and produced a substantial improvement in neurological function. To our knowledge, this is the first example of a Trp channel that must undergo de novo expression for manifestation of central nervous system pathology.", + "TAG_DATA": [ + "75, in {'context': 'B-in vitro'}", + "76, vitro {'context': 'I-in vitro'}", + "78, COS-7 {'context': 'B-cells'}", + "79, cells {'context': 'I-cells'}", + "95, in {'context': 'B-in vivo'}", + "96, vivo {'context': 'I-in vivo'}", + "97, gene {'perturbing_action': 'B-rnai/knockdown'}", + "98, suppression {'perturbing_action': 'I-rnai/knockdown'}", + "100, rats {'context': 'B-organism'}", + "103, Trpm4 {'perturbing_action': 'B-rnai/knockdown'}", + "104, antisense {'perturbing_action': 'I-rnai/knockdown'}", + "107, Trpm4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "108, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "75, in ['l0', 'l1', 'l2']", + "76, vitro ['l0', 'l3', 'l4']", + "78, COS-7 ['l1', 'l3', 'l5']", + "79, cells ['l2', 'l4', 'l5']", + "95, in ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "96, vivo ['l6', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "97, gene ['l7', 'l12', 'l18', 'l19', 'l20', 'l21']", + "98, suppression ['l8', 'l13', 'l18', 'l22', 'l23', 'l24']", + "100, rats ['l9', 'l14', 'l19', 'l22', 'l25', 'l26']", + "103, Trpm4 ['l10', 'l15', 'l20', 'l23', 'l25', 'l27', 'l28']", + "104, antisense ['l11', 'l16', 'l21', 'l24', 'l26', 'l27']", + "107, Trpm4(-/-) ['l29']", + "108, mice ['l17', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "gene", + "suppression", + "Trpm4", + "antisense" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "gene", + "suppression", + "Trpm4", + "antisense" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trpm4(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "19136964", + "TEXT": "A main function of white adipose tissue is to release fatty acids from stored triacylglycerol for other tissues to use as an energy source. Whereas endocrine regulation of lipolysis has been extensively studied, autocrine and paracrine regulation is not well understood. Here we describe the role of the newly identified major adipocyte phospholipase A(2), AdPLA (encoded by Pla2g16, also called HREV107), in the regulation of lipolysis and adiposity. AdPLA-null mice have a markedly higher rate of lipolysis owing to increased cyclic AMP levels arising from the marked reduction in the amount of adipose prostaglandin E(2) that binds the Galpha(i)-coupled receptor, EP3. AdPLA-null mice have markedly reduced adipose tissue mass and triglyceride content but normal adipogenesis. They also have higher energy expenditure with increased fatty acid oxidation within adipocytes. AdPLA-deficient ob/ob mice remain hyperphagic but lean, with increased energy expenditure, yet have ectopic triglyceride storage and insulin resistance. AdPLA is a major regulator of adipocyte lipolysis and is crucial for the development of obesity.", + "TAG_DATA": [ + "68, AdPLA-null {'perturbing_action': 'B-gene loss-of-function'}", + "69, mice {'context': 'B-organism'}", + "101, AdPLA-null {'perturbing_action': 'B-gene loss-of-function'}", + "102, mice {'context': 'B-organism'}", + "127, adipocytes. {'context': 'B-cells'}", + "128, AdPLA-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "129, ob/ob {'perturbing_action': 'B-gene loss-of-function', 'context': 'B-organism'}", + "130, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "68, AdPLA-null ['l0']", + "69, mice ['l0']", + "101, AdPLA-null ['l1', 'l2']", + "102, mice ['l1']", + "127, adipocytes. ['l2']", + "128, AdPLA-deficient ['l3', 'l4']", + "129, ob/ob ['l3', 'l5']", + "130, mice ['l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "AdPLA-null", + "AdPLA-deficient", + "ob/ob" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "ob/ob" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "AdPLA-null" + ] + }, + "context": { + "val": "cells", + "words": [ + "adipocytes." + ] + } + } + ] + }, + { + "PMID": "19136963", + "TEXT": "Ethylmalonic encephalopathy is an autosomal recessive, invariably fatal disorder characterized by early-onset encephalopathy, microangiopathy, chronic diarrhea, defective cytochrome c oxidase (COX) in muscle and brain, high concentrations of C4 and C5 acylcarnitines in blood and high excretion of ethylmalonic acid in urine. ETHE1, a gene encoding a beta-lactamase-like, iron-coordinating metalloprotein, is mutated in ethylmalonic encephalopathy. In bacteria, ETHE1-like sequences are in the same operon of, or fused with, orthologs of TST, the gene encoding rhodanese, a sulfurtransferase. In eukaryotes, both ETHE1 and rhodanese are located within the mitochondrial matrix. We created a Ethe1(-/-) mouse that showed the cardinal features of ethylmalonic encephalopathy. We found that thiosulfate was excreted in massive amounts in urine of both Ethe1(-/-) mice and humans with ethylmalonic encephalopathy. High thiosulfate and sulfide concentrations were present in Ethe1(-/-) mouse tissues. Sulfide is a powerful inhibitor of COX and short-chain fatty acid oxidation, with vasoactive and vasotoxic effects that explain the microangiopathy in ethylmalonic encephalopathy patients. Sulfide is detoxified by a mitochondrial pathway that includes a sulfur dioxygenase. Sulfur dioxygenase activity was absent in Ethe1(-/-) mice, whereas it was markedly increased by ETHE1 overexpression in HeLa cells and Escherichia coli. Therefore, ETHE1 is a mitochondrial sulfur dioxygenase involved in catabolism of sulfide that accumulates to toxic levels in ethylmalonic encephalopathy.", + "TAG_DATA": [ + "92, Ethe1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "93, mouse {'context': 'B-organism'}", + "115, Ethe1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "116, mice {'context': 'B-organism'}", + "130, Ethe1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "131, mouse {'context': 'B-tissue/organ'}", + "132, tissues. {'context': 'I-tissue/organ'}", + "176, Ethe1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "177, mice, {'context': 'B-organism'}", + "184, ETHE1 {'perturbing_action': 'B-gene gain-of-function'}", + "185, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "187, HeLa {'context': 'B-transformed cells'}", + "188, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "92, Ethe1(-/-) ['l0', 'l1', 'l2']", + "93, mouse ['l0', 'l3', 'l4']", + "115, Ethe1(-/-) ['l1', 'l3', 'l5', 'l6']", + "116, mice ['l2', 'l4', 'l5', 'l7']", + "118, humans ['l6', 'l7']", + "130, Ethe1(-/-) ['l8', 'l9']", + "131, mouse ['l8', 'l10']", + "132, tissues. ['l9', 'l10']", + "176, Ethe1(-/-) ['l11', 'l12', 'l13', 'l14', 'l15']", + "177, mice, ['l11', 'l16', 'l17', 'l18', 'l19']", + "184, ETHE1 ['l12', 'l16', 'l20', 'l21', 'l22']", + "185, overexpression ['l13', 'l17', 'l20', 'l23', 'l24']", + "187, HeLa ['l14', 'l18', 'l21', 'l23', 'l25']", + "188, cells ['l15', 'l19', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ethe1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ethe1(-/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "tissues." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ethe1(-/-)" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HeLa", + "cells" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ETHE1", + "overexpression" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ETHE1", + "overexpression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HeLa", + "cells" + ] + } + } + ] + }, + { + "PMID": "19060905", + "TEXT": "The extracellular-regulated kinases ERK1 and ERK2 (commonly referred to as ERK1/2) have a crucial role in cardiac hypertrophy. ERK1/2 is activated by mitogen-activated protein kinase kinase-1 (MEK1) and MEK2 (commonly referred to as MEK1/2)-dependent phosphorylation in the TEY motif of the activation loop, but how ERK1/2 is targeted toward specific substrates is not well understood. Here we show that autophosphorylation of ERK1/2 on Thr188 directs ERK1/2 to phosphorylate nuclear targets known to cause cardiac hypertrophy. Thr188 autophosphorylation requires the activation and assembly of the entire Raf-MEK-ERK kinase cascade, phosphorylation of the TEY motif, dimerization of ERK1/2 and binding to G protein betagamma subunits released from activated G(q). Thr188 phosphorylation of ERK1/2 was observed in isolated cardiomyocytes induced to undergo hypertrophic growth, in mice upon stimulation of G(q)-coupled receptors or after aortic banding and in failing human hearts. Experiments using transgenic mouse models carrying mutations at the Thr188 phosphorylation site of ERK2 suggested a causal relationship to cardiac hypertrophy. We propose that specific phosphorylation events on ERK1/2 integrate differing upstream signals (Raf1-MEK1/2 or G protein-coupled receptor-G(q)) to induce cardiac hypertrophy.", + "TAG_DATA": [ + "115, cardiomyocytes {'context': 'B-cells'}", + "122, mice {'context': 'B-organism'}", + "134, failing {'context': 'B-tissue/organ'}", + "135, human {'context': 'I-tissue/organ'}", + "136, hearts. {'context': 'I-tissue/organ'}", + "139, transgenic {'context': 'B-organism'}", + "140, mouse {'context': 'I-organism'}", + "141, models {'context': 'I-organism'}", + "143, mutations {'perturbing_action': 'B-other'}", + "144, at {'perturbing_action': 'I-other'}", + "145, the {'perturbing_action': 'I-other'}", + "146, Thr188 {'perturbing_action': 'I-other'}", + "147, phosphorylation {'perturbing_action': 'I-other'}", + "148, site {'perturbing_action': 'I-other'}", + "149, of {'perturbing_action': 'I-other'}", + "150, ERK2 {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "122, mice ['l0', 'l1', 'l2']", + "134, failing ['l0', 'l3', 'l4']", + "135, human ['l1', 'l3', 'l5']", + "136, hearts. ['l2', 'l4', 'l5']", + "139, transgenic ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "140, mouse ['l6', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "141, models ['l7', 'l16', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "143, mutations ['l8', 'l17', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "144, at ['l9', 'l18', 'l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "145, the ['l10', 'l19', 'l27', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "146, Thr188 ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "147, phosphorylation ['l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57']", + "148, site ['l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l58', 'l59']", + "149, of ['l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58', 'l60']", + "150, ERK2 ['l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mouse", + "models" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutations", + "at", + "the", + "Thr188", + "phosphorylation", + "site", + "of", + "ERK2" + ] + } + } + ] + }, + { + "PMID": "18997777", + "TEXT": "HIV's considerable capacity to vary its HLA-I-restricted peptide antigens allows it to escape from host cytotoxic T lymphocytes (CTLs). Nevertheless, therapeutics able to target HLA-I-associated antigens, with specificity for the spectrum of preferred CTL escape mutants, could prove effective. Here we use phage display to isolate and enhance a T-cell antigen receptor (TCR) originating from a CTL line derived from an infected person and specific for the immunodominant HLA-A(*)02-restricted, HIVgag-specific peptide SLYNTVATL (SL9). High-affinity (K(D) < 400 pM) TCRs were produced that bound with a half-life in excess of 2.5 h, retained specificity, targeted HIV-infected cells and recognized all common escape variants of this epitope. CD8 T cells transduced with this supraphysiologic TCR produced a greater range of soluble factors and more interleukin-2 than those transduced with natural SL9-specific TCR, and they effectively controlled wild-type and mutant strains of HIV at effector-to-target ratios that could be achieved by T-cell therapy.", + "TAG_DATA": [ + "56, CTL {'context': 'B-cells'}", + "57, line {'context': 'I-cells'}", + "94, HIV-infected {'context': 'B-cells'}", + "95, cells {'context': 'I-cells'}", + "105, CD8 {'context': 'B-cells'}", + "106, T {'context': 'I-cells'}", + "107, cells {'context': 'I-cells'}", + "108, transduced {'perturbing_action': 'B-gene gain-of-function'}" + ], + "LINK_DATA": [ + "56, CTL ['l0']", + "57, line ['l0']", + "94, HIV-infected ['l1']", + "95, cells ['l1']", + "105, CD8 ['l2', 'l3', 'l4']", + "106, T ['l2', 'l5', 'l6']", + "107, cells ['l3', 'l5', 'l7']", + "108, transduced ['l4', 'l6', 'l7']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD8", + "T", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced" + ] + } + } + ] + }, + { + "PMID": "18776891", + "TEXT": "We investigated the possibility of using a pharmacologic agent to modulate viral gene expression to target radiotherapy to tumor tissue. In a mouse xenograft model, we had previously shown targeting of [(125)I]2'-fluoro-2'-deoxy-beta-D-5-iodouracil-arabinofuranoside ([(125)I]FIAU) to tumors engineered to express the Epstein-Barr virus thymidine kinase (EBV-TK). Here we extend those results to targeting of a therapeutic radiopharmaceutical [(131)I]FIAU to slow or stop tumor growth or to achieve tumor regression. These outcomes were achieved in xenografts with tumors that constitutively expressed the EBV-TK. With naturally infected EBV tumor cell lines (Burkitt's lymphoma and gastric carcinoma), activation of viral gene expression by pretreatment with bortezomib was required. Marked changes in tumor growth could also be achieved in naturally infected Kaposi's sarcoma herpesvirus tumors after pretreatment with bortezomib. Bortezomib-induced enzyme-targeted radiation therapy illustrates the possibility of pharmacologically modulating tumor gene expression to result in targeted radiotherapy.", + "TAG_DATA": [ + "22, mouse {'context': 'B-xenograft'}", + "23, xenograft {'context': 'I-xenograft'}", + "24, model, {'context': 'I-xenograft'}", + "57, slow {'effect': 'B-negative'}", + "59, stop {'effect': 'B-negative'}", + "60, tumor {'phenotype': 'B-tumour growth'}", + "61, growth {'phenotype': 'I-tumour growth'}", + "64, achieve {'effect': 'B-positive'}", + "65, tumor {'phenotype': 'B-tumour regression'}", + "66, regression. {'phenotype': 'I-tumour regression'}", + "72, xenografts {'context': 'B-xenograft'}", + "74, tumors {'context': 'B-neoplasm'}", + "83, EBV {'context': 'B-transformed cells'}", + "84, tumor {'context': 'I-transformed cells'}", + "85, cell {'context': 'I-transformed cells'}", + "86, lines {'context': 'I-transformed cells'}", + "87, (Burkitt's {'context': 'I-transformed cells'}", + "88, lymphoma {'context': 'I-transformed cells'}", + "89, and {'context': 'I-transformed cells'}", + "90, gastric {'context': 'I-transformed cells'}", + "91, carcinoma), {'context': 'I-transformed cells'}", + "104, changes {'effect': 'B-regulates'}", + "106, tumor {'phenotype': 'B-tumour growth'}", + "107, growth {'phenotype': 'I-tumour growth'}", + "115, Kaposi's {'context': 'B-neoplasm'}", + "116, sarcoma {'context': 'I-neoplasm'}", + "117, herpesvirus {'context': 'I-neoplasm'}", + "118, tumors {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "22, mouse ['l0', 'l1', 'l2', 'l3']", + "23, xenograft ['l0', 'l4', 'l5', 'l6']", + "24, model, ['l1', 'l4', 'l7', 'l8']", + "57, slow ['l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "59, stop ['l9', 'l15', 'l16', 'l17', 'l18', 'l19']", + "60, tumor ['l2', 'l5', 'l7', 'l10', 'l15', 'l20', 'l21', 'l22', 'l23']", + "61, growth ['l3', 'l6', 'l8', 'l11', 'l16', 'l20', 'l24', 'l25', 'l26']", + "64, achieve ['l12', 'l17', 'l21', 'l24', 'l27', 'l28']", + "65, tumor ['l13', 'l18', 'l22', 'l25', 'l27', 'l29']", + "66, regression. ['l14', 'l19', 'l23', 'l26', 'l28', 'l29', 'l30']", + "72, xenografts ['l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "74, tumors ['l31', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "83, EBV ['l38', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "84, tumor ['l39', 'l47', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "85, cell ['l40', 'l48', 'l55', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "86, lines ['l32', 'l41', 'l49', 'l56', 'l62', 'l68', 'l69', 'l70', 'l71', 'l72']", + "87, (Burkitt's ['l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l73', 'l74', 'l75', 'l76']", + "88, lymphoma ['l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l77', 'l78', 'l79']", + "89, and ['l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l80', 'l81']", + "90, gastric ['l36', 'l45', 'l53', 'l60', 'l66', 'l71', 'l75', 'l78', 'l80', 'l82']", + "91, carcinoma), ['l37', 'l46', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l81', 'l82']", + "104, changes ['l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "106, tumor ['l83', 'l89', 'l90', 'l91', 'l92', 'l93']", + "107, growth ['l84', 'l89', 'l94', 'l95', 'l96', 'l97']", + "115, Kaposi's ['l85', 'l90', 'l94', 'l98', 'l99', 'l100']", + "116, sarcoma ['l86', 'l91', 'l95', 'l98', 'l101', 'l102']", + "117, herpesvirus ['l87', 'l92', 'l96', 'l99', 'l101', 'l103']", + "118, tumors ['l88', 'l93', 'l97', 'l100', 'l102', 'l103']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "xenograft", + "words": [ + "mouse", + "xenograft", + "model," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "slow", + "stop" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "slow", + "stop" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "effect": { + "val": "positive", + "words": [ + "achieve" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "achieve" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression." + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression." + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenografts" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "changes" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "changes" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "Kaposi's", + "sarcoma", + "herpesvirus", + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "Kaposi's", + "sarcoma", + "herpesvirus", + "tumors" + ] + } + } + ] + }, + { + "PMID": "18758446", + "TEXT": "The adipocyte-derived hormone leptin maintains energy balance by acting on hypothalamic leptin receptors (Leprs) that act on the signal transducer and activator of transcription 3 (Stat3). Although disruption of Lepr-Stat3 signaling promotes obesity in mice, other features of Lepr function, such as fertility, seem normal, pointing to the involvement of additional regulators. Here we show that the cyclic AMP responsive element-binding protein-1 (Creb1)-regulated transcription coactivator-1 (Crtc1) is required for energy balance and reproduction-Crtc1(-/-) mice are hyperphagic, obese and infertile. Hypothalamic Crtc1 was phosphorylated and inactive in leptin-deficient ob/ob mice, while leptin administration increased amounts of dephosphorylated nuclear Crtc1. Dephosphorylated Crtc1 stimulated expression of the Cartpt and Kiss1 genes, which encode hypothalamic neuropeptides that mediate leptin's effects on satiety and fertility. Crtc1 overexpression in hypothalamic cells increased Cartpt and Kiss1 gene expression, whereas Crtc1 depletion decreased it. Indeed, leptin enhanced Crtc1 activity over the Cartpt and Kiss1 promoters in cells overexpressing Lepr, and these effects were disrupted by expression of a dominant-negative Creb1 polypeptide. As leptin administration increased recruitment of hypothalamic Crtc1 to Cartpt and Kiss1 promoters, our results indicate that the Creb1-Crtc1 pathway mediates the central effects of hormones and nutrients on energy balance and fertility.", + "TAG_DATA": [ + "73, mice {'context': 'B-organism'}", + "86, leptin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "87, ob/ob {'perturbing_action': 'B-gene loss-of-function', 'context': 'B-organism'}", + "88, mice, {'context': 'B-organism'}", + "120, Crtc1 {'perturbing_action': 'B-gene gain-of-function'}", + "121, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "123, hypothalamic {'context': 'B-cells'}", + "124, cells {'context': 'I-cells'}", + "132, Crtc1 {'perturbing_action': 'B-gene loss-of-function'}", + "133, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "148, cells {'context': 'B-cells'}", + "149, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "150, Lepr, {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "73, mice ['l0', 'l1', 'l2']", + "86, leptin-deficient ['l0', 'l3', 'l4']", + "87, ob/ob ['l1', 'l3', 'l5', 'l6']", + "88, mice, ['l2', 'l4', 'l5']", + "120, Crtc1 ['l7', 'l8', 'l9']", + "121, overexpression ['l7', 'l10', 'l11']", + "123, hypothalamic ['l8', 'l10', 'l12']", + "124, cells ['l6', 'l9', 'l11', 'l12']", + "132, Crtc1 ['l13']", + "133, depletion ['l13']", + "148, cells ['l14', 'l15']", + "149, overexpressing ['l14', 'l16']", + "150, Lepr, ['l15', 'l16']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "ob/ob", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "leptin-deficient", + "ob/ob" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ob/ob" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Crtc1", + "overexpression", + "overexpressing", + "Lepr," + ] + }, + "context": { + "val": "cells", + "words": [ + "hypothalamic", + "cells" + ] + } + } + ] + }, + { + "PMID": "18587406", + "TEXT": "Several human progerias, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by the accumulation at the nuclear envelope of farnesylated forms of truncated prelamin A, a protein that is also altered during normal aging. Previous studies in cells from individuals with HGPS have shown that farnesyltransferase inhibitors (FTIs) improve nuclear abnormalities associated with prelamin A accumulation, suggesting that these compounds could represent a therapeutic approach for this devastating progeroid syndrome. We show herein that both prelamin A and its truncated form progerin/LADelta50 undergo alternative prenylation by geranylgeranyltransferase in the setting of farnesyltransferase inhibition, which could explain the low efficiency of FTIs in ameliorating the phenotypes of progeroid mouse models. We also show that a combination of statins and aminobisphosphonates efficiently inhibits both farnesylation and geranylgeranylation of progerin and prelamin A and markedly improves the aging-like phenotypes of mice deficient in the metalloproteinase Zmpste24, including growth retardation, loss of weight, lipodystrophy, hair loss and bone defects. Likewise, the longevity of these mice is substantially extended. These findings open a new therapeutic approach for human progeroid syndromes associated with nuclear-envelope abnormalities.", + "TAG_DATA": [ + "136, mice {'context': 'B-organism'}", + "137, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "138, in {'perturbing_action': 'I-gene loss-of-function'}", + "139, the {'perturbing_action': 'I-gene loss-of-function'}", + "140, metalloproteinase {'perturbing_action': 'I-gene loss-of-function'}", + "141, Zmpste24, {'perturbing_action': 'I-gene loss-of-function'}", + "159, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "136, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "137, deficient ['l0', 'l5', 'l6', 'l7', 'l8', 'l9']", + "138, in ['l1', 'l5', 'l10', 'l11', 'l12', 'l13']", + "139, the ['l2', 'l6', 'l10', 'l14', 'l15', 'l16']", + "140, metalloproteinase ['l3', 'l7', 'l11', 'l14', 'l17', 'l18']", + "141, Zmpste24, ['l4', 'l8', 'l12', 'l15', 'l17', 'l19']", + "159, mice ['l9', 'l13', 'l16', 'l18', 'l19']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "the", + "metalloproteinase", + "Zmpste24," + ] + } + } + ] + }, + { + "PMID": "18454156", + "TEXT": "The function of the C5a receptors, C5ar (encoded by C5ar) and C5l2 (encoded by Gpr77), especially of C5l2, which was originally termed a 'default receptor', remains a controversial topic. Here we investigated the role of each receptor in the setting of cecal ligation and puncture-induced sepsis by using antibody-induced blockade of C5a receptors and knockout mice. In 'mid-grade' sepsis (30-40% survival), blockade or absence of either C5ar or C5l2 greatly improved survival and attenuated the buildup of proinflammatory mediators in plasma. In vivo appearance or in vitro release of high mobility group box 1 protein (HMGB1) required C5l2 but not C5ar. In 'high-grade' sepsis (100% lethality), the only protective condition was the combined blockade of C5l2 and C5ar. These data suggest that C5ar and C5l2 contribute synergistically to the harmful consequences in sepsis and that C5l2 is required for the release of HMGB1. Thus, contrary to earlier speculation, C5l2 is a functional receptor rather than merely a default receptor.", + "TAG_DATA": [ + "55, mice. {'context': 'B-organism'}", + "63, absence {'perturbing_action': 'B-gene loss-of-function'}", + "64, of {'perturbing_action': 'I-gene loss-of-function'}", + "65, either {'perturbing_action': 'I-gene loss-of-function'}", + "66, C5ar {'perturbing_action': 'I-gene loss-of-function'}", + "67, or {'perturbing_action': 'I-gene loss-of-function'}", + "68, C5l2 {'perturbing_action': 'I-gene loss-of-function'}", + "81, In {'context': 'B-in vivo'}", + "82, vivo {'context': 'I-in vivo'}", + "85, in {'context': 'B-in vitro'}", + "86, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "55, mice. ['l0', 'l1', 'l2', 'l3']", + "63, absence ['l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "64, of ['l4', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "65, either ['l0', 'l5', 'l13', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "66, C5ar ['l1', 'l6', 'l14', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "67, or ['l2', 'l7', 'l15', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "68, C5l2 ['l3', 'l8', 'l16', 'l23', 'l28', 'l32', 'l36', 'l37', 'l38']", + "81, In ['l9', 'l17', 'l24', 'l29', 'l33', 'l36', 'l39', 'l40', 'l41']", + "82, vivo ['l10', 'l18', 'l25', 'l30', 'l34', 'l37', 'l39', 'l42', 'l43']", + "85, in ['l11', 'l19', 'l40', 'l42', 'l44']", + "86, vitro ['l12', 'l20', 'l26', 'l31', 'l35', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "either", + "C5ar", + "or", + "C5l2" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "either", + "C5ar", + "or", + "C5l2" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "either", + "C5ar", + "or", + "C5l2" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "18345012", + "TEXT": "Intestinal adhesions are bands of fibrous tissue that connect the loops of the intestine to each other, to other abdominal organs or to the abdominal wall. Fibrous tissue formation is regulated by the balance between plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (tPA), which reciprocally regulate fibrin deposition. Several components of the inflammatory system, including cytokines, chemokines, cell adhesion molecules and neuropeptide substance P, have been reported to participate in adhesion formation. We have used cecal cauterization to develop a unique experimental mouse model of intestinal adhesion. Mice developed severe intestinal adhesion after this treatment. Adhesion development depended upon the interferon-gamma (IFN-gamma) and signal transducer and activator of transcription-1 (STAT1) system. Natural killer T (NKT) cell-deficient mice developed adhesion poorly, whereas they developed severe adhesion after reconstitution with NKT cells from wild-type mice, suggesting that NKT cell IFN-gamma production is indispensable for adhesion formation. This response does not depend on STAT4, STAT6, interleukin-12 (IL-12), IL-18, tumor necrosis factor-alpha, Toll-like receptor 4 or myeloid differentiation factor-88-mediated signals. Wild-type mice increased the ratio of PAI-1 to tPA after cecal cauterization, whereas Ifng(-/-) or Stat1(-/-) mice did not, suggesting that IFN-gamma has a crucial role in the differential regulation of PAI-1 and tPA. Additionally, hepatocyte growth factor, a potent mitogenic factor for hepatocytes, strongly inhibited intestinal adhesion by diminishing IFN-gamma production, providing a potential new way to prevent postoperative adhesions.", + "TAG_DATA": [ + "90, Mice {'context': 'B-organism'}", + "114, Natural {'perturbing_action': 'B-gene loss-of-function'}", + "115, killer {'perturbing_action': 'I-gene loss-of-function'}", + "116, T {'perturbing_action': 'I-gene loss-of-function'}", + "117, (NKT) {'perturbing_action': 'I-gene loss-of-function'}", + "118, cell-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "119, mice {'context': 'B-organism'}", + "131, NKT {'context': 'B-cells'}", + "132, cells {'context': 'I-cells'}", + "135, mice, {'context': 'B-organism'}", + "170, mice {'context': 'B-organism'}", + "182, Ifng(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "183, or {'perturbing_action': 'I-gene loss-of-function'}", + "184, Stat1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "185, mice {'context': 'B-organism'}", + "214, inhibited {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "114, Natural ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "115, killer ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "116, T ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21']", + "117, (NKT) ['l2', 'l10', 'l17', 'l22', 'l23', 'l24', 'l25']", + "118, cell-deficient ['l3', 'l11', 'l18', 'l22', 'l26', 'l27', 'l28']", + "119, mice ['l4', 'l12', 'l19', 'l23', 'l26', 'l29']", + "121, adhesion ['l5', 'l13', 'l20', 'l24', 'l27', 'l29']", + "127, adhesion ['l6', 'l14', 'l21', 'l25', 'l28', 'l30', 'l31', 'l32']", + "131, NKT ['l30', 'l33', 'l34', 'l35']", + "132, cells ['l7', 'l15', 'l31', 'l33', 'l36', 'l37']", + "135, mice, ['l8', 'l16', 'l32', 'l34', 'l36']", + "170, mice ['l35', 'l37']", + "182, Ifng(-/-) ['l38', 'l39', 'l40', 'l41', 'l42']", + "183, or ['l38', 'l43', 'l44', 'l45', 'l46']", + "184, Stat1(-/-) ['l39', 'l43', 'l47', 'l48', 'l49']", + "185, mice ['l40', 'l44', 'l47', 'l50', 'l51']", + "214, inhibited ['l41', 'l45', 'l48', 'l50', 'l52']", + "215, intestinal ['l42', 'l46', 'l49', 'l51', 'l52']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Natural", + "killer", + "T", + "(NKT)", + "cell-deficient", + "Ifng(-/-)", + "or", + "Stat1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Natural", + "killer" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ifng(-/-)", + "or", + "Stat1(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + } + ] + }, + { + "PMID": "18345009", + "TEXT": "The angiogenic sprout has been compared to the growing axon, and indeed, many proteins direct pathfinding by both structures. The Roundabout (Robo) proteins are guidance receptors with well-established functions in the nervous system; however, their role in the mammalian vasculature remains ill defined. Here we show that an endothelial-specific Robo, Robo4, maintains vascular integrity. Activation of Robo4 by Slit2 inhibits vascular endothelial growth factor (VEGF)-165-induced migration, tube formation and permeability in vitro and VEGF-165-stimulated vascular leak in vivo by blocking Src family kinase activation. In mouse models of retinal and choroidal vascular disease, Slit2 inhibited angiogenesis and vascular leak, whereas deletion of Robo4 enhanced these pathologic processes. Our results define a previously unknown function for Robo receptors in stabilizing the vasculature and suggest that activating Robo4 may have broad therapeutic application in diseases characterized by excessive angiogenesis and/or vascular leak.", + "TAG_DATA": [ + "54, Activation {'perturbing_action': 'B-pharmacological augmentation'}", + "55, of {'perturbing_action': 'I-pharmacological augmentation'}", + "56, Robo4 {'perturbing_action': 'I-pharmacological augmentation'}", + "57, by {'perturbing_action': 'I-pharmacological augmentation'}", + "58, Slit2 {'perturbing_action': 'I-pharmacological augmentation'}", + "59, inhibits {'effect': 'B-negative'}", + "65, migration, {'phenotype': 'B-migration'}", + "66, tube {'phenotype': 'B-colony formation'}", + "67, formation {'phenotype': 'I-colony formation'}", + "70, in {'context': 'B-in vitro'}", + "71, vitro {'context': 'I-in vitro'}", + "76, in {'context': 'B-in vivo'}", + "77, vivo {'context': 'I-in vivo'}", + "85, mouse {'context': 'B-organism'}", + "86, models {'context': 'I-organism'}", + "100, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "101, of {'perturbing_action': 'I-gene loss-of-function'}", + "102, Robo4 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "54, Activation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "55, of ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "56, Robo4 ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "57, by ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "58, Slit2 ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "59, inhibits ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54']", + "65, migration, ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l55', 'l56', 'l57', 'l58']", + "66, tube ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l55', 'l59', 'l60', 'l61']", + "67, formation ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l56', 'l59', 'l62']", + "70, in ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l57', 'l60', 'l62', 'l63']", + "71, vitro ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l58', 'l61', 'l63']", + "76, in ['l10', 'l21', 'l31', 'l40', 'l48', 'l64']", + "77, vivo ['l11', 'l22', 'l32', 'l41', 'l49', 'l64']", + "85, mouse ['l65', 'l66', 'l67', 'l68']", + "86, models ['l65', 'l69', 'l70', 'l71']", + "88, retinal ['l66', 'l69', 'l72', 'l73']", + "89, and ['l67', 'l70', 'l72', 'l74']", + "90, choroidal ['l68', 'l71', 'l73', 'l74']", + "100, deletion ['l75', 'l76']", + "101, of ['l75', 'l77']", + "102, Robo4 ['l76', 'l77']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "Robo4", + "by", + "Slit2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "Robo4", + "by", + "Slit2" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "Robo4", + "by", + "Slit2" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "tube", + "formation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "Robo4", + "by", + "Slit2" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "Robo4", + "by", + "Slit2" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "tube", + "formation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "tube", + "formation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "18278053", + "TEXT": "Integrin-mediated platelet adhesion and aggregation are essential for sealing injured blood vessels and preventing blood loss, and excessive platelet aggregation can initiate arterial thrombosis, causing heart attacks and stroke. To ensure that platelets aggregate only at injury sites, integrins on circulating platelets exist in a low-affinity state and shift to a high-affinity state (in a process known as integrin activation or priming) after contacting a wounded vessel. The shift is mediated through binding of the cytoskeletal protein Talin to the beta subunit cytoplasmic tail. Here we show that platelets lacking the adhesion plaque protein Kindlin-3 cannot activate integrins despite normal Talin expression. As a direct consequence, Kindlin-3 deficiency results in severe bleeding and resistance to arterial thrombosis. Mechanistically, Kindlin-3 can directly bind to regions of beta-integrin tails distinct from those of Talin and trigger integrin activation. We have therefore identified Kindlin-3 as a novel and essential element for platelet integrin activation in hemostasis and thrombosis.", + "TAG_DATA": [ + "88, platelets {'context': 'B-cells'}", + "89, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "90, the {'perturbing_action': 'I-gene loss-of-function'}", + "91, adhesion {'perturbing_action': 'I-gene loss-of-function'}", + "92, plaque {'perturbing_action': 'I-gene loss-of-function'}", + "93, protein {'perturbing_action': 'I-gene loss-of-function'}", + "94, Kindlin-3 {'perturbing_action': 'I-gene loss-of-function'}", + "106, Kindlin-3 {'perturbing_action': 'B-gene loss-of-function'}", + "107, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "113, resistance {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "88, platelets ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "89, lacking ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "90, the ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "91, adhesion ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "92, plaque ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "93, protein ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "94, Kindlin-3 ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "106, Kindlin-3 ['l21', 'l22']", + "107, deficiency ['l21', 'l23']", + "113, resistance ['l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "platelets" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "adhesion", + "plaque", + "protein", + "Kindlin-3" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Kindlin-3", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + } + } + ] + }, + { + "PMID": "18264109", + "TEXT": "Infections by attaching and effacing (A/E) bacterial pathogens, such as Escherichia coli O157:H7, pose a serious threat to public health. Using a mouse A/E pathogen, Citrobacter rodentium, we show that interleukin-22 (IL-22) has a crucial role in the early phase of host defense against C. rodentium. Infection of IL-22 knockout mice results in increased intestinal epithelial damage, systemic bacterial burden and mortality. We also find that IL-23 is required for the early induction of IL-22 during C. rodentium infection, and adaptive immunity is not essential for the protective role of IL-22 in this model. Instead, IL-22 is required for the direct induction of the Reg family of antimicrobial proteins, including RegIIIbeta and RegIIIgamma, in colonic epithelial cells. Exogenous mouse or human RegIIIgamma substantially improves survival of IL-22 knockout mice after C. rodentium infection. Together, our data identify a new innate immune function for IL-22 in regulating early defense mechanisms against A/E bacterial pathogens.", + "TAG_DATA": [ + "48, IL-22 {'perturbing_action': 'B-gene loss-of-function'}", + "49, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "50, mice {'context': 'B-organism'}", + "114, colonic {'context': 'B-cells'}", + "115, epithelial {'context': 'I-cells'}", + "116, cells. {'context': 'I-cells'}", + "118, mouse {'perturbing_action': 'I-gene gain-of-function'}", + "120, human {'perturbing_action': 'I-gene gain-of-function'}", + "126, IL-22 {'perturbing_action': 'B-gene loss-of-function'}", + "127, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "128, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "48, IL-22 ['l0', 'l1']", + "49, knockout ['l0', 'l2']", + "50, mice ['l1', 'l2']", + "114, colonic ['l3', 'l4']", + "115, epithelial ['l3', 'l5']", + "116, cells. ['l4', 'l5']", + "118, mouse ['l6', 'l7', 'l8', 'l9']", + "120, human ['l6', 'l10', 'l11', 'l12']", + "126, IL-22 ['l7', 'l10', 'l13', 'l14']", + "127, knockout ['l8', 'l11', 'l13', 'l15']", + "128, mice ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IL-22", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "mouse", + "human" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "18223655", + "TEXT": "The proapoptotic BCL-2 family member BAD resides in a glucokinase-containing complex that regulates glucose-driven mitochondrial respiration. Here, we present genetic evidence of a physiologic role for BAD in glucose-stimulated insulin secretion by beta cells. This novel function of BAD is specifically dependent upon the phosphorylation of its BH3 sequence, previously defined as an essential death domain. We highlight the pharmacologic relevance of phosphorylated BAD BH3 by using cell-permeable, hydrocarbon-stapled BAD BH3 helices that target glucokinase, restore glucose-driven mitochondrial respiration and correct the insulin secretory response in Bad-deficient islets. Our studies uncover an alternative target and function for the BAD BH3 domain and emphasize the therapeutic potential of phosphorylated BAD BH3 mimetics in selectively restoring beta cell function. Furthermore, we show that BAD regulates the physiologic adaptation of beta cell mass during high-fat feeding. Our findings provide genetic proof of the bifunctional activities of BAD in both beta cell survival and insulin secretion.", + "TAG_DATA": [ + "86, Bad-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "87, islets. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "86, Bad-deficient ['l0']", + "87, islets. ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bad-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "islets." + ] + } + } + ] + }, + { + "PMID": "18157141", + "TEXT": "Conditional targeted cell ablation is a powerful approach for investigating the pathogenesis of human diseases and in vivo cellular functions. Intermedilysin (ILY) is a cytolytic pore-forming toxin secreted by Streptococcus intermedius that lyses human cells exclusively, owing to its receptor specificity for human CD59. We generated two transgenic mouse strains that express human CD59 either on erythrocytes (strain ThCD59(RBC)) or on endothelia (strain ThCD59(END)). Intravenous injection of ILY in ThCD59(RBC) mice induced acute intravascular hemolysis, leading to reduced nitric oxide bioavailability, increased platelet activation and rapid death. In ThCD59(END) mice, ILY induced rapid endothelial damage, leading to acute death and disseminated intravascular coagulation. Additionally, we show that human serum contains ILY-specific neutralizing antibodies not found in any other animal species. Together, these results suggest that this new rapid conditional targeted ILY-mediated cell ablation technique can be used in combination with any available transgenic expression system to study the physiologic role of specific cell populations.", + "TAG_DATA": [ + "47, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "48, mouse {'context': 'I-organism'}", + "49, strains {'context': 'I-organism'}", + "51, express {'perturbing_action': 'I-gene gain-of-function'}", + "52, human {'perturbing_action': 'I-gene gain-of-function'}", + "53, CD59 {'perturbing_action': 'I-gene gain-of-function'}", + "69, ThCD59(RBC) {'perturbing_action': 'B-other'}", + "70, mice {'context': 'B-organism'}", + "82, platelet {'context': 'B-cells'}", + "88, ThCD59(END) {'perturbing_action': 'B-other'}", + "89, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "47, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "48, mouse ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "49, strains ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "51, express ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "52, human ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "53, CD59 ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "69, ThCD59(RBC) ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "70, mice ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "82, platelet ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "88, ThCD59(END) ['l36']", + "89, mice, ['l36']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "express", + "human", + "CD59" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "strains", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "express", + "human", + "CD59" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelet" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "strains", + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "ThCD59(RBC)", + "ThCD59(END)" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "ThCD59(RBC)" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelet" + ] + } + } + ] + }, + { + "PMID": "18059283", + "TEXT": "Exercise has many health benefits, including antidepressant actions in depressed human subjects, but the mechanisms underlying these effects have not been elucidated. We used a custom microarray to identify a previously undescribed profile of exercise-regulated genes in the mouse hippocampus, a brain region implicated in mood and antidepressant response. Pathway analysis of the regulated genes shows that exercise upregulates a neurotrophic factor signaling cascade that has been implicated in the actions of antidepressants. One of the most highly regulated target genes of exercise and of the growth factor pathway is the gene encoding the VGF nerve growth factor, a peptide precursor previously shown to influence synaptic plasticity and metabolism. We show that administration of a synthetic VGF-derived peptide produces a robust antidepressant response in mice and, conversely, that mutation of VGF in mice produces the opposite effects. The results suggest a new role for VGF and identify VGF signaling as a potential therapeutic target for antidepressant drug development.", + "TAG_DATA": [ + "124, mice {'context': 'B-organism'}", + "128, mutation {'perturbing_action': 'B-other'}", + "129, of {'perturbing_action': 'I-other'}", + "130, VGF {'perturbing_action': 'I-other'}", + "132, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "128, mutation ['l0', 'l1', 'l2']", + "129, of ['l0', 'l3', 'l4']", + "130, VGF ['l1', 'l3', 'l5']", + "132, mice ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "of", + "VGF" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "18037896", + "TEXT": "The serine-threonine kinases Pim-1 and Akt regulate cellular proliferation and survival. Although Akt is known to be a crucial signaling protein in the myocardium, the role of Pim-1 has been overlooked. Pim-1 expression in the myocardium of mice decreased during postnatal development, re-emerged after acute pathological injury in mice and was increased in failing hearts of both mice and humans. Cardioprotective stimuli associated with Akt activation induced Pim-1 expression, but compensatory increases in Akt abundance and phosphorylation after pathological injury by infarction or pressure overload did not protect the myocardium in Pim-1-deficient mice. Transgenic expression of Pim-1 in the myocardium protected mice from infarction injury, and Pim-1 expression inhibited cardiomyocyte apoptosis with concomitant increases in Bcl-2 and Bcl-X(L) protein levels, as well as in Bad phosphorylation levels. Relative to nontransgenic controls, calcium dynamics were significantly enhanced in Pim-1-overexpressing transgenic hearts, associated with increased expression of SERCA2a, and were depressed in Pim-1-deficient hearts. Collectively, these data suggest that Pim-1 is a crucial facet of cardioprotection downstream of Akt.", + "TAG_DATA": [ + "89, myocardium {'context': 'B-tissue/organ'}", + "91, Pim-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "92, mice. {'context': 'B-organism'}", + "93, Transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "94, expression {'perturbing_action': 'I-gene gain-of-function'}", + "95, of {'perturbing_action': 'I-gene gain-of-function'}", + "96, Pim-1 {'perturbing_action': 'I-gene gain-of-function'}", + "99, myocardium {'context': 'B-tissue/organ'}", + "101, mice {'context': 'B-organism'}", + "106, Pim-1 {'perturbing_action': 'B-gene gain-of-function'}", + "107, expression {'perturbing_action': 'I-gene gain-of-function'}", + "108, inhibited {'effect': 'B-negative'}", + "109, cardiomyocyte {'context': 'B-cells'}", + "110, apoptosis {'phenotype': 'B-apoptosis'}", + "137, Pim-1-overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "138, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "139, hearts, {'context': 'B-tissue/organ'}", + "150, Pim-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "151, hearts. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "89, myocardium ['l0', 'l1']", + "91, Pim-1-deficient ['l0', 'l2']", + "92, mice. ['l1', 'l2']", + "93, Transgenic ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "94, expression ['l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "95, of ['l4', 'l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "96, Pim-1 ['l5', 'l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "99, myocardium ['l6', 'l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "101, mice ['l7', 'l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "106, Pim-1 ['l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "107, expression ['l30', 'l37', 'l38', 'l39']", + "108, inhibited ['l31', 'l37', 'l40', 'l41']", + "109, cardiomyocyte ['l8', 'l14', 'l19', 'l23', 'l26', 'l28', 'l32', 'l38', 'l40', 'l42']", + "110, apoptosis ['l9', 'l15', 'l20', 'l24', 'l27', 'l29', 'l33', 'l39', 'l41', 'l42']", + "137, Pim-1-overexpressing ['l34', 'l43', 'l44', 'l45', 'l46']", + "138, transgenic ['l35', 'l43', 'l47', 'l48']", + "139, hearts, ['l36', 'l44', 'l47', 'l49']", + "150, Pim-1-deficient ['l45', 'l50']", + "151, hearts. ['l46', 'l48', 'l49', 'l50']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "myocardium", + "hearts." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pim-1-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pim-1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgenic", + "expression", + "of", + "Pim-1", + "Pim-1-overexpressing", + "transgenic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "myocardium", + "hearts,", + "hearts." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgenic", + "expression", + "of", + "Pim-1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgenic", + "expression", + "of", + "Pim-1" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgenic", + "expression", + "of", + "Pim-1" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "myocardium" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Pim-1", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocyte" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cardiomyocyte" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "18026113", + "TEXT": "A successful pregnancy requires synchronized adaptation of maternal immune-endocrine mechanisms to the fetus. Here we show that galectin-1 (Gal-1), an immunoregulatory glycan-binding protein, has a pivotal role in conferring fetomaternal tolerance. Consistently with a marked decrease in Gal-1 expression during failing pregnancies, Gal-1-deficient (Lgals1-/-) mice showed higher rates of fetal loss compared to wild-type mice in allogeneic matings, whereas fetal survival was unaffected in syngeneic matings. Treatment with recombinant Gal-1 prevented fetal loss and restored tolerance through multiple mechanisms, including the induction of tolerogenic dendritic cells, which in turn promoted the expansion of interleukin-10 (IL-10)-secreting regulatory T cells in vivo. Accordingly, Gal-1's protective effects were abrogated in mice depleted of regulatory T cells or deficient in IL-10. In addition, we provide evidence for synergy between Gal-1 and progesterone in the maintenance of pregnancy. Thus, Gal-1 is a pivotal regulator of fetomaternal tolerance that has potential therapeutic implications in threatened pregnancies.", + "TAG_DATA": [ + "42, Gal-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "43, (Lgals1-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "44, mice {'context': 'B-organism'}", + "54, mice {'context': 'B-organism'}", + "84, dendritic {'context': 'B-cells'}", + "85, cells, {'context': 'I-cells'}", + "95, regulatory {'context': 'B-cells'}", + "96, T {'context': 'I-cells'}", + "97, cells {'context': 'I-cells'}", + "98, in {'context': 'B-in vivo'}", + "99, vivo. {'context': 'I-in vivo'}", + "107, mice {'context': 'B-organism'}", + "110, regulatory {'context': 'B-cells'}", + "111, T {'context': 'I-cells'}", + "112, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "42, Gal-1-deficient ['l0', 'l1', 'l2']", + "43, (Lgals1-/-) ['l0', 'l3', 'l4']", + "44, mice ['l1', 'l3', 'l5']", + "54, mice ['l2', 'l4', 'l5']", + "84, dendritic ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "85, cells, ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "95, regulatory ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "96, T ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "97, cells ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "98, in ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "99, vivo. ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']", + "107, mice ['l27', 'l28', 'l29']", + "110, regulatory ['l27', 'l30', 'l31']", + "111, T ['l28', 'l30', 'l32']", + "112, cells ['l29', 'l31', 'l32']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gal-1-deficient", + "(Lgals1-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "17982462", + "TEXT": "Anorexia and weight loss are part of the wasting syndrome of late-stage cancer, are a major cause of morbidity and mortality in cancer, and are thought to be cytokine mediated. Macrophage inhibitory cytokine-1 (MIC-1) is produced by many cancers. Examination of sera from individuals with advanced prostate cancer showed a direct relationship between MIC-1 abundance and cancer-associated weight loss. In mice with xenografted prostate tumors, elevated MIC-1 levels were also associated with marked weight, fat and lean tissue loss that was mediated by decreased food intake and was reversed by administration of antibody to MIC-1. Additionally, normal mice given systemic MIC-1 and transgenic mice overexpressing MIC-1 showed hypophagia and reduced body weight. MIC-1 mediates its effects by central mechanisms that implicate the hypothalamic transforming growth factor-beta receptor II, extracellular signal-regulated kinases 1 and 2, signal transducer and activator of transcription-3, neuropeptide Y and pro-opiomelanocortin. Thus, MIC-1 is a newly defined central regulator of appetite and a potential target for the treatment of both cancer anorexia and weight loss, as well as of obesity.", + "TAG_DATA": [ + "60, mice {'context': 'B-organism'}", + "62, xenografted {'context': 'B-xenograft'}", + "63, prostate {'context': 'I-xenograft'}", + "64, tumors, {'context': 'I-xenograft'}", + "97, mice {'context': 'I-organism'}", + "102, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "103, mice {'context': 'I-organism'}", + "104, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "105, MIC-1 {'perturbing_action': 'I-gene gain-of-function'}", + "107, hypophagia {'phenotype': 'B-necrosis'}" + ], + "LINK_DATA": [ + "60, mice ['l0', 'l1', 'l2']", + "62, xenografted ['l0', 'l3', 'l4']", + "63, prostate ['l1', 'l3', 'l5']", + "64, tumors, ['l2', 'l4', 'l5']", + "97, mice ['l6']", + "102, transgenic ['l7', 'l8', 'l9', 'l10']", + "103, mice ['l7', 'l11', 'l12', 'l13']", + "104, overexpressing ['l8', 'l11', 'l14', 'l15']", + "105, MIC-1 ['l9', 'l12', 'l14', 'l16']", + "107, hypophagia ['l6', 'l10', 'l13', 'l15', 'l16']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "hypophagia" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "overexpressing", + "MIC-1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "overexpressing", + "MIC-1" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "hypophagia" + ] + } + } + ] + }, + { + "PMID": "17952091", + "TEXT": "Proteoglycans are a family of extracellular macromolecules comprised of glycosaminoglycan chains of a repeated disaccharide linked to a central core protein. Proteoglycans have critical roles in chondrogenesis and skeletal development. The glycosaminoglycan chains found in cartilage proteoglycans are primarily composed of chondroitin sulfate. The integrity of chondroitin sulfate chains is important to cartilage proteoglycan function; however, chondroitin sulfate metabolism in mammals remains poorly understood. The solute carrier-35 D1 (SLC35D1) gene (SLC35D1) encodes an endoplasmic reticulum nucleotide-sugar transporter (NST) that might transport substrates needed for chondroitin sulfate biosynthesis. Here we created Slc35d1-deficient mice that develop a lethal form of skeletal dysplasia with severe shortening of limbs and facial structures. Epiphyseal cartilage in homozygous mutant mice showed a decreased proliferating zone with round chondrocytes, scarce matrices and reduced proteoglycan aggregates. These mice had short, sparse chondroitin sulfate chains caused by a defect in chondroitin sulfate biosynthesis. We also identified that loss-of-function mutations in human SLC35D1 cause Schneckenbecken dysplasia, a severe skeletal dysplasia. Our findings highlight the crucial role of NSTs in proteoglycan function and cartilage metabolism, thus revealing a new paradigm for skeletal disease and glycobiology.", + "TAG_DATA": [ + "90, Slc35d1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "91, mice {'context': 'B-organism'}", + "113, mice {'context': 'B-organism'}", + "116, decreased {'effect': 'B-negative'}", + "117, proliferating {'phenotype': 'B-proliferation'}", + "118, zone {'phenotype': 'I-proliferation'}", + "129, mice {'context': 'B-organism'}", + "148, loss-of-function {'perturbing_action': 'B-gene loss-of-function'}", + "149, mutations {'perturbing_action': 'I-gene loss-of-function'}", + "150, in {'perturbing_action': 'I-gene loss-of-function'}", + "151, human {'perturbing_action': 'I-gene loss-of-function'}", + "152, SLC35D1 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "90, Slc35d1-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "91, mice ['l0']", + "112, mutant ['l1', 'l6', 'l7', 'l8', 'l9']", + "113, mice ['l2', 'l6', 'l10', 'l11', 'l12']", + "116, decreased ['l3', 'l7', 'l10', 'l13', 'l14']", + "117, proliferating ['l4', 'l8', 'l11', 'l13', 'l15']", + "118, zone ['l5', 'l9', 'l12', 'l14', 'l15']", + "148, loss-of-function ['l16', 'l17', 'l18', 'l19']", + "149, mutations ['l16', 'l20', 'l21', 'l22']", + "150, in ['l17', 'l20', 'l23', 'l24']", + "151, human ['l18', 'l21', 'l23', 'l25']", + "152, SLC35D1 ['l19', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Slc35d1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Slc35d1-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Slc35d1-deficient" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferating", + "zone" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferating", + "zone" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferating", + "zone" + ] + } + } + ] + }, + { + "PMID": "17934471", + "TEXT": "The role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in immune responses mediated by T-helper 2 (T(H)2) lymphocytes is unknown. Here we characterize the development of allergic airway disease in TRAIL-deficient (Tnfsf10(-/-)) mice and in mice exposed to short interfering RNA targeting TRAIL. We show that TRAIL is abundantly expressed in the airway epithelium of allergic mice and that inhibition of signaling impairs production of the chemokine CCL20 and homing of myeloid dendritic cells and T cells expressing CCR6 and CD4 to the airways. Attenuated homing limits T(H)2 cytokine release, inflammation, airway hyperreactivity and expression of the transcriptional activator STAT6. Activation of STAT6 by interleukin-13 restores airway hyperreactivity in Tnfsf10(-/-) mice. Recombinant TRAIL induces pathognomic features of asthma and stimulates the production of CCL20 in primary human bronchial epithelium cells. TRAIL is also increased in sputum of asthmatics. The function of TRAIL in the airway epithelium identifies this molecule as a target for the treatment of asthma.", + "TAG_DATA": [ + "30, TRAIL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "31, (Tnfsf10(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "32, mice {'context': 'B-organism'}", + "35, mice {'context': 'B-organism'}", + "38, short {'perturbing_action': 'B-rnai/knockdown'}", + "39, interfering {'perturbing_action': 'I-rnai/knockdown'}", + "40, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "41, targeting {'perturbing_action': 'I-rnai/knockdown'}", + "42, TRAIL. {'perturbing_action': 'I-rnai/knockdown'}", + "71, myeloid {'context': 'B-cells'}", + "72, dendritic {'context': 'I-cells'}", + "73, cells {'context': 'I-cells'}", + "75, T {'context': 'B-cells'}", + "76, cells {'context': 'B-cells'}", + "109, Tnfsf10(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "110, mice. {'context': 'B-organism'}", + "125, primary {'context': 'B-cells'}", + "126, human {'context': 'I-cells'}", + "127, bronchial {'context': 'I-cells'}", + "128, epithelium {'context': 'I-cells'}", + "129, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "30, TRAIL-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "31, (Tnfsf10(-/-)) ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "32, mice ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "35, mice ['l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "38, short ['l18', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "39, interfering ['l19', 'l28', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "40, RNA ['l20', 'l29', 'l37', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "41, targeting ['l21', 'l30', 'l38', 'l45', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "42, TRAIL. ['l22', 'l31', 'l39', 'l46', 'l52', 'l58', 'l59', 'l60', 'l61', 'l62']", + "71, myeloid ['l2', 'l8', 'l13', 'l23', 'l32', 'l40', 'l47', 'l53', 'l58', 'l63', 'l64', 'l65', 'l66']", + "72, dendritic ['l3', 'l9', 'l14', 'l24', 'l33', 'l41', 'l48', 'l54', 'l59', 'l63', 'l67', 'l68', 'l69']", + "73, cells ['l4', 'l10', 'l15', 'l25', 'l34', 'l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l70', 'l71']", + "75, T ['l5', 'l11', 'l16', 'l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l72']", + "76, cells ['l6', 'l12', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l69', 'l71', 'l72']", + "109, Tnfsf10(-/-) ['l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "110, mice. ['l73', 'l79', 'l80']", + "125, primary ['l74', 'l81', 'l82', 'l83', 'l84']", + "126, human ['l75', 'l81', 'l85', 'l86', 'l87']", + "127, bronchial ['l76', 'l82', 'l85', 'l88', 'l89']", + "128, epithelium ['l77', 'l79', 'l83', 'l86', 'l88', 'l90']", + "129, cells. ['l78', 'l80', 'l84', 'l87', 'l89', 'l90']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TRAIL-deficient", + "(Tnfsf10(-/-))", + "Tnfsf10(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TRAIL-deficient", + "(Tnfsf10(-/-))", + "Tnfsf10(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "dendritic", + "cells", + "T", + "primary", + "human", + "bronchial", + "epithelium", + "cells." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "short", + "interfering", + "RNA", + "targeting", + "TRAIL." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "short", + "interfering", + "RNA", + "targeting", + "TRAIL." + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "dendritic", + "cells", + "T" + ] + } + } + ] + }, + { + "PMID": "17934470", + "TEXT": "Sepsis, a leading cause of death worldwide, involves proinflammatory responses and inefficient bacterial clearance. Phagocytic cells play a crucial part in the prevention of sepsis by clearing bacteria through host innate receptors. Here we show that the FcRgamma adaptor, an immunoreceptor tyrosine-based activation motif (ITAM)-bearing signal transduction subunit of the Fc receptor family, has a deleterious effect on sepsis. FcRgamma(-/-) mice show increased survival during peritonitis, owing to markedly increased E. coli phagocytosis and killing and to lower production of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha. The FcRgamma-associated receptor that inhibits E. coli phagocytosis is FcgammaRIII (also called CD16), and its absence protects mice from sepsis. FcgammaRIII binds E. coli, and this interaction induces FcRgamma phosphorylation, recruitment of the tyrosine phosphatase SHP-1 and phosphatidylinositide-3 kinase (PI3K) dephosphorylation. Decreased PI3K activity inhibits E. coli phagocytosis and increases TNF-alpha production through Toll-like receptor 4. We identified the phagocytic receptor negatively regulated by FcRgamma on macrophages as the class A scavenger receptor MARCO. E. coli-FcgammaRIII interaction induces the recruitment of SHP-1 to MARCO, thereby inhibiting E. coli phagocytosis. Thus, by binding FcgammaRIII, E. coli triggers an inhibitory FcRgamma pathway that both impairs MARCO-mediated bacterial clearance and activates TNF-alpha secretion.", + "TAG_DATA": [ + "59, FcRgamma(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "60, mice {'context': 'B-organism'}", + "91, inhibits {'effect': 'B-negative'}", + "94, phagocytosis {'phenotype': 'B-mitophagy'}", + "104, mice {'context': 'B-organism'}", + "131, inhibits {'effect': 'B-negative'}", + "134, phagocytosis {'phenotype': 'B-mitophagy'}", + "172, inhibiting {'effect': 'B-negative'}", + "175, phagocytosis. {'phenotype': 'B-mitophagy'}" + ], + "LINK_DATA": [ + "59, FcRgamma(-/-) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "60, mice ['l0', 'l6', 'l7', 'l8']", + "91, inhibits ['l1', 'l9', 'l10', 'l11', 'l12']", + "92, E. ['l2', 'l6', 'l9', 'l13', 'l14', 'l15']", + "93, coli ['l3', 'l7', 'l10', 'l13', 'l16', 'l17']", + "94, phagocytosis ['l4', 'l8', 'l11', 'l14', 'l16', 'l18']", + "104, mice ['l5', 'l12', 'l15', 'l17', 'l18']", + "131, inhibits ['l19']", + "134, phagocytosis ['l19']", + "172, inhibiting ['l20', 'l21', 'l22']", + "173, E. ['l20', 'l23', 'l24']", + "174, coli ['l21', 'l23', 'l25']", + "175, phagocytosis. ['l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FcRgamma(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FcRgamma(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FcRgamma(-/-)" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "inhibiting" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis", + "phagocytosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "17767165", + "TEXT": "To identify new components that regulate the inflammatory cascade during sepsis, we characterized the functions of myeloid-related protein-8 (Mrp8, S100A8) and myeloid-related protein-14 (Mrp14, S100A9), two abundant cytoplasmic proteins of phagocytes. We now demonstrate that mice lacking Mrp8-Mrp14 complexes are protected from endotoxin-induced lethal shock and Escherichia coli-induced abdominal sepsis. Both proteins are released during activation of phagocytes, and Mrp8-Mrp14 complexes amplify the endotoxin-triggered inflammatory responses of phagocytes. Mrp8 is the active component that induces intracellular translocation of myeloid differentiation primary response protein 88 and activation of interleukin-1 receptor-associated kinase-1 and nuclear factor-kappaB, resulting in elevated expression of tumor necrosis factor-alpha (TNF-alpha). Using phagocytes expressing a nonfunctional Toll-like receptor 4 (TLR4), HEK293 cells transfected with TLR4, CD14 and MD2, and by surface plasmon resonance studies in vitro, we demonstrate that Mrp8 specifically interacts with the TLR4-MD2 complex, thus representing an endogenous ligand of TLR4. Therefore Mrp8-Mrp14 complexes are new inflammatory components that amplify phagocyte activation during sepsis upstream of TNFalpha-dependent effects.", + "TAG_DATA": [ + "35, mice {'context': 'B-organism'}", + "103, phagocytes {'context': 'B-cells'}", + "111, HEK293 {'context': 'B-cells'}", + "112, cells {'context': 'I-cells'}", + "113, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "114, with {'perturbing_action': 'I-gene gain-of-function'}", + "115, TLR4, {'perturbing_action': 'I-gene gain-of-function'}", + "116, CD14 {'perturbing_action': 'I-gene gain-of-function'}", + "117, and {'perturbing_action': 'I-gene gain-of-function'}", + "118, MD2, {'perturbing_action': 'I-gene gain-of-function'}", + "125, in {'context': 'B-in vitro'}", + "126, vitro, {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "103, phagocytes ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "111, HEK293 ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "112, cells ['l1', 'l8', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "113, transfected ['l2', 'l9', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "114, with ['l3', 'l10', 'l18', 'l25', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "115, TLR4, ['l4', 'l11', 'l19', 'l26', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "116, CD14 ['l5', 'l12', 'l20', 'l27', 'l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "117, and ['l6', 'l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "118, MD2, ['l7', 'l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "125, in ['l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "126, vitro, ['l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l52']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "phagocytes", + "HEK293", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "TLR4,", + "CD14", + "and", + "MD2," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "TLR4,", + "CD14", + "and", + "MD2," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + } + ] + }, + { + "PMID": "17704786", + "TEXT": "Conventional cancer treatments rely on radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Here we show that the success of some protocols for anticancer therapy depends on innate and adaptive antitumor immune responses. We describe in both mice and humans a previously unrecognized pathway for the activation of tumor antigen-specific T-cell immunity that involves secretion of the high-mobility-group box 1 (HMGB1) alarmin protein by dying tumor cells and the action of HMGB1 on Toll-like receptor 4 (TLR4) expressed by dendritic cells (DCs). During chemotherapy or radiotherapy, DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. Patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy and chemotherapy than those carrying the normal TLR4 allele. These results delineate a clinically relevant immunoadjuvant pathway triggered by tumor cell death.", + "TAG_DATA": [ + "94, DCs {'context': 'B-cells'}", + "114, Patients {'context': 'B-patient'}", + "115, with {'context': 'I-patient'}", + "116, breast {'context': 'I-neoplasm'}", + "117, cancer {'context': 'I-neoplasm'}", + "121, TLR4 {'perturbing_action': 'B-gene loss-of-function'}", + "122, loss-of-function {'perturbing_action': 'I-gene loss-of-function'}", + "123, allele {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "114, Patients ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "115, with ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "116, breast ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "117, cancer ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "121, TLR4 ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "122, loss-of-function ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "123, allele ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "patient", + "words": [ + "Patients", + "with" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TLR4", + "loss-of-function", + "allele" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "breast", + "cancer" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TLR4", + "loss-of-function", + "allele" + ] + } + } + ] + }, + { + "PMID": "17643110", + "TEXT": "Sepsis remains a global clinical problem. By using the mouse cecal ligation and puncture model of sepsis, here we identify an important aspect of mast cell (MC)-dependent, innate immune defenses against Gram-negative bacteria by demonstrating that MC protease activity is regulated by interleukin-15 (IL-15). Mouse MCs express both constitutive and lipopolysaccharide-inducible IL-15 and store it intracellularly. Deletion of Il15 in mice markedly increases chymase activities, leading to greater MC bactericidal responses, increased processing and activation of neutrophil-recruiting chemokines, and significantly higher survival rates of mice after septic peritonitis. By showing that intracellular IL-15 acts as a specific negative transcriptional regulator of a mouse MC chymase (mast cell protease-2), we provide evidence that defined MC protease activity is transcriptionally regulated by an intracellularly retained cytokine. Our results identify an unexpected breach in MC-dependent innate immune defenses against sepsis and suggest that inhibiting intracellular IL-15 in MCs may improve survival from sepsis.", + "TAG_DATA": [ + "56, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "57, of {'perturbing_action': 'I-gene loss-of-function'}", + "58, Il15 {'perturbing_action': 'I-gene loss-of-function'}", + "60, mice {'context': 'B-organism'}", + "84, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, Deletion ['l0', 'l1', 'l2', 'l3']", + "57, of ['l0', 'l4', 'l5', 'l6']", + "58, Il15 ['l1', 'l4', 'l7', 'l8']", + "60, mice ['l2', 'l5', 'l7']", + "84, mice ['l3', 'l6', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "Il15" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "17632527", + "TEXT": "Interaction of cancer cells with their microenvironment generated by stromal cells is essential for tumor cell survival and influences the localization of tumor growth. Here we demonstrate that hedgehog ligands secreted by bone-marrow, nodal and splenic stromal cells function as survival factors for malignant lymphoma and plasmacytoma cells derived from transgenic Emu-Myc mice or isolated from humans with these malignancies. Hedgehog pathway inhibition in lymphomas induced apoptosis through downregulation of Bcl2, but was independent of p53 or Bmi1 expression. Blockage of hedgehog signaling in vivo inhibited expansion of mouse lymphoma cells in a syngeneic mouse model and reduced tumor mass in mice with fully developed disease. Our data indicate that stromally induced hedgehog signaling may provide an important survival signal for B- and plasma-cell malignancies in vitro and in vivo. Disruption of this interaction by hedgehog pathway inhibition could provide a new strategy in lymphoma and multiple myeloma therapy.", + "TAG_DATA": [ + "64, lymphomas {'context': 'B-neoplasm'}", + "65, induced {'effect': 'B-positive'}", + "66, apoptosis {'phenotype': 'B-apoptosis'}", + "83, in {'context': 'B-in vivo'}", + "84, vivo {'context': 'I-in vivo'}", + "85, inhibited {'effect': 'B-negative'}", + "88, mouse {'context': 'B-transformed cells'}", + "89, lymphoma {'context': 'I-transformed cells'}", + "90, cells {'context': 'I-transformed cells'}", + "93, syngeneic {'context': 'B-organism'}", + "94, mouse {'context': 'I-organism'}", + "95, model {'context': 'I-organism'}", + "97, reduced {'effect': 'B-negative'}", + "98, tumor {'phenotype': 'B-tumourigenesis'}", + "99, mass {'phenotype': 'I-tumourigenesis'}", + "101, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "64, lymphomas ['l0', 'l1']", + "65, induced ['l0', 'l2']", + "66, apoptosis ['l1', 'l2']", + "83, in ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "84, vivo ['l3', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "85, inhibited ['l4', 'l11', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "88, mouse ['l5', 'l12', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "89, lymphoma ['l6', 'l13', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32']", + "90, cells ['l7', 'l14', 'l20', 'l25', 'l29', 'l33', 'l34']", + "93, syngeneic ['l8', 'l15', 'l21', 'l26', 'l30', 'l35', 'l36']", + "94, mouse ['l9', 'l16', 'l22', 'l27', 'l31', 'l33', 'l35', 'l37']", + "95, model ['l10', 'l17', 'l23', 'l28', 'l32', 'l34', 'l36', 'l37']", + "97, reduced ['l38', 'l39', 'l40']", + "98, tumor ['l38', 'l41', 'l42']", + "99, mass ['l39', 'l41', 'l43']", + "101, mice ['l40', 'l42', 'l43']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "lymphomas" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "lymphomas" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "mouse", + "lymphoma", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "reduced" + ] + }, + "context": { + "val": "organism", + "words": [ + "syngeneic", + "mouse", + "model", + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "mass" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "mass" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "17618294", + "TEXT": "The E3 ubiquitin ligase Cblb has a crucial role in the prevention of chronic inflammation and autoimmunity. Here we show that Cblb also has an unexpected function in acute lung inflammation. Cblb attenuates the sequestration of inflammatory cells in the lungs after administration of lipopolysaccharide (LPS). In a model of polymicrobial sepsis in which acute lung inflammation depends on the LPS receptor (Toll-like receptor 4, TLR-4), the loss of Cblb expression accentuates acute lung inflammation and reduces survival. Loss of Cblb significantly increases sepsis-induced release of inflammatory cytokines and chemokines. Cblb controls the association between TLR4 and the intracellular adaptor MyD88. Expression of wild-type Cblb, but not expression of a Cblb mutant that lacks E3 ubiquitin ligase function, prevents the activity of a reporter gene for the transcription factor nuclear factor-kappaB (NF-kappaB) in monocytes that have been challenged with LPS. The downregulation of TLR4 expression on the cell surface of neutrophils is impaired in the absence of Cblb. Our data reveal that Cblb regulates the TLR4-mediated acute inflammatory response that is induced by sepsis.", + "TAG_DATA": [ + "67, loss {'perturbing_action': 'B-gene loss-of-function'}", + "68, of {'perturbing_action': 'I-gene loss-of-function'}", + "69, Cblb {'perturbing_action': 'I-gene loss-of-function'}", + "70, expression {'perturbing_action': 'I-gene loss-of-function'}", + "73, lung {'context': 'B-tissue/organ'}", + "78, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "79, of {'perturbing_action': 'I-gene loss-of-function'}", + "80, Cblb {'perturbing_action': 'I-gene loss-of-function'}", + "101, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "102, of {'perturbing_action': 'I-gene gain-of-function'}", + "103, wild-type {'perturbing_action': 'I-gene gain-of-function'}", + "104, Cblb, {'perturbing_action': 'I-gene gain-of-function'}", + "110, Cblb {'perturbing_action': 'B-other'}", + "111, mutant {'perturbing_action': 'I-other'}", + "133, monocytes {'context': 'B-cells'}", + "155, absence {'perturbing_action': 'B-gene loss-of-function'}", + "156, of {'perturbing_action': 'I-gene loss-of-function'}", + "157, Cblb. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "67, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "68, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "69, Cblb ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "70, expression ['l2', 'l8', 'l13', 'l18']", + "73, lung ['l3', 'l9', 'l14', 'l18']", + "78, Loss ['l4', 'l10', 'l15', 'l19', 'l20']", + "79, of ['l5', 'l11', 'l16', 'l19', 'l21']", + "80, Cblb ['l6', 'l12', 'l17', 'l20', 'l21']", + "101, Expression ['l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "102, of ['l22', 'l28', 'l29', 'l30', 'l31']", + "103, wild-type ['l23', 'l28', 'l32', 'l33', 'l34', 'l35']", + "104, Cblb, ['l24', 'l29', 'l32', 'l36']", + "110, Cblb ['l25', 'l33', 'l37', 'l38', 'l39', 'l40', 'l41']", + "111, mutant ['l26', 'l30', 'l34', 'l37', 'l42', 'l43', 'l44', 'l45']", + "133, monocytes ['l27', 'l31', 'l35', 'l36', 'l38', 'l42']", + "155, absence ['l39', 'l43', 'l46', 'l47']", + "156, of ['l40', 'l44', 'l46', 'l48']", + "157, Cblb. ['l41', 'l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Cblb", + "expression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "wild-type", + "Cblb," + ] + }, + "context": { + "val": "cells", + "words": [ + "monocytes" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Cblb", + "mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "monocytes" + ] + } + } + ] + }, + { + "PMID": "17589521", + "TEXT": "Functional deficiency of the FEN1 gene has been suggested to cause genomic instability and cancer predisposition. We have identified a group of FEN1 mutations in human cancer specimens. Most of these mutations abrogated two of three nuclease activities of flap endonuclease 1 (FEN1). To demonstrate the etiological significance of these somatic mutations, we inbred a mouse line harboring the E160D mutation representing mutations identified in human cancers. Selective elimination of nuclease activities led to frequent spontaneous mutations and accumulation of incompletely digested DNA fragments in apoptotic cells. The mutant mice were predisposed to autoimmunity, chronic inflammation and cancers. The mutator phenotype results in the initiation of cancer, whereas chronic inflammation promotes the cancer progression. The current work exemplifies the approach of studying the mechanisms of individual polymorphisms and somatic mutations in cancer development, and may serve as a reference in developing new therapeutic regimens through the suppression of inflammatory responses.", + "TAG_DATA": [ + "55, mouse {'context': 'B-organism'}", + "56, line {'context': 'I-organism'}", + "59, E160D {'perturbing_action': 'B-other'}", + "60, mutation {'perturbing_action': 'I-other'}", + "86, cells. {'context': 'B-cells'}", + "89, mice {'context': 'B-organism'}", + "104, initiation {'effect': 'B-positive'}", + "106, cancer, {'phenotype': 'B-tumourigenesis'}", + "110, promotes {'effect': 'B-positive'}", + "112, cancer {'phenotype': 'B-tumour progression'}", + "113, progression. {'phenotype': 'I-tumour progression'}" + ], + "LINK_DATA": [ + "55, mouse ['l0', 'l1', 'l2', 'l3']", + "56, line ['l0', 'l4', 'l5', 'l6']", + "59, E160D ['l1', 'l4', 'l7', 'l8']", + "60, mutation ['l2', 'l5', 'l7', 'l9']", + "86, cells. ['l3', 'l6', 'l8', 'l9']", + "89, mice ['l10', 'l11']", + "104, initiation ['l10', 'l12']", + "106, cancer, ['l11', 'l12']", + "110, promotes ['l13', 'l14']", + "112, cancer ['l13', 'l15']", + "113, progression. ['l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "line" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "E160D", + "mutation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "E160D", + "mutation" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "initiation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "cancer," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiation" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "cancer," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "cancer", + "progression." + ] + } + } + ] + }, + { + "PMID": "17572686", + "TEXT": "Dying cells stimulate inflammation, and this response is thought to contribute to the pathogenesis of many diseases. Very little has been known, however, about how cell death triggers inflammation. We found here that the acute neutrophilic inflammatory response to cell injury requires the signaling protein myeloid differentiation primary response gene 88 (Myd88). Analysis of the contribution of Myd88-dependent receptors to this response revealed only a minor reduction in mice doubly deficient in Toll-like receptor 2 (Tlr2) and Tlr4 and normal responses in mice lacking Tlr1, Tlr3, Tlr6, Tlr7, Tlr9, Tlr11 or the interleukin-18 receptor (IL-18R). However, mice lacking IL-1R showed a markedly reduced neutrophilic inflammatory response to dead cells and tissue injury in vivo as well as greatly decreased collateral damage from inflammation. This inflammatory response required IL-1alpha, and IL-1R function was required on non-bone-marrow-derived cells. Notably, the acute monocyte response to cell death, which is thought to be important for tissue repair, was much less dependent on the IL-1R-Myd88 pathway. Also, this pathway was not required for the neutrophil response to a microbial stimulus. These findings suggest that inhibiting the IL-1R-Myd88 pathway in vivo could block the damage from acute inflammation that occurs in response to sterile cell death, and do so in a way that might not compromise tissue repair or host defense against pathogens.", + "TAG_DATA": [ + "68, mice {'context': 'B-organism'}", + "69, doubly {'perturbing_action': 'B-gene loss-of-function'}", + "70, deficient {'perturbing_action': 'I-gene loss-of-function'}", + "71, in {'perturbing_action': 'I-gene loss-of-function'}", + "72, Toll-like {'perturbing_action': 'I-gene loss-of-function'}", + "73, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "74, 2 {'perturbing_action': 'I-gene loss-of-function'}", + "75, (Tlr2) {'perturbing_action': 'I-gene loss-of-function'}", + "76, and {'perturbing_action': 'I-gene loss-of-function'}", + "77, Tlr4 {'perturbing_action': 'I-gene loss-of-function'}", + "82, mice {'context': 'B-organism'}", + "83, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "84, Tlr1, {'perturbing_action': 'I-gene loss-of-function'}", + "85, Tlr3, {'perturbing_action': 'I-gene loss-of-function'}", + "86, Tlr6, {'perturbing_action': 'I-gene loss-of-function'}", + "87, Tlr7, {'perturbing_action': 'I-gene loss-of-function'}", + "88, Tlr9, {'perturbing_action': 'I-gene loss-of-function'}", + "89, Tlr11 {'perturbing_action': 'I-gene loss-of-function'}", + "91, the {'perturbing_action': 'I-gene loss-of-function'}", + "96, mice {'context': 'B-organism'}", + "97, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "98, IL-1R {'perturbing_action': 'I-gene loss-of-function'}", + "107, dead {'context': 'B-cells'}", + "108, cells {'context': 'I-cells'}", + "112, in {'context': 'B-in vivo'}", + "113, vivo {'context': 'I-in vivo'}", + "134, non-bone-marrow-derived {'context': 'B-cells'}", + "135, cells. {'context': 'I-cells'}", + "139, monocyte {'context': 'B-cells'}", + "142, cell {'phenotype': 'B-cell death'}", + "143, death, {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "68, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "69, doubly ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "70, deficient ['l1', 'l9', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "71, in ['l2', 'l10', 'l31', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "72, Toll-like ['l3', 'l11', 'l32', 'l51', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "73, receptor ['l4', 'l12', 'l33', 'l52', 'l71', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "74, 2 ['l5', 'l13', 'l34', 'l53', 'l72', 'l90', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "75, (Tlr2) ['l6', 'l14', 'l35', 'l54', 'l73', 'l91', 'l108', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139']", + "76, and ['l7', 'l15', 'l36', 'l55', 'l74', 'l92', 'l109', 'l125', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "77, Tlr4 ['l8', 'l16', 'l37', 'l56', 'l75', 'l93', 'l110', 'l126', 'l140', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164']", + "82, mice ['l17', 'l38', 'l57', 'l76', 'l94', 'l111', 'l127', 'l141', 'l154', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177']", + "83, lacking ['l18', 'l39', 'l58', 'l77', 'l95', 'l112', 'l128', 'l142', 'l155', 'l165', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189']", + "84, Tlr1, ['l19', 'l40', 'l59', 'l78', 'l96', 'l113', 'l129', 'l143', 'l156', 'l166', 'l178', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200']", + "85, Tlr3, ['l20', 'l41', 'l60', 'l79', 'l97', 'l114', 'l130', 'l144', 'l157', 'l167', 'l179', 'l190', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210']", + "86, Tlr6, ['l21', 'l42', 'l61', 'l80', 'l98', 'l115', 'l131', 'l145', 'l158', 'l168', 'l180', 'l191', 'l201', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219']", + "87, Tlr7, ['l22', 'l43', 'l62', 'l81', 'l99', 'l116', 'l132', 'l146', 'l159', 'l169', 'l181', 'l192', 'l202', 'l211', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227']", + "88, Tlr9, ['l23', 'l44', 'l63', 'l82', 'l100', 'l117', 'l133', 'l147', 'l160', 'l170', 'l182', 'l193', 'l203', 'l212', 'l220', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234']", + "89, Tlr11 ['l24', 'l45', 'l64', 'l83', 'l101', 'l118', 'l134', 'l148', 'l161', 'l171', 'l183', 'l194', 'l204', 'l213', 'l221', 'l228', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240']", + "90, or ['l25', 'l46', 'l65', 'l84', 'l102', 'l119', 'l135', 'l149', 'l172', 'l184', 'l195', 'l205', 'l214', 'l222', 'l229', 'l235', 'l241', 'l242', 'l243', 'l244', 'l245']", + "91, the ['l26', 'l66', 'l85', 'l103', 'l120', 'l173', 'l185', 'l196', 'l206', 'l215', 'l223', 'l230', 'l236', 'l241', 'l246', 'l247', 'l248', 'l249', 'l250']", + "96, mice ['l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261']", + "97, lacking ['l251', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271']", + "98, IL-1R ['l246', 'l252', 'l262', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280']", + "107, dead ['l27', 'l47', 'l67', 'l86', 'l104', 'l121', 'l136', 'l150', 'l174', 'l186', 'l197', 'l207', 'l216', 'l224', 'l231', 'l237', 'l242', 'l247', 'l253', 'l263', 'l272', 'l281', 'l282', 'l283']", + "108, cells ['l28', 'l48', 'l68', 'l87', 'l105', 'l122', 'l137', 'l151', 'l162', 'l175', 'l187', 'l198', 'l208', 'l217', 'l225', 'l232', 'l238', 'l243', 'l248', 'l254', 'l264', 'l273', 'l281', 'l284', 'l285']", + "112, in ['l29', 'l49', 'l69', 'l88', 'l106', 'l123', 'l138', 'l152', 'l163', 'l176', 'l188', 'l199', 'l209', 'l218', 'l226', 'l233', 'l239', 'l244', 'l249', 'l255', 'l265', 'l274', 'l282', 'l284', 'l286']", + "113, vivo ['l30', 'l50', 'l70', 'l89', 'l107', 'l124', 'l139', 'l153', 'l164', 'l177', 'l189', 'l200', 'l210', 'l219', 'l227', 'l234', 'l240', 'l245', 'l250', 'l256', 'l266', 'l275', 'l283', 'l285', 'l286']", + "134, non-bone-marrow-derived ['l257', 'l267', 'l276', 'l287', 'l288', 'l289', 'l290']", + "135, cells. ['l258', 'l268', 'l277', 'l287', 'l291', 'l292', 'l293']", + "139, monocyte ['l259', 'l269', 'l278', 'l288', 'l291', 'l294', 'l295']", + "142, cell ['l260', 'l270', 'l279', 'l289', 'l292', 'l294', 'l296']", + "143, death, ['l261', 'l271', 'l280', 'l290', 'l293', 'l295', 'l296']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "doubly", + "deficient", + "in", + "Toll-like", + "receptor", + "2", + "(Tlr2)", + "and", + "Tlr4", + "lacking", + "Tlr1,", + "Tlr3,", + "Tlr6,", + "Tlr7,", + "Tlr9,", + "Tlr11", + "the", + "IL-1R" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "doubly", + "deficient", + "in", + "Toll-like", + "receptor", + "2", + "(Tlr2)", + "and", + "Tlr4", + "lacking", + "Tlr1,", + "Tlr3,", + "Tlr6,", + "Tlr7,", + "Tlr9,", + "Tlr11", + "the", + "IL-1R" + ] + }, + "context": { + "val": "cells", + "words": [ + "dead", + "cells", + "non-bone-marrow-derived", + "cells.", + "monocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "doubly", + "deficient", + "in", + "Toll-like", + "receptor", + "2", + "(Tlr2)", + "and", + "Tlr4", + "lacking", + "Tlr1,", + "Tlr3,", + "Tlr6,", + "Tlr7,", + "Tlr9,", + "Tlr11", + "the", + "IL-1R" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "IL-1R" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "non-bone-marrow-derived", + "cells.", + "monocyte" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + } + ] + }, + { + "PMID": "17468766", + "TEXT": "Growing evidence indicates that microRNAs (miRNAs or miRs) are involved in basic cell functions and oncogenesis. Here we report that miR-133 has a critical role in determining cardiomyocyte hypertrophy. We observed decreased expression of both miR-133 and miR-1, which belong to the same transcriptional unit, in mouse and human models of cardiac hypertrophy. In vitro overexpression of miR-133 or miR-1 inhibited cardiac hypertrophy. In contrast, suppression of miR-133 by 'decoy' sequences induced hypertrophy, which was more pronounced than that after stimulation with conventional inducers of hypertrophy. In vivo inhibition of miR-133 by a single infusion of an antagomir caused marked and sustained cardiac hypertrophy. We identified specific targets of miR-133: RhoA, a GDP-GTP exchange protein regulating cardiac hypertrophy; Cdc42, a signal transduction kinase implicated in hypertrophy; and Nelf-A/WHSC2, a nuclear factor involved in cardiogenesis. Our data show that miR-133, and possibly miR-1, are key regulators of cardiac hypertrophy, suggesting their therapeutic application in heart disease.", + "TAG_DATA": [ + "53, In {'context': 'B-in vitro'}", + "54, vitro {'context': 'I-in vitro'}", + "55, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "56, of {'perturbing_action': 'I-gene gain-of-function'}", + "57, miR-133 {'perturbing_action': 'I-gene gain-of-function'}", + "58, or {'perturbing_action': 'I-gene gain-of-function'}", + "59, miR-1 {'perturbing_action': 'I-gene gain-of-function'}", + "65, suppression {'perturbing_action': 'B-pharmacological inhibition'}", + "66, of {'perturbing_action': 'I-rnai/knockdown'}", + "67, miR-133 {'perturbing_action': 'I-pharmacological inhibition'}", + "68, by {'perturbing_action': 'I-rnai/knockdown'}", + "69, 'decoy' {'perturbing_action': 'I-rnai/knockdown'}", + "70, sequences {'perturbing_action': 'I-rnai/knockdown'}", + "86, In {'context': 'B-in vivo'}", + "87, vivo {'context': 'I-in vivo'}", + "88, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "89, of {'perturbing_action': 'I-pharmacological inhibition'}", + "90, miR-133 {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "53, In ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "54, vitro ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "55, overexpression ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "56, of ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "57, miR-133 ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "58, or ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "59, miR-1 ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "65, suppression ['l21', 'l22', 'l23', 'l24', 'l25']", + "66, of ['l21', 'l26', 'l27', 'l28', 'l29']", + "67, miR-133 ['l22', 'l26', 'l30', 'l31', 'l32']", + "68, by ['l23', 'l27', 'l30', 'l33', 'l34']", + "69, 'decoy' ['l24', 'l28', 'l31', 'l33', 'l35']", + "70, sequences ['l25', 'l29', 'l32', 'l34', 'l35']", + "86, In ['l36', 'l37', 'l38', 'l39']", + "87, vivo ['l36', 'l40', 'l41', 'l42']", + "88, inhibition ['l37', 'l40', 'l43', 'l44']", + "89, of ['l38', 'l41', 'l43', 'l45']", + "90, miR-133 ['l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "miR-133", + "or", + "miR-1" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "miR-133" + ] + } + } + ] + }, + { + "PMID": "17384649", + "TEXT": "Treatment with ex vivo-generated regulatory T cells (T-reg) has been regarded as a potentially attractive therapeutic approach for autoimmune diseases. However, the dynamics and function of T-reg in autoimmunity are not well understood. Thus, we developed Foxp3gfp knock-in (Foxp3gfp.KI) mice and myelin oligodendrocyte glycoprotein (MOG)(35-55)/IA(b) (MHC class II) tetramers to track autoantigen-specific effector T cells (T-eff) and T-reg in vivo during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. MOG tetramer-reactive, Foxp3(+) T-reg expanded in the peripheral lymphoid compartment and readily accumulated in the central nervous system (CNS), but did not prevent the onset of disease. Foxp3(+) T cells isolated from the CNS were effective in suppressing naive MOG-specific T cells, but failed to control CNS-derived encephalitogenic T-eff that secreted interleukin (IL)-6 and tumor necrosis factor (TNF). Our data suggest that in order for CD4(+)Foxp3(+) T-reg to effectively control autoimmune reactions in the target organ, it may also be necessary to control tissue inflammation.", + "TAG_DATA": [ + "36, Foxp3gfp {'perturbing_action': 'B-gene loss-of-function'}", + "37, knock-in {'perturbing_action': 'I-gene loss-of-function'}", + "38, (Foxp3gfp.KI) {'perturbing_action': 'I-gene loss-of-function'}", + "39, mice {'context': 'B-organism'}", + "58, in {'context': 'B-in vivo'}", + "59, vivo {'context': 'I-in vivo'}", + "98, Foxp3(+) {'context': 'B-cells'}", + "99, T {'context': 'I-cells'}", + "100, cells {'context': 'I-cells'}", + "101, isolated {'context': 'I-cells'}", + "102, from {'context': 'I-cells'}", + "103, the {'context': 'I-cells'}", + "104, CNS {'context': 'I-cells'}", + "109, naive {'context': 'B-cells'}", + "110, MOG-specific {'context': 'I-cells'}", + "111, T {'context': 'I-cells'}", + "112, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "36, Foxp3gfp ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "37, knock-in ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "38, (Foxp3gfp.KI) ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "39, mice ['l2', 'l8', 'l13', 'l18', 'l19']", + "58, in ['l3', 'l9', 'l14', 'l18', 'l20']", + "59, vivo ['l4', 'l10', 'l15', 'l19', 'l20']", + "79, lymphoid ['l5', 'l11', 'l16', 'l21']", + "80, compartment ['l6', 'l12', 'l17', 'l21']", + "98, Foxp3(+) ['l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "99, T ['l22', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "100, cells ['l23', 'l32', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "101, isolated ['l24', 'l33', 'l41', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "102, from ['l25', 'l34', 'l42', 'l49', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "103, the ['l26', 'l35', 'l43', 'l50', 'l56', 'l62', 'l63', 'l64', 'l65', 'l66']", + "104, CNS ['l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l67', 'l68', 'l69', 'l70']", + "109, naive ['l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l71', 'l72', 'l73']", + "110, MOG-specific ['l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l74', 'l75']", + "111, T ['l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l74', 'l76']", + "112, cells, ['l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l76']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Foxp3gfp", + "knock-in", + "(Foxp3gfp.KI)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Foxp3gfp", + "knock-in", + "(Foxp3gfp.KI)" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "17351623", + "TEXT": "Microglia are the principal immune cells of the brain. In Alzheimer disease, these brain mononuclear phagocytes are recruited from the blood and accumulate in senile plaques. However, the role of microglia in Alzheimer disease has not been resolved. Microglia may be neuroprotective by phagocytosing amyloid-beta (Abeta), but their activation and the secretion of neurotoxins may also cause neurodegeneration. Ccr2 is a chemokine receptor expressed on microglia, which mediates the accumulation of mononuclear phagocytes at sites of inflammation. Here we show that Ccr2 deficiency accelerates early disease progression and markedly impairs microglial accumulation in a transgenic mouse model of Alzheimer disease (Tg2576). Alzheimer disease mice deficient in Ccr2 accumulated Abeta earlier and died prematurely, in a manner that correlated with Ccr2 gene dosage, indicating that absence of early microglial accumulation leads to decreased Abeta clearance and increased mortality. Thus, Ccr2-dependent microglial accumulation plays a protective role in the early stages of Alzheimer disease by promoting Abeta clearance.", + "TAG_DATA": [ + "81, Ccr2 {'perturbing_action': 'B-gene loss-of-function'}", + "82, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "94, transgenic {'context': 'B-organism'}", + "95, mouse {'context': 'I-organism'}", + "96, model {'context': 'I-organism'}", + "97, of {'context': 'I-organism'}", + "98, Alzheimer {'context': 'I-organism'}", + "99, disease {'context': 'I-organism'}", + "100, (Tg2576). {'context': 'I-organism'}", + "101, Alzheimer {'context': 'B-organism'}", + "102, disease {'context': 'I-organism'}", + "103, mice {'context': 'I-organism'}", + "104, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "105, in {'perturbing_action': 'I-gene loss-of-function'}", + "106, Ccr2 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "81, Ccr2 ['l0']", + "82, deficiency ['l0']", + "94, transgenic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "95, mouse ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "96, model ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "97, of ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "98, Alzheimer ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "99, disease ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "100, (Tg2576). ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']", + "101, Alzheimer ['l22', 'l23', 'l24', 'l25', 'l26']", + "102, disease ['l22', 'l27', 'l28', 'l29', 'l30']", + "103, mice ['l23', 'l27', 'l31', 'l32', 'l33']", + "104, deficient ['l24', 'l28', 'l31', 'l34', 'l35']", + "105, in ['l25', 'l29', 'l32', 'l34', 'l36']", + "106, Ccr2 ['l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Alzheimer", + "disease", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Ccr2" + ] + } + } + ] + }, + { + "PMID": "17268472", + "TEXT": "Adiponectin plays a central role as an antidiabetic and antiatherogenic adipokine. AdipoR1 and AdipoR2 serve as receptors for adiponectin in vitro, and their reduction in obesity seems to be correlated with reduced adiponectin sensitivity. Here we show that adenovirus-mediated expression of AdipoR1 and R2 in the liver of Lepr(-/-) mice increased AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor (PPAR)-alpha signaling pathways, respectively. Activation of AMPK reduced gluconeogenesis, whereas expression of the receptors in both cases increased fatty acid oxidation and lead to an amelioration of diabetes. Alternatively, targeted disruption of AdipoR1 resulted in the abrogation of adiponectin-induced AMPK activation, whereas that of AdipoR2 resulted in decreased activity of PPAR-alpha signaling pathways. Simultaneous disruption of both AdipoR1 and R2 abolished adiponectin binding and actions, resulting in increased tissue triglyceride content, inflammation and oxidative stress, and thus leading to insulin resistance and marked glucose intolerance. Therefore, AdipoR1 and R2 serve as the predominant receptors for adiponectin in vivo and play important roles in the regulation of glucose and lipid metabolism, inflammation and oxidative stress in vivo.", + "TAG_DATA": [ + "38, adenovirus-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "39, expression {'perturbing_action': 'I-gene gain-of-function'}", + "40, of {'perturbing_action': 'I-gene gain-of-function'}", + "41, AdipoR1 {'perturbing_action': 'I-gene gain-of-function'}", + "42, and {'perturbing_action': 'I-gene gain-of-function'}", + "43, R2 {'perturbing_action': 'I-gene gain-of-function'}", + "46, liver {'context': 'B-tissue/organ'}", + "48, Lepr(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "49, mice {'context': 'B-organism'}", + "89, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "90, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "91, of {'perturbing_action': 'I-gene loss-of-function'}", + "92, AdipoR1 {'perturbing_action': 'I-gene loss-of-function'}", + "114, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "115, of {'perturbing_action': 'I-gene loss-of-function'}", + "116, both {'perturbing_action': 'I-gene loss-of-function'}", + "117, AdipoR1 {'perturbing_action': 'I-gene loss-of-function'}", + "118, and {'perturbing_action': 'I-gene loss-of-function'}", + "119, R2 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "38, adenovirus-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "39, expression ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "40, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "41, AdipoR1 ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "42, and ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "43, R2 ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "46, liver ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "48, Lepr(-/-) ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "49, mice ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "89, targeted ['l36', 'l37', 'l38']", + "90, disruption ['l36', 'l39', 'l40']", + "91, of ['l37', 'l39', 'l41']", + "92, AdipoR1 ['l38', 'l40', 'l41']", + "114, disruption ['l42', 'l43', 'l44', 'l45', 'l46']", + "115, of ['l42', 'l47', 'l48', 'l49', 'l50']", + "116, both ['l43', 'l47', 'l51', 'l52', 'l53']", + "117, AdipoR1 ['l44', 'l48', 'l51', 'l54', 'l55']", + "118, and ['l45', 'l49', 'l52', 'l54', 'l56']", + "119, R2 ['l46', 'l50', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus-mediated", + "expression", + "of", + "AdipoR1", + "and", + "R2" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus-mediated", + "expression", + "of", + "AdipoR1", + "and", + "R2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lepr(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lepr(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "17237793", + "TEXT": "Degenerative and inflammatory joint diseases lead to a destruction of the joint architecture. Whereas degenerative osteoarthritis results in the formation of new bone, rheumatoid arthritis leads to bone resorption. The molecular basis of these different patterns of joint disease is unknown. By inhibiting Dickkopf-1 (DKK-1), a regulatory molecule of the Wnt pathway, we were able to reverse the bone-destructive pattern of a mouse model of rheumatoid arthritis to the bone-forming pattern of osteoarthritis. In this way, no overall bone erosion resulted, although bony nodules, so-called osteophytes, did form. We identified tumor necrosis factor-alpha (TNF) as a key inducer of DKK-1 in the mouse inflammatory arthritis model and in human rheumatoid arthritis. These results suggest that the Wnt pathway is a key regulator of joint remodeling.", + "TAG_DATA": [ + "42, inhibiting {'perturbing_action': 'B-pharmacological inhibition'}", + "43, Dickkopf-1 {'perturbing_action': 'I-pharmacological inhibition'}", + "44, (DKK-1), {'perturbing_action': 'I-pharmacological inhibition'}", + "62, mouse {'context': 'B-organism'}", + "63, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "42, inhibiting ['l0', 'l1', 'l2', 'l3']", + "43, Dickkopf-1 ['l0', 'l4', 'l5', 'l6']", + "44, (DKK-1), ['l1', 'l4', 'l7', 'l8']", + "62, mouse ['l2', 'l5', 'l7', 'l9']", + "63, model ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibiting", + "Dickkopf-1", + "(DKK-1)," + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + } + ] + }, + { + "PMID": "17195838", + "TEXT": "Lysosome-related organelles have versatile functions, including protein and lipid degradation, signal transduction and protein secretion. The molecular elucidation of rare congenital diseases affecting endosomal-lysosomal biogenesis has given insights into physiological functions of the innate and adaptive immune system. Here, we describe a previously unknown human primary immunodeficiency disorder and provide evidence that the endosomal adaptor protein p14, previously characterized as confining mitogen-activated protein kinase (MAPK) signaling to late endosomes, is crucial for the function of neutrophils, B cells, cytotoxic T cells and melanocytes. Combining genetic linkage studies and transcriptional profiling analysis, we identified a homozygous point mutation in the 3' untranslated region (UTR) of p14 (also known as MAPBPIP), resulting in decreased protein expression. In p14-deficient cells, the distribution of late endosomes was severely perturbed, suggesting a previously unknown role for p14 in endosomal biogenesis. These findings have implications for understanding endosomal membrane dynamics, compartmentalization of cell signal cascades, and their role in immunity.", + "TAG_DATA": [ + "95, point {'perturbing_action': 'I-other'}", + "96, mutation {'perturbing_action': 'I-other'}", + "97, in {'perturbing_action': 'I-other'}", + "98, the {'perturbing_action': 'I-other'}", + "99, 3' {'perturbing_action': 'I-other'}", + "100, untranslated {'perturbing_action': 'I-other'}", + "101, region {'perturbing_action': 'I-other'}", + "103, of {'perturbing_action': 'I-other'}", + "104, p14 {'perturbing_action': 'I-other'}", + "105, (also {'perturbing_action': 'I-other'}", + "115, p14-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "116, cells, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "94, homozygous ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "95, point ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "96, mutation ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "97, in ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "98, the ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "99, 3' ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "100, untranslated ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "101, region ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "102, (UTR) ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "103, of ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "104, p14 ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "105, (also ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "115, p14-deficient ['l66']", + "116, cells, ['l66']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p14-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells," + ] + } + } + ] + }, + { + "PMID": "17159988", + "TEXT": "Interstitial loss of all or part of the long arm of chromosome 5, or del(5q), is a frequent clonal chromosomal abnormality in human myelodysplastic syndrome (MDS, a preleukemic disorder) and acute myeloid leukemia (AML), and is thought to contribute to the pathogenesis of these diseases by deleting one or more tumor-suppressor genes. Although a major commonly deleted region (CDR) has been delineated on chromosome band 5q31.1 (refs. 3-7), attempts to identify tumor suppressors within this band have been unsuccessful. We focused our analysis of gene expression on RNA from primitive leukemia-initiating cells, which harbor 5q deletions, and analyzed 12 genes within the CDR that are expressed by normal hematopoietic stem cells. Here we show that the gene encoding alpha-catenin (CTNNA1) is expressed at a much lower level in leukemia-initiating stem cells from individuals with AML or MDS with a 5q deletion than in individuals with MDS or AML lacking a 5q deletion or in normal hematopoietic stem cells. Analysis of HL-60 cells, a myeloid leukemia line with deletion of the 5q31 region, showed that the CTNNA1 promoter of the retained allele is suppressed by both methylation and histone deacetylation. Restoration of CTNNA1 expression in HL-60 cells resulted in reduced proliferation and apoptotic cell death. Thus, loss of expression of the alpha-catenin tumor suppressor in hematopoietic stem cells may provide a growth advantage that contributes to human MDS or AML with del(5q).", + "TAG_DATA": [ + "155, hematopoietic {'context': 'I-cells'}", + "156, stem {'context': 'I-cells'}", + "157, cells. {'context': 'I-cells'}", + "160, HL-60 {'context': 'B-cells'}", + "161, cells, {'context': 'I-cells'}", + "163, myeloid {'context': 'B-transformed cells'}", + "164, leukemia {'context': 'I-transformed cells'}", + "165, line {'context': 'I-transformed cells'}", + "189, Restoration {'perturbing_action': 'B-gene gain-of-function'}", + "190, of {'perturbing_action': 'I-gene gain-of-function'}", + "191, CTNNA1 {'perturbing_action': 'I-gene gain-of-function'}", + "192, expression {'perturbing_action': 'I-gene gain-of-function'}", + "194, HL-60 {'context': 'B-cells'}", + "195, cells {'context': 'I-cells'}", + "198, reduced {'effect': 'B-negative'}", + "199, proliferation {'phenotype': 'B-proliferation'}", + "201, apoptotic {'phenotype': 'B-apoptosis'}", + "202, cell {'phenotype': 'I-apoptosis'}", + "203, death. {'phenotype': 'I-apoptosis'}" + ], + "LINK_DATA": [ + "155, hematopoietic ['l0', 'l1', 'l2', 'l3']", + "156, stem ['l0', 'l4', 'l5']", + "157, cells. ['l1', 'l4']", + "160, HL-60 ['l2', 'l6', 'l7', 'l8', 'l9']", + "161, cells, ['l3', 'l5', 'l6', 'l10', 'l11', 'l12']", + "163, myeloid ['l7', 'l10', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "164, leukemia ['l8', 'l11', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "165, line ['l9', 'l12', 'l14', 'l19', 'l24', 'l25', 'l26']", + "189, Restoration ['l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "190, of ['l27', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "191, CTNNA1 ['l28', 'l37', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "192, expression ['l29', 'l38', 'l46', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "194, HL-60 ['l30', 'l39', 'l47', 'l54', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "195, cells ['l31', 'l40', 'l48', 'l55', 'l61', 'l67', 'l68', 'l69', 'l70', 'l71']", + "198, reduced ['l15', 'l20', 'l24', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l72', 'l73', 'l74', 'l75']", + "199, proliferation ['l16', 'l21', 'l25', 'l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l76', 'l77', 'l78']", + "201, apoptotic ['l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l76', 'l79', 'l80']", + "202, cell ['l17', 'l22', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l79', 'l81']", + "203, death. ['l18', 'l23', 'l26', 'l36', 'l45', 'l53', 'l60', 'l66', 'l71', 'l75', 'l78', 'l80', 'l81']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "myeloid", + "leukemia", + "line" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "myeloid", + "leukemia", + "line" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "myeloid", + "leukemia", + "line" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoration", + "of", + "CTNNA1", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "HL-60", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoration", + "of", + "CTNNA1", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoration", + "of", + "CTNNA1", + "expression" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoration", + "of", + "CTNNA1", + "expression" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HL-60", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HL-60", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HL-60", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "17128269", + "TEXT": "Calcium (Ca(2+)) signaling is essential for a variety of cellular responses and higher biological functions. Ca(2+)/calmodulin-dependent kinases (CaMKs) and the phosphatase calcineurin activate distinct downstream pathways that are mediated by the transcription factors cAMP response element (CRE)-binding protein (CREB) and nuclear factor of activated T cells (NFAT), respectively. The importance of the calcineurin-NFAT pathway in bone metabolism has been demonstrated in osteoclasts, osteoblasts and chondrocytes. However, the contribution of the CaMK-CREB pathway is poorly understood, partly because of the difficulty of dissecting the functions of homologous family members. Here we show that the CaMKIV-CREB pathway is crucial for osteoclast differentiation and function. Pharmacological inhibition of CaMKs as well as the genetic ablation of Camk4 reduced CREB phosphorylation and downregulated the expression of c-Fos, which is required for the induction of NFATc1 (the master transcription factor for osteoclastogenesis) that is activated by receptor activator of NF-kappaB ligand (RANKL). Furthermore, CREB together with NFATc1 induced the expression of specific genes expressed by differentiated osteoclasts. Thus, the CaMK-CREB pathway biphasically functions to regulate the transcriptional program of osteoclastic bone resorption, by not only enhancing induction of NFATc1 but also facilitating NFATc1-dependent gene regulation once its expression is induced. This provides a molecular basis for a new therapeutic strategy for bone diseases.", + "TAG_DATA": [ + "102, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "103, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "104, of {'perturbing_action': 'I-pharmacological inhibition'}", + "105, CaMKs {'perturbing_action': 'I-pharmacological inhibition'}", + "110, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "111, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "112, of {'perturbing_action': 'I-gene loss-of-function'}", + "113, Camk4 {'perturbing_action': 'I-gene loss-of-function'}", + "161, osteoclasts. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "102, Pharmacological ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "103, inhibition ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "104, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18']", + "105, CaMKs ['l2', 'l9', 'l15', 'l19', 'l20', 'l21', 'l22', 'l23']", + "110, genetic ['l3', 'l10', 'l19', 'l24', 'l25', 'l26', 'l27']", + "111, ablation ['l4', 'l11', 'l20', 'l24', 'l28', 'l29', 'l30']", + "112, of ['l5', 'l12', 'l16', 'l21', 'l25', 'l28', 'l31', 'l32']", + "113, Camk4 ['l6', 'l13', 'l17', 'l22', 'l26', 'l29', 'l31', 'l33']", + "161, osteoclasts. ['l7', 'l14', 'l18', 'l23', 'l27', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "CaMKs" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclasts." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "Camk4" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclasts." + ] + } + } + ] + }, + { + "PMID": "17086189", + "TEXT": "The angiogenic growth factor angiopoietin 2 (Ang2) destabilizes blood vessels, enhances vascular leak and induces vascular regression and endothelial cell apoptosis. We considered that Ang2 might be important in hyperoxic acute lung injury (ALI). Here we have characterized the responses in lungs induced by hyperoxia in wild-type and Ang2-/- mice or those given either recombinant Ang2 or short interfering RNA (siRNA) targeted to Ang2. During hyperoxia Ang2 expression is induced in lung epithelial cells, while hyperoxia-induced oxidant injury, cell death, inflammation, permeability alterations and mortality are ameliorated in Ang2-/- and siRNA-treated mice. Hyperoxia induces and activates the extrinsic and mitochondrial cell death pathways and activates initiator and effector caspases through Ang2-dependent pathways in vivo. Ang2 increases inflammation and cell death during hyperoxia in vivo and stimulates epithelial necrosis in hyperoxia in vitro. Ang2 in plasma and alveolar edema fluid is increased in adults with ALI and pulmonary edema. Tracheal Ang2 is also increased in neonates that develop bronchopulmonary dysplasia. Ang2 is thus a mediator of epithelial necrosis with an important role in hyperoxic ALI and pulmonary edema.", + "TAG_DATA": [ + "41, lungs {'context': 'B-tissue/organ'}", + "48, Ang2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "49, mice {'context': 'B-organism'}", + "57, short {'perturbing_action': 'B-rnai/knockdown'}", + "58, interfering {'perturbing_action': 'I-rnai/knockdown'}", + "59, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "60, (siRNA) {'perturbing_action': 'I-rnai/knockdown'}", + "61, targeted {'perturbing_action': 'I-rnai/knockdown'}", + "62, to {'perturbing_action': 'I-rnai/knockdown'}", + "63, Ang2. {'perturbing_action': 'I-rnai/knockdown'}", + "71, lung {'context': 'B-cells'}", + "72, epithelial {'context': 'I-cells'}", + "73, cells, {'context': 'I-cells'}", + "78, cell {'phenotype': 'B-cell death'}", + "79, death, {'phenotype': 'I-cell death'}", + "88, Ang2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "90, siRNA-treated {'perturbing_action': 'B-rnai/knockdown'}", + "91, mice. {'context': 'B-organism'}", + "93, induces {'effect': 'B-positive'}", + "95, activates {'effect': 'B-positive'}", + "100, cell {'phenotype': 'B-cell death'}", + "101, death {'phenotype': 'I-cell death'}", + "102, pathways {'phenotype': 'I-apoptosis'}", + "112, in {'context': 'B-in vivo'}", + "113, vivo. {'context': 'I-in vivo'}", + "115, increases {'effect': 'B-positive'}", + "118, cell {'phenotype': 'B-cell death'}", + "119, death {'phenotype': 'I-cell death'}", + "122, in {'context': 'B-in vivo'}", + "123, vivo {'context': 'I-in vivo'}", + "125, stimulates {'effect': 'B-positive'}", + "127, necrosis {'phenotype': 'B-necrosis'}", + "130, in {'context': 'B-in vitro'}", + "131, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "41, lungs ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "48, Ang2-/- ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "49, mice ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "57, short ['l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "58, interfering ['l18', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "59, RNA ['l19', 'l46', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "60, (siRNA) ['l20', 'l47', 'l72', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "61, targeted ['l21', 'l48', 'l73', 'l96', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "62, to ['l22', 'l49', 'l74', 'l97', 'l119', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "63, Ang2. ['l23', 'l50', 'l75', 'l98', 'l120', 'l141', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181']", + "71, lung ['l2', 'l8', 'l13', 'l24', 'l51', 'l76', 'l99', 'l121', 'l142', 'l162', 'l182', 'l183', 'l184', 'l185']", + "72, epithelial ['l3', 'l9', 'l14', 'l25', 'l52', 'l77', 'l100', 'l122', 'l143', 'l163', 'l182', 'l186', 'l187', 'l188']", + "73, cells, ['l4', 'l10', 'l15', 'l26', 'l53', 'l78', 'l101', 'l123', 'l144', 'l164', 'l183', 'l186', 'l189', 'l190']", + "78, cell ['l5', 'l11', 'l16', 'l27', 'l54', 'l79', 'l102', 'l124', 'l145', 'l165', 'l184', 'l187', 'l189', 'l191']", + "79, death, ['l6', 'l12', 'l17', 'l28', 'l55', 'l80', 'l103', 'l125', 'l146', 'l166', 'l185', 'l188', 'l190', 'l191']", + "88, Ang2-/- ['l29', 'l56', 'l81', 'l104', 'l126', 'l147', 'l167', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198']", + "90, siRNA-treated ['l30', 'l57', 'l82', 'l105', 'l127', 'l148', 'l168', 'l192', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210']", + "91, mice. ['l31', 'l58', 'l83', 'l106', 'l128', 'l149', 'l169', 'l193', 'l199', 'l211', 'l212', 'l213', 'l214', 'l215']", + "93, induces ['l32', 'l59', 'l84', 'l107', 'l129', 'l150', 'l170', 'l194', 'l200', 'l211', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226']", + "95, activates ['l33', 'l60', 'l85', 'l108', 'l130', 'l151', 'l171', 'l195', 'l201', 'l212', 'l216', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236']", + "100, cell ['l34', 'l61', 'l86', 'l109', 'l131', 'l152', 'l172', 'l196', 'l202', 'l213', 'l217', 'l227', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244']", + "101, death ['l35', 'l62', 'l87', 'l110', 'l132', 'l153', 'l173', 'l197', 'l203', 'l214', 'l218', 'l228', 'l237', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251']", + "102, pathways ['l36', 'l63', 'l88', 'l111', 'l133', 'l154', 'l174', 'l198', 'l204', 'l215', 'l219', 'l229', 'l238', 'l245', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258']", + "112, in ['l37', 'l64', 'l89', 'l112', 'l134', 'l155', 'l175', 'l205', 'l220', 'l230', 'l239', 'l246', 'l252', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265']", + "113, vivo. ['l38', 'l65', 'l90', 'l113', 'l135', 'l156', 'l176', 'l206', 'l221', 'l231', 'l240', 'l247', 'l253', 'l259', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271']", + "115, increases ['l39', 'l66', 'l91', 'l114', 'l136', 'l157', 'l177', 'l207', 'l222', 'l232', 'l241', 'l248', 'l254', 'l260', 'l266', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278']", + "118, cell ['l40', 'l67', 'l92', 'l115', 'l137', 'l158', 'l178', 'l208', 'l223', 'l233', 'l242', 'l249', 'l255', 'l261', 'l267', 'l272', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284']", + "119, death ['l41', 'l68', 'l93', 'l116', 'l138', 'l159', 'l179', 'l209', 'l224', 'l234', 'l243', 'l250', 'l256', 'l262', 'l268', 'l273', 'l279', 'l285', 'l286']", + "122, in ['l42', 'l69', 'l94', 'l117', 'l139', 'l160', 'l180', 'l225', 'l235', 'l257', 'l263', 'l269', 'l274', 'l280', 'l285', 'l287', 'l288', 'l289', 'l290']", + "123, vivo ['l43', 'l70', 'l95', 'l118', 'l140', 'l161', 'l181', 'l210', 'l226', 'l236', 'l244', 'l251', 'l258', 'l264', 'l270', 'l275', 'l281', 'l286', 'l287', 'l291', 'l292']", + "125, stimulates ['l44', 'l276', 'l282', 'l288', 'l291', 'l293', 'l294', 'l295']", + "127, necrosis ['l45', 'l71', 'l265', 'l271', 'l277', 'l283', 'l289', 'l292', 'l293', 'l296', 'l297']", + "130, in ['l278', 'l284', 'l290', 'l294', 'l296', 'l298']", + "131, vitro. ['l295', 'l297', 'l298']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "lungs" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ang2-/-" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "lungs" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ang2-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ang2-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "lung", + "epithelial", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ang2-/-" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death,", + "death" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death,", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "short", + "interfering", + "RNA", + "(siRNA)", + "targeted", + "to", + "Ang2." + ] + }, + "context": { + "val": "cells", + "words": [ + "lung", + "epithelial", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "short", + "interfering", + "RNA", + "(siRNA)", + "targeted", + "to", + "Ang2.", + "siRNA-treated" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death,", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "short", + "interfering", + "RNA", + "(siRNA)", + "targeted", + "to", + "Ang2.", + "siRNA-treated" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "short", + "interfering", + "RNA", + "(siRNA)", + "targeted", + "to", + "Ang2.", + "siRNA-treated" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces", + "activates", + "increases", + "stimulates" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "short", + "interfering", + "RNA", + "(siRNA)", + "targeted", + "to", + "Ang2.", + "siRNA-treated" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "pathways" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "short", + "interfering", + "RNA", + "(siRNA)", + "targeted", + "to", + "Ang2.", + "siRNA-treated" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo.", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "short", + "interfering" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "lung", + "epithelial", + "cells," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ang2-/-" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces", + "activates" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ang2-/-" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "pathways" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces", + "activates" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "pathways" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "activates", + "increases", + "stimulates" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "activates", + "increases" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "pathways" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "activates", + "increases", + "stimulates" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo.", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo.", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "pathways" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo.", + "vivo" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo.", + "vivo" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases", + "stimulates" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases", + "stimulates" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in" + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "17072312", + "TEXT": "Throughout spermatogenesis, developing germ cells remain attached to Sertoli cells via testis-specific anchoring junctions. If adhesion between these cell types is compromised, germ cells detach from the seminiferous epithelium and infertility often results. Previously, we reported that Adjudin is capable of inducing germ cell loss from the epithelium. In a small subset of animals, however, oral administration of Adjudin (50 mg per kg body weight (b.w.) for 29 d) resulted in adverse effects such as liver inflammation and muscle atrophy. Here, we report a novel approach in which Adjudin is specifically targeted to the testis by conjugating Adjudin to a recombinant follicle-stimulating hormone (FSH) mutant, which serves as its 'carrier'. Using this approach, infertility was induced in adult rats when 0.5 microg Adjudin per kg b.w. was administered intraperitoneally, which was similar to results when 50 mg per kg b.w. was given orally. This represents a substantial increase in Adjudin's selectivity and efficacy as a male contraceptive.", + "TAG_DATA": [ + "115, induced {'effect': 'B-positive'}", + "117, adult {'context': 'B-organism'}", + "118, rats {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "113, infertility ['l0', 'l1', 'l2']", + "115, induced ['l0', 'l3', 'l4']", + "117, adult ['l1', 'l3', 'l5']", + "118, rats ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "adult", + "rats" + ] + } + } + ] + }, + { + "PMID": "17072309", + "TEXT": "Ventricular tachycardia is a common and lethal complication after myocardial infarction. Here we show that focal transfer of a gene encoding a dominant-negative version of the KCNH2 potassium channel (KCNH2-G628S) to the infarct scar border eliminated all ventricular arrhythmias in a porcine model. No proarrhythmia or other negative effects were discernable. Our results demonstrate the potential viability of gene therapy for ablation of ventricular arrhythmias.", + "TAG_DATA": [ + "15, focal {'perturbing_action': 'B-other'}", + "16, transfer {'perturbing_action': 'I-other'}", + "17, of {'perturbing_action': 'I-other'}", + "18, a {'perturbing_action': 'I-other'}", + "19, gene {'perturbing_action': 'I-other'}", + "20, encoding {'perturbing_action': 'I-other'}", + "21, a {'perturbing_action': 'I-other'}", + "22, dominant-negative {'perturbing_action': 'I-other'}", + "23, version {'perturbing_action': 'I-other'}", + "24, of {'perturbing_action': 'I-other'}", + "25, the {'perturbing_action': 'I-other'}", + "26, KCNH2 {'perturbing_action': 'I-other'}", + "27, potassium {'perturbing_action': 'I-other'}", + "28, channel {'perturbing_action': 'I-other'}", + "29, (KCNH2-G628S) {'perturbing_action': 'I-other'}", + "30, to {'perturbing_action': 'I-other'}", + "41, porcine {'context': 'B-organism'}", + "42, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "15, focal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "16, transfer ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "17, of ['l1', 'l17', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "18, a ['l2', 'l18', 'l33', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "19, gene ['l3', 'l19', 'l34', 'l48', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "20, encoding ['l4', 'l20', 'l35', 'l49', 'l62', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "21, a ['l5', 'l21', 'l36', 'l50', 'l63', 'l75', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "22, dominant-negative ['l6', 'l22', 'l37', 'l51', 'l64', 'l76', 'l87', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "23, version ['l7', 'l23', 'l38', 'l52', 'l65', 'l77', 'l88', 'l98', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "24, of ['l8', 'l24', 'l39', 'l53', 'l66', 'l78', 'l89', 'l99', 'l108', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "25, the ['l9', 'l25', 'l40', 'l54', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "26, KCNH2 ['l10', 'l26', 'l41', 'l55', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l125', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "27, potassium ['l11', 'l27', 'l42', 'l56', 'l69', 'l81', 'l92', 'l102', 'l111', 'l119', 'l126', 'l132', 'l138', 'l139', 'l140', 'l141', 'l142']", + "28, channel ['l12', 'l28', 'l43', 'l57', 'l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l127', 'l133', 'l138', 'l143', 'l144', 'l145', 'l146']", + "29, (KCNH2-G628S) ['l13', 'l29', 'l44', 'l58', 'l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l128', 'l134', 'l139', 'l143', 'l147', 'l148', 'l149']", + "30, to ['l14', 'l30', 'l45', 'l59', 'l72', 'l84', 'l95', 'l105', 'l114', 'l122', 'l129', 'l135', 'l140', 'l144', 'l147', 'l150', 'l151']", + "41, porcine ['l15', 'l31', 'l46', 'l60', 'l73', 'l85', 'l96', 'l106', 'l115', 'l123', 'l130', 'l136', 'l141', 'l145', 'l148', 'l150', 'l152']", + "42, model. ['l16', 'l32', 'l47', 'l61', 'l74', 'l86', 'l97', 'l107', 'l116', 'l124', 'l131', 'l137', 'l142', 'l146', 'l149', 'l151', 'l152']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "focal", + "transfer", + "of", + "a", + "gene", + "encoding", + "dominant-negative", + "version", + "the", + "KCNH2", + "potassium", + "channel", + "(KCNH2-G628S)", + "to" + ] + }, + "context": { + "val": "organism", + "words": [ + "porcine", + "model." + ] + } + } + ] + }, + { + "PMID": "17041596", + "TEXT": "Persistent viral infections are a major health concern. One obstacle inhibiting the clearance of persistent infections is functional inactivation of antiviral T cells. Although such immunosuppression occurs rapidly after infection, the mechanisms that induce the loss of T-cell activity and promote viral persistence are unknown. Herein we document that persistent viral infection in mice results in a significant upregulation of interleukin (IL)-10 by antigen-presenting cells, leading to impaired T-cell responses. Genetic removal of Il10 resulted in the maintenance of robust effector T-cell responses, the rapid elimination of virus and the development of antiviral memory T-cell responses. Therapeutic administration of an antibody that blocks the IL-10 receptor restored T-cell function and eliminated viral infection. Thus, we identify a single molecule that directly induces immunosuppression leading to viral persistence and demonstrate that a therapy to neutralize IL-10 results in T-cell recovery and the prevention of viral persistence.", + "TAG_DATA": [ + "53, mice {'context': 'B-organism'}", + "63, antigen-presenting {'context': 'B-cells'}", + "64, cells, {'context': 'I-cells'}", + "70, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "71, removal {'perturbing_action': 'I-gene loss-of-function'}", + "72, of {'perturbing_action': 'I-gene loss-of-function'}", + "73, Il10 {'perturbing_action': 'I-gene loss-of-function'}", + "102, blocks {'perturbing_action': 'I-pharmacological inhibition'}", + "103, the {'perturbing_action': 'I-pharmacological inhibition'}", + "104, IL-10 {'perturbing_action': 'I-pharmacological inhibition'}", + "105, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "107, T-cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "53, mice ['l0', 'l1']", + "63, antigen-presenting ['l0', 'l2', 'l3']", + "64, cells, ['l1', 'l2', 'l4']", + "70, Genetic ['l5', 'l6', 'l7']", + "71, removal ['l5', 'l8', 'l9']", + "72, of ['l6', 'l8', 'l10']", + "73, Il10 ['l3', 'l4', 'l7', 'l9', 'l10']", + "102, blocks ['l11', 'l12', 'l13', 'l14']", + "103, the ['l11', 'l15', 'l16', 'l17']", + "104, IL-10 ['l12', 'l15', 'l18', 'l19']", + "105, receptor ['l13', 'l16', 'l18', 'l20']", + "107, T-cell ['l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "antigen-presenting", + "cells," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Il10" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blocks", + "the", + "IL-10", + "receptor" + ] + }, + "context": { + "val": "cells", + "words": [ + "T-cell" + ] + } + } + ] + }, + { + "PMID": "16951684", + "TEXT": "Helicobacter pylori infection causes gastric pathology such as ulcer and carcinoma. Because H. pylori is auxotrophic for cholesterol, we have explored the assimilation of cholesterol by H. pylori in infection. Here we show that H. pylori follows a cholesterol gradient and extracts the lipid from plasma membranes of epithelial cells for subsequent glucosylation. Excessive cholesterol promotes phagocytosis of H. pylori by antigen-presenting cells, such as macrophages and dendritic cells, and enhances antigen-specific T cell responses. A cholesterol-rich diet during bacterial challenge leads to T cell-dependent reduction of the H. pylori burden in the stomach. Intrinsic alpha-glucosylation of cholesterol abrogates phagocytosis of H. pylori and subsequent T cell activation. We identify the gene hp0421 as encoding the enzyme cholesterol-alpha-glucosyltransferase responsible for cholesterol glucosylation. Generation of knockout mutants lacking hp0421 corroborates the importance of cholesteryl glucosides for escaping phagocytosis, T cell activation and bacterial clearance in vivo. Thus, we propose a mechanism regulating the host-pathogen interaction whereby glucosylation of a lipid tips the scales towards immune evasion or response.", + "TAG_DATA": [ + "61, antigen-presenting {'context': 'B-cells'}", + "62, cells, {'context': 'I-cells'}", + "65, macrophages {'context': 'B-cells'}", + "67, dendritic {'context': 'B-cells'}", + "68, cells, {'context': 'I-cells'}", + "72, T {'context': 'B-cells'}", + "73, cell {'context': 'I-cells'}", + "93, stomach. {'context': 'B-tissue/organ'}", + "98, abrogates {'effect': 'B-negative'}", + "99, phagocytosis {'phenotype': 'B-mitophagy'}", + "105, T {'context': 'B-cells'}", + "106, cell {'context': 'B-cells'}", + "126, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "127, hp0421 {'perturbing_action': 'I-gene loss-of-function'}", + "143, in {'context': 'B-in vivo'}", + "144, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "55, promotes ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "61, antigen-presenting ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "62, cells, ['l1', 'l7', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "65, macrophages ['l2', 'l8', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "67, dendritic ['l3', 'l9', 'l15', 'l20', 'l25', 'l26', 'l27', 'l28']", + "68, cells, ['l4', 'l10', 'l16', 'l21', 'l25', 'l29', 'l30', 'l31']", + "72, T ['l5', 'l11', 'l17', 'l22', 'l26', 'l29', 'l32']", + "73, cell ['l6', 'l12', 'l18', 'l23', 'l27', 'l30', 'l32']", + "93, stomach. ['l13', 'l19', 'l24', 'l28', 'l31']", + "98, abrogates ['l33', 'l34', 'l35']", + "99, phagocytosis ['l33', 'l36', 'l37']", + "105, T ['l34', 'l36', 'l38']", + "106, cell ['l35', 'l37', 'l38']", + "125, mutants ['l39', 'l40', 'l41', 'l42']", + "126, lacking ['l39', 'l43', 'l44', 'l45']", + "127, hp0421 ['l40', 'l43', 'l46', 'l47']", + "143, in ['l41', 'l44', 'l46', 'l48']", + "144, vivo. ['l42', 'l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + }, + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + }, + { + "phenotype": { + "val": "mitophagy", + "words": [ + "phagocytosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "hp0421" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "16862154", + "TEXT": "CD82, also known as KAI1, was recently identified as a prostate cancer metastasis suppressor gene on human chromosome 11p1.2 (ref. 1). The product of CD82 is KAI1, a 40- to 75-kDa tetraspanin cell-surface protein also known as the leukocyte cell-surface marker CD82 (refs. 1,2). Downregulation of KAI1 has been found to be clinically associated with metastatic progression in a variety of cancers, whereas overexpression of CD82 specifically suppresses tumor metastasis in various animal models. To define the mechanism of action of KAI1, we used a yeast two-hybrid screen and identified an endothelial cell-surface protein, DARC (also known as gp-Fy), as an interacting partner of KAI1. Our results indicate that the cancer cells expressing KAI1 attach to vascular endothelial cells through direct interaction between KAI1 and DARC, and that this interaction leads to inhibition of tumor cell proliferation and induction of senescence by modulating the expression of TBX2 and p21. Furthermore, the metastasis-suppression activity of KAI1 was significantly compromised in DARC knockout mice, whereas KAI1 completely abrogated pulmonary metastasis in wild-type and heterozygous littermates. These results provide direct evidence that DARC is essential for the function of CD82 as a suppressor of metastasis.", + "TAG_DATA": [ + "132, inhibition {'effect': 'B-negative'}", + "134, tumor {'context': 'B-transformed cells'}", + "135, cell {'context': 'I-transformed cells'}", + "136, proliferation {'phenotype': 'B-proliferation'}", + "138, induction {'effect': 'B-positive'}", + "140, senescence {'phenotype': 'B-senescence'}", + "159, DARC {'perturbing_action': 'B-gene loss-of-function'}", + "160, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "161, mice, {'context': 'B-organism'}", + "165, abrogated {'effect': 'B-negative'}", + "166, pulmonary {'phenotype': 'B-metastasis'}", + "167, metastasis {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "132, inhibition ['l0', 'l1', 'l2', 'l3', 'l4']", + "134, tumor ['l0', 'l5', 'l6', 'l7', 'l8']", + "135, cell ['l1', 'l5', 'l9', 'l10', 'l11']", + "136, proliferation ['l2', 'l6', 'l9', 'l12', 'l13']", + "138, induction ['l3', 'l7', 'l10', 'l12', 'l14']", + "140, senescence ['l4', 'l8', 'l11', 'l13', 'l14']", + "159, DARC ['l15', 'l16']", + "160, knockout ['l15', 'l17']", + "161, mice, ['l16', 'l17']", + "165, abrogated ['l18', 'l19']", + "166, pulmonary ['l18', 'l20']", + "167, metastasis ['l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "DARC", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogated" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "pulmonary", + "metastasis" + ] + } + } + ] + }, + { + "PMID": "16819549", + "TEXT": "The von Hippel-Lindau tumor suppressor, pVHL, forms part of an E3 ubiquitin ligase complex that targets specific substrates for degradation, including hypoxia-inducible factor-1alpha (HIF-1alpha), which is involved in tumor progression and angiogenesis. It remains unclear, however, how pVHL is destabilized. Here we show that E2-EPF ubiquitin carrier protein (UCP) associates with and targets pVHL for ubiquitin-mediated proteolysis in cells, thereby stabilizing HIF-1alpha. UCP is detected coincidently with HIF-1alpha in human primary liver, colon and breast tumors, and metastatic cholangiocarcinoma and colon cancer cells. UCP level correlates inversely with pVHL level in most tumor cell lines. In vitro and in vivo, forced expression of UCP boosts tumor-cell proliferation, invasion and metastasis through effects on the pVHL-HIF pathway. Our results suggest that UCP helps stabilize HIF-1alpha and may be a new molecular target for therapeutic intervention in human cancers.", + "TAG_DATA": [ + "95, In {'context': 'B-in vitro'}", + "96, vitro {'context': 'I-in vitro'}", + "98, in {'context': 'B-in vivo'}", + "99, vivo, {'context': 'I-in vivo'}", + "100, forced {'perturbing_action': 'B-gene gain-of-function'}", + "101, expression {'perturbing_action': 'I-gene gain-of-function'}", + "102, of {'perturbing_action': 'I-gene gain-of-function'}", + "103, UCP {'perturbing_action': 'I-gene gain-of-function'}", + "104, boosts {'effect': 'B-positive'}", + "105, tumor-cell {'context': 'B-cells'}", + "106, proliferation, {'phenotype': 'B-proliferation'}", + "107, invasion {'phenotype': 'B-invasion'}", + "109, metastasis {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "95, In ['l0']", + "96, vitro ['l0']", + "98, in ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "99, vivo, ['l1', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "100, forced ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "101, expression ['l7', 'l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "102, of ['l8', 'l16', 'l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "103, UCP ['l9', 'l17', 'l24', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "104, boosts ['l2', 'l10', 'l18', 'l25', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "105, tumor-cell ['l3', 'l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l45', 'l46', 'l47']", + "106, proliferation, ['l4', 'l12', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l48', 'l49']", + "107, invasion ['l5', 'l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l50']", + "109, metastasis ['l6', 'l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l50']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + }, + "effect": { + "val": "positive", + "words": [ + "boosts" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "vivo," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "UCP" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "forced", + "expression", + "of", + "UCP" + ] + }, + "effect": { + "val": "positive", + "words": [ + "boosts" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "forced", + "expression", + "of", + "UCP" + ] + }, + "context": { + "val": "cells", + "words": [ + "tumor-cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "forced", + "expression", + "of", + "UCP" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "forced", + "expression", + "of", + "UCP" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "forced", + "expression", + "of", + "UCP" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "boosts" + ] + }, + "context": { + "val": "cells", + "words": [ + "tumor-cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "boosts" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "boosts" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "boosts" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "tumor-cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "tumor-cell" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "tumor-cell" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + } + ] + }, + { + "PMID": "16767097", + "TEXT": "Although much is known about environmental factors that predispose individuals to hypertension and cardiovascular disease, little information is available regarding the genetic and signaling events involved. Indeed, few genes associated with the progression of these pathologies have been discovered despite intensive research in animal models and human populations. Here we identify Vav3, a GDP-GTP exchange factor that stimulates Rho and Rac GTPases, as an essential factor regulating the homeostasis of the cardiovascular system. Vav3-deficient mice exhibited tachycardia, systemic arterial hypertension and extensive cardiovascular remodeling. These mice also showed hyperactivity of sympathetic neurons from the time of birth. The high catecholamine levels associated with this condition led to the activation of the renin-angiotensin system, increased levels of kidney-related hormones and the progressive loss of cardiovascular and renal homeostasis. Pharmacological studies with drugs targeting sympathetic and renin-angiotensin responses confirmed the causative role and hierarchy of these events in the development of the Vav3-null mouse phenotype. These observations uncover the crucial role of Vav3 in the regulation of the sympathetic nervous system (SNS) and cardiovascular physiology, and reveal a signaling pathway that could be involved in the pathophysiology of human disease states involving tachycardia and sympathetic hyperactivity with unknown etiologies.", + "TAG_DATA": [ + "73, Vav3-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "74, mice {'context': 'B-organism'}", + "85, mice {'context': 'B-organism'}", + "150, Vav3-null {'perturbing_action': 'B-gene loss-of-function'}", + "151, mouse {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, Vav3-deficient ['l0']", + "74, mice ['l0']", + "150, Vav3-null ['l1']", + "151, mouse ['l1']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Vav3-deficient", + "Vav3-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mouse" + ] + } + } + ] + }, + { + "PMID": "16732281", + "TEXT": "Here we report the presence of hyperphagia, obesity and insulin resistance in knockout mice deficient in IL-18 or IL-18 receptor, and in mice transgenic for expression of IL-18 binding protein. Obesity of Il18-/- mice resulted from accumulation of fat tissue based on increased food intake. Il18-/- mice also had hyperinsulinemia, consistent with insulin resistance and hyperglycemia. Insulin resistance was secondary to obesity induced by increased food intake and occurred at the liver level as well as at the muscle and fat-tissue level. The molecular mechanisms responsible for the hepatic insulin resistance in the Il18-/- mice involved an enhanced expression of genes associated with gluconeogenesis in the liver of Il18-/- mice, resulting from defective phosphorylation of STAT3. Recombinant IL-18 (rIL-18) administered intracerebrally inhibited food intake. In addition, rIL-18 reversed hyperglycemia in Il18-/- mice through activation of STAT3 phosphorylation. These findings indicate a new role of IL-18 in the homeostasis of energy intake and insulin sensitivity.", + "TAG_DATA": [ + "12, knockout {'context': 'B-organism'}", + "13, mice {'context': 'I-organism'}", + "14, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "15, in {'perturbing_action': 'I-gene loss-of-function'}", + "16, IL-18 {'perturbing_action': 'I-gene loss-of-function'}", + "17, or {'perturbing_action': 'I-gene loss-of-function'}", + "18, IL-18 {'perturbing_action': 'I-gene loss-of-function'}", + "19, receptor, {'perturbing_action': 'I-gene loss-of-function'}", + "22, mice {'context': 'B-organism'}", + "23, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "24, for {'perturbing_action': 'I-gene gain-of-function'}", + "25, expression {'perturbing_action': 'I-gene gain-of-function'}", + "26, of {'perturbing_action': 'I-gene gain-of-function'}", + "27, IL-18 {'perturbing_action': 'I-gene gain-of-function'}", + "28, binding {'perturbing_action': 'I-gene gain-of-function'}", + "29, protein. {'perturbing_action': 'I-gene gain-of-function'}", + "32, Il18-/- {'perturbing_action': 'B-gene loss-of-function'}", + "33, mice {'context': 'B-organism'}", + "45, Il18-/- {'perturbing_action': 'B-gene loss-of-function'}", + "46, mice {'context': 'B-organism'}", + "93, Il18-/- {'perturbing_action': 'B-gene loss-of-function'}", + "94, mice {'context': 'B-organism'}", + "106, liver {'context': 'B-tissue/organ'}", + "108, Il18-/- {'perturbing_action': 'B-gene loss-of-function'}", + "109, mice, {'context': 'B-organism'}", + "130, Il18-/- {'perturbing_action': 'B-gene loss-of-function'}", + "131, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "12, knockout ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "13, mice ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "14, deficient ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "15, in ['l2', 'l11', 'l19', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "16, IL-18 ['l3', 'l12', 'l20', 'l31', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "17, or ['l4', 'l13', 'l21', 'l32', 'l46', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "18, IL-18 ['l5', 'l14', 'l22', 'l33', 'l47', 'l57', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "19, receptor, ['l6', 'l15', 'l23', 'l34', 'l48', 'l58', 'l70', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "22, mice ['l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "23, transgenic ['l91', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "24, for ['l92', 'l107', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "25, expression ['l93', 'l108', 'l122', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "26, of ['l94', 'l109', 'l123', 'l136', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160']", + "27, IL-18 ['l71', 'l95', 'l110', 'l124', 'l137', 'l149', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171']", + "28, binding ['l35', 'l59', 'l72', 'l96', 'l111', 'l125', 'l138', 'l150', 'l161', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181']", + "29, protein. ['l36', 'l60', 'l73', 'l97', 'l112', 'l126', 'l139', 'l151', 'l162', 'l172', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190']", + "32, Il18-/- ['l7', 'l16', 'l24', 'l37', 'l49', 'l61', 'l74', 'l83', 'l98', 'l113', 'l127', 'l140', 'l152', 'l163', 'l173', 'l182', 'l191']", + "33, mice ['l8', 'l17', 'l25', 'l38', 'l50', 'l62', 'l75', 'l84', 'l99', 'l114', 'l128', 'l141', 'l153', 'l164', 'l174', 'l183', 'l191']", + "45, Il18-/- ['l26', 'l39', 'l51', 'l63', 'l76', 'l85', 'l100', 'l115', 'l129', 'l142', 'l154', 'l165', 'l175', 'l184', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197']", + "46, mice ['l27', 'l40', 'l52', 'l64', 'l77', 'l86', 'l101', 'l116', 'l130', 'l143', 'l155', 'l166', 'l176', 'l185', 'l192', 'l198', 'l199', 'l200', 'l201']", + "93, Il18-/- ['l28', 'l41', 'l53', 'l65', 'l78', 'l87', 'l102', 'l117', 'l131', 'l144', 'l156', 'l167', 'l177', 'l186', 'l193', 'l198', 'l202', 'l203', 'l204', 'l205']", + "94, mice ['l9', 'l18', 'l29', 'l42', 'l54', 'l66', 'l79', 'l88', 'l103', 'l118', 'l132', 'l145', 'l157', 'l168', 'l178', 'l187', 'l194', 'l199', 'l202', 'l206', 'l207', 'l208']", + "106, liver ['l30', 'l43', 'l55', 'l67', 'l80', 'l89', 'l104', 'l119', 'l133', 'l146', 'l158', 'l169', 'l179', 'l188', 'l195', 'l200', 'l203', 'l206', 'l209', 'l210']", + "108, Il18-/- ['l44', 'l68', 'l81', 'l105', 'l120', 'l134', 'l147', 'l159', 'l170', 'l180', 'l189', 'l196', 'l204', 'l207', 'l209', 'l211']", + "109, mice, ['l45', 'l56', 'l69', 'l82', 'l90', 'l106', 'l121', 'l135', 'l148', 'l160', 'l171', 'l181', 'l190', 'l197', 'l201', 'l205', 'l208', 'l210', 'l211']", + "130, Il18-/- ['l212']", + "131, mice ['l212']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "knockout", + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "IL-18", + "or", + "receptor,", + "Il18-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "IL-18", + "or", + "receptor,", + "Il18-/-" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "expression", + "of", + "IL-18", + "binding", + "protein." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "expression", + "of", + "IL-18", + "binding", + "protein." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "16715087", + "TEXT": "Hepatic fibrosis, the common response associated with chronic liver diseases, ultimately leads to cirrhosis, a major public health problem worldwide. We recently showed that activation of hepatic cannabinoid CB2 receptors limits progression of experimental liver fibrosis. We also found that during the course of chronic hepatitis C, daily cannabis use is an independent predictor of fibrosis progression. Overall, these results suggest that endocannabinoids may drive both CB2-mediated antifibrogenic effects and CB2-independent profibrogenic effects. Here we investigated whether activation of cannabinoid CB1 receptors (encoded by Cnr1) promotes progression of fibrosis. CB1 receptors were highly induced in human cirrhotic samples and in liver fibrogenic cells. Treatment with the CB1 receptor antagonist SR141716A decreased the wound-healing response to acute liver injury and inhibited progression of fibrosis in three models of chronic liver injury. We saw similar changes in Cnr1-/- mice as compared to wild-type mice. Genetic or pharmacological inactivation of CB1 receptors decreased fibrogenesis by lowering hepatic transforming growth factor (TGF)-beta1 and reducing accumulation of fibrogenic cells in the liver after apoptosis and growth inhibition of hepatic myofibroblasts. In conclusion, our study shows that CB1 receptor antagonists hold promise for the treatment of liver fibrosis.", + "TAG_DATA": [ + "116, liver {'context': 'B-tissue/organ'}", + "135, Cnr1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "136, mice {'context': 'B-organism'}", + "141, mice. {'context': 'B-organism'}", + "144, pharmacological {'perturbing_action': 'B-gene loss-of-function'}", + "145, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "146, of {'perturbing_action': 'I-gene loss-of-function'}", + "147, CB1 {'perturbing_action': 'I-gene loss-of-function'}", + "148, receptors {'perturbing_action': 'I-gene loss-of-function'}", + "162, fibrogenic {'context': 'B-cells'}", + "163, cells {'context': 'I-cells'}", + "166, liver {'context': 'B-tissue/organ'}", + "168, apoptosis {'phenotype': 'B-apoptosis'}", + "173, hepatic {'context': 'B-cells'}", + "174, myofibroblasts. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "135, Cnr1-/- ['l0', 'l1', 'l2', 'l3', 'l4']", + "136, mice ['l0', 'l5', 'l6', 'l7', 'l8']", + "141, mice. ['l1', 'l5', 'l9', 'l10', 'l11']", + "144, pharmacological ['l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "145, inactivation ['l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "146, of ['l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "147, CB1 ['l14', 'l23', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "148, receptors ['l15', 'l24', 'l32', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "162, fibrogenic ['l2', 'l6', 'l9', 'l16', 'l25', 'l33', 'l40', 'l46', 'l52', 'l53', 'l54', 'l55', 'l56']", + "163, cells ['l3', 'l7', 'l10', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l57', 'l58', 'l59', 'l60']", + "166, liver ['l4', 'l8', 'l11', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l61', 'l62', 'l63']", + "168, apoptosis ['l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l64', 'l65']", + "173, hepatic ['l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l66']", + "174, myofibroblasts. ['l21', 'l30', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l65', 'l66']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cnr1-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cnr1-/-", + "pharmacological", + "inactivation", + "of", + "CB1", + "receptors" + ] + }, + "context": { + "val": "cells", + "words": [ + "fibrogenic", + "cells", + "hepatic", + "myofibroblasts." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cnr1-/-", + "pharmacological", + "inactivation", + "of", + "CB1", + "receptors" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pharmacological", + "inactivation", + "of", + "CB1", + "receptors" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "fibrogenic", + "cells", + "hepatic", + "myofibroblasts." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "16648859", + "TEXT": "The mechanisms through which hematopoietic cytokines accelerate revascularization are unknown. Here, we show that the magnitude of cytokine-mediated release of SDF-1 from platelets and the recruitment of nonendothelial CXCR4+ VEGFR1+ hematopoietic progenitors, 'hemangiocytes,' constitute the major determinant of revascularization. Soluble Kit-ligand (sKitL), thrombopoietin (TPO, encoded by Thpo) and, to a lesser extent, erythropoietin (EPO) and granulocyte-macrophage colony-stimulating factor (GM-CSF) induced the release of SDF-1 from platelets, enhancing neovascularization through mobilization of CXCR4+ VEGFR1+ hemangiocytes. Although revascularization of ischemic hindlimbs was partially diminished in mice deficient in both GM-CSF and G-CSF (Csf2-/- Csf3-/-), profound impairment in neovascularization was detected in sKitL-deficient Mmp9-/- as well as thrombocytopenic Thpo-/- and TPO receptor-deficient (Mpl-/-) mice. SDF-1-mediated mobilization and incorporation of hemangiocytes into ischemic limbs were impaired in Thpo-/-, Mpl-/- and Mmp9-/- mice. Transplantation of CXCR4+ VEGFR1+ hemangiocytes into Mmp9-/- mice restored revascularization, whereas inhibition of CXCR4 abrogated cytokine- and VEGF-A-mediated mobilization of CXCR4+ VEGFR1+ cells and suppressed angiogenesis. In conclusion, hematopoietic cytokines, through graded deployment of SDF-1 from platelets, support mobilization and recruitment of CXCR4+ VEGFR1+ hemangiocytes, whereas VEGFR1 is essential for their angiogenic competency for augmenting revascularization. Delivery of SDF-1", + "TAG_DATA": [ + "78, hindlimbs {'context': 'B-tissue/organ'}", + "83, mice {'context': 'B-organism'}", + "91, Csf3-/-), {'perturbing_action': 'I-gene loss-of-function'}", + "99, sKitL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "100, Mmp9-/- {'perturbing_action': 'I-gene loss-of-function'}", + "104, thrombocytopenic {'perturbing_action': 'B-gene loss-of-function'}", + "105, Thpo-/- {'perturbing_action': 'I-gene loss-of-function'}", + "106, and {'perturbing_action': 'I-gene loss-of-function'}", + "107, TPO {'perturbing_action': 'I-gene loss-of-function'}", + "108, receptor-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "109, (Mpl-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "110, mice. {'context': 'B-organism'}", + "116, hemangiocytes {'context': 'B-cells'}", + "123, Thpo-/-, {'perturbing_action': 'B-gene loss-of-function'}", + "124, Mpl-/- {'perturbing_action': 'I-gene loss-of-function'}", + "126, Mmp9-/- {'perturbing_action': 'B-gene loss-of-function'}", + "127, mice. {'context': 'B-organism'}", + "128, Transplantation {'context': 'B-xenograft'}", + "130, CXCR4+ {'context': 'B-cells'}", + "131, VEGFR1+ {'context': 'I-cells'}", + "132, hemangiocytes {'context': 'I-cells'}", + "134, Mmp9-/- {'perturbing_action': 'B-gene loss-of-function'}", + "135, mice {'context': 'B-organism'}", + "139, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "140, of {'perturbing_action': 'I-pharmacological inhibition'}", + "141, CXCR4 {'perturbing_action': 'I-pharmacological inhibition'}", + "148, CXCR4+ {'context': 'B-cells'}", + "149, VEGFR1+ {'context': 'I-cells'}", + "150, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "78, hindlimbs ['l0', 'l1']", + "83, mice ['l0', 'l2', 'l3', 'l4']", + "84, deficient ['l2', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "91, Csf3-/-), ['l1', 'l3', 'l5', 'l11', 'l12', 'l13', 'l14', 'l15']", + "99, sKitL-deficient ['l6', 'l11', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "100, Mmp9-/- ['l4', 'l7', 'l12', 'l16', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "104, thrombocytopenic ['l8', 'l13', 'l17', 'l24', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "105, Thpo-/- ['l18', 'l25', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "106, and ['l19', 'l26', 'l32', 'l40', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "107, TPO ['l33', 'l41', 'l50', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "108, receptor-deficient ['l34', 'l42', 'l51', 'l59', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "109, (Mpl-/-) ['l20', 'l27', 'l35', 'l43', 'l52', 'l60', 'l67', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "110, mice. ['l9', 'l14', 'l21', 'l28', 'l36', 'l44', 'l53', 'l61', 'l68', 'l74', 'l80', 'l81']", + "116, hemangiocytes ['l10', 'l15', 'l22', 'l29', 'l37', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l82', 'l83']", + "123, Thpo-/-, ['l38', 'l46', 'l55', 'l63', 'l70', 'l76', 'l82', 'l84', 'l85', 'l86']", + "124, Mpl-/- ['l47', 'l56', 'l64', 'l71', 'l77', 'l84', 'l87', 'l88', 'l89', 'l90']", + "126, Mmp9-/- ['l48', 'l57', 'l65', 'l72', 'l78', 'l85', 'l87', 'l91', 'l92']", + "127, mice. ['l23', 'l30', 'l39', 'l49', 'l58', 'l66', 'l73', 'l79', 'l81', 'l83', 'l86', 'l88', 'l91']", + "128, Transplantation ['l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "130, CXCR4+ ['l93', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "131, VEGFR1+ ['l89', 'l94', 'l101', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "132, hemangiocytes ['l90', 'l92', 'l95', 'l102', 'l108', 'l114', 'l115', 'l116', 'l117', 'l118']", + "134, Mmp9-/- ['l96', 'l103', 'l109', 'l114', 'l119', 'l120', 'l121', 'l122']", + "135, mice ['l97', 'l104', 'l110', 'l115', 'l119']", + "139, inhibition ['l123', 'l124', 'l125', 'l126', 'l127']", + "140, of ['l123', 'l128', 'l129', 'l130', 'l131']", + "141, CXCR4 ['l124', 'l128', 'l132', 'l133', 'l134']", + "148, CXCR4+ ['l98', 'l105', 'l111', 'l116', 'l120', 'l125', 'l129', 'l132', 'l135', 'l136']", + "149, VEGFR1+ ['l99', 'l106', 'l112', 'l117', 'l121', 'l126', 'l130', 'l133', 'l135', 'l137']", + "150, cells ['l100', 'l107', 'l113', 'l118', 'l122', 'l127', 'l131', 'l134', 'l136', 'l137']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "hindlimbs" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Csf3-/-)," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Csf3-/-),", + "Mmp9-/-", + "sKitL-deficient", + "thrombocytopenic", + "Thpo-/-", + "and", + "TPO", + "receptor-deficient", + "(Mpl-/-)", + "Thpo-/-,", + "Mpl-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Csf3-/-),", + "sKitL-deficient", + "Mmp9-/-", + "thrombocytopenic", + "Thpo-/-", + "and", + "TPO", + "receptor-deficient", + "(Mpl-/-)", + "Thpo-/-,", + "Mpl-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "hemangiocytes", + "VEGFR1+", + "CXCR4+", + "cells" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "Transplantation" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mmp9-/-" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "CXCR4" + ] + }, + "context": { + "val": "cells", + "words": [ + "CXCR4+", + "VEGFR1+", + "cells" + ] + } + } + ] + }, + { + "PMID": "16582918", + "TEXT": "The mechanisms underlying leptin resistance are still being defined. We report here the presence in human blood of several serum leptin-interacting proteins (SLIPs), isolated by leptin-affinity chromatography and identified by mass spectrometry and immunochemical analysis. We confirmed that one of the major SLIPs is C-reactive protein (CRP). In vitro, human CRP directly inhibits the binding of leptin to its receptors and blocks its ability to signal in cultured cells. In vivo, infusion of human CRP into ob/ob mice blocked the effects of leptin upon satiety and weight reduction. In mice that express a transgene encoding human CRP, the actions of human leptin were completely blunted. We also found that physiological concentrations of leptin can stimulate expression of CRP in human primary hepatocytes. Recently, human CRP has been correlated with increased adiposity and plasma leptin. Thus, our results suggest a potential mechanism contributing to leptin resistance, by which circulating CRP binds to leptin and attenuates its physiological functions.", + "TAG_DATA": [ + "47, In {'context': 'B-in vitro'}", + "48, vitro, {'context': 'I-in vitro'}", + "67, cultured {'context': 'B-cells'}", + "68, cells. {'context': 'I-cells'}", + "69, In {'context': 'B-in vivo'}", + "70, vivo, {'context': 'I-in vivo'}", + "76, ob/ob {'context': 'B-organism'}", + "77, mice {'context': 'I-organism'}", + "89, mice {'context': 'B-organism'}", + "91, express {'perturbing_action': 'B-gene gain-of-function'}", + "92, a {'perturbing_action': 'I-gene gain-of-function'}", + "93, transgene {'perturbing_action': 'I-gene gain-of-function'}", + "94, encoding {'perturbing_action': 'I-gene gain-of-function'}", + "95, human {'perturbing_action': 'I-gene gain-of-function'}", + "96, CRP, {'perturbing_action': 'I-gene gain-of-function'}", + "119, human {'context': 'B-cells'}", + "120, primary {'context': 'I-cells'}", + "121, hepatocytes. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "47, In ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "48, vitro, ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "67, cultured ['l1', 'l6', 'l11', 'l12']", + "68, cells. ['l2', 'l7', 'l11']", + "69, In ['l3', 'l8', 'l12', 'l13', 'l14', 'l15']", + "70, vivo, ['l4', 'l9', 'l13', 'l16', 'l17']", + "76, ob/ob ['l14', 'l16', 'l18']", + "77, mice ['l5', 'l10', 'l15', 'l17', 'l18']", + "89, mice ['l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "91, express ['l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "92, a ['l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "93, transgene ['l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "94, encoding ['l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "95, human ['l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "96, CRP, ['l24', 'l29', 'l33', 'l36', 'l38', 'l39']", + "119, human ['l40', 'l41']", + "120, primary ['l40', 'l42']", + "121, hepatocytes. ['l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "express", + "a", + "transgene", + "encoding", + "human", + "CRP," + ] + } + } + ] + }, + { + "PMID": "16462802", + "TEXT": "The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the receptor tyrosine kinase Tie-2 (refs. 1,2). Paracrine Ang-1-mediated activation of Tie-2 acts as a regulator of vessel maturation and vascular quiescence. In turn, the antagonistic ligand Ang-2 acts by an autocrine mechanism and is stored in endothelial Weibel-Palade bodies from where it can be rapidly released upon stimulation. The rapid release of Ang-2 implies functions of the angiopoietin-Tie system beyond its established role during vascular morphogenesis as a regulator of rapid vascular responses. Here we show that mice deficient in Ang-2 (encoded by the gene Angpt2) cannot elicit an inflammatory response in thioglycollate-induced or Staphylococcus aureus-induced peritonitis, or in the dorsal skinfold chamber model. Recombinant Ang-2 restores the inflammation defect in Angpt2(-/-) mice. Intravital microscopy showed normal TNF-alpha-induced leukocyte rolling in the vasculature of Angpt2(-/-)mice, but rolling cells did not firmly adhere to activated endothelium. Cellular experiments showed that Ang-2 promotes adhesion by sensitizing endothelial cells toward TNF-alpha and modulating TNF-alpha-induced expression of endothelial cell adhesion molecules. Together, these findings identify Ang-2 as an autocrine regulator of endothelial cell inflammatory responses. Ang-2 thereby acts as a switch of vascular responsiveness exerting a permissive role for the activities of proinflammatory cytokines.", + "TAG_DATA": [ + "89, mice {'context': 'B-organism'}", + "90, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "91, in {'perturbing_action': 'I-gene loss-of-function'}", + "92, Ang-2 {'perturbing_action': 'I-gene loss-of-function'}", + "93, (encoded {'perturbing_action': 'I-gene loss-of-function'}", + "94, by {'perturbing_action': 'I-gene loss-of-function'}", + "95, the {'perturbing_action': 'I-gene loss-of-function'}", + "96, gene {'perturbing_action': 'I-gene loss-of-function'}", + "97, Angpt2) {'perturbing_action': 'I-gene loss-of-function'}", + "112, dorsal {'context': 'B-tissue/organ'}", + "113, skinfold {'context': 'I-tissue/organ'}", + "114, chamber {'context': 'I-tissue/organ'}", + "123, Angpt2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "124, mice. {'context': 'B-organism'}", + "130, leukocyte {'context': 'B-cells'}", + "134, vasculature {'context': 'B-tissue/organ'}", + "136, Angpt2(-/-)mice, {'perturbing_action': 'B-gene loss-of-function'}", + "139, cells {'context': 'B-cells'}", + "152, promotes {'effect': 'B-positive'}", + "153, adhesion {'phenotype': 'B-adhesion'}", + "156, endothelial {'context': 'B-cells'}", + "157, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "89, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "90, deficient ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "91, in ['l1', 'l8', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "92, Ang-2 ['l2', 'l9', 'l19', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "93, (encoded ['l3', 'l10', 'l20', 'l30', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "94, by ['l4', 'l11', 'l21', 'l31', 'l40', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "95, the ['l5', 'l12', 'l22', 'l32', 'l41', 'l49', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "96, gene ['l6', 'l13', 'l23', 'l33', 'l42', 'l50', 'l57', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "97, Angpt2) ['l7', 'l14', 'l24', 'l34', 'l43', 'l51', 'l58', 'l64', 'l70', 'l71', 'l72', 'l73', 'l74']", + "112, dorsal ['l15', 'l25', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l75', 'l76', 'l77', 'l78']", + "113, skinfold ['l16', 'l26', 'l36', 'l45', 'l53', 'l60', 'l66', 'l71', 'l75', 'l79', 'l80', 'l81']", + "114, chamber ['l17', 'l27', 'l37', 'l46', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l82', 'l83']", + "123, Angpt2(-/-) ['l84', 'l85', 'l86', 'l87', 'l88']", + "124, mice. ['l84', 'l89', 'l90', 'l91', 'l92']", + "130, leukocyte ['l18', 'l28', 'l38', 'l47', 'l55', 'l62', 'l68', 'l73', 'l77', 'l80', 'l82', 'l85', 'l89', 'l93']", + "134, vasculature ['l29', 'l39', 'l48', 'l56', 'l63', 'l69', 'l74', 'l78', 'l81', 'l83', 'l86', 'l90', 'l93', 'l94', 'l95']", + "136, Angpt2(-/-)mice, ['l87', 'l91', 'l94', 'l96', 'l97']", + "139, cells ['l88', 'l92', 'l95', 'l96']", + "152, promotes ['l98', 'l99', 'l100']", + "153, adhesion ['l98', 'l101', 'l102']", + "156, endothelial ['l99', 'l101', 'l103']", + "157, cells ['l97', 'l100', 'l102', 'l103']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Ang-2", + "(encoded", + "by", + "the", + "gene", + "Angpt2)", + "Angpt2(-/-)", + "Angpt2(-/-)mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Ang-2", + "(encoded", + "by", + "the", + "gene", + "Angpt2)", + "Angpt2(-/-)", + "Angpt2(-/-)mice," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "dorsal", + "skinfold", + "chamber", + "vasculature" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Ang-2", + "(encoded", + "by", + "the", + "gene", + "Angpt2)", + "Angpt2(-/-)", + "Angpt2(-/-)mice," + ] + }, + "context": { + "val": "cells", + "words": [ + "leukocyte", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + } + }, + { + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + } + } + ] + }, + { + "PMID": "16444265", + "TEXT": "The interferon (IFN)-gamma-induced TRAIL effector mechanism is a vital component of cancer immunosurveillance by natural killer (NK) cells in mice. Here we show that the main source of IFN-gamma is not the conventional NK cell but a subset of B220(+)Ly6C(-) dendritic cells, which are atypical insofar as they express NK cell-surface molecules. Upon contact with a variety of tumor cells that are poorly recognized by NK cells, B220(+)NK1.1(+) dendritic cells secrete high levels of IFN-gamma and mediate TRAIL-dependent lysis of tumor cells. Adoptive transfer of these IFN-producing killer dendritic cells (IKDCs) into tumor-bearing Rag2(-/-)Il2rg(-/-) mice prevented tumor outgrowth, whereas transfer of conventional NK cells did not. In conclusion, we identified IKDCs as pivotal sensors and effectors of the innate antitumor immune response.", + "TAG_DATA": [ + "86, IFN-producing {'context': 'B-cells'}", + "87, killer {'context': 'I-cells'}", + "88, dendritic {'context': 'I-cells'}", + "89, cells {'context': 'I-cells'}", + "90, (IKDCs) {'context': 'I-cells'}", + "92, tumor-bearing {'perturbing_action': 'B-gene loss-of-function'}", + "93, Rag2(-/-)Il2rg(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "94, mice {'context': 'B-organism'}", + "95, prevented {'effect': 'B-negative'}", + "96, tumor {'phenotype': 'B-tumour regression'}", + "97, outgrowth, {'phenotype': 'I-tumour regression'}", + "102, NK {'context': 'I-cells'}", + "103, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "86, IFN-producing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "87, killer ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "88, dendritic ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "89, cells ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "90, (IKDCs) ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "92, tumor-bearing ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "93, Rag2(-/-)Il2rg(-/-) ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "94, mice ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "95, prevented ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "96, tumor ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "97, outgrowth, ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "102, NK ['l55']", + "103, cells ['l55']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "IFN-producing", + "killer", + "dendritic", + "cells", + "(IKDCs)" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "tumor-bearing", + "Rag2(-/-)Il2rg(-/-)" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "IFN-producing", + "killer", + "dendritic", + "cells", + "(IKDCs)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "IFN-producing", + "killer", + "dendritic", + "cells", + "(IKDCs)" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "outgrowth," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "tumor-bearing", + "Rag2(-/-)Il2rg(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "tumor-bearing", + "Rag2(-/-)Il2rg(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "tumor-bearing", + "Rag2(-/-)Il2rg(-/-)" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "outgrowth," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "outgrowth," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "outgrowth," + ] + } + } + ] + }, + { + "PMID": "16327800", + "TEXT": "The structure and function of blood vessels adapt to environmental changes such as physical development and exercise. This phenomenon is based on the ability of the endothelial cells to sense and respond to blood flow; however, the underlying mechanisms remain unclear. Here we show that the ATP-gated P2X4 ion channel, expressed on endothelial cells and encoded by P2rx4 in mice, has a key role in the response of endothelial cells to changes in blood flow. P2rx4(-/-) mice do not have normal endothelial cell responses to flow, such as influx of Ca(2+) and subsequent production of the potent vasodilator nitric oxide (NO). Additionally, vessel dilation induced by acute increases in blood flow is markedly suppressed in P2rx4(-/-) mice. Furthermore, P2rx4(-/-) mice have higher blood pressure and excrete smaller amounts of NO products in their urine than do wild-type mice. Moreover, no adaptive vascular remodeling, that is, a decrease in vessel size in response to a chronic decrease in blood flow, was observed in P2rx4(-/-) mice. Thus, endothelial P2X4 channels are crucial to flow-sensitive mechanisms that regulate blood pressure and vascular remodeling.", + "TAG_DATA": [ + "75, P2rx4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "76, mice {'context': 'B-organism'}", + "81, endothelial {'context': 'B-cells'}", + "82, cell {'context': 'I-cells'}", + "115, P2rx4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "116, mice. {'context': 'B-organism'}", + "118, P2rx4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "119, mice {'context': 'B-organism'}", + "137, mice. {'context': 'B-organism'}", + "162, P2rx4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "163, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "75, P2rx4(-/-) ['l0', 'l1', 'l2', 'l3']", + "76, mice ['l0', 'l4', 'l5']", + "81, endothelial ['l1', 'l4', 'l6']", + "82, cell ['l2', 'l5', 'l6']", + "115, P2rx4(-/-) ['l7']", + "116, mice. ['l3', 'l7']", + "118, P2rx4(-/-) ['l8', 'l9']", + "119, mice ['l8', 'l10']", + "137, mice. ['l9', 'l10']", + "162, P2rx4(-/-) ['l11']", + "163, mice. ['l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "P2rx4(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "P2rx4(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + } + } + ] + }, + { + "PMID": "16288283", + "TEXT": "The immune system can act as an extrinsic suppressor of tumors. Therefore, tumor progression depends in part on mechanisms that downmodulate intrinsic immune surveillance. Identifying these inhibitory pathways may provide promising targets to enhance antitumor immunity. Here, we show that Stat3 is constitutively activated in diverse tumor-infiltrating immune cells, and ablating Stat3 in hematopoietic cells triggers an intrinsic immune-surveillance system that inhibits tumor growth and metastasis. We observed a markedly enhanced function of dendritic cells, T cells, natural killer (NK) cells and neutrophils in tumor-bearing mice with Stat3(-/-) hematopoietic cells, and showed that tumor regression requires immune cells. Targeting Stat3 with a small-molecule drug induces T cell- and NK cell-dependent growth inhibition of established tumors otherwise resistant to direct killing by the inhibitor. Our findings show that Stat3 signaling restrains natural tumor immune surveillance and that inhibiting hematopoietic Stat3 in tumor-bearing hosts elicits multicomponent therapeutic antitumor immunity.", + "TAG_DATA": [ + "50, ablating {'perturbing_action': 'B-gene loss-of-function'}", + "51, Stat3 {'perturbing_action': 'I-gene loss-of-function'}", + "53, hematopoietic {'context': 'B-cells'}", + "54, cells {'context': 'I-cells'}", + "61, inhibits {'effect': 'B-negative'}", + "62, tumor {'phenotype': 'B-tumour growth'}", + "63, growth {'phenotype': 'I-tumour growth'}", + "65, metastasis. {'phenotype': 'B-metastasis'}", + "73, dendritic {'context': 'B-cells'}", + "74, cells, {'context': 'I-cells'}", + "84, tumor-bearing {'context': 'B-organism'}", + "85, mice {'context': 'I-organism'}", + "87, Stat3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "88, hematopoietic {'context': 'B-cells'}", + "89, cells, {'context': 'I-cells'}", + "93, tumor {'phenotype': 'B-tumour regression'}", + "94, regression {'phenotype': 'I-tumour regression'}", + "96, immune {'context': 'B-cells'}", + "97, cells. {'context': 'I-cells'}", + "98, Targeting {'perturbing_action': 'B-other'}", + "99, Stat3 {'perturbing_action': 'I-other'}", + "114, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "50, ablating ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "51, Stat3 ['l0', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "53, hematopoietic ['l1', 'l18', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "54, cells ['l2', 'l19', 'l32', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "61, inhibits ['l3', 'l20', 'l33', 'l44', 'l53', 'l54', 'l55', 'l56', 'l57']", + "62, tumor ['l4', 'l21', 'l34', 'l45', 'l53', 'l58', 'l59', 'l60', 'l61']", + "63, growth ['l5', 'l22', 'l35', 'l46', 'l54', 'l58', 'l62', 'l63', 'l64']", + "65, metastasis. ['l6', 'l23', 'l36', 'l47', 'l55', 'l59', 'l62', 'l65', 'l66']", + "73, dendritic ['l7', 'l24', 'l37', 'l48', 'l56', 'l60', 'l63', 'l65', 'l67', 'l68', 'l69', 'l70', 'l71']", + "74, cells, ['l8', 'l25', 'l38', 'l49', 'l57', 'l61', 'l64', 'l66', 'l67', 'l72', 'l73', 'l74']", + "84, tumor-bearing ['l9', 'l26', 'l39', 'l50', 'l68', 'l72', 'l75', 'l76', 'l77', 'l78', 'l79']", + "85, mice ['l10', 'l27', 'l40', 'l51', 'l69', 'l73', 'l75', 'l80', 'l81', 'l82']", + "87, Stat3(-/-) ['l11', 'l28', 'l41', 'l70', 'l76', 'l80', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "88, hematopoietic ['l12', 'l29', 'l42', 'l77', 'l81', 'l83', 'l89', 'l90', 'l91', 'l92', 'l93']", + "89, cells, ['l13', 'l30', 'l43', 'l52', 'l71', 'l74', 'l78', 'l82', 'l84', 'l89', 'l94', 'l95', 'l96', 'l97']", + "93, tumor ['l14', 'l85', 'l90', 'l94', 'l98', 'l99', 'l100']", + "94, regression ['l15', 'l86', 'l91', 'l95', 'l98', 'l101', 'l102']", + "96, immune ['l16', 'l87', 'l92', 'l96', 'l99', 'l101', 'l103']", + "97, cells. ['l17', 'l31', 'l79', 'l88', 'l93', 'l97', 'l100', 'l102', 'l103']", + "98, Targeting ['l104', 'l105', 'l106', 'l107']", + "99, Stat3 ['l104', 'l108', 'l109', 'l110']", + "100, with ['l105', 'l108', 'l111', 'l112']", + "102, small-molecule ['l106', 'l109', 'l111', 'l113']", + "114, tumors ['l107', 'l110', 'l112', 'l113']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablating", + "Stat3", + "Stat3(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "cells", + "dendritic", + "cells,", + "immune", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablating", + "Stat3" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablating", + "Stat3" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablating", + "Stat3" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablating", + "Stat3", + "Stat3(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "tumor-bearing", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablating", + "Stat3(-/-)" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "cells", + "dendritic", + "cells," + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "cells", + "dendritic", + "cells," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "cells", + "dendritic", + "cells," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "cells,", + "immune", + "cells." + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Targeting", + "Stat3" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + } + ] + }, + { + "PMID": "16288281", + "TEXT": "The discovery of long-lived epithelial stem cells in the bulge region of the hair follicle led to the hypothesis that epidermal renewal and epidermal repair after wounding both depend on these cells. To determine whether bulge cells are necessary for epidermal renewal, here we have ablated these cells by targeting them with a suicide gene encoding herpes simplex virus thymidine kinase (HSV-TK) using a Keratin 1-15 (Krt1-15) promoter. We show that ablation leads to complete loss of hair follicles but survival of the epidermis. Through fate-mapping experiments, we find that stem cells in the hair follicle bulge do not normally contribute cells to the epidermis which is organized into epidermal proliferative units, as previously predicted. After epidermal injury, however, cells from the bulge are recruited into the epidermis and migrate in a linear manner toward the center of the wound, ultimately forming a marked radial pattern. Notably, although the bulge-derived cells acquire an epidermal phenotype, most are eliminated from the epidermis over several weeks, indicating that bulge stem cells respond rapidly to epidermal wounding by generating short-lived 'transient amplifying' cells responsible for acute wound repair. Our findings have implications for both gene therapy and developing treatments for wounds because it will be necessary to consider epidermal and hair follicle stem cells as distinct populations.", + "TAG_DATA": [ + "47, cells {'context': 'B-cells'}", + "49, targeting {'perturbing_action': 'B-other'}", + "83, epidermis. {'context': 'B-tissue/organ'}", + "119, cells {'context': 'B-cells'}", + "149, bulge-derived {'context': 'B-cells'}", + "150, cells {'context': 'I-cells'}", + "160, epidermis {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "47, cells ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "49, targeting ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "53, suicide ['l1', 'l13', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "54, gene ['l2', 'l14', 'l27', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "55, encoding ['l3', 'l15', 'l28', 'l40', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "56, herpes ['l4', 'l16', 'l29', 'l41', 'l52', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "57, simplex ['l5', 'l17', 'l30', 'l42', 'l53', 'l63', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "58, virus ['l6', 'l18', 'l31', 'l43', 'l54', 'l64', 'l73', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "59, thymidine ['l7', 'l19', 'l32', 'l44', 'l55', 'l65', 'l74', 'l82', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "60, kinase ['l8', 'l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l83', 'l90', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "61, (HSV-TK) ['l9', 'l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l84', 'l91', 'l97', 'l103', 'l104', 'l105', 'l106', 'l107']", + "62, using ['l10', 'l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l98', 'l103', 'l108', 'l109', 'l110', 'l111']", + "65, 1-15 ['l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l86', 'l93', 'l99', 'l104', 'l108', 'l112', 'l113', 'l114']", + "66, (Krt1-15) ['l24', 'l37', 'l49', 'l60', 'l70', 'l79', 'l87', 'l94', 'l100', 'l105', 'l109', 'l112', 'l115', 'l116']", + "67, promoter. ['l11', 'l25', 'l38', 'l50', 'l61', 'l71', 'l80', 'l88', 'l95', 'l101', 'l106', 'l110', 'l113', 'l115', 'l117']", + "83, epidermis. ['l12', 'l26', 'l39', 'l51', 'l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l107', 'l111', 'l114', 'l116', 'l117']", + "149, bulge-derived ['l118', 'l119']", + "150, cells ['l118']", + "160, epidermis ['l119']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "targeting" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "targeting" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "epidermis." + ] + } + } + ] + }, + { + "PMID": "16227990", + "TEXT": "Immunodeficiency is a barrier to successful vaccination in individuals with cancer and chronic infection. We performed a randomized phase 1/2 study in lymphopenic individuals after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for myeloma. Combination immunotherapy consisting of a single early post-transplant infusion of in vivo vaccine-primed and ex vivo costimulated autologous T cells followed by post-transplant booster immunizations improved the severe immunodeficiency associated with high-dose chemotherapy and led to the induction of clinically relevant immunity in adults within a month after transplantation. Immune assays showed accelerated restoration of CD4 T-cell numbers and function. Early T-cell infusions also resulted in significantly improved T-cell proliferation in response to antigens that were not contained in the vaccine, as assessed by responses to staphylococcal enterotoxin B and cytomegalovirus antigens (P < 0.05). In the setting of lymphopenia, combined vaccine therapy and adoptive T-cell transfer fosters the development of enhanced memory T-cell responses.", + "TAG_DATA": [ + "53, T {'context': 'I-cells'}", + "54, cells {'context': 'I-cells'}", + "78, adults {'context': 'B-organism'}", + "90, CD4 {'context': 'B-cells'}", + "91, T-cell {'context': 'I-cells'}", + "102, improved {'effect': 'B-positive'}", + "103, T-cell {'context': 'B-cells'}", + "104, proliferation {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "23, individuals ['l0']", + "53, T ['l1', 'l2', 'l3', 'l4']", + "54, cells ['l1', 'l5', 'l6', 'l7']", + "78, adults ['l0', 'l2', 'l5', 'l8']", + "90, CD4 ['l3', 'l6', 'l9']", + "91, T-cell ['l4', 'l7', 'l8', 'l9']", + "102, improved ['l10', 'l11']", + "103, T-cell ['l10', 'l12']", + "104, proliferation ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "improved" + ] + }, + "context": { + "val": "cells", + "words": [ + "T-cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "improved" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T-cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "16208318", + "TEXT": "Host defense against viruses probably depends on targeted death of infected host cells and then clearance of cellular corpses by macrophages. For this process to be effective, the macrophage must presumably avoid its own virus-induced death. Here we identify one such mechanism. We show that mice lacking the chemokine Ccl5 are immune compromised to the point of delayed viral clearance, excessive airway inflammation and respiratory death after mouse parainfluenza or human influenza virus infection. Virus-inducible levels of Ccl5 are required to prevent apoptosis of virus-infected mouse macrophages in vivo and mouse and human macrophages ex vivo. The protective effect of Ccl5 requires activation of the Ccr5 chemokine receptor and consequent bilateral activation of G(alphai)-PI3K-AKT and G(alphai)-MEK-ERK signaling pathways. The antiapoptotic action of chemokine signaling may therefore allow scavengers to finally stop the host cell-to-cell infectious process.", + "TAG_DATA": [ + "45, mice {'context': 'B-organism'}", + "46, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "47, the {'perturbing_action': 'I-gene loss-of-function'}", + "48, chemokine {'perturbing_action': 'I-gene loss-of-function'}", + "49, Ccl5 {'perturbing_action': 'I-gene loss-of-function'}", + "81, prevent {'effect': 'B-negative'}", + "82, apoptosis {'phenotype': 'B-apoptosis'}", + "85, mouse {'context': 'B-cells'}", + "86, macrophages {'context': 'I-cells'}", + "87, in {'context': 'B-in vivo'}", + "88, vivo {'context': 'I-in vivo'}", + "90, mouse {'context': 'B-cells'}", + "91, and {'context': 'I-cells'}", + "92, human {'context': 'I-cells'}", + "93, macrophages {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "46, lacking ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "47, the ['l1', 'l8', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "48, chemokine ['l2', 'l9', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "49, Ccl5 ['l3', 'l10', 'l18', 'l25', 'l32', 'l33', 'l34', 'l35']", + "81, prevent ['l11', 'l19', 'l26', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "82, apoptosis ['l12', 'l20', 'l27', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49']", + "85, mouse ['l4', 'l13', 'l21', 'l28', 'l32', 'l37', 'l45', 'l50', 'l51', 'l52']", + "86, macrophages ['l5', 'l14', 'l22', 'l29', 'l33', 'l38', 'l46', 'l50', 'l53', 'l54']", + "87, in ['l6', 'l15', 'l23', 'l30', 'l34', 'l39', 'l47', 'l51', 'l53', 'l55']", + "88, vivo ['l7', 'l16', 'l24', 'l31', 'l35', 'l40', 'l48', 'l52', 'l54', 'l55']", + "90, mouse ['l41', 'l49', 'l56', 'l57', 'l58']", + "91, and ['l42', 'l56', 'l59', 'l60']", + "92, human ['l43', 'l57', 'l59', 'l61']", + "93, macrophages ['l44', 'l58', 'l60', 'l61']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "chemokine", + "Ccl5" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "chemokine" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "chemokine" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "chemokine", + "Ccl5" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "macrophages" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "chemokine", + "Ccl5" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "macrophages", + "and", + "human" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "macrophages" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "16200071", + "TEXT": "Here we show that a new class of antibiotics-acyldepsipeptides-has antibacterial activity against Gram-positive bacteria in vitro and in several rodent models of bacterial infection. The acyldepsipeptides are active against isolates that are resistant to antibiotics in clinical application, implying a new target, which we identify as ClpP, the core unit of a major bacterial protease complex. ClpP is usually tightly regulated and strictly requires a member of the family of Clp-ATPases and often further accessory proteins for proteolytic activation. Binding of acyldepsipeptides to ClpP eliminates these safeguards. The acyldepsipeptide-activated ClpP core is capable of proteolytic degradation in the absence of the regulatory Clp-ATPases. Such uncontrolled proteolysis leads to inhibition of bacterial cell division and eventually cell death.", + "TAG_DATA": [ + "108, inhibition {'effect': 'B-negative'}", + "111, cell {'phenotype': 'B-proliferation'}", + "112, division {'phenotype': 'I-proliferation'}", + "115, cell {'phenotype': 'B-cell death'}", + "116, death. {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "108, inhibition ['l0', 'l1', 'l2', 'l3']", + "111, cell ['l0', 'l4', 'l5', 'l6']", + "112, division ['l1', 'l4', 'l7', 'l8']", + "115, cell ['l2', 'l5', 'l7', 'l9']", + "116, death. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "16155578", + "TEXT": "Although major histocompatibility complex (MHC) class II-restricted CD4 T cells are well appreciated for their contribution to peripheral tolerance to tissue allografts, little is known regarding MHC class I-dependent reactivity in this process. Here we show a crucial role for host MHC class I-dependent NK cell reactivity for allograft tolerance in mice induced through either costimulation blockade using CD154-specific antibody therapy or by targeting LFA-1 (also known as CD11a). Tolerance induction absolutely required host expression of MHC class I, but was independent of CD8 T cell-dependent immunity. Rather, tolerance required innate immunity involving NK1.1(+) cells, but was independent of CD1d-restricted NKT cells. Therefore, NK cells seem to be generally required for induction of tolerance to islet allografts. Additional studies indicate that CD154-specific antibody-induced allograft tolerance is perforin dependent. Notably, NK cells that are perforin competent are sufficient to restore allograft tolerance in perforin-deficient recipients. Together, these results show an obligatory role for NK cells, through perforin, for induction of tolerance to islet allografts.", + "TAG_DATA": [ + "51, mice {'context': 'B-organism'}", + "63, targeting {'perturbing_action': 'B-other'}", + "64, LFA-1 {'perturbing_action': 'I-other'}", + "65, (also {'perturbing_action': 'I-other'}", + "66, known {'perturbing_action': 'I-other'}", + "67, as {'perturbing_action': 'I-other'}", + "68, CD11a). {'perturbing_action': 'I-other'}", + "129, NK {'context': 'B-cells'}", + "130, cells {'context': 'I-cells'}", + "142, perforin-deficient {'perturbing_action': 'B-gene loss-of-function'}" + ], + "LINK_DATA": [ + "63, targeting ['l0', 'l1', 'l2', 'l3', 'l4']", + "64, LFA-1 ['l0', 'l5', 'l6', 'l7', 'l8']", + "65, (also ['l1', 'l5', 'l9', 'l10', 'l11']", + "66, known ['l2', 'l6', 'l9', 'l12', 'l13']", + "67, as ['l3', 'l7', 'l10', 'l12', 'l14']", + "68, CD11a). ['l4', 'l8', 'l11', 'l13', 'l14']", + "129, NK ['l15', 'l16', 'l17']", + "130, cells ['l15', 'l18', 'l19']", + "142, perforin-deficient ['l16', 'l18', 'l20']", + "143, recipients. ['l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "NK", + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "perforin-deficient" + ] + } + } + ] + }, + { + "PMID": "16142243", + "TEXT": "Nitric oxide (NO) production by endothelial cell nitric oxide synthase (eNOS) in sinusoidal endothelial cells is reduced in the injured liver and leads to intrahepatic portal hypertension. We sought to understand the mechanism underlying defective eNOS function. Phosphorylation of the serine-threonine kinase Akt, which activates eNOS, was substantially reduced in sinusoidal endothelial cells from injured livers. Overexpression of Akt in vivo restored phosphorylation of Akt and production of NO and reduced portal pressure in portal hypertensive rats. We found that Akt physically interacts with G-protein-coupled receptor kinase-2 (GRK2), and that this interaction inhibits Akt activity. Furthermore, GRK2 expression increased in sinusoidal endothelial cells from portal hypertensive rats and knockdown of GRK2 restored Akt phosphorylation and NO production, and normalized portal pressure. Finally, after liver injury, GRK2-deficient mice developed less severe portal hypertension than control mice. Thus, an important mechanism underlying impaired activity of eNOS in injured sinusoidal endothelial cells is defective phosphorylation of Akt caused by overexpression of GRK2 after injury.", + "TAG_DATA": [ + "50, sinusoidal {'context': 'B-cells'}", + "51, endothelial {'context': 'I-cells'}", + "52, cells {'context': 'I-cells'}", + "55, livers. {'context': 'I-tissue/organ'}", + "56, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "57, of {'perturbing_action': 'I-gene gain-of-function'}", + "58, Akt {'perturbing_action': 'I-gene gain-of-function'}", + "59, in {'context': 'B-in vivo'}", + "60, vivo {'context': 'I-in vivo'}", + "76, rats. {'context': 'B-organism'}", + "100, sinusoidal {'context': 'B-cells'}", + "101, endothelial {'context': 'I-cells'}", + "102, cells {'context': 'I-cells'}", + "108, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "109, of {'perturbing_action': 'I-rnai/knockdown'}", + "110, GRK2 {'perturbing_action': 'I-rnai/knockdown'}", + "125, GRK2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "126, mice {'context': 'B-organism'}", + "134, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, sinusoidal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "51, endothelial ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "52, cells ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "55, livers. ['l2', 'l7', 'l11', 'l15']", + "56, Overexpression ['l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "57, of ['l16', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "58, Akt ['l17', 'l24', 'l31', 'l32', 'l33', 'l34', 'l35']", + "59, in ['l3', 'l8', 'l12', 'l18', 'l25', 'l31', 'l36', 'l37', 'l38']", + "60, vivo ['l4', 'l9', 'l13', 'l15', 'l19', 'l26', 'l32', 'l36', 'l39']", + "76, rats. ['l5', 'l10', 'l14', 'l20', 'l27', 'l33', 'l37', 'l39']", + "100, sinusoidal ['l21', 'l28', 'l40', 'l41']", + "101, endothelial ['l22', 'l29', 'l34', 'l40', 'l42']", + "102, cells ['l23', 'l30', 'l35', 'l38', 'l41', 'l42']", + "108, knockdown ['l43', 'l44']", + "109, of ['l43', 'l45']", + "110, GRK2 ['l44', 'l45']", + "125, GRK2-deficient ['l46', 'l47']", + "126, mice ['l46', 'l48']", + "134, mice. ['l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "Akt" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "Akt" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "Akt" + ] + }, + "context": { + "val": "cells", + "words": [ + "sinusoidal", + "endothelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "GRK2-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "16127437", + "TEXT": "Phosphoinositide 3-kinases (PI3K) have long been considered promising drug targets for the treatment of inflammatory and autoimmune disorders as well as cancer and cardiovascular diseases. But the lack of specificity, isoform selectivity and poor biopharmaceutical profile of PI3K inhibitors have so far hampered rigorous disease-relevant target validation. Here we describe the identification and development of specific, selective and orally active small-molecule inhibitors of PI3Kgamma (encoded by Pik3cg). We show that Pik3cg(-/-) mice are largely protected in mouse models of rheumatoid arthritis; this protection correlates with defective neutrophil migration, further validating PI3Kgamma as a therapeutic target. We also describe that oral treatment with a PI3Kgamma inhibitor suppresses the progression of joint inflammation and damage in two distinct mouse models of rheumatoid arthritis, reproducing the protective effects shown by Pik3cg(-/-) mice. Our results identify selective PI3Kgamma inhibitors as potential therapeutic molecules for the treatment of chronic inflammatory disorders such as rheumatoid arthritis.", + "TAG_DATA": [ + "70, Pik3cg(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "71, mice {'context': 'B-organism'}", + "76, mouse {'context': 'B-organism'}", + "77, models {'context': 'I-organism'}", + "103, PI3Kgamma {'perturbing_action': 'B-pharmacological inhibition'}", + "104, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "116, mouse {'context': 'B-organism'}", + "117, models {'context': 'I-organism'}", + "119, rheumatoid {'context': 'I-organism'}", + "120, arthritis, {'context': 'I-organism'}", + "127, Pik3cg(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "128, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "70, Pik3cg(-/-) ['l0', 'l1', 'l2']", + "71, mice ['l0', 'l3', 'l4']", + "76, mouse ['l1', 'l3', 'l5']", + "77, models ['l2', 'l4', 'l5']", + "103, PI3Kgamma ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "104, inhibitor ['l6', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "116, mouse ['l7', 'l13', 'l19', 'l20', 'l21']", + "117, models ['l8', 'l14', 'l19', 'l22', 'l23']", + "119, rheumatoid ['l9', 'l15', 'l20', 'l22', 'l24']", + "120, arthritis, ['l10', 'l16', 'l21', 'l23', 'l24']", + "127, Pik3cg(-/-) ['l11', 'l17', 'l25']", + "128, mice. ['l12', 'l18', 'l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pik3cg(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "models", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PI3Kgamma", + "inhibitor" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "rheumatoid", + "arthritis,", + "mice." + ] + } + } + ] + }, + { + "PMID": "15965483", + "TEXT": "We describe the generation and characterization of the first inducible 'fatless' model system, the FAT-ATTAC mouse (fat apoptosis through targeted activation of caspase 8). This transgenic mouse develops identically to wild-type littermates. Apoptosis of adipocytes can be induced at any developmental stage by administration of a FK1012 analog leading to the dimerization of a membrane-bound, adipocyte-specific caspase 8-FKBP fusion protein. Within 2 weeks of dimerizer administration, FAT-ATTAC mice show near-knockout levels of circulating adipokines and markedly reduced levels of adipose tissue. FAT-ATTAC mice are glucose intolerant, have diminished basal and endotoxin-stimulated systemic inflammation, are less responsive to glucose-stimulated insulin secretion and show increased food intake independent of the effects of leptin. Most importantly, we show that functional adipocytes can be recovered upon cessation of treatment, allowing the study of adipogenesis in vivo, as well as a detailed examination of the importance of the adipocyte in the regulation of multiple physiological functions and pathological states.", + "TAG_DATA": [ + "32, Apoptosis {'phenotype': 'B-apoptosis'}", + "34, adipocytes {'context': 'B-cells'}", + "37, induced {'effect': 'B-positive'}", + "66, FAT-ATTAC {'perturbing_action': 'B-gene loss-of-function'}", + "67, mice {'context': 'B-organism'}", + "81, FAT-ATTAC {'perturbing_action': 'B-gene loss-of-function'}", + "82, mice {'context': 'B-organism'}", + "117, adipocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "32, Apoptosis ['l0', 'l1', 'l2', 'l3']", + "34, adipocytes ['l0', 'l4', 'l5', 'l6']", + "37, induced ['l1', 'l4', 'l7', 'l8']", + "66, FAT-ATTAC ['l2', 'l5', 'l7', 'l9']", + "67, mice ['l3', 'l6', 'l8', 'l9']", + "81, FAT-ATTAC ['l10']", + "82, mice ['l10']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "apoptosis", + "words": [ + "Apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "adipocytes" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "Apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "Apoptosis" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FAT-ATTAC" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "Apoptosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "adipocytes" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "adipocytes" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FAT-ATTAC" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FAT-ATTAC" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FAT-ATTAC" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15951824", + "TEXT": "Efficient boosting of memory T-cell numbers to protective levels generally requires a relatively long interval between immunizations. Decreasing this interval could be crucial in biodefense and cancer immunotherapy, in which rapid protective responses are essential. Here, we show that vaccination with peptide-coated dendritic cells (DCs) generated CD8+ T cells with the phenotype and function of memory cells within 4-6 d. These early memory CD8+ T cells underwent vigorous secondary expansion in response to a variety of booster immunizations, leading to elevated numbers of effector and memory T cells and enhanced protective immunity. Coinjection of CpG oligodeoxynucleotides, potent inducers of inflammation that did not alter the duration of DC antigen display, prevented the rapid generation of memory T cells in wild-type mice but not in mice lacking the interferon (IFN)-gamma receptor. These data show that DC vaccination stimulates a pathway of accelerated generation of memory T cells, and suggest that events of inflammation, including the action of IFN-gamma on the responding T cells, control the rate of development of memory CD8+ T cells.", + "TAG_DATA": [ + "46, CD8+ {'context': 'B-cells'}", + "47, T {'context': 'I-cells'}", + "48, cells {'context': 'I-cells'}", + "55, memory {'context': 'B-cells'}", + "56, cells {'context': 'I-cells'}", + "62, memory {'context': 'B-cells'}", + "63, CD8+ {'context': 'I-cells'}", + "64, T {'context': 'I-cells'}", + "65, cells {'context': 'I-cells'}", + "83, effector {'context': 'B-cells'}", + "84, and {'context': 'I-cells'}", + "85, memory {'context': 'I-cells'}", + "86, T {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}", + "115, memory {'context': 'B-cells'}", + "116, T {'context': 'I-cells'}", + "117, cells {'context': 'I-cells'}", + "120, mice {'context': 'B-organism'}", + "124, mice {'context': 'B-organism'}", + "125, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "126, the {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "46, CD8+ ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "47, T ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "48, cells ['l1', 'l13', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "55, memory ['l2', 'l14', 'l23', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "56, cells ['l3', 'l15', 'l24', 'l32', 'l39', 'l40', 'l41', 'l42']", + "62, memory ['l4', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "63, CD8+ ['l5', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "64, T ['l6', 'l16', 'l25', 'l44', 'l51', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "65, cells ['l7', 'l17', 'l26', 'l33', 'l45', 'l52', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "83, effector ['l8', 'l18', 'l27', 'l34', 'l46', 'l53', 'l59', 'l64', 'l69', 'l70', 'l71', 'l72']", + "84, and ['l9', 'l19', 'l28', 'l35', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l73', 'l74', 'l75']", + "85, memory ['l10', 'l20', 'l29', 'l36', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l76', 'l77']", + "86, T ['l11', 'l21', 'l30', 'l37', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l78']", + "87, cells ['l12', 'l22', 'l31', 'l38', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l77', 'l78']", + "115, memory ['l79', 'l80', 'l81']", + "116, T ['l79', 'l82', 'l83']", + "117, cells ['l80', 'l82', 'l84']", + "120, mice ['l81', 'l83', 'l84']", + "124, mice ['l85', 'l86', 'l87']", + "125, lacking ['l85', 'l88', 'l89']", + "126, the ['l86', 'l88', 'l90']", + "129, receptor. ['l87', 'l89', 'l90']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the" + ] + } + } + ] + }, + { + "PMID": "15908955", + "TEXT": "Accelerated osteoclastic bone resorption has a central role in the pathogenesis of osteoporosis and other bone diseases. Identifying the molecular pathways that regulate osteoclast activity provides a key to understanding the causes of these diseases and to the development of new treatments. Here we show that mice with inactivation of cannabinoid type 1 (CB1) receptors have increased bone mass and are protected from ovariectomy-induced bone loss. Pharmacological antagonists of CB1 and CB2 receptors prevented ovariectomy-induced bone loss in vivo and caused osteoclast inhibition in vitro by promoting osteoclast apoptosis and inhibiting production of several osteoclast survival factors. These studies show that the CB1 receptor has a role in the regulation of bone mass and ovariectomy-induced bone loss and that CB1- and CB2-selective cannabinoid receptor antagonists are a new class of osteoclast inhibitors that may be of value in the treatment of osteoporosis and other bone diseases.", + "TAG_DATA": [ + "46, mice {'context': 'B-organism'}", + "48, inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "49, of {'perturbing_action': 'I-gene loss-of-function'}", + "50, cannabinoid {'perturbing_action': 'I-gene loss-of-function'}", + "51, type {'perturbing_action': 'I-gene loss-of-function'}", + "52, 1 {'perturbing_action': 'I-gene loss-of-function'}", + "53, (CB1) {'perturbing_action': 'I-gene loss-of-function'}", + "54, receptors {'perturbing_action': 'I-gene loss-of-function'}", + "66, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "67, antagonists {'perturbing_action': 'I-pharmacological inhibition'}", + "68, of {'perturbing_action': 'I-pharmacological inhibition'}", + "69, CB1 {'perturbing_action': 'I-pharmacological inhibition'}", + "70, and {'perturbing_action': 'I-pharmacological inhibition'}", + "71, CB2 {'perturbing_action': 'I-pharmacological inhibition'}", + "72, receptors {'perturbing_action': 'I-pharmacological inhibition'}", + "77, in {'context': 'B-in vivo'}", + "78, vivo {'context': 'I-in vivo'}", + "83, in {'context': 'B-in vitro'}", + "84, vitro {'context': 'I-in vitro'}", + "86, promoting {'effect': 'B-positive'}", + "87, osteoclast {'context': 'B-cells'}", + "88, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "46, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "48, inactivation ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "49, of ['l1', 'l8', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "50, cannabinoid ['l2', 'l9', 'l19', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "51, type ['l3', 'l10', 'l20', 'l31', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "52, 1 ['l4', 'l11', 'l21', 'l32', 'l42', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "53, (CB1) ['l5', 'l12', 'l22', 'l33', 'l43', 'l51', 'l59', 'l60', 'l61', 'l62']", + "54, receptors ['l6', 'l13', 'l23', 'l34', 'l44', 'l52', 'l59', 'l63', 'l64']", + "66, Pharmacological ['l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "67, antagonists ['l65', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "68, of ['l66', 'l78', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "69, CB1 ['l67', 'l79', 'l90', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "70, and ['l68', 'l80', 'l91', 'l101', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "71, CB2 ['l69', 'l81', 'l92', 'l102', 'l111', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127']", + "72, receptors ['l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "77, in ['l14', 'l24', 'l35', 'l45', 'l53', 'l60', 'l63', 'l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l128', 'l135', 'l136', 'l137', 'l138']", + "78, vivo ['l7', 'l15', 'l25', 'l36', 'l46', 'l54', 'l61', 'l64', 'l72', 'l84', 'l95', 'l105', 'l114', 'l122', 'l129', 'l135']", + "83, in ['l16', 'l26', 'l37', 'l47', 'l55', 'l73', 'l85', 'l96', 'l106', 'l115', 'l123', 'l130', 'l136', 'l139', 'l140', 'l141', 'l142']", + "84, vitro ['l27', 'l38', 'l74', 'l86', 'l97', 'l107', 'l116', 'l124', 'l131', 'l139', 'l143', 'l144', 'l145']", + "86, promoting ['l17', 'l28', 'l39', 'l48', 'l56', 'l62', 'l75', 'l87', 'l98', 'l108', 'l117', 'l125', 'l132', 'l137', 'l140', 'l143', 'l146', 'l147']", + "87, osteoclast ['l18', 'l29', 'l40', 'l49', 'l57', 'l76', 'l88', 'l99', 'l109', 'l118', 'l126', 'l133', 'l138', 'l141', 'l144', 'l146', 'l148']", + "88, apoptosis ['l30', 'l41', 'l50', 'l58', 'l77', 'l89', 'l100', 'l110', 'l119', 'l127', 'l134', 'l142', 'l145', 'l147', 'l148']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "cannabinoid", + "type", + "1", + "(CB1)", + "receptors" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "cannabinoid", + "type", + "1", + "(CB1)", + "receptors" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "cannabinoid", + "type", + "1" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "cannabinoid", + "type", + "1", + "(CB1)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "cannabinoid", + "type", + "1" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "cannabinoid", + "type", + "1" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "antagonists", + "of", + "CB1", + "and", + "CB2", + "receptors" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "antagonists", + "of", + "CB1", + "and", + "CB2", + "receptors" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "antagonists", + "of", + "CB1", + "and", + "CB2", + "receptors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "antagonists", + "of", + "CB1", + "and", + "CB2", + "receptors" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "antagonists", + "of", + "CB1", + "and", + "CB2", + "receptors" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "15880118", + "TEXT": "Leprosy enables investigation of mechanisms by which the innate immune system contributes to host defense against infection, because in one form, the disease progresses, and in the other, the infection is limited. We report that Toll-like receptor (TLR) activation of human monocytes induces rapid differentiation into two distinct subsets: DC-SIGN+ CD16+ macrophages and CD1b+ DC-SIGN- dendritic cells. DC-SIGN+ phagocytic macrophages were expanded by TLR-mediated upregulation of interleukin (IL)-15 and IL-15 receptor. CD1b+ dendritic cells were expanded by TLR-mediated upregulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) and its receptor, promoted T cell activation and secreted proinflammatory cytokines. Whereas DC-SIGN+ macrophages were detected in lesions and after TLR activation in all leprosy patients, CD1b+ dendritic cells were not detected in lesions or after TLR activation of peripheral monocytes in individuals with the progressive lepromatous form, except during reversal reactions in which bacilli were cleared by T helper type 1 (TH1) responses. In tuberculoid lepromatous lesions, DC-SIGN+ cells were positive for macrophage markers, but negative for dendritic cell markers. Thus, TLR-induced differentiation of monocytes into either macrophages or dendritic cells seems to crucially influence effective host defenses in human infectious disease.", + "TAG_DATA": [ + "40, human {'context': 'B-cells'}", + "41, monocytes {'context': 'I-cells'}", + "42, induces {'effect': 'B-positive'}", + "57, DC-SIGN+ {'context': 'B-cells'}", + "58, phagocytic {'context': 'I-cells'}", + "59, macrophages {'context': 'I-cells'}", + "71, CD1b+ {'context': 'B-cells'}", + "72, dendritic {'context': 'I-cells'}", + "73, cells {'context': 'I-cells'}", + "88, T {'context': 'B-cells'}", + "89, cell {'context': 'B-cells'}", + "96, DC-SIGN+ {'context': 'B-cells'}", + "97, macrophages {'context': 'I-cells'}", + "110, CD1b+ {'context': 'B-cells'}", + "111, dendritic {'context': 'I-cells'}", + "112, cells {'context': 'I-cells'}", + "123, peripheral {'context': 'B-cells'}", + "124, monocytes {'context': 'I-cells'}", + "126, individuals {'context': 'B-patient'}", + "152, DC-SIGN+ {'context': 'B-cells'}", + "153, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "40, human ['l0', 'l1', 'l2', 'l3', 'l4']", + "41, monocytes ['l0', 'l5', 'l6', 'l7', 'l8']", + "42, induces ['l1', 'l5', 'l9']", + "57, DC-SIGN+ ['l2', 'l6', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "58, phagocytic ['l3', 'l7', 'l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "59, macrophages ['l4', 'l8', 'l9', 'l11', 'l17', 'l23', 'l24', 'l25', 'l26']", + "71, CD1b+ ['l12', 'l18', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "72, dendritic ['l13', 'l19', 'l23', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "73, cells ['l14', 'l20', 'l24', 'l28', 'l33', 'l38', 'l39', 'l40', 'l41']", + "88, T ['l15', 'l21', 'l25', 'l29', 'l34', 'l38', 'l42', 'l43']", + "89, cell ['l16', 'l22', 'l26', 'l30', 'l35', 'l39', 'l42', 'l44']", + "96, DC-SIGN+ ['l31', 'l36', 'l40', 'l45', 'l46']", + "97, macrophages ['l32', 'l37', 'l41', 'l43', 'l44', 'l45', 'l47']", + "110, CD1b+ ['l48', 'l49', 'l50', 'l51', 'l52']", + "111, dendritic ['l48', 'l53', 'l54', 'l55', 'l56']", + "112, cells ['l46', 'l47', 'l49', 'l53', 'l57', 'l58', 'l59']", + "123, peripheral ['l50', 'l54', 'l57', 'l60', 'l61']", + "124, monocytes ['l51', 'l55', 'l58', 'l60', 'l62']", + "126, individuals ['l52', 'l56', 'l59', 'l61', 'l62']", + "152, DC-SIGN+ ['l63']", + "153, cells ['l63']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "monocytes", + "macrophages" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + } + ] + }, + { + "PMID": "15852018", + "TEXT": "Alveolar cell apoptosis is involved in the pathogenesis of emphysema, a prevalent disease primarily caused by cigarette smoking. We report that ceramide, a second messenger lipid, is a crucial mediator of alveolar destruction in emphysema. Inhibition of enzymes controlling de novo ceramide synthesis prevented alveolar cell apoptosis, oxidative stress and emphysema caused by blockade of the vascular endothelial growth factor (VEGF) receptors in both rats and mice. Emphysema was reproduced with intratracheal instillation of ceramide in naive mice. Excessive ceramide triggers a feed-forward mechanism mediated by activation of secretory acid sphingomyelinase, as suggested by experiments with neutralizing ceramide antibody in mice and with acid sphingomyelinase-deficient fibroblasts. Concomitant augmentation of signaling initiated by a prosurvival metabolite, sphingosine-1-phosphate, prevented lung apoptosis, implying that a balance between ceramide and sphingosine-1-phosphate is required for maintenance of alveolar septal integrity. Finally, increased lung ceramides in individuals with smoking-induced emphysema suggests that ceramide upregulation may be a crucial pathogenic element and a promising target in this disease that currently lacks effective therapies.", + "TAG_DATA": [ + "43, prevented {'effect': 'B-negative'}", + "44, alveolar {'context': 'B-cells'}", + "45, cell {'context': 'I-cells'}", + "46, apoptosis, {'phenotype': 'B-apoptosis'}", + "53, blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "54, of {'perturbing_action': 'I-pharmacological inhibition'}", + "55, the {'perturbing_action': 'I-pharmacological inhibition'}", + "56, vascular {'perturbing_action': 'I-pharmacological inhibition'}", + "57, endothelial {'perturbing_action': 'I-pharmacological inhibition'}", + "58, growth {'perturbing_action': 'I-pharmacological inhibition'}", + "59, factor {'perturbing_action': 'I-pharmacological inhibition'}", + "60, (VEGF) {'perturbing_action': 'I-pharmacological inhibition'}", + "61, receptors {'perturbing_action': 'I-pharmacological inhibition'}", + "64, rats {'context': 'B-organism'}", + "66, mice. {'context': 'B-organism'}", + "77, mice. {'context': 'I-organism'}", + "100, mice {'context': 'B-organism'}", + "103, acid {'perturbing_action': 'B-gene loss-of-function'}", + "104, sphingomyelinase-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "105, fibroblasts. {'context': 'B-cells'}", + "116, prevented {'effect': 'B-negative'}", + "117, lung {'context': 'B-tissue/organ'}", + "118, apoptosis, {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "43, prevented ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "44, alveolar ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "45, cell ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "46, apoptosis, ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "53, blockade ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "54, of ['l4', 'l17', 'l29', 'l40', 'l50', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "55, the ['l5', 'l18', 'l30', 'l41', 'l51', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "56, vascular ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "57, endothelial ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "58, growth ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l90', 'l91', 'l92', 'l93', 'l94']", + "59, factor ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l95', 'l96', 'l97', 'l98']", + "60, (VEGF) ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l99', 'l100', 'l101']", + "61, receptors ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l102', 'l103']", + "64, rats ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l104']", + "66, mice. ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l104']", + "103, acid ['l105', 'l106', 'l107', 'l108', 'l109']", + "104, sphingomyelinase-deficient ['l105', 'l110', 'l111', 'l112', 'l113']", + "105, fibroblasts. ['l106', 'l110', 'l114', 'l115', 'l116']", + "116, prevented ['l107', 'l111', 'l114', 'l117', 'l118']", + "117, lung ['l108', 'l112', 'l115', 'l117', 'l119']", + "118, apoptosis, ['l109', 'l113', 'l116', 'l118', 'l119']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "cells", + "words": [ + "alveolar", + "cell", + "fibroblasts." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "the", + "vascular", + "endothelial", + "growth", + "factor", + "(VEGF)", + "receptors" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats", + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "alveolar", + "cell", + "fibroblasts." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "alveolar", + "cell" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "the", + "vascular", + "endothelial", + "growth", + "factor", + "(VEGF)", + "receptors" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "the", + "vascular", + "endothelial", + "growth", + "factor", + "(VEGF)", + "receptors" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + }, + "context": { + "val": "organism", + "words": [ + "rats", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "the", + "vascular", + "endothelial", + "growth", + "factor", + "(VEGF)", + "receptors" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "acid", + "sphingomyelinase-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "fibroblasts." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "acid", + "sphingomyelinase-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "acid", + "sphingomyelinase-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "acid", + "sphingomyelinase-deficient" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + } + ] + }, + { + "PMID": "15834430", + "TEXT": "Systemic inflammation induces various adaptive responses including tachycardia. Although inflammation-associated tachycardia has been thought to result from increased sympathetic discharge caused by inflammatory signals of the immune system, definitive proof has been lacking. Prostanoids, including prostaglandin (PG) D(2), PGE(2), PGF(2alpha), PGI(2) and thromboxane (TX) A(2), exert their actions through specific receptors: DP, EP (EP(1), EP(2), EP(3), EP(4)), FP, IP and TP, respectively. Here we have examined the roles of prostanoids in inflammatory tachycardia using mice that lack each of these receptors individually. The TXA(2) analog I-BOP and PGF(2alpha) each increased the beating rate of the isolated atrium of wild-type mice in vitro through interaction with TP and FP receptors, respectively. The cytokine-induced increase in beating rate was markedly inhibited in atria from mice lacking either TP or FP receptors. The tachycardia induced in wild-type mice by injection of lipopolysaccharide (LPS) was greatly attenuated in TP-deficient or FP-deficient mice and was completely absent in mice lacking both TP and FP. The beta-blocker propranolol did not block the LPS-induced increase in heart rate in wild-type animals. Our results show that inflammatory tachycardia is caused by a direct action on the heart of TXA(2) and PGF(2alpha) formed under systemic inflammatory conditions.", + "TAG_DATA": [ + "95, isolated {'context': 'B-tissue/organ'}", + "96, atrium {'context': 'I-tissue/organ'}", + "98, wild-type {'context': 'B-organism'}", + "99, mice {'context': 'B-organism'}", + "100, in {'context': 'B-in vitro'}", + "101, vitro {'context': 'I-in vitro'}", + "120, atria {'context': 'B-tissue/organ'}", + "122, mice {'context': 'B-organism'}", + "123, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "124, either {'perturbing_action': 'I-gene loss-of-function'}", + "125, TP {'perturbing_action': 'I-gene loss-of-function'}", + "126, or {'perturbing_action': 'I-gene loss-of-function'}", + "127, FP {'perturbing_action': 'I-gene loss-of-function'}", + "128, receptors. {'perturbing_action': 'I-gene loss-of-function'}", + "133, wild-type {'context': 'B-organism'}", + "134, mice {'context': 'B-organism'}", + "144, TP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "146, FP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "147, mice {'context': 'B-organism'}", + "153, mice {'context': 'B-organism'}", + "154, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "155, both {'perturbing_action': 'I-gene loss-of-function'}", + "156, TP {'perturbing_action': 'I-gene loss-of-function'}", + "157, and {'perturbing_action': 'I-gene loss-of-function'}", + "158, FP. {'perturbing_action': 'I-gene loss-of-function'}", + "173, animals. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "95, isolated ['l0', 'l1', 'l2', 'l3', 'l4']", + "96, atrium ['l0', 'l5', 'l6', 'l7', 'l8']", + "98, wild-type ['l1', 'l5', 'l9', 'l10', 'l11']", + "99, mice ['l2', 'l6', 'l9', 'l12', 'l13']", + "100, in ['l3', 'l7', 'l10', 'l12', 'l14']", + "101, vitro ['l4', 'l8', 'l11', 'l13', 'l14']", + "120, atria ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "122, mice ['l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "123, lacking ['l16', 'l23', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "124, either ['l17', 'l24', 'l31', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "125, TP ['l18', 'l25', 'l32', 'l38', 'l44', 'l45', 'l46', 'l47', 'l48']", + "126, or ['l19', 'l26', 'l33', 'l39', 'l44', 'l49', 'l50', 'l51', 'l52']", + "127, FP ['l20', 'l27', 'l34', 'l40', 'l45', 'l49', 'l53', 'l54', 'l55']", + "128, receptors. ['l21', 'l28', 'l35', 'l41', 'l46', 'l50', 'l53', 'l56', 'l57']", + "133, wild-type ['l29', 'l36', 'l42', 'l47', 'l51', 'l54', 'l56', 'l58', 'l59']", + "134, mice ['l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l57', 'l58']", + "144, TP-deficient ['l59', 'l60', 'l61']", + "146, FP-deficient ['l60', 'l62']", + "147, mice ['l61', 'l62']", + "153, mice ['l63', 'l64', 'l65', 'l66', 'l67']", + "154, lacking ['l63', 'l68', 'l69', 'l70', 'l71']", + "155, both ['l64', 'l68', 'l72', 'l73', 'l74']", + "156, TP ['l65', 'l69', 'l72', 'l75', 'l76']", + "157, and ['l66', 'l70', 'l73', 'l75', 'l77']", + "158, FP. ['l67', 'l71', 'l74', 'l76', 'l77']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "atria" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "either", + "TP", + "or", + "FP", + "receptors." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "wild-type" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "either", + "TP", + "or", + "FP", + "receptors.", + "TP-deficient", + "FP-deficient", + "both", + "and", + "FP." + ] + } + } + ] + }, + { + "PMID": "15834429", + "TEXT": "Platelet activation at sites of vascular injury is essential for the arrest of bleeding; however, excessive platelet accumulation at regions of atherosclerotic plaque rupture can result in the development of arterial thrombi, precipitating diseases such as acute myocardial infarction and ischemic stroke. Rheological disturbances (high shear stress) have an important role in promoting arterial thrombosis by enhancing the adhesive and signaling function of platelet integrin alpha(IIb)beta(3) (GPIIb-IIIa). In this study we have defined a key role for the Type Ia phosphoinositide 3-kinase (PI3K) p110beta isoform in regulating the formation and stability of integrin alpha(IIb)beta(3) adhesion bonds, necessary for shear activation of platelets. Isoform-selective PI3K p110beta inhibitors have been developed which prevent formation of stable integrin alpha(IIb)beta(3) adhesion contacts, leading to defective platelet thrombus formation. In vivo, these inhibitors eliminate occlusive thrombus formation but do not prolong bleeding time. These studies define PI3K p110beta as an important new target for antithrombotic therapy.", + "TAG_DATA": [ + "102, Isoform-selective {'perturbing_action': 'B-pharmacological inhibition'}", + "103, PI3K {'perturbing_action': 'I-pharmacological inhibition'}", + "104, p110beta {'perturbing_action': 'I-pharmacological inhibition'}", + "105, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "121, platelet {'context': 'B-cells'}", + "124, In {'context': 'B-in vivo'}", + "125, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "102, Isoform-selective ['l0', 'l1', 'l2', 'l3']", + "103, PI3K ['l0', 'l4', 'l5', 'l6']", + "104, p110beta ['l1', 'l4', 'l7', 'l8']", + "105, inhibitors ['l2', 'l5', 'l7', 'l9']", + "121, platelet ['l3', 'l6', 'l8', 'l9']", + "124, In ['l10']", + "125, vivo, ['l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Isoform-selective", + "PI3K", + "p110beta", + "inhibitors" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelet" + ] + } + } + ] + }, + { + "PMID": "15821749", + "TEXT": "Insulin receptor substrate-1 (IRS-1) and IRS-2 are known to transduce and amplify signals emanating from the insulin receptor. Here we show that Grb2-associated binder 1 (Gab1), despite its structural similarity to IRS proteins, is a negative modulator of hepatic insulin action. Liver-specific Gab1 knockout (LGKO) mice showed enhanced hepatic insulin sensitivity with reduced glycemia and improved glucose tolerance. In LGKO liver, basal and insulin-stimulated tyrosine phosphorylation of IRS-1 and IRS-2 was elevated, accompanied by enhanced Akt/PKB activation. Conversely, Erk activation by insulin was suppressed in LGKO liver, leading to defective IRS-1 Ser612 phosphorylation. Thus, Gab1 acts to attenuate, through promotion of the Erk pathway, insulin-elicited signals flowing through IRS and Akt proteins, which represents a novel balancing mechanism for control of insulin signal strength in the liver.", + "TAG_DATA": [ + "41, Liver-specific {'perturbing_action': 'B-gene loss-of-function'}", + "42, Gab1 {'perturbing_action': 'I-gene loss-of-function'}", + "43, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "44, (LGKO) {'perturbing_action': 'I-gene loss-of-function'}", + "45, mice {'context': 'B-organism'}", + "59, LGKO {'perturbing_action': 'B-gene loss-of-function'}", + "60, liver, {'context': 'B-tissue/organ'}", + "85, LGKO {'perturbing_action': 'B-gene loss-of-function'}", + "86, liver, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "41, Liver-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "42, Gab1 ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "43, knockout ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "44, (LGKO) ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "45, mice ['l3', 'l8', 'l12', 'l15']", + "59, LGKO ['l4', 'l9', 'l13', 'l16', 'l18']", + "60, liver, ['l5', 'l10', 'l14', 'l17', 'l18']", + "85, LGKO ['l19']", + "86, liver, ['l19']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Liver-specific", + "Gab1", + "knockout", + "(LGKO)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Liver-specific", + "Gab1", + "knockout", + "(LGKO)", + "LGKO" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver," + ] + } + } + ] + }, + { + "PMID": "15793583", + "TEXT": "High-density lipoproteins (HDLs) are considered antiatherogenic because they mediate reverse cholesterol transport from the periphery to the liver for excretion and degradation. Here we show that mice deficient in apolipoprotein M (apoM), a component of the HDL particle, accumulated cholesterol in large HDL particles (HDL(1)) while the conversion of HDL to prebeta-HDL was impaired. Accordingly, apoM-deficient mice lacked prebeta-HDL, a subclass of lipid-poor apolipoproteins that serves as a key acceptor of peripheral cellular cholesterol. This deficiency led to a markedly reduced cholesterol efflux from macrophages to apoM-deficient HDL compared to normal HDL in vitro. Overexpression of apoM in Ldlr(-/-) mice protected against atherosclerosis when the mice were challenged with a cholesterol-enriched diet, showing that apoM is important for the formation of prebeta-HDL and cholesterol efflux to HDL, and thereby inhibits formation of atherosclerotic lesions.", + "TAG_DATA": [ + "26, mice {'context': 'B-organism'}", + "27, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "28, in {'perturbing_action': 'I-gene loss-of-function'}", + "29, apolipoprotein {'perturbing_action': 'I-gene loss-of-function'}", + "30, M {'perturbing_action': 'I-gene loss-of-function'}", + "31, (apoM), {'perturbing_action': 'I-gene loss-of-function'}", + "55, apoM-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "56, mice {'context': 'B-organism'}", + "84, macrophages {'context': 'B-cells'}", + "86, apoM-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "92, in {'context': 'B-in vitro'}", + "93, vitro. {'context': 'I-in vitro'}", + "94, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "95, of {'perturbing_action': 'I-gene gain-of-function'}", + "96, apoM {'perturbing_action': 'I-gene gain-of-function'}", + "98, Ldlr(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "99, mice {'context': 'B-organism'}", + "100, protected {'effect': 'B-negative'}", + "101, against {'effect': 'I-negative'}", + "105, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "26, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "27, deficient ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "28, in ['l1', 'l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "29, apolipoprotein ['l2', 'l7', 'l12', 'l17', 'l18', 'l19', 'l20', 'l21']", + "30, M ['l3', 'l8', 'l13', 'l17', 'l22', 'l23', 'l24']", + "31, (apoM), ['l4', 'l9', 'l14', 'l18', 'l22', 'l25', 'l26']", + "55, apoM-deficient ['l27', 'l28', 'l29', 'l30', 'l31']", + "56, mice ['l10', 'l15', 'l19', 'l23', 'l25', 'l27', 'l32', 'l33', 'l34', 'l35']", + "84, macrophages ['l5', 'l11', 'l16', 'l20', 'l24', 'l26', 'l28', 'l32', 'l36', 'l37', 'l38']", + "86, apoM-deficient ['l29', 'l33', 'l36', 'l39', 'l40']", + "92, in ['l30', 'l34', 'l37', 'l39', 'l41']", + "93, vitro. ['l21', 'l31', 'l35', 'l38', 'l40', 'l41']", + "94, Overexpression ['l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "95, of ['l42', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "96, apoM ['l43', 'l49', 'l55', 'l56', 'l57', 'l58', 'l59']", + "98, Ldlr(-/-) ['l44', 'l50', 'l55', 'l60', 'l61', 'l62', 'l63']", + "99, mice ['l45', 'l51', 'l56', 'l60', 'l64', 'l65', 'l66']", + "100, protected ['l46', 'l52', 'l57', 'l61', 'l64', 'l67', 'l68']", + "101, against ['l47', 'l53', 'l58', 'l62', 'l65', 'l67', 'l69']", + "105, mice ['l48', 'l54', 'l59', 'l63', 'l66', 'l68', 'l69']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "apolipoprotein", + "M", + "(apoM),", + "apoM-deficient", + "Ldlr(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "apolipoprotein", + "M", + "(apoM),", + "apoM-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "apolipoprotein", + "apoM-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "vitro.", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "apoM" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "apoM" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protected", + "against" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ldlr(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protected", + "against" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protected", + "against" + ] + } + } + ] + }, + { + "PMID": "15750601", + "TEXT": "Morphogenesis and remodeling of bone involve synthesis of bone matrix by osteoblasts and coordinate resorption of bone by osteoclasts. Defective bone remodeling caused by altered osteoclast activity underlies a multitude of osteopenic disorders. Receptor activator of NF-kappaB (RANK) and its ligand RANKL have been identified as essential factors involved in osteoclast development and bone remodeling, but their mechanism and interacting factors have not been fully characterized. Here we report that the molecular adapter Grb-2-associated binder-2 (Gab2) associates with RANK and mediates RANK-induced activation of NF-kappaB, Akt and Jnk. Inactivation of the gene encoding Gab2 in mice results in osteopetrosis and decreased bone resorption as a result of defective osteoclast differentiation. We also show that Gab2 has a crucial role in the differentiation of human progenitor cells into osteoclasts. We have thus identified a new, key regulatory scaffold molecule, Gab2, that controls select RANK signaling pathways and is essential for osteoclastogenesis and bone homeostasis.", + "TAG_DATA": [ + "88, Inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "89, of {'perturbing_action': 'I-gene loss-of-function'}", + "90, the {'perturbing_action': 'I-gene loss-of-function'}", + "91, gene {'perturbing_action': 'I-gene loss-of-function'}", + "92, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "93, Gab2 {'perturbing_action': 'I-gene loss-of-function'}", + "95, mice {'context': 'B-organism'}", + "107, defective {'effect': 'B-negative'}", + "108, osteoclast {'context': 'B-cells'}", + "109, differentiation. {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "88, Inactivation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "89, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "90, the ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "91, gene ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "92, encoding ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "93, Gab2 ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "95, mice ['l5', 'l13', 'l20', 'l26', 'l31', 'l35']", + "107, defective ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l40']", + "108, osteoclast ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l39', 'l41']", + "109, differentiation. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Inactivation", + "of", + "the", + "gene", + "encoding", + "Gab2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Inactivation", + "of", + "the", + "gene", + "encoding", + "Gab2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Inactivation", + "of", + "the", + "gene", + "encoding", + "Gab2" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Inactivation", + "of", + "the", + "gene", + "encoding", + "Gab2" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "defective" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "defective" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + } + ] + }, + { + "PMID": "15723075", + "TEXT": "Short interfering RNA (siRNA) is used in RNA interference technology to avoid non-target-related induction of type I interferon (IFN) typical for long double-stranded RNA. Here we show that in plasmacytoid dendritic cells (PDC), an immune cell subset specialized in the detection of viral nucleic acids and production of type I IFN, some siRNA sequences, independent of their GU content, are potent stimuli of IFN-alpha production. Localization of the immunostimulatory motif on the sense strand of a potent IFN-alpha-inducing siRNA allowed dissection of immunostimulation and target silencing. Injection into mice of immunostimulatory siRNA, when complexed with cationic liposomes, induced systemic immune responses in the same range as the TLR9 ligand CpG, including IFN-alpha in serum and activation of T cells and dendritic cells in spleen. Immunostimulation by siRNA was absent in TLR7-deficient mice. Thus sequence-specific TLR7-dependent immune recognition in PDC needs to be considered as an additional biological activity of siRNA, which then should be termed immunostimulatory RNA (isRNA).", + "TAG_DATA": [ + "88, mice {'context': 'B-organism'}", + "117, T {'context': 'B-cells'}", + "118, cells {'context': 'B-cells'}", + "120, dendritic {'context': 'B-cells'}", + "121, cells {'context': 'I-cells'}", + "123, spleen. {'context': 'B-tissue/organ'}", + "130, TLR7-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "131, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "88, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "117, T ['l0', 'l5', 'l6', 'l7', 'l8']", + "118, cells ['l1', 'l5', 'l9', 'l10', 'l11']", + "120, dendritic ['l2', 'l6', 'l9', 'l12', 'l13']", + "121, cells ['l3', 'l7', 'l10', 'l12', 'l14']", + "123, spleen. ['l4', 'l8', 'l11', 'l13', 'l14']", + "130, TLR7-deficient ['l15']", + "131, mice. ['l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TLR7-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "15723072", + "TEXT": "Granulocyte colony-stimulating factor (G-CSF) was reported to induce myocardial regeneration by promoting mobilization of bone marrow stem cells to the injured heart after myocardial infarction, but the precise mechanisms of the beneficial effects of G-CSF are not fully understood. Here we show that G-CSF acts directly on cardiomyocytes and promotes their survival after myocardial infarction. G-CSF receptor was expressed on cardiomyocytes and G-CSF activated the Jak/Stat pathway in cardiomyocytes. The G-CSF treatment did not affect initial infarct size at 3 d but improved cardiac function as early as 1 week after myocardial infarction. Moreover, the beneficial effects of G-CSF on cardiac function were reduced by delayed start of the treatment. G-CSF induced antiapoptotic proteins and inhibited apoptotic death of cardiomyocytes in the infarcted hearts. G-CSF also reduced apoptosis of endothelial cells and increased vascularization in the infarcted hearts, further protecting against ischemic injury. All these effects of G-CSF on infarcted hearts were abolished by overexpression of a dominant-negative mutant Stat3 protein in cardiomyocytes. These results suggest that G-CSF promotes survival of cardiac myocytes and prevents left ventricular remodeling after myocardial infarction through the functional communication between cardiomyocytes and noncardiomyocytes.", + "TAG_DATA": [ + "115, inhibited {'effect': 'B-negative'}", + "116, apoptotic {'phenotype': 'B-apoptosis'}", + "117, death {'phenotype': 'I-apoptosis'}", + "119, cardiomyocytes {'context': 'B-cells'}", + "123, hearts. {'context': 'B-tissue/organ'}", + "126, reduced {'effect': 'B-negative'}", + "127, apoptosis {'phenotype': 'B-apoptosis'}", + "129, endothelial {'context': 'B-cells'}", + "130, cells {'context': 'I-cells'}", + "137, hearts, {'context': 'B-tissue/organ'}", + "150, hearts {'context': 'I-tissue/organ'}", + "154, overexpression {'perturbing_action': 'B-other'}", + "155, of {'perturbing_action': 'I-other'}", + "156, a {'perturbing_action': 'I-other'}", + "157, dominant-negative {'perturbing_action': 'I-other'}", + "158, mutant {'perturbing_action': 'I-other'}", + "159, Stat3 {'perturbing_action': 'I-other'}", + "160, protein {'perturbing_action': 'I-other'}", + "162, cardiomyocytes. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "115, inhibited ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "116, apoptotic ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "117, death ['l1', 'l8', 'l14', 'l15', 'l16']", + "119, cardiomyocytes ['l2', 'l9', 'l14', 'l17', 'l18']", + "123, hearts. ['l3', 'l10', 'l15', 'l17', 'l19']", + "126, reduced ['l4', 'l20', 'l21', 'l22', 'l23']", + "127, apoptosis ['l20', 'l24', 'l25', 'l26']", + "129, endothelial ['l5', 'l11', 'l21', 'l24', 'l27', 'l28']", + "130, cells ['l6', 'l12', 'l16', 'l18', 'l19', 'l22', 'l25', 'l27', 'l29']", + "137, hearts, ['l7', 'l13', 'l23', 'l26', 'l28', 'l29']", + "150, hearts ['l30']", + "154, overexpression ['l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "155, of ['l31', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "156, a ['l32', 'l38', 'l44', 'l45', 'l46', 'l47', 'l48']", + "157, dominant-negative ['l33', 'l39', 'l44', 'l49', 'l50', 'l51', 'l52']", + "158, mutant ['l34', 'l40', 'l45', 'l49', 'l53', 'l54', 'l55']", + "159, Stat3 ['l35', 'l41', 'l46', 'l50', 'l53', 'l56', 'l57']", + "160, protein ['l36', 'l42', 'l47', 'l51', 'l54', 'l56', 'l58']", + "162, cardiomyocytes. ['l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l57', 'l58']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "reduced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death", + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "reduced" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes", + "endothelial", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited", + "reduced" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hearts.", + "hearts," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death", + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes", + "endothelial", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death", + "apoptosis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hearts.", + "hearts," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "overexpression", + "of", + "a", + "dominant-negative", + "mutant", + "Stat3", + "protein" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes." + ] + } + } + ] + }, + { + "PMID": "15711562", + "TEXT": "The adaptor molecule SAP is expressed in T lymphocytes and natural killer (NK) cells, where it regulates cytokine production and cytotoxicity. Here, we show that SAP, encoded by the SH2D1A gene locus, also has a crucial role during the development of NKT cells, a lymphocyte subset with immunoregulatory functions in response to infection, cancer and autoimmune disease. Following stimulation with the NKT cell-specific agonist alpha-galactosyl ceramide (alphaGC), Sh2d1a-/- splenocytes did not produce cytokines or activate other lymphoid lineages in an NKT cell-dependent manner. While evaluating the abnormalities in alphaGC-induced immune responses, we observed that Sh2d1a-/- animals lacked NKT cells in the thymus and peripheral organs. The defect in NKT cell ontogeny was hematopoietic cell autonomous and could be rescued by reconstitution of SAP expression within Sh2d1a-/- bone marrow cells. Seventeen individuals with X-linked lymphoproliferative disease (XLP), who harbored germline mutations in SH2D1A, also lacked NKT cells. Furthermore, a female XLP carrier showed completely skewed X chromosome inactivation within NKT cells, but not T or B cells. Thus, SAP is a crucial regulator of NKT cell ontogeny in humans and in mice. The absence of NKT cells may contribute to the phenotypes of SAP deficiency, including abnormal antiviral and antitumor immunity and hypogammaglobulinemia.", + "TAG_DATA": [ + "67, Sh2d1a-/- {'perturbing_action': 'B-gene loss-of-function'}", + "68, splenocytes {'context': 'B-cells'}", + "94, Sh2d1a-/- {'perturbing_action': 'B-gene loss-of-function'}", + "95, animals {'context': 'B-organism'}", + "97, NKT {'context': 'B-cells'}", + "98, cells {'context': 'I-cells'}", + "101, thymus {'context': 'B-tissue/organ'}", + "104, organs. {'context': 'I-tissue/organ'}", + "108, NKT {'context': 'B-cells'}", + "109, cell {'context': 'I-cells'}", + "120, reconstitution {'perturbing_action': 'B-gene gain-of-function'}", + "121, of {'perturbing_action': 'I-gene gain-of-function'}", + "122, SAP {'perturbing_action': 'I-gene gain-of-function'}", + "123, expression {'perturbing_action': 'I-gene gain-of-function'}", + "125, Sh2d1a-/- {'perturbing_action': 'B-gene loss-of-function'}", + "126, bone {'context': 'B-cells'}", + "127, marrow {'context': 'I-cells'}", + "128, cells. {'context': 'I-cells'}", + "144, NKT {'context': 'B-cells'}", + "145, cells. {'context': 'I-cells'}", + "158, NKT {'context': 'B-cells'}", + "159, cells, {'context': 'I-cells'}", + "162, T {'context': 'B-cells'}", + "163, or {'context': 'I-cells'}", + "164, B {'context': 'I-cells'}", + "165, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "67, Sh2d1a-/- ['l0']", + "68, splenocytes ['l0']", + "94, Sh2d1a-/- ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "95, animals ['l1', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "97, NKT ['l2', 'l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "98, cells ['l3', 'l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "101, thymus ['l4', 'l12', 'l18', 'l23', 'l28', 'l29', 'l30', 'l31']", + "103, peripheral ['l5', 'l13', 'l19', 'l24', 'l28', 'l32', 'l33', 'l34']", + "104, organs. ['l6', 'l14', 'l20', 'l25', 'l29', 'l32', 'l35', 'l36']", + "108, NKT ['l7', 'l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "109, cell ['l8', 'l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l37', 'l46', 'l47', 'l48']", + "120, reconstitution ['l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "121, of ['l38', 'l49', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "122, SAP ['l39', 'l50', 'l58', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "123, expression ['l40', 'l51', 'l59', 'l66', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "125, Sh2d1a-/- ['l41', 'l52', 'l60', 'l67', 'l73', 'l79', 'l80', 'l81', 'l82', 'l83']", + "126, bone ['l42', 'l46', 'l53', 'l61', 'l68', 'l74', 'l79', 'l84', 'l85', 'l86', 'l87']", + "127, marrow ['l43', 'l47', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l88', 'l89', 'l90']", + "128, cells. ['l9', 'l44', 'l48', 'l55', 'l63', 'l70', 'l76', 'l81', 'l85', 'l88', 'l91', 'l92']", + "144, NKT ['l56', 'l64', 'l71', 'l77', 'l82', 'l86', 'l89', 'l91', 'l93']", + "145, cells. ['l45', 'l57', 'l65', 'l72', 'l78', 'l83', 'l87', 'l90', 'l92', 'l93']", + "158, NKT ['l94', 'l95', 'l96', 'l97', 'l98']", + "159, cells, ['l94', 'l99', 'l100', 'l101', 'l102']", + "162, T ['l95', 'l99', 'l103', 'l104', 'l105']", + "163, or ['l96', 'l100', 'l103', 'l106', 'l107']", + "164, B ['l97', 'l101', 'l104', 'l106', 'l108']", + "165, cells. ['l98', 'l102', 'l105', 'l107', 'l108']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sh2d1a-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "splenocytes", + "NKT", + "cells", + "cell", + "cells.", + "bone", + "marrow" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sh2d1a-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "animals" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sh2d1a-/-" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "thymus", + "organs." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "NKT", + "bone", + "marrow", + "cells." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "SAP", + "expression", + "reconstitution" + ] + } + } + ] + }, + { + "PMID": "15711557", + "TEXT": "Immune escape is a crucial feature of cancer progression about which little is known. Elevation of the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) in tumor cells can facilitate immune escape. Not known is how IDO becomes elevated or whether IDO inhibitors will be useful for cancer treatment. Here we show that IDO is under genetic control of Bin1, which is attenuated in many human malignancies. Mouse knockout studies indicate that Bin1 loss elevates the STAT1- and NF-kappaB-dependent expression of IDO, driving escape of oncogenically transformed cells from T cell-dependent antitumor immunity. In MMTV-Neu mice, an established breast cancer model, we show that small-molecule inhibitors of IDO cooperate with cytotoxic agents to elicit regression of established tumors refractory to single-agent therapy. Our findings suggest that Bin1 loss promotes immune escape in cancer by deregulating IDO and that IDO inhibitors may improve responses to cancer chemotherapy.", + "TAG_DATA": [ + "64, Mouse {'context': 'B-organism'}", + "69, Bin1 {'perturbing_action': 'B-gene loss-of-function'}", + "70, loss {'perturbing_action': 'I-gene loss-of-function'}", + "84, cells {'context': 'I-transformed cells'}", + "91, MMTV-Neu {'perturbing_action': 'B-other'}", + "92, mice, {'context': 'B-organism'}", + "101, small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "102, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "103, of {'perturbing_action': 'I-pharmacological inhibition'}", + "104, IDO {'perturbing_action': 'I-pharmacological inhibition'}", + "110, elicit {'effect': 'B-positive'}", + "111, regression {'phenotype': 'B-tumour regression'}", + "114, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "64, Mouse ['l0', 'l1', 'l2', 'l3']", + "69, Bin1 ['l0', 'l4', 'l5', 'l6']", + "70, loss ['l1', 'l4', 'l7', 'l8']", + "83, transformed ['l2', 'l5', 'l7', 'l9']", + "84, cells ['l3', 'l6', 'l8', 'l9']", + "91, MMTV-Neu ['l10']", + "92, mice, ['l10']", + "101, small-molecule ['l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "102, inhibitors ['l11', 'l17', 'l18', 'l19', 'l20', 'l21']", + "103, of ['l12', 'l17', 'l22', 'l23', 'l24', 'l25']", + "104, IDO ['l13', 'l18', 'l22', 'l26', 'l27', 'l28']", + "110, elicit ['l14', 'l19', 'l23', 'l26', 'l29', 'l30']", + "111, regression ['l15', 'l20', 'l24', 'l27', 'l29', 'l31']", + "114, tumors ['l16', 'l21', 'l25', 'l28', 'l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mouse" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bin1", + "loss" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bin1", + "loss" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "MMTV-Neu" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "inhibitors", + "of", + "IDO" + ] + }, + "effect": { + "val": "positive", + "words": [ + "elicit" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "inhibitors", + "of", + "IDO" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "inhibitors", + "of", + "IDO" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "elicit" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "elicit" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + } + ] + }, + { + "PMID": "15685173", + "TEXT": "We show that NF-kappaB and transcriptional targets are activated in liver by obesity and high-fat diet (HFD). We have matched this state of chronic, subacute 'inflammation' by low-level activation of NF-kappaB in the liver of transgenic mice, designated LIKK, by selectively expressing constitutively active IKK-b in hepatocytes. These mice exhibit a type 2 diabetes phenotype, characterized by hyperglycemia, profound hepatic insulin resistance, and moderate systemic insulin resistance, including effects in muscle. The hepatic production of proinflammatory cytokines, including IL-6, IL-1beta and TNF-alpha, was increased in LIKK mice to a similar extent as induced by HFD in in wild-type mice. Parallel increases were observed in cytokine signaling in liver and mucscle of LIKK mice. Insulin resistance was improved by systemic neutralization of IL-6 or salicylate inhibition of IKK-beta. Hepatic expression of the IkappaBalpha superrepressor (LISR) reversed the phenotype of both LIKK mice and wild-type mice fed an HFD. These findings indicate that lipid accumulation in the liver leads to subacute hepatic 'inflammation' through NF-kappaB activation and downstream cytokine production. This causes insulin resistance both locally in liver and systemically.", + "TAG_DATA": [ + "40, selectively {'perturbing_action': 'B-gene gain-of-function'}", + "41, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "42, constitutively {'perturbing_action': 'I-gene gain-of-function'}", + "43, active {'perturbing_action': 'I-gene gain-of-function'}", + "44, IKK-b {'perturbing_action': 'I-gene gain-of-function'}", + "45, in {'perturbing_action': 'I-gene gain-of-function'}", + "46, hepatocytes. {'context': 'B-cells'}", + "48, mice {'context': 'B-organism'}", + "85, LIKK {'perturbing_action': 'B-other'}", + "86, mice {'context': 'B-organism'}", + "98, mice. {'context': 'B-organism'}", + "107, liver {'context': 'B-tissue/organ'}", + "109, mucscle {'context': 'I-tissue/organ'}", + "111, LIKK {'perturbing_action': 'B-other'}", + "112, mice. {'context': 'B-organism'}", + "123, salicylate {'perturbing_action': 'B-pharmacological inhibition'}", + "124, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "125, of {'perturbing_action': 'I-pharmacological inhibition'}", + "126, IKK-beta. {'perturbing_action': 'I-pharmacological inhibition'}", + "127, Hepatic {'perturbing_action': 'B-gene gain-of-function'}", + "128, expression {'perturbing_action': 'I-gene gain-of-function'}", + "129, of {'perturbing_action': 'I-gene gain-of-function'}", + "130, the {'perturbing_action': 'I-gene gain-of-function'}", + "131, IkappaBalpha {'perturbing_action': 'I-gene gain-of-function'}", + "132, superrepressor {'perturbing_action': 'I-gene gain-of-function'}", + "133, (LISR) {'perturbing_action': 'I-gene gain-of-function'}", + "139, LIKK {'perturbing_action': 'B-other'}", + "140, mice {'context': 'B-organism'}", + "143, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "40, selectively ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "41, expressing ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "42, constitutively ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "43, active ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "44, IKK-b ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "45, in ['l4', 'l17', 'l29', 'l40', 'l50', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "46, hepatocytes. ['l5', 'l18', 'l30', 'l41', 'l51', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "48, mice ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l77', 'l78']", + "85, LIKK ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l79', 'l80', 'l81']", + "86, mice ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l79']", + "98, mice. ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l80', 'l82', 'l83', 'l84', 'l85']", + "107, liver ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l81', 'l82', 'l86', 'l87', 'l88']", + "109, mucscle ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l83', 'l86', 'l89', 'l90']", + "111, LIKK ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l84', 'l87', 'l89', 'l91']", + "112, mice. ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l85', 'l88', 'l90', 'l91']", + "123, salicylate ['l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "124, inhibition ['l92', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "125, of ['l93', 'l102', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "126, IKK-beta. ['l94', 'l103', 'l113', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "127, Hepatic ['l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "128, expression ['l104', 'l114', 'l130', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146']", + "129, of ['l105', 'l115', 'l131', 'l139', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "130, the ['l95', 'l106', 'l116', 'l123', 'l132', 'l140', 'l147', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159']", + "131, IkappaBalpha ['l96', 'l107', 'l117', 'l124', 'l133', 'l141', 'l148', 'l154', 'l160', 'l161', 'l162', 'l163', 'l164']", + "132, superrepressor ['l97', 'l108', 'l118', 'l125', 'l134', 'l142', 'l149', 'l155', 'l160', 'l165', 'l166', 'l167', 'l168']", + "133, (LISR) ['l98', 'l109', 'l119', 'l126', 'l135', 'l143', 'l150', 'l156', 'l161', 'l165', 'l169', 'l170', 'l171']", + "139, LIKK ['l99', 'l110', 'l120', 'l127', 'l136', 'l144', 'l151', 'l157', 'l162', 'l166', 'l169', 'l172', 'l173']", + "140, mice ['l100', 'l111', 'l121', 'l128', 'l137', 'l145', 'l152', 'l158', 'l163', 'l167', 'l170', 'l172', 'l174']", + "143, mice ['l101', 'l112', 'l122', 'l129', 'l138', 'l146', 'l153', 'l159', 'l164', 'l168', 'l171', 'l173', 'l174']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "selectively", + "expressing", + "constitutively", + "active", + "IKK-b", + "in" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "selectively", + "expressing", + "constitutively", + "active", + "IKK-b", + "in", + "Hepatic", + "expression", + "of", + "the", + "IkappaBalpha", + "superrepressor", + "(LISR)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "selectively", + "expressing", + "constitutively", + "active", + "IKK-b", + "in" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver", + "mucscle" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hepatocytes." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "LIKK" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "LIKK" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "LIKK" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver", + "mucscle" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "salicylate", + "inhibition", + "of", + "IKK-beta." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15654326", + "TEXT": "Autoimmune diabetes mellitus in humans is characterized by immunological destruction of pancreatic beta islet cells. We investigated the circumstances under which CD8(+) T cells specific for pancreatic beta-islet antigens induce disease in mice expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) as a transgene under the control of the rat insulin promoter. In contrast to infection with LCMV, immunization with LCMV-GP derived peptide did not induce autoimmune diabetes despite large numbers of autoreactive cytotoxic T cells. Only subsequent treatment with Toll-like receptor ligands elicited overt autoimmune disease. This difference was critically regulated by the peripheral target organ itself, which upregulated class I major histocompatibility complex (MHC) in response to systemic Toll-like receptor-triggered interferon-alpha production. These data identify the 'inflammatory status' of the target organ as a separate and limiting factor determining the development of autoimmune disease.", + "TAG_DATA": [ + "32, mice {'context': 'B-organism'}", + "38, glycoprotein {'perturbing_action': 'I-gene gain-of-function'}", + "39, (GP) {'perturbing_action': 'I-gene gain-of-function'}", + "40, as {'perturbing_action': 'I-gene gain-of-function'}", + "41, a {'perturbing_action': 'I-gene gain-of-function'}", + "42, transgene {'perturbing_action': 'I-gene gain-of-function'}", + "43, under {'perturbing_action': 'I-gene gain-of-function'}", + "44, the {'perturbing_action': 'I-gene gain-of-function'}", + "45, control {'perturbing_action': 'I-gene gain-of-function'}", + "46, of {'perturbing_action': 'I-gene gain-of-function'}", + "47, the {'perturbing_action': 'I-gene gain-of-function'}", + "48, rat {'perturbing_action': 'I-gene gain-of-function'}", + "50, promoter. {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "32, mice ['l0', 'l1', 'l2']", + "35, choriomeningitis ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "36, virus ['l3', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "37, (LCMV) ['l0', 'l4', 'l18', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "38, glycoprotein ['l1', 'l5', 'l19', 'l32', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "39, (GP) ['l2', 'l6', 'l20', 'l33', 'l45', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "40, as ['l7', 'l21', 'l34', 'l46', 'l57', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "41, a ['l8', 'l22', 'l35', 'l47', 'l58', 'l68', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "42, transgene ['l9', 'l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "43, under ['l10', 'l24', 'l37', 'l49', 'l60', 'l70', 'l79', 'l87', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "44, the ['l11', 'l25', 'l38', 'l50', 'l61', 'l71', 'l80', 'l88', 'l95', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "45, control ['l12', 'l26', 'l39', 'l51', 'l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l108', 'l109', 'l110', 'l111', 'l112']", + "46, of ['l13', 'l27', 'l40', 'l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l108', 'l113', 'l114', 'l115', 'l116']", + "47, the ['l14', 'l28', 'l41', 'l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l109', 'l113', 'l117', 'l118', 'l119']", + "48, rat ['l15', 'l29', 'l42', 'l54', 'l65', 'l75', 'l84', 'l92', 'l99', 'l105', 'l110', 'l114', 'l117', 'l120', 'l121']", + "49, insulin ['l16', 'l30', 'l43', 'l55', 'l66', 'l76', 'l85', 'l93', 'l100', 'l106', 'l111', 'l115', 'l118', 'l120', 'l122']", + "50, promoter. ['l17', 'l31', 'l44', 'l56', 'l67', 'l77', 'l86', 'l94', 'l101', 'l107', 'l112', 'l116', 'l119', 'l121', 'l122']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "glycoprotein", + "(GP)" + ] + } + } + ] + }, + { + "PMID": "15558057", + "TEXT": "Cholesterol gallstone disease is characterized by several events, including cholesterol precipitation in bile, increased bile salt hydrophobicity and gallbladder inflammation. Here, we describe the same phenotype in mice lacking the bile acid receptor, FXR. Furthermore, in susceptible wild-type mice that recapitulate human cholesterol gallstone disease, treatment with a synthetic FXR agonist prevented sequelae of the disease. These effects were mediated by FXR-dependent increases in biliary bile salt and phospholipid concentrations, which restored cholesterol solubility and thereby prevented gallstone formation. Taken together, these results indicate that FXR is a promising therapeutic target for treating or preventing cholesterol gallstone disease.", + "TAG_DATA": [ + "27, mice {'context': 'B-organism'}", + "28, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "29, the {'perturbing_action': 'I-gene loss-of-function'}", + "30, bile {'perturbing_action': 'I-gene loss-of-function'}", + "31, acid {'perturbing_action': 'I-gene loss-of-function'}", + "32, receptor, {'perturbing_action': 'I-gene loss-of-function'}", + "33, FXR. {'perturbing_action': 'I-gene loss-of-function'}", + "38, mice {'context': 'B-organism'}", + "48, synthetic {'perturbing_action': 'B-pharmacological augmentation'}", + "49, FXR {'perturbing_action': 'I-pharmacological augmentation'}", + "50, agonist {'perturbing_action': 'I-pharmacological augmentation'}" + ], + "LINK_DATA": [ + "27, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "28, lacking ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "29, the ['l1', 'l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "30, bile ['l2', 'l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "31, acid ['l3', 'l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "32, receptor, ['l4', 'l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "33, FXR. ['l5', 'l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "38, mice ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']", + "48, synthetic ['l27', 'l28']", + "49, FXR ['l27', 'l29']", + "50, agonist ['l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "bile", + "acid", + "receptor,", + "FXR." + ] + } + } + ] + }, + { + "PMID": "15558055", + "TEXT": "West Nile virus (WNV), a mosquito-borne single-stranded (ss)RNA flavivirus, causes human disease of variable severity. We investigated the involvement of Toll-like receptor (Tlr) 3, which recognizes viral double-stranded (ds)RNA, on WNV infection. Tlr3-deficient (Tlr3(-/-)) mice were more resistant to lethal WNV infection and had impaired cytokine production and enhanced viral load in the periphery, whereas in the brain, viral load, inflammatory responses and neuropathology were reduced compared to wild-type mice. Peripheral WNV infection led to a breakdown of the blood-brain barrier and enhanced brain infection in wild-type but not in Tlr3(-/-) mice, although both groups were equally susceptible upon intracerebroventricular administration of the virus. Tumor necrosis factor-alpha receptor 1 signaling is vital for blood-brain barrier compromise upon Tlr3 stimulation by dsRNA or WNV. Collectively, WNV infection leads to a Tlr3-dependent inflammatory response, which is involved in brain penetration of the virus and neuronal injury.", + "TAG_DATA": [ + "32, Tlr3-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "33, (Tlr3(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "34, mice {'context': 'B-organism'}", + "57, brain, {'context': 'B-tissue/organ'}", + "69, mice. {'context': 'B-organism'}", + "83, brain {'context': 'B-tissue/organ'}", + "90, Tlr3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "91, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "32, Tlr3-deficient ['l0', 'l1', 'l2', 'l3', 'l4']", + "33, (Tlr3(-/-)) ['l0', 'l5', 'l6', 'l7']", + "34, mice ['l1', 'l5', 'l8']", + "57, brain, ['l2', 'l6', 'l8']", + "69, mice. ['l3', 'l7']", + "83, brain ['l4', 'l9']", + "90, Tlr3(-/-) ['l10']", + "91, mice, ['l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tlr3-deficient", + "(Tlr3(-/-))", + "Tlr3(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tlr3-deficient", + "(Tlr3(-/-))" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain,", + "brain" + ] + } + } + ] + }, + { + "PMID": "15502845", + "TEXT": "Bioluminescence imaging has previously been used to monitor the formation of grafted tumors in vivo and measure cell number during tumor progression and response to therapy. The development and optimization of successful cancer therapy strategies may well require detailed and specific assessment of biological processes in response to mechanistic intervention. Here, we use bioluminescence imaging to monitor the cell cycle in a genetically engineered, histologically accurate model of glioma in vivo. In these platelet-derived growth factor (PDGF)-driven oligodendrogliomas, G1 cell-cycle arrest is generated by blockade of either the PDGF receptor or mTOR using small-molecule inhibitors.", + "TAG_DATA": [ + "66, model {'context': 'B-neoplasm'}", + "67, of {'context': 'B-neoplasm'}", + "68, glioma {'context': 'B-neoplasm'}", + "69, in {'context': 'B-in vivo'}", + "70, vivo. {'context': 'I-in vivo'}", + "77, oligodendrogliomas, {'context': 'B-neoplasm'}", + "78, G1 {'phenotype': 'B-cell cycle arrest'}", + "79, cell-cycle {'phenotype': 'I-cell cycle arrest'}", + "80, arrest {'phenotype': 'I-cell cycle arrest'}", + "84, blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "85, of {'perturbing_action': 'I-pharmacological inhibition'}", + "86, either {'perturbing_action': 'I-pharmacological inhibition'}", + "87, the {'perturbing_action': 'I-pharmacological inhibition'}", + "88, PDGF {'perturbing_action': 'I-pharmacological inhibition'}", + "89, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "90, or {'perturbing_action': 'I-pharmacological inhibition'}", + "91, mTOR {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "66, model ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "67, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "68, glioma ['l1', 'l7', 'l13', 'l14', 'l15']", + "69, in ['l2', 'l8', 'l13', 'l16', 'l17', 'l18', 'l19']", + "70, vivo. ['l3', 'l9', 'l14', 'l16', 'l20', 'l21', 'l22']", + "77, oligodendrogliomas, ['l4', 'l10', 'l15', 'l17', 'l20', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "78, G1 ['l23', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "79, cell-cycle ['l5', 'l11', 'l18', 'l21', 'l24', 'l34', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "80, arrest ['l6', 'l12', 'l19', 'l22', 'l25', 'l35', 'l44', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "84, blockade ['l26', 'l36', 'l45', 'l53', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "85, of ['l27', 'l37', 'l46', 'l54', 'l61', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "86, either ['l28', 'l38', 'l47', 'l55', 'l62', 'l68', 'l74', 'l75', 'l76', 'l77', 'l78']", + "87, the ['l29', 'l39', 'l48', 'l56', 'l63', 'l69', 'l74', 'l79', 'l80', 'l81', 'l82']", + "88, PDGF ['l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l75', 'l79', 'l83', 'l84', 'l85']", + "89, receptor ['l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l83', 'l86', 'l87']", + "90, or ['l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l86', 'l88']", + "91, mTOR ['l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l87', 'l88']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "model", + "of", + "oligodendrogliomas," + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest", + "G1" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "oligodendrogliomas," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "either", + "the", + "PDGF", + "receptor", + "or", + "mTOR" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G1", + "cell-cycle", + "arrest" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "either", + "the", + "PDGF", + "receptor", + "or", + "mTOR" + ] + } + } + ] + }, + { + "PMID": "15475962", + "TEXT": "Excessive salt intake is a major risk factor for hypertension. Here we identify the role of Na(+)/Ca(2+) exchanger type 1 (NCX1) in salt-sensitive hypertension using SEA0400, a specific inhibitor of Ca(2+) entry through NCX1, and genetically engineered mice. SEA0400 lowers arterial blood pressure in salt-dependent hypertensive rat models, but not in other types of hypertensive rats or in normotensive rats. Infusion of SEA0400 into the femoral artery in salt-dependent hypertensive rats increases arterial blood flow, indicating peripheral vasodilation. SEA0400 reverses ouabain-induced cytosolic Ca(2+) elevation and vasoconstriction in arteries. Furthermore, heterozygous NCX1-deficient mice have low salt sensitivity, whereas transgenic mice that specifically express NCX1.3 in smooth muscle are hypersensitive to salt. SEA0400 lowers the blood pressure in salt-dependent hypertensive mice expressing NCX1.3, but not in SEA0400-insensitive NCX1.3 mutants. These findings indicate that salt-sensitive hypertension is triggered by Ca(2+) entry through NCX1 in arterial smooth muscle and suggest that NCX1 inhibitors might be useful therapeutically.", + "TAG_DATA": [ + "44, salt-dependent {'context': 'B-organism'}", + "46, rat {'context': 'I-organism'}", + "47, models, {'context': 'I-organism'}", + "55, rats {'context': 'I-organism'}", + "58, normotensive {'context': 'B-organism'}", + "59, rats. {'context': 'I-organism'}", + "68, salt-dependent {'context': 'B-organism'}", + "69, hypertensive {'context': 'I-organism'}", + "70, rats {'context': 'I-organism'}", + "87, arteries. {'context': 'B-tissue/organ'}", + "89, heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "90, NCX1-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "91, mice {'context': 'B-organism'}", + "97, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "98, mice {'context': 'I-organism'}", + "116, salt-dependent {'context': 'B-organism'}", + "117, hypertensive {'context': 'I-organism'}", + "118, mice {'context': 'I-organism'}", + "119, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "120, NCX1.3, {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "44, salt-dependent ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "45, hypertensive ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "46, rat ['l1', 'l7', 'l14', 'l15', 'l16', 'l17', 'l18']", + "47, models, ['l2', 'l8', 'l14', 'l19', 'l20']", + "55, rats ['l3', 'l9', 'l15', 'l19', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "58, normotensive ['l21', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "59, rats. ['l4', 'l10', 'l16', 'l22', 'l27', 'l33', 'l34', 'l35', 'l36']", + "66, artery ['l5', 'l11', 'l17', 'l23', 'l28', 'l33', 'l37', 'l38', 'l39', 'l40']", + "68, salt-dependent ['l24', 'l29', 'l34', 'l37', 'l41', 'l42', 'l43']", + "69, hypertensive ['l12', 'l25', 'l30', 'l35', 'l38', 'l41', 'l44', 'l45']", + "70, rats ['l6', 'l13', 'l18', 'l20', 'l26', 'l31', 'l36', 'l39', 'l42', 'l44', 'l46']", + "87, arteries. ['l32', 'l40', 'l43', 'l45', 'l46']", + "89, heterozygous ['l47', 'l48', 'l49']", + "90, NCX1-deficient ['l47', 'l50']", + "91, mice ['l48', 'l50']", + "97, transgenic ['l51', 'l52', 'l53']", + "98, mice ['l49', 'l51']", + "116, salt-dependent ['l54', 'l55', 'l56', 'l57']", + "117, hypertensive ['l52', 'l54', 'l58', 'l59', 'l60']", + "118, mice ['l55', 'l58', 'l61', 'l62']", + "119, expressing ['l53', 'l56', 'l59', 'l61', 'l63']", + "120, NCX1.3, ['l57', 'l60', 'l62', 'l63']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "heterozygous", + "NCX1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "NCX1.3," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "hypertensive", + "salt-dependent" + ] + } + } + ] + }, + { + "PMID": "15467726", + "TEXT": "Autoimmune diseases are often mediated by self-reactive T cells, which must be activated to cause immunopathology. One mechanism, known as molecular mimicry, proposes that self-reactive T cells may be activated by pathogens expressing crossreactive ligands. Here we have developed a model to investigate how the affinity of the T-cell receptor (TCR) for the activating agent influences autoimmunity. Our model shows that an approximately fivefold difference in the TCR affinity for the activating ligand results in a 50% reduction in the incidence of autoimmunity. A reduction in TCR-ligand affinity to approximately 20 times lower than normal does not induce autoimmunity despite the unexpected induction of cytotoxic T lymphocytes (CTLs) and insulitis. Furthermore, in the absence of a key negative regulatory molecule, Cbl-b, 100% of mice develop autoimmunity upon infection with viruses encoding the lower-affinity ligand. Therefore, autoimmune disease is sensitive both to the affinity of the activating ligand and to normal mechanisms that negatively regulate the immune response.", + "TAG_DATA": [ + "113, absence {'perturbing_action': 'B-gene loss-of-function'}", + "123, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "113, absence ['l0']", + "123, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15378055", + "TEXT": "Exaggerated levels of VEGF (vascular endothelial growth factor) are present in persons with asthma, but the role(s) of VEGF in normal and asthmatic lungs has not been defined. We generated lung-targeted VEGF(165) transgenic mice and evaluated the role of VEGF in T-helper type 2 cell (T(H)2)-mediated inflammation. In these mice, VEGF induced, through IL-13-dependent and -independent pathways, an asthma-like phenotype with inflammation, parenchymal and vascular remodeling, edema, mucus metaplasia, myocyte hyperplasia and airway hyper-responsiveness. VEGF also enhanced respiratory antigen sensitization and T(H)2 inflammation and increased the number of activated DC2 dendritic cells. In antigen-induced inflammation, VEGF was produced by epithelial cells and preferentially by T(H)2 versus T(H)1 cells. In this setting, it had a critical role in T(H)2 inflammation, cytokine production and physiologic dysregulation. Thus, VEGF is a mediator of vascular and extravascular remodeling and inflammation that enhances antigen sensitization and is crucial in adaptive T(H)2 inflammation. VEGF regulation may be therapeutic in asthma and other T(H)2 disorders.", + "TAG_DATA": [ + "30, lung-targeted {'perturbing_action': 'B-gene gain-of-function'}", + "31, VEGF(165) {'perturbing_action': 'I-gene gain-of-function'}", + "32, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "33, mice {'context': 'B-organism'}", + "49, mice, {'context': 'B-organism'}", + "89, DC2 {'context': 'B-cells'}", + "90, dendritic {'context': 'I-cells'}", + "91, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "30, lung-targeted ['l0', 'l1', 'l2', 'l3']", + "31, VEGF(165) ['l0', 'l4', 'l5', 'l6']", + "32, transgenic ['l1', 'l4', 'l7', 'l8']", + "33, mice ['l2', 'l5', 'l7', 'l9']", + "49, mice, ['l3', 'l6', 'l8', 'l9']", + "89, DC2 ['l10', 'l11']", + "90, dendritic ['l10', 'l12']", + "91, cells. ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "lung-targeted", + "VEGF(165)", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + } + ] + }, + { + "PMID": "15286785", + "TEXT": "Graft-versus-host disease (GVHD) is a major source of morbidity in allogenic stem cell transplantation. We previously showed that recipient antigen-presenting cells (APCs) are required for CD8-dependent GVHD in a mouse model across only minor histocompatibility antigens (minor H antigens). However, these studies did not address the function of donor-derived APCs after GVHD is initiated. Here we show that GVHD develops in recipients of donor major histocompatibility complex class I-deficient (MHC I(-)) bone marrow. Thus, after initial priming, CD8 cells caused GVHD without a further requirement for hematopoietic APCs, indicating that host APCs are necessary and sufficient for GHVD. Nonetheless, GVHD was less severe in recipients of MHC I(-) bone marrow. Therefore, once initiated, GVHD is intensified by donor-derived cells, most probably donor APCs cross-priming alloreactive CD8 cells. Nevertheless, donor APCs were not required for CD8-mediated graft-versus-leukemia (GVL) against a mouse model of chronic-phase chronic myelogenous leukemia. These studies identify donor APCs as a new target for treating GVHD, which may preserve GVL.", + "TAG_DATA": [ + "63, donor {'perturbing_action': 'B-gene loss-of-function'}", + "64, major {'perturbing_action': 'I-gene loss-of-function'}", + "65, histocompatibility {'perturbing_action': 'I-gene loss-of-function'}", + "66, complex {'perturbing_action': 'I-gene loss-of-function'}", + "67, class {'perturbing_action': 'I-gene loss-of-function'}", + "68, I-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "69, (MHC {'perturbing_action': 'I-gene loss-of-function'}", + "70, I(-)) {'perturbing_action': 'I-gene loss-of-function'}", + "71, bone {'perturbing_action': 'I-gene loss-of-function'}", + "72, marrow. {'perturbing_action': 'I-gene loss-of-function'}", + "77, CD8 {'context': 'B-cells'}", + "78, cells {'context': 'I-cells'}", + "106, MHC {'perturbing_action': 'B-gene loss-of-function'}", + "107, I(-) {'perturbing_action': 'B-gene loss-of-function'}", + "108, bone {'perturbing_action': 'I-gene loss-of-function'}", + "139, mouse {'context': 'B-organism'}", + "140, model {'context': 'I-neoplasm'}", + "141, of {'context': 'I-neoplasm'}", + "142, chronic-phase {'context': 'I-neoplasm'}", + "143, chronic {'context': 'I-neoplasm'}", + "144, myelogenous {'context': 'I-neoplasm'}", + "145, leukemia. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "63, donor ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "64, major ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "65, histocompatibility ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "66, complex ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "67, class ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "68, I-deficient ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "69, (MHC ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "70, I(-)) ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "71, bone ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "72, marrow. ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63']", + "77, CD8 ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l64']", + "78, cells ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l63', 'l64']", + "106, MHC ['l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "107, I(-) ['l65', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "108, bone ['l66', 'l75', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "109, marrow. ['l67', 'l76', 'l83']", + "139, mouse ['l68', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "140, model ['l69', 'l77', 'l84', 'l90', 'l96', 'l97', 'l98', 'l99', 'l100']", + "141, of ['l70', 'l78', 'l85', 'l91', 'l96', 'l101', 'l102', 'l103', 'l104']", + "142, chronic-phase ['l71', 'l79', 'l86', 'l92', 'l97', 'l101', 'l105', 'l106', 'l107']", + "143, chronic ['l72', 'l80', 'l87', 'l93', 'l98', 'l102', 'l105', 'l108', 'l109']", + "144, myelogenous ['l73', 'l81', 'l88', 'l94', 'l99', 'l103', 'l106', 'l108', 'l110']", + "145, leukemia. ['l74', 'l82', 'l89', 'l95', 'l100', 'l104', 'l107', 'l109', 'l110']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "donor", + "major", + "histocompatibility", + "complex", + "class", + "I-deficient", + "(MHC", + "I(-))", + "bone", + "marrow." + ] + }, + "context": { + "val": "cells", + "words": [ + "CD8", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MHC" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MHC", + "I(-)", + "bone" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "model", + "of", + "chronic-phase", + "chronic", + "myelogenous", + "leukemia." + ] + } + } + ] + }, + { + "PMID": "15273746", + "TEXT": "Noonan syndrome is a common human autosomal dominant birth defect, characterized by short stature, facial abnormalities, heart defects and possibly increased risk of leukemia. Mutations of Ptpn11 (also known as Shp2), which encodes the protein-tyrosine phosphatase Shp2, occur in approximately 50% of individuals with Noonan syndrome, but their molecular, cellular and developmental effects, and the relationship between Noonan syndrome and leukemia, are unclear. We generated mice expressing the Noonan syndrome-associated mutant D61G. When homozygous, the D61G mutant is embryonic lethal, whereas heterozygotes have decreased viability. Surviving Ptpn11(D61G/+) embryos ( approximately 50%) have short stature, craniofacial abnormalities similar to those in Noonan syndrome, and myeloproliferative disease. Severely affected Ptpn11(D61G/+) embryos ( approximately 50%) have multiple cardiac defects similar to those in mice lacking the Ras-GAP protein neurofibromin. Their endocardial cushions have increased Erk activation, but Erk hyperactivation is cell and pathway specific. Our results clarify the relationship between Noonan syndrome and leukemia and show that a single Ptpn11 gain-of-function mutation evokes all major features of Noonan syndrome by acting on multiple developmental lineages in a gene dosage-dependent and pathway-selective manner.", + "TAG_DATA": [ + "65, mice {'context': 'B-organism'}", + "68, Noonan {'perturbing_action': 'I-other'}", + "69, syndrome-associated {'perturbing_action': 'I-other'}", + "70, mutant {'perturbing_action': 'I-other'}", + "71, D61G. {'perturbing_action': 'I-other'}", + "75, D61G {'perturbing_action': 'I-other'}", + "76, mutant {'perturbing_action': 'I-other'}", + "86, Ptpn11(D61G/+) {'perturbing_action': 'B-other'}", + "87, embryos {'context': 'I-organism'}", + "107, Ptpn11(D61G/+) {'perturbing_action': 'B-other'}", + "108, embryos {'context': 'I-organism'}", + "120, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "65, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "68, Noonan ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "69, syndrome-associated ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "70, mutant ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "71, D61G. ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "75, D61G ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "76, mutant ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "86, Ptpn11(D61G/+) ['l21', 'l22']", + "87, embryos ['l21']", + "107, Ptpn11(D61G/+) ['l23', 'l24']", + "108, embryos ['l23', 'l25']", + "120, mice ['l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "embryos" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Noonan", + "syndrome-associated", + "mutant", + "D61G.", + "D61G", + "Ptpn11(D61G/+)" + ] + } + } + ] + }, + { + "PMID": "15258577", + "TEXT": "Secondary injury exacerbates the extent of spinal cord insults, yet the mechanistic basis of this phenomenon has largely been unexplored. Here we report that broad regions of the peritraumatic zone are characterized by a sustained process of pathologic, high ATP release. Spinal cord neurons expressed P2X7 purine receptors (P2X7R), and exposure to ATP led to high-frequency spiking, irreversible increases in cytosolic calcium and cell death. To assess the potential effect of P2X7R blockade in ameliorating acute spinal cord injury (SCI), we delivered P2X7R antagonists OxATP or PPADS to rats after acute impact injury. We found that both OxATP and PPADS significantly improved functional recovery and diminished cell death in the peritraumatic zone. These observations demonstrate that SCI is associated with prolonged purinergic receptor activation, which results in excitotoxicity-based neuronal degeneration. P2X7R antagonists inhibit this process, reducing both the histological extent and functional sequelae of acute SCI.", + "TAG_DATA": [ + "63, cell {'phenotype': 'B-cell death'}", + "64, death. {'phenotype': 'I-cell death'}", + "82, P2X7R {'perturbing_action': 'B-pharmacological inhibition'}", + "83, antagonists {'perturbing_action': 'I-pharmacological inhibition'}", + "84, OxATP {'perturbing_action': 'I-pharmacological inhibition'}", + "86, PPADS {'perturbing_action': 'I-pharmacological inhibition'}", + "88, rats {'context': 'B-organism'}", + "105, diminished {'effect': 'B-negative'}", + "106, cell {'phenotype': 'B-cell death'}", + "107, death {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "63, cell ['l0']", + "64, death. ['l0']", + "82, P2X7R ['l1', 'l2', 'l3', 'l4']", + "83, antagonists ['l1', 'l5', 'l6', 'l7']", + "84, OxATP ['l2', 'l5', 'l8', 'l9']", + "86, PPADS ['l3', 'l6', 'l8', 'l10']", + "88, rats ['l4', 'l7', 'l9', 'l10']", + "105, diminished ['l11', 'l12']", + "106, cell ['l11', 'l13']", + "107, death ['l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "P2X7R", + "antagonists", + "OxATP", + "PPADS" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "diminished" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + } + ] + }, + { + "PMID": "15235599", + "TEXT": "There are no studies so far linking molecular regulation of lymphangiogenesis and induction of adaptive immunity. Here, we show that blockade of vascular endothelial growth factor receptor-3 (VEGFR-3) signaling significantly suppresses corneal antigen-presenting (dendritic) cell trafficking to draining lymph nodes, induction of delayed-type hypersensitivity and rejection of corneal transplants. Regulating the function of VEGFR-3 may therefore be a mechanism for modulating adaptive immunity in the periphery.", + "TAG_DATA": [ + "20, blockade {'perturbing_action': 'B-gene loss-of-function'}", + "21, of {'perturbing_action': 'I-gene loss-of-function'}", + "22, vascular {'perturbing_action': 'I-gene loss-of-function'}", + "23, endothelial {'perturbing_action': 'I-gene loss-of-function'}", + "24, growth {'perturbing_action': 'I-gene loss-of-function'}", + "25, factor {'perturbing_action': 'I-gene loss-of-function'}", + "26, receptor-3 {'perturbing_action': 'I-gene loss-of-function'}", + "27, (VEGFR-3) {'perturbing_action': 'I-gene loss-of-function'}", + "28, signaling {'perturbing_action': 'I-gene loss-of-function'}", + "31, corneal {'context': 'B-cells'}", + "32, antigen-presenting {'context': 'B-cells'}", + "33, (dendritic) {'context': 'I-cells'}", + "34, cell {'context': 'I-cells'}", + "37, draining {'context': 'B-cells'}", + "38, lymph {'context': 'I-cells'}", + "39, nodes, {'context': 'I-cells'}", + "47, corneal {'context': 'B-xenograft'}" + ], + "LINK_DATA": [ + "20, blockade ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "21, of ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "22, vascular ['l1', 'l17', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "23, endothelial ['l2', 'l18', 'l33', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "24, growth ['l3', 'l19', 'l34', 'l48', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "25, factor ['l4', 'l20', 'l35', 'l49', 'l62', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "26, receptor-3 ['l5', 'l21', 'l36', 'l50', 'l63', 'l75', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "27, (VEGFR-3) ['l6', 'l22', 'l37', 'l51', 'l64', 'l76', 'l87', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "28, signaling ['l7', 'l23', 'l38', 'l52', 'l65', 'l77', 'l88', 'l98', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "31, corneal ['l8', 'l24', 'l39', 'l53', 'l66', 'l78', 'l89', 'l99', 'l108', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "32, antigen-presenting ['l9', 'l25', 'l40', 'l54', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "33, (dendritic) ['l10', 'l26', 'l41', 'l55', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l123', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "34, cell ['l11', 'l27', 'l42', 'l56', 'l69', 'l81', 'l92', 'l102', 'l111', 'l119', 'l124', 'l129', 'l135', 'l136', 'l137']", + "37, draining ['l12', 'l28', 'l43', 'l57', 'l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l125', 'l130', 'l135', 'l138', 'l139']", + "38, lymph ['l13', 'l29', 'l44', 'l58', 'l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l126', 'l131', 'l136', 'l138', 'l140']", + "39, nodes, ['l14', 'l30', 'l45', 'l59', 'l72', 'l84', 'l95', 'l105', 'l114', 'l122', 'l127', 'l132', 'l137', 'l139', 'l140']", + "47, corneal ['l15', 'l31', 'l46', 'l60', 'l73', 'l85', 'l96', 'l106', 'l115', 'l133', 'l141']", + "48, transplants. ['l16', 'l32', 'l47', 'l61', 'l74', 'l86', 'l97', 'l107', 'l116', 'l128', 'l134', 'l141']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "blockade", + "of", + "vascular", + "endothelial", + "growth", + "factor", + "receptor-3", + "(VEGFR-3)", + "signaling" + ] + }, + "context": { + "val": "cells", + "words": [ + "corneal", + "antigen-presenting", + "(dendritic)", + "cell", + "draining", + "lymph", + "nodes," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "blockade", + "of", + "vascular", + "endothelial", + "growth", + "factor", + "receptor-3", + "(VEGFR-3)", + "signaling" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "corneal" + ] + } + } + ] + }, + { + "PMID": "15235597", + "TEXT": "The trafficking of circulating stem and progenitor cells to areas of tissue damage is poorly understood. The chemokine stromal cell-derived factor-1 (SDF-1 or CXCL12) mediates homing of stem cells to bone marrow by binding to CXCR4 on circulating cells. SDF-1 and CXCR4 are expressed in complementary patterns during embryonic organogenesis and guide primordial stem cells to sites of rapid vascular expansion. However, the regulation of SDF-1 and its physiological role in peripheral tissue repair remain incompletely understood. Here we show that SDF-1 gene expression is regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1) in endothelial cells, resulting in selective in vivo expression of SDF-1 in ischemic tissue in direct proportion to reduced oxygen tension. HIF-1-induced SDF-1 expression increases the adhesion, migration and homing of circulating CXCR4-positive progenitor cells to ischemic tissue. Blockade of SDF-1 in ischemic tissue or CXCR4 on circulating cells prevents progenitor cell recruitment to sites of injury. Discrete regions of hypoxia in the bone marrow compartment also show increased SDF-1 expression and progenitor cell tropism. These data show that the recruitment of CXCR4-positive progenitor cells to regenerating tissues is mediated by hypoxic gradients via HIF-1-induced expression of SDF-1.", + "TAG_DATA": [ + "99, in {'context': 'B-in vivo'}", + "100, vivo {'context': 'I-in vivo'}", + "117, increases {'effect': 'B-positive'}", + "119, adhesion, {'phenotype': 'B-adhesion'}", + "120, migration {'phenotype': 'B-migration'}", + "124, circulating {'context': 'B-cells'}", + "125, CXCR4-positive {'context': 'I-cells'}", + "126, progenitor {'context': 'I-cells'}", + "127, cells {'context': 'I-cells'}", + "131, Blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "132, of {'perturbing_action': 'I-pharmacological inhibition'}", + "133, SDF-1 {'perturbing_action': 'I-pharmacological inhibition'}", + "140, circulating {'context': 'B-cells'}", + "141, cells {'context': 'I-cells'}", + "143, progenitor {'context': 'B-cells'}", + "144, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "99, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "100, vivo ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "117, increases ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "119, adhesion, ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "120, migration ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "124, circulating ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "125, CXCR4-positive ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "126, progenitor ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "127, cells ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "131, Blockade ['l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "132, of ['l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "133, SDF-1 ['l37', 'l42', 'l47', 'l48', 'l49', 'l50']", + "140, circulating ['l38', 'l43', 'l47', 'l51', 'l52', 'l53']", + "141, cells ['l39', 'l44', 'l48', 'l51', 'l54', 'l55']", + "143, progenitor ['l40', 'l45', 'l49', 'l52', 'l54', 'l56']", + "144, cell ['l41', 'l46', 'l50', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increases" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "context": { + "val": "cells", + "words": [ + "circulating", + "CXCR4-positive", + "progenitor", + "cells" + ] + } + }, + { + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + }, + "context": { + "val": "cells", + "words": [ + "circulating", + "CXCR4-positive", + "progenitor", + "cells" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "cells", + "words": [ + "circulating", + "CXCR4-positive", + "progenitor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "SDF-1" + ] + }, + "context": { + "val": "cells", + "words": [ + "circulating", + "cells", + "progenitor", + "cell" + ] + } + } + ] + }, + { + "PMID": "15208706", + "TEXT": "Niemann-Pick type C (NP-C) disease is a fatal, autosomal recessive, childhood neurodegenerative disease. The NP-C mouse recapitulates the cholesterol and sphingolipid storage, onset of neurological deficits, histopathological lesions, Purkinje cell loss and early death typical of the most severe form of human NP-C. Neurosteroids, steroids made in the brain, affect neuronal growth and differentiation, and modulate neurotransmitter receptors. Disordered cholesterol trafficking might disrupt neurosteroidogenesis, thereby contributing to the NP-C phenotype. Here we show that NP-C mouse brain contains substantially less neurosteroid than wild-type brain and has an age-related decrease in the ability to synthesize 5alpha-dihydroprogesterone and allopregnanolone. Immunohistochemical assessment confirms a decrease in expression of 5alpha-reductase and 3alpha-hydroxysteroid dehydrogenase, especially in cerebellum. Neonatal administration of allopregnanolone delays the onset of neurological symptoms, increases Purkinje and granule cell survival, reduces cortical GM2 and GM3 ganglioside accumulation and doubles the lifespan of NP-C mice. Earlier administration increases effectiveness of treatment. Decreased production of allopregnanolone apparently contributes to the pathology of NP-C; thus, neurosteroid treatment may be useful in ameliorating progression of the disease.", + "TAG_DATA": [ + "75, mouse {'context': 'I-tissue/organ'}", + "123, Purkinje {'context': 'B-cells'}", + "124, and {'context': 'I-cells'}", + "125, granule {'context': 'I-cells'}", + "126, cell {'context': 'I-cells'}", + "127, survival, {'phenotype': 'B-cell survival'}", + "140, NP-C {'context': 'B-organism'}", + "141, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "123, Purkinje ['l0', 'l1', 'l2', 'l3']", + "124, and ['l0', 'l4', 'l5', 'l6']", + "125, granule ['l1', 'l4', 'l7', 'l8']", + "126, cell ['l2', 'l5', 'l7', 'l9']", + "127, survival, ['l3', 'l6', 'l8', 'l9']", + "140, NP-C ['l10']", + "141, mice. ['l10']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Purkinje", + "and", + "granule", + "cell" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "survival," + ] + } + } + ] + }, + { + "PMID": "15195085", + "TEXT": "We have previously shown that apolipoprotein E (Apoe) promotes the formation of amyloid in brain and that astrocyte-specific expression of APOE markedly affects the deposition of amyloid-beta peptides (Abeta) in a mouse model of Alzheimer disease. Given the capacity of astrocytes to degrade Abeta, we investigated the potential role of Apoe in this astrocyte-mediated degradation. In contrast to cultured adult wild-type mouse astrocytes, adult Apoe(-/-) astrocytes do not degrade Abeta present in Abeta plaque-bearing brain sections in vitro. Coincubation with antibodies to either Apoe or Abeta, or with RAP, an antagonist of the low-density lipoprotein receptor family, effectively blocks Abeta degradation by astrocytes. Phase-contrast and confocal microscopy show that Apoe(-/-) astrocytes do not respond to or internalize Abeta deposits to the same extent as do wild-type astrocytes. Thus, Apoe seems to be important in the degradation and clearance of deposited Abeta species by astrocytes, a process that may be impaired in Alzheimer disease.", + "TAG_DATA": [ + "59, adult {'context': 'B-cells'}", + "60, wild-type {'context': 'I-cells'}", + "61, mouse {'context': 'I-cells'}", + "62, astrocytes, {'context': 'I-cells'}", + "63, adult {'context': 'B-cells'}", + "64, Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "65, astrocytes {'context': 'B-cells'}", + "76, in {'context': 'B-in vitro'}", + "77, vitro. {'context': 'I-in vitro'}", + "102, astrocytes. {'context': 'B-cells'}", + "109, Apoe(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "110, astrocytes {'context': 'B-cells'}", + "126, astrocytes. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "59, adult ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "60, wild-type ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "61, mouse ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "62, astrocytes, ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "63, adult ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "64, Apoe(-/-) ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "65, astrocytes ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "76, in ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "77, vitro. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "109, Apoe(-/-) ['l36', 'l37']", + "110, astrocytes ['l36', 'l38']", + "126, astrocytes. ['l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "adult", + "wild-type", + "mouse", + "astrocytes,", + "astrocytes", + "astrocytes." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apoe(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apoe(-/-)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "15156201", + "TEXT": "Loss of PTEN function leads to activation of phosphoinositide 3-kinase (PI3K) signaling and Akt. Clinical trials are now testing whether mammalian target of rapamycin (mTOR) inhibition is useful in treating PTEN-null cancers. Here, we report that mTOR inhibition induced apoptosis of epithelial cells and the complete reversal of a neoplastic phenotype in the prostate of mice expressing human AKT1 in the ventral prostate. Induction of cell death required the mitochondrial pathway, as prostate-specific coexpression of BCL2 blocked apoptosis. Thus, there is an mTOR-dependent survival signal required downstream of Akt. Bcl2 expression, however, only partially restored intraluminal cell growth in the setting of mTOR inhibition. Expression profiling showed that Hif-1 alpha targets, including genes encoding most glycolytic enzymes, constituted the dominant transcriptional response to AKT activation and mTOR inhibition. These data suggest that the expansion of AKT-driven prostate epithelial cells requires mTOR-dependent survival signaling and activation of HIF-1 alpha, and that clinical resistance to mTOR inhibitors may emerge through BCL2 expression and/or upregulation of HIF-1 alpha activity.", + "TAG_DATA": [ + "36, mTOR {'perturbing_action': 'B-pharmacological inhibition'}", + "37, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "38, induced {'effect': 'B-positive'}", + "39, apoptosis {'phenotype': 'B-apoptosis'}", + "41, epithelial {'context': 'B-cells'}", + "42, cells {'context': 'I-cells'}", + "49, neoplastic {'phenotype': 'B-tumourigenesis'}", + "50, phenotype {'phenotype': 'I-senescence'}", + "53, prostate {'context': 'B-tissue/organ'}", + "55, mice {'context': 'B-organism'}", + "56, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "57, human {'perturbing_action': 'I-gene gain-of-function'}", + "58, AKT1 {'perturbing_action': 'I-gene gain-of-function'}", + "59, in {'perturbing_action': 'I-gene gain-of-function'}", + "60, the {'perturbing_action': 'I-gene gain-of-function'}", + "61, ventral {'perturbing_action': 'I-gene gain-of-function'}", + "62, prostate. {'perturbing_action': 'I-gene gain-of-function'}", + "63, Induction {'effect': 'B-positive'}", + "65, cell {'phenotype': 'B-cell death'}", + "66, death {'phenotype': 'I-cell death'}", + "72, prostate-specific {'perturbing_action': 'B-gene gain-of-function'}", + "73, coexpression {'perturbing_action': 'I-gene gain-of-function'}", + "74, of {'perturbing_action': 'I-gene gain-of-function'}", + "75, BCL2 {'perturbing_action': 'I-gene gain-of-function'}", + "76, blocked {'effect': 'B-negative'}", + "77, apoptosis. {'phenotype': 'B-apoptosis'}", + "93, partially {'effect': 'B-rescues'}", + "94, restored {'effect': 'I-rescues'}", + "96, cell {'phenotype': 'B-cell growth'}", + "97, growth {'phenotype': 'I-cell growth'}", + "102, mTOR {'perturbing_action': 'B-pharmacological inhibition'}", + "103, inhibition. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "36, mTOR ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "37, inhibition ['l0', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "38, induced ['l1', 'l19', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "39, apoptosis ['l2', 'l20', 'l37', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "41, epithelial ['l3', 'l21', 'l38', 'l43', 'l49', 'l50', 'l51', 'l52']", + "42, cells ['l4', 'l22', 'l39', 'l44', 'l49', 'l53', 'l54']", + "49, neoplastic ['l5', 'l23', 'l40', 'l45', 'l50', 'l53', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "50, phenotype ['l6', 'l24', 'l41', 'l46', 'l51', 'l54', 'l55', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "53, prostate ['l7', 'l25', 'l42', 'l47', 'l52', 'l56', 'l65', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "55, mice ['l8', 'l26', 'l66', 'l75', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "56, expressing ['l9', 'l27', 'l57', 'l67', 'l76', 'l86', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "57, human ['l10', 'l28', 'l77', 'l87', 'l96', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "58, AKT1 ['l11', 'l29', 'l58', 'l68', 'l78', 'l88', 'l97', 'l106', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "59, in ['l12', 'l30', 'l59', 'l69', 'l79', 'l89', 'l98', 'l107', 'l118', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "60, the ['l13', 'l31', 'l48', 'l60', 'l70', 'l80', 'l90', 'l99', 'l108', 'l119', 'l126', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "61, ventral ['l14', 'l32', 'l61', 'l71', 'l81', 'l91', 'l100', 'l109', 'l120', 'l127', 'l133', 'l139', 'l140', 'l141', 'l142']", + "62, prostate. ['l15', 'l33', 'l62', 'l72', 'l82', 'l92', 'l101', 'l110', 'l121', 'l128', 'l134', 'l139', 'l143', 'l144', 'l145']", + "63, Induction ['l16', 'l34', 'l83', 'l93', 'l102', 'l111', 'l122', 'l129', 'l135', 'l140', 'l143', 'l146', 'l147', 'l148']", + "65, cell ['l17', 'l35', 'l63', 'l73', 'l84', 'l94', 'l103', 'l112', 'l123', 'l130', 'l136', 'l141', 'l144', 'l146', 'l149']", + "66, death ['l18', 'l36', 'l64', 'l74', 'l85', 'l95', 'l104', 'l113', 'l124', 'l131', 'l137', 'l142', 'l145', 'l147', 'l149']", + "72, prostate-specific ['l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158']", + "73, coexpression ['l150', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166']", + "74, of ['l114', 'l151', 'l159', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "75, BCL2 ['l115', 'l152', 'l160', 'l167', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179']", + "76, blocked ['l105', 'l116', 'l125', 'l132', 'l138', 'l148', 'l153', 'l161', 'l168', 'l174', 'l180', 'l181', 'l182']", + "77, apoptosis. ['l117', 'l154', 'l162', 'l169', 'l175', 'l180', 'l183', 'l184', 'l185']", + "93, partially ['l155', 'l163', 'l170', 'l176', 'l186', 'l187', 'l188', 'l189', 'l190']", + "94, restored ['l156', 'l164', 'l171', 'l177', 'l183', 'l186', 'l191', 'l192', 'l193', 'l194']", + "96, cell ['l157', 'l165', 'l172', 'l178', 'l181', 'l184', 'l187', 'l191', 'l195', 'l196', 'l197']", + "97, growth ['l158', 'l166', 'l173', 'l179', 'l182', 'l185', 'l188', 'l192', 'l195', 'l198', 'l199']", + "102, mTOR ['l189', 'l193', 'l196', 'l198', 'l200']", + "103, inhibition. ['l190', 'l194', 'l197', 'l199', 'l200']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibition" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "Induction" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibition" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "epithelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibition" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplastic" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibition" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "phenotype" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibition" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "prostate" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibition" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "epithelial", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplastic" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "phenotype" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "Induction" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "prostate" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "epithelial", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "prostate" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "the", + "human", + "prostate-specific", + "coexpression", + "of", + "BCL2" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "epithelial", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplastic" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "epithelial", + "cells" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "phenotype" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplastic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "prostate" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplastic" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "AKT1", + "in", + "the", + "ventral", + "prostate." + ] + } + }, + { + "phenotype": { + "val": "senescence", + "words": [ + "phenotype" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "prostate" + ] + } + }, + { + "phenotype": { + "val": "senescence", + "words": [ + "phenotype" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "senescence", + "words": [ + "phenotype" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "AKT1", + "in", + "the", + "ventral", + "prostate." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "prostate" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "human", + "AKT1", + "in", + "the", + "ventral", + "prostate." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "prostate" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "human", + "AKT1", + "in", + "the", + "ventral", + "prostate." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "Induction" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "human", + "AKT1", + "in", + "the", + "ventral", + "prostate." + ] + }, + "effect": { + "val": "positive", + "words": [ + "Induction" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "human", + "AKT1", + "in", + "the", + "ventral", + "prostate." + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "human", + "AKT1", + "in", + "the", + "prostate-specific", + "coexpression", + "of", + "BCL2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Induction" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "prostate-specific", + "coexpression", + "of", + "BCL2" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "partially", + "restored" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "prostate-specific", + "coexpression", + "of", + "BCL2" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "partially", + "restored" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "partially", + "restored" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibition." + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibition." + ] + } + } + ] + }, + { + "PMID": "15146177", + "TEXT": "Suramin is a polysulfonated derivative of urea and has been widely used both to treat infections and as a chemotherapeutic drug. Suramin has been shown to inhibit growth factor signaling pathways; however, its effect on apoptosis is unknown. Here we show that suramin inhibits apoptosis induced through death receptors in hepatoma and lymphoma cells. It also inhibits the proapoptotic effect of chemotherapeutic drugs. The antiapoptotic mechanism is specific to cell type and is caused by reduced activation, but not altered composition, of the death-inducing signaling complex (DISC), and by inhibition of the initiator caspases 8, 9 and 10. Suramin also shows similar effects in in vivo models: apoptotic liver damage induced by CD95 stimulation and endotoxic shock mediated by tumor-necrosis factor (TNF) are inhibited in mice, but necrotic liver damage is not inhibited in a rat model of liver transplantation. Thus, the antiapoptotic property of suramin in the liver may be therapeutically exploited.", + "TAG_DATA": [ + "43, inhibits {'effect': 'B-negative'}", + "44, apoptosis {'phenotype': 'B-apoptosis'}", + "50, hepatoma {'context': 'B-transformed cells'}", + "51, and {'context': 'I-transformed cells'}", + "52, lymphoma {'context': 'I-transformed cells'}", + "53, cells. {'context': 'I-transformed cells'}", + "104, in {'context': 'B-in vivo'}", + "105, vivo {'context': 'I-in vivo'}", + "106, models: {'context': 'I-in vivo'}", + "107, apoptotic {'phenotype': 'B-apoptosis'}", + "108, liver {'phenotype': 'I-apoptosis'}", + "123, inhibited {'effect': 'B-negative'}", + "125, mice, {'context': 'B-organism'}", + "128, liver {'phenotype': 'I-necrosis'}", + "135, rat {'context': 'B-xenograft'}", + "136, model {'context': 'I-xenograft'}", + "138, liver {'context': 'I-tissue/organ'}", + "139, transplantation. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "43, inhibits ['l0', 'l1', 'l2', 'l3', 'l4']", + "44, apoptosis ['l0', 'l5', 'l6', 'l7', 'l8']", + "50, hepatoma ['l1', 'l5', 'l9', 'l10', 'l11']", + "51, and ['l2', 'l6', 'l9', 'l12', 'l13']", + "52, lymphoma ['l3', 'l7', 'l10', 'l12', 'l14']", + "53, cells. ['l4', 'l8', 'l11', 'l13', 'l14']", + "104, in ['l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "105, vivo ['l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "106, models: ['l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "107, apoptotic ['l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "108, liver ['l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "123, inhibited ['l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "125, mice, ['l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "127, necrotic ['l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "128, liver ['l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "135, rat ['l37', 'l42', 'l47', 'l48', 'l49', 'l50']", + "136, model ['l38', 'l43', 'l47', 'l51', 'l52', 'l53']", + "137, of ['l39', 'l44', 'l48', 'l51', 'l54', 'l55']", + "138, liver ['l40', 'l45', 'l49', 'l52', 'l54', 'l56']", + "139, transplantation. ['l41', 'l46', 'l50', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "inhibited" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptotic", + "liver" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "hepatoma", + "and", + "lymphoma", + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "hepatoma", + "and", + "lymphoma", + "cells." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "models:" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "liver" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "models:" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "liver" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "liver" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "rat", + "model", + "transplantation." + ] + } + }, + { + "phenotype": { + "val": "necrosis", + "words": [ + "liver" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "15034571", + "TEXT": "Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition in which motoneurons of the spinal cord and motor cortex die, resulting in progressive paralysis. This condition has no cure and results in eventual death, usually within 1-5 years of diagnosis. Although the specific etiology of ALS is unknown, 20% of familial cases of the disease carry mutations in the gene encoding Cu/Zn superoxide dismutase-1 (SOD1). Transgenic mice overexpressing human mutant SOD1 have a phenotype and pathology that are very similar to that seen in human ALS patients. Here we show that treatment with arimoclomol, a coinducer of heat shock proteins (HSPs), significantly delays disease progression in mice expressing a SOD1 mutant in which glycine is substituted with alanine at position 93 (SOD1(G93A)). Arimoclomol-treated SOD1(G93A) mice show marked improvement in hind limb muscle function and motoneuron survival in the later stages of the disease, resulting in a 22% increase in lifespan. Pharmacological activation of the heat shock response may therefore be a successful therapeutic approach to treating ALS, and possibly other neurodegenerative diseases.", + "TAG_DATA": [ + "67, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "68, human {'perturbing_action': 'I-gene gain-of-function'}", + "69, mutant {'perturbing_action': 'I-gene gain-of-function'}", + "70, SOD1 {'perturbing_action': 'I-gene gain-of-function'}", + "106, mice {'context': 'B-organism'}", + "109, SOD1 {'perturbing_action': 'B-other'}", + "110, mutant {'perturbing_action': 'I-other'}", + "111, in {'perturbing_action': 'I-other'}", + "112, which {'perturbing_action': 'I-other'}", + "113, glycine {'perturbing_action': 'I-other'}", + "114, is {'perturbing_action': 'I-other'}", + "115, substituted {'perturbing_action': 'I-other'}", + "117, alanine {'perturbing_action': 'I-other'}", + "118, at {'perturbing_action': 'I-other'}", + "119, position {'perturbing_action': 'I-other'}", + "120, 93 {'perturbing_action': 'I-other'}", + "121, (SOD1(G93A)). {'perturbing_action': 'I-other'}", + "124, mice {'context': 'B-organism'}", + "129, hind {'context': 'B-tissue/organ'}", + "130, limb {'context': 'I-tissue/organ'}", + "131, muscle {'context': 'I-tissue/organ'}", + "134, motoneuron {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "67, overexpressing ['l0', 'l1', 'l2']", + "68, human ['l0', 'l3', 'l4']", + "69, mutant ['l1', 'l3', 'l5']", + "70, SOD1 ['l2', 'l4', 'l5']", + "106, mice ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "109, SOD1 ['l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "110, mutant ['l17', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "111, in ['l6', 'l18', 'l32', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "112, which ['l7', 'l19', 'l33', 'l46', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "113, glycine ['l8', 'l20', 'l34', 'l47', 'l59', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "114, is ['l9', 'l21', 'l35', 'l48', 'l60', 'l71', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "115, substituted ['l10', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "116, with ['l11', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "117, alanine ['l12', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "118, at ['l13', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "119, position ['l14', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l122', 'l123', 'l124', 'l125', 'l126']", + "120, 93 ['l15', 'l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l127', 'l128', 'l129', 'l130']", + "121, (SOD1(G93A)). ['l16', 'l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l118', 'l123', 'l127', 'l131', 'l132', 'l133']", + "124, mice ['l134', 'l135', 'l136', 'l137']", + "129, hind ['l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l113', 'l119', 'l124', 'l128', 'l131', 'l134', 'l138', 'l139', 'l140']", + "130, limb ['l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l129', 'l132', 'l135', 'l138', 'l141']", + "131, muscle ['l31', 'l45', 'l58', 'l70', 'l81', 'l91', 'l100', 'l108', 'l115', 'l121', 'l126', 'l130', 'l133', 'l136', 'l139', 'l141']", + "134, motoneuron ['l137', 'l140']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "in", + "which", + "glycine", + "is", + "substituted", + "alanine", + "at", + "position", + "93", + "(SOD1(G93A))." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "SOD1", + "mutant", + "in", + "which", + "glycine", + "is", + "substituted", + "alanine", + "at", + "position", + "93", + "(SOD1(G93A))." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hind", + "limb", + "muscle" + ] + } + } + ] + }, + { + "PMID": "15034570", + "TEXT": "Although Nogo-A has been identified in the central nervous system as an inhibitor of axonal regeneration, the peripheral roles of Nogo isoforms remain virtually unknown. Here, using a proteomic analysis to identify proteins enriched in caveolae and/or lipid rafts (CEM/LR), we show that Nogo-B is highly expressed in cultured endothelial and smooth muscle cells, as well as in intact blood vessels. The N terminus of Nogo-B promotes the migration of endothelial cells but inhibits the migration of vascular smooth muscle (VSM) cells, processes necessary for vascular remodeling. Vascular injury in Nogo-A/B-deficient mice promotes exaggerated neointimal proliferation, and adenoviral-mediated gene transfer of Nogo-B rescues the abnormal vascular expansion in those knockout mice. Our discovery that Nogo-B is a regulator of vascular homeostasis and remodeling broadens the functional scope of this family of proteins.", + "TAG_DATA": [ + "66, promotes {'effect': 'B-positive'}", + "68, migration {'phenotype': 'B-migration'}", + "70, endothelial {'context': 'B-cells'}", + "71, cells {'context': 'I-cells'}", + "73, inhibits {'effect': 'B-negative'}", + "75, migration {'phenotype': 'B-migration'}", + "77, vascular {'context': 'B-cells'}", + "78, smooth {'context': 'I-cells'}", + "79, muscle {'context': 'I-cells'}", + "80, (VSM) {'context': 'I-cells'}", + "81, cells, {'context': 'I-cells'}", + "90, Nogo-A/B-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "91, mice {'context': 'B-organism'}", + "92, promotes {'effect': 'B-positive'}", + "95, proliferation, {'phenotype': 'B-proliferation'}", + "97, adenoviral-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "98, gene {'perturbing_action': 'I-gene gain-of-function'}", + "99, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "100, of {'perturbing_action': 'I-gene gain-of-function'}", + "101, Nogo-B {'perturbing_action': 'I-gene gain-of-function'}", + "102, rescues {'effect': 'B-rescues'}", + "110, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "66, promotes ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "68, migration ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "70, endothelial ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "71, cells ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "73, inhibits ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "75, migration ['l4', 'l13', 'l21', 'l28', 'l34', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "77, vascular ['l5', 'l14', 'l22', 'l29', 'l35', 'l42', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "78, smooth ['l6', 'l15', 'l23', 'l30', 'l36', 'l43', 'l48', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "79, muscle ['l7', 'l16', 'l24', 'l31', 'l37', 'l44', 'l49', 'l56', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "80, (VSM) ['l8', 'l17', 'l25', 'l32', 'l38', 'l45', 'l50', 'l57', 'l63', 'l69', 'l70', 'l71', 'l72', 'l73']", + "81, cells, ['l9', 'l18', 'l26', 'l33', 'l39', 'l46', 'l51', 'l58', 'l64', 'l69', 'l74']", + "90, Nogo-A/B-deficient ['l52', 'l59', 'l65', 'l70', 'l75', 'l76', 'l77']", + "91, mice ['l40', 'l47', 'l53', 'l60', 'l66', 'l71', 'l74', 'l75', 'l78', 'l79']", + "92, promotes ['l41', 'l54', 'l61', 'l67', 'l72', 'l76', 'l78', 'l80']", + "95, proliferation, ['l55', 'l62', 'l68', 'l73', 'l77', 'l79', 'l80']", + "97, adenoviral-mediated ['l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "98, gene ['l81', 'l87', 'l88', 'l89', 'l90', 'l91']", + "99, transfer ['l82', 'l87', 'l92', 'l93', 'l94', 'l95']", + "100, of ['l83', 'l88', 'l92', 'l96', 'l97', 'l98']", + "101, Nogo-B ['l84', 'l89', 'l93', 'l96', 'l99', 'l100']", + "102, rescues ['l85', 'l90', 'l94', 'l97', 'l99', 'l101']", + "110, mice. ['l86', 'l91', 'l95', 'l98', 'l100', 'l101']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells", + "vascular", + "smooth", + "muscle", + "(VSM)", + "cells," + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells", + "vascular", + "smooth", + "muscle", + "(VSM)", + "cells," + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells", + "vascular", + "smooth", + "muscle", + "(VSM)", + "cells," + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "vascular", + "smooth", + "muscle", + "(VSM)" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nogo-A/B-deficient" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "vascular", + "smooth", + "muscle", + "(VSM)" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nogo-A/B-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nogo-A/B-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nogo-A/B-deficient" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral-mediated", + "gene", + "transfer", + "of", + "Nogo-B" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescues" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral-mediated", + "gene", + "transfer", + "of", + "Nogo-B" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescues" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "15034568", + "TEXT": "Genomic amplification at 20q11-13 is a common event in human cancers. We isolated a germline translocation breakpoint at 20q11 from a bladder cancer patient. We identified CDC91L1, the gene encoding CDC91L1 (also called phosphatidylinositol glycan class U (PIG-U), a transamidase complex unit in the glycosylphosphatidylinositol (GPI) anchoring pathway), as the only gene whose expression was affected by the translocation. CDC91L1 was amplified and overexpressed in about one-third of bladder cancer cell lines and primary tumors, as well as in oncogenic uroepithelial cells transformed with human papillomavirus (HPV) E7. Forced overexpression of CDC91L1 malignantly transformed NIH3T3 cells in vitro and in vivo. Overexpression of CDC91L1 also resulted in upregulation of the urokinase receptor (uPAR), a GPI-anchored protein, and in turn increased STAT-3 phosphorylation in bladder cancer cells. Our findings suggest that CDC91L1 is an oncogene in bladder cancer, and implicate the GPI anchoring system as a potential oncogenic pathway and therapeutic target in human cancers.", + "TAG_DATA": [ + "79, oncogenic {'context': 'B-cells'}", + "80, uroepithelial {'context': 'I-cells'}", + "81, cells {'context': 'I-cells'}", + "82, transformed {'phenotype': 'B-transformation'}", + "88, Forced {'perturbing_action': 'B-gene gain-of-function'}", + "89, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "90, of {'perturbing_action': 'I-gene gain-of-function'}", + "91, CDC91L1 {'perturbing_action': 'I-gene gain-of-function'}", + "93, transformed {'phenotype': 'B-transformation'}", + "94, NIH3T3 {'context': 'B-cells'}", + "95, cells {'context': 'I-cells'}", + "96, in {'context': 'B-in vitro'}", + "97, vitro {'context': 'I-in vitro'}", + "99, in {'context': 'B-in vivo'}", + "100, vivo. {'context': 'I-in vivo'}", + "101, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "102, of {'perturbing_action': 'I-gene gain-of-function'}", + "103, CDC91L1 {'perturbing_action': 'I-gene gain-of-function'}", + "123, bladder {'context': 'B-transformed cells'}", + "124, cancer {'context': 'I-transformed cells'}", + "125, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "79, oncogenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "80, uroepithelial ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "81, cells ['l1', 'l8', 'l15', 'l16', 'l17', 'l18']", + "82, transformed ['l2', 'l9', 'l15', 'l19', 'l20', 'l21', 'l22', 'l23']", + "88, Forced ['l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "89, overexpression ['l24', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "90, of ['l25', 'l34', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "91, CDC91L1 ['l26', 'l35', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "93, transformed ['l3', 'l10', 'l16', 'l19', 'l27', 'l36', 'l44', 'l51', 'l58', 'l59', 'l60', 'l61']", + "94, NIH3T3 ['l4', 'l11', 'l17', 'l20', 'l28', 'l37', 'l45', 'l52', 'l58', 'l62', 'l63', 'l64', 'l65', 'l66']", + "95, cells ['l5', 'l12', 'l18', 'l21', 'l29', 'l38', 'l46', 'l53', 'l59', 'l62', 'l67', 'l68']", + "96, in ['l6', 'l13', 'l22', 'l30', 'l39', 'l47', 'l54', 'l60', 'l63', 'l67', 'l69']", + "97, vitro ['l7', 'l14', 'l23', 'l31', 'l40', 'l48', 'l55', 'l61', 'l64', 'l68', 'l69']", + "99, in ['l32', 'l41', 'l49', 'l56', 'l65', 'l70']", + "100, vivo. ['l33', 'l42', 'l50', 'l57', 'l66', 'l70']", + "101, Overexpression ['l71', 'l72', 'l73', 'l74', 'l75']", + "102, of ['l71', 'l76', 'l77', 'l78', 'l79']", + "103, CDC91L1 ['l72', 'l76', 'l80', 'l81', 'l82']", + "123, bladder ['l73', 'l77', 'l80', 'l83', 'l84']", + "124, cancer ['l74', 'l78', 'l81', 'l83', 'l85']", + "125, cells. ['l75', 'l79', 'l82', 'l84', 'l85']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "oncogenic", + "uroepithelial", + "cells", + "NIH3T3" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformed" + ] + } + }, + { + "phenotype": { + "val": "transformation", + "words": [ + "transformed" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "overexpression", + "of", + "CDC91L1" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformed" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "overexpression", + "of", + "CDC91L1" + ] + }, + "context": { + "val": "cells", + "words": [ + "NIH3T3", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "overexpression", + "of", + "CDC91L1" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "overexpression", + "of", + "CDC91L1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "CDC91L1" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "bladder", + "cancer", + "cells." + ] + } + } + ] + }, + { + "PMID": "15004554", + "TEXT": "The clinical outcome of spinal cord injury (SCI) depends in part on the extent of secondary damage, to which apoptosis contributes. The CD95 and tumor necrosis factor (TNF) ligand/receptor systems play an essential role in various apoptotic mechanisms. To determine the involvement of these ligands in SCI-induced damage, we neutralized the activity of CD95 ligand (CD95L) and/or TNF in spinal cord-injured mice. Therapeutic neutralization of CD95L, but not of TNF, significantly decreased apoptotic cell death after SCI. Mice treated with CD95L-specific antibodies were capable of initiating active hind-limb movements several weeks after injury. The improvement in locomotor performance was mirrored by an increase in regenerating fibers and upregulation of growth-associated protein-43 (GAP-43). Thus, neutralization of CD95L promoted axonal regeneration and functional improvement in injured adult animals. This therapeutic strategy may constitute a potent future treatment for human spinal injury.", + "TAG_DATA": [ + "61, mice. {'context': 'B-organism'}", + "62, Therapeutic {'perturbing_action': 'B-pharmacological inhibition'}", + "63, neutralization {'perturbing_action': 'I-pharmacological inhibition'}", + "64, of {'perturbing_action': 'I-pharmacological inhibition'}", + "65, CD95L, {'perturbing_action': 'I-pharmacological inhibition'}", + "71, decreased {'effect': 'B-negative'}", + "72, apoptotic {'phenotype': 'B-apoptosis'}", + "73, cell {'phenotype': 'I-apoptosis'}", + "74, death {'phenotype': 'I-apoptosis'}", + "77, Mice {'context': 'B-organism'}", + "104, regenerating {'context': 'B-cells'}", + "105, fibers {'context': 'I-cells'}", + "113, neutralization {'perturbing_action': 'B-pharmacological inhibition'}", + "114, of {'perturbing_action': 'I-pharmacological inhibition'}", + "124, adult {'context': 'B-organism'}", + "125, animals. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "61, mice. ['l0', 'l1']", + "62, Therapeutic ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "63, neutralization ['l2', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "64, of ['l3', 'l11', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "65, CD95L, ['l4', 'l12', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "71, decreased ['l5', 'l13', 'l19', 'l24', 'l29', 'l30', 'l31']", + "72, apoptotic ['l6', 'l14', 'l20', 'l25', 'l29', 'l32', 'l33']", + "73, cell ['l0', 'l7', 'l15', 'l21', 'l26', 'l30', 'l32', 'l34']", + "74, death ['l1', 'l8', 'l16', 'l22', 'l27', 'l31', 'l33', 'l34']", + "77, Mice ['l9', 'l35', 'l36']", + "87, hind-limb ['l10', 'l17', 'l23', 'l28', 'l35']", + "104, regenerating ['l37']", + "105, fibers ['l36', 'l37']", + "113, neutralization ['l38', 'l39', 'l40', 'l41']", + "114, of ['l38', 'l42', 'l43', 'l44']", + "115, CD95L ['l39', 'l42', 'l45', 'l46']", + "124, adult ['l40', 'l43', 'l45', 'l47']", + "125, animals. ['l41', 'l44', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Therapeutic", + "neutralization", + "of", + "CD95L," + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Therapeutic", + "neutralization", + "of", + "CD95L," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Therapeutic", + "neutralization", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "Mice", + "adult", + "animals." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death" + ] + } + } + ] + }, + { + "PMID": "14991050", + "TEXT": "Autoimmune T-helper cells drive pathogenic autoantibody production in systemic lupus erythematosus (SLE), but the mechanisms maintaining those T cells are unknown. Autoreactive T cells are normally eliminated by functional inactivation (anergy) and activation-induced cell death (AICD) or apoptosis through death receptor (Fas) signaling. However, mutations in the genes encoding Fas and its ligand (FasL) are rare in classical SLE. By gene microarray profiling, validated by functional and biochemical studies, we establish here that activated T cells of lupus patients resist anergy and apoptosis by markedly upregulating and sustaining cyclooxygenase-2 (COX-2) expression. Inhibition of COX-2 caused apoptosis of the anergy-resistant lupus T cells by augmenting Fas signaling and markedly decreasing the survival molecule c-FLIP (cellular homolog of viral FLICE inhibitory protein). Studies with COX-2 inhibitors and Cox-2-deficient mice confirmed that this COX-2/FLIP antiapoptosis program is used selectively by anergy-resistant lupus T cells, and not by cancer cells or other autoimmune T cells. Notably, the gene encoding COX-2 is located in a lupus-susceptibility region on chromosome 1. We also found that only some COX-2 inhibitors were able to suppress the production of pathogenic autoantibodies to DNA by causing autoimmune T-cell apoptosis, an effect that was independent of prostaglandin E(2) (PGE(2)). These findings could be useful in the design of lupus therapies.", + "TAG_DATA": [ + "82, apoptosis {'phenotype': 'B-apoptosis'}", + "91, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "92, of {'perturbing_action': 'I-pharmacological inhibition'}", + "93, COX-2 {'perturbing_action': 'I-pharmacological inhibition'}", + "94, caused {'effect': 'B-positive'}", + "95, apoptosis {'phenotype': 'B-apoptosis'}", + "98, anergy-resistant {'context': 'B-cells'}", + "99, lupus {'context': 'I-cells'}", + "100, T {'context': 'I-cells'}", + "101, cells {'context': 'I-cells'}", + "122, COX-2 {'perturbing_action': 'B-pharmacological inhibition'}", + "123, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "125, Cox-2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "126, mice {'context': 'B-organism'}", + "145, cells {'context': 'I-transformed cells'}", + "171, COX-2 {'perturbing_action': 'B-pharmacological inhibition'}", + "172, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "185, causing {'effect': 'B-positive'}", + "186, autoimmune {'context': 'B-cells'}", + "187, T-cell {'context': 'I-cells'}", + "188, apoptosis, {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "91, Inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "92, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "93, COX-2 ['l1', 'l11', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "94, caused ['l2', 'l12', 'l20', 'l28', 'l29', 'l30', 'l31', 'l32']", + "95, apoptosis ['l3', 'l13', 'l21', 'l28', 'l33', 'l34', 'l35', 'l36']", + "98, anergy-resistant ['l4', 'l14', 'l22', 'l29', 'l33', 'l37', 'l38', 'l39']", + "99, lupus ['l5', 'l15', 'l23', 'l30', 'l34', 'l37', 'l40', 'l41']", + "100, T ['l6', 'l16', 'l24', 'l31', 'l35', 'l38', 'l40', 'l42']", + "101, cells ['l7', 'l17', 'l25', 'l32', 'l36', 'l39', 'l41', 'l42']", + "122, COX-2 ['l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "123, inhibitors ['l43', 'l49', 'l50', 'l51', 'l52', 'l53']", + "125, Cox-2-deficient ['l44', 'l49', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "126, mice ['l45', 'l50', 'l54', 'l62', 'l63', 'l64']", + "139, T ['l8', 'l18', 'l26', 'l46', 'l51', 'l55', 'l62', 'l65', 'l66']", + "140, cells, ['l9', 'l19', 'l27', 'l47', 'l52', 'l56', 'l63', 'l65', 'l67']", + "145, cells ['l10', 'l48', 'l53', 'l57', 'l64', 'l66', 'l67']", + "171, COX-2 ['l68', 'l69', 'l70', 'l71', 'l72']", + "172, inhibitors ['l68', 'l73', 'l74', 'l75', 'l76']", + "185, causing ['l58', 'l69', 'l73', 'l77', 'l78', 'l79']", + "186, autoimmune ['l59', 'l70', 'l74', 'l77', 'l80', 'l81']", + "187, T-cell ['l60', 'l71', 'l75', 'l78', 'l80', 'l82']", + "188, apoptosis, ['l61', 'l72', 'l76', 'l79', 'l81', 'l82']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "COX-2", + "inhibitors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused", + "causing" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "COX-2", + "inhibitors" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "COX-2", + "inhibitors" + ] + }, + "context": { + "val": "cells", + "words": [ + "anergy-resistant", + "lupus", + "T", + "cells", + "autoimmune", + "T-cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "COX-2", + "inhibitors" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused", + "causing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused", + "causing" + ] + }, + "context": { + "val": "cells", + "words": [ + "anergy-resistant", + "lupus", + "T", + "cells", + "autoimmune", + "T-cell" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis," + ] + }, + "context": { + "val": "cells", + "words": [ + "anergy-resistant", + "lupus", + "T", + "cells", + "autoimmune", + "T-cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "COX-2", + "inhibitors" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cox-2-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cox-2-deficient" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cox-2-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "causing" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cox-2-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "autoimmune", + "T-cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cox-2-deficient" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + } + ] + }, + { + "PMID": "14966519", + "TEXT": "Embryonic development of multilineage hematopoiesis requires the precisely regulated expression of lineage-specific transcription factors, including AML-1 (encoded by Runx1; also known as CBFA-2 or PEBP-2alphaB). In vitro studies and findings in human diseases, including leukemias, myelodysplastic syndromes and familial platelet disorder with predisposition to acute myeloid leukemia (AML), suggest that AML-1 has a pivotal role in adult hematopoiesis. However, this role has not been fully uncovered in vivo because of the embryonic lethality of Runx1 knockout in mice. Here we assess the requirement of AML-1/Runx1 in adult hematopoiesis using an inducible gene-targeting method. In the absence of AML-1, hematopoietic progenitors were fully maintained with normal myeloid cell development. However, AML-1-deficient bone marrow showed inhibition of megakaryocytic maturation, increased hematopoietic progenitor cells and defective T- and B-lymphocyte development. AML-1 is thus required for maturation of megakaryocytes and differentiation of T and B cells, but not for maintenance of hematopoietic stem cells (HSCs) in adult hematopoiesis.", + "TAG_DATA": [ + "95, absence {'perturbing_action': 'B-gene loss-of-function'}", + "96, of {'perturbing_action': 'I-gene loss-of-function'}", + "97, AML-1, {'perturbing_action': 'I-gene loss-of-function'}", + "98, hematopoietic {'context': 'B-cells'}", + "99, progenitors {'context': 'I-cells'}", + "105, myeloid {'context': 'B-cells'}", + "106, cell {'context': 'I-cells'}", + "109, AML-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "110, bone {'context': 'B-tissue/organ'}", + "111, marrow {'context': 'I-tissue/organ'}", + "118, hematopoietic {'context': 'B-cells'}", + "119, progenitor {'context': 'I-cells'}", + "120, cells {'context': 'I-cells'}", + "123, T- {'context': 'B-cells'}", + "124, and {'context': 'I-cells'}", + "125, B-lymphocyte {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "95, absence ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "96, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "97, AML-1, ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "98, hematopoietic ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "99, progenitors ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "105, myeloid ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "106, cell ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "109, AML-1-deficient ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "110, bone ['l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "111, marrow ['l22', 'l29', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "118, hematopoietic ['l23', 'l30', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "119, progenitor ['l24', 'l31', 'l37', 'l42', 'l47', 'l48', 'l49', 'l50']", + "120, cells ['l25', 'l32', 'l38', 'l43', 'l47', 'l51', 'l52', 'l53']", + "123, T- ['l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l54', 'l55']", + "124, and ['l27', 'l34', 'l40', 'l45', 'l49', 'l52', 'l54', 'l56']", + "125, B-lymphocyte ['l28', 'l35', 'l41', 'l46', 'l50', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "AML-1,", + "AML-1-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "progenitors", + "myeloid", + "cell", + "progenitor", + "cells", + "T-", + "and", + "B-lymphocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "AML-1-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "bone", + "marrow" + ] + } + } + ] + }, + { + "PMID": "14704791", + "TEXT": "Metastatic cancers, once established, are the primary cause of mortality associated with cancer. Previously, we used a genomic approach to identify metastasis-associated genes in cancer. From this genomic data, we selected ezrin for further study based on its role in physically and functionally connecting the actin cytoskeleton to the cell membrane. In a mouse model of osteosarcoma, a highly metastatic pediatric cancer, we found ezrin to be necessary for metastasis. By imaging metastatic cells in the lungs of mice, we showed that ezrin expression provided an early survival advantage for cancer cells that reached the lung. AKT and MAPK phosphorylation and activity were reduced when ezrin protein was suppressed. Ezrin-mediated early metastatic survival was partially dependent on activation of MAPK, but not AKT. To define the relevance of ezrin in the biology of metastasis, beyond the founding mouse model, we examined ezrin expression in dogs that naturally developed osteosarcoma. High ezrin expression in dog tumors was associated with early development of metastases. Consistent with this data, we found a significant association between high ezrin expression and poor outcome in pediatric osteosarcoma patients.", + "TAG_DATA": [ + "53, mouse {'context': 'B-organism'}", + "54, model {'context': 'I-organism'}", + "55, of {'context': 'I-organism'}", + "56, osteosarcoma, {'context': 'I-organism'}", + "69, metastasis. {'phenotype': 'B-metastasis'}", + "73, cells {'phenotype': 'I-metastasis'}", + "76, lungs {'context': 'B-tissue/organ'}", + "78, mice, {'context': 'B-organism'}", + "90, cancer {'context': 'B-transformed cells'}", + "91, cells {'context': 'I-transformed cells'}", + "111, metastatic {'phenotype': 'B-metastasis'}", + "112, survival {'phenotype': 'I-metastasis'}", + "144, dogs {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "53, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "54, model ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "55, of ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "56, osteosarcoma, ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "69, metastasis. ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42']", + "72, metastatic ['l4', 'l14', 'l23', 'l31', 'l38', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "73, cells ['l5', 'l15', 'l24', 'l32', 'l39', 'l43', 'l49', 'l50', 'l51', 'l52', 'l53']", + "76, lungs ['l6', 'l16', 'l25', 'l33', 'l40', 'l44', 'l49', 'l54', 'l55', 'l56', 'l57']", + "78, mice, ['l7', 'l17', 'l26', 'l34', 'l41', 'l45', 'l50', 'l54', 'l58', 'l59', 'l60']", + "90, cancer ['l8', 'l18', 'l27', 'l35', 'l46', 'l51', 'l55', 'l58', 'l61', 'l62']", + "91, cells ['l9', 'l19', 'l28', 'l36', 'l42', 'l47', 'l52', 'l56', 'l59', 'l61', 'l63']", + "95, lung. ['l10', 'l20', 'l29', 'l37', 'l48', 'l53', 'l57', 'l60', 'l62', 'l63']", + "111, metastatic ['l64', 'l65']", + "112, survival ['l64', 'l66']", + "144, dogs ['l65', 'l66']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "osteosarcoma,", + "mice,", + "dogs" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis.", + "cells", + "metastatic", + "survival" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis.", + "cells" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lungs" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis.", + "cells" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells", + "cancer" + ] + } + } + ] + }, + { + "PMID": "14704789", + "TEXT": "Patients presenting with metastatic rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children, have a very poor clinical prognosis. This is due, in large part, to our rudimentary knowledge of the molecular events that dictate metastatic potential. We used cDNA microarray analysis of RMS cell lines, derived from Ink4a/Arf-deficient mice transgenic for hepatocyte growth factor/scatter factor (HGF/SF), to identify a set of genes whose expression was significantly different between highly and poorly metastatic cells. Subsequent in vivo functional studies revealed that the actin filament-plasma membrane linker ezrin (encoded by Vil2) and the homeodomain-containing transcription factor Six-1 (sine oculis-related homeobox-1 homolog) had essential roles in determining the metastatic fate of RMS cells. VIL2 and SIX1 expression was enhanced in human RMS tissue, significantly correlating with clinical stage. The identification of ezrin and Six-1 as critical regulators of metastasis in RMS provides new mechanistic and therapeutic insights into this pediatric cancer.", + "TAG_DATA": [ + "43, RMS {'context': 'B-transformed cells'}", + "44, cell {'context': 'I-transformed cells'}", + "45, lines, {'context': 'I-transformed cells'}", + "48, Ink4a/Arf-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "49, mice {'context': 'B-organism'}", + "50, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "51, for {'perturbing_action': 'I-gene gain-of-function'}", + "52, hepatocyte {'perturbing_action': 'I-gene gain-of-function'}", + "53, growth {'perturbing_action': 'I-gene gain-of-function'}", + "54, factor/scatter {'perturbing_action': 'I-gene gain-of-function'}", + "55, factor {'perturbing_action': 'I-gene gain-of-function'}", + "56, (HGF/SF), {'perturbing_action': 'I-gene gain-of-function'}", + "75, in {'context': 'B-in vivo'}", + "76, vivo {'context': 'I-in vivo'}", + "109, RMS {'context': 'B-transformed cells'}", + "110, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "43, RMS ['l0', 'l1', 'l2']", + "44, cell ['l0', 'l3', 'l4']", + "45, lines, ['l1', 'l3', 'l5']", + "48, Ink4a/Arf-deficient ['l2', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "49, mice ['l6', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "50, transgenic ['l7', 'l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "51, for ['l8', 'l16', 'l23', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "52, hepatocyte ['l9', 'l17', 'l24', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "53, growth ['l10', 'l18', 'l25', 'l32', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "54, factor/scatter ['l11', 'l19', 'l26', 'l33', 'l40', 'l46', 'l52', 'l53', 'l54', 'l55', 'l56']", + "55, factor ['l12', 'l20', 'l27', 'l34', 'l41', 'l47', 'l52', 'l57', 'l58', 'l59']", + "56, (HGF/SF), ['l13', 'l21', 'l28', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l61', 'l62']", + "75, in ['l29', 'l36', 'l43', 'l49', 'l54', 'l58', 'l60', 'l63', 'l64', 'l65']", + "76, vivo ['l14', 'l22', 'l30', 'l37', 'l44', 'l50', 'l55', 'l59', 'l61', 'l63', 'l66', 'l67']", + "109, RMS ['l64', 'l66', 'l68']", + "110, cells. ['l38', 'l45', 'l51', 'l56', 'l62', 'l65', 'l67', 'l68']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "RMS", + "cell", + "lines," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ink4a/Arf-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ink4a/Arf-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ink4a/Arf-deficient" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "hepatocyte", + "growth", + "factor/scatter", + "factor", + "(HGF/SF)," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "hepatocyte", + "growth", + "factor/scatter", + "factor", + "(HGF/SF)," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "for", + "hepatocyte", + "growth", + "factor/scatter", + "(HGF/SF)," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "14702636", + "TEXT": "The molecular pathways involved in the differentiation of hematopoietic progenitors are unknown. Here we report that chemokine-mediated interactions of megakaryocyte progenitors with sinusoidal bone marrow endothelial cells (BMECs) promote thrombopoietin (TPO)-independent platelet production. Megakaryocyte-active cytokines, including interleukin-6 (IL-6) and IL-11, did not induce platelet production in thrombocytopenic, TPO-deficient (Thpo(-/-)) or TPO receptor-deficient (Mpl(-/-)) mice. In contrast, megakaryocyte-active chemokines, including stromal-derived factor-1 (SDF-1) and fibroblast growth factor-4 (FGF-4), restored thrombopoiesis in Thpo(-/-) and Mpl(-/-) mice. FGF-4 and SDF-1 enhanced vascular cell adhesion molecule-1 (VCAM-1)- and very late antigen-4 (VLA-4)-mediated localization of CXCR4(+) megakaryocyte progenitors to the vascular niche, promoting survival, maturation and platelet release. Disruption of the vascular niche or interference with megakaryocyte motility inhibited thrombopoiesis under physiological conditions and after myelosuppression. SDF-1 and FGF-4 diminished thrombocytopenia after myelosuppression. These data suggest that TPO supports progenitor cell expansion, whereas chemokine-mediated interaction of progenitors with the bone marrow vascular niche allows the progenitors to relocate to a microenvironment that is permissive and instructive for megakaryocyte maturation and thrombopoiesis. Progenitor-active chemokines offer a new strategy to restore hematopoiesis in a clinical setting.", + "TAG_DATA": [ + "47, TPO-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "48, (Thpo(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "50, TPO {'perturbing_action': 'B-gene loss-of-function'}", + "51, receptor-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "52, (Mpl(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "53, mice. {'context': 'B-organism'}", + "70, Thpo(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "71, and {'perturbing_action': 'I-gene loss-of-function'}", + "72, Mpl(-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "73, mice. {'context': 'B-organism'}", + "111, megakaryocyte {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "47, TPO-deficient ['l0', 'l1']", + "48, (Thpo(-/-)) ['l0', 'l2']", + "50, TPO ['l3', 'l4', 'l5', 'l6']", + "51, receptor-deficient ['l3', 'l7', 'l8', 'l9', 'l10', 'l11']", + "52, (Mpl(-/-)) ['l4', 'l7', 'l12', 'l13', 'l14']", + "53, mice. ['l1', 'l2', 'l5', 'l8', 'l12']", + "70, Thpo(-/-) ['l6', 'l9', 'l13', 'l15', 'l16', 'l17']", + "71, and ['l10', 'l15', 'l18', 'l19']", + "72, Mpl(-/-) ['l16', 'l18', 'l20']", + "73, mice. ['l11', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TPO-deficient", + "(Thpo(-/-))", + "TPO", + "receptor-deficient", + "(Mpl(-/-))", + "Thpo(-/-)", + "and", + "Mpl(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "14702633", + "TEXT": "Current antiestrogen therapy for breast cancer is limited by the mixed estrogenic and antiestrogenic activity of selective estrogen receptor modulators. Here we show that the function of zinc fingers in the estrogen receptor DNA-binding domain (DBD) is susceptible to chemical inhibition by electrophilic disulfide benzamide and benzisothiazolone derivatives, which selectively block binding of the estrogen receptor to its responsive element and subsequent transcription. These compounds also significantly inhibit estrogen-stimulated cell proliferation, markedly reduce tumor mass in nude mice bearing human MCF-7 breast cancer xenografts, and interfere with cell-cycle and apoptosis regulatory gene expression. Functional assays and computational analysis support a molecular mechanism whereby electrophilic agents preferentially disrupt the vulnerable C-terminal zinc finger, thus suppressing estrogen receptor-mediated breast carcinoma progression. Our results provide the proof of principle for a new strategy to inhibit breast cancer at the level of DNA binding, rather than the classical antagonism of estrogen binding.", + "TAG_DATA": [ + "67, inhibit {'effect': 'B-negative'}", + "68, estrogen-stimulated {'effect': 'B-positive'}", + "69, cell {'context': 'B-cells'}", + "70, proliferation, {'phenotype': 'B-proliferation'}", + "72, reduce {'effect': 'B-negative'}", + "73, tumor {'phenotype': 'B-tumourigenesis'}", + "74, mass {'phenotype': 'I-tumourigenesis'}", + "76, nude {'context': 'B-organism'}", + "77, mice {'context': 'I-organism'}", + "79, human {'context': 'B-xenograft'}", + "80, MCF-7 {'context': 'I-xenograft'}", + "81, breast {'context': 'I-xenograft'}", + "82, cancer {'context': 'I-xenograft'}", + "83, xenografts, {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "67, inhibit ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "68, estrogen-stimulated ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "69, cell ['l1', 'l6', 'l11']", + "70, proliferation, ['l2', 'l7', 'l11']", + "72, reduce ['l3', 'l8', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "73, tumor ['l4', 'l9', 'l12', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "74, mass ['l5', 'l10', 'l13', 'l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "76, nude ['l14', 'l22', 'l29', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "77, mice ['l15', 'l23', 'l30', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "79, human ['l16', 'l24', 'l31', 'l37', 'l42', 'l47', 'l48', 'l49', 'l50']", + "80, MCF-7 ['l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l51', 'l52', 'l53']", + "81, breast ['l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l54', 'l55']", + "82, cancer ['l19', 'l27', 'l34', 'l40', 'l45', 'l49', 'l52', 'l54', 'l56']", + "83, xenografts, ['l20', 'l28', 'l35', 'l41', 'l46', 'l50', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit", + "reduce" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "mass" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "estrogen-stimulated" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "estrogen-stimulated" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "estrogen-stimulated" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "mass" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduce" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduce" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "human", + "MCF-7", + "breast", + "cancer", + "xenografts," + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "mass" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "mass" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "human", + "MCF-7", + "breast", + "cancer", + "xenografts," + ] + } + } + ] + }, + { + "PMID": "14702631", + "TEXT": "Infection with malaria parasites frequently induces total immune suppression, which makes it difficult for the host to maintain long-lasting immunity. Here we show that depletion of CD4(+)CD25(+) regulatory T cells (T(reg)) protects mice from death when infected with a lethal strain of Plasmodium yoelii, and that this protection is associated with an increased T-cell responsiveness against parasite-derived antigens. These results suggest that activation of T(reg) cells contributes to immune suppression during malaria infection, and helps malaria parasites to escape from host immune responses.", + "TAG_DATA": [ + "24, depletion {'perturbing_action': 'B-gene loss-of-function'}", + "25, of {'perturbing_action': 'I-gene loss-of-function'}", + "26, CD4(+)CD25(+) {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "27, regulatory {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "28, T {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "29, cells {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "30, (T(reg)) {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "32, mice {'context': 'B-organism'}", + "53, T-cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "24, depletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "25, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "26, CD4(+)CD25(+) ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "27, regulatory ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "28, T ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "29, cells ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "30, (T(reg)) ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "32, mice ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "CD4(+)CD25(+)", + "regulatory", + "T", + "cells", + "(T(reg))" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4(+)CD25(+)", + "regulatory", + "T", + "cells", + "(T(reg))" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "CD4(+)CD25(+)", + "regulatory", + "T", + "cells", + "(T(reg))" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "14595407", + "TEXT": "Nitrite anions comprise the largest vascular storage pool of nitric oxide (NO), provided that physiological mechanisms exist to reduce nitrite to NO. We evaluated the vasodilator properties and mechanisms for bioactivation of nitrite in the human forearm. Nitrite infusions of 36 and 0.36 micromol/min into the forearm brachial artery resulted in supra- and near-physiologic intravascular nitrite concentrations, respectively, and increased forearm blood flow before and during exercise, with or without NO synthase inhibition. Nitrite infusions were associated with rapid formation of erythrocyte iron-nitrosylated hemoglobin and, to a lesser extent, S-nitroso-hemoglobin. NO-modified hemoglobin formation was inversely proportional to oxyhemoglobin saturation. Vasodilation of rat aortic rings and formation of both NO gas and NO-modified hemoglobin resulted from the nitrite reductase activity of deoxyhemoglobin and deoxygenated erythrocytes. This finding links tissue hypoxia, hemoglobin allostery and nitrite bioactivation. These results suggest that nitrite represents a major bioavailable pool of NO, and describe a new physiological function for hemoglobin as a nitrite reductase, potentially contributing to hypoxic vasodilation.", + "TAG_DATA": [ + "46, forearm {'context': 'B-tissue/organ'}", + "47, brachial {'context': 'I-tissue/organ'}", + "48, artery {'context': 'I-tissue/organ'}", + "70, NO {'perturbing_action': 'B-pharmacological inhibition'}", + "71, synthase {'perturbing_action': 'I-pharmacological inhibition'}", + "72, inhibition. {'perturbing_action': 'I-pharmacological inhibition'}", + "101, rat {'context': 'B-tissue/organ'}", + "102, aortic {'context': 'I-tissue/organ'}", + "103, rings {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "46, forearm ['l0', 'l1', 'l2', 'l3', 'l4']", + "47, brachial ['l0', 'l5', 'l6', 'l7', 'l8']", + "48, artery ['l1', 'l5', 'l9']", + "60, forearm ['l2', 'l6', 'l9']", + "70, NO ['l3', 'l7', 'l10', 'l11']", + "71, synthase ['l10', 'l12']", + "72, inhibition. ['l4', 'l8', 'l11', 'l12']", + "101, rat ['l13', 'l14']", + "102, aortic ['l13', 'l15']", + "103, rings ['l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "forearm", + "brachial" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NO", + "inhibition." + ] + } + } + ] + }, + { + "PMID": "14502281", + "TEXT": "CD8(+) T cells are essential for long-term, vaccine-induced resistance against intracellular pathogens. Here we show that natural antibodies, acting in concert with complement, are endogenous adjuvants for the generation of protective CD8(+) T cells after vaccination against visceral leishmaniasis. IL-4 was crucial for the priming of vaccine-specific CD8(+) T cells, and we defined the primary source of IL-4 as a CD11b(+)CD11c(lo) phagocyte. IL-4 secretion was not observed in antibody-deficient mice and could be reconstituted with serum from normal, but not Btk immune-deficient, mice. Similarly, no IL-4 response or CD8(+) T-cell priming was seen in C1qa(-/-) mice. These results identify a new pathway by which immune complex-mediated complement activation can regulate T-cell-mediated immunity. We propose that this function of natural antibodies could be exploited when developing new vaccines for infectious diseases.", + "TAG_DATA": [ + "47, CD8(+) {'context': 'B-cells'}", + "48, T {'context': 'I-cells'}", + "49, cells, {'context': 'I-cells'}", + "69, mice {'context': 'B-organism'}", + "80, Btk {'perturbing_action': 'B-gene loss-of-function'}", + "81, immune-deficient, {'perturbing_action': 'I-gene loss-of-function'}", + "82, mice. {'context': 'B-organism'}", + "88, CD8(+) {'context': 'B-cells'}", + "89, T-cell {'context': 'I-cells'}", + "94, C1qa(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "95, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "47, CD8(+) ['l0', 'l1', 'l2']", + "48, T ['l0', 'l3', 'l4']", + "49, cells, ['l1', 'l3', 'l5']", + "69, mice ['l2', 'l4', 'l5']", + "80, Btk ['l6', 'l7']", + "81, immune-deficient, ['l6', 'l8']", + "82, mice. ['l7', 'l8']", + "88, CD8(+) ['l9', 'l10', 'l11']", + "89, T-cell ['l9', 'l12', 'l13']", + "94, C1qa(-/-) ['l10', 'l12', 'l14']", + "95, mice. ['l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Btk", + "immune-deficient,", + "C1qa(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "T-cell" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "C1qa(-/-)" + ] + } + } + ] + }, + { + "PMID": "12949501", + "TEXT": "Glucocorticoids, acting through the glucocorticoid receptor, potently modulate immune function and are a mainstay of therapy for treatment of inflammatory conditions, autoimmune diseases, leukemias and lymphomas. Moreover, removal of systemic glucocorticoids, by adrenalectomy in animal models or adrenal insufficiency in humans, has shown that endogenous glucocorticoid production is required for regulation of physiologic immune responses. These effects have been attributed to suppression of cytokines, although the crucial cellular and molecular targets remain unknown. In addition, considerable controversy remains as to whether glucocorticoids are required for thymocyte development. To assess the role of the glucocorticoid receptor in immune system development and function, we generated T-cell-specific glucocorticoid receptor knockout mice. Here we show that the T-cell is a critical cellular target of glucocorticoid receptor signaling, as immune activation in these mice resulted in significant mortality. This lethal activation is rescued by cyclooxygenase-2 (COX-2) inhibition but not steroid administration or cytokine neutralization. These studies indicate that glucocorticoid receptor suppression of COX-2 is crucial for curtailing lethal immune activation, and suggest new therapeutic approaches for regulation of T-cell-mediated inflammatory diseases.", + "TAG_DATA": [ + "103, T-cell-specific {'perturbing_action': 'B-gene loss-of-function'}", + "104, glucocorticoid {'perturbing_action': 'I-gene loss-of-function'}", + "105, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "106, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "107, mice. {'context': 'B-organism'}", + "128, mice {'context': 'B-organism'}", + "139, cyclooxygenase-2 {'perturbing_action': 'B-pharmacological inhibition'}", + "140, (COX-2) {'perturbing_action': 'I-pharmacological inhibition'}", + "141, inhibition {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "103, T-cell-specific ['l0', 'l1', 'l2', 'l3', 'l4']", + "104, glucocorticoid ['l0', 'l5', 'l6', 'l7', 'l8']", + "105, receptor ['l1', 'l5', 'l9', 'l10', 'l11']", + "106, knockout ['l2', 'l6', 'l9', 'l12', 'l13']", + "107, mice. ['l3', 'l7', 'l10', 'l12', 'l14']", + "128, mice ['l4', 'l8', 'l11', 'l13', 'l14']", + "139, cyclooxygenase-2 ['l15', 'l16']", + "140, (COX-2) ['l15', 'l17']", + "141, inhibition ['l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "T-cell-specific", + "glucocorticoid", + "receptor", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + } + ] + }, + { + "PMID": "12910262", + "TEXT": "Transplantation of adult bone marrow-derived mesenchymal stem cells has been proposed as a strategy for cardiac repair following myocardial damage. However, poor cell viability associated with transplantation has limited the reparative capacity of these cells in vivo. In this study, we genetically engineered rat mesenchymal stem cells using ex vivo retroviral transduction to overexpress the prosurvival gene Akt1 (encoding the Akt protein). Transplantation of 5 x 10(6) cells overexpressing Akt into the ischemic rat myocardium inhibited the process of cardiac remodeling by reducing intramyocardial inflammation, collagen deposition and cardiac myocyte hypertrophy, regenerated 80-90% of lost myocardial volume, and completely normalized systolic and diastolic cardiac function. These observed effects were dose (cell number) dependent. Mesenchymal stem cells transduced with Akt1 restored fourfold greater myocardial volume than equal numbers of cells transduced with the reporter gene lacZ. Thus, mesenchymal stem cells genetically enhanced with Akt1 can repair infarcted myocardium, prevent remodeling and nearly normalize cardiac performance.", + "TAG_DATA": [ + "43, rat {'context': 'B-cells'}", + "44, mesenchymal {'context': 'I-cells'}", + "45, stem {'context': 'I-cells'}", + "46, cells {'context': 'I-cells'}", + "53, overexpress {'perturbing_action': 'B-gene gain-of-function'}", + "64, 5 {'perturbing_action': 'B-gene gain-of-function'}", + "65, x {'perturbing_action': 'B-gene gain-of-function'}", + "66, 10(6) {'perturbing_action': 'B-gene gain-of-function'}", + "67, cells {'perturbing_action': 'I-gene gain-of-function'}", + "68, overexpressing {'perturbing_action': 'I-gene gain-of-function'}", + "69, Akt {'perturbing_action': 'I-gene gain-of-function'}", + "73, rat {'context': 'B-tissue/organ'}", + "74, myocardium {'context': 'I-tissue/organ'}", + "88, cardiac {'context': 'B-cells'}", + "89, myocyte {'context': 'I-cells'}", + "113, Mesenchymal {'context': 'B-cells'}", + "114, stem {'context': 'I-cells'}", + "115, cells {'context': 'I-cells'}", + "116, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "117, with {'perturbing_action': 'I-gene gain-of-function'}", + "118, Akt1 {'perturbing_action': 'I-gene gain-of-function'}", + "128, cells {'context': 'B-cells'}", + "129, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "130, with {'perturbing_action': 'I-gene gain-of-function'}", + "131, the {'perturbing_action': 'I-gene gain-of-function'}", + "132, reporter {'perturbing_action': 'I-gene gain-of-function'}", + "133, gene {'perturbing_action': 'I-gene gain-of-function'}", + "134, lacZ. {'perturbing_action': 'I-gene gain-of-function'}", + "136, mesenchymal {'context': 'B-cells'}", + "137, stem {'context': 'I-cells'}", + "138, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "43, rat ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "44, mesenchymal ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "45, stem ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "46, cells ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "53, overexpress ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "64, 5 ['l4', 'l17', 'l29', 'l40', 'l50', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "65, x ['l5', 'l18', 'l30', 'l41', 'l51', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "66, 10(6) ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "67, cells ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "68, overexpressing ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l90', 'l91', 'l92', 'l93', 'l94']", + "69, Akt ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l95', 'l96', 'l97', 'l98']", + "73, rat ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l99', 'l100', 'l101']", + "74, myocardium ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l102', 'l103']", + "88, cardiac ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l104']", + "89, myocyte ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l104']", + "113, Mesenchymal ['l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "114, stem ['l105', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "115, cells ['l106', 'l120', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146']", + "116, transduced ['l107', 'l121', 'l134', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158']", + "117, with ['l108', 'l122', 'l135', 'l147', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "118, Akt1 ['l109', 'l123', 'l136', 'l148', 'l159', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179']", + "128, cells ['l110', 'l124', 'l137', 'l149', 'l160', 'l170', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "129, transduced ['l111', 'l125', 'l138', 'l150', 'l161', 'l171', 'l180', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196']", + "130, with ['l112', 'l126', 'l139', 'l151', 'l162', 'l172', 'l181', 'l189', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203']", + "131, the ['l113', 'l127', 'l140', 'l152', 'l163', 'l173', 'l182', 'l190', 'l197', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209']", + "132, reporter ['l114', 'l128', 'l141', 'l153', 'l164', 'l174', 'l183', 'l191', 'l198', 'l204', 'l210', 'l211', 'l212', 'l213', 'l214']", + "133, gene ['l115', 'l129', 'l142', 'l154', 'l165', 'l175', 'l184', 'l192', 'l199', 'l205', 'l210', 'l215', 'l216', 'l217', 'l218']", + "134, lacZ. ['l116', 'l130', 'l143', 'l155', 'l166', 'l176', 'l185', 'l193', 'l200', 'l206', 'l211', 'l215', 'l219', 'l220', 'l221']", + "136, mesenchymal ['l117', 'l131', 'l144', 'l156', 'l167', 'l177', 'l186', 'l194', 'l201', 'l207', 'l212', 'l216', 'l219', 'l222', 'l223']", + "137, stem ['l118', 'l132', 'l145', 'l157', 'l168', 'l178', 'l187', 'l195', 'l202', 'l208', 'l213', 'l217', 'l220', 'l222', 'l224']", + "138, cells ['l119', 'l133', 'l146', 'l158', 'l169', 'l179', 'l188', 'l196', 'l203', 'l209', 'l214', 'l218', 'l221', 'l223', 'l224']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "rat", + "mesenchymal", + "stem", + "cells", + "cardiac", + "myocyte", + "Mesenchymal" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpress", + "5", + "x", + "10(6)", + "cells", + "overexpressing", + "Akt", + "transduced", + "with", + "Akt1", + "the", + "reporter", + "gene", + "lacZ." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpress", + "5", + "x", + "10(6)", + "cells", + "overexpressing", + "Akt" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "myocardium" + ] + } + } + ] + }, + { + "PMID": "12872166", + "TEXT": "Protective immunity against Mycobacterium tuberculosis involves major histocompatibility complex class I (MHC-I)- and CD1-restricted CD8 T cells, but the mechanisms underlying antigen delivery to antigen-presenting molecules remain enigmatic. Macrophages, the primary host cells for mycobacteria, are CD1-negative. Here we show that M. tuberculosis phagosomes are secluded from the cytosolic MHC-I processing pathway and that mycobacteria-infected cells lose their antigen-presenting capacity. We also show that mycobacteria induce apoptosis in macrophages, causing the release of apoptotic vesicles that carry mycobacterial antigens to uninfected antigen-presenting cells (APCs). Inhibition of apoptosis reduced transfer of antigens to bystander cells and activation of CD8 T cells. Uninfected dendritic cells, which engulfed extracellular vesicles, were indispensable for subsequent cross-presentation of antigens, through MHC-I and CD1b, to T cells from mycobacteria-sensitized donors. This new 'detour' pathway for presentation of antigens from a phagosome-contained pathogen shows the functional significance of infection-induced apoptosis in the activation of CD8 T cells specific for both protein and glycolipid antigens in tuberculosis.", + "TAG_DATA": [ + "65, induce {'effect': 'B-positive'}", + "66, apoptosis {'phenotype': 'B-apoptosis'}", + "68, macrophages, {'context': 'B-cells'}", + "81, antigen-presenting {'context': 'B-cells'}", + "82, cells {'context': 'I-cells'}", + "83, (APCs). {'context': 'I-cells'}", + "84, Inhibition {'effect': 'B-negative'}", + "86, apoptosis {'phenotype': 'B-apoptosis'}", + "92, bystander {'context': 'B-cells'}", + "93, cells {'context': 'I-cells'}", + "97, CD8 {'context': 'B-cells'}", + "98, T {'context': 'I-cells'}", + "99, cells. {'context': 'I-cells'}", + "101, dendritic {'context': 'I-cells'}", + "102, cells, {'context': 'I-cells'}", + "119, T {'context': 'B-cells'}", + "120, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "65, induce ['l0', 'l1', 'l2', 'l3']", + "66, apoptosis ['l0', 'l4', 'l5', 'l6', 'l7']", + "68, macrophages, ['l1', 'l4', 'l8', 'l9', 'l10']", + "81, antigen-presenting ['l5', 'l8', 'l11', 'l12', 'l13', 'l14', 'l15']", + "82, cells ['l2', 'l6', 'l9', 'l11', 'l16', 'l17', 'l18']", + "83, (APCs). ['l3', 'l7', 'l10', 'l12', 'l16', 'l19', 'l20']", + "84, Inhibition ['l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "86, apoptosis ['l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "92, bystander ['l13', 'l17', 'l19', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "93, cells ['l14', 'l18', 'l20', 'l23', 'l28', 'l32', 'l36']", + "97, CD8 ['l24', 'l29', 'l33', 'l37', 'l38']", + "98, T ['l25', 'l30', 'l34', 'l37', 'l39']", + "99, cells. ['l15', 'l26', 'l31', 'l35', 'l36', 'l38', 'l39']", + "101, dendritic ['l40', 'l41', 'l42']", + "102, cells, ['l40', 'l43', 'l44']", + "119, T ['l41', 'l43', 'l45']", + "120, cells ['l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages,", + "cells", + "(APCs)." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages,", + "antigen-presenting", + "cells", + "(APCs).", + "bystander", + "CD8", + "T", + "cells." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "Inhibition" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "Inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "bystander", + "cells", + "CD8", + "T", + "cells." + ] + } + } + ] + }, + { + "PMID": "12872165", + "TEXT": "Current understanding of key transcription factors regulating angiogenesis is limited. Here we show that RNA-cleaving phosphodiester-linked DNA-based enzymes (DNAzymes), targeting a specific motif in the 5' untranslated region of early growth response (Egr-1) mRNA, inhibit Egr-1 protein expression, microvascular endothelial cell replication and migration, and microtubule network formation on basement membrane matrices. Egr-1 DNAzymes blocked angiogenesis in subcutaneous Matrigel plugs in mice, an observation that was independently confirmed by plug analysis in Egr-1-deficient animals, and inhibited MCF-7 human breast carcinoma growth in nude mice. Egr-1 DNAzymes suppressed tumor growth without influencing body weight, wound healing, blood coagulation or other hematological parameters. These agents inhibited endothelial expression of fibroblast growth factor (FGF)-2, a proangiogenic factor downstream of Egr-1, but not that of vascular endothelial growth factor (VEGF). Egr-1 DNAzymes also repressed neovascularization of rat cornea. Thus, microvascular endothelial cell growth, neovascularization, tumor angiogenesis and tumor growth are processes that are critically dependent on Egr-1.", + "TAG_DATA": [ + "43, migration, {'phenotype': 'B-migration'}", + "61, mice, {'context': 'B-organism'}", + "72, Egr-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "73, animals, {'context': 'B-organism'}", + "75, inhibited {'effect': 'B-negative'}", + "76, MCF-7 {'context': 'B-neoplasm'}", + "77, human {'context': 'I-neoplasm'}", + "78, breast {'context': 'I-neoplasm'}", + "79, carcinoma {'context': 'I-neoplasm'}", + "82, nude {'context': 'B-organism'}", + "83, mice. {'context': 'I-organism'}", + "86, suppressed {'effect': 'B-negative'}", + "87, tumor {'phenotype': 'B-tumour growth'}", + "88, growth {'phenotype': 'I-tumour growth'}", + "129, repressed {'effect': 'B-negative'}", + "132, rat {'context': 'B-tissue/organ'}", + "133, cornea. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "72, Egr-1-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "73, animals, ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "75, inhibited ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "76, MCF-7 ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "77, human ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "78, breast ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "79, carcinoma ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "82, nude ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "83, mice. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "86, suppressed ['l36', 'l37']", + "87, tumor ['l36', 'l38']", + "88, growth ['l37', 'l38']", + "129, repressed ['l39', 'l40']", + "132, rat ['l39', 'l41']", + "133, cornea. ['l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Egr-1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "animals,", + "nude", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Egr-1-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Egr-1-deficient" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "MCF-7", + "human", + "breast", + "carcinoma" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animals,", + "nude", + "mice." + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "MCF-7", + "human", + "breast", + "carcinoma" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "repressed" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "cornea." + ] + } + } + ] + }, + { + "PMID": "12847523", + "TEXT": "Conventional gene therapy of hemophilia A relies on the transfer of factor VIII (FVIII; encoded by the F8 gene) cDNA. We carried out spliceosome-mediated RNA trans-splicing (SMaRT) to repair mutant FVIII mRNA. A pre-trans-splicing molecule (PTM) corrected endogenous FVIII mRNA in F8 knockout mice with the hemophilia A phenotype, producing sufficient functional FVIII to correct the hemophilia A phenotype. This is the first description of phenotypic correction of a genetic defect by RNA repair in a knockout animal model. Our results indicate the feasibility of using SMaRT to repair RNA for the treatment of genetic diseases.", + "TAG_DATA": [ + "41, F8 {'perturbing_action': 'B-gene loss-of-function'}", + "42, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "43, mice {'context': 'B-organism'}", + "78, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "41, F8 ['l0', 'l1']", + "42, knockout ['l0', 'l2']", + "43, mice ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "F8", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "12808448", + "TEXT": "Bone morphogenic protein (BMP)-7 is a 35-kDa homodimeric protein and a member of the transforming growth factor (TGF)-beta superfamily. BMP-7 expression is highest in the kidney, and its genetic deletion in mice leads to severe impairment of eye, skeletal and kidney development. Here we report that BMP-7 reverses TGF-beta1-induced epithelial-to-mesenchymal transition (EMT) by reinduction of E-cadherin, a key epithelial cell adhesion molecule. Additionally, we provide molecular evidence for Smad-dependent reversal of TGF-beta1-induced EMT by BMP-7 in renal tubular epithelial cells and mammary ductal epithelial cells. In the kidney, EMT-induced accumulation of myofibroblasts and subsequent tubular atrophy are considered key determinants of renal fibrosis during chronic renal injury. We therefore tested the potential of BMP-7 to reverse TGF-beta1-induced de novo EMT in a mouse model of chronic renal injury. Our results show that systemic administration of recombinant human BMP-7 leads to repair of severely damaged renal tubular epithelial cells, in association with reversal of chronic renal injury. Collectively, these results provide evidence of cross talk between BMP-7 and TGF-beta1 in the regulation of EMT in health and disease.", + "TAG_DATA": [ + "47, reverses {'effect': 'B-negative'}", + "48, TGF-beta1-induced {'effect': 'B-positive'}", + "49, epithelial-to-mesenchymal {'phenotype': 'B-epithelial-mesenchymal transition'}", + "50, transition {'phenotype': 'I-epithelial-mesenchymal transition'}", + "51, (EMT) {'phenotype': 'I-epithelial-mesenchymal transition'}", + "71, TGF-beta1-induced {'effect': 'B-positive'}", + "72, EMT {'phenotype': 'B-epithelial-mesenchymal transition'}", + "76, renal {'context': 'B-cells'}", + "77, tubular {'context': 'I-cells'}", + "78, epithelial {'context': 'I-cells'}", + "79, cells {'context': 'I-cells'}", + "81, mammary {'context': 'B-cells'}", + "82, ductal {'context': 'I-cells'}", + "83, epithelial {'context': 'I-cells'}", + "84, cells. {'context': 'I-cells'}", + "87, kidney, {'context': 'B-tissue/organ'}", + "91, myofibroblasts {'context': 'B-cells'}", + "115, reverse {'effect': 'B-negative'}", + "116, TGF-beta1-induced {'effect': 'B-positive'}", + "119, EMT {'phenotype': 'B-epithelial-mesenchymal transition'}", + "122, mouse {'context': 'B-organism'}", + "123, model {'context': 'I-organism'}", + "144, renal {'context': 'B-cells'}", + "145, tubular {'context': 'I-cells'}", + "146, epithelial {'context': 'I-cells'}", + "147, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "47, reverses ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "48, TGF-beta1-induced ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "49, epithelial-to-mesenchymal ['l1', 'l9', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "50, transition ['l2', 'l10', 'l19', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "51, (EMT) ['l3', 'l11', 'l20', 'l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "71, TGF-beta1-induced ['l12', 'l21', 'l29', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "72, EMT ['l4', 'l13', 'l22', 'l30', 'l36', 'l41', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "76, renal ['l5', 'l14', 'l23', 'l31', 'l37', 'l42', 'l52', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "77, tubular ['l6', 'l15', 'l24', 'l32', 'l38', 'l43', 'l53', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "78, epithelial ['l7', 'l16', 'l25', 'l33', 'l39', 'l44', 'l54', 'l61', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "79, cells ['l8', 'l17', 'l26', 'l34', 'l40', 'l45', 'l55', 'l62', 'l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88']", + "81, mammary ['l46', 'l63', 'l71', 'l78', 'l84', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "82, ductal ['l47', 'l56', 'l64', 'l72', 'l79', 'l85', 'l89', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "83, epithelial ['l48', 'l57', 'l65', 'l73', 'l80', 'l86', 'l90', 'l98', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "84, cells. ['l18', 'l27', 'l49', 'l58', 'l66', 'l74', 'l81', 'l87', 'l91', 'l99', 'l106', 'l113', 'l114', 'l115']", + "87, kidney, ['l50', 'l59', 'l67', 'l75', 'l82', 'l88', 'l92', 'l100', 'l107', 'l113', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "91, myofibroblasts ['l51', 'l68', 'l76', 'l83', 'l93', 'l101', 'l108', 'l114', 'l116', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "115, reverse ['l117', 'l123', 'l129', 'l130', 'l131', 'l132', 'l133']", + "116, TGF-beta1-induced ['l118', 'l124', 'l129', 'l134', 'l135', 'l136', 'l137']", + "118, novo ['l94', 'l102', 'l109', 'l119', 'l125', 'l130', 'l134', 'l138', 'l139', 'l140']", + "119, EMT ['l95', 'l103', 'l110', 'l115', 'l120', 'l126', 'l131', 'l135', 'l138', 'l141', 'l142']", + "122, mouse ['l96', 'l104', 'l111', 'l121', 'l127', 'l132', 'l136', 'l139', 'l141', 'l143']", + "123, model ['l97', 'l105', 'l112', 'l122', 'l128', 'l133', 'l137', 'l140', 'l142', 'l143']", + "144, renal ['l144', 'l145', 'l146']", + "145, tubular ['l144', 'l147', 'l148']", + "146, epithelial ['l145', 'l147', 'l149']", + "147, cells, ['l146', 'l148', 'l149']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "reverses", + "reverse" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "epithelial-to-mesenchymal", + "transition", + "(EMT)", + "EMT" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reverses", + "reverse" + ] + }, + "context": { + "val": "cells", + "words": [ + "renal", + "tubular", + "epithelial", + "cells", + "myofibroblasts" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "TGF-beta1-induced" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "epithelial-to-mesenchymal", + "transition", + "(EMT)", + "EMT" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "TGF-beta1-induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "renal", + "tubular", + "epithelial", + "cells", + "cells.", + "mammary", + "ductal", + "myofibroblasts" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "epithelial-to-mesenchymal", + "transition", + "(EMT)", + "EMT" + ] + }, + "context": { + "val": "cells", + "words": [ + "renal", + "tubular", + "epithelial", + "cells", + "cells.", + "ductal", + "mammary", + "myofibroblasts" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "TGF-beta1-induced" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidney," + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EMT" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidney," + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "kidney," + ] + }, + "effect": { + "val": "negative", + "words": [ + "reverse" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reverse" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "TGF-beta1-induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EMT" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + } + ] + }, + { + "PMID": "12808447", + "TEXT": "Dengue virus presents a growing threat to public health in the developing world. Four major serotypes of dengue virus have been characterized, and epidemiological evidence shows that dengue hemorrhagic fever (DHF), the more serious manifestation of the disease, occurs more frequently upon reinfection with a second serotype. We have studied dengue virus-specific T-cell responses in Thai children. During acute infection, few dengue-responsive CD8+ T cells were recovered; most of those present showed an activated phenotype and were undergoing programmed cell death. Many dengue-specific T cells were of low affinity for the infecting virus and showed higher affinity for other, probably previously encountered strains. Profound T-cell activation and death may contribute to the systemic disturbances leading to DHF, and original antigenic sin in the T-cell responses may suppress or delay viral elimination, leading to higher viral loads and increased immunopathology.", + "TAG_DATA": [ + "62, CD8+ {'context': 'B-cells'}", + "63, T {'context': 'I-cells'}", + "64, cells {'context': 'I-cells'}", + "79, cell {'phenotype': 'B-cell death'}", + "80, death. {'phenotype': 'I-cell death'}", + "82, dengue-specific {'context': 'B-cells'}", + "83, T {'context': 'I-cells'}", + "84, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "62, CD8+ ['l0', 'l1', 'l2', 'l3']", + "63, T ['l0', 'l4', 'l5', 'l6']", + "64, cells ['l1', 'l4', 'l7', 'l8']", + "79, cell ['l2', 'l5', 'l7', 'l9']", + "80, death. ['l3', 'l6', 'l8', 'l9']", + "82, dengue-specific ['l10', 'l11']", + "83, T ['l10', 'l12']", + "84, cells ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD8+", + "T", + "cells" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "12740571", + "TEXT": "Antigen-specific immune responses in the skin are initiated by antigen uptake into Langerhans cells and the subsequent migration of these cells to draining lymph nodes. Although prostaglandin E2 (PGE2) is produced substantially in skin exposed to antigen, its role remains unclear. Here we show that although Langerhans cells express all four PGE receptor subtypes, their migration to regional lymph nodes was decreased only in EP4-deficient (Ptger4-/-) mice and in wild-type mice treated with an EP4 antagonist. An EP4 agonist promoted the migration of Langerhans cells, increased their expression of costimulatory molecules and enhanced their ability to stimulate T cells in the mixed lymphocyte reaction in vitro. Contact hypersensitivity to antigen was impaired in Ptger4-/- mice and in wild-type mice treated with the EP4 antagonist during sensitization. PGE2-EP4 signaling thus facilitates initiation of skin immune responses by promoting the migration and maturation of Langerhans cells.", + "TAG_DATA": [ + "64, EP4-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "65, (Ptger4-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "66, mice {'context': 'B-organism'}", + "70, mice {'context': 'B-organism'}", + "74, EP4 {'perturbing_action': 'B-pharmacological inhibition'}", + "75, antagonist. {'perturbing_action': 'I-pharmacological augmentation'}", + "77, EP4 {'perturbing_action': 'B-pharmacological augmentation'}", + "78, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "79, promoted {'effect': 'B-positive'}", + "81, migration {'phenotype': 'B-migration'}", + "83, Langerhans {'context': 'B-cells'}", + "84, cells, {'context': 'I-cells'}", + "97, T {'context': 'B-cells'}", + "98, cells {'context': 'B-cells'}", + "104, in {'context': 'B-in vitro'}", + "105, vitro. {'context': 'I-in vitro'}", + "113, Ptger4-/- {'perturbing_action': 'B-gene loss-of-function'}", + "114, mice {'context': 'B-organism'}", + "118, mice {'context': 'B-organism'}", + "122, EP4 {'perturbing_action': 'B-pharmacological inhibition'}", + "123, antagonist {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "64, EP4-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "65, (Ptger4-/-) ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "66, mice ['l1', 'l10', 'l19', 'l20']", + "70, mice ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "74, EP4 ['l21', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "75, antagonist. ['l22', 'l33', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "77, EP4 ['l23', 'l34', 'l44', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "78, agonist ['l24', 'l35', 'l45', 'l54', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "79, promoted ['l2', 'l11', 'l25', 'l36', 'l46', 'l55', 'l63', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "81, migration ['l3', 'l12', 'l26', 'l37', 'l47', 'l56', 'l64', 'l71', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "83, Langerhans ['l4', 'l13', 'l27', 'l38', 'l48', 'l57', 'l65', 'l72', 'l78', 'l84', 'l85', 'l86', 'l87', 'l88']", + "84, cells, ['l5', 'l14', 'l19', 'l28', 'l39', 'l49', 'l58', 'l66', 'l73', 'l79', 'l84', 'l89', 'l90', 'l91', 'l92']", + "97, T ['l6', 'l15', 'l29', 'l40', 'l50', 'l59', 'l67', 'l74', 'l80', 'l85', 'l89', 'l93', 'l94', 'l95']", + "98, cells ['l7', 'l16', 'l20', 'l30', 'l41', 'l51', 'l60', 'l68', 'l75', 'l81', 'l86', 'l90', 'l93', 'l96', 'l97']", + "104, in ['l8', 'l17', 'l31', 'l42', 'l52', 'l61', 'l69', 'l76', 'l82', 'l87', 'l91', 'l94', 'l96', 'l98']", + "105, vitro. ['l9', 'l18', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l83', 'l88', 'l92', 'l95', 'l97', 'l98']", + "113, Ptger4-/- ['l99', 'l100']", + "114, mice ['l99']", + "118, mice ['l100', 'l101', 'l102']", + "122, EP4 ['l101', 'l103']", + "123, antagonist ['l102', 'l103']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EP4-deficient", + "(Ptger4-/-)", + "Ptger4-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EP4-deficient", + "(Ptger4-/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EP4-deficient", + "(Ptger4-/-)" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EP4-deficient", + "(Ptger4-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "Langerhans", + "cells,", + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EP4-deficient", + "(Ptger4-/-)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EP4", + "antagonist" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "antagonist.", + "EP4", + "agonist" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EP4" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EP4" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EP4" + ] + }, + "context": { + "val": "cells", + "words": [ + "Langerhans", + "cells,", + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EP4" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "antagonist.", + "EP4", + "agonist" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "antagonist.", + "EP4", + "agonist" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "antagonist.", + "EP4", + "agonist" + ] + }, + "context": { + "val": "cells", + "words": [ + "Langerhans", + "cells,", + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "antagonist.", + "EP4", + "agonist" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "cells", + "words": [ + "Langerhans", + "cells,", + "T", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "cells", + "words": [ + "Langerhans", + "cells,", + "T", + "cells" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "12704383", + "TEXT": "Suppression of dendritic cell function in cancer patients is thought to contribute to the inhibition of immune responses and disease progression. Molecular mechanisms of this suppression remain elusive, however. Here, we show that a fraction of blood monocyte-derived myeloid dendritic cells (MDCs) express B7-H1, a member of the B7 family, on the cell surface. B7-H1 could be further upregulated by tumor environmental factors. Consistent with this finding, virtually all MDCs isolated from the tissues or draining lymph nodes of ovarian carcinomas express B7-H1. Blockade of B7-H1 enhanced MDC-mediated T-cell activation and was accompanied by downregulation of T-cell interleukin (IL)-10 and upregulation of IL-2 and interferon (IFN)-gamma. T cells conditioned with the B7-H1-blocked MDCs had a more potent ability to inhibit autologous human ovarian carcinoma growth in non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice. Therefore, upregulation of B7-H1 on MDCs in the tumor microenvironment downregulates T-cell immunity. Blockade of B7-H1 represents one approach for cancer immunotherapy.", + "TAG_DATA": [ + "83, Blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "84, of {'perturbing_action': 'I-pharmacological inhibition'}", + "85, B7-H1 {'perturbing_action': 'I-pharmacological inhibition'}", + "88, T-cell {'context': 'B-cells'}", + "106, T {'context': 'B-cells'}", + "107, cells {'context': 'I-cells'}", + "111, B7-H1-blocked {'perturbing_action': 'B-pharmacological inhibition'}", + "112, MDCs {'context': 'B-cells'}", + "120, autologous {'context': 'B-neoplasm'}", + "121, human {'context': 'I-neoplasm'}", + "122, ovarian {'context': 'I-neoplasm'}", + "123, carcinoma {'context': 'I-neoplasm'}", + "126, non-obese {'context': 'B-organism'}", + "127, diabetic-severe {'context': 'I-organism'}", + "128, combined {'context': 'I-organism'}", + "129, immunodeficient {'context': 'I-organism'}", + "131, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "83, Blockade ['l0', 'l1', 'l2']", + "84, of ['l0', 'l3', 'l4']", + "85, B7-H1 ['l1', 'l3', 'l5']", + "88, T-cell ['l2', 'l4', 'l5']", + "106, T ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "107, cells ['l6', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "111, B7-H1-blocked ['l7', 'l19', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "112, MDCs ['l8', 'l20', 'l31', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "120, autologous ['l9', 'l21', 'l32', 'l42', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "121, human ['l10', 'l22', 'l33', 'l43', 'l52', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "122, ovarian ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "123, carcinoma ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "126, non-obese ['l13', 'l25', 'l36', 'l46', 'l55', 'l63', 'l70', 'l76', 'l82', 'l83', 'l84', 'l85', 'l86']", + "127, diabetic-severe ['l14', 'l26', 'l37', 'l47', 'l56', 'l64', 'l71', 'l77', 'l82', 'l87', 'l88', 'l89', 'l90']", + "128, combined ['l15', 'l27', 'l38', 'l48', 'l57', 'l65', 'l72', 'l78', 'l83', 'l87', 'l91', 'l92', 'l93']", + "129, immunodeficient ['l16', 'l28', 'l39', 'l49', 'l58', 'l66', 'l73', 'l79', 'l84', 'l88', 'l91', 'l94', 'l95']", + "130, (NOD-SCID) ['l17', 'l29', 'l40', 'l50', 'l59', 'l67', 'l74', 'l80', 'l85', 'l89', 'l92', 'l94', 'l96']", + "131, mice. ['l18', 'l30', 'l41', 'l51', 'l60', 'l68', 'l75', 'l81', 'l86', 'l90', 'l93', 'l95', 'l96']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "B7-H1", + "B7-H1-blocked" + ] + }, + "context": { + "val": "cells", + "words": [ + "T-cell", + "T", + "cells", + "MDCs" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "B7-H1-blocked" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "autologous", + "human", + "ovarian", + "carcinoma" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "B7-H1-blocked" + ] + }, + "context": { + "val": "organism", + "words": [ + "non-obese", + "diabetic-severe", + "combined", + "immunodeficient", + "mice." + ] + } + } + ] + }, + { + "PMID": "12612547", + "TEXT": "Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by excessive deposition of amyloid-beta (Abeta) peptides in the brain. One of the earliest neuropathological changes in AD is the accumulation of astrocytes at sites of Abeta deposition, but the cause or significance of this cellular response is unclear. Here we show that cultured adult mouse astrocytes migrate in response to monocyte chemoattractant protein-1 (MCP-1), a chemokine present in AD lesions, and cease migration upon interaction with immobilized Abeta(1-42). We also show that astrocytes bind and degrade Abeta(1-42). Astrocytes plated on Abeta-laden brain sections from a mouse model of AD associate with the Abeta deposits and reduce overall Abeta levels in these sections. Our results suggest a novel mechanism for the accumulation of astrocytes around Abeta deposits, indicate a direct role for astrocytes in degradation of Abeta and implicate deficits in astroglial clearance of Abeta in the pathogenesis of AD. Treatments that increase removal of Abeta by astrocytes may therefore be a critical mechanism to reduce the neurodegeneration associated with AD.", + "TAG_DATA": [ + "52, cultured {'context': 'B-cells'}", + "53, adult {'context': 'I-cells'}", + "54, mouse {'context': 'I-cells'}", + "55, astrocytes {'context': 'I-cells'}", + "56, migrate {'phenotype': 'B-migration'}", + "72, migration {'phenotype': 'B-migration'}", + "82, astrocytes {'context': 'B-cells'}", + "87, Astrocytes {'context': 'B-cells'}", + "95, mouse {'context': 'B-organism'}", + "96, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "52, cultured ['l0', 'l1', 'l2', 'l3']", + "53, adult ['l0', 'l4', 'l5', 'l6']", + "54, mouse ['l1', 'l4', 'l7', 'l8']", + "55, astrocytes ['l2', 'l5', 'l7', 'l9']", + "56, migrate ['l3', 'l6', 'l8', 'l9']", + "72, migration ['l10']", + "82, astrocytes ['l10', 'l11']", + "87, Astrocytes ['l11', 'l12', 'l13']", + "95, mouse ['l12', 'l14']", + "96, model ['l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cultured", + "adult", + "mouse", + "astrocytes" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migrate", + "migration" + ] + } + } + ] + }, + { + "PMID": "12563316", + "TEXT": "Activated protein C (APC) is a systemic anti-coagulant and anti-inflammatory factor. It reduces organ damage in animal models of sepsis, ischemic injury and stroke and substantially reduces mortality in patients with severe sepsis. It was not known whether APC acts as a direct cell survival factor or whether its neuroprotective effect is secondary to its anti-coagulant and anti-inflammatory effects. We report that APC directly prevents apoptosis in hypoxic human brain endothelium through transcriptionally dependent inhibition of tumor suppressor protein p53, normalization of the pro-apoptotic Bax/Bcl-2 ratio and reduction of caspase-3 signaling. These mechanisms are distinct from those involving upregulation of the genes encoding the anti-apoptotic Bcl-2 homolog A1 and inhibitor of apoptosis protein-1 (IAP-1) by APC in umbilical vein endothelial cells. Cytoprotection of brain endothelium by APC in vitro required endothelial protein C receptor (EPCR) and protease-activated receptor-1 (PAR-1), as did its in vivo neuroprotective activity in a stroke model of mice with a severe deficiency of EPCR. This is consistent with work showing the direct effects of APC on cultured cells via EPCR and PAR-1 (ref. 9). Moreover, the in vivo neuroprotective effects of low-dose mouse APC seemed to be independent of its anti-coagulant activity. Thus, APC protects the brain from ischemic injury by acting directly on brain cells.", + "TAG_DATA": [ + "64, prevents {'effect': 'B-negative'}", + "65, apoptosis {'phenotype': 'B-apoptosis'}", + "67, hypoxic {'context': 'B-tissue/organ'}", + "68, human {'context': 'I-tissue/organ'}", + "69, brain {'context': 'I-tissue/organ'}", + "70, endothelium {'context': 'I-tissue/organ'}", + "117, umbilical {'context': 'B-cells'}", + "118, vein {'context': 'I-cells'}", + "119, endothelial {'context': 'I-cells'}", + "120, cells. {'context': 'I-cells'}", + "123, brain {'context': 'B-tissue/organ'}", + "124, endothelium {'context': 'I-cells'}", + "127, in {'context': 'B-in vitro'}", + "128, vitro {'context': 'I-in vitro'}", + "142, in {'context': 'B-in vivo'}", + "143, vivo {'context': 'I-in vivo'}", + "151, mice {'context': 'B-organism'}", + "155, deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "180, in {'context': 'B-in vivo'}" + ], + "LINK_DATA": [ + "64, prevents ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "65, apoptosis ['l0', 'l6', 'l7', 'l8', 'l9']", + "67, hypoxic ['l1', 'l6', 'l10', 'l11', 'l12', 'l13']", + "68, human ['l2', 'l7', 'l10', 'l14', 'l15']", + "69, brain ['l3', 'l8', 'l11', 'l14', 'l16']", + "70, endothelium ['l4', 'l9', 'l12', 'l15', 'l16']", + "117, umbilical ['l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "118, vein ['l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "119, endothelial ['l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "120, cells. ['l5', 'l13', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "123, brain ['l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41', 'l42']", + "124, endothelium ['l21', 'l27', 'l32', 'l36', 'l39', 'l43', 'l44']", + "127, in ['l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l45', 'l46']", + "128, vitro ['l23', 'l29', 'l34', 'l38', 'l41', 'l44', 'l45', 'l47']", + "142, in ['l48']", + "143, vivo ['l42', 'l46', 'l47', 'l48']", + "151, mice ['l49']", + "155, deficiency ['l49']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hypoxic", + "human", + "brain", + "endothelium" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hypoxic", + "human", + "brain", + "endothelium" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency" + ] + } + } + ] + }, + { + "PMID": "12539040", + "TEXT": "Hemizygous deletion of chromosome 22q11 (del22q11) causes thymic, parathyroid, craniofacial and life-threatening cardiovascular birth defects in 1 in 4,000 infants. The del22q11 syndrome is likely caused by haploinsufficiency of TBX1, but its variable expressivity indicates the involvement of additional modifiers. Here, we report that absence of the Vegf164 isoform caused birth defects in mice, reminiscent of those found in del22q11 patients. The close correlation of birth and vascular defects indicated that vascular dysgenesis may pathogenetically contribute to the birth defects. Vegf interacted with Tbx1, as Tbx1 expression was reduced in Vegf164-deficient embryos and knocked-down vegf levels enhanced the pharyngeal arch artery defects induced by tbx1 knockdown in zebrafish. Moreover, initial evidence suggested that a VEGF promoter haplotype was associated with an increased risk for cardiovascular birth defects in del22q11 individuals. These genetic data in mouse, fish and human indicate that VEGF is a modifier of cardiovascular birth defects in the del22q11 syndrome.", + "TAG_DATA": [ + "44, absence {'perturbing_action': 'B-gene loss-of-function'}", + "45, of {'perturbing_action': 'I-gene loss-of-function'}", + "46, the {'perturbing_action': 'I-gene loss-of-function'}", + "47, Vegf164 {'perturbing_action': 'I-gene loss-of-function'}", + "48, isoform {'perturbing_action': 'I-gene loss-of-function'}", + "53, mice, {'context': 'B-organism'}", + "90, Vegf164-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "91, embryos {'context': 'B-organism'}", + "93, knocked-down {'perturbing_action': 'B-rnai/knockdown'}", + "94, vegf {'perturbing_action': 'I-rnai/knockdown'}", + "95, levels {'perturbing_action': 'I-rnai/knockdown'}", + "99, arch {'context': 'I-tissue/organ'}", + "104, tbx1 {'perturbing_action': 'B-rnai/knockdown'}", + "105, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "107, zebrafish. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "44, absence ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "45, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "46, the ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "47, Vegf164 ['l2', 'l8', 'l13', 'l18', 'l19', 'l20']", + "48, isoform ['l3', 'l9', 'l14', 'l18', 'l21']", + "53, mice, ['l4', 'l10', 'l15', 'l19', 'l21']", + "90, Vegf164-deficient ['l5', 'l11', 'l16', 'l22', 'l23', 'l24']", + "91, embryos ['l6', 'l12', 'l17', 'l20', 'l22', 'l25']", + "93, knocked-down ['l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "94, vegf ['l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "95, levels ['l27', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "98, pharyngeal ['l23', 'l28', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47']", + "99, arch ['l24', 'l25', 'l29', 'l35', 'l40', 'l44', 'l48', 'l49', 'l50']", + "104, tbx1 ['l30', 'l36', 'l41', 'l45', 'l48', 'l51', 'l52']", + "105, knockdown ['l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l53']", + "107, zebrafish. ['l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l53']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "the", + "Vegf164", + "isoform", + "Vegf164-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "embryos" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Vegf164-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "arch" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knocked-down", + "vegf", + "levels", + "tbx1", + "knockdown" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "arch" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knocked-down", + "vegf", + "levels", + "tbx1", + "knockdown" + ] + }, + "context": { + "val": "organism", + "words": [ + "zebrafish." + ] + } + } + ] + }, + { + "PMID": "12524534", + "TEXT": "Macrophages have important roles in both lipid metabolism and inflammation and are central to the pathogenesis of atherosclerosis. The liver X receptors (LXRs) are established mediators of lipid-inducible gene expression, but their role in inflammation and immunity is unknown. We demonstrate here that LXRs and their ligands are negative regulators of macrophage inflammatory gene expression. Transcriptional profiling of lipopolysaccharide (LPS)-induced macrophages reveals reciprocal LXR-dependent regulation of genes involved in lipid metabolism and the innate immune response. In vitro, LXR ligands inhibit the expression of inflammatory mediators such as inducible nitric oxide synthase, cyclooxygenase (COX)-2 and interleukin-6 (IL-6) in response to bacterial infection or LPS stimulation. In vivo, LXR agonists reduce inflammation in a model of contact dermatitis and inhibit inflammatory gene expression in the aortas of atherosclerotic mice. These findings identify LXRs as lipid-dependent regulators of inflammatory gene expression that may serve to link lipid metabolism and immune functions in macrophages.", + "TAG_DATA": [ + "60, macrophages {'context': 'B-cells'}", + "76, In {'context': 'B-in vitro'}", + "77, vitro, {'context': 'I-in vitro'}", + "105, In {'context': 'B-in vivo'}", + "106, vivo, {'context': 'I-in vivo'}", + "107, LXR {'perturbing_action': 'B-pharmacological augmentation'}", + "108, agonists {'perturbing_action': 'I-pharmacological augmentation'}", + "124, aortas {'context': 'B-tissue/organ'}", + "127, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "60, macrophages ['l0', 'l1']", + "76, In ['l0', 'l2']", + "77, vitro, ['l1', 'l2']", + "105, In ['l3', 'l4', 'l5', 'l6', 'l7']", + "106, vivo, ['l3', 'l8', 'l9', 'l10', 'l11']", + "107, LXR ['l4', 'l8', 'l12', 'l13', 'l14']", + "108, agonists ['l5', 'l9', 'l12', 'l15', 'l16']", + "124, aortas ['l6', 'l10', 'l13', 'l15', 'l17']", + "127, mice. ['l7', 'l11', 'l14', 'l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "LXR", + "agonists" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "LXR", + "agonists" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "aortas" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "LXR", + "agonists" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "12483206", + "TEXT": "Through intracellular receptors, estrogens control growth, differentiation and function of not only reproductive tissues, but also other systems. Estrogen receptors are ligand-dependent transcription factors whose activity is modulated either by estrogens, or by alternative intracellular signaling pathways downstream of growth factors and neurotransmitters. To determine the dynamics of estrogen receptor activity and the dependence of estrogen receptor on 17beta-estradiol in vivo, we generated a transgenic mouse that expresses a luciferase reporter gene under the control of activated estrogen receptors. As expected, luciferase activity, monitored with a cooled charged coupled device camera, paralleled circulating estrogen levels in reproductive tissues and in liver, indicating that the peak transcriptional activity of the estrogen receptor occurred at proestrus. In contrast, in tissues such as bone and brain, the peak activity of estrogen receptors was observed at diestrus. These tissue-specific responses are masked when mice undergo conventional hormone treatment. We also demonstrate that estrogen receptors are active in immature mice before gonadal production of sex hormones as well as in ovariectomized adult mice. These findings emphasize the importance of hormone-independent activation of the estrogen receptor, and have implications for the therapeutic use of estrogens, such as hormone replacement therapy.", + "TAG_DATA": [ + "64, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "65, mouse {'context': 'I-organism'}", + "139, mice {'context': 'B-organism'}", + "153, immature {'context': 'B-organism'}", + "154, mice {'context': 'I-organism'}", + "166, adult {'context': 'B-organism'}", + "167, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "64, transgenic ['l0']", + "65, mouse ['l0']", + "139, mice ['l1', 'l2']", + "153, immature ['l1', 'l3', 'l4', 'l5']", + "154, mice ['l2', 'l3', 'l6', 'l7']", + "166, adult ['l4', 'l6', 'l8']", + "167, mice. ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + } + ] + }, + { + "PMID": "12447356", + "TEXT": "Can T cells be directly activated to de novo gene expression by gonadotropin-releasing hormone-II (GnRH-II), a unique 10-amino-acid neuropeptide conserved through 500 million years of evolution? GnRH-II, which has been identified in mammals, shares 70% homology with the mammalian hypothalamic neurohormone GnRH (GnRH-I), the primary regulator of reproduction, but is encoded by a different gene. Although both neuropeptides are produced mainly in brain, their localization and promoter regulation differ, suggestive of distinct functions. Indeed, GnRH-II barely affects reproduction and its role in mammalian physiology is unknown. We find here that human normal and leukemic T cells produce GnRH-II and GnRH-I. Further, exposure of normal or cancerous human or mouse T cells to GnRH-II or GnRH-I triggered de novo gene transcription and cell-surface expression of a 67-kD non-integrin laminin receptor that is involved in cellular adhesion and migration and in tumor invasion and metastasis. GnRH-II or GnRH-I also induced adhesion to laminin and chemotaxis toward SDF-1alpha, and augmented entry in vivo of metastatic T-lymphoma into the spleen and bone marrow. Homing of normal T cells into specific organs was reduced in mice lacking GnRH-I. A specific GnRH-I-receptor antagonist blocked GnRH-I- but not GnRH-II-induced effects, which is suggestive of signaling through distinct receptors. We suggest that GnRH-II and GnRH-I, secreted from nerves or autocrine or paracrine sources, interact directly with T cells and trigger gene transcription, adhesion, chemotaxis and homing to specific organs, which may be of clinical relevance.", + "TAG_DATA": [ + "91, normal {'context': 'I-cells'}", + "92, and {'context': 'I-cells'}", + "93, leukemic {'context': 'I-cells'}", + "94, T {'context': 'I-cells'}", + "95, cells {'context': 'I-cells'}", + "103, normal {'context': 'B-cells'}", + "104, or {'context': 'I-cells'}", + "105, cancerous {'context': 'I-cells'}", + "106, human {'context': 'I-cells'}", + "107, or {'context': 'I-cells'}", + "108, mouse {'context': 'I-cells'}", + "109, T {'context': 'I-cells'}", + "110, cells {'context': 'I-cells'}", + "147, induced {'effect': 'B-positive'}", + "148, adhesion {'phenotype': 'B-adhesion'}", + "152, chemotaxis {'phenotype': 'B-migration'}", + "158, in {'context': 'B-in vivo'}", + "159, vivo {'context': 'I-in vivo'}", + "161, metastatic {'context': 'B-neoplasm'}", + "162, T-lymphoma {'context': 'I-neoplasm'}", + "165, spleen {'context': 'B-tissue/organ'}", + "168, marrow. {'context': 'I-tissue/organ'}", + "171, normal {'context': 'B-cells'}", + "172, T {'context': 'I-cells'}", + "173, cells {'context': 'I-cells'}", + "180, mice {'context': 'B-organism'}", + "184, specific {'perturbing_action': 'B-pharmacological inhibition'}", + "185, GnRH-I-receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "186, antagonist {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "91, normal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "92, and ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "93, leukemic ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "94, T ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "95, cells ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "103, normal ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "104, or ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "105, cancerous ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "106, human ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "107, or ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "108, mouse ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "109, T ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "110, cells ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "147, induced ['l78', 'l79']", + "148, adhesion ['l78', 'l80', 'l81']", + "152, chemotaxis ['l79', 'l80', 'l82', 'l83', 'l84', 'l85', 'l86']", + "158, in ['l82', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "159, vivo ['l83', 'l87', 'l93', 'l94', 'l95', 'l96', 'l97']", + "161, metastatic ['l88', 'l93', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "162, T-lymphoma ['l89', 'l94', 'l98', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "165, spleen ['l84', 'l90', 'l95', 'l99', 'l105', 'l111', 'l112']", + "167, bone ['l85', 'l91', 'l96', 'l100', 'l106', 'l111', 'l113']", + "168, marrow. ['l81', 'l86', 'l92', 'l97', 'l101', 'l107', 'l112', 'l113']", + "171, normal ['l102', 'l108', 'l114', 'l115', 'l116']", + "172, T ['l103', 'l109', 'l114', 'l117', 'l118']", + "173, cells ['l104', 'l110', 'l115', 'l117']", + "180, mice ['l116', 'l118']", + "184, specific ['l119', 'l120']", + "185, GnRH-I-receptor ['l119', 'l121']", + "186, antagonist ['l120', 'l121']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + } + }, + { + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "marrow." + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "spleen", + "marrow." + ] + } + } + ] + }, + { + "PMID": "12415260", + "TEXT": "Levels of insulin-like growth factor I (IGF-I), a neuroprotective hormone, decrease in serum during aging, whereas amyloid-beta (Abeta), which is involved in the pathogenesis of Alzheimer disease, accumulates in the brain. High brain Abeta levels are found at an early age in mutant mice with low circulating IGF-I, and Abeta burden can be reduced in aging rats by increasing serum IGF-I. This opposing relationship between serum IGF-I and brain Abeta levels reflects the ability of IGF-I to induce clearance of brain Abeta, probably by enhancing transport of Abeta carrier proteins such as albumin and transthyretin into the brain. This effect is antagonized by tumor necrosis factor-alpha, a pro-inflammatory cytokine putatively involved in dementia and aging. Because IGF-I treatment of mice overexpressing mutant amyloid markedly reduces their brain Abeta burden, we consider that circulating IGF-I is a physiological regulator of brain amyloid levels with therapeutic potential.", + "TAG_DATA": [ + "119, mice {'context': 'B-organism'}", + "120, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "121, mutant {'perturbing_action': 'I-gene gain-of-function'}", + "122, amyloid {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "119, mice ['l0', 'l1', 'l2', 'l3']", + "120, overexpressing ['l0', 'l4', 'l5', 'l6']", + "121, mutant ['l1', 'l4', 'l7', 'l8']", + "122, amyloid ['l2', 'l5', 'l7', 'l9']", + "126, brain ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "mutant", + "amyloid" + ] + } + } + ] + }, + { + "PMID": "12415259", + "TEXT": "T cell-mediated loss of insulin-secreting beta cells in the islets of Langerhans is the hallmark of type 1 diabetes. The molecular basis for the directed migration of autoreactive T cells leading to insulitis is presently unknown. Here we demonstrate that in response to inflammation, beta cells secrete the chemokines CXC ligand 10 and CXC ligand 9, which specifically attract T-effector cells via the CXC chemokine receptor 3. In mice deficient for this receptor, the onset of type 1 diabetes is substantially delayed. Thus, in the absence of known etiological agents, CXC receptor 3 represents a novel target for therapeutic interference early in type 1 diabetes.", + "TAG_DATA": [ + "44, beta {'context': 'B-cells'}", + "45, cells {'context': 'I-cells'}", + "68, mice {'context': 'B-organism'}", + "69, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "70, for {'perturbing_action': 'I-gene loss-of-function'}", + "71, this {'perturbing_action': 'I-gene loss-of-function'}", + "72, receptor, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "44, beta ['l0']", + "45, cells ['l0']", + "68, mice ['l1', 'l2', 'l3', 'l4']", + "69, deficient ['l1', 'l5', 'l6', 'l7']", + "70, for ['l2', 'l5', 'l8', 'l9']", + "71, this ['l3', 'l6', 'l8', 'l10']", + "72, receptor, ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "this", + "receptor," + ] + } + } + ] + }, + { + "PMID": "12379847", + "TEXT": "Adrenocorticotrophic hormone (ACTH)-secreting pituitary tumors are associated with high morbidity due to excess glucocorticoid production. No suitable drug therapies are currently available, and surgical excision is not invariably curative. Here we demonstrate immunoreactive expression of the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) exclusively in normal ACTH-secreting human anterior pituitary cells: PPAR-gamma was abundantly expressed in all of six human ACTH-secreting pituitary tumors studied. PPAR-gamma activators induced G0/G1 cell-cycle arrest and apoptosis and suppressed ACTH secretion in human and murine corticotroph tumor cells. Development of murine corticotroph tumors, generated by subcutaneous injection of ACTH-secreting AtT20 cells, was prevented in four of five mice treated with the thiazolidinedione compound rosiglitazone, and ACTH and corticosterone secretion was suppressed in all treated mice. Based on these findings, thiazolidinediones may be an effective therapy for Cushing disease", + "TAG_DATA": [ + "66, induced {'effect': 'B-positive'}", + "67, G0/G1 {'phenotype': 'B-cell cycle arrest'}", + "68, cell-cycle {'phenotype': 'I-cell cycle arrest'}", + "69, arrest {'phenotype': 'I-cell cycle arrest'}", + "71, apoptosis {'phenotype': 'B-apoptosis'}", + "77, human {'context': 'B-transformed cells'}", + "78, and {'context': 'I-transformed cells'}", + "79, murine {'context': 'I-transformed cells'}", + "80, corticotroph {'context': 'I-transformed cells'}", + "81, tumor {'context': 'I-transformed cells'}", + "82, cells. {'context': 'I-transformed cells'}", + "83, Development {'phenotype': 'B-tumourigenesis'}", + "85, murine {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}", + "86, corticotroph {'context': 'I-neoplasm', 'phenotype': 'I-tumourigenesis'}", + "87, tumors, {'context': 'I-neoplasm', 'phenotype': 'I-tumourigenesis'}", + "94, AtT20 {'context': 'B-cells'}", + "95, cells, {'context': 'I-cells'}", + "97, prevented {'effect': 'B-negative'}", + "102, mice {'context': 'B-organism'}", + "119, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "66, induced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "67, G0/G1 ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "68, cell-cycle ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "69, arrest ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31']", + "71, apoptosis ['l3', 'l12', 'l20', 'l27', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "77, human ['l4', 'l13', 'l21', 'l28', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "78, and ['l5', 'l14', 'l22', 'l29', 'l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "79, murine ['l6', 'l15', 'l23', 'l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "80, corticotroph ['l7', 'l16', 'l24', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "81, tumor ['l8', 'l17', 'l25', 'l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "82, cells. ['l9', 'l18', 'l26', 'l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l52']", + "83, Development ['l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "85, murine ['l53', 'l59', 'l60', 'l61', 'l62', 'l63']", + "86, corticotroph ['l54', 'l59', 'l64', 'l65', 'l66', 'l67']", + "87, tumors, ['l55', 'l60', 'l64', 'l68', 'l69', 'l70']", + "94, AtT20 ['l56', 'l61', 'l65', 'l68', 'l71', 'l72', 'l73']", + "95, cells, ['l57', 'l62', 'l66', 'l69', 'l71', 'l74', 'l75']", + "97, prevented ['l58', 'l63', 'l67', 'l70', 'l72', 'l74', 'l76']", + "102, mice ['l73', 'l75', 'l76']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G0/G1", + "cell-cycle", + "arrest" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "and", + "murine", + "corticotroph", + "tumor", + "cells." + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G0/G1", + "cell-cycle", + "arrest" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "and", + "murine", + "corticotroph", + "tumor", + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "and", + "murine", + "corticotroph", + "tumor", + "cells." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "Development", + "murine", + "corticotroph", + "tumors," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "murine", + "corticotroph", + "tumors," + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "Development", + "murine", + "corticotroph", + "tumors," + ] + }, + "context": { + "val": "cells", + "words": [ + "AtT20", + "cells," + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "Development", + "murine", + "corticotroph", + "tumors," + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "murine", + "corticotroph", + "tumors," + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "AtT20", + "cells," + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "12368906", + "TEXT": "Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, yet molecular events associated with the genesis and progression of this potentially fatal disease are largely unknown. For the molecules and pathways that have been implicated, genetic validation has been impeded by lack of a mouse model of RMS. Here we show that simultaneous loss of Ink4a/Arf function and disruption of c-Met signaling in Ink4a/Arf(-/-) mice transgenic for hepatocyte growth factor/scatter factor (HGF/SF) induces RMS with extremely high penetrance and short latency. In cultured myoblasts, c-Met activation and Ink4a/Arf loss suppress myogenesis in an additive fashion. Our data indicate that human c-MET and INK4a/ARF, situated at the nexus of pathways regulating myogenic growth and differentiation, represent critical targets in RMS pathogenesis. The marked synergism in mice between aberrant c-Met signaling and Ink4a/Arf inactivation, lesions individually implicated in human RMS, suggests a therapeutic combination to combat this devastating childhood cancer.", + "TAG_DATA": [ + "54, loss {'perturbing_action': 'B-gene loss-of-function'}", + "55, of {'perturbing_action': 'I-gene loss-of-function'}", + "56, Ink4a/Arf {'perturbing_action': 'I-gene loss-of-function'}", + "57, function {'perturbing_action': 'I-gene loss-of-function'}", + "64, Ink4a/Arf(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "65, mice {'context': 'B-organism'}", + "66, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "67, for {'perturbing_action': 'I-gene gain-of-function'}", + "68, hepatocyte {'perturbing_action': 'I-gene gain-of-function'}", + "69, growth {'perturbing_action': 'I-gene gain-of-function'}", + "70, factor/scatter {'perturbing_action': 'I-gene gain-of-function'}", + "71, factor {'perturbing_action': 'I-gene gain-of-function'}", + "72, (HGF/SF) {'perturbing_action': 'I-gene gain-of-function'}", + "83, cultured {'context': 'B-cells'}", + "84, myoblasts, {'context': 'I-cells'}", + "88, Ink4a/Arf {'perturbing_action': 'B-gene loss-of-function'}", + "89, loss {'perturbing_action': 'I-gene loss-of-function'}", + "90, suppress {'effect': 'B-negative'}", + "125, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "54, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "55, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "56, Ink4a/Arf ['l1', 'l9', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "57, function ['l2', 'l10', 'l20', 'l30', 'l31', 'l32', 'l33', 'l34']", + "64, Ink4a/Arf(-/-) ['l3', 'l11', 'l21', 'l30', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "65, mice ['l4', 'l12', 'l22', 'l31', 'l35', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "66, transgenic ['l5', 'l13', 'l23', 'l36', 'l45', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "67, for ['l37', 'l46', 'l54', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "68, hepatocyte ['l14', 'l24', 'l38', 'l47', 'l55', 'l64', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "69, growth ['l15', 'l25', 'l39', 'l48', 'l56', 'l65', 'l74', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "70, factor/scatter ['l16', 'l26', 'l40', 'l49', 'l57', 'l66', 'l75', 'l83', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "71, factor ['l6', 'l17', 'l27', 'l32', 'l41', 'l50', 'l58', 'l67', 'l76', 'l84', 'l91', 'l98', 'l99', 'l100', 'l101', 'l102']", + "72, (HGF/SF) ['l7', 'l18', 'l28', 'l33', 'l42', 'l51', 'l59', 'l68', 'l77', 'l85', 'l92', 'l98', 'l103', 'l104', 'l105', 'l106']", + "83, cultured ['l43', 'l52', 'l60', 'l69', 'l78', 'l86', 'l93', 'l99', 'l103', 'l107', 'l108']", + "84, myoblasts, ['l8', 'l19', 'l29', 'l34', 'l44', 'l53', 'l61', 'l70', 'l79', 'l87', 'l94', 'l100', 'l104', 'l107']", + "88, Ink4a/Arf ['l71', 'l80', 'l88', 'l95', 'l109', 'l110']", + "89, loss ['l62', 'l72', 'l81', 'l89', 'l96', 'l101', 'l105', 'l109', 'l111']", + "90, suppress ['l63', 'l73', 'l82', 'l90', 'l97', 'l102', 'l106', 'l108', 'l110', 'l111']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Ink4a/Arf", + "function", + "Ink4a/Arf(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Ink4a/Arf", + "function", + "Ink4a/Arf(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "myoblasts,", + "cultured" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "hepatocyte", + "growth", + "factor/scatter", + "factor", + "(HGF/SF)" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "hepatocyte", + "growth", + "factor/scatter", + "factor", + "(HGF/SF)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "myoblasts," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "hepatocyte", + "growth", + "factor/scatter", + "factor", + "(HGF/SF)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppress" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppress" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ink4a/Arf", + "loss" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppress" + ] + } + } + ] + }, + { + "PMID": "12357246", + "TEXT": "Ras acts with other proteins to induce neoplasia. By itself, however, strong Ras signaling can suppress proliferation of normal cells. In primary epidermal cells, we found that oncogenic Ras transiently decreases cyclin-dependent kinase (CDK) 4 expression in association with cell cycle arrest in G1 phase. CDK4 co-expression circumvents Ras growth suppression and induces invasive human neoplasia resembling squamous cell carcinoma. Tumorigenesis is dependent on CDK4 kinase function, with cyclin D1 required but not sufficient for this process. In facilitating escape from G1 growth restraints, Ras and CDK4 alter the composition of cyclin D and cyclin E complexes and promote resistance to growth inhibition by INK4 cyclin-dependent kinase inhibitors. These data identify a new role for oncogenic Ras in CDK4 regulation and highlight the functional importance of CDK4 suppression in preventing uncontrolled growth.", + "TAG_DATA": [ + "21, primary {'context': 'B-cells'}", + "22, epidermal {'context': 'I-cells'}", + "23, cells, {'context': 'I-cells'}", + "39, cell {'phenotype': 'B-cell cycle arrest'}", + "40, cycle {'phenotype': 'I-cell cycle arrest'}", + "41, arrest {'phenotype': 'I-cell cycle arrest'}", + "45, CDK4 {'perturbing_action': 'B-gene gain-of-function'}", + "46, co-expression {'perturbing_action': 'I-gene gain-of-function'}", + "52, induces {'effect': 'B-positive'}", + "54, human {'phenotype': 'B-tumourigenesis'}", + "55, neoplasia {'phenotype': 'I-tumourigenesis'}", + "57, squamous {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}", + "58, cell {'phenotype': 'I-tumourigenesis'}", + "59, carcinoma. {'phenotype': 'I-tumourigenesis'}", + "104, INK4 {'perturbing_action': 'B-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "21, primary ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "22, epidermal ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "23, cells, ['l1', 'l7', 'l13', 'l14', 'l15', 'l16']", + "39, cell ['l2', 'l8', 'l13', 'l17', 'l18', 'l19']", + "40, cycle ['l3', 'l9', 'l14', 'l17', 'l20', 'l21']", + "41, arrest ['l4', 'l10', 'l15', 'l18', 'l20', 'l22']", + "45, CDK4 ['l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "46, co-expression ['l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "52, induces ['l5', 'l11', 'l16', 'l19', 'l21', 'l22', 'l24', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "54, human ['l25', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "55, neoplasia ['l6', 'l12', 'l26', 'l32', 'l37', 'l41', 'l45', 'l46', 'l47']", + "57, squamous ['l27', 'l33', 'l38', 'l42', 'l45', 'l48', 'l49']", + "58, cell ['l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l50']", + "59, carcinoma. ['l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l50']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "primary", + "epidermal", + "cells," + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "primary", + "epidermal", + "cells," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "primary", + "epidermal" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "neoplasia" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "CDK4", + "co-expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "CDK4", + "co-expression" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "human", + "neoplasia", + "squamous", + "cell", + "carcinoma." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "CDK4", + "co-expression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "squamous" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "squamous" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "squamous", + "human", + "neoplasia" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "human", + "neoplasia", + "squamous", + "cell", + "carcinoma." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "squamous" + ] + } + } + ] + }, + { + "PMID": "12244303", + "TEXT": "The cyclin-dependent kinase inhibitor p27(kip1) is a putative tumor suppressor for human cancer. The mechanism underlying p27(kip1) deregulation in human cancer is, however, poorly understood. We demonstrate that the serine/threonine kinase Akt regulates cell proliferation in breast cancer cells by preventing p27(kip1)-mediated growth arrest. Threonine 157 (T157), which maps within the nuclear localization signal of p27(kip1), is a predicted Akt-phosphorylation site. Akt-induced T157 phosphorylation causes retention of p27(kip1) in the cytoplasm, precluding p27(kip1)-induced G1 arrest. Conversely, the p27(kip1)-T157A mutant accumulates in cell nuclei and Akt does not affect p27(kip1)-T157A-mediated cell cycle arrest. Lastly, T157-phosphorylated p27(kip1) accumulates in the cytoplasm of primary human breast cancer cells coincident with Akt activation. Thus, cytoplasmic relocalization of p27(kip1), secondary to Akt-mediated phosphorylation, is a novel mechanism whereby the growth inhibitory properties of p27(kip1) are functionally inactivated and the proliferation of breast cancer cells is sustained.", + "TAG_DATA": [ + "40, preventing {'effect': 'B-negative'}", + "43, arrest. {'phenotype': 'I-cell cycle arrest'}", + "71, precluding {'effect': 'B-negative'}", + "73, G1 {'phenotype': 'B-cell cycle arrest'}", + "74, arrest. {'phenotype': 'I-cell cycle arrest'}", + "77, p27(kip1)-T157A {'perturbing_action': 'B-other'}", + "78, mutant {'perturbing_action': 'I-other'}", + "81, cell {'context': 'B-cells'}", + "85, does {'effect': 'B-no effect'}", + "86, not {'effect': 'B-no effect'}", + "87, affect {'effect': 'I-no effect'}", + "89, cell {'phenotype': 'B-cell cycle arrest'}", + "90, cycle {'phenotype': 'I-cell cycle arrest'}", + "91, arrest. {'phenotype': 'I-cell cycle arrest'}", + "100, primary {'context': 'B-transformed cells'}", + "101, human {'context': 'I-transformed cells'}", + "102, breast {'context': 'I-transformed cells'}", + "103, cancer {'context': 'I-transformed cells'}", + "104, cells {'context': 'I-transformed cells'}", + "134, proliferation {'phenotype': 'B-proliferation'}", + "136, breast {'context': 'B-transformed cells'}", + "137, cancer {'context': 'I-transformed cells'}", + "138, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "40, preventing ['l0', 'l1', 'l2', 'l3', 'l4']", + "42, growth ['l0', 'l5', 'l6', 'l7', 'l8']", + "43, arrest. ['l1', 'l5', 'l9', 'l10', 'l11']", + "71, precluding ['l2', 'l6', 'l9', 'l12', 'l13']", + "73, G1 ['l3', 'l7', 'l10', 'l12', 'l14']", + "74, arrest. ['l4', 'l8', 'l11', 'l13', 'l14']", + "77, p27(kip1)-T157A ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "78, mutant ['l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "81, cell ['l16', 'l23', 'l30', 'l31', 'l32', 'l33']", + "85, does ['l17', 'l24', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "86, not ['l18', 'l25', 'l34', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "87, affect ['l19', 'l26', 'l30', 'l35', 'l41', 'l47', 'l48', 'l49', 'l50']", + "89, cell ['l20', 'l27', 'l31', 'l36', 'l42', 'l47', 'l51', 'l52']", + "90, cycle ['l21', 'l28', 'l32', 'l37', 'l43', 'l48', 'l51', 'l53']", + "91, arrest. ['l22', 'l29', 'l33', 'l38', 'l44', 'l49', 'l52', 'l53']", + "100, primary ['l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "101, human ['l54', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "102, breast ['l55', 'l62', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "103, cancer ['l56', 'l63', 'l69', 'l75', 'l76', 'l77', 'l78', 'l79']", + "104, cells ['l57', 'l64', 'l70', 'l75', 'l80', 'l81', 'l82', 'l83']", + "134, proliferation ['l58', 'l65', 'l71', 'l76', 'l80', 'l84', 'l85', 'l86']", + "136, breast ['l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l87', 'l88']", + "137, cancer ['l39', 'l45', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l87', 'l89']", + "138, cells ['l40', 'l46', 'l50', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l89']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "preventing", + "precluding" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest.", + "G1" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "p27(kip1)-T157A", + "mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "p27(kip1)-T157A", + "mutant" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "does", + "not", + "affect" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "p27(kip1)-T157A", + "mutant" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "affect" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest." + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "does", + "not", + "affect" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest." + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "does", + "not", + "affect" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "primary", + "human", + "breast", + "cancer", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "12244301", + "TEXT": "We have shown a novel mechanism of Akt-mediated regulation of the CDK inhibitor p27(kip1). Blockade of HER2/neu in tumor cells inhibits Akt kinase activity and upregulates nuclear levels of the CDK inhibitor (Kip1). Recombinant Akt and Akt precipitated from tumor cells phosphorylated wild-type p27 in vitro. p27 contains an Akt consensus RXRXXT(157)D within its nuclear localization motif. Active (myristoylated) Akt phosphorylated wild-type p27 in vivo but was unable to phosphorylate a T157A-p27 mutant. Wild-type p27 localized in the cytosol and nucleus, whereas T157A-p27 localized exclusively in the nucleus and was resistant to nuclear exclusion by Akt. T157A-p27 was more effective than wild-type p27 in inhibiting cyclin E/CDK2 activity and cell proliferation; these effects were not rescued by active Akt. Expression of Ser(473) phospho Akt in primary human breast cancers statistically correlated with expression of p27 in tumor cytosol. These data indicate that Akt may contribute to tumor-cell proliferation by phosphorylation and cytosolic retention of p27, thus relieving CDK2 from p27-induced inhibition.", + "TAG_DATA": [ + "18, tumor {'context': 'B-transformed cells'}", + "39, tumor {'context': 'B-transformed cells'}", + "40, cells {'context': 'I-transformed cells'}", + "44, in {'context': 'B-in vitro'}", + "45, vitro. {'context': 'I-in vitro'}", + "63, in {'context': 'B-in vivo'}", + "64, vivo {'context': 'I-in vivo'}", + "104, inhibiting {'effect': 'B-negative'}", + "109, cell {'context': 'B-cells'}", + "110, proliferation; {'phenotype': 'B-proliferation'}", + "117, active {'perturbing_action': 'B-gene gain-of-function'}", + "118, Akt. {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "18, tumor ['l0', 'l1', 'l2', 'l3', 'l4']", + "19, cells ['l0', 'l5']", + "39, tumor ['l1', 'l6', 'l7', 'l8', 'l9', 'l10']", + "40, cells ['l2', 'l5', 'l6', 'l11', 'l12', 'l13']", + "44, in ['l7', 'l11', 'l14', 'l15', 'l16']", + "45, vitro. ['l8', 'l14', 'l17', 'l18']", + "63, in ['l3', 'l9', 'l12', 'l15', 'l17', 'l19']", + "64, vivo ['l4', 'l10', 'l13', 'l16', 'l18', 'l19']", + "104, inhibiting ['l20', 'l21']", + "109, cell ['l20', 'l22']", + "110, proliferation; ['l21', 'l22']", + "117, active ['l23']", + "118, Akt. ['l23']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibiting" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibiting" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation;" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation;" + ] + } + } + ] + }, + { + "PMID": "12219086", + "TEXT": "With the advent of HIV and the widespread emergence of drug-resistant strains of Mycobacterium tuberculosis, newer control strategies in the form of a better vaccine could decrease the global incidence of tuberculosis. A desirable trait in an effective live attenuated vaccine strain is an ability to persist within the host in a limited fashion in order to produce important protective antigens in vivo. Attenuated M. tuberculosis vaccine candidates have been constructed by deleting genes required for growth in mice. These candidate vaccines did not elicit adequate protective immunity in animal models, due to their inability to persist sufficiently long within the host tissues. Here we report that an auxotrophic mutant of M. tuberculosis defective in the de novo biosynthesis of pantothenic acid (vitamin B5) is highly attenuated in immunocompromised SCID mice and in immunocompetent BALB/c mice. SCID mice infected with the pantothenate auxotroph survived significantly longer (250 days) than mice infected with either bacille Calmette-Guerin (BCG) vaccine or virulent M. tuberculosis (77 and 35 days, respectively). Subcutaneous immunization with this auxotroph conferred protection in C57BL/6J mice against an aerosol challenge with virulent M. tuberculosis, which was comparable with that afforded by BCG vaccination. Our findings highlight the importance of de novo pantothenate biosynthesis in limiting the intracellular survival and pathogenesis of M. tuberculosis without reducing its immunogenicity in vaccinated mice.", + "TAG_DATA": [ + "108, auxotrophic {'perturbing_action': 'B-other'}", + "109, mutant {'perturbing_action': 'I-other'}", + "110, of {'perturbing_action': 'I-other'}", + "111, M. {'perturbing_action': 'I-other'}", + "112, tuberculosis {'perturbing_action': 'I-other'}", + "130, mice {'context': 'I-organism'}", + "133, immunocompetent {'context': 'B-organism'}", + "134, BALB/c {'context': 'I-organism'}", + "135, mice. {'context': 'I-organism'}", + "136, SCID {'context': 'B-organism'}", + "137, mice {'context': 'I-organism'}", + "149, mice {'context': 'B-organism'}", + "174, C57BL/6J {'context': 'B-organism'}", + "175, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "108, auxotrophic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "109, mutant ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "110, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "111, M. ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "112, tuberculosis ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "130, mice ['l4', 'l12', 'l19', 'l25', 'l30']", + "133, immunocompetent ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l36', 'l37']", + "134, BALB/c ['l6', 'l14', 'l21', 'l27', 'l32', 'l35', 'l38', 'l39', 'l40', 'l41']", + "135, mice. ['l7', 'l15', 'l22', 'l28', 'l33', 'l36', 'l38', 'l42']", + "136, SCID ['l39', 'l43', 'l44']", + "137, mice ['l40', 'l43', 'l45']", + "149, mice ['l8', 'l16', 'l23', 'l29', 'l34', 'l37', 'l41', 'l42', 'l44', 'l45']", + "174, C57BL/6J ['l46']", + "175, mice ['l46']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "auxotrophic", + "mutant", + "of", + "M.", + "tuberculosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "immunocompetent", + "BALB/c", + "mice." + ] + } + } + ] + }, + { + "PMID": "12219085", + "TEXT": "The intracellular signaling mechanisms that specify tissue-specific responses to the interleukin-6 (IL-6) family of cytokines are not well understood. Here, we evaluated the functions of the two major signaling pathways, the signal transducers and activators of transcription 1 and 3 (STAT1/3) and the Src-homology tyrosine phosphatase 2 (SHP2)-Ras-ERK, emanating from the common signal transducer, gp130, in the gastrointestinal tract. Gp130(757F) mice, with a 'knock-in' mutation abrogating SHP2-Ras-ERK signaling, developed gastric adenomas by three months of age. In contrast, mice harboring the reciprocal mutation ablating STAT1/3 signaling (gp130(Delta STAT)), or deficient in IL-6-mediated gp130 signaling (IL-6(-/-) mice), showed impaired colonic mucosal wound healing. These gastrointestinal phenotypes are highly similar to the phenotypes exhibited by mice deficient in trefoil factor 1 (pS2/TFF1) and intestinal trefoil factor (ITF)/TFF3, respectively, and corresponded closely with the capacity of the two pathways to stimulate transcription of the genes encoding pS2/TFF1 and ITF/TFF3. We propose a model whereby mucosal wound healing depends solely on activation of STAT1/3, whereas gastric hyperplasia ensues when the coordinated activation of the STAT1/3 and SHP2-Ras-ERK pathways is disrupted.", + "TAG_DATA": [ + "59, Gp130(757F) {'perturbing_action': 'B-other'}", + "60, mice, {'context': 'B-organism'}", + "63, 'knock-in' {'perturbing_action': 'B-gene loss-of-function'}", + "64, mutation {'perturbing_action': 'I-rnai/knockdown'}", + "65, abrogating {'perturbing_action': 'I-rnai/knockdown'}", + "69, gastric {'phenotype': 'B-tumourigenesis'}", + "70, adenomas {'phenotype': 'I-tumourigenesis'}", + "78, mice {'context': 'B-organism'}", + "81, reciprocal {'perturbing_action': 'I-other'}", + "82, mutation {'perturbing_action': 'I-other'}", + "83, ablating {'perturbing_action': 'I-gene loss-of-function'}", + "84, STAT1/3 {'perturbing_action': 'I-gene loss-of-function'}", + "85, signaling {'perturbing_action': 'I-other'}", + "86, (gp130(Delta {'perturbing_action': 'I-other'}", + "87, STAT)), {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "59, Gp130(757F) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "60, mice, ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "63, 'knock-in' ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "64, mutation ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "65, abrogating ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "69, gastric ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "70, adenomas ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "78, mice ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "81, reciprocal ['l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "82, mutation ['l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "83, ablating ['l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "84, STAT1/3 ['l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "85, signaling ['l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "86, (gp130(Delta ['l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "87, STAT)), ['l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Gp130(757F)", + "reciprocal", + "mutation", + "signaling", + "(gp130(Delta" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Gp130(757F)" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "gastric", + "adenomas" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "'knock-in'", + "ablating", + "STAT1/3", + "STAT))," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "mutation", + "abrogating" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "gastric", + "adenomas" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "'knock-in'" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "gastric", + "adenomas" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "mutation", + "abrogating" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "gastric", + "adenomas" + ] + } + } + ] + }, + { + "PMID": "12185361", + "TEXT": "Angiogenesis is a highly regulated process that results from the sequential actions of naturally occurring stimulators and inhibitors. Here, we show that parathyroid hormone-related peptide, a peptide hormone derived from normal and tumor cells that regulates bone metabolism and vascular tone, is a naturally occurring angiogenesis inhibitor. Parathyroid hormone-related peptide or a ten-amino-acid peptide from its N terminus inhibits endothelial cell migration in vitro and angiogenesis in vivo by activating endothelial cell protein kinase A. Activation of protein kinase A inhibits cell migration and angiogenesis by inhibiting the small GTPase Rac. In contrast, inhibition of protein kinase A reverses the anti-migratory and anti-angiogenic properties of parathyroid hormone-related peptide. These studies show that parathyroid hormone-related peptide is a naturally occurring angiogenesis inhibitor that functions by activation of protein kinase A.", + "TAG_DATA": [ + "58, inhibits {'effect': 'B-negative'}", + "59, endothelial {'context': 'B-cells'}", + "60, cell {'context': 'I-cells'}", + "61, migration {'phenotype': 'B-migration'}", + "62, in {'context': 'B-in vitro'}", + "63, vitro {'context': 'I-in vitro'}", + "66, in {'context': 'B-in vivo'}", + "67, vivo {'context': 'I-in vivo'}", + "70, endothelial {'context': 'B-cells'}", + "71, cell {'context': 'I-cells'}", + "75, Activation {'perturbing_action': 'B-pharmacological augmentation'}", + "76, of {'perturbing_action': 'I-pharmacological augmentation'}", + "77, protein {'perturbing_action': 'I-pharmacological augmentation'}", + "78, kinase {'perturbing_action': 'I-pharmacological augmentation'}", + "79, A {'perturbing_action': 'I-pharmacological augmentation'}", + "80, inhibits {'effect': 'B-negative'}", + "81, cell {'context': 'B-cells'}", + "82, migration {'phenotype': 'B-migration'}", + "93, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "94, of {'perturbing_action': 'I-pharmacological inhibition'}", + "95, protein {'perturbing_action': 'I-pharmacological inhibition'}", + "96, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "97, A {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "58, inhibits ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "59, endothelial ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "60, cell ['l1', 'l7', 'l12', 'l13', 'l14']", + "61, migration ['l2', 'l8', 'l12', 'l15', 'l16']", + "62, in ['l3', 'l9', 'l13', 'l15', 'l17']", + "63, vitro ['l4', 'l10', 'l14', 'l16', 'l17', 'l18']", + "66, in ['l5', 'l19', 'l20', 'l21']", + "67, vivo ['l6', 'l11', 'l18', 'l19', 'l22', 'l23']", + "70, endothelial ['l20', 'l22', 'l24', 'l25', 'l26', 'l27']", + "71, cell ['l21', 'l23', 'l24', 'l28', 'l29', 'l30']", + "75, Activation ['l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "76, of ['l31', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "77, protein ['l32', 'l38', 'l44', 'l45', 'l46', 'l47', 'l48']", + "78, kinase ['l33', 'l39', 'l44', 'l49', 'l50', 'l51', 'l52']", + "79, A ['l34', 'l40', 'l45', 'l49', 'l53', 'l54', 'l55']", + "80, inhibits ['l25', 'l28', 'l35', 'l41', 'l46', 'l50', 'l53', 'l56', 'l57']", + "81, cell ['l26', 'l29', 'l36', 'l42', 'l47', 'l51', 'l54', 'l56', 'l58']", + "82, migration ['l27', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l57', 'l58']", + "93, inhibition ['l59', 'l60', 'l61', 'l62']", + "94, of ['l59', 'l63', 'l64', 'l65']", + "95, protein ['l60', 'l63', 'l66', 'l67']", + "96, kinase ['l61', 'l64', 'l66', 'l68']", + "97, A ['l62', 'l65', 'l67', 'l68']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "protein", + "kinase", + "A" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "protein", + "kinase", + "A" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "protein", + "kinase", + "A" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + } + ] + }, + { + "PMID": "12172542", + "TEXT": "The prevalence of asthma continues to increase and its optimal treatment remains a challenge. Here, we investigated the actions of lipoxin A(4) (LXA(4)) and its leukocyte receptor in pulmonary inflammation using a murine model of asthma. Allergen challenge initiated airway biosynthesis of LXA(4) and increased expression of its receptor. Administration of a stable analog of LXA(4) blocked both airway hyper-responsiveness and pulmonary inflammation, as shown by decreased leukocytes and mediators, including interleukin-5, interleukin-13, eotaxin, prostanoids and cysteinyl leukotrienes. Moreover, transgenic expression of human LXA(4) receptors in murine leukocytes led to significant inhibition of pulmonary inflammation and eicosanoid-initiated eosinophil tissue infiltration. Inhibition of airway hyper-responsiveness and allergic airway inflammation with a stable LXA(4) analog highlights a unique counter-regulatory profile for the LXA(4) system and its leukocyte receptor in airway responses. Moreover, our findings suggest that lipoxin and related pathways offer novel multi-pronged therapeutic approaches for human asthma.", + "TAG_DATA": [ + "79, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "80, expression {'perturbing_action': 'I-gene gain-of-function'}", + "81, of {'perturbing_action': 'I-gene gain-of-function'}", + "82, human {'perturbing_action': 'I-gene gain-of-function'}", + "83, LXA(4) {'perturbing_action': 'I-gene gain-of-function'}", + "84, receptors {'perturbing_action': 'I-gene gain-of-function'}", + "86, murine {'context': 'B-cells'}", + "87, leukocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "79, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "80, expression ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "81, of ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "82, human ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "83, LXA(4) ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "84, receptors ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "86, murine ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "87, leukocytes ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "of", + "human", + "LXA(4)", + "receptors" + ] + }, + "context": { + "val": "cells", + "words": [ + "murine", + "leukocytes" + ] + } + } + ] + }, + { + "PMID": "12118247", + "TEXT": "Melanin concentrating hormone (MCH) is an orexigenic hypothalamic neuropeptide, which plays an important role in the complex regulation of energy balance and body weight. Here we show that SNAP-7941, a selective, high-affinity MCH1 receptor (MCH1-R) antagonist, inhibited food intake stimulated by central administration of MCH, reduced consumption of palatable food, and, after chronic administration to rats with diet-induced obesity, resulted in a marked, sustained decrease in body weight. In addition, after mapping the binding sites for [(3)H]SNAP-7941 in rat brain, we evaluated its effects in a series of behavioral models. SNAP-7941 produced effects similar to clinically used antidepressants and anxiolytics in three animal models of depression/anxiety: the rat forced-swim test, rat social interaction and guinea pig maternal-separation vocalization tests. Given these observations, an MCH1-R antagonist may be useful not only in the management of obesity but also as a treatment for depression and/or anxiety.", + "TAG_DATA": [ + "28, SNAP-7941, {'perturbing_action': 'B-pharmacological inhibition'}", + "29, a {'perturbing_action': 'I-pharmacological inhibition'}", + "30, selective, {'perturbing_action': 'I-pharmacological inhibition'}", + "31, high-affinity {'perturbing_action': 'I-pharmacological inhibition'}", + "32, MCH1 {'perturbing_action': 'I-pharmacological inhibition'}", + "33, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "34, (MCH1-R) {'perturbing_action': 'I-pharmacological inhibition'}", + "35, antagonist, {'perturbing_action': 'I-pharmacological inhibition'}", + "55, rats {'context': 'B-organism'}", + "107, rat {'context': 'B-organism'}", + "110, rat {'context': 'B-organism'}", + "114, guinea {'context': 'B-organism'}", + "115, pig {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "28, SNAP-7941, ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "29, a ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "30, selective, ['l1', 'l7', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "31, high-affinity ['l2', 'l8', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "32, MCH1 ['l3', 'l9', 'l15', 'l20', 'l25', 'l26', 'l27', 'l28']", + "33, receptor ['l4', 'l10', 'l16', 'l21', 'l25', 'l29', 'l30', 'l31']", + "34, (MCH1-R) ['l5', 'l11', 'l17', 'l22', 'l26', 'l29', 'l32', 'l33']", + "35, antagonist, ['l6', 'l12', 'l18', 'l23', 'l27', 'l30', 'l32']", + "55, rats ['l13', 'l19', 'l24', 'l28', 'l31', 'l33']", + "107, rat ['l34']", + "110, rat ['l34']", + "114, guinea ['l35']", + "115, pig ['l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "a", + "selective,", + "high-affinity", + "MCH1", + "receptor", + "(MCH1-R)" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + } + ] + }, + { + "PMID": "12091880", + "TEXT": "The mechanism by which angiogenic factors recruit bone marrow (BM)-derived quiescent endothelial and hematopoietic stem cells (HSCs) is not known. Here, we report that functional vascular endothelial growth factor receptor-1 (VEGFR1) is expressed on human CD34(+) and mouse Lin(-)Sca-1(+)c-Kit(+) BM-repopulating stem cells, conveying signals for recruitment of HSCs and reconstitution of hematopoiesis. Inhibition of VEGFR1, but not VEGFR2, blocked HSC cell cycling, differentiation and hematopoietic recovery after BM suppression, resulting in the demise of the treated mice. Placental growth factor (PlGF), which signals through VEGFR1, restored early and late phases of hematopoiesis following BM suppression. PlGF enhanced early phases of BM recovery directly through rapid chemotaxis of VEGFR1(+) BM-repopulating and progenitor cells. The late phase of hematopoietic recovery was driven by PlGF-induced upregulation of matrix metalloproteinase-9, mediating the release of soluble Kit ligand. Thus, PlGF promotes recruitment of VEGFR1(+) HSCs from a quiescent to a proliferative BM microenvironment, favoring differentiation, mobilization and reconstitution of hematopoiesis.", + "TAG_DATA": [ + "52, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "53, of {'perturbing_action': 'I-pharmacological inhibition'}", + "54, VEGFR1, {'perturbing_action': 'I-pharmacological inhibition'}", + "58, blocked {'effect': 'B-negative'}", + "59, HSC {'context': 'B-transformed cells'}", + "62, differentiation {'phenotype': 'B-differentiation'}", + "76, mice. {'context': 'B-organism'}", + "105, chemotaxis {'phenotype': 'B-migration'}", + "107, VEGFR1(+) {'context': 'B-cells'}", + "108, BM-repopulating {'context': 'I-cells'}", + "109, and {'context': 'I-cells'}", + "110, progenitor {'context': 'I-cells'}", + "111, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "52, Inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "53, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "54, VEGFR1, ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "58, blocked ['l2', 'l7', 'l11', 'l15', 'l16']", + "59, HSC ['l3', 'l8', 'l12', 'l15', 'l17']", + "62, differentiation ['l4', 'l9', 'l13', 'l16', 'l17']", + "76, mice. ['l5', 'l10', 'l14']", + "105, chemotaxis ['l18', 'l19', 'l20', 'l21', 'l22']", + "107, VEGFR1(+) ['l18', 'l23', 'l24', 'l25', 'l26']", + "108, BM-repopulating ['l19', 'l23', 'l27', 'l28', 'l29']", + "109, and ['l20', 'l24', 'l27', 'l30', 'l31']", + "110, progenitor ['l21', 'l25', 'l28', 'l30', 'l32']", + "111, cells. ['l22', 'l26', 'l29', 'l31', 'l32']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "VEGFR1," + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "VEGFR1," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "VEGFR1," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "VEGFR1," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + }, + "context": { + "val": "cells", + "words": [ + "VEGFR1(+)", + "BM-repopulating", + "and", + "progenitor", + "cells." + ] + } + } + ] + }, + { + "PMID": "12091879", + "TEXT": "Asthma is an increasingly common disease that remains poorly understood and difficult to manage. This disease is characterized by airway hyperreactivity (AHR, defined by exaggerated airflow obstruction in response to bronchoconstrictors), mucus overproduction and chronic eosinophilic inflammation. AHR and mucus overproduction are consistently linked to asthma symptoms and morbidity. Asthma is mediated by Th2 lymphocytes, which produce a limited repertoire of cytokines, including interleukin-4 (IL-4), IL-5, IL-9 and IL-13. Although each of these cytokines has been implicated in asthma, IL-13 is now thought to be especially critical. In animal models of allergic asthma, blockade of IL-13 markedly inhibits allergen-induced AHR, mucus production and eosinophilia. Furthermore, IL-13 delivery to the airway causes all of these effects. IL-13 is thus both necessary and sufficient for experimental models of asthma. However, the IL-13-responsive cells causing these effects have not been identified. Here we show that mice lacking signal transducer and activator of transcription 6 (STAT6) were protected from all pulmonary effects of IL-13. Reconstitution of STAT6 only in epithelial cells was sufficient for IL-13-induced AHR and mucus production in the absence of inflammation, fibrosis or other lung pathology. These results demonstrate the importance of direct effects of IL-13 on epithelial cells in causing two central features of asthma.", + "TAG_DATA": [ + "142, mice {'context': 'B-organism'}", + "143, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "144, signal {'perturbing_action': 'I-gene loss-of-function'}", + "145, transducer {'perturbing_action': 'I-gene loss-of-function'}", + "146, and {'perturbing_action': 'I-gene loss-of-function'}", + "147, activator {'perturbing_action': 'I-gene loss-of-function'}", + "148, of {'perturbing_action': 'I-gene loss-of-function'}", + "149, transcription {'perturbing_action': 'I-gene loss-of-function'}", + "150, 6 {'perturbing_action': 'I-gene loss-of-function'}", + "151, (STAT6) {'perturbing_action': 'I-gene loss-of-function'}", + "160, Reconstitution {'perturbing_action': 'B-gene gain-of-function'}", + "161, of {'perturbing_action': 'I-gene loss-of-function'}", + "162, STAT6 {'perturbing_action': 'I-gene loss-of-function'}", + "165, epithelial {'context': 'B-cells'}", + "166, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "142, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "143, lacking ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "144, signal ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "145, transducer ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "146, and ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "147, activator ['l4', 'l12', 'l19', 'l25', 'l30', 'l36', 'l37', 'l38', 'l39']", + "148, of ['l5', 'l13', 'l20', 'l26', 'l31', 'l36', 'l40', 'l41', 'l42']", + "149, transcription ['l6', 'l14', 'l21', 'l27', 'l32', 'l37', 'l40', 'l43', 'l44']", + "150, 6 ['l7', 'l15', 'l22', 'l28', 'l33', 'l38', 'l41', 'l43', 'l45']", + "151, (STAT6) ['l8', 'l16', 'l23', 'l29', 'l34', 'l39', 'l42', 'l44', 'l45']", + "160, Reconstitution ['l46', 'l47', 'l48', 'l49']", + "161, of ['l46', 'l50', 'l51', 'l52']", + "162, STAT6 ['l47', 'l50', 'l53', 'l54']", + "165, epithelial ['l48', 'l51', 'l53', 'l55']", + "166, cells ['l35', 'l49', 'l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "signal", + "transducer", + "and", + "activator", + "of", + "transcription", + "6", + "(STAT6)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "and", + "of", + "STAT6" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "epithelial" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reconstitution" + ] + }, + "context": { + "val": "cells", + "words": [ + "epithelial", + "cells" + ] + } + } + ] + }, + { + "PMID": "12091878", + "TEXT": "The Lyme disease vaccine is based on the outer-surface lipoprotein (OspA) of the pathogen Borrelia burgdorferi, and 95% of vaccine recipients develop substantial titers of antibodies against OspA. Here, we identified seven individuals with very low antibody titers after vaccination (low responders). The macrophages of low responders produced less tumor necrosis factor-alpha and interleukin-6 after OspA stimulation and had lower cell-surface expression of Toll-like receptor (TLR) 1 as compared to normal cells, but normal expression of TLR2. TLRs activate innate responses to pathogens, and TLR2 recognizes lipoproteins and peptidoglycan (PGN). After OspA immunization, mice genetically deficient in either TLR2 (TLR2(-/-)) or TLR1 (TLR1(-/-)) produced low titers of antibodies against OspA. Notably, macrophages from TLR2(-/-) mice were unresponsive to OspA and PGN, whereas those from TLR1(-/-) mice responded normally to PGN but not to OspA. These data indicate that TLR1 and TLR2 are required for lipoprotein recognition and that defects in the TLR1/2 signaling pathway may account for human hyporesponsiveness to OspA vaccination.", + "TAG_DATA": [ + "43, macrophages {'context': 'B-cells'}", + "93, mice {'context': 'B-organism'}", + "95, deficient {'perturbing_action': 'I-gene loss-of-function'}", + "96, in {'perturbing_action': 'I-gene loss-of-function'}", + "97, either {'perturbing_action': 'I-gene loss-of-function'}", + "98, TLR2 {'perturbing_action': 'I-gene loss-of-function'}", + "99, (TLR2(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "100, or {'perturbing_action': 'I-gene loss-of-function'}", + "101, TLR1 {'perturbing_action': 'I-gene loss-of-function'}", + "102, (TLR1(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "111, macrophages {'context': 'B-cells'}", + "113, TLR2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "114, mice {'context': 'B-organism'}", + "124, TLR1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "125, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "93, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "95, deficient ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "96, in ['l1', 'l8', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "97, either ['l2', 'l9', 'l18', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "98, TLR2 ['l3', 'l10', 'l19', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "99, (TLR2(-/-)) ['l4', 'l11', 'l20', 'l27', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "100, or ['l5', 'l12', 'l21', 'l28', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47', 'l48']", + "101, TLR1 ['l6', 'l13', 'l22', 'l29', 'l35', 'l40', 'l44', 'l49', 'l50', 'l51', 'l52']", + "102, (TLR1(-/-)) ['l7', 'l14', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l53', 'l54', 'l55']", + "111, macrophages ['l15', 'l24', 'l31', 'l37', 'l42', 'l46', 'l50', 'l53', 'l56', 'l57', 'l58']", + "113, TLR2(-/-) ['l16', 'l47', 'l51', 'l54', 'l56', 'l59', 'l60', 'l61']", + "114, mice ['l17', 'l25', 'l32', 'l38', 'l43', 'l48', 'l52', 'l55', 'l57', 'l59']", + "124, TLR1(-/-) ['l60', 'l62']", + "125, mice ['l58', 'l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "either", + "TLR2", + "(TLR2(-/-))", + "or", + "TLR1", + "(TLR1(-/-))", + "TLR2(-/-)", + "TLR1(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "either", + "TLR2", + "(TLR2(-/-))", + "or", + "TLR1", + "(TLR1(-/-))", + "TLR2(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages" + ] + } + } + ] + }, + { + "PMID": "12091877", + "TEXT": "The therapeutic potential of placental growth factor (PlGF) and its receptor Flt1 in angiogenesis is poorly understood. Here, we report that PlGF stimulated angiogenesis and collateral growth in ischemic heart and limb with at least a comparable efficiency to vascular endothelial growth factor (VEGF). An antibody against Flt1 suppressed neovascularization in tumors and ischemic retina, and angiogenesis and inflammatory joint destruction in autoimmune arthritis. Anti-Flt1 also reduced atherosclerotic plaque growth and vulnerability, but the atheroprotective effect was not attributable to reduced plaque neovascularization. Inhibition of VEGF receptor Flk1 did not affect arthritis or atherosclerosis, indicating that inhibition of Flk1-driven angiogenesis alone was not sufficient to halt disease progression. The anti-inflammatory effects of anti-Flt1 were attributable to reduced mobilization of bone marrow-derived myeloid progenitors into the peripheral blood; impaired infiltration of Flt1-expressing leukocytes in inflamed tissues; and defective activation of myeloid cells. Thus, PlGF and Flt1 constitute potential candidates for therapeutic modulation of angiogenesis and inflammation.", + "TAG_DATA": [ + "29, heart {'context': 'I-tissue/organ'}", + "31, limb {'context': 'I-tissue/organ'}", + "45, antibody {'perturbing_action': 'B-rnai/knockdown'}", + "46, against {'perturbing_action': 'I-rnai/knockdown'}", + "47, Flt1 {'perturbing_action': 'I-rnai/knockdown'}", + "51, tumors {'context': 'B-neoplasm'}", + "53, ischemic {'context': 'B-tissue/organ'}", + "54, retina, {'context': 'I-tissue/organ'}", + "83, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "84, of {'perturbing_action': 'I-pharmacological inhibition'}", + "85, VEGF {'perturbing_action': 'I-pharmacological inhibition'}", + "86, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "87, Flk1 {'perturbing_action': 'I-pharmacological inhibition'}", + "89, not {'effect': 'I-no effect'}", + "90, affect {'effect': 'I-no effect'}", + "119, bone {'context': 'B-cells'}", + "120, marrow-derived {'context': 'I-cells'}", + "121, myeloid {'context': 'I-cells'}", + "122, progenitors {'context': 'I-cells'}", + "131, leukocytes {'context': 'I-cells'}", + "139, myeloid {'context': 'B-cells'}", + "140, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "29, heart ['l0', 'l1', 'l2', 'l3']", + "31, limb ['l0', 'l4', 'l5', 'l6']", + "45, antibody ['l7', 'l8', 'l9', 'l10', 'l11']", + "46, against ['l7', 'l12', 'l13', 'l14', 'l15']", + "47, Flt1 ['l8', 'l12', 'l16', 'l17', 'l18']", + "51, tumors ['l1', 'l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "53, ischemic ['l2', 'l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "54, retina, ['l3', 'l6', 'l11', 'l15', 'l18', 'l20', 'l21']", + "83, Inhibition ['l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "84, of ['l22', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "85, VEGF ['l23', 'l35', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "86, receptor ['l24', 'l36', 'l46', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "87, Flk1 ['l25', 'l37', 'l47', 'l56', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "89, not ['l26', 'l38', 'l48', 'l57', 'l64', 'l71']", + "90, affect ['l27', 'l39', 'l49', 'l58', 'l65', 'l71']", + "119, bone ['l28', 'l40', 'l50', 'l59', 'l66', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "120, marrow-derived ['l29', 'l41', 'l51', 'l60', 'l67', 'l72', 'l78', 'l79', 'l80', 'l81', 'l82']", + "121, myeloid ['l30', 'l42', 'l52', 'l61', 'l68', 'l73', 'l78', 'l83', 'l84', 'l85', 'l86']", + "122, progenitors ['l31', 'l43', 'l53', 'l62', 'l69', 'l74', 'l79', 'l83', 'l87', 'l88', 'l89']", + "131, leukocytes ['l32', 'l44', 'l54', 'l63', 'l70', 'l75', 'l80', 'l84', 'l87', 'l90', 'l91']", + "139, myeloid ['l33', 'l76', 'l81', 'l85', 'l88', 'l90', 'l92']", + "140, cells. ['l34', 'l45', 'l55', 'l77', 'l82', 'l86', 'l89', 'l91', 'l92']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antibody", + "against", + "Flt1" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antibody", + "against", + "Flt1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "ischemic", + "retina," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "VEGF", + "receptor", + "Flk1" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "affect" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "VEGF", + "receptor", + "Flk1" + ] + }, + "context": { + "val": "cells", + "words": [ + "bone", + "marrow-derived", + "myeloid", + "progenitors", + "leukocytes", + "cells." + ] + } + } + ] + }, + { + "PMID": "12068290", + "TEXT": "Secretion of gastric inhibitory polypeptide (GIP), a duodenal hormone, is primarily induced by absorption of ingested fat. Here we describe a novel pathway of obesity promotion via GIP. Wild-type mice fed a high-fat diet exhibited both hypersecretion of GIP and extreme visceral and subcutaneous fat deposition with insulin resistance. In contrast, mice lacking the GIP receptor (Gipr(-/-)) fed a high-fat diet were clearly protected from both the obesity and the insulin resistance. Moreover, double-homozygous mice (Gipr(-/-), Lep(ob)/Lep(ob)) generated by crossbreeding Gipr(-/-) and obese ob/ob (Lep(ob)/Lep(ob)) mice gained less weight and had lower adiposity than Lep(ob)/Lep(ob) mice. The Gipr(-/-) mice had a lower respiratory quotient and used fat as the preferred energy substrate, and were thus resistant to obesity. Therefore, GIP directly links overnutrition to obesity and it is a potential target for anti-obesity drugs.", + "TAG_DATA": [ + "29, mice {'context': 'B-organism'}", + "51, mice {'context': 'B-organism'}", + "52, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "53, the {'perturbing_action': 'I-gene loss-of-function'}", + "54, GIP {'perturbing_action': 'I-gene loss-of-function'}", + "55, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "56, (Gipr(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "73, double-homozygous {'perturbing_action': 'B-gene loss-of-function'}", + "74, mice {'context': 'B-organism'}", + "75, (Gipr(-/-), {'perturbing_action': 'I-gene loss-of-function'}", + "76, Lep(ob)/Lep(ob)) {'perturbing_action': 'I-gene loss-of-function'}", + "80, Gipr(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "82, obese {'perturbing_action': 'B-other'}", + "83, ob/ob {'perturbing_action': 'B-other'}", + "84, (Lep(ob)/Lep(ob)) {'perturbing_action': 'I-gene loss-of-function'}", + "85, mice {'context': 'B-organism'}", + "94, Lep(ob)/Lep(ob) {'perturbing_action': 'B-gene loss-of-function'}", + "95, mice. {'context': 'B-organism'}", + "97, Gipr(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "98, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "51, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "52, lacking ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "53, the ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "54, GIP ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "55, receptor ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "56, (Gipr(-/-)) ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "73, double-homozygous ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "74, mice ['l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "75, (Gipr(-/-), ['l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "76, Lep(ob)/Lep(ob)) ['l5', 'l10', 'l14', 'l17', 'l19', 'l20', 'l23', 'l32', 'l40']", + "80, Gipr(-/-) ['l24', 'l33', 'l41', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "82, obese ['l25', 'l34', 'l42', 'l48', 'l54', 'l55', 'l56', 'l57', 'l58']", + "83, ob/ob ['l26', 'l35', 'l43', 'l49', 'l54', 'l59', 'l60', 'l61', 'l62']", + "84, (Lep(ob)/Lep(ob)) ['l27', 'l36', 'l44', 'l50', 'l55', 'l59', 'l63', 'l64', 'l65']", + "85, mice ['l28', 'l37', 'l45', 'l51', 'l56', 'l60', 'l63', 'l66', 'l67']", + "94, Lep(ob)/Lep(ob) ['l29', 'l38', 'l46', 'l52', 'l57', 'l61', 'l64', 'l66', 'l68']", + "95, mice. ['l30', 'l39', 'l47', 'l53', 'l58', 'l62', 'l65', 'l67', 'l68']", + "97, Gipr(-/-) ['l69']", + "98, mice ['l69']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "GIP", + "receptor", + "(Gipr(-/-))", + "Lep(ob)/Lep(ob))", + "double-homozygous", + "(Gipr(-/-),", + "Gipr(-/-)", + "(Lep(ob)/Lep(ob))", + "Lep(ob)/Lep(ob)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "obese", + "ob/ob" + ] + } + } + ] + }, + { + "PMID": "12042811", + "TEXT": "The mechanism by which dopaminergic neurons are selectively lost in Parkinson disease (PD) is unknown. Here we show that accumulation of alpha-synuclein in cultured human dopaminergic neurons results in apoptosis that requires endogenous dopamine production and is mediated by reactive oxygen species. In contrast, alpha-synuclein is not toxic in non-dopaminergic human cortical neurons, but rather exhibits neuroprotective activity. Dopamine-dependent neurotoxicity is mediated by 54 83-kD soluble protein complexes that contain alpha-synuclein and 14-3-3 protein, which are elevated selectively in the substantia nigra in PD. Thus, accumulation of soluble alpha-synuclein protein complexes can render endogenous dopamine toxic, suggesting a potential mechanism for the selectivity of neuronal loss in PD.", + "TAG_DATA": [ + "23, cultured {'context': 'B-cells'}", + "24, human {'context': 'I-cells'}", + "25, dopaminergic {'context': 'I-cells'}", + "26, neurons {'context': 'I-cells'}", + "27, results {'effect': 'B-positive'}", + "28, in {'effect': 'I-positive'}", + "29, apoptosis {'phenotype': 'B-apoptosis'}", + "49, non-dopaminergic {'context': 'B-cells'}", + "50, human {'context': 'I-cells'}", + "51, cortical {'context': 'I-cells'}", + "52, neurons, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "23, cultured ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "24, human ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "25, dopaminergic ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "26, neurons ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "27, results ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "28, in ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "29, apoptosis ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "49, non-dopaminergic ['l28', 'l29', 'l30']", + "50, human ['l28', 'l31', 'l32']", + "51, cortical ['l29', 'l31', 'l33']", + "52, neurons, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cultured", + "human", + "dopaminergic", + "neurons", + "neurons," + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "human", + "dopaminergic", + "neurons", + "neurons," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "12042809", + "TEXT": "CD1d-restricted T cells are implicated as key players in host defense against various microbial infections. However, the mechanisms involved and the role they play, if any, at the mucosal surfaces where pathogenic infections are initiated is unknown. In a murine pneumonia model established by intranasal application of Pseudomonas aeruginosa, CD1d(-/-) mice showed markedly reduced pulmonary eradication of P. aeruginosa compared with wild-type mice; this was associated with significantly lower amounts of macrophage inflammatory protein-2 and reduced numbers of neutrophils within the bronchoalveolar lavage fluid. Corollarily, treatment of mice with alpha-galactosylceramide--a lipid that activates CD1d-restricted T cells--increased the amount of interferon-gamma; this was associated with rapid pulmonary clearance through enhanced phagocytosis of P. aeruginosa by alveolar macrophages. These results reveal a crucial role played by CD1d-restricted T cells in regulating the antimicrobial immune functions of macrophages at the lung mucosal surface.", + "TAG_DATA": [ + "39, murine {'context': 'B-organism'}", + "40, pneumonia {'context': 'I-organism'}", + "41, model {'context': 'I-organism'}", + "49, CD1d(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "50, mice {'context': 'B-organism'}", + "62, mice; {'context': 'B-organism'}", + "87, mice {'context': 'B-organism'}", + "93, CD1d-restricted {'context': 'B-cells'}", + "94, T {'context': 'I-cells'}", + "95, cells--increased {'context': 'I-cells'}", + "108, enhanced {'effect': 'B-positive'}", + "114, alveolar {'context': 'B-cells'}", + "115, macrophages. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "39, murine ['l0', 'l1', 'l2', 'l3']", + "40, pneumonia ['l0', 'l4', 'l5']", + "41, model ['l1', 'l4', 'l6', 'l7']", + "49, CD1d(-/-) ['l2', 'l5', 'l6', 'l8', 'l9']", + "50, mice ['l3', 'l7', 'l8', 'l10']", + "62, mice; ['l9', 'l10']", + "87, mice ['l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "93, CD1d-restricted ['l11', 'l17', 'l18', 'l19', 'l20', 'l21']", + "94, T ['l12', 'l17', 'l22', 'l23', 'l24', 'l25']", + "95, cells--increased ['l13', 'l18', 'l22', 'l26', 'l27', 'l28']", + "108, enhanced ['l14', 'l19', 'l23', 'l26', 'l29', 'l30']", + "114, alveolar ['l15', 'l20', 'l24', 'l27', 'l29', 'l31']", + "115, macrophages. ['l16', 'l21', 'l25', 'l28', 'l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "murine", + "pneumonia", + "model", + "mice", + "mice;" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD1d(-/-)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD1d-restricted", + "T", + "cells--increased", + "alveolar", + "macrophages." + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + } + ] + }, + { + "PMID": "12042808", + "TEXT": "Accumulating evidence suggests that innate immunity interacts with the adaptive immune system to identify potentially harmful antigens and eliminate them from the host. A central facet of innate immunity is complement, which for some time has been recognized as a contributor to inflammation in transplant rejection but without detailed analysis of its role in what is principally a T cell mediated process. Moreover, epithelial and vascular tissues at local sites of inflammation secrete complement components; however, the role of such local synthesis remains unclear. Here we show that the absence of locally synthesized complement component C3 is capable of modulating the rejection of renal allografts in vivo and regulating T-cell responses in vivo and in vitro. The results indicate that improved success in kidney transplantation could come from therapeutic manipulation of innate immunity in concert with T cell directed immunosuppression.", + "TAG_DATA": [ + "89, absence {'perturbing_action': 'B-gene loss-of-function'}", + "90, of {'perturbing_action': 'I-gene loss-of-function'}", + "95, C3 {'perturbing_action': 'I-gene loss-of-function'}", + "103, renal {'context': 'B-xenograft'}", + "104, allografts {'context': 'I-xenograft'}", + "105, in {'context': 'B-in vivo'}", + "106, vivo {'context': 'I-in vivo'}", + "109, T-cell {'context': 'B-cells'}", + "111, in {'context': 'B-in vivo'}", + "112, vivo {'context': 'I-in vivo'}", + "114, in {'context': 'B-in vitro'}", + "115, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "89, absence ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "90, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "95, C3 ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "103, renal ['l2', 'l12', 'l21', 'l30', 'l31', 'l32']", + "104, allografts ['l3', 'l13', 'l22', 'l30', 'l33', 'l34']", + "105, in ['l4', 'l14', 'l23', 'l31', 'l33', 'l35']", + "106, vivo ['l5', 'l15', 'l24', 'l32', 'l34', 'l35']", + "109, T-cell ['l6', 'l16', 'l25', 'l36', 'l37', 'l38', 'l39']", + "111, in ['l7', 'l17', 'l26', 'l36', 'l40', 'l41', 'l42']", + "112, vivo ['l8', 'l18', 'l27', 'l37', 'l40', 'l43']", + "114, in ['l9', 'l19', 'l28', 'l38', 'l41', 'l44']", + "115, vitro. ['l10', 'l20', 'l29', 'l39', 'l42', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "C3" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "renal", + "allografts" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "C3" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "C3" + ] + }, + "context": { + "val": "cells", + "words": [ + "T-cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "C3" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "11984591", + "TEXT": "Corticosteroids have been shown to exert beneficial effects in the treatment of acute myocardial infarction, but the precise mechanisms underlying their protective effects are unknown. Here we show that high-dose corticosteroids exert cardiovascular protection through a novel mechanism involving the rapid, non-transcriptional activation of endothelial nitric oxide synthase (eNOS). Binding of corticosteroids to the glucocorticoid receptor (GR) stimulated phosphatidylinositol 3-kinase and protein kinase Akt, leading to eNOS activation and nitric oxide dependent vasorelaxation. Acute administration of pharmacological concentrations of corticosteroids in mice led to decreased vascular inflammation and reduced myocardial infarct size following ischemia and reperfusion injury. These beneficial effects of corticosteroids were abolished by GR antagonists or eNOS inhibitors in wild-type mice and were completely absent in eNOS-deficient (Nos3(-/-)) mice. The rapid activation of eNOS by the non-nuclear actions of GR, therefore, represents an important cardiovascular protective effect of acute high-dose corticosteroid therapy.", + "TAG_DATA": [ + "81, mice {'context': 'B-organism'}", + "105, GR {'perturbing_action': 'B-pharmacological inhibition'}", + "106, antagonists {'perturbing_action': 'I-pharmacological inhibition'}", + "108, eNOS {'perturbing_action': 'B-pharmacological inhibition'}", + "109, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "112, mice {'context': 'B-organism'}", + "118, eNOS-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "119, (Nos3(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "120, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "105, GR ['l0', 'l1', 'l2', 'l3']", + "106, antagonists ['l0', 'l4', 'l5', 'l6']", + "108, eNOS ['l1', 'l4', 'l7', 'l8', 'l9', 'l10', 'l11']", + "109, inhibitors ['l2', 'l5', 'l7', 'l12', 'l13', 'l14']", + "112, mice ['l3', 'l6', 'l8', 'l12']", + "118, eNOS-deficient ['l9', 'l15', 'l16']", + "119, (Nos3(-/-)) ['l10', 'l13', 'l15', 'l17']", + "120, mice. ['l11', 'l14', 'l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "GR", + "antagonists", + "eNOS", + "inhibitors" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "eNOS-deficient", + "(Nos3(-/-))" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "11927941", + "TEXT": "CD39, the endothelial ecto-nucleoside triphosphate diphosphohydrolase (NTPDase), regulates vascular inflammation and thrombosis by hydrolyzing ATP and ADP. Although ecto-NTPDase activities have been used as a marker of epidermal dendritic cells (DCs) known as Langerhans cells, the identity and function of these activities remain unknown. Here we report that Langerhans cells in CD39-/- mice express no detectable ecto-NTPDase activity. Irritant chemicals triggered rapid ATP and ADP release from keratinocytes and caused exacerbated skin inflammation in CD39-/- mice. Paradoxically, T cell-mediated allergic contact hypersensitivity was severely attenuated in CD39-/- mice. As to mechanisms, T cells increased pericellular ATP concentrations upon activation, and CD39-/- DCs showed ATP unresponsiveness (secondary to P2-receptor desensitization) and impaired antigen-presenting capacity. Our results show opposing outcomes of CD39 deficiency in irritant versus allergic contact dermatitis, reflecting its diverse roles in regulating extracellular nucleotide-mediated signaling in inflammatory responses to environmental insults and DC-T cell communication in antigen presentation.", + "TAG_DATA": [ + "48, Langerhans {'context': 'B-cells'}", + "49, cells {'context': 'I-cells'}", + "51, CD39-/- {'perturbing_action': 'B-gene loss-of-function'}", + "52, mice {'context': 'B-organism'}", + "67, keratinocytes {'context': 'B-cells'}", + "71, skin {'context': 'B-tissue/organ'}", + "74, CD39-/- {'perturbing_action': 'B-gene loss-of-function'}", + "75, mice. {'context': 'B-organism'}", + "86, CD39-/- {'perturbing_action': 'B-gene loss-of-function'}", + "87, mice. {'context': 'B-organism'}", + "91, T {'context': 'B-cells'}", + "92, cells {'context': 'B-cells'}", + "100, CD39-/- {'perturbing_action': 'B-gene loss-of-function'}", + "101, DCs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "48, Langerhans ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "49, cells ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "51, CD39-/- ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "52, mice ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "67, keratinocytes ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "71, skin ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "74, CD39-/- ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "75, mice. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "86, CD39-/- ['l28', 'l29', 'l30']", + "87, mice. ['l28', 'l31', 'l32']", + "91, T ['l29', 'l31', 'l33']", + "92, cells ['l30', 'l32', 'l33']", + "100, CD39-/- ['l34']", + "101, DCs ['l34']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Langerhans", + "cells", + "keratinocytes", + "T", + "DCs" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD39-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD39-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD39-/-" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skin" + ] + } + } + ] + }, + { + "PMID": "11875500", + "TEXT": "The tumor suppressor p53 inhibits tumor growth primarily through its ability to induce apoptosis. Mutations in p53 occur in at least 50% of human tumors. We hypothesized that reactivation of mutant p53 in such tumors should trigger massive apoptosis and eliminate the tumor cells. To test this, we screened a library of low-molecular-weight compounds in order to identify compounds that can restore wild-type function to mutant p53. We found one compound capable of inducing apoptosis in human tumor cells through restoration of the transcriptional transactivation function to mutant p53. This molecule, named PRIMA-1, restored sequence-specific DNA binding and the active conformation to mutant p53 proteins in vitro and in living cells. PRIMA-1 rescued both DNA contact and structural p53 mutants. In vivo studies in mice revealed an antitumor effect with no apparent toxicity. This molecule may serve as a lead compound for the development of anticancer drugs targeting mutant p53.", + "TAG_DATA": [ + "73, inducing {'effect': 'B-positive'}", + "74, apoptosis {'phenotype': 'B-apoptosis'}", + "76, human {'context': 'B-transformed cells'}", + "77, tumor {'context': 'I-transformed cells'}", + "78, cells {'context': 'I-transformed cells'}", + "105, in {'context': 'B-in vitro'}", + "106, vitro {'context': 'I-in vitro'}", + "109, living {'context': 'B-cells'}", + "110, cells. {'context': 'I-cells'}", + "120, In {'context': 'B-in vivo'}", + "121, vivo {'context': 'I-in vivo'}", + "124, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, inducing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "74, apoptosis ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "76, human ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "77, tumor ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "78, cells ['l3', 'l9', 'l14', 'l18']", + "105, in ['l4', 'l10', 'l15', 'l19', 'l22', 'l23', 'l24']", + "106, vitro ['l5', 'l11', 'l16', 'l20', 'l22', 'l25', 'l26']", + "109, living ['l23', 'l25', 'l27']", + "110, cells. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "120, In ['l28', 'l29']", + "121, vivo ['l28', 'l30']", + "124, mice ['l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "tumor", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "tumor", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "11875499", + "TEXT": "The importance of Bax for induction of tumor apoptosis through death receptors remains unclear. Here we show that Bax can be essential for death receptor--mediated apoptosis in cancer cells. Bax-deficient human colon carcinoma cells were resistant to death-receptor ligands, whereas Bax-expressing sister clones were sensitive. Bax was dispensable for apical death-receptor signaling events including caspase-8 activation, but crucial for mitochondrial changes and downstream caspase activation. Treatment of colon tumor cells deficient in DNA mismatch repair with the death-receptor ligand apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selected in vitro or in vivo for refractory subclones with Bax frameshift mutations including deletions at a novel site. Chemotherapeutic agents upregulated expression of the Apo2L/TRAIL receptor DR5 and the Bax homolog Bak in Baxminus sign/minus sign cells, and restored Apo2L/TRAIL sensitivity in vitro and in vivo. Thus, Bax mutation in mismatch repair--deficient tumors can cause resistance to death receptor--targeted therapy, but pre-exposure to chemotherapy rescues tumor sensitivity.", + "TAG_DATA": [ + "29, Bax-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "30, human {'context': 'B-transformed cells'}", + "31, colon {'context': 'I-transformed cells'}", + "32, carcinoma {'context': 'I-transformed cells'}", + "33, cells {'context': 'I-transformed cells'}", + "40, Bax-expressing {'context': 'B-cells'}", + "41, sister {'context': 'I-cells'}", + "42, clones {'context': 'I-cells'}", + "67, colon {'context': 'B-transformed cells'}", + "68, tumor {'context': 'I-transformed cells'}", + "69, cells {'context': 'I-transformed cells'}", + "88, in {'context': 'B-in vitro'}", + "89, vitro {'context': 'I-in vitro'}", + "91, in {'context': 'B-in vivo'}", + "92, vivo {'context': 'I-in vivo'}", + "124, cells, {'context': 'B-cells'}", + "129, in {'context': 'B-in vitro'}", + "130, vitro {'context': 'I-in vitro'}", + "132, in {'context': 'B-in vivo'}", + "133, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "29, Bax-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "30, human ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "31, colon ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "32, carcinoma ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "33, cells ['l3', 'l9', 'l14', 'l18', 'l22']", + "40, Bax-expressing ['l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "41, sister ['l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "42, clones ['l24', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "67, colon ['l4', 'l10', 'l15', 'l19', 'l25', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "68, tumor ['l5', 'l11', 'l16', 'l20', 'l26', 'l32', 'l37', 'l41', 'l45', 'l46', 'l47']", + "69, cells ['l6', 'l12', 'l17', 'l21', 'l22', 'l27', 'l33', 'l38', 'l42', 'l45', 'l48', 'l49']", + "88, in ['l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l50']", + "89, vitro ['l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l50']", + "91, in ['l51']", + "92, vivo ['l51']", + "124, cells, ['l52', 'l53', 'l54', 'l55']", + "129, in ['l52', 'l56', 'l57', 'l58']", + "130, vitro ['l53', 'l56', 'l59', 'l60']", + "132, in ['l54', 'l57', 'l59', 'l61']", + "133, vivo. ['l55', 'l58', 'l60', 'l61']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bax-deficient" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "colon", + "carcinoma", + "cells", + "tumor" + ] + } + } + ] + }, + { + "PMID": "11875498", + "TEXT": "The concept of stem-cell plasticity received strong support from a recent observation that extensively passaged, clonally derived neural stem cells could contribute to hematopoiesis. We investigated whether hematopoietic potential was a consistent or unusual feature of neural stem cells, and whether it depended on the extent of in vitro passaging before transplantation. Here we transplanted over 128 x 10(6) neurosphere cells into 128 host animals; however, we never observed contribution to hematopoiesis, irrespective of the number of passages and despite the use of an assay that could detect the contribution of a single blood stem cell to hematopoietic repopulation. Although extensively cultured neurosphere cells continued to generate neural progeny, marked changes in their growth properties occurred, including changes in growth-factor dependence, cell-cycle kinetics, cell adhesion and gene expression. Our results exclude hematopoietic competence as a consistent property of intravenously infused neural stem cells. However, the consistent changes that occurred during extended passaging are compatible with genetic or epigenetic alterations and suggest that rare transformation events may account for the neural-to-blood fate switch originally reported.", + "TAG_DATA": [ + "59, neurosphere {'context': 'B-cells'}", + "60, cells {'context': 'I-cells'}", + "64, animals; {'context': 'B-organism'}", + "102, neurosphere {'context': 'B-cells'}", + "103, cells {'context': 'I-cells'}", + "123, cell {'context': 'B-cells'}", + "124, adhesion {'phenotype': 'B-adhesion'}" + ], + "LINK_DATA": [ + "59, neurosphere ['l0', 'l1']", + "60, cells ['l0', 'l2']", + "64, animals; ['l1', 'l2']", + "102, neurosphere ['l3', 'l4', 'l5']", + "103, cells ['l3']", + "123, cell ['l4', 'l6']", + "124, adhesion ['l5', 'l6']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "neurosphere", + "cell" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + } + ] + }, + { + "PMID": "11875492", + "TEXT": "Treatment with HIV-1 protease inhibitors (PI) is associated with a reduced incidence or regression of Kaposi sarcoma (KS). Here we show that systemic administration of the PIs indinavir or saquinavir to nude mice blocks the development and induces regression of angioproliferative KS-like lesions promoted by primary human KS cells, basic fibroblast growth factor (bFGF), or bFGF and vascular endothelial growth factor (VEGF) combined. These PIs also block bFGF or VEGF-induced angiogenesis in the chorioallantoic membrane assay with a potency similar to paclitaxel (Taxol). These effects are mediated by the inhibition of endothelial- and KS-cell invasion and of matrix metalloproteinase-2 proteolytic activation by PIs at concentrations present in plasma of treated individuals. As PIs also inhibit the in vivo growth and invasion of an angiogenic tumor-cell line, these data indicate that PIs are potent anti-angiogenic and anti-tumor molecules that might be used in treating non-HIV KS and in other HIV-associated tumors.", + "TAG_DATA": [ + "31, nude {'context': 'B-organism'}", + "32, mice {'context': 'I-organism'}", + "37, induces {'effect': 'B-positive'}", + "38, regression {'phenotype': 'B-tumour regression'}", + "45, primary {'context': 'B-transformed cells'}", + "46, human {'context': 'I-transformed cells'}", + "47, KS {'context': 'I-transformed cells'}", + "48, cells, {'context': 'I-transformed cells'}", + "89, inhibition {'effect': 'B-negative'}", + "91, endothelial- {'context': 'B-cells'}", + "92, and {'context': 'I-cells'}", + "93, KS-cell {'context': 'I-cells'}", + "94, invasion {'phenotype': 'B-invasion'}", + "114, inhibit {'effect': 'B-negative'}", + "116, in {'context': 'B-in vivo'}", + "117, vivo {'context': 'I-in vivo'}", + "120, invasion {'phenotype': 'B-invasion'}", + "123, angiogenic {'context': 'B-transformed cells'}", + "124, tumor-cell {'context': 'I-transformed cells'}", + "125, line, {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "31, nude ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "32, mice ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "37, induces ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "38, regression ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "45, primary ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "46, human ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "47, KS ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "48, cells, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "89, inhibition ['l28', 'l29', 'l30', 'l31']", + "91, endothelial- ['l28', 'l32', 'l33', 'l34']", + "92, and ['l29', 'l32', 'l35', 'l36']", + "93, KS-cell ['l30', 'l33', 'l35', 'l37']", + "94, invasion ['l31', 'l34', 'l36', 'l37']", + "114, inhibit ['l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "116, in ['l38', 'l44', 'l45', 'l46', 'l47', 'l48']", + "117, vivo ['l39', 'l44', 'l49', 'l50', 'l51', 'l52']", + "120, invasion ['l40', 'l45', 'l49', 'l53', 'l54', 'l55']", + "123, angiogenic ['l41', 'l46', 'l50', 'l53', 'l56', 'l57']", + "124, tumor-cell ['l42', 'l47', 'l51', 'l54', 'l56', 'l58']", + "125, line, ['l43', 'l48', 'l52', 'l55', 'l57', 'l58']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "nude", + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "nude", + "mice" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "human", + "KS", + "cells," + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "human", + "KS", + "cells," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial-", + "and", + "KS-cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition", + "inhibit" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial-", + "and", + "KS-cell" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "angiogenic", + "tumor-cell", + "line," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "angiogenic", + "tumor-cell", + "line," + ] + } + } + ] + }, + { + "PMID": "11821901", + "TEXT": "CD4+ T cells are crucial to the development of CD8+ T cell responses against hepatocytes infected with malaria parasites. In the absence of CD4+ T cells, CD8+ T cells initiate a seemingly normal differentiation and proliferation during the first few days after immunization. However, this response fails to develop further and is reduced by more than 90%, compared to that observed in the presence of CD4+ T cells. We report here that interleukin-4 (IL-4) secreted by CD4+ T cells is essential to the full development of this CD8+ T cell response. This is the first demonstration that IL-4 is a mediator of CD4/CD8 cross-talk leading to the development of immunity against an infectious pathogen.", + "TAG_DATA": [ + "26, CD8+ {'context': 'B-cells'}", + "27, T {'context': 'I-cells'}", + "28, cells {'context': 'I-cells'}", + "29, initiate {'effect': 'B-positive'}", + "33, differentiation {'phenotype': 'B-differentiation'}", + "35, proliferation {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "26, CD8+ ['l0', 'l1', 'l2', 'l3', 'l4']", + "27, T ['l0', 'l5', 'l6', 'l7', 'l8']", + "28, cells ['l1', 'l5', 'l9', 'l10', 'l11']", + "29, initiate ['l2', 'l6', 'l9', 'l12', 'l13']", + "33, differentiation ['l3', 'l7', 'l10', 'l12', 'l14']", + "35, proliferation ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD8+", + "T", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD8+", + "T", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD8+", + "T", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "11689889", + "TEXT": "Myocardial hypertrophy is an adaptational response of the heart to increased work load, but it is also associated with a high risk of cardiac mortality due to its established role in the development of cardiac failure, one of the leading causes of death in developed countries. Multiple growth factors and various downstream signaling pathways involving, for example, ras, gp-130 (ref. 4), JNK/p38 (refs. 5,6) and calcineurin/NFAT/CaM-kinase have been implicated in the hypertrophic response. However, there is evidence that the initial phase in the development of myocardial hypertrophy involves the formation of cardiac para- and/or autocrine factors like endothelin-1, norepinephrine or angiotensin II (refs. 7,8), the receptors of which are coupled to G-proteins of the Gq/11-, G12/13- and Gi/o-families. Cardiomyocyte-specific transgenic overexpression of alpha1-adrenergic or angiotensin (AT1)-receptors as well as of the Gq alpha-subunit, Galphaq, results in myocardial hypertrophy. These data demonstrate that chronic activation of the Gq/G11-family is sufficient to induce myocardial hypertrophy. In order to test whether Gq/G11 mediate the physiological hypertrophy response to pressure overload, we generated a mouse line lacking both Galphaq and Galpha11 in cardiomyocytes. These mice showed no detectable ventricular hypertrophy in response to pressure-overload induced by aortic constriction. The complete lack of a hypertrophic response proves that the Gq/G11-mediated pathway is essential for cardiac hypertrophy induced by pressure overload and makes this signaling process an interesting target for interventions to prevent myocardial hypertrophy.", + "TAG_DATA": [ + "118, Cardiomyocyte-specific {'perturbing_action': 'B-gene gain-of-function'}", + "119, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "120, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "121, of {'perturbing_action': 'I-gene gain-of-function'}", + "122, alpha1-adrenergic {'perturbing_action': 'I-gene gain-of-function'}", + "123, or {'perturbing_action': 'I-gene gain-of-function'}", + "124, angiotensin {'perturbing_action': 'I-gene gain-of-function'}", + "170, mouse {'context': 'B-organism'}", + "171, line {'context': 'I-organism'}", + "172, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "173, both {'perturbing_action': 'I-gene loss-of-function'}", + "174, Galphaq {'perturbing_action': 'I-gene loss-of-function'}", + "175, and {'perturbing_action': 'I-gene loss-of-function'}", + "176, Galpha11 {'perturbing_action': 'I-gene loss-of-function'}", + "178, cardiomyocytes. {'context': 'B-cells'}", + "180, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "118, Cardiomyocyte-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "119, transgenic ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "120, overexpression ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "121, of ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "122, alpha1-adrenergic ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "123, or ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "124, angiotensin ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "170, mouse ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "171, line ['l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "172, lacking ['l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "173, both ['l23', 'l29', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "174, Galphaq ['l24', 'l30', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "175, and ['l25', 'l31', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "176, Galpha11 ['l26', 'l32', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "178, cardiomyocytes. ['l27', 'l33', 'l38', 'l43', 'l47', 'l50', 'l52']", + "180, mice ['l39', 'l44', 'l48', 'l51', 'l53']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "line", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "both", + "Galphaq", + "and", + "Galpha11" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "both", + "Galphaq", + "and", + "Galpha11" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes." + ] + } + } + ] + }, + { + "PMID": "11689886", + "TEXT": "A highly conserved signaling property of Nef proteins encoded by human or simian immunodeficiency virus is the binding and activation of a PAK kinase whose function is unclear. Here we show that Nef-mediated p21-activated kinase (PAK) activation involves phosphatidylinositol 3-kinase, which acts upstream of PAK and is bound and activated by Nef similar to the manner of Polyoma virus middle T antigen. The Nef-associated phosphatidylinositol-3-PAK complex phosphorylated the pro-apoptotic Bad protein without involving the protein kinase B-Akt kinase, which is generally believed to inactivate Bad by serine phosphorylation. Consequently, Nef, but not a Nef mutant incapable of activating PAK, blocked apoptosis in T cells induced by serum starvation or HIV replication. Nef anti-apoptotic effects are likely a crucial mechanism for viral replication in the host and thus in AIDS pathogenesis.", + "TAG_DATA": [ + "99, blocked {'effect': 'B-negative'}", + "100, apoptosis {'phenotype': 'B-apoptosis'}", + "102, T {'context': 'B-cells'}", + "103, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "99, blocked ['l0', 'l1', 'l2']", + "100, apoptosis ['l0', 'l3', 'l4']", + "102, T ['l1', 'l3', 'l5']", + "103, cells ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + } + ] + }, + { + "PMID": "11689885", + "TEXT": "Cyclic ADP-ribose is believed to be an important calcium-mobilizing second messenger in invertebrate, mammalian and plant cells. CD38, the best-characterized mammalian ADP-ribosyl cyclase, is postulated to be an important source of cyclic ADP-ribose in vivo. Using CD38-deficient mice, we demonstrate that the loss of CD38 renders mice susceptible to bacterial infections due to an inability of CD38-deficient neutrophils to directionally migrate to the site of infection. Furthermore, we show that cyclic ADP-ribose can directly induce intracellular Ca++ release in neutrophils and is required for sustained extracellular Ca++ influx in neutrophils that have been stimulated by the bacterial chemoattractant, formyl-methionyl-leucyl-phenylalanine (fMLP). Finally, we demonstrate that neutrophil chemotaxis to fMLP is dependent on Ca++ mobilization mediated by cyclic ADP-ribose. Thus, CD38 controls neutrophil chemotaxis to bacterial chemoattractants through its production of cyclic ADP-ribose, and acts as a critical regulator of inflammation and innate immune responses.", + "TAG_DATA": [ + "36, CD38-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "37, mice, {'context': 'B-organism'}", + "42, loss {'perturbing_action': 'B-gene loss-of-function'}", + "43, of {'perturbing_action': 'I-gene loss-of-function'}", + "44, CD38 {'perturbing_action': 'I-gene loss-of-function'}", + "46, mice {'context': 'B-organism'}", + "56, CD38-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "57, neutrophils {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "36, CD38-deficient ['l0', 'l1', 'l2']", + "37, mice, ['l0', 'l3']", + "42, loss ['l4', 'l5', 'l6', 'l7', 'l8']", + "43, of ['l4', 'l9', 'l10', 'l11', 'l12']", + "44, CD38 ['l1', 'l5', 'l9', 'l13', 'l14']", + "46, mice ['l2', 'l3', 'l6', 'l10', 'l13', 'l15']", + "56, CD38-deficient ['l7', 'l11', 'l16']", + "57, neutrophils ['l8', 'l12', 'l14', 'l15', 'l16']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD38-deficient", + "loss", + "of", + "CD38" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "CD38", + "CD38-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "neutrophils" + ] + } + } + ] + }, + { + "PMID": "11590433", + "TEXT": "Loss of p53 gene function, which occurs in most colon cancer cells, has been shown to abolish the apoptotic response to 5-fluorouracil (5-FU). To identify genes downstream of p53 that might mediate these effects, we assessed global patterns of gene expression following 5-FU treatment of isogenic cells differing only in their p53 status. The gene encoding mitochondrial ferredoxin reductase (protein, FR; gene, FDXR) was one of the few genes significantly induced by p53 after 5-FU treatment. The FR protein was localized to mitochondria and suppressed the growth of colon cancer cells when over-expressed. Targeted disruption of the FDXR gene in human colon cancer cells showed that it was essential for viability, and partial disruption of the gene resulted in decreased sensitivity to 5-FU-induced apoptosis. These data, coupled with the effects of pharmacologic inhibitors of reactive oxygen species, indicate that FR contributes to p53-mediated apoptosis through the generation of oxidative stress in mitochondria.", + "TAG_DATA": [ + "46, cells {'context': 'B-cells'}", + "88, colon {'context': 'B-transformed cells'}", + "89, cancer {'context': 'I-transformed cells'}", + "90, cells {'context': 'I-transformed cells'}", + "93, Targeted {'perturbing_action': 'B-gene loss-of-function'}", + "94, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "95, of {'perturbing_action': 'I-gene loss-of-function'}", + "96, the {'perturbing_action': 'I-gene loss-of-function'}", + "97, FDXR {'perturbing_action': 'I-gene loss-of-function'}", + "98, gene {'perturbing_action': 'I-gene loss-of-function'}", + "100, human {'context': 'B-transformed cells'}", + "101, colon {'context': 'I-transformed cells'}", + "102, cancer {'context': 'I-transformed cells'}", + "103, cells {'context': 'I-transformed cells'}", + "119, decreased {'effect': 'B-negative'}", + "120, sensitivity {'effect': 'I-negative'}", + "122, 5-FU-induced {'effect': 'B-positive'}", + "123, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "46, cells ['l0', 'l1', 'l2']", + "88, colon ['l0', 'l3', 'l4']", + "89, cancer ['l1', 'l3', 'l5']", + "90, cells ['l2', 'l4', 'l5']", + "93, Targeted ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "94, disruption ['l6', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "95, of ['l7', 'l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "96, the ['l8', 'l16', 'l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "97, FDXR ['l9', 'l17', 'l24', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "98, gene ['l10', 'l18', 'l25', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "100, human ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l45', 'l46', 'l47']", + "101, colon ['l12', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l48', 'l49']", + "102, cancer ['l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l50']", + "103, cells ['l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l49', 'l50']", + "119, decreased ['l51', 'l52', 'l53']", + "120, sensitivity ['l51', 'l54', 'l55']", + "122, 5-FU-induced ['l52', 'l54', 'l56']", + "123, apoptosis. ['l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Targeted", + "disruption", + "of", + "the", + "FDXR", + "gene" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "colon", + "cancer", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased", + "sensitivity" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "5-FU-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "11533705", + "TEXT": "Deletion of amino-acid residues 1505-1507 (KPQ) in the cardiac SCN5A Na(+) channel causes autosomal dominant prolongation of the electrocardiographic QT interval (long-QT syndrome type 3 or LQT3). Excessive prolongation of the action potential at low heart rates predisposes individuals with LQT3 to fatal arrhythmias, typically at rest or during sleep. Here we report that mice heterozygous for a knock-in KPQ-deletion (SCN5A(Delta/+)) show the essential LQT3 features and spontaneously develop life-threatening polymorphous ventricular arrhythmias. Unexpectedly, sudden accelerations in heart rate or premature beats caused lengthening of the action potential with early afterdepolarization and triggered arrhythmias in Scn5a(Delta/+) mice. Adrenergic agonists normalized the response to rate acceleration in vitro and suppressed arrhythmias upon premature stimulation in vivo. These results show the possible risk of sudden heart-rate accelerations. The Scn5a(Delta/+) mouse with its predisposition for pacing-induced arrhythmia might be useful for the development of new treatments for the LQT3 syndrome.", + "TAG_DATA": [ + "54, mice {'context': 'B-organism'}", + "55, heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "56, for {'perturbing_action': 'I-gene loss-of-function'}", + "57, a {'perturbing_action': 'I-gene loss-of-function'}", + "58, knock-in {'perturbing_action': 'B-gene loss-of-function'}", + "59, KPQ-deletion {'perturbing_action': 'I-gene loss-of-function'}", + "60, (SCN5A(Delta/+)) {'perturbing_action': 'I-gene loss-of-function'}", + "95, Scn5a(Delta/+) {'perturbing_action': 'B-other'}", + "96, mice. {'context': 'B-organism'}", + "105, in {'context': 'B-in vitro'}", + "106, vitro {'context': 'I-in vitro'}", + "113, in {'context': 'B-in vivo'}", + "114, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "54, mice ['l0', 'l1']", + "55, heterozygous ['l0', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "56, for ['l2', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "57, a ['l3', 'l9', 'l15', 'l16', 'l17', 'l18', 'l19']", + "58, knock-in ['l4', 'l10', 'l15', 'l20', 'l21', 'l22', 'l23']", + "59, KPQ-deletion ['l5', 'l11', 'l16', 'l20', 'l24', 'l25', 'l26']", + "60, (SCN5A(Delta/+)) ['l1', 'l6', 'l12', 'l17', 'l21', 'l24']", + "95, Scn5a(Delta/+) ['l7', 'l13', 'l18', 'l22', 'l25', 'l27']", + "96, mice. ['l8', 'l14', 'l19', 'l23', 'l26', 'l27']", + "105, in ['l28']", + "106, vitro ['l28']", + "113, in ['l29']", + "114, vivo. ['l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "heterozygous", + "(SCN5A(Delta/+))", + "for", + "a", + "knock-in", + "KPQ-deletion" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Scn5a(Delta/+)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "11433351", + "TEXT": "Increased secretion and levels of ApoB-containing lipoproteins (BLp) commonly occur in familial hyperlipidemia, obesity and diabetes. The plasma phospholipid-transfer protein (PLTP) is known to mediate transfer of phospholipids between BLp and HDL during their intravascular metabolism. To address a possible role of PLTP in dyslipidemia and atherogenesis, we bred mice deficient in the gene encoding PLTP (PLTP-deficient mice) using different hyperlipidemic mouse strains. In ApoB-transgenic and ApoE-deficient backgrounds, PLTP deficiency resulted in reduced production and levels of BLp and markedly decreased atherosclerosis. BLp secretion was diminished in hepatocytes from ApoB-transgenic PLTP-deficient mice, a defect that was corrected when PLTP was reintroduced in adenovirus. The studies reveal a major, unexpected role of PLTP in regulating the secretion of BLp and identify PLTP as a therapeutic target.", + "TAG_DATA": [ + "49, mice {'context': 'B-organism'}", + "50, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "51, in {'perturbing_action': 'I-gene loss-of-function'}", + "52, the {'perturbing_action': 'I-gene loss-of-function'}", + "53, gene {'perturbing_action': 'I-gene loss-of-function'}", + "54, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "55, PLTP {'perturbing_action': 'I-gene loss-of-function'}", + "56, (PLTP-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "57, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "61, mouse {'context': 'B-organism'}", + "62, strains. {'context': 'I-organism'}", + "64, ApoB-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "66, ApoE-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "68, PLTP {'perturbing_action': 'B-gene loss-of-function'}", + "69, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "80, decreased {'effect': 'B-negative'}", + "87, hepatocytes {'context': 'B-cells'}", + "89, ApoB-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "90, PLTP-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "91, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "49, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "50, deficient ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "51, in ['l1', 'l12', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "52, the ['l2', 'l13', 'l27', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "53, gene ['l3', 'l14', 'l28', 'l41', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "54, encoding ['l4', 'l15', 'l29', 'l42', 'l54', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "55, PLTP ['l5', 'l16', 'l30', 'l43', 'l55', 'l66', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "56, (PLTP-deficient ['l6', 'l17', 'l31', 'l44', 'l56', 'l67', 'l77', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "57, mice) ['l7', 'l18', 'l32', 'l45', 'l57', 'l68', 'l78', 'l87', 'l93', 'l94', 'l95', 'l96']", + "61, mouse ['l8', 'l19', 'l33', 'l46', 'l58', 'l69', 'l79', 'l88', 'l93', 'l97']", + "62, strains. ['l9', 'l20', 'l34', 'l47', 'l59', 'l70', 'l80', 'l89', 'l94', 'l97']", + "64, ApoB-transgenic ['l21', 'l35', 'l48', 'l60', 'l71', 'l81', 'l90', 'l98', 'l99', 'l100', 'l101', 'l102']", + "66, ApoE-deficient ['l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l98', 'l103', 'l104', 'l105', 'l106']", + "68, PLTP ['l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l99', 'l103', 'l107', 'l108', 'l109']", + "69, deficiency ['l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l100', 'l104', 'l107', 'l110', 'l111']", + "80, decreased ['l10', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l91', 'l95', 'l101', 'l105', 'l108', 'l110', 'l112']", + "81, atherosclerosis. ['l11', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l92', 'l96', 'l102', 'l106', 'l109', 'l111', 'l112']", + "87, hepatocytes ['l113', 'l114', 'l115']", + "89, ApoB-transgenic ['l113', 'l116', 'l117']", + "90, PLTP-deficient ['l114', 'l116', 'l118']", + "91, mice, ['l115', 'l117', 'l118']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "strains.", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "the", + "gene", + "encoding", + "PLTP", + "(PLTP-deficient", + "mice)", + "PLTP-deficient" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "the", + "gene", + "encoding", + "PLTP", + "(PLTP-deficient", + "mice)", + "ApoE-deficient", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ApoB-transgenic" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hepatocytes" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ApoB-transgenic" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hepatocytes" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PLTP-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ApoB-transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "11433343", + "TEXT": "Mutations in viral genomes that affect T-cell-receptor recognition by CD8+ cytotoxic T lymphocytes have been shown to allow viral evasion from immune surveillance during persistent viral infections. Although CD4+ T-helper cells are crucially involved in the maintenance of effective cytotoxic T-lymphocyte and neutralizing-antibody responses, their role in viral clearance and therefore in imposing similar selective pressures on the virus is unclear. We show here that transgenic virus-specific CD4+ Tcells, transferred into mice persistently infected with lymphocytic choriomeningitis virus, select for T-helper epitope mutant viruses that are not recognized. Together with the observed antigenic variation of the same T-helper epitope during polyclonal CD4+ T-cell responses in infected pore-forming protein-deficient C57BL/6 mice, this finding indicates that viral escape from CD4+ T lymphocytes is a possible mechanism of virus persistence.", + "TAG_DATA": [ + "65, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "66, virus-specific {'context': 'I-cells'}", + "67, CD4+ {'context': 'I-cells'}", + "68, Tcells, {'context': 'I-cells'}", + "71, mice {'context': 'B-organism'}", + "106, pore-forming {'perturbing_action': 'B-gene loss-of-function'}", + "107, protein-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "108, C57BL/6 {'context': 'B-organism'}", + "109, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "65, transgenic ['l0', 'l1', 'l2', 'l3']", + "66, virus-specific ['l0', 'l4', 'l5', 'l6']", + "67, CD4+ ['l1', 'l4', 'l7', 'l8']", + "68, Tcells, ['l2', 'l5', 'l7', 'l9']", + "71, mice ['l3', 'l6', 'l8', 'l9']", + "106, pore-forming ['l10', 'l11', 'l12']", + "107, protein-deficient ['l10', 'l13', 'l14']", + "108, C57BL/6 ['l11', 'l13', 'l15']", + "109, mice, ['l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "virus-specific", + "CD4+", + "Tcells," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pore-forming", + "protein-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "C57BL/6", + "mice," + ] + } + } + ] + }, + { + "PMID": "11385506", + "TEXT": "Heme oxygenase (HO-1, encoded by Hmox1) is an inducible protein activated in systemic inflammatory conditions by oxidant stress. Vascular injury is characterized by a local reparative process with inflammatory components, indicating a potential protective role for HO-1 in arterial wound repair. Here we report that HO-1 directly reduces vasoconstriction and inhibits cell proliferation during vascular injury. Expression of HO-1 in arteries stimulated vascular relaxation, mediated by guanylate cyclase and cGMP, independent of nitric oxide. The unexpected effects of HO-1 on vascular smooth muscle cell growth were mediated by cell-cycle arrest involving p21Cip1. HO-1 reduced the proliferative response to vascular injury in vivo; expression of HO-1 in pig arteries inhibited lesion formation and Hmox1-/- mice produced hyperplastic arteries compared with controls. Induction of the HO-1 pathway moderates the severity of vascular injury by at least two adaptive mechanisms independent of nitric oxide, and is a potential therapeutic target for diseases of the vasculature.", + "TAG_DATA": [ + "50, inhibits {'effect': 'B-negative'}", + "51, cell {'context': 'B-cells'}", + "52, proliferation {'phenotype': 'B-proliferation'}", + "56, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "57, of {'perturbing_action': 'I-gene gain-of-function'}", + "58, HO-1 {'perturbing_action': 'I-gene gain-of-function'}", + "60, arteries {'context': 'B-tissue/organ'}", + "80, vascular {'context': 'B-cells'}", + "81, smooth {'context': 'I-cells'}", + "82, muscle {'context': 'I-cells'}", + "83, cell {'phenotype': 'B-cell growth'}", + "84, growth {'phenotype': 'I-cell growth'}", + "88, cell-cycle {'phenotype': 'B-cell cycle arrest'}", + "89, arrest {'phenotype': 'I-cell cycle arrest'}", + "93, reduced {'effect': 'B-negative'}", + "95, proliferative {'phenotype': 'B-proliferation'}", + "96, response {'phenotype': 'I-proliferation'}", + "100, in {'context': 'B-in vivo'}", + "101, vivo; {'context': 'I-in vivo'}", + "102, expression {'perturbing_action': 'B-gene gain-of-function'}", + "103, of {'perturbing_action': 'I-gene gain-of-function'}", + "104, HO-1 {'perturbing_action': 'I-gene gain-of-function'}", + "106, pig {'context': 'B-tissue/organ'}", + "107, arteries {'context': 'I-tissue/organ'}", + "108, inhibited {'effect': 'B-negative'}", + "112, Hmox1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "113, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, inhibits ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "51, cell ['l0', 'l8', 'l9']", + "52, proliferation ['l1', 'l8', 'l10']", + "56, Expression ['l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "57, of ['l11', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "58, HO-1 ['l12', 'l26', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "60, arteries ['l2', 'l9', 'l10', 'l13', 'l27', 'l40', 'l53', 'l54', 'l55', 'l56', 'l57']", + "80, vascular ['l3', 'l14', 'l28', 'l41', 'l53', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "81, smooth ['l4', 'l15', 'l29', 'l42', 'l54', 'l58', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "82, muscle ['l5', 'l16', 'l30', 'l43', 'l55', 'l59', 'l69', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "83, cell ['l6', 'l17', 'l31', 'l44', 'l56', 'l60', 'l70', 'l79', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "84, growth ['l7', 'l18', 'l32', 'l45', 'l57', 'l61', 'l71', 'l80', 'l88', 'l95', 'l96', 'l97', 'l98', 'l99']", + "88, cell-cycle ['l19', 'l33', 'l46', 'l62', 'l72', 'l81', 'l89', 'l95', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "89, arrest ['l20', 'l34', 'l47', 'l63', 'l73', 'l82', 'l90', 'l96', 'l100', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "93, reduced ['l21', 'l35', 'l48', 'l64', 'l74', 'l83', 'l91', 'l101', 'l108', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "95, proliferative ['l22', 'l36', 'l49', 'l65', 'l75', 'l84', 'l102', 'l109', 'l114', 'l120', 'l121', 'l122', 'l123', 'l124']", + "96, response ['l23', 'l37', 'l50', 'l66', 'l76', 'l85', 'l92', 'l97', 'l103', 'l110', 'l115', 'l120', 'l125', 'l126']", + "100, in ['l24', 'l38', 'l51', 'l67', 'l77', 'l86', 'l93', 'l98', 'l104', 'l111', 'l116', 'l121', 'l125', 'l127']", + "101, vivo; ['l25', 'l39', 'l52', 'l68', 'l78', 'l87', 'l94', 'l99', 'l105', 'l112', 'l117', 'l122', 'l126', 'l127']", + "102, expression ['l128', 'l129', 'l130', 'l131', 'l132']", + "103, of ['l128', 'l133', 'l134', 'l135', 'l136']", + "104, HO-1 ['l129', 'l133', 'l137', 'l138', 'l139']", + "106, pig ['l106', 'l118', 'l123', 'l130', 'l134', 'l137', 'l140', 'l141']", + "107, arteries ['l107', 'l113', 'l119', 'l124', 'l131', 'l135', 'l138', 'l140', 'l142']", + "108, inhibited ['l132', 'l136', 'l139', 'l141', 'l142']", + "112, Hmox1-/- ['l143']", + "113, mice ['l143']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "reduced" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "vascular", + "smooth", + "muscle" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "reduced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation", + "proliferative", + "response" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "reduced", + "inhibited" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "arteries", + "pig" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "reduced" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell", + "vascular", + "smooth", + "muscle" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation", + "proliferative", + "response" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation", + "proliferative" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "arteries", + "pig" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "HO-1", + "expression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "arteries", + "pig" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "HO-1" + ] + }, + "context": { + "val": "cells", + "words": [ + "vascular", + "smooth", + "muscle" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "HO-1" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "HO-1" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "HO-1", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced", + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "HO-1" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "response" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "HO-1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo;" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "arteries" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "vascular", + "smooth", + "muscle" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "vascular", + "smooth", + "muscle" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest" + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo;" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo;" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "pig", + "arteries" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo;" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "response" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo;" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hmox1-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "11385505", + "TEXT": "The beta2 integrin leukocyte function antigen-1 (LFA-1) has an important role in the pathophysiology of inflammatory and autoimmune diseases. Here we report that statin compounds commonly used for the treatment of hypercholesterolemia selectively blocked LFA-1-mediated adhesion and costimulation of lymphocytes. This effect was unrelated to the statins' inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A reductase; instead it occurred via binding to a novel allosteric site within LFA-1. Subsequent optimization of the statins for LFA-1 binding resulted in potent, selective and orally active LFA-1 inhibitors that suppress the inflammatory response in a murine model of peritonitis. Targeting of the statin-binding site of LFA-1 could be used to treat diseases such as psoriasis, rheumatoid arthritis, ischemia/reperfusion injury and transplant rejection.", + "TAG_DATA": [ + "33, blocked {'effect': 'B-negative'}", + "35, adhesion {'phenotype': 'B-adhesion'}", + "39, lymphocytes. {'context': 'B-cells'}", + "79, LFA-1 {'perturbing_action': 'B-pharmacological inhibition'}", + "80, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "88, murine {'context': 'B-organism'}", + "89, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "33, blocked ['l0', 'l1']", + "35, adhesion ['l0', 'l2']", + "39, lymphocytes. ['l1', 'l2']", + "79, LFA-1 ['l3', 'l4', 'l5']", + "80, inhibitors ['l3', 'l6', 'l7']", + "88, murine ['l4', 'l6', 'l8']", + "89, model ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "context": { + "val": "cells", + "words": [ + "lymphocytes." + ] + } + }, + { + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + }, + "context": { + "val": "cells", + "words": [ + "lymphocytes." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "LFA-1", + "inhibitors" + ] + }, + "context": { + "val": "organism", + "words": [ + "murine", + "model" + ] + } + } + ] + }, + { + "PMID": "11329058", + "TEXT": "Angiogenesis has an essential role in many important pathological and physiological settings. It has been shown that vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), a potent cytokine expressed by most malignant tumors, has critical roles in vasculogenesis and both physiological and pathological angiogenesis. We report here that at non-toxic levels, the neurotransmitter dopamine strongly and selectively inhibited the vascular permeabilizing and angiogenic activities of VPF/VEGF. Dopamine acted through D2 dopamine receptors to induce endocytosis of VEGF receptor 2, which is critical for promoting angiogenesis, thereby preventing VPF/VEGF binding, receptor phosphorylation and subsequent signaling steps. The action of dopamine was specific for VPF/VEGF and did not affect other mediators of microvascular permeability or endothelial-cell proliferation or migration. These results reveal a new link between the nervous system and angiogenesis and indicate that dopamine and other D2 receptors, already in clinical use for other purposes, might have value in anti-angiogenesis therapy.", + "TAG_DATA": [ + "104, not {'effect': 'I-no effect'}", + "105, affect {'effect': 'I-no effect'}", + "112, endothelial-cell {'context': 'B-cells'}", + "113, proliferation {'phenotype': 'B-proliferation'}", + "115, migration. {'phenotype': 'B-migration'}" + ], + "LINK_DATA": [ + "104, not ['l0', 'l1', 'l2', 'l3']", + "105, affect ['l0', 'l4', 'l5', 'l6']", + "112, endothelial-cell ['l1', 'l4', 'l7', 'l8']", + "113, proliferation ['l2', 'l5', 'l7', 'l9']", + "115, migration. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "no effect", + "words": [ + "not", + "affect" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial-cell" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "affect" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "affect" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial-cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial-cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + } + ] + }, + { + "PMID": "11283676", + "TEXT": "Neuronal ceroid lipofuscinoses (NCLs) are the most common hereditary neurodegenerative diseases of childhood. The infantile form, INCL, is caused by lysosomal palmitoyl-protein thioesterase (PPT) deficiency, which impairs the cleavage of thioester linkages in palmitoylated proteins, preventing their hydrolysis by lysosomal proteinases. Consequent accumulation of these lipid-modified proteins (constituents of ceroid) in lysosomes leads to INCL. Because thioester linkages are susceptible to nucleophilic attack, drugs with this property may have therapeutic potential for INCL. We report here that two such drugs, phosphocysteamine and N-acetylcysteine, disrupt thioester linkages in a model thioester compound, [14C]palmitoyl approximately CoA. Most importantly, in lymphoblasts derived from INCL patients, phosphocysteamine, a known lysosomotrophic drug, mediates the depletion of lysosomal ceroids, prevents their re-accumulation and inhibits apoptosis. Our results define a novel pharmacological approach to lysosomal ceroid depletion and raise the possibility that nucleophilic drugs such as phosphocysteamine hold therapeutic potential for INCL.", + "TAG_DATA": [ + "97, lymphoblasts {'context': 'B-cells'}", + "117, inhibits {'effect': 'B-negative'}", + "118, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "97, lymphoblasts ['l0']", + "117, inhibits ['l0', 'l1']", + "118, apoptosis. ['l1']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "lymphoblasts" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "11283671", + "TEXT": "The transcription factor CCAAT/enhancer binding protein alpha, or C/EBPalpha, encoded by the CEBPA gene, is crucial for the differentiation of granulocytes. Conditional expression of C/EBPalpha triggers neutrophilic differentiation, and Cebpa knockout mice exhibit an early block in maturation. Dominant-negative mutations of CEBPA have been found in some patients with acute myeloid leukemia (AML), but not in AML with the t(8;21) translocation which gives rise to the fusion gene RUNX1-CBF2T1 (also known as AML1-ETO) encoding the AML1-ETO fusion protein. RUNX1-CBF2T1 positive-AML blasts had eight-fold lower CEBPA RNA levels and undetectable C/EBPalpha protein levels compared with other subgroups of AML patients. Conditional expression of RUNX1-CBF2T1 in U937 cells downregulated CEBPA mRNA, protein and DNA binding activity. AML1-ETO appears to suppress C/EBPalpha expression indirectly by inhibiting positive autoregulation of the CEBPA promoter. Conditional expression of C/EBPalpha in AML1-ETO-positive Kasumi-1 cells results in neutrophilic differentiation. We suggest that restoring C/EBPalpha expression will have therapeutic implications in RUNX1-CBF2T1-positive leukemias.", + "TAG_DATA": [ + "29, Cebpa {'perturbing_action': 'B-gene loss-of-function'}", + "30, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "31, mice {'context': 'B-organism'}", + "99, Conditional {'perturbing_action': 'B-gene gain-of-function'}", + "100, expression {'perturbing_action': 'I-gene gain-of-function'}", + "101, of {'perturbing_action': 'I-gene gain-of-function'}", + "102, RUNX1-CBF2T1 {'perturbing_action': 'I-gene gain-of-function'}", + "104, U937 {'context': 'B-cells'}", + "105, cells {'context': 'I-cells'}", + "129, Conditional {'perturbing_action': 'B-gene gain-of-function'}", + "130, expression {'perturbing_action': 'I-gene gain-of-function'}", + "131, of {'perturbing_action': 'I-gene gain-of-function'}", + "132, C/EBPalpha {'perturbing_action': 'I-gene gain-of-function'}", + "134, AML1-ETO-positive {'perturbing_action': 'B-other'}", + "135, Kasumi-1 {'context': 'I-cells'}", + "136, cells {'context': 'I-cells'}", + "137, results {'effect': 'B-positive'}", + "138, in {'effect': 'I-positive'}", + "140, differentiation. {'phenotype': 'I-differentiation'}" + ], + "LINK_DATA": [ + "29, Cebpa ['l0', 'l1']", + "30, knockout ['l0', 'l2']", + "31, mice ['l1', 'l2']", + "99, Conditional ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "100, expression ['l3', 'l9', 'l10', 'l11', 'l12']", + "101, of ['l4', 'l9', 'l13', 'l14', 'l15']", + "102, RUNX1-CBF2T1 ['l5', 'l10', 'l13', 'l16', 'l17']", + "104, U937 ['l6', 'l11', 'l14', 'l16', 'l18']", + "105, cells ['l7', 'l12', 'l15', 'l17', 'l18']", + "129, Conditional ['l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "130, expression ['l19', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "131, of ['l20', 'l28', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "132, C/EBPalpha ['l21', 'l29', 'l36', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "134, AML1-ETO-positive ['l22', 'l30', 'l37', 'l43', 'l49', 'l50', 'l51', 'l52', 'l53']", + "135, Kasumi-1 ['l23', 'l31', 'l38', 'l44', 'l49', 'l54', 'l55', 'l56', 'l57']", + "136, cells ['l8', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l58', 'l59', 'l60']", + "137, results ['l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l58', 'l61', 'l62']", + "138, in ['l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l61', 'l63']", + "140, differentiation. ['l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l62', 'l63']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cebpa", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Conditional", + "expression", + "of", + "RUNX1-CBF2T1", + "C/EBPalpha" + ] + }, + "context": { + "val": "cells", + "words": [ + "U937", + "cells", + "Kasumi-1" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Conditional", + "expression", + "of", + "C/EBPalpha" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Conditional", + "expression", + "of", + "C/EBPalpha" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "AML1-ETO-positive" + ] + }, + "context": { + "val": "cells", + "words": [ + "Kasumi-1", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "AML1-ETO-positive" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "AML1-ETO-positive" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Kasumi-1", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Kasumi-1", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + } + ] + }, + { + "PMID": "11283669", + "TEXT": "Left ventricular remodeling is a major cause of progressive heart failure and death after myocardial infarction. Although neoangiogenesis within the infarcted tissue is an integral component of the remodeling process, the capillary network is unable to support the greater demands of the hypertrophied myocardium, resulting in progressive loss of viable tissue, infarct extension and fibrous replacement. Here we show that bone marrow from adult humans contains endothelial precursors with phenotypic and functional characteristics of embryonic hemangioblasts, and that these can be used to directly induce new blood vessel formation in the infarct-bed (vasculogenesis) and proliferation of preexisting vasculature (angiogenesis) after experimental myocardial infarction. The neoangiogenesis resulted in decreased apoptosis of hypertrophied myocytes in the peri-infarct region, long-term salvage and survival of viable myocardium, reduction in collagen deposition and sustained improvement in cardiac function. The use of cytokine-mobilized autologous human bone-marrow-derived angioblasts for revascularization of infarcted myocardium (alone or in conjunction with currently used therapies) has the potential to significantly reduce morbidity and mortality associated with left ventricular remodeling.", + "TAG_DATA": [ + "107, decreased {'effect': 'B-negative'}", + "108, apoptosis {'phenotype': 'B-apoptosis'}", + "110, hypertrophied {'context': 'B-cells'}", + "111, myocytes {'context': 'I-cells'}", + "122, myocardium, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "107, decreased ['l0', 'l1', 'l2', 'l3']", + "108, apoptosis ['l0', 'l4', 'l5', 'l6']", + "110, hypertrophied ['l1', 'l4', 'l7', 'l8']", + "111, myocytes ['l2', 'l5', 'l7', 'l9']", + "122, myocardium, ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "context": { + "val": "cells", + "words": [ + "hypertrophied", + "myocytes" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "myocardium," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "hypertrophied", + "myocytes" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "myocardium," + ] + } + } + ] + }, + { + "PMID": "11231630", + "TEXT": "Oxygen-regulated protein 150 kD (ORP150) is a novel endoplasmic-reticulum-associated chaperone induced by hypoxia/ischemia. Although ORP150 was sparingly upregulated in neurons from human brain undergoing ischemic stress, there was robust induction in astrocytes. Cultured neurons overexpressing ORP150 were resistant to hypoxemic stress, whereas astrocytes with inhibited ORP150 expression were more vulnerable. Mice with targeted neuronal overexpression of ORP150 had smaller strokes compared with controls. Neurons with increased ORP150 demonstrated suppressed caspase-3-like activity and enhanced brain-derived neurotrophic factor (BDNF) under hypoxia signaling. These data indicate that ORP150 is an integral participant in ischemic cytoprotective pathways.", + "TAG_DATA": [ + "32, Cultured {'context': 'B-cells'}", + "33, neurons {'context': 'I-cells'}", + "34, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "35, ORP150 {'perturbing_action': 'I-gene gain-of-function'}", + "42, astrocytes {'context': 'B-cells'}", + "44, inhibited {'perturbing_action': 'B-pharmacological inhibition'}", + "45, ORP150 {'perturbing_action': 'I-rnai/knockdown'}", + "46, expression {'perturbing_action': 'I-rnai/knockdown'}", + "50, Mice {'context': 'B-organism'}", + "52, targeted {'perturbing_action': 'B-gene gain-of-function'}", + "53, neuronal {'perturbing_action': 'I-gene gain-of-function'}", + "54, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "55, of {'perturbing_action': 'I-gene gain-of-function'}", + "56, ORP150 {'perturbing_action': 'I-gene gain-of-function'}", + "63, Neurons {'context': 'B-cells'}", + "65, increased {'perturbing_action': 'B-gene gain-of-function'}" + ], + "LINK_DATA": [ + "32, Cultured ['l0', 'l1', 'l2', 'l3']", + "33, neurons ['l0', 'l4', 'l5', 'l6']", + "34, overexpressing ['l1', 'l4', 'l7', 'l8', 'l9']", + "35, ORP150 ['l2', 'l5', 'l7', 'l10', 'l11']", + "42, astrocytes ['l3', 'l6', 'l8', 'l10', 'l12', 'l13', 'l14']", + "44, inhibited ['l12', 'l15', 'l16', 'l17', 'l18']", + "45, ORP150 ['l13', 'l15', 'l19', 'l20', 'l21']", + "46, expression ['l9', 'l11', 'l14', 'l16', 'l19']", + "50, Mice ['l22', 'l23', 'l24', 'l25', 'l26']", + "52, targeted ['l22', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "53, neuronal ['l23', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "54, overexpression ['l24', 'l28', 'l33', 'l38', 'l39']", + "55, of ['l17', 'l20', 'l25', 'l29', 'l34', 'l38', 'l40']", + "56, ORP150 ['l18', 'l21', 'l26', 'l30', 'l35', 'l39', 'l40']", + "63, Neurons ['l31', 'l36', 'l41']", + "65, increased ['l32', 'l37', 'l41']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Cultured", + "neurons", + "astrocytes", + "Neurons" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "ORP150", + "targeted", + "neuronal", + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "astrocytes" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "astrocytes" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "ORP150", + "expression" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "targeted", + "neuronal", + "overexpression", + "of", + "ORP150" + ] + } + } + ] + }, + { + "PMID": "11175849", + "TEXT": "Metastasis to local lymph nodes via the lymphatic vessels is a common step in the spread of solid tumors. To investigate the molecular mechanisms underlying the spread of cancer by the lymphatics, we examined the ability of vascular endothelial growth factor (VEGF)-D, a ligand for the lymphatic growth factor receptor VEGFR-3/Flt-4, to induce formation of lymphatics in a mouse tumor model. Staining with markers specific for lymphatic endothelium demonstrated that VEGF-D induced the formation of lymphatics within tumors. Moreover, expression of VEGF-D in tumor cells led to spread of the tumor to lymph nodes, whereas expression of VEGF, an angiogenic growth factor which activates VEGFR-2 but not VEGFR-3, did not. VEGF-D also promoted tumor angiogenesis and growth. Lymphatic spread induced by VEGF-D could be blocked with an antibody specific for VEGF-D. This study demonstrates that lymphatics can be established in solid tumors and implicates VEGF family members in determining the route of metastatic spread.", + "TAG_DATA": [ + "58, mouse {'context': 'B-neoplasm'}", + "59, tumor {'context': 'I-neoplasm'}", + "60, model. {'context': 'I-neoplasm'}", + "77, tumors. {'context': 'B-neoplasm'}", + "79, expression {'perturbing_action': 'B-gene gain-of-function'}", + "80, of {'perturbing_action': 'I-gene gain-of-function'}", + "81, VEGF-D {'perturbing_action': 'I-gene gain-of-function'}", + "83, tumor {'context': 'B-transformed cells'}", + "84, cells {'context': 'I-transformed cells'}", + "90, tumor {'context': 'B-neoplasm'}", + "95, expression {'perturbing_action': 'B-gene gain-of-function'}", + "96, of {'perturbing_action': 'I-gene gain-of-function'}", + "97, VEGF, {'perturbing_action': 'I-gene gain-of-function'}", + "113, tumor {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "58, mouse ['l0', 'l1', 'l2']", + "59, tumor ['l0', 'l3', 'l4']", + "60, model. ['l1', 'l3', 'l5']", + "77, tumors. ['l2', 'l4', 'l5']", + "79, expression ['l6', 'l7', 'l8', 'l9', 'l10']", + "80, of ['l6', 'l11', 'l12', 'l13', 'l14']", + "81, VEGF-D ['l7', 'l11', 'l15', 'l16', 'l17']", + "83, tumor ['l8', 'l12', 'l15', 'l18', 'l19']", + "84, cells ['l9', 'l13', 'l16', 'l18', 'l20']", + "90, tumor ['l10', 'l14', 'l17', 'l19', 'l20']", + "95, expression ['l21', 'l22', 'l23']", + "96, of ['l21', 'l24', 'l25']", + "97, VEGF, ['l22', 'l24', 'l26']", + "113, tumor ['l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "VEGF-D" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "VEGF-D", + "VEGF," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + } + ] + }, + { + "PMID": "11135625", + "TEXT": "Interleukin (IL)-2 and IL-15 are redundant in stimulating T-cell proliferation in vitro. Their precise role in vivo in governing T-cell expansion and T-cell homeostasis is less clear. Each may have distinct functions and regulate distinct aspects of T-cell activation. The functional receptors for IL-2 and IL-15 consist of a private alpha-chain, which defines the binding specificity for IL-2 or IL-15, and shared IL-2 receptor beta- and gamma-chains. The gamma-chain is also a critical signaling component of IL-4, IL-7 and IL-9 receptors. Thus, the gamma-chain is called the common gamma or gamma-c. As these receptor subunits can be expressed individually or in various combinations resulting in the formation of receptors with different affinities, distinct signaling capabilities or both, we hypothesized that differential expression of IL-2 and IL-15 receptor subunits on cycling T cells in vivo may direct activated T cells to respond to IL-2 or IL-15, thereby regulating the homeostasis of T-cell response in vivo. By observing in vivo T-cell divisions and expression of IL-2 and IL-15 receptor subunits, we demonstrate that IL-15 is a critical growth factor in initiating T cell divisions in vivo, whereas IL-2 limits continued T-cell expansion via downregulation of the gamma-c expression. Decreased gamma-c expression on cycling T cells reduced sustained Bcl-2 expression and rendered cells susceptible to apoptotic cell death. Our study provides data that IL-2 and IL-15 regulate distinct aspects of primary T-cell expansion in vivo.", + "TAG_DATA": [ + "156, in {'context': 'B-in vivo'}", + "157, vivo {'context': 'I-in vivo'}", + "182, in {'context': 'B-in vivo'}", + "183, vivo, {'context': 'I-in vivo'}", + "188, T-cell {'context': 'B-cells'}", + "200, cycling {'context': 'B-cells'}", + "201, T {'context': 'I-cells'}", + "202, cells {'context': 'I-cells'}", + "209, cells {'context': 'B-cells'}", + "210, susceptible {'effect': 'B-negative'}", + "212, apoptotic {'phenotype': 'B-apoptosis'}", + "213, cell {'phenotype': 'I-apoptosis'}", + "214, death. {'phenotype': 'I-apoptosis'}" + ], + "LINK_DATA": [ + "156, in ['l0']", + "157, vivo ['l0']", + "182, in ['l1']", + "183, vivo, ['l1']", + "188, T-cell ['l2']", + "200, cycling ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "201, T ['l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "202, cells ['l2', 'l4', 'l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "209, cells ['l5', 'l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "210, susceptible ['l6', 'l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "212, apoptotic ['l7', 'l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "213, cell ['l8', 'l14', 'l19', 'l23', 'l26', 'l28', 'l30']", + "214, death. ['l9', 'l15', 'l20', 'l24', 'l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cycling", + "T", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "susceptible" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cycling", + "T", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "susceptible" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "11135622", + "TEXT": "Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various tumor cells in vitro, but its physiological role in tumor surveillance remains unknown. Here, we report that TRAIL is constitutively expressed on murine natural killer (NK) cells in the liver and plays a substantial role in suppressing tumor metastasis. Freshly isolated NK cells, but not natural killer T cells or ordinary T cells, from the liver expressed cell surface TRAIL, which was responsible for spontaneous cytotoxicity against TRAIL-sensitive tumor cells in vitro along with perforin and Fas ligand (FasL). Administration of neutralizing monoclonal antibody against TRAIL significantly increased experimental liver metastases of several TRAIL-sensitive tumor cell lines. Such an anti-metastatic effect of TRAIL was not observed in NK cell-depleted mice or interferon-gamma-deficient mice, the latter of which lacked TRAIL on liver NK cells. These findings provide the first evidence for the physiological function of TRAIL as a tumor suppressor.", + "TAG_DATA": [ + "51, NK {'context': 'B-cells'}", + "52, cells, {'context': 'I-cells'}", + "78, tumor {'context': 'I-transformed cells'}", + "79, cells {'context': 'I-transformed cells'}", + "80, in {'context': 'B-in vitro'}", + "81, vitro {'context': 'I-in vitro'}", + "97, increased {'effect': 'B-positive'}", + "99, liver {'phenotype': 'B-metastasis'}", + "100, metastases {'phenotype': 'I-metastasis'}", + "103, TRAIL-sensitive {'context': 'B-transformed cells'}", + "104, tumor {'context': 'I-transformed cells'}", + "105, cell {'context': 'I-transformed cells'}", + "106, lines. {'context': 'I-transformed cells'}", + "119, mice {'context': 'B-organism'}", + "121, interferon-gamma-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "122, mice, {'context': 'B-organism'}", + "130, liver {'context': 'B-cells'}", + "131, NK {'context': 'I-cells'}", + "132, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "51, NK ['l0', 'l1', 'l2', 'l3', 'l4']", + "52, cells, ['l0', 'l5', 'l6', 'l7', 'l8']", + "78, tumor ['l1', 'l5', 'l9', 'l10', 'l11']", + "79, cells ['l2', 'l6', 'l9', 'l12', 'l13']", + "80, in ['l3', 'l7', 'l10', 'l12', 'l14']", + "81, vitro ['l4', 'l8', 'l11', 'l13', 'l14']", + "97, increased ['l15', 'l16', 'l17', 'l18', 'l19']", + "99, liver ['l15', 'l20', 'l21', 'l22', 'l23', 'l24']", + "100, metastases ['l16', 'l20', 'l25', 'l26', 'l27', 'l28']", + "103, TRAIL-sensitive ['l21', 'l25', 'l29', 'l30', 'l31']", + "104, tumor ['l17', 'l22', 'l26', 'l29', 'l32', 'l33']", + "105, cell ['l18', 'l23', 'l27', 'l30', 'l32', 'l34']", + "106, lines. ['l19', 'l24', 'l28', 'l31', 'l33', 'l34']", + "119, mice ['l35', 'l36', 'l37', 'l38', 'l39']", + "121, interferon-gamma-deficient ['l35', 'l40', 'l41', 'l42', 'l43']", + "122, mice, ['l36', 'l40', 'l44', 'l45', 'l46']", + "130, liver ['l37', 'l41', 'l44', 'l47', 'l48']", + "131, NK ['l38', 'l42', 'l45', 'l47', 'l49']", + "132, cells. ['l39', 'l43', 'l46', 'l48', 'l49']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "liver", + "metastases" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell", + "lines." + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "liver", + "metastases" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TRAIL-sensitive", + "tumor", + "cell", + "lines." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interferon-gamma-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interferon-gamma-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "liver", + "NK", + "cells." + ] + } + } + ] + }, + { + "PMID": "11135607", + "TEXT": "Studies on mice lacking the peroxisome proliferator-activated receptor (PPAR) suggest that PPAR ligands reduce lipid accumulation in foamy macrophages, and may target other receptors. These findings warrant an in-depth investigation into the gene regulatory mechanisms of PPAR ligands, which are currently being developed as drugs to treat atherosclerosis and diabetes.", + "TAG_DATA": [ + "2, mice {'context': 'B-organism'}", + "3, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "4, the {'perturbing_action': 'I-gene loss-of-function'}", + "5, peroxisome {'perturbing_action': 'I-gene loss-of-function'}", + "6, proliferator-activated {'perturbing_action': 'I-gene loss-of-function'}", + "7, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "8, (PPAR) {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "2, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "3, lacking ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "4, the ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "5, peroxisome ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "6, proliferator-activated ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "7, receptor ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "8, (PPAR) ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "peroxisome", + "proliferator-activated", + "receptor", + "(PPAR)" + ] + } + } + ] + }, + { + "PMID": "11100125", + "TEXT": "Progress toward elucidating the function of alpha1B-adrenergic receptors (alpha1BARs) in the central nervous system has been constrained by a lack of agonists and antagonists with adequate alpha1B-specificity. We have obviated this constraint by generating transgenic mice engineered to overexpress either wild-type or constitutively active alpha1BARs in tissues that normally express the receptor, including the brain. All transgenic lines showed granulovacular neurodegeneration, beginning in alpha1B-expressing domains of the brain and progressing with age to encompass all areas. The degeneration was apoptotic and did not occur in non-transgenic mice. Correspondingly, transgenic mice showed an age-progressive hindlimb disorder that was parkinsonian-like, as demonstrated by rescue of the dysfunction by 3, 4-dihydroxyphenylalanine and considerable dopaminergic-neuronal degeneration in the substantia nigra. Transgenic mice also had a grand mal seizure disorder accompanied by a corresponding dysplasia and neurodegeneration of the cerebral cortex. Both behavioral phenotypes (locomotor impairment and seizure) could be partially rescued with the alpha1AR antagonist terazosin, indicating that alpha1AR signaling participated directly in the pathology. Our results indicate that overstimulation of alpha1BAR leads to apoptotic neurodegeneration with a corresponding multiple system atrophy indicative of Shy-Drager syndrome, a disease whose etiology is unknown.", + "TAG_DATA": [ + "35, mice {'context': 'I-organism'}", + "86, mice. {'context': 'I-organism'}", + "89, mice {'context': 'B-organism'}", + "114, substantia {'context': 'B-tissue/organ'}", + "115, nigra. {'context': 'I-cells'}", + "116, Transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "117, mice {'context': 'I-organism'}", + "134, cerebral {'context': 'B-tissue/organ'}", + "135, cortex. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "35, mice ['l0']", + "86, mice. ['l0']", + "89, mice ['l1', 'l2']", + "114, substantia ['l1', 'l3']", + "115, nigra. ['l2', 'l3']", + "116, Transgenic ['l4', 'l5', 'l6']", + "117, mice ['l4', 'l7', 'l8']", + "134, cerebral ['l5', 'l7', 'l9']", + "135, cortex. ['l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgenic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "cerebral", + "cortex." + ] + } + } + ] + }, + { + "PMID": "11100120", + "TEXT": "Activation of the zinc-finger transcription factor early growth response (Egr)-1, initially linked to developmental processes, is shown here to function as a master switch activated by ischemia to trigger expression of pivotal regulators of inflammation, coagulation and vascular hyperpermeability. Chemokine, adhesion receptor, procoagulant and permeability-related genes are coordinately upregulated by rapid ischemia-mediated activation of Egr-1. Deletion of the gene encoding Egr-1 strikingly diminished expression of these mediators of vascular injury in a murine model of lung ischemia/reperfusion, and enhanced animal survival and organ function. Rapid activation of Egr-1 in response to oxygen deprivation primes the vasculature for dysfunction manifest during reperfusion. These studies define a central and unifying role for Egr-1 activation in the pathogenesis of ischemic tissue damage.", + "TAG_DATA": [ + "55, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "56, of {'perturbing_action': 'I-gene loss-of-function'}", + "57, the {'perturbing_action': 'I-gene loss-of-function'}", + "58, gene {'perturbing_action': 'I-gene loss-of-function'}", + "59, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "60, Egr-1 {'perturbing_action': 'I-gene loss-of-function'}", + "72, murine {'context': 'B-organism'}", + "73, model {'context': 'I-organism'}", + "75, lung {'context': 'I-tissue/organ'}", + "95, vasculature {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "55, Deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "56, of ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "57, the ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "58, gene ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "59, encoding ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "60, Egr-1 ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "72, murine ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "73, model ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "75, lung ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "gene", + "encoding", + "Egr-1" + ] + }, + "context": { + "val": "organism", + "words": [ + "murine", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "gene", + "encoding", + "Egr-1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + } + ] + }, + { + "PMID": "11062542", + "TEXT": "Hematopoietic stem cells give rise to progeny that either self-renew in an undifferentiated state or lose self-renewal capabilities and commit to lymphoid or myeloid lineages. Here we evaluated whether hematopoietic stem cell self-renewal is affected by the Notch pathway. Notch signaling controls cell fate choices in both invertebrates and vertebrates by inhibiting certain differentiation pathways, thereby permitting cells to either differentiate along an alternative pathway or to self-renew. Notch receptors are present in hematopoietic precursors and Notch signaling enhances the in vitro generation of human and mouse hematopoietic precursors, determines T- or B-cell lineage specification from a common lymphoid precursor and promotes expansion of CD8(+) cells. Here, we demonstrate that constitutive Notch1 signaling in hematopoietic cells established immortalized, cytokine-dependent cell lines that generated progeny with either lymphoid or myeloid characteristics both in vitro and in vivo. These data support a role for Notch signaling in regulating hematopoietic stem cell self-renewal. Furthermore, the establishment of clonal, pluripotent cell lines provides the opportunity to assess mechanisms regulating stem cell commitment and demonstrates a general method for immortalizing stem cell populations for further analysis.", + "TAG_DATA": [ + "104, CD8(+) {'context': 'B-cells'}", + "110, constitutive {'perturbing_action': 'B-gene gain-of-function'}", + "111, Notch1 {'perturbing_action': 'I-gene gain-of-function'}", + "112, signaling {'perturbing_action': 'I-gene gain-of-function'}", + "114, hematopoietic {'context': 'B-cells'}", + "115, cells {'context': 'I-cells'}", + "119, cell {'context': 'B-cells'}", + "120, lines {'context': 'I-cells'}", + "131, in {'context': 'B-in vitro'}", + "132, vitro {'context': 'I-in vitro'}", + "134, in {'context': 'B-in vivo'}", + "135, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "104, CD8(+) ['l0', 'l1', 'l2', 'l3']", + "110, constitutive ['l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "111, Notch1 ['l0', 'l4', 'l10', 'l11', 'l12', 'l13', 'l14']", + "112, signaling ['l1', 'l5', 'l10', 'l15', 'l16', 'l17', 'l18']", + "114, hematopoietic ['l2', 'l6', 'l11', 'l15', 'l19', 'l20', 'l21']", + "115, cells ['l3', 'l7', 'l12', 'l16', 'l19', 'l22', 'l23']", + "119, cell ['l8', 'l13', 'l17', 'l20', 'l22', 'l24', 'l25']", + "120, lines ['l9', 'l14', 'l18', 'l21', 'l23', 'l24']", + "131, in ['l26', 'l27', 'l28']", + "132, vitro ['l25', 'l26', 'l29', 'l30']", + "134, in ['l27', 'l29', 'l31']", + "135, vivo. ['l28', 'l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "hematopoietic", + "cells", + "cell", + "lines" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Notch1", + "signaling", + "constitutive" + ] + } + } + ] + }, + { + "PMID": "11062535", + "TEXT": "Dysregulation of apoptosis contributes to the pathogenesis of many human diseases. As effectors of the apoptotic machinery, caspases are considered potential therapeutic targets. Using an established in vivo model of Fas-mediated apoptosis, we demonstrate here that elimination of certain caspases was compensated in vivo by the activation of other caspases. Hepatocyte apoptosis and mouse death induced by the Fas agonistic antibody Jo2 required proapoptotic Bcl-2 family member Bid and used a Bid-mediated mitochondrial pathway of caspase activation; deficiency in caspases essential for this pathway, caspase-9 or caspase-3, unexpectedly resulted in rapid activation of alternate caspases after injection of Jo2, and therefore failed to protect mice against Jo2 toxicity. Moreover, both ultraviolet and gamma irradiation, two established inducers of the mitochondrial caspase-activation pathway, also elicited compensatory activation of caspases in cultured caspase-3(-/-) hepatocytes, indicating that the compensatory caspase activation was mediated through the mitochondria. Our findings provide direct experimental evidence for compensatory pathways of caspase activation. This issue should therefore be considered in developing caspase inhibitors for therapeutic applications.", + "TAG_DATA": [ + "42, in {'context': 'B-in vivo'}", + "43, vivo {'context': 'I-in vivo'}", + "50, Hepatocyte {'context': 'B-cells'}", + "51, apoptosis {'phenotype': 'B-apoptosis'}", + "53, mouse {'context': 'B-organism', 'phenotype': 'B-cell death'}", + "54, death {'phenotype': 'I-cell death'}", + "55, induced {'effect': 'B-positive'}", + "104, mice {'context': 'B-organism'}", + "130, caspase-3(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "131, hepatocytes, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "42, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "43, vivo ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "50, Hepatocyte ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "51, apoptosis ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "53, mouse ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "54, death ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "55, induced ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "130, caspase-3(-/-) ['l21']", + "131, hepatocytes, ['l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "mouse", + "death" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "mouse" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Hepatocyte" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Hepatocyte" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "mouse", + "death" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Hepatocyte" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "mouse", + "death" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "caspase-3(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes," + ] + } + } + ] + }, + { + "PMID": "11062534", + "TEXT": "Sustained blood cell production requires preservation of a quiescent, multipotential stem cell pool that intermittently gives rise to progenitors with robust proliferative potential. The ability of cells to shift from a highly constrained to a vigorously active proliferative state is critical for maintaining stem cells while providing the responsiveness necessary for host defense. The cyclin-dependent kinase inhibitor (CDKI), p21(cip1/waf1) (p21) dominates stem cell kinetics. Here we report that another CDKI, p27(kip1) (p27), does not affect stem cell number, cell cycling, or self-renewal, but markedly alters progenitor proliferation and pool size. Therefore, distinct CDKIs govern the highly divergent stem and progenitor cell populations. When competitively transplanted, p27-deficient stem cells generate progenitors that eventually dominate blood cell production. Modulating p27 expression in a small number of stem cells may translate into effects on the majority of mature cells, thereby providing a strategy for potentiating the impact of transduced cells in stem cell gene therapy.", + "TAG_DATA": [ + "73, not {'effect': 'I-no effect'}", + "75, stem {'context': 'B-cells'}", + "76, cell {'context': 'I-cells'}", + "81, self-renewal, {'phenotype': 'B-self-renewal'}", + "84, alters {'effect': 'B-regulates'}", + "86, proliferation {'phenotype': 'B-proliferation'}", + "105, p27-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "106, stem {'context': 'B-cells'}", + "107, cells {'context': 'I-cells'}", + "113, blood {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "73, not ['l0', 'l1', 'l2']", + "75, stem ['l0', 'l3', 'l4']", + "76, cell ['l1', 'l3', 'l5']", + "81, self-renewal, ['l2', 'l4', 'l5']", + "84, alters ['l6']", + "86, proliferation ['l6']", + "105, p27-deficient ['l7', 'l8', 'l9']", + "106, stem ['l7', 'l10', 'l11']", + "107, cells ['l8', 'l10', 'l12']", + "113, blood ['l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "no effect", + "words": [ + "not" + ] + }, + "context": { + "val": "cells", + "words": [ + "stem", + "cell" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "stem", + "cell" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal," + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "alters" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p27-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "stem", + "cells", + "blood" + ] + } + } + ] + }, + { + "PMID": "11017148", + "TEXT": "We have investigated whether dendritic cells genetically modified to express CD40 ligand and pulsed with antigen can trigger B cells to produce antigen-specific antibodies without CD4+ T-cell help. Dendritic cells modified with a recombinant adenovirus vector to express CD40 ligand and pulsed with heat-killed Pseudomonas induced naive B cells to produce antibodies against Pseudomonas in the absence of CD4+ T cells in vitro, initiated Pseudomonas-specific humoral immune responses in vivo in wild-type and CD4-/- mice, and protected immunized wild-type and CD4-/-, but not B-cell -/- mice, from lethal intrapulmonary challenge with Pseudomonas. Thus, genetic modification of dendritic cells with CD40 ligand enables them to present a complex mixture of microbial antigens and establish CD4+ T cell-independent, B cell-mediated protective immunity against a specific microbe.", + "TAG_DATA": [ + "28, Dendritic {'context': 'B-cells'}", + "29, cells {'context': 'I-cells'}", + "46, naive {'context': 'B-cells'}", + "47, B {'context': 'I-cells'}", + "48, cells {'context': 'I-cells'}", + "58, CD4+ {'context': 'B-cells'}", + "59, T {'context': 'I-cells'}", + "60, cells {'context': 'I-cells'}", + "61, in {'context': 'B-in vitro'}", + "62, vitro, {'context': 'I-in vitro'}", + "68, in {'context': 'B-in vivo'}", + "69, vivo {'context': 'I-in vivo'}", + "73, CD4-/- {'perturbing_action': 'B-gene loss-of-function'}", + "74, mice, {'context': 'B-organism'}", + "80, CD4-/-, {'perturbing_action': 'B-gene loss-of-function'}", + "83, B-cell {'perturbing_action': 'B-gene loss-of-function'}", + "84, -/- {'perturbing_action': 'B-gene loss-of-function'}", + "85, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "28, Dendritic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "29, cells ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "46, naive ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "47, B ['l2', 'l14', 'l25', 'l32', 'l33', 'l34', 'l35']", + "48, cells ['l3', 'l15', 'l26', 'l32', 'l36', 'l37', 'l38']", + "58, CD4+ ['l4', 'l16', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "59, T ['l5', 'l17', 'l28', 'l33', 'l36', 'l39', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "60, cells ['l6', 'l18', 'l29', 'l34', 'l37', 'l40', 'l47', 'l53', 'l54', 'l55', 'l56']", + "61, in ['l7', 'l19', 'l30', 'l41', 'l48', 'l53', 'l57', 'l58', 'l59']", + "62, vitro, ['l8', 'l20', 'l31', 'l35', 'l38', 'l42', 'l49', 'l54', 'l57']", + "68, in ['l9', 'l21', 'l43', 'l50', 'l55', 'l58', 'l60', 'l61', 'l62']", + "69, vivo ['l10', 'l22', 'l44', 'l51', 'l56', 'l59', 'l60', 'l63', 'l64']", + "73, CD4-/- ['l11', 'l23', 'l45', 'l61', 'l63', 'l65']", + "74, mice, ['l12', 'l24', 'l46', 'l52', 'l62', 'l64', 'l65']", + "80, CD4-/-, ['l66', 'l67', 'l68']", + "83, B-cell ['l66', 'l69', 'l70']", + "84, -/- ['l67', 'l69', 'l71']", + "85, mice, ['l68', 'l70', 'l71']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Dendritic", + "cells", + "CD4+" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD4-/-" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD4-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD4-/-", + "CD4-/-,", + "B-cell", + "-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "10973316", + "TEXT": "Bone formation by osteoblasts is essential for skeletal growth and remodeling. Fra-1 is a c-Fos-related protein belonging to the AP-1 family of transcription factors. Here we show that transgenic mice overexpressing Fra-1 in various organs develop a progressive increase in bone mass leading to osteosclerosis of the entire skeleton, which is due to a cell-autonomous increase in the number of mature osteoblasts. Moreover, osteoblast differentiation, but not proliferation, was enhanced and osteoclastogenesis was also elevated in vitro. These data indicate that, unlike c-Fos, which causes osteosarcomas, Fra-1 specifically enhances bone formation, which may be exploited to stimulate bone formation in pathological conditions.", + "TAG_DATA": [ + "28, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "29, mice {'context': 'I-organism'}", + "30, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "31, Fra-1 {'perturbing_action': 'I-gene gain-of-function'}", + "48, skeleton, {'context': 'B-tissue/organ'}", + "63, osteoblast {'context': 'B-cells'}", + "64, differentiation, {'phenotype': 'B-differentiation'}", + "67, proliferation, {'phenotype': 'B-proliferation'}", + "69, enhanced {'effect': 'B-positive'}", + "75, in {'context': 'B-in vitro'}", + "76, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "28, transgenic ['l0', 'l1', 'l2', 'l3', 'l4']", + "29, mice ['l0', 'l5', 'l6', 'l7']", + "30, overexpressing ['l1', 'l5', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "31, Fra-1 ['l2', 'l6', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "48, skeleton, ['l3', 'l7', 'l9', 'l14']", + "63, osteoblast ['l10', 'l15', 'l19', 'l20', 'l21']", + "64, differentiation, ['l4', 'l11', 'l16', 'l19', 'l22', 'l23']", + "67, proliferation, ['l12', 'l17', 'l20', 'l22', 'l24']", + "69, enhanced ['l13', 'l18', 'l21', 'l23', 'l24']", + "75, in ['l25']", + "76, vitro. ['l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "overexpressing", + "Fra-1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "overexpressing", + "Fra-1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skeleton," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "overexpressing", + "Fra-1" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "Fra-1" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoblast" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "Fra-1" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "Fra-1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoblast" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoblast" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoblast" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + } + ] + }, + { + "PMID": "10932230", + "TEXT": "One hallmark of Alzheimer disease is the accumulation of amyloid beta-peptide in the brain and its deposition as plaques. Mice transgenic for an amyloid beta precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter (PDAPP mice), which overexpress one of the disease-linked mutant forms of the human amyloid precursor protein, show many of the pathological features of Alzheimer disease, including extensive deposition of extracellular amyloid plaques, astrocytosis and neuritic dystrophy. Active immunization of PDAPP mice with human amyloid beta-peptide reduces plaque burden and its associated pathologies. Several hypotheses have been proposed regarding the mechanism of this response. Here we report that peripheral administration of antibodies against amyloid beta-peptide, was sufficient to reduce amyloid burden. Despite their relatively modest serum levels, the passively administered antibodies were able to enter the central nervous system, decorate plaques and induce clearance of preexisting amyloid. When examined in an ex vivo assay with sections of PDAPP or Alzheimer disease brain tissue, antibodies against amyloid beta-peptide triggered microglial cells to clear plaques through Fc receptor-mediated phagocytosis and subsequent peptide degradation. These results indicate that antibodies can cross the blood-brain barrier to act directly in the central nervous system and should be considered as a therapeutic approach for the treatment of Alzheimer disease and other neurological disorders.", + "TAG_DATA": [ + "19, Mice {'context': 'B-organism'}", + "20, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "21, for {'perturbing_action': 'I-gene gain-of-function'}", + "22, an {'perturbing_action': 'I-gene gain-of-function'}", + "23, amyloid {'perturbing_action': 'I-gene gain-of-function'}", + "24, beta {'perturbing_action': 'I-gene gain-of-function'}", + "25, precursor {'perturbing_action': 'I-gene gain-of-function'}", + "26, protein {'perturbing_action': 'I-gene gain-of-function'}", + "27, (APP) {'perturbing_action': 'I-gene gain-of-function'}", + "28, mini-gene {'perturbing_action': 'I-gene gain-of-function'}", + "29, driven {'perturbing_action': 'I-gene gain-of-function'}", + "30, by {'perturbing_action': 'I-gene gain-of-function'}", + "31, a {'perturbing_action': 'I-gene gain-of-function'}", + "32, platelet-derived {'perturbing_action': 'I-gene gain-of-function'}", + "33, (PD) {'perturbing_action': 'I-gene gain-of-function'}", + "34, growth {'perturbing_action': 'I-gene gain-of-function'}", + "35, factor {'perturbing_action': 'I-gene gain-of-function'}", + "36, promoter {'perturbing_action': 'I-gene gain-of-function'}", + "37, (PDAPP {'perturbing_action': 'I-gene gain-of-function'}", + "38, mice), {'perturbing_action': 'I-gene gain-of-function'}", + "40, overexpress {'perturbing_action': 'I-gene gain-of-function'}", + "41, one {'perturbing_action': 'I-gene gain-of-function'}", + "45, mutant {'perturbing_action': 'I-gene gain-of-function'}", + "46, forms {'perturbing_action': 'I-gene gain-of-function'}", + "47, of {'perturbing_action': 'I-gene gain-of-function'}", + "48, the {'perturbing_action': 'I-gene gain-of-function'}", + "76, PDAPP {'context': 'B-organism'}", + "77, mice {'context': 'I-organism'}", + "164, microglial {'context': 'B-cells'}", + "165, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "19, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "20, transgenic ['l0', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "21, for ['l1', 'l27', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "22, an ['l2', 'l28', 'l53', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "23, amyloid ['l3', 'l29', 'l54', 'l78', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "24, beta ['l4', 'l30', 'l55', 'l79', 'l102', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146']", + "25, precursor ['l5', 'l31', 'l56', 'l80', 'l103', 'l125', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "26, protein ['l6', 'l32', 'l57', 'l81', 'l104', 'l126', 'l147', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "27, (APP) ['l7', 'l33', 'l58', 'l82', 'l105', 'l127', 'l148', 'l168', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206']", + "28, mini-gene ['l8', 'l34', 'l59', 'l83', 'l106', 'l128', 'l149', 'l169', 'l188', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224']", + "29, driven ['l9', 'l35', 'l60', 'l84', 'l107', 'l129', 'l150', 'l170', 'l189', 'l207', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241']", + "30, by ['l10', 'l36', 'l61', 'l85', 'l108', 'l130', 'l151', 'l171', 'l190', 'l208', 'l225', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257']", + "31, a ['l11', 'l37', 'l62', 'l86', 'l109', 'l131', 'l152', 'l172', 'l191', 'l209', 'l226', 'l242', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272']", + "32, platelet-derived ['l12', 'l38', 'l63', 'l87', 'l110', 'l132', 'l153', 'l173', 'l192', 'l210', 'l227', 'l243', 'l258', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286']", + "33, (PD) ['l13', 'l39', 'l64', 'l88', 'l111', 'l133', 'l154', 'l174', 'l193', 'l211', 'l228', 'l244', 'l259', 'l273', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298', 'l299']", + "34, growth ['l14', 'l40', 'l65', 'l89', 'l112', 'l134', 'l155', 'l175', 'l194', 'l212', 'l229', 'l245', 'l260', 'l274', 'l287', 'l300', 'l301', 'l302', 'l303', 'l304', 'l305', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311']", + "35, factor ['l15', 'l41', 'l66', 'l90', 'l113', 'l135', 'l156', 'l176', 'l195', 'l213', 'l230', 'l246', 'l261', 'l275', 'l288', 'l300', 'l312', 'l313', 'l314', 'l315', 'l316', 'l317', 'l318', 'l319', 'l320', 'l321', 'l322']", + "36, promoter ['l16', 'l42', 'l67', 'l91', 'l114', 'l136', 'l157', 'l177', 'l196', 'l214', 'l231', 'l247', 'l262', 'l276', 'l289', 'l301', 'l312', 'l323', 'l324', 'l325', 'l326', 'l327', 'l328', 'l329', 'l330', 'l331', 'l332']", + "37, (PDAPP ['l17', 'l43', 'l68', 'l92', 'l115', 'l137', 'l158', 'l178', 'l197', 'l215', 'l232', 'l248', 'l263', 'l277', 'l290', 'l302', 'l313', 'l323', 'l333', 'l334', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340', 'l341']", + "38, mice), ['l18', 'l44', 'l69', 'l93', 'l116', 'l138', 'l159', 'l179', 'l198', 'l216', 'l233', 'l249', 'l264', 'l278', 'l291', 'l303', 'l314', 'l324', 'l333', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348', 'l349']", + "40, overexpress ['l19', 'l45', 'l70', 'l94', 'l117', 'l139', 'l160', 'l180', 'l199', 'l217', 'l234', 'l250', 'l265', 'l279', 'l292', 'l304', 'l315', 'l325', 'l334', 'l342', 'l350', 'l351', 'l352', 'l353', 'l354', 'l355', 'l356']", + "41, one ['l20', 'l46', 'l71', 'l95', 'l118', 'l140', 'l161', 'l181', 'l200', 'l218', 'l235', 'l251', 'l266', 'l280', 'l293', 'l305', 'l316', 'l326', 'l335', 'l343', 'l350', 'l357', 'l358', 'l359', 'l360', 'l361', 'l362']", + "45, mutant ['l21', 'l47', 'l72', 'l96', 'l119', 'l141', 'l162', 'l182', 'l201', 'l219', 'l236', 'l252', 'l267', 'l281', 'l294', 'l306', 'l317', 'l327', 'l336', 'l344', 'l351', 'l357', 'l363', 'l364', 'l365', 'l366', 'l367']", + "46, forms ['l22', 'l48', 'l73', 'l97', 'l120', 'l142', 'l163', 'l183', 'l202', 'l220', 'l237', 'l253', 'l268', 'l282', 'l295', 'l307', 'l318', 'l328', 'l337', 'l345', 'l352', 'l358', 'l363', 'l368', 'l369', 'l370', 'l371']", + "47, of ['l23', 'l49', 'l74', 'l98', 'l121', 'l143', 'l164', 'l184', 'l203', 'l221', 'l238', 'l254', 'l269', 'l283', 'l296', 'l308', 'l319', 'l329', 'l338', 'l346', 'l353', 'l359', 'l364', 'l368', 'l372', 'l373', 'l374']", + "48, the ['l24', 'l50', 'l75', 'l99', 'l122', 'l144', 'l165', 'l185', 'l204', 'l222', 'l239', 'l255', 'l270', 'l284', 'l297', 'l309', 'l320', 'l330', 'l339', 'l347', 'l354', 'l360', 'l365', 'l369', 'l372', 'l375', 'l376']", + "76, PDAPP ['l25', 'l51', 'l76', 'l100', 'l123', 'l145', 'l166', 'l186', 'l205', 'l223', 'l240', 'l256', 'l271', 'l285', 'l298', 'l310', 'l321', 'l331', 'l340', 'l348', 'l355', 'l361', 'l366', 'l370', 'l373', 'l375', 'l377']", + "77, mice ['l26', 'l52', 'l77', 'l101', 'l124', 'l146', 'l167', 'l187', 'l206', 'l224', 'l241', 'l257', 'l272', 'l286', 'l299', 'l311', 'l322', 'l332', 'l341', 'l349', 'l356', 'l362', 'l367', 'l371', 'l374', 'l376', 'l377']", + "164, microglial ['l378']", + "165, cells ['l378']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice", + "PDAPP", + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "an", + "amyloid", + "beta", + "precursor", + "protein", + "(APP)", + "mini-gene", + "driven", + "by", + "a", + "platelet-derived", + "(PD)", + "growth", + "factor", + "promoter", + "(PDAPP", + "mice),", + "overexpress", + "one", + "mutant", + "forms", + "of", + "the" + ] + } + } + ] + }, + { + "PMID": "10932225", + "TEXT": "Here we defined the main viral determinant of Ebola virus pathogenicity; synthesis of the virion glycoprotein (GP) of Ebola virus Zaire induced cytotoxic effects in human endothelial cells in vitro and in vivo. This effect mapped to a serine-threonine-rich, mucin-like domain of this type I transmembrane glycoprotein, one of seven gene products of the virus. Gene transfer of GP into explanted human or porcine blood vessels caused massive endothelial cell loss within 48 hours that led to a substantial increase in vascular permeability. Deletion of the mucin-like region of GP abolished these effects without affecting protein expression or function. GP derived from the Reston strain of virus, which causes disease in nonhuman primates but not in man, did not disrupt the vasculature of human blood vessels. In contrast, the Zaire GP induced endothelial cell disruption and cytotoxicity in both nonhuman primate and human blood vessels, and the mucin domain was required for this effect. These findings indicate that GP, through its mucin domain, is the viral determinant of Ebola pathogenicity and likely contributes to hemorrhage during infection.", + "TAG_DATA": [ + "25, human {'context': 'B-cells'}", + "26, endothelial {'context': 'I-cells'}", + "27, cells {'context': 'I-cells'}", + "28, in {'context': 'B-in vitro'}", + "29, vitro {'context': 'I-in vitro'}", + "31, in {'context': 'B-in vivo'}", + "32, vivo. {'context': 'I-in vivo'}", + "55, Gene {'perturbing_action': 'B-gene gain-of-function'}", + "56, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "57, of {'perturbing_action': 'I-gene gain-of-function'}", + "58, GP {'perturbing_action': 'I-gene gain-of-function'}", + "61, human {'context': 'B-tissue/organ'}", + "62, or {'context': 'I-tissue/organ'}", + "63, porcine {'context': 'I-tissue/organ'}", + "64, blood {'context': 'I-tissue/organ'}", + "65, vessels {'context': 'I-tissue/organ'}", + "68, endothelial {'context': 'B-cells'}", + "69, cell {'context': 'I-cells'}", + "83, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "84, of {'perturbing_action': 'I-gene loss-of-function'}", + "85, the {'perturbing_action': 'I-gene loss-of-function'}", + "86, mucin-like {'perturbing_action': 'I-gene loss-of-function'}", + "87, region {'perturbing_action': 'I-gene loss-of-function'}", + "88, of {'perturbing_action': 'I-gene loss-of-function'}", + "89, GP {'perturbing_action': 'I-gene loss-of-function'}", + "112, primates {'context': 'I-organism'}", + "123, human {'context': 'B-tissue/organ'}", + "124, blood {'context': 'I-tissue/organ'}", + "125, vessels. {'context': 'I-tissue/organ'}", + "132, endothelial {'context': 'B-cells'}", + "133, cell {'context': 'I-cells'}", + "139, nonhuman {'context': 'B-organism'}", + "140, primate {'context': 'I-organism'}", + "142, human {'context': 'B-tissue/organ'}", + "143, blood {'context': 'I-tissue/organ'}", + "144, vessels, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "25, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "26, endothelial ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "27, cells ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "28, in ['l2', 'l16', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "29, vitro ['l3', 'l17', 'l39', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "31, in ['l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "32, vivo. ['l62', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "55, Gene ['l4', 'l18', 'l29', 'l40', 'l51', 'l63', 'l74', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "56, transfer ['l5', 'l19', 'l41', 'l52', 'l64', 'l75', 'l85', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "57, of ['l6', 'l20', 'l30', 'l42', 'l53', 'l65', 'l76', 'l86', 'l95', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "58, GP ['l7', 'l21', 'l31', 'l43', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "61, human ['l8', 'l22', 'l32', 'l44', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "62, or ['l9', 'l23', 'l33', 'l45', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l113', 'l119', 'l125', 'l126', 'l127', 'l128', 'l129']", + "63, porcine ['l10', 'l24', 'l34', 'l46', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l130', 'l131', 'l132', 'l133']", + "64, blood ['l11', 'l25', 'l35', 'l47', 'l58', 'l70', 'l81', 'l91', 'l100', 'l108', 'l115', 'l121', 'l126', 'l130', 'l134', 'l135', 'l136']", + "65, vessels ['l12', 'l26', 'l36', 'l48', 'l59', 'l71', 'l82', 'l92', 'l101', 'l109', 'l116', 'l122', 'l127', 'l131', 'l134', 'l137', 'l138']", + "68, endothelial ['l13', 'l27', 'l37', 'l49', 'l60', 'l72', 'l83', 'l93', 'l102', 'l110', 'l117', 'l123', 'l128', 'l132', 'l135', 'l137', 'l139']", + "69, cell ['l14', 'l28', 'l38', 'l50', 'l61', 'l73', 'l84', 'l94', 'l103', 'l111', 'l118', 'l124', 'l129', 'l133', 'l136', 'l138', 'l139']", + "83, Deletion ['l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "84, of ['l140', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158']", + "85, the ['l141', 'l150', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166']", + "86, mucin-like ['l142', 'l151', 'l159', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "87, region ['l143', 'l152', 'l160', 'l167', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179']", + "88, of ['l144', 'l153', 'l161', 'l168', 'l174', 'l180', 'l181', 'l182', 'l183', 'l184']", + "89, GP ['l145', 'l154', 'l162', 'l169', 'l175', 'l180', 'l185', 'l186', 'l187', 'l188']", + "112, primates ['l146', 'l155', 'l163', 'l170', 'l176', 'l181', 'l185', 'l189', 'l190', 'l191']", + "123, human ['l147', 'l156', 'l164', 'l171', 'l177', 'l182', 'l186', 'l189', 'l192', 'l193']", + "124, blood ['l148', 'l157', 'l165', 'l172', 'l178', 'l183', 'l187', 'l190', 'l192', 'l194']", + "125, vessels. ['l149', 'l158', 'l166', 'l173', 'l179', 'l184', 'l188', 'l191', 'l193', 'l194']", + "132, endothelial ['l195', 'l196', 'l197', 'l198', 'l199', 'l200']", + "133, cell ['l195', 'l201', 'l202', 'l203', 'l204', 'l205']", + "139, nonhuman ['l196', 'l201', 'l206', 'l207', 'l208', 'l209']", + "140, primate ['l197', 'l202', 'l206', 'l210', 'l211', 'l212']", + "142, human ['l198', 'l203', 'l207', 'l210', 'l213', 'l214']", + "143, blood ['l199', 'l204', 'l208', 'l211', 'l213', 'l215']", + "144, vessels, ['l200', 'l205', 'l209', 'l212', 'l214', 'l215']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "endothelial", + "cells", + "cell" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Gene", + "transfer", + "of", + "GP" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Gene", + "transfer", + "of", + "GP" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Gene", + "transfer", + "of", + "GP" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Gene", + "transfer", + "of", + "GP" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "human", + "or", + "porcine", + "blood", + "vessels" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "mucin-like", + "region", + "GP" + ] + }, + "context": { + "val": "organism", + "words": [ + "primates" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "mucin-like", + "region", + "GP" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "human", + "blood", + "vessels." + ] + } + } + ] + }, + { + "PMID": "10835684", + "TEXT": "The use of agonistic monoclonal antibody against CD40 has emerged as one the most effective ways to boost immune responses against infectious agents or to fight cancer. Here, we report that the same monoclonal antibodies against CD40 (FGK45 and 3/23) previously used to elicit protective immune responses treated the autoimmune inflammatory process of chronic collagen-induced arthritis in DBA/1-TCR-beta transgenic mice, as well as collagen-induced arthritis in DBA/1 mice, both animal models of rheumatoid arthritis. This study indicates that agonistic monoclonal antibody against CD40 can potentially be used to treat chronic autoimmune inflammatory processes.", + "TAG_DATA": [ + "57, DBA/1-TCR-beta {'perturbing_action': 'B-gene gain-of-function'}", + "58, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "59, mice, {'context': 'B-organism'}", + "66, DBA/1 {'context': 'B-organism'}", + "67, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "57, DBA/1-TCR-beta ['l0', 'l1']", + "58, transgenic ['l0', 'l2']", + "59, mice, ['l1', 'l2']", + "66, DBA/1 ['l3']", + "67, mice, ['l3']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "DBA/1-TCR-beta", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "10802714", + "TEXT": "Insulin gene expression is restricted to islet beta cells of the mammalian pancreas through specific control mechanisms mediated in part by specific transcription factors. The protein encoded by the pancreatic and duodenal homeobox gene 1 (PDX-1) is central in regulating pancreatic development and islet cell function. PDX-1 regulates insulin gene expression and is involved in islet cell-specific expression of various genes. Involvement of PDX-1 in islet-cell differentiation and function has been demonstrated mainly by 'loss-of-function' studies. We used a 'gain-of-function' approach to test whether PDX-1 could endow a non-islet tissue with pancreatic beta-cell characteristics in vivo. Recombinant-adenovirus-mediated gene transfer of PDX-1 to the livers of BALB/C and C57BL/6 mice activated expression of the endogenous, otherwise silent, genes for mouse insulin 1 and 2 and prohormone convertase 1/3 (PC 1/3). Expression of PDX-1 resulted in a substantial increase in hepatic immunoreactive insulin content and an increase of 300% in plasma immunoreactive insulin levels, compared with that in mice treated with control adenovirus. Hepatic immunoreactive insulin induced by PDX-1 was processed to mature mouse insulin 1 and 2 and was biologically active; it ameliorated hyperglycemia in diabetic mice treated with streptozotocin. These data indicate the capacity of PDX-1 to reprogram extrapancreatic tissue towards a beta-cell phenotype, may provide a valuable approach for generating 'self' surrogate beta cells, suitable for replacing impaired islet-cell function in diabetics.", + "TAG_DATA": [ + "96, Recombinant-adenovirus-mediated {'perturbing_action': 'B-gene gain-of-function'}", + "97, gene {'perturbing_action': 'I-gene gain-of-function'}", + "98, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "99, of {'perturbing_action': 'I-gene gain-of-function'}", + "100, PDX-1 {'perturbing_action': 'I-gene gain-of-function'}", + "103, livers {'context': 'B-tissue/organ'}", + "105, BALB/C {'context': 'B-organism'}", + "107, C57BL/6 {'context': 'B-organism'}", + "108, mice {'context': 'I-organism'}", + "129, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "130, of {'perturbing_action': 'I-gene gain-of-function'}", + "131, PDX-1 {'perturbing_action': 'I-gene gain-of-function'}", + "156, mice {'context': 'B-organism'}", + "184, diabetic {'context': 'B-organism'}", + "185, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "96, Recombinant-adenovirus-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "97, gene ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "98, transfer ['l1', 'l11', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "99, of ['l2', 'l12', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "100, PDX-1 ['l3', 'l13', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32']", + "103, livers ['l4', 'l14', 'l20', 'l25', 'l29', 'l33', 'l34', 'l35']", + "105, BALB/C ['l5', 'l15', 'l21', 'l26', 'l30', 'l33', 'l36', 'l37']", + "107, C57BL/6 ['l6', 'l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l38', 'l39', 'l40', 'l41', 'l42']", + "108, mice ['l7', 'l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l38']", + "129, Expression ['l8', 'l39', 'l43', 'l44', 'l45']", + "130, of ['l9', 'l40', 'l43', 'l46', 'l47']", + "131, PDX-1 ['l41', 'l44', 'l46', 'l48']", + "156, mice ['l10', 'l42', 'l45', 'l47', 'l48']", + "184, diabetic ['l49']", + "185, mice ['l49']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Recombinant-adenovirus-mediated", + "gene", + "transfer", + "of", + "PDX-1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "livers" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Recombinant-adenovirus-mediated", + "gene", + "transfer", + "of", + "PDX-1", + "Expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "BALB/C", + "C57BL/6", + "mice" + ] + } + } + ] + }, + { + "PMID": "10742152", + "TEXT": "Inhibitory receptors have been proposed to modulate the in vivo cytotoxic response against tumor targets for both spontaneous and antibody-dependent pathways. Using a variety of syngenic and xenograft models, we demonstrate here that the inhibitory FcgammaRIIB molecule is a potent regulator of antibody-dependent cell-mediated cytotoxicity in vivo, modulating the activity of FcgammaRIII on effector cells. Although many mechanisms have been proposed to account for the anti-tumor activities of therapeutic antibodies, including extended half-life, blockade of signaling pathways, activation of apoptosis and effector-cell-mediated cytotoxicity, we show here that engagement of Fcgamma receptors on effector cells is a dominant component of the in vivo activity of antibodies against tumors. Mouse monoclonal antibodies, as well as the humanized, clinically effective therapeutic agents trastuzumab (Herceptin(R)) and rituximab (Rituxan(R)), engaged both activation (FcgammaRIII) and inhibitory (FcgammaRIIB) antibody receptors on myeloid cells, thus modulating their cytotoxic potential. Mice deficient in FcgammaRIIB showed much more antibody-dependent cell-mediated cytotoxicity; in contrast, mice deficient in activating Fc receptors as well as antibodies engineered to disrupt Fc binding to those receptors were unable to arrest tumor growth in vivo. These results demonstrate that Fc-receptor-dependent mechanisms contribute substantially to the action of cytotoxic antibodies against tumors and indicate that an optimal antibody against tumors would bind preferentially to activation Fc receptors and minimally to the inhibitory partner FcgammaRIIB.", + "TAG_DATA": [ + "134, myeloid {'context': 'B-cells'}", + "135, cells, {'context': 'I-cells'}", + "141, Mice {'context': 'B-organism'}", + "142, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "143, in {'perturbing_action': 'I-gene loss-of-function'}", + "144, FcgammaRIIB {'perturbing_action': 'I-gene loss-of-function'}", + "153, mice {'context': 'B-organism'}", + "172, unable {'effect': 'B-no effect'}", + "173, to {'effect': 'I-no effect'}", + "174, arrest {'effect': 'I-negative'}", + "175, tumor {'phenotype': 'B-tumour growth'}", + "176, growth {'phenotype': 'I-tumour growth'}", + "177, in {'context': 'B-in vivo'}", + "178, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "134, myeloid ['l0', 'l1', 'l2', 'l3', 'l4']", + "135, cells, ['l0', 'l5', 'l6', 'l7', 'l8']", + "141, Mice ['l1', 'l5', 'l9', 'l10', 'l11']", + "142, deficient ['l2', 'l6', 'l9', 'l12', 'l13']", + "143, in ['l3', 'l7', 'l10', 'l12', 'l14']", + "144, FcgammaRIIB ['l4', 'l8', 'l11', 'l13', 'l14']", + "153, mice ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "172, unable ['l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "173, to ['l16', 'l22', 'l28', 'l29', 'l30', 'l31', 'l32']", + "174, arrest ['l17', 'l23', 'l28', 'l33', 'l34', 'l35', 'l36']", + "175, tumor ['l18', 'l24', 'l29', 'l33', 'l37', 'l38', 'l39']", + "176, growth ['l19', 'l25', 'l30', 'l34', 'l37', 'l40', 'l41']", + "177, in ['l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l42']", + "178, vivo. ['l21', 'l27', 'l32', 'l36', 'l39', 'l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "myeloid", + "cells," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "FcgammaRIIB" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "FcgammaRIIB" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "unable", + "to" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "unable", + "to" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "unable", + "to" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "arrest" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "arrest" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "10655108", + "TEXT": "Because HER-2/neu overexpression is important in cancer development, we looked for a method of suppressing the cell transformation mediated by HER-2/neu overexpression. We have identified that the DNA-binding protein PEA3, which is encoded by a previously isolated gene of the ets family, specifically targeted a DNA sequence on the HER-2/neu promoter and downregulated the promoter activity. Expression of PEA3 resulted in preferential inhibition of cell growth and tumor development of HER-2/neu-overexpressing cancer cells. This is a new approach to targeting HER-2/neu overexpression and also provides a rationale to the design for repressors of diseases caused by overexpression of pathogenic genes.", + "TAG_DATA": [ + "56, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "57, of {'perturbing_action': 'I-gene gain-of-function'}", + "58, PEA3 {'perturbing_action': 'I-gene gain-of-function'}", + "62, inhibition {'effect': 'B-negative'}", + "64, cell {'phenotype': 'B-cell growth'}", + "65, growth {'phenotype': 'I-cell growth'}", + "67, tumor {'phenotype': 'B-tumourigenesis'}", + "68, development {'phenotype': 'I-tumourigenesis'}", + "70, HER-2/neu-overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "71, cancer {'context': 'B-transformed cells'}", + "72, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "56, Expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "57, of ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "58, PEA3 ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "62, inhibition ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "64, cell ['l3', 'l12', 'l20', 'l27', 'l33', 'l34', 'l35']", + "65, growth ['l4', 'l13', 'l21', 'l28', 'l33', 'l36', 'l37']", + "67, tumor ['l5', 'l14', 'l22', 'l29', 'l34', 'l36', 'l38', 'l39', 'l40', 'l41']", + "68, development ['l6', 'l15', 'l23', 'l30', 'l35', 'l37', 'l38', 'l42', 'l43', 'l44']", + "70, HER-2/neu-overexpressing ['l7', 'l16', 'l24', 'l39', 'l42', 'l45', 'l46']", + "71, cancer ['l8', 'l17', 'l25', 'l31', 'l40', 'l43', 'l45', 'l47']", + "72, cells. ['l9', 'l18', 'l26', 'l32', 'l41', 'l44', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "PEA3" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "PEA3" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "PEA3", + "HER-2/neu-overexpressing" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "PEA3", + "HER-2/neu-overexpressing" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "development" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells." + ] + } + } + ] + }, + { + "PMID": "10655106", + "TEXT": "Sickle cell disease is a hereditary disorder characterized by erythrocyte deformity due to hemoglobin polymerization. We assessed in vivo the potential curative threshold of fetal hemoglobin in the SAD transgenic mouse model of sickle cell disease using mating with mice expressing the human fetal Agamma-globin gene. With increasing levels of HbF, AgammaSAD mice showed considerable improvement in all hematologic parameters, morphopathologic features and life span/survival. We established the direct therapeutic effect of fetal hemoglobin on sickle cell disease and demonstrated correction by increasing fetal hemoglobin to about 9-16% in this mouse model. This in vivo study emphasizes the potential of the SAD mouse models for quantitative analysis of gene therapy approaches.", + "TAG_DATA": [ + "39, mice {'context': 'B-organism'}", + "40, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "41, the {'perturbing_action': 'I-gene gain-of-function'}", + "42, human {'perturbing_action': 'I-gene gain-of-function'}", + "43, fetal {'perturbing_action': 'I-gene gain-of-function'}", + "44, Agamma-globin {'perturbing_action': 'I-gene gain-of-function'}", + "45, gene. {'perturbing_action': 'I-gene gain-of-function'}", + "51, AgammaSAD {'perturbing_action': 'B-other'}", + "52, mice {'context': 'B-organism'}", + "90, mouse {'context': 'B-organism'}", + "91, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "39, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "40, expressing ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "41, the ['l1', 'l6', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "42, human ['l2', 'l7', 'l12', 'l18', 'l19', 'l20', 'l21', 'l22']", + "43, fetal ['l3', 'l8', 'l13', 'l18', 'l23', 'l24', 'l25', 'l26']", + "44, Agamma-globin ['l4', 'l9', 'l14', 'l19', 'l23', 'l27', 'l28', 'l29']", + "45, gene. ['l5', 'l10', 'l15', 'l20', 'l24', 'l27']", + "51, AgammaSAD ['l16', 'l21', 'l25', 'l28', 'l30']", + "52, mice ['l11', 'l17', 'l22', 'l26', 'l29', 'l30']", + "90, mouse ['l31']", + "91, model. ['l31']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "the", + "human", + "fetal", + "Agamma-globin", + "gene." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "AgammaSAD" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "10655104", + "TEXT": "Identification of new therapeutic targets for the management of septic shock remains imperative as all investigational therapies, including anti-tumor necrosis factor (TNF) and anti-interleukin (IL)-1 agents, have uniformly failed to lower the mortality of critically ill patients with severe sepsis. We report here that macrophage migration inhibitory factor (MIF) is a critical mediator of septic shock. High concentrations of MIF were detected in the peritoneal exudate fluid and in the systemic circulation of mice with bacterial peritonitis. Experiments performed in TNFalpha knockout mice allowed a direct evaluation of the part played by MIF in sepsis in the absence of this pivotal cytokine of inflammation. Anti-MIF antibody protected TNFalpha knockout from lethal peritonitis induced by cecal ligation and puncture (CLP), providing evidence of an intrinsic contribution of MIF to the pathogenesis of sepsis. Anti-MIF antibody also protected normal mice from lethal peritonitis induced by both CLP and Escherichia coli, even when treatment was started up to 8 hours after CLP. Conversely, co-injection of recombinant MIF and E. coli markedly increased the lethality of peritonitis. Finally, high concentrations of MIF were detected in the plasma of patients with severe sepsis or septic shock. These studies define a critical part for MIF in the pathogenesis of septic shock and identify a new target for therapeutic intervention.", + "TAG_DATA": [ + "73, mice {'context': 'B-organism'}", + "80, TNFalpha {'perturbing_action': 'B-gene loss-of-function'}", + "81, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "82, mice {'context': 'B-organism'}", + "137, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, mice ['l0', 'l1']", + "80, TNFalpha ['l0', 'l2', 'l3']", + "81, knockout ['l2', 'l4']", + "82, mice ['l1', 'l3', 'l4']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TNFalpha", + "knockout" + ] + } + } + ] + }, + { + "PMID": "10655103", + "TEXT": "Cerebral edema contributes significantly to morbidity and death associated with many common neurological disorders. However, current treatment options are limited to hyperosmolar agents and surgical decompression, therapies introduced more than 70 years ago. Here we show that mice deficient in aquaporin-4 (AQP4), a glial membrane water channel, have much better survival than wild-type mice in a model of brain edema caused by acute water intoxication. Brain tissue water content and swelling of pericapillary astrocytic foot processes in AQP4-deficient mice were significantly reduced. In another model of brain edema, focal ischemic stroke produced by middle cerebral artery occlusion, AQP4-deficient mice had improved neurological outcome. Cerebral edema, as measured by percentage of hemispheric enlargement at 24 h, was decreased by 35% in AQP4-deficient mice. These results implicate a key role for AQP4 in modulating brain water transport, and suggest that AQP4 inhibition may provide a new therapeutic option for reducing brain edema in a wide variety of cerebral disorders.", + "TAG_DATA": [ + "37, mice {'context': 'B-organism'}", + "38, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "39, in {'perturbing_action': 'I-gene loss-of-function'}", + "40, aquaporin-4 {'perturbing_action': 'I-gene loss-of-function'}", + "41, (AQP4), {'perturbing_action': 'I-gene loss-of-function'}", + "77, AQP4-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "78, mice {'context': 'B-organism'}", + "97, AQP4-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "98, mice {'context': 'B-organism'}", + "120, AQP4-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "121, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "37, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "38, deficient ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "39, in ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "40, aquaporin-4 ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "41, (AQP4), ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "77, AQP4-deficient ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "78, mice ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "97, AQP4-deficient ['l21']", + "98, mice ['l21']", + "120, AQP4-deficient ['l22']", + "121, mice. ['l22']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "aquaporin-4", + "(AQP4),", + "AQP4-deficient" + ] + } + } + ] + }, + { + "PMID": "10655101", + "TEXT": "Alzheimer amyloid beta-peptide (Abeta) is a physiological peptide constantly anabolized and catabolized under normal conditions. We investigated the mechanism of catabolism by tracing multiple-radiolabeled synthetic peptide injected into rat hippocampus. The Abeta1-42 peptide underwent full degradation through limited proteolysis conducted by neutral endopeptidase (NEP) similar or identical to neprilysin as biochemically analyzed. Consistently, NEP inhibitor infusion resulted in both biochemical and pathological deposition of endogenous Abeta42 in brain. This NEP-catalyzed proteolysis therefore limits the rate of Abeta42 catabolism, up-regulation of which could reduce the risk of developing Alzheimer's disease by preventing Abeta accumulation.", + "TAG_DATA": [ + "53, NEP {'perturbing_action': 'B-pharmacological inhibition'}", + "54, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "67, brain. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "53, NEP ['l0', 'l1']", + "54, inhibitor ['l0', 'l2']", + "67, brain. ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NEP", + "inhibitor" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain." + ] + } + } + ] + }, + { + "PMID": "10613824", + "TEXT": "Intrathymic expression of tissue-specific self antigens may be involved in immunological tolerance and protection from autoimmune disease. We have analyzed the role of T-cell tolerance to proteolipid protein (PLP), the main protein of the myelin sheath, in susceptibility to experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Intrathymic expression of PLP was largely restricted to the shorter splice variant, DM20. Expression of DM20 by thymic epithelium was sufficient to confer T-cell tolerance to all epitopes of PLP in EAE-resistant C57BL/6 mice. In contrast, the major T-cell epitope in SJL/J mice was only encoded by the central nervous system-specific exon of PLP, but not by thymic DM20. Thus, lack of tolerance to this epitope offers an explanation for the exquisite susceptibility of SJL/J mice to EAE. As PLP expression in the human thymus is also restricted to the DM20 isoform, these findings have implications for selection of the autoimmune T-cell repertoire in multiple sclerosis.", + "TAG_DATA": [ + "62, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "63, of {'perturbing_action': 'I-gene gain-of-function'}", + "64, DM20 {'perturbing_action': 'I-gene gain-of-function'}", + "65, by {'perturbing_action': 'I-gene gain-of-function'}", + "67, epithelium {'context': 'I-tissue/organ'}", + "81, C57BL/6 {'context': 'B-organism'}", + "82, mice. {'context': 'I-organism'}", + "91, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "62, Expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "63, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "64, DM20 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "65, by ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "66, thymic ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "67, epithelium ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "81, C57BL/6 ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "82, mice. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "DM20", + "by" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "epithelium" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "DM20", + "by" + ] + }, + "context": { + "val": "organism", + "words": [ + "C57BL/6", + "mice." + ] + } + } + ] + }, + { + "PMID": "10581083", + "TEXT": "MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) damages dopaminergic neurons as seen in Parkinson disease. Here we show that after administration of MPTP to mice, there was a robust gliosis in the substantia nigra pars compacta associated with significant upregulation of inducible nitric oxide synthase (iNOS). These changes preceded or paralleled MPTP-induced dopaminergic neurodegeneration. We also show that mutant mice lacking the iNOS gene were significantly more resistant to MPTP than their wild-type littermates. This study demonstrates that iNOS is important in the MPTP neurotoxic process and indicates that inhibitors of iNOS may provide protective benefit in the treatment of Parkinson disease.", + "TAG_DATA": [ + "19, mice, {'context': 'B-organism'}", + "27, substantia {'context': 'B-tissue/organ'}", + "28, nigra {'context': 'I-tissue/organ'}", + "29, pars {'context': 'I-tissue/organ'}", + "30, compacta {'context': 'I-tissue/organ'}", + "54, mice {'context': 'B-organism'}", + "55, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "56, the {'perturbing_action': 'I-gene loss-of-function'}", + "57, iNOS {'perturbing_action': 'I-gene loss-of-function'}", + "58, gene {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "19, mice, ['l0', 'l1']", + "24, gliosis ['l0', 'l2', 'l3', 'l4', 'l5']", + "27, substantia ['l2', 'l6', 'l7', 'l8']", + "28, nigra ['l3', 'l6', 'l9', 'l10']", + "29, pars ['l4', 'l7', 'l9', 'l11']", + "30, compacta ['l1', 'l5', 'l8', 'l10', 'l11']", + "54, mice ['l12', 'l13', 'l14', 'l15']", + "55, lacking ['l12', 'l16', 'l17', 'l18']", + "56, the ['l13', 'l16', 'l19', 'l20']", + "57, iNOS ['l14', 'l17', 'l19', 'l21']", + "58, gene ['l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "iNOS", + "gene" + ] + } + } + ] + }, + { + "PMID": "10581077", + "TEXT": "The B7 family members B7-1 and B7-2 interact with CD28 and constitute an essential T-cell co-stimulatory pathway in the initiation of antigen-specific humoral and cell-mediated immune response. Here, we describe a third member of the B7 family, called B7-H1 that does not bind CD28, cytotoxic T-lymphocyte A4 or ICOS (inducible co-stimulator). Ligation of B7-H1 co-stimulated T-cell responses to polyclonal stimuli and allogeneic antigens, and preferentially stimulated the production of interleukin-10. Interleukin-2, although produced in small amounts, was required for the effect of B7-H1 co-stimulation. Our studies thus define a previously unknown co-stimulatory molecule that may be involved in the negative regulation of cell-mediated immune responses.", + "TAG_DATA": [ + "51, Ligation {'perturbing_action': 'B-pharmacological augmentation'}", + "52, of {'perturbing_action': 'I-pharmacological augmentation'}", + "53, B7-H1 {'perturbing_action': 'I-pharmacological augmentation'}", + "55, T-cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "51, Ligation ['l0', 'l1', 'l2']", + "52, of ['l0', 'l3', 'l4']", + "53, B7-H1 ['l1', 'l3', 'l5']", + "55, T-cell ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Ligation", + "of", + "B7-H1" + ] + }, + "context": { + "val": "cells", + "words": [ + "T-cell" + ] + } + } + ] + }, + { + "PMID": "10545998", + "TEXT": "The mechanisms of allograft tolerance have been classified as deletion, anergy, ignorance and suppression/regulation. Deletion has been implicated in central tolerance, whereas peripheral tolerance has generally been ascribed to clonal anergy and/or active immunoregulatory states. Here, we used two distinct systems to assess the requirement for T-cell deletion in peripheral tolerance induction. In mice transgenic for Bcl-xL, T cells were resistant to passive cell death through cytokine withdrawal, whereas T cells from interleukin-2-deficient mice did not undergo activation-induced cell death. Using either agents that block co-stimulatory pathways or the immunosuppressive drug rapamycin, which we have shown here blocks the proliferative component of interleukin-2 signaling but does not inhibit priming for activation-induced cell death, we found that mice with defective passive or active T-cell apoptotic pathways were resistant to induction of transplantation tolerance. Thus, deletion of activated T cells through activation-induced cell death or growth factor withdrawal seems necessary to achieve peripheral tolerance across major histocompatibility complex barriers.", + "TAG_DATA": [ + "53, mice {'context': 'B-organism'}", + "54, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "55, for {'perturbing_action': 'I-gene gain-of-function'}", + "56, Bcl-xL, {'perturbing_action': 'I-gene gain-of-function'}", + "57, T {'context': 'B-cells'}", + "58, cells {'context': 'I-cells'}", + "60, resistant {'effect': 'B-negative'}", + "63, cell {'phenotype': 'B-cell death'}", + "64, death {'phenotype': 'I-cell death'}", + "69, T {'context': 'B-cells'}", + "70, cells {'context': 'B-cells'}", + "72, interleukin-2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "73, mice {'context': 'B-organism'}", + "74, did {'effect': 'B-negative'}", + "75, not {'effect': 'I-no effect'}", + "76, undergo {'effect': 'I-no effect'}", + "77, activation-induced {'effect': 'B-positive'}", + "78, cell {'phenotype': 'B-cell death'}", + "79, death. {'phenotype': 'I-cell death'}", + "110, activation-induced {'effect': 'B-positive'}", + "111, cell {'phenotype': 'B-cell death'}", + "112, death, {'phenotype': 'I-cell death'}", + "116, mice {'context': 'B-organism'}", + "122, T-cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "53, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "54, transgenic ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "55, for ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "56, Bcl-xL, ['l2', 'l9', 'l15', 'l25', 'l26', 'l27', 'l28', 'l29']", + "57, T ['l3', 'l10', 'l16', 'l25', 'l30', 'l31', 'l32', 'l33']", + "58, cells ['l4', 'l11', 'l17', 'l26', 'l30', 'l34', 'l35', 'l36']", + "60, resistant ['l5', 'l12', 'l18', 'l27', 'l31', 'l34', 'l37', 'l38']", + "63, cell ['l6', 'l13', 'l19', 'l28', 'l32', 'l35', 'l37', 'l39']", + "64, death ['l7', 'l14', 'l20', 'l29', 'l33', 'l36', 'l38', 'l39']", + "69, T ['l21', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "70, cells ['l22', 'l40', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "72, interleukin-2-deficient ['l41', 'l49', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "73, mice ['l42', 'l50', 'l57', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "74, did ['l43', 'l51', 'l58', 'l64', 'l70', 'l71', 'l72', 'l73', 'l74']", + "75, not ['l44', 'l52', 'l59', 'l65', 'l70', 'l75', 'l76', 'l77', 'l78']", + "76, undergo ['l45', 'l53', 'l60', 'l66', 'l71', 'l75', 'l79', 'l80', 'l81']", + "77, activation-induced ['l46', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l82', 'l83']", + "78, cell ['l23', 'l47', 'l55', 'l62', 'l68', 'l73', 'l77', 'l80', 'l82', 'l84']", + "79, death. ['l24', 'l48', 'l56', 'l63', 'l69', 'l74', 'l78', 'l81', 'l83', 'l84']", + "110, activation-induced ['l85', 'l86']", + "111, cell ['l85', 'l87']", + "112, death, ['l86', 'l87']", + "116, mice ['l88']", + "122, T-cell ['l88']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "Bcl-xL," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant", + "did" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "Bcl-xL," + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "Bcl-xL," + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "Bcl-xL," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death", + "death." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant", + "did" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death", + "death." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistant", + "did" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death", + "death." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interleukin-2-deficient" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "undergo" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "activation-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interleukin-2-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interleukin-2-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "did" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interleukin-2-deficient" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "undergo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interleukin-2-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "activation-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interleukin-2-deficient" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "undergo" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "activation-induced" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "undergo" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "activation-induced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death.", + "death," + ] + } + } + ] + }, + { + "PMID": "10545991", + "TEXT": "The long-term consequences of adenovirus-mediated conditional cytotoxic gene therapy for gliomas remain uncharacterized. We report here detection of active brain inflammation 3 months after successful inhibition of syngeneic glioma growth. The inflammatory infiltrate consisted of activated macrophages/microglia and astrocytes, and T lymphocytes positive for leucosyalin, CD3 and CD8, and included secondary demyelination. We detected strong widespread herpes simplex virus 1 thymidine kinase immunoreactivity and vector genomes throughout large areas of the brain. Thus, patient evaluation and the design of clinical trials in ongoing and future gene therapy for brain glioblastoma must address not only tumor-killing efficiency, but also long-term active brain inflammation, loss of myelin fibers and persistent transgene expression.", + "TAG_DATA": [ + "25, inhibition {'effect': 'B-negative'}", + "27, syngeneic {'context': 'B-neoplasm'}", + "28, glioma {'context': 'I-neoplasm'}", + "36, macrophages/microglia {'context': 'B-cells'}", + "38, astrocytes, {'context': 'B-cells'}", + "40, T {'context': 'B-cells'}", + "41, lymphocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "25, inhibition ['l0', 'l1', 'l2', 'l3', 'l4']", + "27, syngeneic ['l0', 'l5', 'l6', 'l7', 'l8']", + "28, glioma ['l1', 'l5', 'l9', 'l10', 'l11']", + "29, growth. ['l2', 'l6', 'l9', 'l12']", + "36, macrophages/microglia ['l3', 'l7', 'l10', 'l13', 'l14', 'l15']", + "38, astrocytes, ['l4', 'l8', 'l11', 'l12', 'l13', 'l16', 'l17']", + "40, T ['l14', 'l16', 'l18']", + "41, lymphocytes ['l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "syngeneic", + "glioma" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages/microglia", + "astrocytes," + ] + } + } + ] + }, + { + "PMID": "10502827", + "TEXT": "Angiogenesis inhibitors produced by a primary tumor can create a systemic anti-angiogenic environment and maintain metastatic tumor cells in a state of dormancy. We show here that the gallbladder microenvironment modulates the production of transforming growth factor (TGF)-beta1, a multifunctional cytokine that functions as an endogenous anti-angiogenic and anti-tumor factor in a cranial window preparation. We found that a wide variety of human gallbladder tumors express TGF-beta1 irrespective of histologic type. We implanted a gel impregnated with basic fibroblast growth factor or Mz-ChA-2 tumor in the cranial windows of mice without tumors or mice with subcutaneous or gallbladder tumors to study angiogenesis and tumor growth at a secondary site. Angiogenesis, leukocyte-endothelial interaction in vessels and tumor growth in the cranial window were substantially inhibited in mice with gallbladder tumors. The concentration of TGF-beta1 in the plasma of mice with gallbladder tumors was 300% higher than that in the plasma of mice without tumors or with subcutaneous tumors. In contrast, there was no difference in the plasma levels of other anti- and pro-angiogenic factors. Treatment with neutralizing antibody against TGF-beta1 reversed both angiogenesis suppression and inhibition of leukocyte rolling induced by gallbladder tumors. TGF-beta1 also inhibited Mz-ChA-2 tumor cell proliferation. Our results indicate that the production of anti-angiogenesis/proliferation factors is regulated by tumor-host interactions.", + "TAG_DATA": [ + "89, mice {'context': 'B-organism'}", + "91, tumors {'context': 'B-neoplasm'}", + "93, mice {'context': 'B-organism'}", + "115, tumor {'phenotype': 'B-tumour growth'}", + "116, growth {'phenotype': 'I-tumour growth'}", + "123, inhibited {'effect': 'B-negative'}", + "125, mice {'context': 'B-organism'}", + "127, gallbladder {'context': 'B-neoplasm'}", + "128, tumors. {'context': 'I-neoplasm'}", + "137, mice {'context': 'B-organism'}", + "139, gallbladder {'context': 'B-neoplasm'}", + "140, tumors {'context': 'I-neoplasm'}", + "150, mice {'context': 'B-organism'}", + "152, tumors {'context': 'B-neoplasm'}", + "186, leukocyte {'context': 'B-cells'}", + "194, inhibited {'effect': 'B-negative'}", + "195, Mz-ChA-2 {'context': 'B-transformed cells'}", + "196, tumor {'context': 'I-transformed cells'}", + "197, cell {'context': 'I-transformed cells'}", + "198, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "89, mice ['l0', 'l1', 'l2', 'l3']", + "91, tumors ['l0', 'l4', 'l5', 'l6']", + "93, mice ['l7', 'l8', 'l9', 'l10', 'l11']", + "115, tumor ['l1', 'l4', 'l7', 'l12', 'l13', 'l14', 'l15']", + "116, growth ['l2', 'l5', 'l8', 'l12', 'l16', 'l17']", + "123, inhibited ['l3', 'l6', 'l9', 'l13', 'l16', 'l18', 'l19', 'l20']", + "125, mice ['l10', 'l14', 'l18', 'l21', 'l22', 'l23']", + "127, gallbladder ['l19', 'l21', 'l24', 'l25', 'l26', 'l27', 'l28']", + "128, tumors. ['l11', 'l15', 'l17', 'l20', 'l22', 'l24', 'l29']", + "137, mice ['l25', 'l30', 'l31', 'l32', 'l33']", + "139, gallbladder ['l26', 'l30', 'l34', 'l35', 'l36']", + "140, tumors ['l23', 'l27', 'l29', 'l31', 'l34', 'l37', 'l38']", + "150, mice ['l32', 'l35', 'l37', 'l39']", + "152, tumors ['l28', 'l33', 'l36', 'l38', 'l39']", + "186, leukocyte ['l40']", + "191, tumors. ['l40']", + "194, inhibited ['l41', 'l42', 'l43', 'l44']", + "195, Mz-ChA-2 ['l41', 'l45', 'l46', 'l47']", + "196, tumor ['l42', 'l45', 'l48', 'l49']", + "197, cell ['l43', 'l46', 'l48', 'l50']", + "198, proliferation. ['l44', 'l47', 'l49', 'l50']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "tumors." + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "gallbladder", + "tumors." + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "Mz-ChA-2", + "tumor", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "Mz-ChA-2", + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "10502825", + "TEXT": "Huntington disease (HD) is a genetically dominant condition caused by expanded CAG repeats coding for glutamine in the HD gene product huntingtin. Although HD symptoms reflect preferential neuronal death in specific brain regions, huntingtin is expressed in almost all tissues, so abnormalities outside the brain might be expected. Although involvement of nuclei and mitochondria in HD pathophysiology has been suggested, specific intracellular defects that might elicit cell death have been unclear. Mitochondria dysfunction is reported in HD brains; mitochondria are organelles that regulates apoptotic cell death. We now report that lymphoblasts derived from HD patients showed increased stress-induced apoptotic cell death associated with caspase-3 activation. When subjected to stress, HD lymphoblasts also manifested a considerable increase in mitochondrial depolarization correlated with increased glutamine repeats.", + "TAG_DATA": [ + "90, lymphoblasts {'context': 'B-cells'}", + "96, increased {'effect': 'B-positive'}", + "97, stress-induced {'effect': 'B-positive'}", + "98, apoptotic {'phenotype': 'B-apoptosis'}", + "99, cell {'phenotype': 'I-apoptosis'}", + "100, death {'phenotype': 'I-apoptosis'}", + "109, HD {'context': 'B-transformed cells'}", + "110, lymphoblasts {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "90, lymphoblasts ['l0', 'l1', 'l2', 'l3', 'l4']", + "96, increased ['l0', 'l5', 'l6', 'l7', 'l8']", + "97, stress-induced ['l1', 'l5', 'l9', 'l10', 'l11']", + "98, apoptotic ['l2', 'l6', 'l9', 'l12', 'l13']", + "99, cell ['l3', 'l7', 'l10', 'l12', 'l14']", + "100, death ['l4', 'l8', 'l11', 'l13', 'l14']", + "109, HD ['l15']", + "110, lymphoblasts ['l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "lymphoblasts" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "stress-induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "lymphoblasts" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased", + "stress-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cell", + "death" + ] + } + } + ] + }, + { + "PMID": "10395321", + "TEXT": "Definitive cure of an animal model of a human disease by gene transfer into hematopoietic stem cells has not yet been accomplished in the absence of spontaneous in vivo selection for transduced cells. Erythropoietic protoporphyria is a genetic disease in which ferrochelatase is defective. Protoporphyrin accumulates in erythrocytes, leaks into the plasma and results in severe skin photosensitivity. Using a mouse model of erythropoietic protoporphyria, we demonstrate here that ex vivo preselection of hematopoietic stem cells transduced with a polycistronic retrovirus expressing both human ferrochelatase and green fluorescent protein results in complete and long-term correction of skin photosensitivity in all transplanted mice.", + "TAG_DATA": [ + "73, hematopoietic {'context': 'B-cells'}", + "74, stem {'context': 'I-cells'}", + "75, cells {'context': 'I-cells'}", + "76, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "77, with {'perturbing_action': 'I-gene gain-of-function'}", + "78, a {'perturbing_action': 'I-gene gain-of-function'}", + "79, polycistronic {'perturbing_action': 'I-gene gain-of-function'}", + "80, retrovirus {'perturbing_action': 'I-gene gain-of-function'}", + "81, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "82, both {'perturbing_action': 'I-gene gain-of-function'}", + "83, human {'perturbing_action': 'I-gene gain-of-function'}", + "84, ferrochelatase {'perturbing_action': 'I-gene gain-of-function'}", + "85, and {'perturbing_action': 'I-gene gain-of-function'}", + "86, green {'perturbing_action': 'I-gene gain-of-function'}", + "87, fluorescent {'perturbing_action': 'I-gene gain-of-function'}", + "88, protein {'perturbing_action': 'I-gene gain-of-function'}", + "101, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, hematopoietic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "74, stem ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "75, cells ['l1', 'l16', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "76, transduced ['l2', 'l17', 'l31', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "77, with ['l3', 'l18', 'l32', 'l45', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "78, a ['l4', 'l19', 'l33', 'l46', 'l58', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "79, polycistronic ['l5', 'l20', 'l34', 'l47', 'l59', 'l70', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "80, retrovirus ['l6', 'l21', 'l35', 'l48', 'l60', 'l71', 'l81', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "81, expressing ['l7', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "82, both ['l8', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l100', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "83, human ['l9', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l108', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "84, ferrochelatase ['l10', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l115', 'l121', 'l122', 'l123', 'l124', 'l125']", + "85, and ['l11', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l121', 'l126', 'l127', 'l128', 'l129']", + "86, green ['l12', 'l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l126', 'l130', 'l131', 'l132']", + "87, fluorescent ['l13', 'l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l118', 'l123', 'l127', 'l130', 'l133', 'l134']", + "88, protein ['l14', 'l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l113', 'l119', 'l124', 'l128', 'l131', 'l133', 'l135']", + "101, mice. ['l15', 'l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l129', 'l132', 'l134', 'l135']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "a", + "polycistronic", + "retrovirus", + "expressing", + "both", + "human", + "ferrochelatase", + "and", + "green", + "fluorescent", + "protein" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "a", + "polycistronic", + "retrovirus", + "expressing", + "both", + "human", + "ferrochelatase", + "and", + "green", + "fluorescent", + "protein" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "10371499", + "TEXT": "Hypertrophic chondrocytes in the epiphyseal growth plate express the angiogenic protein vascular endothelial growth factor (VEGF). To determine the role of VEGF in endochondral bone formation, we inactivated this factor through the systemic administration of a soluble receptor chimeric protein (Flt-(1-3)-IgG) to 24-day-old mice. Blood vessel invasion was almost completely suppressed, concomitant with impaired trabecular bone formation and expansion of hypertrophic chondrocyte zone. Recruitment and/or differentiation of chondroclasts, which express gelatinase B/matrix metalloproteinase-9, and resorption of terminal chondrocytes decreased. Although proliferation, differentiation and maturation of chondrocytes were apparently normal, resorption was inhibited. Cessation of the anti-VEGF treatment was followed by capillary invasion, restoration of bone growth, resorption of the hypertrophic cartilage and normalization of the growth plate architecture. These findings indicate that VEGF-mediated capillary invasion is an essential signal that regulates growth plate morphogenesis and triggers cartilage remodeling. Thus, VEGF is an essential coordinator of chondrocyte death, chondroclast function, extracellular matrix remodeling, angiogenesis and bone formation in the growth plate.", + "TAG_DATA": [ + "42, 24-day-old {'context': 'B-organism'}", + "43, mice. {'context': 'I-organism'}", + "80, proliferation, {'phenotype': 'B-proliferation'}", + "81, differentiation {'phenotype': 'B-differentiation'}", + "85, chondrocytes {'context': 'B-cells'}", + "88, normal, {'effect': 'B-no effect'}", + "102, restoration {'effect': 'B-rescues'}", + "104, bone {'phenotype': 'B-tumour growth'}", + "105, growth, {'phenotype': 'I-tumour growth'}", + "115, growth {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "42, 24-day-old ['l0', 'l1']", + "43, mice. ['l0']", + "80, proliferation, ['l2', 'l3', 'l4']", + "81, differentiation ['l2', 'l5', 'l6']", + "85, chondrocytes ['l1', 'l3', 'l5', 'l7']", + "88, normal, ['l4', 'l6', 'l7']", + "102, restoration ['l8', 'l9']", + "104, bone ['l8', 'l10']", + "105, growth, ['l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "context": { + "val": "cells", + "words": [ + "chondrocytes" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "normal," + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "chondrocytes" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "normal," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "chondrocytes" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "normal," + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restoration" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "bone", + "growth," + ] + } + } + ] + }, + { + "PMID": "10229234", + "TEXT": "Familial Alzheimer disease mutations of presenilin 1 (PS-1) enhance the generation of A beta1-42, indicating that PS-1 is involved in amyloidogenesis. However, PS-1 transgenic mice have failed to show amyloid plaques in their brains. Because PS-1 mutations facilitate apoptotic neuronal death in vitro, we did careful quantitative studies in PS-1 transgenic mice and found that neurodegeneration was significantly accelerated in mice older than 13 months (aged mice) with familial Alzheimer disease mutant PS-1, without amyloid plaque formation. However, there were significantly more neurons containing intracellularly deposited A beta42 in aged mutant transgenic mice. Our data indicate that the pathogenic role of the PS-1 mutation is upstream of the amyloid cascade.", + "TAG_DATA": [ + "35, PS-1 {'perturbing_action': 'B-other'}", + "36, mutations {'perturbing_action': 'I-other'}", + "37, facilitate {'effect': 'B-positive'}", + "41, in {'context': 'B-in vitro'}", + "42, vitro, {'context': 'I-in vitro'}", + "49, PS-1 {'perturbing_action': 'B-gene gain-of-function'}", + "50, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "51, mice {'context': 'B-organism'}", + "60, mice {'context': 'B-organism'}", + "66, mice) {'context': 'I-organism'}", + "68, familial {'perturbing_action': 'B-other'}", + "69, Alzheimer {'perturbing_action': 'I-other'}", + "70, disease {'perturbing_action': 'I-other'}", + "71, mutant {'perturbing_action': 'I-other'}", + "72, PS-1, {'perturbing_action': 'I-other'}", + "82, neurons {'context': 'B-cells'}", + "91, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "92, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "35, PS-1 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "36, mutations ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "37, facilitate ['l1', 'l9', 'l15', 'l16', 'l17', 'l18', 'l19']", + "41, in ['l2', 'l10', 'l15', 'l20', 'l21', 'l22', 'l23']", + "42, vitro, ['l3', 'l11', 'l16', 'l20', 'l24', 'l25', 'l26']", + "49, PS-1 ['l4', 'l12', 'l17', 'l21', 'l24', 'l27', 'l28']", + "50, transgenic ['l5', 'l13', 'l18', 'l22', 'l25', 'l27', 'l29']", + "51, mice ['l6', 'l14', 'l19', 'l23', 'l26', 'l28', 'l29']", + "60, mice ['l7', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "66, mice) ['l8', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "68, familial ['l31', 'l36', 'l41', 'l42', 'l43', 'l44', 'l45']", + "69, Alzheimer ['l32', 'l37', 'l41', 'l46', 'l47', 'l48', 'l49']", + "70, disease ['l33', 'l38', 'l42', 'l46', 'l50', 'l51', 'l52']", + "71, mutant ['l34', 'l39', 'l43', 'l47', 'l50', 'l53', 'l54']", + "72, PS-1, ['l35', 'l40', 'l44', 'l48', 'l51', 'l53', 'l55']", + "82, neurons ['l45', 'l49', 'l52', 'l54', 'l55', 'l56', 'l57']", + "91, transgenic ['l56', 'l58']", + "92, mice. ['l57', 'l58']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "PS-1", + "mutations" + ] + }, + "effect": { + "val": "positive", + "words": [ + "facilitate" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "PS-1", + "mutations" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "PS-1", + "mutations", + "familial", + "Alzheimer", + "disease", + "mutant", + "PS-1," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice)" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "facilitate" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "facilitate" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PS-1", + "transgenic" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "facilitate" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PS-1", + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PS-1", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "familial", + "Alzheimer", + "disease", + "mutant", + "PS-1," + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neurons" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + } + } + ] + }, + { + "PMID": "10202930", + "TEXT": "Programmed cell death (apoptosis) seems to be the principal mechanism whereby anti-oncogenic therapies such as chemotherapy and radiation effect their responses. Resistance to apoptosis, therefore, is probably a principal mechanism whereby tumors are able to overcome these cancer therapies. The transcription factor NF-kappaB is activated by chemotherapy and by irradiation in some cancer cell lines. Furthermore, inhibition of NF-kappaB in vitro leads to enhanced apoptosis in response to a variety of different stimuli. We show here that inhibition of NF-kappaB through the adenoviral delivery of a modified form of IkappaBalpha, the inhibitor of NF-kappaB, sensitizes chemoresistant tumors to the apoptotic potential of TNFalpha and of the chemotherapeutic compound CPT-11, resulting in tumor regression. These results demonstrate that the activation of NF-kappaB in response to chemotherapy is a principal mechanism of inducible tumor chemoresistance, and establish the inhibition of NF-kappaB as a new approach to adjuvant therapy in cancer treatment.", + "TAG_DATA": [ + "52, cancer {'context': 'B-transformed cells'}", + "53, cell {'context': 'I-transformed cells'}", + "54, lines. {'context': 'I-transformed cells'}", + "56, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "57, of {'perturbing_action': 'I-pharmacological inhibition'}", + "58, NF-kappaB {'perturbing_action': 'I-pharmacological inhibition'}", + "59, in {'context': 'B-in vitro'}", + "60, vitro {'context': 'I-in vitro'}", + "63, enhanced {'effect': 'B-positive'}", + "64, apoptosis {'phenotype': 'B-apoptosis'}", + "77, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "78, of {'perturbing_action': 'I-pharmacological inhibition'}", + "79, NF-kappaB {'perturbing_action': 'I-pharmacological inhibition'}", + "80, through {'perturbing_action': 'I-other'}", + "82, adenoviral {'perturbing_action': 'B-other'}", + "83, delivery {'perturbing_action': 'I-other'}", + "84, of {'perturbing_action': 'I-other'}", + "85, a {'perturbing_action': 'I-other'}", + "86, modified {'perturbing_action': 'I-other'}", + "87, form {'perturbing_action': 'I-other'}", + "88, of {'perturbing_action': 'I-other'}", + "89, IkappaBalpha, {'perturbing_action': 'I-other'}", + "95, chemoresistant {'context': 'B-neoplasm'}", + "96, tumors {'context': 'I-neoplasm'}", + "99, apoptotic {'phenotype': 'B-apoptosis'}", + "100, potential {'phenotype': 'I-apoptosis'}", + "109, resulting {'effect': 'B-positive'}", + "110, in {'effect': 'I-positive'}", + "111, tumor {'phenotype': 'B-tumour regression'}", + "112, regression. {'phenotype': 'I-tumour regression'}" + ], + "LINK_DATA": [ + "52, cancer ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "53, cell ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "54, lines. ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "56, inhibition ['l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "57, of ['l2', 'l9', 'l15', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "58, NF-kappaB ['l3', 'l10', 'l16', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "59, in ['l4', 'l11', 'l17', 'l23', 'l28', 'l32', 'l36', 'l37', 'l38']", + "60, vitro ['l5', 'l12', 'l18', 'l24', 'l29', 'l33', 'l36', 'l39', 'l40']", + "63, enhanced ['l6', 'l13', 'l19', 'l25', 'l30', 'l34', 'l37', 'l39', 'l41']", + "64, apoptosis ['l7', 'l14', 'l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l41']", + "77, inhibition ['l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "78, of ['l42', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "79, NF-kappaB ['l43', 'l58', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "80, through ['l44', 'l59', 'l73', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "82, adenoviral ['l45', 'l60', 'l74', 'l87', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "83, delivery ['l46', 'l61', 'l75', 'l88', 'l101', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "84, of ['l47', 'l62', 'l76', 'l89', 'l102', 'l114', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "85, a ['l48', 'l63', 'l77', 'l90', 'l103', 'l115', 'l126', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146']", + "86, modified ['l49', 'l64', 'l78', 'l91', 'l104', 'l116', 'l127', 'l137', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "87, form ['l50', 'l65', 'l79', 'l92', 'l105', 'l117', 'l128', 'l138', 'l147', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163']", + "88, of ['l51', 'l66', 'l80', 'l93', 'l106', 'l118', 'l129', 'l139', 'l148', 'l156', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170']", + "89, IkappaBalpha, ['l52', 'l67', 'l81', 'l94', 'l107', 'l119', 'l130', 'l140', 'l149', 'l157', 'l164', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176']", + "95, chemoresistant ['l53', 'l68', 'l82', 'l95', 'l108', 'l120', 'l131', 'l141', 'l150', 'l158', 'l165', 'l171', 'l177', 'l178', 'l179', 'l180', 'l181']", + "96, tumors ['l54', 'l69', 'l83', 'l96', 'l109', 'l121', 'l132', 'l142', 'l151', 'l159', 'l166', 'l172', 'l177', 'l182', 'l183', 'l184']", + "99, apoptotic ['l55', 'l70', 'l84', 'l97', 'l110', 'l122', 'l133', 'l143', 'l152', 'l160', 'l167', 'l173', 'l178', 'l182', 'l185', 'l186', 'l187']", + "100, potential ['l56', 'l71', 'l85', 'l98', 'l111', 'l123', 'l134', 'l144', 'l153', 'l161', 'l168', 'l174', 'l179', 'l183', 'l185', 'l188', 'l189']", + "109, resulting ['l57', 'l72', 'l86', 'l99', 'l112', 'l124', 'l135', 'l145', 'l154', 'l162', 'l169', 'l175', 'l180', 'l184', 'l186', 'l188', 'l190', 'l191', 'l192']", + "110, in ['l100', 'l113', 'l125', 'l136', 'l146', 'l155', 'l163', 'l170', 'l176', 'l181', 'l187', 'l189', 'l190', 'l193', 'l194']", + "111, tumor ['l191', 'l193', 'l195']", + "112, regression. ['l192', 'l194', 'l195']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cell", + "lines." + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "of", + "NF-kappaB" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cell", + "lines." + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cell", + "lines." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "NF-kappaB" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "NF-kappaB" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced", + "resulting" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "NF-kappaB" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptotic", + "potential" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced", + "resulting", + "in" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptotic", + "potential" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "NF-kappaB" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "chemoresistant", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "through", + "adenoviral", + "delivery", + "of", + "a", + "modified", + "form", + "IkappaBalpha," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "chemoresistant", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "through", + "adenoviral", + "delivery", + "of", + "a", + "modified", + "form", + "IkappaBalpha," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "potential" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "through", + "adenoviral", + "delivery", + "of", + "a", + "modified", + "form", + "IkappaBalpha," + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "chemoresistant", + "tumors" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "potential" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "chemoresistant", + "tumors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression." + ] + } + } + ] + }, + { + "PMID": "10202926", + "TEXT": "Food allergy is a common and often fatal disease with no effective treatment. We describe here a new immunoprophylactic strategy using oral allergen-gene immunization to modulate peanut antigen-induced murine anaphylactic responses. Oral administration of DNA nanoparticles synthesized by complexing plasmid DNA with chitosan, a natural biocompatible polysaccharide, resulted in transduced gene expression in the intestinal epithelium. Mice receiving nanoparticles containing a dominant peanut allergen gene (pCMVArah2) produced secretory IgA and serum IgG2a. Compared with non-immunized mice or mice treated with 'naked' DNA, mice immunized with nanoparticles showed a substantial reduction in allergen-induced anaphylaxis associated with reduced levels of IgE, plasma histamine and vascular leakage. These results demonstrate that oral allergen-gene immunization with chitosan-DNA nanoparticles is effective in modulating murine anaphylactic responses, and indicate its prophylactic utility in treating food allergy.", + "TAG_DATA": [ + "54, intestinal {'context': 'B-tissue/organ'}", + "55, epithelium. {'context': 'I-tissue/organ'}", + "56, Mice {'context': 'B-organism'}", + "75, mice {'context': 'B-organism'}", + "77, mice {'context': 'B-organism'}", + "82, mice {'context': 'B-organism'}", + "89, reduction {'effect': 'B-negative'}", + "91, allergen-induced {'effect': 'B-positive'}", + "92, anaphylaxis {'phenotype': 'B-autophagy'}" + ], + "LINK_DATA": [ + "54, intestinal ['l0']", + "55, epithelium. ['l0']", + "77, mice ['l1', 'l2', 'l3', 'l4']", + "82, mice ['l1', 'l5', 'l6', 'l7']", + "89, reduction ['l2', 'l5', 'l8', 'l9']", + "91, allergen-induced ['l3', 'l6', 'l8', 'l10']", + "92, anaphylaxis ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduction" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "allergen-induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "anaphylaxis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduction" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "anaphylaxis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "allergen-induced" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "anaphylaxis" + ] + } + } + ] + }, + { + "PMID": "10086392", + "TEXT": "The tumor suppressor protein p53 is an essential molecule in cell proliferation and programmed cell death (apoptosis), and has been postulated to play a principal part in the development of atherosclerosis. We have examined the effect of p53 inactivation on atherogenesis in apoE-knockout mice, an animal model for atherosclerosis. We found that, compared with p53+/+/apoE-/- mice, p53-/-/apoE-/- mice developed considerably accelerated aortic atherosclerosis in the presence of a similar serum cholesterol in response to a high-fat diet. Furthermore, the atherosclerotic lesions in p53-/-/apoE-/- mice had a significant (approximately 280%) increase in cell proliferation rate and an insignificant (approximately 180%) increase in apoptosis compared with those in p53+/+/apoE-/- mice. Our observations indicate that the role of p53 in atherosclerotic lesion development might be associated with its function in cell replication control, and that p53-independent mechanisms can mediate the apoptotic response in atherosclerosis.", + "TAG_DATA": [ + "42, apoE-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "43, mice, {'context': 'B-organism'}", + "54, p53+/+/apoE-/- {'perturbing_action': 'B-gene loss-of-function'}", + "55, mice, {'context': 'B-organism'}", + "56, p53-/-/apoE-/- {'perturbing_action': 'B-gene loss-of-function'}", + "57, mice {'context': 'B-organism'}", + "61, aortic {'context': 'B-tissue/organ'}", + "82, p53-/-/apoE-/- {'perturbing_action': 'B-gene loss-of-function'}", + "83, mice {'context': 'B-organism'}", + "89, increase {'effect': 'B-positive'}", + "91, cell {'context': 'B-cells'}", + "92, proliferation {'phenotype': 'B-proliferation'}", + "99, increase {'effect': 'B-positive'}", + "101, apoptosis {'phenotype': 'B-apoptosis'}", + "106, p53+/+/apoE-/- {'perturbing_action': 'B-gene loss-of-function'}", + "107, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "42, apoE-knockout ['l0', 'l1']", + "43, mice, ['l0', 'l2']", + "54, p53+/+/apoE-/- ['l3', 'l4', 'l5', 'l6']", + "55, mice, ['l3', 'l7', 'l8', 'l9']", + "56, p53-/-/apoE-/- ['l4', 'l7', 'l10', 'l11']", + "57, mice ['l5', 'l8', 'l10', 'l12']", + "61, aortic ['l1', 'l2', 'l6', 'l9', 'l11', 'l12']", + "82, p53-/-/apoE-/- ['l13', 'l14', 'l15', 'l16', 'l17']", + "83, mice ['l13', 'l18', 'l19', 'l20']", + "89, increase ['l14', 'l18', 'l21', 'l22']", + "91, cell ['l15', 'l19', 'l21', 'l23']", + "92, proliferation ['l16', 'l20', 'l22', 'l23']", + "99, increase ['l17', 'l24', 'l25']", + "101, apoptosis ['l24', 'l26', 'l27']", + "106, p53+/+/apoE-/- ['l26', 'l28']", + "107, mice. ['l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "apoE-knockout", + "p53+/+/apoE-/-", + "p53-/-/apoE-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "apoE-knockout", + "p53+/+/apoE-/-", + "p53-/-/apoE-/-" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "aortic" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-/-/apoE-/-" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increase" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-/-/apoE-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-/-/apoE-/-" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "effect": { + "val": "positive", + "words": [ + "increase" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53+/+/apoE-/-" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "10086382", + "TEXT": "Prostate cancer progresses from a hormone-sensitive, androgen-dependent stage to a hormone-refractory, androgen-independent tumor. The androgen receptor pathway functions in these androgen-independent tumors despite anti-androgen therapy. In our LAPC-4 prostate cancer model, androgen-independent sublines expressed higher levels of the HER-2/neu receptor tyrosine kinase than their androgen-dependent counterparts. Forced overexpression of HER-2/neu in androgen-dependent prostate cancer cells allowed ligand-independent growth. HER-2/neu activated the androgen receptor pathway in the absence of ligand and synergized with low levels of androgen to 'superactivate' the pathway. By modulating the response to low doses of androgen, a tyrosine kinase receptor can restore androgen receptor function to prostate cancer cells, a finding directly related to the clinical progression of prostate cancer.", + "TAG_DATA": [ + "46, Forced {'perturbing_action': 'B-gene gain-of-function'}", + "47, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "48, of {'perturbing_action': 'I-gene gain-of-function'}", + "49, HER-2/neu {'perturbing_action': 'I-gene gain-of-function'}", + "51, androgen-dependent {'context': 'B-transformed cells'}", + "52, prostate {'context': 'I-transformed cells'}", + "53, cancer {'context': 'I-transformed cells'}", + "54, cells {'context': 'I-transformed cells'}", + "99, prostate {'context': 'B-transformed cells'}", + "100, cancer {'context': 'I-transformed cells'}", + "101, cells, {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "46, Forced ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "47, overexpression ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "48, of ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "49, HER-2/neu ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "51, androgen-dependent ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "52, prostate ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "53, cancer ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "54, cells ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "99, prostate ['l28', 'l29']", + "100, cancer ['l28', 'l30']", + "101, cells, ['l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "overexpression", + "of", + "HER-2/neu" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "androgen-dependent", + "prostate", + "cancer", + "cells" + ] + } + } + ] + }, + { + "PMID": "9930871", + "TEXT": "Prostaglandins (PGs) are ubiquitous lipid mediators derived from cyclooxygenase metabolism of arachidonic acid that exert a broad range of physiologic activities, including modulation of inflammation, ovulation and arterial blood pressure. PGE2, a chief cyclooxygenase product, modulates blood pressure and fertility, although the specific G protein-coupled receptors mediating these effects remain poorly defined. To evaluate the physiologic role of the PGE2 EP2 receptor subtype, we created mice with targeted disruption of this gene (EP2-/-). EP2-/- mice develop normally but produce small litters and have slightly elevated baseline systolic blood pressure. In EP2-/- mice, the characteristic hypotensive effect of intravenous PGE2 infusion was absent; PGE2 infusion instead produced hypertension. When fed a diet high in salt, the EP2-/- mice developed profound systolic hypertension, whereas wild-type mice showed no change in systolic blood pressure. Analysis of wild-type and EP2-/- mice on day 5 of pregnancy indicated that the reduced litter size of EP2-/- mice is due to a pre-implantation defect. This reduction of implanted embryos could be accounted for by impaired ovulation and dramatic reductions in fertilization observed on day 2 of pregnancy. These data demonstrate that the EP2 receptor mediates arterial dilatation, salt-sensitive hypertension, and also plays an essential part in female fertility.", + "TAG_DATA": [ + "65, mice {'context': 'B-organism'}", + "67, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "68, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "69, of {'perturbing_action': 'I-gene loss-of-function'}", + "70, this {'perturbing_action': 'I-gene loss-of-function'}", + "71, gene {'perturbing_action': 'I-gene loss-of-function'}", + "72, (EP2-/-). {'perturbing_action': 'I-gene loss-of-function'}", + "73, EP2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "74, mice {'context': 'B-organism'}", + "90, EP2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "91, mice, {'context': 'B-organism'}", + "115, EP2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "116, mice {'context': 'B-organism'}", + "123, mice {'context': 'B-organism'}", + "135, EP2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "136, mice {'context': 'B-organism'}", + "149, EP2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "150, mice {'context': 'B-organism'}", + "167, impaired {'effect': 'B-negative'}", + "171, reductions {'effect': 'B-negative'}", + "173, fertilization {'phenotype': 'B-ferroptosis'}" + ], + "LINK_DATA": [ + "65, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "67, targeted ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "68, disruption ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "69, of ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "70, this ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "71, gene ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "72, (EP2-/-). ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "73, EP2-/- ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35', 'l36']", + "74, mice ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "90, EP2-/- ['l37']", + "91, mice, ['l36', 'l37']", + "115, EP2-/- ['l38', 'l39']", + "116, mice ['l38']", + "123, mice ['l39', 'l40', 'l41']", + "135, EP2-/- ['l40', 'l42', 'l43', 'l44', 'l45', 'l46']", + "136, mice ['l41', 'l42', 'l47', 'l48', 'l49']", + "149, EP2-/- ['l43', 'l47', 'l50', 'l51', 'l52', 'l53', 'l54']", + "150, mice ['l44', 'l48', 'l50', 'l55', 'l56']", + "161, embryos ['l45', 'l49', 'l51', 'l55', 'l57', 'l58', 'l59']", + "167, impaired ['l46', 'l52', 'l56', 'l57', 'l60', 'l61']", + "171, reductions ['l53', 'l58', 'l60', 'l62']", + "173, fertilization ['l54', 'l59', 'l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "disruption", + "of", + "this", + "gene", + "(EP2-/-).", + "EP2-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EP2-/-" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired", + "reductions" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EP2-/-" + ] + }, + "phenotype": { + "val": "ferroptosis", + "words": [ + "fertilization" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired", + "reductions" + ] + }, + "phenotype": { + "val": "ferroptosis", + "words": [ + "fertilization" + ] + } + } + ] + }, + { + "PMID": "9930868", + "TEXT": "A substantial risk in using live attenuated, multiply deleted viruses as vaccines against AIDS is their potential to induce AIDS. A mutant of the simian immunodeficiency virus (SIV) with large deletions in nef and vpr and in the negative regulatory element induced AIDS in six of eight infant macaques vaccinated orally or intravenously. Early signs of immune dysfunction were seen in the remaining two offspring. Prolonged follow-up of sixteen vaccinated adult macaques also showed resurgence of chronic viremia in four animals: two of these developed early signs of disease and one died of AIDS. We conclude that this multiply deleted SIV is pathogenic and that human AIDS vaccines built on similar prototypes may cause AIDS.", + "TAG_DATA": [ + "21, mutant {'perturbing_action': 'B-other'}", + "22, of {'perturbing_action': 'I-other'}", + "23, the {'perturbing_action': 'I-other'}", + "24, simian {'perturbing_action': 'I-other'}", + "25, immunodeficiency {'perturbing_action': 'I-other'}", + "26, virus {'perturbing_action': 'I-other'}", + "27, (SIV) {'perturbing_action': 'I-other'}", + "28, with {'perturbing_action': 'I-other'}", + "29, large {'perturbing_action': 'I-other'}", + "30, deletions {'perturbing_action': 'I-other'}", + "31, in {'perturbing_action': 'I-other'}", + "32, nef {'perturbing_action': 'I-gene loss-of-function'}", + "33, and {'perturbing_action': 'I-gene loss-of-function'}", + "34, vpr {'perturbing_action': 'I-gene loss-of-function'}", + "35, and {'perturbing_action': 'I-other'}", + "36, in {'perturbing_action': 'I-other'}", + "37, the {'perturbing_action': 'I-other'}", + "38, negative {'perturbing_action': 'I-other'}", + "39, regulatory {'perturbing_action': 'I-other'}", + "40, element {'perturbing_action': 'I-other'}", + "47, infant {'context': 'B-organism'}", + "48, macaques {'context': 'I-organism'}", + "70, adult {'context': 'B-organism'}", + "71, macaques {'context': 'I-organism'}", + "80, animals: {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "21, mutant ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "22, of ['l0', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "23, the ['l1', 'l21', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "24, simian ['l2', 'l22', 'l41', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "25, immunodeficiency ['l3', 'l23', 'l42', 'l59', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "26, virus ['l4', 'l24', 'l43', 'l60', 'l76', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "27, (SIV) ['l5', 'l25', 'l44', 'l61', 'l77', 'l91', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "28, with ['l6', 'l26', 'l45', 'l62', 'l78', 'l92', 'l105', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "29, large ['l7', 'l27', 'l46', 'l63', 'l79', 'l93', 'l106', 'l117', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "30, deletions ['l8', 'l28', 'l47', 'l64', 'l80', 'l94', 'l107', 'l118', 'l131', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "31, in ['l9', 'l29', 'l48', 'l65', 'l81', 'l95', 'l108', 'l119', 'l132', 'l144', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166']", + "32, nef ['l10', 'l30', 'l49', 'l66', 'l82', 'l96', 'l109', 'l120', 'l133', 'l145', 'l156', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176']", + "33, and ['l11', 'l31', 'l50', 'l67', 'l83', 'l97', 'l110', 'l121', 'l134', 'l146', 'l157', 'l167', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185']", + "34, vpr ['l12', 'l32', 'l51', 'l68', 'l84', 'l98', 'l111', 'l122', 'l135', 'l147', 'l158', 'l168', 'l177', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "35, and ['l13', 'l33', 'l52', 'l69', 'l85', 'l99', 'l112', 'l123', 'l136', 'l148', 'l159', 'l169', 'l178', 'l186', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200']", + "36, in ['l14', 'l34', 'l53', 'l70', 'l86', 'l100', 'l113', 'l124', 'l137', 'l149', 'l160', 'l170', 'l179', 'l187', 'l194', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206']", + "37, the ['l15', 'l35', 'l54', 'l71', 'l87', 'l101', 'l114', 'l125', 'l138', 'l150', 'l161', 'l171', 'l180', 'l188', 'l195', 'l201', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213']", + "38, negative ['l16', 'l36', 'l126', 'l139', 'l151', 'l162', 'l172', 'l181', 'l189', 'l196', 'l202', 'l207', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220']", + "39, regulatory ['l17', 'l37', 'l55', 'l72', 'l127', 'l140', 'l152', 'l163', 'l173', 'l182', 'l190', 'l197', 'l203', 'l208', 'l214', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226']", + "40, element ['l18', 'l38', 'l56', 'l73', 'l88', 'l102', 'l128', 'l141', 'l153', 'l164', 'l174', 'l183', 'l191', 'l198', 'l204', 'l209', 'l215', 'l221', 'l227', 'l228', 'l229', 'l230']", + "47, infant ['l19', 'l39', 'l57', 'l74', 'l89', 'l103', 'l115', 'l129', 'l142', 'l154', 'l165', 'l175', 'l184', 'l192', 'l199', 'l205', 'l210', 'l216', 'l222', 'l227', 'l231']", + "48, macaques ['l20', 'l40', 'l58', 'l75', 'l90', 'l104', 'l116', 'l130', 'l143', 'l155', 'l166', 'l176', 'l185', 'l193', 'l200', 'l206', 'l211', 'l217', 'l223', 'l228', 'l231']", + "70, adult ['l212', 'l218', 'l224', 'l229', 'l232', 'l233']", + "71, macaques ['l213', 'l219', 'l225', 'l230', 'l232', 'l234']", + "80, animals: ['l220', 'l226', 'l233', 'l234']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "of", + "the", + "simian", + "immunodeficiency", + "virus", + "(SIV)", + "with", + "large", + "deletions", + "in", + "and", + "negative", + "regulatory", + "element" + ] + }, + "context": { + "val": "organism", + "words": [ + "infant", + "macaques", + "adult", + "animals:" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nef", + "and", + "vpr" + ] + }, + "context": { + "val": "organism", + "words": [ + "infant", + "macaques" + ] + } + } + ] + }, + { + "PMID": "9883845", + "TEXT": "Fas ligand (FasL) triggers apoptosis during cytotoxicity mediated by cytotoxic T lymphocytes and during immune downregulation. The ability of T cells and natural killer cells to trigger apoptosis through this mechanism is controlled by the cell surface expression of FasL (ref. 2). Because FasL expression is up-regulated on activation, FasL was thought to be delivered directly to the cell surface. Here we show that newly synthesized FasL is stored in specialized secretory lysosomes in both CD4+ and CD8+ T cells and natural killer cells, and that polarized degranulation controls the delivery of FasL to the cell surface. In this way, FasL-mediated apoptosis is finely controlled by receptor-mediated target-cell recognition. The cytoplasmic tail of FasL contains signals that sort FasL to secretory lysosomes in hemopoietic cells. This pathway may provide a general mechanism for controlling the cell surface appearance of proteins involved in immune regulation.", + "TAG_DATA": [ + "100, FasL-mediated {'effect': 'B-regulates'}", + "101, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "100, FasL-mediated ['l0']", + "101, apoptosis ['l0']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "regulates", + "words": [ + "FasL-mediated" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "9883842", + "TEXT": "Adeno-associated virus 2 (AAV)-based vectors have gained attention as a potentially useful alternative to the more commonly used retroviral and adenoviral vectors for human gene therapy. Although AAV uses the ubiquitously expressed cell surface heparan sulfate proteoglycan (HSPG) as a receptor, the transduction efficiency of AAV vectors varies greatly in different cells and tissues in vitro and in vivo. We demonstrate here that cell surface expression of HSPG alone is insufficient for AAV infection, and that AAV also requires human fibroblast growth factor receptor 1 (FGFR1) as a co-receptor for successful viral entry into the host cell. We document that cells that do not express either HSPG or FGFR1 fail to bind AAV and, consequently, are resistant to infection by AAV. These non-permissive cells are successfully transduced by AAV vectors after stable transfections with cDNAs encoding the murine HSPG and the human FGFR1. Furthermore, AAV infection of permissive cells, known to express both FGFR1 and the epidermal growth factor receptor, is abrogated by treatment of cells with basic fibroblast growth factor, but not with epidermal growth factor. The identification of FGFR1 as a co-receptor for AAV should provide new insights not only into its role in the life cycle of AAV, but also in the optimal use of AAV vectors in human gene therapy.", + "TAG_DATA": [ + "100, cells {'context': 'B-cells'}", + "122, non-permissive {'context': 'B-cells'}", + "123, cells {'context': 'I-cells'}", + "131, stable {'perturbing_action': 'B-gene gain-of-function'}", + "132, transfections {'perturbing_action': 'I-gene gain-of-function'}", + "133, with {'perturbing_action': 'I-gene gain-of-function'}", + "134, cDNAs {'perturbing_action': 'I-gene gain-of-function'}", + "135, encoding {'perturbing_action': 'I-gene gain-of-function'}", + "136, the {'perturbing_action': 'I-gene gain-of-function'}", + "137, murine {'perturbing_action': 'I-gene gain-of-function'}", + "138, HSPG {'perturbing_action': 'I-gene gain-of-function'}", + "139, and {'perturbing_action': 'I-gene gain-of-function'}", + "140, the {'perturbing_action': 'I-gene gain-of-function'}", + "141, human {'perturbing_action': 'I-gene gain-of-function'}", + "142, FGFR1. {'perturbing_action': 'I-gene gain-of-function'}", + "147, permissive {'context': 'B-cells'}", + "148, cells, {'context': 'I-cells'}", + "165, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "122, non-permissive ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "123, cells ['l0', 'l10', 'l11', 'l12', 'l13', 'l14']", + "131, stable ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "132, transfections ['l15', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "133, with ['l1', 'l16', 'l28', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "134, cDNAs ['l17', 'l29', 'l40', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "135, encoding ['l2', 'l18', 'l30', 'l41', 'l51', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "136, the ['l3', 'l10', 'l19', 'l31', 'l42', 'l52', 'l61', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "137, murine ['l4', 'l11', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "138, HSPG ['l5', 'l12', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "139, and ['l6', 'l13', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l91', 'l92', 'l93', 'l94', 'l95']", + "140, the ['l7', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l96', 'l97', 'l98', 'l99']", + "141, human ['l8', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l100', 'l101', 'l102']", + "142, FGFR1. ['l9', 'l14', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l103', 'l104']", + "147, permissive ['l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l105', 'l106']", + "148, cells, ['l27', 'l39', 'l50', 'l60', 'l69', 'l77', 'l84', 'l90', 'l95', 'l99', 'l102', 'l104', 'l105', 'l107']", + "165, cells ['l106', 'l107']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "non-permissive", + "cells", + "permissive", + "cells," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "with", + "encoding", + "the", + "murine", + "HSPG", + "and", + "human", + "FGFR1.", + "stable", + "transfections", + "cDNAs" + ] + } + } + ] + }, + { + "PMID": "9846576", + "TEXT": "We investigated the pathogenesis of chronic allograft rejection in mouse cardiac allografts. Long-term survival occurred after administration of monoclonal antibody to CD4 or CD40-ligand (CD40L) plus donor cells. Both treatments induced permanent graft survival, but, in contrast to transplants in mice treated with CD4 monoclonal antibody, grafts in mice treated with CD40L monoclonal antibody lacked evidence of chronic rejection, including transplant arteriosclerosis. Freedom from chronic rejection in the group treated with CD40L monoclonal antibody correlated with vascular expression of the 'protective' genes heme oxygenase-1 (HO-1), Bcl-xL and A20. Moreover, arteriosclerosis was induced in allografts in immunoglobulin-deficient mice by antibody transfer only when the transfer was done before expression of protective genes. A direct role for protective gene expression in endothelial cells was demonstrated by in vitro experiments in which induction of HO-1 or Bcl-xL suppressed alloantibody-stimulated endothelial activation. Finally, induction of HO-1 in vivo protected allografts against chronic injury. These data show a role for protective genes in the prevention of chronic rejection, and indicate new approaches to protect grafts against development of transplant arteriosclerosis.", + "TAG_DATA": [ + "40, mice {'context': 'B-organism'}", + "46, grafts {'context': 'B-xenograft'}", + "48, mice {'context': 'B-organism'}", + "93, allografts {'context': 'B-xenograft'}", + "95, immunoglobulin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "96, mice {'context': 'B-organism'}", + "124, in {'context': 'B-in vitro'}", + "125, vitro {'context': 'I-in vitro'}", + "129, induction {'perturbing_action': 'B-gene gain-of-function'}", + "130, of {'perturbing_action': 'I-gene gain-of-function'}", + "131, HO-1 {'perturbing_action': 'I-gene gain-of-function'}", + "132, or {'perturbing_action': 'I-gene gain-of-function'}", + "133, Bcl-xL {'perturbing_action': 'I-gene gain-of-function'}", + "139, induction {'perturbing_action': 'B-gene gain-of-function'}", + "140, of {'perturbing_action': 'I-gene gain-of-function'}", + "141, HO-1 {'perturbing_action': 'I-pharmacological augmentation'}", + "142, in {'context': 'B-in vivo'}", + "143, vivo {'context': 'I-in vivo'}", + "145, allografts {'context': 'B-xenograft'}" + ], + "LINK_DATA": [ + "40, mice ['l0', 'l1', 'l2']", + "46, grafts ['l0', 'l3', 'l4', 'l5']", + "48, mice ['l1', 'l3', 'l6', 'l7']", + "93, allografts ['l2', 'l4', 'l6', 'l8', 'l9']", + "95, immunoglobulin-deficient ['l8', 'l10', 'l11']", + "96, mice ['l5', 'l7', 'l9', 'l10']", + "124, in ['l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "125, vitro ['l12', 'l18', 'l19', 'l20', 'l21', 'l22']", + "129, induction ['l13', 'l18', 'l23', 'l24', 'l25', 'l26', 'l27']", + "130, of ['l14', 'l19', 'l23', 'l28', 'l29', 'l30']", + "131, HO-1 ['l15', 'l20', 'l24', 'l28', 'l31', 'l32']", + "132, or ['l16', 'l21', 'l25', 'l29', 'l31', 'l33']", + "133, Bcl-xL ['l17', 'l22', 'l26', 'l30', 'l32', 'l33']", + "139, induction ['l34', 'l35', 'l36', 'l37', 'l38']", + "140, of ['l34', 'l39', 'l40', 'l41', 'l42']", + "141, HO-1 ['l35', 'l39', 'l43', 'l44', 'l45']", + "142, in ['l36', 'l40', 'l43', 'l46', 'l47']", + "143, vivo ['l37', 'l41', 'l44', 'l46', 'l48']", + "145, allografts ['l27', 'l38', 'l42', 'l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "xenograft", + "words": [ + "allografts" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immunoglobulin-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immunoglobulin-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immunoglobulin-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "induction", + "of", + "HO-1", + "or", + "Bcl-xL" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "induction", + "of" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "allografts" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "induction", + "of" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "HO-1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "HO-1" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "allografts" + ] + } + } + ] + }, + { + "PMID": "9846574", + "TEXT": "Fas Ligand (FasL) can induce apoptosis of Fas-bearing cells. It is expressed on the cell surface of many tumor cells, immune-privileged tissues and activated lymphocytes. We report here that FasL can itself transduce signals, leading to cell-cycle arrest and cell death in CD4+ T cells. In vitro, FasL engagement inhibited CD4+ T-cell proliferation, cell-cycle progression, and IL-2 secretion. In vivo, FasL engagement prevented superantigen-mediated CD4+, but not CD8+, T-cell expansion. These findings demonstrate that FasL engagement regulates cell-cycle progression, and show that FasL engagement in vivo has a potent anti-inflammatory effect specific for CD4+ T cells.", + "TAG_DATA": [ + "36, cell-cycle {'phenotype': 'B-cell cycle arrest'}", + "37, arrest {'phenotype': 'I-cell cycle arrest'}", + "39, cell {'phenotype': 'B-cell death'}", + "40, death {'phenotype': 'I-cell death'}", + "42, CD4+ {'context': 'B-cells'}", + "43, T {'context': 'I-cells'}", + "44, cells. {'context': 'I-cells'}", + "45, In {'context': 'B-in vitro'}", + "46, vitro, {'context': 'I-in vitro'}", + "49, inhibited {'effect': 'B-negative'}", + "50, CD4+ {'context': 'B-cells'}", + "51, T-cell {'context': 'I-cells'}", + "52, proliferation, {'phenotype': 'B-proliferation'}", + "58, In {'context': 'B-in vivo'}", + "59, vivo, {'context': 'I-in vivo'}", + "64, CD4+, {'context': 'B-cells'}", + "67, CD8+, {'context': 'B-cells'}", + "68, T-cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "36, cell-cycle ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "37, arrest ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "39, cell ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "40, death ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "42, CD4+ ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "43, T ['l4', 'l12', 'l19', 'l25', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "44, cells. ['l5', 'l13', 'l20', 'l26', 'l31', 'l38', 'l44', 'l45', 'l46']", + "45, In ['l6', 'l14', 'l21', 'l27', 'l32', 'l39', 'l44', 'l47', 'l48', 'l49', 'l50', 'l51']", + "46, vitro, ['l7', 'l15', 'l22', 'l28', 'l33', 'l40', 'l45', 'l47', 'l52', 'l53', 'l54', 'l55']", + "49, inhibited ['l34', 'l48', 'l52', 'l56', 'l57', 'l58']", + "50, CD4+ ['l35', 'l41', 'l49', 'l53', 'l56', 'l59', 'l60']", + "51, T-cell ['l36', 'l42', 'l50', 'l54', 'l57', 'l59', 'l61']", + "52, proliferation, ['l8', 'l16', 'l23', 'l29', 'l37', 'l43', 'l46', 'l51', 'l55', 'l58', 'l60', 'l61']", + "58, In ['l62', 'l63', 'l64', 'l65']", + "59, vivo, ['l62', 'l66', 'l67', 'l68']", + "64, CD4+, ['l63', 'l66', 'l69', 'l70']", + "67, CD8+, ['l64', 'l67', 'l69', 'l71']", + "68, T-cell ['l65', 'l68', 'l70', 'l71']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells." + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells." + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4+", + "T-cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells.", + "T-cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + } + ] + }, + { + "PMID": "9809547", + "TEXT": "Modifying bacterial virulence genes to probe the nature of host immunity is mostly unexplored. Here we investigate whether host immune responses can be regulated by modification of bacterial virulence genes. In mice, attenuated Salmonella mutant strains with clinical relevance elicited differential host immune responses. Oral administration of a mutant strain with a PhoP-null phenotype promoted potent innate immune responses of macrophages that were sufficient for host defense. In contrast, administration of an Aro- mutant strain elicited stronger specific antibody and T-helper (Th)-cell responses, wherein Th1-type cells were required for clearance. Thus, genetic manipulation of bacteria may be used to broadly alter immune mechanisms that regulate attenuation within the host and to tailor host immunity to specific bacterial pathogens.", + "TAG_DATA": [ + "31, mice, {'context': 'B-organism'}", + "49, strain {'perturbing_action': 'I-other'}", + "52, PhoP-null {'perturbing_action': 'B-gene loss-of-function'}", + "53, phenotype {'perturbing_action': 'I-gene loss-of-function'}", + "60, macrophages {'context': 'B-cells'}", + "72, Aro- {'perturbing_action': 'B-other'}", + "73, mutant {'perturbing_action': 'B-other'}", + "74, strain {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "49, strain ['l0', 'l1', 'l2', 'l3', 'l4']", + "52, PhoP-null ['l0', 'l5', 'l6', 'l7', 'l8', 'l9']", + "53, phenotype ['l1', 'l5', 'l10', 'l11', 'l12', 'l13']", + "60, macrophages ['l2', 'l6', 'l10']", + "72, Aro- ['l7', 'l11', 'l14', 'l15']", + "73, mutant ['l3', 'l8', 'l12', 'l14', 'l16']", + "74, strain ['l4', 'l9', 'l13', 'l15', 'l16']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "strain" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PhoP-null", + "phenotype" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages" + ] + } + } + ] + }, + { + "PMID": "9771755", + "TEXT": "Oxidative modification of low density lipoprotein (LDL) has been implicated in atherogenesis. Evidence consistent with this hypothesis includes the presence of oxidized lipids in atherosclerotic lesions, the newly discovered biological properties conferred on LDL by oxidation and the acceleration of atherogenesis by in vivo delivery of the gene for 15-lipoxygenase, an oxidizing enzyme present in atherosclerotic lesions. However, it is still unknown whether oxidative stress actually coincides with the evolution of the disease or whether it is of functional relevance to atherogenesis in vivo. Isoprostanes are products of arachidonic acid catalyzed by free radicals, which reflect oxidative stress and lipid peroxidation in vivo. Elevation of tissue and urinary isoprostanes is characteristic of human atherosclerosis. Here, deficiency in apolipoprotein E in the mouse (apoE-/-) resulted in atherogenesis and an increase in iPF2alpha-VI, an F2-isoprostane, in urine, plasma and vascular tissue. Supplementation with vitamin E significantly reduced isoprostane generation, but had no effect on plasma cholesterol levels in apoE-/- mice. Aortic lesion areas and iPF2alpha-VI levels in the arterial wall were also reduced significantly by vitamin E. Our results indicate that oxidative stress is increased in the apoE-/- mouse, is of functional importance in the evolution of atherosclerosis and can be suppressed by oral administration of vitamin E.", + "TAG_DATA": [ + "115, deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "116, in {'perturbing_action': 'I-gene loss-of-function'}", + "117, apolipoprotein {'perturbing_action': 'I-gene loss-of-function'}", + "118, E {'perturbing_action': 'I-gene loss-of-function'}", + "121, mouse {'context': 'B-organism'}", + "156, apoE-/- {'perturbing_action': 'B-gene loss-of-function'}", + "157, mice. {'context': 'B-organism'}", + "166, arterial {'context': 'B-tissue/organ'}", + "167, wall {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "115, deficiency ['l0', 'l1', 'l2', 'l3']", + "116, in ['l0', 'l4', 'l5', 'l6']", + "117, apolipoprotein ['l1', 'l4', 'l7', 'l8']", + "118, E ['l2', 'l5', 'l7', 'l9']", + "121, mouse ['l3', 'l6', 'l8', 'l9']", + "156, apoE-/- ['l10']", + "157, mice. ['l10']", + "166, arterial ['l11']", + "167, wall ['l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "in", + "apolipoprotein", + "E", + "apoE-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "mice." + ] + } + } + ] + }, + { + "PMID": "9771748", + "TEXT": "Brain serotonin and leptin signaling contribute substantially to the regulation of feeding and energy expenditure. Here we show that young adult mice with a targeted mutation of the serotonin 5-HT2C receptor gene consume more food despite normal responses to exogenous leptin administration. Chronic hyperphagia leads to a 'middle-aged'-onset obesity associated with a partial leptin resistance of late onset. In addition, older mice develop insulin resistance and impaired glucose tolerance. Mutant mice also responded more to high-fat feeding, leading to hyperglycemia without hyperlipidemia. These findings demonstrate a dissociation of serotonin and leptin signaling in the regulation of feeding and indicate that a perturbation of brain serotonin systems can predispose to type 2 diabetes.", + "TAG_DATA": [ + "19, young {'context': 'B-organism'}", + "20, adult {'context': 'I-organism'}", + "21, mice {'context': 'I-organism'}", + "24, targeted {'perturbing_action': 'B-other'}", + "25, mutation {'perturbing_action': 'I-other'}", + "26, of {'perturbing_action': 'I-other'}", + "27, the {'perturbing_action': 'I-other'}", + "28, serotonin {'perturbing_action': 'I-other'}", + "29, 5-HT2C {'perturbing_action': 'I-other'}", + "30, receptor {'perturbing_action': 'I-other'}", + "31, gene {'perturbing_action': 'I-other'}", + "60, older {'context': 'B-organism'}", + "61, mice {'context': 'I-organism'}", + "69, Mutant {'perturbing_action': 'B-other'}", + "70, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "19, young ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "20, adult ['l0', 'l9', 'l10', 'l11', 'l12', 'l13']", + "21, mice ['l1', 'l9', 'l14', 'l15']", + "24, targeted ['l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "25, mutation ['l2', 'l16', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "26, of ['l3', 'l17', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "27, the ['l4', 'l10', 'l18', 'l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "28, serotonin ['l5', 'l19', 'l27', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "29, 5-HT2C ['l6', 'l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "30, receptor ['l7', 'l12', 'l14', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57']", + "31, gene ['l8', 'l13', 'l15', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l58']", + "60, older ['l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l59']", + "61, mice ['l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l58', 'l59']", + "69, Mutant ['l60']", + "70, mice ['l60']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "young", + "adult", + "mice", + "older" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "of", + "the", + "serotonin", + "5-HT2C", + "receptor", + "gene", + "targeted", + "Mutant" + ] + } + } + ] + }, + { + "PMID": "9734403", + "TEXT": "The p53 tumor suppressor protein binds to both cellular and viral proteins, which influence its biological activity. One such protein is the large E1b tumor antigen (E1b58kDa) from adenoviruses (Ads), which abrogates the ability of p53 to transactivate various promoters. This inactivation of p53 function is believed to be the mechanism by which E1b58kDa contributes to the cell transformation process. Although the p53-E1b58kDa complex occurs during infection and is conserved among different serotypes, there are limited data demonstrating that it has a role in virus replication. However, loss of p53 expression occurs after adenovirus infection of human cells and an E1b58kDa deletion mutant (Onyx-015, also called dl 1520) selectively replicates in p53-defective cells. These (and other) data indicate a plausible hypothesis is that loss of p53 function may be conducive to efficient adenovirus replication. However, wild-type (wt) Ad5 grows more efficiently in cells expressing a wt p53 protein. These studies indicate that the hypothesis may be an oversimplification. Here, we show that cells expressing wt p53, as well as p53-defective cells, allow adenovirus replication, but only cells expressing wt p53 show evidence of virus-induced cytopathic effect. This correlates with the ability of adenovirus to induce cell death. Our data indicate that p53 plays a necessary part in mediating cellular destruction to allow a productive adenovirus infection. In contrast, p53-deficient cells are less sensitive to the cytolytic effects of adenovirus and as such raise questions about the use of E1b58kDa-deficient adenoviruses in tumor therapy.", + "TAG_DATA": [ + "100, E1b58kDa {'perturbing_action': 'B-gene loss-of-function'}", + "101, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "102, mutant {'perturbing_action': 'I-gene loss-of-function'}", + "103, (Onyx-015, {'perturbing_action': 'I-gene loss-of-function'}", + "104, also {'perturbing_action': 'I-gene loss-of-function'}", + "106, dl {'perturbing_action': 'I-gene loss-of-function'}", + "107, 1520) {'perturbing_action': 'I-gene loss-of-function'}", + "112, cells. {'context': 'B-cells'}", + "142, cells {'context': 'B-cells'}", + "162, cells {'context': 'B-cells'}", + "164, wt {'perturbing_action': 'I-gene gain-of-function'}", + "165, p53, {'perturbing_action': 'I-gene gain-of-function'}", + "170, cells, {'context': 'B-cells'}", + "176, cells {'context': 'B-cells'}", + "178, wt {'perturbing_action': 'I-gene gain-of-function'}", + "179, p53 {'perturbing_action': 'I-gene gain-of-function'}", + "194, induce {'effect': 'B-positive'}", + "195, cell {'phenotype': 'B-cell death'}", + "196, death. {'phenotype': 'I-cell death'}", + "218, p53-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "219, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "100, E1b58kDa ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "101, deletion ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "102, mutant ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "103, (Onyx-015, ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "104, also ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "106, dl ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "107, 1520) ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l56', 'l57', 'l58', 'l59']", + "112, cells. ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l56']", + "142, cells ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l57', 'l60', 'l61', 'l62', 'l63']", + "162, cells ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l58', 'l60', 'l64', 'l65', 'l66']", + "164, wt ['l9', 'l20', 'l30', 'l39', 'l47', 'l61', 'l64', 'l67', 'l68']", + "165, p53, ['l10', 'l21', 'l31', 'l40', 'l48', 'l54', 'l59', 'l62', 'l65', 'l67', 'l69']", + "170, cells, ['l11', 'l22', 'l32', 'l41', 'l49', 'l55', 'l63', 'l66', 'l68', 'l69']", + "176, cells ['l70', 'l71', 'l72', 'l73', 'l74']", + "178, wt ['l70', 'l75', 'l76', 'l77', 'l78', 'l79']", + "179, p53 ['l71', 'l75', 'l80', 'l81', 'l82', 'l83']", + "194, induce ['l72', 'l76', 'l80', 'l84', 'l85']", + "195, cell ['l73', 'l77', 'l81', 'l84', 'l86']", + "196, death. ['l74', 'l78', 'l82', 'l85', 'l86']", + "218, p53-deficient ['l87']", + "219, cells ['l79', 'l83', 'l87']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "E1b58kDa", + "deletion", + "mutant", + "(Onyx-015,", + "also", + "dl", + "1520)", + "p53-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells.", + "cells", + "cells," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "cells," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "wt", + "p53,", + "p53" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "wt", + "p53" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "wt", + "p53" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "9734398", + "TEXT": "PPARgamma is a nuclear receptor that has a dominant regulatory role in differentiation of cells of the adipose lineage, and has recently been shown to be expressed in the colon. We show here that PPARgamma is expressed at high levels in both well- and poorly-differentiated adenocarcinomas, in normal colonic mucosa and in human colon cancer cell lines. Ligand activation of this receptor in colon cancer cells causes a considerable reduction in linear and clonogenic growth, increased expression of carcinoembryonic antigen and the reversal of many gene expression events specifically associated with colon cancer. Transplantable tumors derived from human colon cancer cells show a significant reduction of growth when mice are treated with troglitazone, a PPARgamma ligand. These results indicate that the growth and differentiation of colon cancer cells can be modulated through PPARgamma.", + "TAG_DATA": [ + "57, Ligand {'perturbing_action': 'B-pharmacological augmentation'}", + "58, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "59, of {'perturbing_action': 'I-pharmacological augmentation'}", + "60, this {'perturbing_action': 'I-pharmacological augmentation'}", + "61, receptor {'perturbing_action': 'I-pharmacological augmentation'}", + "63, colon {'context': 'B-transformed cells'}", + "64, cancer {'context': 'I-transformed cells'}", + "65, cells {'context': 'I-transformed cells'}", + "69, reduction {'effect': 'B-negative'}", + "73, clonogenic {'phenotype': 'B-colony formation'}", + "74, growth, {'phenotype': 'I-colony formation'}", + "93, Transplantable {'context': 'B-neoplasm'}", + "94, tumors {'context': 'I-neoplasm'}", + "95, derived {'context': 'I-xenograft'}", + "96, from {'context': 'I-transformed cells'}", + "97, human {'context': 'I-transformed cells'}", + "98, colon {'context': 'I-transformed cells'}", + "99, cancer {'context': 'I-transformed cells'}", + "100, cells {'context': 'I-transformed cells'}", + "108, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "57, Ligand ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "58, activation ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "59, of ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "60, this ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "61, receptor ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "63, colon ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "64, cancer ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "65, cells ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "69, reduction ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "73, clonogenic ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "74, growth, ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "93, Transplantable ['l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "94, tumors ['l55', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "95, derived ['l56', 'l62', 'l68', 'l69', 'l70', 'l71', 'l72']", + "96, from ['l57', 'l63', 'l68', 'l73', 'l74', 'l75', 'l76']", + "97, human ['l58', 'l64', 'l69', 'l73', 'l77', 'l78', 'l79']", + "98, colon ['l59', 'l65', 'l70', 'l74', 'l77', 'l80', 'l81']", + "99, cancer ['l60', 'l66', 'l71', 'l75', 'l78', 'l80', 'l82']", + "100, cells ['l61', 'l67', 'l72', 'l76', 'l79', 'l81', 'l82']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Ligand", + "activation", + "of", + "this", + "receptor" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "colon", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Ligand", + "activation", + "of", + "this", + "receptor" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduction" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Ligand", + "activation", + "of", + "this", + "receptor" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenic", + "growth," + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "colon", + "cancer", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduction" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "colon", + "cancer", + "cells" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenic", + "growth," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduction" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonogenic", + "growth," + ] + } + } + ] + }, + { + "PMID": "9701246", + "TEXT": "Mutations in the low density lipoprotein (LDL) receptor gene cause familial hypercholesterolemia, a human disease characterized by premature atherosclerosis and markedly elevated plasma levels of LDL cholesterol and apolipoprotein (apo) B100. In contrast, mice deficient for the LDL receptor (Ldlr-/-) have only mildly elevated LDL cholesterol levels and little atherosclerosis. This difference results from extensive editing of the hepatic apoB mRNA in the mouse, which limits apoB100 synthesis in favor of apoB48 synthesis. We have generated Ldlr-/- mice that cannot edit the apoB mRNA and therefore synthesize exclusively apoB100. These mice had markedly elevated LDL cholesterol and apoB100 levels and developed extensive atherosclerosis on a chow diet. This authentic model of human familial hypercholesterolemia will provide a new tool for studying atherosclerosis.", + "TAG_DATA": [ + "33, mice {'context': 'B-organism'}", + "34, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "35, for {'perturbing_action': 'I-gene loss-of-function'}", + "36, the {'perturbing_action': 'I-gene loss-of-function'}", + "37, LDL {'perturbing_action': 'I-gene loss-of-function'}", + "38, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "39, (Ldlr-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "76, Ldlr-/- {'perturbing_action': 'B-gene loss-of-function'}", + "77, mice {'context': 'B-organism'}", + "90, mice {'context': 'B-organism'}", + "102, atherosclerosis {'phenotype': 'B-necrosis'}" + ], + "LINK_DATA": [ + "33, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "34, deficient ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "35, for ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "36, the ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "37, LDL ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "38, receptor ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "39, (Ldlr-/-) ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "76, Ldlr-/- ['l21']", + "77, mice ['l21']", + "90, mice ['l22']", + "102, atherosclerosis ['l22']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "the", + "LDL", + "receptor", + "(Ldlr-/-)", + "Ldlr-/-" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "atherosclerosis" + ] + } + } + ] + }, + { + "PMID": "9662381", + "TEXT": "The CD4+ T-cell pool in HIV-infected patients is in a constant state of flux as CD4+ T cells are infected and destroyed by HIV and new cells take their place. To study T-cell survival, we adoptively transferred peripheral blood lymphocytes transduced with the neomycin phosphotransferase gene between syngeneic twin pairs discordant for HIV infection. A stable fraction of marked CD4+ T cells persisted in the circulation for four to eighteen weeks after transfer in all patients. After this time there was a precipitous decline in marked cells in three of the patients. At approximately six months, marked cells were in lymphoid tissues in proportions comparable to those found in peripheral blood. In two patients, the proportion of total signal for the transgene (found by PCR analysis) in the CD4/CD45RA+ T-cell population relative to the CD4/CD45RO+ population increased in the weeks after cell infusion. These findings indicate that genetically-marked CD4+ T cells persist in vivo for weeks to months and that the CD4+ T-cell pool in adults is maintained mostly by the division of mature T cells rather than by differentiation of prethymic stem cells. Thus, after elements of the T-cell repertoire are lost through HIV infection, they may be difficult to replace.", + "TAG_DATA": [ + "37, peripheral {'context': 'B-cells'}", + "38, blood {'context': 'I-cells'}", + "39, lymphocytes {'context': 'I-cells'}", + "40, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "41, with {'perturbing_action': 'I-gene gain-of-function'}", + "42, the {'perturbing_action': 'I-gene gain-of-function'}", + "43, neomycin {'perturbing_action': 'I-gene gain-of-function'}", + "44, phosphotransferase {'perturbing_action': 'I-gene gain-of-function'}", + "45, gene {'perturbing_action': 'I-gene gain-of-function'}", + "59, CD4+ {'context': 'B-cells'}", + "60, T {'context': 'I-cells'}", + "61, cells {'context': 'I-cells'}", + "86, cells {'context': 'B-cells'}", + "128, CD4/CD45RA+ {'context': 'B-cells'}", + "129, T-cell {'context': 'I-cells'}", + "130, population {'context': 'I-cells'}", + "134, CD4/CD45RO+ {'context': 'B-cells'}", + "152, in {'context': 'B-in vivo'}", + "153, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "37, peripheral ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "38, blood ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "39, lymphocytes ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "40, transduced ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "41, with ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "42, the ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "43, neomycin ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "44, phosphotransferase ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "45, gene ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "59, CD4+ ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "60, T ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "61, cells ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "86, cells ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "128, CD4/CD45RA+ ['l78', 'l79', 'l80']", + "129, T-cell ['l78', 'l81', 'l82']", + "130, population ['l79', 'l81', 'l83']", + "134, CD4/CD45RO+ ['l80', 'l82', 'l83', 'l84', 'l85']", + "152, in ['l84', 'l86']", + "153, vivo ['l85', 'l86']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "peripheral", + "blood", + "lymphocytes", + "CD4+", + "T", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "the", + "neomycin", + "phosphotransferase", + "gene" + ] + } + } + ] + }, + { + "PMID": "9585231", + "TEXT": "The cyclin-dependent kinase inhibitor p27Kip1 controls cell proliferation in response to normal mitogenic stimuli. We show here that p27Kip1 also safeguards against excessive cell proliferation in specific pathophysiologic settings. We used experimental glomerulonephritis as a paradigm for immune mediated inflammation and ureteral obstruction as a model for non-immune mediated inflammation. Renal function was substantially decreased in nephritic p27-/- mice compared with control mice, and this was associated with increased glomerular cell proliferation, apoptosis and matrix protein accumulation. Tubular epithelial cell proliferation and apoptosis was also increased in p27-/- mice following ureteral obstruction. p27Kip1 may have a general role in protecting cells and tissues from inflammatory injury.", + "TAG_DATA": [ + "56, nephritic {'perturbing_action': 'B-gene loss-of-function'}", + "57, p27-/- {'perturbing_action': 'B-gene loss-of-function'}", + "58, mice {'context': 'B-organism'}", + "62, mice, {'context': 'B-organism'}", + "68, increased {'effect': 'B-positive'}", + "69, glomerular {'context': 'B-cells'}", + "70, cell {'context': 'I-cells'}", + "71, proliferation, {'phenotype': 'B-proliferation'}", + "72, apoptosis {'phenotype': 'B-apoptosis'}", + "77, Tubular {'context': 'B-cells'}", + "78, epithelial {'context': 'I-cells'}", + "79, cell {'context': 'I-cells'}", + "80, proliferation {'phenotype': 'B-proliferation'}", + "82, apoptosis {'phenotype': 'B-apoptosis'}", + "85, increased {'effect': 'B-positive'}", + "87, p27-/- {'perturbing_action': 'B-gene loss-of-function'}", + "88, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, nephritic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "57, p27-/- ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "58, mice ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "62, mice, ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "68, increased ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "69, glomerular ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "70, cell ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "71, proliferation, ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "72, apoptosis ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "77, Tubular ['l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "78, epithelial ['l36', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "79, cell ['l37', 'l43', 'l49', 'l50', 'l51', 'l52']", + "80, proliferation ['l38', 'l44', 'l49', 'l53', 'l54', 'l55']", + "82, apoptosis ['l39', 'l45', 'l50', 'l53', 'l56', 'l57', 'l58']", + "85, increased ['l40', 'l46', 'l51', 'l54', 'l56', 'l59', 'l60']", + "87, p27-/- ['l41', 'l47', 'l57', 'l59', 'l61']", + "88, mice ['l42', 'l48', 'l52', 'l55', 'l58', 'l60', 'l61']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nephritic", + "p27-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nephritic", + "p27-/-" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nephritic", + "p27-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "glomerular", + "cell", + "Tubular", + "epithelial" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nephritic", + "p27-/-" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nephritic", + "p27-/-" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation,", + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "cells", + "words": [ + "glomerular", + "cell", + "Tubular", + "epithelial" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation,", + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "glomerular", + "cell", + "Tubular", + "epithelial" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation,", + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "glomerular", + "cell", + "Tubular", + "epithelial" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "9546793", + "TEXT": "The central biochemical mechanisms involved in primate parturition are still unclear. Studies in both humans and nonhuman primates such as the baboon and rhesus monkey indicate that many factors play a part in the cascade of interactive positive feedforward loops that progressively promote parturition: changes in maternal endocrinology, a nocturnal switch in myometrial activity from low amplitude, infrequent contractures to high amplitude, high frequency contractions (see Fig. 1), dilation of the cervix and biochemical changes in the fetal membranes that lead to rupture. Here we demonstrate that infusion of the aromatase inhibitor 4-hydroxyandrostenedione (4OHA) inhibits conversion of androgen to estrogen and prevents premature delivery caused by administration of androgen to pregnant rhesus monkeys at 0.8 of pregnancy term. 4OHA also inhibited the androstenedione induced maternal endocrine and fetal membrane biochemical changes, and alteration of myometrial activity patterns. Secondly, peripheral estrogen infusions increased myometrial activity but did not produce preterm delivery or fetal membrane changes. We conclude that paracrine functions of estrogen at its site of production play critical and central roles in delivery in the non-human primate.", + "TAG_DATA": [ + "88, of {'perturbing_action': 'I-pharmacological inhibition'}", + "89, the {'perturbing_action': 'I-pharmacological inhibition'}", + "90, aromatase {'perturbing_action': 'I-pharmacological inhibition'}", + "91, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "92, 4-hydroxyandrostenedione {'perturbing_action': 'I-pharmacological inhibition'}", + "93, (4OHA) {'perturbing_action': 'I-pharmacological inhibition'}", + "111, rhesus {'context': 'B-organism'}", + "112, monkeys {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "88, of ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "89, the ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "90, aromatase ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "91, inhibitor ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "92, 4-hydroxyandrostenedione ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "93, (4OHA) ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "111, rhesus ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "112, monkeys ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "of", + "the", + "aromatase", + "inhibitor", + "4-hydroxyandrostenedione", + "(4OHA)" + ] + }, + "context": { + "val": "organism", + "words": [ + "rhesus", + "monkeys" + ] + } + } + ] + }, + { + "PMID": "9500605", + "TEXT": "Successful tumor immunotherapy with peptides requires the induction of cytotoxic T lymphocytes (CTLs) rather than antibodies. Mice immunized with mannan conjugated to MUC1, a peptide found in large amounts in breast cancer, develop CTL responses. In contrast, immunized patients produce high antibodies with poor CTL responses to MUC1. Here, we provide evidence that this \"switch\" in the immune response is due to the fact that antibodies against the Gal alpha(1,3)Gal epitope, which are normally present in humans but not mice, cross-react with MUC1 peptides. In particular, mice that lack the gene for the epitope (and that produce anti-Gal antibodies) (Gal-/- mice) are like humans in their response to MUC1 immunization in that they develop antibody rather than CTL responses. After we exposed macrophages from Gal-/- mice in vitro to MUC1, in the absence of Gal antibody, and adoptively transferred them into the mice, Gal-/- mice produced a predominantly CTL response. The findings are of relevance for immunotherapy studies in humans and emphasize the differences seen in preclinical testing in rodents before clinical trials.", + "TAG_DATA": [ + "122, macrophages {'context': 'B-cells'}", + "124, Gal-/- {'perturbing_action': 'B-gene loss-of-function'}", + "125, mice {'context': 'B-organism'}", + "126, in {'context': 'B-in vitro'}", + "127, vitro {'context': 'I-in vitro'}", + "142, mice, {'context': 'B-organism'}", + "143, Gal-/- {'perturbing_action': 'B-gene loss-of-function'}", + "144, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "122, macrophages ['l0', 'l1', 'l2', 'l3']", + "124, Gal-/- ['l0', 'l4', 'l5', 'l6']", + "125, mice ['l1', 'l4', 'l7', 'l8']", + "126, in ['l2', 'l5', 'l7', 'l9']", + "127, vitro ['l3', 'l6', 'l8', 'l9']", + "142, mice, ['l10', 'l11']", + "143, Gal-/- ['l10', 'l12']", + "144, mice ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "macrophages" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gal-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gal-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gal-/-" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "9500603", + "TEXT": "During early pregnancy, in response to the implanting embryo, the surrounding uterine stroma undergoes a dramatic transformation into a specialized tissue known as the decidua. The decidua encapsulates the developing embryo, facilitating nutrient transfer and limiting trophoblast invasion. Here we show that female mice with a null mutation of the interleukin-11 receptor alpha chain are infertile because of defective decidualization. A temporal analysis revealed IL-11 expression is maximal in the normal pregnant uterus at the time of decidualization, and in situ hybridization studies showed expression of the IL-11 and the IL-11 receptor alpha chain in the developing decidual cells. These observations reveal a previously unrecognized critical role for IL-11 signaling in female reproduction.", + "TAG_DATA": [ + "42, female {'context': 'B-organism'}", + "43, mice {'context': 'I-organism'}", + "46, null {'perturbing_action': 'B-gene loss-of-function'}", + "47, mutation {'perturbing_action': 'I-gene loss-of-function'}", + "48, of {'perturbing_action': 'I-gene loss-of-function'}", + "49, the {'perturbing_action': 'I-gene loss-of-function'}", + "50, interleukin-11 {'perturbing_action': 'I-gene loss-of-function'}", + "51, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "52, alpha {'perturbing_action': 'I-gene loss-of-function'}", + "53, chain {'perturbing_action': 'I-gene loss-of-function'}", + "97, decidual {'context': 'B-cells'}", + "98, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "42, female ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "43, mice ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "46, null ['l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "47, mutation ['l13', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "48, of ['l1', 'l7', 'l14', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "49, the ['l2', 'l8', 'l15', 'l22', 'l28', 'l34', 'l35', 'l36', 'l37']", + "50, interleukin-11 ['l3', 'l9', 'l16', 'l23', 'l29', 'l34', 'l38', 'l39', 'l40']", + "51, receptor ['l4', 'l10', 'l17', 'l24', 'l30', 'l35', 'l38', 'l41', 'l42']", + "52, alpha ['l5', 'l11', 'l18', 'l25', 'l31', 'l36', 'l39', 'l41', 'l43']", + "53, chain ['l6', 'l12', 'l19', 'l26', 'l32', 'l37', 'l40', 'l42', 'l43']", + "97, decidual ['l44']", + "98, cells. ['l20', 'l27', 'l33', 'l44']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "female", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "the", + "interleukin-11", + "receptor", + "alpha", + "chain" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "null", + "mutation", + "of" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "9461197", + "TEXT": "We postulated that activation of a genetic program that tonically inhibits intimal cell death is a necessary condition for the pathogenesis of vascular disease. Studies of vascular lesions in humans and animal models documented increased expression of the anti-apoptotic gene product Bcl-xL within intimal cells. Downregulation of intimal cell bcl-xL expression with the use of antisense oligonucleotides induced apoptosis and acute regression of vascular lesions. These findings indicate that apoptosis regulatory genes such as bcl-xL are critical determinants of intimal lesion formation and that targeted apoptosis may be a novel therapy for intimal vascular disease.", + "TAG_DATA": [ + "45, Downregulation {'perturbing_action': 'B-gene loss-of-function'}", + "46, of {'perturbing_action': 'I-gene loss-of-function'}", + "47, intimal {'perturbing_action': 'I-gene loss-of-function'}", + "48, cell {'perturbing_action': 'I-gene loss-of-function'}", + "49, bcl-xL {'perturbing_action': 'I-gene loss-of-function'}", + "50, expression {'perturbing_action': 'I-rnai/knockdown'}", + "57, induced {'effect': 'B-positive'}", + "58, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "45, Downregulation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "46, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "47, intimal ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "48, cell ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "49, bcl-xL ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "50, expression ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "57, induced ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "58, apoptosis ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Downregulation", + "of", + "intimal", + "cell", + "bcl-xL" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Downregulation", + "of", + "intimal", + "cell", + "bcl-xL" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "9461189", + "TEXT": "In order to treat common cancers with immunotherapy, chimeric receptors have been developed that combine the tumor specificity of antibodies with T-cell effector functions. Previously, we demonstrated that T cells transduced with a chimeric receptor gene against human ovarian cancer were able to recognize ovarian cancer cells in vitro and in vivo. We now report that recipients of bone marrow cells transduced with these genes exhibited significant antitumor activity in vivo. Moreover, in vivo depletion of T cells in reconstituted mice did not affect antitumor activity, suggesting that other immune cells expressing the chimeric receptor gene may play an important role in tumor rejection.", + "TAG_DATA": [ + "28, T {'context': 'B-cells'}", + "29, cells {'context': 'B-cells'}", + "30, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "31, with {'perturbing_action': 'I-gene gain-of-function'}", + "32, a {'perturbing_action': 'I-gene gain-of-function'}", + "33, chimeric {'perturbing_action': 'I-gene gain-of-function'}", + "34, receptor {'perturbing_action': 'I-gene gain-of-function'}", + "35, gene {'perturbing_action': 'I-gene gain-of-function'}", + "36, against {'perturbing_action': 'I-rnai/knockdown'}", + "37, human {'context': 'B-neoplasm'}", + "38, ovarian {'context': 'I-transformed cells'}", + "39, cancer {'context': 'I-transformed cells'}", + "44, ovarian {'context': 'B-transformed cells'}", + "45, cancer {'context': 'I-transformed cells'}", + "46, cells {'context': 'I-transformed cells'}", + "47, in {'context': 'B-in vitro'}", + "48, vitro {'context': 'I-in vitro'}", + "50, in {'context': 'B-in vivo'}", + "51, vivo. {'context': 'I-in vivo'}", + "58, bone {'context': 'B-cells'}", + "59, marrow {'context': 'I-cells'}", + "60, cells {'context': 'I-cells'}", + "61, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "62, with {'perturbing_action': 'I-gene gain-of-function'}", + "63, these {'perturbing_action': 'I-gene gain-of-function'}", + "64, genes {'perturbing_action': 'I-gene gain-of-function'}", + "69, in {'context': 'B-in vivo'}", + "70, vivo. {'context': 'I-in vivo'}", + "72, in {'context': 'B-in vivo'}", + "73, vivo {'context': 'I-in vivo'}", + "76, T {'context': 'B-cells'}", + "77, cells {'context': 'B-cells'}", + "80, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "28, T ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "29, cells ['l0', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "30, transduced ['l1', 'l18', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "31, with ['l2', 'l19', 'l35', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "32, a ['l3', 'l20', 'l36', 'l51', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "33, chimeric ['l4', 'l21', 'l37', 'l52', 'l66', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "34, receptor ['l5', 'l22', 'l38', 'l53', 'l67', 'l80', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "35, gene ['l6', 'l23', 'l39', 'l54', 'l68', 'l81', 'l93', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "36, against ['l7', 'l24', 'l40', 'l55', 'l69', 'l82', 'l94', 'l105', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "37, human ['l8', 'l25', 'l41', 'l56', 'l70', 'l83', 'l95', 'l106', 'l116', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "38, ovarian ['l9', 'l26', 'l42', 'l57', 'l71', 'l84', 'l96', 'l107', 'l117', 'l126', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "39, cancer ['l10', 'l27', 'l43', 'l58', 'l72', 'l85', 'l97', 'l108', 'l118', 'l127', 'l135', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "44, ovarian ['l11', 'l28', 'l44', 'l59', 'l73', 'l86', 'l98', 'l109', 'l119', 'l128', 'l136', 'l143', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "45, cancer ['l12', 'l29', 'l45', 'l60', 'l74', 'l87', 'l99', 'l110', 'l120', 'l129', 'l137', 'l144', 'l149', 'l155', 'l156', 'l157', 'l158', 'l159']", + "46, cells ['l13', 'l30', 'l46', 'l61', 'l75', 'l88', 'l100', 'l111', 'l121', 'l130', 'l138', 'l145', 'l150', 'l155', 'l160', 'l161', 'l162']", + "47, in ['l14', 'l31', 'l47', 'l62', 'l76', 'l89', 'l101', 'l112', 'l122', 'l131', 'l139', 'l146', 'l151', 'l156', 'l160', 'l163', 'l164']", + "48, vitro ['l15', 'l32', 'l48', 'l63', 'l77', 'l90', 'l102', 'l113', 'l123', 'l132', 'l140', 'l147', 'l152', 'l157', 'l161', 'l163', 'l165']", + "50, in ['l16', 'l33', 'l49', 'l64', 'l78', 'l91', 'l103', 'l114', 'l124', 'l133', 'l141', 'l153', 'l158', 'l166']", + "51, vivo. ['l17', 'l34', 'l50', 'l65', 'l79', 'l92', 'l104', 'l115', 'l125', 'l134', 'l142', 'l148', 'l154', 'l159', 'l162', 'l164', 'l165', 'l166']", + "58, bone ['l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "59, marrow ['l167', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181']", + "60, cells ['l168', 'l175', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "61, transduced ['l169', 'l176', 'l182', 'l188', 'l189', 'l190', 'l191', 'l192']", + "62, with ['l170', 'l177', 'l183', 'l188', 'l193', 'l194', 'l195', 'l196']", + "63, these ['l171', 'l178', 'l184', 'l189', 'l193', 'l197', 'l198', 'l199']", + "64, genes ['l172', 'l179', 'l185', 'l190', 'l194', 'l197', 'l200', 'l201']", + "69, in ['l173', 'l180', 'l186', 'l191', 'l195', 'l198', 'l200', 'l202']", + "70, vivo. ['l174', 'l181', 'l187', 'l192', 'l196', 'l199', 'l201', 'l202']", + "72, in ['l203', 'l204', 'l205', 'l206']", + "73, vivo ['l203', 'l207', 'l208', 'l209']", + "76, T ['l204', 'l207', 'l210', 'l211']", + "77, cells ['l205', 'l208', 'l210', 'l212']", + "80, mice ['l206', 'l209', 'l211', 'l212']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "bone", + "marrow" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "a", + "chimeric", + "receptor", + "gene", + "these", + "genes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "against" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "a", + "chimeric", + "receptor", + "gene" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "a", + "chimeric", + "receptor", + "gene" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "a", + "chimeric", + "receptor", + "gene" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "a", + "chimeric", + "receptor", + "gene", + "these", + "genes" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "against" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "against" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ovarian", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "against" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "against" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "9427606", + "TEXT": "Neutral endopeptidase 24.11 (NEP) is a cell-surface enzyme expressed by prostatic epithelial cells that cleaves and inactivates neuropeptides implicated in the growth of androgen-independent prostate cancer (PC). We report that NEP expression and catalytic activity are lost in vitro in androgen-independent but not androgen-dependent PC cell lines. In vivo, NEP protein expression is commonly decreased in cancer cells of metastatic PC specimens from patients with androgen-independent but not androgen-dependent PC. Overexpression of NEP in androgen-independent PC cells or incubation with recombinant NEP inhibits PC cell growth. Furthermore, in androgen-dependent PC cells, expression of NEP is transcriptionally regulated by androgen and decreases with androgen withdrawal. These data suggest that decreased NEP expression, common in androgen-independent PCs, is facilitated by the elimination of androgens, and that NEP loss plays an important role in the development of androgen-independent PC by allowing PC cells to use mitogenic neuropeptides as an alternate source to androgen in order to stimulate cell proliferation.", + "TAG_DATA": [ + "44, PC {'context': 'I-transformed cells'}", + "45, cell {'context': 'I-transformed cells'}", + "46, lines. {'context': 'I-transformed cells'}", + "70, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "71, of {'perturbing_action': 'I-gene gain-of-function'}", + "72, NEP {'perturbing_action': 'I-gene gain-of-function'}", + "74, androgen-independent {'context': 'B-transformed cells'}", + "75, PC {'context': 'I-transformed cells'}", + "76, cells {'context': 'I-transformed cells'}", + "82, inhibits {'effect': 'B-negative'}", + "83, PC {'context': 'B-neoplasm'}", + "84, cell {'phenotype': 'B-cell growth'}", + "85, growth. {'phenotype': 'I-cell growth'}", + "88, androgen-dependent {'context': 'B-transformed cells'}", + "89, PC {'context': 'I-transformed cells'}", + "90, cells, {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "44, PC ['l0', 'l1']", + "45, cell ['l0', 'l2']", + "46, lines. ['l1', 'l2']", + "70, Overexpression ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "71, of ['l3', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "72, NEP ['l4', 'l12', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "74, androgen-independent ['l5', 'l13', 'l20', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "75, PC ['l6', 'l14', 'l21', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "76, cells ['l7', 'l15', 'l22', 'l28', 'l33', 'l38', 'l39', 'l40', 'l41']", + "82, inhibits ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l42', 'l43', 'l44']", + "83, PC ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l45', 'l46']", + "84, cell ['l10', 'l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l47']", + "85, growth. ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l47']", + "88, androgen-dependent ['l48', 'l49']", + "89, PC ['l48', 'l50']", + "90, cells, ['l49', 'l50']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "NEP" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "androgen-independent", + "PC", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "NEP" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "NEP" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "PC" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "NEP" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "androgen-independent", + "PC", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "androgen-independent", + "PC", + "cells" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "PC" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "PC" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth." + ] + } + } + ] + }, + { + "PMID": "9427605", + "TEXT": "A number of adenocarcinomas abundantly express and secrete underglycosylated MUC1 mucin. Underglycosylation exposes tandem repeat peptide sequences on cancer-associated MUC1 mucin that are normally cryptic. High levels of MUC1 mucin are correlated with a poor prognosis and immunosuppression in adenocarcinoma patients. In this report we show that cancer-associated MUC1 mucin, affinity-purified from ascites fluids of cancer patients, and synthetic tandem repeats of MUC1 mucin core peptide can suppress human T-cell proliferative responses. This MUC1 mucin-induced suppression of T-cell responses can be reversed by the addition of exogenous IL-2 or anti-CD28 monoclonal antibody. These results are consistent with other studies showing that lymphocytes present in the vicinity of tumor cells are anergic and can be reactivated with exogenous interleukin-2. Overcoming MUC1 mucin-induced immunosuppression with IL-2 combined with active specific immunotherapy might be an effective immunotherapeutic strategy against human adenocarcinomas.", + "TAG_DATA": [ + "67, suppress {'effect': 'B-negative'}", + "68, human {'context': 'B-cells'}", + "69, T-cell {'context': 'I-cells'}", + "70, proliferative {'phenotype': 'B-proliferation'}", + "71, responses. {'phenotype': 'I-proliferation'}", + "77, T-cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "67, suppress ['l0', 'l1', 'l2', 'l3']", + "68, human ['l0', 'l4', 'l5', 'l6']", + "69, T-cell ['l1', 'l4', 'l7', 'l8']", + "70, proliferative ['l2', 'l5', 'l7', 'l9']", + "71, responses. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "suppress" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "T-cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppress" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "responses." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "T-cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "responses." + ] + } + } + ] + }, + { + "PMID": "9396613", + "TEXT": "The ability of adenovirus (Ad) to transfect most cell types efficiently has already resulted in human gene therapy trials involving the systemic administration of adenoviral constructs. However, because of the complexity of brain function and the difficulty in noninvasively monitoring alterations in neuronal gene expression, the potential of Ad gene therapy strategies for treating disorders of the CNS has been difficult to assess. In the present study, we have used an Ad encoding the arginine vasopressin cDNA (AdAVP) in an AVP-deficient animal model of diabetes insipidus (the Brattleboro rat), which allowed us to monitor chronically the success of the gene therapy treatment by noninvasive assays. Injection of AdAVP into the supraoptic nuclei (SON) of the hypothalamus resulted in expression of AVP in magnocellular neurons. This was accompanied by reduced daily water intake and urine volume, as well as increased urine osmolality lasting 4 months. These data show that a single gene defect leading to a neurological disorder can be corrected with an adenovirus-based strategy. This study highlights the potential of using Ad gene therapy for the long-term treatment of disorders of the CNS.", + "TAG_DATA": [ + "80, AVP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "81, animal {'context': 'B-organism'}", + "82, model {'context': 'I-organism'}", + "87, Brattleboro {'context': 'B-organism'}", + "88, rat), {'context': 'I-organism'}", + "110, supraoptic {'context': 'B-tissue/organ'}", + "111, nuclei {'context': 'I-tissue/organ'}", + "112, (SON) {'context': 'I-tissue/organ'}", + "113, of {'context': 'I-tissue/organ'}", + "114, the {'context': 'I-tissue/organ'}", + "115, hypothalamus {'context': 'I-tissue/organ'}", + "122, magnocellular {'context': 'B-cells'}", + "123, neurons. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "80, AVP-deficient ['l0', 'l1', 'l2', 'l3', 'l4']", + "81, animal ['l0', 'l5', 'l6', 'l7', 'l8']", + "82, model ['l1', 'l5', 'l9', 'l10', 'l11']", + "83, of ['l2', 'l6', 'l9', 'l12', 'l13']", + "87, Brattleboro ['l3', 'l7', 'l10', 'l12', 'l14']", + "88, rat), ['l4', 'l8', 'l11', 'l13', 'l14']", + "110, supraoptic ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "111, nuclei ['l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "112, (SON) ['l16', 'l22', 'l28', 'l29', 'l30', 'l31', 'l32']", + "113, of ['l17', 'l23', 'l28', 'l33', 'l34', 'l35', 'l36']", + "114, the ['l18', 'l24', 'l29', 'l33', 'l37', 'l38', 'l39']", + "115, hypothalamus ['l19', 'l25', 'l30', 'l34', 'l37', 'l40', 'l41']", + "122, magnocellular ['l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l42']", + "123, neurons. ['l21', 'l27', 'l32', 'l36', 'l39', 'l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "AVP-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "animal", + "model", + "Brattleboro", + "rat)," + ] + } + } + ] + }, + { + "PMID": "9396612", + "TEXT": "During development, semaphorins (collapsin, fasciclin) mediate repulsive and inhibitory guidance of neurons. Semaphorin III, a secretable member of this family, is expressed by the ventral spinal cord at the time corresponding to projection of sensory afferents from the dorsal root ganglion (DRG) into the spinal cord. The inhibitory effect of E14 ventral cord is active only on nerve growth factor (NGF)-responsive sensory afferents (small-diameter A-delta and C fibers subserving sensations of temperature and pain). Similarly, COS cells secreting recombinant semaphorin III are able to selectively repel DRG afferents whose growth is stimulated by NGF and not NT-3. However, it is not known whether these molecules can exert a functional role in the fully developed adult peripheral nervous system. In this study, we demonstrated that gene gun transfection and production of semaphorin III in corneal epithelial cells in adult rabbits in vivo can cause repulsion of established A-delta and C fiber trigeminal sensory afferents. In addition, it is shown that, following epithelial wounding and denervation, semaphorin III is able to inhibit collateral nerve sprouts from innervating the reepithelialized tissue. These findings are significant in that they provide direct evidence that small-diameter adult sensory neurons retain the ability to respond to semaphorin III. In addition, the corneal gene gun technique may be generally used to study the in vivo effects of neural growth modulators by quantifying the amount of sensory nerve growth.", + "TAG_DATA": [ + "86, DRG {'context': 'B-cells'}", + "87, afferents {'context': 'I-cells'}", + "133, corneal {'context': 'B-cells'}", + "134, epithelial {'context': 'I-cells'}", + "135, cells {'context': 'I-cells'}", + "137, adult {'context': 'B-organism'}", + "138, rabbits {'context': 'I-organism'}", + "139, in {'context': 'B-in vivo'}", + "140, vivo {'context': 'I-in vivo'}", + "146, A-delta {'context': 'B-cells'}", + "147, and {'context': 'I-cells'}", + "148, C {'context': 'I-cells'}", + "149, fiber {'context': 'I-cells'}", + "150, trigeminal {'context': 'I-cells'}", + "151, sensory {'context': 'I-cells'}", + "152, afferents. {'context': 'I-cells'}", + "169, inhibit {'effect': 'B-negative'}", + "170, collateral {'context': 'B-cells'}", + "171, nerve {'context': 'I-cells'}", + "172, sprouts {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "86, DRG ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "87, afferents ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "125, gun ['l1', 'l8', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "126, transfection ['l2', 'l9', 'l17', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "133, corneal ['l10', 'l18', 'l32', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "134, epithelial ['l3', 'l11', 'l19', 'l33', 'l46', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "135, cells ['l4', 'l12', 'l20', 'l34', 'l47', 'l59', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "137, adult ['l5', 'l13', 'l21', 'l35', 'l48', 'l60', 'l71', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "138, rabbits ['l6', 'l14', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "139, in ['l15', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "140, vivo ['l7', 'l16', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "146, A-delta ['l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "147, and ['l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l122', 'l123', 'l124', 'l125', 'l126']", + "148, C ['l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l127', 'l128', 'l129', 'l130']", + "149, fiber ['l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l118', 'l123', 'l127', 'l131', 'l132', 'l133']", + "150, trigeminal ['l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l113', 'l119', 'l124', 'l128', 'l131', 'l134', 'l135']", + "151, sensory ['l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l129', 'l132', 'l134', 'l136']", + "152, afferents. ['l31', 'l45', 'l58', 'l70', 'l81', 'l91', 'l100', 'l108', 'l115', 'l121', 'l126', 'l130', 'l133', 'l135', 'l136']", + "169, inhibit ['l137', 'l138', 'l139']", + "170, collateral ['l137', 'l140', 'l141']", + "171, nerve ['l138', 'l140', 'l142']", + "172, sprouts ['l139', 'l141', 'l142']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "context": { + "val": "cells", + "words": [ + "collateral", + "nerve", + "sprouts" + ] + } + } + ] + }, + { + "PMID": "9359695", + "TEXT": "Dystrophin-deficient mice (mdx) expressing a truncated (trc) utrophin transgene show amelioration of the dystrophic phenotype. Here we report a multifunctional study demonstrating that trcutrophin expression leads to major improvements of the mechanical performance of muscle (that is, force development, mechanical resistance to forced lengthenings and maximal spontaneous activity) and of the maintenance of the intracellular calcium homeostasis. These are two essential functions of muscle fibers, known to be impaired in mdx mouse muscles and Duchenne muscular dystrophy (DMD) patients. Our results bring strong support to the hypothesis that muscle wasting in dystrophin-deficient DMD patients could be prevented by upregulation of utrophin.", + "TAG_DATA": [ + "1, mice {'context': 'B-organism'}", + "3, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "4, a {'perturbing_action': 'I-gene gain-of-function'}", + "5, truncated {'perturbing_action': 'I-gene gain-of-function'}", + "6, (trc) {'perturbing_action': 'I-gene gain-of-function'}", + "7, utrophin {'perturbing_action': 'I-gene gain-of-function'}", + "8, transgene {'perturbing_action': 'I-gene gain-of-function'}", + "23, trcutrophin {'perturbing_action': 'B-gene gain-of-function'}", + "24, expression {'perturbing_action': 'I-gene gain-of-function'}", + "34, muscle {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "1, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "3, expressing ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "4, a ['l1', 'l8', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "5, truncated ['l9', 'l16', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "6, (trc) ['l2', 'l10', 'l17', 'l23', 'l29', 'l30', 'l31', 'l32', 'l33']", + "7, utrophin ['l3', 'l11', 'l18', 'l24', 'l29', 'l34', 'l35', 'l36', 'l37']", + "8, transgene ['l4', 'l12', 'l19', 'l25', 'l30', 'l34', 'l38', 'l39', 'l40']", + "23, trcutrophin ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l41', 'l42']", + "24, expression ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l41', 'l43']", + "34, muscle ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l43']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "a", + "(trc)", + "utrophin", + "transgene", + "trcutrophin", + "expression" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "a", + "truncated", + "(trc)", + "utrophin", + "transgene", + "trcutrophin", + "expression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscle" + ] + } + } + ] + }, + { + "PMID": "9334728", + "TEXT": "The decline of growth hormone (GH) and insulin-like growth factor I (IGF-I) production during aging has been likened to the decrease in gonadal steroids in menopause. The repletion of GH/IGF-I levels in aging individuals is suggested to restore the lean tissue anabolism characteristic of youth. In addition to anabolic effects on musculo-skeletal tissues, GH also stimulates mammary glandular growth in some species, although its effects on primate mammary growth remain unclear. Some clinical observations implicate GH in human mammary growth, for example, gynecomastia occurs in some children treated with GH (ref. 6), and tall stature and acromegaly are associated with an increased incidence of breast cancer. To investigate the effects of GH/IGF-I augmentation on mammary tissue in a model relevant to aging humans, we treated aged female rhesus monkeys with GH, IGF-I, GH + IGF-I or saline diluent for 7 weeks. IGF-I treatment was associated with a twofold increase, GH with a three- to fourfold increase, and GH + IGF-I with a four'-to fivefold increase in mammary glandular size and epithelial proliferation index. These mitogenic effects were directly correlated with circulating GH and IGF-I levels, suggesting that either GH or its downstream effector IGF-I stimulates primate mammary epithelial proliferation.", + "TAG_DATA": [ + "125, aged {'context': 'B-organism'}", + "126, female {'context': 'I-organism'}", + "127, rhesus {'context': 'I-organism'}", + "128, monkeys {'context': 'I-organism'}", + "171, proliferation {'phenotype': 'B-proliferation'}", + "194, stimulates {'effect': 'B-positive'}", + "198, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "125, aged ['l0', 'l1', 'l2']", + "126, female ['l0', 'l3', 'l4']", + "127, rhesus ['l1', 'l3', 'l5']", + "128, monkeys ['l2', 'l4', 'l5']", + "194, stimulates ['l6']", + "198, proliferation. ['l6']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "9334723", + "TEXT": "The HIV-1 accessory gene product Vpr can influence viral pathogenesis by affecting viral replication as well as host cell transcription and proliferation. We have investigated the effects of Vpr on host cell activation and confirm that it influences cellular proliferation. However, we have also found that Vpr modulates T-cell receptor (TCR)-triggered apoptosis in a manner similar to that of glucocorticoids. In the absence of TCR-mediated activation, Vpr induces apoptosis whereas in its presence, Vpr interrupts the expected induction of apoptosis. This regulation of apoptosis is linked to Vpr suppression of NF-kappa B activity via the induction of I kappa B, an inhibitor of NF-kappa B. Further, Vpr suppresses expression of IL-2, IL-10, IL-12, TNF alpha and IL-4, all of which are NF-kappa B-dependent. The effects of Vpr could be reversed by RU486. Our finding that Vpr can regulate NF-kappa B supports the hypothesis that some aspects of viral pathogenesis are the consequence of cell dysregulation by Vpr.", + "TAG_DATA": [ + "47, modulates {'effect': 'B-regulates'}", + "51, apoptosis {'phenotype': 'B-apoptosis'}", + "67, induces {'effect': 'B-positive'}", + "68, apoptosis {'phenotype': 'B-apoptosis'}", + "74, interrupts {'effect': 'B-negative'}", + "77, induction {'effect': 'B-positive'}", + "79, apoptosis. {'phenotype': 'B-apoptosis'}", + "81, regulation {'effect': 'B-regulates'}", + "83, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "47, modulates ['l0', 'l1', 'l2']", + "51, apoptosis ['l0', 'l3', 'l4']", + "67, induces ['l1', 'l3', 'l5']", + "68, apoptosis ['l2', 'l4', 'l5']", + "74, interrupts ['l6', 'l7', 'l8', 'l9']", + "77, induction ['l6', 'l10', 'l11', 'l12']", + "79, apoptosis. ['l7', 'l10', 'l13', 'l14']", + "81, regulation ['l8', 'l11', 'l13', 'l15']", + "83, apoptosis ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "regulates", + "words": [ + "modulates", + "regulation" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces", + "induction" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "interrupts" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis.", + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "9256276", + "TEXT": "The nef gene of simian immunodeficiency virus (SIV) is essential for high viral load and induction of AIDS in rhesus monkeys. A mutant form of the SIVmac239 Nef, which contains changes in a putative SH3-binding domain (amino acids 104 and 107 have been changed from PxxP to AxxA), does not associate with cellular serine/threonine kinases, but is fully active in CD4 downregulation and associates with the cellular tyrosine kinase Src. Infection of two rhesus macaques with SIVmac239 containing the mutant AxxA-Nef caused AIDS and rapid death in both animals. No reversions were observed in the majority of nef sequences analyzed from different time points during infection and from lymphatic tissues at the time of death. Our findings indicate that the putative SH3-ligand domain in SIVmac Nef and the association with cellular serine/threonine kinases are not important for efficient replication and pathogenicity of SIVmac in rhesus macaques.", + "TAG_DATA": [ + "73, rhesus {'context': 'B-organism'}", + "74, macaques {'context': 'I-organism'}", + "77, containing {'perturbing_action': 'I-other'}", + "78, the {'perturbing_action': 'I-other'}", + "79, mutant {'perturbing_action': 'I-other'}", + "80, AxxA-Nef {'perturbing_action': 'I-other'}", + "88, animals. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, rhesus ['l0', 'l1']", + "74, macaques ['l0', 'l2']", + "77, containing ['l3', 'l4', 'l5', 'l6']", + "78, the ['l3', 'l7', 'l8', 'l9']", + "79, mutant ['l4', 'l7', 'l10', 'l11']", + "80, AxxA-Nef ['l5', 'l8', 'l10', 'l12']", + "88, animals. ['l1', 'l2', 'l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "containing", + "the", + "mutant", + "AxxA-Nef" + ] + }, + "context": { + "val": "organism", + "words": [ + "animals." + ] + } + } + ] + }, + { + "PMID": "9212101", + "TEXT": "Mice were constructed carrying prion protein (PrP) transgenes with individual regions of putative secondary structure deleted. Transgenic mice with amino-terminal regions deleted remained healthy at >400 days of age, whereas those with either of carboxy-terminal alpha-helices deleted spontaneously developed fatal CNS illnesses similar to neuronal storage diseases. Deletion of either C-terminal helix resulted in PrP accumulation within cytoplasmic inclusions in enlarged neurons. Deletion of the penultimate C-terminal helix resulted in proliferation of rough endoplasmic reticulum. Mice with the C-terminal helix deleted were affected with nerve cell loss in the hippocampus and proliferation of smooth endoplasmic reticulum. Whether children with the human counterpart of this malady will be found remains to be determined.", + "TAG_DATA": [ + "17, mice {'context': 'B-organism'}", + "35, alpha-helices {'perturbing_action': 'I-gene loss-of-function'}", + "36, deleted {'perturbing_action': 'I-gene loss-of-function'}", + "47, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "48, of {'perturbing_action': 'I-gene loss-of-function'}", + "49, either {'perturbing_action': 'I-gene loss-of-function'}", + "50, C-terminal {'perturbing_action': 'I-gene loss-of-function'}", + "51, helix {'perturbing_action': 'I-gene loss-of-function'}", + "61, neurons. {'context': 'B-cells'}", + "62, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "63, of {'perturbing_action': 'I-gene loss-of-function'}", + "64, the {'perturbing_action': 'I-gene loss-of-function'}", + "65, penultimate {'perturbing_action': 'I-gene loss-of-function'}", + "66, C-terminal {'perturbing_action': 'I-gene loss-of-function'}", + "67, helix {'perturbing_action': 'I-gene loss-of-function'}", + "68, resulted {'effect': 'B-positive'}", + "69, in {'effect': 'I-positive'}", + "70, proliferation {'phenotype': 'B-proliferation'}", + "75, Mice {'context': 'B-organism'}", + "78, C-terminal {'perturbing_action': 'B-gene loss-of-function'}", + "79, helix {'perturbing_action': 'I-gene loss-of-function'}", + "80, deleted {'perturbing_action': 'I-gene loss-of-function'}", + "84, nerve {'context': 'B-cells'}", + "89, hippocampus {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "17, mice ['l0']", + "35, alpha-helices ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "36, deleted ['l1', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "47, Deletion ['l2', 'l20', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "48, of ['l3', 'l21', 'l36', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "49, either ['l4', 'l22', 'l37', 'l51', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "50, C-terminal ['l5', 'l23', 'l38', 'l52', 'l65', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "51, helix ['l6', 'l24', 'l39', 'l53', 'l66', 'l79', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "61, neurons. ['l0', 'l7', 'l25', 'l40', 'l54', 'l67', 'l80', 'l92']", + "62, Deletion ['l8', 'l26', 'l41', 'l55', 'l68', 'l81', 'l93', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "63, of ['l9', 'l27', 'l42', 'l56', 'l69', 'l82', 'l94', 'l103', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "64, the ['l10', 'l28', 'l43', 'l57', 'l70', 'l83', 'l95', 'l104', 'l114', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "65, penultimate ['l11', 'l29', 'l44', 'l58', 'l71', 'l84', 'l96', 'l105', 'l115', 'l124', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "66, C-terminal ['l12', 'l30', 'l45', 'l59', 'l72', 'l85', 'l97', 'l106', 'l116', 'l125', 'l133', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "67, helix ['l13', 'l31', 'l46', 'l60', 'l73', 'l86', 'l98', 'l107', 'l117', 'l126', 'l134', 'l141', 'l148', 'l149', 'l150', 'l151']", + "68, resulted ['l14', 'l32', 'l47', 'l61', 'l74', 'l87', 'l99', 'l108', 'l118', 'l127', 'l135', 'l142', 'l148', 'l152', 'l153', 'l154']", + "69, in ['l15', 'l33', 'l48', 'l62', 'l75', 'l88', 'l100', 'l109', 'l119', 'l128', 'l136', 'l143', 'l149', 'l152', 'l155', 'l156']", + "70, proliferation ['l16', 'l34', 'l49', 'l63', 'l76', 'l89', 'l101', 'l110', 'l120', 'l129', 'l137', 'l144', 'l150', 'l153', 'l155', 'l157']", + "75, Mice ['l158', 'l159', 'l160', 'l161', 'l162', 'l163']", + "78, C-terminal ['l158', 'l164', 'l165', 'l166', 'l167', 'l168']", + "79, helix ['l159', 'l164', 'l169', 'l170', 'l171', 'l172']", + "80, deleted ['l160', 'l165', 'l169', 'l173', 'l174', 'l175']", + "84, nerve ['l17', 'l77', 'l90', 'l111', 'l121', 'l130', 'l138', 'l145', 'l161', 'l166', 'l170', 'l173', 'l176', 'l177']", + "85, cell ['l18', 'l35', 'l50', 'l64', 'l78', 'l91', 'l102', 'l112', 'l122', 'l131', 'l139', 'l146', 'l151', 'l154', 'l156', 'l157', 'l162', 'l167', 'l171', 'l174', 'l176', 'l178']", + "89, hippocampus ['l19', 'l113', 'l123', 'l132', 'l140', 'l147', 'l163', 'l168', 'l172', 'l175', 'l177', 'l178']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha-helices", + "deleted", + "Deletion", + "of", + "either", + "C-terminal", + "helix", + "the", + "penultimate" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons.", + "nerve" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha-helices", + "deleted", + "Deletion", + "of", + "either", + "C-terminal", + "helix", + "the", + "penultimate" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha-helices", + "deleted", + "Deletion", + "of", + "either", + "C-terminal", + "helix", + "the", + "penultimate" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha-helices", + "Deletion", + "of", + "the", + "penultimate", + "C-terminal", + "helix", + "deleted" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "C-terminal", + "helix", + "deleted" + ] + } + } + ] + }, + { + "PMID": "9176499", + "TEXT": "Lung cancer causes more than 140,000 deaths annually in the United States alone, and the prognosis for non-small cell lung cancer (NSCLC) is particularly poor. Therapies using small molecules that preferentially kill lung tumor cells by inducing cellular suicide (apoptosis) would therefore be highly desirable. Retinoids have shown promise as cancer preventive and cancer therapeutic agents. Retinoid signals are mediated by two classes of nuclear receptors: the retinoic acid receptors (RAR alpha, beta, and gamma) and the retinoid X receptors (RXR alpha, beta and gamma). These receptors usually bind as heterodimers to specific DNA sequences and/or interact with other transcriptional regulators, such as AP-1 (ref. 10) to regulate gene transcription. Synthetic retinoids can be made that activate only specific portions of the complex retinoid response network and activate selective biological programs. To identify retinoids with novel biological activities, we used a high-throughput \"biological activity fingerprint\" screen on a large library of retinoids and retinoid-related molecules (RRMs). We identified new structures that are highly effective against lung cancer cells in vitro, inducing apoptosis. We show here for one of these compounds that it is very effective against a human NSCLC in vivo in an animal model. These new molecules show a distinct pattern of receptor signaling.", + "TAG_DATA": [ + "165, lung {'context': 'B-transformed cells'}", + "166, cancer {'context': 'I-transformed cells'}", + "167, cells {'context': 'I-transformed cells'}", + "168, in {'context': 'B-in vitro'}", + "169, vitro, {'context': 'I-in vitro'}", + "170, inducing {'effect': 'B-positive'}", + "171, apoptosis. {'phenotype': 'B-apoptosis'}", + "187, human {'context': 'B-neoplasm'}", + "188, NSCLC {'context': 'I-neoplasm'}", + "189, in {'context': 'B-in vivo'}", + "190, vivo {'context': 'I-in vivo'}", + "193, animal {'context': 'B-organism'}", + "194, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "165, lung ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "166, cancer ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "167, cells ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "168, in ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "169, vitro, ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "170, inducing ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "171, apoptosis. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "187, human ['l21', 'l22', 'l23', 'l24', 'l25']", + "188, NSCLC ['l21', 'l26', 'l27', 'l28', 'l29']", + "189, in ['l22', 'l26', 'l30', 'l31', 'l32']", + "190, vivo ['l23', 'l27', 'l30', 'l33', 'l34']", + "193, animal ['l24', 'l28', 'l31', 'l33', 'l35']", + "194, model. ['l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "lung", + "cancer", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "lung", + "cancer", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + }, + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "9142124", + "TEXT": "The atheroprotective effects of estrogen in women are well recognized, but the underlying mechanisms responsible are not well understood. Blood vessel cells express the classic estrogen receptor, ER alpha (ref. 2-6), and are directly affected by estrogen, which inhibits the development of atherosclerotic and injury-induced vascular lesions. We have generated mice in which the ER alpha gene is disrupted and have used a mouse model of carotid arterial injury to compare the effects of estrogen on wild-type and estrogen receptor-deficient mice. Increases in vascular medial area and smooth muscle cell proliferation were quantified following vascular injury in ovariectomized mice treated with vehicle or with physiologic levels of 17 beta-estradiol. Surprisingly, in both wild-type and estrogen receptor-deficient mice, 17 beta-estradiol markedly inhibited to the same degree all measures of vascular injury. These data demonstrate that estrogen inhibits vascular by a novel mechanism that is independent of the classic estrogen receptor, ER alpha.", + "TAG_DATA": [ + "50, mice {'context': 'B-organism'}", + "53, the {'perturbing_action': 'I-gene loss-of-function'}", + "54, ER {'perturbing_action': 'I-gene loss-of-function'}", + "55, alpha {'perturbing_action': 'I-gene loss-of-function'}", + "56, gene {'perturbing_action': 'I-gene loss-of-function'}", + "57, is {'perturbing_action': 'I-gene loss-of-function'}", + "58, disrupted {'perturbing_action': 'I-gene loss-of-function'}", + "63, mouse {'context': 'B-organism'}", + "64, model {'context': 'I-organism'}", + "78, estrogen {'perturbing_action': 'B-gene loss-of-function'}", + "79, receptor-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "80, mice. {'context': 'B-organism'}", + "87, smooth {'context': 'B-cells'}", + "88, muscle {'context': 'I-cells'}", + "89, cell {'context': 'I-cells'}", + "90, proliferation {'phenotype': 'B-proliferation'}", + "98, mice {'context': 'B-organism'}", + "114, estrogen {'perturbing_action': 'B-gene loss-of-function'}", + "115, receptor-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "116, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "53, the ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "54, ER ['l1', 'l16', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "55, alpha ['l2', 'l17', 'l31', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "56, gene ['l3', 'l18', 'l32', 'l45', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "57, is ['l4', 'l19', 'l33', 'l46', 'l58', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "58, disrupted ['l5', 'l20', 'l34', 'l47', 'l59', 'l70', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "63, mouse ['l6', 'l21', 'l35', 'l48', 'l60', 'l71', 'l81', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "64, model ['l7', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l97', 'l98', 'l99', 'l100', 'l101']", + "78, estrogen ['l8', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "79, receptor-deficient ['l9', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l102', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "80, mice. ['l10', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l92', 'l97', 'l103', 'l109', 'l115', 'l116', 'l117', 'l118']", + "87, smooth ['l11', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l93', 'l98', 'l104', 'l110', 'l115', 'l119', 'l120', 'l121', 'l122']", + "88, muscle ['l12', 'l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l94', 'l99', 'l105', 'l111', 'l116', 'l119', 'l123', 'l124', 'l125']", + "89, cell ['l13', 'l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l95', 'l100', 'l106', 'l112', 'l117', 'l120', 'l123', 'l126']", + "90, proliferation ['l14', 'l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l96', 'l101', 'l107', 'l113', 'l118', 'l121', 'l124', 'l126']", + "98, mice ['l15', 'l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l108', 'l114', 'l122', 'l125']", + "114, estrogen ['l127', 'l128']", + "115, receptor-deficient ['l127', 'l129']", + "116, mice, ['l128', 'l129']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "model", + "mice.", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "ER", + "alpha", + "gene", + "is", + "disrupted", + "estrogen", + "receptor-deficient" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mouse", + "model", + "mice." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "ER", + "alpha", + "gene", + "is", + "disrupted", + "estrogen", + "receptor-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "smooth", + "muscle", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "ER", + "alpha", + "gene", + "is", + "disrupted", + "estrogen", + "receptor-deficient" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "smooth", + "muscle", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "9055866", + "TEXT": "Apoptotic cell death in the retina was recently demonstrated in animal models of the hereditary human retinal dystrophy known as retinitis pigmentosa. Although recent evidence indicates that the proto-oncogene c-fos is a mediator of apoptosis, its precise role is unclear. In fact, under some conditions, c-fos may even protect against apoptotic cell death. In the retina, c-fos is physiologically expressed in a diurnal manner and is inducible by light. We previously observed a light-elicited, dose-dependent apoptotic response in rat photoreceptors. To determine whether c-fos is involved in the light-induced apoptotic pathway we have used control mice and mice lacking c-fos. We found that following dark adaptation and two hours of light exposure both groups of animals exhibited only a few apoptotic cells. However, at 12 and 24 additional hours after light exposure, apoptosis increased dramatically in controls but was virtually absent in those mice lacking c-fos. Therefore, c-fos is essential for light-induced apoptosis of photoreceptors. Notably, c-fos is continuously upregulated concomitant with apoptotic photoreceptor death in our system and in animal models of retinitis pigmentosa (Agarwal, N. et al., Invest. Ophthalmol. Vis.Sci. Suppl. 36, S638 and Rich, K.A. et al., Invest. Ophthalmol. Vis. Sci. Suppl. 35, 1833). Inhibition of c-fos expression might therefore represent a novel therapeutic strategy to retard the time course of retinal dystrophies and light-induced retinal degeneration.", + "TAG_DATA": [ + "78, rat {'context': 'B-cells'}", + "79, photoreceptors. {'context': 'I-cells'}", + "95, mice {'context': 'B-organism'}", + "97, mice {'context': 'B-organism'}", + "98, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "99, c-fos. {'perturbing_action': 'I-gene loss-of-function'}", + "115, animals {'context': 'B-organism'}", + "120, apoptotic {'phenotype': 'B-apoptosis'}", + "121, cells. {'context': 'B-cells', 'phenotype': 'I-apoptosis'}", + "132, apoptosis {'phenotype': 'B-apoptosis'}", + "133, increased {'effect': 'B-positive'}", + "143, mice {'context': 'B-organism'}", + "144, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "145, c-fos. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "78, rat ['l0', 'l1']", + "79, photoreceptors. ['l0', 'l2']", + "95, mice ['l1', 'l2', 'l3']", + "97, mice ['l3', 'l4', 'l5', 'l6']", + "98, lacking ['l4', 'l7', 'l8', 'l9', 'l10']", + "99, c-fos. ['l5', 'l7', 'l11', 'l12', 'l13']", + "115, animals ['l8', 'l11', 'l14', 'l15']", + "120, apoptotic ['l9', 'l12', 'l14', 'l16']", + "121, cells. ['l6', 'l10', 'l13', 'l15', 'l16']", + "132, apoptosis ['l17', 'l18']", + "133, increased ['l17']", + "143, mice ['l19', 'l20']", + "144, lacking ['l19', 'l21']", + "145, c-fos. ['l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "animals" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "c-fos." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "animals" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "cells.", + "apoptotic" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "cells.", + "apoptotic" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "c-fos." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "cells.", + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "c-fos." + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + } + ] + }, + { + "PMID": "9055859", + "TEXT": "Repression of cell cycle progression by tumor suppressors might provide a means for tumor therapy. Here we demonstrate that ectopic overexpression of the p16INK4/CDKN2 tumor suppressor from an adenovirus vector in various cell lines results in block of cell division and, subsequently, in a gradual reduction of the levels of the product of retinoblastoma susceptibility gene, pRb. Overexpression of p53 and p16INK4/CDKN2, but not p53 on its own, induces apoptotic death only in tumor cells. Simultaneous adenoviral transfer of p16 and p53 genes leads to inhibition of tumor growth in nude mice. These results suggest that combined delivery of two cooperating genes like p16 and p53 could be the basis for the development of a new strategy for cancer gene therapy.", + "TAG_DATA": [ + "19, ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "20, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "21, of {'perturbing_action': 'I-gene gain-of-function'}", + "22, the {'perturbing_action': 'I-gene gain-of-function'}", + "23, p16INK4/CDKN2 {'perturbing_action': 'I-gene gain-of-function'}", + "24, tumor {'perturbing_action': 'I-gene gain-of-function'}", + "25, suppressor {'perturbing_action': 'I-gene gain-of-function'}", + "26, from {'perturbing_action': 'I-gene gain-of-function'}", + "27, an {'perturbing_action': 'I-gene gain-of-function'}", + "28, adenovirus {'perturbing_action': 'I-gene gain-of-function'}", + "29, vector {'perturbing_action': 'I-gene gain-of-function'}", + "32, cell {'context': 'B-cells'}", + "33, lines {'context': 'I-cells'}", + "36, block {'effect': 'B-negative'}", + "38, cell {'phenotype': 'B-proliferation'}", + "39, division {'phenotype': 'I-proliferation'}", + "57, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "58, of {'perturbing_action': 'I-gene gain-of-function'}", + "59, p53 {'perturbing_action': 'I-gene gain-of-function'}", + "60, and {'perturbing_action': 'I-gene gain-of-function'}", + "61, p16INK4/CDKN2, {'perturbing_action': 'I-gene gain-of-function'}", + "68, induces {'effect': 'B-positive'}", + "69, apoptotic {'phenotype': 'B-apoptosis'}", + "70, death {'phenotype': 'I-apoptosis'}", + "73, tumor {'context': 'B-transformed cells'}", + "74, cells. {'context': 'I-transformed cells'}", + "75, Simultaneous {'perturbing_action': 'B-gene gain-of-function'}", + "76, adenoviral {'perturbing_action': 'I-gene gain-of-function'}", + "77, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "78, of {'perturbing_action': 'I-gene gain-of-function'}", + "79, p16 {'perturbing_action': 'I-gene gain-of-function'}", + "80, and {'perturbing_action': 'I-gene gain-of-function'}", + "81, p53 {'perturbing_action': 'I-gene gain-of-function'}", + "82, genes {'perturbing_action': 'I-gene gain-of-function'}", + "85, inhibition {'effect': 'B-negative'}", + "87, tumor {'phenotype': 'B-tumour growth'}", + "88, growth {'phenotype': 'I-tumour growth'}", + "90, nude {'context': 'B-organism'}", + "91, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "19, ectopic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "20, overexpression ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "21, of ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "22, the ['l2', 'l21', 'l39', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "23, p16INK4/CDKN2 ['l3', 'l22', 'l40', 'l57', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "24, tumor ['l4', 'l23', 'l41', 'l58', 'l74', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "25, suppressor ['l5', 'l24', 'l42', 'l59', 'l75', 'l90', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "26, from ['l6', 'l25', 'l43', 'l60', 'l76', 'l91', 'l105', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "27, an ['l7', 'l26', 'l44', 'l61', 'l77', 'l92', 'l106', 'l119', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "28, adenovirus ['l8', 'l27', 'l45', 'l62', 'l78', 'l93', 'l107', 'l120', 'l132', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154']", + "29, vector ['l9', 'l28', 'l46', 'l63', 'l79', 'l94', 'l108', 'l121', 'l133', 'l144', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164']", + "32, cell ['l10', 'l29', 'l47', 'l64', 'l80', 'l95', 'l109', 'l122', 'l134', 'l145', 'l155', 'l165']", + "33, lines ['l11', 'l30', 'l48', 'l65', 'l81', 'l96', 'l110', 'l123', 'l135', 'l146', 'l156', 'l165']", + "36, block ['l12', 'l31', 'l49', 'l66', 'l82', 'l97', 'l111', 'l124', 'l136', 'l147', 'l157', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "38, cell ['l13', 'l32', 'l50', 'l67', 'l83', 'l98', 'l112', 'l125', 'l137', 'l148', 'l158', 'l166', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "39, division ['l14', 'l33', 'l51', 'l68', 'l84', 'l99', 'l113', 'l126', 'l138', 'l149', 'l159', 'l167', 'l173', 'l179', 'l180', 'l181', 'l182', 'l183']", + "57, Overexpression ['l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "58, of ['l184', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202']", + "59, p53 ['l185', 'l194', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209']", + "60, and ['l186', 'l195', 'l203', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216']", + "61, p16INK4/CDKN2, ['l187', 'l196', 'l204', 'l210', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222']", + "68, induces ['l15', 'l34', 'l52', 'l69', 'l85', 'l100', 'l114', 'l127', 'l139', 'l150', 'l160', 'l168', 'l174', 'l179', 'l188', 'l197', 'l205', 'l211', 'l217', 'l223', 'l224', 'l225', 'l226']", + "69, apoptotic ['l16', 'l35', 'l53', 'l70', 'l86', 'l101', 'l115', 'l128', 'l140', 'l151', 'l161', 'l169', 'l175', 'l180', 'l189', 'l198', 'l206', 'l212', 'l218', 'l223', 'l227', 'l228', 'l229']", + "70, death ['l17', 'l36', 'l54', 'l71', 'l87', 'l102', 'l116', 'l129', 'l141', 'l152', 'l162', 'l170', 'l176', 'l181', 'l190', 'l199', 'l207', 'l213', 'l219', 'l224', 'l227', 'l230', 'l231']", + "73, tumor ['l18', 'l37', 'l55', 'l72', 'l88', 'l103', 'l117', 'l130', 'l142', 'l153', 'l163', 'l171', 'l177', 'l182', 'l191', 'l200', 'l208', 'l214', 'l220', 'l225', 'l228', 'l230', 'l232']", + "74, cells. ['l19', 'l38', 'l56', 'l73', 'l89', 'l104', 'l118', 'l131', 'l143', 'l154', 'l164', 'l172', 'l178', 'l183', 'l192', 'l201', 'l209', 'l215', 'l221', 'l226', 'l229', 'l231', 'l232']", + "75, Simultaneous ['l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244']", + "76, adenoviral ['l233', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255']", + "77, transfer ['l234', 'l245', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265']", + "78, of ['l235', 'l246', 'l256', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274']", + "79, p16 ['l236', 'l247', 'l257', 'l266', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282']", + "80, and ['l237', 'l248', 'l258', 'l267', 'l275', 'l283', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289']", + "81, p53 ['l238', 'l249', 'l259', 'l268', 'l276', 'l283', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295']", + "82, genes ['l239', 'l250', 'l260', 'l269', 'l277', 'l284', 'l290', 'l296', 'l297', 'l298', 'l299', 'l300']", + "85, inhibition ['l240', 'l251', 'l261', 'l270', 'l278', 'l285', 'l291', 'l296', 'l301', 'l302', 'l303', 'l304']", + "87, tumor ['l241', 'l252', 'l262', 'l271', 'l279', 'l286', 'l292', 'l297', 'l301', 'l305', 'l306', 'l307']", + "88, growth ['l193', 'l202', 'l216', 'l222', 'l242', 'l253', 'l263', 'l272', 'l280', 'l287', 'l293', 'l298', 'l302', 'l305', 'l308', 'l309']", + "90, nude ['l243', 'l254', 'l264', 'l273', 'l281', 'l288', 'l294', 'l299', 'l303', 'l306', 'l308', 'l310']", + "91, mice. ['l244', 'l255', 'l265', 'l274', 'l282', 'l289', 'l295', 'l300', 'l304', 'l307', 'l309', 'l310']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "the", + "p16INK4/CDKN2", + "tumor", + "suppressor", + "from", + "an", + "adenovirus", + "vector" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "the", + "p16INK4/CDKN2", + "tumor", + "suppressor", + "from", + "an", + "adenovirus", + "vector", + "Simultaneous", + "adenoviral", + "transfer", + "p16", + "and", + "p53", + "genes" + ] + }, + "effect": { + "val": "negative", + "words": [ + "block", + "inhibition" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "the", + "p16INK4/CDKN2", + "tumor", + "suppressor", + "from", + "an", + "adenovirus", + "vector" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "the", + "p16INK4/CDKN2", + "tumor", + "suppressor", + "from", + "an", + "adenovirus", + "vector", + "Overexpression", + "p53", + "and", + "p16INK4/CDKN2," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "the", + "p16INK4/CDKN2", + "tumor", + "suppressor", + "from", + "an", + "adenovirus", + "vector", + "Overexpression", + "p53", + "and", + "p16INK4/CDKN2," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "the", + "p16INK4/CDKN2", + "tumor", + "suppressor", + "from", + "an", + "adenovirus", + "vector", + "Overexpression", + "p53", + "and", + "p16INK4/CDKN2," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "block" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "block" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "block" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "and", + "p16INK4/CDKN2,", + "Simultaneous", + "adenoviral", + "transfer", + "p16", + "p53", + "genes" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "growth", + "tumor" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Simultaneous", + "adenoviral", + "transfer", + "of", + "p16", + "and", + "p53", + "genes" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice." + ] + } + } + ] + }, + { + "PMID": "9018239", + "TEXT": "Organ xenografts under certain circumstances survive in the presence of anti-graft antibodies and complement, a situation referred to as \"accommodation.\" We find that the endothelial cells (ECs) in hamster hearts that accommodate themselves in rats express genes, such as A20 and bcl-2, that in vitro protect ECs from apoptosis and prevent upregulation in those cells of proinflammatory genes such as cytokines, procoagulant and adhesion molecules. Hearts that are rejected do not express these genes. In addition, vessels of rejected hearts show florid transplant arteriosclerosis whereas those of accommodated hearts do not. Accommodated xenografts have an ongoing T helper cell type 2 (Th2) cytokine immune response, whereas the rejected grafts have a Th1 response. We propose a model for factors that contribute to the survival of xenografts and the avoidance of transplant arteriosclerosis.", + "TAG_DATA": [ + "24, endothelial {'context': 'B-cells'}", + "25, cells {'context': 'I-cells'}", + "26, (ECs) {'context': 'I-cells'}", + "28, hamster {'context': 'B-tissue/organ'}", + "29, hearts {'context': 'I-tissue/organ'}", + "34, rats {'context': 'B-organism'}", + "43, in {'context': 'B-in vitro'}", + "44, vitro {'context': 'I-in vitro'}", + "46, ECs {'context': 'B-cells'}", + "48, apoptosis {'phenotype': 'B-apoptosis'}", + "76, vessels {'context': 'B-tissue/organ'}", + "92, xenografts {'context': 'B-xenograft'}" + ], + "LINK_DATA": [ + "24, endothelial ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "25, cells ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "26, (ECs) ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "28, hamster ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "29, hearts ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "34, rats ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "43, in ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "44, vitro ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "46, ECs ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "48, apoptosis ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells", + "(ECs)", + "ECs" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "hamster", + "hearts" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rats" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "8986743", + "TEXT": "The mechanism by which mutations in the presenilin (PS) genes cause the most aggressive form of early-onset Alzheimer's disease (AD) is unknown, but fibroblasts from mutation carriers secrete increased levels of the amyloidogenic A beta 42 peptide, the main component of AD plaques. We established transfected cell and transgenic mouse models that coexpress human PS and amyloid beta-protein precursor (APP) genes and analyzed quantitatively the effects of PS expression on APP processing. In both models, expression of wild-type PS genes did not alter APP levels, alpha- and beta-secretase activity and A beta production. In the transfected cells, PS1 and PS2 mutations caused a highly significant increase in A beta 42 secretion in all mutant clones. Likewise, mutant but not wildtype PS1 transgenic mice showed significant overproduction of A beta 42 in the brain, and this effect was detectable as early as 2-4 months of age. Different PS mutations had differential effects on A beta generation. The extent of A beta 42 increase did not correlate with presenilin expression levels. Our data demonstrate that the presenilin mutations cause a dominant gain of function and may induce AD by enhancing A beta 42 production, thus promoting cerebral beta-amyloidosis.", + "TAG_DATA": [ + "49, mouse {'context': 'I-organism'}", + "50, models {'context': 'I-organism'}", + "96, cells, {'context': 'B-cells'}", + "97, PS1 {'perturbing_action': 'B-other'}", + "98, and {'perturbing_action': 'I-other'}", + "99, PS2 {'perturbing_action': 'I-other'}", + "100, mutations {'perturbing_action': 'I-other'}", + "120, PS1 {'perturbing_action': 'I-gene gain-of-function'}", + "121, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "122, mice {'context': 'B-organism'}", + "132, brain, {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "46, cell ['l0']", + "48, transgenic ['l1', 'l2', 'l3', 'l4', 'l5']", + "49, mouse ['l1', 'l6', 'l7', 'l8']", + "50, models ['l0', 'l2', 'l6']", + "96, cells, ['l3', 'l7', 'l9', 'l10', 'l11', 'l12']", + "97, PS1 ['l9', 'l13', 'l14', 'l15']", + "98, and ['l4', 'l10', 'l13', 'l16', 'l17']", + "99, PS2 ['l11', 'l14', 'l16', 'l18']", + "100, mutations ['l5', 'l8', 'l12', 'l15', 'l17', 'l18']", + "120, PS1 ['l19', 'l20', 'l21']", + "121, transgenic ['l19', 'l22', 'l23']", + "122, mice ['l20', 'l22', 'l24']", + "132, brain, ['l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutations" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells," + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "PS1", + "and", + "PS2", + "mutations" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PS1", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PS1", + "transgenic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain," + ] + } + } + ] + }, + { + "PMID": "8946837", + "TEXT": "Given the plethora of well-documented breast carcinoma-associated antigens in humans including MAGE-1, -2 and -3, mutated p53, p21ras, HER-2/neu and DF3/MUC-1, coupled with evidence that humoral and cytotoxic T-cell responses against these antigens exist, the central dilemma facing tumor immunologists is why the host immune response is so inefficient. One possibility is that tumor cells themselves are either inefficient or ineffective antigen-presenting cells (APCs). The failure of tumor cells to function as APCs may be due to their inability to process and present the antigen, the absence or insufficient numbers of adhesion and costimulatory molecules or, potentially, the secretion of inhibitory cytokines. Therefore, we sought to determine whether human breast cancer cell lines could function as APCs and, if not, to identify mechanism(s) responsible for this defect. Here, we show that human breast cancer cell lines fail to present alloantigen. This defect does not reside in their inherent capacity to present antigen but rather is due to apoptosis of activated T cells induced by exposure to the breast carcinoma-associated mucin antigen, DF3/MUC1. These results support the hypothesis that DF3/MUC1 may contribute to the paucity of clinically significant anticarcinoma-specific immune responses.", + "TAG_DATA": [ + "131, human {'context': 'B-transformed cells'}", + "132, breast {'context': 'I-transformed cells'}", + "133, cancer {'context': 'I-transformed cells'}", + "134, cell {'context': 'I-transformed cells'}", + "135, lines {'context': 'I-transformed cells'}", + "157, apoptosis {'phenotype': 'B-apoptosis'}", + "159, activated {'context': 'B-cells'}", + "160, T {'context': 'B-cells'}", + "161, cells {'context': 'I-cells'}", + "162, induced {'effect': 'B-positive'}" + ], + "LINK_DATA": [ + "131, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "132, breast ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "133, cancer ['l1', 'l7', 'l13', 'l14', 'l15', 'l16']", + "134, cell ['l2', 'l8', 'l13', 'l17', 'l18', 'l19']", + "135, lines ['l3', 'l9', 'l14', 'l17', 'l20', 'l21']", + "157, apoptosis ['l22', 'l23', 'l24', 'l25']", + "159, activated ['l4', 'l10', 'l22', 'l26', 'l27', 'l28']", + "160, T ['l5', 'l11', 'l15', 'l18', 'l20', 'l23', 'l26', 'l29', 'l30']", + "161, cells ['l6', 'l12', 'l16', 'l19', 'l21', 'l24', 'l27', 'l29', 'l31']", + "162, induced ['l25', 'l28', 'l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "activated", + "T", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "activated", + "T", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "8898758", + "TEXT": "Lamellar ichthyosis (LI) is a disfiguring skin disease characterized by abnormal epidermal differentiation and defective cutaneous barrier function. LI has been associated with loss of keratinocyte transglutaminase 1 (TGase1), an enzyme believed necessary for normal formation of the cornified epidermal barrier. Using LI as a prototype for therapeutic cutaneous gene delivery, we have used the human skin/immunodeficient mouse xenograft model to correct the molecular, histologic and functional abnormalities of LI patient skin in vivo. We have used TGase1-deficient primary keratinocytes from LI patients combined with high-efficiency transfer of functional TGase1 to regenerate engineered human LI epidermis on immunodeficient mice. Engineered LI epidermis displayed normal TGase1 expression in vivo, unlike unengineered LI epidermis where TGase1 was absent. Epidermal architecture was also normalized by TGase1 restoration, as was expression of the epidermal differentiation marker filaggrin. Engineered LI skin demonstrated restoration of cutaneous barrier function measures to levels seen in epidermis regenerated by keratinocytes from patients with normal skin, indicating functional correction in vivo of the proposed primary pathophysiologic defect in LI. These results confirm a major role for TGase1 in epidermal differentiation and demonstrate a potential future approach to therapeutic gene delivery in human skin.", + "TAG_DATA": [ + "55, human {'context': 'B-xenograft'}", + "56, skin/immunodeficient {'context': 'I-xenograft'}", + "57, mouse {'context': 'I-xenograft'}", + "58, xenograft {'context': 'I-xenograft'}", + "59, model {'context': 'I-xenograft'}", + "72, in {'context': 'B-in vivo'}", + "73, vivo. {'context': 'I-in vivo'}", + "77, TGase1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "78, primary {'context': 'B-cells'}", + "79, keratinocytes {'context': 'I-cells'}", + "93, human {'context': 'B-tissue/organ'}", + "94, LI {'context': 'I-tissue/organ'}", + "95, epidermis {'context': 'I-tissue/organ'}", + "97, immunodeficient {'context': 'B-organism'}", + "98, mice. {'context': 'I-organism'}", + "100, LI {'context': 'I-tissue/organ'}", + "101, epidermis {'context': 'I-tissue/organ'}", + "106, in {'context': 'B-in vivo'}", + "107, vivo, {'context': 'I-in vivo'}", + "110, LI {'context': 'B-tissue/organ'}", + "111, epidermis {'context': 'I-tissue/organ'}", + "134, LI {'context': 'I-tissue/organ'}", + "135, skin {'context': 'I-tissue/organ'}", + "150, keratinocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "55, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "56, skin/immunodeficient ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "57, mouse ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "58, xenograft ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "59, model ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "72, in ['l4', 'l12', 'l19', 'l25', 'l30', 'l35']", + "73, vivo. ['l5', 'l13', 'l20', 'l26', 'l31', 'l35']", + "77, TGase1-deficient ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "78, primary ['l7', 'l15', 'l22', 'l28', 'l33', 'l36', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "79, keratinocytes ['l8', 'l16', 'l23', 'l29', 'l34', 'l37', 'l43', 'l49', 'l50', 'l51', 'l52']", + "93, human ['l38', 'l44', 'l49', 'l53', 'l54', 'l55', 'l56', 'l57']", + "94, LI ['l39', 'l45', 'l50', 'l53', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "95, epidermis ['l40', 'l46', 'l51', 'l54', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "97, immunodeficient ['l41', 'l47', 'l55', 'l59', 'l64', 'l69', 'l70', 'l71', 'l72', 'l73']", + "98, mice. ['l42', 'l48', 'l52', 'l56', 'l60', 'l65', 'l69', 'l74']", + "100, LI ['l61', 'l66', 'l70', 'l75', 'l76', 'l77', 'l78', 'l79']", + "101, epidermis ['l57', 'l62', 'l67', 'l71', 'l74', 'l75', 'l80', 'l81', 'l82', 'l83']", + "106, in ['l72', 'l76', 'l80', 'l84', 'l85', 'l86']", + "107, vivo, ['l63', 'l68', 'l73', 'l77', 'l81', 'l84', 'l87', 'l88']", + "110, LI ['l78', 'l82', 'l85', 'l87', 'l89']", + "111, epidermis ['l79', 'l83', 'l86', 'l88', 'l89']", + "134, LI ['l90', 'l91']", + "135, skin ['l90', 'l92']", + "150, keratinocytes ['l91', 'l92']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "xenograft", + "words": [ + "human", + "skin/immunodeficient", + "mouse", + "xenograft", + "model" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TGase1-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TGase1-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "primary", + "keratinocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TGase1-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "human", + "LI", + "epidermis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TGase1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "immunodeficient", + "mice." + ] + } + } + ] + }, + { + "PMID": "8837615", + "TEXT": "The induction of tumor cell death by anticancer therapy results from a genetic program of autonomous cell death termed apoptosis. Because the p53 tumor suppressor gene is a critical component for induction of apoptosis in response to DNA damage, its inactivation in cancers may be responsible for their resistance to genotoxic anticancer agents. The cellular response to DNA damage involves a cell-cycle arrest at both the G1/S and G2/M transitions; these checkpoints maintain viability by preventing the replication or segregation of damaged DNA. The arrest at the G1 checkpoint is mediated by p53-dependent induction of p21WAF1/CIP1, whereas the G2 arrest involves inactivation of p34cdc2 kinase. Following DNA damage, p53-deficient cells fail to arrest at G1 and accumulate at the G2/M transition. We demonstrate that abrogation of G2 arrest by caffeine-mediated activation of p34cdc2 kinase results in the selective sensitization of p53-deficient primary and tumor cells to irradiation-induced apoptosis. These data suggest that pharmacologic activation of p34cdc2 kinase may be a useful therapeutic strategy for circumventing the resistance of p53-deficient cancers to genotoxic anticancer agents.", + "TAG_DATA": [ + "108, p53-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "109, cells {'context': 'B-cells'}", + "110, fail {'effect': 'B-negative'}", + "111, to {'effect': 'I-negative', 'phenotype': 'I-cell cycle arrest'}", + "112, arrest {'phenotype': 'I-cell cycle arrest'}", + "113, at {'phenotype': 'I-cell cycle arrest'}", + "114, G1 {'phenotype': 'I-cell cycle arrest'}", + "124, abrogation {'effect': 'B-negative'}", + "126, G2 {'phenotype': 'B-cell cycle arrest'}", + "127, arrest {'phenotype': 'I-cell cycle arrest'}", + "138, sensitization {'effect': 'B-positive'}", + "140, p53-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "141, primary {'context': 'B-transformed cells'}", + "142, and {'context': 'I-transformed cells'}", + "143, tumor {'context': 'I-transformed cells'}", + "144, cells {'context': 'I-transformed cells'}", + "146, irradiation-induced {'effect': 'B-positive'}", + "147, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "108, p53-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "109, cells ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "110, fail ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "111, to ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "112, arrest ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "113, at ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "114, G1 ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "124, abrogation ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "126, G2 ['l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "127, arrest ['l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "138, sensitization ['l23', 'l32', 'l40', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "140, p53-deficient ['l24', 'l33', 'l41', 'l48', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "141, primary ['l25', 'l34', 'l42', 'l49', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "142, and ['l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "143, tumor ['l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l70', 'l71', 'l72']", + "144, cells ['l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l70', 'l73', 'l74']", + "146, irradiation-induced ['l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l73', 'l75']", + "147, apoptosis. ['l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "fail", + "to", + "abrogation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "to", + "arrest", + "at", + "G1", + "G2" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "to", + "fail", + "abrogation" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "to", + "arrest", + "at", + "G1", + "G2" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "fail", + "to" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "to", + "arrest", + "at", + "G1" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "and", + "tumor", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogation" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G2", + "arrest" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitization", + "irradiation-induced" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G2", + "arrest" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "and", + "tumor", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitization", + "irradiation-induced" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitization", + "irradiation-induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "and", + "tumor", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitization", + "irradiation-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "and", + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "primary", + "and", + "tumor", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "8837613", + "TEXT": "Postmenopausal osteoporosis, the most common bone disease in the developed world, is associated with estrogen deficiency. This deficiency induces increased generation and activity of osteoclasts, which perforate bone trabeculae, thus reducing their strength and increasing fracture risk. Estrogen replacement prevents these effects, indicating that estrogen negatively regulates osteoclast formation and function, but how it does this is unclear. Because functional osteoclast life span and thus the amount of bone that osteoclasts resorb could also be enhanced following estrogen deficiency, and since sex steroids regulate apoptosis in other target tissues, we investigated whether estrogen may affect osteoclast function by promoting apoptosis. 17 beta-Estradiol promoted apoptosis of murine osteoclasts in vitro and in vivo by two- to threefold. Tamoxifen, which has estrogenic effects on bone resorption, and transforming growth factor-beta 1 (TGF-beta), whose production by osteoblasts is increased by estrogen, had similar effects in vitro. Anti-TGF-beta antibody inhibited TGF-beta-, estrogen- and tamoxifen-induced osteoclast apoptosis, indicating that TGF-beta might mediate this effect. These findings suggest that estrogen may prevent excessive bone loss before and after the menopause by limiting osteoclast life span through promotion of apoptosis. The development of analogues to promote this mechanism specifically could be a useful and novel therapeutic approach to prevent postmenopausal osteoporosis.", + "TAG_DATA": [ + "102, promoted {'effect': 'B-positive'}", + "103, apoptosis {'phenotype': 'B-apoptosis'}", + "105, murine {'context': 'B-cells'}", + "106, osteoclasts {'context': 'I-cells'}", + "107, in {'context': 'B-in vitro'}", + "108, vitro {'context': 'I-in vitro'}", + "110, in {'context': 'B-in vivo'}", + "111, vivo {'context': 'I-in vivo'}", + "141, in {'context': 'B-in vitro'}", + "142, vitro. {'context': 'I-in vitro'}", + "145, inhibited {'effect': 'B-negative'}", + "150, osteoclast {'context': 'B-cells'}", + "151, apoptosis, {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "102, promoted ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "103, apoptosis ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "105, murine ['l1', 'l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "106, osteoclasts ['l2', 'l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "107, in ['l3', 'l8', 'l13', 'l17', 'l21']", + "108, vitro ['l4', 'l9', 'l14', 'l18', 'l21']", + "110, in ['l10', 'l15', 'l19', 'l22']", + "111, vivo ['l5', 'l11', 'l16', 'l20', 'l22']", + "141, in ['l23']", + "142, vitro. ['l23']", + "145, inhibited ['l24', 'l25']", + "150, osteoclast ['l24', 'l26']", + "151, apoptosis, ['l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "cells", + "words": [ + "murine", + "osteoclasts" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis," + ] + }, + "context": { + "val": "cells", + "words": [ + "murine", + "osteoclasts", + "osteoclast" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + } + ] + }, + { + "PMID": "8782458", + "TEXT": "Soluble HLA class I molecules (sHLAs) have been identified in the serum of patients with inflammatory diseases, allografts and autoimmune diseases and in serum of healthy individuals. The biological significance of these molecules, particularly after allogeneic organ transplantation, has been enigmatic. Here we show that primary alloreactive CD8+ T cells interact with sHLA and undergo apoptosis in the absence of a second signal. Ligation of CD28 rescued T cells from death, implying that sHLAs induce apoptosis through selective stimulation of the T-cell receptor. CD95-L was upregulated after cytotoxic T lymphocytes were incubated with sHLAs, and cell death was blocked by a neutralizing anti-CD95-L antibody, suggesting that sHLAs induce endogenous mutual killing of activated T cells. These results provide a molecular basis for the capacity of sHLAs to downregulate T-cell responses, which may be especially relevant to organ transplantation.", + "TAG_DATA": [ + "46, alloreactive {'context': 'I-cells'}", + "47, CD8+ {'context': 'I-cells'}", + "48, T {'context': 'I-cells'}", + "49, cells {'context': 'I-cells'}", + "54, undergo {'effect': 'B-positive'}", + "55, apoptosis {'phenotype': 'B-apoptosis'}", + "63, Ligation {'perturbing_action': 'B-pharmacological augmentation'}", + "64, of {'perturbing_action': 'I-pharmacological augmentation'}", + "65, CD28 {'perturbing_action': 'I-pharmacological augmentation'}", + "67, T {'context': 'B-cells'}", + "68, cells {'context': 'B-cells'}", + "74, induce {'effect': 'B-positive'}", + "75, apoptosis {'phenotype': 'B-apoptosis'}", + "95, cell {'phenotype': 'B-cell death'}", + "96, death {'phenotype': 'I-cell death'}", + "98, blocked {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "46, alloreactive ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "47, CD8+ ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "48, T ['l1', 'l11', 'l21', 'l22', 'l23', 'l24']", + "49, cells ['l2', 'l12', 'l21', 'l25', 'l26', 'l27']", + "54, undergo ['l3', 'l13', 'l22', 'l25', 'l28', 'l29']", + "55, apoptosis ['l4', 'l14', 'l23', 'l26', 'l28', 'l30', 'l31']", + "63, Ligation ['l5', 'l15', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "64, of ['l6', 'l16', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "65, CD28 ['l7', 'l17', 'l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "67, T ['l8', 'l18', 'l30', 'l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "68, cells ['l9', 'l19', 'l24', 'l27', 'l29', 'l31', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "74, induce ['l10', 'l20', 'l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "75, apoptosis ['l37', 'l42', 'l46', 'l49', 'l51', 'l52']", + "95, cell ['l53', 'l54']", + "96, death ['l53', 'l55']", + "98, blocked ['l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "alloreactive", + "CD8+", + "T", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "undergo", + "induce" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "alloreactive", + "CD8+", + "T", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "alloreactive", + "CD8+", + "T", + "cells" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Ligation", + "of", + "CD28" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "undergo", + "induce" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Ligation", + "of", + "CD28" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Ligation", + "of", + "CD28" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + } + ] + }, + { + "PMID": "8673925", + "TEXT": "Brain injury, as occurs in stroke or head trauma, induces a dramatic increase in levels of tumor necrosis factor-alpha (TNF), but its role in brain injury response is unknown. We generated mice genetically deficient in TNF receptors (TNFR-KO) to determine the role of TNF in brain cell injury responses. Damage to neurons caused by focal cerebral ischemia and epileptic seizures was exacerbated in TNFR-KO mice, indicating that TNF serves a neuroprotective function. Oxidative stress was increased and levels of an antioxidant enzyme reduced in brain cells of TNFR-KO mice, indicating that TNF protects neurons by stimulating antioxidant pathways. Injury-induced microglial activation was suppressed in TNFR-KO mice, demonstrating a key role for TNF in injury-induced immune response. Drugs that target TNF signaling pathways may prove beneficial in treating stroke and traumatic brain injury.", + "TAG_DATA": [ + "31, mice {'context': 'B-organism'}", + "33, deficient {'perturbing_action': 'I-gene loss-of-function'}", + "34, in {'perturbing_action': 'I-gene loss-of-function'}", + "35, TNF {'perturbing_action': 'I-gene loss-of-function'}", + "36, receptors {'perturbing_action': 'I-gene loss-of-function'}", + "37, (TNFR-KO) {'perturbing_action': 'I-gene loss-of-function'}", + "51, neurons {'context': 'B-cells'}", + "63, TNFR-KO {'perturbing_action': 'B-gene loss-of-function'}", + "64, mice, {'context': 'B-organism'}", + "84, brain {'context': 'B-cells'}", + "85, cells {'context': 'I-cells'}", + "87, TNFR-KO {'perturbing_action': 'B-gene loss-of-function'}", + "88, mice, {'context': 'B-organism'}", + "93, neurons {'context': 'B-cells'}", + "104, TNFR-KO {'perturbing_action': 'B-gene loss-of-function'}", + "105, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "31, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "32, genetically ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "33, deficient ['l1', 'l7', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "34, in ['l2', 'l8', 'l14', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "35, TNF ['l3', 'l9', 'l15', 'l22', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "36, receptors ['l4', 'l10', 'l16', 'l23', 'l29', 'l35', 'l36', 'l37', 'l38']", + "37, (TNFR-KO) ['l5', 'l11', 'l17', 'l24', 'l30', 'l35', 'l39']", + "51, neurons ['l6', 'l12', 'l18', 'l25', 'l31', 'l36', 'l39', 'l40']", + "63, TNFR-KO ['l19', 'l26', 'l32', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "64, mice, ['l13', 'l20', 'l27', 'l33', 'l37', 'l40', 'l41', 'l47', 'l48', 'l49', 'l50', 'l51']", + "84, brain ['l42', 'l47', 'l52', 'l53', 'l54', 'l55']", + "85, cells ['l21', 'l28', 'l34', 'l38', 'l43', 'l48', 'l52', 'l56', 'l57', 'l58']", + "87, TNFR-KO ['l44', 'l49', 'l53', 'l56', 'l59', 'l60']", + "88, mice, ['l45', 'l50', 'l54', 'l57', 'l59', 'l61']", + "93, neurons ['l46', 'l51', 'l55', 'l58', 'l60', 'l61']", + "104, TNFR-KO ['l62']", + "105, mice, ['l62']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "TNF", + "receptors", + "(TNFR-KO)", + "TNFR-KO" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "TNF", + "receptors", + "(TNFR-KO)", + "TNFR-KO" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons", + "cells", + "brain" + ] + } + } + ] + }, + { + "PMID": "8673924", + "TEXT": "Microtubule-associated protein tau becomes abnormally hyperphosphorylated in Alzheimer's disease (AD) and accumulates as tangles of paired helical filaments in neurons undergoing degeneration. We now show that in solution normal tau associates with the AD hyperphosphorylated tau (AD P-tau) in a nonsaturable fashion, forming large tangles of filaments 3.3 +/- 0.7 nm in diameter. These tangles, which are not detected in identically treated normal tau or AD P-tau alone, are made up of filaments several microns in length and are labeled with tau antibodies. Dephosphorylation with alkaline phosphatase abolishes the ability of AD P-tau to aggregate with normal tau and prevents tangle formation. AD P-tau disassembles microtubules assembled from normal tau and tubulin. These data provide insight into how the hyperphosphorylation of tau might lead to the formation of the neurofibrillary tangles and the degeneration of the affected neurons in AD.", + "TAG_DATA": [ + "99, prevents {'effect': 'B-negative'}", + "101, formation. {'phenotype': 'I-tumourigenesis'}" + ], + "LINK_DATA": [ + "99, prevents ['l0', 'l1']", + "100, tangle ['l0', 'l2']", + "101, formation. ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation." + ] + } + } + ] + }, + { + "PMID": "8612229", + "TEXT": "Most patients with rheumatoid arthritis express particular HLA-DR alleles. The DRbeta1 chains of these alleles share a highly homologous amino acid motif, in their third hypervariable (HV3) region, and this motif seems to help the development of rheumatoid arthritis via unknown mechanisms. In an attempt to identify a ligand of this motif, we screened bacterial proteins. HV3 peptides from HLA-DRB1 alleles containing a QKRAA or RRRAA motif bound the 70-kD heat shock protein (HSP) from Escherichia coli, dnaK. In lymphoblastoid cells homozygous for these same HLA-DRB1 alleles the constitutive 70-kD HSP, HSP73, that targets selected proteins to lysosomes coprecipitated with HLA-DR. Thus the QKRAA and RRRAA amino acid motifs of HLA-DR mediate binding of HLA-DR to HSP73. This property may influence the intracellular route, processing or peptide associations of the HLA-DRbeta1 chain in these two rheumatoid arthritis-associated alleles.", + "TAG_DATA": [ + "79, lymphoblastoid {'context': 'B-cells'}", + "80, cells {'context': 'I-cells'}", + "81, homozygous {'perturbing_action': 'B-other'}", + "82, for {'perturbing_action': 'I-other'}", + "84, same {'perturbing_action': 'I-other'}", + "85, HLA-DRB1 {'perturbing_action': 'I-other'}", + "86, alleles {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "79, lymphoblastoid ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "80, cells ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "81, homozygous ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "82, for ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "84, same ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "85, HLA-DRB1 ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "86, alleles ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "lymphoblastoid", + "cells" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "homozygous", + "for", + "same", + "HLA-DRB1", + "alleles" + ] + } + } + ] + }, + { + "PMID": "8574965", + "TEXT": "Recently, cases have been reported in which a mixed chimeric state of blood cells is established after liver transplantation. Because the established chimerism may have aided in the induction of donor-specific tolerance, the mechanism responsible for this chimerism is of clinical importance. To establish this, we examined cells in adult mouse liver and identified the presence of c-kit+ Sca-1+ Lin(lo/-) cells. These cells were capable of forming in vivo as well as in vitro colonies. Furthermore, the cells could reconstitute bone marrow of lethally irradiated recipient mice for at least 12 months. These data obtained from the mouse study strongly suggest that hematopoietic stem cells residing in the donor liver are responsible for mixed chimerism and maintenance of tolerance after liver transplantation.", + "TAG_DATA": [ + "49, adult {'context': 'B-tissue/organ'}", + "50, mouse {'context': 'I-tissue/organ'}", + "51, liver {'context': 'I-tissue/organ'}", + "62, cells {'context': 'B-cells'}", + "66, forming {'phenotype': 'B-colony formation'}", + "67, in {'context': 'B-in vivo'}", + "68, vivo {'context': 'I-in vivo'}", + "72, in {'context': 'B-in vitro'}", + "73, vitro {'context': 'I-in vitro'}", + "74, colonies. {'phenotype': 'I-colony formation'}", + "86, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "49, adult ['l0', 'l1']", + "50, mouse ['l0', 'l2']", + "51, liver ['l1', 'l2']", + "62, cells ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "66, forming ['l3', 'l9', 'l10', 'l11', 'l12', 'l13']", + "67, in ['l4', 'l9', 'l14', 'l15', 'l16', 'l17']", + "68, vivo ['l5', 'l10', 'l14', 'l18', 'l19', 'l20']", + "72, in ['l6', 'l11', 'l15', 'l18', 'l21', 'l22']", + "73, vitro ['l7', 'l12', 'l16', 'l19', 'l21', 'l23']", + "74, colonies. ['l8', 'l13', 'l17', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "forming", + "colonies." + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "forming", + "colonies." + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "forming", + "colonies." + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "8564843", + "TEXT": "We studied prion proteins (PrP) in skin and brains of Libyan Jews carrying the E200K mutation who died of familial Creutzfeldt-Jakob disease (CJD). Unexpectedly, studies with brain showed that PrP molecules encoded both by the wild-type (wt) and mutant alleles exhibit altered properties characteristic of the prion protein associated with prion diseases (PrPSc). Using monospecific antisera, we found that wtPrP was insoluble in the brains of three patients who were heterozygous for the E200K mutation, whereas mutant PrP was both insoluble and protease-resistant. Our results argue that both wild-type and mutant PrP undergo conformational changes and are particularly intriguing, because the normal isoform PrPc is soluble in nondenaturing detergents and is readily digested by proteases, whereas PrPSc is insoluble and resistant to proteolytic digestion. Our findings indicate that insoluble wtPrP represents a conformational intermediate, the first to be identified, within a pathway in which PrPc is converted to PrPSc.", + "TAG_DATA": [ + "64, brains {'context': 'B-tissue/organ'}", + "67, patients {'context': 'B-patient'}", + "70, heterozygous {'perturbing_action': 'B-other'}", + "71, for {'perturbing_action': 'I-other'}", + "72, the {'perturbing_action': 'I-other'}", + "73, E200K {'perturbing_action': 'I-other'}", + "74, mutation, {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "64, brains ['l0', 'l1', 'l2', 'l3']", + "67, patients ['l0', 'l4', 'l5', 'l6', 'l7', 'l8']", + "70, heterozygous ['l4', 'l9', 'l10', 'l11', 'l12']", + "71, for ['l5', 'l9', 'l13', 'l14', 'l15']", + "72, the ['l1', 'l6', 'l10', 'l13', 'l16', 'l17']", + "73, E200K ['l2', 'l7', 'l11', 'l14', 'l16', 'l18']", + "74, mutation, ['l3', 'l8', 'l12', 'l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "brains" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "the", + "E200K", + "mutation," + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "heterozygous", + "for", + "the", + "E200K", + "mutation," + ] + } + } + ] + }, + { + "PMID": "7584996", + "TEXT": "In early gestation the internal surface of the lung is structurally simple and an ideal target for somatic gene transfer. The transfer of genes into the growing lung would be particularly useful in the prenatal correction of cystic fibrosis, which has devastating pulmonary complications. In addition, in utero gene therapy has the potential to immunotolerize the individual, and thereby to avoid the immune reactions now seen with the current generation of adenoviral vectors. We injected a replication-defective adenoviral vector containing the lacZ reporter gene (Ad5.CMVlacZ) into the amniotic fluid of rat pups on the 16th day of gestation. At 16 days of gestation, rat lungs are equivalent in maturity to those of a 22-week human fetus as their airways are lined with undifferentiated multipotential stem cells. The pups showed high-level reporter gene expression in their airways a week following birth (13 days following infection). The expression was maintained during a time when the lung volume increased approximately 20-fold, alveolarization occurred, and the epithelial cells differentiated. These data establish gene targeting of undifferentiated fetal cells as an effective means of gene therapy.", + "TAG_DATA": [ + "90, rat {'context': 'B-organism'}", + "91, pups {'context': 'I-organism'}", + "103, rat {'context': 'B-tissue/organ'}", + "104, lungs {'context': 'I-tissue/organ'}", + "127, pups {'context': 'B-organism'}", + "153, lung {'context': 'B-tissue/organ'}", + "162, epithelial {'context': 'B-cells'}", + "163, cells {'context': 'I-cells'}", + "164, differentiated. {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "90, rat ['l0', 'l1', 'l2']", + "91, pups ['l0', 'l3', 'l4']", + "103, rat ['l1', 'l3', 'l5']", + "104, lungs ['l2', 'l4', 'l5']", + "127, pups ['l6', 'l7']", + "153, lung ['l6', 'l8']", + "162, epithelial ['l9', 'l10']", + "163, cells ['l7', 'l8', 'l9', 'l11']", + "164, differentiated. ['l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "epithelial", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiated." + ] + } + } + ] + }, + { + "PMID": "7489362", + "TEXT": "The p21 gene encodes a cyclin-dependent kinase inhibitor that affects cell-cycle progression, but the potential of this gene product to serve as a tumour suppressor in vivo has not been established. In this report, we show that the growth of malignant cells in vitro and in vivo is inhibited by expression of p21. Expression of p21 resulted in an accumulation of cells in G0/G1, altered morphology, and cell differentiation, but apoptosis was not induced. Introduction of p21 with adenoviral vectors into malignant cells completely suppressed their growth in vivo and also reduced the growth of established pre-existing tumours. Gene transfer of p21 may provide a molecular genetic approach to arresting cancer cell growth by committing malignant cells irreversibly to a pathway of terminal differentiation.", + "TAG_DATA": [ + "40, malignant {'context': 'B-transformed cells'}", + "41, cells {'context': 'I-transformed cells'}", + "42, in {'context': 'B-in vitro'}", + "43, vitro {'context': 'I-in vitro'}", + "45, in {'context': 'B-in vivo'}", + "46, vivo {'context': 'I-in vivo'}", + "50, expression {'perturbing_action': 'B-gene gain-of-function'}", + "51, of {'perturbing_action': 'I-gene gain-of-function'}", + "52, p21. {'perturbing_action': 'I-gene gain-of-function'}", + "53, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "54, of {'perturbing_action': 'I-gene gain-of-function'}", + "55, p21 {'perturbing_action': 'I-gene gain-of-function'}", + "61, cells {'context': 'B-cells', 'phenotype': 'I-cell cycle arrest'}", + "63, G0/G1, {'phenotype': 'I-cell cycle arrest'}", + "67, cell {'context': 'B-cells'}", + "68, differentiation, {'phenotype': 'B-differentiation'}", + "70, apoptosis {'phenotype': 'B-apoptosis'}", + "72, not {'effect': 'B-no effect'}", + "73, induced. {'effect': 'B-positive'}", + "74, Introduction {'perturbing_action': 'B-gene gain-of-function'}", + "75, of {'perturbing_action': 'I-gene gain-of-function'}", + "76, p21 {'perturbing_action': 'I-gene gain-of-function'}", + "77, with {'perturbing_action': 'I-gene gain-of-function'}", + "78, adenoviral {'perturbing_action': 'I-gene gain-of-function'}", + "79, vectors {'perturbing_action': 'I-gene gain-of-function'}", + "81, malignant {'context': 'B-transformed cells'}", + "82, cells {'context': 'I-transformed cells'}", + "87, in {'context': 'B-in vivo'}", + "88, vivo {'context': 'I-in vivo'}", + "97, tumours. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "40, malignant ['l0', 'l1', 'l2']", + "41, cells ['l0', 'l3', 'l4']", + "42, in ['l1', 'l3', 'l5']", + "43, vitro ['l2', 'l4', 'l5']", + "45, in ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "46, vivo ['l6', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "50, expression ['l7', 'l20', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "51, of ['l8', 'l21', 'l33', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "52, p21. ['l9', 'l22', 'l34', 'l47', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "53, Expression ['l35', 'l48', 'l60', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "54, of ['l10', 'l23', 'l36', 'l49', 'l61', 'l72', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "55, p21 ['l11', 'l24', 'l37', 'l50', 'l62', 'l73', 'l84', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "56, resulted ['l12', 'l25', 'l38', 'l51', 'l63', 'l74', 'l85', 'l95', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "61, cells ['l13', 'l26', 'l39', 'l52', 'l64', 'l75', 'l86', 'l96', 'l105', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "63, G0/G1, ['l14', 'l27', 'l40', 'l53', 'l65', 'l76', 'l87', 'l97', 'l106', 'l113', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "64, altered ['l15', 'l28', 'l41', 'l54', 'l66', 'l77', 'l88', 'l98', 'l107', 'l114', 'l120', 'l126', 'l127', 'l128', 'l129', 'l130']", + "67, cell ['l16', 'l29', 'l42', 'l55', 'l67', 'l78', 'l89', 'l99', 'l108', 'l115', 'l121', 'l126', 'l131', 'l132', 'l133', 'l134']", + "68, differentiation, ['l17', 'l30', 'l43', 'l56', 'l68', 'l79', 'l90', 'l100', 'l109', 'l116', 'l122', 'l127', 'l131', 'l135', 'l136', 'l137']", + "70, apoptosis ['l44', 'l57', 'l69', 'l80', 'l91', 'l101', 'l110', 'l117', 'l123', 'l128', 'l132', 'l135', 'l138', 'l139']", + "72, not ['l18', 'l31', 'l45', 'l58', 'l70', 'l81', 'l92', 'l102', 'l111', 'l118', 'l124', 'l129', 'l133', 'l136', 'l138', 'l140']", + "73, induced. ['l19', 'l32', 'l46', 'l59', 'l71', 'l82', 'l93', 'l103', 'l112', 'l119', 'l125', 'l130', 'l134', 'l137', 'l139', 'l140']", + "74, Introduction ['l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150']", + "75, of ['l141', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159']", + "76, p21 ['l142', 'l151', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "77, with ['l143', 'l152', 'l160', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "78, adenoviral ['l144', 'l153', 'l161', 'l168', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180']", + "79, vectors ['l145', 'l154', 'l162', 'l169', 'l175', 'l181', 'l182', 'l183', 'l184', 'l185']", + "81, malignant ['l146', 'l155', 'l163', 'l170', 'l176', 'l181', 'l186', 'l187', 'l188', 'l189']", + "82, cells ['l83', 'l94', 'l104', 'l147', 'l156', 'l164', 'l171', 'l177', 'l182', 'l186', 'l190', 'l191']", + "87, in ['l148', 'l157', 'l165', 'l172', 'l178', 'l183', 'l187', 'l190', 'l192', 'l193']", + "88, vivo ['l149', 'l158', 'l166', 'l173', 'l179', 'l184', 'l188', 'l191', 'l192', 'l194']", + "97, tumours. ['l150', 'l159', 'l167', 'l174', 'l180', 'l185', 'l189', 'l193', 'l194']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "p21.", + "p21", + "Introduction", + "with", + "adenoviral", + "vectors" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cells", + "G0/G1," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "cell" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cells", + "G0/G1," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "p21.", + "Expression", + "p21" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "p21.", + "Expression", + "p21" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cells", + "G0/G1," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "p21.", + "Expression", + "p21" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "p21.", + "Expression", + "p21" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "p21.", + "Expression", + "p21" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "p21.", + "Expression", + "p21" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "p21", + "Introduction", + "with", + "adenoviral", + "vectors" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells", + "malignant" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "cell" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "cell" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cells", + "G0/G1," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced." + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cells", + "G0/G1," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Introduction", + "of", + "p21", + "with", + "adenoviral", + "vectors" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumours." + ] + } + } + ] + }, + { + "PMID": "7489357", + "TEXT": "Retinopathy of prematurity (ROP) is initiated by hyperoxia-induced obliteration of newly formed blood vessels in the retina of the premature newborn. We propose that vessel regression is a consequence of hyperoxia-induced withdrawal of a critical vascular survival factor. We show that regression of retinal capillaries in neonatal rats exposed to high oxygen, is preceded by a shut-off of vascular endothelial growth factor (VEGF) production by nearby neuroglial cells. Vessel regression occurs via selective apoptosis of endothelial cells. Intraocular injection of VEGF at the onset of experimental hyperoxia prevents apoptotic death of endothelial cells and rescues the retinal vasculature. These findings provide evidence for a specific angiogenic factor acting as a vascular survival factor in vivo. The system also provides a paradigm for vascular remodelling as an adaptive response to an increase in oxygen tension and suggests a novel approach to prevention of ROP.", + "TAG_DATA": [ + "46, neonatal {'context': 'B-organism'}", + "47, rats {'context': 'I-organism'}", + "73, apoptosis {'phenotype': 'B-apoptosis'}", + "75, endothelial {'context': 'B-cells'}", + "76, cells. {'context': 'I-cells'}", + "87, prevents {'effect': 'B-negative'}", + "88, apoptotic {'phenotype': 'B-apoptosis'}", + "89, death {'phenotype': 'I-apoptosis'}", + "91, endothelial {'context': 'B-cells'}", + "92, cells {'context': 'I-cells'}", + "96, retinal {'context': 'B-tissue/organ'}", + "97, vasculature. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "46, neonatal ['l0', 'l1', 'l2', 'l3']", + "47, rats ['l0', 'l4', 'l5', 'l6']", + "73, apoptosis ['l1', 'l4', 'l7', 'l8']", + "75, endothelial ['l2', 'l5', 'l7', 'l9']", + "76, cells. ['l3', 'l6', 'l8', 'l9']", + "87, prevents ['l10', 'l11', 'l12', 'l13']", + "88, apoptotic ['l10', 'l14', 'l15', 'l16']", + "89, death ['l11', 'l14', 'l17', 'l18']", + "91, endothelial ['l12', 'l15', 'l17', 'l19']", + "92, cells ['l13', 'l16', 'l18', 'l19']", + "96, retinal ['l20']", + "97, vasculature. ['l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "neonatal", + "rats" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptotic", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells.", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + } + } + ] + }, + { + "PMID": "7585223", + "TEXT": "Obesity is accompanied by complications such as hypertension, non-insulin-dependent diabetes mellitus and atherosclerosis, which in turn cause ischaemic heart disease, stroke and premature death. The underlying mechanisms behind imbalance in energy intake and energy expenditure that lead to obesity are still controversial. In most populations, obesity is more common among women than men and is a multifactorial phenotype, which may result from a complex network of genetic and nongenetic factors. The relative importance of genetic factors for obesity is under debate. Genome searches using polymorphic markers in inbred mice with phenotypes that result in extreme obesity and studies of human candidate genes are being performed in an attempt to identify genes that contribute to obesity. There is evidence that body weight is physiologically regulated and it has been postulated that the storage of fat may provide signals to the brain that the body is obese, which in turn may make the subject eat less and burn more fuel. One of the molecules that may be involved in such signalling is the obese (ob) gene product. Mutations in ob result in profound obesity and type II diabetes in mice. The mouse ob gene and its human homologue have been cloned and sequenced. The gene is expressed in adipose tissue and the product has features of a secreted protein. We have investigated human ob expression in subcutaneous and omental adipose tissue obtained from non-obese and massively obese subjects using in situ hybridization histochemistry and report on overexpression in obese people.", + "TAG_DATA": [ + "175, Mutations {'perturbing_action': 'B-other'}", + "176, in {'perturbing_action': 'I-other'}", + "177, ob {'perturbing_action': 'I-other'}", + "187, mice. {'context': 'B-organism'}", + "225, and {'context': 'I-tissue/organ'}", + "226, omental {'context': 'I-tissue/organ'}", + "227, adipose {'context': 'I-tissue/organ'}", + "228, tissue {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "175, Mutations ['l0', 'l1', 'l2', 'l3']", + "176, in ['l0', 'l4', 'l5']", + "177, ob ['l1', 'l4', 'l6']", + "187, mice. ['l2', 'l5', 'l6']", + "224, subcutaneous ['l7', 'l8', 'l9', 'l10', 'l11']", + "225, and ['l7', 'l12', 'l13', 'l14']", + "226, omental ['l8', 'l12', 'l15', 'l16']", + "227, adipose ['l9', 'l13', 'l15', 'l17']", + "228, tissue ['l3', 'l10', 'l14', 'l16', 'l17']", + "246, obese ['l18']", + "247, people. ['l11', 'l18']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Mutations", + "in", + "ob" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Mutations" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tissue" + ] + } + } + ] + }, + { + "PMID": "7585149", + "TEXT": "We have tested a novel strategy of intracellular immunization to block human immunodeficiency virus (HIV) infection. The expression of a specific antibody within a cell was achieved by transduction of genes that encode for immunoglobulin chains with specificity to viral reverse transcriptase. We demonstrated that inhibition of this enzyme makes cells resistant to HIV infection by blocking an early stage of viral replication. If high efficiency transduction with a stable vector into lymphohaematopoietic stem cells or mature lymphocytes can be achieved, gene transfer-mediated intracellular immunization might be a feasible treatment strategy in AIDS.", + "TAG_DATA": [ + "45, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "46, of {'perturbing_action': 'I-pharmacological inhibition'}", + "50, cells {'context': 'B-cells'}", + "72, lymphohaematopoietic {'context': 'B-cells'}", + "73, stem {'context': 'I-cells'}", + "74, cells {'context': 'I-cells'}", + "76, mature {'context': 'B-cells'}", + "77, lymphocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, inhibition ['l0', 'l1', 'l2', 'l3', 'l4']", + "46, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "50, cells ['l1', 'l5']", + "72, lymphohaematopoietic ['l2', 'l6', 'l9', 'l10', 'l11', 'l12']", + "73, stem ['l3', 'l7', 'l9', 'l13', 'l14', 'l15']", + "74, cells ['l4', 'l8', 'l10', 'l13', 'l16', 'l17']", + "76, mature ['l11', 'l14', 'l16', 'l18']", + "77, lymphocytes ['l12', 'l15', 'l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "lymphohaematopoietic", + "stem" + ] + } + } + ] + }, + { + "PMID": "7585145", + "TEXT": "Cytotoxic T lymphocytes (CTLs) kill neoplastic or virally infected cells after recognizing on their surface antigenic peptides bound to major histocompatibility complex class I molecules. These peptides are derived from antigens that are degraded in the cytosol of the affected cell. Because exogenous proteins cannot enter the cytosol, immunizations with killed pathogens or their proteins do not generally elicit CTLs. However, antigens that are internalized into phagocytic cells can enter the cytosol and be processed for class I presentation. Here we show that immunization with a purified antigen on an avidly phagocytized particle primes CTLs, which in turn protect animals from subsequent challenge with tumours transfected with the antigen gene. Interestingly, these animals also become immune to other antigens expressed by the tumour. This approach could be exploited to develop tumour and viral vaccines.", + "TAG_DATA": [ + "94, CTLs, {'context': 'B-cells'}", + "99, animals {'context': 'B-organism'}", + "104, tumours {'context': 'B-neoplasm'}", + "105, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "106, with {'perturbing_action': 'I-gene gain-of-function'}", + "107, the {'perturbing_action': 'I-gene gain-of-function'}", + "108, antigen {'perturbing_action': 'I-gene gain-of-function'}", + "109, gene. {'perturbing_action': 'I-gene gain-of-function'}", + "112, animals {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "94, CTLs, ['l0']", + "99, animals ['l0', 'l1']", + "104, tumours ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "105, transfected ['l2', 'l7', 'l8', 'l9', 'l10']", + "106, with ['l3', 'l7', 'l11', 'l12', 'l13']", + "107, the ['l4', 'l8', 'l11', 'l14', 'l15', 'l16']", + "108, antigen ['l5', 'l9', 'l12', 'l14', 'l17', 'l18']", + "109, gene. ['l6', 'l10', 'l13', 'l15', 'l17', 'l19']", + "112, animals ['l16', 'l18', 'l19']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "tumours" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "the", + "antigen", + "gene." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "the", + "antigen", + "gene." + ] + }, + "context": { + "val": "organism", + "words": [ + "animals" + ] + } + } + ] + }, + { + "PMID": "7585144", + "TEXT": "Certain strains of transgenic mice that express the rat neu oncogene (neuT) in mammary epithelial cells develop breast tumours at an average of 44 weeks of age. In this study, intraperitoneal injection of a monoclonal anti-receptor antibody specific for the rat neuT oncogene product dramatically affected tumour development in these transgenic mice in a dose-dependent manner. A significant proportion (50%) of mice, when injected with anti-receptor antibodies, did not develop tumours even after 90 weeks of age. The phosphotyrosine levels of the membrane fraction of breast tissues in the anti-receptor antibody-treated mice were almost completely abolished when a higher dose of antibodies was used. This study demonstrates, for the first time, that immunologic manipulation of an oncogene product can effectively prevent the development of tumours in a rodent transgenic model.", + "TAG_DATA": [ + "45, affected {'effect': 'B-regulates'}", + "46, tumour {'phenotype': 'B-tumourigenesis'}", + "47, development {'phenotype': 'I-tumourigenesis'}", + "50, transgenic {'context': 'B-organism'}", + "51, mice {'context': 'I-organism'}", + "61, mice, {'context': 'B-organism'}", + "68, not {'effect': 'I-no effect'}", + "69, develop {'effect': 'I-no effect', 'phenotype': 'B-tumourigenesis'}", + "70, tumours {'phenotype': 'B-tumourigenesis'}", + "91, mice {'context': 'B-organism'}", + "120, prevent {'effect': 'B-negative'}", + "127, rodent {'context': 'B-organism'}", + "129, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "45, affected ['l0', 'l1', 'l2', 'l3']", + "46, tumour ['l0', 'l4', 'l5', 'l6']", + "47, development ['l1', 'l4', 'l7']", + "50, transgenic ['l2', 'l5', 'l8']", + "51, mice ['l3', 'l6', 'l7', 'l8']", + "61, mice, ['l9', 'l10', 'l11', 'l12']", + "68, not ['l9', 'l13', 'l14', 'l15']", + "69, develop ['l10', 'l13', 'l16', 'l17']", + "70, tumours ['l11', 'l14', 'l16', 'l18']", + "91, mice ['l12', 'l15', 'l17', 'l18']", + "120, prevent ['l19', 'l20', 'l21']", + "127, rodent ['l19', 'l22', 'l23']", + "128, transgenic ['l20', 'l22', 'l24']", + "129, model. ['l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "regulates", + "words": [ + "affected" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumour", + "development" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "affected" + ] + }, + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumour", + "development", + "develop", + "tumours" + ] + }, + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice", + "mice," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "develop" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "develop", + "not" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "develop", + "tumours" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "context": { + "val": "organism", + "words": [ + "rodent", + "model." + ] + } + } + ] + }, + { + "PMID": "7585063", + "TEXT": "Various types of alcoholics have been described and heredity has been shown to be involved in some of these types. An important role of the mesolimbic dopamine system has been suggested in the reinforcing effects of alcohol and recent molecular genetic studies are implicating the gene for the D2 dopamine receptor (DRD2) in alcoholism. In a double-blind study, bromocriptine, a DRD2 agonist, or placebo was administered to alcoholics with either the A1 (A1/A1 and A1/A2 genotypes) or only the A2 (A2/A2 genotype) allele of the DRD2 gene. The greatest improvement in craving and anxiety occurred in the bromocriptine-treated A1 alcoholics and attrition was highest in the placebo-treated A1 alcoholics. The feasibility of a pharmacogenetic approach in treating certain types of alcoholics is suggested.", + "TAG_DATA": [ + "58, bromocriptine, {'perturbing_action': 'B-pharmacological augmentation'}", + "59, a {'perturbing_action': 'I-pharmacological augmentation'}", + "60, DRD2 {'perturbing_action': 'I-pharmacological augmentation'}", + "61, agonist, {'perturbing_action': 'I-pharmacological augmentation'}", + "67, alcoholics {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "58, bromocriptine, ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "59, a ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "60, DRD2 ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "61, agonist, ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "67, alcoholics ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "82, allele ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "83, of ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "84, the ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "85, DRD2 ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "86, gene. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "bromocriptine,", + "a", + "DRD2", + "agonist," + ] + }, + "context": { + "val": "cells", + "words": [ + "alcoholics" + ] + } + } + ] + }, + { + "PMID": "7585008", + "TEXT": "Although 13 years have passed since identification of human immunodeficiency virus-1 (HIV-1) as the cause of AIDS, we do not yet know how HIV kills its primary target, the T cell that carries the CD4 antigen. We and others have shown an increase in the percentage of apoptotic cells among circulating CD4+ (and CD8+) T cells of HIV-seropositive individuals and an increase in frequency of apoptosis with disease progression. However, it is not known if this apoptosis occurs in infected or uninfected T cells. We show here, using in situ labelling of lymph nodes from HIV-infected children and SIV-infected macaques, that apoptosis occurs predominantly in bystander cells and not in the productively infected cells themselves. These data have implications for pathogenesis and therapy, namely, arguing that rational drug therapy may involve combination agents targeting viral replication in infected cells and apoptosis of uninfected cells.", + "TAG_DATA": [ + "99, macaques, {'context': 'B-organism'}", + "101, apoptosis {'phenotype': 'B-apoptosis'}", + "106, cells {'context': 'I-cells'}", + "113, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "99, macaques, ['l0', 'l1', 'l2']", + "101, apoptosis ['l0', 'l3', 'l4']", + "106, cells ['l1', 'l3']", + "113, cells ['l2', 'l4']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "macaques," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "16715092", + "TEXT": "Glutamatergic signaling and intracellular calcium mobilization in the spinal cord are crucial for the development of nociceptive plasticity, which is associated with chronic pathological pain. Long-form Homer proteins anchor glutamatergic receptors to sources of calcium influx and release at synapses, which is antagonized by the short, activity-dependent splice variant Homer1a. We show here that Homer1a operates in a negative feedback loop to regulate the excitability of the pain pathway in an activity-dependent manner. Homer1a is rapidly and selectively upregulated in spinal cord neurons after peripheral inflammation in an NMDA receptor-dependent manner. Homer1a strongly attenuates calcium mobilization as well as MAP kinase activation induced by glutamate receptors and reduces synaptic contacts on spinal cord neurons that process pain inputs. Preventing activity-induced upregulation of Homer1a using shRNAs in mice in vivo exacerbates inflammatory pain. Thus, activity-dependent uncoupling of glutamate receptors from intracellular signaling mediators is a novel, endogenous physiological mechanism for counteracting sensitization at the first, crucial synapse in the pain pathway. Furthermore, we observed that targeted gene transfer of Homer1a to specific spinal segments in vivo reduces inflammatory hyperalgesia. Thus, Homer1 function is crucially involved in pain plasticity and constitutes a promising therapeutic target for the treatment of chronic inflammatory pain.", + "TAG_DATA": [ + "111, spinal {'context': 'B-cells'}", + "112, cord {'context': 'I-cells'}", + "113, neurons {'context': 'I-cells'}", + "126, mice {'context': 'B-organism'}", + "127, in {'context': 'B-in vivo'}", + "128, vivo {'context': 'I-in vivo'}", + "164, targeted {'perturbing_action': 'B-gene gain-of-function'}", + "165, gene {'perturbing_action': 'I-gene gain-of-function'}", + "166, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "167, of {'perturbing_action': 'I-gene gain-of-function'}", + "168, Homer1a {'perturbing_action': 'I-gene gain-of-function'}", + "171, spinal {'context': 'B-tissue/organ'}", + "172, segments {'context': 'I-tissue/organ'}", + "173, in {'context': 'B-in vivo'}", + "174, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "111, spinal ['l0', 'l1']", + "112, cord ['l0', 'l2']", + "113, neurons ['l1', 'l2']", + "126, mice ['l3', 'l4']", + "127, in ['l3', 'l5']", + "128, vivo ['l4', 'l5']", + "164, targeted ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "165, gene ['l6', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "166, transfer ['l7', 'l14', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "167, of ['l8', 'l15', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "168, Homer1a ['l9', 'l16', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "171, spinal ['l10', 'l17', 'l23', 'l28', 'l32', 'l36', 'l37', 'l38']", + "172, segments ['l11', 'l18', 'l24', 'l29', 'l33', 'l36', 'l39', 'l40']", + "173, in ['l12', 'l19', 'l25', 'l30', 'l34', 'l37', 'l39', 'l41']", + "174, vivo ['l13', 'l20', 'l26', 'l31', 'l35', 'l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "targeted", + "gene", + "transfer", + "of", + "Homer1a" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "spinal", + "segments" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "targeted", + "gene", + "transfer", + "of", + "Homer1a" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "15711558", + "TEXT": "Osteoporosis, a leading cause of morbidity in the elderly, is characterized by progressive loss of bone mass resulting from excess osteoclastic bone resorption relative to osteoblastic bone formation. Here we identify Vav3, a Rho family guanine nucleotide exchange factor, as essential for stimulated osteoclast activation and bone density in vivo. Vav3-deficient osteoclasts show defective actin cytoskeleton organization, polarization, spreading and resorptive activity resulting from impaired signaling downstream of the M-CSF receptor and alpha(v)beta3 integrin. Vav3-deficient mice have increased bone mass and are protected from bone loss induced by systemic bone resorption stimuli such as parathyroid hormone or RANKL. Moreover, we provide genetic and biochemical evidence for the role of Syk tyrosine kinase as a crucial upstream regulator of Vav3 in osteoclasts. Thus, Vav3 is a potential new target for antiosteoporosis therapy.", + "TAG_DATA": [ + "50, Vav3-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "51, osteoclasts {'context': 'B-cells'}", + "74, Vav3-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "75, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, Vav3-deficient ['l0']", + "51, osteoclasts ['l0']", + "74, Vav3-deficient ['l1']", + "75, mice ['l1']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Vav3-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclasts" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Vav3-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "11927948", + "TEXT": "Excessive accumulation of smooth-muscle cells (SMCs) has a key role in the pathogenesis of vascular diseases. It has been assumed that SMCs derived from the outer medial layer migrate, proliferate and synthesize extracellular matrix components on the luminal side of the vessel. Although much effort has been devoted to targeting migration and proliferation of medial SMCs, there is no effective therapy that prevents occlusive vascular remodeling. We show here that in models of post-angioplasty restenosis, graft vasculopathy and hyperlipidemia-induced atherosclerosis, bone-marrow cells give rise to most of the SMCs that contribute to arterial remodeling. Notably, purified hematopoietic stem cells differentiate into SMCs in vitro and in vivo. Our findings indicate that somatic stem cells contribute to pathological remodeling of remote organs, and may provide the basis for the development of new therapeutic strategies for vascular diseases through targeting mobilization, homing, differentiation and proliferation of bone marrow-derived vascular progenitor cells.", + "TAG_DATA": [ + "80, bone-marrow {'context': 'B-cells'}", + "81, cells {'context': 'I-cells'}", + "88, SMCs {'context': 'B-cells'}", + "96, hematopoietic {'context': 'I-cells'}", + "97, stem {'context': 'I-cells'}", + "98, cells {'context': 'I-cells'}", + "99, differentiate {'phenotype': 'B-differentiation'}", + "101, SMCs {'context': 'B-cells'}", + "102, in {'context': 'B-in vitro'}", + "103, vitro {'context': 'I-in vitro'}", + "105, in {'context': 'B-in vivo'}", + "106, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "80, bone-marrow ['l0', 'l1']", + "81, cells ['l0', 'l2']", + "88, SMCs ['l1', 'l2']", + "96, hematopoietic ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "97, stem ['l3', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "98, cells ['l4', 'l11', 'l18', 'l19', 'l20', 'l21']", + "99, differentiate ['l5', 'l12', 'l18', 'l22', 'l23', 'l24']", + "101, SMCs ['l6', 'l13', 'l19', 'l22', 'l25', 'l26']", + "102, in ['l7', 'l14', 'l20', 'l23', 'l25', 'l27']", + "103, vitro ['l8', 'l15', 'l21', 'l24', 'l26', 'l27']", + "105, in ['l9', 'l16', 'l28']", + "106, vivo. ['l10', 'l17', 'l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cells", + "SMCs" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "11100118", + "TEXT": "The importance of cholesterol ester synthesis by acyl CoA:cholesterol acyltransferase (ACAT) enzymes in intestinal and hepatic cholesterol metabolism has been unclear. We now demonstrate that ACAT2 is the major ACAT in mouse small intestine and liver, and suggest that ACAT2 deficiency has profound effects on cholesterol metabolism in mice fed a cholesterol-rich diet, including complete resistance to diet-induced hypercholesterolemia and cholesterol gallstone formation. The underlying mechanism involves the lack of cholesterol ester synthesis in the intestine and a resultant reduced capacity to absorb cholesterol. Our results indicate that ACAT2 has an important role in the response to dietary cholesterol, and suggest that ACAT2 inhibition may be a useful strategy for treating hypercholesterolemia or cholesterol gallstones.", + "TAG_DATA": [ + "39, ACAT2 {'perturbing_action': 'B-gene loss-of-function'}", + "40, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "48, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "39, ACAT2 ['l0', 'l1']", + "40, deficiency ['l0', 'l2']", + "48, mice ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ACAT2", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "10742150", + "TEXT": "Infections are thought to be important in the pathogenesis of many heart diseases. Coxsackievirus B3 (CVB3) has been linked to chronic dilated cardiomyopathy, a common cause of progressive heart disease, heart failure and sudden death. We show here that the sarcoma (Src) family kinase Lck (p56lck) is required for efficient CVB3 replication in T-cell lines and for viral replication and persistence in vivo. Whereas infection of wild-type mice with human pathogenic CVB3 caused acute and very severe myocarditis, meningitis, hepatitis, pancreatitis and dilated cardiomyopathy, mice lacking the p56lck gene were completely protected from CVB3-induced acute pathogenicity and chronic heart disease. These data identify a previously unknown function of Src family kinases and indicate that p56lck is the essential host factor that controls the replication and pathogenicity of CVB3.", + "TAG_DATA": [ + "53, T-cell {'context': 'B-cells'}", + "54, lines {'context': 'I-cells'}", + "61, in {'context': 'B-in vivo'}", + "62, vivo. {'context': 'I-in vivo'}", + "67, mice {'context': 'B-organism'}", + "84, mice {'context': 'B-organism'}", + "85, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "86, the {'perturbing_action': 'I-gene loss-of-function'}", + "87, p56lck {'perturbing_action': 'I-gene loss-of-function'}", + "88, gene {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "53, T-cell ['l0', 'l1', 'l2']", + "54, lines ['l0', 'l3', 'l4']", + "61, in ['l1', 'l3', 'l5']", + "62, vivo. ['l2', 'l4', 'l5']", + "84, mice ['l6', 'l7', 'l8', 'l9']", + "85, lacking ['l6', 'l10', 'l11', 'l12']", + "86, the ['l7', 'l10', 'l13', 'l14']", + "87, p56lck ['l8', 'l11', 'l13', 'l15']", + "88, gene ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "p56lck", + "gene" + ] + } + } + ] + }, + { + "PMID": "10470078", + "TEXT": "The molecular mechanism(s) of immunoglobulin A (IgA) nephropathy, the most common primary renal glomerular disease worldwide, is unknown. Its pathologic features include hematuria, high levels of circulating IgA-fibronectin (Fn) complexes, and glomerular deposition of IgA, complement C3, Fn and collagen. We report here that two independent mouse models (gene knockout and antisense transgenic), both manifesting deficiency of an anti-inflammatory protein, uteroglobin (UG), develop almost all of the pathologic features of human IgA nephropathy. We further demonstrate that Fn-UG heteromerization, reported to prevent abnormal glomerular deposition of Fn and collagen, also abrogates both the formation of IgA-Fn complexes and their binding to glomerular cells. Moreover, UG prevents glomerular accumulation of exogenous IgA in UG-null mice. These results define an essential role for UG in preventing mouse IgA nephropathy and warrant further studies to determine if a similar mechanism(s) underlies the human disease.", + "TAG_DATA": [ + "46, mouse {'context': 'B-organism'}", + "47, models {'context': 'I-organism'}", + "49, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "101, glomerular {'context': 'B-cells'}", + "102, cells. {'context': 'I-cells'}", + "112, UG-null {'perturbing_action': 'B-gene loss-of-function'}", + "113, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "46, mouse ['l0', 'l1', 'l2']", + "47, models ['l0', 'l3', 'l4']", + "49, knockout ['l1', 'l3', 'l5', 'l6']", + "101, glomerular ['l5', 'l7']", + "102, cells. ['l2', 'l4', 'l6', 'l7']", + "112, UG-null ['l8']", + "113, mice. ['l8']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout", + "UG-null" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout" + ] + }, + "context": { + "val": "cells", + "words": [ + "glomerular", + "cells." + ] + } + } + ] + }, + { + "PMID": "32747828", + "TEXT": "Colonic antigen-experienced lymphocytes such as tissue-resident memory CD8+ T cells can respond rapidly to repeated antigen exposure. However, their cellular phenotypes and the mechanisms by which they drive immune regulation and inflammation remain unclear. Here we compiled an unbiased atlas of human colonic CD8+ T cells in health and ulcerative colitis (UC) using single-cell transcriptomics with T-cell receptor repertoire analysis and mass cytometry. We reveal extensive heterogeneity in CD8+ T-cell composition, including expanded effector and post-effector terminally differentiated CD8+ T cells. While UC-associated CD8+ effector T cells can trigger tissue destruction and produce tumor necrosis factor (TNF)-α, post-effector cells acquire innate signatures to adopt regulatory functions that may mitigate excessive inflammation. Thus, we identify colonic CD8+ T-cell phenotypes in health and UC, define their clonal relationships and characterize terminally differentiated dysfunctional UC CD8+ T cells expressing IL-26, which attenuate acute colitis in a humanized IL-26 transgenic mouse model.", + "TAG_DATA": [ + "94, cells {'context': 'I-cells'}", + "138, humanized {'perturbing_action': 'B-gene gain-of-function'}", + "139, IL-26 {'perturbing_action': 'I-gene gain-of-function'}", + "140, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "141, mouse {'context': 'B-organism'}", + "142, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "138, humanized ['l0', 'l1', 'l2', 'l3']", + "139, IL-26 ['l0', 'l4', 'l5', 'l6']", + "140, transgenic ['l1', 'l4', 'l7', 'l8']", + "141, mouse ['l2', 'l5', 'l7', 'l9']", + "142, model. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "humanized", + "IL-26", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model." + ] + } + } + ] + }, + { + "PMID": "32451498", + "TEXT": "The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (TFH) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of TFH cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of TFH cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1+ TFH cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC.", + "TAG_DATA": [ + "69, Suppression {'effect': 'B-negative'}", + "71, IEC {'context': 'B-cells'}", + "72, apoptosis {'phenotype': 'B-apoptosis'}", + "81, mice. {'context': 'B-organism'}", + "106, ileal {'context': 'B-cells'}", + "107, IECs {'context': 'I-cells'}", + "110, TFH {'context': 'I-cells'}", + "111, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "69, Suppression ['l0', 'l1', 'l2']", + "71, IEC ['l0', 'l3', 'l4']", + "72, apoptosis ['l1', 'l3', 'l5']", + "81, mice. ['l2', 'l4', 'l5']", + "106, ileal ['l6', 'l7', 'l8']", + "107, IECs ['l6', 'l9', 'l10']", + "110, TFH ['l7', 'l9', 'l11']", + "111, cells ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "Suppression" + ] + }, + "context": { + "val": "cells", + "words": [ + "IEC" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "Suppression" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "Suppression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "IEC" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "32284611", + "TEXT": "The primary human immunodeficiency virus (HIV) reservoir is composed of resting memory CD4+ T cells, which often express the immune checkpoint receptors programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which limit T cell activation via synergistic mechanisms. Using simian immunodeficiency virus (SIV)-infected, long-term antiretroviral therapy (ART)-treated rhesus macaques, we demonstrate that PD-1, CTLA-4 and dual CTLA-4/PD-1 immune checkpoint blockade using monoclonal antibodies is well tolerated, with evidence of bioactivity in blood and lymph nodes. Dual blockade was remarkably more effective than PD-1 blockade alone in enhancing T cell cycling and differentiation, expanding effector-memory T cells and inducing robust viral reactivation in plasma and peripheral blood mononuclear cells. In lymph nodes, dual CTLA-4/PD-1 blockade, but not PD-1 alone, decreased the total and intact SIV-DNA in CD4+ T cells, and SIV-DNA and SIV-RNA in B cell follicles, a major site of viral persistence during ART. None of the tested interventions enhanced SIV-specific CD8+ T cell responses during ART or viral control after ART interruption. Thus, despite CTLA-4/PD-1 blockade inducing robust latency reversal and reducing total levels of integrated virus, the degree of reservoir clearance was still insufficient to achieve viral control. These results suggest that immune checkpoint blockade regimens targeting PD-1 and/or CTLA-4, if performed in people living with HIV with sustained aviremia, are unlikely to induce HIV remission in the absence of additional interventions.", + "TAG_DATA": [ + "52, rhesus {'context': 'B-organism'}", + "53, macaques, {'context': 'I-organism'}", + "91, enhancing {'effect': 'B-positive'}", + "92, T {'context': 'B-cells'}", + "93, cell {'context': 'B-cells'}", + "96, differentiation, {'phenotype': 'B-differentiation'}", + "98, effector-memory {'context': 'B-cells'}", + "99, T {'context': 'I-cells'}", + "100, cells {'context': 'I-cells'}", + "109, peripheral {'context': 'B-cells'}", + "110, blood {'context': 'I-cells'}", + "111, mononuclear {'context': 'I-cells'}", + "112, cells. {'context': 'I-cells'}", + "114, lymph {'context': 'B-tissue/organ'}", + "115, nodes, {'context': 'I-tissue/organ'}", + "130, CD4+ {'context': 'B-cells'}", + "131, T {'context': 'I-cells'}", + "132, cells, {'context': 'I-cells'}", + "138, B {'context': 'B-cells'}", + "139, cell {'context': 'I-cells'}", + "140, follicles, {'context': 'I-cells'}", + "156, CD8+ {'context': 'B-cells'}", + "157, T {'context': 'I-cells'}", + "158, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "52, rhesus ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "53, macaques, ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "91, enhancing ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "92, T ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "93, cell ['l3', 'l10', 'l16', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "96, differentiation, ['l4', 'l11', 'l17', 'l22', 'l30', 'l36', 'l37', 'l38']", + "98, effector-memory ['l23', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "99, T ['l5', 'l12', 'l18', 'l24', 'l32', 'l36', 'l39', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "100, cells ['l6', 'l13', 'l19', 'l25', 'l33', 'l37', 'l40', 'l53', 'l60', 'l61', 'l62', 'l63']", + "109, peripheral ['l26', 'l41', 'l54', 'l60', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "110, blood ['l27', 'l34', 'l42', 'l55', 'l61', 'l64', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "111, mononuclear ['l28', 'l43', 'l56', 'l62', 'l65', 'l75', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "112, cells. ['l7', 'l14', 'l20', 'l29', 'l35', 'l38', 'l44', 'l57', 'l63', 'l66', 'l76', 'l85', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "114, lymph ['l45', 'l67', 'l77', 'l86', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "115, nodes, ['l46', 'l68', 'l78', 'l87', 'l94', 'l101', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "130, CD4+ ['l47', 'l69', 'l79', 'l88', 'l95', 'l102', 'l108', 'l114', 'l115', 'l116', 'l117', 'l118']", + "131, T ['l48', 'l58', 'l70', 'l80', 'l89', 'l96', 'l103', 'l109', 'l114', 'l119', 'l120', 'l121', 'l122']", + "132, cells, ['l49', 'l59', 'l71', 'l81', 'l90', 'l97', 'l104', 'l110', 'l115', 'l119', 'l123', 'l124', 'l125']", + "138, B ['l50', 'l72', 'l82', 'l91', 'l98', 'l105', 'l111', 'l116', 'l120', 'l123', 'l126', 'l127']", + "139, cell ['l51', 'l73', 'l83', 'l92', 'l99', 'l106', 'l112', 'l117', 'l121', 'l124', 'l126', 'l128']", + "140, follicles, ['l52', 'l74', 'l84', 'l93', 'l100', 'l107', 'l113', 'l118', 'l122', 'l125', 'l127', 'l128']", + "156, CD8+ ['l129', 'l130']", + "157, T ['l129', 'l131']", + "158, cell ['l130', 'l131']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "rhesus", + "macaques," + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhancing" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rhesus", + "macaques," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhancing" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell", + "cells", + "cells." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhancing" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cell", + "cells", + "cells." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + } + ] + }, + { + "PMID": "32284589", + "TEXT": "Among the most urgent public health threats is the worldwide emergence of carbapenem-resistant Enterobacteriaceae1-4, which are resistant to the antibiotic class of 'last resort'. In the United States and Europe, carbapenem-resistant strains of the Klebsiella pneumoniae ST258 (ref. 5) sequence type are dominant, endemic6-8 and associated with high mortality6,9,10. We report the global evolution of pathogenicity in carbapenem-resistant K. pneumoniae, resulting in the repeated convergence of virulence and carbapenem resistance in the United States and Europe, dating back to as early as 2009. We demonstrate that K. pneumoniae can enhance its pathogenicity by adopting two opposing infection programs through easily acquired gain- and loss-of-function mutations. Single-nucleotide polymorphisms in the capsule biosynthesis gene wzc lead to hypercapsule production, which confers phagocytosis resistance, enhanced dissemination and increased mortality in animal models. In contrast, mutations disrupting capsule biosynthesis genes impair capsule production, which enhances epithelial cell invasion, in vitro biofilm formation and persistence in urinary tract infections. These two types of capsule mutants have emerged repeatedly and independently in Europe and the United States, with hypercapsule mutants associated with bloodstream infections and capsule-deficient mutants associated with urinary tract infections. In the latter case, drug-tolerant K. pneumoniae can persist to yield potentially untreatable, persistent infection.", + "TAG_DATA": [ + "107, in {'perturbing_action': 'I-other'}", + "108, the {'perturbing_action': 'I-other'}", + "109, capsule {'perturbing_action': 'I-other'}", + "110, biosynthesis {'perturbing_action': 'I-other'}", + "111, gene {'perturbing_action': 'I-other'}", + "112, wzc {'perturbing_action': 'I-other'}", + "127, animal {'context': 'B-organism'}", + "128, models. {'context': 'I-organism'}", + "131, mutations {'perturbing_action': 'B-other'}", + "132, disrupting {'perturbing_action': 'I-other'}", + "133, capsule {'perturbing_action': 'I-other'}", + "134, biosynthesis {'perturbing_action': 'I-other'}", + "135, genes {'perturbing_action': 'I-other'}", + "140, enhances {'effect': 'B-positive'}", + "141, epithelial {'context': 'B-cells'}", + "142, cell {'context': 'I-cells'}", + "143, invasion, {'phenotype': 'B-invasion'}", + "144, in {'context': 'B-in vitro'}", + "145, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "107, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "108, the ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "109, capsule ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "110, biosynthesis ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "111, gene ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "112, wzc ['l4', 'l17', 'l29', 'l40', 'l50', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "127, animal ['l5', 'l18', 'l30', 'l41', 'l51', 'l60', 'l68', 'l69', 'l70']", + "128, models. ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l68', 'l71']", + "131, mutations ['l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "132, disrupting ['l72', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "133, capsule ['l73', 'l82', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "134, biosynthesis ['l74', 'l83', 'l91', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "135, genes ['l7', 'l20', 'l32', 'l43', 'l53', 'l75', 'l84', 'l92', 'l99', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "140, enhances ['l8', 'l21', 'l33', 'l44', 'l54', 'l62', 'l76', 'l85', 'l93', 'l100', 'l106', 'l112', 'l113', 'l114', 'l115', 'l116']", + "141, epithelial ['l9', 'l22', 'l34', 'l45', 'l55', 'l63', 'l77', 'l86', 'l94', 'l101', 'l107', 'l112', 'l117', 'l118', 'l119', 'l120']", + "142, cell ['l10', 'l23', 'l35', 'l46', 'l56', 'l64', 'l69', 'l71', 'l78', 'l87', 'l95', 'l102', 'l108', 'l113', 'l117', 'l121', 'l122', 'l123']", + "143, invasion, ['l11', 'l24', 'l36', 'l47', 'l57', 'l65', 'l70', 'l79', 'l88', 'l96', 'l103', 'l109', 'l114', 'l118', 'l121', 'l124', 'l125']", + "144, in ['l12', 'l25', 'l37', 'l48', 'l58', 'l66', 'l80', 'l89', 'l97', 'l104', 'l110', 'l115', 'l119', 'l122', 'l124', 'l126']", + "145, vitro ['l13', 'l26', 'l38', 'l49', 'l59', 'l67', 'l81', 'l90', 'l98', 'l105', 'l111', 'l116', 'l120', 'l123', 'l125', 'l126']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "in", + "the", + "capsule", + "biosynthesis", + "gene", + "wzc" + ] + }, + "context": { + "val": "organism", + "words": [ + "animal", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "in", + "the", + "capsule", + "biosynthesis", + "gene", + "wzc", + "mutations", + "disrupting", + "genes" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "in", + "the", + "capsule", + "biosynthesis", + "gene", + "wzc", + "mutations", + "disrupting", + "genes" + ] + }, + "context": { + "val": "cells", + "words": [ + "epithelial", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "in", + "the", + "capsule", + "biosynthesis", + "gene", + "wzc", + "mutations", + "disrupting", + "genes" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "in", + "the", + "capsule", + "biosynthesis", + "gene", + "wzc", + "mutations", + "disrupting", + "genes" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animal" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "context": { + "val": "cells", + "words": [ + "epithelial", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "epithelial", + "cell" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion," + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "31988462", + "TEXT": "Frameshift mutations in the DMD gene, encoding dystrophin, cause Duchenne muscular dystrophy (DMD), leading to terminal muscle and heart failure in patients. Somatic gene editing by sequence-specific nucleases offers new options for restoring the DMD reading frame, resulting in expression of a shortened but largely functional dystrophin protein. Here, we validated this approach in a pig model of DMD lacking exon 52 of DMD (DMDΔ52), as well as in a corresponding patient-derived induced pluripotent stem cell model. In DMDΔ52 pigs1, intramuscular injection of adeno-associated viral vectors of serotype 9 carrying an intein-split Cas9 (ref. 2) and a pair of guide RNAs targeting sequences flanking exon 51 (AAV9-Cas9-gE51) induced expression of a shortened dystrophin (DMDΔ51-52) and improved skeletal muscle function. Moreover, systemic application of AAV9-Cas9-gE51 led to widespread dystrophin expression in muscle, including diaphragm and heart, prolonging survival and reducing arrhythmogenic vulnerability. Similarly, in induced pluripotent stem cell-derived myoblasts and cardiomyocytes of a patient lacking DMDΔ52, AAV6-Cas9-g51-mediated excision of exon 51 restored dystrophin expression and amelioreate skeletal myotube formation as well as abnormal cardiomyocyte Ca2+ handling and arrhythmogenic susceptibility. The ability of Cas9-mediated exon excision to improve DMD pathology in these translational models paves the way for new treatment approaches in patients with this devastating disease.", + "TAG_DATA": [ + "55, pig {'context': 'B-organism'}", + "56, model {'context': 'I-organism'}", + "72, induced {'context': 'I-cells'}", + "73, pluripotent {'context': 'I-cells'}", + "74, stem {'context': 'I-cells'}", + "75, cell {'context': 'I-cells'}", + "76, model. {'context': 'I-cells'}", + "116, skeletal {'context': 'B-tissue/organ'}", + "117, muscle {'context': 'I-tissue/organ'}", + "143, induced {'context': 'B-cells'}", + "144, pluripotent {'context': 'I-cells'}", + "145, stem {'context': 'I-cells'}", + "146, cell-derived {'context': 'I-cells'}", + "147, myoblasts {'context': 'I-cells'}", + "149, cardiomyocytes {'context': 'B-cells'}", + "152, patient {'context': 'B-patient'}", + "153, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "154, DMDΔ52, {'perturbing_action': 'I-gene loss-of-function'}", + "155, AAV6-Cas9-g51-mediated {'perturbing_action': 'B-gene loss-of-function'}", + "156, excision {'perturbing_action': 'I-gene loss-of-function'}", + "157, of {'perturbing_action': 'I-gene loss-of-function'}", + "158, exon {'perturbing_action': 'I-gene loss-of-function'}", + "159, 51 {'perturbing_action': 'I-gene loss-of-function'}", + "164, amelioreate {'effect': 'B-negative'}", + "165, skeletal {'context': 'B-tissue/organ'}", + "166, myotube {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "55, pig ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "56, model ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "71, patient-derived ['l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "72, induced ['l1', 'l8', 'l14', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "73, pluripotent ['l2', 'l15', 'l22', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "74, stem ['l3', 'l9', 'l16', 'l23', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "75, cell ['l4', 'l10', 'l17', 'l24', 'l30', 'l35', 'l40', 'l41', 'l42']", + "76, model. ['l5', 'l11', 'l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l44']", + "116, skeletal ['l6', 'l12', 'l19', 'l26', 'l32', 'l37', 'l41', 'l43', 'l45', 'l46']", + "117, muscle ['l7', 'l13', 'l20', 'l27', 'l33', 'l38', 'l42', 'l44', 'l45']", + "130, muscle, ['l21', 'l28', 'l34', 'l39', 'l46']", + "143, induced ['l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "144, pluripotent ['l47', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "145, stem ['l48', 'l55', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "146, cell-derived ['l49', 'l56', 'l62', 'l68', 'l69', 'l70', 'l71', 'l72']", + "147, myoblasts ['l50', 'l57', 'l63', 'l68', 'l73', 'l74', 'l75', 'l76']", + "149, cardiomyocytes ['l51', 'l58', 'l64', 'l69', 'l73', 'l77', 'l78', 'l79']", + "152, patient ['l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l80', 'l81', 'l82', 'l83', 'l84']", + "153, lacking ['l53', 'l60', 'l66', 'l71', 'l75', 'l78', 'l80', 'l85', 'l86', 'l87', 'l88']", + "154, DMDΔ52, ['l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l81', 'l85', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "155, AAV6-Cas9-g51-mediated ['l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "156, excision ['l95', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "157, of ['l89', 'l96', 'l102', 'l108', 'l109', 'l110', 'l111', 'l112']", + "158, exon ['l90', 'l97', 'l103', 'l108', 'l113', 'l114', 'l115', 'l116']", + "159, 51 ['l91', 'l98', 'l104', 'l109', 'l113', 'l117', 'l118', 'l119']", + "164, amelioreate ['l82', 'l86', 'l92', 'l99', 'l105', 'l110', 'l114', 'l117', 'l120', 'l121']", + "165, skeletal ['l83', 'l87', 'l93', 'l100', 'l106', 'l111', 'l115', 'l118', 'l120', 'l122']", + "166, myotube ['l84', 'l88', 'l94', 'l101', 'l107', 'l112', 'l116', 'l119', 'l121', 'l122']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "induced", + "pluripotent", + "stem", + "cell-derived", + "myoblasts", + "cardiomyocytes", + "myotube" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "DMDΔ52,", + "AAV6-Cas9-g51-mediated", + "excision", + "of", + "exon", + "51" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patient" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "DMDΔ52," + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "amelioreate" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "DMDΔ52,", + "AAV6-Cas9-g51-mediated", + "excision", + "of", + "exon", + "51" + ] + }, + "effect": { + "val": "negative", + "words": [ + "amelioreate" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "DMDΔ52,", + "AAV6-Cas9-g51-mediated", + "excision", + "of", + "exon", + "51" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skeletal" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "amelioreate" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skeletal" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "amelioreate" + ] + }, + "context": { + "val": "cells", + "words": [ + "myotube" + ] + } + } + ] + }, + { + "PMID": "31959990", + "TEXT": "Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) is a potentially fatal multiorgan inflammatory disease associated with herpesvirus reactivation and subsequent onset of autoimmune diseases1-4. Pathophysiology remains elusive and therapeutic options are limited. Cases refractory to corticosteroid therapy pose a clinical challenge1,5 and approximately 30% of patients with DiHS/DRESS develop complications, including infections and inflammatory and autoimmune diseases1,2,5. Progress in single-cell RNA sequencing (scRNA-seq) provides an opportunity to dissect human disease pathophysiology at unprecedented resolutions6, particularly in diseases lacking animal models, such as DiHS/DRESS. We performed scRNA-seq on skin and blood from a patient with refractory DiHS/DRESS, identifying the JAK-STAT signaling pathway as a potential target. We further showed that central memory CD4+ T cells were enriched with DNA from human herpesvirus 6b. Intervention via tofacitinib enabled disease control and tapering of other immunosuppressive agents. Tofacitinib, as well as antiviral agents, suppressed culprit-induced T cell proliferation in vitro, further supporting the roles of the JAK-STAT pathway and herpesviruses in mediating the adverse drug reaction. Thus, scRNA-seq analyses guided successful therapeutic intervention in the patient with refractory DiHS/DRESS. scRNA-seq may improve our understanding of complicated human disease pathophysiology and provide an alternative approach in personalized medicine.", + "TAG_DATA": [ + "112, central {'context': 'B-cells'}", + "113, memory {'context': 'I-cells'}", + "114, CD4+ {'context': 'I-cells'}", + "115, T {'context': 'I-cells'}", + "116, cells {'context': 'I-cells'}", + "143, suppressed {'effect': 'B-negative'}", + "145, T {'context': 'B-cells'}", + "146, cell {'context': 'B-cells'}", + "147, proliferation {'phenotype': 'B-proliferation'}", + "148, in {'context': 'B-in vitro'}", + "149, vitro, {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "112, central ['l0', 'l1', 'l2', 'l3']", + "113, memory ['l0', 'l4', 'l5', 'l6']", + "114, CD4+ ['l1', 'l4', 'l7', 'l8']", + "115, T ['l2', 'l5', 'l7', 'l9']", + "116, cells ['l3', 'l6', 'l8', 'l9']", + "143, suppressed ['l10', 'l11', 'l12', 'l13', 'l14']", + "145, T ['l10', 'l15', 'l16', 'l17', 'l18']", + "146, cell ['l11', 'l15', 'l19', 'l20', 'l21']", + "147, proliferation ['l12', 'l16', 'l19', 'l22', 'l23']", + "148, in ['l13', 'l17', 'l20', 'l22', 'l24']", + "149, vitro, ['l14', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + } + ] + }, + { + "PMID": "31932797", + "TEXT": "Glia have been implicated in Alzheimer's disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscovered Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.", + "TAG_DATA": [ + "112, Astrocyte {'context': 'B-cells'}", + "125, microglia {'context': 'B-cells'}", + "130, TREM2-R47H {'perturbing_action': 'B-other'}", + "132, TREM2-R62H {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "112, Astrocyte ['l0', 'l1', 'l2']", + "125, microglia ['l0', 'l3', 'l4', 'l5']", + "130, TREM2-R47H ['l1', 'l3', 'l6', 'l7']", + "132, TREM2-R62H ['l4', 'l6', 'l8']", + "133, carriers ['l2', 'l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Astrocyte", + "microglia" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "TREM2-R47H", + "TREM2-R62H" + ] + } + } + ] + }, + { + "PMID": "31700187", + "TEXT": "Millions of people worldwide with incurable end-stage lung disease die because of inadequate treatment options and limited availability of donor organs for lung transplantation1. Current bioengineering strategies to regenerate the lung have not been able to replicate its extraordinary cellular diversity and complex three-dimensional arrangement, which are indispensable for life-sustaining gas exchange2,3. Here we report the successful generation of functional lungs in mice through a conditional blastocyst complementation (CBC) approach that vacates a specific niche in chimeric hosts and allows for initiation of organogenesis by donor mouse pluripotent stem cells (PSCs). We show that wild-type donor PSCs rescued lung formation in genetically defective recipient mouse embryos unable to specify (due to Ctnnb1cnull mutation) or expand (due to Fgfr2cnull mutation) early respiratory endodermal progenitors. Rescued neonates survived into adulthood and had lungs functionally indistinguishable from those of wild-type littermates. Efficient chimera formation and lung complementation required newly developed culture conditions that maintained the developmental potential of the donor PSCs and were associated with global DNA hypomethylation and increased H4 histone acetylation. These results pave the way for the development of new strategies for generating lungs in large animals to enable modeling of human lung disease as well as cell-based therapeutic interventions4-6.", + "TAG_DATA": [ + "62, mice {'context': 'B-organism'}", + "97, rescued {'effect': 'B-rescues'}", + "98, lung {'context': 'B-tissue/organ'}", + "103, recipient {'context': 'B-organism'}", + "104, mouse {'context': 'I-organism'}", + "105, embryos {'context': 'I-organism'}", + "116, to {'perturbing_action': 'I-other'}", + "117, Fgfr2cnull {'perturbing_action': 'I-other'}", + "118, mutation) {'perturbing_action': 'I-other'}", + "124, neonates {'context': 'B-organism'}", + "130, lungs {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "97, rescued ['l0']", + "98, lung ['l0']", + "103, recipient ['l1', 'l2', 'l3', 'l4', 'l5']", + "104, mouse ['l1', 'l6', 'l7', 'l8', 'l9']", + "105, embryos ['l2', 'l6', 'l10', 'l11', 'l12']", + "116, to ['l3', 'l7', 'l10', 'l13', 'l14', 'l15']", + "117, Fgfr2cnull ['l4', 'l8', 'l11', 'l13', 'l16', 'l17']", + "118, mutation) ['l5', 'l9', 'l12', 'l14', 'l16', 'l18']", + "124, neonates ['l15', 'l17', 'l18', 'l19']", + "130, lungs ['l19']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "recipient", + "mouse", + "embryos", + "neonates" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "to", + "Fgfr2cnull", + "mutation)" + ] + } + } + ] + }, + { + "PMID": "31700184", + "TEXT": "A sedentary lifestyle, chronic inflammation and leukocytosis increase atherosclerosis; however, it remains unclear whether regular physical activity influences leukocyte production. Here we show that voluntary running decreases hematopoietic activity in mice. Exercise protects mice and humans with atherosclerosis from chronic leukocytosis but does not compromise emergency hematopoiesis in mice. Mechanistically, exercise diminishes leptin production in adipose tissue, augmenting quiescence-promoting hematopoietic niche factors in leptin-receptor-positive stromal bone marrow cells. Induced deletion of the leptin receptor in Prrx1-creERT2; Leprfl/fl mice reveals that leptin's effect on bone marrow niche cells regulates hematopoietic stem and progenitor cell (HSPC) proliferation and leukocyte production, as well as cardiovascular inflammation and outcomes. Whereas running wheel withdrawal quickly reverses leptin levels, the impact of exercise on leukocyte production and on the HSPC epigenome and transcriptome persists for several weeks. Together, these data show that physical activity alters HSPCs via modulation of their niche, reducing hematopoietic output of inflammatory leukocytes.", + "TAG_DATA": [ + "30, mice. {'context': 'B-organism'}", + "48, mice. {'context': 'B-organism'}", + "55, adipose {'context': 'B-tissue/organ'}", + "56, tissue, {'context': 'I-tissue/organ'}", + "63, leptin-receptor-positive {'context': 'B-cells'}", + "64, stromal {'context': 'I-cells'}", + "65, bone {'context': 'I-cells'}", + "66, marrow {'context': 'I-cells'}", + "67, cells. {'context': 'I-cells'}", + "68, Induced {'perturbing_action': 'B-gene loss-of-function'}", + "69, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "70, of {'perturbing_action': 'I-gene loss-of-function'}", + "71, the {'perturbing_action': 'I-gene loss-of-function'}", + "72, leptin {'perturbing_action': 'I-gene loss-of-function'}", + "73, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "75, Prrx1-creERT2; {'perturbing_action': 'B-gene loss-of-function'}", + "76, Leprfl/fl {'perturbing_action': 'B-gene loss-of-function'}", + "77, mice {'context': 'B-organism'}", + "87, regulates {'effect': 'B-regulates'}", + "88, hematopoietic {'context': 'B-cells'}", + "89, stem {'context': 'I-cells'}", + "90, and {'context': 'I-cells'}", + "91, progenitor {'context': 'I-cells'}", + "92, cell {'context': 'I-cells'}", + "93, (HSPC) {'context': 'I-cells'}", + "94, proliferation {'phenotype': 'B-proliferation'}", + "96, leukocyte {'context': 'B-cells'}", + "118, leukocyte {'context': 'B-cells'}", + "123, HSPC {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "30, mice. ['l0', 'l1', 'l2']", + "48, mice. ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "55, adipose ['l0', 'l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "56, tissue, ['l1', 'l4', 'l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "63, leptin-receptor-positive ['l5', 'l11', 'l16', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "64, stromal ['l6', 'l12', 'l17', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "65, bone ['l7', 'l13', 'l18', 'l22', 'l28', 'l34', 'l35', 'l36', 'l37']", + "66, marrow ['l8', 'l14', 'l19', 'l23', 'l29', 'l34', 'l38', 'l39', 'l40']", + "67, cells. ['l2', 'l9', 'l15', 'l20', 'l24', 'l30', 'l35', 'l38']", + "68, Induced ['l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "69, deletion ['l41', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "70, of ['l42', 'l58', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "71, the ['l43', 'l59', 'l74', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "72, leptin ['l44', 'l60', 'l75', 'l89', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "73, receptor ['l45', 'l61', 'l76', 'l90', 'l103', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127']", + "75, Prrx1-creERT2; ['l46', 'l62', 'l77', 'l91', 'l104', 'l116', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "76, Leprfl/fl ['l47', 'l63', 'l78', 'l92', 'l105', 'l117', 'l128', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148']", + "77, mice ['l48', 'l64', 'l79', 'l93', 'l106', 'l118', 'l129', 'l139', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "87, regulates ['l25', 'l31', 'l49', 'l65', 'l80', 'l94', 'l107', 'l119', 'l130', 'l140', 'l149', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "88, hematopoietic ['l50', 'l66', 'l81', 'l95', 'l108', 'l120', 'l131', 'l141', 'l150', 'l158', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "89, stem ['l51', 'l67', 'l82', 'l96', 'l109', 'l121', 'l132', 'l142', 'l151', 'l159', 'l166', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "90, and ['l52', 'l68', 'l83', 'l97', 'l110', 'l122', 'l133', 'l143', 'l152', 'l160', 'l167', 'l173', 'l179', 'l180', 'l181', 'l182', 'l183']", + "91, progenitor ['l53', 'l69', 'l84', 'l98', 'l111', 'l123', 'l134', 'l144', 'l153', 'l161', 'l168', 'l174', 'l179', 'l184', 'l185', 'l186', 'l187']", + "92, cell ['l26', 'l32', 'l36', 'l39', 'l54', 'l70', 'l85', 'l99', 'l112', 'l124', 'l135', 'l145', 'l154', 'l162', 'l169', 'l175', 'l180', 'l184', 'l188', 'l189', 'l190']", + "93, (HSPC) ['l55', 'l71', 'l86', 'l100', 'l113', 'l125', 'l136', 'l146', 'l155', 'l163', 'l170', 'l176', 'l181', 'l185', 'l188', 'l191', 'l192']", + "94, proliferation ['l27', 'l33', 'l37', 'l40', 'l56', 'l72', 'l87', 'l101', 'l114', 'l126', 'l137', 'l147', 'l156', 'l164', 'l171', 'l177', 'l182', 'l186', 'l189', 'l191', 'l193']", + "96, leukocyte ['l57', 'l73', 'l88', 'l102', 'l115', 'l127', 'l138', 'l148', 'l157', 'l165', 'l172', 'l178', 'l183', 'l187', 'l190', 'l192', 'l193']", + "118, leukocyte ['l194']", + "123, HSPC ['l194']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "leptin-receptor-positive", + "stromal", + "hematopoietic", + "stem", + "and", + "progenitor", + "cell", + "(HSPC)", + "leukocyte" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "regulates" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "leptin-receptor-positive", + "stromal", + "bone", + "marrow", + "hematopoietic", + "stem", + "and", + "progenitor", + "cell", + "(HSPC)", + "leukocyte" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Induced", + "deletion", + "of", + "the", + "leptin", + "receptor", + "Prrx1-creERT2;", + "Leprfl/fl" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Induced", + "deletion", + "of", + "the", + "leptin", + "receptor", + "Prrx1-creERT2;", + "Leprfl/fl" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "regulates" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Induced", + "deletion", + "of", + "the", + "leptin", + "receptor", + "Prrx1-creERT2;", + "Leprfl/fl" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "and", + "progenitor", + "cell", + "(HSPC)", + "leukocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Induced", + "deletion", + "of", + "the", + "leptin", + "receptor", + "Prrx1-creERT2;", + "Leprfl/fl" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "regulates" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "regulates" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "31700175", + "TEXT": "Proinflammatory cytokines in the tumor microenvironment can promote tumor growth, yet their value as therapeutic targets remains underexploited. We validated the functional significance of the cardiotrophin-like cytokine factor 1 (CLCF1)-ciliary neurotrophic factor receptor (CNTFR) signaling axis in lung adenocarcinoma (LUAD) and generated a high-affinity soluble receptor (eCNTFR-Fc) that sequesters CLCF1, thereby inhibiting its oncogenic effects. eCNTFR-Fc inhibits tumor growth in multiple xenograft models and in an autochthonous, highly aggressive genetically engineered mouse model of LUAD, driven by activation of oncogenic Kras and loss of Trp53. Abrogation of CLCF1 through eCNTFR-Fc appears most effective in tumors driven by oncogenic KRAS. We observed a correlation between the effectiveness of eCNTFR-Fc and the presence of KRAS mutations that retain the intrinsic capacity to hydrolyze guanosine triphosphate, suggesting that the mechanism of action may be related to altered guanosine triphosphate loading. Overall, we nominate blockade of CLCF1-CNTFR signaling as a novel therapeutic opportunity for LUAD and potentially for other tumor types in which CLCF1 is present in the tumor microenvironment.", + "TAG_DATA": [ + "56, inhibits {'effect': 'B-negative'}", + "57, tumor {'phenotype': 'B-tumour growth'}", + "58, growth {'phenotype': 'I-tumour growth'}", + "61, xenograft {'context': 'B-xenograft'}", + "62, models {'context': 'I-xenograft'}", + "70, engineered {'context': 'I-organism'}", + "71, mouse {'context': 'B-neoplasm'}", + "72, model {'context': 'I-neoplasm'}", + "73, of {'context': 'I-neoplasm'}", + "74, LUAD, {'context': 'I-neoplasm'}", + "82, loss {'perturbing_action': 'B-gene loss-of-function'}", + "83, of {'perturbing_action': 'I-gene loss-of-function'}", + "84, Trp53. {'perturbing_action': 'I-gene loss-of-function'}", + "94, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "56, inhibits ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "57, tumor ['l0', 'l6', 'l7', 'l8']", + "58, growth ['l1', 'l6', 'l9', 'l10']", + "61, xenograft ['l2', 'l7', 'l9', 'l11']", + "62, models ['l3', 'l8', 'l10', 'l11']", + "69, genetically ['l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "70, engineered ['l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "71, mouse ['l13', 'l22', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "72, model ['l14', 'l23', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "73, of ['l15', 'l24', 'l32', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "74, LUAD, ['l4', 'l16', 'l25', 'l33', 'l40', 'l46', 'l52', 'l53', 'l54', 'l55', 'l56']", + "77, activation ['l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l57', 'l58', 'l59', 'l60']", + "80, Kras ['l5', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l61', 'l62', 'l63']", + "82, loss ['l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l64', 'l65']", + "83, of ['l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l66']", + "84, Trp53. ['l21', 'l30', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l65', 'l66']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "models" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "LUAD," + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "models" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "engineered" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Trp53." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "LUAD," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Trp53." + ] + } + } + ] + }, + { + "PMID": "31591594", + "TEXT": "The ability to expand hematopoietic stem and progenitor cells (HSPCs) ex vivo is critical to fully realize the potential of HSPC-based therapies. In particular, the application of clinically effective therapies, such as cord blood transplantation, has been impeded because of limited HSPC availability. Here, using 3D culture of human HSPCs in a degradable zwitterionic hydrogel, we achieved substantial expansion of phenotypically primitive CD34+ cord blood and bone-marrow-derived HSPCs. This culture system led to a 73-fold increase in long-term hematopoietic stem cell (LT-HSC) frequency, as demonstrated by limiting dilution assays, and the expanded HSPCs were capable of hematopoietic reconstitution for at least 24 weeks in immunocompromised mice. Both the zwitterionic characteristics of the hydrogel and the 3D format were important for HSPC self-renewal. Mechanistically, the impact of 3D zwitterionic hydrogel culture on mitigating HSPC differentiation and promoting self-renewal might result from an inhibition of excessive reactive oxygen species (ROS) production via suppression of O2-related metabolism. HSPC expansion using zwitterionic hydrogels has the potential to facilitate the clinical application of hematopoietic-stem-cell therapies.", + "TAG_DATA": [ + "45, 3D {'context': 'B-in vitro'}", + "46, culture {'context': 'I-in vitro'}", + "48, human {'context': 'B-cells'}", + "49, HSPCs {'context': 'I-cells'}", + "62, CD34+ {'context': 'B-cells'}", + "63, cord {'context': 'I-cells'}", + "64, blood {'context': 'I-cells'}", + "66, bone-marrow-derived {'context': 'B-cells'}", + "67, HSPCs. {'context': 'I-cells'}", + "92, HSPCs {'context': 'B-cells'}", + "105, mice. {'context': 'I-organism'}", + "120, HSPC {'context': 'B-cells'}", + "121, self-renewal. {'phenotype': 'B-self-renewal'}", + "132, HSPC {'context': 'B-cells'}", + "135, promoting {'effect': 'B-positive'}", + "136, self-renewal {'phenotype': 'B-self-renewal'}" + ], + "LINK_DATA": [ + "45, 3D ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "46, culture ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "48, human ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "49, HSPCs ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "62, CD34+ ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "63, cord ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "64, blood ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "66, bone-marrow-derived ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "67, HSPCs. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "92, HSPCs ['l36']", + "105, mice. ['l36']", + "120, HSPC ['l37', 'l38', 'l39']", + "121, self-renewal. ['l37']", + "132, HSPC ['l38', 'l40', 'l41']", + "135, promoting ['l39', 'l40', 'l42']", + "136, self-renewal ['l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "HSPC" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal.", + "self-renewal" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSPC" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal" + ] + } + } + ] + }, + { + "PMID": "31235962", + "TEXT": "The role of dysbiosis in food allergy (FA) remains unclear. We found that dysbiotic fecal microbiota in FA infants evolved compositionally over time and failed to protect against FA in mice. Infants and mice with FA had decreased IgA and increased IgE binding to fecal bacteria, indicative of a broader breakdown of oral tolerance than hitherto appreciated. Therapy with Clostridiales species impacted by dysbiosis, either as a consortium or as monotherapy with Subdoligranulum variabile, suppressed FA in mice as did a separate immunomodulatory Bacteroidales consortium. Bacteriotherapy induced expression by regulatory T (Treg) cells of the transcription factor ROR-γt in a MyD88-dependent manner, which was deficient in FA infants and mice and ineffectively induced by their microbiota. Deletion of Myd88 or Rorc in Treg cells abrogated protection by bacteriotherapy. Thus, commensals activate a MyD88/ROR-γt pathway in nascent Treg cells to protect against FA, while dysbiosis impairs this regulatory response to promote disease.", + "TAG_DATA": [ + "33, mice {'context': 'B-organism'}", + "77, mice {'context': 'B-organism'}", + "89, regulatory T {'context': 'B-cells'}", + "90, (Treg) {'context': 'I-cells'}", + "91, cells {'context': 'I-cells'}", + "108, mice {'context': 'B-organism'}", + "115, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "116, of {'perturbing_action': 'I-gene loss-of-function'}", + "117, Myd88 {'perturbing_action': 'I-gene loss-of-function'}", + "118, or {'perturbing_action': 'I-gene loss-of-function'}", + "119, Rorc {'perturbing_action': 'I-gene loss-of-function'}", + "121, Treg {'context': 'B-cells'}", + "122, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "89, regulatory T ['l0', 'l1', 'l2']", + "90, (Treg) ['l0', 'l3', 'l4']", + "91, cells ['l1', 'l3', 'l5']", + "108, mice ['l2', 'l4', 'l5']", + "115, Deletion ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "116, of ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "117, Myd88 ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "118, or ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "119, Rorc ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "121, Treg ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "122, cells ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "Myd88", + "or", + "Rorc" + ] + }, + "context": { + "val": "cells", + "words": [ + "Treg", + "cells" + ] + } + } + ] + }, + { + "PMID": "31086348", + "TEXT": "An aged circulatory environment can activate microglia, reduce neural precursor cell activity and impair cognition in mice. We hypothesized that brain endothelial cells (BECs) mediate at least some of these effects. We observe that BECs in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of vascular cell adhesion molecule 1 (VCAM1), a protein that facilitates vascular-immune cell interactions. Concomitantly, levels of the shed, soluble form of VCAM1 are prominently increased in the plasma of aged humans and mice, and their plasma is sufficient to increase VCAM1 expression in cultured BECs and the hippocampi of young mice. Systemic administration of anti-VCAM1 antibody or genetic ablation of Vcam1 in BECs counteracts the detrimental effects of plasma from aged individuals on young brains and reverses aging aspects, including microglial reactivity and cognitive deficits, in the brains of aged mice. Together, these findings establish brain endothelial VCAM1 at the blood-brain barrier as a possible target to treat age-related neurodegeneration.", + "TAG_DATA": [ + "37, aged {'context': 'B-tissue/organ'}", + "38, mouse {'context': 'I-tissue/organ'}", + "39, hippocampus {'context': 'I-tissue/organ'}", + "93, BECs {'context': 'B-cells'}", + "96, hippocampi {'context': 'B-tissue/organ'}", + "98, young {'context': 'B-organism'}", + "99, mice. {'context': 'I-organism'}", + "106, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "107, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "108, of {'perturbing_action': 'I-gene loss-of-function'}", + "109, Vcam1 {'perturbing_action': 'I-gene loss-of-function'}", + "111, BECs {'context': 'B-cells'}", + "136, brains {'context': 'B-tissue/organ'}", + "138, aged {'context': 'B-organism'}", + "139, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "37, aged ['l0', 'l1', 'l2']", + "38, mouse ['l0', 'l3', 'l4']", + "39, hippocampus ['l1', 'l3', 'l5']", + "93, BECs ['l2', 'l4', 'l5', 'l6', 'l7', 'l8']", + "96, hippocampi ['l6', 'l9', 'l10']", + "98, young ['l7', 'l9', 'l11']", + "99, mice. ['l8', 'l10', 'l11']", + "106, genetic ['l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "107, ablation ['l12', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "108, of ['l13', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "109, Vcam1 ['l14', 'l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "111, BECs ['l15', 'l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "136, brains ['l16', 'l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "138, aged ['l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "139, mice. ['l18', 'l24', 'l29', 'l33', 'l36', 'l38', 'l39']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "Vcam1" + ] + }, + "context": { + "val": "cells", + "words": [ + "BECs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "Vcam1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brains" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "Vcam1" + ] + }, + "context": { + "val": "organism", + "words": [ + "aged", + "mice." + ] + } + } + ] + }, + { + "PMID": "31061538", + "TEXT": "Understanding cellular metabolism holds immense potential for developing new classes of therapeutics that target metabolic pathways in cancer. Metabolic pathways are altered in bulk neoplastic cells in comparison to normal tissues. However, carcinoma cells within tumors are heterogeneous, and tumor-initiating cells (TICs) are important therapeutic targets that have remained metabolically uncharacterized. To understand their metabolic alterations, we performed metabolomics and metabolite tracing analyses, which revealed that TICs have highly elevated methionine cycle activity and transmethylation rates that are driven by MAT2A. High methionine cycle activity causes methionine consumption to far outstrip its regeneration, leading to addiction to exogenous methionine. Pharmacological inhibition of the methionine cycle, even transiently, is sufficient to cripple the tumor-initiating capability of these cells. Methionine cycle flux specifically influences the epigenetic state of cancer cells and drives tumor initiation. Methionine cycle enzymes are also enriched in other tumor types, and MAT2A expression impinges upon the sensitivity of certain cancer cells to therapeutic inhibition.", + "TAG_DATA": [ + "110, cripple {'effect': 'B-negative'}", + "112, tumor-initiating {'phenotype': 'B-tumour initiation'}", + "113, capability {'phenotype': 'I-tumour initiation'}", + "116, cells. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "110, cripple ['l0', 'l1', 'l2']", + "112, tumor-initiating ['l0', 'l3', 'l4']", + "113, capability ['l1', 'l3', 'l5']", + "116, cells. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "cripple" + ] + }, + "phenotype": { + "val": "tumour initiation", + "words": [ + "tumor-initiating", + "capability" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "cripple" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "phenotype": { + "val": "tumour initiation", + "words": [ + "tumor-initiating", + "capability" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "30858616", + "TEXT": "Malformations of the human cortex represent a major cause of disability1. Mouse models with mutations in known causal genes only partially recapitulate the phenotypes and are therefore not unlimitedly suited for understanding the molecular and cellular mechanisms responsible for these conditions2. Here we study periventricular heterotopia (PH) by analyzing cerebral organoids derived from induced pluripotent stem cells (iPSCs) of patients with mutations in the cadherin receptor-ligand pair DCHS1 and FAT4 or from isogenic knockout (KO) lines1,3. Our results show that human cerebral organoids reproduce the cortical heterotopia associated with PH. Mutations in DCHS1 and FAT4 or knockdown of their expression causes changes in the morphology of neural progenitor cells and result in defective neuronal migration dynamics only in a subset of neurons. Single-cell RNA-sequencing (scRNA-seq) data reveal a subpopulation of mutant neurons with dysregulated genes involved in axon guidance, neuronal migration and patterning. We suggest that defective neural progenitor cell (NPC) morphology and an altered navigation system in a subset of neurons underlie this form of PH.", + "TAG_DATA": [ + "49, cerebral {'context': 'B-organoid'}", + "50, organoids {'context': 'I-organoid'}", + "53, induced {'context': 'B-cells'}", + "54, pluripotent {'context': 'I-cells'}", + "55, stem {'context': 'I-cells'}", + "56, cells {'context': 'I-cells'}", + "57, (iPSCs) {'context': 'I-cells'}", + "59, patients {'context': 'B-patient'}", + "61, mutations {'perturbing_action': 'B-other'}", + "62, in {'perturbing_action': 'I-other'}", + "63, the {'perturbing_action': 'I-other'}", + "64, cadherin {'perturbing_action': 'I-other'}", + "65, receptor-ligand {'perturbing_action': 'I-other'}", + "66, pair {'perturbing_action': 'I-other'}", + "67, DCHS1 {'perturbing_action': 'I-other'}", + "68, and {'perturbing_action': 'I-other'}", + "69, FAT4 {'perturbing_action': 'I-other'}", + "72, isogenic {'perturbing_action': 'B-gene loss-of-function'}", + "73, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "74, (KO) {'perturbing_action': 'I-gene loss-of-function'}", + "75, lines1,3. {'perturbing_action': 'I-gene loss-of-function'}", + "80, human {'context': 'B-organoid'}", + "81, cerebral {'context': 'I-organoid'}", + "82, organoids {'context': 'I-organoid'}", + "90, Mutations {'perturbing_action': 'B-other'}", + "91, in {'perturbing_action': 'I-other'}", + "92, DCHS1 {'perturbing_action': 'I-other'}", + "93, and {'perturbing_action': 'I-other'}", + "94, FAT4 {'perturbing_action': 'I-other'}", + "96, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "97, of {'perturbing_action': 'I-rnai/knockdown'}", + "98, their {'perturbing_action': 'I-rnai/knockdown'}", + "99, expression {'perturbing_action': 'I-rnai/knockdown'}", + "106, neural {'context': 'B-cells'}", + "107, progenitor {'context': 'I-cells'}", + "108, cells {'context': 'I-cells'}", + "112, defective {'effect': 'B-negative'}", + "114, migration {'phenotype': 'B-migration'}", + "121, neurons. {'context': 'B-cells'}", + "131, neurons {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "49, cerebral ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "50, organoids ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "53, induced ['l1', 'l17', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "54, pluripotent ['l2', 'l18', 'l32', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "55, stem ['l3', 'l19', 'l33', 'l51', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "56, cells ['l4', 'l20', 'l34', 'l52', 'l74', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "57, (iPSCs) ['l5', 'l21', 'l35', 'l53', 'l75', 'l90', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "59, patients ['l6', 'l22', 'l36', 'l54', 'l76', 'l91', 'l105', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "61, mutations ['l7', 'l23', 'l37', 'l55', 'l77', 'l92', 'l106', 'l119', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151']", + "62, in ['l8', 'l24', 'l38', 'l56', 'l78', 'l93', 'l107', 'l120', 'l133', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "63, the ['l9', 'l25', 'l39', 'l57', 'l79', 'l94', 'l108', 'l121', 'l134', 'l152', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186']", + "64, cadherin ['l10', 'l26', 'l40', 'l58', 'l80', 'l95', 'l109', 'l122', 'l135', 'l153', 'l170', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203']", + "65, receptor-ligand ['l11', 'l27', 'l41', 'l59', 'l81', 'l96', 'l110', 'l123', 'l136', 'l154', 'l171', 'l187', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219']", + "66, pair ['l12', 'l28', 'l42', 'l60', 'l82', 'l97', 'l111', 'l124', 'l137', 'l155', 'l172', 'l188', 'l204', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233']", + "67, DCHS1 ['l13', 'l29', 'l43', 'l61', 'l83', 'l98', 'l112', 'l125', 'l138', 'l156', 'l173', 'l189', 'l205', 'l220', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246']", + "68, and ['l14', 'l30', 'l44', 'l62', 'l84', 'l99', 'l113', 'l126', 'l139', 'l157', 'l174', 'l190', 'l206', 'l221', 'l234', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258']", + "69, FAT4 ['l15', 'l31', 'l45', 'l63', 'l85', 'l100', 'l114', 'l127', 'l140', 'l158', 'l175', 'l191', 'l207', 'l222', 'l235', 'l247', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268']", + "72, isogenic ['l64', 'l141', 'l159', 'l176', 'l192', 'l208', 'l223', 'l236', 'l248', 'l259', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283']", + "73, knockout ['l65', 'l142', 'l160', 'l177', 'l193', 'l209', 'l224', 'l237', 'l249', 'l260', 'l269', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298']", + "74, (KO) ['l66', 'l143', 'l161', 'l178', 'l194', 'l210', 'l225', 'l238', 'l250', 'l261', 'l270', 'l284', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304', 'l305', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311', 'l312']", + "75, lines1,3. ['l46', 'l67', 'l86', 'l101', 'l115', 'l128', 'l144', 'l162', 'l179', 'l195', 'l211', 'l226', 'l239', 'l251', 'l262', 'l271', 'l285', 'l299', 'l313', 'l314', 'l315', 'l316', 'l317', 'l318', 'l319']", + "80, human ['l47', 'l68', 'l87', 'l102', 'l116', 'l129', 'l145', 'l163', 'l180', 'l196', 'l212', 'l227', 'l240', 'l252', 'l263', 'l272', 'l286', 'l300', 'l313', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325']", + "81, cerebral ['l48', 'l69', 'l88', 'l103', 'l117', 'l130', 'l146', 'l164', 'l181', 'l197', 'l213', 'l228', 'l241', 'l253', 'l264', 'l273', 'l287', 'l301', 'l314', 'l320', 'l326', 'l327', 'l328', 'l329', 'l330', 'l331']", + "82, organoids ['l16', 'l49', 'l70', 'l89', 'l104', 'l118', 'l131', 'l147', 'l165', 'l182', 'l198', 'l214', 'l229', 'l242', 'l254', 'l265', 'l274', 'l288', 'l302', 'l315', 'l321', 'l326', 'l332', 'l333', 'l334', 'l335']", + "90, Mutations ['l336', 'l337', 'l338', 'l339', 'l340', 'l341', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348']", + "91, in ['l289', 'l303', 'l336', 'l349', 'l350', 'l351', 'l352', 'l353', 'l354', 'l355', 'l356', 'l357', 'l358', 'l359', 'l360']", + "92, DCHS1 ['l275', 'l290', 'l304', 'l337', 'l349', 'l361', 'l362', 'l363', 'l364', 'l365', 'l366', 'l367', 'l368']", + "93, and ['l276', 'l291', 'l305', 'l338', 'l350', 'l361', 'l369', 'l370', 'l371', 'l372', 'l373', 'l374', 'l375']", + "94, FAT4 ['l277', 'l292', 'l306', 'l339', 'l351', 'l362', 'l369', 'l376', 'l377', 'l378', 'l379', 'l380', 'l381']", + "96, knockdown ['l382', 'l383', 'l384', 'l385', 'l386', 'l387', 'l388', 'l389', 'l390']", + "97, of ['l340', 'l352', 'l382', 'l391', 'l392', 'l393', 'l394', 'l395', 'l396', 'l397', 'l398']", + "98, their ['l341', 'l353', 'l383', 'l391', 'l399', 'l400', 'l401', 'l402', 'l403', 'l404', 'l405']", + "99, expression ['l342', 'l354', 'l384', 'l392', 'l399', 'l406', 'l407', 'l408', 'l409', 'l410', 'l411']", + "106, neural ['l148', 'l166', 'l183', 'l199', 'l215', 'l230', 'l243', 'l255', 'l278', 'l293', 'l307', 'l316', 'l322', 'l327', 'l332', 'l343', 'l355', 'l363', 'l370', 'l376', 'l385', 'l393', 'l400', 'l406', 'l412', 'l413', 'l414', 'l415', 'l416']", + "107, progenitor ['l71', 'l149', 'l167', 'l184', 'l200', 'l216', 'l231', 'l244', 'l256', 'l266', 'l279', 'l294', 'l308', 'l317', 'l323', 'l328', 'l333', 'l344', 'l356', 'l364', 'l371', 'l377', 'l386', 'l394', 'l401', 'l407', 'l412', 'l417', 'l418', 'l419', 'l420']", + "108, cells ['l50', 'l72', 'l132', 'l150', 'l168', 'l185', 'l201', 'l217', 'l232', 'l245', 'l257', 'l267', 'l280', 'l295', 'l309', 'l318', 'l324', 'l329', 'l334', 'l345', 'l357', 'l365', 'l372', 'l378', 'l387', 'l395', 'l402', 'l408', 'l413', 'l417', 'l421', 'l422', 'l423']", + "112, defective ['l281', 'l296', 'l310', 'l346', 'l358', 'l366', 'l373', 'l379', 'l388', 'l396', 'l403', 'l409', 'l414', 'l418', 'l421', 'l424', 'l425']", + "114, migration ['l73', 'l151', 'l169', 'l186', 'l202', 'l218', 'l233', 'l246', 'l258', 'l268', 'l282', 'l297', 'l311', 'l319', 'l325', 'l330', 'l335', 'l347', 'l359', 'l367', 'l374', 'l380', 'l389', 'l397', 'l404', 'l410', 'l415', 'l419', 'l422', 'l424', 'l426']", + "121, neurons. ['l203', 'l219', 'l283', 'l298', 'l312', 'l331', 'l348', 'l360', 'l368', 'l375', 'l381', 'l390', 'l398', 'l405', 'l411', 'l416', 'l420', 'l423', 'l425', 'l426']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organoid", + "words": [ + "cerebral", + "organoids", + "human" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutations", + "in", + "the", + "cadherin", + "receptor-ligand", + "pair", + "DCHS1", + "and", + "FAT4" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "induced", + "pluripotent", + "stem", + "cells", + "(iPSCs)", + "neural", + "progenitor", + "neurons." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutations", + "in", + "the", + "cadherin", + "receptor-ligand", + "pair", + "DCHS1", + "and", + "FAT4", + "Mutations" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "induced", + "pluripotent", + "stem", + "cells", + "(iPSCs)", + "neural", + "progenitor", + "neurons." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lines1,3.", + "isogenic", + "knockout", + "(KO)" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pluripotent", + "neural", + "progenitor", + "cells", + "neurons." + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutations", + "in", + "the", + "cadherin", + "receptor-ligand", + "pair", + "DCHS1", + "and", + "FAT4" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lines1,3." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutations", + "in", + "the", + "cadherin", + "receptor-ligand", + "pair", + "DCHS1", + "and", + "FAT4", + "Mutations" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "isogenic", + "knockout", + "(KO)", + "lines1,3." + ] + }, + "context": { + "val": "organoid", + "words": [ + "human", + "cerebral", + "organoids" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "isogenic", + "knockout", + "(KO)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "isogenic", + "knockout", + "(KO)", + "lines1,3." + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "human", + "cerebral", + "organoids" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Mutations", + "in", + "DCHS1", + "and", + "FAT4" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "their", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "neural", + "progenitor", + "cells", + "neurons." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "their", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "their", + "expression" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neural", + "progenitor", + "cells", + "neurons." + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "defective" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + } + ] + }, + { + "PMID": "30833752", + "TEXT": "Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent tumorigenic growth, but the role of KRAS in supporting autophagy has not been established. We show that, to our surprise, suppression of KRAS increased autophagic flux, as did pharmacological inhibition of its effector ERK MAPK. Furthermore, we demonstrate that either KRAS suppression or ERK inhibition decreased both glycolytic and mitochondrial functions. We speculated that ERK inhibition might thus enhance PDAC dependence on autophagy, in part by impairing other KRAS- or ERK-driven metabolic processes. Accordingly, we found that the autophagy inhibitor chloroquine and genetic or pharmacologic inhibition of specific autophagy regulators synergistically enhanced the ability of ERK inhibitors to mediate antitumor activity in KRAS-driven PDAC. We conclude that combinations of pharmacologic inhibitors that concurrently block both ERK MAPK and autophagic processes that are upregulated in response to ERK inhibition may be effective treatments for PDAC.", + "TAG_DATA": [ + "30, suppression {'perturbing_action': 'B-pharmacological inhibition'}", + "31, of {'perturbing_action': 'I-pharmacological inhibition'}", + "32, KRAS {'perturbing_action': 'I-pharmacological inhibition'}", + "33, increased {'effect': 'B-positive'}", + "34, autophagic {'phenotype': 'B-autophagy'}", + "35, flux, {'phenotype': 'I-autophagy'}", + "38, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "39, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "40, of {'perturbing_action': 'I-pharmacological inhibition'}", + "41, its {'perturbing_action': 'I-pharmacological inhibition'}", + "42, effector {'perturbing_action': 'I-pharmacological inhibition'}", + "43, ERK {'perturbing_action': 'I-pharmacological inhibition'}", + "44, MAPK. {'perturbing_action': 'I-pharmacological inhibition'}", + "50, KRAS {'perturbing_action': 'B-pharmacological inhibition'}", + "51, suppression {'perturbing_action': 'I-pharmacological inhibition'}", + "53, ERK {'perturbing_action': 'B-pharmacological inhibition'}", + "54, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "94, pharmacologic {'perturbing_action': 'B-pharmacological inhibition'}", + "95, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "96, of {'perturbing_action': 'I-pharmacological inhibition'}", + "97, specific {'perturbing_action': 'I-pharmacological inhibition'}", + "98, autophagy {'perturbing_action': 'I-pharmacological inhibition'}", + "99, regulators {'perturbing_action': 'I-pharmacological inhibition'}", + "105, ERK {'perturbing_action': 'B-pharmacological inhibition'}", + "106, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "113, PDAC. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "30, suppression ['l0', 'l1', 'l2', 'l3', 'l4']", + "31, of ['l0', 'l5', 'l6', 'l7', 'l8', 'l9']", + "32, KRAS ['l1', 'l5', 'l10', 'l11', 'l12']", + "33, increased ['l2', 'l6', 'l10', 'l13', 'l14']", + "34, autophagic ['l3', 'l7', 'l11', 'l13', 'l15', 'l16']", + "35, flux, ['l4', 'l8', 'l12', 'l14', 'l15']", + "38, pharmacological ['l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "39, inhibition ['l17', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "40, of ['l18', 'l27', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "41, its ['l19', 'l28', 'l36', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "42, effector ['l20', 'l29', 'l37', 'l44', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "43, ERK ['l21', 'l30', 'l38', 'l45', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "44, MAPK. ['l22', 'l31', 'l39', 'l46', 'l52', 'l57', 'l62', 'l63', 'l64', 'l65']", + "50, KRAS ['l23', 'l32', 'l40', 'l47', 'l53', 'l58', 'l62', 'l66', 'l67', 'l68']", + "51, suppression ['l9', 'l16', 'l24', 'l33', 'l41', 'l48', 'l54', 'l59', 'l63', 'l66', 'l69', 'l70']", + "53, ERK ['l25', 'l34', 'l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l71']", + "54, inhibition ['l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l71']", + "94, pharmacologic ['l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "95, inhibition ['l72', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "96, of ['l73', 'l80', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "97, specific ['l74', 'l81', 'l87', 'l93', 'l94', 'l95', 'l96', 'l97']", + "98, autophagy ['l75', 'l82', 'l88', 'l93', 'l98', 'l99', 'l100', 'l101']", + "99, regulators ['l76', 'l83', 'l89', 'l94', 'l98', 'l102', 'l103', 'l104']", + "105, ERK ['l77', 'l84', 'l90', 'l95', 'l99', 'l102', 'l105', 'l106']", + "106, inhibitors ['l78', 'l85', 'l91', 'l96', 'l100', 'l103', 'l105', 'l107']", + "113, PDAC. ['l79', 'l86', 'l92', 'l97', 'l101', 'l104', 'l106', 'l107']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "suppression", + "of", + "KRAS" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "suppression", + "of", + "KRAS" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagic", + "flux," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagic", + "flux," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "specific", + "autophagy", + "regulators", + "ERK", + "inhibitors" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "PDAC." + ] + } + } + ] + }, + { + "PMID": "30692699", + "TEXT": "Apolipoprotein-E (ApoE) has been implicated in Alzheimer's disease, atherosclerosis, and other unresolvable inflammatory conditions but a common mechanism of action remains elusive. We found in ApoE-deficient mice that oxidized lipids activated the classical complement cascade (CCC), resulting in leukocyte infiltration of the choroid plexus (ChP). All human ApoE isoforms attenuated CCC activity via high-affinity binding to the activated CCC-initiating C1q protein (KD~140-580 pM) in vitro, and C1q-ApoE complexes emerged as markers for ongoing complement activity of diseased ChPs, Aβ plaques, and atherosclerosis in vivo. C1q-ApoE complexes in human ChPs, Aβ plaques, and arteries correlated with cognitive decline and atherosclerosis, respectively. Treatment with small interfering RNA (siRNA) against C5, which is formed by all complement pathways, attenuated murine ChP inflammation, Aβ-associated microglia accumulation, and atherosclerosis. Thus, ApoE is a direct checkpoint inhibitor of unresolvable inflammation, and reducing C5 attenuates disease burden.", + "TAG_DATA": [ + "25, ApoE-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "26, mice {'context': 'B-organism'}", + "63, in {'context': 'B-in vitro'}", + "64, vitro, {'context': 'I-in vitro'}", + "82, in {'context': 'B-in vivo'}", + "83, vivo. {'context': 'I-in vivo'}", + "102, small {'perturbing_action': 'B-rnai/knockdown'}", + "103, interfering {'perturbing_action': 'I-rnai/knockdown'}", + "104, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "105, (siRNA) {'perturbing_action': 'I-rnai/knockdown'}", + "106, against {'perturbing_action': 'I-rnai/knockdown'}", + "107, C5, {'perturbing_action': 'I-rnai/knockdown'}", + "116, murine {'context': 'B-organism'}", + "119, Aβ-associated {'context': 'B-cells'}", + "120, microglia {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "25, ApoE-deficient ['l0', 'l1', 'l2', 'l3', 'l4']", + "26, mice ['l0', 'l5', 'l6', 'l7']", + "63, in ['l1', 'l5', 'l8', 'l9', 'l10']", + "64, vitro, ['l2', 'l6', 'l8', 'l11', 'l12']", + "82, in ['l3', 'l9', 'l11', 'l13']", + "83, vivo. ['l4', 'l7', 'l10', 'l12', 'l13']", + "102, small ['l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "103, interfering ['l14', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "104, RNA ['l15', 'l22', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "105, (siRNA) ['l16', 'l23', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "106, against ['l17', 'l24', 'l30', 'l35', 'l40', 'l41', 'l42', 'l43']", + "107, C5, ['l18', 'l25', 'l31', 'l36', 'l40', 'l44', 'l45', 'l46']", + "116, murine ['l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l47', 'l48']", + "119, Aβ-associated ['l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l49']", + "120, microglia ['l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l49']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ApoE-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ApoE-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ApoE-deficient" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "small", + "interfering", + "RNA", + "(siRNA)", + "against", + "C5," + ] + }, + "context": { + "val": "organism", + "words": [ + "murine" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "small", + "interfering", + "RNA", + "(siRNA)", + "against", + "C5," + ] + }, + "context": { + "val": "cells", + "words": [ + "Aβ-associated", + "microglia" + ] + } + } + ] + }, + { + "PMID": "30664781", + "TEXT": "ß-thalassemia is caused by ß-globin gene mutations resulting in reduced (β+) or absent (β0) hemoglobin production. Patient life expectancy has recently increased, but the need for chronic transfusions in transfusion-dependent thalassemia (TDT) and iron chelation impairs quality of life1. Allogeneic hematopoietic stem cell (HSC) transplantation represents the curative treatment, with thalassemia-free survival exceeding 80%. However, it is available to a minority of patients and is associated with morbidity, rejection and graft-versus-host disease2. Gene therapy with autologous HSCs modified to express ß-globin represents a potential therapeutic option. We treated three adults and six children with ß0 or severe ß+ mutations in a phase 1/2 trial ( NCT02453477 ) with an intrabone administration of HSCs transduced with the lentiviral vector GLOBE. Rapid hematopoietic recovery with polyclonal multilineage engraftment of vector-marked cells was achieved, with a median of 37.5% (range 12.6-76.4%) in hematopoietic progenitors and a vector copy number per cell (VCN) of 0.58 (range 0.10-1.97) in erythroid precursors at 1 year, in absence of clonal dominance. Transfusion requirement was reduced in the adults. Three out of four evaluable pediatric participants discontinued transfusions after gene therapy and were transfusion independent at the last follow-up. Younger age and persistence of higher VCN in the repopulating hematopoietic cells are associated with better outcome.", + "TAG_DATA": [ + "89, adults {'context': 'B-patient'}", + "92, children {'context': 'I-organism'}", + "112, HSCs {'context': 'B-cells'}", + "113, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "114, with {'perturbing_action': 'I-gene gain-of-function'}", + "115, the {'perturbing_action': 'I-gene gain-of-function'}", + "116, lentiviral {'perturbing_action': 'I-gene gain-of-function'}", + "117, vector {'perturbing_action': 'I-gene gain-of-function'}", + "118, GLOBE. {'perturbing_action': 'I-gene gain-of-function'}", + "128, cells {'context': 'B-cells'}", + "139, hematopoietic {'context': 'B-cells'}", + "140, progenitors {'context': 'I-cells'}", + "154, erythroid {'context': 'B-cells'}", + "155, precursors {'context': 'I-cells'}", + "169, adults. {'context': 'B-patient'}", + "175, pediatric {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "89, adults ['l0']", + "92, children ['l0']", + "112, HSCs ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "113, transduced ['l1', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "114, with ['l2', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "115, the ['l3', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "116, lentiviral ['l4', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "117, vector ['l5', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "118, GLOBE. ['l6', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61']", + "128, cells ['l7', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l63', 'l64', 'l65']", + "139, hematopoietic ['l8', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l62', 'l66', 'l67', 'l68']", + "140, progenitors ['l9', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l63', 'l66', 'l69', 'l70']", + "154, erythroid ['l10', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l64', 'l67', 'l69', 'l71', 'l72']", + "155, precursors ['l11', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l65', 'l68', 'l70', 'l71', 'l73']", + "169, adults. ['l22', 'l32', 'l41', 'l49', 'l56', 'l72', 'l73']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "HSCs", + "cells", + "hematopoietic", + "progenitors", + "erythroid", + "precursors" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "the", + "lentiviral", + "vector", + "GLOBE." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "with", + "the", + "lentiviral", + "vector" + ] + }, + "context": { + "val": "patient", + "words": [ + "adults." + ] + } + } + ] + }, + { + "PMID": "30510251", + "TEXT": "In T lymphocytes, the Wiskott-Aldrich Syndrome protein (WASP) and WASP-interacting-protein (WIP) regulate T cell antigen receptor (TCR) signaling, but their role in lymphoma is largely unknown. Here we show that the expression of WASP and WIP is frequently low or absent in anaplastic large cell lymphoma (ALCL) compared to other T cell lymphomas. In anaplastic lymphoma kinase-positive (ALK+) ALCL, WASP and WIP expression is regulated by ALK oncogenic activity via its downstream mediators STAT3 and C/EBP-β. ALK+ lymphomas were accelerated in WASP- and WIP-deficient mice. In the absence of WASP, active GTP-bound CDC42 was increased and the genetic deletion of one CDC42 allele was sufficient to impair lymphoma growth. WASP-deficient lymphoma showed increased mitogen-activated protein kinase (MAPK) pathway activation that could be exploited as a therapeutic vulnerability. Our findings demonstrate that WASP and WIP are tumor suppressors in T cell lymphoma and suggest that MAP-kinase kinase (MEK) inhibitors combined with ALK inhibitors could achieve a more potent therapeutic effect in ALK+ ALCL.", + "TAG_DATA": [ + "81, WASP- {'perturbing_action': 'B-gene loss-of-function'}", + "82, and {'perturbing_action': 'B-gene loss-of-function'}", + "83, WIP-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "84, mice. {'context': 'B-organism'}", + "87, absence {'perturbing_action': 'B-gene loss-of-function'}", + "88, of {'perturbing_action': 'I-gene loss-of-function'}", + "89, WASP, {'perturbing_action': 'I-gene loss-of-function'}", + "97, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "98, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "99, of {'perturbing_action': 'I-gene loss-of-function'}", + "100, one {'perturbing_action': 'I-gene loss-of-function'}", + "101, CDC42 {'perturbing_action': 'I-gene loss-of-function'}", + "102, allele {'perturbing_action': 'I-gene loss-of-function'}", + "106, impair {'effect': 'B-negative'}", + "107, lymphoma {'context': 'B-neoplasm'}", + "109, WASP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "110, lymphoma {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "81, WASP- ['l0', 'l1', 'l2']", + "82, and ['l0', 'l3', 'l4']", + "83, WIP-deficient ['l1', 'l3', 'l5']", + "84, mice. ['l2', 'l4', 'l5']", + "87, absence ['l6', 'l7', 'l8', 'l9']", + "88, of ['l6', 'l10', 'l11', 'l12']", + "89, WASP, ['l7', 'l10', 'l13', 'l14']", + "97, genetic ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "98, deletion ['l15', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "99, of ['l16', 'l23', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "100, one ['l17', 'l24', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "101, CDC42 ['l18', 'l25', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "102, allele ['l19', 'l26', 'l32', 'l37', 'l41', 'l45', 'l46']", + "106, impair ['l8', 'l11', 'l13', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47']", + "107, lymphoma ['l9', 'l12', 'l14', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l47']", + "109, WASP-deficient ['l48']", + "110, lymphoma ['l22', 'l29', 'l35', 'l40', 'l44', 'l48']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "WASP-", + "and", + "WIP-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "WASP,", + "genetic", + "deletion", + "one", + "CDC42", + "allele" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impair" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "WASP,", + "genetic", + "deletion", + "one", + "CDC42", + "allele", + "WASP-deficient" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lymphoma" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impair" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lymphoma" + ] + } + } + ] + }, + { + "PMID": "30478424", + "TEXT": "Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance.", + "TAG_DATA": [ + "40, epidermal {'perturbing_action': 'B-other'}", + "41, growth {'perturbing_action': 'B-other'}", + "42, factor {'perturbing_action': 'I-other'}", + "43, receptor {'perturbing_action': 'I-other'}", + "44, (EGFR)-mutant {'perturbing_action': 'I-other'}", + "45, lung {'context': 'B-transformed cells'}", + "46, adenocarcinoma {'context': 'I-transformed cells'}", + "47, cells, {'context': 'I-transformed cells'}", + "83, EGFR {'perturbing_action': 'B-pharmacological inhibition'}", + "84, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "87, mitigates {'effect': 'B-negative'}", + "88, drug-induced {'effect': 'B-positive'}", + "89, apoptosis. {'phenotype': 'B-apoptosis'}", + "90, Aurora {'perturbing_action': 'B-pharmacological inhibition'}", + "91, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "92, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "108, preclinical {'context': 'B-organism'}", + "109, models. {'context': 'I-organism'}", + "121, in {'context': 'B-in vitro'}", + "122, vitro, {'context': 'I-in vitro'}", + "123, in {'context': 'B-in vivo'}", + "124, vivo {'context': 'I-in vivo'}", + "130, EGFR-mutant {'perturbing_action': 'B-other'}", + "131, lung {'context': 'B-neoplasm'}", + "132, adenocarcinoma. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "40, epidermal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "41, growth ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "42, factor ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "43, receptor ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "44, (EGFR)-mutant ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "45, lung ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "46, adenocarcinoma ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "47, cells, ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "83, EGFR ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "84, inhibition ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "87, mitigates ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "88, drug-induced ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "89, apoptosis. ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "90, Aurora ['l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "91, kinase ['l78', 'l84', 'l85', 'l86', 'l87', 'l88']", + "92, inhibitors ['l79', 'l84', 'l89', 'l90', 'l91', 'l92']", + "108, preclinical ['l80', 'l85', 'l89', 'l93']", + "109, models. ['l81', 'l86', 'l90', 'l93']", + "121, in ['l82', 'l87', 'l91', 'l94', 'l95', 'l96']", + "122, vitro, ['l83', 'l88', 'l92', 'l94', 'l97', 'l98']", + "123, in ['l95', 'l97', 'l99', 'l100', 'l101', 'l102']", + "124, vivo ['l96', 'l98', 'l99', 'l103', 'l104', 'l105']", + "130, EGFR-mutant ['l100', 'l103', 'l106', 'l107']", + "131, lung ['l101', 'l104', 'l106', 'l108']", + "132, adenocarcinoma. ['l102', 'l105', 'l107', 'l108']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "epidermal", + "growth", + "factor", + "receptor", + "(EGFR)-mutant" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "lung", + "adenocarcinoma", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "epidermal", + "growth", + "factor", + "receptor", + "(EGFR)-mutant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "mitigates" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "epidermal", + "growth", + "factor", + "receptor", + "(EGFR)-mutant" + ] + }, + "effect": { + "val": "positive", + "words": [ + "drug-induced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "epidermal", + "growth", + "factor", + "receptor", + "(EGFR)-mutant" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "lung", + "adenocarcinoma", + "cells," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EGFR", + "inhibition" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "lung", + "adenocarcinoma", + "cells," + ] + }, + "effect": { + "val": "negative", + "words": [ + "mitigates" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "lung", + "adenocarcinoma", + "cells," + ] + }, + "effect": { + "val": "positive", + "words": [ + "drug-induced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "lung", + "adenocarcinoma", + "cells," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EGFR", + "inhibition" + ] + }, + "effect": { + "val": "negative", + "words": [ + "mitigates" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EGFR", + "inhibition" + ] + }, + "effect": { + "val": "positive", + "words": [ + "drug-induced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EGFR", + "inhibition" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "mitigates" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "drug-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Aurora", + "kinase", + "inhibitors" + ] + }, + "context": { + "val": "organism", + "words": [ + "preclinical", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Aurora", + "kinase", + "inhibitors" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "EGFR-mutant" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "EGFR-mutant" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lung", + "adenocarcinoma." + ] + } + } + ] + }, + { + "PMID": "30478421", + "TEXT": "Treatment of prostate cancer (PC) by androgen suppression promotes the emergence of aggressive variants that are androgen receptor (AR) independent. Here we identify the transcription factor ONECUT2 (OC2) as a master regulator of AR networks in metastatic castration-resistant prostate cancer (mCRPC). OC2 acts as a survival factor in mCRPC models, suppresses the AR transcriptional program by direct regulation of AR target genes and the AR licensing factor FOXA1, and activates genes associated with neural differentiation and progression to lethal disease. OC2 appears active in a substantial subset of human prostate adenocarcinoma and neuroendocrine tumors. Inhibition of OC2 by a newly identified small molecule suppresses metastasis in mice. These findings suggest that OC2 displaces AR-dependent growth and survival mechanisms in many cases where AR remains expressed, but where its activity is bypassed. OC2 is also a potential drug target in the metastatic phase of aggressive PC.", + "TAG_DATA": [ + "94, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "95, of {'perturbing_action': 'I-pharmacological inhibition'}", + "96, OC2 {'perturbing_action': 'I-pharmacological inhibition'}", + "97, by {'perturbing_action': 'I-pharmacological inhibition'}", + "98, a {'perturbing_action': 'I-pharmacological inhibition'}", + "99, newly {'perturbing_action': 'I-pharmacological inhibition'}", + "100, identified {'perturbing_action': 'I-pharmacological inhibition'}", + "101, small {'perturbing_action': 'I-pharmacological inhibition'}", + "102, molecule {'perturbing_action': 'I-pharmacological inhibition'}", + "103, suppresses {'effect': 'B-negative'}", + "104, metastasis {'phenotype': 'B-metastasis'}", + "106, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "94, Inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "95, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "96, OC2 ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "97, by ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "98, a ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "99, newly ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "100, identified ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "101, small ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "102, molecule ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "103, suppresses ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "104, metastasis ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "106, mice. ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "OC2", + "by", + "a", + "newly", + "identified", + "small", + "molecule" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "OC2", + "by", + "a", + "newly", + "identified", + "small", + "molecule" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "OC2", + "by", + "a", + "newly", + "identified", + "small", + "molecule" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "30224758", + "TEXT": "Cancer cells rely on dysregulated gene expression. This establishes specific transcriptional addictions that may be therapeutically exploited. Yet, the mechanisms that are ultimately responsible for these addictions are poorly understood. Here, we investigated the transcriptional dependencies of transformed cells to the transcription factors YAP and TAZ. YAP/TAZ physically engage the general coactivator bromodomain-containing protein 4 (BRD4), dictating the genome-wide association of BRD4 to chromatin. YAP/TAZ flag a large set of enhancers with super-enhancer-like functional properties. YAP/TAZ-bound enhancers mediate the recruitment of BRD4 and RNA polymerase II at YAP/TAZ-regulated promoters, boosting the expression of a host of growth-regulating genes. Treatment with small-molecule inhibitors of BRD4 blunts YAP/TAZ pro-tumorigenic activity in several cell or tissue contexts, causes the regression of pre-established, YAP/TAZ-addicted neoplastic lesions and reverts drug resistance. This work sheds light on essential mediators, mechanisms and genome-wide regulatory elements that are responsible for transcriptional addiction in cancer and lays the groundwork for a rational use of BET inhibitors according to YAP/TAZ biology.", + "TAG_DATA": [ + "100, small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "101, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "102, of {'perturbing_action': 'I-pharmacological inhibition'}", + "103, BRD4 {'perturbing_action': 'I-pharmacological inhibition'}", + "112, tissue {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "100, small-molecule ['l0', 'l1', 'l2', 'l3']", + "101, inhibitors ['l0', 'l4', 'l5', 'l6']", + "102, of ['l1', 'l4', 'l7', 'l8']", + "103, BRD4 ['l2', 'l5', 'l7', 'l9']", + "112, tissue ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "inhibitors", + "of", + "BRD4" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tissue" + ] + } + } + ] + }, + { + "PMID": "30061698", + "TEXT": "Sarcopenia, the degenerative loss of skeletal muscle mass, quality and strength, lacks early diagnostic tools and new therapeutic strategies to prevent the frailty-to-disability transition often responsible for the medical institutionalization of elderly individuals. Herein we report that production of the endogenous peptide apelin, induced by muscle contraction, is reduced in an age-dependent manner in humans and rodents and is positively associated with the beneficial effects of exercise in older persons. Mice deficient in either apelin or its receptor (APLNR) presented dramatic alterations in muscle function with increasing age. Various strategies that restored apelin signaling during aging further demonstrated that this peptide considerably enhanced muscle function by triggering mitochondriogenesis, autophagy and anti-inflammatory pathways in myofibers as well as enhancing the regenerative capacity by targeting muscle stem cells. Taken together, these findings revealed positive regulatory feedback between physical activity, apelin and muscle function and identified apelin both as a tool for diagnosis of early sarcopenia and as the target of an innovative pharmacological strategy to prevent age-associated muscle weakness and restore physical autonomy.", + "TAG_DATA": [ + "70, Mice {'context': 'B-organism'}", + "71, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "72, in {'perturbing_action': 'I-gene loss-of-function'}", + "73, either {'perturbing_action': 'I-gene loss-of-function'}", + "74, apelin {'perturbing_action': 'I-gene loss-of-function'}", + "75, or {'perturbing_action': 'I-gene loss-of-function'}", + "76, its {'perturbing_action': 'I-gene loss-of-function'}", + "77, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "78, (APLNR) {'perturbing_action': 'I-gene loss-of-function'}", + "83, muscle {'context': 'B-tissue/organ'}", + "103, muscle {'context': 'B-tissue/organ'}", + "106, triggering {'effect': 'B-positive'}", + "108, autophagy {'phenotype': 'B-autophagy'}", + "113, myofibers {'context': 'B-cells'}", + "123, muscle {'context': 'B-cells'}", + "124, stem {'context': 'I-cells'}", + "125, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "70, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "71, deficient ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "72, in ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "73, either ['l2', 'l14', 'l25', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "74, apelin ['l3', 'l15', 'l26', 'l37', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "75, or ['l4', 'l16', 'l27', 'l38', 'l48', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "76, its ['l5', 'l17', 'l28', 'l39', 'l49', 'l58', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "77, receptor ['l6', 'l18', 'l29', 'l40', 'l50', 'l59', 'l68', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "78, (APLNR) ['l7', 'l19', 'l30', 'l41', 'l51', 'l60', 'l69', 'l77', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "83, muscle ['l8', 'l20', 'l31', 'l42', 'l52', 'l61', 'l70', 'l78', 'l85']", + "103, muscle ['l9', 'l21', 'l32', 'l43', 'l53', 'l62', 'l71', 'l79', 'l86', 'l92', 'l93', 'l94']", + "106, triggering ['l10', 'l22', 'l33', 'l44', 'l54', 'l63', 'l72', 'l80', 'l87', 'l92', 'l95', 'l96']", + "108, autophagy ['l11', 'l23', 'l34', 'l45', 'l55', 'l64', 'l73', 'l81', 'l88', 'l93', 'l95', 'l97']", + "113, myofibers ['l12', 'l24', 'l35', 'l46', 'l56', 'l65', 'l74', 'l82', 'l89', 'l94', 'l96', 'l97']", + "123, muscle ['l98', 'l99']", + "124, stem ['l66', 'l75', 'l83', 'l90', 'l98', 'l100']", + "125, cells. ['l36', 'l47', 'l57', 'l67', 'l76', 'l84', 'l91', 'l99', 'l100']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "either", + "apelin", + "or", + "its", + "receptor", + "(APLNR)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "either", + "apelin", + "or", + "its", + "receptor", + "(APLNR)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscle" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "either", + "apelin", + "or", + "its", + "receptor", + "(APLNR)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "either", + "apelin", + "or", + "its", + "receptor", + "(APLNR)" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "either", + "apelin", + "or", + "its", + "receptor", + "(APLNR)" + ] + }, + "context": { + "val": "cells", + "words": [ + "myofibers", + "cells.", + "stem" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "muscle" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "muscle" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + }, + "context": { + "val": "cells", + "words": [ + "myofibers" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + }, + "context": { + "val": "cells", + "words": [ + "myofibers" + ] + } + } + ] + }, + { + "PMID": "29988128", + "TEXT": "Itch and pain are refractory symptoms of many ocular conditions. Ocular itch is generated mainly in the conjunctiva and is absent from the cornea. In contrast, most ocular pain arises from the cornea. However, the underlying mechanisms remain unknown. Using genetic axonal tracing approaches, we discover distinct sensory innervation patterns between the conjunctiva and cornea. Further genetic and functional analyses in rodent models show that a subset of conjunctival-selective sensory fibers marked by MrgprA3 expression, rather than corneal sensory fibers, mediates ocular itch. Importantly, the actions of both histamine and nonhistamine pruritogens converge onto this unique subset of conjunctiva sensory fibers and enable them to play a key role in mediating itch associated with allergic conjunctivitis. This is distinct from skin itch, in which discrete populations of sensory neurons cooperate to carry itch. Finally, we provide proof of concept that selective silencing of conjunctiva itch-sensing fibers by pruritogen-mediated entry of sodium channel blocker QX-314 is a feasible therapeutic strategy to treat ocular itch in mice. Itch-sensing fibers also innervate the human conjunctiva and allow pharmacological silencing using QX-314. Our results cast new light on the neural mechanisms of ocular itch and open a new avenue for developing therapeutic strategies.", + "TAG_DATA": [ + "61, rodent {'context': 'B-organism'}", + "62, models {'context': 'I-organism'}", + "141, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "143, conjunctiva {'context': 'B-cells'}", + "145, fibers {'context': 'I-cells'}", + "164, mice. {'context': 'B-organism'}", + "165, Itch-sensing {'context': 'B-cells'}", + "170, human {'context': 'B-tissue/organ'}", + "171, conjunctiva {'context': 'I-tissue/organ'}", + "174, pharmacological {'perturbing_action': 'B-rnai/knockdown'}", + "175, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "176, using {'perturbing_action': 'I-rnai/knockdown'}", + "177, QX-314. {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "61, rodent ['l0']", + "62, models ['l0']", + "141, silencing ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "143, conjunctiva ['l1', 'l9', 'l10', 'l11']", + "144, itch-sensing ['l2', 'l9', 'l12', 'l13']", + "145, fibers ['l3', 'l10', 'l12', 'l14']", + "164, mice. ['l4', 'l11', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "165, Itch-sensing ['l5', 'l15', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "166, fibers ['l6', 'l16', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "170, human ['l7', 'l17', 'l20', 'l26', 'l32', 'l33', 'l34', 'l35', 'l36']", + "171, conjunctiva ['l8', 'l18', 'l21', 'l27', 'l32', 'l37', 'l38', 'l39', 'l40']", + "174, pharmacological ['l22', 'l28', 'l33', 'l37', 'l41', 'l42', 'l43']", + "175, silencing ['l23', 'l29', 'l34', 'l38', 'l41', 'l44', 'l45']", + "176, using ['l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l46']", + "177, QX-314. ['l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l46']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "pharmacological", + "using", + "QX-314." + ] + }, + "context": { + "val": "cells", + "words": [ + "conjunctiva", + "fibers", + "Itch-sensing" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "pharmacological", + "using", + "QX-314." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "human", + "conjunctiva" + ] + } + } + ] + }, + { + "PMID": "29988124", + "TEXT": "The oncometabolite (R)-2-hydroxyglutarate (R-2-HG) produced by isocitrate dehydrogenase (IDH) mutations promotes gliomagenesis via DNA and histone methylation. Here, we identify an additional activity of R-2-HG: tumor cell-derived R-2-HG is taken up by T cells where it induces a perturbation of nuclear factor of activated T cells transcriptional activity and polyamine biosynthesis, resulting in suppression of T cell activity. IDH1-mutant gliomas display reduced T cell abundance and altered calcium signaling. Antitumor immunity to experimental syngeneic IDH1-mutant tumors induced by IDH1-specific vaccine or checkpoint inhibition is improved by inhibition of the neomorphic enzymatic function of mutant IDH1. These data attribute a novel, non-tumor cell-autonomous role to an oncometabolite in shaping the tumor immune microenvironment.", + "TAG_DATA": [ + "55, T {'context': 'B-cells'}", + "56, cell {'context': 'B-cells'}", + "58, IDH1-mutant {'perturbing_action': 'B-other'}", + "59, gliomas {'context': 'B-neoplasm'}", + "62, T {'context': 'B-cells'}", + "63, cell {'context': 'B-cells'}", + "73, syngeneic {'perturbing_action': 'B-other'}", + "74, IDH1-mutant {'perturbing_action': 'B-other'}", + "75, tumors {'context': 'B-neoplasm'}", + "93, mutant {'perturbing_action': 'B-other'}", + "94, IDH1. {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "55, T ['l0']", + "56, cell ['l0']", + "58, IDH1-mutant ['l1', 'l2', 'l3']", + "59, gliomas ['l1', 'l4', 'l5']", + "62, T ['l2', 'l4', 'l6']", + "63, cell ['l3', 'l5', 'l6']", + "73, syngeneic ['l7', 'l8']", + "74, IDH1-mutant ['l7', 'l9']", + "75, tumors ['l8', 'l9']", + "93, mutant ['l10']", + "94, IDH1. ['l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "IDH1-mutant", + "syngeneic" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "gliomas", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "IDH1-mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + } + } + ] + }, + { + "PMID": "29967351", + "TEXT": "Fibrosis is a pathological result of a dysfunctional repair response to tissue injury and occurs in a number of organs, including the lungs1. Cellular metabolism regulates tissue repair and remodelling responses to injury2-4. AMPK is a critical sensor of cellular bioenergetics and controls the switch from anabolic to catabolic metabolism5. However, the role of AMPK in fibrosis is not well understood. Here, we demonstrate that in humans with idiopathic pulmonary fibrosis (IPF) and in an experimental mouse model of lung fibrosis, AMPK activity is lower in fibrotic regions associated with metabolically active and apoptosis-resistant myofibroblasts. Pharmacological activation of AMPK in myofibroblasts from lungs of humans with IPF display lower fibrotic activity, along with enhanced mitochondrial biogenesis and normalization of sensitivity to apoptosis. In a bleomycin model of lung fibrosis in mice, metformin therapeutically accelerates the resolution of well-established fibrosis in an AMPK-dependent manner. These studies implicate deficient AMPK activation in non-resolving, pathologic fibrotic processes, and support a role for metformin (or other AMPK activators) to reverse established fibrosis by facilitating deactivation and apoptosis of myofibroblasts.", + "TAG_DATA": [ + "95, Pharmacological {'perturbing_action': 'B-pharmacological augmentation'}", + "96, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "97, of {'perturbing_action': 'I-pharmacological augmentation'}", + "98, AMPK {'perturbing_action': 'I-pharmacological augmentation'}", + "100, myofibroblasts {'context': 'B-cells'}", + "121, apoptosis. {'phenotype': 'B-apoptosis'}", + "130, mice, {'context': 'B-organism'}", + "169, facilitating {'effect': 'B-positive'}", + "174, myofibroblasts. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "95, Pharmacological ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "96, activation ['l0', 'l6', 'l7', 'l8', 'l9']", + "97, of ['l1', 'l6', 'l10', 'l11', 'l12']", + "98, AMPK ['l2', 'l7', 'l10', 'l13', 'l14']", + "100, myofibroblasts ['l3', 'l8', 'l11', 'l13', 'l15']", + "121, apoptosis. ['l4', 'l9', 'l12', 'l14', 'l15']", + "130, mice, ['l5']", + "169, facilitating ['l16', 'l17']", + "172, apoptosis ['l16', 'l18']", + "174, myofibroblasts. ['l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Pharmacological", + "activation", + "of", + "AMPK" + ] + }, + "context": { + "val": "cells", + "words": [ + "myofibroblasts" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Pharmacological", + "activation", + "of", + "AMPK" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Pharmacological" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "myofibroblasts" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "facilitating" + ] + }, + "context": { + "val": "cells", + "words": [ + "myofibroblasts." + ] + } + } + ] + }, + { + "PMID": "29942089", + "TEXT": "The association between altered gut microbiota, intestinal permeability, inflammation and cardiometabolic diseases is becoming increasingly clear but remains poorly understood1,2. Indoleamine 2,3-dioxygenase is an enzyme induced in many types of immune cells, including macrophages in response to inflammatory stimuli, and catalyzes the degradation of tryptophan along the kynurenine pathway. Indoleamine 2,3-dioxygenase activity is better known for its suppression of effector T cell immunity and its activation of regulatory T cells3,4. However, high indoleamine 2,3-dioxygenase activity predicts worse cardiovascular outcome5-9 and may promote atherosclerosis and vascular inflammation6, suggesting a more complex role in chronic inflammatory settings. Indoleamine 2,3-dioxygenase activity is also increased in obesity10-13, yet its role in metabolic disease is still unexplored. Here, we show that obesity is associated with an increase of intestinal indoleamine 2,3-dioxygenase activity, which shifts tryptophan metabolism from indole derivative and interleukin-22 production toward kynurenine production. Indoleamine 2,3-dioxygenase deletion or inhibition improves insulin sensitivity, preserves the gut mucosal barrier, decreases endotoxemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. These beneficial effects are due to rewiring of tryptophan metabolism toward a microbiota-dependent production of interleukin-22 and are abrogated after treatment with a neutralizing anti-interleukin-22 antibody. In summary, we identify an unexpected function of indoleamine 2,3-dioxygenase in the fine tuning of intestinal tryptophan metabolism with major consequences on microbiota-dependent control of metabolic disease, which suggests indoleamine 2,3-dioxygenase as a potential therapeutic target.", + "TAG_DATA": [ + "140, Indoleamine {'perturbing_action': 'B-gene loss-of-function'}", + "141, 2,3-dioxygenase {'perturbing_action': 'I-gene loss-of-function'}", + "142, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "163, liver {'context': 'B-tissue/organ'}", + "165, adipose {'context': 'I-tissue/organ'}", + "166, tissues. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "140, Indoleamine ['l0', 'l1', 'l2', 'l3', 'l4']", + "141, 2,3-dioxygenase ['l0', 'l5', 'l6', 'l7', 'l8']", + "142, deletion ['l1', 'l5', 'l9', 'l10', 'l11']", + "163, liver ['l2', 'l6', 'l9', 'l12', 'l13']", + "165, adipose ['l3', 'l7', 'l10', 'l12', 'l14']", + "166, tissues. ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Indoleamine", + "2,3-dioxygenase", + "deletion" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver", + "adipose", + "tissues." + ] + } + } + ] + }, + { + "PMID": "29892067", + "TEXT": "Here, we report that genome editing by CRISPR-Cas9 induces a p53-mediated DNA damage response and cell cycle arrest in immortalized human retinal pigment epithelial cells, leading to a selection against cells with a functional p53 pathway. Inhibition of p53 prevents the damage response and increases the rate of homologous recombination from a donor template. These results suggest that p53 inhibition may improve the efficiency of genome editing of untransformed cells and that p53 function should be monitored when developing cell-based therapies utilizing CRISPR-Cas9.", + "TAG_DATA": [ + "8, induces {'effect': 'B-positive'}", + "15, cell {'phenotype': 'B-cell cycle arrest'}", + "16, cycle {'phenotype': 'I-cell cycle arrest'}", + "17, arrest {'phenotype': 'I-cell cycle arrest'}", + "19, immortalized {'context': 'B-cells'}", + "20, human {'context': 'I-cells'}", + "21, retinal {'context': 'I-cells'}", + "22, pigment {'context': 'I-cells'}", + "23, epithelial {'context': 'I-cells'}", + "24, cells, {'context': 'I-cells'}", + "30, cells {'context': 'B-cells'}", + "36, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "37, of {'perturbing_action': 'I-pharmacological inhibition'}", + "38, p53 {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "8, induces ['l0', 'l1', 'l2']", + "15, cell ['l0', 'l3', 'l4', 'l5']", + "16, cycle ['l1', 'l3', 'l6', 'l7']", + "17, arrest ['l2', 'l4', 'l6']", + "19, immortalized ['l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "20, human ['l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "21, retinal ['l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "22, pigment ['l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "23, epithelial ['l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "24, cells, ['l5', 'l7', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "30, cells ['l13', 'l18', 'l22', 'l25', 'l27', 'l28']", + "36, Inhibition ['l29', 'l30']", + "37, of ['l29', 'l31']", + "38, p53 ['l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells," + ] + } + } + ] + }, + { + "PMID": "29875463", + "TEXT": "Patients with metastatic cancer experience a severe loss of skeletal muscle mass and function known as cachexia. Cachexia is associated with poor prognosis and accelerated death in patients with cancer, yet its underlying mechanisms remain poorly understood. Here, we identify the metal-ion transporter ZRT- and IRT-like protein 14 (ZIP14) as a critical mediator of cancer-induced cachexia. ZIP14 is upregulated in cachectic muscles of mice and in patients with metastatic cancer and can be induced by TNF-α and TGF-β cytokines. Strikingly, germline ablation or muscle-specific depletion of Zip14 markedly reduces muscle atrophy in metastatic cancer models. We find that ZIP14-mediated zinc uptake in muscle progenitor cells represses the expression of MyoD and Mef2c and blocks muscle-cell differentiation. Importantly, ZIP14-mediated zinc accumulation in differentiated muscle cells induces myosin heavy chain loss. These results highlight a previously unrecognized role for altered zinc homeostasis in metastatic cancer-induced muscle wasting and implicate ZIP14 as a therapeutic target for its treatment.", + "TAG_DATA": [ + "83, muscle-specific {'perturbing_action': 'B-gene loss-of-function'}", + "84, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "85, of {'perturbing_action': 'I-gene loss-of-function'}", + "86, Zip14 {'perturbing_action': 'I-gene loss-of-function'}", + "92, metastatic {'context': 'B-neoplasm'}", + "93, cancer {'context': 'I-neoplasm'}", + "94, models. {'context': 'I-neoplasm'}", + "102, muscle {'context': 'B-cells'}", + "103, progenitor {'context': 'I-cells'}", + "104, cells {'context': 'I-cells'}", + "113, blocks {'effect': 'B-negative'}", + "114, muscle-cell {'context': 'B-cells'}", + "115, differentiation. {'phenotype': 'B-differentiation'}", + "121, differentiated {'context': 'B-cells'}", + "122, muscle {'context': 'I-cells'}", + "123, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "83, muscle-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "84, depletion ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "85, of ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "86, Zip14 ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "92, metastatic ['l3', 'l14', 'l24', 'l33', 'l42', 'l43']", + "93, cancer ['l4', 'l15', 'l25', 'l34', 'l42', 'l44']", + "94, models. ['l5', 'l16', 'l26', 'l35', 'l43', 'l44']", + "102, muscle ['l6', 'l17', 'l27', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49']", + "103, progenitor ['l7', 'l18', 'l28', 'l37', 'l45', 'l50', 'l51', 'l52', 'l53']", + "104, cells ['l8', 'l19', 'l29', 'l38', 'l46', 'l50', 'l54', 'l55', 'l56']", + "113, blocks ['l9', 'l20', 'l30', 'l39', 'l47', 'l51', 'l54', 'l57', 'l58']", + "114, muscle-cell ['l10', 'l21', 'l31', 'l40', 'l48', 'l52', 'l55', 'l57', 'l59']", + "115, differentiation. ['l11', 'l22', 'l32', 'l41', 'l49', 'l53', 'l56', 'l58', 'l59']", + "121, differentiated ['l60', 'l61']", + "122, muscle ['l60', 'l62']", + "123, cells ['l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "muscle-specific", + "depletion", + "of", + "Zip14" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "metastatic", + "cancer", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "muscle-specific", + "depletion", + "of", + "Zip14" + ] + }, + "context": { + "val": "cells", + "words": [ + "muscle", + "progenitor", + "cells", + "muscle-cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "muscle-specific", + "depletion", + "of", + "Zip14" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "muscle-specific", + "depletion", + "of", + "Zip14" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "muscle", + "progenitor", + "cells", + "muscle-cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "muscle", + "progenitor", + "cells", + "muscle-cell" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + } + ] + }, + { + "PMID": "29785024", + "TEXT": "Recent studies have identified a specialized subset of CD31hiendomucinhi (CD31hiEMCNhi) vascular endothelium that positively regulates bone formation. However, it remains unclear how CD31hiEMCNhi endothelium levels are coupled to anabolic bone formation. Mice with an osteoblast-specific deletion of Shn3, which have markedly elevated bone formation, demonstrated an increase in CD31hiEMCNhi endothelium. Transcriptomic analysis identified SLIT3 as an osteoblast-derived, SHN3-regulated proangiogenic factor. Genetic deletion of Slit3 reduced skeletal CD31hiEMCNhi endothelium, resulted in low bone mass because of impaired bone formation and partially reversed the high bone mass phenotype of Shn3-/- mice. This coupling between osteoblasts and CD31hiEMCNhi endothelium is essential for bone healing, as shown by defective fracture repair in SLIT3-mutant mice and enhanced fracture repair in SHN3-mutant mice. Finally, administration of recombinant SLIT3 both enhanced bone fracture healing and counteracted bone loss in a mouse model of postmenopausal osteoporosis. Thus, drugs that target the SLIT3 pathway may represent a new approach for vascular-targeted osteoanabolic therapy to treat bone loss.", + "TAG_DATA": [ + "31, Mice {'context': 'B-organism'}", + "34, osteoblast-specific {'perturbing_action': 'B-gene loss-of-function'}", + "35, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "36, of {'perturbing_action': 'I-gene loss-of-function'}", + "37, Shn3, {'perturbing_action': 'I-gene loss-of-function'}", + "60, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "61, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "62, of {'perturbing_action': 'I-gene loss-of-function'}", + "63, Slit3 {'perturbing_action': 'I-gene loss-of-function'}", + "87, Shn3-/- {'perturbing_action': 'B-gene loss-of-function'}", + "88, mice. {'context': 'B-organism'}", + "108, SLIT3-mutant {'perturbing_action': 'B-other'}", + "109, mice {'context': 'B-organism'}", + "115, SHN3-mutant {'perturbing_action': 'B-other'}", + "116, mice. {'context': 'B-organism'}", + "133, mouse {'context': 'B-organism'}", + "134, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "31, Mice ['l0', 'l1', 'l2', 'l3']", + "34, osteoblast-specific ['l0', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "35, deletion ['l1', 'l4', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "36, of ['l2', 'l5', 'l11', 'l17', 'l18', 'l19', 'l20', 'l21']", + "37, Shn3, ['l3', 'l6', 'l12', 'l17', 'l22', 'l23']", + "60, Genetic ['l7', 'l13', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "61, deletion ['l8', 'l14', 'l19', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "62, of ['l9', 'l15', 'l20', 'l22', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "63, Slit3 ['l10', 'l16', 'l21', 'l23', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "87, Shn3-/- ['l27', 'l32', 'l36', 'l39', 'l42', 'l43', 'l44', 'l45']", + "88, mice. ['l28', 'l33', 'l37', 'l40', 'l42', 'l46', 'l47']", + "108, SLIT3-mutant ['l43', 'l46', 'l48', 'l49', 'l50']", + "109, mice ['l29', 'l34', 'l38', 'l41', 'l44', 'l47', 'l48', 'l51']", + "115, SHN3-mutant ['l49', 'l52']", + "116, mice. ['l45', 'l50', 'l51', 'l52']", + "133, mouse ['l53']", + "134, model ['l53']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice", + "mice.", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "osteoblast-specific", + "deletion", + "of", + "Shn3,", + "Genetic", + "Slit3", + "Shn3-/-" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "SLIT3-mutant", + "SHN3-mutant" + ] + } + } + ] + }, + { + "PMID": "29736027", + "TEXT": "Depression, a devastating psychiatric disorder, is a leading cause of disability worldwide. Current antidepressants address specific symptoms of the disease, but there is vast room for improvement 1 . In this respect, new compounds that act beyond classical antidepressants to target signal transduction pathways governing synaptic plasticity and cellular resilience are highly warranted2-4. The extracellular signal-regulated kinase (ERK) pathway is implicated in mood regulation5-7, but its pleiotropic functions and lack of target specificity prohibit optimal drug development. Here, we identified the transcription factor ELK-1, an ERK downstream partner 8 , as a specific signaling module in the pathophysiology and treatment of depression that can be targeted independently of ERK. ELK1 mRNA was upregulated in postmortem hippocampal tissues from depressed suicides; in blood samples from depressed individuals, failure to reduce ELK1 expression was associated with resistance to treatment. In mice, hippocampal ELK-1 overexpression per se produced depressive behaviors; conversely, the selective inhibition of ELK-1 activation prevented depression-like molecular, plasticity and behavioral states induced by stress. Our work stresses the importance of target selectivity for a successful approach for signal-transduction-based antidepressants, singles out ELK-1 as a depression-relevant transducer downstream of ERK and brings proof-of-concept evidence for the druggability of ELK-1.", + "TAG_DATA": [ + "138, mice, {'context': 'B-organism'}", + "139, hippocampal {'perturbing_action': 'B-gene gain-of-function'}", + "140, ELK-1 {'perturbing_action': 'I-gene gain-of-function'}", + "141, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "149, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "150, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "151, of {'perturbing_action': 'I-pharmacological inhibition'}", + "152, ELK-1 {'perturbing_action': 'I-pharmacological inhibition'}", + "153, activation {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "138, mice, ['l0', 'l1', 'l2']", + "139, hippocampal ['l0', 'l3', 'l4']", + "140, ELK-1 ['l1', 'l3', 'l5']", + "141, overexpression ['l2', 'l4', 'l5']", + "149, selective ['l6', 'l7', 'l8', 'l9']", + "150, inhibition ['l6', 'l10', 'l11', 'l12']", + "151, of ['l7', 'l10', 'l13', 'l14']", + "152, ELK-1 ['l8', 'l11', 'l13', 'l15']", + "153, activation ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hippocampal", + "ELK-1", + "overexpression" + ] + } + } + ] + }, + { + "PMID": "29662202", + "TEXT": "Major depressive disorder (MDD) is considered a 'circuitopathy', and brain stimulation therapies hold promise for ameliorating MDD symptoms, including hippocampal dysfunction. It is unknown whether stimulation of upstream hippocampal circuitry, such as the entorhinal cortex (Ent), is antidepressive, although Ent stimulation improves learning and memory in mice and humans. Here we show that molecular targeting (Ent-specific knockdown of a psychosocial stress-induced protein) and chemogenetic stimulation of Ent neurons induce antidepressive-like effects in mice. Mechanistically, we show that Ent-stimulation-induced antidepressive-like behavior relies on the generation of new hippocampal neurons. Thus, controlled stimulation of Ent hippocampal afferents is antidepressive via increased hippocampal neurogenesis. These findings emphasize the power and potential of Ent glutamatergic afferent stimulation-previously well-known for its ability to influence learning and memory-for MDD treatment.", + "TAG_DATA": [ + "56, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "57, of {'perturbing_action': 'I-rnai/knockdown'}", + "58, a {'perturbing_action': 'I-rnai/knockdown'}", + "59, psychosocial {'perturbing_action': 'I-rnai/knockdown'}", + "60, stress-induced {'perturbing_action': 'I-rnai/knockdown'}", + "61, protein) {'perturbing_action': 'I-rnai/knockdown'}", + "66, Ent {'context': 'B-cells'}", + "67, neurons {'context': 'I-cells'}", + "72, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, knockdown ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "57, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "58, a ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "59, psychosocial ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "60, stress-induced ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "61, protein) ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "66, Ent ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "67, neurons ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "72, mice. ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "87, neurons. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "a", + "psychosocial", + "stress-induced", + "protein)" + ] + }, + "context": { + "val": "cells", + "words": [ + "Ent", + "neurons" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "a", + "psychosocial", + "stress-induced", + "protein)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "29662200", + "TEXT": "Sphingosine-1-phosphate (S1P) signaling influences bone metabolism, but its therapeutic potential in bone disorders has remained unexplored. We show that raising S1P levels in adult mice through conditionally deleting or pharmacologically inhibiting S1P lyase, the sole enzyme responsible for irreversibly degrading S1P, markedly increased bone formation, mass and strength and substantially decreased white adipose tissue. S1P signaling through S1P2 potently stimulated osteoblastogenesis at the expense of adipogenesis by inversely regulating osterix and PPAR-γ, and it simultaneously inhibited osteoclastogenesis by inducing osteoprotegerin through newly discovered p38-GSK3β-β-catenin and WNT5A-LRP5 pathways. Accordingly, S1P2-deficient mice were osteopenic and obese. In ovariectomy-induced osteopenia, S1P lyase inhibition was as effective as intermittent parathyroid hormone (iPTH) treatment in increasing bone mass and was superior to iPTH in enhancing bone strength. Furthermore, lyase inhibition in mice successfully corrected severe genetic osteoporosis caused by osteoprotegerin deficiency. Human data from 4,091 participants of the SHIP-Trend population-based study revealed a positive association between serum levels of S1P and bone formation markers, but not resorption markers. Furthermore, serum S1P levels were positively associated with serum calcium , negatively with PTH , and curvilinearly with body mass index. Bone stiffness, as determined through quantitative ultrasound, was inversely related to levels of both S1P and the bone formation marker PINP, suggesting that S1P stimulates osteoanabolic activity to counteract decreasing bone quality. S1P-based drugs should be considered as a promising therapeutic avenue for the treatment of osteoporotic diseases.", + "TAG_DATA": [ + "23, adult {'context': 'B-organism'}", + "24, mice {'context': 'I-organism'}", + "52, adipose {'context': 'I-tissue/organ'}", + "53, tissue. {'context': 'I-tissue/organ'}", + "86, S1P2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "87, mice {'context': 'B-organism'}", + "124, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "23, adult ['l0', 'l1', 'l2', 'l3']", + "24, mice ['l0', 'l4', 'l5', 'l6']", + "51, white ['l1', 'l4', 'l7', 'l8']", + "52, adipose ['l2', 'l5', 'l7', 'l9']", + "53, tissue. ['l3', 'l6', 'l8', 'l9']", + "86, S1P2-deficient ['l10']", + "87, mice ['l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "S1P2-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "29578539", + "TEXT": "Glucagon levels increase under homeostatic, fasting conditions, promoting the release of glucose from the liver by accelerating the breakdown of glycogen (also known as glycogenolysis). Glucagon also enhances gluconeogenic flux, including from an increase in the hepatic consumption of amino acids. In type 2 diabetes, dysregulated glucagon signaling contributes to the elevated hepatic glucose output and fasting hyperglycemia that occur in this condition. Yet, the mechanism by which glucagon stimulates gluconeogenesis remains incompletely understood. Contrary to the prevailing belief that glucagon acts primarily on cytoplasmic and nuclear targets, we find glucagon-dependent stimulation of mitochondrial anaplerotic flux from glutamine that increases the contribution of this amino acid to the carbons of glucose generated during gluconeogenesis. This enhanced glucose production is dependent on protein kinase A (PKA) and is associated with glucagon-stimulated calcium release from the endoplasmic reticulum, activation of mitochondrial α-ketoglutarate dehydrogenase, and increased glutaminolysis. Mice with reduced levels of hepatic glutaminase 2 (GLS2), the enzyme that catalyzes the first step in glutamine metabolism, show lower glucagon-stimulated glutamine-to-glucose flux in vivo, and GLS2 knockout results in higher fasting plasma glucagon and glutamine levels with lower fasting blood glucose levels in insulin-resistant conditions. As found in genome-wide association studies (GWAS), human genetic variation in the region of GLS2 is associated with higher fasting plasma glucose; here we show in human cryopreserved primary hepatocytes in vitro that these natural gain-of-function missense mutations in GLS2 result in higher glutaminolysis and glucose production. These data emphasize the importance of gluconeogenesis from glutamine, particularly in pathological states of increased glucagon signaling, while suggesting a possible new therapeutic avenue to treat hyperglycemia.", + "TAG_DATA": [ + "144, Mice {'context': 'B-organism'}", + "168, in {'context': 'B-in vivo'}", + "169, vivo, {'context': 'I-in vivo'}", + "171, GLS2 {'perturbing_action': 'B-gene loss-of-function'}", + "172, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "217, human {'context': 'B-cells'}", + "218, cryopreserved {'context': 'I-cells'}", + "219, primary {'context': 'I-cells'}", + "220, hepatocytes {'context': 'I-cells'}", + "221, in {'context': 'B-in vitro'}", + "222, vitro {'context': 'I-in vitro'}", + "228, mutations {'perturbing_action': 'I-gene loss-of-function'}", + "229, in {'perturbing_action': 'I-rnai/knockdown'}", + "230, GLS2 {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "144, Mice ['l0', 'l1']", + "168, in ['l0', 'l2']", + "169, vivo, ['l1', 'l2']", + "171, GLS2 ['l3']", + "172, knockout ['l3']", + "217, human ['l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "218, cryopreserved ['l4', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "219, primary ['l5', 'l13', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "220, hepatocytes ['l6', 'l14', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "221, in ['l7', 'l15', 'l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "222, vitro ['l8', 'l16', 'l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "227, missense ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "228, mutations ['l10', 'l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l46', 'l47']", + "229, in ['l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l48']", + "230, GLS2 ['l12', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "cryopreserved", + "primary", + "hepatocytes" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "mutations" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "cryopreserved", + "primary", + "hepatocytes" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "in", + "GLS2" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "mutations" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "in", + "GLS2" + ] + } + } + ] + }, + { + "PMID": "29529015", + "TEXT": "Breast tumors of the basal-like, hormone receptor-negative subtype remain an unmet clinical challenge, as there is high rate of recurrence and poor survival in patients following treatment. Coevolution of the malignant mammary epithelium and its underlying stroma instigates cancer-associated fibroblasts (CAFs) to support most, if not all, hallmarks of cancer progression. Here we delineate a previously unappreciated role for CAFs as determinants of the molecular subtype of breast cancer. We identified paracrine crosstalk between cancer cells expressing platelet-derived growth factor (PDGF)-CC and CAFs expressing the cognate receptors in human basal-like mammary carcinomas. Genetic or pharmacological intervention of PDGF-CC activity in mouse models of cancer resulted in conversion of basal-like breast cancers into a hormone receptor-positive state that enhanced sensitivity to endocrine therapy in previously resistant tumors. We conclude that specification of breast cancer to the basal-like subtype is under microenvironmental control and is therapeutically actionable.", + "TAG_DATA": [ + "98, activity {'perturbing_action': 'I-pharmacological augmentation'}", + "100, mouse {'context': 'B-neoplasm'}", + "101, models {'context': 'I-neoplasm'}", + "102, of {'context': 'I-neoplasm'}", + "103, cancer {'context': 'I-neoplasm'}", + "108, basal-like {'context': 'B-neoplasm'}", + "109, breast {'context': 'I-neoplasm'}", + "110, cancers {'context': 'I-neoplasm'}", + "125, tumors. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "95, intervention ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "97, PDGF-CC ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "98, activity ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "100, mouse ['l2', 'l11', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "101, models ['l3', 'l12', 'l20', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "102, of ['l4', 'l13', 'l21', 'l27', 'l33', 'l39', 'l40', 'l41', 'l42']", + "103, cancer ['l5', 'l14', 'l22', 'l28', 'l34', 'l39', 'l43', 'l44', 'l45']", + "108, basal-like ['l6', 'l15', 'l23', 'l29', 'l35', 'l40', 'l43', 'l46', 'l47', 'l48']", + "109, breast ['l7', 'l16', 'l24', 'l30', 'l36', 'l41', 'l44', 'l46', 'l49', 'l50']", + "110, cancers ['l8', 'l17', 'l25', 'l31', 'l37', 'l42', 'l45', 'l47', 'l49', 'l51']", + "125, tumors. ['l9', 'l18', 'l32', 'l38', 'l48', 'l50', 'l51']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activity" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "models", + "of", + "cancer", + "basal-like", + "breast", + "cancers" + ] + } + } + ] + }, + { + "PMID": "29431744", + "TEXT": "Deficits in Schwann cell-mediated remyelination impair functional restoration after nerve damage, contributing to peripheral neuropathies. The mechanisms mediating block of remyelination remain elusive. Here, through small-molecule screening focusing on epigenetic modulators, we identified histone deacetylase 3 (HDAC3; a histone-modifying enzyme) as a potent inhibitor of peripheral myelinogenesis. Inhibition of HDAC3 enhanced myelin growth and regeneration and improved functional recovery after peripheral nerve injury in mice. HDAC3 antagonizes the myelinogenic neuregulin-PI3K-AKT signaling axis. Moreover, genome-wide profiling analyses revealed that HDAC3 represses promyelinating programs through epigenetic silencing while coordinating with p300 histone acetyltransferase to activate myelination-inhibitory programs that include the HIPPO signaling effector TEAD4 to inhibit myelin growth. Schwann cell-specific deletion of either Hdac3 or Tead4 in mice resulted in an elevation of myelin thickness in sciatic nerves. Thus, our findings identify the HDAC3-TEAD4 network as a dual-function switch of cell-intrinsic inhibitory machinery that counters myelinogenic signals and maintains peripheral myelin homeostasis, highlighting the therapeutic potential of transient HDAC3 inhibition for improving peripheral myelin repair.", + "TAG_DATA": [ + "47, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "48, of {'perturbing_action': 'I-pharmacological inhibition'}", + "49, HDAC3 {'perturbing_action': 'I-pharmacological inhibition'}", + "64, mice. {'context': 'B-organism'}", + "106, Schwann {'perturbing_action': 'B-gene loss-of-function'}", + "107, cell-specific {'perturbing_action': 'I-gene loss-of-function'}", + "108, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "109, of {'perturbing_action': 'I-gene loss-of-function'}", + "110, either {'perturbing_action': 'I-gene loss-of-function'}", + "111, Hdac3 {'perturbing_action': 'I-gene loss-of-function'}", + "112, or {'perturbing_action': 'I-gene loss-of-function'}", + "113, Tead4 {'perturbing_action': 'I-gene loss-of-function'}", + "115, mice {'context': 'B-organism'}", + "124, sciatic {'context': 'B-tissue/organ'}", + "125, nerves. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "47, Inhibition ['l0', 'l1', 'l2']", + "48, of ['l0', 'l3', 'l4']", + "49, HDAC3 ['l1', 'l3', 'l5']", + "64, mice. ['l2', 'l4', 'l5']", + "106, Schwann ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "107, cell-specific ['l6', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "108, deletion ['l7', 'l16', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "109, of ['l8', 'l17', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "110, either ['l9', 'l18', 'l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "111, Hdac3 ['l10', 'l19', 'l27', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "112, or ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "113, Tead4 ['l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57']", + "115, mice ['l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l58', 'l59']", + "124, sciatic ['l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58', 'l60']", + "125, nerves. ['l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "HDAC3" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Schwann", + "cell-specific", + "deletion", + "of", + "either", + "Hdac3", + "or", + "Tead4" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Schwann", + "cell-specific", + "deletion", + "of", + "either", + "Hdac3", + "or", + "Tead4" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "sciatic", + "nerves." + ] + } + } + ] + }, + { + "PMID": "29400713", + "TEXT": "Adipocytes possess remarkable adaptive capacity to respond to nutrient excess, fasting or cold exposure, and they are thus an important cell type for the maintenance of proper metabolic health. Although the endoplasmic reticulum (ER) is a critical organelle for cellular homeostasis, the mechanisms that mediate adaptation of the ER to metabolic challenges in adipocytes are unclear. Here we show that brown adipose tissue (BAT) thermogenic function requires an adaptive increase in proteasomal activity to secure cellular protein quality control, and we identify the ER-localized transcription factor nuclear factor erythroid 2-like 1 (Nfe2l1, also known as Nrf1) as a critical driver of this process. We show that cold adaptation induces Nrf1 in BAT to increase proteasomal activity and that this is crucial for maintaining ER homeostasis and cellular integrity, specifically when the cells are in a state of high thermogenic activity. In mice, under thermogenic conditions, brown-adipocyte-specific deletion of Nfe2l1 (Nrf1) resulted in ER stress, tissue inflammation, markedly diminished mitochondrial function and whitening of the BAT. In mouse models of both genetic and dietary obesity, stimulation of proteasomal activity by exogenously expressing Nrf1 or by treatment with the proteasome activator PA28α in BAT resulted in improved insulin sensitivity. In conclusion, Nrf1 emerges as a novel guardian of brown adipocyte function, providing increased proteometabolic quality control for adapting to cold or to obesity.", + "TAG_DATA": [ + "141, mice, {'context': 'B-organism'}", + "145, brown-adipocyte-specific {'perturbing_action': 'B-gene loss-of-function'}", + "146, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "147, of {'perturbing_action': 'I-gene loss-of-function'}", + "148, Nfe2l1 {'perturbing_action': 'I-gene loss-of-function'}", + "149, (Nrf1) {'perturbing_action': 'I-gene loss-of-function'}", + "166, mouse {'context': 'B-organism'}", + "167, models {'context': 'I-organism'}", + "179, exogenously {'perturbing_action': 'B-gene gain-of-function'}", + "180, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "181, Nrf1 {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "141, mice, ['l0', 'l1', 'l2', 'l3', 'l4']", + "145, brown-adipocyte-specific ['l0', 'l5', 'l6', 'l7', 'l8']", + "146, deletion ['l1', 'l5', 'l9', 'l10', 'l11']", + "147, of ['l2', 'l6', 'l9', 'l12', 'l13']", + "148, Nfe2l1 ['l3', 'l7', 'l10', 'l12', 'l14']", + "149, (Nrf1) ['l4', 'l8', 'l11', 'l13', 'l14']", + "166, mouse ['l15', 'l16', 'l17', 'l18']", + "167, models ['l15', 'l19', 'l20', 'l21']", + "179, exogenously ['l16', 'l19', 'l22', 'l23']", + "180, expressing ['l17', 'l20', 'l22', 'l24']", + "181, Nrf1 ['l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "brown-adipocyte-specific", + "deletion", + "of", + "Nfe2l1", + "(Nrf1)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "exogenously", + "expressing", + "Nrf1" + ] + } + } + ] + }, + { + "PMID": "29400711", + "TEXT": "Diffuse white-matter disease associated with small-vessel disease and dementia is prevalent in the elderly. The biological mechanisms, however, remain elusive. Using pericyte-deficient mice, magnetic resonance imaging, viral-based tract-tracing, and behavior and tissue analysis, we found that pericyte degeneration disrupted white-matter microcirculation, resulting in an accumulation of toxic blood-derived fibrin(ogen) deposits and blood-flow reductions, which triggered a loss of myelin, axons and oligodendrocytes. This disrupted brain circuits, leading to white-matter functional deficits before neuronal loss occurs. Fibrinogen and fibrin fibrils initiated autophagy-dependent cell death in oligodendrocyte and pericyte cultures, whereas pharmacological and genetic manipulations of systemic fibrinogen levels in pericyte-deficient, but not control mice, influenced the degree of white-matter fibrin(ogen) deposition, pericyte degeneration, vascular pathology and white-matter changes. Thus, our data indicate that pericytes control white-matter structure and function, which has implications for the pathogenesis and treatment of human white-matter disease associated with small-vessel disease.", + "TAG_DATA": [ + "21, pericyte-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "22, mice, {'context': 'B-organism'}", + "79, initiated {'effect': 'B-positive'}", + "81, cell {'phenotype': 'B-cell death'}", + "82, death {'phenotype': 'I-cell death'}", + "84, oligodendrocyte {'context': 'B-cells'}", + "85, and {'context': 'I-cells'}", + "86, pericyte {'context': 'I-cells'}", + "87, cultures, {'context': 'I-cells'}", + "98, pericyte-deficient, {'perturbing_action': 'B-gene loss-of-function'}", + "102, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "21, pericyte-deficient ['l0']", + "22, mice, ['l0']", + "79, initiated ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "81, cell ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "82, death ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "84, oligodendrocyte ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "85, and ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "86, pericyte ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "87, cultures, ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']", + "98, pericyte-deficient, ['l22']", + "102, mice, ['l22']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pericyte-deficient", + "pericyte-deficient," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiated" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiated" + ] + }, + "context": { + "val": "cells", + "words": [ + "oligodendrocyte", + "and", + "pericyte", + "cultures," + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "oligodendrocyte", + "and", + "pericyte", + "cultures," + ] + } + } + ] + }, + { + "PMID": "29309056", + "TEXT": "There is a substantial unmet clinical need for new strategies to protect the hematopoietic stem cell (HSC) pool and regenerate hematopoiesis after radiation injury from either cancer therapy or accidental exposure. Increasing evidence suggests that sex hormones, beyond their role in promoting sexual dimorphism, regulate HSC self-renewal, differentiation, and proliferation. We and others have previously reported that sex-steroid ablation promotes bone marrow (BM) lymphopoiesis and HSC recovery in aged and immunodepleted mice. Here we found that a luteinizing hormone (LH)-releasing hormone antagonist (LHRH-Ant), currently in wide clinical use for sex-steroid inhibition, promoted hematopoietic recovery and mouse survival when administered 24 h after an otherwise-lethal dose of total-body irradiation (L-TBI). Unexpectedly, this protective effect was independent of sex steroids and instead relied on suppression of LH levels. Human and mouse long-term self-renewing HSCs (LT-HSCs) expressed high levels of the LH/choriogonadotropin receptor (LHCGR) and expanded ex vivo when stimulated with LH. In contrast, the suppression of LH after L-TBI inhibited entry of HSCs into the cell cycle, thus promoting HSC quiescence and protecting the cells from exhaustion. These findings reveal a role of LH in regulating HSC function and offer a new therapeutic approach for hematopoietic regeneration after hematopoietic injury.", + "TAG_DATA": [ + "68, aged {'context': 'B-organism'}", + "71, mice. {'context': 'B-organism'}", + "77, luteinizing {'perturbing_action': 'B-pharmacological inhibition'}", + "78, hormone {'perturbing_action': 'I-pharmacological inhibition'}", + "79, (LH)-releasing {'perturbing_action': 'I-pharmacological inhibition'}", + "80, hormone {'perturbing_action': 'I-pharmacological inhibition'}", + "81, antagonist {'perturbing_action': 'I-pharmacological inhibition'}", + "82, (LHRH-Ant), {'perturbing_action': 'I-pharmacological inhibition'}", + "95, mouse {'context': 'B-organism'}", + "126, Human {'context': 'B-cells'}", + "127, and {'context': 'I-cells'}", + "128, mouse {'context': 'I-cells'}", + "129, long-term {'context': 'I-cells'}", + "130, self-renewing {'context': 'I-cells'}", + "131, HSCs {'context': 'I-cells'}", + "132, (LT-HSCs) {'context': 'I-cells'}", + "160, HSCs {'context': 'B-cells'}", + "166, promoting {'effect': 'B-positive'}", + "167, HSC {'context': 'B-cells'}", + "168, quiescence {'phenotype': 'B-quiescence'}", + "172, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "68, aged ['l0']", + "71, mice. ['l0']", + "77, luteinizing ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "78, hormone ['l1', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "79, (LH)-releasing ['l2', 'l14', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "80, hormone ['l3', 'l15', 'l26', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "81, antagonist ['l4', 'l16', 'l27', 'l37', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "82, (LHRH-Ant), ['l5', 'l17', 'l28', 'l38', 'l47', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "95, mouse ['l6', 'l18', 'l29', 'l39', 'l48', 'l56']", + "126, Human ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "127, and ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l64', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "128, mouse ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l65', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "129, long-term ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l66', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "130, self-renewing ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l67', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "131, HSCs ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l68', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "132, (LT-HSCs) ['l13', 'l25', 'l36', 'l46', 'l55', 'l63', 'l69', 'l74', 'l79', 'l83', 'l86', 'l88']", + "160, HSCs ['l75', 'l80', 'l84', 'l87', 'l89', 'l90', 'l91', 'l92', 'l93']", + "166, promoting ['l90', 'l94', 'l95', 'l96']", + "167, HSC ['l91', 'l94', 'l97', 'l98']", + "168, quiescence ['l92', 'l95', 'l97', 'l99']", + "172, cells ['l93', 'l96', 'l98', 'l99']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "luteinizing", + "hormone", + "(LH)-releasing", + "antagonist", + "(LHRH-Ant)," + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "luteinizing", + "hormone", + "(LH)-releasing", + "antagonist", + "(LHRH-Ant)," + ] + }, + "context": { + "val": "cells", + "words": [ + "Human", + "and", + "mouse", + "long-term", + "self-renewing", + "HSCs", + "(LT-HSCs)" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSCs", + "HSC", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSCs", + "HSC", + "cells" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + } + } + ] + }, + { + "PMID": "29227474", + "TEXT": "The stress-responsive epigenetic repressor histone deacetylase 4 (HDAC4) regulates cardiac gene expression. Here we show that the levels of an N-terminal proteolytically derived fragment of HDAC4, termed HDAC4-NT, are lower in failing mouse hearts than in healthy control hearts. Virus-mediated transfer of the portion of the Hdac4 gene encoding HDAC4-NT into the mouse myocardium protected the heart from remodeling and failure; this was associated with decreased expression of Nr4a1, which encodes a nuclear orphan receptor, and decreased NR4A1-dependent activation of the hexosamine biosynthetic pathway (HBP). Conversely, exercise enhanced HDAC4-NT levels, and mice with a cardiomyocyte-specific deletion of Hdac4 show reduced exercise capacity, which was characterized by cardiac fatigue and increased expression of Nr4a1. Mechanistically, we found that NR4A1 negatively regulated contractile function in a manner that depended on the HBP and the calcium sensor STIM1. Our work describes a new regulatory axis in which epigenetic regulation of a metabolic pathway affects calcium handling. Activation of this axis during intermittent physiological stress promotes cardiac function, whereas its impairment in sustained pathological cardiac stress leads to heart failure.", + "TAG_DATA": [ + "56, heart {'context': 'B-tissue/organ'}", + "91, mice {'context': 'B-organism'}", + "94, cardiomyocyte-specific {'perturbing_action': 'B-gene loss-of-function'}", + "95, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "96, of {'perturbing_action': 'I-gene loss-of-function'}", + "97, Hdac4 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "91, mice ['l0', 'l1', 'l2', 'l3']", + "94, cardiomyocyte-specific ['l0', 'l4', 'l5', 'l6']", + "95, deletion ['l1', 'l4', 'l7', 'l8']", + "96, of ['l2', 'l5', 'l7', 'l9']", + "97, Hdac4 ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cardiomyocyte-specific", + "deletion", + "of", + "Hdac4" + ] + } + } + ] + }, + { + "PMID": "29131160", + "TEXT": "Human liver cancer research currently lacks in vitro models that can faithfully recapitulate the pathophysiology of the original tumor. We recently described a novel, near-physiological organoid culture system, wherein primary human healthy liver cells form long-term expanding organoids that retain liver tissue function and genetic stability. Here we extend this culture system to the propagation of primary liver cancer (PLC) organoids from three of the most common PLC subtypes: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and combined HCC/CC (CHC) tumors. PLC-derived organoid cultures preserve the histological architecture, gene expression and genomic landscape of the original tumor, allowing for discrimination between different tumor tissues and subtypes, even after long-term expansion in culture in the same medium conditions. Xenograft studies demonstrate that the tumorogenic potential, histological features and metastatic properties of PLC-derived organoids are preserved in vivo. PLC-derived organoids are amenable for biomarker identification and drug-screening testing and led to the identification of the ERK inhibitor SCH772984 as a potential therapeutic agent for primary liver cancer. We thus demonstrate the wide-ranging biomedical utilities of PLC-derived organoid models in furthering the understanding of liver cancer biology and in developing personalized-medicine approaches for the disease.", + "TAG_DATA": [ + "79, PLC-derived {'context': 'B-organoid'}", + "80, organoid {'context': 'I-organoid'}", + "81, cultures {'context': 'I-organoid'}", + "115, Xenograft {'context': 'B-xenograft'}", + "120, tumorogenic {'phenotype': 'B-tumourigenesis'}", + "121, potential, {'phenotype': 'I-tumour initiation'}", + "125, metastatic {'phenotype': 'B-metastasis'}", + "126, properties {'phenotype': 'I-metastasis'}", + "128, PLC-derived {'context': 'B-organoid'}", + "129, organoids {'context': 'I-organoid'}", + "131, preserved {'effect': 'B-no effect'}", + "132, in {'context': 'B-in vivo'}", + "133, vivo. {'context': 'I-in vivo'}", + "134, PLC-derived {'context': 'B-organoid'}", + "135, organoids {'context': 'I-organoid'}" + ], + "LINK_DATA": [ + "79, PLC-derived ['l0', 'l1']", + "80, organoid ['l0', 'l2']", + "81, cultures ['l1', 'l2']", + "115, Xenograft ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "120, tumorogenic ['l3', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "121, potential, ['l4', 'l12', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "125, metastatic ['l5', 'l13', 'l20', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "126, properties ['l6', 'l14', 'l21', 'l27', 'l35', 'l36', 'l37', 'l38', 'l39']", + "128, PLC-derived ['l7', 'l15', 'l22', 'l28', 'l35', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "129, organoids ['l8', 'l16', 'l23', 'l29', 'l36', 'l40', 'l46', 'l47', 'l48', 'l49']", + "131, preserved ['l9', 'l17', 'l24', 'l30', 'l37', 'l41', 'l46', 'l50', 'l51']", + "132, in ['l10', 'l18', 'l25', 'l31', 'l38', 'l42', 'l47', 'l50', 'l52', 'l53']", + "133, vivo. ['l11', 'l19', 'l26', 'l32', 'l39', 'l43', 'l48', 'l51', 'l52', 'l54']", + "134, PLC-derived ['l33', 'l44', 'l55']", + "135, organoids ['l34', 'l45', 'l49', 'l53', 'l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "xenograft", + "words": [ + "Xenograft" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorogenic" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "Xenograft" + ] + }, + "phenotype": { + "val": "tumour initiation", + "words": [ + "potential," + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "Xenograft" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "properties" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "Xenograft" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "preserved" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorogenic" + ] + }, + "context": { + "val": "organoid", + "words": [ + "PLC-derived", + "organoids" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorogenic" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "preserved" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorogenic" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "tumour initiation", + "words": [ + "potential," + ] + }, + "context": { + "val": "organoid", + "words": [ + "PLC-derived", + "organoids" + ] + } + }, + { + "phenotype": { + "val": "tumour initiation", + "words": [ + "potential," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "preserved" + ] + } + }, + { + "phenotype": { + "val": "tumour initiation", + "words": [ + "potential," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "properties" + ] + }, + "context": { + "val": "organoid", + "words": [ + "PLC-derived", + "organoids" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "properties" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "preserved" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "properties" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "PLC-derived", + "organoids" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "preserved" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "preserved" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "29131158", + "TEXT": "Uncoupling protein 1 (UCP1) plays a central role in nonshivering thermogenesis in brown fat; however, its role in beige fat remains unclear. Here we report a robust UCP1-independent thermogenic mechanism in beige fat that involves enhanced ATP-dependent Ca2+ cycling by sarco/endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) and ryanodine receptor 2 (RyR2). Inhibition of SERCA2b impairs UCP1-independent beige fat thermogenesis in humans and mice as well as in pigs, a species that lacks a functional UCP1 protein. Conversely, enhanced Ca2+ cycling by activation of α1- and/or β3-adrenergic receptors or the SERCA2b-RyR2 pathway stimulates UCP1-independent thermogenesis in beige adipocytes. In the absence of UCP1, beige fat dynamically expends glucose through enhanced glycolysis, tricarboxylic acid metabolism and pyruvate dehydrogenase activity for ATP-dependent thermogenesis through the SERCA2b pathway; beige fat thereby functions as a 'glucose sink' and improves glucose tolerance independently of body weight loss. Our study uncovers a noncanonical thermogenic mechanism through which beige fat controls whole-body energy homeostasis via Ca2+ cycling.", + "TAG_DATA": [ + "50, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "51, of {'perturbing_action': 'I-pharmacological inhibition'}", + "52, SERCA2b {'perturbing_action': 'I-pharmacological inhibition'}", + "56, fat {'context': 'I-tissue/organ'}", + "59, humans {'context': 'B-organism'}", + "61, mice {'context': 'B-organism'}", + "66, pigs, {'context': 'B-organism'}", + "94, beige {'context': 'B-cells'}", + "95, adipocytes. {'context': 'I-cells'}", + "98, absence {'perturbing_action': 'B-gene loss-of-function'}", + "99, of {'perturbing_action': 'I-gene loss-of-function'}", + "100, UCP1, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "50, Inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "51, of ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "52, SERCA2b ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "55, beige ['l2', 'l9', 'l15', 'l21', 'l22', 'l23']", + "56, fat ['l3', 'l10', 'l16', 'l21', 'l24', 'l25']", + "59, humans ['l4', 'l11', 'l17', 'l22', 'l24', 'l26']", + "61, mice ['l5', 'l12', 'l18', 'l23', 'l25', 'l26']", + "66, pigs, ['l6', 'l13', 'l19', 'l27']", + "94, beige ['l28']", + "95, adipocytes. ['l7', 'l14', 'l20', 'l27', 'l28']", + "98, absence ['l29', 'l30']", + "99, of ['l29', 'l31']", + "100, UCP1, ['l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "SERCA2b" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "fat" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "SERCA2b" + ] + }, + "context": { + "val": "organism", + "words": [ + "humans", + "mice", + "pigs," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "SERCA2b" + ] + }, + "context": { + "val": "cells", + "words": [ + "adipocytes." + ] + } + } + ] + }, + { + "PMID": "29106400", + "TEXT": "Cancer-specific cell-surface antigens are ideal targets for monoclonal antibody (mAb)-based immunotherapy but are likely to have previously been identified in transcriptome or proteome analyses. Here, we show that the active conformer of an integrin can serve as a specific therapeutic target for multiple myeloma (MM). We screened >10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb specifically recognizing a subset of integrin β7 molecules. The MMG49 epitope, in the N-terminal region of the β7 chain, is predicted to be inaccessible in the resting integrin conformer but exposed in the active conformation. Elevated expression and constitutive activation of integrin β7 conferred high MMG49 reactivity on MM cells, whereas MMG49 binding was scarcely detectable in other cell types including normal integrin β7+ lymphocytes. T cells transduced with MMG49-derived chimeric antigen receptor (CAR) exerted anti-MM effects without damaging normal hematopoietic cells. Thus, MMG49 CAR T cell therapy is promising for MM, and a receptor protein with a rare but physiologically relevant conformation can serve as a cancer immunotherapy target.", + "TAG_DATA": [ + "96, constitutive {'perturbing_action': 'B-gene gain-of-function'}", + "97, activation {'perturbing_action': 'I-gene gain-of-function'}", + "98, of {'perturbing_action': 'I-gene gain-of-function'}", + "99, integrin {'perturbing_action': 'I-gene gain-of-function'}", + "100, β7 {'perturbing_action': 'I-gene gain-of-function'}", + "106, MM {'context': 'B-transformed cells'}", + "107, cells, {'context': 'I-transformed cells'}", + "116, cell {'context': 'B-cells'}", + "117, types {'context': 'I-cells'}", + "123, T {'context': 'B-cells'}", + "124, cells {'context': 'B-cells'}", + "125, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "126, with {'perturbing_action': 'I-gene gain-of-function'}", + "127, MMG49-derived {'perturbing_action': 'I-gene gain-of-function'}", + "128, chimeric {'perturbing_action': 'I-gene gain-of-function'}", + "129, antigen {'perturbing_action': 'I-gene gain-of-function'}", + "130, receptor {'perturbing_action': 'I-gene gain-of-function'}", + "131, (CAR) {'perturbing_action': 'I-gene gain-of-function'}", + "138, hematopoietic {'context': 'I-cells'}", + "139, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "96, constitutive ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "97, activation ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "98, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "99, integrin ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "100, β7 ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "106, MM ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "107, cells, ['l5', 'l12', 'l18', 'l23', 'l27', 'l30']", + "116, cell ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33']", + "117, types ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l33']", + "123, T ['l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "124, cells ['l34', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "125, transduced ['l35', 'l44', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "126, with ['l36', 'l45', 'l53', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "127, MMG49-derived ['l37', 'l46', 'l54', 'l61', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "128, chimeric ['l38', 'l47', 'l55', 'l62', 'l68', 'l74', 'l75', 'l76', 'l77', 'l78']", + "129, antigen ['l39', 'l48', 'l56', 'l63', 'l69', 'l74', 'l79', 'l80', 'l81', 'l82']", + "130, receptor ['l40', 'l49', 'l57', 'l64', 'l70', 'l75', 'l79', 'l83', 'l84', 'l85']", + "131, (CAR) ['l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l83', 'l86', 'l87']", + "138, hematopoietic ['l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l86', 'l88']", + "139, cells. ['l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l87', 'l88']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutive", + "activation", + "of", + "integrin", + "β7" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MM", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutive", + "activation", + "of", + "integrin", + "β7", + "transduced", + "with", + "MMG49-derived", + "chimeric", + "antigen", + "receptor", + "(CAR)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "types", + "T", + "cells", + "hematopoietic", + "cells." + ] + } + } + ] + }, + { + "PMID": "29106399", + "TEXT": "Over 40% of microRNAs (miRNAs) are located in introns of protein-coding genes, and many of these intronic miRNAs are co-regulated with their host genes. In such cases of co-regulation, the products of host genes and their intronic miRNAs can cooperate to coordinately regulate biologically important pathways. Therefore, we screened intronic miRNAs dysregulated in the livers of mouse models of obesity to identify previously uncharacterized protein-coding host genes that may contribute to the pathogenesis of obesity-associated insulin resistance and type 2 diabetes mellitus. Our approach revealed that expression of both the gene encoding ectodysplasin A (Eda), the causal gene in X-linked hypohidrotic ectodermal dysplasia (XLHED), and its intronic miRNA, miR-676, was increased in the livers of obese mice. Moreover, hepatic EDA expression is increased in obese human subjects and reduced upon weight loss, and its hepatic expression correlates with systemic insulin resistance. We also found that reducing miR-676 expression in db/db mice increases the expression of proteins involved in fatty acid oxidation and reduces the expression of inflammatory signaling components in the liver. Further, we found that Eda expression in mouse liver is controlled via PPARγ and RXR-α, increases in circulation under conditions of obesity, and promotes JNK activation and inhibitory serine phosphorylation of IRS1 in skeletal muscle. In accordance with these findings, gain- and loss-of-function approaches reveal that liver-derived EDA regulates systemic glucose metabolism, suggesting that EDA is a hepatokine that can contribute to impaired skeletal muscle insulin sensitivity in obesity.", + "TAG_DATA": [ + "115, obese {'context': 'B-organism'}", + "116, mice. {'context': 'I-organism'}", + "145, reducing {'perturbing_action': 'B-gene loss-of-function'}", + "146, miR-676 {'perturbing_action': 'I-rnai/knockdown'}", + "147, expression {'perturbing_action': 'I-rnai/knockdown'}", + "149, db/db {'context': 'B-organism'}", + "150, mice {'context': 'I-organism'}", + "180, liver {'context': 'I-tissue/organ'}", + "205, skeletal {'context': 'B-tissue/organ'}", + "206, muscle. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "115, obese ['l0']", + "116, mice. ['l0']", + "145, reducing ['l1', 'l2', 'l3', 'l4']", + "146, miR-676 ['l1', 'l5', 'l6', 'l7']", + "147, expression ['l2', 'l5', 'l8', 'l9']", + "149, db/db ['l3', 'l6', 'l8', 'l10']", + "150, mice ['l4', 'l7', 'l9', 'l10']", + "179, mouse ['l11', 'l12', 'l13']", + "180, liver ['l11', 'l14', 'l15']", + "205, skeletal ['l12', 'l14', 'l16']", + "206, muscle. ['l13', 'l15', 'l16']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "reducing" + ] + }, + "context": { + "val": "organism", + "words": [ + "db/db", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "miR-676", + "expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "db/db", + "mice" + ] + } + } + ] + }, + { + "PMID": "29035369", + "TEXT": "The calcium-binding protein calbindin-D28k is critical for hippocampal function and cognition, but its expression is markedly decreased in various neurological disorders associated with epileptiform activity and seizures. In Alzheimer's disease (AD) and epilepsy, both of which are accompanied by recurrent seizures, the severity of cognitive deficits reflects the degree of calbindin reduction in the hippocampal dentate gyrus (DG). However, despite the importance of calbindin in both neuronal physiology and pathology, the regulatory mechanisms that control its expression in the hippocampus are poorly understood. Here we report an epigenetic mechanism through which seizures chronically suppress hippocampal calbindin expression and impair cognition. We demonstrate that ΔFosB, a highly stable transcription factor, is induced in the hippocampus in mouse models of AD and seizures, in which it binds and triggers histone deacetylation at the promoter of the calbindin gene (Calb1) and downregulates Calb1 transcription. Notably, increasing DG calbindin levels, either by direct virus-mediated expression or inhibition of ΔFosB signaling, improves spatial memory in a mouse model of AD. Moreover, levels of ΔFosB and calbindin expression are inversely related in the DG of individuals with temporal lobe epilepsy (TLE) or AD and correlate with performance on the Mini-Mental State Examination (MMSE). We propose that chronic suppression of calbindin by ΔFosB is one mechanism through which intermittent seizures drive persistent cognitive deficits in conditions accompanied by recurrent seizures.", + "TAG_DATA": [ + "156, improves {'effect': 'B-positive'}", + "161, mouse {'context': 'B-organism'}", + "162, model {'context': 'I-organism'}", + "164, AD. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "156, improves ['l0', 'l1', 'l2', 'l3']", + "161, mouse ['l0', 'l4', 'l5', 'l6']", + "162, model ['l1', 'l4', 'l7', 'l8']", + "163, of ['l2', 'l5', 'l7', 'l9']", + "164, AD. ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "improves" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "AD." + ] + } + } + ] + }, + { + "PMID": "29035367", + "TEXT": "Glioblastomas are lethal cancers defined by angiogenesis and pseudopalisading necrosis. Here, we demonstrate that these histological features are associated with distinct transcriptional programs, with vascular regions showing a proneural profile, and hypoxic regions showing a mesenchymal pattern. As these regions harbor glioma stem cells (GSCs), we investigated the epigenetic regulation of these two niches. Proneural, perivascular GSCs activated EZH2, whereas mesenchymal GSCs in hypoxic regions expressed BMI1 protein, which promoted cellular survival under stress due to downregulation of the E3 ligase RNF144A. Using both genetic and pharmacologic inhibition, we found that proneural GSCs are preferentially sensitive to EZH2 disruption, whereas mesenchymal GSCs are more sensitive to BMI1 inhibition. Given that glioblastomas contain both proneural and mesenchymal GSCs, combined EZH2 and BMI1 targeting proved more effective than either agent alone both in culture and in vivo, suggesting that strategies that simultaneously target multiple epigenetic regulators within glioblastomas may be effective in overcoming therapy resistance caused by intratumoral heterogeneity.", + "TAG_DATA": [ + "91, proneural {'context': 'B-transformed cells'}", + "92, GSCs {'context': 'I-transformed cells'}", + "100, mesenchymal {'context': 'B-transformed cells'}", + "101, GSCs {'context': 'I-transformed cells'}", + "106, BMI1 {'perturbing_action': 'B-pharmacological inhibition'}", + "107, inhibition. {'perturbing_action': 'I-pharmacological inhibition'}", + "131, culture {'context': 'I-in vitro'}", + "133, in {'context': 'B-in vivo'}", + "134, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "91, proneural ['l0', 'l1']", + "92, GSCs ['l0', 'l2']", + "100, mesenchymal ['l3', 'l4', 'l5', 'l6', 'l7']", + "101, GSCs ['l1', 'l2', 'l3', 'l8', 'l9', 'l10']", + "106, BMI1 ['l4', 'l8', 'l11', 'l12', 'l13', 'l14']", + "107, inhibition. ['l5', 'l9', 'l11', 'l15', 'l16', 'l17']", + "131, culture ['l6', 'l10', 'l12', 'l15', 'l18', 'l19']", + "133, in ['l7', 'l13', 'l16', 'l18', 'l20']", + "134, vivo, ['l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "mesenchymal", + "GSCs" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BMI1", + "inhibition." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BMI1", + "inhibition." + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BMI1", + "inhibition." + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + } + ] + }, + { + "PMID": "29035366", + "TEXT": "Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies.", + "TAG_DATA": [ + "27, induces {'effect': 'B-positive'}", + "30, cell {'phenotype': 'B-cell death'}", + "31, death, {'phenotype': 'I-cell death'}", + "41, patient-derived {'context': 'B-transformed cells'}", + "42, glioblastoma {'context': 'I-transformed cells'}", + "43, (GBM) {'context': 'I-transformed cells'}", + "44, cells. {'context': 'I-transformed cells'}", + "58, triggering {'effect': 'B-positive'}", + "60, apoptosis. {'phenotype': 'B-apoptosis'}", + "71, stabilization {'perturbing_action': 'I-other'}", + "72, of {'perturbing_action': 'I-other'}", + "73, p53 {'perturbing_action': 'I-other'}", + "85, orthotopic {'context': 'B-xenograft'}", + "86, glioblastoma {'context': 'I-xenograft'}", + "87, xenograft {'context': 'I-xenograft'}", + "88, models. {'context': 'I-xenograft'}", + "132, in {'context': 'B-in vivo'}", + "133, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "27, induces ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "30, cell ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "31, death, ['l1', 'l7', 'l12', 'l13', 'l14', 'l15']", + "41, patient-derived ['l2', 'l8', 'l12', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "42, glioblastoma ['l3', 'l9', 'l13', 'l16', 'l22', 'l23', 'l24', 'l25']", + "43, (GBM) ['l4', 'l10', 'l14', 'l17', 'l22', 'l26', 'l27', 'l28']", + "44, cells. ['l5', 'l11', 'l15', 'l18', 'l23', 'l26', 'l29', 'l30']", + "58, triggering ['l19', 'l24', 'l27', 'l29', 'l31']", + "60, apoptosis. ['l6', 'l20', 'l25', 'l28', 'l30', 'l31']", + "71, stabilization ['l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "72, of ['l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "73, p53 ['l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "85, orthotopic ['l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "86, glioblastoma ['l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "87, xenograft ['l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "88, models. ['l21', 'l37', 'l42', 'l46', 'l49', 'l51', 'l52']", + "132, in ['l53']", + "133, vivo. ['l53']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "triggering" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "patient-derived", + "glioblastoma", + "(GBM)", + "cells." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "triggering" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "patient-derived", + "glioblastoma", + "(GBM)", + "cells." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "patient-derived", + "glioblastoma", + "(GBM)", + "cells." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "stabilization", + "of", + "p53" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "orthotopic", + "glioblastoma", + "xenograft", + "models." + ] + } + } + ] + }, + { + "PMID": "28920958", + "TEXT": "N6-methyladenosine (m6A) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the m6A modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the m6A-forming enzyme METTL3 in human hematopoietic stem/progenitor cells (HSPCs) promotes cell differentiation, coupled with reduced cell proliferation. Conversely, overexpression of wild-type METTL3, but not of a catalytically inactive form of METTL3, inhibits cell differentiation and increases cell growth. METTL3 mRNA and protein are expressed more abundantly in acute myeloid leukemia (AML) cells than in healthy HSPCs or other types of tumor cells. Furthermore, METTL3 depletion in human myeloid leukemia cell lines induces cell differentiation and apoptosis and delays leukemia progression in recipient mice in vivo. Single-nucleotide-resolution mapping of m6A coupled with ribosome profiling reveals that m6A promotes the translation of c-MYC, BCL2 and PTEN mRNAs in the human acute myeloid leukemia MOLM-13 cell line. Moreover, loss of METTL3 leads to increased levels of phosphorylated AKT, which contributes to the differentiation-promoting effects of METTL3 depletion. Overall, these results provide a rationale for the therapeutic targeting of METTL3 in myeloid leukemia.", + "TAG_DATA": [ + "42, shRNA-mediated {'perturbing_action': 'B-gene loss-of-function'}", + "43, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "44, of {'perturbing_action': 'I-gene loss-of-function'}", + "45, the {'perturbing_action': 'I-gene loss-of-function'}", + "46, m6A-forming {'perturbing_action': 'I-gene loss-of-function'}", + "47, enzyme {'perturbing_action': 'I-gene loss-of-function'}", + "48, METTL3 {'perturbing_action': 'I-gene loss-of-function'}", + "50, human {'context': 'B-cells'}", + "51, hematopoietic {'context': 'I-cells'}", + "52, stem/progenitor {'context': 'I-cells'}", + "53, cells {'context': 'I-cells'}", + "54, (HSPCs) {'context': 'I-cells'}", + "55, promotes {'effect': 'B-positive'}", + "56, cell {'context': 'B-cells'}", + "57, differentiation, {'phenotype': 'B-differentiation'}", + "60, reduced {'effect': 'B-negative'}", + "61, cell {'context': 'B-cells'}", + "62, proliferation. {'phenotype': 'B-proliferation'}", + "64, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "65, of {'perturbing_action': 'I-gene gain-of-function'}", + "66, wild-type {'perturbing_action': 'I-gene gain-of-function'}", + "67, METTL3, {'perturbing_action': 'I-gene gain-of-function'}", + "77, inhibits {'effect': 'B-negative'}", + "78, cell {'context': 'B-cells'}", + "79, differentiation {'phenotype': 'B-differentiation'}", + "81, increases {'effect': 'B-positive'}", + "82, cell {'phenotype': 'B-cell growth'}", + "83, growth. {'phenotype': 'I-cell growth'}", + "100, healthy {'context': 'B-cells'}", + "101, HSPCs {'context': 'I-cells'}", + "109, METTL3 {'perturbing_action': 'B-gene loss-of-function'}", + "110, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "112, human {'context': 'B-transformed cells'}", + "113, myeloid {'context': 'I-transformed cells'}", + "114, leukemia {'context': 'I-transformed cells'}", + "115, cell {'context': 'I-transformed cells'}", + "116, lines {'context': 'I-transformed cells'}", + "117, induces {'effect': 'B-positive'}", + "118, cell {'context': 'B-cells'}", + "119, differentiation {'phenotype': 'B-differentiation'}", + "121, apoptosis {'phenotype': 'B-apoptosis'}", + "123, delays {'effect': 'B-negative'}", + "124, leukemia {'context': 'B-neoplasm'}", + "128, mice {'context': 'B-organism'}", + "129, in {'context': 'B-in vivo'}", + "130, vivo. {'context': 'I-in vivo'}", + "153, human {'context': 'B-transformed cells'}", + "154, acute {'context': 'I-transformed cells'}", + "155, myeloid {'context': 'I-transformed cells'}", + "156, leukemia {'context': 'I-transformed cells'}", + "157, MOLM-13 {'context': 'I-transformed cells'}", + "158, cell {'context': 'I-transformed cells'}", + "159, line. {'context': 'I-transformed cells'}", + "161, loss {'perturbing_action': 'B-gene loss-of-function'}", + "162, of {'perturbing_action': 'I-gene loss-of-function'}", + "163, METTL3 {'perturbing_action': 'I-gene loss-of-function'}", + "178, METTL3 {'perturbing_action': 'B-gene loss-of-function'}", + "179, depletion. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "42, shRNA-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "43, depletion ['l0', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "44, of ['l1', 'l23', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "45, the ['l2', 'l24', 'l45', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "46, m6A-forming ['l3', 'l25', 'l46', 'l66', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "47, enzyme ['l4', 'l26', 'l47', 'l67', 'l86', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "48, METTL3 ['l5', 'l27', 'l48', 'l68', 'l87', 'l105', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139']", + "50, human ['l6', 'l28', 'l49', 'l69', 'l88', 'l106', 'l123', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150']", + "51, hematopoietic ['l7', 'l29', 'l50', 'l70', 'l89', 'l107', 'l124', 'l140', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "52, stem/progenitor ['l8', 'l30', 'l51', 'l71', 'l90', 'l108', 'l125', 'l141', 'l151', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "53, cells ['l9', 'l31', 'l52', 'l72', 'l91', 'l109', 'l126', 'l142', 'l152', 'l162', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180']", + "54, (HSPCs) ['l10', 'l32', 'l53', 'l73', 'l92', 'l110', 'l127', 'l143', 'l153', 'l163', 'l173', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "55, promotes ['l11', 'l33', 'l54', 'l74', 'l93', 'l111', 'l128', 'l144', 'l154', 'l164', 'l174', 'l181', 'l188', 'l189', 'l190', 'l191', 'l192']", + "56, cell ['l12', 'l34', 'l55', 'l75', 'l94', 'l112', 'l129', 'l145', 'l155', 'l165', 'l175', 'l182', 'l188', 'l193', 'l194', 'l195', 'l196']", + "57, differentiation, ['l13', 'l35', 'l56', 'l76', 'l95', 'l113', 'l130', 'l146', 'l156', 'l166', 'l176', 'l183', 'l189', 'l193', 'l197', 'l198', 'l199']", + "60, reduced ['l14', 'l36', 'l57', 'l77', 'l96', 'l114', 'l131', 'l147', 'l157', 'l167', 'l177', 'l184', 'l190', 'l194', 'l197', 'l200', 'l201']", + "61, cell ['l15', 'l37', 'l58', 'l78', 'l97', 'l115', 'l132', 'l148', 'l158', 'l168', 'l178', 'l185', 'l191', 'l195', 'l198', 'l200', 'l202']", + "62, proliferation. ['l16', 'l38', 'l59', 'l79', 'l98', 'l116', 'l133', 'l149', 'l159', 'l169', 'l179', 'l186', 'l192', 'l196', 'l199', 'l201', 'l202']", + "64, overexpression ['l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229']", + "65, of ['l203', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255']", + "66, wild-type ['l204', 'l230', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280']", + "67, METTL3, ['l205', 'l231', 'l256', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302']", + "77, inhibits ['l17', 'l39', 'l60', 'l80', 'l99', 'l117', 'l134', 'l206', 'l232', 'l257', 'l281', 'l303', 'l304', 'l305', 'l306', 'l307', 'l308', 'l309', 'l310']", + "78, cell ['l18', 'l40', 'l61', 'l81', 'l100', 'l118', 'l135', 'l160', 'l170', 'l207', 'l233', 'l258', 'l282', 'l303', 'l311', 'l312', 'l313', 'l314']", + "79, differentiation ['l19', 'l41', 'l62', 'l82', 'l101', 'l119', 'l136', 'l150', 'l161', 'l171', 'l180', 'l187', 'l208', 'l234', 'l259', 'l283', 'l304', 'l311', 'l315', 'l316', 'l317']", + "81, increases ['l20', 'l42', 'l63', 'l83', 'l102', 'l120', 'l137', 'l209', 'l235', 'l260', 'l284', 'l305', 'l312', 'l315', 'l318', 'l319', 'l320']", + "82, cell ['l21', 'l43', 'l64', 'l84', 'l103', 'l121', 'l138', 'l210', 'l236', 'l261', 'l285', 'l306', 'l313', 'l316', 'l318', 'l321', 'l322', 'l323', 'l324']", + "83, growth. ['l22', 'l44', 'l65', 'l85', 'l104', 'l122', 'l139', 'l172', 'l211', 'l237', 'l262', 'l286', 'l307', 'l314', 'l317', 'l319', 'l321']", + "100, healthy ['l212', 'l238', 'l263', 'l287', 'l308', 'l322', 'l325', 'l326', 'l327', 'l328', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334', 'l335', 'l336']", + "101, HSPCs ['l213', 'l239', 'l264', 'l288', 'l309', 'l320', 'l323', 'l325', 'l337', 'l338', 'l339', 'l340', 'l341', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347']", + "109, METTL3 ['l214', 'l240', 'l265', 'l289', 'l348', 'l349', 'l350', 'l351', 'l352', 'l353', 'l354', 'l355', 'l356', 'l357', 'l358', 'l359', 'l360', 'l361', 'l362', 'l363', 'l364', 'l365', 'l366', 'l367', 'l368']", + "110, depletion ['l215', 'l241', 'l266', 'l290', 'l326', 'l337', 'l348', 'l369', 'l370', 'l371', 'l372', 'l373', 'l374', 'l375', 'l376', 'l377', 'l378', 'l379', 'l380', 'l381', 'l382']", + "112, human ['l216', 'l242', 'l267', 'l291', 'l327', 'l338', 'l349', 'l369', 'l383', 'l384', 'l385', 'l386', 'l387', 'l388', 'l389', 'l390', 'l391', 'l392', 'l393', 'l394', 'l395']", + "113, myeloid ['l217', 'l243', 'l268', 'l292', 'l328', 'l339', 'l350', 'l370', 'l383', 'l396', 'l397', 'l398', 'l399', 'l400', 'l401', 'l402', 'l403', 'l404', 'l405', 'l406', 'l407']", + "114, leukemia ['l218', 'l244', 'l269', 'l293', 'l329', 'l340', 'l351', 'l371', 'l384', 'l396', 'l408', 'l409', 'l410', 'l411', 'l412', 'l413', 'l414', 'l415', 'l416', 'l417', 'l418']", + "115, cell ['l219', 'l245', 'l270', 'l294', 'l330', 'l341', 'l352', 'l372', 'l385', 'l397', 'l408', 'l419', 'l420', 'l421', 'l422', 'l423', 'l424', 'l425', 'l426', 'l427']", + "116, lines ['l220', 'l246', 'l271', 'l295', 'l310', 'l324', 'l331', 'l342', 'l353', 'l373', 'l386', 'l398', 'l409', 'l419', 'l428', 'l429', 'l430', 'l431', 'l432', 'l433', 'l434']", + "117, induces ['l221', 'l247', 'l272', 'l296', 'l332', 'l343', 'l354', 'l374', 'l387', 'l399', 'l410', 'l420', 'l428', 'l435', 'l436', 'l437', 'l438', 'l439']", + "118, cell ['l222', 'l248', 'l273', 'l297', 'l333', 'l344', 'l355', 'l375', 'l388', 'l400', 'l411', 'l421', 'l429', 'l435', 'l440', 'l441', 'l442', 'l443', 'l444']", + "119, differentiation ['l223', 'l249', 'l274', 'l298', 'l334', 'l345', 'l356', 'l376', 'l389', 'l401', 'l412', 'l422', 'l430', 'l436', 'l440', 'l445', 'l446', 'l447', 'l448']", + "121, apoptosis ['l224', 'l250', 'l275', 'l299', 'l335', 'l346', 'l357', 'l377', 'l390', 'l402', 'l413', 'l423', 'l431', 'l437', 'l441', 'l445', 'l449', 'l450', 'l451', 'l452', 'l453']", + "123, delays ['l225', 'l251', 'l276', 'l300', 'l336', 'l347', 'l358', 'l378', 'l391', 'l403', 'l414', 'l424', 'l432', 'l438', 'l442', 'l446', 'l449', 'l454', 'l455']", + "124, leukemia ['l226', 'l252', 'l277', 'l301', 'l359', 'l379', 'l392', 'l404', 'l415', 'l425', 'l433', 'l439', 'l443', 'l447', 'l450', 'l454', 'l456', 'l457', 'l458']", + "128, mice ['l227', 'l253', 'l278', 'l302', 'l360', 'l380', 'l393', 'l405', 'l416', 'l426', 'l434', 'l444', 'l448', 'l451', 'l455', 'l456', 'l459', 'l460']", + "129, in ['l228', 'l254', 'l279', 'l361', 'l381', 'l394', 'l406', 'l417', 'l452', 'l457', 'l459', 'l461', 'l462', 'l463', 'l464', 'l465', 'l466', 'l467', 'l468']", + "130, vivo. ['l229', 'l255', 'l280', 'l362', 'l382', 'l395', 'l407', 'l418', 'l427', 'l453', 'l458', 'l460', 'l461', 'l469', 'l470', 'l471', 'l472', 'l473', 'l474', 'l475']", + "153, human ['l462', 'l469', 'l476', 'l477', 'l478', 'l479', 'l480', 'l481']", + "154, acute ['l363', 'l463', 'l470', 'l476', 'l482', 'l483', 'l484', 'l485', 'l486']", + "155, myeloid ['l364', 'l464', 'l471', 'l477', 'l482', 'l487', 'l488', 'l489', 'l490']", + "156, leukemia ['l365', 'l465', 'l472', 'l478', 'l483', 'l487', 'l491', 'l492', 'l493']", + "157, MOLM-13 ['l366', 'l466', 'l473', 'l479', 'l484', 'l488', 'l491', 'l494', 'l495']", + "158, cell ['l367', 'l467', 'l474', 'l480', 'l485', 'l489', 'l492', 'l494', 'l496']", + "159, line. ['l368', 'l468', 'l475', 'l481', 'l486', 'l490', 'l493', 'l495', 'l496']", + "161, loss ['l497', 'l498', 'l499', 'l500']", + "162, of ['l497', 'l501', 'l502', 'l503']", + "163, METTL3 ['l498', 'l501', 'l504', 'l505']", + "178, METTL3 ['l499', 'l502', 'l504', 'l506']", + "179, depletion. ['l500', 'l503', 'l505', 'l506']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "shRNA-mediated", + "depletion", + "of", + "the", + "m6A-forming", + "enzyme", + "METTL3" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "hematopoietic", + "stem/progenitor", + "cells", + "(HSPCs)", + "cell", + "healthy", + "HSPCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "shRNA-mediated", + "depletion", + "of", + "the", + "m6A-forming", + "enzyme", + "METTL3" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes", + "increases", + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "shRNA-mediated", + "depletion", + "of", + "the", + "m6A-forming", + "enzyme", + "METTL3" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation,", + "differentiation" + ] + } + }, + { + "perturbing_action": { 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"in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "delays" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "lines", + "human", + "myeloid", + "leukemia", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "cell", + "growth." + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "cell" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "lines" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "healthy", + "HSPCs", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "METTL3", + "depletion" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "myeloid", + "leukemia", + "cell", + "lines", + "acute", + "MOLM-13", + "line." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "METTL3", + "depletion" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "METTL3", + "depletion" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "METTL3", + "depletion" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "METTL3", + "depletion" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "myeloid", + "leukemia", + "cell", + "lines" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "myeloid", + "leukemia", + "cell", + "lines" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "myeloid", + "leukemia", + "cell", + "lines" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "negative", + "words": [ + "delays" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "delays" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "delays" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "28920956", + "TEXT": "Mutations in MECP2 cause Rett syndrome (RTT), an X-linked neurological disorder characterized by regressive loss of neurodevelopmental milestones and acquired psychomotor deficits. However, the cellular heterogeneity of the brain impedes an understanding of how MECP2 mutations contribute to RTT. Here we developed a Cre-inducible method for cell-type-specific biotin tagging of MeCP2 in mice. Combining this approach with an allelic series of knock-in mice carrying frequent RTT-associated mutations (encoding T158M and R106W) enabled the selective profiling of RTT-associated nuclear transcriptomes in excitatory and inhibitory cortical neurons. We found that most gene-expression changes were largely specific to each RTT-associated mutation and cell type. Lowly expressed cell-type-enriched genes were preferentially disrupted by MeCP2 mutations, with upregulated and downregulated genes reflecting distinct functional categories. Subcellular RNA analysis in MeCP2-mutant neurons further revealed reductions in the nascent transcription of long genes and uncovered widespread post-transcriptional compensation at the cellular level. Finally, we overcame X-linked cellular mosaicism in female RTT models and identified distinct gene-expression changes between neighboring wild-type and mutant neurons, providing contextual insights into RTT etiology that support personalized therapeutic interventions.", + "TAG_DATA": [ + "52, mice. {'context': 'B-organism'}", + "62, mice {'context': 'B-organism'}", + "65, RTT-associated {'perturbing_action': 'I-other'}", + "66, mutations {'perturbing_action': 'I-other'}", + "80, excitatory {'context': 'B-cells'}", + "81, and {'context': 'I-cells'}", + "82, inhibitory {'context': 'I-cells'}", + "83, cortical {'context': 'I-cells'}", + "84, neurons. {'context': 'I-cells'}", + "109, MeCP2 {'perturbing_action': 'B-other'}", + "110, mutations, {'perturbing_action': 'I-other'}", + "124, MeCP2-mutant {'perturbing_action': 'B-other'}", + "125, neurons {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "52, mice. ['l0', 'l1', 'l2', 'l3', 'l4']", + "62, mice ['l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "65, RTT-associated ['l5', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "66, mutations ['l6', 'l14', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "67, (encoding ['l7', 'l15', 'l22', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "68, T158M ['l8', 'l16', 'l23', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "80, excitatory ['l0', 'l9', 'l17', 'l24', 'l30', 'l35', 'l40', 'l41', 'l42', 'l43']", + "81, and ['l1', 'l10', 'l18', 'l25', 'l31', 'l36', 'l40', 'l44', 'l45', 'l46']", + "82, inhibitory ['l2', 'l11', 'l19', 'l26', 'l32', 'l37', 'l41', 'l44', 'l47', 'l48']", + "83, cortical ['l3', 'l12', 'l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47', 'l49']", + "84, neurons. ['l4', 'l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l48', 'l49']", + "109, MeCP2 ['l50', 'l51']", + "110, mutations, ['l50', 'l52']", + "124, MeCP2-mutant ['l53']", + "125, neurons ['l51', 'l52', 'l53']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "RTT-associated", + "mutations" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "RTT-associated", + "mutations", + "MeCP2", + "mutations,", + "MeCP2-mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "excitatory", + "and", + "inhibitory", + "cortical", + "neurons.", + "neurons" + ] + } + } + ] + }, + { + "PMID": "28825716", + "TEXT": "Aging is associated with increased cellular senescence, which is hypothesized to drive the eventual development of multiple comorbidities. Here we investigate a role for senescent cells in age-related bone loss through multiple approaches. In particular, we used either genetic (i.e., the INK-ATTAC 'suicide' transgene encoding an inducible caspase 8 expressed specifically in senescent cells) or pharmacological (i.e., 'senolytic' compounds) means to eliminate senescent cells. We also inhibited the production of the proinflammatory secretome of senescent cells using a JAK inhibitor (JAKi). In aged (20- to 22-month-old) mice with established bone loss, activation of the INK-ATTAC caspase 8 in senescent cells or treatment with senolytics or the JAKi for 2-4 months resulted in higher bone mass and strength and better bone microarchitecture than in vehicle-treated mice. The beneficial effects of targeting senescent cells were due to lower bone resorption with either maintained (trabecular) or higher (cortical) bone formation as compared to vehicle-treated mice. In vitro studies demonstrated that senescent-cell conditioned medium impaired osteoblast mineralization and enhanced osteoclast-progenitor survival, leading to increased osteoclastogenesis. Collectively, these data establish a causal role for senescent cells in bone loss with aging, and demonstrate that targeting these cells has both anti-resorptive and anabolic effects on bone. Given that eliminating senescent cells and/or inhibiting their proinflammatory secretome also improves cardiovascular function, enhances insulin sensitivity, and reduces frailty, targeting this fundamental mechanism to prevent age-related bone loss suggests a novel treatment strategy not only for osteoporosis, but also for multiple age-related comorbidities.", + "TAG_DATA": [ + "74, senescent {'context': 'B-cells'}", + "75, cells {'context': 'I-cells'}", + "78, JAK {'perturbing_action': 'B-pharmacological inhibition'}", + "79, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "80, (JAKi). {'perturbing_action': 'I-pharmacological inhibition'}", + "82, aged {'context': 'B-organism'}", + "83, (20- {'context': 'I-organism'}", + "86, mice {'context': 'I-organism'}", + "91, activation {'perturbing_action': 'B-pharmacological augmentation'}", + "92, of {'perturbing_action': 'I-pharmacological augmentation'}", + "93, the {'perturbing_action': 'I-pharmacological augmentation'}", + "94, INK-ATTAC {'perturbing_action': 'I-pharmacological augmentation'}", + "95, caspase {'perturbing_action': 'I-pharmacological augmentation'}", + "96, 8 {'perturbing_action': 'I-pharmacological augmentation'}", + "98, senescent {'context': 'B-cells'}", + "99, cells {'context': 'I-cells'}", + "124, mice. {'context': 'B-organism'}", + "130, senescent {'context': 'B-cells'}", + "131, cells {'context': 'I-cells'}", + "151, mice. {'context': 'B-organism'}", + "152, In {'context': 'B-in vitro'}", + "153, vitro {'context': 'I-in vitro'}", + "161, osteoblast {'context': 'B-cells'}", + "165, osteoclast-progenitor {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "74, senescent ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "75, cells ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "78, JAK ['l1', 'l17', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "79, inhibitor ['l2', 'l18', 'l31', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "80, (JAKi). ['l3', 'l19', 'l32', 'l47', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "82, aged ['l4', 'l20', 'l33', 'l48', 'l61', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "83, (20- ['l5', 'l21', 'l34', 'l49', 'l62', 'l74', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "84, to ['l6', 'l22', 'l35', 'l50', 'l63', 'l75', 'l84', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "85, 22-month-old) ['l7', 'l23', 'l36', 'l51', 'l64', 'l76', 'l85', 'l91', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "86, mice ['l8', 'l24', 'l37', 'l52', 'l65', 'l77', 'l86', 'l92', 'l99', 'l106', 'l107']", + "91, activation ['l9', 'l25', 'l38', 'l53', 'l66', 'l78', 'l93', 'l100', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "92, of ['l10', 'l26', 'l39', 'l54', 'l67', 'l79', 'l94', 'l101', 'l108', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "93, the ['l11', 'l40', 'l55', 'l68', 'l109', 'l117', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "94, INK-ATTAC ['l12', 'l41', 'l56', 'l69', 'l110', 'l118', 'l125', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "95, caspase ['l13', 'l27', 'l42', 'l57', 'l70', 'l80', 'l87', 'l95', 'l102', 'l111', 'l119', 'l126', 'l133', 'l141', 'l142', 'l143', 'l144', 'l145']", + "96, 8 ['l14', 'l28', 'l43', 'l58', 'l71', 'l81', 'l88', 'l96', 'l103', 'l112', 'l120', 'l127', 'l134', 'l141', 'l146', 'l147', 'l148', 'l149']", + "98, senescent ['l15', 'l29', 'l44', 'l59', 'l72', 'l82', 'l89', 'l97', 'l104', 'l106', 'l113', 'l121', 'l128', 'l135', 'l142', 'l146', 'l150', 'l151']", + "99, cells ['l16', 'l30', 'l45', 'l60', 'l73', 'l83', 'l90', 'l98', 'l105', 'l107', 'l114', 'l122', 'l129', 'l136', 'l143', 'l147', 'l150']", + "124, mice. ['l115', 'l123', 'l130', 'l137', 'l144', 'l148', 'l152', 'l153', 'l154']", + "130, senescent ['l131', 'l138', 'l152', 'l155', 'l156', 'l157']", + "131, cells ['l46', 'l116', 'l124', 'l132', 'l139', 'l145', 'l149', 'l151', 'l153', 'l155', 'l158']", + "151, mice. ['l140', 'l154', 'l156', 'l158', 'l159']", + "152, In ['l160', 'l161', 'l162']", + "153, vitro ['l160', 'l163', 'l164']", + "161, osteoblast ['l157', 'l159', 'l161', 'l163', 'l165']", + "165, osteoclast-progenitor ['l162', 'l164', 'l165']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "senescent", + "cells" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "JAK", + "inhibitor", + "(JAKi)." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "senescent", + "cells" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "of", + "the", + "INK-ATTAC", + "caspase", + "8" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "JAK", + "inhibitor", + "(JAKi)." + ] + }, + "context": { + "val": "organism", + "words": [ + "aged", + "(20-", + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "aged", + "(20-", + "mice." + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "of", + "caspase", + "8", + "the", + "INK-ATTAC" + ] + } + } + ] + }, + { + "PMID": "28714989", + "TEXT": "Splice-site defects account for about 10% of pathogenic mutations that cause Mendelian diseases. Prevalence is higher in neuromuscular disorders (NMDs), owing to the unusually large size and multi-exonic nature of genes encoding muscle structural proteins. Therapeutic genome editing to correct disease-causing splice-site mutations has been accomplished only through the homology-directed repair pathway, which is extremely inefficient in postmitotic tissues such as skeletal muscle. Here we describe a strategy using nonhomologous end-joining (NHEJ) to correct a pathogenic splice-site mutation. As a proof of principle, we focus on congenital muscular dystrophy type 1A (MDC1A), which is characterized by severe muscle wasting and paralysis. Specifically, we correct a splice-site mutation that causes the exclusion of exon 2 from Lama2 mRNA and the truncation of Lama2 protein in the dy2J/dy2J mouse model of MDC1A. Through systemic delivery of adeno-associated virus (AAV) carrying clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 genome-editing components, we simultaneously excise an intronic region containing the mutation and create a functional donor splice site through NHEJ. This strategy leads to the inclusion of exon 2 in the Lama2 transcript and restoration of full-length Lama2 protein. Treated dy2J/dy2J mice display substantial improvement in muscle histopathology and function without signs of paralysis.", + "TAG_DATA": [ + "125, dy2J/dy2J {'perturbing_action': 'B-other'}", + "126, mouse {'context': 'B-organism'}", + "127, model {'context': 'I-organism'}", + "128, of {'context': 'I-organism'}", + "129, MDC1A. {'context': 'I-organism'}", + "185, dy2J/dy2J {'perturbing_action': 'B-other', 'context': 'B-organism'}", + "186, mice {'context': 'I-organism'}", + "191, muscle {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "125, dy2J/dy2J ['l0', 'l1', 'l2', 'l3']", + "126, mouse ['l0', 'l4', 'l5', 'l6']", + "127, model ['l1', 'l4', 'l7', 'l8']", + "128, of ['l2', 'l5', 'l7', 'l9']", + "129, MDC1A. ['l3', 'l6', 'l8', 'l9']", + "185, dy2J/dy2J ['l10', 'l11']", + "186, mice ['l10', 'l12']", + "191, muscle ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "dy2J/dy2J" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "MDC1A.", + "dy2J/dy2J" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "dy2J/dy2J" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscle" + ] + } + } + ] + }, + { + "PMID": "28714988", + "TEXT": "Previous studies have reported associations of IFITM3 SNP rs12252 with severe influenza, but evidence of association and the mechanism by which risk is conferred remain controversial. We prioritized SNPs in IFITM3 on the basis of putative biological function and identified rs34481144 in the 5' UTR. We found evidence of a new association of rs34481144 with severe influenza in three influenza-infected cohorts characterized by different levels of influenza illness severity. We determined a role for rs34481144 as an expression quantitative trait locus (eQTL) for IFITM3, with the risk allele associated with lower mRNA expression. The risk allele was found to have decreased IRF3 binding and increased CTCF binding in promoter-binding assays, and risk allele carriage diminished transcriptional correlations among IFITM3-neighboring genes, indicative of CTCF boundary activity. Furthermore, the risk allele disrupts a CpG site that undergoes differential methylation in CD8+ T cell subsets. Carriers of the risk allele had reduced numbers of CD8+ T cells in their airways during natural influenza infection, consistent with IFITM3 promoting accumulation of CD8+ T cells in airways and indicating that a critical function for IFITM3 may be to promote immune cell persistence at mucosal sites.Our study identifies a new regulator of IFITM3 expression that associates with CD8+ T cell levels in the airways and a spectrum of clinical outcomes.", + "TAG_DATA": [ + "138, CD8+ {'context': 'B-cells'}", + "139, T {'context': 'I-cells'}", + "140, cell {'context': 'I-cells'}", + "142, Carriers {'perturbing_action': 'B-other'}", + "143, of {'perturbing_action': 'I-other'}", + "144, the {'perturbing_action': 'I-other'}", + "145, risk {'perturbing_action': 'I-other'}", + "146, allele {'perturbing_action': 'I-other'}", + "151, CD8+ {'context': 'B-cells'}", + "152, T {'context': 'I-cells'}", + "153, cells {'context': 'I-cells'}", + "156, airways {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "138, CD8+ ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "139, T ['l0', 'l8', 'l9', 'l10', 'l11', 'l12']", + "140, cell ['l1', 'l8', 'l13', 'l14', 'l15', 'l16']", + "142, Carriers ['l2', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "143, of ['l17', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "144, the ['l18', 'l25', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "145, risk ['l19', 'l26', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "146, allele ['l3', 'l20', 'l27', 'l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "151, CD8+ ['l4', 'l9', 'l13', 'l21', 'l28', 'l34', 'l39', 'l43', 'l47', 'l48', 'l49']", + "152, T ['l5', 'l10', 'l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l47', 'l50', 'l51']", + "153, cells ['l6', 'l11', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l50', 'l52']", + "156, airways ['l7', 'l12', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l52']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD8+", + "T", + "cells" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Carriers", + "allele", + "of", + "the", + "risk" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Carriers", + "of", + "the", + "risk", + "allele" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "airways" + ] + } + } + ] + }, + { + "PMID": "28628110", + "TEXT": "With the goal of modeling human disease of the large intestine, we sought to develop an effective protocol for deriving colonic organoids (COs) from differentiated human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs). Extensive gene and immunohistochemical profiling confirmed that the derived COs represent colon rather than small intestine, containing stem cells, transit-amplifying cells, and the expected spectrum of differentiated cells, including goblet and endocrine cells. We applied this strategy to iPSCs derived from patients with familial adenomatous polyposis (FAP-iPSCs) harboring germline mutations in the WNT-signaling-pathway-regulator gene encoding APC, and we generated COs that exhibit enhanced WNT activity and increased epithelial cell proliferation, which we used as a platform for drug testing. Two potential compounds, XAV939 and rapamycin, decreased proliferation in FAP-COs, but also affected cell proliferation in wild-type COs, which thus limits their therapeutic application. By contrast, we found that geneticin, a ribosome-binding antibiotic with translational 'read-through' activity, efficiently targeted abnormal WNT activity and restored normal proliferation specifically in APC-mutant FAP-COs. These studies provide an efficient strategy for deriving human COs, which can be used in disease modeling and drug discovery for colorectal disease.", + "TAG_DATA": [ + "102, increased {'effect': 'B-positive'}", + "103, epithelial {'context': 'B-cells'}", + "104, cell {'context': 'I-cells'}", + "105, proliferation, {'phenotype': 'B-proliferation'}", + "121, decreased {'effect': 'B-negative'}", + "122, proliferation {'phenotype': 'B-proliferation'}", + "124, FAP-COs, {'context': 'B-cells'}", + "127, affected {'effect': 'B-regulates'}", + "128, cell {'context': 'B-cells'}", + "129, proliferation {'phenotype': 'B-proliferation'}", + "158, restored {'effect': 'B-rescues'}", + "160, proliferation {'phenotype': 'B-proliferation'}", + "163, APC-mutant {'perturbing_action': 'B-other'}" + ], + "LINK_DATA": [ + "102, increased ['l0', 'l1', 'l2']", + "103, epithelial ['l0', 'l3', 'l4']", + "104, cell ['l1', 'l3', 'l5']", + "105, proliferation, ['l2', 'l4', 'l5']", + "121, decreased ['l6', 'l7', 'l8', 'l9', 'l10']", + "122, proliferation ['l6', 'l11', 'l12', 'l13', 'l14']", + "124, FAP-COs, ['l7', 'l11', 'l15', 'l16', 'l17']", + "127, affected ['l8', 'l12', 'l15', 'l18', 'l19']", + "128, cell ['l9', 'l13', 'l16', 'l18', 'l20']", + "129, proliferation ['l10', 'l14', 'l17', 'l19', 'l20']", + "158, restored ['l21', 'l22']", + "160, proliferation ['l21', 'l23']", + "163, APC-mutant ['l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "cells", + "words": [ + "epithelial", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "epithelial", + "cell", + "FAP-COs," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation,", + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "context": { + "val": "cells", + "words": [ + "FAP-COs,", + "cell" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "affected" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "FAP-COs,", + "cell" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "affected" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "APC-mutant" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "APC-mutant" + ] + } + } + ] + }, + { + "PMID": "28604704", + "TEXT": "Nonalcoholic fatty liver disease (NAFLD), a common prelude to cirrhosis and hepatocellular carcinoma, is the most common chronic liver disease worldwide. Defining the molecular mechanisms underlying the pathogenesis of NAFLD has been hampered by a lack of animal models that closely recapitulate the severe end of the disease spectrum in humans, including bridging hepatic fibrosis. Here we demonstrate that a novel experimental model employing thermoneutral housing, as opposed to standard housing, resulted in lower stress-driven production of corticosterone, augmented mouse proinflammatory immune responses and markedly exacerbated high-fat diet (HFD)-induced NAFLD pathogenesis. Disease exacerbation at thermoneutrality was conserved across multiple mouse strains and was associated with augmented intestinal permeability, an altered microbiome and activation of inflammatory pathways that are associated with the disease in humans. Depletion of Gram-negative microbiota, hematopoietic cell deletion of Toll-like receptor 4 (TLR4) and inactivation of the IL-17 axis resulted in altered immune responsiveness and protection from thermoneutral-housing-driven NAFLD amplification. Finally, female mice, typically resistant to HFD-induced obesity and NAFLD, develop full disease characteristics at thermoneutrality. Thus, thermoneutral housing provides a sex-independent model of exacerbated NAFLD in mice and represents a novel approach for interrogation of the cellular and molecular mechanisms underlying disease pathogenesis.", + "TAG_DATA": [ + "99, mouse {'context': 'B-organism'}", + "100, strains {'context': 'I-organism'}", + "128, hematopoietic {'context': 'B-cells'}", + "129, cell {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "130, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "131, of {'perturbing_action': 'I-gene loss-of-function'}", + "132, Toll-like {'perturbing_action': 'I-gene loss-of-function'}", + "133, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "134, 4 {'perturbing_action': 'I-gene loss-of-function'}", + "135, (TLR4) {'perturbing_action': 'I-gene loss-of-function'}", + "154, female {'context': 'B-organism'}", + "155, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "99, mouse ['l0']", + "100, strains ['l0']", + "128, hematopoietic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "129, cell ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "130, deletion ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "131, of ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "132, Toll-like ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "133, receptor ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "134, 4 ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "135, (TLR4) ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']", + "154, female ['l29']", + "155, mice, ['l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "cell" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cell", + "deletion", + "of", + "Toll-like", + "receptor", + "4", + "(TLR4)" + ] + } + } + ] + }, + { + "PMID": "28553932", + "TEXT": "Clear cell renal cell carcinomas (ccRCCs) frequently exhibit inactivation of the von Hippel-Lindau tumor-suppressor gene, VHL, and often harbor multiple copy-number alterations in genes that regulate cell cycle progression. We show here that modeling these genetic alterations by combined deletion of Vhl, Trp53 and Rb1 specifically in renal epithelial cells in mice caused ccRCC. These tumors arose from proximal tubule epithelial cells and shared molecular markers and mRNA expression profiles with human ccRCC. Exome sequencing revealed that mouse and human ccRCCs exhibit recurrent mutations in genes associated with the primary cilium, uncovering a mutational convergence on this organelle and implicating a subset of ccRCCs as genetic ciliopathies. Different mouse tumors responded differently to standard therapies for advanced human ccRCC, mimicking the range of clinical behaviors in the human disease. Inhibition of hypoxia-inducible factor (HIF)-α transcription factors with acriflavine as third-line therapy had therapeutic effects in some tumors, providing preclinical evidence for further investigation of HIF-α inhibition as a ccRCC treatment. This autochthonous mouse ccRCC model represents a tool to investigate the biology of ccRCC and to identify new treatment strategies.", + "TAG_DATA": [ + "39, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "40, of {'perturbing_action': 'I-gene loss-of-function'}", + "41, Vhl, {'perturbing_action': 'I-gene loss-of-function'}", + "42, Trp53 {'perturbing_action': 'I-gene loss-of-function'}", + "43, and {'perturbing_action': 'I-gene loss-of-function'}", + "44, Rb1 {'perturbing_action': 'I-gene loss-of-function'}", + "47, renal {'context': 'B-cells'}", + "48, epithelial {'context': 'I-cells'}", + "49, cells {'context': 'I-cells'}", + "51, mice {'context': 'B-organism'}", + "108, mouse {'context': 'B-neoplasm'}", + "109, tumors {'context': 'I-neoplasm'}", + "146, tumors, {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "39, deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "40, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "41, Vhl, ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "42, Trp53 ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "43, and ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "44, Rb1 ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "47, renal ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "48, epithelial ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "49, cells ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "51, mice ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "108, mouse ['l45']", + "109, tumors ['l45']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Vhl,", + "Trp53", + "and", + "Rb1" + ] + }, + "context": { + "val": "cells", + "words": [ + "renal", + "epithelial", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Vhl,", + "Trp53", + "and", + "Rb1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "28481357", + "TEXT": "Non-alcoholic steatohepatitis (NASH) is an increasingly prevalent liver pathology that can progress from non-alcoholic fatty liver disease (NAFLD), and it is a leading cause of cirrhosis and hepatocellular carcinoma. There is currently no pharmacological therapy for NASH. Defective lysosome-mediated protein degradation is a key process that underlies steatohepatitis and a well-recognized drug target in a variety of diseases; however, whether it can serve as a therapeutic target for NAFLD and NASH remains unknown. Here we report that transmembrane BAX inhibitor motif-containing 1 (TMBIM1) is an effective suppressor of steatohepatitis and a previously unknown regulator of the multivesicular body (MVB)-lysosomal pathway. Tmbim1 expression in hepatocytes substantially inhibited high-fat diet-induced insulin resistance, hepatic steatosis and inflammation in mice. Mechanistically, Tmbim1 promoted the lysosomal degradation of toll-like receptor 4 by cooperating with the ESCRT endosomal sorting complex to facilitate MVB formation, and the ubiquitination of Tmbim1 by the E3 ubiquitin ligase Nedd4l was required for this process. We also found that overexpression of Tmbim1 in the liver effectively inhibited a severe form of NAFLD in mice and NASH progression in monkeys. Taken together, these findings could lead to the development of promising strategies to treat NASH by targeting MVB regulators to properly orchestrate the lysosome-mediated protein degradation of key mediators of the disease.", + "TAG_DATA": [ + "100, Tmbim1 {'perturbing_action': 'B-gene gain-of-function'}", + "101, expression {'perturbing_action': 'I-gene gain-of-function'}", + "103, hepatocytes {'context': 'B-cells'}", + "115, mice. {'context': 'B-organism'}", + "158, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "159, of {'perturbing_action': 'I-gene gain-of-function'}", + "160, Tmbim1 {'perturbing_action': 'I-gene gain-of-function'}", + "163, liver {'context': 'B-tissue/organ'}", + "172, mice {'context': 'B-organism'}", + "177, monkeys. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "100, Tmbim1 ['l0', 'l1', 'l2']", + "101, expression ['l0', 'l3', 'l4']", + "103, hepatocytes ['l1', 'l3', 'l5']", + "115, mice. ['l2', 'l4', 'l5']", + "158, overexpression ['l6', 'l7', 'l8', 'l9', 'l10']", + "159, of ['l6', 'l11', 'l12', 'l13', 'l14']", + "160, Tmbim1 ['l7', 'l11', 'l15', 'l16', 'l17']", + "163, liver ['l8', 'l12', 'l15', 'l18', 'l19']", + "172, mice ['l9', 'l13', 'l16', 'l18']", + "177, monkeys. ['l10', 'l14', 'l17', 'l19']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Tmbim1", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Tmbim1", + "expression", + "overexpression", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice", + "monkeys." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Tmbim1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "28436958", + "TEXT": "Senescent cells (SnCs) accumulate in many vertebrate tissues with age and contribute to age-related pathologies, presumably through their secretion of factors contributing to the senescence-associated secretory phenotype (SASP). Removal of SnCs delays several pathologies and increases healthy lifespan. Aging and trauma are risk factors for the development of osteoarthritis (OA), a chronic disease characterized by degeneration of articular cartilage leading to pain and physical disability. Senescent chondrocytes are found in cartilage tissue isolated from patients undergoing joint replacement surgery, yet their role in disease pathogenesis is unknown. To test the idea that SnCs might play a causative role in OA, we used the p16-3MR transgenic mouse, which harbors a p16INK4a (Cdkn2a) promoter driving the expression of a fusion protein containing synthetic Renilla luciferase and monomeric red fluorescent protein domains, as well as a truncated form of herpes simplex virus 1 thymidine kinase (HSV-TK). This mouse strain allowed us to selectively follow and remove SnCs after anterior cruciate ligament transection (ACLT). We found that SnCs accumulated in the articular cartilage and synovium after ACLT, and selective elimination of these cells attenuated the development of post-traumatic OA, reduced pain and increased cartilage development. Intra-articular injection of a senolytic molecule that selectively killed SnCs validated these results in transgenic, non-transgenic and aged mice. Selective removal of the SnCs from in vitro cultures of chondrocytes isolated from patients with OA undergoing total knee replacement decreased expression of senescent and inflammatory markers while also increasing expression of cartilage tissue extracellular matrix proteins. Collectively, these findings support the use of SnCs as a therapeutic target for treating degenerative joint disease.", + "TAG_DATA": [ + "103, p16-3MR {'context': 'B-organism'}", + "104, transgenic {'context': 'I-organism'}", + "105, mouse, {'context': 'I-organism'}", + "108, a {'perturbing_action': 'I-gene gain-of-function'}", + "109, p16INK4a {'perturbing_action': 'I-other'}", + "110, (Cdkn2a) {'perturbing_action': 'I-other'}", + "111, promoter {'perturbing_action': 'I-other'}", + "144, mouse {'context': 'B-organism'}", + "145, strain {'context': 'I-organism'}", + "178, cells {'context': 'B-cells'}", + "200, SnCs {'context': 'B-cells'}", + "208, aged {'context': 'B-organism'}", + "209, mice. {'context': 'I-organism'}", + "216, in {'context': 'B-in vitro'}", + "217, vitro {'context': 'I-in vitro'}", + "218, cultures {'context': 'I-in vitro'}", + "220, chondrocytes {'context': 'B-cells'}", + "221, isolated {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "103, p16-3MR ['l0', 'l1']", + "104, transgenic ['l0', 'l2']", + "105, mouse, ['l1', 'l2']", + "108, a ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "109, p16INK4a ['l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "110, (Cdkn2a) ['l4', 'l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "111, promoter ['l5', 'l11', 'l16', 'l21', 'l22', 'l23']", + "112, driving ['l6', 'l12', 'l17', 'l21', 'l24', 'l25']", + "144, mouse ['l7', 'l13', 'l18', 'l22', 'l24', 'l26']", + "145, strain ['l8', 'l14', 'l19', 'l23', 'l25', 'l26']", + "178, cells ['l9', 'l15', 'l20']", + "200, SnCs ['l27', 'l28', 'l29']", + "208, aged ['l27', 'l30']", + "209, mice. ['l28', 'l30']", + "216, in ['l31', 'l32', 'l33', 'l34']", + "217, vitro ['l31', 'l35', 'l36', 'l37']", + "218, cultures ['l32', 'l35', 'l38', 'l39']", + "220, chondrocytes ['l33', 'l36', 'l38', 'l40']", + "221, isolated ['l29', 'l34', 'l37', 'l39', 'l40']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "a" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "strain" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "a" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "p16INK4a", + "(Cdkn2a)", + "promoter" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "strain" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "p16INK4a", + "(Cdkn2a)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "28394328", + "TEXT": "Zika virus (ZIKV) infection of pregnant women can cause a wide range of congenital abnormalities, including microcephaly, in the infant, a condition now collectively known as congenital ZIKV syndrome. A vaccine to prevent or significantly attenuate viremia in pregnant women who are residents of or travelers to epidemic or endemic regions is needed to avert congenital ZIKV syndrome, and might also help to suppress epidemic transmission. Here we report on a live-attenuated vaccine candidate that contains a 10-nucleotide deletion in the 3' untranslated region of the ZIKV genome (10-del ZIKV). The 10-del ZIKV is highly attenuated, immunogenic, and protective in type 1 interferon receptor-deficient A129 mice. Crucially, a single dose of 10-del ZIKV induced sterilizing immunity with a saturated neutralizing antibody titer, which no longer increased after challenge with an epidemic ZIKV, and completely prevented viremia. The immunized mice also developed a robust T cell response. Intracranial inoculation of 1-d-old immunocompetent CD-1 mice with 1 × 104 infectious focus units (IFU) of 10-del ZIKV caused no mortality, whereas infections with 10 IFU of wild-type ZIKV were lethal. Mechanistically, the attenuated virulence of 10-del ZIKV may be due to decreased viral RNA synthesis and increased sensitivity to type-1-interferon inhibition. The attenuated 10-del ZIKV was incapable of infecting mosquitoes after oral feeding of spiked-blood meals, representing an additional safety feature. Collectively, the safety and efficacy results suggest that further development of this promising, live-attenuated ZIKV vaccine candidate is warranted.", + "TAG_DATA": [ + "100, type {'perturbing_action': 'B-gene loss-of-function'}", + "101, 1 {'perturbing_action': 'B-gene loss-of-function'}", + "102, interferon {'perturbing_action': 'I-gene loss-of-function'}", + "103, receptor-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "104, A129 {'context': 'B-organism'}", + "105, mice. {'context': 'I-organism'}", + "138, mice {'context': 'B-organism'}", + "143, T {'context': 'B-cells'}", + "144, cell {'context': 'B-cells'}", + "150, immunocompetent {'context': 'B-organism'}", + "151, CD-1 {'context': 'I-organism'}", + "152, mice {'context': 'I-organism'}", + "206, mosquitoes {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "100, type ['l0', 'l1', 'l2', 'l3', 'l4']", + "101, 1 ['l0', 'l5', 'l6', 'l7', 'l8']", + "102, interferon ['l1', 'l5', 'l9', 'l10', 'l11']", + "103, receptor-deficient ['l2', 'l6', 'l9', 'l12', 'l13']", + "104, A129 ['l3', 'l7', 'l10', 'l12', 'l14']", + "105, mice. ['l4', 'l8', 'l11', 'l13', 'l14']", + "138, mice ['l15', 'l16']", + "143, T ['l15', 'l17', 'l18', 'l19']", + "144, cell ['l16', 'l17', 'l20']", + "150, immunocompetent ['l21', 'l22']", + "151, CD-1 ['l18', 'l21', 'l23']", + "152, mice ['l19', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "type", + "1", + "interferon", + "receptor-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "A129", + "mice." + ] + } + } + ] + }, + { + "PMID": "28263310", + "TEXT": "Exercise has numerous health-promoting effects in humans; however, individual responsiveness to exercise with regard to endurance or metabolic health differs markedly. This 'exercise resistance' is considered to be congenital, with no evident acquired causative factors. Here we show that the anti-oxidative hepatokine selenoprotein P (SeP) causes exercise resistance through its muscle receptor low-density lipoprotein receptor-related protein 1 (LRP1). SeP-deficient mice showed a 'super-endurance' phenotype after exercise training, as well as enhanced reactive oxygen species (ROS) production, AMP-activated protein kinase (AMPK) phosphorylation and peroxisome proliferative activated receptor γ coactivator (Ppargc)-1α (also known as PGC-1α; encoded by Ppargc1a) expression in skeletal muscle. Supplementation with the anti-oxidant N-acetylcysteine (NAC) reduced ROS production and the endurance capacity in SeP-deficient mice. SeP treatment impaired hydrogen-peroxide-induced adaptations through LRP1 in cultured myotubes and suppressed exercise-induced AMPK phosphorylation and Ppargc1a gene expression in mouse skeletal muscle-effects which were blunted in mice with a muscle-specific LRP1 deficiency. Furthermore, we found that increased amounts of circulating SeP predicted the ineffectiveness of training on endurance capacity in humans. Our study suggests that inhibitors of the SeP-LRP1 axis may function as exercise-enhancing drugs to treat diseases associated with a sedentary lifestyle.", + "TAG_DATA": [ + "58, SeP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "59, mice {'context': 'B-organism'}", + "114, SeP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "115, mice. {'context': 'B-organism'}", + "124, cultured {'context': 'B-cells'}", + "125, myotubes {'context': 'I-cells'}", + "136, mouse {'context': 'B-tissue/organ'}", + "137, skeletal {'context': 'I-tissue/organ'}", + "138, muscle-effects {'context': 'I-tissue/organ'}", + "143, mice {'context': 'B-organism'}", + "146, muscle-specific {'perturbing_action': 'B-gene loss-of-function'}", + "147, LRP1 {'perturbing_action': 'I-gene loss-of-function'}", + "148, deficiency. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "58, SeP-deficient ['l0']", + "59, mice ['l0']", + "114, SeP-deficient ['l1', 'l2', 'l3']", + "115, mice. ['l1']", + "124, cultured ['l2', 'l4']", + "125, myotubes ['l3', 'l4']", + "136, mouse ['l5', 'l6']", + "137, skeletal ['l5', 'l7']", + "138, muscle-effects ['l6', 'l7']", + "143, mice ['l8', 'l9', 'l10']", + "146, muscle-specific ['l8', 'l11', 'l12']", + "147, LRP1 ['l9', 'l11', 'l13']", + "148, deficiency. ['l10', 'l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SeP-deficient", + "muscle-specific", + "LRP1", + "deficiency." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SeP-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "myotubes" + ] + } + } + ] + }, + { + "PMID": "28191887", + "TEXT": "Expression of the MECOM (also known as EVI1) proto-oncogene is deregulated by chromosomal translocations in some cases of acute myeloid leukemia (AML) and is associated with poor clinical outcome. Here, through transcriptomic and metabolomic profiling of hematopoietic cells, we reveal that EVI1 overexpression alters cellular metabolism. A screen using pooled short hairpin RNAs (shRNAs) identified the ATP-buffering, mitochondrial creatine kinase CKMT1 as necessary for survival of EVI1-expressing cells in subjects with EVI1-positive AML. EVI1 promotes CKMT1 expression by repressing the myeloid differentiation regulator RUNX1. Suppression of arginine-creatine metabolism by CKMT1-directed shRNAs or by the small molecule cyclocreatine selectively decreased the viability, promoted the cell cycle arrest and apoptosis of human EVI1-positive cell lines, and prolonged survival in both orthotopic xenograft models and mouse models of primary AML. CKMT1 inhibition altered mitochondrial respiration and ATP production, an effect that was abrogated by phosphocreatine-mediated reactivation of the arginine-creatine pathway. Targeting CKMT1 is thus a promising therapeutic strategy for this EVI1-driven AML subtype that is highly resistant to current treatment regimens.", + "TAG_DATA": [ + "89, CKMT1-directed {'perturbing_action': 'B-rnai/knockdown'}", + "90, shRNAs {'perturbing_action': 'I-rnai/knockdown'}", + "101, promoted {'effect': 'B-positive'}", + "103, cell {'phenotype': 'B-cell cycle arrest'}", + "104, cycle {'phenotype': 'I-cell cycle arrest'}", + "105, arrest {'phenotype': 'I-cell cycle arrest'}", + "107, apoptosis {'phenotype': 'B-apoptosis'}", + "109, human {'context': 'B-cells'}", + "110, EVI1-positive {'context': 'I-cells'}", + "111, cell {'context': 'I-cells'}", + "112, lines, {'context': 'I-cells'}", + "118, orthotopic {'context': 'B-xenograft'}", + "119, xenograft {'context': 'I-xenograft'}", + "120, models {'context': 'I-xenograft'}", + "122, mouse {'context': 'B-neoplasm'}", + "123, models {'context': 'I-neoplasm'}", + "124, of {'context': 'I-neoplasm'}", + "125, primary {'context': 'I-neoplasm'}", + "126, AML. {'context': 'I-neoplasm'}", + "127, CKMT1 {'perturbing_action': 'B-pharmacological inhibition'}", + "128, inhibition {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "89, CKMT1-directed ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "90, shRNAs ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "101, promoted ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "103, cell ['l2', 'l14', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "104, cycle ['l3', 'l15', 'l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "105, arrest ['l4', 'l16', 'l27', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "107, apoptosis ['l5', 'l17', 'l28', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "109, human ['l6', 'l18', 'l29', 'l36', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57', 'l58', 'l59']", + "110, EVI1-positive ['l7', 'l19', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l60', 'l61', 'l62', 'l63', 'l64']", + "111, cell ['l8', 'l20', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l60', 'l65']", + "112, lines, ['l9', 'l21', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l61', 'l65']", + "118, orthotopic ['l10', 'l22', 'l62', 'l66', 'l67']", + "119, xenograft ['l11', 'l23', 'l58', 'l63', 'l66', 'l68']", + "120, models ['l12', 'l24', 'l59', 'l64', 'l67', 'l68']", + "122, mouse ['l69', 'l70', 'l71', 'l72', 'l73']", + "123, models ['l69', 'l74', 'l75', 'l76']", + "124, of ['l70', 'l74', 'l77', 'l78']", + "125, primary ['l71', 'l75', 'l77', 'l79', 'l80']", + "126, AML. ['l72', 'l76', 'l78', 'l79']", + "127, CKMT1 ['l81']", + "128, inhibition ['l73', 'l80', 'l81']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "CKMT1-directed", + "shRNAs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "CKMT1-directed", + "shRNAs" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "CKMT1-directed", + "shRNAs" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "CKMT1-directed", + "shRNAs" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "EVI1-positive", + "cell", + "lines," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "CKMT1-directed", + "shRNAs" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "orthotopic", + "xenograft", + "models" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "EVI1-positive", + "cell", + "lines," + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "EVI1-positive", + "cell", + "lines," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "EVI1-positive", + "cell", + "lines," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "primary" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition" + ] + } + } + ] + }, + { + "PMID": "28134928", + "TEXT": "Opiates are essential for treating pain, but termination of opiate therapy can cause a debilitating withdrawal syndrome in chronic users. To alleviate or avoid the aversive symptoms of withdrawal, many of these individuals continue to use opiates. Withdrawal is therefore a key determinant of opiate use in dependent individuals, yet its underlying mechanisms are poorly understood and effective therapies are lacking. Here, we identify the pannexin-1 (Panx1) channel as a therapeutic target in opiate withdrawal. We show that withdrawal from morphine induces long-term synaptic facilitation in lamina I and II neurons within the rodent spinal dorsal horn, a principal site of action for opiate analgesia. Genetic ablation of Panx1 in microglia abolished the spinal synaptic facilitation and ameliorated the sequelae of morphine withdrawal. Panx1 is unique in its permeability to molecules up to 1 kDa in size and its release of ATP. We show that Panx1 activation drives ATP release from microglia during morphine withdrawal and that degrading endogenous spinal ATP by administering apyrase produces a reduction in withdrawal behaviors. Conversely, we found that pharmacological inhibition of ATP breakdown exacerbates withdrawal. Treatment with a Panx1-blocking peptide (10panx) or the clinically used broad-spectrum Panx1 blockers, mefloquine or probenecid, suppressed ATP release and reduced withdrawal severity. Our results demonstrate that Panx1-mediated ATP release from microglia is required for morphine withdrawal in rodents and that blocking Panx1 alleviates the severity of withdrawal without affecting opiate analgesia.", + "TAG_DATA": [ + "86, lamina {'context': 'B-cells'}", + "87, I {'context': 'I-cells'}", + "88, and {'context': 'I-cells'}", + "89, II {'context': 'I-cells'}", + "90, neurons {'context': 'I-cells'}", + "93, rodent {'context': 'B-tissue/organ'}", + "94, spinal {'context': 'I-tissue/organ'}", + "95, dorsal {'context': 'I-tissue/organ'}", + "96, horn, {'context': 'I-tissue/organ'}", + "105, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "106, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "107, of {'perturbing_action': 'I-gene loss-of-function'}", + "108, Panx1 {'perturbing_action': 'I-gene loss-of-function'}", + "110, microglia {'context': 'B-cells'}", + "192, Panx1 {'perturbing_action': 'I-pharmacological inhibition'}", + "193, blockers, {'perturbing_action': 'I-pharmacological inhibition'}", + "222, blocking {'perturbing_action': 'B-pharmacological inhibition'}", + "223, Panx1 {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "86, lamina ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "87, I ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "88, and ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "89, II ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "90, neurons ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "93, rodent ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "94, spinal ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "95, dorsal ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "96, horn, ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "105, Genetic ['l36', 'l37', 'l38', 'l39']", + "106, ablation ['l36', 'l40', 'l41', 'l42']", + "107, of ['l37', 'l40', 'l43', 'l44']", + "108, Panx1 ['l38', 'l41', 'l43', 'l45']", + "110, microglia ['l39', 'l42', 'l44', 'l45']", + "191, broad-spectrum ['l46', 'l47', 'l48', 'l49']", + "192, Panx1 ['l46', 'l50', 'l51', 'l52']", + "193, blockers, ['l47', 'l50', 'l53', 'l54']", + "222, blocking ['l48', 'l51', 'l53', 'l55']", + "223, Panx1 ['l49', 'l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "ablation", + "of", + "Panx1" + ] + }, + "context": { + "val": "cells", + "words": [ + "microglia" + ] + } + } + ] + }, + { + "PMID": "28067900", + "TEXT": "Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. However, graft-versus-host disease (GVHD) and relapse after allo-HSCT remain major impediments to the success of allo-HSCT. Chimeric antigen receptors (CARs) direct tumor cell recognition of adoptively transferred T cells. CD19 is an attractive CAR target, which is expressed in most B cell malignancies, as well as in healthy B cells. Clinical trials using autologous CD19-targeted T cells have shown remarkable promise in various B cell malignancies. However, the use of allogeneic CAR T cells poses a concern in that it may increase risk of the occurrence of GVHD, although this has not been reported in selected patients infused with donor-derived CD19 CAR T cells after allo-HSCT. To understand the mechanism whereby allogeneic CD19 CAR T cells may mediate anti-lymphoma activity without causing a significant increase in the incidence of GVHD, we studied donor-derived CD19 CAR T cells in allo-HSCT and lymphoma models in mice. We demonstrate that alloreactive T cells expressing CD28-costimulated CD19 CARs experience enhanced stimulation, resulting in the progressive loss of both their effector function and proliferative potential, clonal deletion, and significantly decreased occurrence of GVHD. Concurrently, the other CAR T cells that were present in bulk donor T cell populations retained their anti-lymphoma activity in accordance with the requirement that both the T cell receptor (TCR) and CAR be engaged to accelerate T cell exhaustion. In contrast, first-generation and 4-1BB-costimulated CAR T cells increased the occurrence of GVHD. These findings could explain the reduced risk of GVHD occurring with cumulative TCR and CAR signaling.", + "TAG_DATA": [ + "157, mice. {'context': 'B-organism'}", + "161, alloreactive {'context': 'B-cells'}", + "162, T {'context': 'I-cells'}", + "163, cells {'context': 'I-cells'}", + "182, proliferative {'phenotype': 'B-proliferation'}", + "183, potential, {'phenotype': 'I-proliferation'}" + ], + "LINK_DATA": [ + "157, mice. ['l0', 'l1', 'l2']", + "161, alloreactive ['l3', 'l4', 'l5', 'l6']", + "162, T ['l3', 'l7', 'l8', 'l9']", + "163, cells ['l0', 'l4', 'l7', 'l10', 'l11']", + "182, proliferative ['l1', 'l5', 'l8', 'l10', 'l12']", + "183, potential, ['l2', 'l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "potential," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "alloreactive", + "T", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "potential," + ] + } + } + ] + }, + { + "PMID": "27941792", + "TEXT": "In acute myeloid leukemia (AML), therapy resistance frequently occurs, leading to high mortality among patients. However, the mechanisms that render leukemic cells drug resistant remain largely undefined. Here, we identified loss of the histone methyltransferase EZH2 and subsequent reduction of histone H3K27 trimethylation as a novel pathway of acquired resistance to tyrosine kinase inhibitors (TKIs) and cytotoxic drugs in AML. Low EZH2 protein levels correlated with poor prognosis in AML patients. Suppression of EZH2 protein expression induced chemoresistance of AML cell lines and primary cells in vitro and in vivo. Low EZH2 levels resulted in derepression of HOX genes, and knockdown of HOXB7 and HOXA9 in the resistant cells was sufficient to improve sensitivity to TKIs and cytotoxic drugs. The endogenous loss of EZH2 expression in resistant cells and primary blasts from a subset of relapsed AML patients resulted from enhanced CDK1-dependent phosphorylation of EZH2 at Thr487. This interaction was stabilized by heat shock protein 90 (HSP90) and followed by proteasomal degradation of EZH2 in drug-resistant cells. Accordingly, inhibitors of HSP90, CDK1 and the proteasome prevented EZH2 degradation, decreased HOX gene expression and restored drug sensitivity. Finally, patients with reduced EZH2 levels at progression to standard therapy responded to the combination of bortezomib and cytarabine, concomitant with the re-establishment of EZH2 expression and blast clearance. These data suggest restoration of EZH2 protein as a viable approach to overcome treatment resistance in this AML patient population.", + "TAG_DATA": [ + "71, Suppression {'perturbing_action': 'B-rnai/knockdown'}", + "72, of {'perturbing_action': 'I-rnai/knockdown'}", + "73, EZH2 {'perturbing_action': 'I-rnai/knockdown'}", + "74, protein {'perturbing_action': 'I-rnai/knockdown'}", + "75, expression {'perturbing_action': 'I-rnai/knockdown'}", + "79, AML {'context': 'B-transformed cells'}", + "80, cell {'context': 'I-transformed cells'}", + "81, lines {'context': 'I-transformed cells'}", + "83, primary {'context': 'B-cells'}", + "84, cells {'context': 'I-cells'}", + "85, in {'context': 'B-in vitro'}", + "86, vitro {'context': 'I-in vitro'}", + "88, in {'context': 'B-in vivo'}", + "89, vivo. {'context': 'I-in vivo'}", + "100, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "101, of {'perturbing_action': 'I-rnai/knockdown'}", + "102, HOXB7 {'perturbing_action': 'I-rnai/knockdown'}", + "103, and {'perturbing_action': 'I-rnai/knockdown'}", + "104, HOXA9 {'perturbing_action': 'I-rnai/knockdown'}", + "107, resistant {'context': 'B-cells'}", + "108, cells {'context': 'I-cells'}", + "121, loss {'perturbing_action': 'I-gene loss-of-function'}", + "122, of {'perturbing_action': 'I-gene loss-of-function'}", + "123, EZH2 {'perturbing_action': 'I-gene loss-of-function'}", + "124, expression {'perturbing_action': 'I-gene loss-of-function'}", + "126, resistant {'context': 'B-cells'}", + "127, cells {'context': 'I-cells'}", + "129, primary {'context': 'B-transformed cells'}", + "130, blasts {'context': 'I-transformed cells'}", + "165, drug-resistant {'context': 'B-cells'}", + "166, cells. {'context': 'I-cells'}", + "168, inhibitors {'perturbing_action': 'B-pharmacological inhibition'}", + "169, of {'perturbing_action': 'I-pharmacological inhibition'}", + "170, HSP90, {'perturbing_action': 'I-pharmacological inhibition'}", + "171, CDK1 {'perturbing_action': 'I-pharmacological inhibition'}", + "172, and {'perturbing_action': 'I-pharmacological inhibition'}", + "173, the {'perturbing_action': 'I-pharmacological inhibition'}", + "174, proteasome {'perturbing_action': 'I-pharmacological inhibition'}", + "187, patients {'context': 'B-patient'}" + ], + "LINK_DATA": [ + "71, Suppression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "72, of ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "73, EZH2 ['l1', 'l14', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "74, protein ['l2', 'l15', 'l26', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "75, expression ['l3', 'l16', 'l27', 'l37', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "79, AML ['l4', 'l17', 'l28', 'l38', 'l47', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "80, cell ['l5', 'l18', 'l29', 'l39', 'l48', 'l56', 'l62', 'l63', 'l64', 'l65']", + "81, lines ['l6', 'l19', 'l30', 'l40', 'l49', 'l57', 'l62', 'l66', 'l67']", + "83, primary ['l7', 'l20', 'l31', 'l41', 'l50', 'l58', 'l63', 'l66', 'l68', 'l69', 'l70']", + "84, cells ['l8', 'l21', 'l32', 'l42', 'l51', 'l59', 'l64', 'l67', 'l68', 'l71']", + "85, in ['l9', 'l22', 'l33', 'l43', 'l52', 'l60', 'l69', 'l72']", + "86, vitro ['l10', 'l23', 'l34', 'l44', 'l53', 'l61', 'l65', 'l70', 'l71', 'l72']", + "88, in ['l11', 'l24', 'l35', 'l45', 'l54', 'l73']", + "89, vivo. ['l12', 'l25', 'l36', 'l46', 'l55', 'l73']", + "100, knockdown ['l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "101, of ['l74', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "102, HOXB7 ['l75', 'l90', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "103, and ['l76', 'l91', 'l105', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "104, HOXA9 ['l77', 'l92', 'l106', 'l119', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "107, resistant ['l78', 'l93', 'l107', 'l120', 'l132', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "108, cells ['l13', 'l79', 'l94', 'l108', 'l121', 'l133', 'l144', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159']", + "121, loss ['l80', 'l95', 'l109', 'l122', 'l134', 'l145', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168']", + "122, of ['l81', 'l96', 'l110', 'l123', 'l135', 'l146', 'l154', 'l160', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176']", + "123, EZH2 ['l82', 'l97', 'l111', 'l124', 'l136', 'l147', 'l155', 'l161', 'l169', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183']", + "124, expression ['l83', 'l98', 'l112', 'l125', 'l137', 'l148', 'l156', 'l162', 'l170', 'l177', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189']", + "126, resistant ['l84', 'l99', 'l113', 'l126', 'l138', 'l149', 'l157', 'l163', 'l171', 'l178', 'l184', 'l190', 'l191', 'l192', 'l193', 'l194']", + "127, cells ['l85', 'l100', 'l114', 'l127', 'l139', 'l150', 'l158', 'l164', 'l172', 'l179', 'l185', 'l190', 'l195', 'l196', 'l197', 'l198']", + "129, primary ['l86', 'l101', 'l115', 'l128', 'l140', 'l151', 'l165', 'l173', 'l180', 'l186', 'l191', 'l195', 'l199', 'l200', 'l201']", + "130, blasts ['l87', 'l102', 'l116', 'l129', 'l141', 'l152', 'l159', 'l166', 'l174', 'l181', 'l187', 'l192', 'l196', 'l199', 'l202', 'l203']", + "165, drug-resistant ['l88', 'l103', 'l117', 'l130', 'l142', 'l167', 'l175', 'l182', 'l188', 'l193', 'l197', 'l200', 'l202', 'l204']", + "166, cells. ['l89', 'l104', 'l118', 'l131', 'l143', 'l153', 'l168', 'l176', 'l183', 'l189', 'l194', 'l198', 'l201', 'l203', 'l204']", + "168, inhibitors ['l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211']", + "169, of ['l205', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217']", + "170, HSP90, ['l206', 'l212', 'l218', 'l219', 'l220', 'l221', 'l222']", + "171, CDK1 ['l207', 'l213', 'l218', 'l223', 'l224', 'l225', 'l226']", + "172, and ['l208', 'l214', 'l219', 'l223', 'l227', 'l228', 'l229']", + "173, the ['l209', 'l215', 'l220', 'l224', 'l227', 'l230', 'l231']", + "174, proteasome ['l210', 'l216', 'l221', 'l225', 'l228', 'l230', 'l232']", + "187, patients ['l211', 'l217', 'l222', 'l226', 'l229', 'l231', 'l232']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Suppression", + "of", + "EZH2", + "protein", + "expression", + "knockdown", + "HOXB7", + "and", + "HOXA9" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "AML", + "cell", + "lines", + "primary", + "blasts" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Suppression", + "of", + "EZH2", + "protein", + "expression", + "knockdown", + "HOXB7", + "and", + "HOXA9" + ] + }, + "context": { + "val": "cells", + "words": [ + "primary", + "cells", + "resistant", + "drug-resistant", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Suppression", + "of", + "EZH2", + "protein", + "expression" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Suppression", + "of", + "EZH2", + "protein", + "expression" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "resistant", + "cells", + "drug-resistant", + "cells." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "EZH2", + "expression" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "EZH2", + "expression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "blasts" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "HSP90,", + "CDK1", + "and", + "the", + "proteasome" + ] + }, + "context": { + "val": "patient", + "words": [ + "patients" + ] + } + } + ] + }, + { + "PMID": "27869805", + "TEXT": "The enteric nervous system (ENS) of the gastrointestinal tract controls many diverse functions, including motility and epithelial permeability. Perturbations in ENS development or function are common, yet there is no human model for studying ENS-intestinal biology and disease. We used a tissue-engineering approach with embryonic and induced pluripotent stem cells (PSCs) to generate human intestinal tissue containing a functional ENS. We recapitulated normal intestinal ENS development by combining human-PSC-derived neural crest cells (NCCs) and developing human intestinal organoids (HIOs). NCCs recombined with HIOs in vitro migrated into the mesenchyme, differentiated into neurons and glial cells and showed neuronal activity, as measured by rhythmic waves of calcium transients. ENS-containing HIOs grown in vivo formed neuroglial structures similar to a myenteric and submucosal plexus, had functional interstitial cells of Cajal and had an electromechanical coupling that regulated waves of propagating contraction. Finally, we used this system to investigate the cellular and molecular basis for Hirschsprung's disease caused by a mutation in the gene PHOX2B. This is, to the best of our knowledge, the first demonstration of human-PSC-derived intestinal tissue with a functional ENS and how this system can be used to study motility disorders of the human gastrointestinal tract.", + "TAG_DATA": [ + "75, human {'context': 'B-organoid'}", + "76, intestinal {'context': 'I-organoid'}", + "77, organoids {'context': 'I-organoid'}", + "78, (HIOs). {'context': 'I-organoid'}", + "79, NCCs {'context': 'B-cells'}", + "83, in {'context': 'B-in vitro'}", + "84, vitro {'context': 'I-in vitro'}", + "88, mesenchyme, {'context': 'B-tissue/organ'}", + "89, differentiated {'phenotype': 'B-differentiation'}", + "91, neurons {'context': 'B-cells', 'phenotype': 'B-differentiation'}", + "93, glial {'context': 'B-cells'}", + "94, cells {'context': 'I-cells'}", + "110, in {'context': 'B-in vivo'}", + "111, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "75, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "76, intestinal ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "77, organoids ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "78, (HIOs). ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "79, NCCs ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "83, in ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "84, vitro ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "88, mesenchyme, ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "89, differentiated ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "91, neurons ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "93, glial ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "94, cells ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "110, in ['l66']", + "111, vivo ['l66']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organoid", + "words": [ + "human", + "intestinal", + "organoids", + "(HIOs)." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiated", + "neurons" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neurons", + "NCCs", + "glial", + "cells" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "neurons", + "differentiated" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiated", + "neurons" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mesenchyme," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiated", + "neurons" + ] + } + } + ] + }, + { + "PMID": "27869804", + "TEXT": "Cancer cells experience higher oxidative stress from reactive oxygen species (ROS) than do non-malignant cells because of genetic alterations and abnormal growth; as a result, maintenance of the antioxidant glutathione (GSH) is essential for their survival and proliferation. Under conditions of elevated ROS, endogenous L-cysteine (L-Cys) production is insufficient for GSH synthesis. This necessitates uptake of L-Cys that is predominantly in its disulfide form, L-cystine (CSSC), via the xCT(-) transporter. We show that administration of an engineered and pharmacologically optimized human cyst(e)inase enzyme mediates sustained depletion of the extracellular L-Cys and CSSC pool in mice and non-human primates. Treatment with this enzyme selectively causes cell cycle arrest and death in cancer cells due to depletion of intracellular GSH and ensuing elevated ROS; yet this treatment results in no apparent toxicities in mice even after months of continuous treatment. Cyst(e)inase suppressed the growth of prostate carcinoma allografts, reduced tumor growth in both prostate and breast cancer xenografts and doubled the median survival time of TCL1-Tg:p53-/- mice, which develop disease resembling human chronic lymphocytic leukemia. It was observed that enzyme-mediated depletion of the serum L-Cys and CSSC pool suppresses the growth of multiple tumors, yet is very well tolerated for prolonged periods, suggesting that cyst(e)inase represents a safe and effective therapeutic modality for inactivating antioxidant cellular responses in a wide range of malignancies.", + "TAG_DATA": [ + "94, mice {'context': 'B-organism'}", + "96, non-human {'context': 'B-organism'}", + "97, primates. {'context': 'I-organism'}", + "103, causes {'effect': 'B-positive'}", + "104, cell {'phenotype': 'B-cell cycle arrest'}", + "105, cycle {'phenotype': 'I-cell cycle arrest'}", + "106, arrest {'phenotype': 'I-cell cycle arrest'}", + "110, cancer {'context': 'B-transformed cells'}", + "111, cells {'context': 'I-transformed cells'}", + "131, mice {'context': 'B-organism'}", + "143, prostate {'context': 'B-xenograft'}", + "144, carcinoma {'context': 'I-xenograft'}", + "145, allografts, {'context': 'I-xenograft'}", + "146, reduced {'effect': 'B-negative'}", + "147, tumor {'phenotype': 'B-tumour growth'}", + "148, growth {'phenotype': 'I-tumour growth'}", + "151, prostate {'context': 'B-xenograft'}", + "152, and {'context': 'I-xenograft'}", + "153, breast {'context': 'I-xenograft'}", + "154, cancer {'context': 'I-xenograft'}", + "155, xenografts {'context': 'I-xenograft'}", + "163, TCL1-Tg:p53-/- {'perturbing_action': 'B-gene loss-of-function'}", + "164, mice, {'context': 'B-organism'}", + "186, suppresses {'effect': 'B-negative'}", + "191, tumors, {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "94, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "96, non-human ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "97, primates. ['l1', 'l6', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "103, causes ['l7', 'l14', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "104, cell ['l2', 'l8', 'l15', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "105, cycle ['l3', 'l9', 'l16', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "106, arrest ['l4', 'l10', 'l17', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "110, cancer ['l11', 'l18', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "111, cells ['l5', 'l12', 'l19', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58']", + "131, mice ['l13', 'l20', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l60', 'l61']", + "143, prostate ['l27', 'l35', 'l42', 'l48', 'l53', 'l59', 'l62', 'l63', 'l64', 'l65', 'l66']", + "144, carcinoma ['l28', 'l36', 'l43', 'l49', 'l54', 'l57', 'l60', 'l62', 'l67', 'l68', 'l69', 'l70']", + "145, allografts, ['l29', 'l37', 'l44', 'l50', 'l55', 'l58', 'l61', 'l63', 'l67', 'l71', 'l72']", + "146, reduced ['l64', 'l68', 'l71', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "147, tumor ['l65', 'l69', 'l73', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "148, growth ['l66', 'l70', 'l72', 'l74', 'l80', 'l86', 'l87', 'l88', 'l89', 'l90']", + "151, prostate ['l75', 'l81', 'l86', 'l91', 'l92', 'l93', 'l94']", + "152, and ['l76', 'l82', 'l87', 'l91', 'l95', 'l96', 'l97']", + "153, breast ['l77', 'l83', 'l88', 'l92', 'l95', 'l98', 'l99']", + "154, cancer ['l78', 'l84', 'l89', 'l93', 'l96', 'l98', 'l100']", + "155, xenografts ['l79', 'l85', 'l90', 'l94', 'l97', 'l99', 'l100']", + "163, TCL1-Tg:p53-/- ['l101']", + "164, mice, ['l101']", + "186, suppresses ['l102']", + "191, tumors, ['l102']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "non-human", + "primates." + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "non-human", + "primates.", + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "causes" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "prostate", + "carcinoma", + "allografts," + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "prostate", + "carcinoma", + "allografts," + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "prostate", + "carcinoma", + "allografts,", + "and", + "breast", + "cancer", + "xenografts" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "prostate", + "carcinoma", + "allografts,", + "and", + "breast", + "cancer", + "xenografts" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TCL1-Tg:p53-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors," + ] + } + } + ] + }, + { + "PMID": "27841872", + "TEXT": "The cellular inhibitors of apoptosis (cIAP) 1 and 2 are amplified in about 3% of cancers and have been identified in multiple malignancies as being potential therapeutic targets as a result of their role in the evasion of apoptosis. Consequently, small-molecule IAP antagonists, such as LCL161, have entered clinical trials for their ability to induce tumor necrosis factor (TNF)-mediated apoptosis of cancer cells. However, cIAP1 and cIAP2 are recurrently homozygously deleted in multiple myeloma (MM), resulting in constitutive activation of the noncanonical nuclear factor (NF)-κB pathway. To our surprise, we observed robust in vivo anti-myeloma activity of LCL161 in a transgenic myeloma mouse model and in patients with relapsed-refractory MM, where the addition of cyclophosphamide resulted in a median progression-free-survival of 10 months. This effect was not a result of direct induction of tumor cell death, but rather of upregulation of tumor-cell-autonomous type I interferon (IFN) signaling and a strong inflammatory response that resulted in the activation of macrophages and dendritic cells, leading to phagocytosis of tumor cells. Treatment of a MM mouse model with LCL161 established long-term anti-tumor protection and induced regression in a fraction of the mice. Notably, combination of LCL161 with the immune-checkpoint inhibitor anti-PD1 was curative in all of the treated mice.", + "TAG_DATA": [ + "100, transgenic {'context': 'B-organism'}", + "101, myeloma {'context': 'I-organism'}", + "102, mouse {'context': 'I-organism'}", + "103, model {'context': 'I-organism'}", + "106, patients {'context': 'B-patient'}", + "109, MM, {'context': 'B-neoplasm'}", + "131, induction {'effect': 'B-positive'}", + "133, tumor {'context': 'B-neoplasm'}", + "134, cell {'phenotype': 'B-cell death'}", + "135, death, {'phenotype': 'I-cell death'}", + "158, macrophages {'context': 'B-cells'}", + "160, dendritic {'context': 'B-cells'}", + "161, cells, {'context': 'I-cells'}", + "166, tumor {'context': 'B-transformed cells'}", + "167, cells. {'context': 'I-transformed cells'}", + "171, MM {'context': 'B-organism'}", + "172, mouse {'context': 'I-organism'}", + "173, model {'context': 'I-organism'}", + "181, induced {'effect': 'B-positive'}", + "182, regression {'phenotype': 'B-tumour regression'}", + "188, mice. {'context': 'B-organism'}", + "205, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "100, transgenic ['l0', 'l1', 'l2']", + "101, myeloma ['l0', 'l3', 'l4']", + "102, mouse ['l1', 'l3', 'l5']", + "103, model ['l2', 'l4', 'l5']", + "106, patients ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "109, MM, ['l6', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "131, induction ['l7', 'l16', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "133, tumor ['l8', 'l17', 'l25', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "134, cell ['l9', 'l18', 'l26', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "135, death, ['l10', 'l19', 'l27', 'l34', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "158, macrophages ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l51', 'l52', 'l53', 'l54']", + "160, dendritic ['l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l55', 'l56', 'l57']", + "161, cells, ['l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l58', 'l59']", + "166, tumor ['l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l56', 'l58', 'l60']", + "167, cells. ['l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l59', 'l60']", + "171, MM ['l61', 'l62', 'l63', 'l64', 'l65']", + "172, mouse ['l61', 'l66', 'l67', 'l68', 'l69']", + "173, model ['l62', 'l66', 'l70', 'l71', 'l72']", + "181, induced ['l63', 'l67', 'l70', 'l73', 'l74']", + "182, regression ['l64', 'l68', 'l71', 'l73', 'l75']", + "188, mice. ['l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "patients" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "MM,", + "tumor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "MM,", + "tumor" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages", + "dendritic", + "cells," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages", + "dendritic", + "cells," + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "MM", + "mouse", + "model", + "mice." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "MM", + "mouse", + "model", + "mice." + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "regression" + ] + } + } + ] + }, + { + "PMID": "27820603", + "TEXT": "Pharmacological manipulation of specific neural circuits to optimize therapeutic index is an unrealized goal in neurology and psychiatry. AMPA receptors are important for excitatory synaptic transmission, and their antagonists are antiepileptic. Although efficacious, AMPA-receptor antagonists, including perampanel (Fycompa), the only approved antagonist for epilepsy, induce dizziness and motor impairment. We hypothesized that blockade of forebrain AMPA receptors without blocking cerebellar AMPA receptors would be antiepileptic and devoid of motor impairment. Taking advantage of an AMPA receptor auxiliary protein, TARP γ-8, which is selectively expressed in the forebrain and modulates the pharmacological properties of AMPA receptors, we discovered that LY3130481 selectively antagonized recombinant and native AMPA receptors containing γ-8, but not γ-2 (cerebellum) or other TARP members. Two amino acid residues unique to γ-8 determined this selectivity. We also observed antagonism of AMPA receptors expressed in hippocampal, but not cerebellar, tissue from an patient with epilepsy. Corresponding to this selective activity, LY3130481 prevented multiple seizure types in rats and mice and without motor side effects. These findings demonstrate the first rationally discovered molecule targeting specific neural circuitries for therapeutic advantage.", + "TAG_DATA": [ + "151, prevented {'effect': 'B-negative'}", + "156, rats {'context': 'B-organism'}", + "158, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "151, prevented ['l0', 'l1', 'l2']", + "154, types ['l0', 'l3', 'l4']", + "156, rats ['l1', 'l3', 'l5']", + "158, mice ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats", + "mice" + ] + } + } + ] + }, + { + "PMID": "27775704", + "TEXT": "Triple-negative breast cancers (TNBCs) have poor prognosis and lack targeted therapies. Here we identified increased copy number and expression of the PIM1 proto-oncogene in genomic data sets of patients with TNBC. TNBC cells, but not nonmalignant mammary epithelial cells, were dependent on PIM1 for proliferation and protection from apoptosis. PIM1 knockdown reduced expression of the anti-apoptotic factor BCL2, and dynamic BH3 profiling of apoptotic priming revealed that PIM1 prevents mitochondrial-mediated apoptosis in TNBC cell lines. In TNBC tumors and their cellular models, PIM1 expression was associated with several transcriptional signatures involving the transcription factor MYC, and PIM1 depletion in TNBC cell lines decreased, in a MYC-dependent manner, cell population growth and expression of the MYC target gene MCL1. Treatment with the pan-PIM kinase inhibitor AZD1208 impaired the growth of both cell line and patient-derived xenografts and sensitized them to standard-of-care chemotherapy. This work identifies PIM1 as a malignant-cell-selective target in TNBC and the potential use of PIM1 inhibitors for sensitizing TNBC to chemotherapy-induced apoptotic cell death.", + "TAG_DATA": [ + "49, PIM1 {'perturbing_action': 'B-rnai/knockdown'}", + "50, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "68, prevents {'effect': 'B-negative'}", + "70, apoptosis {'phenotype': 'B-apoptosis'}", + "72, TNBC {'context': 'B-transformed cells'}", + "73, cell {'context': 'I-transformed cells'}", + "74, lines. {'context': 'I-transformed cells'}", + "96, PIM1 {'perturbing_action': 'B-gene loss-of-function'}", + "97, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "99, TNBC {'context': 'B-transformed cells'}", + "100, cell {'context': 'I-transformed cells'}", + "101, lines {'context': 'I-transformed cells'}", + "102, decreased, {'effect': 'B-negative'}", + "107, cell {'context': 'B-cells'}", + "108, population {'phenotype': 'I-cell growth'}", + "109, growth {'phenotype': 'I-cell growth'}", + "130, cell {'context': 'B-cells'}", + "131, line {'context': 'I-cells'}", + "133, patient-derived {'context': 'B-xenograft'}", + "134, xenografts {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "49, PIM1 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "50, knockdown ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "68, prevents ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "70, apoptosis ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "72, TNBC ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "73, cell ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "74, lines. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "96, PIM1 ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "97, depletion ['l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "99, TNBC ['l22', 'l31', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "100, cell ['l23', 'l32', 'l38', 'l44', 'l45', 'l46', 'l47', 'l48']", + "101, lines ['l24', 'l33', 'l39', 'l44', 'l49', 'l50', 'l51', 'l52']", + "102, decreased, ['l25', 'l34', 'l40', 'l45', 'l49', 'l53', 'l54', 'l55']", + "107, cell ['l26', 'l35', 'l41', 'l46', 'l50', 'l53', 'l56', 'l57']", + "108, population ['l27', 'l36', 'l42', 'l47', 'l51', 'l54', 'l56', 'l58']", + "109, growth ['l28', 'l37', 'l43', 'l48', 'l52', 'l55', 'l57', 'l58']", + "130, cell ['l29', 'l59', 'l60', 'l61']", + "131, line ['l30', 'l59', 'l62', 'l63']", + "133, patient-derived ['l60', 'l62', 'l64']", + "134, xenografts ['l61', 'l63', 'l64']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PIM1", + "knockdown" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PIM1", + "knockdown" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PIM1", + "knockdown" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cell", + "lines." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents", + "decreased," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cell", + "lines.", + "lines" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cell", + "lines." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PIM1", + "depletion" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cell", + "lines" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PIM1", + "depletion" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PIM1", + "depletion" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "line" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PIM1", + "depletion" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "population", + "growth" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "TNBC", + "cell", + "lines" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "population", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased," + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased," + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "population", + "growth" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "population", + "growth" + ] + } + } + ] + }, + { + "PMID": "27748748", + "TEXT": "Pediatric glioblastoma is one of the most common and most deadly brain tumors in childhood. Using an integrative genetic analysis of 53 pediatric glioblastomas and five in vitro model systems, we identified previously unidentified gene fusions involving the MET oncogene in ∼10% of cases. These MET fusions activated mitogen-activated protein kinase (MAPK) signaling and, in cooperation with lesions compromising cell cycle regulation, induced aggressive glial tumors in vivo. MET inhibitors suppressed MET tumor growth in xenograft models. Finally, we treated a pediatric patient bearing a MET-fusion-expressing glioblastoma with the targeted inhibitor crizotinib. This therapy led to substantial tumor shrinkage and associated relief of symptoms, but new treatment-resistant lesions appeared, indicating that combination therapies are likely necessary to achieve a durable clinical response.", + "TAG_DATA": [ + "64, glial {'context': 'B-neoplasm'}", + "65, tumors {'context': 'I-neoplasm'}", + "66, in {'context': 'B-in vivo'}", + "67, vivo. {'context': 'I-in vivo'}", + "70, suppressed {'effect': 'B-negative'}", + "72, tumor {'phenotype': 'B-tumour growth'}", + "73, growth {'phenotype': 'I-tumour growth'}", + "75, xenograft {'context': 'B-xenograft'}", + "76, models. {'context': 'I-xenograft'}", + "81, pediatric {'context': 'B-patient'}", + "82, patient {'context': 'I-patient'}", + "86, glioblastoma {'context': 'I-neoplasm'}", + "94, led {'effect': 'B-positive'}", + "95, to {'effect': 'I-positive'}", + "97, tumor {'phenotype': 'B-tumour regression'}", + "98, shrinkage {'phenotype': 'I-tumour regression'}" + ], + "LINK_DATA": [ + "64, glial ['l0', 'l1', 'l2']", + "65, tumors ['l0', 'l3', 'l4']", + "66, in ['l1', 'l3', 'l5']", + "67, vivo. ['l2', 'l4', 'l5']", + "70, suppressed ['l6', 'l7', 'l8', 'l9']", + "72, tumor ['l6', 'l10', 'l11', 'l12']", + "73, growth ['l7', 'l10', 'l13', 'l14']", + "75, xenograft ['l8', 'l11', 'l13', 'l15']", + "76, models. ['l9', 'l12', 'l14', 'l15']", + "81, pediatric ['l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "82, patient ['l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "86, glioblastoma ['l17', 'l22', 'l27', 'l28', 'l29', 'l30']", + "94, led ['l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "95, to ['l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "97, tumor ['l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "98, shrinkage ['l21', 'l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "models." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "models." + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "pediatric", + "patient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "pediatric", + "patient" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "shrinkage" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "glioblastoma" + ] + }, + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "glioblastoma" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "shrinkage" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "shrinkage" + ] + } + } + ] + }, + { + "PMID": "27618650", + "TEXT": "Epigenetic reprogramming is a critical process of pathological gene induction during cardiac hypertrophy and remodeling, but the underlying regulatory mechanisms remain to be elucidated. Here we identified a heart-enriched long noncoding (lnc)RNA, named cardiac-hypertrophy-associated epigenetic regulator (Chaer), which is necessary for the development of cardiac hypertrophy. Mechanistically, Chaer directly interacts with the catalytic subunit of polycomb repressor complex 2 (PRC2). This interaction, which is mediated by a 66-mer motif in Chaer, interferes with PRC2 targeting to genomic loci, thereby inhibiting histone H3 lysine 27 methylation at the promoter regions of genes involved in cardiac hypertrophy. The interaction between Chaer and PRC2 is transiently induced after hormone or stress stimulation in a process involving mammalian target of rapamycin complex 1, and this interaction is a prerequisite for epigenetic reprogramming and induction of genes involved in hypertrophy. Inhibition of Chaer expression in the heart before, but not after, the onset of pressure overload substantially attenuates cardiac hypertrophy and dysfunction. Our study reveals that stress-induced pathological gene activation in the heart requires a previously uncharacterized lncRNA-dependent epigenetic checkpoint.", + "TAG_DATA": [ + "135, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "136, of {'perturbing_action': 'I-pharmacological inhibition'}", + "137, Chaer {'perturbing_action': 'I-pharmacological inhibition'}", + "138, expression {'perturbing_action': 'I-pharmacological inhibition'}", + "141, heart {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "135, Inhibition ['l0', 'l1', 'l2', 'l3']", + "136, of ['l0', 'l4', 'l5', 'l6']", + "137, Chaer ['l1', 'l4', 'l7', 'l8']", + "138, expression ['l2', 'l5', 'l7', 'l9']", + "141, heart ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "Chaer", + "expression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "heart" + ] + } + } + ] + }, + { + "PMID": "27595325", + "TEXT": "Adenosine-to-inosine (A-to-I) RNA editing, which is catalyzed by a family of adenosine deaminase acting on RNA (ADAR) enzymes, is important in the epitranscriptomic regulation of RNA metabolism. However, the role of A-to-I RNA editing in vascular disease is unknown. Here we show that cathepsin S mRNA (CTSS), which encodes a cysteine protease associated with angiogenesis and atherosclerosis, is highly edited in human endothelial cells. The 3' untranslated region (3' UTR) of the CTSS transcript contains two inverted repeats, the AluJo and AluSx+ regions, which form a long stem-loop structure that is recognized by ADAR1 as a substrate for editing. RNA editing enables the recruitment of the stabilizing RNA-binding protein human antigen R (HuR; encoded by ELAVL1) to the 3' UTR of the CTSS transcript, thereby controlling CTSS mRNA stability and expression. In endothelial cells, ADAR1 overexpression or treatment of cells with hypoxia or with the inflammatory cytokines interferon-γ and tumor-necrosis-factor-α induces CTSS RNA editing and consequently increases cathepsin S expression. ADAR1 levels and the extent of CTSS RNA editing are associated with changes in cathepsin S levels in patients with atherosclerotic vascular diseases, including subclinical atherosclerosis, coronary artery disease, aortic aneurysms and advanced carotid atherosclerotic disease. These results reveal a previously unrecognized role of RNA editing in gene expression in human atherosclerotic vascular diseases.", + "TAG_DATA": [ + "132, endothelial {'context': 'B-cells'}", + "133, cells, {'context': 'I-cells'}", + "134, ADAR1 {'perturbing_action': 'B-gene gain-of-function'}", + "135, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "139, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "132, endothelial ['l0', 'l1', 'l2']", + "133, cells, ['l0', 'l3', 'l4']", + "134, ADAR1 ['l1', 'l3', 'l5', 'l6']", + "135, overexpression ['l2', 'l4', 'l5', 'l7']", + "139, cells ['l6', 'l7']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells,", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ADAR1", + "overexpression" + ] + } + } + ] + }, + { + "PMID": "27571348", + "TEXT": "Cachexia represents a fatal energy-wasting syndrome in a large number of patients with cancer that mostly results in a pathological loss of skeletal muscle and adipose tissue. Here we show that tumor cell exposure and tumor growth in mice triggered a futile energy-wasting cycle in cultured white adipocytes and white adipose tissue (WAT), respectively. Although uncoupling protein 1 (Ucp1)-dependent thermogenesis was dispensable for tumor-induced body wasting, WAT from cachectic mice and tumor-cell-supernatant-treated adipocytes were consistently characterized by the simultaneous induction of both lipolytic and lipogenic pathways. Paradoxically, this was accompanied by an inactivated AMP-activated protein kinase (Ampk), which is normally activated in peripheral tissues during states of low cellular energy. Ampk inactivation correlated with its degradation and with upregulation of the Ampk-interacting protein Cidea. Therefore, we developed an Ampk-stabilizing peptide, ACIP, which was able to ameliorate WAT wasting in vitro and in vivo by shielding the Cidea-targeted interaction surface on Ampk. Thus, our data establish the Ucp1-independent remodeling of adipocyte lipid homeostasis as a key event in tumor-induced WAT wasting, and we propose the ACIP-dependent preservation of Ampk integrity in the WAT as a concept in future therapies for cachexia.", + "TAG_DATA": [ + "35, tumor {'phenotype': 'B-tumour growth'}", + "36, growth {'phenotype': 'I-tumour growth'}", + "38, mice {'context': 'B-organism'}", + "45, cultured {'context': 'B-cells'}", + "46, white {'context': 'I-cells'}", + "47, adipocytes {'context': 'I-cells'}", + "49, white {'context': 'B-tissue/organ'}", + "50, adipose {'context': 'I-tissue/organ'}", + "51, tissue {'context': 'I-tissue/organ'}", + "52, (WAT), {'context': 'I-cells'}", + "72, adipocytes {'context': 'B-cells'}", + "138, in {'context': 'B-in vitro'}", + "139, vitro {'context': 'I-in vitro'}", + "141, in {'context': 'B-in vivo'}", + "142, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "35, tumor ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "36, growth ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "38, mice ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21']", + "45, cultured ['l2', 'l10', 'l17', 'l22', 'l23', 'l24', 'l25']", + "46, white ['l3', 'l11', 'l18', 'l22', 'l26', 'l27', 'l28']", + "47, adipocytes ['l4', 'l12', 'l19', 'l23', 'l26', 'l29', 'l30']", + "49, white ['l5', 'l13', 'l31', 'l32', 'l33', 'l34']", + "50, adipose ['l6', 'l14', 'l31', 'l35', 'l36', 'l37']", + "51, tissue ['l7', 'l15', 'l20', 'l24', 'l27', 'l29', 'l32', 'l35', 'l38', 'l39']", + "52, (WAT), ['l8', 'l16', 'l21', 'l25', 'l28', 'l30', 'l33', 'l36', 'l38']", + "72, adipocytes ['l34', 'l37', 'l39']", + "138, in ['l40']", + "139, vitro ['l40']", + "141, in ['l41']", + "142, vivo ['l41']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "white", + "adipocytes", + "(WAT)," + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "white", + "adipose", + "tissue" + ] + } + } + ] + }, + { + "PMID": "27500726", + "TEXT": "The protein kinase B-Raf proto-oncogene, serine/threonine kinase (BRAF) is an oncogenic driver and therapeutic target in melanoma. Inhibitors of BRAF (BRAFi) have shown high response rates and extended survival in patients with melanoma who bear tumors that express mutations encoding BRAF proteins mutant at Val600, but a vast majority of these patients develop drug resistance. Here we show that loss of stromal antigen 2 (STAG2) or STAG3, which encode subunits of the cohesin complex, in melanoma cells results in resistance to BRAFi. We identified loss-of-function mutations in STAG2, as well as decreased expression of STAG2 or STAG3 proteins in several tumor samples from patients with acquired resistance to BRAFi and in BRAFi-resistant melanoma cell lines. Knockdown of STAG2 or STAG3 expression decreased sensitivity of BRAF(Val600Glu)-mutant melanoma cells and xenograft tumors to BRAFi. Loss of STAG2 inhibited CCCTC-binding-factor-mediated expression of dual specificity phosphatase 6 (DUSP6), leading to reactivation of mitogen-activated protein kinase (MAPK) signaling (via the MAPKs ERK1 and ERK2; hereafter referred to as ERK). Our studies unveil a previously unknown genetic mechanism of BRAFi resistance and provide new insights into the tumor suppressor function of STAG2 and STAG3.", + "TAG_DATA": [ + "75, melanoma {'context': 'B-transformed cells'}", + "76, cells {'context': 'I-transformed cells'}", + "112, melanoma {'context': 'B-transformed cells'}", + "113, cell {'context': 'I-transformed cells'}", + "114, lines. {'context': 'I-transformed cells'}", + "115, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "116, of {'perturbing_action': 'I-rnai/knockdown'}", + "117, STAG2 {'perturbing_action': 'I-rnai/knockdown'}", + "118, or {'perturbing_action': 'I-rnai/knockdown'}", + "119, STAG3 {'perturbing_action': 'I-rnai/knockdown'}", + "120, expression {'perturbing_action': 'I-rnai/knockdown'}", + "124, BRAF(Val600Glu)-mutant {'perturbing_action': 'B-other'}", + "125, melanoma {'context': 'B-transformed cells'}", + "126, cells {'context': 'I-transformed cells'}", + "128, xenograft {'context': 'B-xenograft'}", + "129, tumors {'context': 'I-xenograft'}", + "132, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "133, of {'perturbing_action': 'I-gene loss-of-function'}", + "134, STAG2 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "75, melanoma ['l0']", + "76, cells ['l0']", + "112, melanoma ['l1', 'l2']", + "113, cell ['l1', 'l3']", + "114, lines. ['l2', 'l3']", + "115, Knockdown ['l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "116, of ['l4', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "117, STAG2 ['l5', 'l14', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "118, or ['l6', 'l15', 'l23', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "119, STAG3 ['l7', 'l16', 'l24', 'l31', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "120, expression ['l8', 'l17', 'l25', 'l32', 'l38', 'l44', 'l45', 'l46', 'l47', 'l48']", + "124, BRAF(Val600Glu)-mutant ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l49', 'l50', 'l51', 'l52']", + "125, melanoma ['l10', 'l19', 'l27', 'l34', 'l40', 'l45', 'l49', 'l53', 'l54', 'l55']", + "126, cells ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l50', 'l53', 'l56']", + "128, xenograft ['l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l54', 'l57']", + "129, tumors ['l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l56', 'l57']", + "132, Loss ['l58', 'l59']", + "133, of ['l58', 'l60']", + "134, STAG2 ['l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "STAG2", + "or", + "STAG3", + "expression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "STAG2", + "or", + "STAG3", + "expression" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BRAF(Val600Glu)-mutant" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "melanoma", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BRAF(Val600Glu)-mutant" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "tumors" + ] + } + } + ] + }, + { + "PMID": "27428899", + "TEXT": "Disseminated candidiasis has become one of the leading causes of hospital-acquired blood stream infections with high mobility and mortality. However, the molecular basis of host defense against disseminated candidiasis remains elusive, and treatment options are limited. Here we report that the E3 ubiquitin ligase CBLB directs polyubiquitination of dectin-1 and dectin-2, two key pattern-recognition receptors for sensing Candida albicans, and their downstream kinase SYK, thus inhibiting dectin-1- and dectin-2-mediated innate immune responses. CBLB deficiency or inactivation protects mice from systemic infection with a lethal dose of C. albicans, and deficiency of dectin-1, dectin-2, or both in Cblb(-/-) mice abrogates this protection. Notably, silencing the Cblb gene in vivo protects mice from lethal systemic C. albicans infection. Our data reveal that CBLB is crucial for homeostatic control of innate immune responses mediated by dectin-1 and dectin-2. Our data also indicate that CBLB represents a potential therapeutic target for protection from disseminated candidiasis.", + "TAG_DATA": [ + "72, CBLB {'perturbing_action': 'B-gene loss-of-function'}", + "73, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "77, mice {'context': 'B-organism'}", + "89, deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "90, of {'perturbing_action': 'I-gene loss-of-function'}", + "91, dectin-1, {'perturbing_action': 'I-gene loss-of-function'}", + "92, dectin-2, {'perturbing_action': 'I-gene loss-of-function'}", + "96, Cblb(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "97, mice {'context': 'B-organism'}", + "102, silencing {'perturbing_action': 'B-rnai/knockdown'}", + "103, the {'perturbing_action': 'I-rnai/knockdown'}", + "104, Cblb {'perturbing_action': 'I-rnai/knockdown'}", + "105, gene {'perturbing_action': 'I-rnai/knockdown'}", + "106, in {'context': 'B-in vivo'}", + "107, vivo {'context': 'I-in vivo'}", + "109, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "72, CBLB ['l0', 'l1']", + "73, deficiency ['l0', 'l2']", + "77, mice ['l1', 'l2']", + "89, deficiency ['l3', 'l4', 'l5', 'l6', 'l7']", + "90, of ['l3', 'l8', 'l9', 'l10', 'l11']", + "91, dectin-1, ['l4', 'l8', 'l12', 'l13', 'l14']", + "92, dectin-2, ['l5', 'l9', 'l12', 'l15', 'l16']", + "96, Cblb(-/-) ['l6', 'l10', 'l13', 'l15', 'l17']", + "97, mice ['l7', 'l11', 'l14', 'l16', 'l17']", + "102, silencing ['l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "103, the ['l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "104, Cblb ['l19', 'l24', 'l29', 'l30', 'l31', 'l32']", + "105, gene ['l20', 'l25', 'l29', 'l33', 'l34', 'l35']", + "106, in ['l21', 'l26', 'l30', 'l33', 'l36', 'l37']", + "107, vivo ['l22', 'l27', 'l31', 'l34', 'l36', 'l38']", + "109, mice ['l23', 'l28', 'l32', 'l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CBLB", + "deficiency", + "of", + "dectin-1,", + "dectin-2,", + "Cblb(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "the", + "Cblb", + "gene" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "the", + "Cblb", + "gene" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "27135740", + "TEXT": "Mutations in genes encoding splicing factors (which we refer to as spliceosomal genes) are commonly found in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). These mutations recurrently affect specific amino acid residues, leading to perturbed normal splice site and exon recognition. Spliceosomal gene mutations are always heterozygous and rarely occur together with one another, suggesting that cells may tolerate only a partial deviation from normal splicing activity. To test this hypothesis, we engineered mice to express a mutated allele of serine/arginine-rich splicing factor 2 (Srsf2(P95H))-which commonly occurs in individuals with MDS and AML-in an inducible, hemizygous manner in hematopoietic cells. These mice rapidly succumbed to fatal bone marrow failure, demonstrating that Srsf2-mutated cells depend on the wild-type Srsf2 allele for survival. In the context of leukemia, treatment with the spliceosome inhibitor E7107 (refs. 7,8) resulted in substantial reductions in leukemic burden, specifically in isogenic mouse leukemias and patient-derived xenograft AMLs carrying spliceosomal mutations. Whereas E7107 treatment of mice resulted in widespread intron retention and cassette exon skipping in leukemic cells regardless of Srsf2 genotype, the magnitude of splicing inhibition following E7107 treatment was greater in Srsf2-mutated than in Srsf2-wild-type leukemia, consistent with the differential effect of E7107 on survival. Collectively, these data provide genetic and pharmacologic evidence that leukemias with spliceosomal gene mutations are preferentially susceptible to additional splicing perturbations in vivo as compared to leukemias without such mutations. Modulation of spliceosome function may thus provide a new therapeutic avenue in genetically defined subsets of individuals with MDS or AML.", + "TAG_DATA": [ + "76, mice {'context': 'B-organism'}", + "78, express {'perturbing_action': 'B-other'}", + "79, a {'perturbing_action': 'I-other'}", + "80, mutated {'perturbing_action': 'B-other'}", + "81, allele {'perturbing_action': 'I-other'}", + "82, of {'perturbing_action': 'I-other'}", + "83, serine/arginine-rich {'perturbing_action': 'I-other'}", + "84, splicing {'perturbing_action': 'I-other'}", + "85, factor {'perturbing_action': 'I-other'}", + "86, 2 {'perturbing_action': 'I-other'}", + "87, (Srsf2(P95H))-which {'perturbing_action': 'I-other'}", + "101, hematopoietic {'context': 'B-cells'}", + "102, cells. {'context': 'I-cells'}", + "104, mice {'context': 'B-organism'}", + "114, Srsf2-mutated {'perturbing_action': 'B-other'}", + "115, cells {'context': 'B-cells'}", + "147, mouse {'context': 'B-neoplasm'}", + "148, leukemias {'context': 'I-neoplasm'}", + "150, patient-derived {'context': 'B-xenograft'}", + "151, xenograft {'context': 'I-xenograft'}", + "152, AMLs {'context': 'I-xenograft'}", + "160, mice {'context': 'B-organism'}", + "171, leukemic {'context': 'B-transformed cells'}", + "172, cells {'context': 'I-transformed cells'}", + "188, Srsf2-mutated {'perturbing_action': 'B-other'}", + "192, leukemia, {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "76, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "78, express ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "79, a ['l1', 'l14', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "80, mutated ['l2', 'l15', 'l30', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "81, allele ['l3', 'l16', 'l31', 'l45', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "82, of ['l4', 'l17', 'l32', 'l46', 'l59', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "83, serine/arginine-rich ['l5', 'l18', 'l33', 'l47', 'l60', 'l72', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "84, splicing ['l6', 'l19', 'l34', 'l48', 'l61', 'l73', 'l84', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "85, factor ['l7', 'l20', 'l35', 'l49', 'l62', 'l74', 'l85', 'l96', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "86, 2 ['l8', 'l21', 'l36', 'l50', 'l63', 'l75', 'l86', 'l97', 'l107', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "87, (Srsf2(P95H))-which ['l9', 'l22', 'l37', 'l51', 'l64', 'l76', 'l87', 'l98', 'l108', 'l116', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "101, hematopoietic ['l10', 'l23', 'l38', 'l52', 'l65', 'l77', 'l88', 'l99', 'l109', 'l117', 'l124', 'l131', 'l132', 'l133']", + "102, cells. ['l11', 'l24', 'l39', 'l53', 'l66', 'l78', 'l89', 'l100', 'l110', 'l118', 'l125', 'l131', 'l134', 'l135']", + "104, mice ['l12', 'l25', 'l40', 'l54', 'l67', 'l79', 'l90', 'l101', 'l111', 'l119', 'l126', 'l132', 'l134', 'l136', 'l137', 'l138']", + "114, Srsf2-mutated ['l26', 'l41', 'l55', 'l68', 'l80', 'l91', 'l102', 'l112', 'l120', 'l127', 'l136', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "115, cells ['l13', 'l27', 'l42', 'l56', 'l69', 'l81', 'l92', 'l103', 'l113', 'l121', 'l128', 'l133', 'l135', 'l137', 'l139', 'l145', 'l146']", + "147, mouse ['l28', 'l43', 'l57', 'l70', 'l82', 'l93', 'l104', 'l114', 'l122', 'l129', 'l140', 'l145', 'l147', 'l148']", + "148, leukemias ['l29', 'l44', 'l58', 'l71', 'l83', 'l94', 'l105', 'l115', 'l123', 'l130', 'l138', 'l141', 'l146', 'l147', 'l149', 'l150', 'l151']", + "150, patient-derived ['l142', 'l149', 'l152', 'l153']", + "151, xenograft ['l143', 'l150', 'l152', 'l154']", + "152, AMLs ['l95', 'l106', 'l144', 'l148', 'l151', 'l153', 'l154']", + "160, mice ['l155', 'l156']", + "171, leukemic ['l155', 'l157']", + "172, cells ['l156', 'l157']", + "188, Srsf2-mutated ['l158']", + "192, leukemia, ['l158']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "express", + "a", + "mutated", + "allele", + "of", + "serine/arginine-rich", + "splicing", + "factor", + "2", + "(Srsf2(P95H))-which", + "Srsf2-mutated" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "express", + "a", + "mutated", + "allele", + "of", + "serine/arginine-rich", + "splicing", + "factor", + "2", + "(Srsf2(P95H))-which", + "Srsf2-mutated" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "cells.", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "express", + "a", + "mutated", + "allele", + "of", + "serine/arginine-rich", + "splicing", + "factor", + "2", + "(Srsf2(P95H))-which", + "Srsf2-mutated" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "leukemias", + "leukemia," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "serine/arginine-rich", + "splicing", + "Srsf2-mutated" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "AMLs", + "patient-derived", + "xenograft" + ] + } + } + ] + }, + { + "PMID": "26974309", + "TEXT": "Upregulation of the persistent sodium current (I(NaP)) in motoneurons contributes to the development of spasticity after spinal cord injury (SCI). We investigated the mechanisms that regulate I(NaP) and observed elevated expression of voltage-gated sodium (Nav) 1.6 channels in spinal lumbar motoneurons of adult rats with SCI. Furthermore, immunoblots revealed a proteolysis of Nav channels, and biochemical assays identified calpain as the main proteolytic factor. Calpain-dependent cleavage of Nav channels after neonatal SCI was associated with an upregulation of I(NaP) in motoneurons. Similarly, the calpain-dependent cleavage of Nav1.6 channels expressed in human embryonic kidney (HEK) 293 cells caused the upregulation of I(NaP). The pharmacological inhibition of calpain activity by MDL28170 reduced the cleavage of Nav channels, I(NaP) in motoneurons and spasticity in rats with SCI. Similarly, the blockade of I(NaP) by riluzole alleviated spasticity. This study demonstrates that Nav channel expression in lumbar motoneurons is altered after SCI, and it shows a tight relationship between the calpain-dependent proteolysis of Nav1.6 channels, the upregulation of I(NaP) and spasticity.", + "TAG_DATA": [ + "90, human {'context': 'B-cells'}", + "91, embryonic {'context': 'I-cells'}", + "92, kidney {'context': 'I-cells'}", + "93, (HEK) {'context': 'I-cells'}", + "94, 293 {'context': 'I-cells'}", + "95, cells {'context': 'I-cells'}", + "102, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "103, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "104, of {'perturbing_action': 'I-pharmacological inhibition'}", + "105, calpain {'perturbing_action': 'I-pharmacological inhibition'}", + "106, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "107, by {'perturbing_action': 'I-pharmacological inhibition'}", + "108, MDL28170 {'perturbing_action': 'I-pharmacological inhibition'}", + "117, motoneurons {'context': 'B-cells'}", + "121, rats {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "90, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "91, embryonic ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "92, kidney ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "93, (HEK) ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "94, 293 ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "95, cells ['l4', 'l12', 'l19', 'l25', 'l30', 'l35']", + "102, pharmacological ['l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "103, inhibition ['l36', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "104, of ['l37', 'l44', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "105, calpain ['l38', 'l45', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "106, activity ['l39', 'l46', 'l52', 'l57', 'l62', 'l63', 'l64', 'l65']", + "107, by ['l5', 'l13', 'l20', 'l26', 'l31', 'l40', 'l47', 'l53', 'l58', 'l62', 'l66', 'l67', 'l68']", + "108, MDL28170 ['l6', 'l14', 'l21', 'l27', 'l32', 'l41', 'l48', 'l54', 'l59', 'l63', 'l66', 'l69', 'l70']", + "117, motoneurons ['l7', 'l15', 'l22', 'l28', 'l33', 'l35', 'l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l71']", + "121, rats ['l8', 'l16', 'l23', 'l29', 'l34', 'l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l71']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "embryonic", + "kidney", + "(HEK)", + "293", + "motoneurons" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "by", + "MDL28170", + "pharmacological", + "inhibition", + "of", + "calpain", + "activity" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "calpain", + "activity", + "by", + "MDL28170" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + } + ] + }, + { + "PMID": "26950362", + "TEXT": "Cellular senescence is thought to contribute to age-associated deterioration of tissue physiology. The senescence effector p16(Ink4a) is expressed in pancreatic beta cells during aging and limits their proliferative potential; however, its effects on beta cell function are poorly characterized. We found that beta cell-specific activation of p16(Ink4a) in transgenic mice enhances glucose-stimulated insulin secretion (GSIS). In mice with diabetes, this leads to improved glucose homeostasis, providing an unexpected functional benefit. Expression of p16(Ink4a) in beta cells induces hallmarks of senescence--including cell enlargement, and greater glucose uptake and mitochondrial activity--which promote increased insulin secretion. GSIS increases during the normal aging of mice and is driven by elevated p16(Ink4a) activity. We found that islets from human adults contain p16(Ink4a)-expressing senescent beta cells and that senescence induced by p16(Ink4a) in a human beta cell line increases insulin secretion in a manner dependent, in part, on the activity of the mechanistic target of rapamycin (mTOR) and the peroxisome proliferator-activated receptor (PPAR)-γ proteins. Our findings reveal a novel role for p16(Ink4a) and cellular senescence in promoting insulin secretion by beta cells and in regulating normal functional tissue maturation with age.", + "TAG_DATA": [ + "42, beta {'perturbing_action': 'B-pharmacological augmentation'}", + "43, cell-specific {'perturbing_action': 'I-pharmacological augmentation'}", + "44, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "45, of {'perturbing_action': 'I-pharmacological augmentation'}", + "46, p16(Ink4a) {'perturbing_action': 'I-pharmacological augmentation'}", + "48, transgenic {'perturbing_action': 'B-gene gain-of-function', 'context': 'B-organism'}", + "49, mice {'context': 'I-organism'}", + "56, mice {'context': 'B-organism'}", + "70, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "71, of {'perturbing_action': 'I-gene gain-of-function'}", + "72, p16(Ink4a) {'perturbing_action': 'I-gene gain-of-function'}", + "74, beta {'context': 'B-cells'}", + "75, cells {'context': 'I-cells'}", + "76, induces {'effect': 'B-positive'}", + "79, senescence--including {'phenotype': 'B-senescence'}", + "100, mice {'context': 'B-organism'}", + "111, islets {'context': 'B-cells'}", + "122, senescence {'phenotype': 'B-senescence'}", + "123, induced {'effect': 'B-positive'}", + "128, human {'context': 'B-cells'}", + "129, beta {'context': 'I-cells'}", + "130, cell {'context': 'I-cells'}", + "131, line {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "42, beta ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "43, cell-specific ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "44, activation ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "45, of ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "46, p16(Ink4a) ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "48, transgenic ['l4', 'l17', 'l29', 'l40', 'l50', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "49, mice ['l5', 'l18', 'l30', 'l41', 'l51', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73']", + "56, mice ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l74', 'l75', 'l76', 'l77']", + "70, Expression ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "71, of ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l78', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "72, p16(Ink4a) ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l79', 'l85', 'l91', 'l92', 'l93', 'l94', 'l95']", + "74, beta ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l70', 'l74', 'l80', 'l86', 'l91', 'l96', 'l97', 'l98']", + "75, cells ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l71', 'l75', 'l81', 'l87', 'l92', 'l96', 'l99', 'l100']", + "76, induces ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l72', 'l76', 'l82', 'l88', 'l93', 'l97', 'l99', 'l101']", + "79, senescence--including ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l73', 'l77', 'l83', 'l89', 'l94', 'l98', 'l100', 'l101']", + "100, mice ['l84', 'l90', 'l95']", + "122, senescence ['l102', 'l103', 'l104', 'l105', 'l106']", + "123, induced ['l102', 'l107', 'l108', 'l109', 'l110']", + "128, human ['l103', 'l107', 'l111', 'l112', 'l113']", + "129, beta ['l104', 'l108', 'l111', 'l114', 'l115']", + "130, cell ['l105', 'l109', 'l112', 'l114', 'l116']", + "131, line ['l106', 'l110', 'l113', 'l115', 'l116']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "beta", + "cell-specific", + "activation", + "of", + "p16(Ink4a)" + ] + }, + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "Expression", + "of", + "p16(Ink4a)" + ] + }, + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "beta", + "cell-specific", + "activation", + "of", + "p16(Ink4a)" + ] + }, + "context": { + "val": "cells", + "words": [ + "beta", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "beta", + "cell-specific", + "activation", + "of", + "p16(Ink4a)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "beta", + "cell-specific", + "activation", + "of", + "p16(Ink4a)" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence--including" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "Expression", + "of", + "p16(Ink4a)" + ] + }, + "context": { + "val": "cells", + "words": [ + "beta", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "Expression", + "of", + "p16(Ink4a)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "Expression", + "of", + "p16(Ink4a)" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence--including" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence--including" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "beta", + "cells", + "human", + "cell", + "line" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces", + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "beta", + "cells", + "human", + "cell", + "line" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence--including", + "senescence" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "induced" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence--including", + "senescence" + ] + } + } + ] + }, + { + "PMID": "26752517", + "TEXT": "Protozoan infections are a serious global health problem. Natural killer (NK) cells and cytolytic T lymphocytes (CTLs) eliminate pathogen-infected cells by releasing cytolytic granule contents--granzyme (Gzm) proteases and the pore-forming perforin (PFN)--into the infected cell. However, these cytotoxic molecules do not kill intracellular parasites. CD8(+) CTLs protect against parasite infections in mice primarily by secreting interferon (IFN)-γ. However, human, but not rodent, cytotoxic granules contain the antimicrobial peptide granulysin (GNLY), which selectively destroys cholesterol-poor microbial membranes, and GNLY, PFN and Gzms rapidly kill intracellular bacteria. Here we show that GNLY delivers Gzms into three protozoan parasites (Trypanosoma cruzi, Toxoplasma gondii and Leishmania major), in which the Gzms generate superoxide and inactivate oxidative defense enzymes to kill the parasite. PFN delivers GNLY and Gzms into infected cells, and GNLY then delivers Gzms to the intracellular parasites. Killer cell-mediated parasite death, which we term 'microbe-programmed cell death' or 'microptosis', is caspase independent but resembles mammalian apoptosis, causing mitochondrial swelling, transmembrane potential dissipation, membrane blebbing, phosphatidylserine exposure, DNA damage and chromatin condensation. GNLY-transgenic mice are protected against infection by T. cruzi and T. gondii, and survive infections that are lethal to wild-type mice. Thus, GNLY-, PFN- and Gzm-mediated elimination of intracellular protozoan parasites is an unappreciated immune defense mechanism.", + "TAG_DATA": [ + "125, cells, {'context': 'B-cells'}", + "169, GNLY-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "170, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "169, GNLY-transgenic ['l0']", + "170, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GNLY-transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "26642438", + "TEXT": "Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, which encodes a polyglutamine tract in the HTT protein. We found that peroxisome proliferator-activated receptor delta (PPAR-δ) interacts with HTT and that mutant HTT represses PPAR-δ-mediated transactivation. Increased PPAR-δ transactivation ameliorated mitochondrial dysfunction and improved cell survival of neurons from mouse models of HD. Expression of dominant-negative PPAR-δ in the central nervous system of mice was sufficient to induce motor dysfunction, neurodegeneration, mitochondrial abnormalities and transcriptional alterations that recapitulated HD-like phenotypes. Expression of dominant-negative PPAR-δ specifically in the striatum of medium spiny neurons in mice yielded HD-like motor phenotypes, accompanied by striatal neuron loss. In mouse models of HD, pharmacologic activation of PPAR-δ using the agonist KD3010 improved motor function, reduced neurodegeneration and increased survival. PPAR-δ activation also reduced HTT-induced neurotoxicity in vitro and in medium spiny-like neurons generated from stem cells derived from individuals with HD, indicating that PPAR-δ activation may be beneficial in HD and related disorders.", + "TAG_DATA": [ + "54, improved {'effect': 'B-positive'}", + "55, cell {'phenotype': 'B-cell survival'}", + "56, survival {'phenotype': 'I-cell survival'}", + "58, neurons {'context': 'B-cells'}", + "64, Expression {'perturbing_action': 'B-other'}", + "65, of {'perturbing_action': 'I-other'}", + "66, dominant-negative {'perturbing_action': 'I-other'}", + "67, PPAR-δ {'perturbing_action': 'I-other'}", + "68, in {'perturbing_action': 'I-other'}", + "69, the {'perturbing_action': 'I-other'}", + "70, central {'perturbing_action': 'I-other'}", + "71, nervous {'perturbing_action': 'I-other', 'context': 'I-tissue/organ'}", + "72, system {'perturbing_action': 'I-other', 'context': 'I-tissue/organ'}", + "74, mice {'context': 'B-organism'}", + "91, Expression {'perturbing_action': 'B-other'}", + "92, of {'perturbing_action': 'I-other'}", + "93, dominant-negative {'perturbing_action': 'I-other'}", + "94, PPAR-δ {'perturbing_action': 'I-other'}", + "95, specifically {'perturbing_action': 'I-other'}", + "96, in {'perturbing_action': 'I-other'}", + "97, the {'perturbing_action': 'I-other'}", + "98, striatum {'perturbing_action': 'I-other'}", + "99, of {'perturbing_action': 'I-other'}", + "100, medium {'context': 'B-cells'}", + "101, spiny {'context': 'I-cells'}", + "102, neurons {'context': 'I-cells'}", + "104, mice {'context': 'B-organism'}", + "111, striatal {'context': 'B-cells'}", + "112, neuron {'context': 'I-cells'}", + "115, mouse {'context': 'B-organism'}", + "116, models {'context': 'I-organism'}", + "119, pharmacologic {'perturbing_action': 'B-pharmacological augmentation'}", + "120, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "121, of {'perturbing_action': 'I-pharmacological augmentation'}", + "122, PPAR-δ {'perturbing_action': 'I-pharmacological augmentation'}", + "123, using {'perturbing_action': 'I-pharmacological augmentation'}", + "124, the {'perturbing_action': 'I-pharmacological augmentation'}", + "125, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "126, KD3010 {'perturbing_action': 'I-pharmacological augmentation'}", + "135, PPAR-δ {'perturbing_action': 'B-pharmacological augmentation'}", + "136, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "141, in {'context': 'B-in vitro'}", + "142, vitro {'context': 'I-in vitro'}", + "145, medium {'context': 'B-cells'}", + "146, spiny-like {'context': 'I-cells'}", + "147, neurons {'context': 'I-cells'}", + "148, generated {'context': 'I-cells'}", + "149, from {'context': 'I-cells'}", + "150, stem {'context': 'I-cells'}", + "151, cells {'context': 'I-cells'}", + "152, derived {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "54, improved ['l0', 'l1', 'l2', 'l3']", + "55, cell ['l0', 'l4', 'l5', 'l6']", + "56, survival ['l1', 'l4', 'l7', 'l8']", + "58, neurons ['l2', 'l5', 'l7', 'l9']", + "61, models ['l3', 'l6', 'l8', 'l9']", + "64, Expression ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "65, of ['l10', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "66, dominant-negative ['l11', 'l26', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "67, PPAR-δ ['l12', 'l27', 'l43', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "68, in ['l13', 'l28', 'l44', 'l59', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "69, the ['l14', 'l29', 'l45', 'l60', 'l76', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "70, central ['l15', 'l30', 'l46', 'l61', 'l77', 'l88', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "71, nervous ['l16', 'l31', 'l47', 'l62', 'l78', 'l89', 'l98', 'l104', 'l105', 'l106', 'l107', 'l108']", + "72, system ['l17', 'l32', 'l48', 'l63', 'l79', 'l90', 'l99', 'l104', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "74, mice ['l18', 'l33', 'l49', 'l64', 'l80', 'l91', 'l100', 'l105', 'l109']", + "91, Expression ['l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "92, of ['l115', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "93, dominant-negative ['l116', 'l130', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156']", + "94, PPAR-δ ['l117', 'l131', 'l144', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168']", + "95, specifically ['l65', 'l118', 'l132', 'l145', 'l157', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "96, in ['l66', 'l119', 'l133', 'l146', 'l158', 'l169', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "97, the ['l34', 'l50', 'l67', 'l120', 'l134', 'l147', 'l159', 'l170', 'l179', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195']", + "98, striatum ['l35', 'l51', 'l68', 'l121', 'l135', 'l148', 'l160', 'l171', 'l180', 'l188', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202']", + "99, of ['l19', 'l36', 'l52', 'l69', 'l81', 'l92', 'l110', 'l122', 'l136', 'l149', 'l161', 'l172', 'l181', 'l189', 'l196', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208']", + "100, medium ['l20', 'l37', 'l53', 'l70', 'l82', 'l93', 'l111', 'l123', 'l137', 'l150', 'l162', 'l173', 'l182', 'l190', 'l197', 'l203', 'l209', 'l210', 'l211', 'l212', 'l213']", + "101, spiny ['l21', 'l38', 'l54', 'l71', 'l83', 'l94', 'l101', 'l106', 'l112', 'l124', 'l138', 'l151', 'l163', 'l174', 'l183', 'l191', 'l198', 'l204', 'l209', 'l214', 'l215', 'l216', 'l217']", + "102, neurons ['l22', 'l39', 'l55', 'l72', 'l84', 'l95', 'l102', 'l107', 'l113', 'l125', 'l139', 'l152', 'l164', 'l175', 'l184', 'l192', 'l199', 'l205', 'l210', 'l214', 'l218', 'l219', 'l220']", + "104, mice ['l23', 'l40', 'l56', 'l73', 'l85', 'l126', 'l140', 'l153', 'l165', 'l176', 'l185', 'l193', 'l200', 'l206', 'l211', 'l215', 'l218', 'l221', 'l222']", + "111, striatal ['l24', 'l41', 'l57', 'l74', 'l86', 'l96', 'l127', 'l141', 'l154', 'l166', 'l177', 'l186', 'l194', 'l201', 'l207', 'l212', 'l216', 'l219', 'l221', 'l223']", + "112, neuron ['l25', 'l42', 'l58', 'l75', 'l87', 'l97', 'l103', 'l108', 'l114', 'l128', 'l142', 'l155', 'l167', 'l178', 'l187', 'l195', 'l202', 'l208', 'l213', 'l217', 'l220', 'l222', 'l223']", + "115, mouse ['l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232']", + "116, models ['l129', 'l143', 'l156', 'l168', 'l224', 'l233', 'l234', 'l235', 'l236']", + "119, pharmacologic ['l225', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255']", + "120, activation ['l226', 'l237', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273']", + "121, of ['l227', 'l233', 'l238', 'l256', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290']", + "122, PPAR-δ ['l228', 'l234', 'l239', 'l257', 'l274', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304', 'l305']", + "123, using ['l229', 'l240', 'l258', 'l275', 'l291', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315', 'l316', 'l317', 'l318', 'l319', 'l320']", + "124, the ['l230', 'l235', 'l241', 'l259', 'l276', 'l292', 'l306', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327', 'l328', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334']", + "125, agonist ['l231', 'l242', 'l260', 'l277', 'l293', 'l307', 'l321', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340', 'l341', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347']", + "126, KD3010 ['l232', 'l236', 'l243', 'l261', 'l278', 'l294', 'l308', 'l322', 'l335', 'l348', 'l349', 'l350', 'l351', 'l352', 'l353', 'l354', 'l355', 'l356', 'l357', 'l358']", + "135, PPAR-δ ['l244', 'l262', 'l279', 'l309', 'l323', 'l336', 'l359', 'l360', 'l361', 'l362', 'l363', 'l364', 'l365', 'l366', 'l367', 'l368', 'l369']", + "136, activation ['l245', 'l263', 'l280', 'l295', 'l310', 'l324', 'l337', 'l348', 'l359', 'l370', 'l371', 'l372', 'l373', 'l374', 'l375', 'l376', 'l377', 'l378', 'l379']", + "141, in ['l246', 'l264', 'l281', 'l296', 'l311', 'l325', 'l338', 'l349', 'l360', 'l370', 'l380', 'l381', 'l382', 'l383', 'l384', 'l385', 'l386', 'l387', 'l388']", + "142, vitro ['l247', 'l265', 'l282', 'l297', 'l312', 'l326', 'l339', 'l350', 'l361', 'l371', 'l380', 'l389', 'l390', 'l391', 'l392', 'l393', 'l394', 'l395', 'l396']", + "145, medium ['l248', 'l266', 'l283', 'l298', 'l313', 'l327', 'l340', 'l351', 'l362', 'l372', 'l381', 'l389', 'l397', 'l398', 'l399', 'l400', 'l401', 'l402', 'l403']", + "146, spiny-like ['l249', 'l267', 'l284', 'l299', 'l314', 'l328', 'l341', 'l352', 'l363', 'l373', 'l382', 'l390', 'l397', 'l404', 'l405', 'l406', 'l407', 'l408', 'l409']", + "147, neurons ['l250', 'l268', 'l285', 'l300', 'l315', 'l329', 'l342', 'l353', 'l364', 'l374', 'l383', 'l391', 'l398', 'l404', 'l410', 'l411', 'l412', 'l413', 'l414']", + "148, generated ['l251', 'l269', 'l286', 'l301', 'l316', 'l330', 'l343', 'l354', 'l365', 'l375', 'l384', 'l392', 'l399', 'l405', 'l410', 'l415', 'l416', 'l417', 'l418']", + "149, from ['l252', 'l270', 'l287', 'l302', 'l317', 'l331', 'l344', 'l355', 'l366', 'l376', 'l385', 'l393', 'l400', 'l406', 'l411', 'l415', 'l419', 'l420', 'l421']", + "150, stem ['l253', 'l271', 'l288', 'l303', 'l318', 'l332', 'l345', 'l356', 'l367', 'l377', 'l386', 'l394', 'l401', 'l407', 'l412', 'l416', 'l419', 'l422', 'l423']", + "151, cells ['l254', 'l272', 'l289', 'l304', 'l319', 'l333', 'l346', 'l357', 'l368', 'l378', 'l387', 'l395', 'l402', 'l408', 'l413', 'l417', 'l420', 'l422', 'l424']", + "152, derived ['l255', 'l273', 'l290', 'l305', 'l320', 'l334', 'l347', 'l358', 'l369', 'l379', 'l388', 'l396', 'l403', 'l409', 'l414', 'l418', 'l421', 'l423', 'l424']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "improved" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "survival" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "improved" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons" + ] + } + }, + { + "phenotype": { + "val": "cell survival", + "words": [ + "cell", + "survival" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Expression", + "of", + "dominant-negative", + "PPAR-δ", + "in", + "the", + "central", + "nervous", + "system" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "nervous", + "system" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Expression", + "of", + "dominant-negative", + "PPAR-δ", + "in", + "the", + "central", + "nervous", + "system", + "specifically", + "striatum" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "models" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Expression", + "of", + "dominant-negative", + "PPAR-δ", + "in", + "the", + "central", + "nervous", + "system", + "specifically", + "striatum" + ] + }, + "context": { + "val": "cells", + "words": [ + "medium", + "spiny", + "neurons", + "striatal", + "neuron" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "pharmacologic", + "activation", + "of", + "PPAR-δ", + "using", + "the", + "agonist", + "KD3010" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "pharmacologic", + "activation", + "of", + "PPAR-δ", + "using", + "the", + "agonist", + "KD3010" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "pharmacologic", + "activation", + "of", + "PPAR-δ", + "using", + "the", + "agonist", + "KD3010" + ] + }, + "context": { + "val": "cells", + "words": [ + "medium", + "spiny-like", + "neurons", + "generated", + "from", + "stem", + "cells", + "derived" + ] + } + } + ] + }, + { + "PMID": "26642437", + "TEXT": "The glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor transduce nutrient-stimulated signals to control beta cell function. Although the GLP-1 receptor (GLP-1R) is a validated drug target for diabetes, the importance of the GIP receptor (GIPR) for the function of beta cells remains uncertain. We demonstrate that mice with selective ablation of GIPR in beta cells (MIP-Cre:Gipr(Flox/Flox); Gipr(-/-βCell)) exhibit lower levels of meal-stimulated insulin secretion, decreased expansion of adipose tissue mass and preservation of insulin sensitivity when compared to MIP-Cre controls. Beta cells from Gipr(-/-βCell) mice display greater sensitivity to apoptosis and markedly lower islet expression of T cell-specific transcription factor-1 (TCF1, encoded by Tcf7), a protein not previously characterized in beta cells. GIP, but not GLP-1, promotes beta cell Tcf7 expression via a cyclic adenosine monophosphate (cAMP)-independent and extracellular signal-regulated kinase (ERK)-dependent pathway. Tcf7 (in mice) or TCF7 (in humans) levels are lower in islets taken from diabetic mice and in humans with type 2 diabetes; knockdown of TCF7 in human and mouse islets impairs the cytoprotective responsiveness to GIP and enhances the magnitude of apoptotic injury, whereas restoring TCF1 levels in beta cells from Gipr(-/-βCell) mice lowers the number of apoptotic cells compared to that seen in MIP-Cre controls. Tcf7(-/-) mice show impaired insulin secretion, deterioration of glucose tolerance with either aging and/or high-fat feeding and increased sensitivity to beta cell injury relative to wild-type (WT) controls. Hence the GIPR-TCF1 axis represents a potential therapeutic target for preserving both the function and survival of vulnerable, diabetic beta cells.", + "TAG_DATA": [ + "50, mice {'context': 'B-organism'}", + "52, selective {'perturbing_action': 'B-gene loss-of-function'}", + "53, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "54, of {'perturbing_action': 'I-gene loss-of-function'}", + "55, GIPR {'perturbing_action': 'I-gene loss-of-function'}", + "56, in {'perturbing_action': 'I-gene loss-of-function'}", + "57, beta {'perturbing_action': 'I-gene loss-of-function'}", + "58, cells {'perturbing_action': 'I-gene loss-of-function'}", + "59, (MIP-Cre:Gipr(Flox/Flox); {'perturbing_action': 'I-gene loss-of-function'}", + "60, Gipr(-/-βCell)) {'perturbing_action': 'I-gene loss-of-function'}", + "84, Beta {'context': 'B-cells'}", + "85, cells {'context': 'I-cells'}", + "87, Gipr(-/-βCell) {'perturbing_action': 'B-gene loss-of-function'}", + "88, mice {'context': 'B-organism'}", + "90, greater {'effect': 'B-positive'}", + "91, sensitivity {'effect': 'I-positive'}", + "93, apoptosis {'phenotype': 'B-apoptosis'}", + "160, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "161, of {'perturbing_action': 'I-rnai/knockdown'}", + "162, TCF7 {'perturbing_action': 'I-rnai/knockdown'}", + "164, human {'context': 'B-cells'}", + "165, and {'context': 'I-cells'}", + "166, mouse {'context': 'I-cells'}", + "167, islets {'context': 'I-cells'}", + "186, beta {'context': 'B-cells'}", + "187, cells {'context': 'I-cells'}", + "189, Gipr(-/-βCell) {'perturbing_action': 'B-gene loss-of-function'}", + "190, mice {'context': 'B-organism'}", + "196, cells {'phenotype': 'I-apoptosis'}", + "204, Tcf7(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "205, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "52, selective ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "53, ablation ['l1', 'l9', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "54, of ['l2', 'l10', 'l24', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "55, GIPR ['l3', 'l11', 'l25', 'l38', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "56, in ['l4', 'l12', 'l26', 'l39', 'l51', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "57, beta ['l5', 'l13', 'l27', 'l40', 'l52', 'l63', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "58, cells ['l6', 'l14', 'l28', 'l41', 'l53', 'l64', 'l74', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "59, (MIP-Cre:Gipr(Flox/Flox); ['l7', 'l15', 'l29', 'l42', 'l54', 'l65', 'l75', 'l82', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "60, Gipr(-/-βCell)) ['l8', 'l16', 'l30', 'l43', 'l55', 'l66', 'l76', 'l83', 'l89', 'l97', 'l98', 'l99', 'l100', 'l101']", + "84, Beta ['l17', 'l31', 'l44', 'l56', 'l67', 'l77', 'l84', 'l90', 'l97', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "85, cells ['l18', 'l32', 'l45', 'l57', 'l68', 'l78', 'l85', 'l91', 'l98', 'l102', 'l112', 'l113', 'l114', 'l115', 'l116']", + "87, Gipr(-/-βCell) ['l19', 'l33', 'l46', 'l58', 'l69', 'l92', 'l103', 'l112', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "88, mice ['l20', 'l34', 'l47', 'l59', 'l70', 'l79', 'l86', 'l93', 'l99', 'l104', 'l113', 'l117', 'l125', 'l126', 'l127']", + "90, greater ['l21', 'l35', 'l48', 'l60', 'l71', 'l80', 'l87', 'l94', 'l100', 'l105', 'l114', 'l118', 'l125', 'l128', 'l129']", + "91, sensitivity ['l22', 'l36', 'l49', 'l61', 'l72', 'l81', 'l88', 'l95', 'l101', 'l106', 'l115', 'l119', 'l126', 'l128', 'l130']", + "93, apoptosis ['l23', 'l37', 'l50', 'l62', 'l73', 'l96', 'l107', 'l116', 'l120', 'l127', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "160, knockdown ['l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141']", + "161, of ['l135', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "162, TCF7 ['l136', 'l142', 'l148', 'l149', 'l150', 'l151', 'l152']", + "164, human ['l108', 'l121', 'l131', 'l137', 'l143', 'l148', 'l153', 'l154', 'l155']", + "165, and ['l109', 'l122', 'l132', 'l138', 'l144', 'l149', 'l153', 'l156', 'l157']", + "166, mouse ['l110', 'l123', 'l133', 'l139', 'l145', 'l150', 'l154', 'l156', 'l158']", + "167, islets ['l111', 'l124', 'l134', 'l140', 'l146', 'l151', 'l155', 'l157', 'l158', 'l159']", + "186, beta ['l160', 'l161', 'l162', 'l163']", + "187, cells ['l160', 'l164', 'l165', 'l166']", + "189, Gipr(-/-βCell) ['l161', 'l164', 'l167', 'l168', 'l169']", + "190, mice ['l162', 'l165', 'l167', 'l170']", + "196, cells ['l141', 'l147', 'l152', 'l159', 'l163', 'l166', 'l168', 'l170']", + "204, Tcf7(-/-) ['l171']", + "205, mice ['l169', 'l171']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "ablation", + "of", + "GIPR", + "in", + "beta", + "cells", + "(MIP-Cre:Gipr(Flox/Flox);", + "Gipr(-/-βCell))", + "Gipr(-/-βCell)", + "Tcf7(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "ablation", + "of", + "GIPR", + "in", + "beta", + "cells", + "(MIP-Cre:Gipr(Flox/Flox);", + "Gipr(-/-βCell))", + "Gipr(-/-βCell)" + ] + }, + "context": { + "val": "cells", + "words": [ + "Beta", + "cells", + "human", + "and", + "mouse", + "islets", + "beta" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "ablation", + "of", + "GIPR", + "in", + "beta", + "cells", + "(MIP-Cre:Gipr(Flox/Flox);", + "Gipr(-/-βCell))", + "Gipr(-/-βCell)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "greater", + "sensitivity" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "ablation", + "of", + "GIPR", + "in", + "(MIP-Cre:Gipr(Flox/Flox);", + "Gipr(-/-βCell)" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "cells" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Beta", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "greater", + "sensitivity" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Beta", + "cells", + "human", + "and", + "mouse", + "islets", + "beta" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "cells" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "greater", + "sensitivity" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "greater", + "sensitivity" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "TCF7" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "and", + "mouse", + "islets" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "TCF7" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "26594844", + "TEXT": "The nervous system is vulnerable to perturbations during specific developmental periods. Insults during such susceptible time windows can have long-term consequences, including the development of neurological diseases such as epilepsy. Here we report that a pharmacological intervention timed during a vulnerable neonatal period of cortical development prevents pathology in a genetic epilepsy model. By using mice with dysfunctional Kv7 voltage-gated K(+) channels, which are mutated in human neonatal epilepsy syndromes, we demonstrate the safety and efficacy of the sodium-potassium-chloride cotransporter NKCC1 antagonist bumetanide, which was administered during the first two postnatal weeks. In Kv7 current-deficient mice, which normally display epilepsy, hyperactivity and stereotypies as adults, transient bumetanide treatment normalized neonatal in vivo cortical network and hippocampal neuronal activity, prevented structural damage in the hippocampus and restored wild-type adult behavioral phenotypes. Furthermore, bumetanide treatment did not adversely affect control mice. These results suggest that in individuals with disease susceptibility, timing prophylactically safe interventions to specific windows during development may prevent or arrest disease progression.", + "TAG_DATA": [ + "55, mice {'context': 'B-organism'}", + "93, Kv7 {'perturbing_action': 'B-gene loss-of-function'}", + "94, current-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "95, mice, {'context': 'B-organism'}", + "110, in {'context': 'B-in vivo'}", + "111, vivo {'context': 'I-in vivo'}", + "115, hippocampal {'context': 'B-cells'}", + "123, hippocampus {'context': 'B-tissue/organ'}", + "138, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "93, Kv7 ['l0', 'l1', 'l2', 'l3', 'l4']", + "94, current-deficient ['l0', 'l5', 'l6', 'l7', 'l8']", + "95, mice, ['l1', 'l5', 'l9', 'l10']", + "110, in ['l2', 'l6', 'l11', 'l12']", + "111, vivo ['l3', 'l7', 'l9', 'l11', 'l13']", + "115, hippocampal ['l4', 'l8', 'l10', 'l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Kv7", + "current-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Kv7", + "current-deficient" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Kv7", + "current-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "hippocampal" + ] + } + } + ] + }, + { + "PMID": "26594843", + "TEXT": "Acute myeloid leukemia (AML) is mostly driven by oncogenic transcription factors, which have been classically viewed as intractable targets using small-molecule inhibitor approaches. Here we demonstrate that AML driven by repressive transcription factors, including AML1-ETO (encoded by the fusion oncogene RUNX1-RUNX1T1) and PML-RARα fusion oncoproteins (encoded by PML-RARA) are extremely sensitive to poly (ADP-ribose) polymerase (PARP) inhibition, in part owing to their suppressed expression of key homologous recombination (HR)-associated genes and their compromised DNA-damage response (DDR). In contrast, leukemia driven by mixed-lineage leukemia (MLL, encoded by KMT2A) fusions with dominant transactivation ability is proficient in DDR and insensitive to PARP inhibition. Intriguingly, genetic or pharmacological inhibition of an MLL downstream target, HOXA9, which activates expression of various HR-associated genes, impairs DDR and sensitizes MLL leukemia to PARP inhibitors (PARPis). Conversely, HOXA9 overexpression confers PARPi resistance to AML1-ETO and PML-RARα transformed cells. Together, these studies describe a potential utility of PARPi-induced synthetic lethality for leukemia treatment and reveal a novel molecular mechanism governing PARPi sensitivity in AML.", + "TAG_DATA": [ + "104, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "105, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "106, of {'perturbing_action': 'I-pharmacological inhibition'}", + "107, an {'perturbing_action': 'I-pharmacological inhibition'}", + "108, MLL {'perturbing_action': 'I-pharmacological inhibition'}", + "109, downstream {'perturbing_action': 'I-pharmacological inhibition'}", + "110, target, {'perturbing_action': 'I-pharmacological inhibition'}", + "111, HOXA9, {'perturbing_action': 'I-pharmacological inhibition'}", + "123, MLL {'context': 'B-neoplasm'}", + "124, leukemia {'context': 'I-neoplasm'}", + "130, HOXA9 {'perturbing_action': 'B-gene gain-of-function'}", + "131, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "139, transformed {'phenotype': 'B-transformation'}", + "140, cells. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "104, pharmacological ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "105, inhibition ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "106, of ['l1', 'l11', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "107, an ['l2', 'l12', 'l19', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "108, MLL ['l3', 'l13', 'l20', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "109, downstream ['l4', 'l14', 'l21', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "110, target, ['l5', 'l15', 'l22', 'l30', 'l35', 'l39', 'l45', 'l46', 'l47']", + "111, HOXA9, ['l6', 'l16', 'l23', 'l31', 'l36', 'l40', 'l45', 'l48', 'l49']", + "123, MLL ['l7', 'l17', 'l24', 'l32', 'l37', 'l41', 'l46', 'l48', 'l50']", + "124, leukemia ['l8', 'l18', 'l25', 'l33', 'l38', 'l42', 'l47', 'l49', 'l50']", + "130, HOXA9 ['l51', 'l52', 'l53', 'l54']", + "131, overexpression ['l51', 'l55', 'l56', 'l57']", + "138, PML-RARα ['l52', 'l55', 'l58', 'l59']", + "139, transformed ['l9', 'l26', 'l43', 'l53', 'l56', 'l58', 'l60']", + "140, cells. ['l10', 'l27', 'l44', 'l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "an", + "MLL", + "downstream", + "target,", + "HOXA9," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "MLL", + "leukemia" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "of", + "downstream" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformed" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "of", + "downstream" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "HOXA9", + "overexpression" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformed" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "HOXA9", + "overexpression" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "phenotype": { + "val": "transformation", + "words": [ + "transformed" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "26569382", + "TEXT": "Primary myelofibrosis (PMF) is characterized by bone marrow fibrosis, myeloproliferation, extramedullary hematopoiesis, splenomegaly and leukemic progression. Moreover, the bone marrow and spleens of individuals with PMF contain large numbers of atypical megakaryocytes that are postulated to contribute to fibrosis through the release of cytokines, including transforming growth factor (TGF)-β. Although the Janus kinase inhibitor ruxolitinib provides symptomatic relief, it does not reduce the mutant allele burden or substantially reverse fibrosis. Here we show through pharmacologic and genetic studies that aurora kinase A (AURKA) represents a new therapeutic target in PMF. Treatment with MLN8237, a selective AURKA inhibitor, promoted polyploidization and differentiation of megakaryocytes with PMF-associated mutations and had potent antifibrotic and antitumor activity in vivo in mouse models of PMF. Moreover, heterozygous deletion of Aurka was sufficient to ameliorate fibrosis and other PMF features in vivo. Our data suggest that megakaryocytes drive fibrosis in PMF and that targeting them with AURKA inhibitors has the potential to provide therapeutic benefit.", + "TAG_DATA": [ + "92, MLN8237, {'perturbing_action': 'B-pharmacological inhibition'}", + "93, a {'perturbing_action': 'I-pharmacological inhibition'}", + "94, selective {'perturbing_action': 'I-pharmacological inhibition'}", + "95, AURKA {'perturbing_action': 'I-pharmacological inhibition'}", + "96, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "97, promoted {'effect': 'B-positive'}", + "100, differentiation {'phenotype': 'B-differentiation'}", + "102, megakaryocytes {'context': 'B-cells'}", + "113, in {'context': 'B-in vivo'}", + "114, vivo {'context': 'I-in vivo'}", + "116, mouse {'context': 'B-organism'}", + "117, models {'context': 'I-organism'}", + "118, of {'context': 'I-organism'}", + "119, PMF. {'context': 'I-organism'}", + "121, heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "122, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "123, of {'perturbing_action': 'I-gene loss-of-function'}", + "124, Aurka {'perturbing_action': 'I-gene loss-of-function'}", + "134, in {'context': 'B-in vivo'}", + "135, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "92, MLN8237, ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "93, a ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "94, selective ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "95, AURKA ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "96, inhibitor, ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "97, promoted ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "100, differentiation ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "102, megakaryocytes ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "113, in ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "114, vivo ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "116, mouse ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "117, models ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "118, of ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "119, PMF. ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']", + "121, heterozygous ['l91', 'l92', 'l93', 'l94', 'l95']", + "122, deletion ['l91', 'l96', 'l97', 'l98', 'l99']", + "123, of ['l92', 'l96', 'l100', 'l101', 'l102']", + "124, Aurka ['l93', 'l97', 'l100', 'l103', 'l104']", + "134, in ['l94', 'l98', 'l101', 'l103', 'l105']", + "135, vivo. ['l95', 'l99', 'l102', 'l104', 'l105']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "MLN8237,", + "a", + "selective", + "AURKA", + "inhibitor," + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "MLN8237,", + "a", + "selective", + "AURKA", + "inhibitor," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "MLN8237,", + "a", + "selective", + "AURKA", + "inhibitor," + ] + }, + "context": { + "val": "cells", + "words": [ + "megakaryocytes" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "MLN8237,", + "a", + "selective", + "AURKA", + "inhibitor," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "MLN8237,", + "a", + "selective", + "AURKA", + "inhibitor," + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "of", + "PMF." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "cells", + "words": [ + "megakaryocytes" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "of", + "PMF." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "megakaryocytes" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "of", + "PMF." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "heterozygous", + "deletion", + "of", + "Aurka" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "26479921", + "TEXT": "Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive neoplasm characterized by a marked fibro-inflammatory microenvironment, the presence of which can promote both cancer induction and growth. Therefore, selective manipulation of local cytokines is an attractive, although unrealized, therapeutic approach. T cells possess a unique mechanism of p38 mitogen-activated protein kinase (MAPK) activation downstream of T cell receptor (TCR) engagement through the phosphorylation of Tyr323 (pY323). This alternative p38 activation pathway is required for pro-inflammatory cytokine production. Here we show in human PDAC that a high percentage of infiltrating pY323(+) T cells was associated with large numbers of tumor necrosis factor (TNF)-α- and interleukin (IL)-17-producing CD4(+) tumor-infiltrating lymphocytes (TILs) and aggressive disease. The growth of mouse pancreatic tumors was inhibited by genetic ablation of the alternative p38 pathway, and transfer of wild-type CD4(+) T cells, but not those lacking the alternative pathway, enhanced tumor growth in T cell-deficient mice. Notably, a plasma membrane-permeable peptide derived from GADD45-α, the naturally occurring inhibitor of p38 pY323(+) (ref. 7), reduced CD4(+) TIL production of TNF-α, IL-17A, IL-10 and secondary cytokines, halted growth of implanted tumors and inhibited progression of spontaneous KRAS-driven adenocarcinoma in mice. Thus, TCR-mediated activation of CD4(+) TILs results in alternative p38 activation and production of protumorigenic factors and can be targeted for therapeutic benefit.", + "TAG_DATA": [ + "114, mouse {'context': 'B-neoplasm'}", + "115, pancreatic {'context': 'I-neoplasm'}", + "116, tumors {'context': 'I-neoplasm'}", + "120, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "121, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "122, of {'perturbing_action': 'I-gene loss-of-function'}", + "123, the {'perturbing_action': 'I-gene loss-of-function'}", + "124, alternative {'perturbing_action': 'I-gene loss-of-function'}", + "125, p38 {'perturbing_action': 'I-gene loss-of-function'}", + "126, pathway, {'perturbing_action': 'I-gene loss-of-function'}", + "131, CD4(+) {'context': 'B-cells'}", + "132, T {'context': 'I-cells'}", + "133, cells, {'context': 'I-cells'}", + "141, enhanced {'effect': 'B-positive'}", + "142, tumor {'phenotype': 'B-tumour growth'}", + "143, growth {'phenotype': 'I-tumour growth'}", + "145, T {'perturbing_action': 'B-gene loss-of-function'}", + "146, cell-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "147, mice. {'context': 'B-organism'}", + "166, CD4(+) {'context': 'B-cells'}", + "167, TIL {'context': 'I-cells'}", + "180, tumors {'context': 'I-xenograft'}", + "186, KRAS-driven {'perturbing_action': 'B-other', 'context': 'B-neoplasm'}", + "187, adenocarcinoma {'context': 'I-neoplasm'}", + "189, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "114, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "115, pancreatic ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "116, tumors ['l1', 'l9', 'l17']", + "120, genetic ['l2', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "121, ablation ['l3', 'l11', 'l18', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "122, of ['l4', 'l12', 'l19', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "123, the ['l5', 'l13', 'l20', 'l27', 'l33', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "124, alternative ['l6', 'l14', 'l21', 'l28', 'l34', 'l40', 'l47', 'l48', 'l49', 'l50']", + "125, p38 ['l7', 'l15', 'l22', 'l29', 'l35', 'l41', 'l47', 'l51', 'l52', 'l53', 'l54']", + "126, pathway, ['l8', 'l16', 'l17', 'l23', 'l30', 'l36', 'l42', 'l48', 'l51', 'l55']", + "131, CD4(+) ['l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "132, T ['l56', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "133, cells, ['l57', 'l65', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "141, enhanced ['l37', 'l43', 'l52', 'l58', 'l66', 'l73', 'l79', 'l80', 'l81', 'l82', 'l83']", + "142, tumor ['l24', 'l31', 'l38', 'l44', 'l49', 'l53', 'l59', 'l67', 'l74', 'l79', 'l84', 'l85', 'l86', 'l87']", + "143, growth ['l25', 'l32', 'l39', 'l45', 'l50', 'l54', 'l55', 'l60', 'l68', 'l75', 'l80', 'l84', 'l88', 'l89', 'l90']", + "145, T ['l61', 'l69', 'l76', 'l81', 'l85', 'l88', 'l91', 'l92']", + "146, cell-deficient ['l46', 'l62', 'l70', 'l77', 'l82', 'l86', 'l89', 'l91', 'l93']", + "147, mice. ['l63', 'l71', 'l78', 'l83', 'l87', 'l90', 'l92', 'l93']", + "166, CD4(+) ['l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "167, TIL ['l94', 'l100', 'l101', 'l102', 'l103', 'l104']", + "179, implanted ['l95', 'l100', 'l105', 'l106']", + "180, tumors ['l64', 'l72', 'l96', 'l101', 'l105']", + "186, KRAS-driven ['l97', 'l102', 'l107', 'l108']", + "187, adenocarcinoma ['l98', 'l103', 'l106', 'l107', 'l109']", + "189, mice. ['l99', 'l104', 'l108', 'l109']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "pancreatic", + "tumors" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "the", + "alternative", + "p38", + "pathway," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "the", + "alternative", + "p38", + "pathway,", + "T", + "cell-deficient" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "the", + "p38", + "T", + "cell-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cells," + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cells," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "T", + "cells," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "T", + "cell-deficient" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "T", + "cell-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD4(+)", + "TIL" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "KRAS-driven" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "KRAS-driven" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "KRAS-driven" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "KRAS-driven" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "26437366", + "TEXT": "The tumor suppressors BAP1 and ASXL1 interact to form a polycomb deubiquitinase complex that removes monoubiquitin from histone H2A lysine 119 (H2AK119Ub). However, BAP1 and ASXL1 are mutated in distinct cancer types, consistent with independent roles in regulating epigenetic state and malignant transformation. Here we demonstrate that Bap1 loss in mice results in increased trimethylated histone H3 lysine 27 (H3K27me3), elevated enhancer of zeste 2 polycomb repressive complex 2 subunit (Ezh2) expression, and enhanced repression of polycomb repressive complex 2 (PRC2) targets. These findings contrast with the reduction in H3K27me3 levels seen with Asxl1 loss. Conditional deletion of Bap1 and Ezh2 in vivo abrogates the myeloid progenitor expansion induced by Bap1 loss alone. Loss of BAP1 results in a marked decrease in H4K20 monomethylation (H4K20me1). Consistent with a role for H4K20me1 in the transcriptional regulation of EZH2, expression of SETD8-the H4K20me1 methyltransferase-reduces EZH2 expression and abrogates the proliferation of BAP1-mutant cells. Furthermore, mesothelioma cells that lack BAP1 are sensitive to EZH2 pharmacologic inhibition, suggesting a novel therapeutic approach for BAP1-mutant malignancies.", + "TAG_DATA": [ + "47, Bap1 {'perturbing_action': 'B-gene loss-of-function'}", + "48, loss {'perturbing_action': 'I-gene loss-of-function'}", + "50, mice {'context': 'B-organism'}", + "93, Asxl1 {'perturbing_action': 'B-gene loss-of-function'}", + "94, loss. {'perturbing_action': 'I-gene loss-of-function'}", + "95, Conditional {'perturbing_action': 'B-gene loss-of-function'}", + "96, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "97, of {'perturbing_action': 'I-gene loss-of-function'}", + "98, Bap1 {'perturbing_action': 'I-gene loss-of-function'}", + "99, and {'perturbing_action': 'I-gene loss-of-function'}", + "100, Ezh2 {'perturbing_action': 'I-gene loss-of-function'}", + "101, in {'context': 'B-in vivo'}", + "102, vivo {'context': 'I-in vivo'}", + "105, myeloid {'context': 'B-cells'}", + "106, progenitor {'context': 'I-cells'}", + "110, Bap1 {'perturbing_action': 'B-gene loss-of-function'}", + "111, loss {'perturbing_action': 'I-gene loss-of-function'}", + "113, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "114, of {'perturbing_action': 'I-gene loss-of-function'}", + "115, BAP1 {'perturbing_action': 'I-gene loss-of-function'}", + "145, abrogates {'effect': 'B-negative'}", + "147, proliferation {'phenotype': 'B-proliferation'}", + "149, BAP1-mutant {'perturbing_action': 'B-other'}", + "150, cells. {'context': 'B-cells'}", + "152, mesothelioma {'context': 'B-transformed cells'}", + "153, cells {'context': 'I-transformed cells'}", + "155, lack {'perturbing_action': 'B-gene loss-of-function'}", + "156, BAP1 {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "47, Bap1 ['l0', 'l1', 'l2', 'l3']", + "48, loss ['l0', 'l4', 'l5', 'l6']", + "50, mice ['l1', 'l4']", + "93, Asxl1 ['l2', 'l5', 'l7']", + "94, loss. ['l3', 'l6', 'l7']", + "95, Conditional ['l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "96, deletion ['l8', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "97, of ['l9', 'l22', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "98, Bap1 ['l10', 'l23', 'l38', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "99, and ['l11', 'l24', 'l39', 'l48', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "100, Ezh2 ['l12', 'l25', 'l40', 'l49', 'l56', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "101, in ['l13', 'l26', 'l41', 'l50', 'l57', 'l63', 'l69', 'l70', 'l71', 'l72', 'l73']", + "102, vivo ['l14', 'l27', 'l42', 'l51', 'l58', 'l64', 'l69', 'l74', 'l75', 'l76', 'l77']", + "105, myeloid ['l15', 'l28', 'l43', 'l52', 'l59', 'l65', 'l70', 'l74', 'l78', 'l79', 'l80']", + "106, progenitor ['l16', 'l29', 'l44', 'l53', 'l60', 'l66', 'l71', 'l75', 'l78', 'l81', 'l82']", + "110, Bap1 ['l17', 'l30', 'l45', 'l54', 'l61', 'l67', 'l72', 'l76', 'l79', 'l81', 'l83']", + "111, loss ['l18', 'l31', 'l46', 'l55', 'l62', 'l68', 'l73', 'l77', 'l80', 'l82', 'l83']", + "113, Loss ['l19', 'l32', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "114, of ['l33', 'l84', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "115, BAP1 ['l20', 'l34', 'l85', 'l90', 'l96', 'l97', 'l98', 'l99']", + "145, abrogates ['l21', 'l35', 'l47', 'l86', 'l91', 'l96', 'l100', 'l101', 'l102']", + "147, proliferation ['l36', 'l87', 'l92', 'l97', 'l100', 'l103', 'l104']", + "149, BAP1-mutant ['l88', 'l93', 'l98', 'l101', 'l103', 'l105']", + "150, cells. ['l37', 'l89', 'l94', 'l99', 'l102', 'l104', 'l105']", + "152, mesothelioma ['l106', 'l107', 'l108']", + "153, cells ['l95', 'l106', 'l109', 'l110']", + "155, lack ['l107', 'l109', 'l111']", + "156, BAP1 ['l108', 'l110', 'l111']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bap1", + "loss" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "deletion", + "of", + "Bap1", + "and", + "Ezh2", + "loss" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "deletion", + "of", + "Bap1", + "and", + "Ezh2", + "loss", + "Loss", + "BAP1" + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "progenitor", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "deletion", + "of", + "Loss", + "BAP1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "Loss", + "of", + "BAP1" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "lack", + "BAP1" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cells", + "mesothelioma" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "BAP1-mutant" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "BAP1-mutant" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BAP1-mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "26398868", + "TEXT": "The vast majority of disease-associated single-nucleotide polymorphisms (SNPs) mapped by genome-wide association studies (GWASs) are located in the non-protein-coding genome, but establishing the functional and mechanistic roles of these sequence variants has proven challenging. Here we describe a general pipeline in which candidate functional SNPs are first evaluated by fine mapping, epigenomic profiling, and epigenome editing, and then interrogated for causal function by using genome editing to create isogenic cell lines followed by phenotypic characterization. To validate this approach, we analyzed the 6q22.1 prostate cancer risk locus and identified rs339331 as the top-scoring SNP. Epigenome editing confirmed that the rs339331 region possessed regulatory potential. By using transcription activator-like effector nuclease (TALEN)-mediated genome editing, we created a panel of isogenic 22Rv1 prostate cancer cell lines representing all three genotypes (TT, TC, CC) at rs339331. Introduction of the 'T' risk allele increased transcription of the regulatory factor 6 (RFX6) gene, increased homeobox B13 (HOXB13) binding at the rs339331 region, and increased deposition of the enhancer-associated H3K4me2 histone mark at the rs339331 region compared to lines homozygous for the 'C' protective allele. The cell lines also differed in cellular morphology and adhesion, and pathway analysis of differentially expressed genes suggested an influence of androgens. In summary, we have developed and validated a widely accessible approach that can be used to establish functional causality for noncoding sequence variants identified by GWASs.", + "TAG_DATA": [ + "120, prostate {'context': 'B-transformed cells'}", + "121, cancer {'context': 'I-transformed cells'}", + "122, cell {'context': 'I-transformed cells'}", + "123, lines {'context': 'I-transformed cells'}", + "180, cell {'context': 'B-cells'}", + "181, lines {'context': 'I-cells'}", + "188, adhesion, {'phenotype': 'B-adhesion'}" + ], + "LINK_DATA": [ + "120, prostate ['l0', 'l1', 'l2']", + "121, cancer ['l0', 'l3', 'l4']", + "122, cell ['l1', 'l3', 'l5']", + "123, lines ['l2', 'l4', 'l5']", + "180, cell ['l6', 'l7']", + "181, lines ['l6', 'l8']", + "188, adhesion, ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cell", + "lines" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion," + ] + } + } + ] + }, + { + "PMID": "26390244", + "TEXT": "Activating mutations in NOTCH1 are common in T cell acute lymphoblastic leukemia (T-ALL). Here we identify glutaminolysis as a critical pathway for leukemia cell growth downstream of NOTCH1 and a key determinant of the response to anti-NOTCH1 therapies in vivo. Mechanistically, inhibition of NOTCH1 signaling in T-ALL induces a metabolic shutdown, with prominent inhibition of glutaminolysis and triggers autophagy as a salvage pathway supporting leukemia cell metabolism. Consequently, inhibition of glutaminolysis and inhibition of autophagy strongly and synergistically enhance the antileukemic effects of anti-NOTCH1 therapy in mice harboring T-ALL. Moreover, we demonstrate that Pten loss upregulates glycolysis and consequently rescues leukemic cell metabolism, thereby abrogating the antileukemic effects of NOTCH1 inhibition. Overall, these results identify glutaminolysis as a major node in cancer metabolism controlled by NOTCH1 and as therapeutic target for the treatment of T-ALL.", + "TAG_DATA": [ + "46, T-ALL {'context': 'B-neoplasm'}", + "57, triggers {'effect': 'B-positive'}", + "58, autophagy {'phenotype': 'B-autophagy'}", + "64, leukemia {'context': 'B-transformed cells'}", + "72, inhibition {'effect': 'B-negative'}", + "86, mice {'context': 'B-organism'}", + "88, T-ALL. {'context': 'B-neoplasm'}", + "93, Pten {'perturbing_action': 'B-gene loss-of-function'}", + "94, loss {'perturbing_action': 'I-gene loss-of-function'}", + "100, leukemic {'context': 'B-cells'}", + "101, cell {'context': 'I-cells'}", + "109, NOTCH1 {'perturbing_action': 'B-pharmacological inhibition'}", + "110, inhibition. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "46, T-ALL ['l0', 'l1', 'l2']", + "57, triggers ['l0', 'l3', 'l4']", + "58, autophagy ['l1', 'l3', 'l5']", + "64, leukemia ['l2', 'l4', 'l5']", + "72, inhibition ['l6', 'l7']", + "86, mice ['l6', 'l8']", + "88, T-ALL. ['l7', 'l8']", + "93, Pten ['l9', 'l10', 'l11', 'l12', 'l13']", + "94, loss ['l9', 'l14', 'l15', 'l16', 'l17']", + "100, leukemic ['l10', 'l14', 'l18', 'l19', 'l20']", + "101, cell ['l11', 'l15', 'l18', 'l21', 'l22']", + "109, NOTCH1 ['l12', 'l16', 'l19', 'l21', 'l23']", + "110, inhibition. ['l13', 'l17', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "T-ALL" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "T-ALL" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "leukemia" + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "autophagy" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "leukemia" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "T-ALL." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pten", + "loss" + ] + }, + "context": { + "val": "cells", + "words": [ + "leukemic", + "cell" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "leukemic", + "cell" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NOTCH1", + "inhibition." + ] + } + } + ] + }, + { + "PMID": "26366712", + "TEXT": "Mutations in the gene encoding the KMT2D (or MLL2) methyltransferase are highly recurrent and occur early during tumorigenesis in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). However, the functional consequences of these mutations and their role in lymphomagenesis are unknown. Here we show that FL- and DLBCL-associated KMT2D mutations impair KMT2D enzymatic activity, leading to diminished global H3K4 methylation in germinal-center (GC) B cells and DLBCL cells. Conditional deletion of Kmt2d early during B cell development, but not after initiation of the GC reaction, results in an increase in GC B cells and enhances B cell proliferation in mice. Moreover, genetic ablation of Kmt2d in mice overexpressing Bcl2 increases the incidence of GC-derived lymphomas resembling human tumors. These findings suggest that KMT2D acts as a tumor suppressor gene whose early loss facilitates lymphomagenesis by remodeling the epigenetic landscape of the cancer precursor cells. Eradication of KMT2D-deficient cells may thus represent a rational therapeutic approach for targeting early tumorigenic events.", + "TAG_DATA": [ + "66, cells {'context': 'I-cells'}", + "68, DLBCL {'context': 'B-transformed cells'}", + "69, cells. {'context': 'I-transformed cells'}", + "70, Conditional {'perturbing_action': 'B-gene loss-of-function'}", + "71, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "72, of {'perturbing_action': 'I-gene loss-of-function'}", + "73, Kmt2d {'perturbing_action': 'I-gene loss-of-function'}", + "92, GC {'context': 'B-transformed cells'}", + "93, B {'context': 'I-transformed cells'}", + "94, cells {'context': 'I-transformed cells'}", + "96, enhances {'effect': 'B-positive'}", + "97, B {'context': 'B-cells'}", + "98, cell {'context': 'I-cells'}", + "99, proliferation {'phenotype': 'B-proliferation'}", + "101, mice. {'context': 'B-organism'}", + "103, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "104, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "105, of {'perturbing_action': 'I-gene loss-of-function'}", + "106, Kmt2d {'perturbing_action': 'I-gene loss-of-function'}", + "108, mice {'context': 'B-organism'}", + "109, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "110, Bcl2 {'perturbing_action': 'I-gene gain-of-function'}", + "115, GC-derived {'context': 'B-neoplasm'}", + "116, lymphomas {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "65, B ['l0', 'l1', 'l2']", + "66, cells ['l0', 'l3', 'l4']", + "68, DLBCL ['l1', 'l3', 'l5']", + "69, cells. ['l2', 'l4', 'l5']", + "70, Conditional ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "71, deletion ['l6', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "72, of ['l7', 'l17', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "73, Kmt2d ['l8', 'l18', 'l27', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "92, GC ['l9', 'l19', 'l28', 'l36', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "93, B ['l10', 'l20', 'l29', 'l37', 'l44', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "94, cells ['l11', 'l21', 'l30', 'l38', 'l45', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "96, enhances ['l12', 'l22', 'l31', 'l39', 'l46', 'l52', 'l57', 'l62', 'l63', 'l64', 'l65']", + "97, B ['l13', 'l23', 'l32', 'l40', 'l47', 'l53', 'l58', 'l62', 'l66', 'l67', 'l68']", + "98, cell ['l14', 'l24', 'l33', 'l41', 'l48', 'l54', 'l59', 'l63', 'l66', 'l69', 'l70']", + "99, proliferation ['l15', 'l25', 'l34', 'l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l71']", + "101, mice. ['l16', 'l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l71']", + "103, genetic ['l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "104, ablation ['l72', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "105, of ['l73', 'l80', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "106, Kmt2d ['l74', 'l81', 'l87', 'l93', 'l94', 'l95', 'l96', 'l97']", + "108, mice ['l75', 'l82', 'l88', 'l93', 'l98', 'l99', 'l100', 'l101']", + "109, overexpressing ['l76', 'l83', 'l89', 'l94', 'l98', 'l102', 'l103', 'l104']", + "110, Bcl2 ['l77', 'l84', 'l90', 'l95', 'l99', 'l102', 'l105', 'l106']", + "115, GC-derived ['l78', 'l85', 'l91', 'l96', 'l100', 'l103', 'l105', 'l107']", + "116, lymphomas ['l79', 'l86', 'l92', 'l97', 'l101', 'l104', 'l106', 'l107']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "deletion", + "of", + "Kmt2d" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "GC", + "B", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "deletion", + "of", + "Kmt2d" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "deletion", + "of", + "Kmt2d" + ] + }, + "context": { + "val": "cells", + "words": [ + "B", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "deletion", + "of", + "Kmt2d" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "deletion", + "of", + "Kmt2d", + "genetic", + "ablation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "GC", + "B", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "GC", + "B", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "context": { + "val": "cells", + "words": [ + "B", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "B", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "Kmt2d" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "GC-derived", + "lymphomas" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "Bcl2" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "Bcl2" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "GC-derived", + "lymphomas" + ] + } + } + ] + }, + { + "PMID": "26366710", + "TEXT": "The gene encoding the lysine-specific histone methyltransferase KMT2D has emerged as one of the most frequently mutated genes in follicular lymphoma and diffuse large B cell lymphoma; however, the biological consequences of KMT2D mutations on lymphoma development are not known. Here we show that KMT2D functions as a bona fide tumor suppressor and that its genetic ablation in B cells promotes lymphoma development in mice. KMT2D deficiency also delays germinal center involution and impedes B cell differentiation and class switch recombination. Integrative genomic analyses indicate that KMT2D affects methylation of lysine 4 on histone H3 (H3K4) and expression of a set of genes, including those in the CD40, JAK-STAT, Toll-like receptor and B cell receptor signaling pathways. Notably, other KMT2D target genes include frequently mutated tumor suppressor genes such as TNFAIP3, SOCS3 and TNFRSF14. Therefore, KMT2D mutations may promote malignant outgrowth by perturbing the expression of tumor suppressor genes that control B cell-activating pathways.", + "TAG_DATA": [ + "55, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "56, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "58, B {'context': 'B-cells'}", + "59, cells {'context': 'I-cells'}", + "60, promotes {'effect': 'B-positive'}", + "61, lymphoma {'phenotype': 'B-tumourigenesis'}", + "62, development {'phenotype': 'I-tumourigenesis'}", + "64, mice. {'context': 'B-organism'}", + "65, KMT2D {'perturbing_action': 'B-gene loss-of-function'}", + "66, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "73, impedes {'effect': 'B-negative'}", + "74, B {'context': 'B-cells'}", + "75, cell {'context': 'I-cells'}", + "76, differentiation {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "55, genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "56, ablation ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "58, B ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19']", + "59, cells ['l2', 'l9', 'l15', 'l20', 'l21', 'l22', 'l23']", + "60, promotes ['l3', 'l10', 'l16', 'l20', 'l24', 'l25', 'l26']", + "61, lymphoma ['l4', 'l11', 'l17', 'l21', 'l24', 'l27', 'l28']", + "62, development ['l5', 'l12', 'l18', 'l22', 'l25', 'l27', 'l29']", + "64, mice. ['l6', 'l13', 'l19', 'l23', 'l26', 'l28', 'l29']", + "65, KMT2D ['l30', 'l31', 'l32', 'l33', 'l34']", + "66, deficiency ['l30', 'l35', 'l36', 'l37', 'l38']", + "73, impedes ['l31', 'l35', 'l39', 'l40', 'l41']", + "74, B ['l32', 'l36', 'l39', 'l42', 'l43']", + "75, cell ['l7', 'l14', 'l33', 'l37', 'l40', 'l42', 'l44']", + "76, differentiation ['l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "KMT2D", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "B", + "cells", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma", + "development" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "B", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "B", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma", + "development" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma", + "development" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma", + "development" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "KMT2D", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impedes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "KMT2D", + "deficiency" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impedes" + ] + }, + "context": { + "val": "cells", + "words": [ + "B", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impedes" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "B", + "cell" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "26236989", + "TEXT": "Progressive kidney fibrosis contributes greatly to end-stage renal failure, and no specific treatment is available to preserve organ function. During renal fibrosis, myofibroblasts accumulate in the interstitium of the kidney, leading to massive deposition of extracellular matrix and organ dysfunction. The origin of myofibroblasts is manifold, but the contribution of an epithelial-to-mesenchymal transition (EMT) undergone by renal epithelial cells during kidney fibrosis is still debated. We show that the reactivation of Snai1 (encoding snail family zinc finger 1, known as Snail1) in mouse renal epithelial cells is required for the development of fibrosis in the kidney. Damage-mediated Snail1 reactivation induces a partial EMT in tubular epithelial cells that, without directly contributing to the myofibroblast population, relays signals to the interstitium to promote myofibroblast differentiation and fibrogenesis and to sustain inflammation. We also show that Snail1-induced fibrosis can be reversed in vivo and that obstructive nephropathy can be therapeutically ameliorated in mice by targeting Snail1 expression. These results reconcile conflicting data on the role of the EMT in renal fibrosis and provide avenues for the design of novel anti-fibrotic therapies.", + "TAG_DATA": [ + "82, mouse {'context': 'B-cells'}", + "83, renal {'context': 'I-cells'}", + "84, epithelial {'context': 'I-cells'}", + "85, cells {'context': 'I-cells'}", + "99, induces {'effect': 'B-positive'}", + "102, EMT {'phenotype': 'B-epithelial-mesenchymal transition'}", + "104, tubular {'context': 'B-cells'}", + "105, epithelial {'context': 'I-cells'}", + "106, cells {'context': 'I-cells'}", + "139, in {'context': 'B-in vivo'}", + "140, vivo {'context': 'I-in vivo'}", + "150, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "82, mouse ['l0', 'l1', 'l2']", + "83, renal ['l0', 'l3', 'l4']", + "84, epithelial ['l1', 'l3', 'l5']", + "85, cells ['l2', 'l4', 'l5']", + "99, induces ['l6', 'l7', 'l8', 'l9']", + "102, EMT ['l6', 'l10', 'l11', 'l12']", + "104, tubular ['l7', 'l10', 'l13', 'l14']", + "105, epithelial ['l8', 'l11', 'l13', 'l15']", + "106, cells ['l9', 'l12', 'l14', 'l15']", + "139, in ['l16']", + "140, vivo ['l16']", + "150, mice ['l17']", + "152, targeting ['l17']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EMT" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "cells", + "words": [ + "tubular", + "epithelial", + "cells" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EMT" + ] + }, + "context": { + "val": "cells", + "words": [ + "tubular", + "epithelial", + "cells" + ] + } + } + ] + }, + { + "PMID": "26193341", + "TEXT": "Chronic itch is an intractable symptom of inflammatory skin diseases, such as atopic and contact dermatitis. Recent studies have revealed neuronal pathways selective for itch, but the mechanisms by which itch turns into a pathological chronic state are poorly understood. Using mouse models of atopic and contact dermatitis, we demonstrate a long-term reactive state of astrocytes in the dorsal horn of the spinal segments that corresponds to lesioned, itchy skin. We found that reactive astrogliosis depended on the activation of signal transducer and activator of transcription 3 (STAT3). Conditional disruption of astrocytic STAT3 suppressed chronic itch, and pharmacological inhibition of spinal STAT3 ameliorated the fully developed chronic itch. Mice with atopic dermatitis exhibited an increase in scratching elicited by intrathecal administration of the itch-inducer gastrin-releasing peptide (GRP), and this enhancement was normalized by suppressing STAT3-mediated reactive astrogliosis. Moreover, we identified lipocalin-2 (LCN2) as an astrocytic STAT3-dependent upregulated factor that was crucial for chronic itch, and we demonstrated that intrathecal administration of LCN2 to normal mice increased spinal GRP-evoked scratching. Our findings indicate that STAT3-dependent reactive astrocytes act as critical amplifiers of itching through a mechanism involving the enhancement of spinal itch signals by LCN2, thereby providing a previously unrecognized target for treating chronic itch.", + "TAG_DATA": [ + "88, Conditional {'perturbing_action': 'B-gene loss-of-function'}", + "89, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "90, of {'perturbing_action': 'I-gene loss-of-function'}", + "91, astrocytic {'perturbing_action': 'I-gene loss-of-function'}", + "92, STAT3 {'perturbing_action': 'I-gene loss-of-function'}", + "97, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "98, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "99, of {'perturbing_action': 'I-pharmacological inhibition'}", + "100, spinal {'perturbing_action': 'I-pharmacological inhibition'}", + "101, STAT3 {'perturbing_action': 'I-pharmacological inhibition'}", + "108, Mice {'context': 'B-organism'}", + "164, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "88, Conditional ['l0', 'l1', 'l2', 'l3']", + "89, disruption ['l0', 'l4', 'l5', 'l6']", + "90, of ['l1', 'l4', 'l7', 'l8']", + "91, astrocytic ['l2', 'l5', 'l7', 'l9']", + "92, STAT3 ['l3', 'l6', 'l8', 'l9']", + "97, pharmacological ['l10', 'l11', 'l12', 'l13', 'l14']", + "98, inhibition ['l10', 'l15', 'l16', 'l17', 'l18']", + "99, of ['l11', 'l15', 'l19', 'l20', 'l21']", + "100, spinal ['l12', 'l16', 'l19', 'l22', 'l23']", + "101, STAT3 ['l13', 'l17', 'l20', 'l22', 'l24']", + "108, Mice ['l14', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "spinal", + "STAT3" + ] + }, + "context": { + "val": "organism", + "words": [ + "Mice" + ] + } + } + ] + }, + { + "PMID": "26168293", + "TEXT": "Nicotinamide N-methyltransferase (Nnmt) methylates nicotinamide, a form of vitamin B3, to produce N(1)-methylnicotinamide (MNAM). Nnmt has emerged as a metabolic regulator in adipocytes, but its role in the liver, the tissue with the strongest Nnmt expression, is not known. In spite of its overall high expression, here we find that hepatic expression of Nnmt is highly variable and correlates with multiple metabolic parameters in mice and humans. Further, we find that suppression of hepatic Nnmt expression in vivo alters glucose and cholesterol metabolism and that the metabolic effects of Nnmt in the liver are mediated by its product MNAM. Supplementation of high-fat diet with MNAM decreases serum and liver cholesterol and liver triglycerides levels in mice. Mechanistically, increasing Nnmt expression or MNAM levels stabilizes sirtuin 1 protein, an effect that is required for their metabolic benefits. In summary, we describe here a novel regulatory pathway for vitamin B3 that could provide a new opportunity for metabolic disease therapy.", + "TAG_DATA": [ + "71, suppression {'perturbing_action': 'B-other'}", + "72, of {'perturbing_action': 'I-other'}", + "73, hepatic {'perturbing_action': 'I-other'}", + "74, Nnmt {'perturbing_action': 'I-other'}", + "75, expression {'perturbing_action': 'I-other'}", + "76, in {'context': 'B-in vivo'}", + "77, vivo {'context': 'I-in vivo'}", + "92, liver {'context': 'B-tissue/organ'}", + "115, mice. {'context': 'B-organism'}", + "117, increasing {'perturbing_action': 'B-gene gain-of-function'}", + "118, Nnmt {'perturbing_action': 'I-gene gain-of-function'}", + "119, expression {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "71, suppression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "72, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "73, hepatic ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "74, Nnmt ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "75, expression ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "76, in ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "77, vivo ['l5', 'l11', 'l16', 'l20', 'l23', 'l25']", + "92, liver ['l6', 'l12', 'l17', 'l21', 'l24', 'l26']", + "117, increasing ['l27', 'l28']", + "118, Nnmt ['l27', 'l29']", + "119, expression ['l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "suppression", + "of", + "hepatic", + "Nnmt", + "expression" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "suppression", + "of", + "hepatic", + "Nnmt", + "expression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "26107252", + "TEXT": "The inflammasome activates caspase-1 and the release of interleukin-1β (IL-1β) and IL-18, and several inflammasomes protect against intestinal inflammation and colitis-associated colon cancer (CAC) in animal models. The absent in melanoma 2 (AIM2) inflammasome is activated by double-stranded DNA, and AIM2 expression is reduced in several types of cancer, but the mechanism by which AIM2 restricts tumor growth remains unclear. We found that Aim2-deficient mice had greater tumor load than Asc-deficient mice in the azoxymethane/dextran sodium sulfate (AOM/DSS) model of colorectal cancer. Tumor burden was also higher in Aim2(-/-)/Apc(Min/+) than in APC(Min/+) mice. The effects of AIM2 on CAC were independent of inflammasome activation and IL-1β and were primarily mediated by a non-bone marrow source of AIM2. In resting cells, AIM2 physically interacted with and limited activation of DNA-dependent protein kinase (DNA-PK), a PI3K-related family member that promotes Akt phosphorylation, whereas loss of AIM2 promoted DNA-PK-mediated Akt activation. AIM2 reduced Akt activation and tumor burden in colorectal cancer models, while an Akt inhibitor reduced tumor load in Aim2(-/-) mice. These findings suggest that Akt inhibitors could be used to treat AIM2-deficient human cancers.", + "TAG_DATA": [ + "63, Aim2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "64, mice {'context': 'B-organism'}", + "66, greater {'effect': 'B-positive'}", + "67, tumor {'phenotype': 'B-tumourigenesis'}", + "68, load {'phenotype': 'I-tumourigenesis'}", + "70, Asc-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "71, mice {'context': 'B-organism'}", + "79, of {'context': 'B-neoplasm'}", + "80, colorectal {'context': 'B-neoplasm'}", + "81, cancer. {'context': 'I-neoplasm'}", + "82, Tumor {'phenotype': 'B-tumourigenesis'}", + "83, burden {'phenotype': 'I-tumourigenesis'}", + "86, higher {'effect': 'B-positive'}", + "88, Aim2(-/-)/Apc(Min/+) {'perturbing_action': 'B-gene loss-of-function'}", + "92, mice. {'context': 'B-organism'}", + "118, resting {'context': 'B-cells'}", + "119, cells, {'context': 'I-cells'}", + "141, loss {'perturbing_action': 'B-gene loss-of-function'}", + "142, of {'perturbing_action': 'I-gene loss-of-function'}", + "143, AIM2 {'perturbing_action': 'I-gene loss-of-function'}", + "153, tumor {'phenotype': 'B-tumourigenesis'}", + "154, burden {'phenotype': 'I-tumourigenesis'}", + "156, colorectal {'context': 'B-neoplasm'}", + "157, cancer {'context': 'I-neoplasm'}", + "158, models, {'context': 'I-neoplasm'}", + "161, Akt {'perturbing_action': 'B-pharmacological inhibition'}", + "162, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "163, reduced {'effect': 'B-negative'}", + "164, tumor {'phenotype': 'B-tumourigenesis'}", + "165, load {'phenotype': 'I-tumourigenesis'}", + "167, Aim2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "168, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "63, Aim2-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "64, mice ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "66, greater ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "67, tumor ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "68, load ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33']", + "70, Asc-deficient ['l4', 'l12', 'l19', 'l25', 'l30', 'l34', 'l35', 'l36', 'l37']", + "71, mice ['l5', 'l13', 'l20', 'l26', 'l31', 'l34', 'l38', 'l39', 'l40']", + "79, of ['l6', 'l14', 'l21', 'l27', 'l32', 'l35', 'l38', 'l41', 'l42']", + "80, colorectal ['l7', 'l15', 'l22', 'l28', 'l36', 'l39', 'l41', 'l43']", + "81, cancer. ['l8', 'l16', 'l23', 'l29', 'l33', 'l37', 'l40', 'l42', 'l43']", + "82, Tumor ['l44', 'l45', 'l46', 'l47', 'l48']", + "83, burden ['l44', 'l49', 'l50', 'l51']", + "86, higher ['l45', 'l49', 'l52', 'l53']", + "88, Aim2(-/-)/Apc(Min/+) ['l46', 'l50', 'l52', 'l54', 'l55', 'l56', 'l57', 'l58']", + "92, mice. ['l54', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "118, resting ['l47', 'l55', 'l59', 'l65', 'l66', 'l67', 'l68', 'l69']", + "119, cells, ['l48', 'l51', 'l53', 'l56', 'l60', 'l65', 'l70', 'l71', 'l72']", + "141, loss ['l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "142, of ['l73', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "143, AIM2 ['l74', 'l80', 'l86', 'l87', 'l88', 'l89', 'l90']", + "153, tumor ['l75', 'l81', 'l86', 'l91', 'l92', 'l93', 'l94']", + "154, burden ['l61', 'l66', 'l70', 'l76', 'l82', 'l87', 'l91', 'l95', 'l96', 'l97']", + "156, colorectal ['l62', 'l67', 'l77', 'l83', 'l88', 'l92', 'l95', 'l98', 'l99']", + "157, cancer ['l57', 'l63', 'l68', 'l71', 'l78', 'l84', 'l89', 'l93', 'l96', 'l98', 'l100']", + "158, models, ['l58', 'l64', 'l69', 'l72', 'l79', 'l85', 'l90', 'l94', 'l97', 'l99', 'l100']", + "161, Akt ['l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "162, inhibitor ['l101', 'l107', 'l108', 'l109', 'l110', 'l111']", + "163, reduced ['l102', 'l107', 'l112', 'l113', 'l114', 'l115']", + "164, tumor ['l103', 'l108', 'l112', 'l116', 'l117', 'l118']", + "165, load ['l104', 'l109', 'l113', 'l116', 'l119', 'l120']", + "167, Aim2(-/-) ['l105', 'l110', 'l114', 'l117', 'l119', 'l121']", + "168, mice. ['l106', 'l111', 'l115', 'l118', 'l120', 'l121']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Aim2-deficient", + "Asc-deficient", + "Aim2(-/-)/Apc(Min/+)", + "Aim2(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Aim2-deficient", + "Asc-deficient", + "Aim2(-/-)/Apc(Min/+)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "greater", + "higher" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Aim2-deficient", + "Asc-deficient", + "Aim2(-/-)/Apc(Min/+)", + "loss", + "of", + "AIM2", + "Aim2(-/-)" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "load", + "Tumor", + "burden" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Aim2-deficient", + "Asc-deficient", + "Aim2(-/-)/Apc(Min/+)", + "loss", + "of", + "AIM2" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "of", + "colorectal", + "cancer.", + "cancer", + "models," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "greater" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "load", + "burden" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "greater", + "higher" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "load", + "Tumor", + "burden" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "greater" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "of", + "colorectal", + "cancer." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "load", + "burden" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "of", + "colorectal", + "cancer.", + "cancer", + "models," + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "Tumor", + "burden" + ] + }, + "context": { + "val": "cells", + "words": [ + "resting", + "cells," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "higher" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Aim2(-/-)/Apc(Min/+)" + ] + }, + "context": { + "val": "cells", + "words": [ + "resting", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Akt", + "inhibitor" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Akt", + "inhibitor" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "load" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Akt", + "inhibitor" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "load" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Aim2(-/-)" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "26076037", + "TEXT": "Wound healing is impaired in diabetes, resulting in significant morbidity and mortality. Neutrophils are the main leukocytes involved in the early phase of healing. As part of their anti-microbial defense, neutrophils form extracellular traps (NETs) by releasing decondensed chromatin lined with cytotoxic proteins. NETs, however, can also induce tissue damage. Here we show that neutrophils isolated from type 1 and type 2 diabetic humans and mice were primed to produce NETs (a process termed NETosis). Expression of peptidylarginine deiminase 4 (PAD4, encoded by Padi4 in mice), an enzyme important in chromatin decondensation, was elevated in neutrophils from individuals with diabetes. When subjected to excisional skin wounds, wild-type (WT) mice produced large quantities of NETs in wounds, but this was not observed in Padi4(-/-) mice. In diabetic mice, higher levels of citrullinated histone H3 (H3Cit, a NET marker) were found in their wounds than in normoglycemic mice and healing was delayed. Wound healing was accelerated in Padi4(-/-) mice as compared to WT mice, and it was not compromised by diabetes. DNase 1, which disrupts NETs, accelerated wound healing in diabetic and normoglycemic WT mice. Thus, NETs impair wound healing, particularly in diabetes, in which neutrophils are more susceptible to NETosis. Inhibiting NETosis or cleaving NETs may improve wound healing and reduce NET-driven chronic inflammation in diabetes.", + "TAG_DATA": [ + "65, mice {'context': 'B-organism'}", + "108, mice {'context': 'B-organism'}", + "122, Padi4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "123, mice. {'context': 'B-organism'}", + "125, diabetic {'context': 'B-organism'}", + "126, mice, {'context': 'I-organism'}", + "145, mice {'context': 'I-organism'}", + "155, Padi4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "156, mice {'context': 'B-organism'}", + "182, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "108, mice ['l0', 'l1', 'l2']", + "122, Padi4(-/-) ['l3', 'l4', 'l5', 'l6']", + "123, mice. ['l0', 'l3', 'l7', 'l8', 'l9']", + "125, diabetic ['l4', 'l7', 'l10', 'l11']", + "126, mice, ['l1', 'l5', 'l8', 'l10', 'l12']", + "145, mice ['l2', 'l6', 'l9', 'l11', 'l12']", + "153, accelerated ['l13', 'l14']", + "155, Padi4(-/-) ['l13', 'l15']", + "156, mice ['l14', 'l15']", + "174, accelerated ['l16']", + "182, mice. ['l16']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Padi4(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "diabetic", + "mice,", + "mice" + ] + } + } + ] + }, + { + "PMID": "26076036", + "TEXT": "Targeting brown adipose tissue (BAT) content or activity has therapeutic potential for treating obesity and the metabolic syndrome by increasing energy expenditure. However, both inter- and intra-individual differences contribute to heterogeneity in human BAT and potentially to differential thermogenic capacity in human populations. Here we generated clones of brown and white preadipocytes from human neck fat and characterized their adipogenic and thermogenic differentiation. We combined an uncoupling protein 1 (UCP1) reporter system and expression profiling to define novel sets of gene signatures in human preadipocytes that could predict the thermogenic potential of the cells once they were maturated. Knocking out the positive UCP1 regulators, PREX1 and EDNRB, in brown preadipocytes using CRISPR-Cas9 markedly abolished the high level of UCP1 in brown adipocytes differentiated from the preadipocytes. Finally, we were able to prospectively isolate adipose progenitors with great thermogenic potential using the cell surface marker CD29. These data provide new insights into the cellular heterogeneity in human fat and offer potential biomarkers for identifying thermogenically competent preadipocytes.", + "TAG_DATA": [ + "83, human {'context': 'B-cells'}", + "84, preadipocytes {'context': 'I-cells'}", + "98, Knocking {'perturbing_action': 'B-gene loss-of-function'}", + "99, out {'perturbing_action': 'I-gene loss-of-function'}", + "100, the {'perturbing_action': 'I-gene loss-of-function'}", + "101, positive {'perturbing_action': 'I-gene loss-of-function'}", + "102, UCP1 {'perturbing_action': 'I-gene loss-of-function'}", + "103, regulators, {'perturbing_action': 'I-gene loss-of-function'}", + "104, PREX1 {'perturbing_action': 'I-gene loss-of-function'}", + "105, and {'perturbing_action': 'I-gene loss-of-function'}", + "106, EDNRB, {'perturbing_action': 'I-gene loss-of-function'}", + "108, brown {'context': 'B-cells'}", + "109, preadipocytes {'context': 'I-cells'}", + "110, using {'perturbing_action': 'I-gene loss-of-function'}", + "111, CRISPR-Cas9 {'perturbing_action': 'I-gene loss-of-function'}", + "120, brown {'context': 'B-cells'}", + "121, adipocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "83, human ['l0']", + "84, preadipocytes ['l0']", + "98, Knocking ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "99, out ['l1', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "100, the ['l2', 'l15', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "101, positive ['l3', 'l16', 'l28', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "102, UCP1 ['l4', 'l17', 'l29', 'l40', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "103, regulators, ['l5', 'l18', 'l30', 'l41', 'l51', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "104, PREX1 ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "105, and ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "106, EDNRB, ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "108, brown ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l91', 'l92', 'l93']", + "109, preadipocytes ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l94', 'l95']", + "110, using ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l94', 'l96']", + "111, CRISPR-Cas9 ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l95', 'l96', 'l97', 'l98']", + "120, brown ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l97', 'l99']", + "121, adipocytes ['l14', 'l27', 'l39', 'l50', 'l60', 'l69', 'l77', 'l84', 'l90', 'l98', 'l99']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Knocking", + "out", + "the", + "positive", + "UCP1", + "regulators,", + "PREX1", + "and", + "EDNRB,", + "using", + "CRISPR-Cas9" + ] + }, + "context": { + "val": "cells", + "words": [ + "brown", + "preadipocytes", + "adipocytes" + ] + } + } + ] + }, + { + "PMID": "26076035", + "TEXT": "The peptide hormone urocortin3 (Ucn3) is abundantly expressed by mature beta cells, yet its physiological role is unknown. Here we demonstrate that Ucn3 is stored and co-released with insulin and potentiates glucose-stimulated somatostatin secretion via cognate receptors on delta cells. Further, we found that islets lacking endogenous Ucn3 have fewer delta cells, reduced somatostatin content, impaired somatostatin secretion, and exaggerated insulin release, and that these defects are rectified by treatment with synthetic Ucn3 in vitro. Our observations indicate that the paracrine actions of Ucn3 activate a negative feedback loop that promotes somatostatin release to ensure the timely reduction of insulin secretion upon normalization of plasma glucose. Moreover, Ucn3 is markedly depleted from beta cells in mouse and macaque models of diabetes and in human diabetic islets. This suggests that Ucn3 is a key contributor to stable glycemic control, whose reduction during diabetes aggravates glycemic volatility and contributes to the pathophysiology of this disease.", + "TAG_DATA": [ + "44, islets {'context': 'B-cells'}", + "45, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "46, endogenous {'perturbing_action': 'I-gene loss-of-function'}", + "47, Ucn3 {'perturbing_action': 'I-gene loss-of-function'}", + "50, delta {'context': 'B-cells'}", + "51, cells, {'context': 'I-cells'}", + "73, in {'context': 'B-in vitro'}", + "74, vitro. {'context': 'I-in vitro'}", + "112, beta {'context': 'B-cells'}", + "113, cells {'context': 'I-cells'}", + "115, mouse {'context': 'B-organism'}", + "117, macaque {'context': 'I-organism'}", + "123, human {'context': 'B-cells'}", + "124, diabetic {'context': 'I-cells'}", + "125, islets. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "44, islets ['l0', 'l1', 'l2', 'l3', 'l4']", + "45, lacking ['l0', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "46, endogenous ['l1', 'l5', 'l11', 'l12', 'l13', 'l14', 'l15']", + "47, Ucn3 ['l2', 'l6', 'l11', 'l16', 'l17', 'l18', 'l19']", + "50, delta ['l3', 'l7', 'l12', 'l16', 'l20', 'l21']", + "51, cells, ['l4', 'l8', 'l13', 'l17', 'l20']", + "73, in ['l9', 'l14', 'l18', 'l22']", + "74, vitro. ['l10', 'l15', 'l19', 'l21', 'l22']", + "112, beta ['l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "113, cells ['l23', 'l29', 'l30', 'l31', 'l32', 'l33']", + "115, mouse ['l24', 'l29', 'l34']", + "117, macaque ['l25', 'l30', 'l34']", + "123, human ['l26', 'l31', 'l35', 'l36']", + "124, diabetic ['l27', 'l32', 'l35', 'l37']", + "125, islets. ['l28', 'l33', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "islets", + "delta", + "cells," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "endogenous", + "Ucn3" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "endogenous", + "Ucn3" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "26005855", + "TEXT": "Our understanding of the pathways that regulate lymphocyte metabolism, as well as the effects of metabolism and its products on the immune response, is still limited. We report that a metabolic program controlled by the transcription factors hypoxia inducible factor-1α (HIF1-α) and aryl hydrocarbon receptor (AHR) supports the differentiation of type 1 regulatory T cell (Tr1) cells. HIF1-α controls the early metabolic reprograming of Tr1 cells. At later time points, AHR promotes HIF1-α degradation and takes control of Tr1 cell metabolism. Extracellular ATP (eATP) and hypoxia, linked to inflammation, trigger AHR inactivation by HIF1-α and inhibit Tr1 cell differentiation. Conversely, CD39 promotes Tr1 cell differentiation by depleting eATP. CD39 also contributes to Tr1 suppressive activity by generating adenosine in cooperation with CD73 expressed by responder T cells and antigen-presenting cells. These results suggest that HIF1-α and AHR integrate immunological, metabolic and environmental signals to regulate the immune response.", + "TAG_DATA": [ + "95, inhibit {'effect': 'B-negative'}", + "96, Tr1 {'context': 'B-cells'}", + "97, cell {'context': 'I-cells'}", + "98, differentiation. {'phenotype': 'B-differentiation'}", + "101, promotes {'effect': 'B-positive'}", + "102, Tr1 {'context': 'B-cells'}", + "103, cell {'context': 'I-cells'}", + "104, differentiation {'phenotype': 'B-differentiation'}" + ], + "LINK_DATA": [ + "95, inhibit ['l0', 'l1', 'l2']", + "96, Tr1 ['l0', 'l3', 'l4']", + "97, cell ['l1', 'l3', 'l5']", + "98, differentiation. ['l2', 'l4', 'l5']", + "101, promotes ['l6', 'l7', 'l8']", + "102, Tr1 ['l6', 'l9', 'l10']", + "103, cell ['l7', 'l9', 'l11']", + "104, differentiation ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "context": { + "val": "cells", + "words": [ + "Tr1", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Tr1", + "cell" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation.", + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "cells", + "words": [ + "Tr1", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "25894826", + "TEXT": "Ocular neovascular diseases are a leading cause of blindness. Vascular endothelial growth factor (VEGF) blockade improves vision, but not all individuals respond to anti-VEGF treatment, making additional means to prevent neovascularization necessary. Slit-family proteins (Slits) are ligands of Roundabout (Robo) receptors that repel developing axons in the nervous system. Robo1 expression is altered in ocular neovascular diseases, and previous in vitro studies have reported both pro- and anti-angiogenic effects of Slits. However, genetic evidence supporting a role for Slits in ocular neovascularization is lacking. Here we generated conditional knockout mice deficient in various Slit and Robo proteins and found that Slit2 potently and selectively promoted angiogenesis via Robo1 and Robo2 in mouse postnatal retina and in a model of ocular neovascular disease. Mechanistically, Slit2 acting through Robo1 and Robo2 promoted the migration of endothelial cells. These receptors are required for both Slit2- and VEGF-induced Rac1 activation and lamellipodia formation. Thus, Slit2 blockade could potentially be used therapeutically to inhibit angiogenesis in individuals with ocular neovascular disease.", + "TAG_DATA": [ + "87, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "88, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "89, mice {'context': 'B-organism'}", + "111, mouse {'context': 'B-tissue/organ'}", + "112, postnatal {'context': 'I-tissue/organ'}", + "113, retina {'context': 'I-tissue/organ'}", + "129, promoted {'effect': 'B-positive'}", + "131, migration {'phenotype': 'B-migration'}", + "133, endothelial {'context': 'B-cells'}", + "134, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "87, conditional ['l0', 'l1', 'l2']", + "88, knockout ['l0', 'l3', 'l4']", + "89, mice ['l1', 'l3', 'l5']", + "111, mouse ['l6', 'l7']", + "112, postnatal ['l6', 'l8']", + "113, retina ['l2', 'l4', 'l5', 'l7', 'l8']", + "129, promoted ['l9', 'l10', 'l11']", + "131, migration ['l9', 'l12', 'l13']", + "133, endothelial ['l10', 'l12', 'l14']", + "134, cells. ['l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "knockout" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "retina" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells." + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells." + ] + } + } + ] + }, + { + "PMID": "25894825", + "TEXT": "Tumors are complex ecosystems composed of networks of interacting 'normal' and malignant cells. It is well recognized that cytokine-mediated cross-talk between normal stromal cells, including cancer-associated fibroblasts (CAFs), vascular endothelial cells, immune cells, and cancer cells, influences all aspects of tumor biology. Here we demonstrate that the cross-talk between CAFs and cancer cells leads to enhanced growth of oncolytic virus (OV)-based therapeutics. Transforming growth factor-β (TGF-β) produced by tumor cells reprogrammed CAFs, dampened their steady-state level of antiviral transcripts and rendered them sensitive to virus infection. In turn, CAFs produced high levels of fibroblast growth factor 2 (FGF2), initiating a signaling cascade in cancer cells that reduced retinoic acid-inducible gene I (RIG-I) expression and impeded the ability of malignant cells to detect and respond to virus. In xenografts derived from individuals with pancreatic cancer, the expression of FGF2 correlated with the susceptibility of the cancer cells to OV infection, and local application of FGF2 to resistant tumor samples sensitized them to virotherapy both in vitro and in vivo. An OV engineered to express FGF2 was safe in tumor-bearing mice, showed improved therapeutic efficacy compared to parental virus and merits consideration for clinical testing.", + "TAG_DATA": [ + "103, cancer {'context': 'B-transformed cells'}", + "104, cells {'context': 'I-transformed cells'}", + "118, malignant {'context': 'B-transformed cells'}", + "119, cells {'context': 'I-transformed cells'}", + "127, xenografts {'context': 'B-xenograft'}", + "128, derived {'context': 'I-xenograft'}", + "129, from {'context': 'I-xenograft'}", + "130, individuals {'context': 'I-xenograft'}", + "131, with {'context': 'I-xenograft'}", + "132, pancreatic {'context': 'I-xenograft'}", + "133, cancer, {'context': 'I-xenograft'}", + "144, cancer {'context': 'B-transformed cells'}", + "145, cells {'context': 'I-transformed cells'}", + "156, tumor {'context': 'B-transformed cells'}", + "163, in {'context': 'B-in vitro'}", + "164, vitro {'context': 'I-in vitro'}", + "166, in {'context': 'B-in vivo'}", + "167, vivo. {'context': 'I-in vivo'}", + "170, engineered {'perturbing_action': 'I-gene gain-of-function'}", + "171, to {'perturbing_action': 'I-gene gain-of-function'}", + "172, express {'perturbing_action': 'I-gene gain-of-function'}", + "173, FGF2 {'perturbing_action': 'I-gene gain-of-function'}", + "177, tumor-bearing {'context': 'B-organism'}", + "178, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "103, cancer ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "104, cells ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "118, malignant ['l1', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "119, cells ['l2', 'l13', 'l22', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "127, xenografts ['l3', 'l14', 'l23', 'l32', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "128, derived ['l4', 'l15', 'l24', 'l33', 'l39', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "129, from ['l5', 'l16', 'l25', 'l34', 'l40', 'l47', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "130, individuals ['l6', 'l17', 'l26', 'l35', 'l41', 'l48', 'l54', 'l60', 'l61', 'l62', 'l63', 'l64']", + "131, with ['l7', 'l18', 'l27', 'l36', 'l42', 'l49', 'l55', 'l60', 'l65', 'l66', 'l67', 'l68']", + "132, pancreatic ['l8', 'l19', 'l28', 'l37', 'l43', 'l50', 'l56', 'l61', 'l65', 'l69', 'l70', 'l71']", + "133, cancer, ['l9', 'l20', 'l29', 'l38', 'l44', 'l51', 'l57', 'l62', 'l66', 'l69', 'l72', 'l73']", + "144, cancer ['l10', 'l30', 'l45', 'l52', 'l58', 'l63', 'l67', 'l70', 'l72', 'l74']", + "145, cells ['l11', 'l21', 'l31', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l73', 'l74']", + "156, tumor ['l75', 'l76', 'l77', 'l78']", + "163, in ['l75', 'l79', 'l80', 'l81']", + "164, vitro ['l76', 'l79', 'l82', 'l83']", + "166, in ['l77', 'l80', 'l82', 'l84']", + "167, vivo. ['l78', 'l81', 'l83', 'l84']", + "170, engineered ['l85', 'l86', 'l87', 'l88', 'l89']", + "171, to ['l85', 'l90', 'l91', 'l92', 'l93']", + "172, express ['l86', 'l90', 'l94', 'l95', 'l96']", + "173, FGF2 ['l87', 'l91', 'l94', 'l97', 'l98']", + "177, tumor-bearing ['l88', 'l92', 'l95', 'l97', 'l99']", + "178, mice, ['l89', 'l93', 'l96', 'l98', 'l99']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "engineered", + "to", + "express", + "FGF2" + ] + }, + "context": { + "val": "organism", + "words": [ + "tumor-bearing", + "mice," + ] + } + } + ] + }, + { + "PMID": "25849132", + "TEXT": "Hemophilia A and B are inherited bleeding disorders characterized by deficiencies in procoagulant factor VIII (FVIII) or factor IX (FIX), respectively. There remains a substantial unmet medical need in hemophilia, especially in patients with inhibitory antibodies against replacement factor therapy, for novel and improved therapeutic agents that can be used prophylactically to provide effective hemostasis. Guided by reports suggesting that co-inheritance of prothrombotic mutations may ameliorate the clinical phenotype in hemophilia, we developed an RNA interference (RNAi) therapeutic (ALN-AT3) targeting antithrombin (AT) as a means to promote hemostasis in hemophilia. When administered subcutaneously, ALN-AT3 showed potent, dose-dependent, and durable reduction of AT levels in wild-type mice, mice with hemophilia A, and nonhuman primates (NHPs). In NHPs, a 50% reduction in AT levels was achieved with weekly dosing at approximately 0.125 mg/kg, and a near-complete reduction in AT levels was achieved with weekly dosing at 1.5 mg/kg. Treatment with ALN-AT3 promoted hemostasis in mouse models of hemophilia and led to improved thrombin generation in an NHP model of hemophilia A with anti-factor VIII inhibitors. This investigational compound is currently in phase 1 clinical testing in subjects with hemophilia A or B.", + "TAG_DATA": [ + "77, therapeutic {'perturbing_action': 'I-rnai/knockdown'}", + "105, mice, {'context': 'B-organism'}", + "106, mice {'context': 'B-organism'}", + "111, nonhuman {'context': 'B-organism'}", + "112, primates {'context': 'I-organism'}", + "113, (NHPs). {'context': 'I-organism'}", + "115, NHPs, {'context': 'B-organism'}", + "152, mouse {'context': 'B-organism'}", + "153, models {'context': 'I-organism'}", + "154, of {'context': 'I-organism'}", + "155, hemophilia {'context': 'I-organism'}", + "164, NHP {'context': 'B-organism'}", + "165, model {'context': 'I-organism'}", + "167, hemophilia {'context': 'I-organism'}", + "168, A {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "77, therapeutic ['l0', 'l1', 'l2', 'l3']", + "105, mice, ['l0', 'l4', 'l5', 'l6', 'l7']", + "106, mice ['l1', 'l4', 'l8', 'l9', 'l10', 'l11']", + "111, nonhuman ['l5', 'l8', 'l12', 'l13', 'l14']", + "112, primates ['l2', 'l6', 'l9', 'l12', 'l15', 'l16']", + "113, (NHPs). ['l3', 'l7', 'l10', 'l13', 'l15', 'l17']", + "115, NHPs, ['l11', 'l14', 'l16', 'l17']", + "152, mouse ['l18', 'l19', 'l20', 'l21', 'l22']", + "153, models ['l18', 'l23', 'l24', 'l25']", + "154, of ['l19', 'l23', 'l26']", + "155, hemophilia ['l20', 'l24', 'l26', 'l27', 'l28', 'l29', 'l30']", + "164, NHP ['l31', 'l32', 'l33', 'l34']", + "165, model ['l27', 'l31', 'l35', 'l36', 'l37']", + "166, of ['l21', 'l28', 'l32', 'l35', 'l38', 'l39']", + "167, hemophilia ['l29', 'l33', 'l36', 'l38', 'l40']", + "168, A ['l22', 'l25', 'l30', 'l34', 'l37', 'l39', 'l40']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "therapeutic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice", + "primates", + "(NHPs)." + ] + } + } + ] + }, + { + "PMID": "25774850", + "TEXT": "In the nervous system, NMDA receptors (NMDARs) participate in neurotransmission and modulate the viability of neurons. In contrast, little is known about the role of NMDARs in pancreatic islets and the insulin-secreting beta cells whose functional impairment contributes to diabetes mellitus. Here we found that inhibition of NMDARs in mouse and human islets enhanced their glucose-stimulated insulin secretion (GSIS) and survival of islet cells. Further, NMDAR inhibition prolonged the amount of time that glucose-stimulated beta cells spent in a depolarized state with high cytosolic Ca(2+) concentrations. We also noticed that, in vivo, the NMDAR antagonist dextromethorphan (DXM) enhanced glucose tolerance in mice, and that in vitro dextrorphan, the main metabolite of DXM, amplified the stimulatory effect of exendin-4 on GSIS. In a mouse model of type 2 diabetes mellitus (T2DM), long-term treatment with DXM improved islet insulin content, islet cell mass and blood glucose control. Further, in a small clinical trial we found that individuals with T2DM treated with DXM showed enhanced serum insulin concentrations and glucose tolerance. Our data highlight the possibility that antagonists of NMDARs may provide a useful adjunct treatment for diabetes.", + "TAG_DATA": [ + "45, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "46, of {'perturbing_action': 'I-pharmacological inhibition'}", + "47, NMDARs {'perturbing_action': 'I-pharmacological inhibition'}", + "49, mouse {'context': 'B-cells'}", + "50, and {'context': 'I-cells'}", + "51, human {'context': 'I-cells'}", + "52, islets {'context': 'I-cells'}", + "62, islet {'context': 'B-cells'}", + "63, cells. {'context': 'I-cells'}", + "65, NMDAR {'perturbing_action': 'B-pharmacological inhibition'}", + "66, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "74, beta {'context': 'B-cells'}", + "75, cells {'context': 'I-cells'}", + "90, in {'context': 'B-in vivo'}", + "91, vivo, {'context': 'I-in vivo'}", + "101, mice, {'context': 'B-organism'}", + "104, in {'context': 'B-in vitro'}", + "105, vitro {'context': 'I-in vitro'}", + "122, mouse {'context': 'B-organism'}", + "123, model {'context': 'I-organism'}", + "138, islet {'context': 'B-cells'}", + "139, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "46, of ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "47, NMDARs ['l1', 'l11', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "49, mouse ['l2', 'l12', 'l22', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "50, and ['l3', 'l13', 'l23', 'l32', 'l38', 'l39', 'l40', 'l41', 'l42']", + "51, human ['l4', 'l14', 'l24', 'l33', 'l38', 'l43', 'l44', 'l45', 'l46']", + "52, islets ['l5', 'l15', 'l25', 'l34', 'l39', 'l43', 'l47', 'l48']", + "62, islet ['l6', 'l16', 'l26', 'l35', 'l40', 'l44', 'l47', 'l49', 'l50', 'l51']", + "63, cells. ['l7', 'l17', 'l27', 'l36', 'l41', 'l45', 'l48', 'l49']", + "65, NMDAR ['l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "66, inhibition ['l52', 'l58', 'l59', 'l60', 'l61', 'l62']", + "74, beta ['l8', 'l18', 'l28', 'l50', 'l53', 'l58', 'l63', 'l64', 'l65', 'l66']", + "75, cells ['l9', 'l19', 'l29', 'l37', 'l42', 'l46', 'l51', 'l54', 'l59', 'l63', 'l67', 'l68', 'l69']", + "90, in ['l55', 'l60', 'l64', 'l67', 'l70', 'l71']", + "91, vivo, ['l20', 'l30', 'l56', 'l61', 'l65', 'l68', 'l70', 'l72']", + "101, mice, ['l10', 'l21', 'l31', 'l57', 'l62', 'l66', 'l69', 'l71', 'l72']", + "104, in ['l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "105, vitro ['l73', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "122, mouse ['l74', 'l80', 'l86', 'l87', 'l88', 'l89', 'l90']", + "123, model ['l75', 'l81', 'l86', 'l91', 'l92', 'l93', 'l94']", + "125, type ['l76', 'l82', 'l87', 'l91', 'l95', 'l96', 'l97']", + "126, 2 ['l77', 'l83', 'l88', 'l92', 'l95', 'l98', 'l99']", + "138, islet ['l78', 'l84', 'l89', 'l93', 'l96', 'l98', 'l100']", + "139, cell ['l79', 'l85', 'l90', 'l94', 'l97', 'l99', 'l100']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "NMDARs", + "NMDAR" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "and", + "human", + "islets", + "islet", + "cells.", + "beta", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "NMDARs", + "NMDAR" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "of", + "NMDARs", + "NMDAR", + "inhibition" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo,", + "in" + ] + } + } + ] + }, + { + "PMID": "25774849", + "TEXT": "Down syndrome (DS) is the most frequent genetic cause of intellectual disability, and altered GABAergic transmission through Cl(-)-permeable GABAA receptors (GABAARs) contributes considerably to learning and memory deficits in DS mouse models. However, the efficacy of GABAergic transmission has never been directly assessed in DS. Here GABAAR signaling was found to be excitatory rather than inhibitory, and the reversal potential for GABAAR-driven Cl(-) currents (ECl) was shifted toward more positive potentials in the hippocampi of adult DS mice. Accordingly, hippocampal expression of the cation Cl(-) cotransporter NKCC1 was increased in both trisomic mice and individuals with DS. Notably, NKCC1 inhibition by the FDA-approved drug bumetanide restored ECl, synaptic plasticity and hippocampus-dependent memory in adult DS mice. Our findings demonstrate that GABA is excitatory in adult DS mice and identify a new therapeutic approach for the potential rescue of cognitive disabilities in individuals with DS.", + "TAG_DATA": [ + "76, DS {'context': 'I-organism'}", + "77, mice. {'context': 'I-organism'}", + "98, NKCC1 {'perturbing_action': 'B-pharmacological inhibition'}", + "99, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "100, by {'perturbing_action': 'I-pharmacological inhibition'}", + "101, the {'perturbing_action': 'I-pharmacological inhibition'}", + "102, FDA-approved {'perturbing_action': 'I-pharmacological inhibition'}", + "103, drug {'perturbing_action': 'I-pharmacological inhibition'}", + "104, bumetanide {'perturbing_action': 'I-pharmacological inhibition'}", + "113, adult {'context': 'B-organism'}", + "114, DS {'context': 'I-organism'}", + "115, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "76, DS ['l0']", + "77, mice. ['l0']", + "98, NKCC1 ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "99, inhibition ['l1', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "100, by ['l2', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "101, the ['l3', 'l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "102, FDA-approved ['l4', 'l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "103, drug ['l5', 'l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "104, bumetanide ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "113, adult ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "114, DS ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "115, mice. ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NKCC1", + "inhibition", + "by", + "the", + "FDA-approved", + "drug", + "bumetanide" + ] + }, + "context": { + "val": "organism", + "words": [ + "adult", + "DS", + "mice." + ] + } + } + ] + }, + { + "PMID": "25706875", + "TEXT": "Human colorectal tumors bear recurrent mutations in genes encoding proteins operative in the WNT, MAPK, TGF-β, TP53 and PI3K pathways. Although these pathways influence intestinal stem cell niche signaling, the extent to which mutations in these pathways contribute to human colorectal carcinogenesis remains unclear. Here we use the CRISPR-Cas9 genome-editing system to introduce multiple such mutations into organoids derived from normal human intestinal epithelium. By modulating the culture conditions to mimic that of the intestinal niche, we selected isogenic organoids harboring mutations in the tumor suppressor genes APC, SMAD4 and TP53, and in the oncogenes KRAS and/or PIK3CA. Organoids engineered to express all five mutations grew independently of niche factors in vitro, and they formed tumors after implantation under the kidney subcapsule in mice. Although they formed micrometastases containing dormant tumor-initiating cells after injection into the spleen of mice, they failed to colonize in the liver. In contrast, engineered organoids derived from chromosome-instable human adenomas formed macrometastatic colonies. These results suggest that 'driver' pathway mutations enable stem cell maintenance in the hostile tumor microenvironment, but that additional molecular lesions are required for invasive behavior.", + "TAG_DATA": [ + "79, organoids {'context': 'B-organoid'}", + "98, Organoids {'context': 'B-organoid'}", + "110, in {'context': 'B-in vitro'}", + "111, vitro, {'context': 'I-in vitro'}", + "115, tumors {'phenotype': 'B-tumourigenesis'}", + "120, kidney {'context': 'B-tissue/organ'}", + "121, subcapsule {'context': 'I-tissue/organ'}", + "123, mice. {'context': 'B-organism'}", + "131, cells {'context': 'I-cells'}", + "136, spleen {'context': 'B-tissue/organ'}", + "138, mice, {'context': 'B-organism'}", + "145, liver. {'context': 'B-tissue/organ'}", + "149, organoids {'context': 'B-organoid'}", + "153, human {'context': 'B-neoplasm'}", + "154, adenomas {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "98, Organoids ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "110, in ['l0', 'l7', 'l8', 'l9', 'l10', 'l11']", + "111, vitro, ['l1', 'l7', 'l12', 'l13', 'l14', 'l15']", + "115, tumors ['l2', 'l8', 'l12', 'l16', 'l17', 'l18']", + "120, kidney ['l3', 'l9', 'l13', 'l16', 'l19', 'l20', 'l21']", + "121, subcapsule ['l4', 'l10', 'l14', 'l17', 'l19', 'l22', 'l23']", + "123, mice. ['l5', 'l11', 'l15', 'l18', 'l20', 'l22']", + "130, tumor-initiating ['l24', 'l25', 'l26', 'l27']", + "131, cells ['l6', 'l21', 'l23', 'l24', 'l28', 'l29', 'l30']", + "136, spleen ['l25', 'l28', 'l31', 'l32']", + "138, mice, ['l26', 'l29', 'l31', 'l33']", + "145, liver. ['l27', 'l30', 'l32', 'l33']", + "149, organoids ['l34', 'l35']", + "153, human ['l34', 'l36']", + "154, adenomas ['l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organoid", + "words": [ + "Organoids" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidney", + "subcapsule" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "25706874", + "TEXT": "Insulin resistance results from several pathophysiologic mechanisms, including chronic tissue inflammation and defective insulin signaling. We found that liver, muscle and adipose tissue exhibit higher levels of the chemotactic eicosanoid LTB4 in obese high-fat diet (HFD)-fed mice. Inhibition of the LTB4 receptor Ltb4r1, through either genetic or pharmacologic loss of function, led to an anti-inflammatory phenotype with protection from insulin resistance and hepatic steatosis. In vitro treatment with LTB4 directly enhanced macrophage chemotaxis, stimulated inflammatory pathways, reduced insulin-stimulated glucose uptake in L6 myocytes, and impaired insulin-mediated suppression of hepatic glucose output in primary mouse hepatocytes. This was accompanied by lower insulin-stimulated Akt phosphorylation and higher Irs-1/2 serine phosphorylation, and all of these events were dependent on Gαi and Jnk1, two downstream mediators of Ltb4r1 signaling. These observations elucidate a novel role of the LTB4-Ltb4r1 signaling pathway in hepatocyte and myocyte insulin resistance, and they show that in vivo inhibition of Ltb4r1 leads to robust insulin-sensitizing effects.", + "TAG_DATA": [ + "37, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "38, of {'perturbing_action': 'I-pharmacological inhibition'}", + "39, the {'perturbing_action': 'I-pharmacological inhibition'}", + "40, LTB4 {'perturbing_action': 'I-pharmacological inhibition'}", + "41, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "42, Ltb4r1, {'perturbing_action': 'I-pharmacological inhibition'}", + "47, pharmacologic {'perturbing_action': 'B-gene loss-of-function'}", + "48, loss {'perturbing_action': 'I-gene loss-of-function'}", + "49, of {'perturbing_action': 'I-gene loss-of-function'}", + "50, function, {'perturbing_action': 'I-gene loss-of-function'}", + "64, In {'context': 'B-in vitro'}", + "65, vitro {'context': 'I-in vitro'}", + "70, enhanced {'effect': 'B-positive'}", + "71, macrophage {'context': 'B-cells'}", + "72, chemotaxis, {'phenotype': 'B-migration'}", + "81, L6 {'context': 'B-cells'}", + "82, myocytes, {'context': 'I-cells'}", + "92, primary {'context': 'B-cells'}", + "93, mouse {'context': 'I-cells'}", + "94, hepatocytes. {'context': 'I-cells'}", + "146, in {'context': 'B-in vivo'}", + "147, vivo {'context': 'I-in vivo'}", + "148, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "149, of {'perturbing_action': 'I-pharmacological inhibition'}", + "150, Ltb4r1 {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "37, Inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "38, of ['l0', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "39, the ['l1', 'l19', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "40, LTB4 ['l2', 'l20', 'l37', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "41, receptor ['l3', 'l21', 'l38', 'l54', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "42, Ltb4r1, ['l4', 'l22', 'l39', 'l55', 'l70', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "47, pharmacologic ['l5', 'l23', 'l40', 'l56', 'l71', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "48, loss ['l6', 'l24', 'l41', 'l57', 'l72', 'l85', 'l97', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "49, of ['l7', 'l25', 'l42', 'l58', 'l73', 'l86', 'l98', 'l110', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132']", + "50, function, ['l8', 'l26', 'l43', 'l59', 'l74', 'l87', 'l99', 'l111', 'l122', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "64, In ['l9', 'l27', 'l44', 'l60', 'l75', 'l88', 'l100', 'l112', 'l123', 'l133', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151']", + "65, vitro ['l10', 'l28', 'l45', 'l61', 'l76', 'l89', 'l101', 'l113', 'l124', 'l134', 'l143', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159']", + "70, enhanced ['l11', 'l29', 'l46', 'l62', 'l77', 'l90', 'l102', 'l114', 'l125', 'l135', 'l144', 'l152', 'l160', 'l161', 'l162', 'l163']", + "71, macrophage ['l12', 'l30', 'l47', 'l63', 'l78', 'l91', 'l103', 'l115', 'l126', 'l136', 'l145', 'l153', 'l160', 'l164', 'l165', 'l166']", + "72, chemotaxis, ['l13', 'l31', 'l48', 'l64', 'l79', 'l92', 'l104', 'l116', 'l127', 'l137', 'l146', 'l154', 'l161', 'l164', 'l167', 'l168']", + "81, L6 ['l14', 'l32', 'l49', 'l65', 'l80', 'l93', 'l105', 'l117', 'l128', 'l138', 'l147', 'l155', 'l162', 'l165', 'l167', 'l169']", + "82, myocytes, ['l15', 'l33', 'l50', 'l66', 'l81', 'l94', 'l106', 'l118', 'l129', 'l139', 'l148', 'l156', 'l163', 'l166', 'l168', 'l169']", + "92, primary ['l16', 'l34', 'l51', 'l67', 'l82', 'l95', 'l107', 'l119', 'l130', 'l140', 'l149', 'l157', 'l170', 'l171']", + "93, mouse ['l17', 'l35', 'l52', 'l68', 'l83', 'l108', 'l120', 'l131', 'l141', 'l150', 'l158', 'l170', 'l172']", + "94, hepatocytes. ['l18', 'l36', 'l53', 'l69', 'l84', 'l96', 'l109', 'l121', 'l132', 'l142', 'l151', 'l159', 'l171', 'l172']", + "146, in ['l173', 'l174', 'l175', 'l176']", + "147, vivo ['l173', 'l177', 'l178', 'l179']", + "148, inhibition ['l174', 'l177', 'l180', 'l181']", + "149, of ['l175', 'l178', 'l180', 'l182']", + "150, Ltb4r1 ['l176', 'l179', 'l181', 'l182']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "the", + "LTB4", + "receptor", + "Ltb4r1," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "the", + "LTB4", + "receptor", + "Ltb4r1," + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "the", + "LTB4", + "receptor", + "Ltb4r1," + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophage", + "L6", + "myocytes,", + "primary", + "mouse", + "hepatocytes." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "the", + "LTB4", + "receptor", + "Ltb4r1," + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pharmacologic", + "loss", + "of", + "function," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pharmacologic", + "loss", + "of", + "function," + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pharmacologic", + "loss", + "of", + "function," + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophage", + "L6", + "myocytes,", + "primary", + "mouse", + "hepatocytes." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pharmacologic", + "loss", + "of", + "function," + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis," + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophage", + "L6", + "myocytes," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "macrophage", + "L6", + "myocytes," + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "Ltb4r1" + ] + } + } + ] + }, + { + "PMID": "25665180", + "TEXT": "One function of the glucocorticoid receptor (GR) in corticotroph cells is to suppress the transcription of the gene encoding proopiomelanocortin (POMC), the precursor of the stress hormone adrenocorticotropin (ACTH). Cushing disease is a neuroendocrine condition caused by partially glucocorticoid-resistant corticotroph adenomas that excessively secrete ACTH, which leads to hypercortisolism. Mutations that impair GR function explain glucocorticoid resistance only in sporadic cases. However, the proper folding of GR depends on direct interactions with the chaperone heat shock protein 90 (HSP90, refs. 7,8). We show here that corticotroph adenomas overexpress HSP90 compared to the normal pituitary. N- and C-terminal HSP90 inhibitors act at different steps of the HSP90 catalytic cycle to regulate corticotroph cell proliferation and GR transcriptional activity. C-terminal inhibitors cause the release of mature GR from HSP90, which promotes its exit from the chaperone cycle and potentiates its transcriptional activity in a corticotroph cell line and in primary cultures of human corticotroph adenomas. In an allograft mouse model, the C-terminal HSP90 inhibitor silibinin showed anti-tumorigenic effects, partially reverted hormonal alterations, and alleviated symptoms of Cushing disease. These results suggest that the pathogenesis of Cushing disease caused by overexpression of heat shock proteins and consequently misregulated GR sensitivity may be overcome pharmacologically with an appropriate HSP90 inhibitor.", + "TAG_DATA": [ + "97, HSP90 {'perturbing_action': 'I-pharmacological inhibition'}", + "110, corticotroph {'context': 'B-cells'}", + "111, cell {'context': 'I-cells'}", + "142, corticotroph {'context': 'B-cells'}", + "143, cell {'context': 'I-cells'}", + "144, line {'context': 'I-cells'}", + "147, primary {'context': 'B-cells'}", + "148, cultures {'context': 'I-cells'}", + "150, human {'context': 'B-neoplasm'}", + "151, corticotroph {'context': 'I-neoplasm'}", + "152, adenomas. {'context': 'I-neoplasm'}", + "155, allograft {'context': 'B-organism'}", + "156, mouse {'context': 'I-organism'}", + "157, model, {'context': 'I-organism'}", + "159, C-terminal {'perturbing_action': 'B-pharmacological inhibition'}", + "160, HSP90 {'perturbing_action': 'I-pharmacological inhibition'}", + "161, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "162, silibinin {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "97, HSP90 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "98, inhibitors ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "110, corticotroph ['l1', 'l11', 'l21', 'l22', 'l23', 'l24']", + "111, cell ['l2', 'l12', 'l21', 'l25', 'l26']", + "142, corticotroph ['l3', 'l13', 'l22', 'l27', 'l28', 'l29', 'l30', 'l31']", + "143, cell ['l4', 'l14', 'l23', 'l25', 'l27', 'l32']", + "144, line ['l5', 'l15', 'l24', 'l26', 'l28', 'l32']", + "147, primary ['l6', 'l16', 'l29', 'l33', 'l34', 'l35', 'l36']", + "148, cultures ['l7', 'l17', 'l30', 'l33', 'l37', 'l38', 'l39']", + "150, human ['l8', 'l18', 'l34', 'l37', 'l40', 'l41']", + "151, corticotroph ['l9', 'l19', 'l35', 'l38', 'l40', 'l42']", + "152, adenomas. ['l10', 'l20', 'l31', 'l36', 'l39', 'l41', 'l42']", + "155, allograft ['l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "156, mouse ['l43', 'l49', 'l50', 'l51', 'l52']", + "157, model, ['l44', 'l49', 'l53']", + "159, C-terminal ['l45', 'l54', 'l55', 'l56']", + "160, HSP90 ['l46', 'l50', 'l54', 'l57', 'l58']", + "161, inhibitor ['l47', 'l51', 'l55', 'l57', 'l59']", + "162, silibinin ['l48', 'l52', 'l53', 'l56', 'l58', 'l59']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "HSP90" + ] + }, + "context": { + "val": "cells", + "words": [ + "corticotroph", + "cell", + "line", + "primary", + "cultures" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "HSP90" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "corticotroph", + "adenomas." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "allograft", + "mouse", + "model," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "C-terminal", + "HSP90", + "inhibitor", + "silibinin" + ] + } + } + ] + }, + { + "PMID": "25665179", + "TEXT": "Currently, major concerns about the safety and efficacy of RNA interference (RNAi)-based bone anabolic strategies still exist because of the lack of direct osteoblast-specific delivery systems for osteogenic siRNAs. Here we screened the aptamer CH6 by cell-SELEX, specifically targeting both rat and human osteoblasts, and then we developed CH6 aptamer-functionalized lipid nanoparticles (LNPs) encapsulating osteogenic pleckstrin homology domain-containing family O member 1 (Plekho1) siRNA (CH6-LNPs-siRNA). Our results showed that CH6 facilitated in vitro osteoblast-selective uptake of Plekho1 siRNA, mainly via macropinocytosis, and boosted in vivo osteoblast-specific Plekho1 gene silencing, which promoted bone formation, improved bone microarchitecture, increased bone mass and enhanced mechanical properties in both osteopenic and healthy rodents. These results indicate that osteoblast-specific aptamer-functionalized LNPs could act as a new RNAi-based bone anabolic strategy, advancing the targeted delivery selectivity of osteogenic siRNAs from the tissue level to the cellular level.", + "TAG_DATA": [ + "40, rat {'context': 'B-cells'}", + "41, and {'context': 'I-cells'}", + "42, human {'context': 'I-cells'}", + "43, osteoblasts, {'context': 'I-cells'}", + "71, in {'context': 'B-in vitro'}", + "72, vitro {'context': 'I-in vitro'}", + "76, Plekho1 {'perturbing_action': 'B-rnai/knockdown'}", + "77, siRNA, {'perturbing_action': 'I-rnai/knockdown'}", + "82, boosted {'effect': 'B-positive'}", + "83, in {'context': 'B-in vivo'}", + "84, vivo {'context': 'I-in vivo'}", + "85, osteoblast-specific {'perturbing_action': 'B-rnai/knockdown'}", + "86, Plekho1 {'perturbing_action': 'I-rnai/knockdown'}", + "87, gene {'perturbing_action': 'I-rnai/knockdown'}", + "88, silencing, {'perturbing_action': 'I-rnai/knockdown'}", + "90, promoted {'effect': 'B-positive'}", + "91, bone {'phenotype': 'B-colony formation'}", + "92, formation, {'phenotype': 'I-tumourigenesis'}", + "107, healthy {'context': 'I-organism'}", + "108, rodents. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "40, rat ['l0', 'l1', 'l2']", + "41, and ['l0', 'l3', 'l4']", + "42, human ['l1', 'l3', 'l5']", + "43, osteoblasts, ['l2', 'l4', 'l5']", + "71, in ['l6', 'l7', 'l8']", + "72, vitro ['l6', 'l9', 'l10']", + "76, Plekho1 ['l7', 'l9', 'l11', 'l12', 'l13']", + "77, siRNA, ['l8', 'l10', 'l11', 'l14']", + "82, boosted ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "83, in ['l15', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "84, vivo ['l16', 'l24', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "85, osteoblast-specific ['l17', 'l25', 'l34', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "86, Plekho1 ['l18', 'l26', 'l35', 'l43', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "87, gene ['l19', 'l27', 'l36', 'l44', 'l51', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "88, silencing, ['l20', 'l28', 'l37', 'l45', 'l52', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68']", + "90, promoted ['l21', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l69', 'l70', 'l71']", + "91, bone ['l12', 'l22', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72']", + "92, formation, ['l13', 'l14', 'l23', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l72']", + "107, healthy ['l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l73']", + "108, rodents. ['l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l73']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Plekho1", + "siRNA," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Plekho1", + "osteoblast-specific", + "gene", + "silencing," + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "bone" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Plekho1", + "siRNA,", + "osteoblast-specific", + "gene", + "silencing," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "boosted", + "promoted" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "boosted", + "promoted" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "osteoblast-specific", + "Plekho1", + "gene", + "silencing," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "boosted", + "promoted" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "bone" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "boosted", + "promoted" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "osteoblast-specific", + "Plekho1", + "gene", + "silencing," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "bone" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "osteoblast-specific", + "Plekho1", + "gene", + "silencing," + ] + }, + "context": { + "val": "organism", + "words": [ + "healthy", + "rodents." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "organism", + "words": [ + "healthy" + ] + } + } + ] + }, + { + "PMID": "25501905", + "TEXT": "CD4+ T cells differentiate into memory T cells that protect the host from subsequent infection. In contrast, autoreactive memory CD4+ T cells harm the body by persisting in the tissues. The underlying pathways controlling the maintenance of memory CD4+ T cells remain undefined. We show here that memory CD4+ T cell survival is impaired in the absence of the Notch signaling protein known as recombination signal binding protein for immunoglobulin κ J region (Rbpj). Treatment of mice with a Notch inhibitor reduced memory CD4+ T cell numbers and prevented the recurrent induction of experimental autoimmune encephalomyelitis. Rbpj-deficient CD4+ memory T cells exhibit reduced glucose uptake due to impaired AKT phosphorylation, resulting in low Glut1 expression. Treating mice with pyruvic acid, which bypasses glucose uptake and supplies the metabolite downstream of glucose uptake, inhibited the decrease of autoimmune memory CD4+ T cells in the absence of Notch signaling, suggesting memory CD4+ T cell survival relies on glucose metabolism. Together, these data define a central role for Notch signaling in maintaining memory CD4+ T cells through the regulation of glucose uptake.", + "TAG_DATA": [ + "76, mice {'context': 'B-organism'}", + "79, Notch {'perturbing_action': 'B-pharmacological inhibition'}", + "80, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "82, memory {'context': 'B-cells'}", + "83, CD4+ {'context': 'I-cells'}", + "84, T {'context': 'I-cells'}", + "85, cell {'context': 'I-cells'}", + "96, Rbpj-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "97, CD4+ {'context': 'B-cells'}", + "98, memory {'context': 'I-cells'}", + "99, T {'context': 'I-cells'}", + "100, cells {'context': 'I-cells'}", + "116, mice {'context': 'B-organism'}", + "136, autoimmune {'context': 'B-cells'}", + "137, memory {'context': 'I-cells'}", + "138, CD4+ {'context': 'I-cells'}", + "139, T {'context': 'I-cells'}", + "140, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "76, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "79, Notch ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "80, inhibitor ['l1', 'l8', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "82, memory ['l2', 'l9', 'l16', 'l23', 'l24', 'l25']", + "83, CD4+ ['l3', 'l10', 'l17', 'l23', 'l26', 'l27']", + "84, T ['l4', 'l11', 'l18', 'l24', 'l26', 'l28']", + "85, cell ['l5', 'l12', 'l19', 'l25', 'l27', 'l28']", + "96, Rbpj-deficient ['l29', 'l30', 'l31', 'l32']", + "97, CD4+ ['l29', 'l33', 'l34', 'l35']", + "98, memory ['l13', 'l20', 'l30', 'l33', 'l36', 'l37']", + "99, T ['l6', 'l14', 'l21', 'l31', 'l34', 'l36', 'l38']", + "100, cells ['l7', 'l15', 'l22', 'l32', 'l35', 'l37', 'l38']", + "116, mice ['l39', 'l40', 'l41', 'l42', 'l43']", + "136, autoimmune ['l39', 'l44', 'l45', 'l46', 'l47']", + "137, memory ['l40', 'l44', 'l48', 'l49', 'l50']", + "138, CD4+ ['l41', 'l45', 'l48', 'l51', 'l52']", + "139, T ['l42', 'l46', 'l49', 'l51', 'l53']", + "140, cells ['l43', 'l47', 'l50', 'l52', 'l53']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Notch", + "inhibitor" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Notch", + "inhibitor" + ] + }, + "context": { + "val": "cells", + "words": [ + "memory", + "CD4+", + "T", + "cell", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rbpj-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "memory", + "T", + "cells" + ] + } + } + ] + }, + { + "PMID": "25485911", + "TEXT": "Mitochondrial uncoupling protein 1 (UCP1) is enriched within interscapular brown adipose tissue (iBAT) and beige (also known as brite) adipose tissue, but its thermogenic potential is reduced with obesity and type 2 diabetes for reasons that are not understood. Serotonin (5-hydroxytryptamine, 5-HT) is a highly conserved biogenic amine that resides in non-neuronal and neuronal tissues that are specifically regulated via tryptophan hydroxylase 1 (Tph1) and Tph2, respectively. Recent findings suggest that increased peripheral serotonin and polymorphisms in TPH1 are associated with obesity; however, whether this is directly related to reduced BAT thermogenesis and obesity is not known. We find that Tph1-deficient mice fed a high-fat diet (HFD) are protected from obesity, insulin resistance and nonalcoholic fatty liver disease (NAFLD) while exhibiting greater energy expenditure by BAT. Small-molecule chemical inhibition of Tph1 in HFD-fed mice mimics the benefits ascribed to Tph1 genetic deletion, effects that depend on UCP1-mediated thermogenesis. The inhibitory effects of serotonin on energy expenditure are cell autonomous, as serotonin blunts β-adrenergic induction of the thermogenic program in brown and beige adipocytes in vitro. As obesity increases peripheral serotonin, the inhibition of serotonin signaling or its synthesis in adipose tissue may be an effective treatment for obesity and its comorbidities.", + "TAG_DATA": [ + "100, Tph1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "101, mice {'context': 'B-organism'}", + "126, Small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "127, chemical {'perturbing_action': 'I-pharmacological inhibition'}", + "128, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "129, of {'perturbing_action': 'I-pharmacological inhibition'}", + "130, Tph1 {'perturbing_action': 'I-pharmacological inhibition'}", + "133, mice {'context': 'B-organism'}", + "139, Tph1 {'perturbing_action': 'B-gene loss-of-function'}", + "140, genetic {'perturbing_action': 'I-gene loss-of-function'}", + "141, deletion, {'perturbing_action': 'I-gene loss-of-function'}", + "169, brown {'context': 'B-cells'}", + "170, and {'context': 'I-cells'}", + "171, beige {'context': 'I-cells'}", + "172, adipocytes {'context': 'I-cells'}", + "173, in {'context': 'B-in vitro'}", + "174, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "100, Tph1-deficient ['l0']", + "101, mice ['l0']", + "126, Small-molecule ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "127, chemical ['l1', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "128, inhibition ['l2', 'l15', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "129, of ['l3', 'l16', 'l28', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "130, Tph1 ['l4', 'l17', 'l29', 'l40', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "133, mice ['l5', 'l18', 'l30', 'l41', 'l50', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "139, Tph1 ['l6', 'l19', 'l31', 'l42', 'l51', 'l58', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "140, genetic ['l7', 'l20', 'l32', 'l43', 'l52', 'l59', 'l64', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "141, deletion, ['l8', 'l21', 'l33', 'l44', 'l53', 'l60', 'l65', 'l72', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "169, brown ['l9', 'l22', 'l34', 'l45', 'l54', 'l61', 'l66', 'l73', 'l79', 'l85', 'l86', 'l87', 'l88', 'l89']", + "170, and ['l10', 'l23', 'l35', 'l46', 'l55', 'l62', 'l67', 'l74', 'l80', 'l85', 'l90', 'l91', 'l92', 'l93']", + "171, beige ['l11', 'l24', 'l36', 'l47', 'l56', 'l68', 'l75', 'l81', 'l86', 'l90', 'l94', 'l95', 'l96']", + "172, adipocytes ['l12', 'l25', 'l37', 'l48', 'l57', 'l63', 'l69', 'l76', 'l82', 'l87', 'l91', 'l94', 'l97', 'l98']", + "173, in ['l13', 'l26', 'l38', 'l49', 'l70', 'l77', 'l83', 'l88', 'l92', 'l95', 'l97', 'l99']", + "174, vitro. ['l14', 'l27', 'l39', 'l71', 'l78', 'l84', 'l89', 'l93', 'l96', 'l98', 'l99']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tph1-deficient", + "Tph1", + "genetic", + "deletion," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Small-molecule", + "chemical", + "inhibition", + "of", + "Tph1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Small-molecule", + "chemical", + "inhibition", + "of", + "Tph1" + ] + }, + "context": { + "val": "cells", + "words": [ + "brown", + "and", + "beige", + "adipocytes" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Small-molecule", + "chemical", + "inhibition", + "of" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tph1", + "genetic", + "deletion," + ] + }, + "context": { + "val": "cells", + "words": [ + "brown", + "and", + "beige", + "adipocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tph1", + "genetic", + "deletion," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "25485908", + "TEXT": "Epilepsy is one of the most common and intractable brain disorders. Mutations in the human gene LGI1, encoding a neuronal secreted protein, cause autosomal dominant lateral temporal lobe epilepsy (ADLTE). However, the pathogenic mechanisms of LGI1 mutations remain unclear. We classified 22 reported LGI1 missense mutations as either secretion defective or secretion competent, and we generated and analyzed two mouse models of ADLTE encoding mutant proteins representative of the two groups. The secretion-defective LGI1(E383A) protein was recognized by the ER quality-control machinery and prematurely degraded, whereas the secretable LGI1(S473L) protein abnormally dimerized and was selectively defective in binding to one of its receptors, ADAM22. Both mutations caused a loss of function, compromising intracellular trafficking or ligand activity of LGI1 and converging on reduced synaptic LGI1-ADAM22 interaction. A chemical corrector, 4-phenylbutyrate (4PBA), restored LGI1(E383A) folding and binding to ADAM22 and ameliorated the increased seizure susceptibility of the LGI1(E383A) model mice. This study establishes LGI1-related epilepsy as a conformational disease and suggests new therapeutic options for human epilepsy.", + "TAG_DATA": [ + "146, LGI1(E383A) {'perturbing_action': 'B-other'}", + "147, model {'perturbing_action': 'I-other'}", + "148, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "146, LGI1(E383A) ['l0', 'l1']", + "147, model ['l0', 'l2']", + "148, mice. ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "LGI1(E383A)", + "model" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "25419710", + "TEXT": "Proper function of the endoplasmic reticulum (ER) and mitochondria is crucial for cellular homeostasis, and dysfunction at either site has been linked to pathophysiological states, including metabolic diseases. Although the ER and mitochondria play distinct cellular roles, these organelles also form physical interactions with each other at sites defined as mitochondria-associated ER membranes (MAMs), which are essential for calcium, lipid and metabolite exchange. Here we show that in the liver, obesity leads to a marked reorganization of MAMs resulting in mitochondrial calcium overload, compromised mitochondrial oxidative capacity and augmented oxidative stress. Experimental induction of ER-mitochondria interactions results in oxidative stress and impaired metabolic homeostasis, whereas downregulation of PACS-2 or IP3R1, proteins important for ER-mitochondria tethering or calcium transport, respectively, improves mitochondrial oxidative capacity and glucose metabolism in obese animals. These findings establish excessive ER-mitochondrial coupling as an essential component of organelle dysfunction in obesity that may contribute to the development of metabolic pathologies such as insulin resistance and diabetes.", + "TAG_DATA": [ + "69, liver, {'context': 'B-tissue/organ'}", + "105, downregulation {'perturbing_action': 'B-gene loss-of-function'}", + "106, of {'perturbing_action': 'I-gene loss-of-function'}", + "107, PACS-2 {'perturbing_action': 'I-gene loss-of-function'}", + "108, or {'perturbing_action': 'I-gene loss-of-function'}", + "109, IP3R1, {'perturbing_action': 'I-gene loss-of-function'}", + "127, obese {'context': 'B-organism'}", + "128, animals. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "105, downregulation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "106, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "107, PACS-2 ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "108, or ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "109, IP3R1, ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "127, obese ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "128, animals. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "downregulation", + "of", + "PACS-2", + "or", + "IP3R1," + ] + }, + "context": { + "val": "organism", + "words": [ + "obese", + "animals." + ] + } + } + ] + }, + { + "PMID": "25401692", + "TEXT": "Neurodegenerative diseases, such as frontotemporal dementia (FTD), are often associated with behavioral deficits, but the underlying anatomical and molecular causes remain poorly understood. Here we show that forebrain-specific expression of FTD-associated mutant CHMP2B in mice causes several age-dependent neurodegenerative phenotypes, including social behavioral impairments. The social deficits were accompanied by a change in AMPA receptor (AMPAR) composition, leading to an imbalance between Ca(2+)-permeable and Ca(2+)-impermeable AMPARs. Expression of most AMPAR subunits was regulated by the brain-enriched microRNA miR-124, whose abundance was markedly decreased in the superficial layers of the cerebral cortex of mice expressing the mutant CHMP2B. We found similar changes in miR-124 and AMPAR levels in the frontal cortex and induced pluripotent stem cell-derived neurons from subjects with behavioral variant FTD. Moreover, ectopic miR-124 expression in the medial prefrontal cortex of mutant mice decreased AMPAR levels and partially rescued behavioral deficits. Knockdown of the AMPAR subunit Gria2 also alleviated social impairments. Our results identify a previously undescribed mechanism involving miR-124 and AMPARs in regulating social behavior in FTD and suggest a potential therapeutic avenue.", + "TAG_DATA": [ + "27, forebrain-specific {'perturbing_action': 'B-other'}", + "28, expression {'perturbing_action': 'I-other'}", + "29, of {'perturbing_action': 'I-other'}", + "30, FTD-associated {'perturbing_action': 'I-other'}", + "31, mutant {'perturbing_action': 'I-other'}", + "32, CHMP2B {'perturbing_action': 'I-other'}", + "92, mice {'context': 'B-organism'}", + "95, mutant {'perturbing_action': 'B-other'}", + "96, CHMP2B. {'perturbing_action': 'I-other'}", + "112, pluripotent {'context': 'B-cells'}", + "113, stem {'context': 'I-cells'}", + "114, cell-derived {'context': 'I-cells'}", + "115, neurons {'context': 'I-cells'}", + "123, ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "124, miR-124 {'perturbing_action': 'I-gene gain-of-function'}", + "125, expression {'perturbing_action': 'I-gene gain-of-function'}", + "128, medial {'context': 'B-tissue/organ'}", + "129, prefrontal {'context': 'I-tissue/organ'}", + "130, cortex {'context': 'I-tissue/organ'}", + "133, mice {'context': 'B-organism'}", + "142, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "143, of {'perturbing_action': 'I-rnai/knockdown'}", + "144, the {'perturbing_action': 'I-rnai/knockdown'}", + "145, AMPAR {'perturbing_action': 'I-rnai/knockdown'}", + "146, subunit {'perturbing_action': 'I-rnai/knockdown'}", + "147, Gria2 {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "27, forebrain-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "28, expression ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "29, of ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "30, FTD-associated ['l2', 'l8', 'l13', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "31, mutant ['l3', 'l9', 'l14', 'l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "32, CHMP2B ['l4', 'l10', 'l15', 'l21', 'l26', 'l31', 'l32']", + "92, mice ['l5', 'l11', 'l16', 'l22', 'l27', 'l31', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "95, mutant ['l33', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "96, CHMP2B. ['l34', 'l39', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "112, pluripotent ['l35', 'l40', 'l49', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "113, stem ['l17', 'l23', 'l28', 'l36', 'l41', 'l50', 'l56', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "114, cell-derived ['l18', 'l24', 'l29', 'l37', 'l42', 'l51', 'l57', 'l66', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "115, neurons ['l6', 'l12', 'l19', 'l25', 'l30', 'l32', 'l38', 'l43', 'l52', 'l58', 'l67', 'l73', 'l79', 'l80', 'l81']", + "123, ectopic ['l44', 'l53', 'l59', 'l68', 'l74', 'l79', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "124, miR-124 ['l45', 'l54', 'l60', 'l69', 'l75', 'l80', 'l82', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "125, expression ['l46', 'l55', 'l61', 'l70', 'l76', 'l81', 'l83', 'l89', 'l95', 'l96', 'l97', 'l98', 'l99']", + "127, the ['l62', 'l84', 'l90', 'l95', 'l100', 'l101', 'l102', 'l103']", + "128, medial ['l63', 'l85', 'l91', 'l96', 'l100', 'l104', 'l105', 'l106']", + "129, prefrontal ['l47', 'l64', 'l71', 'l77', 'l86', 'l92', 'l97', 'l101', 'l104', 'l107', 'l108']", + "130, cortex ['l48', 'l65', 'l72', 'l78', 'l87', 'l93', 'l98', 'l102', 'l105', 'l107', 'l109']", + "133, mice ['l88', 'l94', 'l99', 'l103', 'l106', 'l108', 'l109']", + "142, Knockdown ['l110', 'l111', 'l112', 'l113', 'l114']", + "143, of ['l110', 'l115', 'l116', 'l117', 'l118']", + "144, the ['l111', 'l115', 'l119', 'l120', 'l121']", + "145, AMPAR ['l112', 'l116', 'l119', 'l122', 'l123']", + "146, subunit ['l113', 'l117', 'l120', 'l122', 'l124']", + "147, Gria2 ['l114', 'l118', 'l121', 'l123', 'l124']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "forebrain-specific", + "expression", + "of", + "FTD-associated", + "mutant", + "CHMP2B", + "CHMP2B." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "forebrain-specific", + "expression", + "of", + "FTD-associated", + "mutant", + "CHMP2B", + "CHMP2B." + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons", + "stem", + "cell-derived", + "pluripotent" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "prefrontal", + "cortex" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pluripotent", + "stem", + "cell-derived", + "neurons" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "miR-124", + "expression" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "miR-124", + "expression" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "medial", + "prefrontal", + "cortex" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "miR-124", + "expression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "25384087", + "TEXT": "The dynamics of β-amyloid deposition and related second-order physiological effects, such as regional cerebral blood flow (rCBF), are key factors for a deeper understanding of Alzheimer's disease (AD). We present longitudinal in vivo data on the dynamics of β-amyloid deposition and the decline of rCBF in two different amyloid precursor protein (APP) transgenic mouse models of AD. Using a multiparametric positron emission tomography and magnetic resonance imaging approach, we demonstrate that in the presence of cerebral β-amyloid angiopathy (CAA), β-amyloid deposition is accompanied by a decline of rCBF. Loss of perfusion correlates with the growth of β-amyloid plaque burden but is not related to the number of CAA-induced microhemorrhages. However, in a mouse model of parenchymal β-amyloidosis and negligible CAA, rCBF is unchanged. Because synaptically driven spontaneous network activity is similar in both transgenic mouse strains, we conclude that the disease-related decline of rCBF is caused by CAA.", + "TAG_DATA": [ + "48, amyloid {'perturbing_action': 'B-gene gain-of-function'}", + "49, precursor {'perturbing_action': 'I-gene gain-of-function'}", + "50, protein {'perturbing_action': 'I-gene gain-of-function'}", + "51, (APP) {'perturbing_action': 'I-gene gain-of-function'}", + "52, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "53, mouse {'context': 'B-organism'}", + "54, models {'context': 'I-organism'}", + "55, of {'context': 'I-organism'}", + "56, AD. {'context': 'I-organism'}", + "112, mouse {'context': 'B-organism'}", + "113, model {'context': 'I-organism'}", + "133, transgenic {'context': 'B-organism'}", + "134, mouse {'context': 'I-organism'}", + "135, strains, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "48, amyloid ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "49, precursor ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "50, protein ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "51, (APP) ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "52, transgenic ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "53, mouse ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "54, models ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "55, of ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "56, AD. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "112, mouse ['l36']", + "113, model ['l36']", + "133, transgenic ['l37', 'l38']", + "134, mouse ['l37', 'l39']", + "135, strains, ['l38', 'l39']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "amyloid", + "precursor", + "protein", + "(APP)", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "of", + "AD." + ] + } + } + ] + }, + { + "PMID": "25344738", + "TEXT": "Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell-mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN-α and IFN-β receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release of chemokine (C-X-C motif) ligand 10 (CXCL10). Tumors lacking Tlr3 or Ifnar failed to respond to chemotherapy unless type I IFN or Cxcl10, respectively, was artificially supplied. Moreover, a type I IFN-related signature predicted clinical responses to anthracycline-based chemotherapy in several independent cohorts of patients with breast carcinoma characterized by poor prognosis. Our data suggest that anthracycline-mediated immune responses mimic those induced by viral pathogens. We surmise that such 'viral mimicry' constitutes a hallmark of successful chemotherapy.", + "TAG_DATA": [ + "36, malignant {'context': 'B-transformed cells'}", + "81, Tumors {'context': 'B-neoplasm'}", + "82, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "83, Tlr3 {'perturbing_action': 'I-gene loss-of-function'}", + "84, or {'perturbing_action': 'I-gene loss-of-function'}", + "85, Ifnar {'perturbing_action': 'I-gene loss-of-function'}", + "86, failed {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "81, Tumors ['l0', 'l1', 'l2', 'l3', 'l4']", + "82, lacking ['l0', 'l5', 'l6', 'l7', 'l8']", + "83, Tlr3 ['l1', 'l5', 'l9', 'l10', 'l11']", + "84, or ['l2', 'l6', 'l9', 'l12', 'l13']", + "85, Ifnar ['l3', 'l7', 'l10', 'l12', 'l14']", + "86, failed ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "Tumors" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "Tlr3", + "or", + "Ifnar" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "Tumors" + ] + }, + "effect": { + "val": "negative", + "words": [ + "failed" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "Tlr3", + "or", + "Ifnar" + ] + }, + "effect": { + "val": "negative", + "words": [ + "failed" + ] + } + } + ] + }, + { + "PMID": "25326802", + "TEXT": "In the bone marrow, hematopoietic stem cells (HSCs) lodge in specialized microenvironments that tightly control the proliferative state of HSCs to adapt to the varying needs for replenishment of blood cells while also preventing HSC exhaustion. All putative niche cells suggested thus far have a nonhematopoietic origin. Thus, it remains unclear how feedback from mature cells is conveyed to HSCs to adjust their proliferation. Here we show that megakaryocytes (MKs) can directly regulate HSC pool size in mice. Three-dimensional whole-mount imaging revealed that endogenous HSCs are frequently located adjacent to MKs in a nonrandom fashion. Selective in vivo depletion of MKs resulted in specific loss of HSC quiescence and led to a marked expansion of functional HSCs. Gene expression analyses revealed that MKs are the source of chemokine C-X-C motif ligand 4 (CXCL4, also named platelet factor 4 or PF4) in the bone marrow, and we found that CXCL4 regulates HSC cell cycle activity. CXCL4 injection into mice resulted in a reduced number of HSCs because of their increased quiescence. By contrast, Cxcl4(-/-) mice exhibited an increased number of HSCs and increased HSC proliferation. Combined use of whole-mount imaging and computational modeling was highly suggestive of a megakaryocytic niche capable of independently influencing HSC maintenance by regulating quiescence. These results indicate that a terminally differentiated cell type derived from HSCs contributes to the HSC niche, directly regulating HSC behavior.", + "TAG_DATA": [ + "96, in {'context': 'B-in vivo'}", + "97, vivo {'context': 'I-in vivo'}", + "98, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "99, of {'perturbing_action': 'I-gene loss-of-function'}", + "100, MKs {'perturbing_action': 'I-gene loss-of-function'}", + "104, loss {'effect': 'B-negative'}", + "106, HSC {'context': 'B-cells'}", + "107, quiescence {'phenotype': 'B-quiescence'}", + "116, HSCs. {'context': 'B-cells'}", + "157, mice {'context': 'B-organism'}", + "164, HSCs {'context': 'B-cells'}", + "168, increased {'effect': 'B-positive'}", + "169, quiescence. {'phenotype': 'B-quiescence'}", + "172, Cxcl4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "173, mice {'context': 'B-organism'}", + "179, HSCs {'context': 'B-cells'}", + "181, increased {'effect': 'B-positive'}", + "182, HSC {'context': 'B-cells'}", + "183, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "96, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "97, vivo ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "98, depletion ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "99, of ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "100, MKs ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "104, loss ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "106, HSC ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "107, quiescence ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "116, HSCs. ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35', 'l36', 'l37', 'l38']", + "157, mice ['l39', 'l40', 'l41']", + "164, HSCs ['l36', 'l39', 'l42', 'l43']", + "168, increased ['l37', 'l40', 'l42', 'l44']", + "169, quiescence. ['l38', 'l41', 'l43', 'l44']", + "172, Cxcl4(-/-) ['l45', 'l46', 'l47', 'l48', 'l49']", + "173, mice ['l45', 'l50', 'l51', 'l52', 'l53']", + "179, HSCs ['l46', 'l50']", + "181, increased ['l47', 'l51', 'l54', 'l55']", + "182, HSC ['l48', 'l52', 'l54', 'l56']", + "183, proliferation. ['l49', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "MKs" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "MKs" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "MKs", + "Cxcl4(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC", + "HSCs.", + "HSCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "MKs" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "loss" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC", + "HSCs." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "loss" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSC", + "HSCs.", + "HSCs" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence", + "quiescence." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSCs.", + "HSCs", + "HSC" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "quiescence", + "words": [ + "quiescence." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cxcl4(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cxcl4(-/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cxcl4(-/-)" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSC" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "25326801", + "TEXT": "Regulatory B cells (Breg cells) differentiate in response to inflammation and subsequently restrain excessive immune responses via the release of interleukin-10 (IL-10). However, the precise inflammatory signals governing their differentiation remain to be elucidated. Here we show that the gut microbiota promotes the differentiation of Breg cells in the spleen as well as in the mesenteric lymph nodes. Perturbation of the gut microbiome imposed either by antibiotic treatment or by changes in the sterility of housing conditions reduces the number and function of Breg cells. Following the induction of arthritis, IL-1β and IL-6 are produced only in conventionally housed mice and both cytokines directly promote Breg cell differentiation and IL-10 production. Mice lacking IL-6 receptor (IL-6R) or IL-1 receptor 1 (IL-1R1) specifically on B cells have a reduced number of IL-10-producing B cells and develop exacerbated arthritis compared to control animals. Thus, in response to inflammatory signals induced by both the gut flora and arthritis, Breg cells increase in number and restrain excessive inflammation.", + "TAG_DATA": [ + "45, Breg {'context': 'B-cells'}", + "46, cells {'context': 'I-cells'}", + "49, spleen {'context': 'B-tissue/organ'}", + "55, mesenteric {'context': 'B-tissue/organ'}", + "56, lymph {'context': 'I-tissue/organ'}", + "57, nodes. {'context': 'I-tissue/organ'}", + "83, Breg {'context': 'B-cells'}", + "84, cells. {'context': 'I-cells'}", + "104, promote {'effect': 'B-positive'}", + "105, Breg {'context': 'B-cells'}", + "106, cell {'context': 'I-cells'}", + "107, differentiation {'phenotype': 'B-differentiation'}", + "111, Mice {'context': 'B-organism'}", + "112, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "113, IL-6 {'perturbing_action': 'I-gene loss-of-function'}", + "114, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "115, (IL-6R) {'perturbing_action': 'I-gene loss-of-function'}", + "116, or {'perturbing_action': 'I-gene loss-of-function'}", + "117, IL-1 {'perturbing_action': 'I-gene loss-of-function'}", + "118, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "119, 1 {'perturbing_action': 'I-gene loss-of-function'}", + "120, (IL-1R1) {'perturbing_action': 'I-gene loss-of-function'}", + "121, specifically {'perturbing_action': 'I-gene loss-of-function'}", + "122, on {'perturbing_action': 'I-gene loss-of-function'}", + "123, B {'context': 'B-cells'}", + "124, cells {'context': 'I-cells'}", + "131, B {'context': 'B-cells'}", + "132, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, Breg ['l0', 'l1', 'l2', 'l3', 'l4']", + "46, cells ['l0', 'l5', 'l6', 'l7', 'l8']", + "49, spleen ['l1', 'l5', 'l9', 'l10', 'l11', 'l12']", + "55, mesenteric ['l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "56, lymph ['l9', 'l13', 'l19', 'l20', 'l21']", + "57, nodes. ['l2', 'l6', 'l10', 'l14', 'l19', 'l22', 'l23']", + "83, Breg ['l3', 'l7', 'l11', 'l15', 'l20', 'l22', 'l24']", + "84, cells. ['l4', 'l8', 'l12', 'l16', 'l21', 'l23', 'l24']", + "104, promote ['l25', 'l26', 'l27']", + "105, Breg ['l25', 'l28', 'l29']", + "106, cell ['l17', 'l26', 'l28', 'l30']", + "107, differentiation ['l18', 'l27', 'l29', 'l30']", + "111, Mice ['l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "112, lacking ['l31', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "113, IL-6 ['l32', 'l46', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "114, receptor ['l33', 'l47', 'l60', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "115, (IL-6R) ['l34', 'l48', 'l61', 'l73', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "116, or ['l35', 'l49', 'l62', 'l74', 'l85', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "117, IL-1 ['l36', 'l50', 'l63', 'l75', 'l86', 'l96', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "118, receptor ['l37', 'l51', 'l64', 'l76', 'l87', 'l97', 'l106', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "119, 1 ['l38', 'l52', 'l65', 'l77', 'l88', 'l98', 'l107', 'l115', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "120, (IL-1R1) ['l39', 'l53', 'l66', 'l78', 'l89', 'l99', 'l108', 'l116', 'l123', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "121, specifically ['l40', 'l54', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l124', 'l130', 'l136', 'l137', 'l138', 'l139', 'l140']", + "122, on ['l41', 'l55', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l125', 'l131', 'l136', 'l141', 'l142', 'l143', 'l144']", + "123, B ['l42', 'l56', 'l69', 'l81', 'l92', 'l102', 'l111', 'l119', 'l126', 'l132', 'l137', 'l141', 'l145', 'l146', 'l147']", + "124, cells ['l43', 'l57', 'l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l127', 'l133', 'l138', 'l142', 'l145', 'l148', 'l149']", + "131, B ['l44', 'l58', 'l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l128', 'l134', 'l139', 'l143', 'l146', 'l148', 'l150']", + "132, cells ['l45', 'l59', 'l72', 'l84', 'l95', 'l105', 'l114', 'l122', 'l129', 'l135', 'l140', 'l144', 'l147', 'l149', 'l150']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "mesenteric" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote" + ] + }, + "context": { + "val": "cells", + "words": [ + "Breg", + "cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Breg", + "cell" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "IL-6", + "receptor", + "(IL-6R)", + "or", + "IL-1", + "1", + "(IL-1R1)", + "specifically", + "on" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "IL-6", + "receptor", + "(IL-6R)", + "or", + "IL-1", + "1", + "(IL-1R1)", + "specifically", + "on" + ] + }, + "context": { + "val": "cells", + "words": [ + "B", + "cells" + ] + } + } + ] + }, + { + "PMID": "25282359", + "TEXT": "Interleukin-17 (IL-17)-secreting T cells of the T helper 17 (TH17) lineage play a pathogenic role in multiple inflammatory and autoimmune conditions and thus represent a highly attractive target for therapeutic intervention. We report that inhibition of acetyl-CoA carboxylase 1 (ACC1) restrains the formation of human and mouse TH17 cells and promotes the development of anti-inflammatory Foxp3(+) regulatory T (Treg) cells. We show that TH17 cells, but not Treg cells, depend on ACC1-mediated de novo fatty acid synthesis and the underlying glycolytic-lipogenic metabolic pathway for their development. Although TH17 cells use this pathway to produce phospholipids for cellular membranes, Treg cells readily take up exogenous fatty acids for this purpose. Notably, pharmacologic inhibition or T cell-specific deletion of ACC1 not only blocks de novo fatty acid synthesis but also interferes with the metabolic flux of glucose-derived carbon via glycolysis and the tricarboxylic acid cycle. In vivo, treatment with the ACC-specific inhibitor soraphen A or T cell-specific deletion of ACC1 in mice attenuates TH17 cell-mediated autoimmune disease. Our results indicate fundamental differences between TH17 cells and Treg cells regarding their dependency on ACC1-mediated de novo fatty acid synthesis, which might be exploited as a new strategy for metabolic immune modulation of TH17 cell-mediated inflammatory diseases.", + "TAG_DATA": [ + "34, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "35, of {'perturbing_action': 'I-pharmacological inhibition'}", + "36, acetyl-CoA {'perturbing_action': 'I-pharmacological inhibition'}", + "37, carboxylase {'perturbing_action': 'I-pharmacological inhibition'}", + "38, 1 {'perturbing_action': 'I-pharmacological inhibition'}", + "39, (ACC1) {'perturbing_action': 'I-pharmacological inhibition'}", + "44, human {'context': 'B-cells'}", + "45, and {'context': 'I-cells'}", + "46, mouse {'context': 'I-cells'}", + "47, TH17 {'context': 'I-cells'}", + "48, cells {'context': 'I-cells'}", + "98, Treg {'context': 'B-cells'}", + "99, cells {'context': 'I-cells'}", + "113, T {'perturbing_action': 'B-gene loss-of-function'}", + "114, cell-specific {'perturbing_action': 'I-gene loss-of-function'}", + "115, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "116, of {'perturbing_action': 'I-gene loss-of-function'}", + "117, ACC1 {'perturbing_action': 'I-gene loss-of-function'}", + "143, In {'context': 'B-in vivo'}", + "144, vivo, {'context': 'I-in vivo'}", + "153, T {'perturbing_action': 'B-gene loss-of-function'}", + "154, cell-specific {'perturbing_action': 'B-gene loss-of-function'}", + "155, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "156, of {'perturbing_action': 'I-gene loss-of-function'}", + "157, ACC1 {'perturbing_action': 'I-gene loss-of-function'}", + "159, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "34, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "35, of ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "36, acetyl-CoA ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "37, carboxylase ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "38, 1 ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "39, (ACC1) ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "44, human ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60']", + "45, and ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l61', 'l62', 'l63']", + "46, mouse ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l61', 'l64', 'l65']", + "47, TH17 ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l62', 'l64', 'l66']", + "48, cells ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l63', 'l65', 'l66']", + "98, Treg ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l67', 'l68', 'l69']", + "99, cells ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l67']", + "113, T ['l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "114, cell-specific ['l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "115, deletion ['l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "116, of ['l68', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "117, ACC1 ['l69', 'l73', 'l78', 'l82', 'l85']", + "143, In ['l74', 'l79', 'l83', 'l86', 'l88']", + "144, vivo, ['l75', 'l80', 'l84', 'l87', 'l88']", + "153, T ['l89', 'l90', 'l91', 'l92', 'l93']", + "154, cell-specific ['l89', 'l94', 'l95', 'l96', 'l97']", + "155, deletion ['l90', 'l94', 'l98', 'l99', 'l100']", + "156, of ['l91', 'l95', 'l98', 'l101', 'l102']", + "157, ACC1 ['l92', 'l96', 'l99', 'l101', 'l103']", + "159, mice ['l93', 'l97', 'l100', 'l102', 'l103']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "acetyl-CoA", + "carboxylase", + "1", + "(ACC1)" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "and", + "mouse", + "TH17", + "cells", + "Treg" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Treg" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "ACC1" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "T", + "cell-specific", + "deletion", + "of" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "T", + "cell-specific", + "deletion", + "of", + "ACC1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "25282358", + "TEXT": "Osteogenesis during bone modeling and remodeling is coupled with angiogenesis. A recent study showed that a specific vessel subtype, strongly positive for CD31 and endomucin (CD31(hi)Emcn(hi)), couples angiogenesis and osteogenesis. Here, we found that platelet-derived growth factor-BB (PDGF-BB) secreted by preosteoclasts induces CD31(hi)Emcn(hi) vessel formation during bone modeling and remodeling. Mice with depletion of PDGF-BB in the tartrate-resistant acid phosphatase-positive cell lineage show significantly lower trabecular and cortical bone mass, serum and bone marrow PDGF-BB concentrations, and fewer CD31(hi)Emcn(hi) vessels compared to wild-type mice. In the ovariectomy (OVX)-induced osteoporotic mouse model, serum and bone marrow levels of PDGF-BB and numbers of CD31(hi)Emcn(hi) vessels are significantly lower compared to sham-operated controls. Treatment with exogenous PDGF-BB or inhibition of cathepsin K to increase the number of preosteoclasts, and thus the endogenous levels of PDGF-BB, increases CD31(hi)Emcn(hi) vessel number and stimulates bone formation in OVX mice. Thus, pharmacotherapies that increase PDGF-BB secretion from preosteoclasts offer a new therapeutic target for treating osteoporosis by promoting angiogenesis and thus bone formation.", + "TAG_DATA": [ + "50, Mice {'context': 'B-organism'}", + "52, depletion {'perturbing_action': 'B-gene loss-of-function'}", + "53, of {'perturbing_action': 'I-gene loss-of-function'}", + "54, PDGF-BB {'perturbing_action': 'I-gene loss-of-function'}", + "55, in {'perturbing_action': 'I-gene loss-of-function'}", + "56, the {'perturbing_action': 'I-gene loss-of-function'}", + "57, tartrate-resistant {'perturbing_action': 'I-gene loss-of-function'}", + "58, acid {'perturbing_action': 'I-gene loss-of-function'}", + "59, phosphatase-positive {'perturbing_action': 'I-gene loss-of-function'}", + "60, cell {'perturbing_action': 'I-gene loss-of-function'}", + "61, lineage {'perturbing_action': 'I-gene loss-of-function'}", + "89, mouse {'context': 'B-organism'}", + "90, model, {'context': 'I-organism'}", + "115, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "116, of {'perturbing_action': 'I-pharmacological inhibition'}", + "117, cathepsin {'perturbing_action': 'I-pharmacological inhibition'}", + "118, K {'perturbing_action': 'I-pharmacological inhibition'}", + "124, preosteoclasts, {'context': 'B-cells'}", + "137, stimulates {'effect': 'B-positive'}", + "138, bone {'phenotype': 'B-autophagy'}", + "139, formation {'phenotype': 'I-tumourigenesis'}", + "142, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "50, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "52, depletion ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "53, of ['l1', 'l10', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "54, PDGF-BB ['l2', 'l11', 'l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "55, in ['l3', 'l12', 'l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "56, the ['l4', 'l13', 'l23', 'l32', 'l40', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "57, tartrate-resistant ['l5', 'l14', 'l24', 'l33', 'l41', 'l48', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "58, acid ['l6', 'l15', 'l25', 'l34', 'l42', 'l49', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "59, phosphatase-positive ['l7', 'l16', 'l26', 'l35', 'l43', 'l50', 'l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "60, cell ['l8', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l66', 'l70', 'l71', 'l72']", + "61, lineage ['l9', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l70', 'l73', 'l74']", + "89, mouse ['l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71', 'l73', 'l75']", + "90, model, ['l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l74', 'l75']", + "115, inhibition ['l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "116, of ['l76', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "117, cathepsin ['l77', 'l84', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "118, K ['l78', 'l85', 'l91', 'l97', 'l98', 'l99', 'l100', 'l101']", + "124, preosteoclasts, ['l79', 'l86', 'l92', 'l97', 'l102', 'l103', 'l104', 'l105']", + "137, stimulates ['l80', 'l87', 'l93', 'l98', 'l102', 'l106', 'l107', 'l108']", + "138, bone ['l81', 'l88', 'l94', 'l99', 'l103', 'l106', 'l109', 'l110']", + "139, formation ['l82', 'l89', 'l95', 'l100', 'l104', 'l107', 'l109', 'l111']", + "142, mice. ['l83', 'l90', 'l96', 'l101', 'l105', 'l108', 'l110', 'l111']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice", + "mouse", + "model," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "PDGF-BB", + "in", + "the", + "tartrate-resistant", + "acid", + "phosphatase-positive", + "cell", + "lineage" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "cathepsin", + "K" + ] + }, + "context": { + "val": "cells", + "words": [ + "preosteoclasts," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "cathepsin", + "K" + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "cathepsin", + "K" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "bone" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "cathepsin", + "K" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "cathepsin", + "K" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "preosteoclasts," + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "preosteoclasts," + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "bone" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "preosteoclasts," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "bone" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "autophagy", + "words": [ + "bone" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "formation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "25150498", + "TEXT": "Duplication of the gene encoding the peripheral myelin protein of 22 kDa (PMP22) underlies the most common inherited neuropathy, Charcot-Marie-Tooth 1A (CMT1A), a disease without a known cure. Although demyelination represents a characteristic feature, the clinical phenotype of CMT1A is determined by the degree of axonal loss, and patients suffer from progressive muscle weakness and impaired sensation. CMT1A disease manifests within the first two decades of life, and walking disabilities, foot deformities and electrophysiological abnormalities are already present in childhood. Here, we show in Pmp22-transgenic rodent models of CMT1A that Schwann cells acquire a persistent differentiation defect during early postnatal development, caused by imbalanced activity of the PI3K-Akt and the Mek-Erk signaling pathways. We demonstrate that enhanced PI3K-Akt signaling by axonally overexpressed neuregulin-1 (NRG1) type I drives diseased Schwann cells toward differentiation and preserves peripheral nerve axons. Notably, in a preclinical experimental therapy using a CMT1A rat model, when treatment is restricted to early postnatal development, soluble NRG1 effectively overcomes impaired peripheral nerve development and restores axon survival into adulthood. Our findings suggest a model in which Schwann cell differentiation within a limited time window is crucial for the long-term maintenance of axonal support.", + "TAG_DATA": [ + "84, Pmp22-transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "85, rodent {'context': 'B-organism'}", + "86, models {'context': 'I-organism'}", + "87, of {'context': 'I-organism'}", + "88, CMT1A {'context': 'I-organism'}", + "90, Schwann {'context': 'B-cells'}", + "91, cells {'context': 'I-cells'}", + "92, acquire {'effect': 'B-positive'}", + "95, differentiation {'phenotype': 'B-differentiation'}", + "96, defect {'effect': 'B-negative', 'phenotype': 'I-differentiation'}", + "120, axonally {'perturbing_action': 'B-gene gain-of-function'}", + "121, overexpressed {'perturbing_action': 'I-gene gain-of-function'}", + "122, neuregulin-1 {'perturbing_action': 'I-gene gain-of-function'}", + "123, (NRG1) {'perturbing_action': 'I-gene gain-of-function'}", + "124, type {'perturbing_action': 'I-gene gain-of-function'}", + "125, I {'perturbing_action': 'I-gene gain-of-function'}", + "128, Schwann {'context': 'B-cells'}", + "129, cells {'context': 'I-cells'}", + "131, differentiation {'phenotype': 'B-differentiation'}", + "134, peripheral {'context': 'B-cells'}", + "135, nerve {'context': 'I-cells'}", + "136, axons. {'context': 'I-cells'}", + "145, CMT1A {'context': 'B-organism'}", + "146, rat {'context': 'I-organism'}", + "147, model, {'context': 'I-organism'}", + "161, peripheral {'context': 'B-tissue/organ'}", + "162, nerve {'context': 'I-tissue/organ'}", + "166, axon {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "84, Pmp22-transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "85, rodent ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "86, models ['l1', 'l12', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "87, of ['l2', 'l13', 'l21', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "88, CMT1A ['l3', 'l14', 'l22', 'l29', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "90, Schwann ['l4', 'l15', 'l23', 'l30', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "91, cells ['l5', 'l16', 'l24', 'l31', 'l37', 'l42', 'l49', 'l50', 'l51', 'l52']", + "92, acquire ['l6', 'l17', 'l25', 'l32', 'l38', 'l43', 'l49', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "95, differentiation ['l7', 'l18', 'l26', 'l33', 'l39', 'l44', 'l50', 'l53', 'l59', 'l60', 'l61', 'l62', 'l63']", + "96, defect ['l8', 'l19', 'l27', 'l34', 'l40', 'l45', 'l51', 'l54', 'l59', 'l64', 'l65', 'l66', 'l67']", + "120, axonally ['l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "121, overexpressed ['l68', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "122, neuregulin-1 ['l69', 'l80', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "123, (NRG1) ['l70', 'l81', 'l91', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "124, type ['l71', 'l82', 'l92', 'l101', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "125, I ['l72', 'l83', 'l93', 'l102', 'l110', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "126, drives ['l55', 'l60', 'l64', 'l73', 'l84', 'l94', 'l103', 'l111', 'l118', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "128, Schwann ['l9', 'l46', 'l56', 'l61', 'l65', 'l74', 'l85', 'l95', 'l104', 'l112', 'l119', 'l125', 'l131', 'l132', 'l133', 'l134', 'l135']", + "129, cells ['l10', 'l20', 'l28', 'l35', 'l41', 'l47', 'l52', 'l57', 'l62', 'l66', 'l75', 'l86', 'l96', 'l105', 'l113', 'l120', 'l126', 'l131', 'l136', 'l137', 'l138', 'l139']", + "131, differentiation ['l11', 'l48', 'l58', 'l63', 'l67', 'l76', 'l87', 'l97', 'l106', 'l114', 'l121', 'l127', 'l132', 'l136', 'l140', 'l141', 'l142']", + "134, peripheral ['l77', 'l88', 'l98', 'l107', 'l115', 'l122', 'l128', 'l133', 'l137', 'l140', 'l143', 'l144']", + "135, nerve ['l78', 'l89', 'l99', 'l108', 'l116', 'l123', 'l129', 'l134', 'l138', 'l141', 'l143', 'l145']", + "136, axons. ['l79', 'l90', 'l100', 'l109', 'l117', 'l124', 'l130', 'l135', 'l139', 'l142', 'l144', 'l145']", + "145, CMT1A ['l146', 'l147', 'l148', 'l149', 'l150']", + "146, rat ['l146', 'l151', 'l152', 'l153', 'l154']", + "147, model, ['l147', 'l151', 'l155', 'l156', 'l157']", + "161, peripheral ['l148', 'l152', 'l155', 'l158', 'l159']", + "162, nerve ['l149', 'l153', 'l156', 'l158', 'l160']", + "166, axon ['l150', 'l154', 'l157', 'l159', 'l160']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Pmp22-transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "rodent", + "models", + "of", + "CMT1A" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Pmp22-transgenic", + "axonally", + "overexpressed", + "neuregulin-1", + "(NRG1)", + "type", + "I" + ] + }, + "context": { + "val": "cells", + "words": [ + "Schwann", + "cells", + "peripheral", + "nerve", + "axons." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Pmp22-transgenic" + ] + }, + "effect": { + "val": "positive", + "words": [ + "acquire" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Pmp22-transgenic", + "axonally", + "overexpressed", + "neuregulin-1", + "(NRG1)", + "type", + "I" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "defect" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Pmp22-transgenic" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defect" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "defect" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "defect", + "differentiation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rodent", + "models", + "of", + "CMT1A" + ] + }, + "effect": { + "val": "positive", + "words": [ + "acquire" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rodent", + "models", + "of", + "CMT1A" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "defect" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rodent", + "models", + "of", + "CMT1A" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defect" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Schwann", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "acquire" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Schwann", + "cells", + "peripheral", + "nerve", + "axons." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "defect" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Schwann", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defect" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "acquire" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation", + "defect" + ] + } + } + ] + }, + { + "PMID": "25150496", + "TEXT": "Medulloblastoma, the most common malignant childhood brain tumor, exhibits distinct molecular subtypes and cellular origins. Genetic alterations driving medulloblastoma initiation and progression remain poorly understood. Herein, we identify GNAS, encoding the G protein Gαs, as a potent tumor suppressor gene that, when expressed at low levels, defines a subset of aggressive Sonic hedgehog (SHH)-driven human medulloblastomas. Ablation of the single Gnas gene in anatomically distinct progenitors in mice is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. Gαs is highly enriched at the primary cilium of granule neuron precursors and suppresses Shh signaling by regulating both the cAMP-dependent pathway and ciliary trafficking of Hedgehog pathway components. Elevation in levels of a Gαs effector, cAMP, effectively inhibits tumor cell proliferation and progression in Gnas-ablated mice. Thus, our gain- and loss-of-function studies identify a previously unrecognized tumor suppressor function for Gαs that can be found consistently across Shh-group medulloblastomas of disparate cellular and anatomical origins, highlighting G protein modulation as a potential therapeutic avenue.", + "TAG_DATA": [ + "56, Ablation {'perturbing_action': 'B-gene loss-of-function'}", + "57, of {'perturbing_action': 'I-gene loss-of-function'}", + "58, the {'perturbing_action': 'I-gene loss-of-function'}", + "59, single {'perturbing_action': 'I-gene loss-of-function'}", + "60, Gnas {'perturbing_action': 'I-gene loss-of-function'}", + "61, gene {'perturbing_action': 'I-gene loss-of-function'}", + "67, mice {'context': 'B-organism'}", + "71, induce {'effect': 'B-positive'}", + "73, medulloblastomas, {'phenotype': 'I-tumourigenesis'}", + "117, inhibits {'effect': 'B-negative'}", + "118, tumor {'context': 'B-transformed cells'}", + "119, cell {'context': 'I-transformed cells'}", + "120, proliferation {'phenotype': 'B-proliferation'}", + "124, Gnas-ablated {'perturbing_action': 'B-gene loss-of-function'}", + "125, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, Ablation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "57, of ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "58, the ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "59, single ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "60, Gnas ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "61, gene ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "67, mice ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "71, induce ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "73, medulloblastomas, ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "117, inhibits ['l36', 'l37', 'l38', 'l39', 'l40']", + "118, tumor ['l36', 'l41', 'l42', 'l43', 'l44']", + "119, cell ['l37', 'l41', 'l45', 'l46', 'l47']", + "120, proliferation ['l38', 'l42', 'l45', 'l48', 'l49']", + "124, Gnas-ablated ['l39', 'l43', 'l46', 'l48', 'l50']", + "125, mice. ['l40', 'l44', 'l47', 'l49', 'l50']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "the", + "single", + "Gnas", + "gene", + "Gnas-ablated" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "the", + "single", + "Gnas", + "gene" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "the", + "single", + "Gnas", + "gene" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "medulloblastomas," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "medulloblastomas," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "medulloblastomas," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gnas-ablated" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gnas-ablated" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gnas-ablated" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "25129479", + "TEXT": "Anxiety disorders are highly prevalent psychiatric diseases. There is need for a deeper understanding of anxiety control mechanisms in the mammalian brain and for development of new anxiolytic agents. Here we report that the coupling between neuronal nitric oxide synthase (nNOS) and its carboxy-terminal PDZ ligand (CAPON) can serve as a target for developing new anxiolytic agents. Augmenting nNOS-CAPON interaction in the hippocampus of mice by overexpressing full-length CAPON gave rise to anxiogenic-like behaviors, whereas dissociating CAPON from nNOS by overexpressing CAPON-125C or CAPON-20C (the C-terminal 125 or 20 amino acids of CAPON) or delivering Tat-CAPON-12C (a peptide comprising Tat and the 12 C-terminal amino acids of CAPON) in the hippocampus of mice produced anxiolytic-like effects. Mice subjected to chronic mild stress (CMS) displayed a substantial increase in nNOS-CAPON coupling in the hippocampus and a consequent anxiogenic-like phenotype. Disrupting nNOS-CAPON coupling reversed the CMS-induced anxiogenic-like behaviors. Moreover, small-molecule blockers of nNOS-CAPON binding rapidly produced anxiolytic-like effects. Dexamethasone-induced ras protein 1 (Dexras1)-extracellular signal-regulated kinase (ERK) signaling was involved in the behavioral effects of nNOS-CAPON association. Thus, nNOS-CAPON association contributes to the modulation of anxiety-related behaviors via regulating Dexras1-ERK signaling and can serve as a target for developing potential anxiolytics.", + "TAG_DATA": [ + "62, hippocampus {'context': 'B-tissue/organ'}", + "64, mice {'context': 'B-organism'}", + "66, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "67, full-length {'perturbing_action': 'I-gene gain-of-function'}", + "68, CAPON {'perturbing_action': 'I-gene gain-of-function'}", + "80, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "81, CAPON-125C {'perturbing_action': 'I-gene gain-of-function'}", + "82, or {'perturbing_action': 'I-gene gain-of-function'}", + "83, CAPON-20C {'perturbing_action': 'I-gene gain-of-function'}", + "84, (the {'perturbing_action': 'I-gene gain-of-function'}", + "110, hippocampus {'context': 'B-tissue/organ'}", + "112, mice {'context': 'B-organism'}", + "116, Mice {'context': 'B-organism'}", + "132, hippocampus {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "62, hippocampus ['l0', 'l1', 'l2', 'l3']", + "64, mice ['l0', 'l4', 'l5', 'l6']", + "66, overexpressing ['l1', 'l4', 'l7', 'l8']", + "67, full-length ['l2', 'l5', 'l7', 'l9']", + "68, CAPON ['l3', 'l6', 'l8', 'l9']", + "80, overexpressing ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "81, CAPON-125C ['l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "82, or ['l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "83, CAPON-20C ['l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "84, (the ['l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "110, hippocampus ['l14', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "112, mice ['l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "116, Mice ['l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "132, hippocampus ['l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "full-length", + "CAPON", + "CAPON-125C", + "or", + "CAPON-20C", + "(the" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "Mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "full-length", + "CAPON", + "CAPON-125C", + "or", + "CAPON-20C", + "(the" + ] + } + } + ] + }, + { + "PMID": "25038828", + "TEXT": "An imbalance of tau isoforms containing either three or four microtubule-binding repeats causes frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) in families with intronic mutations in the MAPT gene. Here we report equivalent imbalances at the mRNA and protein levels and increased total tau levels in the brains of subjects with Huntington's disease (HD) together with rod-like tau deposits along neuronal nuclei. These tau nuclear rods show an ordered filamentous ultrastructure and can be found filling the neuronal nuclear indentations previously reported in HD brains. Finally, alterations in serine/arginine-rich splicing factor-6 coincide with tau missplicing, and a role of tau in HD pathogenesis is evidenced by the attenuation of motor abnormalities of mutant HTT transgenic mice in tau knockout backgrounds.", + "TAG_DATA": [ + "114, mutant {'perturbing_action': 'B-gene gain-of-function'}", + "115, HTT {'perturbing_action': 'I-gene gain-of-function'}", + "116, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "117, mice {'context': 'B-organism'}", + "119, tau {'perturbing_action': 'B-gene loss-of-function'}", + "120, knockout {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "114, mutant ['l0', 'l1', 'l2', 'l3', 'l4']", + "115, HTT ['l0', 'l5', 'l6', 'l7', 'l8']", + "116, transgenic ['l1', 'l5', 'l9', 'l10', 'l11']", + "117, mice ['l2', 'l6', 'l9', 'l12', 'l13']", + "119, tau ['l3', 'l7', 'l10', 'l12', 'l14']", + "120, knockout ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "mutant", + "HTT", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "tau", + "knockout" + ] + } + } + ] + }, + { + "PMID": "25038827", + "TEXT": "The HIV-1 restriction factor SAM domain- and HD domain-containing protein 1 (SAMHD1) is proposed to inhibit HIV-1 replication by depleting the intracellular dNTP pool. However, phosphorylation of SAMHD1 regulates its ability to restrict HIV-1 without decreasing cellular dNTP levels, which is not consistent with a role for SAMHD1 dNTPase activity in HIV-1 restriction. Here, we show that SAMHD1 possesses RNase activity and that the RNase but not the dNTPase function is essential for HIV-1 restriction. By enzymatically characterizing Aicardi-Goutières syndrome (AGS)-associated SAMHD1 mutations and mutations in the allosteric dGTP-binding site of SAMHD1 for defects in RNase or dNTPase activity, we identify SAMHD1 point mutants that cause loss of one or both functions. The RNase-positive and dNTPase-negative SAMHD1D137N mutant is able to restrict HIV-1 infection, whereas the RNase-negative and dNTPase-positive SAMHD1Q548A mutant is defective for HIV-1 restriction. SAMHD1 associates with HIV-1 RNA and degrades it during the early phases of cell infection. SAMHD1 silencing in macrophages and CD4(+) T cells from healthy donors increases HIV-1 RNA stability, rendering the cells permissive for HIV-1 infection. Furthermore, phosphorylation of SAMHD1 at T592 negatively regulates its RNase activity in cells and impedes HIV-1 restriction. Our results reveal that the RNase activity of SAMHD1 is responsible for preventing HIV-1 infection by directly degrading the HIV-1 RNA.", + "TAG_DATA": [ + "113, RNase-positive {'perturbing_action': 'B-other'}", + "114, and {'perturbing_action': 'I-other'}", + "115, dNTPase-negative {'perturbing_action': 'I-other'}", + "116, SAMHD1D137N {'perturbing_action': 'I-other'}", + "117, mutant {'perturbing_action': 'I-other'}", + "126, RNase-negative {'perturbing_action': 'B-other'}", + "127, and {'perturbing_action': 'I-other'}", + "128, dNTPase-positive {'perturbing_action': 'I-other'}", + "129, SAMHD1Q548A {'perturbing_action': 'I-other'}", + "130, mutant {'perturbing_action': 'I-other'}", + "151, SAMHD1 {'perturbing_action': 'B-rnai/knockdown'}", + "152, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "154, macrophages {'context': 'B-cells'}", + "156, CD4(+) {'context': 'B-cells'}", + "157, T {'context': 'I-cells'}", + "158, cells {'context': 'I-cells'}", + "168, cells {'context': 'B-cells'}", + "185, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "113, RNase-positive ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "114, and ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "115, dNTPase-negative ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "116, SAMHD1D137N ['l2', 'l8', 'l13', 'l20', 'l21']", + "117, mutant ['l3', 'l9', 'l14', 'l20']", + "126, RNase-negative ['l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "127, and ['l22', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "128, dNTPase-positive ['l23', 'l33', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "129, SAMHD1Q548A ['l15', 'l24', 'l34', 'l43', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "130, mutant ['l4', 'l10', 'l16', 'l21', 'l25', 'l35', 'l44', 'l52', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "151, SAMHD1 ['l26', 'l36', 'l45', 'l53', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "152, silencing ['l27', 'l37', 'l46', 'l54', 'l60', 'l66', 'l73', 'l74', 'l75', 'l76', 'l77']", + "154, macrophages ['l5', 'l11', 'l17', 'l28', 'l38', 'l47', 'l55', 'l61', 'l67', 'l73', 'l78', 'l79', 'l80', 'l81']", + "156, CD4(+) ['l29', 'l39', 'l48', 'l56', 'l62', 'l68', 'l74', 'l78', 'l82', 'l83', 'l84']", + "157, T ['l18', 'l30', 'l40', 'l49', 'l57', 'l63', 'l69', 'l75', 'l79', 'l82', 'l85', 'l86']", + "158, cells ['l6', 'l12', 'l19', 'l31', 'l41', 'l50', 'l58', 'l64', 'l70', 'l76', 'l80', 'l83', 'l85', 'l87']", + "168, cells ['l32', 'l42', 'l51', 'l59', 'l65', 'l71', 'l77', 'l81', 'l84', 'l86', 'l87']", + "185, cells ['l72']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "RNase-positive", + "and", + "dNTPase-negative", + "RNase-negative", + "dNTPase-positive", + "SAMHD1Q548A", + "mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages", + "cells", + "T", + "CD4(+)" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "SAMHD1", + "silencing" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages", + "CD4(+)", + "T", + "cells" + ] + } + } + ] + }, + { + "PMID": "24859528", + "TEXT": "The application of primary organoid cultures containing epithelial and mesenchymal elements to cancer modeling holds promise for combining the accurate multilineage differentiation and physiology of in vivo systems with the facile in vitro manipulation of transformed cell lines. Here we used a single air-liquid interface culture method without modification to engineer oncogenic mutations into primary epithelial and mesenchymal organoids from mouse colon, stomach and pancreas. Pancreatic and gastric organoids exhibited dysplasia as a result of expression of Kras carrying the G12D mutation (Kras(G12D)), p53 loss or both and readily generated adenocarcinoma after in vivo transplantation. In contrast, primary colon organoids required combinatorial Apc, p53, Kras(G12D) and Smad4 mutations for progressive transformation to invasive adenocarcinoma-like histology in vitro and tumorigenicity in vivo, recapitulating multi-hit models of colorectal cancer (CRC), as compared to the more promiscuous transformation of small intestinal organoids. Colon organoid culture functionally validated the microRNA miR-483 as a dominant driver oncogene at the IGF2 (insulin-like growth factor-2) 11p15.5 CRC amplicon, inducing dysplasia in vitro and tumorigenicity in vivo. These studies demonstrate the general utility of a highly tractable primary organoid system for cancer modeling and driver oncogene validation in diverse gastrointestinal tissues.", + "TAG_DATA": [ + "58, organoids {'context': 'I-organoid'}", + "60, mouse {'context': 'B-tissue/organ'}", + "61, colon, {'context': 'I-tissue/organ'}", + "62, stomach {'context': 'I-tissue/organ'}", + "64, pancreas. {'context': 'I-tissue/organ'}", + "65, Pancreatic {'context': 'B-organoid'}", + "66, and {'context': 'I-organoid'}", + "67, gastric {'context': 'I-organoid'}", + "68, organoids {'context': 'I-organoid'}", + "90, adenocarcinoma {'phenotype': 'B-tumourigenesis'}", + "92, in {'context': 'B-in vivo'}", + "93, vivo {'context': 'I-in vivo'}", + "97, primary {'context': 'B-organoid'}", + "98, colon {'context': 'I-organoid'}", + "99, organoids {'context': 'I-organoid'}", + "110, transformation {'phenotype': 'B-transformation'}", + "115, in {'context': 'B-in vitro'}", + "116, vitro {'context': 'I-in vitro'}", + "118, tumorigenicity {'phenotype': 'B-tumourigenesis'}", + "119, in {'context': 'B-in vivo'}", + "120, vivo, {'context': 'I-in vivo'}", + "136, small {'context': 'B-organoid'}", + "137, intestinal {'context': 'I-organoid'}", + "138, organoids. {'context': 'I-organoid'}", + "139, Colon {'context': 'B-organoid'}", + "140, organoid {'context': 'I-organoid'}", + "161, inducing {'effect': 'B-positive'}", + "163, in {'context': 'B-in vitro'}", + "164, vitro {'context': 'I-in vitro'}", + "166, tumorigenicity {'phenotype': 'B-tumourigenesis'}", + "167, in {'context': 'B-in vivo'}", + "168, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "55, epithelial ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "56, and ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "57, mesenchymal ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "58, organoids ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "60, mouse ['l3', 'l16', 'l28', 'l39', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "61, colon, ['l4', 'l17', 'l29', 'l40', 'l49', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "62, stomach ['l5', 'l18', 'l30', 'l41', 'l50', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "64, pancreas. ['l6', 'l19', 'l31', 'l42', 'l51', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71', 'l72']", + "65, Pancreatic ['l7', 'l20', 'l32', 'l43', 'l52', 'l59', 'l64', 'l68', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "66, and ['l8', 'l21', 'l33', 'l44', 'l53', 'l60', 'l65', 'l69', 'l73', 'l79', 'l80', 'l81', 'l82']", + "67, gastric ['l9', 'l22', 'l34', 'l45', 'l54', 'l61', 'l66', 'l70', 'l74', 'l79', 'l83', 'l84', 'l85']", + "68, organoids ['l10', 'l23', 'l35', 'l46', 'l55', 'l62', 'l67', 'l71', 'l75', 'l80', 'l83', 'l86', 'l87']", + "89, generated ['l11', 'l24', 'l36', 'l47', 'l76', 'l81', 'l84', 'l86', 'l88', 'l89', 'l90']", + "90, adenocarcinoma ['l12', 'l25', 'l37', 'l48', 'l56', 'l72', 'l77', 'l82', 'l85', 'l87', 'l88', 'l91', 'l92']", + "92, in ['l89', 'l91', 'l93']", + "93, vivo ['l13', 'l26', 'l38', 'l78', 'l90', 'l92', 'l93']", + "97, primary ['l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "98, colon ['l94', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "99, organoids ['l95', 'l102', 'l109', 'l110', 'l111', 'l112', 'l113']", + "110, transformation ['l96', 'l103', 'l109', 'l114', 'l115', 'l116']", + "115, in ['l97', 'l104', 'l110', 'l114', 'l117', 'l118', 'l119']", + "116, vitro ['l98', 'l105', 'l111', 'l115', 'l117', 'l120']", + "118, tumorigenicity ['l99', 'l106', 'l112', 'l118', 'l121', 'l122']", + "119, in ['l100', 'l107', 'l121', 'l123']", + "120, vivo, ['l101', 'l108', 'l113', 'l116', 'l119', 'l120', 'l122', 'l123']", + "136, small ['l124', 'l125', 'l126', 'l127']", + "137, intestinal ['l124', 'l128', 'l129', 'l130']", + "138, organoids. ['l125', 'l128', 'l131']", + "139, Colon ['l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "140, organoid ['l132', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "161, inducing ['l133', 'l139', 'l145', 'l146', 'l147', 'l148', 'l149']", + "163, in ['l126', 'l129', 'l131', 'l134', 'l140', 'l145', 'l150', 'l151', 'l152', 'l153']", + "164, vitro ['l127', 'l130', 'l135', 'l141', 'l146', 'l150', 'l154', 'l155', 'l156']", + "166, tumorigenicity ['l136', 'l142', 'l147', 'l151', 'l154', 'l157', 'l158']", + "167, in ['l137', 'l143', 'l148', 'l152', 'l155', 'l157', 'l159']", + "168, vivo. ['l138', 'l144', 'l149', 'l153', 'l156', 'l158', 'l159']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organoid", + "words": [ + "organoids", + "Pancreatic", + "and", + "gastric", + "primary", + "colon", + "Colon", + "organoid" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "adenocarcinoma", + "tumorigenicity" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "pancreas." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "adenocarcinoma" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "adenocarcinoma", + "tumorigenicity" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "vivo,", + "vivo." + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "primary", + "colon", + "organoids" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + } + }, + { + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo," + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity" + ] + } + }, + { + "context": { + "val": "organoid", + "words": [ + "Colon", + "organoid" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "24836575", + "TEXT": "Acute graft-versus-host disease (GVHD) considerably limits wider usage of allogeneic hematopoietic cell transplantation (allo-HCT). Antigen-presenting cells and T cells are populations customarily associated with GVHD pathogenesis. Of note, neutrophils are the largest human white blood cell population. The cells cleave chemokines and produce reactive oxygen species, thereby promoting T cell activation. Therefore, during an allogeneic immune response, neutrophils could amplify tissue damage caused by conditioning regimens. We analyzed neutrophil infiltration of the mouse ileum after allo-HCT by in vivo myeloperoxidase imaging and found that infiltration levels were dependent on the local microbial flora and were not detectable under germ-free conditions. Physical or genetic depletion of neutrophils reduced GVHD-related mortality. The contribution of neutrophils to GVHD severity required reactive oxygen species (ROS) because selective Cybb (encoding cytochrome b-245, beta polypeptide, also known as NOX2) deficiency in neutrophils impairing ROS production led to lower levels of tissue damage, GVHD-related mortality and effector phenotype T cells. Enhanced survival of Bcl-xL transgenic neutrophils increased GVHD severity. In contrast, when we transferred neutrophils lacking Toll-like receptor-2 (TLR2), TLR3, TLR4, TLR7 and TLR9, which are normally less strongly activated by translocating bacteria, into wild-type C57BL/6 mice, GVHD severity was reduced. In humans, severity of intestinal GVHD strongly correlated with levels of neutrophils present in GVHD lesions. This study describes a new potential role for neutrophils in the pathogenesis of GVHD in both mice and humans.", + "TAG_DATA": [ + "72, mouse {'context': 'B-tissue/organ'}", + "73, ileum {'context': 'I-tissue/organ'}", + "122, selective {'perturbing_action': 'B-gene loss-of-function'}", + "123, Cybb {'perturbing_action': 'B-gene loss-of-function'}", + "132, NOX2) {'perturbing_action': 'I-gene loss-of-function'}", + "133, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "151, T {'context': 'I-cells'}", + "152, cells. {'context': 'I-cells'}", + "156, Bcl-xL {'perturbing_action': 'B-gene gain-of-function'}", + "157, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "188, C57BL/6 {'context': 'B-organism'}", + "189, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "72, mouse ['l0']", + "73, ileum ['l0']", + "122, selective ['l1', 'l2', 'l3', 'l4', 'l5']", + "123, Cybb ['l1', 'l6', 'l7', 'l8', 'l9']", + "132, NOX2) ['l2', 'l6', 'l10', 'l11', 'l12']", + "133, deficiency ['l3', 'l7', 'l10', 'l13', 'l14']", + "151, T ['l4', 'l8', 'l11', 'l13', 'l15']", + "152, cells. ['l5', 'l9', 'l12', 'l14', 'l15']", + "156, Bcl-xL ['l16']", + "157, transgenic ['l16']", + "188, C57BL/6 ['l17']", + "189, mice, ['l17']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "Cybb", + "NOX2)", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells." + ] + } + } + ] + }, + { + "PMID": "24784230", + "TEXT": "Huntington's disease (HD) is a fatal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion leading to an elongated polyglutamine stretch in huntingtin. Mutant huntingtin (mHTT) is ubiquitously expressed in all cells but elicits selective cortical and striatal neurodegeneration in HD. The mechanistic basis for such selective neuronal vulnerability remains unclear. A necessary step toward resolving this enigma is to define the cell types in which mHTT expression is causally linked to the disease pathogenesis. Using a conditional transgenic mouse model of HD, in which the mice express full-length human mHTT from a bacterial artificial chromosome transgene (BACHD), we genetically reduced mHTT expression in neuronal populations in the striatum, cortex or both. We show that reduction of cortical mHTT expression in BACHD mice partially improves motor and psychiatric-like behavioral deficits but does not improve neurodegeneration, whereas reduction of mHTT expression in both neuronal populations consistently ameliorates all behavioral deficits and selective brain atrophy in this HD model. Furthermore, whereas reduction of mHTT expression in cortical or striatal neurons partially ameliorates corticostriatal synaptic deficits, further restoration of striatal synaptic function can be achieved by reduction of mHTT expression in both neuronal cell types. Our study demonstrates distinct but interacting roles of cortical and striatal mHTT in HD pathogenesis and suggests that optimal HD therapeutics may require targeting mHTT in both cortical and striatal neurons.", + "TAG_DATA": [ + "78, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "79, transgenic {'perturbing_action': 'I-gene loss-of-function'}", + "80, mouse {'context': 'I-organism'}", + "81, model {'context': 'I-organism'}", + "87, mice {'context': 'B-organism'}", + "94, bacterial {'perturbing_action': 'I-gene loss-of-function'}", + "95, artificial {'perturbing_action': 'I-gene loss-of-function'}", + "96, chromosome {'perturbing_action': 'I-gene loss-of-function'}", + "97, transgene {'perturbing_action': 'I-gene loss-of-function'}", + "98, (BACHD), {'perturbing_action': 'I-gene loss-of-function'}", + "101, reduced {'perturbing_action': 'I-gene loss-of-function'}", + "102, mHTT {'perturbing_action': 'I-rnai/knockdown'}", + "105, neuronal {'context': 'B-cells'}", + "106, populations {'context': 'I-cells'}", + "107, in {'context': 'I-cells'}", + "108, the {'context': 'I-cells'}", + "109, striatum, {'context': 'I-cells'}", + "110, cortex {'context': 'I-cells'}", + "116, reduction {'perturbing_action': 'B-other'}", + "117, of {'perturbing_action': 'I-rnai/knockdown'}", + "118, cortical {'perturbing_action': 'I-rnai/knockdown'}", + "119, mHTT {'perturbing_action': 'I-rnai/knockdown'}", + "120, expression {'perturbing_action': 'I-rnai/knockdown'}", + "123, mice {'context': 'B-organism'}", + "137, reduction {'perturbing_action': 'B-other'}", + "138, of {'perturbing_action': 'I-other'}", + "139, mHTT {'perturbing_action': 'I-other'}", + "140, expression {'perturbing_action': 'I-rnai/knockdown'}", + "143, neuronal {'context': 'B-cells'}", + "144, populations {'context': 'I-cells'}", + "160, reduction {'perturbing_action': 'B-gene loss-of-function'}", + "161, of {'perturbing_action': 'I-rnai/knockdown'}", + "162, mHTT {'perturbing_action': 'I-rnai/knockdown'}", + "163, expression {'perturbing_action': 'I-rnai/knockdown'}", + "165, cortical {'context': 'B-cells'}", + "166, or {'context': 'I-cells'}", + "167, striatal {'context': 'I-cells'}", + "168, neurons {'context': 'I-cells'}", + "184, reduction {'perturbing_action': 'B-gene loss-of-function'}", + "185, of {'perturbing_action': 'I-rnai/knockdown'}", + "186, mHTT {'perturbing_action': 'I-rnai/knockdown'}", + "187, expression {'perturbing_action': 'I-rnai/knockdown'}", + "190, neuronal {'context': 'B-cells'}", + "191, cell {'context': 'I-cells'}", + "192, types. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "78, conditional ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "79, transgenic ['l0', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "80, mouse ['l1', 'l24', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "81, model ['l2', 'l25', 'l42', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "82, of ['l3', 'l26', 'l43', 'l59', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "83, HD, ['l4', 'l27', 'l44', 'l60', 'l75', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "87, mice ['l5', 'l28', 'l45', 'l61', 'l76', 'l89', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "90, human ['l6', 'l29', 'l46', 'l62', 'l77', 'l90', 'l100', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "91, mHTT ['l7', 'l30', 'l47', 'l63', 'l78', 'l91', 'l101', 'l121', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "92, from ['l8', 'l31', 'l48', 'l64', 'l79', 'l92', 'l102', 'l122', 'l144', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186']", + "93, a ['l9', 'l32', 'l49', 'l65', 'l103', 'l123', 'l145', 'l166', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206']", + "94, bacterial ['l10', 'l104', 'l124', 'l146', 'l167', 'l187', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225']", + "95, artificial ['l11', 'l105', 'l125', 'l147', 'l168', 'l188', 'l207', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243']", + "96, chromosome ['l12', 'l33', 'l50', 'l66', 'l80', 'l106', 'l126', 'l148', 'l169', 'l189', 'l208', 'l226', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260']", + "97, transgene ['l13', 'l34', 'l51', 'l67', 'l81', 'l107', 'l127', 'l149', 'l170', 'l190', 'l209', 'l227', 'l244', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276']", + "98, (BACHD), ['l14', 'l35', 'l52', 'l68', 'l82', 'l93', 'l108', 'l128', 'l150', 'l171', 'l191', 'l210', 'l228', 'l245', 'l261', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291']", + "101, reduced ['l15', 'l36', 'l53', 'l69', 'l83', 'l94', 'l109', 'l129', 'l151', 'l172', 'l192', 'l211', 'l229', 'l246', 'l262', 'l277', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304', 'l305']", + "102, mHTT ['l16', 'l110', 'l130', 'l152', 'l173', 'l193', 'l212', 'l230', 'l247', 'l263', 'l278', 'l292', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315', 'l316', 'l317', 'l318']", + "103, expression ['l17', 'l111', 'l131', 'l153', 'l174', 'l194', 'l213', 'l231', 'l248', 'l264', 'l279', 'l293', 'l306', 'l319', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327', 'l328', 'l329', 'l330']", + "105, neuronal ['l18', 'l112', 'l132', 'l154', 'l175', 'l195', 'l214', 'l232', 'l249', 'l265', 'l280', 'l294', 'l307', 'l319', 'l331', 'l332', 'l333', 'l334', 'l335', 'l336', 'l337', 'l338', 'l339', 'l340', 'l341']", + "106, populations ['l19', 'l37', 'l54', 'l70', 'l84', 'l95', 'l113', 'l133', 'l155', 'l176', 'l196', 'l215', 'l233', 'l250', 'l266', 'l281', 'l295', 'l308', 'l320', 'l331', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348', 'l349', 'l350', 'l351']", + "107, in ['l20', 'l38', 'l55', 'l71', 'l85', 'l96', 'l114', 'l134', 'l156', 'l177', 'l197', 'l216', 'l234', 'l251', 'l267', 'l282', 'l296', 'l309', 'l321', 'l332', 'l342', 'l352', 'l353', 'l354', 'l355', 'l356', 'l357', 'l358', 'l359', 'l360']", + "108, the ['l21', 'l39', 'l56', 'l72', 'l86', 'l97', 'l115', 'l135', 'l157', 'l178', 'l198', 'l217', 'l235', 'l252', 'l268', 'l283', 'l297', 'l310', 'l322', 'l333', 'l343', 'l352', 'l361', 'l362', 'l363', 'l364', 'l365', 'l366', 'l367', 'l368']", + "109, striatum, ['l22', 'l40', 'l57', 'l73', 'l87', 'l98', 'l116', 'l136', 'l158', 'l179', 'l199', 'l218', 'l236', 'l253', 'l269', 'l284', 'l298', 'l311', 'l323', 'l334', 'l344', 'l353', 'l361', 'l369', 'l370', 'l371', 'l372', 'l373', 'l374', 'l375']", + "110, cortex ['l23', 'l41', 'l58', 'l74', 'l88', 'l99', 'l117', 'l137', 'l159', 'l180', 'l200', 'l219', 'l237', 'l254', 'l270', 'l285', 'l299', 'l312', 'l324', 'l335', 'l345', 'l354', 'l362', 'l369', 'l376', 'l377']", + "116, reduction ['l138', 'l160', 'l181', 'l201', 'l220', 'l238', 'l255', 'l271', 'l286', 'l300', 'l313', 'l325', 'l336', 'l346', 'l355', 'l363', 'l370', 'l378', 'l379', 'l380', 'l381', 'l382']", + "117, of ['l118', 'l139', 'l161', 'l182', 'l202', 'l221', 'l239', 'l256', 'l272', 'l287', 'l301', 'l314', 'l326', 'l337', 'l347', 'l356', 'l364', 'l371', 'l376', 'l378', 'l383', 'l384', 'l385', 'l386']", + "118, cortical ['l119', 'l140', 'l162', 'l183', 'l203', 'l222', 'l240', 'l257', 'l273', 'l288', 'l302', 'l315', 'l327', 'l338', 'l348', 'l357', 'l365', 'l372', 'l379', 'l383', 'l387', 'l388', 'l389']", + "119, mHTT ['l141', 'l163', 'l184', 'l204', 'l223', 'l241', 'l258', 'l274', 'l289', 'l303', 'l316', 'l328', 'l339', 'l349', 'l358', 'l366', 'l373', 'l380', 'l384', 'l387', 'l390', 'l391']", + "120, expression ['l142', 'l164', 'l185', 'l205', 'l224', 'l242', 'l259', 'l275', 'l290', 'l304', 'l317', 'l329', 'l340', 'l350', 'l359', 'l367', 'l374', 'l381', 'l385', 'l388', 'l390', 'l392']", + "123, mice ['l120', 'l143', 'l165', 'l186', 'l206', 'l225', 'l243', 'l260', 'l276', 'l291', 'l305', 'l318', 'l330', 'l341', 'l351', 'l360', 'l368', 'l375', 'l377', 'l382', 'l386', 'l389', 'l391', 'l392']", + "137, reduction ['l393', 'l394', 'l395', 'l396', 'l397', 'l398', 'l399', 'l400', 'l401']", + "138, of ['l393', 'l402', 'l403', 'l404', 'l405', 'l406', 'l407']", + "139, mHTT ['l394', 'l402', 'l408', 'l409', 'l410', 'l411']", + "140, expression ['l395', 'l403', 'l408', 'l412', 'l413', 'l414']", + "142, both ['l396', 'l404', 'l409', 'l412', 'l415', 'l416']", + "143, neuronal ['l397', 'l405', 'l410', 'l413', 'l415', 'l417']", + "144, populations ['l398', 'l406', 'l411', 'l414', 'l416', 'l417']", + "160, reduction ['l418', 'l419', 'l420', 'l421', 'l422', 'l423', 'l424']", + "161, of ['l418', 'l425', 'l426', 'l427', 'l428', 'l429', 'l430']", + "162, mHTT ['l419', 'l425', 'l431', 'l432', 'l433', 'l434', 'l435']", + "163, expression ['l420', 'l426', 'l431', 'l436', 'l437', 'l438', 'l439']", + "165, cortical ['l399', 'l421', 'l427', 'l432', 'l436', 'l440', 'l441', 'l442']", + "166, or ['l422', 'l428', 'l433', 'l437', 'l440', 'l443', 'l444']", + "167, striatal ['l400', 'l423', 'l429', 'l434', 'l438', 'l441', 'l443', 'l445']", + "168, neurons ['l401', 'l407', 'l424', 'l430', 'l435', 'l439', 'l442', 'l444', 'l445']", + "184, reduction ['l446', 'l447', 'l448', 'l449', 'l450', 'l451']", + "185, of ['l446', 'l452', 'l453', 'l454', 'l455', 'l456']", + "186, mHTT ['l447', 'l452', 'l457', 'l458', 'l459', 'l460']", + "187, expression ['l448', 'l453', 'l457', 'l461', 'l462', 'l463']", + "190, neuronal ['l449', 'l454', 'l458', 'l461', 'l464', 'l465']", + "191, cell ['l450', 'l455', 'l459', 'l462', 'l464', 'l466']", + "192, types. ['l451', 'l456', 'l460', 'l463', 'l465', 'l466']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "transgenic", + "chromosome", + "transgene", + "(BACHD),", + "reduced", + "bacterial", + "artificial" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "transgenic", + "bacterial", + "artificial", + "chromosome", + "transgene", + "(BACHD),", + "reduced", + "reduction" + ] + }, + "context": { + "val": "cells", + "words": [ + "neuronal", + "populations", + "in", + "the", + "striatum,", + "cortex", + "cortical", + "or", + "striatal", + "neurons", + "cell", + "types." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "mHTT", + "of", + "cortical", + "expression" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "mHTT", + "of", + "cortical", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "neuronal", + "populations", + "in", + "the", + "striatum,", + "cortex", + "cortical", + "or", + "striatal", + "neurons", + "cell", + "types." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neuronal", + "populations", + "in", + "the", + "striatum,", + "cortical", + "striatal", + "neurons" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "reduction", + "of", + "mHTT" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "reduction" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "24658077", + "TEXT": "The pathophysiology of ineffective erythropoiesis in β-thalassemia is poorly understood. We report that RAP-011, an activin receptor IIA (ActRIIA) ligand trap, improved ineffective erythropoiesis, corrected anemia and limited iron overload in a mouse model of β-thalassemia intermedia. Expression of growth differentiation factor 11 (GDF11), an ActRIIA ligand, was increased in splenic erythroblasts from thalassemic mice and in erythroblasts and sera from subjects with β-thalassemia. Inactivation of GDF11 decreased oxidative stress and the amount of α-globin membrane precipitates, resulting in increased terminal erythroid differentiation. Abnormal GDF11 expression was dependent on reactive oxygen species, suggesting the existence of an autocrine amplification loop in β-thalassemia. GDF11 inactivation also corrected the abnormal ratio of immature/mature erythroblasts by inducing apoptosis of immature erythroblasts through the Fas-Fas ligand pathway. Taken together, these observations suggest that ActRIIA ligand traps may have therapeutic relevance in β-thalassemia by suppressing the deleterious effects of GDF11, a cytokine which blocks terminal erythroid maturation through an autocrine amplification loop involving oxidative stress and α-globin precipitation.", + "TAG_DATA": [ + "32, mouse {'context': 'B-organism'}", + "33, model {'context': 'I-organism'}", + "34, of {'context': 'I-organism'}", + "35, β-thalassemia {'context': 'I-organism'}", + "36, intermedia. {'context': 'I-organism'}", + "50, splenic {'context': 'B-cells'}", + "51, erythroblasts {'context': 'I-cells'}", + "57, erythroblasts {'context': 'B-cells'}", + "64, Inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "65, of {'perturbing_action': 'I-gene loss-of-function'}", + "66, GDF11 {'perturbing_action': 'I-gene loss-of-function'}", + "79, increased {'effect': 'B-positive'}", + "80, terminal {'phenotype': 'B-differentiation'}", + "81, erythroid {'phenotype': 'I-differentiation'}", + "82, differentiation. {'phenotype': 'I-differentiation'}", + "102, GDF11 {'perturbing_action': 'B-gene loss-of-function'}", + "103, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "110, immature/mature {'context': 'B-cells'}", + "111, erythroblasts {'context': 'I-cells'}", + "113, inducing {'effect': 'B-positive'}", + "114, apoptosis {'phenotype': 'B-apoptosis'}", + "116, immature {'context': 'B-cells'}", + "117, erythroblasts {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "32, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "33, model ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "34, of ['l1', 'l9', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "35, β-thalassemia ['l2', 'l10', 'l18', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "36, intermedia. ['l3', 'l11', 'l19', 'l27', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "50, splenic ['l4', 'l12', 'l20', 'l28', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "51, erythroblasts ['l5', 'l13', 'l21', 'l29', 'l37', 'l42', 'l47', 'l48', 'l49']", + "57, erythroblasts ['l22', 'l30', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "64, Inactivation ['l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "65, of ['l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "66, GDF11 ['l31', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "79, increased ['l6', 'l14', 'l23', 'l32', 'l38', 'l43', 'l47', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "80, terminal ['l7', 'l15', 'l24', 'l33', 'l39', 'l44', 'l48', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "81, erythroid ['l16', 'l25', 'l34', 'l40', 'l45', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "82, differentiation. ['l8', 'l17', 'l26', 'l35', 'l41', 'l46', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "102, GDF11 ['l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "103, inactivation ['l78', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "110, immature/mature ['l79', 'l85', 'l91']", + "111, erythroblasts ['l80', 'l86', 'l91']", + "113, inducing ['l81', 'l87', 'l92', 'l93', 'l94']", + "114, apoptosis ['l82', 'l88', 'l92', 'l95', 'l96']", + "116, immature ['l83', 'l89', 'l93', 'l95', 'l97']", + "117, erythroblasts ['l84', 'l90', 'l94', 'l96', 'l97']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "β-thalassemia", + "intermedia." + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "β-thalassemia", + "intermedia." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "terminal", + "differentiation.", + "erythroid" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "β-thalassemia" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "GDF11" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "splenic", + "erythroblasts", + "immature" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "inducing" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "splenic", + "erythroblasts" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "terminal", + "erythroid", + "differentiation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "erythroblasts", + "immature/mature", + "immature" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Inactivation", + "of", + "GDF11", + "inactivation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Inactivation", + "of", + "GDF11", + "inactivation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "inducing" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Inactivation", + "of", + "GDF11" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "terminal", + "erythroid", + "differentiation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "terminal", + "erythroid", + "differentiation." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "GDF11", + "inactivation" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "immature", + "erythroblasts" + ] + } + } + ] + }, + { + "PMID": "24531379", + "TEXT": "Skeletal muscle aging results in a gradual loss of skeletal muscle mass, skeletal muscle function and regenerative capacity, which can lead to sarcopenia and increased mortality. Although the mechanisms underlying sarcopenia remain unclear, the skeletal muscle stem cell, or satellite cell, is required for muscle regeneration. Therefore, identification of signaling pathways affecting satellite cell function during aging may provide insights into therapeutic targets for combating sarcopenia. Here, we show that a cell-autonomous loss in self-renewal occurs via alterations in fibroblast growth factor receptor-1, p38α and p38β mitogen-activated protein kinase signaling in satellite cells from aged mice. We further demonstrate that pharmacological manipulation of these pathways can ameliorate age-associated self-renewal defects. Thus, our data highlight an age-associated deregulation of a satellite cell homeostatic network and reveal potential therapeutic opportunities for the treatment of progressive muscle wasting.", + "TAG_DATA": [ + "72, loss {'effect': 'B-negative'}", + "74, self-renewal {'phenotype': 'B-self-renewal'}", + "91, satellite {'context': 'B-cells'}", + "92, cells {'context': 'I-cells'}", + "94, aged {'context': 'B-organism'}", + "95, mice. {'context': 'I-organism'}", + "106, ameliorate {'effect': 'B-negative'}", + "108, self-renewal {'phenotype': 'B-self-renewal'}", + "109, defects. {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "72, loss ['l0', 'l1', 'l2', 'l3', 'l4']", + "74, self-renewal ['l0', 'l5', 'l6', 'l7', 'l8']", + "91, satellite ['l1', 'l5', 'l9', 'l10', 'l11']", + "92, cells ['l2', 'l6', 'l9', 'l12', 'l13']", + "94, aged ['l3', 'l7', 'l10', 'l12', 'l14']", + "95, mice. ['l4', 'l8', 'l11', 'l13', 'l14']", + "106, ameliorate ['l15', 'l16']", + "108, self-renewal ['l15', 'l17']", + "109, defects. ['l16', 'l17']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "loss", + "ameliorate", + "defects." + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "loss" + ] + }, + "context": { + "val": "cells", + "words": [ + "satellite", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "loss" + ] + }, + "context": { + "val": "organism", + "words": [ + "aged", + "mice." + ] + } + }, + { + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal" + ] + }, + "context": { + "val": "cells", + "words": [ + "satellite", + "cells" + ] + } + }, + { + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renewal" + ] + }, + "context": { + "val": "organism", + "words": [ + "aged", + "mice." + ] + } + } + ] + }, + { + "PMID": "24487434", + "TEXT": "Loss of function of the tumor suppressor gene PRDM1 (also known as BLIMP1) or deregulated expression of the oncogene BCL6 occurs in a large proportion of diffuse large B cell lymphoma (DLBCL) cases. However, targeted mutation of either gene in mice leads to only slow and infrequent development of malignant lymphoma, and despite frequent mutation of BCL6 in activated B cells of healthy individuals, lymphoma development is rare. Here we show that T cells prevent the development of overt lymphoma in mice caused by Blimp1 deficiency or overexpression of Bcl6 in the B cell lineage. Impairment of T cell control results in rapid development of DLBCL-like disease, which can be eradicated by polyclonal CD8(+) T cells in a T cell receptor-, CD28- and Fas ligand-dependent manner. Thus, malignant transformation of mature B cells requires mutations that impair intrinsic differentiation processes and permit escape from T cell-mediated tumor surveillance.", + "TAG_DATA": [ + "72, T {'context': 'B-cells'}", + "73, cells {'context': 'B-cells'}", + "74, prevent {'effect': 'B-negative'}", + "79, lymphoma {'phenotype': 'B-tumourigenesis'}", + "81, mice {'context': 'B-organism'}", + "84, Blimp1 {'perturbing_action': 'B-gene loss-of-function'}", + "85, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "87, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "88, of {'perturbing_action': 'I-gene gain-of-function'}", + "89, Bcl6 {'perturbing_action': 'I-gene gain-of-function'}", + "91, the {'perturbing_action': 'I-gene gain-of-function'}", + "92, B {'context': 'B-cells'}", + "93, cell {'context': 'I-cells'}", + "94, lineage. {'context': 'I-cells'}", + "113, CD8(+) {'context': 'B-cells'}", + "114, T {'context': 'I-cells'}", + "115, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "72, T ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "73, cells ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "74, prevent ['l1', 'l11', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "76, development ['l2', 'l12', 'l20', 'l32', 'l33', 'l34', 'l35', 'l36']", + "79, lymphoma ['l3', 'l13', 'l21', 'l32', 'l37', 'l38', 'l39', 'l40']", + "81, mice ['l4', 'l14', 'l22', 'l33', 'l37', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "84, Blimp1 ['l5', 'l15', 'l23', 'l34', 'l38', 'l41', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "85, deficiency ['l6', 'l16', 'l24', 'l35', 'l39', 'l42', 'l48', 'l56', 'l57', 'l58', 'l59']", + "87, overexpression ['l25', 'l49', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "88, of ['l26', 'l43', 'l50', 'l60', 'l66', 'l67', 'l68', 'l69', 'l70']", + "89, Bcl6 ['l27', 'l51', 'l61', 'l66', 'l71', 'l72', 'l73', 'l74']", + "91, the ['l7', 'l28', 'l44', 'l52', 'l56', 'l62', 'l67', 'l71', 'l75', 'l76', 'l77']", + "92, B ['l8', 'l17', 'l29', 'l45', 'l53', 'l57', 'l63', 'l68', 'l72', 'l75', 'l78', 'l79']", + "93, cell ['l9', 'l18', 'l30', 'l36', 'l40', 'l46', 'l54', 'l58', 'l64', 'l69', 'l73', 'l76', 'l78', 'l80']", + "94, lineage. ['l10', 'l19', 'l31', 'l47', 'l55', 'l59', 'l65', 'l70', 'l74', 'l77', 'l79', 'l80']", + "113, CD8(+) ['l81', 'l82']", + "114, T ['l81', 'l83']", + "115, cells ['l82', 'l83']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "B", + "cell", + "lineage." + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "cell" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "B", + "cell", + "lineage." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Blimp1", + "deficiency" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "B", + "cell", + "lineage." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "the", + "overexpression", + "of", + "Bcl6" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Blimp1", + "deficiency" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Bcl6", + "the" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphoma" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Blimp1", + "deficiency" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Blimp1", + "deficiency" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "the" + ] + } + } + ] + }, + { + "PMID": "24441829", + "TEXT": "Fatty acids are integral mediators of energy storage, membrane formation and cell signaling. The pathways that orchestrate uptake of fatty acids remain incompletely understood. Expression of the integrin ligand Mfge8 is increased in human obesity and in mice on a high-fat diet, but its role in obesity is unknown. We show here that Mfge8 promotes the absorption of dietary triglycerides and the cellular uptake of fatty acid and that Mfge8-deficient (Mfge8(-/-)) mice are protected from diet-induced obesity, steatohepatitis and insulin resistance. Mechanistically, we found that Mfge8 coordinates fatty acid uptake through αvβ3 integrin- and αvβ5 integrin-dependent phosphorylation of Akt by phosphatidylinositide-3 kinase and mTOR complex 2, leading to translocation of Cd36 and Fatp1 from cytoplasmic vesicles to the cell surface. Collectively, our results imply a role for Mfge8 in regulating the absorption and storage of dietary fats, as well as in the development of obesity and its complications.", + "TAG_DATA": [ + "69, Mfge8-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "70, (Mfge8(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "71, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "69, Mfge8-deficient ['l0', 'l1']", + "70, (Mfge8(-/-)) ['l0', 'l2']", + "71, mice ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mfge8-deficient", + "(Mfge8(-/-))" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "24292392", + "TEXT": "Tumor recurrence following treatment remains a major clinical challenge. Evidence from xenograft models and human trials indicates selective enrichment of cancer-initiating cells (CICs) in tumors that survive therapy. Together with recent reports showing that CIC gene signatures influence patient survival, these studies predict that targeting self-renewal, the key 'stemness' property unique to CICs, may represent a new paradigm in cancer therapy. Here we demonstrate that tumor formation and, more specifically, human colorectal CIC function are dependent on the canonical self-renewal regulator BMI-1. Downregulation of BMI-1 inhibits the ability of colorectal CICs to self-renew, resulting in the abrogation of their tumorigenic potential. Treatment of primary colorectal cancer xenografts with a small-molecule BMI-1 inhibitor resulted in colorectal CIC loss with long-term and irreversible impairment of tumor growth. Targeting the BMI-1-related self-renewal machinery provides the basis for a new therapeutic approach in the treatment of colorectal cancer.", + "TAG_DATA": [ + "82, Downregulation {'perturbing_action': 'B-gene loss-of-function'}", + "83, of {'perturbing_action': 'I-gene loss-of-function'}", + "84, BMI-1 {'perturbing_action': 'I-gene loss-of-function'}", + "85, inhibits {'effect': 'B-negative'}", + "87, ability {'effect': 'I-negative'}", + "89, colorectal {'context': 'B-cells'}", + "90, CICs {'context': 'I-cells'}", + "92, self-renew, {'phenotype': 'B-self-renewal'}", + "96, abrogation {'effect': 'B-negative'}", + "99, tumorigenic {'phenotype': 'B-tumourigenesis'}", + "100, potential. {'phenotype': 'I-tumour initiation'}", + "103, primary {'context': 'B-xenograft'}", + "104, colorectal {'context': 'I-xenograft'}", + "105, cancer {'context': 'I-xenograft'}", + "106, xenografts {'context': 'I-xenograft'}", + "109, small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "110, BMI-1 {'perturbing_action': 'I-pharmacological inhibition'}", + "111, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "114, colorectal {'context': 'B-cells'}", + "115, CIC {'context': 'I-cells'}", + "121, impairment {'effect': 'B-negative'}", + "123, tumor {'phenotype': 'B-tumour growth'}", + "124, growth. {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "82, Downregulation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "83, of ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "84, BMI-1 ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "85, inhibits ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "87, ability ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "89, colorectal ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "90, CICs ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "92, self-renew, ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "96, abrogation ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "99, tumorigenic ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "100, potential. ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "103, primary ['l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "104, colorectal ['l55', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "105, cancer ['l56', 'l66', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "106, xenografts ['l57', 'l67', 'l76', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "109, small-molecule ['l58', 'l68', 'l77', 'l85', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "110, BMI-1 ['l59', 'l69', 'l78', 'l86', 'l93', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "111, inhibitor ['l60', 'l70', 'l79', 'l87', 'l94', 'l100', 'l106', 'l107', 'l108', 'l109', 'l110']", + "114, colorectal ['l61', 'l71', 'l80', 'l88', 'l95', 'l101', 'l106', 'l111', 'l112', 'l113', 'l114']", + "115, CIC ['l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l107', 'l111', 'l115', 'l116', 'l117']", + "121, impairment ['l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l108', 'l112', 'l115', 'l118', 'l119']", + "123, tumor ['l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l109', 'l113', 'l116', 'l118', 'l120']", + "124, growth. ['l65', 'l75', 'l84', 'l92', 'l99', 'l105', 'l110', 'l114', 'l117', 'l119', 'l120']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Downregulation", + "of", + "BMI-1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits", + "ability", + "abrogation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Downregulation", + "of", + "BMI-1" + ] + }, + "context": { + "val": "cells", + "words": [ + "colorectal", + "CICs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Downregulation", + "of", + "BMI-1" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renew," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Downregulation", + "of", + "BMI-1" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Downregulation", + "of", + "BMI-1" + ] + }, + "phenotype": { + "val": "tumour initiation", + "words": [ + "potential." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "ability", + "abrogation", + "impairment" + ] + }, + "context": { + "val": "cells", + "words": [ + "colorectal", + "CICs", + "CIC" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "ability", + "abrogation" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renew," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "ability", + "abrogation" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenic" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits", + "ability", + "abrogation" + ] + }, + "phenotype": { + "val": "tumour initiation", + "words": [ + "potential." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "colorectal", + "CICs" + ] + }, + "phenotype": { + "val": "self-renewal", + "words": [ + "self-renew," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "colorectal", + "CICs" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenic" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "colorectal", + "CICs" + ] + }, + "phenotype": { + "val": "tumour initiation", + "words": [ + "potential." + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "primary", + "colorectal", + "cancer", + "xenografts" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "BMI-1", + "inhibitor" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "primary", + "colorectal", + "cancer", + "xenografts" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impairment" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "primary", + "colorectal", + "cancer", + "xenografts" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "BMI-1", + "inhibitor" + ] + }, + "context": { + "val": "cells", + "words": [ + "colorectal", + "CIC" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "BMI-1", + "inhibitor" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impairment" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "BMI-1", + "inhibitor" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "colorectal", + "CIC" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impairment" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + } + ] + }, + { + "PMID": "24270546", + "TEXT": "Hepatitis C virus (HCV) is endemic in many countries due to its high propensity for establishing persistence. The presence of HCV-specific T cells in subjects repeatedly exposed to HCV who test negative for HCV RNA and antibodies and who do not have any history of HCV infection has been interpreted as T cell-mediated protection. Here, we show in nonhuman primates that repeated exposure to human plasma with trace amounts of HCV induced HCV-specific T cells without seroconversion and systemic viremia but did not protect upon subsequent HCV challenge. Rather, HCV-specific recall and de novo T cell responses, as well as intrahepatic T cell recruitment and interferon-γ (IFN-γ) production, were suppressed upon HCV challenge, concomitant with quantitative and qualitative changes in regulatory T cells (T(reg) cells) that occurred after subinfectious HCV exposure and increased after HCV challenge. In vitro T(reg) cell depletion restored HCV-specific T cell responses. Thus, T cells primed by trace amounts of HCV do not generate effective recall responses upon subsequent HCV infection. Subinfectious HCV exposure predisposes to T(reg) cell expansion, which suppresses effector T cells during subsequent infection. Strategies to reverse this exposure-induced immune suppression should be examined to aid in the development of T cell-based vaccines against HCV and other endemic pathogens.", + "TAG_DATA": [ + "58, nonhuman {'context': 'B-organism'}", + "59, primates {'context': 'I-organism'}", + "73, T {'context': 'B-cells'}", + "74, cells {'context': 'I-cells'}", + "94, T {'context': 'B-cells'}", + "95, cell {'context': 'B-cells'}", + "120, regulatory {'context': 'B-cells'}", + "121, T {'context': 'I-cells'}", + "122, cells {'context': 'I-cells'}", + "136, In {'context': 'B-in vitro'}", + "137, vitro {'context': 'I-in vitro'}", + "138, T(reg) {'context': 'B-cells'}", + "139, cell {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "140, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "143, T {'context': 'B-cells'}", + "144, cell {'context': 'B-cells'}", + "147, T {'context': 'B-cells'}", + "148, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "58, nonhuman ['l0', 'l1', 'l2', 'l3', 'l4']", + "59, primates ['l0', 'l5', 'l6', 'l7', 'l8']", + "73, T ['l1', 'l5', 'l9']", + "74, cells ['l2', 'l6', 'l9']", + "94, T ['l3', 'l7', 'l10']", + "95, cell ['l4', 'l8', 'l10']", + "120, regulatory ['l11', 'l12']", + "121, T ['l11', 'l13']", + "122, cells ['l12', 'l13']", + "136, In ['l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "137, vitro ['l14', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "138, T(reg) ['l15', 'l22', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "139, cell ['l16', 'l23', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "140, depletion ['l17', 'l24', 'l30', 'l35', 'l40', 'l41', 'l42', 'l43']", + "143, T ['l18', 'l25', 'l31', 'l36', 'l40', 'l44', 'l45', 'l46']", + "144, cell ['l19', 'l26', 'l32', 'l37', 'l41', 'l44']", + "147, T ['l20', 'l27', 'l33', 'l38', 'l42', 'l45', 'l47']", + "148, cells ['l21', 'l28', 'l34', 'l39', 'l43', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cell", + "depletion" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cell", + "depletion" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "T(reg)", + "T", + "cells" + ] + } + } + ] + }, + { + "PMID": "24270545", + "TEXT": "Activation of self-reactive T cells and their trafficking to target tissues leads to autoimmune organ destruction. Mice lacking the co-inhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) develop fatal autoimmunity characterized by lymphocytic infiltration into nonlymphoid tissues. Here, we demonstrate that the CD28 co-stimulatory pathway regulates the trafficking of self-reactive Ctla4(-/-) T cells to tissues. Concurrent ablation of the CD28-activated Tec family kinase ITK does not block spontaneous T cell activation but instead causes self-reactive Ctla4(-/-) T cells to accumulate in secondary lymphoid organs. Despite excessive spontaneous T cell activation and proliferation in lymphoid organs, Itk(-/-); Ctla4(-/-) mice are otherwise healthy, mount antiviral immune responses and exhibit a long lifespan. We propose that ITK specifically licenses autoreactive T cells to enter tissues to mount destructive immune responses. Notably, ITK inhibitors mimic the null mutant phenotype and also prevent pancreatic islet infiltration by diabetogenic T cells in mouse models of type 1 diabetes, highlighting their potential utility for the treatment of human autoimmune disorders.", + "TAG_DATA": [ + "55, ablation {'perturbing_action': 'B-gene loss-of-function'}", + "56, of {'perturbing_action': 'I-gene loss-of-function'}", + "57, the {'perturbing_action': 'I-gene loss-of-function'}", + "58, CD28-activated {'perturbing_action': 'I-gene loss-of-function'}", + "59, Tec {'perturbing_action': 'I-gene loss-of-function'}", + "60, family {'perturbing_action': 'I-gene loss-of-function'}", + "61, kinase {'perturbing_action': 'I-gene loss-of-function'}", + "62, ITK {'perturbing_action': 'I-gene loss-of-function'}", + "67, T {'context': 'B-cells'}", + "68, cell {'context': 'B-cells'}", + "74, Ctla4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "75, T {'context': 'B-cells'}", + "76, cells {'context': 'B-cells'}", + "80, secondary {'context': 'B-tissue/organ'}", + "81, lymphoid {'context': 'I-tissue/organ'}", + "82, organs. {'context': 'I-tissue/organ'}", + "86, T {'context': 'B-cells'}", + "87, cell {'context': 'B-cells'}", + "90, proliferation {'phenotype': 'B-proliferation'}", + "92, lymphoid {'context': 'B-tissue/organ'}", + "93, organs, {'context': 'I-tissue/organ'}", + "94, Itk(-/-); {'perturbing_action': 'B-gene loss-of-function'}", + "95, Ctla4(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "96, mice {'context': 'B-organism'}", + "127, ITK {'perturbing_action': 'B-pharmacological inhibition'}", + "128, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "137, pancreatic {'context': 'B-cells'}", + "141, diabetogenic {'context': 'B-cells'}", + "142, T {'context': 'I-cells'}", + "143, cells {'context': 'I-cells'}", + "145, mouse {'context': 'B-organism'}", + "146, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "55, ablation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "56, of ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "57, the ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "58, CD28-activated ['l2', 'l21', 'l39', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "59, Tec ['l3', 'l22', 'l40', 'l57', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "60, family ['l4', 'l23', 'l41', 'l58', 'l74', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "61, kinase ['l5', 'l24', 'l42', 'l59', 'l75', 'l90', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "62, ITK ['l6', 'l25', 'l43', 'l60', 'l76', 'l91', 'l105', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "67, T ['l7', 'l26', 'l44', 'l61', 'l77', 'l92', 'l106', 'l119', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "68, cell ['l8', 'l27', 'l45', 'l62', 'l78', 'l93', 'l107', 'l120', 'l132', 'l138', 'l139', 'l140', 'l141', 'l142']", + "74, Ctla4(-/-) ['l9', 'l28', 'l46', 'l63', 'l79', 'l94', 'l108', 'l121', 'l143', 'l144', 'l145', 'l146', 'l147']", + "75, T ['l10', 'l29', 'l47', 'l64', 'l80', 'l95', 'l109', 'l122', 'l133', 'l138', 'l143', 'l148', 'l149', 'l150', 'l151']", + "76, cells ['l11', 'l30', 'l48', 'l65', 'l81', 'l96', 'l110', 'l123', 'l134', 'l139', 'l144', 'l148', 'l152', 'l153', 'l154']", + "80, secondary ['l12', 'l31', 'l49', 'l66', 'l82', 'l97', 'l111', 'l124', 'l135', 'l140', 'l145', 'l149', 'l152', 'l155', 'l156']", + "81, lymphoid ['l13', 'l32', 'l50', 'l67', 'l83', 'l98', 'l112', 'l125', 'l136', 'l141', 'l146', 'l150', 'l153', 'l155', 'l157']", + "82, organs. ['l14', 'l33', 'l51', 'l68', 'l84', 'l99', 'l113', 'l126', 'l137', 'l142', 'l147', 'l151', 'l154', 'l156', 'l157']", + "86, T ['l15', 'l34', 'l52', 'l69', 'l85', 'l100', 'l114', 'l127', 'l158', 'l159', 'l160', 'l161']", + "87, cell ['l16', 'l35', 'l53', 'l70', 'l86', 'l101', 'l115', 'l128', 'l158', 'l162', 'l163', 'l164']", + "90, proliferation ['l17', 'l36', 'l54', 'l71', 'l87', 'l102', 'l116', 'l129', 'l159', 'l162', 'l165', 'l166']", + "92, lymphoid ['l18', 'l37', 'l55', 'l72', 'l88', 'l103', 'l117', 'l130', 'l160', 'l163', 'l165', 'l167']", + "93, organs, ['l19', 'l38', 'l56', 'l73', 'l89', 'l104', 'l118', 'l131', 'l161', 'l164', 'l166', 'l167']", + "94, Itk(-/-); ['l168', 'l169']", + "95, Ctla4(-/-) ['l168', 'l170', 'l171', 'l172', 'l173']", + "96, mice ['l169', 'l170']", + "127, ITK ['l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181']", + "128, inhibitors ['l174', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "137, pancreatic ['l175', 'l182', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "138, islet ['l176', 'l183', 'l189', 'l195', 'l196', 'l197', 'l198', 'l199']", + "141, diabetogenic ['l177', 'l184', 'l190', 'l195', 'l200', 'l201', 'l202', 'l203']", + "142, T ['l171', 'l178', 'l185', 'l191', 'l196', 'l200', 'l204', 'l205', 'l206']", + "143, cells ['l172', 'l179', 'l186', 'l192', 'l197', 'l201', 'l204', 'l207', 'l208']", + "145, mouse ['l180', 'l187', 'l193', 'l198', 'l202', 'l205', 'l207', 'l209']", + "146, models ['l173', 'l181', 'l188', 'l194', 'l199', 'l203', 'l206', 'l208', 'l209']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablation", + "of", + "the", + "CD28-activated", + "Tec", + "family", + "kinase", + "ITK", + "Ctla4(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cell", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablation", + "of", + "the", + "CD28-activated", + "Tec", + "family", + "kinase", + "ITK", + "Ctla4(-/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "secondary", + "lymphoid", + "organs.", + "organs," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablation", + "of", + "the", + "CD28-activated", + "Tec", + "family", + "kinase", + "ITK" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lymphoid", + "organs," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Itk(-/-);", + "Ctla4(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "models" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ITK", + "inhibitors" + ] + }, + "context": { + "val": "cells", + "words": [ + "pancreatic", + "diabetogenic", + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ITK", + "inhibitors" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + } + } + ] + }, + { + "PMID": "24185692", + "TEXT": "The obesity epidemic has led to an increased incidence of nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. AMP-activated protein kinase (Ampk) regulates energy homeostasis and is activated by cellular stress, hormones and the widely prescribed type 2 diabetes drug metformin. Ampk phosphorylates mouse acetyl-CoA carboxylase 1 (Acc1; refs. 3,4) at Ser79 and Acc2 at Ser212, inhibiting the conversion of acetyl-CoA to malonyl-CoA. The latter metabolite is a precursor in fatty acid synthesis and an allosteric inhibitor of fatty acid transport into mitochondria for oxidation. To test the physiological impact of these phosphorylation events, we generated mice with alanine knock-in mutations in both Acc1 (at Ser79) and Acc2 (at Ser212) (Acc double knock-in, AccDKI). Compared to wild-type mice, these mice have elevated lipogenesis and lower fatty acid oxidation, which contribute to the progression of insulin resistance, glucose intolerance and NAFLD, but not obesity. Notably, AccDKI mice made obese by high-fat feeding are refractory to the lipid-lowering and insulin-sensitizing effects of metformin. These findings establish that inhibitory phosphorylation of Acc by Ampk is essential for the control of lipid metabolism and, in the setting of obesity, for metformin-induced improvements in insulin action.", + "TAG_DATA": [ + "97, mice {'context': 'B-organism'}", + "99, alanine {'perturbing_action': 'B-other'}", + "100, knock-in {'perturbing_action': 'I-gene loss-of-function'}", + "101, mutations {'perturbing_action': 'I-gene loss-of-function'}", + "102, in {'perturbing_action': 'I-gene loss-of-function'}", + "103, both {'perturbing_action': 'I-rnai/knockdown'}", + "104, Acc1 {'perturbing_action': 'I-rnai/knockdown'}", + "105, (at {'perturbing_action': 'I-rnai/knockdown'}", + "106, Ser79) {'perturbing_action': 'I-rnai/knockdown'}", + "107, and {'perturbing_action': 'I-gene loss-of-function'}", + "108, Acc2 {'perturbing_action': 'I-rnai/knockdown'}", + "109, (at {'perturbing_action': 'I-rnai/knockdown'}", + "110, Ser212) {'perturbing_action': 'I-gene loss-of-function'}", + "111, (Acc {'perturbing_action': 'I-gene loss-of-function'}", + "112, double {'perturbing_action': 'I-gene loss-of-function'}", + "113, knock-in, {'perturbing_action': 'I-gene loss-of-function'}", + "114, AccDKI). {'perturbing_action': 'I-gene loss-of-function'}", + "120, mice {'context': 'B-organism'}", + "145, AccDKI {'perturbing_action': 'B-other'}", + "146, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "97, mice ['l0']", + "99, alanine ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "100, knock-in ['l1', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "101, mutations ['l2', 'l17', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "102, in ['l3', 'l18', 'l32', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "103, both ['l4', 'l19', 'l33', 'l46', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "104, Acc1 ['l5', 'l20', 'l34', 'l47', 'l59', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "105, (at ['l6', 'l21', 'l35', 'l48', 'l60', 'l71', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "106, Ser79) ['l7', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "107, and ['l8', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "108, Acc2 ['l9', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "109, (at ['l10', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "110, Ser212) ['l11', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l122', 'l123', 'l124', 'l125', 'l126']", + "111, (Acc ['l12', 'l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l127', 'l128', 'l129', 'l130']", + "112, double ['l13', 'l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l97', 'l105', 'l112', 'l118', 'l123', 'l127', 'l131', 'l132', 'l133']", + "113, knock-in, ['l14', 'l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l98', 'l106', 'l113', 'l119', 'l124', 'l128', 'l131', 'l134', 'l135']", + "114, AccDKI). ['l15', 'l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l99', 'l107', 'l114', 'l120', 'l125', 'l129', 'l132', 'l134', 'l136']", + "120, mice ['l0', 'l16', 'l31', 'l45', 'l58', 'l70', 'l81', 'l91', 'l100', 'l108', 'l115', 'l121', 'l126', 'l130', 'l133', 'l135', 'l136']", + "145, AccDKI ['l137']", + "146, mice ['l137']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "alanine", + "AccDKI" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knock-in", + "mutations", + "in", + "and", + "Ser212)", + "(Acc", + "double", + "knock-in,", + "AccDKI)." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "both", + "Acc1", + "(at", + "Ser79)", + "Acc2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "24162813", + "TEXT": "Like their normal hematopoietic stem cell counterparts, leukemia stem cells (LSCs) in chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) are presumed to reside in specific niches in the bone marrow microenvironment (BMM) and may be the cause of relapse following chemotherapy. Targeting the niche is a new strategy to eliminate persistent and drug-resistant LSCs. CD44 (refs. 3,4) and interleukin-6 (ref. 5) have been implicated previously in the LSC niche. Transforming growth factor-β1 (TGF-β1) is released during bone remodeling and plays a part in maintenance of CML LSCs, but a role for TGF-β1 from the BMM has not been defined. Here, we show that alteration of the BMM by osteoblastic cell-specific activation of the parathyroid hormone (PTH) receptor attenuates BCR-ABL1 oncogene-induced CML-like myeloproliferative neoplasia (MPN) but enhances MLL-AF9 oncogene-induced AML in mouse transplantation models, possibly through opposing effects of increased TGF-β1 on the respective LSCs. PTH treatment caused a 15-fold decrease in LSCs in wild-type mice with CML-like MPN and reduced engraftment of immune-deficient mice with primary human CML cells. These results demonstrate that LSC niches in CML and AML are distinct and suggest that modulation of the BMM by PTH may be a feasible strategy to reduce LSCs, a prerequisite for the cure of CML.", + "TAG_DATA": [ + "110, osteoblastic {'perturbing_action': 'B-pharmacological augmentation'}", + "111, cell-specific {'perturbing_action': 'I-pharmacological augmentation'}", + "112, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "113, of {'perturbing_action': 'I-pharmacological augmentation'}", + "114, the {'perturbing_action': 'I-pharmacological augmentation'}", + "115, parathyroid {'perturbing_action': 'I-pharmacological augmentation'}", + "116, hormone {'perturbing_action': 'I-pharmacological augmentation'}", + "117, (PTH) {'perturbing_action': 'I-pharmacological augmentation'}", + "118, receptor {'perturbing_action': 'I-pharmacological augmentation'}", + "127, enhances {'effect': 'B-positive'}", + "130, AML {'phenotype': 'B-differentiation'}", + "132, mouse {'context': 'B-organism'}", + "133, transplantation {'context': 'I-organism'}", + "134, models, {'context': 'I-xenograft'}", + "156, mice {'context': 'B-organism'}", + "164, immune-deficient {'perturbing_action': 'B-gene loss-of-function', 'context': 'B-organism'}", + "165, mice {'context': 'I-organism'}", + "167, primary {'context': 'B-transformed cells'}", + "168, human {'context': 'I-transformed cells'}", + "169, CML {'context': 'I-transformed cells'}", + "170, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "110, osteoblastic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "111, cell-specific ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "112, activation ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "113, of ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "114, the ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "115, parathyroid ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "116, hormone ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "117, (PTH) ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "118, receptor ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "127, enhances ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "130, AML ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "132, mouse ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "133, transplantation ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "134, models, ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']", + "164, immune-deficient ['l91', 'l92', 'l93', 'l94', 'l95']", + "165, mice ['l91', 'l96', 'l97', 'l98', 'l99']", + "167, primary ['l92', 'l96', 'l100', 'l101', 'l102']", + "168, human ['l93', 'l97', 'l100', 'l103', 'l104']", + "169, CML ['l94', 'l98', 'l101', 'l103', 'l105']", + "170, cells. ['l95', 'l99', 'l102', 'l104', 'l105']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "osteoblastic", + "cell-specific", + "activation", + "of", + "the", + "parathyroid", + "hormone", + "(PTH)", + "receptor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "osteoblastic", + "cell-specific", + "activation", + "of", + "the", + "parathyroid", + "hormone", + "(PTH)", + "receptor" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "AML" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "osteoblastic", + "cell-specific", + "activation", + "of", + "the", + "parathyroid", + "hormone", + "(PTH)", + "receptor" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "transplantation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "osteoblastic", + "cell-specific", + "activation", + "of", + "the", + "parathyroid", + "hormone", + "(PTH)", + "receptor" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "models," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "AML" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "transplantation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "models," + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "AML" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "transplantation" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "AML" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "models," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immune-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "immune-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immune-deficient" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "human", + "CML", + "cells." + ] + } + } + ] + }, + { + "PMID": "24141422", + "TEXT": "Fragile X syndrome (FXS), the most common cause of inherited mental retardation and autism, is caused by transcriptional silencing of FMR1, which encodes the translational repressor fragile X mental retardation protein (FMRP). FMRP and cytoplasmic polyadenylation element-binding protein (CPEB), an activator of translation, are present in neuronal dendrites, are predicted to bind many of the same mRNAs and may mediate a translational homeostasis that, when imbalanced, results in FXS. Consistent with this possibility, Fmr1(-/y); Cpeb1(-/-) double-knockout mice displayed amelioration of biochemical, morphological, electrophysiological and behavioral phenotypes associated with FXS. Acute depletion of CPEB1 in the hippocampus of adult Fmr1(-/y) mice rescued working memory deficits, demonstrating reversal of this FXS phenotype. Finally, we find that FMRP and CPEB1 balance translation at the level of polypeptide elongation. Our results suggest that disruption of translational homeostasis is causal for FXS and that the maintenance of this homeostasis by FMRP and CPEB1 is necessary for normal neurologic function.", + "TAG_DATA": [ + "73, Fmr1(-/y); {'perturbing_action': 'B-gene loss-of-function'}", + "74, Cpeb1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "75, double-knockout {'perturbing_action': 'I-gene loss-of-function'}", + "76, mice {'context': 'B-organism'}", + "89, Acute {'perturbing_action': 'B-gene loss-of-function'}", + "90, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "91, of {'perturbing_action': 'I-gene loss-of-function'}", + "92, CPEB1 {'perturbing_action': 'I-gene loss-of-function'}", + "95, hippocampus {'context': 'B-tissue/organ'}", + "98, Fmr1(-/y) {'perturbing_action': 'B-gene loss-of-function'}", + "99, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "73, Fmr1(-/y); ['l0', 'l1', 'l2']", + "74, Cpeb1(-/-) ['l0', 'l3', 'l4']", + "75, double-knockout ['l1', 'l3', 'l5']", + "76, mice ['l2', 'l4', 'l5']", + "89, Acute ['l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "90, depletion ['l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "91, of ['l7', 'l12', 'l17', 'l18', 'l19', 'l20']", + "92, CPEB1 ['l8', 'l13', 'l17', 'l21', 'l22', 'l23']", + "95, hippocampus ['l9', 'l14', 'l18', 'l21', 'l24', 'l25']", + "98, Fmr1(-/y) ['l10', 'l15', 'l19', 'l22', 'l24', 'l26']", + "99, mice ['l11', 'l16', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fmr1(-/y);", + "Cpeb1(-/-)", + "double-knockout", + "Acute", + "depletion", + "of", + "CPEB1", + "Fmr1(-/y)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Acute", + "depletion", + "of", + "CPEB1", + "Fmr1(-/y)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus" + ] + } + } + ] + }, + { + "PMID": "24076665", + "TEXT": "In glioblastoma, phosphatidylinositol 3-kinase (PI3K) signaling is frequently activated by loss of the tumor suppressor phosphatase and tensin homolog (PTEN). However, it is not known whether inhibiting PI3K represents a selective and effective approach for treatment. We interrogated large databases and found that sonic hedgehog (SHH) signaling is activated in PTEN-deficient glioblastoma. We demonstrate that the SHH and PI3K pathways synergize to promote tumor growth and viability in human PTEN-deficient glioblastomas. A combination of PI3K and SHH signaling inhibitors not only suppressed the activation of both pathways but also abrogated S6 kinase (S6K) signaling. Accordingly, targeting both pathways simultaneously resulted in mitotic catastrophe and tumor apoptosis and markedly reduced the growth of PTEN-deficient glioblastomas in vitro and in vivo. The drugs tested here appear to be safe in humans; therefore, this combination may provide a new targeted treatment for glioblastoma.", + "TAG_DATA": [ + "50, PTEN-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "62, promote {'effect': 'B-positive'}", + "63, tumor {'phenotype': 'B-tumour growth'}", + "64, growth {'phenotype': 'I-tumour growth'}", + "68, human {'perturbing_action': 'B-gene loss-of-function'}", + "69, PTEN-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "70, glioblastomas. {'context': 'I-neoplasm'}", + "99, resulted {'effect': 'B-positive'}", + "100, in {'effect': 'I-positive'}", + "104, tumor {'context': 'B-neoplasm'}", + "105, apoptosis {'phenotype': 'B-apoptosis'}", + "112, PTEN-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "113, glioblastomas {'context': 'B-neoplasm'}", + "114, in {'context': 'B-in vitro'}", + "115, vitro {'context': 'I-in vitro'}", + "117, in {'context': 'B-in vivo'}", + "118, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "50, PTEN-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "62, promote ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "63, tumor ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "64, growth ['l2', 'l7', 'l11', 'l15', 'l16']", + "68, human ['l3', 'l8', 'l12', 'l15', 'l17', 'l18']", + "69, PTEN-deficient ['l4', 'l9', 'l13', 'l17', 'l19']", + "70, glioblastomas. ['l5', 'l10', 'l14', 'l16', 'l18', 'l19']", + "99, resulted ['l20', 'l21', 'l22']", + "100, in ['l20', 'l23', 'l24']", + "104, tumor ['l21', 'l23', 'l25']", + "105, apoptosis ['l22', 'l24', 'l25']", + "112, PTEN-deficient ['l26', 'l27', 'l28', 'l29', 'l30']", + "113, glioblastomas ['l26', 'l31', 'l32', 'l33', 'l34']", + "114, in ['l27', 'l31', 'l35', 'l36', 'l37']", + "115, vitro ['l28', 'l32', 'l35', 'l38', 'l39']", + "117, in ['l29', 'l33', 'l36', 'l38', 'l40']", + "118, vivo. ['l30', 'l34', 'l37', 'l39', 'l40']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PTEN-deficient", + "human" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promote" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PTEN-deficient", + "human" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PTEN-deficient", + "human" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "glioblastomas.", + "glioblastomas" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote", + "resulted", + "in" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "glioblastomas.", + "tumor" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "glioblastomas." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PTEN-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PTEN-deficient" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "24056772", + "TEXT": "Endothelial secretion of von Willebrand factor (VWF) from intracellular organelles known as Weibel-Palade bodies (WPBs) is required for platelet adhesion to the injured vessel wall. Here we demonstrate that WPBs are often found near or within autophagosomes and that endothelial autophagosomes contain abundant VWF protein. Pharmacological inhibitors of autophagy or knockdown of the essential autophagy genes Atg5 or Atg7 inhibits the in vitro secretion of VWF. Furthermore, although mice with endothelial-specific deletion of Atg7 have normal vessel architecture and capillary density, they exhibit impaired epinephrine-stimulated VWF release, reduced levels of high-molecular weight VWF multimers and a corresponding prolongation of bleeding times. Endothelial-specific deletion of Atg5 or pharmacological inhibition of autophagic flux results in a similar in vivo alteration of hemostasis. Thus, autophagy regulates endothelial VWF secretion, and transient pharmacological inhibition of autophagic flux may be a useful strategy to prevent thrombotic events.", + "TAG_DATA": [ + "50, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "51, of {'perturbing_action': 'I-rnai/knockdown'}", + "52, the {'perturbing_action': 'I-rnai/knockdown'}", + "53, essential {'perturbing_action': 'I-rnai/knockdown'}", + "54, autophagy {'perturbing_action': 'I-rnai/knockdown'}", + "55, genes {'perturbing_action': 'I-rnai/knockdown'}", + "56, Atg5 {'perturbing_action': 'I-rnai/knockdown'}", + "57, or {'perturbing_action': 'I-rnai/knockdown'}", + "58, Atg7 {'perturbing_action': 'I-rnai/knockdown'}", + "61, in {'context': 'B-in vitro'}", + "62, vitro {'context': 'I-in vitro'}", + "68, mice {'context': 'B-organism'}", + "70, endothelial-specific {'perturbing_action': 'B-gene loss-of-function'}", + "71, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "72, of {'perturbing_action': 'I-gene loss-of-function'}", + "73, Atg7 {'perturbing_action': 'I-gene loss-of-function'}", + "101, Endothelial-specific {'perturbing_action': 'B-gene loss-of-function'}", + "102, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "103, of {'perturbing_action': 'I-gene loss-of-function'}", + "104, Atg5 {'perturbing_action': 'I-gene loss-of-function'}", + "115, in {'context': 'B-in vivo'}", + "116, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "50, knockdown ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "51, of ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "52, the ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "53, essential ['l2', 'l16', 'l29', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "54, autophagy ['l3', 'l17', 'l30', 'l42', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "55, genes ['l4', 'l18', 'l31', 'l43', 'l54', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "56, Atg5 ['l5', 'l19', 'l32', 'l44', 'l55', 'l65', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "57, or ['l6', 'l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "58, Atg7 ['l7', 'l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l84', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "61, in ['l8', 'l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l99']", + "62, vitro ['l9', 'l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l86', 'l93', 'l99']", + "68, mice ['l10', 'l24', 'l37', 'l49', 'l60', 'l70', 'l79', 'l87', 'l94', 'l100', 'l101', 'l102', 'l103']", + "70, endothelial-specific ['l11', 'l25', 'l38', 'l50', 'l61', 'l71', 'l80', 'l88', 'l95', 'l100', 'l104', 'l105', 'l106']", + "71, deletion ['l12', 'l26', 'l39', 'l51', 'l62', 'l72', 'l81', 'l89', 'l96', 'l101', 'l104', 'l107', 'l108']", + "72, of ['l13', 'l27', 'l40', 'l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l102', 'l105', 'l107', 'l109']", + "73, Atg7 ['l14', 'l28', 'l41', 'l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l103', 'l106', 'l108', 'l109']", + "101, Endothelial-specific ['l110', 'l111', 'l112', 'l113', 'l114']", + "102, deletion ['l110', 'l115', 'l116', 'l117', 'l118']", + "103, of ['l111', 'l115', 'l119', 'l120', 'l121']", + "104, Atg5 ['l112', 'l116', 'l119', 'l122', 'l123']", + "115, in ['l113', 'l117', 'l120', 'l122', 'l124']", + "116, vivo ['l114', 'l118', 'l121', 'l123', 'l124']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "the", + "essential", + "autophagy", + "genes", + "Atg5", + "or", + "Atg7" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "the", + "essential", + "autophagy", + "genes", + "Atg5", + "or", + "Atg7" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "endothelial-specific", + "deletion", + "of", + "Atg7" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Endothelial-specific", + "deletion", + "of", + "Atg5" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "24037091", + "TEXT": "Acute myocardial infarction is a severe ischemic disease responsible for heart failure and sudden death. Here, we show that after acute myocardial infarction in mice, mature B lymphocytes selectively produce Ccl7 and induce Ly6C(hi) monocyte mobilization and recruitment to the heart, leading to enhanced tissue injury and deterioration of myocardial function. Genetic (Baff receptor deficiency) or antibody-mediated (CD20- or Baff-specific antibody) depletion of mature B lymphocytes impeded Ccl7 production and monocyte mobilization, limited myocardial injury and improved heart function. These effects were recapitulated in mice with B cell-selective Ccl7 deficiency. We also show that high circulating concentrations of CCL7 and BAFF in patients with acute myocardial infarction predict increased risk of death or recurrent myocardial infarction. This work identifies a crucial interaction between mature B lymphocytes and monocytes after acute myocardial ischemia and identifies new therapeutic targets for acute myocardial infarction.", + "TAG_DATA": [ + "52, (Baff {'perturbing_action': 'I-gene loss-of-function'}", + "53, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "54, deficiency) {'perturbing_action': 'I-gene loss-of-function'}", + "63, mature {'context': 'B-cells'}", + "64, B {'context': 'I-cells'}", + "65, lymphocytes {'context': 'I-cells'}", + "70, monocyte {'context': 'B-cells'}", + "77, heart {'context': 'B-tissue/organ'}", + "84, mice {'context': 'B-organism'}", + "86, B {'perturbing_action': 'B-gene loss-of-function'}", + "87, cell-selective {'perturbing_action': 'I-gene loss-of-function'}", + "88, Ccl7 {'perturbing_action': 'I-gene loss-of-function'}", + "89, deficiency. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "52, (Baff ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "53, receptor ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "54, deficiency) ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "63, mature ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "64, B ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "65, lymphocytes ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "70, monocyte ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "77, heart ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "84, mice ['l28', 'l29', 'l30', 'l31']", + "86, B ['l28', 'l32', 'l33', 'l34']", + "87, cell-selective ['l29', 'l32', 'l35', 'l36']", + "88, Ccl7 ['l30', 'l33', 'l35', 'l37']", + "89, deficiency. ['l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "(Baff", + "receptor", + "deficiency)" + ] + }, + "context": { + "val": "cells", + "words": [ + "mature", + "B", + "lymphocytes", + "monocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "(Baff", + "receptor", + "deficiency)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "heart" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "B", + "cell-selective", + "Ccl7", + "deficiency." + ] + } + } + ] + }, + { + "PMID": "23852341", + "TEXT": "The B cell-specific transcription factor BACH2 is required for affinity maturation of B cells. Here we show that Bach2-mediated activation of p53 is required for stringent elimination of pre-B cells that failed to productively rearrange immunoglobulin VH-DJH gene segments. After productive VH-DJH gene rearrangement, pre-B cell receptor signaling ends BACH2-mediated negative selection through B cell lymphoma 6 (BCL6)-mediated repression of p53. In patients with pre-B acute lymphoblastic leukemia, the BACH2-mediated checkpoint control is compromised by deletions, rare somatic mutations and loss of its upstream activator, PAX5. Low levels of BACH2 expression in these patients represent a strong independent predictor of poor clinical outcome. In this study, we demonstrate that Bach2(+/+) pre-B cells resist leukemic transformation by Myc through Bach2-dependent upregulation of p53 and do not initiate fatal leukemia in transplant-recipient mice. Chromatin immunoprecipitation sequencing and gene expression analyses carried out by us revealed that BACH2 competes with BCL6 for promoter binding and reverses BCL6-mediated repression of p53 and other cell cycle checkpoint-control genes. These findings identify BACH2 as a crucial mediator of negative selection at the pre-B cell receptor checkpoint and a safeguard against leukemogenesis.", + "TAG_DATA": [ + "109, Bach2(+/+) {'perturbing_action': 'B-gene loss-of-function'}", + "110, pre-B {'context': 'B-cells'}", + "111, cells {'context': 'I-cells'}", + "112, resist {'effect': 'B-negative'}", + "113, leukemic {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}", + "114, transformation {'phenotype': 'B-transformation'}", + "124, not {'effect': 'I-no effect'}", + "125, initiate {'effect': 'I-no effect'}", + "127, leukemia {'phenotype': 'B-tumourigenesis'}", + "130, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "109, Bach2(+/+) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "110, pre-B ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "111, cells ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "112, resist ['l2', 'l10', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "113, leukemic ['l3', 'l11', 'l18', 'l23', 'l29', 'l30', 'l31', 'l32', 'l33']", + "114, transformation ['l4', 'l12', 'l19', 'l24', 'l29', 'l34', 'l35', 'l36']", + "124, not ['l5', 'l13', 'l20', 'l25', 'l30', 'l34', 'l37', 'l38', 'l39']", + "125, initiate ['l6', 'l14', 'l21', 'l26', 'l31', 'l35', 'l37', 'l40', 'l41']", + "127, leukemia ['l7', 'l15', 'l22', 'l27', 'l32', 'l36', 'l38', 'l40', 'l42']", + "130, mice. ['l8', 'l16', 'l28', 'l33', 'l39', 'l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bach2(+/+)" + ] + }, + "context": { + "val": "cells", + "words": [ + "pre-B", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bach2(+/+)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resist" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bach2(+/+)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemic" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bach2(+/+)" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemic", + "leukemia" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "leukemic" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemic" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bach2(+/+)" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bach2(+/+)" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "initiate" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bach2(+/+)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pre-B", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resist" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pre-B", + "cells" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemic", + "leukemia" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pre-B", + "cells" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pre-B", + "cells" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "initiate" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resist" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemic" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resist" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemic", + "leukemia" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resist" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resist" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "leukemic" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "leukemic" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "initiate" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemic", + "leukemia" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "initiate" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemic", + "leukemia" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "transformation", + "words": [ + "transformation" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "initiate" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "initiate" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "23817022", + "TEXT": "Myofibroblasts are associated with organ fibrosis, but their precise origin and functional role remain unknown. We used multiple genetically engineered mice to track, fate map and ablate cells to determine the source and function of myofibroblasts in kidney fibrosis. Through this comprehensive analysis, we identified that the total pool of myofibroblasts is split, with 50% arising from local resident fibroblasts through proliferation. The nonproliferating myofibroblasts derive through differentiation from bone marrow (35%), the endothelial-to-mesenchymal transition program (10%) and the epithelial-to-mesenchymal transition program (5%). Specific deletion of Tgfbr2 in α-smooth muscle actin (αSMA)(+) cells revealed the importance of this pathway in the recruitment of myofibroblasts through differentiation. Using genetic mouse models and a fate-mapping strategy, we determined that vascular pericytes probably do not contribute to the emergence of myofibroblasts or fibrosis. Our data suggest that targeting diverse pathways is required to substantially inhibit the composite accumulation of myofibroblasts in kidney fibrosis.", + "TAG_DATA": [ + "63, nonproliferating {'context': 'B-cells'}", + "64, myofibroblasts {'context': 'I-cells'}", + "84, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "85, of {'perturbing_action': 'I-gene loss-of-function'}", + "86, Tgfbr2 {'perturbing_action': 'I-gene loss-of-function'}", + "88, α-smooth {'context': 'B-cells'}", + "89, muscle {'context': 'I-cells'}", + "90, actin {'context': 'I-cells'}", + "91, (αSMA)(+) {'context': 'I-cells'}", + "92, cells {'context': 'I-cells'}", + "107, genetic {'context': 'B-organism'}", + "108, mouse {'context': 'I-organism'}", + "109, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "63, nonproliferating ['l0']", + "64, myofibroblasts ['l0']", + "84, deletion ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "85, of ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "86, Tgfbr2 ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "88, α-smooth ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "89, muscle ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "90, actin ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "91, (αSMA)(+) ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "92, cells ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']", + "107, genetic ['l29', 'l30']", + "108, mouse ['l29', 'l31']", + "109, models ['l30', 'l31']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Tgfbr2" + ] + }, + "context": { + "val": "cells", + "words": [ + "α-smooth", + "muscle", + "actin", + "(αSMA)(+)", + "cells" + ] + } + } + ] + }, + { + "PMID": "23727932", + "TEXT": "Understanding molecular mechanisms for regeneration of hair follicles provides new opportunities for developing treatments for hair loss and other skin disorders. Here we show that fibroblast growth factor 9 (Fgf9), initially secreted by γδ T cells, modulates hair follicle regeneration after wounding the skin of adult mice. Reducing Fgf9 expression decreases this wound-induced hair neogenesis (WIHN). Conversely, overexpression of Fgf9 results in a two- to threefold increase in the number of neogenic hair follicles. We found that Fgf9 from γδ T cells triggers Wnt expression and subsequent Wnt activation in wound fibroblasts. Through a unique feedback mechanism, activated fibroblasts then express Fgf9, thus amplifying Wnt activity throughout the wound dermis during a crucial phase of skin regeneration. Notably, humans lack a robust population of resident dermal γδ T cells, potentially explaining their inability to regenerate hair after wounding. These findings highlight the essential relationship between the immune system and tissue regeneration. The importance of Fgf9 in hair follicle regeneration suggests that it could be used therapeutically in humans.", + "TAG_DATA": [ + "45, adult {'context': 'B-organism'}", + "46, mice. {'context': 'I-organism'}", + "47, Reducing {'perturbing_action': 'B-gene loss-of-function'}", + "48, Fgf9 {'perturbing_action': 'I-gene loss-of-function'}", + "49, expression {'perturbing_action': 'I-gene loss-of-function'}", + "57, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "58, of {'perturbing_action': 'I-gene gain-of-function'}", + "59, Fgf9 {'perturbing_action': 'I-gene gain-of-function'}", + "79, γδ {'context': 'B-cells'}", + "80, T {'context': 'I-cells'}", + "81, cells {'context': 'I-cells'}", + "90, wound {'context': 'B-cells'}", + "91, fibroblasts. {'context': 'I-cells'}", + "98, fibroblasts {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "45, adult ['l0']", + "46, mice. ['l0']", + "47, Reducing ['l1', 'l2', 'l3']", + "48, Fgf9 ['l1', 'l4', 'l5']", + "49, expression ['l2', 'l4']", + "57, overexpression ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "58, of ['l6', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "59, Fgf9 ['l7', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "79, γδ ['l8', 'l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "80, T ['l9', 'l15', 'l20', 'l24', 'l28', 'l29', 'l30']", + "81, cells ['l3', 'l5', 'l10', 'l16', 'l21', 'l25', 'l28', 'l31', 'l32']", + "90, wound ['l11', 'l17', 'l22', 'l26', 'l29', 'l31', 'l33']", + "91, fibroblasts. ['l12', 'l18', 'l23', 'l27', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Reducing", + "Fgf9" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Fgf9" + ] + }, + "context": { + "val": "cells", + "words": [ + "γδ", + "T", + "cells", + "wound", + "fibroblasts." + ] + } + } + ] + }, + { + "PMID": "23685840", + "TEXT": "Osteoarthritis is a highly prevalent and debilitating joint disorder. There is no effective medical therapy for the condition because of limited understanding of its pathogenesis. We show that transforming growth factor β1 (TGF-β1) is activated in subchondral bone in response to altered mechanical loading in an anterior cruciate ligament transection (ACLT) mouse model of osteoarthritis. TGF-β1 concentrations are also high in subchondral bone from humans with osteoarthritis. High concentrations of TGF-β1 induced formation of nestin-positive mesenchymal stem cell (MSC) clusters, leading to formation of marrow osteoid islets accompanied by high levels of angiogenesis. We found that transgenic expression of active TGF-β1 in osteoblastic cells induced osteoarthritis, whereas inhibition of TGF-β activity in subchondral bone attenuated the degeneration of articular cartilage. In particular, knockout of the TGF-β type II receptor (TβRII) in nestin-positive MSCs led to less development of osteoarthritis relative to wild-type mice after ACLT. Thus, high concentrations of active TGF-β1 in subchondral bone seem to initiate the pathological changes of osteoarthritis, and inhibition of this process could be a potential therapeutic approach to treating this disease.", + "TAG_DATA": [ + "96, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "97, expression {'perturbing_action': 'I-gene gain-of-function'}", + "98, of {'perturbing_action': 'I-gene gain-of-function'}", + "99, active {'perturbing_action': 'I-gene gain-of-function'}", + "100, TGF-β1 {'perturbing_action': 'I-gene gain-of-function'}", + "102, osteoblastic {'context': 'B-cells'}", + "103, cells {'context': 'I-cells'}", + "112, subchondral {'context': 'B-tissue/organ'}", + "113, bone {'context': 'I-tissue/organ'}", + "122, knockout {'perturbing_action': 'B-gene loss-of-function'}", + "123, of {'perturbing_action': 'I-gene loss-of-function'}", + "124, the {'perturbing_action': 'I-gene loss-of-function'}", + "125, TGF-β {'perturbing_action': 'I-gene loss-of-function'}", + "126, type {'perturbing_action': 'I-gene loss-of-function'}", + "127, II {'perturbing_action': 'I-gene loss-of-function'}", + "128, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "129, (TβRII) {'perturbing_action': 'I-gene loss-of-function'}", + "131, nestin-positive {'context': 'B-cells'}", + "132, MSCs {'context': 'I-cells'}", + "142, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "96, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "97, expression ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "98, of ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "99, active ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "100, TGF-β1 ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "102, osteoblastic ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "103, cells ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "112, subchondral ['l21', 'l22']", + "113, bone ['l21']", + "122, knockout ['l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "123, of ['l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "124, the ['l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "125, TGF-β ['l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "126, type ['l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "127, II ['l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "128, receptor ['l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "129, (TβRII) ['l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "131, nestin-positive ['l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "132, MSCs ['l22', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "142, mice ['l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "of", + "active", + "TGF-β1" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoblastic", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout", + "of", + "the", + "TGF-β", + "type", + "II", + "receptor", + "(TβRII)" + ] + }, + "context": { + "val": "cells", + "words": [ + "nestin-positive", + "MSCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout", + "of", + "the", + "TGF-β", + "type", + "II", + "receptor", + "(TβRII)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23652105", + "TEXT": "A study now links platelet generation and cholesterol metabolism, providing new understanding of the mechanisms involved in thrombocytosis and atherogenesis. The authors show that the cholesterol transporter ABCG4 is highly expressed in bone marrow megakaryocyte progenitors, and in its absence, these cells have defective cholesterol efflux and increased proliferation, leading to increased megakaryocyte production, thrombocytosis and accelerated atherogenesis in atherosclerosis-prone mice (pages 586–594).", + "TAG_DATA": [ + "41, cells {'context': 'B-cells'}", + "47, increased {'effect': 'B-positive'}", + "48, proliferation, {'phenotype': 'B-proliferation'}", + "52, megakaryocyte {'context': 'B-cells'}", + "60, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "41, cells ['l0', 'l1', 'l2', 'l3']", + "47, increased ['l0', 'l4', 'l5', 'l6']", + "48, proliferation, ['l1', 'l4', 'l7', 'l8']", + "52, megakaryocyte ['l2', 'l5', 'l7', 'l9']", + "60, mice ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells", + "megakaryocyte" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "megakaryocyte" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23563705", + "TEXT": "Intestinal microbiota metabolism of choline and phosphatidylcholine produces trimethylamine (TMA), which is further metabolized to a proatherogenic species, trimethylamine-N-oxide (TMAO). We demonstrate here that metabolism by intestinal microbiota of dietary L-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosis in mice. Omnivorous human subjects produced more TMAO than did vegans or vegetarians following ingestion of L-carnitine through a microbiota-dependent mechanism. The presence of specific bacterial taxa in human feces was associated with both plasma TMAO concentration and dietary status. Plasma L-carnitine levels in subjects undergoing cardiac evaluation (n = 2,595) predicted increased risks for both prevalent cardiovascular disease (CVD) and incident major adverse cardiac events (myocardial infarction, stroke or death), but only among subjects with concurrently high TMAO levels. Chronic dietary L-carnitine supplementation in mice altered cecal microbial composition, markedly enhanced synthesis of TMA and TMAO, and increased atherosclerosis, but this did not occur if intestinal microbiota was concurrently suppressed. In mice with an intact intestinal microbiota, dietary supplementation with TMAO or either carnitine or choline reduced in vivo reverse cholesterol transport. Intestinal microbiota may thus contribute to the well-established link between high levels of red meat consumption and CVD risk.", + "TAG_DATA": [ + "44, mice. {'context': 'B-organism'}", + "128, mice {'context': 'B-organism'}", + "141, increased {'effect': 'B-positive'}", + "142, atherosclerosis, {'phenotype': 'B-autophagy'}", + "155, mice {'context': 'B-organism'}", + "171, in {'context': 'B-in vivo'}", + "172, vivo {'context': 'B-in vivo'}" + ], + "LINK_DATA": [ + "44, mice. ['l0', 'l1']", + "46, human ['l0', 'l2']", + "47, subjects ['l1', 'l2']", + "128, mice ['l3', 'l4']", + "141, increased ['l3', 'l5']", + "142, atherosclerosis, ['l4', 'l5']", + "155, mice ['l6', 'l7', 'l8', 'l9']", + "159, intestinal ['l6', 'l10', 'l11', 'l12']", + "160, microbiota, ['l7', 'l10', 'l13', 'l14']", + "171, in ['l8', 'l11', 'l13', 'l15']", + "172, vivo ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "atherosclerosis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "autophagy", + "words": [ + "atherosclerosis," + ] + } + } + ] + }, + { + "PMID": "23524344", + "TEXT": "Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by bilateral renal cyst formation. Recent identification of signaling cascades deregulated in ADPKD has led to the initiation of several clinical trials, but an approved therapy is still lacking. Using a metabolomic approach, we identify a pathogenic pathway in this disease that can be safely targeted for therapy. We show that mutation of PKD1 results in enhanced glycolysis in cells in a mouse model of PKD and in kidneys from humans with ADPKD. Glucose deprivation resulted in lower proliferation and higher apoptotic rates in PKD1-mutant cells than in nondeprived cells. Notably, two distinct PKD mouse models treated with 2-deoxyglucose (2DG), to inhibit glycolysis, had lower kidney weight, volume, cystic index and proliferation rates as compared to nontreated mice. These metabolic alterations depend on the extracellular signal-related kinase (ERK) pathway acting in a dual manner by inhibiting the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) axis on the one hand while activating the mTOR complex 1 (mTORC1)-glycolytic cascade on the other. Enhanced metabolic rates further inhibit AMPK. Forced activation of AMPK acts in a negative feedback loop, restoring normal ERK activity. Taken together, these data indicate that defective glucose metabolism is intimately involved in the pathobiology of ADPKD. Our findings provide a strong rationale for a new therapeutic strategy using existing drugs, either individually or in combination.", + "TAG_DATA": [ + "63, mutation {'perturbing_action': 'B-other'}", + "64, of {'perturbing_action': 'I-other'}", + "65, PKD1 {'perturbing_action': 'I-other'}", + "71, cells {'context': 'B-cells'}", + "74, mouse {'context': 'B-organism'}", + "75, model {'context': 'I-organism'}", + "76, of {'context': 'I-organism'}", + "77, PKD {'context': 'I-organism'}", + "80, kidneys {'context': 'B-tissue/organ'}", + "82, humans {'context': 'B-patient'}", + "89, lower {'effect': 'B-negative'}", + "90, proliferation {'phenotype': 'B-proliferation'}", + "92, higher {'effect': 'B-positive'}", + "93, apoptotic {'phenotype': 'B-apoptosis'}", + "94, rates {'phenotype': 'I-apoptosis'}", + "96, PKD1-mutant {'perturbing_action': 'B-other'}", + "97, cells {'context': 'B-cells'}", + "101, cells. {'context': 'B-cells'}", + "105, PKD {'context': 'B-organism'}", + "106, mouse {'context': 'I-organism'}", + "107, models {'context': 'I-organism'}", + "116, lower {'effect': 'B-negative'}", + "117, kidney {'context': 'B-tissue/organ'}", + "123, proliferation {'phenotype': 'B-proliferation'}", + "129, mice. {'context': 'B-organism'}", + "178, Forced {'perturbing_action': 'B-gene gain-of-function'}", + "179, activation {'perturbing_action': 'I-gene gain-of-function'}", + "180, of {'perturbing_action': 'I-gene gain-of-function'}", + "181, AMPK {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "63, mutation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "64, of ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "65, PKD1 ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "71, cells ['l2', 'l16', 'l29', 'l42', 'l43', 'l44', 'l45']", + "74, mouse ['l3', 'l17', 'l30', 'l42', 'l46', 'l47', 'l48', 'l49']", + "75, model ['l4', 'l18', 'l31', 'l43', 'l46', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "76, of ['l5', 'l19', 'l32', 'l44', 'l47', 'l50', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "77, PKD ['l6', 'l20', 'l33', 'l45', 'l48', 'l51', 'l56', 'l62', 'l63', 'l64']", + "80, kidneys ['l7', 'l21', 'l34', 'l57', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "82, humans ['l8', 'l22', 'l35', 'l65', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "89, lower ['l9', 'l23', 'l36', 'l52', 'l58', 'l66', 'l72', 'l80', 'l81', 'l82', 'l83', 'l84']", + "90, proliferation ['l10', 'l24', 'l37', 'l49', 'l53', 'l59', 'l62', 'l67', 'l73', 'l80', 'l85', 'l86', 'l87']", + "92, higher ['l11', 'l25', 'l38', 'l54', 'l60', 'l63', 'l68', 'l74', 'l81', 'l85', 'l88', 'l89', 'l90']", + "93, apoptotic ['l12', 'l26', 'l39', 'l69', 'l75', 'l82', 'l86', 'l88', 'l91', 'l92', 'l93']", + "94, rates ['l13', 'l27', 'l40', 'l55', 'l61', 'l64', 'l70', 'l76', 'l83', 'l87', 'l89', 'l91']", + "96, PKD1-mutant ['l77', 'l94', 'l95']", + "97, cells ['l14', 'l28', 'l41', 'l71', 'l78', 'l84', 'l90', 'l92', 'l94', 'l96']", + "101, cells. ['l79', 'l93', 'l95', 'l96']", + "105, PKD ['l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "106, mouse ['l97', 'l103', 'l104', 'l105', 'l106', 'l107']", + "107, models ['l98', 'l103', 'l108', 'l109', 'l110', 'l111']", + "116, lower ['l99', 'l104', 'l108', 'l112', 'l113', 'l114']", + "117, kidney ['l100', 'l105', 'l109', 'l112', 'l115', 'l116']", + "123, proliferation ['l101', 'l106', 'l110', 'l113', 'l115', 'l117']", + "129, mice. ['l102', 'l107', 'l111', 'l114', 'l116', 'l117']", + "178, Forced ['l118', 'l119', 'l120']", + "179, activation ['l118', 'l121', 'l122']", + "180, of ['l119', 'l121', 'l123']", + "181, AMPK ['l120', 'l122', 'l123']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "of", + "PKD1", + "PKD1-mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "of", + "PKD1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "PKD" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "of", + "PKD1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidneys" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "of", + "PKD1", + "PKD1-mutant" + ] + }, + "context": { + "val": "patient", + "words": [ + "humans" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "of", + "PKD1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "of", + "PKD1" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "of", + "PKD1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "higher" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "of", + "PKD1" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "rates" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "of", + "PKD", + "models", + "mice." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "model", + "of", + "PKD", + "mouse", + "models", + "mice." + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "model", + "of", + "PKD" + ] + }, + "effect": { + "val": "positive", + "words": [ + "higher" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "model", + "of", + "PKD" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "rates" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "kidneys", + "kidney" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "kidneys", + "kidney" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "kidneys" + ] + }, + "effect": { + "val": "positive", + "words": [ + "higher" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "kidneys" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "rates" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "humans" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "humans" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "humans" + ] + }, + "effect": { + "val": "positive", + "words": [ + "higher" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "humans" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "rates" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "lower" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "lower" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "rates" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "lower" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "higher" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "higher" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "rates" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "higher" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "cells." + ] + } + } + ] + }, + { + "PMID": "23455711", + "TEXT": "A previous study reported the use of luminol for the detection of myeloperoxidase (MPO) activity using optical imaging in infiltrating neutrophils under inflammatory disease conditions. The detection is based on a photon-emitting reaction between luminol and an MPO metabolite. Because of tissue absorption and scattering, however, luminol-emitted blue light can be efficiently detected from superficial inflammatory foci only. In this study we report a chemiluminescence resonance energy transfer (CRET) methodology in which luminol-generated blue light excites nanoparticles to emit light in the near-infrared spectral range, resulting in remarkable improvement of MPO detectability in vivo. CRET caused a 37-fold increase in luminescence emission over luminol alone in detecting MPO activity in lung tissues after lipopolysaccharide challenge. We demonstrated a dependence of the chemiluminescent signal on MPO activity using MPO-deficient mice. In addition, co-administration of 4-aminobenzoic acid hydrazide (4-ABAH), an irreversible inhibitor of MPO, significantly attenuated luminescent emission from inflamed lungs. Inhibition of nitric oxide synthase with a nonspecific inhibitor, L-NAME, had no effect on luminol-mediated chemiluminescence production. Pretreatment of mice with MLN120B, a selective inhibitor of IKK-2, resulted in suppression of neutrophil infiltration to the lung tissues and reduction of MPO activity. We also demonstrated that CRET can effectively detect MPO activity at deep tissue tumor foci due to tumor development-associated neutrophil infiltration. We developed a sensitive MPO detection methodology that provides a means for visualizing and quantifying oxidative stress in deep tissue. This method is amenable to rapid evaluation of anti-inflammatory agents in animal models.", + "TAG_DATA": [ + "92, in {'context': 'B-in vivo'}", + "93, vivo. {'context': 'I-in vivo'}", + "110, lung {'context': 'B-tissue/organ'}", + "111, tissues {'context': 'I-tissue/organ'}", + "127, MPO-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "128, mice. {'context': 'B-organism'}", + "148, lungs. {'context': 'B-tissue/organ'}", + "149, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "168, mice {'context': 'B-organism'}", + "171, a {'perturbing_action': 'I-pharmacological inhibition'}", + "172, selective {'perturbing_action': 'I-pharmacological inhibition'}", + "173, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "174, of {'perturbing_action': 'I-pharmacological inhibition'}", + "175, IKK-2, {'perturbing_action': 'I-pharmacological inhibition'}", + "184, lung {'context': 'B-tissue/organ'}", + "185, tissues {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "92, in ['l0', 'l1', 'l2']", + "93, vivo. ['l0', 'l3', 'l4']", + "110, lung ['l1', 'l3', 'l5']", + "111, tissues ['l2', 'l4', 'l5']", + "127, MPO-deficient ['l6', 'l7']", + "128, mice. ['l6']", + "148, lungs. ['l7']", + "149, Inhibition ['l8', 'l9']", + "168, mice ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "171, a ['l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "172, selective ['l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "173, inhibitor ['l12', 'l18', 'l23', 'l28', 'l29', 'l30', 'l31']", + "174, of ['l13', 'l19', 'l24', 'l28', 'l32', 'l33', 'l34']", + "175, IKK-2, ['l14', 'l20', 'l25', 'l29', 'l32', 'l35', 'l36']", + "184, lung ['l8', 'l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l37']", + "185, tissues ['l9', 'l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MPO-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MPO-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lungs." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "a", + "selective", + "inhibitor", + "of", + "IKK-2," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung", + "tissues" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "a", + "selective", + "inhibitor", + "of", + "IKK-2," + ] + } + } + ] + }, + { + "PMID": "23396207", + "TEXT": "EF-hand proteins are ubiquitous in cell signaling. Parvalbumin (Parv), the archetypal EF-hand protein, is a high-affinity Ca(2+) buffer in many biological systems. Given the centrality of Ca(2+) signaling in health and disease, EF-hand motifs designed to have new biological activities may have widespread utility. Here, an EF-hand motif substitution that had been presumed to destroy EF-hand function, that of glutamine for glutamate at position 12 of the second cation binding loop domain of Parv (ParvE101Q), markedly inverted relative cation affinities: Mg(2+) affinity increased, whereas Ca(2+) affinity decreased, forming a new ultra-delayed Ca(2+) buffer with favorable properties for promoting cardiac relaxation. In therapeutic testing, expression of ParvE101Q fully reversed the severe myocyte intrinsic contractile defect inherent to expression of native Parv and corrected abnormal myocardial relaxation in diastolic dysfunction disease models in vitro and in vivo. Strategic design of new EF-hand motif domains to modulate intracellular Ca(2+) signaling could benefit many biological systems with abnormal Ca(2+) handling, including the diseased heart.", + "TAG_DATA": [ + "103, expression {'perturbing_action': 'B-other'}", + "104, of {'perturbing_action': 'I-other'}", + "105, ParvE101Q {'perturbing_action': 'I-other'}", + "130, in {'context': 'B-in vitro'}", + "131, vitro {'context': 'I-in vitro'}", + "133, in {'context': 'B-in vivo'}", + "134, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "103, expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "104, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "105, ParvE101Q ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "130, in ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "131, vitro ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "133, in ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "134, vivo. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "ParvE101Q" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "ParvE101Q" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "23334847", + "TEXT": "Allergic airway inflammation is associated with activation of innate immune pathways by allergens. Acute exacerbations of asthma are commonly associated with rhinovirus infection. Here we show that, after exposure to house dust mite (HDM) or rhinovirus infection, the E3 ubiquitin ligase midline 1 (MID1) is upregulated in mouse bronchial epithelium. HDM regulates MID1 expression in a Toll-like receptor 4 (TLR4)- and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-dependent manner. MID1 decreases protein phosphatase 2A (PP2A) activity through association with its catalytic subunit PP2Ac. siRNA-mediated knockdown of MID1 or pharmacological activation of PP2A using a nonphosphorylatable FTY720 analog in mice exposed to HDM reduces airway hyperreactivity and inflammation, including the expression of interleukin-25 (IL-25), IL-33 and CCL20, IL-5 and IL-13 release, nuclear factor (NF)κB activity, p38 mitogen-activated protein kinase (MAPK) phosphorylation, accumulation of eosinophils, T lymphocytes and myeloid dendritic cells, and the number of mucus-producing cells. MID1 inhibition also limited rhinovirus-induced exacerbation of allergic airway disease. We found that MID1 was upregulated in primary human bronchial epithelial cells upon HDM or rhinovirus exposure, and this correlated with TRAIL and CCL20 expression. Together, these findings identify a key role of MID1 in allergic airway inflammation and links innate immune pathway activation to the development and exacerbation of asthma.", + "TAG_DATA": [ + "82, siRNA-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "83, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "84, of {'perturbing_action': 'I-rnai/knockdown'}", + "85, MID1 {'perturbing_action': 'I-rnai/knockdown'}", + "87, pharmacological {'perturbing_action': 'B-pharmacological augmentation'}", + "88, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "89, of {'perturbing_action': 'I-pharmacological augmentation'}", + "90, PP2A {'perturbing_action': 'I-pharmacological augmentation'}", + "91, using {'perturbing_action': 'I-pharmacological augmentation'}", + "92, a {'perturbing_action': 'I-pharmacological augmentation'}", + "94, FTY720 {'perturbing_action': 'I-pharmacological augmentation'}", + "97, mice {'context': 'B-organism'}", + "135, myeloid {'context': 'B-cells'}", + "136, dendritic {'context': 'I-cells'}", + "137, cells, {'context': 'I-cells'}", + "144, MID1 {'perturbing_action': 'B-pharmacological inhibition'}", + "145, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "161, primary {'context': 'B-cells'}", + "162, human {'context': 'I-cells'}", + "163, bronchial {'context': 'I-cells'}", + "164, epithelial {'context': 'I-cells'}", + "165, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "82, siRNA-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "83, knockdown ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "84, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "85, MID1 ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "87, pharmacological ['l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "88, activation ['l26', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "89, of ['l27', 'l39', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "90, PP2A ['l28', 'l40', 'l51', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "91, using ['l29', 'l41', 'l52', 'l62', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "92, a ['l30', 'l42', 'l53', 'l63', 'l72', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "93, nonphosphorylatable ['l31', 'l43', 'l54', 'l64', 'l73', 'l81', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "94, FTY720 ['l32', 'l44', 'l55', 'l65', 'l74', 'l82', 'l89', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "95, analog ['l33', 'l45', 'l56', 'l66', 'l75', 'l83', 'l90', 'l96', 'l102', 'l103', 'l104', 'l105', 'l106']", + "97, mice ['l3', 'l10', 'l16', 'l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l84', 'l91', 'l97', 'l102', 'l107', 'l108', 'l109', 'l110']", + "135, myeloid ['l4', 'l11', 'l17', 'l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l98', 'l103', 'l107', 'l111', 'l112', 'l113']", + "136, dendritic ['l5', 'l12', 'l18', 'l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l86', 'l93', 'l99', 'l104', 'l108', 'l111', 'l114', 'l115']", + "137, cells, ['l6', 'l13', 'l19', 'l24', 'l37', 'l49', 'l60', 'l70', 'l79', 'l87', 'l94', 'l100', 'l105', 'l109', 'l112', 'l114', 'l116']", + "143, cells. ['l7', 'l14', 'l20', 'l25', 'l38', 'l50', 'l61', 'l71', 'l80', 'l88', 'l95', 'l101', 'l106', 'l110', 'l113', 'l115', 'l116']", + "144, MID1 ['l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "145, inhibition ['l117', 'l123', 'l124', 'l125', 'l126', 'l127']", + "161, primary ['l118', 'l123', 'l128', 'l129', 'l130', 'l131']", + "162, human ['l119', 'l124', 'l128', 'l132', 'l133', 'l134']", + "163, bronchial ['l120', 'l125', 'l129', 'l132', 'l135', 'l136']", + "164, epithelial ['l121', 'l126', 'l130', 'l133', 'l135', 'l137']", + "165, cells ['l122', 'l127', 'l131', 'l134', 'l136', 'l137']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA-mediated", + "knockdown", + "of", + "MID1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA-mediated", + "knockdown", + "of", + "MID1" + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "dendritic", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "pharmacological", + "activation", + "of", + "PP2A", + "using", + "a", + "FTY720" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "pharmacological", + "activation", + "of", + "PP2A", + "using", + "a", + "FTY720" + ] + }, + "context": { + "val": "cells", + "words": [ + "myeloid", + "dendritic", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "MID1", + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "primary", + "human", + "bronchial", + "epithelial", + "cells" + ] + } + } + ] + }, + { + "PMID": "23291629", + "TEXT": "Obesity develops as a result of altered energy homeostasis favoring fat storage. Here we describe a new transcription co-regulator for adiposity and energy metabolism, SERTA domain containing 2 (TRIP-Br2, also called SERTAD2). TRIP-Br2-null mice are resistant to obesity and obesity-related insulin resistance. Adipocytes of these knockout mice showed greater stimulated lipolysis secondary to enhanced expression of hormone sensitive lipase (HSL) and β3-adrenergic (Adrb3) receptors. The knockout mice also have higher energy expenditure because of increased adipocyte thermogenesis and oxidative metabolism caused by upregulating key enzymes in their respective processes. Our data show that a cell-cycle transcriptional co-regulator, TRIP-Br2, modulates fat storage through simultaneous regulation of lipolysis, thermogenesis and oxidative metabolism. These data, together with the observation that TRIP-Br2 expression is selectively elevated in visceral fat in obese humans, suggests that this transcriptional co-regulator is a new therapeutic target for counteracting the development of obesity, insulin resistance and hyperlipidemia.", + "TAG_DATA": [ + "32, TRIP-Br2-null {'perturbing_action': 'B-gene loss-of-function'}", + "33, mice {'context': 'B-organism'}", + "42, Adipocytes {'context': 'B-cells'}", + "46, mice {'context': 'B-organism'}", + "66, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "32, TRIP-Br2-null ['l0', 'l1', 'l2', 'l3']", + "33, mice ['l0', 'l4', 'l5']", + "42, Adipocytes ['l1', 'l4', 'l6']", + "46, mice ['l2', 'l5', 'l6']", + "66, mice ['l3']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TRIP-Br2-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TRIP-Br2-null" + ] + }, + "context": { + "val": "cells", + "words": [ + "Adipocytes" + ] + } + } + ] + }, + { + "PMID": "23263626", + "TEXT": "Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling associated with obliteration of pulmonary arterioles and formation of plexiform lesions composed of hyperproliferative endothelial and vascular smooth-muscle cells. Here we describe a microRNA (miRNA)-dependent association between apelin (APLN) and fibroblast growth factor 2 (FGF2) signaling in pulmonary artery endothelial cells (PAECs). APLN deficiency in these cells led to increased expression of FGF2 and its receptor FGFR1 as a consequence of decreased expression of miR-424 and miR-503, which directly target FGF2 and FGFR1. miR-424 and miR-503 were downregulated in PAH, exerted antiproliferative effects in PAECs and inhibited the capacity of PAEC-conditioned medium to induce the proliferation of pulmonary artery smooth-muscle cells. Reconstitution of miR-424 and miR-503 in vivo ameliorated pulmonary hypertension in experimental models. These studies identify an APLN-dependent miRNA-FGF signaling axis needed for the maintenance of pulmonary vascular homeostasis.", + "TAG_DATA": [ + "51, APLN {'perturbing_action': 'B-gene loss-of-function'}", + "52, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "55, cells {'context': 'B-cells'}", + "93, PAECs {'context': 'B-cells'}", + "95, inhibited {'effect': 'B-negative'}", + "102, induce {'effect': 'B-positive'}", + "104, proliferation {'phenotype': 'B-proliferation'}", + "106, pulmonary {'context': 'B-cells'}", + "107, artery {'context': 'I-cells'}", + "108, smooth-muscle {'context': 'I-cells'}", + "109, cells. {'context': 'I-cells'}", + "110, Reconstitution {'perturbing_action': 'B-gene gain-of-function'}", + "111, of {'perturbing_action': 'I-gene gain-of-function'}", + "112, miR-424 {'perturbing_action': 'I-gene gain-of-function'}", + "113, and {'perturbing_action': 'I-gene gain-of-function'}", + "114, miR-503 {'perturbing_action': 'I-gene gain-of-function'}", + "115, in {'context': 'B-in vivo'}", + "116, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "51, APLN ['l0', 'l1']", + "52, deficiency ['l0', 'l2']", + "55, cells ['l1', 'l2']", + "93, PAECs ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "95, inhibited ['l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "102, induce ['l4', 'l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "104, proliferation ['l5', 'l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "106, pulmonary ['l6', 'l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "107, artery ['l7', 'l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "108, smooth-muscle ['l8', 'l14', 'l19', 'l23', 'l26', 'l28', 'l30']", + "109, cells. ['l9', 'l15', 'l20', 'l24', 'l27', 'l29', 'l30']", + "110, Reconstitution ['l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "111, of ['l31', 'l37', 'l38', 'l39', 'l40', 'l41']", + "112, miR-424 ['l32', 'l37', 'l42', 'l43', 'l44', 'l45']", + "113, and ['l33', 'l38', 'l42', 'l46', 'l47', 'l48']", + "114, miR-503 ['l34', 'l39', 'l43', 'l46', 'l49', 'l50']", + "115, in ['l35', 'l40', 'l44', 'l47', 'l49', 'l51']", + "116, vivo ['l36', 'l41', 'l45', 'l48', 'l50', 'l51']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "APLN", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "PAECs", + "pulmonary", + "artery", + "smooth-muscle", + "cells." + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "PAECs", + "pulmonary", + "artery", + "smooth-muscle", + "cells." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "PAECs", + "pulmonary", + "artery", + "smooth-muscle", + "cells." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reconstitution", + "of", + "miR-424", + "and", + "miR-503" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "23223005", + "TEXT": "Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response that is specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that loss of Polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) activates HIF-driven chemokine (C-X-C motif) receptor 4 (CXCR4) expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven cytohesin 1 interacting protein (CYTIP) expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway.", + "TAG_DATA": [ + "82, VHL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "83, ccRCC {'context': 'B-transformed cells'}", + "84, cells, {'context': 'I-transformed cells'}", + "133, support {'effect': 'B-regulates'}", + "135, chemotactic {'phenotype': 'B-migration'}", + "136, cell {'phenotype': 'B-migration'}", + "137, invasion, {'phenotype': 'B-invasion'}", + "153, cancer {'context': 'B-transformed cells'}", + "154, cells {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "82, VHL-deficient ['l0', 'l1', 'l2', 'l3']", + "83, ccRCC ['l0', 'l4']", + "84, cells, ['l1', 'l4']", + "133, support ['l5', 'l6', 'l7']", + "135, chemotactic ['l5', 'l8', 'l9']", + "136, cell ['l2', 'l6', 'l8', 'l10']", + "137, invasion, ['l3', 'l7', 'l9', 'l10']", + "153, cancer ['l11']", + "154, cells ['l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "VHL-deficient" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "ccRCC", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "VHL-deficient" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "VHL-deficient" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion," + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "support" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotactic", + "cell" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "support" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion," + ] + } + } + ] + }, + { + "PMID": "23223004", + "TEXT": "Emerging evidence indicates that microRNAs (miRNAs) have important roles in regulating osteogenic differentiation and bone formation. Thus far, no study has established the pathophysiological role for miRNAs identified in human osteoporotic bone specimens. Here we found that elevated miR-214 levels correlated with a lower degree of bone formation in bone specimens from aged patients with fractures. We also found that osteoblast-specific manipulation of miR-214 levels by miR-214 antagomir treatment in miR-214 transgenic, ovariectomized, or hindlimb-unloaded mice revealed an inhibitory role of miR-214 in regulating bone formation. Further, in vitro osteoblast activity and matrix mineralization were promoted by antagomir-214 and decreased by agomir-214, and miR-214 directly targeted ATF4 to inhibit osteoblast activity. These data suggest that miR-214 has a crucial role in suppressing bone formation and that miR-214 inhibition in osteoblasts may be a potential anabolic strategy for ameliorating osteoporosis.", + "TAG_DATA": [ + "66, miR-214 {'perturbing_action': 'B-rnai/knockdown'}", + "67, antagomir {'perturbing_action': 'I-rnai/knockdown'}", + "68, treatment {'perturbing_action': 'I-rnai/knockdown'}", + "70, miR-214 {'perturbing_action': 'B-gene gain-of-function'}", + "71, transgenic, {'perturbing_action': 'I-gene gain-of-function'}", + "75, mice {'context': 'B-organism'}", + "87, in {'context': 'B-in vitro'}", + "88, vitro {'context': 'I-in vitro'}", + "89, osteoblast {'context': 'B-cells'}", + "109, osteoblast {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "66, miR-214 ['l0', 'l1', 'l2', 'l3', 'l4']", + "67, antagomir ['l0', 'l5', 'l6', 'l7', 'l8', 'l9']", + "68, treatment ['l1', 'l5', 'l10', 'l11']", + "70, miR-214 ['l2', 'l6', 'l10', 'l12', 'l13', 'l14', 'l15']", + "71, transgenic, ['l3', 'l7', 'l11', 'l12', 'l16', 'l17', 'l18', 'l19']", + "75, mice ['l8', 'l13', 'l16', 'l20', 'l21', 'l22']", + "87, in ['l17', 'l20', 'l23', 'l24']", + "88, vitro ['l14', 'l18', 'l21', 'l23', 'l25']", + "89, osteoblast ['l4', 'l9', 'l15', 'l19', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "miR-214", + "antagomir" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoblast" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antagomir" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "miR-214", + "transgenic," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "miR-214", + "transgenic," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "vitro", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "miR-214", + "transgenic," + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoblast" + ] + } + } + ] + }, + { + "PMID": "23160237", + "TEXT": "Hydrocephalus is a common neurological disorder that leads to expansion of the cerebral ventricles and is associated with a high rate of morbidity and mortality. Most neonatal cases are of unknown etiology and are likely to have complex inheritance involving multiple genes and environmental factors. Identifying molecular mechanisms for neonatal hydrocephalus and developing noninvasive treatment modalities are high priorities. Here we use a hydrocephalic mouse model of the human ciliopathy Bardet-Biedl Syndrome (BBS) and identify a role for neural progenitors in the pathogenesis of neonatal hydrocephalus. We found that hydrocephalus in this mouse model is caused by aberrant platelet-derived growth factor receptor α (PDGFR-α) signaling, resulting in increased apoptosis and impaired proliferation of chondroitin sulfate proteoglycan 4 (also known as neuron-glial antigen 2 or NG2)(+)PDGFR-α(+) neural progenitors. Targeting this pathway with lithium treatment rescued NG2(+)PDGFR-α(+) progenitor cell proliferation in BBS mutant mice, reducing their ventricular volume. Our findings demonstrate that neural progenitors are crucial in the pathogenesis of neonatal hydrocephalus, and we identify new therapeutic targets for this common neurological disorder.", + "TAG_DATA": [ + "92, mouse {'context': 'B-organism'}", + "93, model {'context': 'I-organism'}", + "107, increased {'effect': 'B-positive'}", + "108, apoptosis {'phenotype': 'B-apoptosis'}", + "110, impaired {'effect': 'B-negative'}", + "111, proliferation {'phenotype': 'B-proliferation'}", + "133, rescued {'effect': 'B-rescues'}", + "134, NG2(+)PDGFR-α(+) {'context': 'B-cells'}", + "135, progenitor {'context': 'I-cells'}", + "136, cell {'context': 'I-cells'}", + "137, proliferation {'phenotype': 'B-proliferation'}", + "139, BBS {'perturbing_action': 'B-other'}", + "140, mutant {'perturbing_action': 'I-other'}", + "141, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "92, mouse ['l0', 'l1', 'l2', 'l3', 'l4']", + "93, model ['l0', 'l5', 'l6', 'l7', 'l8']", + "107, increased ['l1', 'l5', 'l9', 'l10', 'l11']", + "108, apoptosis ['l2', 'l6', 'l9', 'l12', 'l13']", + "110, impaired ['l3', 'l7', 'l10', 'l12', 'l14']", + "111, proliferation ['l4', 'l8', 'l11', 'l13', 'l14']", + "133, rescued ['l15', 'l16', 'l17', 'l18']", + "134, NG2(+)PDGFR-α(+) ['l15', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "135, progenitor ['l16', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "136, cell ['l17', 'l20', 'l25', 'l30', 'l31', 'l32']", + "137, proliferation ['l18', 'l21', 'l26', 'l30', 'l33']", + "139, BBS ['l22', 'l27', 'l34', 'l35']", + "140, mutant ['l23', 'l28', 'l31', 'l34', 'l36']", + "141, mice, ['l24', 'l29', 'l32', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "mice," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "context": { + "val": "cells", + "words": [ + "NG2(+)PDGFR-α(+)", + "progenitor", + "cell" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "NG2(+)PDGFR-α(+)", + "progenitor", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "NG2(+)PDGFR-α(+)", + "progenitor", + "cell" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "BBS", + "mutant" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BBS", + "mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "23104132", + "TEXT": "Doxorubicin is believed to cause dose-dependent cardiotoxicity through redox cycling and the generation of reactive oxygen species (ROS). Here we show that cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks and transcriptome changes that are responsible for defective mitochondrial biogenesis and ROS formation. Furthermore, cardiomyocyte-specific deletion of Top2b protects mice from the development of doxorubicin-induced progressive heart failure, suggesting that doxorubicin-induced cardiotoxicity is mediated by topoisomerase-IIβ in cardiomyocytes.", + "TAG_DATA": [ + "22, cardiomyocyte-specific {'perturbing_action': 'B-gene loss-of-function'}", + "23, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "24, of {'perturbing_action': 'I-gene loss-of-function'}", + "25, Top2b {'perturbing_action': 'I-gene loss-of-function'}", + "26, (encoding {'perturbing_action': 'I-gene loss-of-function'}", + "27, topoisomerase-IIβ) {'perturbing_action': 'I-gene loss-of-function'}", + "29, cardiomyocytes {'context': 'B-cells'}", + "49, cardiomyocyte-specific {'perturbing_action': 'B-gene loss-of-function'}", + "50, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "51, of {'perturbing_action': 'I-gene loss-of-function'}", + "52, Top2b {'perturbing_action': 'I-gene loss-of-function'}", + "54, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "22, cardiomyocyte-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "23, deletion ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "24, of ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "25, Top2b ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "26, (encoding ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "27, topoisomerase-IIβ) ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "29, cardiomyocytes ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "49, cardiomyocyte-specific ['l21', 'l22', 'l23', 'l24']", + "50, deletion ['l21', 'l25', 'l26', 'l27']", + "51, of ['l22', 'l25', 'l28', 'l29']", + "52, Top2b ['l23', 'l26', 'l28', 'l30']", + "54, mice ['l24', 'l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cardiomyocyte-specific", + "deletion", + "of", + "Top2b", + "(encoding", + "topoisomerase-IIβ)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiomyocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cardiomyocyte-specific", + "deletion", + "of", + "Top2b" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "23086478", + "TEXT": "Reactive oxygen species (ROS), a byproduct of cellular metabolism, damage intracellular macromolecules and, when present in excess, can promote normal hematopoietic stem cell differentiation and exhaustion. However, mechanisms that regulate the amount of ROS in leukemia-initiating cells (LICs) and the biological role of ROS in these cells are largely unknown. We show here that the ROS(low) subset of CD44(+) cells in T cell acute lymphoblastic leukemia (T-ALL), a malignancy of immature T cell progenitors, is highly enriched in the most aggressive LICs and that ROS accumulation is restrained by downregulation of protein kinase C θ (PKC-θ). Notably, primary mouse T-ALLs lacking PKC-θ show improved LIC activity, whereas enforced PKC-θ expression in both mouse and human primary T-ALLs compromised LIC activity. We also show that PKC-θ is regulated by a new pathway in which NOTCH1 induces runt-related transcription factor 3 (RUNX3), RUNX3 represses RUNX1 and RUNX1 induces PKC-θ. NOTCH1, which is frequently activated by mutation in T-ALL and required for LIC activity in both mouse and human models, thus acts to repress PKC-θ. These results reveal key functional roles for PKC-θ and ROS in T-ALL and suggest that aggressive biological behavior in vivo could be limited by therapeutic strategies that promote PKC-θ expression or activity, or the accumulation of ROS.", + "TAG_DATA": [ + "97, primary {'context': 'B-neoplasm'}", + "98, mouse {'context': 'I-neoplasm'}", + "99, T-ALLs {'context': 'I-neoplasm'}", + "100, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "101, PKC-θ {'perturbing_action': 'I-gene loss-of-function'}", + "107, enforced {'perturbing_action': 'B-gene gain-of-function'}", + "108, PKC-θ {'perturbing_action': 'I-gene gain-of-function'}", + "109, expression {'perturbing_action': 'I-gene gain-of-function'}", + "112, mouse {'context': 'B-neoplasm'}", + "113, and {'context': 'I-neoplasm'}", + "114, human {'context': 'I-neoplasm'}", + "115, primary {'context': 'I-neoplasm'}", + "116, T-ALLs {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "97, primary ['l0', 'l1', 'l2', 'l3']", + "98, mouse ['l0', 'l4', 'l5', 'l6']", + "99, T-ALLs ['l1', 'l4', 'l7', 'l8']", + "100, lacking ['l2', 'l5', 'l7', 'l9']", + "101, PKC-θ ['l3', 'l6', 'l8', 'l9']", + "107, enforced ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "108, PKC-θ ['l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "109, expression ['l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "112, mouse ['l12', 'l18', 'l23', 'l28', 'l29', 'l30', 'l31']", + "113, and ['l13', 'l19', 'l24', 'l28', 'l32', 'l33', 'l34']", + "114, human ['l14', 'l20', 'l25', 'l29', 'l32', 'l35', 'l36']", + "115, primary ['l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l37']", + "116, T-ALLs ['l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "primary", + "mouse", + "T-ALLs" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "PKC-θ" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "enforced", + "PKC-θ", + "expression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "and", + "human", + "primary", + "T-ALLs" + ] + } + } + ] + }, + { + "PMID": "23086477", + "TEXT": "Abnormal activation of insulin-like growth factor (IGF)-Akt signaling is implicated in the development of various diseases, including heart failure. However, the molecular mechanisms that regulate activation of this signaling pathway are not completely understood. Here we show that sirtuin 6 (SIRT6), a nuclear histone deacetylase, functions at the level of chromatin to directly attenuate IGF-Akt signaling. SIRT6-deficient mice developed cardiac hypertrophy and heart failure, whereas SIRT6 transgenic mice were protected from hypertrophic stimuli, indicating that SIRT6 acts as a negative regulator of cardiac hypertrophy. SIRT6-deficient mouse hearts showed hyperactivation of IGF signaling-related genes and their downstream targets. Mechanistically, SIRT6 binds to and suppresses the promoter of IGF signaling-related genes by interacting with c-Jun and deacetylating histone 3 at Lys9 (H3K9). We also found reduced SIRT6 expression in human failing hearts. These findings disclose a new link between SIRT6 and IGF-Akt signaling and implicate SIRT6 in the development of cardiac hypertrophy and failure.", + "TAG_DATA": [ + "56, SIRT6-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "57, mice {'context': 'B-organism'}", + "65, SIRT6 {'perturbing_action': 'B-gene gain-of-function'}", + "66, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "67, mice {'context': 'B-organism'}", + "84, SIRT6-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "85, mouse {'context': 'B-tissue/organ'}", + "86, hearts {'context': 'I-tissue/organ'}", + "128, failing {'context': 'I-tissue/organ'}", + "129, hearts. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "56, SIRT6-deficient ['l0']", + "57, mice ['l0']", + "65, SIRT6 ['l1', 'l2', 'l3']", + "66, transgenic ['l1', 'l4', 'l5']", + "67, mice ['l2', 'l4']", + "84, SIRT6-deficient ['l6', 'l7']", + "85, mouse ['l6', 'l8']", + "86, hearts ['l3', 'l5', 'l7', 'l8']", + "127, human ['l9', 'l10']", + "128, failing ['l9', 'l11']", + "129, hearts. ['l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SIRT6-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "SIRT6", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "SIRT6", + "transgenic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hearts" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SIRT6-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "hearts" + ] + } + } + ] + }, + { + "PMID": "23001181", + "TEXT": "A noninvasive technology that quantitatively measures the activity of oncogenic signaling pathways could have a broad impact on cancer diagnosis and treatment with targeted therapies. Here we describe the development of (89)Zr-desferrioxamine-labeled transferrin ((89)Zr-transferrin), a new positron emission tomography (PET) radiotracer that binds the transferrin receptor 1 (TFRC, CD71) with high avidity. The use of (89)Zr-transferrin produces high-contrast PET images that quantitatively reflect treatment-induced changes in MYC-regulated TFRC expression in a MYC-driven prostate cancer xenograft model. Moreover, (89)Zr-transferrin imaging can detect the in situ development of prostate cancer in a transgenic MYC prostate cancer model, as well as in prostatic intraepithelial neoplasia (PIN) before histological or anatomic evidence of invasive cancer. These preclinical data establish (89)Zr-transferrin as a sensitive tool for noninvasive measurement of oncogene-driven TFRC expression in prostate and potentially other cancers, with prospective near-term clinical application.", + "TAG_DATA": [ + "71, MYC-driven {'context': 'B-xenograft'}", + "72, prostate {'context': 'I-xenograft'}", + "73, cancer {'context': 'I-xenograft'}", + "74, xenograft {'context': 'I-xenograft'}", + "75, model. {'context': 'I-xenograft'}", + "86, prostate {'context': 'B-neoplasm'}", + "87, cancer {'context': 'I-neoplasm'}", + "90, transgenic {'perturbing_action': 'B-other'}", + "92, prostate {'context': 'I-transformed cells'}", + "93, cancer {'context': 'I-neoplasm'}", + "94, model, {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "71, MYC-driven ['l0', 'l1', 'l2', 'l3']", + "72, prostate ['l0', 'l4', 'l5', 'l6']", + "73, cancer ['l1', 'l4', 'l7', 'l8']", + "74, xenograft ['l2', 'l5', 'l7', 'l9']", + "75, model. ['l3', 'l6', 'l8', 'l9']", + "86, prostate ['l10']", + "87, cancer ['l10']", + "90, transgenic ['l11', 'l12', 'l13', 'l14']", + "91, MYC ['l11', 'l15', 'l16', 'l17']", + "92, prostate ['l12', 'l15', 'l18', 'l19']", + "93, cancer ['l13', 'l16', 'l18', 'l20']", + "94, model, ['l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "prostate" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "cancer", + "model," + ] + } + } + ] + }, + { + "PMID": "22983396", + "TEXT": "The discovery of potent inhibitors of the BRAF proto-oncogene has revolutionized therapy for melanoma harboring mutations in BRAF, yet NRAS-mutant melanoma remains without an effective therapy. Because direct pharmacological inhibition of the RAS proto-oncogene has thus far been unsuccessful, we explored systems biology approaches to identify synergistic drug combination(s) that can mimic RAS inhibition. Here, leveraging an inducible mouse model of NRAS-mutant melanoma, we show that pharmacological inhibition of mitogen-activated protein kinase kinase (MEK) activates apoptosis but not cell-cycle arrest, which is in contrast to complete genetic neuroblastoma RAS homolog (NRAS) extinction, which triggers both of these effects. Network modeling pinpointed cyclin-dependent kinase 4 (CDK4) as a key driver of this differential phenotype. Accordingly, combined pharmacological inhibition of MEK and CDK4 in vivo led to substantial synergy in therapeutic efficacy. We suggest a gradient model of oncogenic NRAS signaling in which the output is gated, resulting in the decoupling of discrete downstream biological phenotypes as a result of incomplete inhibition. Such a gated signaling model offers a new framework to identify nonobvious coextinction target(s) for combined pharmacological inhibition in NRAS-mutant melanomas.", + "TAG_DATA": [ + "57, inducible {'context': 'B-organism'}", + "58, mouse {'context': 'I-organism'}", + "59, model {'context': 'I-neoplasm'}", + "60, of {'context': 'I-neoplasm'}", + "61, NRAS-mutant {'context': 'I-organism'}", + "62, melanoma, {'context': 'I-neoplasm'}", + "66, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "67, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "68, of {'perturbing_action': 'I-pharmacological inhibition'}", + "69, mitogen-activated {'perturbing_action': 'I-pharmacological inhibition'}", + "70, protein {'perturbing_action': 'I-pharmacological inhibition'}", + "71, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "72, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "73, (MEK) {'perturbing_action': 'I-pharmacological inhibition'}", + "74, activates {'effect': 'B-positive'}", + "75, apoptosis {'phenotype': 'B-apoptosis'}", + "78, cell-cycle {'phenotype': 'B-cell cycle arrest'}", + "79, arrest, {'phenotype': 'I-cell cycle arrest'}", + "114, combined {'perturbing_action': 'B-pharmacological inhibition'}", + "115, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "116, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "117, of {'perturbing_action': 'I-pharmacological inhibition'}", + "118, MEK {'perturbing_action': 'I-pharmacological inhibition'}", + "119, and {'perturbing_action': 'I-pharmacological inhibition'}", + "120, CDK4 {'perturbing_action': 'I-pharmacological inhibition'}", + "121, in {'context': 'B-in vivo'}", + "122, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "57, inducible ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "58, mouse ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "59, model ['l1', 'l15', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "60, of ['l2', 'l16', 'l25', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "61, NRAS-mutant ['l3', 'l17', 'l26', 'l34', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "62, melanoma, ['l4', 'l18', 'l27', 'l35', 'l41', 'l53', 'l54', 'l55', 'l56']", + "66, pharmacological ['l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "67, inhibition ['l5', 'l42', 'l57', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "68, of ['l6', 'l43', 'l58', 'l68', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "69, mitogen-activated ['l7', 'l44', 'l59', 'l69', 'l78', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "70, protein ['l45', 'l60', 'l70', 'l79', 'l87', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "71, kinase ['l8', 'l46', 'l61', 'l71', 'l80', 'l88', 'l95', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "72, kinase ['l9', 'l19', 'l28', 'l47', 'l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l108', 'l109', 'l110', 'l111', 'l112']", + "73, (MEK) ['l10', 'l20', 'l29', 'l36', 'l48', 'l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l108', 'l113', 'l114', 'l115', 'l116']", + "74, activates ['l11', 'l21', 'l30', 'l37', 'l49', 'l53', 'l64', 'l74', 'l83', 'l91', 'l98', 'l104', 'l109', 'l113', 'l117', 'l118', 'l119']", + "75, apoptosis ['l12', 'l22', 'l31', 'l38', 'l50', 'l54', 'l65', 'l75', 'l84', 'l92', 'l99', 'l105', 'l110', 'l114', 'l117', 'l120', 'l121']", + "78, cell-cycle ['l13', 'l23', 'l32', 'l39', 'l51', 'l55', 'l66', 'l76', 'l85', 'l93', 'l100', 'l106', 'l111', 'l115', 'l118', 'l120', 'l122']", + "79, arrest, ['l14', 'l24', 'l33', 'l40', 'l52', 'l56', 'l67', 'l77', 'l86', 'l94', 'l101', 'l107', 'l112', 'l116', 'l119', 'l121', 'l122']", + "114, combined ['l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "115, pharmacological ['l123', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137']", + "116, inhibition ['l124', 'l131', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "117, of ['l125', 'l132', 'l138', 'l144', 'l145', 'l146', 'l147', 'l148']", + "118, MEK ['l126', 'l133', 'l139', 'l144', 'l149', 'l150', 'l151', 'l152']", + "119, and ['l127', 'l134', 'l140', 'l145', 'l149', 'l153', 'l154', 'l155']", + "120, CDK4 ['l128', 'l135', 'l141', 'l146', 'l150', 'l153', 'l156', 'l157']", + "121, in ['l129', 'l136', 'l142', 'l147', 'l151', 'l154', 'l156', 'l158']", + "122, vivo ['l130', 'l137', 'l143', 'l148', 'l152', 'l155', 'l157', 'l158']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "inducible", + "mouse", + "NRAS-mutant" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "mitogen-activated", + "kinase", + "(MEK)", + "protein" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "inducible", + "mouse", + "NRAS-mutant" + ] + }, + "effect": { + "val": "positive", + "words": [ + "activates" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "inducible", + "mouse", + "NRAS-mutant" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "inducible", + "mouse", + "NRAS-mutant" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest," + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "model", + "of" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "kinase", + "(MEK)" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "model", + "of", + "melanoma," + ] + }, + "effect": { + "val": "positive", + "words": [ + "activates" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "model", + "of", + "melanoma," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "model", + "of", + "melanoma," + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "mitogen-activated", + "protein", + "kinase", + "(MEK)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "activates" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "mitogen-activated", + "protein", + "kinase", + "(MEK)" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "mitogen-activated", + "protein", + "kinase", + "(MEK)" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "activates" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "activates" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell-cycle", + "arrest," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "combined", + "pharmacological", + "inhibition", + "of", + "MEK", + "and", + "CDK4" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "22961106", + "TEXT": "The role of skeletal muscle in nonshivering thermogenesis (NST) is not well understood. Here we show that sarcolipin (Sln), a newly identified regulator of the sarco/endoplasmic reticulum Ca(2+)-ATPase (Serca) pump, is necessary for muscle-based thermogenesis. When challenged to acute cold (4 °C), Sln(-/-) mice were not able to maintain their core body temperature (37 °C) and developed hypothermia. Surgical ablation of brown adipose tissue and functional knockdown of Ucp1 allowed us to highlight the role of muscle in NST. Overexpression of Sln in the Sln-null background fully restored muscle-based thermogenesis, suggesting that Sln is the basis for Serca-mediated heat production. We show that ryanodine receptor 1 (Ryr1)-mediated Ca(2+) leak is an important mechanism for Serca-activated heat generation. Here we present data to suggest that Sln can continue to interact with Serca in the presence of Ca(2+), which can promote uncoupling of the Serca pump and cause futile cycling. We further show that loss of Sln predisposes mice to diet-induced obesity, which suggests that Sln-mediated NST is recruited during metabolic overload. These data collectively suggest that SLN is an important mediator of muscle thermogenesis and whole-body energy metabolism.", + "TAG_DATA": [ + "42, Sln(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "43, mice {'context': 'B-organism'}", + "58, Surgical {'perturbing_action': 'B-gene loss-of-function'}", + "59, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "60, of {'perturbing_action': 'I-gene loss-of-function'}", + "61, brown {'perturbing_action': 'I-gene loss-of-function'}", + "62, adipose {'perturbing_action': 'I-gene loss-of-function'}", + "63, tissue {'perturbing_action': 'I-gene loss-of-function'}", + "65, functional {'perturbing_action': 'B-rnai/knockdown'}", + "66, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "67, of {'perturbing_action': 'I-rnai/knockdown'}", + "68, Ucp1 {'perturbing_action': 'I-rnai/knockdown'}", + "79, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "80, of {'perturbing_action': 'I-gene gain-of-function'}", + "81, Sln {'perturbing_action': 'I-gene gain-of-function'}", + "84, Sln-null {'perturbing_action': 'B-gene loss-of-function'}", + "152, loss {'perturbing_action': 'B-gene loss-of-function'}", + "153, of {'perturbing_action': 'I-gene loss-of-function'}", + "154, Sln {'perturbing_action': 'I-gene loss-of-function'}", + "156, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "42, Sln(-/-) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "43, mice ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "58, Surgical ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "59, ablation ['l2', 'l8', 'l13', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "60, of ['l3', 'l9', 'l14', 'l20', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "61, brown ['l4', 'l10', 'l15', 'l21', 'l26', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "62, adipose ['l5', 'l11', 'l16', 'l22', 'l27', 'l34', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "63, tissue ['l6', 'l12', 'l17', 'l23', 'l28', 'l35', 'l41', 'l47', 'l48']", + "65, functional ['l29', 'l36', 'l42', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "66, knockdown ['l30', 'l37', 'l43', 'l49', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "67, of ['l18', 'l24', 'l31', 'l38', 'l44', 'l47', 'l50', 'l56', 'l62', 'l63', 'l64', 'l65', 'l66']", + "68, Ucp1 ['l19', 'l25', 'l32', 'l39', 'l45', 'l48', 'l51', 'l57', 'l62', 'l67', 'l68', 'l69', 'l70']", + "79, Overexpression ['l52', 'l58', 'l63', 'l67', 'l71', 'l72', 'l73']", + "80, of ['l53', 'l59', 'l64', 'l68', 'l71', 'l74', 'l75']", + "81, Sln ['l54', 'l60', 'l65', 'l69', 'l72', 'l74', 'l76']", + "84, Sln-null ['l33', 'l40', 'l46', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l76']", + "152, loss ['l77', 'l78', 'l79']", + "153, of ['l77', 'l80', 'l81']", + "154, Sln ['l78', 'l80', 'l82']", + "156, mice ['l79', 'l81', 'l82']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sln(-/-)", + "Surgical", + "ablation", + "of", + "brown", + "adipose", + "tissue", + "loss", + "Sln" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "22902876", + "TEXT": "Stem-cell function is an exquisitely regulated process. Thus far, the contribution of metabolic cues to stem-cell function has not been well understood. Here we identify a previously unknown promyelocytic leukemia (PML)–peroxisome proliferator-activated receptor δ (PPAR-δ)–fatty-acid oxidation (FAO) pathway for the maintenance of hematopoietic stem cells (HSCs). We have found that loss of PPAR-δ or inhibition of mitochondrial FAO induces loss of HSC maintenance, whereas treatment with PPAR-δ agonists improved HSC maintenance. PML exerts its essential role in HSC maintenance through regulation of PPAR signaling and FAO. Mechanistically, the PML–PPAR-δ–FAO pathway controls the asymmetric division of HSCs. Deletion of Ppard or Pml as well as inhibition of FAO results in the symmetric commitment of HSC daughter cells, whereas PPAR-δ activation increased asymmetric cell division. Thus, our findings identify a metabolic switch for the control of HSC cell fate with potential therapeutic implications.", + "TAG_DATA": [ + "50, loss {'perturbing_action': 'B-gene loss-of-function'}", + "51, of {'perturbing_action': 'I-gene loss-of-function'}", + "52, PPAR-δ {'perturbing_action': 'I-gene loss-of-function'}", + "54, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "55, of {'perturbing_action': 'I-pharmacological inhibition'}", + "56, mitochondrial {'perturbing_action': 'I-pharmacological inhibition'}", + "57, FAO {'perturbing_action': 'I-pharmacological inhibition'}", + "61, HSC {'context': 'B-transformed cells'}", + "66, PPAR-δ {'perturbing_action': 'B-pharmacological augmentation'}", + "67, agonists {'perturbing_action': 'I-pharmacological augmentation'}", + "69, HSC {'context': 'B-transformed cells'}", + "96, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "97, of {'perturbing_action': 'I-gene loss-of-function'}", + "98, Ppard {'perturbing_action': 'I-gene loss-of-function'}", + "99, or {'perturbing_action': 'I-gene loss-of-function'}", + "100, Pml {'perturbing_action': 'I-gene loss-of-function'}", + "104, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "106, FAO {'perturbing_action': 'I-pharmacological inhibition'}", + "113, HSC {'context': 'B-transformed cells'}", + "114, daughter {'context': 'I-cells'}", + "115, cells, {'context': 'I-cells'}", + "118, activation {'perturbing_action': 'I-pharmacological augmentation'}", + "119, increased {'effect': 'B-positive'}", + "121, cell {'phenotype': 'B-proliferation'}", + "122, division. {'phenotype': 'I-proliferation'}" + ], + "LINK_DATA": [ + "50, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "51, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "52, PPAR-δ ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "54, inhibition ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21', 'l22']", + "55, of ['l3', 'l9', 'l14', 'l18', 'l23', 'l24', 'l25', 'l26']", + "56, mitochondrial ['l4', 'l10', 'l15', 'l19', 'l23', 'l27', 'l28', 'l29']", + "57, FAO ['l5', 'l11', 'l16', 'l20', 'l24', 'l27', 'l30', 'l31']", + "61, HSC ['l6', 'l12', 'l17', 'l21', 'l25', 'l28', 'l30']", + "66, PPAR-δ ['l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "67, agonists ['l32', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "69, HSC ['l22', 'l26', 'l29', 'l31', 'l33', 'l43']", + "96, Deletion ['l34', 'l44', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "97, of ['l35', 'l45', 'l53', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "98, Ppard ['l36', 'l46', 'l54', 'l65', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "99, or ['l37', 'l47', 'l55', 'l66', 'l76', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "100, Pml ['l38', 'l48', 'l56', 'l67', 'l77', 'l85', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "104, inhibition ['l57', 'l68', 'l78', 'l86', 'l93', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "106, FAO ['l39', 'l49', 'l58', 'l69', 'l79', 'l87', 'l94', 'l100', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "113, HSC ['l40', 'l50', 'l59', 'l70', 'l80', 'l88', 'l95', 'l101', 'l108', 'l114', 'l115']", + "114, daughter ['l41', 'l51', 'l60', 'l71', 'l81', 'l89', 'l96', 'l102', 'l109', 'l114', 'l116']", + "115, cells, ['l42', 'l52', 'l61', 'l72', 'l82', 'l90', 'l97', 'l103', 'l110', 'l115', 'l116']", + "118, activation ['l104', 'l117', 'l118', 'l119']", + "119, increased ['l62', 'l73', 'l105', 'l111', 'l117', 'l120', 'l121']", + "121, cell ['l63', 'l74', 'l83', 'l91', 'l98', 'l106', 'l112', 'l118', 'l120', 'l122']", + "122, division. ['l64', 'l75', 'l84', 'l92', 'l99', 'l107', 'l113', 'l119', 'l121', 'l122']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "PPAR-δ", + "Deletion", + "Ppard", + "or", + "Pml" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "mitochondrial", + "FAO" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "PPAR-δ", + "agonists" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "HSC" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "PPAR-δ", + "agonists" + ] + }, + "context": { + "val": "cells", + "words": [ + "daughter", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "Ppard", + "or", + "Pml" + ] + }, + "context": { + "val": "cells", + "words": [ + "daughter", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "Ppard", + "or", + "Pml" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "FAO" + ] + }, + "context": { + "val": "cells", + "words": [ + "daughter", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "FAO" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "FAO" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "cell", + "division." + ] + } + } + ] + }, + { + "PMID": "22863785", + "TEXT": "T cell immunoglobulin and mucin domain–containing 3 (Tim-3) is an inhibitory receptor that is expressed on exhausted T cells during infection with HIV-1 and hepatitis C virus. By contrast, Tim-3 expression and function are defective in multiple human autoimmune diseases. However, the molecular mechanisms modulating Tim-3 function are not well understood. Here we show that human leukocyte antigen B (HLA-B)-associated transcript 3 (Bat3) binds to, and represses the function of, Tim-3. Bat3 protects T helper type 1 (TH1) cells from galectin-9–mediated cell death and promotes both proliferation and proinflammatory cytokine production. Bat3-deficient T cells have elevated expression of exhaustion-associated molecules such as Tim-3, Lag3, Prdm1 and Pbx3, and Bat3 knockdown in myelin-antigen–specific CD4+ T cells markedly inhibits the development of experimental autoimmune encephalomyelitis while promoting the expansion of a dysfunctional Tim-3hi, interferon-γ (IFN-γ)loCD4+ cell population. Furthermore, expression of Bat3 is reduced in exhausted Tim-3+ T cells from mouse tumors and HIV-1–infected individuals. These data indicate that Bat3 acts as an inhibitor of Tim-3–dependent exhaustion and cell death. Bat3 may thus represent a viable therapeutic target in autoimmune disorders, chronic infections and cancers.", + "TAG_DATA": [ + "73, T {'context': 'B-cells'}", + "74, helper {'context': 'I-cells'}", + "75, type {'context': 'I-cells'}", + "76, 1 {'context': 'I-cells'}", + "77, (TH1) {'context': 'I-cells'}", + "78, cells {'context': 'I-cells'}", + "81, cell {'phenotype': 'B-cell death'}", + "82, death {'phenotype': 'I-cell death'}", + "84, promotes {'effect': 'B-positive'}", + "86, proliferation {'phenotype': 'B-proliferation'}", + "91, Bat3-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "92, T {'context': 'B-cells'}", + "93, cells {'context': 'I-cells'}", + "108, Bat3 {'perturbing_action': 'B-rnai/knockdown'}", + "109, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "111, myelin-antigen–specific {'context': 'B-cells'}", + "112, CD4+ {'context': 'I-cells'}", + "113, T {'context': 'I-cells'}", + "114, cells {'context': 'I-cells'}", + "133, cell {'context': 'I-cells'}", + "134, population. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "73, T ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "74, helper ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "75, type ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "76, 1 ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "77, (TH1) ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "78, cells ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "81, cell ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "82, death ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "84, promotes ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "86, proliferation ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "91, Bat3-deficient ['l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "92, T ['l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "93, cells ['l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "108, Bat3 ['l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "109, knockdown ['l60', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "111, myelin-antigen–specific ['l47', 'l52', 'l56', 'l61', 'l67', 'l73', 'l74', 'l75', 'l76', 'l77']", + "112, CD4+ ['l48', 'l53', 'l57', 'l62', 'l68', 'l73', 'l78', 'l79', 'l80', 'l81']", + "113, T ['l49', 'l54', 'l58', 'l63', 'l69', 'l74', 'l78', 'l82']", + "114, cells ['l50', 'l55', 'l59', 'l64', 'l70', 'l75', 'l79', 'l82']", + "133, cell ['l65', 'l71', 'l76', 'l80', 'l83']", + "134, population. ['l66', 'l72', 'l77', 'l81', 'l83']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "helper", + "type", + "1", + "(TH1)", + "cells" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "helper", + "type", + "1", + "(TH1)", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "helper", + "type", + "1", + "(TH1)", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bat3-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "myelin-antigen–specific", + "CD4+" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Bat3", + "knockdown" + ] + }, + "context": { + "val": "cells", + "words": [ + "myelin-antigen–specific", + "CD4+", + "T", + "cells", + "cell", + "population." + ] + } + } + ] + }, + { + "PMID": "22842476", + "TEXT": "Profibrotic cells that develop upon injury generate permanent scar tissue and impair organ recovery, though their origin and fate are unclear. Here we show that transient expression of ADAM12 (a disintegrin and metalloprotease 12) identifies a distinct proinflammatory subset of platelet-derived growth factor receptor-α-positive stromal cells that are activated upon acute injury in the muscle and dermis. By inducible genetic fate mapping, we demonstrate in vivo that injury-induced ADAM12(+) cells are specific progenitors of a major fraction of collagen-overproducing cells generated during scarring, which are progressively eliminated during healing. Genetic ablation of ADAM12(+) cells, or knockdown of ADAM12, is sufficient to limit generation of profibrotic cells and interstitial collagen accumulation. ADAM12(+) cells induced upon injury are developmentally distinct from muscle and skin lineage cells and are derived from fetal ADAM12(+) cells programmed during vascular wall development. Thus, our data identify injury-activated profibrotic progenitors residing in the perivascular space that can be targeted through ADAM12 to limit tissue scarring.", + "TAG_DATA": [ + "64, in {'context': 'B-in vivo'}", + "65, vivo {'context': 'I-in vivo'}", + "89, Genetic {'perturbing_action': 'B-gene loss-of-function'}", + "90, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "92, ADAM12(+) {'context': 'B-cells'}", + "93, cells, {'context': 'I-cells'}", + "95, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "96, of {'perturbing_action': 'I-rnai/knockdown'}", + "97, ADAM12, {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "64, in ['l0']", + "65, vivo ['l0']", + "89, Genetic ['l1', 'l2', 'l3']", + "90, ablation ['l1', 'l4', 'l5']", + "92, ADAM12(+) ['l2', 'l4', 'l6']", + "93, cells, ['l3', 'l5', 'l6']", + "95, knockdown ['l7', 'l8']", + "96, of ['l7', 'l9']", + "97, ADAM12, ['l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "ablation" + ] + }, + "context": { + "val": "cells", + "words": [ + "ADAM12(+)", + "cells," + ] + } + } + ] + }, + { + "PMID": "22820645", + "TEXT": "Primary astrocytomas of grade 3 or 4 according to the classification system of the World Health Organization (high-grade astrocytomas or HGAs) are preponderant among adults and are almost invariably fatal despite the use of multimodal therapy. Here we show that the juvenile brain has an endogenous defense mechanism against HGAs. Neural precursor cells (NPCs) migrate to HGAs, reduce glioma expansion and prolong survival time by releasing endovanilloids that activate the vanilloid receptor (transient receptor potential vanilloid subfamily member-1 or TRPV1) on HGA cells. TRPV1 is highly expressed in tumor and weakly expressed in tumor-free brain. TRPV1 stimulation triggers tumor cell death through the branch of the endoplasmic reticulum stress pathway that is controlled by activating transcription factor-3 (ATF3). The antitumorigenic response of NPCs is lost with aging. NPC-mediated tumor suppression can be mimicked in the adult brain by systemic administration of the synthetic vanilloid arvanil, suggesting that TRPV1 agonists have potential as new HGA therapeutics.", + "TAG_DATA": [ + "50, Neural {'context': 'B-cells'}", + "51, precursor {'context': 'I-cells'}", + "52, cells {'context': 'I-cells'}", + "58, glioma {'context': 'B-neoplasm'}", + "81, HGA {'context': 'B-transformed cells'}", + "82, cells. {'context': 'I-transformed cells'}", + "97, triggers {'effect': 'B-positive'}", + "98, tumor {'context': 'B-neoplasm'}", + "99, cell {'phenotype': 'B-cell death'}", + "100, death {'phenotype': 'I-cell death'}", + "122, NPCs {'context': 'B-cells'}", + "135, adult {'context': 'B-tissue/organ'}", + "136, brain {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "50, Neural ['l0', 'l1', 'l2', 'l3', 'l4']", + "51, precursor ['l0', 'l5', 'l6', 'l7', 'l8']", + "52, cells ['l1', 'l5', 'l9', 'l10', 'l11']", + "58, glioma ['l2', 'l6', 'l9', 'l12']", + "81, HGA ['l3', 'l7', 'l10', 'l13']", + "82, cells. ['l4', 'l8', 'l11', 'l12', 'l13']", + "97, triggers ['l14', 'l15', 'l16']", + "98, tumor ['l14', 'l17', 'l18']", + "99, cell ['l15', 'l17', 'l19']", + "100, death ['l16', 'l18', 'l19']", + "122, NPCs ['l20', 'l21']", + "135, adult ['l20', 'l22']", + "136, brain ['l21', 'l22']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + } + ] + }, + { + "PMID": "22820643", + "TEXT": "The inactivation of the p53 tumor suppressor pathway, which often occurs through mutations in TP53 (encoding tumor protein 53) is a common step in human cancer. However, in melanoma-a highly chemotherapy-resistant disease-TP53 mutations are rare, raising the possibility that this cancer uses alternative ways to overcome p53-mediated tumor suppression. Here we show that Mdm4 p53 binding protein homolog (MDM4), a negative regulator of p53, is upregulated in a substantial proportion (∼65%) of stage I-IV human melanomas and that melanocyte-specific Mdm4 overexpression enhanced tumorigenesis in a mouse model of melanoma induced by the oncogene Nras. MDM4 promotes the survival of human metastatic melanoma by antagonizing p53 proapoptotic function. Notably, inhibition of the MDM4-p53 interaction restored p53 function in melanoma cells, resulting in increased sensitivity to cytotoxic chemotherapy and to inhibitors of the BRAF (V600E) oncogene. Our results identify MDM4 as a key determinant of impaired p53 function in human melanoma and designate MDM4 as a promising target for antimelanoma combination therapy.", + "TAG_DATA": [ + "78, melanocyte-specific {'perturbing_action': 'B-gene gain-of-function'}", + "79, Mdm4 {'perturbing_action': 'I-gene gain-of-function'}", + "80, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "81, enhanced {'effect': 'B-positive'}", + "82, tumorigenesis {'phenotype': 'B-tumourigenesis'}", + "85, mouse {'context': 'B-neoplasm'}", + "86, model {'context': 'I-neoplasm'}", + "87, of {'context': 'I-neoplasm'}", + "88, melanoma {'context': 'I-neoplasm'}", + "89, induced {'effect': 'B-positive'}", + "99, human {'context': 'B-neoplasm'}", + "100, metastatic {'context': 'I-neoplasm'}", + "101, melanoma {'context': 'I-neoplasm'}", + "117, melanoma {'context': 'B-transformed cells'}", + "118, cells, {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "78, melanocyte-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "79, Mdm4 ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "80, overexpression ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "81, enhanced ['l2', 'l10', 'l17', 'l24']", + "82, tumorigenesis ['l3', 'l11', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "85, mouse ['l4', 'l12', 'l19', 'l25', 'l30', 'l31', 'l32', 'l33']", + "86, model ['l5', 'l13', 'l20', 'l26', 'l30', 'l34', 'l35', 'l36', 'l37']", + "87, of ['l6', 'l14', 'l21', 'l27', 'l31', 'l34', 'l38', 'l39', 'l40']", + "88, melanoma ['l7', 'l15', 'l22', 'l28', 'l32', 'l35', 'l38', 'l41', 'l42', 'l43', 'l44']", + "89, induced ['l8', 'l16', 'l23', 'l29', 'l33', 'l36', 'l39', 'l41', 'l45', 'l46', 'l47']", + "99, human ['l42', 'l45', 'l48', 'l49']", + "100, metastatic ['l43', 'l46', 'l48', 'l50']", + "101, melanoma ['l37', 'l40', 'l44', 'l47', 'l49', 'l50']", + "117, melanoma ['l51']", + "118, cells, ['l51']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "melanocyte-specific", + "Mdm4", + "overexpression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced", + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "melanocyte-specific", + "Mdm4", + "overexpression" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "melanocyte-specific", + "Mdm4", + "overexpression" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "melanoma" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced", + "induced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "melanoma" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "model", + "of", + "melanoma", + "human", + "metastatic" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "22820642", + "TEXT": "Breast cancer metastasis is a key determinant of long-term patient survival. By comparing the transcriptomes of primary and metastatic tumor cells in a mouse model of spontaneous bone metastasis, we found that a substantial number of genes suppressed in bone metastases are targets of the interferon regulatory factor Irf7. Restoration of Irf7 in tumor cells or administration of interferon led to reduced bone metastases and prolonged survival time. In mice deficient in the interferon (IFN) receptor or in natural killer (NK) and CD8(+) T cell responses, metastasis was accelerated, indicating that Irf7-driven suppression of metastasis was reliant on IFN signaling to host immune cells. We confirmed the clinical relevance of these findings in over 800 patients in which high expression of Irf7-regulated genes in primary tumors was associated with prolonged bone metastasis-free survival. This gene signature may identify patients that could benefit from IFN-based therapies. Thus, we have identified an innate immune pathway intrinsic to breast cancer cells, the suppression of which restricts immunosurveillance to enable metastasis.", + "TAG_DATA": [ + "23, mouse {'context': 'B-organism'}", + "24, model {'context': 'I-organism'}", + "49, Restoration {'perturbing_action': 'B-gene gain-of-function'}", + "50, of {'perturbing_action': 'I-gene gain-of-function'}", + "51, Irf7 {'perturbing_action': 'I-gene gain-of-function'}", + "53, tumor {'context': 'B-transformed cells'}", + "54, cells {'context': 'I-transformed cells'}", + "61, reduced {'effect': 'B-negative'}", + "62, bone {'phenotype': 'B-metastasis'}", + "63, metastases {'phenotype': 'I-metastasis'}", + "69, mice {'context': 'B-organism'}", + "70, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "71, in {'perturbing_action': 'I-gene loss-of-function'}", + "72, the {'perturbing_action': 'I-gene loss-of-function'}", + "86, metastasis {'phenotype': 'B-metastasis'}", + "88, accelerated, {'effect': 'B-positive'}" + ], + "LINK_DATA": [ + "23, mouse ['l0', 'l1', 'l2', 'l3']", + "24, model ['l0', 'l4', 'l5', 'l6']", + "49, Restoration ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "50, of ['l7', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "51, Irf7 ['l8', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "53, tumor ['l9', 'l15', 'l20', 'l25', 'l26', 'l27', 'l28']", + "54, cells ['l10', 'l16', 'l21', 'l25', 'l29', 'l30', 'l31']", + "61, reduced ['l1', 'l4', 'l11', 'l17', 'l22', 'l26', 'l29', 'l32', 'l33']", + "62, bone ['l2', 'l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l32', 'l34']", + "63, metastases ['l3', 'l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l34']", + "69, mice ['l35', 'l36', 'l37', 'l38', 'l39']", + "70, deficient ['l35', 'l40', 'l41', 'l42', 'l43']", + "71, in ['l36', 'l40', 'l44', 'l45', 'l46']", + "72, the ['l37', 'l41', 'l44', 'l47', 'l48']", + "86, metastasis ['l38', 'l42', 'l45', 'l47', 'l49']", + "88, accelerated, ['l39', 'l43', 'l46', 'l48', 'l49']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "mice" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "bone", + "metastases", + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoration", + "of", + "Irf7" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoration", + "of", + "Irf7" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoration", + "of", + "Irf7" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "bone", + "metastases" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "bone", + "metastases" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "bone", + "metastases" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "the" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerated," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "the" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "the" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerated," + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerated," + ] + } + } + ] + }, + { + "PMID": "22797810", + "TEXT": "Temporal lobe epilepsy (TLE) is accompanied by an abnormal location of granule cells in the dentate gyrus. Using a rat model of complex febrile seizures, which are thought to be a precipitating insult of TLE later in life, we report that aberrant migration of neonatal-generated granule cells results in granule cell ectopia that persists into adulthood. Febrile seizures induced an upregulation of GABA(A) receptors (GABA(A)-Rs) in neonatally generated granule cells, and hyperactivation of excitatory GABA(A)-Rs caused a reversal in the direction of granule cell migration. This abnormal migration was prevented by RNAi-mediated knockdown of the Na(+)K(+)2Cl(-) co-transporter (NKCC1), which regulates the excitatory action of GABA. NKCC1 inhibition with bumetanide after febrile seizures rescued the granule cell ectopia, susceptibility to limbic seizures and development of epilepsy. Thus, this work identifies a previously unknown pathogenic role of excitatory GABA(A)-R signaling and highlights NKCC1 as a potential therapeutic target for preventing granule cell ectopia and the development of epilepsy after febrile seizures.", + "TAG_DATA": [ + "44, neonatal-generated {'context': 'B-cells'}", + "45, granule {'context': 'I-cells'}", + "46, cells {'context': 'I-cells'}", + "66, neonatally {'context': 'B-cells'}", + "67, generated {'context': 'B-cells'}", + "68, granule {'context': 'I-cells'}", + "69, cells, {'context': 'I-cells'}", + "82, granule {'context': 'B-cells'}", + "83, cell {'context': 'I-cells'}", + "84, migration. {'phenotype': 'B-migration'}", + "87, migration {'phenotype': 'B-migration'}", + "91, RNAi-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "92, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "93, of {'perturbing_action': 'I-rnai/knockdown'}", + "94, the {'perturbing_action': 'I-rnai/knockdown'}", + "95, Na(+)K(+)2Cl(-) {'perturbing_action': 'I-rnai/knockdown'}", + "96, co-transporter {'perturbing_action': 'I-rnai/knockdown'}", + "97, (NKCC1), {'perturbing_action': 'I-rnai/knockdown'}", + "105, NKCC1 {'perturbing_action': 'B-pharmacological inhibition'}", + "106, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "107, with {'perturbing_action': 'I-pharmacological inhibition'}", + "108, bumetanide {'perturbing_action': 'I-pharmacological inhibition'}", + "112, rescued {'effect': 'B-rescues'}", + "114, granule {'context': 'B-cells'}", + "115, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "44, neonatal-generated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "45, granule ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "46, cells ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "66, neonatally ['l2', 'l10', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "67, generated ['l3', 'l11', 'l18', 'l23', 'l30', 'l31', 'l32', 'l33', 'l34']", + "68, granule ['l4', 'l12', 'l19', 'l24', 'l30', 'l35', 'l36', 'l37', 'l38']", + "69, cells, ['l5', 'l13', 'l20', 'l25', 'l31', 'l35', 'l39', 'l40', 'l41']", + "82, granule ['l6', 'l14', 'l26', 'l32', 'l36', 'l39', 'l42', 'l43', 'l44']", + "83, cell ['l7', 'l15', 'l21', 'l27', 'l33', 'l37', 'l40', 'l42', 'l45']", + "84, migration. ['l8', 'l16', 'l22', 'l28', 'l34', 'l38', 'l41', 'l43', 'l45']", + "87, migration ['l29', 'l44']", + "91, RNAi-mediated ['l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "92, knockdown ['l46', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "93, of ['l47', 'l53', 'l59', 'l60', 'l61', 'l62', 'l63']", + "94, the ['l48', 'l54', 'l59', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "95, Na(+)K(+)2Cl(-) ['l49', 'l55', 'l60', 'l64', 'l70', 'l71', 'l72', 'l73', 'l74']", + "96, co-transporter ['l50', 'l56', 'l61', 'l65', 'l70', 'l75', 'l76', 'l77', 'l78']", + "97, (NKCC1), ['l51', 'l57', 'l62', 'l66', 'l71', 'l75', 'l79', 'l80']", + "105, NKCC1 ['l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "106, inhibition ['l81', 'l87', 'l88', 'l89', 'l90', 'l91']", + "107, with ['l82', 'l87', 'l92', 'l93', 'l94', 'l95']", + "108, bumetanide ['l83', 'l88', 'l92', 'l96', 'l97', 'l98']", + "112, rescued ['l67', 'l72', 'l76', 'l84', 'l89', 'l93', 'l96', 'l99', 'l100']", + "114, granule ['l68', 'l73', 'l77', 'l79', 'l85', 'l90', 'l94', 'l97', 'l99', 'l101']", + "115, cell ['l52', 'l58', 'l63', 'l69', 'l74', 'l78', 'l80', 'l86', 'l91', 'l95', 'l98', 'l100', 'l101']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "neonatal-generated", + "granule", + "cells", + "neonatally", + "generated", + "cells,", + "cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration.", + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "RNAi-mediated", + "knockdown", + "of", + "the", + "Na(+)K(+)2Cl(-)", + "co-transporter", + "(NKCC1)," + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "granule" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "the", + "Na(+)K(+)2Cl(-)", + "co-transporter" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NKCC1", + "inhibition", + "with", + "bumetanide" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NKCC1", + "inhibition", + "with", + "bumetanide" + ] + }, + "context": { + "val": "cells", + "words": [ + "granule", + "cell" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "context": { + "val": "cells", + "words": [ + "granule", + "cell" + ] + } + } + ] + }, + { + "PMID": "22772464", + "TEXT": "Interleukin-9 (IL-9) is a T cell cytokine that acts through a γC-family receptor on target cells and is associated with inflammation and allergy. We determined that T cells from mice deficient in the T helper type 17 (T(H)17) pathway genes encoding retinoid-related orphan receptor γ (ROR-γ) and IL-23 receptor (IL-23R) produced abundant IL-9, and we found substantial growth inhibition of B16F10 melanoma in these mice. IL-9-blocking antibodies reversed this tumor growth inhibition and enhanced tumor growth in wild-type (WT) mice. Il9r(-/-) mice showed accelerated tumor growth, and administration of recombinant IL-9 (rIL-9) to tumor-bearing WT and Rag1(-/-) mice inhibited melanoma as well as lung carcinoma growth. Adoptive transfer of tumor-antigen-specific T(H)9 cells into both WT and Rag1(-/-) mice suppressed melanoma growth; this effect was abrogated by treatment with neutralizing antibodies to IL-9. Exogenous rIL-9 inhibited tumor growth in Rag1(-/-) mice but not in mast-cell-deficient mice, suggesting that the targets of IL-9 in this setting include mast cells but not T or B cells. In addition, we found higher numbers of T(H)9 cells in normal human skin and blood compared to metastatic lesions of subjects with progressive stage IV melanoma. These results suggest a role for IL-9 in tumor immunity and offer insight into potential therapeutic strategies.", + "TAG_DATA": [ + "26, T {'context': 'B-cells'}", + "27, cells {'context': 'B-cells'}", + "29, mice {'context': 'B-organism'}", + "60, B16F10 {'context': 'B-neoplasm'}", + "61, melanoma {'context': 'I-neoplasm'}", + "64, mice. {'context': 'B-organism'}", + "67, reversed {'effect': 'B-rescues'}", + "69, tumor {'phenotype': 'B-tumour growth'}", + "70, growth {'phenotype': 'I-tumour growth'}", + "71, inhibition {'effect': 'B-negative'}", + "73, enhanced {'effect': 'B-positive'}", + "74, tumor {'phenotype': 'B-tumour growth'}", + "75, growth {'phenotype': 'I-tumour growth'}", + "79, mice. {'context': 'B-organism'}", + "80, Il9r(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "81, mice {'context': 'B-organism'}", + "83, accelerated {'effect': 'B-positive'}", + "84, tumor {'phenotype': 'B-tumour growth'}", + "85, growth, {'phenotype': 'I-tumour growth'}", + "94, WT {'context': 'I-organism'}", + "96, Rag1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "97, mice {'context': 'B-organism'}", + "98, inhibited {'effect': 'B-negative'}", + "99, melanoma {'context': 'B-neoplasm'}", + "103, lung {'context': 'B-neoplasm'}", + "104, carcinoma {'context': 'I-neoplasm'}", + "110, T(H)9 {'context': 'I-cells'}", + "111, cells {'context': 'I-cells'}", + "116, Rag1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "117, mice {'context': 'B-organism'}", + "118, suppressed {'effect': 'B-negative'}", + "119, melanoma {'context': 'B-neoplasm'}", + "134, inhibited {'effect': 'B-negative'}", + "135, tumor {'phenotype': 'B-tumour growth'}", + "136, growth {'phenotype': 'I-tumour growth'}", + "138, Rag1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "139, mice {'context': 'B-organism'}", + "143, mast-cell-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "144, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "26, T ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "27, cells ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "29, mice ['l1', 'l12', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "60, B16F10 ['l2', 'l13', 'l24', 'l35', 'l36', 'l37', 'l38', 'l39']", + "61, melanoma ['l3', 'l14', 'l25', 'l35', 'l40']", + "64, mice. ['l4', 'l15', 'l26', 'l36', 'l40', 'l41', 'l42']", + "67, reversed ['l5', 'l16', 'l27', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "69, tumor ['l6', 'l17', 'l28', 'l37', 'l41', 'l43', 'l50', 'l51', 'l52']", + "70, growth ['l7', 'l18', 'l29', 'l38', 'l42', 'l44', 'l50', 'l53', 'l54', 'l55']", + "71, inhibition ['l8', 'l19', 'l30', 'l39', 'l45', 'l51', 'l53', 'l56', 'l57']", + "73, enhanced ['l9', 'l20', 'l31', 'l46', 'l58', 'l59', 'l60']", + "74, tumor ['l10', 'l21', 'l32', 'l47', 'l54', 'l56', 'l58', 'l61']", + "75, growth ['l11', 'l22', 'l33', 'l48', 'l52', 'l55', 'l57', 'l59', 'l61']", + "79, mice. ['l23', 'l34', 'l49', 'l60']", + "80, Il9r(-/-) ['l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "81, mice ['l62', 'l73', 'l74', 'l75', 'l76']", + "83, accelerated ['l63', 'l73', 'l77', 'l78']", + "84, tumor ['l64', 'l74', 'l77', 'l79']", + "85, growth, ['l65', 'l75', 'l78', 'l79']", + "93, tumor-bearing ['l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "94, WT ['l66', 'l80', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "96, Rag1(-/-) ['l67', 'l81', 'l87', 'l93', 'l94', 'l95', 'l96', 'l97']", + "97, mice ['l68', 'l82', 'l88', 'l93', 'l98', 'l99', 'l100', 'l101']", + "98, inhibited ['l69', 'l83', 'l89', 'l94', 'l98', 'l102', 'l103', 'l104']", + "99, melanoma ['l70', 'l76', 'l84', 'l90', 'l95', 'l99', 'l102', 'l105', 'l106']", + "103, lung ['l71', 'l85', 'l91', 'l96', 'l100', 'l103', 'l105', 'l107']", + "104, carcinoma ['l72', 'l86', 'l92', 'l97', 'l101', 'l104', 'l106', 'l107']", + "110, T(H)9 ['l108', 'l109', 'l110', 'l111', 'l112']", + "111, cells ['l108', 'l113', 'l114', 'l115', 'l116']", + "116, Rag1(-/-) ['l109', 'l113', 'l117', 'l118', 'l119']", + "117, mice ['l110', 'l114', 'l117', 'l120', 'l121']", + "118, suppressed ['l111', 'l115', 'l118', 'l120', 'l122']", + "119, melanoma ['l112', 'l116', 'l119', 'l121', 'l122']", + "134, inhibited ['l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "135, tumor ['l123', 'l129', 'l130', 'l131', 'l132', 'l133']", + "136, growth ['l124', 'l129', 'l134', 'l135', 'l136', 'l137']", + "138, Rag1(-/-) ['l125', 'l130', 'l134', 'l138', 'l139', 'l140']", + "139, mice ['l126', 'l131', 'l135', 'l138', 'l141', 'l142']", + "143, mast-cell-deficient ['l127', 'l132', 'l136', 'l139', 'l141', 'l143']", + "144, mice, ['l128', 'l133', 'l137', 'l140', 'l142', 'l143']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "reversed" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "T(H)9" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition", + "suppressed" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "effect": { + "val": "rescues", + "words": [ + "reversed" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "mice," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth", + "growth," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "WT", + "mice," + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition", + "inhibited", + "suppressed" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced", + "accelerated" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "B16F10" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "B16F10", + "melanoma", + "lung", + "carcinoma" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition", + "inhibited", + "suppressed" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "reversed" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition", + "inhibited" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced", + "accelerated" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth", + "growth," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Il9r(-/-)", + "Rag1(-/-)", + "mast-cell-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "WT", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Il9r(-/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerated" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Il9r(-/-)", + "Rag1(-/-)", + "mast-cell-deficient" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth,", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Il9r(-/-)", + "Rag1(-/-)", + "mast-cell-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Il9r(-/-)", + "Rag1(-/-)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "melanoma", + "lung", + "carcinoma" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T(H)9", + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rag1(-/-)" + ] + } + } + ] + }, + { + "PMID": "22729284", + "TEXT": "Embryo implantation remains a poorly understood process. We demonstrate here that activation of the epithelial Na⁺ channel (ENaC) in mouse endometrial epithelial cells by an embryo-released serine protease, trypsin, triggers Ca²⁺ influx that leads to prostaglandin E₂ (PGE₂) release, phosphorylation of the transcription factor CREB and upregulation of cyclooxygenase 2, the enzyme required for prostaglandin production and implantation. We detected maximum ENaC activation, as indicated by ENaC cleavage, at the time of implantation in mice. Blocking or knocking down uterine ENaC in mice resulted in implantation failure. Furthermore, we found that uterine ENaC expression before in vitro fertilization (IVF) treatment is markedly lower in women with implantation failure as compared to those with successful pregnancy. These results indicate a previously undefined role of ENaC in regulating the PGE₂ production and release required for embryo implantation, defects that may be a cause of miscarriage and low success rates in IVF.", + "TAG_DATA": [ + "19, mouse {'context': 'B-cells'}", + "20, endometrial {'context': 'I-cells'}", + "21, epithelial {'context': 'I-cells'}", + "22, cells {'context': 'I-cells'}", + "74, mice. {'context': 'B-organism'}", + "77, knocking {'perturbing_action': 'B-rnai/knockdown'}", + "78, down {'perturbing_action': 'I-rnai/knockdown'}", + "79, uterine {'perturbing_action': 'I-rnai/knockdown'}", + "80, ENaC {'perturbing_action': 'I-rnai/knockdown'}", + "82, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "19, mouse ['l0', 'l1', 'l2', 'l3']", + "20, endometrial ['l0', 'l4', 'l5', 'l6']", + "21, epithelial ['l1', 'l4', 'l7', 'l8']", + "22, cells ['l2', 'l5', 'l7', 'l9']", + "74, mice. ['l3', 'l6', 'l8', 'l9']", + "77, knocking ['l10', 'l11', 'l12', 'l13', 'l14']", + "78, down ['l10', 'l15', 'l16', 'l17', 'l18']", + "79, uterine ['l11', 'l15', 'l19', 'l20', 'l21']", + "80, ENaC ['l12', 'l16', 'l19', 'l22', 'l23']", + "82, mice ['l13', 'l17', 'l20', 'l22', 'l24']", + "85, implantation ['l14', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knocking", + "down", + "uterine", + "ENaC" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "22729283", + "TEXT": "Insulin-like growth factor 1 (IGF-1), the most abundant growth factor in the bone matrix, maintains bone mass in adulthood. We now report that IGF-1 released from the bone matrix during bone remodeling stimulates osteoblastic differentiation of recruited mesenchymal stem cells (MSCs) by activation of mammalian target of rapamycin (mTOR), thus maintaining proper bone microarchitecture and mass. Mice with knockout of the IGF-1 receptor (Igf1r) in their pre-osteoblastic cells showed lower bone mass and mineral deposition rates than wild-type mice. Further, MSCs from Igf1rflox/flox mice with Igf1r deleted by a Cre adenovirus in vitro, although recruited to the bone surface after implantation, were unable to differentiate into osteoblasts. We also found that the concentrations of IGF-1 in the bone matrix and marrow of aged rats were lower than in those of young rats and directly correlated with the age-related decrease in bone mass. Likewise, in age-related osteoporosis in humans, we found that bone marrow IGF-1 concentrations were 40% lower in individuals with osteoporosis than in individuals without osteoporosis. Notably, injection of IGF-1 plus IGF binding protein 3 (IGFBP3), but not injection of IGF-1 alone, increased the concentration of IGF-1 in the bone matrix and stimulated new bone formation in aged rats. Together, these results provide mechanistic insight into how IGF-1 maintains adult bone mass, while also providing a further rationale for its therapeutic targeting to treat age-related osteoporosis.", + "TAG_DATA": [ + "56, Mice {'context': 'B-organism'}", + "58, knockout {'perturbing_action': 'B-gene loss-of-function'}", + "59, of {'perturbing_action': 'I-gene loss-of-function'}", + "60, the {'perturbing_action': 'I-gene loss-of-function'}", + "61, IGF-1 {'perturbing_action': 'I-gene loss-of-function'}", + "62, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "63, (Igf1r) {'perturbing_action': 'I-gene loss-of-function'}", + "66, pre-osteoblastic {'context': 'B-cells'}", + "67, cells {'context': 'I-cells'}", + "78, mice. {'context': 'B-organism'}", + "80, MSCs {'context': 'B-cells'}", + "82, Igf1rflox/flox {'perturbing_action': 'B-gene loss-of-function'}", + "83, mice {'context': 'B-organism'}", + "85, Igf1r {'perturbing_action': 'B-gene loss-of-function'}", + "86, deleted {'perturbing_action': 'I-gene loss-of-function'}", + "87, by {'perturbing_action': 'I-gene loss-of-function'}", + "88, a {'perturbing_action': 'I-gene loss-of-function'}", + "89, Cre {'perturbing_action': 'I-gene loss-of-function'}", + "90, adenovirus {'perturbing_action': 'I-gene loss-of-function'}", + "91, in {'context': 'B-in vitro'}", + "92, vitro, {'context': 'I-in vitro'}", + "102, unable {'effect': 'B-negative'}", + "104, differentiate {'phenotype': 'B-differentiation'}", + "106, osteoblasts. {'phenotype': 'B-differentiation'}", + "122, aged {'context': 'B-organism'}", + "123, rats {'context': 'I-organism'}", + "193, stimulated {'effect': 'B-positive'}", + "198, aged {'context': 'B-organism'}", + "199, rats. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "56, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "58, knockout ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "59, of ['l1', 'l9', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "60, the ['l2', 'l10', 'l18', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "61, IGF-1 ['l3', 'l11', 'l19', 'l29', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "62, receptor ['l4', 'l12', 'l20', 'l30', 'l40', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "63, (Igf1r) ['l5', 'l13', 'l21', 'l31', 'l41', 'l50', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "66, pre-osteoblastic ['l6', 'l14', 'l22', 'l32', 'l42', 'l51', 'l59', 'l66', 'l67']", + "67, cells ['l7', 'l15', 'l23', 'l33', 'l43', 'l52', 'l60', 'l66', 'l68']", + "78, mice. ['l8', 'l16', 'l24', 'l34', 'l44', 'l53', 'l61', 'l67', 'l68']", + "80, MSCs ['l17', 'l25', 'l35', 'l45', 'l54', 'l62', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "82, Igf1rflox/flox ['l26', 'l36', 'l46', 'l55', 'l63', 'l69', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "83, mice ['l70', 'l83', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "85, Igf1r ['l84', 'l98', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "86, deleted ['l85', 'l99', 'l112', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "87, by ['l71', 'l86', 'l100', 'l113', 'l125', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "88, a ['l72', 'l87', 'l101', 'l114', 'l126', 'l137', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "89, Cre ['l73', 'l88', 'l102', 'l115', 'l127', 'l138', 'l148', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166']", + "90, adenovirus ['l74', 'l89', 'l103', 'l116', 'l128', 'l139', 'l149', 'l158', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "91, in ['l75', 'l90', 'l104', 'l117', 'l129', 'l140', 'l150', 'l159', 'l167', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181']", + "92, vitro, ['l37', 'l47', 'l56', 'l76', 'l91', 'l105', 'l118', 'l130', 'l141', 'l151', 'l160', 'l168', 'l175', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "102, unable ['l77', 'l92', 'l106', 'l119', 'l131', 'l142', 'l152', 'l161', 'l169', 'l176', 'l182', 'l188', 'l189', 'l190', 'l191', 'l192']", + "103, to ['l78', 'l93', 'l107', 'l120', 'l132', 'l143', 'l153', 'l162', 'l170', 'l177', 'l183', 'l188', 'l193', 'l194', 'l195', 'l196']", + "104, differentiate ['l79', 'l94', 'l108', 'l121', 'l133', 'l144', 'l154', 'l163', 'l171', 'l178', 'l184', 'l189', 'l193', 'l197', 'l198', 'l199']", + "106, osteoblasts. ['l80', 'l95', 'l109', 'l122', 'l134', 'l145', 'l155', 'l164', 'l172', 'l179', 'l185', 'l190', 'l194', 'l197', 'l200', 'l201']", + "122, aged ['l27', 'l38', 'l48', 'l57', 'l64', 'l81', 'l96', 'l110', 'l123', 'l135', 'l146', 'l156', 'l165', 'l173', 'l180', 'l186', 'l191', 'l195', 'l198', 'l200', 'l202']", + "123, rats ['l28', 'l39', 'l49', 'l58', 'l65', 'l82', 'l97', 'l111', 'l124', 'l136', 'l147', 'l157', 'l166', 'l174', 'l181', 'l187', 'l192', 'l196', 'l199', 'l201', 'l202']", + "193, stimulated ['l203', 'l204']", + "198, aged ['l203', 'l205']", + "199, rats. ['l204', 'l205']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice", + "mice.", + "aged", + "rats", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout", + "of", + "the", + "IGF-1", + "receptor", + "(Igf1r)", + "Igf1rflox/flox", + "Igf1r", + "deleted", + "by", + "a", + "Cre", + "adenovirus" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout", + "of", + "the", + "IGF-1", + "receptor", + "(Igf1r)", + "Igf1rflox/flox", + "by", + "a", + "Cre", + "adenovirus" + ] + }, + "context": { + "val": "cells", + "words": [ + "pre-osteoblastic", + "cells", + "MSCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "IGF-1", + "receptor", + "Igf1rflox/flox", + "Igf1r", + "deleted", + "by", + "a", + "Cre", + "adenovirus" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "vitro,", + "in" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "MSCs" + ] + }, + "effect": { + "val": "negative", + "words": [ + "unable" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "MSCs" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate", + "osteoblasts." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Igf1rflox/flox", + "Igf1r", + "deleted", + "by", + "a", + "Cre", + "adenovirus" + ] + }, + "effect": { + "val": "negative", + "words": [ + "unable" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Igf1rflox/flox", + "Igf1r", + "deleted", + "by", + "a", + "Cre", + "adenovirus" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate", + "osteoblasts." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "aged", + "rats" + ] + }, + "effect": { + "val": "negative", + "words": [ + "unable" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "aged", + "rats" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate", + "osteoblasts." + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + }, + "effect": { + "val": "negative", + "words": [ + "unable" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate", + "osteoblasts." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "unable" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiate", + "osteoblasts." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + }, + "context": { + "val": "organism", + "words": [ + "aged", + "rats." + ] + } + } + ] + }, + { + "PMID": "22635005", + "TEXT": "Tumor-derived exosomes are emerging mediators of tumorigenesis. We explored the function of melanoma-derived exosomes in the formation of primary tumors and metastases in mice and human subjects. Exosomes from highly metastatic melanomas increased the metastatic behavior of primary tumors by permanently 'educating' bone marrow progenitors through the receptor tyrosine kinase MET. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites and reprogrammed bone marrow progenitors toward a pro-vasculogenic phenotype that was positive for c-Kit, the receptor tyrosine kinase Tie2 and Met. Reducing Met expression in exosomes diminished the pro-metastatic behavior of bone marrow cells. Notably, MET expression was elevated in circulating CD45(-)C-KIT(low/+)TIE2(+) bone marrow progenitors from individuals with metastatic melanoma. RAB1A, RAB5B, RAB7 and RAB27A, regulators of membrane trafficking and exosome formation, were highly expressed in melanoma cells. Rab27A RNA interference decreased exosome production, preventing bone marrow education and reducing, tumor growth and metastasis. In addition, we identified an exosome-specific melanoma signature with prognostic and therapeutic potential comprised of TYRP2, VLA-4, HSP70, an HSP90 isoform and the MET oncoprotein. Our data show that exosome production, transfer and education of bone marrow cells supports tumor growth and metastasis, has prognostic value and offers promise for new therapeutic directions in the metastatic process.", + "TAG_DATA": [ + "62, bone {'context': 'B-cells'}", + "63, marrow {'context': 'I-cells'}", + "64, progenitors {'context': 'I-cells'}", + "91, bone {'context': 'B-cells'}", + "92, marrow {'context': 'I-cells'}", + "93, cells. {'context': 'I-cells'}", + "128, Rab27A {'perturbing_action': 'B-rnai/knockdown'}", + "129, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "130, interference {'perturbing_action': 'I-rnai/knockdown'}", + "139, reducing, {'effect': 'B-negative'}", + "140, tumor {'phenotype': 'B-tumour growth'}", + "141, growth {'phenotype': 'I-tumour growth'}", + "143, metastasis. {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "62, bone ['l0', 'l1', 'l2', 'l3', 'l4']", + "63, marrow ['l0', 'l5', 'l6', 'l7', 'l8']", + "64, progenitors ['l1', 'l5', 'l9', 'l10', 'l11']", + "91, bone ['l2', 'l6', 'l9', 'l12', 'l13']", + "92, marrow ['l3', 'l7', 'l10', 'l12', 'l14']", + "93, cells. ['l4', 'l8', 'l11', 'l13', 'l14']", + "128, Rab27A ['l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "129, RNA ['l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "130, interference ['l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "139, reducing, ['l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "140, tumor ['l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "141, growth ['l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "143, metastasis. ['l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Rab27A", + "RNA", + "interference" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reducing," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Rab27A", + "RNA", + "interference" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Rab27A", + "RNA", + "interference" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reducing," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reducing," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + } + ] + }, + { + "PMID": "22561688", + "TEXT": "Smoking is the only modifiable risk factor that is associated with the development, expansion and rupture of abdominal aortic aneurysm (AAA). However, the causative link between cigarette smoke and AAA is unknown. Here we report a causative link between smoking and AAA in vivo. Acute infusion of angiotensin II (AngII) or nicotine, a major component of cigarette smoke, markedly increased the incidence of AAA in apolipoprotein E (apoE) knockout (Apoe(-/-)) mice and in mice deficient in both apoE and the AMP-activated kinase α1 subunit (AMPK-α1) (Apoe(-/-); Prkaa1(-/-) mice). In contrast, genetic deletion of AMPK-α2 (Apoe(-/-); Prkaa2(-/-) mice) ablated nicotine- or AngII-triggered AAA in vivo. Mechanistically, we found that both nicotine and AngII activated AMPK-α2 in cultured vascular smooth muscle cells (VSMCs), resulting in the phosphorylation of activator protein 2α (AP-2α) and consequent matrix metallopeptidase 2 (MMP2) gene expression. We conclude that smoking (through nicotine) instigates AAA through AMPK-α2–mediated AP-2α–dependent MMP2 expression in VSMCs.", + "TAG_DATA": [ + "63, AAA {'context': 'B-neoplasm'}", + "65, apolipoprotein {'perturbing_action': 'B-gene loss-of-function'}", + "66, E {'perturbing_action': 'I-gene loss-of-function'}", + "67, (apoE) {'perturbing_action': 'I-gene loss-of-function'}", + "68, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "69, (Apoe(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "70, mice {'context': 'B-organism'}", + "73, mice {'context': 'B-organism'}", + "74, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "75, in {'perturbing_action': 'I-gene loss-of-function'}", + "76, both {'perturbing_action': 'I-gene loss-of-function'}", + "77, apoE {'perturbing_action': 'I-gene loss-of-function'}", + "78, and {'perturbing_action': 'I-gene loss-of-function'}", + "79, the {'perturbing_action': 'I-gene loss-of-function'}", + "80, AMP-activated {'perturbing_action': 'I-gene loss-of-function'}", + "81, kinase {'perturbing_action': 'I-gene loss-of-function'}", + "82, α1 {'perturbing_action': 'I-gene loss-of-function'}", + "83, subunit {'perturbing_action': 'I-gene loss-of-function'}", + "84, (AMPK-α1) {'perturbing_action': 'I-gene loss-of-function'}", + "85, (Apoe(-/-); {'perturbing_action': 'I-gene loss-of-function'}", + "86, Prkaa1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "87, mice). {'context': 'B-organism'}", + "90, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "91, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "92, of {'perturbing_action': 'I-gene loss-of-function'}", + "93, AMPK-α2 {'perturbing_action': 'I-gene loss-of-function'}", + "94, (Apoe(-/-); {'perturbing_action': 'I-gene loss-of-function'}", + "95, Prkaa2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "96, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "101, AAA {'context': 'B-neoplasm'}", + "102, in {'context': 'B-in vivo'}", + "103, vivo. {'context': 'I-in vivo'}", + "116, vascular {'context': 'B-cells'}", + "117, smooth {'context': 'I-cells'}", + "118, muscle {'context': 'I-cells'}", + "119, cells {'context': 'I-cells'}", + "120, (VSMCs), {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "63, AAA ['l0', 'l1', 'l2']", + "65, apolipoprotein ['l3', 'l4', 'l5', 'l6', 'l7']", + "66, E ['l3', 'l8', 'l9', 'l10', 'l11']", + "67, (apoE) ['l4', 'l8', 'l12', 'l13', 'l14']", + "68, knockout ['l0', 'l5', 'l9', 'l12', 'l15', 'l16']", + "69, (Apoe(-/-)) ['l1', 'l6', 'l10', 'l13', 'l15', 'l17']", + "70, mice ['l2', 'l7', 'l11', 'l14', 'l16', 'l17']", + "73, mice ['l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "74, deficient ['l18', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "75, in ['l19', 'l32', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "76, both ['l20', 'l33', 'l46', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "77, apoE ['l21', 'l34', 'l47', 'l65', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "78, and ['l22', 'l35', 'l48', 'l66', 'l81', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "79, the ['l23', 'l36', 'l49', 'l67', 'l82', 'l93', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "80, AMP-activated ['l24', 'l37', 'l50', 'l68', 'l83', 'l94', 'l108', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "81, kinase ['l25', 'l38', 'l51', 'l69', 'l84', 'l95', 'l109', 'l123', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "82, α1 ['l26', 'l39', 'l52', 'l70', 'l85', 'l96', 'l110', 'l124', 'l137', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "83, subunit ['l27', 'l40', 'l53', 'l71', 'l86', 'l97', 'l111', 'l125', 'l138', 'l150', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "84, (AMPK-α1) ['l28', 'l41', 'l54', 'l72', 'l87', 'l98', 'l112', 'l126', 'l139', 'l151', 'l162', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "85, (Apoe(-/-); ['l29', 'l42', 'l55', 'l73', 'l88', 'l99', 'l113', 'l127', 'l140', 'l152', 'l163', 'l173', 'l183', 'l184', 'l185']", + "86, Prkaa1(-/-) ['l30', 'l43', 'l56', 'l74', 'l89', 'l100', 'l114', 'l128', 'l141', 'l153', 'l164', 'l174', 'l183', 'l186', 'l187', 'l188']", + "87, mice). ['l31', 'l44', 'l57', 'l75', 'l90', 'l101', 'l115', 'l129', 'l142', 'l154', 'l165', 'l175', 'l184', 'l186']", + "90, genetic ['l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202']", + "91, deletion ['l189', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215']", + "92, of ['l190', 'l203', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227']", + "93, AMPK-α2 ['l191', 'l204', 'l216', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238']", + "94, (Apoe(-/-); ['l192', 'l205', 'l217', 'l228', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248']", + "95, Prkaa2(-/-) ['l193', 'l206', 'l218', 'l229', 'l239', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257']", + "96, mice) ['l194', 'l207', 'l219', 'l230', 'l240', 'l249', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265']", + "101, AAA ['l58', 'l76', 'l102', 'l116', 'l130', 'l143', 'l155', 'l166', 'l176', 'l195', 'l208', 'l220', 'l231', 'l241', 'l250', 'l258', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272']", + "102, in ['l196', 'l209', 'l221', 'l232', 'l242', 'l251', 'l259', 'l266', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278']", + "103, vivo. ['l59', 'l103', 'l117', 'l131', 'l144', 'l156', 'l167', 'l177', 'l197', 'l210', 'l222', 'l233', 'l243', 'l252', 'l260', 'l267', 'l273', 'l279', 'l280', 'l281', 'l282', 'l283']", + "116, vascular ['l60', 'l118', 'l132', 'l145', 'l157', 'l168', 'l178', 'l198', 'l211', 'l223', 'l234', 'l244', 'l253', 'l261', 'l268', 'l274', 'l279', 'l284', 'l285', 'l286', 'l287']", + "117, smooth ['l61', 'l77', 'l104', 'l119', 'l133', 'l146', 'l158', 'l169', 'l179', 'l199', 'l212', 'l224', 'l235', 'l245', 'l254', 'l262', 'l269', 'l275', 'l280', 'l284', 'l288', 'l289', 'l290']", + "118, muscle ['l62', 'l78', 'l91', 'l105', 'l120', 'l134', 'l147', 'l159', 'l170', 'l180', 'l187', 'l200', 'l213', 'l225', 'l236', 'l246', 'l255', 'l263', 'l270', 'l276', 'l281', 'l285', 'l288', 'l291', 'l292']", + "119, cells ['l45', 'l63', 'l79', 'l92', 'l106', 'l121', 'l135', 'l148', 'l160', 'l171', 'l181', 'l185', 'l188', 'l201', 'l214', 'l226', 'l237', 'l247', 'l256', 'l264', 'l271', 'l277', 'l282', 'l286', 'l289', 'l291', 'l293']", + "120, (VSMCs), ['l64', 'l80', 'l107', 'l122', 'l136', 'l149', 'l161', 'l172', 'l182', 'l202', 'l215', 'l227', 'l238', 'l248', 'l257', 'l265', 'l272', 'l278', 'l283', 'l287', 'l290', 'l292', 'l293']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "AAA" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "knockout", + "(Apoe(-/-))", + "in", + "both", + "and", + "the", + "AMP-activated", + "kinase", + "α1", + "subunit", + "(AMPK-α1)", + "genetic", + "deletion", + "of", + "AMPK-α2", + "(Apoe(-/-);", + "Prkaa2(-/-)", + "mice)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "apolipoprotein", + "E", + "(apoE)", + "knockout", + "(Apoe(-/-))", + "deficient", + "in", + "both", + "apoE", + "and", + "the", + "AMP-activated", + "kinase", + "α1", + "subunit", + "(AMPK-α1)", + "(Apoe(-/-);", + "Prkaa1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice)." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "both", + "apoE", + "and", + "the", + "AMP-activated", + "kinase", + "α1", + "subunit", + "(AMPK-α1)", + "(Apoe(-/-);", + "Prkaa1(-/-)", + "genetic", + "deletion", + "of", + "AMPK-α2", + "Prkaa2(-/-)", + "mice)" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "vascular", + "smooth", + "muscle", + "(VSMCs)," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "in", + "and", + "the", + "AMP-activated", + "kinase", + "α1", + "subunit", + "(AMPK-α1)", + "genetic", + "deletion", + "of", + "AMPK-α2", + "(Apoe(-/-);", + "Prkaa2(-/-)", + "mice)" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo.", + "in" + ] + } + } + ] + }, + { + "PMID": "22543263", + "TEXT": "Interleukin-25 (IL-25) is a cytokine associated with allergy and asthma that functions to promote type 2 immune responses at mucosal epithelial surfaces and serves to protect against helminth parasitic infections in the intestinal tract. This study identifies the IL-25 receptor, IL-17RB, as a key mediator of both innate and adaptive pulmonary type 2 immune responses. Allergen exposure upregulated IL-25 and induced type 2 cytokine production in a previously undescribed granulocytic population, termed type 2 myeloid (T2M) cells. Il17rb(-/-) mice showed reduced lung pathology after chronic allergen exposure and decreased type 2 cytokine production in T2M cells and CD4(+) T lymphocytes. Airway instillation of IL-25 induced IL-4 and IL-13 production in T2M cells, demonstrating their importance in eliciting T cell-independent inflammation. The adoptive transfer of T2M cells reconstituted IL-25-mediated responses in Il17rb(-/-) mice. High-dose dexamethasone treatment did not reduce the IL-25-induced T2M pulmonary response. Finally, a similar IL-4- and IL-13-producing granulocytic population was identified in peripheral blood of human subjects with asthma. These data establish IL-25 and its receptor IL-17RB as targets for innate and adaptive immune responses in chronic allergic airway disease and identify T2M cells as a new steroid-resistant cell population.", + "TAG_DATA": [ + "77, Il17rb(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "78, mice {'context': 'B-organism'}", + "81, lung {'context': 'B-tissue/organ'}", + "94, T2M {'context': 'B-cells'}", + "95, cells {'context': 'I-cells'}", + "97, CD4(+) {'context': 'B-cells'}", + "98, T {'context': 'I-cells'}", + "99, lymphocytes. {'context': 'I-cells'}", + "110, T2M {'context': 'B-cells'}", + "111, cells, {'context': 'I-cells'}", + "124, T2M {'context': 'B-cells'}", + "125, cells {'context': 'I-cells'}", + "130, Il17rb(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "131, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "77, Il17rb(-/-) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "78, mice ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "81, lung ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21']", + "94, T2M ['l2', 'l10', 'l17', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "95, cells ['l3', 'l11', 'l18', 'l22', 'l28', 'l29', 'l30']", + "97, CD4(+) ['l4', 'l12', 'l23', 'l31', 'l32', 'l33', 'l34']", + "98, T ['l5', 'l13', 'l19', 'l24', 'l28', 'l31', 'l35', 'l36', 'l37']", + "99, lymphocytes. ['l6', 'l14', 'l20', 'l25', 'l29', 'l32', 'l35', 'l38', 'l39']", + "110, T2M ['l7', 'l15', 'l26', 'l33', 'l36', 'l38', 'l40', 'l41']", + "111, cells, ['l8', 'l16', 'l21', 'l27', 'l30', 'l34', 'l37', 'l39', 'l40']", + "124, T2M ['l42', 'l43', 'l44']", + "125, cells ['l41', 'l42', 'l45']", + "130, Il17rb(-/-) ['l43', 'l45', 'l46']", + "131, mice. ['l44', 'l46']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Il17rb(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Il17rb(-/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Il17rb(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "T2M", + "cells", + "CD4(+)", + "T", + "lymphocytes.", + "cells," + ] + } + } + ] + }, + { + "PMID": "22466705", + "TEXT": "The transfer of high-avidity T cell receptor (TCR) genes isolated from rare tumor-specific lymphocytes into polyclonal T cells is an attractive cancer immunotherapy strategy. However, TCR gene transfer results in competition for surface expression and inappropriate pairing between the exogenous and endogenous TCR chains, resulting in suboptimal activity and potentially harmful unpredicted antigen specificities of the resultant TCRs. We designed zinc-finger nucleases (ZFNs) that promoted the disruption of endogenous TCR β- and α-chain genes. Lymphocytes treated with ZFNs lacked surface expression of CD3-TCR and expanded with the addition of interleukin-7 (IL-7) and IL-15. After lentiviral transfer of a TCR specific for the Wilms tumor 1 (WT1) antigen, these TCR-edited cells expressed the new TCR at high levels, were easily expanded to near purity and were superior at specific antigen recognition compared to donor-matched, unedited TCR-transferred cells. In contrast to unedited TCR-transferred cells, the TCR-edited lymphocytes did not mediate off-target reactivity while maintaining their anti-tumor activity in vivo, thus showing that complete editing of T cell specificity generates tumor-specific lymphocytes with improved biosafety profiles.", + "TAG_DATA": [ + "74, Lymphocytes {'context': 'B-cells'}", + "94, lentiviral {'perturbing_action': 'B-gene gain-of-function'}", + "95, transfer {'perturbing_action': 'I-other'}", + "96, of {'perturbing_action': 'I-other'}", + "97, a {'perturbing_action': 'I-other'}", + "98, TCR {'perturbing_action': 'I-other'}", + "99, specific {'perturbing_action': 'I-other'}", + "100, for {'perturbing_action': 'I-other'}", + "101, the {'perturbing_action': 'I-other'}", + "102, Wilms {'perturbing_action': 'I-other'}", + "103, tumor {'perturbing_action': 'I-other'}", + "104, 1 {'perturbing_action': 'I-other'}", + "105, (WT1) {'perturbing_action': 'I-other'}", + "106, antigen, {'perturbing_action': 'I-other'}", + "109, cells {'context': 'B-cells'}", + "144, lymphocytes {'context': 'B-cells'}", + "155, in {'context': 'B-in vivo'}", + "156, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "94, lentiviral ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "95, transfer ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "96, of ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "97, a ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "98, TCR ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "99, specific ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "100, for ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "101, the ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "102, Wilms ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "103, tumor ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "104, 1 ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "105, (WT1) ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "106, antigen, ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "109, cells ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']", + "144, lymphocytes ['l91', 'l92']", + "155, in ['l91', 'l93']", + "156, vivo, ['l92', 'l93']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "lentiviral" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "transfer", + "of", + "a", + "TCR", + "specific", + "for", + "the", + "Wilms", + "tumor", + "1", + "(WT1)", + "antigen," + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "22388091", + "TEXT": "Emerging evidence suggests that the T helper 17 (T(H)17) subset of αβ T cells contributes to the development of allergic asthma. In this study, we found that mice lacking the αvβ8 integrin on dendritic cells did not generate T(H)17 cells in the lung and were protected from airway hyper-responsiveness in response to house dust mite and ovalbumin sensitization and challenge. Because loss of T(H)17 cells inhibited airway narrowing without any obvious effects on airway inflammation or epithelial morphology, we examined the direct effects of T(H)17 cytokines on mouse and human airway smooth muscle function. Interleukin-17A (IL-17A), but not IL-17F or IL-22, enhanced contractile force generation of airway smooth muscle through an IL-17 receptor A (IL-17RA)-IL-17RC, nuclear factor κ light-chain enhancer of activated B cells (NF-κB)-ras homolog gene family, member A (RhoA)-Rho-associated coiled-coil containing protein kinase 2 (ROCK2) signaling cascade. Mice lacking integrin αvβ8 on dendritic cells showed impaired activation of this pathway after ovalbumin sensitization and challenge, and the diminished contraction of the tracheal rings in these mice was reversed by IL-17A. These data indicate that the IL-17A produced by T(H)17 cells contributes to allergen-induced airway hyper-responsiveness through direct effects on airway smooth muscle.", + "TAG_DATA": [ + "27, mice {'context': 'B-organism'}", + "28, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "29, the {'perturbing_action': 'I-gene loss-of-function'}", + "30, αvβ8 {'perturbing_action': 'I-gene loss-of-function'}", + "31, integrin {'perturbing_action': 'I-gene loss-of-function'}", + "32, on {'perturbing_action': 'I-gene loss-of-function'}", + "33, dendritic {'perturbing_action': 'I-gene loss-of-function'}", + "34, cells {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "42, lung {'context': 'B-tissue/organ'}", + "61, loss {'perturbing_action': 'B-gene loss-of-function'}", + "62, of {'perturbing_action': 'I-gene loss-of-function'}", + "63, T(H)17 {'perturbing_action': 'I-gene loss-of-function'}", + "64, cells {'perturbing_action': 'I-gene loss-of-function'}", + "106, airway {'context': 'B-tissue/organ'}", + "107, smooth {'context': 'I-tissue/organ'}", + "108, muscle {'context': 'I-tissue/organ'}", + "139, Mice {'context': 'B-organism'}", + "140, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "141, integrin {'perturbing_action': 'I-gene loss-of-function'}", + "142, αvβ8 {'perturbing_action': 'I-gene loss-of-function'}", + "143, on {'perturbing_action': 'I-gene loss-of-function'}", + "144, dendritic {'context': 'B-cells'}", + "145, cells {'context': 'I-cells'}", + "163, tracheal {'context': 'B-tissue/organ'}", + "164, rings {'context': 'I-tissue/organ'}", + "167, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "27, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "28, lacking ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "29, the ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "30, αvβ8 ['l2', 'l13', 'l23', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "31, integrin ['l3', 'l14', 'l24', 'l36', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "32, on ['l4', 'l15', 'l25', 'l37', 'l48', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "33, dendritic ['l5', 'l16', 'l26', 'l38', 'l49', 'l59', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "34, cells ['l6', 'l17', 'l27', 'l39', 'l50', 'l60', 'l68', 'l75', 'l76', 'l77', 'l78', 'l79']", + "42, lung ['l7', 'l18', 'l28', 'l40', 'l51', 'l61', 'l69', 'l75']", + "61, loss ['l8', 'l19', 'l29', 'l41', 'l52', 'l62', 'l70', 'l76', 'l80', 'l81', 'l82', 'l83', 'l84']", + "62, of ['l9', 'l20', 'l30', 'l42', 'l53', 'l63', 'l71', 'l77', 'l80', 'l85', 'l86', 'l87', 'l88', 'l89']", + "63, T(H)17 ['l10', 'l21', 'l31', 'l43', 'l54', 'l64', 'l72', 'l78', 'l81', 'l85', 'l90', 'l91', 'l92', 'l93']", + "64, cells ['l11', 'l22', 'l32', 'l44', 'l55', 'l65', 'l73', 'l79', 'l82', 'l86', 'l90']", + "106, airway ['l33', 'l45', 'l56', 'l87', 'l91', 'l94', 'l95']", + "107, smooth ['l34', 'l46', 'l57', 'l66', 'l83', 'l88', 'l92', 'l94', 'l96']", + "108, muscle ['l35', 'l47', 'l58', 'l67', 'l74', 'l84', 'l89', 'l93', 'l95', 'l96']", + "139, Mice ['l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "140, lacking ['l97', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "141, integrin ['l98', 'l104', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "142, αvβ8 ['l99', 'l105', 'l112', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "143, on ['l100', 'l106', 'l113', 'l119', 'l125', 'l126', 'l127']", + "144, dendritic ['l101', 'l107', 'l114', 'l120', 'l125', 'l128', 'l129']", + "145, cells ['l102', 'l108', 'l115', 'l121', 'l126', 'l128']", + "163, tracheal ['l109', 'l116', 'l122', 'l130', 'l131']", + "164, rings ['l103', 'l110', 'l117', 'l123', 'l127', 'l129', 'l130', 'l132']", + "167, mice ['l111', 'l118', 'l124', 'l131', 'l132']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "αvβ8", + "integrin", + "on", + "dendritic", + "cells", + "loss", + "of", + "T(H)17" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cells", + "lacking", + "the", + "αvβ8", + "integrin", + "on", + "dendritic" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells", + "dendritic" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "αvβ8", + "integrin", + "on", + "dendritic", + "cells", + "loss", + "of", + "T(H)17" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung", + "airway", + "smooth", + "muscle", + "tracheal", + "rings" + ] + } + } + ] + }, + { + "PMID": "22388088", + "TEXT": "New cancer therapies are likely to arise from an in-depth understanding of the signaling networks influencing tumor initiation, progression and metastasis. We show a fundamental role for Src-homology 2 domain-containing phosphatase 2 (SHP2) in these processes in human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancers. Knockdown of SHP2 eradicated breast tumor-initiating cells in xenograft models, and SHP2 depletion also prevented invasion in three-dimensional cultures and in a transductal invasion assay in vivo. Notably, SHP2 knockdown in established breast tumors blocked their growth and reduced metastasis. Mechanistically, SHP2 activated stemness-associated transcription factors, including v-myc myelocytomatosis viral oncogene homolog (c-Myc) and zinc finger E-box binding homeobox 1 (ZEB1), which resulted in the repression of let-7 microRNA and the expression of a set of 'SHP2 signature' genes. We found these genes to be simultaneously activated in a large subset of human primary breast tumors that are associated with invasive behavior and poor prognosis. These results provide new insights into the signaling cascades influencing tumor-initiating cells as well as a rationale for targeting SHP2 in breast cancer.", + "TAG_DATA": [ + "48, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "49, of {'perturbing_action': 'I-rnai/knockdown'}", + "50, SHP2 {'perturbing_action': 'I-rnai/knockdown'}", + "52, breast {'context': 'B-transformed cells'}", + "53, tumor-initiating {'context': 'I-transformed cells'}", + "54, cells {'context': 'I-transformed cells'}", + "56, xenograft {'context': 'B-xenograft'}", + "57, models, {'context': 'I-xenograft'}", + "59, SHP2 {'perturbing_action': 'B-gene loss-of-function'}", + "60, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "62, prevented {'effect': 'B-negative'}", + "63, invasion {'phenotype': 'B-invasion'}", + "65, three-dimensional {'context': 'B-in vitro'}", + "66, cultures {'context': 'I-in vitro'}", + "73, in {'context': 'B-in vivo'}", + "74, vivo. {'context': 'I-in vivo'}", + "76, SHP2 {'perturbing_action': 'B-rnai/knockdown'}", + "77, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "80, breast {'context': 'B-neoplasm'}", + "81, tumors {'context': 'I-neoplasm'}", + "86, reduced {'effect': 'B-negative'}", + "87, metastasis. {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "48, Knockdown ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "49, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "50, SHP2 ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "52, breast ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40']", + "53, tumor-initiating ['l3', 'l15', 'l26', 'l36', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "54, cells ['l4', 'l16', 'l27', 'l37', 'l41', 'l47', 'l48', 'l49']", + "56, xenograft ['l5', 'l17', 'l28', 'l38', 'l42', 'l47', 'l50', 'l51', 'l52', 'l53', 'l54']", + "57, models, ['l6', 'l18', 'l29', 'l39', 'l43', 'l48', 'l50', 'l55', 'l56']", + "59, SHP2 ['l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "60, depletion ['l57', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "62, prevented ['l7', 'l19', 'l30', 'l51', 'l58', 'l66', 'l75', 'l76', 'l77', 'l78', 'l79']", + "63, invasion ['l8', 'l20', 'l31', 'l44', 'l52', 'l55', 'l59', 'l67', 'l75', 'l80', 'l81']", + "65, three-dimensional ['l9', 'l21', 'l32', 'l45', 'l53', 'l60', 'l68', 'l76', 'l80', 'l82', 'l83', 'l84']", + "66, cultures ['l10', 'l22', 'l33', 'l40', 'l46', 'l49', 'l54', 'l56', 'l61', 'l69', 'l77', 'l81', 'l82']", + "73, in ['l11', 'l23', 'l34', 'l62', 'l70', 'l78', 'l83', 'l85']", + "74, vivo. ['l12', 'l24', 'l35', 'l63', 'l71', 'l79', 'l84', 'l85']", + "76, SHP2 ['l86', 'l87', 'l88', 'l89', 'l90']", + "77, knockdown ['l86', 'l91', 'l92', 'l93', 'l94']", + "80, breast ['l64', 'l72', 'l87', 'l91', 'l95', 'l96', 'l97']", + "81, tumors ['l65', 'l73', 'l88', 'l92', 'l95', 'l98', 'l99']", + "86, reduced ['l74', 'l89', 'l93', 'l96', 'l98', 'l100']", + "87, metastasis. ['l90', 'l94', 'l97', 'l99', 'l100']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "SHP2" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "breast", + "tumor-initiating", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "SHP2" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "models," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "SHP2", + "knockdown" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented", + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "SHP2" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "SHP2" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "three-dimensional", + "cultures" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "SHP2" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor-initiating" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenograft" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "models," + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHP2", + "depletion" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented", + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHP2", + "depletion" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHP2", + "depletion" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "three-dimensional", + "cultures" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHP2", + "depletion" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHP2", + "depletion" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "breast", + "tumors" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "three-dimensional", + "cultures" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "invasion" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "three-dimensional", + "cultures" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "SHP2", + "knockdown" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "breast", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "SHP2", + "knockdown" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "breast", + "tumors" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "breast", + "tumors" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis." + ] + } + } + ] + }, + { + "PMID": "22366948", + "TEXT": "Germline stem cells that produce oocytes in vitro and fertilization-competent eggs in vivo have been identified in and isolated from adult mouse ovaries. Here we describe and validate a fluorescence-activated cell sorting-based protocol that can be used with adult mouse ovaries and human ovarian cortical tissue to purify rare mitotically active cells that have a gene expression profile that is consistent with primitive germ cells. Once established in vitro, these cells can be expanded for months and can spontaneously generate 35- to 50-μm oocytes, as determined by morphology, gene expression and haploid (1n) status. Injection of the human germline cells, engineered to stably express GFP, into human ovarian cortical biopsies leads to formation of follicles containing GFP-positive oocytes 1-2 weeks after xenotransplantation into immunodeficient female mice. Thus, ovaries of reproductive-age women, similar to adult mice, possess rare mitotically active germ cells that can be propagated in vitro as well as generate oocytes in vitro and in vivo.", + "TAG_DATA": [ + "97, human {'context': 'B-cells'}", + "98, germline {'context': 'I-cells'}", + "99, cells, {'context': 'I-cells'}", + "101, to {'perturbing_action': 'B-gene gain-of-function'}", + "102, stably {'perturbing_action': 'B-gene gain-of-function'}", + "103, express {'perturbing_action': 'I-gene gain-of-function'}", + "104, GFP, {'perturbing_action': 'I-gene gain-of-function'}", + "106, human {'context': 'B-tissue/organ'}", + "107, ovarian {'context': 'I-patient'}", + "108, cortical {'context': 'I-patient'}", + "109, biopsies {'context': 'I-patient'}", + "121, xenotransplantation {'context': 'B-xenograft'}", + "123, immunodeficient {'context': 'B-organism'}", + "124, female {'context': 'I-organism'}", + "125, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "97, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "98, germline ['l0', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "99, cells, ['l1', 'l15', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "100, engineered ['l2', 'l16', 'l29', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "101, to ['l3', 'l17', 'l30', 'l41', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "102, stably ['l4', 'l18', 'l31', 'l42', 'l53', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "103, express ['l5', 'l19', 'l32', 'l43', 'l54', 'l64', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "104, GFP, ['l6', 'l20', 'l33', 'l44', 'l55', 'l65', 'l74', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "106, human ['l7', 'l21', 'l34', 'l45', 'l56', 'l66', 'l75', 'l83', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "107, ovarian ['l8', 'l22', 'l35', 'l46', 'l57', 'l67', 'l76', 'l84', 'l91', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "108, cortical ['l9', 'l23', 'l36', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l98', 'l104', 'l105', 'l106', 'l107', 'l108']", + "109, biopsies ['l10', 'l24', 'l37', 'l48', 'l59', 'l69', 'l78', 'l86', 'l93', 'l99', 'l104', 'l109', 'l110', 'l111', 'l112']", + "121, xenotransplantation ['l11', 'l25', 'l49', 'l60', 'l70', 'l79', 'l87', 'l94', 'l100', 'l105', 'l109', 'l113', 'l114', 'l115']", + "123, immunodeficient ['l12', 'l26', 'l38', 'l50', 'l61', 'l71', 'l80', 'l88', 'l95', 'l101', 'l106', 'l110', 'l113', 'l116', 'l117']", + "124, female ['l13', 'l27', 'l39', 'l51', 'l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l107', 'l111', 'l114', 'l116', 'l118']", + "125, mice. ['l14', 'l28', 'l40', 'l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l108', 'l112', 'l115', 'l117', 'l118']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "germline", + "cells," + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "to", + "stably", + "express", + "GFP," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "to", + "stably", + "express", + "GFP," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "human" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "to", + "stably", + "express", + "GFP," + ] + }, + "context": { + "val": "patient", + "words": [ + "ovarian", + "cortical", + "biopsies" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "to", + "stably", + "express", + "GFP," + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenotransplantation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "to", + "stably", + "express", + "GFP," + ] + }, + "context": { + "val": "organism", + "words": [ + "immunodeficient", + "female", + "mice." + ] + } + } + ] + }, + { + "PMID": "22344299", + "TEXT": "The signaling molecule Wnt regulates bone homeostasis through β-catenin-dependent canonical and β-catenin-independent noncanonical pathways. Impairment of canonical Wnt signaling causes bone loss in arthritis and osteoporosis; however, it is unclear how noncanonical Wnt signaling regulates bone resorption. Wnt5a activates noncanonical Wnt signaling through receptor tyrosine kinase-like orphan receptor (Ror) proteins. We showed that Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhanced osteoclastogenesis. Osteoblast-lineage cells expressed Wnt5a, whereas osteoclast precursors expressed Ror2. Mice deficient in either Wnt5a or Ror2, and those with either osteoclast precursor-specific Ror2 deficiency or osteoblast-lineage cell-specific Wnt5a deficiency showed impaired osteoclastogenesis. Wnt5a-Ror2 signals enhanced receptor activator of nuclear factor-κB (RANK) expression in osteoclast precursors by activating JNK and recruiting c-Jun on the promoter of the gene encoding RANK, thereby enhancing RANK ligand (RANKL)-induced osteoclastogenesis. A soluble form of Ror2 acted as a decoy receptor of Wnt5a and abrogated bone destruction in mouse arthritis models. Our results suggest that the Wnt5a-Ror2 pathway is crucial for osteoclastogenesis in physiological and pathological environments and represents a therapeutic target for bone diseases, including arthritis.", + "TAG_DATA": [ + "72, Mice {'context': 'B-organism'}", + "73, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "74, in {'perturbing_action': 'I-gene loss-of-function'}", + "75, either {'perturbing_action': 'I-gene loss-of-function'}", + "76, Wnt5a {'perturbing_action': 'I-gene loss-of-function'}", + "77, or {'perturbing_action': 'I-gene loss-of-function'}", + "78, Ror2, {'perturbing_action': 'I-gene loss-of-function'}", + "83, osteoclast {'perturbing_action': 'B-gene loss-of-function'}", + "84, precursor-specific {'perturbing_action': 'I-gene loss-of-function'}", + "85, Ror2 {'perturbing_action': 'I-gene loss-of-function'}", + "86, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "88, osteoblast-lineage {'perturbing_action': 'B-gene loss-of-function'}", + "89, cell-specific {'perturbing_action': 'I-gene loss-of-function'}", + "90, Wnt5a {'perturbing_action': 'I-gene loss-of-function'}", + "91, deficiency {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "72, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "73, deficient ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "74, in ['l1', 'l6', 'l12', 'l13', 'l14', 'l15', 'l16']", + "75, either ['l2', 'l7', 'l12', 'l17', 'l18', 'l19']", + "76, Wnt5a ['l3', 'l8', 'l13', 'l17', 'l20', 'l21', 'l22']", + "77, or ['l4', 'l9', 'l14', 'l18', 'l20', 'l23']", + "78, Ror2, ['l5', 'l10', 'l15', 'l19', 'l21', 'l23', 'l24', 'l25', 'l26']", + "83, osteoclast ['l24', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "84, precursor-specific ['l11', 'l16', 'l22', 'l25', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "85, Ror2 ['l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "86, deficiency ['l26', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "88, osteoblast-lineage ['l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "89, cell-specific ['l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "90, Wnt5a ['l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "91, deficiency ['l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "either", + "Wnt5a", + "or", + "Ror2," + ] + } + } + ] + }, + { + "PMID": "22286308", + "TEXT": "The microtubule-associated protein tau has risk alleles for both Alzheimer's disease and Parkinson's disease and mutations that cause brain degenerative diseases termed tauopathies. Aggregated tau forms neurofibrillary tangles in these pathologies, but little is certain about the function of tau or its mode of involvement in pathogenesis. Neuronal iron accumulation has been observed pathologically in the cortex in Alzheimer's disease, the substantia nigra (SN) in Parkinson's disease and various brain regions in the tauopathies. Here we report that tau-knockout mice develop age-dependent brain atrophy, iron accumulation and SN neuronal loss, with concomitant cognitive deficits and parkinsonism. These changes are prevented by oral treatment with a moderate iron chelator, clioquinol. Amyloid precursor protein (APP) ferroxidase activity couples with surface ferroportin to export iron, but its activity is inhibited in Alzheimer's disease, thereby causing neuronal iron accumulation. In primary neuronal culture, we found loss of tau also causes iron retention, by decreasing surface trafficking of APP. Soluble tau levels fall in affected brain regions in Alzheimer's disease and tauopathies, and we found a similar decrease of soluble tau in the SN in both Parkinson's disease and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. These data suggest that the loss of soluble tau could contribute to toxic neuronal iron accumulation in Alzheimer's disease, Parkinson's disease and tauopathies, and that it can be rescued pharmacologically.", + "TAG_DATA": [ + "78, tau-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "79, mice {'context': 'B-organism'}", + "136, primary {'context': 'B-cells'}", + "137, neuronal {'context': 'I-cells'}", + "138, culture, {'context': 'I-cells'}", + "141, loss {'perturbing_action': 'B-gene loss-of-function'}", + "142, of {'perturbing_action': 'I-gene loss-of-function'}", + "143, tau {'perturbing_action': 'I-gene loss-of-function'}", + "187, mouse {'context': 'B-organism'}", + "188, model. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "78, tau-knockout ['l0']", + "79, mice ['l0']", + "136, primary ['l1', 'l2', 'l3', 'l4', 'l5']", + "137, neuronal ['l1', 'l6', 'l7', 'l8', 'l9']", + "138, culture, ['l2', 'l6', 'l10', 'l11', 'l12']", + "141, loss ['l3', 'l7', 'l10', 'l13', 'l14']", + "142, of ['l4', 'l8', 'l11', 'l13', 'l15']", + "143, tau ['l5', 'l9', 'l12', 'l14', 'l15']", + "187, mouse ['l16']", + "188, model. ['l16']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "tau-knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "primary", + "neuronal", + "culture," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "tau" + ] + } + } + ] + }, + { + "PMID": "22286305", + "TEXT": "Leprosy provides a model to investigate mechanisms of immune regulation in humans, given that the disease forms a spectrum of clinical presentations that correlate with host immune responses. Here we identified 13 miRNAs that were differentially expressed in the lesions of subjects with progressive lepromatous (L-lep) versus the self-limited tuberculoid (T-lep) disease. Bioinformatic analysis revealed a significant enrichment of L-lep-specific miRNAs that preferentially target key immune genes downregulated in L-lep versus T-lep lesions. The most differentially expressed miRNA in L-lep lesions, hsa-mir-21, was upregulated in Mycobacterium leprae-infected monocytes. By directly downregulating Toll-like receptor 2/1 heterodimer (TLR2/1)-induced CYP27B1 and IL1B expression as well as indirectly upregulating interleukin-10 (IL-10), hsa-mir-21 inhibited expression of the genes encoding two vitamin D-dependent antimicrobial peptides, CAMP and DEFB4A. Conversely, knockdown of hsa-mir-21 in M. leprae-infected monocytes enhanced expression of CAMP and DEFB4A and restored TLR2/1-mediated antimicrobial activity against M. leprae. Therefore, the ability of M. leprae to upregulate hsa-mir-21 targets multiple genes associated with the immunologically localized disease form, providing an effective mechanism to escape from the vitamin D-dependent antimicrobial pathway.", + "TAG_DATA": [ + "123, knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "124, of {'perturbing_action': 'I-rnai/knockdown'}", + "125, hsa-mir-21 {'perturbing_action': 'I-rnai/knockdown'}", + "129, monocytes {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "123, knockdown ['l0', 'l1', 'l2']", + "124, of ['l0', 'l3', 'l4']", + "125, hsa-mir-21 ['l1', 'l3', 'l5']", + "129, monocytes ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "hsa-mir-21" + ] + }, + "context": { + "val": "cells", + "words": [ + "monocytes" + ] + } + } + ] + }, + { + "PMID": "22270723", + "TEXT": "Although aberrant DNA methylation is considered to be one of the key ways by which tumor-suppressor and DNA-repair genes are silenced during tumor initiation and progression, the mechanisms underlying DNA methylation alterations in cancer remain unclear. Here we show that prostaglandin E(2) (PGE(2)) silences certain tumor-suppressor and DNA-repair genes through DNA methylation to promote tumor growth. These findings uncover a previously unrecognized role for PGE(2) in the promotion of tumor progression.", + "TAG_DATA": [ + "53, promote {'effect': 'B-positive'}", + "54, tumor {'phenotype': 'B-tumour growth'}", + "55, growth. {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "53, promote ['l0', 'l1']", + "54, tumor ['l0', 'l2']", + "55, growth. ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promote" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + } + ] + }, + { + "PMID": "22245780", + "TEXT": "Adequate lipid secretion by mammary glands during lactation is essential for the survival of mammalian offspring. However, the mechanism governing this process is poorly understood. Here we show that Cidea is expressed at high levels in lactating mammary glands and its deficiency leads to premature pup death as a result of severely reduced milk lipids. Furthermore, the expression of xanthine oxidoreductase (XOR), an essential factor for milk lipid secretion, is markedly lower in Cidea-deficient mammary glands. Conversely, ectopic Cidea expression induces the expression of XOR and enhances lipid secretion in vivo. Unexpectedly, as Cidea has heretofore been thought of as a cytoplasmic protein, we detected it in the nucleus and found it to physically interact with transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) in mammary epithelial cells. We also observed that Cidea induces XOR expression by promoting the association of C/EBPβ onto, and the dissociation of HDAC1 from, the promoter of the Xdh gene encoding XOR. Finally, we found that Fsp27, another CIDE family protein, is detected in the nucleus and interacts with C/EBPβ to regulate expression of a subset of C/EBPβ downstream genes in adipocytes. Thus, Cidea acts as a previously unknown transcriptional coactivator of C/EBPβ in mammary glands to control lipid secretion and pup survival.", + "TAG_DATA": [ + "73, Cidea-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "77, ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "78, Cidea {'perturbing_action': 'I-gene gain-of-function'}", + "79, expression {'perturbing_action': 'I-gene gain-of-function'}", + "89, in {'context': 'B-in vivo'}", + "90, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "73, Cidea-deficient ['l0', 'l1']", + "77, ectopic ['l2', 'l3', 'l4', 'l5']", + "78, Cidea ['l2', 'l6', 'l7', 'l8']", + "79, expression ['l3', 'l6', 'l9', 'l10']", + "89, in ['l0', 'l4', 'l7', 'l9', 'l11']", + "90, vivo. ['l1', 'l5', 'l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cidea-deficient" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "Cidea", + "expression" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "22157679", + "TEXT": "Screening for genes that reprogram cancer cells for the tumor reversion switch identified TCTP (encoding translationally controlled tumor protein) as a crucial regulator of apoptosis. Here we report a negative feedback loop between P53 and TCTP. TCTP promotes P53 degradation by competing with NUMB for binding to P53-MDM2-containing complexes. TCTP inhibits MDM2 auto-ubiquitination and promotes MDM2-mediated ubiquitination and degradation of P53. Notably, Tctp haploinsufficient mice are sensitized to P53-dependent apoptosis. In addition, P53 directly represses TCTP transcription. In 508 breast cancers, high-TCTP status associates with poorly differentiated, aggressive G3-grade tumors, predicting poor prognosis (P < 0.0005). Tctp knockdown in primary mammary tumor cells from ErbB2 transgenic mice results in increased P53 expression and a decreased number of stem-like cancer cells. The pharmacological compounds sertraline and thioridazine increase the amount of P53 by neutralizing TCTP's action on the MDM2-P53 axis. This study links TCTP and P53 in a previously unidentified regulatory circuitry that may underlie the relevance of TCTP in cancer.", + "TAG_DATA": [ + "62, Tctp {'perturbing_action': 'B-gene loss-of-function'}", + "63, haploinsufficient {'perturbing_action': 'I-gene loss-of-function'}", + "64, mice {'context': 'B-organism'}", + "66, sensitized {'effect': 'B-positive'}", + "69, apoptosis. {'phenotype': 'B-apoptosis'}", + "96, Tctp {'perturbing_action': 'B-rnai/knockdown'}", + "97, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "99, primary {'context': 'B-transformed cells'}", + "100, mammary {'context': 'I-transformed cells'}", + "101, tumor {'context': 'I-transformed cells'}", + "102, cells {'context': 'I-transformed cells'}", + "104, ErbB2 {'perturbing_action': 'B-gene gain-of-function'}", + "105, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "106, mice {'context': 'B-organism'}", + "117, stem-like {'context': 'B-transformed cells'}", + "118, cancer {'context': 'I-transformed cells'}", + "119, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "62, Tctp ['l0', 'l1', 'l2', 'l3']", + "63, haploinsufficient ['l0', 'l4', 'l5', 'l6']", + "64, mice ['l1', 'l4', 'l7', 'l8']", + "66, sensitized ['l2', 'l5', 'l7', 'l9']", + "69, apoptosis. ['l3', 'l6', 'l8', 'l9']", + "96, Tctp ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "97, knockdown ['l10', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "99, primary ['l11', 'l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "100, mammary ['l12', 'l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "101, tumor ['l13', 'l23', 'l32', 'l40', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "102, cells ['l14', 'l24', 'l33', 'l41', 'l47', 'l53', 'l54', 'l55', 'l56']", + "104, ErbB2 ['l15', 'l25', 'l34', 'l42', 'l48', 'l53', 'l57', 'l58', 'l59', 'l60', 'l61']", + "105, transgenic ['l16', 'l26', 'l35', 'l43', 'l49', 'l54', 'l57', 'l62', 'l63', 'l64', 'l65']", + "106, mice ['l17', 'l27', 'l36', 'l44', 'l50', 'l55', 'l58', 'l62', 'l66', 'l67', 'l68']", + "117, stem-like ['l18', 'l28', 'l37', 'l59', 'l63', 'l66', 'l69', 'l70']", + "118, cancer ['l19', 'l29', 'l38', 'l45', 'l51', 'l60', 'l64', 'l67', 'l69', 'l71']", + "119, cells. ['l20', 'l30', 'l39', 'l46', 'l52', 'l56', 'l61', 'l65', 'l68', 'l70', 'l71']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tctp", + "haploinsufficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tctp", + "haploinsufficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tctp", + "haploinsufficient" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Tctp", + "knockdown" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "primary", + "mammary", + "tumor", + "cells", + "stem-like", + "cancer", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Tctp", + "knockdown" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "primary", + "mammary", + "tumor", + "cells", + "stem-like", + "cancer", + "cells." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ErbB2", + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ErbB2", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "22138754", + "TEXT": "The platelet-derived growth factor (PDGF) signaling system contributes to tumor angiogenesis and vascular remodeling. Here we show in mouse tumor models that PDGF-BB induces erythropoietin (EPO) mRNA and protein expression by targeting stromal and perivascular cells that express PDGF receptor-β (PDGFR-β). Tumor-derived PDGF-BB promoted tumor growth, angiogenesis and extramedullary hematopoiesis at least in part through modulation of EPO expression. Moreover, adenoviral delivery of PDGF-BB to tumor-free mice increased both EPO production and erythropoiesis, as well as protecting from irradiation-induced anemia. At the molecular level, we show that the PDGF-BB-PDGFR-bβ signaling system activates the EPO promoter, acting in part through transcriptional regulation by the transcription factor Atf3, possibly through its association with two additional transcription factors, c-Jun and Sp1. Our findings suggest that PDGF-BB-induced EPO promotes tumor growth through two mechanisms: first, paracrine stimulation of tumor angiogenesis by direct induction of endothelial cell proliferation, migration, sprouting and tube formation, and second, endocrine stimulation of extramedullary hematopoiesis leading to increased oxygen perfusion and protection against tumor-associated anemia.", + "TAG_DATA": [ + "18, mouse {'context': 'B-neoplasm'}", + "19, tumor {'context': 'I-neoplasm'}", + "20, models {'context': 'I-neoplasm'}", + "32, stromal {'context': 'B-cells'}", + "33, and {'context': 'I-cells'}", + "34, perivascular {'context': 'I-cells'}", + "35, cells {'context': 'I-cells'}", + "43, promoted {'effect': 'B-positive'}", + "44, tumor {'phenotype': 'B-tumour growth'}", + "45, growth, {'phenotype': 'I-tumour growth'}", + "60, adenoviral {'perturbing_action': 'B-gene gain-of-function'}", + "61, delivery {'perturbing_action': 'I-gene gain-of-function'}", + "62, of {'perturbing_action': 'I-gene gain-of-function'}", + "63, PDGF-BB {'perturbing_action': 'I-gene gain-of-function'}", + "65, tumor-free {'context': 'B-organism'}", + "66, mice {'context': 'I-organism'}", + "124, promotes {'effect': 'B-positive'}", + "125, tumor {'phenotype': 'B-tumour growth'}", + "126, growth {'phenotype': 'I-tumour growth'}", + "138, induction {'effect': 'B-positive'}", + "140, endothelial {'context': 'B-cells'}", + "141, cell {'context': 'I-cells'}", + "142, proliferation, {'phenotype': 'B-proliferation'}", + "143, migration, {'phenotype': 'B-migration'}", + "146, tube {'phenotype': 'B-tumourigenesis'}", + "147, formation, {'phenotype': 'I-tumourigenesis'}" + ], + "LINK_DATA": [ + "18, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "19, tumor ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "20, models ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "32, stromal ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "33, and ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "34, perivascular ['l4', 'l12', 'l19', 'l25', 'l30', 'l36', 'l37', 'l38', 'l39', 'l40']", + "35, cells ['l5', 'l13', 'l20', 'l26', 'l31', 'l36', 'l41', 'l42', 'l43', 'l44']", + "43, promoted ['l6', 'l14', 'l21', 'l27', 'l32', 'l37', 'l41', 'l45', 'l46']", + "44, tumor ['l7', 'l15', 'l22', 'l28', 'l33', 'l38', 'l42', 'l45', 'l47']", + "45, growth, ['l8', 'l16', 'l23', 'l29', 'l34', 'l39', 'l43', 'l46', 'l47']", + "60, adenoviral ['l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "61, delivery ['l48', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "62, of ['l49', 'l60', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "63, PDGF-BB ['l50', 'l61', 'l70', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "65, tumor-free ['l51', 'l62', 'l71', 'l79', 'l87']", + "66, mice ['l35', 'l40', 'l44', 'l52', 'l63', 'l72', 'l80', 'l87']", + "124, promotes ['l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "125, tumor ['l88', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "126, growth ['l89', 'l97', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "138, induction ['l53', 'l90', 'l98', 'l105', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "140, endothelial ['l54', 'l64', 'l73', 'l81', 'l91', 'l99', 'l106', 'l112', 'l118', 'l119', 'l120', 'l121', 'l122']", + "141, cell ['l55', 'l65', 'l74', 'l82', 'l92', 'l100', 'l107', 'l113', 'l118', 'l123', 'l124', 'l125', 'l126']", + "142, proliferation, ['l56', 'l66', 'l75', 'l83', 'l93', 'l101', 'l108', 'l114', 'l119', 'l123', 'l127', 'l128', 'l129']", + "143, migration, ['l57', 'l67', 'l76', 'l84', 'l94', 'l102', 'l109', 'l115', 'l120', 'l124', 'l127', 'l130', 'l131']", + "146, tube ['l58', 'l68', 'l77', 'l85', 'l95', 'l103', 'l110', 'l116', 'l121', 'l125', 'l128', 'l130', 'l132']", + "147, formation, ['l59', 'l69', 'l78', 'l86', 'l96', 'l104', 'l111', 'l117', 'l122', 'l126', 'l129', 'l131', 'l132']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "tumor", + "models" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "tumor", + "models" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "stromal", + "and", + "perivascular", + "cells", + "endothelial", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted", + "promotes", + "induction" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "stromal", + "and", + "perivascular", + "cells", + "endothelial", + "cell" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth,", + "growth" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted", + "promotes", + "induction" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth,", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral", + "delivery", + "of", + "PDGF-BB" + ] + }, + "context": { + "val": "organism", + "words": [ + "tumor-free", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral", + "delivery", + "of", + "PDGF-BB" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral", + "delivery", + "of", + "PDGF-BB" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral", + "delivery", + "of", + "PDGF-BB" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral", + "delivery", + "of", + "PDGF-BB" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tube", + "formation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes", + "induction" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes", + "induction" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes", + "induction" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tube", + "formation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cell" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tube", + "formation," + ] + } + } + ] + }, + { + "PMID": "22101768", + "TEXT": "Using a systems biology approach, we discovered and dissected a three-way interaction between the immune system, the intestinal epithelium and the microbiota. We found that, in the absence of B cells, or of IgA, and in the presence of the microbiota, the intestinal epithelium launches its own protective mechanisms, upregulating interferon-inducible immune response pathways and simultaneously repressing Gata4-related metabolic functions. This shift in intestinal function leads to lipid malabsorption and decreased deposition of body fat. Network analysis revealed the presence of two interconnected epithelial-cell gene networks, one governing lipid metabolism and another regulating immunity, that were inversely expressed. Gene expression patterns in gut biopsies from individuals with common variable immunodeficiency or with HIV infection and intestinal malabsorption were very similar to those of the B cell-deficient mice, providing a possible explanation for a longstanding enigmatic association between immunodeficiency and defective lipid absorption in humans.", + "TAG_DATA": [ + "124, B {'perturbing_action': 'B-gene loss-of-function'}", + "125, cell-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "126, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "124, B ['l0', 'l1']", + "125, cell-deficient ['l0', 'l2']", + "126, mice, ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "B", + "cell-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "22081021", + "TEXT": "Nitric oxide (NO) is crucial in diverse physiological and pathological processes. We show that a hypomorphic mouse model of argininosuccinate lyase (encoded by Asl) deficiency has a distinct phenotype of multiorgan dysfunction and NO deficiency. Loss of Asl in both humans and mice leads to reduced NO synthesis, owing to both decreased endogenous arginine synthesis and an impaired ability to use extracellular arginine for NO production. Administration of nitrite, which can be converted into NO in vivo, rescued the manifestations of NO deficiency in hypomorphic Asl mice, and a nitric oxide synthase (NOS)-independent NO donor restored NO-dependent vascular reactivity in humans with ASL deficiency. Mechanistic studies showed that ASL has a structural function in addition to its catalytic activity, by which it contributes to the formation of a multiprotein complex required for NO production. Our data demonstrate a previously unappreciated role for ASL in NOS function and NO homeostasis. Hence, ASL may serve as a target for manipulating NO production in experimental models, as well as for the treatment of NO-related diseases.", + "TAG_DATA": [ + "16, mouse {'context': 'I-organism'}", + "17, model {'context': 'I-organism'}", + "35, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "36, of {'perturbing_action': 'I-gene loss-of-function'}", + "37, Asl {'perturbing_action': 'I-gene loss-of-function'}", + "40, humans {'context': 'B-organism'}", + "42, mice {'context': 'B-organism'}", + "84, hypomorphic {'perturbing_action': 'B-gene loss-of-function'}", + "86, mice, {'context': 'B-organism'}", + "100, humans {'context': 'B-patient'}", + "102, ASL {'perturbing_action': 'B-gene loss-of-function'}", + "103, deficiency. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "16, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "17, model ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "35, Loss ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "36, of ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "37, Asl ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "40, humans ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "42, mice ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "84, hypomorphic ['l21']", + "86, mice, ['l21']", + "100, humans ['l22', 'l23']", + "102, ASL ['l22', 'l24']", + "103, deficiency. ['l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "humans", + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Loss", + "of", + "Asl", + "hypomorphic" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "humans" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ASL", + "deficiency." + ] + } + } + ] + }, + { + "PMID": "22057348", + "TEXT": "Three major modes of cancer therapy (surgery, radiation and chemotherapy) are the mainstay of modern oncologic therapy. To minimize the side effects of these therapies, molecular-targeted cancer therapies, including armed antibody therapy, have been developed with limited success. In this study, we have developed a new type of molecular-targeted cancer therapy, photoimmunotherapy (PIT), that uses a target-specific photosensitizer based on a near-infrared (NIR) phthalocyanine dye, IR700, conjugated to monoclonal antibodies (mAbs) targeting epidermal growth factor receptors. Cell death was induced immediately after irradiating mAb-IR700-bound target cells with NIR light. We observed in vivo tumor shrinkage after irradiation with NIR light in target cells expressing the epidermal growth factor receptor. The mAb-IR700 conjugates were most effective when bound to the cell membrane and produced no phototoxicity when not bound, suggesting a different mechanism for PIT as compared to conventional photodynamic therapies. Target-selective PIT enables treatment of cancer based on mAb binding to the cell membrane.", + "TAG_DATA": [ + "76, Cell {'phenotype': 'B-cell death'}", + "77, death {'phenotype': 'I-cell death'}", + "79, induced {'effect': 'B-positive'}", + "84, target {'context': 'B-cells'}", + "85, cells {'context': 'I-cells'}", + "91, in {'context': 'B-in vivo'}", + "92, vivo {'context': 'I-in vivo'}", + "93, tumor {'phenotype': 'B-tumour regression'}", + "94, shrinkage {'phenotype': 'I-tumour regression'}", + "101, target {'context': 'B-cells'}", + "102, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "76, Cell ['l0', 'l1', 'l2', 'l3']", + "77, death ['l0', 'l4', 'l5', 'l6']", + "79, induced ['l1', 'l4', 'l7', 'l8']", + "84, target ['l2', 'l5', 'l7', 'l9']", + "85, cells ['l3', 'l6', 'l8', 'l9']", + "91, in ['l10', 'l11', 'l12', 'l13', 'l14']", + "92, vivo ['l10', 'l15', 'l16', 'l17', 'l18']", + "93, tumor ['l11', 'l15', 'l19', 'l20', 'l21']", + "94, shrinkage ['l12', 'l16', 'l19', 'l22', 'l23']", + "101, target ['l13', 'l17', 'l20', 'l22', 'l24']", + "102, cells ['l14', 'l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "cell death", + "words": [ + "Cell", + "death" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "Cell", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "target", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "target", + "cells" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "shrinkage" + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "shrinkage" + ] + }, + "context": { + "val": "cells", + "words": [ + "target", + "cells" + ] + } + } + ] + }, + { + "PMID": "22057346", + "TEXT": "Osteoarthritis, characterized by the breakdown of articular cartilage in synovial joints, has long been viewed as the result of 'wear and tear'. Although low-grade inflammation is detected in osteoarthritis, its role is unclear. Here we identify a central role for the inflammatory complement system in the pathogenesis of osteoarthritis. Through proteomic and transcriptomic analyses of synovial fluids and membranes from individuals with osteoarthritis, we find that expression and activation of complement is abnormally high in human osteoarthritic joints. Using mice genetically deficient in complement component 5 (C5), C6 or the complement regulatory protein CD59a, we show that complement, specifically, the membrane attack complex (MAC)-mediated arm of complement, is crucial to the development of arthritis in three different mouse models of osteoarthritis. Pharmacological modulation of complement in wild-type mice confirmed the results obtained with genetically deficient mice. Expression of inflammatory and degradative molecules was lower in chondrocytes from destabilized joints from C5-deficient mice than C5-sufficient mice, and MAC induced production of these molecules in cultured chondrocytes. Further, MAC colocalized with matrix metalloprotease 13 (MMP13) and with activated extracellular signal-regulated kinase (ERK) around chondrocytes in human osteoarthritic cartilage. Our findings indicate that dysregulation of complement in synovial joints has a key role in the pathogenesis of osteoarthritis.", + "TAG_DATA": [ + "79, mice {'context': 'B-organism'}", + "80, genetically {'perturbing_action': 'B-gene loss-of-function'}", + "81, deficient {'perturbing_action': 'I-gene loss-of-function'}", + "82, in {'perturbing_action': 'I-gene loss-of-function'}", + "83, complement {'perturbing_action': 'I-gene loss-of-function'}", + "84, component {'perturbing_action': 'I-gene loss-of-function'}", + "85, 5 {'perturbing_action': 'I-gene loss-of-function'}", + "86, (C5), {'perturbing_action': 'I-gene loss-of-function'}", + "87, C6 {'perturbing_action': 'I-gene loss-of-function'}", + "88, or {'perturbing_action': 'I-gene loss-of-function'}", + "89, the {'perturbing_action': 'I-gene loss-of-function'}", + "127, mice {'context': 'B-organism'}", + "135, mice. {'context': 'B-organism'}", + "145, chondrocytes {'context': 'B-cells'}", + "150, C5-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "151, mice {'context': 'B-organism'}", + "164, chondrocytes. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "79, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "80, genetically ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "81, deficient ['l1', 'l9', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "82, in ['l2', 'l10', 'l18', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "83, complement ['l3', 'l11', 'l19', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "84, component ['l4', 'l12', 'l20', 'l27', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "85, 5 ['l5', 'l13', 'l21', 'l28', 'l34', 'l39', 'l44', 'l45', 'l46', 'l47']", + "86, (C5), ['l6', 'l14', 'l22', 'l29', 'l35', 'l40', 'l44', 'l48', 'l49', 'l50']", + "87, C6 ['l7', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l51', 'l52']", + "88, or ['l8', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l51', 'l53']", + "89, the ['l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l53', 'l54']", + "127, mice ['l55', 'l56', 'l57', 'l58', 'l59']", + "135, mice. ['l55', 'l60', 'l61', 'l62', 'l63']", + "145, chondrocytes ['l54', 'l56', 'l60', 'l64', 'l65', 'l66']", + "150, C5-deficient ['l57', 'l61', 'l64', 'l67', 'l68']", + "151, mice ['l58', 'l62', 'l65', 'l67', 'l69']", + "164, chondrocytes. ['l59', 'l63', 'l66', 'l68', 'l69']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetically", + "deficient", + "in", + "complement", + "component", + "5", + "(C5),", + "C6", + "or", + "C5-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "C5-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "chondrocytes", + "chondrocytes." + ] + } + } + ] + }, + { + "PMID": "21926978", + "TEXT": "Staphylococcus aureus is a major cause of human disease, responsible for half a million infections and approximately 20,000 deaths per year in the United States alone. This pathogen secretes α-hemolysin, a pore-forming cytotoxin that contributes to the pathogenesis of pneumonia. α-hemolysin injures epithelial cells in vitro by interacting with its receptor, the zinc-dependent metalloprotease ADAM10 (ref. 6). We show here that mice harboring a conditional disruption of the Adam10 gene in lung epithelium are resistant to lethal pneumonia. Investigation of the molecular mechanism of toxin-receptor function revealed that α-hemolysin upregulates ADAM10 metalloprotease activity in alveolar epithelial cells, resulting in cleavage of the adherens junction protein E-cadherin. Cleavage is associated with disruption of epithelial barrier function, contributing to the pathogenesis of lethal acute lung injury. A metalloprotease inhibitor of ADAM10 prevents E-cadherin cleavage in response to Hla; similarly, toxin-dependent E-cadherin proteolysis and barrier disruption is attenuated in ADAM10-knockout mice. Together, these data attest to the function of ADAM10 as the cellular receptor for α-hemolysin. The observation that α-hemolysin can usurp the metalloprotease activity of its receptor reveals a previously unknown mechanism of pore-forming cytotoxin action in which pathologic insults are not solely the result of irreversible membrane injury and defines ADAM10 inhibition as a strategy to attenuate α-hemolysin-induced disease.", + "TAG_DATA": [ + "61, mice {'context': 'B-organism'}", + "64, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "65, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "66, of {'perturbing_action': 'I-gene loss-of-function'}", + "67, the {'perturbing_action': 'I-gene loss-of-function'}", + "68, Adam10 {'perturbing_action': 'I-gene loss-of-function'}", + "69, gene {'perturbing_action': 'I-gene loss-of-function'}", + "71, lung {'context': 'B-tissue/organ'}", + "72, epithelium {'context': 'I-tissue/organ'}", + "94, alveolar {'context': 'B-cells'}", + "95, epithelial {'context': 'I-cells'}", + "96, cells, {'context': 'I-cells'}", + "125, metalloprotease {'perturbing_action': 'B-pharmacological inhibition'}", + "126, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "127, of {'perturbing_action': 'I-pharmacological inhibition'}", + "128, ADAM10 {'perturbing_action': 'I-pharmacological inhibition'}", + "146, ADAM10-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "147, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "61, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "64, conditional ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "65, disruption ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "66, of ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "67, the ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "68, Adam10 ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "69, gene ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "71, lung ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "72, epithelium ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "94, alveolar ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "95, epithelial ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "96, cells, ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "125, metalloprotease ['l66', 'l67', 'l68']", + "126, inhibitor ['l66', 'l69', 'l70']", + "127, of ['l67', 'l69', 'l71']", + "128, ADAM10 ['l68', 'l70', 'l71']", + "146, ADAM10-knockout ['l72']", + "147, mice. ['l72']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "disruption", + "of", + "the", + "Adam10", + "gene", + "ADAM10-knockout" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "disruption", + "of", + "the", + "Adam10", + "gene" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung", + "epithelium" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "disruption", + "of", + "the", + "Adam10", + "gene" + ] + }, + "context": { + "val": "cells", + "words": [ + "alveolar", + "epithelial", + "cells," + ] + } + } + ] + }, + { + "PMID": "21873989", + "TEXT": "Imatinib mesylate targets mutated KIT oncoproteins in gastrointestinal stromal tumor (GIST) and produces a clinical response in 80% of patients. The mechanism is believed to depend predominantly on the inhibition of KIT-driven signals for tumor-cell survival and proliferation. Using a mouse model of spontaneous GIST, we found that the immune system contributes substantially to the antitumor effects of imatinib. Imatinib therapy activated CD8(+) T cells and induced regulatory T cell (T(reg) cell) apoptosis within the tumor by reducing tumor-cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido). Concurrent immunotherapy augmented the efficacy of imatinib in mouse GIST. In freshly obtained human GIST specimens, the T cell profile correlated with imatinib sensitivity and IDO expression. Thus, T cells are crucial to the antitumor effects of imatinib in GIST, and concomitant immunotherapy may further improve outcomes in human cancers treated with targeted agents.", + "TAG_DATA": [ + "40, mouse {'context': 'B-organism'}", + "41, model {'context': 'I-organism'}", + "62, CD8(+) {'context': 'B-cells'}", + "63, T {'context': 'I-cells'}", + "64, cells {'context': 'I-cells'}", + "66, induced {'effect': 'B-positive'}", + "67, regulatory {'context': 'B-cells'}", + "68, T {'context': 'I-cells'}", + "69, cell {'context': 'I-cells'}", + "70, (T(reg) {'context': 'I-cells'}", + "71, cell) {'context': 'I-cells'}", + "72, apoptosis {'phenotype': 'B-apoptosis'}", + "75, tumor {'context': 'B-neoplasm'}", + "78, tumor-cell {'context': 'B-cells'}", + "95, mouse {'context': 'B-neoplasm'}", + "96, GIST. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "40, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "41, model ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "62, CD8(+) ['l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "63, T ['l1', 'l6', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "64, cells ['l2', 'l7', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "66, induced ['l3', 'l8', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "67, regulatory ['l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "68, T ['l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "69, cell ['l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "70, (T(reg) ['l9', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "71, cell) ['l4', 'l10', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "72, apoptosis ['l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "75, tumor ['l5', 'l11', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "78, tumor-cell ['l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "95, mouse ['l78']", + "96, GIST. ['l78']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "T", + "cells", + "regulatory", + "cell", + "(T(reg)", + "cell)", + "tumor-cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "T", + "cells", + "regulatory", + "cell", + "(T(reg)", + "cell)", + "tumor-cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor" + ] + } + } + ] + }, + { + "PMID": "21873987", + "TEXT": "Previous studies have proposed roles for hypothalamic reactive oxygen species (ROS) in the modulation of circuit activity of the melanocortin system. Here we show that suppression of ROS diminishes pro-opiomelanocortin (POMC) cell activation and promotes the activity of neuropeptide Y (NPY)- and agouti-related peptide (AgRP)-co-producing (NPY/AgRP) neurons and feeding, whereas ROS-activates POMC neurons and reduces feeding. The levels of ROS in POMC neurons were positively correlated with those of leptin in lean and ob/ob mice, a relationship that was diminished in diet-induced obese (DIO) mice. High-fat feeding resulted in proliferation of peroxisomes and elevated peroxisome proliferator-activated receptor γ (PPAR-γ) mRNA levels within the hypothalamus. The proliferation of peroxisomes in POMC neurons induced by the PPAR-γ agonist rosiglitazone decreased ROS levels and increased food intake in lean mice on high-fat diet. Conversely, the suppression of peroxisome proliferation by the PPAR antagonist GW9662 increased ROS concentrations and c-fos expression in POMC neurons. Also, it reversed high-fat feeding-triggered elevated NPY/AgRP and low POMC neuronal firing, and resulted in decreased feeding of DIO mice. Finally, central administration of ROS alone increased c-fos and phosphorylated signal transducer and activator of transcription 3 (pStat3) expression in POMC neurons and reduced feeding of DIO mice. These observations unmask a previously unknown hypothalamic cellular process associated with peroxisomes and ROS in the central regulation of energy metabolism in states of leptin resistance.", + "TAG_DATA": [ + "89, proliferation {'phenotype': 'B-proliferation'}", + "105, proliferation {'phenotype': 'B-proliferation'}", + "107, peroxisomes {'context': 'B-cells'}", + "109, POMC {'context': 'B-cells'}", + "110, neurons {'context': 'I-cells'}", + "111, induced {'effect': 'B-positive'}", + "115, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "116, rosiglitazone {'perturbing_action': 'I-pharmacological augmentation'}", + "125, lean {'context': 'B-organism'}", + "126, mice {'context': 'I-organism'}", + "132, suppression {'effect': 'B-negative'}", + "135, proliferation {'phenotype': 'B-proliferation'}", + "148, POMC {'context': 'B-cells'}", + "149, neurons. {'context': 'I-cells'}", + "159, POMC {'context': 'B-cells'}", + "160, neuronal {'context': 'I-cells'}", + "169, mice. {'context': 'I-organism'}", + "190, POMC {'context': 'B-cells'}", + "191, neurons {'context': 'I-cells'}", + "197, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "89, proliferation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "105, proliferation ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "107, peroxisomes ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "109, POMC ['l2', 'l11', 'l19', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "110, neurons ['l3', 'l12', 'l20', 'l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "111, induced ['l4', 'l13', 'l21', 'l29', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "114, PPAR-γ ['l5', 'l14', 'l22', 'l30', 'l36', 'l41', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "115, agonist ['l6', 'l15', 'l23', 'l31', 'l37', 'l42', 'l46', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "116, rosiglitazone ['l7', 'l16', 'l24', 'l32', 'l38', 'l43', 'l47', 'l53', 'l59', 'l60', 'l61', 'l62']", + "125, lean ['l8', 'l17', 'l25', 'l33', 'l39', 'l44', 'l48', 'l54', 'l59', 'l63']", + "126, mice ['l9', 'l18', 'l26', 'l34', 'l40', 'l45', 'l49', 'l55', 'l60', 'l63']", + "132, suppression ['l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "135, proliferation ['l50', 'l56', 'l64', 'l70', 'l71']", + "148, POMC ['l51', 'l57', 'l61', 'l65', 'l70', 'l72']", + "149, neurons. ['l27', 'l52', 'l58', 'l62', 'l66', 'l71', 'l72']", + "159, POMC ['l67', 'l73', 'l74']", + "160, neuronal ['l68', 'l73', 'l75']", + "169, mice. ['l69', 'l74', 'l75']", + "190, POMC ['l76', 'l77']", + "191, neurons ['l76', 'l78']", + "197, mice. ['l77', 'l78']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "peroxisomes", + "POMC", + "neurons", + "neurons." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "agonist", + "rosiglitazone" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "organism", + "words": [ + "lean", + "mice" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "peroxisomes", + "POMC", + "neurons" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "peroxisomes", + "POMC", + "neurons", + "neurons." + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "agonist", + "rosiglitazone" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "agonist", + "rosiglitazone" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "lean", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "agonist", + "rosiglitazone" + ] + }, + "context": { + "val": "organism", + "words": [ + "lean", + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppression" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppression" + ] + }, + "context": { + "val": "cells", + "words": [ + "POMC", + "neurons.", + "neuronal" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "21841784", + "TEXT": "Human respiratory syncytial virus (RSV) causes a large burden of disease worldwide. There is no effective vaccine or therapy, and the use of passive immunoprophylaxis with RSV-specific antibodies is limited to high-risk patients. The cellular receptor (or receptors) required for viral entry and replication has yet to be described; its identification will improve understanding of the pathogenesis of infection and provide a target for the development of novel antiviral interventions. Here we show that RSV interacts with host-cell nucleolin via the viral fusion envelope glycoprotein and binds specifically to nucleolin at the apical cell surface in vitro. We observed decreased RSV infection in vitro in neutralization experiments using nucleolin-specific antibodies before viral inoculation, in competition experiments in which virus was incubated with soluble nucleolin before inoculation of cells, and upon RNA interference (RNAi) to silence cellular nucleolin expression. Transfection of nonpermissive Spodoptera frugiperda Sf9 insect cells with human nucleolin conferred susceptibility to RSV infection. RNAi-mediated knockdown of lung nucleolin was associated with a significant reduction in RSV infection in mice (P = 0.0004), confirming that nucleolin is a functional RSV receptor in vivo.", + "TAG_DATA": [ + "102, in {'context': 'B-in vitro'}", + "103, vitro {'context': 'I-in vitro'}", + "127, cells, {'context': 'B-cells'}", + "130, RNA {'perturbing_action': 'B-rnai/knockdown'}", + "131, interference {'perturbing_action': 'I-rnai/knockdown'}", + "132, (RNAi) {'perturbing_action': 'I-rnai/knockdown'}", + "133, to {'perturbing_action': 'I-rnai/knockdown'}", + "134, silence {'perturbing_action': 'I-rnai/knockdown'}", + "135, cellular {'perturbing_action': 'I-rnai/knockdown'}", + "136, nucleolin {'perturbing_action': 'I-rnai/knockdown'}", + "137, expression. {'perturbing_action': 'I-rnai/knockdown'}", + "138, Transfection {'perturbing_action': 'B-gene gain-of-function'}", + "140, nonpermissive {'context': 'B-cells'}", + "141, Spodoptera {'context': 'B-organism'}", + "142, frugiperda {'context': 'I-organism'}", + "143, Sf9 {'context': 'I-cells'}", + "144, insect {'context': 'I-cells'}", + "145, cells {'context': 'I-cells'}", + "146, with {'perturbing_action': 'I-gene gain-of-function'}", + "147, human {'perturbing_action': 'I-gene gain-of-function'}", + "148, nucleolin {'perturbing_action': 'I-gene gain-of-function'}", + "154, RNAi-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "155, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "156, of {'perturbing_action': 'I-rnai/knockdown'}", + "157, lung {'perturbing_action': 'I-rnai/knockdown'}", + "158, nucleolin {'perturbing_action': 'I-rnai/knockdown'}", + "169, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "102, in ['l0']", + "103, vitro ['l0']", + "127, cells, ['l1', 'l2', 'l3']", + "130, RNA ['l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "131, interference ['l4', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "132, (RNAi) ['l1', 'l5', 'l21', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "133, to ['l6', 'l22', 'l37', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "134, silence ['l7', 'l23', 'l38', 'l52', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "135, cellular ['l8', 'l24', 'l39', 'l53', 'l66', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "136, nucleolin ['l2', 'l9', 'l25', 'l40', 'l54', 'l67', 'l79', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "137, expression. ['l3', 'l10', 'l26', 'l41', 'l55', 'l68', 'l80', 'l91', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "138, Transfection ['l11', 'l27', 'l42', 'l56', 'l69', 'l81', 'l92', 'l102', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "140, nonpermissive ['l12', 'l28', 'l43', 'l57', 'l70', 'l82', 'l93', 'l103', 'l112', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "141, Spodoptera ['l13', 'l29', 'l44', 'l58', 'l71', 'l83', 'l94', 'l104', 'l113', 'l122', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "142, frugiperda ['l14', 'l30', 'l45', 'l59', 'l72', 'l84', 'l95', 'l105', 'l114', 'l123', 'l131', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145']", + "143, Sf9 ['l15', 'l31', 'l46', 'l60', 'l73', 'l85', 'l96', 'l106', 'l115', 'l124', 'l132', 'l139', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151']", + "144, insect ['l16', 'l32', 'l47', 'l61', 'l74', 'l86', 'l97', 'l107', 'l116', 'l125', 'l133', 'l140', 'l146', 'l152', 'l153', 'l154', 'l155']", + "145, cells ['l17', 'l33', 'l48', 'l62', 'l75', 'l87', 'l98', 'l108', 'l117', 'l126', 'l134', 'l141', 'l147', 'l152', 'l156', 'l157', 'l158']", + "146, with ['l18', 'l34', 'l49', 'l63', 'l76', 'l88', 'l99', 'l109', 'l118', 'l127', 'l135', 'l142', 'l148', 'l153', 'l156', 'l159', 'l160']", + "147, human ['l19', 'l35', 'l50', 'l64', 'l77', 'l89', 'l100', 'l110', 'l119', 'l128', 'l136', 'l143', 'l149', 'l154', 'l157', 'l159', 'l161']", + "148, nucleolin ['l20', 'l36', 'l51', 'l65', 'l78', 'l90', 'l101', 'l111', 'l120', 'l129', 'l137', 'l144', 'l150', 'l155', 'l158', 'l160', 'l161']", + "154, RNAi-mediated ['l162', 'l163', 'l164', 'l165', 'l166']", + "155, knockdown ['l162', 'l167', 'l168', 'l169', 'l170']", + "156, of ['l163', 'l167', 'l171', 'l172', 'l173']", + "157, lung ['l164', 'l168', 'l171', 'l174', 'l175']", + "158, nucleolin ['l165', 'l169', 'l172', 'l174', 'l176']", + "169, mice ['l121', 'l130', 'l138', 'l145', 'l151', 'l166', 'l170', 'l173', 'l175', 'l176']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells,", + "nonpermissive", + "Sf9", + "insect", + "cells" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "(RNAi)", + "nucleolin", + "expression.", + "RNA", + "interference", + "to", + "silence", + "cellular" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "RNA", + "interference", + "(RNAi)", + "to", + "silence", + "cellular", + "nucleolin", + "expression.", + "RNAi-mediated", + "knockdown", + "of", + "lung" + ] + }, + "context": { + "val": "organism", + "words": [ + "Spodoptera", + "frugiperda", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transfection", + "with", + "human", + "nucleolin" + ] + }, + "context": { + "val": "cells", + "words": [ + "nonpermissive", + "Sf9", + "insect", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transfection", + "with", + "human", + "nucleolin" + ] + }, + "context": { + "val": "organism", + "words": [ + "Spodoptera", + "frugiperda", + "mice" + ] + } + } + ] + }, + { + "PMID": "21822287", + "TEXT": "PIK3CA gain-of-function mutations are a common oncogenic event in human malignancy, making phosphatidylinositol 3-kinase (PI3K) a target for cancer therapy. Despite the promise of targeted therapy, resistance often develops, leading to treatment failure. To elucidate mechanisms of resistance to PI3K-targeted therapy, we constructed a mouse model of breast cancer conditionally expressing human PIK3CA(H1047R). Notably, most PIK3CA(H1047R)-driven mammary tumors recurred after PIK3CA(H1047R) inactivation. Genomic analyses of recurrent tumors revealed multiple lesions, including focal amplification of Met or Myc (also known as c-Met and c-Myc, respectively). Whereas Met amplification led to tumor survival dependent on activation of endogenous PI3K, tumors with Myc amplification became independent of the PI3K pathway. Functional analyses showed that Myc contributed to oncogene independence and resistance to PI3K inhibition. Notably, PIK3CA mutations and c-MYC elevation co-occur in a substantial fraction of human breast tumors. Together, these data suggest that c-MYC elevation represents a potential mechanism by which tumors develop resistance to current PI3K-targeted therapies.", + "TAG_DATA": [ + "44, mouse {'context': 'B-organism'}", + "45, model {'context': 'I-organism'}", + "46, of {'context': 'I-neoplasm'}", + "47, breast {'context': 'I-neoplasm'}", + "48, cancer {'context': 'I-neoplasm'}", + "49, conditionally {'perturbing_action': 'B-gene gain-of-function'}", + "50, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "51, human {'perturbing_action': 'I-gene gain-of-function'}", + "52, PIK3CA(H1047R). {'perturbing_action': 'I-gene gain-of-function'}", + "56, mammary {'context': 'B-neoplasm'}", + "57, tumors {'context': 'I-neoplasm'}", + "60, PIK3CA(H1047R) {'perturbing_action': 'B-gene loss-of-function'}", + "61, inactivation. {'perturbing_action': 'I-gene loss-of-function'}", + "88, to {'effect': 'I-positive'}", + "89, tumor {'phenotype': 'B-tumour progression'}", + "90, survival {'phenotype': 'I-cell survival'}", + "97, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "44, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "45, model ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "46, of ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "47, breast ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "48, cancer ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "49, conditionally ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "50, expressing ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "51, human ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l47', 'l53', 'l54', 'l55', 'l56', 'l57']", + "52, PIK3CA(H1047R). ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l48', 'l53', 'l58', 'l59', 'l60', 'l61']", + "56, mammary ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l49', 'l54', 'l58', 'l62', 'l63']", + "57, tumors ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l50', 'l55', 'l59', 'l62']", + "60, PIK3CA(H1047R) ['l45', 'l51', 'l56', 'l60', 'l64']", + "61, inactivation. ['l46', 'l52', 'l57', 'l61', 'l63', 'l64']", + "87, led ['l65', 'l66', 'l67']", + "88, to ['l65', 'l68', 'l69']", + "89, tumor ['l66', 'l68', 'l70', 'l71']", + "90, survival ['l67', 'l69', 'l70']", + "97, tumors ['l71']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "conditionally", + "expressing", + "human", + "PIK3CA(H1047R)." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "of", + "breast", + "cancer", + "mammary", + "tumors" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "conditionally", + "expressing", + "human", + "PIK3CA(H1047R)." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mammary" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "to" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "to" + ] + }, + "phenotype": { + "val": "cell survival", + "words": [ + "survival" + ] + } + }, + { + "phenotype": { + "val": "tumour progression", + "words": [ + "tumor" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + } + ] + }, + { + "PMID": "21725297", + "TEXT": "Survival and differentiation of oligodendrocytes are important for the myelination of central nervous system (CNS) axons during development and crucial for myelin repair in CNS demyelinating diseases such as multiple sclerosis. Here we show that death receptor 6 (DR6) is a negative regulator of oligodendrocyte maturation. DR6 is expressed strongly in immature oligodendrocytes and weakly in mature myelin basic protein (MBP)-positive oligodendrocytes. Overexpression of DR6 in oligodendrocytes leads to caspase 3 (casp3) activation and cell death. Attenuation of DR6 function leads to enhanced oligodendrocyte maturation, myelination and downregulation of casp3. Treatment with a DR6 antagonist antibody promotes remyelination in both lysolecithin-induced demyelination and experimental autoimmune encephalomyelitis (EAE) models. Consistent with the DR6 antagoinst antibody studies, DR6-null mice show enhanced remyelination in both demyelination models. These studies reveal a pivotal role for DR6 signaling in immature oligodendrocyte maturation and myelination that may provide new therapeutic avenues for the treatment of demyelination disorders such as multiple sclerosis.", + "TAG_DATA": [ + "62, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "63, of {'perturbing_action': 'I-gene gain-of-function'}", + "64, DR6 {'perturbing_action': 'I-gene gain-of-function'}", + "66, oligodendrocytes {'context': 'B-cells'}", + "67, leads {'effect': 'B-positive'}", + "68, to {'effect': 'I-positive'}", + "74, cell {'phenotype': 'B-cell death'}", + "75, death. {'phenotype': 'I-cell death'}", + "76, Attenuation {'perturbing_action': 'B-other'}", + "77, of {'perturbing_action': 'I-other'}", + "78, DR6 {'perturbing_action': 'I-other'}", + "79, function {'perturbing_action': 'I-other'}", + "83, oligodendrocyte {'context': 'B-cells'}", + "93, DR6 {'perturbing_action': 'B-pharmacological inhibition'}", + "94, antagonist {'perturbing_action': 'I-rnai/knockdown'}", + "95, antibody {'perturbing_action': 'I-rnai/knockdown'}", + "115, DR6-null {'perturbing_action': 'B-gene loss-of-function'}", + "116, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "62, Overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "63, of ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "64, DR6 ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "66, oligodendrocytes ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "67, leads ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "68, to ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "74, cell ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "75, death. ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "76, Attenuation ['l36', 'l37', 'l38', 'l39']", + "77, of ['l36', 'l40', 'l41', 'l42']", + "78, DR6 ['l37', 'l40', 'l43', 'l44']", + "79, function ['l38', 'l41', 'l43', 'l45']", + "83, oligodendrocyte ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35', 'l39', 'l42', 'l44', 'l45']", + "93, DR6 ['l46', 'l47']", + "94, antagonist ['l46', 'l48']", + "95, antibody ['l47', 'l48']", + "115, DR6-null ['l49']", + "116, mice ['l49']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "DR6" + ] + }, + "context": { + "val": "cells", + "words": [ + "oligodendrocytes", + "oligodendrocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "DR6" + ] + }, + "effect": { + "val": "positive", + "words": [ + "leads", + "to" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "DR6" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "oligodendrocytes", + "oligodendrocyte" + ] + }, + "effect": { + "val": "positive", + "words": [ + "leads", + "to" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "oligodendrocytes", + "oligodendrocyte" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "leads", + "to" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Attenuation", + "of", + "DR6", + "function" + ] + }, + "context": { + "val": "cells", + "words": [ + "oligodendrocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "DR6-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "21666694", + "TEXT": "Here we report that the transcription factor cyclic AMP-responsive element-binding protein H (CREB-H, encoded by CREB3L3) is required for the maintenance of normal plasma triglyceride concentrations. CREB-H-deficient mice showed hypertriglyceridemia secondary to inefficient triglyceride clearance catalyzed by lipoprotein lipase (Lpl), partly due to defective expression of the Lpl coactivators Apoc2, Apoa4 and Apoa5 (encoding apolipoproteins C2, A4 and A5, respectively) and concurrent augmentation of the Lpl inhibitor Apoc3. We identified multiple nonsynonymous mutations in CREB3L3 that produced hypomorphic or nonfunctional CREB-H protein in humans with extreme hypertriglyceridemia, implying a crucial role for CREB-H in human triglyceride metabolism.", + "TAG_DATA": [ + "26, CREB-H-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "27, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "26, CREB-H-deficient ['l0']", + "27, mice ['l0']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CREB-H-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "21623382", + "TEXT": "The ciliopathy Joubert syndrome is marked by cerebellar vermis hypoplasia, a phenotype for which the pathogenic mechanism is unclear. To investigate Joubert syndrome pathogenesis, we have examined mice with mutated Ahi1, the first identified Joubert syndrome-associated gene. These mice show cerebellar hypoplasia with a vermis-midline fusion defect early in development. This defect is concomitant with expansion of the roof plate and is also evident in a mouse mutant for another Joubert syndrome-associated gene, Cep290. Furthermore, fetal magnetic resonance imaging (MRI) of human subjects with Joubert syndrome reveals a similar midline cleft, suggesting parallel pathogenic mechanisms. Previous evidence has suggested a role for Jouberin (Jbn), the protein encoded by Ahi1, in canonical Wnt signaling. Consistent with this, we found decreased Wnt reporter activity at the site of hemisphere fusion in the developing cerebellum of Ahi1-mutant mice. This decrease was accompanied by reduced proliferation at the site of fusion. Finally, treatment with lithium, a Wnt pathway agonist, partially rescued this phenotype. Our findings implicate a defect in Wnt signaling in the cerebellar midline phenotype seen in Joubert syndrome that can be overcome with Wnt stimulation.", + "TAG_DATA": [ + "27, mice {'context': 'B-organism'}", + "29, mutated {'perturbing_action': 'B-other'}", + "30, Ahi1, {'perturbing_action': 'I-other'}", + "38, mice {'context': 'B-organism'}", + "66, mouse {'perturbing_action': 'B-other'}", + "67, mutant {'perturbing_action': 'I-other'}", + "131, cerebellum {'context': 'I-tissue/organ'}", + "133, Ahi1-mutant {'perturbing_action': 'B-other'}", + "134, mice. {'context': 'B-organism'}", + "140, reduced {'effect': 'B-negative'}", + "141, proliferation {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "27, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "29, mutated ['l0', 'l5', 'l6', 'l7', 'l8']", + "30, Ahi1, ['l1', 'l5', 'l9', 'l10', 'l11']", + "38, mice ['l2', 'l6', 'l9', 'l12', 'l13']", + "66, mouse ['l3', 'l7', 'l10', 'l12', 'l14']", + "67, mutant ['l4', 'l8', 'l11', 'l13', 'l14']", + "131, cerebellum ['l15', 'l16', 'l17', 'l18']", + "133, Ahi1-mutant ['l15', 'l19', 'l20', 'l21']", + "134, mice. ['l16', 'l19', 'l22', 'l23']", + "140, reduced ['l17', 'l20', 'l22', 'l24']", + "141, proliferation ['l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "Ahi1,", + "mouse", + "mutant", + "Ahi1-mutant" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "cerebellum" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Ahi1-mutant" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "cerebellum" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "cerebellum" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Ahi1-mutant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Ahi1-mutant" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "21602804", + "TEXT": "Therapies targeting estrogen receptor α (ERα, encoded by ESR1) have transformed the treatment of breast cancer. However, large numbers of women relapse, highlighting the need for the discovery of new regulatory targets modulating ERα pathways. An siRNA screen identified kinases whose silencing alters the estrogen response including those previously implicated in regulating ERα activity (such as mitogen-activated protein kinase and AKT). Among the most potent regulators was lemur tyrosine kinase-3 (LMTK3), for which a role has not previously been assigned. In contrast to other modulators of ERα activity, LMTK3 seems to have been subject to Darwinian positive selection, a noteworthy result given the unique susceptibility of humans to ERα+ breast cancer. LMTK3 acts by decreasing the activity of protein kinase C (PKC) and the phosphorylation of AKT (Ser473), thereby increasing binding of forkhead box O3 (FOXO3) to the ESR1 promoter. LMTK3 phosphorylated ERα, protecting it from proteasomal degradation in vitro. Silencing of LMTK3 reduced tumor volume in an orthotopic mouse model and abrogated proliferation of ERα+ but not ERα- cells, indicative of its role in ERα activity. In human cancers, LMTK3 abundance and intronic polymorphisms were significantly associated with disease-free and overall survival and predicted response to endocrine therapies. These findings yield insights into the natural history of breast cancer in humans and reveal LMTK3 as a new therapeutic target.", + "TAG_DATA": [ + "150, Silencing {'perturbing_action': 'B-rnai/knockdown'}", + "151, of {'perturbing_action': 'I-rnai/knockdown'}", + "152, LMTK3 {'perturbing_action': 'I-rnai/knockdown'}", + "153, reduced {'effect': 'B-negative'}", + "154, tumor {'phenotype': 'B-tumourigenesis'}", + "155, volume {'phenotype': 'I-tumourigenesis'}", + "158, orthotopic {'context': 'B-organism'}", + "159, mouse {'context': 'I-organism'}", + "160, model {'context': 'I-organism'}", + "162, abrogated {'effect': 'B-negative'}", + "163, proliferation {'phenotype': 'B-proliferation'}", + "165, ERα+ {'context': 'B-cells'}", + "168, ERα- {'context': 'B-cells'}", + "169, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "150, Silencing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "151, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "152, LMTK3 ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "153, reduced ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40']", + "154, tumor ['l3', 'l15', 'l26', 'l36', 'l41', 'l42', 'l43', 'l44']", + "155, volume ['l4', 'l16', 'l27', 'l37', 'l41', 'l45', 'l46', 'l47']", + "158, orthotopic ['l5', 'l17', 'l28', 'l38', 'l42', 'l45', 'l48', 'l49']", + "159, mouse ['l6', 'l18', 'l29', 'l39', 'l43', 'l46', 'l48', 'l50']", + "160, model ['l7', 'l19', 'l30', 'l40', 'l44', 'l47', 'l49', 'l50']", + "162, abrogated ['l8', 'l20', 'l31', 'l51', 'l52', 'l53', 'l54']", + "163, proliferation ['l9', 'l21', 'l32', 'l51', 'l55', 'l56', 'l57']", + "165, ERα+ ['l10', 'l22', 'l33', 'l52', 'l55', 'l58', 'l59']", + "168, ERα- ['l11', 'l23', 'l34', 'l53', 'l56', 'l58', 'l60']", + "169, cells, ['l12', 'l24', 'l35', 'l54', 'l57', 'l59', 'l60']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "LMTK3" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced", + "abrogated" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "LMTK3" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "volume" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "LMTK3" + ] + }, + "context": { + "val": "organism", + "words": [ + "orthotopic", + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "LMTK3" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "LMTK3" + ] + }, + "context": { + "val": "cells", + "words": [ + "ERα+", + "ERα-", + "cells," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "volume" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "organism", + "words": [ + "orthotopic", + "mouse", + "model" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "volume" + ] + }, + "context": { + "val": "organism", + "words": [ + "orthotopic", + "mouse", + "model" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogated" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogated" + ] + }, + "context": { + "val": "cells", + "words": [ + "ERα+", + "ERα-", + "cells," + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "ERα+", + "ERα-", + "cells," + ] + } + } + ] + }, + { + "PMID": "21499267", + "TEXT": "Individuals with chronic asthma show a progressive decline in lung function that is thought to be due to structural remodeling of the airways characterized by subepithelial fibrosis and smooth muscle hyperplasia. Here we show that the tumor necrosis factor (TNF) family member LIGHT is expressed on lung inflammatory cells after allergen exposure. Pharmacological inhibition of LIGHT using a fusion protein between the IgG Fc domain and lymphotoxin β receptor (LTβR) reduces lung fibrosis, smooth muscle hyperplasia and airway hyperresponsiveness in mouse models of chronic asthma, despite having little effect on airway eosinophilia. LIGHT-deficient mice also show a similar impairment in fibrosis and smooth muscle accumulation. Blockade of LIGHT suppresses expression of lung transforming growth factor-β (TGF-β) and interleukin-13 (IL-13), cytokines implicated in remodeling in humans, whereas exogenous administration of LIGHT to the airways induces fibrosis and smooth muscle hyperplasia, Thus, LIGHT may be targeted to prevent asthma-related airway remodeling.", + "TAG_DATA": [ + "52, Pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "53, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "54, of {'perturbing_action': 'I-pharmacological inhibition'}", + "55, LIGHT {'perturbing_action': 'I-pharmacological inhibition'}", + "56, using {'perturbing_action': 'I-pharmacological inhibition'}", + "57, a {'perturbing_action': 'I-pharmacological inhibition'}", + "58, fusion {'perturbing_action': 'I-pharmacological inhibition'}", + "59, protein {'perturbing_action': 'I-pharmacological inhibition'}", + "60, between {'perturbing_action': 'I-pharmacological inhibition'}", + "61, the {'perturbing_action': 'I-pharmacological inhibition'}", + "62, IgG {'perturbing_action': 'I-pharmacological inhibition'}", + "63, Fc {'perturbing_action': 'I-pharmacological inhibition'}", + "64, domain {'perturbing_action': 'I-pharmacological inhibition'}", + "65, and {'perturbing_action': 'I-pharmacological inhibition'}", + "66, lymphotoxin {'perturbing_action': 'I-pharmacological inhibition'}", + "67, β {'perturbing_action': 'I-pharmacological inhibition'}", + "68, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "71, lung {'context': 'B-tissue/organ'}", + "80, mouse {'context': 'B-organism'}", + "81, models {'context': 'I-organism'}", + "92, LIGHT-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "93, mice {'context': 'B-organism'}", + "105, Blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "106, of {'perturbing_action': 'I-pharmacological inhibition'}", + "107, LIGHT {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "52, Pharmacological ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "53, inhibition ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "54, of ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "55, LIGHT ['l2', 'l21', 'l39', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "56, using ['l3', 'l22', 'l40', 'l57', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "57, a ['l4', 'l23', 'l41', 'l58', 'l74', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "58, fusion ['l5', 'l24', 'l42', 'l59', 'l75', 'l90', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "59, protein ['l6', 'l25', 'l43', 'l60', 'l76', 'l91', 'l105', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "60, between ['l7', 'l26', 'l44', 'l61', 'l77', 'l92', 'l106', 'l120', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "61, the ['l8', 'l27', 'l45', 'l62', 'l78', 'l93', 'l107', 'l121', 'l134', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160']", + "62, IgG ['l9', 'l28', 'l46', 'l63', 'l79', 'l94', 'l108', 'l122', 'l135', 'l148', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172']", + "63, Fc ['l10', 'l29', 'l47', 'l64', 'l80', 'l95', 'l109', 'l123', 'l136', 'l149', 'l161', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183']", + "64, domain ['l11', 'l30', 'l48', 'l65', 'l81', 'l96', 'l110', 'l124', 'l137', 'l150', 'l162', 'l173', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "65, and ['l12', 'l31', 'l49', 'l66', 'l82', 'l97', 'l111', 'l125', 'l138', 'l151', 'l163', 'l174', 'l184', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202']", + "66, lymphotoxin ['l13', 'l32', 'l50', 'l67', 'l83', 'l98', 'l112', 'l126', 'l139', 'l152', 'l164', 'l175', 'l185', 'l194', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210']", + "67, β ['l14', 'l33', 'l51', 'l68', 'l84', 'l99', 'l113', 'l127', 'l140', 'l153', 'l165', 'l176', 'l186', 'l195', 'l203', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217']", + "68, receptor ['l15', 'l34', 'l52', 'l69', 'l85', 'l100', 'l114', 'l128', 'l141', 'l154', 'l166', 'l177', 'l187', 'l196', 'l204', 'l211', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223']", + "69, (LTβR) ['l16', 'l35', 'l53', 'l70', 'l86', 'l101', 'l115', 'l129', 'l142', 'l155', 'l167', 'l178', 'l188', 'l197', 'l205', 'l212', 'l218', 'l224', 'l225', 'l226', 'l227']", + "71, lung ['l17', 'l36', 'l54', 'l71', 'l87', 'l102', 'l116', 'l130', 'l143', 'l156', 'l168', 'l179', 'l189', 'l198', 'l206', 'l213', 'l219', 'l224', 'l228', 'l229']", + "80, mouse ['l18', 'l37', 'l55', 'l72', 'l88', 'l103', 'l117', 'l131', 'l144', 'l157', 'l169', 'l180', 'l190', 'l199', 'l207', 'l214', 'l220', 'l225', 'l228', 'l230']", + "81, models ['l19', 'l38', 'l56', 'l73', 'l89', 'l104', 'l118', 'l132', 'l145', 'l158', 'l170', 'l181', 'l191', 'l200', 'l208', 'l215', 'l221', 'l226', 'l229', 'l230']", + "92, LIGHT-deficient ['l146', 'l159', 'l171', 'l182', 'l192', 'l201', 'l209', 'l216', 'l222', 'l231']", + "93, mice ['l119', 'l133', 'l147', 'l160', 'l172', 'l183', 'l193', 'l202', 'l210', 'l217', 'l223', 'l227', 'l231']", + "105, Blockade ['l232', 'l233', 'l234']", + "106, of ['l232', 'l235', 'l236']", + "107, LIGHT ['l233', 'l235', 'l237']", + "132, airways ['l234', 'l236', 'l237']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "LIGHT", + "using", + "a", + "fusion", + "protein", + "between", + "the", + "IgG", + "Fc", + "domain", + "and", + "lymphotoxin", + "β", + "receptor" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "inhibition", + "of", + "LIGHT", + "using", + "a", + "fusion", + "protein", + "between", + "the", + "IgG", + "Fc", + "domain", + "and", + "lymphotoxin", + "β", + "receptor" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "LIGHT-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "21399647", + "TEXT": "Trastuzumab is a successful rationally designed ERBB2-targeted therapy. However, about half of individuals with ERBB2-overexpressing breast cancer do not respond to trastuzumab-based therapies, owing to various resistance mechanisms. Clinically applicable regimens for overcoming trastuzumab resistance of different mechanisms are not yet available. We show that the nonreceptor tyrosine kinase c-SRC (SRC) is a key modulator of trastuzumab response and a common node downstream of multiple trastuzumab resistance pathways. We find that SRC is activated in both acquired and de novo trastuzumab-resistant cells and uncover a novel mechanism of SRC regulation involving dephosphorylation by PTEN. Increased SRC activation conferred considerable trastuzumab resistance in breast cancer cells and correlated with trastuzumab resistance in patients. Targeting SRC in combination with trastuzumab sensitized multiple lines of trastuzumab-resistant cells to trastuzumab and eliminated trastuzumab-resistant tumors in vivo, suggesting the potential clinical application of this strategy to overcome trastuzumab resistance.", + "TAG_DATA": [ + "102, breast {'context': 'B-transformed cells'}", + "103, cancer {'context': 'I-transformed cells'}", + "104, cells {'context': 'I-transformed cells'}", + "112, Targeting {'perturbing_action': 'B-other'}", + "113, SRC {'perturbing_action': 'I-other'}", + "122, trastuzumab-resistant {'context': 'B-transformed cells'}", + "123, cells {'context': 'I-cells'}", + "128, trastuzumab-resistant {'context': 'B-neoplasm'}", + "129, tumors {'context': 'I-neoplasm'}", + "130, in {'context': 'B-in vivo'}", + "131, vivo, {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "102, breast ['l0', 'l1']", + "103, cancer ['l0', 'l2']", + "104, cells ['l1', 'l2']", + "112, Targeting ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "113, SRC ['l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "122, trastuzumab-resistant ['l4', 'l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "123, cells ['l5', 'l11', 'l16']", + "128, trastuzumab-resistant ['l6', 'l12', 'l17', 'l21', 'l22', 'l23']", + "129, tumors ['l7', 'l13', 'l18', 'l21', 'l24', 'l25']", + "130, in ['l8', 'l14', 'l19', 'l22', 'l24', 'l26']", + "131, vivo, ['l9', 'l15', 'l20', 'l23', 'l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Targeting", + "SRC" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "trastuzumab-resistant" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Targeting", + "SRC" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Targeting", + "SRC" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "trastuzumab-resistant", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Targeting", + "SRC" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + } + ] + }, + { + "PMID": "21240263", + "TEXT": "The combination of intravital microscopy and animal models of disease has propelled studies of disease mechanisms and treatments. However, many disorders afflict tissues inaccessible to light microscopy in live subjects. Here we introduce cellular-level time-lapse imaging deep within the live mammalian brain by one- and two-photon fluorescence microendoscopy over multiple weeks. Bilateral imaging sites allowed longitudinal comparisons within individual subjects, including of normal and diseased tissues. Using this approach, we tracked CA1 hippocampal pyramidal neuron dendrites in adult mice, revealing these dendrites' extreme stability and rare examples of their structural alterations. To illustrate disease studies, we tracked deep lying gliomas by observing tumor growth, visualizing three-dimensional vasculature structure and determining microcirculatory speeds. Average erythrocyte speeds in gliomas declined markedly as the disease advanced, notwithstanding significant increases in capillary diameters. Time-lapse microendoscopy will be applicable to studies of numerous disorders, including neurovascular, neurological, cancerous and trauma-induced conditions.", + "TAG_DATA": [ + "71, CA1 {'context': 'B-cells'}", + "72, hippocampal {'context': 'I-cells'}", + "73, pyramidal {'context': 'I-cells'}", + "74, neuron {'context': 'I-cells'}", + "75, dendrites {'context': 'I-cells'}", + "77, adult {'context': 'B-organism'}", + "78, mice, {'context': 'I-organism'}", + "99, gliomas {'context': 'B-neoplasm'}", + "102, tumor {'phenotype': 'B-tumour growth'}", + "103, growth, {'phenotype': 'I-tumour growth'}", + "116, gliomas {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "71, CA1 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "72, hippocampal ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "73, pyramidal ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "74, neuron ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "75, dendrites ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "77, adult ['l4', 'l10', 'l15', 'l19', 'l22', 'l25']", + "78, mice, ['l5', 'l11', 'l16', 'l20', 'l23', 'l25']", + "99, gliomas ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "102, tumor ['l26', 'l28']", + "103, growth, ['l27', 'l28']", + "113, erythrocyte ['l29']", + "116, gliomas ['l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "gliomas" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth," + ] + } + } + ] + }, + { + "PMID": "21170045", + "TEXT": "Histidine decarboxylase (HDC), the unique enzyme responsible for histamine generation, is highly expressed in myeloid cells, but its function in these cells is poorly understood. Here we show that Hdc-knockout mice show a high rate of colon and skin carcinogenesis. Using Hdc-EGFP bacterial artificial chromosome (BAC) transgenic mice in which EGFP expression is controlled by the Hdc promoter, we show that Hdc is expressed primarily in CD11b(+)Ly6G(+) immature myeloid cells (IMCs) that are recruited early on in chemical carcinogenesis. Transplant of Hdc-deficient bone marrow to wild-type recipients results in increased CD11b(+)Ly6G(+) cell mobilization and reproduces the cancer susceptibility phenotype of Hdc-knockout mice. In addition, Hdc-deficient IMCs promote the growth of tumor allografts, whereas mouse CT26 colon cancer cells downregulate Hdc expression through promoter hypermethylation and inhibit myeloid cell maturation. Exogenous histamine induces the differentiation of IMCs and suppresses their ability to support the growth of tumor allografts. These data indicate key roles for Hdc and histamine in myeloid cell differentiation and CD11b(+)Ly6G(+) IMCs in early cancer development.", + "TAG_DATA": [ + "29, Hdc-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "41, Hdc-EGFP {'perturbing_action': 'B-gene gain-of-function'}", + "42, bacterial {'perturbing_action': 'I-gene gain-of-function'}", + "43, artificial {'perturbing_action': 'I-gene gain-of-function'}", + "44, chromosome {'perturbing_action': 'I-gene gain-of-function'}", + "46, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "47, mice {'context': 'B-organism'}", + "81, Hdc-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "82, bone {'context': 'B-tissue/organ'}", + "83, marrow {'context': 'I-tissue/organ'}", + "90, CD11b(+)Ly6G(+) {'context': 'B-cells'}", + "100, Hdc-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "101, mice. {'context': 'B-organism'}", + "104, Hdc-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "105, IMCs {'context': 'B-cells'}", + "110, tumor {'context': 'B-xenograft'}", + "111, allografts, {'context': 'I-xenograft'}", + "113, mouse {'context': 'B-transformed cells'}", + "114, CT26 {'context': 'I-transformed cells'}", + "115, colon {'context': 'I-transformed cells'}", + "116, cancer {'context': 'I-transformed cells'}", + "117, cells {'context': 'I-transformed cells'}", + "126, myeloid {'context': 'B-cells'}", + "127, cell {'context': 'I-cells'}", + "131, induces {'effect': 'B-positive'}", + "133, differentiation {'phenotype': 'B-differentiation'}", + "135, IMCs {'context': 'B-cells'}", + "145, tumor {'context': 'B-xenograft'}", + "146, allografts. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "29, Hdc-knockout ['l0', 'l1', 'l2']", + "41, Hdc-EGFP ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "42, bacterial ['l3', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "43, artificial ['l4', 'l13', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "44, chromosome ['l0', 'l5', 'l14', 'l22', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "45, (BAC) ['l6', 'l15', 'l23', 'l30', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "46, transgenic ['l1', 'l7', 'l16', 'l24', 'l31', 'l37', 'l43', 'l44', 'l45', 'l46']", + "47, mice ['l2', 'l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l48', 'l49']", + "81, Hdc-deficient ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l47', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "82, bone ['l10', 'l19', 'l27', 'l34', 'l40', 'l45', 'l48', 'l50', 'l56', 'l57', 'l58', 'l59', 'l60']", + "83, marrow ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l49', 'l51', 'l56', 'l61', 'l62']", + "90, CD11b(+)Ly6G(+) ['l12', 'l21', 'l29', 'l36', 'l42', 'l52', 'l57', 'l61', 'l63', 'l64', 'l65', 'l66']", + "100, Hdc-knockout ['l53', 'l58', 'l63', 'l67', 'l68', 'l69', 'l70', 'l71']", + "101, mice. ['l54', 'l59', 'l62', 'l64', 'l67', 'l72']", + "104, Hdc-deficient ['l68', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "105, IMCs ['l69', 'l73', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "110, tumor ['l65', 'l70', 'l74', 'l83', 'l92', 'l93', 'l94', 'l95', 'l96']", + "111, allografts, ['l55', 'l60', 'l66', 'l71', 'l72', 'l75', 'l84', 'l92', 'l97', 'l98', 'l99']", + "113, mouse ['l76', 'l85', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "114, CT26 ['l77', 'l86', 'l100', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120']", + "115, colon ['l78', 'l87', 'l93', 'l101', 'l111', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126']", + "116, cancer ['l79', 'l88', 'l94', 'l97', 'l102', 'l112', 'l121', 'l127', 'l128', 'l129', 'l130', 'l131']", + "117, cells ['l80', 'l89', 'l95', 'l98', 'l103', 'l113', 'l122', 'l127', 'l132', 'l133', 'l134', 'l135']", + "126, myeloid ['l81', 'l90', 'l104', 'l114', 'l123', 'l128', 'l132', 'l136', 'l137', 'l138', 'l139', 'l140']", + "127, cell ['l82', 'l91', 'l96', 'l99', 'l105', 'l115', 'l124', 'l129', 'l133', 'l136', 'l141', 'l142']", + "131, induces ['l106', 'l116', 'l143', 'l144', 'l145', 'l146']", + "133, differentiation ['l107', 'l117', 'l137', 'l143', 'l147', 'l148', 'l149']", + "135, IMCs ['l108', 'l118', 'l138', 'l144', 'l147', 'l150', 'l151']", + "145, tumor ['l109', 'l119', 'l125', 'l130', 'l134', 'l139', 'l141', 'l145', 'l148', 'l150', 'l152']", + "146, allografts. ['l110', 'l120', 'l126', 'l131', 'l135', 'l140', 'l142', 'l146', 'l149', 'l151', 'l152']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hdc-knockout", + "Hdc-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Hdc-EGFP", + "bacterial", + "artificial", + "chromosome", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Hdc-EGFP", + "bacterial", + "artificial", + "chromosome", + "transgenic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "bone", + "marrow" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Hdc-EGFP", + "bacterial", + "artificial", + "chromosome" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD11b(+)Ly6G(+)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hdc-deficient", + "Hdc-knockout" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "bone", + "marrow" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hdc-deficient", + "Hdc-knockout" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD11b(+)Ly6G(+)", + "IMCs", + "myeloid", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hdc-deficient", + "Hdc-knockout" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "allografts,", + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hdc-deficient" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "mouse", + "CT26", + "colon", + "cancer", + "cells" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "mouse", + "CT26" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "mouse", + "CT26" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "myeloid", + "IMCs" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "cells", + "words": [ + "IMCs" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "tumor", + "allografts." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "tumor", + "allografts." + ] + } + } + ] + }, + { + "PMID": "21102461", + "TEXT": "Stroke is a major public health problem leading to high rates of death and disability in adults. Excessive stimulation of N-methyl-D-aspartate receptors (NMDARs) and the resulting neuronal nitric oxide synthase (nNOS) activation are crucial for neuronal injury after stroke insult. However, directly inhibiting NMDARs or nNOS can cause severe side effects because they have key physiological functions in the CNS. Here we show that cerebral ischemia induces the interaction of nNOS with postsynaptic density protein-95 (PSD-95). Disrupting nNOS-PSD-95 interaction via overexpressing the N-terminal amino acid residues 1-133 of nNOS (nNOS-N(1-133)) prevented glutamate-induced excitotoxicity and cerebral ischemic damage. Given the mechanism of nNOS-PSD-95 interaction, we developed a series of compounds and discovered a small-molecular inhibitor of the nNOS-PSD-95 interaction, ZL006. This drug blocked the ischemia-induced nNOS-PSD-95 association selectively, had potent neuroprotective activity in vitro and ameliorated focal cerebral ischemic damage in mice and rats subjected to middle cerebral artery occlusion (MCAO) and reperfusion. Moreover, it readily crossed the blood-brain barrier, did not inhibit NMDAR function, catalytic activity of nNOS or spatial memory, and had no effect on aggressive behaviors. Thus, this new drug may serve as a treatment for stroke, perhaps without major side effects.", + "TAG_DATA": [ + "80, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "81, the {'perturbing_action': 'I-gene gain-of-function'}", + "82, N-terminal {'perturbing_action': 'I-gene gain-of-function'}", + "83, amino {'perturbing_action': 'I-gene gain-of-function'}", + "84, acid {'perturbing_action': 'I-gene gain-of-function'}", + "85, residues {'perturbing_action': 'I-gene gain-of-function'}", + "86, 1-133 {'perturbing_action': 'I-gene gain-of-function'}", + "87, of {'perturbing_action': 'I-gene gain-of-function'}", + "88, nNOS {'perturbing_action': 'I-gene gain-of-function'}", + "89, (nNOS-N(1-133)) {'perturbing_action': 'I-gene gain-of-function'}", + "131, in {'context': 'B-in vitro'}", + "132, vitro {'context': 'I-in vitro'}", + "140, mice {'context': 'B-organism'}", + "142, rats {'context': 'B-organism'}", + "173, no {'effect': 'B-no effect'}", + "174, effect {'effect': 'I-no effect'}" + ], + "LINK_DATA": [ + "80, overexpressing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "81, the ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "82, N-terminal ['l1', 'l12', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "83, amino ['l2', 'l13', 'l24', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "84, acid ['l3', 'l14', 'l25', 'l35', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "85, residues ['l4', 'l15', 'l26', 'l36', 'l45', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "86, 1-133 ['l5', 'l16', 'l27', 'l37', 'l46', 'l54', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "87, of ['l6', 'l17', 'l28', 'l38', 'l47', 'l55', 'l62', 'l69', 'l70', 'l71', 'l72', 'l73']", + "88, nNOS ['l7', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l69', 'l74', 'l75', 'l76', 'l77']", + "89, (nNOS-N(1-133)) ['l8', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l74', 'l78', 'l79', 'l80']", + "131, in ['l9', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l75', 'l78', 'l81', 'l82', 'l83']", + "132, vitro ['l10', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l76', 'l79', 'l81', 'l84', 'l85']", + "140, mice ['l11', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l77', 'l80', 'l82', 'l84', 'l86']", + "142, rats ['l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l83', 'l85', 'l86']", + "173, no ['l87']", + "174, effect ['l87']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "the", + "N-terminal", + "amino", + "acid", + "residues", + "1-133", + "of", + "nNOS", + "(nNOS-N(1-133))" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "the", + "N-terminal", + "amino", + "acid", + "residues", + "1-133", + "of", + "nNOS", + "(nNOS-N(1-133))" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "rats" + ] + } + } + ] + }, + { + "PMID": "21102459", + "TEXT": "Refined cancer models are required if researchers are to assess the burgeoning number of potential targets for cancer therapeutics in a clinically relevant context that allows a fast turnaround. Here we use tumor-associated genetic pathways to transform primary human epithelial cells from the epidermis, oropharynx, esophagus and cervix into genetically defined tumors in a human three-dimensional (3D) tissue environment that incorporates cell-populated stroma and intact basement membrane. These engineered organotypic tissues recapitulated natural features of tumor progression, including epithelial invasion through basement membrane, a complex process that is necessary for biological malignancy in 90% of human cancers. Invasion was rapid and was potentiated by stromal cells. Oncogenic signals in 3D tissue, but not 2D culture, resembled gene expression profiles from spontaneous human cancers. We screened 3D organotypic neoplasia with well-characterized signaling pathway inhibitors to distill a clinically faithful cancer gene signature. Multitissue 3D human tissue cancer models may provide an efficient and relevant complement to current approaches to characterizing cancer progression.", + "TAG_DATA": [ + "37, primary {'context': 'B-cells'}", + "38, human {'context': 'I-cells'}", + "39, epithelial {'context': 'I-cells'}", + "40, cells {'context': 'I-cells'}", + "97, Invasion {'phenotype': 'B-invasion'}", + "102, potentiated {'effect': 'B-positive'}", + "104, stromal {'context': 'B-cells'}", + "105, cells. {'context': 'I-cells'}", + "109, 3D {'context': 'B-tissue/organ'}", + "110, tissue, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "37, primary ['l0', 'l1', 'l2', 'l3']", + "38, human ['l0', 'l4', 'l5', 'l6']", + "39, epithelial ['l1', 'l4', 'l7', 'l8']", + "40, cells ['l2', 'l5', 'l7', 'l9']", + "41, from ['l3', 'l6', 'l8', 'l9']", + "97, Invasion ['l10', 'l11', 'l12']", + "102, potentiated ['l10', 'l13', 'l14']", + "104, stromal ['l11', 'l13', 'l15']", + "105, cells. ['l12', 'l14', 'l15']", + "109, 3D ['l16']", + "110, tissue, ['l16']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "invasion", + "words": [ + "Invasion" + ] + }, + "effect": { + "val": "positive", + "words": [ + "potentiated" + ] + } + }, + { + "phenotype": { + "val": "invasion", + "words": [ + "Invasion" + ] + }, + "context": { + "val": "cells", + "words": [ + "stromal", + "cells." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "potentiated" + ] + }, + "context": { + "val": "cells", + "words": [ + "stromal", + "cells." + ] + } + } + ] + }, + { + "PMID": "21076395", + "TEXT": "Aberrant activation of the Hedgehog (Hh) pathway can drive tumorigenesis. To investigate the mechanism by which glioma-associated oncogene family zinc finger-1 (GLI1), a crucial effector of Hh signaling, regulates Hh pathway activation, we searched for GLI1-interacting proteins. We report that the chromatin remodeling protein SNF5 (encoded by SMARCB1, hereafter called SNF5), which is inactivated in human malignant rhabdoid tumors (MRTs), interacts with GLI1. We show that Snf5 localizes to Gli1-regulated promoters and that loss of Snf5 leads to activation of the Hh-Gli pathway. Conversely, re-expression of SNF5 in MRT cells represses GLI1. Consistent with this, we show the presence of a Hh-Gli-activated gene expression profile in primary MRTs and show that GLI1 drives the growth of SNF5-deficient MRT cells in vitro and in vivo. Therefore, our studies reveal that SNF5 is a key mediator of Hh signaling and that aberrant activation of GLI1 is a previously undescribed targetable mechanism contributing to the growth of MRT cells.", + "TAG_DATA": [ + "73, loss {'perturbing_action': 'B-gene loss-of-function'}", + "74, of {'perturbing_action': 'I-gene loss-of-function'}", + "75, Snf5 {'perturbing_action': 'I-gene loss-of-function'}", + "84, re-expression {'perturbing_action': 'B-gene gain-of-function'}", + "85, of {'perturbing_action': 'I-gene gain-of-function'}", + "86, SNF5 {'perturbing_action': 'I-gene gain-of-function'}", + "88, MRT {'context': 'B-cells'}", + "89, cells {'context': 'I-cells'}", + "116, SNF5-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "117, MRT {'context': 'B-cells'}", + "118, cells {'context': 'I-cells'}", + "119, in {'context': 'B-in vitro'}", + "120, vitro {'context': 'I-in vitro'}", + "122, in {'context': 'B-in vivo'}", + "123, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "73, loss ['l0', 'l1']", + "74, of ['l0', 'l2']", + "75, Snf5 ['l1', 'l2']", + "84, re-expression ['l3', 'l4', 'l5', 'l6']", + "85, of ['l3', 'l7', 'l8', 'l9']", + "86, SNF5 ['l4', 'l7', 'l10', 'l11']", + "88, MRT ['l5', 'l8', 'l10', 'l12']", + "89, cells ['l6', 'l9', 'l11', 'l12']", + "116, SNF5-deficient ['l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "117, MRT ['l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "118, cells ['l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "119, in ['l15', 'l20', 'l24', 'l28', 'l29', 'l30']", + "120, vitro ['l16', 'l21', 'l25', 'l28', 'l31', 'l32']", + "122, in ['l17', 'l22', 'l26', 'l29', 'l31', 'l33']", + "123, vivo. ['l18', 'l23', 'l27', 'l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "re-expression", + "of", + "SNF5" + ] + }, + "context": { + "val": "cells", + "words": [ + "MRT", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SNF5-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "MRT", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SNF5-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SNF5-deficient" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "20972433", + "TEXT": "The TLX1 oncogene (encoding the transcription factor T cell leukemia homeobox protein-1) has a major role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL). However, the specific mechanisms of T cell transformation downstream of TLX1 remain to be elucidated. Here we show that transgenic expression of human TLX1 in mice induces T-ALL with frequent deletions and mutations in Bcl11b (encoding B cell leukemia/lymphoma-11B) and identify the presence of recurrent mutations and deletions in BCL11B in 16% of human T-ALLs. Most notably, mouse TLX1 tumors were typically aneuploid and showed a marked defect in the activation of the mitotic checkpoint. Mechanistically, TLX1 directly downregulates the expression of CHEK1 (encoding CHK1 checkpoint homolog) and additional mitotic control genes and induces loss of the mitotic checkpoint in nontransformed preleukemic thymocytes. These results identify a previously unrecognized mechanism contributing to chromosomal missegregation and aneuploidy active at the earliest stages of tumor development in the pathogenesis of cancer.", + "TAG_DATA": [ + "45, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "46, expression {'perturbing_action': 'I-gene gain-of-function'}", + "47, of {'perturbing_action': 'I-gene gain-of-function'}", + "48, human {'perturbing_action': 'I-gene gain-of-function'}", + "49, TLX1 {'perturbing_action': 'I-gene gain-of-function'}", + "51, mice {'context': 'B-organism'}", + "52, induces {'effect': 'B-positive'}", + "53, T-ALL {'phenotype': 'B-transformation'}", + "83, mouse {'context': 'B-neoplasm'}", + "84, TLX1 {'context': 'I-neoplasm'}", + "85, tumors {'context': 'I-neoplasm'}", + "126, nontransformed {'context': 'B-cells'}", + "127, preleukemic {'context': 'B-cells'}", + "128, thymocytes. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "46, expression ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "47, of ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "48, human ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "49, TLX1 ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "51, mice ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "52, induces ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "53, T-ALL ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "83, mouse ['l28', 'l29']", + "84, TLX1 ['l28', 'l30']", + "85, tumors ['l29', 'l30']", + "126, nontransformed ['l31', 'l32']", + "127, preleukemic ['l31', 'l33']", + "128, thymocytes. ['l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "of", + "human", + "TLX1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "of", + "human", + "TLX1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "of", + "human", + "TLX1" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "T-ALL" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "T-ALL" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "transformation", + "words": [ + "T-ALL" + ] + } + } + ] + }, + { + "PMID": "20871610", + "TEXT": "Mobilization of hematopoietic stem and progenitor cells (HSPCs) from bone marrow into peripheral blood by the cytokine granulocyte colony-stimulating factor (G-CSF) has become the preferred source of HSPCs for stem cell transplants. However, G-CSF fails to mobilize sufficient numbers of stem cells in up to 10% of donors, precluding autologous transplantation in those donors or substantially delaying transplant recovery time. Consequently, new regimens are needed to increase the number of stem cells in peripheral blood upon mobilization. Using a forward genetic approach in mice, we mapped the gene encoding the epidermal growth factor receptor (Egfr) to a genetic region modifying G-CSF-mediated HSPC mobilization. Amounts of EGFR in HSPCs inversely correlated with the cells' ability to be mobilized by G-CSF, implying a negative role for EGFR signaling in mobilization. In combination with G-CSF treatment, genetic reduction of EGFR activity in HSPCs (in waved-2 mutant mice) or treatment with the EGFR inhibitor erlotinib increased mobilization. Increased mobilization due to suppression of EGFR activity correlated with reduced activity of cell division control protein-42 (Cdc42), and genetic Cdc42 deficiency in vivo also enhanced G-CSF-induced mobilization. Our findings reveal a previously unknown signaling pathway regulating stem cell mobilization and provide a new pharmacological approach for improving HSPC mobilization and thereby transplantation outcomes.", + "TAG_DATA": [ + "133, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "134, reduction {'perturbing_action': 'I-gene loss-of-function'}", + "135, of {'perturbing_action': 'I-gene loss-of-function'}", + "136, EGFR {'perturbing_action': 'I-gene loss-of-function'}", + "137, activity {'perturbing_action': 'I-gene loss-of-function'}", + "139, HSPCs {'context': 'B-cells'}", + "141, waved-2 {'perturbing_action': 'B-other'}", + "142, mutant {'perturbing_action': 'I-other'}", + "143, mice) {'context': 'B-organism'}", + "172, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "173, Cdc42 {'perturbing_action': 'I-gene loss-of-function'}", + "174, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "175, in {'context': 'B-in vivo'}", + "176, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "133, genetic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "134, reduction ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "135, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "136, EGFR ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "137, activity ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "139, HSPCs ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "141, waved-2 ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "142, mutant ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "143, mice) ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "172, genetic ['l36', 'l37', 'l38', 'l39']", + "173, Cdc42 ['l36', 'l40', 'l41', 'l42']", + "174, deficiency ['l37', 'l40', 'l43', 'l44']", + "175, in ['l38', 'l41', 'l43', 'l45']", + "176, vivo ['l39', 'l42', 'l44', 'l45']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "reduction", + "of", + "EGFR", + "activity" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSPCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "reduction", + "of", + "EGFR", + "activity" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice)" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "HSPCs" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "waved-2", + "mutant" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "waved-2", + "mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "Cdc42", + "deficiency" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "20852621", + "TEXT": "During fasting, mammals maintain normal glucose homeostasis by stimulating hepatic gluconeogenesis. Elevations in circulating glucagon and epinephrine, two hormones that activate hepatic gluconeogenesis, trigger the cAMP-mediated phosphorylation of cAMP response element-binding protein (Creb) and dephosphorylation of the Creb-regulated transcription coactivator-2 (Crtc2)--two key transcriptional regulators of this process. Although the underlying mechanism is unclear, hepatic gluconeogenesis is also regulated by the circadian clock, which coordinates glucose metabolism with changes in the external environment. Circadian control of gene expression is achieved by two transcriptional activators, Clock and Bmal1, which stimulate cryptochrome (Cry1 and Cry2) and Period (Per1, Per2 and Per3) repressors that feed back on Clock-Bmal1 activity. Here we show that Creb activity during fasting is modulated by Cry1 and Cry2, which are rhythmically expressed in the liver. Cry1 expression was elevated during the night-day transition, when it reduced fasting gluconeogenic gene expression by blocking glucagon-mediated increases in intracellular cAMP concentrations and in the protein kinase A-mediated phosphorylation of Creb. In biochemical reconstitution studies, we found that Cry1 inhibited accumulation of cAMP in response to G protein-coupled receptor (GPCR) activation but not to forskolin, a direct activator of adenyl cyclase. Cry proteins seemed to modulate GPCR activity directly through interaction with G(s)α. As hepatic overexpression of Cry1 lowered blood glucose concentrations and improved insulin sensitivity in insulin-resistant db/db mice, our results suggest that compounds that enhance cryptochrome activity may provide therapeutic benefit to individuals with type 2 diabetes.", + "TAG_DATA": [ + "201, hepatic {'perturbing_action': 'B-gene gain-of-function'}", + "202, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "203, of {'perturbing_action': 'I-gene gain-of-function'}", + "204, Cry1 {'perturbing_action': 'I-gene gain-of-function'}", + "214, insulin-resistant {'context': 'B-organism'}", + "215, db/db {'context': 'I-organism'}", + "216, mice, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "201, hepatic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "202, overexpression ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "203, of ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "204, Cry1 ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "214, insulin-resistant ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "215, db/db ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "216, mice, ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hepatic", + "overexpression", + "of", + "Cry1" + ] + }, + "context": { + "val": "organism", + "words": [ + "insulin-resistant", + "db/db", + "mice," + ] + } + } + ] + }, + { + "PMID": "20802499", + "TEXT": "Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here we demonstrate that either whole-body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Similarly, inhibition of thyroid hormone receptors in the VMH reverses the weight loss associated with hyperthyroidism. This regulatory mechanism depends on AMPK inactivation, as genetic inhibition of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increases expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockade of the SNS. Thus, thyroid hormone-induced modulation of AMPK activity and lipid metabolism in the hypothalamus is a major regulator of whole-body energy homeostasis.", + "TAG_DATA": [ + "91, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "92, of {'perturbing_action': 'I-pharmacological inhibition'}", + "93, thyroid {'perturbing_action': 'I-pharmacological inhibition'}", + "94, hormone {'perturbing_action': 'I-pharmacological inhibition'}", + "95, receptors {'perturbing_action': 'I-pharmacological inhibition'}", + "96, in {'perturbing_action': 'I-pharmacological inhibition'}", + "97, the {'perturbing_action': 'I-pharmacological inhibition'}", + "98, VMH {'perturbing_action': 'I-pharmacological inhibition'}", + "114, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "115, inhibition {'perturbing_action': 'I-gene loss-of-function'}", + "116, of {'perturbing_action': 'I-gene loss-of-function'}", + "117, this {'perturbing_action': 'I-gene loss-of-function'}", + "118, enzyme {'perturbing_action': 'I-gene loss-of-function'}", + "120, the {'perturbing_action': 'I-gene loss-of-function'}", + "121, VMH {'perturbing_action': 'I-gene loss-of-function'}", + "124, rats {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "91, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "92, of ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "93, thyroid ['l1', 'l16', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "94, hormone ['l2', 'l17', 'l31', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "95, receptors ['l3', 'l18', 'l32', 'l44', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "96, in ['l4', 'l19', 'l33', 'l45', 'l57', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "97, the ['l5', 'l20', 'l34', 'l46', 'l58', 'l68', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "98, VMH ['l6', 'l21', 'l35', 'l47', 'l59', 'l69', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "114, genetic ['l7', 'l22', 'l48', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "115, inhibition ['l8', 'l23', 'l36', 'l49', 'l60', 'l90', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "116, of ['l9', 'l24', 'l37', 'l50', 'l61', 'l70', 'l91', 'l98', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "117, this ['l10', 'l25', 'l38', 'l51', 'l62', 'l71', 'l78', 'l84', 'l92', 'l99', 'l105', 'l111', 'l112', 'l113', 'l114', 'l115']", + "118, enzyme ['l11', 'l26', 'l39', 'l52', 'l63', 'l72', 'l79', 'l85', 'l93', 'l100', 'l106', 'l111', 'l116', 'l117', 'l118', 'l119']", + "119, in ['l12', 'l27', 'l40', 'l53', 'l64', 'l73', 'l80', 'l86', 'l94', 'l101', 'l107', 'l112', 'l116', 'l120', 'l121', 'l122']", + "120, the ['l13', 'l28', 'l41', 'l54', 'l65', 'l74', 'l81', 'l87', 'l95', 'l102', 'l108', 'l113', 'l117', 'l120', 'l123', 'l124']", + "121, VMH ['l14', 'l29', 'l42', 'l55', 'l66', 'l75', 'l82', 'l88', 'l96', 'l103', 'l109', 'l114', 'l118', 'l121', 'l123', 'l125']", + "124, rats ['l15', 'l30', 'l43', 'l56', 'l67', 'l76', 'l83', 'l89', 'l97', 'l104', 'l110', 'l115', 'l119', 'l122', 'l124', 'l125']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "thyroid", + "hormone", + "receptors", + "in", + "the", + "VMH" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inhibition", + "of", + "this", + "enzyme", + "the", + "VMH" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + } + ] + }, + { + "PMID": "20729865", + "TEXT": "There is no effective treatment for cocaine addiction despite extensive knowledge of the neurobiology of drug addiction. Here we show that a selective aldehyde dehydrogenase-2 (ALDH-2) inhibitor, ALDH2i, suppresses cocaine self-administration in rats and prevents cocaine- or cue-induced reinstatement in a rat model of cocaine relapse-like behavior. We also identify a molecular mechanism by which ALDH-2 inhibition reduces cocaine-seeking behavior: increases in tetrahydropapaveroline (THP) formation due to inhibition of ALDH-2 decrease cocaine-stimulated dopamine production and release in vitro and in vivo. Cocaine increases extracellular dopamine concentration, which activates dopamine D2 autoreceptors to stimulate cAMP-dependent protein kinase A (PKA) and protein kinase C (PKC) in primary ventral tegmental area (VTA) neurons. PKA and PKC phosphorylate and activate tyrosine hydroxylase, further increasing dopamine synthesis in a positive-feedback loop. Monoamine oxidase converts dopamine to 3,4-dihydroxyphenylacetaldehyde (DOPAL), a substrate for ALDH-2. Inhibition of ALDH-2 enables DOPAL to condense with dopamine to form THP in VTA neurons. THP selectively inhibits phosphorylated (activated) tyrosine hydroxylase to reduce dopamine production via negative-feedback signaling. Reducing cocaine- and craving-associated increases in dopamine release seems to account for the effectiveness of ALDH2i in suppressing cocaine-seeking behavior. Selective inhibition of ALDH-2 may have therapeutic potential for treating human cocaine addiction and preventing relapse.", + "TAG_DATA": [ + "22, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "23, aldehyde {'perturbing_action': 'I-pharmacological inhibition'}", + "24, dehydrogenase-2 {'perturbing_action': 'I-pharmacological inhibition'}", + "25, (ALDH-2) {'perturbing_action': 'I-pharmacological inhibition'}", + "26, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "27, ALDH2i, {'perturbing_action': 'I-pharmacological inhibition'}", + "32, rats {'context': 'B-organism'}", + "41, rat {'context': 'B-organism'}", + "42, model {'context': 'I-organism'}", + "55, ALDH-2 {'perturbing_action': 'B-pharmacological inhibition'}", + "56, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "67, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "68, of {'perturbing_action': 'I-pharmacological inhibition'}", + "69, ALDH-2 {'perturbing_action': 'I-pharmacological inhibition'}", + "76, in {'context': 'B-in vitro'}", + "77, vitro {'context': 'I-in vitro'}", + "79, in {'context': 'B-in vivo'}", + "80, vivo. {'context': 'I-in vivo'}", + "104, primary {'context': 'B-cells'}", + "105, ventral {'context': 'I-cells'}", + "106, tegmental {'context': 'I-cells'}", + "107, area {'context': 'I-cells'}", + "108, (VTA) {'context': 'I-cells'}", + "109, neurons. {'context': 'I-cells'}", + "137, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "138, of {'perturbing_action': 'I-pharmacological inhibition'}", + "139, ALDH-2 {'perturbing_action': 'I-pharmacological inhibition'}", + "150, VTA {'context': 'B-cells'}", + "151, neurons. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "22, selective ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "23, aldehyde ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "24, dehydrogenase-2 ['l1', 'l20', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "25, (ALDH-2) ['l2', 'l21', 'l42', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "26, inhibitor, ['l3', 'l22', 'l43', 'l63', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "27, ALDH2i, ['l4', 'l23', 'l44', 'l64', 'l78', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "32, rats ['l5', 'l24', 'l45', 'l65', 'l79', 'l92', 'l104', 'l105', 'l106']", + "41, rat ['l6', 'l25', 'l46', 'l66', 'l80', 'l93', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "42, model ['l7', 'l26', 'l47', 'l67', 'l81', 'l94', 'l107', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "55, ALDH-2 ['l8', 'l27', 'l48', 'l68', 'l82', 'l95', 'l104', 'l108', 'l117', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "56, inhibition ['l9', 'l28', 'l49', 'l69', 'l83', 'l96', 'l109', 'l118', 'l126', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "67, inhibition ['l10', 'l29', 'l50', 'l70', 'l84', 'l97', 'l110', 'l119', 'l127', 'l134', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "68, of ['l11', 'l30', 'l51', 'l71', 'l85', 'l98', 'l111', 'l120', 'l128', 'l135', 'l141', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163']", + "69, ALDH-2 ['l12', 'l31', 'l52', 'l72', 'l86', 'l99', 'l112', 'l121', 'l129', 'l136', 'l142', 'l153', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "76, in ['l13', 'l32', 'l53', 'l73', 'l87', 'l100', 'l105', 'l113', 'l122', 'l130', 'l137', 'l143', 'l154', 'l164', 'l174', 'l175', 'l176']", + "77, vitro ['l14', 'l33', 'l54', 'l74', 'l88', 'l101', 'l106', 'l114', 'l123', 'l131', 'l138', 'l144', 'l155', 'l165', 'l174', 'l177', 'l178']", + "79, in ['l15', 'l34', 'l55', 'l75', 'l89', 'l102', 'l115', 'l124', 'l132', 'l139', 'l145', 'l156', 'l166', 'l175', 'l177', 'l179']", + "80, vivo. ['l16', 'l35', 'l56', 'l76', 'l90', 'l103', 'l116', 'l125', 'l133', 'l140', 'l146', 'l157', 'l167', 'l176', 'l178', 'l179']", + "104, primary ['l17', 'l36', 'l57', 'l147', 'l158', 'l168', 'l180', 'l181', 'l182', 'l183', 'l184']", + "105, ventral ['l37', 'l58', 'l148', 'l159', 'l169', 'l180', 'l185', 'l186', 'l187', 'l188', 'l189']", + "106, tegmental ['l38', 'l59', 'l149', 'l160', 'l170', 'l181', 'l185', 'l190', 'l191', 'l192', 'l193']", + "107, area ['l18', 'l39', 'l60', 'l150', 'l161', 'l171', 'l182', 'l186', 'l190', 'l194', 'l195']", + "108, (VTA) ['l40', 'l61', 'l151', 'l162', 'l172', 'l183', 'l187', 'l191', 'l194', 'l196', 'l197']", + "109, neurons. ['l19', 'l41', 'l62', 'l77', 'l91', 'l152', 'l163', 'l173', 'l184', 'l188', 'l192', 'l195', 'l196']", + "137, Inhibition ['l198', 'l199', 'l200', 'l201']", + "138, of ['l198', 'l202', 'l203', 'l204']", + "139, ALDH-2 ['l199', 'l202', 'l205', 'l206']", + "150, VTA ['l200', 'l203', 'l205', 'l207']", + "151, neurons. ['l189', 'l193', 'l197', 'l201', 'l204', 'l206', 'l207']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "aldehyde", + "dehydrogenase-2", + "(ALDH-2)", + "inhibitor,", + "ALDH2i,", + "ALDH-2", + "inhibition", + "of" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats", + "rat", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "aldehyde", + "dehydrogenase-2", + "(ALDH-2)", + "inhibitor,", + "ALDH2i,", + "ALDH-2", + "inhibition", + "of" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "aldehyde", + "dehydrogenase-2", + "(ALDH-2)", + "inhibitor,", + "ALDH2i,", + "ALDH-2", + "inhibition", + "of" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "aldehyde", + "dehydrogenase-2", + "(ALDH-2)", + "inhibitor,", + "inhibition", + "of", + "ALDH-2", + "Inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "primary", + "area", + "neurons.", + "ventral", + "tegmental", + "(VTA)", + "VTA" + ] + } + } + ] + }, + { + "PMID": "20657581", + "TEXT": "High amounts of glutamate are found in the brains of people with multiple sclerosis, an inflammatory disease marked by progressive demyelination. Glutamate might affect neuroinflammation via effects on immune cells. Knockout mice lacking metabotropic glutamate receptor-4 (mGluR4) were markedly vulnerable to experimental autoimmune encephalomyelitis (EAE, a mouse model of multiple sclerosis) and developed responses dominated by interleukin-17-producing T helper (T(H)17) cells. In dendritic cells (DCs) from those mice, defective mGluR4 signaling-which would normally decrease intracellular cAMP formation-biased T(H) cell commitment to the T(H)17 phenotype. In wild-type mice, mGluR4 was constitutively expressed in all peripheral DCs, and this expression increased after cell activation. Treatment of wild-type mice with a selective mGluR4 enhancer increased EAE resistance via regulatory T (T(reg)) cells. The high amounts of glutamate in neuroinflammation might reflect a counterregulatory mechanism that is protective in nature and might be harnessed therapeutically for restricting immunopathology in multiple sclerosis.", + "TAG_DATA": [ + "30, Knockout {'perturbing_action': 'B-gene loss-of-function'}", + "31, mice {'context': 'B-organism'}", + "32, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "33, metabotropic {'perturbing_action': 'I-gene loss-of-function'}", + "34, glutamate {'perturbing_action': 'I-gene loss-of-function'}", + "35, receptor-4 {'perturbing_action': 'I-gene loss-of-function'}", + "36, (mGluR4) {'perturbing_action': 'I-gene loss-of-function'}", + "62, dendritic {'context': 'B-cells'}", + "63, cells {'context': 'I-cells'}", + "64, (DCs) {'context': 'I-cells'}", + "67, mice, {'context': 'B-organism'}", + "77, T(H) {'context': 'B-cells'}", + "78, cell {'context': 'I-cells'}", + "86, mice, {'context': 'B-organism'}", + "93, peripheral {'context': 'B-cells'}", + "94, DCs, {'context': 'I-cells'}", + "105, mice {'context': 'B-organism'}", + "108, selective {'perturbing_action': 'B-gene gain-of-function'}", + "109, mGluR4 {'perturbing_action': 'I-gene gain-of-function'}", + "110, enhancer {'perturbing_action': 'I-gene gain-of-function'}", + "115, regulatory {'context': 'B-cells'}", + "116, T {'context': 'I-cells'}", + "117, (T(reg)) {'context': 'I-cells'}", + "118, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "30, Knockout ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "31, mice ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "32, lacking ['l1', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "33, metabotropic ['l2', 'l13', 'l22', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "34, glutamate ['l3', 'l14', 'l23', 'l32', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "35, receptor-4 ['l4', 'l15', 'l24', 'l33', 'l41', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "36, (mGluR4) ['l5', 'l16', 'l25', 'l34', 'l42', 'l49', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "62, dendritic ['l6', 'l17', 'l26', 'l35', 'l43', 'l50', 'l56', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "63, cells ['l7', 'l18', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l68', 'l69', 'l70', 'l71']", + "64, (DCs) ['l8', 'l19', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l72', 'l73', 'l74']", + "67, mice, ['l9', 'l20', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l69', 'l72', 'l75', 'l76']", + "77, T(H) ['l10', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l70', 'l73', 'l75', 'l77', 'l78', 'l79']", + "78, cell ['l11', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l71', 'l74', 'l76', 'l77']", + "86, mice, ['l80', 'l81']", + "93, peripheral ['l78', 'l80', 'l82']", + "94, DCs, ['l67', 'l79', 'l81', 'l82']", + "105, mice ['l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "108, selective ['l83', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "109, mGluR4 ['l84', 'l90', 'l96', 'l97', 'l98', 'l99', 'l100']", + "110, enhancer ['l85', 'l91', 'l96', 'l101', 'l102', 'l103', 'l104']", + "115, regulatory ['l86', 'l92', 'l97', 'l101', 'l105', 'l106', 'l107']", + "116, T ['l87', 'l93', 'l98', 'l102', 'l105', 'l108', 'l109']", + "117, (T(reg)) ['l88', 'l94', 'l99', 'l103', 'l106', 'l108', 'l110']", + "118, cells. ['l89', 'l95', 'l100', 'l104', 'l107', 'l109', 'l110']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Knockout", + "lacking", + "metabotropic", + "glutamate", + "receptor-4", + "(mGluR4)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Knockout", + "lacking", + "metabotropic", + "glutamate", + "receptor-4", + "(mGluR4)" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cells", + "(DCs)", + "T(H)", + "cell" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "selective", + "mGluR4", + "enhancer" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "selective", + "mGluR4", + "enhancer" + ] + }, + "context": { + "val": "cells", + "words": [ + "regulatory", + "T", + "(T(reg))", + "cells." + ] + } + } + ] + }, + { + "PMID": "20639889", + "TEXT": "Hypertrophic heart disease is a leading health problem in Western countries. Here we identified the small EF hand domain-containing protein Ca(2+) and integrin-binding protein-1 (CIB1) in a screen for previously unknown regulators of cardiomyocyte hypertrophy. Yeast two-hybrid screening for CIB1-interacting partners identified a related EF hand domain-containing protein, calcineurin B, the regulatory subunit of the prohypertrophic protein phosphatase calcineurin. CIB1 localizes primarily to the sarcolemma in mouse and human myocardium, where it anchors calcineurin to control its activation in coordination with the L-type Ca(2+) channel. CIB1 protein amounts and membrane association were enhanced in cardiac pathological hypertrophy, but not in physiological hypertrophy. Consistent with these observations, Cib1-deleted mice showed a marked reduction in myocardial hypertrophy, fibrosis, cardiac dysfunction and calcineurin-nuclear factor of activated T cells (NFAT) activity after pressure overload, whereas the degree of physiologic hypertrophy after swimming exercise was not altered. Transgenic mice with inducible and cardiac-specific overexpression of CIB1 showed enhanced cardiac hypertrophy in response to pressure overload or calcineurin signaling. Moreover, mice lacking Ppp3cb (encoding calcineurin A, beta isozyme) showed no enhancement in cardiac hypertrophy associated with CIB1 overexpression. Thus, CIB1 functions as a previously undescribed regulator of cardiac hypertrophy through its ability to regulate the association of calcineurin with the sarcolemma and its activation.", + "TAG_DATA": [ + "106, Cib1-deleted {'perturbing_action': 'B-gene loss-of-function'}", + "107, mice {'context': 'B-organism'}", + "142, Transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "143, mice {'context': 'I-organism'}", + "145, inducible {'perturbing_action': 'B-gene gain-of-function'}", + "146, and {'perturbing_action': 'I-gene gain-of-function'}", + "147, cardiac-specific {'perturbing_action': 'I-gene gain-of-function'}", + "148, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "149, of {'perturbing_action': 'I-gene gain-of-function'}", + "150, CIB1 {'perturbing_action': 'I-gene gain-of-function'}", + "164, mice {'context': 'B-organism'}", + "165, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "166, Ppp3cb {'perturbing_action': 'I-gene loss-of-function'}", + "167, (encoding {'perturbing_action': 'I-gene loss-of-function'}", + "180, CIB1 {'perturbing_action': 'B-gene gain-of-function'}", + "181, overexpression. {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "106, Cib1-deleted ['l0']", + "107, mice ['l0']", + "142, Transgenic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "143, mice ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "145, inducible ['l2', 'l8', 'l14', 'l15', 'l16', 'l17', 'l18']", + "146, and ['l3', 'l9', 'l14', 'l19', 'l20', 'l21', 'l22']", + "147, cardiac-specific ['l4', 'l10', 'l15', 'l19', 'l23', 'l24', 'l25']", + "148, overexpression ['l5', 'l11', 'l16', 'l20', 'l23', 'l26', 'l27']", + "149, of ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l28']", + "150, CIB1 ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l28']", + "164, mice ['l29', 'l30', 'l31', 'l32', 'l33']", + "165, lacking ['l29', 'l34', 'l35', 'l36', 'l37']", + "166, Ppp3cb ['l30', 'l34', 'l38', 'l39', 'l40']", + "167, (encoding ['l31', 'l35', 'l38', 'l41', 'l42']", + "180, CIB1 ['l32', 'l36', 'l39', 'l41', 'l43']", + "181, overexpression. ['l33', 'l37', 'l40', 'l42', 'l43']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cib1-deleted", + "lacking", + "Ppp3cb", + "(encoding" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgenic", + "inducible", + "and", + "cardiac-specific", + "overexpression", + "of", + "CIB1", + "overexpression." + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "20495569", + "TEXT": "Osteoarthritic cartilage destruction is caused by an imbalance between anabolic and catabolic factors. Here, we show that hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by EPAS1) is a catabolic transcription factor in the osteoarthritic process. HIF-2alpha directly induces the expression in chondrocytes of genes encoding catabolic factors, including matrix metalloproteinases (MMP1, MMP3, MMP9, MMP12 and MMP13), aggrecanase-1 (ADAMTS4), nitric oxide synthase-2 (NOS2) and prostaglandin-endoperoxide synthase-2 (PTGS2). HIF-2alpha expression was markedly increased in human and mouse osteoarthritic cartilage, and its ectopic expression triggered articular cartilage destruction in mice and rabbits. Moreover, mice transgenic for Epas1 only in chondrocytes showed spontaneous cartilage destruction, whereas heterozygous genetic deletion of Epas1 in mice suppressed cartilage destruction caused by destabilization of the medial meniscus (DMM) or collagenase injection, with concomitant modulation of catabolic factors. Our results collectively demonstrate that HIF-2alpha causes cartilage destruction by regulating crucial catabolic genes.", + "TAG_DATA": [ + "83, mice {'context': 'B-organism'}", + "85, rabbits. {'context': 'B-organism'}", + "87, mice {'context': 'B-organism'}", + "88, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "89, for {'perturbing_action': 'I-gene gain-of-function'}", + "90, Epas1 {'perturbing_action': 'I-gene gain-of-function'}", + "93, chondrocytes {'context': 'B-cells'}", + "99, heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "100, genetic {'perturbing_action': 'I-gene loss-of-function'}", + "101, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "102, of {'perturbing_action': 'I-gene loss-of-function'}", + "103, Epas1 {'perturbing_action': 'I-gene loss-of-function'}", + "105, mice {'context': 'B-organism'}", + "114, medial {'context': 'B-tissue/organ'}", + "115, meniscus {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "83, mice ['l0']", + "85, rabbits. ['l0']", + "87, mice ['l1', 'l2', 'l3', 'l4']", + "88, transgenic ['l1', 'l5', 'l6', 'l7']", + "89, for ['l2', 'l5', 'l8', 'l9']", + "90, Epas1 ['l3', 'l6', 'l8', 'l10']", + "93, chondrocytes ['l4', 'l7', 'l9', 'l10']", + "99, heterozygous ['l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "100, genetic ['l11', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "101, deletion ['l12', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "102, of ['l13', 'l20', 'l26', 'l32', 'l33', 'l34', 'l35', 'l36']", + "103, Epas1 ['l14', 'l21', 'l27', 'l32', 'l37', 'l38', 'l39', 'l40']", + "105, mice ['l15', 'l22', 'l28', 'l33', 'l37', 'l41', 'l42', 'l43']", + "114, medial ['l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l44', 'l45']", + "115, meniscus ['l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l46']", + "116, (DMM) ['l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l46']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "Epas1" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "Epas1" + ] + }, + "context": { + "val": "cells", + "words": [ + "chondrocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "heterozygous", + "genetic", + "deletion", + "of", + "Epas1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "heterozygous", + "genetic", + "deletion", + "of", + "Epas1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "medial", + "meniscus" + ] + } + } + ] + }, + { + "PMID": "20473309", + "TEXT": "Toll-like receptor (TLR) signaling is essential for intestinal tumorigenesis in Apc(min/+) mice, but the mechanisms by which Apc enhances tumor growth are unknown. Here we show that microflora-MyD88-ERK signaling in intestinal epithelial cells (IECs) promotes tumorigenesis by increasing the stability of the c-Myc oncoprotein. Activation of ERK (extracellular signal-related kinase) phosphorylates c-Myc, preventing its ubiquitination and subsequent proteasomal degradation. Accordingly, Apc(min/+)/Myd88(-/-) mice have lower phospho-ERK (p-ERK) levels and fewer and smaller IEC tumors than Apc(min/+) mice. MyD88 (myeloid differentiation primary response gene 88)-independent activation of ERK by epidermal growth factor (EGF) increased p-ERK and c-Myc and restored the multiple intestinal neoplasia (Min) phenotype in Apc(min/+)/Myd88(-/-) mice. Administration of an ERK inhibitor suppressed intestinal tumorigenesis in EGF-treated Apc(min/+)/Myd88(-/-) and Apc(min/+) mice and increased their survival. Our data reveal a new facet of oncogene-environment interaction, in which microflora-induced TLR activation regulates oncogene expression and related IEC tumor growth in a susceptible host.", + "TAG_DATA": [ + "34, promotes {'effect': 'B-positive'}", + "35, tumorigenesis {'phenotype': 'B-tumourigenesis'}", + "60, Apc(min/+)/Myd88(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "61, mice {'context': 'B-organism'}", + "71, IEC {'context': 'B-neoplasm'}", + "72, tumors {'context': 'I-neoplasm'}", + "74, Apc(min/+) {'perturbing_action': 'B-other'}", + "75, mice. {'context': 'B-organism'}", + "100, neoplasia {'phenotype': 'I-epithelial-mesenchymal transition'}", + "104, Apc(min/+)/Myd88(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "105, mice. {'context': 'B-organism'}", + "109, ERK {'perturbing_action': 'B-pharmacological inhibition'}", + "110, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "111, suppressed {'effect': 'B-negative'}", + "112, intestinal {'context': 'B-tissue/organ'}", + "113, tumorigenesis {'phenotype': 'B-tumourigenesis'}", + "116, Apc(min/+)/Myd88(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "118, Apc(min/+) {'perturbing_action': 'B-other'}", + "119, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "34, promotes ['l0', 'l1', 'l2', 'l3']", + "35, tumorigenesis ['l0', 'l4', 'l5']", + "60, Apc(min/+)/Myd88(-/-) ['l1', 'l4', 'l6', 'l7', 'l8', 'l9']", + "61, mice ['l2', 'l5', 'l6', 'l10', 'l11']", + "71, IEC ['l7', 'l10', 'l12', 'l13', 'l14', 'l15']", + "72, tumors ['l3', 'l8', 'l11', 'l12']", + "74, Apc(min/+) ['l13', 'l16', 'l17', 'l18', 'l19', 'l20']", + "75, mice. ['l9', 'l14', 'l16', 'l21', 'l22', 'l23']", + "98, multiple ['l17', 'l24', 'l25', 'l26', 'l27', 'l28']", + "99, intestinal ['l18', 'l21', 'l24', 'l29', 'l30', 'l31', 'l32']", + "100, neoplasia ['l19', 'l22', 'l25', 'l29', 'l33', 'l34', 'l35']", + "101, (Min) ['l15', 'l20', 'l23', 'l26', 'l30', 'l33', 'l36', 'l37']", + "104, Apc(min/+)/Myd88(-/-) ['l27', 'l31', 'l34', 'l36', 'l38']", + "105, mice. ['l28', 'l32', 'l35', 'l37', 'l38']", + "109, ERK ['l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "110, inhibitor ['l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "111, suppressed ['l40', 'l46', 'l52', 'l53', 'l54', 'l55']", + "112, intestinal ['l41', 'l47', 'l52', 'l56', 'l57', 'l58']", + "113, tumorigenesis ['l42', 'l48', 'l53', 'l56', 'l59', 'l60']", + "116, Apc(min/+)/Myd88(-/-) ['l43', 'l49', 'l54', 'l57', 'l59', 'l61', 'l62']", + "118, Apc(min/+) ['l44', 'l50', 'l61', 'l63']", + "119, mice ['l45', 'l51', 'l55', 'l58', 'l60', 'l62', 'l63']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apc(min/+)/Myd88(-/-)" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apc(min/+)/Myd88(-/-)" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apc(min/+)/Myd88(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apc(min/+)/Myd88(-/-)" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "IEC", + "tumors" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "IEC" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Apc(min/+)" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Apc(min/+)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Apc(min/+)" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "neoplasia" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice." + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "neoplasia" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "neoplasia" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apc(min/+)/Myd88(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ERK", + "inhibitor" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ERK", + "inhibitor" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "intestinal" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ERK", + "inhibitor" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ERK", + "inhibitor" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "intestinal" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apc(min/+)/Myd88(-/-)" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "intestinal" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "intestinal" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apc(min/+)/Myd88(-/-)" + ] + } + } + ] + }, + { + "PMID": "20473305", + "TEXT": "Rtp801 (also known as Redd1, and encoded by Ddit4), a stress-related protein triggered by adverse environmental conditions, inhibits mammalian target of rapamycin (mTOR) by stabilizing the TSC1-TSC2 inhibitory complex and enhances oxidative stress-dependent cell death. We postulated that Rtp801 acts as a potential amplifying switch in the development of cigarette smoke-induced lung injury, leading to emphysema. Rtp801 mRNA and protein were overexpressed in human emphysematous lungs and in lungs of mice exposed to cigarette smoke. The regulation of Rtp801 expression by cigarette smoke may rely on oxidative stress-dependent activation of the CCAAT response element in its promoter. We also found that Rtp801 was necessary and sufficient for nuclear factor-kappaB (NF-kappaB) activation in cultured cells and, when forcefully expressed in mouse lungs, it promoted NF-kappaB activation, alveolar inflammation, oxidative stress and apoptosis of alveolar septal cells. In contrast, Rtp801 knockout mice were markedly protected against acute cigarette smoke-induced lung injury, partly via increased mTOR signaling, and, when exposed chronically to cigarette smoke, against emphysema. Our data support the notion that Rtp801 may represent a major molecular sensor and mediator of cigarette smoke-induced lung injury.", + "TAG_DATA": [ + "64, emphysematous {'context': 'I-tissue/organ'}", + "65, lungs {'context': 'I-tissue/organ'}", + "68, lungs {'context': 'B-tissue/organ'}", + "70, mice {'context': 'B-organism'}", + "112, cultured {'context': 'B-cells'}", + "113, cells {'context': 'I-cells'}", + "119, mouse {'context': 'B-tissue/organ'}", + "120, lungs, {'context': 'I-tissue/organ'}", + "122, promoted {'effect': 'B-positive'}", + "130, apoptosis {'phenotype': 'B-apoptosis'}", + "132, alveolar {'context': 'B-cells'}", + "133, septal {'context': 'I-cells'}", + "134, cells. {'context': 'I-cells'}", + "137, Rtp801 {'perturbing_action': 'B-gene loss-of-function'}", + "138, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "139, mice {'context': 'B-organism'}", + "147, lung {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "64, emphysematous ['l0', 'l1', 'l2', 'l3']", + "65, lungs ['l0', 'l4']", + "68, lungs ['l1', 'l4', 'l5', 'l6', 'l7']", + "70, mice ['l2', 'l5', 'l8', 'l9', 'l10']", + "112, cultured ['l6', 'l8', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "113, cells ['l3', 'l7', 'l9', 'l11', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "119, mouse ['l12', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "120, lungs, ['l13', 'l20', 'l26', 'l32', 'l33', 'l34', 'l35', 'l36']", + "122, promoted ['l10', 'l14', 'l21', 'l27', 'l32', 'l37', 'l38', 'l39', 'l40']", + "130, apoptosis ['l15', 'l22', 'l28', 'l33', 'l37', 'l41', 'l42', 'l43']", + "132, alveolar ['l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l44', 'l45']", + "133, septal ['l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l46']", + "134, cells. ['l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l46']", + "137, Rtp801 ['l47', 'l48', 'l49']", + "138, knockout ['l47', 'l50', 'l51']", + "139, mice ['l48', 'l50', 'l52']", + "147, lung ['l49', 'l51', 'l52']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "cells", + "alveolar", + "septal", + "cells." + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "cells", + "alveolar", + "septal", + "cells." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "lungs," + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "lungs," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rtp801", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rtp801", + "knockout" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + } + ] + }, + { + "PMID": "20473304", + "TEXT": "Sepsis is a systemic inflammatory condition following bacterial infection with a high mortality rate and limited therapeutic options. Here we show that interleukin-33 (IL-33) reduces mortality in mice with experimental sepsis from cecal ligation and puncture (CLP). IL-33-treated mice developed increased neutrophil influx into the peritoneal cavity and more efficient bacterial clearance than untreated mice. IL-33 reduced the systemic but not the local proinflammatory response, and it did not induce a T helper type 1 (T(H)1) to T(H)2 shift. The chemokine receptor CXCR2 is crucial for recruitment of neutrophils from the circulation to the site of infection. Activation of Toll-like receptors (TLRs) in neutrophils downregulates CXCR2 expression and impairs neutrophil migration. We show here that IL-33 prevents the downregulation of CXCR2 and inhibition of chemotaxis induced by the activation of TLR4 in mouse and human neutrophils. Furthermore, we show that IL-33 reverses the TLR4-induced reduction of CXCR2 expression in neutrophils via the inhibition of expression of G protein-coupled receptor kinase-2 (GRK2), a serine-threonine protein kinase that induces internalization of chemokine receptors. Finally, we find that individuals who did not recover from sepsis had significantly more soluble ST2 (sST2, the decoy receptor of IL-33) than those who did recover. Together, our results indicate a previously undescribed mechanism of action of IL-33 and suggest a therapeutic potential of IL-33 in sepsis.", + "TAG_DATA": [ + "27, mice {'context': 'B-organism'}", + "38, mice {'context': 'B-organism'}", + "54, mice. {'context': 'B-organism'}", + "108, impairs {'effect': 'B-negative'}", + "109, neutrophil {'context': 'B-cells'}", + "110, migration. {'phenotype': 'B-migration'}", + "122, inhibition {'effect': 'B-negative'}", + "124, chemotaxis {'phenotype': 'B-migration'}", + "132, mouse {'context': 'B-cells'}", + "133, and {'context': 'I-cells'}", + "134, human {'context': 'I-cells'}", + "135, neutrophils. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "38, mice ['l0', 'l1']", + "54, mice. ['l0', 'l2']", + "108, impairs ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "109, neutrophil ['l3', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "110, migration. ['l1', 'l2', 'l4', 'l11', 'l18', 'l19', 'l20', 'l21']", + "122, inhibition ['l5', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26']", + "124, chemotaxis ['l6', 'l13', 'l22', 'l27', 'l28', 'l29', 'l30']", + "132, mouse ['l7', 'l14', 'l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "133, and ['l8', 'l15', 'l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "134, human ['l9', 'l16', 'l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "135, neutrophils. ['l10', 'l17', 'l21', 'l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impairs", + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "neutrophil", + "mouse", + "and", + "human", + "neutrophils." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impairs", + "inhibition" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration.", + "chemotaxis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neutrophil", + "mouse", + "and", + "human", + "neutrophils." + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration.", + "chemotaxis" + ] + } + } + ] + }, + { + "PMID": "20448575", + "TEXT": "Approximately 5% of people that are hospitalized for any reason develop acute kidney failure, which, in some cases, progresses to a chronic condition resulting in fibrosis of the kidney and permanent changes in the organ’s function. Two new studies suggest that cell cycle arrest of epithelial cells and epigenetic modifications have key roles in the switch to chronic disease (pages 535–543 and 544–550).", + "TAG_DATA": [ + "41, cell {'phenotype': 'B-cell cycle arrest'}", + "42, cycle {'phenotype': 'I-cell cycle arrest'}", + "43, arrest {'phenotype': 'I-cell cycle arrest'}", + "45, epithelial {'context': 'B-cells'}", + "46, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "41, cell ['l0', 'l1', 'l2', 'l3']", + "42, cycle ['l0', 'l4', 'l5', 'l6']", + "43, arrest ['l1', 'l4', 'l7', 'l8']", + "45, epithelial ['l2', 'l5', 'l7', 'l9']", + "46, cells ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "cell", + "cycle", + "arrest" + ] + }, + "context": { + "val": "cells", + "words": [ + "epithelial", + "cells" + ] + } + } + ] + }, + { + "PMID": "20436483", + "TEXT": "Fibrosis is responsible for chronic progressive kidney failure, which is present in a large number of adults in the developed world. It is increasingly appreciated that acute kidney injury (AKI), resulting in aberrant incomplete repair, is a major contributor to chronic fibrotic kidney disease. The mechanism that triggers the fibrogenic response after injury is not well understood. In ischemic, toxic and obstructive models of AKI, we demonstrate a causal association between epithelial cell cycle G2/M arrest and a fibrotic outcome. G2/M-arrested proximal tubular cells activate c-jun NH(2)-terminal kinase (JNK) signaling, which acts to upregulate profibrotic cytokine production. Treatment with a JNK inhibitor, or bypassing the G2/M arrest by administration of a p53 inhibitor or the removal of the contralateral kidney, rescues fibrosis in the unilateral ischemic injured kidney. Hence, epithelial cell cycle arrest at G2/M and its subsequent downstream signaling are hitherto unrecognized therapeutic targets for the prevention of fibrosis and interruption of the accelerated progression of kidney disease.", + "TAG_DATA": [ + "80, G2/M-arrested {'phenotype': 'I-cell cycle arrest'}", + "81, proximal {'context': 'B-cells'}", + "82, tubular {'context': 'I-cells'}", + "83, cells {'context': 'I-cells'}", + "100, JNK {'perturbing_action': 'B-pharmacological inhibition'}", + "101, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "106, arrest {'phenotype': 'I-cell cycle arrest'}", + "111, p53 {'perturbing_action': 'B-pharmacological inhibition'}", + "112, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "119, kidney, {'context': 'I-tissue/organ'}", + "127, kidney. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "80, G2/M-arrested ['l0', 'l1', 'l2']", + "81, proximal ['l0', 'l3', 'l4']", + "82, tubular ['l1', 'l3', 'l5']", + "83, cells ['l2', 'l4', 'l5']", + "100, JNK ['l6', 'l7', 'l8', 'l9', 'l10']", + "101, inhibitor, ['l6']", + "106, arrest ['l7', 'l11', 'l12', 'l13', 'l14', 'l15']", + "111, p53 ['l8', 'l11', 'l16', 'l17', 'l18', 'l19']", + "112, inhibitor ['l9', 'l12', 'l16', 'l20', 'l21', 'l22']", + "118, contralateral ['l13', 'l17', 'l20', 'l23', 'l24']", + "119, kidney, ['l10', 'l14', 'l18', 'l21', 'l23', 'l25']", + "127, kidney. ['l15', 'l19', 'l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G2/M-arrested" + ] + }, + "context": { + "val": "cells", + "words": [ + "proximal", + "tubular", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "JNK", + "p53", + "inhibitor" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "JNK", + "p53", + "inhibitor" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidney,", + "kidney." + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidney,", + "kidney." + ] + } + } + ] + }, + { + "PMID": "20418886", + "TEXT": "Leukemias and other cancers possess self-renewing stem cells that help to maintain the cancer. Cancer stem cell eradication is thought to be crucial for successful anticancer therapy. Using an acute myeloid leukemia (AML) model induced by the leukemia-associated monocytic leukemia zinc finger (MOZ)-TIF2 fusion protein, we show here that AML can be cured by the ablation of leukemia stem cells. The MOZ fusion proteins MOZ-TIF2 and MOZ-CBP interacted with the transcription factor PU.1 to stimulate the expression of macrophage colony-stimulating factor receptor (CSF1R, also known as M-CSFR, c-FMS or CD115). Studies using PU.1-deficient mice showed that PU.1 is essential for the ability of MOZ-TIF2 to establish and maintain AML stem cells. Cells expressing high amounts of CSF1R (CSF1R(high) cells), but not those expressing low amounts of CSF1R (CSF1R(low) cells), showed potent leukemia-initiating activity. Using transgenic mice expressing a drug-inducible suicide gene controlled by the CSF1R promoter, we cured AML by ablation of CSF1R(high) cells. Moreover, induction of AML was suppressed in CSF1R-deficient mice and CSF1R inhibitors slowed the progression of MOZ-TIF2-induced leukemia. Thus, in this subtype of AML, leukemia stem cells are contained within the CSF1R(high) cell population, and we suggest that targeting of PU.1-mediated upregulation of CSF1R expression might be a useful therapeutic approach.", + "TAG_DATA": [ + "92, PU.1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "93, mice {'context': 'B-organism'}", + "134, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "135, mice {'context': 'I-organism'}", + "148, AML {'context': 'B-neoplasm'}", + "155, induction {'effect': 'B-positive'}", + "159, suppressed {'effect': 'B-negative'}", + "161, CSF1R-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "162, mice {'context': 'B-organism'}", + "164, CSF1R {'perturbing_action': 'B-pharmacological inhibition'}", + "165, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "170, MOZ-TIF2-induced {'effect': 'B-positive'}", + "171, leukemia. {'phenotype': 'B-tumourigenesis'}" + ], + "LINK_DATA": [ + "92, PU.1-deficient ['l0']", + "93, mice ['l0']", + "134, transgenic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "135, mice ['l1', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "140, gene ['l2', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "141, controlled ['l3', 'l11', 'l18', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "142, by ['l4', 'l12', 'l19', 'l25', 'l31', 'l32', 'l33', 'l34', 'l35']", + "143, the ['l5', 'l13', 'l20', 'l26', 'l31', 'l36', 'l37', 'l38', 'l39']", + "144, CSF1R ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l40', 'l41', 'l42']", + "145, promoter, ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l43', 'l44']", + "148, AML ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l45']", + "153, cells. ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l45']", + "155, induction ['l46', 'l47', 'l48', 'l49']", + "157, AML ['l46', 'l50', 'l51', 'l52', 'l53', 'l54']", + "159, suppressed ['l47', 'l50', 'l55', 'l56']", + "161, CSF1R-deficient ['l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "162, mice ['l48', 'l52', 'l55', 'l57', 'l62', 'l63']", + "164, CSF1R ['l58', 'l64', 'l65', 'l66']", + "165, inhibitors ['l59', 'l64', 'l67', 'l68']", + "170, MOZ-TIF2-induced ['l53', 'l60', 'l62', 'l65', 'l67', 'l69']", + "171, leukemia. ['l49', 'l54', 'l56', 'l61', 'l63', 'l66', 'l68', 'l69']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PU.1-deficient", + "CSF1R-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "AML" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction", + "MOZ-TIF2-induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction", + "MOZ-TIF2-induced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CSF1R-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "MOZ-TIF2-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CSF1R-deficient" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CSF1R", + "inhibitors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "MOZ-TIF2-induced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CSF1R", + "inhibitors" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia." + ] + } + } + ] + }, + { + "PMID": "20418884", + "TEXT": "Giardia lamblia is a human intestinal pathogen. Like many protozoan microorganisms, Giardia undergoes antigenic variation, a mechanism assumed to allow parasites to evade the host's immune response, producing chronic and/or recurrent infections. Recently, we found that the mechanism controlling variant-specific surface protein (VSP) switching in Giardia involves components of the RNA interference machinery and that disruption of this pathway generates trophozoites simultaneously expressing many VSPs. Here we use these altered trophozoites to determine the role of antigenic variation in a gerbil model of giardiasis. Our results show that either primary infection with trophozoites simultaneously expressing many VSPs or immunization with purified VSPs from the transgenic cells protects gerbils from subsequent Giardia infections. These results constitute, to our knowledge, the first experimental evidence that antigenic variation is essential for parasite survival within hosts and that artificial disruption of this mechanism might be useful in generating vaccines against major pathogens that show similar behavior.", + "TAG_DATA": [ + "80, gerbil {'context': 'B-organism'}", + "81, model {'context': 'I-organism'}", + "104, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "105, cells {'context': 'B-cells'}", + "107, gerbils {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "80, gerbil ['l0']", + "81, model ['l0']", + "104, transgenic ['l1', 'l2']", + "105, cells ['l1', 'l3']", + "107, gerbils ['l2', 'l3']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "gerbils" + ] + } + } + ] + }, + { + "PMID": "20037595", + "TEXT": "Sterol metabolism has recently been linked to innate and adaptive immune responses through liver X receptor (LXR) signaling. Whether products of sterol metabolism interfere with antitumor responses is currently unknown. Dendritic cells (DCs) initiate immune responses, including antitumor activity after their CC chemokine receptor-7 (CCR7)-dependent migration to lymphoid organs. Here we report that human and mouse tumors produce LXR ligands that inhibit CCR7 expression on maturing DCs and, therefore, their migration to lymphoid organs. In agreement with this observation, we detected CD83(+)CCR7(-) DCs within human tumors. Mice injected with tumors expressing the LXR ligand-inactivating enzyme sulfotransferase 2B1b (SULT2B1b) successfully controlled tumor growth by regaining DC migration to tumor-draining lymph nodes and by developing overt inflammation within tumors. The control of tumor growth was also observed in chimeric mice transplanted with bone marrow from mice lacking the gene encoding LXR-alpha (Nr1h3(-/-) mice) Thus, we show a new mechanism of tumor immunoescape involving products of cholesterol metabolism. The manipulation of this pathway could restore antitumor immunity in individuals with cancer.", + "TAG_DATA": [ + "86, Mice {'context': 'B-organism'}", + "89, tumors {'context': 'B-neoplasm'}", + "90, expressing {'perturbing_action': 'B-other'}", + "91, the {'perturbing_action': 'I-other'}", + "92, LXR {'perturbing_action': 'I-other'}", + "93, ligand-inactivating {'perturbing_action': 'I-other'}", + "94, enzyme {'perturbing_action': 'I-other'}", + "95, sulfotransferase {'perturbing_action': 'I-other'}", + "96, 2B1b {'perturbing_action': 'I-other'}", + "97, (SULT2B1b) {'perturbing_action': 'I-other'}", + "99, controlled {'effect': 'B-regulates'}", + "100, tumor {'phenotype': 'B-tumour growth'}", + "101, growth {'phenotype': 'I-tumour growth'}", + "104, DC {'context': 'B-cells'}", + "105, migration {'phenotype': 'B-migration'}", + "107, tumor-draining {'context': 'B-tissue/organ'}", + "116, tumors. {'context': 'B-neoplasm'}", + "118, control {'effect': 'B-regulates'}", + "120, tumor {'phenotype': 'B-tumour growth'}", + "121, growth {'phenotype': 'I-tumour growth'}", + "126, chimeric {'context': 'B-organism'}", + "127, mice {'context': 'I-organism'}", + "133, mice {'context': 'B-organism'}", + "134, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "135, the {'perturbing_action': 'I-gene loss-of-function'}", + "136, gene {'perturbing_action': 'I-gene loss-of-function'}", + "137, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "138, LXR-alpha {'perturbing_action': 'I-gene loss-of-function'}", + "140, mice) {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "86, Mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "89, tumors ['l0', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "90, expressing ['l1', 'l18', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "91, the ['l2', 'l19', 'l35', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "92, LXR ['l3', 'l20', 'l36', 'l51', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "93, ligand-inactivating ['l4', 'l21', 'l37', 'l52', 'l66', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "94, enzyme ['l5', 'l22', 'l38', 'l53', 'l67', 'l80', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "95, sulfotransferase ['l6', 'l23', 'l39', 'l54', 'l68', 'l81', 'l93', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "96, 2B1b ['l7', 'l24', 'l40', 'l55', 'l69', 'l82', 'l94', 'l105', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "97, (SULT2B1b) ['l8', 'l25', 'l41', 'l56', 'l70', 'l83', 'l95', 'l106', 'l116', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "99, controlled ['l9', 'l26', 'l42', 'l57', 'l71', 'l84', 'l96', 'l107', 'l117', 'l126', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "100, tumor ['l10', 'l27', 'l43', 'l58', 'l72', 'l85', 'l97', 'l108', 'l118', 'l127', 'l135', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "101, growth ['l11', 'l28', 'l44', 'l59', 'l73', 'l86', 'l98', 'l109', 'l119', 'l128', 'l136', 'l143', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "104, DC ['l12', 'l29', 'l45', 'l60', 'l74', 'l87', 'l99', 'l110', 'l120', 'l129', 'l137', 'l144', 'l150', 'l156', 'l157', 'l158', 'l159', 'l160']", + "105, migration ['l13', 'l30', 'l46', 'l61', 'l75', 'l88', 'l100', 'l111', 'l121', 'l130', 'l138', 'l145', 'l151', 'l156', 'l161', 'l162', 'l163', 'l164']", + "107, tumor-draining ['l14', 'l31', 'l47', 'l62', 'l76', 'l89', 'l101', 'l112', 'l122', 'l131', 'l139', 'l146', 'l152', 'l157', 'l161', 'l165', 'l166', 'l167']", + "108, lymph ['l15', 'l32', 'l48', 'l63', 'l77', 'l90', 'l102', 'l113', 'l123', 'l132', 'l140', 'l147', 'l153', 'l158', 'l162', 'l165', 'l168', 'l169']", + "109, nodes ['l16', 'l33', 'l49', 'l64', 'l78', 'l91', 'l103', 'l114', 'l124', 'l133', 'l141', 'l148', 'l154', 'l159', 'l163', 'l166', 'l168', 'l170']", + "116, tumors. ['l17', 'l34', 'l50', 'l65', 'l79', 'l92', 'l104', 'l115', 'l125', 'l134', 'l142', 'l149', 'l155', 'l160', 'l164', 'l167', 'l169', 'l170']", + "118, control ['l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180']", + "120, tumor ['l171', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190']", + "121, growth ['l172', 'l181', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198']", + "126, chimeric ['l173', 'l182', 'l191', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206']", + "127, mice ['l174', 'l183', 'l192', 'l199', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213']", + "133, mice ['l175', 'l184', 'l193', 'l200', 'l207', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219']", + "134, lacking ['l176', 'l185', 'l194', 'l201', 'l208', 'l214', 'l220', 'l221', 'l222', 'l223', 'l224']", + "135, the ['l177', 'l186', 'l195', 'l202', 'l209', 'l215', 'l220', 'l225', 'l226', 'l227', 'l228']", + "136, gene ['l178', 'l187', 'l196', 'l203', 'l210', 'l216', 'l221', 'l225', 'l229', 'l230', 'l231']", + "137, encoding ['l179', 'l188', 'l197', 'l204', 'l211', 'l217', 'l222', 'l226', 'l229', 'l232', 'l233']", + "138, LXR-alpha ['l180', 'l189', 'l198', 'l205', 'l212', 'l218', 'l223', 'l227', 'l230', 'l232', 'l234']", + "140, mice) ['l190', 'l206', 'l213', 'l219', 'l224', 'l228', 'l231', 'l233', 'l234']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "the", + "LXR", + "ligand-inactivating", + "enzyme", + "sulfotransferase", + "2B1b", + "(SULT2B1b)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice", + "chimeric", + "mice" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "controlled", + "control" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice", + "chimeric", + "mice", + "mice)" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "tumors." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "the", + "LXR", + "ligand-inactivating", + "enzyme", + "sulfotransferase", + "2B1b", + "(SULT2B1b)" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "tumors." + ] + }, + "effect": { + "val": "regulates", + "words": [ + "controlled" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "tumors." + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "tumors." + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "the", + "LXR", + "ligand-inactivating", + "enzyme", + "sulfotransferase", + "2B1b", + "(SULT2B1b)" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "controlled" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "the", + "LXR", + "ligand-inactivating", + "enzyme", + "sulfotransferase", + "2B1b", + "(SULT2B1b)" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "the", + "LXR", + "ligand-inactivating", + "enzyme", + "sulfotransferase", + "2B1b", + "(SULT2B1b)" + ] + }, + "context": { + "val": "cells", + "words": [ + "DC" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "the", + "LXR", + "ligand-inactivating", + "enzyme", + "sulfotransferase", + "2B1b", + "(SULT2B1b)" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "the", + "LXR", + "ligand-inactivating", + "enzyme", + "sulfotransferase", + "2B1b", + "(SULT2B1b)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tumor-draining" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "controlled", + "control" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "controlled" + ] + }, + "context": { + "val": "cells", + "words": [ + "DC" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "controlled" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "controlled" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tumor-draining" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "cells", + "words": [ + "DC" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tumor-draining" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "DC" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tumor-draining" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "control" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "gene", + "encoding", + "LXR-alpha" + ] + } + }, + { + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "gene", + "encoding", + "LXR-alpha" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "chimeric", + "mice", + "mice)" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "gene", + "encoding", + "LXR-alpha" + ] + } + } + ] + }, + { + "PMID": "20023637", + "TEXT": "Malfunction of the circadian clock has been linked to the pathogenesis of a variety of diseases. We show that mice lacking the core clock components Cryptochrome-1 (Cry1) and Cryptochrome-2 (Cry2) (Cry-null mice) show salt-sensitive hypertension due to abnormally high synthesis of the mineralocorticoid aldosterone by the adrenal gland. An extensive search for the underlying cause led us to identify type VI 3beta-hydroxyl-steroid dehydrogenase (Hsd3b6) as a new hypertension risk factor in mice. Hsd3b6 is expressed exclusively in aldosterone-producing cells and is under transcriptional control of the circadian clock. In Cry-null mice, Hsd3b6 messenger RNA and protein levels are constitutively high, leading to a marked increase in 3beta-hydroxysteroid dehydrogenase-isomerase (3beta-HSD) enzymatic activity and, as a consequence, enhanced aldosterone production. These data place Hsd3b6 in a pivotal position through which circadian clock malfunction is coupled to the development of hypertension. Translation of these findings to humans will require clinical examination of human HSD3B1 gene, which we found to be functionally similar to mouse Hsd3b6.", + "TAG_DATA": [ + "19, mice {'context': 'B-organism'}", + "20, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "21, the {'perturbing_action': 'I-gene loss-of-function'}", + "22, core {'perturbing_action': 'I-gene loss-of-function'}", + "23, clock {'perturbing_action': 'I-gene loss-of-function'}", + "24, components {'perturbing_action': 'I-gene loss-of-function'}", + "25, Cryptochrome-1 {'perturbing_action': 'I-gene loss-of-function'}", + "26, (Cry1) {'perturbing_action': 'I-gene loss-of-function'}", + "27, and {'perturbing_action': 'I-gene loss-of-function'}", + "28, Cryptochrome-2 {'perturbing_action': 'I-gene loss-of-function'}", + "29, (Cry2) {'perturbing_action': 'I-gene loss-of-function'}", + "30, (Cry-null {'perturbing_action': 'I-gene loss-of-function'}", + "31, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "89, Cry-null {'perturbing_action': 'B-gene loss-of-function'}", + "90, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "19, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "20, lacking ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "21, the ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "22, core ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "23, clock ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "24, components ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "25, Cryptochrome-1 ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "26, (Cry1) ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l57', 'l63', 'l64', 'l65', 'l66', 'l67']", + "27, and ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l68', 'l69', 'l70', 'l71']", + "28, Cryptochrome-2 ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l72', 'l73', 'l74']", + "29, (Cry2) ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l75', 'l76']", + "30, (Cry-null ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l75', 'l77']", + "31, mice) ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l74', 'l76', 'l77']", + "89, Cry-null ['l78']", + "90, mice, ['l78']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "core", + "clock", + "components", + "Cryptochrome-1", + "(Cry1)", + "and", + "Cryptochrome-2", + "(Cry2)", + "(Cry-null", + "mice)", + "Cry-null" + ] + } + } + ] + }, + { + "PMID": "20023634", + "TEXT": "Brain metastasis frequently occurs in individuals with cancer and is often fatal. We used multiphoton laser scanning microscopy to image the single steps of metastasis formation in real time. Thus, it was possible to track the fate of individual metastasizing cancer cells in vivo in relation to blood vessels deep in the mouse brain over minutes to months. The essential steps in this model were arrest at vascular branch points, early extravasation, persistent close contacts to microvessels and perivascular growth by vessel cooption (melanoma) or early angiogenesis (lung cancer). Inefficient steps differed between the tumor types. Long-term dormancy was only observed for single perivascular cancer cells, some of which moved continuously. Vascular endothelial growth factor-A (VEGF-A) inhibition induced long-term dormancy of lung cancer micrometastases by preventing angiogenic growth to macrometastases. The ability to image the establishment of brain metastases in vivo provides new insights into their evolution and response to therapies.", + "TAG_DATA": [ + "103, perivascular {'context': 'B-transformed cells'}", + "104, cancer {'context': 'I-transformed cells'}", + "105, cells, {'context': 'I-transformed cells'}", + "111, Vascular {'perturbing_action': 'B-pharmacological inhibition'}", + "112, endothelial {'perturbing_action': 'I-pharmacological inhibition'}", + "113, growth {'perturbing_action': 'I-pharmacological inhibition'}", + "114, factor-A {'perturbing_action': 'I-pharmacological inhibition'}", + "115, (VEGF-A) {'perturbing_action': 'I-pharmacological inhibition'}", + "116, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "121, lung {'context': 'B-neoplasm'}", + "122, cancer {'context': 'I-neoplasm'}", + "123, micrometastases {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "103, perivascular ['l0', 'l1']", + "104, cancer ['l0', 'l2']", + "105, cells, ['l1', 'l2']", + "111, Vascular ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "112, endothelial ['l3', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "113, growth ['l4', 'l11', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "114, factor-A ['l5', 'l12', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "115, (VEGF-A) ['l6', 'l13', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32']", + "116, inhibition ['l7', 'l14', 'l20', 'l25', 'l29', 'l33', 'l34', 'l35']", + "121, lung ['l8', 'l15', 'l21', 'l26', 'l30', 'l33', 'l36', 'l37']", + "122, cancer ['l9', 'l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l38']", + "123, micrometastases ['l10', 'l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Vascular", + "endothelial", + "growth", + "factor-A", + "(VEGF-A)", + "inhibition" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lung", + "cancer" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Vascular", + "endothelial", + "growth", + "factor-A", + "(VEGF-A)", + "inhibition" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "micrometastases" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "lung", + "cancer" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "micrometastases" + ] + } + } + ] + }, + { + "PMID": "19966781", + "TEXT": "Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix (ECM) proteins, which lead to distorted lung architecture and function. Given that anti-inflammatory or immunosuppressive therapy currently used for IPF does not improve disease progression therapies targeted to blocking the mechanisms of fibrogenesis are needed. Although transforming growth factor-beta (TGF-beta) functions are crucial in fibrosis, antagonizing this pathway in bleomycin-induced pulmonary fibrosis, an animal model of IPF, does not prevent fibrosis completely, indicating an additional pathway also has a key role in fibrogenesis. Given that the loss of cytosolic phospholipase A(2) (cPLA(2)) suppresses bleomycin-induced pulmonary fibrosis, we examined the roles of prostaglandins using mice lacking each prostoaglandin receptor. Here we show that loss of prostaglandin F (PGF) receptor (FP) selectively attenuates pulmonary fibrosis while maintaining similar levels of alveolar inflammation and TGF-beta stimulation as compared to wild-type (WT) mice, and that FP deficiency and inhibition of TGF-beta signaling additively decrease fibrosis. Furthermore, PGF(2alpha) is abundant in bronchoalveolar lavage fluid (BALF) of subjects with IPF and stimulates proliferation and collagen production of lung fibroblasts via FP, independently of TGF-beta. These findings show that PGF(2alpha)-FP signaling facilitates pulmonary fibrosis independently of TGF-beta and suggests this signaling pathway as a therapeutic target for IPF.", + "TAG_DATA": [ + "97, loss {'perturbing_action': 'B-gene loss-of-function'}", + "98, of {'perturbing_action': 'I-gene loss-of-function'}", + "99, cytosolic {'perturbing_action': 'I-gene loss-of-function'}", + "100, phospholipase {'perturbing_action': 'I-gene loss-of-function'}", + "101, A(2) {'perturbing_action': 'I-gene loss-of-function'}", + "102, (cPLA(2)) {'perturbing_action': 'I-gene loss-of-function'}", + "114, mice {'context': 'B-organism'}", + "123, loss {'perturbing_action': 'B-gene loss-of-function'}", + "124, of {'perturbing_action': 'I-gene loss-of-function'}", + "125, prostaglandin {'perturbing_action': 'I-gene loss-of-function'}", + "126, F {'perturbing_action': 'I-gene loss-of-function'}", + "127, (PGF) {'perturbing_action': 'I-gene loss-of-function'}", + "128, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "129, (FP) {'perturbing_action': 'I-gene loss-of-function'}", + "149, mice, {'context': 'B-organism'}", + "152, FP {'perturbing_action': 'B-gene loss-of-function'}", + "153, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "176, stimulates {'effect': 'B-positive'}", + "177, proliferation {'phenotype': 'B-proliferation'}", + "182, lung {'context': 'B-cells'}", + "183, fibroblasts {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "97, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "98, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "99, cytosolic ['l1', 'l13', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "100, phospholipase ['l2', 'l14', 'l26', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "101, A(2) ['l3', 'l15', 'l27', 'l38', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "102, (cPLA(2)) ['l4', 'l16', 'l28', 'l39', 'l49', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "114, mice ['l5', 'l17', 'l29', 'l40', 'l50', 'l59', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "123, loss ['l6', 'l18', 'l30', 'l41', 'l51', 'l60', 'l68', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "124, of ['l7', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l75', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "125, prostaglandin ['l8', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l76', 'l82', 'l88', 'l89', 'l90', 'l91', 'l92']", + "126, F ['l9', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l77', 'l83', 'l88', 'l93', 'l94', 'l95', 'l96']", + "127, (PGF) ['l10', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l78', 'l84', 'l89', 'l93', 'l97', 'l98', 'l99']", + "128, receptor ['l11', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l79', 'l85', 'l90', 'l94', 'l97', 'l100', 'l101']", + "129, (FP) ['l12', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l80', 'l86', 'l91', 'l95', 'l98', 'l100', 'l102']", + "149, mice, ['l25', 'l37', 'l48', 'l58', 'l67', 'l81', 'l87', 'l92', 'l96', 'l99', 'l101', 'l102']", + "152, FP ['l103']", + "153, deficiency ['l103']", + "176, stimulates ['l104', 'l105', 'l106']", + "177, proliferation ['l104', 'l107', 'l108']", + "182, lung ['l105', 'l107', 'l109']", + "183, fibroblasts ['l106', 'l108', 'l109']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "cytosolic", + "phospholipase", + "A(2)", + "(cPLA(2))", + "prostaglandin", + "F", + "(PGF)", + "receptor", + "(FP)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "context": { + "val": "cells", + "words": [ + "lung", + "fibroblasts" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "lung", + "fibroblasts" + ] + } + } + ] + }, + { + "PMID": "19966776", + "TEXT": "We report that heat shock protein 90 (Hsp90) inhibitors selectively kill diffuse large B cell lymphomas (DLBCLs) that depend on the BCL-6 transcriptional repressor. We found that endogenous Hsp90 interacts with BCL-6 in DLBCL cells and can stabilize BCL-6 mRNA and protein. Hsp90 formed a complex with BCL-6 at its target promoters, and Hsp90 inhibitors derepressed BCL-6 target genes. A stable mutant of BCL-6 rescued DLBCL cells from Hsp90 inhibitor-induced apoptosis. BCL-6 and Hsp90 were almost invariantly coexpressed in the nuclei of primary DLBCL cells, suggesting that their interaction is relevant in this disease. We examined the pharmacokinetics, toxicity and efficacy of PU-H71, a recently developed purine-derived Hsp90 inhibitor. PU-H71 preferentially accumulated in lymphomas compared to normal tissues and selectively suppressed BCL-6-dependent DLBCLs in vivo, inducing reactivation of key BCL-6 target genes and apoptosis. PU-H71 also induced cell death in primary human DLBCL specimens.", + "TAG_DATA": [ + "53, Hsp90 {'perturbing_action': 'B-pharmacological inhibition'}", + "54, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "60, stable {'perturbing_action': 'B-other'}", + "61, mutant {'perturbing_action': 'I-other'}", + "62, of {'perturbing_action': 'I-other'}", + "63, BCL-6 {'perturbing_action': 'I-other'}", + "64, rescued {'effect': 'B-rescues'}", + "65, DLBCL {'context': 'B-transformed cells'}", + "66, cells {'context': 'I-transformed cells'}", + "68, Hsp90 {'perturbing_action': 'B-pharmacological inhibition'}", + "69, inhibitor-induced {'perturbing_action': 'I-pharmacological inhibition', 'effect': 'B-positive'}", + "70, apoptosis. {'phenotype': 'B-apoptosis'}", + "122, DLBCLs {'context': 'B-neoplasm'}", + "123, in {'context': 'B-in vivo'}", + "124, vivo, {'context': 'I-in vivo'}", + "125, inducing {'effect': 'B-positive'}", + "133, apoptosis. {'phenotype': 'B-apoptosis'}", + "136, induced {'effect': 'B-positive'}", + "137, cell {'phenotype': 'B-cell death'}", + "138, death {'phenotype': 'I-cell death'}", + "140, primary {'context': 'B-neoplasm'}", + "141, human {'context': 'I-transformed cells'}", + "142, DLBCL {'context': 'I-transformed cells'}", + "143, specimens. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "53, Hsp90 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "54, inhibitors ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "60, stable ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "61, mutant ['l15', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "62, of ['l1', 'l16', 'l24', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "63, BCL-6 ['l2', 'l17', 'l25', 'l32', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "64, rescued ['l3', 'l9', 'l18', 'l26', 'l33', 'l39', 'l45', 'l46', 'l47', 'l48', 'l49']", + "65, DLBCL ['l4', 'l10', 'l19', 'l27', 'l34', 'l40', 'l45', 'l50', 'l51', 'l52', 'l53']", + "66, cells ['l5', 'l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l50', 'l54']", + "68, Hsp90 ['l6', 'l12', 'l21', 'l29', 'l36', 'l42', 'l47', 'l51', 'l55', 'l56']", + "69, inhibitor-induced ['l7', 'l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l52', 'l55', 'l57']", + "70, apoptosis. ['l8', 'l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l54', 'l56', 'l57']", + "122, DLBCLs ['l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "123, in ['l58', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "124, vivo, ['l59', 'l69', 'l79', 'l80', 'l81', 'l82', 'l83']", + "125, inducing ['l60', 'l70', 'l79', 'l84', 'l85', 'l86']", + "133, apoptosis. ['l61', 'l71', 'l80', 'l84', 'l87', 'l88', 'l89']", + "136, induced ['l62', 'l72', 'l81', 'l85', 'l87', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "137, cell ['l63', 'l73', 'l82', 'l88', 'l90', 'l96', 'l97', 'l98', 'l99', 'l100']", + "138, death ['l64', 'l74', 'l83', 'l86', 'l89', 'l91', 'l96', 'l101', 'l102', 'l103', 'l104']", + "140, primary ['l65', 'l75', 'l92', 'l97', 'l101', 'l105', 'l106', 'l107']", + "141, human ['l66', 'l76', 'l93', 'l98', 'l102', 'l105', 'l108', 'l109']", + "142, DLBCL ['l67', 'l77', 'l94', 'l99', 'l103', 'l106', 'l108', 'l110']", + "143, specimens. ['l68', 'l78', 'l95', 'l100', 'l104', 'l107', 'l109', 'l110']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Hsp90", + "inhibitors", + "inhibitor-induced" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Hsp90", + "inhibitors", + "inhibitor-induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "DLBCL", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Hsp90", + "inhibitors", + "inhibitor-induced" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inhibitor-induced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Hsp90", + "inhibitors", + "inhibitor-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "stable", + "mutant", + "of", + "BCL-6" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "stable", + "mutant", + "of", + "BCL-6" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "DLBCL", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "stable", + "mutant", + "of", + "BCL-6" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inhibitor-induced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "stable", + "mutant", + "of", + "BCL-6" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "DLBCL", + "cells" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "DLBCL", + "human", + "specimens." + ] + }, + "effect": { + "val": "positive", + "words": [ + "inhibitor-induced", + "induced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "DLBCL", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inhibitor-induced", + "inducing", + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "DLBCLs", + "primary" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inducing", + "induced" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "DLBCLs" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "DLBCLs", + "primary" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + }, + "effect": { + "val": "positive", + "words": [ + "inducing", + "induced" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing", + "induced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "death", + "cell" + ] + } + }, + { + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "DLBCL", + "specimens." + ] + } + } + ] + }, + { + "PMID": "19881493", + "TEXT": "Cellular apoptosis induced by hyperglycemia occurs in many vascular cells and is crucial for the initiation of diabetic pathologies. In the retina, pericyte apoptosis and the formation of acellular capillaries, the most specific vascular pathologies attributed to hyperglycemia, is linked to the loss of platelet-derived growth factor (PDGF)-mediated survival actions owing to unknown mechanisms. Here we show that hyperglycemia persistently activates protein kinase C-delta (PKC-delta, encoded by Prkcd) and p38alpha mitogen-activated protein kinase (MAPK) to increase the expression of a previously unknown target of PKC-delta signaling, Src homology-2 domain-containing phosphatase-1 (SHP-1), a protein tyrosine phosphatase. This signaling cascade leads to PDGF receptor-beta dephosphorylation and a reduction in downstream signaling from this receptor, resulting in pericyte apoptosis independently of nuclear factor-kappaB (NF-kappaB) signaling. We observed increased PKC-delta activity and an increase in the number of acellular capillaries in diabetic mouse retinas, which were not reversible with insulin treatment that achieved normoglycemia. Unlike diabetic age-matched wild-type mice, diabetic Prkcd(-/-) mice did not show activation of p38alpha MAPK or SHP-1, inhibition of PDGF signaling in vascular cells or the presence of acellular capillaries. We also observed PKC-delta, p38alpha MAPK and SHP-1 activation in brain pericytes and in the renal cortex of diabetic mice. These findings elucidate a new signaling pathway by which hyperglycemia can induce PDGF resistance and increase vascular cell apoptosis to cause diabetic vascular complications.", + "TAG_DATA": [ + "114, pericyte {'context': 'B-cells'}", + "115, apoptosis {'phenotype': 'B-apoptosis'}", + "137, diabetic {'context': 'B-tissue/organ'}", + "138, mouse {'context': 'I-tissue/organ'}", + "139, retinas, {'context': 'I-tissue/organ'}", + "155, diabetic {'context': 'B-organism'}", + "156, Prkcd(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "157, mice {'context': 'B-organism'}", + "172, vascular {'context': 'B-cells'}", + "173, cells {'context': 'I-cells'}", + "190, brain {'context': 'B-cells'}", + "191, pericytes {'context': 'I-cells'}", + "195, renal {'context': 'B-tissue/organ'}", + "196, cortex {'context': 'I-tissue/organ'}", + "198, diabetic {'context': 'B-organism'}", + "199, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "114, pericyte ['l0', 'l1', 'l2', 'l3']", + "115, apoptosis ['l0', 'l4', 'l5', 'l6']", + "137, diabetic ['l1', 'l4', 'l7', 'l8']", + "138, mouse ['l2', 'l5', 'l7', 'l9']", + "139, retinas, ['l3', 'l6', 'l8', 'l9']", + "155, diabetic ['l10', 'l11', 'l12', 'l13']", + "156, Prkcd(-/-) ['l10', 'l14', 'l15', 'l16']", + "157, mice ['l11', 'l14', 'l17', 'l18']", + "172, vascular ['l12', 'l15', 'l17', 'l19']", + "173, cells ['l13', 'l16', 'l18', 'l19']", + "190, brain ['l20', 'l21', 'l22', 'l23', 'l24']", + "191, pericytes ['l20', 'l25', 'l26', 'l27', 'l28']", + "195, renal ['l21', 'l25', 'l29', 'l30', 'l31']", + "196, cortex ['l22', 'l26', 'l29', 'l32', 'l33']", + "198, diabetic ['l23', 'l27', 'l30', 'l32', 'l34']", + "199, mice. ['l24', 'l28', 'l31', 'l33', 'l34']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "pericyte" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "diabetic", + "mouse", + "retinas," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "diabetic", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Prkcd(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Prkcd(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "vascular", + "cells" + ] + } + } + ] + }, + { + "PMID": "19838201", + "TEXT": "Type 2 diabetes is a complex disease that is marked by the dysfunction of glucose and lipid metabolism. Hepatic insulin resistance is especially pathogenic in type 2 diabetes, as it dysregulates fasting and postprandial glucose tolerance and promotes systemic dyslipidemia and nonalcoholic fatty liver disease. Mitochondrial dysfunction is closely associated with insulin resistance and might contribute to the progression of diabetes. Here we used previously generated mice with hepatic insulin resistance owing to the deletion of the genes encoding insulin receptor substrate-1 (Irs-1) and Irs-2 (referred to here as double-knockout (DKO) mice) to establish the molecular link between dysregulated insulin action and mitochondrial function. The expression of several forkhead box O1 (Foxo1) target genes increased in the DKO liver, including heme oxygenase-1 (Hmox1), which disrupts complex III and IV of the respiratory chain and lowers the NAD(+)/NADH ratio and ATP production. Although peroxisome proliferator-activated receptor-gamma coactivator-1alpha (Ppargc-1alpha) was also upregulated in DKO liver, it was acetylated and failed to promote compensatory mitochondrial biogenesis or function. Deletion of hepatic Foxo1 in DKO liver normalized the expression of Hmox1 and the NAD(+)/NADH ratio, reduced Ppargc-1alpha acetylation and restored mitochondrial oxidative metabolism and biogenesis. Thus, Foxo1 integrates insulin signaling with mitochondrial function, and inhibition of Foxo1 can improve hepatic metabolism during insulin resistance and the metabolic syndrome.", + "TAG_DATA": [ + "66, mice {'context': 'B-organism'}", + "74, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "75, of {'perturbing_action': 'I-gene loss-of-function'}", + "76, the {'perturbing_action': 'I-gene loss-of-function'}", + "77, genes {'perturbing_action': 'I-gene loss-of-function'}", + "78, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "79, insulin {'perturbing_action': 'I-gene loss-of-function'}", + "80, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "81, substrate-1 {'perturbing_action': 'I-gene loss-of-function'}", + "82, (Irs-1) {'perturbing_action': 'I-gene loss-of-function'}", + "83, and {'perturbing_action': 'I-gene loss-of-function'}", + "84, Irs-2 {'perturbing_action': 'I-gene loss-of-function'}", + "89, double-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "90, (DKO) {'perturbing_action': 'I-gene loss-of-function'}", + "118, liver, {'context': 'B-tissue/organ'}", + "152, liver, {'context': 'B-tissue/organ'}", + "165, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "166, of {'perturbing_action': 'I-gene loss-of-function'}", + "167, hepatic {'perturbing_action': 'I-gene loss-of-function'}", + "168, Foxo1 {'perturbing_action': 'I-gene loss-of-function'}", + "171, liver {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "66, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "74, deletion ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "75, of ['l1', 'l14', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "76, the ['l2', 'l15', 'l28', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "77, genes ['l3', 'l16', 'l29', 'l41', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "78, encoding ['l4', 'l17', 'l30', 'l42', 'l53', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "79, insulin ['l5', 'l18', 'l31', 'l43', 'l54', 'l64', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "80, receptor ['l6', 'l19', 'l32', 'l44', 'l55', 'l65', 'l74', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "81, substrate-1 ['l7', 'l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l83', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "82, (Irs-1) ['l8', 'l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l84', 'l91', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "83, and ['l9', 'l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l98', 'l104', 'l105', 'l106', 'l107', 'l108']", + "84, Irs-2 ['l10', 'l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l86', 'l93', 'l99', 'l104', 'l109', 'l110', 'l111', 'l112']", + "89, double-knockout ['l11', 'l24', 'l37', 'l49', 'l60', 'l70', 'l79', 'l87', 'l94', 'l100', 'l105', 'l109', 'l113', 'l114', 'l115']", + "90, (DKO) ['l12', 'l25', 'l38', 'l50', 'l61', 'l71', 'l80', 'l88', 'l95', 'l101', 'l106', 'l110', 'l113', 'l116']", + "118, liver, ['l13', 'l26', 'l39', 'l51', 'l62', 'l72', 'l81', 'l89', 'l96', 'l102', 'l107', 'l111', 'l114', 'l116', 'l117']", + "152, liver, ['l27', 'l40', 'l52', 'l63', 'l73', 'l82', 'l90', 'l97', 'l103', 'l108', 'l112', 'l115', 'l117']", + "165, Deletion ['l118', 'l119', 'l120', 'l121']", + "166, of ['l118', 'l122', 'l123', 'l124']", + "167, hepatic ['l119', 'l122', 'l125', 'l126']", + "168, Foxo1 ['l120', 'l123', 'l125', 'l127']", + "171, liver ['l121', 'l124', 'l126', 'l127']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "genes", + "encoding", + "insulin", + "receptor", + "substrate-1", + "(Irs-1)", + "and", + "Irs-2", + "double-knockout", + "(DKO)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "genes", + "encoding", + "insulin", + "receptor", + "substrate-1", + "(Irs-1)", + "and", + "Irs-2", + "double-knockout", + "(DKO)", + "Deletion", + "hepatic", + "Foxo1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver,", + "liver" + ] + } + } + ] + }, + { + "PMID": "19767733", + "TEXT": "Thyroid dysfunction is a global health concern, causing defects including neurodevelopmental disorders, dwarfism and cardiac arrhythmia. Here, we show that the potassium channel subunits KCNQ1 and KCNE2 form a thyroid-stimulating hormone-stimulated, constitutively active, thyrocyte K+ channel required for normal thyroid hormone biosynthesis. Targeted disruption of Kcne2 in mice impaired thyroid iodide accumulation up to eightfold, impaired maternal milk ejection, halved milk tetraiodothyronine (T4) content and halved litter size. Kcne2-deficient mice had hypothyroidism, dwarfism, alopecia, goiter and cardiac abnormalities including hypertrophy, fibrosis, and reduced fractional shortening. The alopecia, dwarfism and cardiac abnormalities were alleviated by triiodothyronine (T3) and T4 administration to pups, by supplementing dams with T(4) before and after they gave birth or by feeding the pups exclusively from Kcne2+/+ dams; conversely, these symptoms were elicited in Kcne2+/+ pups by feeding exclusively from Kcne2-/- dams. These data provide a new potential therapeutic target for thyroid disorders and raise the possibility of an endocrine component to previously identified KCNE2- and KCNQ1-linked human cardiac arrhythmias.", + "TAG_DATA": [ + "42, Targeted {'perturbing_action': 'B-gene loss-of-function'}", + "43, disruption {'perturbing_action': 'I-gene loss-of-function'}", + "44, of {'perturbing_action': 'I-gene loss-of-function'}", + "45, Kcne2 {'perturbing_action': 'I-gene loss-of-function'}", + "47, mice {'context': 'B-organism'}", + "68, Kcne2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "69, mice {'context': 'B-organism'}", + "100, pups, {'context': 'B-organism'}", + "116, pups {'context': 'B-organism'}", + "127, Kcne2+/+ {'perturbing_action': 'B-gene loss-of-function'}", + "128, pups {'context': 'I-organism'}", + "133, Kcne2-/- {'perturbing_action': 'B-gene loss-of-function'}" + ], + "LINK_DATA": [ + "42, Targeted ['l0', 'l1', 'l2', 'l3']", + "43, disruption ['l0', 'l4', 'l5', 'l6']", + "44, of ['l1', 'l4', 'l7', 'l8']", + "45, Kcne2 ['l2', 'l5', 'l7', 'l9']", + "47, mice ['l3', 'l6', 'l8', 'l9']", + "68, Kcne2-deficient ['l10', 'l11']", + "69, mice ['l10']", + "100, pups, ['l11', 'l12']", + "116, pups ['l12']", + "127, Kcne2+/+ ['l13', 'l14']", + "128, pups ['l13', 'l15']", + "133, Kcne2-/- ['l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Targeted", + "disruption", + "of", + "Kcne2", + "Kcne2-deficient", + "Kcne2+/+", + "Kcne2-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "pups,", + "pups" + ] + } + } + ] + }, + { + "PMID": "19718038", + "TEXT": "Bone metabolism results from a balance between osteoclast-driven bone resorption and osteoblast-mediated bone formation. Diseases such as periodontitis and rheumatoid arthritis are characterized by increased bone destruction due to enhanced osteoclastogenesis. Here we report that interferon regulatory factor-8 (IRF-8), a transcription factor expressed in immune cells, is a key regulatory molecule for osteoclastogenesis. IRF-8 expression in osteoclast precursors was downregulated during the initial phase of osteoclast differentiation induced by receptor activator of nuclear factor-kappaB ligand (RANKL), which is encoded by the Tnfsf11 gene. Mice deficient in Irf8 showed severe osteoporosis, owing to increased numbers of osteoclasts, and also showed enhanced bone destruction after lipopolysaccharide (LPS) administration. Irf8-/- osteoclast precursors underwent increased osteoclastogenesis in response to RANKL and tumor necrosis factor-alpha (TNF-alpha). IRF-8 suppressed osteoclastogenesis by inhibiting the function and expression of nuclear factor of activated T cells c1 (NFATc1). Our results show that IRF-8 inhibits osteoclast formation under physiological and pathological conditions and suggest a model where downregulation of inhibitory factors such as IRF-8 contributes to RANKL-mediated osteoclastogenesis.", + "TAG_DATA": [ + "83, Mice {'context': 'B-organism'}", + "84, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "85, in {'perturbing_action': 'I-gene loss-of-function'}", + "86, Irf8 {'perturbing_action': 'I-gene loss-of-function'}", + "106, Irf8-/- {'perturbing_action': 'B-gene loss-of-function'}", + "107, osteoclast {'context': 'B-cells'}", + "108, precursors {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "83, Mice ['l0', 'l1', 'l2']", + "84, deficient ['l0', 'l3', 'l4']", + "85, in ['l1', 'l3', 'l5']", + "86, Irf8 ['l2', 'l4', 'l5']", + "106, Irf8-/- ['l6', 'l7']", + "107, osteoclast ['l6', 'l8']", + "108, precursors ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Irf8" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Irf8-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "osteoclast", + "precursors" + ] + } + } + ] + }, + { + "PMID": "19718037", + "TEXT": "Various stimuli, such as telomere dysfunction and oxidative stress, can induce irreversible cell growth arrest, which is termed 'cellular senescence'. This response is controlled by tumor suppressor proteins such as p53 and pRb. There is also evidence that senescent cells promote changes related to aging or age-related diseases. Here we show that p53 expression in adipose tissue is crucially involved in the development of insulin resistance, which underlies age-related cardiovascular and metabolic disorders. We found that excessive calorie intake led to the accumulation of oxidative stress in the adipose tissue of mice with type 2 diabetes-like disease and promoted senescence-like changes, such as increased activity of senescence-associated beta-galactosidase, increased expression of p53 and increased production of proinflammatory cytokines. Inhibition of p53 activity in adipose tissue markedly ameliorated these senescence-like changes, decreased the expression of proinflammatory cytokines and improved insulin resistance in mice with type 2 diabetes-like disease. Conversely, upregulation of p53 in adipose tissue caused an inflammatory response that led to insulin resistance. Adipose tissue from individuals with diabetes also showed senescence-like features. Our results show a previously unappreciated role of adipose tissue p53 expression in the regulation of insulin resistance and suggest that cellular aging signals in adipose tissue could be a new target for the treatment of diabetes (pages 996-967).", + "TAG_DATA": [ + "88, adipose {'context': 'B-tissue/organ'}", + "89, tissue {'context': 'I-tissue/organ'}", + "91, mice {'context': 'B-organism'}", + "118, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "119, of {'perturbing_action': 'I-pharmacological inhibition'}", + "120, p53 {'perturbing_action': 'I-pharmacological inhibition'}", + "121, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "123, adipose {'context': 'B-tissue/organ'}", + "124, tissue {'context': 'I-tissue/organ'}", + "141, mice {'context': 'B-organism'}", + "148, upregulation {'perturbing_action': 'B-gene gain-of-function'}", + "149, of {'perturbing_action': 'I-gene gain-of-function'}", + "150, p53 {'perturbing_action': 'I-gene gain-of-function'}", + "152, adipose {'context': 'B-tissue/organ'}", + "153, tissue {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "88, adipose ['l0', 'l1']", + "89, tissue ['l0', 'l2']", + "91, mice ['l1', 'l2']", + "118, Inhibition ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "119, of ['l3', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "120, p53 ['l4', 'l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "121, activity ['l5', 'l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "123, adipose ['l6', 'l12', 'l17', 'l21', 'l25', 'l26']", + "124, tissue ['l7', 'l13', 'l18', 'l22', 'l25', 'l27']", + "141, mice ['l8', 'l14', 'l19', 'l23', 'l26', 'l27']", + "148, upregulation ['l28', 'l29', 'l30', 'l31']", + "149, of ['l28', 'l32', 'l33', 'l34']", + "150, p53 ['l29', 'l32', 'l35', 'l36']", + "152, adipose ['l30', 'l33', 'l35', 'l37']", + "153, tissue ['l9', 'l15', 'l20', 'l24', 'l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "p53", + "activity" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "adipose", + "tissue" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "p53", + "activity" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "upregulation", + "of", + "p53" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "adipose", + "tissue" + ] + } + } + ] + }, + { + "PMID": "19701204", + "TEXT": "A subset of central glutamatergic synapses are coordinately pruned and matured by unresolved mechanisms during postnatal development. We report that the human epilepsy gene LGI1, encoding leucine-rich, glioma-inactivated protein-1 and mutated in autosomal dominant lateral temporal lobe epilepsy (ADLTE), mediates this process in hippocampus. We created transgenic mice either expressing a truncated mutant LGI1 (835delC) found in ADLTE or overexpressing a wild-type LGI1. We discovered that the normal postnatal maturation of presynaptic and postsynaptic functions was arrested by the 835delC mutant LGI1, and contrastingly, was magnified by excess wild-type LGI1. Concurrently, mutant LGI1 inhibited dendritic pruning and increased the spine density to markedly increase excitatory synaptic transmission. Inhibitory transmission, by contrast, was unaffected. Furthermore, mutant LGI1 promoted epileptiform discharge in vitro and kindling epileptogenesis in vivo with partial gamma-aminobutyric acid(A) (GABA(A)) receptor blockade. Thus, LGI1 represents a human gene mutated to promote epilepsy through impaired postnatal development of glutamatergic circuits.", + "TAG_DATA": [ + "47, mice {'context': 'B-organism'}", + "49, expressing {'perturbing_action': 'B-other'}", + "50, a {'perturbing_action': 'I-other'}", + "51, truncated {'perturbing_action': 'I-other'}", + "52, mutant {'perturbing_action': 'I-other'}", + "53, LGI1 {'perturbing_action': 'I-other'}", + "54, (835delC) {'perturbing_action': 'I-other'}", + "55, found {'perturbing_action': 'I-other'}", + "59, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "60, a {'perturbing_action': 'I-gene gain-of-function'}", + "61, wild-type {'perturbing_action': 'I-gene gain-of-function'}", + "62, LGI1. {'perturbing_action': 'I-gene gain-of-function'}", + "79, 835delC {'perturbing_action': 'B-other'}", + "80, mutant {'perturbing_action': 'I-other'}", + "81, LGI1, {'perturbing_action': 'I-other'}", + "91, mutant {'perturbing_action': 'B-other'}", + "92, LGI1 {'perturbing_action': 'I-other'}", + "114, mutant {'perturbing_action': 'B-other'}", + "115, LGI1 {'perturbing_action': 'I-other'}", + "116, promoted {'effect': 'B-positive'}", + "119, in {'context': 'B-in vitro'}", + "120, vitro {'context': 'I-in vitro'}", + "124, in {'context': 'B-in vivo'}", + "125, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "47, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "49, expressing ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "50, a ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "51, truncated ['l2', 'l11', 'l19', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "52, mutant ['l3', 'l12', 'l20', 'l29', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "53, LGI1 ['l4', 'l13', 'l21', 'l30', 'l39', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "54, (835delC) ['l5', 'l14', 'l22', 'l31', 'l40', 'l47', 'l53', 'l54', 'l55', 'l56', 'l57']", + "55, found ['l6', 'l15', 'l23', 'l32', 'l41', 'l48', 'l53', 'l58', 'l59', 'l60']", + "59, overexpressing ['l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "60, a ['l24', 'l33', 'l42', 'l61', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "61, wild-type ['l34', 'l62', 'l69', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "62, LGI1. ['l25', 'l35', 'l43', 'l49', 'l54', 'l63', 'l70', 'l76', 'l82', 'l83', 'l84', 'l85', 'l86']", + "79, 835delC ['l7', 'l16', 'l26', 'l36', 'l44', 'l50', 'l55', 'l58', 'l64', 'l71', 'l77', 'l82', 'l87', 'l88']", + "80, mutant ['l8', 'l17', 'l27', 'l37', 'l45', 'l51', 'l56', 'l59', 'l65', 'l72', 'l78', 'l83', 'l87', 'l89']", + "81, LGI1, ['l9', 'l18', 'l28', 'l38', 'l46', 'l52', 'l57', 'l60', 'l66', 'l73', 'l79', 'l84', 'l88', 'l89']", + "91, mutant ['l67', 'l74', 'l80', 'l85', 'l90']", + "92, LGI1 ['l68', 'l75', 'l81', 'l86', 'l90']", + "114, mutant ['l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "115, LGI1 ['l91', 'l97', 'l98', 'l99', 'l100', 'l101']", + "116, promoted ['l92', 'l97', 'l102', 'l103', 'l104', 'l105']", + "119, in ['l93', 'l98', 'l102', 'l106']", + "120, vitro ['l94', 'l99', 'l103', 'l106']", + "124, in ['l95', 'l100', 'l104', 'l107']", + "125, vivo ['l96', 'l101', 'l105', 'l107']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "a", + "truncated", + "mutant", + "LGI1", + "(835delC)", + "found", + "835delC", + "LGI1," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "LGI1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "LGI1" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "LGI1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "19701202", + "TEXT": "The intestinal flora may promote colon tumor formation. Here we explore immunologic mechanisms of colonic carcinogenesis by a human colonic bacterium, enterotoxigenic Bacteroides fragilis (ETBF). ETBF that secretes B. fragilis toxin (BFT) causes human inflammatory diarrhea but also asymptomatically colonizes a proportion of the human population. Our results indicate that whereas both ETBF and nontoxigenic B. fragilis (NTBF) chronically colonize mice, only ETBF triggers colitis and strongly induces colonic tumors in multiple intestinal neoplasia (Min) mice. ETBF induces robust, selective colonic signal transducer and activator of transcription-3 (Stat3) activation with colitis characterized by a selective T helper type 17 (T(H)17) response distributed between CD4+ T cell receptor-alphabeta (TCRalphabeta)+ and CD4-8-TCRgammadelta+ T cells. Antibody-mediated blockade of interleukin-17 (IL-17) as well as the receptor for IL-23, a key cytokine amplifying T(H)17 responses, inhibits ETBF-induced colitis, colonic hyperplasia and tumor formation. These results show a Stat3- and T(H)17-dependent pathway for inflammation-induced cancer by a common human commensal bacterium, providing new mechanistic insight into human colon carcinogenesis.", + "TAG_DATA": [ + "60, mice, {'context': 'B-organism'}", + "67, induces {'effect': 'B-positive'}", + "68, colonic {'phenotype': 'B-tumourigenesis'}", + "69, tumors {'phenotype': 'I-tumourigenesis'}", + "73, neoplasia {'phenotype': 'I-tumourigenesis'}", + "75, mice. {'context': 'B-organism'}", + "136, tumor {'phenotype': 'B-tumourigenesis'}", + "137, formation. {'phenotype': 'I-tumourigenesis'}" + ], + "LINK_DATA": [ + "60, mice, ['l0', 'l1', 'l2']", + "67, induces ['l0', 'l3', 'l4', 'l5']", + "68, colonic ['l1', 'l3', 'l6', 'l7']", + "69, tumors ['l2', 'l4', 'l6']", + "71, multiple ['l8', 'l9', 'l10']", + "72, intestinal ['l8', 'l11', 'l12']", + "73, neoplasia ['l9', 'l11', 'l13']", + "75, mice. ['l5', 'l7', 'l10', 'l12', 'l13']", + "136, tumor ['l14']", + "137, formation. ['l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice,", + "mice." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice,", + "mice." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "colonic", + "tumors", + "neoplasia" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "colonic", + "tumors" + ] + } + } + ] + }, + { + "PMID": "19684581", + "TEXT": "T cells are crucial mediators of the skin damage in psoriasis. We here show that interleukin-21 (IL-21), a T cell-derived cytokine, is highly expressed in the skin of individuals with psoriasis, stimulates human keratinocytes to proliferate and causes epidermal hyperplasia when injected intradermally into mice. In the human psoriasis xenograft mouse model, blockade of IL-21 activity resolves inflammation and reduces keratinocyte proliferation. Blocking IL-21 may represent a new therapeutic strategy in psoriasis.", + "TAG_DATA": [ + "31, stimulates {'effect': 'B-positive'}", + "32, human {'context': 'B-cells'}", + "33, keratinocytes {'context': 'I-cells'}", + "35, proliferate {'phenotype': 'B-proliferation'}", + "44, mice. {'context': 'B-organism'}", + "47, human {'context': 'B-xenograft'}", + "48, psoriasis {'context': 'I-xenograft'}", + "49, xenograft {'context': 'I-xenograft'}", + "50, mouse {'context': 'I-xenograft'}", + "51, model, {'context': 'I-xenograft'}", + "52, blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "53, of {'perturbing_action': 'I-pharmacological inhibition'}", + "54, IL-21 {'perturbing_action': 'I-pharmacological inhibition'}", + "55, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "59, reduces {'effect': 'B-negative'}", + "60, keratinocyte {'context': 'B-cells'}", + "61, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "31, stimulates ['l0', 'l1', 'l2', 'l3']", + "32, human ['l0', 'l4', 'l5', 'l6']", + "33, keratinocytes ['l1', 'l4', 'l7', 'l8']", + "35, proliferate ['l2', 'l5', 'l7', 'l9']", + "44, mice. ['l3', 'l6', 'l8', 'l9']", + "47, human ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "48, psoriasis ['l10', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "49, xenograft ['l11', 'l21', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "50, mouse ['l12', 'l22', 'l31', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "51, model, ['l13', 'l23', 'l32', 'l40', 'l46', 'l47', 'l48', 'l49', 'l50']", + "52, blockade ['l14', 'l24', 'l33', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "53, of ['l15', 'l25', 'l34', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "54, IL-21 ['l16', 'l26', 'l35', 'l41', 'l46', 'l52', 'l57', 'l62', 'l63', 'l64', 'l65']", + "55, activity ['l17', 'l27', 'l36', 'l42', 'l47', 'l53', 'l58', 'l62', 'l66', 'l67', 'l68']", + "59, reduces ['l18', 'l28', 'l37', 'l43', 'l48', 'l54', 'l59', 'l63', 'l66', 'l69', 'l70']", + "60, keratinocyte ['l19', 'l29', 'l38', 'l44', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l71']", + "61, proliferation. ['l20', 'l30', 'l39', 'l45', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l71']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "keratinocytes" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "keratinocytes", + "keratinocyte" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate", + "proliferation." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "human", + "psoriasis", + "xenograft", + "mouse", + "model," + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "IL-21", + "activity" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "human", + "psoriasis", + "xenograft", + "mouse", + "model," + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "human", + "psoriasis", + "xenograft", + "mouse", + "model," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "IL-21", + "activity" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "IL-21", + "activity" + ] + }, + "context": { + "val": "cells", + "words": [ + "keratinocyte" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "IL-21", + "activity" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "context": { + "val": "cells", + "words": [ + "keratinocyte" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "19633658", + "TEXT": "Inflammation is increasingly regarded as a key process underlying metabolic diseases in obese individuals. In particular, obese adipose tissue shows features characteristic of active local inflammation. At present, however, little is known about the sequence of events that comprises the inflammatory cascade or the mechanism by which inflammation develops. We found that large numbers of CD8(+) effector T cells infiltrated obese epididymal adipose tissue in mice fed a high-fat diet, whereas the numbers of CD4(+) helper and regulatory T cells were diminished. The infiltration by CD8(+) T cells preceded the accumulation of macrophages, and immunological and genetic depletion of CD8(+) T cells lowered macrophage infiltration and adipose tissue inflammation and ameliorated systemic insulin resistance. Conversely, adoptive transfer of CD8(+) T cells to CD8-deficient mice aggravated adipose inflammation. Coculture and other in vitro experiments revealed a vicious cycle of interactions between CD8(+) T cells, macrophages and adipose tissue. Our findings suggest that obese adipose tissue activates CD8(+) T cells, which, in turn, promote the recruitment and activation of macrophages in this tissue. These results support the notion that CD8(+) T cells have an essential role in the initiation and propagation of adipose inflammation.", + "TAG_DATA": [ + "55, CD8(+) {'context': 'B-cells'}", + "56, effector {'context': 'I-cells'}", + "57, T {'context': 'I-cells'}", + "58, cells {'context': 'I-cells'}", + "60, obese {'context': 'B-tissue/organ'}", + "61, epididymal {'context': 'I-tissue/organ'}", + "62, adipose {'context': 'I-tissue/organ'}", + "63, tissue {'context': 'I-tissue/organ'}", + "65, mice {'context': 'B-organism'}", + "74, CD4(+) {'context': 'B-cells'}", + "75, helper {'context': 'I-cells'}", + "76, and {'context': 'I-cells'}", + "77, regulatory {'context': 'I-cells'}", + "78, T {'context': 'I-cells'}", + "79, cells {'context': 'I-cells'}", + "85, CD8(+) {'context': 'B-cells'}", + "86, T {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}", + "99, CD8(+) {'context': 'B-cells'}", + "100, T {'context': 'I-cells'}", + "101, cells {'context': 'I-cells'}", + "103, macrophage {'context': 'B-cells'}", + "106, adipose {'context': 'B-tissue/organ'}", + "118, CD8(+) {'context': 'B-cells'}", + "119, T {'context': 'I-cells'}", + "120, cells {'context': 'I-cells'}", + "122, CD8-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "123, mice {'context': 'B-organism'}", + "130, in {'context': 'B-in vitro'}", + "131, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "55, CD8(+) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "56, effector ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "57, T ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "58, cells ['l2', 'l21', 'l39', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "60, obese ['l3', 'l22', 'l40', 'l55', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "61, epididymal ['l4', 'l23', 'l41', 'l56', 'l70', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "62, adipose ['l5', 'l24', 'l42', 'l57', 'l71', 'l83', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "63, tissue ['l6', 'l25', 'l43', 'l58', 'l72', 'l84', 'l95', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "65, mice ['l7', 'l26', 'l44', 'l59', 'l73', 'l85', 'l96', 'l105', 'l111', 'l112', 'l113', 'l114', 'l115']", + "74, CD4(+) ['l8', 'l27', 'l45', 'l60', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "75, helper ['l9', 'l28', 'l46', 'l61', 'l74', 'l86', 'l116', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139']", + "76, and ['l10', 'l29', 'l47', 'l62', 'l75', 'l87', 'l97', 'l117', 'l129', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "77, regulatory ['l11', 'l30', 'l48', 'l63', 'l76', 'l88', 'l98', 'l118', 'l130', 'l140', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "78, T ['l12', 'l31', 'l49', 'l64', 'l77', 'l89', 'l99', 'l106', 'l111', 'l119', 'l131', 'l141', 'l150', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164']", + "79, cells ['l13', 'l32', 'l50', 'l65', 'l78', 'l90', 'l100', 'l107', 'l112', 'l120', 'l132', 'l142', 'l151', 'l158', 'l165', 'l166', 'l167', 'l168', 'l169']", + "85, CD8(+) ['l14', 'l33', 'l51', 'l66', 'l79', 'l91', 'l101', 'l108', 'l113', 'l121', 'l133', 'l143', 'l152', 'l159', 'l165', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175']", + "86, T ['l15', 'l34', 'l52', 'l67', 'l80', 'l92', 'l102', 'l109', 'l114', 'l122', 'l134', 'l144', 'l153', 'l160', 'l166', 'l170', 'l176', 'l177', 'l178', 'l179', 'l180']", + "87, cells ['l16', 'l35', 'l53', 'l68', 'l81', 'l93', 'l103', 'l110', 'l115', 'l123', 'l135', 'l145', 'l154', 'l161', 'l167', 'l171', 'l176', 'l181', 'l182', 'l183']", + "99, CD8(+) ['l184', 'l185', 'l186', 'l187', 'l188']", + "100, T ['l124', 'l184', 'l189', 'l190', 'l191', 'l192']", + "101, cells ['l125', 'l136', 'l146', 'l172', 'l177', 'l185', 'l189', 'l193', 'l194', 'l195']", + "103, macrophage ['l17', 'l36', 'l126', 'l137', 'l147', 'l155', 'l162', 'l173', 'l178', 'l181', 'l186', 'l190', 'l193', 'l196', 'l197']", + "106, adipose ['l18', 'l37', 'l127', 'l138', 'l148', 'l156', 'l163', 'l168', 'l174', 'l179', 'l182', 'l187', 'l191', 'l194', 'l196', 'l198']", + "107, tissue ['l19', 'l38', 'l54', 'l69', 'l82', 'l94', 'l104', 'l128', 'l139', 'l149', 'l157', 'l164', 'l169', 'l175', 'l180', 'l183', 'l188', 'l192', 'l195', 'l197', 'l198']", + "118, CD8(+) ['l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "119, T ['l199', 'l205', 'l206', 'l207']", + "120, cells ['l200', 'l205', 'l208', 'l209']", + "122, CD8-deficient ['l201', 'l206', 'l208', 'l210', 'l211', 'l212']", + "123, mice ['l202', 'l207', 'l209', 'l210']", + "130, in ['l203', 'l211', 'l213']", + "131, vitro ['l204', 'l212', 'l213']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "T", + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD8-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD8-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD8-deficient" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "19597504", + "TEXT": "Although the transforming growth factor-beta (TGF-beta) pathway has been implicated in breast cancer metastasis, its in vivo dynamics and temporal-spatial involvement in organ-specific metastasis have not been investigated. Here we engineered a xenograft model system with a conditional control of the TGF-beta-SMAD signaling pathway and a dual-luciferase reporter system for tracing both metastatic burden and TGF-beta signaling activity in vivo. Strong TGF-beta signaling in osteolytic bone lesions is suppressed directly by genetic and pharmacological disruption of the TGF-beta-SMAD pathway and indirectly by inhibition of osteoclast function with bisphosphonates. Notably, disruption of TGF-beta signaling early in metastasis can substantially reduce metastasis burden but becomes less effective when bone lesions are well established. Our in vivo system for real-time manipulation and detection of TGF-beta signaling provides a proof of principle for using similar strategies to analyze the in vivo dynamics of other metastasis-associated signaling pathways and will expedite the development and characterization of therapeutic agents.", + "TAG_DATA": [ + "32, xenograft {'context': 'B-xenograft'}", + "33, model {'context': 'I-xenograft'}", + "34, system {'context': 'I-xenograft'}", + "58, in {'context': 'B-in vivo'}", + "59, vivo. {'context': 'I-in vivo'}", + "98, reduce {'effect': 'B-negative'}", + "99, metastasis {'phenotype': 'B-metastasis'}" + ], + "LINK_DATA": [ + "32, xenograft ['l0', 'l1', 'l2', 'l3']", + "33, model ['l0', 'l4', 'l5', 'l6']", + "34, system ['l1', 'l4', 'l7', 'l8']", + "58, in ['l2', 'l5', 'l7', 'l9']", + "59, vivo. ['l3', 'l6', 'l8', 'l9']", + "98, reduce ['l10', 'l11']", + "99, metastasis ['l10', 'l12']", + "100, burden ['l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "reduce" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis" + ] + } + } + ] + }, + { + "PMID": "19584867", + "TEXT": "Bone remodeling depends on the precise coordination of bone resorption and subsequent bone formation. Disturbances of this process are associated with skeletal diseases, such as Camurati-Engelmann disease (CED). We show using in vitro and in vivo models that active TGF-beta1 released during bone resorption coordinates bone formation by inducing migration of bone marrow stromal cells, also known as bone mesenchymal stem cells, to the bone resorptive sites and that this process is mediated through a SMAD signaling pathway. Analyzing mice carrying a CED-derived mutant TGFB1 (encoding TGF-beta1), which show the typical progressive diaphyseal dysplasia seen in the human disease, we found high levels of active TGF-beta1 in the bone marrow. Treatment with a TGF-beta type I receptor inhibitor partially rescued the uncoupled bone remodeling and prevented the fractures. Thus, as TGF-beta1 functions to couple bone resorption and formation, modulation of TGF-beta1 activity could be an effective treatment for bone remodeling diseases.", + "TAG_DATA": [ + "79, mice {'context': 'B-organism'}", + "82, CED-derived {'perturbing_action': 'B-other'}", + "83, mutant {'perturbing_action': 'I-other'}", + "84, TGFB1 {'perturbing_action': 'I-other'}", + "85, (encoding {'perturbing_action': 'I-other'}", + "86, TGF-beta1), {'perturbing_action': 'I-other'}", + "113, TGF-beta {'perturbing_action': 'B-pharmacological inhibition'}", + "114, type {'perturbing_action': 'I-pharmacological inhibition'}", + "115, I {'perturbing_action': 'I-pharmacological inhibition'}", + "116, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "117, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "79, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "82, CED-derived ['l0', 'l5', 'l6', 'l7', 'l8']", + "83, mutant ['l1', 'l5', 'l9', 'l10', 'l11']", + "84, TGFB1 ['l2', 'l6', 'l9', 'l12', 'l13']", + "85, (encoding ['l3', 'l7', 'l10', 'l12', 'l14']", + "86, TGF-beta1), ['l4', 'l8', 'l11', 'l13', 'l14']", + "113, TGF-beta ['l15', 'l16', 'l17', 'l18']", + "114, type ['l15', 'l19', 'l20', 'l21']", + "115, I ['l16', 'l19', 'l22', 'l23']", + "116, receptor ['l17', 'l20', 'l22', 'l24']", + "117, inhibitor ['l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "CED-derived", + "mutant", + "TGFB1", + "(encoding", + "TGF-beta1)," + ] + } + } + ] + }, + { + "PMID": "19525963", + "TEXT": "African green monkeys (genus Chlorocebus) can be infected with species-specific simian immunodeficiency virus (SIVagm) but do not develop AIDS. These natural hosts of SIV, like sooty mangabeys, maintain high levels of SIV replication but have evolved to avoid immunodeficiency. Elucidating the mechanisms that allow natural hosts to coexist with SIV without overt disease may provide crucial information for understanding AIDS pathogenesis. Here we show that many CD4(+) T cells from African green monkeys downregulate CD4 in vivo as they enter the memory pool; that downregulation of CD4 by memory T cells is independent of SIV infection; that the CD4(-) memory T cells maintain functions that are normally attributed to CD4(+) T cells, including production of interleukin-2 (IL-2), production of IL-17, expression of forkhead box P3 and expression of CD40 ligand; that loss of CD4 expression protects these T cells from infection by SIVagm in vivo; and that these CD4(-) T cells can maintain major histocompatibility complex class II restriction. These data show that the absence of SIV-induced disease progression in natural host species may be partially explained by preservation of a subset of T cells that maintain CD4(+) T cell function while being resistant to SIV infection in vivo.", + "TAG_DATA": [ + "66, CD4(+) {'context': 'B-cells'}", + "67, T {'context': 'I-cells'}", + "68, cells {'context': 'I-cells'}", + "70, African {'context': 'B-organism'}", + "71, green {'context': 'I-organism'}", + "72, monkeys {'context': 'I-organism'}", + "75, in {'context': 'B-in vivo'}", + "76, vivo {'context': 'I-in vivo'}", + "88, memory {'context': 'B-cells'}", + "89, T {'context': 'I-cells'}", + "90, cells {'context': 'I-cells'}", + "98, CD4(-) {'context': 'B-cells'}", + "99, memory {'context': 'I-cells'}", + "100, T {'context': 'I-cells'}", + "101, cells {'context': 'I-cells'}", + "131, loss {'perturbing_action': 'B-gene loss-of-function'}", + "132, of {'perturbing_action': 'I-gene loss-of-function'}", + "133, CD4 {'perturbing_action': 'I-gene loss-of-function'}", + "134, expression {'perturbing_action': 'I-gene loss-of-function'}", + "137, T {'context': 'B-cells'}", + "138, cells {'context': 'B-cells'}", + "143, in {'context': 'B-in vivo'}", + "144, vivo; {'context': 'I-in vivo'}", + "148, CD4(-) {'context': 'B-cells'}", + "149, T {'context': 'I-cells'}", + "150, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "66, CD4(+) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "67, T ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "68, cells ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "70, African ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "71, green ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "72, monkeys ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "75, in ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "76, vivo ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "88, memory ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "89, T ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l58', 'l59', 'l60', 'l61']", + "90, cells ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l58', 'l62', 'l63']", + "98, CD4(-) ['l54', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "99, memory ['l55', 'l59', 'l64', 'l71', 'l72', 'l73', 'l74']", + "100, T ['l56', 'l60', 'l62', 'l65', 'l71', 'l75', 'l76']", + "101, cells ['l57', 'l61', 'l63', 'l66', 'l72', 'l75']", + "131, loss ['l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "132, of ['l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "133, CD4 ['l78', 'l84', 'l90', 'l91', 'l92', 'l93', 'l94']", + "134, expression ['l79', 'l85', 'l90', 'l95', 'l96', 'l97', 'l98']", + "137, T ['l67', 'l73', 'l80', 'l86', 'l91', 'l95', 'l99', 'l100', 'l101']", + "138, cells ['l68', 'l74', 'l76', 'l81', 'l87', 'l92', 'l96', 'l99', 'l102', 'l103']", + "143, in ['l69', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l104']", + "144, vivo; ['l70', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l104']", + "148, CD4(-) ['l105', 'l106']", + "149, T ['l105', 'l107']", + "150, cells ['l106', 'l107']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "CD4", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "CD4", + "expression" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo;" + ] + } + } + ] + }, + { + "PMID": "19465928", + "TEXT": "Two distinct helper T (TH) subsets, TH1 and TH17, mediate tissue damage and inflammation in animal models of various immune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases and allergic skin disorders. These experimental findings, and the implication of these TH subsets in human diseases, suggest the need for pharmacological measures to manipulate these TH subsets. Here we show that prostaglandin E2 (PGE2) acting on its receptor EP4 on T cells and dendritic cells not only facilitates TH1 cell differentiation but also amplifies interleukin-23-mediated TH17 cell expansion in vitro. Administration of an EP4-selective antagonist in vivo decreases accumulation of both TH1 and TH17 cells in regional lymph nodes and suppresses the disease progression in mice subjected to experimental autoimmune encephalomyelitis or contact hypersensitivity. Thus, PGE2-EP4 signaling promotes immune inflammation through TH1 differentiation and TH17 expansion, and EP4 antagonism may be therapeutically useful for various immune diseases.", + "TAG_DATA": [ + "71, T {'context': 'B-cells'}", + "72, cells {'context': 'B-cells'}", + "74, dendritic {'context': 'B-cells'}", + "78, facilitates {'effect': 'B-positive'}", + "79, TH1 {'context': 'B-cells'}", + "80, cell {'context': 'I-cells'}", + "81, differentiation {'phenotype': 'B-differentiation'}", + "86, TH17 {'context': 'B-cells'}", + "87, cell {'context': 'I-cells'}", + "89, in {'context': 'B-in vitro'}", + "90, vitro. {'context': 'I-in vitro'}", + "94, EP4-selective {'perturbing_action': 'B-pharmacological inhibition'}", + "95, antagonist {'perturbing_action': 'I-pharmacological inhibition'}", + "96, in {'context': 'B-in vivo'}", + "97, vivo {'context': 'I-in vivo'}", + "102, TH1 {'context': 'B-cells'}", + "103, and {'context': 'I-cells'}", + "104, TH17 {'context': 'I-cells'}", + "105, cells {'context': 'I-cells'}", + "107, regional {'context': 'B-tissue/organ'}", + "108, lymph {'context': 'I-tissue/organ'}", + "109, nodes {'context': 'I-tissue/organ'}", + "116, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "71, T ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "72, cells ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "74, dendritic ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "78, facilitates ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "79, TH1 ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "80, cell ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "81, differentiation ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "86, TH17 ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "87, cell ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "89, in ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "90, vitro. ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "94, EP4-selective ['l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "95, antagonist ['l55', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "96, in ['l56', 'l66', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84']", + "97, vivo ['l57', 'l67', 'l76', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "102, TH1 ['l58', 'l68', 'l77', 'l85', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "103, and ['l59', 'l69', 'l78', 'l86', 'l93', 'l99', 'l100', 'l101', 'l102', 'l103']", + "104, TH17 ['l60', 'l70', 'l79', 'l87', 'l94', 'l99', 'l104', 'l105', 'l106', 'l107']", + "105, cells ['l61', 'l71', 'l80', 'l88', 'l95', 'l100', 'l104', 'l108', 'l109', 'l110']", + "107, regional ['l62', 'l72', 'l81', 'l89', 'l96', 'l101', 'l105', 'l108', 'l111', 'l112']", + "108, lymph ['l63', 'l73', 'l82', 'l90', 'l97', 'l102', 'l106', 'l109', 'l111', 'l113']", + "109, nodes ['l64', 'l74', 'l83', 'l91', 'l98', 'l103', 'l107', 'l110', 'l112', 'l113']", + "116, mice ['l65', 'l75', 'l84', 'l92']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "dendritic", + "TH1", + "cell", + "TH17" + ] + }, + "effect": { + "val": "positive", + "words": [ + "facilitates" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "dendritic", + "TH1", + "cell", + "TH17" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "facilitates" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "facilitates" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EP4-selective", + "antagonist" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EP4-selective", + "antagonist" + ] + }, + "context": { + "val": "cells", + "words": [ + "TH1", + "and", + "TH17", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EP4-selective", + "antagonist" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "regional", + "lymph", + "nodes" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EP4-selective", + "antagonist" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "19448637", + "TEXT": "An imbalance in bone formation relative to bone resorption results in the net bone loss that occurs in osteoporosis and inflammatory bone diseases. Although it is well known how bone resorption is stimulated, the molecular mechanisms that mediate impaired bone formation are poorly understood. Here we show that the time- and stage-specific inhibition of endogenous inhibitor of kappaB kinase (IKK)--nuclear factor-kappaB (NF-kappaB) in differentiated osteoblasts substantially increases trabecular bone mass and bone mineral density without affecting osteoclast activities in young mice. Moreover, inhibition of IKK-NF-kappaB in differentiated osteoblasts maintains bone formation, thereby preventing osteoporotic bone loss induced by ovariectomy in adult mice. Inhibition of IKK-NF-kappaB enhances the expression of Fos-related antigen-1 (Fra-1), an essential transcription factor involved in bone matrix formation in vitro and in vivo. Taken together, our results suggest that targeting IKK-NF-kappaB may help to promote bone formation in the treatment of osteoporosis and other bone diseases.", + "TAG_DATA": [ + "49, time- {'perturbing_action': 'B-pharmacological inhibition'}", + "50, and {'perturbing_action': 'B-pharmacological inhibition'}", + "51, stage-specific {'perturbing_action': 'B-pharmacological inhibition'}", + "52, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "53, of {'perturbing_action': 'I-pharmacological inhibition'}", + "54, endogenous {'perturbing_action': 'I-pharmacological inhibition'}", + "55, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "56, of {'perturbing_action': 'I-pharmacological inhibition'}", + "57, kappaB {'perturbing_action': 'I-pharmacological inhibition'}", + "58, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "59, (IKK)--nuclear {'perturbing_action': 'I-pharmacological inhibition'}", + "60, factor-kappaB {'perturbing_action': 'I-pharmacological inhibition'}", + "61, (NF-kappaB) {'perturbing_action': 'I-pharmacological inhibition'}", + "63, differentiated {'context': 'B-cells'}", + "64, osteoblasts {'context': 'I-cells'}", + "79, young {'context': 'B-organism'}", + "80, mice. {'context': 'I-organism'}", + "82, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "83, of {'perturbing_action': 'I-pharmacological inhibition'}", + "84, IKK-NF-kappaB {'perturbing_action': 'I-pharmacological inhibition'}", + "86, differentiated {'context': 'B-cells'}", + "87, osteoblasts {'context': 'I-cells'}", + "100, adult {'context': 'B-organism'}", + "101, mice. {'context': 'I-organism'}", + "102, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "103, of {'perturbing_action': 'I-pharmacological inhibition'}", + "104, IKK-NF-kappaB {'perturbing_action': 'I-pharmacological inhibition'}", + "121, in {'context': 'B-in vitro'}", + "122, vitro {'context': 'I-in vitro'}", + "124, in {'context': 'B-in vivo'}", + "125, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "49, time- ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "50, and ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "51, stage-specific ['l1', 'l17', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "52, inhibition ['l2', 'l18', 'l33', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "53, of ['l3', 'l19', 'l34', 'l48', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "54, endogenous ['l4', 'l20', 'l35', 'l49', 'l63', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "55, inhibitor ['l5', 'l21', 'l36', 'l50', 'l64', 'l79', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "56, of ['l6', 'l22', 'l37', 'l51', 'l65', 'l80', 'l94', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "57, kappaB ['l7', 'l23', 'l38', 'l52', 'l66', 'l81', 'l95', 'l108', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "58, kinase ['l8', 'l24', 'l39', 'l53', 'l67', 'l82', 'l96', 'l109', 'l120', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "59, (IKK)--nuclear ['l9', 'l25', 'l40', 'l54', 'l68', 'l83', 'l97', 'l110', 'l121', 'l131', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "60, factor-kappaB ['l10', 'l26', 'l41', 'l55', 'l69', 'l84', 'l98', 'l111', 'l122', 'l132', 'l141', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158']", + "61, (NF-kappaB) ['l11', 'l27', 'l42', 'l56', 'l70', 'l85', 'l99', 'l112', 'l123', 'l133', 'l142', 'l150', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "63, differentiated ['l12', 'l28', 'l43', 'l57', 'l71', 'l86', 'l100', 'l113', 'l124', 'l134', 'l143', 'l151', 'l159', 'l166', 'l167', 'l168']", + "64, osteoblasts ['l13', 'l29', 'l44', 'l58', 'l72', 'l87', 'l101', 'l114', 'l125', 'l135', 'l144', 'l152', 'l160', 'l166', 'l169', 'l170']", + "79, young ['l14', 'l30', 'l45', 'l59', 'l73', 'l88', 'l102', 'l115', 'l126', 'l136', 'l145', 'l153', 'l161', 'l167', 'l169', 'l171']", + "80, mice. ['l15', 'l31', 'l46', 'l60', 'l74', 'l89', 'l103', 'l116', 'l127', 'l137', 'l146', 'l154', 'l162', 'l168', 'l170', 'l171']", + "82, inhibition ['l172', 'l173', 'l174', 'l175', 'l176', 'l177']", + "83, of ['l172', 'l178', 'l179', 'l180', 'l181', 'l182']", + "84, IKK-NF-kappaB ['l173', 'l178', 'l183', 'l184', 'l185', 'l186']", + "86, differentiated ['l61', 'l75', 'l90', 'l104', 'l117', 'l128', 'l138', 'l147', 'l155', 'l163', 'l174', 'l179', 'l183', 'l187', 'l188', 'l189']", + "87, osteoblasts ['l16', 'l32', 'l47', 'l62', 'l76', 'l91', 'l105', 'l118', 'l129', 'l139', 'l148', 'l156', 'l164', 'l175', 'l180', 'l184', 'l187', 'l190', 'l191']", + "100, adult ['l77', 'l92', 'l106', 'l157', 'l176', 'l181', 'l185', 'l188', 'l190', 'l192']", + "101, mice. ['l78', 'l93', 'l107', 'l119', 'l130', 'l140', 'l149', 'l158', 'l165', 'l177', 'l182', 'l186', 'l189', 'l191', 'l192']", + "102, Inhibition ['l193', 'l194', 'l195', 'l196', 'l197', 'l198']", + "103, of ['l193', 'l199', 'l200', 'l201', 'l202', 'l203']", + "104, IKK-NF-kappaB ['l194', 'l199', 'l204', 'l205', 'l206', 'l207']", + "121, in ['l195', 'l200', 'l204', 'l208', 'l209', 'l210']", + "122, vitro ['l196', 'l201', 'l205', 'l208', 'l211', 'l212']", + "124, in ['l197', 'l202', 'l206', 'l209', 'l211', 'l213']", + "125, vivo. ['l198', 'l203', 'l207', 'l210', 'l212', 'l213']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "time-", + "and", + "stage-specific", + "inhibition", + "of", + "endogenous", + "inhibitor", + "kappaB", + "kinase", + "(IKK)--nuclear", + "factor-kappaB", + "(NF-kappaB)", + "IKK-NF-kappaB" + ] + }, + "context": { + "val": "cells", + "words": [ + "differentiated", + "osteoblasts" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "time-", + "and", + "stage-specific", + "inhibition", + "of", + "endogenous", + "inhibitor", + "kappaB", + "kinase", + "(IKK)--nuclear", + "factor-kappaB", + "(NF-kappaB)", + "IKK-NF-kappaB" + ] + }, + "context": { + "val": "organism", + "words": [ + "young", + "mice.", + "adult" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "IKK-NF-kappaB" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "IKK-NF-kappaB" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "19448635", + "TEXT": "Activation of osteoclasts and their acidification-dependent resorption of bone is thought to maintain proper serum calcium levels. Here we show that osteoclast dysfunction alone does not generally affect calcium homeostasis. Indeed, mice deficient in Src, encoding a tyrosine kinase critical for osteoclast activity, show signs of osteopetrosis, but without hypocalcemia or defects in bone mineralization. Mice deficient in Cckbr, encoding a gastrin receptor that affects acid secretion by parietal cells, have the expected defects in gastric acidification but also secondary hyperparathyroidism and osteoporosis and modest hypocalcemia. These results suggest that alterations in calcium homeostasis can be driven by defects in gastric acidification, especially given that calcium gluconate supplementation fully rescues the phenotype of the Cckbr-mutant mice. Finally, mice deficient in Tcirg1, encoding a subunit of the vacuolar proton pump specifically expressed in both osteoclasts and parietal cells, show hypocalcemia and osteopetrorickets. Although neither Src- nor Cckbr-deficient mice have this latter phenotype, the combined deficiency of both genes results in osteopetrorickets. Thus, we find that osteopetrosis and osteopetrorickets are distinct phenotypes, depending on the site or sites of defective acidification.", + "TAG_DATA": [ + "31, mice {'context': 'B-organism'}", + "32, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "33, in {'perturbing_action': 'I-gene loss-of-function'}", + "34, Src, {'perturbing_action': 'I-gene loss-of-function'}", + "55, Mice {'context': 'B-organism'}", + "56, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "57, in {'perturbing_action': 'I-gene loss-of-function'}", + "58, Cckbr, {'perturbing_action': 'I-gene loss-of-function'}", + "114, Cckbr-mutant {'perturbing_action': 'B-other'}", + "115, mice. {'context': 'B-organism'}", + "117, mice {'context': 'B-organism'}", + "118, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "119, in {'perturbing_action': 'I-gene loss-of-function'}", + "120, Tcirg1, {'perturbing_action': 'I-gene loss-of-function'}", + "143, Src- {'perturbing_action': 'B-gene loss-of-function'}", + "144, nor {'perturbing_action': 'B-gene loss-of-function'}", + "145, Cckbr-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "146, mice {'context': 'B-organism'}", + "154, of {'perturbing_action': 'I-gene loss-of-function'}", + "155, both {'perturbing_action': 'I-gene loss-of-function'}", + "156, genes {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "31, mice ['l0', 'l1', 'l2']", + "32, deficient ['l0', 'l3', 'l4']", + "33, in ['l1', 'l3', 'l5']", + "34, Src, ['l2', 'l4', 'l5']", + "55, Mice ['l6', 'l7', 'l8']", + "56, deficient ['l6', 'l9', 'l10', 'l11']", + "57, in ['l7', 'l9', 'l12', 'l13']", + "58, Cckbr, ['l8', 'l10', 'l12', 'l14']", + "114, Cckbr-mutant ['l15', 'l16', 'l17', 'l18', 'l19']", + "115, mice. ['l11', 'l13', 'l14', 'l15', 'l20', 'l21']", + "117, mice ['l16', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "118, deficient ['l17', 'l22', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "119, in ['l18', 'l20', 'l23', 'l29', 'l35', 'l36', 'l37', 'l38', 'l39']", + "120, Tcirg1, ['l19', 'l21', 'l24', 'l30', 'l35', 'l40', 'l41', 'l42', 'l43']", + "143, Src- ['l25', 'l31', 'l36', 'l40', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "144, nor ['l26', 'l32', 'l37', 'l41', 'l44', 'l50', 'l51', 'l52', 'l53', 'l54']", + "145, Cckbr-deficient ['l27', 'l33', 'l38', 'l42', 'l45', 'l50', 'l55', 'l56', 'l57', 'l58']", + "146, mice ['l28', 'l34', 'l39', 'l43', 'l46', 'l51', 'l55', 'l59']", + "154, of ['l47', 'l52', 'l56', 'l60', 'l61']", + "155, both ['l48', 'l53', 'l57', 'l60', 'l62']", + "156, genes ['l49', 'l54', 'l58', 'l59', 'l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "Mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "Src,", + "Cckbr,", + "Tcirg1,", + "Src-", + "nor", + "Cckbr-deficient", + "genes" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Cckbr-mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + } + ] + }, + { + "PMID": "19412172", + "TEXT": "Organized neuronal firing is crucial for cortical processing and is disrupted in schizophrenia. Using rapid amplification of 5' complementary DNA ends in human brain, we identified a primate-specific isoform (3.1) of the ether-a-go-go-related K(+) channel KCNH2 that modulates neuronal firing. KCNH2-3.1 messenger RNA levels are comparable to full-length KCNH2 (1A) levels in brain but three orders of magnitude lower in heart. In hippocampus from individuals with schizophrenia, KCNH2-3.1 expression is 2.5-fold greater than KCNH2-1A expression. A meta-analysis of five clinical data sets (367 families, 1,158 unrelated cases and 1,704 controls) shows association of single nucleotide polymorphisms in KCNH2 with schizophrenia. Risk-associated alleles predict lower intelligence quotient scores and speed of cognitive processing, altered memory-linked functional magnetic resonance imaging signals and increased KCNH2-3.1 mRNA levels in postmortem hippocampus. KCNH2-3.1 lacks a domain that is crucial for slow channel deactivation. Overexpression of KCNH2-3.1 in primary cortical neurons induces a rapidly deactivating K(+) current and a high-frequency, nonadapting firing pattern. These results identify a previously undescribed KCNH2 channel isoform involved in cortical physiology, cognition and psychosis, providing a potential new therapeutic drug target.", + "TAG_DATA": [ + "138, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "139, of {'perturbing_action': 'I-gene gain-of-function'}", + "140, KCNH2-3.1 {'perturbing_action': 'I-gene gain-of-function'}", + "142, primary {'context': 'B-cells'}", + "143, cortical {'context': 'I-cells'}", + "144, neurons {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "138, Overexpression ['l0', 'l1', 'l2', 'l3', 'l4']", + "139, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "140, KCNH2-3.1 ['l1', 'l5', 'l9', 'l10', 'l11']", + "142, primary ['l2', 'l6', 'l9', 'l12', 'l13']", + "143, cortical ['l3', 'l7', 'l10', 'l12', 'l14']", + "144, neurons ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "KCNH2-3.1" + ] + }, + "context": { + "val": "cells", + "words": [ + "primary", + "cortical", + "neurons" + ] + } + } + ] + }, + { + "PMID": "19396174", + "TEXT": "Identifying key factors that enhance immune responses is crucial for manipulating immunity to tumors. We show that after a vaccine-induced immune response, adjuvant interleukin-7 (IL-7) improves antitumor responses and survival in an animal model. The improved immune response is associated with increased IL-6 production and augmented T helper type 17 cell differentiation. Furthermore, IL-7 modulates the expression of two ubiquitin ligases: Casitas B-lineage lymphoma b (Cbl-b), a negative regulator of T cell activation, is repressed, and SMAD-specific E3 ubiquitin protein ligase-2 (Smurf2) is enhanced, which antagonizes transforming growth factor-beta signaling. Notably, we show that although short term IL-7 therapy potently enhances vaccine-mediated immunity, in the absence of vaccination it is inefficient in promoting antitumor immune responses, despite inducing homeostatic proliferation of T cells. The ability of adjuvant IL-7 to antagonize inhibitory networks at the cellular and molecular level has major implications for immunotherapy in the treatment of tumors.", + "TAG_DATA": [ + "32, animal {'context': 'B-organism'}", + "33, model. {'context': 'I-organism'}", + "45, augmented {'effect': 'B-positive'}", + "46, T {'context': 'B-cells'}", + "47, helper {'context': 'I-cells'}", + "48, type {'context': 'I-cells'}", + "49, 17 {'context': 'I-cells'}", + "50, cell {'context': 'I-cells'}", + "51, differentiation. {'phenotype': 'B-differentiation'}", + "117, inducing {'effect': 'B-positive'}", + "119, proliferation {'phenotype': 'B-proliferation'}", + "121, T {'context': 'B-cells'}", + "122, cells. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "32, animal ['l0', 'l1', 'l2', 'l3']", + "33, model. ['l0', 'l4', 'l5', 'l6']", + "45, augmented ['l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "46, T ['l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "47, helper ['l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "48, type ['l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "49, 17 ['l1', 'l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "50, cell ['l2', 'l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "51, differentiation. ['l3', 'l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "117, inducing ['l28', 'l29', 'l30']", + "119, proliferation ['l28', 'l31', 'l32']", + "121, T ['l29', 'l31', 'l33']", + "122, cells. ['l30', 'l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "animal", + "model." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "augmented", + "inducing" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "helper", + "type", + "17", + "cell", + "cells." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "augmented" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T", + "helper", + "type", + "17", + "cell" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells." + ] + } + } + ] + }, + { + "PMID": "19169263", + "TEXT": "Systemic and local inflammatory processes have a key, mainly detrimental role in the pathophysiology of ischemic stroke. Currently, little is known about endogenous counterregulatory immune mechanisms. We examined the role of the key immunomodulators CD4(+)CD25(+) forkhead box P3 (Foxp3)(+) regulatory T lymphocytes (T(reg) cells), after experimental brain ischemia. Depletion of T(reg) cells profoundly increased delayed brain damage and deteriorated functional outcome. Absence of T(reg) cells augmented postischemic activation of resident and invading inflammatory cells including microglia and T cells, the main sources of deleterious cerebral tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), respectively. Early antagonization of TNF-alpha and delayed neutralization of IFN-gamma prevented infarct growth in T(reg) cell-depleted mice. Intracerebral interleukin-10 (IL-10) substitution abrogated the cytokine overexpression after T(reg) cell depletion and prevented secondary infarct growth, whereas transfer of IL-10-deficient T(reg) cells in an adoptive transfer model was ineffective. In conclusion, T(reg) cells are major cerebroprotective modulators of postischemic inflammatory brain damage targeting multiple inflammatory pathways. IL-10 signaling is essential for their immunomodulatory effect.", + "TAG_DATA": [ + "48, Depletion {'perturbing_action': 'B-gene loss-of-function'}", + "49, of {'perturbing_action': 'I-gene loss-of-function'}", + "50, T(reg) {'perturbing_action': 'I-gene loss-of-function', 'context': 'B-cells'}", + "51, cells {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-cells'}", + "61, Absence {'perturbing_action': 'B-gene loss-of-function'}", + "62, of {'perturbing_action': 'I-gene loss-of-function'}", + "63, T(reg) {'perturbing_action': 'I-gene loss-of-function'}", + "64, cells {'perturbing_action': 'I-gene loss-of-function'}", + "77, T {'context': 'B-cells'}", + "78, cells, {'context': 'B-cells'}", + "106, T(reg) {'perturbing_action': 'B-gene loss-of-function'}", + "107, cell-depleted {'perturbing_action': 'I-gene loss-of-function'}", + "108, mice. {'context': 'B-organism'}", + "118, T(reg) {'perturbing_action': 'B-gene loss-of-function'}", + "119, cell {'perturbing_action': 'I-gene loss-of-function'}", + "120, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "129, IL-10-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "130, T(reg) {'context': 'B-cells'}", + "131, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "48, Depletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "49, of ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "50, T(reg) ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "51, cells ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "61, Absence ['l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "62, of ['l18', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "63, T(reg) ['l19', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "64, cells ['l3', 'l8', 'l12', 'l15', 'l20', 'l27', 'l33', 'l39', 'l40', 'l41', 'l42', 'l43']", + "77, T ['l4', 'l9', 'l13', 'l16', 'l21', 'l28', 'l34', 'l39', 'l44', 'l45', 'l46']", + "78, cells, ['l5', 'l10', 'l14', 'l17', 'l22', 'l29', 'l35', 'l40', 'l44']", + "106, T(reg) ['l23', 'l30', 'l36', 'l41', 'l47', 'l48']", + "107, cell-depleted ['l24', 'l31', 'l37', 'l42', 'l45', 'l47', 'l49']", + "108, mice. ['l25', 'l32', 'l38', 'l43', 'l46', 'l48', 'l49']", + "118, T(reg) ['l50', 'l51']", + "119, cell ['l50', 'l52']", + "120, depletion ['l51', 'l52']", + "129, IL-10-deficient ['l53', 'l54', 'l55', 'l56']", + "130, T(reg) ['l53', 'l57', 'l58', 'l59']", + "131, cells ['l54', 'l57', 'l60', 'l61']", + "134, adoptive ['l55', 'l58', 'l60', 'l62']", + "135, transfer ['l56', 'l59', 'l61', 'l62']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Depletion", + "of", + "T(reg)", + "cells", + "Absence", + "cell-depleted", + "IL-10-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "T(reg)", + "cells", + "T", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Absence", + "of", + "T(reg)", + "cells", + "cell-depleted" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "19122657", + "TEXT": "Atherosclerosis is characterized by chronic inflammation of the arterial wall due to chemokine-driven mononuclear cell recruitment. Activated platelets can synergize with chemokines to exacerbate atherogenesis; for example, by deposition of the chemokines platelet factor-4 (PF4, also known as CXCL4) and RANTES (CCL5), triggering monocyte arrest on inflamed endothelium. Homo-oligomerization is required for the recruitment functions of CCL5, and chemokine heteromerization has more recently emerged as an additional regulatory mechanism, as evidenced by a mutual modulation of CXCL8 and CXCL4 activities and by enhanced monocyte arrest resulting from CCL5-CXCL4 interactions. The CCL5 antagonist Met-RANTES reduces diet-induced atherosclerosis; however, CCL5 antagonism may not be therapeutically feasible, as suggested by studies using Ccl5-deficient mice which imply that direct CCL5 blockade would severely compromise systemic immune responses, delay macrophage-mediated viral clearance and impair normal T cell functions. Here we determined structural features of CCL5-CXCL4 heteromers and designed stable peptide inhibitors that specifically disrupt proinflammatory CCL5-CXCL4 interactions, thereby attenuating monocyte recruitment and reducing atherosclerosis without the aforementioned side effects. These results establish the in vivo relevance of chemokine heteromers and show the potential of targeting heteromer formation to achieve therapeutic effects.", + "TAG_DATA": [ + "90, CCL5 {'perturbing_action': 'B-pharmacological inhibition'}", + "91, antagonist {'perturbing_action': 'I-pharmacological inhibition'}", + "92, Met-RANTES {'perturbing_action': 'I-pharmacological inhibition'}", + "97, CCL5 {'perturbing_action': 'B-pharmacological inhibition'}", + "98, antagonism {'perturbing_action': 'I-pharmacological inhibition'}", + "109, Ccl5-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "110, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "90, CCL5 ['l0', 'l1', 'l2', 'l3']", + "91, antagonist ['l0', 'l4', 'l5', 'l6']", + "92, Met-RANTES ['l1', 'l4', 'l7', 'l8']", + "97, CCL5 ['l9', 'l10', 'l11']", + "98, antagonism ['l9', 'l12', 'l13']", + "109, Ccl5-deficient ['l2', 'l5', 'l7', 'l10', 'l12', 'l14']", + "110, mice ['l3', 'l6', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CCL5", + "antagonist", + "Met-RANTES", + "antagonism" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ccl5-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "19029982", + "TEXT": "Fibrodysplasia ossificans progressiva (FOP) is a congenital disorder of progressive and widespread postnatal ossification of soft tissues and is without known effective treatments. Affected individuals harbor conserved mutations in the ACVR1 gene that are thought to cause constitutive activation of the bone morphogenetic protein (BMP) type I receptor, activin receptor-like kinase-2 (ALK2). Here we show that intramuscular expression in the mouse of an inducible transgene encoding constitutively active ALK2 (caALK2), resulting from a glutamine to aspartic acid change at amino acid position 207, leads to ectopic endochondral bone formation, joint fusion and functional impairment, thus phenocopying key aspects of human FOP. A selective inhibitor of BMP type I receptor kinases, LDN-193189 (ref. 6), inhibits activation of the BMP signaling effectors SMAD1, SMAD5 and SMAD8 in tissues expressing caALK2 induced by adenovirus specifying Cre (Ad.Cre). This treatment resulted in a reduction in ectopic ossification and functional impairment. In contrast to localized induction of caALK2 by Ad.Cre (which entails inflammation), global postnatal expression of caALK2 (induced without the use of Ad.Cre and thus without inflammation) does not lead to ectopic ossification. However, if in this context an inflammatory stimulus was provided with a control adenovirus, ectopic bone formation was induced. Like LDN-193189, corticosteroid inhibits ossification in Ad.Cre-injected mutant mice, suggesting caALK2 expression and an inflammatory milieu are both required for the development of ectopic ossification in this model. These results support the role of dysregulated ALK2 kinase activity in the pathogenesis of FOP and suggest that small molecule inhibition of BMP type I receptor activity may be useful in treating FOP and heterotopic ossification syndromes associated with excessive BMP signaling.", + "TAG_DATA": [ + "56, intramuscular {'perturbing_action': 'B-gene gain-of-function'}", + "57, expression {'perturbing_action': 'I-gene gain-of-function'}", + "60, mouse {'context': 'B-organism'}", + "61, of {'perturbing_action': 'I-gene gain-of-function'}", + "62, an {'perturbing_action': 'I-gene gain-of-function'}", + "63, inducible {'perturbing_action': 'I-gene gain-of-function'}", + "64, transgene {'perturbing_action': 'I-gene gain-of-function'}", + "65, encoding {'perturbing_action': 'I-gene gain-of-function'}", + "66, constitutively {'perturbing_action': 'I-gene gain-of-function'}", + "67, active {'perturbing_action': 'I-gene gain-of-function'}", + "68, ALK2 {'perturbing_action': 'I-gene gain-of-function'}", + "69, (caALK2), {'perturbing_action': 'I-gene gain-of-function'}", + "70, resulting {'perturbing_action': 'I-gene gain-of-function'}", + "102, selective {'perturbing_action': 'B-pharmacological inhibition'}", + "103, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "104, of {'perturbing_action': 'I-pharmacological inhibition'}", + "105, BMP {'perturbing_action': 'I-pharmacological inhibition'}", + "106, type {'perturbing_action': 'I-pharmacological inhibition'}", + "107, I {'perturbing_action': 'I-pharmacological inhibition'}", + "108, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "109, kinases, {'perturbing_action': 'I-pharmacological inhibition'}", + "110, LDN-193189 {'perturbing_action': 'I-pharmacological inhibition'}", + "111, (ref. {'perturbing_action': 'I-pharmacological inhibition'}", + "125, tissues {'context': 'B-tissue/organ'}", + "126, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "127, caALK2 {'perturbing_action': 'I-gene gain-of-function'}", + "130, adenovirus {'perturbing_action': 'B-gene gain-of-function'}", + "131, specifying {'perturbing_action': 'I-gene gain-of-function'}", + "132, Cre {'perturbing_action': 'I-other'}", + "133, (Ad.Cre). {'perturbing_action': 'I-gene gain-of-function'}", + "158, global {'perturbing_action': 'B-gene gain-of-function'}", + "159, postnatal {'perturbing_action': 'I-gene gain-of-function'}", + "160, expression {'perturbing_action': 'I-gene gain-of-function'}", + "161, of {'perturbing_action': 'I-gene gain-of-function'}", + "162, caALK2 {'perturbing_action': 'I-gene gain-of-function'}", + "194, bone {'phenotype': 'I-tumourigenesis'}", + "195, formation {'phenotype': 'I-tumourigenesis'}", + "197, induced. {'effect': 'B-positive'}", + "204, Ad.Cre-injected {'perturbing_action': 'B-other'}", + "206, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, intramuscular ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "57, expression ['l0', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "60, mouse ['l1', 'l23', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "61, of ['l2', 'l24', 'l45', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "62, an ['l3', 'l25', 'l46', 'l64', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "63, inducible ['l4', 'l26', 'l47', 'l65', 'l84', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "64, transgene ['l5', 'l27', 'l48', 'l66', 'l85', 'l104', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "65, encoding ['l6', 'l28', 'l49', 'l67', 'l86', 'l105', 'l123', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "66, constitutively ['l7', 'l29', 'l50', 'l68', 'l87', 'l106', 'l124', 'l141', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173']", + "67, active ['l8', 'l30', 'l51', 'l69', 'l88', 'l107', 'l125', 'l142', 'l158', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188']", + "68, ALK2 ['l9', 'l31', 'l52', 'l70', 'l89', 'l108', 'l126', 'l143', 'l159', 'l174', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202']", + "69, (caALK2), ['l10', 'l32', 'l53', 'l71', 'l90', 'l109', 'l127', 'l144', 'l160', 'l175', 'l189', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215']", + "70, resulting ['l11', 'l33', 'l54', 'l72', 'l91', 'l110', 'l128', 'l145', 'l161', 'l176', 'l190', 'l203', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227']", + "71, from ['l12', 'l34', 'l55', 'l73', 'l92', 'l111', 'l129', 'l146', 'l162', 'l177', 'l191', 'l204', 'l216', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238']", + "73, glutamine ['l13', 'l35', 'l56', 'l74', 'l93', 'l112', 'l130', 'l147', 'l163', 'l178', 'l192', 'l205', 'l217', 'l228', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248']", + "77, change ['l14', 'l36', 'l57', 'l75', 'l94', 'l113', 'l131', 'l148', 'l164', 'l179', 'l193', 'l206', 'l218', 'l229', 'l239', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257']", + "102, selective ['l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273']", + "103, inhibitor ['l258', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286', 'l287', 'l288']", + "104, of ['l259', 'l274', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302']", + "105, BMP ['l260', 'l275', 'l289', 'l303', 'l304', 'l305', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315']", + "106, type ['l261', 'l276', 'l290', 'l303', 'l316', 'l317', 'l318', 'l319', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327']", + "107, I ['l262', 'l277', 'l291', 'l304', 'l316', 'l328', 'l329', 'l330', 'l331', 'l332', 'l333', 'l334', 'l335', 'l336', 'l337', 'l338']", + "108, receptor ['l263', 'l278', 'l292', 'l305', 'l317', 'l328', 'l339', 'l340', 'l341', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348']", + "109, kinases, ['l264', 'l279', 'l293', 'l306', 'l318', 'l329', 'l339', 'l349', 'l350', 'l351', 'l352', 'l353', 'l354', 'l355', 'l356', 'l357']", + "110, LDN-193189 ['l95', 'l114', 'l132', 'l149', 'l165', 'l180', 'l194', 'l207', 'l219', 'l230', 'l240', 'l249', 'l265', 'l280', 'l294', 'l307', 'l319', 'l330', 'l340', 'l349', 'l358', 'l359', 'l360', 'l361', 'l362', 'l363', 'l364', 'l365']", + "111, (ref. ['l15', 'l37', 'l76', 'l96', 'l115', 'l133', 'l150', 'l166', 'l181', 'l195', 'l208', 'l220', 'l231', 'l241', 'l250', 'l266', 'l281', 'l295', 'l308', 'l320', 'l331', 'l341', 'l350', 'l358', 'l366', 'l367', 'l368', 'l369', 'l370', 'l371', 'l372']", + "125, tissues ['l16', 'l38', 'l58', 'l77', 'l97', 'l116', 'l134', 'l151', 'l167', 'l182', 'l196', 'l209', 'l221', 'l232', 'l242', 'l251', 'l267', 'l282', 'l296', 'l309', 'l321', 'l332', 'l342', 'l351', 'l359', 'l366', 'l373', 'l374', 'l375', 'l376', 'l377', 'l378']", + "126, expressing ['l17', 'l39', 'l59', 'l78', 'l98', 'l117', 'l135', 'l152', 'l168', 'l183', 'l197', 'l210', 'l222', 'l233', 'l243', 'l252', 'l268', 'l283', 'l297', 'l310', 'l322', 'l333', 'l343', 'l352', 'l360', 'l367', 'l373', 'l379', 'l380', 'l381', 'l382', 'l383']", + "127, caALK2 ['l18', 'l40', 'l60', 'l79', 'l99', 'l118', 'l136', 'l153', 'l169', 'l184', 'l198', 'l211', 'l223', 'l234', 'l244', 'l253', 'l269', 'l284', 'l298', 'l311', 'l323', 'l334', 'l344', 'l353', 'l361', 'l368', 'l374', 'l379', 'l384', 'l385', 'l386', 'l387']", + "130, adenovirus ['l19', 'l41', 'l61', 'l80', 'l100', 'l119', 'l137', 'l154', 'l170', 'l185', 'l199', 'l212', 'l224', 'l235', 'l245', 'l254', 'l270', 'l285', 'l299', 'l312', 'l324', 'l335', 'l345', 'l354', 'l362', 'l369', 'l375', 'l380', 'l384', 'l388', 'l389', 'l390']", + "131, specifying ['l20', 'l42', 'l81', 'l101', 'l120', 'l138', 'l155', 'l171', 'l186', 'l200', 'l213', 'l225', 'l236', 'l246', 'l255', 'l271', 'l286', 'l300', 'l313', 'l325', 'l336', 'l346', 'l355', 'l363', 'l370', 'l376', 'l381', 'l385', 'l388', 'l391', 'l392']", + "132, Cre ['l21', 'l43', 'l62', 'l82', 'l102', 'l121', 'l139', 'l156', 'l172', 'l187', 'l201', 'l214', 'l226', 'l237', 'l247', 'l256', 'l272', 'l287', 'l301', 'l314', 'l326', 'l337', 'l347', 'l356', 'l364', 'l371', 'l377', 'l382', 'l386', 'l389', 'l391', 'l393']", + "133, (Ad.Cre). ['l22', 'l44', 'l63', 'l83', 'l103', 'l122', 'l140', 'l157', 'l173', 'l188', 'l202', 'l215', 'l227', 'l238', 'l248', 'l257', 'l273', 'l288', 'l302', 'l315', 'l327', 'l338', 'l348', 'l357', 'l365', 'l372', 'l378', 'l383', 'l387', 'l390', 'l392', 'l393']", + "158, global ['l394', 'l395', 'l396', 'l397', 'l398', 'l399', 'l400']", + "159, postnatal ['l394', 'l401', 'l402', 'l403', 'l404', 'l405', 'l406']", + "160, expression ['l395', 'l401', 'l407', 'l408', 'l409', 'l410', 'l411']", + "161, of ['l396', 'l402', 'l407', 'l412', 'l413', 'l414', 'l415']", + "162, caALK2 ['l397', 'l403', 'l408', 'l412', 'l416', 'l417', 'l418']", + "194, bone ['l398', 'l404', 'l409', 'l413', 'l416', 'l419', 'l420']", + "195, formation ['l399', 'l405', 'l410', 'l414', 'l417', 'l419', 'l421']", + "197, induced. ['l400', 'l406', 'l411', 'l415', 'l418', 'l420', 'l421']", + "204, Ad.Cre-injected ['l422', 'l423']", + "205, mutant ['l422', 'l424']", + "206, mice, ['l423', 'l424']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "intramuscular", + "expression", + "of", + "an", + "inducible", + "transgene", + "encoding", + "constitutively", + "active", + "ALK2", + "(caALK2),", + "resulting", + "expressing", + "caALK2", + "adenovirus", + "(Ad.Cre)." + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "intramuscular", + "expression", + "of", + "an", + "inducible", + "transgene", + "encoding", + "constitutively", + "active", + "ALK2", + "(caALK2),", + "resulting", + "expressing", + "caALK2", + "adenovirus", + "specifying", + "(Ad.Cre)." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tissues" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "mice," + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Cre", + "Ad.Cre-injected" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "inhibitor", + "of", + "BMP", + "type", + "I", + "receptor", + "kinases,", + "LDN-193189", + "(ref." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tissues" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "tissues" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Cre" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "global", + "postnatal", + "expression", + "of", + "caALK2" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "bone", + "formation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "global", + "postnatal", + "expression", + "of", + "caALK2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "bone", + "formation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced." + ] + } + } + ] + }, + { + "PMID": "19029981", + "TEXT": "Somatic mutations that activate phosphoinositide 3-kinase (PI3K) have been identified in the p110-alpha catalytic subunit (encoded by PIK3CA). They are most frequently observed in two hotspots: the helical domain (E545K and E542K) and the kinase domain (H1047R). Although the p110-alpha mutants are transforming in vitro, their oncogenic potential has not been assessed in genetically engineered mouse models. Furthermore, clinical trials with PI3K inhibitors have recently been initiated, and it is unknown if their efficacy will be restricted to specific, genetically defined malignancies. In this study, we engineered a mouse model of lung adenocarcinomas initiated and maintained by expression of p110-alpha H1047R. Treatment of these tumors with NVP-BEZ235, a dual pan-PI3K and mammalian target of rapamycin (mTOR) inhibitor in clinical development, led to marked tumor regression as shown by positron emission tomography-computed tomography, magnetic resonance imaging and microscopic examination. In contrast, mouse lung cancers driven by mutant Kras did not substantially respond to single-agent NVP-BEZ235. However, when NVP-BEZ235 was combined with a mitogen-activated protein kinase kinase (MEK) inhibitor, ARRY-142886, there was marked synergy in shrinking these Kras-mutant cancers. These in vivo studies suggest that inhibitors of the PI3K-mTOR pathway may be active in cancers with PIK3CA mutations and, when combined with MEK inhibitors, may effectively treat KRAS mutated lung cancers.", + "TAG_DATA": [ + "88, mouse {'context': 'B-organism'}", + "89, model {'context': 'I-neoplasm'}", + "90, of {'context': 'I-neoplasm'}", + "91, lung {'context': 'I-neoplasm'}", + "92, adenocarcinomas {'context': 'I-neoplasm'}", + "104, tumors {'context': 'B-neoplasm'}", + "120, led {'effect': 'B-positive'}", + "121, to {'effect': 'I-positive'}", + "123, tumor {'phenotype': 'B-tumour regression'}", + "124, regression {'phenotype': 'I-tumour regression'}", + "140, mouse {'context': 'B-neoplasm'}", + "141, lung {'context': 'I-neoplasm'}", + "142, cancers {'context': 'I-neoplasm'}", + "145, mutant {'perturbing_action': 'B-other'}", + "146, Kras {'perturbing_action': 'I-other'}", + "161, mitogen-activated {'perturbing_action': 'B-pharmacological inhibition'}", + "162, protein {'perturbing_action': 'I-pharmacological inhibition'}", + "163, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "164, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "165, (MEK) {'perturbing_action': 'I-pharmacological inhibition'}", + "166, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "167, ARRY-142886, {'perturbing_action': 'I-pharmacological inhibition'}", + "175, Kras-mutant {'perturbing_action': 'B-other'}", + "176, cancers. {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "88, mouse ['l0', 'l1', 'l2', 'l3', 'l4']", + "89, model ['l0', 'l5', 'l6', 'l7', 'l8']", + "90, of ['l1', 'l5', 'l9', 'l10', 'l11']", + "91, lung ['l2', 'l6', 'l9', 'l12', 'l13']", + "92, adenocarcinomas ['l3', 'l7', 'l10', 'l12', 'l14']", + "104, tumors ['l4', 'l8', 'l11', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "120, led ['l15', 'l19', 'l20', 'l21']", + "121, to ['l16', 'l19', 'l22', 'l23']", + "123, tumor ['l17', 'l20', 'l22', 'l24']", + "124, regression ['l18', 'l21', 'l23', 'l24']", + "140, mouse ['l25', 'l26', 'l27', 'l28']", + "141, lung ['l25', 'l29', 'l30', 'l31']", + "142, cancers ['l26', 'l29', 'l32', 'l33']", + "145, mutant ['l27', 'l30', 'l32', 'l34']", + "146, Kras ['l28', 'l31', 'l33', 'l34']", + "161, mitogen-activated ['l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "162, protein ['l35', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "163, kinase ['l36', 'l43', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "164, kinase ['l37', 'l44', 'l50', 'l56', 'l57', 'l58', 'l59', 'l60']", + "165, (MEK) ['l38', 'l45', 'l51', 'l56', 'l61', 'l62', 'l63', 'l64']", + "166, inhibitor, ['l39', 'l46', 'l52', 'l57', 'l61', 'l65', 'l66', 'l67']", + "167, ARRY-142886, ['l40', 'l47', 'l53', 'l58', 'l62', 'l65', 'l68', 'l69']", + "175, Kras-mutant ['l41', 'l48', 'l54', 'l59', 'l63', 'l66', 'l68', 'l70']", + "176, cancers. ['l42', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l70']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "regression" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "lung", + "cancers", + "cancers." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "Kras", + "Kras-mutant" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mitogen-activated", + "protein", + "kinase", + "(MEK)", + "inhibitor,", + "ARRY-142886," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "cancers." + ] + } + } + ] + }, + { + "PMID": "18978796", + "TEXT": "Genetic and epigenetic plasticity allows tumors to evade single-targeted treatments. Here we direct Bcl2-specific short interfering RNA (siRNA) with 5'-triphosphate ends (3p-siRNA) against melanoma. Recognition of 5'-triphosphate by the cytosolic antiviral helicase retinoic acid-induced protein I (Rig-I, encoded by Ddx58) activated innate immune cells such as dendritic cells and directly induced expression of interferons (IFNs) and apoptosis in tumor cells. These Rig-I-mediated activities synergized with siRNA-mediated Bcl2 silencing to provoke massive apoptosis of tumor cells in lung metastases in vivo. The therapeutic activity required natural killer cells and IFN, as well as silencing of Bcl2, as evidenced by rescue with a mutated Bcl2 target, by site-specific cleavage of Bcl2 messenger RNA in lung metastases and downregulation of Bcl-2 protein in tumor cells in vivo. Together, 3p-siRNA represents a single molecule-based approach in which Rig-I activation on both the immune- and tumor cell level corrects immune ignorance and in which gene silencing corrects key molecular events that govern tumor cell survival.", + "TAG_DATA": [ + "50, induced {'effect': 'B-positive'}", + "56, apoptosis {'phenotype': 'B-apoptosis'}", + "58, tumor {'context': 'B-transformed cells'}", + "59, cells. {'context': 'I-transformed cells'}", + "65, siRNA-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "66, Bcl2 {'perturbing_action': 'I-rnai/knockdown'}", + "67, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "69, provoke {'effect': 'B-positive'}", + "71, apoptosis {'phenotype': 'B-apoptosis'}", + "73, tumor {'context': 'B-transformed cells'}", + "74, cells {'context': 'I-transformed cells'}", + "76, lung {'phenotype': 'B-metastasis'}", + "77, metastases {'phenotype': 'I-metastasis'}", + "78, in {'context': 'B-in vivo'}", + "79, vivo. {'context': 'I-in vivo'}", + "92, silencing {'perturbing_action': 'B-rnai/knockdown'}", + "93, of {'perturbing_action': 'I-rnai/knockdown'}", + "94, Bcl2, {'perturbing_action': 'I-rnai/knockdown'}", + "101, mutated {'perturbing_action': 'B-other'}", + "102, Bcl2 {'perturbing_action': 'I-other'}", + "103, target, {'perturbing_action': 'I-other'}", + "112, lung {'context': 'B-neoplasm', 'phenotype': 'B-metastasis'}", + "113, metastases {'phenotype': 'I-metastasis'}", + "120, tumor {'context': 'B-transformed cells'}", + "121, cells {'context': 'I-transformed cells'}", + "122, in {'context': 'B-in vivo'}", + "123, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "50, induced ['l0', 'l1', 'l2']", + "56, apoptosis ['l0', 'l3', 'l4', 'l5']", + "58, tumor ['l1', 'l3', 'l6', 'l7']", + "59, cells. ['l2', 'l4', 'l6']", + "65, siRNA-mediated ['l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "66, Bcl2 ['l8', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "67, silencing ['l9', 'l18', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "69, provoke ['l10', 'l19', 'l27', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "71, apoptosis ['l11', 'l20', 'l28', 'l35', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "73, tumor ['l12', 'l21', 'l29', 'l36', 'l42', 'l48', 'l49', 'l50', 'l51', 'l52']", + "74, cells ['l5', 'l7', 'l13', 'l22', 'l30', 'l37', 'l43', 'l48', 'l53', 'l54', 'l55', 'l56']", + "76, lung ['l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l53', 'l57', 'l58', 'l59']", + "77, metastases ['l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l57', 'l60', 'l61']", + "78, in ['l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l58', 'l60', 'l62']", + "79, vivo. ['l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l61', 'l62']", + "92, silencing ['l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "93, of ['l63', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "94, Bcl2, ['l64', 'l74', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "101, mutated ['l65', 'l75', 'l84', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "102, Bcl2 ['l66', 'l76', 'l85', 'l93', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "103, target, ['l67', 'l77', 'l86', 'l94', 'l101', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "112, lung ['l68', 'l78', 'l87', 'l95', 'l102', 'l108', 'l114', 'l115', 'l116', 'l117', 'l118']", + "113, metastases ['l69', 'l79', 'l88', 'l96', 'l103', 'l109', 'l114', 'l119', 'l120', 'l121', 'l122']", + "120, tumor ['l70', 'l80', 'l89', 'l97', 'l104', 'l110', 'l115', 'l119', 'l123', 'l124', 'l125']", + "121, cells ['l71', 'l81', 'l90', 'l98', 'l105', 'l111', 'l116', 'l120', 'l123', 'l126', 'l127']", + "122, in ['l72', 'l82', 'l91', 'l99', 'l106', 'l112', 'l117', 'l121', 'l124', 'l126', 'l128']", + "123, vivo. ['l73', 'l83', 'l92', 'l100', 'l107', 'l113', 'l118', 'l122', 'l125', 'l127', 'l128']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced", + "provoke" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "provoke" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells.", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells.", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA-mediated", + "Bcl2", + "silencing" + ] + }, + "effect": { + "val": "positive", + "words": [ + "provoke" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA-mediated", + "Bcl2", + "silencing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA-mediated", + "Bcl2", + "silencing", + "of", + "Bcl2," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA-mediated", + "Bcl2", + "silencing", + "of", + "Bcl2," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "lung", + "metastases" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA-mediated", + "Bcl2", + "silencing", + "of", + "Bcl2," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "provoke" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "lung", + "metastases" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "provoke" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "lung", + "metastases" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "lung", + "metastases" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "of", + "Bcl2," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lung" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "lung" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "Bcl2", + "target," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "Bcl2", + "target," + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "lung", + "metastases" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "Bcl2", + "target," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "Bcl2", + "target," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "18758447", + "TEXT": "Malaria continues to devastate sub-Saharan Africa owing to the emergence of drug resistance to established antimalarials and to the lack of an efficacious vaccine. Plasmodium species have a unique streamlined purine pathway in which the dual specificity enzyme purine nucleoside phosphorylase (PNP) functions in both purine recycling and purine salvage. To evaluate the importance of PNP in an in vivo model of malaria, we disrupted PyPNP, the gene encoding PNP in the lethal Plasmodium yoelii YM strain. P. yoelii parasites lacking PNP were attenuated and cleared in mice. Although able to form gametocytes, PNP-deficient parasites did not form oocysts in mosquito midguts and were not transmitted from mosquitoes to mice. Mice given PNP-deficient parasites were immune to subsequent challenge to a lethal inoculum of P. yoelii YM and to challenge from P. yoelii 17XNL, another strain. These in vivo studies with PNP-deficient parasites support purine salvage as a target for antimalarials. They also suggest a strategy for the development of attenuated nontransmissible metabolic mutants as blood-stage malaria vaccine strains.", + "TAG_DATA": [ + "77, P. {'context': 'B-organism'}", + "78, yoelii {'context': 'I-organism'}", + "79, parasites {'context': 'I-organism'}", + "80, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "81, PNP {'perturbing_action': 'I-gene loss-of-function'}", + "87, mice. {'context': 'B-organism'}", + "93, PNP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "94, parasites {'context': 'B-neoplasm'}", + "100, mosquito {'context': 'B-tissue/organ'}", + "101, midguts {'context': 'I-tissue/organ'}", + "107, mosquitoes {'context': 'B-organism'}", + "109, mice. {'context': 'B-organism'}", + "110, Mice {'context': 'B-organism'}", + "112, PNP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "113, parasites {'context': 'B-neoplasm'}", + "141, PNP-deficient {'perturbing_action': 'B-gene loss-of-function'}" + ], + "LINK_DATA": [ + "77, P. ['l0', 'l1', 'l2', 'l3', 'l4']", + "78, yoelii ['l0', 'l5', 'l6', 'l7', 'l8']", + "79, parasites ['l1', 'l5', 'l9', 'l10', 'l11']", + "80, lacking ['l2', 'l6', 'l9', 'l12', 'l13']", + "81, PNP ['l3', 'l7', 'l10', 'l12', 'l14', 'l15']", + "87, mice. ['l4', 'l8', 'l11', 'l13', 'l14']", + "93, PNP-deficient ['l16', 'l17', 'l18', 'l19', 'l20']", + "94, parasites ['l16', 'l21', 'l22', 'l23', 'l24']", + "100, mosquito ['l17', 'l21', 'l25', 'l26', 'l27']", + "101, midguts ['l15', 'l18', 'l22', 'l25', 'l28', 'l29']", + "107, mosquitoes ['l19', 'l23', 'l26', 'l28', 'l30']", + "109, mice. ['l20', 'l24', 'l27', 'l29', 'l30']", + "110, Mice ['l31', 'l32']", + "112, PNP-deficient ['l31', 'l33']", + "113, parasites ['l32', 'l33']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "P.", + "yoelii", + "parasites", + "mice.", + "mosquitoes", + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "PNP", + "PNP-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PNP", + "PNP-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "midguts", + "mosquito" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PNP-deficient" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "parasites" + ] + } + } + ] + }, + { + "PMID": "18724378", + "TEXT": "Drug resistance acquired by cancer cells has led to treatment failure. To understand the regulatory network underlying docetaxel resistance in breast cancer cells and to identify molecular targets for therapy, we tested small interfering RNAs (siRNAs) against 36 genes whose expression was elevated in human nonresponders to docetaxel for the ability to promote apoptosis of docetaxel-resistant human breast cancer cells (MCF7-ADR cells). The results indicate that the downregulation of the gene encoding ribophorin [corrected] II (RPN2), which is part of an N-oligosaccharyl transferase complex, most efficiently induces apoptosis of MCF7-ADR cells in the presence of docetaxel. RPN2 silencing induced reduced glycosylation of the P-glycoprotein, as well as decreased membrane localization, thereby sensitizing MCF7-ADR cells to docetaxel. Moreover, in vivo delivery of siRNA specific for RPN2 markedly reduced tumor growth in two types of models for drug resistance. Thus, RPN2 silencing makes cancer cells hypersensitive response to docetaxel, and RPN2 might be a new target for RNA interference-based therapeutics against drug resistance.", + "TAG_DATA": [ + "52, promote {'effect': 'B-positive'}", + "53, apoptosis {'phenotype': 'B-apoptosis'}", + "55, docetaxel-resistant {'context': 'B-transformed cells'}", + "56, human {'context': 'I-transformed cells'}", + "57, breast {'context': 'I-transformed cells'}", + "58, cancer {'context': 'I-transformed cells'}", + "59, cells {'context': 'I-transformed cells'}", + "60, (MCF7-ADR {'context': 'I-transformed cells'}", + "61, cells). {'context': 'I-transformed cells'}", + "67, downregulation {'perturbing_action': 'B-rnai/knockdown'}", + "68, of {'perturbing_action': 'I-rnai/knockdown'}", + "69, the {'perturbing_action': 'I-rnai/knockdown'}", + "70, gene {'perturbing_action': 'I-rnai/knockdown'}", + "71, encoding {'perturbing_action': 'I-rnai/knockdown'}", + "72, ribophorin {'perturbing_action': 'I-rnai/knockdown'}", + "73, [corrected] {'perturbing_action': 'I-rnai/knockdown'}", + "74, II {'perturbing_action': 'I-rnai/knockdown'}", + "75, (RPN2), {'perturbing_action': 'I-rnai/knockdown'}", + "86, induces {'effect': 'B-positive'}", + "87, apoptosis {'phenotype': 'B-apoptosis'}", + "89, MCF7-ADR {'context': 'B-transformed cells'}", + "90, cells {'context': 'I-transformed cells'}", + "96, RPN2 {'perturbing_action': 'B-rnai/knockdown'}", + "97, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "112, MCF7-ADR {'context': 'B-transformed cells'}", + "113, cells {'context': 'I-transformed cells'}", + "117, in {'context': 'B-in vivo'}", + "118, vivo {'context': 'I-in vivo'}", + "121, siRNA {'perturbing_action': 'B-rnai/knockdown'}", + "122, specific {'perturbing_action': 'I-rnai/knockdown'}", + "123, for {'perturbing_action': 'I-rnai/knockdown'}", + "124, RPN2 {'perturbing_action': 'I-rnai/knockdown'}", + "126, reduced {'effect': 'B-negative'}", + "127, tumor {'phenotype': 'B-tumour growth'}", + "128, growth {'phenotype': 'I-tumour growth'}", + "138, RPN2 {'perturbing_action': 'B-rnai/knockdown'}", + "139, silencing {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "52, promote ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "53, apoptosis ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "55, docetaxel-resistant ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "56, human ['l2', 'l13', 'l23', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "57, breast ['l3', 'l14', 'l24', 'l35', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "58, cancer ['l4', 'l15', 'l25', 'l36', 'l46', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "59, cells ['l5', 'l16', 'l26', 'l37', 'l47', 'l63', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "60, (MCF7-ADR ['l6', 'l17', 'l27', 'l38', 'l48', 'l64', 'l72', 'l78', 'l79', 'l80', 'l81', 'l82']", + "61, cells). ['l7', 'l18', 'l28', 'l39', 'l49', 'l65', 'l73', 'l78', 'l83', 'l84', 'l85', 'l86']", + "67, downregulation ['l50', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "68, of ['l29', 'l40', 'l51', 'l66', 'l87', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "69, the ['l30', 'l41', 'l52', 'l67', 'l88', 'l101', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "70, gene ['l53', 'l89', 'l102', 'l114', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "71, encoding ['l54', 'l90', 'l103', 'l115', 'l126', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "72, ribophorin ['l55', 'l91', 'l104', 'l116', 'l127', 'l137', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157']", + "73, [corrected] ['l56', 'l92', 'l105', 'l117', 'l128', 'l138', 'l148', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166']", + "74, II ['l57', 'l93', 'l106', 'l118', 'l129', 'l139', 'l149', 'l158', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "75, (RPN2), ['l58', 'l94', 'l107', 'l119', 'l130', 'l140', 'l150', 'l159', 'l167', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181']", + "86, induces ['l8', 'l19', 'l31', 'l42', 'l59', 'l68', 'l74', 'l79', 'l83', 'l95', 'l108', 'l120', 'l131', 'l141', 'l151', 'l160', 'l168', 'l175', 'l182', 'l183', 'l184']", + "87, apoptosis ['l9', 'l20', 'l32', 'l43', 'l60', 'l69', 'l75', 'l80', 'l84', 'l96', 'l109', 'l121', 'l132', 'l142', 'l152', 'l161', 'l169', 'l176', 'l182', 'l185', 'l186']", + "89, MCF7-ADR ['l10', 'l21', 'l33', 'l44', 'l61', 'l70', 'l76', 'l81', 'l85', 'l97', 'l110', 'l122', 'l133', 'l143', 'l153', 'l162', 'l170', 'l177', 'l183', 'l185', 'l187']", + "90, cells ['l11', 'l22', 'l34', 'l45', 'l62', 'l71', 'l77', 'l82', 'l86', 'l98', 'l111', 'l123', 'l134', 'l144', 'l154', 'l163', 'l171', 'l178', 'l184', 'l186', 'l187']", + "96, RPN2 ['l188', 'l189', 'l190']", + "97, silencing ['l145', 'l155', 'l164', 'l172', 'l179', 'l188', 'l191', 'l192']", + "112, MCF7-ADR ['l99', 'l112', 'l124', 'l135', 'l146', 'l156', 'l165', 'l173', 'l180', 'l189', 'l191', 'l193']", + "113, cells ['l100', 'l113', 'l125', 'l136', 'l147', 'l157', 'l166', 'l174', 'l181', 'l190', 'l192', 'l193']", + "117, in ['l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203']", + "118, vivo ['l194', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212']", + "121, siRNA ['l195', 'l204', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220']", + "122, specific ['l196', 'l205', 'l213', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227']", + "123, for ['l197', 'l206', 'l214', 'l221', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233']", + "124, RPN2 ['l198', 'l207', 'l215', 'l222', 'l228', 'l234', 'l235', 'l236', 'l237', 'l238']", + "126, reduced ['l199', 'l208', 'l216', 'l223', 'l229', 'l234', 'l239', 'l240']", + "127, tumor ['l200', 'l209', 'l217', 'l224', 'l230', 'l235', 'l239', 'l241']", + "128, growth ['l201', 'l210', 'l218', 'l225', 'l231', 'l236', 'l240', 'l241']", + "138, RPN2 ['l202', 'l211', 'l219', 'l226', 'l232', 'l237', 'l242']", + "139, silencing ['l203', 'l212', 'l220', 'l227', 'l233', 'l238', 'l242']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promote", + "induces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promote", + "induces" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "docetaxel-resistant", + "human", + "breast", + "cancer", + "cells", + "(MCF7-ADR", + "cells).", + "MCF7-ADR" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "docetaxel-resistant", + "human", + "breast", + "cancer", + "cells", + "(MCF7-ADR", + "cells).", + "MCF7-ADR" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "docetaxel-resistant", + "human", + "breast", + "cancer", + "MCF7-ADR", + "cells" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "the", + "downregulation", + "gene", + "encoding", + "ribophorin", + "[corrected]", + "II", + "(RPN2),", + "RPN2", + "silencing" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "downregulation", + "of", + "the", + "gene", + "encoding", + "ribophorin", + "[corrected]", + "II", + "(RPN2)," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "downregulation", + "of", + "the", + "gene", + "encoding", + "ribophorin", + "[corrected]", + "II", + "(RPN2)," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA", + "specific", + "for", + "RPN2", + "silencing" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA", + "specific", + "for", + "RPN2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA", + "specific", + "for", + "RPN2" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + } + ] + }, + { + "PMID": "18660816", + "TEXT": "Production of bile by the liver is crucial for the absorption of lipophilic nutrients. Dysregulation of bile acid homeostasis can lead to cholestatic liver disease and endoplasmic reticulum (ER) stress. We show by global location analysis ('ChIP-on-chip') and cell type-specific gene ablation that the winged helix transcription factor Foxa2 is required for normal bile acid homeostasis. As suggested by the location analysis, deletion of Foxa2 in hepatocytes in mice using the Cre-lox system leads to decreased transcription of genes encoding bile acid transporters on both the basolateral and canalicular membranes, resulting in intrahepatic cholestasis. Foxa2-deficient mice are strikingly sensitive to a diet containing cholic acid, which results in toxic accumulation of hepatic bile salts, ER stress and liver injury. In addition, we show that expression of FOXA2 is markedly decreased in liver samples from individuals with different cholestatic syndromes, suggesting that reduced FOXA2 abundance could exacerbate the injury.", + "TAG_DATA": [ + "62, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "63, of {'perturbing_action': 'I-gene loss-of-function'}", + "64, Foxa2 {'perturbing_action': 'I-gene loss-of-function'}", + "66, hepatocytes {'context': 'B-cells'}", + "68, mice {'context': 'B-organism'}", + "94, Foxa2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "95, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "62, deletion ['l0', 'l1', 'l2', 'l3']", + "63, of ['l0', 'l4', 'l5', 'l6']", + "64, Foxa2 ['l1', 'l4', 'l7', 'l8']", + "66, hepatocytes ['l2', 'l5', 'l7', 'l9']", + "68, mice ['l3', 'l6', 'l8', 'l9']", + "94, Foxa2-deficient ['l10']", + "95, mice ['l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Foxa2" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Foxa2", + "Foxa2-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "18641659", + "TEXT": "Acidification of the phagosome is considered to be a major mechanism used by macrophages against bacteria, including Mycobacterium tuberculosis (Mtb). Mtb blocks phagosome acidification, but interferon-gamma (IFN-gamma) restores acidification and confers antimycobacterial activity. Nonetheless, it remains unclear whether acid kills Mtb, whether the intrabacterial pH of any pathogen falls when it is in the phagosome and whether acid resistance is required for mycobacterial virulence. In vitro at pH 4.5, Mtb survived in a simple buffer and maintained intrabacterial pH. Therefore, Mtb resists phagolysosomal concentrations of acid. Mtb also maintained its intrabacterial pH and survived when phagocytosed by IFN-gamma-activated macrophages. We used transposon mutagenesis to identify genes responsible for Mtb's acid resistance. A strain disrupted in Rv3671c, a previously uncharacterized gene encoding a membrane-associated protein, was sensitive to acid and failed to maintain intrabacterial pH in acid in vitro and in activated macrophages. Growth of the mutant was also severely attenuated in mice. Thus, Mtb is able to resist acid, owing in large part to Rv3671c, and this resistance is essential for virulence. Disruption of Mtb's acid resistance and intrabacterial pH maintenance systems is an attractive target for chemotherapy.", + "TAG_DATA": [ + "64, In {'context': 'B-in vitro'}", + "65, vitro {'context': 'I-in vitro'}", + "113, disrupted {'perturbing_action': 'B-gene loss-of-function'}", + "114, in {'perturbing_action': 'I-gene loss-of-function'}", + "115, Rv3671c, {'perturbing_action': 'I-gene loss-of-function'}", + "136, in {'context': 'B-in vitro'}", + "137, vitro {'context': 'I-in vitro'}", + "141, macrophages. {'context': 'B-cells'}", + "151, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "64, In ['l0']", + "65, vitro ['l0']", + "113, disrupted ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "114, in ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "115, Rv3671c, ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "136, in ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "137, vitro ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "140, activated ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "141, macrophages. ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "disrupted", + "in", + "Rv3671c," + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "disrupted", + "in", + "Rv3671c," + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages." + ] + } + } + ] + }, + { + "PMID": "18516054", + "TEXT": "The coupling of hemoglobin sensing of physiological oxygen gradients to stimulation of nitric oxide (NO) bioactivity is an established principle of hypoxic blood flow. One mechanism proposed to explain this oxygen-sensing-NO bioactivity linkage postulates an essential role for the conserved Cys93 residue of the hemoglobin beta-chain (betaCys93) and, specifically, for S-nitrosation of betaCys93 to form S-nitrosohemoglobin (SNO-Hb). The SNO-Hb hypothesis, which conceptually links hemoglobin and NO biology, has been debated intensely in recent years. This debate has precluded a consensus on physiological mechanisms and on assessment of the potential role of SNO-Hb in pathology. Here we describe new mouse models that exclusively express either human wild-type hemoglobin or human hemoglobin in which the betaCys93 residue is replaced with alanine to assess the role of SNO-Hb in red blood cell-mediated hypoxic vasodilation. Substitution of this residue, precluding hemoglobin S-nitrosation, did not change total red blood cell S-nitrosothiol abundance but did shift S-nitrosothiol distribution to lower molecular weight species, consistent with the loss of SNO-Hb. Loss of betaCys93 resulted in no deficits in systemic or pulmonary hemodynamics under basal conditions and, notably, did not affect isolated red blood cell-dependent hypoxic vasodilation. These results demonstrate that SNO-Hb is not essential for the physiologic coupling of erythrocyte deoxygenation with increased NO bioactivity in vivo.", + "TAG_DATA": [ + "98, mouse {'context': 'B-organism'}", + "99, models {'context': 'I-organism'}", + "132, of {'perturbing_action': 'I-other'}", + "133, this {'perturbing_action': 'I-other'}", + "134, residue, {'perturbing_action': 'I-other'}", + "142, red {'context': 'B-cells'}", + "143, blood {'context': 'B-cells'}", + "144, cell {'context': 'I-cells'}", + "163, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "164, of {'perturbing_action': 'I-gene loss-of-function'}", + "165, betaCys93 {'perturbing_action': 'I-gene loss-of-function'}", + "184, red {'context': 'B-cells'}", + "185, blood {'context': 'I-cells'}", + "186, cell-dependent {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "98, mouse ['l0']", + "99, models ['l0']", + "131, Substitution ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "132, of ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "133, this ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "134, residue, ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "142, red ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "143, blood ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "144, cell ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']", + "163, Loss ['l22', 'l23', 'l24', 'l25', 'l26']", + "164, of ['l22', 'l27', 'l28', 'l29', 'l30']", + "165, betaCys93 ['l23', 'l27', 'l31', 'l32', 'l33']", + "184, red ['l24', 'l28', 'l31', 'l34', 'l35']", + "185, blood ['l25', 'l29', 'l32', 'l34', 'l36']", + "186, cell-dependent ['l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "of", + "this", + "residue," + ] + }, + "context": { + "val": "cells", + "words": [ + "red", + "blood", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Loss", + "of", + "betaCys93" + ] + }, + "context": { + "val": "cells", + "words": [ + "red", + "blood", + "cell-dependent" + ] + } + } + ] + }, + { + "PMID": "18376409", + "TEXT": "Cell transplantation with embryonic stem (ES) cell progeny requires immunological compatibility with host tissue. 'Therapeutic cloning' is a strategy to overcome this limitation by generating nuclear transfer (nt)ES cells that are genetically matched to an individual. Here we establish the feasibility of treating individual mice via therapeutic cloning. Derivation of 187 ntES cell lines from 24 parkinsonian mice, dopaminergic differentiation, and transplantation into individually matched host mice showed therapeutic efficacy and lack of immunological response.", + "TAG_DATA": [ + "51, ntES {'context': 'B-cells'}", + "52, cell {'context': 'I-cells'}", + "53, lines {'context': 'I-cells'}", + "56, parkinsonian {'context': 'B-organism'}", + "57, mice, {'context': 'I-organism'}", + "59, differentiation, {'phenotype': 'I-differentiation'}", + "66, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "51, ntES ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "52, cell ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "53, lines ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "56, parkinsonian ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "57, mice, ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "59, differentiation, ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "66, mice ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "ntES", + "cell", + "lines" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "parkinsonian", + "mice,", + "mice" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation," + ] + } + } + ] + }, + { + "PMID": "18297084", + "TEXT": "Notch signaling is a key mechanism in the control of embryogenesis. However, its in vivo function during mesenchymal cell differentiation, and, specifically, in bone homeostasis, remains largely unknown. Here, we show that osteoblast-specific gain of Notch function causes severe osteosclerosis owing to increased proliferation of immature osteoblasts. Under these pathological conditions, Notch stimulates early osteoblastic proliferation by upregulating the genes encoding cyclin D, cyclin E and Sp7 (osterix). The intracellular domain of Notch1 also regulates terminal osteoblastic differentiation by directly binding Runx2 and repressing its transactivation function. In contrast, loss of all Notch signaling in osteoblasts, generated by deletion of the genes encoding presenilin-1 and presenilin-2 in bone, is associated with late-onset, age-related osteoporosis, which in turn results from increased osteoblast-dependent osteoclastic activity due to decreased osteoprotegerin mRNA expression in these cells. Together, these findings highlight the potential dimorphic effects of Notch signaling in bone homeostasis and may provide direction for novel therapeutic applications.", + "TAG_DATA": [ + "32, osteoblast-specific {'perturbing_action': 'B-gene gain-of-function'}", + "33, gain {'perturbing_action': 'I-gene gain-of-function'}", + "34, of {'perturbing_action': 'I-gene gain-of-function'}", + "35, Notch {'perturbing_action': 'I-gene gain-of-function'}", + "36, function {'perturbing_action': 'I-gene gain-of-function'}", + "42, increased {'effect': 'B-positive'}", + "43, proliferation {'phenotype': 'B-proliferation'}", + "45, immature {'context': 'B-cells'}", + "46, osteoblasts. {'context': 'I-cells'}", + "52, stimulates {'effect': 'B-positive'}", + "55, proliferation {'phenotype': 'B-proliferation'}", + "95, osteoblasts, {'context': 'B-cells'}", + "98, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "99, of {'perturbing_action': 'I-gene loss-of-function'}", + "100, the {'perturbing_action': 'I-gene loss-of-function'}", + "101, genes {'perturbing_action': 'I-gene loss-of-function'}", + "102, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "103, presenilin-1 {'perturbing_action': 'I-gene loss-of-function'}", + "104, and {'perturbing_action': 'I-gene loss-of-function'}", + "105, presenilin-2 {'perturbing_action': 'I-gene loss-of-function'}", + "106, in {'perturbing_action': 'I-gene loss-of-function'}", + "107, bone, {'perturbing_action': 'I-gene loss-of-function'}", + "131, cells. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "32, osteoblast-specific ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "33, gain ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "34, of ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "35, Notch ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "36, function ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "42, increased ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "43, proliferation ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "45, immature ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "46, osteoblasts. ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "52, stimulates ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "55, proliferation ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "95, osteoblasts, ['l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "98, deletion ['l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70']", + "99, of ['l61', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "100, the ['l62', 'l71', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "101, genes ['l55', 'l63', 'l72', 'l80', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "102, encoding ['l64', 'l73', 'l81', 'l88', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100']", + "103, presenilin-1 ['l56', 'l65', 'l74', 'l82', 'l89', 'l95', 'l101', 'l102', 'l103', 'l104', 'l105']", + "104, and ['l57', 'l66', 'l75', 'l83', 'l90', 'l96', 'l101', 'l106', 'l107', 'l108', 'l109']", + "105, presenilin-2 ['l58', 'l67', 'l76', 'l84', 'l91', 'l97', 'l102', 'l106', 'l110', 'l111', 'l112']", + "106, in ['l59', 'l68', 'l77', 'l85', 'l92', 'l98', 'l103', 'l107', 'l110', 'l113', 'l114']", + "107, bone, ['l60', 'l69', 'l78', 'l86', 'l93', 'l99', 'l104', 'l108', 'l111', 'l113', 'l115']", + "131, cells. ['l70', 'l79', 'l87', 'l94', 'l100', 'l105', 'l109', 'l112', 'l114', 'l115']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "osteoblast-specific", + "gain", + "of", + "Notch", + "function" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "stimulates" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "osteoblast-specific", + "gain", + "of", + "Notch", + "function" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "osteoblast-specific", + "gain", + "of", + "Notch", + "function" + ] + }, + "context": { + "val": "cells", + "words": [ + "immature", + "osteoblasts." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased", + "stimulates" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased", + "stimulates" + ] + }, + "context": { + "val": "cells", + "words": [ + "immature", + "osteoblasts." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "immature", + "osteoblasts." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "osteoblasts,", + "cells." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genes", + "presenilin-1", + "and", + "presenilin-2", + "in", + "bone,", + "deletion", + "of", + "the", + "encoding" + ] + } + } + ] + }, + { + "PMID": "18264108", + "TEXT": "Treatment of neuropathic pain, triggered by multiple insults to the nervous system, is a clinical challenge because the underlying mechanisms of neuropathic pain development remain poorly understood. Most treatments do not differentiate between different phases of neuropathic pain pathophysiology and simply focus on blocking neurotransmission, producing transient pain relief. Here, we report that early- and late-phase neuropathic pain development in rats and mice after nerve injury require different matrix metalloproteinases (MMPs). After spinal nerve ligation, MMP-9 shows a rapid and transient upregulation in injured dorsal root ganglion (DRG) primary sensory neurons consistent with an early phase of neuropathic pain, whereas MMP-2 shows a delayed response in DRG satellite cells and spinal astrocytes consistent with a late phase of neuropathic pain. Local inhibition of MMP-9 by an intrathecal route inhibits the early phase of neuropathic pain, whereas inhibition of MMP-2 suppresses the late phase of neuropathic pain. Further, intrathecal administration of MMP-9 or MMP-2 is sufficient to produce neuropathic pain symptoms. After nerve injury, MMP-9 induces neuropathic pain through interleukin-1beta cleavage and microglial activation at early times, whereas MMP-2 maintains neuropathic pain through interleukin-1beta cleavage and astrocyte activation at later times. Inhibition of MMP may provide a novel therapeutic approach for the treatment of neuropathic pain at different phases.", + "TAG_DATA": [ + "60, rats {'context': 'B-organism'}", + "62, mice {'context': 'B-organism'}", + "84, dorsal {'context': 'B-cells'}", + "85, root {'context': 'I-cells'}", + "86, ganglion {'context': 'I-cells'}", + "87, (DRG) {'context': 'I-cells'}", + "88, primary {'context': 'I-cells'}", + "89, sensory {'context': 'I-cells'}", + "90, neurons {'context': 'I-cells'}", + "106, DRG {'context': 'B-cells'}", + "107, satellite {'context': 'I-cells'}", + "108, cells {'context': 'I-cells'}", + "110, spinal {'context': 'B-cells'}", + "111, astrocytes {'context': 'I-cells'}", + "120, Local {'perturbing_action': 'B-pharmacological inhibition'}", + "121, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "122, of {'perturbing_action': 'I-pharmacological inhibition'}", + "123, MMP-9 {'perturbing_action': 'I-pharmacological inhibition'}", + "124, by {'perturbing_action': 'I-pharmacological inhibition'}", + "126, intrathecal {'perturbing_action': 'I-pharmacological inhibition'}", + "127, route {'perturbing_action': 'I-pharmacological inhibition'}", + "136, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "137, of {'perturbing_action': 'I-pharmacological inhibition'}", + "138, MMP-2 {'perturbing_action': 'I-pharmacological inhibition'}", + "185, astrocyte {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "60, rats ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "62, mice ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "84, dorsal ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "85, root ['l2', 'l9', 'l15', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "86, ganglion ['l3', 'l10', 'l16', 'l26', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "87, (DRG) ['l4', 'l11', 'l17', 'l27', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "88, primary ['l5', 'l12', 'l18', 'l28', 'l37', 'l45', 'l53', 'l54', 'l55']", + "89, sensory ['l6', 'l13', 'l19', 'l29', 'l38', 'l46', 'l53', 'l56', 'l57']", + "90, neurons ['l7', 'l14', 'l20', 'l30', 'l39', 'l47', 'l54', 'l56']", + "106, DRG ['l21', 'l31', 'l40', 'l48', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "107, satellite ['l22', 'l32', 'l41', 'l49', 'l58', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "108, cells ['l23', 'l33', 'l42', 'l50', 'l55', 'l57', 'l59', 'l66', 'l72', 'l73']", + "110, spinal ['l24', 'l34', 'l43', 'l51', 'l60', 'l67', 'l72', 'l74', 'l75', 'l76', 'l77', 'l78']", + "111, astrocytes ['l25', 'l35', 'l44', 'l52', 'l61', 'l68', 'l73', 'l74', 'l79', 'l80', 'l81', 'l82']", + "120, Local ['l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "121, inhibition ['l83', 'l89', 'l90', 'l91', 'l92', 'l93']", + "122, of ['l84', 'l89', 'l94', 'l95', 'l96', 'l97']", + "123, MMP-9 ['l62', 'l69', 'l75', 'l79', 'l85', 'l90', 'l94', 'l98', 'l99', 'l100']", + "124, by ['l63', 'l70', 'l76', 'l80', 'l86', 'l91', 'l95', 'l98', 'l101', 'l102']", + "126, intrathecal ['l64', 'l77', 'l81', 'l87', 'l92', 'l96', 'l99', 'l101', 'l103']", + "127, route ['l65', 'l71', 'l78', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l103']", + "136, inhibition ['l104', 'l105']", + "137, of ['l104', 'l106']", + "138, MMP-2 ['l105', 'l106']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "DRG", + "satellite", + "spinal", + "astrocytes" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "MMP-9", + "by", + "intrathecal", + "route" + ] + } + } + ] + }, + { + "PMID": "18193057", + "TEXT": "Interactions between the herpesvirus entry mediator (HVEM) and the B- and T-lymphocyte attenuator (BTLA) inhibit B and T cell activation. HVEM-BTLA interactions are blocked by herpes simplex virus (HSV) glycoprotein D (gD) through binding of its N-terminal domain to the BTLA binding site of HVEM. In this study, we inserted viral antigens into the C-terminal domain of gD and expressed these antigens with plasmid or E1-deleted (replication-defective) adenovirus vectors. Viral antigens fused to gD induced T and B cell responses to the antigen that were far more potent than those elicited by the same antigen expressed without gD. The immunopotentiating effect required binding of the gD chimeric protein to HVEM. Overall, the studies demonstrate that targeting of antigen to the BTLA binding site of HVEM augments the immunogenicity of vaccines.", + "TAG_DATA": [ + "65, E1-deleted {'perturbing_action': 'B-gene loss-of-function'}", + "66, (replication-defective) {'perturbing_action': 'I-gene loss-of-function'}", + "75, T {'context': 'B-cells'}", + "76, and {'context': 'B-cells'}", + "77, B {'context': 'I-cells'}", + "78, cell {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "65, E1-deleted ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "66, (replication-defective) ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "67, adenovirus ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "68, vectors. ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "75, T ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "76, and ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "77, B ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "78, cell ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "E1-deleted", + "(replication-defective)" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "and", + "B", + "cell" + ] + } + } + ] + }, + { + "PMID": "18157138", + "TEXT": "Recent successes in treating genetic immunodeficiencies have demonstrated the therapeutic potential of stem cell gene therapy. However, the use of gammaretroviral vectors in these trials led to insertional activation of nearby oncogenes and leukemias in some study subjects, prompting studies of modified or alternative vector systems. Here we describe the use of foamy virus vectors to treat canine leukocyte adhesion deficiency (CLAD). Four of five dogs with CLAD that received nonmyeloablative conditioning and infusion of autologous, CD34+ hematopoietic stem cells transduced by a foamy virus vector expressing canine CD18 had complete reversal of the CLAD phenotype, which was sustained more than 2 years after infusion. In vitro assays showed correction of the lymphocyte proliferation and neutrophil adhesion defects that characterize CLAD. There were no genotoxic complications, and integration site analysis showed polyclonality of transduced cells and a decreased risk of integration near oncogenes as compared to gammaretroviral vectors. These results represent the first successful use of a foamy virus vector to treat a genetic disease, to our knowledge, and suggest that foamy virus vectors will be effective in treating human hematopoietic diseases.", + "TAG_DATA": [ + "65, dogs {'context': 'B-organism'}", + "75, autologous, {'perturbing_action': 'I-gene gain-of-function'}", + "76, CD34+ {'context': 'I-cells'}", + "77, hematopoietic {'context': 'I-cells'}", + "78, stem {'context': 'I-cells'}", + "79, cells {'context': 'I-cells'}", + "80, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "81, by {'perturbing_action': 'I-gene gain-of-function'}", + "82, a {'perturbing_action': 'I-gene gain-of-function'}", + "83, foamy {'perturbing_action': 'I-gene gain-of-function'}", + "84, virus {'perturbing_action': 'I-gene gain-of-function'}", + "85, vector {'perturbing_action': 'I-gene gain-of-function'}", + "86, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "87, canine {'perturbing_action': 'I-gene gain-of-function'}", + "88, CD18 {'perturbing_action': 'I-gene gain-of-function'}", + "105, In {'context': 'B-in vitro'}", + "106, vitro {'context': 'I-in vitro'}", + "109, correction {'effect': 'B-regulates'}", + "112, lymphocyte {'context': 'B-cells'}", + "113, proliferation {'phenotype': 'B-proliferation'}", + "116, adhesion {'phenotype': 'B-adhesion'}", + "134, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "65, dogs ['l0', 'l1', 'l2']", + "75, autologous, ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "76, CD34+ ['l3', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "77, hematopoietic ['l0', 'l4', 'l19', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "78, stem ['l1', 'l5', 'l20', 'l36', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63']", + "79, cells ['l2', 'l6', 'l21', 'l37', 'l51', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "80, transduced ['l7', 'l22', 'l38', 'l52', 'l64', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "81, by ['l8', 'l23', 'l39', 'l53', 'l65', 'l76', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "82, a ['l9', 'l24', 'l40', 'l54', 'l66', 'l77', 'l90', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114']", + "83, foamy ['l10', 'l25', 'l41', 'l55', 'l67', 'l78', 'l91', 'l103', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "84, virus ['l11', 'l26', 'l42', 'l56', 'l68', 'l79', 'l92', 'l104', 'l115', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "85, vector ['l12', 'l27', 'l43', 'l57', 'l69', 'l80', 'l93', 'l105', 'l116', 'l126', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "86, expressing ['l13', 'l28', 'l44', 'l58', 'l70', 'l81', 'l94', 'l106', 'l117', 'l127', 'l136', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152']", + "87, canine ['l14', 'l29', 'l45', 'l59', 'l71', 'l82', 'l95', 'l107', 'l118', 'l128', 'l137', 'l145', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159']", + "88, CD18 ['l15', 'l30', 'l46', 'l60', 'l72', 'l83', 'l96', 'l108', 'l119', 'l129', 'l138', 'l146', 'l153', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "105, In ['l84', 'l97', 'l109', 'l120', 'l130', 'l139', 'l147', 'l154', 'l160', 'l166', 'l167', 'l168', 'l169', 'l170']", + "106, vitro ['l31', 'l85', 'l98', 'l110', 'l121', 'l131', 'l140', 'l148', 'l155', 'l161', 'l166', 'l171', 'l172', 'l173', 'l174']", + "109, correction ['l32', 'l47', 'l86', 'l99', 'l111', 'l122', 'l132', 'l141', 'l149', 'l156', 'l162', 'l167', 'l171', 'l175', 'l176', 'l177']", + "112, lymphocyte ['l16', 'l33', 'l48', 'l61', 'l73', 'l87', 'l100', 'l112', 'l123', 'l133', 'l142', 'l150', 'l157', 'l163', 'l168', 'l172', 'l175', 'l178', 'l179']", + "113, proliferation ['l17', 'l34', 'l49', 'l62', 'l74', 'l88', 'l101', 'l113', 'l124', 'l134', 'l143', 'l151', 'l158', 'l164', 'l169', 'l173', 'l176', 'l178', 'l180']", + "116, adhesion ['l18', 'l35', 'l50', 'l63', 'l75', 'l89', 'l102', 'l114', 'l125', 'l135', 'l144', 'l152', 'l159', 'l165', 'l170', 'l174', 'l177', 'l179', 'l180']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "autologous,", + "transduced", + "by", + "a", + "foamy", + "virus", + "vector", + "expressing", + "canine", + "CD18" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD34+", + "hematopoietic", + "stem", + "cells", + "lymphocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "autologous,", + "transduced", + "by", + "a", + "foamy", + "virus", + "vector", + "expressing", + "canine", + "CD18" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "autologous,", + "transduced", + "by", + "a", + "foamy", + "virus", + "vector", + "expressing", + "canine", + "CD18" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD34+", + "hematopoietic", + "lymphocyte" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "correction" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD34+", + "hematopoietic", + "stem", + "cells", + "lymphocyte" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD34+", + "hematopoietic", + "stem", + "cells", + "lymphocyte" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "by", + "a", + "foamy", + "virus", + "vector", + "expressing", + "canine", + "CD18" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "by", + "a", + "foamy", + "virus", + "vector", + "expressing", + "canine", + "CD18" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "correction" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "correction" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "correction" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "correction" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + } + ] + }, + { + "PMID": "18084301", + "TEXT": "Podocyte dysfunction, represented by foot process effacement and proteinuria, is often the starting point for progressive kidney disease. Therapies aimed at the cellular level of the disease are currently not available. Here we show that induction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement and urinary protein loss via a mechanism that includes lipid-dependent activation of alphavbeta3 integrin. Mice lacking uPAR (Plaur-/-) are protected from lipopolysaccharide (LPS)-mediated proteinuria but develop disease after expression of a constitutively active beta3 integrin. Gene transfer studies reveal a prerequisite for uPAR expression in podocytes, but not in endothelial cells, for the development of LPS-mediated proteinuria. Mechanistically, uPAR is required to activate alphavbeta3 integrin in podocytes, promoting cell motility and activation of the small GTPases Cdc42 and Rac1. Blockade of alphavbeta3 integrin reduces podocyte motility in vitro and lowers proteinuria in mice. Our findings show a physiological role for uPAR signaling in the regulation of kidney permeability.", + "TAG_DATA": [ + "62, Mice {'context': 'B-organism'}", + "63, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "64, uPAR {'perturbing_action': 'I-gene loss-of-function'}", + "65, (Plaur-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "114, podocytes, {'context': 'B-cells'}", + "115, promoting {'effect': 'B-positive'}", + "116, cell {'context': 'B-cells'}", + "117, motility {'phenotype': 'B-migration'}", + "127, Blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "128, of {'perturbing_action': 'I-pharmacological inhibition'}", + "129, alphavbeta3 {'perturbing_action': 'I-pharmacological inhibition'}", + "130, integrin {'perturbing_action': 'I-pharmacological inhibition'}", + "131, reduces {'effect': 'B-negative'}", + "132, podocyte {'context': 'B-cells'}", + "134, in {'context': 'B-in vitro'}", + "135, vitro {'context': 'I-in vitro'}", + "140, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "62, Mice ['l0', 'l1', 'l2']", + "63, lacking ['l0', 'l3', 'l4']", + "64, uPAR ['l1', 'l3', 'l5']", + "65, (Plaur-/-) ['l2', 'l4', 'l5']", + "114, podocytes, ['l6', 'l7', 'l8', 'l9']", + "115, promoting ['l6', 'l10', 'l11']", + "116, cell ['l7', 'l10', 'l12']", + "117, motility ['l8', 'l11', 'l12']", + "127, Blockade ['l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "128, of ['l13', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "129, alphavbeta3 ['l14', 'l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "130, integrin ['l15', 'l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "131, reduces ['l9', 'l16', 'l23', 'l29', 'l34', 'l39', 'l40', 'l41']", + "132, podocyte ['l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l43', 'l44']", + "134, in ['l18', 'l25', 'l31', 'l36', 'l40', 'l42', 'l45']", + "135, vitro ['l19', 'l26', 'l32', 'l37', 'l41', 'l43', 'l45']", + "140, mice. ['l20', 'l27', 'l33', 'l38', 'l44']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "uPAR", + "(Plaur-/-)" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "podocytes,", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "podocytes,", + "cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "motility" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "podocytes,", + "podocyte" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "motility" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "alphavbeta3", + "integrin" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "alphavbeta3", + "integrin" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocyte" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "alphavbeta3", + "integrin" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "alphavbeta3", + "integrin" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "18066076", + "TEXT": "In many common cancers, dissemination of secondary tumors via the lymph nodes poses the most significant threat to the affected individual. Metastatic cells often reach the lymph nodes by mimicking the molecular mechanisms used by hematopoietic cells to traffic to peripheral lymphoid organs. Therefore, we exploited naive T cell trafficking in order to chaperone an oncolytic virus to lymphoid organs harboring metastatic cells. Metastatic burden was initially reduced by viral oncolysis and was then eradicated, as tumor cell killing in the lymph node and spleen generated protective antitumor immunity. Lymph node purging of tumor cells was possible even in virus-immune mice. Adoptive transfer of normal T cells loaded with oncolytic virus into individuals with cancer would be technically easy to implement both to reduce the distribution of metastases and to vaccinate the affected individual in situ against micrometastatic disease. As such, this adoptive transfer could have a great therapeutic impact, in the adjuvant setting, on many different cancer types.", + "TAG_DATA": [ + "63, Metastatic {'phenotype': 'B-metastasis'}", + "64, burden {'phenotype': 'I-metastasis'}", + "67, reduced {'effect': 'B-negative'}", + "76, tumor {'context': 'B-transformed cells'}", + "77, cell {'context': 'I-transformed cells'}", + "81, lymph {'context': 'B-tissue/organ'}", + "82, node {'context': 'B-tissue/organ'}", + "84, spleen {'context': 'B-tissue/organ'}", + "93, tumor {'context': 'B-transformed cells'}", + "94, cells {'context': 'I-transformed cells'}", + "100, mice. {'context': 'B-organism'}", + "104, normal {'context': 'B-cells'}", + "105, T {'context': 'I-cells'}", + "106, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "63, Metastatic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "64, burden ['l0', 'l7', 'l8', 'l9', 'l10']", + "67, reduced ['l1', 'l7', 'l11', 'l12', 'l13', 'l14']", + "76, tumor ['l2', 'l8', 'l11', 'l15', 'l16', 'l17', 'l18']", + "77, cell ['l3', 'l9', 'l12', 'l15', 'l19', 'l20', 'l21']", + "81, lymph ['l4', 'l13', 'l16', 'l19', 'l22', 'l23']", + "82, node ['l5', 'l10', 'l14', 'l17', 'l20', 'l22', 'l24']", + "84, spleen ['l6', 'l18', 'l21', 'l23', 'l24']", + "93, tumor ['l25', 'l26']", + "94, cells ['l25', 'l27']", + "100, mice. ['l26', 'l27']", + "104, normal ['l28', 'l29']", + "105, T ['l28', 'l30']", + "106, cells ['l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "metastasis", + "words": [ + "Metastatic", + "burden" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "Metastatic", + "burden" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "Metastatic", + "burden" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lymph", + "node", + "spleen" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lymph", + "node" + ] + } + } + ] + }, + { + "PMID": "18037895", + "TEXT": "Metastasis is the primary cause of mortality from cancer, but the mechanisms leading to metastasis are poorly understood. In particular, relatively little is known about metastasis in cancers of mesenchymal origins, which are known as sarcomas. Approximately ten proteins have been characterized as 'metastasis suppressors', but how these proteins function and are regulated is, in general, not well understood. Gp78 (also known as AMFR or RNF45) is a RING finger E3 ubiquitin ligase that is integral to the endoplasmic reticulum (ER) and involved in ER-associated degradation (ERAD) of diverse substrates. Here we report that expression of gp78 has a causal role in the metastasis of an aggressive human sarcoma and that this prometastatic activity requires the E3 activity of gp78. Further, gp78 associates with and targets the transmembrane metastasis suppressor, KAI1 (also known as CD82), for degradation. Suppression of gp78 increases KAI1 abundance and reduces the metastatic potential of tumor cells, an effect that is largely blocked by concomitant suppression of KAI1. An inverse relationship between these proteins was confirmed in a human sarcoma tissue microarray. Whereas most previous efforts have focused on genetic mechanisms for the loss of metastasis suppressor genes, our results provide new evidence for post-translational downregulation of a metastasis suppressor by its ubiquitin ligase, resulting in abrogation of its metastasis-suppressing effects.", + "TAG_DATA": [ + "137, Suppression {'perturbing_action': 'B-pharmacological inhibition'}", + "138, of {'perturbing_action': 'I-pharmacological inhibition'}", + "139, gp78 {'perturbing_action': 'I-pharmacological inhibition'}", + "144, reduces {'effect': 'B-negative'}", + "146, metastatic {'phenotype': 'B-metastasis'}", + "147, potential {'phenotype': 'I-metastasis'}", + "149, tumor {'context': 'B-transformed cells'}", + "150, cells, {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "137, Suppression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "138, of ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "139, gp78 ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "144, reduces ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "146, metastatic ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "147, potential ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "149, tumor ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "150, cells, ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Suppression", + "of", + "gp78" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Suppression", + "of", + "gp78" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "potential" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Suppression", + "of", + "gp78" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "potential" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells," + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastatic", + "potential" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells," + ] + } + } + ] + }, + { + "PMID": "17965720", + "TEXT": "Autosomal dominant polycystic kidney disease is an important cause of end-stage renal disease, for which there is no proven therapy. Mutations in PKD1 (the gene encoding polycystin-1) are the principal cause of this disease. The disease begins in utero and is slowly progressive, but it is not known whether cystogenesis is an ongoing process during adult life. We now show that inactivation of Pkd1 in mice before postnatal day 13 results in severely cystic kidneys within 3 weeks, whereas inactivation at day 14 and later results in cysts only after 5 months. We found that cellular proliferation was not appreciably higher in cystic specimens than in age-matched controls, but the abrupt change in response to Pkd1 inactivation corresponded to a previously unrecognized brake point during renal growth and significant changes in gene expression. These findings suggest that the effects of Pkd1 inactivation are defined by a developmental switch that signals the end of the terminal renal maturation process. Our studies show that Pkd1 regulates tubular morphology in both developing and adult kidney, but the pathologic consequences of inactivation are defined by the organ's developmental status. These results have important implications for clinical understanding of the disease and therapeutic approaches.", + "TAG_DATA": [ + "61, inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "62, of {'perturbing_action': 'I-gene loss-of-function'}", + "63, Pkd1 {'perturbing_action': 'I-gene loss-of-function'}", + "65, mice {'context': 'B-organism'}", + "74, kidneys {'context': 'B-tissue/organ'}", + "96, proliferation {'phenotype': 'B-proliferation'}", + "115, Pkd1 {'perturbing_action': 'B-gene loss-of-function'}", + "116, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "140, Pkd1 {'perturbing_action': 'B-gene loss-of-function'}", + "141, inactivation {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "61, inactivation ['l0', 'l1', 'l2', 'l3']", + "62, of ['l0', 'l4', 'l5', 'l6']", + "63, Pkd1 ['l1', 'l4', 'l7', 'l8']", + "65, mice ['l2', 'l5', 'l7', 'l9']", + "74, kidneys ['l3', 'l6', 'l8', 'l9']", + "115, Pkd1 ['l10']", + "116, inactivation ['l10']", + "140, Pkd1 ['l11']", + "141, inactivation ['l11']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "Pkd1" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "Pkd1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "kidneys" + ] + } + } + ] + }, + { + "PMID": "17922010", + "TEXT": "Histone/protein deacetylases (HDACs) regulate chromatin remodeling and gene expression as well as the functions of more than 50 transcription factors and nonhistone proteins. We found that administration of an HDAC inhibitor (HDACi) in vivo increased Foxp3 gene expression, as well as the production and suppressive function of regulatory T cells (T(reg) cells). Although T(reg) cells express multiple HDACs, HDAC9 proved particularly important in regulating Foxp3-dependent suppression. Optimal T(reg) function required acetylation of several lysines in the forkhead domain of Foxp3, and Foxp3 acetylation enhanced binding of Foxp3 to the Il2 promoter and suppressed endogenous IL-2 production. HDACi therapy in vivo enhanced T(reg)-mediated suppression of homeostatic proliferation, decreased inflammatory bowel disease through T(reg)-dependent effects, and, in conjunction with a short course of low-dose rapamycin, induced permanent, T(reg)-dependent cardiac and islet allograft survival and donor-specific allograft tolerance. Our data show that use of HDACi allows the beneficial pharmacologic enhancement of both the numbers and suppressive function of Foxp3(+) T(reg) cells.", + "TAG_DATA": [ + "32, in {'context': 'B-in vivo'}", + "33, vivo {'context': 'I-in vivo'}", + "47, regulatory {'context': 'B-cells'}", + "48, T {'context': 'I-cells'}", + "49, cells {'context': 'I-cells'}", + "50, (T(reg) {'context': 'I-cells'}", + "51, cells). {'context': 'I-cells'}", + "98, in {'context': 'B-in vivo'}", + "99, vivo {'context': 'I-in vivo'}", + "105, proliferation, {'phenotype': 'B-proliferation'}", + "126, cardiac {'context': 'B-xenograft'}", + "127, and {'context': 'I-xenograft'}", + "128, islet {'context': 'I-xenograft'}", + "129, allograft {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "32, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "33, vivo ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "47, regulatory ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "48, T ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "49, cells ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "50, (T(reg) ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "51, cells). ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "98, in ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "99, vivo ['l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "102, suppression ['l22', 'l28', 'l34']", + "105, proliferation, ['l23', 'l29', 'l34']", + "126, cardiac ['l24', 'l30', 'l35', 'l36', 'l37', 'l38']", + "127, and ['l25', 'l31', 'l35', 'l39', 'l40', 'l41']", + "128, islet ['l26', 'l32', 'l36', 'l39', 'l42', 'l43']", + "129, allograft ['l27', 'l33', 'l37', 'l40', 'l42', 'l44']", + "133, allograft ['l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + } + ] + }, + { + "PMID": "17694068", + "TEXT": "The serine/threonine kinase Akt mediates mitogenic and anti-apoptotic responses that result from activation of multiple signaling cascades. It is considered a key determinant of tumor aggressiveness and is a major target for anticancer drug development. Here, we describe a new reporter molecule whose bioluminescence activity within live cells and in mice can be used to measure Akt activity. Akt activity in cultured cells and tumor xenografts was monitored quantitatively and dynamically in response to activation or inhibition of receptor tyrosine kinase, inhibition of phosphoinositide 3-kinase, or direct inhibition of Akt. The results provide unique insights into the pharmacokinetics and pharmacodynamics of agents that modulate Akt activity, revealing the usefulness of this reporter for rapid dose and schedule optimization in the drug development process.", + "TAG_DATA": [ + "61, cultured {'context': 'B-cells'}", + "62, cells {'context': 'I-cells'}", + "64, tumor {'context': 'B-xenograft'}", + "65, xenografts {'context': 'I-xenograft'}", + "76, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "77, of {'perturbing_action': 'I-pharmacological inhibition'}", + "78, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "79, tyrosine {'perturbing_action': 'I-pharmacological inhibition'}", + "80, kinase, {'perturbing_action': 'I-pharmacological inhibition'}", + "86, direct {'perturbing_action': 'B-pharmacological inhibition'}", + "87, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "88, of {'perturbing_action': 'I-pharmacological inhibition'}", + "89, Akt. {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "61, cultured ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "62, cells ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "64, tumor ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "65, xenografts ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "76, inhibition ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "77, of ['l4', 'l11', 'l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "78, receptor ['l5', 'l12', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "79, tyrosine ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "80, kinase, ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']", + "86, direct ['l36', 'l37', 'l38']", + "87, inhibition ['l36', 'l39', 'l40']", + "88, of ['l37', 'l39', 'l41']", + "89, Akt. ['l38', 'l40', 'l41']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cultured", + "cells" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "receptor", + "tyrosine", + "kinase," + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "tumor", + "xenografts" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "receptor", + "tyrosine", + "kinase," + ] + } + } + ] + }, + { + "PMID": "17676052", + "TEXT": "Soft tissue sarcomas are mesenchymal tumors that are fatal in approximately one-third of patients. To explore mechanisms of sarcoma pathogenesis, we have generated a mouse model of soft tissue sarcoma. Intramuscular delivery of an adenovirus expressing Cre recombinase in mice with conditional mutations in Kras and Trp53 was sufficient to initiate high-grade sarcomas with myofibroblastic differentiation. Like human sarcomas, these tumors show a predilection for lung rather than lymph node metastasis. Using this model, we showed that a prototype handheld imaging device can identify residual tumor during intraoperative molecular imaging. Deletion of the Ink4a-Arf locus (Cdkn2a), but not Bak1 and Bax, could substitute for mutation of Trp53 in this model. Deletion of Bak1 and Bax, however, was able to substitute for mutation of Trp53 in the development of sinonasal adenocarcinoma. Therefore, the intrinsic pathway of apoptosis seems sufficient to mediate p53 tumor suppression in an epithelial cancer, but not in this model of soft tissue sarcoma.", + "TAG_DATA": [ + "24, mouse {'context': 'B-organism'}", + "25, model {'context': 'I-organism'}", + "34, adenovirus {'perturbing_action': 'B-gene loss-of-function'}", + "35, expressing {'perturbing_action': 'I-gene loss-of-function'}", + "36, Cre {'perturbing_action': 'I-gene loss-of-function'}", + "37, recombinase {'perturbing_action': 'I-gene loss-of-function'}", + "39, mice {'context': 'B-organism'}", + "41, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "42, mutations {'perturbing_action': 'I-gene loss-of-function'}", + "43, in {'perturbing_action': 'I-gene loss-of-function'}", + "44, Kras {'perturbing_action': 'I-gene loss-of-function'}", + "45, and {'perturbing_action': 'I-gene loss-of-function'}", + "46, Trp53 {'perturbing_action': 'I-gene loss-of-function'}", + "50, initiate {'effect': 'B-positive'}", + "51, high-grade {'phenotype': 'B-tumourigenesis'}", + "52, sarcomas {'phenotype': 'I-tumourigenesis'}", + "54, myofibroblastic {'phenotype': 'B-differentiation'}", + "55, differentiation. {'phenotype': 'I-differentiation'}", + "90, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "91, of {'perturbing_action': 'I-gene loss-of-function'}", + "92, the {'perturbing_action': 'I-gene loss-of-function'}", + "93, Ink4a-Arf {'perturbing_action': 'I-gene loss-of-function'}", + "94, locus {'perturbing_action': 'I-gene loss-of-function'}", + "95, (Cdkn2a), {'perturbing_action': 'I-gene loss-of-function'}", + "110, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "111, of {'perturbing_action': 'I-gene loss-of-function'}", + "112, Bak1 {'perturbing_action': 'I-gene loss-of-function'}", + "113, and {'perturbing_action': 'I-gene loss-of-function'}", + "114, Bax, {'perturbing_action': 'I-gene loss-of-function'}", + "128, sinonasal {'context': 'B-neoplasm'}", + "129, adenocarcinoma. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "24, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "25, model ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "34, adenovirus ['l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "35, expressing ['l11', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "36, Cre ['l12', 'l26', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "37, recombinase ['l13', 'l27', 'l40', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "39, mice ['l14', 'l28', 'l41', 'l53', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "41, conditional ['l15', 'l29', 'l42', 'l54', 'l65', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "42, mutations ['l16', 'l30', 'l43', 'l55', 'l66', 'l76', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "43, in ['l17', 'l31', 'l44', 'l56', 'l67', 'l77', 'l86', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "44, Kras ['l18', 'l32', 'l45', 'l57', 'l68', 'l78', 'l87', 'l95', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "45, and ['l19', 'l33', 'l46', 'l58', 'l69', 'l79', 'l88', 'l96', 'l103', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "46, Trp53 ['l20', 'l34', 'l47', 'l59', 'l70', 'l80', 'l89', 'l97', 'l104', 'l110', 'l116', 'l117', 'l118', 'l119', 'l120']", + "50, initiate ['l1', 'l6', 'l21', 'l35', 'l48', 'l60', 'l71', 'l81', 'l90', 'l98', 'l105', 'l111', 'l116', 'l121', 'l122', 'l123', 'l124']", + "51, high-grade ['l2', 'l7', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l99', 'l106', 'l112', 'l117', 'l121', 'l125', 'l126', 'l127']", + "52, sarcomas ['l3', 'l8', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l92', 'l100', 'l107', 'l113', 'l118', 'l122', 'l125', 'l128', 'l129']", + "54, myofibroblastic ['l4', 'l9', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l93', 'l101', 'l108', 'l114', 'l119', 'l123', 'l126', 'l128', 'l130']", + "55, differentiation. ['l5', 'l10', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l115', 'l120', 'l124', 'l127', 'l129', 'l130']", + "90, Deletion ['l131', 'l132', 'l133', 'l134', 'l135']", + "91, of ['l131', 'l136', 'l137', 'l138', 'l139']", + "92, the ['l132', 'l136', 'l140', 'l141', 'l142']", + "93, Ink4a-Arf ['l133', 'l137', 'l140', 'l143', 'l144']", + "94, locus ['l134', 'l138', 'l141', 'l143', 'l145']", + "95, (Cdkn2a), ['l135', 'l139', 'l142', 'l144', 'l145']", + "110, Deletion ['l146', 'l147', 'l148', 'l149', 'l150', 'l151']", + "111, of ['l146', 'l152', 'l153', 'l154', 'l155', 'l156']", + "112, Bak1 ['l147', 'l152', 'l157', 'l158', 'l159', 'l160']", + "113, and ['l148', 'l153', 'l157', 'l161', 'l162', 'l163']", + "114, Bax, ['l149', 'l154', 'l158', 'l161', 'l164', 'l165']", + "128, sinonasal ['l150', 'l155', 'l159', 'l162', 'l164', 'l166']", + "129, adenocarcinoma. ['l151', 'l156', 'l160', 'l163', 'l165', 'l166']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "high-grade", + "sarcomas" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "mice" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "myofibroblastic", + "differentiation." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adenovirus", + "expressing", + "Cre", + "recombinase", + "conditional", + "mutations", + "in", + "Kras", + "and", + "Trp53" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adenovirus", + "expressing", + "Cre", + "recombinase", + "conditional", + "mutations", + "in", + "Kras", + "and", + "Trp53" + ] + }, + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adenovirus", + "expressing", + "Cre", + "recombinase", + "conditional", + "mutations", + "in", + "Kras", + "and", + "Trp53" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "high-grade", + "sarcomas" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adenovirus", + "expressing", + "Cre", + "recombinase", + "conditional", + "mutations", + "in", + "Kras", + "and", + "Trp53" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "myofibroblastic", + "differentiation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "high-grade", + "sarcomas" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "myofibroblastic", + "differentiation." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "Bak1", + "and", + "Bax," + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "sinonasal", + "adenocarcinoma." + ] + } + } + ] + }, + { + "PMID": "17676051", + "TEXT": "Acne rosacea is an inflammatory skin disease that affects 3% of the US population over 30 years of age and is characterized by erythema, papulopustules and telangiectasia. The etiology of this disorder is unknown, although symptoms are exacerbated by factors that trigger innate immune responses, such as the release of cathelicidin antimicrobial peptides. Here we show that individuals with rosacea express abnormally high levels of cathelicidin in their facial skin and that the proteolytically processed forms of cathelicidin peptides found in rosacea are different from those present in normal individuals. These cathelicidin peptides are a result of a post-translational processing abnormality associated with an increase in stratum corneum tryptic enzyme (SCTE) in the epidermis. In mice, injection of the cathelicidin peptides found in rosacea, addition of SCTE, and increasing protease activity by targeted deletion of the serine protease inhibitor gene Spink5 each increases inflammation in mouse skin. The role of cathelicidin in enabling SCTE-mediated inflammation is verified in mice with a targeted deletion of Camp, the gene encoding cathelicidin. These findings confirm the role of cathelicidin in skin inflammatory responses and suggest an explanation for the pathogenesis of rosacea by demonstrating that an exacerbated innate immune response can reproduce elements of this disease.", + "TAG_DATA": [ + "115, mice, {'context': 'B-organism'}", + "132, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "133, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "134, of {'perturbing_action': 'I-gene loss-of-function'}", + "135, the {'perturbing_action': 'I-gene loss-of-function'}", + "136, serine {'perturbing_action': 'I-gene loss-of-function'}", + "137, protease {'perturbing_action': 'I-gene loss-of-function'}", + "138, inhibitor {'perturbing_action': 'I-gene loss-of-function'}", + "139, gene {'perturbing_action': 'I-gene loss-of-function'}", + "140, Spink5 {'perturbing_action': 'I-gene loss-of-function'}", + "145, mouse {'context': 'B-tissue/organ'}", + "146, skin. {'context': 'I-tissue/organ'}", + "158, mice {'context': 'B-organism'}", + "161, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "162, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "163, of {'perturbing_action': 'I-gene loss-of-function'}", + "164, Camp, {'perturbing_action': 'I-gene loss-of-function'}", + "165, the {'perturbing_action': 'I-gene loss-of-function'}", + "166, gene {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "132, targeted ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "133, deletion ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "134, of ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "135, the ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "136, serine ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "137, protease ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "138, inhibitor ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "139, gene ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "140, Spink5 ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "145, mouse ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "146, skin. ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "158, mice ['l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "161, targeted ['l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "162, deletion ['l56', 'l61', 'l66', 'l67', 'l68', 'l69']", + "163, of ['l57', 'l62', 'l66', 'l70', 'l71', 'l72']", + "164, Camp, ['l58', 'l63', 'l67', 'l70', 'l73', 'l74']", + "165, the ['l59', 'l64', 'l68', 'l71', 'l73', 'l75']", + "166, gene ['l60', 'l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "deletion", + "of", + "the", + "serine", + "protease", + "inhibitor", + "gene", + "Spink5" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "skin." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "targeted", + "deletion", + "of", + "Camp,", + "the", + "gene" + ] + } + } + ] + }, + { + "PMID": "17660828", + "TEXT": "Cardiac fibrosis, associated with a decreased extent of microvasculature and with disruption of normal myocardial structures, results from excessive deposition of extracellular matrix, which is mediated by the recruitment of fibroblasts. The source of these fibroblasts is unclear and specific anti-fibrotic therapies are not currently available. Here we show that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart. Transforming growth factor-beta1 (TGF-beta1) induced endothelial cells to undergo EndMT, whereas bone morphogenic protein 7 (BMP-7) preserved the endothelial phenotype. The systemic administration of recombinant human BMP-7 (rhBMP-7) significantly inhibited EndMT and the progression of cardiac fibrosis in mouse models of pressure overload and chronic allograft rejection. Our findings show that EndMT contributes to the progression of cardiac fibrosis and that rhBMP-7 can be used to inhibit EndMT and to intervene in the progression of chronic heart disease associated with fibrosis.", + "TAG_DATA": [ + "87, induced {'effect': 'B-positive'}", + "88, endothelial {'context': 'B-cells'}", + "89, cells {'context': 'I-cells'}", + "92, EndMT, {'phenotype': 'B-epithelial-mesenchymal transition'}", + "112, inhibited {'effect': 'B-negative'}", + "113, EndMT {'phenotype': 'B-epithelial-mesenchymal transition'}", + "121, mouse {'context': 'B-organism'}", + "122, models {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "87, induced ['l0', 'l1', 'l2']", + "88, endothelial ['l0', 'l3', 'l4']", + "89, cells ['l1', 'l3', 'l5']", + "92, EndMT, ['l2', 'l4', 'l5']", + "112, inhibited ['l6', 'l7', 'l8']", + "113, EndMT ['l6', 'l9', 'l10']", + "121, mouse ['l7', 'l9', 'l11']", + "122, models ['l8', 'l10', 'l11']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EndMT," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EndMT," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EndMT" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + } + }, + { + "phenotype": { + "val": "epithelial-mesenchymal transition", + "words": [ + "EndMT" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models" + ] + } + } + ] + }, + { + "PMID": "17589519", + "TEXT": "Tumor cells have a dysregulated cell cycle that may render their proliferation especially sensitive to the inhibition of cyclin-dependent kinases (CDKs), important regulators of cell cycle progression. We examined the effects of CDK1 inhibition in the context of different oncogenic signals. Cells transformed with MYC, but not cells transformed by a panel of other activated oncogenes, rapidly underwent apoptosis when treated with small-molecule CDK1 inhibitors. The inhibitor of apoptosis protein BIRC5 (survivin), a known CDK1 target, is required for the survival of cells overexpressing MYC. Inhibition of CDK1 rapidly downregulates survivin expression and induces MYC-dependent apoptosis. CDK1 inhibitor treatment of MYC-dependent mouse lymphoma and hepatoblastoma tumors decreased tumor growth and prolonged their survival. As there are no effective small-molecule inhibitors that selectively target the MYC pathway, we propose that CDK1 inhibition might therefore be useful in the treatment of human malignancies that overexpress MYC.", + "TAG_DATA": [ + "41, Cells {'context': 'B-cells'}", + "47, cells {'context': 'B-cells'}", + "57, underwent {'effect': 'B-positive'}", + "58, apoptosis {'phenotype': 'B-apoptosis'}", + "62, small-molecule {'perturbing_action': 'B-pharmacological inhibition'}", + "63, CDK1 {'perturbing_action': 'I-pharmacological inhibition'}", + "64, inhibitors. {'perturbing_action': 'I-pharmacological inhibition'}", + "82, cells {'context': 'B-cells'}", + "85, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "86, of {'perturbing_action': 'I-pharmacological inhibition'}", + "87, CDK1 {'perturbing_action': 'I-pharmacological inhibition'}", + "93, induces {'effect': 'B-positive'}", + "95, apoptosis. {'phenotype': 'B-apoptosis'}", + "96, CDK1 {'perturbing_action': 'B-pharmacological inhibition'}", + "97, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "98, treatment {'perturbing_action': 'I-pharmacological inhibition'}", + "100, MYC-dependent {'context': 'B-neoplasm'}", + "101, mouse {'context': 'I-neoplasm'}", + "102, lymphoma {'context': 'I-neoplasm'}", + "104, hepatoblastoma {'context': 'B-neoplasm'}", + "105, tumors {'context': 'I-neoplasm'}", + "106, decreased {'effect': 'B-negative'}", + "107, tumor {'phenotype': 'B-tumour growth'}", + "108, growth {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "41, Cells ['l0']", + "47, cells ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "57, underwent ['l1', 'l12', 'l13', 'l14', 'l15']", + "58, apoptosis ['l2', 'l12', 'l16', 'l17', 'l18', 'l19']", + "62, small-molecule ['l3', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "63, CDK1 ['l4', 'l20', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "64, inhibitors. ['l5', 'l16', 'l21', 'l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "82, cells ['l0', 'l6', 'l13', 'l17', 'l22', 'l29', 'l35', 'l41', 'l42']", + "85, Inhibition ['l7', 'l23', 'l30', 'l36', 'l43', 'l44', 'l45', 'l46']", + "86, of ['l8', 'l24', 'l31', 'l37', 'l43', 'l47', 'l48', 'l49']", + "87, CDK1 ['l9', 'l25', 'l32', 'l38', 'l44', 'l47', 'l50', 'l51']", + "93, induces ['l10', 'l14', 'l18', 'l26', 'l33', 'l39', 'l41', 'l45', 'l48', 'l50', 'l52']", + "95, apoptosis. ['l11', 'l15', 'l19', 'l27', 'l34', 'l40', 'l42', 'l46', 'l49', 'l51', 'l52']", + "96, CDK1 ['l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "97, inhibitor ['l53', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "98, treatment ['l54', 'l63', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "100, MYC-dependent ['l55', 'l64', 'l72', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "101, mouse ['l56', 'l65', 'l73', 'l80', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "102, lymphoma ['l57', 'l66', 'l74', 'l81', 'l87', 'l93', 'l94', 'l95', 'l96', 'l97']", + "104, hepatoblastoma ['l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l98', 'l99', 'l100', 'l101']", + "105, tumors ['l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l102', 'l103', 'l104']", + "106, decreased ['l60', 'l69', 'l77', 'l84', 'l90', 'l95', 'l99', 'l102', 'l105', 'l106']", + "107, tumor ['l61', 'l70', 'l78', 'l85', 'l91', 'l96', 'l100', 'l103', 'l105', 'l107']", + "108, growth ['l62', 'l71', 'l79', 'l86', 'l92', 'l97', 'l101', 'l104', 'l106', 'l107']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "underwent", + "induces" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "CDK1", + "inhibitors.", + "Inhibition", + "of" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "underwent", + "induces" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis." + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors.", + "small-molecule", + "CDK1", + "Inhibition", + "of" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "CDK1", + "inhibitors.", + "Inhibition", + "of" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK1", + "inhibitor", + "treatment" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "MYC-dependent", + "mouse", + "lymphoma", + "hepatoblastoma", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK1", + "inhibitor", + "treatment" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK1", + "inhibitor", + "treatment" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "MYC-dependent", + "mouse", + "lymphoma", + "hepatoblastoma", + "tumors" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "MYC-dependent", + "mouse", + "lymphoma", + "hepatoblastoma", + "tumors" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + } + ] + }, + { + "PMID": "17546038", + "TEXT": "Mast cells contribute importantly to allergic and innate immune responses by releasing various preformed and newly synthesized mediators. Previous studies have shown mast cell accumulation in human atherosclerotic lesions. This report establishes the direct participation of mast cells in atherogenesis in low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice. Atheromata from compound mutant Ldlr(-/-) Kit(W-sh)(/W-sh) mice showed decreased lesion size, lipid deposition, T-cell and macrophage numbers, cell proliferation and apoptosis, but increased collagen content and fibrous cap development. In vivo, adoptive transfer of syngeneic wild-type or tumor necrosis factor (TNF)-alpha-deficient mast cells restored atherogenesis to Ldlr(-/-)Kit(W-sh/W-sh) mice. Notably, neither interleukin (IL)-6- nor interferon (IFN)-gamma-deficient mast cells did so, indicating that the inhibition of atherogenesis in Ldlr(-/-)Kit(W-sh/W-sh) mice resulted from the absence of mast cells and mast cell-derived IL-6 and IFN-gamma. Compared with wild-type or TNF-alpha-deficient mast cells, those lacking IL-6 or IFN-gamma did not induce expression of proatherogenic cysteine proteinase cathepsins from vascular cells in vitro or affect cathepsin and matrix metalloproteinase activities in atherosclerotic lesions, implying that mast cell-derived IL-6 and IFN-gamma promote atherogenesis by augmenting the expression of matrix-degrading proteases. These observations establish direct participation of mast cells and mast cell-derived IL-6 and IFN-gamma in mouse atherogenesis and provide new mechanistic insight into the pathogenesis of this common disease.", + "TAG_DATA": [ + "41, low-density {'perturbing_action': 'B-gene loss-of-function'}", + "43, receptor-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "44, (Ldlr(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "45, mice. {'context': 'B-organism'}", + "48, compound {'perturbing_action': 'B-other'}", + "49, mutant {'perturbing_action': 'I-other'}", + "50, Ldlr(-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "51, Kit(W-sh)(/W-sh) {'perturbing_action': 'I-gene loss-of-function'}", + "52, mice {'context': 'B-organism'}", + "54, decreased {'effect': 'B-negative'}", + "59, T-cell {'context': 'B-cells'}", + "60, and {'context': 'I-cells'}", + "61, macrophage {'context': 'I-cells'}", + "63, cell {'context': 'B-cells'}", + "64, proliferation {'phenotype': 'B-proliferation'}", + "66, apoptosis, {'phenotype': 'B-apoptosis'}", + "75, In {'context': 'B-in vivo'}", + "76, vivo, {'context': 'I-in vivo'}", + "83, tumor {'perturbing_action': 'B-gene loss-of-function'}", + "84, necrosis {'perturbing_action': 'I-gene loss-of-function'}", + "85, factor {'perturbing_action': 'I-gene loss-of-function'}", + "86, (TNF)-alpha-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "87, mast {'context': 'B-cells'}", + "88, cells {'context': 'I-cells'}", + "92, Ldlr(-/-)Kit(W-sh/W-sh) {'perturbing_action': 'B-gene loss-of-function'}", + "93, mice. {'context': 'B-organism'}", + "101, mast {'context': 'B-cells'}", + "102, cells {'context': 'I-cells'}", + "112, Ldlr(-/-)Kit(W-sh/W-sh) {'perturbing_action': 'B-gene loss-of-function'}", + "113, mice {'context': 'B-organism'}", + "119, mast {'context': 'B-cells'}", + "120, cells {'context': 'I-cells'}", + "131, TNF-alpha-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "132, mast {'context': 'B-cells'}", + "133, cells, {'context': 'I-cells'}", + "136, IL-6 {'perturbing_action': 'I-gene loss-of-function'}", + "138, IFN-gamma {'perturbing_action': 'I-gene loss-of-function'}", + "149, vascular {'context': 'B-cells'}", + "150, cells {'context': 'I-cells'}", + "151, in {'context': 'B-in vitro'}", + "152, vitro {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "41, low-density ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "43, receptor-deficient ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "44, (Ldlr(-/-)) ['l1', 'l17', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "45, mice. ['l2', 'l18', 'l32', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "48, compound ['l3', 'l19', 'l33', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "49, mutant ['l4', 'l20', 'l34', 'l46', 'l57', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "50, Ldlr(-/-) ['l5', 'l21', 'l35', 'l47', 'l58', 'l70', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "51, Kit(W-sh)(/W-sh) ['l6', 'l22', 'l36', 'l48', 'l59', 'l71', 'l82', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "52, mice ['l7', 'l23', 'l37', 'l49', 'l60', 'l72', 'l83', 'l93', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "54, decreased ['l8', 'l24', 'l38', 'l50', 'l61', 'l73', 'l84', 'l94', 'l103', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "59, T-cell ['l9', 'l25', 'l39', 'l51', 'l62', 'l74', 'l85', 'l95', 'l104', 'l110', 'l116', 'l117', 'l118', 'l119', 'l120']", + "60, and ['l10', 'l26', 'l40', 'l52', 'l63', 'l75', 'l86', 'l96', 'l105', 'l111', 'l116', 'l121', 'l122', 'l123', 'l124']", + "61, macrophage ['l11', 'l27', 'l41', 'l53', 'l64', 'l76', 'l87', 'l97', 'l106', 'l112', 'l117', 'l121', 'l125', 'l126', 'l127']", + "63, cell ['l12', 'l28', 'l42', 'l54', 'l65', 'l77', 'l88', 'l98', 'l107', 'l113', 'l118', 'l122', 'l125', 'l128', 'l129']", + "64, proliferation ['l13', 'l29', 'l43', 'l55', 'l66', 'l78', 'l89', 'l99', 'l108', 'l114', 'l119', 'l123', 'l126', 'l128', 'l130']", + "66, apoptosis, ['l14', 'l30', 'l44', 'l56', 'l67', 'l79', 'l90', 'l100', 'l109', 'l115', 'l120', 'l124', 'l127', 'l129', 'l130']", + "75, In ['l15', 'l68', 'l80', 'l91', 'l101', 'l131', 'l132']", + "76, vivo, ['l16', 'l31', 'l45', 'l69', 'l81', 'l92', 'l102', 'l131']", + "83, tumor ['l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "84, necrosis ['l133', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "85, factor ['l134', 'l144', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162']", + "86, (TNF)-alpha-deficient ['l135', 'l145', 'l154', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170']", + "87, mast ['l136', 'l146', 'l155', 'l163', 'l171', 'l172', 'l173']", + "88, cells ['l132', 'l137', 'l147', 'l156', 'l164', 'l171', 'l174', 'l175']", + "92, Ldlr(-/-)Kit(W-sh/W-sh) ['l138', 'l148', 'l157', 'l165', 'l172', 'l174', 'l176', 'l177', 'l178', 'l179']", + "93, mice. ['l139', 'l149', 'l158', 'l166', 'l173', 'l175', 'l176']", + "101, mast ['l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189']", + "102, cells ['l180', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197']", + "112, Ldlr(-/-)Kit(W-sh/W-sh) ['l140', 'l150', 'l159', 'l167', 'l181', 'l190', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "113, mice ['l141', 'l151', 'l160', 'l168', 'l177', 'l182', 'l191', 'l198', 'l205', 'l206', 'l207']", + "119, mast ['l142', 'l152', 'l161', 'l169', 'l178', 'l183', 'l192', 'l199', 'l205', 'l208', 'l209', 'l210', 'l211', 'l212']", + "120, cells ['l143', 'l153', 'l162', 'l170', 'l179', 'l184', 'l193', 'l200', 'l206', 'l208', 'l213', 'l214']", + "131, TNF-alpha-deficient ['l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222']", + "132, mast ['l215', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229']", + "133, cells, ['l216', 'l223', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235']", + "136, IL-6 ['l217', 'l224', 'l230', 'l236', 'l237', 'l238', 'l239', 'l240']", + "138, IFN-gamma ['l185', 'l218', 'l225', 'l231', 'l236', 'l241', 'l242', 'l243', 'l244']", + "149, vascular ['l186', 'l194', 'l201', 'l209', 'l213', 'l219', 'l226', 'l232', 'l237', 'l241', 'l245', 'l246', 'l247']", + "150, cells ['l187', 'l195', 'l202', 'l207', 'l210', 'l214', 'l220', 'l227', 'l233', 'l238', 'l242', 'l245', 'l248', 'l249']", + "151, in ['l188', 'l196', 'l203', 'l211', 'l221', 'l228', 'l234', 'l239', 'l243', 'l246', 'l248', 'l250']", + "152, vitro ['l189', 'l197', 'l204', 'l212', 'l222', 'l229', 'l235', 'l240', 'l244', 'l247', 'l249', 'l250']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "low-density", + "receptor-deficient", + "(Ldlr(-/-))", + "Ldlr(-/-)", + "Kit(W-sh)(/W-sh)", + "tumor", + "necrosis", + "factor", + "(TNF)-alpha-deficient", + "Ldlr(-/-)Kit(W-sh/W-sh)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "low-density", + "receptor-deficient", + "(Ldlr(-/-))", + "Ldlr(-/-)", + "Kit(W-sh)(/W-sh)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "low-density", + "receptor-deficient", + "(Ldlr(-/-))", + "Ldlr(-/-)", + "Kit(W-sh)(/W-sh)", + "tumor", + "necrosis", + "factor", + "(TNF)-alpha-deficient", + "Ldlr(-/-)Kit(W-sh/W-sh)", + "IFN-gamma", + "TNF-alpha-deficient", + "IL-6" + ] + }, + "context": { + "val": "cells", + "words": [ + "T-cell", + "and", + "macrophage", + "cell", + "mast", + "cells", + "vascular", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "low-density", + "receptor-deficient", + "(Ldlr(-/-))", + "Ldlr(-/-)", + "Kit(W-sh)(/W-sh)" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "low-density", + "receptor-deficient", + "(Ldlr(-/-))", + "Ldlr(-/-)", + "Kit(W-sh)(/W-sh)" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "low-density", + "receptor-deficient", + "(Ldlr(-/-))", + "Ldlr(-/-)", + "Kit(W-sh)(/W-sh)" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "compound" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "compound", + "mutant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "compound", + "mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "T-cell", + "and", + "macrophage", + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "compound", + "mutant" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "compound", + "mutant" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "compound", + "mutant" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "context": { + "val": "cells", + "words": [ + "T-cell", + "and", + "macrophage", + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T-cell", + "and", + "macrophage", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T-cell", + "and", + "macrophage", + "cell" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ldlr(-/-)Kit(W-sh/W-sh)", + "TNF-alpha-deficient", + "IL-6", + "IFN-gamma" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "17515895", + "TEXT": "Calcineurin is a calcium-activated serine/threonine phosphatase critical to a number of developmental processes in the cardiovascular, nervous and immune systems. In the T-cell lineage, calcineurin activation is important for pre-T-cell receptor (TCR) signaling, TCR-mediated positive selection of thymocytes into mature T cells, and many aspects of the immune response. The critical role of calcineurin in the immune response is underscored by the fact that calcineurin inhibitors, such as cyclosporin A (CsA) and FK506, are powerful immunosuppressants in wide clinical use. We observed sustained calcineurin activation in human B- and T-cell lymphomas and in all mouse models of lymphoid malignancies analyzed. In intracellular NOTCH1 (ICN1)- and TEL-JAK2-induced T-cell lymphoblastic leukemia, two mouse models relevant to human malignancies, in vivo inhibition of calcineurin activity by CsA or FK506 induced apoptosis of leukemic cells and rapid tumor clearance, and substantially prolonged mouse survival. In contrast, ectopic expression of a constitutively activated mutant of calcineurin favored leukemia progression. Moreover, CsA treatment induced apoptosis in human lymphoma and leukemia cell lines. Thus, calcineurin activation is critical for the maintenance of the leukemic phenotype in vivo, identifying this pathway as a relevant therapeutic target in lymphoid malignancies.", + "TAG_DATA": [ + "86, human {'context': 'B-neoplasm'}", + "87, B- {'context': 'I-neoplasm'}", + "88, and {'context': 'I-neoplasm'}", + "89, T-cell {'context': 'I-neoplasm'}", + "90, lymphomas {'context': 'I-neoplasm'}", + "94, mouse {'context': 'B-neoplasm'}", + "95, models {'context': 'I-neoplasm'}", + "96, of {'context': 'I-neoplasm'}", + "97, lymphoid {'context': 'I-neoplasm'}", + "98, malignancies {'context': 'I-neoplasm'}", + "116, in {'context': 'B-in vivo'}", + "117, vivo {'context': 'I-in vivo'}", + "118, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "119, of {'perturbing_action': 'I-pharmacological inhibition'}", + "120, calcineurin {'perturbing_action': 'I-pharmacological inhibition'}", + "121, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "122, by {'perturbing_action': 'I-pharmacological inhibition'}", + "123, CsA {'perturbing_action': 'I-pharmacological inhibition'}", + "124, or {'perturbing_action': 'I-pharmacological inhibition'}", + "125, FK506 {'perturbing_action': 'I-pharmacological inhibition'}", + "126, induced {'effect': 'B-positive'}", + "127, apoptosis {'phenotype': 'B-apoptosis'}", + "129, leukemic {'context': 'B-transformed cells'}", + "130, cells {'context': 'I-transformed cells'}", + "133, tumor {'phenotype': 'B-tumour regression'}", + "134, clearance, {'phenotype': 'I-tumour regression'}", + "138, mouse {'context': 'B-organism'}", + "142, ectopic {'perturbing_action': 'B-other'}", + "143, expression {'perturbing_action': 'I-other'}", + "144, of {'perturbing_action': 'I-other'}", + "145, a {'perturbing_action': 'I-other'}", + "146, constitutively {'perturbing_action': 'I-other'}", + "147, activated {'perturbing_action': 'I-other'}", + "148, mutant {'perturbing_action': 'I-other'}", + "149, of {'perturbing_action': 'I-other'}", + "150, calcineurin {'perturbing_action': 'I-other'}", + "152, leukemia {'context': 'B-neoplasm'}", + "157, induced {'effect': 'B-positive'}", + "158, apoptosis {'phenotype': 'B-apoptosis'}", + "160, human {'context': 'B-neoplasm'}", + "161, lymphoma {'context': 'I-neoplasm'}", + "163, leukemia {'context': 'B-transformed cells'}", + "164, cell {'context': 'I-transformed cells'}", + "165, lines. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "86, human ['l0', 'l1', 'l2', 'l3']", + "87, B- ['l0', 'l4', 'l5', 'l6']", + "88, and ['l1', 'l4', 'l7', 'l8']", + "89, T-cell ['l2', 'l5', 'l7', 'l9']", + "90, lymphomas ['l3', 'l6', 'l8', 'l9']", + "94, mouse ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "95, models ['l10', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "96, of ['l11', 'l26', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "97, lymphoid ['l12', 'l27', 'l37', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "98, malignancies ['l13', 'l28', 'l38', 'l50', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "106, T-cell ['l14', 'l29', 'l39', 'l51', 'l63', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "107, lymphoblastic ['l15', 'l30', 'l40', 'l52', 'l64', 'l74', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "108, leukemia, ['l16', 'l31', 'l41', 'l53', 'l65', 'l75', 'l87', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "116, in ['l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "117, vivo ['l110', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "118, inhibition ['l111', 'l126', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "119, of ['l112', 'l127', 'l141', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169']", + "120, calcineurin ['l113', 'l128', 'l142', 'l156', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182']", + "121, activity ['l114', 'l129', 'l143', 'l157', 'l170', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "122, by ['l76', 'l88', 'l99', 'l115', 'l130', 'l144', 'l158', 'l171', 'l183', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "123, CsA ['l17', 'l54', 'l77', 'l89', 'l100', 'l116', 'l131', 'l145', 'l159', 'l172', 'l184', 'l195', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213']", + "124, or ['l18', 'l42', 'l55', 'l66', 'l78', 'l90', 'l101', 'l117', 'l132', 'l146', 'l160', 'l173', 'l185', 'l196', 'l205', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221']", + "125, FK506 ['l19', 'l43', 'l56', 'l67', 'l79', 'l91', 'l102', 'l118', 'l133', 'l147', 'l161', 'l174', 'l186', 'l197', 'l206', 'l214', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228']", + "126, induced ['l20', 'l32', 'l44', 'l57', 'l68', 'l80', 'l92', 'l103', 'l119', 'l134', 'l148', 'l162', 'l175', 'l187', 'l198', 'l207', 'l215', 'l222', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234']", + "127, apoptosis ['l21', 'l45', 'l58', 'l69', 'l81', 'l93', 'l104', 'l120', 'l135', 'l149', 'l163', 'l176', 'l188', 'l199', 'l208', 'l216', 'l223', 'l229', 'l235', 'l236', 'l237', 'l238', 'l239']", + "129, leukemic ['l22', 'l33', 'l46', 'l59', 'l70', 'l82', 'l94', 'l105', 'l121', 'l136', 'l150', 'l164', 'l177', 'l189', 'l200', 'l209', 'l217', 'l224', 'l230', 'l235', 'l240', 'l241', 'l242', 'l243']", + "130, cells ['l23', 'l34', 'l47', 'l60', 'l71', 'l83', 'l95', 'l106', 'l122', 'l137', 'l151', 'l165', 'l178', 'l190', 'l201', 'l210', 'l218', 'l225', 'l231', 'l236', 'l240', 'l244', 'l245']", + "133, tumor ['l24', 'l35', 'l48', 'l61', 'l72', 'l84', 'l96', 'l107', 'l123', 'l138', 'l152', 'l166', 'l179', 'l191', 'l202', 'l211', 'l219', 'l226', 'l232', 'l237', 'l241', 'l244', 'l246', 'l247']", + "134, clearance, ['l25', 'l36', 'l49', 'l62', 'l73', 'l85', 'l97', 'l108', 'l124', 'l139', 'l153', 'l167', 'l180', 'l192', 'l203', 'l212', 'l220', 'l227', 'l233', 'l238', 'l242', 'l245', 'l246', 'l248']", + "138, mouse ['l86', 'l98', 'l109', 'l125', 'l140', 'l154', 'l168', 'l181', 'l193', 'l204', 'l213', 'l221', 'l228', 'l234', 'l239', 'l243', 'l247', 'l248']", + "142, ectopic ['l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264']", + "143, expression ['l249', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279']", + "144, of ['l250', 'l265', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291', 'l292', 'l293']", + "145, a ['l251', 'l266', 'l280', 'l294', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302', 'l303', 'l304', 'l305', 'l306']", + "146, constitutively ['l252', 'l267', 'l281', 'l294', 'l307', 'l308', 'l309', 'l310', 'l311', 'l312', 'l313', 'l314', 'l315', 'l316', 'l317', 'l318']", + "147, activated ['l253', 'l268', 'l282', 'l295', 'l307', 'l319', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327', 'l328', 'l329']", + "148, mutant ['l254', 'l269', 'l283', 'l296', 'l308', 'l319', 'l330', 'l331', 'l332', 'l333', 'l334', 'l335', 'l336', 'l337', 'l338', 'l339']", + "149, of ['l255', 'l270', 'l284', 'l297', 'l309', 'l320', 'l330', 'l340', 'l341', 'l342', 'l343', 'l344', 'l345', 'l346', 'l347', 'l348']", + "150, calcineurin ['l256', 'l271', 'l285', 'l298', 'l310', 'l321', 'l331', 'l340', 'l349', 'l350', 'l351', 'l352', 'l353']", + "152, leukemia ['l155', 'l169', 'l182', 'l194', 'l257', 'l272', 'l286', 'l299', 'l311', 'l322', 'l332', 'l341', 'l349']", + "157, induced ['l258', 'l273', 'l287', 'l300', 'l312', 'l323', 'l333', 'l342', 'l350', 'l354', 'l355', 'l356', 'l357', 'l358', 'l359']", + "158, apoptosis ['l259', 'l274', 'l288', 'l301', 'l313', 'l324', 'l334', 'l343', 'l354', 'l360', 'l361', 'l362', 'l363', 'l364']", + "160, human ['l260', 'l275', 'l289', 'l302', 'l314', 'l325', 'l335', 'l344', 'l355', 'l360', 'l365', 'l366', 'l367', 'l368']", + "161, lymphoma ['l261', 'l276', 'l290', 'l303', 'l315', 'l326', 'l336', 'l345', 'l351', 'l356', 'l361', 'l365', 'l369', 'l370', 'l371']", + "163, leukemia ['l262', 'l277', 'l291', 'l304', 'l316', 'l327', 'l337', 'l346', 'l357', 'l362', 'l366', 'l369', 'l372', 'l373']", + "164, cell ['l263', 'l278', 'l292', 'l305', 'l317', 'l328', 'l338', 'l347', 'l352', 'l358', 'l363', 'l367', 'l370', 'l372', 'l374']", + "165, lines. ['l264', 'l279', 'l293', 'l306', 'l318', 'l329', 'l339', 'l348', 'l353', 'l359', 'l364', 'l368', 'l371', 'l373', 'l374']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "of", + "lymphoid", + "malignancies", + "leukemia" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CsA", + "or", + "FK506", + "inhibition", + "of", + "calcineurin", + "activity" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "models", + "of", + "lymphoid", + "malignancies", + "human", + "lymphoma" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "of", + "lymphoid", + "malignancies", + "human", + "lymphoma" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "models", + "of", + "lymphoid", + "malignancies" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "clearance," + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "calcineurin", + "activity", + "by", + "CsA", + "or", + "FK506" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "clearance," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "calcineurin", + "activity", + "by", + "CsA", + "or", + "FK506" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "calcineurin", + "activity", + "by", + "CsA", + "or", + "FK506" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "calcineurin", + "activity", + "by", + "CsA", + "or", + "FK506" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "leukemic", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "calcineurin", + "activity", + "by", + "CsA", + "or", + "FK506" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "clearance," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "calcineurin", + "activity", + "by", + "CsA", + "or", + "FK506" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "leukemic", + "cells", + "leukemia", + "cell", + "lines." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "clearance," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "leukemic", + "cells", + "leukemia", + "cell", + "lines." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "leukemic", + "cells" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "clearance," + ] + } + }, + { + "phenotype": { + "val": "tumour regression", + "words": [ + "tumor", + "clearance," + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "ectopic", + "expression", + "of", + "a", + "constitutively", + "activated", + "mutant", + "calcineurin" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "leukemia", + "human", + "lymphoma" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "ectopic", + "expression", + "of", + "a", + "constitutively", + "activated", + "mutant", + "calcineurin" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "ectopic", + "expression", + "of", + "a", + "constitutively", + "activated", + "mutant" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "ectopic", + "expression", + "of", + "a", + "constitutively", + "activated", + "mutant", + "calcineurin" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "leukemia", + "cell", + "lines." + ] + } + } + ] + }, + { + "PMID": "17496899", + "TEXT": "Cerebral malaria claims more than 1 million lives per year. We report that heme oxygenase-1 (HO-1, encoded by Hmox1) prevents the development of experimental cerebral malaria (ECM). BALB/c mice infected with Plasmodium berghei ANKA upregulated HO-1 expression and activity and did not develop ECM. Deletion of Hmox1 and inhibition of HO activity increased ECM incidence to 83% and 78%, respectively. HO-1 upregulation was lower in infected C57BL/6 compared to BALB/c mice, and all infected C57BL/6 mice developed ECM (100% incidence). Pharmacological induction of HO-1 and exposure to the end-product of HO-1 activity, carbon monoxide (CO), reduced ECM incidence in C57BL/6 mice to 10% and 0%, respectively. Whereas neither HO-1 nor CO affected parasitemia, both prevented blood-brain barrier (BBB) disruption, brain microvasculature congestion and neuroinflammation, including CD8(+) T-cell brain sequestration. These effects were mediated by the binding of CO to hemoglobin, preventing hemoglobin oxidation and the generation of free heme, a molecule that triggers ECM pathogenesis.", + "TAG_DATA": [ + "27, BALB/c {'context': 'B-organism'}", + "28, mice {'context': 'I-organism'}", + "44, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "45, of {'perturbing_action': 'I-gene loss-of-function'}", + "46, Hmox1 {'perturbing_action': 'I-gene loss-of-function'}", + "48, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "49, of {'perturbing_action': 'I-pharmacological inhibition'}", + "50, HO {'perturbing_action': 'I-pharmacological inhibition'}", + "51, activity {'perturbing_action': 'I-pharmacological inhibition'}", + "66, C57BL/6 {'context': 'B-organism'}", + "74, C57BL/6 {'context': 'B-organism'}", + "75, mice {'context': 'I-organism'}", + "80, Pharmacological {'perturbing_action': 'B-pharmacological augmentation'}", + "81, induction {'perturbing_action': 'I-pharmacological augmentation'}", + "82, of {'perturbing_action': 'I-pharmacological augmentation'}", + "83, HO-1 {'perturbing_action': 'I-pharmacological augmentation'}", + "99, C57BL/6 {'context': 'B-organism'}", + "100, mice {'context': 'I-organism'}", + "119, brain {'context': 'B-tissue/organ'}", + "120, microvasculature {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "27, BALB/c ['l0', 'l1', 'l2']", + "28, mice ['l0']", + "44, Deletion ['l3', 'l4', 'l5', 'l6', 'l7']", + "45, of ['l3', 'l8', 'l9', 'l10', 'l11']", + "46, Hmox1 ['l1', 'l4', 'l8', 'l12', 'l13', 'l14']", + "48, inhibition ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "49, of ['l15', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "50, HO ['l16', 'l22', 'l28', 'l29', 'l30', 'l31']", + "51, activity ['l17', 'l23', 'l28', 'l32', 'l33', 'l34']", + "66, C57BL/6 ['l2', 'l5', 'l9', 'l12', 'l18', 'l24', 'l29', 'l32', 'l35', 'l36']", + "74, C57BL/6 ['l6', 'l10', 'l13', 'l19', 'l25', 'l30', 'l33', 'l35', 'l37']", + "75, mice ['l7', 'l11', 'l14', 'l20', 'l26', 'l31', 'l34', 'l36', 'l37']", + "80, Pharmacological ['l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "81, induction ['l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "82, of ['l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "83, HO-1 ['l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "99, C57BL/6 ['l41', 'l47', 'l52', 'l56', 'l60']", + "100, mice ['l21', 'l27', 'l42', 'l48', 'l53', 'l57', 'l60']", + "119, brain ['l43', 'l49', 'l54', 'l58', 'l61']", + "120, microvasculature ['l44', 'l50', 'l55', 'l59', 'l61']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "BALB/c", + "C57BL/6", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Hmox1", + "Deletion", + "of" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "HO", + "activity" + ] + }, + "context": { + "val": "organism", + "words": [ + "C57BL/6", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Pharmacological", + "induction", + "of", + "HO-1" + ] + }, + "context": { + "val": "organism", + "words": [ + "C57BL/6", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Pharmacological", + "induction", + "of", + "HO-1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brain", + "microvasculature" + ] + } + } + ] + }, + { + "PMID": "17486088", + "TEXT": "Cell-intrinsic checkpoints limit the proliferative capacity of primary cells in response to telomere dysfunction. It is not known, however, whether telomere dysfunction contributes to cell-extrinsic alterations that impair stem cell function and organ homeostasis. Here we show that telomere dysfunction provokes defects of the hematopoietic environment that impair B lymphopoiesis but increase myeloid proliferation in aging telomerase knockout (Terc(-/-)) mice. Moreover, the dysfunctional environment limited the engraftment of transplanted wild-type hematopoietic stem cells (HSCs). Dysfunction of the hematopoietic environment was age dependent and correlated with progressive telomere shortening in bone marrow stromal cells. Telomere dysfunction impaired mesenchymal progenitor cell function, reduced the capacity of bone marrow stromal cells to maintain functional HSCs, and increased the expression of various cytokines, including granulocyte colony-stimulating factor (G-CSF), in the plasma of aging mice. Administration of G-CSF to wild-type mice mimicked some of the defects seen in aging Terc(-/-) mice, including impairment of B lymphopoiesis and HSC engraftment. Conversely, inhibition of G-CSF improved HSC engraftment in aged Terc(-/-) mice. Taken together, these results show that telomere dysfunction induces alterations of the environment that can have implications for organismal aging and cell transplantation therapies.", + "TAG_DATA": [ + "51, increase {'effect': 'B-positive'}", + "53, proliferation {'phenotype': 'B-proliferation'}", + "56, telomerase {'perturbing_action': 'B-gene loss-of-function'}", + "57, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "58, (Terc(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "59, mice. {'context': 'B-organism'}", + "70, hematopoietic {'context': 'I-cells'}", + "71, stem {'context': 'I-cells'}", + "72, cells {'context': 'I-cells'}", + "73, (HSCs). {'context': 'I-cells'}", + "89, bone {'context': 'B-cells'}", + "90, marrow {'context': 'I-cells'}", + "91, stromal {'context': 'I-cells'}", + "92, cells. {'context': 'I-cells'}", + "96, mesenchymal {'context': 'B-cells'}", + "97, progenitor {'context': 'I-cells'}", + "98, cell {'context': 'I-cells'}", + "104, bone {'context': 'B-cells'}", + "105, marrow {'context': 'I-cells'}", + "106, stromal {'context': 'I-cells'}", + "107, cells {'context': 'I-cells'}", + "111, HSCs, {'context': 'B-cells'}", + "128, aging {'context': 'B-organism'}", + "129, mice. {'context': 'I-organism'}", + "135, mice {'context': 'B-organism'}", + "144, Terc(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "145, mice, {'context': 'B-organism'}", + "152, HSC {'context': 'B-cells'}", + "155, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "156, of {'perturbing_action': 'I-pharmacological inhibition'}", + "157, G-CSF {'perturbing_action': 'I-pharmacological inhibition'}", + "159, HSC {'context': 'B-cells'}", + "162, aged {'context': 'B-organism'}", + "163, Terc(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "164, mice. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "51, increase ['l0', 'l1', 'l2', 'l3']", + "53, proliferation ['l0', 'l4', 'l5']", + "56, telomerase ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "57, knockout ['l6', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "58, (Terc(-/-)) ['l1', 'l4', 'l7', 'l24', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "59, mice. ['l2', 'l5', 'l8', 'l25', 'l41', 'l55']", + "69, wild-type ['l9', 'l26', 'l42', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "70, hematopoietic ['l10', 'l27', 'l43', 'l56', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "71, stem ['l11', 'l28', 'l44', 'l57', 'l74', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "72, cells ['l12', 'l29', 'l45', 'l58', 'l75', 'l91', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "73, (HSCs). ['l13', 'l30', 'l46', 'l59', 'l76', 'l92', 'l107', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "89, bone ['l14', 'l31', 'l47', 'l60', 'l77', 'l93', 'l108', 'l120', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "90, marrow ['l15', 'l32', 'l48', 'l61', 'l78', 'l94', 'l109', 'l121', 'l132', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156']", + "91, stromal ['l16', 'l33', 'l49', 'l62', 'l79', 'l95', 'l110', 'l122', 'l133', 'l145', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167']", + "92, cells. ['l3', 'l17', 'l34', 'l50', 'l55', 'l63', 'l80', 'l96', 'l111', 'l123', 'l134', 'l146', 'l157', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "96, mesenchymal ['l18', 'l35', 'l51', 'l64', 'l81', 'l97', 'l112', 'l124', 'l135', 'l147', 'l158', 'l168', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183']", + "97, progenitor ['l19', 'l36', 'l52', 'l65', 'l82', 'l98', 'l113', 'l125', 'l136', 'l148', 'l159', 'l169', 'l175', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191']", + "98, cell ['l20', 'l37', 'l53', 'l66', 'l83', 'l99', 'l114', 'l126', 'l137', 'l149', 'l160', 'l170', 'l176', 'l184', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198']", + "104, bone ['l67', 'l84', 'l100', 'l138', 'l150', 'l161', 'l177', 'l185', 'l192', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "105, marrow ['l68', 'l85', 'l101', 'l139', 'l151', 'l162', 'l178', 'l186', 'l193', 'l199', 'l205', 'l206', 'l207', 'l208', 'l209']", + "106, stromal ['l69', 'l86', 'l102', 'l115', 'l127', 'l140', 'l152', 'l163', 'l179', 'l187', 'l194', 'l200', 'l205', 'l210', 'l211', 'l212', 'l213']", + "107, cells ['l21', 'l38', 'l54', 'l70', 'l87', 'l103', 'l116', 'l128', 'l141', 'l153', 'l164', 'l171', 'l180', 'l188', 'l195', 'l201', 'l206', 'l210', 'l214', 'l215', 'l216']", + "111, HSCs, ['l22', 'l39', 'l71', 'l88', 'l104', 'l117', 'l129', 'l142', 'l154', 'l165', 'l172', 'l181', 'l189', 'l196', 'l202', 'l207', 'l211', 'l214', 'l217', 'l218']", + "128, aging ['l72', 'l89', 'l105', 'l118', 'l130', 'l143', 'l155', 'l166', 'l173', 'l182', 'l190', 'l197', 'l203', 'l208', 'l212', 'l215', 'l217', 'l219']", + "129, mice. ['l23', 'l40', 'l73', 'l90', 'l106', 'l119', 'l131', 'l144', 'l156', 'l167', 'l174', 'l183', 'l191', 'l198', 'l204', 'l209', 'l213', 'l216', 'l218', 'l219']", + "135, mice ['l220', 'l221', 'l222']", + "144, Terc(-/-) ['l220', 'l223', 'l224']", + "145, mice, ['l221', 'l223', 'l225']", + "152, HSC ['l222', 'l224', 'l225']", + "155, inhibition ['l226', 'l227', 'l228', 'l229', 'l230', 'l231']", + "156, of ['l226', 'l232', 'l233', 'l234', 'l235', 'l236']", + "157, G-CSF ['l227', 'l232', 'l237', 'l238', 'l239', 'l240']", + "159, HSC ['l228', 'l233', 'l237', 'l241', 'l242', 'l243']", + "162, aged ['l229', 'l234', 'l238', 'l241', 'l244', 'l245']", + "163, Terc(-/-) ['l230', 'l235', 'l239', 'l242', 'l244', 'l246']", + "164, mice. ['l231', 'l236', 'l240', 'l243', 'l245', 'l246']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "(Terc(-/-))" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "(Terc(-/-))" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "telomerase", + "knockout", + "(Terc(-/-))", + "Terc(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice", + "mice,", + "aged" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "telomerase", + "knockout", + "(Terc(-/-))", + "Terc(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cells", + "(HSCs).", + "bone", + "marrow", + "stromal", + "cells.", + "mesenchymal", + "progenitor", + "cell", + "HSCs,", + "HSC" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "G-CSF" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "G-CSF" + ] + }, + "context": { + "val": "organism", + "words": [ + "aged", + "mice." + ] + } + } + ] + }, + { + "PMID": "17468767", + "TEXT": "During physical exercise, increases in motor neuron activity stimulate the expression of muscle-specific genes through the myocyte enhancer factor 2 (MEF2) family of transcription factors. Elevations in intracellular calcium increase MEF2 activity via the phosphorylation-dependent inactivation of class II histone deacetylases (HDACs). In studies to determine the role of the cAMP responsive element binding protein (CREB) in skeletal muscle, we found that mice expressing a dominant-negative CREB transgene (M-ACREB mice) exhibited a dystrophic phenotype along with reduced MEF2 activity. Class II HDAC phosphorylation was decreased in M-ACREB myofibers due to a reduction in amounts of Snf1lk (encoding salt inducible kinase, SIK1), a CREB target gene that functions as a class II HDAC kinase. Inhibiting class II HDAC activity either by viral expression of Snf1lk or by the administration of a small molecule antagonist improved the dystrophic phenotype in M-ACREB mice, pointing to an important role for the SIK1-HDAC pathway in regulating muscle function.", + "TAG_DATA": [ + "62, mice {'context': 'B-organism'}", + "63, expressing {'perturbing_action': 'B-other'}", + "64, a {'perturbing_action': 'I-other'}", + "65, dominant-negative {'perturbing_action': 'I-other'}", + "66, CREB {'perturbing_action': 'I-other'}", + "67, transgene {'perturbing_action': 'I-other'}", + "68, (M-ACREB {'perturbing_action': 'I-other'}", + "69, mice) {'perturbing_action': 'I-other'}", + "87, myofibers {'context': 'I-cells'}", + "120, viral {'perturbing_action': 'B-gene gain-of-function'}", + "121, expression {'perturbing_action': 'I-gene gain-of-function'}", + "122, of {'perturbing_action': 'I-gene gain-of-function'}", + "123, Snf1lk {'perturbing_action': 'I-gene gain-of-function'}", + "138, M-ACREB {'perturbing_action': 'B-other', 'context': 'B-organism'}", + "139, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "62, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "63, expressing ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "64, a ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "65, dominant-negative ['l2', 'l8', 'l13', 'l19', 'l20', 'l21', 'l22', 'l23']", + "66, CREB ['l3', 'l9', 'l14', 'l19', 'l24', 'l25', 'l26', 'l27']", + "67, transgene ['l4', 'l10', 'l15', 'l20', 'l24', 'l28', 'l29', 'l30']", + "68, (M-ACREB ['l5', 'l11', 'l16', 'l21', 'l25', 'l28', 'l31']", + "69, mice) ['l6', 'l12', 'l17', 'l22', 'l26', 'l29', 'l31']", + "87, myofibers ['l18', 'l23', 'l27', 'l30']", + "120, viral ['l32', 'l33', 'l34', 'l35', 'l36']", + "121, expression ['l32', 'l37', 'l38', 'l39', 'l40']", + "122, of ['l33', 'l37', 'l41', 'l42', 'l43']", + "123, Snf1lk ['l34', 'l38', 'l41', 'l44', 'l45']", + "138, M-ACREB ['l35', 'l39', 'l42', 'l44', 'l46']", + "139, mice, ['l36', 'l40', 'l43', 'l45', 'l46']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "M-ACREB" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "a", + "dominant-negative", + "CREB", + "transgene", + "(M-ACREB", + "mice)", + "M-ACREB" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "a", + "dominant-negative", + "CREB", + "transgene" + ] + }, + "context": { + "val": "cells", + "words": [ + "myofibers" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "viral", + "expression", + "of", + "Snf1lk" + ] + }, + "context": { + "val": "organism", + "words": [ + "M-ACREB", + "mice," + ] + } + } + ] + }, + { + "PMID": "17435771", + "TEXT": "The cytokine macrophage migration inhibitory factor (MIF) plays a critical role in inflammatory diseases and atherogenesis. We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF. MIF triggered G(alphai)- and integrin-dependent arrest and chemotaxis of monocytes and T cells, rapid integrin activation and calcium influx through CXCR2 or CXCR4. MIF competed with cognate ligands for CXCR4 and CXCR2 binding, and directly bound to CXCR2. CXCR2 and CD74 formed a receptor complex, and monocyte arrest elicited by MIF in inflamed or atherosclerotic arteries involved both CXCR2 and CD74. In vivo, Mif deficiency impaired monocyte adhesion to the arterial wall in atherosclerosis-prone mice, and MIF-induced leukocyte recruitment required Il8rb (which encodes Cxcr2). Blockade of Mif but not of canonical ligands of Cxcr2 or Cxcr4 in mice with advanced atherosclerosis led to plaque regression and reduced monocyte and T-cell content in plaques. By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis. Targeting MIF in individuals with manifest atherosclerosis can potentially be used to treat this condition.", + "TAG_DATA": [ + "36, chemotaxis {'phenotype': 'B-migration'}", + "38, monocytes {'context': 'B-cells'}", + "40, T {'context': 'B-cells'}", + "41, cells, {'context': 'B-cells'}", + "75, monocyte {'context': 'B-cells'}", + "84, arteries {'context': 'B-tissue/organ'}", + "90, In {'context': 'B-in vivo'}", + "91, vivo, {'context': 'I-in vivo'}", + "92, Mif {'perturbing_action': 'B-gene loss-of-function'}", + "93, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "94, impaired {'effect': 'B-negative'}", + "95, monocyte {'context': 'B-cells'}", + "103, mice, {'context': 'B-organism'}", + "106, leukocyte {'context': 'B-cells'}", + "113, Blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "114, of {'perturbing_action': 'I-pharmacological inhibition'}", + "115, Mif {'perturbing_action': 'I-pharmacological inhibition'}", + "126, mice {'context': 'B-organism'}", + "136, monocyte {'context': 'B-cells'}", + "138, T-cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "36, chemotaxis ['l0', 'l1', 'l2', 'l3', 'l4']", + "38, monocytes ['l0', 'l5', 'l6', 'l7', 'l8']", + "40, T ['l1', 'l5', 'l9', 'l10', 'l11']", + "41, cells, ['l2', 'l6', 'l9', 'l12', 'l13']", + "75, monocyte ['l3', 'l7', 'l10', 'l12', 'l14', 'l15', 'l16', 'l17']", + "84, arteries ['l4', 'l8', 'l11', 'l13', 'l14', 'l18', 'l19', 'l20']", + "90, In ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "91, vivo, ['l21', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "92, Mif ['l22', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "93, deficiency ['l23', 'l29', 'l34', 'l39', 'l40', 'l41', 'l42']", + "94, impaired ['l15', 'l18', 'l24', 'l30', 'l35', 'l39', 'l43', 'l44', 'l45']", + "95, monocyte ['l16', 'l19', 'l25', 'l31', 'l36', 'l40', 'l43', 'l46']", + "103, mice, ['l17', 'l20', 'l26', 'l32', 'l37', 'l41', 'l44', 'l46']", + "106, leukocyte ['l27', 'l33', 'l38', 'l42', 'l45']", + "113, Blockade ['l47', 'l48', 'l49', 'l50', 'l51']", + "114, of ['l47', 'l52', 'l53', 'l54', 'l55']", + "115, Mif ['l48', 'l52', 'l56', 'l57', 'l58']", + "126, mice ['l49', 'l53', 'l56', 'l59', 'l60']", + "136, monocyte ['l50', 'l54', 'l57', 'l59', 'l61']", + "138, T-cell ['l51', 'l55', 'l58', 'l60', 'l61']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + }, + "context": { + "val": "cells", + "words": [ + "monocytes", + "T", + "cells,", + "monocyte" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "arteries" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "monocyte", + "leukocyte" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "arteries" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mif", + "deficiency" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mif", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mif", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "monocyte", + "leukocyte" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mif", + "deficiency" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "Mif" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "Mif" + ] + }, + "context": { + "val": "cells", + "words": [ + "monocyte", + "T-cell" + ] + } + } + ] + }, + { + "PMID": "17401374", + "TEXT": "MicroRNAs (miRNAs) are endogenous noncoding RNAs, about 22 nucleotides in length, that mediate post-transcriptional gene silencing by annealing to inexactly complementary sequences in the 3'-untranslated regions of target mRNAs. Our current understanding of the functions of miRNAs relies mainly on their tissue-specific or developmental stage-dependent expression and their evolutionary conservation, and therefore is primarily limited to their involvement in developmental regulation and oncogenesis. Of more than 300 miRNAs that have been identified, miR-1 and miR-133 are considered to be muscle specific. Here we show that miR-1 is overexpressed in individuals with coronary artery disease, and that when overexpressed in normal or infarcted rat hearts, it exacerbates arrhythmogenesis. Elimination of miR-1 by an antisense inhibitor in infarcted rat hearts relieved arrhythmogenesis. miR-1 overexpression slowed conduction and depolarized the cytoplasmic membrane by post-transcriptionally repressing KCNJ2 (which encodes the K(+) channel subunit Kir2.1) and GJA1 (which encodes connexin 43), and this likely accounts at least in part for its arrhythmogenic potential. Thus, miR-1 may have important pathophysiological functions in the heart, and is a potential antiarrhythmic target.", + "TAG_DATA": [ + "102, rat {'context': 'B-tissue/organ'}", + "103, hearts, {'context': 'I-tissue/organ'}", + "107, Elimination {'perturbing_action': 'B-gene loss-of-function'}", + "108, of {'perturbing_action': 'I-gene loss-of-function'}", + "109, miR-1 {'perturbing_action': 'I-gene loss-of-function'}", + "110, by {'perturbing_action': 'I-rnai/knockdown'}", + "116, rat {'context': 'I-tissue/organ'}", + "117, hearts {'context': 'I-tissue/organ'}", + "120, miR-1 {'perturbing_action': 'B-gene gain-of-function'}", + "121, overexpression {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "102, rat ['l0']", + "103, hearts, ['l0']", + "107, Elimination ['l1', 'l2', 'l3', 'l4', 'l5']", + "108, of ['l1', 'l6', 'l7', 'l8', 'l9']", + "109, miR-1 ['l2', 'l6', 'l10', 'l11', 'l12']", + "110, by ['l3', 'l7', 'l10', 'l13', 'l14']", + "116, rat ['l4', 'l8', 'l11', 'l13', 'l15']", + "117, hearts ['l5', 'l9', 'l12', 'l14', 'l15']", + "120, miR-1 ['l16']", + "121, overexpression ['l16']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Elimination", + "of", + "miR-1" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "hearts" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "by" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "hearts" + ] + } + } + ] + }, + { + "PMID": "17369837", + "TEXT": "Hepatic adeno-associated virus (AAV)-serotype 2 mediated gene transfer results in transgene product expression that is sustained in experimental animals but not in human subjects. We hypothesize that this is caused by rejection of transduced hepatocytes by AAV capsid-specific memory CD8(+) T cells reactivated by AAV vectors. Here we show that healthy subjects carry AAV capsid-specific CD8(+) T cells and that AAV-mediated gene transfer results in their expansion. No such expansion occurs in mice after AAV-mediated gene transfer. In addition, we show that AAV-2 induced human T cells proliferate upon exposure to alternate AAV serotypes, indicating that other serotypes are unlikely to evade capsid-specific immune responses.", + "TAG_DATA": [ + "72, mice {'context': 'B-organism'}", + "83, induced {'effect': 'B-positive'}", + "84, human {'context': 'B-cells'}", + "85, T {'context': 'I-cells'}", + "86, cells {'context': 'I-cells'}", + "87, proliferate {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "83, induced ['l0', 'l1', 'l2', 'l3']", + "84, human ['l0', 'l4', 'l5', 'l6']", + "85, T ['l1', 'l4', 'l7', 'l8']", + "86, cells ['l2', 'l5', 'l7', 'l9']", + "87, proliferate ['l3', 'l6', 'l8', 'l9']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "T", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "T", + "cells" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferate" + ] + } + } + ] + }, + { + "PMID": "17351627", + "TEXT": "Ferritin, the iron storage protein, was recently suggested to be a candidate reporter for the detection of gene expression by magnetic resonance imaging (MRI). Here we report the generation of TET:EGFP-HAferritin (tet-hfer) transgenic mice, in which tissue-specific inducible transcriptional regulation of expression of the heavy chain of ferritin could be detected in vivo by MRI. We show organ specificity by mating the tet-hfer mice with transgenic mice expressing tetracycline transactivator (tTA) in liver hepatocytes and in vascular endothelial cells. Tetracycline-regulated overexpression of ferritin resulted in specific alterations of the transverse relaxation rate (R(2)) of water. Transgene-dependent changes in R(2) were detectable by MRI in adult mice, and we also found fetal developmental induction of transgene expression in utero. Thus, the tet-hfer MRI reporter mice provide a new transgenic mouse platform for in vivo molecular imaging of reporter gene expression by MRI during both embryonic and adult life.", + "TAG_DATA": [ + "30, TET:EGFP-HAferritin {'perturbing_action': 'B-gene gain-of-function'}", + "31, (tet-hfer) {'perturbing_action': 'I-gene gain-of-function'}", + "32, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "33, mice, {'context': 'B-organism'}", + "63, mice {'context': 'I-organism'}", + "65, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "66, mice {'context': 'I-organism'}", + "67, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "68, tetracycline {'perturbing_action': 'I-gene gain-of-function'}", + "69, transactivator {'perturbing_action': 'I-gene gain-of-function'}", + "70, (tTA) {'perturbing_action': 'I-gene gain-of-function'}", + "72, liver {'context': 'B-cells'}", + "73, hepatocytes {'context': 'I-cells'}", + "76, vascular {'context': 'B-cells'}", + "77, endothelial {'context': 'I-cells'}", + "78, cells. {'context': 'I-cells'}", + "79, Tetracycline-regulated {'perturbing_action': 'B-gene gain-of-function'}", + "80, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "81, of {'perturbing_action': 'I-gene gain-of-function'}", + "82, ferritin {'perturbing_action': 'I-gene gain-of-function'}", + "104, adult {'context': 'B-organism'}", + "105, mice, {'context': 'I-organism'}", + "116, in {'context': 'B-in vivo'}", + "117, utero. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "30, TET:EGFP-HAferritin ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "31, (tet-hfer) ['l0', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "32, transgenic ['l1', 'l18', 'l31', 'l32', 'l33', 'l34', 'l35']", + "33, mice, ['l2', 'l19', 'l31', 'l36', 'l37', 'l38', 'l39']", + "63, mice ['l3', 'l20', 'l32', 'l36', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "65, transgenic ['l4', 'l40', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "66, mice ['l5', 'l41', 'l53', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "67, expressing ['l6', 'l21', 'l42', 'l54', 'l67', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "68, tetracycline ['l7', 'l43', 'l55', 'l68', 'l80', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "69, transactivator ['l8', 'l22', 'l44', 'l56', 'l69', 'l81', 'l92', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "70, (tTA) ['l9', 'l23', 'l45', 'l57', 'l70', 'l82', 'l93', 'l103', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "72, liver ['l10', 'l24', 'l33', 'l37', 'l46', 'l58', 'l71', 'l83', 'l94', 'l104', 'l113', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "73, hepatocytes ['l11', 'l25', 'l34', 'l38', 'l47', 'l59', 'l72', 'l84', 'l95', 'l105', 'l114', 'l122', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "76, vascular ['l12', 'l26', 'l48', 'l60', 'l73', 'l85', 'l96', 'l106', 'l115', 'l123', 'l129', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140']", + "77, endothelial ['l13', 'l27', 'l49', 'l61', 'l74', 'l86', 'l97', 'l107', 'l116', 'l124', 'l130', 'l135', 'l141', 'l142', 'l143', 'l144', 'l145']", + "78, cells. ['l14', 'l28', 'l35', 'l39', 'l50', 'l62', 'l75', 'l87', 'l98', 'l108', 'l117', 'l125', 'l131', 'l136', 'l141', 'l146', 'l147', 'l148', 'l149']", + "79, Tetracycline-regulated ['l63', 'l76', 'l88', 'l99', 'l109', 'l118', 'l137', 'l142', 'l146', 'l150', 'l151', 'l152']", + "80, overexpression ['l15', 'l64', 'l77', 'l89', 'l100', 'l110', 'l119', 'l126', 'l132', 'l138', 'l143', 'l147', 'l150', 'l153', 'l154']", + "81, of ['l16', 'l29', 'l51', 'l65', 'l78', 'l90', 'l101', 'l111', 'l120', 'l127', 'l133', 'l139', 'l144', 'l148', 'l151', 'l153', 'l155']", + "82, ferritin ['l17', 'l30', 'l52', 'l66', 'l79', 'l91', 'l102', 'l112', 'l121', 'l128', 'l134', 'l140', 'l145', 'l149', 'l152', 'l154', 'l155']", + "104, adult ['l156']", + "105, mice, ['l156']", + "116, in ['l157']", + "117, utero. ['l157']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "TET:EGFP-HAferritin", + "(tet-hfer)", + "transgenic", + "expressing", + "tetracycline", + "transactivator", + "(tTA)", + "of", + "ferritin", + "Tetracycline-regulated", + "overexpression" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "TET:EGFP-HAferritin", + "(tet-hfer)", + "transgenic", + "expressing", + "tetracycline", + "transactivator", + "(tTA)", + "overexpression", + "of", + "ferritin", + "Tetracycline-regulated" + ] + }, + "context": { + "val": "cells", + "words": [ + "liver", + "hepatocytes", + "vascular", + "endothelial", + "cells." + ] + } + } + ] + }, + { + "PMID": "17334373", + "TEXT": "Human immunodeficiency virus-1 (HIV-1) is primarily transmitted sexually. Dendritic cells (DCs) in the subepithelium transmit HIV-1 to T cells through the C-type lectin DC-specific intercellular adhesion molecule (ICAM)-3-grabbing nonintegrin (DC-SIGN). However, the epithelial Langerhans cells (LCs) are the first DC subset to encounter HIV-1. It has generally been assumed that LCs mediate the transmission of HIV-1 to T cells through the C-type lectin Langerin, similarly to transmission by DC-SIGN on dendritic cells (DCs). Here we show that in stark contrast to DC-SIGN, Langerin prevents HIV-1 transmission by LCs. HIV-1 captured by Langerin was internalized into Birbeck granules and degraded. Langerin inhibited LC infection and this mechanism kept LCs refractory to HIV-1 transmission; inhibition of Langerin allowed LC infection and subsequent HIV-1 transmission. Notably, LCs also inhibited T-cell infection by viral clearance through Langerin. Thus Langerin is a natural barrier to HIV-1 infection, and strategies to combat infection must enhance, preserve or, at the very least, not interfere with Langerin expression and function.", + "TAG_DATA": [ + "101, LC {'context': 'B-cells'}", + "107, LCs {'context': 'B-cells'}", + "112, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "113, of {'perturbing_action': 'I-pharmacological inhibition'}", + "114, Langerin {'perturbing_action': 'I-pharmacological inhibition'}", + "116, LC {'context': 'B-cells'}", + "126, T-cell {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "101, LC ['l0']", + "107, LCs ['l0', 'l1']", + "112, inhibition ['l2', 'l3', 'l4', 'l5']", + "113, of ['l2', 'l6', 'l7', 'l8']", + "114, Langerin ['l3', 'l6', 'l9', 'l10']", + "116, LC ['l1', 'l4', 'l7', 'l9']", + "126, T-cell ['l5', 'l8', 'l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "Langerin" + ] + }, + "context": { + "val": "cells", + "words": [ + "LC", + "T-cell" + ] + } + } + ] + }, + { + "PMID": "17322897", + "TEXT": "Transmissibility of characteristic lesions to experimental animals may help us understand the pathomechanism of human autoimmune disease. Here we show that human autoimmune disease can be reproduced using genetically engineered model mice. Bullous pemphigoid (BP) is the most common serious autoimmune blistering skin disease, with a considerable body of indirect evidence indicating that the underlying autoantigen is collagen XVII (COL17). Passive transfer of human BP autoantibodies into mice does not induce skin lesions, probably because of differences between humans and mice in the amino acid sequence of the COL17 pathogenic epitope. We injected human BP autoantibody into Col17-knockout mice rescued by the human ortholog. This resulted in BP-like skin lesions and a human disease phenotype. Humanization of autoantigens is a new approach to the study of human autoimmune diseases.", + "TAG_DATA": [ + "67, mice {'context': 'B-organism'}", + "97, Col17-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "98, mice {'context': 'B-organism'}", + "99, rescued {'effect': 'B-rescues'}" + ], + "LINK_DATA": [ + "97, Col17-knockout ['l0', 'l1']", + "98, mice ['l0', 'l2']", + "99, rescued ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Col17-knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Col17-knockout" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + } + ] + }, + { + "PMID": "17259995", + "TEXT": "Wilson disease is caused by accumulation of Cu(2+) in cells, which results in liver cirrhosis and, occasionally, anemia. Here, we show that Cu(2+) triggers hepatocyte apoptosis through activation of acid sphingomyelinase (Asm) and release of ceramide. Genetic deficiency or pharmacological inhibition of Asm prevented Cu(2+)-induced hepatocyte apoptosis and protected rats, genetically prone to develop Wilson disease, from acute hepatocyte death, liver failure and early death. Cu(2+) induced the secretion of activated Asm from leukocytes, leading to ceramide release in and phosphatidylserine exposure on erythrocytes, events also prevented by inhibition of Asm. Phosphatidylserine exposure resulted in immediate clearance of affected erythrocytes from the blood in mice. Accordingly, individuals with Wilson disease showed elevated plasma levels of Asm, and displayed a constitutive increase of ceramide- and phosphatidylserine-positive erythrocytes. Our data suggest a previously unidentified mechanism for liver cirrhosis and anemia in Wilson disease.", + "TAG_DATA": [ + "23, triggers {'effect': 'B-positive'}", + "24, hepatocyte {'context': 'B-cells'}", + "25, apoptosis {'phenotype': 'B-apoptosis'}", + "39, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "40, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "41, of {'perturbing_action': 'I-pharmacological inhibition'}", + "42, Asm {'perturbing_action': 'I-pharmacological inhibition'}", + "43, prevented {'effect': 'B-negative'}", + "44, Cu(2+)-induced {'effect': 'B-positive'}", + "45, hepatocyte {'context': 'B-cells'}", + "46, apoptosis {'phenotype': 'B-apoptosis'}", + "49, rats, {'context': 'B-organism'}", + "58, hepatocyte {'context': 'B-cells'}", + "83, erythrocytes, {'context': 'B-cells'}", + "88, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "89, of {'perturbing_action': 'I-pharmacological inhibition'}", + "90, Asm. {'perturbing_action': 'I-pharmacological inhibition'}", + "99, erythrocytes {'context': 'B-cells'}", + "104, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "23, triggers ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "24, hepatocyte ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "25, apoptosis ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "39, pharmacological ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "40, inhibition ['l15', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "41, of ['l16', 'l28', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "42, Asm ['l17', 'l29', 'l38', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "43, prevented ['l2', 'l7', 'l11', 'l18', 'l30', 'l39', 'l47', 'l54', 'l55', 'l56', 'l57', 'l58']", + "44, Cu(2+)-induced ['l3', 'l8', 'l12', 'l19', 'l31', 'l40', 'l48', 'l54', 'l59', 'l60', 'l61', 'l62']", + "45, hepatocyte ['l4', 'l9', 'l13', 'l20', 'l32', 'l41', 'l49', 'l55', 'l59', 'l63', 'l64']", + "46, apoptosis ['l5', 'l10', 'l14', 'l21', 'l33', 'l42', 'l50', 'l56', 'l60', 'l63', 'l65']", + "49, rats, ['l22', 'l34', 'l43', 'l51', 'l57', 'l61', 'l66', 'l67']", + "58, hepatocyte ['l23', 'l35', 'l44', 'l52', 'l58', 'l62', 'l64', 'l65', 'l66']", + "83, erythrocytes, ['l24', 'l36', 'l45', 'l53', 'l67']", + "88, inhibition ['l68', 'l69', 'l70', 'l71']", + "89, of ['l25', 'l68', 'l72', 'l73', 'l74']", + "90, Asm. ['l26', 'l37', 'l46', 'l69', 'l72', 'l75', 'l76']", + "99, erythrocytes ['l27', 'l70', 'l73', 'l75', 'l77']", + "104, mice. ['l71', 'l74', 'l76', 'l77']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "triggers", + "Cu(2+)-induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocyte" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggers", + "Cu(2+)-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hepatocyte" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hepatocyte" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "Asm" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "Asm" + ] + }, + "effect": { + "val": "positive", + "words": [ + "Cu(2+)-induced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "Asm", + "Asm." + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocyte", + "erythrocytes,", + "erythrocytes" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "Asm" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "Asm", + "Asm." + ] + }, + "context": { + "val": "organism", + "words": [ + "rats,", + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Cu(2+)-induced" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats," + ] + } + } + ] + }, + { + "PMID": "17259994", + "TEXT": "Orexins are hypothalamic peptides that play an important role in maintaining wakefulness in mammals. Permanent deficit in orexinergic function is a pathophysiological hallmark of rodent, canine and human narcolepsy. Here we report that in rats, dogs and humans, somnolence is induced by pharmacological blockade of both orexin OX(1) and OX(2) receptors. When administered orally during the active period of the circadian cycle, a dual antagonist increased, in rats, electrophysiological indices of both non-REM and, particularly, REM sleep, in contrast to GABA(A) receptor modulators; in dogs, it caused somnolence and increased surrogate markers of REM sleep; and in humans, it caused subjective and objective electrophysiological signs of sleep. No signs of cataplexy were observed, in contrast to the rodent, dog or human narcolepsy syndromes. These results open new perspectives for investigating the role of endogenous orexins in sleep-wake regulation.", + "TAG_DATA": [ + "34, rats, {'context': 'B-organism'}", + "35, dogs {'context': 'B-organism'}", + "42, pharmacological {'perturbing_action': 'B-pharmacological inhibition'}", + "43, blockade {'perturbing_action': 'I-pharmacological inhibition'}", + "44, of {'perturbing_action': 'I-pharmacological inhibition'}", + "45, both {'perturbing_action': 'I-pharmacological inhibition'}", + "46, orexin {'perturbing_action': 'I-pharmacological inhibition'}", + "47, OX(1) {'perturbing_action': 'I-pharmacological inhibition'}", + "48, and {'perturbing_action': 'I-pharmacological inhibition'}", + "49, OX(2) {'perturbing_action': 'I-pharmacological inhibition'}", + "50, receptors. {'perturbing_action': 'I-pharmacological inhibition'}", + "67, rats, {'context': 'B-organism'}", + "84, dogs, {'context': 'B-organism'}", + "97, humans, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "34, rats, ['l0']", + "35, dogs ['l0']", + "42, pharmacological ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "43, blockade ['l1', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "44, of ['l2', 'l11', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "45, both ['l3', 'l12', 'l20', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "46, orexin ['l4', 'l13', 'l21', 'l28', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "47, OX(1) ['l5', 'l14', 'l22', 'l29', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "48, and ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l46', 'l47', 'l48', 'l49']", + "49, OX(2) ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l50', 'l51', 'l52']", + "50, receptors. ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l53', 'l54']", + "67, rats, ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53']", + "84, dogs, ['l10', 'l19', 'l27', 'l34', 'l40', 'l45', 'l49', 'l52', 'l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "blockade", + "of", + "both", + "orexin", + "OX(1)", + "and", + "OX(2)", + "receptors." + ] + }, + "context": { + "val": "organism", + "words": [ + "rats,", + "dogs," + ] + } + } + ] + }, + { + "PMID": "17237794", + "TEXT": "Skeletal muscle has the ability to achieve rapid repair in response to injury or disease. Many individuals with Marfan syndrome (MFS), caused by a deficiency of extracellular fibrillin-1, exhibit myopathy and often are unable to increase muscle mass despite physical exercise. Evidence suggests that selected manifestations of MFS reflect excessive signaling by transforming growth factor (TGF)-beta (refs. 2,3). TGF-beta is a known inhibitor of terminal differentiation of cultured myoblasts; however, the functional contribution of TGF-beta signaling to disease pathogenesis in various inherited myopathic states in vivo remains unknown. Here we show that increased TGF-beta activity leads to failed muscle regeneration in fibrillin-1-deficient mice. Systemic antagonism of TGF-beta through administration of TGF-beta-neutralizing antibody or the angiotensin II type 1 receptor blocker losartan normalizes muscle architecture, repair and function in vivo. Moreover, we show TGF-beta-induced failure of muscle regeneration and a similar therapeutic response in a dystrophin-deficient mouse model of Duchenne muscular dystrophy.", + "TAG_DATA": [ + "101, fibrillin-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "102, mice. {'context': 'B-organism'}", + "104, antagonism {'perturbing_action': 'I-pharmacological inhibition'}", + "105, of {'perturbing_action': 'I-pharmacological inhibition'}", + "106, TGF-beta {'perturbing_action': 'I-pharmacological inhibition'}", + "114, angiotensin {'perturbing_action': 'B-pharmacological inhibition'}", + "115, II {'perturbing_action': 'I-pharmacological inhibition'}", + "116, type {'perturbing_action': 'I-pharmacological inhibition'}", + "117, 1 {'perturbing_action': 'I-pharmacological inhibition'}", + "118, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "119, blocker {'perturbing_action': 'I-pharmacological inhibition'}", + "122, muscle {'context': 'B-tissue/organ'}", + "127, in {'context': 'B-in vivo'}", + "128, vivo. {'context': 'I-in vivo'}", + "144, dystrophin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "145, mouse {'context': 'B-organism'}", + "146, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "98, muscle ['l0', 'l1']", + "99, regeneration ['l0', 'l2']", + "101, fibrillin-1-deficient ['l3']", + "102, mice. ['l1', 'l2', 'l3']", + "104, antagonism ['l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "105, of ['l4', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "106, TGF-beta ['l5', 'l16', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "114, angiotensin ['l6', 'l17', 'l27', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "115, II ['l7', 'l18', 'l28', 'l37', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "116, type ['l8', 'l19', 'l29', 'l38', 'l48', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "117, 1 ['l9', 'l20', 'l30', 'l39', 'l49', 'l58', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "118, receptor ['l10', 'l21', 'l31', 'l40', 'l50', 'l59', 'l67', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "119, blocker ['l11', 'l22', 'l32', 'l41', 'l51', 'l60', 'l68', 'l75', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "122, muscle ['l12', 'l23', 'l33', 'l42', 'l52', 'l61', 'l69', 'l76', 'l82', 'l88', 'l89']", + "127, in ['l13', 'l24', 'l34', 'l43', 'l53', 'l62', 'l70', 'l77', 'l83', 'l88', 'l90']", + "128, vivo. ['l14', 'l25', 'l35', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l89', 'l90']", + "144, dystrophin-deficient ['l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l91', 'l92']", + "145, mouse ['l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l93']", + "146, model ['l15', 'l26', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l93']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "fibrillin-1-deficient", + "dystrophin-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antagonism", + "of", + "TGF-beta", + "angiotensin", + "II", + "type", + "1", + "receptor", + "blocker" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "muscle" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antagonism", + "of", + "TGF-beta", + "angiotensin", + "II", + "type", + "1", + "receptor", + "blocker" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antagonism", + "of", + "TGF-beta", + "angiotensin", + "II", + "type", + "1", + "receptor", + "blocker" + ] + }, + "context": { + "val": "organism", + "words": [ + "model", + "mouse" + ] + } + } + ] + }, + { + "PMID": "17195839", + "TEXT": "Metabolic hormones, such as leptin, alter the input organization of hypothalamic circuits, resulting in increased pro-opiomelanocortin (POMC) tone, followed by decreased food intake and adiposity. The gonadal steroid estradiol can also reduce appetite and adiposity, and it influences synaptic plasticity. Here we report that estradiol (E2) triggers a robust increase in the number of excitatory inputs to POMC neurons in the arcuate nucleus of wild-type rats and mice. This rearrangement of synapses in the arcuate nucleus is leptin independent because it also occurred in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice, and was paralleled by decreased food intake and body weight gain as well as increased energy expenditure. However, estrogen-induced decrease in body weight was dependent on Stat3 activation in the brain. These observations support the notion that synaptic plasticity of arcuate nucleus feeding circuits is an inherent element in body weight regulation and offer alternative approaches to reducing adiposity under conditions of failed leptin receptor signaling.", + "TAG_DATA": [ + "58, neurons {'context': 'I-cells'}", + "61, arcuate {'context': 'B-cells'}", + "62, nucleus {'context': 'I-cells'}", + "65, rats {'context': 'B-organism'}", + "67, mice. {'context': 'B-organism'}", + "84, leptin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "85, (ob/ob) {'perturbing_action': 'I-gene loss-of-function'}", + "87, leptin {'perturbing_action': 'B-gene loss-of-function'}", + "88, receptor-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "89, (db/db) {'perturbing_action': 'I-gene loss-of-function'}", + "90, mice, {'context': 'B-organism'}", + "121, brain. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "58, neurons ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "61, arcuate ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "62, nucleus ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "65, rats ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "67, mice. ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "84, leptin-deficient ['l4', 'l9', 'l13', 'l16', 'l18', 'l20', 'l21']", + "85, (ob/ob) ['l5', 'l10', 'l14', 'l17', 'l19', 'l20', 'l22']", + "87, leptin ['l23', 'l24', 'l25']", + "88, receptor-deficient ['l23', 'l26', 'l27']", + "89, (db/db) ['l24', 'l26', 'l28']", + "90, mice, ['l21', 'l22', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "neurons", + "arcuate", + "nucleus" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "leptin-deficient", + "(ob/ob)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rats", + "mice.", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "leptin-deficient", + "(ob/ob)", + "leptin", + "receptor-deficient", + "(db/db)" + ] + } + } + ] + }, + { + "PMID": "17115047", + "TEXT": "The continuous renewal of human epidermis is sustained by stem cells contained in the epidermal basal layer and in hair follicles. Cultured keratinocyte stem cells, known as holoclones, generate sheets of epithelium used to restore severe skin, mucosal and corneal defects. Mutations in genes encoding the basement membrane component laminin 5 (LAM5) cause junctional epidermolysis bullosa (JEB), a devastating and often fatal skin adhesion disorder. Epidermal stem cells from an adult patient affected by LAM5-beta3-deficient JEB were transduced with a retroviral vector expressing LAMB3 cDNA (encoding LAM5-beta3), and used to prepare genetically corrected cultured epidermal grafts. Nine grafts were transplanted onto surgically prepared regions of the patient's legs. Engraftment was complete after 8 d. Synthesis and proper assembly of normal levels of functional LAM5 were observed, together with the development of a firmly adherent epidermis that remained stable for the duration of the follow-up (1 year) in the absence of blisters, infections, inflammation or immune response. Retroviral integration site analysis indicated that the regenerated epidermis is maintained by a defined repertoire of transduced stem cells. These data show that ex vivo gene therapy of JEB is feasible and leads to full functional correction of the disease.", + "TAG_DATA": [ + "65, Epidermal {'context': 'B-cells'}", + "66, stem {'context': 'I-cells'}", + "67, cells {'context': 'I-cells'}", + "68, from {'context': 'I-cells'}", + "70, adult {'context': 'B-patient'}", + "71, patient {'context': 'I-patient'}", + "74, LAM5-beta3-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "77, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "78, with {'perturbing_action': 'I-gene gain-of-function'}", + "79, a {'perturbing_action': 'I-gene gain-of-function'}", + "80, retroviral {'perturbing_action': 'I-gene gain-of-function'}", + "81, vector {'perturbing_action': 'I-gene gain-of-function'}", + "82, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "83, LAMB3 {'perturbing_action': 'I-gene gain-of-function'}", + "84, cDNA {'perturbing_action': 'I-gene gain-of-function'}", + "85, (encoding {'perturbing_action': 'I-gene gain-of-function'}", + "86, LAM5-beta3), {'perturbing_action': 'I-gene gain-of-function'}", + "106, patient's {'context': 'B-tissue/organ'}", + "107, legs. {'context': 'I-tissue/organ'}", + "134, epidermis {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "65, Epidermal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "66, stem ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "67, cells ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "68, from ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "70, adult ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "71, patient ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "74, LAM5-beta3-deficient ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "75, JEB ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "77, transduced ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "78, with ['l28', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "79, a ['l29', 'l37', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "80, retroviral ['l30', 'l38', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "81, vector ['l31', 'l39', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "82, expressing ['l32', 'l40', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "83, LAMB3 ['l33', 'l41', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "84, cDNA ['l34', 'l42', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "85, (encoding ['l35', 'l43', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "86, LAM5-beta3), ['l36', 'l44', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "106, patient's ['l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90', 'l91']", + "107, legs. ['l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90', 'l92']", + "134, epidermis ['l91', 'l92']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Epidermal", + "stem", + "cells", + "from" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "LAM5-beta3-deficient" + ] + } + }, + { + "context": { + "val": "patient", + "words": [ + "adult", + "patient" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "LAM5-beta3-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "with", + "a", + "retroviral", + "vector", + "expressing", + "LAMB3", + "cDNA", + "(encoding", + "LAM5-beta3)," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "legs.", + "patient's" + ] + } + } + ] + }, + { + "PMID": "17057711", + "TEXT": "We report that GTP cyclohydrolase (GCH1), the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis, is a key modulator of peripheral neuropathic and inflammatory pain. BH4 is an essential cofactor for catecholamine, serotonin and nitric oxide production. After axonal injury, concentrations of BH4 rose in primary sensory neurons, owing to upregulation of GCH1. After peripheral inflammation, BH4 also increased in dorsal root ganglia (DRGs), owing to enhanced GCH1 enzyme activity. Inhibiting this de novo BH4 synthesis in rats attenuated neuropathic and inflammatory pain and prevented nerve injury-evoked excess nitric oxide production in the DRG, whereas administering BH4 intrathecally exacerbated pain. In humans, a haplotype of the GCH1 gene (population frequency 15.4%) was significantly associated with less pain following diskectomy for persistent radicular low back pain. Healthy individuals homozygous for this haplotype exhibited reduced experimental pain sensitivity, and forskolin-stimulated immortalized leukocytes from haplotype carriers upregulated GCH1 less than did controls. BH4 is therefore an intrinsic regulator of pain sensitivity and chronicity, and the GTP cyclohydrolase haplotype is a marker for these traits.", + "TAG_DATA": [ + "75, rats {'context': 'B-organism'}", + "91, DRG, {'context': 'B-tissue/organ'}", + "124, individuals {'context': 'I-cells'}", + "125, homozygous {'perturbing_action': 'B-other'}", + "126, for {'perturbing_action': 'I-other'}", + "136, immortalized {'context': 'B-cells'}", + "137, leukocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "124, individuals ['l0', 'l1', 'l2', 'l3']", + "125, homozygous ['l0', 'l4', 'l5', 'l6', 'l7']", + "126, for ['l1', 'l4', 'l8', 'l9', 'l10']", + "128, haplotype ['l2', 'l5', 'l8', 'l11', 'l12']", + "136, immortalized ['l6', 'l9', 'l11', 'l13']", + "137, leukocytes ['l3', 'l7', 'l10', 'l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "individuals", + "immortalized", + "leukocytes" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "homozygous", + "for" + ] + } + } + ] + }, + { + "PMID": "16998483", + "TEXT": "In individuals with chronic myeloid leukemia (CML) treated by autologous hematopoietic stem cell (HSC) transplantation, malignant progenitors in the graft contribute to leukemic relapse, but the mechanisms of homing and engraftment of leukemic CML stem cells are unknown. Here we show that CD44 expression is increased on mouse stem-progenitor cells expressing BCR-ABL and that CD44 contributes functional E-selectin ligands. In a mouse retroviral transplantation model of CML, BCR-ABL1-transduced progenitors from CD44-mutant donors are defective in homing to recipient marrow, resulting in decreased engraftment and impaired induction of CML-like myeloproliferative disease. By contrast, CD44-deficient stem cells transduced with empty retrovirus engraft as efficiently as do wild-type HSCs. CD44 is dispensable for induction of acute B-lymphoblastic leukemia by BCR-ABL, indicating that CD44 is specifically required on leukemic cells that initiate CML. The requirement for donor CD44 is bypassed by direct intrafemoral injection of BCR-ABL1-transduced CD44-deficient stem cells or by coexpression of human CD44. Antibody to CD44 attenuates induction of CML-like leukemia in recipients. These results show that BCR-ABL-expressing leukemic stem cells depend to a greater extent on CD44 for homing and engraftment than do normal HSCs, and argue that CD44 blockade may be beneficial in autologous transplantation in CML.", + "TAG_DATA": [ + "67, BCR-ABL1-transduced {'perturbing_action': 'B-gene gain-of-function'}", + "68, progenitors {'context': 'B-cells'}", + "70, CD44-mutant {'perturbing_action': 'B-other'}", + "92, CD44-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "93, stem {'context': 'B-cells'}", + "94, cells {'context': 'I-cells'}", + "95, transduced {'perturbing_action': 'B-gene gain-of-function'}", + "105, HSCs. {'context': 'B-cells'}", + "112, acute {'context': 'B-neoplasm'}", + "113, B-lymphoblastic {'context': 'I-neoplasm'}", + "114, leukemia {'context': 'I-neoplasm'}", + "141, BCR-ABL1-transduced {'perturbing_action': 'B-gene gain-of-function'}", + "142, CD44-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "143, stem {'context': 'B-cells'}", + "144, cells {'context': 'I-cells'}", + "147, coexpression {'perturbing_action': 'B-gene gain-of-function'}", + "148, of {'perturbing_action': 'I-gene gain-of-function'}", + "149, human {'perturbing_action': 'I-gene gain-of-function'}", + "150, CD44. {'perturbing_action': 'I-gene gain-of-function'}", + "151, Antibody {'perturbing_action': 'B-rnai/knockdown'}", + "152, to {'perturbing_action': 'I-rnai/knockdown'}", + "154, attenuates {'effect': 'B-negative'}", + "155, induction {'effect': 'B-positive'}", + "157, CML-like {'phenotype': 'B-tumourigenesis'}", + "158, leukemia {'phenotype': 'I-tumourigenesis'}" + ], + "LINK_DATA": [ + "67, BCR-ABL1-transduced ['l0', 'l1']", + "68, progenitors ['l0', 'l2']", + "70, CD44-mutant ['l1', 'l2']", + "92, CD44-deficient ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "93, stem ['l3', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "94, cells ['l4', 'l14', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "95, transduced ['l5', 'l15', 'l23', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "97, empty ['l6', 'l16', 'l24', 'l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "98, retrovirus ['l7', 'l17', 'l25', 'l32', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "105, HSCs. ['l8', 'l18', 'l26', 'l33', 'l40', 'l46', 'l52', 'l53', 'l54', 'l55']", + "112, acute ['l9', 'l19', 'l27', 'l34', 'l41', 'l47', 'l52', 'l56', 'l57', 'l58']", + "113, B-lymphoblastic ['l10', 'l20', 'l28', 'l35', 'l42', 'l48', 'l53', 'l56', 'l59', 'l60']", + "114, leukemia ['l11', 'l21', 'l29', 'l36', 'l43', 'l49', 'l54', 'l57', 'l59', 'l61']", + "141, BCR-ABL1-transduced ['l62', 'l63', 'l64', 'l65', 'l66', 'l67']", + "142, CD44-deficient ['l62', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "143, stem ['l12', 'l37', 'l44', 'l50', 'l63', 'l68', 'l76', 'l77']", + "144, cells ['l13', 'l22', 'l30', 'l38', 'l45', 'l51', 'l55', 'l58', 'l60', 'l61', 'l64', 'l69', 'l76']", + "147, coexpression ['l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "148, of ['l70', 'l78', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "149, human ['l71', 'l79', 'l88', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "150, CD44. ['l65', 'l72', 'l80', 'l89', 'l97', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "151, Antibody ['l81', 'l90', 'l98', 'l105', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "152, to ['l82', 'l91', 'l99', 'l106', 'l112', 'l118', 'l119', 'l120', 'l121', 'l122']", + "153, CD44 ['l83', 'l92', 'l100', 'l107', 'l113', 'l118', 'l123', 'l124', 'l125', 'l126']", + "154, attenuates ['l84', 'l93', 'l101', 'l108', 'l114', 'l119', 'l123', 'l127', 'l128', 'l129']", + "155, induction ['l73', 'l85', 'l94', 'l102', 'l109', 'l115', 'l120', 'l124', 'l127', 'l130', 'l131']", + "157, CML-like ['l66', 'l74', 'l86', 'l95', 'l103', 'l110', 'l116', 'l121', 'l125', 'l128', 'l130', 'l132']", + "158, leukemia ['l67', 'l75', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l126', 'l129', 'l131', 'l132']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "BCR-ABL1-transduced", + "transduced" + ] + }, + "context": { + "val": "cells", + "words": [ + "progenitors", + "stem", + "cells", + "HSCs." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "progenitors" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "CD44-mutant" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD44-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "stem", + "cells", + "HSCs." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD44-deficient" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "acute", + "B-lymphoblastic", + "leukemia" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "acute", + "B-lymphoblastic", + "leukemia" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "BCR-ABL1-transduced", + "coexpression", + "of", + "human", + "CD44." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "CML-like", + "leukemia" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD44-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD44-deficient" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "CML-like", + "leukemia" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "stem" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "leukemia" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "coexpression", + "of", + "human", + "CD44." + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuates" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "coexpression", + "of", + "human", + "CD44." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antibody", + "to" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuates" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antibody", + "to" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antibody", + "to" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "CML-like", + "leukemia" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuates" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "CML-like", + "leukemia" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "CML-like", + "leukemia" + ] + } + } + ] + }, + { + "PMID": "16980969", + "TEXT": "The avascularity of cardiac valves is abrogated in several valvular heart diseases (VHDs). This study investigated the molecular mechanisms underlying valvular avascularity and its correlation with VHD. Chondromodulin-I, an antiangiogenic factor isolated from cartilage, is abundantly expressed in cardiac valves. Gene targeting of chondromodulin-I resulted in enhanced Vegf-A expression, angiogenesis, lipid deposition and calcification in the cardiac valves of aged mice. Echocardiography showed aortic valve thickening, calcification and turbulent flow, indicative of early changes in aortic stenosis. Conditioned medium obtained from cultured valvular interstitial cells strongly inhibited tube formation and mobilization of endothelial cells and induced their apoptosis; these effects were partially inhibited by chondromodulin-I small interfering RNA. In human VHD, including cases associated with infective endocarditis, rheumatic heart disease and atherosclerosis, VEGF-A expression, neovascularization and calcification were observed in areas of chondromodulin-I downregulation. These findings provide evidence that chondromodulin-I has a pivotal role in maintaining valvular normal function by preventing angiogenesis that may lead to VHD.", + "TAG_DATA": [ + "40, Gene {'perturbing_action': 'B-rnai/knockdown'}", + "41, targeting {'perturbing_action': 'I-rnai/knockdown'}", + "42, of {'perturbing_action': 'I-rnai/knockdown'}", + "43, chondromodulin-I {'perturbing_action': 'I-rnai/knockdown'}", + "56, cardiac {'context': 'B-tissue/organ'}", + "57, valves {'context': 'I-tissue/organ'}", + "59, aged {'context': 'B-organism'}", + "60, mice. {'context': 'I-organism'}", + "82, valvular {'context': 'B-cells'}", + "83, interstitial {'context': 'I-cells'}", + "84, cells {'context': 'I-cells'}", + "86, inhibited {'effect': 'B-negative'}", + "87, tube {'phenotype': 'B-colony formation'}", + "88, formation {'phenotype': 'I-colony formation'}", + "92, endothelial {'context': 'B-cells'}", + "93, cells {'context': 'I-cells'}", + "95, induced {'effect': 'B-positive'}", + "97, apoptosis; {'phenotype': 'B-apoptosis'}", + "104, chondromodulin-I {'perturbing_action': 'B-rnai/knockdown'}", + "105, small {'perturbing_action': 'I-rnai/knockdown'}", + "106, interfering {'perturbing_action': 'I-rnai/knockdown'}", + "107, RNA. {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "40, Gene ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "41, targeting ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "42, of ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17']", + "43, chondromodulin-I ['l2', 'l8', 'l13', 'l18', 'l19', 'l20', 'l21']", + "56, cardiac ['l3', 'l9', 'l14', 'l18', 'l22', 'l23', 'l24']", + "57, valves ['l4', 'l10', 'l15', 'l19', 'l22', 'l25', 'l26']", + "59, aged ['l5', 'l11', 'l16', 'l20', 'l23', 'l25', 'l27']", + "60, mice. ['l6', 'l12', 'l17', 'l21', 'l24', 'l26', 'l27']", + "82, valvular ['l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "83, interstitial ['l28', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "84, cells ['l29', 'l37', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "86, inhibited ['l30', 'l38', 'l45', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "87, tube ['l31', 'l39', 'l46', 'l52', 'l58', 'l59', 'l60', 'l61']", + "88, formation ['l32', 'l40', 'l47', 'l53', 'l58', 'l62', 'l63', 'l64']", + "92, endothelial ['l33', 'l41', 'l48', 'l54', 'l59', 'l62', 'l65', 'l66', 'l67']", + "93, cells ['l34', 'l42', 'l49', 'l55', 'l60', 'l63', 'l65', 'l68']", + "95, induced ['l35', 'l43', 'l50', 'l56', 'l61', 'l64', 'l66', 'l68', 'l69']", + "97, apoptosis; ['l36', 'l44', 'l51', 'l57', 'l67', 'l69']", + "104, chondromodulin-I ['l70', 'l71', 'l72']", + "105, small ['l70', 'l73', 'l74']", + "106, interfering ['l71', 'l73', 'l75']", + "107, RNA. ['l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Gene", + "targeting", + "of", + "chondromodulin-I" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "cardiac", + "valves" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Gene", + "targeting", + "of", + "chondromodulin-I" + ] + }, + "context": { + "val": "organism", + "words": [ + "aged", + "mice." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "valvular", + "interstitial", + "cells", + "endothelial" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "valvular", + "interstitial", + "cells", + "endothelial" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "tube", + "formation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "valvular", + "interstitial", + "cells", + "endothelial" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "valvular", + "interstitial", + "cells", + "endothelial" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis;" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "tube", + "formation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis;" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "tube", + "formation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis;" + ] + } + } + ] + }, + { + "PMID": "16951685", + "TEXT": "Apoptosis is essential for clearance of potentially injurious inflammatory cells and subsequent efficient resolution of inflammation. Here we report that human neutrophils contain functionally active cyclin-dependent kinases (CDKs), and that structurally diverse CDK inhibitors induce caspase-dependent apoptosis and override powerful anti-apoptosis signals from survival factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF). We show that the CDK inhibitor R-roscovitine (Seliciclib or CYC202) markedly enhances resolution of established neutrophil-dependent inflammation in carrageenan-elicited acute pleurisy, bleomycin-induced lung injury, and passively induced arthritis in mice. In the pleurisy model, the caspase inhibitor zVAD-fmk prevents R-roscovitine-enhanced resolution of inflammation, indicating that this CDK inhibitor augments inflammatory cell apoptosis. We also provide evidence that R-roscovitine promotes apoptosis by reducing concentrations of the anti-apoptotic protein Mcl-1. Thus, CDK inhibitors enhance the resolution of established inflammation by promoting apoptosis of inflammatory cells, thereby demonstrating a hitherto unrecognized potential for the treatment of inflammatory disorders.", + "TAG_DATA": [ + "55, CDK {'perturbing_action': 'B-pharmacological inhibition'}", + "56, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "57, R-roscovitine {'perturbing_action': 'I-pharmacological inhibition'}", + "58, (Seliciclib {'perturbing_action': 'I-pharmacological inhibition'}", + "60, CYC202) {'perturbing_action': 'I-pharmacological inhibition'}", + "73, lung {'context': 'B-tissue/organ'}", + "80, mice. {'context': 'B-organism'}", + "97, CDK {'perturbing_action': 'B-pharmacological inhibition'}", + "98, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "99, augments {'effect': 'B-positive'}", + "100, inflammatory {'context': 'B-cells'}", + "101, cell {'context': 'I-cells'}", + "102, apoptosis. {'phenotype': 'B-apoptosis'}", + "109, promotes {'effect': 'B-positive'}", + "110, apoptosis {'phenotype': 'B-apoptosis'}", + "129, promoting {'effect': 'B-positive'}", + "130, apoptosis {'phenotype': 'B-apoptosis'}", + "132, inflammatory {'context': 'B-cells'}", + "133, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "55, CDK ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "56, inhibitor ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "57, R-roscovitine ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "58, (Seliciclib ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "60, CYC202) ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "73, lung ['l4', 'l9', 'l13', 'l16', 'l18']", + "80, mice. ['l5', 'l10', 'l14', 'l17', 'l19']", + "97, CDK ['l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "98, inhibitor ['l20', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "99, augments ['l21', 'l31', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "100, inflammatory ['l22', 'l32', 'l41', 'l50', 'l51', 'l52', 'l53']", + "101, cell ['l23', 'l33', 'l42', 'l50', 'l54', 'l55', 'l56']", + "102, apoptosis. ['l24', 'l34', 'l43', 'l51', 'l54', 'l57', 'l58', 'l59', 'l60']", + "109, promotes ['l25', 'l35', 'l44', 'l52', 'l55', 'l57', 'l61', 'l62', 'l63', 'l64', 'l65']", + "110, apoptosis ['l26', 'l36', 'l45', 'l58', 'l61', 'l66', 'l67', 'l68', 'l69']", + "129, promoting ['l27', 'l37', 'l46', 'l62', 'l66', 'l70', 'l71', 'l72']", + "130, apoptosis ['l28', 'l38', 'l47', 'l63', 'l67', 'l70', 'l73', 'l74']", + "132, inflammatory ['l29', 'l39', 'l48', 'l59', 'l64', 'l68', 'l71', 'l73', 'l75']", + "133, cells, ['l30', 'l40', 'l49', 'l53', 'l56', 'l60', 'l65', 'l69', 'l72', 'l74', 'l75']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK", + "inhibitor", + "R-roscovitine", + "(Seliciclib", + "CYC202)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK", + "inhibitor", + "R-roscovitine", + "(Seliciclib", + "CYC202)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK", + "inhibitor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "augments", + "promotes", + "promoting" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK", + "inhibitor" + ] + }, + "context": { + "val": "cells", + "words": [ + "inflammatory", + "cell", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK", + "inhibitor" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis.", + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "augments", + "promotes", + "promoting" + ] + }, + "context": { + "val": "cells", + "words": [ + "inflammatory", + "cell", + "cells," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "augments", + "promotes", + "promoting" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis.", + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "inflammatory", + "cell", + "cells," + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis.", + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "16936725", + "TEXT": "Immunoincompetence after allogeneic hematopoietic stem cell transplantation (HSCT) affects in particular the T-cell lineage and is associated with an increased risk for infections, graft failure and malignant relapse. To generate large numbers of T-cell precursors for adoptive therapy, we cultured mouse hematopoietic stem cells (HSCs) in vitro on OP9 mouse stromal cells expressing the Notch-1 ligand Delta-like-1 (OP9-DL1). We infused these cells, together with T-cell-depleted mouse bone marrow or purified HSCs, into lethally irradiated allogeneic recipients and determined their effect on T-cell reconstitution after transplantation. Recipients of OP9-DL1-derived T-cell precursors showed increased thymic cellularity and substantially improved donor T-cell chimerism (versus recipients of bone marrow or HSCs only). OP9-DL1-derived T-cell precursors gave rise to host-tolerant CD4+ and CD8+ populations with normal T-cell antigen receptor repertoires, cytokine secretion and proliferative responses to antigen. Administration of OP9-DL1-derived T-cell precursors increased resistance to infection with Listeria monocytogenes and mediated significant graft-versus-tumor (GVT) activity but not graft-versus-host disease (GVHD). We conclude that the adoptive transfer of OP9-DL1-derived T-cell precursors markedly enhances T-cell reconstitution after transplantation, resulting in GVT activity without GVHD.", + "TAG_DATA": [ + "40, mouse {'context': 'B-cells'}", + "41, hematopoietic {'context': 'I-cells'}", + "42, stem {'context': 'I-cells'}", + "43, cells {'context': 'I-cells'}", + "44, (HSCs) {'context': 'I-cells'}", + "45, in {'context': 'B-in vitro'}", + "46, vitro {'context': 'I-in vitro'}", + "48, OP9 {'context': 'B-cells'}", + "49, mouse {'context': 'I-cells'}", + "50, stromal {'context': 'I-cells'}", + "51, cells {'context': 'I-cells'}", + "87, OP9-DL1-derived {'context': 'B-cells'}", + "88, T-cell {'context': 'I-cells'}", + "89, precursors {'context': 'I-cells'}", + "97, donor {'context': 'B-cells'}", + "98, T-cell {'context': 'I-cells'}", + "108, OP9-DL1-derived {'context': 'B-cells'}", + "109, T-cell {'context': 'I-cells'}", + "110, precursors {'context': 'I-cells'}", + "115, CD4+ {'context': 'B-cells'}", + "116, and {'context': 'I-cells'}", + "117, CD8+ {'context': 'I-cells'}", + "118, populations {'context': 'I-cells'}", + "128, proliferative {'phenotype': 'B-proliferation'}", + "129, responses {'phenotype': 'I-proliferation'}", + "134, OP9-DL1-derived {'context': 'B-cells'}", + "135, T-cell {'context': 'I-cells'}", + "136, precursors {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "40, mouse ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "41, hematopoietic ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "42, stem ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "43, cells ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "44, (HSCs) ['l3', 'l12', 'l20', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "45, in ['l4', 'l13', 'l21', 'l28', 'l33', 'l39', 'l40']", + "46, vitro ['l5', 'l14', 'l22', 'l29', 'l34', 'l39', 'l41']", + "48, OP9 ['l6', 'l15', 'l23', 'l30', 'l35', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "49, mouse ['l7', 'l16', 'l24', 'l31', 'l36', 'l42', 'l46', 'l47', 'l48', 'l49', 'l50']", + "50, stromal ['l8', 'l17', 'l25', 'l37', 'l43', 'l46', 'l51', 'l52', 'l53', 'l54', 'l55']", + "51, cells ['l9', 'l18', 'l26', 'l32', 'l38', 'l44', 'l47', 'l51', 'l56', 'l57', 'l58']", + "87, OP9-DL1-derived ['l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "88, T-cell ['l52', 'l59', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81']", + "89, precursors ['l48', 'l53', 'l56', 'l60', 'l72', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "97, donor ['l49', 'l54', 'l57', 'l61', 'l73', 'l82', 'l90']", + "98, T-cell ['l45', 'l50', 'l55', 'l58', 'l62', 'l74', 'l83', 'l90']", + "108, OP9-DL1-derived ['l63', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98']", + "109, T-cell ['l64', 'l75', 'l91', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105']", + "110, precursors ['l65', 'l76', 'l84', 'l92', 'l99', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "115, CD4+ ['l66', 'l77', 'l85', 'l93', 'l100', 'l106', 'l112', 'l113', 'l114', 'l115', 'l116']", + "116, and ['l67', 'l78', 'l86', 'l94', 'l101', 'l107', 'l112', 'l117', 'l118', 'l119', 'l120']", + "117, CD8+ ['l68', 'l79', 'l87', 'l95', 'l102', 'l108', 'l113', 'l117', 'l121', 'l122', 'l123']", + "118, populations ['l69', 'l80', 'l88', 'l96', 'l103', 'l109', 'l114', 'l118', 'l121', 'l124', 'l125']", + "128, proliferative ['l70', 'l97', 'l104', 'l110', 'l115', 'l119', 'l122', 'l124', 'l126']", + "129, responses ['l71', 'l81', 'l89', 'l98', 'l105', 'l111', 'l116', 'l120', 'l123', 'l125', 'l126']", + "134, OP9-DL1-derived ['l127', 'l128']", + "135, T-cell ['l127', 'l129']", + "136, precursors ['l128', 'l129']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "OP9-DL1-derived", + "T-cell", + "precursors", + "CD4+", + "and", + "CD8+", + "populations" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferative", + "responses" + ] + } + } + ] + }, + { + "PMID": "16921377", + "TEXT": "TRAF6 has a key role in the regulation of innate immune responses by mediating signals from both TNF receptor and interleukin-1 receptor/Toll-like receptor superfamilies. Here we show that T cell-specific deletion of TRAF6 unexpectedly results in multiorgan inflammatory disease. TRAF6-deficient T cells exhibit hyperactivation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway compared with wild-type T cells and, as a result, become resistant to suppression by CD4+ CD25+ regulatory T cells. These data identify a previously unrecognized role for TRAF6 in the maintenance of peripheral tolerance, and suggest the presence of a T cell-intrinsic control mechanism to render responder T cells susceptible to tolerizing signals.", + "TAG_DATA": [ + "28, T {'perturbing_action': 'B-gene loss-of-function'}", + "29, cell-specific {'perturbing_action': 'B-gene loss-of-function'}", + "30, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "31, of {'perturbing_action': 'I-gene loss-of-function'}", + "32, TRAF6 {'perturbing_action': 'I-gene loss-of-function'}", + "39, TRAF6-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "40, T {'context': 'B-cells'}", + "41, cells {'context': 'I-cells'}", + "53, T {'context': 'B-cells'}", + "54, cells {'context': 'I-cells'}", + "64, CD4+ {'context': 'B-cells'}", + "65, CD25+ {'context': 'I-cells'}", + "66, regulatory {'context': 'I-cells'}", + "67, T {'context': 'I-cells'}", + "68, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "28, T ['l0', 'l1', 'l2', 'l3']", + "29, cell-specific ['l0', 'l4', 'l5', 'l6']", + "30, deletion ['l1', 'l4', 'l7', 'l8']", + "31, of ['l2', 'l5', 'l7', 'l9']", + "32, TRAF6 ['l3', 'l6', 'l8', 'l9']", + "39, TRAF6-deficient ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "40, T ['l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "41, cells ['l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31']", + "53, T ['l12', 'l20', 'l27', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "54, cells ['l13', 'l21', 'l28', 'l32', 'l38', 'l39', 'l40']", + "64, CD4+ ['l14', 'l22', 'l33', 'l41', 'l42', 'l43', 'l44']", + "65, CD25+ ['l15', 'l23', 'l34', 'l41', 'l45', 'l46', 'l47']", + "66, regulatory ['l16', 'l24', 'l29', 'l35', 'l38', 'l42', 'l45', 'l48', 'l49']", + "67, T ['l17', 'l25', 'l30', 'l36', 'l39', 'l43', 'l46', 'l48', 'l50']", + "68, cells. ['l18', 'l26', 'l31', 'l37', 'l40', 'l44', 'l47', 'l49', 'l50']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TRAF6-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells", + "CD4+", + "CD25+", + "regulatory", + "cells." + ] + } + } + ] + }, + { + "PMID": "16906157", + "TEXT": "Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome characterized by loss of renal function within days to weeks and by glomerular crescents on biopsy. The pathogenesis of this disease is unclear, but circulating factors are believed to have a major role. Here, we show that deletion of the Von Hippel-Lindau gene (Vhlh) from intrinsic glomerular cells of mice is sufficient to initiate a necrotizing crescentic glomerulonephritis and the clinical features that accompany RPGN. Loss of Vhlh leads to stabilization of hypoxia-inducible factor alpha subunits (HIFs). Using gene expression profiling, we identified de novo expression of the HIF target gene Cxcr4 (ref. 3) in glomeruli from both mice and humans with RPGN. The course of RPGN is markedly improved in mice treated with a blocking antibody to Cxcr4, whereas overexpression of Cxcr4 alone in podocytes of transgenic mice is sufficient to cause glomerular disease. Collectively, these results indicate an alternative mechanism for the pathogenesis of RPGN and glomerular disease in an animal model and suggest novel molecular pathways for intervention in this disease.", + "TAG_DATA": [ + "45, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "46, of {'perturbing_action': 'I-gene loss-of-function'}", + "47, the {'perturbing_action': 'I-gene loss-of-function'}", + "48, Von {'perturbing_action': 'I-gene loss-of-function'}", + "49, Hippel-Lindau {'perturbing_action': 'I-gene loss-of-function'}", + "50, gene {'perturbing_action': 'I-gene loss-of-function'}", + "51, (Vhlh) {'perturbing_action': 'I-gene loss-of-function'}", + "53, intrinsic {'context': 'B-cells'}", + "54, glomerular {'context': 'I-cells'}", + "55, cells {'context': 'I-cells'}", + "57, mice {'context': 'B-organism'}", + "73, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "74, of {'perturbing_action': 'I-gene loss-of-function'}", + "75, Vhlh {'perturbing_action': 'I-gene loss-of-function'}", + "119, mice {'context': 'B-organism'}", + "128, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "129, of {'perturbing_action': 'I-gene gain-of-function'}", + "130, Cxcr4 {'perturbing_action': 'I-gene gain-of-function'}", + "133, podocytes {'context': 'B-cells'}", + "135, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "136, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "45, deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "46, of ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "47, the ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "48, Von ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "49, Hippel-Lindau ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "50, gene ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "51, (Vhlh) ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "53, intrinsic ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "54, glomerular ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "55, cells ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "57, mice ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "73, Loss ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "74, of ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "75, Vhlh ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']", + "128, overexpression ['l91', 'l92', 'l93', 'l94', 'l95']", + "129, of ['l91', 'l96', 'l97', 'l98', 'l99']", + "130, Cxcr4 ['l92', 'l96', 'l100', 'l101', 'l102']", + "133, podocytes ['l93', 'l97', 'l100', 'l103', 'l104']", + "135, transgenic ['l94', 'l98', 'l101', 'l103', 'l105']", + "136, mice ['l95', 'l99', 'l102', 'l104', 'l105']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "Von", + "Hippel-Lindau", + "gene", + "(Vhlh)", + "Loss", + "Vhlh" + ] + }, + "context": { + "val": "cells", + "words": [ + "intrinsic", + "glomerular", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "Von", + "Hippel-Lindau", + "gene", + "(Vhlh)", + "Loss", + "Vhlh" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Cxcr4", + "transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "podocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Cxcr4", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "16799557", + "TEXT": "Vascular endothelial growth factor (VEGF) exerts crucial functions during pathological angiogenesis and normal physiology. We observed increased hematocrit (60-75%) after high-grade inhibition of VEGF by diverse methods, including adenoviral expression of soluble VEGF receptor (VEGFR) ectodomains, recombinant VEGF Trap protein and the VEGFR2-selective antibody DC101. Increased production of red blood cells (erythrocytosis) occurred in both mouse and primate models, and was associated with near-complete neutralization of VEGF corneal micropocket angiogenesis. High-grade inhibition of VEGF induced hepatic synthesis of erythropoietin (Epo, encoded by Epo) >40-fold through a HIF-1alpha-independent mechanism, in parallel with suppression of renal Epo mRNA. Studies using hepatocyte-specific deletion of the Vegfa gene and hepatocyte-endothelial cell cocultures indicated that blockade of VEGF induced hepatic Epo by interfering with homeostatic VEGFR2-dependent paracrine signaling involving interactions between hepatocytes and endothelial cells. These data indicate that VEGF is a previously unsuspected negative regulator of hepatic Epo synthesis and erythropoiesis and suggest that levels of Epo and erythrocytosis could represent noninvasive surrogate markers for stringent blockade of VEGF in vivo.", + "TAG_DATA": [ + "21, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "22, of {'perturbing_action': 'I-pharmacological inhibition'}", + "23, VEGF {'perturbing_action': 'I-pharmacological inhibition'}", + "28, adenoviral {'perturbing_action': 'B-rnai/knockdown'}", + "29, expression {'perturbing_action': 'I-rnai/knockdown'}", + "30, of {'perturbing_action': 'I-rnai/knockdown'}", + "31, soluble {'perturbing_action': 'I-rnai/knockdown'}", + "32, VEGF {'perturbing_action': 'I-rnai/knockdown'}", + "33, receptor {'perturbing_action': 'I-rnai/knockdown'}", + "34, (VEGFR) {'perturbing_action': 'I-rnai/knockdown'}", + "35, ectodomains, {'perturbing_action': 'I-rnai/knockdown'}", + "37, VEGF {'perturbing_action': 'I-rnai/knockdown'}", + "38, Trap {'perturbing_action': 'I-rnai/knockdown'}", + "39, protein {'perturbing_action': 'I-rnai/knockdown'}", + "55, mouse {'context': 'B-organism'}", + "57, primate {'context': 'B-organism'}", + "58, models, {'context': 'I-organism'}", + "71, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "72, of {'perturbing_action': 'I-pharmacological inhibition'}", + "73, VEGF {'perturbing_action': 'I-pharmacological inhibition'}", + "98, hepatocyte-specific {'perturbing_action': 'B-gene loss-of-function'}", + "99, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "100, of {'perturbing_action': 'I-gene loss-of-function'}", + "101, the {'perturbing_action': 'I-gene loss-of-function'}", + "102, Vegfa {'perturbing_action': 'I-gene loss-of-function'}", + "103, gene {'perturbing_action': 'I-gene loss-of-function'}", + "105, hepatocyte-endothelial {'context': 'B-cells'}", + "106, cell {'context': 'I-cells'}", + "111, of {'perturbing_action': 'I-pharmacological inhibition'}", + "112, VEGF {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "20, high-grade ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "21, inhibition ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "22, of ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "23, VEGF ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "28, adenoviral ['l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "29, expression ['l18', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "30, of ['l19', 'l35', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "31, soluble ['l20', 'l36', 'l51', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "32, VEGF ['l21', 'l37', 'l52', 'l66', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "33, receptor ['l22', 'l38', 'l53', 'l67', 'l80', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "34, (VEGFR) ['l23', 'l39', 'l54', 'l68', 'l81', 'l93', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "35, ectodomains, ['l24', 'l40', 'l55', 'l69', 'l82', 'l94', 'l105', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "36, recombinant ['l25', 'l41', 'l56', 'l70', 'l83', 'l95', 'l106', 'l116', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "37, VEGF ['l26', 'l42', 'l57', 'l71', 'l84', 'l96', 'l107', 'l117', 'l126', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "38, Trap ['l27', 'l43', 'l58', 'l72', 'l85', 'l97', 'l108', 'l118', 'l127', 'l135', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "39, protein ['l28', 'l44', 'l59', 'l73', 'l86', 'l98', 'l109', 'l119', 'l128', 'l136', 'l143', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "55, mouse ['l3', 'l8', 'l12', 'l15', 'l29', 'l45', 'l60', 'l74', 'l87', 'l99', 'l110', 'l120', 'l129', 'l137', 'l144', 'l150', 'l156', 'l157']", + "57, primate ['l4', 'l9', 'l13', 'l16', 'l30', 'l46', 'l61', 'l75', 'l88', 'l100', 'l111', 'l121', 'l130', 'l138', 'l145', 'l151', 'l156', 'l158']", + "58, models, ['l5', 'l10', 'l14', 'l17', 'l31', 'l47', 'l62', 'l76', 'l89', 'l101', 'l112', 'l122', 'l131', 'l139', 'l146', 'l152', 'l157', 'l158']", + "71, inhibition ['l32', 'l48', 'l63', 'l77', 'l90', 'l102', 'l113', 'l123', 'l132', 'l140', 'l147', 'l153', 'l159', 'l160']", + "72, of ['l33', 'l49', 'l64', 'l78', 'l91', 'l103', 'l114', 'l124', 'l133', 'l141', 'l148', 'l154', 'l159', 'l161']", + "73, VEGF ['l34', 'l50', 'l65', 'l79', 'l92', 'l104', 'l115', 'l125', 'l134', 'l142', 'l149', 'l155', 'l160', 'l161']", + "98, hepatocyte-specific ['l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170']", + "99, deletion ['l162', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178']", + "100, of ['l163', 'l171', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185']", + "101, the ['l164', 'l172', 'l179', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191']", + "102, Vegfa ['l165', 'l173', 'l180', 'l186', 'l192', 'l193', 'l194', 'l195', 'l196']", + "103, gene ['l166', 'l174', 'l181', 'l187', 'l192', 'l197', 'l198', 'l199', 'l200']", + "105, hepatocyte-endothelial ['l167', 'l175', 'l182', 'l188', 'l193', 'l197', 'l201', 'l202', 'l203']", + "106, cell ['l168', 'l176', 'l183', 'l189', 'l194', 'l198', 'l201', 'l204', 'l205']", + "111, of ['l169', 'l177', 'l184', 'l190', 'l195', 'l199', 'l202', 'l204', 'l206']", + "112, VEGF ['l170', 'l178', 'l185', 'l191', 'l196', 'l200', 'l203', 'l205', 'l206']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "VEGF" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "primate", + "models," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "adenoviral", + "expression", + "of", + "soluble", + "VEGF", + "receptor", + "(VEGFR)", + "ectodomains,", + "Trap", + "protein" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "primate", + "models," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "hepatocyte-specific", + "deletion", + "of", + "the", + "Vegfa", + "gene" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocyte-endothelial", + "cell" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "hepatocyte-endothelial", + "cell" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "of", + "VEGF" + ] + } + } + ] + }, + { + "PMID": "16715089", + "TEXT": "Here we investigated the potential role of bone-resorbing osteoclasts in homeostasis and stress-induced mobilization of hematopoietic progenitors. Different stress situations induced activity of osteoclasts (OCLs) along the stem cell-rich endosteum region of bone, secretion of proteolytic enzymes and mobilization of progenitors. Specific stimulation of OCLs with RANKL recruited mainly immature progenitors to the circulation in a CXCR4- and MMP-9-dependent manner; however, RANKL did not induce mobilization in young female PTPepsilon-knockout mice with defective OCL bone adhesion and resorption. Inhibition of OCLs with calcitonin reduced progenitor egress in homeostasis, G-CSF mobilization and stress situations. RANKL-stimulated bone-resorbing OCLs also reduced the stem cell niche components SDF-1, stem cell factor (SCF) and osteopontin along the endosteum, which was associated with progenitor mobilization. Finally, the major bone-resorbing proteinase, cathepsin K, also cleaved SDF-1 and SCF. Our findings indicate involvement of OCLs in selective progenitor recruitment as part of homeostasis and host defense, linking bone remodeling with regulation of hematopoiesis.", + "TAG_DATA": [ + "44, OCLs {'context': 'B-cells'}", + "67, young {'context': 'B-organism'}", + "68, female {'context': 'I-organism'}", + "69, PTPepsilon-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "70, mice {'context': 'B-organism'}", + "73, OCL {'context': 'B-cells'}", + "80, OCLs {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "44, OCLs ['l0', 'l1', 'l2', 'l3', 'l4']", + "67, young ['l0', 'l5', 'l6', 'l7', 'l8']", + "68, female ['l1', 'l5', 'l9', 'l10', 'l11']", + "69, PTPepsilon-knockout ['l2', 'l6', 'l9', 'l12', 'l13']", + "70, mice ['l3', 'l7', 'l10', 'l12', 'l14']", + "73, OCL ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "OCLs", + "OCL" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PTPepsilon-knockout" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "young", + "female", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PTPepsilon-knockout" + ] + } + } + ] + }, + { + "PMID": "16680150", + "TEXT": "Mice transgenic for antisense Notch and normal mice treated with inhibitors of the Notch-activating enzyme gamma-secretase showed reduced damage to brain cells and improved functional outcome in a model of focal ischemic stroke. Notch endangers neurons by modulating pathways that increase their vulnerability to apoptosis, and by activating microglial cells and stimulating the infiltration of proinflammatory leukocytes. These findings suggest that Notch signaling may be a therapeutic target for treatment of stroke and related neurodegenerative conditions.", + "TAG_DATA": [ + "1, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "2, for {'perturbing_action': 'I-gene gain-of-function'}", + "3, antisense {'perturbing_action': 'I-gene gain-of-function'}", + "4, Notch {'perturbing_action': 'I-gene gain-of-function'}", + "7, mice {'context': 'I-organism'}", + "10, inhibitors {'perturbing_action': 'B-pharmacological inhibition'}", + "11, of {'perturbing_action': 'I-pharmacological inhibition'}", + "12, the {'perturbing_action': 'I-pharmacological inhibition'}", + "13, Notch-activating {'perturbing_action': 'I-pharmacological inhibition'}", + "14, enzyme {'perturbing_action': 'I-pharmacological inhibition'}", + "15, gamma-secretase {'perturbing_action': 'I-pharmacological inhibition'}", + "20, brain {'context': 'B-cells'}", + "21, cells {'context': 'I-cells'}", + "35, neurons {'context': 'B-cells'}", + "44, apoptosis, {'phenotype': 'B-apoptosis'}", + "48, microglial {'context': 'B-cells'}", + "49, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "1, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "2, for ['l0', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "3, antisense ['l1', 'l17', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "4, Notch ['l2', 'l18', 'l33', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "7, mice ['l3', 'l19', 'l34', 'l48', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "10, inhibitors ['l4', 'l20', 'l35', 'l61', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "11, of ['l5', 'l21', 'l36', 'l49', 'l62', 'l74', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "12, the ['l6', 'l22', 'l37', 'l50', 'l63', 'l75', 'l86', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106']", + "13, Notch-activating ['l7', 'l23', 'l38', 'l51', 'l64', 'l76', 'l87', 'l97', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "14, enzyme ['l8', 'l24', 'l39', 'l52', 'l65', 'l77', 'l88', 'l98', 'l107', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "15, gamma-secretase ['l9', 'l25', 'l40', 'l53', 'l66', 'l78', 'l89', 'l99', 'l108', 'l116', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "20, brain ['l10', 'l26', 'l41', 'l54', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l124', 'l131', 'l132', 'l133', 'l134']", + "21, cells ['l11', 'l27', 'l42', 'l55', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l125', 'l131', 'l135', 'l136']", + "35, neurons ['l12', 'l28', 'l43', 'l56', 'l69', 'l81', 'l92', 'l102', 'l111', 'l119', 'l126', 'l132', 'l137', 'l138', 'l139', 'l140']", + "42, vulnerability ['l13', 'l29', 'l44', 'l57', 'l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l127', 'l133', 'l135', 'l137', 'l141', 'l142', 'l143']", + "44, apoptosis, ['l14', 'l30', 'l45', 'l58', 'l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l128', 'l134', 'l136', 'l138', 'l141', 'l144', 'l145']", + "48, microglial ['l15', 'l31', 'l46', 'l59', 'l72', 'l84', 'l95', 'l105', 'l114', 'l122', 'l129', 'l139', 'l142', 'l144', 'l146']", + "49, cells ['l16', 'l32', 'l47', 'l60', 'l73', 'l85', 'l96', 'l106', 'l115', 'l123', 'l130', 'l140', 'l143', 'l145', 'l146']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "antisense", + "Notch" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "antisense", + "Notch" + ] + }, + "context": { + "val": "cells", + "words": [ + "brain", + "cells", + "neurons", + "microglial" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "antisense", + "Notch" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "the", + "Notch-activating", + "enzyme", + "gamma-secretase" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "the", + "Notch-activating", + "enzyme", + "gamma-secretase" + ] + }, + "context": { + "val": "cells", + "words": [ + "brain", + "cells", + "neurons", + "microglial" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "the", + "Notch-activating", + "enzyme", + "gamma-secretase" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "brain", + "cells", + "neurons", + "microglial" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + } + ] + }, + { + "PMID": "16680149", + "TEXT": "Tumor-cell apoptosis is the basis of many cancer therapies, and tumor-specific T cells are the principal effectors of successful antitumor immunotherapies. Here we show that induction of tumor-cell apoptosis by an agonistic monoclonal antibody to DR5, the apoptosis-inducing receptor for TNF-related apoptosis-inducing ligand (TRAIL), combined with T-cell activation by agonistic monoclonal antibodies to the costimulatory molecules CD40 and CD137, potently and rapidly stimulated tumor-specific effector CD8+ T cells capable of eradicating preestablished tumors. Primary fibrosarcomas initiated with the carcinogen 3-methylcholanthrene (MCA), multiorgan metastases and a primary tumor containing as many as 90% tumor cells resistant to DR5-specific monoclonal antibody were rejected without apparent toxicity or induction of autoimmunity. This combination therapy of three monoclonal antibodies (trimAb) rapidly induced tumor-specific CD8+ T cells producing interferon (IFN)-gamma in the tumor-draining lymph node, consistent with a crucial requirement for CD8+ T cells and IFN-gamma in the tumor rejection process. These results in mice indicate that a rational monoclonal antibody-based therapy that both causes tumor-cell apoptosis through DR5 and activates T cells may be an effective strategy for cancer immunotherapy in humans.", + "TAG_DATA": [ + "25, induction {'effect': 'B-positive'}", + "28, apoptosis {'phenotype': 'B-apoptosis'}", + "46, T-cell {'context': 'B-cells'}", + "63, tumor-specific {'context': 'B-cells'}", + "64, effector {'context': 'I-cells'}", + "65, CD8+ {'context': 'I-cells'}", + "66, T {'context': 'I-cells'}", + "67, cells {'context': 'I-cells'}", + "72, tumors. {'context': 'B-neoplasm'}", + "73, Primary {'context': 'B-neoplasm'}", + "74, fibrosarcomas {'context': 'I-neoplasm'}", + "81, multiorgan {'phenotype': 'B-metastasis'}", + "82, metastases {'phenotype': 'I-metastasis'}", + "85, primary {'context': 'B-neoplasm'}", + "86, tumor {'context': 'I-neoplasm'}", + "92, tumor {'context': 'B-transformed cells'}", + "93, cells {'context': 'I-transformed cells'}", + "119, CD8+ {'context': 'I-cells'}", + "120, T {'context': 'I-cells'}", + "121, cells {'context': 'I-cells'}", + "127, tumor-draining {'context': 'B-tissue/organ'}", + "128, lymph {'context': 'I-tissue/organ'}", + "129, node, {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "25, induction ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "27, tumor-cell ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "28, apoptosis ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "46, T-cell ['l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "63, tumor-specific ['l2', 'l9', 'l15', 'l21', 'l31', 'l32', 'l33', 'l34', 'l35']", + "64, effector ['l3', 'l10', 'l16', 'l22', 'l31', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "65, CD8+ ['l4', 'l11', 'l17', 'l23', 'l32', 'l36', 'l42', 'l43', 'l44', 'l45', 'l46']", + "66, T ['l5', 'l12', 'l18', 'l24', 'l33', 'l37', 'l42', 'l47', 'l48', 'l49', 'l50']", + "67, cells ['l6', 'l13', 'l19', 'l25', 'l34', 'l38', 'l43', 'l47', 'l51']", + "72, tumors. ['l7', 'l14', 'l20', 'l26', 'l35', 'l39', 'l44', 'l48', 'l51']", + "73, Primary ['l27', 'l40', 'l45', 'l49', 'l52', 'l53', 'l54']", + "74, fibrosarcomas ['l28', 'l41', 'l46', 'l50', 'l52', 'l55', 'l56']", + "81, multiorgan ['l29', 'l53', 'l55', 'l57', 'l58', 'l59', 'l60']", + "82, metastases ['l30', 'l54', 'l56', 'l57', 'l61', 'l62']", + "85, primary ['l63', 'l64', 'l65']", + "86, tumor ['l58', 'l63', 'l66', 'l67']", + "92, tumor ['l59', 'l61', 'l64', 'l66', 'l68']", + "93, cells ['l60', 'l62', 'l65', 'l67', 'l68']", + "119, CD8+ ['l69', 'l70', 'l71', 'l72', 'l73']", + "120, T ['l69', 'l74', 'l75', 'l76', 'l77']", + "121, cells ['l70', 'l74', 'l78', 'l79', 'l80']", + "127, tumor-draining ['l71', 'l75', 'l78', 'l81', 'l82']", + "128, lymph ['l72', 'l76', 'l79', 'l81', 'l83']", + "129, node, ['l73', 'l77', 'l80', 'l82', 'l83']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "context": { + "val": "cells", + "words": [ + "tumor-specific", + "effector", + "CD8+", + "T", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "tumor-specific", + "effector", + "CD8+", + "T", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "T-cell" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "multiorgan", + "metastases" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "Primary", + "fibrosarcomas", + "tumor" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "multiorgan", + "metastases" + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "multiorgan", + "metastases" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + } + ] + }, + { + "PMID": "16648858", + "TEXT": "The growing number of recently identified negative feedback regulators of receptor tyrosine kinases (RTKs) highlights the importance of signal attenuation and modulation for correct signaling outcome. Mitogen-inducible gene 6 (Mig6 also known as RALT or Gene 33) is a multiadaptor protein thought to be involved in the regulation of RTK and stress signaling. Here, we show that deletion of the mouse gene encoding Mig6 (designated Errfi1, which stands for ERBB receptor feedback inhibitor 1) causes hyperactivation of endogenous epidermal growth factor receptor (EGFR) and sustained signaling through the mitogen-activated protein kinase (MAPK) pathway, resulting in overproliferation and impaired differentiation of epidermal keratinocytes. Furthermore, Errfi1-/- mice develop spontaneous tumors in various organs and are highly susceptible to chemically induced formation of skin tumors. A tumor-suppressive role for Mig6 is supported by our finding that MIG6 is downregulated in various human cancers. Inhibition of endogenous Egfr signaling with the Egfr inhibitor gefitinib (Iressa) or replacement of wild-type Egfr with the kinase-deficient protein encoded by the hypomorphic Egfr(wa2) allele completely rescued skin defects in Erffi1-/- mice. Carcinogen-induced tumors displayed by Errfi1-/- mice were highly sensitive to gefitinib. These results indicate that Mig6 is a specific negative regulator of Egfr signaling in skin morphogenesis and is a novel tumor suppressor of Egfr-dependent carcinogenesis.", + "TAG_DATA": [ + "57, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "58, of {'perturbing_action': 'I-gene loss-of-function'}", + "59, the {'perturbing_action': 'I-gene loss-of-function'}", + "60, mouse {'perturbing_action': 'I-gene loss-of-function'}", + "61, gene {'perturbing_action': 'I-gene loss-of-function'}", + "62, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "63, Mig6 {'perturbing_action': 'I-gene loss-of-function'}", + "64, (designated {'perturbing_action': 'I-gene loss-of-function'}", + "65, Errfi1, {'perturbing_action': 'I-gene loss-of-function'}", + "95, overproliferation {'phenotype': 'B-proliferation'}", + "97, impaired {'effect': 'B-negative'}", + "98, differentiation {'phenotype': 'B-differentiation'}", + "100, epidermal {'context': 'B-cells'}", + "101, keratinocytes. {'context': 'I-cells'}", + "103, Errfi1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "104, mice {'context': 'B-organism'}", + "107, tumors {'phenotype': 'B-tumourigenesis'}", + "110, organs {'context': 'B-tissue/organ'}", + "121, tumors. {'phenotype': 'I-tumourigenesis'}", + "152, replacement {'perturbing_action': 'B-other'}", + "153, of {'perturbing_action': 'I-other'}", + "154, wild-type {'perturbing_action': 'I-other'}", + "155, Egfr {'perturbing_action': 'I-other'}", + "156, with {'perturbing_action': 'I-other'}", + "157, the {'perturbing_action': 'I-gene loss-of-function'}", + "158, kinase-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "159, protein {'perturbing_action': 'I-gene loss-of-function'}", + "160, encoded {'perturbing_action': 'I-gene loss-of-function'}", + "161, by {'perturbing_action': 'I-gene loss-of-function'}", + "162, the {'perturbing_action': 'I-gene loss-of-function'}", + "163, hypomorphic {'perturbing_action': 'I-gene loss-of-function'}", + "164, Egfr(wa2) {'perturbing_action': 'I-gene loss-of-function'}", + "165, allele {'perturbing_action': 'I-gene loss-of-function'}", + "168, skin {'context': 'B-tissue/organ'}", + "171, Erffi1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "172, mice. {'context': 'B-organism'}", + "173, Carcinogen-induced {'phenotype': 'B-tumourigenesis'}", + "174, tumors {'phenotype': 'I-tumourigenesis'}", + "177, Errfi1-/- {'perturbing_action': 'B-gene loss-of-function'}", + "178, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "57, deletion ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "58, of ['l0', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "59, the ['l1', 'l18', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "60, mouse ['l2', 'l19', 'l35', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "61, gene ['l3', 'l20', 'l36', 'l51', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "62, encoding ['l4', 'l21', 'l37', 'l52', 'l66', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "63, Mig6 ['l5', 'l22', 'l38', 'l53', 'l67', 'l80', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "64, (designated ['l6', 'l23', 'l39', 'l54', 'l68', 'l81', 'l93', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "65, Errfi1, ['l7', 'l24', 'l40', 'l55', 'l69', 'l82', 'l94', 'l105', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "95, overproliferation ['l8', 'l25', 'l41', 'l56', 'l70', 'l83', 'l95', 'l106', 'l116', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "97, impaired ['l9', 'l26', 'l42', 'l57', 'l71', 'l84', 'l96', 'l107', 'l117', 'l126', 'l132', 'l133', 'l134', 'l135', 'l136']", + "98, differentiation ['l10', 'l27', 'l43', 'l58', 'l72', 'l85', 'l97', 'l108', 'l118', 'l127', 'l132', 'l137', 'l138', 'l139', 'l140', 'l141']", + "100, epidermal ['l11', 'l28', 'l44', 'l59', 'l73', 'l86', 'l98', 'l109', 'l119', 'l128', 'l133', 'l137', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "101, keratinocytes. ['l12', 'l29', 'l45', 'l60', 'l74', 'l87', 'l99', 'l110', 'l120', 'l129', 'l134', 'l138', 'l142', 'l148', 'l149', 'l150', 'l151', 'l152']", + "103, Errfi1-/- ['l13', 'l30', 'l46', 'l61', 'l75', 'l88', 'l100', 'l111', 'l121', 'l143', 'l148', 'l153', 'l154', 'l155', 'l156']", + "104, mice ['l14', 'l31', 'l47', 'l62', 'l76', 'l89', 'l101', 'l112', 'l122', 'l139', 'l144', 'l149', 'l153', 'l157', 'l158', 'l159']", + "107, tumors ['l15', 'l32', 'l48', 'l63', 'l77', 'l90', 'l102', 'l113', 'l123', 'l130', 'l135', 'l140', 'l145', 'l150', 'l154', 'l157', 'l160', 'l161']", + "110, organs ['l16', 'l33', 'l49', 'l64', 'l78', 'l91', 'l103', 'l114', 'l124', 'l131', 'l136', 'l141', 'l146', 'l151', 'l155', 'l158', 'l160', 'l162']", + "121, tumors. ['l17', 'l34', 'l50', 'l65', 'l79', 'l92', 'l104', 'l115', 'l125', 'l147', 'l152', 'l156', 'l159', 'l161', 'l162']", + "152, replacement ['l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181']", + "153, of ['l163', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199']", + "154, wild-type ['l164', 'l182', 'l200', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215']", + "155, Egfr ['l165', 'l183', 'l200', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230']", + "156, with ['l166', 'l184', 'l201', 'l216', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246']", + "157, the ['l167', 'l185', 'l202', 'l217', 'l231', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261']", + "158, kinase-deficient ['l168', 'l186', 'l203', 'l218', 'l232', 'l247', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271', 'l272', 'l273', 'l274', 'l275']", + "159, protein ['l169', 'l187', 'l204', 'l219', 'l233', 'l248', 'l262', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282', 'l283', 'l284', 'l285', 'l286', 'l287', 'l288']", + "160, encoded ['l170', 'l188', 'l205', 'l220', 'l234', 'l249', 'l263', 'l276', 'l289', 'l290', 'l291', 'l292', 'l293', 'l294', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300']", + "161, by ['l171', 'l189', 'l206', 'l221', 'l235', 'l250', 'l264', 'l277', 'l289', 'l301', 'l302', 'l303', 'l304', 'l305', 'l306', 'l307', 'l308', 'l309', 'l310', 'l311']", + "162, the ['l172', 'l190', 'l207', 'l222', 'l236', 'l251', 'l265', 'l278', 'l290', 'l301', 'l312', 'l313', 'l314', 'l315', 'l316', 'l317', 'l318', 'l319', 'l320', 'l321']", + "163, hypomorphic ['l173', 'l191', 'l208', 'l223', 'l237', 'l252', 'l266', 'l279', 'l291', 'l302', 'l312', 'l322', 'l323', 'l324', 'l325', 'l326', 'l327', 'l328', 'l329', 'l330']", + "164, Egfr(wa2) ['l174', 'l192', 'l209', 'l224', 'l238', 'l253', 'l267', 'l280', 'l292', 'l303', 'l313', 'l322', 'l331', 'l332', 'l333', 'l334', 'l335', 'l336', 'l337', 'l338']", + "165, allele ['l175', 'l193', 'l210', 'l225', 'l239', 'l254', 'l268', 'l281', 'l293', 'l304', 'l314', 'l323', 'l331', 'l339', 'l340', 'l341', 'l342', 'l343']", + "168, skin ['l176', 'l194', 'l211', 'l226', 'l240', 'l255', 'l269', 'l282', 'l294', 'l305', 'l315', 'l324', 'l332', 'l339', 'l344', 'l345']", + "171, Erffi1-/- ['l177', 'l195', 'l212', 'l227', 'l241', 'l256', 'l270', 'l283', 'l295', 'l306', 'l316', 'l325', 'l333', 'l340', 'l344', 'l346']", + "172, mice. ['l178', 'l196', 'l213', 'l228', 'l242', 'l257', 'l271', 'l284', 'l296', 'l307', 'l317', 'l326', 'l334', 'l341', 'l345', 'l346']", + "173, Carcinogen-induced ['l243', 'l258', 'l272', 'l285', 'l297', 'l308', 'l318', 'l327', 'l335', 'l347', 'l348', 'l349']", + "174, tumors ['l179', 'l197', 'l214', 'l229', 'l244', 'l259', 'l273', 'l286', 'l298', 'l309', 'l319', 'l328', 'l336', 'l342', 'l347', 'l350', 'l351']", + "177, Errfi1-/- ['l180', 'l198', 'l245', 'l260', 'l274', 'l287', 'l299', 'l310', 'l320', 'l329', 'l337', 'l348', 'l350', 'l352']", + "178, mice ['l181', 'l199', 'l215', 'l230', 'l246', 'l261', 'l275', 'l288', 'l300', 'l311', 'l321', 'l330', 'l338', 'l343', 'l349', 'l351', 'l352']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "mouse", + "gene", + "encoding", + "Mig6", + "(designated", + "Errfi1," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "overproliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "mouse", + "gene", + "encoding", + "Mig6", + "(designated", + "Errfi1," + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "mouse", + "gene", + "encoding", + "Mig6", + "(designated", + "Errfi1," + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "mouse", + "gene", + "encoding", + "Mig6", + "(designated", + "Errfi1,", + "Errfi1-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "epidermal", + "keratinocytes." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "mouse", + "gene", + "encoding", + "Mig6", + "(designated", + "Errfi1,", + "Errfi1-/-", + "kinase-deficient", + "protein", + "encoded", + "by", + "hypomorphic", + "Egfr(wa2)", + "allele", + "Erffi1-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "mouse", + "gene", + "encoding", + "Mig6", + "(designated", + "Errfi1,", + "Errfi1-/-", + "kinase-deficient", + "protein", + "encoded", + "by", + "hypomorphic", + "Egfr(wa2)", + "allele" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors", + "tumors.", + "Carcinogen-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "mouse", + "gene", + "encoding", + "Mig6", + "(designated", + "Errfi1,", + "Errfi1-/-", + "kinase-deficient", + "protein", + "encoded", + "by", + "hypomorphic", + "Egfr(wa2)", + "allele", + "Erffi1-/-" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "organs", + "skin" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "overproliferation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "overproliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "epidermal", + "keratinocytes." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "overproliferation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "organs" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "cells", + "words": [ + "epidermal", + "keratinocytes." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "organs" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "epidermal", + "keratinocytes." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "organs" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "epidermal", + "keratinocytes." + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors", + "tumors." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors", + "tumors.", + "Carcinogen-induced" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors", + "tumors." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "organs" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "replacement", + "of", + "wild-type", + "Egfr", + "with" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skin" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "replacement", + "of", + "wild-type", + "Egfr", + "with" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "replacement", + "of", + "wild-type", + "Egfr", + "with" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumors", + "Carcinogen-induced" + ] + } + } + ] + }, + { + "PMID": "16633347", + "TEXT": "Neurons have been neglected as cells with a major immune-regulatory function because they do not express major histocompatibility complex class II. Our data show that neurons are highly immune regulatory, having a crucial role in governing T-cell response and central nervous system (CNS) inflammation. Neurons induce the proliferation of activated CD4+ T cells through B7-CD28 and transforming growth factor (TGF)-beta1-TGF-beta receptor signaling pathways, resulting in amplification of T-cell receptor signaling through phosphorylated ZAP-70, interleukin (IL)-2 and IL-9. The interaction between neurons and T cells results in the conversion of encephalitogenic T cells to CD25+ TGF-beta1+ CTLA-4+ FoxP3+ T regulatory (Treg) cells that suppress encephalitogenic T cells and inhibit experimental autoimmune encephalomyelitis. Suppression is dependent on cytotoxic T lymphocyte antigen (CTLA)-4 but not TGF-beta1. Autocrine action of TGF-beta1, however, is important for the proliferative arrest of Treg cells. Blocking the B7 and TGF-beta pathways prevents the CNS-specific generation of Treg cells. These findings show that generation of neuron-dependent Treg cells in the CNS is instrumental in regulating CNS inflammation.", + "TAG_DATA": [ + "45, induce {'effect': 'B-positive'}", + "47, proliferation {'phenotype': 'B-proliferation'}", + "50, CD4+ {'context': 'B-cells'}", + "51, T {'context': 'I-cells'}", + "52, cells {'context': 'I-cells'}", + "89, encephalitogenic {'context': 'B-cells'}", + "90, T {'context': 'I-cells'}", + "91, cells {'context': 'I-cells'}", + "97, T {'context': 'I-cells'}", + "98, regulatory {'context': 'I-cells'}", + "100, cells {'context': 'I-cells'}", + "104, T {'context': 'I-cells'}", + "105, cells {'context': 'I-cells'}", + "133, arrest {'phenotype': 'I-proliferation'}", + "135, Treg {'context': 'B-cells'}", + "136, cells. {'context': 'I-cells'}", + "148, Treg {'context': 'B-cells'}", + "149, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, induce ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "47, proliferation ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "50, CD4+ ['l1', 'l6', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "51, T ['l2', 'l7', 'l11', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "52, cells ['l3', 'l8', 'l12', 'l19', 'l25', 'l26']", + "89, encephalitogenic ['l13', 'l20', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "90, T ['l4', 'l9', 'l14', 'l21', 'l25', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "91, cells ['l5', 'l10', 'l15', 'l22', 'l26', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "97, T ['l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "98, regulatory ['l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "100, cells ['l16', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "104, T ['l17', 'l23', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "105, cells ['l18', 'l24', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "133, arrest ['l55', 'l56', 'l57']", + "135, Treg ['l55', 'l58', 'l59', 'l60']", + "136, cells. ['l56', 'l58']", + "148, Treg ['l59', 'l61']", + "149, cells. ['l57', 'l60', 'l61']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induce" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation", + "arrest" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells", + "Treg", + "cells." + ] + } + } + ] + }, + { + "PMID": "16474401", + "TEXT": "The widespread distribution of the tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) in the adult brain suggests its role in a broad range of brain functions. Here we show evidence supporting a physical interaction of PTEN with a region in the third intracellular loop (3L4F) of the serotonin 5-HT2C receptor (5-HT2cR, formerly 5-HT1c receptor) in cell cultures. PTEN limits agonist-induced phosphorylation of 5-HT2cR through its protein phosphatase activity. We showed the probable existence of PTEN:5-HT2cR complexes in putative dopaminergic neurons in the rat ventral tegmental area (VTA), a brain region in which virtually all abused drugs exert rewarding effects by activating its dopamine neurons. We synthesized the interfering peptide Tat-3L4F, which is able to disrupt PTEN coupling with 5-HT2cR. Systemic application of Tat-3L4F or the 5-HT2cR agonist Ro600175 suppressed the increased firing rate of VTA dopaminergic neurons induced by delta9-tetrahydrocannabinol (THC), the psychoactive ingredient of marijuana. Using behavioral tests, we found that Tat-3L4F or Ro600175 blocks conditioned place preference of THC or nicotine, and that Ro600175, but not Tat-3L4F, produces anxiogenic effects, penile erection, hypophagia and motor functional suppression. These results suggest a potential strategy for treating drug addiction with the Tat-3L4F peptide.", + "TAG_DATA": [ + "129, 5-HT2cR {'perturbing_action': 'I-pharmacological augmentation'}", + "130, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "131, Ro600175 {'perturbing_action': 'I-pharmacological augmentation'}", + "138, VTA {'context': 'B-cells'}", + "139, dopaminergic {'context': 'I-cells'}", + "140, neurons {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "129, 5-HT2cR ['l0', 'l1', 'l2', 'l3', 'l4']", + "130, agonist ['l0', 'l5', 'l6', 'l7', 'l8']", + "131, Ro600175 ['l1', 'l5', 'l9', 'l10', 'l11']", + "138, VTA ['l2', 'l6', 'l9', 'l12', 'l13']", + "139, dopaminergic ['l3', 'l7', 'l10', 'l12', 'l14']", + "140, neurons ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "5-HT2cR", + "agonist", + "Ro600175" + ] + }, + "context": { + "val": "cells", + "words": [ + "VTA", + "dopaminergic", + "neurons" + ] + } + } + ] + }, + { + "PMID": "16462800", + "TEXT": "Atherosclerosis is an immunoinflammatory disease elicited by accumulation of lipids in the artery wall and leads to myocardial infarction and stroke. Here, we show that naturally arising CD4(+)CD25(+) regulatory T cells, which actively maintain immunological tolerance to self and nonself antigens, are powerful inhibitors of atherosclerosis in several mouse models. These results provide new insights into the immunopathogenesis of atherosclerosis and could lead to new therapeutic approaches that involve immune modulation using regulatory T cells.", + "TAG_DATA": [ + "43, inhibitors {'effect': 'B-negative'}", + "45, atherosclerosis {'phenotype': 'B-tumourigenesis'}", + "48, mouse {'context': 'B-organism'}", + "49, models. {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "43, inhibitors ['l0', 'l1', 'l2']", + "45, atherosclerosis ['l0', 'l3', 'l4']", + "48, mouse ['l1', 'l3', 'l5']", + "49, models. ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibitors" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "atherosclerosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibitors" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "atherosclerosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + } + ] + }, + { + "PMID": "16415877", + "TEXT": "Control of inflammation is crucial to prevent damage to the host during infection. Lipoxins and aspirin-triggered lipoxins are crucial modulators of proinflammatory responses; however, their intracellular mechanisms have not been completely elucidated. We previously showed that lipoxin A4 (LXA4) controls migration of dendritic cells (DCs) and production of interleukin (IL)-12 in vivo. In the absence of LXA4 biosynthetic pathways, the resulting uncontrolled inflammation during infection is lethal, despite pathogen clearance. Here we show that lipoxins activate two receptors in DCs, AhR and LXAR, and that this activation triggers expression of suppressor of cytokine signaling (SOCS)-2. SOCS-2-deficient DCs are hyper-responsive to microbial stimuli, as well as refractory to the inhibitory actions of LXA4, but not to IL-10. Upon infection with an intracellular pathogen, SOCS-2-deficient mice had uncontrolled production of proinflammatory cytokines, decreased microbial proliferation, aberrant leukocyte infiltration and elevated mortality. We also show that SOCS-2 is a crucial intracellular mediator of the anti-inflammatory actions of aspirin-induced lipoxins in vivo.", + "TAG_DATA": [ + "95, SOCS-2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "96, DCs {'context': 'B-cells'}", + "122, SOCS-2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "123, mice {'context': 'B-organism'}", + "130, decreased {'effect': 'B-negative'}", + "132, proliferation, {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "95, SOCS-2-deficient ['l0', 'l1', 'l2']", + "96, DCs ['l0']", + "122, SOCS-2-deficient ['l3', 'l4', 'l5']", + "123, mice ['l3', 'l6', 'l7']", + "130, decreased ['l1', 'l4', 'l6', 'l8']", + "132, proliferation, ['l2', 'l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SOCS-2-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "DCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SOCS-2-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SOCS-2-deficient" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SOCS-2-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + } + ] + }, + { + "PMID": "16369543", + "TEXT": "The scaffolding adapter GAB2 maps to a region (11q13-14) commonly amplified in human breast cancer, and is overexpressed in breast cancer cell lines and primary tumors, but its functional role in mammary carcinogenesis has remained unexplored. We found that overexpression of GAB2 (Grb2-associated binding protein 2) increases proliferation of MCF10A mammary cells in three-dimensional culture. Coexpression of GAB2 with antiapoptotic oncogenes causes lumenal filling, whereas coexpression with Neu (also known as ErbB2 and HER2) results in an invasive phenotype. These effects of GAB2 are mediated by hyperactivation of the Shp2-Erk pathway. Furthermore, overexpression of Gab2 potentiates, whereas deficiency of Gab2 ameliorates, Neu-evoked breast carcinogenesis in mice. Finally, GAB2 is amplified in some GAB2-overexpressing human breast tumors. Our data suggest that GAB2 may be a key gene within an 11q13 amplicon in human breast cancer and propose a role for overexpression of GAB2 in mammary carcinogenesis. Agents that target GAB2 or GAB2-dependent pathways may be useful for treating breast tumors that overexpress GAB2 or HER2 or both.", + "TAG_DATA": [ + "39, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "40, of {'perturbing_action': 'I-gene gain-of-function'}", + "41, GAB2 {'perturbing_action': 'I-gene gain-of-function'}", + "42, (Grb2-associated {'perturbing_action': 'I-gene gain-of-function'}", + "43, binding {'perturbing_action': 'I-gene gain-of-function'}", + "44, protein {'perturbing_action': 'I-gene gain-of-function'}", + "45, 2) {'perturbing_action': 'I-gene gain-of-function'}", + "46, increases {'effect': 'B-positive'}", + "47, proliferation {'phenotype': 'B-proliferation'}", + "49, MCF10A {'context': 'B-transformed cells'}", + "50, mammary {'context': 'I-transformed cells'}", + "51, cells {'context': 'I-transformed cells'}", + "53, three-dimensional {'context': 'B-in vitro'}", + "54, culture. {'context': 'I-in vitro'}", + "55, Coexpression {'perturbing_action': 'B-gene gain-of-function'}", + "56, of {'perturbing_action': 'I-gene gain-of-function'}", + "57, GAB2 {'perturbing_action': 'I-gene gain-of-function'}", + "58, with {'perturbing_action': 'I-gene gain-of-function'}", + "59, antiapoptotic {'perturbing_action': 'I-gene gain-of-function'}", + "65, coexpression {'perturbing_action': 'B-gene gain-of-function'}", + "66, with {'perturbing_action': 'I-gene gain-of-function'}", + "67, Neu {'perturbing_action': 'I-gene gain-of-function'}", + "74, results {'effect': 'B-positive'}", + "92, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "93, of {'perturbing_action': 'I-gene gain-of-function'}", + "94, Gab2 {'perturbing_action': 'I-gene gain-of-function'}", + "95, potentiates, {'effect': 'B-positive'}", + "97, deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "98, of {'perturbing_action': 'I-gene loss-of-function'}", + "99, Gab2 {'perturbing_action': 'I-gene loss-of-function'}", + "100, ameliorates, {'effect': 'B-negative'}", + "101, Neu-evoked {'effect': 'B-positive'}", + "102, breast {'context': 'B-tissue/organ'}", + "103, carcinogenesis {'phenotype': 'B-tumourigenesis'}", + "105, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "39, overexpression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "40, of ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "41, GAB2 ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "42, (Grb2-associated ['l2', 'l21', 'l39', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "43, binding ['l3', 'l22', 'l40', 'l57', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "44, protein ['l4', 'l23', 'l41', 'l58', 'l74', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "45, 2) ['l5', 'l24', 'l42', 'l59', 'l75', 'l90', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "46, increases ['l6', 'l25', 'l43', 'l60', 'l76', 'l91', 'l105', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "47, proliferation ['l7', 'l26', 'l44', 'l61', 'l77', 'l92', 'l106', 'l118', 'l124', 'l125', 'l126', 'l127', 'l128']", + "49, MCF10A ['l8', 'l27', 'l45', 'l62', 'l78', 'l93', 'l107', 'l119', 'l124', 'l129', 'l130', 'l131', 'l132']", + "50, mammary ['l9', 'l28', 'l46', 'l63', 'l79', 'l94', 'l108', 'l120', 'l125', 'l129', 'l133', 'l134', 'l135']", + "51, cells ['l10', 'l29', 'l47', 'l64', 'l80', 'l95', 'l109', 'l121', 'l126', 'l130', 'l133', 'l136', 'l137']", + "53, three-dimensional ['l11', 'l30', 'l48', 'l65', 'l81', 'l96', 'l110', 'l122', 'l127', 'l131', 'l134', 'l136', 'l138']", + "54, culture. ['l12', 'l31', 'l49', 'l66', 'l82', 'l97', 'l111', 'l123', 'l128', 'l132', 'l135', 'l137', 'l138']", + "55, Coexpression ['l13', 'l32', 'l50', 'l67', 'l83', 'l98', 'l112', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146']", + "56, of ['l14', 'l33', 'l51', 'l68', 'l84', 'l99', 'l113', 'l139', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153']", + "57, GAB2 ['l15', 'l34', 'l52', 'l69', 'l85', 'l100', 'l114', 'l140', 'l147', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159']", + "58, with ['l16', 'l35', 'l53', 'l70', 'l86', 'l101', 'l115', 'l141', 'l148', 'l154', 'l160', 'l161', 'l162', 'l163', 'l164']", + "59, antiapoptotic ['l17', 'l36', 'l54', 'l71', 'l87', 'l102', 'l116', 'l142', 'l149', 'l155', 'l160', 'l165', 'l166', 'l167', 'l168']", + "65, coexpression ['l143', 'l150', 'l156', 'l161', 'l165', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "66, with ['l144', 'l151', 'l157', 'l162', 'l166', 'l169', 'l175', 'l176', 'l177', 'l178', 'l179']", + "67, Neu ['l18', 'l37', 'l55', 'l72', 'l88', 'l103', 'l145', 'l152', 'l158', 'l163', 'l167', 'l170', 'l175', 'l180', 'l181', 'l182', 'l183']", + "74, results ['l19', 'l38', 'l56', 'l73', 'l89', 'l104', 'l117', 'l146', 'l153', 'l159', 'l164', 'l168', 'l171', 'l176', 'l180']", + "92, overexpression ['l184', 'l185', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191']", + "93, of ['l184', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198']", + "94, Gab2 ['l185', 'l192', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "95, potentiates, ['l172', 'l177', 'l181', 'l186', 'l193', 'l199', 'l205', 'l206', 'l207', 'l208']", + "97, deficiency ['l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215']", + "98, of ['l209', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221']", + "99, Gab2 ['l210', 'l216', 'l222', 'l223', 'l224', 'l225', 'l226']", + "100, ameliorates, ['l187', 'l194', 'l200', 'l211', 'l217', 'l222', 'l227', 'l228', 'l229', 'l230']", + "101, Neu-evoked ['l188', 'l195', 'l201', 'l205', 'l212', 'l218', 'l223', 'l227', 'l231', 'l232', 'l233']", + "102, breast ['l173', 'l178', 'l182', 'l189', 'l196', 'l202', 'l206', 'l213', 'l219', 'l224', 'l228', 'l231', 'l234', 'l235']", + "103, carcinogenesis ['l174', 'l179', 'l183', 'l190', 'l197', 'l203', 'l207', 'l214', 'l220', 'l225', 'l229', 'l232', 'l234', 'l236']", + "105, mice. ['l191', 'l198', 'l204', 'l208', 'l215', 'l221', 'l226', 'l230', 'l233', 'l235', 'l236']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "GAB2", + "(Grb2-associated", + "binding", + "protein", + "2)", + "Coexpression", + "with", + "antiapoptotic", + "coexpression", + "Neu", + "Gab2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increases", + "results", + "potentiates,", + "Neu-evoked" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "GAB2", + "(Grb2-associated", + "binding", + "protein", + "2)" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "GAB2", + "(Grb2-associated", + "binding", + "protein", + "2)" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MCF10A", + "mammary", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "GAB2", + "(Grb2-associated", + "binding", + "protein", + "2)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "three-dimensional", + "culture." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MCF10A", + "mammary", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "three-dimensional", + "culture." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "MCF10A", + "mammary", + "cells" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "three-dimensional", + "culture." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "coexpression", + "with", + "Neu", + "overexpression", + "of", + "Gab2" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "breast" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "coexpression", + "with", + "Neu", + "overexpression", + "of", + "Gab2" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "carcinogenesis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Gab2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "ameliorates," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Gab2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "potentiates,", + "Neu-evoked" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "breast" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "potentiates,", + "Neu-evoked" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "carcinogenesis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "potentiates,", + "Neu-evoked" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "of", + "Gab2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "ameliorates," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "of", + "Gab2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "Neu-evoked" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "of", + "Gab2" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "breast" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "of", + "Gab2" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "carcinogenesis" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "of", + "Gab2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "ameliorates," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "breast" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "ameliorates," + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "carcinogenesis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "ameliorates," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "breast" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "carcinogenesis" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "carcinogenesis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "16341243", + "TEXT": "Inhibitors of the kinase mammalian target of rapamycin (mTOR) have shown sporadic activity in cancer trials, leading to confusion about the appropriate clinical setting for their use. Here we show that loss of the Von Hippel-Lindau tumor suppressor gene (VHL) sensitizes kidney cancer cells to the mTOR inhibitor CCI-779 in vitro and in mouse models. Growth arrest caused by CCI-779 correlates with a block in translation of mRNA encoding hypoxia-inducible factor (HIF1A), and is rescued by expression of a VHL-resistant HIF1A cDNA lacking the 5' untranslated region. VHL-deficient tumors show increased uptake of the positron emission tomography (PET) tracer fluorodeoxyglucose (FDG) in an mTOR-dependent manner. Our findings provide preclinical rationale for prospective, biomarker-driven clinical studies of mTOR inhibitors in kidney cancer and suggest that FDG-PET scans may have use as a pharmacodynamic marker in this setting.", + "TAG_DATA": [ + "31, loss {'perturbing_action': 'B-gene loss-of-function'}", + "32, of {'perturbing_action': 'I-gene loss-of-function'}", + "33, the {'perturbing_action': 'I-gene loss-of-function'}", + "34, Von {'perturbing_action': 'I-gene loss-of-function'}", + "35, Hippel-Lindau {'perturbing_action': 'I-gene loss-of-function'}", + "36, tumor {'perturbing_action': 'I-gene loss-of-function'}", + "37, suppressor {'perturbing_action': 'I-gene loss-of-function'}", + "38, gene {'perturbing_action': 'I-gene loss-of-function'}", + "39, (VHL) {'perturbing_action': 'I-gene loss-of-function'}", + "41, kidney {'context': 'B-transformed cells'}", + "42, cancer {'context': 'I-transformed cells'}", + "43, cells {'context': 'I-transformed cells'}", + "46, mTOR {'perturbing_action': 'B-pharmacological inhibition'}", + "47, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "48, CCI-779 {'perturbing_action': 'I-pharmacological inhibition'}", + "49, in {'context': 'B-in vitro'}", + "50, vitro {'context': 'I-in vitro'}", + "53, mouse {'context': 'B-organism'}", + "54, models. {'context': 'I-organism'}", + "55, Growth {'phenotype': 'B-cell growth'}", + "56, arrest {'effect': 'B-negative'}", + "76, expression {'perturbing_action': 'B-gene gain-of-function'}", + "77, of {'perturbing_action': 'I-other'}", + "78, a {'perturbing_action': 'I-rnai/knockdown'}", + "80, HIF1A {'perturbing_action': 'I-gene gain-of-function'}", + "81, cDNA {'perturbing_action': 'I-rnai/knockdown'}", + "87, VHL-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "88, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "31, loss ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "32, of ['l0', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "33, the ['l1', 'l20', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "34, Von ['l2', 'l21', 'l39', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "35, Hippel-Lindau ['l3', 'l22', 'l40', 'l57', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "36, tumor ['l4', 'l23', 'l41', 'l58', 'l74', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "37, suppressor ['l5', 'l24', 'l42', 'l59', 'l75', 'l90', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "38, gene ['l6', 'l25', 'l43', 'l60', 'l76', 'l91', 'l105', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131']", + "39, (VHL) ['l7', 'l26', 'l44', 'l61', 'l77', 'l92', 'l106', 'l119', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142']", + "41, kidney ['l8', 'l27', 'l45', 'l62', 'l78', 'l93', 'l107', 'l120', 'l132', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149']", + "42, cancer ['l9', 'l28', 'l46', 'l63', 'l79', 'l94', 'l108', 'l121', 'l133', 'l143', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "43, cells ['l10', 'l29', 'l47', 'l64', 'l80', 'l95', 'l109', 'l122', 'l134', 'l144', 'l150', 'l156', 'l157', 'l158', 'l159', 'l160']", + "46, mTOR ['l11', 'l30', 'l48', 'l65', 'l81', 'l96', 'l110', 'l123', 'l135', 'l145', 'l151', 'l156', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166']", + "47, inhibitor ['l12', 'l31', 'l49', 'l66', 'l82', 'l97', 'l111', 'l124', 'l136', 'l146', 'l152', 'l157', 'l161', 'l167', 'l168', 'l169', 'l170', 'l171']", + "48, CCI-779 ['l13', 'l32', 'l50', 'l67', 'l83', 'l98', 'l112', 'l125', 'l137', 'l147', 'l153', 'l158', 'l162', 'l167', 'l172', 'l173', 'l174', 'l175']", + "49, in ['l14', 'l33', 'l51', 'l68', 'l84', 'l99', 'l113', 'l126', 'l138', 'l148', 'l154', 'l159', 'l163', 'l168', 'l172', 'l176']", + "50, vitro ['l15', 'l34', 'l52', 'l69', 'l85', 'l100', 'l114', 'l127', 'l139', 'l149', 'l155', 'l160', 'l164', 'l169', 'l173', 'l176']", + "53, mouse ['l16', 'l35', 'l53', 'l70', 'l86', 'l101', 'l115', 'l128', 'l177', 'l178', 'l179']", + "54, models. ['l17', 'l36', 'l54', 'l71', 'l87', 'l102', 'l116', 'l129', 'l140', 'l177', 'l180', 'l181']", + "55, Growth ['l18', 'l37', 'l55', 'l72', 'l88', 'l103', 'l117', 'l130', 'l141', 'l165', 'l170', 'l174', 'l178', 'l180', 'l182']", + "56, arrest ['l19', 'l38', 'l56', 'l73', 'l89', 'l104', 'l118', 'l131', 'l142', 'l166', 'l171', 'l175', 'l179', 'l181', 'l182']", + "76, expression ['l183', 'l184', 'l185', 'l186', 'l187']", + "77, of ['l183', 'l188', 'l189', 'l190', 'l191']", + "78, a ['l184', 'l188', 'l192', 'l193', 'l194']", + "79, VHL-resistant ['l185', 'l189', 'l192', 'l195', 'l196']", + "80, HIF1A ['l186', 'l190', 'l193', 'l195', 'l197']", + "81, cDNA ['l187', 'l191', 'l194', 'l196', 'l197']", + "87, VHL-deficient ['l198']", + "88, tumors ['l198']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Von", + "Hippel-Lindau", + "tumor", + "suppressor", + "gene", + "(VHL)" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "kidney", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Von", + "Hippel-Lindau", + "tumor", + "suppressor", + "gene", + "(VHL)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Von", + "Hippel-Lindau", + "tumor", + "suppressor", + "gene", + "(VHL)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Von", + "Hippel-Lindau", + "tumor", + "suppressor", + "gene", + "(VHL)" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "Growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Von", + "Hippel-Lindau", + "tumor", + "suppressor", + "gene", + "(VHL)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "kidney", + "cancer", + "cells" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibitor", + "CCI-779" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibitor", + "CCI-779" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibitor", + "CCI-779" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "Growth" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibitor", + "CCI-779" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "Growth" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "models." + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest" + ] + } + }, + { + "phenotype": { + "val": "cell growth", + "words": [ + "Growth" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "VHL-deficient" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + } + ] + }, + { + "PMID": "16327802", + "TEXT": "Interleukin (IL)-13 is a major inducer of fibrosis in many chronic infectious and autoimmune diseases. In studies of the mechanisms underlying such induction, we found that IL-13 induces transforming growth factor (TGF)-beta(1) in macrophages through a two-stage process involving, first, the induction of a receptor formerly considered to function only as a decoy receptor, IL-13Ralpha(2). Such induction requires IL-13 (or IL-4) and tumor necrosis factor (TNF)-alpha. Second, it involves IL-13 signaling through IL-13Ralpha(2) to activate an AP-1 variant containing c-jun and Fra-2, which then activates the TGFB1 promoter. In vivo, we found that prevention of IL-13Ralpha(2) expression reduced production of TGF-beta(1) in oxazolone-induced colitis and that prevention of IL-13Ralpha(2) expression, Il13ra2 gene silencing or blockade of IL-13Ralpha(2) signaling led to marked downregulation of TGF-beta(1) production and collagen deposition in bleomycin-induced lung fibrosis. These data suggest that IL-13Ralpha(2) signaling during prolonged inflammation is an important therapeutic target for the prevention of TGF-beta(1)-mediated fibrosis.", + "TAG_DATA": [ + "88, In {'context': 'B-in vivo'}", + "89, vivo, {'context': 'I-in vivo'}", + "93, prevention {'perturbing_action': 'B-other'}", + "94, of {'perturbing_action': 'I-rnai/knockdown'}", + "95, IL-13Ralpha(2) {'perturbing_action': 'I-other'}", + "96, expression {'perturbing_action': 'I-other'}", + "106, prevention {'perturbing_action': 'B-other'}", + "107, of {'perturbing_action': 'I-rnai/knockdown'}", + "108, IL-13Ralpha(2) {'perturbing_action': 'I-rnai/knockdown'}", + "109, expression, {'perturbing_action': 'I-rnai/knockdown'}", + "110, Il13ra2 {'perturbing_action': 'B-rnai/knockdown'}", + "111, gene {'perturbing_action': 'I-rnai/knockdown'}", + "112, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "130, lung {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "88, In ['l0']", + "89, vivo, ['l0']", + "93, prevention ['l1', 'l2', 'l3']", + "94, of ['l1', 'l4', 'l5']", + "95, IL-13Ralpha(2) ['l2', 'l4', 'l6']", + "96, expression ['l3', 'l5', 'l6']", + "106, prevention ['l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "107, of ['l7', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "108, IL-13Ralpha(2) ['l8', 'l14', 'l20', 'l21', 'l22', 'l23', 'l24']", + "109, expression, ['l9', 'l15', 'l20', 'l25', 'l26', 'l27', 'l28']", + "110, Il13ra2 ['l10', 'l16', 'l21', 'l25', 'l29', 'l30', 'l31']", + "111, gene ['l11', 'l17', 'l22', 'l26', 'l29', 'l32', 'l33']", + "112, silencing ['l12', 'l18', 'l23', 'l27', 'l30', 'l32', 'l34']", + "130, lung ['l13', 'l19', 'l24', 'l28', 'l31', 'l33', 'l34']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "prevention" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "IL-13Ralpha(2)", + "expression,", + "Il13ra2", + "gene", + "silencing" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + } + } + ] + }, + { + "PMID": "16286925", + "TEXT": "It is widely accepted that the p53 tumor suppressor restricts abnormal cells by induction of growth arrest or by triggering apoptosis. Here we show that, in addition, p53 protects the genome from oxidation by reactive oxygen species (ROS), a major cause of DNA damage and genetic instability. In the absence of severe stresses, relatively low levels of p53 are sufficient for upregulation of several genes with antioxidant products, which is associated with a decrease in intracellular ROS. Downregulation of p53 results in excessive oxidation of DNA, increased mutation rate and karyotype instability, which are prevented by incubation with the antioxidant N-acetylcysteine (NAC). Dietary supplementation with NAC prevented frequent lymphomas characteristic of Trp53-knockout mice, and slowed the growth of lung cancer xenografts deficient in p53. Our results provide a new paradigm for a nonrestrictive tumor suppressor function of p53 and highlight the potential importance of antioxidants in the prophylaxis and treatment of cancer.", + "TAG_DATA": [ + "77, Downregulation {'perturbing_action': 'B-gene loss-of-function'}", + "78, of {'perturbing_action': 'I-gene loss-of-function'}", + "79, p53 {'perturbing_action': 'I-gene loss-of-function'}", + "106, prevented {'effect': 'B-negative'}", + "108, lymphomas {'phenotype': 'B-tumourigenesis'}", + "111, Trp53-knockout {'perturbing_action': 'B-gene loss-of-function'}", + "112, mice, {'context': 'B-organism'}", + "118, lung {'context': 'B-xenograft'}", + "119, cancer {'context': 'I-xenograft'}", + "120, xenografts {'context': 'I-xenograft'}", + "121, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "122, in {'perturbing_action': 'I-gene loss-of-function'}", + "123, p53. {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "77, Downregulation ['l0', 'l1']", + "78, of ['l0', 'l2']", + "79, p53 ['l1', 'l2']", + "106, prevented ['l3', 'l4', 'l5']", + "108, lymphomas ['l3', 'l6', 'l7']", + "111, Trp53-knockout ['l4', 'l6', 'l8']", + "112, mice, ['l5', 'l7', 'l8']", + "118, lung ['l9', 'l10', 'l11', 'l12', 'l13']", + "119, cancer ['l9', 'l14', 'l15', 'l16', 'l17']", + "120, xenografts ['l10', 'l14', 'l18', 'l19', 'l20']", + "121, deficient ['l11', 'l15', 'l18', 'l21', 'l22']", + "122, in ['l12', 'l16', 'l19', 'l21', 'l23']", + "123, p53. ['l13', 'l17', 'l20', 'l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphomas" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trp53-knockout" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphomas" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trp53-knockout" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "lymphomas" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trp53-knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "lung", + "cancer", + "xenografts" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "p53." + ] + } + } + ] + }, + { + "PMID": "16244652", + "TEXT": "Sonic hedgehog (Shh) is a crucial regulator of organ development during embryogenesis. We investigated whether intramyocardial gene transfer of naked DNA encoding human Shh (phShh) could promote a favorable effect on recovery from acute and chronic myocardial ischemia in adult animals, not only by promoting neovascularization, but by broader effects, consistent with the role of this morphogen in embryogenesis. After Shh gene transfer, the hedgehog pathway was upregulated in mammalian fibroblasts and cardiomyocytes. This resulted in preservation of left ventricular function in both acute and chronic myocardial ischemia by enhanced neovascularization, and reduced fibrosis and cardiac apoptosis. Shh gene transfer also enhanced the contribution of bone marrow-derived endothelial progenitor cells to myocardial neovascularization. These data suggest that Shh gene therapy may have considerable therapeutic potential in individuals with acute and chronic myocardial ischemia by triggering expression of multiple trophic factors and engendering tissue repair in the adult heart.", + "TAG_DATA": [ + "61, gene {'perturbing_action': 'I-gene gain-of-function'}", + "62, transfer, {'perturbing_action': 'I-gene gain-of-function'}", + "69, mammalian {'context': 'B-cells'}", + "70, fibroblasts {'context': 'I-cells'}", + "72, cardiomyocytes. {'context': 'B-cells'}", + "92, reduced {'effect': 'B-negative'}", + "95, cardiac {'context': 'B-cells'}", + "96, apoptosis. {'phenotype': 'B-apoptosis'}", + "98, gene {'perturbing_action': 'I-gene gain-of-function'}", + "99, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "105, bone {'context': 'B-cells'}", + "106, marrow-derived {'context': 'I-cells'}", + "107, endothelial {'context': 'I-cells'}", + "108, progenitor {'context': 'I-cells'}", + "109, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "61, gene ['l0', 'l1', 'l2', 'l3', 'l4']", + "62, transfer, ['l0', 'l5', 'l6', 'l7', 'l8']", + "69, mammalian ['l1', 'l5', 'l9', 'l10', 'l11', 'l12', 'l13']", + "70, fibroblasts ['l2', 'l6', 'l9', 'l14', 'l15']", + "72, cardiomyocytes. ['l3', 'l7', 'l10', 'l14', 'l16']", + "92, reduced ['l4', 'l8', 'l11', 'l15', 'l16', 'l17', 'l18']", + "95, cardiac ['l12', 'l17', 'l19']", + "96, apoptosis. ['l13', 'l18', 'l19']", + "97, Shh ['l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "98, gene ['l20', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "99, transfer ['l21', 'l27', 'l33', 'l34', 'l35', 'l36', 'l37']", + "105, bone ['l22', 'l28', 'l33', 'l38', 'l39', 'l40', 'l41']", + "106, marrow-derived ['l23', 'l29', 'l34', 'l38', 'l42', 'l43', 'l44']", + "107, endothelial ['l24', 'l30', 'l35', 'l39', 'l42', 'l45', 'l46']", + "108, progenitor ['l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l47']", + "109, cells ['l26', 'l32', 'l37', 'l41', 'l44', 'l46', 'l47']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "gene", + "transfer,", + "transfer" + ] + }, + "context": { + "val": "cells", + "words": [ + "mammalian", + "fibroblasts", + "cardiomyocytes.", + "bone", + "marrow-derived", + "endothelial", + "progenitor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "gene", + "transfer," + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mammalian", + "fibroblasts", + "cardiomyocytes.", + "cardiac" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "mammalian", + "cardiac" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "16227992", + "TEXT": "Akt kinases control essential cellular functions, including proliferation, apoptosis, metabolism and transcription, and have been proposed as promising targets for treatment of angiogenesis-dependent pathologies, such as cancer and ischemic injury. But their precise roles in neovascularization remain elusive. Here we show that Akt1 is the predominant isoform in vascular cells and describe the unexpected consequences of Akt1 knockout on vascular integrity and pathological angiogenesis. Angiogenic responses in three distinct in vivo models were enhanced in Akt1(-/-) mice; these enhanced responses were associated with impairment of blood vessel maturation and increased vascular permeability. Although impaired vascular maturation in Akt1(-/-) mice may be attributed to reduced activation of endothelial nitric oxide synthase (eNOS), the major phenotypic changes in vascular permeability and angiogenesis were linked to reduced expression of two endogenous vascular regulators, thrombospondins 1 (TSP-1) and 2 (TSP-2). Re-expression of TSP-1 and TSP-2 in mice transplanted with wild-type bone marrow corrected the angiogenic abnormalities in Akt1(-/-) mice. These findings establish a crucial role of an Akt-thrombospondin axis in angiogenesis.", + "TAG_DATA": [ + "56, Akt1 {'perturbing_action': 'B-gene loss-of-function'}", + "69, in {'context': 'B-in vivo'}", + "70, vivo {'context': 'I-in vivo'}", + "75, Akt1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "76, mice; {'context': 'B-organism'}", + "97, Akt1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "98, mice {'context': 'B-organism'}", + "136, Re-expression {'perturbing_action': 'B-gene gain-of-function'}", + "137, of {'perturbing_action': 'I-gene gain-of-function'}", + "138, TSP-1 {'perturbing_action': 'I-gene gain-of-function'}", + "139, and {'perturbing_action': 'I-gene gain-of-function'}", + "140, TSP-2 {'perturbing_action': 'I-gene gain-of-function'}", + "142, mice {'context': 'B-organism'}", + "153, Akt1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "154, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, Akt1 ['l0', 'l1', 'l2', 'l3']", + "69, in ['l0', 'l4', 'l5', 'l6']", + "70, vivo ['l1', 'l4', 'l7', 'l8']", + "75, Akt1(-/-) ['l2', 'l5', 'l7', 'l9']", + "76, mice; ['l3', 'l6', 'l8', 'l9']", + "97, Akt1(-/-) ['l10']", + "98, mice ['l10']", + "136, Re-expression ['l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "137, of ['l11', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "138, TSP-1 ['l12', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "139, and ['l13', 'l20', 'l26', 'l32', 'l33', 'l34', 'l35', 'l36']", + "140, TSP-2 ['l14', 'l21', 'l27', 'l32', 'l37', 'l38', 'l39', 'l40']", + "142, mice ['l15', 'l22', 'l28', 'l33', 'l37', 'l41', 'l42', 'l43']", + "147, marrow ['l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l44', 'l45']", + "153, Akt1(-/-) ['l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l46']", + "154, mice. ['l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l46']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Akt1", + "Akt1(-/-)" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Akt1", + "Akt1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice;", + "mice", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Re-expression", + "of", + "TSP-1", + "and", + "TSP-2" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "16041382", + "TEXT": "We developed a new class of vaccines, based on killed but metabolically active (KBMA) bacteria, that simultaneously takes advantage of the potency of live vaccines and the safety of killed vaccines. We removed genes required for nucleotide excision repair (uvrAB), rendering microbial-based vaccines exquisitely sensitive to photochemical inactivation with psoralen and long-wavelength ultraviolet light. Colony formation of the nucleotide excision repair mutants was blocked by infrequent, randomly distributed psoralen crosslinks, but the bacterial population was able to express its genes, synthesize and secrete proteins. Using the intracellular pathogen Listeria monocytogenes as a model platform, recombinant psoralen-inactivated Lm DeltauvrAB vaccines induced potent CD4(+) and CD8(+) T-cell responses and protected mice against virus challenge in an infectious disease model and provided therapeutic benefit in a mouse cancer model. Microbial KBMA vaccines used either as a recombinant vaccine platform or as a modified form of the pathogen itself may have broad use for the treatment of infectious disease and cancer.", + "TAG_DATA": [ + "54, Colony {'phenotype': 'B-colony formation'}", + "55, formation {'phenotype': 'I-colony formation'}", + "63, blocked {'effect': 'B-negative'}", + "108, mice {'context': 'B-organism'}", + "123, mouse {'context': 'B-neoplasm'}", + "124, cancer {'context': 'I-neoplasm'}", + "125, model. {'context': 'I-neoplasm'}" + ], + "LINK_DATA": [ + "54, Colony ['l0', 'l1']", + "55, formation ['l0', 'l2']", + "63, blocked ['l1', 'l2']", + "123, mouse ['l3', 'l4']", + "124, cancer ['l3', 'l5']", + "125, model. ['l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "colony formation", + "words": [ + "Colony", + "formation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + } + ] + }, + { + "PMID": "16025125", + "TEXT": "The molecular events that regulate engraftment and mobilization of hematopoietic stem cells and progenitors (HSC/Ps) are still incompletely defined. We have examined the role of the Rho GTPases Rac1 and Rac2 in HSC engraftment and mobilization. Rac1, but not the hematopoietic-specific Rac2, is required for the engraftment phase of hematopoietic reconstitution, because Rac1(-/-) HSCs did not rescue in vivo hematopoiesis after transplantation, but deletion of Rac1 after engraftment did not impair steady-state hematopoiesis. Rac1(-/-) HSC/Ps showed impaired spatial localization to the endosteum but near-normal homing to the medullary cavity in vivo. Interaction with the bone marrow microenvironment in vitro was markedly altered. Whereas post-engraftment deletion of Rac1 alone did not impair hematopoiesis, deficiency of both Rac1 and Rac2 led to massive mobilization of HSCs from the marrow associated with ineffective hematopoiesis and intense selection for Rac-expressing HSCs. This mobilization was reversible by re-expression of Rac1. In addition, a rationally designed, reversible small-molecule inhibitor of Rac activation led to transient mobilization of engraftable HSC/Ps. Rac proteins thus differentially regulate engraftment and mobilization phenotypes, suggesting that these biological processes and steady-state hematopoiesis are biochemically separable and that Rac proteins may be important molecular targets for stem cell modification.", + "TAG_DATA": [ + "52, Rac1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "53, HSCs {'context': 'B-cells'}", + "57, in {'context': 'B-in vivo'}", + "58, vivo {'context': 'I-in vivo'}", + "63, deletion {'perturbing_action': 'B-gene loss-of-function'}", + "64, of {'perturbing_action': 'I-gene loss-of-function'}", + "65, Rac1 {'perturbing_action': 'I-gene loss-of-function'}", + "73, Rac1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "74, HSC/Ps {'context': 'B-cells'}", + "89, in {'context': 'B-in vivo'}", + "90, vivo. {'context': 'I-in vivo'}", + "97, in {'context': 'B-in vitro'}", + "98, vitro {'context': 'I-in vitro'}", + "104, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "105, of {'perturbing_action': 'I-gene loss-of-function'}", + "106, Rac1 {'perturbing_action': 'I-gene loss-of-function'}", + "112, deficiency {'perturbing_action': 'B-gene loss-of-function'}", + "113, of {'perturbing_action': 'I-gene loss-of-function'}", + "114, both {'perturbing_action': 'I-gene loss-of-function'}", + "115, Rac1 {'perturbing_action': 'I-gene loss-of-function'}", + "116, and {'perturbing_action': 'I-gene loss-of-function'}", + "117, Rac2 {'perturbing_action': 'I-gene loss-of-function'}", + "123, HSCs {'context': 'B-cells'}", + "135, Rac-expressing {'context': 'B-transformed cells'}", + "136, HSCs. {'context': 'I-transformed cells'}", + "142, re-expression {'perturbing_action': 'B-gene gain-of-function'}", + "143, of {'perturbing_action': 'I-gene gain-of-function'}", + "144, Rac1. {'perturbing_action': 'I-gene gain-of-function'}", + "150, reversible {'perturbing_action': 'I-pharmacological inhibition'}", + "151, small-molecule {'perturbing_action': 'I-pharmacological inhibition'}", + "152, inhibitor {'perturbing_action': 'I-pharmacological inhibition'}", + "153, of {'perturbing_action': 'I-pharmacological inhibition'}", + "154, Rac {'perturbing_action': 'I-pharmacological inhibition'}", + "155, activation {'perturbing_action': 'I-pharmacological inhibition'}", + "162, HSC/Ps. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "52, Rac1(-/-) ['l0', 'l1', 'l2']", + "53, HSCs ['l0', 'l3', 'l4']", + "57, in ['l1', 'l3', 'l5']", + "58, vivo ['l2', 'l4', 'l5']", + "63, deletion ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "64, of ['l6', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "65, Rac1 ['l7', 'l14', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "73, Rac1(-/-) ['l8', 'l15', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "74, HSC/Ps ['l9', 'l16', 'l22', 'l27', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "89, in ['l10', 'l17', 'l23', 'l28', 'l36', 'l42', 'l43', 'l44']", + "90, vivo. ['l11', 'l18', 'l24', 'l29', 'l37', 'l42', 'l45', 'l46']", + "97, in ['l12', 'l19', 'l25', 'l30', 'l38', 'l43', 'l45', 'l47', 'l48', 'l49']", + "98, vitro ['l13', 'l20', 'l26', 'l31', 'l39', 'l44', 'l46', 'l47', 'l50', 'l51']", + "104, deletion ['l32', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "105, of ['l33', 'l40', 'l48', 'l50', 'l52', 'l60', 'l61', 'l62', 'l63', 'l64']", + "106, Rac1 ['l34', 'l41', 'l49', 'l51', 'l53', 'l60', 'l65', 'l66', 'l67', 'l68']", + "112, deficiency ['l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "113, of ['l69', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88']", + "114, both ['l70', 'l79', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "115, Rac1 ['l54', 'l71', 'l80', 'l89', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "116, and ['l55', 'l72', 'l81', 'l90', 'l97', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109']", + "117, Rac2 ['l56', 'l61', 'l65', 'l73', 'l82', 'l91', 'l98', 'l104', 'l110', 'l111', 'l112']", + "123, HSCs ['l35', 'l57', 'l62', 'l66', 'l74', 'l83', 'l92', 'l99', 'l105', 'l110', 'l113', 'l114']", + "135, Rac-expressing ['l58', 'l63', 'l67', 'l75', 'l84', 'l93', 'l100', 'l106', 'l111', 'l113', 'l115']", + "136, HSCs. ['l59', 'l64', 'l68', 'l76', 'l85', 'l94', 'l101', 'l107', 'l112', 'l114', 'l115']", + "142, re-expression ['l86', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "143, of ['l77', 'l87', 'l95', 'l102', 'l108', 'l116', 'l122', 'l123', 'l124', 'l125', 'l126']", + "144, Rac1. ['l78', 'l88', 'l96', 'l103', 'l109', 'l117', 'l122', 'l127', 'l128']", + "150, reversible ['l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "151, small-molecule ['l129', 'l135', 'l136', 'l137', 'l138', 'l139']", + "152, inhibitor ['l130', 'l135', 'l140', 'l141', 'l142', 'l143']", + "153, of ['l118', 'l123', 'l131', 'l136', 'l140', 'l144', 'l145', 'l146']", + "154, Rac ['l119', 'l124', 'l132', 'l137', 'l141', 'l144', 'l147', 'l148']", + "155, activation ['l120', 'l125', 'l127', 'l133', 'l138', 'l142', 'l145', 'l147', 'l149']", + "162, HSC/Ps. ['l121', 'l126', 'l128', 'l134', 'l139', 'l143', 'l146', 'l148', 'l149']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rac1(-/-)", + "deletion", + "of", + "Rac1", + "deficiency", + "both", + "and", + "Rac2" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSCs", + "HSC/Ps" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rac1(-/-)", + "deletion", + "of", + "Rac1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Rac1", + "Rac1(-/-)" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Rac1", + "deficiency", + "both", + "and", + "Rac2" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "Rac-expressing", + "HSCs." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "re-expression", + "of", + "Rac1." + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC/Ps." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "reversible", + "small-molecule", + "inhibitor", + "of", + "Rac", + "activation" + ] + }, + "context": { + "val": "cells", + "words": [ + "HSC/Ps." + ] + } + } + ] + }, + { + "PMID": "15908956", + "TEXT": "The cellular targets of primary mutations and malignant transformation remain elusive in most cancers. Here, we show that clinically and genetically different subtypes of acute lymphoblastic leukemia (ALL) originate and transform at distinct stages of hematopoietic development. Primary ETV6-RUNX1 (also known as TEL-AML1) fusions and subsequent leukemic transformations were targeted to committed B-cell progenitors. Major breakpoint BCR-ABL1 fusions (encoding P210 BCR-ABL1) originated in hematopoietic stem cells (HSCs), whereas minor BCR-ABL1 fusions (encoding P190 BCR-ABL1) had a B-cell progenitor origin, suggesting that P190 and P210 BCR-ABL1 ALLs represent largely distinct tumor biological and clinical entities. The transformed leukemia-initiating stem cells in both P190 and P210 BCR-ABL1 ALLs had, as in ETV6-RUNX1 ALLs, a committed B progenitor phenotype. In all patients, normal and leukemic repopulating stem cells could successfully be separated prospectively, and notably, the size of the normal HSC compartment in ETV6-RUNX1 and P190 BCR-ABL1 ALLs was found to be unaffected by the expansive leukemic stem cell population.", + "TAG_DATA": [ + "95, transformed {'phenotype': 'B-transformation'}", + "96, leukemia-initiating {'context': 'B-cells'}", + "97, stem {'context': 'I-cells'}", + "98, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "95, transformed ['l0', 'l1', 'l2']", + "96, leukemia-initiating ['l0', 'l3', 'l4']", + "97, stem ['l1', 'l3', 'l5']", + "98, cells ['l2', 'l4', 'l5']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "transformation", + "words": [ + "transformed" + ] + }, + "context": { + "val": "cells", + "words": [ + "leukemia-initiating", + "stem", + "cells" + ] + } + } + ] + }, + { + "PMID": "15895074", + "TEXT": "In inflammatory arthridities such as rheumatoid arthritis, cognate lymphocytes have long been considered instigators of autoimmunity, but accumulating evidence indicates that innate immune cells such as neutrophils and mast cells are responsible for a vast majority of acute and ongoing inflammation; however, the molecular mechanisms that govern them remain largely unknown. Here we show that such inflammation requires the forkhead transcription factor Foxo3a: Foxo3a-deficient mice are resistant to two models of neutrophilic inflammation, immune complex-mediated inflammatory arthritis and thioglycollate-induced peritonitis. This reflects a need for Foxo3a to maintain neutrophil vitality during inflammation by suppressing Fas ligand; because Foxo3a can bind and suppress the Fasl promoter, Foxo3a-deficient neutrophils upregulate Fas ligand and undergo apoptosis in response to TNF-alpha and IL-1, and Fas ligand blockade renders Foxo3a-deficient mice susceptible to both arthritis and peritonitis. Thus, Foxo3a ensures neutrophil survival during inflammation, identifying Foxo3a as therapeutic target in inflammation.", + "TAG_DATA": [ + "63, Foxo3a-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "64, mice {'context': 'B-organism'}", + "105, Foxo3a-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "106, neutrophils {'context': 'B-cells'}", + "111, undergo {'effect': 'B-positive'}", + "112, apoptosis {'phenotype': 'B-apoptosis'}", + "124, Foxo3a-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "125, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "63, Foxo3a-deficient ['l0']", + "64, mice ['l0']", + "105, Foxo3a-deficient ['l1', 'l2', 'l3']", + "106, neutrophils ['l1', 'l4', 'l5']", + "111, undergo ['l2', 'l4', 'l6']", + "112, apoptosis ['l3', 'l5', 'l6']", + "124, Foxo3a-deficient ['l7']", + "125, mice ['l7']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Foxo3a-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Foxo3a-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "neutrophils" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Foxo3a-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "undergo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Foxo3a-deficient" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neutrophils" + ] + }, + "effect": { + "val": "positive", + "words": [ + "undergo" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neutrophils" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "undergo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "15852017", + "TEXT": "Cholinergic neuron loss is a cardinal feature of Alzheimer disease. Nerve growth factor (NGF) stimulates cholinergic function, improves memory and prevents cholinergic degeneration in animal models of injury, amyloid overexpression and aging. We performed a phase 1 trial of ex vivo NGF gene delivery in eight individuals with mild Alzheimer disease, implanting autologous fibroblasts genetically modified to express human NGF into the forebrain. After mean follow-up of 22 months in six subjects, no long-term adverse effects of NGF occurred. Evaluation of the Mini-Mental Status Examination and Alzheimer Disease Assessment Scale-Cognitive subcomponent suggested improvement in the rate of cognitive decline. Serial PET scans showed significant (P < 0.05) increases in cortical 18-fluorodeoxyglucose after treatment. Brain autopsy from one subject suggested robust growth responses to NGF. Additional clinical trials of NGF for Alzheimer disease are warranted.", + "TAG_DATA": [ + "46, individuals {'context': 'B-patient'}", + "52, autologous {'context': 'B-cells'}", + "53, fibroblasts {'context': 'I-cells'}", + "54, genetically {'perturbing_action': 'I-gene gain-of-function'}", + "55, modified {'perturbing_action': 'I-gene gain-of-function'}", + "56, to {'perturbing_action': 'I-gene gain-of-function'}", + "57, express {'perturbing_action': 'I-gene gain-of-function'}", + "58, human {'perturbing_action': 'I-gene gain-of-function'}", + "59, NGF {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "46, individuals ['l0', 'l1']", + "52, autologous ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "53, fibroblasts ['l0', 'l2', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "54, genetically ['l3', 'l9', 'l15', 'l16', 'l17', 'l18', 'l19']", + "55, modified ['l4', 'l10', 'l15', 'l20', 'l21', 'l22', 'l23']", + "56, to ['l5', 'l11', 'l16', 'l20', 'l24', 'l25', 'l26']", + "57, express ['l6', 'l12', 'l17', 'l21', 'l24', 'l27', 'l28']", + "58, human ['l7', 'l13', 'l18', 'l22', 'l25', 'l27', 'l29']", + "59, NGF ['l1', 'l8', 'l14', 'l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "patient", + "words": [ + "individuals" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "NGF" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "autologous", + "fibroblasts" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "genetically", + "modified", + "to", + "express", + "human", + "NGF" + ] + } + } + ] + }, + { + "PMID": "15834427", + "TEXT": "One of the most clinically advanced forms of experimental disease-modifying treatment for Alzheimer disease is immunization against the amyloid beta protein (Abeta), but how this may prevent cognitive impairment is unclear. We hypothesized that antibodies to Abeta could exert a beneficial action by directly neutralizing potentially synaptotoxic soluble Abeta species in the brain. Intracerebroventricular injection of naturally secreted human Abeta inhibited long-term potentiation (LTP), a correlate of learning and memory, in rat hippocampus in vivo but a monoclonal antibody to Abeta completely prevented the inhibition of LTP when injected after Abeta. Size fractionation showed that Abeta oligomers, not monomers or fibrils, were responsible for inhibiting LTP, and an Abeta antibody again prevented such inhibition. Active immunization against Abeta was partially effective, and the effects correlated positively with levels of antibodies to Abeta oligomers. The ability of exogenous and endogenous antibodies to rapidly neutralize soluble Abeta oligomers that disrupt synaptic plasticity in vivo suggests that treatment with such antibodies might show reversible cognitive deficits in early Alzheimer disease.", + "TAG_DATA": [ + "60, inhibited {'effect': 'B-negative'}", + "71, rat {'context': 'B-tissue/organ'}", + "72, hippocampus {'context': 'I-tissue/organ'}", + "73, in {'context': 'B-in vivo'}", + "74, vivo {'context': 'I-in vivo'}", + "84, inhibition {'effect': 'B-negative'}", + "104, inhibiting {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "60, inhibited ['l0', 'l1', 'l2', 'l3', 'l4']", + "61, long-term ['l0', 'l5', 'l6', 'l7', 'l8']", + "71, rat ['l1', 'l5', 'l9', 'l10', 'l11']", + "72, hippocampus ['l2', 'l6', 'l9', 'l12', 'l13']", + "73, in ['l3', 'l7', 'l10', 'l12', 'l14']", + "74, vivo ['l4', 'l8', 'l11', 'l13', 'l14']", + "77, monoclonal ['l15', 'l16', 'l17']", + "78, antibody ['l15', 'l18', 'l19']", + "84, inhibition ['l16', 'l18']", + "104, inhibiting ['l17', 'l19']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "rat", + "hippocampus" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "15821748", + "TEXT": "Nijmegen breakage syndrome (NBS), ataxia telangiectasia and ataxia telangiectasia-like disorder (ATLD) show overlapping phenotypes such as growth retardation, microcephaly, cerebellar developmental defects and ataxia. However, the molecular pathogenesis of these neurological defects remains elusive. Here we show that inactivation of the Nbn gene (also known as Nbs1) in mouse neural tissues results in a combination of the neurological anomalies characteristic of NBS, ataxia telangiectasia and ATLD, including microcephaly, growth retardation, cerebellar defects and ataxia. Loss of Nbn causes proliferation arrest of granule cell progenitors and apoptosis of postmitotic neurons in the cerebellum. Furthermore, Nbn-deficient neuroprogenitors show proliferation defects (but not increased apoptosis) and contain more chromosomal breaks, which are accompanied by ataxia telangiectasia mutated protein (ATM)-mediated p53 activation. Notably, depletion of p53 substantially rescues the neurological defects of Nbn mutant mice. This study gives insight into the physiological function of NBS1 (the Nbn gene product) and the function of the DNA damage response in the neurological anomalies of NBS, ataxia telangiectasia and ATLD.", + "TAG_DATA": [ + "38, inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "39, of {'perturbing_action': 'I-gene loss-of-function'}", + "40, the {'perturbing_action': 'I-gene loss-of-function'}", + "41, Nbn {'perturbing_action': 'I-gene loss-of-function'}", + "42, gene {'perturbing_action': 'I-gene loss-of-function'}", + "43, (also {'perturbing_action': 'I-gene loss-of-function'}", + "48, mouse {'context': 'B-tissue/organ'}", + "49, neural {'context': 'I-tissue/organ'}", + "50, tissues {'context': 'I-tissue/organ'}", + "74, Loss {'perturbing_action': 'B-gene loss-of-function'}", + "75, of {'perturbing_action': 'I-gene loss-of-function'}", + "76, Nbn {'perturbing_action': 'I-gene loss-of-function'}", + "77, causes {'effect': 'B-positive'}", + "78, proliferation {'phenotype': 'B-proliferation'}", + "79, arrest {'effect': 'B-negative', 'phenotype': 'I-cell cycle arrest'}", + "81, granule {'context': 'B-cells'}", + "82, cell {'context': 'I-cells'}", + "83, progenitors {'context': 'I-cells'}", + "85, apoptosis {'phenotype': 'B-apoptosis'}", + "87, postmitotic {'context': 'B-cells'}", + "88, neurons {'context': 'I-cells'}", + "91, cerebellum. {'context': 'B-tissue/organ'}", + "93, Nbn-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "94, neuroprogenitors {'context': 'B-cells'}", + "96, proliferation {'phenotype': 'B-proliferation'}", + "97, defects {'effect': 'B-negative'}", + "100, increased {'effect': 'B-positive'}", + "101, apoptosis) {'phenotype': 'B-apoptosis'}", + "119, depletion {'perturbing_action': 'B-gene loss-of-function'}", + "120, of {'perturbing_action': 'I-gene loss-of-function'}", + "121, p53 {'perturbing_action': 'I-gene loss-of-function'}", + "128, Nbn {'perturbing_action': 'B-other'}", + "129, mutant {'perturbing_action': 'I-other'}", + "130, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "38, inactivation ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "39, of ['l0', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "40, the ['l1', 'l21', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "41, Nbn ['l2', 'l22', 'l41', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "42, gene ['l3', 'l23', 'l42', 'l60', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "43, (also ['l4', 'l24', 'l43', 'l61', 'l78', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "48, mouse ['l5', 'l25', 'l44', 'l62', 'l79', 'l95', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "49, neural ['l6', 'l26', 'l45', 'l63', 'l80', 'l96', 'l111', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "50, tissues ['l7', 'l27', 'l46', 'l64', 'l81', 'l97', 'l112', 'l123', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143']", + "74, Loss ['l8', 'l28', 'l47', 'l65', 'l82', 'l98', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155']", + "75, of ['l9', 'l29', 'l48', 'l66', 'l83', 'l99', 'l144', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165', 'l166']", + "76, Nbn ['l10', 'l30', 'l49', 'l67', 'l84', 'l100', 'l145', 'l156', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176']", + "77, causes ['l11', 'l31', 'l50', 'l68', 'l85', 'l101', 'l113', 'l124', 'l134', 'l146', 'l157', 'l167', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185']", + "78, proliferation ['l12', 'l32', 'l51', 'l69', 'l86', 'l102', 'l114', 'l125', 'l135', 'l147', 'l158', 'l168', 'l177', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "79, arrest ['l13', 'l33', 'l52', 'l70', 'l87', 'l103', 'l115', 'l126', 'l136', 'l148', 'l159', 'l169', 'l178', 'l186', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200']", + "81, granule ['l14', 'l34', 'l53', 'l71', 'l88', 'l104', 'l116', 'l127', 'l137', 'l149', 'l160', 'l170', 'l179', 'l187', 'l194', 'l201', 'l202', 'l203', 'l204', 'l205', 'l206']", + "82, cell ['l15', 'l35', 'l54', 'l72', 'l89', 'l105', 'l117', 'l128', 'l138', 'l150', 'l161', 'l171', 'l180', 'l188', 'l195', 'l201', 'l207', 'l208', 'l209', 'l210', 'l211']", + "83, progenitors ['l16', 'l36', 'l55', 'l73', 'l90', 'l106', 'l118', 'l129', 'l139', 'l151', 'l162', 'l172', 'l181', 'l189', 'l196', 'l202', 'l207', 'l212', 'l213', 'l214', 'l215']", + "85, apoptosis ['l17', 'l37', 'l56', 'l74', 'l91', 'l107', 'l119', 'l130', 'l140', 'l152', 'l163', 'l173', 'l182', 'l190', 'l197', 'l203', 'l208', 'l212', 'l216', 'l217', 'l218']", + "87, postmitotic ['l18', 'l38', 'l57', 'l75', 'l92', 'l108', 'l120', 'l131', 'l141', 'l153', 'l164', 'l174', 'l183', 'l191', 'l198', 'l204', 'l209', 'l213', 'l216', 'l219', 'l220']", + "88, neurons ['l19', 'l39', 'l58', 'l76', 'l93', 'l109', 'l121', 'l132', 'l142', 'l154', 'l165', 'l175', 'l184', 'l192', 'l199', 'l205', 'l210', 'l214', 'l217', 'l219', 'l221']", + "91, cerebellum. ['l20', 'l40', 'l59', 'l77', 'l94', 'l110', 'l122', 'l133', 'l143', 'l155', 'l166', 'l176', 'l185', 'l193', 'l200', 'l206', 'l211', 'l215', 'l218', 'l220', 'l221']", + "93, Nbn-deficient ['l222', 'l223', 'l224', 'l225', 'l226']", + "94, neuroprogenitors ['l222', 'l227', 'l228', 'l229', 'l230']", + "96, proliferation ['l223', 'l227', 'l231', 'l232', 'l233']", + "97, defects ['l224', 'l228', 'l231', 'l234', 'l235']", + "100, increased ['l225', 'l229', 'l232', 'l234', 'l236']", + "101, apoptosis) ['l226', 'l230', 'l233', 'l235', 'l236']", + "119, depletion ['l237', 'l238', 'l239', 'l240', 'l241']", + "120, of ['l237', 'l242', 'l243', 'l244', 'l245']", + "121, p53 ['l238', 'l242', 'l246', 'l247', 'l248']", + "128, Nbn ['l239', 'l243', 'l246', 'l249', 'l250']", + "129, mutant ['l240', 'l244', 'l247', 'l249', 'l251']", + "130, mice. ['l241', 'l245', 'l248', 'l250', 'l251']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "the", + "Nbn", + "gene", + "(also", + "Loss" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "neural", + "tissues", + "cerebellum." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "the", + "Nbn", + "gene", + "(also", + "Loss", + "Nbn-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "causes", + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "the", + "Nbn", + "gene", + "(also", + "Loss", + "Nbn-deficient" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "the", + "Nbn", + "gene", + "(also", + "Loss", + "Nbn-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest", + "defects" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "the", + "Nbn", + "gene", + "(also", + "Loss" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "arrest" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "the", + "Nbn", + "gene", + "(also", + "Loss", + "Nbn-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "granule", + "cell", + "progenitors", + "postmitotic", + "neurons", + "neuroprogenitors" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "the", + "Nbn", + "gene", + "(also", + "Loss", + "Nbn-deficient" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis)" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "neural", + "tissues", + "cerebellum." + ] + }, + "effect": { + "val": "positive", + "words": [ + "causes" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "neural", + "tissues", + "cerebellum." + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "neural", + "tissues", + "cerebellum." + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "neural", + "tissues", + "cerebellum." + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "neural", + "tissues", + "cerebellum." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes", + "increased" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes", + "increased" + ] + }, + "context": { + "val": "cells", + "words": [ + "granule", + "cell", + "progenitors", + "postmitotic", + "neurons", + "neuroprogenitors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "causes", + "increased" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis)" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest", + "defects" + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "granule", + "cell", + "progenitors", + "postmitotic", + "neurons", + "neuroprogenitors" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "arrest", + "defects" + ] + }, + "context": { + "val": "cells", + "words": [ + "granule", + "cell", + "progenitors", + "postmitotic", + "neurons", + "neuroprogenitors" + ] + } + }, + { + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "arrest" + ] + }, + "context": { + "val": "cells", + "words": [ + "granule", + "cell", + "progenitors", + "postmitotic", + "neurons" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "arrest", + "defects" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis)" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "granule", + "cell", + "progenitors", + "postmitotic", + "neurons", + "neuroprogenitors" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "p53" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Nbn", + "mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "15793581", + "TEXT": "The bone morphogenetic proteins (BMPs) profoundly affect embryonic development, differentiation and disease. BMP signaling is suppressed by cysteine-rich domain proteins, such as chordin, that sequester ligands from the BMP receptor. We describe a novel protein, KCP, with 18 cysteine-rich domains. Unlike chordin, KCP enhances BMP signaling in a paracrine manner. Smad1-dependent transcription and phosphorylated Smad1 (P-Smad1) levels are increased, as KCP binds to BMP7 and enhances binding to the type I receptor. In vivo, Kcp(-/-) mice are viable and fertile. Because BMPs have a pivotal role in renal disease, we examined the phenotype of Kcp(-/-) mice in two different models of renal injury. Kcp(-/-) animals show reduced levels of P-Smad1, are more susceptible to developing renal interstitial fibrosis, are more sensitive to tubular injury and show substantial pathology after recovery. The data indicate an important role for KCP in attenuating the pathology of renal fibrotic disease.", + "TAG_DATA": [ + "72, In {'context': 'B-in vivo'}", + "73, vivo, {'context': 'I-in vivo'}", + "74, Kcp(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "75, mice {'context': 'B-organism'}", + "94, Kcp(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "95, mice {'context': 'B-organism'}", + "103, Kcp(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "104, animals {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "72, In ['l0', 'l1', 'l2']", + "73, vivo, ['l0', 'l3', 'l4']", + "74, Kcp(-/-) ['l1', 'l3', 'l5']", + "75, mice ['l2', 'l4', 'l5']", + "94, Kcp(-/-) ['l6']", + "95, mice ['l6']", + "103, Kcp(-/-) ['l7']", + "104, animals ['l7']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Kcp(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Kcp(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "animals" + ] + } + } + ] + }, + { + "PMID": "15778720", + "TEXT": "Angiopoietin-related growth factor (AGF), a member of the angiopoietin-like protein (Angptl) family, is secreted predominantly from the liver into the systemic circulation. Here, we show that most (>80%) of the AGF-deficient mice die at about embryonic day 13, whereas the surviving AGF-deficient mice develop marked obesity, lipid accumulation in skeletal muscle and liver, and insulin resistance accompanied by reduced energy expenditure relative to controls. In parallel, mice with targeted activation of AGF show leanness and increased insulin sensitivity resulting from increased energy expenditure. They are also protected from high-fat diet-induced obesity, insulin resistance and nonadipose tissue steatosis. Hepatic overexpression of AGF by adenoviral transduction, which leads to an approximately 2.5-fold increase in serum AGF concentrations, results in a significant (P < 0.01) body weight loss and increases insulin sensitivity in mice fed a high-fat diet. This study establishes AGF as a new hepatocyte-derived circulating factor that counteracts obesity and related insulin resistance.", + "TAG_DATA": [ + "30, AGF-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "31, mice {'context': 'B-organism'}", + "41, AGF-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "42, mice {'context': 'B-organism'}", + "66, mice {'context': 'B-organism'}", + "68, targeted {'perturbing_action': 'B-other'}", + "69, activation {'perturbing_action': 'I-other'}", + "70, of {'perturbing_action': 'I-other'}", + "71, AGF {'perturbing_action': 'I-other'}", + "97, Hepatic {'perturbing_action': 'B-gene gain-of-function'}", + "98, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "99, of {'perturbing_action': 'I-gene gain-of-function'}", + "100, AGF {'perturbing_action': 'I-gene gain-of-function'}", + "101, by {'perturbing_action': 'I-gene gain-of-function'}", + "102, adenoviral {'perturbing_action': 'I-gene gain-of-function'}", + "103, transduction, {'perturbing_action': 'I-gene gain-of-function'}", + "130, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "30, AGF-deficient ['l0']", + "31, mice ['l0']", + "41, AGF-deficient ['l1', 'l2', 'l3']", + "42, mice ['l1']", + "66, mice ['l2', 'l4', 'l5']", + "68, targeted ['l6', 'l7', 'l8']", + "69, activation ['l6', 'l9', 'l10']", + "70, of ['l4', 'l7', 'l9', 'l11']", + "71, AGF ['l3', 'l5', 'l8', 'l10', 'l11']", + "97, Hepatic ['l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "98, overexpression ['l12', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "99, of ['l13', 'l19', 'l25', 'l26', 'l27', 'l28', 'l29']", + "100, AGF ['l14', 'l20', 'l25', 'l30', 'l31', 'l32', 'l33']", + "101, by ['l15', 'l21', 'l26', 'l30', 'l34', 'l35', 'l36']", + "102, adenoviral ['l16', 'l22', 'l27', 'l31', 'l34', 'l37', 'l38']", + "103, transduction, ['l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l39']", + "130, mice ['l18', 'l24', 'l29', 'l33', 'l36', 'l38', 'l39']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "AGF-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "of", + "AGF" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Hepatic", + "overexpression", + "of", + "AGF", + "by", + "adenoviral", + "transduction," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15768029", + "TEXT": "Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease resulting in the selective death of motor neurons in the brain and spinal cord. Some familial cases of ALS are caused by dominant mutations in the gene encoding superoxide dismutase (SOD1). The emergence of interfering RNA (RNAi) for specific gene silencing could be therapeutically beneficial for the treatment of such dominantly inherited diseases. We generated a lentiviral vector to mediate expression of RNAi molecules specifically targeting the human SOD1 gene (SOD1). Injection of this vector into various muscle groups of mice engineered to overexpress a mutated form of human SOD1 (SOD1(G93A)) resulted in an efficient and specific reduction of SOD1 expression and improved survival of vulnerable motor neurons in the brainstem and spinal cord. Furthermore, SOD1 silencing mediated an improved motor performance in these animals, resulting in a considerable delay in the onset of ALS symptoms by more than 100% and an extension in survival by nearly 80% of their normal life span. These data are the first to show a substantial extension of survival in an animal model of a fatal, dominantly inherited neurodegenerative condition using RNAi and provide the highest therapeutic efficacy observed in this field to date.", + "TAG_DATA": [ + "89, mice {'context': 'B-organism'}", + "91, to {'perturbing_action': 'B-other'}", + "92, overexpress {'perturbing_action': 'B-other'}", + "93, a {'perturbing_action': 'I-other'}", + "94, mutated {'perturbing_action': 'I-other'}", + "95, form {'perturbing_action': 'I-other'}", + "96, of {'perturbing_action': 'I-other'}", + "97, human {'perturbing_action': 'I-other'}", + "98, SOD1 {'perturbing_action': 'I-other'}", + "99, (SOD1(G93A)) {'perturbing_action': 'I-other'}", + "115, motor {'context': 'B-cells'}", + "116, neurons {'context': 'I-cells'}", + "117, in {'context': 'I-cells'}", + "118, the {'context': 'I-cells'}", + "119, brainstem {'context': 'B-tissue/organ'}", + "121, spinal {'context': 'I-tissue/organ'}", + "122, cord. {'context': 'I-tissue/organ'}", + "124, SOD1 {'perturbing_action': 'B-rnai/knockdown'}", + "125, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "133, animals, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "89, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "91, to ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "92, overexpress ['l1', 'l16', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "93, a ['l2', 'l17', 'l32', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "94, mutated ['l3', 'l18', 'l33', 'l48', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "95, form ['l4', 'l19', 'l34', 'l49', 'l63', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "96, of ['l5', 'l20', 'l35', 'l50', 'l64', 'l77', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "97, human ['l6', 'l21', 'l36', 'l51', 'l65', 'l78', 'l90', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "98, SOD1 ['l7', 'l22', 'l37', 'l52', 'l66', 'l79', 'l91', 'l102', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "99, (SOD1(G93A)) ['l8', 'l23', 'l38', 'l53', 'l67', 'l80', 'l92', 'l103', 'l113', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "115, motor ['l9', 'l24', 'l39', 'l54', 'l68', 'l81', 'l93', 'l104', 'l114', 'l122', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136']", + "116, neurons ['l10', 'l25', 'l40', 'l55', 'l69', 'l82', 'l94', 'l105', 'l115', 'l123', 'l131', 'l137', 'l138', 'l139', 'l140', 'l141']", + "117, in ['l11', 'l26', 'l41', 'l56', 'l70', 'l83', 'l95', 'l106', 'l116', 'l124', 'l132', 'l137', 'l142', 'l143', 'l144', 'l145']", + "118, the ['l12', 'l27', 'l42', 'l57', 'l71', 'l84', 'l96', 'l107', 'l117', 'l125', 'l133', 'l138', 'l142', 'l146', 'l147', 'l148']", + "119, brainstem ['l13', 'l28', 'l43', 'l58', 'l72', 'l85', 'l97', 'l108', 'l118', 'l126', 'l134', 'l139', 'l143', 'l146', 'l149', 'l150']", + "121, spinal ['l14', 'l29', 'l44', 'l59', 'l73', 'l86', 'l98', 'l109', 'l119', 'l127', 'l135', 'l140', 'l144', 'l147', 'l149', 'l151']", + "122, cord. ['l15', 'l30', 'l45', 'l60', 'l74', 'l87', 'l99', 'l110', 'l120', 'l128', 'l136', 'l141', 'l145', 'l148', 'l150', 'l151']", + "124, SOD1 ['l152', 'l153']", + "125, silencing ['l46', 'l61', 'l75', 'l88', 'l100', 'l111', 'l129', 'l152', 'l154']", + "133, animals, ['l31', 'l47', 'l62', 'l76', 'l89', 'l101', 'l112', 'l121', 'l130', 'l153', 'l154']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "animals," + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "to", + "overexpress", + "a", + "mutated", + "form", + "of", + "human", + "SOD1", + "(SOD1(G93A))" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "to", + "overexpress", + "a", + "mutated", + "form", + "of", + "human", + "SOD1", + "(SOD1(G93A))" + ] + }, + "context": { + "val": "cells", + "words": [ + "motor", + "neurons", + "in", + "the" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "to", + "overexpress", + "a", + "mutated", + "form", + "of", + "human", + "SOD1", + "(SOD1(G93A))" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "brainstem", + "spinal", + "cord." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "SOD1", + "silencing" + ] + }, + "context": { + "val": "organism", + "words": [ + "animals," + ] + } + } + ] + }, + { + "PMID": "15768028", + "TEXT": "Mutations in Cu/Zn superoxide dismutase (encoded by SOD1), one of the causes of familial amyotrophic lateral sclerosis (ALS), lead to progressive death of motoneurons through a gain-of-function mechanism. RNA interference (RNAi) mediated by viral vectors allows for long-term reduction in gene expression and represents an attractive therapeutic approach for genetic diseases characterized by acquired toxic properties. We report that in SOD1(G93A) transgenic mice, a model for familial ALS, intraspinal injection of a lentiviral vector that produces RNAi-mediated silencing of SOD1 substantially retards both the onset and the progression rate of the disease.", + "TAG_DATA": [ + "60, SOD1(G93A) {'perturbing_action': 'B-gene gain-of-function'}", + "61, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "62, mice, {'context': 'B-organism'}", + "72, lentiviral {'perturbing_action': 'B-rnai/knockdown'}", + "73, vector {'perturbing_action': 'I-rnai/knockdown'}", + "75, produces {'perturbing_action': 'B-rnai/knockdown'}", + "76, RNAi-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "77, silencing {'perturbing_action': 'I-rnai/knockdown'}", + "78, of {'perturbing_action': 'I-rnai/knockdown'}", + "79, SOD1 {'perturbing_action': 'I-rnai/knockdown'}" + ], + "LINK_DATA": [ + "60, SOD1(G93A) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "61, transgenic ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "62, mice, ['l1', 'l8', 'l14']", + "72, lentiviral ['l2', 'l9', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "73, vector ['l3', 'l10', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "75, produces ['l4', 'l11', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "76, RNAi-mediated ['l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "77, silencing ['l5', 'l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "78, of ['l6', 'l12', 'l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "79, SOD1 ['l7', 'l13', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "SOD1(G93A)", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "SOD1" + ] + } + } + ] + }, + { + "PMID": "15723074", + "TEXT": "Vanishing white matter disease (VWM) is a heritable leukodystrophy linked to mutations in translation initiation factor 2B (eIF2B). Although the clinical course of this disease has been relatively well described, the cellular consequences of EIF2B mutations on neural cells are unknown. Here we have established cell cultures from the brain of an individual with VWM carrying mutations in subunit 5 of eIF2B (encoded by EIF2B5). Despite the extensive demyelination apparent in this VWM patient, normal-appearing oligodendrocytes were readily generated in vitro. In contrast, few GFAP-expressing (GFAP+) astrocytes were present in primary cultures, induction of astrocytes was severely compromised, and the few astrocytes generated showed abnormal morphologies and antigenic phenotypes. Lesions in vivo also lacked GFAP+ astrocytes. RNAi targeting of EIF2B5 severely compromised the induction of GFAP+ cells from normal human glial progenitors. This raises the possibility that a deficiency in astrocyte function may contribute to the loss of white matter in VWM leukodystrophy.", + "TAG_DATA": [ + "45, cell {'context': 'B-cells'}", + "46, cultures {'context': 'I-cells'}", + "56, mutations {'perturbing_action': 'B-other'}", + "57, in {'perturbing_action': 'I-other'}", + "79, in {'context': 'B-in vitro'}", + "80, vitro. {'context': 'I-in vitro'}", + "84, GFAP-expressing {'context': 'B-cells'}", + "86, astrocytes {'context': 'I-cells'}", + "90, primary {'context': 'B-cells'}", + "91, cultures, {'context': 'I-in vitro'}", + "94, astrocytes {'context': 'B-cells'}", + "101, astrocytes {'context': 'B-cells'}", + "110, in {'context': 'B-in vivo'}", + "111, vivo {'context': 'I-in vivo'}", + "114, GFAP+ {'context': 'B-cells'}", + "115, astrocytes. {'context': 'I-cells'}", + "116, RNAi {'perturbing_action': 'B-rnai/knockdown'}", + "117, targeting {'perturbing_action': 'I-rnai/knockdown'}", + "118, of {'perturbing_action': 'I-rnai/knockdown'}", + "119, EIF2B5 {'perturbing_action': 'I-rnai/knockdown'}", + "125, GFAP+ {'context': 'B-cells'}", + "126, cells {'context': 'I-cells'}", + "128, normal {'context': 'B-cells'}", + "129, human {'context': 'I-cells'}", + "130, glial {'context': 'I-cells'}", + "131, progenitors. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "45, cell ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "46, cultures ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "56, mutations ['l1', 'l9', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "57, in ['l2', 'l10', 'l16', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "79, in ['l3', 'l11', 'l17', 'l23', 'l30', 'l31', 'l32']", + "80, vitro. ['l4', 'l12', 'l18', 'l24', 'l30', 'l33', 'l34']", + "84, GFAP-expressing ['l5', 'l13', 'l19', 'l25', 'l31', 'l33', 'l35', 'l36', 'l37', 'l38']", + "86, astrocytes ['l6', 'l14', 'l20', 'l26', 'l32', 'l34', 'l35', 'l39', 'l40']", + "90, primary ['l7', 'l21', 'l27', 'l36', 'l39', 'l41']", + "91, cultures, ['l8', 'l15', 'l22', 'l28', 'l37', 'l40', 'l41']", + "94, astrocytes ['l29', 'l38']", + "101, astrocytes ['l42']", + "110, in ['l43', 'l44', 'l45']", + "111, vivo ['l43', 'l46', 'l47']", + "114, GFAP+ ['l44', 'l46', 'l48']", + "115, astrocytes. ['l42', 'l45', 'l47', 'l48']", + "116, RNAi ['l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "117, targeting ['l49', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "118, of ['l50', 'l58', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "119, EIF2B5 ['l51', 'l59', 'l66', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "125, GFAP+ ['l52', 'l60', 'l67', 'l73', 'l79', 'l80', 'l81', 'l82', 'l83']", + "126, cells ['l53', 'l61', 'l68', 'l74', 'l79', 'l84', 'l85', 'l86', 'l87']", + "128, normal ['l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l88', 'l89', 'l90']", + "129, human ['l55', 'l63', 'l70', 'l76', 'l81', 'l85', 'l88', 'l91', 'l92']", + "130, glial ['l56', 'l64', 'l71', 'l77', 'l82', 'l86', 'l89', 'l91', 'l93']", + "131, progenitors. ['l57', 'l65', 'l72', 'l78', 'l83', 'l87', 'l90', 'l92', 'l93']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cell", + "cultures", + "GFAP-expressing", + "astrocytes", + "primary" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutations", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutations", + "in" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro.", + "cultures," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "RNAi", + "targeting", + "of", + "EIF2B5" + ] + }, + "context": { + "val": "cells", + "words": [ + "GFAP+", + "cells", + "normal", + "human", + "glial", + "progenitors." + ] + } + } + ] + }, + { + "PMID": "15723073", + "TEXT": "In the event of a myocardial infarction, current interventions aim to reopen the occluded vessel to reduce myocardial damage and injury. Although reperfusion is essential for tissue salvage, it can cause further damage and the onset of inflammation. We show a novel anti-inflammatory effect of a fibrin-derived peptide, Bbeta15-42. This peptide competes with the fibrin fragment N-terminal disulfide knot-II (an analog of the fibrin E1 fragment) for binding to vascular endothelial (VE)-cadherin, thereby preventing transmigration of leukocytes across endothelial cell monolayers. In acute or chronic rat models of myocardial ischemia-reperfusion injury, Bbeta15-42 substantially reduces leukocyte infiltration, infarct size and subsequent scar formation. The pathogenic role of fibrinogen products is further confirmed in fibrinogen knockout mice, in which infarct size was substantially smaller than in wild-type animals. Our findings conclude that the interplay of fibrin fragments, leukocytes and VE-cadherin contribute to the pathogenesis of myocardial damage and reperfusion injury. The naturally occurring peptide Bbeta15-42 represents a potential candidate for reperfusion therapy in humans.", + "TAG_DATA": [ + "85, rat {'context': 'B-organism'}", + "86, models {'context': 'I-organism'}", + "94, leukocyte {'context': 'B-cells'}", + "112, fibrinogen {'perturbing_action': 'B-gene loss-of-function'}", + "113, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "114, mice, {'context': 'B-organism'}", + "125, animals. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "85, rat ['l0', 'l1']", + "86, models ['l0', 'l2']", + "94, leukocyte ['l1', 'l2']", + "112, fibrinogen ['l3', 'l4', 'l5']", + "113, knockout ['l3', 'l6', 'l7']", + "114, mice, ['l4', 'l6', 'l8']", + "125, animals. ['l5', 'l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "fibrinogen", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "animals." + ] + } + } + ] + }, + { + "PMID": "15685170", + "TEXT": "Inflammation may underlie the metabolic disorders of insulin resistance and type 2 diabetes. IkappaB kinase beta (IKK-beta, encoded by Ikbkb) is a central coordinator of inflammatory responses through activation of NF-kappaB. To understand the role of IKK-beta in insulin resistance, we used mice lacking this enzyme in hepatocytes (Ikbkb(Deltahep)) or myeloid cells (Ikbkb(Deltamye)). Ikbkb(Deltahep) mice retain liver insulin responsiveness, but develop insulin resistance in muscle and fat in response to high fat diet, obesity or aging. In contrast, Ikbkb(Deltamye) mice retain global insulin sensitivity and are protected from insulin resistance. Thus, IKK-beta acts locally in liver and systemically in myeloid cells, where NF-kappaB activation induces inflammatory mediators that cause insulin resistance. These findings demonstrate the importance of liver cell IKK-beta in hepatic insulin resistance and the central role of myeloid cells in development of systemic insulin resistance. We suggest that inhibition of IKK-beta, especially in myeloid cells, may be used to treat insulin resistance.", + "TAG_DATA": [ + "42, mice {'context': 'B-organism'}", + "43, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "44, this {'perturbing_action': 'I-gene loss-of-function'}", + "45, enzyme {'perturbing_action': 'I-gene loss-of-function'}", + "46, in {'perturbing_action': 'I-gene loss-of-function'}", + "47, hepatocytes {'context': 'B-cells'}", + "50, myeloid {'context': 'B-cells'}", + "51, cells {'context': 'I-cells'}", + "53, Ikbkb(Deltahep) {'perturbing_action': 'B-gene loss-of-function'}", + "54, mice {'context': 'B-organism'}", + "56, liver {'context': 'B-tissue/organ'}", + "78, Ikbkb(Deltamye) {'perturbing_action': 'B-gene loss-of-function'}", + "79, mice {'context': 'B-organism'}", + "99, myeloid {'context': 'B-cells'}", + "100, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "42, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "43, lacking ['l0', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "44, this ['l1', 'l6', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "45, enzyme ['l2', 'l7', 'l13', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "46, in ['l3', 'l8', 'l14', 'l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "47, hepatocytes ['l4', 'l9', 'l15', 'l21', 'l26', 'l31', 'l32', 'l33', 'l34']", + "50, myeloid ['l16', 'l22', 'l27', 'l31', 'l35', 'l36', 'l37', 'l38']", + "51, cells ['l10', 'l17', 'l23', 'l28', 'l32', 'l35', 'l39', 'l40', 'l41']", + "53, Ikbkb(Deltahep) ['l36', 'l39', 'l42', 'l43']", + "54, mice ['l11', 'l18', 'l24', 'l29', 'l33', 'l37', 'l40', 'l42', 'l44']", + "56, liver ['l5', 'l12', 'l19', 'l25', 'l30', 'l34', 'l38', 'l41', 'l43', 'l44']", + "78, Ikbkb(Deltamye) ['l45', 'l46', 'l47']", + "79, mice ['l45', 'l48']", + "99, myeloid ['l46', 'l49']", + "100, cells, ['l47', 'l48', 'l49']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "this", + "enzyme", + "in", + "Ikbkb(Deltahep)", + "Ikbkb(Deltamye)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "this", + "enzyme", + "in", + "Ikbkb(Deltahep)", + "Ikbkb(Deltamye)" + ] + }, + "context": { + "val": "cells", + "words": [ + "hepatocytes", + "cells", + "myeloid", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "this", + "enzyme", + "in", + "Ikbkb(Deltahep)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + } + ] + }, + { + "PMID": "15685168", + "TEXT": "The protein p27(Kip1) regulates cell cycle progression in mammals by inhibiting the activity of cyclin-dependent kinases (CDKs). Here we show that p27(Kip1) progressively accumulates in the nucleus of pancreatic beta cells in mice that lack either insulin receptor substrate 2 (Irs2(-/-)) or the long form of the leptin receptor (Lepr(-/-) or db/db). Deletion of the gene encoding p27(Kip1) (Cdkn1b) ameliorated hyperglycemia in these animal models of type 2 diabetes mellitus by increasing islet mass and maintaining compensatory hyperinsulinemia, effects that were attributable predominantly to stimulation of pancreatic beta-cell proliferation. Thus, p27(Kip1) contributes to beta-cell failure during the development of type 2 diabetes in Irs2(-/-) and Lepr(-/-) mice and represents a potential new target for the treatment of this condition.", + "TAG_DATA": [ + "32, mice {'context': 'B-organism'}", + "34, lack {'perturbing_action': 'B-gene loss-of-function'}", + "35, either {'perturbing_action': 'I-gene loss-of-function'}", + "36, insulin {'perturbing_action': 'I-gene loss-of-function'}", + "37, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "38, substrate {'perturbing_action': 'I-gene loss-of-function'}", + "39, 2 {'perturbing_action': 'I-gene loss-of-function'}", + "40, (Irs2(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "41, or {'perturbing_action': 'I-gene loss-of-function'}", + "42, the {'perturbing_action': 'I-gene loss-of-function'}", + "43, long {'perturbing_action': 'I-gene loss-of-function'}", + "44, form {'perturbing_action': 'I-gene loss-of-function'}", + "45, of {'perturbing_action': 'I-gene loss-of-function'}", + "46, the {'perturbing_action': 'I-gene loss-of-function'}", + "47, leptin {'perturbing_action': 'I-gene loss-of-function'}", + "48, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "49, (Lepr(-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "51, db/db). {'perturbing_action': 'I-gene loss-of-function'}", + "52, Deletion {'perturbing_action': 'B-gene loss-of-function'}", + "53, of {'perturbing_action': 'I-gene loss-of-function'}", + "54, the {'perturbing_action': 'I-gene loss-of-function'}", + "55, gene {'perturbing_action': 'I-gene loss-of-function'}", + "56, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "57, p27(Kip1) {'perturbing_action': 'I-gene loss-of-function'}", + "58, (Cdkn1b) {'perturbing_action': 'I-gene loss-of-function'}", + "63, animal {'context': 'B-organism'}", + "64, models {'context': 'I-organism'}", + "72, islet {'context': 'B-cells'}", + "84, stimulation {'effect': 'B-positive'}", + "86, pancreatic {'context': 'B-cells'}", + "87, beta-cell {'context': 'I-cells'}", + "88, proliferation. {'phenotype': 'B-proliferation'}", + "103, Irs2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "104, and {'perturbing_action': 'I-gene loss-of-function'}", + "105, Lepr(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "106, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "29, beta ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "32, mice ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "34, lack ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "35, either ['l2', 'l10', 'l17', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "36, insulin ['l3', 'l11', 'l18', 'l34', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "37, receptor ['l4', 'l12', 'l19', 'l35', 'l47', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "38, substrate ['l5', 'l13', 'l20', 'l36', 'l48', 'l62', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "39, 2 ['l6', 'l14', 'l21', 'l37', 'l49', 'l63', 'l77', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102']", + "40, (Irs2(-/-)) ['l7', 'l15', 'l22', 'l38', 'l50', 'l64', 'l78', 'l91', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "41, or ['l8', 'l16', 'l23', 'l39', 'l51', 'l65', 'l79', 'l92', 'l103', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "42, the ['l24', 'l52', 'l66', 'l80', 'l93', 'l104', 'l113', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135']", + "43, long ['l25', 'l53', 'l67', 'l81', 'l94', 'l105', 'l114', 'l124', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147']", + "44, form ['l26', 'l54', 'l68', 'l82', 'l95', 'l115', 'l125', 'l136', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161']", + "45, of ['l27', 'l40', 'l55', 'l69', 'l83', 'l96', 'l106', 'l116', 'l126', 'l137', 'l148', 'l162', 'l163', 'l164', 'l165', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174']", + "46, the ['l28', 'l41', 'l56', 'l70', 'l84', 'l97', 'l107', 'l117', 'l127', 'l138', 'l149', 'l162', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186']", + "47, leptin ['l29', 'l42', 'l57', 'l71', 'l85', 'l98', 'l108', 'l118', 'l128', 'l139', 'l150', 'l163', 'l175', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193']", + "48, receptor ['l30', 'l43', 'l58', 'l72', 'l86', 'l99', 'l109', 'l119', 'l129', 'l140', 'l151', 'l164', 'l176', 'l187', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200']", + "49, (Lepr(-/-) ['l31', 'l44', 'l59', 'l73', 'l87', 'l100', 'l110', 'l120', 'l130', 'l141', 'l152', 'l165', 'l177', 'l188', 'l194', 'l201', 'l202', 'l203', 'l204']", + "51, db/db). ['l32', 'l45', 'l60', 'l74', 'l88', 'l101', 'l111', 'l121', 'l131', 'l142', 'l153', 'l166', 'l178', 'l189', 'l195', 'l201', 'l205', 'l206', 'l207', 'l208']", + "52, Deletion ['l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221']", + "53, of ['l209', 'l222', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233']", + "54, the ['l154', 'l167', 'l179', 'l210', 'l222', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239', 'l240', 'l241', 'l242', 'l243', 'l244']", + "55, gene ['l155', 'l168', 'l180', 'l211', 'l223', 'l234', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254']", + "56, encoding ['l156', 'l169', 'l181', 'l212', 'l224', 'l235', 'l245', 'l255', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263']", + "57, p27(Kip1) ['l143', 'l157', 'l170', 'l182', 'l196', 'l213', 'l225', 'l236', 'l246', 'l255', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270', 'l271']", + "58, (Cdkn1b) ['l132', 'l144', 'l158', 'l171', 'l183', 'l190', 'l197', 'l205', 'l214', 'l226', 'l237', 'l247', 'l256', 'l264', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278']", + "63, animal ['l75', 'l89', 'l122', 'l133', 'l145', 'l159', 'l172', 'l184', 'l191', 'l198', 'l202', 'l206', 'l215', 'l227', 'l238', 'l248', 'l257', 'l265', 'l272', 'l279', 'l280']", + "64, models ['l33', 'l46', 'l61', 'l76', 'l90', 'l102', 'l112', 'l123', 'l134', 'l146', 'l160', 'l173', 'l185', 'l192', 'l199', 'l203', 'l207', 'l216', 'l228', 'l239', 'l249', 'l258', 'l266', 'l273', 'l279', 'l281']", + "72, islet ['l135', 'l147', 'l161', 'l174', 'l186', 'l193', 'l200', 'l204', 'l208', 'l217', 'l229', 'l240', 'l250', 'l259', 'l267', 'l274', 'l280', 'l281']", + "84, stimulation ['l218', 'l230', 'l241', 'l251', 'l260', 'l268', 'l275', 'l282', 'l283', 'l284']", + "86, pancreatic ['l219', 'l231', 'l242', 'l252', 'l261', 'l269', 'l276', 'l282', 'l285', 'l286']", + "87, beta-cell ['l220', 'l232', 'l243', 'l253', 'l262', 'l270', 'l277', 'l283', 'l285', 'l287']", + "88, proliferation. ['l221', 'l233', 'l244', 'l254', 'l263', 'l271', 'l278', 'l284', 'l286', 'l287']", + "103, Irs2(-/-) ['l288', 'l289', 'l290']", + "104, and ['l288', 'l291', 'l292']", + "105, Lepr(-/-) ['l289', 'l291', 'l293']", + "106, mice ['l290', 'l292', 'l293']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "models", + "animal" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "either", + "insulin", + "receptor", + "substrate", + "2", + "(Irs2(-/-))", + "or", + "the", + "long", + "form", + "of", + "leptin", + "(Lepr(-/-)", + "db/db).", + "Deletion", + "gene", + "encoding", + "p27(Kip1)", + "(Cdkn1b)", + "Irs2(-/-)", + "and", + "Lepr(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "the", + "long", + "form", + "of", + "leptin", + "receptor", + "(Lepr(-/-)", + "db/db).", + "Deletion", + "gene", + "encoding", + "p27(Kip1)", + "(Cdkn1b)" + ] + }, + "context": { + "val": "cells", + "words": [ + "islet", + "pancreatic", + "beta-cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "gene", + "encoding", + "p27(Kip1)", + "(Cdkn1b)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "gene", + "encoding", + "p27(Kip1)", + "(Cdkn1b)" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulation" + ] + }, + "context": { + "val": "cells", + "words": [ + "pancreatic", + "beta-cell" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulation" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "pancreatic", + "beta-cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "15665832", + "TEXT": "The angiotensin-converting enzyme (ACE) is a key regulator of blood pressure. It is known to cleave small peptides, such as angiotensin I and bradykinin and changes their biological activities, leading to upregulation of blood pressure. Here we describe a new activity for ACE: a glycosylphosphatidylinositol (GPI)-anchored protein releasing activity (GPIase activity). Unlike its peptidase activity, GPIase activity is weakly inhibited by the tightly binding ACE inhibitor and not inactivated by substitutions of core amino acid residues for the peptidase activity, suggesting that the active site elements for GPIase differ from those for peptidase activity. ACE shed various GPI-anchored proteins from the cell surface, and the process was accelerated by the lipid raft disruptor filipin. The released products carried portions of the GPI anchor, indicating cleavage within the GPI moiety. Further analysis by high-performance liquid chromatography-mass spectrometry predicted the cleavage site at the mannose-mannose linkage. GPI-anchored proteins such as TESP5 and PH-20 were released from the sperm membrane of wild-type mice but not in Ace knockout sperm in vivo. Moreover, peptidase-inactivated E414D mutant ACE and also PI-PLC rescued the egg-binding deficiency of Ace knockout sperms, implying that ACE plays a crucial role in fertilization through this activity.", + "TAG_DATA": [ + "159, mice {'context': 'B-organism'}", + "163, Ace {'perturbing_action': 'B-gene loss-of-function'}", + "164, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "165, sperm {'context': 'B-cells'}", + "166, in {'context': 'B-in vivo'}", + "167, vivo. {'context': 'I-in vivo'}", + "170, E414D {'perturbing_action': 'I-other'}", + "171, mutant {'perturbing_action': 'I-other'}", + "181, Ace {'perturbing_action': 'B-gene loss-of-function'}", + "182, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "183, sperms, {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "159, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "163, Ace ['l0', 'l5', 'l6', 'l7', 'l8']", + "164, knockout ['l1', 'l5', 'l9', 'l10', 'l11']", + "165, sperm ['l2', 'l6', 'l9', 'l12', 'l13']", + "166, in ['l3', 'l7', 'l10', 'l12', 'l14']", + "167, vivo. ['l4', 'l8', 'l11', 'l13', 'l14']", + "170, E414D ['l15', 'l16', 'l17', 'l18']", + "171, mutant ['l15', 'l19', 'l20', 'l21']", + "181, Ace ['l16', 'l19', 'l22', 'l23']", + "182, knockout ['l17', 'l20', 'l22', 'l24']", + "183, sperms, ['l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ace", + "knockout" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ace", + "knockout" + ] + }, + "context": { + "val": "cells", + "words": [ + "sperm", + "sperms," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ace", + "knockout" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "E414D", + "mutant" + ] + }, + "context": { + "val": "cells", + "words": [ + "sperms," + ] + } + } + ] + }, + { + "PMID": "15654327", + "TEXT": "The upregulation of TGF-beta1 and integrin expression during wound healing has implicated these molecules in this process, but their precise regulation and roles remain unclear. Here we report that, notably, mice lacking beta(3)-integrins show enhanced wound healing with re-epithelialization complete several days earlier than in wild-type mice. We show that this effect is the result of an increase in TGF-beta1 and enhanced dermal fibroblast infiltration into wounds of beta(3)-null mice. Specifically, beta(3)-integrin deficiency is associated with elevated TGF-beta receptor I and receptor II expression, reduced Smad3 levels, sustained Smad2 and Smad4 nuclear localization and enhanced TGF-beta1-mediated dermal fibroblast migration. These data indicate that alpha(v)beta(3)-integrin can suppress TGF-beta1-mediated signaling, thereby controlling the rate of wound healing, and highlight a new mechanism for TGF-beta1 regulation by beta(3)-integrins.", + "TAG_DATA": [ + "30, mice {'context': 'B-organism'}", + "31, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "32, beta(3)-integrins {'perturbing_action': 'I-gene loss-of-function'}", + "62, dermal {'context': 'B-cells'}", + "63, fibroblast {'context': 'I-cells'}", + "68, beta(3)-null {'perturbing_action': 'B-gene loss-of-function'}", + "69, mice. {'context': 'B-organism'}", + "71, beta(3)-integrin {'perturbing_action': 'B-gene loss-of-function'}", + "72, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "94, enhanced {'effect': 'B-positive'}", + "96, dermal {'context': 'B-cells'}", + "97, fibroblast {'context': 'I-cells'}", + "98, migration. {'phenotype': 'B-migration'}" + ], + "LINK_DATA": [ + "30, mice ['l0', 'l1', 'l2', 'l3']", + "31, lacking ['l0', 'l4', 'l5', 'l6']", + "32, beta(3)-integrins ['l1', 'l4', 'l7', 'l8', 'l9']", + "62, dermal ['l2', 'l5', 'l7', 'l10', 'l11', 'l12']", + "63, fibroblast ['l3', 'l6', 'l8', 'l10', 'l13']", + "68, beta(3)-null ['l9', 'l11', 'l13', 'l14']", + "69, mice. ['l12', 'l14']", + "71, beta(3)-integrin ['l15', 'l16', 'l17', 'l18', 'l19']", + "72, deficiency ['l15', 'l20', 'l21', 'l22', 'l23']", + "94, enhanced ['l16', 'l20', 'l24', 'l25', 'l26']", + "96, dermal ['l17', 'l21', 'l24', 'l27', 'l28']", + "97, fibroblast ['l18', 'l22', 'l25', 'l27', 'l29']", + "98, migration. ['l19', 'l23', 'l26', 'l28', 'l29']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "beta(3)-integrins", + "beta(3)-null" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "beta(3)-integrins", + "beta(3)-null", + "beta(3)-integrin", + "deficiency" + ] + }, + "context": { + "val": "cells", + "words": [ + "dermal", + "fibroblast" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "beta(3)-integrin", + "deficiency" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "beta(3)-integrin", + "deficiency" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "context": { + "val": "cells", + "words": [ + "dermal", + "fibroblast" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "dermal", + "fibroblast" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration." + ] + } + } + ] + }, + { + "PMID": "15654325", + "TEXT": "Genetic ablation of Inppl1, which encodes SHIP2 (SH2-domain containing inositol 5-phosphatase 2), was previously reported to induce severe insulin sensitivity, leading to early postnatal death. In the previous study, the targeting construct left the first eighteen exons encoding Inppl1 intact, generating a Inppl1(EX19-28-/-) mouse, and apparently also deleted a second gene, Phox2a. We report a new SHIP2 knockout (Inppl1(-/-)) targeted to the translation-initiating ATG, which is null for Inppl1 mRNA and protein. Inppl1(-/-) mice are viable, have normal glucose and insulin levels, and normal insulin and glucose tolerances. The Inppl1(-/-) mice are, however, highly resistant to weight gain when placed on a high-fat diet. These results suggest that inhibition of SHIP2 would be useful in the effort to ameliorate diet-induced obesity, but call into question a dominant role of SHIP2 in modulating glucose homeostasis.", + "TAG_DATA": [ + "56, SHIP2 {'perturbing_action': 'B-gene loss-of-function'}", + "57, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "58, (Inppl1(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "59, targeted {'perturbing_action': 'I-gene loss-of-function'}", + "60, to {'perturbing_action': 'I-other'}", + "61, the {'perturbing_action': 'I-other'}", + "62, translation-initiating {'perturbing_action': 'I-other'}", + "63, ATG, {'perturbing_action': 'I-other'}", + "72, Inppl1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "73, mice {'context': 'B-organism'}", + "89, Inppl1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "90, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, SHIP2 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "57, knockout ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "58, (Inppl1(-/-)) ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "59, targeted ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "60, to ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "61, the ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "62, translation-initiating ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "63, ATG, ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "72, Inppl1(-/-) ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "73, mice ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "89, Inppl1(-/-) ['l45']", + "90, mice ['l45']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHIP2", + "knockout", + "(Inppl1(-/-))", + "targeted", + "Inppl1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "to", + "the", + "translation-initiating", + "ATG," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15619628", + "TEXT": "Hearts from alpha1,3-galactosyltransferase knockout pigs (GalT-KO, n = 8) were transplanted heterotopically into baboons using an anti-CD154 monoclonal antibody-based regimen. The elimination of the galactose-alpha1,3-galactose epitope prevented hyperacute rejection and extended survival of pig hearts in baboons for 2-6 months (median, 78 d); the predominant lesion associated with graft failure was a thrombotic microangiopathy, with resulting ischemic injury. There were no infectious complications directly related to the immunosuppressive regimen. The transplantation of hearts from GalT-KO pigs increased graft survival over previous studies.", + "TAG_DATA": [ + "2, alpha1,3-galactosyltransferase {'perturbing_action': 'I-gene loss-of-function'}", + "3, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "4, pigs {'context': 'B-organism'}", + "13, baboons {'context': 'B-organism'}", + "33, pig {'context': 'B-tissue/organ'}", + "34, hearts {'context': 'I-tissue/organ'}", + "36, baboons {'context': 'B-organism'}", + "72, hearts {'context': 'B-tissue/organ'}", + "74, GalT-KO {'perturbing_action': 'B-gene loss-of-function'}", + "75, pigs {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "2, alpha1,3-galactosyltransferase ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "3, knockout ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "4, pigs ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "13, baboons ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "33, pig ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "34, hearts ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "36, baboons ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "72, hearts ['l21', 'l22']", + "74, GalT-KO ['l21', 'l23']", + "75, pigs ['l22', 'l23']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha1,3-galactosyltransferase", + "knockout", + "GalT-KO" + ] + }, + "context": { + "val": "organism", + "words": [ + "pigs", + "baboons" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha1,3-galactosyltransferase", + "knockout", + "GalT-KO" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "pig", + "hearts" + ] + } + } + ] + }, + { + "PMID": "15619626", + "TEXT": "Epithelial ovarian tumors present a complex clinical, diagnostic and therapeutic challenge because of the difficulty of early detection, lack of known precursor lesions and high mortality rates. Endometrioid ovarian carcinomas are frequently associated with endometriosis, but the mechanism for this association remains unknown. Here we present the first genetic models of peritoneal endometriosis and endometrioid ovarian adenocarcinoma in mice, both based on the activation of an oncogenic K-ras allele. In addition, we find that expression of oncogenic K-ras or conditional Pten deletion within the ovarian surface epithelium gives rise to preneoplastic ovarian lesions with an endometrioid glandular morphology. Furthermore, the combination of the two mutations in the ovary leads to the induction of invasive and widely metastatic endometrioid ovarian adenocarcinomas with complete penetrance and a disease latency of only 7 weeks. The ovarian cancer model described in this study recapitulates the specific tumor histomorphology and metastatic potential of the human disease.", + "TAG_DATA": [ + "58, mice, {'context': 'B-organism'}", + "74, expression {'perturbing_action': 'B-gene gain-of-function'}", + "75, of {'perturbing_action': 'I-gene gain-of-function'}", + "76, oncogenic {'perturbing_action': 'I-gene gain-of-function'}", + "77, K-ras {'perturbing_action': 'I-gene gain-of-function'}", + "79, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "80, Pten {'perturbing_action': 'I-gene loss-of-function'}", + "81, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "84, ovarian {'perturbing_action': 'I-gene loss-of-function', 'context': 'B-tissue/organ'}", + "85, surface {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-tissue/organ'}", + "86, epithelium {'perturbing_action': 'I-gene loss-of-function', 'context': 'I-tissue/organ'}", + "107, ovary {'context': 'B-tissue/organ'}", + "111, induction {'effect': 'B-positive'}", + "117, endometrioid {'context': 'B-neoplasm', 'phenotype': 'B-tumourigenesis'}", + "118, ovarian {'context': 'I-neoplasm', 'phenotype': 'I-tumourigenesis'}", + "119, adenocarcinomas {'context': 'I-neoplasm', 'phenotype': 'I-tumourigenesis'}" + ], + "LINK_DATA": [ + "74, expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "75, of ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "76, oncogenic ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "77, K-ras ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "79, conditional ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "80, Pten ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "81, deletion ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "84, ovarian ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "85, surface ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "86, epithelium ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "107, ovary ['l45', 'l46', 'l47', 'l48']", + "111, induction ['l45', 'l49', 'l50', 'l51']", + "117, endometrioid ['l46', 'l49', 'l52', 'l53']", + "118, ovarian ['l47', 'l50', 'l52', 'l54']", + "119, adenocarcinomas ['l48', 'l51', 'l53', 'l54']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "oncogenic", + "K-ras" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "ovarian", + "surface", + "epithelium" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ovarian", + "surface", + "epithelium", + "conditional", + "Pten", + "deletion" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "ovarian", + "surface", + "epithelium" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "ovary" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "ovary" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "endometrioid", + "ovarian", + "adenocarcinomas" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "endometrioid", + "ovarian", + "adenocarcinomas" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "endometrioid", + "ovarian", + "adenocarcinomas" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "endometrioid", + "ovarian", + "adenocarcinomas" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induction" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "endometrioid", + "ovarian", + "adenocarcinomas" + ] + } + } + ] + }, + { + "PMID": "15619625", + "TEXT": "Respiratory syncytial virus (RSV) infection is one of the major causes of respiratory tract infection for which no vaccine or antiviral treatment is available. The RSV NS1 protein seems to antagonize the host interferon (IFN) response; however, its mechanism is unknown. Here, we used a plasmid-borne small interfering RNA targeting the NS1 gene (siNS1) to examine the role of NS1 in modulating RSV infection. RSV replication was reduced in A549 cells, but not IFN-deficient Vero cells, transfected with siNS1. siNS1 induced upregulated expression of IFN-beta and IFN-inducible genes in A549 cells. siNS1-transfected human dendritic cells, upon RSV infection, produced elevated type-1 IFN and induced differentiation of naive CD4+ T cells to T helper type 1 (TH1) cells. Mice treated intranasally with siNS1 nanoparticles before or after infection with RSV showed substantially decreased virus titers in the lung and decreased inflammation and airway reactivity compared to controls. Thus, siNS1 nanoparticles may provide an effective inhibition of RSV infection in humans.", + "TAG_DATA": [ + "69, A549 {'context': 'B-cells'}", + "70, cells, {'context': 'I-cells'}", + "74, Vero {'context': 'B-cells'}", + "75, cells, {'context': 'I-cells'}", + "76, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "77, with {'perturbing_action': 'I-gene gain-of-function'}", + "78, siNS1. {'perturbing_action': 'I-gene gain-of-function'}", + "79, siNS1 {'perturbing_action': 'I-rnai/knockdown'}", + "89, A549 {'context': 'B-cells'}", + "90, cells. {'context': 'I-cells'}", + "91, siNS1-transfected {'perturbing_action': 'B-gene gain-of-function'}", + "92, human {'context': 'B-cells'}", + "93, dendritic {'context': 'I-cells'}", + "94, cells, {'context': 'I-cells'}", + "103, induced {'effect': 'B-positive'}", + "104, differentiation {'phenotype': 'B-differentiation'}", + "106, naive {'context': 'B-cells'}", + "107, CD4+ {'context': 'I-cells'}", + "108, T {'context': 'I-cells'}", + "109, cells {'context': 'I-cells'}", + "111, T {'context': 'B-cells'}", + "112, helper {'context': 'I-cells'}", + "113, type {'context': 'I-cells'}", + "114, 1 {'context': 'I-cells'}", + "115, (TH1) {'context': 'I-cells'}", + "116, cells. {'context': 'I-cells'}", + "117, Mice {'context': 'B-organism'}", + "136, lung {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "69, A549 ['l0', 'l1', 'l2']", + "70, cells, ['l0']", + "74, Vero ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "75, cells, ['l1', 'l3', 'l10', 'l11', 'l12', 'l13']", + "76, transfected ['l4', 'l14', 'l15', 'l16', 'l17', 'l18']", + "77, with ['l5', 'l14', 'l19', 'l20', 'l21', 'l22', 'l23']", + "78, siNS1. ['l6', 'l10', 'l15', 'l19', 'l24', 'l25', 'l26']", + "79, siNS1 ['l7', 'l11', 'l16', 'l20', 'l24', 'l27', 'l28']", + "89, A549 ['l8', 'l12', 'l17', 'l21', 'l25', 'l27', 'l29']", + "90, cells. ['l2', 'l9', 'l13', 'l18', 'l22', 'l26', 'l28', 'l29']", + "91, siNS1-transfected ['l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "92, human ['l30', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "93, dendritic ['l31', 'l45', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "94, cells, ['l32', 'l46', 'l59', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "103, induced ['l33', 'l47', 'l60', 'l72', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "104, differentiation ['l34', 'l48', 'l61', 'l73', 'l84', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "106, naive ['l35', 'l49', 'l62', 'l74', 'l85', 'l95', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113']", + "107, CD4+ ['l36', 'l50', 'l63', 'l75', 'l86', 'l96', 'l105', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121']", + "108, T ['l37', 'l51', 'l64', 'l76', 'l87', 'l97', 'l106', 'l114', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128']", + "109, cells ['l23', 'l38', 'l52', 'l65', 'l77', 'l88', 'l98', 'l107', 'l115', 'l122', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "111, T ['l39', 'l53', 'l66', 'l78', 'l89', 'l99', 'l108', 'l116', 'l123', 'l129', 'l135', 'l136', 'l137', 'l138', 'l139']", + "112, helper ['l40', 'l54', 'l67', 'l79', 'l90', 'l100', 'l109', 'l117', 'l124', 'l130', 'l135', 'l140', 'l141', 'l142', 'l143']", + "113, type ['l41', 'l55', 'l68', 'l80', 'l91', 'l101', 'l110', 'l118', 'l125', 'l131', 'l136', 'l140', 'l144', 'l145', 'l146']", + "114, 1 ['l42', 'l56', 'l69', 'l81', 'l92', 'l102', 'l111', 'l119', 'l126', 'l132', 'l137', 'l141', 'l144', 'l147', 'l148']", + "115, (TH1) ['l43', 'l57', 'l70', 'l82', 'l93', 'l103', 'l112', 'l120', 'l127', 'l133', 'l138', 'l142', 'l145', 'l147', 'l149']", + "116, cells. ['l44', 'l58', 'l71', 'l83', 'l94', 'l104', 'l113', 'l121', 'l128', 'l134', 'l139', 'l143', 'l146', 'l148', 'l149']", + "117, Mice ['l150']", + "136, lung ['l150']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "Vero", + "cells,", + "A549", + "cells.", + "cells", + "human", + "dendritic", + "naive", + "CD4+", + "T", + "helper", + "type", + "1", + "(TH1)" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "with", + "siNS1.", + "siNS1-transfected" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Vero", + "cells,", + "A549", + "cells." + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siNS1" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "siNS1-transfected" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "siNS1-transfected" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "dendritic", + "cells,", + "naive", + "CD4+", + "T", + "cells", + "helper", + "type", + "1", + "(TH1)", + "cells." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "dendritic", + "cells,", + "naive", + "CD4+", + "T", + "cells", + "helper", + "type", + "1", + "(TH1)", + "cells." + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "15592573", + "TEXT": "Here we report that epidermal keratinocytes in psoriatic lesions are characterized by activated Stat3. Transgenic mice with keratinocytes expressing a constitutively active Stat3 (K5.Stat3C mice) develop a skin phenotype either spontaneously, or in response to wounding, that closely resembles psoriasis. Keratinocytes from K5.Stat3C mice show upregulation of several molecules linked to the pathogenesis of psoriasis. In addition, the development of psoriatic lesions in K5.Stat3C mice requires cooperation between Stat3 activation in keratinocytes and activated T cells. Finally, abrogation of Stat3 function by a decoy oligonucleotide inhibits the onset and reverses established psoriatic lesions in K5.Stat3C mice. Thus, targeting Stat3 may be potentially therapeutic in the treatment of psoriasis.", + "TAG_DATA": [ + "15, mice {'context': 'B-organism'}", + "17, keratinocytes {'context': 'B-cells'}", + "18, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "19, a {'perturbing_action': 'I-gene gain-of-function'}", + "20, constitutively {'perturbing_action': 'I-gene gain-of-function'}", + "21, active {'perturbing_action': 'I-gene gain-of-function'}", + "22, Stat3 {'perturbing_action': 'I-gene gain-of-function'}", + "40, Keratinocytes {'context': 'B-cells'}", + "42, K5.Stat3C {'perturbing_action': 'B-other'}", + "43, mice {'context': 'B-organism'}", + "63, K5.Stat3C {'perturbing_action': 'B-other'}", + "64, mice {'context': 'B-organism'}", + "77, abrogation {'perturbing_action': 'B-gene loss-of-function'}", + "78, of {'perturbing_action': 'I-gene loss-of-function'}", + "79, Stat3 {'perturbing_action': 'I-gene loss-of-function'}", + "80, function {'perturbing_action': 'I-gene loss-of-function'}", + "81, by {'perturbing_action': 'I-gene loss-of-function'}", + "82, a {'perturbing_action': 'I-rnai/knockdown'}", + "83, decoy {'perturbing_action': 'I-rnai/knockdown'}", + "84, oligonucleotide {'perturbing_action': 'I-gene loss-of-function'}", + "94, K5.Stat3C {'perturbing_action': 'B-other'}", + "95, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "15, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "17, keratinocytes ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "18, expressing ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "19, a ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "20, constitutively ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "21, active ['l4', 'l14', 'l23', 'l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "22, Stat3 ['l5', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "40, Keratinocytes ['l6', 'l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "42, K5.Stat3C ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "43, mice ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "63, K5.Stat3C ['l9', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "64, mice ['l10', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']", + "77, abrogation ['l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "78, of ['l66', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "79, Stat3 ['l67', 'l75', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "80, function ['l68', 'l76', 'l83', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "81, by ['l69', 'l77', 'l84', 'l90', 'l96', 'l97', 'l98', 'l99', 'l100']", + "82, a ['l70', 'l78', 'l85', 'l91', 'l96', 'l101', 'l102', 'l103', 'l104']", + "83, decoy ['l71', 'l79', 'l86', 'l92', 'l97', 'l101', 'l105', 'l106', 'l107']", + "84, oligonucleotide ['l72', 'l80', 'l87', 'l93', 'l98', 'l102', 'l105', 'l108', 'l109']", + "94, K5.Stat3C ['l73', 'l81', 'l88', 'l94', 'l99', 'l103', 'l106', 'l108', 'l110']", + "95, mice. ['l74', 'l82', 'l89', 'l95', 'l100', 'l104', 'l107', 'l109', 'l110']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "a", + "constitutively", + "active", + "Stat3" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "K5.Stat3C" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "keratinocytes", + "Keratinocytes" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "a", + "constitutively", + "active", + "Stat3" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "keratinocytes", + "Keratinocytes" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "K5.Stat3C" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "abrogation", + "of", + "Stat3", + "function", + "by", + "oligonucleotide" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "a", + "decoy" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "15558054", + "TEXT": "In tumors that retain wild-type p53, its tumor-suppressor function is often impaired as a result of the deregulation of HDM-2, which binds to p53 and targets it for proteasomal degradation. We have screened a chemical library and identified a small molecule named RITA (reactivation of p53 and induction of tumor cell apoptosis), which bound to p53 and induced its accumulation in tumor cells. RITA prevented p53-HDM-2 interaction in vitro and in vivo and affected p53 interaction with several negative regulators. RITA induced expression of p53 target genes and massive apoptosis in various tumor cells lines expressing wild-type p53. RITA suppressed the growth of human fibroblasts and lymphoblasts only upon oncogene expression and showed substantial p53-dependent antitumor effect in vivo. RITA may serve as a lead compound for the development of an anticancer drug that targets tumors with wild-type p53.", + "TAG_DATA": [ + "47, induction {'effect': 'B-positive'}", + "61, tumor {'context': 'B-transformed cells'}", + "62, cells. {'context': 'I-transformed cells'}", + "67, in {'context': 'B-in vitro'}", + "68, vitro {'context': 'I-in vitro'}", + "70, in {'context': 'B-in vivo'}", + "71, vivo {'context': 'I-in vivo'}", + "81, induced {'effect': 'B-positive'}", + "89, apoptosis {'phenotype': 'B-apoptosis'}", + "92, tumor {'context': 'B-transformed cells'}", + "93, cells {'context': 'I-transformed cells'}", + "94, lines {'context': 'I-transformed cells'}", + "103, human {'context': 'B-cells'}", + "104, fibroblasts {'context': 'I-cells'}", + "106, lymphoblasts {'context': 'B-cells'}", + "117, in {'context': 'B-in vivo'}", + "118, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "47, induction ['l0', 'l1']", + "61, tumor ['l0', 'l2', 'l3', 'l4']", + "62, cells. ['l1', 'l2']", + "67, in ['l3', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "68, vitro ['l4', 'l5', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "70, in ['l6', 'l13', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "71, vivo ['l7', 'l14', 'l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "81, induced ['l8', 'l15', 'l21', 'l26', 'l31', 'l32', 'l33', 'l34']", + "89, apoptosis ['l9', 'l16', 'l22', 'l27', 'l31', 'l35', 'l36', 'l37']", + "92, tumor ['l10', 'l17', 'l23', 'l28', 'l32', 'l35', 'l38', 'l39']", + "93, cells ['l11', 'l18', 'l24', 'l29', 'l33', 'l36', 'l38', 'l40']", + "94, lines ['l12', 'l19', 'l25', 'l30', 'l34', 'l37', 'l39', 'l40']", + "103, human ['l41', 'l42']", + "104, fibroblasts ['l41', 'l43']", + "106, lymphoblasts ['l42', 'l43']", + "117, in ['l44']", + "118, vivo. ['l44']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induction", + "induced" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells.", + "cells", + "lines" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells", + "lines" + ] + } + } + ] + }, + { + "PMID": "15516929", + "TEXT": "Although thrombolytic effects of tissue plasminogen activator (tPA) are beneficial, its neurotoxicity is problematic. Here, we report that tPA potentiates apoptosis in ischemic human brain endothelium and in mouse cortical neurons treated with N-methyl-D-aspartate (NMDA) by shifting the apoptotic pathways from caspase-9 to caspase-8, which directly activates caspase-3 without amplification through the Bid-mediated mitochondrial pathway. In vivo, tPA-induced cerebral ischemic injury in mice was reduced by intracerebroventricular administration of caspase-8 inhibitor, but not by caspase-9 inhibitor, in contrast to controls in which caspase-9 inhibitor, but not caspase-8 inhibitor, was protective. Activated protein C (APC), a serine protease with anticoagulant, anti-inflammatory and antiapoptotic activities, which is neuroprotective during transient ischemia and promotes activation of antiapoptotic mechanisms in brain cells by acting directly on endothelium and neurons, blocked tPA vascular and neuronal toxicities in vitro and in vivo. APC inhibited tPA-induced caspase-8 activation of caspase-3 in endothelium and caspase-3-dependent nuclear translocation of apoptosis-inducing factor in NMDA-treated neurons and reduced tPA-mediated cerebral ischemic injury in mice. Data suggest that tPA shifts the apoptotic signal in stressed brain cells from the intrinsic to the extrinsic pathway which requires caspase-8. APC blocks tPA's neurovascular toxicity and may add substantially to the effectiveness of tPA therapy for stroke.", + "TAG_DATA": [ + "19, potentiates {'effect': 'B-positive'}", + "20, apoptosis {'phenotype': 'B-apoptosis'}", + "23, human {'context': 'B-tissue/organ'}", + "24, brain {'context': 'I-tissue/organ'}", + "25, endothelium {'context': 'I-tissue/organ'}", + "28, mouse {'context': 'B-cells'}", + "29, cortical {'context': 'I-cells'}", + "30, neurons {'context': 'I-cells'}", + "55, In {'context': 'B-in vivo'}", + "56, vivo, {'context': 'I-in vivo'}", + "62, mice {'context': 'B-organism'}", + "69, caspase-8 {'perturbing_action': 'B-pharmacological inhibition'}", + "70, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "74, caspase-9 {'perturbing_action': 'B-pharmacological inhibition'}", + "75, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "82, caspase-9 {'perturbing_action': 'B-pharmacological inhibition'}", + "83, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "86, caspase-8 {'perturbing_action': 'B-pharmacological inhibition'}", + "87, inhibitor, {'perturbing_action': 'I-pharmacological inhibition'}", + "131, in {'context': 'B-in vitro'}", + "132, vitro {'context': 'I-in vitro'}", + "134, in {'context': 'B-in vivo'}", + "135, vivo. {'context': 'I-in vivo'}", + "144, endothelium {'context': 'B-tissue/organ'}", + "154, neurons {'context': 'B-cells'}", + "162, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "19, potentiates ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "20, apoptosis ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "23, human ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "24, brain ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "25, endothelium ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "28, mouse ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "29, cortical ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "30, neurons ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l51', 'l52', 'l53']", + "55, In ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l51', 'l54', 'l55']", + "56, vivo, ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l52', 'l54', 'l56']", + "62, mice ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l53', 'l55', 'l56', 'l57', 'l58']", + "69, caspase-8 ['l49', 'l57', 'l59', 'l60', 'l61']", + "70, inhibitor, ['l50', 'l58', 'l59', 'l62', 'l63']", + "74, caspase-9 ['l60', 'l62', 'l64']", + "75, inhibitor, ['l61', 'l63', 'l64']", + "82, caspase-9 ['l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "83, inhibitor, ['l65', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "86, caspase-8 ['l66', 'l73', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "87, inhibitor, ['l67', 'l74', 'l80', 'l86', 'l87', 'l88', 'l89', 'l90']", + "131, in ['l68', 'l75', 'l81', 'l86', 'l91']", + "132, vitro ['l69', 'l76', 'l82', 'l87', 'l91']", + "134, in ['l70', 'l77', 'l83', 'l88', 'l92', 'l93']", + "135, vivo. ['l71', 'l78', 'l84', 'l89', 'l92', 'l94']", + "144, endothelium ['l72', 'l79', 'l85', 'l90', 'l93', 'l94', 'l95']", + "154, neurons ['l95', 'l96']", + "162, mice. ['l96']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "potentiates" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "potentiates" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "human", + "brain", + "endothelium" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "potentiates" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "cortical", + "neurons" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "potentiates" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "potentiates" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "human", + "brain", + "endothelium" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "cortical", + "neurons" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cortical" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "caspase-8", + "inhibitor," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "caspase-8", + "inhibitor," + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "caspase-9", + "inhibitor,", + "caspase-8" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "caspase-9", + "inhibitor,", + "caspase-8" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "caspase-9", + "inhibitor,", + "caspase-8" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "endothelium" + ] + } + } + ] + }, + { + "PMID": "15502840", + "TEXT": "We studied the effects of Lyn ablation on the survival of drug-resistant chronic myelogenous leukemia (CML) blast crisis cells using siRNA. Lyn siRNA reduced Lyn protein in both normal hematopoietic cells and BCR-ABL1-expressing (BCR-ABL1(+)) blasts by 80-95%. Within 48 h, siRNA-treated BCR-ABL1(+) blasts underwent apoptosis, whereas normal cells remained viable. This increased dependence on Lyn signaling for BCR-ABL1(+) blast survival provides the basis for rational treatment of drug-resistant CML blast crisis, particularly when lymphoid in nature.", + "TAG_DATA": [ + "21, Lyn {'perturbing_action': 'B-rnai/knockdown'}", + "22, siRNA {'perturbing_action': 'I-rnai/knockdown'}", + "28, normal {'context': 'B-cells'}", + "29, hematopoietic {'context': 'I-cells'}", + "30, cells {'context': 'I-cells'}", + "32, BCR-ABL1-expressing {'context': 'B-transformed cells'}", + "33, (BCR-ABL1(+)) {'context': 'I-transformed cells'}", + "34, blasts {'context': 'I-transformed cells'}", + "40, siRNA-treated {'perturbing_action': 'B-rnai/knockdown'}", + "41, BCR-ABL1(+) {'context': 'B-transformed cells'}", + "42, blasts {'context': 'I-transformed cells'}", + "44, apoptosis, {'phenotype': 'B-apoptosis'}", + "46, normal {'context': 'B-cells'}", + "47, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "21, Lyn ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "22, siRNA ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "28, normal ['l1', 'l7', 'l13', 'l14', 'l15', 'l16']", + "29, hematopoietic ['l2', 'l8', 'l13', 'l17', 'l18', 'l19', 'l20']", + "30, cells ['l3', 'l9', 'l14', 'l17', 'l21', 'l22']", + "32, BCR-ABL1-expressing ['l4', 'l10', 'l18', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "33, (BCR-ABL1(+)) ['l5', 'l11', 'l15', 'l19', 'l21', 'l23', 'l30', 'l31', 'l32', 'l33']", + "34, blasts ['l6', 'l12', 'l16', 'l20', 'l22', 'l24', 'l30', 'l34']", + "40, siRNA-treated ['l25', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "41, BCR-ABL1(+) ['l26', 'l35', 'l41', 'l42', 'l43', 'l44', 'l45']", + "42, blasts ['l27', 'l31', 'l34', 'l36', 'l41', 'l46', 'l47']", + "43, underwent ['l28', 'l32', 'l37', 'l42', 'l46', 'l48']", + "44, apoptosis, ['l29', 'l33', 'l38', 'l43', 'l47', 'l48', 'l49']", + "46, normal ['l39', 'l44', 'l50']", + "47, cells ['l40', 'l45', 'l49', 'l50']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Lyn", + "siRNA", + "siRNA-treated" + ] + }, + "context": { + "val": "cells", + "words": [ + "normal", + "hematopoietic", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Lyn", + "siRNA", + "siRNA-treated" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "BCR-ABL1-expressing", + "(BCR-ABL1(+))", + "blasts", + "BCR-ABL1(+)" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "BCR-ABL1-expressing", + "(BCR-ABL1(+))", + "BCR-ABL1(+)", + "blasts" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA-treated" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + }, + "context": { + "val": "cells", + "words": [ + "cells" + ] + } + } + ] + }, + { + "PMID": "15475963", + "TEXT": "Fatty acid oxidation (FAO) is a primary energy source for meeting the heart's energy requirements. Peroxisome proliferator-activated receptor-delta (PPAR-delta) may have important roles in FAO. But it remains unclear whether PPAR-delta is required for maintaining basal myocardial FAO. We show that cre-loxP-mediated cardiomyocyte-restricted deletion of PPAR-delta in mice downregulates constitutive expression of key FAO genes and decreases basal myocardial FAO. These mice have cardiac dysfunction, progressive myocardial lipid accumulation, cardiac hypertrophy and congestive heart failure with reduced survival. Thus, chronic myocardial PPAR-delta deficiency leads to lipotoxic cardiomyopathy. Together, our data show that PPAR-delta is a crucial determinant of constitutive myocardial FAO and is necessary to maintain energy balance and normal cardiac function. We suggest that PPAR-delta is a potential therapeutic target in treating lipotoxic cardiomyopathy and other heart diseases.", + "TAG_DATA": [ + "41, cre-loxP-mediated {'perturbing_action': 'B-gene loss-of-function'}", + "42, cardiomyocyte-restricted {'perturbing_action': 'I-gene loss-of-function'}", + "43, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "44, of {'perturbing_action': 'I-gene loss-of-function'}", + "45, PPAR-delta {'perturbing_action': 'I-gene loss-of-function'}", + "47, mice {'context': 'B-organism'}", + "61, mice {'context': 'B-organism'}", + "79, chronic {'perturbing_action': 'B-gene loss-of-function'}", + "80, myocardial {'perturbing_action': 'I-gene loss-of-function'}", + "81, PPAR-delta {'perturbing_action': 'I-gene loss-of-function'}", + "82, deficiency {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "41, cre-loxP-mediated ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "42, cardiomyocyte-restricted ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "43, deletion ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "44, of ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "45, PPAR-delta ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "47, mice ['l4', 'l9', 'l13', 'l16', 'l18']", + "61, mice ['l5', 'l10', 'l14', 'l17', 'l19']", + "79, chronic ['l20', 'l21', 'l22']", + "80, myocardial ['l20', 'l23', 'l24']", + "81, PPAR-delta ['l21', 'l23', 'l25']", + "82, deficiency ['l22', 'l24', 'l25']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cre-loxP-mediated", + "cardiomyocyte-restricted", + "deletion", + "of", + "PPAR-delta" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "15448684", + "TEXT": "Neuromedin U (NMU) is a hypothalamic neuropeptide that regulates body weight and composition. Here we show that mice lacking the gene encoding NMU (Nmu(-/-) mice) develop obesity. Nmu(-/-) mice showed increased body weight and adiposity, hyperphagia, and decreased locomotor activity and energy expenditure. Obese Nmu(-/-) mice developed hyperleptinemia, hyperinsulinemia, late-onset hyperglycemia and hyperlipidemia. Notably, however, treatment with exogenous leptin was effective in reducing body weight in obese Nmu(-/-) mice. In addition, central leptin administration did not affect NMU gene expression in the hypothalamus of rats. These results indicate that NMU plays an important role in the regulation of feeding behavior and energy metabolism independent of the leptin signaling pathway. These characteristic functions of NMU may provide new insight for understanding the pathophysiological basis of obesity.", + "TAG_DATA": [ + "17, mice {'context': 'B-organism'}", + "18, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "19, the {'perturbing_action': 'I-gene loss-of-function'}", + "20, gene {'perturbing_action': 'I-gene loss-of-function'}", + "21, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "22, NMU {'perturbing_action': 'I-gene loss-of-function'}", + "23, (Nmu(-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "24, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "27, Nmu(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "28, mice {'context': 'B-organism'}", + "44, Nmu(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "45, mice {'context': 'B-organism'}", + "66, obese {'perturbing_action': 'B-gene loss-of-function'}", + "67, Nmu(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "68, mice. {'context': 'B-organism'}", + "82, hypothalamus {'context': 'B-tissue/organ'}", + "84, rats. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "17, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "18, lacking ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "19, the ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "20, gene ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "21, encoding ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "22, NMU ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "23, (Nmu(-/-) ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "24, mice) ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "27, Nmu(-/-) ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "28, mice ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "44, Nmu(-/-) ['l45']", + "45, mice ['l45']", + "66, obese ['l46', 'l47']", + "67, Nmu(-/-) ['l46', 'l48']", + "68, mice. ['l47', 'l48']", + "82, hypothalamus ['l49']", + "84, rats. ['l49']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "gene", + "encoding", + "NMU", + "(Nmu(-/-)", + "mice)", + "Nmu(-/-)", + "obese" + ] + } + } + ] + }, + { + "PMID": "15334074", + "TEXT": "Signaling through the second messengers calcium and diacylglycerol (DAG) is a critical element in many biological systems. Integration of calcium and DAG signals has been suggested to occur primarily through protein kinase C family members, which bind both calcium and DAG. However, an alternative pathway may involve members of the CalDAG-GEF/RasGRP protein family, which have structural features (calcium-binding EF hands and DAG-binding C1 domains) that suggest they can function in calcium and DAG signal integration. To gain insight into the signaling systems that may be regulated by CalDAG-GEF/RasGRP family members, we have focused on CalDAG-GEFI, which is expressed preferentially in the brain and blood. Through genetic ablation in the mouse, we have found that CalDAG-GEFI is crucial for signal integration in platelets. Mouse platelets that lack CalDAG-GEFI are severely compromised in integrin-dependent aggregation as a consequence of their inability to signal through CalDAG-GEFI to its target, the small GTPase Rap1. These results suggest that analogous signaling defects are likely to occur in the central nervous system when CalDAG-GEFI is absent or compromised in function.", + "TAG_DATA": [ + "105, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "106, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "109, mouse, {'context': 'B-organism'}", + "122, Mouse {'context': 'B-cells'}", + "123, platelets {'context': 'I-cells'}", + "125, lack {'perturbing_action': 'B-gene loss-of-function'}", + "126, CalDAG-GEFI {'perturbing_action': 'I-gene loss-of-function'}", + "129, compromised {'effect': 'B-negative'}" + ], + "LINK_DATA": [ + "105, genetic ['l0', 'l1']", + "106, ablation ['l0', 'l2']", + "109, mouse, ['l1', 'l2']", + "122, Mouse ['l3', 'l4', 'l5', 'l6']", + "123, platelets ['l3', 'l7', 'l8', 'l9']", + "125, lack ['l4', 'l7', 'l10', 'l11']", + "126, CalDAG-GEFI ['l5', 'l8', 'l10', 'l12']", + "129, compromised ['l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Mouse", + "platelets" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "CalDAG-GEFI" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Mouse", + "platelets" + ] + }, + "effect": { + "val": "negative", + "words": [ + "compromised" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "CalDAG-GEFI" + ] + }, + "effect": { + "val": "negative", + "words": [ + "compromised" + ] + } + } + ] + }, + { + "PMID": "15334073", + "TEXT": "The involvement of immune mechanisms in tumor angiogenesis is unclear. Here we describe a new mechanism of tumor vasculogenesis mediated by dendritic cell (DC) precursors through the cooperation of beta-defensins and vascular endothelial growth factor-A (Vegf-A). Expression of mouse beta-defensin-29 recruited DC precursors to tumors and enhanced tumor vascularization and growth in the presence of increased Vegf-A expression. A new leukocyte population expressing DC and endothelial markers was uncovered in mouse and human ovarian carcinomas coexpressing Vegf-A and beta-defensins. Tumor-infiltrating DCs migrated to tumor vessels and independently assembled neovasculature in vivo. Bone marrow-derived DCs underwent endothelial-like differentiation ex vivo, migrated to blood vessels and promoted the growth of tumors expressing high levels of Vegf-A. We show that beta-defensins and Vegf-A cooperate to promote tumor vasculogenesis by carrying out distinct tasks: beta-defensins chemoattract DC precursors through CCR6, whereas Vegf-A primarily induces their endothelial-like specialization and migration to vessels, which is mediated by Vegf receptor-2.", + "TAG_DATA": [ + "36, Expression {'perturbing_action': 'B-gene gain-of-function'}", + "37, of {'perturbing_action': 'I-gene gain-of-function'}", + "38, mouse {'perturbing_action': 'I-gene gain-of-function'}", + "39, beta-defensin-29 {'perturbing_action': 'I-gene gain-of-function'}", + "41, DC {'context': 'B-cells'}", + "42, precursors {'context': 'I-cells'}", + "44, tumors {'context': 'B-neoplasm'}", + "47, tumor {'context': 'B-neoplasm'}", + "80, DCs {'context': 'B-cells'}", + "89, in {'context': 'B-in vivo'}", + "90, vivo. {'context': 'I-in vivo'}", + "91, Bone {'context': 'B-cells'}", + "92, marrow-derived {'context': 'I-cells'}", + "93, DCs {'context': 'I-cells'}", + "108, tumors {'context': 'B-neoplasm'}" + ], + "LINK_DATA": [ + "36, Expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "37, of ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "38, mouse ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "39, beta-defensin-29 ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "41, DC ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36']", + "42, precursors ['l4', 'l13', 'l21', 'l28', 'l34', 'l37', 'l38']", + "44, tumors ['l5', 'l14', 'l22', 'l29', 'l35', 'l37', 'l39']", + "47, tumor ['l6', 'l15', 'l23', 'l30', 'l36', 'l38', 'l39']", + "80, DCs ['l7', 'l16', 'l24', 'l31', 'l40', 'l41']", + "89, in ['l8', 'l17', 'l25', 'l32', 'l40', 'l42']", + "90, vivo. ['l9', 'l18', 'l26', 'l33', 'l41', 'l42']", + "91, Bone ['l43', 'l44', 'l45']", + "92, marrow-derived ['l43', 'l46', 'l47']", + "93, DCs ['l44', 'l46', 'l48']", + "108, tumors ['l45', 'l47', 'l48']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "mouse", + "beta-defensin-29" + ] + }, + "context": { + "val": "cells", + "words": [ + "DC", + "precursors", + "DCs" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "mouse", + "beta-defensin-29" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors", + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "mouse", + "beta-defensin-29" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "15311276", + "TEXT": "Thyroid autoimmune disorders comprise more than 30% of all organ-specific autoimmune diseases and are characterized by autoantibodies and infiltrating T cells. The pathologic role of infiltrating T cells is not well defined. To address this issue, we generated transgenic mice expressing a human T-cell receptor derived from the thyroid-infiltrating T cell of a patient with thyroiditis and specific for a cryptic thyroid-peroxidase epitope. Here we show that mouse major histocompatibility complex molecules sustain selection and activation of the transgenic T cells, as coexpression of histocompatibility leukocyte antigen molecules was not needed. Furthermore, the transgenic T cells had an activated phenotype in vivo, and mice spontaneously developed destructive thyroiditis with histological, clinical and hormonal signs comparable with human autoimmune hypothyroidism. These results highlight the pathogenic role of human T cells specific for cryptic self epitopes. This new 'humanized' model will provide a unique tool to investigate how human pathogenic self-reactive T cells initiate autoimmune diseases and to determine how autoimmunity can be modulated in vivo.", + "TAG_DATA": [ + "38, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "39, mice {'context': 'I-organism'}", + "40, expressing {'perturbing_action': 'B-gene gain-of-function'}", + "41, a {'perturbing_action': 'I-gene gain-of-function'}", + "42, human {'perturbing_action': 'I-gene gain-of-function'}", + "43, T-cell {'perturbing_action': 'I-gene gain-of-function'}", + "44, receptor {'perturbing_action': 'I-gene gain-of-function'}", + "79, T {'context': 'B-cells'}", + "80, cells, {'context': 'I-cells'}", + "94, T {'context': 'B-cells'}", + "95, cells {'context': 'I-cells'}", + "100, in {'context': 'B-in vivo'}", + "101, vivo, {'context': 'I-in vivo'}", + "103, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "38, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "39, mice ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "40, expressing ['l1', 'l7', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19']", + "41, a ['l2', 'l8', 'l13', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "42, human ['l3', 'l9', 'l14', 'l20', 'l26', 'l27', 'l28', 'l29', 'l30']", + "43, T-cell ['l4', 'l10', 'l15', 'l21', 'l26', 'l31', 'l32', 'l33', 'l34']", + "44, receptor ['l5', 'l11', 'l16', 'l22', 'l27', 'l31', 'l35', 'l36', 'l37']", + "45, derived ['l6', 'l12', 'l17', 'l23', 'l28', 'l32', 'l35', 'l38', 'l39']", + "78, transgenic ['l40', 'l41', 'l42']", + "79, T ['l18', 'l24', 'l29', 'l33', 'l36', 'l38', 'l40', 'l43']", + "80, cells, ['l19', 'l25', 'l30', 'l34', 'l37', 'l39', 'l41', 'l43']", + "93, transgenic ['l44', 'l45', 'l46', 'l47']", + "94, T ['l44', 'l48', 'l49', 'l50']", + "95, cells ['l42', 'l45', 'l48', 'l51', 'l52']", + "100, in ['l46', 'l49', 'l51', 'l53']", + "101, vivo, ['l47', 'l50', 'l52', 'l53']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "a", + "human", + "T-cell", + "receptor" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "a", + "human", + "T-cell", + "receptor" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells," + ] + } + } + ] + }, + { + "PMID": "15258576", + "TEXT": "Allergic asthma is a complex syndrome characterized by airway obstruction, airway inflammation and airway hyper-responsiveness (AHR). Using a mouse model of allergen-induced AHR, we previously demonstrated that CD8-deficient mice develop significantly lower AHR, eosinophilic inflammation and interleukin (IL)-13 levels in bronchoalveolar lavage fluid compared with wild-type mice. These responses were restored by adoptive transfer of antigen-primed CD8(+) T cells. Previously, two distinct populations of antigen-experienced CD8(+) T cells, termed effector (T(EFF)) and central memory (T(CM)) cells, have been described. After adoptive transfer into CD8-deficient mice, T(EFF), but not T(CM), cells restored AHR, eosinophilic inflammation and IL-13 levels. T(EFF), but not T(CM), cells accumulated in the lungs, and intracellular cytokine staining showed that the transferred T(EFF) cells were a source of IL-13. These data suggest an important role for effector CD8(+) T cells in the development of AHR and airway inflammation, which may be associated with their Tc2-type cytokine production and their capacity to migrate into the lung.", + "TAG_DATA": [ + "27, CD8-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "28, mice {'context': 'B-organism'}", + "56, CD8(+) {'context': 'B-cells'}", + "57, T {'context': 'I-cells'}", + "58, cells. {'context': 'I-cells'}", + "83, CD8-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "84, mice, {'context': 'B-organism'}", + "88, T(CM), {'context': 'B-cells'}", + "89, cells {'context': 'I-cells'}", + "100, T(CM), {'context': 'B-cells'}", + "101, cells {'context': 'I-cells'}", + "105, lungs, {'context': 'B-tissue/organ'}", + "114, T(EFF) {'context': 'B-cells'}", + "115, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "27, CD8-deficient ['l0']", + "28, mice ['l0']", + "56, CD8(+) ['l1', 'l2', 'l3', 'l4', 'l5']", + "57, T ['l1', 'l6', 'l7', 'l8']", + "58, cells. ['l2', 'l6']", + "83, CD8-deficient ['l3', 'l9', 'l10', 'l11', 'l12', 'l13']", + "84, mice, ['l4', 'l7', 'l9', 'l14', 'l15']", + "88, T(CM), ['l10', 'l14', 'l16', 'l17', 'l18', 'l19']", + "89, cells ['l5', 'l8', 'l11', 'l15', 'l16']", + "100, T(CM), ['l17', 'l20', 'l21', 'l22', 'l23']", + "101, cells ['l12', 'l18', 'l20', 'l24', 'l25']", + "105, lungs, ['l13', 'l19', 'l21', 'l24', 'l26', 'l27']", + "114, T(EFF) ['l22', 'l26', 'l28']", + "115, cells ['l23', 'l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD8-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "CD8(+)", + "T(CM),", + "cells" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD8-deficient" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD8-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lungs," + ] + } + } + ] + }, + { + "PMID": "15195088", + "TEXT": "Liver repopulation with bone marrow-derived hepatocytes (BMHs) can cure the genetic liver disease fumarylacetoacetate hydrolase (Fah) deficiency. BMHs emerge from fusion between donor bone marrow-derived cells and host hepatocytes. To use such in vivo cell fusion efficiently for therapy requires knowing the nature of the hematopoietic cells that fuse with hepatocytes. Here we show that the transplantation into Fah(-/-) mice of hematopoietic stem cells (HSCs) from lymphocyte-deficient Rag1(-/-) mice, lineage-committed granulocyte-macrophage progenitors (GMPs) or bone marrow-derived macrophages (BMMs) results in the robust production of BMHs. These results provide direct evidence that committed myelomonocytic cells such as macrophages can produce functional epithelial cells by in vivo fusion. Because stable bone marrow engraftment or HSCs are not required for this process, macrophages or their highly proliferative progenitors provide potential for targeted and well-tolerated cell therapy aimed at organ regeneration.", + "TAG_DATA": [ + "58, Fah(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "59, mice {'context': 'B-organism'}", + "61, hematopoietic {'context': 'B-cells'}", + "62, stem {'context': 'I-cells'}", + "63, cells {'context': 'I-cells'}", + "64, (HSCs) {'context': 'I-cells'}", + "66, lymphocyte-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "67, Rag1(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "68, mice, {'context': 'B-organism'}", + "69, lineage-committed {'context': 'B-cells'}", + "70, granulocyte-macrophage {'context': 'I-cells'}", + "71, progenitors {'context': 'I-cells'}", + "72, (GMPs) {'context': 'I-cells'}", + "74, bone {'context': 'B-cells'}", + "75, marrow-derived {'context': 'I-cells'}", + "76, macrophages {'context': 'I-cells'}", + "77, (BMMs) {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "58, Fah(-/-) ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "59, mice ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "61, hematopoietic ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "62, stem ['l2', 'l9', 'l15', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "63, cells ['l3', 'l10', 'l16', 'l25', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "64, (HSCs) ['l4', 'l11', 'l17', 'l26', 'l34', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "66, lymphocyte-deficient ['l5', 'l12', 'l18', 'l27', 'l35', 'l42', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "67, Rag1(-/-) ['l6', 'l13', 'l19', 'l28', 'l36', 'l43', 'l49', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "68, mice, ['l7', 'l14', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l61', 'l62', 'l63', 'l64', 'l65']", + "69, lineage-committed ['l21', 'l30', 'l38', 'l45', 'l51', 'l56', 'l61', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "70, granulocyte-macrophage ['l22', 'l31', 'l39', 'l46', 'l52', 'l57', 'l62', 'l66', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "71, progenitors ['l23', 'l32', 'l40', 'l47', 'l53', 'l58', 'l63', 'l67', 'l73', 'l79', 'l80', 'l81', 'l82', 'l83']", + "72, (GMPs) ['l24', 'l33', 'l41', 'l48', 'l54', 'l59', 'l64', 'l68', 'l74', 'l79', 'l84', 'l85', 'l86', 'l87']", + "74, bone ['l69', 'l75', 'l80', 'l84', 'l88', 'l89', 'l90']", + "75, marrow-derived ['l70', 'l76', 'l81', 'l85', 'l88', 'l91', 'l92']", + "76, macrophages ['l71', 'l77', 'l82', 'l86', 'l89', 'l91', 'l93']", + "77, (BMMs) ['l60', 'l65', 'l72', 'l78', 'l83', 'l87', 'l90', 'l92', 'l93']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fah(-/-)", + "lymphocyte-deficient", + "Rag1(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Fah(-/-)", + "lymphocyte-deficient", + "Rag1(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "hematopoietic", + "stem", + "cells", + "(HSCs)", + "lineage-committed", + "granulocyte-macrophage", + "progenitors", + "(GMPs)", + "(BMMs)" + ] + } + } + ] + }, + { + "PMID": "15195086", + "TEXT": "Lysophosphatidic acid (LPA) is a bioactive lipid with activity in the nervous system mediated by G-protein-coupled receptors. Here, we examined the role of LPA signaling in the development of neuropathic pain by pharmacological and genetic approaches, including the use of mice lacking the LPA(1) receptor. Wild-type animals with nerve injury develop behavioral allodynia and hyperalgesia paralleled by demyelination in the dorsal root and increased expression of both the protein kinase C gamma-isoform within the spinal cord dorsal horn and the alpha(2)delta(1) calcium channel subunit in dorsal root ganglia. Intrathecal injection of LPA induced behavioral, morphological and biochemical changes similar to those observed after nerve ligation. In contrast, mice lacking a single LPA receptor (LPA(1), also known as EDG2) that activates the Rho-Rho kinase pathway do not develop signs of neuropathic pain after peripheral nerve injury. Inhibitors of Rho and Rho kinase also prevented these signs of neuropathic pain. These results imply that receptor-mediated LPA signaling is crucial in the initiation of neuropathic pain.", + "TAG_DATA": [ + "41, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "42, the {'perturbing_action': 'I-gene loss-of-function'}", + "43, LPA(1) {'perturbing_action': 'I-gene loss-of-function'}", + "44, receptor. {'perturbing_action': 'I-gene loss-of-function'}", + "46, animals {'context': 'B-organism'}", + "60, dorsal {'context': 'B-tissue/organ'}", + "61, root {'context': 'I-tissue/organ'}", + "77, horn {'context': 'I-tissue/organ'}", + "85, dorsal {'context': 'B-cells'}", + "86, root {'context': 'I-cells'}", + "87, ganglia. {'context': 'I-tissue/organ'}", + "107, mice {'context': 'B-organism'}", + "108, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "109, a {'perturbing_action': 'I-gene loss-of-function'}", + "110, single {'perturbing_action': 'I-gene loss-of-function'}", + "111, LPA {'perturbing_action': 'I-gene loss-of-function'}", + "112, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "113, (LPA(1), {'perturbing_action': 'I-gene loss-of-function'}", + "135, Inhibitors {'perturbing_action': 'B-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "41, lacking ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "42, the ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "43, LPA(1) ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "44, receptor. ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "46, animals ['l3', 'l15', 'l26', 'l36', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "60, dorsal ['l4', 'l16', 'l27', 'l37', 'l46', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "61, root ['l5', 'l17', 'l28', 'l38', 'l47', 'l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "74, spinal ['l6', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "75, cord ['l7', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l69', 'l75', 'l76', 'l77', 'l78', 'l79']", + "76, dorsal ['l8', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l70', 'l75', 'l80', 'l81', 'l82', 'l83']", + "77, horn ['l9', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l71', 'l76', 'l80', 'l84', 'l85', 'l86']", + "85, dorsal ['l10', 'l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l72', 'l77', 'l81', 'l84', 'l87', 'l88']", + "86, root ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l73', 'l78', 'l82', 'l85', 'l87', 'l89']", + "87, ganglia. ['l12', 'l24', 'l35', 'l45', 'l54', 'l62', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l89']", + "107, mice ['l90', 'l91', 'l92', 'l93', 'l94', 'l95']", + "108, lacking ['l90', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "109, a ['l91', 'l96', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112']", + "110, single ['l92', 'l97', 'l105', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "111, LPA ['l93', 'l98', 'l106', 'l113', 'l120', 'l121', 'l122', 'l123', 'l124']", + "112, receptor ['l94', 'l99', 'l107', 'l114', 'l120', 'l125', 'l126', 'l127', 'l128']", + "113, (LPA(1), ['l95', 'l100', 'l108', 'l115', 'l121', 'l125', 'l129']", + "135, Inhibitors ['l101', 'l109', 'l116', 'l130', 'l131', 'l132']", + "136, of ['l102', 'l110', 'l117', 'l122', 'l126', 'l130', 'l133', 'l134']", + "137, Rho ['l103', 'l111', 'l118', 'l123', 'l127', 'l131', 'l133', 'l135']", + "140, kinase ['l104', 'l112', 'l119', 'l124', 'l128', 'l129', 'l132', 'l134', 'l135']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "LPA(1)", + "receptor.", + "a", + "single", + "LPA", + "receptor", + "(LPA(1)," + ] + }, + "context": { + "val": "organism", + "words": [ + "animals", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "LPA(1)", + "receptor." + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "dorsal", + "root", + "horn", + "ganglia." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "LPA(1)", + "receptor." + ] + }, + "context": { + "val": "cells", + "words": [ + "dorsal", + "root" + ] + } + } + ] + }, + { + "PMID": "15107844", + "TEXT": "Insulin resistance is a major hallmark in the development of type 2 diabetes, which is characterized by an impaired ability of insulin to inhibit glucose output from the liver and to promote glucose uptake in muscle. The nuclear hormone receptor coactivator PGC-1 (peroxisome proliferator-activated (PPAR)-gamma coactivator-1) has been implicated in the onset of type 2 diabetes. Hepatic PGC-1 expression is elevated in mouse models of this disease, where it promotes constitutive activation of gluconeogenesis and fatty acid oxidation through its association with the nuclear hormone receptors HNF-4 and PPAR-alpha, respectively. Here we show that PGC-1-deficient mice, generated by adenoviral delivery of PGC-1 RNA interference (RNAi) to the liver, experience fasting hypoglycemia. Hepatic insulin sensitivity was enhanced in PGC-1-deficient mice, reflecting in part the reduced expression of the mammalian tribbles homolog TRB-3, a fasting-inducible inhibitor of the serine-threonine kinase Akt/PKB (ref. 6). We show here that, in the liver, TRB-3 is a target for PPAR-alpha. Knockdown of hepatic TRB-3 expression improved glucose tolerance, whereas hepatic overexpression of TRB-3 reversed the insulin-sensitive phenotype of PGC-1-deficient mice. These results indicate a link between nuclear hormone receptor and insulin signaling pathways, and suggest a potential role for TRB-3 inhibitors in the treatment of type 2 diabetes.", + "TAG_DATA": [ + "94, PGC-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "95, mice, {'context': 'B-organism'}", + "98, adenoviral {'perturbing_action': 'B-rnai/knockdown'}", + "99, delivery {'perturbing_action': 'I-rnai/knockdown'}", + "100, of {'perturbing_action': 'I-rnai/knockdown'}", + "101, PGC-1 {'perturbing_action': 'I-rnai/knockdown'}", + "102, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "103, interference {'perturbing_action': 'I-rnai/knockdown'}", + "104, (RNAi) {'perturbing_action': 'I-rnai/knockdown'}", + "105, to {'perturbing_action': 'I-rnai/knockdown'}", + "107, liver, {'context': 'B-tissue/organ'}", + "117, PGC-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "118, mice, {'context': 'B-organism'}", + "154, Knockdown {'perturbing_action': 'B-rnai/knockdown'}", + "155, of {'perturbing_action': 'I-rnai/knockdown'}", + "156, hepatic {'perturbing_action': 'I-rnai/knockdown'}", + "157, TRB-3 {'perturbing_action': 'I-rnai/knockdown'}", + "158, expression {'perturbing_action': 'I-rnai/knockdown'}", + "163, hepatic {'perturbing_action': 'B-gene gain-of-function'}", + "164, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "165, of {'perturbing_action': 'I-gene gain-of-function'}", + "166, TRB-3 {'perturbing_action': 'I-gene gain-of-function'}", + "172, PGC-1-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "173, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "94, PGC-1-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "95, mice, ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "98, adenoviral ['l1', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "99, delivery ['l2', 'l11', 'l17', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "100, of ['l3', 'l12', 'l18', 'l26', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "101, PGC-1 ['l4', 'l19', 'l27', 'l34', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47']", + "102, RNA ['l5', 'l20', 'l28', 'l35', 'l41', 'l48', 'l49', 'l50', 'l51', 'l52']", + "103, interference ['l6', 'l21', 'l29', 'l36', 'l42', 'l48', 'l53', 'l54', 'l55', 'l56']", + "104, (RNAi) ['l7', 'l13', 'l22', 'l30', 'l37', 'l43', 'l49', 'l53', 'l57', 'l58', 'l59']", + "105, to ['l8', 'l14', 'l23', 'l31', 'l38', 'l44', 'l50', 'l54', 'l57', 'l60', 'l61']", + "106, the ['l9', 'l15', 'l24', 'l32', 'l39', 'l45', 'l51', 'l55', 'l58', 'l60', 'l62']", + "107, liver, ['l10', 'l16', 'l25', 'l33', 'l40', 'l46', 'l52', 'l56', 'l59', 'l61', 'l62']", + "117, PGC-1-deficient ['l63', 'l64', 'l65', 'l66']", + "118, mice, ['l47', 'l63']", + "154, Knockdown ['l67', 'l68', 'l69', 'l70']", + "155, of ['l67', 'l71', 'l72', 'l73']", + "156, hepatic ['l64', 'l68', 'l71', 'l74', 'l75']", + "157, TRB-3 ['l65', 'l69', 'l72', 'l74', 'l76']", + "158, expression ['l66', 'l70', 'l73', 'l75', 'l76']", + "163, hepatic ['l77', 'l78', 'l79', 'l80', 'l81']", + "164, overexpression ['l77', 'l82', 'l83', 'l84', 'l85']", + "165, of ['l78', 'l82', 'l86', 'l87', 'l88']", + "166, TRB-3 ['l79', 'l83', 'l86', 'l89', 'l90']", + "172, PGC-1-deficient ['l80', 'l84', 'l87', 'l89', 'l91']", + "173, mice. ['l81', 'l85', 'l88', 'l90', 'l91']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PGC-1-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PGC-1-deficient" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "delivery", + "of", + "(RNAi)", + "to", + "PGC-1" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "adenoviral", + "delivery", + "of", + "PGC-1", + "RNA", + "interference", + "(RNAi)", + "to" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hepatic", + "overexpression", + "of", + "TRB-3" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "15098029", + "TEXT": "The mammalian target of rapamycin, mTOR, regulates cell growth and proliferation. Here we show that the initiation factor of translation (eIF-4E), a downstream effector of mTOR, has oncogenic effects in vivo and cooperates with c-Myc in B-cell lymphomagenesis. We found that c-Myc overrides eIF-4E-induced cellular senescence, whereas eIF-4E antagonizes c-Myc-dependent apoptosis in vivo. Our results implicate activation of eIF-4E as a key event in oncogenic transformation by phosphoinositide-3 kinase and Akt.", + "TAG_DATA": [ + "42, overrides {'effect': 'B-negative'}", + "43, eIF-4E-induced {'effect': 'B-positive'}", + "45, senescence, {'phenotype': 'B-senescence'}", + "48, antagonizes {'effect': 'B-negative'}", + "49, c-Myc-dependent {'effect': 'B-regulates'}", + "50, apoptosis {'phenotype': 'B-apoptosis'}", + "51, in {'context': 'B-in vivo'}", + "52, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "42, overrides ['l0', 'l1']", + "43, eIF-4E-induced ['l0', 'l2']", + "45, senescence, ['l1', 'l2']", + "48, antagonizes ['l3', 'l4', 'l5', 'l6']", + "49, c-Myc-dependent ['l3', 'l7', 'l8', 'l9']", + "50, apoptosis ['l4', 'l7', 'l10', 'l11']", + "51, in ['l5', 'l8', 'l10', 'l12']", + "52, vivo. ['l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "overrides" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "eIF-4E-induced" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "antagonizes" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "antagonizes" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "c-Myc-dependent" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "c-Myc-dependent" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "15077107", + "TEXT": "Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene result in defective epithelial cAMP-dependent Cl(-) secretion and increased airway Na(+) absorption. The mechanistic links between these altered ion transport processes and the pathogenesis of cystic fibrosis lung disease, however, are unclear. To test the hypothesis that accelerated Na(+) transport alone can produce cystic fibrosis-like lung disease, we generated mice with airway-specific overexpression of epithelial Na(+) channels (ENaC). Here we show that increased airway Na(+) absorption in vivo caused airway surface liquid (ASL) volume depletion, increased mucus concentration, delayed mucus transport and mucus adhesion to airway surfaces. Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation and poor bacterial clearance. We conclude that increasing airway Na(+) absorption initiates cystic fibrosis-like lung disease and produces a model for the study of the pathogenesis and therapy of this disease.", + "TAG_DATA": [ + "59, mice {'context': 'B-organism'}", + "61, airway-specific {'perturbing_action': 'B-gene gain-of-function'}", + "62, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "63, of {'perturbing_action': 'I-gene gain-of-function'}", + "64, epithelial {'perturbing_action': 'I-gene gain-of-function'}", + "65, Na(+) {'perturbing_action': 'I-gene gain-of-function'}", + "66, channels {'perturbing_action': 'I-gene gain-of-function'}", + "67, (ENaC). {'perturbing_action': 'I-gene gain-of-function'}", + "76, in {'context': 'B-in vivo'}", + "77, vivo {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "59, mice ['l0', 'l1', 'l2']", + "61, airway-specific ['l0', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "62, overexpression ['l3', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "63, of ['l4', 'l11', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "64, epithelial ['l5', 'l12', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "65, Na(+) ['l6', 'l13', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32']", + "66, channels ['l7', 'l14', 'l20', 'l25', 'l29', 'l33', 'l34', 'l35']", + "67, (ENaC). ['l8', 'l15', 'l21', 'l26', 'l30', 'l33', 'l36', 'l37']", + "76, in ['l1', 'l9', 'l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l38']", + "77, vivo ['l2', 'l10', 'l17', 'l23', 'l28', 'l32', 'l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "airway-specific" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "airway-specific", + "overexpression", + "of", + "epithelial", + "Na(+)", + "channels", + "(ENaC)." + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "14702637", + "TEXT": "Achondroplasia is the most common genetic form of human dwarfism, for which there is presently no effective therapy. C-type natriuretic peptide (CNP) is a newly identified molecule that regulates endochondral bone growth through GC-B, a subtype of particulate guanylyl cyclase. Here we show that targeted overexpression of CNP in chondrocytes counteracts dwarfism in a mouse model of achondroplasia with activated fibroblast growth factor receptor 3 (FGFR-3) in the cartilage. CNP prevented the shortening of achondroplastic bones by correcting the decreased extracellular matrix synthesis in the growth plate through inhibition of the MAPK pathway of FGF signaling. CNP had no effect on the STAT-1 pathway of FGF signaling that mediates the decreased proliferation and the delayed differentiation of achondroplastic chondrocytes. These results demonstrate that activation of the CNP-GC-B system in endochondral bone formation constitutes a new therapeutic strategy for human achondroplasia.", + "TAG_DATA": [ + "44, targeted {'perturbing_action': 'B-gene gain-of-function'}", + "45, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "46, of {'perturbing_action': 'I-gene gain-of-function'}", + "47, CNP {'perturbing_action': 'I-gene gain-of-function'}", + "49, chondrocytes {'context': 'B-cells'}", + "54, mouse {'context': 'B-organism'}", + "55, model {'context': 'I-organism'}", + "75, bones {'context': 'I-tissue/organ'}", + "110, decreased {'effect': 'B-negative'}", + "111, proliferation {'phenotype': 'B-proliferation'}", + "114, delayed {'effect': 'B-negative'}", + "115, differentiation {'phenotype': 'B-differentiation'}", + "117, achondroplastic {'context': 'B-cells'}", + "118, chondrocytes. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "44, targeted ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "45, overexpression ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "46, of ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "47, CNP ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "49, chondrocytes ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "54, mouse ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "55, model ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "56, of ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "74, achondroplastic ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "75, bones ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']", + "110, decreased ['l45', 'l46', 'l47', 'l48', 'l49']", + "111, proliferation ['l45', 'l50', 'l51', 'l52', 'l53']", + "114, delayed ['l46', 'l50', 'l54', 'l55', 'l56']", + "115, differentiation ['l47', 'l51', 'l54', 'l57', 'l58']", + "117, achondroplastic ['l48', 'l52', 'l55', 'l57', 'l59']", + "118, chondrocytes. ['l49', 'l53', 'l56', 'l58', 'l59']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "targeted", + "overexpression", + "of", + "CNP" + ] + }, + "context": { + "val": "cells", + "words": [ + "chondrocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "targeted", + "overexpression", + "of", + "CNP" + ] + }, + "context": { + "val": "organism", + "words": [ + "mouse", + "model" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "targeted", + "overexpression", + "of", + "CNP" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "bones" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased", + "delayed" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased", + "delayed" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased", + "delayed" + ] + }, + "context": { + "val": "cells", + "words": [ + "achondroplastic", + "chondrocytes." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "cells", + "words": [ + "achondroplastic", + "chondrocytes." + ] + } + }, + { + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + }, + "context": { + "val": "cells", + "words": [ + "achondroplastic", + "chondrocytes." + ] + } + } + ] + }, + { + "PMID": "14702634", + "TEXT": "Although tumor progression involves processes such as tissue invasion that can activate inflammatory responses, the immune system largely ignores or tolerates disseminated cancers. The mechanisms that block initiation of immune responses during cancer development are poorly understood. We report here that constitutive activation of Stat-3, a common oncogenic signaling pathway, suppresses tumor expression of proinflammatory mediators. Blocking Stat-3 in tumor cells increases expression of proinflammatory cytokines and chemokines that activate innate immunity and dendritic cells, leading to tumor-specific T-cell responses. In addition, constitutive Stat-3 activity induces production of pleiotropic factors that inhibit dendritic cell functional maturation. Tumor-derived factors inhibit dendritic cell maturation through Stat-3 activation in progenitor cells. Thus, inhibition of antitumor immunity involves a cascade of Stat-3 activation propagating from tumor to dendritic cells. We propose that tumor Stat-3 activity can mediate immune evasion by blocking both the production and sensing of inflammatory signals by multiple components of the immune system.", + "TAG_DATA": [ + "41, constitutive {'perturbing_action': 'B-gene gain-of-function'}", + "42, activation {'perturbing_action': 'I-gene gain-of-function'}", + "43, of {'perturbing_action': 'I-gene gain-of-function'}", + "44, Stat-3, {'perturbing_action': 'I-gene gain-of-function'}", + "56, Blocking {'perturbing_action': 'B-pharmacological inhibition'}", + "57, Stat-3 {'perturbing_action': 'I-pharmacological inhibition'}", + "59, tumor {'context': 'B-transformed cells'}", + "60, cells {'context': 'I-transformed cells'}", + "82, constitutive {'perturbing_action': 'B-gene gain-of-function'}", + "83, Stat-3 {'perturbing_action': 'I-gene gain-of-function'}", + "84, activity {'perturbing_action': 'I-gene gain-of-function'}", + "92, dendritic {'context': 'B-cells'}", + "93, cell {'context': 'I-cells'}", + "99, dendritic {'context': 'B-cells'}", + "100, cell {'context': 'I-cells'}", + "106, progenitor {'context': 'B-cells'}", + "107, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "41, constitutive ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "42, activation ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "43, of ['l1', 'l8', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "44, Stat-3, ['l2', 'l9', 'l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "56, Blocking ['l3', 'l10', 'l16', 'l21', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "57, Stat-3 ['l4', 'l11', 'l17', 'l22', 'l26', 'l33', 'l34', 'l35', 'l36', 'l37']", + "59, tumor ['l5', 'l12', 'l18', 'l23', 'l27', 'l33', 'l38', 'l39']", + "60, cells ['l6', 'l13', 'l19', 'l24', 'l28', 'l34', 'l38']", + "82, constitutive ['l40', 'l41', 'l42', 'l43']", + "83, Stat-3 ['l29', 'l40', 'l44', 'l45', 'l46']", + "84, activity ['l30', 'l35', 'l41', 'l44', 'l47', 'l48']", + "92, dendritic ['l31', 'l36', 'l42', 'l45', 'l47', 'l49']", + "93, cell ['l7', 'l14', 'l20', 'l25', 'l32', 'l37', 'l39', 'l43', 'l46', 'l48', 'l49']", + "99, dendritic ['l50', 'l51', 'l52']", + "100, cell ['l50', 'l53', 'l54']", + "106, progenitor ['l51', 'l53', 'l55']", + "107, cells. ['l52', 'l54', 'l55']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutive", + "activation", + "of", + "Stat-3," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutive", + "activation", + "of", + "Stat-3,", + "Stat-3", + "activity" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "dendritic" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blocking", + "Stat-3" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blocking", + "Stat-3" + ] + }, + "context": { + "val": "cells", + "words": [ + "dendritic", + "cell" + ] + } + } + ] + }, + { + "PMID": "14566335", + "TEXT": "Group B adenoviruses, a subgenus of human Adenoviridae, are associated with a variety of often-fatal illnesses in immunocompromised individuals, including bone marrow transplant recipients and cancer and AIDS patients. Recently, group B adenovirus derivatives have gained interest as attractive gene therapy vectors because they can transduce target tissues, such as hematopoietic stem cells, dendritic cells and malignant tumor cells, that are refractory to infection by commonly used adenoviral vectors. Whereas many adenoviruses infect cells through the coxsackievirus and adenovirus receptor (CAR), group B adenoviruses use an alternate, as-yet-unidentified cellular attachment receptor. Using mass spectrometric analysis of proteins interacting with a group B fiber, we identified human CD46 as a cellular attachment receptor for most group B adenoviruses. We show that ectopic expression of human CD46 rendered nonhuman cells susceptible to infection with group B viruses in vitro and in vivo. In addition, both siRNA-mediated knockdown of CD46 and a soluble form of CD46 blocked infection of human cell lines and primary human cells. The discovery that group B adenoviruses use CD46, a ubiquitously expressed complement regulatory protein, as a cellular attachment receptor elucidates the diverse clinical manifestation of group B virus infections, and bears directly on the application of these vectors for gene therapy.", + "TAG_DATA": [ + "120, ectopic {'perturbing_action': 'B-gene gain-of-function'}", + "121, expression {'perturbing_action': 'I-gene gain-of-function'}", + "122, of {'perturbing_action': 'I-gene gain-of-function'}", + "123, human {'perturbing_action': 'I-gene gain-of-function'}", + "124, CD46 {'perturbing_action': 'I-gene gain-of-function'}", + "126, nonhuman {'context': 'B-cells'}", + "127, cells {'context': 'I-cells'}", + "135, in {'context': 'B-in vitro'}", + "136, vitro {'context': 'I-in vitro'}", + "138, in {'context': 'B-in vivo'}", + "139, vivo. {'context': 'I-in vivo'}", + "143, siRNA-mediated {'perturbing_action': 'B-rnai/knockdown'}", + "144, knockdown {'perturbing_action': 'I-rnai/knockdown'}", + "145, of {'perturbing_action': 'I-rnai/knockdown'}", + "146, CD46 {'perturbing_action': 'I-rnai/knockdown'}", + "150, form {'perturbing_action': 'I-gene gain-of-function'}", + "156, human {'context': 'B-cells'}", + "157, cell {'context': 'I-cells'}", + "158, lines {'context': 'I-cells'}", + "160, primary {'context': 'B-cells'}", + "161, human {'context': 'I-cells'}", + "162, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "120, ectopic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "121, expression ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "122, of ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "123, human ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "124, CD46 ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "126, nonhuman ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "127, cells ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47']", + "135, in ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l48', 'l49', 'l50']", + "136, vitro ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l48', 'l51', 'l52']", + "138, in ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l49', 'l51', 'l53']", + "139, vivo. ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l47', 'l50', 'l52', 'l53']", + "143, siRNA-mediated ['l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "144, knockdown ['l54', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "145, of ['l55', 'l67', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "146, CD46 ['l56', 'l68', 'l79', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "149, soluble ['l57', 'l69', 'l80', 'l90', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108']", + "150, form ['l58', 'l70', 'l81', 'l91', 'l100', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "151, of ['l59', 'l71', 'l82', 'l92', 'l101', 'l109', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123']", + "152, CD46 ['l60', 'l72', 'l83', 'l93', 'l102', 'l110', 'l117', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129']", + "156, human ['l61', 'l73', 'l84', 'l94', 'l103', 'l111', 'l118', 'l124', 'l130', 'l131', 'l132', 'l133', 'l134']", + "157, cell ['l62', 'l74', 'l85', 'l95', 'l104', 'l112', 'l119', 'l125', 'l130', 'l135', 'l136', 'l137', 'l138']", + "158, lines ['l63', 'l75', 'l86', 'l96', 'l105', 'l113', 'l120', 'l126', 'l131', 'l135', 'l139', 'l140', 'l141']", + "160, primary ['l64', 'l76', 'l87', 'l97', 'l106', 'l114', 'l121', 'l127', 'l132', 'l136', 'l139', 'l142', 'l143']", + "161, human ['l65', 'l77', 'l88', 'l98', 'l107', 'l115', 'l122', 'l128', 'l133', 'l137', 'l140', 'l142', 'l144']", + "162, cells. ['l66', 'l78', 'l89', 'l99', 'l108', 'l116', 'l123', 'l129', 'l134', 'l138', 'l141', 'l143', 'l144']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "expression", + "of", + "human", + "CD46", + "form" + ] + }, + "context": { + "val": "cells", + "words": [ + "nonhuman", + "cells", + "human", + "cell", + "lines", + "primary", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "expression", + "of", + "human", + "CD46" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "expression", + "of", + "human", + "CD46" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA-mediated", + "knockdown", + "of", + "CD46" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "cell", + "lines", + "primary", + "cells." + ] + } + } + ] + }, + { + "PMID": "14502280", + "TEXT": "To understand the integrin requirements of T-helper (T(H)) effector subsets, we investigated the contribution of CD18 (beta(2) integrin) to T(H)1 and T(H)2 function in vitro and in relevant disease models. CD18-deficient (Itgb2(-/-)) T cells showed largely normal in vitro function. Compared with wild-type mice, Itgb2(-/-) mice were better able to resolve Leishmania major infection and generated a superior T(H)1 immune response, as assessed from draining lymph nodes. In contrast, T(H)2-dependent allergic lung disease was markedly impaired in mutant mice. In both models, development of T(H)1 and T(H)2 cells in spleens was normal, but accumulation of T(H)2 (not T(H)1) cells at inflammatory sites was reduced. Thus, CD18 is selectively required for T(H)2, but not T(H)1, homing and has a minimal influence on T-effector development. These findings suggest a new integrin-based therapeutic approach in which the outcomes of diverse diseases may be favorably influenced by altering the homing of T(H)2 cells.", + "TAG_DATA": [ + "30, CD18-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "31, (Itgb2(-/-)) {'perturbing_action': 'I-gene loss-of-function'}", + "32, T {'context': 'B-cells'}", + "33, cells {'context': 'I-cells'}", + "37, in {'context': 'B-in vitro'}", + "38, vitro {'context': 'I-in vitro'}", + "43, mice, {'context': 'B-organism'}", + "44, Itgb2(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "45, mice {'context': 'B-organism'}", + "78, mice. {'context': 'B-organism'}", + "84, T(H)1 {'context': 'B-cells'}", + "85, and {'context': 'I-cells'}", + "86, T(H)2 {'context': 'I-cells'}", + "87, cells {'context': 'I-cells'}", + "89, spleens {'context': 'B-tissue/organ'}", + "95, T(H)2 {'context': 'B-cells'}", + "96, (not {'context': 'I-cells'}", + "98, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "30, CD18-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "31, (Itgb2(-/-)) ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "32, T ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21']", + "33, cells ['l2', 'l10', 'l17', 'l22', 'l23', 'l24']", + "37, in ['l3', 'l11', 'l18', 'l22', 'l25']", + "38, vitro ['l4', 'l12', 'l19', 'l23', 'l25']", + "43, mice, ['l5', 'l13', 'l20', 'l26', 'l27']", + "44, Itgb2(-/-) ['l6', 'l14', 'l26', 'l28', 'l29']", + "45, mice ['l7', 'l15', 'l21', 'l24', 'l27', 'l28']", + "78, mice. ['l8', 'l16', 'l29']", + "84, T(H)1 ['l30', 'l31', 'l32', 'l33']", + "85, and ['l30', 'l34', 'l35', 'l36']", + "86, T(H)2 ['l31', 'l34', 'l37', 'l38']", + "87, cells ['l32', 'l35', 'l37', 'l39']", + "89, spleens ['l33', 'l36', 'l38', 'l39']", + "95, T(H)2 ['l40', 'l41']", + "96, (not ['l40', 'l42']", + "98, cells ['l41', 'l42']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD18-deficient", + "(Itgb2(-/-))" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD18-deficient", + "(Itgb2(-/-))" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD18-deficient", + "(Itgb2(-/-))", + "Itgb2(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "14502279", + "TEXT": "Although the underlying mechanisms are not well understood, it is generally believed that antigen recognition by T cells in the absence of costimulation may alter the immune response, leading to anergy or tolerance. Further support for this concept comes from animal models of autoimmunity and transplantation, where treatments based on costimulation blockade, in particular CD40 ligand (CD40L)-specific antibodies, have been highly effective. We investigated the mechanisms of action of an antibody to CD40L and provide evidence that its effects are dependent on the constant (Fc) region. Prolongation of graft survival is dependent on both complement- and Fc receptor-mediated mechanisms in a major histocompatibility complex (MHC)-mismatched skin transplant model. These data suggest that antibodies to CD40L act through selective depletion of activated T cells, rather than exerting immune modulation by costimulation blockade as currently postulated. This finding opens new avenues for treatment of immune disorders based on selective targeting of activated T cells.", + "TAG_DATA": [ + "88, graft {'phenotype': 'B-cell survival'}", + "89, survival {'phenotype': 'I-cell survival'}", + "105, skin {'context': 'B-tissue/organ'}", + "121, T {'context': 'B-cells'}", + "122, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "88, graft ['l0', 'l1', 'l2', 'l3']", + "89, survival ['l0', 'l4', 'l5', 'l6']", + "105, skin ['l1', 'l4', 'l7', 'l8']", + "106, transplant ['l2', 'l5', 'l7', 'l9']", + "107, model. ['l3', 'l6', 'l8', 'l9']", + "121, T ['l10']", + "122, cells, ['l10']" + ], + "LINKED_TAGS": [ + { + "phenotype": { + "val": "cell survival", + "words": [ + "graft", + "survival" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skin" + ] + } + } + ] + }, + { + "PMID": "12960961", + "TEXT": "Although thrombolysis with tissue plasminogen activator (tPA) is a stroke therapy approved by the US Food and Drug Administration, its efficacy may be limited by neurotoxic side effects. Recently, proteolytic damage involving matrix metalloproteinases (MMPs) have been implicated. In experimental embolic stroke models, MMP inhibitors decreased cerebral hemorrhage and injury after treatment with tPA. MMPs comprise a family of zinc endopeptidases that can modify several components of the extracellular matrix. In particular, the gelatinases MMP-2 and MMP-9 can degrade neurovascular matrix integrity. MMP-9 promotes neuronal death by disrupting cell-matrix interactions, and MMP-9 knockout mice have reduced blood-brain barrier leakage and infarction after cerebral ischemia. Hence it is possible that tPA upregulates MMPs in the brain, and that subsequent matrix degradation causes brain injury. Here we show that tPA upregulates MMP-9 in cell culture and in vivo. MMP-9 levels were lower in tPA knockouts compared with wild-type mice after focal cerebral ischemia. In human cerebral microvascular endothelial cells, MMP-9 was upregulated when recombinant tPA was added. RNA interference (RNAi) suggested that this response was mediated by the low-density lipoprotein receptor-related protein (LRP), which avidly binds tPA and possesses signaling properties. Targeting the tPA-LRP signaling pathway in brain may offer new approaches for decreasing neurotoxicity and improving stroke therapy.", + "TAG_DATA": [ + "91, MMP-9 {'perturbing_action': 'B-gene loss-of-function'}", + "92, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "93, mice {'context': 'B-organism'}", + "131, cell {'context': 'B-cells'}", + "132, culture {'context': 'I-in vitro'}", + "134, in {'context': 'B-in vivo'}", + "135, vivo. {'context': 'I-in vivo'}", + "141, tPA {'perturbing_action': 'B-gene loss-of-function'}", + "142, knockouts {'perturbing_action': 'I-gene loss-of-function'}", + "146, mice {'context': 'B-organism'}", + "152, human {'context': 'B-cells'}", + "153, cerebral {'context': 'I-cells'}", + "154, microvascular {'context': 'I-cells'}", + "155, endothelial {'context': 'I-cells'}", + "156, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "91, MMP-9 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "92, knockout ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "93, mice ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "131, cell ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "132, culture ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "134, in ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "135, vivo. ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "141, tPA ['l21', 'l22', 'l23', 'l24']", + "142, knockouts ['l21', 'l25', 'l26']", + "146, mice ['l22', 'l25', 'l27']", + "152, human ['l28', 'l29', 'l30', 'l31']", + "153, cerebral ['l28', 'l32', 'l33', 'l34']", + "154, microvascular ['l29', 'l32', 'l35', 'l36']", + "155, endothelial ['l23', 'l30', 'l33', 'l35', 'l37']", + "156, cells, ['l24', 'l26', 'l27', 'l31', 'l34', 'l36', 'l37']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MMP-9", + "knockout", + "tPA", + "knockouts" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MMP-9", + "knockout", + "tPA", + "knockouts" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell", + "endothelial", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MMP-9", + "knockout" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "culture" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MMP-9", + "knockout" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "12937413", + "TEXT": "Under conditions of iron overload, which are now reaching epidemic proportions worldwide, iron-overload cardiomyopathy is the most important prognostic factor in patient survival. We hypothesize that in iron-overload disorders, iron accumulation in the heart depends on ferrous iron (Fe2+) permeation through the L-type voltage-dependent Ca2+ channel (LVDCC), a promiscuous divalent cation transporter. Iron overload in mice was associated with increased mortality, systolic and diastolic dysfunction, bradycardia, hypotension, increased myocardial fibrosis and elevated oxidative stress. Treatment with LVDCC blockers (CCBs; amlodipine and verapamil) at therapeutic levels inhibited the LVDCC current in cardiomyocytes, attenuated myocardial iron accumulation and oxidative stress, improved survival, prevented hypotension and preserved heart structure and function. Consistent with the role of LVDCCs in myocardial iron uptake, iron-overloaded transgenic mice with cardiac-specific overexpression of the LVDCC alpha1-subunit had twofold higher myocardial iron and oxidative stress levels, as well as greater impairment in cardiac function, compared with littermate controls; LVDCC blockade was again protective. Our results indicate that cardiac LVDCCs are key transporters of iron into cardiomyocytes under iron-overloaded conditions, and potentially represent a new therapeutic target to reduce the cardiovascular burden from iron overload.", + "TAG_DATA": [ + "55, mice {'context': 'B-organism'}", + "90, cardiomyocytes, {'context': 'B-cells'}", + "104, heart {'context': 'B-tissue/organ'}", + "119, transgenic {'context': 'B-organism'}", + "120, mice {'context': 'I-organism'}", + "122, cardiac-specific {'perturbing_action': 'B-gene gain-of-function'}", + "123, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "124, of {'perturbing_action': 'I-gene gain-of-function'}", + "125, the {'perturbing_action': 'I-gene gain-of-function'}", + "126, LVDCC {'perturbing_action': 'I-gene gain-of-function'}", + "127, alpha1-subunit {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "90, cardiomyocytes, ['l0']", + "104, heart ['l0']", + "119, transgenic ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "120, mice ['l1', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "122, cardiac-specific ['l2', 'l9', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "123, overexpression ['l3', 'l10', 'l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "124, of ['l4', 'l11', 'l17', 'l22', 'l27', 'l28', 'l29', 'l30']", + "125, the ['l5', 'l12', 'l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "126, LVDCC ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "127, alpha1-subunit ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "143, cardiac ['l8', 'l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "cardiac-specific", + "overexpression", + "of", + "the", + "LVDCC", + "alpha1-subunit" + ] + } + } + ] + }, + { + "PMID": "12925848", + "TEXT": "Glucagon-like peptide-1 (GLP-1) is a gut peptide that, together with its receptor, GLP-1R, is expressed in the brain. Here we show that intracerebroventricular (i.c.v.) GLP-1 and [Ser(2)]exendin(1-9) (HSEGTFTSD; homologous to a conserved domain in the glucagon/GLP-1 family) enhance associative and spatial learning through GLP-1R. [Ser(2)]exendin(1-9), but not GLP-1, is also active when administered peripherally. GLP-1R-deficient mice have a phenotype characterized by a learning deficit that is restored after hippocampal Glp1r gene transfer. In addition, rats overexpressing GLP-1R in the hippocampus show improved learning and memory. GLP-1R-deficient mice also have enhanced seizure severity and neuronal injury after kainate administration, with an intermediate phenotype in heterozygotes and phenotypic correction after Glp1r gene transfer in hippocampal somatic cells. Systemic administration of [Ser(2)]exendin(1-9) in wild-type animals prevents kainate-induced apoptosis of hippocampal neurons. Brain GLP-1R represents a promising new target for both cognitive-enhancing and neuroprotective agents.", + "TAG_DATA": [ + "54, GLP-1R-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "55, mice {'context': 'B-organism'}", + "68, hippocampal {'perturbing_action': 'B-gene gain-of-function'}", + "69, Glp1r {'perturbing_action': 'I-gene gain-of-function'}", + "70, gene {'perturbing_action': 'I-gene gain-of-function'}", + "71, transfer. {'perturbing_action': 'I-gene gain-of-function'}", + "74, rats {'context': 'B-organism'}", + "75, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "76, GLP-1R {'perturbing_action': 'I-gene gain-of-function'}", + "77, in {'perturbing_action': 'I-gene gain-of-function'}", + "78, the {'perturbing_action': 'I-gene gain-of-function'}", + "79, hippocampus {'context': 'B-tissue/organ'}", + "85, GLP-1R-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "86, mice {'context': 'B-organism'}", + "108, Glp1r {'perturbing_action': 'B-gene gain-of-function'}", + "109, gene {'perturbing_action': 'I-gene gain-of-function'}", + "110, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "112, hippocampal {'context': 'B-cells'}", + "113, somatic {'context': 'I-cells'}", + "114, cells. {'context': 'I-cells'}", + "121, animals {'context': 'B-organism'}", + "122, prevents {'effect': 'B-negative'}", + "123, kainate-induced {'effect': 'B-positive'}", + "124, apoptosis {'phenotype': 'B-apoptosis'}", + "126, hippocampal {'context': 'B-cells'}", + "127, neurons. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "54, GLP-1R-deficient ['l0', 'l1', 'l2', 'l3', 'l4']", + "55, mice ['l0', 'l5', 'l6', 'l7', 'l8']", + "68, hippocampal ['l1', 'l5', 'l9', 'l10', 'l11', 'l12']", + "69, Glp1r ['l2', 'l6', 'l9', 'l13', 'l14', 'l15']", + "70, gene ['l3', 'l7', 'l10', 'l13', 'l16']", + "71, transfer. ['l4', 'l8', 'l11', 'l14', 'l16']", + "74, rats ['l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "75, overexpressing ['l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "76, GLP-1R ['l18', 'l24', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "77, in ['l19', 'l25', 'l31', 'l37', 'l38', 'l39', 'l40']", + "78, the ['l20', 'l26', 'l32', 'l37', 'l41', 'l42']", + "79, hippocampus ['l12', 'l15', 'l21', 'l27', 'l33', 'l38', 'l41', 'l43']", + "85, GLP-1R-deficient ['l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "86, mice ['l22', 'l28', 'l34', 'l39', 'l42', 'l43', 'l44', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "108, Glp1r ['l45', 'l51', 'l57', 'l58', 'l59', 'l60', 'l61']", + "109, gene ['l46', 'l52', 'l57', 'l62', 'l63', 'l64', 'l65']", + "110, transfer ['l47', 'l53', 'l58', 'l62', 'l66', 'l67', 'l68']", + "112, hippocampal ['l48', 'l54', 'l59', 'l63', 'l66', 'l69', 'l70']", + "113, somatic ['l29', 'l35', 'l49', 'l55', 'l60', 'l64', 'l67', 'l69', 'l71']", + "114, cells. ['l23', 'l30', 'l36', 'l40', 'l50', 'l56', 'l61', 'l65', 'l68', 'l70', 'l71']", + "121, animals ['l72', 'l73', 'l74', 'l75', 'l76']", + "122, prevents ['l72', 'l77', 'l78', 'l79', 'l80']", + "123, kainate-induced ['l73', 'l77', 'l81', 'l82', 'l83']", + "124, apoptosis ['l74', 'l78', 'l81', 'l84', 'l85']", + "126, hippocampal ['l75', 'l79', 'l82', 'l84', 'l86']", + "127, neurons. ['l76', 'l80', 'l83', 'l85', 'l86']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "GLP-1R-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice", + "rats" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hippocampal", + "Glp1r", + "gene", + "transfer.", + "overexpressing", + "GLP-1R", + "in", + "the", + "transfer" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "hippocampal", + "Glp1r", + "overexpressing", + "GLP-1R", + "in", + "the" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hippocampus" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "GLP-1R", + "in", + "Glp1r", + "gene", + "transfer" + ] + }, + "context": { + "val": "cells", + "words": [ + "somatic", + "cells.", + "hippocampal" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "GLP-1R-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "hippocampal", + "somatic", + "cells." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animals" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animals" + ] + }, + "effect": { + "val": "positive", + "words": [ + "kainate-induced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "animals" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "context": { + "val": "cells", + "words": [ + "hippocampal", + "neurons." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "kainate-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "kainate-induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "hippocampal", + "neurons." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "cells", + "words": [ + "hippocampal", + "neurons." + ] + } + } + ] + }, + { + "PMID": "12858170", + "TEXT": "Whereas uncoupling protein 1 (UCP-1) is clearly involved in thermogenesis, the role of UCP-2 is less clear. Using hybridization, cloning techniques and cDNA array analysis to identify inducible neuroprotective genes, we found that neuronal survival correlates with increased expression of Ucp2. In mice overexpressing human UCP-2, brain damage was diminished after experimental stroke and traumatic brain injury, and neurological recovery was enhanced. In cultured cortical neurons, UCP-2 reduced cell death and inhibited caspase-3 activation induced by oxygen and glucose deprivation. Mild mitochondrial uncoupling by 2,4-dinitrophenol (DNP) reduced neuronal death, and UCP-2 activity was enhanced by palmitic acid in isolated mitochondria. Also in isolated mitochondria, UCP-2 shifted the release of reactive oxygen species from the mitochondrial matrix to the extramitochondrial space. We propose that UCP-2 is an inducible protein that is neuroprotective by activating cellular redox signaling or by inducing mild mitochondrial uncoupling that prevents the release of apoptogenic proteins.", + "TAG_DATA": [ + "42, mice {'context': 'B-organism'}", + "43, overexpressing {'perturbing_action': 'B-gene gain-of-function'}", + "44, human {'perturbing_action': 'I-gene gain-of-function'}", + "45, UCP-2, {'perturbing_action': 'I-gene gain-of-function'}", + "63, cultured {'context': 'B-cells'}", + "64, cortical {'context': 'I-cells'}", + "65, neurons, {'context': 'I-cells'}", + "67, reduced {'effect': 'B-negative'}", + "68, cell {'phenotype': 'B-cell death'}", + "69, death {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "42, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "43, overexpressing ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "44, human ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "45, UCP-2, ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "63, cultured ['l3', 'l11', 'l18', 'l24', 'l30', 'l31', 'l32', 'l33', 'l34']", + "64, cortical ['l4', 'l12', 'l19', 'l25', 'l30', 'l35', 'l36', 'l37', 'l38']", + "65, neurons, ['l5', 'l13', 'l20', 'l26', 'l31', 'l35', 'l39', 'l40', 'l41']", + "67, reduced ['l6', 'l14', 'l21', 'l27', 'l32', 'l36', 'l39', 'l42', 'l43']", + "68, cell ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l40', 'l42', 'l44']", + "69, death ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l43', 'l44']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "human", + "UCP-2," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "human", + "UCP-2," + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "cortical", + "neurons," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "human", + "UCP-2," + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "human", + "UCP-2," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "cortical", + "neurons," + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "cortical", + "neurons," + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death" + ] + } + } + ] + }, + { + "PMID": "12858169", + "TEXT": "It has been suggested that environmental contaminants that mimic the effects of estrogen contribute to disruption of the reproductive systems of animals in the wild, and to the high incidence of hormone-related cancers and diseases in Western populations. Previous studies have shown that functionally, cadmium acts like steroidal estrogens in breast cancer cells as a result of its ability to form a high-affinity complex with the hormone binding domain of the estrogen receptor. The results of the present study show that cadmium also has potent estrogen-like activity in vivo. Exposure to cadmium increased uterine wet weight, promoted growth and development of the mammary glands and induced hormone-regulated genes in ovariectomized animals. In the uterus, the increase in wet weight was accompanied by proliferation of the endometrium and induction of progesterone receptor (PgR) and complement component C3. In the mammary gland, cadmium promoted an increase in the formation of side branches and alveolar buds and the induction of casein, whey acidic protein, PgR and C3. In utero exposure to the metal also mimicked the effects of estrogens. Female offspring experienced an earlier onset of puberty and an increase in the epithelial area and the number of terminal end buds in the mammary gland.", + "TAG_DATA": [ + "102, mammary {'context': 'B-tissue/organ'}", + "103, glands {'context': 'I-tissue/organ'}", + "110, animals. {'context': 'B-organism'}", + "113, uterus, {'context': 'B-tissue/organ'}", + "122, proliferation {'phenotype': 'B-proliferation'}", + "125, endometrium {'context': 'B-tissue/organ'}", + "138, mammary {'context': 'B-tissue/organ'}", + "139, gland, {'context': 'I-tissue/organ'}", + "164, In {'context': 'B-in vivo'}", + "165, utero {'context': 'I-in vivo'}", + "176, Female {'context': 'B-organism'}", + "177, offspring {'context': 'I-organism'}", + "200, mammary {'context': 'B-tissue/organ'}", + "201, gland. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "102, mammary ['l0']", + "103, glands ['l0']", + "113, uterus, ['l1', 'l2']", + "122, proliferation ['l1', 'l3', 'l4']", + "125, endometrium ['l2', 'l3']", + "138, mammary ['l5']", + "139, gland, ['l4', 'l5']", + "164, In ['l6', 'l7', 'l8', 'l9', 'l10']", + "165, utero ['l6', 'l11', 'l12', 'l13', 'l14']", + "176, Female ['l7', 'l11', 'l15', 'l16', 'l17']", + "177, offspring ['l8', 'l12', 'l15', 'l18', 'l19']", + "200, mammary ['l9', 'l13', 'l16', 'l18', 'l20']", + "201, gland. ['l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "tissue/organ", + "words": [ + "uterus,", + "endometrium", + "gland," + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + } + ] + }, + { + "PMID": "12858168", + "TEXT": "Seizure disorders present an attractive gene therapy target, particularly because viral vectors such as adeno-associated virus (AAV) and lentivirus can stably transduce neurons. When we targeted the N-methyl-D-aspartic acid (NMDA) excitatory amino acid receptor with an AAV-delivered antisense oligonucleotide, however, the promoter determined whether focal seizure sensitivity was significantly attenuated or facilitated. One potential means to circumvent this liability would be to express an inhibitory neuroactive peptide and constitutively secrete the peptide from the transduced cell. The neuropeptide galanin can modulate seizure activity in vivo, and the laminar protein fibronectin is usually secreted through a constitutive pathway. Initially, inclusion of the fibronectin secretory signal sequence (FIB) in an AAV vector caused significant gene product secretion in vitro. More importantly, the combination of this secretory signal with the coding sequence for the active galanin peptide significantly attenuated in vivo focal seizure sensitivity, even with different promoters, and prevented kainic acid-induced hilar cell death. Thus, neuroactive peptide expression and local secretion provides a new gene therapy platform for the treatment of neurological disorders.", + "TAG_DATA": [ + "115, in {'context': 'B-in vitro'}", + "116, vitro. {'context': 'I-in vitro'}", + "136, in {'context': 'B-in vivo'}", + "137, vivo {'context': 'I-in vivo'}", + "146, prevented {'effect': 'B-negative'}", + "149, hilar {'context': 'B-tissue/organ'}", + "150, cell {'phenotype': 'B-cell death'}", + "151, death. {'phenotype': 'I-cell death'}" + ], + "LINK_DATA": [ + "115, in ['l0']", + "116, vitro. ['l0']", + "136, in ['l1', 'l2', 'l3', 'l4', 'l5']", + "137, vivo ['l1', 'l6', 'l7', 'l8', 'l9']", + "146, prevented ['l2', 'l6', 'l10', 'l11', 'l12']", + "149, hilar ['l3', 'l7', 'l10', 'l13', 'l14']", + "150, cell ['l4', 'l8', 'l11', 'l13', 'l15']", + "151, death. ['l5', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hilar" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "hilar" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + } + ] + }, + { + "PMID": "12847522", + "TEXT": "Hypertension and diabetes are common side effects of glucocorticoid treatment. To determine whether peroxisome proliferator-activated receptor-alpha (PPAR-alpha) mediates these sequelae, mice deficient in low-density lipoprotein receptor (Ldlr-/-), with (Ppara+/+) or without (Ppara-/-) PPAR-alpha, were treated chronically with dexamethasone. Ppara+/+, but not Ppara-/-, mice developed hyperglycemia, hyperinsulinemia and hypertension. Similar effects on glucose metabolism were seen in a different model using C57BL/6 mice. Hepatic gluconeogenic gene expression was increased and insulin-mediated suppression of endogenous glucose production was less effective in dexamethasone-treated Ppara+/+ mice. Adenoviral reconstitution of PPAR-alpha in the livers of nondiabetic, normotensive, dexamethasone-treated Ppara-/- mice induced hyperglycemia, hyperinsulinemia and increased gluconeogenic gene expression. It also increased blood pressure, renin activity, sympathetic nervous activity and renal sodium retention. Human hepatocytes treated with dexamethasone and the PPAR-alpha agonist Wy14,643 induced PPARA and gluconeogenic gene expression. These results identify hepatic activation of PPAR-alpha as a mechanism underlying glucocorticoid-induced insulin resistance.", + "TAG_DATA": [ + "20, mice {'context': 'B-organism'}", + "21, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "22, in {'perturbing_action': 'I-gene loss-of-function'}", + "23, low-density {'perturbing_action': 'I-gene loss-of-function'}", + "24, lipoprotein {'perturbing_action': 'I-gene loss-of-function'}", + "25, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "26, (Ldlr-/-), {'perturbing_action': 'I-gene loss-of-function'}", + "27, with {'perturbing_action': 'B-gene loss-of-function'}", + "28, (Ppara+/+) {'perturbing_action': 'I-gene loss-of-function'}", + "30, without {'perturbing_action': 'B-gene loss-of-function'}", + "31, (Ppara-/-) {'perturbing_action': 'I-gene loss-of-function'}", + "32, PPAR-alpha, {'perturbing_action': 'I-gene loss-of-function'}", + "41, Ppara-/-, {'perturbing_action': 'B-gene loss-of-function'}", + "42, mice {'context': 'B-organism'}", + "81, mice. {'context': 'B-organism'}", + "82, Adenoviral {'perturbing_action': 'B-gene gain-of-function'}", + "83, reconstitution {'perturbing_action': 'I-gene gain-of-function'}", + "84, of {'perturbing_action': 'I-gene gain-of-function'}", + "85, PPAR-alpha {'perturbing_action': 'I-gene gain-of-function'}", + "88, livers {'context': 'B-tissue/organ'}", + "90, nondiabetic, {'context': 'B-organism'}", + "91, normotensive, {'context': 'I-cells'}", + "93, Ppara-/- {'perturbing_action': 'B-gene loss-of-function'}", + "94, mice {'context': 'B-organism'}", + "117, Human {'context': 'B-cells'}", + "118, hepatocytes {'context': 'I-cells'}", + "124, PPAR-alpha {'perturbing_action': 'B-pharmacological augmentation'}", + "125, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "126, Wy14,643 {'perturbing_action': 'I-pharmacological augmentation'}" + ], + "LINK_DATA": [ + "20, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "21, deficient ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "22, in ['l1', 'l9', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "23, low-density ['l2', 'l10', 'l19', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "24, lipoprotein ['l3', 'l11', 'l20', 'l28', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "25, receptor ['l4', 'l12', 'l21', 'l29', 'l36', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "26, (Ldlr-/-), ['l5', 'l13', 'l22', 'l30', 'l37', 'l43', 'l49', 'l50', 'l51', 'l52', 'l53']", + "27, with ['l14', 'l23', 'l31', 'l38', 'l44', 'l49', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "28, (Ppara+/+) ['l6', 'l15', 'l24', 'l32', 'l39', 'l45', 'l50', 'l54', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "30, without ['l55', 'l62', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "31, (Ppara-/-) ['l56', 'l63', 'l69', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "32, PPAR-alpha, ['l57', 'l64', 'l70', 'l80', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99']", + "41, Ppara-/-, ['l16', 'l25', 'l33', 'l40', 'l46', 'l51', 'l58', 'l65', 'l71', 'l81', 'l91', 'l100', 'l101', 'l102']", + "42, mice ['l7', 'l17', 'l26', 'l34', 'l41', 'l47', 'l52', 'l59', 'l66', 'l72', 'l82', 'l92', 'l100', 'l103']", + "61, mice. ['l8', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l60', 'l67', 'l73', 'l83', 'l93', 'l101', 'l103']", + "81, mice. ['l61', 'l68', 'l74', 'l84', 'l94', 'l102']", + "82, Adenoviral ['l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "83, reconstitution ['l104', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "84, of ['l75', 'l85', 'l95', 'l105', 'l112', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124']", + "85, PPAR-alpha ['l76', 'l86', 'l96', 'l106', 'l113', 'l119', 'l125', 'l126', 'l127', 'l128', 'l129']", + "88, livers ['l77', 'l87', 'l97', 'l107', 'l114', 'l120', 'l125', 'l130', 'l131', 'l132', 'l133']", + "90, nondiabetic, ['l78', 'l88', 'l98', 'l108', 'l115', 'l121', 'l126', 'l130', 'l134', 'l135', 'l136']", + "91, normotensive, ['l89', 'l109', 'l116', 'l122', 'l127', 'l131', 'l134', 'l137', 'l138']", + "93, Ppara-/- ['l110', 'l117', 'l123', 'l128', 'l132', 'l135', 'l137', 'l139']", + "94, mice ['l79', 'l90', 'l99', 'l111', 'l118', 'l124', 'l129', 'l133', 'l136', 'l138', 'l139']", + "117, Human ['l140', 'l141', 'l142', 'l143']", + "118, hepatocytes ['l140', 'l144', 'l145', 'l146']", + "124, PPAR-alpha ['l141', 'l144', 'l147', 'l148']", + "125, agonist ['l142', 'l145', 'l147', 'l149']", + "126, Wy14,643 ['l143', 'l146', 'l148', 'l149']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice.", + "nondiabetic," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "low-density", + "lipoprotein", + "receptor", + "(Ldlr-/-),", + "(Ppara+/+)", + "with", + "without", + "(Ppara-/-)", + "PPAR-alpha,", + "Ppara-/-,", + "Ppara-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "without", + "(Ppara-/-)", + "PPAR-alpha,", + "Ppara-/-" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "livers" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "(Ppara-/-)", + "Ppara-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "normotensive," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenoviral", + "reconstitution", + "of", + "PPAR-alpha" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "livers" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenoviral", + "reconstitution", + "of", + "PPAR-alpha" + ] + }, + "context": { + "val": "organism", + "words": [ + "nondiabetic,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenoviral", + "reconstitution", + "of", + "PPAR-alpha" + ] + }, + "context": { + "val": "cells", + "words": [ + "normotensive," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "Human", + "hepatocytes" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "PPAR-alpha", + "agonist", + "Wy14,643" + ] + } + } + ] + }, + { + "PMID": "12847521", + "TEXT": "As a target for gene therapy, Duchenne muscular dystrophy (DMD) presents many obstacles but also an unparalleled prospect for correction by alternative splicing. The majority of mutations in the dystrophin gene occur in the region encoding the spectrin-like central rod domain, which is largely dispensable. Thus, splicing around mutations can generate a shortened but in-frame transcript, permitting translation of a partially functional dystrophin protein. We have tested this idea in vivo in the mdx dystrophic mouse (carrying a mutation in exon 23 of the dystrophin gene) by combining a potent transfection protocol with a 2-O-methylated phosphorothioated antisense oligoribonucleotide (2OMeAO) designed to promote skipping of the mutated exon*. The treated mice show persistent production of dystrophin at normal levels in large numbers of muscle fibers and show functional improvement of the treated muscle. Repeated administration enhances dystrophin expression without eliciting immune responses. Our data establishes the realistic practicality of an approach that is applicable, in principle, to a majority of cases of severe dystrophinopathy.", + "TAG_DATA": [ + "69, in {'context': 'B-in vivo'}", + "70, vivo {'context': 'I-in vivo'}", + "73, mdx {'context': 'B-organism'}", + "74, dystrophic {'context': 'I-organism'}", + "75, mouse {'context': 'I-organism'}", + "76, (carrying {'context': 'I-organism'}", + "77, a {'perturbing_action': 'I-other'}", + "78, mutation {'perturbing_action': 'I-other'}", + "79, in {'perturbing_action': 'I-other'}", + "80, exon {'perturbing_action': 'I-other'}", + "81, 23 {'perturbing_action': 'I-other'}", + "82, of {'perturbing_action': 'I-other'}", + "83, the {'perturbing_action': 'I-other'}", + "84, dystrophin {'perturbing_action': 'I-other'}", + "85, gene) {'perturbing_action': 'I-other'}", + "109, mice {'context': 'B-organism'}", + "122, muscle {'context': 'B-cells'}", + "123, fibers {'context': 'I-cells'}", + "131, muscle. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "69, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "70, vivo ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "73, mdx ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "74, dystrophic ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "75, mouse ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "76, (carrying ['l4', 'l17', 'l29', 'l40', 'l50', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "77, a ['l5', 'l18', 'l30', 'l41', 'l51', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "78, mutation ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "79, in ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "80, exon ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l90', 'l91', 'l92', 'l93', 'l94']", + "81, 23 ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l95', 'l96', 'l97', 'l98']", + "82, of ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l95', 'l99', 'l100', 'l101']", + "83, the ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l96', 'l99', 'l102', 'l103']", + "84, dystrophin ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l97', 'l100', 'l102', 'l104']", + "85, gene) ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l94', 'l98', 'l101', 'l103', 'l104']", + "109, mice ['l105', 'l106', 'l107']", + "122, muscle ['l105', 'l108']", + "123, fibers ['l106', 'l108']", + "131, muscle. ['l107']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "a", + "mutation", + "in", + "exon", + "23", + "of", + "the", + "dystrophin", + "gene)" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mdx", + "dystrophic", + "mouse", + "(carrying" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "a", + "mutation", + "in", + "exon", + "23", + "of", + "the", + "dystrophin", + "gene)" + ] + } + } + ] + }, + { + "PMID": "12847520", + "TEXT": "Members of the suppressor of cytokine signaling (SOCS) family are involved in the pathogenesis of many inflammatory diseases. SOCS-3 is predominantly expressed in T-helper type 2 (T(H)2) cells, but its role in T(H)2-related allergic diseases remains to be investigated. In this study we provide a strong correlation between SOCS-3 expression and the pathology of asthma and atopic dermatitis, as well as serum IgE levels in allergic human patients. SOCS-3 transgenic mice showed increased T(H)2 responses and multiple pathological features characteristic of asthma in an airway hypersensitivity model system. In contrast, dominant-negative mutant SOCS-3 transgenic mice, as well as mice with a heterozygous deletion of Socs3, had decreased T(H)2 development. These data indicate that SOCS-3 has an important role in regulating the onset and maintenance of T(H)2-mediated allergic immune disease, and suggest that SOCS-3 may be a new therapeutic target for the development of antiallergic drugs.", + "TAG_DATA": [ + "68, SOCS-3 {'perturbing_action': 'B-gene gain-of-function'}", + "69, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "70, mice {'context': 'B-organism'}", + "90, dominant-negative {'perturbing_action': 'B-other'}", + "91, mutant {'perturbing_action': 'I-other'}", + "92, SOCS-3 {'perturbing_action': 'I-other'}", + "93, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "94, mice, {'context': 'B-organism'}", + "98, mice {'context': 'B-organism'}", + "101, heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "102, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "103, of {'perturbing_action': 'I-gene loss-of-function'}", + "104, Socs3, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "68, SOCS-3 ['l0', 'l1']", + "69, transgenic ['l0', 'l2']", + "70, mice ['l1', 'l2']", + "90, dominant-negative ['l3', 'l4', 'l5', 'l6']", + "91, mutant ['l3', 'l7', 'l8', 'l9']", + "92, SOCS-3 ['l4', 'l7', 'l10', 'l11']", + "93, transgenic ['l5', 'l8', 'l10', 'l12']", + "94, mice, ['l6', 'l9', 'l11', 'l12']", + "98, mice ['l13', 'l14', 'l15', 'l16']", + "101, heterozygous ['l13', 'l17', 'l18', 'l19']", + "102, deletion ['l14', 'l17', 'l20', 'l21']", + "103, of ['l15', 'l18', 'l20', 'l22']", + "104, Socs3, ['l16', 'l19', 'l21', 'l22']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "SOCS-3", + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "dominant-negative", + "mutant", + "SOCS-3" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "heterozygous", + "deletion", + "of", + "Socs3," + ] + } + } + ] + }, + { + "PMID": "12754501", + "TEXT": "The enzyme carnitine palmitoyltransferase-1 (CPT1) regulates long-chain fatty acid (LCFA) entry into mitochondria, where the LCFAs undergo beta-oxidation. To investigate the mechanism(s) by which central metabolism of lipids can modulate energy balance, we selectively reduced lipid oxidation in the hypothalamus. We decreased the activity of CPT1 by administering to rats a ribozyme-containing plasmid designed specifically to decrease the expression of this enzyme or by infusing pharmacological inhibitors of its activity into the third cerebral ventricle. Either genetic or biochemical inhibition of hypothalamic CPT1 activity was sufficient to substantially diminish food intake and endogenous glucose production. These results indicated that changes in the rate of lipid oxidation in selective hypothalamic neurons signaled nutrient availability to the hypothalamus, which in turn modulated the exogenous and endogenous inputs of nutrients into the circulation.", + "TAG_DATA": [ + "41, decreased {'perturbing_action': 'B-gene loss-of-function'}", + "42, the {'perturbing_action': 'I-rnai/knockdown'}", + "43, activity {'perturbing_action': 'I-gene loss-of-function'}", + "44, of {'perturbing_action': 'I-gene loss-of-function'}", + "45, CPT1 {'perturbing_action': 'I-gene loss-of-function'}", + "49, rats {'context': 'B-organism'}", + "51, ribozyme-containing {'perturbing_action': 'B-rnai/knockdown'}", + "52, plasmid {'perturbing_action': 'I-rnai/knockdown'}", + "53, designed {'perturbing_action': 'I-rnai/knockdown'}", + "54, specifically {'perturbing_action': 'I-rnai/knockdown'}", + "55, to {'perturbing_action': 'I-rnai/knockdown'}", + "56, decrease {'perturbing_action': 'I-rnai/knockdown'}", + "57, the {'perturbing_action': 'I-rnai/knockdown'}", + "58, expression {'perturbing_action': 'I-rnai/knockdown'}", + "59, of {'perturbing_action': 'I-rnai/knockdown'}", + "60, this {'perturbing_action': 'I-rnai/knockdown'}", + "61, enzyme {'perturbing_action': 'I-rnai/knockdown'}", + "78, biochemical {'perturbing_action': 'B-pharmacological inhibition'}", + "79, inhibition {'perturbing_action': 'I-pharmacological inhibition'}", + "80, of {'perturbing_action': 'I-pharmacological inhibition'}", + "81, hypothalamic {'perturbing_action': 'I-pharmacological inhibition'}", + "82, CPT1 {'perturbing_action': 'I-pharmacological inhibition'}", + "83, activity {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "41, decreased ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "42, the ['l0', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "43, activity ['l1', 'l16', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "44, of ['l2', 'l17', 'l31', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "45, CPT1 ['l3', 'l18', 'l32', 'l45', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "49, rats ['l4', 'l19', 'l33', 'l46', 'l58', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "51, ribozyme-containing ['l5', 'l20', 'l34', 'l47', 'l59', 'l70', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "52, plasmid ['l6', 'l21', 'l35', 'l48', 'l60', 'l71', 'l81', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "53, designed ['l7', 'l22', 'l36', 'l49', 'l61', 'l72', 'l82', 'l93', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115']", + "54, specifically ['l8', 'l23', 'l37', 'l50', 'l62', 'l73', 'l83', 'l94', 'l105', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125']", + "55, to ['l9', 'l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l95', 'l106', 'l116', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133']", + "56, decrease ['l10', 'l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l96', 'l107', 'l117', 'l126', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139']", + "57, the ['l11', 'l26', 'l40', 'l53', 'l65', 'l76', 'l86', 'l97', 'l108', 'l118', 'l127', 'l134', 'l140', 'l141', 'l142', 'l143', 'l144']", + "58, expression ['l12', 'l27', 'l41', 'l54', 'l66', 'l77', 'l87', 'l98', 'l109', 'l119', 'l128', 'l135', 'l140', 'l145', 'l146', 'l147', 'l148']", + "59, of ['l13', 'l28', 'l42', 'l55', 'l67', 'l78', 'l88', 'l99', 'l110', 'l120', 'l129', 'l136', 'l141', 'l145', 'l149', 'l150', 'l151']", + "60, this ['l14', 'l29', 'l43', 'l56', 'l68', 'l79', 'l89', 'l100', 'l111', 'l121', 'l130', 'l137', 'l142', 'l146', 'l149', 'l152', 'l153']", + "61, enzyme ['l15', 'l30', 'l44', 'l57', 'l69', 'l80', 'l90', 'l101', 'l112', 'l122', 'l131', 'l138', 'l143', 'l147', 'l150', 'l152', 'l154']", + "78, biochemical ['l155', 'l156', 'l157', 'l158', 'l159']", + "79, inhibition ['l155', 'l160', 'l161', 'l162', 'l163']", + "80, of ['l156', 'l160', 'l164', 'l165', 'l166']", + "81, hypothalamic ['l102', 'l113', 'l123', 'l157', 'l161', 'l164', 'l167', 'l168']", + "82, CPT1 ['l91', 'l103', 'l114', 'l124', 'l132', 'l158', 'l162', 'l165', 'l167', 'l169']", + "83, activity ['l92', 'l104', 'l115', 'l125', 'l133', 'l139', 'l144', 'l148', 'l151', 'l153', 'l154', 'l159', 'l163', 'l166', 'l168', 'l169']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "decreased", + "activity", + "of", + "CPT1" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "the", + "ribozyme-containing", + "plasmid", + "designed", + "specifically", + "to", + "decrease", + "expression", + "of", + "this", + "enzyme" + ] + }, + "context": { + "val": "organism", + "words": [ + "rats" + ] + } + } + ] + }, + { + "PMID": "12740573", + "TEXT": "During the progression of atherosclerosis, autoantibodies are induced to epitopes of oxidized low-density lipoprotein (oxLDL) and active immunization of hypercholesterolemic mice with oxLDL ameliorates atherogenesis. We unexpectedly found that many autoantibodies to oxLDL derived from 'naive' atherosclerotic mice share complete genetic and structural identity with antibodies from the classic anti-phosphorylcholine B-cell clone, T15, which protect against common infectious pathogens, including pneumococci. To investigate whether in vivo exposure to pneumococci can affect atherogenesis, we immunized Ldlr(-/-) mice with Streptococcus pneumoniae. This induced high circulating levels of oxLDL-specific IgM and a persistent expansion of oxLDL-specific T15 IgM-secreting B cells primarily in the spleen, which were cross-reactive with pneumococcal determinants. Pneumococcal immunization decreased the extent of atherosclerosis, and plasma from these mice had an enhanced capacity to block the binding of oxLDL to macrophages. These studies show molecular mimicry between epitopes of oxLDL and S. pneumoniae and indicate that these immune responses can have beneficial effects.", + "TAG_DATA": [ + "74, Ldlr(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "75, mice {'context': 'B-organism'}", + "95, B {'context': 'B-cells'}", + "96, cells {'context': 'I-cells'}", + "100, spleen, {'context': 'B-tissue/organ'}", + "109, decreased {'effect': 'B-negative'}", + "113, atherosclerosis, {'phenotype': 'B-oncosis'}", + "118, mice {'context': 'B-organism'}", + "130, macrophages. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "74, Ldlr(-/-) ['l0', 'l1', 'l2', 'l3']", + "75, mice ['l0', 'l4']", + "95, B ['l1', 'l5', 'l6']", + "96, cells ['l2', 'l4', 'l5', 'l7']", + "100, spleen, ['l3', 'l6', 'l7']", + "109, decreased ['l8', 'l9']", + "113, atherosclerosis, ['l8', 'l10', 'l11']", + "118, mice ['l10', 'l12']", + "130, macrophages. ['l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ldlr(-/-)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ldlr(-/-)" + ] + }, + "context": { + "val": "cells", + "words": [ + "B", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ldlr(-/-)" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "spleen," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "phenotype": { + "val": "oncosis", + "words": [ + "atherosclerosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages." + ] + } + }, + { + "phenotype": { + "val": "oncosis", + "words": [ + "atherosclerosis," + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "phenotype": { + "val": "oncosis", + "words": [ + "atherosclerosis," + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages." + ] + } + } + ] + }, + { + "PMID": "12740572", + "TEXT": "In monkeys rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), expression of the dopamine D3 receptor was decreased. However, levodopa-induced dyskinesia (LID), similar to the debilitating and pharmacoresistant involuntary movements elicited after long-term treatment with levodopa in patients with Parkinson disease (PD), was associated with overexpression of this receptor. Administration of a D3 receptor-selective partial agonist strongly attenuated levodopa-induced dyskinesia, but left unaffected the therapeutic effect of levodopa. In contrast, attenuation of dyskinesia by D3 receptor antagonists was accompanied by the reappearance of PD-like symptoms. These results indicated that the D3 receptor participated in both dyskinesia and the therapeutic action of levodopa, and that partial agonists may normalize D3 receptor function and correct side effects of levodopa therapy in patients with PD.", + "TAG_DATA": [ + "1, monkeys {'context': 'B-organism'}", + "42, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "43, of {'perturbing_action': 'I-gene gain-of-function'}", + "44, this {'perturbing_action': 'I-gene gain-of-function'}", + "45, receptor. {'perturbing_action': 'I-gene gain-of-function'}", + "49, D3 {'perturbing_action': 'B-pharmacological augmentation'}", + "50, receptor-selective {'perturbing_action': 'I-pharmacological augmentation'}", + "51, partial {'perturbing_action': 'I-pharmacological augmentation'}", + "52, agonist {'perturbing_action': 'I-pharmacological augmentation'}", + "71, D3 {'perturbing_action': 'B-pharmacological inhibition'}", + "72, receptor {'perturbing_action': 'I-pharmacological inhibition'}", + "73, antagonists {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "1, monkeys ['l0', 'l1', 'l2', 'l3']", + "42, overexpression ['l0', 'l4', 'l5', 'l6']", + "43, of ['l1', 'l4', 'l7', 'l8']", + "44, this ['l2', 'l5', 'l7', 'l9']", + "45, receptor. ['l3', 'l6', 'l8', 'l9']", + "49, D3 ['l10', 'l11', 'l12']", + "50, receptor-selective ['l10', 'l13', 'l14']", + "51, partial ['l11', 'l13', 'l15']", + "52, agonist ['l12', 'l14', 'l15']", + "71, D3 ['l16', 'l17']", + "72, receptor ['l16', 'l18']", + "73, antagonists ['l17', 'l18']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "monkeys" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "this", + "receptor." + ] + } + } + ] + }, + { + "PMID": "12740570", + "TEXT": "Angiogenic tumor vessels are promising targets for the activity and the selective delivery of cancer therapeutics. The bone marrow contributes different cell types to the tumor stroma, including hematopoietic cells and, as recently suggested, vascular endothelial cells (ECs). Thus, transplantation of genetically modified bone marrow progenitors may represent a vehicle for the transport of gene therapy to tumors. We transduced bone marrow progenitors with lentiviral vectors expressing genes from transcription-regulatory elements of Tie2/Tek gene. When tumors were grown in the transplanted mice, the new vector marked a distinct hematopoietic population that 'homed' to the tumor and closely interacted with vascular ECs at the tumor periphery. These Tie2-expressing mononuclear (TEM) cells had a distinguishable phenotype and were present selectively at angiogenic sites. Unexpectedly, we did not find bone marrow-derived ECs in tumor vessels when we transplanted bone marrow progenitors constitutively expressing a marker gene from the Tie2 or ubiquitously active promoters. By delivering a 'suicide' gene, we selectively eliminated the TEM cells and achieved substantial inhibition of angiogenesis and slower tumor growth without systemic toxicity. Thus, TEM cells may account for the proangiogenic activity of bone marrow-derived cells in tumors, may represent a new target for drug development and may provide the means for selective gene delivery and targeted inhibition of tumor angiogenesis.", + "TAG_DATA": [ + "60, bone {'context': 'B-cells'}", + "61, marrow {'context': 'I-cells'}", + "62, progenitors {'context': 'I-cells'}", + "81, mice, {'context': 'B-organism'}", + "106, Tie2-expressing {'context': 'B-cells'}", + "107, mononuclear {'context': 'I-cells'}", + "108, (TEM) {'context': 'I-cells'}", + "109, cells {'context': 'I-cells'}", + "126, bone {'context': 'B-cells'}", + "127, marrow-derived {'context': 'I-cells'}", + "128, ECs {'context': 'I-cells'}", + "135, bone {'context': 'B-cells'}", + "136, marrow {'context': 'I-cells'}", + "137, progenitors {'context': 'I-cells'}", + "138, constitutively {'perturbing_action': 'B-gene gain-of-function'}", + "159, TEM {'context': 'B-cells'}", + "160, cells {'context': 'I-cells'}", + "168, slower {'effect': 'B-negative'}", + "169, tumor {'phenotype': 'B-tumour growth'}", + "170, growth {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "60, bone ['l0', 'l1', 'l2', 'l3']", + "61, marrow ['l0', 'l4', 'l5', 'l6']", + "62, progenitors ['l1', 'l4', 'l7', 'l8']", + "75, tumors ['l2', 'l5', 'l7', 'l9']", + "81, mice, ['l3', 'l6', 'l8', 'l9']", + "106, Tie2-expressing ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "107, mononuclear ['l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "108, (TEM) ['l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "109, cells ['l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "126, bone ['l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "127, marrow-derived ['l14', 'l19', 'l23', 'l26', 'l28', 'l30']", + "128, ECs ['l15', 'l20', 'l24', 'l27', 'l29', 'l30']", + "135, bone ['l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "136, marrow ['l31', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "137, progenitors ['l32', 'l39', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "138, constitutively ['l33', 'l40', 'l46', 'l52', 'l53', 'l54', 'l55', 'l56']", + "159, TEM ['l34', 'l41', 'l47', 'l52', 'l57', 'l58', 'l59', 'l60']", + "160, cells ['l35', 'l42', 'l48', 'l53', 'l57', 'l61', 'l62', 'l63']", + "168, slower ['l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l64', 'l65']", + "169, tumor ['l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l66']", + "170, growth ['l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l65', 'l66']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "bone", + "marrow", + "progenitors", + "TEM", + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutively" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "bone", + "marrow", + "progenitors", + "TEM", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "slower" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "bone", + "marrow", + "progenitors", + "TEM", + "cells" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutively" + ] + }, + "effect": { + "val": "negative", + "words": [ + "slower" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutively" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "slower" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + } + ] + }, + { + "PMID": "12740569", + "TEXT": "Angiogenesis sustains tumor growth and metastasis, and recent studies indicate that the vascular endothelium regulates tissue mass. In the prostate, androgens drive angiogenic inducers to stimulate growth, whereas androgen withdrawal leads to decreased vascular endothelial growth factor, vascular regression and epithelial cell apoptosis. Here, we identify the angiogenesis inhibitor pigment epithelium-derived factor (PEDF) as a key inhibitor of stromal vasculature and epithelial tissue growth in mouse prostate and pancreas. In PEDF-deficient mice, stromal vessels were increased and associated with epithelial cell hyperplasia. Androgens inhibited prostatic PEDF expression in cultured cells. In vivo, androgen ablation increased PEDF in normal rat prostates and in human cancer biopsies. Exogenous PEDF induced tumor epithelial apoptosis in vitro and limited in vivo tumor xenograft growth, triggering endothelial apoptosis. Thus, PEDF regulates normal pancreas and prostate mass. Its androgen sensitivity makes PEDF a likely contributor to the anticancer effects of androgen ablation.", + "TAG_DATA": [ + "70, PEDF-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "71, mice, {'context': 'B-organism'}", + "88, cultured {'context': 'B-cells'}", + "89, cells. {'context': 'I-cells'}", + "90, In {'context': 'B-in vivo'}", + "91, vivo, {'context': 'I-in vivo'}", + "92, androgen {'perturbing_action': 'B-gene loss-of-function'}", + "93, ablation {'perturbing_action': 'I-gene loss-of-function'}", + "97, normal {'context': 'B-tissue/organ'}", + "98, rat {'context': 'I-tissue/organ'}", + "99, prostates {'context': 'I-tissue/organ'}", + "102, human {'context': 'B-neoplasm'}", + "103, cancer {'context': 'I-neoplasm'}", + "104, biopsies. {'context': 'I-patient'}", + "107, induced {'effect': 'B-positive'}", + "108, tumor {'context': 'B-neoplasm'}", + "109, epithelial {'context': 'I-neoplasm'}", + "110, apoptosis {'phenotype': 'B-apoptosis'}", + "111, in {'context': 'B-in vitro'}", + "112, vitro {'context': 'I-in vitro'}", + "114, limited {'effect': 'B-negative'}", + "115, in {'context': 'B-in vivo'}", + "116, vivo {'context': 'I-in vivo'}", + "117, tumor {'context': 'B-xenograft'}", + "118, xenograft {'context': 'I-xenograft'}", + "120, triggering {'effect': 'B-positive'}", + "121, endothelial {'context': 'B-tissue/organ'}", + "122, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "70, PEDF-deficient ['l0', 'l1', 'l2']", + "71, mice, ['l0', 'l3']", + "88, cultured ['l1', 'l4']", + "89, cells. ['l2', 'l3', 'l4']", + "90, In ['l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "91, vivo, ['l5', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "92, androgen ['l6', 'l14', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "93, ablation ['l7', 'l15', 'l22', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "97, normal ['l8', 'l16', 'l23', 'l33', 'l43', 'l44', 'l45', 'l46', 'l47']", + "98, rat ['l9', 'l17', 'l24', 'l34', 'l43', 'l48', 'l49', 'l50', 'l51']", + "99, prostates ['l10', 'l18', 'l25', 'l35', 'l44', 'l48', 'l52', 'l53', 'l54']", + "102, human ['l11', 'l19', 'l26', 'l36', 'l45', 'l49', 'l52', 'l55', 'l56']", + "103, cancer ['l12', 'l20', 'l27', 'l37', 'l46', 'l50', 'l53', 'l55', 'l57']", + "104, biopsies. ['l13', 'l21', 'l28', 'l38', 'l47', 'l51', 'l54', 'l56', 'l57']", + "107, induced ['l29', 'l39', 'l58', 'l59', 'l60', 'l61', 'l62']", + "108, tumor ['l30', 'l40', 'l58', 'l63', 'l64', 'l65', 'l66']", + "109, epithelial ['l31', 'l41', 'l59', 'l63', 'l67', 'l68', 'l69']", + "110, apoptosis ['l32', 'l42', 'l60', 'l64', 'l67', 'l70', 'l71']", + "111, in ['l61', 'l65', 'l68', 'l70', 'l72']", + "112, vitro ['l62', 'l66', 'l69', 'l71', 'l72']", + "114, limited ['l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "115, in ['l73', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "116, vivo ['l74', 'l80', 'l86', 'l87', 'l88', 'l89', 'l90']", + "117, tumor ['l75', 'l81', 'l86', 'l91', 'l92', 'l93', 'l94']", + "118, xenograft ['l76', 'l82', 'l87', 'l91', 'l95', 'l96', 'l97']", + "120, triggering ['l77', 'l83', 'l88', 'l92', 'l95', 'l98', 'l99']", + "121, endothelial ['l78', 'l84', 'l89', 'l93', 'l96', 'l98', 'l100']", + "122, apoptosis. ['l79', 'l85', 'l90', 'l94', 'l97', 'l99', 'l100']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PEDF-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PEDF-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cultured", + "cells." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "androgen", + "ablation" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "androgen", + "ablation" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "normal", + "rat", + "prostates" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "androgen", + "ablation" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "human", + "cancer", + "tumor", + "epithelial" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "androgen", + "ablation" + ] + }, + "context": { + "val": "patient", + "words": [ + "biopsies." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "androgen", + "ablation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "androgen", + "ablation" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor", + "epithelial" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced", + "triggering" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumor", + "epithelial" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limited" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limited" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "tumor", + "xenograft" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limited" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "endothelial" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limited" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "tumor", + "xenograft" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "tumor", + "xenograft" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "endothelial" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "endothelial" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "12692542", + "TEXT": "X-linked hypohidrotic ectodermal dysplasia (XLHED; OMIM 305100) is a genetic disorder characterized by absence or deficient function of hair, teeth and sweat glands. Affected children may experience life-threatening high fever resulting from reduced ability to sweat. Mice with the Tabby phenotype share many symptoms with human XLHED patients because both phenotypes are caused by mutations of the syntenic ectodysplasin A gene (Eda) on the X chromosome. Two main splice variants of Eda, encoding EDA1 and EDA2, engage the tumor necrosis factor (TNF) family receptors EDAR and XEDAR, respectively. The EDA1 protein, acting through EDAR, is essential for proper formation of skin appendages; the functions of EDA2 and XEDAR are not known. EDA1 must be proteolytically processed to a soluble form to be active. Here, we show that treatment of pregnant Tabby mice with a recombinant form of EDA1, engineered to cross the placental barrier, permanently rescues the Tabby phenotype in the offspring. Notably, sweat glands can also be induced by EDA1 after birth. This is the first example of a developmental genetic defect that can be permanently corrected by short-term treatment with a recombinant protein.", + "TAG_DATA": [ + "130, Tabby {'context': 'B-organism'}", + "131, mice {'context': 'I-organism'}", + "134, recombinant {'perturbing_action': 'I-gene gain-of-function'}", + "135, form {'perturbing_action': 'I-gene gain-of-function'}", + "136, of {'perturbing_action': 'I-gene gain-of-function'}", + "137, EDA1, {'perturbing_action': 'I-gene gain-of-function'}" + ], + "LINK_DATA": [ + "130, Tabby ['l0', 'l1', 'l2', 'l3', 'l4']", + "131, mice ['l0', 'l5', 'l6', 'l7', 'l8']", + "134, recombinant ['l1', 'l5', 'l9', 'l10', 'l11']", + "135, form ['l2', 'l6', 'l9', 'l12', 'l13']", + "136, of ['l3', 'l7', 'l10', 'l12', 'l14']", + "137, EDA1, ['l4', 'l8', 'l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Tabby", + "mice" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "recombinant", + "form", + "of", + "EDA1," + ] + } + } + ] + }, + { + "PMID": "12598893", + "TEXT": "Multiple sclerosis (MS) is a devastating neuroinflammatory disorder of the central nervous system (CNS) in which T cells that are reactive with major components of myelin sheaths have a central role. The receptor for advanced glycation end products (RAGE) is present on T cells, mononuclear phagocytes and endothelium. Its pro-inflammatory ligands, S100-calgranulins, are upregulated in MS and in the related rodent model, experimental autoimmune encephalomyelitis (EAE). Blockade of RAGE suppressed EAE when disease was induced by myelin basic protein (MBP) peptide or encephalitogenic T cells, or when EAE occurred spontaneously in T-cell receptor (TCR)-transgenic mice devoid of endogenous TCR-alpha and TCR-beta chains. Inhibition of RAGE markedly decreased infiltration of the CNS by immune and inflammatory cells. Transgenic mice with targeted overexpression of dominant-negative RAGE in CD4+ T cells were resistant to MBP-induced EAE. These data reinforce the importance of RAGE-ligand interactions in modulating properties of CD4+ T cells that infiltrate the CNS.", + "TAG_DATA": [ + "66, Blockade {'perturbing_action': 'B-pharmacological inhibition'}", + "67, of {'perturbing_action': 'I-pharmacological inhibition'}", + "68, RAGE {'perturbing_action': 'I-pharmacological inhibition'}", + "83, T {'context': 'B-cells'}", + "84, cells, {'context': 'I-cells'}", + "91, T-cell {'perturbing_action': 'B-gene gain-of-function'}", + "92, receptor {'perturbing_action': 'I-gene gain-of-function'}", + "93, (TCR)-transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "94, mice {'context': 'B-organism'}", + "102, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "103, of {'perturbing_action': 'I-pharmacological inhibition'}", + "104, RAGE {'perturbing_action': 'I-pharmacological inhibition'}", + "110, CNS {'context': 'B-tissue/organ'}", + "112, immune {'context': 'B-cells'}", + "116, Transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "117, mice {'context': 'I-organism'}", + "119, targeted {'perturbing_action': 'B-other'}", + "120, overexpression {'perturbing_action': 'I-other'}", + "121, of {'perturbing_action': 'I-other'}", + "122, dominant-negative {'perturbing_action': 'I-other'}", + "123, RAGE {'perturbing_action': 'I-other'}", + "125, CD4+ {'context': 'B-cells'}", + "126, T {'context': 'I-cells'}", + "127, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "66, Blockade ['l0', 'l1', 'l2', 'l3', 'l4']", + "67, of ['l0', 'l5', 'l6', 'l7']", + "68, RAGE ['l1', 'l5', 'l8', 'l9']", + "83, T ['l2', 'l6', 'l8', 'l10']", + "84, cells, ['l3', 'l7', 'l9', 'l10']", + "91, T-cell ['l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "92, receptor ['l11', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "93, (TCR)-transgenic ['l12', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "94, mice ['l13', 'l20', 'l26', 'l32', 'l33', 'l34', 'l35', 'l36']", + "102, Inhibition ['l14', 'l21', 'l27', 'l32', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "103, of ['l15', 'l22', 'l28', 'l33', 'l37', 'l43', 'l44', 'l45']", + "104, RAGE ['l16', 'l23', 'l29', 'l34', 'l38', 'l43', 'l46', 'l47']", + "110, CNS ['l17', 'l24', 'l30', 'l35', 'l39', 'l44', 'l46', 'l48']", + "112, immune ['l4', 'l18', 'l25', 'l31', 'l36', 'l40', 'l45', 'l47', 'l48']", + "116, Transgenic ['l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57']", + "117, mice ['l49', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "119, targeted ['l50', 'l58', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "120, overexpression ['l51', 'l59', 'l66', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "121, of ['l52', 'l60', 'l67', 'l73', 'l79', 'l80', 'l81', 'l82', 'l83']", + "122, dominant-negative ['l53', 'l61', 'l68', 'l74', 'l79', 'l84', 'l85', 'l86', 'l87']", + "123, RAGE ['l54', 'l62', 'l69', 'l75', 'l80', 'l84', 'l88', 'l89', 'l90']", + "125, CD4+ ['l55', 'l63', 'l70', 'l76', 'l81', 'l85', 'l88', 'l91', 'l92']", + "126, T ['l41', 'l56', 'l64', 'l71', 'l77', 'l82', 'l86', 'l89', 'l91', 'l93']", + "127, cells ['l42', 'l57', 'l65', 'l72', 'l78', 'l83', 'l87', 'l90', 'l92', 'l93']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "RAGE", + "Inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells,", + "immune", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "T-cell", + "receptor", + "(TCR)-transgenic", + "Transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "T-cell", + "receptor", + "(TCR)-transgenic" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "CNS" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "T-cell", + "receptor", + "(TCR)-transgenic", + "Transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "immune", + "CD4+", + "T", + "cells" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "RAGE" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "RAGE" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "CNS" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "targeted", + "overexpression", + "of", + "dominant-negative", + "RAGE" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "targeted", + "overexpression", + "of", + "dominant-negative", + "RAGE" + ] + }, + "context": { + "val": "cells", + "words": [ + "CD4+", + "T", + "cells" + ] + } + } + ] + }, + { + "PMID": "12592400", + "TEXT": "The Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) is expressed in all KSHV-associated tumors, including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). We found that beta-catenin is overexpressed in both PEL cells and KS tissue. Introduction of anti-LANA small interfering RNA (siRNA) into PEL cells eliminated beta-catenin accumulation; LANA itself upregulated expression of beta-catenin in transfected cells. LANA stabilizes beta-catenin by binding to the negative regulator GSK-3beta, causing a cell cycle-dependent nuclear accumulation of GSK-3beta. The LANA C terminus contains sequences similar to the GSK-3beta-binding domain of Axin. Disruption of this region resulted in a mutant LANA that failed to re-localize GSK-3beta or stabilize beta-catenin. The importance of this pathway to KSHV-driven cell proliferation was highlighted by the observation that LANA, but not mutant LANA, stimulates entry into S phase. Redistribution of GSK-3beta can therefore be a source of beta-catenin dysregulation in human cancers.", + "TAG_DATA": [ + "39, anti-LANA {'perturbing_action': 'B-rnai/knockdown'}", + "40, small {'perturbing_action': 'I-rnai/knockdown'}", + "41, interfering {'perturbing_action': 'I-rnai/knockdown'}", + "42, RNA {'perturbing_action': 'I-rnai/knockdown'}", + "43, (siRNA) {'perturbing_action': 'I-rnai/knockdown'}", + "45, PEL {'context': 'B-cells'}", + "46, cells {'context': 'I-cells'}", + "58, cells. {'context': 'B-cells'}", + "97, mutant {'perturbing_action': 'B-other'}", + "98, LANA {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "39, anti-LANA ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "40, small ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "41, interfering ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "42, RNA ['l2', 'l7', 'l11', 'l15', 'l16', 'l17']", + "43, (siRNA) ['l3', 'l8', 'l12', 'l15', 'l18', 'l19']", + "45, PEL ['l4', 'l9', 'l13', 'l16', 'l18', 'l20']", + "46, cells ['l5', 'l10', 'l14', 'l17', 'l19', 'l20']", + "97, mutant ['l21']", + "98, LANA ['l21']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "anti-LANA", + "small", + "interfering", + "RNA", + "(siRNA)" + ] + }, + "context": { + "val": "cells", + "words": [ + "PEL", + "cells" + ] + } + } + ] + }, + { + "PMID": "12563315", + "TEXT": "Nicotinic acid (niacin), a vitamin of the B complex, has been used for almost 50 years as a lipid-lowering drug. The pharmacological effect of nicotinic acid requires doses that are much higher than those provided by a normal diet. Its primary action is to decrease lipolysis in adipose tissue by inhibiting hormone-sensitive triglyceride lipase. This anti-lipolytic effect of nicotinic acid involves the inhibition of cyclic adenosine monophosphate (cAMP) accumulation in adipose tissue through a G(i)-protein-mediated inhibition of adenylyl cyclase. A G-protein-coupled receptor for nicotinic acid has been proposed in adipocytes. Here, we show that the orphan G-protein-coupled receptor, 'protein upregulated in macrophages by interferon-gamma' (mouse PUMA-G, human HM74), is highly expressed in adipose tissue and is a nicotinic acid receptor. Binding of nicotinic acid to PUMA-G or HM74 results in a G(i)-mediated decrease in cAMP levels. In mice lacking PUMA-G, the nicotinic acid-induced decrease in free fatty acid (FFA) and triglyceride plasma levels was abrogated, indicating that PUMA-G mediates the anti-lipolytic and lipid-lowering effects of nicotinic acid in vivo. The identification of the nicotinic acid receptor may be useful in the development of new drugs to treat dyslipidemia.", + "TAG_DATA": [ + "137, mice {'context': 'B-organism'}", + "138, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "139, PUMA-G, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "137, mice ['l0', 'l1']", + "138, lacking ['l0', 'l2']", + "139, PUMA-G, ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "PUMA-G," + ] + } + } + ] + }, + { + "PMID": "12539039", + "TEXT": "Pancreatic islets of Langerhans are enveloped by peri-islet Schwann cells (pSC), which express glial fibrillary acidic protein (GFAP) and S100beta. pSC-autoreactive T- and B-cell responses arise in 3- to 4-week-old diabetes-prone non-obese diabetic (NOD) mice, followed by progressive pSC destruction before detectable beta-cell death. Humans with probable prediabetes generate similar autoreactivities, and autoantibodies in islet-cell autoantibody (lCA) -positive sera co-localize to pSC. Moreover, GFAP-specific NOD T-cell lines transferred pathogenic peri-insulitis to NOD/severe combined immunodeficient (NOD/SCID) mice, and immunotherapy with GFAP or S100beta prevented diabetes. pSC survived in rat insulin promoter Iymphocytic choriomeningitis virus (rip-LCMV) glycoprotein/CD8+ T-cell receptor(gp) double-transgenic mice with virus-induced diabetes, suggesting that pSC death is not an obligate consequence of local inflammation and beta-cell destruction. However, pSC were deleted in spontaneously diabetic NOD mice carrying the CD8+/8.3 T-cell receptor transgene, a T cell receptor commonly expressed in earliest islet infiltrates. Autoimmune targeting of pancreatic nervous system tissue elements seems to be an integral, early part of natural type 1 diabetes.", + "TAG_DATA": [ + "64, NOD {'context': 'B-cells'}", + "65, T-cell {'context': 'I-cells'}", + "66, lines {'context': 'I-cells'}", + "71, NOD/severe {'context': 'B-organism'}", + "72, combined {'context': 'I-organism'}", + "73, immunodeficient {'context': 'I-organism'}", + "74, (NOD/SCID) {'context': 'I-organism'}", + "75, mice, {'context': 'I-organism'}", + "89, promoter {'perturbing_action': 'I-gene gain-of-function'}", + "90, Iymphocytic {'perturbing_action': 'I-gene gain-of-function'}", + "91, choriomeningitis {'perturbing_action': 'I-gene gain-of-function'}", + "92, virus {'perturbing_action': 'I-gene gain-of-function'}", + "93, (rip-LCMV) {'perturbing_action': 'I-gene gain-of-function'}", + "94, glycoprotein/CD8+ {'perturbing_action': 'I-gene gain-of-function'}", + "95, T-cell {'perturbing_action': 'I-gene gain-of-function'}", + "96, receptor(gp) {'perturbing_action': 'I-gene gain-of-function'}", + "97, double-transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "98, mice {'context': 'B-organism'}", + "124, NOD {'context': 'I-organism'}", + "125, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "64, NOD ['l0', 'l1', 'l2']", + "65, T-cell ['l0', 'l3', 'l4']", + "66, lines ['l1', 'l3']", + "71, NOD/severe ['l5', 'l6', 'l7', 'l8']", + "72, combined ['l5', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "73, immunodeficient ['l6', 'l9', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "74, (NOD/SCID) ['l7', 'l10', 'l16', 'l22']", + "75, mice, ['l2', 'l4', 'l8', 'l11', 'l17', 'l22']", + "87, rat ['l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "88, insulin ['l23', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "89, promoter ['l24', 'l38', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "90, Iymphocytic ['l12', 'l18', 'l25', 'l39', 'l49', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "91, choriomeningitis ['l13', 'l19', 'l26', 'l40', 'l50', 'l59', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "92, virus ['l14', 'l20', 'l27', 'l41', 'l51', 'l60', 'l67', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "93, (rip-LCMV) ['l15', 'l21', 'l28', 'l42', 'l52', 'l61', 'l68', 'l74', 'l80', 'l81', 'l82', 'l83', 'l84']", + "94, glycoprotein/CD8+ ['l29', 'l43', 'l53', 'l62', 'l69', 'l75', 'l80', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91']", + "95, T-cell ['l30', 'l44', 'l54', 'l63', 'l70', 'l76', 'l81', 'l85', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "96, receptor(gp) ['l31', 'l45', 'l55', 'l64', 'l71', 'l77', 'l82', 'l86', 'l92', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "97, double-transgenic ['l32', 'l46', 'l56', 'l65', 'l72', 'l78', 'l83', 'l87', 'l93', 'l98', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "98, mice ['l33', 'l47', 'l57', 'l66', 'l73', 'l79', 'l84', 'l88', 'l94', 'l99', 'l105']", + "118, pSC ['l34', 'l48', 'l58', 'l89', 'l95', 'l100', 'l106', 'l112', 'l113', 'l114', 'l115', 'l116']", + "124, NOD ['l101', 'l107', 'l112', 'l117', 'l118', 'l119', 'l120']", + "125, mice ['l35', 'l90', 'l96', 'l102', 'l108', 'l113', 'l117', 'l121', 'l122', 'l123']", + "129, T-cell ['l36', 'l91', 'l97', 'l103', 'l109', 'l114', 'l118', 'l121', 'l124', 'l125']", + "130, receptor ['l37', 'l104', 'l110', 'l115', 'l119', 'l122', 'l124', 'l126']", + "131, transgene, ['l111', 'l116', 'l120', 'l123', 'l125', 'l126']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "combined", + "immunodeficient", + "mice", + "NOD" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Iymphocytic", + "choriomeningitis", + "virus", + "(rip-LCMV)", + "promoter", + "glycoprotein/CD8+", + "T-cell", + "receptor(gp)", + "double-transgenic" + ] + } + } + ] + }, + { + "PMID": "12514743", + "TEXT": "The drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4) is thought to be involved in the metabolism of nearly 50% of all the drugs currently prescribed. Alteration in the activity or expression of this enzyme seems to be a key predictor of drug responsiveness and toxicity. Currently available studies indicate that the ligand-activated nuclear receptors pregnane X receptor (PXR; NR1I2) and constitutive androstane receptor (CAR; NR1I3) regulate CYP3A4 expression. However, in cell-based reporter assays, CYP3A4 promoter activity was most pronounced in liver-derived cells and minimal or modest in non-hepatic cells, indicating that a liver-specific factor is required for physiological transcriptional response. Here we show that the orphan nuclear receptor hepatocyte nuclear factor-4alpha (HNF4alpha; HNF4A) is critically involved in the PXR- and CAR-mediated transcriptional activation of CYP3A4. We identified a specific cis-acting element in the CYP3A4 gene enhancer that confers HNF4alpha binding and thereby permits PXR- and CAR-mediated gene activation. Fetal mice with conditional deletion of Hnf4alpha had reduced or absent expression of CYP3A. Furthermore, adult mice with conditional hepatic deletion of Hnf4alpha had reduced basal and inducible expression of CYP3A. These data identify HNF4alpha as an important regulator of coordinate nuclear-receptor-mediated response to xenobiotics.", + "TAG_DATA": [ + "148, Fetal {'context': 'B-organism'}", + "149, mice {'context': 'I-organism'}", + "151, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "152, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "153, of {'perturbing_action': 'I-gene loss-of-function'}", + "154, Hnf4alpha {'perturbing_action': 'I-gene loss-of-function'}", + "163, adult {'context': 'B-organism'}", + "164, mice {'context': 'I-organism'}", + "166, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "167, hepatic {'perturbing_action': 'I-gene loss-of-function'}", + "168, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "169, of {'perturbing_action': 'I-gene loss-of-function'}", + "170, Hnf4alpha {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "148, Fetal ['l0', 'l1', 'l2', 'l3', 'l4']", + "149, mice ['l0', 'l5', 'l6', 'l7', 'l8']", + "151, conditional ['l1', 'l5', 'l9', 'l10', 'l11']", + "152, deletion ['l2', 'l6', 'l9', 'l12', 'l13']", + "153, of ['l3', 'l7', 'l10', 'l12', 'l14']", + "154, Hnf4alpha ['l4', 'l8', 'l11', 'l13', 'l14']", + "163, adult ['l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "164, mice ['l15', 'l21', 'l22', 'l23', 'l24', 'l25']", + "166, conditional ['l16', 'l21', 'l26', 'l27', 'l28', 'l29']", + "167, hepatic ['l17', 'l22', 'l26', 'l30', 'l31', 'l32']", + "168, deletion ['l18', 'l23', 'l27', 'l30', 'l33', 'l34']", + "169, of ['l19', 'l24', 'l28', 'l31', 'l33', 'l35']", + "170, Hnf4alpha ['l20', 'l25', 'l29', 'l32', 'l34', 'l35']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "Fetal", + "mice", + "adult" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "deletion", + "of", + "Hnf4alpha", + "hepatic" + ] + } + } + ] + }, + { + "PMID": "12496958", + "TEXT": "Cardiac hypertrophy is an adaptive response to a variety of mechanical and hormonal stimuli, and represents an early event in the clinical course leading to heart failure. By gene inactivation, we demonstrate here a crucial role of melusin, a muscle-specific protein that interacts with the integrin beta1 cytoplasmic domain, in the hypertrophic response to mechanical overload. Melusin-null mice showed normal cardiac structure and function in physiological conditions, but when subjected to pressure overload--a condition that induces a hypertrophic response in wild-type controls--they developed an abnormal cardiac remodeling that evolved into dilated cardiomyopathy and contractile dysfunction. In contrast, the hypertrophic response was identical in wild-type and melusin-null mice after chronic administration of angiotensin II or phenylephrine at doses that do not increase blood pressure--that is, in the absence of cardiac biomechanical stress. Analysis of intracellular signaling events induced by pressure overload indicated that phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) was specifically blunted in melusin-null hearts. Thus, melusin prevents cardiac dilation during chronic pressure overload by specifically sensing mechanical stress.", + "TAG_DATA": [ + "56, Melusin-null {'perturbing_action': 'B-gene loss-of-function'}", + "57, mice {'context': 'B-organism'}", + "105, melusin-null {'perturbing_action': 'B-gene loss-of-function'}", + "106, mice {'context': 'B-organism'}", + "152, melusin-null {'perturbing_action': 'B-gene loss-of-function'}", + "153, hearts. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "56, Melusin-null ['l0']", + "57, mice ['l0']", + "105, melusin-null ['l1']", + "106, mice ['l1']", + "152, melusin-null ['l2']", + "153, hearts. ['l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Melusin-null", + "melusin-null" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "melusin-null" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "hearts." + ] + } + } + ] + }, + { + "PMID": "12379849", + "TEXT": "The four MEF2 transcription factors (MEF2A, -B, -C, and -D) regulate differentiation and calcium-dependent gene expression in muscle cells. We generated mice deficient in MEF2A, the predominant Mef2 gene product expressed in post-natal cardiac muscle. Most mice lacking Mef2a died suddenly within the first week of life and exhibited pronounced dilation of the right ventricle, myofibrillar fragmentation, mitochondrial disorganization and activation of a fetal cardiac gene program. The few Mef2a(-/-) mice that survived to adulthood also showed a deficiency of cardiac mitochondria and susceptibility to sudden death. Paradoxically, MEF2 transcriptional activity, revealed by the expression of a MEF2-dependent transgene, was enhanced in the hearts of Mef2a-mutant mice, reflecting the transcriptional activation of residual MEF2D. These findings reveal specific roles for MEF2A in maintaining appropriate mitochondrial content and cyto-architectural integrity in the post-natal heart and show that other MEF2 isoforms cannot support these activities.", + "TAG_DATA": [ + "21, mice {'context': 'B-organism'}", + "22, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "36, mice {'context': 'B-organism'}", + "37, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "38, Mef2a {'perturbing_action': 'I-gene loss-of-function'}", + "69, Mef2a(-/-) {'perturbing_action': 'B-gene loss-of-function'}", + "70, mice {'context': 'B-organism'}", + "103, hearts {'context': 'B-tissue/organ'}", + "105, Mef2a-mutant {'perturbing_action': 'B-other'}", + "106, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "21, mice ['l0', 'l1', 'l2', 'l3']", + "22, deficient ['l0', 'l4', 'l5', 'l6']", + "36, mice ['l1', 'l4', 'l7', 'l8']", + "37, lacking ['l2', 'l5', 'l7', 'l9']", + "38, Mef2a ['l3', 'l6', 'l8', 'l9']", + "69, Mef2a(-/-) ['l10']", + "70, mice ['l10']", + "103, hearts ['l11', 'l12']", + "105, Mef2a-mutant ['l11', 'l13']", + "106, mice, ['l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "lacking", + "Mef2a", + "Mef2a(-/-)" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "hearts" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Mef2a-mutant" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Mef2a-mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "12357249", + "TEXT": "Transmembrane signaling through G protein-coupled receptors (GPCRs) controls a diverse array of cellular processes including metabolism, growth, motility, adhesion, neuronal signaling and blood coagulation. The numerous GPCRs and their key roles in both normal physiology and disease have made them the target for more than 50% of all prescribed drugs. GPCR agonists and antagonists act on the extracellular side of the receptors, whereas the intracellular surface has not yet been exploited for development of new therapeutic agents. Here, we demonstrate the utility of novel cell-penetrating peptides, termed 'pepducins', that act as intracellular inhibitors of signal transference from receptors to G proteins. Attachment of a palmitate lipid to peptides based on the third intracellular loop of protease-activated receptor 1 (PAR1) or PAR4 (refs. 3-5) yielded potent inhibitors of thrombin-mediated aggregation of human platelets. Infusion of the anti-PAR4 pepducin into mice extended bleeding time and protected against systemic platelet activation, consistent with the phenotype of PAR4-deficient mice. We show that pepducins might be used to ascertain the physiological roles of GPCRs and rapidly determine the potential therapeutic value of blockade of a particular signaling pathway.", + "TAG_DATA": [ + "130, human {'context': 'B-cells'}", + "131, platelets. {'context': 'I-cells'}", + "138, mice {'context': 'B-organism'}", + "153, PAR4-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "154, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "130, human ['l0']", + "131, platelets. ['l0']", + "153, PAR4-deficient ['l1']", + "154, mice. ['l1']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PAR4-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + } + ] + }, + { + "PMID": "12244304", + "TEXT": "Primary pulmonary hypertension is a progressive and often fatal disorder in humans that results from an increase in pulmonary blood pressure associated with abnormal vascular proliferation. Dexfenfluramine increases the risk of pulmonary hypertension in humans, and its active metabolite is a selective serotonin 5-hydroxytryptamine 2B (5-HT(2B)) receptor agonist. Thus, we investigated the contribution of the 5-HT(2B)receptor to the pathogenesis of pulmonary hypertension. Using the chronic-hypoxic-mouse model of pulmonary hypertension, we found that the hypoxia-dependent increase in pulmonary blood pressure and lung remodeling are associated with an increase in vascular proliferation, elastase activity and transforming growth factor-beta levels, and that these parameters are potentiated by dexfenfluramine treatment. In contrast, hypoxic mice with genetically or pharmacologically inactive 5-HT(2B)receptors manifested no change in any of these parameters. In both humans and mice, pulmonary hypertension is associated with a substantial increase in 5-HT(2B) receptor expression in pulmonary arteries. These data show that activation of 5-HT(2B) receptors is a limiting step in the development of pulmonary hypertension.", + "TAG_DATA": [ + "86, increase {'effect': 'B-positive'}", + "89, proliferation, {'phenotype': 'B-proliferation'}", + "108, hypoxic {'context': 'B-organism'}", + "109, mice {'context': 'I-organism'}", + "113, pharmacologically {'perturbing_action': 'I-gene loss-of-function'}", + "114, inactive {'perturbing_action': 'I-gene loss-of-function'}", + "115, 5-HT(2B)receptors {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "86, increase ['l0']", + "89, proliferation, ['l0']", + "108, hypoxic ['l1', 'l2', 'l3', 'l4', 'l5']", + "109, mice ['l1', 'l6', 'l7', 'l8', 'l9']", + "112, or ['l2', 'l6', 'l10', 'l11', 'l12']", + "113, pharmacologically ['l3', 'l7', 'l10', 'l13', 'l14']", + "114, inactive ['l4', 'l8', 'l11', 'l13', 'l15']", + "115, 5-HT(2B)receptors ['l5', 'l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "hypoxic", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pharmacologically", + "inactive", + "5-HT(2B)receptors" + ] + } + } + ] + }, + { + "PMID": "12244302", + "TEXT": "Mechanisms linking mitogenic and growth inhibitory cytokine signaling and the cell cycle have not been fully elucidated in either cancer or in normal cells. Here we show that activation of protein kinase B (PKB)/Akt, contributes to resistance to antiproliferative signals and breast cancer progression in part by impairing the nuclear import and action of p27. Akt transfection caused cytoplasmic p27 accumulation and resistance to cytokine-mediated G1 arrest. The nuclear localization signal of p27 contains an Akt consensus site at threonine 157, and p27 phosphorylation by Akt impaired its nuclear import in vitro. Akt phosphorylated wild-type p27 but not p27T157A. In cells transfected with constitutively active Akt(T308DS473D)(PKB(DD)), p27WT mislocalized to the cytoplasm, but p27T157A was nuclear. In cells with activated Akt, p27WT failed to cause G1 arrest, while the antiproliferative effect of p27T157A was not impaired. Cytoplasmic p27 was seen in 41% (52 of 128) of primary human breast cancers in conjunction with Akt activation and was correlated with a poor patient prognosis. Thus, we show a novel mechanism whereby Akt impairs p27 function that is associated with an aggressive phenotype in human breast cancer.", + "TAG_DATA": [ + "55, Akt {'perturbing_action': 'B-gene gain-of-function'}", + "56, transfection {'perturbing_action': 'I-gene gain-of-function'}", + "62, resistance {'effect': 'B-negative'}", + "65, G1 {'phenotype': 'B-cell cycle arrest'}", + "66, arrest. {'phenotype': 'I-cell cycle arrest'}", + "100, cells {'context': 'B-cells'}", + "101, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "102, with {'perturbing_action': 'I-other'}", + "103, constitutively {'perturbing_action': 'I-other'}", + "104, active {'perturbing_action': 'I-other'}", + "105, Akt(T308DS473D)(PKB(DD)), {'perturbing_action': 'I-other'}", + "116, cells {'context': 'B-cells'}", + "118, activated {'perturbing_action': 'B-gene gain-of-function'}", + "119, Akt, {'perturbing_action': 'I-gene gain-of-function'}", + "121, failed {'effect': 'B-no effect'}", + "122, to {'effect': 'I-no effect'}", + "123, cause {'effect': 'I-no effect'}", + "124, G1 {'phenotype': 'B-cell cycle arrest'}", + "125, arrest, {'phenotype': 'I-cell cycle arrest'}" + ], + "LINK_DATA": [ + "55, Akt ['l0', 'l1', 'l2', 'l3']", + "56, transfection ['l0', 'l4', 'l5', 'l6']", + "62, resistance ['l1', 'l4', 'l7', 'l8']", + "65, G1 ['l2', 'l5', 'l7', 'l9']", + "66, arrest. ['l3', 'l6', 'l8', 'l9']", + "100, cells ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "101, transfected ['l10', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "102, with ['l11', 'l23', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "103, constitutively ['l12', 'l24', 'l35', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "104, active ['l13', 'l25', 'l36', 'l46', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "105, Akt(T308DS473D)(PKB(DD)), ['l14', 'l26', 'l37', 'l47', 'l56', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "116, cells ['l15', 'l27', 'l38', 'l48', 'l57', 'l65', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "118, activated ['l16', 'l28', 'l39', 'l49', 'l58', 'l66', 'l73', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "119, Akt, ['l17', 'l29', 'l40', 'l50', 'l59', 'l67', 'l74', 'l80', 'l86', 'l87', 'l88', 'l89', 'l90']", + "121, failed ['l18', 'l30', 'l41', 'l51', 'l60', 'l68', 'l75', 'l81', 'l86', 'l91', 'l92', 'l93', 'l94']", + "122, to ['l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l76', 'l82', 'l87', 'l91', 'l95', 'l96', 'l97']", + "123, cause ['l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l83', 'l88', 'l92', 'l95', 'l98', 'l99']", + "124, G1 ['l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l89', 'l93', 'l96', 'l98', 'l100']", + "125, arrest, ['l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l94', 'l97', 'l99', 'l100']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Akt", + "transfection" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Akt", + "transfection", + "transfected", + "activated", + "Akt," + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G1", + "arrest.", + "arrest," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G1", + "arrest." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "activated", + "Akt," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "with", + "constitutively", + "active", + "Akt(T308DS473D)(PKB(DD))," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "failed", + "to", + "cause" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G1", + "arrest," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "activated", + "Akt," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "failed", + "to", + "cause" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "with", + "constitutively", + "active", + "Akt(T308DS473D)(PKB(DD))," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "failed", + "to", + "cause" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "with", + "constitutively", + "active", + "Akt(T308DS473D)(PKB(DD))," + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G1", + "arrest," + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "failed", + "to", + "cause" + ] + }, + "phenotype": { + "val": "cell cycle arrest", + "words": [ + "G1", + "arrest," + ] + } + } + ] + }, + { + "PMID": "12172541", + "TEXT": "Glioblastoma multiforme is the most undifferentiated type of brain tumor, and its prognosis is extremely poor. Glioblastoma cells exhibit highly migratory and invasive behavior, which makes surgical intervention unsuccessful. Here, we showed that glioblastoma cells express Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptors assembled from the GluR1 and/or GluR4 subunits, and that their conversion to Ca(2+)-impermeable receptors by adenovirus-mediated transfer of the GluR2 cDNA inhibited cell locomotion and induced apoptosis. In contrast, overexpression of Ca(2+)-permeable AMPA receptors facilitated migration and proliferation of the tumor cells. These findings indicate that Ca(2+)-permeable AMPA receptors have crucial roles in growth of glioblastoma. Blockage of these Ca(2+)-permeable receptors may be a useful therapeutic strategy for the prevention of glioblastoma invasion.", + "TAG_DATA": [ + "60, GluR2 {'perturbing_action': 'I-gene gain-of-function'}", + "61, cDNA {'perturbing_action': 'I-gene gain-of-function'}", + "62, inhibited {'effect': 'B-negative'}", + "63, cell {'context': 'B-cells'}", + "64, locomotion {'phenotype': 'B-migration'}", + "66, induced {'effect': 'B-positive'}", + "67, apoptosis. {'phenotype': 'B-apoptosis'}", + "70, overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "71, of {'perturbing_action': 'I-gene gain-of-function'}", + "72, Ca(2+)-permeable {'perturbing_action': 'I-gene gain-of-function'}", + "73, AMPA {'perturbing_action': 'I-gene gain-of-function'}", + "74, receptors {'perturbing_action': 'I-gene gain-of-function'}", + "75, facilitated {'effect': 'B-positive'}", + "76, migration {'phenotype': 'B-migration'}", + "78, proliferation {'phenotype': 'B-proliferation'}", + "81, tumor {'context': 'B-transformed cells'}", + "82, cells. {'context': 'I-transformed cells'}" + ], + "LINK_DATA": [ + "60, GluR2 ['l0', 'l1', 'l2', 'l3', 'l4', 'l5']", + "61, cDNA ['l0', 'l6', 'l7', 'l8', 'l9', 'l10']", + "62, inhibited ['l1', 'l6', 'l11', 'l12', 'l13', 'l14']", + "63, cell ['l2', 'l7', 'l11', 'l15', 'l16']", + "64, locomotion ['l3', 'l8', 'l12', 'l15', 'l17', 'l18']", + "66, induced ['l4', 'l9', 'l13', 'l16', 'l17', 'l19']", + "67, apoptosis. ['l5', 'l10', 'l14', 'l18', 'l19']", + "70, overexpression ['l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28']", + "71, of ['l20', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "72, Ca(2+)-permeable ['l21', 'l29', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "73, AMPA ['l22', 'l30', 'l37', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "74, receptors ['l23', 'l31', 'l38', 'l44', 'l50', 'l51', 'l52', 'l53', 'l54']", + "75, facilitated ['l24', 'l32', 'l39', 'l45', 'l50', 'l55', 'l56', 'l57', 'l58']", + "76, migration ['l25', 'l33', 'l40', 'l46', 'l51', 'l55', 'l59', 'l60', 'l61']", + "78, proliferation ['l26', 'l34', 'l41', 'l47', 'l52', 'l56', 'l59', 'l62', 'l63']", + "81, tumor ['l27', 'l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l62', 'l64']", + "82, cells. ['l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l64']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GluR2", + "cDNA" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GluR2", + "cDNA" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GluR2", + "cDNA", + "overexpression", + "of", + "Ca(2+)-permeable", + "AMPA", + "receptors" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "locomotion", + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GluR2", + "cDNA", + "overexpression", + "of", + "Ca(2+)-permeable", + "AMPA", + "receptors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "facilitated" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GluR2", + "cDNA" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "locomotion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "locomotion" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "locomotion", + "migration" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "facilitated" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Ca(2+)-permeable", + "AMPA", + "receptors" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Ca(2+)-permeable", + "AMPA", + "receptors" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "facilitated" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "facilitated" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + } + ] + }, + { + "PMID": "12134142", + "TEXT": "The feasibility of gene therapy for cardiomyopathy, heart failure and other chronic cardiac muscle diseases is so far unproven. Here, we developed an in vivo recombinant adeno-associated virus (rAAV) transcoronary delivery system that allows stable, high efficiency and relatively cardiac-selective gene expression. We used rAAV to express a pseudophosphorylated mutant of human phospholamban (PLN), a key regulator of cardiac sarcoplasmic reticulum (SR) Ca(2+) cycling in BIO14.6 cardiomyopathic hamsters. The rAAV/S16EPLN treatment enhanced myocardial SR Ca(2+) uptake and suppressed progressive impairment of left ventricular (LV) systolic function and contractility for 28-30 weeks, thereby protecting cardiac myocytes from cytopathic plasma-membrane disruption. Low LV systolic pressure and deterioration in LV relaxation were also largely prevented by rAAV/S16EPLN treatment. Thus, transcoronary gene transfer of S16EPLN via rAAV vector is a potential therapy for progressive dilated cardiomyopathy and associated heart failure.", + "TAG_DATA": [ + "44, rAAV {'perturbing_action': 'B-other'}", + "45, to {'perturbing_action': 'I-other'}", + "46, express {'perturbing_action': 'I-other'}", + "47, a {'perturbing_action': 'I-other'}", + "48, pseudophosphorylated {'perturbing_action': 'I-other'}", + "49, mutant {'perturbing_action': 'I-other'}", + "50, of {'perturbing_action': 'I-other'}", + "51, human {'perturbing_action': 'I-other'}", + "52, phospholamban {'perturbing_action': 'I-other'}", + "53, (PLN), {'perturbing_action': 'I-other'}", + "67, hamsters. {'context': 'B-organism'}", + "93, cardiac {'context': 'B-cells'}", + "94, myocytes {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "44, rAAV ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "45, to ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "46, express ['l1', 'l12', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "47, a ['l2', 'l13', 'l22', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40']", + "48, pseudophosphorylated ['l3', 'l14', 'l23', 'l32', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "49, mutant ['l4', 'l15', 'l24', 'l33', 'l41', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "50, of ['l5', 'l16', 'l25', 'l34', 'l42', 'l49', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "51, human ['l6', 'l17', 'l26', 'l35', 'l43', 'l50', 'l56', 'l62', 'l63', 'l64', 'l65', 'l66']", + "52, phospholamban ['l7', 'l18', 'l27', 'l36', 'l44', 'l51', 'l57', 'l62', 'l67', 'l68', 'l69', 'l70']", + "53, (PLN), ['l8', 'l19', 'l28', 'l37', 'l45', 'l52', 'l58', 'l63', 'l67', 'l71', 'l72', 'l73']", + "67, hamsters. ['l9', 'l20', 'l29', 'l38', 'l46', 'l53', 'l59', 'l64', 'l68', 'l71']", + "93, cardiac ['l10', 'l30', 'l39', 'l47', 'l54', 'l60', 'l65', 'l69', 'l72', 'l74']", + "94, myocytes ['l11', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l70', 'l73', 'l74']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "rAAV", + "to", + "express", + "a", + "pseudophosphorylated", + "mutant", + "of", + "human", + "phospholamban", + "(PLN)," + ] + }, + "context": { + "val": "organism", + "words": [ + "hamsters." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "rAAV", + "to", + "express", + "a", + "pseudophosphorylated", + "mutant", + "of", + "human", + "phospholamban", + "(PLN)," + ] + }, + "context": { + "val": "cells", + "words": [ + "cardiac", + "myocytes" + ] + } + } + ] + }, + { + "PMID": "12091906", + "TEXT": "The t(8;21) is one of the most frequent chromosomal translocations associated with acute leukemia. This translocation creates a fusion protein consisting of the acute myeloid leukemia-1 transcription factor and the eight-twenty-one corepressor (AML1 ETO), which represses transcription through AML1 (RUNX1) DNA binding sites and immortalizes hematopoietic progenitor cells. We have identified the p14(ARF) tumor suppressor, a mediator of the p53 oncogene checkpoint, as a direct transcriptional target of AML1 ETO. AML1 ETO repressed the p14(ARF) promoter and reduced endogenous levels of p14(ARF) expression in multiple cell types. In contrast, AML1 stimulated p14(ARF) expression and induced phenotypes consistent with cellular senescence. Chromatin immunoprecipitation assays demonstrated that AML1 ETO was specifically bound to the p14(ARF) promoter. In acute myeloid leukemia samples containing the t(8;21), levels of p14(ARF) mRNA were markedly lower when compared with other acute myeloid leukemias lacking this translocation. Repression of p14(ARF) may explain why p53 is not mutated in t(8;21)-containing leukemias and suggests that p14(ARF) is an important tumor suppressor in a large number of human leukemias.", + "TAG_DATA": [ + "85, cell {'context': 'B-cells'}", + "86, types. {'context': 'I-cells'}", + "94, induced {'effect': 'B-positive'}", + "99, senescence. {'phenotype': 'B-senescence'}" + ], + "LINK_DATA": [ + "85, cell ['l0']", + "86, types. ['l0']", + "94, induced ['l1']", + "99, senescence. ['l1']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "phenotype": { + "val": "senescence", + "words": [ + "senescence." + ] + } + } + ] + }, + { + "PMID": "12091876", + "TEXT": "B7-H1, a recently described member of the B7 family of costimulatory molecules, is thought to be involved in the regulation of cellular and humoral immune responses through the PD-1 receptor on activated T and B cells. We report here that, except for cells of the macrophage lineage, normal human tissues do not express B7-H1. In contrast, B7-H1 is abundant in human carcinomas of lung, ovary and colon and in melanomas. The pro-inflammatory cytokine interferon-gamma upregulates B7-H1 on the surface of tumor cell lines. Cancer cell-associated B7-H1 increases apoptosis of antigen-specific human T-cell clones in vitro, and the apoptotic effect of B7-H1 is mediated largely by one or more receptors other than PD-1. In addition, expression of B7-H1 on mouse P815 tumor increases apoptosis of activated tumor-reactive T cells and promotes the growth of highly immunogenic B7-1(+) tumors in vivo. These findings have implications for the design of T cell-based cancer immunotherapy.", + "TAG_DATA": [ + "80, tumor {'context': 'B-transformed cells'}", + "81, cell {'context': 'I-transformed cells'}", + "82, lines. {'context': 'I-transformed cells'}", + "86, increases {'effect': 'B-positive'}", + "87, apoptosis {'phenotype': 'B-apoptosis'}", + "89, antigen-specific {'context': 'B-cells'}", + "90, human {'context': 'I-cells'}", + "91, T-cell {'context': 'I-cells'}", + "92, clones {'context': 'I-cells'}", + "93, in {'context': 'B-in vitro'}", + "94, vitro, {'context': 'I-in vitro'}", + "97, apoptotic {'phenotype': 'B-apoptosis'}", + "98, effect {'phenotype': 'I-apoptosis'}", + "114, expression {'perturbing_action': 'B-gene gain-of-function'}", + "115, of {'perturbing_action': 'I-gene gain-of-function'}", + "116, B7-H1 {'perturbing_action': 'I-gene gain-of-function'}", + "118, mouse {'context': 'B-neoplasm'}", + "119, P815 {'context': 'I-neoplasm'}", + "120, tumor {'context': 'I-neoplasm'}", + "121, increases {'effect': 'B-positive'}", + "122, apoptosis {'phenotype': 'B-apoptosis'}", + "125, tumor-reactive {'context': 'B-cells'}", + "126, T {'context': 'I-cells'}", + "127, cells {'context': 'I-cells'}", + "133, highly {'context': 'B-neoplasm'}", + "135, B7-1(+) {'context': 'I-neoplasm'}", + "136, tumors {'context': 'I-neoplasm'}", + "137, in {'context': 'B-in vivo'}", + "138, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "80, tumor ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "81, cell ['l0', 'l7', 'l8', 'l9']", + "82, lines. ['l1', 'l7']", + "86, increases ['l2', 'l8', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "87, apoptosis ['l3', 'l10', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "89, antigen-specific ['l11', 'l17', 'l23', 'l24', 'l25', 'l26', 'l27']", + "90, human ['l4', 'l12', 'l18', 'l23', 'l28', 'l29', 'l30', 'l31']", + "91, T-cell ['l5', 'l13', 'l19', 'l24', 'l28', 'l32', 'l33', 'l34']", + "92, clones ['l6', 'l9', 'l14', 'l20', 'l25', 'l29', 'l32', 'l35', 'l36']", + "93, in ['l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l37']", + "94, vitro, ['l16', 'l22', 'l27', 'l31', 'l34', 'l36', 'l37']", + "97, apoptotic ['l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "98, effect ['l38', 'l45', 'l46', 'l47', 'l48', 'l49']", + "114, expression ['l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "115, of ['l50', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "116, B7-H1 ['l51', 'l66', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "118, mouse ['l52', 'l67', 'l81', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "119, P815 ['l53', 'l68', 'l82', 'l95', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119']", + "120, tumor ['l39', 'l54', 'l69', 'l83', 'l96', 'l108', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "121, increases ['l40', 'l45', 'l55', 'l70', 'l84', 'l97', 'l109', 'l120', 'l131', 'l132', 'l133', 'l134']", + "122, apoptosis ['l41', 'l46', 'l56', 'l71', 'l85', 'l98', 'l110', 'l121', 'l131', 'l135', 'l136', 'l137', 'l138']", + "125, tumor-reactive ['l42', 'l47', 'l57', 'l72', 'l86', 'l99', 'l111', 'l122', 'l132', 'l135', 'l139', 'l140', 'l141', 'l142']", + "126, T ['l43', 'l48', 'l58', 'l73', 'l87', 'l100', 'l112', 'l123', 'l133', 'l136', 'l139', 'l143']", + "127, cells ['l44', 'l49', 'l59', 'l74', 'l88', 'l101', 'l113', 'l124', 'l134', 'l137', 'l140', 'l143']", + "133, highly ['l60', 'l75', 'l89', 'l102', 'l114', 'l125', 'l144', 'l145', 'l146', 'l147', 'l148']", + "134, immunogenic ['l61', 'l76', 'l90', 'l103', 'l115', 'l126', 'l141', 'l144', 'l149', 'l150', 'l151', 'l152']", + "135, B7-1(+) ['l62', 'l77', 'l91', 'l104', 'l116', 'l127', 'l145', 'l149', 'l153', 'l154', 'l155']", + "136, tumors ['l63', 'l78', 'l92', 'l105', 'l117', 'l128', 'l138', 'l142', 'l146', 'l150', 'l153', 'l156', 'l157']", + "137, in ['l64', 'l79', 'l93', 'l106', 'l118', 'l129', 'l147', 'l151', 'l154', 'l156', 'l158']", + "138, vivo. ['l65', 'l80', 'l94', 'l107', 'l119', 'l130', 'l148', 'l152', 'l155', 'l157', 'l158']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cell" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increases" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "tumor" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptotic", + "effect" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "context": { + "val": "cells", + "words": [ + "antigen-specific", + "human", + "T-cell", + "clones", + "tumor-reactive", + "T", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increases" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptotic", + "effect" + ] + }, + "context": { + "val": "cells", + "words": [ + "antigen-specific", + "human", + "T-cell", + "clones", + "tumor-reactive", + "T", + "cells" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "apoptosis" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumor", + "mouse", + "P815", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "B7-H1" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "P815", + "tumor", + "highly", + "B7-1(+)", + "tumors" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "B7-H1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increases" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "B7-H1" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "B7-H1" + ] + }, + "context": { + "val": "cells", + "words": [ + "tumor-reactive", + "T", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "B7-H1" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "P815", + "tumor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increases" + ] + } + } + ] + }, + { + "PMID": "12042814", + "TEXT": "Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). So far, immunological mechanisms responsible for demyelination have been the focus of interest. However, mechanisms regulating axon maintenance as well as glial precursor-cell proliferation and oligodendrocyte survival might also influence disease outcome. The cytokine ciliary neurotrophic factor (CNTF), which was originally identified as a survival factor for isolated neurons, promotes differentiation, maturation and survival of oligodendrocytes. To investigate the role of endogenous CNTF in inflammatory demyelinating disease, we studied myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in CNTF-deficient and wild-type C57BL/6 mice. Disease was more severe in CNTF-deficient mice and recovery was poor, with a 60% decrease in the number of proliferating oligodendrocyte precursor cells (OPCs) and a more than 50% increase in the rate of oligodendrocyte apoptosis. In addition, vacuolar dystrophy of myelin and axonal damage were more severe in CNTF-deficient mice. These specific pathological features could be prevented by treatment with an antiserum against tumor necrosis factor-alpha, suggesting that endogenous CNTF may counterbalance this effect of TNF-alpha (ref. 7). Here we identify a factor that modulates, in an inflammatory environment, glial cell survival and is an outcome determinant of EAE.", + "TAG_DATA": [ + "92, CNTF-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "96, mice. {'context': 'I-organism'}", + "102, CNTF-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "103, mice {'context': 'B-organism'}", + "111, decrease {'effect': 'B-negative'}", + "116, proliferating {'context': 'B-cells'}", + "117, oligodendrocyte {'context': 'I-cells'}", + "118, precursor {'context': 'I-cells'}", + "119, cells {'context': 'I-cells'}", + "120, (OPCs) {'context': 'I-cells'}", + "126, increase {'effect': 'B-positive'}", + "131, oligodendrocyte {'context': 'B-cells'}", + "132, apoptosis. {'phenotype': 'B-apoptosis'}", + "146, CNTF-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "147, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "92, CNTF-deficient ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "96, mice. ['l0', 'l12']", + "102, CNTF-deficient ['l1', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "103, mice ['l2', 'l13', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "111, decrease ['l3', 'l14', 'l23', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "116, proliferating ['l4', 'l15', 'l24', 'l32', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "117, oligodendrocyte ['l5', 'l16', 'l25', 'l33', 'l40', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "118, precursor ['l6', 'l17', 'l26', 'l34', 'l41', 'l47', 'l53', 'l54', 'l55', 'l56', 'l57']", + "119, cells ['l7', 'l12', 'l18', 'l27', 'l35', 'l42', 'l48', 'l53', 'l58', 'l59', 'l60', 'l61']", + "120, (OPCs) ['l8', 'l19', 'l28', 'l36', 'l43', 'l49', 'l54', 'l58', 'l62', 'l63', 'l64']", + "126, increase ['l9', 'l20', 'l29', 'l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l65', 'l66']", + "131, oligodendrocyte ['l10', 'l21', 'l30', 'l38', 'l45', 'l51', 'l56', 'l60', 'l63', 'l65', 'l67']", + "132, apoptosis. ['l11', 'l22', 'l31', 'l39', 'l46', 'l52', 'l57', 'l61', 'l64', 'l66', 'l67']", + "146, CNTF-deficient ['l68']", + "147, mice. ['l68']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CNTF-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice.", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CNTF-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decrease" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CNTF-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "proliferating", + "oligodendrocyte", + "precursor", + "cells", + "(OPCs)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CNTF-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increase" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CNTF-deficient" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decrease" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increase" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decrease" + ] + }, + "context": { + "val": "cells", + "words": [ + "proliferating", + "oligodendrocyte", + "precursor", + "cells", + "(OPCs)" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decrease" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "proliferating", + "oligodendrocyte", + "precursor", + "cells", + "(OPCs)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increase" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "proliferating", + "oligodendrocyte", + "precursor", + "cells", + "(OPCs)" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "11984592", + "TEXT": "Pulmonary fibrosis is an interstitial disorder of the lung parenchyma whose mechanism is poorly understood. Potential mechanisms include the infiltration of inflammatory cells to the lungs and the generation of pro-inflammatory mediators. In particular, idiopathic pulmonary fibrosis is a progressive and fatal form of the disorder characterized by alveolar inflammation, fibroblast proliferation and collagen deposition. Here, we investigated the role of cytosolic phospholipase A(2) (cPLA(2)) in pulmonary fibrosis using cPLA(2)-null mutant mice, as cPLA(2) is a key enzyme in the generation of pro-inflammatory eicosanoids. Disruption of the gene encoding cPLA(2) (Pla2g4a) attenuated IPF and inflammation induced by bleomycin administration. Bleomycin-induced overproduction of thromboxanes and leukotrienes in lung was significantly reduced in cPLA(2)-null mice. Our data suggest that cPLA(2) has an important role in the pathogenesis of pulmonary fibrosis. The inhibition of cPLA(2)-initiated pathways might provide a novel therapeutic approach to pulmonary fibrosis, for which no pharmaceutical agents are currently available.", + "TAG_DATA": [ + "69, cPLA(2)-null {'perturbing_action': 'B-gene loss-of-function'}", + "70, mutant {'perturbing_action': 'I-gene loss-of-function'}", + "71, mice, {'context': 'B-organism'}", + "84, Disruption {'perturbing_action': 'B-gene loss-of-function'}", + "85, of {'perturbing_action': 'I-gene loss-of-function'}", + "86, the {'perturbing_action': 'I-gene loss-of-function'}", + "87, gene {'perturbing_action': 'I-gene loss-of-function'}", + "88, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "89, cPLA(2) {'perturbing_action': 'I-gene loss-of-function'}", + "90, (Pla2g4a) {'perturbing_action': 'I-gene loss-of-function'}", + "106, lung {'context': 'B-tissue/organ'}", + "111, cPLA(2)-null {'perturbing_action': 'B-gene loss-of-function'}", + "112, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "69, cPLA(2)-null ['l0', 'l1']", + "70, mutant ['l0', 'l2']", + "71, mice, ['l1', 'l2']", + "84, Disruption ['l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "85, of ['l3', 'l9', 'l10', 'l11', 'l12', 'l13']", + "86, the ['l4', 'l9', 'l14', 'l15', 'l16', 'l17']", + "87, gene ['l5', 'l10', 'l14', 'l18', 'l19', 'l20']", + "88, encoding ['l6', 'l11', 'l15', 'l18', 'l21', 'l22']", + "89, cPLA(2) ['l7', 'l12', 'l16', 'l19', 'l21', 'l23']", + "90, (Pla2g4a) ['l8', 'l13', 'l17', 'l20', 'l22', 'l23']", + "106, lung ['l24', 'l25']", + "111, cPLA(2)-null ['l24', 'l26']", + "112, mice. ['l25', 'l26']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cPLA(2)-null", + "mutant" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice." + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "lung" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cPLA(2)-null" + ] + } + } + ] + }, + { + "PMID": "11984590", + "TEXT": "The inwardly rectifying K(+) channel Kir6.1 forms K(+) channels by coupling with a sulfonylurea receptor in reconstituted systems, but the physiological roles of Kir6.1-containing K(+) channels have not been determined. We report here that mice lacking the gene encoding Kir6.1 (known as Kcnj8) have a high rate of sudden death associated with spontaneous ST elevation followed by atrioventricular block as seen on an electrocardiogram. The K(+) channel opener pinacidil did not induce K(+) currents in vascular smooth-muscle cells of Kir6.1-null mice, and there was no vasodilation response to pinacidil. The administration of methylergometrine, a vasoconstrictive agent, elicited ST elevation followed by cardiac death in Kir6.1-null mice but not in wild-type mice, indicating a phenotype characterized by hypercontractility of coronary arteries and resembling Prinzmetal (or variant) angina in humans. The Kir6.1-containing K(+) channel is critical in the regulation of vascular tonus, especially in the coronary arteries, and its disruption may cause Prinzmetal angina.", + "TAG_DATA": [ + "34, mice {'context': 'B-organism'}", + "35, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "36, the {'perturbing_action': 'I-gene loss-of-function'}", + "37, gene {'perturbing_action': 'I-gene loss-of-function'}", + "38, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "39, Kir6.1 {'perturbing_action': 'I-gene loss-of-function'}", + "40, (known {'perturbing_action': 'I-gene loss-of-function'}", + "41, as {'perturbing_action': 'I-gene loss-of-function'}", + "42, Kcnj8) {'perturbing_action': 'I-gene loss-of-function'}", + "75, vascular {'context': 'B-cells'}", + "76, smooth-muscle {'context': 'I-cells'}", + "77, cells {'context': 'I-cells'}", + "79, Kir6.1-null {'perturbing_action': 'B-gene loss-of-function'}", + "80, mice, {'context': 'B-organism'}", + "104, Kir6.1-null {'perturbing_action': 'B-gene loss-of-function'}", + "105, mice {'context': 'B-organism'}", + "110, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "34, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "35, lacking ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "36, the ['l1', 'l12', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34']", + "37, gene ['l2', 'l13', 'l24', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "38, encoding ['l3', 'l14', 'l25', 'l35', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "39, Kir6.1 ['l4', 'l15', 'l26', 'l36', 'l45', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "40, (known ['l5', 'l16', 'l27', 'l37', 'l46', 'l54', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "41, as ['l6', 'l17', 'l28', 'l38', 'l47', 'l55', 'l62', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74']", + "42, Kcnj8) ['l7', 'l18', 'l29', 'l39', 'l48', 'l56', 'l63', 'l69', 'l75', 'l76', 'l77', 'l78', 'l79']", + "75, vascular ['l8', 'l19', 'l30', 'l40', 'l49', 'l57', 'l64', 'l70', 'l75', 'l80', 'l81', 'l82', 'l83']", + "76, smooth-muscle ['l9', 'l20', 'l31', 'l41', 'l50', 'l58', 'l65', 'l71', 'l76', 'l80', 'l84', 'l85', 'l86']", + "77, cells ['l10', 'l21', 'l32', 'l42', 'l51', 'l59', 'l66', 'l72', 'l77', 'l81', 'l84', 'l87', 'l88']", + "79, Kir6.1-null ['l22', 'l33', 'l43', 'l52', 'l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l87', 'l89']", + "80, mice, ['l11', 'l23', 'l34', 'l44', 'l53', 'l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l89']", + "104, Kir6.1-null ['l90', 'l91']", + "105, mice ['l90', 'l92']", + "110, mice, ['l91', 'l92']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "gene", + "encoding", + "Kir6.1", + "(known", + "as", + "Kcnj8)", + "Kir6.1-null" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "gene", + "encoding", + "Kir6.1", + "(known", + "as", + "Kcnj8)", + "Kir6.1-null" + ] + }, + "context": { + "val": "cells", + "words": [ + "vascular", + "smooth-muscle", + "cells" + ] + } + } + ] + }, + { + "PMID": "11984589", + "TEXT": "Amplification of the gene encoding the ErbB2 (Her2/neu) receptor tyrosine kinase is critical for the progression of several forms of breast cancer. In a large-scale clinical trial, treatment with Herceptin (trastuzumab), a humanized blocking antibody against ErbB2, led to marked improvement in survival. However, cardiomyopathy was uncovered as a mitigating side effect, thereby suggesting an important role for ErbB2 signaling as a modifier of human heart failure. To investigate the physiological role of ErbB2 signaling in the adult heart, we generated mice with a ventricular-restricted deletion of Erbb2. These ErbB2-deficient conditional mutant mice were viable and displayed no overt phenotype. However, physiological analysis revealed the onset of multiple independent parameters of dilated cardiomyopathy, including chamber dilation, wall thinning and decreased contractility. Additionally, cardiomyocytes isolated from these conditional mutants were more susceptible to anthracycline toxicity. ErbB2 signaling in cardiomyocytes is therefore essential for the prevention of dilated cardiomyopathy.", + "TAG_DATA": [ + "81, mice {'context': 'B-organism'}", + "84, ventricular-restricted {'perturbing_action': 'B-gene loss-of-function'}", + "85, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "86, of {'perturbing_action': 'I-gene loss-of-function'}", + "87, Erbb2. {'perturbing_action': 'I-gene loss-of-function'}", + "89, ErbB2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "90, conditional {'perturbing_action': 'B-gene loss-of-function'}", + "91, mutant {'perturbing_action': 'I-gene loss-of-function'}", + "92, mice {'context': 'B-organism'}", + "122, cardiomyocytes {'context': 'B-cells'}", + "127, mutants {'perturbing_action': 'I-other'}" + ], + "LINK_DATA": [ + "81, mice ['l0']", + "84, ventricular-restricted ['l1', 'l2', 'l3', 'l4', 'l5']", + "85, deletion ['l1', 'l6', 'l7']", + "86, of ['l2', 'l6', 'l8']", + "87, Erbb2. ['l0', 'l3', 'l7', 'l8']", + "89, ErbB2-deficient ['l9', 'l10', 'l11']", + "90, conditional ['l9', 'l12', 'l13']", + "91, mutant ['l4', 'l10', 'l12', 'l14']", + "92, mice ['l5', 'l11', 'l13', 'l14']", + "122, cardiomyocytes ['l15']", + "127, mutants ['l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Erbb2.", + "ventricular-restricted", + "ErbB2-deficient", + "conditional", + "mutant" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cardiomyocytes" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutants" + ] + } + } + ] + }, + { + "PMID": "11927947", + "TEXT": "The influence of maternally transmitted immunoglobulins on the development of autoimmune diabetes mellitus in genetically susceptible human progeny remains unknown. Given the presence of islet beta cell-reactive autoantibodies in prediabetic nonobese diabetic (NOD) mice, we abrogated the maternal transmission of such antibodies in order to assess their influence on the susceptibility of progeny to diabetes. First, we used B cell-deficient NOD mothers to eliminate the transmission of maternal immunoglobulins. In a complementary approach, we used immunoglobulin transgenic NOD mothers to exclude autoreactive specificities from the maternal B-cell repertoire. Finally, we implanted NOD embryos in pseudopregnant mothers of a non-autoimmune strain. The NOD progeny in all three groups were protected from spontaneous diabetes. These findings demonstrate that the maternal transmission of antibodies is a critical environmental parameter influencing the ontogeny of T cell-mediated destruction of islet beta cells in NOD mice. It will be important to definitively determine whether the transmission of maternal autoantibodies in humans affects diabetes progression in susceptible offspring.", + "TAG_DATA": [ + "58, B {'perturbing_action': 'B-gene loss-of-function'}", + "59, cell-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "60, NOD {'context': 'B-organism'}", + "61, mothers {'context': 'I-organism'}", + "77, NOD {'context': 'B-organism'}", + "78, mothers {'context': 'I-organism'}", + "91, NOD {'context': 'B-organism'}", + "92, embryos {'context': 'I-organism'}", + "95, mothers {'context': 'I-organism'}", + "99, strain. {'context': 'I-organism'}", + "101, NOD {'context': 'B-organism'}", + "102, progeny {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "58, B ['l0', 'l1', 'l2', 'l3']", + "59, cell-deficient ['l0', 'l4', 'l5', 'l6']", + "60, NOD ['l1', 'l4', 'l7']", + "61, mothers ['l2', 'l5', 'l7']", + "77, NOD ['l8', 'l9', 'l10', 'l11', 'l12']", + "78, mothers ['l3', 'l6', 'l8', 'l13', 'l14', 'l15']", + "91, NOD ['l9', 'l13', 'l16', 'l17', 'l18']", + "92, embryos ['l10', 'l14', 'l16', 'l19', 'l20']", + "95, mothers ['l11', 'l15', 'l17', 'l19', 'l21']", + "99, strain. ['l12', 'l18', 'l20', 'l21']", + "101, NOD ['l22']", + "102, progeny ['l22']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "B", + "cell-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "NOD", + "mothers" + ] + } + } + ] + }, + { + "PMID": "11927943", + "TEXT": "The complement cascade defines an important link between the innate and the specific immune system. Here we show that mice deficient for the third component of complement (C3-/- mice) are highly susceptible to primary infection with influenza virus. C3-/- mice showed delayed viral clearance and increased viral titers in lung, whereas mice deficient for complement receptors CR1 and CR2 (Cr2-/- mice) cleared the infection normally. Priming of T-helper cells and cytotoxic T cells (CTLs) in lung-draining lymph nodes was reduced, and the recruitment into the lung of virus-specific CD4+ and CD8+ effector T cells producing interferon-gamma was severely impaired in C3-/- but not in Cr2-/- mice. Consequently, T-helper cell-dependent IgG responses were reduced in C3-/- mice but remained intact in Cr2-/- mice. These results demonstrate that complement induces specific immunity by promoting T-cell responses.", + "TAG_DATA": [ + "19, mice {'context': 'B-organism'}", + "20, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "21, for {'perturbing_action': 'I-gene loss-of-function'}", + "22, the {'perturbing_action': 'I-gene loss-of-function'}", + "23, third {'perturbing_action': 'I-gene loss-of-function'}", + "24, component {'perturbing_action': 'I-gene loss-of-function'}", + "25, of {'perturbing_action': 'I-gene loss-of-function'}", + "26, complement {'perturbing_action': 'I-gene loss-of-function'}", + "28, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "38, C3-/- {'perturbing_action': 'B-gene loss-of-function'}", + "39, mice {'context': 'B-organism'}", + "49, lung, {'context': 'B-tissue/organ'}", + "51, mice {'context': 'B-organism'}", + "52, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "53, for {'perturbing_action': 'I-gene loss-of-function'}", + "54, complement {'perturbing_action': 'I-gene loss-of-function'}", + "55, receptors {'perturbing_action': 'I-gene loss-of-function'}", + "56, CR1 {'perturbing_action': 'I-gene loss-of-function'}", + "57, and {'perturbing_action': 'I-gene loss-of-function'}", + "58, CR2 {'perturbing_action': 'I-gene loss-of-function'}", + "59, (Cr2-/- {'perturbing_action': 'I-gene loss-of-function'}", + "60, mice) {'perturbing_action': 'I-gene loss-of-function'}", + "67, T-helper {'context': 'B-cells'}", + "68, cells {'context': 'I-cells'}", + "75, lung-draining {'context': 'B-tissue/organ'}", + "76, lymph {'context': 'I-tissue/organ'}", + "77, nodes {'context': 'I-tissue/organ'}", + "88, CD4+ {'context': 'B-cells'}", + "89, and {'context': 'I-cells'}", + "90, CD8+ {'context': 'I-cells'}", + "91, effector {'context': 'I-cells'}", + "92, T {'context': 'I-cells'}", + "93, cells {'context': 'I-cells'}", + "100, C3-/- {'perturbing_action': 'B-gene loss-of-function'}", + "104, Cr2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "105, mice. {'context': 'B-organism'}", + "114, C3-/- {'perturbing_action': 'B-gene loss-of-function'}", + "115, mice {'context': 'B-organism'}", + "120, Cr2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "121, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "19, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "20, deficient ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "21, for ['l1', 'l12', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "22, the ['l2', 'l13', 'l26', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "23, third ['l3', 'l14', 'l27', 'l40', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "24, component ['l4', 'l15', 'l28', 'l41', 'l53', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "25, of ['l5', 'l16', 'l29', 'l42', 'l54', 'l65', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "26, complement ['l6', 'l17', 'l30', 'l43', 'l55', 'l66', 'l76', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92']", + "28, mice) ['l7', 'l18', 'l31', 'l44', 'l56', 'l67', 'l77', 'l86', 'l93', 'l94', 'l95', 'l96']", + "38, C3-/- ['l8', 'l19', 'l32', 'l45', 'l57', 'l68', 'l78', 'l87', 'l93', 'l97', 'l98']", + "39, mice ['l9', 'l20', 'l33', 'l46', 'l58', 'l69', 'l79', 'l88', 'l94', 'l97', 'l99']", + "49, lung, ['l10', 'l21', 'l34', 'l47', 'l59', 'l70', 'l80', 'l89', 'l95', 'l98', 'l99']", + "51, mice ['l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122']", + "52, deficient ['l100', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144']", + "53, for ['l101', 'l123', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "54, complement ['l102', 'l124', 'l145', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185']", + "55, receptors ['l103', 'l125', 'l146', 'l166', 'l186', 'l187', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201', 'l202', 'l203', 'l204']", + "56, CR1 ['l104', 'l126', 'l147', 'l167', 'l186', 'l205', 'l206', 'l207', 'l208', 'l209', 'l210', 'l211', 'l212', 'l213', 'l214', 'l215', 'l216', 'l217', 'l218', 'l219', 'l220', 'l221', 'l222']", + "57, and ['l105', 'l127', 'l148', 'l168', 'l187', 'l205', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239']", + "58, CR2 ['l106', 'l128', 'l149', 'l169', 'l188', 'l206', 'l223', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252', 'l253', 'l254', 'l255']", + "59, (Cr2-/- ['l107', 'l129', 'l150', 'l170', 'l189', 'l207', 'l224', 'l240', 'l256', 'l257', 'l258', 'l259', 'l260', 'l261', 'l262', 'l263', 'l264', 'l265', 'l266', 'l267', 'l268', 'l269', 'l270']", + "60, mice) ['l108', 'l130', 'l151', 'l171', 'l190', 'l208', 'l225', 'l241', 'l256', 'l271', 'l272', 'l273', 'l274', 'l275', 'l276', 'l277', 'l278', 'l279', 'l280', 'l281', 'l282']", + "67, T-helper ['l22', 'l35', 'l48', 'l60', 'l71', 'l81', 'l90', 'l109', 'l131', 'l152', 'l172', 'l191', 'l209', 'l226', 'l242', 'l257', 'l271', 'l283', 'l284', 'l285', 'l286', 'l287', 'l288', 'l289', 'l290', 'l291']", + "68, cells ['l11', 'l23', 'l36', 'l49', 'l61', 'l72', 'l82', 'l91', 'l96', 'l110', 'l132', 'l153', 'l173', 'l192', 'l210', 'l227', 'l243', 'l258', 'l272', 'l283', 'l292', 'l293', 'l294']", + "75, lung-draining ['l37', 'l50', 'l62', 'l73', 'l83', 'l111', 'l133', 'l154', 'l174', 'l193', 'l211', 'l228', 'l244', 'l259', 'l273', 'l284', 'l292', 'l295', 'l296', 'l297', 'l298', 'l299', 'l300', 'l301', 'l302']", + "76, lymph ['l24', 'l38', 'l51', 'l63', 'l74', 'l84', 'l112', 'l134', 'l155', 'l175', 'l194', 'l212', 'l229', 'l245', 'l260', 'l274', 'l285', 'l293', 'l295', 'l303', 'l304', 'l305', 'l306', 'l307', 'l308', 'l309']", + "77, nodes ['l25', 'l39', 'l52', 'l64', 'l75', 'l85', 'l92', 'l113', 'l135', 'l156', 'l176', 'l195', 'l213', 'l230', 'l246', 'l261', 'l275', 'l286', 'l294', 'l296', 'l303', 'l310', 'l311']", + "88, CD4+ ['l114', 'l136', 'l157', 'l177', 'l196', 'l214', 'l231', 'l247', 'l262', 'l276', 'l287', 'l297', 'l304', 'l312', 'l313', 'l314', 'l315', 'l316', 'l317', 'l318', 'l319']", + "89, and ['l115', 'l137', 'l158', 'l178', 'l197', 'l215', 'l232', 'l248', 'l263', 'l277', 'l288', 'l298', 'l305', 'l312', 'l320', 'l321', 'l322', 'l323', 'l324', 'l325', 'l326']", + "90, CD8+ ['l116', 'l138', 'l159', 'l179', 'l198', 'l216', 'l233', 'l249', 'l264', 'l278', 'l299', 'l306', 'l313', 'l320', 'l327', 'l328', 'l329', 'l330', 'l331', 'l332']", + "91, effector ['l117', 'l139', 'l160', 'l180', 'l199', 'l217', 'l234', 'l250', 'l265', 'l279', 'l289', 'l300', 'l307', 'l314', 'l321', 'l327', 'l333', 'l334', 'l335', 'l336', 'l337']", + "92, T ['l118', 'l140', 'l161', 'l181', 'l200', 'l218', 'l235', 'l251', 'l266', 'l280', 'l290', 'l301', 'l308', 'l310', 'l315', 'l322', 'l328', 'l333', 'l338', 'l339', 'l340', 'l341']", + "93, cells ['l119', 'l141', 'l162', 'l182', 'l201', 'l219', 'l236', 'l252', 'l267', 'l281', 'l291', 'l302', 'l309', 'l311', 'l316', 'l323', 'l329', 'l334', 'l338', 'l342', 'l343', 'l344']", + "100, C3-/- ['l120', 'l142', 'l163', 'l183', 'l202', 'l220', 'l237', 'l253', 'l268', 'l317', 'l324', 'l330', 'l335', 'l339', 'l342', 'l345', 'l346']", + "104, Cr2-/- ['l121', 'l143', 'l164', 'l184', 'l203', 'l221', 'l238', 'l254', 'l269', 'l318', 'l325', 'l331', 'l336', 'l340', 'l343', 'l345', 'l347']", + "105, mice. ['l122', 'l144', 'l165', 'l185', 'l204', 'l222', 'l239', 'l255', 'l270', 'l282', 'l319', 'l326', 'l332', 'l337', 'l341', 'l344', 'l346', 'l347']", + "114, C3-/- ['l348', 'l349', 'l350']", + "115, mice ['l348', 'l351', 'l352']", + "120, Cr2-/- ['l349', 'l351', 'l353']", + "121, mice. ['l350', 'l352', 'l353']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "the", + "third", + "component", + "of", + "complement", + "mice)", + "C3-/-", + "receptors", + "CR1", + "and", + "CR2", + "(Cr2-/-", + "Cr2-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "the", + "third", + "component", + "of", + "complement", + "mice)", + "C3-/-", + "receptors", + "CR1", + "and", + "CR2", + "(Cr2-/-" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "lung,", + "lymph", + "nodes", + "lung-draining" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "the", + "third", + "component", + "of", + "complement", + "mice)", + "receptors", + "CR1", + "and", + "CR2", + "(Cr2-/-", + "C3-/-", + "Cr2-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "T-helper", + "cells", + "CD4+", + "and", + "CD8+", + "effector", + "T" + ] + } + } + ] + }, + { + "PMID": "11927942", + "TEXT": "Specific interference with molecular mechanisms guiding tissue localization of leukocytes may be of great utility for selective immunosuppressive therapies. We have discovered and characterized efomycines, a new family of selective small-molecule inhibitors of selectin functions. Members of this family significantly inhibited leukocyte adhesion in vitro. Efomycine M, which was nontoxic and showed the most selective inhibitory effects on selectin-mediated leukocyte-endothelial adhesion in vitro, significantly diminished rolling in mouse ear venules in vivo as seen by intravital microscopy. In addition, efomycine M alleviated cutaneous inflammation in two complementary mouse models of psoriasis, one of the most common chronic inflammatory skin disorders. Molecular modeling demonstrated a spatial conformation of efomycines mimicking naturally occurring selectin ligands. Efomycine M might be efficacious in the treatment of human inflammatory disorders through a similar mechanism.", + "TAG_DATA": [ + "40, inhibited {'effect': 'B-negative'}", + "41, leukocyte {'context': 'B-cells'}", + "42, adhesion {'phenotype': 'B-adhesion'}", + "43, in {'context': 'B-in vitro'}", + "44, vitro. {'context': 'I-in vitro'}", + "61, in {'context': 'B-in vitro'}", + "62, vitro, {'context': 'I-in vitro'}", + "67, mouse {'context': 'B-tissue/organ'}", + "68, ear {'context': 'I-tissue/organ'}", + "69, venules {'context': 'I-tissue/organ'}", + "70, in {'context': 'B-in vivo'}", + "71, vivo {'context': 'I-in vivo'}", + "87, mouse {'context': 'I-organism'}", + "88, models {'context': 'I-organism'}", + "89, of {'context': 'I-organism'}", + "90, psoriasis, {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "40, inhibited ['l0', 'l1', 'l2', 'l3', 'l4']", + "41, leukocyte ['l0', 'l5', 'l6', 'l7', 'l8']", + "42, adhesion ['l1', 'l5', 'l9', 'l10']", + "43, in ['l2', 'l6', 'l9', 'l11']", + "44, vitro. ['l3', 'l7', 'l10', 'l11']", + "61, in ['l4', 'l8', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "62, vitro, ['l12', 'l18', 'l19', 'l20', 'l21', 'l22']", + "67, mouse ['l13', 'l18', 'l23', 'l24', 'l25', 'l26']", + "68, ear ['l14', 'l19', 'l23', 'l27', 'l28', 'l29']", + "69, venules ['l15', 'l20', 'l24', 'l27', 'l30', 'l31']", + "70, in ['l16', 'l21', 'l25', 'l28', 'l30', 'l32']", + "71, vivo ['l17', 'l22', 'l26', 'l29', 'l31', 'l32']", + "87, mouse ['l33', 'l34', 'l35']", + "88, models ['l33', 'l36', 'l37']", + "89, of ['l34', 'l36', 'l38']", + "90, psoriasis, ['l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "leukocyte" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "leukocyte" + ] + }, + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + } + }, + { + "phenotype": { + "val": "adhesion", + "words": [ + "adhesion" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + } + } + ] + }, + { + "PMID": "11927940", + "TEXT": "Natural inhibitors of angiogenesis are able to block pathological neovascularization without harming the preexisting vasculature. Here we show that two such inhibitors, thrombospondin-1 and pigment epithelium-derived factor, derive specificity for remodeling vessels from their dependence on Fas/Fas ligand (FasL)-mediated apoptosis to block angiogenesis. Both inhibitors upregulated FasL on endothelial cells. Expression of the essential partner of FasL, Fas/CD95 receptor, was low on quiescent endothelial cells and vessels but greatly enhanced by inducers of angiogenesis, thereby specifically sensitizing the stimulated cells to apoptosis by inhibitor-generated FasL. The anti-angiogenic activity of thrombospondin-1 and pigment epithelium-derived factor both in vitro and in vivo was dependent on this dual induction of Fas and FasL and the resulting apoptosis. This example of cooperation between pro- and anti-angiogenic factors in the inhibition of angiogenesis provides one explanation for the ability of inhibitors to select remodeling capillaries for destruction.", + "TAG_DATA": [ + "48, endothelial {'context': 'B-cells'}", + "49, cells. {'context': 'I-cells'}", + "62, quiescent {'context': 'B-cells'}", + "63, endothelial {'context': 'I-cells'}", + "64, cells {'context': 'I-cells'}", + "76, sensitizing {'effect': 'B-positive'}", + "79, cells {'context': 'B-cells'}", + "81, apoptosis {'phenotype': 'B-apoptosis'}", + "95, in {'context': 'B-in vitro'}", + "96, vitro {'context': 'I-in vitro'}", + "98, in {'context': 'B-in vivo'}", + "99, vivo {'context': 'I-in vivo'}", + "113, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "48, endothelial ['l0', 'l1', 'l2', 'l3']", + "49, cells. ['l0', 'l4', 'l5']", + "62, quiescent ['l1', 'l6', 'l7', 'l8', 'l9']", + "63, endothelial ['l2', 'l4', 'l6', 'l10', 'l11']", + "64, cells ['l3', 'l5', 'l7', 'l10']", + "76, sensitizing ['l8', 'l11', 'l12', 'l13']", + "79, cells ['l9', 'l12', 'l14']", + "81, apoptosis ['l13', 'l14']", + "95, in ['l15', 'l16', 'l17', 'l18']", + "96, vitro ['l15', 'l19', 'l20', 'l21']", + "98, in ['l16', 'l19', 'l22', 'l23']", + "99, vivo ['l17', 'l20', 'l22', 'l24']", + "113, apoptosis. ['l18', 'l21', 'l23', 'l24']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "quiescent", + "endothelial", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitizing" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitizing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "11875501", + "TEXT": "Prostaglandins (PGs), bioactive lipid molecules produced by cyclooxygenase enzymes (COX-1 and COX-2), have diverse biological activities, including growth-promoting actions on gastrointestinal mucosa. They are also implicated in the growth of colonic polyps and cancers. However, the precise mechanisms of these trophic actions of PGs remain unclear. As activation of the epidermal growth factor receptor (EGFR) triggers mitogenic signaling in gastrointestinal mucosa, and its expression is also upregulated in colonic cancers and most neoplasms, we investigated whether PGs transactivate EGFR. Here we provide evidence that prostaglandin E2 (PGE2) rapidly phosphorylates EGFR and triggers the extracellular signal-regulated kinase 2 (ERK2)--mitogenic signaling pathway in normal gastric epithelial (RGM1) and colon cancer (Caco-2, LoVo and HT-29) cell lines. Inactivation of EGFR kinase with selective inhibitors significantly reduces PGE2-induced ERK2 activation, c-fos mRNA expression and cell proliferation. Inhibition of matrix metalloproteinases (MMPs), transforming growth factor-alpha (TGF-alpha) or c-Src blocked PGE2-mediated EGFR transactivation and downstream signaling indicating that PGE2-induced EGFR transactivation involves signaling transduced via TGF-alpha, an EGFR ligand, likely released by c-Src-activated MMP(s). Our findings that PGE2 transactivates EGFR reveal a previously unknown mechanism by which PGE2 mediates trophic actions resulting in gastric and intestinal hypertrophy as well as growth of colonic polyps and cancers.", + "TAG_DATA": [ + "101, normal {'context': 'B-cells'}", + "102, gastric {'context': 'I-cells'}", + "103, epithelial {'context': 'I-cells'}", + "104, (RGM1) {'context': 'I-cells'}", + "105, and {'context': 'I-cells'}", + "106, colon {'context': 'I-transformed cells'}", + "107, cancer {'context': 'I-transformed cells'}", + "108, (Caco-2, {'context': 'I-transformed cells'}", + "109, LoVo {'context': 'I-transformed cells'}", + "110, and {'context': 'I-transformed cells'}", + "111, HT-29) {'context': 'I-transformed cells'}", + "112, cell {'context': 'I-transformed cells'}", + "113, lines. {'context': 'I-transformed cells'}", + "114, Inactivation {'perturbing_action': 'B-pharmacological inhibition'}", + "115, of {'perturbing_action': 'I-pharmacological inhibition'}", + "116, EGFR {'perturbing_action': 'I-pharmacological inhibition'}", + "117, kinase {'perturbing_action': 'I-pharmacological inhibition'}", + "118, with {'perturbing_action': 'I-pharmacological inhibition'}", + "119, selective {'perturbing_action': 'I-pharmacological inhibition'}", + "120, inhibitors {'perturbing_action': 'I-pharmacological inhibition'}", + "122, reduces {'effect': 'B-negative'}", + "130, cell {'context': 'B-cells'}", + "131, proliferation. {'phenotype': 'B-proliferation'}" + ], + "LINK_DATA": [ + "101, normal ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "102, gastric ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "103, epithelial ['l1', 'l13', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "104, (RGM1) ['l2', 'l14', 'l27', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51']", + "105, and ['l3', 'l15', 'l28', 'l40', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61']", + "106, colon ['l4', 'l16', 'l29', 'l41', 'l52', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "107, cancer ['l5', 'l17', 'l30', 'l42', 'l53', 'l62', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "108, (Caco-2, ['l6', 'l18', 'l31', 'l43', 'l54', 'l63', 'l72', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "109, LoVo ['l7', 'l19', 'l32', 'l44', 'l55', 'l64', 'l73', 'l81', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "110, and ['l8', 'l20', 'l33', 'l45', 'l56', 'l65', 'l74', 'l82', 'l90', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110']", + "111, HT-29) ['l9', 'l21', 'l34', 'l46', 'l57', 'l66', 'l75', 'l83', 'l91', 'l102', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "112, cell ['l10', 'l22', 'l35', 'l47', 'l58', 'l67', 'l76', 'l84', 'l92', 'l103', 'l111', 'l119', 'l120']", + "113, lines. ['l11', 'l23', 'l36', 'l48', 'l59', 'l68', 'l77', 'l85', 'l93', 'l104', 'l112', 'l119', 'l121']", + "114, Inactivation ['l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130']", + "115, of ['l94', 'l122', 'l131', 'l132', 'l133', 'l134', 'l135', 'l136', 'l137', 'l138']", + "116, EGFR ['l95', 'l105', 'l113', 'l123', 'l131', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145']", + "117, kinase ['l124', 'l132', 'l139', 'l146', 'l147', 'l148', 'l149', 'l150', 'l151']", + "118, with ['l96', 'l125', 'l133', 'l140', 'l146', 'l152', 'l153', 'l154', 'l155', 'l156']", + "119, selective ['l97', 'l106', 'l114', 'l126', 'l134', 'l141', 'l147', 'l152', 'l157', 'l158', 'l159', 'l160']", + "120, inhibitors ['l86', 'l98', 'l107', 'l115', 'l127', 'l135', 'l142', 'l148', 'l153', 'l157', 'l161', 'l162', 'l163']", + "122, reduces ['l12', 'l24', 'l37', 'l49', 'l60', 'l69', 'l78', 'l87', 'l99', 'l108', 'l116', 'l120', 'l121', 'l128', 'l136', 'l143', 'l149', 'l154', 'l158', 'l161', 'l164', 'l165']", + "130, cell ['l25', 'l38', 'l50', 'l70', 'l79', 'l88', 'l100', 'l109', 'l117', 'l129', 'l137', 'l144', 'l150', 'l155', 'l159', 'l162', 'l164', 'l166']", + "131, proliferation. ['l26', 'l39', 'l51', 'l61', 'l71', 'l80', 'l89', 'l101', 'l110', 'l118', 'l130', 'l138', 'l145', 'l151', 'l156', 'l160', 'l163', 'l165', 'l166']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "normal", + "gastric", + "epithelial", + "(RGM1)", + "and", + "cell" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "gastric", + "epithelial", + "(RGM1)", + "and", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "colon", + "cancer", + "(Caco-2,", + "LoVo", + "and", + "HT-29)", + "cell", + "lines." + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "colon", + "cancer", + "(Caco-2,", + "LoVo", + "and", + "HT-29)" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "(Caco-2,", + "LoVo", + "and", + "HT-29)" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "EGFR", + "with", + "selective" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inactivation", + "of", + "EGFR", + "kinase", + "with", + "selective", + "inhibitors" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inactivation", + "of", + "EGFR", + "kinase", + "with", + "selective", + "inhibitors" + ] + }, + "context": { + "val": "cells", + "words": [ + "cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inactivation", + "of", + "EGFR", + "kinase", + "with", + "selective", + "inhibitors" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + } + ] + }, + { + "PMID": "11875496", + "TEXT": "Attempts to develop gene therapy for Duchenne muscular dystrophy (DMD) have been complicated by the enormous size of the dystrophin gene. We have performed a detailed functional analysis of dystrophin structural domains and show that multiple regions of the protein can be deleted in various combinations to generate highly functional mini- and micro-dystrophins. Studies in transgenic mdx mice, a model for DMD, reveal that a wide variety of functional characteristics of dystrophy are prevented by some of these truncated dystrophins. Muscles expressing the smallest dystrophins are fully protected against damage caused by muscle activity and are not morphologically different from normal muscle. Moreover, injection of adeno-associated viruses carrying micro-dystrophins into dystrophic muscles of immunocompetent mdx mice results in a striking reversal of histopathological features of this disease. These results demonstrate that the dystrophic pathology can be both prevented and reversed by gene therapy using micro-dystrophins.", + "TAG_DATA": [ + "55, transgenic {'perturbing_action': 'B-gene gain-of-function', 'context': 'B-organism'}", + "56, mdx {'perturbing_action': 'I-gene gain-of-function', 'context': 'I-organism'}", + "57, mice, {'context': 'I-organism'}", + "80, Muscles {'context': 'B-cells'}", + "110, dystrophic {'context': 'B-tissue/organ'}", + "111, muscles {'context': 'I-tissue/organ'}", + "113, immunocompetent {'context': 'B-organism'}", + "114, mdx {'context': 'I-organism'}", + "115, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "55, transgenic ['l0', 'l1', 'l2']", + "56, mdx ['l0', 'l3', 'l4']", + "57, mice, ['l1', 'l3', 'l5']", + "80, Muscles ['l2', 'l4', 'l5']", + "110, dystrophic ['l6', 'l7', 'l8', 'l9']", + "111, muscles ['l6', 'l10', 'l11', 'l12']", + "113, immunocompetent ['l7', 'l10', 'l13', 'l14']", + "114, mdx ['l8', 'l11', 'l13', 'l15']", + "115, mice ['l9', 'l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "mdx" + ] + }, + "context": { + "val": "organism", + "words": [ + "transgenic", + "mdx" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "mdx" + ] + }, + "context": { + "val": "cells", + "words": [ + "Muscles" + ] + } + } + ] + }, + { + "PMID": "11786904", + "TEXT": "G-protein-coupled receptor (GPCR) agonists are well-known inducers of cardiac hypertrophy. We found that the shedding of heparin-binding epidermal growth factor (HB-EGF) resulting from metalloproteinase activation and subsequent transactivation of the epidermal growth factor receptor occurred when cardiomyocytes were stimulated by GPCR agonists, leading to cardiac hypertrophy. A new inhibitor of HB-EGF shedding, KB-R7785, blocked this signaling. We cloned a disintegrin and metalloprotease 12 (ADAM12) as a specific enzyme to shed HB-EGF in the heart and found that dominant-negative expression of ADAM12 abrogated this signaling. KB-R7785 bound directly to ADAM12, suggesting that inhibition of ADAM12 blocked the shedding of HB-EGF. In mice with cardiac hypertrophy, KB-R7785 inhibited the shedding of HB-EGF and attenuated hypertrophic changes. These data suggest that shedding of HB-EGF by ADAM12 plays an important role in cardiac hypertrophy, and that inhibition of HB-EGF shedding could be a potent therapeutic strategy for cardiac hypertrophy.", + "TAG_DATA": [ + "36, cardiomyocytes {'context': 'B-cells'}", + "77, dominant-negative {'perturbing_action': 'B-other'}", + "78, expression {'perturbing_action': 'I-other'}", + "79, of {'perturbing_action': 'I-other'}", + "80, ADAM12 {'perturbing_action': 'I-other'}", + "91, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "92, of {'perturbing_action': 'I-pharmacological inhibition'}", + "93, ADAM12 {'perturbing_action': 'I-pharmacological inhibition'}", + "100, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "77, dominant-negative ['l0', 'l1', 'l2', 'l3', 'l4']", + "78, expression ['l0', 'l5', 'l6', 'l7']", + "79, of ['l1', 'l5', 'l8']", + "80, ADAM12 ['l2', 'l6', 'l8']", + "91, inhibition ['l9', 'l10', 'l11']", + "92, of ['l3', 'l9', 'l12', 'l13']", + "93, ADAM12 ['l4', 'l7', 'l10', 'l12', 'l14']", + "100, mice ['l11', 'l13', 'l14']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "ADAM12" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "11786903", + "TEXT": "Inhibition of alphavbeta3 or alphavbeta5 integrin function has been reported to suppress neovascularization and tumor growth, suggesting that these integrins are critical modulators of angiogenesis. Here we report that mice lacking beta3 integrins or both beta3 and beta5 integrins not only support tumorigenesis, but have enhanced tumor growth as well. Moreover, the tumors in these integrin-deficient mice display enhanced angiogenesis, strongly suggesting that neither beta3 nor beta5 integrins are essential for neovascularization. We also observed that angiogenic responses to hypoxia and vascular endothelial growth factor (VEGF) are augmented significantly in the absence of beta3 integrins. We found no evidence that the expression or functions of other integrins were altered as a consequence of the beta3 deficiency, but we did observe elevated levels of VEGF receptor-2 (also called Flk-1) in beta3-null endothelial cells. These data indicate that alphavbeta3 and alphavbeta5 integrins are not essential for vascular development or pathological angiogenesis and highlight the need for further evaluation of the mechanisms of action of alphav-integrin antagonists in anti-angiogenic therapeutics.", + "TAG_DATA": [ + "29, mice {'context': 'B-organism'}", + "30, lacking {'perturbing_action': 'B-gene loss-of-function'}", + "31, beta3 {'perturbing_action': 'I-gene loss-of-function'}", + "32, integrins {'perturbing_action': 'I-gene loss-of-function'}", + "33, or {'perturbing_action': 'I-gene loss-of-function'}", + "34, both {'perturbing_action': 'I-gene loss-of-function'}", + "35, beta3 {'perturbing_action': 'I-gene loss-of-function'}", + "37, beta5 {'perturbing_action': 'I-gene loss-of-function'}", + "38, integrins {'perturbing_action': 'I-gene loss-of-function'}", + "41, support {'effect': 'B-positive'}", + "42, tumorigenesis, {'phenotype': 'B-tumourigenesis'}", + "45, enhanced {'effect': 'B-positive'}", + "46, tumor {'phenotype': 'B-tumour growth'}", + "47, growth {'phenotype': 'I-tumour growth'}", + "52, tumors {'context': 'B-neoplasm'}", + "55, integrin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "56, mice {'context': 'B-organism'}", + "91, absence {'perturbing_action': 'B-gene loss-of-function'}", + "114, beta3 {'perturbing_action': 'B-gene loss-of-function'}", + "115, deficiency, {'perturbing_action': 'I-gene loss-of-function'}", + "129, beta3-null {'perturbing_action': 'B-gene loss-of-function'}", + "130, endothelial {'context': 'B-cells'}", + "131, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "29, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "30, lacking ['l0', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "31, beta3 ['l1', 'l8', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "32, integrins ['l2', 'l9', 'l18', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "33, or ['l10', 'l19', 'l31', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "34, both ['l20', 'l32', 'l43', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "35, beta3 ['l21', 'l33', 'l44', 'l55', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "37, beta5 ['l22', 'l34', 'l45', 'l56', 'l67', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "38, integrins ['l23', 'l35', 'l46', 'l57', 'l68', 'l78', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "41, support ['l3', 'l11', 'l24', 'l36', 'l47', 'l58', 'l69', 'l79', 'l88', 'l97', 'l98', 'l99', 'l100']", + "42, tumorigenesis, ['l4', 'l12', 'l25', 'l37', 'l48', 'l59', 'l70', 'l80', 'l89', 'l97', 'l101', 'l102', 'l103']", + "45, enhanced ['l5', 'l13', 'l26', 'l38', 'l49', 'l60', 'l71', 'l81', 'l90', 'l98', 'l101', 'l104', 'l105']", + "46, tumor ['l6', 'l14', 'l27', 'l39', 'l50', 'l61', 'l72', 'l82', 'l91', 'l99', 'l102', 'l104', 'l106']", + "47, growth ['l7', 'l15', 'l28', 'l40', 'l51', 'l62', 'l73', 'l83', 'l92', 'l100', 'l103', 'l105', 'l106']", + "52, tumors ['l16', 'l29', 'l41', 'l52', 'l63', 'l74', 'l84', 'l93', 'l107', 'l108']", + "55, integrin-deficient ['l53', 'l64', 'l75', 'l85', 'l94', 'l107', 'l109', 'l110']", + "56, mice ['l17', 'l30', 'l42', 'l54', 'l65', 'l76', 'l86', 'l95', 'l108', 'l109']", + "91, absence ['l66', 'l77', 'l87', 'l96', 'l110']", + "114, beta3 ['l111', 'l112', 'l113', 'l114']", + "115, deficiency, ['l111', 'l115', 'l116', 'l117']", + "129, beta3-null ['l112', 'l115', 'l118', 'l119']", + "130, endothelial ['l113', 'l116', 'l118', 'l120']", + "131, cells. ['l114', 'l117', 'l119', 'l120']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "beta3", + "integrins", + "or", + "both", + "beta5", + "integrin-deficient" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "positive", + "words": [ + "support", + "enhanced" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "beta3", + "integrins", + "or", + "both", + "beta5" + ] + }, + "effect": { + "val": "positive", + "words": [ + "support", + "enhanced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "beta3", + "integrins", + "or", + "both", + "beta5" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "beta3", + "integrins", + "or", + "both", + "beta5" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "beta3", + "integrins", + "or", + "both", + "beta5", + "integrin-deficient" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "support", + "enhanced" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenesis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "support", + "enhanced" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "beta3", + "deficiency,", + "beta3-null" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial", + "cells." + ] + } + } + ] + }, + { + "PMID": "11726975", + "TEXT": "Dendritic-cell (DC) trafficking and function in tumors is poorly characterized, with studies confined to myeloid DCs (DC1s). Tumors inhibit DC1 migration and function, likely hindering specific immunity. The role of plasmacytoid DCs (DC2s) in tumor immunity is unknown. We show here that malignant human ovarian epithelial tumor cells express very high levels of stromal-derived factor-1, which induces DC2 precursor (preDC2) chemotaxis and adhesion/transmigration, upregulates preDC2 very late antigen (VLA)-5, and protects preDC2s from tumor macrophage interleukin-10-induced apoptosis, all through CXC chemokine receptor-4. The VLA-5 ligand vascular-cell adhesion molecule-1 mediated preDC2 adhesion/transmigration. Tumor preDC2s induced significant T-cell interleukin-10 unrelated to preDC2 differentiation or activation state, and this contributed to poor T-cell activation. Myeloid precursor DCs (preDC1s) were not detected. Tumors may weaken immunity by attracting preDC2s and protecting them from the harsh microenvironment, and by altering preDC1 distribution.", + "TAG_DATA": [ + "43, human {'context': 'I-transformed cells'}", + "44, ovarian {'context': 'I-transformed cells'}", + "45, epithelial {'context': 'I-transformed cells'}", + "46, tumor {'context': 'I-transformed cells'}", + "47, cells {'context': 'I-transformed cells'}", + "56, induces {'effect': 'B-positive'}", + "57, DC2 {'context': 'B-cells'}", + "70, protects {'effect': 'B-negative'}", + "71, preDC2s {'context': 'B-cells'}", + "72, from {'effect': 'I-negative'}", + "75, interleukin-10-induced {'effect': 'B-positive'}", + "76, apoptosis, {'phenotype': 'B-apoptosis'}", + "91, Tumor {'context': 'B-neoplasm'}", + "109, T-cell {'context': 'B-cells'}", + "111, Myeloid {'context': 'B-cells'}", + "112, precursor {'context': 'I-cells'}", + "113, DCs {'context': 'I-cells'}", + "114, (preDC1s) {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "43, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "44, ovarian ['l0', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22']", + "45, epithelial ['l1', 'l12', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32']", + "46, tumor ['l2', 'l13', 'l23', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "47, cells ['l3', 'l14', 'l24', 'l33', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "56, induces ['l4', 'l15', 'l25', 'l34', 'l42', 'l50', 'l51', 'l52']", + "57, DC2 ['l5', 'l16', 'l26', 'l35', 'l43', 'l50', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58']", + "58, precursor ['l6', 'l17', 'l27', 'l36', 'l44', 'l51', 'l53', 'l59', 'l60', 'l61']", + "70, protects ['l7', 'l18', 'l28', 'l37', 'l45', 'l52', 'l54', 'l59', 'l62', 'l63', 'l64', 'l65']", + "71, preDC2s ['l8', 'l19', 'l29', 'l38', 'l46', 'l55', 'l60', 'l62', 'l66', 'l67', 'l68']", + "72, from ['l9', 'l20', 'l30', 'l39', 'l47', 'l56', 'l61', 'l63', 'l66', 'l69', 'l70']", + "75, interleukin-10-induced ['l10', 'l21', 'l31', 'l40', 'l48', 'l57', 'l64', 'l67', 'l69', 'l71']", + "76, apoptosis, ['l11', 'l22', 'l32', 'l41', 'l49', 'l58', 'l65', 'l68', 'l70', 'l71']", + "91, Tumor ['l72']", + "109, T-cell ['l72', 'l73']", + "111, Myeloid ['l74', 'l75', 'l76']", + "112, precursor ['l74', 'l77', 'l78']", + "113, DCs ['l73', 'l75', 'l77', 'l79']", + "114, (preDC1s) ['l76', 'l78', 'l79']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "ovarian", + "epithelial", + "tumor", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces", + "interleukin-10-induced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "ovarian", + "epithelial", + "tumor", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protects", + "from" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "ovarian", + "epithelial", + "tumor", + "cells" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "interleukin-10-induced" + ] + }, + "context": { + "val": "cells", + "words": [ + "DC2", + "preDC2s" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "DC2", + "preDC2s" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protects", + "from" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "DC2", + "preDC2s" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "protects", + "from" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "interleukin-10-induced" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis," + ] + } + } + ] + }, + { + "PMID": "11726970", + "TEXT": "While searching for alternative reading-frame peptides encoded by influenza A virus that are recognized by CD8+ T cells, we found an abundant immunogenic peptide encoded by the +1 reading frame of PB1. This peptide derives from a novel conserved 87-residue protein, PB1-F2, which has several unusual features compared with other influenza gene products in addition to its mode of translation. These include its absence from some animal (particularly swine) influenza virus isolates, variable expression in individual infected cells, rapid proteasome-dependent degradation and mitochondrial localization. Exposure of cells to a synthetic version of PB1-F2 induces apoptosis, and influenza viruses with targeted mutations that interfere with PB1-F2 expression induce less extensive apoptosis in human monocytic cells than those with intact PB1-F2. We propose that PB1-F2 functions to kill host immune cells responding to influenza virus infection.", + "TAG_DATA": [ + "86, cells {'context': 'B-cells'}", + "93, induces {'effect': 'B-positive'}", + "94, apoptosis, {'phenotype': 'B-apoptosis'}", + "99, targeted {'perturbing_action': 'B-other'}", + "100, mutations {'perturbing_action': 'I-other'}", + "101, that {'perturbing_action': 'I-other'}", + "102, interfere {'perturbing_action': 'I-other'}", + "103, with {'perturbing_action': 'I-other'}", + "104, PB1-F2 {'perturbing_action': 'I-other'}", + "105, expression {'perturbing_action': 'I-other'}", + "106, induce {'effect': 'B-positive'}", + "107, less {'effect': 'B-negative'}", + "109, apoptosis {'phenotype': 'B-apoptosis'}", + "111, human {'context': 'B-cells'}", + "112, monocytic {'context': 'I-cells'}", + "113, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "86, cells ['l0', 'l1']", + "93, induces ['l0', 'l2']", + "94, apoptosis, ['l1', 'l2']", + "99, targeted ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "100, mutations ['l3', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "101, that ['l4', 'l15', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "102, interfere ['l5', 'l16', 'l26', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "103, with ['l6', 'l17', 'l27', 'l36', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52']", + "104, PB1-F2 ['l7', 'l18', 'l28', 'l37', 'l45', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "105, expression ['l8', 'l19', 'l29', 'l38', 'l46', 'l53', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "106, induce ['l9', 'l20', 'l30', 'l39', 'l47', 'l54', 'l60', 'l66', 'l67', 'l68', 'l69', 'l70']", + "107, less ['l10', 'l21', 'l31', 'l40', 'l48', 'l55', 'l61', 'l66', 'l71', 'l72', 'l73', 'l74']", + "109, apoptosis ['l11', 'l22', 'l32', 'l41', 'l49', 'l56', 'l62', 'l67', 'l71', 'l75', 'l76', 'l77']", + "111, human ['l12', 'l23', 'l33', 'l42', 'l50', 'l57', 'l63', 'l68', 'l72', 'l75', 'l78', 'l79']", + "112, monocytic ['l13', 'l24', 'l34', 'l43', 'l51', 'l58', 'l64', 'l69', 'l73', 'l76', 'l78', 'l80']", + "113, cells ['l14', 'l25', 'l35', 'l44', 'l52', 'l59', 'l65', 'l70', 'l74', 'l77', 'l79', 'l80']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "cells", + "human", + "monocytic" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces", + "induce" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cells", + "human", + "monocytic" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis,", + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induces", + "induce" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis,", + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "targeted", + "mutations", + "that", + "interfere", + "with", + "PB1-F2", + "expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "targeted", + "mutations", + "that", + "interfere", + "with", + "PB1-F2", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "less" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "targeted", + "mutations", + "that", + "interfere", + "with", + "PB1-F2", + "expression" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "targeted", + "mutations", + "that", + "interfere", + "with", + "PB1-F2", + "expression" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "monocytic", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "less" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "less" + ] + }, + "context": { + "val": "cells", + "words": [ + "human", + "monocytic", + "cells" + ] + } + } + ] + }, + { + "PMID": "11726968", + "TEXT": "Inflammation involves the sequential activation of signaling pathways leading to the production of both pro- and anti-inflammatory mediators. Although much attention has focused on pro-inflammatory pathways that initiate inflammation, relatively little is known about the mechanisms that switch off inflammation and resolve the inflammatory response. The transcription factor NF-kappaB is thought to have a central role in the induction of pro-inflammatory gene expression and has attracted interest as a new target for the treatment of inflammatory disease. We show here that NF-kappaB activation in leukocytes recruited during the onset of inflammation is associated with pro-inflammatory gene expression, whereas such activation during the resolution of inflammation is associated with the expression of anti-inflammatory genes and the induction of apoptosis. Inhibition of NF-kappaB during the resolution of inflammation protracts the inflammatory response and prevents apoptosis. This suggests that NF-kappaB has an anti-inflammatory role in vivo involving the regulation of inflammatory resolution.", + "TAG_DATA": [ + "115, induction {'effect': 'B-positive'}", + "118, Inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "119, of {'perturbing_action': 'I-pharmacological inhibition'}", + "120, NF-kappaB {'perturbing_action': 'I-pharmacological inhibition'}", + "131, prevents {'effect': 'B-negative'}", + "132, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "115, induction ['l0']", + "117, apoptosis. ['l0']", + "118, Inhibition ['l1', 'l2', 'l3', 'l4']", + "119, of ['l1', 'l5', 'l6', 'l7']", + "120, NF-kappaB ['l2', 'l5', 'l8', 'l9']", + "131, prevents ['l3', 'l6', 'l8', 'l10']", + "132, apoptosis. ['l4', 'l7', 'l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "NF-kappaB" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "NF-kappaB" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "11689882", + "TEXT": "In systemic lupus erythematosus, antibodies against double-stranded DNA are a major contributor to renal disease. We have previously demonstrated that the pentapeptide Asp/Glu-Trp-Asp/Glu-Tyr-Ser/Gly is a molecular mimic of double-stranded DNA. This sequence is also present in the extracellular domain of murine and human NMDA (N-methyl-D-aspartate) receptor subunits NR2a and NR2b. Here we show that the NR2 receptor is recognized by both murine and human anti-DNA antibodies. Moreover, anti-DNA antibodies with this cross-reactivity mediate apoptotic death of neurons in vivo and in vitro. Finally, we show that the cerebrospinal fluid of a patient with systemic lupus erythematosus contains these antibodies and also mediates neuronal death via an apoptotic pathway. These observations indicate that lupus antibodies cross-react with DNA and NMDA receptors, gain access to cerebrospinal fluid and may mediate non-thrombotic and non-vasculitic abnormalities of the central nervous system.", + "TAG_DATA": [ + "72, mediate {'effect': 'B-regulates'}", + "73, apoptotic {'phenotype': 'B-apoptosis'}", + "74, death {'phenotype': 'I-apoptosis'}", + "76, neurons {'context': 'B-cells'}", + "77, in {'context': 'B-in vivo'}", + "78, vivo {'context': 'I-in vivo'}", + "80, in {'context': 'B-in vitro'}", + "81, vitro. {'context': 'I-in vitro'}" + ], + "LINK_DATA": [ + "72, mediate ['l0', 'l1', 'l2', 'l3', 'l4']", + "73, apoptotic ['l0', 'l5', 'l6', 'l7', 'l8']", + "74, death ['l1', 'l5', 'l9', 'l10', 'l11']", + "76, neurons ['l2', 'l6', 'l9', 'l12', 'l13']", + "77, in ['l3', 'l7', 'l10', 'l12', 'l14']", + "78, vivo ['l4', 'l8', 'l11', 'l13', 'l14']", + "80, in ['l15']", + "81, vitro. ['l15']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "regulates", + "words": [ + "mediate" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "mediate" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "mediate" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + } + ] + }, + { + "PMID": "11533708", + "TEXT": "Cyclooxygenase-2 (COX-2), a key enzyme in arachidonic acid metabolism, is overexpressed in many cancers. Inhibition of COX-2 by nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of cancer development in humans and suppresses tumor growth in animal models. The anti-cancer effect of NSAIDs seems to involve suppression of tumor angiogenesis, but the underlying mechanism is not completely understood. Integrin alpha V beta 3 is an adhesion receptor critically involved in mediating tumor angiogenesis. Here we show that inhibition of endothelial-cell COX-2 by NSAIDs suppresses alpha V beta 3-dependent activation of the small GTPases Cdc42 and Rac, resulting in inhibition of endothelial-cell spreading and migration in vitro and suppression of fibroblast growth factor-2-induced angiogenesis in vivo. These results establish a novel functional link between COX-2, integrin alpha V beta 3 and Cdc42-/Rac-dependent endothelial-cell migration. Moreover, they provide a rationale to the understanding of the anti-angiogenic activity of NSAIDs.", + "TAG_DATA": [ + "76, inhibition {'perturbing_action': 'B-pharmacological inhibition'}", + "77, of {'perturbing_action': 'I-pharmacological inhibition'}", + "78, endothelial-cell {'perturbing_action': 'I-pharmacological inhibition'}", + "79, COX-2 {'perturbing_action': 'I-pharmacological inhibition'}", + "80, by {'perturbing_action': 'I-pharmacological inhibition'}", + "81, NSAIDs {'perturbing_action': 'I-pharmacological inhibition'}", + "97, inhibition {'effect': 'B-negative'}", + "99, endothelial-cell {'context': 'B-cells'}", + "102, migration {'phenotype': 'B-migration'}", + "103, in {'context': 'B-in vitro'}", + "104, vitro {'context': 'I-in vitro'}", + "112, in {'context': 'B-in vivo'}", + "113, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "76, inhibition ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "77, of ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "78, endothelial-cell ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "79, COX-2 ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "80, by ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "81, NSAIDs ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "97, inhibition ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "99, endothelial-cell ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "102, migration ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "103, in ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "104, vitro ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "112, in ['l55']", + "113, vivo. ['l55']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "endothelial-cell", + "COX-2", + "by", + "NSAIDs" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "endothelial-cell", + "COX-2", + "by", + "NSAIDs" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial-cell" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "endothelial-cell", + "COX-2", + "by", + "NSAIDs" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "endothelial-cell", + "COX-2", + "by", + "NSAIDs" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "cells", + "words": [ + "endothelial-cell" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "endothelial-cell" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "11385513", + "TEXT": "Long-term solid-organ allografts typically develop diffuse arterial intimal lesions (graft arterial disease; GAD), consisting of smooth-muscle cells (SMC), extracellular matrix and admixed mononuclear leukocytes. GAD eventually culminates in vascular stenosis and ischemic graft failure. Although the exact mechanisms are unknown, chronic low-level alloresponses likely induce inflammatory cells and/or dysfunctional vascular wall cells to secrete growth factors that promote SMC intimal recruitment, proliferation and matrix synthesis. Although prior work demonstrated that the endothelium and medial SMCs lining GAD lesions in cardiac allografts are donor-derived, the intimal SMC origin could not be determined. They are generally presumed to originate from the donor media, leading to interventions that target donor medial SMC proliferation, with limited efficacy. However, other reports indicate that allograft vessels may contain host-derived endothelium and SMCs (refs. 8,9). Moreover, subpopulations of bone-marrow and circulating cells can differentiate into endothelium, and implanted synthetic vascular grafts are seeded by host SMCs and endothelium. Here we used murine aortic transplants to formally identify the source of SMCs in GAD lesions. Allografts in beta-galactosidase transgenic recipients showed that intimal SMCs derived almost exclusively from host cells. Bone-marrow transplantation of beta-galactosidase--expressing cells into aortic allograft recipients demonstrated that intimal cells included those of marrow origin. Thus, smooth-muscle--like cells in GAD lesions can originate from circulating bone--marrow-derived precursors.", + "TAG_DATA": [ + "154, murine {'context': 'B-organism'}", + "155, aortic {'context': 'I-xenograft'}", + "156, transplants {'context': 'I-xenograft'}", + "167, Allografts {'context': 'B-xenograft'}", + "169, beta-galactosidase {'perturbing_action': 'B-gene gain-of-function'}", + "170, transgenic {'perturbing_action': 'I-gene gain-of-function'}", + "174, intimal {'context': 'B-cells'}", + "175, SMCs {'context': 'I-cells'}", + "188, aortic {'context': 'B-xenograft'}", + "189, allograft {'context': 'I-xenograft'}", + "190, recipients {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "154, murine ['l0', 'l1']", + "155, aortic ['l0', 'l2']", + "156, transplants ['l1', 'l2']", + "167, Allografts ['l3', 'l4', 'l5', 'l6', 'l7']", + "169, beta-galactosidase ['l3', 'l8', 'l9', 'l10', 'l11']", + "170, transgenic ['l4', 'l8', 'l12', 'l13', 'l14']", + "171, recipients ['l5', 'l9', 'l12', 'l15', 'l16']", + "174, intimal ['l6', 'l10', 'l13', 'l15', 'l17']", + "175, SMCs ['l7', 'l11', 'l14', 'l16', 'l17']", + "188, aortic ['l18', 'l19']", + "189, allograft ['l18', 'l20']", + "190, recipients ['l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "xenograft", + "words": [ + "Allografts" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "beta-galactosidase", + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "beta-galactosidase", + "transgenic" + ] + }, + "context": { + "val": "cells", + "words": [ + "intimal", + "SMCs" + ] + } + } + ] + }, + { + "PMID": "11385507", + "TEXT": "The adipocyte fatty-acid-binding protein, aP2, has an important role in regulating systemic insulin resistance and lipid metabolism. Here we demonstrate that aP2 is also expressed in macrophages, has a significant role in their biological responses and contributes to the development of atherosclerosis. Apolipoprotein E (ApoE)-deficient mice also deficient for aP2 showed protection from atherosclerosis in the absence of significant differences in serum lipids or insulin sensitivity. aP2-deficient macrophages showed alterations in inflammatory cytokine production and a reduced ability to accumulate cholesterol esters when exposed to modified lipoproteins. Apoe-/- mice with Ap2+/+ adipocytes and Ap2-/- macrophages generated by bone-marrow transplantation showed a comparable reduction in atherosclerotic lesions to those with total aP2 deficiency, indicating an independent role for macrophage aP2 in atherogenesis. Through its distinct actions in adipocytes and macrophages, aP2 provides a link between features of the metabolic syndrome and could be a new therapeutic target for the prevention of atherosclerosis.", + "TAG_DATA": [ + "42, Apolipoprotein {'perturbing_action': 'B-gene loss-of-function'}", + "43, E {'perturbing_action': 'I-gene loss-of-function'}", + "44, (ApoE)-deficient {'perturbing_action': 'I-gene loss-of-function'}", + "45, mice {'context': 'B-organism'}", + "47, deficient {'perturbing_action': 'B-gene loss-of-function'}", + "48, for {'perturbing_action': 'I-gene loss-of-function'}", + "49, aP2 {'perturbing_action': 'I-gene loss-of-function'}", + "51, protection {'effect': 'B-negative'}", + "66, aP2-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "67, macrophages {'context': 'B-cells'}", + "87, Apoe-/- {'perturbing_action': 'B-gene loss-of-function'}", + "88, mice {'context': 'B-organism'}", + "90, Ap2+/+ {'context': 'B-cells'}", + "91, adipocytes {'context': 'I-cells'}", + "93, Ap2-/- {'perturbing_action': 'B-gene loss-of-function'}", + "94, macrophages {'context': 'B-cells'}", + "109, total {'perturbing_action': 'B-gene loss-of-function'}", + "110, aP2 {'perturbing_action': 'I-gene loss-of-function'}", + "111, deficiency, {'perturbing_action': 'I-gene loss-of-function'}" + ], + "LINK_DATA": [ + "42, Apolipoprotein ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "43, E ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "44, (ApoE)-deficient ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "45, mice ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27']", + "47, deficient ['l3', 'l11', 'l18', 'l24', 'l28', 'l29', 'l30', 'l31', 'l32']", + "48, for ['l4', 'l12', 'l19', 'l25', 'l28', 'l33', 'l34', 'l35', 'l36']", + "49, aP2 ['l5', 'l13', 'l20', 'l26', 'l29', 'l33', 'l37', 'l38', 'l39']", + "51, protection ['l6', 'l14', 'l21', 'l27', 'l30', 'l34', 'l37']", + "66, aP2-deficient ['l7', 'l15', 'l22', 'l31', 'l35', 'l38', 'l40']", + "67, macrophages ['l8', 'l16', 'l23', 'l32', 'l36', 'l39', 'l40']", + "87, Apoe-/- ['l41', 'l42', 'l43']", + "88, mice ['l41', 'l44', 'l45']", + "90, Ap2+/+ ['l42', 'l44', 'l46']", + "91, adipocytes ['l43', 'l45', 'l46']", + "93, Ap2-/- ['l47', 'l48', 'l49', 'l50']", + "94, macrophages ['l47', 'l51', 'l52', 'l53']", + "109, total ['l48', 'l51', 'l54', 'l55']", + "110, aP2 ['l49', 'l52', 'l54', 'l56']", + "111, deficiency, ['l50', 'l53', 'l55', 'l56']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apolipoprotein", + "E", + "(ApoE)-deficient", + "deficient", + "for", + "aP2", + "Apoe-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apolipoprotein", + "E", + "(ApoE)-deficient", + "deficient", + "for", + "aP2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protection" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apolipoprotein", + "E", + "(ApoE)-deficient", + "deficient", + "for", + "aP2", + "aP2-deficient", + "Apoe-/-", + "Ap2-/-", + "total", + "deficiency," + ] + }, + "context": { + "val": "cells", + "words": [ + "macrophages", + "Ap2+/+", + "adipocytes" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protection" + ] + } + } + ] + }, + { + "PMID": "11385504", + "TEXT": "The therapeutic and preventive activities of retinoids in cancer are due to their ability to modulate the growth, differentiation, and survival or apoptosis of cancer cells. Here we show that in NB4 acute promyelocytic leukemia cells, retinoids selective for retinoic-acid receptor-alpha induced an autoregulatory circuitry of survival programs followed by expression of the membrane-bound tumor-selective death ligand, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand, also called Apo-2L). In a paracrine mode of action, TRAIL killed NB4 as well as heterologous and retinoic-acid-resistant cells. In the leukemic blasts of freshly diagnosed acute promyelocytic leukemia patients, retinoic-acid-induced expression of TRAIL most likely caused blast apoptosis. Thus, induction of TRAIL-mediated death signaling appears to contribute to the therapeutic value of retinoids.", + "TAG_DATA": [ + "31, NB4 {'context': 'B-transformed cells'}", + "32, acute {'context': 'I-transformed cells'}", + "33, promyelocytic {'context': 'I-transformed cells'}", + "34, leukemia {'context': 'I-transformed cells'}", + "35, cells, {'context': 'I-transformed cells'}", + "74, NB4 {'context': 'B-transformed cells'}", + "84, leukemic {'context': 'B-transformed cells'}", + "85, blasts {'context': 'I-transformed cells'}", + "99, caused {'effect': 'B-positive'}", + "100, blast {'context': 'B-cells'}", + "101, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "31, NB4 ['l0', 'l1', 'l2', 'l3']", + "32, acute ['l0', 'l4', 'l5', 'l6']", + "33, promyelocytic ['l1', 'l4', 'l7', 'l8']", + "34, leukemia ['l2', 'l5', 'l7', 'l9']", + "35, cells, ['l3', 'l6', 'l8', 'l9']", + "84, leukemic ['l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "85, blasts ['l10', 'l16', 'l17', 'l18', 'l19', 'l20']", + "91, leukemia ['l11', 'l16', 'l21', 'l22', 'l23', 'l24']", + "92, patients, ['l12', 'l17', 'l21', 'l25', 'l26', 'l27']", + "99, caused ['l13', 'l18', 'l22', 'l25', 'l28', 'l29']", + "100, blast ['l14', 'l19', 'l23', 'l26', 'l28', 'l30']", + "101, apoptosis. ['l15', 'l20', 'l24', 'l27', 'l29', 'l30']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "transformed cells", + "words": [ + "leukemic", + "blasts" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "leukemic", + "blasts" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "context": { + "val": "cells", + "words": [ + "blast" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "caused" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "blast" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "11283677", + "TEXT": "Following peripheral exposure to transmissible spongiform encephalopathies (TSEs), infectivity usually accumulates in lymphoid tissues before neuroinvasion. The host prion protein (PrPc) is critical for TSE agent replication and accumulates as an abnormal, detergent insoluble, relatively proteinase-resistant isoform (PrPSc) in diseased tissues. Early PrPSc accumulation takes place on follicular dendritic cells (FDCs) within germinal centers in lymphoid tissues of patients with variant Creutzfeldt-Jakob disease (vCJD), sheep with natural scrapie or rodents following experimental peripheral infection with scrapie. In mouse scrapie models, the absence of FDCs blocks scrapie replication and PrPSc accumulation in the spleen, and neuroinvasion is significantly impaired. The mechanisms by which the TSE agent initially localizes to lymphoid follicles and interacts with FDCs are unknown. Antigens are trapped and retained on the surface of FDCs through interactions between complement and cellular complement receptors. Here we show that in mice, both temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays the onset of disease following peripheral infection, and reduces the early accumulation of PrPSc in the spleen. Thus, in the early stages of infection, C3 and perhaps C1q contribute to the localization of TSE infectivity in lymphoid tissue and may be therapeutic targets.", + "TAG_DATA": [ + "83, FDCs {'context': 'B-cells'}", + "92, spleen, {'context': 'B-tissue/organ'}", + "139, mice, {'context': 'B-organism'}", + "141, temporary {'perturbing_action': 'B-gene loss-of-function'}", + "142, depletion {'perturbing_action': 'I-gene loss-of-function'}", + "143, of {'perturbing_action': 'I-gene loss-of-function'}", + "144, complement {'perturbing_action': 'I-gene loss-of-function'}", + "145, component {'perturbing_action': 'I-gene loss-of-function'}", + "146, C3 {'perturbing_action': 'I-gene loss-of-function'}", + "148, genetic {'perturbing_action': 'B-gene loss-of-function'}", + "149, deficiency {'perturbing_action': 'I-gene loss-of-function'}", + "150, of {'perturbing_action': 'I-gene loss-of-function'}", + "151, C1q {'perturbing_action': 'I-gene loss-of-function'}", + "170, spleen. {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "83, FDCs ['l0']", + "92, spleen, ['l0']", + "139, mice, ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7']", + "141, temporary ['l1', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "142, depletion ['l2', 'l8', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "143, of ['l3', 'l9', 'l17', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "144, complement ['l4', 'l10', 'l18', 'l25', 'l31', 'l32', 'l33', 'l34']", + "145, component ['l5', 'l11', 'l19', 'l26', 'l31', 'l35', 'l36', 'l37']", + "146, C3 ['l6', 'l12', 'l20', 'l27', 'l32', 'l35', 'l38', 'l39']", + "148, genetic ['l40', 'l41', 'l42', 'l43']", + "149, deficiency ['l13', 'l21', 'l40', 'l44', 'l45', 'l46']", + "150, of ['l14', 'l22', 'l28', 'l41', 'l44', 'l47', 'l48']", + "151, C1q ['l15', 'l23', 'l29', 'l33', 'l36', 'l38', 'l42', 'l45', 'l47', 'l49']", + "170, spleen. ['l7', 'l16', 'l24', 'l30', 'l34', 'l37', 'l39', 'l43', 'l46', 'l48', 'l49']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice," + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "temporary", + "depletion", + "of", + "complement", + "component", + "C3" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "temporary", + "depletion", + "of", + "complement", + "component", + "C3", + "genetic", + "deficiency", + "C1q" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "spleen." + ] + } + } + ] + }, + { + "PMID": "11231633", + "TEXT": "Clusterin, also known as apolipoprotein J, is a ubiquitously expressed molecule thought to influence a variety of processes including cell death. In the brain, it accumulates in dying neurons following seizures and hypoxic-ischemic (H-I) injury. Despite this, in vivo evidence that clusterin directly influences cell death is lacking. Following neonatal H-I brain injury in mice (a model of cerebral palsy), there was evidence of apoptotic changes (neuronal caspase-3 activation), as well as accumulation of clusterin in dying neurons. Clusterin-deficient mice had 50% less brain injury following neonatal H-I. Surprisingly, the absence of clusterin had no effect on caspase-3 activation, and clusterin accumulation and caspase-3 activation did not colocalize to the same cells. Studies with cultured cortical neurons demonstrated that exogenous purified astrocyte-secreted clusterin exacerbated oxygen/glucose-deprivation-induced necrotic death. These results indicate that clusterin may be a new therapeutic target to modulate non-caspase-dependent neuronal death following acute brain injury.", + "TAG_DATA": [ + "54, mice {'context': 'B-organism'}", + "77, neurons. {'context': 'B-cells'}", + "78, Clusterin-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "79, mice {'context': 'B-organism'}", + "90, absence {'perturbing_action': 'B-gene loss-of-function'}", + "91, of {'perturbing_action': 'I-gene loss-of-function'}", + "92, clusterin {'perturbing_action': 'I-gene loss-of-function'}", + "111, cells. {'context': 'B-cells'}", + "114, cultured {'context': 'B-cells'}", + "115, cortical {'context': 'I-cells'}", + "116, neurons {'context': 'I-cells'}", + "123, exacerbated {'effect': 'B-positive'}", + "125, necrotic {'phenotype': 'B-necrosis'}", + "126, death. {'phenotype': 'I-necrosis'}" + ], + "LINK_DATA": [ + "54, mice ['l0']", + "77, neurons. ['l0']", + "78, Clusterin-deficient ['l1']", + "79, mice ['l1']", + "90, absence ['l2', 'l3', 'l4']", + "91, of ['l2', 'l5', 'l6']", + "92, clusterin ['l3', 'l5', 'l7']", + "111, cells. ['l4', 'l6', 'l7']", + "114, cultured ['l8', 'l9', 'l10', 'l11', 'l12']", + "115, cortical ['l8', 'l13', 'l14', 'l15', 'l16']", + "116, neurons ['l9', 'l13', 'l17', 'l18', 'l19']", + "123, exacerbated ['l10', 'l14', 'l17', 'l20', 'l21']", + "125, necrotic ['l11', 'l15', 'l18', 'l20', 'l22']", + "126, death. ['l12', 'l16', 'l19', 'l21', 'l22']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Clusterin-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "clusterin" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "cortical", + "neurons" + ] + }, + "effect": { + "val": "positive", + "words": [ + "exacerbated" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "cortical", + "neurons" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrotic", + "death." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "exacerbated" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrotic", + "death." + ] + } + } + ] + }, + { + "PMID": "11231629", + "TEXT": "Metachromatic leukodystrophy (MLD) is a lipidosis caused by deficiency of arylsulfatase A (ARSA). Although the genetics of MLD are known, its pathophysiology is not understood. The disease leads to progressive demyelination and early death and no effective treatment is available. We used lentiviral vectors to deliver a functional ARSA gene (human ARSA) into the brain of adult mice with germ-line inactivation of the mouse gene encoding ARSA, As2. We report sustained expression of active enzyme throughout a large portion of the brain, with long-term protection from development of neuropathology and hippocampal-related learning impairments. We show that selective degeneration of hippocampal neurons is a central step in disease pathogenesis, and provide evidence that in vivo transfer of ARSA by lentiviral vectors reverts the disease phenotype in all investigated areas. Therefore, in vivo gene therapy offers a unique option for MLD and other storage diseases affecting the central nervous system.", + "TAG_DATA": [ + "56, adult {'context': 'B-organism'}", + "57, mice {'context': 'I-organism'}", + "59, germ-line {'perturbing_action': 'B-gene loss-of-function'}", + "60, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "61, of {'perturbing_action': 'I-gene loss-of-function'}", + "62, the {'perturbing_action': 'I-gene loss-of-function'}", + "63, mouse {'perturbing_action': 'I-gene loss-of-function'}", + "64, gene {'perturbing_action': 'I-gene loss-of-function'}", + "65, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "66, ARSA, {'perturbing_action': 'I-gene loss-of-function'}", + "67, As2. {'perturbing_action': 'I-gene loss-of-function'}", + "99, hippocampal {'context': 'B-cells'}", + "100, neurons {'context': 'I-cells'}", + "112, in {'context': 'B-in vivo'}", + "113, vivo {'context': 'B-in vivo'}" + ], + "LINK_DATA": [ + "56, adult ['l0', 'l1']", + "57, mice ['l0', 'l2']", + "59, germ-line ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11']", + "60, inactivation ['l3', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "61, of ['l4', 'l12', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "62, the ['l5', 'l13', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "63, mouse ['l6', 'l14', 'l20', 'l26', 'l32', 'l33', 'l34', 'l35', 'l36']", + "64, gene ['l7', 'l15', 'l21', 'l27', 'l32', 'l37', 'l38', 'l39', 'l40']", + "65, encoding ['l8', 'l16', 'l22', 'l28', 'l33', 'l37', 'l41', 'l42', 'l43']", + "66, ARSA, ['l9', 'l17', 'l23', 'l29', 'l34', 'l38', 'l41', 'l44', 'l45']", + "67, As2. ['l1', 'l2', 'l10', 'l18', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44']", + "99, hippocampal ['l46']", + "100, neurons ['l11', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l46']", + "112, in ['l47']", + "113, vivo ['l47']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "adult", + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "As2." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "germ-line", + "of", + "the", + "mouse", + "gene", + "encoding", + "ARSA," + ] + }, + "context": { + "val": "cells", + "words": [ + "neurons" + ] + } + } + ] + }, + { + "PMID": "11175853", + "TEXT": "The growth arrest-specific gene 6 product (Gas6) is a secreted protein related to the anticoagulant protein S but its role in hemostasis is unknown. Here we show that inactivation of the Gas6 gene prevented venous and arterial thrombosis in mice, and protected against fatal collagen/epinephrine-induced thrombo embolism. Gas6-/- mice did not, however, suffer spontaneous bleeding and had normal bleeding after tail clipping. In addition, we found that Gas6 antibodies inhibited platelet aggregation in vitro and protected mice against fatal thrombo embolism without causing bleeding in vivo. Gas6 amplified platelet aggregation and secretion in response to known agonists. Platelet dysfunction in Gas6-/- mice resembled that of patients with platelet signaling transduction defects. Thus, Gas6 is a platelet-response amplifier that plays a significant role in thrombosis. These findings warrant further evaluation of the possible therapeutic use of Gas6 inhibition for prevention of thrombosis.", + "TAG_DATA": [ + "28, inactivation {'perturbing_action': 'B-gene loss-of-function'}", + "29, of {'perturbing_action': 'I-gene loss-of-function'}", + "30, the {'perturbing_action': 'I-gene loss-of-function'}", + "31, Gas6 {'perturbing_action': 'I-gene loss-of-function'}", + "32, gene {'perturbing_action': 'I-gene loss-of-function'}", + "39, mice, {'context': 'B-organism'}", + "47, Gas6-/- {'perturbing_action': 'B-gene loss-of-function'}", + "48, mice {'context': 'B-organism'}", + "70, platelet {'context': 'B-cells'}", + "72, in {'context': 'B-in vitro'}", + "73, vitro {'context': 'I-in vitro'}", + "76, mice {'context': 'B-organism'}", + "84, in {'context': 'B-in vivo'}", + "85, vivo. {'context': 'I-in vivo'}", + "88, platelet {'context': 'B-cells'}", + "100, Gas6-/- {'perturbing_action': 'B-gene loss-of-function'}", + "101, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "28, inactivation ['l0', 'l1', 'l2', 'l3', 'l4']", + "29, of ['l0', 'l5', 'l6', 'l7', 'l8']", + "30, the ['l1', 'l5', 'l9', 'l10', 'l11']", + "31, Gas6 ['l2', 'l6', 'l9', 'l12', 'l13']", + "32, gene ['l3', 'l7', 'l10', 'l12', 'l14']", + "39, mice, ['l4', 'l8', 'l11', 'l13', 'l14']", + "47, Gas6-/- ['l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "48, mice ['l15', 'l22', 'l23', 'l24', 'l25']", + "70, platelet ['l16', 'l22', 'l26', 'l27', 'l28', 'l29']", + "72, in ['l17', 'l23', 'l26', 'l30', 'l31']", + "73, vitro ['l18', 'l24', 'l27', 'l30', 'l32']", + "76, mice ['l19', 'l25', 'l28', 'l31', 'l32', 'l33']", + "84, in ['l20', 'l34']", + "85, vivo. ['l21', 'l29', 'l33', 'l34']", + "100, Gas6-/- ['l35']", + "101, mice ['l35']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "the", + "Gas6", + "gene", + "Gas6-/-" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice,", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gas6-/-" + ] + }, + "context": { + "val": "cells", + "words": [ + "platelet" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gas6-/-" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gas6-/-" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "11175850", + "TEXT": "Metastasis of breast cancer occurs primarily through the lymphatic system, and the extent of lymph node involvement is a key prognostic factor for the disease. Whereas the significance of angiogenesis for tumor progression has been well documented, the ability of tumor cells to induce the growth of lymphatic vessels (lymphangiogenesis) and the presence of intratumoral lymphatic vessels have been controversial. Using a novel marker for lymphatic endothelium, LYVE-1, we demonstrate here the occurrence of intratumoral lymphangiogenesis within human breast cancers after orthotopic transplantation onto nude mice. Vascular endothelial growth factor (VEGF)-C overexpression in breast cancer cells potently increased intratumoral lymphangiogenesis, resulting in significantly enhanced metastasis to regional lymph nodes and to lungs. The degree of tumor lymphangiogenesis was highly correlated with the extent of lymph node and lung metastases. These results establish the occurrence and biological significance of intratumoral lymphangiogenesis in breast cancer and identify VEGF-C as a molecular link between tumor lymphangiogenesis and metastasis.", + "TAG_DATA": [ + "77, human {'context': 'B-neoplasm'}", + "78, breast {'context': 'I-neoplasm'}", + "79, cancers {'context': 'I-neoplasm'}", + "84, nude {'context': 'B-organism'}", + "85, mice. {'context': 'I-organism'}", + "86, Vascular {'perturbing_action': 'B-gene gain-of-function'}", + "87, endothelial {'perturbing_action': 'I-gene gain-of-function'}", + "88, growth {'perturbing_action': 'I-gene gain-of-function'}", + "89, factor {'perturbing_action': 'I-gene gain-of-function'}", + "90, (VEGF)-C {'perturbing_action': 'I-gene gain-of-function'}", + "91, overexpression {'perturbing_action': 'I-gene gain-of-function'}", + "93, breast {'context': 'B-transformed cells'}", + "94, cancer {'context': 'I-transformed cells'}", + "95, cells {'context': 'I-transformed cells'}", + "103, enhanced {'effect': 'B-positive'}", + "104, metastasis {'phenotype': 'B-metastasis'}", + "107, lymph {'phenotype': 'I-metastasis'}", + "108, nodes {'phenotype': 'I-metastasis'}" + ], + "LINK_DATA": [ + "77, human ['l0', 'l1', 'l2', 'l3']", + "78, breast ['l0', 'l4', 'l5', 'l6']", + "79, cancers ['l1', 'l4', 'l7', 'l8']", + "84, nude ['l2', 'l5', 'l7', 'l9']", + "85, mice. ['l3', 'l6', 'l8', 'l9']", + "86, Vascular ['l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "87, endothelial ['l10', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "88, growth ['l11', 'l24', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "89, factor ['l12', 'l25', 'l37', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "90, (VEGF)-C ['l13', 'l26', 'l38', 'l49', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "91, overexpression ['l14', 'l27', 'l39', 'l50', 'l60', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78']", + "93, breast ['l15', 'l28', 'l40', 'l51', 'l61', 'l70', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "94, cancer ['l16', 'l29', 'l41', 'l52', 'l62', 'l71', 'l79', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93']", + "95, cells ['l17', 'l30', 'l42', 'l53', 'l63', 'l72', 'l80', 'l87', 'l94', 'l95', 'l96', 'l97', 'l98']", + "103, enhanced ['l18', 'l31', 'l43', 'l54', 'l64', 'l73', 'l81', 'l88', 'l94', 'l99', 'l100', 'l101', 'l102', 'l103']", + "104, metastasis ['l19', 'l32', 'l44', 'l55', 'l65', 'l74', 'l82', 'l89', 'l95', 'l99', 'l104', 'l105', 'l106', 'l107']", + "106, regional ['l20', 'l33', 'l45', 'l56', 'l66', 'l75', 'l83', 'l90', 'l96', 'l100', 'l104', 'l108', 'l109', 'l110']", + "107, lymph ['l21', 'l34', 'l46', 'l57', 'l67', 'l76', 'l84', 'l91', 'l97', 'l101', 'l105', 'l108', 'l111', 'l112']", + "108, nodes ['l22', 'l35', 'l47', 'l58', 'l68', 'l77', 'l85', 'l92', 'l98', 'l102', 'l106', 'l109', 'l111', 'l113']", + "111, lungs. ['l23', 'l36', 'l48', 'l59', 'l69', 'l78', 'l86', 'l93', 'l103', 'l107', 'l110', 'l112', 'l113']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Vascular", + "endothelial", + "growth", + "factor", + "(VEGF)-C", + "overexpression" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "breast", + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Vascular", + "endothelial", + "growth", + "factor", + "(VEGF)-C", + "overexpression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Vascular", + "endothelial", + "growth", + "factor", + "(VEGF)-C", + "overexpression" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "lymph", + "nodes" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "breast", + "cancer", + "cells" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "breast", + "cancer", + "cells" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "lymph", + "nodes" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastasis", + "lymph", + "nodes" + ] + } + } + ] + }, + { + "PMID": "11135624", + "TEXT": "Diabetic patients frequently suffer from retinopathy, nephropathy, neuropathy and accelerated atherosclerosis. The loss of endothelial function precedes these vascular alterations. Here we report that activation of poly(ADP-ribose) polymerase (PARP) is an important factor in the pathogenesis of endothelial dysfunction in diabetes. Destruction of islet cells with streptozotocin in mice induced hyperglycemia, intravascular oxidant production, DNA strand breakage, PARP activation and a selective loss of endothelium-dependent vasodilation. Treatment with a novel potent PARP inhibitor, starting after the time of islet destruction, maintained normal vascular responsiveness, despite the persistence of severe hyperglycemia. Endothelial cells incubated in high glucose exhibited production of reactive nitrogen and oxygen species, consequent single-strand DNA breakage, PARP activation and associated metabolic and functional impairment. Basal and high-glucose-induced nuclear factor-kappaB activation were suppressed in the PARP-deficient cells. Our results indicate that PARP may be a novel drug target for the therapy of diabetic endothelial dysfunction.", + "TAG_DATA": [ + "43, islet {'context': 'B-cells'}", + "44, cells {'context': 'I-cells'}", + "48, mice {'context': 'B-organism'}", + "90, Endothelial {'context': 'B-cells'}", + "91, cells {'context': 'I-cells'}", + "126, PARP-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "127, cells. {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "43, islet ['l0', 'l1']", + "44, cells ['l0', 'l2']", + "48, mice ['l1', 'l2']", + "90, Endothelial ['l3']", + "91, cells ['l3']", + "126, PARP-deficient ['l4']", + "127, cells. ['l4']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PARP-deficient" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "11100117", + "TEXT": "Chronic hypoxia, a hallmark of many tumors, is associated with angiogenesis and tumor progression. Strategies to treat tumors have been developed in which tumor cells are targeted with drugs or gene-therapy vectors specifically activated under hypoxic conditions. Here we report a different approach, in which the normal transcriptional response to hypoxia is selectively disrupted. Our data indicate that specific blockade of the interaction of hypoxia-inducible factor with the CH1 domain of its p300 and CREB binding protein transcriptional coactivators leads to attenuation of hypoxia-inducible gene expression and diminution of tumor growth. Thus, disrupting the normal co-activational response to hypoxia may be a new and useful therapeutic strategy.", + "TAG_DATA": [ + "87, diminution {'effect': 'B-negative'}", + "89, tumor {'phenotype': 'B-tumour growth'}", + "90, growth. {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "87, diminution ['l0', 'l1']", + "89, tumor ['l0', 'l2']", + "90, growth. ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "diminution" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth." + ] + } + } + ] + }, + { + "PMID": "11062543", + "TEXT": "Mesenchymal stem cells are multipotent cells that can be isolated from adult bone marrow and can be induced in vitro and in vivo to differentiate into a variety of mesenchymal tissues, including bone, cartilage, tendon, fat, bone marrow stroma, and muscle. Despite their potential clinical utility for cellular and gene therapy, the fate of mesenchymal stem cells after systemic administration is mostly unknown. To address this, we transplanted a well-characterized human mesenchymal stem cell population into fetal sheep early in gestation, before and after the expected development of immunologic competence. In this xenogeneic system, human mesenchymal stem cells engrafted and persisted in multiple tissues for as long as 13 months after transplantation. Transplanted human cells underwent site-specific differentiation into chondrocytes, adipocytes, myocytes and cardiomyocytes, bone marrow stromal cells and thymic stroma. Unexpectedly, there was long-term engraftment even when cells were transplanted after the expected development of immunocompetence. Thus, mesenchymal stem cells maintain their multipotential capacity after transplantation, and seem to have unique immunologic characteristics that allow persistence in a xenogeneic environment. Our data support the possibility of the transplantability of mesenchymal stem cells and their potential utility in tissue engineering, and cellular and gene therapy applications.", + "TAG_DATA": [ + "70, human {'context': 'B-cells'}", + "71, mesenchymal {'context': 'I-cells'}", + "72, stem {'context': 'I-cells'}", + "73, cell {'context': 'I-cells'}", + "74, population {'context': 'I-cells'}", + "76, fetal {'context': 'B-organism'}", + "77, sheep {'context': 'I-organism'}", + "94, human {'context': 'B-cells'}", + "95, mesenchymal {'context': 'I-cells'}", + "96, stem {'context': 'I-cells'}", + "97, cells {'context': 'I-cells'}", + "113, human {'context': 'B-cells'}", + "114, cells {'context': 'I-cells'}", + "115, underwent {'effect': 'B-positive'}", + "117, differentiation {'phenotype': 'B-differentiation'}", + "119, chondrocytes, {'context': 'B-cells'}", + "120, adipocytes, {'context': 'B-cells'}", + "121, myocytes {'context': 'B-cells'}", + "124, bone {'context': 'B-cells'}", + "125, marrow {'context': 'I-cells'}", + "126, stromal {'context': 'I-cells'}", + "127, cells {'context': 'I-cells'}", + "138, cells {'context': 'B-cells'}" + ], + "LINK_DATA": [ + "70, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "71, mesenchymal ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "72, stem ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "73, cell ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "74, population ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "76, fetal ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "77, sheep ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "94, human ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "95, mesenchymal ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "96, stem ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "97, cells ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "113, human ['l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "114, cells ['l55', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77']", + "115, underwent ['l56', 'l67', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87']", + "117, differentiation ['l57', 'l68', 'l78', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96']", + "119, chondrocytes, ['l58', 'l69', 'l79', 'l88', 'l97', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104']", + "120, adipocytes, ['l59', 'l70', 'l80', 'l89', 'l97', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111']", + "121, myocytes ['l60', 'l71', 'l81', 'l90', 'l98', 'l105', 'l112', 'l113', 'l114', 'l115', 'l116', 'l117']", + "124, bone ['l61', 'l72', 'l82', 'l91', 'l99', 'l106', 'l112', 'l118', 'l119', 'l120', 'l121', 'l122']", + "125, marrow ['l62', 'l73', 'l83', 'l92', 'l100', 'l107', 'l113', 'l118', 'l123', 'l124', 'l125', 'l126']", + "126, stromal ['l63', 'l74', 'l84', 'l93', 'l101', 'l108', 'l114', 'l119', 'l123', 'l127', 'l128', 'l129']", + "127, cells ['l64', 'l75', 'l85', 'l94', 'l102', 'l109', 'l115', 'l120', 'l124', 'l127', 'l130', 'l131']", + "129, thymic ['l65', 'l76', 'l86', 'l95', 'l103', 'l110', 'l116', 'l121', 'l125', 'l128', 'l130', 'l132']", + "130, stroma. ['l66', 'l77', 'l87', 'l96', 'l104', 'l111', 'l117', 'l122', 'l126', 'l129', 'l131', 'l132']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "human", + "cells", + "chondrocytes,", + "adipocytes,", + "myocytes", + "bone", + "marrow", + "stromal" + ] + }, + "effect": { + "val": "positive", + "words": [ + "underwent" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "human", + "cells", + "chondrocytes,", + "adipocytes,", + "myocytes", + "bone", + "marrow", + "stromal" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "underwent" + ] + }, + "phenotype": { + "val": "differentiation", + "words": [ + "differentiation" + ] + } + } + ] + }, + { + "PMID": "11017147", + "TEXT": "Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor with anti-microbial properties found in mucosal fluids. It is expressed during cutaneous wound healing. Impaired healing states are characterized by excessive proteolysis and often bacterial infection, leading to the hypothesis that SLPI may have a role in this process. We have generated mice null for the gene encoding SLPI (Slpi), which show impaired cutaneous wound healing with increased inflammation and elastase activity. The altered inflammatory profile involves enhanced activation of local TGF-beta in Slpi-null mice. We propose that SLPI is a pivotal endogenous factor necessary for optimal wound healing.", + "TAG_DATA": [ + "52, mice {'context': 'B-organism'}", + "53, null {'perturbing_action': 'B-gene loss-of-function'}", + "54, for {'perturbing_action': 'I-gene loss-of-function'}", + "55, the {'perturbing_action': 'I-gene loss-of-function'}", + "56, gene {'perturbing_action': 'I-gene loss-of-function'}", + "57, encoding {'perturbing_action': 'I-gene loss-of-function'}", + "58, SLPI {'perturbing_action': 'I-gene loss-of-function'}", + "59, (Slpi), {'perturbing_action': 'I-gene loss-of-function'}", + "83, Slpi-null {'perturbing_action': 'B-gene loss-of-function'}", + "84, mice. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "52, mice ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "53, null ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "54, for ['l1', 'l7', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "55, the ['l2', 'l8', 'l14', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "56, gene ['l3', 'l9', 'l15', 'l21', 'l27', 'l28', 'l29', 'l30', 'l31']", + "57, encoding ['l4', 'l10', 'l16', 'l22', 'l27', 'l32', 'l33', 'l34', 'l35']", + "58, SLPI ['l5', 'l11', 'l17', 'l23', 'l28', 'l32', 'l36', 'l37']", + "59, (Slpi), ['l6', 'l12', 'l18', 'l24', 'l29', 'l33', 'l36']", + "83, Slpi-null ['l19', 'l25', 'l30', 'l34', 'l38']", + "84, mice. ['l13', 'l20', 'l26', 'l31', 'l35', 'l37', 'l38']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice", + "mice." + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "null", + "for", + "the", + "gene", + "encoding", + "SLPI", + "(Slpi),", + "Slpi-null" + ] + } + } + ] + }, + { + "PMID": "11017145", + "TEXT": "Replication-selective oncolytic viruses constitute a rapidly evolving and new treatment platform for cancer. Gene-deleted viruses have been engineered for tumor selectivity, but these gene deletions also reduce the anti-cancer potency of the viruses. We have identified an E1A mutant adenovirus, dl922-947, that replicates in and lyses a broad range of cancer cells with abnormalities in cell-cycle checkpoints. This mutant demonstrated reduced S-phase induction and replication in non-proliferating normal cells, and superior in vivo potency relative to other gene-deleted adenoviruses. In some cancers, its potency was superior to even wild-type adenovirus. Intravenous administration reduced the incidence of metastases in a breast tumor xenograft model. dl922-947 holds promise as a potent, replication-selective virus for the local and systemic treatment of cancer.", + "TAG_DATA": [ + "37, E1A {'perturbing_action': 'B-other'}", + "38, mutant {'perturbing_action': 'I-other'}", + "40, dl922-947, {'perturbing_action': 'I-other'}", + "50, cancer {'context': 'B-transformed cells'}", + "51, cells {'context': 'I-transformed cells'}", + "66, non-proliferating {'context': 'B-cells'}", + "67, normal {'context': 'I-cells'}", + "68, cells, {'context': 'I-cells'}", + "71, in {'context': 'B-in vivo'}", + "72, vivo {'context': 'I-in vivo'}", + "81, cancers, {'context': 'B-neoplasm'}", + "92, reduced {'effect': 'B-negative'}", + "93, the {'effect': 'I-negative'}", + "94, incidence {'effect': 'I-negative'}", + "96, metastases {'phenotype': 'B-metastasis'}", + "99, breast {'context': 'B-xenograft'}", + "100, tumor {'context': 'I-xenograft'}", + "101, xenograft {'context': 'I-xenograft'}", + "102, model. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "37, E1A ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "38, mutant ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "40, dl922-947, ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "50, cancer ['l2', 'l11', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "51, cells ['l3', 'l12', 'l20', 'l26', 'l32', 'l33', 'l34', 'l35', 'l36']", + "66, non-proliferating ['l4', 'l13', 'l21', 'l27', 'l32', 'l37', 'l38', 'l39', 'l40']", + "67, normal ['l5', 'l14', 'l22', 'l28', 'l33', 'l37', 'l41', 'l42', 'l43']", + "68, cells, ['l6', 'l15', 'l23', 'l29', 'l34', 'l38', 'l41', 'l44', 'l45']", + "71, in ['l7', 'l16', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l46']", + "72, vivo ['l8', 'l17', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l46']", + "81, cancers, ['l9', 'l18']", + "92, reduced ['l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "93, the ['l47', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "94, incidence ['l48', 'l54', 'l60', 'l61', 'l62', 'l63', 'l64']", + "96, metastases ['l49', 'l55', 'l60', 'l65', 'l66', 'l67', 'l68']", + "99, breast ['l50', 'l56', 'l61', 'l65', 'l69', 'l70', 'l71']", + "100, tumor ['l51', 'l57', 'l62', 'l66', 'l69', 'l72', 'l73']", + "101, xenograft ['l52', 'l58', 'l63', 'l67', 'l70', 'l72', 'l74']", + "102, model. ['l53', 'l59', 'l64', 'l68', 'l71', 'l73', 'l74']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "E1A", + "mutant", + "dl922-947," + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "cancer", + "cells" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "E1A", + "mutant", + "dl922-947," + ] + }, + "context": { + "val": "cells", + "words": [ + "non-proliferating", + "normal", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "E1A", + "mutant", + "dl922-947," + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "E1A", + "mutant" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "cancers," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced", + "the", + "incidence" + ] + }, + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced", + "the", + "incidence" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "breast", + "tumor", + "xenograft", + "model." + ] + } + }, + { + "phenotype": { + "val": "metastasis", + "words": [ + "metastases" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "breast", + "tumor", + "xenograft", + "model." + ] + } + } + ] + }, + { + "PMID": "11017142", + "TEXT": "To determine whether uncoupling respiration from oxidative phosphorylation in skeletal muscle is a suitable treatment for obesity and type 2 diabetes, we generated transgenic mice expressing the mitochondrial uncoupling protein (Ucp) in skeletal muscle. Skeletal muscle oxygen consumption was 98% higher in Ucp-L mice (with low expression) and 246% higher in Ucp-H mice (with high expression) than in wild-type mice. Ucp mice fed a chow diet had the same food intake as wild-type mice, but weighed less and had lower levels of glucose and triglycerides and better glucose tolerance than did control mice. Ucp-L mice were resistant to obesity induced by two different high-fat diets. Ucp-L mice fed a high-fat diet had less adiposity, lower levels of glucose, insulin and cholesterol, and an increased metabolic rate at rest and with exercise. They were also more responsive to insulin, and had enhanced glucose transport in skeletal muscle in the setting of increased muscle triglyceride content. These data suggest that manipulating respiratory uncoupling in muscle is a viable treatment for obesity and its metabolic sequelae.", + "TAG_DATA": [ + "23, transgenic {'perturbing_action': 'B-gene gain-of-function'}", + "24, mice {'context': 'B-organism'}", + "25, expressing {'perturbing_action': 'I-gene gain-of-function'}", + "26, the {'perturbing_action': 'I-gene gain-of-function'}", + "27, mitochondrial {'perturbing_action': 'I-gene gain-of-function'}", + "28, uncoupling {'perturbing_action': 'I-gene gain-of-function'}", + "29, protein {'perturbing_action': 'I-gene gain-of-function'}", + "30, (Ucp) {'perturbing_action': 'I-gene gain-of-function'}", + "31, in {'perturbing_action': 'I-gene gain-of-function'}", + "32, skeletal {'context': 'B-tissue/organ'}", + "33, muscle. {'context': 'I-tissue/organ'}", + "35, muscle {'context': 'I-tissue/organ'}", + "42, Ucp-L {'perturbing_action': 'B-gene gain-of-function'}", + "43, mice {'context': 'B-organism'}", + "51, Ucp-H {'perturbing_action': 'B-gene gain-of-function'}", + "52, mice {'context': 'B-organism'}", + "60, Ucp {'context': 'B-organism'}", + "61, mice {'context': 'I-organism'}", + "93, Ucp-L {'context': 'B-organism'}", + "94, mice {'context': 'I-organism'}", + "105, Ucp-L {'context': 'B-organism'}", + "106, mice {'context': 'I-organism'}", + "144, skeletal {'context': 'B-tissue/organ'}", + "145, muscle {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "23, transgenic ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "24, mice ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "25, expressing ['l1', 'l13', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35']", + "26, the ['l2', 'l14', 'l25', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46']", + "27, mitochondrial ['l3', 'l15', 'l26', 'l36', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56']", + "28, uncoupling ['l4', 'l16', 'l27', 'l37', 'l47', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65']", + "29, protein ['l5', 'l17', 'l28', 'l38', 'l48', 'l57', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "30, (Ucp) ['l6', 'l18', 'l29', 'l39', 'l49', 'l58', 'l66', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80']", + "31, in ['l7', 'l19', 'l30', 'l40', 'l50', 'l59', 'l67', 'l74', 'l81', 'l82', 'l83', 'l84', 'l85']", + "32, skeletal ['l8', 'l20', 'l31', 'l41', 'l51', 'l60', 'l68', 'l75', 'l81', 'l86', 'l87', 'l88', 'l89']", + "33, muscle. ['l9', 'l21', 'l32', 'l42', 'l52', 'l61', 'l69', 'l76', 'l82', 'l86', 'l90', 'l91', 'l92']", + "35, muscle ['l10', 'l22', 'l33', 'l43', 'l53', 'l62', 'l70', 'l77', 'l83', 'l87', 'l90', 'l93', 'l94']", + "42, Ucp-L ['l11', 'l23', 'l34', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l88', 'l91', 'l93', 'l95', 'l96']", + "43, mice ['l12', 'l24', 'l35', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l89', 'l92', 'l94', 'l95']", + "51, Ucp-H ['l97', 'l98', 'l99']", + "52, mice ['l97', 'l100', 'l101']", + "60, Ucp ['l98', 'l100', 'l102']", + "61, mice ['l46', 'l56', 'l65', 'l73', 'l80', 'l96', 'l99', 'l101', 'l102']", + "93, Ucp-L ['l103', 'l104']", + "94, mice ['l103']", + "105, Ucp-L ['l105']", + "106, mice ['l104', 'l105']", + "144, skeletal ['l106']", + "145, muscle ['l106']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "the", + "mitochondrial", + "uncoupling", + "protein", + "(Ucp)", + "in", + "Ucp-L", + "Ucp-H" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice", + "Ucp" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "the", + "mitochondrial", + "uncoupling", + "protein", + "(Ucp)", + "in", + "Ucp-L" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "skeletal", + "muscle.", + "muscle" + ] + } + } + ] + }, + { + "PMID": "10973320", + "TEXT": "Recent studies suggest that statins can function to protect the vasculature in a manner that is independent of their lipid-lowering activity. We show here that statins rapidly activate the protein kinase Akt/PKB in endothelial cells. Accordingly, simvastatin enhanced phosphorylation of the endogenous Akt substrate endothelial nitric oxide synthase (eNOS), inhibited apoptosis and accelerated vascular structure formation in vitro in an Akt-dependent manner. Similar to vascular endothelial growth factor (VEGF) treatment, both simvastatin administration and enhanced Akt signaling in the endothelium promoted angiogenesis in ischemic limbs of normocholesterolemic rabbits. Therefore, activation of Akt represents a mechanism that can account for some of the beneficial side effects of statins, including the promotion of new blood vessel growth.", + "TAG_DATA": [ + "49, inhibited {'effect': 'B-negative'}", + "50, apoptosis {'phenotype': 'B-apoptosis'}", + "56, in {'context': 'B-in vitro'}", + "57, vitro {'context': 'I-in vitro'}", + "79, endothelium {'context': 'B-cells'}", + "84, limbs {'context': 'I-tissue/organ'}", + "87, rabbits. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "49, inhibited ['l0', 'l1', 'l2']", + "50, apoptosis ['l0', 'l3', 'l4']", + "56, in ['l1', 'l3', 'l5']", + "57, vitro ['l2', 'l4', 'l5']", + "79, endothelium ['l6', 'l7']", + "84, limbs ['l6', 'l8']", + "87, rabbits. ['l7', 'l8']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "10932232", + "TEXT": "The prevalence of type 2 diabetes mellitus is growing worldwide. By the year 2020, 250 million people will be afflicted. Most forms of type 2 diabetes are polygenic with complex inheritance patterns, and penetrance is strongly influenced by environmental factors. The specific genes involved are not yet known, but impaired glucose uptake in skeletal muscle is an early, genetically determined defect that is present in non-diabetic relatives of diabetic subjects. The rate-limiting step in muscle glucose use is the transmembrane transport of glucose mediated by glucose transporter (GLUT) 4 (ref. 4), which is expressed mainly in skeletal muscle, heart and adipose tissue. GLUT4 mediates glucose transport stimulated by insulin and contraction/exercise. The importance of GLUT4 and glucose uptake in muscle, however, was challenged by two recent observations. Whereas heterozygous GLUT4 knockout mice show moderate glucose intolerance, homozygous whole-body GLUT4 knockout (GLUT4-null) mice have only mild perturbations in glucose homeostasis and have growth retardation, depletion of fat stores, cardiac hypertrophy and failure, and a shortened life span. Moreover, muscle-specific inactivation of the insulin receptor results in minimal, if any, change in glucose tolerance. To determine the importance of glucose uptake into muscle for glucose homeostasis, we disrupted GLUT4 selectively in mouse muscles. A profound reduction in basal glucose transport and near-absence of stimulation by insulin or contraction resulted. These mice showed severe insulin resistance and glucose intolerance from an early age. Thus, GLUT4-mediated glucose transport in muscle is essential to the maintenance of normal glucose homeostasis.", + "TAG_DATA": [ + "128, heterozygous {'perturbing_action': 'B-gene loss-of-function'}", + "129, GLUT4 {'perturbing_action': 'I-gene loss-of-function'}", + "130, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "131, mice {'context': 'B-organism'}", + "136, homozygous {'perturbing_action': 'B-gene loss-of-function'}", + "137, whole-body {'perturbing_action': 'I-gene loss-of-function'}", + "138, GLUT4 {'perturbing_action': 'I-gene loss-of-function'}", + "139, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "140, (GLUT4-null) {'perturbing_action': 'I-gene loss-of-function'}", + "141, mice {'context': 'B-organism'}", + "167, muscle-specific {'perturbing_action': 'B-gene loss-of-function'}", + "168, inactivation {'perturbing_action': 'I-gene loss-of-function'}", + "169, of {'perturbing_action': 'I-gene loss-of-function'}", + "170, the {'perturbing_action': 'I-gene loss-of-function'}", + "171, insulin {'perturbing_action': 'I-gene loss-of-function'}", + "172, receptor {'perturbing_action': 'I-gene loss-of-function'}", + "195, disrupted {'perturbing_action': 'B-gene loss-of-function'}", + "196, GLUT4 {'perturbing_action': 'I-gene loss-of-function'}", + "199, mouse {'context': 'B-tissue/organ'}", + "200, muscles. {'context': 'I-tissue/organ'}", + "218, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "128, heterozygous ['l0', 'l1', 'l2']", + "129, GLUT4 ['l0', 'l3', 'l4']", + "130, knockout ['l1', 'l3', 'l5']", + "131, mice ['l2', 'l4', 'l5']", + "136, homozygous ['l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14']", + "137, whole-body ['l6', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24']", + "138, GLUT4 ['l7', 'l15', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "139, knockout ['l8', 'l16', 'l25', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "140, (GLUT4-null) ['l9', 'l17', 'l26', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "141, mice ['l10', 'l18', 'l27', 'l35', 'l40']", + "167, muscle-specific ['l19', 'l28', 'l41', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55']", + "168, inactivation ['l20', 'l29', 'l46', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64']", + "169, of ['l11', 'l21', 'l30', 'l36', 'l42', 'l47', 'l56', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72']", + "170, the ['l12', 'l22', 'l31', 'l37', 'l43', 'l48', 'l57', 'l65', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79']", + "171, insulin ['l13', 'l23', 'l32', 'l38', 'l44', 'l49', 'l58', 'l66', 'l73', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85']", + "172, receptor ['l14', 'l24', 'l33', 'l39', 'l45', 'l50', 'l59', 'l67', 'l74', 'l80', 'l86', 'l87', 'l88', 'l89', 'l90']", + "195, disrupted ['l51', 'l60', 'l68', 'l75', 'l81', 'l86', 'l91', 'l92', 'l93', 'l94']", + "196, GLUT4 ['l52', 'l61', 'l69', 'l76', 'l82', 'l87', 'l91', 'l95', 'l96', 'l97']", + "197, selectively ['l53', 'l62', 'l70', 'l77', 'l83', 'l88', 'l92', 'l95', 'l98', 'l99']", + "199, mouse ['l54', 'l63', 'l71', 'l78', 'l84', 'l89', 'l93', 'l96', 'l98', 'l100']", + "200, muscles. ['l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l94', 'l97', 'l99', 'l100']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "heterozygous", + "GLUT4", + "knockout", + "homozygous", + "whole-body", + "(GLUT4-null)" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "muscle-specific", + "inactivation", + "of", + "the", + "insulin", + "receptor", + "disrupted", + "GLUT4" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "mouse", + "muscles." + ] + } + } + ] + }, + { + "PMID": "10888934", + "TEXT": "Interferons are circulating factors that bind to cell surface receptors, activating a signaling cascade, ultimately leading to both an antiviral response and an induction of growth inhibitory and/or apoptotic signals in normal and tumor cells. Attempts to exploit the ability of interferons to limit the growth of tumors in patients has met with limited results because of cancer-specific mutations of gene products in the interferon pathway. Although interferon-non-responsive cancer cells may have acquired a growth/survival advantage over their normal counterparts, they may have simultaneously compromised their antiviral response. To test this, we used vesicular stomatitis virus (VSV), an enveloped, negative-sense RNA virus exquisitely sensitive to treatment with interferon. VSV rapidly replicated in and selectively killed a variety of human tumor cell lines even in the presence of doses of interferon that completely protected normal human primary cell cultures. A single intratumoral injection of VSV was effective in reducing the tumor burden of nude mice bearing subcutaneous human melanoma xenografts. Our results support the use of VSV as a replication-competent oncolytic virus and demonstrate a new strategy for the treatment of interferon non-responsive tumors.", + "TAG_DATA": [ + "118, human {'context': 'B-transformed cells'}", + "119, tumor {'context': 'I-transformed cells'}", + "120, cell {'context': 'I-transformed cells'}", + "121, lines {'context': 'I-transformed cells'}", + "133, normal {'context': 'B-cells'}", + "134, human {'context': 'I-cells'}", + "135, primary {'context': 'I-cells'}", + "136, cell {'context': 'I-cells'}", + "137, cultures. {'context': 'I-cells'}", + "147, reducing {'effect': 'B-negative'}", + "149, tumor {'phenotype': 'B-tumourigenesis'}", + "150, burden {'phenotype': 'I-tumourigenesis'}", + "152, nude {'context': 'B-organism'}", + "153, mice {'context': 'I-organism'}", + "155, subcutaneous {'context': 'B-xenograft'}", + "156, human {'context': 'I-xenograft'}", + "157, melanoma {'context': 'I-xenograft'}", + "158, xenografts. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "118, human ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "119, tumor ['l0', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "120, cell ['l1', 'l7', 'l14', 'l15', 'l16', 'l17']", + "121, lines ['l2', 'l8', 'l14', 'l18', 'l19']", + "133, normal ['l9', 'l20', 'l21', 'l22', 'l23']", + "134, human ['l3', 'l10', 'l20', 'l24', 'l25', 'l26']", + "135, primary ['l4', 'l11', 'l15', 'l21', 'l24', 'l27', 'l28']", + "136, cell ['l5', 'l12', 'l16', 'l18', 'l22', 'l25', 'l27', 'l29']", + "137, cultures. ['l6', 'l13', 'l17', 'l19', 'l23', 'l26', 'l28', 'l29']", + "147, reducing ['l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "149, tumor ['l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44']", + "150, burden ['l31', 'l38', 'l45', 'l46', 'l47', 'l48', 'l49', 'l50']", + "152, nude ['l32', 'l39', 'l45', 'l51', 'l52', 'l53', 'l54', 'l55']", + "153, mice ['l33', 'l40', 'l46', 'l51', 'l56', 'l57', 'l58', 'l59']", + "155, subcutaneous ['l34', 'l41', 'l47', 'l52', 'l56', 'l60', 'l61', 'l62']", + "156, human ['l35', 'l42', 'l48', 'l53', 'l57', 'l60', 'l63', 'l64']", + "157, melanoma ['l36', 'l43', 'l49', 'l54', 'l58', 'l61', 'l63', 'l65']", + "158, xenografts. ['l37', 'l44', 'l50', 'l55', 'l59', 'l62', 'l64', 'l65']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "reducing" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "burden" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reducing" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reducing" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "subcutaneous", + "human", + "melanoma", + "xenografts." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "burden" + ] + }, + "context": { + "val": "organism", + "words": [ + "nude", + "mice" + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumor", + "burden" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "subcutaneous", + "human", + "melanoma", + "xenografts." + ] + } + } + ] + }, + { + "PMID": "10888929", + "TEXT": "Huntington disease is an autosomal dominant neurodegenerative disease with no effective treatment. Minocycline is a tetracycline derivative with proven safety. After ischemia, minocycline inhibits caspase-1 and inducible nitric oxide synthetase upregulation, and reduces infarction. As caspase-1 and nitric oxide seem to play a role in Huntington disease, we evaluated the therapeutic efficacy of minocycline in the R6/2 mouse model of Huntington disease. We report that minocycline delays disease progression, inhibits caspase-1 and caspase-3 mRNA upregulation, and decreases inducible nitric oxide synthetase activity. In addition, effective pharmacotherapy in R6/2 mice requires caspase-1 and caspase-3 inhibition. This is the first demonstration of caspase-1 and caspase-3 transcriptional regulation in a Huntington disease model.", + "TAG_DATA": [ + "56, R6/2 {'context': 'B-organism'}", + "57, mouse {'context': 'I-organism'}", + "58, model {'context': 'I-organism'}", + "66, delays {'effect': 'B-negative'}", + "67, disease {'phenotype': 'B-tumour progression'}", + "68, progression, {'phenotype': 'I-tumour progression'}", + "87, R6/2 {'context': 'B-organism'}", + "88, mice {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "56, R6/2 ['l0', 'l1', 'l2', 'l3', 'l4']", + "57, mouse ['l0', 'l5', 'l6', 'l7', 'l8']", + "58, model ['l1', 'l5', 'l9', 'l10', 'l11']", + "66, delays ['l2', 'l6', 'l9', 'l12', 'l13']", + "67, disease ['l3', 'l7', 'l10', 'l12', 'l14']", + "68, progression, ['l4', 'l8', 'l11', 'l13', 'l14']", + "87, R6/2 ['l15']", + "88, mice ['l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "R6/2", + "mouse", + "model" + ] + }, + "effect": { + "val": "negative", + "words": [ + "delays" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "R6/2", + "mouse", + "model" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "disease", + "progression," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "delays" + ] + }, + "phenotype": { + "val": "tumour progression", + "words": [ + "disease", + "progression," + ] + } + } + ] + }, + { + "PMID": "10888927", + "TEXT": "Despite increasing evidence for the existence of antigen-specific regulatory T cells, the mechanisms underlying suppression remain unclear. In this study we have identified and cloned a novel subset of antigen-specific regulatory T cells and demonstrated that these T cells possess a unique combination of cell surface markers and array of cytokines. The regulatory T cells are able to inhibit the function of T cells carrying the same T-cell receptor specificity and prevent skin allograft rejection in an antigen-specific, dose-dependent manner. The regulatory T cells are able to acquire alloantigen from antigen-presenting cells, present the alloantigen to activated syngeneic CD8+ T cells and then send death signals to CD8+ T cells. These findings provide a novel mechanism of regulatory T-cell-mediated, antigen-specific suppression.", + "TAG_DATA": [ + "52, regulatory {'context': 'B-cells'}", + "53, T {'context': 'I-cells'}", + "54, cells {'context': 'I-cells'}", + "62, T {'context': 'B-cells'}", + "63, cells {'context': 'B-cells'}", + "71, prevent {'effect': 'B-negative'}", + "72, skin {'context': 'B-xenograft'}", + "73, allograft {'context': 'I-xenograft'}", + "81, regulatory {'context': 'B-cells'}", + "82, T {'context': 'I-cells'}", + "83, cells {'context': 'I-cells'}", + "97, syngeneic {'context': 'B-cells'}", + "98, CD8+ {'context': 'I-cells'}", + "99, T {'context': 'I-cells'}", + "100, cells {'context': 'I-cells'}", + "107, CD8+ {'context': 'B-cells'}", + "108, T {'context': 'I-cells'}", + "109, cells. {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "52, regulatory ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "53, T ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17']", + "54, cells ['l1', 'l10', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "62, T ['l2', 'l11', 'l18', 'l24', 'l25', 'l26', 'l27', 'l28']", + "63, cells ['l3', 'l12', 'l19', 'l24', 'l29', 'l30', 'l31', 'l32', 'l33']", + "71, prevent ['l4', 'l13', 'l20', 'l25', 'l29', 'l34', 'l35']", + "72, skin ['l5', 'l14', 'l21', 'l26', 'l30', 'l34', 'l36']", + "73, allograft ['l6', 'l15', 'l22', 'l27', 'l31', 'l35', 'l36']", + "81, regulatory ['l37', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45']", + "82, T ['l37', 'l46', 'l47', 'l48', 'l49', 'l50', 'l51', 'l52', 'l53']", + "83, cells ['l38', 'l46', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60']", + "97, syngeneic ['l39', 'l47', 'l54', 'l61', 'l62', 'l63', 'l64', 'l65']", + "98, CD8+ ['l7', 'l40', 'l48', 'l55', 'l61', 'l66', 'l67', 'l68', 'l69', 'l70']", + "99, T ['l8', 'l16', 'l32', 'l41', 'l49', 'l56', 'l62', 'l66', 'l71', 'l72', 'l73']", + "100, cells ['l9', 'l17', 'l23', 'l28', 'l33', 'l42', 'l50', 'l57', 'l63', 'l67', 'l71', 'l74', 'l75']", + "107, CD8+ ['l43', 'l51', 'l58', 'l68', 'l76', 'l77']", + "108, T ['l44', 'l52', 'l59', 'l64', 'l69', 'l72', 'l74', 'l76', 'l78']", + "109, cells. ['l45', 'l53', 'l60', 'l65', 'l70', 'l73', 'l75', 'l77', 'l78']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "regulatory", + "T", + "cells" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "skin", + "allograft" + ] + } + } + ] + }, + { + "PMID": "10835689", + "TEXT": "Progression of pulmonary hypertension is associated with increased serine elastase activity and the proteinase-dependent deposition of the extracellular matrix smooth muscle cell survival factor tenascin-C (refs. 1,2). Tenascin-C amplifies the response of smooth muscle cells to growth factors, which are also liberated through matrix proteolysis. Recent organ culture studies using hypertrophied rat pulmonary arteries have shown that elastase inhibitors suppress tenascin-C and induce smooth muscle cell apoptosis. This initiates complete regression of the hypertrophied vessel wall by a coordinated loss of cellularity and extracellular matrix. We now report that elastase inhibitors can reverse advanced pulmonary vascular disease produced in rats by injecting monocrotaline, an endothelial toxin. We began oral administration of the peptidyl trifluoromethylketone serine elastase inhibitors M249314 or ZD0892 21 days after injection of monocrotaline. A 1-week treatment resulted in 92% survival, compared with 39% survival in untreated or vehicle-treated rats. Pulmonary artery pressure and muscularization were reduced by myocyte apoptosis and loss of extracellular matrix, specifically elastin and tenascin-C. After 2 weeks, pulmonary artery pressure and structure normalized, and survival was 86%, compared with 0% in untreated or vehicle-treated rats. Although concomitant treatment with various agents can reduce pulmonary hypertension, we have documented complete regression after establishment of malignant monocrotaline-induced disease.", + "TAG_DATA": [ + "64, muscle {'context': 'B-cells'}", + "99, rats {'context': 'B-organism'}", + "141, rats. {'context': 'B-organism'}", + "150, myocyte {'context': 'B-cells'}", + "151, apoptosis {'phenotype': 'B-apoptosis'}", + "181, rats. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "64, muscle ['l0']", + "99, rats ['l0']", + "141, rats. ['l1', 'l2']", + "150, myocyte ['l1', 'l3']", + "151, apoptosis ['l2', 'l3']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "rats." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "myocyte" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "10802715", + "TEXT": "Based on the essential involvement of NF-kappaB in immune and inflammatory responses and its apoptosis-rescue function in normal and malignant cells, inhibitors of this transcription factor are potential therapeutics for the treatment of a wide range of diseases, from bronchial asthma to cancer. Yet, given the essential function of NF-kappaB in the embryonic liver, it is important to determine its necessity in the liver beyond embryogenesis. NF-kappaB is normally retained in the cytoplasm by its inhibitor IkappaB, which is eliminated upon cell stimulation through phosphorylation-dependent ubiquitin degradation. Here, we directed a degradation-resistant IkappaBalpha transgene to mouse hepatocytes in an inducible manner and showed substantial tissue specificity using various means, including a new method for live-animal imaging. Transgene expression resulted in obstruction of NF-kappaB activation, yet produced no signs of liver dysfunction, even when implemented over 15 months. However, the transgene-expressing mice were very vulnerable both to a severe immune challenge and to a systemic bacterial infection. Despite having intact immunocytes and inflammatory cells, these mice were unable to clear Listeria monocytogenes from the liver and succumbed to sepsis. These findings indicate the essential function of the hepatocyte through NF-kappaB activation in certain systemic infections, possibly by coordinating innate immunity in the liver.", + "TAG_DATA": [ + "92, IkappaBalpha {'perturbing_action': 'I-other'}", + "93, transgene {'perturbing_action': 'I-other'}", + "95, mouse {'context': 'B-cells'}", + "96, hepatocytes {'context': 'I-cells'}", + "116, Transgene {'perturbing_action': 'B-gene gain-of-function'}", + "129, liver {'context': 'B-tissue/organ'}", + "139, transgene-expressing {'perturbing_action': 'B-gene gain-of-function'}", + "140, mice {'context': 'B-organism'}", + "164, mice {'context': 'B-organism'}", + "173, liver {'context': 'B-tissue/organ'}" + ], + "LINK_DATA": [ + "92, IkappaBalpha ['l0', 'l1', 'l2']", + "93, transgene ['l0', 'l3', 'l4']", + "95, mouse ['l1', 'l3', 'l5']", + "96, hepatocytes ['l2', 'l4', 'l5']", + "116, Transgene ['l6']", + "129, liver ['l6']", + "139, transgene-expressing ['l7', 'l8', 'l9']", + "140, mice ['l7']", + "164, mice ['l8', 'l10']", + "173, liver ['l9', 'l10']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "IkappaBalpha", + "transgene" + ] + }, + "context": { + "val": "cells", + "words": [ + "mouse", + "hepatocytes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Transgene", + "transgene-expressing" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "liver" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgene-expressing" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + } + ] + }, + { + "PMID": "10802712", + "TEXT": "The transforming-growth-factor-beta-activated kinase TAK1 is a member of the mitogen-activated protein kinase kinase kinase family, which couples extracellular stimuli to gene transcription. The in vivo function of TAK1 is not understood. Here, we investigated the potential involvement of TAK1 in cardiac hypertrophy. In adult mouse myocardium, TAK1 kinase activity was upregulated 7 days after aortic banding, a mechanical load that induces hypertrophy and expression of transforming growth factor beta. An activating mutation of TAK1 expressed in myocardium of transgenic mice was sufficient to produce p38 mitogen-activated protein kinase phosphorylation in vivo, cardiac hypertrophy, interstitial fibrosis, severe myocardial dysfunction, 'fetal' gene induction, apoptosis and early lethality. Thus, TAK1 activity is induced as a delayed response to mechanical stress, and can suffice to elicit myocardial hypertrophy and fulminant heart failure.", + "TAG_DATA": [ + "43, adult {'context': 'B-tissue/organ'}", + "44, mouse {'context': 'I-tissue/organ'}", + "45, myocardium, {'context': 'I-tissue/organ'}", + "70, activating {'perturbing_action': 'B-other'}", + "71, mutation {'perturbing_action': 'I-other'}", + "72, of {'perturbing_action': 'I-other'}", + "73, TAK1 {'perturbing_action': 'I-other'}", + "74, expressed {'perturbing_action': 'I-other'}", + "76, myocardium {'context': 'B-tissue/organ'}", + "78, transgenic {'perturbing_action': 'B-gene gain-of-function', 'context': 'B-organism'}", + "79, mice {'context': 'I-organism'}", + "89, in {'context': 'B-in vivo'}", + "90, vivo, {'context': 'I-in vivo'}", + "101, apoptosis {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "43, adult ['l0', 'l1']", + "44, mouse ['l0', 'l2']", + "45, myocardium, ['l1', 'l2']", + "70, activating ['l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "71, mutation ['l3', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "72, of ['l4', 'l13', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "73, TAK1 ['l5', 'l14', 'l22', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36']", + "74, expressed ['l6', 'l15', 'l23', 'l30', 'l37', 'l38', 'l39', 'l40', 'l41', 'l42']", + "76, myocardium ['l7', 'l16', 'l24', 'l31', 'l37', 'l43', 'l44', 'l45', 'l46']", + "78, transgenic ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l48', 'l49', 'l50']", + "79, mice ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l47', 'l51', 'l52']", + "89, in ['l10', 'l19', 'l27', 'l34', 'l40', 'l45', 'l48', 'l51', 'l53']", + "90, vivo, ['l11', 'l20', 'l28', 'l35', 'l41', 'l46', 'l49', 'l52', 'l53']", + "101, apoptosis ['l12', 'l21', 'l29', 'l36', 'l42', 'l50']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "activating", + "mutation", + "of", + "TAK1", + "expressed" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "myocardium" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "activating", + "mutation", + "of", + "TAK1", + "expressed" + ] + }, + "context": { + "val": "organism", + "words": [ + "transgenic", + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "organism", + "words": [ + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "activating", + "mutation", + "of", + "TAK1", + "expressed" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "activating", + "mutation", + "of", + "TAK1", + "expressed" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "tissue/organ", + "words": [ + "myocardium" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "transgenic" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + } + ] + }, + { + "PMID": "10742147", + "TEXT": "Ischemic peripheral neuropathy is a frequent, irreversible complication of lower extremity vascular insufficiency. We investigated whether ischemic peripheral neuropathy could be prevented and/or reversed by gene transfer of an endothelial cell mitogen designed to promote therapeutic angiogenesis. Intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor (VEGF) simultaneously with induction of hindlimb ischemia in rabbits abrogated the substantial decrease in motor and sensory nerve parameters, and nerve function recovered promptly. When gene transfer was administered 10 days after induction of ischemia, nerve function was restored earlier and/or recovered faster than in untreated rabbits. These findings are due in part to enhanced hindlimb perfusion. In addition, however, the demonstration of functional VEGF receptor expression by Schwann cells indicates a direct effect of VEGF on neural integrity as well. These findings thus constitute a new paradigm for the treatment of ischemic peripheral neuropathy.", + "TAG_DATA": [ + "37, Intramuscular {'perturbing_action': 'B-gene gain-of-function'}", + "38, gene {'perturbing_action': 'I-gene gain-of-function'}", + "39, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "40, of {'perturbing_action': 'I-gene gain-of-function'}", + "41, naked {'perturbing_action': 'I-gene gain-of-function'}", + "42, DNA {'perturbing_action': 'I-gene gain-of-function'}", + "43, encoding {'perturbing_action': 'I-gene gain-of-function'}", + "44, vascular {'perturbing_action': 'I-gene gain-of-function'}", + "45, endothelial {'perturbing_action': 'I-gene gain-of-function'}", + "46, growth {'perturbing_action': 'I-gene gain-of-function'}", + "47, factor {'perturbing_action': 'I-gene gain-of-function'}", + "48, (VEGF) {'perturbing_action': 'I-gene gain-of-function'}", + "56, rabbits {'context': 'B-organism'}", + "68, nerve {'context': 'B-cells'}", + "83, nerve {'context': 'B-cells'}", + "94, rabbits. {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "37, Intramuscular ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12', 'l13']", + "38, gene ['l0', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "39, transfer ['l1', 'l14', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37', 'l38']", + "40, of ['l2', 'l15', 'l27', 'l39', 'l40', 'l41', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48', 'l49']", + "41, naked ['l3', 'l16', 'l28', 'l39', 'l50', 'l51', 'l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59']", + "42, DNA ['l4', 'l17', 'l29', 'l40', 'l50', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68']", + "43, encoding ['l5', 'l18', 'l30', 'l41', 'l51', 'l60', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "44, vascular ['l6', 'l19', 'l31', 'l42', 'l52', 'l61', 'l69', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83']", + "45, endothelial ['l7', 'l20', 'l32', 'l43', 'l53', 'l62', 'l70', 'l77', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89']", + "46, growth ['l8', 'l21', 'l33', 'l44', 'l54', 'l63', 'l71', 'l78', 'l84', 'l90', 'l91', 'l92', 'l93']", + "47, factor ['l9', 'l22', 'l34', 'l45', 'l55', 'l64', 'l72', 'l79', 'l85', 'l90', 'l94', 'l95', 'l96']", + "48, (VEGF) ['l10', 'l23', 'l35', 'l46', 'l56', 'l65', 'l73', 'l80', 'l86', 'l91', 'l94', 'l97', 'l98']", + "56, rabbits ['l11', 'l24', 'l36', 'l47', 'l57', 'l66', 'l74', 'l81', 'l87', 'l92', 'l95', 'l97', 'l99']", + "68, nerve ['l12', 'l25', 'l37', 'l48', 'l58', 'l67', 'l75', 'l82', 'l88', 'l93', 'l96', 'l98', 'l99']", + "83, nerve ['l13', 'l26', 'l38', 'l49', 'l59', 'l68', 'l76', 'l83', 'l89', 'l100']", + "94, rabbits. ['l100']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Intramuscular", + "gene", + "transfer", + "of", + "naked", + "DNA", + "encoding", + "vascular", + "endothelial", + "growth", + "factor", + "(VEGF)" + ] + }, + "context": { + "val": "organism", + "words": [ + "rabbits" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Intramuscular", + "gene", + "transfer", + "of", + "naked", + "DNA", + "encoding", + "vascular", + "endothelial", + "growth", + "factor", + "(VEGF)" + ] + }, + "context": { + "val": "cells", + "words": [ + "nerve" + ] + } + } + ] + }, + { + "PMID": "10700230", + "TEXT": "LIGHT was recently described as a member of the tumor necrosis factor (TNF) 'superfamily'. We have isolated a mouse homolog of human LIGHT and investigated its immunoregulatory functions in vitro and in vivo. LIGHT has potent, CD28-independent co-stimulatory activity leading to T-cell growth and secretion of gamma interferon and granulocyte-macrophage colony-stimulating factor. Gene transfer of LIGHT induced an antigen-specific cytolytic T-cell response and therapeutic immunity against established mouse P815 tumor. In contrast, blockade of LIGHT by administration of soluble receptor or antibody led to decreased cell-mediated immunity and ameliorated graft-versus-host disease. Our studies identify a previously unknown T-cell co-stimulatory pathway as a potential therapeutic target.", + "TAG_DATA": [ + "41, T-cell {'context': 'B-cells'}", + "42, growth {'phenotype': 'I-cell growth'}", + "52, Gene {'perturbing_action': 'B-gene gain-of-function'}", + "53, transfer {'perturbing_action': 'I-gene gain-of-function'}", + "54, of {'perturbing_action': 'I-gene gain-of-function'}", + "55, LIGHT {'perturbing_action': 'I-gene gain-of-function'}", + "67, mouse {'context': 'B-neoplasm'}", + "68, P815 {'context': 'I-neoplasm'}", + "69, tumor. {'context': 'I-neoplasm'}", + "73, of {'perturbing_action': 'I-pharmacological inhibition'}", + "74, LIGHT {'perturbing_action': 'I-pharmacological inhibition'}" + ], + "LINK_DATA": [ + "41, T-cell ['l0']", + "42, growth ['l0']", + "52, Gene ['l1', 'l2', 'l3', 'l4', 'l5', 'l6']", + "53, transfer ['l1', 'l7', 'l8', 'l9', 'l10', 'l11']", + "54, of ['l2', 'l7', 'l12', 'l13', 'l14', 'l15']", + "55, LIGHT ['l3', 'l8', 'l12', 'l16', 'l17', 'l18']", + "67, mouse ['l4', 'l9', 'l13', 'l16', 'l19', 'l20']", + "68, P815 ['l5', 'l10', 'l14', 'l17', 'l19', 'l21']", + "69, tumor. ['l6', 'l11', 'l15', 'l18', 'l20', 'l21']", + "73, of ['l22']", + "74, LIGHT ['l22']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "T-cell" + ] + }, + "phenotype": { + "val": "cell growth", + "words": [ + "growth" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Gene", + "transfer", + "of", + "LIGHT" + ] + }, + "context": { + "val": "neoplasm", + "words": [ + "mouse", + "P815", + "tumor." + ] + } + } + ] + }, + { + "PMID": "10655112", + "TEXT": "T-cell co-stimulation delivered by the molecules B7-1 or B7-2 through CD28 has a positive effect on T-cell activation, whereas engagement of cytotoxic T-lymphocyte antigen 4 (CTLA-4) by these molecules inhibits activation. In vivo administration to mice of blocking monoclonal antibodies or Fab fragments against CTLA-4 can augment antigen-specific T-cell responses and, thus, therapy with monoclonal antibody against CTLA-4 has potential applications for tumor therapy and enhancement of vaccine immunization. The effects of B7-1 and B7-2 co-stimulation through CD28 depend on the strength of the signal delivered through the T-cell receptor (TCR) and the activation state of T cells during activation. Thus, we sought to determine whether these factors similarly influence the effect of B7-mediated signals delivered through CTLA-4 during T-cell activation. Using freshly isolated human T cells and Fab fragments of a monoclonal antibody against CTLA-4, we demonstrate here that CTLA-4 blockade can enhance or inhibit the clonal expansion of different T cells that respond to the same antigen, depending on both the T-cell activation state and the strength of the T-cell receptor signal delivered during T-cell stimulation. Thus, for whole T-cell populations, blocking a negative signal may paradoxically inhibit immune responses. These results provide a theoretical framework for clinical trials in which co-stimulatory signals are manipulated in an attempt to modulate the immune response in human disease.", + "TAG_DATA": [ + "123, isolated {'context': 'I-cells'}", + "124, human {'context': 'B-cells'}", + "125, T {'context': 'I-cells'}", + "126, cells {'context': 'I-cells'}", + "143, enhance {'effect': 'B-positive'}", + "145, inhibit {'effect': 'B-negative'}", + "147, clonal {'phenotype': 'B-colony formation'}", + "148, expansion {'phenotype': 'I-colony formation'}", + "151, T {'context': 'B-cells'}", + "152, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "123, isolated ['l0', 'l1', 'l2']", + "124, human ['l0', 'l3', 'l4']", + "125, T ['l1', 'l3', 'l5']", + "126, cells ['l2', 'l4', 'l5']", + "143, enhance ['l6', 'l7', 'l8', 'l9', 'l10']", + "145, inhibit ['l6', 'l11', 'l12', 'l13', 'l14']", + "147, clonal ['l7', 'l11', 'l15', 'l16', 'l17']", + "148, expansion ['l8', 'l12', 'l15', 'l18', 'l19']", + "151, T ['l9', 'l13', 'l16', 'l18', 'l20']", + "152, cells ['l10', 'l14', 'l17', 'l19', 'l20']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "enhance" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonal", + "expansion" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "enhance" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "clonal", + "expansion" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + }, + { + "phenotype": { + "val": "colony formation", + "words": [ + "clonal", + "expansion" + ] + }, + "context": { + "val": "cells", + "words": [ + "T", + "cells" + ] + } + } + ] + }, + { + "PMID": "10655109", + "TEXT": "Maspin, a unique member of the serpin family, is a secreted protein encoded by a class II tumor suppressor gene whose downregulation is associated with the development of breast and prostate cancers. Overexpression of maspin in breast tumor cells limits their growth and metastases in vivo. In this report we demonstrate that maspin is an effective inhibitor of angiogenesis. In vitro, it acted directly on cultured endothelial cells to stop their migration towards basic fibroblast growth factor and vascular endothelial growth factor and to limit mitogenesis and tube formation. In vivo, it blocked neovascularization in the rat cornea pocket model. Maspin derivatives mutated in the serpin reactive site lost their ability to inhibit the migration of fibroblasts, keratinocytes, and breast cancer cells but were still able to block angiogenesis in vitro and in vivo. When maspin was delivered locally to human prostate tumor cells in a xenograft mouse model, it blocked tumor growth and dramatically reduced the density of tumor-associated microvessels. These data suggest that the tumor suppressor activity of maspin may depend in large part on its ability to inhibit angiogenesis and raise the possibility that maspin and similar serpins may be excellent leads for the development of drugs that modulate angiogenesis.", + "TAG_DATA": [ + "59, In {'context': 'B-in vitro'}", + "60, vitro, {'context': 'I-in vitro'}", + "65, cultured {'context': 'B-cells'}", + "66, endothelial {'context': 'I-cells'}", + "67, cells {'context': 'I-cells'}", + "84, limit {'effect': 'B-negative'}", + "87, tube {'phenotype': 'B-colony formation'}", + "88, formation. {'phenotype': 'I-colony formation'}", + "89, In {'context': 'B-in vivo'}", + "90, vivo, {'context': 'I-in vivo'}", + "96, rat {'context': 'B-tissue/organ'}", + "97, cornea {'context': 'I-tissue/organ'}", + "98, pocket {'context': 'I-tissue/organ'}", + "99, model. {'context': 'I-tissue/organ'}", + "102, mutated {'perturbing_action': 'B-other'}", + "103, in {'perturbing_action': 'I-other'}", + "104, the {'perturbing_action': 'I-other'}", + "105, serpin {'perturbing_action': 'I-other'}", + "106, reactive {'perturbing_action': 'I-other'}", + "107, site {'perturbing_action': 'I-other'}", + "112, inhibit {'effect': 'B-negative'}", + "114, migration {'phenotype': 'B-migration'}", + "116, fibroblasts, {'context': 'B-cells'}", + "117, keratinocytes, {'context': 'B-cells'}", + "119, breast {'context': 'B-transformed cells'}", + "120, cancer {'context': 'I-transformed cells'}", + "121, cells {'context': 'I-transformed cells'}", + "129, in {'context': 'B-in vitro'}", + "130, vitro {'context': 'I-in vitro'}", + "132, in {'context': 'B-in vivo'}", + "133, vivo. {'context': 'I-in vivo'}", + "140, human {'context': 'B-transformed cells'}", + "141, prostate {'context': 'I-transformed cells'}", + "142, tumor {'context': 'I-transformed cells'}", + "143, cells {'context': 'I-transformed cells'}", + "146, xenograft {'context': 'B-xenograft'}", + "147, mouse {'context': 'I-xenograft'}", + "148, model, {'context': 'I-xenograft'}", + "150, blocked {'effect': 'B-negative'}", + "151, tumor {'phenotype': 'B-tumour growth'}", + "152, growth {'phenotype': 'I-tumour growth'}" + ], + "LINK_DATA": [ + "59, In ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "60, vitro, ['l0', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16']", + "65, cultured ['l1', 'l9', 'l17', 'l18', 'l19', 'l20', 'l21', 'l22', 'l23']", + "66, endothelial ['l2', 'l10', 'l17', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29', 'l30']", + "67, cells ['l3', 'l11', 'l18', 'l24', 'l31', 'l32', 'l33', 'l34']", + "84, limit ['l4', 'l12', 'l19', 'l25', 'l31', 'l35', 'l36']", + "87, tube ['l5', 'l13', 'l20', 'l26', 'l32', 'l35', 'l37']", + "88, formation. ['l6', 'l14', 'l21', 'l27', 'l33', 'l36', 'l37']", + "89, In ['l7', 'l15', 'l22', 'l28', 'l38', 'l39', 'l40', 'l41']", + "90, vivo, ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l42']", + "96, rat ['l43', 'l44', 'l45', 'l46']", + "97, cornea ['l39', 'l43', 'l47', 'l48', 'l49']", + "98, pocket ['l40', 'l44', 'l47', 'l50', 'l51']", + "99, model. ['l30', 'l41', 'l42', 'l45', 'l48', 'l50']", + "101, derivatives ['l52', 'l53', 'l54', 'l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71']", + "102, mutated ['l52', 'l72', 'l73', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "103, in ['l53', 'l72', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107', 'l108', 'l109', 'l110', 'l111', 'l112', 'l113', 'l114', 'l115', 'l116']", + "104, the ['l54', 'l73', 'l98', 'l117', 'l118', 'l119', 'l120', 'l121', 'l122', 'l123', 'l124', 'l125', 'l126', 'l127', 'l128', 'l129', 'l130', 'l131', 'l132', 'l133', 'l134']", + "105, serpin ['l55', 'l74', 'l99', 'l117', 'l135', 'l136', 'l137', 'l138', 'l139', 'l140', 'l141', 'l142', 'l143', 'l144', 'l145', 'l146', 'l147', 'l148', 'l149', 'l150']", + "106, reactive ['l56', 'l75', 'l100', 'l118', 'l135', 'l151', 'l152', 'l153', 'l154', 'l155', 'l156', 'l157', 'l158', 'l159', 'l160', 'l161', 'l162', 'l163', 'l164', 'l165']", + "107, site ['l57', 'l76', 'l101', 'l119', 'l136', 'l151', 'l166', 'l167', 'l168', 'l169', 'l170', 'l171', 'l172', 'l173', 'l174', 'l175', 'l176', 'l177']", + "112, inhibit ['l58', 'l77', 'l102', 'l120', 'l137', 'l152', 'l166', 'l178', 'l179', 'l180', 'l181', 'l182', 'l183', 'l184', 'l185', 'l186', 'l187']", + "114, migration ['l59', 'l78', 'l103', 'l121', 'l138', 'l153', 'l167', 'l178', 'l188', 'l189', 'l190', 'l191', 'l192', 'l193', 'l194']", + "116, fibroblasts, ['l60', 'l79', 'l104', 'l122', 'l139', 'l154', 'l168', 'l179', 'l188', 'l195', 'l196', 'l197', 'l198', 'l199', 'l200', 'l201']", + "117, keratinocytes, ['l61', 'l80', 'l105', 'l123', 'l140', 'l155', 'l169', 'l180', 'l189', 'l195', 'l202', 'l203', 'l204', 'l205', 'l206', 'l207']", + "119, breast ['l62', 'l81', 'l106', 'l124', 'l141', 'l156', 'l170', 'l181', 'l190', 'l196', 'l202', 'l208', 'l209', 'l210', 'l211', 'l212']", + "120, cancer ['l63', 'l82', 'l107', 'l125', 'l142', 'l157', 'l171', 'l182', 'l191', 'l197', 'l203', 'l208', 'l213', 'l214', 'l215']", + "121, cells ['l46', 'l49', 'l51', 'l64', 'l83', 'l108', 'l126', 'l143', 'l158', 'l172', 'l183', 'l192', 'l198', 'l204', 'l209', 'l213', 'l216']", + "129, in ['l65', 'l84', 'l109', 'l127', 'l144', 'l159', 'l173', 'l184', 'l193', 'l199', 'l205', 'l210', 'l214', 'l217', 'l218', 'l219']", + "130, vitro ['l66', 'l85', 'l110', 'l128', 'l145', 'l160', 'l174', 'l185', 'l194', 'l200', 'l206', 'l211', 'l215', 'l216', 'l217', 'l220', 'l221']", + "132, in ['l67', 'l86', 'l111', 'l129', 'l146', 'l161', 'l175', 'l186', 'l218', 'l220', 'l222']", + "133, vivo. ['l68', 'l87', 'l112', 'l130', 'l147', 'l162', 'l176', 'l187', 'l201', 'l207', 'l212', 'l219', 'l221', 'l222']", + "140, human ['l88', 'l113', 'l131', 'l223', 'l224', 'l225', 'l226', 'l227', 'l228', 'l229', 'l230', 'l231']", + "141, prostate ['l69', 'l89', 'l114', 'l132', 'l148', 'l163', 'l223', 'l232', 'l233', 'l234', 'l235', 'l236', 'l237', 'l238', 'l239']", + "142, tumor ['l70', 'l90', 'l115', 'l133', 'l149', 'l164', 'l224', 'l232', 'l240', 'l241', 'l242', 'l243', 'l244', 'l245', 'l246']", + "143, cells ['l71', 'l91', 'l116', 'l134', 'l150', 'l165', 'l177', 'l225', 'l233', 'l240', 'l247', 'l248', 'l249', 'l250', 'l251', 'l252']", + "146, xenograft ['l92', 'l226', 'l234', 'l241', 'l247', 'l253', 'l254', 'l255', 'l256', 'l257']", + "147, mouse ['l93', 'l227', 'l235', 'l242', 'l248', 'l253', 'l258', 'l259', 'l260', 'l261']", + "148, model, ['l94', 'l228', 'l236', 'l243', 'l249', 'l254', 'l258', 'l262', 'l263', 'l264']", + "150, blocked ['l95', 'l229', 'l237', 'l244', 'l250', 'l255', 'l259', 'l262', 'l265', 'l266']", + "151, tumor ['l96', 'l230', 'l238', 'l245', 'l251', 'l256', 'l260', 'l263', 'l265', 'l267']", + "152, growth ['l97', 'l231', 'l239', 'l246', 'l252', 'l257', 'l261', 'l264', 'l266', 'l267']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro,", + "in", + "vitro" + ] + }, + "effect": { + "val": "negative", + "words": [ + "limit", + "inhibit" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "tube", + "formation." + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "endothelial", + "cells", + "fibroblasts,", + "keratinocytes," + ] + }, + "effect": { + "val": "negative", + "words": [ + "limit", + "inhibit" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "cultured", + "endothelial", + "cells" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "tube", + "formation." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "limit" + ] + }, + "phenotype": { + "val": "colony formation", + "words": [ + "tube", + "formation." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "in", + "the", + "serpin", + "reactive", + "site" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibit", + "blocked" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "in", + "the", + "serpin", + "reactive", + "site" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "in", + "the", + "serpin", + "reactive", + "site" + ] + }, + "context": { + "val": "cells", + "words": [ + "fibroblasts,", + "keratinocytes," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "in", + "the", + "serpin", + "reactive", + "site" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "breast", + "cancer", + "cells", + "human", + "prostate", + "tumor" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "in", + "the", + "serpin", + "reactive", + "site" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "in", + "the", + "serpin", + "reactive", + "site" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "mouse", + "model," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit", + "blocked" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "breast", + "cancer", + "cells", + "human", + "prostate", + "tumor" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibit" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "cells", + "words": [ + "fibroblasts,", + "keratinocytes," + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "breast", + "cancer", + "cells" + ] + } + }, + { + "phenotype": { + "val": "migration", + "words": [ + "migration" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "human", + "prostate", + "tumor", + "cells" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "mouse", + "model," + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + }, + { + "context": { + "val": "xenograft", + "words": [ + "xenograft", + "mouse", + "model," + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "phenotype": { + "val": "tumour growth", + "words": [ + "tumor", + "growth" + ] + } + } + ] + }, + { + "PMID": "10613820", + "TEXT": "Azoospermia or oligozoospermia due to disruption of spermatogenesis are common causes of human male infertility. We used the technique of spermatogonial transplantation in two infertile mouse strains, Steel (Sl) and dominant white spotting (W), to determine if stem cells from an infertile male were capable of generating spermatogenesis. Transplantation of germ cells from infertile Sl/Sld mutant male mice to infertile W/Wv or Wv/W54 mutant male mice restored fertility to the recipient mice. Thus, transplantation of spermatogonial stem cells from an infertile donor to a permissive testicular environment can restore fertility and result in progeny with the genetic makeup of the infertile donor male.", + "TAG_DATA": [ + "25, mouse {'context': 'I-organism'}", + "50, germ {'context': 'B-cells'}", + "51, cells {'context': 'I-cells'}", + "53, infertile {'perturbing_action': 'B-other'}", + "54, Sl/Sld {'perturbing_action': 'I-other'}", + "55, mutant {'perturbing_action': 'I-other'}", + "56, male {'context': 'B-organism'}", + "57, mice {'context': 'I-organism'}", + "62, Wv/W54 {'perturbing_action': 'B-other'}", + "63, mutant {'perturbing_action': 'I-other'}", + "64, male {'context': 'B-organism'}", + "65, mice {'context': 'I-organism'}", + "71, mice. {'context': 'B-organism'}", + "76, stem {'context': 'I-cells'}", + "77, cells {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "50, germ ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "51, cells ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "53, infertile ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "54, Sl/Sld ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "55, mutant ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "56, male ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "57, mice ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "62, Wv/W54 ['l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "63, mutant ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l55', 'l56', 'l57']", + "64, male ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l50', 'l55', 'l58', 'l59']", + "65, mice ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l51', 'l56', 'l58', 'l60']", + "71, mice. ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l52', 'l57', 'l59', 'l60']", + "76, stem ['l53', 'l61']", + "77, cells ['l54', 'l61']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "germ", + "cells", + "stem" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "infertile", + "Sl/Sld", + "mutant", + "Wv/W54" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "infertile", + "Sl/Sld", + "mutant", + "Wv/W54" + ] + }, + "context": { + "val": "organism", + "words": [ + "male", + "mice", + "mice." + ] + } + } + ] + }, + { + "PMID": "10581087", + "TEXT": "The possibility that glucocorticoids upregulate the expression of anti-inflammatory mediators is an exciting prospect for therapy in inflammatory diseases, because these molecules could give the therapeutic benefits of steroids without toxic side effects. Supernatants from monocytes and macrophages cultured in the presence of glucocorticoids increase the dispersion of neutrophils from a cell pellet in the capillary tube migration assay. This supernatant factor, unlike other neutrophil agonists, promotes dispersive locomotion of neutrophils at uniform concentration, lowers their adhesion to endothelial cells, inhibits their chemotactic response to fMLP and induces distinctive morphological changes. Here we show that thymosin beta4 sulfoxide is generated by monocytes in the presence of glucocorticoids and acts as a signal to inhibit an inflammatory response. In vitro, thymosin beta4 sulfoxide inhibited neutrophil chemotaxis, and in vivo, the oxidized peptide, but not the native form, was a potent inhibitor of carrageenin-induced edema in the mouse paw. Thymosin beta4 is unique, because oxidation attenuates its intracellular G-actin sequestering activity, but greatly enhances its extracellular signaling properties. This description of methionine oxidation conferring extracellular function on a cytosolic protein may have far-reaching implications for future strategies of anti-inflammatory therapy.", + "TAG_DATA": [ + "117, In {'context': 'B-in vitro'}", + "118, vitro, {'context': 'I-in vitro'}", + "122, inhibited {'effect': 'B-negative'}", + "123, neutrophil {'context': 'B-cells'}", + "124, chemotaxis, {'phenotype': 'B-migration'}", + "126, in {'context': 'B-in vivo'}", + "127, vivo, {'context': 'I-in vivo'}", + "145, mouse {'context': 'B-tissue/organ'}", + "146, paw. {'context': 'I-tissue/organ'}" + ], + "LINK_DATA": [ + "117, In ['l0', 'l1', 'l2', 'l3']", + "118, vitro, ['l0', 'l4', 'l5', 'l6']", + "122, inhibited ['l1', 'l4', 'l7', 'l8']", + "123, neutrophil ['l2', 'l5', 'l7', 'l9']", + "124, chemotaxis, ['l3', 'l6', 'l8', 'l9']", + "126, in ['l10', 'l11', 'l12']", + "127, vivo, ['l10', 'l13', 'l14']", + "145, mouse ['l11', 'l13', 'l15']", + "146, paw. ['l12', 'l14', 'l15']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "In", + "vitro," + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "context": { + "val": "cells", + "words": [ + "neutrophil" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis," + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "neutrophil" + ] + }, + "phenotype": { + "val": "migration", + "words": [ + "chemotaxis," + ] + } + } + ] + }, + { + "PMID": "10502820", + "TEXT": "Telomerase is a ribonucleoprotein enzyme that maintains the protective structures at the ends of eukaryotic chromosomes, called telomeres. In most human somatic cells, telomerase expression is repressed, and telomeres shorten progressively with each cell division. In contrast, most human tumors express telomerase, resulting in stabilized telomere length. These observations indicate that telomere maintenance is essential to the proliferation of tumor cells. We show here that expression of a mutant catalytic subunit of human telomerase results in complete inhibition of telomerase activity, reduction in telomere length and death of tumor cells. Moreover, expression of this mutant telomerase eliminated tumorigenicity in vivo. These observations demonstrate that disruption of telomere maintenance limits cellular lifespan in human cancer cells, thus validating human telomerase reverse transcriptase as an important target for the development of anti-neoplastic therapies.", + "TAG_DATA": [ + "65, expression {'perturbing_action': 'B-other'}", + "66, of {'perturbing_action': 'I-other'}", + "67, a {'perturbing_action': 'I-other'}", + "68, mutant {'perturbing_action': 'I-other'}", + "69, catalytic {'perturbing_action': 'I-other'}", + "70, subunit {'perturbing_action': 'I-other'}", + "71, of {'perturbing_action': 'I-other'}", + "72, human {'perturbing_action': 'I-other'}", + "73, telomerase {'perturbing_action': 'I-other'}", + "88, tumor {'context': 'B-transformed cells'}", + "89, cells. {'context': 'I-transformed cells'}", + "91, expression {'perturbing_action': 'B-other'}", + "92, of {'perturbing_action': 'I-other'}", + "93, this {'perturbing_action': 'I-other'}", + "94, mutant {'perturbing_action': 'I-other'}", + "95, telomerase {'perturbing_action': 'I-other'}", + "96, eliminated {'effect': 'B-negative'}", + "97, tumorigenicity {'phenotype': 'B-tumourigenesis'}", + "98, in {'context': 'B-in vivo'}", + "99, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "65, expression ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "66, of ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "67, a ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "68, mutant ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "69, catalytic ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39']", + "70, subunit ['l4', 'l13', 'l21', 'l28', 'l34', 'l40', 'l41', 'l42', 'l43', 'l44']", + "71, of ['l5', 'l14', 'l22', 'l29', 'l35', 'l40', 'l45', 'l46', 'l47', 'l48']", + "72, human ['l6', 'l15', 'l23', 'l30', 'l36', 'l41', 'l45', 'l49', 'l50', 'l51']", + "73, telomerase ['l7', 'l16', 'l24', 'l31', 'l37', 'l42', 'l46', 'l49', 'l52', 'l53']", + "88, tumor ['l8', 'l17', 'l25', 'l32', 'l38', 'l43', 'l47', 'l50', 'l52', 'l54']", + "89, cells. ['l9', 'l18', 'l26', 'l33', 'l39', 'l44', 'l48', 'l51', 'l53', 'l54']", + "91, expression ['l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62']", + "92, of ['l55', 'l63', 'l64', 'l65', 'l66', 'l67', 'l68', 'l69']", + "93, this ['l56', 'l63', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75']", + "94, mutant ['l57', 'l64', 'l70', 'l76', 'l77', 'l78', 'l79', 'l80']", + "95, telomerase ['l58', 'l65', 'l71', 'l76', 'l81', 'l82', 'l83', 'l84']", + "96, eliminated ['l59', 'l66', 'l72', 'l77', 'l81', 'l85', 'l86', 'l87']", + "97, tumorigenicity ['l60', 'l67', 'l73', 'l78', 'l82', 'l85', 'l88', 'l89']", + "98, in ['l61', 'l68', 'l74', 'l79', 'l83', 'l86', 'l88', 'l90']", + "99, vivo. ['l62', 'l69', 'l75', 'l80', 'l84', 'l87', 'l89', 'l90']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "a", + "mutant", + "catalytic", + "subunit", + "human", + "telomerase" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "tumor", + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "this", + "mutant", + "telomerase" + ] + }, + "effect": { + "val": "negative", + "words": [ + "eliminated" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "this", + "mutant", + "telomerase" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "this", + "mutant", + "telomerase" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "eliminated" + ] + }, + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "eliminated" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + }, + { + "phenotype": { + "val": "tumourigenesis", + "words": [ + "tumorigenicity" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo." + ] + } + } + ] + }, + { + "PMID": "10470077", + "TEXT": "CD39, or vascular adenosine triphosphate diphosphohydrolase, has been considered an important inhibitor of platelet activation. Unexpectedly, cd39-deficient mice had prolonged bleeding times with minimally perturbed coagulation parameters. Platelet interactions with injured mesenteric vasculature were considerably reduced in vivo and purified mutant platelets failed to aggregate to standard agonists in vitro. This platelet hypofunction was reversible and associated with purinergic type P2Y1 receptor desensitization. In keeping with deficient vascular protective mechanisms, fibrin deposition was found at multiple organ sites in cd39-deficient mice and in transplanted cardiac grafts. Our data indicate a dual role for adenosine triphosphate diphosphohydrolase in modulating hemostasis and thrombotic reactions.", + "TAG_DATA": [ + "16, cd39-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "17, mice {'context': 'B-organism'}", + "36, in {'context': 'B-in vivo'}", + "37, vivo {'context': 'I-in vivo'}", + "41, platelets {'context': 'B-cells'}", + "48, in {'context': 'B-in vitro'}", + "49, vitro. {'context': 'I-in vitro'}", + "79, cd39-deficient {'perturbing_action': 'B-gene loss-of-function'}", + "80, mice {'context': 'B-organism'}", + "83, transplanted {'context': 'B-xenograft'}", + "84, cardiac {'context': 'I-xenograft'}", + "85, grafts. {'context': 'I-xenograft'}" + ], + "LINK_DATA": [ + "16, cd39-deficient ['l0', 'l1']", + "17, mice ['l0']", + "36, in ['l2']", + "37, vivo ['l1', 'l2']", + "41, platelets ['l3', 'l4']", + "48, in ['l3', 'l5']", + "49, vitro. ['l4', 'l5']", + "79, cd39-deficient ['l6', 'l7', 'l8', 'l9']", + "80, mice ['l6', 'l10']", + "83, transplanted ['l7', 'l11', 'l12']", + "84, cardiac ['l8', 'l11', 'l13']", + "85, grafts. ['l9', 'l10', 'l12', 'l13']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cd39-deficient" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cd39-deficient" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "cd39-deficient" + ] + }, + "context": { + "val": "xenograft", + "words": [ + "transplanted", + "cardiac", + "grafts." + ] + } + } + ] + }, + { + "PMID": "10426310", + "TEXT": "The occurrence of multiple tumors in an organ heralds a rapidly fatal course. Although intravascular administration may deliver oncolytic viruses/vectors to each of these tumors, its efficiency is impeded by an antiviral activity present in complement-depleted plasma of rodents and humans. Here, this activity was shown to interact with complement in a calcium-dependent fashion, and antibody neutralization studies indicated preimmune IgM has a contributing role. Short-term exposure to cyclophosphamide (CPA) partially suppressed this activity in rodents and humans. At longer time points, cyclophosphamide also abrogated neutralizing antibody responses. Cyclophosphamide treatment of rats with large single or multiple intracerebral tumors substantially increased viral survival and propagation, leading to neoplastic regression.", + "TAG_DATA": [ + "75, rodents {'context': 'B-organism'}", + "77, humans. {'context': 'B-organism'}", + "91, rats {'context': 'B-organism'}", + "97, intracerebral {'context': 'B-neoplasm'}", + "98, tumors {'context': 'I-neoplasm'}", + "105, leading {'effect': 'B-positive'}", + "106, to {'effect': 'I-positive'}", + "107, neoplastic {'phenotype': 'B-tumour regression'}", + "108, regression. {'phenotype': 'I-tumour regression'}" + ], + "LINK_DATA": [ + "75, rodents ['l0']", + "77, humans. ['l0']", + "91, rats ['l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8']", + "94, single ['l1', 'l9', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15']", + "96, multiple ['l2', 'l9', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "97, intracerebral ['l3', 'l10', 'l16', 'l22', 'l23', 'l24', 'l25', 'l26']", + "98, tumors ['l4', 'l11', 'l17', 'l22', 'l27', 'l28', 'l29', 'l30']", + "105, leading ['l5', 'l12', 'l18', 'l23', 'l27', 'l31', 'l32', 'l33']", + "106, to ['l6', 'l13', 'l19', 'l24', 'l28', 'l31', 'l34', 'l35']", + "107, neoplastic ['l7', 'l14', 'l20', 'l25', 'l29', 'l32', 'l34', 'l36']", + "108, regression. ['l8', 'l15', 'l21', 'l26', 'l30', 'l33', 'l35', 'l36']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "rats" + ] + }, + "effect": { + "val": "positive", + "words": [ + "leading", + "to" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "rats" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "neoplastic", + "regression." + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "intracerebral", + "tumors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "leading", + "to" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "intracerebral", + "tumors" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "neoplastic", + "regression." + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "leading", + "to" + ] + }, + "phenotype": { + "val": "tumour regression", + "words": [ + "neoplastic", + "regression." + ] + } + } + ] + }, + { + "PMID": "10395329", + "TEXT": "'Naked' nucleic acid vaccines are potentially useful candidates for the treatment of patients with cancer, but their clinical efficacy has yet to be demonstrated. We sought to enhance the immunogenicity of a nucleic acid vaccine by making it 'self-replicating'. We accomplished this by using a gene encoding an RNA replicase polyprotein derived from the Semliki forest virus, in combination with a model antigen. A single intramuscular injection of a self-replicating RNA immunogen elicited antigen-specific antibody and CD8+ T-cell responses at doses as low as 0.1 microg. Pre-immunization with a self-replicating RNA vector protected mice from tumor challenge, and therapeutic immunization prolonged the survival of mice with established tumors. The self-replicating RNA vectors did not mediate the production of substantially more model antigen than a conventional DNA vaccine did in vitro. However, the enhanced efficacy in vivo correlated with a caspase-dependent apoptotic death in transfected cells. This death facilitated the uptake of apoptotic cells by dendritic cells, providing a potential mechanism for enhanced immunogenicity. Naked, non-infectious, self-replicating RNA may be an excellent candidate for the development of new cancer vaccines.", + "TAG_DATA": [ + "76, CD8+ {'context': 'B-cells'}", + "93, mice {'context': 'B-organism'}", + "104, mice {'context': 'B-organism'}", + "107, tumors. {'context': 'B-neoplasm'}", + "128, in {'context': 'B-in vitro'}", + "129, vitro. {'context': 'I-in vitro'}", + "134, in {'context': 'B-in vivo'}", + "135, vivo {'context': 'I-in vivo'}", + "140, apoptotic {'phenotype': 'B-apoptosis'}", + "141, death {'phenotype': 'I-apoptosis'}", + "143, transfected {'perturbing_action': 'B-gene gain-of-function'}", + "144, cells. {'context': 'B-cells'}", + "154, dendritic {'context': 'B-cells'}", + "155, cells, {'context': 'I-cells'}" + ], + "LINK_DATA": [ + "76, CD8+ ['l0']", + "93, mice ['l0']", + "104, mice ['l1']", + "107, tumors. ['l1']", + "128, in ['l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "129, vitro. ['l2', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "134, in ['l3', 'l11', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25']", + "135, vivo ['l4', 'l12', 'l19', 'l26', 'l27', 'l28', 'l29', 'l30', 'l31']", + "140, apoptotic ['l5', 'l13', 'l20', 'l26', 'l32', 'l33', 'l34', 'l35', 'l36']", + "141, death ['l6', 'l14', 'l21', 'l27', 'l32', 'l37', 'l38', 'l39', 'l40']", + "143, transfected ['l7', 'l15', 'l22', 'l28', 'l33', 'l37', 'l41', 'l42', 'l43']", + "144, cells. ['l8', 'l16', 'l23', 'l29', 'l34', 'l38', 'l41', 'l44', 'l45']", + "154, dendritic ['l9', 'l17', 'l24', 'l30', 'l35', 'l39', 'l42', 'l44', 'l46']", + "155, cells, ['l10', 'l18', 'l25', 'l31', 'l36', 'l40', 'l43', 'l45', 'l46']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + } + }, + { + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro." + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic", + "death" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells.", + "dendritic", + "cells," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells.", + "dendritic", + "cells," + ] + } + } + ] + }, + { + "PMID": "10395320", + "TEXT": "Synovial tissue affected by rheumatoid arthritis is characterized by proliferation, which leads to irreversible cartilage and bone destruction. Current and experimental treatments have been aimed mainly at correcting the underlying immune abnormalities, but these treatments often prove ineffective in preventing the invasive destruction. We studied the expression of cyclin-dependent kinase inhibitors in rheumatoid synovial cells as a means of suppressing synovial cell proliferation. Synovial cells derived from hypertrophic synovial tissue readily expressed p16INK4a when they were growth-inhibited. This was not seen in other fibroblasts, including those derived from normal and osteoarthritis-affected synovial tissues. In vivo adenoviral gene therapy with the p16INK4a gene efficiently inhibited the pathology in an animal model of rheumatoid arthritis. Thus, the induction of p16INK4a may provide a new approach to the effective treatment of rheumatoid arthritis.", + "TAG_DATA": [ + "52, rheumatoid {'context': 'B-cells'}", + "53, synovial {'context': 'I-cells'}", + "54, cells {'context': 'I-cells'}", + "59, suppressing {'effect': 'B-negative'}", + "60, synovial {'context': 'B-cells'}", + "61, cell {'context': 'I-cells'}", + "62, proliferation. {'phenotype': 'B-proliferation'}", + "63, Synovial {'context': 'B-cells'}", + "64, cells {'context': 'I-cells'}", + "65, derived {'context': 'I-cells'}", + "66, from {'context': 'I-cells'}", + "83, fibroblasts, {'context': 'B-cells'}", + "93, In {'context': 'B-in vivo'}", + "94, vivo {'context': 'I-in vivo'}", + "95, adenoviral {'perturbing_action': 'B-gene gain-of-function'}", + "96, gene {'perturbing_action': 'I-gene gain-of-function'}", + "97, therapy {'perturbing_action': 'I-gene gain-of-function'}", + "98, with {'perturbing_action': 'I-gene gain-of-function'}", + "99, the {'perturbing_action': 'I-gene gain-of-function'}", + "100, p16INK4a {'perturbing_action': 'I-gene gain-of-function'}", + "101, gene {'perturbing_action': 'I-gene gain-of-function'}", + "108, animal {'context': 'B-organism'}", + "109, model {'context': 'I-organism'}" + ], + "LINK_DATA": [ + "52, rheumatoid ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10']", + "53, synovial ['l0', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20']", + "54, cells ['l1', 'l11', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27', 'l28', 'l29']", + "59, suppressing ['l2', 'l12', 'l21', 'l30', 'l31', 'l32', 'l33', 'l34', 'l35', 'l36', 'l37']", + "60, synovial ['l3', 'l13', 'l22', 'l30', 'l38', 'l39', 'l40', 'l41', 'l42', 'l43']", + "61, cell ['l4', 'l14', 'l23', 'l31', 'l38', 'l44', 'l45', 'l46']", + "62, proliferation. ['l5', 'l15', 'l24', 'l32', 'l39', 'l44', 'l47', 'l48']", + "63, Synovial ['l6', 'l16', 'l25', 'l33', 'l49', 'l50', 'l51', 'l52', 'l53']", + "64, cells ['l7', 'l17', 'l26', 'l34', 'l40', 'l45', 'l47', 'l49', 'l54', 'l55', 'l56', 'l57']", + "65, derived ['l8', 'l18', 'l27', 'l35', 'l41', 'l50', 'l54', 'l58', 'l59', 'l60']", + "66, from ['l9', 'l19', 'l28', 'l36', 'l42', 'l51', 'l55', 'l58', 'l61', 'l62']", + "69, tissue ['l10', 'l20', 'l29', 'l37', 'l43', 'l46', 'l48', 'l52', 'l56', 'l59', 'l61', 'l63']", + "83, fibroblasts, ['l53', 'l57', 'l60', 'l62', 'l63']", + "93, In ['l64', 'l65', 'l66', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73']", + "94, vivo ['l64', 'l74', 'l75', 'l76', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82']", + "95, adenoviral ['l65', 'l74', 'l83', 'l84', 'l85', 'l86', 'l87', 'l88', 'l89', 'l90']", + "96, gene ['l66', 'l75', 'l83', 'l91', 'l92', 'l93', 'l94', 'l95', 'l96', 'l97']", + "97, therapy ['l67', 'l76', 'l84', 'l91', 'l98', 'l99', 'l100', 'l101', 'l102', 'l103']", + "98, with ['l68', 'l77', 'l85', 'l92', 'l98', 'l104', 'l105', 'l106', 'l107', 'l108']", + "99, the ['l69', 'l78', 'l86', 'l93', 'l99', 'l104', 'l109', 'l110', 'l111', 'l112']", + "100, p16INK4a ['l70', 'l79', 'l87', 'l94', 'l100', 'l105', 'l109', 'l113', 'l114', 'l115']", + "101, gene ['l71', 'l80', 'l88', 'l95', 'l101', 'l106', 'l110', 'l113', 'l116', 'l117']", + "108, animal ['l72', 'l81', 'l89', 'l96', 'l102', 'l107', 'l111', 'l114', 'l116', 'l118']", + "109, model ['l73', 'l82', 'l90', 'l97', 'l103', 'l108', 'l112', 'l115', 'l117', 'l118']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "cells", + "words": [ + "rheumatoid", + "synovial", + "cells", + "cell", + "Synovial", + "derived", + "from" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressing" + ] + } + }, + { + "context": { + "val": "cells", + "words": [ + "rheumatoid", + "synovial", + "cells", + "cell" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressing" + ] + }, + "phenotype": { + "val": "proliferation", + "words": [ + "proliferation." + ] + } + }, + { + "context": { + "val": "in vivo", + "words": [ + "In", + "vivo" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral", + "gene", + "therapy", + "with", + "the", + "p16INK4a" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral", + "gene", + "therapy", + "with", + "the", + "p16INK4a" + ] + }, + "context": { + "val": "organism", + "words": [ + "animal", + "model" + ] + } + } + ] + }, + { + "PMID": "10371509", + "TEXT": "Serum amyloid P component (SAP), a highly conserved plasma protein named for its universal presence in amyloid deposits, is the single normal circulating protein that shows specific calcium-dependent binding to DNA and chromatin in physiological conditions. The avid binding of SAP displaces H1-type histones and thereby solubilizes native long chromatin, which is otherwise profoundly insoluble at the physiological ionic strength of extracellular fluids. Furthermore, SAP binds in vivo both to apoptotic cells, the surface blebs of which bear chromatin fragments, and to nuclear debris released by necrosis. SAP may therefore participate in handling of chromatin exposed by cell death. Here we show that mice with targeted deletion of the SAP gene spontaneously develop antinuclear autoimmunity and severe glomerulonephritis, a phenotype resembling human systemic lupus erythematosus, a serious autoimmune disease. The SAP-/- mice also have enhanced anti-DNA responses to immunization with extrinsic chromatin, and we demonstrate that degradation of long chromatin is retarded in the presence of SAP both in vitro and in vivo. These findings indicate that SAP has an important physiological role, inhibiting the formation of pathogenic autoantibodies against chromatin and DNA, probably by binding to chromatin and regulating its degradation.", + "TAG_DATA": [ + "103, mice {'context': 'B-organism'}", + "105, targeted {'perturbing_action': 'B-gene loss-of-function'}", + "106, deletion {'perturbing_action': 'I-gene loss-of-function'}", + "107, of {'perturbing_action': 'I-gene loss-of-function'}", + "108, the {'perturbing_action': 'I-gene loss-of-function'}", + "109, SAP {'perturbing_action': 'I-gene loss-of-function'}", + "110, gene {'perturbing_action': 'I-gene loss-of-function'}", + "130, SAP-/- {'perturbing_action': 'B-gene loss-of-function'}", + "131, mice {'context': 'B-organism'}", + "158, in {'context': 'B-in vitro'}", + "159, vitro {'context': 'I-in vitro'}", + "161, in {'context': 'B-in vivo'}", + "162, vivo. {'context': 'I-in vivo'}" + ], + "LINK_DATA": [ + "103, mice ['l0', 'l1', 'l2', 'l3', 'l4']", + "105, targeted ['l5', 'l6', 'l7', 'l8', 'l9']", + "106, deletion ['l0', 'l5', 'l10', 'l11', 'l12', 'l13']", + "107, of ['l1', 'l6', 'l10', 'l14', 'l15', 'l16']", + "108, the ['l2', 'l7', 'l11', 'l14', 'l17', 'l18']", + "109, SAP ['l3', 'l8', 'l12', 'l15', 'l17', 'l19']", + "110, gene ['l4', 'l9', 'l13', 'l16', 'l18', 'l19']", + "130, SAP-/- ['l20', 'l21', 'l22']", + "131, mice ['l20']", + "158, in ['l21', 'l23', 'l24', 'l25']", + "159, vitro ['l22', 'l23', 'l26', 'l27']", + "161, in ['l24', 'l26', 'l28']", + "162, vivo. ['l25', 'l27', 'l28']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "organism", + "words": [ + "mice" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "SAP", + "gene", + "SAP-/-" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SAP-/-" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + } + ] + }, + { + "PMID": "10371501", + "TEXT": "The HIV-1 Rev protein facilitates the nuclear export of mRNA containing the Rev response element (RRE) through binding to the export receptor CRM-1. Here we show that a cellular nuclear protein, Sam68 (Src-associated protein in mitosis), specifically interacts with RRE and can partially substitute for as well as synergize with Rev in RRE-mediated gene expression and virus replication. Differential sensitivity to leptomycin B, an inhibitor of CRM-1, indicates that the export pathways mediated by Rev and Sam68 are distinct. C-terminally deleted mutants of Sam68 inhibited the transactivation of RRE-mediated expression by both wild-type Sam68 and Rev. They were retained in the cytoplasm and impeded the nuclear localization of Rev in co-expressed cells. These mutants also inhibited wild-type HIV-1 replication to the same extent as the RevM10 mutant, and may be useful as anti-viral agents in the treatment of AIDS.", + "TAG_DATA": [ + "79, C-terminally {'perturbing_action': 'B-other'}", + "80, deleted {'perturbing_action': 'I-gene loss-of-function'}", + "81, mutants {'perturbing_action': 'I-other'}", + "82, of {'perturbing_action': 'I-other'}", + "83, Sam68 {'perturbing_action': 'I-other'}", + "111, cells. {'context': 'B-cells'}", + "125, RevM10 {'perturbing_action': 'B-other'}" + ], + "LINK_DATA": [ + "79, C-terminally ['l0', 'l1', 'l2', 'l3', 'l4']", + "80, deleted ['l0', 'l5', 'l6', 'l7', 'l8']", + "81, mutants ['l1', 'l5', 'l9', 'l10', 'l11']", + "82, of ['l2', 'l6', 'l9', 'l12', 'l13']", + "83, Sam68 ['l3', 'l7', 'l10', 'l12', 'l14']", + "111, cells. ['l4', 'l8', 'l11', 'l13', 'l14']", + "125, RevM10 ['l15']", + "126, mutant, ['l15']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "C-terminally", + "mutants", + "of", + "Sam68" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deleted" + ] + }, + "context": { + "val": "cells", + "words": [ + "cells." + ] + } + } + ] + }, + { + "PMID": "10229233", + "TEXT": "The transcription factor NF-kappaB is a regulator of cell death or survival. To investigate the role of NF-kappaB in neuronal cell death, we studied its activation in a rodent model of stroke. In the ischemic hemisphere, NF-kappaB was activated, as determined by increased expression of an NF-kappaB-driven reporter transgene, nuclear translocation of NF-kappaB in neurons and enhanced DNA binding of NF-kappaB subunits RelA and p50. In p50 knockout mice, ischemic damage was significantly reduced. This indicates a cell death-promoting role of NF-kappaB in focal ischemia. NF-kappaB may provide a new pharmacological target in neurologic disease.", + "TAG_DATA": [ + "54, neurons {'context': 'B-cells'}", + "66, p50 {'perturbing_action': 'B-gene loss-of-function'}", + "67, knockout {'perturbing_action': 'I-gene loss-of-function'}", + "68, mice, {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "66, p50 ['l0', 'l1']", + "67, knockout ['l0', 'l2']", + "68, mice, ['l1', 'l2']" + ], + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p50", + "knockout" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice," + ] + } + } + ] + }, + { + "PMID": "10229231", + "TEXT": "Programmed cell death is a process required for the normal development of an organism. One of the best understood apoptotic pathways occurs in T lymphocytes and is mediated by Fas/Fas ligand (FasL) interaction. During studies of apoptosis induced by T cell-receptor engagement, we identified ALG-4F, a truncated transcript that prevents T cell-receptor-induced FasL upregulation and cell death. Overexpression of full-length ALG-4 induced transcription of FasL and, consequently, apoptosis. These results indicate that ALG-4 is necessary and sufficient for FasL expression. Fas/FasL interaction initiates cell death in many other systems, and its dysregulation is a mechanism by which several pathologic conditions arise. Understanding the molecular mechanisms of FasL regulation could be very useful in elucidating how these diseases develop and in identifying potential therapeutic targets.", + "TAG_DATA": [ + "49, prevents {'effect': 'B-negative'}", + "55, cell {'phenotype': 'B-cell death'}", + "56, death. {'phenotype': 'I-cell death'}", + "57, Overexpression {'perturbing_action': 'B-gene gain-of-function'}", + "58, of {'perturbing_action': 'I-gene gain-of-function'}", + "59, full-length {'perturbing_action': 'I-gene gain-of-function'}", + "60, ALG-4 {'perturbing_action': 'I-gene gain-of-function'}", + "67, apoptosis. {'phenotype': 'B-apoptosis'}" + ], + "LINK_DATA": [ + "49, prevents ['l0', 'l1']", + "55, cell ['l0', 'l2']", + "56, death. ['l1', 'l2']", + "57, Overexpression ['l3', 'l4', 'l5', 'l6']", + "58, of ['l3', 'l7', 'l8', 'l9']", + "59, full-length ['l4', 'l7', 'l10', 'l11']", + "60, ALG-4 ['l5', 'l8', 'l10', 'l12']", + "67, apoptosis. ['l6', 'l9', 'l11', 'l12']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + }, + "phenotype": { + "val": "cell death", + "words": [ + "cell", + "death." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "full-length", + "ALG-4" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis." + ] + } + } + ] + }, + { + "PMID": "10086390", + "TEXT": "Familial hypertrophic cardiomyopathy (FHC) is a genetic disorder resulting from mutations in genes encoding sarcomeric proteins. This typically induces hyperdynamic ejection, impaired relaxation, delayed early filling, myocyte disarray and fibrosis, and increased chamber end-systolic stiffness. To better understand the disease pathogenesis, early (primary) abnormalities must be distinguished from evolving responses to the genetic defect. We did in vivo analysis using a mouse model of FHC with an Arg403Gln alpha-cardiac myosin heavy chain missense mutation, and used newly developed methods for assessing in situ pressure-volume relations. Hearts of young mutant mice (6 weeks old), which show no chamber morphologic or gross histologic abnormalities, had altered contraction kinetics, with considerably delayed pressure relaxation and chamber filling, yet accelerated systolic pressure rise. Older mutant mice (20 weeks old), which develop fiber disarray and fibrosis, had diastolic and systolic kinetic changes similar to if not slightly less than those of younger mice. However, the hearts of older mutant mice also showed hyperdynamic contraction, with increased end-systolic chamber stiffness, outflow tract pressure gradients and a lower cardiac index due to reduced chamber filling; all 'hallmarks' of human disease. These data provide new insights into the temporal evolution of FHC. Such data may help direct new therapeutic strategies to diminish disease progression.", + "TAG_DATA": [ + "56, in {'context': 'B-in vivo'}", + "57, vivo {'context': 'I-in vivo'}", + "61, mouse {'context': 'B-organism'}", + "62, model {'context': 'I-organism'}", + "67, Arg403Gln {'perturbing_action': 'B-other'}", + "68, alpha-cardiac {'perturbing_action': 'I-other'}", + "69, myosin {'perturbing_action': 'I-other'}", + "70, heavy {'perturbing_action': 'I-other'}", + "71, chain {'perturbing_action': 'I-other'}", + "72, missense {'perturbing_action': 'I-other'}", + "73, mutation, {'perturbing_action': 'I-other'}", + "85, Hearts {'context': 'B-tissue/organ'}", + "89, mice {'context': 'B-organism'}", + "121, mice {'context': 'B-organism'}", + "150, hearts {'context': 'B-tissue/organ'}", + "154, mice {'context': 'B-organism'}" + ], + "LINK_DATA": [ + "56, in ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9']", + "57, vivo ['l0', 'l10', 'l11', 'l12', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18']", + "61, mouse ['l1', 'l10', 'l19', 'l20', 'l21', 'l22', 'l23', 'l24', 'l25', 'l26']", + "62, model ['l2', 'l11', 'l19', 'l27', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "67, Arg403Gln ['l3', 'l12', 'l20', 'l27', 'l34', 'l35', 'l36', 'l37', 'l38', 'l39', 'l40', 'l41']", + "68, alpha-cardiac ['l4', 'l13', 'l21', 'l28', 'l34', 'l42', 'l43', 'l44', 'l45', 'l46', 'l47', 'l48']", + "69, myosin ['l5', 'l14', 'l22', 'l29', 'l35', 'l42', 'l49', 'l50', 'l51', 'l52', 'l53', 'l54']", + "70, heavy ['l6', 'l15', 'l23', 'l30', 'l36', 'l43', 'l49', 'l55', 'l56', 'l57', 'l58', 'l59']", + "71, chain ['l7', 'l16', 'l24', 'l31', 'l37', 'l44', 'l50', 'l55', 'l60', 'l61', 'l62', 'l63']", + "72, missense ['l8', 'l17', 'l25', 'l32', 'l38', 'l45', 'l51', 'l56', 'l60', 'l64', 'l65', 'l66']", + "73, mutation, ['l9', 'l18', 'l26', 'l33', 'l39', 'l46', 'l52', 'l57', 'l61', 'l64', 'l67', 'l68']", + "85, Hearts ['l40', 'l47', 'l53', 'l58', 'l62', 'l65', 'l67', 'l69']", + "89, mice ['l41', 'l48', 'l54', 'l59', 'l63', 'l66', 'l68', 'l69']", + "150, hearts ['l70']", + "154, mice ['l70']" + ], + "LINKED_TAGS": [ + { + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Arg403Gln", + "alpha-cardiac", + "myosin", + "heavy", + "chain", + "missense", + "mutation," + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "mouse", + "model", + "mice" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Arg403Gln", + "alpha-cardiac", + "myosin", + "heavy", + "chain", + "missense", + "mutation," + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Arg403Gln", + "alpha-cardiac", + "myosin", + "heavy", + "chain", + "missense", + "mutation," + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "Hearts" + ] + } + } + ] + }, + { + "PMID": "9930862", + "TEXT": "To evaluate the utility of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a cancer therapeutic, we created leucine zipper (LZ) forms of human (hu) and murine (mu) TRAIL to promote and stabilize the formation of trimers. Both were biologically active, inducing apoptosis of both human and murine target cells in vitro with similar specific activities. In contrast to the fulminant hepatotoxicity of LZ-huCD95L in vivo, administration of either LZ-huTRAIL or LZ-muTRAIL did not seem toxic to normal tissues of mice. Finally, repeated treatments with LZ-huTRAIL actively suppressed growth of the TRAIL-sensitive human mammary adenocarcinoma cell line MDA-231 in CB.17 (SCID) mice, and histologic examination of tumors from SCID mice treated with LZ-huTRAIL demonstrated clear areas of apoptotic necrosis within 9-12 hours of injection.", + "TAG_DATA": [ + "40, inducing {'effect': 'B-positive'}", + "41, apoptosis {'phenotype': 'B-apoptosis'}", + "44, human {'context': 'B-transformed cells'}", + "45, and {'context': 'I-transformed cells'}", + "46, murine {'context': 'I-transformed cells'}", + "47, target {'context': 'I-transformed cells'}", + "48, cells {'context': 'I-transformed cells'}", + "49, in {'context': 'B-in vitro'}", + "50, vitro {'context': 'I-in vitro'}", + "63, in {'context': 'B-in vivo'}", + "64, vivo, {'context': 'I-in vivo'}", + "76, normal {'context': 'B-tissue/organ'}", + "77, tissues {'context': 'I-tissue/organ'}", + "79, mice. {'context': 'B-organism'}", + "90, TRAIL-sensitive {'context': 'B-transformed cells'}", + "91, human {'context': 'I-transformed cells'}", + "92, mammary {'context': 'I-transformed cells'}", + "93, adenocarcinoma {'context': 'I-transformed cells'}", + "94, cell {'context': 'I-transformed cells'}", + "95, line {'context': 'I-transformed cells'}", + "96, MDA-231 {'context': 'I-transformed cells'}", + "98, CB.17 {'context': 'B-organism'}", + "100, mice, {'context': 'B-organism'}", + "105, tumors {'context': 'B-neoplasm'}", + "107, SCID {'context': 'B-organism'}", + "108, mice {'context': 'I-organism'}", + "116, apoptotic {'phenotype': 'B-apoptosis'}", + "117, necrosis {'phenotype': 'B-necrosis'}" + ], + "LINK_DATA": [ + "40, inducing ['l0', 'l1', 'l2', 'l3', 'l4', 'l5', 'l6', 'l7', 'l8', 'l9', 'l10', 'l11', 'l12']", + "41, apoptosis ['l0', 'l13', 'l14', 'l15', 'l16', 'l17', 'l18', 'l19', 'l20', 'l21']", + "44, human ['l1', 'l13', 'l22', 'l23', 'l24', 'l25', 'l26', 'l27']", + "45, and ['l2', 'l14', 'l22', 'l28', 'l29', 'l30', 'l31', 'l32', 'l33']", + "46, murine ['l3', 'l15', 'l23', 'l28', 'l34', 'l35', 'l36', 'l37', 'l38']", + "47, target ['l4', 'l16', 'l24', 'l29', 'l34', 'l39', 'l40', 'l41']", + "48, cells ['l5', 'l17', 'l25', 'l30', 'l35', 'l39', 'l42', 'l43']", + "49, in ['l6', 'l18', 'l26', 'l31', 'l36', 'l40', 'l42', 'l44']", + "50, vitro ['l7', 'l19', 'l27', 'l32', 'l37', 'l41', 'l43', 'l44']", + "63, in ['l8', 'l45', 'l46', 'l47', 'l48']", + "64, vivo, ['l9', 'l20', 'l33', 'l38', 'l45', 'l49', 'l50', 'l51']", + "76, normal ['l10', 'l46', 'l49', 'l52', 'l53']", + "77, tissues ['l11', 'l21', 'l47', 'l50', 'l52', 'l54']", + "79, mice. ['l12', 'l48', 'l51', 'l53', 'l54']", + "90, TRAIL-sensitive ['l55', 'l56', 'l57', 'l58', 'l59', 'l60', 'l61', 'l62', 'l63', 'l64', 'l65', 'l66']", + "91, human ['l55', 'l67', 'l68', 'l69', 'l70', 'l71', 'l72', 'l73', 'l74', 'l75', 'l76']", + "92, mammary ['l56', 'l67', 'l77', 'l78', 'l79', 'l80', 'l81', 'l82', 'l83', 'l84', 'l85', 'l86']", + "93, adenocarcinoma ['l57', 'l68', 'l77', 'l87', 'l88', 'l89', 'l90', 'l91', 'l92', 'l93', 'l94']", + "94, cell ['l58', 'l69', 'l78', 'l87', 'l95', 'l96', 'l97', 'l98', 'l99', 'l100', 'l101']", + "95, line ['l59', 'l70', 'l79', 'l88', 'l95', 'l102', 'l103', 'l104', 'l105', 'l106', 'l107']", + "96, MDA-231 ['l60', 'l71', 'l80', 'l89', 'l96', 'l102', 'l108', 'l109', 'l110', 'l111', 'l112']", + "98, CB.17 ['l61', 'l72', 'l81', 'l90', 'l97', 'l103', 'l108', 'l113', 'l114', 'l115', 'l116', 'l117', 'l118']", + "100, mice, ['l62', 'l73', 'l82', 'l91', 'l98', 'l104', 'l109', 'l113', 'l119', 'l120', 'l121', 'l122']", + "105, tumors ['l63', 'l74', 'l83', 'l92', 'l99', 'l105', 'l110', 'l114', 'l119', 'l123', 'l124', 'l125', 'l126']", + "107, SCID ['l115', 'l123', 'l127', 'l128', 'l129']", + "108, mice ['l64', 'l84', 'l116', 'l120', 'l124', 'l127', 'l130', 'l131']", + "116, apoptotic ['l65', 'l75', 'l85', 'l93', 'l100', 'l106', 'l111', 'l117', 'l121', 'l125', 'l128', 'l130', 'l132']", + "117, necrosis ['l66', 'l76', 'l86', 'l94', 'l101', 'l107', 'l112', 'l118', 'l122', 'l126', 'l129', 'l131', 'l132']" + ], + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "and", + "murine", + "target", + "cells" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "in", + "vivo," + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "normal", + "tissues" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + }, + "context": { + "val": "organism", + "words": [ + "mice." + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis", + "apoptotic" + ] + }, + "context": { + "val": "transformed cells", + "words": [ + "human", + "and", + "murine", + "target", + "cells", + "TRAIL-sensitive", + "mammary", + "adenocarcinoma", + "cell", + "line", + "MDA-231" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vitro", + "words": [ + "in", + "vitro" + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "in vivo", + "words": [ + "vivo," + ] + } + }, + { + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptosis" + ] + }, + "context": { + "val": "tissue/organ", + "words": [ + "tissues" + ] + } + }, + { + "context": { + "val": "transformed cells", + "words": [ + "TRAIL-sensitive", + "human", + "mammary", + "adenocarcinoma", + "cell", + "line", + "MDA-231" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "CB.17", + "mice,", + "SCID", + "mice" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic" + ] + } + }, + { + "context": { + "val": "organism", + "words": [ + "CB.17", + "mice,", + "SCID", + "mice" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "phenotype": { + "val": "apoptosis", + "words": [ + "apoptotic" + ] + } + }, + { + "context": { + "val": "neoplasm", + "words": [ + "tumors" + ] + }, + "phenotype": { + "val": "necrosis", + "words": [ + "necrosis" + ] + } + } + ] + } +] \ No newline at end of file diff --git a/abstract_analysis/pubmed_tag_link_pa_effect.json b/abstract_analysis/pubmed_tag_link_pa_effect.json new file mode 100644 index 0000000..22ef84d --- /dev/null +++ b/abstract_analysis/pubmed_tag_link_pa_effect.json @@ -0,0 +1,13380 @@ +[ + { + "PMID": "33958797", + "TEXT": "Langerhans cell histiocytosis (LCH) is a potentially fatal condition characterized by granulomatous lesions with characteristic clonal mononuclear phagocytes (MNPs) harboring activating somatic mutations in mitogen-activated protein kinase (MAPK) pathway genes, most notably BRAFV600E. We recently discovered that the BRAFV600E mutation can also affect multipotent hematopoietic progenitor cells (HPCs) in multisystem LCH disease. How the BRAFV600E mutation in HPCs leads to LCH is not known. Here we show that enforced expression of the BRAFV600E mutation in early mouse and human multipotent HPCs induced a senescence program that led to HPC growth arrest, apoptosis resistance and a senescence-associated secretory phenotype (SASP). SASP, in turn, promoted HPC skewing toward the MNP lineage, leading to the accumulation of senescent MNPs in tissue and the formation of LCH lesions. Accordingly, elimination of senescent cells using INK-ATTAC transgenic mice, as well as pharmacologic blockade of SASP, improved LCH disease in mice. These results identify senescent cells as a new target for the treatment of LCH.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "enforced", + "expression", + "of", + "the", + "BRAFV600E", + "mutation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "led", + "to" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "enforced", + "expression", + "of", + "the", + "BRAFV600E", + "mutation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest,", + "resistance" + ] + } + } + ] + }, + { + "PMID": "31591596", + "TEXT": "The essential product of the Duchenne muscular dystrophy (DMD) gene is dystrophin1, a rod-like protein2 that protects striated myocytes from contraction-induced injury3,4. Dystrophin-related protein (or utrophin) retains most of the structural and protein binding elements of dystrophin5. Importantly, normal thymic expression in DMD patients6 should protect utrophin by central immunologic tolerance. We designed a codon-optimized, synthetic transgene encoding a miniaturized utrophin (µUtro), deliverable by adeno-associated virus (AAV) vectors. Here, we show that µUtro is a highly functional, non-immunogenic substitute for dystrophin, preventing the most deleterious histological and physiological aspects of muscular dystrophy in small and large animal models. Following systemic administration of an AAV-µUtro to neonatal dystrophin-deficient mdx mice, histological and biochemical markers of myonecrosis and regeneration are completely suppressed throughout growth to adult weight. In the dystrophin-deficient golden retriever model, µUtro non-toxically prevented myonecrosis, even in the most powerful muscles. In a stringent test of immunogenicity, focal expression of µUtro in the deletional-null German shorthaired pointer model produced no evidence of cell-mediated immunity, in contrast to the robust T cell response against similarly constructed µDystrophin (µDystro). These findings support a model in which utrophin-derived therapies might be used to treat clinical dystrophin deficiency, with a favorable immunologic profile and preserved function in the face of extreme miniaturization.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "dystrophin-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + } + ] + }, + { + "PMID": "30833751", + "TEXT": "Cancer cells can evade immune surveillance through the expression of inhibitory ligands that bind their cognate receptors on immune effector cells. Expression of programmed death ligand 1 in tumor microenvironments is a major immune checkpoint for tumor-specific T cell responses as it binds to programmed cell death protein-1 on activated and dysfunctional T cells1. The activity of myeloid cells such as macrophages and neutrophils is likewise regulated by a balance between stimulatory and inhibitory signals. In particular, cell surface expression of the CD47 protein creates a 'don't eat me' signal on tumor cells by binding to SIRPα expressed on myeloid cells2-5. Using a haploid genetic screen, we here identify glutaminyl-peptide cyclotransferase-like protein (QPCTL) as a major component of the CD47-SIRPα checkpoint. Biochemical analysis demonstrates that QPCTL is critical for pyroglutamate formation on CD47 at the SIRPα binding site shortly after biosynthesis. Genetic and pharmacological interference with QPCTL activity enhances antibody-dependent cellular phagocytosis and cellular cytotoxicity of tumor cells. Furthermore, interference with QPCTL expression leads to a major increase in neutrophil-mediated killing of tumor cells in vivo. These data identify QPCTL as a novel target to interfere with the CD47 pathway and thereby augment antibody therapy of cancer.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "activity" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + } + } + ] + }, + { + "PMID": "30833748", + "TEXT": "Pancreatic ductal adenocarcinoma (PDA) was responsible for ~ 44,000 deaths in the United States in 2018 and is the epitome of a recalcitrant cancer driven by a pharmacologically intractable oncoprotein, KRAS1-4. Downstream of KRAS, the RAF→MEK→ERK signaling pathway plays a central role in pancreatic carcinogenesis5. However, paradoxically, inhibition of this pathway has provided no clinical benefit to patients with PDA6. Here we show that inhibition of KRAS→RAF→MEK→ERK signaling elicits autophagy, a process of cellular recycling that protects PDA cells from the cytotoxic effects of KRAS pathway inhibition. Mechanistically, inhibition of MEK1/2 leads to activation of the LKB1→AMPK→ULK1 signaling axis, a key regulator of autophagy. Furthermore, combined inhibition of MEK1/2 plus autophagy displays synergistic anti-proliferative effects against PDA cell lines in vitro and promotes regression of xenografted patient-derived PDA tumors in mice. The observed effect of combination trametinib plus chloroquine was not restricted to PDA as other tumors, including patient-derived xenografts (PDX) of NRAS-mutated melanoma and BRAF-mutated colorectal cancer displayed similar responses. Finally, treatment of a patient with PDA with the combination of trametinib plus hydroxychloroquine resulted in a partial, but nonetheless striking disease response. These data suggest that this combination therapy may represent a novel strategy to target RAS-driven cancers.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "MEK1/2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "elicits", + "promotes" + ] + } + } + ] + }, + { + "PMID": "30510257", + "TEXT": "Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "miR-203," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + } + ] + }, + { + "PMID": "30374199", + "TEXT": "Mutationally activated BRAFV600E influences the behavior of different types of cells in the brain and leads to promotion of seizures as well as brain tumors, indicating how both can be pharmacologically targeted in the clinic.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "activated", + "BRAFV600E" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotion" + ] + } + } + ] + }, + { + "PMID": "29808006", + "TEXT": "RAS mutations are frequent in human cancer, especially in pancreatic, colorectal and non-small-cell lung cancers (NSCLCs)1-3. Inhibition of the RAS oncoproteins has proven difficult4, and attempts to target downstream effectors5-7 have been hampered by the activation of compensatory resistance mechanisms8. It is also well established that KRAS-mutant tumors are insensitive to inhibition of upstream growth factor receptor signaling. Thus, epidermal growth factor receptor antibody therapy is only effective in KRAS wild-type colon cancers9,10. Consistently, inhibition of SHP2 (also known as PTPN11), which links receptor tyrosine kinase signaling to the RAS-RAF-MEK-ERK pathway11,12, was shown to be ineffective in KRAS-mutant or BRAF-mutant cancer cell lines13. Our data also indicate that SHP2 inhibition in KRAS-mutant NSCLC cells under normal cell culture conditions has little effect. By contrast, SHP2 inhibition under growth factor-limiting conditions in vitro results in a senescence response. In vivo, inhibition of SHP2 in KRAS-mutant NSCLC also provokes a senescence response, which is exacerbated by MEK inhibition. Our data identify SHP2 inhibition as an unexpected vulnerability of KRAS-mutant NSCLC cells that remains undetected in cell culture and can be exploited therapeutically.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2", + "(also" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "little", + "effect." + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2", + "(also", + "MEK", + "inhibition." + ] + }, + "effect": { + "val": "positive", + "words": [ + "in", + "results", + "provokes" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BRAF-mutant", + "KRAS-mutant" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "little", + "effect." + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "BRAF-mutant", + "KRAS-mutant" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in", + "provokes" + ] + } + } + ] + }, + { + "PMID": "29662201", + "TEXT": "Proliferating cells, compared with quiescent cells, are more dependent on glucose for their growth. Although glucose transport in keratinocytes is mediated largely by the Glut1 facilitative transporter, we found that keratinocyte-specific ablation of Glut1 did not compromise mouse skin development and homeostasis. Ex vivo metabolic profiling revealed altered sphingolipid, hexose, amino acid, and nucleotide metabolism in Glut1-deficient keratinocytes, thus suggesting metabolic adaptation. However, cultured Glut1-deficient keratinocytes displayed metabolic and oxidative stress and impaired proliferation. Similarly, Glut1 deficiency impaired in vivo keratinocyte proliferation and migration within wounded or UV-damaged mouse skin. Notably, both genetic and pharmacological Glut1 inactivation decreased hyperplasia in mouse models of psoriasis-like disease. Topical application of a Glut1 inhibitor also decreased inflammation in these models. Glut1 inhibition decreased the expression of pathology-associated genes in human psoriatic skin organoids. Thus, Glut1 is selectively required for injury- and inflammation-associated keratinocyte proliferation, and its inhibition offers a novel treatment strategy for psoriasis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "keratinocyte-specific", + "ablation", + "of", + "Glut1", + "Glut1-deficient", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + } + ] + }, + { + "PMID": "29578538", + "TEXT": "Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer diagnosed in more than 200,000 women each year and is recalcitrant to targeted therapies. Although TNBCs harbor multiple hyperactive receptor tyrosine kinases (RTKs), RTK inhibitors have been largely ineffective in TNBC patients thus far. We developed a broadly effective therapeutic strategy for TNBC that is based on combined inhibition of receptors that share the negative regulator PTPN12. Previously, we and others identified the tyrosine phosphatase PTPN12 as a tumor suppressor that is frequently inactivated in TNBC. PTPN12 restrains several RTKs, suggesting that PTPN12 deficiency leads to aberrant activation of multiple RTKs and a co-dependency on these receptors. This in turn leads to the therapeutic hypothesis that PTPN12-deficient TNBCs may be responsive to combined RTK inhibition. However, the repertoire of RTKs that are restrained by PTPN12 in human cells has not been systematically explored. By methodically identifying the suite of RTK substrates (MET, PDGFRβ, EGFR, and others) inhibited by PTPN12, we rationalized a combination RTK-inhibitor therapy that induced potent tumor regression across heterogeneous models of TNBC. Orthogonal approaches revealed that PTPN12 was recruited to and inhibited these receptors after ligand stimulation, thereby serving as a feedback mechanism to limit receptor signaling. Cancer-associated mutation of PTPN12 or reduced PTPN12 protein levels diminished this feedback mechanism, leading to aberrant activity of these receptors. Restoring PTPN12 protein levels restrained signaling from RTKs, including PDGFRβ and MET, and impaired TNBC survival. In contrast with single agents, combined inhibitors targeting the PDGFRβ and MET receptors induced the apoptosis in TNBC cells in vitro and in vivo. This therapeutic strategy resulted in tumor regressions in chemo-refractory patient-derived TNBC models. Notably, response correlated with PTPN12 deficiency, suggesting that impaired receptor feedback may establish a combined addiction to these proto-oncogenic receptors. Taken together, our data provide a rationale", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PTPN12", + "reduced", + "deficiency," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "resulted" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Cancer-associated", + "mutation", + "of", + "PTPN12" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoring", + "PTPN12", + "protein", + "levels" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "resulted" + ] + } + } + ] + }, + { + "PMID": "29334376", + "TEXT": "Metastasis results from a complex set of traits acquired by tumor cells, distinct from those necessary for tumorigenesis. Here, we investigate the contribution of enhancer elements to the metastatic phenotype of osteosarcoma. Through epigenomic profiling, we identify substantial differences in enhancer activity between primary and metastatic human tumors and between near isogenic pairs of highly lung metastatic and nonmetastatic osteosarcoma cell lines. We term these regions metastatic variant enhancer loci (Met-VELs). Met-VELs drive coordinated waves of gene expression during metastatic colonization of the lung. Met-VELs cluster nonrandomly in the genome, indicating that activity of these enhancers and expression of their associated gene targets are positively selected. As evidence of this causal association, osteosarcoma lung metastasis is inhibited by global interruptions of Met-VEL-associated gene expression via pharmacologic BET inhibition, by knockdown of AP-1 transcription factors that occupy Met-VELs, and by knockdown or functional inhibition of individual genes activated by Met-VELs, such as that encoding coagulation factor III/tissue factor (F3). We further show that genetic deletion of a single Met-VEL at the F3 locus blocks metastatic cell outgrowth in the lung. These findings indicate that Met-VELs and the genes they regulate play a functional role in metastasis and may be suitable targets for antimetastatic therapies.", + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "deletion", + "of", + "a", + "single", + "Met-VEL", + "at", + "the", + "F3", + "locus" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + } + } + ] + }, + { + "PMID": "28967920", + "TEXT": "Treating KRAS-mutant lung adenocarcinoma (LUAD) remains a major challenge in cancer treatment given the difficulties associated with directly inhibiting the KRAS oncoprotein. One approach to addressing this challenge is to define mutations that frequently co-occur with those in KRAS, which themselves may lead to therapeutic vulnerabilities in tumors. Approximately 20% of KRAS-mutant LUAD tumors carry loss-of-function mutations in the KEAP1 gene encoding Kelch-like ECH-associated protein 1 (refs. 2, 3, 4), a negative regulator of nuclear factor erythroid 2-like 2 (NFE2L2; hereafter NRF2), which is the master transcriptional regulator of the endogenous antioxidant response. The high frequency of mutations in KEAP1 suggests an important role for the oxidative stress response in lung tumorigenesis. Using a CRISPR-Cas9-based approach in a mouse model of KRAS-driven LUAD, we examined the effects of Keap1 loss in lung cancer progression. We show that loss of Keap1 hyperactivates NRF2 and promotes KRAS-driven LUAD in mice. Through a combination of CRISPR-Cas9-based genetic screening and metabolomic analyses, we show that Keap1- or Nrf2-mutant cancers are dependent on increased glutaminolysis, and this property can be therapeutically exploited through the pharmacological inhibition of glutaminase. Finally, we provide a rationale for stratification of human patients with lung cancer harboring KRAS/KEAP1- or KRAS/NRF2-mutant lung tumors as likely to respond to glutaminase inhibition.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Keap1", + "loss", + "of" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + } + ] + }, + { + "PMID": "28920957", + "TEXT": "A deeper understanding of the metastatic process is required for the development of new therapies that improve patient survival. Metastatic tumor cell growth and survival in distant organs is facilitated by the formation of a pre-metastatic niche that is composed of hematopoietic cells, stromal cells and extracellular matrix (ECM). Perivascular cells, including vascular smooth muscle cells (vSMCs) and pericytes, are involved in new vessel formation and in promoting stem cell maintenance and proliferation. Given the well-described plasticity of perivascular cells, we hypothesized that perivascular cells similarly regulate tumor cell fate at metastatic sites. We used perivascular-cell-specific and pericyte-specific lineage-tracing models to trace the fate of perivascular cells in the pre-metastatic and metastatic microenvironments. We show that perivascular cells lose the expression of traditional vSMC and pericyte markers in response to tumor-secreted factors and exhibit increased proliferation, migration and ECM synthesis. Increased expression of the pluripotency gene Klf4 in these phenotypically switched perivascular cells promoted a less differentiated state, characterized by enhanced ECM production, that established a pro-metastatic fibronectin-rich environment. Genetic inactivation of Klf4 in perivascular cells decreased formation of a pre-metastatic niche and metastasis. Our data revealed a previously unidentified role for perivascular cells in pre-metastatic niche formation and uncovered novel strategies for limiting metastasis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Increased", + "expression", + "of", + "the", + "pluripotency", + "gene", + "Klf4" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "inactivation", + "of", + "Klf4" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + } + ] + }, + { + "PMID": "27571347", + "TEXT": "Orthopedic implants containing biodegradable magnesium have been used for fracture repair with considerable efficacy; however, the underlying mechanisms by which these implants improve fracture healing remain elusive. Here we show the formation of abundant new bone at peripheral cortical sites after intramedullary implantation of a pin containing ultrapure magnesium into the intact distal femur in rats. This response was accompanied by substantial increases of neuronal calcitonin gene-related polypeptide-α (CGRP) in both the peripheral cortex of the femur and the ipsilateral dorsal root ganglia (DRG). Surgical removal of the periosteum, capsaicin denervation of sensory nerves or knockdown in vivo of the CGRP-receptor-encoding genes Calcrl or Ramp1 substantially reversed the magnesium-induced osteogenesis that we observed in this model. Overexpression of these genes, however, enhanced magnesium-induced osteogenesis. We further found that an elevation of extracellular magnesium induces magnesium transporter 1 (MAGT1)-dependent and transient receptor potential cation channel, subfamily M, member 7 (TRPM7)-dependent magnesium entry, as well as an increase in intracellular adenosine triphosphate (ATP) and the accumulation of terminal synaptic vesicles in isolated rat DRG neurons. In isolated rat periosteum-derived stem cells, CGRP induces CALCRL- and RAMP1-dependent activation of cAMP-responsive element binding protein 1 (CREB1) and SP7 (also known as osterix), and thus enhances osteogenic differentiation of these stem cells. Furthermore, we have developed an innovative, magnesium-containing intramedullary nail that facilitates femur fracture repair in rats with ovariectomy-induced osteoporosis. Taken together, these findings reveal a previously undefined role of magnesium in promoting CGRP-mediated osteogenic differentiation, which suggests the therapeutic potential of this ion in orthopedics.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "these", + "genes," + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + } + } + ] + }, + { + "PMID": "27270588", + "TEXT": "Brain metastases represent the greatest clinical challenge in treating HER2-positive breast cancer. We report the development of orthotopic patient-derived xenografts (PDXs) of HER2-expressing breast cancer brain metastases (BCBM), and their use for the identification of targeted combination therapies. Combined inhibition of PI3K and mTOR resulted in durable tumor regressions in three of five PDXs, and therapeutic response was correlated with a reduction in the phosphorylation of 4EBP1, an mTORC1 effector. The two nonresponding PDXs showed hypermutated genomes with enrichment of mutations in DNA-repair genes, which suggests an association of genomic instability with therapeutic resistance. These findings suggest that a biomarker-driven clinical trial of PI3K inhibitor in combination with an mTOR inhibitor should be conducted for patients with HER2-positive BCBM.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Combined", + "inhibition", + "of", + "PI3K", + "and", + "mTOR" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + } + } + ] + }, + { + "PMID": "27089513", + "TEXT": "Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality, yet antistromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor-β (TGF-β) signaling have high epithelial STAT3 activity and develop stiff, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several KRAS-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby STAT3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial STAT3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated STAT3 were associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors and highlight STAT3 and mechanics as key drivers of this phenotype.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "epithelial", + "STAT3", + "ablation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + } + } + ] + }, + { + "PMID": "26974310", + "TEXT": "Phosphatase and tensin homolog (PTEN) is a negative regulator of the phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) signaling pathway and a potent tumor suppressor in many types of cancer. To test a tumor suppressive role for PTEN in pre-B acute lymphoblastic leukemia (ALL), we induced Cre-mediated deletion of Pten in mouse models of pre-B ALL. In contrast to its role as a tumor suppressor in other cancers, loss of one or both alleles of Pten caused rapid cell death of pre-B ALL cells and was sufficient to clear transplant recipient mice of leukemia. Small-molecule inhibition of PTEN in human pre-B ALL cells resulted in hyperactivation of AKT, activation of the p53 tumor suppressor cell cycle checkpoint and cell death. Loss of PTEN function in pre-B ALL cells was functionally equivalent to acute activation of autoreactive pre-B cell receptor signaling, which engaged a deletional checkpoint for the removal of autoreactive B cells. We propose that targeted inhibition of PTEN and hyperactivation of AKT triggers a checkpoint for the elimination of autoreactive B cells and represents a new strategy to overcome drug resistance in human ALL.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "induced", + "Cre-mediated", + "deletion", + "of", + "Pten", + "loss", + "one", + "or", + "both", + "alleles" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused", + "resulted", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Small-molecule", + "inhibition", + "of", + "PTEN" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + } + } + ] + }, + { + "PMID": "26855149", + "TEXT": "Patients with advanced Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant lung adenocarcinoma are currently treated with standard chemotherapy because of a lack of efficacious targeted therapies. We reasoned that the identification of mediators of Kras signaling in early mouse lung hyperplasias might bypass the difficulties that are imposed by intratumor heterogeneity in advanced tumors, and that it might unveil relevant therapeutic targets. Transcriptional profiling of Kras(G12V)-driven mouse hyperplasias revealed intertumor diversity with a subset that exhibited an aggressive transcriptional profile analogous to that of advanced human adenocarcinomas. The top-scoring gene in this profile encodes the tyrosine kinase receptor DDR1. The genetic and pharmacological inhibition of DDR1 blocked tumor initiation and tumor progression, respectively. The concomitant inhibition of both DDR1 and Notch signaling induced the regression of KRAS;TP53-mutant patient-derived lung xenografts (PDX) with a therapeutic efficacy that was at least comparable to that of standard chemotherapy. Our data indicate that the combined inhibition of DDR1 and Notch signaling could be an effective targeted therapy for patients with KRAS-mutant lung adenocarcinoma.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "DDR1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "KRAS;TP53-mutant" + ] + } + } + ] + }, + { + "PMID": "26828195", + "TEXT": "Although mechanisms of acquired resistance of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. Here we observe that acquired resistance caused by the EGFR(T790M) gatekeeper mutation can occur either by selection of pre-existing EGFR(T790M)-positive clones or via genetic evolution of initially EGFR(T790M)-negative drug-tolerant cells. The path to resistance impacts the biology of the resistant clone, as those that evolved from drug-tolerant cells had a diminished apoptotic response to third-generation EGFR inhibitors that target EGFR(T790M); treatment with navitoclax, an inhibitor of the anti-apoptotic factors BCL-xL and BCL-2 restored sensitivity. We corroborated these findings using cultures derived directly from EGFR inhibitor-resistant patient tumors. These findings provide evidence that clinically relevant drug-resistant cancer cells can both pre-exist and evolve from drug-tolerant cells, and they point to therapeutic opportunities to prevent or overcome resistance in the clinic.", + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "diminished" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "third-generation", + "EGFR", + "inhibitors", + "target" + ] + } + } + ] + }, + { + "PMID": "26726877", + "TEXT": "Regulated necrosis (necroptosis) and apoptosis are crucially involved in severe cardiac pathological conditions, including myocardial infarction, ischemia-reperfusion injury and heart failure. Whereas apoptotic signaling is well defined, the mechanisms that underlie cardiomyocyte necroptosis remain elusive. Here we show that receptor-interacting protein 3 (RIP3) triggers myocardial necroptosis, in addition to apoptosis and inflammation, through activation of Ca(2+)-calmodulin-dependent protein kinase (CaMKII) rather than through the well-established RIP3 partners RIP1 and MLKL. In mice, RIP3 deficiency or CaMKII inhibition ameliorates myocardial necroptosis and heart failure induced by ischemia-reperfusion or by doxorubicin treatment. RIP3-induced activation of CaMKII, via phosphorylation or oxidation or both, triggers opening of the mitochondrial permeability transition pore and myocardial necroptosis. These findings identify CaMKII as a new RIP3 substrate and delineate a RIP3-CaMKII-mPTP myocardial necroptosis pathway, a promising target for the treatment of ischemia- and oxidative stress-induced myocardial damage and heart failure.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "RIP3", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "ameliorates" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CaMKII", + "inhibition" + ] + }, + "effect": { + "val": "negative", + "words": [ + "ameliorates" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CaMKII", + "inhibition" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + } + } + ] + }, + { + "PMID": "26618722", + "TEXT": "Mitochondrial dysfunction represents a critical step during the pathogenesis of Parkinson's disease (PD), and increasing evidence suggests abnormal mitochondrial dynamics and quality control as important underlying mechanisms. The VPS35 gene, which encodes a key component of the membrane protein-recycling retromer complex, is the third autosomal-dominant gene associated with PD. However, how VPS35 mutations lead to neurodegeneration remains unclear. Here we demonstrate that PD-associated VPS35 mutations caused mitochondrial fragmentation and cell death in cultured neurons in vitro, in mouse substantia nigra neurons in vivo and in human fibroblasts from an individual with PD who has the VPS35(D620N) mutation. VPS35-induced mitochondrial deficits and neuronal dysfunction could be prevented by inhibition of mitochondrial fission. VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation. Notably, oxidative stress increased the VPS35-DLP1 interaction, which we also found to be increased in the brains of sporadic PD cases. These results revealed a novel cellular mechanism for the involvement of VPS35 in mitochondrial fission, dysregulation of which is probably involved in the pathogenesis of familial, and possibly sporadic, PD.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "PD-associated", + "VPS35", + "mutations" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + } + ] + }, + { + "PMID": "26236991", + "TEXT": "Kidney fibrosis is marked by an epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells (TECs). Here we find that, during renal fibrosis, TECs acquire a partial EMT program during which they remain associated with their basement membrane and express markers of both epithelial and mesenchymal cells. The functional consequence of the EMT program during fibrotic injury is an arrest in the G2 phase of the cell cycle and lower expression of several solute and solvent transporters in TECs. We also found that transgenic expression of either Twist1 (encoding twist family bHLH transcription factor 1, known as Twist) or Snai1 (encoding snail family zinc finger 1, known as Snail) expression is sufficient to promote prolonged TGF-β1-induced G2 arrest of TECs, limiting the cells' potential for repair and regeneration. In mouse models of experimentally induced renal fibrosis, conditional deletion of Twist1 or Snai1 in proximal TECs resulted in inhibition of the EMT program and the maintenance of TEC integrity, while also restoring cell proliferation, dedifferentiation-associated repair and regeneration of the kidney parenchyma and attenuating interstitial fibrosis. Thus, inhibition of the EMT program in TECs during chronic renal injury represents a potential anti-fibrosis therapy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "of", + "either", + "Twist1", + "(encoding", + "twist", + "family", + "bHLH", + "transcription", + "factor", + "1,", + "known", + "as", + "Twist)", + "or", + "Snai1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promote" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "deletion", + "of", + "Twist1", + "or", + "Snai1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "deletion", + "of", + "Twist1", + "or", + "Snai1" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restoring" + ] + } + } + ] + }, + { + "PMID": "25985365", + "TEXT": "Pancreatic beta cell death is a hallmark of type 1 (T1D) and type 2 (T2D) diabetes, but the molecular mechanisms underlying this aspect of diabetic pathology are poorly understood. Here we report that expression of the microRNA (miR)-200 family is strongly induced in islets of diabetic mice and that beta cell-specific overexpression of miR-200 in mice is sufficient to induce beta cell apoptosis and lethal T2D. Conversely, mir-200 ablation in mice reduces beta cell apoptosis and ameliorates T2D. We show that miR-200 negatively regulates a conserved anti-apoptotic and stress-resistance network that includes the essential beta cell chaperone Dnajc3 (also known as p58IPK) and the caspase inhibitor Xiap. We also observed that mir-200 dosage positively controls activation of the tumor suppressor Trp53 and thereby creates a pro-apoptotic gene-expression signature found in islets of diabetic mice. Consequently, miR-200-induced T2D is suppressed by interfering with the signaling of Trp53 and Bax, a proapoptotic member of the B cell lymphoma 2 protein family. Our results reveal a crucial role for the miR-200 family in beta cell survival and the pathophysiology of diabetes.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "beta", + "cell-specific", + "overexpression", + "of", + "miR-200" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "miR-200" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "mir-200", + "ablation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + } + ] + }, + { + "PMID": "25706873", + "TEXT": "Metabolic reprogramming occurs in response to the cellular environment to mediate differentiation, but the fundamental mechanisms linking metabolic processes to differentiation programs remain to be elucidated. During osteoclast differentiation, a shift toward more oxidative metabolic processes occurs. In this study we identified the de novo DNA methyltransferase 3a (Dnmt3a) as a transcription factor that couples these metabolic changes to osteoclast differentiation. We also found that receptor activator of nuclear factor-κB ligand (RANKL), an essential cytokine for osteoclastogenesis, induces this metabolic shift towards oxidative metabolism, which is accompanied by an increase in S-adenosylmethionine (SAM) production. We found that SAM-mediated DNA methylation by Dnmt3a regulates osteoclastogenesis via epigenetic repression of anti-osteoclastogenic genes. The importance of Dnmt3a in bone homeostasis was underscored by the observations that Dnmt3a-deficient osteoclast precursor cells do not differentiate efficiently into osteoclasts and that mice with an osteoclast-specific deficiency in Dnmt3a have elevated bone mass due to a smaller number of osteoclasts. Furthermore, inhibition of DNA methylation by theaflavin-3,3'-digallate abrogated bone loss in models of osteoporosis. Thus, this study reveals the role of epigenetic processes in the regulation of cellular metabolism and differentiation, which may provide the molecular basis for a new therapeutic strategy for a variety of bone disorders.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dnmt3a-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "do" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dnmt3a-deficient" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not" + ] + } + } + ] + }, + { + "PMID": "24681597", + "TEXT": "Kindlin-1 is an integrin tail binding protein that controls integrin activation. Mutations in the FERMT-1 gene, which encodes for Kindlin-1, lead to Kindler syndrome in man, which is characterized by skin blistering, premature skin aging and skin cancer of unknown etiology. Here we show that loss of Kindlin-1 in mouse keratinocytes recapitulates Kindler syndrome and also produces enlarged and hyperactive stem cell compartments, which lead to hyperthickened epidermis, ectopic hair follicle development and increased skin tumor susceptibility. Mechanistically, Kindlin-1 controls keratinocyte adhesion through β1-class integrins and proliferation and differentiation of cutaneous epithelial stem cells by promoting α(v)β(6) integrin-mediated transforming growth factor-β (TGF-β) activation and inhibiting Wnt-β-catenin signaling through integrin-independent regulation of Wnt ligand expression. Our findings assign Kindlin-1 the previously unknown and essential task of controlling cutaneous epithelial stem cell homeostasis by balancing TGF-β-mediated growth-inhibitory signals and Wnt-β-catenin-mediated growth-promoting signals.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Kindlin-1" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "controls" + ] + } + } + ] + }, + { + "PMID": "23793099", + "TEXT": "Here we show that glioblastoma express high levels of branched-chain amino acid transaminase 1 (BCAT1), the enzyme that initiates the catabolism of branched-chain amino acids (BCAAs). Expression of BCAT1 was exclusive to tumors carrying wild-type isocitrate dehydrogenase 1 (IDH1) and IDH2 genes and was highly correlated with methylation patterns in the BCAT1 promoter region. BCAT1 expression was dependent on the concentration of α-ketoglutarate substrate in glioma cell lines and could be suppressed by ectopic overexpression of mutant IDH1 in immortalized human astrocytes, providing a link between IDH1 function and BCAT1 expression. Suppression of BCAT1 in glioma cell lines blocked the excretion of glutamate and led to reduced proliferation and invasiveness in vitro, as well as significant decreases in tumor growth in a glioblastoma xenograft model. These findings suggest a central role for BCAT1 in glioma pathogenesis, making BCAT1 and BCAA metabolism attractive targets for the development of targeted therapeutic approaches to treat patients with glioblastoma.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "mutant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Suppression", + "of", + "BCAT1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced", + "decreases" + ] + } + } + ] + }, + { + "PMID": "23584088", + "TEXT": "Platelets have a key role in atherogenesis and its complications. Both hypercholesterolemia and increased platelet production promote atherothrombosis; however, a potential link between altered cholesterol homeostasis and platelet production has not been explored. Here we show that transplantation of bone marrow deficient in ABCG4, a transporter of unknown function, into Ldlr(-/-) mice resulted in thrombocytosis, accelerated thrombosis and atherosclerosis. Although not detected in atherosclerotic lesions, Abcg4 was highly expressed in bone marrow megakaryocyte progenitors (MkPs). Abcg4(-/-) MkPs had defective cholesterol efflux to high-density lipoprotein (HDL), increased cell surface expression of the thrombopoietin (TPO) receptor (c-MPL) and enhanced proliferation. These consequences of ABCG4 deficiency seemed to reflect disruption of negative feedback regulation of c-MPL signaling by the E3 ligase c-CBL and the cholesterol-sensing LYN kinase. HDL infusion reduced platelet counts in Ldlr(-/-) mice and in a mouse model of myeloproliferative neoplasm in an ABCG4-dependent fashion. HDL infusions may offer a new approach to reducing atherothrombotic events associated with increased platelet production.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "bone", + "marrow", + "deficient", + "in", + "ABCG4,", + "Ldlr(-/-)", + "Abcg4(-/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerated", + "enhanced" + ] + } + } + ] + }, + { + "PMID": "23475202", + "TEXT": "We report that K5.Smad7 mice, which express a Smad7 transgene under the control of a keratin 5 promoter, were resistant to radiation-induced oral mucositis, a painful oral ulceration. In addition to nuclear factor κB (NF-κB) activation, which is known to contribute to oral mucositis, we found activated transforming growth factor β (TGF-β) signaling in cells from this condition. Smad7 dampened both pathways to attenuate inflammation, growth inhibition and apoptosis. Additionally, Smad7 promoted oral epithelial migration to close the wound. Further analyses revealed that TGF-β signaling Smads and their co-repressor C-terminal binding protein 1 (CtBP1) transcriptionally repressed Rac1, and that Smad7 abrogated this repression. Knocking down Rac1 expression in mouse keratinocytes abrogated Smad7-induced migration. Topical application of Smad7 protein conjugated with a cell-permeable Tat tag to oral mucosa showed prophylactic and therapeutic effects on radiation-induced oral mucositis in mice. Thus, we have identified new molecular mechanisms involved in oral mucositis pathogenesis, and our data suggest an alternative therapeutic strategy to block multiple pathological processes in this condition.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "K5.Smad7" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knocking", + "down", + "Rac1", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abrogated" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knocking", + "down", + "Rac1", + "expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "Smad7-induced" + ] + } + } + ] + }, + { + "PMID": "23377280", + "TEXT": "The mechanisms that regulate hematopoietic stem cell (HSC) regeneration after myelosuppressive injury are not well understood. We identified epidermal growth factor (EGF) to be highly enriched in the bone marrow serum of mice bearing deletion of Bak and Bax in TIE2-expressing cells in Tie2Cre; Bak1(-/-); Bax(flox/-) mice. These mice showed radioprotection of the HSC pool and 100% survival after a lethal dose of total-body irradiation (TBI). Bone marrow HSCs from wild-type mice expressed functional EGF receptor (EGFR), and systemic administration of EGF promoted the recovery of the HSC pool in vivo and improved the survival of mice after TBI. Conversely, administration of erlotinib, an EGFR antagonist, decreased both HSC regeneration and the survival of mice after TBI. Mice with EGFR deficiency in VAV-expressing hematopoietic cells also had delayed recovery of bone marrow stem and progenitor cells after TBI. Mechanistically, EGF reduced radiation-induced apoptosis of HSCs and mediated this effect through repression of the proapoptotic protein PUMA. Our findings show that EGFR signaling regulates HSC regeneration after myelosuppressive injury.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antagonist," + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antagonist," + ] + }, + "effect": { + "val": "positive", + "words": [ + "radiation-induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EGFR", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EGFR", + "deficiency" + ] + }, + "effect": { + "val": "positive", + "words": [ + "radiation-induced" + ] + } + } + ] + }, + { + "PMID": "22683778", + "TEXT": "Neoadjuvant chemotherapy (NAC) induces a pathological complete response (pCR) in ~30% of patients with breast cancer. However, many patients have residual cancer after chemotherapy, which correlates with a higher risk of metastatic recurrence and poorer outcome than those who achieve a pCR. We hypothesized that molecular profiling of tumors after NAC would identify genes associated with drug resistance. Digital transcript counting was used to profile surgically resected breast cancers after NAC. Low concentrations of dual specificity protein phosphatase 4 (DUSP4), an ERK phosphatase, correlated with high post-NAC tumor cell proliferation and with basal-like breast cancer (BLBC) status. BLBC had higher DUSP4 promoter methylation and gene expression patterns of Ras-ERK pathway activation relative to other breast cancer subtypes. DUSP4 overexpression increased chemotherapy-induced apoptosis, whereas DUSP4 depletion dampened the response to chemotherapy. Reduced DUSP4 expression in primary tumors after NAC was associated with treatment-refractory high Ki-67 scores and shorter recurrence-free survival. Finally, inhibition of mitogen-activated protein kinase kinase (MEK) synergized with docetaxel treatment in BLBC xenografts. Thus, DUSP4 downregulation activates the Ras-ERK pathway in BLBC, resulting in an attenuated response to anti-cancer chemotherapy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "DUSP4", + "overexpression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "chemotherapy-induced" + ] + } + } + ] + }, + { + "PMID": "22660634", + "TEXT": "Endometriosis is considered to be an estrogen-dependent inflammatory disease, but its etiology is unclear. Thus far, a mechanistic role for steroid receptor coactivators (SRCs) in the progression of endometriosis has not been elucidated. An SRC-1-null mouse model reveals that the mouse SRC-1 gene has an essential role in endometriosis progression. Notably, a previously unidentified 70-kDa SRC-1 proteolytic isoform is highly elevated both in the endometriotic tissue of mice with surgically induced endometriosis and in endometriotic stromal cells biopsied from patients with endometriosis compared to normal endometrium. Tnf⁻/⁻ and Mmp9⁻/⁻ mice with surgically induced endometriosis showed that activation of tumor necrosis factor a (TNF-α)-induced matrix metallopeptidase 9 (MMP9) activity mediates formation of the 70-kDa SRC-1 C-terminal isoform in endometriotic mouse tissue. In contrast to full-length SRC-1, the endometriotic 70-kDa SRC-1 C-terminal fragment prevents TNF-α-mediated apoptosis in human endometrial epithelial cells and causes the epithelial-mesenchymal transition and the invasion of human endometrial cells that are hallmarks of progressive endometriosis. Collectively, the newly identified TNF-α-MMP9-SRC-1 isoform functional axis promotes pathogenic progression of endometriosis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mmp9⁻/⁻" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + } + ] + }, + { + "PMID": "22610277", + "TEXT": "The Wnt–β-catenin and PI3K-AKT-FOXO3a pathways have a central role in cancer. AKT phosporylates FOXO3a, relocating it from the cell nucleus to the cytoplasm, an effect that is reversed by PI3K and AKT inhibitors. Simultaneous hyperactivation of the Wnt–β-catenin pathway and inhibition of PI3K-AKT signaling promote nuclear accumulation of β-catenin and FOXO3a, respectively, promoting cell scattering and metastasis by regulating a defined set of target genes. Indeed, the anti-tumoral AKT inhibitor API-2 promotes nuclear FOXO3a accumulation and metastasis of cells with high nuclear β-catenin content. Nuclear β-catenin confers resistance to the FOXO3a-mediated apoptosis induced by PI3K and AKT inhibitors in patient-derived primary cultures and in corresponding xenograft tumors in mice. This resistance is reversed by XAV-939, an inhibitor of Wnt–β-catenin signaling. In the presence of high nuclear β-catenin content, activation of FOXO3a by PI3K or AKT inhibitors makes it behave as a metastasis inductor rather than a proapoptotic tumor suppressor. We show that it is possible to evaluate the β-catenin status of patients' carcinomas and the response of patient-derived cells to target-directed drugs that accumulate FOXO3a in the nucleus before deciding on a course of treatment. We propose that this evaluation could be essential to the provision of a safer and more effective personalized treatment.", + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PI3K", + "and", + "AKT", + "inhibitors" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "FOXO3a-mediated" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PI3K", + "and", + "AKT", + "inhibitors" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PI3K", + "and", + "AKT", + "inhibitors" + ] + } + } + ] + }, + { + "PMID": "22426419", + "TEXT": "Inflammatory bowel diseases (IBDs) are chronic relapsing and remitting conditions associated with long-term gut dysfunction resulting from alterations to the enteric nervous system and a loss of enteric neurons. The mechanisms underlying inflammation-induced enteric neuron death are unknown. Here using in vivo models of experimental colitis we report that inflammation causes enteric neuron death by activating a neuronal signaling complex composed of P2X7 receptors (P2X7Rs), pannexin-1 (Panx1) channels, the Asc adaptor protein and caspases. Inhibition of P2X7R, Panx1, Asc or caspase activity prevented inflammation-induced neuron cell death. Preservation of enteric neurons by inhibiting Panx1 in vivo prevented the onset of inflammation-induced colonic motor dysfunction. Panx1 expression was reduced in Crohn's disease but not ulcerative colitis. We conclude that activation of neuronal Panx1 underlies neuron death and the subsequent development of abnormal gut motility in IBD. Targeting Panx1 represents a new neuroprotective strategy to ameliorate the progression of IBD-associated dysmotility.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "P2X7R,", + "Panx1,", + "Asc" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "P2X7R,", + "Panx1,", + "Asc" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inflammation-induced" + ] + } + } + ] + }, + { + "PMID": "22179319", + "TEXT": "Huntington's disease is a fatal neurodegenerative disorder caused by an expanded polyglutamine repeat in huntingtin (HTT) protein. We previously showed that calorie restriction ameliorated Huntington's disease pathogenesis and slowed disease progression in mice that model Huntington's disease (Huntington's disease mice). We now report that overexpression of sirtuin 1 (Sirt1), a mediator of the beneficial metabolic effects of calorie restriction, protects neurons against mutant HTT toxicity, whereas reduction of Sirt1 exacerbates mutant HTT toxicity. Overexpression of Sirt1 improves motor function, reduces brain atrophy and attenuates mutant-HTT-mediated metabolic abnormalities in Huntington's disease mice. Further mechanistic studies suggested that Sirt1 prevents the mutant-HTT-induced decline in brain-derived neurotrophic factor (BDNF) concentrations and the signaling of its receptor, TrkB, and restores dopamine- and cAMP-regulated phosphoprotein, 32 kDa (DARPP32) concentrations in the striatum. Sirt1 deacetylase activity is required for Sirt1-mediated neuroprotection in Huntington's disease cell models. Notably, we show that mutant HTT interacts with Sirt1 and inhibits Sirt1 deacetylase activity, which results in hyperacetylation of Sirt1 substrates such as forkhead box O3A (Foxo3a), thereby inhibiting its pro-survival function. Overexpression of Sirt1 counteracts the mutant-HTT-induced deacetylase deficit, enhances the deacetylation of Foxo3a and facilitates cell survival. These findings show a neuroprotective role for Sirt1 in mammalian Huntington's disease models and open new avenues for the development of neuroprotective strategies in Huntington's disease.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "Sirt1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "facilitates" + ] + } + } + ] + }, + { + "PMID": "21983857", + "TEXT": "Small-cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer for which there is no effective treatment. Using a mouse model in which deletion of Rb1 and Trp53 in the lung epithelium of adult mice induces SCLC, we found that the Hedgehog signaling pathway is activated in SCLC cells independently of the lung microenvironment. Constitutive activation of the Hedgehog signaling molecule Smoothened (Smo) promoted the clonogenicity of human SCLC in vitro and the initiation and progression of mouse SCLC in vivo. Reciprocally, deletion of Smo in Rb1 and Trp53-mutant lung epithelial cells strongly suppressed SCLC initiation and progression in mice. Furthermore, pharmacological blockade of Hedgehog signaling inhibited the growth of mouse and human SCLC, most notably following chemotherapy. These findings show a crucial cell-intrinsic role for Hedgehog signaling in the development and maintenance of SCLC and identify Hedgehog pathway inhibition as a therapeutic strategy to slow the progression of disease and delay cancer recurrence in individuals with SCLC.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "Rb1", + "and", + "Trp53", + "in", + "the", + "lung", + "epithelium" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Constitutive", + "activation", + "of", + "the", + "Hedgehog", + "signaling", + "molecule", + "Smoothened", + "(Smo)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + } + ] + }, + { + "PMID": "21317885", + "TEXT": "The TP53 gene (encoding the p53 tumor suppressor) is rarely mutated, although frequently inactivated, in medulloblastoma and ependymoma. Recent work in mouse models showed that the loss of p53 accelerated the development of medulloblastoma. The mechanism underlying p53 inactivation in human brain tumors is not completely understood. We show that ubiquitination factor E4B (UBE4B), an E3 and E4 ubiquitin ligase, physically interacts with p53 and Hdm2 (also known as Mdm2 in mice). UBE4B promotes p53 polyubiquitination and degradation and inhibits p53-dependent transactivation and apoptosis. Notably, silencing UBE4B expression impairs xenotransplanted tumor growth in a p53-dependent manner and overexpression of UBE4B correlates with decreased expression of p53 in these tumors. We also show that UBE4B overexpression is often associated with amplification of its gene in human brain tumors. Our data indicate that amplification and overexpression of UBE4B represent previously undescribed molecular mechanisms of inactivation of p53 in brain tumors.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "UBE4B", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + } + } + ] + }, + { + "PMID": "21258336", + "TEXT": "Hyperglycemia is associated with greater hematoma expansion and poor clinical outcomes after intracerebral hemorrhage. We show that cerebral hematoma expansion triggered by intracerebral infusion of autologous blood is greater in diabetic rats and mice compared to nondiabetic controls and that this augmented expansion is ameliorated by plasma kallikrein (PK) inhibition or deficiency. Intracerebral injection of purified PK augmented hematoma expansion in both diabetic and acutely hyperglycemic rats, whereas injection of bradykinin, plasmin or tissue plasminogen activator did not elicit such a response. This response, which occurs rapidly, was prevented by co-injection of the glycoprotein VI agonist convulxin and was mimicked by glycoprotein VI inhibition or deficiency, implicating an effect of PK on inhibiting platelet aggregation. We show that PK inhibits collagen-induced platelet aggregation by binding collagen, a response enhanced by elevated glucose concentrations. The effect of hyperglycemia on hematoma expansion and PK-mediated inhibition of platelet aggregation could be mimicked by infusing mannitol. These findings suggest that hyperglycemia augments cerebral hematoma expansion by PK-mediated osmotic-sensitive inhibition of hemostasis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "glycoprotein", + "VI", + "agonist" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "glycoprotein", + "VI", + "inhibition" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + } + ] + }, + { + "PMID": "21102457", + "TEXT": "Interleukin-6 (IL-6)-Janus kinase (JAK) signaling is viewed as crucial for persistent signal transducer and activator of transcription-3 (STAT3) activation in cancer. However, IL-6-induced STAT3 activation is normally transient. Here we identify a key mechanism for persistent STAT3 activation in tumor cells and the tumor microenvironment. We show that expression of sphingosine-1-phosphate receptor-1 (S1PR1), a G protein-coupled receptor for the lysophospholipid sphingosine-1-phosphate (S1P), is elevated in STAT3-positive tumors. STAT3 is a transcription factor for the S1pr1 gene. Reciprocally, enhanced S1pr1 expression activates STAT3 and upregulates Il6 gene expression, thereby accelerating tumor growth and metastasis in a STAT3-dependent manner. Silencing S1pr1 in tumor cells or immune cells inhibits tumor STAT3 activity, tumor growth and metastasis. S1P-S1PR1-induced STAT3 activation is persistent, in contrast to transient STAT3 activation by IL-6. S1PR1 activates STAT3 in part by upregulating JAK2 tyrosine kinase activity. We show that STAT3-induced S1PR1 expression, as well as the S1P-S1PR1 pathway reciprocal regulation of STAT3 activity, is a major positive feedback loop for persistent STAT3 activation in cancer cells and the tumor microenvironment and for malignant progression.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "S1pr1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + } + ] + }, + { + "PMID": "21037586", + "TEXT": "Autophagy is crucial in the turnover of cell components, and clearance of damaged organelles by the autophagic-lysosomal pathway is essential for tissue homeostasis. Defects of this degradative system have a role in various diseases, but little is known about autophagy in muscular dystrophies. We have previously found that muscular dystrophies linked to collagen VI deficiency show dysfunctional mitochondria and spontaneous apoptosis, leading to myofiber degeneration. Here we demonstrate that this persistence of abnormal organelles and apoptosis are caused by defective autophagy. Skeletal muscles of collagen VI-knockout (Col6a1(-/-)) mice had impaired autophagic flux, which matched the lower induction of beclin-1 and BCL-2/adenovirus E1B-interacting protein-3 (Bnip3) and the lack of autophagosomes after starvation. Forced activation of autophagy by genetic, dietary and pharmacological approaches restored myofiber survival and ameliorated the dystrophic phenotype of Col6a1(-/-) mice. Furthermore, muscle biopsies from subjects with Bethlem myopathy or Ullrich congenital muscular dystrophy had reduced protein amounts of beclin-1 and Bnip3. These findings indicate that defective activation of the autophagic machinery is pathogenic in some congenital muscular dystrophies.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "collagen", + "VI-knockout", + "(Col6a1(-/-))" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "Forced", + "activation" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Col6a1(-/-)" + ] + } + } + ] + }, + { + "PMID": "20616797", + "TEXT": "RNA-binding proteins of the Musashi (Msi) family are expressed in stem cell compartments and in aggressive tumors, but they have not yet been widely explored in the blood. Here we demonstrate that Msi2 is the predominant form expressed in hematopoietic stem cells (HSCs), and its knockdown leads to reduced engraftment and depletion of HSCs in vivo. Overexpression of human MSI2 in a mouse model increases HSC cell cycle progression and cooperates with the chronic myeloid leukemia-associated BCR-ABL1 oncoprotein to induce an aggressive leukemia. MSI2 is overexpressed in human myeloid leukemia cell lines, and its depletion leads to decreased proliferation and increased apoptosis. Expression levels in human myeloid leukemia directly correlate with decreased survival in patients with the disease, thereby defining MSI2 expression as a new prognostic marker and as a new target for therapy in acute myeloid leukemia (AML).", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + } + ] + }, + { + "PMID": "20348923", + "TEXT": "Class Ia phosphoinositide 3-kinase (PI3K), an essential mediator of the metabolic actions of insulin, is composed of a catalytic (p110alpha or p110beta) and regulatory (p85alphaalpha, p85betaalpha or p55alpha) subunit. Here we show that p85alphaalpha interacts with X-box-binding protein-1 (XBP-1), a transcriptional mediator of the unfolded protein response (UPR), in an endoplasmic reticulum (ER) stress-dependent manner. Cell lines with knockout or knockdown of p85alphaalpha show marked alterations in the UPR, including reduced ER stress-dependent accumulation of nuclear XBP-1, decreased induction of UPR target genes and increased rates of apoptosis. This is associated with a decreased activation of inositol-requiring protein-1alpha (IRE1alpha) and activating transcription factor-6alphaalpha (ATF6alpha). Mice with deletion of p85alpha in liver (L-Pik3r1(-/-)) show a similar attenuated UPR after tunicamycin administration, leading to an increased inflammatory response. Thus, p85alphaalpha forms a previously unrecognized link between the PI3K pathway, which is central to insulin action, and the regulation of the cellular response to ER stress, a state that when unresolved leads to insulin resistance.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "p85alphaalpha" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "rates" + ] + } + } + ] + }, + { + "PMID": "20081861", + "TEXT": "Lung cancer is the leading cause of cancer death worldwide. Recent data suggest that tumor-associated inflammatory cells may modify lung tumor growth and invasiveness. To determine the role of neutrophil elastase (encoded by Elane) on tumor progression, we used the loxP-Stop-loxP K-ras(G12D) (LSL-K-ras) model of mouse lung adenocarcinoma to generate LSL-K-ras-Elane(-/-) mice. Tumor burden was markedly reduced in LSL-K-ras-Elane(-/-) mice at all time points after induction of mutant K-ras expression. Kaplan-Meier survival analysis showed that whereas all LSL-K-ras-Elane(+/+) mice died, none of the mice lacking neutrophil elastase died. Neutrophil elastase directly induced tumor cell proliferation in both human and mouse lung adenocarcinomas by gaining access to an endosomal compartment within tumor cells, where it degraded insulin receptor substrate-1 (IRS-1). Immunoprecipitation studies showed that, as neutrophil elastase degraded IRS-1, there was increased interaction between phosphatidylinositol 3-kinase (PI3K) and the potent mitogen platelet-derived growth factor receptor (PDGFR), thereby skewing the PI3K axis toward tumor cell proliferation. The inverse relationship identified between neutrophil elastase and IRS-1 in LSL-K-ras mice was also identified in human lung adenocarcinomas, thus translating these findings to human disease. This study identifies IRS-1 as a key regulator of PI3K within malignant cells. Additionally, to our knowledge, this is the first description of a secreted proteinase gaining access to the inside of a cell and altering intracellular signaling.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "loxP-Stop-loxP", + "K-ras(G12D)", + "(LSL-K-ras)", + "model", + "of", + "LSL-K-ras-Elane(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "LSL-K-ras-Elane(-/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "K-ras", + "LSL-K-ras-Elane(+/+)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "19966810", + "TEXT": "The identification of the genes associated with chromosomal translocation breakpoints has fundamentally changed understanding of the molecular basis of hematological malignancies. By contrast, the study of chromosomal deletions has been hampered by the large number of genes deleted and the complexity of their analysis. We report the generation of a mouse model for human 5q- syndrome using large-scale chromosomal engineering. Haploinsufficiency of the Cd74-Nid67 interval (containing Rps14, encoding the ribosomal protein S14) caused macrocytic anemia, prominent erythroid dysplasia and monolobulated megakaryocytes in the bone marrow. These effects were associated with defective bone marrow progenitor development, the appearance of bone marrow cells expressing high amounts of the tumor suppressor p53 and increased bone marrow cell apoptosis. Notably, intercrossing with p53-deficient mice completely rescued the progenitor cell defect, restoring common myeloid progenitor and megakaryocytic-erythroid progenitor, granulocyte-monocyte progenitor and hematopoietic stem cell bone marrow populations. This mouse model suggests that a p53-dependent mechanism underlies the pathophysiology of the 5q- syndrome.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Haploinsufficiency", + "of", + "the", + "Cd74-Nid67", + "interval", + "(containing" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + } + ] + }, + { + "PMID": "19767732", + "TEXT": "The therapeutic efficacy of anticancer chemotherapies may depend on dendritic cells (DCs), which present antigens from dying cancer cells to prime tumor-specific interferon-gamma (IFN-gamma)-producing T lymphocytes. Here we show that dying tumor cells release ATP, which then acts on P2X(7) purinergic receptors from DCs and triggers the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3)-dependent caspase-1 activation complex ('inflammasome'), allowing for the secretion of interleukin-1beta (IL-1beta). The priming of IFN-gamma-producing CD8+ T cells by dying tumor cells fails in the absence of a functional IL-1 receptor 1 and in Nlpr3-deficient (Nlrp3(-/-)) or caspase-1-deficient (Casp-1(-/-)) mice unless exogenous IL-1beta is provided. Accordingly, anticancer chemotherapy turned out to be inefficient against tumors established in purinergic receptor P2rx7(-/-) or Nlrp3(-/-) or Casp1(-/-) hosts. Anthracycline-treated individuals with breast cancer carrying a loss-of-function allele of P2RX7 developed metastatic disease more rapidly than individuals bearing the normal allele. These results indicate that the NLRP3 inflammasome links the innate and adaptive immune responses against dying tumor cells.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "a", + "loss-of-function", + "allele", + "of", + "P2RX7" + ] + }, + "effect": { + "val": "negative", + "words": [ + "developed" + ] + } + } + ] + }, + { + "PMID": "19734908", + "TEXT": "Integrins regulate adhesion-dependent growth, survival and invasion of tumor cells. In particular, expression of integrin alpha(v)beta(3) is associated with progression of a variety of human tumors. Here we reveal a previously undescribed adhesion-independent role for integrin alpha(v)beta(3) in pancreatic cancer and other carcinomas. Specifically, alpha(v)beta(3) expressed in carcinoma cells enhanced anchorage-independent tumor growth in vitro and increased lymph node metastases in vivo. These effects required recruitment of c-Src to the beta(3) integrin cytoplasmic tail, leading to c-Src activation, Crk-associated substrate (CAS) phosphorylation and tumor cell survival that, unexpectedly, was independent of cell adhesion or focal adhesion kinase (FAK) activation. Pharmacological blockade of c-Src kinase activity or decreased expression of endogenous alpha(v)beta(3) integrin or c-Src not only inhibited anchorage-independent growth but also suppressed metastasis in vivo, yet these manipulations did not affect tumor cell migration or invasion. These data define an unexpected role for an integrin as a mediator of anchorage independence, suggesting that an alpha(v)beta(3)-c-Src signaling module may account for the aggressive behavior of integrin alpha(v)beta(3)-expressing tumors in humans.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "c-Src", + "kinase", + "activity" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "affect" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "decreased" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "decreased" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "affect" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "endogenous", + "alpha(v)beta(3)", + "integrin", + "or", + "c-Src" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "endogenous", + "alpha(v)beta(3)", + "integrin", + "or", + "c-Src" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "affect" + ] + } + } + ] + }, + { + "PMID": "19398967", + "TEXT": "The in vitro analysis of intestinal epithelium has been hampered by a lack of suitable culture systems. Here we describe robust long-term methodology for small and large intestinal culture, incorporating an air-liquid interface and underlying stromal elements. These cultures showed prolonged intestinal epithelial expansion as sphere-like organoids with proliferation and multilineage differentiation. The Wnt growth factor family positively regulates proliferation of the intestinal epithelium in vivo. Accordingly, culture growth was inhibited by the Wnt antagonist Dickkopf-1 (Dkk1) and markedly stimulated by a fusion protein between the Wnt agonist R-spondin-1 and immunoglobulin Fc (RSpo1-Fc). Furthermore, treatment with the gamma-secretase inhibitor dibenzazepine and neurogenin-3 overexpression induced goblet cell and enteroendocrine cell differentiation, respectively, consistent with endogenous Notch signaling and lineage plasticity. Epithelial cells derived from both leucine-rich repeat-containing G protein-coupled receptor-5-positive (Lgr5(+)) and B lymphoma moloney murine leukemia virus insertion region homolog-1-positive (Bmi1(+)) lineages, representing putative intestinal stem cell (ISC) populations, were present in vitro and were expanded by treatment with RSpo1-Fc; this increased number of Lgr5(+) cells upon RSpo1-Fc treatment was subsequently confirmed in vivo. Our results indicate successful long-term intestinal culture within a microenvironment accurately recapitulating the Wnt- and Notch-dependent ISC niche.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "neurogenin-3", + "overexpression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "19305413", + "TEXT": "Inhibitors of alpha(v)beta(3) and alpha(v)beta(5) integrin have entered clinical trials as antiangiogenic agents for cancer treatment but generally have been unsuccessful. Here we present in vivo evidence that low (nanomolar) concentrations of RGD-mimetic alpha(v)beta(3) and alpha(v)beta(5) inhibitors can paradoxically stimulate tumor growth and tumor angiogenesis. We show that low concentrations of these inhibitors promote VEGF-mediated angiogenesis by altering alpha(v)beta(3) integrin and vascular endothelial growth factor receptor-2 trafficking, thereby promoting endothelial cell migration to VEGF. The proangiogenic effects of low concentrations of RGD-mimetic integrin inhibitors could compromise their efficacy as anticancer agents and have major implications for the use of RGD-mimetic compounds in humans.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "RGD-mimetic", + "alpha(v)beta(3)", + "and", + "alpha(v)beta(5)", + "inhibitors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulate", + "promoting" + ] + } + } + ] + }, + { + "PMID": "19252502", + "TEXT": "Osteoclasts are acid-secreting polykaryons that have high energy demands and contain abundant mitochondria. How mitochondrial biogenesis is integrated with osteoclast differentiation is unknown. We found that the transcription of Ppargc1b, which encodes peroxisome proliferator-activated receptor-gamma coactivator 1beta (PGC-1beta), was induced during osteoclast differentiation by cAMP response element-binding protein (CREB) as a result of reactive oxygen species. Knockdown of Ppargc1b in vitro inhibited osteoclast differentiation and mitochondria biogenesis, whereas deletion of the Ppargc1b gene in mice resulted in increased bone mass due to impaired osteoclast function. We also observed defects in PGC-1beta-deficient osteoblasts. Owing to the heightened iron demand in osteoclast development, transferrin receptor 1 (TfR1) expression was induced post-transcriptionally via iron regulatory protein 2. TfR1-mediated iron uptake promoted osteoclast differentiation and bone-resorbing activity, associated with the induction of mitochondrial respiration, production of reactive oxygen species and accelerated Ppargc1b transcription. Iron chelation inhibited osteoclastic bone resorption and protected against bone loss following estrogen deficiency resulting from ovariectomy. These data establish mitochondrial biogenesis orchestrated by PGC-1beta, coupled with iron uptake through TfR1 and iron supply to mitochondrial respiratory proteins, as a fundamental pathway linked to osteoclast activation and bone metabolism.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "Ppargc1b" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "Ppargc1b", + "gene", + "PGC-1beta-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + } + ] + }, + { + "PMID": "18552856", + "TEXT": "Autosomal dominant polycystic kidney disease (ADPKD) is caused by heterozygous mutations in either PKD1 or PKD2, genes that encode polycystin-1 and polycystin-2, respectively. We show here that tumor necrosis factor-alpha (TNF-alpha), an inflammatory cytokine present in the cystic fluid of humans with ADPKD, disrupts the localization of polycystin-2 to the plasma membrane and primary cilia through a scaffold protein, FIP2, which is induced by TNF-alpha. Treatment of mouse embryonic kidney organ cultures with TNF-alpha resulted in formation of cysts, and this effect was exacerbated in the Pkd2(+/-) kidneys. TNF-alpha also stimulated cyst formation in vivo in Pkd2(+/-) mice. In contrast, treatment of Pkd2(+/-) mice with the TNF-alpha inhibitor etanercept prevented cyst formation. These data reveal a pathway connecting TNF-alpha signaling, polycystins and cystogenesis, the activation of which may reduce functional polycystin-2 below a critical threshold, precipitating the ADPKD cellular phenotype.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pkd2(+/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + } + } + ] + }, + { + "PMID": "18204460", + "TEXT": "Insulin receptor substrate (IRS)-1 and IRS-2 have dominant roles in the action of insulin, but other substrates of the insulin receptor kinase, such as Gab1, c-Cbl, SH2-B and APS, are also of physiological relevance. Although the protein downstream of tyrosine kinases-1 (Dok1) is known to function as a multisite adapter molecule in insulin signaling, its role in energy homeostasis has remained unclear. Here we show that Dok1 regulates adiposity. Expression of Dok1 in white adipose tissue was markedly increased in mice fed a high-fat diet, whereas adipocytes lacking this adapter were smaller and showed a reduced hypertrophic response to this dietary manipulation. Dok1-deficient mice were leaner and showed improved glucose tolerance and insulin sensitivity compared with wild-type mice. Embryonic fibroblasts from Dok1-deficient mice were impaired in adipogenic differentiation, and this defect was accompanied by an increased activity of the protein kinase ERK and a consequent increase in the phosphorylation of peroxisome proliferator-activated receptor (PPAR)-gamma on Ser112. Mutation of this negative regulatory site for the transactivation activity of PPAR-gamma blocked development of the lean phenotype caused by Dok1 ablation. These results indicate that Dok1 promotes adipocyte hypertrophy by counteracting the inhibitory effect of ERK on PPAR-gamma and may thus confer predisposition to diet-induced obesity.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Dok1-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + } + ] + }, + { + "PMID": "18157142", + "TEXT": "In spite of their having sufficient immunogenicity, tumor vaccines remain largely ineffective. The mechanisms underlying this lack of efficacy are still unclear. Here we report a previously undescribed mechanism by which the tumor endothelium prevents T cell homing and hinders tumor immunotherapy. Transcriptional profiling of microdissected tumor endothelial cells from human ovarian cancers revealed genes associated with the absence or presence of tumor-infiltrating lymphocytes (TILs). Overexpression of the endothelin B receptor (ET(B)R) was associated with the absence of TILs and short patient survival time. The ET(B)R inhibitor BQ-788 increased T cell adhesion to human endothelium in vitro, an effect countered by intercellular adhesion molecule-1 (ICAM-1) blockade or treatment with NO donors. In mice, ET(B)R neutralization by BQ-788 increased T cell homing to tumors; this homing required ICAM-1 and enabled tumor response to otherwise ineffective immunotherapy in vivo without changes in systemic antitumor immune response. These findings highlight a molecular mechanism with the potential to be pharmacologically manipulated to enhance the efficacy of tumor immunotherapy in humans.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "the", + "endothelin", + "B", + "receptor", + "(ET(B)R)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ET(B)R", + "inhibitor", + "BQ-788" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + } + ] + }, + { + "PMID": "17828274", + "TEXT": "The repair of injured tendons remains a great challenge, largely owing to a lack of in-depth characterization of tendon cells and their precursors. We show that human and mouse tendons harbor a unique cell population, termed tendon stem/progenitor cells (TSPCs), that has universal stem cell characteristics such as clonogenicity, multipotency and self-renewal capacity. The isolated TSPCs could regenerate tendon-like tissues after extended expansion in vitro and transplantation in vivo. Moreover, we show that TSPCs reside within a unique niche predominantly comprised of an extracellular matrix, and we identify biglycan (Bgn) and fibromodulin (Fmod) as two critical components that organize this niche. Depletion of Bgn and Fmod affects the differentiation of TSPCs by modulating bone morphogenetic protein signaling and impairs tendon formation in vivo. Our results, while offering new insights into the biology of tendon cells, may assist in future strategies to treat tendon diseases.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Depletion", + "of", + "Bgn", + "and", + "Fmod" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "affects" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Depletion", + "of", + "Bgn", + "and", + "Fmod" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + } + } + ] + }, + { + "PMID": "17603494", + "TEXT": "Psoriasis is a common T cell-mediated autoimmune inflammatory disease. We show that blocking the interaction of alpha1beta1 integrin (VLA-1) with collagen prevented accumulation of epidermal T cells and immunopathology of psoriasis. Alpha1beta1 integrin, a major collagen-binding surface receptor, was exclusively expressed by epidermal but not dermal T cells. Alpha1beta1-positive T cells showed characteristic surface markers of effector memory cells and contained high levels of interferon-gamma but not interleukin-4. Blockade of alpha1beta1 inhibited migration of T cells into the epidermis in a clinically relevant xenotransplantation model. This was paralleled by a complete inhibition of psoriasis development, comparable to that caused by tumor necrosis factor-alpha blockers. These results define a crucial role for alpha1beta1 in controlling the accumulation of epidermal type 1 polarized effector memory T cells in a common human immunopathology and provide the basis for new strategies in psoriasis treatment focusing on T cell-extracellular matrix interactions.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "alpha1beta1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + } + ] + }, + { + "PMID": "17401377", + "TEXT": "The germinal matrix of premature infants is selectively vulnerable to hemorrhage within the first 48 h of life. To assess the role of vascular immaturity in germinal matrix hemorrhage (GMH), we evaluated germinal matrix angiogenesis in human fetuses and premature infants, as well as in premature rabbit pups, and noted active vessel remodeling in all three. Vascular endothelial growth factor (VEGF), angiopoietin-2 and endothelial cell proliferation were present at consistently higher levels in the germinal matrix relative to the white matter anlagen and cortical mantle. On that basis, we asked whether prenatal treatment with either of two angiogenic inhibitors, the COX-2 inhibitor celecoxib, or the VEGFR2 inhibitor ZD6474, could suppress the incidence of GMH in premature rabbit pups. Celecoxib treatment decreased angiopoietin-2 and VEGF levels as well as germinal matrix endothelial proliferation. Furthermore, treatment with celecoxib or ZD6474 substantially decreased the incidence of GMH. Thus, by suppressing germinal matrix angiogenesis, prenatal celecoxib or ZD6474 treatment may be able to reduce both the incidence and severity of GMH in susceptible premature infants.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "COX-2", + "inhibitor", + "celecoxib,", + "VEGFR2", + "ZD6474," + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + } + ] + }, + { + "PMID": "17401376", + "TEXT": "The cannabinoid system is immunomodulatory and has been targeted as a treatment for the central nervous system (CNS) autoimmune disease multiple sclerosis. Using an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), we investigated the role of the CB(1) and CB(2) cannabinoid receptors in regulating CNS autoimmunity. We found that CB(1) receptor expression by neurons, but not T cells, was required for cannabinoid-mediated EAE suppression. In contrast, CB(2) receptor expression by encephalitogenic T cells was critical for controlling inflammation associated with EAE. CB(2)-deficient T cells in the CNS during EAE exhibited reduced levels of apoptosis, a higher rate of proliferation and increased production of inflammatory cytokines, resulting in severe clinical disease. Together, our results demonstrate that the cannabinoid system within the CNS plays a critical role in regulating autoimmune inflammation, with the CNS directly suppressing T-cell effector function via the CB(2) receptor.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CB(2)-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CB(2)-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "levels", + "higher", + "rate" + ] + } + } + ] + }, + { + "PMID": "17187072", + "TEXT": "Anthracyclin-treated tumor cells are particularly effective in eliciting an anticancer immune response, whereas other DNA-damaging agents such as etoposide and mitomycin C do not induce immunogenic cell death. Here we show that anthracyclins induce the rapid, preapoptotic translocation of calreticulin (CRT) to the cell surface. Blockade or knockdown of CRT suppressed the phagocytosis of anthracyclin-treated tumor cells by dendritic cells and abolished their immunogenicity in mice. The anthracyclin-induced CRT translocation was mimicked by inhibition of the protein phosphatase 1/GADD34 complex. Administration of recombinant CRT or inhibitors of protein phosphatase 1/GADD34 restored the immunogenicity of cell death elicited by etoposide and mitomycin C, and enhanced their antitumor effects in vivo. These data identify CRT as a key feature determining anticancer immune responses and delineate a possible strategy for immunogenic chemotherapy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "CRT" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "protein", + "phosphatase", + "1/GADD34" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + } + } + ] + }, + { + "PMID": "17128270", + "TEXT": "Matrix-producing osteoblasts and bone-resorbing osteoclasts maintain bone homeostasis. Osteoclasts are multinucleated, giant cells of hematopoietic origin formed by the fusion of mononuclear pre-osteoclasts derived from myeloid cells. Fusion-mediated giant cell formation is critical for osteoclast maturation; without it, bone resorption is inefficient. To understand how osteoclasts differ from other myeloid lineage cells, we previously compared global mRNA expression patterns in these cells and identified genes of unknown function predominantly expressed in osteoclasts, one of which is the d2 isoform of vacuolar (H(+)) ATPase (v-ATPase) V(0) domain (Atp6v0d2). Here we show that inactivation of Atp6v0d2 in mice results in markedly increased bone mass due to defective osteoclasts and enhanced bone formation. Atp6v0d2 deficiency did not affect differentiation or the v-ATPase activity of osteoclasts. Rather, Atp6v0d2 was required for efficient pre-osteoclast fusion. Increased bone formation was probably due to osteoblast-extrinsic factors, as Atp6v02 was not expressed in osteoblasts and their differentiation ex vivo was not altered in the absence of Atp6v02. Our results identify Atp6v0d2 as a regulator of osteoclast fusion and bone formation, and provide genetic data showing that it is possible to simultaneously inhibit osteoclast maturation and stimulate bone formation by therapeutically targeting the function of a single gene.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atp6v0d2", + "deficiency", + "absence", + "of", + "Atp6v02." + ] + }, + "effect": { + "val": "no effect", + "words": [ + "did", + "not", + "affect", + "altered" + ] + } + } + ] + }, + { + "PMID": "17063141", + "TEXT": "We demonstrate here that lymphoid enhancer-binding factor 1 (LEF-1) mediates the proliferation, survival and differentiation of granulocyte progenitor cells. We initially documented the importance of this transcription factor in the bone marrow of individuals with severe congenital neutropenia (CN) with a 'differentiation block' at the promyelocytic stage of myelopoiesis. LEF-1 expression was greatly reduced or even absent in CN arrested promyelocytes, resulting in defective expression of the LEF-1 target genes CCND1, MYC and BIRC5, encoding cyclin D1 (ref. 2), c-Myc and survivin, respectively. In contrast, healthy individuals showed highest LEF-1 expression in promyelocytes. Reconstitution of LEF-1 in early hematopoietic progenitors of two individuals with CN corrected the defective myelopoiesis and resulted in the differentiation of these progenitors into mature granulocytes. Repression of endogenous LEF-1 by specific short hairpin RNA inhibited proliferation and induced apoptosis of CD34(+) progenitors from healthy individuals and of cells from two myeloid lines (HL-60 and K562). C/EBPalpha, a key transcription factor in granulopoiesis, was directly regulated by LEF-1. These observations indicate that LEF-1 is an instructive factor regulating neutrophilic granulopoiesis whose absence plays a critical role in the defective maturation program of myeloid progenitors in individuals with CN.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reconstitution", + "of", + "LEF-1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Repression", + "of", + "endogenous", + "LEF-1", + "by", + "specific", + "short", + "hairpin", + "RNA" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Repression", + "of", + "endogenous", + "LEF-1", + "by", + "specific", + "short", + "hairpin", + "RNA" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "16892061", + "TEXT": "Vascular smooth muscle cell (VSMC) apoptosis occurs in many arterial diseases, including aneurysm formation, angioplasty restenosis and atherosclerosis. Although VSMC apoptosis promotes vessel remodeling, coagulation and inflammation, its precise contribution to these diseases is unknown, given that apoptosis frequently accompanies vessel injury or alterations to flow. To study the direct consequences of VSMC apoptosis, we generated transgenic mice expressing the human diphtheria toxin receptor (hDTR, encoded by HBEGF) from a minimal Tagln (also known as SM22alpha) promoter. Despite apoptosis inducing loss of 50-70% of VSMCs, normal arteries showed no inflammation, reactive proliferation, thrombosis, remodeling or aneurysm formation. In contrast, VSMC apoptosis in atherosclerotic plaques of SM22alpha-hDTR Apoe-/- mice induced marked thinning of fibrous cap, loss of collagen and matrix, accumulation of cell debris and intense intimal inflammation. We conclude that VSMC apoptosis is 'silent' in normal arteries, which have a large capacity to withstand cell loss. In contrast, VSMC apoptosis alone is sufficient to induce features of plaque vulnerability in atherosclerosis. SM22alpha-hDTR Apoe-/- mice may represent an important new model to test agents proposed to stabilize atherosclerotic plaques.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expressing", + "the", + "human", + "diphtheria", + "toxin", + "receptor", + "(hDTR,", + "encoded", + "by", + "HBEGF)", + "from", + "a", + "promoter." + ] + }, + "effect": { + "val": "no effect", + "words": [ + "no" + ] + } + } + ] + }, + { + "PMID": "16751767", + "TEXT": "Preeclampsia is a pregnancy-specific hypertensive syndrome that causes substantial maternal and fetal morbidity and mortality. Maternal endothelial dysfunction mediated by excess placenta-derived soluble VEGF receptor 1 (sVEGFR1 or sFlt1) is emerging as a prominent component in disease pathogenesis. We report a novel placenta-derived soluble TGF-beta coreceptor, endoglin (sEng), which is elevated in the sera of preeclamptic individuals, correlates with disease severity and falls after delivery. sEng inhibits formation of capillary tubes in vitro and induces vascular permeability and hypertension in vivo. Its effects in pregnant rats are amplified by coadministration of sFlt1, leading to severe preeclampsia including the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and restriction of fetal growth. sEng impairs binding of TGF-beta1 to its receptors and downstream signaling including effects on activation of eNOS and vasodilation, suggesting that sEng leads to dysregulated TGF-beta signaling in the vasculature. Our results suggest that sEng may act in concert with sFlt1 to induce severe preeclampsia.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "sFlt1," + ] + }, + "effect": { + "val": "negative", + "words": [ + "restriction" + ] + } + } + ] + }, + { + "PMID": "16565722", + "TEXT": "Hematopoietic stem cells (HSCs) undergo self-renewing cell divisions and maintain blood production for their lifetime. Appropriate control of HSC self-renewal is crucial for the maintenance of hematopoietic homeostasis. Here we show that activation of p38 MAPK in response to increasing levels of reactive oxygen species (ROS) limits the lifespan of HSCs in vivo. In Atm(-/-) mice, elevation of ROS levels induces HSC-specific phosphorylation of p38 MAPK accompanied by a defect in the maintenance of HSC quiescence. Inhibition of p38 MAPK rescued ROS-induced defects in HSC repopulating capacity and in the maintenance of HSC quiescence, indicating that the ROS-p38 MAPK pathway contributes to exhaustion of the stem cell population. Furthermore, prolonged treatment with an antioxidant or an inhibitor of p38 MAPK extended the lifespan of HSCs from wild-type mice in serial transplantation experiments. These data show that inactivation of p38 MAPK protects HSCs against loss of self-renewal capacity. Our characterization of molecular mechanisms that limit HSC lifespan may lead to beneficial therapies for human disease.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Atm(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "maintenance" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "p38", + "MAPK" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "maintenance" + ] + } + } + ] + }, + { + "PMID": "16474399", + "TEXT": "CD8+ T cells can mediate eradication of established tumors, and strategies to amplify tumor-reactive T-cell numbers by immunization or ex vivo expansion followed by adoptive transfer are currently being explored in individuals with cancer. Generating effective CD8+ T cell-mediated responses to tumors is often impeded by T-cell tolerance to relevant tumor antigens, as most of these antigens are also expressed in normal tissues. We examined whether such tolerant T cells could be rescued and functionally restored for use in therapy of established tumors. We used a transgenic T-cell receptor (TCR) mouse model in which peripheral CD8+ T cells specific for a candidate tumor antigen also expressed in liver are tolerant, failing to proliferate or secrete interleukin (IL)-2 in response to antigen. Molecular and cellular analysis showed that these tolerant T cells expressed the IL-15 receptor alpha chain, and could be induced to proliferate in vitro in response to exogenous IL-15. Such proliferation abrogated tolerance and the rescued cells became effective in treating leukemia. Therefore, high-affinity CD8+ T cells are not necessarily deleted by encounter with self-antigen in the periphery, and can potentially be rescued and expanded for use in tumor immunotherapy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "T-cell", + "receptor", + "(TCR)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "failing", + "to" + ] + } + } + ] + }, + { + "PMID": "16311603", + "TEXT": "Abdominal aortic aneurysm (AAA) is a common disease among elderly people that, when surgical treatment is inapplicable, results in progressive expansion and rupture of the aorta with high mortality. Although nonsurgical treatment for AAA is much awaited, few options are available because its molecular pathogenesis remains elusive. Here, we identify JNK as a proximal signaling molecule in the pathogenesis of AAA. Human AAA tissue showed a high level of phosphorylated JNK. We show that JNK programs a gene expression pattern in different cell types that cooperatively enhances the degradation of the extracellular matrix while suppressing biosynthetic enzymes of the extracellular matrix. Selective inhibition of JNK in vivo not only prevented the development of AAA but also caused regression of established AAA in two mouse models. Thus, JNK promotes abnormal extracellular matrix metabolism in the tissue of AAA and may represent a therapeutic target.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Selective", + "inhibition", + "of", + "JNK" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Selective", + "inhibition", + "of", + "JNK" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + } + ] + }, + { + "PMID": "16116431", + "TEXT": "Lymph vessels control fluid homeostasis, immunity and metastasis. Unraveling the molecular basis of lymphangiogenesis has been hampered by the lack of a small animal model that can be genetically manipulated. Here, we show that Xenopus tadpoles develop lymph vessels from lymphangioblasts or, through transdifferentiation, from venous endothelial cells. Lymphangiography showed that these lymph vessels drain lymph, through the lymph heart, to the venous circulation. Morpholino-mediated knockdown of the lymphangiogenic factor Prox1 caused lymph vessel defects and lymphedema by impairing lymphatic commitment. Knockdown of vascular endothelial growth factor C (VEGF-C) also induced lymph vessel defects and lymphedema, but primarily by affecting migration of lymphatic endothelial cells. Knockdown of VEGF-C also resulted in aberrant blood vessel formation in tadpoles. This tadpole model offers opportunities for the discovery of new regulators of lymphangiogenesis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "vascular", + "endothelial", + "growth", + "factor", + "C", + "(VEGF-C)" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "affecting" + ] + } + } + ] + }, + { + "PMID": "16116430", + "TEXT": "Neurovascular dysfunction substantially contributes to Alzheimer disease. Here, we show that transcriptional profiling of human brain endothelial cells (BECs) defines a subset of genes whose expression is age-independent but is considerably altered in Alzheimer disease, including the homeobox gene MEOX2 (also known as GAX), a regulator of vascular differentiation, whose expression is low in Alzheimer disease. By using viral-mediated MEOX2 gene silencing and transfer, we show that restoring expression of the protein it encodes, GAX, in BECs from individuals with Alzheimer disease stimulates angiogenesis, transcriptionally suppresses AFX1 forkhead transcription factor-mediated apoptosis and increases the levels of a major amyloid-beta peptide (Abeta) clearance receptor, the low-density lipoprotein receptor-related protein 1 (LRP), at the blood-brain barrier. In mice, deletion of Meox2 (also known as Gax) results in reductions in brain capillary density and resting cerebral blood flow, loss of the angiogenic response to hypoxia in the brain and an impaired Abeta efflux from brain caused by reduced LRP levels. The link of MEOX2 to neurovascular dysfunction in Alzheimer disease provides new mechanistic and therapeutic insights into this illness.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "viral-mediated", + "MEOX2", + "gene", + "silencing" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "viral-mediated", + "MEOX2", + "gene", + "silencing" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "factor-mediated" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "restoring", + "expression", + "of", + "the", + "protein", + "it", + "encodes,", + "GAX," + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "restoring", + "expression", + "of", + "the", + "protein", + "it", + "encodes,", + "GAX," + ] + }, + "effect": { + "val": "regulates", + "words": [ + "factor-mediated" + ] + } + } + ] + }, + { + "PMID": "15895072", + "TEXT": "Genes involved in fatty acid catabolism have undergone extensive duplication in the genus Mycobacterium, which includes the etiologic agents of leprosy and tuberculosis. Here, we show that prokaryotic- and eukaryotic-like isoforms of the glyoxylate cycle enzyme isocitrate lyase (ICL) are jointly required for fatty acid catabolism and virulence in Mycobacterium tuberculosis. Although deletion of icl1 or icl2, the genes that encode ICL1 and ICL2, respectively, had little effect on bacterial growth in macrophages and mice, deletion of both genes resulted in complete impairment of intracellular replication and rapid elimination from the lungs. The feasibility of targeting ICL1 and ICL2 for chemical inhibition was shown using a dual-specific ICL inhibitor, which blocked growth of M. tuberculosis on fatty acids and in macrophages. The absence of ICL orthologs in mammals should facilitate the development of glyoxylate cycle inhibitors as new drugs for the treatment of tuberculosis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "icl1", + "or", + "icl2," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "little", + "effect" + ] + } + } + ] + }, + { + "PMID": "15502842", + "TEXT": "High-density array comparative genomic hybridization (CGH) showed amplification of chromosome 1q22 centered on the RAB25 small GTPase, which is implicated in apical vesicle trafficking, in approximately half of ovarian and breast cancers. RAB25 mRNA levels were selectively increased in stage III and IV serous epithelial ovarian cancers compared to other genes within the amplified region, implicating RAB25 as a driving event in the development of the amplicon. Increased DNA copy number or RNA level of RAB25 was associated with markedly decreased disease-free survival or overall survival in ovarian and breast cancers, respectively. Forced expression of RAB25 markedly increased anchorage-dependent and anchorage-independent cell proliferation, prevented apoptosis and anoikis, including that induced by chemotherapy, and increased aggressiveness of cancer cells in vivo. The inhibition of apoptosis was associated with a decrease in expression of the proapoptotic molecules, BAK and BAX, and activation of the antiapoptotic phosphatidylinositol 3 kinase (PI3K) and AKT pathway, providing potential mechanisms for the effects of RAB25 on tumor aggressiveness. Overall, these studies implicate RAB25, and thus the RAB family of small G proteins, in aggressiveness of epithelial cancers.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "expression", + "of", + "RAB25" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Forced", + "expression", + "of", + "RAB25" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + } + ] + }, + { + "PMID": "15107843", + "TEXT": "CD1d is a major histocompatibility complex (MHC) class I-related molecule that functions in glycolipid antigen presentation to distinct subsets of T cells that express natural killer receptors and an invariant T-cell receptor-alpha chain (invariant NKT cells). The acquisition of glycolipid antigens by CD1d occurs, in part, in endosomes through the function of resident lipid transfer proteins, namely saposins. Here we show that microsomal triglyceride transfer protein (MTP), a protein that resides in the endoplasmic reticulum of hepatocytes and intestinal epithelial cells (IECs) and is essential for lipidation of apolipoprotein B, associates with CD1d in hepatocytes. Hepatocytes from animals in which Mttp (the gene encoding MTP) has been conditionally deleted, and IECs in which Mttp gene products have been silenced, are unable to activate invariant NKT cells. Conditional deletion of the Mttp gene in hepatocytes is associated with a redistribution of CD1d expression, and Mttp-deleted mice are resistant to immunopathologies associated with invariant NKT cell-mediated hepatitis and colitis. These studies indicate that the CD1d-regulating function of MTP in the endoplasmic reticulum is complementary to that of the saposins in endosomes in vivo.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mttp", + "(the", + "gene", + "encoding", + "MTP)", + "has", + "been", + "conditionally", + "deleted," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "unable" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Mttp", + "gene", + "products", + "have", + "been", + "silenced," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "unable" + ] + } + } + ] + }, + { + "PMID": "15048110", + "TEXT": "Peroxisome proliferator-activated receptor-delta (PPAR-delta; also known as PPAR-beta) is expressed at high levels in colon tumors, but its contribution to colon cancer is unclear. We examined the role of PPAR-delta in colon carcinogenesis using PPAR-delta-deficient (Ppard(-/-)) mice. In both the Min mutant and chemically induced mouse models, colon polyp formation was significantly greater in mice nullizygous for PPAR-delta. In contrast to previous reports suggesting that activation of PPAR-delta potentiates colon polyp formation, here we show that PPAR-delta attenuates colon carcinogenesis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nullizygous" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuates" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "for", + "PPAR-delta." + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuates" + ] + } + } + ] + }, + { + "PMID": "14702635", + "TEXT": "Human and mouse embryonic stem cells (HESCs and MESCs, respectively) self-renew indefinitely while maintaining the ability to generate all three germ-layer derivatives. Despite the importance of ESCs in developmental biology and their potential impact on tissue replacement therapy, the molecular mechanism underlying ESC self-renewal is poorly understood. Here we show that activation of the canonical Wnt pathway is sufficient to maintain self-renewal of both HESCs and MESCs. Although Stat-3 signaling is involved in MESC self-renewal, stimulation of this pathway does not support self-renewal of HESCs. Instead we find that Wnt pathway activation by 6-bromoindirubin-3'-oxime (BIO), a specific pharmacological inhibitor of glycogen synthase kinase-3 (GSK-3), maintains the undifferentiated phenotype in both types of ESCs and sustains expression of the pluripotent state-specific transcription factors Oct-3/4, Rex-1 and Nanog. Wnt signaling is endogenously activated in undifferentiated MESCs and is downregulated upon differentiation. In addition, BIO-mediated Wnt activation is functionally reversible, as withdrawal of the compound leads to normal multidifferentiation programs in both HESCs and MESCs. These results suggest that the use of GSK-3-specific inhibitors such as BIO may have practical applications in regenerative medicine.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "a", + "specific", + "pharmacological", + "inhibitor", + "of", + "glycogen", + "synthase", + "kinase-3", + "(GSK-3)," + ] + }, + "effect": { + "val": "positive", + "words": [ + "maintains" + ] + } + } + ] + }, + { + "PMID": "14608378", + "TEXT": "Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy. The predominant subtype, CMT-1A, accounts for more than 50% of all cases and is associated with an interstitial chromosomal duplication of 17p12 (refs. 2,3). We have generated a model of CMT-1A by introducing extra copies of the responsible disease gene, Pmp22 (encoding the peripheral myelin protein of 22 kDa), into transgenic rats. Here, we used this model to test whether progesterone, a regulator of the myelin genes Pmp22 and myelin protein zero (Mpz) in cultured Schwann cells, can modulate the progressive neuropathy caused by moderate overexpression of Pmp22. Male transgenic rats (n = 84) were randomly assigned into three treatment groups: progesterone, progesterone antagonist (onapristone) and placebo control. Daily administration of progesterone elevated the steady-state levels of Pmp22 and Mpz mRNA in the sciatic nerve, resulting in enhanced Schwann cell pathology and a more progressive clinical neuropathy. In contrast, administration of the selective progesterone receptor antagonist reduced overexpression of Pmp22 and improved the CMT phenotype, without obvious side effects, in wild-type or transgenic rats. Taken together, these data provide proof of principle that the progesterone receptor of myelin-forming Schwann cells is a promising pharmacological target for therapy of CMT-1A.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "receptor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "improved" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "improved" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic" + ] + } + } + ] + }, + { + "PMID": "12579195", + "TEXT": "Disruption of the mouse gene encoding the blood coagulation inhibitor thrombomodulin (Thbd) leads to embryonic lethality caused by an unknown defect in the placenta. We show that the abortion of thrombomodulin-deficient embryos is caused by tissue factor-initiated activation of the blood coagulation cascade at the feto-maternal interface. Activated coagulation factors induce cell death and growth inhibition of placental trophoblast cells by two distinct mechanisms. The death of giant trophoblast cells is caused by conversion of the thrombin substrate fibrinogen to fibrin and subsequent formation of fibrin degradation products. In contrast, the growth arrest of trophoblast cells is not mediated by fibrin, but is a likely result of engagement of protease-activated receptors (PAR)-2 and PAR-4 by coagulation factors. These findings show a new function for the thrombomodulin-protein C system in controlling the growth and survival of trophoblast cells in the placenta. This function is essential for the maintenance of pregnancy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "thrombomodulin-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "thrombomodulin-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + } + ] + }, + { + "PMID": "11689883", + "TEXT": "The role of bone marrow (BM)-derived precursor cells in tumor angiogenesis is not known. We demonstrate here that tumor angiogenesis is associated with recruitment of hematopoietic and circulating endothelial precursor cells (CEPs). We used the angiogenic defective, tumor resistant Id-mutant mice to show that transplantation of wild-type BM or vascular endothelial growth factor (VEGF)-mobilized stem cells restore tumor angiogenesis and growth. We detected donor-derived CEPs throughout the neovessels of tumors and Matrigel-plugs in an Id1+/-Id3-/- host, which were associated with VEGF-receptor-1-positive (VEGFR1+) myeloid cells. The angiogenic defect in Id-mutant mice was due to impaired VEGF-driven mobilization of VEGFR2+ CEPs and impaired proliferation and incorporation of VEGFR1+ cells. Although targeting of either VEGFR1 or VEGFR2 alone partially blocks the growth of tumors, inhibition of both VEGFR1 and VEGFR2 was necessary to completely ablate tumor growth. These data demonstrate that recruitment of VEGF-responsive BM-derived precursors is necessary and sufficient for tumor angiogenesis and suggest new clinical strategies to block tumor growth.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Id1+/-Id3-/-" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Id-mutant", + "targeting", + "of", + "either", + "VEGFR1", + "or", + "VEGFR2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired", + "ablate" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "both", + "VEGFR1", + "and", + "VEGFR2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "ablate" + ] + } + } + ] + }, + { + "PMID": "11433346", + "TEXT": "The Fanconi anemia group C protein (FANCC) plays an important role in hematopoiesis by ensuring the survival of hematopoietic progenitor cells through an unknown mechanism. We investigated the function of FANCC by identifying FANCC-binding proteins in hematopoietic cells. Here we show that glutathione S-transferase P1-1 (GSTP1) interacts with FANCC, and that overexpression of both proteins in a myeloid progenitor cell line prevents apoptosis following factor deprivation. FANCC increases GSTP1 activity after the induction of apoptosis. GSTP1 is an enzyme that catalyzes the detoxification of xenobiotics and by-products of oxidative stress, and it is frequently upregulated in neoplastic cells. Although FANCC lacks homology with conventional disulfide reductases, it functions by preventing the formation of inactivating disulfide bonds within GSTP1 during apoptosis. The prevention of protein oxidation by FANCC reveals a novel mechanism of enzyme regulation during apoptosis and has implications for the treatment of degenerative diseases with thiol reducing agents.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "both", + "proteins" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + } + ] + }, + { + "PMID": "11231631", + "TEXT": "Fibronectin performs essential roles in embryonic development and is prominently expressed during tissue repair. Two forms of fibronectin have been identified: plasma fibronectin (pFn), which is expressed by hepatocytes and secreted in soluble form into plasma; and cellular fibronectin (cFn), an insoluble form expressed locally by fibroblasts and other cell types and deposited and assembled into the extracellular matrix. To investigate the role of pFn in vivo, we generated pFn-deficient adult mice using Cre-loxP conditional gene-knockout technology. Here we show that pFn-deficient mice show increased neuronal apoptosis and larger infarction areas following transient focal cerebral ischemia. However, pFn is dispensable for skin-wound healing and hemostasis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cre-loxP", + "conditional", + "gene-knockout", + "pFn-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + } + ] + }, + { + "PMID": "11175855", + "TEXT": "The chimeric BCR-ABL oncoprotein is the molecular hallmark of chronic myelogenous leukemia (CML). BCR-ABL contains nuclear import and export signals but it is localized only in the cytoplasm where it activates mitogenic and anti-apoptotic pathways. We have found that inhibition of the BCR-ABL tyrosine kinase, either by mutation or by the drug STI571, can stimulate its nuclear entry. By combining STI571 with leptomycin B (LMB) to block nuclear export, we trapped BCR-ABL in the nucleus and the nuclear BCR-ABL tyrosine kinase activates apoptosis. As a result, the combined treatment with STI571 and LMB causes the irreversible and complete killing of BCR-ABL transformed cells, whereas the effect of either drug alone is fully reversible. The combined treatment with STI571 and LMB also preferentially eliminates mouse bone marrow cells that express BCR-ABL. These results indicate that nuclear entrapment of BCR-ABL can be used as a therapeutic strategy to selectively kill chronic myelogenous leukemia cells.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "the", + "BCR-ABL", + "tyrosine", + "kinase,", + "mutation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "activates" + ] + } + } + ] + }, + { + "PMID": "10395330", + "TEXT": "Given the associations between chronic inflammation and epithelial cancer, we studied susceptibility to skin carcinogenesis in mice deficient for the pro-inflammatory cytokine TNF-alpha (refs. 5,6). TNF-alpha(-/-) mice were resistant to development of benign and malignant skin tumors, whether induced by initiation with DMBA and promotion with TPA or by repeated dosing with DMBA. TNF-alpha(-/-) mice developed 5-10% the number of tumors developed by wild-type mice during initiation/promotion and 25% of those in wild-type mice after repeated carcinogen treatment. TNF-alpha could influence tumor and stromal cells during tumor development. The early stages of TPA promotion are characterized by keratinocyte hyperproliferation and inflammation. These were diminished in TNF-alpha(-/-) mice. TNF-alpha was extensively induced in the epidermis, but not the dermis, in TPA-treated wild-type skin, indicating that dermal inflammation is controlled by keratinocyte TNF-alpha production. Deletion of a TNF-alpha inducible chemokine also conferred some resistance to skin tumor development. TNF-alpha has little influence on later stages of carcinogenesis, as tumors in wild-type and TNF-alpha(-/-) mice had similar rates of malignant progression. These data provide evidence that a pro-inflammatory cytokine is required for de novo carcinogenesis and that TNF-alpha is important to the early stages of tumor promotion. Strategies that neutralize TNF-alpha production may be useful in cancer treatment and prevention.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "TNF-alpha(-/-)", + "Deletion", + "of", + "a", + "TNF-alpha", + "inducible", + "chemokine" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant", + "resistance", + "rates" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "for", + "TNF-alpha(-/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "a", + "TNF-alpha", + "inducible", + "chemokine", + "TNF-alpha(-/-)" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "similar" + ] + } + } + ] + }, + { + "PMID": "9930873", + "TEXT": "Liver cirrhosis is the irreversible end result of fibrous scarring and hepatocellular regeneration, characterized by diffuse disorganization of the normal hepatic structure of regenerative nodules and fibrotic tissue. It is associated with prominent morbidity and mortality, and is induced by many factors, including chronic hepatitis virus infections, alcohol drinking and drug abuse. Hepatocyte growth factor (HGF), originally identified and cloned as a potent mitogen for hepatocytes, shows mitogenic, motogenic and morphogenic activities for a wide variety of cells. Moreover, HGF plays an essential part in the development and regeneration of the liver, and shows anti-apoptotic activity in hepatocytes. In a rat model of lethal liver cirrhosis produced by dimethylnitrosamine administrations, repeated transfections of the human HGF gene into skeletal muscles induced a high plasma level of human as well as enodogenous rat HGF, and tyrosine phosphorylation of the c-Met/HGF receptor. Transduction with the HGF gene also suppressed the increase of transforming growth factor-beta1 (TGF-beta1), which plays an essential part in the progression of liver cirrhosis, inhibited fibrogenesis and hepatocyte apoptosis, and produced the complete resolution of fibrosis in the cirrhotic liver, thereby improving the survival rate of rats with this severe illness. Thus, HGF gene therapy may be potentially useful for the treatment of patients with liver cirrhosis, which is otherwise fatal and untreatable by conventional therapy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfections", + "of", + "the", + "human", + "HGF", + "gene", + "Transduction", + "with" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + } + ] + }, + { + "PMID": "9771754", + "TEXT": "Hepatocyte transplantation might represent a potential therapeutic alternative to liver transplantation in the future; however, transplanted cells have a limited capacity to repopulate the liver, as they do not proliferate under normal conditions. Recently, studies in urokinase (uPA) transgenic mice and in fumarylacetoacetate hydrolase (FAH)-deficient mice have shown that the liver can be repopulated by genetically engineered hepatocytes harboring a selective advantage over resident hepatocytes. We have reported that transgenic mice expressing human Bcl-2 in their hepatocytes are protected from Fas/CD95-mediated liver apoptosis. We now show that Bcl-2 transplanted hepatocytes selectively repopulate the liver of mice treated with nonlethal doses of the anti-Fas antibody Jo2. FK 506 immunosuppressed mice were transplanted by splenic injection with Bcl-2 hepatocytes. The livers of female recipients were repopulated by male Bcl-2 transgenic hepatocytes, as much as 16%, after 8 to 12 administrations of Jo2. This only occurred after anti-Fas treatment, confirming that resistance to Fas-induced apoptosis constituted the selective advantage of these transplanted hepatocytes. Thus, we have demonstrated a method for increasing genetic reconstitution of the liver through selective repopulation with modified transgenic hepatocytes, which will allow optimization of cell and gene therapy in the liver.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "urokinase", + "transgenic", + "expressing", + "human", + "Bcl-2", + "male" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protected", + "resistance" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "fumarylacetoacetate", + "hydrolase", + "(FAH)-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protected" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Bcl-2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "Fas-induced" + ] + } + } + ] + }, + { + "PMID": "9734401", + "TEXT": "Although prostate cancer cells are often initially sensitive to androgen ablation, they eventually lose this response and continue to survive, grow and spread in the absence of androgenic steroids. The mechanism(s) that underlie resistance to androgen ablation therapy remain mostly unknown. We have demonstrated that elevated caveolin protein levels are associated with human prostate cancer progression in pathological specimens. Here we show that suppression of caveolin expression by a stably transfected antisense caveolin-1 cDNA vector converted androgen-insensitive metastatic mouse prostate cancer cells to an androgen-sensitive phenotype. Orthotopically grown tumors and low-density cell cultures derived from antisense caveolin clones had increased apoptosis in the absence of androgenic steroids, whereas similarly grown tumors and cells from vector (control) clones and parental cells were not sensitive to androgens. Studies using a representative antisense caveolin clone showed that selection for androgen resistance in vivo correlated with increased caveolin levels, and that adenovirus-mediated caveolin expression blocked androgen sensitivity. Our results identify a new candidate gene for hormone-resistant prostate cancer in man and indicate that androgen insensitivity can be an inherent property of metastatic prostate cancer.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "a", + "stably", + "transfected", + "antisense" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + } + ] + }, + { + "PMID": "9701244", + "TEXT": "Acquisition of invasive/metastatic potential through protease expression is an essential event in tumor progression. High levels of components of the plasminogen activation system, including urokinase, but paradoxically also its inhibitor, plasminogen activator inhibitor 1 (PAI1), have been correlated with a poor prognosis for some cancers. We report here that deficient PAI1 expression in host mice prevented local invasion and tumor vascularization of transplanted malignant keratinocytes. When this PAI1 deficiency was circumvented by intravenous injection of a replication-defective adenoviral vector expressing human PAI1, invasion and associated angiogenesis were restored. This experimental evidence demonstrates that host-produced PAI is essential for cancer cell invasion and angiogenesis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "PAI1", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PAI1", + "deficiency" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "replication-defective", + "adenoviral", + "vector", + "expressing", + "human", + "PAI1," + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored." + ] + } + } + ] + }, + { + "PMID": "9701242", + "TEXT": "Although the involvement of soluble and matrix-immobilized proteases in tumor cell invasion and metastasis is well recognized, the role of proteolytically activated cell surface receptors has not been elucidated. We report here that thrombin receptor, a member of the protease-activated receptor family, is preferentially expressed in highly metastatic human breast carcinoma cell lines and breast carcinoma biopsy specimens. Introduction of thrombin receptor antisense cDNA considerably inhibited the invasion of metastatic breast carcinoma cells in culture through a reconstituted basement membrane. During placental implantation of the human embryo, thrombin receptor is transiently expressed in the invading cytotrophoblasts. These results emphasize the involvement of thrombin receptor in cell invasion associated with tumor progression and normal embryonic development.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "receptor", + "antisense", + "cDNA" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + } + ] + }, + { + "PMID": "9500609", + "TEXT": "The development and endocrine function of the ovarian corpus luteum (CL) are dependent on the growth of new capillary vessels. Although several molecules have been implicated as mediators of CL angiogenesis, at present there is no direct evidence for the involvement of any. Here we report the unexpected finding that treatment with truncated soluble Flt-1 receptors, which inhibit vascular endothelial growth factor (VEGF) bioactivity, resulted in virtually complete suppression of CL angiogenesis in a rat model of hormonally induced ovulation. This effect was associated with inhibition of CL development and progesterone release. Failure of maturation of the endometrium was also observed. Areas of ischemic necrosis were demonstrated in the corpora lutea (CLs) of treated animals. However, no effect on the preexisting ovarian vasculature was observed. These findings demonstrate that, in spite of the redundancy of potential mediators, VEGF is essential for CL angiogenesis. Furthermore, they have implications for the control of fertility and the treatment of ovarian disorders characterized by hypervascularity and hyperplasia.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "truncated", + "soluble", + "Flt-1", + "receptors," + ] + }, + "effect": { + "val": "positive", + "words": [ + "hormonally", + "induced" + ] + } + } + ] + }, + { + "PMID": "8898746", + "TEXT": "A low proliferating fraction in solid tumors limits the effectiveness of cell cycle-dependent chemotherapeutic agents. To understand the molecular basis of such \"kinetic\" resistance we cultured tumor cells as multicellular spheroids and examined levels of p27Kip1, a cyclin-dependent kinase inhibitor known to be upregulated by intercellular contact in normal cells. When transferred from monolayer to three-dimensional culture, a consistent upregulation (up to 15-fold) of p27 protein was observed in a panel of mouse and human carcinoma cell lines. Antisense-oligonucleotide-mediated downregulation of p27 in EMT-6 mammary tumor cell spheroids reduced intercellular adhesion, increased cell proliferation, sensitized tumor cells to 4-hydroperoxycyclophosphamide, and restored drug- or radiation-induced cell-cycle perturbations repressed in spheroid culture. Our results implicate p27 as a regulator of drug resistance in solid tumors and suggest that tumor-targeted p27 antagonists may be useful chemosensitizers in conjunction with conventional anticancer therapy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antisense-oligonucleotide-mediated", + "downregulation", + "of", + "p27" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antisense-oligonucleotide-mediated", + "downregulation", + "of", + "p27" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + } + ] + }, + { + "PMID": "8837614", + "TEXT": "Loss of receptor hair cells in the cochlea accounts for a significant proportion of hearing impairment in the population. Hair cells can be lost as a consequence of viral or bacterial insult, aging, and damage from intense sound or aminoglycoside antibiotics. The generation of replacement hair cells following damage by sound or drugs has been clearly demonstrated in birds; the chick is the best-studied model for auditory hair cell regeneration. New hair cells arise as progeny from an otherwise nondividing supporting cell population induced to proliferate by the damage. Functional recovery of hearing accompanies this cellular recovery process. The signals and pathways responsible for regenerative proliferation are unknown. Here we show that proliferation is induced in the undamaged receptor epithelium by agents that increase cyclic AMP levels, and that following this stimulation hair cells become labeled with proliferation markers. This remarkable proliferative response is blocked by inhibitors of the cAMP-regulated protein kinase A (PKA). In addition we show that the proliferative response induced by in vitro gentamicin damage is also significantly blocked by PKA inhibitors. These observations are the first to identify a signaling pathway that plays a role in regenerative proliferation in the auditory receptor epithelium.", + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "PKA", + "inhibitors." + ] + } + } + ] + }, + { + "PMID": "8837606", + "TEXT": "The probability of producing a specific antitumor response should be increased by multiplying the number of T lymphocytes that encounter the malignant cells. We tested this prediction in a murine model, using a recently discovered T-cell chemokine, lymphotactin (Lptn). This chemokine increased tumor cell infiltration with CD4+ lymphocytes but generated little antitumor activity. Coexpression of the T-cell growth factor interleukin-2, however, greatly expanded the T lymphocytes attracted by Lptn, affording protection from the growth of established tumor in a CD4+ and CD8+ T cell-dependent manner. Lesser synergy was seen with GM-CSF. Hence coexpression of a T-cell chemokine and T-cell growth factor potentiates antitumor responses in vivo, suggesting a general strategy to improve cancer immunotherapy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Coexpression", + "of", + "the", + "T-cell", + "growth", + "factor", + "interleukin-2," + ] + }, + "effect": { + "val": "negative", + "words": [ + "protection" + ] + } + } + ] + }, + { + "PMID": "7585181", + "TEXT": "Activation of transcription of the Egr-1 gene by X-rays is regulated by the promoter region of this gene. We linked the radiation-inducible promoter region of the Egr-1 gene to the gene encoding the radiosensitizing and tumoricidal cytokine, tumour necrosis factor-alpha (TNF-alpha) and used a replication-deficient adenovirus to deliver the Egr-TNF construct to human tumours growing in nude mice. Combined treatment with Ad5.Egr-TNF and 5,000 cGy (rad) resulted in increased intratumoral TNF-alpha production and increased tumour control compared with treatment with Ad5.Egr-TNF alone or with radiation alone. The increase in tumour control was achieved without an increase in normal tissue damage when compared to tissue injury from radiation alone. Control of gene transcription by ionizing radiation in vivo represents a novel method of spatial and temporal regulation of gene-based medical treatments.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "replication-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + } + ] + }, + { + "PMID": "27643638", + "TEXT": "Continuous de novo fatty acid synthesis is a common feature of cancer that is required to meet the biosynthetic demands of a growing tumor. This process is controlled by the rate-limiting enzyme acetyl-CoA carboxylase (ACC), an attractive but traditionally intractable drug target. Here we provide genetic and pharmacological evidence that in preclinical models ACC is required to maintain the de novo fatty acid synthesis needed for growth and viability of non-small-cell lung cancer (NSCLC) cells. We describe the ability of ND-646-an allosteric inhibitor of the ACC enzymes ACC1 and ACC2 that prevents ACC subunit dimerization-to suppress fatty acid synthesis in vitro and in vivo. Chronic ND-646 treatment of xenograft and genetically engineered mouse models of NSCLC inhibited tumor growth. When administered as a single agent or in combination with the standard-of-care drug carboplatin, ND-646 markedly suppressed lung tumor growth in the Kras;Trp53-/- (also known as KRAS p53) and Kras;Stk11-/- (also known as KRAS Lkb1) mouse models of NSCLC. These findings demonstrate that ACC mediates a metabolic liability of NSCLC and that ACC inhibition by ND-646 is detrimental to NSCLC growth, supporting further examination of the use of ACC inhibitors in oncology.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "allosteric", + "inhibitor", + "of", + "the", + "ACC", + "enzymes", + "ACC1", + "and", + "ACC2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Kras;Trp53-/-", + "(also", + "KRAS", + "Lkb1)" + ] + } + } + ] + }, + { + "PMID": "31700183", + "TEXT": "Type 2 diabetes is characterized by insulin resistance and a gradual loss of pancreatic beta cell mass and function1,2. Currently, there are no therapies proven to prevent beta cell loss and some, namely insulin secretagogues, have been linked to accelerated beta cell failure, thereby limiting their use in type 2 diabetes3,4. The adipokine adipsin/complement factor D controls the alternative complement pathway and generation of complement component C3a, which acts to augment beta cell insulin secretion5. In contrast to other insulin secretagogues, we show that chronic replenishment of adipsin in diabetic db/db mice ameliorates hyperglycemia and increases insulin levels while preserving beta cells by blocking dedifferentiation and death. Mechanistically, we find that adipsin/C3a decreases the phosphatase Dusp26; forced expression of Dusp26 in beta cells decreases expression of core beta cell identity genes and sensitizes to cell death. In contrast, pharmacological inhibition of DUSP26 improves hyperglycemia in diabetic mice and protects human islet cells from cell death. Pertaining to human health, we show that higher concentrations of circulating adipsin are associated with a significantly lower risk of developing future diabetes among middle-aged adults after adjusting for body mass index (BMI). Collectively, these data suggest that adipsin/C3a and DUSP26-directed therapies may represent a novel approach to achieve beta cell health to treat and prevent type 2 diabetes.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "forced", + "expression", + "of", + "Dusp26" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitizes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "forced", + "expression", + "of", + "Dusp26" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protects" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "DUSP26" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protects" + ] + } + } + ] + }, + { + "PMID": "31270502", + "TEXT": "Bladder cancer is lethal in its advanced, muscle-invasive phase with very limited therapeutic advances1,2. Recent molecular characterization has defined new (epi)genetic drivers and potential targets for bladder cancer3,4. The immune checkpoint inhibitors have shown remarkable efficacy but only in a limited fraction of bladder cancer patients5-8. Here, we show that high G9a (EHMT2) expression is associated with poor clinical outcome in bladder cancer and that targeting G9a/DNMT methyltransferase activity with a novel inhibitor (CM-272) induces apoptosis and immunogenic cell death. Using an immunocompetent quadruple-knockout (PtenloxP/loxP; Trp53loxP/loxP; Rb1loxP/loxP; Rbl1-/-) transgenic mouse model of aggressive metastatic, muscle-invasive bladder cancer, we demonstrate that CM-272 + cisplatin treatment results in statistically significant regression of established tumors and metastases. The antitumor effect is significantly improved when CM-272 is combined with anti-programmed cell death ligand 1, even in the absence of cisplatin. These effects are associated with an endogenous antitumor immune response and immunogenic cell death with the conversion of a cold immune tumor into a hot tumor. Finally, increased G9a expression was associated with resistance to programmed cell death protein 1 inhibition in a cohort of patients with bladder cancer. In summary, these findings support new and promising opportunities for the treatment of bladder cancer using a combination of epigenetic inhibitors and immune checkpoint blockade.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "immunocompetent", + "quadruple-knockout", + "(PtenloxP/loxP;", + "Trp53loxP/loxP;", + "Rb1loxP/loxP;", + "Rbl1-/-)", + "transgenic" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + } + ] + }, + { + "PMID": "30833750", + "TEXT": "Overexpression of the B7-H1 (PD-L1) molecule in the tumor microenvironment (TME) is a major immune evasion mechanism in some patients with cancer, and antibody blockade of the B7-H1/PD-1 interaction can normalize compromised immunity without excessive side-effects. Using a genome-scale T cell activity array, we identified Siglec-15 as a critical immune suppressor. While only expressed on some myeloid cells normally, Siglec-15 is broadly upregulated on human cancer cells and tumor-infiltrating myeloid cells, and its expression is mutually exclusive to B7-H1, partially due to its induction by macrophage colony-stimulating factor and downregulation by IFN-γ. We demonstrate that Siglec-15 suppresses antigen-specific T cell responses in vitro and in vivo. Genetic ablation or antibody blockade of Siglec-15 amplifies anti-tumor immunity in the TME and inhibits tumor growth in some mouse models. Taken together, our results support Siglec-15 as a potential target for normalization cancer immunotherapy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "antibody", + "blockade" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "of", + "Siglec-15" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + } + ] + }, + { + "PMID": "30664779", + "TEXT": "Chordoma is a primary bone cancer with no approved therapy1. The identification of therapeutic targets in this disease has been challenging due to the infrequent occurrence of clinically actionable somatic mutations in chordoma tumors2,3. Here we describe the discovery of therapeutically targetable chordoma dependencies via genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling. These systematic approaches reveal that the developmental transcription factor T (brachyury; TBXT) is the top selectively essential gene in chordoma, and that transcriptional cyclin-dependent kinase (CDK) inhibitors targeting CDK7/12/13 and CDK9 potently suppress chordoma cell proliferation. In other cancer types, transcriptional CDK inhibitors have been observed to downregulate highly expressed, enhancer-associated oncogenic transcription factors4,5. In chordoma, we find that T is associated with a 1.5-Mb region containing 'super-enhancers' and is the most highly expressed super-enhancer-associated transcription factor. Notably, transcriptional CDK inhibition leads to preferential and concentration-dependent downregulation of cellular brachyury protein levels in all models tested. In vivo, CDK7/12/13-inhibitor treatment substantially reduces tumor growth. Together, these data demonstrate small-molecule targeting of brachyury transcription factor addiction in chordoma, identify a mechanism of T gene regulation that underlies this therapeutic strategy, and provide a blueprint for applying systematic genetic and chemical screening approaches to discover vulnerabilities in genomically quiet cancers.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "transcriptional", + "cyclin-dependent", + "kinase", + "(CDK)", + "inhibitors", + "targeting", + "CDK7/12/13", + "and", + "CDK9", + "CDK7/12/13-inhibitor", + "treatment" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppress", + "reduces" + ] + } + } + ] + }, + { + "PMID": "30643286", + "TEXT": "Cancer cells develop mechanisms to escape immunosurveillance, among which modulating the expression of immune suppressive messenger RNAs is most well-documented. However, how this is molecularly achieved remains largely unresolved. Here, we develop an in vivo mouse model of liver cancer to study oncogene cooperation in immunosurveillance. We show that MYC overexpression (MYCTg) synergizes with KRASG12D to induce an aggressive liver tumor leading to metastasis formation and reduced mouse survival compared with KRASG12D alone. Genome-wide ribosomal footprinting of MYCTg;KRASG12 tumors compared with KRASG12D revealed potential alterations in translation of mRNAs, including programmed-death-ligand 1 (PD-L1). Further analysis revealed that PD-L1 translation is repressed in KRASG12D tumors by functional, non-canonical upstream open reading frames in its 5' untranslated region, which is bypassed in MYCTg;KRASG12D tumors to evade immune attack. We show that this mechanism of PD-L1 translational upregulation was effectively targeted by a potent, clinical compound that inhibits eIF4E phosphorylation, eFT508, which reverses the aggressive and metastatic characteristics of MYCTg;KRASG12D tumors. Together, these studies reveal how immune-checkpoint proteins are manipulated by distinct oncogenes at the level of mRNA translation, which can be exploited for new immunotherapies.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "MYC", + "overexpression", + "(MYCTg)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce", + "leading", + "to" + ] + } + } + ] + }, + { + "PMID": "30013198", + "TEXT": "Mutations in the gene encoding isocitrate dehydrogenase 2 (IDH2) occur in several types of cancer, including acute myeloid leukemia (AML). In model systems, mutant IDH2 causes hematopoietic differentiation arrest. Enasidenib, a selective small-molecule inhibitor of mutant IDH2, produces a clinical response in 40% of treated patients with relapsed/refractory AML by promoting leukemic cell differentiation. Here, we studied the clonal basis of response and acquired resistance to enasidenib treatment. Using sequential patient samples, we determined the clonal structure of hematopoietic cell populations at different stages of differentiation. Before therapy, IDH2-mutant clones showed variable differentiation arrest. Enasidenib treatment promoted hematopoietic differentiation from either terminal or ancestral mutant clones; less frequently, treatment promoted differentiation of nonmutant cells. Analysis of paired diagnosis/relapse samples did not identify second-site mutations in IDH2 at relapse. Instead, relapse arose by clonal evolution or selection of terminal or ancestral clones, thus highlighting multiple bypass pathways that could potentially be targeted to restore differentiation arrest. These results show how mapping of clonal structure in cell populations at different stages of differentiation can reveal the response and evolution of clones during treatment response and relapse.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "IDH2-mutant" + ] + }, + "effect": { + "val": "positive", + "words": [ + "arrest." + ] + } + } + ] + }, + { + "PMID": "29967349", + "TEXT": "Small-molecule inhibitors of the serine dipeptidases DPP8 and DPP9 (DPP8/9) induce a lytic form of cell death called pyroptosis in mouse and human monocytes and macrophages1,2. In mouse myeloid cells, Dpp8/9 inhibition activates the inflammasome sensor Nlrp1b, which in turn activates pro-caspase-1 to mediate cell death3, but the mechanism of DPP8/9 inhibitor-induced pyroptosis in human myeloid cells is not yet known. Here we show that the CARD-containing protein CARD8 mediates DPP8/9 inhibitor-induced pro-caspase-1-dependent pyroptosis in human myeloid cells. We further show that DPP8/9 inhibitors induce pyroptosis in the majority of human acute myeloid leukemia (AML) cell lines and primary AML samples, but not in cells from many other lineages, and that these inhibitors inhibit human AML progression in mouse models. Overall, this work identifies an activator of CARD8 in human cells and indicates that its activation by small-molecule DPP8/9 inhibitors represents a new potential therapeutic strategy for AML.", + "LINKED_TAGS": [ + { + "effect": { + "val": "regulates", + "words": [ + "mediates" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitor-induced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitor-induced", + "DPP8/9", + "inhibitors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inhibitor-induced", + "induce" + ] + } + } + ] + }, + { + "PMID": "29892060", + "TEXT": "It has long been assumed that p53 suppresses tumor development through induction of apoptosis, possibly with contributions by cell cycle arrest and cell senescence1,2. However, combined deficiency in these three processes does not result in spontaneous tumor formation as observed upon loss of p53, suggesting the existence of additional mechanisms that are critical mediators of p53-dependent tumor suppression function3-5. To define such mechanisms, we performed in vivo shRNA screens targeting p53-regulated genes in sensitized genetic backgrounds. We found that knockdown of Zmat3, Ctsf and Cav1, promoted lymphoma/leukemia development only when PUMA and p21, the critical effectors of p53-driven apoptosis, cell cycle arrest and senescence, were also absent. Notably, loss of the DNA repair gene Mlh1 caused lymphoma in a wild-type background, and its enforced expression was able to delay tumor development driven by loss of p53. Further examination of direct p53 target genes implicated in DNA repair showed that knockdown of Mlh1, Msh2, Rnf144b, Cav1 and Ddit4 accelerated MYC-driven lymphoma development to a similar extent as knockdown of p53. Collectively, these findings demonstrate that extensive functional overlap of several p53-regulated processes safeguards against cancer and that coordination of DNA repair appears to be an important process by which p53 suppresses tumor development.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "Zmat3,", + "Ctsf", + "and", + "Cav1,", + "Mlh1,", + "Msh2,", + "Rnf144b,", + "Cav1", + "Ddit4", + "p53." + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted", + "accelerated" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "DNA", + "repair", + "gene", + "Mlh1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "DNA", + "repair", + "gene", + "Mlh1", + "p53." + ] + }, + "effect": { + "val": "negative", + "words": [ + "delay" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "delay" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Msh2,", + "Rnf144b,", + "Cav1" + ] + } + } + ] + }, + { + "PMID": "29808009", + "TEXT": "The ubiquitously expressed non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, is involved in signal transduction downstream of multiple growth factor, cytokine and integrin receptors1. Its requirement for complete RAS-MAPK activation and its role as a negative regulator of JAK-STAT signaling have established SHP2 as an essential player in oncogenic signaling pathways1-7. Recently, a novel potent allosteric SHP2 inhibitor was presented as a viable therapeutic option for receptor tyrosine kinase-driven cancers, but was shown to be ineffective in KRAS-mutant tumor cell lines in vitro8. Here, we report a central and indispensable role for SHP2 in oncogenic KRAS-driven tumors. Genetic deletion of Ptpn11 profoundly inhibited tumor development in mutant KRAS-driven murine models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. We provide evidence for a critical dependence of mutant KRAS on SHP2 during carcinogenesis. Deletion or inhibition of SHP2 in established tumors delayed tumor progression but was not sufficient to achieve tumor regression. However, SHP2 was necessary for resistance mechanisms upon blockade of MEK. Synergy was observed when both SHP2 and MEK were targeted, resulting in sustained tumor growth control in murine and human patient-derived organoids and xenograft models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. Our data indicate the clinical utility of dual SHP2/MEK inhibition as a targeted therapy approach for KRAS-mutant cancers.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "deletion", + "of", + "Ptpn11" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "KRAS-driven" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "delayed" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "SHP2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "achieve" + ] + } + } + ] + }, + { + "PMID": "29431745", + "TEXT": "Immunotherapy offers new options for cancer treatment, but efficacy varies across cancer types. Colorectal cancers (CRCs) are largely refractory to immune-checkpoint blockade, which suggests the presence of yet uncharacterized immune-suppressive mechanisms. Here we report that the loss of adenomatosis polyposis coli (APC) in intestinal tumor cells or of the tumor suppressor PTEN in melanoma cells upregulates the expression of Dickkopf-related protein 2 (DKK2), which, together with its receptor LRP5, provides an unconventional mechanism for tumor immune evasion. DKK2 secreted by tumor cells acts on cytotoxic lymphocytes, inhibiting STAT5 signaling by impeding STAT5 nuclear localization via LRP5, but independently of LRP6 and the Wnt-β-catenin pathway. Genetic or antibody-mediated ablation of DKK2 activates natural killer (NK) cells and CD8+ T cells in tumors, impedes tumor progression, and enhances the effects of PD-1 blockade. Thus, we have identified a previously unknown tumor immune-suppressive mechanism and immunotherapeutic targets particularly relevant for CRCs and a subset of melanomas.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "antibody-mediated", + "ablation", + "of", + "DKK2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impedes" + ] + } + } + ] + }, + { + "PMID": "28869610", + "TEXT": "Basal cell carcinoma (BCC), the most common human cancer, results from aberrant activation of the Hedgehog signaling pathway. Although most cases of BCC are sporadic, some forms are inherited, such as Bazex-Dupré-Christol syndrome (BDCS)-a cancer-prone genodermatosis with an X-linked, dominant inheritance pattern. We have identified mutations in the ACTRT1 gene, which encodes actin-related protein T1 (ARP-T1), in two of the six families with BDCS that were examined in this study. High-throughput sequencing in the four remaining families identified germline mutations in noncoding sequences surrounding ACTRT1. These mutations were located in transcribed sequences encoding enhancer RNAs (eRNAs) and were shown to impair enhancer activity and ACTRT1 expression. ARP-T1 was found to directly bind to the GLI1 promoter, thus inhibiting GLI1 expression, and loss of ARP-T1 led to activation of the Hedgehog pathway in individuals with BDCS. Moreover, exogenous expression of ACTRT1 reduced the in vitro and in vivo proliferation rates of cell lines with aberrant activation of the Hedgehog signaling pathway. In summary, our study identifies a disease mechanism in BCC involving mutations in regulatory noncoding elements and uncovers the tumor-suppressor properties of ACTRT1.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "exogenous", + "expression", + "of", + "ACTRT1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + } + ] + }, + { + "PMID": "28504723", + "TEXT": "Impaired learning and cognitive function often occurs during systemic infection or inflammation. Although activation of the innate immune system has been linked to the behavioral and cognitive effects that are associated with infection, the underlying mechanisms remain poorly understood. Here we mimicked viral immune activation with poly(I:C), a synthetic analog of double-stranded RNA, and longitudinally imaged postsynaptic dendritic spines of layer V pyramidal neurons in the mouse primary motor cortex using two-photon microscopy. We found that peripheral immune activation caused dendritic spine loss, impairments in learning-dependent dendritic spine formation and deficits in multiple learning tasks in mice. These observed synaptic alterations in the cortex were mediated by peripheral-monocyte-derived cells and did not require microglial function in the central nervous system. Furthermore, activation of CX3CR1highLy6Clow monocytes impaired motor learning and learning-related dendritic spine plasticity through tumor necrosis factor (TNF)-α-dependent mechanisms. Taken together, our results highlight CX3CR1high monocytes and TNF-α as potential therapeutic targets for preventing infection-induced cognitive dysfunction.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation", + "of" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "CX3CR1highLy6Clow" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + } + ] + }, + { + "PMID": "28319094", + "TEXT": "Tyrosine-kinase inhibitor (TKI) therapy for human cancers is not curative, and relapse occurs owing to the continued presence of tumor cells, referred to as minimal residual disease (MRD). The survival of MRD stem or progenitor cells in the absence of oncogenic kinase signaling, a phenomenon referred to as intrinsic resistance, depends on diverse growth factors. Here we report that oncogenic kinase and growth-factor signaling converge to induce the expression of the signaling proteins FBJ osteosarcoma oncogene (c-FOS, encoded by Fos) and dual-specificity phosphatase 1 (DUSP1). Genetic deletion of Fos and Dusp1 suppressed tumor growth in a BCR-ABL fusion protein kinase-induced mouse model of chronic myeloid leukemia (CML). Pharmacological inhibition of c-FOS, DUSP1 and BCR-ABL eradicated MRD in multiple in vivo models, as well as in mice xenotransplanted with patient-derived primary CML cells. Growth-factor signaling also conferred TKI resistance and induced FOS and DUSP1 expression in tumor cells modeling other types of kinase-driven leukemias. Our data demonstrate that c-FOS and DUSP1 expression levels determine the threshold of TKI efficacy, such that growth-factor-induced expression of c-FOS and DUSP1 confers intrinsic resistance to TKI therapy in a wide-ranging set of leukemias, and might represent a unifying Achilles' heel of kinase-driven cancers.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "deletion", + "of", + "Fos", + "and", + "Dusp1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + } + ] + }, + { + "PMID": "28263309", + "TEXT": "Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor that is located in the pons and primarily affects children. Nearly 80% of DIPGs harbor mutations in histone H3 genes, wherein lysine 27 is substituted with methionine (H3K27M). H3K27M has been shown to inhibit polycomb repressive complex 2 (PRC2), a multiprotein complex responsible for the methylation of H3 at lysine 27 (H3K27me), by binding to its catalytic subunit EZH2. Although DIPGs with the H3K27M mutation show global loss of H3K27me3, several genes retain H3K27me3. Here we describe a mouse model of DIPG in which H3K27M potentiates tumorigenesis. Using this model and primary patient-derived DIPG cell lines, we show that H3K27M-expressing tumors require PRC2 for proliferation. Furthermore, we demonstrate that small-molecule EZH2 inhibitors abolish tumor cell growth through a mechanism that is dependent on the induction of the tumor-suppressor protein p16INK4A. Genome-wide enrichment analyses show that the genes that retain H3K27me3 in H3K27M cells are strong polycomb targets. Furthermore, we find a highly significant overlap between genes that retain H3K27me3 in the DIPG mouse model and in human primary DIPGs expressing H3K27M. Taken together, these results show that residual PRC2 activity is required for the proliferation of H3K27M-expressing DIPGs, and that inhibition of EZH2 is a potential therapeutic strategy for the treatment of these tumors.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "EZH2", + "inhibitors" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abolish" + ] + } + } + ] + }, + { + "PMID": "28165480", + "TEXT": "Cystinuria is an incompletely dominant disorder characterized by defective urinary cystine reabsorption that results in the formation of cystine-based urinary stones. Current treatment options are limited in their effectiveness at preventing stone recurrence and are often poorly tolerated. We report that the nutritional supplement α-lipoic acid inhibits cystine stone formation in the Slc3a1-/- mouse model of cystinuria by increasing the solubility of urinary cystine. These findings identify a novel therapeutic strategy for the clinical treatment of cystinuria.", + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Slc3a1-/-" + ] + } + } + ] + }, + { + "PMID": "27376578", + "TEXT": "In a search for mediators of the p53 tumor suppressor pathway, which induces pleiotropic and often antagonistic cellular responses, we identified the long noncoding RNA (lncRNA) NEAT1. NEAT1 is an essential architectural component of paraspeckle nuclear bodies, whose pathophysiological relevance remains unclear. Activation of p53, pharmacologically or by oncogene-induced replication stress, stimulated the formation of paraspeckles in mouse and human cells. Silencing Neat1 expression in mice, which prevents paraspeckle formation, sensitized preneoplastic cells to DNA-damage-induced cell death and impaired skin tumorigenesis. We provide mechanistic evidence that NEAT1 promotes ATR signaling in response to replication stress and is thereby engaged in a negative feedback loop that attenuates oncogene-dependent activation of p53. NEAT1 targeting in established human cancer cell lines induced synthetic lethality with genotoxic chemotherapeutics, including PARP inhibitors, and nongenotoxic activation of p53. This study establishes a key genetic link between NEAT1 paraspeckles, p53 biology and tumorigenesis and identifies NEAT1 as a promising target to enhance sensitivity of cancer cells to both chemotherapy and p53 reactivation therapy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "p53," + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "Neat1", + "expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "Neat1", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + } + ] + }, + { + "PMID": "27376576", + "TEXT": "Single-agent immunotherapy has achieved limited clinical benefit to date in patients with pancreatic ductal adenocarcinoma (PDAC). This may be a result of the presence of a uniquely immunosuppressive tumor microenvironment (TME). Critical obstacles to immunotherapy in PDAC tumors include a high number of tumor-associated immunosuppressive cells and a uniquely desmoplastic stroma that functions as a barrier to T cell infiltration. We identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as an important regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlated with high levels of fibrosis and poor CD8(+) cytotoxic T cell infiltration. Single-agent FAK inhibition using the selective FAK inhibitor VS-4718 substantially limited tumor progression, resulting in a doubling of survival in the p48-Cre;LSL-Kras(G12D);Trp53(flox/+) (KPC) mouse model of human PDAC. This delay in tumor progression was associated with markedly reduced tumor fibrosis and decreased numbers of tumor-infiltrating immunosuppressive cells. We also found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to T cell immunotherapy and PD-1 antagonists. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and renders tumors responsive to immunotherapy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Single-agent", + "FAK", + "inhibition", + "using", + "the", + "selective", + "inhibitor", + "VS-4718" + ] + }, + "effect": { + "val": "negative", + "words": [ + "limited", + "delay" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "p48-Cre;LSL-Kras(G12D);Trp53(flox/+)", + "(KPC)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "delay" + ] + } + } + ] + }, + { + "PMID": "26523971", + "TEXT": "Focal malformations of cortical development (FMCDs) account for the majority of drug-resistant pediatric epilepsy. Postzygotic somatic mutations activating the phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway are found in a wide range of brain diseases, including FMCDs. It remains unclear how a mutation in a small fraction of cells disrupts the architecture of the entire hemisphere. Within human FMCD-affected brain, we found that cells showing activation of the PI3K-AKT-mTOR pathway were enriched for the AKT3(E17K) mutation. Introducing the FMCD-causing mutation into mouse brain resulted in electrographic seizures and impaired hemispheric architecture. Mutation-expressing neural progenitors showed misexpression of reelin, which led to a non-cell autonomous migration defect in neighboring cells, due at least in part to derepression of reelin transcription in a manner dependent on the forkhead box (FOX) transcription factor FOXG1. Treatments aimed at either blocking downstream AKT signaling or inactivating reelin restored migration. These findings suggest a central AKT-FOXG1-reelin signaling pathway in FMCD and support pathway inhibitors as potential treatments or therapies for some forms of focal epilepsy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Introducing", + "the", + "FMCD-causing", + "mutation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defect" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivating", + "reelin" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + } + } + ] + }, + { + "PMID": "26390243", + "TEXT": "Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and shows resistance to any therapeutic strategy used. Here we tested small-molecule inhibitors targeting chromatin regulators as possible therapeutic agents in PDAC. We show that JQ1, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, suppresses PDAC development in mice by inhibiting both MYC activity and inflammatory signals. The histone deacetylase (HDAC) inhibitor SAHA synergizes with JQ1 to augment cell death and more potently suppress advanced PDAC. Finally, using a CRISPR-Cas9-based method for gene editing directly in the mouse adult pancreas, we show that de-repression of p57 (also known as KIP2 or CDKN1C) upon combined BET and HDAC inhibition is required for the induction of combination therapy-induced cell death in PDAC. SAHA is approved for human use, and molecules similar to JQ1 are being tested in clinical trials. Thus, these studies identify a promising epigenetic-based therapeutic strategy that may be rapidly implemented in fatal human tumors.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "de-repression", + "of", + "p57", + "(also" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction", + "therapy-induced" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "KIP2", + "CDKN1C)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction", + "therapy-induced" + ] + } + } + ] + }, + { + "PMID": "26280119", + "TEXT": "T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) elicits antitumor activity in various tumor models; however, the underlying mechanism of action remains unclear. Here we demonstrate a crucial role for interleukin (IL)-9 in antitumor immunity generated by the GITR agonistic antibody DTA-1. IL-4 receptor knockout (Il4ra(-/-)) mice, which have reduced expression of IL-9, were resistant to tumor growth inhibition by DTA-1. Notably, neutralization of IL-9 considerably impaired tumor rejection induced by DTA-1. In particular, DTA-1-induced IL-9 promoted tumor-specific cytotoxic T lymphocyte (CTL) responses by enhancing the function of dendritic cells in vivo. Furthermore, GITR signaling enhanced the differentiation of IL-9-producing CD4(+) T-helper (TH9) cells in a TNFR-associated factor 6 (TRAF6)- and NF-κB-dependent manner and inhibited the generation of induced regulatory T cells in vitro. Our findings demonstrate that GITR co-stimulation mediates antitumor immunity by promoting TH9 cell differentiation and enhancing CTL responses and thus provide a mechanism of action for GITR agonist-mediated cancer immunotherapies.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "IL-4", + "receptor", + "knockout", + "(Il4ra(-/-))" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant", + "inhibition", + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "neutralization" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + } + ] + }, + { + "PMID": "25686104", + "TEXT": "The gene encoding ARID1A, a chromatin remodeler, shows one of the highest mutation rates across many cancer types. Notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas, which currently have no effective therapy. To date, clinically applicable targeted cancer therapy based on ARID1A mutational status has not been described. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer cells and that ARID1A mutational status correlated with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct target of ARID1A and EZH2 that is upregulated by EZH2 inhibition and contributed to the observed synthetic lethality by inhibiting PI3K-AKT signaling. Importantly, EZH2 inhibition caused regression of ARID1A-mutated ovarian tumors in vivo. To our knowledge, this is the first data set to demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. Our data indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for cancers involving ARID1A mutations.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EZH2", + "inhibition" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + } + ] + }, + { + "PMID": "25599133", + "TEXT": "Mutant isocitrate dehydrogenase (IDH) 1 and 2 proteins alter the epigenetic landscape in acute myeloid leukemia (AML) cells through production of the oncometabolite (R)-2-hydroxyglutarate (2-HG). Here we performed a large-scale RNA interference (RNAi) screen to identify genes that are synthetic lethal to the IDH1(R132H) mutation in AML and identified the anti-apoptotic gene BCL-2. IDH1- and IDH2-mutant primary human AML cells were more sensitive than IDH1/2 wild-type cells to ABT-199, a highly specific BCL-2 inhibitor that is currently in clinical trials for hematologic malignancies, both ex vivo and in xenotransplant models. This sensitization effect was induced by (R)-2-HG-mediated inhibition of the activity of cytochrome c oxidase (COX) in the mitochondrial electron transport chain (ETC); suppression of COX activity lowered the mitochondrial threshold to trigger apoptosis upon BCL-2 inhibition. Our findings indicate that IDH1/2 mutation status may identify patients that are likely to respond to pharmacologic BCL-2 inhibition and form the rational basis for combining agents that disrupt ETC activity with ABT-199 in future clinical studies.", + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "trigger" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BCL-2", + "inhibition." + ] + } + } + ] + }, + { + "PMID": "25419709", + "TEXT": "We searched for genetic alterations in human B cell lymphoma that affect the ubiquitin-proteasome system. This approach identified FBXO25 within a minimal common region of frequent deletion in mantle cell lymphoma (MCL). FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)(FBXO25) ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase Cδ (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1. Our analyses in primary human MCL identify monoallelic loss of FBXO25 and stabilizing HAX1 phosphodegron mutations. Accordingly, FBXO25 re-expression in FBXO25-deleted MCL cells promotes cell death, whereas expression of the HAX-1 phosphodegron mutant inhibits apoptosis. In addition, knockdown of FBXO25 significantly accelerated lymphoma development in Eμ-Myc mice and in a human MCL xenotransplant model. Together we identify a PRKCD-dependent proapoptotic mechanism controlling HAX-1 stability, and we propose that FBXO25 functions as a haploinsufficient tumor suppressor and that HAX1 is a proto-oncogene in MCL.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "FBXO25", + "re-expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "FBXO25", + "re-expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FBXO25-deleted", + "Eμ-Myc" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes", + "accelerated" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FBXO25-deleted" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "the", + "HAX-1", + "phosphodegron", + "mutant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "FBXO25" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerated" + ] + } + } + ] + }, + { + "PMID": "25326798", + "TEXT": "Multiple bone marrow stromal cell types have been identified as hematopoietic stem cell (HSC)-regulating niche cells. However, whether HSC progeny can serve directly as HSC niche cells has not previously been shown. Here we report a dichotomous role of megakaryocytes (MKs) in both maintaining HSC quiescence during homeostasis and promoting HSC regeneration after chemotherapeutic stress. We show that MKs are physically associated with HSCs in the bone marrow of mice and that MK ablation led to activation of quiescent HSCs and increased HSC proliferation. RNA sequencing (RNA-seq) analysis revealed that transforming growth factor β1 (encoded by Tgfb1) is expressed at higher levels in MKs as compared to other stromal niche cells. MK ablation led to reduced levels of biologically active TGF-β1 protein in the bone marrow and nuclear-localized phosphorylated SMAD2/3 (pSMAD2/3) in HSCs, suggesting that MKs maintain HSC quiescence through TGF-β-SMAD signaling. Indeed, TGF-β1 injection into mice in which MKs had been ablated restored HSC quiescence, and conditional deletion of Tgfb1 in MKs increased HSC activation and proliferation. These data demonstrate that TGF-β1 is a dominant signal emanating from MKs that maintains HSC quiescence. However, under conditions of chemotherapeutic challenge, MK ablation resulted in a severe defect in HSC expansion. In response to stress, fibroblast growth factor 1 (FGF1) signaling from MKs transiently dominates over TGF-β inhibitory signaling to stimulate HSC expansion. Overall, these observations demonstrate that MKs serve as HSC-derived niche cells to dynamically regulate HSC function.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MK", + "ablation", + "conditional", + "deletion", + "of", + "Tgfb1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "MK", + "ablation", + "MKs", + "been", + "ablated" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + } + } + ] + }, + { + "PMID": "25306233", + "TEXT": "The WNT16 locus is a major determinant of cortical bone thickness and nonvertebral fracture risk in humans. The disability, mortality and costs caused by osteoporosis-induced nonvertebral fractures are enormous. We demonstrate here that Wnt16-deficient mice develop spontaneous fractures as a result of low cortical thickness and high cortical porosity. In contrast, trabecular bone volume is not altered in these mice. Mechanistic studies revealed that WNT16 is osteoblast derived and inhibits human and mouse osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts. The signaling pathway activated by WNT16 in osteoclast progenitors is noncanonical, whereas the pathway activated in osteoblasts is both canonical and noncanonical. Conditional Wnt16 inactivation revealed that osteoblast-lineage cells are the principal source of WNT16, and its targeted deletion in osteoblasts increases fracture susceptibility. Thus, osteoblast-derived WNT16 is a previously unreported key regulator of osteoclastogenesis and fracture susceptibility. These findings open new avenues for the specific prevention or treatment of nonvertebral fractures, a substantial unmet medical need.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Wnt16-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + } + ] + }, + { + "PMID": "25194568", + "TEXT": "The Notch signaling pathway controls cell fates through interactions between neighboring cells by positively or negatively affecting the processes of proliferation, differentiation and apoptosis in a context-dependent manner. This pathway has been implicated in human cancer as both an oncogene and a tumor suppressor. Here we report new inactivating mutations in Notch pathway components in over 40% of human bladder cancers examined. Bladder cancer is the fourth most commonly diagnosed malignancy in the male population of the United States. Thus far, driver mutations in fibroblast growth factor receptor 3 (FGFR3) and, less commonly, in RAS proteins have been identified. We show that Notch activation in bladder cancer cells suppresses proliferation both in vitro and in vivo by directly upregulating dual-specificity phosphatases (DUSPs), thus reducing the phosphorylation of ERK1 and ERK2 (ERK1/2). In mouse models, genetic inactivation of Notch signaling leads to Erk1/2 phosphorylation, resulting in tumorigenesis in the urinary tract. Collectively our findings show that loss of Notch activity is a driving event in urothelial cancer.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inactivation", + "of", + "Notch", + "signaling" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + } + } + ] + }, + { + "PMID": "24813251", + "TEXT": "Oncogene-induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and the mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies, including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53-independent, proapoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway coactivator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1-induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine-threonine kinase, STK4. Notably, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a new synthetic-lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inactivation", + "of", + "STK4" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + } + } + ] + }, + { + "PMID": "24793239", + "TEXT": "We describe a new mechanism regulating the tumor endothelial barrier and T cell infiltration into tumors. We detected selective expression of the death mediator Fas ligand (FasL, also called CD95L) in the vasculature of human and mouse solid tumors but not in normal vasculature. In these tumors, FasL expression was associated with scarce CD8(+) infiltration and a predominance of FoxP3(+) T regulatory (Treg) cells. Tumor-derived vascular endothelial growth factor A (VEGF-A), interleukin 10 (IL-10) and prostaglandin E2 (PGE2) cooperatively induced FasL expression in endothelial cells, which acquired the ability to kill effector CD8(+) T cells but not Treg cells because of higher levels of c-FLIP expression in Treg cells. In mice, genetic or pharmacologic suppression of FasL produced a substantial increase in the influx of tumor-rejecting CD8(+) over FoxP3(+) T cells. Pharmacologic inhibition of VEGF and PGE2 produced a marked increase in the influx of tumor-rejecting CD8(+) over FoxP3(+) T cells that was dependent on attenuation of FasL expression and led to CD8-dependent tumor growth suppression. Thus, tumor paracrine mechanisms establish a tumor endothelial death barrier, which has a critical role in establishing immune tolerance and determining the fate of tumors.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacologic", + "inhibition", + "of", + "VEGF", + "and", + "PGE2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppression." + ] + } + } + ] + }, + { + "PMID": "24584117", + "TEXT": "Atherosclerosis, a hyperlipidemia-induced chronic inflammatory process of the arterial wall, develops preferentially at sites where disturbed laminar flow compromises endothelial cell (EC) function. Here we show that endothelial miR-126-5p maintains a proliferative reserve in ECs through suppression of the Notch1 inhibitor delta-like 1 homolog (Dlk1) and thereby prevents atherosclerotic lesion formation. Endothelial recovery after denudation was impaired in Mir126(-/-) mice because lack of miR-126-5p, but not miR-126-3p, reduced EC proliferation by derepressing Dlk1. At nonpredilection sites, high miR-126-5p levels in endothelial cells confer a proliferative reserve that compensates for the antiproliferative effects of hyperlipidemia, such that atherosclerosis was exacerbated in Mir126(-/-) mice. In contrast, downregulation of miR-126-5p by disturbed flow abrogated EC proliferation at predilection sites in response to hyperlipidemic stress through upregulation of Dlk1 expression. Administration of miR-126-5p rescued EC proliferation at predilection sites and limited atherosclerosis, introducing a potential therapeutic approach.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "miR-126-5p,", + "Mir126(-/-)", + "downregulation", + "miR-126-5p" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced", + "abrogated" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "downregulation", + "of" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + } + ] + }, + { + "PMID": "24562383", + "TEXT": "Recent studies have revealed that ARID1A, encoding AT-rich interactive domain 1A (SWI-like), is frequently mutated across a variety of human cancers and also has bona fide tumor suppressor properties. Consequently, identification of vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. Here, using a broad screening approach, we identify ARID1B, an ARID1A homolog whose gene product is mutually exclusive with ARID1A in SWI/SNF complexes, as the number 1 gene preferentially required for the survival of ARID1A-mutant cancer cell lines. We show that loss of ARID1B in ARID1A-deficient backgrounds destabilizes SWI/SNF and impairs proliferation in both cancer cells and primary cells. We also find that ARID1A and ARID1B are frequently co-mutated in cancer but that ARID1A-deficient cancers retain at least one functional ARID1B allele. These results suggest that loss of ARID1A and ARID1B alleles cooperatively promotes cancer formation but also results in a unique functional dependence. The results further identify ARID1B as a potential therapeutic target for ARID1A-mutant cancers.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "ARID1B", + "ARID1A-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impairs" + ] + } + } + ] + }, + { + "PMID": "24076664", + "TEXT": "Heterotopic ossification, the pathologic formation of extraskeletal bone, occurs as a common complication of trauma or in genetic disorders and can be disabling and lethal. However, the underlying molecular mechanisms are largely unknown. Here we demonstrate that Gαs restricts bone formation to the skeleton by inhibiting Hedgehog signaling in mesenchymal progenitor cells. In progressive osseous heteroplasia, a human disease caused by null mutations in GNAS, which encodes Gαs, Hedgehog signaling is upregulated in ectopic osteoblasts and progenitor cells. In animal models, we show that genetically-mediated ectopic Hedgehog signaling is sufficient to induce heterotopic ossification, whereas inhibition of this signaling pathway by genetic or pharmacological means strongly reduces the severity of this condition. As our previous work has shown that GNAS gain-of-function mutations upregulate WNT-β-catenin signaling in osteoblast progenitor cells, resulting in their defective differentiation and fibrous dysplasia, we identify Gαs as a key regulator of proper osteoblast differentiation through its maintenance of a balance between the Wnt-β-catenin and Hedgehog pathways. Also, given the results here of the pharmacological studies in our mouse model, we propose that Hedgehog inhibitors currently used in the clinic for other conditions, such as cancer, may possibly be repurposed for treating heterotopic ossification and other diseases caused by GNAS inactivation.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GNAS", + "gain-of-function", + "mutations" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + } + ] + }, + { + "PMID": "23955711", + "TEXT": "Forkhead box P3 (Foxp3)(+) T regulatory (T(reg)) cells maintain immune homeostasis and limit autoimmunity but can also curtail host immune responses to various types of tumors. Foxp3(+) T(reg) cells are therefore considered promising targets to enhance antitumor immunity, and approaches for their therapeutic modulation are being developed. However, although studies showing that experimentally depleting Foxp3(+) T(reg) cells can enhance antitumor responses provide proof of principle, these studies lack clear translational potential and have various shortcomings. Histone/protein acetyltransferases (HATs) promote chromatin accessibility, gene transcription and the function of multiple transcription factors and nonhistone proteins. We now report that conditional deletion or pharmacologic inhibition of one HAT, p300 (also known as Ep300 or KAT3B), in Foxp3(+) T(reg) cells increased T cell receptor-induced apoptosis in T(reg) cells, impaired T(reg) cell suppressive function and peripheral T(reg) cell induction, and limited tumor growth in immunocompetent but not in immunodeficient mice. Our data thereby demonstrate that p300 is important for Foxp3(+) T(reg) cell function and homeostasis in vivo and in vitro, and identify mechanisms by which appropriate small-molecule inhibitors can diminish T(reg) cell function without overtly impairing T effector cell responses or inducing autoimmunity. Collectively, these data suggest a new approach for cancer immunotherapy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "one", + "HAT,", + "p300", + "(also", + "KAT3B)," + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "cell", + "receptor-induced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "one", + "HAT,", + "p300", + "(also", + "KAT3B)," + ] + }, + "effect": { + "val": "negative", + "words": [ + "limited" + ] + } + } + ] + }, + { + "PMID": "23933981", + "TEXT": "The blood-brain barrier (BBB) is an integral part of the neurovascular unit (NVU). The NVU is comprised of endothelial cells that are interconnected by tight junctions resting on a parenchymal basement membrane ensheathed by pericytes, smooth muscle cells and a layer of astrocyte end feet. Circulating blood cells, such as leukocytes, complete the NVU. BBB disruption is common in several neurological diseases, but the molecular mechanisms involved remain largely unknown. We analyzed the role of TWIK-related potassium channel-1 (TREK1, encoded by KCNK2) in human and mouse endothelial cells and the BBB. TREK1 was downregulated in endothelial cells by treatment with interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). Blocking TREK1 increased leukocyte transmigration, whereas TREK1 activation had the opposite effect. We identified altered mitogen-activated protein (MAP) kinase signaling, actin remodeling and upregulation of cellular adhesion molecules as potential mechanisms of increased migration in TREK1-deficient (Kcnk2(-/-)) cells. In Kcnk2(-/-) mice, brain endothelial cells showed an upregulation of the cellular adhesion molecules ICAM1, VCAM1 and PECAM1 and facilitated leukocyte trafficking into the CNS. Following the induction of experimental autoimmune encephalomyelitis (EAE) by immunization with a myelin oligodendrocyte protein (MOG)35-55 peptide, Kcnk2(-/-) mice showed higher EAE severity scores that were accompanied by increased cellular infiltrates in the central nervous system (CNS). The severity of EAE was attenuated in mice given the amyotrophic lateral sclerosis drug riluzole or fed a diet enriched with linseed oil (which contains the TREK-1 activating omega-3 fatty acid α-linolenic acid). These beneficial effects were reduced in Kcnk2(-/-) mice, suggesting TREK-1", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blocking", + "TREK1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "TREK1", + "activation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "increased" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TREK1-deficient", + "(Kcnk2(-/-))" + ] + } + } + ] + }, + { + "PMID": "23749231", + "TEXT": "Hyperlipidemia is a risk factor for various cardiovascular and metabolic disorders. Overproduction of lipoproteins, a process that is dependent on microsomal triglyceride transfer protein (MTP), can contribute to hyperlipidemia. We show that microRNA-30c (miR-30c) interacts with the 3' untranslated region of MTP mRNA and induces its degradation, leading to reductions in MTP activity and in apolipoprotein B (APOB) secretion. miR-30c also reduces lipid synthesis independently of MTP. Hepatic overexpression of miR-30c reduced hyperlipidemia in Western diet-fed mice by decreasing lipid synthesis and the secretion of triglyceride-rich ApoB-containing lipoproteins and decreased atherosclerosis in Apoe(-/-) mice. Furthermore, inhibition of hepatic miR-30c by anti-miR-30c increased hyperlipidemia and atherosclerosis. Therefore, miR-30c coordinately reduces lipid biosynthesis and lipoprotein secretion, thereby regulating hepatic and plasma lipid concentrations. Raising miR-30c levels might be useful in treating hyperlipidemias and associated disorders.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Hepatic", + "overexpression", + "of", + "miR-30c" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apoe(-/-)" + ] + } + } + ] + }, + { + "PMID": "23142821", + "TEXT": "Live, attenuated RNA virus vaccines are efficacious but subject to reversion to virulence. Among RNA viruses, replication fidelity is recognized as a key determinant of virulence and escape from antiviral therapy; increased fidelity is attenuating for some viruses. Coronavirus (CoV) replication fidelity is approximately 20-fold greater than that of other RNA viruses and is mediated by a 3'→5' exonuclease (ExoN) activity that probably functions in RNA proofreading. In this study we demonstrate that engineered inactivation of severe acute respiratory syndrome (SARS)-CoV ExoN activity results in a stable mutator phenotype with profoundly decreased fidelity in vivo and attenuation of pathogenesis in young, aged and immunocompromised mice. The ExoN inactivation genotype and mutator phenotype are stable and do not revert to virulence, even after serial passage or long-term persistent infection in vivo. ExoN inactivation has potential for broad applications in the stable attenuation of CoVs and, perhaps, other RNA viruses.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "engineered", + "inactivation", + "of", + "severe", + "acute", + "respiratory", + "syndrome", + "(SARS)-CoV", + "ExoN", + "activity" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuation" + ] + } + } + ] + }, + { + "PMID": "23001183", + "TEXT": "There is a pressing need to identify prognostic markers of metastatic disease and targets for treatment. Combining high-throughput RNA sequencing, functional characterization, mechanistic studies and clinical validation, we identify leukemia inhibitory factor receptor (LIFR) as a breast cancer metastasis suppressor downstream of the microRNA miR-9 and upstream of Hippo signaling. Restoring LIFR expression in highly malignant tumor cells suppresses metastasis by triggering a Hippo kinase cascade that leads to phosphorylation, cytoplasmic retention and functional inactivation of the transcriptional coactivator YES-associated protein (YAP). Conversely, loss of LIFR in nonmetastatic breast cancer cells induces migration, invasion and metastatic colonization through activation of YAP. LIFR is downregulated in human breast carcinomas and inversely correlates with metastasis. Notably, in approximately 1,000 nonmetastatic breast tumors, LIFR expression status correlated with metastasis-free, recurrence-free and overall survival outcomes in the patients. These findings identify LIFR as a metastasis suppressor that functions through the Hippo-YAP pathway and has significant prognostic power.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "LIFR" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + } + ] + }, + { + "PMID": "22983395", + "TEXT": "The class II α-isoform of phosphatidylinositol 3-kinase (PI3K-C2α) is localized in endosomes, the trans-Golgi network and clathrin-coated vesicles; however, its functional role is not well understood. Global or endothelial-cell-specific deficiency of PI3K-C2α resulted in embryonic lethality caused by defects in sprouting angiogenesis and vascular maturation. PI3K-C2α knockdown in endothelial cells resulted in a decrease in the number of PI3-phosphate-enriched endosomes, impaired endosomal trafficking, defective delivery of VE-cadherin to endothelial cell junctions and defective junction assembly. PI3K-C2α knockdown also impaired endothelial cell signaling, including vascular endothelial growth factor receptor internalization and endosomal RhoA activation. Together, the effects of PI3K-C2α knockdown led to defective endothelial cell migration, proliferation, tube formation and barrier integrity. Endothelial PI3K-C2α deficiency in vivo suppressed postischemic and tumor angiogenesis and diminished vascular barrier function with a greatly augmented susceptibility to anaphylaxis and a higher incidence of dissecting aortic aneurysm formation in response to angiotensin II infusion. Thus, PI3K-C2α has a crucial role in vascular formation and barrier integrity and represents a new therapeutic target for vascular disease.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PI3K-C2α", + "knockdown" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + } + ] + }, + { + "PMID": "22057347", + "TEXT": "Ubiquitin-tagged substrates are degraded by the 26S proteasome, which is a multisubunit complex comprising a proteolytic 20S core particle capped by 19S regulatory particles. The approval of bortezomib for the treatment of multiple myeloma validated the 20S core particle as an anticancer drug target. Here we describe the small molecule b-AP15 as a previously unidentified class of proteasome inhibitor that abrogates the deubiquitinating activity of the 19S regulatory particle. b-AP15 inhibited the activity of two 19S regulatory-particle-associated deubiquitinases, ubiquitin C-terminal hydrolase 5 (UCHL5) and ubiquitin-specific peptidase 14 (USP14), resulting in accumulation of polyubiquitin. b-AP15 induced tumor cell apoptosis that was insensitive to TP53 status and overexpression of the apoptosis inhibitor BCL2. We show that treatment with b-AP15 inhibited tumor progression in four different in vivo solid tumor models and inhibited organ infiltration in an acute myeloid leukemia model. Our results show that the deubiquitinating activity of the 19S regulatory particle is a new anticancer drug target.", + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "the", + "apoptosis", + "inhibitor", + "BCL2." + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "of", + "the", + "inhibitor", + "BCL2." + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + } + ] + }, + { + "PMID": "22001908", + "TEXT": "Infertility and recurrent pregnancy loss (RPL) are prevalent but distinct causes of reproductive failure that often remain unexplained despite extensive investigations. Analysis of midsecretory endometrial samples revealed that SGK1, a kinase involved in epithelial ion transport and cell survival, is upregulated in unexplained infertility, most prominently in the luminal epithelium, but downregulated in the endometrium of women suffering from RPL. To determine the functional importance of these observations, we first expressed a constitutively active SGK1 mutant in the luminal epithelium of the mouse uterus. This prevented expression of certain endometrial receptivity genes, perturbed uterine fluid handling and abolished embryo implantation. By contrast, implantation was unhindered in Sgk1-/- mice, but pregnancy was often complicated by bleeding at the decidual-placental interface and fetal growth retardation and subsequent demise. Compared to wild-type mice, Sgk1-/- mice had gross impairment of pregnancy-dependent induction of genes involved in oxidative stress defenses. Relative SGK1 deficiency was also a hallmark of decidualizing stromal cells from human subjects with RPL and sensitized these cells to oxidative cell death. Thus, depending on the cellular compartment, deregulated SGK1 activity in cycling endometrium interferes with embryo implantation, leading to infertility, or predisposes to pregnancy complications by rendering the feto-maternal interface vulnerable to oxidative damage.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "constitutively", + "active", + "SGK1", + "mutant", + "in", + "the", + "luminal", + "epithelium", + "of" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abolished" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Sgk1-/-", + "SGK1", + "deficiency" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + } + } + ] + }, + { + "PMID": "21804542", + "TEXT": "PICT1 (also known as GLTSCR2) is considered a tumor suppressor because it stabilizes phosphatase and tensin homolog (PTEN), but individuals with oligodendrogliomas lacking chromosome 19q13, where PICT1 is located, have better prognoses than other oligodendroglioma patients. To clarify the function of PICT1, we generated Pict1-deficient mice and embryonic stem (ES) cells. Pict1 is a nucleolar protein essential for embryogenesis and ES cell survival. Even without DNA damage, Pict1 loss led to p53-dependent arrest of cell cycle phase G(1) and apoptosis. Pict1-deficient cells accumulated p53, owing to impaired Mdm2 function. Pict1 binds Rpl11, and Rpl11 is released from nucleoli in the absence of Pict1. In Pict1-deficient cells, increased binding of Rpl11 to Mdm2 blocks Mdm2-mediated ubiquitination of p53. In human cancer, individuals whose tumors express less PICT1 have better prognoses. When PICT1 is depleted in tumor cells with intact P53 signaling, the cells grow more slowly and accumulate P53. Thus, PICT1 is a potent regulator of the MDM2-P53 pathway and promotes tumor progression by retaining RPL11 in the nucleolus.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Pict1-deficient", + "Pict1", + "loss" + ] + }, + "effect": { + "val": "positive", + "words": [ + "led", + "to" + ] + } + } + ] + }, + { + "PMID": "21785432", + "TEXT": "Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. Mutations in the 27-kDa small heat-shock protein gene (HSPB1) cause axonal CMT or distal hereditary motor neuropathy (distal HMN). We developed and characterized transgenic mice expressing two different HSPB1 mutations (S135F and P182L) in neurons only. These mice showed all features of CMT or distal HMN dependent on the mutation. Expression of mutant HSPB1 decreased acetylated α-tubulin abundance and induced severe axonal transport deficits. An increase of α-tubulin acetylation induced by pharmacological inhibition of histone deacetylase 6 (HDAC6) corrected the axonal transport defects caused by HSPB1 mutations and rescued the CMT phenotype of symptomatic mutant HSPB1 mice. Our findings demonstrate the pathogenic role of α-tubulin deacetylation in mutant HSPB1-induced neuropathies and offer perspectives for using HDAC6 inhibitors as a therapeutic strategy for hereditary axonopathies.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "histone", + "deacetylase", + "6", + "(HDAC6)" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + } + ] + }, + { + "PMID": "21423182", + "TEXT": "In multiple sclerosis, activated CD4(+) T cells initiate an immune response in the brain and spinal cord, resulting in demyelination, degeneration and progressive paralysis. Repulsive guidance molecule-a (RGMa) is an axon guidance molecule that has a role in the visual system and in neural tube closure. Our study shows that RGMa is expressed in bone marrow-derived dendritic cells (BMDCs) and that CD4(+) T cells express neogenin, a receptor for RGMa. Binding of RGMa to CD4(+) T cells led to activation of the small GTPase Rap1 and increased adhesion of T cells to intracellular adhesion molecule-1 (ICAM-1). Neutralizing antibodies to RGMa attenuated clinical symptoms of mouse myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) and reduced invasion of inflammatory cells into the CNS. Silencing of RGMa in MOG-pulsed BMDCs reduced their capacity to induce EAE following adoptive transfer to naive C57BL/6 mice. CD4(+) T cells isolated from mice treated with an RGMa-specific antibody showed diminished proliferative responses and reduced interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-4 and IL-17 secretion. Incubation of PBMCs from patients with multiple sclerosis with an RGMa-specific antibody reduced proliferative responses and pro-inflammatory cytokine expression. These results demonstrate that an RGMa-specific antibody suppresses T cell responses, and suggest that RGMa could be a promising molecular target for the treatment of multiple sclerosis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "RGMa" + ] + }, + "effect": { + "val": "negative", + "words": [ + "diminished" + ] + } + } + ] + }, + { + "PMID": "21057494", + "TEXT": "The transition from androgen-dependent to castration-resistant prostate cancer (CRPC) is a lethal event of uncertain molecular etiology. Comparing gene expression in isogenic androgen-dependent and CRPC xenografts, we found a reproducible increase in N-cadherin expression, which was also elevated in primary and metastatic tumors of individuals with CRPC. Ectopic expression of N-cadherin in nonmetastatic, androgen-dependent prostate cancer models caused castration resistance, invasion and metastasis. Monoclonal antibodies against the ectodomain of N-cadherin reduced proliferation, adhesion and invasion of prostate cancer cells in vitro. In vivo, these antibodies slowed the growth of multiple established CRPC xenografts, blocked local invasion and metastasis and, at higher doses, led to complete regression. N-cadherin-specific antibodies markedly delayed the time to emergence of castration resistance, markedly affected tumor histology and angiogenesis, and reduced both AKT serine-threonine kinase activity and serum interleukin-8 (IL-8) secretion. These data indicate that N-cadherin is a major cause of both prostate cancer metastasis and castration resistance. Therapeutic targeting of this factor with monoclonal antibodies may have considerable clinical benefit.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "N-cadherin" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "N-cadherin" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Monoclonal", + "antibodies", + "against", + "the", + "ectodomain", + "of", + "N-cadherin" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced", + "blocked" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "against", + "ectodomain" + ] + }, + "effect": { + "val": "positive", + "words": [ + "led" + ] + } + } + ] + }, + { + "PMID": "20890291", + "TEXT": "CD8(+) T cells in chronic viral infections such as HIV develop functional defects including loss of interleukin-2 (IL-2) secretion and decreased proliferative potential that are collectively termed 'exhaustion'. Exhausted T cells express increased amounts of multiple inhibitory receptors, such as programmed death-1 (PD-1), that contribute to impaired virus-specific T cell function. Although reversing PD-1 inhibition is therefore an attractive therapeutic strategy, the cellular mechanisms by which PD-1 ligation results in T cell inhibition are not fully understood. PD-1 is thought to limit T cell activation by attenuating T cell receptor (TCR) signaling. It is not known whether PD-1 also acts by upregulating genes in exhausted T cells that impair their function. Here we analyzed gene expression profiles from HIV-specific CD8(+) T cells in individuals with HIV and show that PD-1 coordinately upregulates a program of genes in exhausted CD8(+) T cells from humans and mice. This program includes upregulation of basic leucine transcription factor, ATF-like (BATF), a transcription factor in the AP-1 family. Enforced expression of BATF was sufficient to impair T cell proliferation and cytokine secretion, whereas BATF knockdown reduced PD-1 inhibition. Silencing BATF in T cells from individuals with chronic viremia rescued HIV-specific T cell function. Thus, inhibitory receptors can cause T cell exhaustion by upregulating genes--such as BATF--that inhibit T cell function. Such genes may provide new therapeutic opportunities to improve T cell immunity to HIV.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced", + "expression", + "of", + "BATF" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impair" + ] + } + } + ] + }, + { + "PMID": "20676106", + "TEXT": "Although it is well established that tumors initiate an angiogenic switch, the molecular basis of this process remains incompletely understood. Here we show that the miRNA miR-132 acts as an angiogenic switch by targeting p120RasGAP in the endothelium and thereby inducing neovascularization. We identified miR-132 as a highly upregulated miRNA in a human embryonic stem cell model of vasculogenesis and found that miR-132 was highly expressed in the endothelium of human tumors and hemangiomas but was undetectable in normal endothelium. Ectopic expression of miR-132 in endothelial cells in vitro increased their proliferation and tube-forming capacity, whereas intraocular injection of an antagomir targeting miR-132, anti-miR-132, reduced postnatal retinal vascular development in mice. Among the top-ranking predicted targets of miR-132 was p120RasGAP, which we found to be expressed in normal but not tumor endothelium. Endothelial expression of miR-132 suppressed p120RasGAP expression and increased Ras activity, whereas a miRNA-resistant version of p120RasGAP reversed the vascular response induced by miR-132. Notably, administration of anti-miR-132 inhibited angiogenesis in wild-type mice but not in mice with an inducible deletion of Rasa1 (encoding p120RasGAP). Finally, vessel-targeted nanoparticle delivery of anti-miR-132 restored p120RasGAP expression in the tumor endothelium, suppressed angiogenesis and decreased tumor burden in an orthotopic xenograft mouse model of human breast carcinoma. We conclude that miR-132 acts as an angiogenic switch by suppressing endothelial p120RasGAP expression, leading to Ras activation and the induction of neovascularization, whereas the application of anti-miR-132 inhibits neovascularization by maintaining vessels in the resting state.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "miR-132" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inducible", + "deletion", + "of", + "Rasa1", + "(encoding", + "p120RasGAP)." + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + } + ] + }, + { + "PMID": "19966812", + "TEXT": "Nucleotide-binding oligomerization domain-containing-2 (NOD2) acts as a bacterial sensor in dendritic cells (DCs), but it is not clear how bacterial recognition links with antigen presentation after NOD2 stimulation. NOD2 variants are associated with Crohn's disease, where breakdown in self-recognition of commensal bacteria leads to gastrointestinal inflammation. Here we show NOD2 triggering by muramyldipeptide induces autophagy in DCs. This effect requires receptor-interacting serine-threonine kinase-2 (RIPK-2), autophagy-related protein-5 (ATG5), ATG7 and ATG16L1 but not NLR family, pyrin domain containing-3 (NALP3).We show that NOD2-mediated autophagy is required for both bacterial handling and generation of major histocompatibility complex (MHC) class II antigen-specific CD4(+) T cell responses in DCs. DCs from individuals with Crohn's disease expressing Crohn's disease-associated NOD2 or ATG16L1 risk variants are defective in autophagy induction, bacterial trafficking and antigen presentation. Our findings link two Crohn's disease-associated susceptibility genes in a single functional pathway and reveal defects in this pathway in Crohn's disease DCs that could lead to bacterial persistence via impaired lysosomal destruction and immune mediated clearance.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "triggering" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + } + ] + }, + { + "PMID": "19701203", + "TEXT": "Recent work has shown that primary cilia are essential for Hedgehog (Hh) signaling during mammalian development. It is also known that aberrant Hh signaling can lead to cancer, but the role of primary cilia in oncogenesis is not known. Cerebellar granule neuron precursors (GNPs) can give rise to medulloblastomas, the most common malignant brain tumor in children. The primary cilium and Hh signaling are required for GNP proliferation. We asked whether primary cilia in GNPs have a role in medulloblastoma growth in mice. Genetic ablation of primary cilia blocked medulloblastoma formation when this tumor was driven by a constitutively active Smoothened protein (Smo), an upstream activator of Hh signaling. In contrast, removal of cilia was required for medulloblastoma growth by a constitutively active glioma-associated oncogene family zinc finger-2 (GLI2), a downstream transcription factor. Thus, primary cilia are either required for or inhibit medulloblastoma formation, depending on the initiating oncogenic event. Remarkably, the presence or absence of cilia was associated with specific variants of human medulloblastomas; primary cilia were found in medulloblastomas with activation in HH or WNT signaling but not in most medulloblastomas in other distinct molecular subgroups. Primary cilia could serve as a diagnostic tool and provide new insights into the mechanism of tumorigenesis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "ablation", + "of", + "primary", + "cilia" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + } + ] + }, + { + "PMID": "19252503", + "TEXT": "The variable efficacy of Bacille Calmette Guerin (BCG) vaccination against tuberculosis has prompted efforts to improve the vaccine. In this study, we used autophagy to enhance vaccine efficacy against tuberculosis in a mouse model. We examined the effect of autophagy on the processing of the immunodominant mycobacterial antigen Ag85B by antigen presenting cells (APCs), macrophages and dendritic cells (DCs). We found that rapamycin-induced autophagy enhanced Ag85B presentation by APCs infected with wild-type Mycobacterium tuberculosis H37Rv, H37Rv-derived DeltafbpA attenuated candidate vaccine or BCG. Furthermore, rapamycin enhanced localization of mycobacteria with autophagosomes and lysosomes. Rapamycin-enhanced antigen presentation was attenuated when autophagy was suppressed by 3-methyladenine or by small interfering RNA against beclin-1. Notably, mice immunized with rapamycin-treated DCs infected with either DeltafbpA or BCG showed enhanced T helper type 1-mediated protection when challenged with virulent Mycobacterium tuberculosis. Finally, overexpression of Ag85B in BCG induced autophagy in APCs and enhanced immunogenicity in mice, suggesting that vaccine efficacy can be enhanced by augmenting autophagy-mediated antigen presentation.", + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "small", + "interfering", + "RNA", + "against", + "beclin-1." + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "small", + "interfering", + "RNA", + "against" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Ag85B", + "in", + "BCG" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "19234463", + "TEXT": "Integrins are the major adhesion receptors of leukocytes and platelets. Beta1 and beta2 integrin function on leukocytes is crucial for a successful immune response and the platelet integrin alpha(IIb)beta3 initiates the process of blood clotting through binding fibrinogen. Integrins on circulating cells bind poorly to their ligands but become active after 'inside-out' signaling through other membrane receptors. Subjects with leukocyte adhesion deficiency-1 (LAD-I) do not express beta2 integrins because of mutations in the gene specifying the beta2 subunit, and they suffer recurrent bacterial infections. Mutations affecting alpha(IIb)beta3 integrin cause the bleeding disorder termed Glanzmann's thrombasthenia. Subjects with LAD-III show symptoms of both LAD-I and Glanzmann's thrombasthenia. Their hematopoietically-derived cells express beta1, beta2 and beta3 integrins, but defective inside-out signaling causes immune deficiency and bleeding problems. The LAD-III lesion has been attributed to a C --> A mutation in the gene encoding calcium and diacylglycerol guanine nucleotide exchange factor (CALDAGGEF1; official symbol RASGRP2) specifying the CALDAG-GEF1 protein, but we show that this change is not responsible for the LAD-III disorder. Instead, we identify mutations in the KINDLIN3 (official symbol FERMT3) gene specifying the KINDLIN-3 protein as the cause of LAD-III in Maltese and Turkish subjects. Two independent mutations result in decreased KINDLIN3 messenger RNA levels and loss of protein expression. Notably, transfection of the subjects' lymphocytes with KINDLIN3 complementary DNA but not CALDAGGEF1 cDNA reverses the LAD-III defect, restoring integrin-mediated adhesion and migration.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfection", + "with", + "KINDLIN3", + "complementary", + "DNA" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "restoring" + ] + } + } + ] + }, + { + "PMID": "19234461", + "TEXT": "Integrin activation is essential for the function of all blood cells, including platelets and leukocytes. The blood cell-specific FERM domain protein Kindlin-3 is required for the activation of the beta1 and beta3 integrins on platelets. Impaired activation of beta1, beta2 and beta3 integrins on platelets and leukocytes is the hallmark of a rare autosomal recessive leukocyte adhesion deficiency syndrome in humans called LAD-III, characterized by severe bleeding and impaired adhesion of leukocytes to inflamed endothelia. Here we show that Kindlin-3 also binds the beta2 integrin cytoplasmic domain and is essential for neutrophil binding and spreading on beta2 integrin-dependent ligands such as intercellular adhesion molecule-1 and the complement C3 activation product iC3b. Moreover, loss of Kindlin-3 expression abolished firm adhesion and arrest of neutrophils on activated endothelial cells in vitro and in vivo, whereas selectin-mediated rolling was unaffected. Thus, Kindlin-3 is essential to activate the beta1, beta2 and beta3 integrin classes, and loss of Kindlin-3 function is sufficient to cause a LAD-III-like phenotype in mice.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "Kindlin-3", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abolished" + ] + } + } + ] + }, + { + "PMID": "19098909", + "TEXT": "Disorders of neuronal migration can lead to malformations of the cerebral neocortex that greatly increase the risk of seizures. It remains untested whether malformations caused by disorders in neuronal migration can be reduced by reactivating cellular migration and whether such repair can decrease seizure risk. Here we show, in a rat model of subcortical band heterotopia (SBH) generated by in utero RNA interference of the Dcx gene, that aberrantly positioned neurons can be stimulated to migrate by reexpressing Dcx after birth. Restarting migration in this way both reduces neocortical malformations and restores neuronal patterning. We further find that the capacity to reduce SBH continues into early postnatal development. Moreover, intervention after birth reduces the convulsant-induced seizure threshold to a level similar to that in malformation-free controls. These results suggest that disorders of neuronal migration may be eventually treatable by reengaging developmental programs both to reduce the size of cortical malformations and to reduce seizure risk.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "RNA", + "interference", + "of", + "the", + "Dcx", + "gene," + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "stimulated" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "reexpressing", + "Dcx" + ] + } + } + ] + }, + { + "PMID": "19029985", + "TEXT": "The mechanisms involved in the pathogenesis of epilepsy, a chronic neurological disorder that affects approximately one percent of the world population, are not well understood. Using a mouse model of epilepsy, we show that seizures induce elevated expression of vascular cell adhesion molecules and enhanced leukocyte rolling and arrest in brain vessels mediated by the leukocyte mucin P-selectin glycoprotein ligand-1 (PSGL-1, encoded by Selplg) and leukocyte integrins alpha(4)beta(1) and alpha(L)beta(2). Inhibition of leukocyte-vascular interactions, either with blocking antibodies or by genetically interfering with PSGL-1 function in mice, markedly reduced seizures. Treatment with blocking antibodies after acute seizures prevented the development of epilepsy. Neutrophil depletion also inhibited acute seizure induction and chronic spontaneous recurrent seizures. Blood-brain barrier (BBB) leakage, which is known to enhance neuronal excitability, was induced by acute seizure activity but was prevented by blockade of leukocyte-vascular adhesion, suggesting a pathogenetic link between leukocyte-vascular interactions, BBB damage and seizure generation. Consistent with the potential leukocyte involvement in epilepsy in humans, leukocytes were more abundant in brains of individuals with epilepsy than in controls. Our results suggest leukocyte-endothelial interaction as a potential target for the prevention and treatment of epilepsy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "genetically", + "interfering" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + } + ] + }, + { + "PMID": "19029980", + "TEXT": "Retinoic acid and arsenic trioxide target the protein stability and transcriptional repression activity of the fusion oncoprotein PML-RARA, resulting in regression of acute promyelocytic leukemia (APL). Phenotypically, retinoic acid induces differentiation of APL cells. Here we show that retinoic acid also triggers growth arrest of leukemia-initiating cells (LICs) ex vivo and their clearance in PML-RARA mouse APL in vivo. Retinoic acid treatment of mouse APLs expressing the fusion protein PLZF-RARA triggers full differentiation, but not LIC loss or disease remission, establishing that differentiation and LIC loss can be uncoupled. Although retinoic acid and arsenic synergize to clear LICs through cooperative PML-RARA degradation, this combination does not enhance differentiation. A cyclic AMP (cAMP)-dependent phosphorylation site in PML-RARA is crucial for retinoic acid-induced PML-RARA degradation and LIC clearance. Moreover, activation of cAMP signaling enhances LIC loss by retinoic acid, identifying cAMP as another potential APL therapy. Thus, whereas transcriptional activation of PML-RARA is likely to control differentiation, its catabolism triggers LIC eradication and long-term remission of mouse APL. Therapy-triggered degradation of oncoproteins could be a general strategy to eradicate cancer stem cells.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "the", + "fusion", + "protein", + "PLZF-RARA" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + } + } + ] + }, + { + "PMID": "18931683", + "TEXT": "MicroRNAs (miRNAs) are noncoding small RNAs that repress protein translation by targeting specific messenger RNAs. miR-15a and miR-16-1 act as putative tumor suppressors by targeting the oncogene BCL2. These miRNAs form a cluster at the chromosomal region 13q14, which is frequently deleted in cancer. Here, we report that the miR-15a and miR-16-1 cluster targets CCND1 (encoding cyclin D1) and WNT3A, which promotes several tumorigenic features such as survival, proliferation and invasion. In cancer cells of advanced prostate tumors, the miR-15a and miR-16 level is significantly decreased, whereas the expression of BCL2, CCND1 and WNT3A is inversely upregulated. Delivery of antagomirs specific for miR-15a and miR-16 to normal mouse prostate results in marked hyperplasia, and knockdown of miR-15a and miR-16 promotes survival, proliferation and invasiveness of untransformed prostate cells, which become tumorigenic in immunodeficient NOD-SCID mice. Conversely, reconstitution of miR-15a and miR-16-1 expression results in growth arrest, apoptosis and marked regression of prostate tumor xenografts. Altogether, we propose that miR-15a and miR-16 act as tumor suppressor genes in prostate cancer through the control of cell survival, proliferation and invasion. These findings have therapeutic implications and may be exploited for future treatment of prostate cancer.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "antagomirs", + "specific", + "for", + "miR-15a", + "and", + "miR-16", + "knockdown", + "of" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "miR-15a", + "and", + "miR-16" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest," + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "reconstitution", + "of", + "miR-15a", + "and", + "miR-16-1", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest," + ] + } + } + ] + }, + { + "PMID": "18806802", + "TEXT": "Cyclophilin D (CypD, encoded by Ppif) is an integral part of the mitochondrial permeability transition pore, whose opening leads to cell death. Here we show that interaction of CypD with mitochondrial amyloid-beta protein (Abeta) potentiates mitochondrial, neuronal and synaptic stress. The CypD-deficient cortical mitochondria are resistant to Abeta- and Ca(2+)-induced mitochondrial swelling and permeability transition. Additionally, they have an increased calcium buffering capacity and generate fewer mitochondrial reactive oxygen species. Furthermore, the absence of CypD protects neurons from Abeta- and oxidative stress-induced cell death. Notably, CypD deficiency substantially improves learning and memory and synaptic function in an Alzheimer's disease mouse model and alleviates Abeta-mediated reduction of long-term potentiation. Thus, the CypD-mediated mitochondrial permeability transition pore is directly linked to the cellular and synaptic perturbations observed in the pathogenesis of Alzheimer's disease. Blockade of CypD may be a therapeutic strategy in Alzheimer's disease.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CypD-deficient", + "absence", + "of", + "CypD" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protects" + ] + } + } + ] + }, + { + "PMID": "18311147", + "TEXT": "Albuminuria associated with sclerosis of the glomerulus leads to a progressive decline in renal function affecting millions of people. Here we report that activation of the Notch pathway, which is critical in glomerular patterning, contributes to the development of glomerular disease. Expression of the intracellular domain of Notch1 (ICN1) was increased in glomerular epithelial cells in diabetic nephropathy and in focal segmental glomerulosclerosis. Conditional re-expression of ICN1 in vivo exclusively in podocytes caused proteinuria and glomerulosclerosis. In vitro and in vivo studies showed that ICN1 induced apoptosis of podocytes through the activation of p53. Genetic deletion of a Notch transcriptional partner (Rbpj) specifically in podocytes or pharmacological inhibition of the Notch pathway (with a gamma-secretase inhibitor) protected rats with proteinuric kidney diseases. Collectively, our observations suggest that Notch activation in mature podocytes is a new mechanism in the pathogenesis of glomerular disease and thus could represent a new therapeutic target.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Conditional", + "re-expression", + "of", + "ICN1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "18246078", + "TEXT": "Treacher Collins syndrome (TCS) is a congenital disorder of craniofacial development arising from mutations in TCOF1, which encodes the nucleolar phosphoprotein Treacle. Haploinsufficiency of Tcof1 perturbs mature ribosome biogenesis, resulting in stabilization of p53 and the cyclin G1-mediated cell-cycle arrest that underpins the specificity of neuroepithelial apoptosis and neural crest cell hypoplasia characteristic of TCS. Here we show that inhibition of p53 prevents cyclin G1-driven apoptotic elimination of neural crest cells while rescuing the craniofacial abnormalities associated with mutations in Tcof1 and extending life span. These improvements, however, occur independently of the effects on ribosome biogenesis; thus suggesting that it is p53-dependent neuroepithelial apoptosis that is the primary mechanism underlying the pathogenesis of TCS. Our work further implies that neuroepithelial and neural crest cells are particularly sensitive to cellular stress during embryogenesis and that suppression of p53 function provides an attractive avenue for possible clinical prevention of TCS craniofacial birth defects and possibly those of other neurocristopathies.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "p53" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + } + ] + }, + { + "PMID": "18059282", + "TEXT": "Osteoclasts are bone-resorbing cells derived from hematopoietic precursors of the monocyte-macrophage lineage. Regulation of osteoclast function is central to the understanding of bone diseases such as osteoporosis, rheumatoid arthritis and osteopetrosis. Although peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been shown to inhibit osteoblast differentiation, its role, if any, in osteoclasts is unknown. This is a clinically crucial question because PPAR-gamma agonists, \"such as thiazolidinediones-\" a class of insulin-sensitizing drugs, have been reported to cause a higher rate of fractures in human patients. Here we have uncovered a pro-osteoclastogenic effect of PPAR-gamma by using a Tie2Cre/flox mouse model in which PPAR-gamma is deleted in osteoclasts but not in osteoblasts. These mice develop osteopetrosis characterized by increased bone mass, reduced medullary cavity space and extramedullary hematopoiesis in the spleen. These defects are the result of impaired osteoclast differentiation and compromised receptor activator of nuclear factor-kappaB ligand signaling and can be rescued by bone marrow transplantation. Moreover, ligand activation of PPAR-gamma by rosiglitazone exacerbates osteoclast differentiation in a receptor-dependent manner. Our examination of the underlying mechanisms suggested that PPAR-gamma functions as a direct regulator of c-fos expression, an essential mediator of osteoclastogenesis. Therefore, PPAR-gamma and its ligands have a previously unrecognized role in promoting osteoclast differentiation and bone resorption.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PPAR-gamma", + "is", + "deleted" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + } + ] + }, + { + "PMID": "17952090", + "TEXT": "Hepatic injury is associated with a defective intestinal barrier and increased hepatic exposure to bacterial products. Here we report that the intestinal bacterial microflora and a functional Toll-like receptor 4 (TLR4), but not TLR2, are required for hepatic fibrogenesis. Using Tlr4-chimeric mice and in vivo lipopolysaccharide (LPS) challenge, we demonstrate that quiescent hepatic stellate cells (HSCs), the main precursors for myofibroblasts in the liver, are the predominant target through which TLR4 ligands promote fibrogenesis. In quiescent HSCs, TLR4 activation not only upregulates chemokine secretion and induces chemotaxis of Kupffer cells, but also downregulates the transforming growth factor (TGF)-beta pseudoreceptor Bambi to sensitize HSCs to TGF-beta-induced signals and allow for unrestricted activation by Kupffer cells. LPS-induced Bambi downregulation and sensitization to TGF-beta is mediated by a MyD88-NF-kappaB-dependent pathway. Accordingly, Myd88-deficient mice have decreased hepatic fibrosis. Thus, modulation of TGF-beta signaling by a TLR4-MyD88-NF-kappaB axis provides a novel link between proinflammatory and profibrogenic signals.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Tlr4-chimeric" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + } + ] + }, + { + "PMID": "17906636", + "TEXT": "An association between inflammation and cancer has long been recognized, but the cause and effect relationship linking the two remains unclear. Myc is a pleiotropic transcription factor that is overexpressed in many human cancers and instructs many extracellular aspects of the tumor tissue phenotype, including remodeling of tumor stroma and angiogenesis. Here we show in a beta-cell tumor model that activation of Myc in vivo triggers rapid recruitment of mast cells to the tumor site-a recruitment that is absolutely required for macroscopic tumor expansion. In addition, treatment of established beta-cell tumors with a mast cell inhibitor rapidly triggers hypoxia and cell death of tumor and endothelial cells. Inhibitors of mast cell function may therefore prove therapeutically useful in restraining expansion and survival of pancreatic and other cancers.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mast", + "inhibitor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + } + } + ] + }, + { + "PMID": "17694067", + "TEXT": "Transformation and cancer growth are regulated by the coordinate actions of oncogenes and tumor suppressors. Here, we show that the novel E3 ubiquitin ligase HACE1 is frequently downregulated in human tumors and maps to a region of chromosome 6q21 implicated in multiple human cancers. Genetic inactivation of HACE1 in mice results in the development of spontaneous, late-onset cancer. A second hit from either environmental triggers or genetic heterozygosity of another tumor suppressor, p53, markedly increased tumor incidence in a Hace1-deficient background. Re-expression of HACE1 in human tumor cells directly abrogates in vitro and in vivo tumor growth, whereas downregulation of HACE1 via siRNA allows non-tumorigenic human cells to form tumors in vivo. Mechanistically, the tumor-suppressor function of HACE1 is dependent on its E3 ligase activity and HACE1 controls adhesion-dependent growth and cell cycle progression during cell stress through degradation of cyclin D1. Thus, HACE1 is a candidate chromosome 6q21 tumor-suppressor gene involved in multiple cancers.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic", + "inactivation", + "of", + "HACE1", + "Hace1-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "Hace1-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetic", + "heterozygosity", + "of", + "another", + "tumor", + "suppressor,", + "p53," + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "genetic", + "heterozygosity", + "of", + "another", + "tumor", + "suppressor,", + "p53," + ] + }, + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Re-expression", + "of", + "HACE1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "downregulation", + "of", + "HACE1", + "via", + "siRNA" + ] + }, + "effect": { + "val": "positive", + "words": [ + "allows" + ] + } + } + ] + }, + { + "PMID": "17515894", + "TEXT": "Loss of cone function in the central retina is a pivotal event in the development of severe vision impairment for many prevalent blinding diseases. Complete achromatopsia is a genetic defect resulting in cone vision loss in 1 in 30,000 individuals. Using adeno-associated virus (AAV) gene therapy, we show that it is possible to target cones and rescue both the cone-mediated electroretinogram response and visual acuity in the Gnat2 ( cpfl3 ) mouse model of achromatopsia.", + "LINKED_TAGS": [ + { + "effect": { + "val": "rescues", + "words": [ + "rescue" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Gnat2", + "(", + "cpfl3", + ")" + ] + } + } + ] + }, + { + "PMID": "17496901", + "TEXT": "We analyzed the PI3K-AKT signaling cascade in a cohort of sarcomas and found a marked induction of insulin receptor substrate-2 (IRS2) and phosphorylated AKT and a concomitant upregulation of downstream effectors in most leiomyosarcomas. To determine the role of aberrant PI3K-AKT signaling in leiomyosarcoma pathogenesis, we genetically inactivated Pten in the smooth muscle cell lineage by cross-breeding Pten(loxP/loxP) mice with Tagln-cre mice. Mice carrying homozygous deletion of Pten alleles developed widespread smooth muscle cell hyperplasia and abdominal leiomyosarcomas, with a very rapid onset and elevated incidence (approximately 80%) compared to other animal models. Constitutive mTOR activation was restricted to the leiomyosarcomas, revealing the requirement for additional molecular events besides Pten loss. The rapamycin derivative everolimus substantially decelerated tumor growth on Tagln-cre/Pten(loxP/loxP) mice and prolonged their lifespan. Our data show a new and critical role for the AKT-mTOR pathway in smooth muscle transformation and leiomyosarcoma genesis, and support treatment of selected sarcomas by the targeting of this pathway with new compounds or combinations of these with conventional chemotherapy agents.", + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "decelerated" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "Tagln-cre/Pten(loxP/loxP)" + ] + } + } + ] + }, + { + "PMID": "16892037", + "TEXT": "The t(8;21)(q22;q22) translocation is one of the most common genetic abnormalities in acute myeloid leukemia (AML), identified in 15% of all cases of AML, including 40-50% of FAB M2 subtype and rare cases of M0, M1 and M4 subtypes. The most commonly known AML1-ETO fusion protein (full-length AML1-ETO) from this translocation has 752 amino acids and contains the N-terminal portion of RUNX1 (also known as AML1, CBFalpha2 or PEBP2alphaB), including its DNA binding domain, and almost the entire RUNX1T1 (also known as MTG8 or ETO) protein. Although alterations of gene expression and hematopoietic cell proliferation have been reported in the presence of AML1-ETO, its expression does not lead to the development of leukemia. Here, we report the identification of a previously unknown alternatively spliced isoform of the AML1-ETO transcript, AML1-ETO9a, that includes an extra exon, exon 9a, of the ETO gene. AML1-ETO9a encodes a C-terminally truncated AML1-ETO protein of 575 amino acids. Expression of AML1-ETO9a leads to rapid development of leukemia in a mouse retroviral transduction-transplantation model. More importantly, coexpression of AML1-ETO and AML1-ETO9a results in the substantially earlier onset of AML and blocks myeloid cell differentiation at a more immature stage. These results indicate that fusion proteins from alternatively spliced isoforms of a chromosomal translocation may work together to induce cancer development.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "AML1-ETO9a" + ] + }, + "effect": { + "val": "positive", + "words": [ + "leads", + "to" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "coexpression", + "of", + "AML1-ETO", + "and", + "AML1-ETO9a" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + } + } + ] + }, + { + "PMID": "16783372", + "TEXT": "In the injured central nervous system (CNS), reactive astrocytes form a glial scar and are considered to be detrimental for axonal regeneration, but their function remains elusive. Here we show that reactive astrocytes have a crucial role in wound healing and functional recovery by using mice with a selective deletion of the protein signal transducer and activator of transcription 3 (Stat3) or the protein suppressor of cytokine signaling 3 (Socs3) under the control of the Nes promoter-enhancer (Nes-Stat3(-/-), Nes-Socs3(-/-)). Reactive astrocytes in Nes-Stat3(-/-) mice showed limited migration and resulted in markedly widespread infiltration of inflammatory cells, neural disruption and demyelination with severe motor deficits after contusive spinal cord injury (SCI). On the contrary, we observed rapid migration of reactive astrocytes to seclude inflammatory cells, enhanced contraction of lesion area and notable improvement in functional recovery in Nes-Socs3(-/-) mice. These results suggest that Stat3 is a key regulator of reactive astrocytes in the healing process after SCI, providing a potential target for intervention in the treatment of CNS injury.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "deletion", + "of", + "the", + "protein", + "signal", + "and", + "activator", + "transcription", + "3", + "(Stat3)", + "or", + "suppressor", + "cytokine", + "signaling", + "(Socs3)", + "Nes", + "(Nes-Stat3(-/-),", + "Nes-Socs3(-/-)).", + "Nes-Stat3(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "limited" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "under", + "control", + "promoter-enhancer" + ] + }, + "effect": { + "val": "negative", + "words": [ + "limited" + ] + } + } + ] + }, + { + "PMID": "16286924", + "TEXT": "The IkappaB kinase complex IKK is a central component of the signaling cascade that controls NF-kappaB-dependent gene transcription. So far, its function in the brain is largely unknown. Here, we show that IKK is activated in a mouse model of stroke. To investigate the function of IKK in brain ischemia we generated mice that contain a targeted deletion of Ikbkb (which encodes IKK2) in mouse neurons and mice that express a dominant inhibitor of IKK in neurons. In both lines, inhibition of IKK activity markedly reduced infarct size. In contrast, constitutive activation of IKK2 enlarged the infarct size. A selective small-molecule inhibitor of IKK mimicked the effect of genetic IKK inhibition in neurons, reducing the infarct volume and cell death in a therapeutic time window of 4.5 h. These data indicate a key function of IKK in ischemic brain damage and suggest a potential role for IKK inhibitors in stroke therapy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "selective", + "small-molecule", + "inhibitor", + "of", + "IKK", + "genetic", + "inhibition" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reducing" + ] + } + } + ] + }, + { + "PMID": "16244651", + "TEXT": "Mechanisms that regulate inflammation and repair after acute lung injury are incompletely understood. The extracellular matrix glycosaminoglycan hyaluronan is produced after tissue injury and impaired clearance results in unremitting inflammation. Here we report that hyaluronan degradation products require MyD88 and both Toll-like receptor (TLR)4 and TLR2 in vitro and in vivo to initiate inflammatory responses in acute lung injury. Hyaluronan fragments isolated from serum of individuals with acute lung injury stimulated macrophage chemokine production in a TLR4- and TLR2-dependent manner. Myd88(-/-) and Tlr4(-/-)Tlr2(-/-) mice showed impaired transepithelial migration of inflammatory cells but decreased survival and enhanced epithelial cell apoptosis after lung injury. Lung epithelial cell-specific overexpression of high-molecular-mass hyaluronan was protective against acute lung injury. Furthermore, epithelial cell-surface hyaluronan was protective against apoptosis, in part, through TLR-dependent basal activation of NF-kappaB. Hyaluronan-TLR2 and hyaluronan-TLR4 interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity and promote recovery from acute lung injury.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Myd88(-/-)", + "Tlr4(-/-)Tlr2(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Myd88(-/-)", + "Tlr4(-/-)Tlr2(-/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Lung", + "epithelial", + "cell-specific", + "overexpression", + "of", + "high-molecular-mass", + "hyaluronan" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protective", + "against" + ] + } + } + ] + }, + { + "PMID": "16041384", + "TEXT": "Immunosuppressants are crucial in the prevention of detrimental immune reactions associated with allogenic organ transplantation, but they often cause adverse effects in a number of biological systems, including the skeletal system. Calcineurin inhibitors FK506 and cyclosporin A inhibit nuclear factor of activated T cells (NFAT) activity and induce strong immunosuppression. Among NFAT proteins, NFATc1 is crucial for the differentiation of bone-resorbing osteoclasts. Here we show FK506 administration induces the reduction of bone mass despite a blockade of osteoclast differentiation. This reduction is caused by severe impairment of bone formation, suggesting that NFAT transcription factors also have an important role in the transcriptional program of osteoblasts. In fact, bone formation is inhibited in Nfatc1- and Nfatc2-deficient cells as well as in FK506-treated osteoblasts. Overexpression of NFATc1 stimulates Osterix-dependent activation of the Col1a1 (encoding type I collagen) promoter, but not Runx2-dependent activation of the Bglap1 (encoding osteocalcin) promoter. NFAT and Osterix form a complex that binds to DNA, and this interaction is important for the transcriptional activity of Osterix. Thus, NFAT and Osterix cooperatively control osteoblastic bone formation. These results may provide important insight into the management of post-transplantation osteoporosis as well as a new strategy for promoting bone regeneration in osteopenic disease.", + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nfatc1-", + "and", + "Nfatc2-deficient" + ] + } + } + ] + }, + { + "PMID": "15821746", + "TEXT": "Although epithelial ovarian cancers (EOCs) have been thought to arise from the simple epithelium lining the ovarian surface or inclusion cysts, the major subtypes of EOCs show morphologic features that resemble those of the müllerian duct-derived epithelia of the reproductive tract. We found that HOX genes, which normally regulate mullerian duct differentiation, are not expressed in normal ovarian surface epithelium (OSE), but are expressed in different EOC subtypes according to the pattern of mullerian-like differentiation of these cancers. Ectopic expression of Hoxa9 in tumorigenic mouse OSE cells gave rise to papillary tumors resembling serous EOCs. In contrast, Hoxa10 and Hoxa11 induced morphogenesis of endometrioid-like and mucinous-like EOCs, respectively. Hoxa7 showed no lineage specificity, but promoted the abilities of Hoxa9, Hoxa10 and Hoxa11 to induce differentiation along their respective pathways. Therefore, inappropriate activation of a molecular program that controls patterning of the reproductive tract could explain the morphologic heterogeneity of EOCs and their assumption of müllerian-like features.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Ectopic", + "expression", + "of", + "Hoxa9" + ] + }, + "effect": { + "val": "positive", + "words": [ + "gave", + "rise", + "to" + ] + } + } + ] + }, + { + "PMID": "15034566", + "TEXT": "Atherosclerosis, the leading cause of death in developed countries, has been linked to hypercholesterolemia for decades. More recently, atherosclerotic lesion progression has been shown to depend on persistent, chronic inflammation in the artery wall. Although several studies have implicated infectious agents in this process, the role of infection in atherosclerosis remains controversial. Because the involvement of monocytes and macrophages in the pathogenesis of atherosclerosis is well established, we investigated the possibility that macrophage innate immunity signaling pathways normally activated by pathogens might also be activated in response to hyperlipidemia. We examined atherosclerotic lesion development in uninfected, hyperlipidemic mice lacking expression of either lipopolysaccharide (LPS) receptor CD14 or myeloid differentiation protein-88 (MyD88), which transduces cell signaling events downstream of the Toll-like receptors (TLRs), as well as receptors for interleukin-1 (IL-1) and IL-18. Whereas the MyD88-deficient mice evinced a marked reduction in early atherosclerosis, mice deficient in CD14 had no decrease in early lesion development. Inactivation of the MyD88 pathway led to a reduction in atherosclerosis through a decrease in macrophage recruitment to the artery wall that was associated with reduced chemokine levels. These findings link elevated serum lipid levels to a proinflammatory signaling cascade that is also engaged by microbial pathogens.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "expression", + "of", + "either", + "lipopolysaccharide", + "receptor", + "CD14", + "myeloid", + "MyD88-deficient", + "Inactivation", + "the", + "MyD88", + "pathway" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduction" + ] + } + } + ] + }, + { + "PMID": "14981513", + "TEXT": "The Aurora kinases are essential for the regulation of chromosome segregation and cytokinesis during mitosis. Aberrant expression and activity of these kinases occur in a wide range of human tumors, and lead to aneuploidy and tumorigenesis. Here we report the discovery of a highly potent and selective small-molecule inhibitor of Aurora kinases, VX-680, that blocks cell-cycle progression and induces apoptosis in a diverse range of human tumor types. This compound causes profound inhibition of tumor growth in a variety of in vivo xenograft models, leading to regression of leukemia, colon and pancreatic tumors at well-tolerated doses. Our data indicate that Aurora kinase inhibition provides a new approach for the treatment of multiple human malignancies.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "potent", + "selective", + "small-molecule", + "inhibitor", + "of", + "Aurora", + "kinases,", + "VX-680," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces", + "leading", + "to" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "potent", + "selective", + "small-molecule", + "inhibitor", + "of", + "Aurora", + "kinases,", + "VX-680," + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + } + ] + }, + { + "PMID": "14758355", + "TEXT": "Colonization of the anterior nares in approximately 37% of the population is a major risk factor for severe Staphylococcus aureus infections. Here we show that wall teichoic acid (WTA), a surface-exposed staphylococcal polymer, is essential for nasal colonization and mediates interaction with human nasal epithelial cells. WTA-deficient mutants were impaired in their adherence to nasal cells, and were completely unable to colonize cotton rat nares. This study describes the first essential factor for S. aureus nasal colonization.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "WTA-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + } + ] + }, + { + "PMID": "14528298", + "TEXT": "Platelet activation at sites of vascular injury is essential for primary hemostasis, but also underlies arterial thrombosis leading to myocardial infarction or stroke. Platelet activators such as adenosine diphosphate, thrombin or thromboxane A(2) (TXA(2)) activate receptors that are coupled to heterotrimeric G proteins. Activation of platelets through these receptors involves signaling through G(q), G(i) and G(z) (refs. 4-6). However, the role and relative importance of G(12) and G(13), which are activated by various platelet stimuli, are unclear. Here we show that lack of Galpha(13), but not Galpha(12), severely reduced the potency of thrombin, TXA(2) and collagen to induce platelet shape changes and aggregation in vitro. These defects were accompanied by reduced activation of RhoA and inability to form stable platelet thrombi under high shear stress ex vivo. Galpha(13) deficiency in platelets resulted in a severe defect in primary hemostasis and complete protection against arterial thrombosis in vivo. We conclude that G(13)-mediated signaling processes are required for normal hemostasis and thrombosis and may serve as a new target for antiplatelet drugs.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "Galpha(13)," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + } + ] + }, + { + "PMID": "12592402", + "TEXT": "Polymorphonuclear leukocytes (PMNs) are critical effector cells of the innate immune system that protect the host by migrating to inflammatory sites and killing pathogenic microbes. We addressed the role of chemokine receptor desensitization induced by G-protein-coupled receptor kinases (GRKs) in the feedback control of PMN migration. We show that the chemokine macrophage inflammatory protein-2 (MIP-2) induces GRK2 and GRK5 expression in PMNs through phosphoinositide-3-kinase (PI3K)-gamma signaling. We also show that lipopolysaccharide (LPS)-activated signaling through the Toll-like receptor (TLR)-4 pathway transcriptionally downregulates the expression of GRK2 and GRK5 in response to MIP-2. The reduced expression of GRKs lowers chemokine receptor desensitization and markedly augments the PMN migratory response. These data indicate that TLR4 modulation of PMN surface chemokine receptor expression subsequent to the downregulation of GRK2 and GRK5 expression is a critical determinant of PMN migration.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "GRKs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "augments" + ] + } + } + ] + }, + { + "PMID": "12579197", + "TEXT": "RNA interference (RNAi) is a powerful tool to silence gene expression post-transcriptionally. However, its potential to treat or prevent disease remains unproven. Fas-mediated apoptosis is implicated in a broad spectrum of liver diseases, where inhibiting hepatocyte death is life-saving. We investigated the in vivo silencing effect of small interfering RNA (siRNA) duplexes targeting the gene Fas (also known as Tnfrsf6), encoding the Fas receptor, to protect mice from liver failure and fibrosis in two models of autoimmune hepatitis. Intravenous injection of Fas siRNA specifically reduced Fas mRNA levels and expression of Fas protein in mouse hepatocytes, and the effects persisted without diminution for 10 days. Hepatocytes isolated from mice treated with Fas siRNA were resistant to apoptosis when exposed to Fas-specific antibody or co-cultured with concanavalin A (ConA)-stimulated hepatic mononuclear cells. Treatment with Fas siRNA 2 days before ConA challenge abrogated hepatocyte necrosis and inflammatory infiltration and markedly reduced serum concentrations of transaminases. Administering Fas siRNA beginning one week after initiating weekly ConA injections protected mice from liver fibrosis. In a more fulminant hepatitis induced by injecting agonistic Fas-specific antibody, 82% of mice treated with siRNA that effectively silenced Fas survived for 10 days of observation, whereas all control mice died within 3 days. Silencing Fas expression with RNAi holds therapeutic promise to prevent liver injury by protecting hepatocytes from cytotoxicity.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Fas", + "siRNA" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant", + "abrogated" + ] + } + } + ] + }, + { + "PMID": "12172543", + "TEXT": "Survivin (also termed Birc5) belongs to the family of genes known as inhibitors of apoptosis, and it has been implicated in both prevention of cell death and control of mitosis. The survivin pathway is exploited in cancer, but its potential role in vascular injury is unknown. Here, we show that balloon-mediated arterial injury in rabbits resulted in expression of survivin in vascular cells. Serum or PDGF-AB stimulated survivin expression in cultured smooth-muscle cells (SMCs), which suppressed apoptosis and prevented caspase activation. Adenoviral delivery of a phosphorylation-defective survivin mutant reversed the cytoprotective effect of PDGF in SMCs without affecting mitotic progression, suppressed neointimal formation in wire-injured mouse femoral arteries, and induced vascular cell apoptosis in vivo. These data identify survivin as a critical regulator of SMC apoptosis after acute vascular injury. Disrupting the survivin pathway may provide a novel therapy to limit pathological vessel-wall remodeling.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Adenoviral", + "phosphorylation-defective", + "survivin", + "mutant" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "without", + "affecting" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Adenoviral", + "phosphorylation-defective", + "survivin", + "mutant" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "12118245", + "TEXT": "A major concern in cancer therapy is resistance of tumors such as glioblastoma to current treatment protocols. Here, we report that transfer of the gene encoding second mitochondria-derived activator of caspase (Smac) or Smac peptides sensitized various tumor cells in vitro and malignant glioma cells in vivo for apoptosis induced by death-receptor ligation or cytotoxic drugs. Expression of a cytosolic active form of Smac or cell-permeable Smac peptides bypassed the Bcl-2 block, which prevented the release of Smac from mitochondria, and also sensitized resistant neuroblastoma or melanoma cells and patient-derived primary neuroblastoma cells ex vivo. Most importantly, Smac peptides strongly enhanced the antitumor activity of Apo-2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in an intracranial malignant glioma xenograft model in vivo. Complete eradication of established tumors and survival of mice was only achieved upon combined treatment with Smac peptides and Apo2L/TRAIL without detectable toxicity to normal brain tissue. Thus, Smac agonists are promising candidates for cancer therapy by potentiating cytotoxic therapies.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfer", + "of", + "the", + "gene", + "encoding", + "second", + "mitochondria-derived" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "11689884", + "TEXT": "Acute and fulminant liver failure induced by viral hepatitis, alcohol or other hepatotoxic drugs, are associated with tumor necrosis factor (TNF) production. In a mouse model of lethal hepatitis induced by TNF, apoptosis and necrosis of hepatocytes, but also lethality, hypothermia and influx of leukocytes into the liver, are prevented by a broad-spectrum matrix metalloproteinase (MMP) inhibitor, BB-94. Mice deficient in MMP-2, MMP-3 or MMP-9 had lower levels of apoptosis and necrosis of hepatocytes, and better survival. We found induction of MMP-9 activity and fibronectin degradation. Our findings suggest that several MMPs play a critical role in acute, fulminant hepatitis by degrading the extracellular matrix and allowing massive leukocyte influx in the liver. BB-94 also prevented lethality in TNF/interferon-gamma therapy in tumor-bearing mice. A broad-spectrum MMP inhibitor may be potentially useful for the treatment of patients with acute and perhaps chronic liver failure, and in cancer therapies using inflammatory cytokines.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "broad-spectrum", + "matrix", + "metalloproteinase", + "(MMP)", + "inhibitor,", + "BB-94." + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "broad-spectrum", + "matrix", + "metalloproteinase", + "(MMP)", + "inhibitor,", + "BB-94." + ] + }, + "effect": { + "val": "positive", + "words": [ + "levels" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "MMP-2,", + "MMP-3", + "or", + "MMP-9" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "MMP-2,", + "MMP-3", + "or", + "MMP-9" + ] + }, + "effect": { + "val": "positive", + "words": [ + "levels" + ] + } + } + ] + }, + { + "PMID": "11135623", + "TEXT": "The transcription factor early growth response protein 1 (EGR1) is overexpressed in a majority of human prostate cancers and is implicated in the regulation of several genes important for prostate tumor progression. Here we have assessed the effect of Egr1 deficiency on tumor development in two transgenic mouse models of prostate cancer (CR2-T-Ag and TRAMP). Using a combination of high-resolution magnetic resonance imaging and histopathological and survival analyses, we show that tumor progression was significantly impaired in Egr1-/- mice. Tumor initiation and tumor growth rate were not affected by the lack of Egr1; however, Egr1 deficiency significantly delayed the progression from prostatic intra-epithelial neoplasia to invasive carcinoma. These results indicate a unique role for Egr1 in regulating the transition from localized, carcinoma in situ to invasive carcinoma.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Egr1", + "deficiency", + "Egr1-/-" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired", + "delayed" + ] + } + }, + { + "effect": { + "val": "no effect", + "words": [ + "not", + "affected" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "of", + "Egr1;" + ] + } + } + ] + }, + { + "PMID": "11135616", + "TEXT": "Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate lipid and glucose metabolism and cellular differentiation. PPAR-alpha and PPAR-gamma are both expressed in human macrophages where they exert anti-inflammatory effects. The activation of PPAR-alpha may promote foam-cell formation by inducing expression of the macrophage scavenger receptor CD36. This prompted us to investigate the influence of different PPAR-activators on cholesterol metabolism and foam-cell formation of human primary and THP-1 macrophages. Here we show that PPAR-alpha and PPAR-gamma activators do not influence acetylated low density lipoprotein-induced foam-cell formation of human macrophages. In contrast, PPAR-alpha and PPAR-gamma activators induce the expression of the gene encoding ABCA1, a transporter that controls apoAI-mediated cholesterol efflux from macrophages. These effects are likely due to enhanced expression of liver-x-receptor alpha, an oxysterol-activated nuclear receptor which induces ABCA1-promoter transcription. Moreover, PPAR-alpha and PPAR-gamma activators increase apoAI-induced cholesterol efflux from normal macrophages. In contrast, PPAR-alpha or PPAR-gamma activation does not influence cholesterol efflux from macrophages isolated from patients with Tangier disease, which is due to a genetic defect in ABCA1. Here we identify a regulatory role for PPAR-alpha and PPAR-gamma in the first steps of the reverse-cholesterol-transport pathway through the activation of ABCA1-mediated cholesterol efflux in human macrophages.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PPAR-alpha" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "influence" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "and", + "PPAR-gamma", + "activators" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "influence" + ] + } + } + ] + }, + { + "PMID": "11017141", + "TEXT": "The time at which ovarian failure (menopause) occurs in females is determined by the size of the oocyte reserve provided at birth, as well as by the rate at which this endowment is depleted throughout post-natal life. Here we show that disruption of the gene for acid sphingomyelinase in female mice suppressed the normal apoptotic deletion of fetal oocytes, leading to neonatal ovarian hyperplasia. Ex vivo, oocytes lacking the gene for acid sphingomyelinase or wild-type oocytes treated with sphingosine-1-phosphate resisted developmental apoptosis and apoptosis induced by anti-cancer therapy, confirming cell autonomy of the death defect. Moreover, radiation-induced oocyte loss in adult wild-type female mice, the event that drives premature ovarian failure and infertility in female cancer patients, was completely prevented by in vivo therapy with sphingosine-1-phosphate. Thus, the sphingomyelin pathway regulates developmental death of oocytes, and sphingosine-1-phosphate provides a new approach to preserve ovarian function in vivo.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "disruption", + "of", + "the", + "gene", + "for", + "acid", + "sphingomyelinase", + "lacking" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed", + "resisted" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "gene", + "for", + "acid", + "sphingomyelinase" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "10973323", + "TEXT": "A combination of two drugs afforded remarkable protection from intestinal neoplasia in APC(Min/+) mice, a murine model of human familial adenomatous polyposis (FAP). One of the drugs was sulindac, a prototypical non-steroidal anti-inflammatory drug with established chemopreventative activity. The second drug was EKI-569, a newly developed, irreversible inhibitor of the epidermal growth factor receptor kinase. Although 100% of the untreated APC(Min/+) mice developed approximately 20 polyps, nearly half the mice treated with these two agents developed no polyps at all. These results suggest a powerful strategy for the chemoprevention of human colonic neoplasia.", + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "protection" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "APC(Min/+)" + ] + } + } + ] + }, + { + "PMID": "10888935", + "TEXT": "Medulloblastoma is the most malignant pediatric brain tumor. It is believed to originate from the undifferentiated external granule layer cells in the cerebellum, but the mechanism of tumorigenesis remains unknown. Here we studied three types of human medulloblastoma cells that express markers corresponding to different levels of neuronal differentiation. They expressed the neuronal repressor element 1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF; refs. 7-10) at very high levels compared with either neuronal progenitor NTera2 (NT2) cells or fully differentiated human neuron teratocarcinoma (hNT cells). To counter the effect of REST/NRSF, we used a recombinant transcription factor, REST-VP16, constructed by replacing repressor domains of REST/NRSF with the activation domain of viral protein (VP16). Transient expression of REST-VP16 in medulloblastoma cells was able to compete with the endogenous REST/NRSF for DNA binding and stimulate neuronal promoters. High-efficiency expression of REST-VP16 mediated by adenovirus vectors (Ad.REST-VP16) in medulloblastoma cells was able to counter REST/NRSF-mediated repression of neuronal promoters, stimulate expression of endogenous neuronal genes and trigger apoptosis through the activation of caspase cascades. Furthermore, intratumoral injection of Ad.REST-VP16 in established medulloblastoma tumors in nude mice inhibited their growth. Therefore, REST/NRSF may serve as a new target for therapeutic interventions for medulloblastoma through agents such as REST-VP16.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "REST-VP16" + ] + }, + "effect": { + "val": "positive", + "words": [ + "trigger" + ] + } + } + ] + }, + { + "PMID": "10802717", + "TEXT": "The pro-inflammatory cytokine interleukin (IL)-6 (refs. 1-5) can bind to cells lacking the IL-6 receptor (IL-6R) when it forms a complex with the soluble IL-6R (sIL-6R) (trans signaling). Here, we have assessed the contribution of this system to the increased resistance of mucosal T cells against apoptosis in Crohn disease (CD), a chronic inflammatory disease of the gastrointestinal tract. A neutralizing antibody against IL-6R suppressed established experimental colitis in various animal models of CD mediated by type 1 T-helper cells, by inducing apoptosis of lamina propria T cells. Similarly, specific neutralization of sIL-6R in vivo by a newly designed gp130-Fc fusion protein caused suppression of colitis activity and induction of apoptosis, indicating that sIL-6R prevents mucosal T-cell apoptosis. In patients with CD, mucosal T cells showed strong evidence for IL-6 trans signaling, with activation of signal transducer and activator of transcription 3, bcl-2 and bcl-xl. Blockade of IL-6 trans signaling caused T-cell apoptosis, indicating that the IL-6-sIL-6R system mediates the resistance of T cells to apoptosis in CD. These data indicate that a pathway of T-cell activation driven by IL-6-sIL-6R contributes to the perpetuation of chronic intestinal inflammation. Specific targeting of this pathway may be a promising new approach for the treatment of CD.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "neutralization", + "of", + "sIL-6R" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "specific", + "neutralization", + "of", + "sIL-6R" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + } + ] + }, + { + "PMID": "10802708", + "TEXT": "Caspase 8 is a cysteine protease regulated in both a death-receptor-dependent and -independent manner during apoptosis. Here, we report that the gene for caspase 8 is frequently inactivated in neuroblastoma, a childhood tumor of the peripheral nervous system. The gene is silenced through DNA methylation as well as through gene deletion. Complete inactivation of CASP8 occurred almost exclusively in neuroblastomas with amplification of the oncogene MYCN. Caspase 8-null neuroblastoma cells were resistant to death receptor- and doxorubicin-mediated apoptosis, deficits that were corrected by programmed expression of the enzyme. Thus, caspase 8 acts as a tumor suppressor in neuroblastomas with amplification of MYCN.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Caspase", + "8-null" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant" + ] + } + } + ] + }, + { + "PMID": "10700233", + "TEXT": "Golgi beta1,6N-acetylglucosaminyltransferase V (MGAT5) is required in the biosynthesis of beta1,6GlcNAc-branched N-linked glycans attached to cell surface and secreted glycoproteins. Amounts of MGAT5 glycan products are commonly increased in malignancies, and correlate with disease progression. To study the functions of these N-glycans in development and disease, we generated mice deficient in Mgat5 by targeted gene mutation. These Mgat5-/- mice lacked Mgat5 products and appeared normal, but differed in their responses to certain extrinsic conditions. Mammary tumor growth and metastases induced by the polyomavirus middle T oncogene was considerably less in Mgat5-/- mice than in transgenic littermates expressing Mgat5. Furthermore, Mgat5 glycan products stimulated membrane ruffling and phosphatidylinositol 3 kinase-protein kinase B activation, fueling a positive feedback loop that amplified oncogene signaling and tumor growth in vivo. Our results indicate that inhibitors of MGAT5 might be useful in the treatment of malignancies by targeting their dependency on focal adhesion signaling for growth and metastasis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mgat5-/-" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mgat5-/-" + ] + }, + "effect": { + "val": "negative", + "words": [ + "less" + ] + } + } + ] + }, + { + "PMID": "10470075", + "TEXT": "Infection of macrophage lineage cells is a feature of primate lentivirus replication, and several properties of primate lentiviruses seem to have evolved to promote the infection of macrophages. Here we demonstrate that the accessory gene product Nef induces the production of two CC-chemokines, macrophage inflammatory proteins 1alpha and 1beta, by HIV-1-infected macrophages. Adenovirus-mediated expression of Nef in primary macrophages was sufficient for chemokine induction. Supernatants from Nef-expressing macrophages induced both the chemotaxis and activation of resting T lymphocytes, permitting productive HIV-1 infection. These results indicate a role for Nef in lymphocyte recruitment and activation at sites of virus replication.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Adenovirus-mediated", + "expression", + "of", + "Nef" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "10426313", + "TEXT": "Intestinal inflammatory diseases are mediated by dysregulated immune responses to undefined luminal antigens. Feeding hen egg-white lysozyme to mice expressing a transgenic T-cell receptor that recognizes hen egg-white lysozyme peptide 46-61 resulted in no intestinal pathology; however, simultaneous administration of cyclooxygenase-2 inhibitors and dietary hen egg-white lysozyme resulted in increased proliferation of lamina propria mononuclear cells and crypt epithelial cells, crypt expansion and villus blunting. Lamina propria mononuclear cells produce high levels of cyclooxygenase-2-dependent arachidonic acid metabolites, which act as immunomodulators in the immune response to dietary antigen. These findings establish that cyclooxygenase-2-dependent arachidonic acid metabolites are essential in the development and maintenance of intestinal immune homeostasis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "T-cell", + "receptor", + "that", + "recognizes" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "a", + "transgenic" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "cyclooxygenase-2", + "inhibitors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + } + ] + }, + { + "PMID": "10371506", + "TEXT": "Blockage in myeloid differentiation characterizes acute myeloid leukemia (AML); the stage of the blockage defines distinct AML subtypes (AML1/2 to AML5). Differentiation therapy in AML has recently raised interest because the survival of AML3 patients has been greatly improved using the differentiating agent retinoic acid. However, this molecule is ineffective in other AML subtypes. The CD44 surface antigen, on leukemic blasts from most AML patients, is involved in myeloid differentiation. Here, we report that ligation of CD44 with specific anti-CD44 monoclonal antibodies or with hyaluronan, its natural ligand, can reverse myeloid differentiation blockage in AML1/2 to AML5 subtypes. The differentiation of AML blasts was evidenced by the ability to produce oxidative bursts, the expression of lineage antigens and cytological modifications, all specific to normal differentiated myeloid cells. These results indicate new possibilities for the development of CD44-targeted differentiation therapy in the AML1/2 to AML5 subtypes.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "ligation", + "of", + "CD44" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reverse", + "blockage" + ] + } + } + ] + }, + { + "PMID": "10086384", + "TEXT": "A principal cause of blindness is subretinal neovascularization associated with age-related macular degeneration. Excised neovascular membranes from patients with age-related macular degeneration demonstrated a pattern of Fas+ new vessels in the center of the vascular complex, surrounded by FasL+ retinal pigment epithelial cells. In a murine model, Fas (CD95)-deficient (Ipr) and FasL-defective (gld) mice had a significantly increased incidence of neovascularization compared with normal mice. Furthermore, in gld mice there is massive subretinal neovascularization with uncontrolled growth of vessels. We found that cultured choroidal endothelial cells were induced to undergo apoptosis by retinal pigment epithelial cells through a Fas-FasL interaction. In addition, antibody against Fas prevented vascular tube formation of choroidal endothelial cells derived from the eye in a three-dimensional in vitro assay. Thus, FasL expressed on retinal pigment epithelial cells may control the growth and development of new subretinal vessels that can damage vision.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FasL-defective", + "(gld)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "10086383", + "TEXT": "As in the development of many human cancers, in a transgenic mouse model of beta-cell carcinogenesis (Rip1Tag2), expression of neural cell adhesion molecule (NCAM) changes from the 120-kDa isoform in normal tissue to the 140/180-kDa isoforms in tumors. NCAM-deficient RiplTag2 mice, generated by crossing Rip1Tag2 mice with NCAM knockout mice, develop metastases, a tumor stage that is not seen in normal Rip1Tag2 mice. In contrast, overexpression of NCAM 120 in NCAM-deficient Rip1Tag2 mice prevents tumor metastasis. The results indicate that the loss of NCAM-mediated cell adhesion is one rate-limiting step in the actual metastatic dissemination of beta tumor cells.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NCAM-deficient", + "RiplTag2", + "NCAM", + "knockout" + ] + }, + "effect": { + "val": "positive", + "words": [ + "develop" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "NCAM", + "120" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "NCAM-deficient", + "Rip1Tag2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + } + ] + }, + { + "PMID": "9930872", + "TEXT": "Adhesion of tumor cells to host cell layers and subsequent transcellular migration are pivotal steps in cancer invasion and metastasis. The small GTPase Rho controls cell adhesion and motility through reorganization of the actin cytoskeleton and regulation of actomyosin contractility. Cultured rat MM1 hepatoma cells migrate through a mesothelial cell monolayer in vitro in a serum-dependent, Rho-mediated manners. Among several proteins isolated as putative target molecules of Rho, the ROCK (ROK) family of Rho-associated serine-threonine protein kinases are thought to participate in the induction of focal adhesions and stress fibers in cultured cells, and to mediate calcium sensitization of smooth muscle contraction by enhancing phosphorylation of the regulatory light chain of myosin. Transfection of MM1 cells with cDNA encoding a dominant active mutant of ROCK conferred invasive activity independently of serum and Rho. In contrast, expression of a dominant negative, kinase-defective ROCK mutant substantially attenuated the invasive phenotype. A specific ROCK inhibitor (Y-27632) blocked both Rho-mediated activation of actomyosin and invasive activity of these cells. Furthermore, continuous delivery of this inhibitor using osmotic pumps considerably reduced the dissemination of MM1 cells implanted into the peritoneal cavity of syngeneic rats. These results indicate that ROCK plays an essential part in tumor cell invasion, and demonstrate its potential as a therapeutic target for the prevention of cancer invasion and metastasis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "cDNA", + "encoding", + "a", + "dominant", + "active", + "mutant", + "of", + "ROCK", + "expression", + "negative,", + "kinase-defective" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuated", + "blocked" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "attenuated", + "blocked" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "(Y-27632)", + "specific", + "ROCK", + "inhibitor" + ] + } + } + ] + }, + { + "PMID": "9701251", + "TEXT": "Prostate apoptosis response-4 (Par-4) is a protein containing both a leucine zipper and a death domain that was isolated by differential screening for genes upregulated in prostate cancer cells undergoing apoptosis. Par-4 is expressed in the nervous system, where its function is unknown. In Alzheimer disease (AD), neurons may die by apoptosis, and amyloid beta-protein (A beta) may play a role in this. We report here that Par-4 expression is increased in vulnerable neurons in AD brain and is induced in cultured neurons undergoing apoptosis. Blockade of Par-4 expression or function prevented neuronal apoptosis induced by Ab and trophic factor withdrawal. Par-4 expression was enhanced, and mitochondrial dysfunction and apoptosis exacerbated, in cells expressing presenilin-1 mutations associated with early-onset inherited AD.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Blockade", + "of", + "Par-4", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Blockade", + "of", + "Par-4", + "expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "9662378", + "TEXT": "The p53 tumor suppressor gene, which is induced by DNA damage and/or stress stimuli, causes cells to undergo G1-arrest or apoptotic death; thus it plays an essential role in human carcinogenesis. We have searched for p53-related genes by using degenerate PCR, and have identified two cDNA fragments similar to but distinct from p53: one previously reported, p73, and the other new. We cloned two major splicing variants of the latter gene and named these p51A and p51B (a human homologue of rat Ket). The p51A gene encodes a 448-amino-acid protein with a molecular weight of 50.9 kDa; and p51B, a 641-amino-acid protein with a molecular weight of 71.9 kDa. In contrast with the ubiquitous expression of p53, expression of p51 mRNA was found in a limited number of tissues, including skeletal muscle, placenta, mammary gland, prostate, trachea, thymus, salivary gland, uterus, heart and lung. In p53-deficient cells, p51A induced growth-suppression and apoptosis, and upregulated p21waf-1 through p53 regulatory elements. Mutations in p51 were found in some human epidermal tumors.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "9662377", + "TEXT": "Previously, we cloned a cDNA fragment, TSIP 2 (tumor suppressor inhibited pathway clone 2), that detects by northern blot analysis of M1-LTR6 cells a 3-kb mRNA downregulated during p53-induced apoptosis. Cloning the full-length TSIP 2 cDNA showed that it corresponds to the presenilin 1 (PS1) gene, in which mutations have been reported in early-onset familial Alzheimer's disease. Here we demonstrate that PS1 is downregulated in a series of model systems for p53-dependent and p53-independent apoptosis and tumor suppression. To investigate the biological relevance of this downregulation, we stably transfected U937 cells with antisense PS1 cDNA. The downregulation of PS1 in these U937 transfectants results in reduced growth with an increased fraction of the cells in apoptosis. When injected into mice homozygous for severe combined immunodeficiency disease (scid/scid mice), these cells show a suppression of their malignant phenotype. Our results indicate that PS1, initially identified in a neurodegenerative disease, may also be involved in the regulation of cancer-related pathways.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "stably", + "transfected", + "with", + "antisense", + "PS1", + "cDNA." + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "downregulation", + "of" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PS1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + } + ] + }, + { + "PMID": "9623977", + "TEXT": "The transfer of apoptosis genes to tumors is one of the most promising strategies for cancer gene therapy. We have shown that massive apoptosis occurs when wild-type p53 expression is induced in glioma cells carrying a p53 gene mutation. However, adenovirus-mediated p53 gene transfer is ineffective in causing apoptosis in glioma cells that retain a wild-type p53 genotype. We evaluated the effect of E2F-1 overexpression on the growth of gliomas in vitro and in vivo. In the in vitro study, the adenovirus-mediated transfer of exogenous E2F-1 protein precipitated generalized apoptosis in gliomas. The treatment with Ad5CMV-E2F-1 of nude mice carrying subcutaneous gliomas arrested tumor growth. Our results indicate that E2F-1 has anti-glioma activity in vitro and in vivo.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "E2F-1", + "overexpression", + "adenovirus-mediated", + "transfer", + "of", + "exogenous", + "protein" + ] + }, + "effect": { + "val": "positive", + "words": [ + "precipitated" + ] + } + } + ] + }, + { + "PMID": "9585232", + "TEXT": "In situ killing of tumor cells using suicide gene transfer to generate death by a non-apoptotic pathway was associated with high immunogenicity and induction of heat shock protein (hsp) expression. In contrast, a syngeneic colorectal tumor line, CMT93, killed predominantly by apoptosis, showed low levels of hsp expression and less immunogenicity. When apoptosis was inhibited in CMT93 cells by overexpression of bcl-2, hsp was also induced. Furthermore, when cDNA encoding hsp70 was stably transfected into B16 and CMT93 cells, its expression significantly enhanced the immunogenicity of both tumors. Increased levels of hsp, induced by non-apoptotic cell killing, may provide an immunostimulatory signal in vivo which helps break tolerance to tumor antigens. These findings have important implications for the development of novel anti-cancer therapies aimed at promoting patients' immune responses to their own tumors.", + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "bcl-2," + ] + } + } + ] + }, + { + "PMID": "9546789", + "TEXT": "At a position equivalent to the gene encoding the saimiri transforming protein (STP) of herpesvirus saimiri (HVS), Kaposi's sarcoma-associated herpesvirus (KSHV) contains a distinct open reading frame called K1. Although KSHV and HVS are related members of the rhadinovirus subgroup of gamma herpesviruses, K1 and STP exhibit no similarity in amino acid sequence or in structural organization. Since STP is required for the oncogenic potential of HVS, we investigated the functional consequence of K1 expression. Expression of the K1 gene in rodent fibroblasts produced morphologic changes and focus formation indicative of transformation. A recombinant herpesvirus in which the STP oncogene of HVS was replaced with K1, immortalized primary T lymphocytes to IL-2 independent growth and induced lymphoma in common marmosets. These results demonstrate the transforming potential of the K1 gene of KSHV.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "the", + "STP", + "oncogene", + "of", + "HVS", + "was", + "replaced", + "with", + "K1," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "9546786", + "TEXT": "It is generally believed that the vascular endothelium serves as an inflammatory barrier by providing a nonadherent surface to leukocytes. Here, we report that Fas ligand (FasL) is expressed on vascular endothelial cells (ECs) and that it may function to actively inhibit leukocyte extravasation. TNFalpha downregulates FasL expression with an accompanying decrease in EC cytotoxicity toward co-cultured Fas-bearing cells. Local administration of TNFalpha to arteries downregulates endothelial FasL expression and induces mononuclear cell infiltration. Constitutive FasL expression markedly attenuates TNFalpha-induced cell infiltration and adherent mononuclear cells undergo apoptosis under these conditions. These findings suggest that endothelial FasL expression can negatively regulate leukocyte extravasation.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Constitutive", + "FasL", + "expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "undergo" + ] + } + } + ] + }, + { + "PMID": "9359707", + "TEXT": "The nfkb1 and nfkb2 genes encode closely related products regulating immune and inflammatory responses. Their role during development and differentiation remains unclear. The generation of nfkb1 null mice (p50-/-) resulted in altered immune responses, but had no effect on development. Similarly, nfkb2 knockout mice (p52-/-) did not show developmental defects (J.C. et al., manuscript submitted). We have investigated the potential for in vivo compensatory functions of these genes by generating double-knockout mice. The surprising result was that the animals developed osteopetrosis because of a defect in osteoclast differentiation, suggesting redundant functions of NF-kappaB1 and NF-kappaB2 proteins in the development of this cell lineage. The osteopetrotic phenotype was rescued by bone marrow transplantation, indicating that the hematopoietic component was impaired. These results define a new mouse osteopetrotic mutant and implicate NF-kappaB proteins in bone development, raising new directions in the treatment of bone disorders.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nfkb2", + "knockout", + "(p52-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defect" + ] + } + } + ] + }, + { + "PMID": "9359697", + "TEXT": "Female sterility resulting from oocyte destruction is an unfortunate, and in many cases inevitable, consequence of chemotherapy. We show that unfertilized mouse oocytes exposed to therapeutic levels of the antitumor drug, doxorubicin (DXR), undergo apoptosis; however, fertilized oocytes do not initiate apoptosis, but enter cell-cycle arrest, when treated with DXR. Apoptosis induced by DXR in oocytes is blocked by sphingosine-1-phosphate, an inhibitor of ceramide-promoted cell death. Oocytes from Bax-deficient, but not p53-null, female mice display complete resistance to DXR-induced apoptosis in vivo and in vitro. Pretreatment of oocytes with a specific peptide inhibitor of caspases also abrogates the apoptotic response to DXR. These findings indicate that oocyte destruction caused by chemotherapy can be prevented by manipulation of apoptosis-associated signaling pathways.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bax-deficient,", + "p53-null," + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bax-deficient,", + "p53-null," + ] + }, + "effect": { + "val": "positive", + "words": [ + "DXR-induced" + ] + } + } + ] + }, + { + "PMID": "9359696", + "TEXT": "The importance of angiogenesis in malignant tumor growth has been interpreted mainly in terms of oxygen and nutrient supply. Here we demonstrate its fundamental role for tumor invasion of malignant human keratinocytes in surface transplants on nude mice. Distinct patterns of angiogenesis and vascular endothelial growth factor receptor-2 (VEGFR-2) expression allowed us to distinguish between benign and malignant cells. Functional inactivation of VEGF-R2 by a blocking antibody disrupted ongoing angiogenesis and prevented invasion of malignant cells, without reducing tumor cell proliferation. The reversion of a malignant into a benign phenotype by halting angiogenesis demonstrates a significant function of vascular endothelium for tumor invasion.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Functional", + "inactivation", + "of", + "VEGF-R2", + "by" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Functional", + "inactivation", + "of", + "VEGF-R2", + "by" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "without", + "reducing" + ] + } + } + ] + }, + { + "PMID": "9095178", + "TEXT": "Chronic systemic delivery of therapeutic proteins, such as inhibitors of angiogenesis, present a number of difficult pharmacological challenges. To overcome these problems for one such protein, we constructed retroviral and adenoviral vectors that express a novel, secretable form of the antiangiogenic protein, platelet factor 4 (sPF4). Vector-mediated sPF4 transduction selectively inhibits endothelial cell proliferation in vitro, and results in hypovascular tumors that grow slowly in vivo. Additionally, tumor-associated angiogenesis is inhibited and animal survival is prolonged, following transduction of established intracerebral gliomas by an sPF4-expressing adenoviral vector. These data support the concept that targeted antiangiogenesis, using virally mediated gene transfer, represents a promising strategy for delivering antiangiogenic therapy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Vector-mediated", + "sPF4", + "transduction" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + } + ] + }, + { + "PMID": "8946829", + "TEXT": "The retinoblastoma gene (RB) is the prototypic tumor suppressor. Studies to date have demonstrated cancer suppression with tumor cells reconstituted with RB ex vivo and implanted into immunodeficient mice, as well as with germline transmission of a human RB transgene into tumor-prone Rb +/- mice. To mimic the therapy of cancer more closely, spontaneous pituitary melanotroph tumors arising in immunocompetent Rb +/- mice were treated with a recombinant adenovirus carrying RB cDNA. Intratumoral RB gene transfer decreased tumor cell proliferation, reestablished innervation by growth-regulatory dopaminergic neurons, inhibited the growth of tumors, and prolonged the life spans of treated animals.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rb", + "+/-" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased", + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenovirus", + "carrying", + "RB", + "gene", + "transfer" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased", + "inhibited" + ] + } + } + ] + }, + { + "PMID": "7585187", + "TEXT": "A partial cDNA sequence for the gene linked to the von Hippel-Lindau (VHL) syndrome was reported in 1993. Mutation or loss of both VHL alleles has been documented in sporadic renal cell carcinomas and in the neoplasms that arise in von Hippel-Lindau kindreds. We have determined that the protein product of the VHL gene is an approximately 30 kilodalton cytoplasmic protein. The renal carcinoma cell line 786-O is known to harbour a VHL mutation and, as shown here, fails to produce a wild-type VHL protein. Reintroduction of wild-type, but not mutant, VHL into these cells had no demonstrable effect on their growth in vitro but inhibited their ability to form tumours in nude mice.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Reintroduction", + "of", + "wild-type,", + "VHL" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "ability" + ] + } + } + ] + }, + { + "PMID": "7585182", + "TEXT": "For Ras oncoproteins to transform mammalian cells, they must be post-translationally modified with a farnesyl group in a reaction catalysed by the enzyme farnesyl-protein transferase (FPTase). Inhibitors of FPTase have therefore been proposed as anti-cancer agents. We show that L-744,832, which mimics the CaaX motif to which the farnesyl group is added, is a potent and selective inhibitor of FPTase. In MMTV-v-Ha-ras mice bearing palpable tumours, daily administration of L-744,832 caused tumour regression. Following cessation of treatment, tumours reappeared, the majority of which regressed upon retreatment. No systemic toxicity was found upon necropsy of L-744,832-treated mice. This first demonstration of anti-FPTase-mediated tumour regression suggests that FPTase inhibitors may be safe and effective anti-tumour agents in some cancers.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "MMTV-v-Ha-ras" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + } + ] + }, + { + "PMID": "18836458", + "TEXT": "Pauci-immune focal necrotizing glomerulonephritis (FNGN) is a severe inflammatory disease associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA). Here we characterize autoantibodies to lysosomal membrane protein-2 (LAMP-2) and show that they are a new ANCA subtype present in almost all individuals with FNGN. Consequently, its prevalence is nearly twice that of the classical ANCAs that recognize myeloperoxidase or proteinase-3. Furthermore, antibodies to LAMP-2 cause pauci-immune FNGN when injected into rats, and a monoclonal antibody to human LAMP-2 (H4B4) induces apoptosis of human microvascular endothelium in vitro. The autoantibodies in individuals with pauci-immune FNGN commonly recognize a human LAMP-2 epitope (designated P(41-49)) with 100% homology to the bacterial adhesin FimH, with which they cross-react. Rats immunized with FimH develop pauci-immune FNGN and also develop antibodies to rat and human LAMP-2. Finally, we show that infections with fimbriated pathogens are common before the onset of FNGN. Thus, FimH-triggered autoimmunity to LAMP-2 provides a previously undescribed clinically relevant molecular mechanism for the development of pauci-immune FNGN.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "monoclonal", + "human", + "LAMP-2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "to", + "(H4B4)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + } + ] + }, + { + "PMID": "16155579", + "TEXT": "Obesity-related disorders are associated with the development of ischemic heart disease. Adiponectin is a circulating adipose-derived cytokine that is downregulated in obese individuals and after myocardial infarction. Here, we examine the role of adiponectin in myocardial remodeling in response to acute injury. Ischemia-reperfusion in adiponectin-deficient (APN-KO) mice resulted in increased myocardial infarct size, myocardial apoptosis and tumor necrosis factor (TNF)-alpha expression compared with wild-type mice. Administration of adiponectin diminished infarct size, apoptosis and TNF-alpha production in both APN-KO and wild-type mice. In cultured cardiac cells, adiponectin inhibited apoptosis and TNF-alpha production. Dominant negative AMP-activated protein kinase (AMPK) reversed the inhibitory effects of adiponectin on apoptosis but had no effect on the suppressive effect of adiponectin on TNF-alpha production. Adiponectin induced cyclooxygenase (COX)-2-dependent synthesis of prostaglandin E(2) in cardiac cells, and COX-2 inhibition reversed the inhibitory effects of adiponectin on TNF-alpha production and infarct size. These data suggest that adiponectin protects the heart from ischemia-reperfusion injury through both AMPK- and COX-2-dependent mechanisms.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "APN-KO" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Dominant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibitory" + ] + } + } + ] + }, + { + "PMID": "32451497", + "TEXT": "Common germline variants of the APOE gene are major risk modifiers of neurodegenerative and atherosclerotic diseases1-3, but their effect on cancer outcome is poorly defined. Here we report that, in a reversal of their effect on Alzheimer's disease, the APOE4 and APOE2 variants confer favorable and poor outcomes in melanoma, respectively. Mice expressing the human APOE4 allele exhibited reduced melanoma progression and metastasis relative to APOE2 mice. APOE4 mice exhibited enhanced anti-tumor immune activation relative to APOE2 mice, and T cell depletion experiments showed that the effect of APOE genotype on melanoma progression was mediated by altered anti-tumor immunity. Consistently, patients with melanoma carrying the APOE4 variant experienced improved survival in comparison to carriers of APOE2. Notably, APOE4 mice also showed improved outcomes under PD1 immune checkpoint blockade relative to APOE2 mice, and patients carrying APOE4 experienced improved anti-PD1 immunotherapy survival after progression on frontline regimens. Finally, enhancing APOE expression via pharmacologic activation of liver X receptors, previously shown to boost anti-tumor immunity4, exhibited therapeutic efficacy in APOE4 mice but not in APOE2 mice. These findings demonstrate that pre-existing hereditary genetics can impact progression and survival outcomes of a future malignancy and warrant prospective investigation of APOE genotype as a biomarker for melanoma outcome and therapeutic response.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "the", + "human", + "allele" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "APOE4" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + } + ] + }, + { + "PMID": "32094924", + "TEXT": "Transmembrane protein 30A (TMEM30A) maintains the asymmetric distribution of phosphatidylserine, an integral component of the cell membrane and 'eat-me' signal recognized by macrophages. Integrative genomic and transcriptomic analysis of diffuse large B-cell lymphoma (DLBCL) from the British Columbia population-based registry uncovered recurrent biallelic TMEM30A loss-of-function mutations, which were associated with a favorable outcome and uniquely observed in DLBCL. Using TMEM30A-knockout systems, increased accumulation of chemotherapy drugs was observed in TMEM30A-knockout cell lines and TMEM30A-mutated primary cells, explaining the improved treatment outcome. Furthermore, we found increased tumor-associated macrophages and an enhanced effect of anti-CD47 blockade limiting tumor growth in TMEM30A-knockout models. By contrast, we show that TMEM30A loss-of-function increases B-cell signaling following antigen stimulation-a mechanism conferring selective advantage during B-cell lymphoma development. Our data highlight a multifaceted role for TMEM30A in B-cell lymphomagenesis, and characterize intrinsic and extrinsic vulnerabilities of cancer cells that can be therapeutically exploited.", + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "limiting" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "TMEM30A-knockout" + ] + } + } + ] + }, + { + "PMID": "29785026", + "TEXT": "The lysine methyltransferase KMT2C (also known as MLL3), a subunit of the COMPASS complex, implements monomethylation of Lys4 on histone H3 (H3K4) at gene enhancers. KMT2C (hereafter referred to as MLL3) frequently incurs point mutations across a range of human tumor types, but precisely how these lesions alter MLL3 function and contribute to oncogenesis is unclear. Here we report a cancer mutational hotspot in MLL3 within the region encoding its plant homeodomain (PHD) repeats and demonstrate that this domain mediates association of MLL3 with the histone H2A deubiquitinase and tumor suppressor BAP1. Cancer-associated mutations in the sequence encoding the MLL3 PHD repeats disrupt the interaction between MLL3 and BAP1 and correlate with poor patient survival. Cancer cells that had PHD-associated MLL3 mutations or lacked BAP1 showed reduced recruitment of MLL3 and the H3K27 demethylase KDM6A (also known as UTX) to gene enhancers. As a result, inhibition of the H3K27 methyltransferase activity of the Polycomb repressive complex 2 (PRC2) in tumor cells harboring BAP1 or MLL3 mutations restored normal gene expression patterns and impaired cell proliferation in vivo. This study provides mechanistic insight into the oncogenic effects of PHD-associated mutations in MLL3 and suggests that restoration of a balanced state of Polycomb-COMPASS activity may have therapeutic efficacy in tumors that bear mutations in the genes encoding these epigenetic factors.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "BAP1", + "or", + "MLL3", + "mutations" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + } + ] + }, + { + "PMID": "29505034", + "TEXT": "Leukemia stem cells (LSCs) in individuals with chronic myelogenous leukemia (CML) (hereafter referred to as CML LSCs) are responsible for initiating and maintaining clonal hematopoiesis. These cells persist in the bone marrow (BM) despite effective inhibition of BCR-ABL kinase activity by tyrosine kinase inhibitors (TKIs). Here we show that although the microRNA (miRNA) miR-126 supported the quiescence, self-renewal and engraftment capacity of CML LSCs, miR-126 levels were lower in CML LSCs than in long-term hematopoietic stem cells (LT-HSCs) from healthy individuals. Downregulation of miR-126 levels in CML LSCs was due to phosphorylation of Sprouty-related EVH1-domain-containing 1 (SPRED1) by BCR-ABL, which led to inhibition of the RAN-exportin-5-RCC1 complex that mediates miRNA maturation. Endothelial cells (ECs) in the BM supply miR-126 to CML LSCs to support quiescence and leukemia growth, as shown using mouse models of CML in which Mir126a (encoding miR-126) was conditionally knocked out in ECs and/or LSCs. Inhibition of BCR-ABL by TKI treatment caused an undesired increase in endogenous miR-126 levels, which enhanced LSC quiescence and persistence. Mir126a knockout in LSCs and/or ECs, or treatment with a miR-126 inhibitor that targets miR-126 expression in both LSCs and ECs, enhanced the in vivo anti-leukemic effects of TKI treatment and strongly diminished LSC leukemia-initiating capacity, providing a new strategy for the elimination of LSCs in individuals with CML.", + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "support", + "enhanced" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Mir126a", + "(encoding", + "miR-126)" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "support", + "enhanced" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "was", + "out", + "conditionally", + "knocked" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "BCR-ABL" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + } + ] + }, + { + "PMID": "29334372", + "TEXT": "The unique metabolic demands of cancer cells underscore potentially fruitful opportunities for drug discovery in the era of precision medicine. However, therapeutic targeting of cancer metabolism has led to surprisingly few new drugs to date. The neutral amino acid glutamine serves as a key intermediate in numerous metabolic processes leveraged by cancer cells, including biosynthesis, cell signaling, and oxidative protection. Herein we report the preclinical development of V-9302, a competitive small molecule antagonist of transmembrane glutamine flux that selectively and potently targets the amino acid transporter ASCT2. Pharmacological blockade of ASCT2 with V-9302 resulted in attenuated cancer cell growth and proliferation, increased cell death, and increased oxidative stress, which collectively contributed to antitumor responses in vitro and in vivo. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of glutamine transport in oncology, representing a new class of targeted therapy and laying a framework for paradigm-shifting therapies targeting cancer cell metabolism.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "ASCT2", + "with", + "V-9302" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuated" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "blockade", + "of", + "ASCT2", + "with", + "V-9302" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + } + ] + }, + { + "PMID": "28805820", + "TEXT": "The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer. Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer; they are therefore being pursued as attractive therapeutic targets for selective inhibition in patients with cancer. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed and have shown promising outcomes in early clinical trials. Although resistance to BET inhibitors has been documented in preclinical models, the molecular mechanisms underlying acquired resistance are largely unknown. Here we report that cullin-3SPOP earmarks BET proteins, including BRD2, BRD3 and BRD4, for ubiquitination-mediated degradation. Pathologically, prostate cancer-associated SPOP mutants fail to interact with and promote the degradation of BET proteins, leading to their elevated abundance in SPOP-mutant prostate cancer. As a result, prostate cancer cell lines and organoids derived from individuals harboring SPOP mutations are more resistant to BET-inhibitor-induced cell growth arrest and apoptosis. Therefore, our results elucidate the tumor-suppressor role of SPOP in prostate cancer in which it acts as a negative regulator of BET protein stability and also provide a molecular mechanism for resistance to BET inhibitors in individuals with prostate cancer bearing SPOP mutations.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "SPOP", + "mutations" + ] + }, + "effect": { + "val": "negative", + "words": [ + "more", + "resistant", + "arrest" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "more", + "resistant", + "arrest" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "BET-inhibitor-induced" + ] + } + } + ] + }, + { + "PMID": "28714991", + "TEXT": "Inflammatory diseases such as arthritis are chronic conditions that fail to resolve spontaneously. While the cytokine and cellular pathways triggering arthritis are well defined, those responsible for the resolution of inflammation are incompletely characterized. Here we identified interleukin (IL)-9-producing type 2 innate lymphoid cells (ILC2s) as the mediators of a molecular and cellular pathway that orchestrates the resolution of chronic inflammation. In mice, the absence of IL-9 impaired ILC2 proliferation and activation of regulatory T (Treg) cells, and resulted in chronic arthritis with excessive cartilage destruction and bone loss. In contrast, treatment with IL-9 promoted ILC2-dependent Treg activation and effectively induced resolution of inflammation and protection of bone. Patients with rheumatoid arthritis in remission exhibited high numbers of IL-9+ ILC2s in joints and the circulation. Hence, fostering IL-9-mediated ILC2 activation may offer a novel therapeutic approach inducing resolution of inflammation rather than suppression of inflammatory responses.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "IL-9" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + } + ] + }, + { + "PMID": "27918563", + "TEXT": "The role of osteolineage cells in regulating hematopoietic stem cell (HSC) regeneration following myelosuppression is not well understood. Here we show that deletion of the pro-apoptotic genes Bak and Bax in osterix (Osx, also known as Sp7 transcription factor 7)-expressing cells in mice promotes HSC regeneration and hematopoietic radioprotection following total body irradiation. These mice showed increased bone marrow (BM) levels of the protein dickkopf-1 (Dkk1), which was produced in Osx-expressing BM cells. Treatment of irradiated HSCs with Dkk1 in vitro increased the recovery of both long-term repopulating HSCs and progenitor cells, and systemic administration of Dkk1 to irradiated mice increased hematopoietic recovery and improved survival. Conversely, inducible deletion of one allele of Dkk1 in Osx-expressing cells in adult mice inhibited the recovery of BM stem and progenitor cells and of complete blood counts following irradiation. Dkk1 promoted hematopoietic regeneration via both direct effects on HSCs, in which treatment with Dkk1 decreased the levels of mitochondrial reactive oxygen species and suppressed senescence, and indirect effects on BM endothelial cells, in which treatment with Dkk1 induced epidermal growth factor (EGF) secretion. Accordingly, blockade of the EGF receptor partially abrogated Dkk1-mediated hematopoietic recovery. These data identify Dkk1 as a regulator of hematopoietic regeneration and demonstrate paracrine cross-talk between BM osteolineage cells and endothelial cells in regulating hematopoietic reconstitution following injury.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inducible", + "deletion", + "of", + "one", + "allele", + "Dkk1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + } + ] + }, + { + "PMID": "27869803", + "TEXT": "Forward genetic screens with CRISPR-Cas9 genome editing enable high-resolution detection of genetic vulnerabilities in cancer cells. We conducted genome-wide CRISPR-Cas9 screens in RNF43-mutant pancreatic ductal adenocarcinoma (PDAC) cells, which rely on Wnt signaling for proliferation. Through these screens, we discovered a unique requirement for a Wnt signaling circuit: engaging FZD5, one of the ten Frizzled receptors encoded in the human genome. Our results uncover an underappreciated level of context-dependent specificity at the Wnt receptor level. We further derived a panel of recombinant antibodies that reports the expression of nine FZD proteins and confirms that FZD5 functional specificity cannot be explained by protein expression patterns. Additionally, antibodies that specifically bind FZD5 and FZD8 robustly inhibited the growth of RNF43-mutant PDAC cells grown in vitro and as xenografts in vivo, providing orthogonal support for the functional specificity observed genetically. Proliferation of a patient-derived PDAC cell line harboring an RNF43 variant was also selectively inhibited by the FZD5 antibodies, further demonstrating their use as a potential targeted therapy. Tumor organoid cultures from colorectal carcinoma patients that carried RNF43 mutations were also sensitive to the FZD5 antibodies, highlighting the potential generalizability of these findings beyond PDAC. Our results show that CRIPSR-based genetic screens can be leveraged to identify and validate cell surface targets for antibody development and therapy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "RNF43", + "variant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + } + ] + }, + { + "PMID": "27694932", + "TEXT": "Successful recovery from lung injury requires the repair and regeneration of alveolar epithelial cells to restore the integrity of gas-exchanging regions within the lung and preserve organ function. Improper regeneration of the alveolar epithelium is often associated with severe pulmonary fibrosis, the latter of which involves the recruitment and activation of fibroblasts, as well as matrix accumulation. Type 2 alveolar epithelial cells (AEC2s) are stem cells in the adult lung that contribute to the lung repair process. The mechanisms that regulate AEC2 renewal are incompletely understood. We provide evidence that expression of the innate immune receptor Toll-like receptor 4 (TLR4) and the extracellular matrix glycosaminoglycan hyaluronan (HA) on AEC2s are important for AEC2 renewal, repair of lung injury and limiting the extent of fibrosis. Either deletion of TLR4 or HA synthase 2 in surfactant-protein-C-positive AEC2s leads to impaired renewal capacity, severe fibrosis and mortality. Furthermore, AEC2s from patients with severe pulmonary fibrosis have reduced cell surface HA and impaired renewal capacity, suggesting that HA and TLR4 are key contributors to lung stem cell renewal and that severe pulmonary fibrosis is the result of distal epithelial stem cell failure.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "TLR4", + "or" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + } + ] + }, + { + "PMID": "27322743", + "TEXT": "Individuals who have mutations in the breast-cancer-susceptibility gene BRCA1 (hereafter referred to as BRCA1-mutation carriers) frequently undergo prophylactic mastectomy to minimize their risk of breast cancer. The identification of an effective prevention therapy therefore remains a 'holy grail' for the field. Precancerous BRCA1(mut/+) tissue harbors an aberrant population of luminal progenitor cells, and deregulated progesterone signaling has been implicated in BRCA1-associated oncogenesis. Coupled with the findings that tumor necrosis factor superfamily member 11 (TNFSF11; also known as RANKL) is a key paracrine effector of progesterone signaling and that RANKL and its receptor TNFRSF11A (also known as RANK) contribute to mammary tumorigenesis, we investigated a role for this pathway in the pre-neoplastic phase of BRCA1-mutation carriers. We identified two subsets of luminal progenitors (RANK(+) and RANK(-)) in histologically normal tissue of BRCA1-mutation carriers and showed that RANK(+) cells are highly proliferative, have grossly aberrant DNA repair and bear a molecular signature similar to that of basal-like breast cancer. These data suggest that RANK(+) and not RANK(-) progenitors are a key target population in these women. Inhibition of RANKL signaling by treatment with denosumab in three-dimensional breast organoids derived from pre-neoplastic BRCA1(mut/+) tissue attenuated progesterone-induced proliferation. Notably, proliferation was markedly reduced in breast biopsies from BRCA1-mutation carriers who were treated with denosumab. Furthermore, inhibition of RANKL in a Brca1-deficient mouse model substantially curtailed mammary tumorigenesis. Taken together, these findings identify a targetable pathway in a putative cell-of-origin population in BRCA1-mutation carriers and implicate RANKL blockade as a promising strategy in the prevention of breast cancer.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "RANKL" + ] + }, + "effect": { + "val": "negative", + "words": [ + "curtailed" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Brca1-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "curtailed" + ] + } + } + ] + }, + { + "PMID": "27213815", + "TEXT": "MYC oncoproteins are involved in the genesis and maintenance of the majority of human tumors but are considered undruggable. By using a direct in vivo shRNA screen, we show that liver cancer cells that have mutations in the gene encoding the tumor suppressor protein p53 (Trp53 in mice and TP53 in humans) and that are driven by the oncoprotein NRAS become addicted to MYC stabilization via a mechanism mediated by aurora kinase A (AURKA). This MYC stabilization enables the tumor cells to overcome a latent G2/M cell cycle arrest that is mediated by AURKA and the tumor suppressor protein p19(ARF). MYC directly binds to AURKA, and inhibition of this protein-protein interaction by conformation-changing AURKA inhibitors results in subsequent MYC degradation and cell death. These conformation-changing AURKA inhibitors, with one of them currently being tested in early clinical trials, suppressed tumor growth and prolonged survival in mice bearing Trp53-deficient, NRAS-driven MYC-expressing hepatocellular carcinomas (HCCs). TP53-mutated human HCCs revealed increased AURKA expression and a positive correlation between AURKA and MYC expression. In xenograft models, mice bearing TP53-mutated or TP53-deleted human HCCs were hypersensitive to treatment with conformation-changing AURKA inhibitors, thus suggesting a therapeutic strategy for this subgroup of human HCCs.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "conformation-changing", + "AURKA", + "inhibitors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "conformation-changing", + "AURKA", + "inhibitors", + "inhibitors," + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trp53-deficient," + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trp53-deficient," + ] + } + } + ] + }, + { + "PMID": "27019329", + "TEXT": "The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC). However, the determinants of AR overexpression in CRPC are poorly defined. Here we show that retinoic acid receptor-related orphan receptor γ (ROR-γ) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors. ROR-γ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an AR-ROR response element (RORE) to stimulate AR gene transcription. ROR-γ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-γ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR target gene network. Finally, ROR-γ antagonists suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPC tumors to enzalutamide, without overt toxicity, in mice. Taken together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ROR-γ", + "antagonists" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + } + ] + }, + { + "PMID": "26950360", + "TEXT": "Expression of the oncogenic transcription factor MYC is disproportionately elevated in triple-negative breast cancer (TNBC), as compared to estrogen receptor-, progesterone receptor- or human epidermal growth factor 2 receptor-positive (RP) breast cancer. We and others have shown that MYC alters metabolism during tumorigenesis. However, the role of MYC in TNBC metabolism remains mostly unexplored. We hypothesized that MYC-dependent metabolic dysregulation is essential for the growth of MYC-overexpressing TNBC cells and may identify new therapeutic targets for this clinically challenging subset of breast cancer. Using a targeted metabolomics approach, we identified fatty acid oxidation (FAO) intermediates as being dramatically upregulated in a MYC-driven model of TNBC. We also identified a lipid metabolism gene signature in patients with TNBC that were identified from The Cancer Genome Atlas database and from multiple other clinical data sets, implicating FAO as a dysregulated pathway that is critical for TNBC cell metabolism. We found that pharmacologic inhibition of FAO catastrophically decreased energy metabolism in MYC-overexpressing TNBC cells and blocked tumor growth in a MYC-driven transgenic TNBC model and in a MYC-overexpressing TNBC patient-derived xenograft. These findings demonstrate that MYC-overexpressing TNBC shows an increased bioenergetic reliance on FAO and identify the inhibition of FAO as a potential therapeutic strategy for this subset of breast cancer.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacologic", + "inhibition", + "of", + "FAO" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + } + ] + }, + { + "PMID": "26878232", + "TEXT": "Impaired erythropoiesis in the deletion 5q (del(5q)) subtype of myelodysplastic syndrome (MDS) has been linked to heterozygous deletion of RPS14, which encodes the ribosomal protein small subunit 14. We generated mice with conditional inactivation of Rps14 and demonstrated an erythroid differentiation defect that is dependent on the tumor suppressor protein p53 (encoded by Trp53 in mice) and is characterized by apoptosis at the transition from polychromatic to orthochromatic erythroblasts. This defect resulted in age-dependent progressive anemia, megakaryocyte dysplasia and loss of hematopoietic stem cell (HSC) quiescence. As assessed by quantitative proteomics, mutant erythroblasts expressed higher levels of proteins involved in innate immune signaling, notably the heterodimeric S100 calcium-binding proteins S100a8 and S100a9. S100a8--whose expression was increased in mutant erythroblasts, monocytes and macrophages--is functionally involved in the erythroid defect caused by the Rps14 deletion, as addition of recombinant S100a8 was sufficient to induce a differentiation defect in wild-type erythroid cells, and genetic inactivation of S100a8 expression rescued the erythroid differentiation defect of Rps14-haploinsufficient HSCs. Our data link Rps14 haploinsufficiency in del(5q) MDS to activation of the innate immune system and induction of S100A8-S100A9 expression, leading to a p53-dependent erythroid differentiation defect.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "conditional", + "inactivation", + "of", + "Rps14", + "genetic", + "S100a8", + "expression", + "Rps14-haploinsufficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss", + "defect" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Rps14" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inactivation", + "of", + "S100a8", + "expression", + "Rps14-haploinsufficient" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + } + ] + }, + { + "PMID": "26343801", + "TEXT": "Modest transcriptional changes caused by genetic or epigenetic mechanisms are frequent in human cancer. Although loss or near-complete loss of the hematopoietic transcription factor PU.1 induces acute myeloid leukemia (AML) in mice, a similar degree of PU.1 impairment is exceedingly rare in human AML; yet, moderate PU.1 inhibition is common in AML patients. We assessed functional consequences of modest reductions in PU.1 expression on leukemia development in mice harboring DNA lesions resembling those acquired during human stem cell aging. Heterozygous deletion of an enhancer of PU.1, which resulted in a 35% reduction of PU.1 expression, was sufficient to induce myeloid-biased preleukemic stem cells and their subsequent transformation to AML in a DNA mismatch repair-deficient background. AML progression was mediated by inhibition of expression of a PU.1-cooperating transcription factor, Irf8. Notably, we found marked molecular similarities between the disease in these mice and human myelodysplastic syndrome and AML. This study demonstrates that minimal reduction of a key lineage-specific transcription factor, which commonly occurs in human disease, is sufficient to initiate cancer development, and it provides mechanistic insight into the formation and progression of preleukemic stem cells in AML.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Heterozygous", + "deletion", + "of", + "an", + "enhancer", + "PU.1," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + } + ] + }, + { + "PMID": "25849135", + "TEXT": "A common key regulator of oncogenic signaling pathways in multiple tumor types is the unique isomerase Pin1. However, available Pin1 inhibitors lack the required specificity and potency for inhibiting Pin1 function in vivo. By using mechanism-based screening, here we find that all-trans retinoic acid (ATRA)--a therapy for acute promyelocytic leukemia (APL) that is considered the first example of targeted therapy in cancer, but whose drug target remains elusive--inhibits and degrades active Pin1 selectively in cancer cells by directly binding to the substrate phosphate- and proline-binding pockets in the Pin1 active site. ATRA-induced Pin1 ablation degrades the protein encoded by the fusion oncogene PML-RARA and treats APL in APL cell and animal models as well as in human patients. ATRA-induced Pin1 ablation also potently inhibits triple-negative breast cancer cell growth in human cells and in animal models by acting on many Pin1 substrate oncogenes and tumor suppressors. Thus, ATRA simultaneously blocks multiple Pin1-regulated cancer-driving pathways, an attractive property for treating aggressive and drug-resistant tumors.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ATRA-induced", + "Pin1", + "ablation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + } + ] + }, + { + "PMID": "25799227", + "TEXT": "Focal cortical dysplasia type II (FCDII) is a sporadic developmental malformation of the cerebral cortex characterized by dysmorphic neurons, dyslamination and medically refractory epilepsy. It has been hypothesized that FCD is caused by somatic mutations in affected regions. Here, we used deep whole-exome sequencing (read depth, 412-668×) validated by site-specific amplicon sequencing (100-347,499×) in paired brain-blood DNA from four subjects with FCDII and uncovered a de novo brain somatic mutation, mechanistic target of rapamycin (MTOR) c.7280T>C (p.Leu2427Pro) in two subjects. Deep sequencing of the MTOR gene in an additional 73 subjects with FCDII using hybrid capture and PCR amplicon sequencing identified eight different somatic missense mutations found in multiple brain tissue samples of ten subjects. The identified mutations accounted for 15.6% of all subjects with FCDII studied (12 of 77). The identified mutations induced the hyperactivation of mTOR kinase. Focal cortical expression of mutant MTOR by in utero electroporation in mice was sufficient to disrupt neuronal migration and cause spontaneous seizures and cytomegalic neurons. Inhibition of mTOR with rapamycin suppressed cytomegalic neurons and epileptic seizures. This study provides, to our knowledge, the first evidence that brain somatic activating mutations in MTOR cause FCD and identifies mTOR as a treatment target for intractable epilepsy in FCD.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Focal", + "cortical" + ] + }, + "effect": { + "val": "negative", + "words": [ + "disrupt" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "mutant", + "MTOR" + ] + }, + "effect": { + "val": "negative", + "words": [ + "disrupt" + ] + } + } + ] + }, + { + "PMID": "25730264", + "TEXT": "Detection of cyclic-di-adenosine monophosphate (c-di-AMP), a bacterial second messenger, by the host cytoplasmic surveillance pathway (CSP) is known to elicit type I interferon (IFN) responses, which are crucial to antimicrobial defense. However, the mechanisms and role of c-di-AMP signaling in Mycobacterium tuberculosis virulence remain unclear. Here we show that resistance to tuberculosis requires CSP-mediated detection of c-di-AMP produced by M. tuberculosis and that levels of c-di-AMP modulate the fate of infection. We found that a di-adenylate cyclase (disA or dacA)-overexpressing M. tuberculosis strain that secretes excess c-di-AMP activates the interferon regulatory factor (IRF) pathway with enhanced levels of IFN-β, elicits increased macrophage autophagy, and exhibits substantial virulence attenuation in mice. We show that c-di-AMP-mediated IFN-β induction during M. tuberculosis infection requires stimulator of interferon genes (STING)-signaling. We observed that c-di-AMP induction of IFN-β is independent of the cytosolic nucleic acid receptor cyclic GMP-AMP (cGAMP) synthase (cGAS), but cGAS nevertheless contributes substantially to the overall IFN-β response to M. tuberculosis infection. In sum, our results reveal c-di-AMP to be a key mycobacterial pathogen-associated molecular pattern (PAMP) driving host type I IFN responses and autophagy. These findings suggest that modulating the levels of this small molecule may lead to novel immunotherapeutic strategies against tuberculosis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "di-adenylate", + "(disA", + "or", + "dacA)-overexpressing" + ] + }, + "effect": { + "val": "positive", + "words": [ + "elicits", + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "tuberculosis", + "strain" + ] + }, + "effect": { + "val": "positive", + "words": [ + "elicits", + "increased" + ] + } + } + ] + }, + { + "PMID": "25419705", + "TEXT": "Renal fibrosis is the histological manifestation of a progressive, usually irreversible process causing chronic and end-stage kidney disease. We performed genome-wide transcriptome studies of a large cohort (n = 95) of normal and fibrotic human kidney tubule samples followed by systems and network analyses and identified inflammation and metabolism as the top dysregulated pathways in the diseased kidneys. In particular, we found that humans and mouse models with tubulointerstitial fibrosis had lower expression of key enzymes and regulators of fatty acid oxidation (FAO) and higher intracellular lipid deposition compared to controls. In vitro experiments indicated that inhibition of FAO in tubule epithelial cells caused ATP depletion, cell death, dedifferentiation and intracellular lipid deposition, phenotypes observed in fibrosis. In contrast, restoring fatty acid metabolism by genetic or pharmacological methods protected mice from tubulointerstitial fibrosis. Our results raise the possibility that correcting the metabolic defect in FAO may be useful for preventing and treating chronic kidney disease.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "FAO" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + } + ] + }, + { + "PMID": "25194572", + "TEXT": "The progressive loss of muscle regenerative capacity with age or disease results in part from a decline in the number and function of satellite cells, the direct cellular contributors to muscle repair. However, little is known about the molecular effectors underlying satellite cell impairment and depletion. Elevated levels of inflammatory cytokines, including interleukin-6 (IL-6), are associated with both age-related and muscle-wasting conditions. The levels of STAT3, a downstream effector of IL-6, are also elevated with muscle wasting, and STAT3 has been implicated in the regulation of self-renewal and stem cell fate in several tissues. Here we show that IL-6-activated Stat3 signaling regulates satellite cell behavior, promoting myogenic lineage progression through myogenic differentiation 1 (Myod1) regulation. Conditional ablation of Stat3 in Pax7-expressing satellite cells resulted in their increased expansion during regeneration, but compromised myogenic differentiation prevented the contribution of these cells to regenerating myofibers. In contrast, transient Stat3 inhibition promoted satellite cell expansion and enhanced tissue repair in both aged and dystrophic muscle. The effects of STAT3 inhibition on cell fate and proliferation were conserved in human myoblasts. The results of this study indicate that pharmacological manipulation of STAT3 activity can be used to counteract the functional exhaustion of satellite cells in pathological conditions, thereby maintaining the endogenous regenerative response and ameliorating muscle-wasting diseases.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "ablation", + "of", + "Stat3" + ] + }, + "effect": { + "val": "negative", + "words": [ + "compromised" + ] + } + } + ] + }, + { + "PMID": "24997609", + "TEXT": "Individuals with neurofibromatosis type-1 (NF1) can manifest focal skeletal dysplasias that remain extremely difficult to treat. NF1 is caused by mutations in the NF1 gene, which encodes the RAS GTPase-activating protein neurofibromin. We report here that ablation of Nf1 in bone-forming cells leads to supraphysiologic accumulation of pyrophosphate (PPi), a strong inhibitor of hydroxyapatite formation, and that a chronic extracellular signal-regulated kinase (ERK)-dependent increase in expression of genes promoting PPi synthesis and extracellular transport, namely Enpp1 and Ank, causes this phenotype. Nf1 ablation also prevents bone morphogenic protein-2-induced osteoprogenitor differentiation and, consequently, expression of alkaline phosphatase and PPi breakdown, further contributing to PPi accumulation. The short stature and impaired bone mineralization and strength in mice lacking Nf1 in osteochondroprogenitors or osteoblasts can be corrected by asfotase-α enzyme therapy aimed at reducing PPi concentration. These results establish neurofibromin as an essential regulator of bone mineralization. They also suggest that altered PPi homeostasis contributes to the skeletal dysplasias associated with NF1 and that some of the NF1 skeletal conditions could be prevented pharmacologically.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nf1", + "ablation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nf1", + "ablation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "protein-2-induced" + ] + } + } + ] + }, + { + "PMID": "24880616", + "TEXT": "Despite the fact that genitourinary defects are among the most common birth defects in newborns, little is known about their etiology. Here we analyzed children born with congenital genitourinary tract masculinization disorders by array-comparative genomic hybridization, which revealed in 1.35% of cases the presence of de novo copy number gains at Xq28 encompassing the VAMP7 gene, which encodes a vesicle-trafficking protein that is part of the SNARE complex. Transgenic mice carrying a bacterial artificial chromosome encoding human VAMP7 mimicked the defective urogenital traits observed in boys with masculinization disorders such as cryptorchidism, urethral defects and hypospadias. Transgenic mice also exhibited reduced penile length, focal spermatogenic anomalies, diminished sperm motility and subfertility. VAMP7 colocalized with estrogen receptor α (ESR1) in the presence of its cognate ligand, 17β-estradiol. Elevated levels of VAMP7 markedly intensified ESR1-potentiated transcriptional activity by increasing ESR1 protein cellular content upon ligand stimulation and upregulated the expression of estrogen-responsive genes including ATF3, CYR61 and CTGF, all of which have been implicated in human hypospadias. Hence, increased gene dosage of VAMP7, and thus higher expression levels of its protein product, enhances estrogen receptor action in male genitourinary tissues, affects the virilization of the reproductive tract and results in genitourinary birth defects in humans.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "carrying", + "a", + "bacterial", + "artificial", + "chromosome", + "encoding", + "human", + "VAMP7", + "Transgenic" + ] + }, + "effect": { + "val": "negative", + "words": [ + "diminished" + ] + } + } + ] + }, + { + "PMID": "23817023", + "TEXT": "Successful pregnancy requires coordination of an array of signals and factors from multiple tissues. One such element, liver receptor homolog-1 (Lrh-1), is an orphan nuclear receptor that regulates metabolism and hormone synthesis. It is strongly expressed in granulosa cells of ovarian follicles and in the corpus luteum of rodents and humans. Germline ablation of Nr5a2 (also called Lrh-1), the gene coding for Lrh-1, in mice is embryonically lethal at gastrulation. Depletion of Lrh-1 in the ovarian follicle shows that it regulates genes required for both steroid synthesis and ovulation. To study the effects of Lrh-1 on mouse gestation, we genetically disrupted its expression in the corpus luteum, resulting in luteal insufficiency. Hormone replacement permitted embryo implantation but was followed by gestational failure with impaired endometrial decidualization, compromised placental formation, fetal growth retardation and fetal death. Lrh-1 is also expressed in the mouse and human endometrium, and in a primary culture of human endometrial stromal cells, reduction of NR5A2 transcript abundance by RNA interference abrogated decidualization. These findings show that Lrh-1 is necessary for maintenance of the corpus luteum, for promotion of decidualization and for formation of the placenta. It therefore has multiple, indispensible roles in establishing and sustaining pregnancy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "called" + ] + }, + "effect": { + "val": "positive", + "words": [ + "permitted" + ] + } + } + ] + }, + { + "PMID": "23770692", + "TEXT": "Major depression is a highly prevalent severe mood disorder that is treated with antidepressants. The molecular targets of antidepressants require definition. We investigated the role of the acid sphingomyelinase (Asm)-ceramide system as a target for antidepressants. Therapeutic concentrations of the antidepressants amitriptyline and fluoxetine reduced Asm activity and ceramide concentrations in the hippocampus, increased neuronal proliferation, maturation and survival and improved behavior in mouse models of stress-induced depression. Genetic Asm deficiency abrogated these effects. Mice overexpressing Asm, heterozygous for acid ceramidase, treated with blockers of ceramide metabolism or directly injected with C16 ceramide in the hippocampus had higher ceramide concentrations and lower rates of neuronal proliferation, maturation and survival compared with controls and showed depression-like behavior even in the absence of stress. The decrease of ceramide abundance achieved by antidepressant-mediated inhibition of Asm normalized these effects. Lowering ceramide abundance may thus be a central goal for the future development of antidepressants.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Genetic" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "Asm," + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + } + ] + }, + { + "PMID": "23435171", + "TEXT": "Previous attempts to identify neuroprotective targets by studying the ischemic cascade and devising ways to suppress it have failed to translate to efficacious therapies for acute ischemic stroke. We hypothesized that studying the molecular determinants of endogenous neuroprotection in two well-established paradigms, the resistance of CA3 hippocampal neurons to global ischemia and the tolerance conferred by ischemic preconditioning (IPC), would reveal new neuroprotective targets. We found that the product of the tuberous sclerosis complex 1 gene (TSC1), hamartin, is selectively induced by ischemia in hippocampal CA3 neurons. In CA1 neurons, hamartin was unaffected by ischemia but was upregulated by IPC preceding ischemia, which protects the otherwise vulnerable CA1 cells. Suppression of hamartin expression with TSC1 shRNA viral vectors both in vitro and in vivo increased the vulnerability of neurons to cell death following oxygen glucose deprivation (OGD) and ischemia. In vivo, suppression of TSC1 expression increased locomotor activity and decreased habituation in a hippocampal-dependent task. Overexpression of hamartin increased resistance to OGD by inducing productive autophagy through an mTORC1-dependent mechanism.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Suppression", + "of", + "hamartin", + "expression", + "with", + "TSC1", + "shRNA", + "viral", + "vectors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "hamartin" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inducing" + ] + } + } + ] + }, + { + "PMID": "23086476", + "TEXT": "The microenvironment, or niche, surrounding a stem cell largely governs its cellular fate. Two anatomical niches for hematopoietic stem cells (HSCs) have been reported in the bone marrow, but a distinct function for each of these niches remains unclear. Here we report a new role for the adhesion molecule E-selectin expressed exclusively by bone marrow endothelial cells in the vascular HSC niche. HSC quiescence was enhanced and self-renewal potential was increased in E-selectin knockout (Sele(-/-)) mice or after administration of an E-selectin antagonist, demonstrating that E-selectin promotes HSC proliferation and is a crucial component of the vascular niche. These effects are not mediated by canonical E-selectin ligands. Deletion or blockade of E-selectin enhances HSC survival threefold to sixfold after treatment of mice with chemotherapeutic agents or irradiation and accelerates blood neutrophil recovery. As bone marrow suppression is a severe side effect of high-dose chemotherapy, transient blockade of E-selectin is potentially a promising treatment for the protection of HSCs during chemotherapy or irradiation.", + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "increased", + "promotes" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "E-selectin", + "knockout", + "(Sele(-/-))" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "E-selectin", + "antagonist," + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + } + ] + }, + { + "PMID": "23023500", + "TEXT": "The ability of the human immune system to respond to vaccination declines with age. We identified an age-associated defect in T cell receptor (TCR)-induced extracellular signal-regulated kinase (ERK) phosphorylation in naive CD4(+) T cells, whereas other signals, such as ζ chain-associated protein kinase 70 (ZAP70) and phospholipase C-γ1 phosphorylation, were not impaired. The defective ERK signaling was caused by the dual specific phosphatase 6 (DUSP6), whose protein expression increased with age due to a decline in repression by miR-181a. Reconstitution of miR-181a lowered DUSP6 expression in naive CD4(+) T cells in elderly individuals. DUSP6 repression using miR-181a or specific siRNA and DUSP6 inhibition by the allosteric inhibitor (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one improved CD4(+) T cell responses, as seen by increased expression of activation markers, improved proliferation and supported preferential T helper type 1 cell differentiation. DUSP6 is a potential intervention target for restoring T cell responses in the elderly, which may augment the effectiveness of vaccination.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "DUSP6", + "repression", + "using", + "miR-181a", + "specific", + "siRNA" + ] + }, + "effect": { + "val": "positive", + "words": [ + "improved", + "supported" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "DUSP6", + "inhibition", + "by", + "the", + "allosteric", + "inhibitor", + "(E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one" + ] + }, + "effect": { + "val": "positive", + "words": [ + "improved", + "supported" + ] + } + } + ] + }, + { + "PMID": "22344298", + "TEXT": "In advanced cancer, including glioblastoma, the transforming growth factor β (TGF-β) pathway acts as an oncogenic factor and is considered to be a therapeutic target. Using a functional RNAi screen, we identified the deubiquitinating enzyme ubiquitin-specific peptidase 15 (USP15) as a key component of the TGF-β signaling pathway. USP15 binds to the SMAD7-SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) complex and deubiquitinates and stabilizes type I TGF-β receptor (TβR-I), leading to an enhanced TGF-β signal. High expression of USP15 correlates with high TGF-β activity, and the USP15 gene is found amplified in glioblastoma, breast and ovarian cancer. USP15 amplification confers poor prognosis in individuals with glioblastoma. Downregulation or inhibition of USP15 in a patient-derived orthotopic mouse model of glioblastoma decreases TGF-β activity. Moreover, depletion of USP15 decreases the oncogenic capacity of patient-derived glioma-initiating cells due to the repression of TGF-β signaling. Our results show that USP15 regulates the TGF-β pathway and is a key factor in glioblastoma pathogenesis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "USP15" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreases" + ] + } + } + ] + }, + { + "PMID": "22101765", + "TEXT": "Although there is evidence that redox regulation has an essential role in malignancies, its impact on tumor prognosis remains unclear. Here we show crosstalk between oxidative stress and the miR-200 family of microRNAs that affects tumorigenesis and chemosensitivity. miR-141 and miR-200a target p38α and modulate the oxidative stress response. Enhanced expression of these microRNAs mimics p38α deficiency and increases tumor growth in mouse models, but it also improves the response to chemotherapeutic agents. High-grade human ovarian adenocarcinomas that accumulate miR-200a have low concentrations of p38α and an associated oxidative stress signature. The miR200a-dependent stress signature correlates with improved survival of patients in response to treatment. Therefore, the role of miR-200a in stress could be a predictive marker for clinical outcome in ovarian cancer. In addition, although oxidative stress promotes tumor growth, it also sensitizes tumors to treatment, which could account for the limited success of antioxidants in clinical trials.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enhanced", + "expression", + "of", + "these", + "microRNAs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increases" + ] + } + } + ] + }, + { + "PMID": "22081024", + "TEXT": "RAF kinases regulate cell proliferation and survival and can be dysregulated in tumors. The role of RAF in cell proliferation has been linked to its ability to activate mitogen-activated protein kinase kinase 1 (MEK) and mitogen-activated protein kinase 1 (ERK). Here we identify a MEK-independent role for RAF in tumor growth. Specifically, in mitotic cells, CRAF becomes phosphorylated on Ser338 and localizes to the mitotic spindle of proliferating tumor cells in vitro as well as in murine tumor models and in biopsies from individuals with cancer. Treatment of tumors with allosteric inhibitors, but not ATP-competitive RAF inhibitors, prevents CRAF phosphorylation on Ser338 and localization to the mitotic spindle and causes cell-cycle arrest at prometaphase. Furthermore, we identify phospho-Ser338 CRAF as a potential biomarker for tumor progression and a surrogate marker for allosteric RAF blockade. Mechanistically, CRAF, but not BRAF, associates with Aurora kinase A (Aurora-A) and Polo-like kinase 1 (Plk1) at the centrosomes and spindle poles during G2/M. Indeed, allosteric or genetic inhibition of phospho-Ser338 CRAF impairs Plk1 activation and accumulation at the kinetochores, causing prometaphase arrest, whereas a phospho-mimetic Ser338D CRAF mutant potentiates Plk1 activation, mitosis and tumor progression in mice. These findings show a previously undefined role for RAF in tumor progression beyond the RAF-MEK-ERK paradigm, opening new avenues for targeting RAF in cancer.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "inhibition", + "of", + "phospho-Ser338", + "CRAF" + ] + }, + "effect": { + "val": "positive", + "words": [ + "causing" + ] + } + } + ] + }, + { + "PMID": "22037646", + "TEXT": "Intra-abdominal tumors, such as ovarian cancer, have a clear predilection for metastasis to the omentum, an organ primarily composed of adipocytes. Currently, it is unclear why tumor cells preferentially home to and proliferate in the omentum, yet omental metastases typically represent the largest tumor in the abdominal cavities of women with ovarian cancer. We show here that primary human omental adipocytes promote homing, migration and invasion of ovarian cancer cells, and that adipokines including interleukin-8 (IL-8) mediate these activities. Adipocyte-ovarian cancer cell coculture led to the direct transfer of lipids from adipocytes to ovarian cancer cells and promoted in vitro and in vivo tumor growth. Furthermore, coculture induced lipolysis in adipocytes and β-oxidation in cancer cells, suggesting adipocytes act as an energy source for the cancer cells. A protein array identified upregulation of fatty acid-binding protein 4 (FABP4, also known as aP2) in omental metastases as compared to primary ovarian tumors, and FABP4 expression was detected in ovarian cancer cells at the adipocyte-tumor cell interface. FABP4 deficiency substantially impaired metastatic tumor growth in mice, indicating that FABP4 has a key role in ovarian cancer metastasis. These data indicate adipocytes provide fatty acids for rapid tumor growth, identifying lipid metabolism and transport as new targets for the treatment of cancers where adipocytes are a major component of the microenvironment.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FABP4", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + } + ] + }, + { + "PMID": "22019886", + "TEXT": "Anemia because of insufficient production of and/or response to erythropoietin (Epo) is a major complication of chronic kidney disease and cancer. The mechanisms modulating the sensitivity of erythroblasts to Epo remain poorly understood. We show that, when cultured with Epo at suboptimal concentrations, the growth and clonogenic potential of erythroblasts was rescued by transferrin receptor 1 (TfR1)-bound polymeric IgA1 (pIgA1). Under homeostatic conditions, erythroblast numbers were increased in mice expressing human IgA1 compared to control mice. Hypoxic stress of these mice led to increased amounts of pIgA1 and erythroblast expansion. Expression of human IgA1 or treatment of wild-type mice with the TfR1 ligands pIgA1 or iron-loaded transferrin (Fe-Tf) accelerated recovery from acute anemia. TfR1 engagement by either pIgA1 or Fe-Tf increased cell sensitivity to Epo by inducing activation of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways. These cellular responses were mediated through the TfR1-internalization motif, YXXΦ. Our results show that pIgA1 and TfR1 are positive regulators of erythropoiesis in both physiological and pathological situations. Targeting this pathway may provide alternate approaches to the treatment of ineffective erythropoiesis and anemia.", + "LINKED_TAGS": [ + { + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "human", + "IgA1" + ] + } + } + ] + }, + { + "PMID": "21822286", + "TEXT": "Although the role of miR-200s in regulating E-cadherin expression and epithelial-to-mesenchymal transition is well established, their influence on metastatic colonization remains controversial. Here we have used clinical and experimental models of breast cancer metastasis to discover a pro-metastatic role of miR-200s that goes beyond their regulation of E-cadherin and epithelial phenotype. Overexpression of miR-200s is associated with increased risk of metastasis in breast cancer and promotes metastatic colonization in mouse models, phenotypes that cannot be recapitulated by E-cadherin expression alone. Genomic and proteomic analyses revealed global shifts in gene expression upon miR-200 overexpression toward that of highly metastatic cells. miR-200s promote metastatic colonization partly through direct targeting of Sec23a, which mediates secretion of metastasis-suppressive proteins, including Igfbp4 and Tinagl1, as validated by functional and clinical correlation studies. Overall, these findings suggest a pleiotropic role of miR-200s in promoting metastatic colonization by influencing E-cadherin-dependent epithelial traits and Sec23a-mediated tumor cell secretome.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "miR-200s" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + } + ] + }, + { + "PMID": "21706030", + "TEXT": "Cells that are deficient in homologous recombination, such as those that lack functional breast cancer-associated 1 (BRCA1) or BRCA2, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, BRCA-deficient tumors represent only a small fraction of adult cancers, which might restrict the therapeutic utility of PARP inhibitor monotherapy. Cyclin-dependent kinase 1 (Cdk1) phosphorylates BRCA1, and this is essential for efficient formation of BRCA1 foci. Here we show that depletion or inhibition of Cdk1 compromises the ability of cells to repair DNA by homologous recombination. Combined inhibition of Cdk1 and PARP in BRCA-wild-type cancer cells resulted in reduced colony formation, delayed growth of human tumor xenografts and tumor regression with prolonged survival in a mouse model of lung adenocarcinoma. Inhibition of Cdk1 did not sensitize nontransformed cells or tissues to inhibition of PARP. Because reduced Cdk1 activity impaired BRCA1 function and consequently, repair by homologous recombination, inhibition of Cdk1 represents a plausible strategy for expanding the utility of PARP inhibitors to BRCA-proficient cancers.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "Combined", + "Cdk1", + "and", + "PARP" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + } + ] + }, + { + "PMID": "21240262", + "TEXT": "Cancer stem cells (CSCs), or tumor-initiating cells, are involved in tumor progression and metastasis. MicroRNAs (miRNAs) regulate both normal stem cells and CSCs, and dysregulation of miRNAs has been implicated in tumorigenesis. CSCs in many tumors--including cancers of the breast, pancreas, head and neck, colon, small intestine, liver, stomach, bladder and ovary--have been identified using the adhesion molecule CD44, either individually or in combination with other marker(s). Prostate CSCs with enhanced clonogenic and tumor-initiating and metastatic capacities are enriched in the CD44(+) cell population, but whether miRNAs regulate CD44(+) prostate cancer cells and prostate cancer metastasis remains unclear. Here we show, through expression analysis, that miR-34a, a p53 target, was underexpressed in CD44(+) prostate cancer cells purified from xenograft and primary tumors. Enforced expression of miR-34a in bulk or purified CD44(+) prostate cancer cells inhibited clonogenic expansion, tumor regeneration, and metastasis. In contrast, expression of miR-34a antagomirs in CD44(-) prostate cancer cells promoted tumor development and metastasis. Systemically delivered miR-34a inhibited prostate cancer metastasis and extended survival of tumor-bearing mice. We identified and validated CD44 as a direct and functional target of miR-34a and found that CD44 knockdown phenocopied miR-34a overexpression in inhibiting prostate cancer regeneration and metastasis. Our study shows that miR-34a is a key negative regulator of CD44(+) prostate cancer cells and establishes a strong rationale for developing miR-34a as a novel therapeutic agent against prostate CSCs.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced", + "expression", + "of", + "miR-34a", + "Systemically", + "delivered", + "overexpression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "inhibiting" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Enforced" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression", + "of", + "miR-34a", + "antagomirs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "CD44", + "knockdown" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibiting" + ] + } + } + ] + }, + { + "PMID": "21186369", + "TEXT": "The adipocyte-derived secretory factor adiponectin promotes insulin sensitivity, decreases inflammation and promotes cell survival. No unifying mechanism has yet explained how adiponectin can exert such a variety of beneficial systemic effects. Here, we show that adiponectin potently stimulates a ceramidase activity associated with its two receptors, AdipoR1 and AdipoR2, and enhances ceramide catabolism and formation of its antiapoptotic metabolite--sphingosine-1-phosphate (S1P)--independently of AMP-dependent kinase (AMPK). Using models of inducible apoptosis in pancreatic beta cells and cardiomyocytes, we show that transgenic overproduction of adiponectin decreases caspase-8-mediated death, whereas genetic ablation of adiponectin enhances apoptosis in vivo through a sphingolipid-mediated pathway. Ceramidase activity is impaired in cells lacking both adiponectin receptor isoforms, leading to elevated ceramide levels and enhanced susceptibility to palmitate-induced cell death. Combined, our observations suggest a unifying mechanism of action for the beneficial systemic effects exerted by adiponectin, with sphingolipid metabolism as its core upstream signaling component.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation", + "of", + "adiponectin", + "lacking", + "both", + "receptor", + "isoforms," + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances", + "enhanced", + "susceptibility", + "palmitate-induced" + ] + } + } + ] + }, + { + "PMID": "21102460", + "TEXT": "Mesenchymal stem cells can give rise to several cell types, but varying results depending on isolation methods and tissue source have led to controversies about their usefulness in clinical medicine. Here we show that vascular endothelial cells can transform into multipotent stem-like cells by an activin-like kinase-2 (ALK2) receptor-dependent mechanism. In lesions from individuals with fibrodysplasia ossificans progressiva (FOP), a disease in which heterotopic ossification occurs as a result of activating ALK2 mutations, or from transgenic mice expressing constitutively active ALK2, chondrocytes and osteoblasts expressed endothelial markers. Lineage tracing of heterotopic ossification in mice using a Tie2-Cre construct also suggested an endothelial origin of these cell types. Expression of constitutively active ALK2 in endothelial cells caused endothelial-to-mesenchymal transition and acquisition of a stem cell-like phenotype. Similar results were obtained by treatment of untransfected endothelial cells with the ligands transforming growth factor-β2 (TGF-β2) or bone morphogenetic protein-4 (BMP4) in an ALK2-dependent manner. These stem-like cells could be triggered to differentiate into osteoblasts, chondrocytes or adipocytes. We suggest that conversion of endothelial cells to stem-like cells may provide a new approach to tissue engineering.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "constitutively", + "active", + "Expression", + "of", + "ALK2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused" + ] + } + } + ] + }, + { + "PMID": "20871609", + "TEXT": "Inactivation of the p53 tumor suppressor pathway allows cell survival in times of stress and occurs in many human cancers; however, normal embryonic stem cells and some cancers such as neuroblastoma maintain wild-type human TP53 and mouse Trp53 (referred to collectively as p53 herein). Here we describe a miRNA, miR-380-5p, that represses p53 expression via a conserved sequence in the p53 3' untranslated region (UTR). miR-380-5p is highly expressed in mouse embryonic stem cells and neuroblastomas, and high expression correlates with poor outcome in neuroblastomas with neuroblastoma derived v-myc myelocytomatosis viral-related oncogene (MYCN) amplification. miR-380 overexpression cooperates with activated HRAS oncoprotein to transform primary cells, block oncogene-induced senescence and form tumors in mice. Conversely, inhibition of endogenous miR-380-5p in embryonic stem or neuroblastoma cells results in induction of p53, and extensive apoptotic cell death. In vivo delivery of a miR-380-5p antagonist decreases tumor size in an orthotopic mouse model of neuroblastoma. We demonstrate a new mechanism of p53 regulation in cancer and stem cells and uncover a potential therapeutic target for neuroblastoma.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "miR-380", + "overexpression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "block" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "miR-380", + "overexpression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "oncogene-induced" + ] + } + } + ] + }, + { + "PMID": "20613753", + "TEXT": "A popular—and controversial—theory is that tumors are initiated and maintained by a fixed population of stem cell–like tumor cells. Research on human cells and mice adds a twist to this theory, suggesting that such stem cell–like cells might be more plastic than previously thought. Alexander Roesch et al. find that a group of cells, which divide slowly, can sustain melanoma growth and self-renew—hallmarks of cancer stem cells. However, the cells can switch phenotype through epigenetic changes mediated by JARID1B, a histone modifier, suggesting a plastic process. They found that human cells expressing JAR1D1B could initiate and sustain melanoma growth when implanted into mice, whereas JARD1B-negative cells could only initiate tumors. JARD1B-negative cells, however, could switch on JARD1B to support tumor growth. Might cancer stem cells be ‘moving’ targets? What, then, are the therapeutic implications?", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "JAR1D1B" + ] + }, + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "JARD1B-negative" + ] + }, + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + } + } + ] + }, + { + "PMID": "20601951", + "TEXT": "Candida albicans is a major fungal pathogen that causes serious systemic and mucosal infections in immunocompromised individuals. In yeast, histone H3 Lys56 acetylation (H3K56ac) is an abundant modification regulated by enzymes that have fungal-specific properties, making them appealing targets for antifungal therapy. Here we demonstrate that H3K56ac in C. albicans is regulated by the RTT109 and HST3 genes, which respectively encode the H3K56 acetyltransferase (Rtt109p) and deacetylase (Hst3p). We show that reduced levels of H3K56ac sensitize C. albicans to genotoxic and antifungal agents. Inhibition of Hst3p activity by conditional gene repression or nicotinamide treatment results in a loss of cell viability associated with abnormal filamentous growth, histone degradation and gross aberrations in DNA staining. We show that genetic or pharmacological alterations in H3K56ac levels reduce virulence in a mouse model of C. albicans infection. Our results demonstrate that modulation of H3K56ac is a unique strategy for treatment of C. albicans and, possibly, other fungal infections.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "of", + "Hst3p", + "activity", + "by", + "conditional", + "gene", + "repression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + } + ] + }, + { + "PMID": "20512127", + "TEXT": "In systemic lupus erythematosus (SLE), self-reactive antibodies can target the kidney (lupus nephritis), leading to functional failure and possible mortality. We report that activation of basophils by autoreactive IgE causes their homing to lymph nodes, promoting T helper type 2 (T(H)2) cell differentiation and enhancing the production of self-reactive antibodies that cause lupus-like nephritis in mice lacking the Src family protein tyrosine kinase Lyn (Lyn(-/-) mice). Individuals with SLE also have elevated serum IgE, self-reactive IgEs and activated basophils that express CD62 ligand (CD62L) and the major histocompatibility complex (MHC) class II molecule human leukocyte antigen-DR (HLA-DR), parameters that are associated with increased disease activity and active lupus nephritis. Basophils were also present in the lymph nodes and spleen of subjects with SLE. Thus, in Lyn(-/-) mice, basophils and IgE autoantibodies amplify autoantibody production that leads to lupus nephritis, and in individuals with SLE IgE autoantibodies and activated basophils are factors associated with disease activity and nephritis.", + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "mice)." + ] + } + } + ] + }, + { + "PMID": "20305661", + "TEXT": "The peptidoglycan layer is a vital component of the bacterial cell wall. The existing paradigm describes the peptidoglycan network as a static structure that is cross-linked predominantly by 4-->3 transpeptide linkages. However, the nonclassical 3-->3 linkages predominate the transpeptide networking of the peptidoglycan layer of nonreplicating Mycobacterium tuberculosis. The molecular basis of these linkages and their role in the physiology of the peptidoglycan layer, virulence and susceptibility of M. tuberculosis to drugs remain undefined. Here we identify MT2594 as an L,D-transpeptidase that generates 3-->3 linkages in M. tuberculosis. We show that the loss of this protein leads to altered colony morphology, loss of virulence and increased susceptibility to amoxicillin-clavulanate during the chronic phase of infection. This suggests that 3-->3 cross-linking is vital to the physiology of the peptidoglycan layer. Although a functional homolog exists, expression of ldtMt2 is dominant throughout the growth phases of M. tuberculosis. 4-->3 transpeptide linkages are targeted by one of the most widely used classes of antibacterial drugs in human clinical use today, beta-lactams. Recently, meropenem-clavulanate was shown to be effective against drug-resistant M. tuberculosis. Our study suggests that a combination of L,D-transpeptidase and beta-lactamase inhibitors could effectively target persisting bacilli during the chronic phase of tuberculosis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "this", + "protein" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + } + ] + }, + { + "PMID": "20154697", + "TEXT": "Metastasis is responsible for the majority of prostate cancer-related deaths; however, little is known about the molecular mechanisms that underlie this process. Here we identify an oncogene-tumor suppressor cascade that promotes prostate cancer growth and metastasis by coordinately activating the small GTPase Ras and nuclear factor-kappaB (NF-kappaB). Specifically, we show that loss of the Ras GTPase-activating protein (RasGAP) gene DAB2IP induces metastatic prostate cancer in an orthotopic mouse tumor model. Notably, DAB2IP functions as a signaling scaffold that coordinately regulates Ras and NF-kappaB through distinct domains to promote tumor growth and metastasis, respectively. DAB2IP is suppressed in human prostate cancer, where its expression inversely correlates with tumor grade and predicts prognosis. Moreover, we report that epigenetic silencing of DAB2IP is a key mechanism by which the polycomb-group protein histone-lysine N-methyltransferase EZH2 activates Ras and NF-kappaB and triggers metastasis. These studies define the mechanism by which two major pathways can be simultaneously activated in metastatic prostate cancer and establish EZH2 as a driver of metastasis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Ras", + "GTPase-activating", + "protein", + "(RasGAP)", + "gene", + "DAB2IP" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces", + "promote" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "silencing", + "of", + "DAB2IP" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggers" + ] + } + } + ] + }, + { + "PMID": "19966811", + "TEXT": "Hepatocyte nuclear factor-1beta (HNF-1beta) is a transcription factor required for the expression of several renal cystic genes and whose prenatal deletion leads to polycystic kidney disease (PKD). We show here that inactivation of Hnf1b from postnatal day 10 onward does not elicit cystic dilations in tubules after their proliferative morphogenetic elongation is over. Cystogenic resistance is intrinsically linked to the quiescent state of cells. In fact, when Hnf1b deficient quiescent cells are forced to proliferate by an ischemia-reperfusion injury, they give rise to cysts, owing to loss of oriented cell division. Remarkably, in quiescent cells, the transcription of crucial cystogenic target genes is maintained even in the absence of HNF-1beta. However, their expression is lost as soon as cells proliferate and the chromatin of target genes acquires heterochromatin marks. These results unveil a previously undescribed aspect of gene regulation. It is well established that transcription is shut off during the mitotic condensation of chromatin. We propose that transcription factors such as HNF-1beta might be involved in reprogramming gene expression after transcriptional silencing is induced by mitotic chromatin condensation. Notably, HNF-1beta remains associated with the mitotically condensed chromosomal barrels. This association suggests that HNF-1beta is a bookmarking factor that is necessary for reopening the chromatin of target genes after mitotic silencing.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "Hnf1b", + "deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "forced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "Hnf1b", + "deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + } + ] + }, + { + "PMID": "19734909", + "TEXT": "Lissencephaly is a devastating neurological disorder caused by defective neuronal migration. LIS1 (official symbol PAFAH1B1, for platelet-activating factor acetylhydrolase, isoform 1b, subunit 1) was identified as the gene mutated in individuals with lissencephaly, and it was found to regulate cytoplasmic dynein function and localization. Here we show that inhibition or knockdown of calpains protects LIS1 from proteolysis, resulting in the augmentation of LIS1 amounts in Lis1(+/-) mouse embryonic fibroblast cells and rescue of the aberrant distribution of cytoplasmic dynein, mitochondria and beta-COP-positive vesicles. We also show that calpain inhibitors improve neuronal migration of Lis1(+/-) cerebellar granular neurons. Intraperitoneal injection of the calpain inhibitor ALLN to pregnant Lis1(+/-) dams rescued apoptotic neuronal cell death and neuronal migration defects in Lis1(+/-) offspring. Furthermore, in utero knockdown of calpain by short hairpin RNA rescued defective cortical layering in Lis1(+/-) mice. Thus, calpain inhibition is a potential therapeutic intervention for lissencephaly.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "calpains" + ] + }, + "effect": { + "val": "positive", + "words": [ + "improve" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "calpain", + "inhibitors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "improve" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "calpain", + "inhibitors", + "inhibitor", + "ALLN" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "improve" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lis1(+/-)" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Lis1(+/-)" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + } + ] + }, + { + "PMID": "19701205", + "TEXT": "Primary cilia are present on most mammalian cells and are implicated in transducing Hedgehog (Hh) signals during development; however, the prevalence of cilia on human tumors remains unclear, and the role of cilia in cancer has not been examined. Here we show that human basal cell carcinomas (BCCs) are frequently ciliated, and we test the role of cilia in BCC by conditionally deleting Kif3a (encoding kinesin family member 3A) or Ift88 (encoding intraflagellar transport protein 88), genes required for ciliogenesis, in two Hh pathway-dependent mouse tumor models. Ciliary ablation strongly inhibited BCC-like tumors induced by an activated form of Smoothened. In contrast, removal of cilia accelerated tumors induced by activated Gli2, a transcriptional effector of Hh signaling. These seemingly paradoxical effects are consistent with a dual role for cilia in mediating both the activation and the repression of the Hh signaling pathway. Our findings demonstrate that cilia function as unique signaling organelles that can either mediate or suppress tumorigenesis depending on the nature of the oncogenic initiating event.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ciliary", + "ablation" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + } + ] + }, + { + "PMID": "19525962", + "TEXT": "Self-renewing cell populations such as hematopoietic stem cells and memory B and T lymphocytes might be regulated by shared signaling pathways. The Wnt-beta-catenin pathway is an evolutionarily conserved pathway that promotes hematopoietic stem cell self-renewal and multipotency by limiting stem cell proliferation and differentiation, but its role in the generation and maintenance of memory T cells is unknown. We found that induction of Wnt-beta-catenin signaling by inhibitors of glycogen sythase kinase-3beta or the Wnt protein family member Wnt3a arrested CD8(+) T cell development into effector cells. By blocking T cell differentiation, Wnt signaling promoted the generation of CD44(low)CD62L(high)Sca-1(high)CD122(high)Bcl-2(high) self-renewing multipotent CD8(+) memory stem cells with proliferative and antitumor capacities exceeding those of central and effector memory T cell subsets. These findings reveal a key role for Wnt signaling in the maintenance of 'stemness' in mature memory CD8(+) T cells and have major implications for the design of new vaccination strategies and adoptive immunotherapies.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibitors", + "of", + "glycogen", + "sythase", + "kinase-3beta", + "or", + "the", + "Wnt3a" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocking" + ] + } + } + ] + }, + { + "PMID": "19377486", + "TEXT": "H2A histone family member X (H2AX, encoded by H2AFX) and its C-terminal phosphorylation (gamma-H2AX) participates in the DNA damage response and mediates DNA repair. Hypoxia is a physiological stress that induces a replication-associated DNA damage response. Moreover, hypoxia is the major driving force for neovascularization, as the hypoxia-mediated induction of vascular growth factors triggers endothelial cell proliferation. Here we studied the role of the hypoxia-induced DNA damage response in endothelial cell function and in hypoxia-driven neovascularization in vivo. Hypoxia induced replication-associated generation of gamma-H2AX in endothelial cells in vitro and in mice. Both in cultured cells and in mice, endothelial cell proliferation under hypoxic conditions was reduced by H2AX deficiency. Whereas developmental angiogenesis was not affected in H2afx(-/-) mice, hypoxia-induced neovascularization during pathologic proliferative retinopathy, in response to hind limb ischemia or during tumor angiogenesis was substantially lower in H2afx(-/-) mice. Moreover, endothelial-specific H2afx deletion resulted in reduced hypoxia-driven retina neovascularization and tumor neovascularization. Our findings establish that H2AX, and hence activation of the DNA repair response, is needed for endothelial cells to maintain their proliferation under hypoxic conditions and is crucial for hypoxia-driven neovascularization.", + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "H2AX", + "deficiency.", + "H2afx(-/-)" + ] + } + } + ] + }, + { + "PMID": "19287391", + "TEXT": "Amyloid-beta (Abeta) peptides, found in Alzheimer's disease brain, accumulate rapidly after traumatic brain injury (TBI) in both humans and animals. Here we show that blocking either beta- or gamma-secretase, enzymes required for production of Abeta from amyloid precursor protein (APP), can ameliorate motor and cognitive deficits and reduce cell loss after experimental TBI in mice. Thus, APP secretases are promising targets for treatment of TBI.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blocking" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduce" + ] + } + } + ] + }, + { + "PMID": "18345012", + "TEXT": "Intestinal adhesions are bands of fibrous tissue that connect the loops of the intestine to each other, to other abdominal organs or to the abdominal wall. Fibrous tissue formation is regulated by the balance between plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (tPA), which reciprocally regulate fibrin deposition. Several components of the inflammatory system, including cytokines, chemokines, cell adhesion molecules and neuropeptide substance P, have been reported to participate in adhesion formation. We have used cecal cauterization to develop a unique experimental mouse model of intestinal adhesion. Mice developed severe intestinal adhesion after this treatment. Adhesion development depended upon the interferon-gamma (IFN-gamma) and signal transducer and activator of transcription-1 (STAT1) system. Natural killer T (NKT) cell-deficient mice developed adhesion poorly, whereas they developed severe adhesion after reconstitution with NKT cells from wild-type mice, suggesting that NKT cell IFN-gamma production is indispensable for adhesion formation. This response does not depend on STAT4, STAT6, interleukin-12 (IL-12), IL-18, tumor necrosis factor-alpha, Toll-like receptor 4 or myeloid differentiation factor-88-mediated signals. Wild-type mice increased the ratio of PAI-1 to tPA after cecal cauterization, whereas Ifng(-/-) or Stat1(-/-) mice did not, suggesting that IFN-gamma has a crucial role in the differential regulation of PAI-1 and tPA. Additionally, hepatocyte growth factor, a potent mitogenic factor for hepatocytes, strongly inhibited intestinal adhesion by diminishing IFN-gamma production, providing a potential new way to prevent postoperative adhesions.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ifng(-/-)", + "or", + "Stat1(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + } + ] + }, + { + "PMID": "18345009", + "TEXT": "The angiogenic sprout has been compared to the growing axon, and indeed, many proteins direct pathfinding by both structures. The Roundabout (Robo) proteins are guidance receptors with well-established functions in the nervous system; however, their role in the mammalian vasculature remains ill defined. Here we show that an endothelial-specific Robo, Robo4, maintains vascular integrity. Activation of Robo4 by Slit2 inhibits vascular endothelial growth factor (VEGF)-165-induced migration, tube formation and permeability in vitro and VEGF-165-stimulated vascular leak in vivo by blocking Src family kinase activation. In mouse models of retinal and choroidal vascular disease, Slit2 inhibited angiogenesis and vascular leak, whereas deletion of Robo4 enhanced these pathologic processes. Our results define a previously unknown function for Robo receptors in stabilizing the vasculature and suggest that activating Robo4 may have broad therapeutic application in diseases characterized by excessive angiogenesis and/or vascular leak.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "Robo4", + "by", + "Slit2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + } + ] + }, + { + "PMID": "18278053", + "TEXT": "Integrin-mediated platelet adhesion and aggregation are essential for sealing injured blood vessels and preventing blood loss, and excessive platelet aggregation can initiate arterial thrombosis, causing heart attacks and stroke. To ensure that platelets aggregate only at injury sites, integrins on circulating platelets exist in a low-affinity state and shift to a high-affinity state (in a process known as integrin activation or priming) after contacting a wounded vessel. The shift is mediated through binding of the cytoskeletal protein Talin to the beta subunit cytoplasmic tail. Here we show that platelets lacking the adhesion plaque protein Kindlin-3 cannot activate integrins despite normal Talin expression. As a direct consequence, Kindlin-3 deficiency results in severe bleeding and resistance to arterial thrombosis. Mechanistically, Kindlin-3 can directly bind to regions of beta-integrin tails distinct from those of Talin and trigger integrin activation. We have therefore identified Kindlin-3 as a novel and essential element for platelet integrin activation in hemostasis and thrombosis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Kindlin-3", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + } + } + ] + }, + { + "PMID": "18037896", + "TEXT": "The serine-threonine kinases Pim-1 and Akt regulate cellular proliferation and survival. Although Akt is known to be a crucial signaling protein in the myocardium, the role of Pim-1 has been overlooked. Pim-1 expression in the myocardium of mice decreased during postnatal development, re-emerged after acute pathological injury in mice and was increased in failing hearts of both mice and humans. Cardioprotective stimuli associated with Akt activation induced Pim-1 expression, but compensatory increases in Akt abundance and phosphorylation after pathological injury by infarction or pressure overload did not protect the myocardium in Pim-1-deficient mice. Transgenic expression of Pim-1 in the myocardium protected mice from infarction injury, and Pim-1 expression inhibited cardiomyocyte apoptosis with concomitant increases in Bcl-2 and Bcl-X(L) protein levels, as well as in Bad phosphorylation levels. Relative to nontransgenic controls, calcium dynamics were significantly enhanced in Pim-1-overexpressing transgenic hearts, associated with increased expression of SERCA2a, and were depressed in Pim-1-deficient hearts. Collectively, these data suggest that Pim-1 is a crucial facet of cardioprotection downstream of Akt.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Pim-1", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + } + ] + }, + { + "PMID": "17952091", + "TEXT": "Proteoglycans are a family of extracellular macromolecules comprised of glycosaminoglycan chains of a repeated disaccharide linked to a central core protein. Proteoglycans have critical roles in chondrogenesis and skeletal development. The glycosaminoglycan chains found in cartilage proteoglycans are primarily composed of chondroitin sulfate. The integrity of chondroitin sulfate chains is important to cartilage proteoglycan function; however, chondroitin sulfate metabolism in mammals remains poorly understood. The solute carrier-35 D1 (SLC35D1) gene (SLC35D1) encodes an endoplasmic reticulum nucleotide-sugar transporter (NST) that might transport substrates needed for chondroitin sulfate biosynthesis. Here we created Slc35d1-deficient mice that develop a lethal form of skeletal dysplasia with severe shortening of limbs and facial structures. Epiphyseal cartilage in homozygous mutant mice showed a decreased proliferating zone with round chondrocytes, scarce matrices and reduced proteoglycan aggregates. These mice had short, sparse chondroitin sulfate chains caused by a defect in chondroitin sulfate biosynthesis. We also identified that loss-of-function mutations in human SLC35D1 cause Schneckenbecken dysplasia, a severe skeletal dysplasia. Our findings highlight the crucial role of NSTs in proteoglycan function and cartilage metabolism, thus revealing a new paradigm for skeletal disease and glycobiology.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Slc35d1-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + } + ] + }, + { + "PMID": "17934470", + "TEXT": "Sepsis, a leading cause of death worldwide, involves proinflammatory responses and inefficient bacterial clearance. Phagocytic cells play a crucial part in the prevention of sepsis by clearing bacteria through host innate receptors. Here we show that the FcRgamma adaptor, an immunoreceptor tyrosine-based activation motif (ITAM)-bearing signal transduction subunit of the Fc receptor family, has a deleterious effect on sepsis. FcRgamma(-/-) mice show increased survival during peritonitis, owing to markedly increased E. coli phagocytosis and killing and to lower production of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha. The FcRgamma-associated receptor that inhibits E. coli phagocytosis is FcgammaRIII (also called CD16), and its absence protects mice from sepsis. FcgammaRIII binds E. coli, and this interaction induces FcRgamma phosphorylation, recruitment of the tyrosine phosphatase SHP-1 and phosphatidylinositide-3 kinase (PI3K) dephosphorylation. Decreased PI3K activity inhibits E. coli phagocytosis and increases TNF-alpha production through Toll-like receptor 4. We identified the phagocytic receptor negatively regulated by FcRgamma on macrophages as the class A scavenger receptor MARCO. E. coli-FcgammaRIII interaction induces the recruitment of SHP-1 to MARCO, thereby inhibiting E. coli phagocytosis. Thus, by binding FcgammaRIII, E. coli triggers an inhibitory FcRgamma pathway that both impairs MARCO-mediated bacterial clearance and activates TNF-alpha secretion.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FcRgamma(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + } + ] + }, + { + "PMID": "17159988", + "TEXT": "Interstitial loss of all or part of the long arm of chromosome 5, or del(5q), is a frequent clonal chromosomal abnormality in human myelodysplastic syndrome (MDS, a preleukemic disorder) and acute myeloid leukemia (AML), and is thought to contribute to the pathogenesis of these diseases by deleting one or more tumor-suppressor genes. Although a major commonly deleted region (CDR) has been delineated on chromosome band 5q31.1 (refs. 3-7), attempts to identify tumor suppressors within this band have been unsuccessful. We focused our analysis of gene expression on RNA from primitive leukemia-initiating cells, which harbor 5q deletions, and analyzed 12 genes within the CDR that are expressed by normal hematopoietic stem cells. Here we show that the gene encoding alpha-catenin (CTNNA1) is expressed at a much lower level in leukemia-initiating stem cells from individuals with AML or MDS with a 5q deletion than in individuals with MDS or AML lacking a 5q deletion or in normal hematopoietic stem cells. Analysis of HL-60 cells, a myeloid leukemia line with deletion of the 5q31 region, showed that the CTNNA1 promoter of the retained allele is suppressed by both methylation and histone deacetylation. Restoration of CTNNA1 expression in HL-60 cells resulted in reduced proliferation and apoptotic cell death. Thus, loss of expression of the alpha-catenin tumor suppressor in hematopoietic stem cells may provide a growth advantage that contributes to human MDS or AML with del(5q).", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoration", + "of", + "CTNNA1", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + } + ] + }, + { + "PMID": "17086189", + "TEXT": "The angiogenic growth factor angiopoietin 2 (Ang2) destabilizes blood vessels, enhances vascular leak and induces vascular regression and endothelial cell apoptosis. We considered that Ang2 might be important in hyperoxic acute lung injury (ALI). Here we have characterized the responses in lungs induced by hyperoxia in wild-type and Ang2-/- mice or those given either recombinant Ang2 or short interfering RNA (siRNA) targeted to Ang2. During hyperoxia Ang2 expression is induced in lung epithelial cells, while hyperoxia-induced oxidant injury, cell death, inflammation, permeability alterations and mortality are ameliorated in Ang2-/- and siRNA-treated mice. Hyperoxia induces and activates the extrinsic and mitochondrial cell death pathways and activates initiator and effector caspases through Ang2-dependent pathways in vivo. Ang2 increases inflammation and cell death during hyperoxia in vivo and stimulates epithelial necrosis in hyperoxia in vitro. Ang2 in plasma and alveolar edema fluid is increased in adults with ALI and pulmonary edema. Tracheal Ang2 is also increased in neonates that develop bronchopulmonary dysplasia. Ang2 is thus a mediator of epithelial necrosis with an important role in hyperoxic ALI and pulmonary edema.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "short", + "interfering", + "RNA", + "(siRNA)", + "targeted", + "to", + "Ang2.", + "siRNA-treated" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces", + "activates", + "increases", + "stimulates" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ang2-/-" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces", + "activates" + ] + } + } + ] + }, + { + "PMID": "16819549", + "TEXT": "The von Hippel-Lindau tumor suppressor, pVHL, forms part of an E3 ubiquitin ligase complex that targets specific substrates for degradation, including hypoxia-inducible factor-1alpha (HIF-1alpha), which is involved in tumor progression and angiogenesis. It remains unclear, however, how pVHL is destabilized. Here we show that E2-EPF ubiquitin carrier protein (UCP) associates with and targets pVHL for ubiquitin-mediated proteolysis in cells, thereby stabilizing HIF-1alpha. UCP is detected coincidently with HIF-1alpha in human primary liver, colon and breast tumors, and metastatic cholangiocarcinoma and colon cancer cells. UCP level correlates inversely with pVHL level in most tumor cell lines. In vitro and in vivo, forced expression of UCP boosts tumor-cell proliferation, invasion and metastasis through effects on the pVHL-HIF pathway. Our results suggest that UCP helps stabilize HIF-1alpha and may be a new molecular target for therapeutic intervention in human cancers.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "forced", + "expression", + "of", + "UCP" + ] + }, + "effect": { + "val": "positive", + "words": [ + "boosts" + ] + } + } + ] + }, + { + "PMID": "16444265", + "TEXT": "The interferon (IFN)-gamma-induced TRAIL effector mechanism is a vital component of cancer immunosurveillance by natural killer (NK) cells in mice. Here we show that the main source of IFN-gamma is not the conventional NK cell but a subset of B220(+)Ly6C(-) dendritic cells, which are atypical insofar as they express NK cell-surface molecules. Upon contact with a variety of tumor cells that are poorly recognized by NK cells, B220(+)NK1.1(+) dendritic cells secrete high levels of IFN-gamma and mediate TRAIL-dependent lysis of tumor cells. Adoptive transfer of these IFN-producing killer dendritic cells (IKDCs) into tumor-bearing Rag2(-/-)Il2rg(-/-) mice prevented tumor outgrowth, whereas transfer of conventional NK cells did not. In conclusion, we identified IKDCs as pivotal sensors and effectors of the innate antitumor immune response.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "tumor-bearing", + "Rag2(-/-)Il2rg(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + } + ] + }, + { + "PMID": "16288283", + "TEXT": "The immune system can act as an extrinsic suppressor of tumors. Therefore, tumor progression depends in part on mechanisms that downmodulate intrinsic immune surveillance. Identifying these inhibitory pathways may provide promising targets to enhance antitumor immunity. Here, we show that Stat3 is constitutively activated in diverse tumor-infiltrating immune cells, and ablating Stat3 in hematopoietic cells triggers an intrinsic immune-surveillance system that inhibits tumor growth and metastasis. We observed a markedly enhanced function of dendritic cells, T cells, natural killer (NK) cells and neutrophils in tumor-bearing mice with Stat3(-/-) hematopoietic cells, and showed that tumor regression requires immune cells. Targeting Stat3 with a small-molecule drug induces T cell- and NK cell-dependent growth inhibition of established tumors otherwise resistant to direct killing by the inhibitor. Our findings show that Stat3 signaling restrains natural tumor immune surveillance and that inhibiting hematopoietic Stat3 in tumor-bearing hosts elicits multicomponent therapeutic antitumor immunity.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "ablating", + "Stat3" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + } + ] + }, + { + "PMID": "16208318", + "TEXT": "Host defense against viruses probably depends on targeted death of infected host cells and then clearance of cellular corpses by macrophages. For this process to be effective, the macrophage must presumably avoid its own virus-induced death. Here we identify one such mechanism. We show that mice lacking the chemokine Ccl5 are immune compromised to the point of delayed viral clearance, excessive airway inflammation and respiratory death after mouse parainfluenza or human influenza virus infection. Virus-inducible levels of Ccl5 are required to prevent apoptosis of virus-infected mouse macrophages in vivo and mouse and human macrophages ex vivo. The protective effect of Ccl5 requires activation of the Ccr5 chemokine receptor and consequent bilateral activation of G(alphai)-PI3K-AKT and G(alphai)-MEK-ERK signaling pathways. The antiapoptotic action of chemokine signaling may therefore allow scavengers to finally stop the host cell-to-cell infectious process.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "chemokine" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + } + } + ] + }, + { + "PMID": "15965483", + "TEXT": "We describe the generation and characterization of the first inducible 'fatless' model system, the FAT-ATTAC mouse (fat apoptosis through targeted activation of caspase 8). This transgenic mouse develops identically to wild-type littermates. Apoptosis of adipocytes can be induced at any developmental stage by administration of a FK1012 analog leading to the dimerization of a membrane-bound, adipocyte-specific caspase 8-FKBP fusion protein. Within 2 weeks of dimerizer administration, FAT-ATTAC mice show near-knockout levels of circulating adipokines and markedly reduced levels of adipose tissue. FAT-ATTAC mice are glucose intolerant, have diminished basal and endotoxin-stimulated systemic inflammation, are less responsive to glucose-stimulated insulin secretion and show increased food intake independent of the effects of leptin. Most importantly, we show that functional adipocytes can be recovered upon cessation of treatment, allowing the study of adipogenesis in vivo, as well as a detailed examination of the importance of the adipocyte in the regulation of multiple physiological functions and pathological states.", + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "FAT-ATTAC" + ] + } + } + ] + }, + { + "PMID": "15908955", + "TEXT": "Accelerated osteoclastic bone resorption has a central role in the pathogenesis of osteoporosis and other bone diseases. Identifying the molecular pathways that regulate osteoclast activity provides a key to understanding the causes of these diseases and to the development of new treatments. Here we show that mice with inactivation of cannabinoid type 1 (CB1) receptors have increased bone mass and are protected from ovariectomy-induced bone loss. Pharmacological antagonists of CB1 and CB2 receptors prevented ovariectomy-induced bone loss in vivo and caused osteoclast inhibition in vitro by promoting osteoclast apoptosis and inhibiting production of several osteoclast survival factors. These studies show that the CB1 receptor has a role in the regulation of bone mass and ovariectomy-induced bone loss and that CB1- and CB2-selective cannabinoid receptor antagonists are a new class of osteoclast inhibitors that may be of value in the treatment of osteoporosis and other bone diseases.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "cannabinoid", + "type", + "1", + "(CB1)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Pharmacological", + "antagonists", + "of", + "CB1", + "and", + "CB2", + "receptors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoting" + ] + } + } + ] + }, + { + "PMID": "15852018", + "TEXT": "Alveolar cell apoptosis is involved in the pathogenesis of emphysema, a prevalent disease primarily caused by cigarette smoking. We report that ceramide, a second messenger lipid, is a crucial mediator of alveolar destruction in emphysema. Inhibition of enzymes controlling de novo ceramide synthesis prevented alveolar cell apoptosis, oxidative stress and emphysema caused by blockade of the vascular endothelial growth factor (VEGF) receptors in both rats and mice. Emphysema was reproduced with intratracheal instillation of ceramide in naive mice. Excessive ceramide triggers a feed-forward mechanism mediated by activation of secretory acid sphingomyelinase, as suggested by experiments with neutralizing ceramide antibody in mice and with acid sphingomyelinase-deficient fibroblasts. Concomitant augmentation of signaling initiated by a prosurvival metabolite, sphingosine-1-phosphate, prevented lung apoptosis, implying that a balance between ceramide and sphingosine-1-phosphate is required for maintenance of alveolar septal integrity. Finally, increased lung ceramides in individuals with smoking-induced emphysema suggests that ceramide upregulation may be a crucial pathogenic element and a promising target in this disease that currently lacks effective therapies.", + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "the", + "vascular", + "endothelial", + "growth", + "factor", + "(VEGF)", + "receptors" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "acid", + "sphingomyelinase-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + } + ] + }, + { + "PMID": "15793583", + "TEXT": "High-density lipoproteins (HDLs) are considered antiatherogenic because they mediate reverse cholesterol transport from the periphery to the liver for excretion and degradation. Here we show that mice deficient in apolipoprotein M (apoM), a component of the HDL particle, accumulated cholesterol in large HDL particles (HDL(1)) while the conversion of HDL to prebeta-HDL was impaired. Accordingly, apoM-deficient mice lacked prebeta-HDL, a subclass of lipid-poor apolipoproteins that serves as a key acceptor of peripheral cellular cholesterol. This deficiency led to a markedly reduced cholesterol efflux from macrophages to apoM-deficient HDL compared to normal HDL in vitro. Overexpression of apoM in Ldlr(-/-) mice protected against atherosclerosis when the mice were challenged with a cholesterol-enriched diet, showing that apoM is important for the formation of prebeta-HDL and cholesterol efflux to HDL, and thereby inhibits formation of atherosclerotic lesions.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "apoM" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protected", + "against" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ldlr(-/-)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protected", + "against" + ] + } + } + ] + }, + { + "PMID": "15750601", + "TEXT": "Morphogenesis and remodeling of bone involve synthesis of bone matrix by osteoblasts and coordinate resorption of bone by osteoclasts. Defective bone remodeling caused by altered osteoclast activity underlies a multitude of osteopenic disorders. Receptor activator of NF-kappaB (RANK) and its ligand RANKL have been identified as essential factors involved in osteoclast development and bone remodeling, but their mechanism and interacting factors have not been fully characterized. Here we report that the molecular adapter Grb-2-associated binder-2 (Gab2) associates with RANK and mediates RANK-induced activation of NF-kappaB, Akt and Jnk. Inactivation of the gene encoding Gab2 in mice results in osteopetrosis and decreased bone resorption as a result of defective osteoclast differentiation. We also show that Gab2 has a crucial role in the differentiation of human progenitor cells into osteoclasts. We have thus identified a new, key regulatory scaffold molecule, Gab2, that controls select RANK signaling pathways and is essential for osteoclastogenesis and bone homeostasis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Inactivation", + "of", + "the", + "gene", + "encoding", + "Gab2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + } + ] + }, + { + "PMID": "15711557", + "TEXT": "Immune escape is a crucial feature of cancer progression about which little is known. Elevation of the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) in tumor cells can facilitate immune escape. Not known is how IDO becomes elevated or whether IDO inhibitors will be useful for cancer treatment. Here we show that IDO is under genetic control of Bin1, which is attenuated in many human malignancies. Mouse knockout studies indicate that Bin1 loss elevates the STAT1- and NF-kappaB-dependent expression of IDO, driving escape of oncogenically transformed cells from T cell-dependent antitumor immunity. In MMTV-Neu mice, an established breast cancer model, we show that small-molecule inhibitors of IDO cooperate with cytotoxic agents to elicit regression of established tumors refractory to single-agent therapy. Our findings suggest that Bin1 loss promotes immune escape in cancer by deregulating IDO and that IDO inhibitors may improve responses to cancer chemotherapy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "inhibitors", + "of", + "IDO" + ] + }, + "effect": { + "val": "positive", + "words": [ + "elicit" + ] + } + } + ] + }, + { + "PMID": "15156201", + "TEXT": "Loss of PTEN function leads to activation of phosphoinositide 3-kinase (PI3K) signaling and Akt. Clinical trials are now testing whether mammalian target of rapamycin (mTOR) inhibition is useful in treating PTEN-null cancers. Here, we report that mTOR inhibition induced apoptosis of epithelial cells and the complete reversal of a neoplastic phenotype in the prostate of mice expressing human AKT1 in the ventral prostate. Induction of cell death required the mitochondrial pathway, as prostate-specific coexpression of BCL2 blocked apoptosis. Thus, there is an mTOR-dependent survival signal required downstream of Akt. Bcl2 expression, however, only partially restored intraluminal cell growth in the setting of mTOR inhibition. Expression profiling showed that Hif-1 alpha targets, including genes encoding most glycolytic enzymes, constituted the dominant transcriptional response to AKT activation and mTOR inhibition. These data suggest that the expansion of AKT-driven prostate epithelial cells requires mTOR-dependent survival signaling and activation of HIF-1 alpha, and that clinical resistance to mTOR inhibitors may emerge through BCL2 expression and/or upregulation of HIF-1 alpha activity.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibition" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "Induction" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "human", + "AKT1", + "in", + "the", + "ventral", + "prostate." + ] + }, + "effect": { + "val": "positive", + "words": [ + "Induction" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expressing", + "human", + "AKT1", + "in", + "the", + "prostate-specific", + "coexpression", + "of", + "BCL2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "prostate-specific", + "coexpression", + "of", + "BCL2" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "partially", + "restored" + ] + } + }, + { + "effect": { + "val": "rescues", + "words": [ + "partially", + "restored" + ] + }, + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibition." + ] + } + } + ] + }, + { + "PMID": "15034570", + "TEXT": "Although Nogo-A has been identified in the central nervous system as an inhibitor of axonal regeneration, the peripheral roles of Nogo isoforms remain virtually unknown. Here, using a proteomic analysis to identify proteins enriched in caveolae and/or lipid rafts (CEM/LR), we show that Nogo-B is highly expressed in cultured endothelial and smooth muscle cells, as well as in intact blood vessels. The N terminus of Nogo-B promotes the migration of endothelial cells but inhibits the migration of vascular smooth muscle (VSM) cells, processes necessary for vascular remodeling. Vascular injury in Nogo-A/B-deficient mice promotes exaggerated neointimal proliferation, and adenoviral-mediated gene transfer of Nogo-B rescues the abnormal vascular expansion in those knockout mice. Our discovery that Nogo-B is a regulator of vascular homeostasis and remodeling broadens the functional scope of this family of proteins.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Nogo-A/B-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral-mediated", + "gene", + "transfer", + "of", + "Nogo-B" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescues" + ] + } + } + ] + }, + { + "PMID": "15004554", + "TEXT": "The clinical outcome of spinal cord injury (SCI) depends in part on the extent of secondary damage, to which apoptosis contributes. The CD95 and tumor necrosis factor (TNF) ligand/receptor systems play an essential role in various apoptotic mechanisms. To determine the involvement of these ligands in SCI-induced damage, we neutralized the activity of CD95 ligand (CD95L) and/or TNF in spinal cord-injured mice. Therapeutic neutralization of CD95L, but not of TNF, significantly decreased apoptotic cell death after SCI. Mice treated with CD95L-specific antibodies were capable of initiating active hind-limb movements several weeks after injury. The improvement in locomotor performance was mirrored by an increase in regenerating fibers and upregulation of growth-associated protein-43 (GAP-43). Thus, neutralization of CD95L promoted axonal regeneration and functional improvement in injured adult animals. This therapeutic strategy may constitute a potent future treatment for human spinal injury.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Therapeutic", + "neutralization", + "of", + "CD95L," + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + } + ] + }, + { + "PMID": "14991050", + "TEXT": "Autoimmune T-helper cells drive pathogenic autoantibody production in systemic lupus erythematosus (SLE), but the mechanisms maintaining those T cells are unknown. Autoreactive T cells are normally eliminated by functional inactivation (anergy) and activation-induced cell death (AICD) or apoptosis through death receptor (Fas) signaling. However, mutations in the genes encoding Fas and its ligand (FasL) are rare in classical SLE. By gene microarray profiling, validated by functional and biochemical studies, we establish here that activated T cells of lupus patients resist anergy and apoptosis by markedly upregulating and sustaining cyclooxygenase-2 (COX-2) expression. Inhibition of COX-2 caused apoptosis of the anergy-resistant lupus T cells by augmenting Fas signaling and markedly decreasing the survival molecule c-FLIP (cellular homolog of viral FLICE inhibitory protein). Studies with COX-2 inhibitors and Cox-2-deficient mice confirmed that this COX-2/FLIP antiapoptosis program is used selectively by anergy-resistant lupus T cells, and not by cancer cells or other autoimmune T cells. Notably, the gene encoding COX-2 is located in a lupus-susceptibility region on chromosome 1. We also found that only some COX-2 inhibitors were able to suppress the production of pathogenic autoantibodies to DNA by causing autoimmune T-cell apoptosis, an effect that was independent of prostaglandin E(2) (PGE(2)). These findings could be useful in the design of lupus therapies.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "COX-2", + "inhibitors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "caused", + "causing" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cox-2-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "causing" + ] + } + } + ] + }, + { + "PMID": "12872165", + "TEXT": "Current understanding of key transcription factors regulating angiogenesis is limited. Here we show that RNA-cleaving phosphodiester-linked DNA-based enzymes (DNAzymes), targeting a specific motif in the 5' untranslated region of early growth response (Egr-1) mRNA, inhibit Egr-1 protein expression, microvascular endothelial cell replication and migration, and microtubule network formation on basement membrane matrices. Egr-1 DNAzymes blocked angiogenesis in subcutaneous Matrigel plugs in mice, an observation that was independently confirmed by plug analysis in Egr-1-deficient animals, and inhibited MCF-7 human breast carcinoma growth in nude mice. Egr-1 DNAzymes suppressed tumor growth without influencing body weight, wound healing, blood coagulation or other hematological parameters. These agents inhibited endothelial expression of fibroblast growth factor (FGF)-2, a proangiogenic factor downstream of Egr-1, but not that of vascular endothelial growth factor (VEGF). Egr-1 DNAzymes also repressed neovascularization of rat cornea. Thus, microvascular endothelial cell growth, neovascularization, tumor angiogenesis and tumor growth are processes that are critically dependent on Egr-1.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Egr-1-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + } + ] + }, + { + "PMID": "12740571", + "TEXT": "Antigen-specific immune responses in the skin are initiated by antigen uptake into Langerhans cells and the subsequent migration of these cells to draining lymph nodes. Although prostaglandin E2 (PGE2) is produced substantially in skin exposed to antigen, its role remains unclear. Here we show that although Langerhans cells express all four PGE receptor subtypes, their migration to regional lymph nodes was decreased only in EP4-deficient (Ptger4-/-) mice and in wild-type mice treated with an EP4 antagonist. An EP4 agonist promoted the migration of Langerhans cells, increased their expression of costimulatory molecules and enhanced their ability to stimulate T cells in the mixed lymphocyte reaction in vitro. Contact hypersensitivity to antigen was impaired in Ptger4-/- mice and in wild-type mice treated with the EP4 antagonist during sensitization. PGE2-EP4 signaling thus facilitates initiation of skin immune responses by promoting the migration and maturation of Langerhans cells.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EP4-deficient", + "(Ptger4-/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EP4" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "antagonist.", + "EP4", + "agonist" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + } + ] + }, + { + "PMID": "12368906", + "TEXT": "Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, yet molecular events associated with the genesis and progression of this potentially fatal disease are largely unknown. For the molecules and pathways that have been implicated, genetic validation has been impeded by lack of a mouse model of RMS. Here we show that simultaneous loss of Ink4a/Arf function and disruption of c-Met signaling in Ink4a/Arf(-/-) mice transgenic for hepatocyte growth factor/scatter factor (HGF/SF) induces RMS with extremely high penetrance and short latency. In cultured myoblasts, c-Met activation and Ink4a/Arf loss suppress myogenesis in an additive fashion. Our data indicate that human c-MET and INK4a/ARF, situated at the nexus of pathways regulating myogenic growth and differentiation, represent critical targets in RMS pathogenesis. The marked synergism in mice between aberrant c-Met signaling and Ink4a/Arf inactivation, lesions individually implicated in human RMS, suggests a therapeutic combination to combat this devastating childhood cancer.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "hepatocyte", + "growth", + "factor/scatter", + "factor", + "(HGF/SF)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppress" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ink4a/Arf", + "loss" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppress" + ] + } + } + ] + }, + { + "PMID": "12357246", + "TEXT": "Ras acts with other proteins to induce neoplasia. By itself, however, strong Ras signaling can suppress proliferation of normal cells. In primary epidermal cells, we found that oncogenic Ras transiently decreases cyclin-dependent kinase (CDK) 4 expression in association with cell cycle arrest in G1 phase. CDK4 co-expression circumvents Ras growth suppression and induces invasive human neoplasia resembling squamous cell carcinoma. Tumorigenesis is dependent on CDK4 kinase function, with cyclin D1 required but not sufficient for this process. In facilitating escape from G1 growth restraints, Ras and CDK4 alter the composition of cyclin D and cyclin E complexes and promote resistance to growth inhibition by INK4 cyclin-dependent kinase inhibitors. These data identify a new role for oncogenic Ras in CDK4 regulation and highlight the functional importance of CDK4 suppression in preventing uncontrolled growth.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "CDK4", + "co-expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + } + ] + }, + { + "PMID": "12244303", + "TEXT": "The cyclin-dependent kinase inhibitor p27(kip1) is a putative tumor suppressor for human cancer. The mechanism underlying p27(kip1) deregulation in human cancer is, however, poorly understood. We demonstrate that the serine/threonine kinase Akt regulates cell proliferation in breast cancer cells by preventing p27(kip1)-mediated growth arrest. Threonine 157 (T157), which maps within the nuclear localization signal of p27(kip1), is a predicted Akt-phosphorylation site. Akt-induced T157 phosphorylation causes retention of p27(kip1) in the cytoplasm, precluding p27(kip1)-induced G1 arrest. Conversely, the p27(kip1)-T157A mutant accumulates in cell nuclei and Akt does not affect p27(kip1)-T157A-mediated cell cycle arrest. Lastly, T157-phosphorylated p27(kip1) accumulates in the cytoplasm of primary human breast cancer cells coincident with Akt activation. Thus, cytoplasmic relocalization of p27(kip1), secondary to Akt-mediated phosphorylation, is a novel mechanism whereby the growth inhibitory properties of p27(kip1) are functionally inactivated and the proliferation of breast cancer cells is sustained.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "p27(kip1)-T157A", + "mutant" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "does", + "not", + "affect" + ] + } + } + ] + }, + { + "PMID": "12185361", + "TEXT": "Angiogenesis is a highly regulated process that results from the sequential actions of naturally occurring stimulators and inhibitors. Here, we show that parathyroid hormone-related peptide, a peptide hormone derived from normal and tumor cells that regulates bone metabolism and vascular tone, is a naturally occurring angiogenesis inhibitor. Parathyroid hormone-related peptide or a ten-amino-acid peptide from its N terminus inhibits endothelial cell migration in vitro and angiogenesis in vivo by activating endothelial cell protein kinase A. Activation of protein kinase A inhibits cell migration and angiogenesis by inhibiting the small GTPase Rac. In contrast, inhibition of protein kinase A reverses the anti-migratory and anti-angiogenic properties of parathyroid hormone-related peptide. These studies show that parathyroid hormone-related peptide is a naturally occurring angiogenesis inhibitor that functions by activation of protein kinase A.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Activation", + "of", + "protein", + "kinase", + "A" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + } + ] + }, + { + "PMID": "12091880", + "TEXT": "The mechanism by which angiogenic factors recruit bone marrow (BM)-derived quiescent endothelial and hematopoietic stem cells (HSCs) is not known. Here, we report that functional vascular endothelial growth factor receptor-1 (VEGFR1) is expressed on human CD34(+) and mouse Lin(-)Sca-1(+)c-Kit(+) BM-repopulating stem cells, conveying signals for recruitment of HSCs and reconstitution of hematopoiesis. Inhibition of VEGFR1, but not VEGFR2, blocked HSC cell cycling, differentiation and hematopoietic recovery after BM suppression, resulting in the demise of the treated mice. Placental growth factor (PlGF), which signals through VEGFR1, restored early and late phases of hematopoiesis following BM suppression. PlGF enhanced early phases of BM recovery directly through rapid chemotaxis of VEGFR1(+) BM-repopulating and progenitor cells. The late phase of hematopoietic recovery was driven by PlGF-induced upregulation of matrix metalloproteinase-9, mediating the release of soluble Kit ligand. Thus, PlGF promotes recruitment of VEGFR1(+) HSCs from a quiescent to a proliferative BM microenvironment, favoring differentiation, mobilization and reconstitution of hematopoiesis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "VEGFR1," + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocked" + ] + } + } + ] + }, + { + "PMID": "12091877", + "TEXT": "The therapeutic potential of placental growth factor (PlGF) and its receptor Flt1 in angiogenesis is poorly understood. Here, we report that PlGF stimulated angiogenesis and collateral growth in ischemic heart and limb with at least a comparable efficiency to vascular endothelial growth factor (VEGF). An antibody against Flt1 suppressed neovascularization in tumors and ischemic retina, and angiogenesis and inflammatory joint destruction in autoimmune arthritis. Anti-Flt1 also reduced atherosclerotic plaque growth and vulnerability, but the atheroprotective effect was not attributable to reduced plaque neovascularization. Inhibition of VEGF receptor Flk1 did not affect arthritis or atherosclerosis, indicating that inhibition of Flk1-driven angiogenesis alone was not sufficient to halt disease progression. The anti-inflammatory effects of anti-Flt1 were attributable to reduced mobilization of bone marrow-derived myeloid progenitors into the peripheral blood; impaired infiltration of Flt1-expressing leukocytes in inflamed tissues; and defective activation of myeloid cells. Thus, PlGF and Flt1 constitute potential candidates for therapeutic modulation of angiogenesis and inflammation.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "VEGF", + "receptor", + "Flk1" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "affect" + ] + } + } + ] + }, + { + "PMID": "11433351", + "TEXT": "Increased secretion and levels of ApoB-containing lipoproteins (BLp) commonly occur in familial hyperlipidemia, obesity and diabetes. The plasma phospholipid-transfer protein (PLTP) is known to mediate transfer of phospholipids between BLp and HDL during their intravascular metabolism. To address a possible role of PLTP in dyslipidemia and atherogenesis, we bred mice deficient in the gene encoding PLTP (PLTP-deficient mice) using different hyperlipidemic mouse strains. In ApoB-transgenic and ApoE-deficient backgrounds, PLTP deficiency resulted in reduced production and levels of BLp and markedly decreased atherosclerosis. BLp secretion was diminished in hepatocytes from ApoB-transgenic PLTP-deficient mice, a defect that was corrected when PLTP was reintroduced in adenovirus. The studies reveal a major, unexpected role of PLTP in regulating the secretion of BLp and identify PLTP as a therapeutic target.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "the", + "gene", + "encoding", + "PLTP", + "(PLTP-deficient", + "mice)", + "ApoE-deficient", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ApoB-transgenic" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + } + ] + }, + { + "PMID": "11385506", + "TEXT": "Heme oxygenase (HO-1, encoded by Hmox1) is an inducible protein activated in systemic inflammatory conditions by oxidant stress. Vascular injury is characterized by a local reparative process with inflammatory components, indicating a potential protective role for HO-1 in arterial wound repair. Here we report that HO-1 directly reduces vasoconstriction and inhibits cell proliferation during vascular injury. Expression of HO-1 in arteries stimulated vascular relaxation, mediated by guanylate cyclase and cGMP, independent of nitric oxide. The unexpected effects of HO-1 on vascular smooth muscle cell growth were mediated by cell-cycle arrest involving p21Cip1. HO-1 reduced the proliferative response to vascular injury in vivo; expression of HO-1 in pig arteries inhibited lesion formation and Hmox1-/- mice produced hyperplastic arteries compared with controls. Induction of the HO-1 pathway moderates the severity of vascular injury by at least two adaptive mechanisms independent of nitric oxide, and is a potential therapeutic target for diseases of the vasculature.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "HO-1", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced", + "inhibited" + ] + } + } + ] + }, + { + "PMID": "11283671", + "TEXT": "The transcription factor CCAAT/enhancer binding protein alpha, or C/EBPalpha, encoded by the CEBPA gene, is crucial for the differentiation of granulocytes. Conditional expression of C/EBPalpha triggers neutrophilic differentiation, and Cebpa knockout mice exhibit an early block in maturation. Dominant-negative mutations of CEBPA have been found in some patients with acute myeloid leukemia (AML), but not in AML with the t(8;21) translocation which gives rise to the fusion gene RUNX1-CBF2T1 (also known as AML1-ETO) encoding the AML1-ETO fusion protein. RUNX1-CBF2T1 positive-AML blasts had eight-fold lower CEBPA RNA levels and undetectable C/EBPalpha protein levels compared with other subgroups of AML patients. Conditional expression of RUNX1-CBF2T1 in U937 cells downregulated CEBPA mRNA, protein and DNA binding activity. AML1-ETO appears to suppress C/EBPalpha expression indirectly by inhibiting positive autoregulation of the CEBPA promoter. Conditional expression of C/EBPalpha in AML1-ETO-positive Kasumi-1 cells results in neutrophilic differentiation. We suggest that restoring C/EBPalpha expression will have therapeutic implications in RUNX1-CBF2T1-positive leukemias.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Conditional", + "expression", + "of", + "C/EBPalpha" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "AML1-ETO-positive" + ] + }, + "effect": { + "val": "positive", + "words": [ + "results", + "in" + ] + } + } + ] + }, + { + "PMID": "10973316", + "TEXT": "Bone formation by osteoblasts is essential for skeletal growth and remodeling. Fra-1 is a c-Fos-related protein belonging to the AP-1 family of transcription factors. Here we show that transgenic mice overexpressing Fra-1 in various organs develop a progressive increase in bone mass leading to osteosclerosis of the entire skeleton, which is due to a cell-autonomous increase in the number of mature osteoblasts. Moreover, osteoblast differentiation, but not proliferation, was enhanced and osteoclastogenesis was also elevated in vitro. These data indicate that, unlike c-Fos, which causes osteosarcomas, Fra-1 specifically enhances bone formation, which may be exploited to stimulate bone formation in pathological conditions.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "Fra-1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + } + ] + }, + { + "PMID": "10655108", + "TEXT": "Because HER-2/neu overexpression is important in cancer development, we looked for a method of suppressing the cell transformation mediated by HER-2/neu overexpression. We have identified that the DNA-binding protein PEA3, which is encoded by a previously isolated gene of the ets family, specifically targeted a DNA sequence on the HER-2/neu promoter and downregulated the promoter activity. Expression of PEA3 resulted in preferential inhibition of cell growth and tumor development of HER-2/neu-overexpressing cancer cells. This is a new approach to targeting HER-2/neu overexpression and also provides a rationale to the design for repressors of diseases caused by overexpression of pathogenic genes.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Expression", + "of", + "PEA3" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + } + ] + }, + { + "PMID": "10545998", + "TEXT": "The mechanisms of allograft tolerance have been classified as deletion, anergy, ignorance and suppression/regulation. Deletion has been implicated in central tolerance, whereas peripheral tolerance has generally been ascribed to clonal anergy and/or active immunoregulatory states. Here, we used two distinct systems to assess the requirement for T-cell deletion in peripheral tolerance induction. In mice transgenic for Bcl-xL, T cells were resistant to passive cell death through cytokine withdrawal, whereas T cells from interleukin-2-deficient mice did not undergo activation-induced cell death. Using either agents that block co-stimulatory pathways or the immunosuppressive drug rapamycin, which we have shown here blocks the proliferative component of interleukin-2 signaling but does not inhibit priming for activation-induced cell death, we found that mice with defective passive or active T-cell apoptotic pathways were resistant to induction of transplantation tolerance. Thus, deletion of activated T cells through activation-induced cell death or growth factor withdrawal seems necessary to achieve peripheral tolerance across major histocompatibility complex barriers.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "for", + "Bcl-xL," + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistant" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interleukin-2-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "did" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interleukin-2-deficient" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "undergo" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "interleukin-2-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "activation-induced" + ] + } + } + ] + }, + { + "PMID": "10229234", + "TEXT": "Familial Alzheimer disease mutations of presenilin 1 (PS-1) enhance the generation of A beta1-42, indicating that PS-1 is involved in amyloidogenesis. However, PS-1 transgenic mice have failed to show amyloid plaques in their brains. Because PS-1 mutations facilitate apoptotic neuronal death in vitro, we did careful quantitative studies in PS-1 transgenic mice and found that neurodegeneration was significantly accelerated in mice older than 13 months (aged mice) with familial Alzheimer disease mutant PS-1, without amyloid plaque formation. However, there were significantly more neurons containing intracellularly deposited A beta42 in aged mutant transgenic mice. Our data indicate that the pathogenic role of the PS-1 mutation is upstream of the amyloid cascade.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "PS-1", + "mutations" + ] + }, + "effect": { + "val": "positive", + "words": [ + "facilitate" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "facilitate" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "PS-1", + "transgenic" + ] + } + } + ] + }, + { + "PMID": "10202930", + "TEXT": "Programmed cell death (apoptosis) seems to be the principal mechanism whereby anti-oncogenic therapies such as chemotherapy and radiation effect their responses. Resistance to apoptosis, therefore, is probably a principal mechanism whereby tumors are able to overcome these cancer therapies. The transcription factor NF-kappaB is activated by chemotherapy and by irradiation in some cancer cell lines. Furthermore, inhibition of NF-kappaB in vitro leads to enhanced apoptosis in response to a variety of different stimuli. We show here that inhibition of NF-kappaB through the adenoviral delivery of a modified form of IkappaBalpha, the inhibitor of NF-kappaB, sensitizes chemoresistant tumors to the apoptotic potential of TNFalpha and of the chemotherapeutic compound CPT-11, resulting in tumor regression. These results demonstrate that the activation of NF-kappaB in response to chemotherapy is a principal mechanism of inducible tumor chemoresistance, and establish the inhibition of NF-kappaB as a new approach to adjuvant therapy in cancer treatment.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "NF-kappaB" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced", + "resulting" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "through", + "adenoviral", + "delivery", + "of", + "a", + "modified", + "form", + "IkappaBalpha," + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulting", + "in" + ] + } + } + ] + }, + { + "PMID": "10086392", + "TEXT": "The tumor suppressor protein p53 is an essential molecule in cell proliferation and programmed cell death (apoptosis), and has been postulated to play a principal part in the development of atherosclerosis. We have examined the effect of p53 inactivation on atherogenesis in apoE-knockout mice, an animal model for atherosclerosis. We found that, compared with p53+/+/apoE-/- mice, p53-/-/apoE-/- mice developed considerably accelerated aortic atherosclerosis in the presence of a similar serum cholesterol in response to a high-fat diet. Furthermore, the atherosclerotic lesions in p53-/-/apoE-/- mice had a significant (approximately 280%) increase in cell proliferation rate and an insignificant (approximately 180%) increase in apoptosis compared with those in p53+/+/apoE-/- mice. Our observations indicate that the role of p53 in atherosclerotic lesion development might be associated with its function in cell replication control, and that p53-independent mechanisms can mediate the apoptotic response in atherosclerosis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-/-/apoE-/-" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increase" + ] + } + } + ] + }, + { + "PMID": "9930871", + "TEXT": "Prostaglandins (PGs) are ubiquitous lipid mediators derived from cyclooxygenase metabolism of arachidonic acid that exert a broad range of physiologic activities, including modulation of inflammation, ovulation and arterial blood pressure. PGE2, a chief cyclooxygenase product, modulates blood pressure and fertility, although the specific G protein-coupled receptors mediating these effects remain poorly defined. To evaluate the physiologic role of the PGE2 EP2 receptor subtype, we created mice with targeted disruption of this gene (EP2-/-). EP2-/- mice develop normally but produce small litters and have slightly elevated baseline systolic blood pressure. In EP2-/- mice, the characteristic hypotensive effect of intravenous PGE2 infusion was absent; PGE2 infusion instead produced hypertension. When fed a diet high in salt, the EP2-/- mice developed profound systolic hypertension, whereas wild-type mice showed no change in systolic blood pressure. Analysis of wild-type and EP2-/- mice on day 5 of pregnancy indicated that the reduced litter size of EP2-/- mice is due to a pre-implantation defect. This reduction of implanted embryos could be accounted for by impaired ovulation and dramatic reductions in fertilization observed on day 2 of pregnancy. These data demonstrate that the EP2 receptor mediates arterial dilatation, salt-sensitive hypertension, and also plays an essential part in female fertility.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "EP2-/-" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired", + "reductions" + ] + } + } + ] + }, + { + "PMID": "9734403", + "TEXT": "The p53 tumor suppressor protein binds to both cellular and viral proteins, which influence its biological activity. One such protein is the large E1b tumor antigen (E1b58kDa) from adenoviruses (Ads), which abrogates the ability of p53 to transactivate various promoters. This inactivation of p53 function is believed to be the mechanism by which E1b58kDa contributes to the cell transformation process. Although the p53-E1b58kDa complex occurs during infection and is conserved among different serotypes, there are limited data demonstrating that it has a role in virus replication. However, loss of p53 expression occurs after adenovirus infection of human cells and an E1b58kDa deletion mutant (Onyx-015, also called dl 1520) selectively replicates in p53-defective cells. These (and other) data indicate a plausible hypothesis is that loss of p53 function may be conducive to efficient adenovirus replication. However, wild-type (wt) Ad5 grows more efficiently in cells expressing a wt p53 protein. These studies indicate that the hypothesis may be an oversimplification. Here, we show that cells expressing wt p53, as well as p53-defective cells, allow adenovirus replication, but only cells expressing wt p53 show evidence of virus-induced cytopathic effect. This correlates with the ability of adenovirus to induce cell death. Our data indicate that p53 plays a necessary part in mediating cellular destruction to allow a productive adenovirus infection. In contrast, p53-deficient cells are less sensitive to the cytolytic effects of adenovirus and as such raise questions about the use of E1b58kDa-deficient adenoviruses in tumor therapy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "wt", + "p53" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + } + ] + }, + { + "PMID": "9734398", + "TEXT": "PPARgamma is a nuclear receptor that has a dominant regulatory role in differentiation of cells of the adipose lineage, and has recently been shown to be expressed in the colon. We show here that PPARgamma is expressed at high levels in both well- and poorly-differentiated adenocarcinomas, in normal colonic mucosa and in human colon cancer cell lines. Ligand activation of this receptor in colon cancer cells causes a considerable reduction in linear and clonogenic growth, increased expression of carcinoembryonic antigen and the reversal of many gene expression events specifically associated with colon cancer. Transplantable tumors derived from human colon cancer cells show a significant reduction of growth when mice are treated with troglitazone, a PPARgamma ligand. These results indicate that the growth and differentiation of colon cancer cells can be modulated through PPARgamma.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Ligand", + "activation", + "of", + "this", + "receptor" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduction" + ] + } + } + ] + }, + { + "PMID": "9585231", + "TEXT": "The cyclin-dependent kinase inhibitor p27Kip1 controls cell proliferation in response to normal mitogenic stimuli. We show here that p27Kip1 also safeguards against excessive cell proliferation in specific pathophysiologic settings. We used experimental glomerulonephritis as a paradigm for immune mediated inflammation and ureteral obstruction as a model for non-immune mediated inflammation. Renal function was substantially decreased in nephritic p27-/- mice compared with control mice, and this was associated with increased glomerular cell proliferation, apoptosis and matrix protein accumulation. Tubular epithelial cell proliferation and apoptosis was also increased in p27-/- mice following ureteral obstruction. p27Kip1 may have a general role in protecting cells and tissues from inflammatory injury.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "nephritic", + "p27-/-" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + } + ] + }, + { + "PMID": "9461197", + "TEXT": "We postulated that activation of a genetic program that tonically inhibits intimal cell death is a necessary condition for the pathogenesis of vascular disease. Studies of vascular lesions in humans and animal models documented increased expression of the anti-apoptotic gene product Bcl-xL within intimal cells. Downregulation of intimal cell bcl-xL expression with the use of antisense oligonucleotides induced apoptosis and acute regression of vascular lesions. These findings indicate that apoptosis regulatory genes such as bcl-xL are critical determinants of intimal lesion formation and that targeted apoptosis may be a novel therapy for intimal vascular disease.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Downregulation", + "of", + "intimal", + "cell", + "bcl-xL" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "9427606", + "TEXT": "Neutral endopeptidase 24.11 (NEP) is a cell-surface enzyme expressed by prostatic epithelial cells that cleaves and inactivates neuropeptides implicated in the growth of androgen-independent prostate cancer (PC). We report that NEP expression and catalytic activity are lost in vitro in androgen-independent but not androgen-dependent PC cell lines. In vivo, NEP protein expression is commonly decreased in cancer cells of metastatic PC specimens from patients with androgen-independent but not androgen-dependent PC. Overexpression of NEP in androgen-independent PC cells or incubation with recombinant NEP inhibits PC cell growth. Furthermore, in androgen-dependent PC cells, expression of NEP is transcriptionally regulated by androgen and decreases with androgen withdrawal. These data suggest that decreased NEP expression, common in androgen-independent PCs, is facilitated by the elimination of androgens, and that NEP loss plays an important role in the development of androgen-independent PC by allowing PC cells to use mitogenic neuropeptides as an alternate source to androgen in order to stimulate cell proliferation.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "NEP" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + } + } + ] + }, + { + "PMID": "9212101", + "TEXT": "Mice were constructed carrying prion protein (PrP) transgenes with individual regions of putative secondary structure deleted. Transgenic mice with amino-terminal regions deleted remained healthy at >400 days of age, whereas those with either of carboxy-terminal alpha-helices deleted spontaneously developed fatal CNS illnesses similar to neuronal storage diseases. Deletion of either C-terminal helix resulted in PrP accumulation within cytoplasmic inclusions in enlarged neurons. Deletion of the penultimate C-terminal helix resulted in proliferation of rough endoplasmic reticulum. Mice with the C-terminal helix deleted were affected with nerve cell loss in the hippocampus and proliferation of smooth endoplasmic reticulum. Whether children with the human counterpart of this malady will be found remains to be determined.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "alpha-helices", + "deleted", + "Deletion", + "of", + "either", + "C-terminal", + "helix", + "the", + "penultimate" + ] + }, + "effect": { + "val": "positive", + "words": [ + "resulted", + "in" + ] + } + } + ] + }, + { + "PMID": "9055859", + "TEXT": "Repression of cell cycle progression by tumor suppressors might provide a means for tumor therapy. Here we demonstrate that ectopic overexpression of the p16INK4/CDKN2 tumor suppressor from an adenovirus vector in various cell lines results in block of cell division and, subsequently, in a gradual reduction of the levels of the product of retinoblastoma susceptibility gene, pRb. Overexpression of p53 and p16INK4/CDKN2, but not p53 on its own, induces apoptotic death only in tumor cells. Simultaneous adenoviral transfer of p16 and p53 genes leads to inhibition of tumor growth in nude mice. These results suggest that combined delivery of two cooperating genes like p16 and p53 could be the basis for the development of a new strategy for cancer gene therapy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "the", + "p16INK4/CDKN2", + "tumor", + "suppressor", + "from", + "an", + "adenovirus", + "vector", + "Simultaneous", + "adenoviral", + "transfer", + "p16", + "and", + "p53", + "genes" + ] + }, + "effect": { + "val": "negative", + "words": [ + "block", + "inhibition" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "ectopic", + "overexpression", + "of", + "the", + "p16INK4/CDKN2", + "tumor", + "suppressor", + "from", + "an", + "adenovirus", + "vector", + "Overexpression", + "p53", + "and", + "p16INK4/CDKN2," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + } + ] + }, + { + "PMID": "8837615", + "TEXT": "The induction of tumor cell death by anticancer therapy results from a genetic program of autonomous cell death termed apoptosis. Because the p53 tumor suppressor gene is a critical component for induction of apoptosis in response to DNA damage, its inactivation in cancers may be responsible for their resistance to genotoxic anticancer agents. The cellular response to DNA damage involves a cell-cycle arrest at both the G1/S and G2/M transitions; these checkpoints maintain viability by preventing the replication or segregation of damaged DNA. The arrest at the G1 checkpoint is mediated by p53-dependent induction of p21WAF1/CIP1, whereas the G2 arrest involves inactivation of p34cdc2 kinase. Following DNA damage, p53-deficient cells fail to arrest at G1 and accumulate at the G2/M transition. We demonstrate that abrogation of G2 arrest by caffeine-mediated activation of p34cdc2 kinase results in the selective sensitization of p53-deficient primary and tumor cells to irradiation-induced apoptosis. These data suggest that pharmacologic activation of p34cdc2 kinase may be a useful therapeutic strategy for circumventing the resistance of p53-deficient cancers to genotoxic anticancer agents.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "fail", + "to", + "abrogation" + ] + } + }, + { + "effect": { + "val": "positive", + "words": [ + "sensitization", + "irradiation-induced" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "p53-deficient" + ] + } + } + ] + }, + { + "PMID": "8782458", + "TEXT": "Soluble HLA class I molecules (sHLAs) have been identified in the serum of patients with inflammatory diseases, allografts and autoimmune diseases and in serum of healthy individuals. The biological significance of these molecules, particularly after allogeneic organ transplantation, has been enigmatic. Here we show that primary alloreactive CD8+ T cells interact with sHLA and undergo apoptosis in the absence of a second signal. Ligation of CD28 rescued T cells from death, implying that sHLAs induce apoptosis through selective stimulation of the T-cell receptor. CD95-L was upregulated after cytotoxic T lymphocytes were incubated with sHLAs, and cell death was blocked by a neutralizing anti-CD95-L antibody, suggesting that sHLAs induce endogenous mutual killing of activated T cells. These results provide a molecular basis for the capacity of sHLAs to downregulate T-cell responses, which may be especially relevant to organ transplantation.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "Ligation", + "of", + "CD28" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + } + ] + }, + { + "PMID": "7489362", + "TEXT": "The p21 gene encodes a cyclin-dependent kinase inhibitor that affects cell-cycle progression, but the potential of this gene product to serve as a tumour suppressor in vivo has not been established. In this report, we show that the growth of malignant cells in vitro and in vivo is inhibited by expression of p21. Expression of p21 resulted in an accumulation of cells in G0/G1, altered morphology, and cell differentiation, but apoptosis was not induced. Introduction of p21 with adenoviral vectors into malignant cells completely suppressed their growth in vivo and also reduced the growth of established pre-existing tumours. Gene transfer of p21 may provide a molecular genetic approach to arresting cancer cell growth by committing malignant cells irreversibly to a pathway of terminal differentiation.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "p21.", + "Expression", + "p21" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "p21.", + "Expression", + "p21" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced." + ] + } + } + ] + }, + { + "PMID": "32284589", + "TEXT": "Among the most urgent public health threats is the worldwide emergence of carbapenem-resistant Enterobacteriaceae1-4, which are resistant to the antibiotic class of 'last resort'. In the United States and Europe, carbapenem-resistant strains of the Klebsiella pneumoniae ST258 (ref. 5) sequence type are dominant, endemic6-8 and associated with high mortality6,9,10. We report the global evolution of pathogenicity in carbapenem-resistant K. pneumoniae, resulting in the repeated convergence of virulence and carbapenem resistance in the United States and Europe, dating back to as early as 2009. We demonstrate that K. pneumoniae can enhance its pathogenicity by adopting two opposing infection programs through easily acquired gain- and loss-of-function mutations. Single-nucleotide polymorphisms in the capsule biosynthesis gene wzc lead to hypercapsule production, which confers phagocytosis resistance, enhanced dissemination and increased mortality in animal models. In contrast, mutations disrupting capsule biosynthesis genes impair capsule production, which enhances epithelial cell invasion, in vitro biofilm formation and persistence in urinary tract infections. These two types of capsule mutants have emerged repeatedly and independently in Europe and the United States, with hypercapsule mutants associated with bloodstream infections and capsule-deficient mutants associated with urinary tract infections. In the latter case, drug-tolerant K. pneumoniae can persist to yield potentially untreatable, persistent infection.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "in", + "the", + "capsule", + "biosynthesis", + "gene", + "wzc", + "mutations", + "disrupting", + "genes" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + } + } + ] + }, + { + "PMID": "31988462", + "TEXT": "Frameshift mutations in the DMD gene, encoding dystrophin, cause Duchenne muscular dystrophy (DMD), leading to terminal muscle and heart failure in patients. Somatic gene editing by sequence-specific nucleases offers new options for restoring the DMD reading frame, resulting in expression of a shortened but largely functional dystrophin protein. Here, we validated this approach in a pig model of DMD lacking exon 52 of DMD (DMDΔ52), as well as in a corresponding patient-derived induced pluripotent stem cell model. In DMDΔ52 pigs1, intramuscular injection of adeno-associated viral vectors of serotype 9 carrying an intein-split Cas9 (ref. 2) and a pair of guide RNAs targeting sequences flanking exon 51 (AAV9-Cas9-gE51) induced expression of a shortened dystrophin (DMDΔ51-52) and improved skeletal muscle function. Moreover, systemic application of AAV9-Cas9-gE51 led to widespread dystrophin expression in muscle, including diaphragm and heart, prolonging survival and reducing arrhythmogenic vulnerability. Similarly, in induced pluripotent stem cell-derived myoblasts and cardiomyocytes of a patient lacking DMDΔ52, AAV6-Cas9-g51-mediated excision of exon 51 restored dystrophin expression and amelioreate skeletal myotube formation as well as abnormal cardiomyocyte Ca2+ handling and arrhythmogenic susceptibility. The ability of Cas9-mediated exon excision to improve DMD pathology in these translational models paves the way for new treatment approaches in patients with this devastating disease.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "DMDΔ52,", + "AAV6-Cas9-g51-mediated", + "excision", + "of", + "exon", + "51" + ] + }, + "effect": { + "val": "negative", + "words": [ + "amelioreate" + ] + } + } + ] + }, + { + "PMID": "31700184", + "TEXT": "A sedentary lifestyle, chronic inflammation and leukocytosis increase atherosclerosis; however, it remains unclear whether regular physical activity influences leukocyte production. Here we show that voluntary running decreases hematopoietic activity in mice. Exercise protects mice and humans with atherosclerosis from chronic leukocytosis but does not compromise emergency hematopoiesis in mice. Mechanistically, exercise diminishes leptin production in adipose tissue, augmenting quiescence-promoting hematopoietic niche factors in leptin-receptor-positive stromal bone marrow cells. Induced deletion of the leptin receptor in Prrx1-creERT2; Leprfl/fl mice reveals that leptin's effect on bone marrow niche cells regulates hematopoietic stem and progenitor cell (HSPC) proliferation and leukocyte production, as well as cardiovascular inflammation and outcomes. Whereas running wheel withdrawal quickly reverses leptin levels, the impact of exercise on leukocyte production and on the HSPC epigenome and transcriptome persists for several weeks. Together, these data show that physical activity alters HSPCs via modulation of their niche, reducing hematopoietic output of inflammatory leukocytes.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Induced", + "deletion", + "of", + "the", + "leptin", + "receptor", + "Prrx1-creERT2;", + "Leprfl/fl" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "regulates" + ] + } + } + ] + }, + { + "PMID": "30858616", + "TEXT": "Malformations of the human cortex represent a major cause of disability1. Mouse models with mutations in known causal genes only partially recapitulate the phenotypes and are therefore not unlimitedly suited for understanding the molecular and cellular mechanisms responsible for these conditions2. Here we study periventricular heterotopia (PH) by analyzing cerebral organoids derived from induced pluripotent stem cells (iPSCs) of patients with mutations in the cadherin receptor-ligand pair DCHS1 and FAT4 or from isogenic knockout (KO) lines1,3. Our results show that human cerebral organoids reproduce the cortical heterotopia associated with PH. Mutations in DCHS1 and FAT4 or knockdown of their expression causes changes in the morphology of neural progenitor cells and result in defective neuronal migration dynamics only in a subset of neurons. Single-cell RNA-sequencing (scRNA-seq) data reveal a subpopulation of mutant neurons with dysregulated genes involved in axon guidance, neuronal migration and patterning. We suggest that defective neural progenitor cell (NPC) morphology and an altered navigation system in a subset of neurons underlie this form of PH.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "isogenic", + "knockout", + "(KO)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "Mutations", + "in", + "DCHS1", + "and", + "FAT4" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "knockdown", + "of", + "their", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defective" + ] + } + } + ] + }, + { + "PMID": "30833752", + "TEXT": "Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent tumorigenic growth, but the role of KRAS in supporting autophagy has not been established. We show that, to our surprise, suppression of KRAS increased autophagic flux, as did pharmacological inhibition of its effector ERK MAPK. Furthermore, we demonstrate that either KRAS suppression or ERK inhibition decreased both glycolytic and mitochondrial functions. We speculated that ERK inhibition might thus enhance PDAC dependence on autophagy, in part by impairing other KRAS- or ERK-driven metabolic processes. Accordingly, we found that the autophagy inhibitor chloroquine and genetic or pharmacologic inhibition of specific autophagy regulators synergistically enhanced the ability of ERK inhibitors to mediate antitumor activity in KRAS-driven PDAC. We conclude that combinations of pharmacologic inhibitors that concurrently block both ERK MAPK and autophagic processes that are upregulated in response to ERK inhibition may be effective treatments for PDAC.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "suppression", + "of", + "KRAS" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + } + ] + }, + { + "PMID": "30510251", + "TEXT": "In T lymphocytes, the Wiskott-Aldrich Syndrome protein (WASP) and WASP-interacting-protein (WIP) regulate T cell antigen receptor (TCR) signaling, but their role in lymphoma is largely unknown. Here we show that the expression of WASP and WIP is frequently low or absent in anaplastic large cell lymphoma (ALCL) compared to other T cell lymphomas. In anaplastic lymphoma kinase-positive (ALK+) ALCL, WASP and WIP expression is regulated by ALK oncogenic activity via its downstream mediators STAT3 and C/EBP-β. ALK+ lymphomas were accelerated in WASP- and WIP-deficient mice. In the absence of WASP, active GTP-bound CDC42 was increased and the genetic deletion of one CDC42 allele was sufficient to impair lymphoma growth. WASP-deficient lymphoma showed increased mitogen-activated protein kinase (MAPK) pathway activation that could be exploited as a therapeutic vulnerability. Our findings demonstrate that WASP and WIP are tumor suppressors in T cell lymphoma and suggest that MAP-kinase kinase (MEK) inhibitors combined with ALK inhibitors could achieve a more potent therapeutic effect in ALK+ ALCL.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "absence", + "of", + "WASP,", + "genetic", + "deletion", + "one", + "CDC42", + "allele" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impair" + ] + } + } + ] + }, + { + "PMID": "30478424", + "TEXT": "Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "epidermal", + "growth", + "factor", + "receptor", + "(EGFR)-mutant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "mitigates" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "epidermal", + "growth", + "factor", + "receptor", + "(EGFR)-mutant" + ] + }, + "effect": { + "val": "positive", + "words": [ + "drug-induced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EGFR", + "inhibition" + ] + }, + "effect": { + "val": "negative", + "words": [ + "mitigates" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "EGFR", + "inhibition" + ] + }, + "effect": { + "val": "positive", + "words": [ + "drug-induced" + ] + } + } + ] + }, + { + "PMID": "30478421", + "TEXT": "Treatment of prostate cancer (PC) by androgen suppression promotes the emergence of aggressive variants that are androgen receptor (AR) independent. Here we identify the transcription factor ONECUT2 (OC2) as a master regulator of AR networks in metastatic castration-resistant prostate cancer (mCRPC). OC2 acts as a survival factor in mCRPC models, suppresses the AR transcriptional program by direct regulation of AR target genes and the AR licensing factor FOXA1, and activates genes associated with neural differentiation and progression to lethal disease. OC2 appears active in a substantial subset of human prostate adenocarcinoma and neuroendocrine tumors. Inhibition of OC2 by a newly identified small molecule suppresses metastasis in mice. These findings suggest that OC2 displaces AR-dependent growth and survival mechanisms in many cases where AR remains expressed, but where its activity is bypassed. OC2 is also a potential drug target in the metastatic phase of aggressive PC.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "OC2", + "by", + "a", + "newly", + "identified", + "small", + "molecule" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppresses" + ] + } + } + ] + }, + { + "PMID": "30061698", + "TEXT": "Sarcopenia, the degenerative loss of skeletal muscle mass, quality and strength, lacks early diagnostic tools and new therapeutic strategies to prevent the frailty-to-disability transition often responsible for the medical institutionalization of elderly individuals. Herein we report that production of the endogenous peptide apelin, induced by muscle contraction, is reduced in an age-dependent manner in humans and rodents and is positively associated with the beneficial effects of exercise in older persons. Mice deficient in either apelin or its receptor (APLNR) presented dramatic alterations in muscle function with increasing age. Various strategies that restored apelin signaling during aging further demonstrated that this peptide considerably enhanced muscle function by triggering mitochondriogenesis, autophagy and anti-inflammatory pathways in myofibers as well as enhancing the regenerative capacity by targeting muscle stem cells. Taken together, these findings revealed positive regulatory feedback between physical activity, apelin and muscle function and identified apelin both as a tool for diagnosis of early sarcopenia and as the target of an innovative pharmacological strategy to prevent age-associated muscle weakness and restore physical autonomy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "either", + "apelin", + "or", + "its", + "receptor", + "(APLNR)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "triggering" + ] + } + } + ] + }, + { + "PMID": "29875463", + "TEXT": "Patients with metastatic cancer experience a severe loss of skeletal muscle mass and function known as cachexia. Cachexia is associated with poor prognosis and accelerated death in patients with cancer, yet its underlying mechanisms remain poorly understood. Here, we identify the metal-ion transporter ZRT- and IRT-like protein 14 (ZIP14) as a critical mediator of cancer-induced cachexia. ZIP14 is upregulated in cachectic muscles of mice and in patients with metastatic cancer and can be induced by TNF-α and TGF-β cytokines. Strikingly, germline ablation or muscle-specific depletion of Zip14 markedly reduces muscle atrophy in metastatic cancer models. We find that ZIP14-mediated zinc uptake in muscle progenitor cells represses the expression of MyoD and Mef2c and blocks muscle-cell differentiation. Importantly, ZIP14-mediated zinc accumulation in differentiated muscle cells induces myosin heavy chain loss. These results highlight a previously unrecognized role for altered zinc homeostasis in metastatic cancer-induced muscle wasting and implicate ZIP14 as a therapeutic target for its treatment.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "muscle-specific", + "depletion", + "of", + "Zip14" + ] + }, + "effect": { + "val": "negative", + "words": [ + "blocks" + ] + } + } + ] + }, + { + "PMID": "28920958", + "TEXT": "N6-methyladenosine (m6A) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the m6A modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the m6A-forming enzyme METTL3 in human hematopoietic stem/progenitor cells (HSPCs) promotes cell differentiation, coupled with reduced cell proliferation. Conversely, overexpression of wild-type METTL3, but not of a catalytically inactive form of METTL3, inhibits cell differentiation and increases cell growth. METTL3 mRNA and protein are expressed more abundantly in acute myeloid leukemia (AML) cells than in healthy HSPCs or other types of tumor cells. Furthermore, METTL3 depletion in human myeloid leukemia cell lines induces cell differentiation and apoptosis and delays leukemia progression in recipient mice in vivo. Single-nucleotide-resolution mapping of m6A coupled with ribosome profiling reveals that m6A promotes the translation of c-MYC, BCL2 and PTEN mRNAs in the human acute myeloid leukemia MOLM-13 cell line. Moreover, loss of METTL3 leads to increased levels of phosphorylated AKT, which contributes to the differentiation-promoting effects of METTL3 depletion. Overall, these results provide a rationale for the therapeutic targeting of METTL3 in myeloid leukemia.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "shRNA-mediated", + "depletion", + "of", + "the", + "m6A-forming", + "enzyme", + "METTL3" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes", + "increases", + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "shRNA-mediated", + "depletion", + "of", + "the", + "m6A-forming", + "enzyme", + "METTL3" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced", + "inhibits", + "delays" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "wild-type", + "METTL3," + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits", + "delays" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "wild-type", + "METTL3," + ] + }, + "effect": { + "val": "positive", + "words": [ + "increases", + "induces" + ] + } + } + ] + }, + { + "PMID": "28628110", + "TEXT": "With the goal of modeling human disease of the large intestine, we sought to develop an effective protocol for deriving colonic organoids (COs) from differentiated human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs). Extensive gene and immunohistochemical profiling confirmed that the derived COs represent colon rather than small intestine, containing stem cells, transit-amplifying cells, and the expected spectrum of differentiated cells, including goblet and endocrine cells. We applied this strategy to iPSCs derived from patients with familial adenomatous polyposis (FAP-iPSCs) harboring germline mutations in the WNT-signaling-pathway-regulator gene encoding APC, and we generated COs that exhibit enhanced WNT activity and increased epithelial cell proliferation, which we used as a platform for drug testing. Two potential compounds, XAV939 and rapamycin, decreased proliferation in FAP-COs, but also affected cell proliferation in wild-type COs, which thus limits their therapeutic application. By contrast, we found that geneticin, a ribosome-binding antibiotic with translational 'read-through' activity, efficiently targeted abnormal WNT activity and restored normal proliferation specifically in APC-mutant FAP-COs. These studies provide an efficient strategy for deriving human COs, which can be used in disease modeling and drug discovery for colorectal disease.", + "LINKED_TAGS": [ + { + "effect": { + "val": "rescues", + "words": [ + "restored" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "APC-mutant" + ] + } + } + ] + }, + { + "PMID": "28191887", + "TEXT": "Expression of the MECOM (also known as EVI1) proto-oncogene is deregulated by chromosomal translocations in some cases of acute myeloid leukemia (AML) and is associated with poor clinical outcome. Here, through transcriptomic and metabolomic profiling of hematopoietic cells, we reveal that EVI1 overexpression alters cellular metabolism. A screen using pooled short hairpin RNAs (shRNAs) identified the ATP-buffering, mitochondrial creatine kinase CKMT1 as necessary for survival of EVI1-expressing cells in subjects with EVI1-positive AML. EVI1 promotes CKMT1 expression by repressing the myeloid differentiation regulator RUNX1. Suppression of arginine-creatine metabolism by CKMT1-directed shRNAs or by the small molecule cyclocreatine selectively decreased the viability, promoted the cell cycle arrest and apoptosis of human EVI1-positive cell lines, and prolonged survival in both orthotopic xenograft models and mouse models of primary AML. CKMT1 inhibition altered mitochondrial respiration and ATP production, an effect that was abrogated by phosphocreatine-mediated reactivation of the arginine-creatine pathway. Targeting CKMT1 is thus a promising therapeutic strategy for this EVI1-driven AML subtype that is highly resistant to current treatment regimens.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "CKMT1-directed", + "shRNAs" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + } + ] + }, + { + "PMID": "27775704", + "TEXT": "Triple-negative breast cancers (TNBCs) have poor prognosis and lack targeted therapies. Here we identified increased copy number and expression of the PIM1 proto-oncogene in genomic data sets of patients with TNBC. TNBC cells, but not nonmalignant mammary epithelial cells, were dependent on PIM1 for proliferation and protection from apoptosis. PIM1 knockdown reduced expression of the anti-apoptotic factor BCL2, and dynamic BH3 profiling of apoptotic priming revealed that PIM1 prevents mitochondrial-mediated apoptosis in TNBC cell lines. In TNBC tumors and their cellular models, PIM1 expression was associated with several transcriptional signatures involving the transcription factor MYC, and PIM1 depletion in TNBC cell lines decreased, in a MYC-dependent manner, cell population growth and expression of the MYC target gene MCL1. Treatment with the pan-PIM kinase inhibitor AZD1208 impaired the growth of both cell line and patient-derived xenografts and sensitized them to standard-of-care chemotherapy. This work identifies PIM1 as a malignant-cell-selective target in TNBC and the potential use of PIM1 inhibitors for sensitizing TNBC to chemotherapy-induced apoptotic cell death.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "PIM1", + "knockdown" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PIM1", + "depletion" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased," + ] + } + } + ] + }, + { + "PMID": "26950362", + "TEXT": "Cellular senescence is thought to contribute to age-associated deterioration of tissue physiology. The senescence effector p16(Ink4a) is expressed in pancreatic beta cells during aging and limits their proliferative potential; however, its effects on beta cell function are poorly characterized. We found that beta cell-specific activation of p16(Ink4a) in transgenic mice enhances glucose-stimulated insulin secretion (GSIS). In mice with diabetes, this leads to improved glucose homeostasis, providing an unexpected functional benefit. Expression of p16(Ink4a) in beta cells induces hallmarks of senescence--including cell enlargement, and greater glucose uptake and mitochondrial activity--which promote increased insulin secretion. GSIS increases during the normal aging of mice and is driven by elevated p16(Ink4a) activity. We found that islets from human adults contain p16(Ink4a)-expressing senescent beta cells and that senescence induced by p16(Ink4a) in a human beta cell line increases insulin secretion in a manner dependent, in part, on the activity of the mechanistic target of rapamycin (mTOR) and the peroxisome proliferator-activated receptor (PPAR)-γ proteins. Our findings reveal a novel role for p16(Ink4a) and cellular senescence in promoting insulin secretion by beta cells and in regulating normal functional tissue maturation with age.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "beta", + "cell-specific", + "activation", + "of", + "p16(Ink4a)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "Expression", + "of", + "p16(Ink4a)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + } + ] + }, + { + "PMID": "26642437", + "TEXT": "The glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor transduce nutrient-stimulated signals to control beta cell function. Although the GLP-1 receptor (GLP-1R) is a validated drug target for diabetes, the importance of the GIP receptor (GIPR) for the function of beta cells remains uncertain. We demonstrate that mice with selective ablation of GIPR in beta cells (MIP-Cre:Gipr(Flox/Flox); Gipr(-/-βCell)) exhibit lower levels of meal-stimulated insulin secretion, decreased expansion of adipose tissue mass and preservation of insulin sensitivity when compared to MIP-Cre controls. Beta cells from Gipr(-/-βCell) mice display greater sensitivity to apoptosis and markedly lower islet expression of T cell-specific transcription factor-1 (TCF1, encoded by Tcf7), a protein not previously characterized in beta cells. GIP, but not GLP-1, promotes beta cell Tcf7 expression via a cyclic adenosine monophosphate (cAMP)-independent and extracellular signal-regulated kinase (ERK)-dependent pathway. Tcf7 (in mice) or TCF7 (in humans) levels are lower in islets taken from diabetic mice and in humans with type 2 diabetes; knockdown of TCF7 in human and mouse islets impairs the cytoprotective responsiveness to GIP and enhances the magnitude of apoptotic injury, whereas restoring TCF1 levels in beta cells from Gipr(-/-βCell) mice lowers the number of apoptotic cells compared to that seen in MIP-Cre controls. Tcf7(-/-) mice show impaired insulin secretion, deterioration of glucose tolerance with either aging and/or high-fat feeding and increased sensitivity to beta cell injury relative to wild-type (WT) controls. Hence the GIPR-TCF1 axis represents a potential therapeutic target for preserving both the function and survival of vulnerable, diabetic beta cells.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "selective", + "ablation", + "of", + "GIPR", + "in", + "beta", + "cells", + "(MIP-Cre:Gipr(Flox/Flox);", + "Gipr(-/-βCell))", + "Gipr(-/-βCell)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "greater", + "sensitivity" + ] + } + } + ] + }, + { + "PMID": "26569382", + "TEXT": "Primary myelofibrosis (PMF) is characterized by bone marrow fibrosis, myeloproliferation, extramedullary hematopoiesis, splenomegaly and leukemic progression. Moreover, the bone marrow and spleens of individuals with PMF contain large numbers of atypical megakaryocytes that are postulated to contribute to fibrosis through the release of cytokines, including transforming growth factor (TGF)-β. Although the Janus kinase inhibitor ruxolitinib provides symptomatic relief, it does not reduce the mutant allele burden or substantially reverse fibrosis. Here we show through pharmacologic and genetic studies that aurora kinase A (AURKA) represents a new therapeutic target in PMF. Treatment with MLN8237, a selective AURKA inhibitor, promoted polyploidization and differentiation of megakaryocytes with PMF-associated mutations and had potent antifibrotic and antitumor activity in vivo in mouse models of PMF. Moreover, heterozygous deletion of Aurka was sufficient to ameliorate fibrosis and other PMF features in vivo. Our data suggest that megakaryocytes drive fibrosis in PMF and that targeting them with AURKA inhibitors has the potential to provide therapeutic benefit.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "MLN8237,", + "a", + "selective", + "AURKA", + "inhibitor," + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + } + ] + }, + { + "PMID": "26479921", + "TEXT": "Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive neoplasm characterized by a marked fibro-inflammatory microenvironment, the presence of which can promote both cancer induction and growth. Therefore, selective manipulation of local cytokines is an attractive, although unrealized, therapeutic approach. T cells possess a unique mechanism of p38 mitogen-activated protein kinase (MAPK) activation downstream of T cell receptor (TCR) engagement through the phosphorylation of Tyr323 (pY323). This alternative p38 activation pathway is required for pro-inflammatory cytokine production. Here we show in human PDAC that a high percentage of infiltrating pY323(+) T cells was associated with large numbers of tumor necrosis factor (TNF)-α- and interleukin (IL)-17-producing CD4(+) tumor-infiltrating lymphocytes (TILs) and aggressive disease. The growth of mouse pancreatic tumors was inhibited by genetic ablation of the alternative p38 pathway, and transfer of wild-type CD4(+) T cells, but not those lacking the alternative pathway, enhanced tumor growth in T cell-deficient mice. Notably, a plasma membrane-permeable peptide derived from GADD45-α, the naturally occurring inhibitor of p38 pY323(+) (ref. 7), reduced CD4(+) TIL production of TNF-α, IL-17A, IL-10 and secondary cytokines, halted growth of implanted tumors and inhibited progression of spontaneous KRAS-driven adenocarcinoma in mice. Thus, TCR-mediated activation of CD4(+) TILs results in alternative p38 activation and production of protumorigenic factors and can be targeted for therapeutic benefit.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "of", + "the", + "p38", + "T", + "cell-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + } + ] + }, + { + "PMID": "26437366", + "TEXT": "The tumor suppressors BAP1 and ASXL1 interact to form a polycomb deubiquitinase complex that removes monoubiquitin from histone H2A lysine 119 (H2AK119Ub). However, BAP1 and ASXL1 are mutated in distinct cancer types, consistent with independent roles in regulating epigenetic state and malignant transformation. Here we demonstrate that Bap1 loss in mice results in increased trimethylated histone H3 lysine 27 (H3K27me3), elevated enhancer of zeste 2 polycomb repressive complex 2 subunit (Ezh2) expression, and enhanced repression of polycomb repressive complex 2 (PRC2) targets. These findings contrast with the reduction in H3K27me3 levels seen with Asxl1 loss. Conditional deletion of Bap1 and Ezh2 in vivo abrogates the myeloid progenitor expansion induced by Bap1 loss alone. Loss of BAP1 results in a marked decrease in H4K20 monomethylation (H4K20me1). Consistent with a role for H4K20me1 in the transcriptional regulation of EZH2, expression of SETD8-the H4K20me1 methyltransferase-reduces EZH2 expression and abrogates the proliferation of BAP1-mutant cells. Furthermore, mesothelioma cells that lack BAP1 are sensitive to EZH2 pharmacologic inhibition, suggesting a novel therapeutic approach for BAP1-mutant malignancies.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "deletion", + "of", + "Loss", + "BAP1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "abrogates" + ] + }, + "perturbing_action": { + "val": "other", + "words": [ + "BAP1-mutant" + ] + } + } + ] + }, + { + "PMID": "26366712", + "TEXT": "Mutations in the gene encoding the KMT2D (or MLL2) methyltransferase are highly recurrent and occur early during tumorigenesis in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). However, the functional consequences of these mutations and their role in lymphomagenesis are unknown. Here we show that FL- and DLBCL-associated KMT2D mutations impair KMT2D enzymatic activity, leading to diminished global H3K4 methylation in germinal-center (GC) B cells and DLBCL cells. Conditional deletion of Kmt2d early during B cell development, but not after initiation of the GC reaction, results in an increase in GC B cells and enhances B cell proliferation in mice. Moreover, genetic ablation of Kmt2d in mice overexpressing Bcl2 increases the incidence of GC-derived lymphomas resembling human tumors. These findings suggest that KMT2D acts as a tumor suppressor gene whose early loss facilitates lymphomagenesis by remodeling the epigenetic landscape of the cancer precursor cells. Eradication of KMT2D-deficient cells may thus represent a rational therapeutic approach for targeting early tumorigenic events.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Conditional", + "deletion", + "of", + "Kmt2d" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + } + } + ] + }, + { + "PMID": "26366710", + "TEXT": "The gene encoding the lysine-specific histone methyltransferase KMT2D has emerged as one of the most frequently mutated genes in follicular lymphoma and diffuse large B cell lymphoma; however, the biological consequences of KMT2D mutations on lymphoma development are not known. Here we show that KMT2D functions as a bona fide tumor suppressor and that its genetic ablation in B cells promotes lymphoma development in mice. KMT2D deficiency also delays germinal center involution and impedes B cell differentiation and class switch recombination. Integrative genomic analyses indicate that KMT2D affects methylation of lysine 4 on histone H3 (H3K4) and expression of a set of genes, including those in the CD40, JAK-STAT, Toll-like receptor and B cell receptor signaling pathways. Notably, other KMT2D target genes include frequently mutated tumor suppressor genes such as TNFAIP3, SOCS3 and TNFRSF14. Therefore, KMT2D mutations may promote malignant outgrowth by perturbing the expression of tumor suppressor genes that control B cell-activating pathways.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "genetic", + "ablation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "KMT2D", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impedes" + ] + } + } + ] + }, + { + "PMID": "26107252", + "TEXT": "The inflammasome activates caspase-1 and the release of interleukin-1β (IL-1β) and IL-18, and several inflammasomes protect against intestinal inflammation and colitis-associated colon cancer (CAC) in animal models. The absent in melanoma 2 (AIM2) inflammasome is activated by double-stranded DNA, and AIM2 expression is reduced in several types of cancer, but the mechanism by which AIM2 restricts tumor growth remains unclear. We found that Aim2-deficient mice had greater tumor load than Asc-deficient mice in the azoxymethane/dextran sodium sulfate (AOM/DSS) model of colorectal cancer. Tumor burden was also higher in Aim2(-/-)/Apc(Min/+) than in APC(Min/+) mice. The effects of AIM2 on CAC were independent of inflammasome activation and IL-1β and were primarily mediated by a non-bone marrow source of AIM2. In resting cells, AIM2 physically interacted with and limited activation of DNA-dependent protein kinase (DNA-PK), a PI3K-related family member that promotes Akt phosphorylation, whereas loss of AIM2 promoted DNA-PK-mediated Akt activation. AIM2 reduced Akt activation and tumor burden in colorectal cancer models, while an Akt inhibitor reduced tumor load in Aim2(-/-) mice. These findings suggest that Akt inhibitors could be used to treat AIM2-deficient human cancers.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Aim2-deficient", + "Asc-deficient", + "Aim2(-/-)/Apc(Min/+)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "greater", + "higher" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Akt", + "inhibitor" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Aim2(-/-)" + ] + } + } + ] + }, + { + "PMID": "25706874", + "TEXT": "Insulin resistance results from several pathophysiologic mechanisms, including chronic tissue inflammation and defective insulin signaling. We found that liver, muscle and adipose tissue exhibit higher levels of the chemotactic eicosanoid LTB4 in obese high-fat diet (HFD)-fed mice. Inhibition of the LTB4 receptor Ltb4r1, through either genetic or pharmacologic loss of function, led to an anti-inflammatory phenotype with protection from insulin resistance and hepatic steatosis. In vitro treatment with LTB4 directly enhanced macrophage chemotaxis, stimulated inflammatory pathways, reduced insulin-stimulated glucose uptake in L6 myocytes, and impaired insulin-mediated suppression of hepatic glucose output in primary mouse hepatocytes. This was accompanied by lower insulin-stimulated Akt phosphorylation and higher Irs-1/2 serine phosphorylation, and all of these events were dependent on Gαi and Jnk1, two downstream mediators of Ltb4r1 signaling. These observations elucidate a novel role of the LTB4-Ltb4r1 signaling pathway in hepatocyte and myocyte insulin resistance, and they show that in vivo inhibition of Ltb4r1 leads to robust insulin-sensitizing effects.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "the", + "LTB4", + "receptor", + "Ltb4r1," + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "pharmacologic", + "loss", + "of", + "function," + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + } + ] + }, + { + "PMID": "25665179", + "TEXT": "Currently, major concerns about the safety and efficacy of RNA interference (RNAi)-based bone anabolic strategies still exist because of the lack of direct osteoblast-specific delivery systems for osteogenic siRNAs. Here we screened the aptamer CH6 by cell-SELEX, specifically targeting both rat and human osteoblasts, and then we developed CH6 aptamer-functionalized lipid nanoparticles (LNPs) encapsulating osteogenic pleckstrin homology domain-containing family O member 1 (Plekho1) siRNA (CH6-LNPs-siRNA). Our results showed that CH6 facilitated in vitro osteoblast-selective uptake of Plekho1 siRNA, mainly via macropinocytosis, and boosted in vivo osteoblast-specific Plekho1 gene silencing, which promoted bone formation, improved bone microarchitecture, increased bone mass and enhanced mechanical properties in both osteopenic and healthy rodents. These results indicate that osteoblast-specific aptamer-functionalized LNPs could act as a new RNAi-based bone anabolic strategy, advancing the targeted delivery selectivity of osteogenic siRNAs from the tissue level to the cellular level.", + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "boosted", + "promoted" + ] + }, + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "osteoblast-specific", + "Plekho1", + "gene", + "silencing," + ] + } + } + ] + }, + { + "PMID": "25344738", + "TEXT": "Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell-mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN-α and IFN-β receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release of chemokine (C-X-C motif) ligand 10 (CXCL10). Tumors lacking Tlr3 or Ifnar failed to respond to chemotherapy unless type I IFN or Cxcl10, respectively, was artificially supplied. Moreover, a type I IFN-related signature predicted clinical responses to anthracycline-based chemotherapy in several independent cohorts of patients with breast carcinoma characterized by poor prognosis. Our data suggest that anthracycline-mediated immune responses mimic those induced by viral pathogens. We surmise that such 'viral mimicry' constitutes a hallmark of successful chemotherapy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "Tlr3", + "or", + "Ifnar" + ] + }, + "effect": { + "val": "negative", + "words": [ + "failed" + ] + } + } + ] + }, + { + "PMID": "25326802", + "TEXT": "In the bone marrow, hematopoietic stem cells (HSCs) lodge in specialized microenvironments that tightly control the proliferative state of HSCs to adapt to the varying needs for replenishment of blood cells while also preventing HSC exhaustion. All putative niche cells suggested thus far have a nonhematopoietic origin. Thus, it remains unclear how feedback from mature cells is conveyed to HSCs to adjust their proliferation. Here we show that megakaryocytes (MKs) can directly regulate HSC pool size in mice. Three-dimensional whole-mount imaging revealed that endogenous HSCs are frequently located adjacent to MKs in a nonrandom fashion. Selective in vivo depletion of MKs resulted in specific loss of HSC quiescence and led to a marked expansion of functional HSCs. Gene expression analyses revealed that MKs are the source of chemokine C-X-C motif ligand 4 (CXCL4, also named platelet factor 4 or PF4) in the bone marrow, and we found that CXCL4 regulates HSC cell cycle activity. CXCL4 injection into mice resulted in a reduced number of HSCs because of their increased quiescence. By contrast, Cxcl4(-/-) mice exhibited an increased number of HSCs and increased HSC proliferation. Combined use of whole-mount imaging and computational modeling was highly suggestive of a megakaryocytic niche capable of independently influencing HSC maintenance by regulating quiescence. These results indicate that a terminally differentiated cell type derived from HSCs contributes to the HSC niche, directly regulating HSC behavior.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "depletion", + "of", + "MKs" + ] + }, + "effect": { + "val": "negative", + "words": [ + "loss" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Cxcl4(-/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + } + ] + }, + { + "PMID": "25282358", + "TEXT": "Osteogenesis during bone modeling and remodeling is coupled with angiogenesis. A recent study showed that a specific vessel subtype, strongly positive for CD31 and endomucin (CD31(hi)Emcn(hi)), couples angiogenesis and osteogenesis. Here, we found that platelet-derived growth factor-BB (PDGF-BB) secreted by preosteoclasts induces CD31(hi)Emcn(hi) vessel formation during bone modeling and remodeling. Mice with depletion of PDGF-BB in the tartrate-resistant acid phosphatase-positive cell lineage show significantly lower trabecular and cortical bone mass, serum and bone marrow PDGF-BB concentrations, and fewer CD31(hi)Emcn(hi) vessels compared to wild-type mice. In the ovariectomy (OVX)-induced osteoporotic mouse model, serum and bone marrow levels of PDGF-BB and numbers of CD31(hi)Emcn(hi) vessels are significantly lower compared to sham-operated controls. Treatment with exogenous PDGF-BB or inhibition of cathepsin K to increase the number of preosteoclasts, and thus the endogenous levels of PDGF-BB, increases CD31(hi)Emcn(hi) vessel number and stimulates bone formation in OVX mice. Thus, pharmacotherapies that increase PDGF-BB secretion from preosteoclasts offer a new therapeutic target for treating osteoporosis by promoting angiogenesis and thus bone formation.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "cathepsin", + "K" + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulates" + ] + } + } + ] + }, + { + "PMID": "25150498", + "TEXT": "Duplication of the gene encoding the peripheral myelin protein of 22 kDa (PMP22) underlies the most common inherited neuropathy, Charcot-Marie-Tooth 1A (CMT1A), a disease without a known cure. Although demyelination represents a characteristic feature, the clinical phenotype of CMT1A is determined by the degree of axonal loss, and patients suffer from progressive muscle weakness and impaired sensation. CMT1A disease manifests within the first two decades of life, and walking disabilities, foot deformities and electrophysiological abnormalities are already present in childhood. Here, we show in Pmp22-transgenic rodent models of CMT1A that Schwann cells acquire a persistent differentiation defect during early postnatal development, caused by imbalanced activity of the PI3K-Akt and the Mek-Erk signaling pathways. We demonstrate that enhanced PI3K-Akt signaling by axonally overexpressed neuregulin-1 (NRG1) type I drives diseased Schwann cells toward differentiation and preserves peripheral nerve axons. Notably, in a preclinical experimental therapy using a CMT1A rat model, when treatment is restricted to early postnatal development, soluble NRG1 effectively overcomes impaired peripheral nerve development and restores axon survival into adulthood. Our findings suggest a model in which Schwann cell differentiation within a limited time window is crucial for the long-term maintenance of axonal support.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Pmp22-transgenic" + ] + }, + "effect": { + "val": "positive", + "words": [ + "acquire" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Pmp22-transgenic" + ] + }, + "effect": { + "val": "negative", + "words": [ + "defect" + ] + } + } + ] + }, + { + "PMID": "25150496", + "TEXT": "Medulloblastoma, the most common malignant childhood brain tumor, exhibits distinct molecular subtypes and cellular origins. Genetic alterations driving medulloblastoma initiation and progression remain poorly understood. Herein, we identify GNAS, encoding the G protein Gαs, as a potent tumor suppressor gene that, when expressed at low levels, defines a subset of aggressive Sonic hedgehog (SHH)-driven human medulloblastomas. Ablation of the single Gnas gene in anatomically distinct progenitors in mice is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. Gαs is highly enriched at the primary cilium of granule neuron precursors and suppresses Shh signaling by regulating both the cAMP-dependent pathway and ciliary trafficking of Hedgehog pathway components. Elevation in levels of a Gαs effector, cAMP, effectively inhibits tumor cell proliferation and progression in Gnas-ablated mice. Thus, our gain- and loss-of-function studies identify a previously unrecognized tumor suppressor function for Gαs that can be found consistently across Shh-group medulloblastomas of disparate cellular and anatomical origins, highlighting G protein modulation as a potential therapeutic avenue.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Ablation", + "of", + "the", + "single", + "Gnas", + "gene" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "inhibits" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Gnas-ablated" + ] + } + } + ] + }, + { + "PMID": "24658077", + "TEXT": "The pathophysiology of ineffective erythropoiesis in β-thalassemia is poorly understood. We report that RAP-011, an activin receptor IIA (ActRIIA) ligand trap, improved ineffective erythropoiesis, corrected anemia and limited iron overload in a mouse model of β-thalassemia intermedia. Expression of growth differentiation factor 11 (GDF11), an ActRIIA ligand, was increased in splenic erythroblasts from thalassemic mice and in erythroblasts and sera from subjects with β-thalassemia. Inactivation of GDF11 decreased oxidative stress and the amount of α-globin membrane precipitates, resulting in increased terminal erythroid differentiation. Abnormal GDF11 expression was dependent on reactive oxygen species, suggesting the existence of an autocrine amplification loop in β-thalassemia. GDF11 inactivation also corrected the abnormal ratio of immature/mature erythroblasts by inducing apoptosis of immature erythroblasts through the Fas-Fas ligand pathway. Taken together, these observations suggest that ActRIIA ligand traps may have therapeutic relevance in β-thalassemia by suppressing the deleterious effects of GDF11, a cytokine which blocks terminal erythroid maturation through an autocrine amplification loop involving oxidative stress and α-globin precipitation.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Inactivation", + "of", + "GDF11", + "inactivation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "inducing" + ] + } + } + ] + }, + { + "PMID": "24487434", + "TEXT": "Loss of function of the tumor suppressor gene PRDM1 (also known as BLIMP1) or deregulated expression of the oncogene BCL6 occurs in a large proportion of diffuse large B cell lymphoma (DLBCL) cases. However, targeted mutation of either gene in mice leads to only slow and infrequent development of malignant lymphoma, and despite frequent mutation of BCL6 in activated B cells of healthy individuals, lymphoma development is rare. Here we show that T cells prevent the development of overt lymphoma in mice caused by Blimp1 deficiency or overexpression of Bcl6 in the B cell lineage. Impairment of T cell control results in rapid development of DLBCL-like disease, which can be eradicated by polyclonal CD8(+) T cells in a T cell receptor-, CD28- and Fas ligand-dependent manner. Thus, malignant transformation of mature B cells requires mutations that impair intrinsic differentiation processes and permit escape from T cell-mediated tumor surveillance.", + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Blimp1", + "deficiency" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "prevent" + ] + }, + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Bcl6", + "the" + ] + } + } + ] + }, + { + "PMID": "24292392", + "TEXT": "Tumor recurrence following treatment remains a major clinical challenge. Evidence from xenograft models and human trials indicates selective enrichment of cancer-initiating cells (CICs) in tumors that survive therapy. Together with recent reports showing that CIC gene signatures influence patient survival, these studies predict that targeting self-renewal, the key 'stemness' property unique to CICs, may represent a new paradigm in cancer therapy. Here we demonstrate that tumor formation and, more specifically, human colorectal CIC function are dependent on the canonical self-renewal regulator BMI-1. Downregulation of BMI-1 inhibits the ability of colorectal CICs to self-renew, resulting in the abrogation of their tumorigenic potential. Treatment of primary colorectal cancer xenografts with a small-molecule BMI-1 inhibitor resulted in colorectal CIC loss with long-term and irreversible impairment of tumor growth. Targeting the BMI-1-related self-renewal machinery provides the basis for a new therapeutic approach in the treatment of colorectal cancer.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Downregulation", + "of", + "BMI-1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibits", + "ability", + "abrogation" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "BMI-1", + "inhibitor" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impairment" + ] + } + } + ] + }, + { + "PMID": "24162813", + "TEXT": "Like their normal hematopoietic stem cell counterparts, leukemia stem cells (LSCs) in chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) are presumed to reside in specific niches in the bone marrow microenvironment (BMM) and may be the cause of relapse following chemotherapy. Targeting the niche is a new strategy to eliminate persistent and drug-resistant LSCs. CD44 (refs. 3,4) and interleukin-6 (ref. 5) have been implicated previously in the LSC niche. Transforming growth factor-β1 (TGF-β1) is released during bone remodeling and plays a part in maintenance of CML LSCs, but a role for TGF-β1 from the BMM has not been defined. Here, we show that alteration of the BMM by osteoblastic cell-specific activation of the parathyroid hormone (PTH) receptor attenuates BCR-ABL1 oncogene-induced CML-like myeloproliferative neoplasia (MPN) but enhances MLL-AF9 oncogene-induced AML in mouse transplantation models, possibly through opposing effects of increased TGF-β1 on the respective LSCs. PTH treatment caused a 15-fold decrease in LSCs in wild-type mice with CML-like MPN and reduced engraftment of immune-deficient mice with primary human CML cells. These results demonstrate that LSC niches in CML and AML are distinct and suggest that modulation of the BMM by PTH may be a feasible strategy to reduce LSCs, a prerequisite for the cure of CML.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "osteoblastic", + "cell-specific", + "activation", + "of", + "the", + "parathyroid", + "hormone", + "(PTH)", + "receptor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhances" + ] + } + } + ] + }, + { + "PMID": "24076665", + "TEXT": "In glioblastoma, phosphatidylinositol 3-kinase (PI3K) signaling is frequently activated by loss of the tumor suppressor phosphatase and tensin homolog (PTEN). However, it is not known whether inhibiting PI3K represents a selective and effective approach for treatment. We interrogated large databases and found that sonic hedgehog (SHH) signaling is activated in PTEN-deficient glioblastoma. We demonstrate that the SHH and PI3K pathways synergize to promote tumor growth and viability in human PTEN-deficient glioblastomas. A combination of PI3K and SHH signaling inhibitors not only suppressed the activation of both pathways but also abrogated S6 kinase (S6K) signaling. Accordingly, targeting both pathways simultaneously resulted in mitotic catastrophe and tumor apoptosis and markedly reduced the growth of PTEN-deficient glioblastomas in vitro and in vivo. The drugs tested here appear to be safe in humans; therefore, this combination may provide a new targeted treatment for glioblastoma.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "PTEN-deficient", + "human" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promote" + ] + } + } + ] + }, + { + "PMID": "23852341", + "TEXT": "The B cell-specific transcription factor BACH2 is required for affinity maturation of B cells. Here we show that Bach2-mediated activation of p53 is required for stringent elimination of pre-B cells that failed to productively rearrange immunoglobulin VH-DJH gene segments. After productive VH-DJH gene rearrangement, pre-B cell receptor signaling ends BACH2-mediated negative selection through B cell lymphoma 6 (BCL6)-mediated repression of p53. In patients with pre-B acute lymphoblastic leukemia, the BACH2-mediated checkpoint control is compromised by deletions, rare somatic mutations and loss of its upstream activator, PAX5. Low levels of BACH2 expression in these patients represent a strong independent predictor of poor clinical outcome. In this study, we demonstrate that Bach2(+/+) pre-B cells resist leukemic transformation by Myc through Bach2-dependent upregulation of p53 and do not initiate fatal leukemia in transplant-recipient mice. Chromatin immunoprecipitation sequencing and gene expression analyses carried out by us revealed that BACH2 competes with BCL6 for promoter binding and reverses BCL6-mediated repression of p53 and other cell cycle checkpoint-control genes. These findings identify BACH2 as a crucial mediator of negative selection at the pre-B cell receptor checkpoint and a safeguard against leukemogenesis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bach2(+/+)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resist" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Bach2(+/+)" + ] + }, + "effect": { + "val": "no effect", + "words": [ + "not", + "initiate" + ] + } + } + ] + }, + { + "PMID": "23524344", + "TEXT": "Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by bilateral renal cyst formation. Recent identification of signaling cascades deregulated in ADPKD has led to the initiation of several clinical trials, but an approved therapy is still lacking. Using a metabolomic approach, we identify a pathogenic pathway in this disease that can be safely targeted for therapy. We show that mutation of PKD1 results in enhanced glycolysis in cells in a mouse model of PKD and in kidneys from humans with ADPKD. Glucose deprivation resulted in lower proliferation and higher apoptotic rates in PKD1-mutant cells than in nondeprived cells. Notably, two distinct PKD mouse models treated with 2-deoxyglucose (2DG), to inhibit glycolysis, had lower kidney weight, volume, cystic index and proliferation rates as compared to nontreated mice. These metabolic alterations depend on the extracellular signal-related kinase (ERK) pathway acting in a dual manner by inhibiting the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) axis on the one hand while activating the mTOR complex 1 (mTORC1)-glycolytic cascade on the other. Enhanced metabolic rates further inhibit AMPK. Forced activation of AMPK acts in a negative feedback loop, restoring normal ERK activity. Taken together, these data indicate that defective glucose metabolism is intimately involved in the pathobiology of ADPKD. Our findings provide a strong rationale for a new therapeutic strategy using existing drugs, either individually or in combination.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "of", + "PKD1" + ] + }, + "effect": { + "val": "negative", + "words": [ + "lower" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "mutation", + "of", + "PKD1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "higher" + ] + } + } + ] + }, + { + "PMID": "22983396", + "TEXT": "The discovery of potent inhibitors of the BRAF proto-oncogene has revolutionized therapy for melanoma harboring mutations in BRAF, yet NRAS-mutant melanoma remains without an effective therapy. Because direct pharmacological inhibition of the RAS proto-oncogene has thus far been unsuccessful, we explored systems biology approaches to identify synergistic drug combination(s) that can mimic RAS inhibition. Here, leveraging an inducible mouse model of NRAS-mutant melanoma, we show that pharmacological inhibition of mitogen-activated protein kinase kinase (MEK) activates apoptosis but not cell-cycle arrest, which is in contrast to complete genetic neuroblastoma RAS homolog (NRAS) extinction, which triggers both of these effects. Network modeling pinpointed cyclin-dependent kinase 4 (CDK4) as a key driver of this differential phenotype. Accordingly, combined pharmacological inhibition of MEK and CDK4 in vivo led to substantial synergy in therapeutic efficacy. We suggest a gradient model of oncogenic NRAS signaling in which the output is gated, resulting in the decoupling of discrete downstream biological phenotypes as a result of incomplete inhibition. Such a gated signaling model offers a new framework to identify nonobvious coextinction target(s) for combined pharmacological inhibition in NRAS-mutant melanomas.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "mitogen-activated", + "protein", + "kinase", + "(MEK)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "activates" + ] + } + } + ] + }, + { + "PMID": "22902876", + "TEXT": "Stem-cell function is an exquisitely regulated process. Thus far, the contribution of metabolic cues to stem-cell function has not been well understood. Here we identify a previously unknown promyelocytic leukemia (PML)–peroxisome proliferator-activated receptor δ (PPAR-δ)–fatty-acid oxidation (FAO) pathway for the maintenance of hematopoietic stem cells (HSCs). We have found that loss of PPAR-δ or inhibition of mitochondrial FAO induces loss of HSC maintenance, whereas treatment with PPAR-δ agonists improved HSC maintenance. PML exerts its essential role in HSC maintenance through regulation of PPAR signaling and FAO. Mechanistically, the PML–PPAR-δ–FAO pathway controls the asymmetric division of HSCs. Deletion of Ppard or Pml as well as inhibition of FAO results in the symmetric commitment of HSC daughter cells, whereas PPAR-δ activation increased asymmetric cell division. Thus, our findings identify a metabolic switch for the control of HSC cell fate with potential therapeutic implications.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "FAO" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "activation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased" + ] + } + } + ] + }, + { + "PMID": "22820643", + "TEXT": "The inactivation of the p53 tumor suppressor pathway, which often occurs through mutations in TP53 (encoding tumor protein 53) is a common step in human cancer. However, in melanoma-a highly chemotherapy-resistant disease-TP53 mutations are rare, raising the possibility that this cancer uses alternative ways to overcome p53-mediated tumor suppression. Here we show that Mdm4 p53 binding protein homolog (MDM4), a negative regulator of p53, is upregulated in a substantial proportion (∼65%) of stage I-IV human melanomas and that melanocyte-specific Mdm4 overexpression enhanced tumorigenesis in a mouse model of melanoma induced by the oncogene Nras. MDM4 promotes the survival of human metastatic melanoma by antagonizing p53 proapoptotic function. Notably, inhibition of the MDM4-p53 interaction restored p53 function in melanoma cells, resulting in increased sensitivity to cytotoxic chemotherapy and to inhibitors of the BRAF (V600E) oncogene. Our results identify MDM4 as a key determinant of impaired p53 function in human melanoma and designate MDM4 as a promising target for antimelanoma combination therapy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "melanocyte-specific", + "Mdm4", + "overexpression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced", + "induced" + ] + } + } + ] + }, + { + "PMID": "22820642", + "TEXT": "Breast cancer metastasis is a key determinant of long-term patient survival. By comparing the transcriptomes of primary and metastatic tumor cells in a mouse model of spontaneous bone metastasis, we found that a substantial number of genes suppressed in bone metastases are targets of the interferon regulatory factor Irf7. Restoration of Irf7 in tumor cells or administration of interferon led to reduced bone metastases and prolonged survival time. In mice deficient in the interferon (IFN) receptor or in natural killer (NK) and CD8(+) T cell responses, metastasis was accelerated, indicating that Irf7-driven suppression of metastasis was reliant on IFN signaling to host immune cells. We confirmed the clinical relevance of these findings in over 800 patients in which high expression of Irf7-regulated genes in primary tumors was associated with prolonged bone metastasis-free survival. This gene signature may identify patients that could benefit from IFN-based therapies. Thus, we have identified an innate immune pathway intrinsic to breast cancer cells, the suppression of which restricts immunosurveillance to enable metastasis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Restoration", + "of", + "Irf7" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficient", + "in", + "the" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerated," + ] + } + } + ] + }, + { + "PMID": "22797810", + "TEXT": "Temporal lobe epilepsy (TLE) is accompanied by an abnormal location of granule cells in the dentate gyrus. Using a rat model of complex febrile seizures, which are thought to be a precipitating insult of TLE later in life, we report that aberrant migration of neonatal-generated granule cells results in granule cell ectopia that persists into adulthood. Febrile seizures induced an upregulation of GABA(A) receptors (GABA(A)-Rs) in neonatally generated granule cells, and hyperactivation of excitatory GABA(A)-Rs caused a reversal in the direction of granule cell migration. This abnormal migration was prevented by RNAi-mediated knockdown of the Na(+)K(+)2Cl(-) co-transporter (NKCC1), which regulates the excitatory action of GABA. NKCC1 inhibition with bumetanide after febrile seizures rescued the granule cell ectopia, susceptibility to limbic seizures and development of epilepsy. Thus, this work identifies a previously unknown pathogenic role of excitatory GABA(A)-R signaling and highlights NKCC1 as a potential therapeutic target for preventing granule cell ectopia and the development of epilepsy after febrile seizures.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "the", + "Na(+)K(+)2Cl(-)", + "co-transporter" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "NKCC1", + "inhibition", + "with", + "bumetanide" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + } + ] + }, + { + "PMID": "22772464", + "TEXT": "Interleukin-9 (IL-9) is a T cell cytokine that acts through a γC-family receptor on target cells and is associated with inflammation and allergy. We determined that T cells from mice deficient in the T helper type 17 (T(H)17) pathway genes encoding retinoid-related orphan receptor γ (ROR-γ) and IL-23 receptor (IL-23R) produced abundant IL-9, and we found substantial growth inhibition of B16F10 melanoma in these mice. IL-9-blocking antibodies reversed this tumor growth inhibition and enhanced tumor growth in wild-type (WT) mice. Il9r(-/-) mice showed accelerated tumor growth, and administration of recombinant IL-9 (rIL-9) to tumor-bearing WT and Rag1(-/-) mice inhibited melanoma as well as lung carcinoma growth. Adoptive transfer of tumor-antigen-specific T(H)9 cells into both WT and Rag1(-/-) mice suppressed melanoma growth; this effect was abrogated by treatment with neutralizing antibodies to IL-9. Exogenous rIL-9 inhibited tumor growth in Rag1(-/-) mice but not in mast-cell-deficient mice, suggesting that the targets of IL-9 in this setting include mast cells but not T or B cells. In addition, we found higher numbers of T(H)9 cells in normal human skin and blood compared to metastatic lesions of subjects with progressive stage IV melanoma. These results suggest a role for IL-9 in tumor immunity and offer insight into potential therapeutic strategies.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Il9r(-/-)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "accelerated" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Il9r(-/-)", + "Rag1(-/-)", + "mast-cell-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited", + "suppressed" + ] + } + } + ] + }, + { + "PMID": "22729283", + "TEXT": "Insulin-like growth factor 1 (IGF-1), the most abundant growth factor in the bone matrix, maintains bone mass in adulthood. We now report that IGF-1 released from the bone matrix during bone remodeling stimulates osteoblastic differentiation of recruited mesenchymal stem cells (MSCs) by activation of mammalian target of rapamycin (mTOR), thus maintaining proper bone microarchitecture and mass. Mice with knockout of the IGF-1 receptor (Igf1r) in their pre-osteoblastic cells showed lower bone mass and mineral deposition rates than wild-type mice. Further, MSCs from Igf1rflox/flox mice with Igf1r deleted by a Cre adenovirus in vitro, although recruited to the bone surface after implantation, were unable to differentiate into osteoblasts. We also found that the concentrations of IGF-1 in the bone matrix and marrow of aged rats were lower than in those of young rats and directly correlated with the age-related decrease in bone mass. Likewise, in age-related osteoporosis in humans, we found that bone marrow IGF-1 concentrations were 40% lower in individuals with osteoporosis than in individuals without osteoporosis. Notably, injection of IGF-1 plus IGF binding protein 3 (IGFBP3), but not injection of IGF-1 alone, increased the concentration of IGF-1 in the bone matrix and stimulated new bone formation in aged rats. Together, these results provide mechanistic insight into how IGF-1 maintains adult bone mass, while also providing a further rationale for its therapeutic targeting to treat age-related osteoporosis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Igf1rflox/flox", + "Igf1r", + "deleted", + "by", + "a", + "Cre", + "adenovirus" + ] + }, + "effect": { + "val": "negative", + "words": [ + "unable" + ] + } + } + ] + }, + { + "PMID": "22635005", + "TEXT": "Tumor-derived exosomes are emerging mediators of tumorigenesis. We explored the function of melanoma-derived exosomes in the formation of primary tumors and metastases in mice and human subjects. Exosomes from highly metastatic melanomas increased the metastatic behavior of primary tumors by permanently 'educating' bone marrow progenitors through the receptor tyrosine kinase MET. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites and reprogrammed bone marrow progenitors toward a pro-vasculogenic phenotype that was positive for c-Kit, the receptor tyrosine kinase Tie2 and Met. Reducing Met expression in exosomes diminished the pro-metastatic behavior of bone marrow cells. Notably, MET expression was elevated in circulating CD45(-)C-KIT(low/+)TIE2(+) bone marrow progenitors from individuals with metastatic melanoma. RAB1A, RAB5B, RAB7 and RAB27A, regulators of membrane trafficking and exosome formation, were highly expressed in melanoma cells. Rab27A RNA interference decreased exosome production, preventing bone marrow education and reducing, tumor growth and metastasis. In addition, we identified an exosome-specific melanoma signature with prognostic and therapeutic potential comprised of TYRP2, VLA-4, HSP70, an HSP90 isoform and the MET oncoprotein. Our data show that exosome production, transfer and education of bone marrow cells supports tumor growth and metastasis, has prognostic value and offers promise for new therapeutic directions in the metastatic process.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Rab27A", + "RNA", + "interference" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reducing," + ] + } + } + ] + }, + { + "PMID": "22388088", + "TEXT": "New cancer therapies are likely to arise from an in-depth understanding of the signaling networks influencing tumor initiation, progression and metastasis. We show a fundamental role for Src-homology 2 domain-containing phosphatase 2 (SHP2) in these processes in human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancers. Knockdown of SHP2 eradicated breast tumor-initiating cells in xenograft models, and SHP2 depletion also prevented invasion in three-dimensional cultures and in a transductal invasion assay in vivo. Notably, SHP2 knockdown in established breast tumors blocked their growth and reduced metastasis. Mechanistically, SHP2 activated stemness-associated transcription factors, including v-myc myelocytomatosis viral oncogene homolog (c-Myc) and zinc finger E-box binding homeobox 1 (ZEB1), which resulted in the repression of let-7 microRNA and the expression of a set of 'SHP2 signature' genes. We found these genes to be simultaneously activated in a large subset of human primary breast tumors that are associated with invasive behavior and poor prognosis. These results provide new insights into the signaling cascades influencing tumor-initiating cells as well as a rationale for targeting SHP2 in breast cancer.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Knockdown", + "of", + "SHP2", + "knockdown" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented", + "reduced" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SHP2", + "depletion" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented", + "reduced" + ] + } + } + ] + }, + { + "PMID": "22157679", + "TEXT": "Screening for genes that reprogram cancer cells for the tumor reversion switch identified TCTP (encoding translationally controlled tumor protein) as a crucial regulator of apoptosis. Here we report a negative feedback loop between P53 and TCTP. TCTP promotes P53 degradation by competing with NUMB for binding to P53-MDM2-containing complexes. TCTP inhibits MDM2 auto-ubiquitination and promotes MDM2-mediated ubiquitination and degradation of P53. Notably, Tctp haploinsufficient mice are sensitized to P53-dependent apoptosis. In addition, P53 directly represses TCTP transcription. In 508 breast cancers, high-TCTP status associates with poorly differentiated, aggressive G3-grade tumors, predicting poor prognosis (P < 0.0005). Tctp knockdown in primary mammary tumor cells from ErbB2 transgenic mice results in increased P53 expression and a decreased number of stem-like cancer cells. The pharmacological compounds sertraline and thioridazine increase the amount of P53 by neutralizing TCTP's action on the MDM2-P53 axis. This study links TCTP and P53 in a previously unidentified regulatory circuitry that may underlie the relevance of TCTP in cancer.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Tctp", + "haploinsufficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "sensitized" + ] + } + } + ] + }, + { + "PMID": "22138754", + "TEXT": "The platelet-derived growth factor (PDGF) signaling system contributes to tumor angiogenesis and vascular remodeling. Here we show in mouse tumor models that PDGF-BB induces erythropoietin (EPO) mRNA and protein expression by targeting stromal and perivascular cells that express PDGF receptor-β (PDGFR-β). Tumor-derived PDGF-BB promoted tumor growth, angiogenesis and extramedullary hematopoiesis at least in part through modulation of EPO expression. Moreover, adenoviral delivery of PDGF-BB to tumor-free mice increased both EPO production and erythropoiesis, as well as protecting from irradiation-induced anemia. At the molecular level, we show that the PDGF-BB-PDGFR-bβ signaling system activates the EPO promoter, acting in part through transcriptional regulation by the transcription factor Atf3, possibly through its association with two additional transcription factors, c-Jun and Sp1. Our findings suggest that PDGF-BB-induced EPO promotes tumor growth through two mechanisms: first, paracrine stimulation of tumor angiogenesis by direct induction of endothelial cell proliferation, migration, sprouting and tube formation, and second, endocrine stimulation of extramedullary hematopoiesis leading to increased oxygen perfusion and protection against tumor-associated anemia.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "adenoviral" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + } + ] + }, + { + "PMID": "21873987", + "TEXT": "Previous studies have proposed roles for hypothalamic reactive oxygen species (ROS) in the modulation of circuit activity of the melanocortin system. Here we show that suppression of ROS diminishes pro-opiomelanocortin (POMC) cell activation and promotes the activity of neuropeptide Y (NPY)- and agouti-related peptide (AgRP)-co-producing (NPY/AgRP) neurons and feeding, whereas ROS-activates POMC neurons and reduces feeding. The levels of ROS in POMC neurons were positively correlated with those of leptin in lean and ob/ob mice, a relationship that was diminished in diet-induced obese (DIO) mice. High-fat feeding resulted in proliferation of peroxisomes and elevated peroxisome proliferator-activated receptor γ (PPAR-γ) mRNA levels within the hypothalamus. The proliferation of peroxisomes in POMC neurons induced by the PPAR-γ agonist rosiglitazone decreased ROS levels and increased food intake in lean mice on high-fat diet. Conversely, the suppression of peroxisome proliferation by the PPAR antagonist GW9662 increased ROS concentrations and c-fos expression in POMC neurons. Also, it reversed high-fat feeding-triggered elevated NPY/AgRP and low POMC neuronal firing, and resulted in decreased feeding of DIO mice. Finally, central administration of ROS alone increased c-fos and phosphorylated signal transducer and activator of transcription 3 (pStat3) expression in POMC neurons and reduced feeding of DIO mice. These observations unmask a previously unknown hypothalamic cellular process associated with peroxisomes and ROS in the central regulation of energy metabolism in states of leptin resistance.", + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "induced" + ] + }, + "perturbing_action": { + "val": "pharmacological augmentation", + "words": [ + "agonist", + "rosiglitazone" + ] + } + } + ] + }, + { + "PMID": "21725297", + "TEXT": "Survival and differentiation of oligodendrocytes are important for the myelination of central nervous system (CNS) axons during development and crucial for myelin repair in CNS demyelinating diseases such as multiple sclerosis. Here we show that death receptor 6 (DR6) is a negative regulator of oligodendrocyte maturation. DR6 is expressed strongly in immature oligodendrocytes and weakly in mature myelin basic protein (MBP)-positive oligodendrocytes. Overexpression of DR6 in oligodendrocytes leads to caspase 3 (casp3) activation and cell death. Attenuation of DR6 function leads to enhanced oligodendrocyte maturation, myelination and downregulation of casp3. Treatment with a DR6 antagonist antibody promotes remyelination in both lysolecithin-induced demyelination and experimental autoimmune encephalomyelitis (EAE) models. Consistent with the DR6 antagoinst antibody studies, DR6-null mice show enhanced remyelination in both demyelination models. These studies reveal a pivotal role for DR6 signaling in immature oligodendrocyte maturation and myelination that may provide new therapeutic avenues for the treatment of demyelination disorders such as multiple sclerosis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Overexpression", + "of", + "DR6" + ] + }, + "effect": { + "val": "positive", + "words": [ + "leads", + "to" + ] + } + } + ] + }, + { + "PMID": "21623382", + "TEXT": "The ciliopathy Joubert syndrome is marked by cerebellar vermis hypoplasia, a phenotype for which the pathogenic mechanism is unclear. To investigate Joubert syndrome pathogenesis, we have examined mice with mutated Ahi1, the first identified Joubert syndrome-associated gene. These mice show cerebellar hypoplasia with a vermis-midline fusion defect early in development. This defect is concomitant with expansion of the roof plate and is also evident in a mouse mutant for another Joubert syndrome-associated gene, Cep290. Furthermore, fetal magnetic resonance imaging (MRI) of human subjects with Joubert syndrome reveals a similar midline cleft, suggesting parallel pathogenic mechanisms. Previous evidence has suggested a role for Jouberin (Jbn), the protein encoded by Ahi1, in canonical Wnt signaling. Consistent with this, we found decreased Wnt reporter activity at the site of hemisphere fusion in the developing cerebellum of Ahi1-mutant mice. This decrease was accompanied by reduced proliferation at the site of fusion. Finally, treatment with lithium, a Wnt pathway agonist, partially rescued this phenotype. Our findings implicate a defect in Wnt signaling in the cerebellar midline phenotype seen in Joubert syndrome that can be overcome with Wnt stimulation.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "Ahi1-mutant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + } + ] + }, + { + "PMID": "21602804", + "TEXT": "Therapies targeting estrogen receptor α (ERα, encoded by ESR1) have transformed the treatment of breast cancer. However, large numbers of women relapse, highlighting the need for the discovery of new regulatory targets modulating ERα pathways. An siRNA screen identified kinases whose silencing alters the estrogen response including those previously implicated in regulating ERα activity (such as mitogen-activated protein kinase and AKT). Among the most potent regulators was lemur tyrosine kinase-3 (LMTK3), for which a role has not previously been assigned. In contrast to other modulators of ERα activity, LMTK3 seems to have been subject to Darwinian positive selection, a noteworthy result given the unique susceptibility of humans to ERα+ breast cancer. LMTK3 acts by decreasing the activity of protein kinase C (PKC) and the phosphorylation of AKT (Ser473), thereby increasing binding of forkhead box O3 (FOXO3) to the ESR1 promoter. LMTK3 phosphorylated ERα, protecting it from proteasomal degradation in vitro. Silencing of LMTK3 reduced tumor volume in an orthotopic mouse model and abrogated proliferation of ERα+ but not ERα- cells, indicative of its role in ERα activity. In human cancers, LMTK3 abundance and intronic polymorphisms were significantly associated with disease-free and overall survival and predicted response to endocrine therapies. These findings yield insights into the natural history of breast cancer in humans and reveal LMTK3 as a new therapeutic target.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Silencing", + "of", + "LMTK3" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced", + "abrogated" + ] + } + } + ] + }, + { + "PMID": "20972433", + "TEXT": "The TLX1 oncogene (encoding the transcription factor T cell leukemia homeobox protein-1) has a major role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL). However, the specific mechanisms of T cell transformation downstream of TLX1 remain to be elucidated. Here we show that transgenic expression of human TLX1 in mice induces T-ALL with frequent deletions and mutations in Bcl11b (encoding B cell leukemia/lymphoma-11B) and identify the presence of recurrent mutations and deletions in BCL11B in 16% of human T-ALLs. Most notably, mouse TLX1 tumors were typically aneuploid and showed a marked defect in the activation of the mitotic checkpoint. Mechanistically, TLX1 directly downregulates the expression of CHEK1 (encoding CHK1 checkpoint homolog) and additional mitotic control genes and induces loss of the mitotic checkpoint in nontransformed preleukemic thymocytes. These results identify a previously unrecognized mechanism contributing to chromosomal missegregation and aneuploidy active at the earliest stages of tumor development in the pathogenesis of cancer.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transgenic", + "expression", + "of", + "human", + "TLX1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + } + ] + }, + { + "PMID": "20473309", + "TEXT": "Toll-like receptor (TLR) signaling is essential for intestinal tumorigenesis in Apc(min/+) mice, but the mechanisms by which Apc enhances tumor growth are unknown. Here we show that microflora-MyD88-ERK signaling in intestinal epithelial cells (IECs) promotes tumorigenesis by increasing the stability of the c-Myc oncoprotein. Activation of ERK (extracellular signal-related kinase) phosphorylates c-Myc, preventing its ubiquitination and subsequent proteasomal degradation. Accordingly, Apc(min/+)/Myd88(-/-) mice have lower phospho-ERK (p-ERK) levels and fewer and smaller IEC tumors than Apc(min/+) mice. MyD88 (myeloid differentiation primary response gene 88)-independent activation of ERK by epidermal growth factor (EGF) increased p-ERK and c-Myc and restored the multiple intestinal neoplasia (Min) phenotype in Apc(min/+)/Myd88(-/-) mice. Administration of an ERK inhibitor suppressed intestinal tumorigenesis in EGF-treated Apc(min/+)/Myd88(-/-) and Apc(min/+) mice and increased their survival. Our data reveal a new facet of oncogene-environment interaction, in which microflora-induced TLR activation regulates oncogene expression and related IEC tumor growth in a susceptible host.", + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "promotes" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apc(min/+)/Myd88(-/-)" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "ERK", + "inhibitor" + ] + }, + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + } + }, + { + "effect": { + "val": "negative", + "words": [ + "suppressed" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apc(min/+)/Myd88(-/-)" + ] + } + } + ] + }, + { + "PMID": "20418886", + "TEXT": "Leukemias and other cancers possess self-renewing stem cells that help to maintain the cancer. Cancer stem cell eradication is thought to be crucial for successful anticancer therapy. Using an acute myeloid leukemia (AML) model induced by the leukemia-associated monocytic leukemia zinc finger (MOZ)-TIF2 fusion protein, we show here that AML can be cured by the ablation of leukemia stem cells. The MOZ fusion proteins MOZ-TIF2 and MOZ-CBP interacted with the transcription factor PU.1 to stimulate the expression of macrophage colony-stimulating factor receptor (CSF1R, also known as M-CSFR, c-FMS or CD115). Studies using PU.1-deficient mice showed that PU.1 is essential for the ability of MOZ-TIF2 to establish and maintain AML stem cells. Cells expressing high amounts of CSF1R (CSF1R(high) cells), but not those expressing low amounts of CSF1R (CSF1R(low) cells), showed potent leukemia-initiating activity. Using transgenic mice expressing a drug-inducible suicide gene controlled by the CSF1R promoter, we cured AML by ablation of CSF1R(high) cells. Moreover, induction of AML was suppressed in CSF1R-deficient mice and CSF1R inhibitors slowed the progression of MOZ-TIF2-induced leukemia. Thus, in this subtype of AML, leukemia stem cells are contained within the CSF1R(high) cell population, and we suggest that targeting of PU.1-mediated upregulation of CSF1R expression might be a useful therapeutic approach.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CSF1R-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "MOZ-TIF2-induced" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CSF1R", + "inhibitors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "MOZ-TIF2-induced" + ] + } + } + ] + }, + { + "PMID": "20037595", + "TEXT": "Sterol metabolism has recently been linked to innate and adaptive immune responses through liver X receptor (LXR) signaling. Whether products of sterol metabolism interfere with antitumor responses is currently unknown. Dendritic cells (DCs) initiate immune responses, including antitumor activity after their CC chemokine receptor-7 (CCR7)-dependent migration to lymphoid organs. Here we report that human and mouse tumors produce LXR ligands that inhibit CCR7 expression on maturing DCs and, therefore, their migration to lymphoid organs. In agreement with this observation, we detected CD83(+)CCR7(-) DCs within human tumors. Mice injected with tumors expressing the LXR ligand-inactivating enzyme sulfotransferase 2B1b (SULT2B1b) successfully controlled tumor growth by regaining DC migration to tumor-draining lymph nodes and by developing overt inflammation within tumors. The control of tumor growth was also observed in chimeric mice transplanted with bone marrow from mice lacking the gene encoding LXR-alpha (Nr1h3(-/-) mice) Thus, we show a new mechanism of tumor immunoescape involving products of cholesterol metabolism. The manipulation of this pathway could restore antitumor immunity in individuals with cancer.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "expressing", + "the", + "LXR", + "ligand-inactivating", + "enzyme", + "sulfotransferase", + "2B1b", + "(SULT2B1b)" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "controlled" + ] + } + }, + { + "effect": { + "val": "regulates", + "words": [ + "control" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "the", + "gene", + "encoding", + "LXR-alpha" + ] + } + } + ] + }, + { + "PMID": "19966776", + "TEXT": "We report that heat shock protein 90 (Hsp90) inhibitors selectively kill diffuse large B cell lymphomas (DLBCLs) that depend on the BCL-6 transcriptional repressor. We found that endogenous Hsp90 interacts with BCL-6 in DLBCL cells and can stabilize BCL-6 mRNA and protein. Hsp90 formed a complex with BCL-6 at its target promoters, and Hsp90 inhibitors derepressed BCL-6 target genes. A stable mutant of BCL-6 rescued DLBCL cells from Hsp90 inhibitor-induced apoptosis. BCL-6 and Hsp90 were almost invariantly coexpressed in the nuclei of primary DLBCL cells, suggesting that their interaction is relevant in this disease. We examined the pharmacokinetics, toxicity and efficacy of PU-H71, a recently developed purine-derived Hsp90 inhibitor. PU-H71 preferentially accumulated in lymphomas compared to normal tissues and selectively suppressed BCL-6-dependent DLBCLs in vivo, inducing reactivation of key BCL-6 target genes and apoptosis. PU-H71 also induced cell death in primary human DLBCL specimens.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Hsp90", + "inhibitors", + "inhibitor-induced" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Hsp90", + "inhibitors", + "inhibitor-induced" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inhibitor-induced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "stable", + "mutant", + "of", + "BCL-6" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "stable", + "mutant", + "of", + "BCL-6" + ] + }, + "effect": { + "val": "positive", + "words": [ + "inhibitor-induced" + ] + } + } + ] + }, + { + "PMID": "19701204", + "TEXT": "A subset of central glutamatergic synapses are coordinately pruned and matured by unresolved mechanisms during postnatal development. We report that the human epilepsy gene LGI1, encoding leucine-rich, glioma-inactivated protein-1 and mutated in autosomal dominant lateral temporal lobe epilepsy (ADLTE), mediates this process in hippocampus. We created transgenic mice either expressing a truncated mutant LGI1 (835delC) found in ADLTE or overexpressing a wild-type LGI1. We discovered that the normal postnatal maturation of presynaptic and postsynaptic functions was arrested by the 835delC mutant LGI1, and contrastingly, was magnified by excess wild-type LGI1. Concurrently, mutant LGI1 inhibited dendritic pruning and increased the spine density to markedly increase excitatory synaptic transmission. Inhibitory transmission, by contrast, was unaffected. Furthermore, mutant LGI1 promoted epileptiform discharge in vitro and kindling epileptogenesis in vivo with partial gamma-aminobutyric acid(A) (GABA(A)) receptor blockade. Thus, LGI1 represents a human gene mutated to promote epilepsy through impaired postnatal development of glutamatergic circuits.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutant", + "LGI1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "promoted" + ] + } + } + ] + }, + { + "PMID": "19684581", + "TEXT": "T cells are crucial mediators of the skin damage in psoriasis. We here show that interleukin-21 (IL-21), a T cell-derived cytokine, is highly expressed in the skin of individuals with psoriasis, stimulates human keratinocytes to proliferate and causes epidermal hyperplasia when injected intradermally into mice. In the human psoriasis xenograft mouse model, blockade of IL-21 activity resolves inflammation and reduces keratinocyte proliferation. Blocking IL-21 may represent a new therapeutic strategy in psoriasis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "blockade", + "of", + "IL-21", + "activity" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + } + ] + }, + { + "PMID": "19029982", + "TEXT": "Fibrodysplasia ossificans progressiva (FOP) is a congenital disorder of progressive and widespread postnatal ossification of soft tissues and is without known effective treatments. Affected individuals harbor conserved mutations in the ACVR1 gene that are thought to cause constitutive activation of the bone morphogenetic protein (BMP) type I receptor, activin receptor-like kinase-2 (ALK2). Here we show that intramuscular expression in the mouse of an inducible transgene encoding constitutively active ALK2 (caALK2), resulting from a glutamine to aspartic acid change at amino acid position 207, leads to ectopic endochondral bone formation, joint fusion and functional impairment, thus phenocopying key aspects of human FOP. A selective inhibitor of BMP type I receptor kinases, LDN-193189 (ref. 6), inhibits activation of the BMP signaling effectors SMAD1, SMAD5 and SMAD8 in tissues expressing caALK2 induced by adenovirus specifying Cre (Ad.Cre). This treatment resulted in a reduction in ectopic ossification and functional impairment. In contrast to localized induction of caALK2 by Ad.Cre (which entails inflammation), global postnatal expression of caALK2 (induced without the use of Ad.Cre and thus without inflammation) does not lead to ectopic ossification. However, if in this context an inflammatory stimulus was provided with a control adenovirus, ectopic bone formation was induced. Like LDN-193189, corticosteroid inhibits ossification in Ad.Cre-injected mutant mice, suggesting caALK2 expression and an inflammatory milieu are both required for the development of ectopic ossification in this model. These results support the role of dysregulated ALK2 kinase activity in the pathogenesis of FOP and suggest that small molecule inhibition of BMP type I receptor activity may be useful in treating FOP and heterotopic ossification syndromes associated with excessive BMP signaling.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "global", + "postnatal", + "expression", + "of", + "caALK2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced." + ] + } + } + ] + }, + { + "PMID": "18978796", + "TEXT": "Genetic and epigenetic plasticity allows tumors to evade single-targeted treatments. Here we direct Bcl2-specific short interfering RNA (siRNA) with 5'-triphosphate ends (3p-siRNA) against melanoma. Recognition of 5'-triphosphate by the cytosolic antiviral helicase retinoic acid-induced protein I (Rig-I, encoded by Ddx58) activated innate immune cells such as dendritic cells and directly induced expression of interferons (IFNs) and apoptosis in tumor cells. These Rig-I-mediated activities synergized with siRNA-mediated Bcl2 silencing to provoke massive apoptosis of tumor cells in lung metastases in vivo. The therapeutic activity required natural killer cells and IFN, as well as silencing of Bcl2, as evidenced by rescue with a mutated Bcl2 target, by site-specific cleavage of Bcl2 messenger RNA in lung metastases and downregulation of Bcl-2 protein in tumor cells in vivo. Together, 3p-siRNA represents a single molecule-based approach in which Rig-I activation on both the immune- and tumor cell level corrects immune ignorance and in which gene silencing corrects key molecular events that govern tumor cell survival.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA-mediated", + "Bcl2", + "silencing" + ] + }, + "effect": { + "val": "positive", + "words": [ + "provoke" + ] + } + } + ] + }, + { + "PMID": "18724378", + "TEXT": "Drug resistance acquired by cancer cells has led to treatment failure. To understand the regulatory network underlying docetaxel resistance in breast cancer cells and to identify molecular targets for therapy, we tested small interfering RNAs (siRNAs) against 36 genes whose expression was elevated in human nonresponders to docetaxel for the ability to promote apoptosis of docetaxel-resistant human breast cancer cells (MCF7-ADR cells). The results indicate that the downregulation of the gene encoding ribophorin [corrected] II (RPN2), which is part of an N-oligosaccharyl transferase complex, most efficiently induces apoptosis of MCF7-ADR cells in the presence of docetaxel. RPN2 silencing induced reduced glycosylation of the P-glycoprotein, as well as decreased membrane localization, thereby sensitizing MCF7-ADR cells to docetaxel. Moreover, in vivo delivery of siRNA specific for RPN2 markedly reduced tumor growth in two types of models for drug resistance. Thus, RPN2 silencing makes cancer cells hypersensitive response to docetaxel, and RPN2 might be a new target for RNA interference-based therapeutics against drug resistance.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "downregulation", + "of", + "the", + "gene", + "encoding", + "ribophorin", + "[corrected]", + "II", + "(RPN2)," + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "siRNA", + "specific", + "for", + "RPN2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + } + ] + }, + { + "PMID": "18297084", + "TEXT": "Notch signaling is a key mechanism in the control of embryogenesis. However, its in vivo function during mesenchymal cell differentiation, and, specifically, in bone homeostasis, remains largely unknown. Here, we show that osteoblast-specific gain of Notch function causes severe osteosclerosis owing to increased proliferation of immature osteoblasts. Under these pathological conditions, Notch stimulates early osteoblastic proliferation by upregulating the genes encoding cyclin D, cyclin E and Sp7 (osterix). The intracellular domain of Notch1 also regulates terminal osteoblastic differentiation by directly binding Runx2 and repressing its transactivation function. In contrast, loss of all Notch signaling in osteoblasts, generated by deletion of the genes encoding presenilin-1 and presenilin-2 in bone, is associated with late-onset, age-related osteoporosis, which in turn results from increased osteoblast-dependent osteoclastic activity due to decreased osteoprotegerin mRNA expression in these cells. Together, these findings highlight the potential dimorphic effects of Notch signaling in bone homeostasis and may provide direction for novel therapeutic applications.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "osteoblast-specific", + "gain", + "of", + "Notch", + "function" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increased", + "stimulates" + ] + } + } + ] + }, + { + "PMID": "18157138", + "TEXT": "Recent successes in treating genetic immunodeficiencies have demonstrated the therapeutic potential of stem cell gene therapy. However, the use of gammaretroviral vectors in these trials led to insertional activation of nearby oncogenes and leukemias in some study subjects, prompting studies of modified or alternative vector systems. Here we describe the use of foamy virus vectors to treat canine leukocyte adhesion deficiency (CLAD). Four of five dogs with CLAD that received nonmyeloablative conditioning and infusion of autologous, CD34+ hematopoietic stem cells transduced by a foamy virus vector expressing canine CD18 had complete reversal of the CLAD phenotype, which was sustained more than 2 years after infusion. In vitro assays showed correction of the lymphocyte proliferation and neutrophil adhesion defects that characterize CLAD. There were no genotoxic complications, and integration site analysis showed polyclonality of transduced cells and a decreased risk of integration near oncogenes as compared to gammaretroviral vectors. These results represent the first successful use of a foamy virus vector to treat a genetic disease, to our knowledge, and suggest that foamy virus vectors will be effective in treating human hematopoietic diseases.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transduced", + "by", + "a", + "foamy", + "virus", + "vector", + "expressing", + "canine", + "CD18" + ] + }, + "effect": { + "val": "regulates", + "words": [ + "correction" + ] + } + } + ] + }, + { + "PMID": "18084301", + "TEXT": "Podocyte dysfunction, represented by foot process effacement and proteinuria, is often the starting point for progressive kidney disease. Therapies aimed at the cellular level of the disease are currently not available. Here we show that induction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement and urinary protein loss via a mechanism that includes lipid-dependent activation of alphavbeta3 integrin. Mice lacking uPAR (Plaur-/-) are protected from lipopolysaccharide (LPS)-mediated proteinuria but develop disease after expression of a constitutively active beta3 integrin. Gene transfer studies reveal a prerequisite for uPAR expression in podocytes, but not in endothelial cells, for the development of LPS-mediated proteinuria. Mechanistically, uPAR is required to activate alphavbeta3 integrin in podocytes, promoting cell motility and activation of the small GTPases Cdc42 and Rac1. Blockade of alphavbeta3 integrin reduces podocyte motility in vitro and lowers proteinuria in mice. Our findings show a physiological role for uPAR signaling in the regulation of kidney permeability.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Blockade", + "of", + "alphavbeta3", + "integrin" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + } + ] + }, + { + "PMID": "18037895", + "TEXT": "Metastasis is the primary cause of mortality from cancer, but the mechanisms leading to metastasis are poorly understood. In particular, relatively little is known about metastasis in cancers of mesenchymal origins, which are known as sarcomas. Approximately ten proteins have been characterized as 'metastasis suppressors', but how these proteins function and are regulated is, in general, not well understood. Gp78 (also known as AMFR or RNF45) is a RING finger E3 ubiquitin ligase that is integral to the endoplasmic reticulum (ER) and involved in ER-associated degradation (ERAD) of diverse substrates. Here we report that expression of gp78 has a causal role in the metastasis of an aggressive human sarcoma and that this prometastatic activity requires the E3 activity of gp78. Further, gp78 associates with and targets the transmembrane metastasis suppressor, KAI1 (also known as CD82), for degradation. Suppression of gp78 increases KAI1 abundance and reduces the metastatic potential of tumor cells, an effect that is largely blocked by concomitant suppression of KAI1. An inverse relationship between these proteins was confirmed in a human sarcoma tissue microarray. Whereas most previous efforts have focused on genetic mechanisms for the loss of metastasis suppressor genes, our results provide new evidence for post-translational downregulation of a metastasis suppressor by its ubiquitin ligase, resulting in abrogation of its metastasis-suppressing effects.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Suppression", + "of", + "gp78" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + } + ] + }, + { + "PMID": "17676052", + "TEXT": "Soft tissue sarcomas are mesenchymal tumors that are fatal in approximately one-third of patients. To explore mechanisms of sarcoma pathogenesis, we have generated a mouse model of soft tissue sarcoma. Intramuscular delivery of an adenovirus expressing Cre recombinase in mice with conditional mutations in Kras and Trp53 was sufficient to initiate high-grade sarcomas with myofibroblastic differentiation. Like human sarcomas, these tumors show a predilection for lung rather than lymph node metastasis. Using this model, we showed that a prototype handheld imaging device can identify residual tumor during intraoperative molecular imaging. Deletion of the Ink4a-Arf locus (Cdkn2a), but not Bak1 and Bax, could substitute for mutation of Trp53 in this model. Deletion of Bak1 and Bax, however, was able to substitute for mutation of Trp53 in the development of sinonasal adenocarcinoma. Therefore, the intrinsic pathway of apoptosis seems sufficient to mediate p53 tumor suppression in an epithelial cancer, but not in this model of soft tissue sarcoma.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "adenovirus", + "expressing", + "Cre", + "recombinase", + "conditional", + "mutations", + "in", + "Kras", + "and", + "Trp53" + ] + }, + "effect": { + "val": "positive", + "words": [ + "initiate" + ] + } + } + ] + }, + { + "PMID": "17589519", + "TEXT": "Tumor cells have a dysregulated cell cycle that may render their proliferation especially sensitive to the inhibition of cyclin-dependent kinases (CDKs), important regulators of cell cycle progression. We examined the effects of CDK1 inhibition in the context of different oncogenic signals. Cells transformed with MYC, but not cells transformed by a panel of other activated oncogenes, rapidly underwent apoptosis when treated with small-molecule CDK1 inhibitors. The inhibitor of apoptosis protein BIRC5 (survivin), a known CDK1 target, is required for the survival of cells overexpressing MYC. Inhibition of CDK1 rapidly downregulates survivin expression and induces MYC-dependent apoptosis. CDK1 inhibitor treatment of MYC-dependent mouse lymphoma and hepatoblastoma tumors decreased tumor growth and prolonged their survival. As there are no effective small-molecule inhibitors that selectively target the MYC pathway, we propose that CDK1 inhibition might therefore be useful in the treatment of human malignancies that overexpress MYC.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "small-molecule", + "CDK1", + "inhibitors.", + "Inhibition", + "of" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induces" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK1", + "inhibitor", + "treatment" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + } + ] + }, + { + "PMID": "17546038", + "TEXT": "Mast cells contribute importantly to allergic and innate immune responses by releasing various preformed and newly synthesized mediators. Previous studies have shown mast cell accumulation in human atherosclerotic lesions. This report establishes the direct participation of mast cells in atherogenesis in low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice. Atheromata from compound mutant Ldlr(-/-) Kit(W-sh)(/W-sh) mice showed decreased lesion size, lipid deposition, T-cell and macrophage numbers, cell proliferation and apoptosis, but increased collagen content and fibrous cap development. In vivo, adoptive transfer of syngeneic wild-type or tumor necrosis factor (TNF)-alpha-deficient mast cells restored atherogenesis to Ldlr(-/-)Kit(W-sh/W-sh) mice. Notably, neither interleukin (IL)-6- nor interferon (IFN)-gamma-deficient mast cells did so, indicating that the inhibition of atherogenesis in Ldlr(-/-)Kit(W-sh/W-sh) mice resulted from the absence of mast cells and mast cell-derived IL-6 and IFN-gamma. Compared with wild-type or TNF-alpha-deficient mast cells, those lacking IL-6 or IFN-gamma did not induce expression of proatherogenic cysteine proteinase cathepsins from vascular cells in vitro or affect cathepsin and matrix metalloproteinase activities in atherosclerotic lesions, implying that mast cell-derived IL-6 and IFN-gamma promote atherogenesis by augmenting the expression of matrix-degrading proteases. These observations establish direct participation of mast cells and mast cell-derived IL-6 and IFN-gamma in mouse atherogenesis and provide new mechanistic insight into the pathogenesis of this common disease.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "low-density", + "receptor-deficient", + "(Ldlr(-/-))", + "Ldlr(-/-)", + "Kit(W-sh)(/W-sh)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "compound", + "mutant" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + } + ] + }, + { + "PMID": "17515895", + "TEXT": "Calcineurin is a calcium-activated serine/threonine phosphatase critical to a number of developmental processes in the cardiovascular, nervous and immune systems. In the T-cell lineage, calcineurin activation is important for pre-T-cell receptor (TCR) signaling, TCR-mediated positive selection of thymocytes into mature T cells, and many aspects of the immune response. The critical role of calcineurin in the immune response is underscored by the fact that calcineurin inhibitors, such as cyclosporin A (CsA) and FK506, are powerful immunosuppressants in wide clinical use. We observed sustained calcineurin activation in human B- and T-cell lymphomas and in all mouse models of lymphoid malignancies analyzed. In intracellular NOTCH1 (ICN1)- and TEL-JAK2-induced T-cell lymphoblastic leukemia, two mouse models relevant to human malignancies, in vivo inhibition of calcineurin activity by CsA or FK506 induced apoptosis of leukemic cells and rapid tumor clearance, and substantially prolonged mouse survival. In contrast, ectopic expression of a constitutively activated mutant of calcineurin favored leukemia progression. Moreover, CsA treatment induced apoptosis in human lymphoma and leukemia cell lines. Thus, calcineurin activation is critical for the maintenance of the leukemic phenotype in vivo, identifying this pathway as a relevant therapeutic target in lymphoid malignancies.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "calcineurin", + "activity", + "by", + "CsA", + "or", + "FK506" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "ectopic", + "expression", + "of", + "a", + "constitutively", + "activated", + "mutant", + "calcineurin" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "17486088", + "TEXT": "Cell-intrinsic checkpoints limit the proliferative capacity of primary cells in response to telomere dysfunction. It is not known, however, whether telomere dysfunction contributes to cell-extrinsic alterations that impair stem cell function and organ homeostasis. Here we show that telomere dysfunction provokes defects of the hematopoietic environment that impair B lymphopoiesis but increase myeloid proliferation in aging telomerase knockout (Terc(-/-)) mice. Moreover, the dysfunctional environment limited the engraftment of transplanted wild-type hematopoietic stem cells (HSCs). Dysfunction of the hematopoietic environment was age dependent and correlated with progressive telomere shortening in bone marrow stromal cells. Telomere dysfunction impaired mesenchymal progenitor cell function, reduced the capacity of bone marrow stromal cells to maintain functional HSCs, and increased the expression of various cytokines, including granulocyte colony-stimulating factor (G-CSF), in the plasma of aging mice. Administration of G-CSF to wild-type mice mimicked some of the defects seen in aging Terc(-/-) mice, including impairment of B lymphopoiesis and HSC engraftment. Conversely, inhibition of G-CSF improved HSC engraftment in aged Terc(-/-) mice. Taken together, these results show that telomere dysfunction induces alterations of the environment that can have implications for organismal aging and cell transplantation therapies.", + "LINKED_TAGS": [ + { + "effect": { + "val": "positive", + "words": [ + "increase" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "(Terc(-/-))" + ] + } + } + ] + }, + { + "PMID": "17435771", + "TEXT": "The cytokine macrophage migration inhibitory factor (MIF) plays a critical role in inflammatory diseases and atherogenesis. We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF. MIF triggered G(alphai)- and integrin-dependent arrest and chemotaxis of monocytes and T cells, rapid integrin activation and calcium influx through CXCR2 or CXCR4. MIF competed with cognate ligands for CXCR4 and CXCR2 binding, and directly bound to CXCR2. CXCR2 and CD74 formed a receptor complex, and monocyte arrest elicited by MIF in inflamed or atherosclerotic arteries involved both CXCR2 and CD74. In vivo, Mif deficiency impaired monocyte adhesion to the arterial wall in atherosclerosis-prone mice, and MIF-induced leukocyte recruitment required Il8rb (which encodes Cxcr2). Blockade of Mif but not of canonical ligands of Cxcr2 or Cxcr4 in mice with advanced atherosclerosis led to plaque regression and reduced monocyte and T-cell content in plaques. By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis. Targeting MIF in individuals with manifest atherosclerosis can potentially be used to treat this condition.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Mif", + "deficiency" + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + } + ] + }, + { + "PMID": "17322897", + "TEXT": "Transmissibility of characteristic lesions to experimental animals may help us understand the pathomechanism of human autoimmune disease. Here we show that human autoimmune disease can be reproduced using genetically engineered model mice. Bullous pemphigoid (BP) is the most common serious autoimmune blistering skin disease, with a considerable body of indirect evidence indicating that the underlying autoantigen is collagen XVII (COL17). Passive transfer of human BP autoantibodies into mice does not induce skin lesions, probably because of differences between humans and mice in the amino acid sequence of the COL17 pathogenic epitope. We injected human BP autoantibody into Col17-knockout mice rescued by the human ortholog. This resulted in BP-like skin lesions and a human disease phenotype. Humanization of autoantigens is a new approach to the study of human autoimmune diseases.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Col17-knockout" + ] + }, + "effect": { + "val": "rescues", + "words": [ + "rescued" + ] + } + } + ] + }, + { + "PMID": "17259995", + "TEXT": "Wilson disease is caused by accumulation of Cu(2+) in cells, which results in liver cirrhosis and, occasionally, anemia. Here, we show that Cu(2+) triggers hepatocyte apoptosis through activation of acid sphingomyelinase (Asm) and release of ceramide. Genetic deficiency or pharmacological inhibition of Asm prevented Cu(2+)-induced hepatocyte apoptosis and protected rats, genetically prone to develop Wilson disease, from acute hepatocyte death, liver failure and early death. Cu(2+) induced the secretion of activated Asm from leukocytes, leading to ceramide release in and phosphatidylserine exposure on erythrocytes, events also prevented by inhibition of Asm. Phosphatidylserine exposure resulted in immediate clearance of affected erythrocytes from the blood in mice. Accordingly, individuals with Wilson disease showed elevated plasma levels of Asm, and displayed a constitutive increase of ceramide- and phosphatidylserine-positive erythrocytes. Our data suggest a previously unidentified mechanism for liver cirrhosis and anemia in Wilson disease.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "Asm" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "pharmacological", + "inhibition", + "of", + "Asm" + ] + }, + "effect": { + "val": "positive", + "words": [ + "Cu(2+)-induced" + ] + } + } + ] + }, + { + "PMID": "16998483", + "TEXT": "In individuals with chronic myeloid leukemia (CML) treated by autologous hematopoietic stem cell (HSC) transplantation, malignant progenitors in the graft contribute to leukemic relapse, but the mechanisms of homing and engraftment of leukemic CML stem cells are unknown. Here we show that CD44 expression is increased on mouse stem-progenitor cells expressing BCR-ABL and that CD44 contributes functional E-selectin ligands. In a mouse retroviral transplantation model of CML, BCR-ABL1-transduced progenitors from CD44-mutant donors are defective in homing to recipient marrow, resulting in decreased engraftment and impaired induction of CML-like myeloproliferative disease. By contrast, CD44-deficient stem cells transduced with empty retrovirus engraft as efficiently as do wild-type HSCs. CD44 is dispensable for induction of acute B-lymphoblastic leukemia by BCR-ABL, indicating that CD44 is specifically required on leukemic cells that initiate CML. The requirement for donor CD44 is bypassed by direct intrafemoral injection of BCR-ABL1-transduced CD44-deficient stem cells or by coexpression of human CD44. Antibody to CD44 attenuates induction of CML-like leukemia in recipients. These results show that BCR-ABL-expressing leukemic stem cells depend to a greater extent on CD44 for homing and engraftment than do normal HSCs, and argue that CD44 blockade may be beneficial in autologous transplantation in CML.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CD44-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "coexpression", + "of", + "human", + "CD44." + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuates" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "coexpression", + "of", + "human", + "CD44." + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antibody", + "to" + ] + }, + "effect": { + "val": "negative", + "words": [ + "attenuates" + ] + } + }, + { + "perturbing_action": { + "val": "rnai/knockdown", + "words": [ + "Antibody", + "to" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induction" + ] + } + } + ] + }, + { + "PMID": "16951685", + "TEXT": "Apoptosis is essential for clearance of potentially injurious inflammatory cells and subsequent efficient resolution of inflammation. Here we report that human neutrophils contain functionally active cyclin-dependent kinases (CDKs), and that structurally diverse CDK inhibitors induce caspase-dependent apoptosis and override powerful anti-apoptosis signals from survival factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF). We show that the CDK inhibitor R-roscovitine (Seliciclib or CYC202) markedly enhances resolution of established neutrophil-dependent inflammation in carrageenan-elicited acute pleurisy, bleomycin-induced lung injury, and passively induced arthritis in mice. In the pleurisy model, the caspase inhibitor zVAD-fmk prevents R-roscovitine-enhanced resolution of inflammation, indicating that this CDK inhibitor augments inflammatory cell apoptosis. We also provide evidence that R-roscovitine promotes apoptosis by reducing concentrations of the anti-apoptotic protein Mcl-1. Thus, CDK inhibitors enhance the resolution of established inflammation by promoting apoptosis of inflammatory cells, thereby demonstrating a hitherto unrecognized potential for the treatment of inflammatory disorders.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "CDK", + "inhibitor" + ] + }, + "effect": { + "val": "positive", + "words": [ + "augments", + "promotes", + "promoting" + ] + } + } + ] + }, + { + "PMID": "16648858", + "TEXT": "The growing number of recently identified negative feedback regulators of receptor tyrosine kinases (RTKs) highlights the importance of signal attenuation and modulation for correct signaling outcome. Mitogen-inducible gene 6 (Mig6 also known as RALT or Gene 33) is a multiadaptor protein thought to be involved in the regulation of RTK and stress signaling. Here, we show that deletion of the mouse gene encoding Mig6 (designated Errfi1, which stands for ERBB receptor feedback inhibitor 1) causes hyperactivation of endogenous epidermal growth factor receptor (EGFR) and sustained signaling through the mitogen-activated protein kinase (MAPK) pathway, resulting in overproliferation and impaired differentiation of epidermal keratinocytes. Furthermore, Errfi1-/- mice develop spontaneous tumors in various organs and are highly susceptible to chemically induced formation of skin tumors. A tumor-suppressive role for Mig6 is supported by our finding that MIG6 is downregulated in various human cancers. Inhibition of endogenous Egfr signaling with the Egfr inhibitor gefitinib (Iressa) or replacement of wild-type Egfr with the kinase-deficient protein encoded by the hypomorphic Egfr(wa2) allele completely rescued skin defects in Erffi1-/- mice. Carcinogen-induced tumors displayed by Errfi1-/- mice were highly sensitive to gefitinib. These results indicate that Mig6 is a specific negative regulator of Egfr signaling in skin morphogenesis and is a novel tumor suppressor of Egfr-dependent carcinogenesis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deletion", + "of", + "the", + "mouse", + "gene", + "encoding", + "Mig6", + "(designated", + "Errfi1," + ] + }, + "effect": { + "val": "negative", + "words": [ + "impaired" + ] + } + } + ] + }, + { + "PMID": "16415877", + "TEXT": "Control of inflammation is crucial to prevent damage to the host during infection. Lipoxins and aspirin-triggered lipoxins are crucial modulators of proinflammatory responses; however, their intracellular mechanisms have not been completely elucidated. We previously showed that lipoxin A4 (LXA4) controls migration of dendritic cells (DCs) and production of interleukin (IL)-12 in vivo. In the absence of LXA4 biosynthetic pathways, the resulting uncontrolled inflammation during infection is lethal, despite pathogen clearance. Here we show that lipoxins activate two receptors in DCs, AhR and LXAR, and that this activation triggers expression of suppressor of cytokine signaling (SOCS)-2. SOCS-2-deficient DCs are hyper-responsive to microbial stimuli, as well as refractory to the inhibitory actions of LXA4, but not to IL-10. Upon infection with an intracellular pathogen, SOCS-2-deficient mice had uncontrolled production of proinflammatory cytokines, decreased microbial proliferation, aberrant leukocyte infiltration and elevated mortality. We also show that SOCS-2 is a crucial intracellular mediator of the anti-inflammatory actions of aspirin-induced lipoxins in vivo.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "SOCS-2-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decreased" + ] + } + } + ] + }, + { + "PMID": "16369543", + "TEXT": "The scaffolding adapter GAB2 maps to a region (11q13-14) commonly amplified in human breast cancer, and is overexpressed in breast cancer cell lines and primary tumors, but its functional role in mammary carcinogenesis has remained unexplored. We found that overexpression of GAB2 (Grb2-associated binding protein 2) increases proliferation of MCF10A mammary cells in three-dimensional culture. Coexpression of GAB2 with antiapoptotic oncogenes causes lumenal filling, whereas coexpression with Neu (also known as ErbB2 and HER2) results in an invasive phenotype. These effects of GAB2 are mediated by hyperactivation of the Shp2-Erk pathway. Furthermore, overexpression of Gab2 potentiates, whereas deficiency of Gab2 ameliorates, Neu-evoked breast carcinogenesis in mice. Finally, GAB2 is amplified in some GAB2-overexpressing human breast tumors. Our data suggest that GAB2 may be a key gene within an 11q13 amplicon in human breast cancer and propose a role for overexpression of GAB2 in mammary carcinogenesis. Agents that target GAB2 or GAB2-dependent pathways may be useful for treating breast tumors that overexpress GAB2 or HER2 or both.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "GAB2", + "(Grb2-associated", + "binding", + "protein", + "2)", + "Coexpression", + "with", + "antiapoptotic", + "coexpression", + "Neu", + "Gab2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increases", + "results", + "potentiates,", + "Neu-evoked" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpression", + "of", + "Gab2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "ameliorates," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "of", + "Gab2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "ameliorates," + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "deficiency", + "of", + "Gab2" + ] + }, + "effect": { + "val": "positive", + "words": [ + "Neu-evoked" + ] + } + } + ] + }, + { + "PMID": "16341243", + "TEXT": "Inhibitors of the kinase mammalian target of rapamycin (mTOR) have shown sporadic activity in cancer trials, leading to confusion about the appropriate clinical setting for their use. Here we show that loss of the Von Hippel-Lindau tumor suppressor gene (VHL) sensitizes kidney cancer cells to the mTOR inhibitor CCI-779 in vitro and in mouse models. Growth arrest caused by CCI-779 correlates with a block in translation of mRNA encoding hypoxia-inducible factor (HIF1A), and is rescued by expression of a VHL-resistant HIF1A cDNA lacking the 5' untranslated region. VHL-deficient tumors show increased uptake of the positron emission tomography (PET) tracer fluorodeoxyglucose (FDG) in an mTOR-dependent manner. Our findings provide preclinical rationale for prospective, biomarker-driven clinical studies of mTOR inhibitors in kidney cancer and suggest that FDG-PET scans may have use as a pharmacodynamic marker in this setting.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "loss", + "of", + "the", + "Von", + "Hippel-Lindau", + "tumor", + "suppressor", + "gene", + "(VHL)" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest" + ] + } + }, + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "mTOR", + "inhibitor", + "CCI-779" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest" + ] + } + } + ] + }, + { + "PMID": "16286925", + "TEXT": "It is widely accepted that the p53 tumor suppressor restricts abnormal cells by induction of growth arrest or by triggering apoptosis. Here we show that, in addition, p53 protects the genome from oxidation by reactive oxygen species (ROS), a major cause of DNA damage and genetic instability. In the absence of severe stresses, relatively low levels of p53 are sufficient for upregulation of several genes with antioxidant products, which is associated with a decrease in intracellular ROS. Downregulation of p53 results in excessive oxidation of DNA, increased mutation rate and karyotype instability, which are prevented by incubation with the antioxidant N-acetylcysteine (NAC). Dietary supplementation with NAC prevented frequent lymphomas characteristic of Trp53-knockout mice, and slowed the growth of lung cancer xenografts deficient in p53. Our results provide a new paradigm for a nonrestrictive tumor suppressor function of p53 and highlight the potential importance of antioxidants in the prophylaxis and treatment of cancer.", + "LINKED_TAGS": [ + { + "effect": { + "val": "negative", + "words": [ + "prevented" + ] + }, + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Trp53-knockout" + ] + } + } + ] + }, + { + "PMID": "16244652", + "TEXT": "Sonic hedgehog (Shh) is a crucial regulator of organ development during embryogenesis. We investigated whether intramyocardial gene transfer of naked DNA encoding human Shh (phShh) could promote a favorable effect on recovery from acute and chronic myocardial ischemia in adult animals, not only by promoting neovascularization, but by broader effects, consistent with the role of this morphogen in embryogenesis. After Shh gene transfer, the hedgehog pathway was upregulated in mammalian fibroblasts and cardiomyocytes. This resulted in preservation of left ventricular function in both acute and chronic myocardial ischemia by enhanced neovascularization, and reduced fibrosis and cardiac apoptosis. Shh gene transfer also enhanced the contribution of bone marrow-derived endothelial progenitor cells to myocardial neovascularization. These data suggest that Shh gene therapy may have considerable therapeutic potential in individuals with acute and chronic myocardial ischemia by triggering expression of multiple trophic factors and engendering tissue repair in the adult heart.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "gene", + "transfer," + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + } + ] + }, + { + "PMID": "15895074", + "TEXT": "In inflammatory arthridities such as rheumatoid arthritis, cognate lymphocytes have long been considered instigators of autoimmunity, but accumulating evidence indicates that innate immune cells such as neutrophils and mast cells are responsible for a vast majority of acute and ongoing inflammation; however, the molecular mechanisms that govern them remain largely unknown. Here we show that such inflammation requires the forkhead transcription factor Foxo3a: Foxo3a-deficient mice are resistant to two models of neutrophilic inflammation, immune complex-mediated inflammatory arthritis and thioglycollate-induced peritonitis. This reflects a need for Foxo3a to maintain neutrophil vitality during inflammation by suppressing Fas ligand; because Foxo3a can bind and suppress the Fasl promoter, Foxo3a-deficient neutrophils upregulate Fas ligand and undergo apoptosis in response to TNF-alpha and IL-1, and Fas ligand blockade renders Foxo3a-deficient mice susceptible to both arthritis and peritonitis. Thus, Foxo3a ensures neutrophil survival during inflammation, identifying Foxo3a as therapeutic target in inflammation.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Foxo3a-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "undergo" + ] + } + } + ] + }, + { + "PMID": "15821748", + "TEXT": "Nijmegen breakage syndrome (NBS), ataxia telangiectasia and ataxia telangiectasia-like disorder (ATLD) show overlapping phenotypes such as growth retardation, microcephaly, cerebellar developmental defects and ataxia. However, the molecular pathogenesis of these neurological defects remains elusive. Here we show that inactivation of the Nbn gene (also known as Nbs1) in mouse neural tissues results in a combination of the neurological anomalies characteristic of NBS, ataxia telangiectasia and ATLD, including microcephaly, growth retardation, cerebellar defects and ataxia. Loss of Nbn causes proliferation arrest of granule cell progenitors and apoptosis of postmitotic neurons in the cerebellum. Furthermore, Nbn-deficient neuroprogenitors show proliferation defects (but not increased apoptosis) and contain more chromosomal breaks, which are accompanied by ataxia telangiectasia mutated protein (ATM)-mediated p53 activation. Notably, depletion of p53 substantially rescues the neurological defects of Nbn mutant mice. This study gives insight into the physiological function of NBS1 (the Nbn gene product) and the function of the DNA damage response in the neurological anomalies of NBS, ataxia telangiectasia and ATLD.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "the", + "Nbn", + "gene", + "(also", + "Loss", + "Nbn-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "causes", + "increased" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "inactivation", + "of", + "the", + "Nbn", + "gene", + "(also", + "Loss", + "Nbn-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "arrest", + "defects" + ] + } + } + ] + }, + { + "PMID": "15685168", + "TEXT": "The protein p27(Kip1) regulates cell cycle progression in mammals by inhibiting the activity of cyclin-dependent kinases (CDKs). Here we show that p27(Kip1) progressively accumulates in the nucleus of pancreatic beta cells in mice that lack either insulin receptor substrate 2 (Irs2(-/-)) or the long form of the leptin receptor (Lepr(-/-) or db/db). Deletion of the gene encoding p27(Kip1) (Cdkn1b) ameliorated hyperglycemia in these animal models of type 2 diabetes mellitus by increasing islet mass and maintaining compensatory hyperinsulinemia, effects that were attributable predominantly to stimulation of pancreatic beta-cell proliferation. Thus, p27(Kip1) contributes to beta-cell failure during the development of type 2 diabetes in Irs2(-/-) and Lepr(-/-) mice and represents a potential new target for the treatment of this condition.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Deletion", + "of", + "the", + "gene", + "encoding", + "p27(Kip1)", + "(Cdkn1b)" + ] + }, + "effect": { + "val": "positive", + "words": [ + "stimulation" + ] + } + } + ] + }, + { + "PMID": "15654327", + "TEXT": "The upregulation of TGF-beta1 and integrin expression during wound healing has implicated these molecules in this process, but their precise regulation and roles remain unclear. Here we report that, notably, mice lacking beta(3)-integrins show enhanced wound healing with re-epithelialization complete several days earlier than in wild-type mice. We show that this effect is the result of an increase in TGF-beta1 and enhanced dermal fibroblast infiltration into wounds of beta(3)-null mice. Specifically, beta(3)-integrin deficiency is associated with elevated TGF-beta receptor I and receptor II expression, reduced Smad3 levels, sustained Smad2 and Smad4 nuclear localization and enhanced TGF-beta1-mediated dermal fibroblast migration. These data indicate that alpha(v)beta(3)-integrin can suppress TGF-beta1-mediated signaling, thereby controlling the rate of wound healing, and highlight a new mechanism for TGF-beta1 regulation by beta(3)-integrins.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "beta(3)-integrin", + "deficiency" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + } + ] + }, + { + "PMID": "15619625", + "TEXT": "Respiratory syncytial virus (RSV) infection is one of the major causes of respiratory tract infection for which no vaccine or antiviral treatment is available. The RSV NS1 protein seems to antagonize the host interferon (IFN) response; however, its mechanism is unknown. Here, we used a plasmid-borne small interfering RNA targeting the NS1 gene (siNS1) to examine the role of NS1 in modulating RSV infection. RSV replication was reduced in A549 cells, but not IFN-deficient Vero cells, transfected with siNS1. siNS1 induced upregulated expression of IFN-beta and IFN-inducible genes in A549 cells. siNS1-transfected human dendritic cells, upon RSV infection, produced elevated type-1 IFN and induced differentiation of naive CD4+ T cells to T helper type 1 (TH1) cells. Mice treated intranasally with siNS1 nanoparticles before or after infection with RSV showed substantially decreased virus titers in the lung and decreased inflammation and airway reactivity compared to controls. Thus, siNS1 nanoparticles may provide an effective inhibition of RSV infection in humans.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "siNS1-transfected" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "15334074", + "TEXT": "Signaling through the second messengers calcium and diacylglycerol (DAG) is a critical element in many biological systems. Integration of calcium and DAG signals has been suggested to occur primarily through protein kinase C family members, which bind both calcium and DAG. However, an alternative pathway may involve members of the CalDAG-GEF/RasGRP protein family, which have structural features (calcium-binding EF hands and DAG-binding C1 domains) that suggest they can function in calcium and DAG signal integration. To gain insight into the signaling systems that may be regulated by CalDAG-GEF/RasGRP family members, we have focused on CalDAG-GEFI, which is expressed preferentially in the brain and blood. Through genetic ablation in the mouse, we have found that CalDAG-GEFI is crucial for signal integration in platelets. Mouse platelets that lack CalDAG-GEFI are severely compromised in integrin-dependent aggregation as a consequence of their inability to signal through CalDAG-GEFI to its target, the small GTPase Rap1. These results suggest that analogous signaling defects are likely to occur in the central nervous system when CalDAG-GEFI is absent or compromised in function.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lack", + "CalDAG-GEFI" + ] + }, + "effect": { + "val": "negative", + "words": [ + "compromised" + ] + } + } + ] + }, + { + "PMID": "12858170", + "TEXT": "Whereas uncoupling protein 1 (UCP-1) is clearly involved in thermogenesis, the role of UCP-2 is less clear. Using hybridization, cloning techniques and cDNA array analysis to identify inducible neuroprotective genes, we found that neuronal survival correlates with increased expression of Ucp2. In mice overexpressing human UCP-2, brain damage was diminished after experimental stroke and traumatic brain injury, and neurological recovery was enhanced. In cultured cortical neurons, UCP-2 reduced cell death and inhibited caspase-3 activation induced by oxygen and glucose deprivation. Mild mitochondrial uncoupling by 2,4-dinitrophenol (DNP) reduced neuronal death, and UCP-2 activity was enhanced by palmitic acid in isolated mitochondria. Also in isolated mitochondria, UCP-2 shifted the release of reactive oxygen species from the mitochondrial matrix to the extramitochondrial space. We propose that UCP-2 is an inducible protein that is neuroprotective by activating cellular redox signaling or by inducing mild mitochondrial uncoupling that prevents the release of apoptogenic proteins.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "overexpressing", + "human", + "UCP-2," + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduced" + ] + } + } + ] + }, + { + "PMID": "12740570", + "TEXT": "Angiogenic tumor vessels are promising targets for the activity and the selective delivery of cancer therapeutics. The bone marrow contributes different cell types to the tumor stroma, including hematopoietic cells and, as recently suggested, vascular endothelial cells (ECs). Thus, transplantation of genetically modified bone marrow progenitors may represent a vehicle for the transport of gene therapy to tumors. We transduced bone marrow progenitors with lentiviral vectors expressing genes from transcription-regulatory elements of Tie2/Tek gene. When tumors were grown in the transplanted mice, the new vector marked a distinct hematopoietic population that 'homed' to the tumor and closely interacted with vascular ECs at the tumor periphery. These Tie2-expressing mononuclear (TEM) cells had a distinguishable phenotype and were present selectively at angiogenic sites. Unexpectedly, we did not find bone marrow-derived ECs in tumor vessels when we transplanted bone marrow progenitors constitutively expressing a marker gene from the Tie2 or ubiquitously active promoters. By delivering a 'suicide' gene, we selectively eliminated the TEM cells and achieved substantial inhibition of angiogenesis and slower tumor growth without systemic toxicity. Thus, TEM cells may account for the proangiogenic activity of bone marrow-derived cells in tumors, may represent a new target for drug development and may provide the means for selective gene delivery and targeted inhibition of tumor angiogenesis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "constitutively" + ] + }, + "effect": { + "val": "negative", + "words": [ + "slower" + ] + } + } + ] + }, + { + "PMID": "12740569", + "TEXT": "Angiogenesis sustains tumor growth and metastasis, and recent studies indicate that the vascular endothelium regulates tissue mass. In the prostate, androgens drive angiogenic inducers to stimulate growth, whereas androgen withdrawal leads to decreased vascular endothelial growth factor, vascular regression and epithelial cell apoptosis. Here, we identify the angiogenesis inhibitor pigment epithelium-derived factor (PEDF) as a key inhibitor of stromal vasculature and epithelial tissue growth in mouse prostate and pancreas. In PEDF-deficient mice, stromal vessels were increased and associated with epithelial cell hyperplasia. Androgens inhibited prostatic PEDF expression in cultured cells. In vivo, androgen ablation increased PEDF in normal rat prostates and in human cancer biopsies. Exogenous PEDF induced tumor epithelial apoptosis in vitro and limited in vivo tumor xenograft growth, triggering endothelial apoptosis. Thus, PEDF regulates normal pancreas and prostate mass. Its androgen sensitivity makes PEDF a likely contributor to the anticancer effects of androgen ablation.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "androgen", + "ablation" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced" + ] + } + } + ] + }, + { + "PMID": "12244302", + "TEXT": "Mechanisms linking mitogenic and growth inhibitory cytokine signaling and the cell cycle have not been fully elucidated in either cancer or in normal cells. Here we show that activation of protein kinase B (PKB)/Akt, contributes to resistance to antiproliferative signals and breast cancer progression in part by impairing the nuclear import and action of p27. Akt transfection caused cytoplasmic p27 accumulation and resistance to cytokine-mediated G1 arrest. The nuclear localization signal of p27 contains an Akt consensus site at threonine 157, and p27 phosphorylation by Akt impaired its nuclear import in vitro. Akt phosphorylated wild-type p27 but not p27T157A. In cells transfected with constitutively active Akt(T308DS473D)(PKB(DD)), p27WT mislocalized to the cytoplasm, but p27T157A was nuclear. In cells with activated Akt, p27WT failed to cause G1 arrest, while the antiproliferative effect of p27T157A was not impaired. Cytoplasmic p27 was seen in 41% (52 of 128) of primary human breast cancers in conjunction with Akt activation and was correlated with a poor patient prognosis. Thus, we show a novel mechanism whereby Akt impairs p27 function that is associated with an aggressive phenotype in human breast cancer.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Akt", + "transfection" + ] + }, + "effect": { + "val": "negative", + "words": [ + "resistance" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "transfected", + "activated", + "Akt," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "failed", + "to", + "cause" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "with", + "constitutively", + "active", + "Akt(T308DS473D)(PKB(DD))," + ] + }, + "effect": { + "val": "no effect", + "words": [ + "failed", + "to", + "cause" + ] + } + } + ] + }, + { + "PMID": "12172541", + "TEXT": "Glioblastoma multiforme is the most undifferentiated type of brain tumor, and its prognosis is extremely poor. Glioblastoma cells exhibit highly migratory and invasive behavior, which makes surgical intervention unsuccessful. Here, we showed that glioblastoma cells express Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptors assembled from the GluR1 and/or GluR4 subunits, and that their conversion to Ca(2+)-impermeable receptors by adenovirus-mediated transfer of the GluR2 cDNA inhibited cell locomotion and induced apoptosis. In contrast, overexpression of Ca(2+)-permeable AMPA receptors facilitated migration and proliferation of the tumor cells. These findings indicate that Ca(2+)-permeable AMPA receptors have crucial roles in growth of glioblastoma. Blockage of these Ca(2+)-permeable receptors may be a useful therapeutic strategy for the prevention of glioblastoma invasion.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GluR2", + "cDNA" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibited" + ] + } + }, + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "GluR2", + "cDNA", + "overexpression", + "of", + "Ca(2+)-permeable", + "AMPA", + "receptors" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induced", + "facilitated" + ] + } + } + ] + }, + { + "PMID": "12091876", + "TEXT": "B7-H1, a recently described member of the B7 family of costimulatory molecules, is thought to be involved in the regulation of cellular and humoral immune responses through the PD-1 receptor on activated T and B cells. We report here that, except for cells of the macrophage lineage, normal human tissues do not express B7-H1. In contrast, B7-H1 is abundant in human carcinomas of lung, ovary and colon and in melanomas. The pro-inflammatory cytokine interferon-gamma upregulates B7-H1 on the surface of tumor cell lines. Cancer cell-associated B7-H1 increases apoptosis of antigen-specific human T-cell clones in vitro, and the apoptotic effect of B7-H1 is mediated largely by one or more receptors other than PD-1. In addition, expression of B7-H1 on mouse P815 tumor increases apoptosis of activated tumor-reactive T cells and promotes the growth of highly immunogenic B7-1(+) tumors in vivo. These findings have implications for the design of T cell-based cancer immunotherapy.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "expression", + "of", + "B7-H1" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increases" + ] + } + } + ] + }, + { + "PMID": "12042814", + "TEXT": "Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). So far, immunological mechanisms responsible for demyelination have been the focus of interest. However, mechanisms regulating axon maintenance as well as glial precursor-cell proliferation and oligodendrocyte survival might also influence disease outcome. The cytokine ciliary neurotrophic factor (CNTF), which was originally identified as a survival factor for isolated neurons, promotes differentiation, maturation and survival of oligodendrocytes. To investigate the role of endogenous CNTF in inflammatory demyelinating disease, we studied myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in CNTF-deficient and wild-type C57BL/6 mice. Disease was more severe in CNTF-deficient mice and recovery was poor, with a 60% decrease in the number of proliferating oligodendrocyte precursor cells (OPCs) and a more than 50% increase in the rate of oligodendrocyte apoptosis. In addition, vacuolar dystrophy of myelin and axonal damage were more severe in CNTF-deficient mice. These specific pathological features could be prevented by treatment with an antiserum against tumor necrosis factor-alpha, suggesting that endogenous CNTF may counterbalance this effect of TNF-alpha (ref. 7). Here we identify a factor that modulates, in an inflammatory environment, glial cell survival and is an outcome determinant of EAE.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CNTF-deficient" + ] + }, + "effect": { + "val": "negative", + "words": [ + "decrease" + ] + } + }, + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "CNTF-deficient" + ] + }, + "effect": { + "val": "positive", + "words": [ + "increase" + ] + } + } + ] + }, + { + "PMID": "11875501", + "TEXT": "Prostaglandins (PGs), bioactive lipid molecules produced by cyclooxygenase enzymes (COX-1 and COX-2), have diverse biological activities, including growth-promoting actions on gastrointestinal mucosa. They are also implicated in the growth of colonic polyps and cancers. However, the precise mechanisms of these trophic actions of PGs remain unclear. As activation of the epidermal growth factor receptor (EGFR) triggers mitogenic signaling in gastrointestinal mucosa, and its expression is also upregulated in colonic cancers and most neoplasms, we investigated whether PGs transactivate EGFR. Here we provide evidence that prostaglandin E2 (PGE2) rapidly phosphorylates EGFR and triggers the extracellular signal-regulated kinase 2 (ERK2)--mitogenic signaling pathway in normal gastric epithelial (RGM1) and colon cancer (Caco-2, LoVo and HT-29) cell lines. Inactivation of EGFR kinase with selective inhibitors significantly reduces PGE2-induced ERK2 activation, c-fos mRNA expression and cell proliferation. Inhibition of matrix metalloproteinases (MMPs), transforming growth factor-alpha (TGF-alpha) or c-Src blocked PGE2-mediated EGFR transactivation and downstream signaling indicating that PGE2-induced EGFR transactivation involves signaling transduced via TGF-alpha, an EGFR ligand, likely released by c-Src-activated MMP(s). Our findings that PGE2 transactivates EGFR reveal a previously unknown mechanism by which PGE2 mediates trophic actions resulting in gastric and intestinal hypertrophy as well as growth of colonic polyps and cancers.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inactivation", + "of", + "EGFR", + "kinase", + "with", + "selective", + "inhibitors" + ] + }, + "effect": { + "val": "negative", + "words": [ + "reduces" + ] + } + } + ] + }, + { + "PMID": "11786903", + "TEXT": "Inhibition of alphavbeta3 or alphavbeta5 integrin function has been reported to suppress neovascularization and tumor growth, suggesting that these integrins are critical modulators of angiogenesis. Here we report that mice lacking beta3 integrins or both beta3 and beta5 integrins not only support tumorigenesis, but have enhanced tumor growth as well. Moreover, the tumors in these integrin-deficient mice display enhanced angiogenesis, strongly suggesting that neither beta3 nor beta5 integrins are essential for neovascularization. We also observed that angiogenic responses to hypoxia and vascular endothelial growth factor (VEGF) are augmented significantly in the absence of beta3 integrins. We found no evidence that the expression or functions of other integrins were altered as a consequence of the beta3 deficiency, but we did observe elevated levels of VEGF receptor-2 (also called Flk-1) in beta3-null endothelial cells. These data indicate that alphavbeta3 and alphavbeta5 integrins are not essential for vascular development or pathological angiogenesis and highlight the need for further evaluation of the mechanisms of action of alphav-integrin antagonists in anti-angiogenic therapeutics.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "lacking", + "beta3", + "integrins", + "or", + "both", + "beta5" + ] + }, + "effect": { + "val": "positive", + "words": [ + "support", + "enhanced" + ] + } + } + ] + }, + { + "PMID": "11726970", + "TEXT": "While searching for alternative reading-frame peptides encoded by influenza A virus that are recognized by CD8+ T cells, we found an abundant immunogenic peptide encoded by the +1 reading frame of PB1. This peptide derives from a novel conserved 87-residue protein, PB1-F2, which has several unusual features compared with other influenza gene products in addition to its mode of translation. These include its absence from some animal (particularly swine) influenza virus isolates, variable expression in individual infected cells, rapid proteasome-dependent degradation and mitochondrial localization. Exposure of cells to a synthetic version of PB1-F2 induces apoptosis, and influenza viruses with targeted mutations that interfere with PB1-F2 expression induce less extensive apoptosis in human monocytic cells than those with intact PB1-F2. We propose that PB1-F2 functions to kill host immune cells responding to influenza virus infection.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "targeted", + "mutations", + "that", + "interfere", + "with", + "PB1-F2", + "expression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "induce" + ] + } + }, + { + "perturbing_action": { + "val": "other", + "words": [ + "targeted", + "mutations", + "that", + "interfere", + "with", + "PB1-F2", + "expression" + ] + }, + "effect": { + "val": "negative", + "words": [ + "less" + ] + } + } + ] + }, + { + "PMID": "11726968", + "TEXT": "Inflammation involves the sequential activation of signaling pathways leading to the production of both pro- and anti-inflammatory mediators. Although much attention has focused on pro-inflammatory pathways that initiate inflammation, relatively little is known about the mechanisms that switch off inflammation and resolve the inflammatory response. The transcription factor NF-kappaB is thought to have a central role in the induction of pro-inflammatory gene expression and has attracted interest as a new target for the treatment of inflammatory disease. We show here that NF-kappaB activation in leukocytes recruited during the onset of inflammation is associated with pro-inflammatory gene expression, whereas such activation during the resolution of inflammation is associated with the expression of anti-inflammatory genes and the induction of apoptosis. Inhibition of NF-kappaB during the resolution of inflammation protracts the inflammatory response and prevents apoptosis. This suggests that NF-kappaB has an anti-inflammatory role in vivo involving the regulation of inflammatory resolution.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "Inhibition", + "of", + "NF-kappaB" + ] + }, + "effect": { + "val": "negative", + "words": [ + "prevents" + ] + } + } + ] + }, + { + "PMID": "11533708", + "TEXT": "Cyclooxygenase-2 (COX-2), a key enzyme in arachidonic acid metabolism, is overexpressed in many cancers. Inhibition of COX-2 by nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of cancer development in humans and suppresses tumor growth in animal models. The anti-cancer effect of NSAIDs seems to involve suppression of tumor angiogenesis, but the underlying mechanism is not completely understood. Integrin alpha V beta 3 is an adhesion receptor critically involved in mediating tumor angiogenesis. Here we show that inhibition of endothelial-cell COX-2 by NSAIDs suppresses alpha V beta 3-dependent activation of the small GTPases Cdc42 and Rac, resulting in inhibition of endothelial-cell spreading and migration in vitro and suppression of fibroblast growth factor-2-induced angiogenesis in vivo. These results establish a novel functional link between COX-2, integrin alpha V beta 3 and Cdc42-/Rac-dependent endothelial-cell migration. Moreover, they provide a rationale to the understanding of the anti-angiogenic activity of NSAIDs.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "pharmacological inhibition", + "words": [ + "inhibition", + "of", + "endothelial-cell", + "COX-2", + "by", + "NSAIDs" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibition" + ] + } + } + ] + }, + { + "PMID": "11385507", + "TEXT": "The adipocyte fatty-acid-binding protein, aP2, has an important role in regulating systemic insulin resistance and lipid metabolism. Here we demonstrate that aP2 is also expressed in macrophages, has a significant role in their biological responses and contributes to the development of atherosclerosis. Apolipoprotein E (ApoE)-deficient mice also deficient for aP2 showed protection from atherosclerosis in the absence of significant differences in serum lipids or insulin sensitivity. aP2-deficient macrophages showed alterations in inflammatory cytokine production and a reduced ability to accumulate cholesterol esters when exposed to modified lipoproteins. Apoe-/- mice with Ap2+/+ adipocytes and Ap2-/- macrophages generated by bone-marrow transplantation showed a comparable reduction in atherosclerotic lesions to those with total aP2 deficiency, indicating an independent role for macrophage aP2 in atherogenesis. Through its distinct actions in adipocytes and macrophages, aP2 provides a link between features of the metabolic syndrome and could be a new therapeutic target for the prevention of atherosclerosis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene loss-of-function", + "words": [ + "Apolipoprotein", + "E", + "(ApoE)-deficient", + "deficient", + "for", + "aP2" + ] + }, + "effect": { + "val": "negative", + "words": [ + "protection" + ] + } + } + ] + }, + { + "PMID": "11175850", + "TEXT": "Metastasis of breast cancer occurs primarily through the lymphatic system, and the extent of lymph node involvement is a key prognostic factor for the disease. Whereas the significance of angiogenesis for tumor progression has been well documented, the ability of tumor cells to induce the growth of lymphatic vessels (lymphangiogenesis) and the presence of intratumoral lymphatic vessels have been controversial. Using a novel marker for lymphatic endothelium, LYVE-1, we demonstrate here the occurrence of intratumoral lymphangiogenesis within human breast cancers after orthotopic transplantation onto nude mice. Vascular endothelial growth factor (VEGF)-C overexpression in breast cancer cells potently increased intratumoral lymphangiogenesis, resulting in significantly enhanced metastasis to regional lymph nodes and to lungs. The degree of tumor lymphangiogenesis was highly correlated with the extent of lymph node and lung metastases. These results establish the occurrence and biological significance of intratumoral lymphangiogenesis in breast cancer and identify VEGF-C as a molecular link between tumor lymphangiogenesis and metastasis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "gene gain-of-function", + "words": [ + "Vascular", + "endothelial", + "growth", + "factor", + "(VEGF)-C", + "overexpression" + ] + }, + "effect": { + "val": "positive", + "words": [ + "enhanced" + ] + } + } + ] + }, + { + "PMID": "10655109", + "TEXT": "Maspin, a unique member of the serpin family, is a secreted protein encoded by a class II tumor suppressor gene whose downregulation is associated with the development of breast and prostate cancers. Overexpression of maspin in breast tumor cells limits their growth and metastases in vivo. In this report we demonstrate that maspin is an effective inhibitor of angiogenesis. In vitro, it acted directly on cultured endothelial cells to stop their migration towards basic fibroblast growth factor and vascular endothelial growth factor and to limit mitogenesis and tube formation. In vivo, it blocked neovascularization in the rat cornea pocket model. Maspin derivatives mutated in the serpin reactive site lost their ability to inhibit the migration of fibroblasts, keratinocytes, and breast cancer cells but were still able to block angiogenesis in vitro and in vivo. When maspin was delivered locally to human prostate tumor cells in a xenograft mouse model, it blocked tumor growth and dramatically reduced the density of tumor-associated microvessels. These data suggest that the tumor suppressor activity of maspin may depend in large part on its ability to inhibit angiogenesis and raise the possibility that maspin and similar serpins may be excellent leads for the development of drugs that modulate angiogenesis.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "mutated", + "in", + "the", + "serpin", + "reactive", + "site" + ] + }, + "effect": { + "val": "negative", + "words": [ + "inhibit", + "blocked" + ] + } + } + ] + }, + { + "PMID": "10502820", + "TEXT": "Telomerase is a ribonucleoprotein enzyme that maintains the protective structures at the ends of eukaryotic chromosomes, called telomeres. In most human somatic cells, telomerase expression is repressed, and telomeres shorten progressively with each cell division. In contrast, most human tumors express telomerase, resulting in stabilized telomere length. These observations indicate that telomere maintenance is essential to the proliferation of tumor cells. We show here that expression of a mutant catalytic subunit of human telomerase results in complete inhibition of telomerase activity, reduction in telomere length and death of tumor cells. Moreover, expression of this mutant telomerase eliminated tumorigenicity in vivo. These observations demonstrate that disruption of telomere maintenance limits cellular lifespan in human cancer cells, thus validating human telomerase reverse transcriptase as an important target for the development of anti-neoplastic therapies.", + "LINKED_TAGS": [ + { + "perturbing_action": { + "val": "other", + "words": [ + "expression", + "of", + "this", + "mutant", + "telomerase" + ] + }, + "effect": { + "val": "negative", + "words": [ + "eliminated" + ] + } + } + ] + } +] \ No newline at end of file diff --git a/active.sh b/active.sh index 47bb62b..712b147 100644 --- a/active.sh +++ b/active.sh @@ -1,5 +1,5 @@ #!/bin/sh -. ~/user_venv/bin/activate +conda activate tfm_nlp python3 main.py -f configs/active -vr diff --git a/active_l.sh b/active_l.sh index 4648f38..579d74c 100644 --- a/active_l.sh +++ b/active_l.sh @@ -1,5 +1,5 @@ #!/bin/sh -. ~/user_venv/bin/activate +conda activate tfm_nlp python3 -u main.py -f configs/active -vr > outputs/log.txt 2>&1 diff --git a/analysis/cc2_comparison.md b/analysis/cc2_comparison.md new file mode 100644 index 0000000..8ceaf85 --- /dev/null +++ b/analysis/cc2_comparison.md @@ -0,0 +1,1124 @@ +--- +title: Rough Analysis of cc2_comparison.json +geometry: margin=2cm +--- + +# General Information + +* Num. Entries: 50 +* Tokenizer used: dmis-lab/biobert-v1.1 + +### Definitions: + +* Words represent the number of entities that have been considered distinct during the proccess of assigning tags to part of the text, it is essentially the text split on spaces +* Tokens are the actual pieces of data going into the model, punctuation is split from words and some large words are split down into smaller parts +* Total tags is the total number of tags across all words (If two or more words are part of the same tag this counts as a tag for each word) +* Unique tags is the total number of tags that are unique (not part of same tag) +* Max tags is the most tags a single word has +* Tagged words is the number of words that have at least one tag +* Tagged words % is the percentage of words that are tagged, it's given in brackets for individual entries. +* Avg tags is the average number of tags per word that is tagged +* MC words is the number of words with tags across multiple categories +* Total links is the total number of links across all tags (If two or more tags are linked this counts as a link for each one) +* Unique links is the total number of links that are unique (not part of the same link) +* Max links is the most amount of links a single tag or word has associated with it +* Linked tags, words is the number of tags or words that have links +* Linked % tags, words is the percentage of tags or words with links +* Avg links per tag, word is the average number of links per tag or word +* The schema used is BIES as it is all encompassing and models can convert to a lower resolution if wanted (Beginning, Inner, End, Singleton) + +## Sizes + +* Average words: 208.9 +* Maximum words: 286 +* Minimum words: 11\ +* Average tokens: 387.0 +* Maximum tokens: 578 +* Minimum tokens: 29\ +* Entries with over 512 tokens: 4/50, 8.0% + + +## Tags + +### Maximums + +* Total tags: 66 +* Unique tags: 35 +* Max tags: 2 +* Tagged words: 66 +* Tagged words %: 25.19% +* Avg tags: 1.03 +* MC words: 1 + +### Averages + +* Total tags: 21.96 +* Unique tags: 12.52 +* Max tags: 0.94 +* Tagged words: 21.94 +* Tagged words %: 9.84% +* Avg tags: 0.92 +* MC words: 0.02 + + +## Links + +### Maximums + +* Total links: 52 +* Unique links: 8 +* Max links per tag, word: 4, 4 +* Linked tags, words: 27, 27 +* Linked % tags, words: 100.0%, 10.31% +* Avg links per tag, word: 2.54, 2.54 + +### Averages + +* Total links: 5.46 +* Unique links: 0.7 +* Max links per tag, word: 0.5, 0.5 +* Linked tags, words: 3.58, 3.58 +* Linked % tags, words: 13.07%, 1.69% +* Avg links per tag, word: 0.41, 0.41 + + +## Schema + +* Maximums (B, I, E, S): 13, 18, 13, 22 +* Averages (B, I, E, S): 4.86, 4.58, 4.86, 7.66 + + +## Labels + +* Label: Total, Maximum per entry, Average per entry + +### Categories + +* Perturbing_Action: 229, 35, 4.58 +* Context: 474, 32, 9.48 +* Effect: 172, 11, 3.44 +* Phenotype: 223, 17, 4.46 + +### Perturbing_Action + +* -: 0, 0, 0.0 +* Gene Loss-Of-Function: 32, 14, 0.64 +* Gene Gain-Of-Function: 21, 11, 0.42 +* Rnai/Knockdown: 87, 32, 1.74 +* Pharmacological Inhibition: 63, 9, 1.26 +* Pharmacological Augmentation: 0, 0, 0.0 +* Other: 26, 19, 0.52 + +### Context + +* -: 2, 2, 0.04 +* Patient: 2, 2, 0.04 +* Organism: 33, 5, 0.66 +* Tissue/Organ: 22, 7, 0.44 +* Neoplasm: 15, 4, 0.3 +* Graft: 0, 0, 0.0 +* Xenograft: 5, 5, 0.1 +* Cells: 263, 28, 5.26 +* Transformed Cells: 96, 14, 1.92 +* Organoid: 0, 0, 0.0 +* In Vitro: 24, 6, 0.48 +* In Vivo: 12, 2, 0.24 + +### Effect + +* -: 0, 0, 0.0 +* Positive: 97, 9, 1.94 +* Negative: 58, 3, 1.16 +* Regulates: 9, 2, 0.18 +* Rescues: 0, 0, 0.0 +* No Effect: 8, 4, 0.16 + +### Phenotype + +* -: 0, 0, 0.0 +* Adhesion: 0, 0, 0.0 +* Apoptosis: 121, 8, 2.42 +* Anoikis: 0, 0, 0.0 +* Autophagy: 15, 5, 0.3 +* Cell Cycle Arrest: 24, 7, 0.48 +* Cell Death: 24, 12, 0.48 +* Cell Growth: 4, 2, 0.08 +* Cell Survival: 14, 7, 0.28 +* Colony Formation: 2, 2, 0.04 +* Differentiation: 0, 0, 0.0 +* Entosis: 0, 0, 0.0 +* Epithelial-Mesenchymal Transition: 0, 0, 0.0 +* Ferroptosis: 0, 0, 0.0 +* Invasion: 1, 1, 0.02 +* Metastasis: 3, 3, 0.06 +* Migration: 1, 1, 0.02 +* Mitophagy: 0, 0, 0.0 +* Necroptosis: 2, 2, 0.04 +* Necrosis: 1, 1, 0.02 +* Oncosis: 0, 0, 0.0 +* Proliferation: 4, 1, 0.08 +* Pyroptosis: 0, 0, 0.0 +* Quiescence: 0, 0, 0.0 +* Self-Renewal: 0, 0, 0.0 +* Senescence: 0, 0, 0.0 +* Transformation: 0, 0, 0.0 +* Tumour Growth: 6, 4, 0.12 +* Tumourigenesis: 1, 1, 0.02 +* Tumour Initiation: 0, 0, 0.0 +* Tumour Progression: 0, 0, 0.0 +* Tumour Regression: 0, 0, 0.0 + + +# Information on each entry + +**Title**: +570_PMID29858716.txt.xml, +Words: 266, +Tokens: 423\ +Tag data: +Total: 26, +Unique: 15, +Max tags: 1, +Tagged words: 26 (10%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (8, 3, 8, 7) + +**Title**: +582_PMID30778709.txt.xml, +Words: 256, +Tokens: 501\ +Tag data: +Total: 17, +Unique: 11, +Max tags: 1, +Tagged words: 17 (7%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (3, 3, 3, 8) + +**Title**: +573_PMID30515612.txt.xml, +Words: 225, +Tokens: 381\ +Tag data: +Total: 36, +Unique: 21, +Max tags: 1, +Tagged words: 36 (16%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 39, +Unique: 3, +Max links (tag, word): (3, 3), +Linked (tags, words): (17 (47.22%), 17 (7.56%))\ +Avg links (tag, word): (2.29, 2.29), +Schema counts (B, I, E, S): (6, 9, 6, 15) + +**Title**: +557_PMID32632545.txt.xml, +Words: 184, +Tokens: 377\ +Tag data: +Total: 12, +Unique: 8, +Max tags: 1, +Tagged words: 12 (7%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (2, 2, 2, 6) + +**Title**: +556_PMID29435687.txt.xml, +Words: 146, +Tokens: 283\ +Tag data: +Total: 10, +Unique: 6, +Max tags: 1, +Tagged words: 10 (7%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (4, 0, 4, 2) + +**Title**: +553_PMID29236198.txt.xml, +Words: 263, +Tokens: 444\ +Tag data: +Total: 18, +Unique: 12, +Max tags: 1, +Tagged words: 18 (7%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (2, 4, 2, 10) + +**Title**: +586_PMID31342239.txt.xml, +Words: 209, +Tokens: 397\ +Tag data: +Total: 33, +Unique: 18, +Max tags: 1, +Tagged words: 33 (16%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 8, +Unique: 1, +Max links (tag, word): (1, 1), +Linked (tags, words): (8 (24.24%), 8 (3.83%))\ +Avg links (tag, word): (1.0, 1.0), +Schema counts (B, I, E, S): (7, 8, 7, 11) + +**Title**: +572_PMID30430397.txt.xml, +Words: 215, +Tokens: 408\ +Tag data: +Total: 22, +Unique: 18, +Max tags: 1, +Tagged words: 22 (10%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (3, 1, 3, 15) + +**Title**: +590_PMID26386572.txt.xml, +Words: 220, +Tokens: 428\ +Tag data: +Total: 13, +Unique: 11, +Max tags: 1, +Tagged words: 13 (6%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (2, 0, 2, 9) + +**Title**: +566_PMID30421279.txt.xml, +Words: 39, +Tokens: 68\ +Tag data: +Total: 0, +Unique: 0, +Max tags: 0, +Tagged words: 0 (0%), +Avg tags: 0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (0, 0, 0, 0) + +**Title**: +583_PMID32409930.txt.xml, +Words: 208, +Tokens: 327\ +Tag data: +Total: 18, +Unique: 14, +Max tags: 1, +Tagged words: 18 (9%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (4, 0, 4, 10) + +**Title**: +576_PMID30610505.txt.xml, +Words: 251, +Tokens: 478\ +Tag data: +Total: 23, +Unique: 10, +Max tags: 1, +Tagged words: 23 (9%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (8, 5, 8, 2) + +**Title**: +554_PMID31489517.txt.xml, +Words: 168, +Tokens: 288\ +Tag data: +Total: 0, +Unique: 0, +Max tags: 0, +Tagged words: 0 (0%), +Avg tags: 0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (0, 0, 0, 0) + +**Title**: +559_PMID30911960.txt.xml, +Words: 219, +Tokens: 409\ +Tag data: +Total: 13, +Unique: 9, +Max tags: 1, +Tagged words: 13 (6%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 8, +Unique: 1, +Max links (tag, word): (1, 1), +Linked (tags, words): (8 (61.54%), 8 (3.65%))\ +Avg links (tag, word): (1.0, 1.0), +Schema counts (B, I, E, S): (1, 3, 1, 8) + +**Title**: +561_PMID32737651.txt.xml, +Words: 249, +Tokens: 458\ +Tag data: +Total: 40, +Unique: 19, +Max tags: 2, +Tagged words: 39 (16%), +Avg tags: 1.03, +MC words: 1\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (13, 8, 13, 6) + +**Title**: +562_PMID31641960.txt.xml, +Words: 236, +Tokens: 456\ +Tag data: +Total: 25, +Unique: 6, +Max tags: 1, +Tagged words: 25 (11%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (4, 15, 4, 2) + +**Title**: +563_PMID29978434.txt.xml, +Words: 195, +Tokens: 302\ +Tag data: +Total: 20, +Unique: 8, +Max tags: 1, +Tagged words: 20 (10%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (7, 5, 7, 1) + +**Title**: +592_PMID30426280.txt.xml, +Words: 148, +Tokens: 243\ +Tag data: +Total: 11, +Unique: 5, +Max tags: 1, +Tagged words: 11 (7%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 19, +Unique: 2, +Max links (tag, word): (2, 2), +Linked (tags, words): (11 (100.0%), 11 (7.43%))\ +Avg links (tag, word): (1.73, 1.73), +Schema counts (B, I, E, S): (3, 3, 3, 2) + +**Title**: +595_PMID30578463.txt.xml, +Words: 262, +Tokens: 543\ +Tag data: +Total: 42, +Unique: 24, +Max tags: 1, +Tagged words: 42 (16%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (11, 7, 11, 13) + +**Title**: +588_PMID26801321.txt.xml, +Words: 224, +Tokens: 398\ +Tag data: +Total: 10, +Unique: 9, +Max tags: 1, +Tagged words: 10 (4%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (1, 0, 1, 8) + +**Title**: +574_PMID25953318.txt.xml, +Words: 249, +Tokens: 498\ +Tag data: +Total: 25, +Unique: 18, +Max tags: 1, +Tagged words: 25 (10%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (2, 5, 2, 16) + +**Title**: +598_PMID25218423.txt.xml, +Words: 220, +Tokens: 456\ +Tag data: +Total: 29, +Unique: 21, +Max tags: 1, +Tagged words: 29 (13%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 16, +Unique: 3, +Max links (tag, word): (2, 2), +Linked (tags, words): (12 (41.38%), 12 (5.45%))\ +Avg links (tag, word): (1.33, 1.33), +Schema counts (B, I, E, S): (6, 2, 6, 15) + +**Title**: +567_PMID27770267.txt.xml, +Words: 286, +Tokens: 479\ +Tag data: +Total: 38, +Unique: 18, +Max tags: 1, +Tagged words: 38 (13%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (8, 12, 8, 10) + +**Title**: +591_PMID32901335.txt.xml, +Words: 145, +Tokens: 265\ +Tag data: +Total: 28, +Unique: 15, +Max tags: 1, +Tagged words: 28 (19%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 33, +Unique: 3, +Max links (tag, word): (3, 3), +Linked (tags, words): (13 (46.43%), 13 (8.97%))\ +Avg links (tag, word): (2.54, 2.54), +Schema counts (B, I, E, S): (4, 9, 4, 11) + +**Title**: +569_PMID28012059.txt.xml, +Words: 205, +Tokens: 402\ +Tag data: +Total: 38, +Unique: 20, +Max tags: 1, +Tagged words: 38 (19%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (9, 9, 9, 11) + +**Title**: +597_PMID30680481.txt.xml, +Words: 255, +Tokens: 524\ +Tag data: +Total: 19, +Unique: 13, +Max tags: 1, +Tagged words: 19 (7%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 7, +Unique: 1, +Max links (tag, word): (1, 1), +Linked (tags, words): (7 (36.84%), 7 (2.75%))\ +Avg links (tag, word): (1.0, 1.0), +Schema counts (B, I, E, S): (5, 1, 5, 8) + +**Title**: +560_PMID32591959.txt.xml, +Words: 196, +Tokens: 351\ +Tag data: +Total: 16, +Unique: 8, +Max tags: 1, +Tagged words: 16 (8%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (5, 3, 5, 3) + +**Title**: +584_PMID32026186.txt.xml, +Words: 11, +Tokens: 29\ +Tag data: +Total: 0, +Unique: 0, +Max tags: 0, +Tagged words: 0 (0%), +Avg tags: 0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (0, 0, 0, 0) + +**Title**: +571_PMID31583496.txt.xml, +Words: 213, +Tokens: 399\ +Tag data: +Total: 47, +Unique: 27, +Max tags: 1, +Tagged words: 47 (22%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 52, +Unique: 8, +Max links (tag, word): (4, 4), +Linked (tags, words): (21 (44.68%), 21 (9.86%))\ +Avg links (tag, word): (2.48, 2.48), +Schema counts (B, I, E, S): (12, 8, 12, 15) + +**Title**: +599_PMID32036474.txt.xml, +Words: 266, +Tokens: 538\ +Tag data: +Total: 36, +Unique: 18, +Max tags: 1, +Tagged words: 36 (14%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (10, 8, 10, 8) + +**Title**: +575_PMID28879567.txt.xml, +Words: 196, +Tokens: 452\ +Tag data: +Total: 30, +Unique: 21, +Max tags: 1, +Tagged words: 30 (15%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 14, +Unique: 2, +Max links (tag, word): (1, 1), +Linked (tags, words): (14 (46.67%), 14 (7.14%))\ +Avg links (tag, word): (1.0, 1.0), +Schema counts (B, I, E, S): (5, 4, 5, 16) + +**Title**: +568_PMID32405891.txt.xml, +Words: 262, +Tokens: 469\ +Tag data: +Total: 35, +Unique: 15, +Max tags: 1, +Tagged words: 35 (13%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 7, +Unique: 1, +Max links (tag, word): (1, 1), +Linked (tags, words): (7 (20.0%), 7 (2.67%))\ +Avg links (tag, word): (1.0, 1.0), +Schema counts (B, I, E, S): (8, 12, 8, 7) + +**Title**: +577_PMID31867678.txt.xml, +Words: 240, +Tokens: 388\ +Tag data: +Total: 5, +Unique: 3, +Max tags: 1, +Tagged words: 5 (2%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (1, 1, 1, 2) + +**Title**: +589_PMID31177396.txt.xml, +Words: 201, +Tokens: 336\ +Tag data: +Total: 12, +Unique: 8, +Max tags: 1, +Tagged words: 12 (6%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 7, +Unique: 1, +Max links (tag, word): (1, 1), +Linked (tags, words): (7 (58.33%), 7 (3.48%))\ +Avg links (tag, word): (1.0, 1.0), +Schema counts (B, I, E, S): (3, 1, 3, 5) + +**Title**: +565_PMID31768842.txt.xml, +Words: 225, +Tokens: 424\ +Tag data: +Total: 16, +Unique: 11, +Max tags: 1, +Tagged words: 16 (7%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (1, 4, 1, 10) + +**Title**: +552_PMID29058102.txt.xml, +Words: 201, +Tokens: 393\ +Tag data: +Total: 7, +Unique: 3, +Max tags: 1, +Tagged words: 7 (3%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (3, 1, 3, 0) + +**Title**: +581_PMID32468177.txt.xml, +Words: 231, +Tokens: 427\ +Tag data: +Total: 16, +Unique: 9, +Max tags: 1, +Tagged words: 16 (7%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (3, 4, 3, 6) + +**Title**: +564_PMID30879166.txt.xml, +Words: 235, +Tokens: 450\ +Tag data: +Total: 32, +Unique: 11, +Max tags: 1, +Tagged words: 32 (14%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 7, +Unique: 1, +Max links (tag, word): (1, 1), +Linked (tags, words): (7 (21.88%), 7 (2.98%))\ +Avg links (tag, word): (1.0, 1.0), +Schema counts (B, I, E, S): (5, 16, 5, 6) + +**Title**: +578_PMID31538267.txt.xml, +Words: 185, +Tokens: 350\ +Tag data: +Total: 24, +Unique: 20, +Max tags: 1, +Tagged words: 24 (13%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (3, 1, 3, 17) + +**Title**: +551_PMID31605257.txt.xml, +Words: 258, +Tokens: 412\ +Tag data: +Total: 14, +Unique: 8, +Max tags: 1, +Tagged words: 14 (5%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (3, 3, 3, 5) + +**Title**: +558_PMID31691131.txt.xml, +Words: 167, +Tokens: 294\ +Tag data: +Total: 19, +Unique: 12, +Max tags: 1, +Tagged words: 19 (11%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 6, +Unique: 1, +Max links (tag, word): (1, 1), +Linked (tags, words): (6 (31.58%), 6 (3.59%))\ +Avg links (tag, word): (1.0, 1.0), +Schema counts (B, I, E, S): (6, 1, 6, 6) + +**Title**: +587_PMID28176146.txt.xml, +Words: 248, +Tokens: 419\ +Tag data: +Total: 27, +Unique: 13, +Max tags: 1, +Tagged words: 27 (11%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (6, 8, 6, 7) + +**Title**: +600_PMID26467923.txt.xml, +Words: 283, +Tokens: 504\ +Tag data: +Total: 44, +Unique: 22, +Max tags: 1, +Tagged words: 44 (16%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 14, +Unique: 2, +Max links (tag, word): (1, 1), +Linked (tags, words): (14 (31.82%), 14 (4.95%))\ +Avg links (tag, word): (1.0, 1.0), +Schema counts (B, I, E, S): (12, 10, 12, 10) + +**Title**: +555_PMID33230593.txt.xml, +Words: 230, +Tokens: 468\ +Tag data: +Total: 18, +Unique: 15, +Max tags: 1, +Tagged words: 18 (8%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (3, 0, 3, 12) + +**Title**: +594_PMID28168327.txt.xml, +Words: 207, +Tokens: 369\ +Tag data: +Total: 24, +Unique: 13, +Max tags: 1, +Tagged words: 24 (12%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (6, 5, 6, 7) + +**Title**: +580_PMID30084053.txt.xml, +Words: 215, +Tokens: 409\ +Tag data: +Total: 15, +Unique: 9, +Max tags: 1, +Tagged words: 15 (7%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (4, 2, 4, 5) + +**Title**: +585_PMID30879165.txt.xml, +Words: 94, +Tokens: 149\ +Tag data: +Total: 10, +Unique: 4, +Max tags: 1, +Tagged words: 10 (11%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (3, 3, 3, 1) + +**Title**: +593_PMID32583319.txt.xml, +Words: 19, +Tokens: 45\ +Tag data: +Total: 0, +Unique: 0, +Max tags: 0, +Tagged words: 0 (0%), +Avg tags: 0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (0, 0, 0, 0) + +**Title**: +579_PMID30788651.txt.xml, +Words: 255, +Tokens: 463\ +Tag data: +Total: 19, +Unique: 12, +Max tags: 1, +Tagged words: 19 (7%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (5, 2, 5, 7) + +**Title**: +596_PMID26456506.txt.xml, +Words: 262, +Tokens: 578\ +Tag data: +Total: 66, +Unique: 35, +Max tags: 1, +Tagged words: 66 (25%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 36, +Unique: 5, +Max links (tag, word): (2, 2), +Linked (tags, words): (27 (40.91%), 27 (10.31%))\ +Avg links (tag, word): (1.33, 1.33), +Schema counts (B, I, E, S): (13, 18, 13, 22) + + diff --git a/analysis/cc2_comparison.pdf b/analysis/cc2_comparison.pdf new file mode 100644 index 0000000..1ff8201 Binary files /dev/null and b/analysis/cc2_comparison.pdf differ diff --git a/analysis/hz_comparison.md b/analysis/hz_comparison.md new file mode 100644 index 0000000..2466b43 --- /dev/null +++ b/analysis/hz_comparison.md @@ -0,0 +1,1124 @@ +--- +title: Rough Analysis of hz_comparison.json +geometry: margin=2cm +--- + +# General Information + +* Num. Entries: 50 +* Tokenizer used: dmis-lab/biobert-v1.1 + +### Definitions: + +* Words represent the number of entities that have been considered distinct during the proccess of assigning tags to part of the text, it is essentially the text split on spaces +* Tokens are the actual pieces of data going into the model, punctuation is split from words and some large words are split down into smaller parts +* Total tags is the total number of tags across all words (If two or more words are part of the same tag this counts as a tag for each word) +* Unique tags is the total number of tags that are unique (not part of same tag) +* Max tags is the most tags a single word has +* Tagged words is the number of words that have at least one tag +* Tagged words % is the percentage of words that are tagged, it's given in brackets for individual entries. +* Avg tags is the average number of tags per word that is tagged +* MC words is the number of words with tags across multiple categories +* Total links is the total number of links across all tags (If two or more tags are linked this counts as a link for each one) +* Unique links is the total number of links that are unique (not part of the same link) +* Max links is the most amount of links a single tag or word has associated with it +* Linked tags, words is the number of tags or words that have links +* Linked % tags, words is the percentage of tags or words with links +* Avg links per tag, word is the average number of links per tag or word +* The schema used is BIES as it is all encompassing and models can convert to a lower resolution if wanted (Beginning, Inner, End, Singleton) + +## Sizes + +* Average words: 208.9 +* Maximum words: 286 +* Minimum words: 11\ +* Average tokens: 387.0 +* Maximum tokens: 578 +* Minimum tokens: 29\ +* Entries with over 512 tokens: 4/50, 8.0% + + +## Tags + +### Maximums + +* Total tags: 41 +* Unique tags: 23 +* Max tags: 2 +* Tagged words: 41 +* Tagged words %: 19.62% +* Avg tags: 1.05 +* MC words: 0 + +### Averages + +* Total tags: 16.18 +* Unique tags: 9.46 +* Max tags: 0.94 +* Tagged words: 16.14 +* Tagged words %: 7.31% +* Avg tags: 0.92 +* MC words: 0.0 + + +## Links + +### Maximums + +* Total links: 14 +* Unique links: 2 +* Max links per tag, word: 1, 1 +* Linked tags, words: 14, 14 +* Linked % tags, words: 52.94%, 6.7% +* Avg links per tag, word: 1.0, 1.0 + +### Averages + +* Total links: 1.28 +* Unique links: 0.2 +* Max links per tag, word: 0.18, 0.18 +* Linked tags, words: 1.28, 1.28 +* Linked % tags, words: 5.59%, 0.62% +* Avg links per tag, word: 0.18, 0.18 + + +## Schema + +* Maximums (B, I, E, S): 13, 13, 13, 22 +* Averages (B, I, E, S): 3.78, 2.94, 3.78, 5.68 + + +## Labels + +* Label: Total, Maximum per entry, Average per entry + +### Categories + +* Perturbing_Action: 170, 15, 3.4 +* Context: 353, 27, 7.06 +* Effect: 124, 10, 2.48 +* Phenotype: 162, 13, 3.24 + +### Perturbing_Action + +* -: 15, 12, 0.3 +* Gene Loss-Of-Function: 21, 10, 0.42 +* Gene Gain-Of-Function: 15, 4, 0.3 +* Rnai/Knockdown: 50, 12, 1.0 +* Pharmacological Inhibition: 64, 10, 1.28 +* Pharmacological Augmentation: 0, 0, 0.0 +* Other: 5, 3, 0.1 + +### Context + +* -: 16, 13, 0.32 +* Patient: 3, 3, 0.06 +* Organism: 19, 5, 0.38 +* Tissue/Organ: 20, 7, 0.4 +* Neoplasm: 4, 4, 0.08 +* Graft: 0, 0, 0.0 +* Xenograft: 0, 0, 0.0 +* Cells: 194, 24, 3.88 +* Transformed Cells: 69, 9, 1.38 +* Organoid: 0, 0, 0.0 +* In Vitro: 16, 4, 0.32 +* In Vivo: 12, 4, 0.24 + +### Effect + +* -: 8, 4, 0.16 +* Positive: 70, 5, 1.4 +* Negative: 36, 3, 0.72 +* Regulates: 3, 2, 0.06 +* Rescues: 3, 2, 0.06 +* No Effect: 4, 4, 0.08 + +### Phenotype + +* -: 6, 4, 0.12 +* Adhesion: 0, 0, 0.0 +* Apoptosis: 80, 5, 1.6 +* Anoikis: 0, 0, 0.0 +* Autophagy: 10, 4, 0.2 +* Cell Cycle Arrest: 16, 4, 0.32 +* Cell Death: 21, 8, 0.42 +* Cell Growth: 2, 2, 0.04 +* Cell Survival: 10, 4, 0.2 +* Colony Formation: 0, 0, 0.0 +* Differentiation: 0, 0, 0.0 +* Entosis: 0, 0, 0.0 +* Epithelial-Mesenchymal Transition: 0, 0, 0.0 +* Ferroptosis: 0, 0, 0.0 +* Invasion: 1, 1, 0.02 +* Metastasis: 1, 1, 0.02 +* Migration: 1, 1, 0.02 +* Mitophagy: 0, 0, 0.0 +* Necroptosis: 0, 0, 0.0 +* Necrosis: 1, 1, 0.02 +* Oncosis: 0, 0, 0.0 +* Proliferation: 6, 2, 0.12 +* Pyroptosis: 0, 0, 0.0 +* Quiescence: 0, 0, 0.0 +* Self-Renewal: 0, 0, 0.0 +* Senescence: 0, 0, 0.0 +* Transformation: 0, 0, 0.0 +* Tumour Growth: 6, 4, 0.12 +* Tumourigenesis: 1, 1, 0.02 +* Tumour Initiation: 0, 0, 0.0 +* Tumour Progression: 0, 0, 0.0 +* Tumour Regression: 0, 0, 0.0 + + +# Information on each entry + +**Title**: +562_PMID31641960.txt.xml, +Words: 236, +Tokens: 456\ +Tag data: +Total: 5, +Unique: 5, +Max tags: 1, +Tagged words: 5 (2%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (0, 0, 0, 5) + +**Title**: +568_PMID32405891.txt.xml, +Words: 262, +Tokens: 469\ +Tag data: +Total: 27, +Unique: 10, +Max tags: 1, +Tagged words: 27 (10%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (6, 11, 6, 4) + +**Title**: +555_PMID33230593.txt.xml, +Words: 230, +Tokens: 468\ +Tag data: +Total: 13, +Unique: 10, +Max tags: 1, +Tagged words: 13 (6%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (3, 0, 3, 7) + +**Title**: +579_PMID30788651.txt.xml, +Words: 255, +Tokens: 463\ +Tag data: +Total: 0, +Unique: 0, +Max tags: 0, +Tagged words: 0 (0%), +Avg tags: 0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (0, 0, 0, 0) + +**Title**: +589_PMID31177396.txt.xml, +Words: 201, +Tokens: 336\ +Tag data: +Total: 17, +Unique: 8, +Max tags: 1, +Tagged words: 17 (8%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 7, +Unique: 1, +Max links (tag, word): (1, 1), +Linked (tags, words): (7 (41.18%), 7 (3.48%))\ +Avg links (tag, word): (1.0, 1.0), +Schema counts (B, I, E, S): (5, 4, 5, 3) + +**Title**: +598_PMID25218423.txt.xml, +Words: 220, +Tokens: 456\ +Tag data: +Total: 17, +Unique: 14, +Max tags: 1, +Tagged words: 17 (8%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 5, +Unique: 1, +Max links (tag, word): (1, 1), +Linked (tags, words): (5 (29.41%), 5 (2.27%))\ +Avg links (tag, word): (1.0, 1.0), +Schema counts (B, I, E, S): (2, 1, 2, 12) + +**Title**: +597_PMID30680481.txt.xml, +Words: 255, +Tokens: 524\ +Tag data: +Total: 16, +Unique: 7, +Max tags: 1, +Tagged words: 16 (6%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 7, +Unique: 1, +Max links (tag, word): (1, 1), +Linked (tags, words): (7 (43.75%), 7 (2.75%))\ +Avg links (tag, word): (1.0, 1.0), +Schema counts (B, I, E, S): (5, 4, 5, 2) + +**Title**: +552_PMID29058102.txt.xml, +Words: 201, +Tokens: 393\ +Tag data: +Total: 6, +Unique: 3, +Max tags: 1, +Tagged words: 6 (3%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (3, 0, 3, 0) + +**Title**: +572_PMID30430397.txt.xml, +Words: 215, +Tokens: 408\ +Tag data: +Total: 24, +Unique: 16, +Max tags: 1, +Tagged words: 24 (11%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (4, 4, 4, 12) + +**Title**: +565_PMID31768842.txt.xml, +Words: 225, +Tokens: 424\ +Tag data: +Total: 13, +Unique: 8, +Max tags: 1, +Tagged words: 13 (6%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (1, 4, 1, 7) + +**Title**: +570_PMID29858716.txt.xml, +Words: 266, +Tokens: 423\ +Tag data: +Total: 20, +Unique: 14, +Max tags: 1, +Tagged words: 20 (8%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (6, 0, 6, 8) + +**Title**: +563_PMID29978434.txt.xml, +Words: 195, +Tokens: 302\ +Tag data: +Total: 11, +Unique: 7, +Max tags: 1, +Tagged words: 11 (6%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (4, 0, 4, 3) + +**Title**: +599_PMID32036474.txt.xml, +Words: 266, +Tokens: 538\ +Tag data: +Total: 27, +Unique: 17, +Max tags: 1, +Tagged words: 27 (10%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (9, 1, 9, 8) + +**Title**: +569_PMID28012059.txt.xml, +Words: 205, +Tokens: 402\ +Tag data: +Total: 24, +Unique: 10, +Max tags: 1, +Tagged words: 24 (12%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (7, 7, 7, 3) + +**Title**: +551_PMID31605257.txt.xml, +Words: 258, +Tokens: 412\ +Tag data: +Total: 9, +Unique: 4, +Max tags: 1, +Tagged words: 9 (3%), +Avg tags: 1.0, +MC words: 0\ +Link data: +Total: 0, +Unique: 0, +Max links (tag, word): (0, 0), +Linked (tags, words): (0 (0.0%), 0 (0%))\ +Avg links (tag, word): (0, 0), +Schema counts (B, I, E, S): (2, 3, 2, 2) + +**Title**: +574_PMID25953318.txt.xml, +Words: 249, 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a/analysis/v2_marked_and_linked.pdf b/analysis/v2_marked_and_linked.pdf new file mode 100644 index 0000000..6d56cd0 Binary files /dev/null and b/analysis/v2_marked_and_linked.pdf differ diff --git a/analysis/v2_unmarked.pdf b/analysis/v2_unmarked.pdf new file mode 100644 index 0000000..b885ffa Binary files /dev/null and b/analysis/v2_unmarked.pdf differ diff --git a/configs/analysis/bert_base/link.json b/configs/analysis/bert_base/link.json new file mode 100644 index 0000000..9a41187 --- /dev/null +++ b/configs/analysis/bert_base/link.json @@ -0,0 +1,91 @@ +{ + "MODE": "analyse", + "HISTORY_DATA": { + "PATH": "outputs/outputs_db.json", + "MODELS": [ + "BERTBase_link_both_heads_v2_bl05_k4_2023-08-01_13-59" + ] + }, + "ANALYSIS": { + "GRAPHING": { + "OUTPUT": "save", + "FOLDER": "model_analysis/bert_base/link_graphs", + "GRAPHS": [ + { + "TITLE": "Train Losses", + "VALUES": { + "train_losses": null + }, + "HEAD_NAMES": [ + "link_only", + "link_same_tag_only" + ] + }, + { + "TITLE": "Val 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a/configs/analysis/bio_clin_bert/link.json b/configs/analysis/bio_clin_bert/link.json new file mode 100644 index 0000000..a0866df --- /dev/null +++ b/configs/analysis/bio_clin_bert/link.json @@ -0,0 +1,91 @@ +{ + "MODE": "analyse", + "HISTORY_DATA": { + "PATH": "outputs/outputs_db.json", + "MODELS": [ + "BioBERTv11_link_both_heads_v2_bl05_k4_2023-07-27_15-24" + ] + }, + "ANALYSIS": { + "GRAPHING": { + "OUTPUT": "save", + "FOLDER": "model_analysis/bio_clin_bert/link_graphs", + "GRAPHS": [ + { + "TITLE": "Train Losses", + "VALUES": { + "train_losses": null + }, + "HEAD_NAMES": [ + "link_only", + "link_same_tag_only" + ] + }, + { + "TITLE": "Val Losses", + "VALUES": { + "validation_losses": null + }, + "HEAD_NAMES": [ + "link_only", + "link_same_tag_only" + ] + }, + { + "TITLE": "F1 Scores", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "link_only", + "link_same_tag_only" + ] + } + ] + }, + "REPORT": { + "OUTPUT": "md", + "PATH": "model_analysis/link_report", + "TITLE": "Report on link models", + "REPORTS": [ + { + "TITLE": "Train Losses", + "VALUES": { + "train_losses": null + }, + "HEAD_NAMES": [ + "link_only", + "link_same_tag_only" + ], + "BEST_IS_MIN": true + }, + { + "TITLE": "Val Losses", + "VALUES": { + "validation_losses": null + }, + "HEAD_NAMES": [ + "link_only", + "link_same_tag_only" + ], + "BEST_IS_MIN": true + }, + { + "TITLE": "F1 Scores", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "link_only", + "link_same_tag_only" + ] + } + ] + } + } +} + diff --git a/configs/analysis/bio_clin_bert/tag.json b/configs/analysis/bio_clin_bert/tag.json new file mode 100644 index 0000000..2353e7c --- /dev/null +++ b/configs/analysis/bio_clin_bert/tag.json @@ -0,0 +1,202 @@ +{ + "MODE": "analyse", + "HISTORY_DATA": { + "PATH": "outputs/outputs_db.json", + "MODELS": [ + "BioBERTv11_multi_output_v2_single_label_bio_bl05_k4_e36_2023-07-27_19-55", + "BioBERTv11_multi_output_v2_single_label_bl05_k4_e36_2023-07-28_00-24" + ] + }, + "ANALYSIS": { + "GRAPHING": { + "OUTPUT": "save", + "FOLDER": "model_analysis/bio_clin_bert/tag_graphs", + "GRAPHS": [ + { + "TITLE": "Combined Train Losses", + "VALUES": { + "train_losses": null + }, + "HEAD_COMBINE": "sum" + }, + { + "TITLE": "Combined Val Losses", + "VALUES": { + "validation_losses": null + }, + "HEAD_COMBINE": "sum" + }, + { + "TITLE": "F1 Geometric Mean", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_COMBINE": "g_mean" + }, + { + "TITLE": "F1 Arithmetic Mean", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_COMBINE": "mean" + }, + { + "TITLE": "Cateogry F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "category" + ] + }, + { + "TITLE": "Perturbing Action F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "perturbing_action" + ] + }, + { + "TITLE": "Context F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "context" + ] + }, + { + "TITLE": "Effect F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "effect" + ] + }, + { + "TITLE": "Phenotype F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "phenotype" + ] + } + ] + }, + "REPORT": { + "OUTPUT": "md", + "PATH": "model_analysis/tag_report", + "TITLE": "Report on tag models", + "REPORTS": [ + { + "TITLE": "Combined Train Losses", + "VALUES": { + "train_losses": null + }, + "HEAD_COMBINE": "sum", + "BEST_IS_MIN": true + }, + { + "TITLE": "Combined Val Losses", + "VALUES": { + "validation_losses": null + }, + "HEAD_COMBINE": "sum", + "BEST_IS_MIN": true + }, + { + "TITLE": "F1 Geometric Mean", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_COMBINE": "g_mean" + }, + { + "TITLE": "F1 Arithmetic Mean", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_COMBINE": "mean" + }, + { + "TITLE": "Cateogry F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "category" + ] + }, + { + "TITLE": "Perturbing Action F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "perturbing_action" + ] + }, + { + "TITLE": "Context F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "context" + ] + }, + { + "TITLE": "Effect F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "effect" + ] + }, + { + "TITLE": "Phenotype F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "phenotype" + ] + } + ] + } + } +} + diff --git a/configs/analysis/current_best/link.json b/configs/analysis/current_best/link.json new file mode 100644 index 0000000..20020c0 --- /dev/null +++ b/configs/analysis/current_best/link.json @@ -0,0 +1,91 @@ +{ + "MODE": "analyse", + "HISTORY_DATA": { + "PATH": "outputs/outputs_db.json", + "MODELS": [ + "BioBERTv11_link_both_heads_v2_bl05_k4_2023-07-25_15-24" + ] + }, + "ANALYSIS": { + "GRAPHING": { + "OUTPUT": "save", + "FOLDER": "model_analysis/link_graphs", + "GRAPHS": [ + { + "TITLE": "Train Losses", + "VALUES": { + "train_losses": null + }, + "HEAD_NAMES": [ + "link_only", + "link_same_tag_only" + ] + }, + { + "TITLE": "Val Losses", + "VALUES": { + "validation_losses": null + }, + "HEAD_NAMES": [ + "link_only", + "link_same_tag_only" + ] + }, + { + "TITLE": "F1 Scores", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "link_only", + "link_same_tag_only" + ] + } + ] + }, + "REPORT": { + "OUTPUT": "md", + "PATH": "model_analysis/link_report", + "TITLE": "Report on link models", + "REPORTS": [ + { + "TITLE": "Train Losses", + "VALUES": { + "train_losses": null + }, + "HEAD_NAMES": [ + "link_only", + "link_same_tag_only" + ], + "BEST_IS_MIN": true + }, + { + "TITLE": "Val Losses", + "VALUES": { + "validation_losses": null + }, + "HEAD_NAMES": [ + "link_only", + "link_same_tag_only" + ], + "BEST_IS_MIN": true + }, + { + "TITLE": "F1 Scores", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "link_only", + "link_same_tag_only" + ] + } + ] + } + } +} + diff --git a/configs/analysis/current_best/tag.json b/configs/analysis/current_best/tag.json new file mode 100644 index 0000000..a831d2d --- /dev/null +++ b/configs/analysis/current_best/tag.json @@ -0,0 +1,202 @@ +{ + "MODE": "analyse", + "HISTORY_DATA": { + "PATH": "outputs/outputs_db.json", + "MODELS": [ + "BioBERTv11_multi_output_v2_single_label_bio_bl05_k4_e36_2023-07-26_00-19", + "BioBERTv11_multi_output_v2_single_label_bl05_k4_e36_2023-07-25_19-52" + ] + }, + "ANALYSIS": { + "GRAPHING": { + "OUTPUT": "save", + "FOLDER": "model_analysis/tag_graphs", + "GRAPHS": [ + { + "TITLE": "Combined Train Losses", + "VALUES": { + "train_losses": null + }, + "HEAD_COMBINE": "sum" + }, + { + "TITLE": "Combined Val Losses", + "VALUES": { + "validation_losses": null + }, + "HEAD_COMBINE": "sum" + }, + { + "TITLE": "F1 Geometric Mean", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_COMBINE": "g_mean" + }, + { + "TITLE": "F1 Arithmetic Mean", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_COMBINE": "mean" + }, + { + "TITLE": "Cateogry F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "category" + ] + }, + { + "TITLE": "Perturbing Action F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "perturbing_action" + ] + }, + { + "TITLE": "Context F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "context" + ] + }, + { + "TITLE": "Effect F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "effect" + ] + }, + { + "TITLE": "Phenotype F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "phenotype" + ] + } + ] + }, + "REPORT": { + "OUTPUT": "md", + "PATH": "model_analysis/tag_report", + "TITLE": "Report on tag models", + "REPORTS": [ + { + "TITLE": "Combined Train Losses", + "VALUES": { + "train_losses": null + }, + "HEAD_COMBINE": "sum", + "BEST_IS_MIN": true + }, + { + "TITLE": "Combined Val Losses", + "VALUES": { + "validation_losses": null + }, + "HEAD_COMBINE": "sum", + "BEST_IS_MIN": true + }, + { + "TITLE": "F1 Geometric Mean", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_COMBINE": "g_mean" + }, + { + "TITLE": "F1 Arithmetic Mean", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_COMBINE": "mean" + }, + { + "TITLE": "Cateogry F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "category" + ] + }, + { + "TITLE": "Perturbing Action F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "perturbing_action" + ] + }, + { + "TITLE": "Context F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "context" + ] + }, + { + "TITLE": "Effect F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "effect" + ] + }, + { + "TITLE": "Phenotype F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "phenotype" + ] + } + ] + } + } +} + diff --git a/configs/analysis/single_heads/link.json b/configs/analysis/single_heads/link.json new file mode 100644 index 0000000..baf7de3 --- /dev/null +++ b/configs/analysis/single_heads/link.json @@ -0,0 +1,85 @@ +{ + "MODE": "analyse", + "HISTORY_DATA": { + "PATH": "outputs/outputs_db.json", + "MODELS": [ + "BioBERTv11_link_both_heads_v2_bl05_k4_2023-07-25_15-24" + ] + }, + "ANALYSIS": { + "GRAPHING": { + "OUTPUT": "save", + "FOLDER": "model_analysis/single_heads/link_graphs", + "GRAPHS": [ + { + "TITLE": "Train Losses", + "VALUES": { + "train_losses": null + }, + "HEAD_NAMES": [ + "link_only" + ] + }, + { + "TITLE": "Val Losses", + "VALUES": { + "validation_losses": null + }, + "HEAD_NAMES": [ + "link_only" + ] + }, + { + "TITLE": "F1 Scores", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "link_only" + ] + } + ] + }, + "REPORT": { + "OUTPUT": "md", + "PATH": "model_analysis/single_heads/link_report", + "TITLE": "Report on link models", + "REPORTS": [ + { + "TITLE": "Train Losses", + "VALUES": { + "train_losses": null + }, + "HEAD_NAMES": [ + "link_only" + ], + "BEST_IS_MIN": true + }, + { + "TITLE": "Val Losses", + "VALUES": { + "validation_losses": null + }, + "HEAD_NAMES": [ + "link_only" + ], + "BEST_IS_MIN": true + }, + { + "TITLE": "F1 Scores", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "link_only" + ] + } + ] + } + } +} + diff --git a/configs/analysis/single_heads/tag.json b/configs/analysis/single_heads/tag.json new file mode 100644 index 0000000..25187ea --- /dev/null +++ b/configs/analysis/single_heads/tag.json @@ -0,0 +1,206 @@ +{ + "MODE": "analyse", + "HISTORY_DATA": { + "PATH": "outputs/outputs_db.json", + "MODELS": [ + "BioBERTv11_multi_output_v2_single_label_bio_bl05_k4_e36_2023-07-26_00-19", + "BioBERTv11_category_v2_single_label_bio_bl05_k4_e36_2023-08-15_16-10", + "BioBERTv11_perturbing_action_v2_single_label_bio_bl05_k4_e36_2023-08-15_18-42", + "BioBERTv11_context_v2_single_label_bio_bl05_k4_e36_2023-08-15_21-15", + "BioBERTv11_effect_v2_single_label_bio_bl05_k4_e36_2023-08-15_23-47", + "BioBERTv11_phenotype_v2_single_label_bio_bl05_k4_e36_2023-08-17_16-12" + ] + }, + "ANALYSIS": { + "GRAPHING": { + "OUTPUT": "save", + "FOLDER": "model_analysis/single_heads/tag_graphs", + "GRAPHS": [ + { + "TITLE": "Combined Train Losses", + "VALUES": { + "train_losses": null + }, + "HEAD_COMBINE": "sum" + }, + { + "TITLE": "Combined Val Losses", + "VALUES": { + "validation_losses": null + }, + "HEAD_COMBINE": "sum" + }, + { + "TITLE": "F1 Geometric Mean", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_COMBINE": "g_mean" + }, + { + "TITLE": "F1 Arithmetic Mean", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_COMBINE": "mean" + }, + { + "TITLE": "Cateogry F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "category" + ] + }, + { + "TITLE": "Perturbing Action F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "perturbing_action" + ] + }, + { + "TITLE": "Context F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "context" + ] + }, + { + "TITLE": "Effect F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "effect" + ] + }, + { + "TITLE": "Phenotype F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "phenotype" + ] + } + ] + }, + "REPORT": { + "OUTPUT": "md", + "PATH": "model_analysis/single_heads/tag_report", + "TITLE": "Report on tag models", + "REPORTS": [ + { + "TITLE": "Combined Train Losses", + "VALUES": { + "train_losses": null + }, + "HEAD_COMBINE": "sum", + "BEST_IS_MIN": true + }, + { + "TITLE": "Combined Val Losses", + "VALUES": { + "validation_losses": null + }, + "HEAD_COMBINE": "sum", + "BEST_IS_MIN": true + }, + { + "TITLE": "F1 Geometric Mean", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_COMBINE": "g_mean" + }, + { + "TITLE": "F1 Arithmetic Mean", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_COMBINE": "mean" + }, + { + "TITLE": "Cateogry F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "category" + ] + }, + { + "TITLE": "Perturbing Action F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "perturbing_action" + ] + }, + { + "TITLE": "Context F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "context" + ] + }, + { + "TITLE": "Effect F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "effect" + ] + }, + { + "TITLE": "Phenotype F1", + "VALUES": { + "validation_accuracies": [ + "f1" + ] + }, + "HEAD_NAMES": [ + "phenotype" + ] + } + ] + } + } +} + diff --git a/configs/bert_base/v2_link_both_heads_bl05_k4.json b/configs/bert_base/v2_link_both_heads_bl05_k4.json new file mode 100644 index 0000000..3b401c8 --- /dev/null +++ b/configs/bert_base/v2_link_both_heads_bl05_k4.json @@ -0,0 +1,40 @@ +{ + "MODE": "train", + "VERBOSE": 1, + "MODEL": { + "TYPE": "pretrained", + "TRANSFORMER_MODEL": "bert-base-uncased", + "HEADS": { + "link_same_tag_only": {"htype": "link", "num_labels": 1}, + "link_only": {"htype": "link", "num_labels": 1} + }, + "TAG_CATEGORY_DEFINITIONS": "tag_categories_v2.json", + "MAX_TOKEN_LENGTH": 512 + }, + "DATA": { + "PATH": "json_data/v2_marked_and_linked_train.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 1, + "BALANCE_CLASSES": 0.5 + }, + "TRAINING": { + "TRAINED_NAME": "BERTBase_link_both_heads_v2_bl05_k4", + "OPTIMIZER_CLASS": "AdamW", + "OPTIMIZER_KWARGS": { + "lr": 3e-5, + "eps": 1e-8 + }, + "FULL_FINETUNING": true, + "EPOCHS": 6, + "MAX_GRAD_NORM": 1, + "VERBOSE": 2, + "K_FOLDS": 4 + }, + "TEST_DATA": { + "PATH": "json_data/v2_marked_and_linked_test.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 8, + "BALANCE_CLASSES": 0 + }, + "TESTING": {} +} diff --git a/configs/bert_base/v2_single_label_bio_bl05_k4_e36.json b/configs/bert_base/v2_single_label_bio_bl05_k4_e36.json new file mode 100644 index 0000000..6b56a7d --- /dev/null +++ b/configs/bert_base/v2_single_label_bio_bl05_k4_e36.json @@ -0,0 +1,43 @@ +{ + "MODE": "train", + "VERBOSE": 1, + "MODEL": { + "TYPE": "pretrained", + "TRANSFORMER_MODEL": "bert-base-uncased", + "HEADS": { + "category": {"htype": "single_label", "num_labels": 9, "schema": "BIO"}, + "perturbing_action": {"htype": "single_label", "num_labels": 15, "schema": "BIO"}, + "context": {"htype": "single_label", "num_labels": 25, "schema": "BIO"}, + "effect": {"htype": "single_label", "num_labels": 13, "schema": "BIO"}, + "phenotype": {"htype": "single_label", "num_labels": 65, "schema": "BIO"} + }, + "TAG_LIST_DEFINITIONS": "tag_list_definitions_v2.json", + "TAG_CATEGORY_DEFINITIONS": "tag_categories_v2.json", + "MAX_TOKEN_LENGTH": 512 + }, + "DATA": { + "PATH": "json_data/v2_all_marked_train.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 1, + "BALANCE_CLASSES": 0.5 + }, + "TRAINING": { + "TRAINED_NAME": "BERTBase_multi_output_v2_single_label_bio_bl05_k4_e36", + "OPTIMIZER_CLASS": "AdamW", + "OPTIMIZER_KWARGS": { + "lr": 3e-5, + "eps": 1e-8 + }, + "FULL_FINETUNING": true, + "EPOCHS": 36, + "MAX_GRAD_NORM": 1, + "K_FOLDS": 4 + }, + "TEST_DATA": { + "PATH": "json_data/v2_all_marked_test.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 8, + "BALANCE_CLASSES": 0 + }, + "TESTING": {} +} diff --git a/configs/bert_base/v2_single_label_bl05_k4_e36.json b/configs/bert_base/v2_single_label_bl05_k4_e36.json new file mode 100644 index 0000000..fc0a8e5 --- /dev/null +++ b/configs/bert_base/v2_single_label_bl05_k4_e36.json @@ -0,0 +1,43 @@ +{ + "MODE": "train", + "VERBOSE": 1, + "MODEL": { + "TYPE": "pretrained", + "TRANSFORMER_MODEL": "bert-base-uncased", + "HEADS": { + "category": {"htype": "single_label", "num_labels": 5}, + "perturbing_action": {"htype": "single_label", "num_labels": 8}, + "context": {"htype": "single_label", "num_labels": 13}, + "effect": {"htype": "single_label", "num_labels": 7}, + "phenotype": {"htype": "single_label", "num_labels": 33} + }, + "TAG_LIST_DEFINITIONS": "tag_list_definitions_v2.json", + "TAG_CATEGORY_DEFINITIONS": "tag_categories_v2.json", + "MAX_TOKEN_LENGTH": 512 + }, + "DATA": { + "PATH": "json_data/v2_all_marked_train.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 1, + "BALANCE_CLASSES": 0.5 + }, + "TRAINING": { + "TRAINED_NAME": "BERTBase_multi_output_v2_single_label_bl05_k4_e36", + "OPTIMIZER_CLASS": "AdamW", + "OPTIMIZER_KWARGS": { + "lr": 3e-5, + "eps": 1e-8 + }, + "FULL_FINETUNING": true, + "EPOCHS": 36, + "MAX_GRAD_NORM": 1, + "K_FOLDS": 4 + }, + "TEST_DATA": { + "PATH": "json_data/v2_all_marked_test.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 8, + "BALANCE_CLASSES": 0 + }, + "TESTING": {} +} diff --git a/configs/bio_clin_bert/v2_link_both_heads_bl05_k4.json b/configs/bio_clin_bert/v2_link_both_heads_bl05_k4.json new file mode 100644 index 0000000..b28e242 --- /dev/null +++ b/configs/bio_clin_bert/v2_link_both_heads_bl05_k4.json @@ -0,0 +1,40 @@ +{ + "MODE": "train", + "VERBOSE": 1, + "MODEL": { + "TYPE": "pretrained", + "TRANSFORMER_MODEL": "emilyalsentzer/Bio_ClinicalBERT", + "HEADS": { + "link_same_tag_only": {"htype": "link", "num_labels": 1}, + "link_only": {"htype": "link", "num_labels": 1} + }, + "TAG_CATEGORY_DEFINITIONS": "tag_categories_v2.json", + "MAX_TOKEN_LENGTH": 512 + }, + "DATA": { + "PATH": "json_data/v2_marked_and_linked_train.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 1, + "BALANCE_CLASSES": 0.5 + }, + "TRAINING": { + "TRAINED_NAME": "BioBERTv11_link_both_heads_v2_bl05_k4", + "OPTIMIZER_CLASS": "AdamW", + "OPTIMIZER_KWARGS": { + "lr": 3e-5, + "eps": 1e-8 + }, + "FULL_FINETUNING": true, + "EPOCHS": 6, + "MAX_GRAD_NORM": 1, + "VERBOSE": 2, + "K_FOLDS": 4 + }, + "TEST_DATA": { + "PATH": "json_data/v2_marked_and_linked_test.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 8, + "BALANCE_CLASSES": 0 + }, + "TESTING": {} +} diff --git a/configs/bio_clin_bert/v2_single_label_bio_bl05_k4_e36.json b/configs/bio_clin_bert/v2_single_label_bio_bl05_k4_e36.json new file mode 100644 index 0000000..f8d4ab2 --- /dev/null +++ b/configs/bio_clin_bert/v2_single_label_bio_bl05_k4_e36.json @@ -0,0 +1,43 @@ +{ + "MODE": "train", + "VERBOSE": 1, + "MODEL": { + "TYPE": "pretrained", + "TRANSFORMER_MODEL": "emilyalsentzer/Bio_ClinicalBERT", + "HEADS": { + "category": {"htype": "single_label", "num_labels": 9, "schema": "BIO"}, + "perturbing_action": {"htype": "single_label", "num_labels": 15, "schema": "BIO"}, + "context": {"htype": "single_label", "num_labels": 25, "schema": "BIO"}, + "effect": {"htype": "single_label", "num_labels": 13, "schema": "BIO"}, + "phenotype": {"htype": "single_label", "num_labels": 65, "schema": "BIO"} + }, + "TAG_LIST_DEFINITIONS": "tag_list_definitions_v2.json", + "TAG_CATEGORY_DEFINITIONS": "tag_categories_v2.json", + "MAX_TOKEN_LENGTH": 512 + }, + "DATA": { + "PATH": "json_data/v2_all_marked_train.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 1, + "BALANCE_CLASSES": 0.5 + }, + "TRAINING": { + "TRAINED_NAME": "BioBERTv11_multi_output_v2_single_label_bio_bl05_k4_e36", + "OPTIMIZER_CLASS": "AdamW", + "OPTIMIZER_KWARGS": { + "lr": 3e-5, + "eps": 1e-8 + }, + "FULL_FINETUNING": true, + "EPOCHS": 36, + "MAX_GRAD_NORM": 1, + "K_FOLDS": 4 + }, + "TEST_DATA": { + "PATH": "json_data/v2_all_marked_test.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 8, + "BALANCE_CLASSES": 0 + }, + "TESTING": {} +} diff --git a/configs/bio_clin_bert/v2_single_label_bl05_k4_e36.json b/configs/bio_clin_bert/v2_single_label_bl05_k4_e36.json new file mode 100644 index 0000000..74d1bcd --- /dev/null +++ b/configs/bio_clin_bert/v2_single_label_bl05_k4_e36.json @@ -0,0 +1,43 @@ +{ + "MODE": "train", + "VERBOSE": 1, + "MODEL": { + "TYPE": "pretrained", + "TRANSFORMER_MODEL": "emilyalsentzer/Bio_ClinicalBERT", + "HEADS": { + "category": {"htype": "single_label", "num_labels": 5}, + "perturbing_action": {"htype": "single_label", "num_labels": 8}, + "context": {"htype": "single_label", "num_labels": 13}, + "effect": {"htype": "single_label", "num_labels": 7}, + "phenotype": {"htype": "single_label", "num_labels": 33} + }, + "TAG_LIST_DEFINITIONS": "tag_list_definitions_v2.json", + "TAG_CATEGORY_DEFINITIONS": "tag_categories_v2.json", + "MAX_TOKEN_LENGTH": 512 + }, + "DATA": { + "PATH": "json_data/v2_all_marked_train.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 1, + "BALANCE_CLASSES": 0.5 + }, + "TRAINING": { + "TRAINED_NAME": "BioBERTv11_multi_output_v2_single_label_bl05_k4_e36", + "OPTIMIZER_CLASS": "AdamW", + "OPTIMIZER_KWARGS": { + "lr": 3e-5, + "eps": 1e-8 + }, + "FULL_FINETUNING": true, + "EPOCHS": 36, + "MAX_GRAD_NORM": 1, + "K_FOLDS": 4 + }, + "TEST_DATA": { + "PATH": "json_data/v2_all_marked_test.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 8, + "BALANCE_CLASSES": 0 + }, + "TESTING": {} +} diff --git a/configs/deploy/biobert_tag.json b/configs/deploy/biobert_tag.json index 8958b96..7d134e7 100644 --- a/configs/deploy/biobert_tag.json +++ b/configs/deploy/biobert_tag.json @@ -2,7 +2,7 @@ "MODE": "deploy", "MODEL": { "TYPE": "existing", - "PATH": "outputs/models/BioBERTv11_multi_output_bl05_k4_e36_2021-08-28_00-45.pkl" + "PATH": "outputs/models/BioBERTv11_multi_output_v2_single_label_bio_bl05_k4_e36_2021-11-02_17-03.pkl" }, "DATA": { "PATH": "test_deploy_data/test1.txt", diff --git a/configs/deploy/biobert_tag_link.json b/configs/deploy/biobert_tag_link.json index 3876288..3dfb066 100644 --- a/configs/deploy/biobert_tag_link.json +++ b/configs/deploy/biobert_tag_link.json @@ -2,9 +2,9 @@ "MODE": "deploy", "MODEL": { "TYPE": "existing", - "PATH": "outputs/models/BioBERTv11_multi_output_bl05_k4_e36_2021-08-28_00-45.pkl", + "PATH": "outputs/models/BioBERTv11_multi_output_v2_single_label_bio_bl05_k4_e36_2021-11-02_17-03.pkl", "EXTRA_PATHS": { - "link": "outputs/models/BioBERTv12_linking_bl05_bs4_k4_2021-09-02_08-32.pkl" + "link": "outputs/models/BioBERTv11_link_both_heads_v2_bl05_k4_2021-10-30_18-27.pkl" } }, "DATA": { diff --git a/configs/deploy/biobert_tag_link_test.json b/configs/deploy/biobert_tag_link_test.json deleted file mode 100644 index 259af6b..0000000 --- a/configs/deploy/biobert_tag_link_test.json +++ /dev/null @@ -1,19 +0,0 @@ -{ - "MODE": "deploy", - "MODEL": { - "TYPE": "existing", - "PATH": "outputs/models/BioBERTv11_multi_output_bl05_k4_e36_2021-08-28_00-45.pkl" - }, - "DATA": { - "PATH": "test_deploy_data/test1.txt", - "FILETYPE": "txt", - "BATCH_SIZE": 8 - }, - "DEPLOY": { - "LINK": true, - "IGNORED_HEADS": ["category"], - "OUTPUT": "print", - "NEWLINE_WORDS": true - } -} - diff --git a/configs/deploy/pubmed_10k.json b/configs/deploy/pubmed_10k.json new file mode 100644 index 0000000..bb52223 --- /dev/null +++ b/configs/deploy/pubmed_10k.json @@ -0,0 +1,28 @@ +{ + "MODE": "deploy", + "MODEL": { + "TYPE": "existing", + "PATH": "outputs/models/BioBERTv11_multi_output_v2_single_label_bio_bl05_k4_e36_2021-11-02_17-03.pkl", + "EXTRA_MODELS": { + "link": "outputs/models/BioBERTv11_link_both_heads_v2_bl05_k4_2021-10-30_18-27.pkl" + } + }, + "DATA": { + "PATH": "abstract_analysis/pubmed_10k_abstracts.json", + "FILETYPE": "json_raw", + "BATCH_SIZE": 64 + }, + "DEPLOY": { + "VERBOSE": 2, + "OUTPUT": "json", + "SAVE_MODEL_OUTPUT_FOLDER": "tmp_out", + "JSON_FIELDS": ["PMID", "TEXT", "LINKED_TAGS"], + "IGNORED_HEADS": ["category"], + "NEWLINE_WORDS": true, + "PATH": "abstract_analysis/pubmed.json", + "LINK": { + "SPECIFIC_HEAD": "link_only" + } + } +} + diff --git a/configs/deploy/pubmed_10k_wd.json b/configs/deploy/pubmed_10k_wd.json new file mode 100644 index 0000000..cbc5d99 --- /dev/null +++ b/configs/deploy/pubmed_10k_wd.json @@ -0,0 +1,25 @@ +{ + "MODE": "deploy", + "MODEL": { + "TYPE": "existing", + "PATH": "outputs/models/BioBERTv11_multi_output_v2_single_label_bio_bl05_k4_e36_2021-11-02_17-03.pkl", + "EXTRA_MODELS": { + "link": "outputs/models/BioBERTv11_link_both_heads_v2_bl05_k4_2021-10-30_18-27.pkl" + } + }, + "DATA": { + "EXISTING_OUTPUT_FOLDER": "tmp_out" + }, + "DEPLOY": { + "VERBOSE": 2, + "OUTPUT": "json", + "JSON_FIELDS": ["PMID", "TEXT", "TAG_DATA", "LINK_DATA", "LINKED_TAGS"], + "IGNORED_HEADS": ["category"], + "NEWLINE_WORDS": true, + "PATH": "abstract_analysis/pubmed_new.json", + "LINK": { + "SPECIFIC_HEAD": "link_only" + } + } +} + diff --git a/configs/active/crfs_bl05_bs4_k4_e12.json b/configs/old/crfs_bl05_bs4_k4_e12.json similarity index 100% rename from configs/active/crfs_bl05_bs4_k4_e12.json rename to configs/old/crfs_bl05_bs4_k4_e12.json diff --git a/configs/active/crfs_bl1_bs4_k4_e12.json b/configs/old/crfs_bl1_bs4_k4_e12.json similarity index 100% rename from configs/active/crfs_bl1_bs4_k4_e12.json rename to configs/old/crfs_bl1_bs4_k4_e12.json diff --git a/configs/active/crfs_bs4_k4_e12.json b/configs/old/crfs_bs4_k4_e12.json similarity index 100% rename from configs/active/crfs_bs4_k4_e12.json rename to configs/old/crfs_bs4_k4_e12.json diff --git a/configs/current_best_analysis/link.json b/configs/old/current_best_analysis/link.json similarity index 100% rename from configs/current_best_analysis/link.json rename to configs/old/current_best_analysis/link.json diff --git a/configs/current_best_analysis/tag.json b/configs/old/current_best_analysis/tag.json similarity index 100% rename from configs/current_best_analysis/tag.json rename to configs/old/current_best_analysis/tag.json diff --git a/configs/old/current_best_analysis/tag_complete.json b/configs/old/current_best_analysis/tag_complete.json new file mode 100644 index 0000000..01646f7 --- /dev/null +++ b/configs/old/current_best_analysis/tag_complete.json @@ -0,0 +1,89 @@ +{ + "MODE": "analyse", + "HISTORY_DATA": { + "PATH": "outputs/outputs_db.json", + "MODELS": [ + "BioBERTv11_multi_output_v2_single_label_bio_bl05_k4_e36_2021-11-02_17-03" + ] + }, + "ANALYSIS": { + "REPORT": { + "OUTPUT": "md", + "PATH": "model_analysis/tag_report_full", + "TITLE": "Report on tag models", + "REPORTS": [ + { + "TITLE": "Cateogry All", + "VALUES": { + "validation_accuracies": [ + "accuracy", + "precision", + "recall", + "f1" + ] + }, + "HEAD_NAMES": [ + "category" + ] + }, + { + "TITLE": "Perturbing Action All", + "VALUES": { + "validation_accuracies": [ + "accuracy", + "precision", + "recall", + "f1" + ] + }, + "HEAD_NAMES": [ + "perturbing_action" + ] + }, + { + "TITLE": "Context All", + "VALUES": { + "validation_accuracies": [ + "accuracy", + "precision", + "recall", + "f1" + ] + }, + "HEAD_NAMES": [ + "context" + ] + }, + { + "TITLE": "Effect All", + "VALUES": { + "validation_accuracies": [ + "accuracy", + "precision", + "recall", + "f1" + ] + }, + "HEAD_NAMES": [ + "effect" + ] + }, + { + "TITLE": "Phenotype All", + "VALUES": { + "validation_accuracies": [ + "accuracy", + "precision", + "recall", + "f1" + ] + }, + "HEAD_NAMES": [ + "phenotype" + ] + } + ] + } + } +} + diff --git a/configs/active/link_both_heads_bl05_k4.json b/configs/old/link_both_heads_bl05_k4.json similarity index 100% rename from configs/active/link_both_heads_bl05_k4.json rename to configs/old/link_both_heads_bl05_k4.json diff --git a/configs/single_heads/v2_category_single_label_bio_bl05_k4_e36.json b/configs/single_heads/v2_category_single_label_bio_bl05_k4_e36.json new file mode 100644 index 0000000..5c4f81a --- /dev/null +++ b/configs/single_heads/v2_category_single_label_bio_bl05_k4_e36.json @@ -0,0 +1,39 @@ +{ + "MODE": "train", + "VERBOSE": 1, + "MODEL": { + "TYPE": "pretrained", + "TRANSFORMER_MODEL": "dmis-lab/biobert-v1.1", + "HEADS": { + "category": {"htype": "single_label", "num_labels": 9, "schema": "BIO"} + }, + "TAG_LIST_DEFINITIONS": "tag_list_definitions_v2.json", + "TAG_CATEGORY_DEFINITIONS": "tag_categories_v2.json", + "MAX_TOKEN_LENGTH": 512 + }, + "DATA": { + "PATH": "json_data/v2_all_marked_train.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 1, + "BALANCE_CLASSES": 0.5 + }, + "TRAINING": { + "TRAINED_NAME": "BioBERTv11_category_v2_single_label_bio_bl05_k4_e36", + "OPTIMIZER_CLASS": "AdamW", + "OPTIMIZER_KWARGS": { + "lr": 3e-5, + "eps": 1e-8 + }, + "FULL_FINETUNING": true, + "EPOCHS": 36, + "MAX_GRAD_NORM": 1, + "K_FOLDS": 4 + }, + "TEST_DATA": { + "PATH": "json_data/v2_all_marked_test.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 8, + "BALANCE_CLASSES": 0 + }, + "TESTING": {} +} diff --git a/configs/single_heads/v2_context_single_label_bio_bl05_k4_e36.json b/configs/single_heads/v2_context_single_label_bio_bl05_k4_e36.json new file mode 100644 index 0000000..5868ace --- /dev/null +++ b/configs/single_heads/v2_context_single_label_bio_bl05_k4_e36.json @@ -0,0 +1,39 @@ +{ + "MODE": "train", + "VERBOSE": 1, + "MODEL": { + "TYPE": "pretrained", + "TRANSFORMER_MODEL": "dmis-lab/biobert-v1.1", + "HEADS": { + "context": {"htype": "single_label", "num_labels": 25, "schema": "BIO"} + }, + "TAG_LIST_DEFINITIONS": "tag_list_definitions_v2.json", + "TAG_CATEGORY_DEFINITIONS": "tag_categories_v2.json", + "MAX_TOKEN_LENGTH": 512 + }, + "DATA": { + "PATH": "json_data/v2_all_marked_train.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 1, + "BALANCE_CLASSES": 0.5 + }, + "TRAINING": { + "TRAINED_NAME": "BioBERTv11_context_v2_single_label_bio_bl05_k4_e36", + "OPTIMIZER_CLASS": "AdamW", + "OPTIMIZER_KWARGS": { + "lr": 3e-5, + "eps": 1e-8 + }, + "FULL_FINETUNING": true, + "EPOCHS": 36, + "MAX_GRAD_NORM": 1, + "K_FOLDS": 4 + }, + "TEST_DATA": { + "PATH": "json_data/v2_all_marked_test.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 8, + "BALANCE_CLASSES": 0 + }, + "TESTING": {} +} diff --git a/configs/single_heads/v2_effect_single_label_bio_bl05_k4_e36.json b/configs/single_heads/v2_effect_single_label_bio_bl05_k4_e36.json new file mode 100644 index 0000000..40c3872 --- /dev/null +++ b/configs/single_heads/v2_effect_single_label_bio_bl05_k4_e36.json @@ -0,0 +1,39 @@ +{ + "MODE": "train", + "VERBOSE": 1, + "MODEL": { + "TYPE": "pretrained", + "TRANSFORMER_MODEL": "dmis-lab/biobert-v1.1", + "HEADS": { + "effect": {"htype": "single_label", "num_labels": 13, "schema": "BIO"} + }, + "TAG_LIST_DEFINITIONS": "tag_list_definitions_v2.json", + "TAG_CATEGORY_DEFINITIONS": "tag_categories_v2.json", + "MAX_TOKEN_LENGTH": 512 + }, + "DATA": { + "PATH": "json_data/v2_all_marked_train.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 1, + "BALANCE_CLASSES": 0.5 + }, + "TRAINING": { + "TRAINED_NAME": "BioBERTv11_effect_v2_single_label_bio_bl05_k4_e36", + "OPTIMIZER_CLASS": "AdamW", + "OPTIMIZER_KWARGS": { + "lr": 3e-5, + "eps": 1e-8 + }, + "FULL_FINETUNING": true, + "EPOCHS": 36, + "MAX_GRAD_NORM": 1, + "K_FOLDS": 4 + }, + "TEST_DATA": { + "PATH": "json_data/v2_all_marked_test.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 8, + "BALANCE_CLASSES": 0 + }, + "TESTING": {} +} diff --git a/configs/single_heads/v2_link_only_bl05_k4.json b/configs/single_heads/v2_link_only_bl05_k4.json new file mode 100644 index 0000000..7c2882e --- /dev/null +++ b/configs/single_heads/v2_link_only_bl05_k4.json @@ -0,0 +1,39 @@ +{ + "MODE": "train", + "VERBOSE": 1, + "MODEL": { + "TYPE": "pretrained", + "TRANSFORMER_MODEL": "dmis-lab/biobert-v1.1", + "HEADS": { + "link_only": {"htype": "link", "num_labels": 1} + }, + "TAG_CATEGORY_DEFINITIONS": "tag_categories_v2.json", + "MAX_TOKEN_LENGTH": 512 + }, + "DATA": { + "PATH": "json_data/v2_marked_and_linked_train.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 1, + "BALANCE_CLASSES": 0.5 + }, + "TRAINING": { + "TRAINED_NAME": "BioBERTv11_link_only_v2_bl05_k4", + "OPTIMIZER_CLASS": "AdamW", + "OPTIMIZER_KWARGS": { + "lr": 3e-5, + "eps": 1e-8 + }, + "FULL_FINETUNING": true, + "EPOCHS": 6, + "MAX_GRAD_NORM": 1, + "VERBOSE": 2, + "K_FOLDS": 4 + }, + "TEST_DATA": { + "PATH": "json_data/v2_marked_and_linked_test.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 8, + "BALANCE_CLASSES": 0 + }, + "TESTING": {} +} diff --git a/configs/single_heads/v2_perturbing_action_single_label_bio_bl05_k4_e36.json b/configs/single_heads/v2_perturbing_action_single_label_bio_bl05_k4_e36.json new file mode 100644 index 0000000..020834d --- /dev/null +++ b/configs/single_heads/v2_perturbing_action_single_label_bio_bl05_k4_e36.json @@ -0,0 +1,39 @@ +{ + "MODE": "train", + "VERBOSE": 1, + "MODEL": { + "TYPE": "pretrained", + "TRANSFORMER_MODEL": "dmis-lab/biobert-v1.1", + "HEADS": { + "perturbing_action": {"htype": "single_label", "num_labels": 15, "schema": "BIO"} + }, + "TAG_LIST_DEFINITIONS": "tag_list_definitions_v2.json", + "TAG_CATEGORY_DEFINITIONS": "tag_categories_v2.json", + "MAX_TOKEN_LENGTH": 512 + }, + "DATA": { + "PATH": "json_data/v2_all_marked_train.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 1, + "BALANCE_CLASSES": 0.5 + }, + "TRAINING": { + "TRAINED_NAME": "BioBERTv11_perturbing_action_v2_single_label_bio_bl05_k4_e36", + "OPTIMIZER_CLASS": "AdamW", + "OPTIMIZER_KWARGS": { + "lr": 3e-5, + "eps": 1e-8 + }, + "FULL_FINETUNING": true, + "EPOCHS": 36, + "MAX_GRAD_NORM": 1, + "K_FOLDS": 4 + }, + "TEST_DATA": { + "PATH": "json_data/v2_all_marked_test.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 8, + "BALANCE_CLASSES": 0 + }, + "TESTING": {} +} diff --git a/configs/single_heads/v2_phenotype_single_label_bio_bl05_k4_e36.json b/configs/single_heads/v2_phenotype_single_label_bio_bl05_k4_e36.json new file mode 100644 index 0000000..6442574 --- /dev/null +++ b/configs/single_heads/v2_phenotype_single_label_bio_bl05_k4_e36.json @@ -0,0 +1,39 @@ +{ + "MODE": "train", + "VERBOSE": 1, + "MODEL": { + "TYPE": "pretrained", + "TRANSFORMER_MODEL": "dmis-lab/biobert-v1.1", + "HEADS": { + "phenotype": {"htype": "single_label", "num_labels": 65, "schema": "BIO"} + }, + "TAG_LIST_DEFINITIONS": "tag_list_definitions_v2.json", + "TAG_CATEGORY_DEFINITIONS": "tag_categories_v2.json", + "MAX_TOKEN_LENGTH": 512 + }, + "DATA": { + "PATH": "json_data/v2_all_marked_train.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 1, + "BALANCE_CLASSES": 0.5 + }, + "TRAINING": { + "TRAINED_NAME": "BioBERTv11_phenotype_v2_single_label_bio_bl05_k4_e36", + "OPTIMIZER_CLASS": "AdamW", + "OPTIMIZER_KWARGS": { + "lr": 3e-5, + "eps": 1e-8 + }, + "FULL_FINETUNING": true, + "EPOCHS": 36, + "MAX_GRAD_NORM": 1, + "K_FOLDS": 4 + }, + "TEST_DATA": { + "PATH": "json_data/v2_all_marked_test.json", + "FILETYPE": "json_fgeom", + "BATCH_SIZE": 8, + "BALANCE_CLASSES": 0 + }, + "TESTING": {} +} diff --git a/create_venv.sh b/create_venv.sh index 639326a..af5b7fa 100644 --- a/create_venv.sh +++ b/create_venv.sh @@ -1,7 +1,7 @@ #!/bin/sh python3 -m venv ~/user_venv -. ~/user_venv/bin/activate +conda activate tfm_nlp pip install -r requirements.txt deactivate diff --git a/current_best.sh b/current_best.sh index 309eee5..234bef7 100644 --- a/current_best.sh +++ b/current_best.sh @@ -1,5 +1,5 @@ #!/bin/sh -. ~/user_venv/bin/activate +conda activate tfm_nlp python3 main.py -f configs/current_best -v diff --git a/current_best_l.sh b/current_best_l.sh index c0ccf62..140ea66 100644 --- a/current_best_l.sh +++ b/current_best_l.sh @@ -1,5 +1,5 @@ #!/bin/sh -. ~/user_venv/bin/activate +conda activate tfm_nlp python3 -u main.py -f configs/current_best -v > outputs/log.txt 2>&1 diff --git a/debug.sh b/debug.sh index 8d34e7f..8074bf8 100644 --- a/debug.sh +++ b/debug.sh @@ -1,5 +1,5 @@ #!/bin/sh -. ~/user_venv/bin/activate +conda activate tfm_nlp python3 main.py -f configs/debug -v diff --git a/deploy.sh b/deploy.sh index 6ad5052..b4d1b43 100644 --- a/deploy.sh +++ b/deploy.sh @@ -1,5 +1,5 @@ #!/bin/sh -. ~/user_venv/bin/activate +conda activate tfm_nlp python3 main.py -f configs/deploy -v diff --git a/main.py b/main.py index 06a7933..158a411 100644 --- a/main.py +++ b/main.py @@ -3,6 +3,7 @@ import json import traceback +from datetime import datetime from util.core import printv, ensure_file_ext from src.model_handler import ModelHandler from src.analysis import analyse_mode @@ -50,6 +51,9 @@ def main(config_path): v = args.verbose r = args.recursive + printv("[I] Program starting...", verbose_flag=v) + printv(f"[T] {datetime.now()}", verbose_flag=v) + if args.config_paths is None and args.config_folders is None: raise Exception("[E] No configs provided, see main.py -h") @@ -87,6 +91,7 @@ def get_configs_from_folder(path): try: c = ensure_file_ext(c, "json") printv(f"[I] Loading config {i+1}/{len(configs)} {c}", verbose_flag=v) + printv(f"[T] {datetime.now()}", verbose_flag=v) main(c) except Exception as e: print(f"[E] Got an error in config {c}:") @@ -101,5 +106,6 @@ def get_configs_from_folder(path): printv("[I] Finished", verbose_flag=v) printv(f"[I] Successful: {s_string}", verbose_flag=v) printv(f"[I] Failed: {f_string}", verbose_flag=v) + printv(f"[T] {datetime.now()}", verbose_flag=v) printv("[I] Program exiting...", verbose_flag=v) diff --git a/manual_analysis.py b/manual_analysis.py new file mode 100644 index 0000000..33265a6 --- /dev/null +++ b/manual_analysis.py @@ -0,0 +1,96 @@ +import json +from typing import Union + + +def a_avg(xs): + return sum(xs)/len(xs) + + +def get_table_str(caption: str, data: dict[str,dict[str,str]]): + headings = ["accuracy", "precision", "recall", "f1"] + heading_str = f"& {' & '.join(headings)} \\\\" + + def get_cols_of_row(d): + return ' & '.join(f"{d[k]:.3f}" for k in headings) + + data_strs = [f"{k} & {get_cols_of_row(v)} \\\\" + for k, v in data.items()] + row_strs = "\n ".join(data_strs) + + def get_cols_of_mean(): + return ' & '.join(f"{a_avg([v[k] for v in data.values()]):.3f}" for k in headings) + mean_str = f"mean & {get_cols_of_mean()} \\\\" + + return f"""\\begin{{table}}[htb] + \\caption{{{caption}}} + \\centering + \\begin{{tabular}}{{c | c c c c}} + {heading_str} + \\hline + {row_strs} + {mean_str} + \\end{{tabular}} +\\end{{table}}""" + + +def get_val_test_tag_stats(db, model_id: Union[str, list[str]] + ) -> tuple[dict[str,dict[str,str]],dict[str,dict[str,str]]]: + if isinstance(model_id, list): + assert len(model_id) >= 2 + val_accs_all_epochs_all_models = [db[m_id]["history"]["validation_accuracies"] + for m_id in model_id] + val_accs_all_epochs = val_accs_all_epochs_all_models[0] + + for v in val_accs_all_epochs_all_models[1:]: + for i, d in enumerate(v): + val_accs_all_epochs[i].update(d) + + test_accs_all_models = [db[m_id]["testing"]["accuracy"] + for m_id in model_id] + test_accs = test_accs_all_models[0] + + for v in test_accs_all_models[1:]: + test_accs.update(v) + + else: + val_accs_all_epochs = db[model_id]["history"]["validation_accuracies"] + test_accs = db[model_id]["testing"]["accuracy"] + + val_accs_f1_means = [a_avg([prf1a["f1"] for prf1a in epoch.values()]) + for epoch in val_accs_all_epochs] + val_accs = val_accs_all_epochs[val_accs_f1_means.index(max(val_accs_f1_means))] + + return val_accs, test_accs + + +def print_tag_stats(db): + model_stat_output_model_type_ids = { + "BioBERT multi-head": "BioBERTv11_multi_output_v2_single_label_bio_bl05_k4_e36_2023-07-26_00-19", + "BioClinicalBERT multi-head": "BioBERTv11_multi_output_v2_single_label_bio_bl05_k4_e36_2023-07-27_19-55", + "BERTBase": "BERTBase_multi_output_v2_single_label_bio_bl05_k4_e36_2023-08-01_18-30", + "BioBERT single-heads": [ + "BioBERTv11_category_v2_single_label_bio_bl05_k4_e36_2023-08-15_16-10", + "BioBERTv11_perturbing_action_v2_single_label_bio_bl05_k4_e36_2023-08-15_18-42", + "BioBERTv11_context_v2_single_label_bio_bl05_k4_e36_2023-08-15_21-15", + "BioBERTv11_effect_v2_single_label_bio_bl05_k4_e36_2023-08-15_23-47", + "BioBERTv11_phenotype_v2_single_label_bio_bl05_k4_e36_2023-08-17_16-12", + ], + "BioBERT link both heads": "BioBERTv11_link_both_heads_v2_bl05_k4_2023-07-25_15-24", + "BioClinicalBERT link both heads": "BioBERTv11_link_both_heads_v2_bl05_k4_2023-07-27_15-24", + "BERTBase link both heads": "BERTBase_link_both_heads_v2_bl05_k4_2023-08-01_13-59", + "BioBERT link only": "BioBERTv11_link_only_v2_bl05_k4_2023-08-15_13-36", + } + + for model_type, model_id in model_stat_output_model_type_ids.items(): + val_tag_stats, test_tag_stats = get_val_test_tag_stats(db, model_id) + print(get_table_str(f"Validation stats for {model_type}", val_tag_stats)) + print("\n") + print(get_table_str(f"Testing stats for {model_type}", test_tag_stats)) + print("\n") + + +if __name__ == "__main__": + with open("outputs/outputs_db.json") as f: + db = json.load(f) + print_tag_stats(db) + diff --git a/model_analysis/bert_base/link_graphs/F1 Scores.png b/model_analysis/bert_base/link_graphs/F1 Scores.png new file mode 100644 index 0000000..850bfff Binary files /dev/null and b/model_analysis/bert_base/link_graphs/F1 Scores.png differ diff --git a/model_analysis/bert_base/link_graphs/Train Losses.png b/model_analysis/bert_base/link_graphs/Train Losses.png new file mode 100644 index 0000000..6a79cd1 Binary files /dev/null and b/model_analysis/bert_base/link_graphs/Train Losses.png differ diff --git a/model_analysis/bert_base/link_graphs/Val Losses.png b/model_analysis/bert_base/link_graphs/Val Losses.png new file mode 100644 index 0000000..7f7416b Binary files /dev/null and b/model_analysis/bert_base/link_graphs/Val Losses.png differ diff --git a/model_analysis/bert_base/link_report.md b/model_analysis/bert_base/link_report.md new file mode 100644 index 0000000..d778459 --- /dev/null +++ b/model_analysis/bert_base/link_report.md @@ -0,0 +1,59 @@ +--- +geometry: margin=2.5cm +--- + +# Report on link models + + +## Train Losses + +BERTBase_link_both_heads_v2_bl05_k4_2023-08-01_13-59 train_losses link_only: + +* Best (Epoch 5): 0.0004461235062399572 +* Last (Epoch 6): 0.0004461235062399572 + +BERTBase_link_both_heads_v2_bl05_k4_2023-08-01_13-59 train_losses link_same_tag_only: + +* Best (Epoch 5): 0.0019395569988020702 +* Last (Epoch 6): 0.0019395569988020702 + +Overall best: + +* Name: BERTBase_link_both_heads_v2_bl05_k4_2023-08-01_13-59 train_losses link_only +* Value (Epoch 5): 0.0004461235062399572 + + +## Val Losses + +BERTBase_link_both_heads_v2_bl05_k4_2023-08-01_13-59 validation_losses link_only: + +* Best (Epoch 5): 0.0007513747114262224 +* Last (Epoch 6): 0.0007513747114262224 + +BERTBase_link_both_heads_v2_bl05_k4_2023-08-01_13-59 validation_losses link_same_tag_only: + +* Best (Epoch 5): 0.0026217335985842137 +* Last (Epoch 6): 0.0026217335985842137 + +Overall best: + +* Name: BERTBase_link_both_heads_v2_bl05_k4_2023-08-01_13-59 validation_losses link_only +* Value (Epoch 5): 0.0007513747114262224 + + +## F1 Scores + +BERTBase_link_both_heads_v2_bl05_k4_2023-08-01_13-59 validation_accuracies link_only f1: + +* Best (Epoch 5): 0.8530103691039963 +* Last (Epoch 6): 0.8530103691039963 + +BERTBase_link_both_heads_v2_bl05_k4_2023-08-01_13-59 validation_accuracies link_same_tag_only f1: + +* Best (Epoch 5): 0.6009477773439202 +* Last (Epoch 6): 0.6009477773439202 + +Overall best: + +* Name: BERTBase_link_both_heads_v2_bl05_k4_2023-08-01_13-59 validation_accuracies link_only f1 +* Value (Epoch 5): 0.8530103691039963 \ No newline at end of file diff --git a/model_analysis/bert_base/slurm-12559.out b/model_analysis/bert_base/slurm-12559.out new file mode 100644 index 0000000..9769c2c --- /dev/null +++ b/model_analysis/bert_base/slurm-12559.out @@ -0,0 +1,1157 @@ +/var/spool/slurmd/job12559/slurm_script: line 19: cd: /mnt/nas_home/jasonb/transformer_nlp: No such file or directory +Changed directory to /mnt/nas_home/jrb239/transformer_nlp. + +JobID: 12559 +====== +Time: Tue 1 Aug 12:38:10 BST 2023 +Current directory: /mnt/nas_home/jrb239/transformer_nlp + +Executing command: +================== +python3 main.py -f /mnt/nas_home/jrb239/transformer_nlp/to_run_config_folders/bert_base -v + +[I] Program starting... +[T] 2023-08-01 12:38:12.752508 +[I] Found 3 configs: +/mnt/nas_home/jrb239/transformer_nlp/to_run_config_folders/bert_base/v2_link_both_heads_bl05_k4.json +/mnt/nas_home/jrb239/transformer_nlp/to_run_config_folders/bert_base/v2_single_label_bio_bl05_k4_e36.json +/mnt/nas_home/jrb239/transformer_nlp/to_run_config_folders/bert_base/v2_single_label_bl05_k4_e36.json +[I] Loading config 1/3 /mnt/nas_home/jrb239/transformer_nlp/to_run_config_folders/bert_base/v2_link_both_heads_bl05_k4.json +[T] 2023-08-01 12:38:12.753114 +[I|Model] Loading Tokenizer + Downloading: 0%| | 0.00/28.0 [00:00 0 +Using CPU [I|Data] Loading data from file [I|Data] Pre-processing input data [I|Data] Processing transformer data [I|Data] Processing tag data [W] The following tags were not found in the new tag list: - - + cell transplantation [W] The following tags were not found in the new tag list: - graft -[W] The following tags were not found in the new tag list: - anoikis entosis + netosis +[I|Data] Tag list: {'category': ['CONTEXT', 'EFFECT', 'O', 'PERTURBING_ACTION', 'PAD'], 'description': ['conditional knock in', 'conditional knock out', 'decreased expression level', 'increased expression level', 'knock down', 'knock in', 'knock out', 'other', 'pharmacological inhibition', 'plasmid vector', 'viral vector', 'PAD'], 'experiment_type': ['cell line', 'cell transplantation', 'cells', 'not stated', 'organism', 'organoid culture', 'other', 'primary culture', 'transformed cell line', 'tumour', 'xenotransplantation', 'PAD'], 'species': ['bacterium', 'fish', 'fly', 'human', 'mouse', 'not stated', 'other', 'rat', 'yeast', 'PAD'], 'phenotype': ['adhesion', 'anoikis', 'apoptosis', 'autophagy', 'cell cycle arrest', 'cell death', 'cell growth', 'cell survival', 'colony formation', 'differentiation', 'entosis', 'epithelial-mesenchymal transition', 'ferroptosis', 'invasion', 'metastasis', 'migration', 'mitophagy', 'necroptosis', 'necrosis', 'netosis', 'oncosis', 'proliferation', 'pyroptosis', 'quiescence', 'self-renewal', 'senescence', 'transformation', 'tumour growth', 'tumourigenesis', 'PAD'], 'activity': ['causes', 'decreases', 'increases', 'inhibits', 'no effect', 'not stated', 'regulates', 'PAD']} +[I|Data] Tag weights: {'category': tensor([0.3101, 0.3512, 0.0650, 0.2737]), 'description': tensor([67.9400, 22.1435, 14.2349, 14.8797, 13.3102, 62.7447, 13.1441, 11.9698, + 11.9310, 44.0388, 48.4554]), 'experiment_type': tensor([ 27.3692, 517.4708, 9.3350, 172.4877, 14.1540, 49.3289, 182.9512, + 48.4554, 12.8537, 19.5051, 22.6925]), 'species': tensor([118.7119, 211.2546, 115.7059, 18.0764, 14.4009, 6.9216, 58.2115, + 47.8298, 138.2965]), 'phenotype': tensor([105.6237, 163.6359, 14.9991, 14.5380, 43.4137, 26.2856, 37.5280, + 47.4260, 101.4796, 43.1110, 517.4708, 40.6441, 27.5632, 55.7915, + 28.2127, 39.3299, 44.0388, 54.5371, 57.4882, 517.4708, 97.7878, + 28.2548, 67.9400, 92.9353, 59.3497, 38.7733, 56.4519, 29.2790, + 26.0176]), 'activity': tensor([12.7584, 14.2841, 13.6380, 15.2533, 36.5771, 33.8859, 32.2635])} [I|Train Handler] Training model -[I|Train Handler] Fold 1/4... -[I|Train] Epoch 0/36 -[I|Train] Epoch took 00:01:40, predicted 00:58:49 left -[I|Train] Epoch 1/36 -[I|Train] Epoch took 00:01:41, predicted 00:57:43 left -[I|Train] Epoch 2/36 -[I|Train] Epoch took 00:01:42, predicted 00:56:23 left -[I|Train] Epoch 3/36 -[I|Train] Epoch took 00:01:43, predicted 00:55:17 left -[I|Train] Epoch 4/36 -[I|Train] Epoch took 00:01:43, predicted 00:53:25 left -[I|Train] Epoch 5/36 -[I|Train] Epoch took 00:01:43, predicted 00:51:49 left -[I|Train] Epoch 6/36 -[I|Train] Epoch took 00:01:43, predicted 00:50:05 left -[I|Train] Epoch 7/36 -[I|Train] Epoch took 00:01:42, predicted 00:47:41 left -[I|Train] Epoch 8/36 -[I|Train] Epoch took 00:01:40, predicted 00:45:26 left -[I|Train] Epoch 9/36 -[I|Train] Epoch took 00:01:40, predicted 00:43:34 left -[I|Train] Epoch 10/36 -[I|Train] Epoch took 00:01:41, predicted 00:42:09 left -[I|Train] Epoch 11/36 -[I|Train] Epoch took 00:01:41, predicted 00:40:43 left -[I|Train] Epoch 12/36 -[I|Train] Epoch took 00:01:41, predicted 00:38:45 left -[I|Train] Epoch 13/36 -[I|Train] Epoch took 00:01:40, predicted 00:36:46 left -[I|Train] Epoch 14/36 -[I|Train] Epoch took 00:01:40, predicted 00:35:11 left -[I|Train] Epoch 15/36 -[I|Train] Epoch took 00:01:40, predicted 00:33:30 left -[I|Train] Epoch 16/36 -[I|Train] Epoch took 00:01:40, predicted 00:31:49 left -[I|Train] Epoch 17/36 -[I|Train] Epoch took 00:01:41, predicted 00:30:19 left -[I|Train] Epoch 18/36 -[I|Train] Epoch took 00:01:40, predicted 00:28:32 left -[I|Train] Epoch 19/36 -[I|Train] Epoch took 00:01:42, predicted 00:27:13 left -[I|Train] Epoch 20/36 -[I|Train] Epoch took 00:01:42, predicted 00:25:32 left -[I|Train] Epoch 21/36 -[I|Train] Epoch took 00:01:43, predicted 00:24:03 left -[I|Train] Epoch 22/36 -[I|Train] Epoch took 00:01:43, predicted 00:22:19 left -[I|Train] Epoch 23/36 -[I|Train] Epoch took 00:01:42, predicted 00:20:24 left -[I|Train] Epoch 24/36 -[I|Train] Epoch took 00:01:41, predicted 00:18:32 left -[I|Train] Epoch 25/36 -[I|Train] Epoch took 00:01:37, predicted 00:16:19 left -[I|Train] Epoch 26/36 -[I|Train] Epoch took 00:01:40, predicted 00:15:07 left -[I|Train] Epoch 27/36 -[I|Train] Epoch took 00:01:40, predicted 00:13:25 left -[I|Train] Epoch 28/36 -[I|Train] Epoch took 00:01:40, predicted 00:11:44 left -[I|Train] Epoch 29/36 -[I|Train] Epoch took 00:01:40, predicted 00:10:03 left -[I|Train] Epoch 30/36 -[I|Train] Epoch took 00:01:40, predicted 00:08:24 left -[I|Train] Epoch 31/36 -[I|Train] Epoch took 00:01:40, predicted 00:06:43 left -[I|Train] Epoch 32/36 -[I|Train] Epoch took 00:01:40, predicted 00:05:02 left -[I|Train] Epoch 33/36 -[I|Train] Epoch took 00:01:40, predicted 00:03:21 left -[I|Train] Epoch 34/36 -[I|Train] Epoch took 00:01:40, predicted 00:01:40 left -[I|Train] Epoch 35/36 -[I|Train] Epoch took 00:01:40, predicted 00:00:00 left -[I|Train Handler] Resetting model -[I|Model] Loading tags from file -[I|Model] Loading tag categories from file -Found CUDA devices: -TITAN Xp -TITAN X (Pascal) -[I|Train Handler] Fold 2/4... -[I|Train] Epoch 0/36 -[I|Train] Epoch took 00:01:41, predicted 00:59:26 left -[I|Train] Epoch 1/36 -[I|Train] Epoch took 00:01:41, predicted 00:57:47 left -[I|Train] Epoch 2/36 -[I|Train] Epoch took 00:01:42, predicted 00:56:07 left -[I|Train] Epoch 3/36 -[I|Train] Epoch took 00:01:43, predicted 00:55:03 left -[I|Train] Epoch 4/36 -[I|Train] Epoch took 00:01:41, predicted 00:52:30 left -[I|Train] Epoch 5/36 -[I|Train] Epoch took 00:01:43, predicted 00:51:37 left -[I|Train] Epoch 6/36 -[I|Train] Epoch took 00:01:38, predicted 00:47:32 left -[I|Train] Epoch 7/36 -[I|Train] Epoch took 00:01:34, predicted 00:44:16 left -[I|Train] Epoch 8/36 -[I|Train] Epoch took 00:01:31, predicted 00:41:02 left -[I|Train] Epoch 9/36 -[I|Train] Epoch took 00:01:31, predicted 00:39:26 left -[I|Train] Epoch 10/36 -[I|Train] Epoch took 00:01:30, predicted 00:37:52 left -[I|Train] Epoch 11/36 -[I|Train] Epoch took 00:01:31, predicted 00:36:24 left -[I|Train] Epoch 12/36 -[I|Train] Epoch took 00:01:31, predicted 00:34:58 left -[I|Train] Epoch 13/36 -[I|Train] Epoch took 00:01:31, predicted 00:33:22 left -[I|Train] Epoch 14/36 -[I|Train] Epoch took 00:01:30, predicted 00:31:48 left -[I|Train] Epoch 15/36 -[I|Train] Epoch took 00:01:30, predicted 00:30:18 left -[I|Train] Epoch 16/36 -[I|Train] Epoch took 00:01:30, predicted 00:28:45 left -[I|Train] Epoch 17/36 -[I|Train] Epoch took 00:01:30, predicted 00:27:14 left -[I|Train] Epoch 18/36 -[I|Train] Epoch took 00:01:30, predicted 00:25:44 left -[I|Train] Epoch 19/36 -[I|Train] Epoch took 00:01:30, predicted 00:24:12 left -[I|Train] Epoch 20/36 -[I|Train] Epoch took 00:01:30, predicted 00:22:40 left -[I|Train] Epoch 21/36 -[I|Train] Epoch took 00:01:30, predicted 00:21:09 left -[I|Train] Epoch 22/36 -[I|Train] Epoch took 00:01:30, predicted 00:19:40 left -[I|Train] Epoch 23/36 -[I|Train] Epoch took 00:01:30, predicted 00:18:09 left -[I|Train] Epoch 24/36 -[I|Train] Epoch took 00:01:30, predicted 00:16:38 left -[I|Train] Epoch 25/36 -[I|Train] Epoch took 00:01:31, predicted 00:15:11 left -[I|Train] Epoch 26/36 -[I|Train] Epoch took 00:01:31, predicted 00:13:40 left -[I|Train] Epoch 27/36 -[I|Train] Epoch took 00:01:31, predicted 00:12:08 left -[I|Train] Epoch 28/36 -[I|Train] Epoch took 00:01:31, predicted 00:10:37 left -[I|Train] Epoch 29/36 -[I|Train] Epoch took 00:01:30, predicted 00:09:05 left -[I|Train] Epoch 30/36 -[I|Train] Epoch took 00:01:31, predicted 00:07:35 left -[I|Train] Epoch 31/36 -[I|Train] Epoch took 00:01:30, predicted 00:06:03 left -[I|Train] Epoch 32/36 -[I|Train] Epoch took 00:01:31, predicted 00:04:33 left -[I|Train] Epoch 33/36 -[I|Train] Epoch took 00:01:30, predicted 00:03:01 left -[I|Train] Epoch 34/36 -[I|Train] Epoch took 00:01:31, predicted 00:01:31 left -[I|Train] Epoch 35/36 -[I|Train] Epoch took 00:01:31, predicted 00:00:00 left -[I|Train Handler] Resetting model -[I|Model] Loading tags from file -[I|Model] Loading tag categories from file -Found CUDA devices: -TITAN Xp -TITAN X (Pascal) -[I|Train Handler] Fold 3/4... -[I|Train] Epoch 0/36 -[I|Train] Epoch took 00:01:32, predicted 00:53:41 left -[I|Train] Epoch 1/36 -[I|Train] Epoch took 00:01:32, predicted 00:52:08 left -[I|Train] Epoch 2/36 -[I|Train] Epoch took 00:01:31, predicted 00:50:35 left -[I|Train] Epoch 3/36 -[I|Train] Epoch took 00:01:31, predicted 00:49:03 left -[I|Train] Epoch 4/36 -[I|Train] Epoch took 00:01:31, predicted 00:47:18 left -[I|Train] Epoch 5/36 -[I|Train] Epoch took 00:01:31, predicted 00:45:39 left -[I|Train] Epoch 6/36 -[I|Train] Epoch took 00:01:31, predicted 00:44:06 left -[I|Train] Epoch 7/36 -[I|Train] Epoch took 00:01:31, predicted 00:42:35 left -[I|Train] Epoch 8/36 -[I|Train] Epoch took 00:01:31, predicted 00:41:02 left -[I|Train] Epoch 9/36 -[I|Train] Epoch took 00:01:31, predicted 00:39:26 left -[I|Train] Epoch 10/36 -[I|Train] Epoch took 00:01:30, predicted 00:37:53 left -[I|Train] Epoch 11/36 -[I|Train] Epoch took 00:01:30, predicted 00:36:21 left -[I|Train] Epoch 12/36 -[I|Train] Epoch took 00:01:30, predicted 00:34:49 left -[I|Train] Epoch 13/36 -[I|Train] Epoch took 00:01:30, predicted 00:33:21 left -[I|Train] Epoch 14/36 -[I|Train] Epoch took 00:01:30, predicted 00:31:47 left -[I|Train] Epoch 15/36 -[I|Train] Epoch took 00:01:31, predicted 00:30:21 left -[I|Train] Epoch 16/36 -[I|Train] Epoch took 00:01:31, predicted 00:28:52 left -[I|Train] Epoch 17/36 -[I|Train] Epoch took 00:01:31, predicted 00:27:18 left -[I|Train] Epoch 18/36 -[I|Train] Epoch took 00:01:31, predicted 00:25:47 left -[I|Train] Epoch 19/36 -[I|Train] Epoch took 00:01:30, predicted 00:24:15 left -[I|Train] Epoch 20/36 -[I|Train] Epoch took 00:01:30, predicted 00:22:43 left -[I|Train] Epoch 21/36 -[I|Train] Epoch took 00:01:30, predicted 00:21:13 left -[I|Train] Epoch 22/36 -[I|Train] Epoch took 00:01:30, predicted 00:19:42 left -[I|Train] Epoch 23/36 -[I|Train] Epoch took 00:01:30, predicted 00:18:10 left -[I|Train] Epoch 24/36 -[I|Train] Epoch took 00:01:30, predicted 00:16:40 left -[I|Train] Epoch 25/36 -[I|Train] Epoch took 00:01:30, predicted 00:15:09 left -[I|Train] Epoch 26/36 -[I|Train] Epoch took 00:01:30, predicted 00:13:37 left -[I|Train] Epoch 27/36 -[I|Train] Epoch took 00:01:30, predicted 00:12:07 left -[I|Train] Epoch 28/36 -[I|Train] Epoch took 00:01:30, predicted 00:10:36 left -[I|Train] Epoch 29/36 -[I|Train] Epoch took 00:01:30, predicted 00:09:05 left -[I|Train] Epoch 30/36 -[I|Train] Epoch took 00:01:30, predicted 00:07:33 left -[I|Train] Epoch 31/36 -[I|Train] Epoch took 00:01:30, predicted 00:06:03 left -[I|Train] Epoch 32/36 -[I|Train] Epoch took 00:01:30, predicted 00:04:32 left -[I|Train] Epoch 33/36 -[I|Train] Epoch took 00:01:30, predicted 00:03:01 left -[I|Train] Epoch 34/36 -[I|Train] Epoch took 00:01:30, predicted 00:01:30 left -[I|Train] Epoch 35/36 -[I|Train] Epoch took 00:01:30, predicted 00:00:00 left -[I|Train Handler] Resetting model -[I|Model] Loading tags from file -[I|Model] Loading tag categories from file -Found CUDA devices: -TITAN Xp -TITAN X (Pascal) -[I|Train Handler] Fold 4/4... -[I|Train] Epoch 0/36 -[I|Train] Epoch took 00:01:32, predicted 00:53:47 left -[I|Train] Epoch 1/36 -[I|Train] Epoch took 00:01:40, predicted 00:56:43 left -[I|Train] Epoch 2/36 -[I|Train] Epoch took 00:01:42, predicted 00:56:35 left -[I|Train] Epoch 3/36 -[I|Train] Epoch took 00:01:43, predicted 00:54:56 left -[I|Train] Epoch 4/36 -[I|Train] Epoch took 00:01:42, predicted 00:53:08 left -[I|Train] Epoch 5/36 -[I|Train] Epoch took 00:01:43, predicted 00:51:37 left -[I|Train] Epoch 6/36 -[I|Train] Epoch took 00:01:43, predicted 00:50:01 left -[I|Train] Epoch 7/36 -[I|Train] Epoch took 00:01:42, predicted 00:47:40 left -[I|Train] Epoch 8/36 -[I|Train] Epoch took 00:01:43, predicted 00:46:40 left -[I|Train] Epoch 9/36 -[I|Train] Epoch took 00:01:43, predicted 00:44:45 left -[I|Train] Epoch 10/36 -[I|Train] Epoch took 00:01:43, predicted 00:43:11 left -[I|Train] Epoch 11/36 -[I|Train] Epoch took 00:01:42, predicted 00:41:01 left -[I|Train] Epoch 12/36 -[I|Train] Epoch took 00:01:41, predicted 00:39:02 left -[I|Train] Epoch 13/36 -[I|Train] Epoch took 00:01:43, predicted 00:37:50 left -[I|Train] Epoch 14/36 -[I|Train] Epoch took 00:01:43, predicted 00:36:13 left -[I|Train] Epoch 15/36 -[I|Train] Epoch took 00:01:43, predicted 00:34:29 left -[I|Train] Epoch 16/36 -[I|Train] Epoch took 00:01:43, predicted 00:32:44 left -[I|Train] Epoch 17/36 -[I|Train] Epoch took 00:01:43, predicted 00:30:59 left -[I|Train] Epoch 18/36 -[I|Train] Epoch took 00:01:42, predicted 00:29:00 left -[I|Train] Epoch 19/36 -[I|Train] Epoch took 00:01:43, predicted 00:27:37 left -[I|Train] Epoch 20/36 -[I|Train] Epoch took 00:01:43, predicted 00:25:58 left -[I|Train] Epoch 21/36 -[I|Train] Epoch took 00:01:43, predicted 00:24:10 left -[I|Train] Epoch 22/36 -[I|Train] Epoch took 00:01:44, predicted 00:22:34 left -[I|Train] Epoch 23/36 -[I|Train] Epoch took 00:01:43, predicted 00:20:43 left -[I|Train] Epoch 24/36 -[I|Train] Epoch took 00:01:42, predicted 00:18:44 left -[I|Train] Epoch 25/36 -[I|Train] Epoch took 00:01:42, predicted 00:17:04 left -[I|Train] Epoch 26/36 -[I|Train] Epoch took 00:01:42, predicted 00:15:20 left -[I|Train] Epoch 27/36 -[I|Train] Epoch took 00:01:42, predicted 00:13:39 left -[I|Train] Epoch 28/36 -[I|Train] Epoch took 00:01:42, predicted 00:11:56 left -[I|Train] Epoch 29/36 -[I|Train] Epoch took 00:01:42, predicted 00:10:13 left -[I|Train] Epoch 30/36 -[I|Train] Epoch took 00:01:43, predicted 00:08:36 left -[I|Train] Epoch 31/36 -[I|Train] Epoch took 00:01:44, predicted 00:06:58 left -[I|Train] Epoch 32/36 -[I|Train] Epoch took 00:01:44, predicted 00:05:13 left -[I|Train] Epoch 33/36 -[I|Train] Epoch took 00:01:42, predicted 00:03:25 left -[I|Train] Epoch 34/36 -[I|Train] Epoch took 00:01:42, predicted 00:01:42 left -[I|Train] Epoch 35/36 -[I|Train] Epoch took 00:01:42, predicted 00:00:00 left -[I|Train Handler] Resetting model -[I|Model] Loading tags from file -[I|Model] Loading tag categories from file -Found CUDA devices: -TITAN Xp -TITAN X (Pascal) -[I|Train Handler] Final training -[I|Train] Epoch 0/36 -[I|Train] Epoch took 00:01:49, predicted 01:03:56 left -[I|Train] Epoch 1/36 -[I|Train] Epoch took 00:01:49, predicted 01:02:00 left -[I|Train] Epoch 2/36 -[I|Train] Epoch took 00:01:48, predicted 00:59:52 left -[I|Train] Epoch 3/36 -[I|Train] Epoch took 00:01:48, predicted 00:57:53 left -[I|Train] Epoch 4/36 -[I|Train] Epoch took 00:01:48, predicted 00:56:05 left -[I|Train] Epoch 5/36 -[I|Train] Epoch took 00:01:48, predicted 00:54:20 left -[I|Train] Epoch 6/36 -[I|Train] Epoch took 00:01:48, predicted 00:52:28 left -[I|Train] Epoch 7/36 -[I|Train] Epoch took 00:01:48, predicted 00:50:50 left -[I|Train] Epoch 8/36 -[I|Train] Epoch took 00:01:49, predicted 00:49:11 left -[I|Train] Epoch 9/36 -[I|Train] Epoch took 00:01:49, predicted 00:47:20 left -[I|Train] Epoch 10/36 -[I|Train] Epoch took 00:01:49, predicted 00:45:37 left -[I|Train] Epoch 11/36 -[I|Train] Epoch took 00:01:51, predicted 00:44:25 left -[I|Train] Epoch 12/36 -[I|Train] Epoch took 00:01:49, predicted 00:42:00 left -[I|Train] Epoch 13/36 -[I|Train] Epoch took 00:01:49, predicted 00:39:59 left -[I|Train] Epoch 14/36 -[I|Train] Epoch took 00:01:50, predicted 00:38:44 left -[I|Train] Epoch 15/36 -[I|Train] Epoch took 00:01:48, predicted 00:36:19 left -[I|Train] Epoch 16/36 -[I|Train] Epoch took 00:01:48, predicted 00:34:29 left -[I|Train] Epoch 17/36 -[I|Train] Epoch took 00:01:48, predicted 00:32:33 left -[I|Train] Epoch 18/36 -[I|Train] Epoch took 00:01:48, predicted 00:30:47 left -[I|Train] Epoch 19/36 -[I|Train] Epoch took 00:01:48, predicted 00:29:00 left -[I|Train] Epoch 20/36 -[I|Train] Epoch took 00:01:49, predicted 00:27:19 left -[I|Train] Epoch 21/36 -[I|Train] Epoch took 00:01:49, predicted 00:25:36 left -[I|Train] Epoch 22/36 -[I|Train] Epoch took 00:01:48, predicted 00:23:29 left -[I|Train] Epoch 23/36 -[I|Train] Epoch took 00:01:48, predicted 00:21:42 left -[I|Train] Epoch 24/36 -[I|Train] Epoch took 00:01:48, predicted 00:19:48 left -[I|Train] Epoch 25/36 -[I|Train] Epoch took 00:01:47, predicted 00:17:58 left -[I|Train] Epoch 26/36 -[I|Train] Epoch took 00:01:49, predicted 00:16:21 left -[I|Train] Epoch 27/36 -[I|Train] Epoch took 00:01:49, predicted 00:14:33 left -[I|Train] Epoch 28/36 -[I|Train] Epoch took 00:01:49, predicted 00:12:45 left -[I|Train] Epoch 29/36 -[I|Train] Epoch took 00:01:48, predicted 00:10:48 left -[I|Train] Epoch 30/36 -[I|Train] Epoch took 00:01:49, predicted 00:09:05 left -[I|Train] Epoch 31/36 -[I|Train] Epoch took 00:01:48, predicted 00:07:15 left -[I|Train] Epoch 32/36 -[I|Train] Epoch took 00:01:48, predicted 00:05:26 left -[I|Train] Epoch 33/36 -[I|Train] Epoch took 00:01:48, predicted 00:03:36 left -[I|Train] Epoch 34/36 -[I|Train] Epoch took 00:01:46, predicted 00:01:46 left -[I|Train] Epoch 35/36 -[I|Train] Epoch took 00:01:48, predicted 00:00:00 left -[I|Train Handler] Testing model -[I|Data] Loading data from file -[I|Data] Pre-processing input data -[I|Data] Processing transformer data -[I|Data] Processing tag data -[W] The following tags were not found in the new tag list: - - -[W] The following tags were not found in the new tag list: - - - graft -[W] The following tags were not found in the new tag list: - - -[W] The following tags were not found in the new tag list: - - - adhesion - colony formation - entosis - necroptosis - necrosis - oncosis - quiescence - transformation - tumour progression - tumourigenesis -[I|Test] Testing model -[I|Test] Test loss: {'category': 0.10313283186405897, 'perturbing_action': 0.04599648201838136, 'context': 0.04943356988951564, 'effect': 0.01171770627843216, 'phenotype': 0.02357738488353789} -[I|Test] Test accuracy: {'category': {'precision': 0.8070766638584668, 'recall': 0.8661844484629295, 'f1': 0.8355865678150894, 'accuracy': 0.7176029962546816}, 'perturbing_action': {'precision': 0.7537796976241901, 'recall': 0.8660049627791563, 'f1': 0.8060046189376444, 'accuracy': 0.6750483558994197}, 'context': {'precision': 0.7289293849658315, 'recall': 0.7785888077858881, 'f1': 0.7529411764705883, 'accuracy': 0.6037735849056604}, 'effect': {'precision': 0.7890625, 'recall': 0.7651515151515151, 'f1': 0.7769230769230769, 'accuracy': 0.6352201257861635}, 'phenotype': {'precision': 0.8313953488372093, 'recall': 0.8881987577639752, 'f1': 0.8588588588588588, 'accuracy': 0.7526315789473684}} -[I|Train Handler] Saving model -[I|Train Handler] Saving training history -[I] Loading config 2/2 configs/current_best/v2_single_label_bio_bl05_k4_e36.json -[I|Model] Loading Tokenizer -[I|Model] Loading Model -[I|Model] Loading tags from file -[I|Model] Loading tag categories from file -Found CUDA devices: -TITAN Xp -TITAN X (Pascal) -[I|Data] Loading data from file -[I|Data] Pre-processing input data -[I|Data] Processing transformer data -[I|Data] Processing tag data -[W] The following tags were not found in the new tag list: - B-- - I-- -[W] The following tags were not found in the new tag list: - B-graft - I-graft -[W] The following tags were not found in the new tag list: - I-- -[W] The following tags were not found in the new tag list: - B-anoikis - B-entosis - I-- - I-adhesion - I-anoikis - I-entosis - I-mitophagy - I-pyroptosis - I-transformation -[I|Train Handler] Training model -[I|Train Handler] Fold 1/4... -[I|Train] Epoch 0/36 -[I|Train] Epoch took 00:01:42, predicted 00:59:47 left -[I|Train] Epoch 1/36 -[I|Train] Epoch took 00:01:42, predicted 00:57:56 left -[I|Train] Epoch 2/36 -[I|Train] Epoch took 00:01:44, predicted 00:57:23 left -[I|Train] Epoch 3/36 -[I|Train] Epoch took 00:01:44, predicted 00:55:43 left -[I|Train] Epoch 4/36 -[I|Train] Epoch took 00:01:43, predicted 00:53:22 left -[I|Train] Epoch 5/36 -[I|Train] Epoch took 00:01:42, predicted 00:51:01 left -[I|Train] Epoch 6/36 -[I|Train] Epoch took 00:01:41, predicted 00:49:16 left -[I|Train] Epoch 7/36 -[I|Train] Epoch took 00:01:41, predicted 00:47:35 left -[I|Train] Epoch 8/36 -[I|Train] Epoch took 00:01:41, predicted 00:45:48 left -[I|Train] Epoch 9/36 -[I|Train] Epoch took 00:01:41, predicted 00:44:00 left -[I|Train] Epoch 10/36 -[I|Train] Epoch took 00:01:41, predicted 00:42:23 left -[I|Train] Epoch 11/36 -[I|Train] Epoch took 00:01:42, predicted 00:40:49 left -[I|Train] Epoch 12/36 -[I|Train] Epoch took 00:01:41, predicted 00:38:57 left -[I|Train] Epoch 13/36 -[I|Train] Epoch took 00:01:41, predicted 00:37:17 left -[I|Train] Epoch 14/36 -[I|Train] Epoch took 00:01:36, predicted 00:33:48 left -[I|Train] Epoch 15/36 -[I|Train] Epoch took 00:01:31, predicted 00:30:30 left -[I|Train] Epoch 16/36 -[I|Train] Epoch took 00:01:31, predicted 00:29:03 left -[I|Train] Epoch 17/36 -[I|Train] Epoch took 00:01:31, predicted 00:27:27 left -[I|Train] Epoch 18/36 -[I|Train] Epoch took 00:01:31, predicted 00:25:54 left -[I|Train] Epoch 19/36 -[I|Train] Epoch took 00:01:31, predicted 00:24:18 left -[I|Train] Epoch 20/36 -[I|Train] Epoch took 00:01:31, predicted 00:22:48 left -[I|Train] Epoch 21/36 -[I|Train] Epoch took 00:01:31, predicted 00:21:22 left -[I|Train] Epoch 22/36 -[I|Train] Epoch took 00:01:31, predicted 00:19:45 left -[I|Train] Epoch 23/36 -[I|Train] Epoch took 00:01:31, predicted 00:18:16 left -[I|Train] Epoch 24/36 -[I|Train] Epoch took 00:01:31, predicted 00:16:48 left -[I|Train] Epoch 25/36 -[I|Train] Epoch took 00:01:31, predicted 00:15:18 left -[I|Train] Epoch 26/36 -[I|Train] Epoch took 00:01:31, predicted 00:13:39 left -[I|Train] Epoch 27/36 -[I|Train] Epoch took 00:01:31, predicted 00:12:09 left -[I|Train] Epoch 28/36 -[I|Train] Epoch took 00:01:31, predicted 00:10:38 left -[I|Train] Epoch 29/36 -[I|Train] Epoch took 00:01:31, predicted 00:09:07 left -[I|Train] Epoch 30/36 -[I|Train] Epoch took 00:01:31, predicted 00:07:35 left -[I|Train] Epoch 31/36 -[I|Train] Epoch took 00:01:31, predicted 00:06:04 left -[I|Train] Epoch 32/36 -[I|Train] Epoch took 00:01:31, predicted 00:04:33 left -[I|Train] Epoch 33/36 -[I|Train] Epoch took 00:01:31, predicted 00:03:02 left -[I|Train] Epoch 34/36 -[I|Train] Epoch took 00:01:31, predicted 00:01:31 left -[I|Train] Epoch 35/36 -[I|Train] Epoch took 00:01:31, predicted 00:00:00 left -[I|Train Handler] Resetting model -[I|Model] Loading tags from file -[I|Model] Loading tag categories from file -Found CUDA devices: -TITAN Xp -TITAN X (Pascal) -[I|Train Handler] Fold 2/4... -[I|Train] Epoch 0/36 -[I|Train] Epoch took 00:01:32, predicted 00:53:58 left -[I|Train] Epoch 1/36 -[I|Train] Epoch took 00:01:32, predicted 00:52:23 left -[I|Train] Epoch 2/36 -[I|Train] Epoch took 00:01:32, predicted 00:50:57 left -[I|Train] Epoch 3/36 -[I|Train] Epoch took 00:01:32, predicted 00:49:23 left -[I|Train] Epoch 4/36 -[I|Train] Epoch took 00:01:32, predicted 00:47:46 left -[I|Train] Epoch 5/36 -[I|Train] Epoch took 00:01:32, predicted 00:46:08 left -[I|Train] Epoch 6/36 -[I|Train] Epoch took 00:01:32, predicted 00:44:33 left -[I|Train] Epoch 7/36 -[I|Train] Epoch took 00:01:32, predicted 00:42:59 left -[I|Train] Epoch 8/36 -[I|Train] Epoch took 00:01:31, predicted 00:41:22 left -[I|Train] Epoch 9/36 -[I|Train] Epoch took 00:01:32, predicted 00:39:59 left -[I|Train] Epoch 10/36 -[I|Train] Epoch took 00:01:31, predicted 00:38:13 left -[I|Train] Epoch 11/36 -[I|Train] Epoch took 00:01:31, predicted 00:36:37 left -[I|Train] Epoch 12/36 -[I|Train] Epoch took 00:01:31, predicted 00:34:59 left -[I|Train] Epoch 13/36 -[I|Train] Epoch took 00:01:31, predicted 00:33:30 left -[I|Train] Epoch 14/36 -[I|Train] Epoch took 00:01:31, predicted 00:31:57 left -[I|Train] Epoch 15/36 -[I|Train] Epoch took 00:01:31, predicted 00:30:27 left -[I|Train] Epoch 16/36 -[I|Train] Epoch took 00:01:31, predicted 00:28:57 left -[I|Train] Epoch 17/36 -[I|Train] Epoch took 00:01:31, predicted 00:27:23 left -[I|Train] Epoch 18/36 -[I|Train] Epoch took 00:01:31, predicted 00:25:51 left -[I|Train] Epoch 19/36 -[I|Train] Epoch took 00:01:31, predicted 00:24:18 left -[I|Train] Epoch 20/36 -[I|Train] Epoch took 00:01:31, predicted 00:22:49 left -[I|Train] Epoch 21/36 -[I|Train] Epoch took 00:01:31, predicted 00:21:17 left -[I|Train] Epoch 22/36 -[I|Train] Epoch took 00:01:31, predicted 00:19:44 left -[I|Train] Epoch 23/36 -[I|Train] Epoch took 00:01:31, predicted 00:18:13 left -[I|Train] Epoch 24/36 -[I|Train] Epoch took 00:01:31, predicted 00:16:42 left -[I|Train] Epoch 25/36 -[I|Train] Epoch took 00:01:30, predicted 00:15:09 left -[I|Train] Epoch 26/36 -[I|Train] Epoch took 00:01:31, predicted 00:13:40 left -[I|Train] Epoch 27/36 -[I|Train] Epoch took 00:01:31, predicted 00:12:08 left -[I|Train] Epoch 28/36 -[I|Train] Epoch took 00:01:30, predicted 00:10:36 left -[I|Train] Epoch 29/36 -[I|Train] Epoch took 00:01:31, predicted 00:09:06 left -[I|Train] Epoch 30/36 -[I|Train] Epoch took 00:01:31, predicted 00:07:35 left -[I|Train] Epoch 31/36 -[I|Train] Epoch took 00:01:31, predicted 00:06:04 left -[I|Train] Epoch 32/36 -[I|Train] Epoch took 00:01:31, predicted 00:04:33 left -[I|Train] Epoch 33/36 -[I|Train] Epoch took 00:01:31, predicted 00:03:02 left -[I|Train] Epoch 34/36 -[I|Train] Epoch took 00:01:31, predicted 00:01:31 left -[I|Train] Epoch 35/36 -[I|Train] Epoch took 00:01:31, predicted 00:00:00 left -[I|Train Handler] Resetting model -[I|Model] Loading tags from file -[I|Model] Loading tag categories from file -Found CUDA devices: -TITAN Xp -TITAN X (Pascal) -[I|Train Handler] Fold 3/4... -[I|Train] Epoch 0/36 -[I|Train] Epoch took 00:01:32, predicted 00:54:00 left -[I|Train] Epoch 1/36 -[I|Train] Epoch took 00:01:32, predicted 00:52:31 left -[I|Train] Epoch 2/36 -[I|Train] Epoch took 00:01:32, predicted 00:50:52 left -[I|Train] Epoch 3/36 -[I|Train] Epoch took 00:01:32, predicted 00:49:16 left -[I|Train] Epoch 4/36 -[I|Train] Epoch took 00:01:32, predicted 00:47:48 left -[I|Train] Epoch 5/36 -[I|Train] Epoch took 00:01:32, predicted 00:46:11 left -[I|Train] Epoch 6/36 -[I|Train] Epoch took 00:01:32, predicted 00:44:36 left -[I|Train] Epoch 7/36 -[I|Train] Epoch took 00:01:32, predicted 00:43:02 left -[I|Train] Epoch 8/36 -[I|Train] Epoch took 00:01:32, predicted 00:41:27 left -[I|Train] Epoch 9/36 -[I|Train] Epoch took 00:01:32, predicted 00:39:55 left -[I|Train] Epoch 10/36 -[I|Train] Epoch took 00:01:31, predicted 00:38:19 left -[I|Train] Epoch 11/36 -[I|Train] Epoch took 00:01:32, predicted 00:36:48 left -[I|Train] Epoch 12/36 -[I|Train] Epoch took 00:01:31, predicted 00:35:13 left -[I|Train] Epoch 13/36 -[I|Train] Epoch took 00:01:31, predicted 00:33:43 left -[I|Train] Epoch 14/36 -[I|Train] Epoch took 00:01:31, predicted 00:32:08 left -[I|Train] Epoch 15/36 -[I|Train] Epoch took 00:01:31, predicted 00:30:37 left -[I|Train] Epoch 16/36 -[I|Train] Epoch took 00:01:31, predicted 00:29:04 left -[I|Train] Epoch 17/36 -[I|Train] Epoch took 00:01:31, predicted 00:27:30 left -[I|Train] Epoch 18/36 -[I|Train] Epoch took 00:01:31, predicted 00:25:59 left -[I|Train] Epoch 19/36 -[I|Train] Epoch took 00:01:31, predicted 00:24:27 left -[I|Train] Epoch 20/36 -[I|Train] Epoch took 00:01:31, predicted 00:22:54 left -[I|Train] Epoch 21/36 -[I|Train] Epoch took 00:01:31, predicted 00:21:23 left -[I|Train] Epoch 22/36 -[I|Train] Epoch took 00:01:31, predicted 00:19:50 left -[I|Train] Epoch 23/36 -[I|Train] Epoch took 00:01:31, predicted 00:18:20 left -[I|Train] Epoch 24/36 -[I|Train] Epoch took 00:01:31, predicted 00:16:47 left -[I|Train] Epoch 25/36 -[I|Train] Epoch took 00:01:31, predicted 00:15:16 left -[I|Train] Epoch 26/36 -[I|Train] Epoch took 00:01:31, predicted 00:13:45 left -[I|Train] Epoch 27/36 -[I|Train] Epoch took 00:01:31, predicted 00:12:11 left -[I|Train] Epoch 28/36 -[I|Train] Epoch took 00:01:31, predicted 00:10:41 left -[I|Train] Epoch 29/36 -[I|Train] Epoch took 00:01:31, predicted 00:09:09 left -[I|Train] Epoch 30/36 -[I|Train] Epoch took 00:01:31, predicted 00:07:38 left -[I|Train] Epoch 31/36 -[I|Train] Epoch took 00:01:31, predicted 00:06:06 left -[I|Train] Epoch 32/36 -[I|Train] Epoch took 00:01:31, predicted 00:04:34 left -[I|Train] Epoch 33/36 -[I|Train] Epoch took 00:01:31, predicted 00:03:03 left -[I|Train] Epoch 34/36 -[I|Train] Epoch took 00:01:31, predicted 00:01:31 left -[I|Train] Epoch 35/36 -[I|Train] Epoch took 00:01:31, predicted 00:00:00 left -[I|Train Handler] Resetting model -[I|Model] Loading tags from file -[I|Model] Loading tag categories from file -Found CUDA devices: -TITAN Xp -TITAN X (Pascal) -[I|Train Handler] Fold 4/4... -[I|Train] Epoch 0/36 -[I|Train] Epoch took 00:01:32, predicted 00:53:58 left -[I|Train] Epoch 1/36 -[I|Train] Epoch took 00:01:32, predicted 00:52:31 left -[I|Train] Epoch 2/36 -[I|Train] Epoch took 00:01:32, predicted 00:50:50 left -[I|Train] Epoch 3/36 -[I|Train] Epoch took 00:01:32, predicted 00:49:17 left -[I|Train] Epoch 4/36 -[I|Train] Epoch took 00:01:32, predicted 00:47:42 left -[I|Train] Epoch 5/36 -[I|Train] Epoch took 00:01:31, predicted 00:45:58 left -[I|Train] Epoch 6/36 -[I|Train] Epoch took 00:01:31, predicted 00:44:24 left -[I|Train] Epoch 7/36 -[I|Train] Epoch took 00:01:31, predicted 00:42:48 left -[I|Train] Epoch 8/36 -[I|Train] Epoch took 00:01:31, predicted 00:41:14 left -[I|Train] Epoch 9/36 -[I|Train] Epoch took 00:01:31, predicted 00:39:36 left -[I|Train] Epoch 10/36 -[I|Train] Epoch took 00:01:31, predicted 00:38:10 left -[I|Train] Epoch 11/36 -[I|Train] Epoch took 00:01:31, predicted 00:36:38 left -[I|Train] Epoch 12/36 -[I|Train] Epoch took 00:01:31, predicted 00:35:04 left -[I|Train] Epoch 13/36 -[I|Train] Epoch took 00:01:31, predicted 00:33:38 left -[I|Train] Epoch 14/36 -[I|Train] Epoch took 00:01:31, predicted 00:32:00 left -[I|Train] Epoch 15/36 -[I|Train] Epoch took 00:01:31, predicted 00:30:26 left -[I|Train] Epoch 16/36 -[I|Train] Epoch took 00:01:31, predicted 00:28:54 left -[I|Train] Epoch 17/36 -[I|Train] Epoch took 00:01:31, predicted 00:27:23 left -[I|Train] Epoch 18/36 -[I|Train] Epoch took 00:01:31, predicted 00:25:53 left -[I|Train] Epoch 19/36 -[I|Train] Epoch took 00:01:31, predicted 00:24:19 left -[I|Train] Epoch 20/36 -[I|Train] Epoch took 00:01:31, predicted 00:22:51 left -[I|Train] Epoch 21/36 -[I|Train] Epoch took 00:01:31, predicted 00:21:18 left -[I|Train] Epoch 22/36 -[I|Train] Epoch took 00:01:31, predicted 00:19:45 left -[I|Train] Epoch 23/36 -[I|Train] Epoch took 00:01:31, predicted 00:18:13 left -[I|Train] Epoch 24/36 -[I|Train] Epoch took 00:01:31, predicted 00:16:51 left -[I|Train] Epoch 25/36 -[I|Train] Epoch took 00:01:31, predicted 00:15:12 left -[I|Train] Epoch 26/36 -[I|Train] Epoch took 00:01:31, predicted 00:13:39 left -[I|Train] Epoch 27/36 -[I|Train] Epoch took 00:01:31, predicted 00:12:09 left -[I|Train] Epoch 28/36 -[I|Train] Epoch took 00:01:31, predicted 00:10:38 left -[I|Train] Epoch 29/36 -[I|Train] Epoch took 00:01:31, predicted 00:09:06 left -[I|Train] Epoch 30/36 -[I|Train] Epoch took 00:01:31, predicted 00:07:36 left -[I|Train] Epoch 31/36 -[I|Train] Epoch took 00:01:31, predicted 00:06:05 left -[I|Train] Epoch 32/36 -[I|Train] Epoch took 00:01:31, predicted 00:04:34 left -[I|Train] Epoch 33/36 -[I|Train] Epoch took 00:01:31, predicted 00:03:02 left -[I|Train] Epoch 34/36 -[I|Train] Epoch took 00:01:31, predicted 00:01:31 left -[I|Train] Epoch 35/36 -[I|Train] Epoch took 00:01:31, predicted 00:00:00 left -[I|Train Handler] Resetting model -[I|Model] Loading tags from file -[I|Model] Loading tag categories from file -Found CUDA devices: -TITAN Xp -TITAN X (Pascal) -[I|Train Handler] Final training -[I|Train] Epoch 0/36 -[I|Train] Epoch took 00:01:39, predicted 00:58:03 left -[I|Train] Epoch 1/36 -[I|Train] Epoch took 00:01:39, predicted 00:56:29 left -[I|Train] Epoch 2/36 -[I|Train] Epoch took 00:01:39, predicted 00:54:48 left -[I|Train] Epoch 3/36 -[I|Train] Epoch took 00:01:39, predicted 00:52:58 left -[I|Train] Epoch 4/36 -[I|Train] Epoch took 00:01:39, predicted 00:51:14 left -[I|Train] Epoch 5/36 -[I|Train] Epoch took 00:01:39, predicted 00:49:31 left -[I|Train] Epoch 6/36 -[I|Train] Epoch took 00:01:38, predicted 00:47:47 left -[I|Train] Epoch 7/36 -[I|Train] Epoch took 00:01:38, predicted 00:46:06 left -[I|Train] Epoch 8/36 -[I|Train] Epoch took 00:01:38, predicted 00:44:25 left -[I|Train] Epoch 9/36 -[I|Train] Epoch took 00:01:38, predicted 00:42:41 left -[I|Train] Epoch 10/36 -[I|Train] Epoch took 00:01:38, predicted 00:41:03 left -[I|Train] Epoch 11/36 -[I|Train] Epoch took 00:01:38, predicted 00:39:25 left -[I|Train] Epoch 12/36 -[I|Train] Epoch took 00:01:38, predicted 00:37:41 left -[I|Train] Epoch 13/36 -[I|Train] Epoch took 00:01:38, predicted 00:36:03 left -[I|Train] Epoch 14/36 -[I|Train] Epoch took 00:01:38, predicted 00:34:24 left -[I|Train] Epoch 15/36 -[I|Train] Epoch took 00:01:38, predicted 00:32:45 left -[I|Train] Epoch 16/36 -[I|Train] Epoch took 00:01:38, predicted 00:31:04 left -[I|Train] Epoch 17/36 -[I|Train] Epoch took 00:01:38, predicted 00:29:27 left -[I|Train] Epoch 18/36 -[I|Train] Epoch took 00:01:38, predicted 00:27:49 left -[I|Train] Epoch 19/36 -[I|Train] Epoch took 00:01:38, predicted 00:26:08 left -[I|Train] Epoch 20/36 -[I|Train] Epoch took 00:01:38, predicted 00:24:30 left -[I|Train] Epoch 21/36 -[I|Train] Epoch took 00:01:38, predicted 00:22:52 left -[I|Train] Epoch 22/36 -[I|Train] Epoch took 00:01:38, predicted 00:21:15 left -[I|Train] Epoch 23/36 -[I|Train] Epoch took 00:01:38, predicted 00:19:40 left -[I|Train] Epoch 24/36 -[I|Train] Epoch took 00:01:38, predicted 00:18:02 left -[I|Train] Epoch 25/36 -[I|Train] Epoch took 00:01:38, predicted 00:16:22 left -[I|Train] Epoch 26/36 -[I|Train] Epoch took 00:01:38, predicted 00:14:44 left -[I|Train] Epoch 27/36 -[I|Train] Epoch took 00:01:38, predicted 00:13:06 left -[I|Train] Epoch 28/36 -[I|Train] Epoch took 00:01:38, predicted 00:11:27 left -[I|Train] Epoch 29/36 -[I|Train] Epoch took 00:01:38, predicted 00:09:49 left -[I|Train] Epoch 30/36 -[I|Train] Epoch took 00:01:38, predicted 00:08:11 left -[I|Train] Epoch 31/36 -[I|Train] Epoch took 00:01:38, predicted 00:06:32 left -[I|Train] Epoch 32/36 -[I|Train] Epoch took 00:01:37, predicted 00:04:53 left -[I|Train] Epoch 33/36 -[I|Train] Epoch took 00:01:37, predicted 00:03:15 left -[I|Train] Epoch 34/36 -[I|Train] Epoch took 00:01:37, predicted 00:01:37 left -[I|Train] Epoch 35/36 -[I|Train] Epoch took 00:01:37, predicted 00:00:00 left -[I|Train Handler] Testing model -[I|Data] Loading data from file -[I|Data] Pre-processing input data -[I|Data] Processing transformer data -[I|Data] Processing tag data -[W] The following tags were not found in the new tag list: - B-- - I-- -[W] The following tags were not found in the new tag list: - B-- - B-graft - I-- - I-graft -[W] The following tags were not found in the new tag list: - B-- - I-- - I-regulates - I-rescues -[W] The following tags were not found in the new tag list: - B-- - B-adhesion - B-colony formation - B-entosis - B-necroptosis - B-necrosis - B-oncosis - B-quiescence - B-transformation - B-tumour progression - B-tumourigenesis - I-- - I-adhesion - I-anoikis - I-colony formation - I-differentiation - I-entosis - I-invasion - I-migration - I-mitophagy - I-necroptosis - I-necrosis - I-oncosis - I-proliferation - I-pyroptosis - I-quiescence - I-transformation - I-tumour progression - I-tumourigenesis -[I|Test] Testing model -[I|Test] Test loss: {'category': 0.12676049955189228, 'perturbing_action': 0.057775139808654785, 'context': 0.04819931508973241, 'effect': 0.009943735261913389, 'phenotype': 0.01939043588936329} -[I|Test] Test accuracy: {'category': {'precision': 0.7854671280276817, 'recall': 0.8209764918625678, 'f1': 0.8028293545534925, 'accuracy': 0.670605612998523}, 'perturbing_action': {'precision': 0.6966292134831461, 'recall': 0.7692307692307693, 'f1': 0.7311320754716981, 'accuracy': 0.5762081784386617}, 'context': {'precision': 0.6960556844547564, 'recall': 0.7299270072992701, 'f1': 0.7125890736342043, 'accuracy': 0.5535055350553506}, 'effect': {'precision': 0.856, 'recall': 0.8106060606060606, 'f1': 0.8326848249027238, 'accuracy': 0.7133333333333334}, 'phenotype': {'precision': 0.8544303797468354, 'recall': 0.8385093167701864, 'f1': 0.8463949843260188, 'accuracy': 0.7336956521739131}} -[I|Train Handler] Saving model -[I|Train Handler] Saving training history -[I] Finished -[I] Successful: configs/current_best/v2_single_label_bl05_k4_e36.json, configs/current_best/v2_single_label_bio_bl05_k4_e36.json -[I] Failed: None -[I] Program exiting... +[I|Train] Epoch 0/6 +Traceback (most recent call last): + File "/mnt/nas_home/jrb239/transformer_nlp/main.py", line 90, in + main(c) + File "/mnt/nas_home/jrb239/transformer_nlp/main.py", line 32, in main + mode_funcs[config["MODE"]](config) + File "/mnt/nas_home/jrb239/transformer_nlp/src/model_handler.py", line 450, in train_mode + history = self.train(*dataloaders, config=config["TRAINING"]) + File "/mnt/nas_home/jrb239/transformer_nlp/src/model_handler.py", line 122, in train + return self.model.train_model(train_dataloader, val_dataloader, + File "/mnt/nas_home/jrb239/transformer_nlp/src/model.py", line 274, in train_model + outputs = self.forward_batch(batch, class_loss_weights=class_loss_weights) + File "/mnt/nas_home/jrb239/transformer_nlp/src/model.py", line 211, in forward_batch + outputs = self(model_data, class_loss_weights=class_loss_weights, calc_loss=calc_loss) + File "/mnt/nas_home/jrb239/miniconda3/envs/tfm_nlp/lib/python3.9/site-packages/torch/nn/modules/module.py", line 1051, in _call_impl + return forward_call(*input, **kwargs) + File "/mnt/nas_home/jrb239/transformer_nlp/src/model.py", line 181, in forward + outputs = {kh: {ki: get_output(vi) for ki, vi in vh.items()} + File "/mnt/nas_home/jrb239/transformer_nlp/src/model.py", line 182, in + if kh != "default" else get_output(vh) + File "/mnt/nas_home/jrb239/transformer_nlp/src/model.py", line 179, in get_output + return self.dropout(self.tfm(i_dict["iids"], attention_mask=i_dict["masks"])[0]) + File "/mnt/nas_home/jrb239/miniconda3/envs/tfm_nlp/lib/python3.9/site-packages/torch/nn/modules/module.py", line 1051, in _call_impl + return forward_call(*input, **kwargs) + File "/mnt/nas_home/jrb239/miniconda3/envs/tfm_nlp/lib/python3.9/site-packages/transformers/models/distilbert/modeling_distilbert.py", line 481, in forward + return self.transformer( + File "/mnt/nas_home/jrb239/miniconda3/envs/tfm_nlp/lib/python3.9/site-packages/torch/nn/modules/module.py", line 1051, in _call_impl + return forward_call(*input, **kwargs) + File "/mnt/nas_home/jrb239/miniconda3/envs/tfm_nlp/lib/python3.9/site-packages/transformers/models/distilbert/modeling_distilbert.py", line 306, in forward + layer_outputs = layer_module( + File "/mnt/nas_home/jrb239/miniconda3/envs/tfm_nlp/lib/python3.9/site-packages/torch/nn/modules/module.py", line 1051, in _call_impl + return forward_call(*input, **kwargs) + File "/mnt/nas_home/jrb239/miniconda3/envs/tfm_nlp/lib/python3.9/site-packages/transformers/models/distilbert/modeling_distilbert.py", line 264, in forward + ffn_output = self.ffn(sa_output) # (bs, seq_length, dim) + File "/mnt/nas_home/jrb239/miniconda3/envs/tfm_nlp/lib/python3.9/site-packages/torch/nn/modules/module.py", line 1051, in _call_impl + return forward_call(*input, **kwargs) + File "/mnt/nas_home/jrb239/miniconda3/envs/tfm_nlp/lib/python3.9/site-packages/transformers/models/distilbert/modeling_distilbert.py", line 215, in forward + return apply_chunking_to_forward(self.ff_chunk, self.chunk_size_feed_forward, self.seq_len_dim, input) + File "/mnt/nas_home/jrb239/miniconda3/envs/tfm_nlp/lib/python3.9/site-packages/transformers/modeling_utils.py", line 2001, in apply_chunking_to_forward + return forward_fn(*input_tensors) + File "/mnt/nas_home/jrb239/miniconda3/envs/tfm_nlp/lib/python3.9/site-packages/transformers/models/distilbert/modeling_distilbert.py", line 218, in ff_chunk + x = self.lin1(input) + File "/mnt/nas_home/jrb239/miniconda3/envs/tfm_nlp/lib/python3.9/site-packages/torch/nn/modules/module.py", line 1051, in _call_impl + return forward_call(*input, **kwargs) + File "/mnt/nas_home/jrb239/miniconda3/envs/tfm_nlp/lib/python3.9/site-packages/torch/nn/modules/linear.py", line 96, in forward + return F.linear(input, self.weight, self.bias) + File "/mnt/nas_home/jrb239/miniconda3/envs/tfm_nlp/lib/python3.9/site-packages/torch/nn/functional.py", line 1847, in linear + return torch._C._nn.linear(input, weight, bias) +KeyboardInterrupt diff --git a/outputs/outputs_db.json b/outputs/outputs_db.json index a814037..afee1c5 100644 --- a/outputs/outputs_db.json +++ b/outputs/outputs_db.json @@ -440793,5 +440793,67192 @@ } } } + }, + 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"recall": 0.7679180887372014, + "f1": 0.7537688442211056, + "accuracy": 0.6302521008403361 + } + }, + { + "phenotype": { + "precision": 0.6899696048632219, + "recall": 0.7747440273037542, + "f1": 0.7299035369774919, + "accuracy": 0.5989445910290238 + } + }, + { + "phenotype": { + "precision": 0.6593406593406593, + "recall": 0.8191126279863481, + "f1": 0.730593607305936, + "accuracy": 0.6045340050377834 + } + }, + { + "phenotype": { + "precision": 0.7508650519031141, + "recall": 0.7406143344709898, + "f1": 0.7457044673539519, + "accuracy": 0.6217765042979942 + } + }, + { + "phenotype": { + "precision": 0.7560137457044673, + "recall": 0.7508532423208191, + "f1": 0.7534246575342465, + "accuracy": 0.6303724928366762 + } + }, + { + "phenotype": { + "precision": 0.7709090909090909, + "recall": 0.7235494880546075, + "f1": 0.7464788732394366, + "accuracy": 0.6235294117647059 + } + }, + { + "phenotype": { + "precision": 0.7474402730375427, + "recall": 0.7474402730375427, + "f1": 0.7474402730375427, + "accuracy": 0.6221590909090909 + } + }, + { + "phenotype": { + "precision": 0.7408637873754153, + "recall": 0.7610921501706485, + "f1": 0.7508417508417509, + "accuracy": 0.6264044943820225 + } + }, + { + "phenotype": { + "precision": 0.7586206896551724, + "recall": 0.7508532423208191, + "f1": 0.7547169811320754, + "accuracy": 0.632183908045977 + } + }, + { + "phenotype": { + "precision": 0.7441077441077442, + "recall": 0.7542662116040956, + "f1": 0.7491525423728813, + "accuracy": 0.6242937853107344 + } + }, + { + "phenotype": { + "precision": 0.7441077441077442, + "recall": 0.7542662116040956, + "f1": 0.7491525423728813, + "accuracy": 0.6242937853107344 + } + } + ] + } + ] + }, + "testing": { + "loss": { + "phenotype": 0.027654941892251372 + }, + "accuracy": { + "phenotype": { + "precision": 0.8125, + "recall": 0.8881987577639752, + "f1": 0.8486646884272997, + "accuracy": 0.7409326424870466 + } + } + } } } \ No newline at end of file diff --git a/requirements.txt b/requirements.txt index c1d1914..6ff929c 100644 --- a/requirements.txt +++ b/requirements.txt @@ -1,4 +1,3 @@ -allennlp~=2.6.0 matplotlib~=3.4.2 numpy~=1.19.5 pandas~=1.3.0 diff --git a/src/analysis.py b/src/analysis.py index 3511dae..d53dd96 100644 --- a/src/analysis.py +++ b/src/analysis.py @@ -1,10 +1,44 @@ from matplotlib import pyplot as plt +from argparse import ArgumentParser import matplotlib import json import numpy as np -from util.core import printv, ensure_file_ext -from src.misc import txt_str_to_md + +def printv(*args, verbose_flag): + if verbose_flag: + print(*args) + +def ensure_suffix(txt: str, suffix: str) -> str: + return txt if txt[-len(suffix):] == suffix else txt + suffix + +def txt_str_to_md(string, bullet_consecutive_lines=False): + + # Make things titles based on newlines + string = '\n\n\n## '.join(string.split('\n\n\n')) + + # If applicable, make lists out of consective, non-empty lines + if bullet_consecutive_lines: + s_split = string.split('\n') + new_string = [s_split[0], s_split[1]] + + # We want to bullet when the previous line is not empty and neither is the current + # If we're at the top of the bullets we need to insert a newline + for l1, l2, l3 in zip(s_split, s_split[1:], s_split[2:]): + if l2 != '' and l3 != '': + if l1 == '': + new_string.append("\n* " + l3) + else: + new_string.append("* " + l3) + else: + new_string.append(l3) + + string = '\n'.join(new_string) + + # Insert header and make first line title + string = "---\ngeometry: margin=2.5cm\n---\n\n# " + string + + return string styles = ["r-", "b-", "g-", "y-", "k-", @@ -185,12 +219,12 @@ def report(history_data, config): print(report_str) elif config["OUTPUT"] == "txt": - p = ensure_file_ext(config["PATH"], "txt") + p = ensure_suffix(config["PATH"], ".txt") with open(p, 'w') as f: f.write(report_str) elif config["OUTPUT"] == "md": - p = ensure_file_ext(config["PATH"], "md") + p = ensure_suffix(config["PATH"], ".md") with open(p, 'w') as f: f.write(txt_str_to_md(report_str, bullet_consecutive_lines=True)) @@ -213,3 +247,12 @@ def analyse_mode(config): printv("[I] Analysing...", verbose_flag=v) analyse(history_data, config["ANALYSIS"]) + +if __name__ == "__main__": + parser = ArgumentParser(description="Analysis of metrics") + parser.add_argument("config_path") + args = parser.parse_args() + with open(args.config_path) as f: + config = json.load(f) + analyse_mode(config) + diff --git a/src/datahandler.py b/src/datahandler.py index 82a565e..34160da 100644 --- a/src/datahandler.py +++ b/src/datahandler.py @@ -225,6 +225,12 @@ def _tokenize_entry(self, entry_words): return tokenized_entry, tkns_per_tag + def update_model_data(self, new_data): + # NOTE: The use case for this method is for adding in active tkn idxs for existing data + # For the initial input of data, use the set data functions + self._model_data.update(new_data) + + def get_dataloader(self, batch_size=1, sampler=None): return dataloader(self._model_data, batch_size=batch_size, sampler=sampler) diff --git a/src/dataloading.py b/src/dataloading.py index 7fa7174..e3568f8 100644 --- a/src/dataloading.py +++ b/src/dataloading.py @@ -93,7 +93,7 @@ def process_tags(tag_schema_pairs, multilabel, schema_func): elif k == "link_same_tag_only_split": link_sets = set([l_type for xs in raw_link_data for x in xs for l_type, _, _ in x if l_type != "links"]) - link_data = {k: [[[] for x in xs] for xs in raw_link_data] for k in link_sets} + link_data = {k: [[[] for _ in xs] for xs in raw_link_data] for k in link_sets} for i, xs in enumerate(raw_link_data): for j, x in enumerate(xs): for l_type, l_id, l in x: @@ -125,3 +125,11 @@ def load_txt_data(path): words = [entry.split(' ') for entry in entries if entry != ''] return {"tfm": words, "head": {}}, None +def load_raw_json_data(path): + with open(path) as f: + entries = json.load(f) + pairs = list(entries.items()) + words = [entry_txt.split(' ') for _, entry_txt in pairs] + entry_idxs = {k: i for i, (k, _) in enumerate(pairs)} + return {"tfm": words, "head": {}}, None, entry_idxs + diff --git a/src/heads.py b/src/heads.py index 17eef44..b30a6af 100644 --- a/src/heads.py +++ b/src/heads.py @@ -3,7 +3,7 @@ import torch from torch import nn -from allennlp.modules.conditional_random_field import ConditionalRandomField, allowed_transitions +# from allennlp.modules.conditional_random_field import ConditionalRandomField, allowed_transitions from src.misc import get_prf1a, check_tag_list, pad_sequences, copy_type @@ -187,9 +187,14 @@ def bblabels2blabels(b_b_labels): def b_tags2lists_of_tags(b_tags): raise NotImplementedError - def tag2str(self, tag): + @classmethod + def tag2str(cls, tag): raise NotImplementedError + @classmethod + def clean_tag(cls, tag): + return None if tag == cls._none_tag else tag + @staticmethod def apply_schema_to_tag_list(tag_list, schema): raise NotImplementedError @@ -394,14 +399,15 @@ def accuracy(self, b_true_labels, b_pred_labels): fp += t != p and p != self._none_label fn += t != p and t != self._none_label total_Neg += t != p - return get_prf1a(tp, fp, fn, (fp + fn)) + return get_prf1a(tp, fp, fn, total_Neg) def get_loss_masks(self, b_labels): return [[float(label != self._full_pad_label) for label in labels] for labels in b_labels] - def tag2str(self, tag): - return '' if tag == self._none_tag else str(tag) + @classmethod + def tag2str(cls, tag): + return '' if tag == cls._none_tag else str(tag) class CRF(Single_Label): @@ -409,6 +415,7 @@ class CRF(Single_Label): predic_func = nn.Identity() # Viterbi tags algorithm expects logits def __init__(self, schema, **kwargs): + raise Exception("Currently deactivated") assert schema == "BIO" # Only supported at the moment super().__init__(schema=schema, **kwargs) self._crf = None @@ -534,8 +541,9 @@ def get_loss_masks(self, b_labels): return [[float(any(label != self._full_pad_label)) for label in labels] for labels in b_labels] - def tag2str(self, tag): - return "" if tag == self._none_tag else ', '.join([str(t) for t in tag]) + @classmethod + def tag2str(cls, tag): + return "" if tag == cls._none_tag else ', '.join([str(t) for t in tag]) class Multi_Label_Seq(Multi_Label): @@ -792,10 +800,11 @@ def m_func(xs, i, j, ni, nj): def b_tags2lists_of_tags(b_tags): return [dl2ld(tags) for tags in dl2ld(b_tags)] - def tag2str(self, tag_dict): + @classmethod + def tag2str(cls, tag_dict): tag_strs = [] - for k, v in tag_dict: - if v != self._none_tag: + for k, v in tag_dict.items(): + if v != cls._none_tag: tag_strs.append(', '.join([f"{k}_{i}_{t}" for i, t in v])) return ', '.join(tag_strs) @@ -803,6 +812,26 @@ def tag2str(self, tag_dict): def apply_schema_to_tag_list(tag_list, schema): return tag_list + def clean_tag(self, tag): + return_obj = None + + # If we have multiple link types, check the dictionary of links + if isinstance(tag, dict): + if len(tag) == 1: # Only one link type so flatten out the dict + tag_val = list(tag.values())[0] + return_obj = None if tag_val == self._none_tag else tag_val + else: + r_dict = {k: v for k, v in tag.items() if v != self._none_tag} + return_obj = None if r_dict == {} else r_dict + else: + return_obj = None if tag == self._none_tag else tag + + # If we only have 1 tag in our prediction, flatten that out (i.e. binary classification) + if len(self.tag_list) == 1 and return_obj is not None: + return_obj = [x for (x, _) in return_obj] + + return return_obj + # DERIVATIVE CLASSES diff --git a/src/model.py b/src/model.py index d73152e..d745295 100644 --- a/src/model.py +++ b/src/model.py @@ -173,7 +173,7 @@ def set_custom_ps2ls(self, func_name): self.custom_predictions2labels = predictions2labels_funcs[func_name] - def forward(self, model_data, class_loss_weights=None): + def forward(self, model_data, class_loss_weights=None, calc_loss=True): def get_output(i_dict): return self.dropout(self.tfm(i_dict["iids"], attention_mask=i_dict["masks"])[0]) @@ -182,16 +182,17 @@ def get_output(i_dict): if kh != "default" else get_output(vh) for kh, vh in model_data["tfm"].items()} - logits = {k: h(dict_dget(outputs, k, "default"), model_data["heads"][k]) + logits = {k: h(dict_dget(outputs, k, "default"), model_data["heads"].get(k, None)) for k, h in self._heads.items()} losses = {} - for k, h_data in model_data["heads"].items(): - clw = class_loss_weights[k].to(self.cuda_device) - losses[k] = self._heads[k].loss_calc( - logits[k], head_data=h_data, tfm_data=dict_dget(model_data["tfm"], k, "default"), - class_loss_weights=clw - ) + if calc_loss: + for k, h_data in model_data["heads"].items(): + clw = class_loss_weights[k].to(self.cuda_device) + losses[k] = self._heads[k].loss_calc( + logits[k], head_data=h_data, tfm_data=dict_dget(model_data["tfm"], k, "default"), + class_loss_weights=clw + ) losses = deep_eD(losses) @@ -202,23 +203,27 @@ def get_output(i_dict): } - def forward_batch(self, batch, grad=True, class_loss_weights=None): + def forward_batch(self, batch, grad=True, class_loss_weights=None, calc_loss=True): model_data, = batch model_data = deep_eD(model_data).to(self.cuda_device) if grad: - outputs = self(model_data, class_loss_weights=class_loss_weights) + outputs = self(model_data, class_loss_weights=class_loss_weights, calc_loss=calc_loss) else: with torch.no_grad(): - outputs = self(model_data, class_loss_weights=class_loss_weights) + outputs = self(model_data, class_loss_weights=class_loss_weights, + calc_loss=calc_loss) # TODO: Make this work for multi-input, WIP outputs["b_n_tkns_per_word"] = {kh: {ki: vi["ntpw"].to('cpu').numpy for ki, vi in vh.items()} if kh != "default" else vh["ntpw"].to('cpu').numpy() for kh, vh in model_data["tfm"].items()} - outputs["b_labels"] = {k: self._heads[k].get_labels(v) - for k, v in model_data["heads"].items()} + try: + outputs["b_labels"] = {k: self._heads[k].get_labels(v) + for k, v in model_data["heads"].items()} + except KeyError: + outputs["b_labels"] = {} outputs["predictions"] = outputs["predictions"].detach().to('cpu').numpy() return outputs @@ -350,13 +355,15 @@ def validate(self, val_dataloader, class_loss_weights, v3=False, recombination_m return eval_loss, val_acuracy - def predict_tags(self, dataloader, heads=None, recombination_method="first"): + def predict_tags(self, dataloader, heads=None, recombination_method="first", + verbose_flag=False): heads = self._heads.keys() if heads is None else heads self.eval() pred_labels = {k: [] for k in heads} - for batch in dataloader: - outputs = self.forward_batch(batch, grad=False) + for step, batch in enumerate(dataloader): + printv(f"[I|Predict] Batch {step}/{len(dataloader)}", verbose_flag=verbose_flag) + outputs = self.forward_batch(batch, grad=False, calc_loss=False) new_pred_labels = self.predictions2condensed_labels(outputs["predictions"], outputs["b_n_tkns_per_word"], method=recombination_method) @@ -452,11 +459,9 @@ def get_tagged_word_idxs(self, b_tags): b_tagged_word_idxs.append(list(set(tagged_word_idxs))) return b_tagged_word_idxs - def get_word_tag_pairs(self, b_words, b_tags, ignored_heads=None): + def get_word_tag_pairs(self, b_words, b_tags): b_tags = {k: self._heads[k].b_tags2lists_of_tags(v) for k, v in b_tags.items()} - return [[(str(word), self.tag2str(tag, ignored_heads=ignored_heads)) - for word, tag in zip(words, dl2ld(tags))] - for words, tags in zip(b_words, dl2ld(b_tags))] + return [list(zip(words, dl2ld(tags))) for words, tags in zip(b_words, dl2ld(b_tags))] def tag2str(self, tag, ignored_heads=None): str_dict = {k: self._heads[k].tag2str(t) for k, t in tag.items()} @@ -469,3 +474,31 @@ def tag2str(self, tag, ignored_heads=None): r_str = f"({' | '.join([f'{k}: {v}' for k, v in str_dict.items() if v != ''])})" return r_str if r_str != "()" else '' + def clean_tag(self, tag, ignored_heads=None, specific_head=None): + assert ignored_heads is None or specific_head is None # Can't use both + + tag_dict = {k: self._heads[k].clean_tag(t) for k, t in tag.items()} + tag_dict = {k: v for k, v in tag_dict.items() if v is not None} + + if ignored_heads is not None: + for head in ignored_heads: + if head in tag_dict.keys(): + del tag_dict[head] + + # If we have an empty dict, return None as no relevant tags for this word + if tag_dict == {}: + return None + + elif specific_head is not None: + if specific_head in tag_dict.keys(): + return tag_dict[specific_head] + else: + return None + + else: + return tag_dict + + def clean_word_tag_pairs(self, wt_pairs, ignored_heads=None, specific_head=None): + return [[(w, self.clean_tag(t, ignored_heads, specific_head)) for w, t in entry] + for entry in wt_pairs] + diff --git a/src/model_handler.py b/src/model_handler.py index cd4d613..c2c948e 100644 --- a/src/model_handler.py +++ b/src/model_handler.py @@ -1,17 +1,15 @@ -import numpy as np import json import torch from transformers import AutoTokenizer -from src.misc import pad_sequences -from src.dataloading import load_txt_data +from src.dataloading import load_txt_data, load_raw_json_data from src.datahandler import DataHandler from src.model import Custom_Model from src.custom_datatypes import deep_eD -from util.core import printv, get_time_stamp, ensure_file_ext +from util.core import printv, get_time_stamp, ensure_file_ext, pairs # Note: # For clarity tags will refer to the actual tags on the data e.g. "PAD" and label will @@ -40,6 +38,9 @@ def __init__(self, config): # Bit hacky but helps for some deploy stuff self.extra_models = {} + # For when we need to label entry inputs, use this dict + self.entry_names = None + @classmethod def get(cls, config): if config["TYPE"] == "pretrained": @@ -47,7 +48,7 @@ def get(cls, config): elif config["TYPE"] == "existing": mh = cls.load(config["PATH"]) mh.extra_models = {k: cls.load(p).model - for k, p in config.get("EXTRA_PATHS", {}).items()} + for k, p in config.get("EXTRA_MODELS", {}).items()} return mh else: raise Exception("[UE] Model type error not caught") @@ -88,6 +89,11 @@ def get_file_data(self, config): sep_sentences=sep_sentences) elif config["FILETYPE"] == "txt": input_data, tag_data = load_txt_data(config["PATH"]) + + elif config["FILETYPE"] == "json_raw": + input_data, tag_data, entry_idxs = load_raw_json_data(config["PATH"]) + self.entry_names = entry_idxs + else: raise Exception(f"Unrecognised filetype {config['FILETYPE']} in config") @@ -134,40 +140,275 @@ def test(self, test_dataloader, config): def deploy_mode(self, config): - self.get_file_data(config["DATA"]) - d_dataloader = self.dh.get_dataloader(batch_size=config["DATA"]["BATCH_SIZE"]) - v1 = config["DEPLOY"].get("VERBOSE", 0) >= 1 + v2 = config["DEPLOY"].get("VERBOSE", 0) >= 2 + link_mode = "LINK" in config["DEPLOY"] + + if "EXISTING_OUTPUT_FOLDER" in config["DATA"]: + folder = config["DATA"]["EXISTING_OUTPUT_FOLDER"] + printv(f"[I|DEPLOY] Using existing data from {folder}", verbose_flag=v1) - printv("[I|Deploy] Predicting tags", verbose_flag=v1) - b_tags = self.model.predict_tags(d_dataloader) + printv(f"[I|DEPLOY] Loading tag output", verbose_flag=v1) + with open(f"{folder}/b_word_tag_pairs.json") as f: + b_word_tag_pairs = json.load(f) - if config["DEPLOY"].get("LINK", False): - # assert "link" in self.extra_models.keys() - active_tkn_idxs = self.model.get_tagged_word_idxs(b_tags) - print(active_tkn_idxs) + with open(f"{folder}/tag_entry_names.json") as f: + self.entry_names = json.load(f) - printv("[I|Deploy] Generating output", verbose_flag=v1) - ignored_heads = config["DEPLOY"].get("IGNORED_HEADS", None) + if link_mode: + if "link" not in self.extra_models.keys(): + raise Exception("Link prediction is in deploy config but there was no link model") - # TODO: Make this function with multi-input / make less hacky - b_word_tag_pairs = self.model.get_word_tag_pairs( - self.dh._text_data["default"]["raw_texts"], b_tags, ignored_heads=ignored_heads) + link_model = self.extra_models["link"] - w_sep, e_sep = ("\n", "\n\n") if config["DEPLOY"].get("NEWLINE_WORDS", False) else (" ", "\n") - output_str = e_sep.join([w_sep.join([f"{w} {t}" if t != "" else w for w, t in wtps]) - for wtps in b_word_tag_pairs]) + printv(f"[I|DEPLOY] Loading link output", verbose_flag=v1) + with open(f"{folder}/b_word_link_pairs.json") as f: + b_word_link_pairs = json.load(f) - printv("[I|Deploy] Outputting", verbose_flag=v1) - if config["DEPLOY"]["OUTPUT"] == "print": - print(output_str) + else: + link_model = None + b_word_link_pairs = None - elif config["DEPLOY"]["OUTPUT"] == "txt": - with open(config["DEPLOY"].get("PATH", "model_output.txt"), 'w') as f: - f.write(output_str) + else: + printv("[I|Deploy] Loading tag data", verbose_flag=v1) + self.get_file_data(config["DATA"]) + d_dataloader = self.dh.get_dataloader(batch_size=config["DATA"]["BATCH_SIZE"]) + + # TODO: Make this function with multi-input / make less hacky + raw_texts = self.dh._text_data["default"]["raw_texts"] + + printv("[I|Deploy] Predicting tags", verbose_flag=v1) + b_tags = self.model.predict_tags(d_dataloader, verbose_flag=v2) + + printv("[I|Deploy] Generating tag output", verbose_flag=v1) + b_word_tag_pairs = self.model.get_word_tag_pairs(raw_texts, b_tags) + + if link_mode: + printv("[I|Deploy] Loading link data", verbose_flag=v1) + if "link" not in self.extra_models.keys(): + raise Exception("Link prediction is in deploy config but there was no link model") + + link_model = self.extra_models["link"] + active_tkn_idxs = self.model.get_tagged_word_idxs(b_tags) + + # This code is very hacky and should almost certainly be rewritten + # Essentially taking the words which are marked as to get links for + # And then accounting for the tokenization and max input length + # This is also written to match a specific model and will easily break with other setups + tkns_per_word = self.dh._text_data["default"]["n_tkns_per_word"] + active_tkn_idxs = [[i in idxs for i in range(link_model.max_input_length)] + for idxs in active_tkn_idxs] + active_tkn_idxs = [[i for idx, n in zip(idxs, tkns_per_tag) for i in [idx]*n] + for idxs, tkns_per_tag in zip(active_tkn_idxs, tkns_per_word)] + active_tkn_idxs = [[entry[i] if i < len(entry) else False + for i in range(link_model.max_input_length)] + for entry in active_tkn_idxs] + extra_model_data = {"heads": {k: {"extra_inputs": + {"active_tkn_idxs": {"all": active_tkn_idxs}}} + for k in link_model._heads.keys()}} + + self.dh.update_model_data(extra_model_data) + l_dataloader = self.dh.get_dataloader(batch_size=config["DATA"]["BATCH_SIZE"]) + + printv("[I|Deploy] Predicting links", verbose_flag=v1) + b_link_tags = link_model.predict_tags(l_dataloader, verbose_flag=v2) + + printv("[I|Deploy] Generating link output", verbose_flag=v1) + b_word_link_pairs = link_model.get_word_tag_pairs(raw_texts, b_link_tags) + + else: + b_word_link_pairs = None + link_model = None + + if "SAVE_MODEL_OUTPUT_FOLDER" in config["DEPLOY"]: + folder = config["DEPLOY"]["SAVE_MODEL_OUTPUT_FOLDER"] + printv("[I|Deploy] Saving intermediate output", verbose_flag=v1) + + with open(f"{folder}/b_word_tag_pairs.json", 'w', encoding="utf-8") as f: + json.dump(b_word_tag_pairs, f, ensure_ascii=False, indent=4) + + if not hasattr(self, "entry_names"): + self.entry_names = None + + with open(f"{folder}/tag_entry_names.json", 'w', encoding="utf-8") as f: + json.dump(self.entry_names, f, ensure_ascii=False, indent=4) + + if link_mode: + with open(f"{folder}/b_word_link_pairs.json", 'w', encoding="utf-8") as f: + json.dump(b_word_link_pairs, f, ensure_ascii=False, indent=4) + + self.deploy_output(config["DEPLOY"], b_word_tag_pairs, b_word_link_pairs, link_model, + verbose=v1) + + def deploy_output(self, config, b_word_tag_pairs, b_word_link_pairs=None, link_model=None, + verbose=False): + ignored_heads = config.get("IGNORED_HEADS", None) + specific_head = config.get("SPECIFIC_HEAD", None) + output_type = config["OUTPUT"] + + assert (b_word_link_pairs is None) == (link_model is None) + + if link_model is not None: + link_ignored_heads = config["LINK"].get("IGNORED_HEADS", None) + specific_link_head = config["LINK"].get("SPECIFIC_HEAD", None) + b_word_data_pairs = [[(w, (t, b_word_link_pairs[i][j][1])) + for j, (w, t) in enumerate(entry)] + for i, entry in enumerate(b_word_tag_pairs)] + + if output_type in ["print", "txt"]: + printv("[I|Deploy] Processing output", verbose_flag=verbose) + w_sep, e_sep = ("\n", "\n\n") if config.get("NEWLINE_WORDS", False) else (" ", "\n") + + if link_model is not None: + entry_txts = [w_sep.join([f"{str(w)} {self.model.tag2str(t, ignored_heads)} {link_model.tag2str(l, ['link_same_tag_only'])}" + if t != "" else w for w, (t, l) in wtps]) + for wtps in b_word_data_pairs] + else: + entry_txts = [w_sep.join([f"{str(w)} {self.model.tag2str(t, ignored_heads)}" + if t != "" else w for w, t in wtps]) + for wtps in b_word_tag_pairs] + + if hasattr(self, "entry_names") and self.entry_names is not None: + for n, i in self.entry_names.items(): + entry_txts[i] = f"{n}:\n{entry_txts[i]}" + + output_str = e_sep.join(entry_txts) + + printv("[I|Deploy] Outputting", verbose_flag=verbose) + if config["OUTPUT"] == "print": + print(output_str) + + elif output_type == "txt": + with open(config.get("PATH", "model_output.txt"), 'w') as f: + f.write(output_str) + + else: + raise Exception("Bad code - make sure all options in this branch are covered") + + elif output_type == "json": + printv("[I|Deploy] Processing output", verbose_flag=verbose) + if self.entry_names is None: + raise Exception("To output as json you need named entries, try using json input") + + b_word_tag_pairs = self.model.clean_word_tag_pairs(b_word_tag_pairs, ignored_heads, + specific_head) + + if link_model is not None: + # This applies the general link cleaning + b_word_link_pairs = link_model.clean_word_tag_pairs(b_word_link_pairs, + link_ignored_heads, + specific_link_head) + # This is a specific clean that ought to be refactored nicely into the general one + pass + + result_obj = [] + + for n, i in self.entry_names.items(): + entry_obj = {"PMID": n, "TEXT": ' '.join(w for w, _ in b_word_tag_pairs[i])} + entry_obj["TAG_DATA"] = [f"{j}, {w} {t}" + for j, (w, t) in enumerate(b_word_tag_pairs[i]) + if t is not None] + + if link_model is not None: + entry_obj["LINK_DATA"] = [f"{j}, {w} {l}" + for j, (w, l) in enumerate(b_word_link_pairs[i]) + if l is not None] + + # Get a dict of link ids and have vals be lists of word indices + link_group_word_idxs = {} + for j, (_, ls) in enumerate(b_word_link_pairs[i]): + if ls is not None: + for l in ls: + if l in link_group_word_idxs.keys(): + if j not in link_group_word_idxs[l]: + link_group_word_idxs[l].append(j) + else: + link_group_word_idxs[l] = [j] + + entry_obj["LINK_WORD_GROUPS"] = list(link_group_word_idxs.values()) + + # Get the tags from the words and return the sets of linked tags + raw_linked_tags = [] + for idxs in link_group_word_idxs.values(): + tags = [] + + for idx in idxs: + word, tag = b_word_tag_pairs[i][idx] + if tag is not None: + # The [2:] removes the Schema (Hacky yes, should be done properly) + word_tags = [(k, v[2:]) for k, v in tag.items()] + for (tt1, tv1) in word_tags: + present = False + for (_, tt2, tv2) in tags: + if tt1 == tt2 and tv1 == tv2: + present = True + break + if not present: + tags.append((word, tt1,tv1)) + + raw_linked_tags.append(tags) + + entry_obj["LINKED_TAGS_RAW"] = raw_linked_tags + + # Convert the groups of linked tags into pairs of linked head outputs + linked_tags = [] + for lset in raw_linked_tags: + + for ((w1, k1, v1), (w2, k2, v2)) in pairs(lset): + if k1 != k2: + pair_dict = {k1: {"val": v1, "words": [w1]}, + k2: {"val": v2, "words": [w2]}} + + present = False + for j, existing_pair_dict in enumerate(linked_tags): + ((ek1, d1), (ek2, d2)) = existing_pair_dict.items() + + ev1 = d1["val"] + ev2 = d2["val"] + + if all([ek1==k1, ek2==k2, ev1==v1, ev2==v2]): + present = True + if w1 not in linked_tags[j][ek1]["words"]: + linked_tags[j][ek1]["words"].append(w1) + if w2 not in linked_tags[j][ek2]["words"]: + linked_tags[j][ek2]["words"].append(w2) + if all([ek1==k2, ek2==k1, ev1==v2, ev2==v1]): + present = True + if w2 not in linked_tags[j][ek1]["words"]: + linked_tags[j][ek1]["words"].append(w2) + if w1 not in linked_tags[j][ek2]["words"]: + linked_tags[j][ek2]["words"].append(w1) + + if not present: + linked_tags.append(pair_dict) + + # Filter if we are looking for specific combinations + if "LINKED_TAGS_PAIRS" in config["LINK"]: + ltps = config["LINK"]["LINKED_TAGS_PAIRS"] + new_linked_tags = [] + for pair_dict in linked_tags: + ((k1, _), (k2, _)) = pair_dict.items() + for (ltp1, ltp2) in ltps: + if (k1 == ltp1 and k2 == ltp2) or (k1 == ltp2 and k2 == ltp1): + new_linked_tags.append(pair_dict) + break + linked_tags = new_linked_tags + + entry_obj["LINKED_TAGS"] = linked_tags + + if "JSON_FIELDS" in config: + keys_to_write = config["JSON_FIELDS"] + entry_obj = {k: v for k, v in entry_obj.items() if k in keys_to_write} + + result_obj.append(entry_obj) + + printv("[I|Deploy] Outputting", verbose_flag=verbose) + with open(config.get("PATH", "model_output.json"), + 'w', encoding="utf-8") as f: + json.dump(result_obj, f, ensure_ascii=False, indent=4) else: - raise Exception(f"Unrecognised output type {config['DEPLOY']['OUTPUT']}") + raise Exception(f"Unrecognised output type {config['OUTPUT']}") def train_mode(self, config): diff --git a/src/src b/src/src new file mode 120000 index 0000000..5cd551c --- /dev/null +++ b/src/src @@ -0,0 +1 @@ +../src \ No newline at end of file diff --git a/tools/combine_jsons.py b/tools/combine_jsons.py index b699152..008b40f 100644 --- a/tools/combine_jsons.py +++ b/tools/combine_jsons.py @@ -3,8 +3,6 @@ if __name__ == "__main__": - - # CLI parser = argparse.ArgumentParser(description="Combine two or more json databases") parser.add_argument("dbs", nargs='+', help="Paths to json database files") parser.add_argument("-n", "--name", default=None, help="Name of output file") diff --git a/tools/json_fmap.py b/tools/json_fmap.py new file mode 100644 index 0000000..88a904e --- /dev/null +++ b/tools/json_fmap.py @@ -0,0 +1,65 @@ +import json +import argparse +import copy + + +def pa_effect_pairs(json_obj): + + def keep_specific_tag_pairs(in_dict, pairs): + assert all(len(x) == 2 for x in pairs) + + def matching(present_keys): + assert len(present_keys) == 2 + + for p1, p2 in pairs: + if (p1 in present_keys) and (p2 in present_keys): + return True + + return False + + out_dict = copy.deepcopy(in_dict) + out_dict["LINKED_TAGS"] = [pair_dict for pair_dict in out_dict["LINKED_TAGS"] + if matching(pair_dict.keys())] + return out_dict + + return [keep_specific_tag_pairs(entry, [("effect", "perturbing_action")]) for entry in json_obj] + + +def filter_empty_linked_tags(json_obj): + return [entry for entry in json_obj + if entry["LINKED_TAGS"] != []] + +def filter_data_fields(json_obj): + black_list = ["TAG_DATA", "LINK_DATA"] + return [{k: v for k, v in entry.items() if k not in black_list} + for entry in json_obj] + + +arg_func_map = { + "pa_effect_pairs": pa_effect_pairs, + "filter_empty_linked_tags": filter_empty_linked_tags, + "filter_data_fields": filter_data_fields +} + + +def main(args): + with open(args.inp) as f: + json_obj = json.load(f) + + for func in args.funcs: + json_obj = arg_func_map[func](json_obj) + + with open(args.out, 'w', encoding='utf-8') as f: + json.dump(json_obj, f, ensure_ascii=False, indent=4) + + +if __name__ == "__main__": + + parser = argparse.ArgumentParser(description="Map functions over json files") + parser.add_argument("inp", help="Name of input json file") + parser.add_argument("funcs", nargs="+", + help=f"Function to use, current options: {', '.join(arg_func_map.keys())}") + parser.add_argument("out", help="Name of output json file") + + main(parser.parse_args()) + diff --git a/tools/rough_analyser.py b/tools/rough_analyser.py index 48b0687..0ac9ec5 100644 --- a/tools/rough_analyser.py +++ b/tools/rough_analyser.py @@ -1,6 +1,7 @@ import json import argparse import numpy as np +from pprint import pprint from util.core import ensure_file_ext @@ -151,7 +152,12 @@ def get_tag_label_counts_of_word(word_datum, tag_lists, tag_categories): for category, data in tag_categories.items(): for f in data["fields"].keys(): parent_key[f] = category - labels = {k: [x[k] for x in word_datum[pk]] for k, pk in parent_key.items()} + try: + labels = {k: [x[k] for x in word_datum[pk]] for k, pk in parent_key.items()} + except KeyError as e: + pprint(word_datum) + pprint(parent_key) + raise e return {k: {l: labels[k].count(l) for l in ls} for k, ls in tag_lists.items()} diff --git a/v2_single_heads.sh b/v2_single_heads.sh index 7d565ce..018f0d5 100644 --- a/v2_single_heads.sh +++ b/v2_single_heads.sh @@ -1,5 +1,5 @@ #!/bin/sh -. ~/user_venv/bin/activate +conda activate tfm_nlp python3 main.py -f configs/v2_single_heads -v diff --git a/v2_single_heads_l.sh b/v2_single_heads_l.sh index 335d711..5717f44 100644 --- a/v2_single_heads_l.sh +++ b/v2_single_heads_l.sh @@ -1,5 +1,5 @@ #!/bin/sh -. ~/user_venv/bin/activate +conda activate tfm_nlp python3 -u main.py -f configs/v2_single_heads -v > outputs/log.txt 2>&1 diff --git a/verify.sh b/verify.sh index 4c948fe..bc252fc 100644 --- a/verify.sh +++ b/verify.sh @@ -1,5 +1,5 @@ #!/bin/sh -. ~/user_venv/bin/activate +conda activate tfm_nlp python3 main.py -f configs/verification -v diff --git a/verify_l.sh b/verify_l.sh old mode 100644 new mode 100755 index 3261fdc..3f0810c --- a/verify_l.sh +++ b/verify_l.sh @@ -1,5 +1,5 @@ #!/bin/sh -. ~/user_venv/bin/activate +conda activate tfm_nlp python3 -u main.py -f configs/verification -v > outputs/log.txt 2>&1